BR112017024846B1 - 4-HYDROXY-3-(HETEROARYL)PYRIDINE-2-ONE APJ AGONISTS, THEIR USE AND PHARMACEUTICAL COMPOSITION COMPRISING THEM - Google Patents

Abstract

4-HYDROXY-3-(HETEROARYL)PYRIDINE-2-ONE APJ AGONISTS FOR USE IN THE TREATMENT OF CARDIOVASCULAR DISORDERS. The present invention provides compounds of formula (I): wherein all variables are as defined in the specification and compositions comprising any of such new compounds. These compounds are APJ agonists that can be used as medicines.

Description

CROSS REFERENCE TO RELATED ORDERS

[001] This application has priority under 35 U.S.C. §119(e) to United States Provisional Patent Application No. 62/170,215, filed June 3, 2015, which is incorporated herein in its entirety.

FIELD OF INVENTION

[002] The present invention provides new 4-hydroxyl-3-(heteroaryl)pyridine-2-one compounds and analogues thereof, which are APJ agonists, compositions containing them and methods of using them, e.g. for the treatment or prophylaxis of heart failure, atherosclerosis, ischemic heart disease and related conditions.

BACKGROUND OF THE INVENTION

[003] Heart failure (HF) and related complications constitute a major health burden in developed countries with an estimated prevalence of 5,700,000 in the United States alone (Roger, V.L. et al., Circulation, 125(1):e2-e220 ( 2012)). Despite considerable advances over the past two decades, the prognosis remains very poor, with survival rates of only ~50% within 5 years of diagnosis (Roger, V.L. et al., JAMA, 292(3):344- 350 (2004)). In addition to poor survival, impaired quality of life and recurrent hospitalizations constitute a clear unmet medical need for the development of new treatment options.

[004] HF is a clinical syndrome characterized by the inability of the heart to release sufficient supply of blood and oxygen to meet the metabolic demands of organs in the body. The main symptoms associated with FH include shortness of breath due to pulmonary edema, fatigue, reduced exercise tolerance, and lower extremity edema. The etiology of FH is highly complex with multiple associated risk factors and potential causes.

[005] Among the causes of HF induction are coronary artery disease and cardiac ischemia, acute myocardial infarction, intrinsic cardiomyopathies and chronic uncontrolled hypertension. HF can develop acutely (functional impairment after myocardial infarction) or as a chronic condition, characterized by long-term maladaptive cardiac tissue remodeling, hypertrophy, and cardiac dysfunction (e.g., due to long-term uncontrolled hypertension). According to the diagnostic criteria and type of ventricular dysfunction, HF is classified into two main groups, HF with "reduced ejection fraction" (HFrEF) or HF with "preserved ejection fraction" (HFpEF). Both types are associated with similar signs and symptoms, but differ in the type of ventricular functional impairment (Borlaug, B.A. et al. eur. Heart J., 32(6):670-679 (2011)).

[006] The APJ receptor (APLNR) and its endogenous peptide ligand, apelin, have been implicated as important modulators of cardiovascular function and candidates for therapeutic intervention in HF (for review see Japp, A.G. et al., Biochem. Pharmacol., 75(10):1882-1892 (2008)).

[007] Accumulating evidence from preclinical disease models and human heart failure patients has implicated APJ and apelin agonism as beneficial in the setting of HF. Mice lacking the APJ or Apelin gene have impaired myocyte contractility (Charo, D.N. et al., Am. J. Physiol. Heart Circ. Physiol., 297(5):H1904-H1913 (2009)). Apelin knockout (KO) mice develop progressive cardiac dysfunction with aging and are more susceptible to HF in the trans-aortic constriction (TAC) model (Kuba, K. et al., Circ. Res., 101(4): e32-42 (2007)). Functional impairment in rhonic HF is a result of prolonged demand on the heart and is associated with maladaptive cardiac remodeling, manifested by cardiac hypertrophy, increased inflammation and interstitial fibrosis that eventually induces a decrease in cardiac performance.

[008] Acute administration of apelin increases cardiac output in rodents under normal conditions and also in models of heart failure (Berry, M.F., Circulation, 110(11 Suppl. 1):II187-II193 (2004)). Increased cardiac output is a result of direct increases in cardiac contractility and peripheral vascular resistance in arterial and venous beds (Ashley e.A., Cardiovasc. Res., 65(1):73-82 (2005)). The reduction in vascular resistance induces lower preload and afterload on the heart and thus lower workload (Cheng, X. et al., Eur. J. Pharmacol., 470(3):171-175 (2003)). Similar to the rodent studies, acute infusion of apelin to healthy human subjects and patients with heart failure produces similar hemodibamic responses with increased cardiac output and increased vasodilatory response in peripheral and coronary arteries (Japp, A.G. et al., Circulation, 121(16) :1818- 1827 (2010)).

[009] The mechanisms underlying the inotropic action of apelin are not well understood, but appear to be distinct from clinically used e1-adrenergic agonists (dobutamine) due to the lack of increase in heart rate. The vasodilatory action is primarily mediated through an endothelial nitric oxide synthase reaction series (Tatemoto, K., Regul. Pept., 99(2-3):87-92 (2001)). Apelin is induced under hypoxic conditions, promotes angiogenesis, and has been shown to limit infarct size in ischemia-reperfusion models (Simpkin, J.C., Basic Res. Cardiol., 102(6):518-528 (2007)).

[0010] In addition to the previously mentioned studies evaluating the acute administration of apelin, several studies have clearly demonstrated beneficial effects of prolonged administration of apelin in several chronic rodent models of HF, including the angiotensin II model, TAC model and sensitive model. Dahl rat salt (Siddiquee, K. et al., J. Hypertens., 29(4):724-731 (2011); Scimia, M.C. et al., Nature, 488(7411):394-398 (2012) ; Koguchi, W. et al., Circ. J., 76(1):137-144 (2012)). In these studies, prolonged apelin infusion reduced cardiac hypertrophy and cardiac fibrosis and was associated with improved cardiac performance.

[0011] Genetic evidence that is also emerging is that polymorphisms in the APJ gene are associated with slower progression of FH (Sarzani, R. et al., J. Card. Fail., 13(7):521-529 (2007)). Importantly while expression of APJ and apelin may be reduced or vary considerably with progression of FH, the cardiovascular hemodynamic effects of apelin are prolonged in patients with developed FH and receiving standard of care therapy (Japp, A.G. et al., Circulation, 121(16):1818-1827 (2010)).

[0012] In summary, there is a significant amount of evidence to indicate that APJ receptor agonism plays a cardioprotective role in HF and would be of potential benefit to HF patients. The very short half-life of apelin in circulation limits its therapeutic utility and consequently there is a need for APJ receptor agonists with improved pharmacokinetic and signaling profiles while maintaining or enhancing the beneficial effects of the endogenous APJ agonist, apelin.

SUMMARY OF THE INVENTION

[0013] The present invention provides 4-hydroxylpyridine-2-one compounds and analogues thereof, which are useful as APJ agonists, including stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof.

[0014] The present invention also provides processes and intermediates for preparing the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof.

[0015] The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof.

[0016] The compounds of the invention can be used in the treatment and/or prophylaxis of multiple diseases or disorders associated with PJA, such as heart failure, coronary artery disease, cardiomyopathy, diabetes and related conditions including, but not limited to, acute coronary syndrome , myocardial ischemia, hypertension, pulmonary hypertension, coronary vasospasm, cerebral vasospasm, ischemia/reperfusion injury, angina, renal disease, metabolic syndrome and insulin resistance.

[0017] The compounds of the invention can be used in therapy.

[0018] The compounds of the invention can be used to manufacture a medicine for the treatment and/or prophylaxis of multiple diseases or disorders associated with PJA.

[0019] The compounds of the invention can be used alone in combination with other compounds of the present invention, or in combination with one or more other agents.

[0020] Other features and advantages of the invention will be evident from the following detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION I. COMPOUNDS OF THE INVENTION

[0021] In a first aspect, the present invention provides, among other things, a compound of formula (I):

[0022] or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof in which:

[0023] alk is C1-6 alkyl substituted with 0-5 Re;

[0024] ring A is independently selected from: , , , , , , , , , and ;

[0025] ring B is independently selected from: , and 6-membered heteroaryl;

[0026] R1 is independently selected from: halogen, NO2, -(CH2)nORb, (CH2)nS(O)pRc, -(CH2)nC(=O)Rb, -(CH2)nNRaRa, -(CH2)nCN , -(CH2)nC(=O)NRaRa, -(CH2)nNRaC(=O)Rb, -(CH2)nNRaC(=O)NRaRa, -(CH2)nNRaC(=O)ORb, -(CH2)nOC (=O)NRaRa, -(CH2)nC(=O)ORb, -(CH2)nS(O)pNRaRa, -(CH2)nNRaS(O)pNRaRa, -(CH2)nNRaS(O)pRc, C1-4 alkyl substituted with 0-3 Re, -(CH2)n-C3-6 carbocyclyl substituted with 0-3 Re and -(CH2)n-heterocyclyl substituted with 0-3 Re;

[0027] R2 is independently selected from: C1-5 alkyl substituted with 0-3 Re; C1-5 alkenyl substituted with 0-3 Re and C1-6 cycloalkyl substituted with 0-3 Re; wherein the carbon atom other than that attached to the C1-5 alkyl ring and the groups attached thereto can be replaced by O, N and S;

[0028] R3 is independently selected from:

[0029] (1) -(CR4R4)nC(=O)OC1-4 alkyl substituted with 0-5 Re,

[0030] (2) -(CR4R4)nNRaRa,

[0031] (3) -(CR4R4)nC(=O)NRaRa,

[0032] (4) -(CR4R4)nNRaC(=O) C1-4 alkyl substituted with 0-5 Re,

[0033] (5) -(CR4R4)nNRaC(=O)(CR4R4 )nOC1-4 alkyl substituted with 0-5 Re,

[0034] (6) -(CR4R4)n-R5,

[0035] (7) -(CR4R4)n- OR5 and

[0036] (8) -(CR4R4)nNRaC(=O)(CR4R4)nR5;

[0037] R4 is independently selected from: H, halogen, NRaRa, OC1-4 alkyl and C1-4 alkyl; or R4 and R4 together with the carbon atom to which they are both attached form C3-6 cycloalkyl substituted with 0-5 Re;

[0038] R5 is independently selected from: -(CH2)n-C3-10 carbocycle and -(CH2)n-heterocycle, each substituted with 0-3 R6;

[0039] R6 is independently selected from: H, halogen, =O, - (CH2)nORb, (CH2)nS(O)pRc, -(CH2)nC(=O)Rb, -(CH2)nNRaRa, - ( CH2)nCN, -(CH2)nC(=O)NRaRa, -(CH2)nNRaC(=O)Rb, - (CH2)nNRaC(=O)NRaRa, -(CH2)nNRaC(=O)ORb, -( CH2)nOC(=O)NRaRa, -(CH2)nC(=O)ORb, -(CH2)nS(O)pNRaRa, -(CH2)nNRaS(O)pNRaRa, - (CH2)nNRaS(O)pRc, C1-5 alkyl substituted with 0-3 Re, (CH2)n-C3-6 carbocyclyl substituted with 0-3 Re, and -(CH2)n-heterocyclyl substituted with 0-3 Re;

[0040] Ra is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, -(CH2)n-C3 -10carbocyclyl substituted with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are attached form a heterocyclic ring with 0-5 Re;

[0041] Rb is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, -(CH2)n-C3 -10carbocyclyl substituted with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re;

[0042] Rc is independently selected from C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, C3-6 carbocyclyl and heterocyclyl;

[0043] Rd is independently selected from H and C1-4 alkyl substituted with 0-5 Re;

[0044] Re is independently selected from C1-6 alkyl substituted with 0-5 Rf, C2-6 alkenyl, C2-6 alkynyl, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl , -(CH2)n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H, -(CH2)nORf, S(O)pRf, C(=O)NRfRf , NRfC(=O)Rf, S(O)pNRfRf, NRfS(O)pRf, NRfC(=O)ORf, OC(=O)NRfRf and -(CH2)nNRfRf;

[0045] Rf is independently selected from H, F, Cl, Br, CN, OH, C1-5 alkyl (optionally substituted with halogen and OH), C3-6 cycloalkyl and phenyl, or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C1-4 alkyl;

[0046] n is independently selected from zero, 1, 2 and 3; and

[0047] p is independently selected from zero, 1 and 2.

[0048] In a second aspect, the present invention provides a compound of formula (II):

[0049] or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, within the scope of the first aspect in which:

[0050] R1 is independently selected from: F, Cl, Br, NO2, -(CH2)nORb, -(CH2)nC(=O)Rb, -(CH2)nNRaRa, -(CH2)nC(=O)NRaRa , -(CH2)nNRaC(=O)Rb, C1-4 alkyl substituted with 0-3 Re and C3-6 cycloalkyl substituted with 0-3 Re;

[0051] R2 is independently selected from: C1-5 alkyl substituted with 0-3 Re; C1-5 alkenyl and C1-6 cycloalkyl; wherein the carbon atom other than that attached to the C1-5 alkyl ring and the groups attached thereto are replaced by O, N and S;

[0052] R3 is independently selected from:

[0053] (1) -(CR4R4)nC(=O)OC1-4 alkyl substituted with 0-5 Re,

[0054] (2) -(CR4R4)nNRaRa,

[0055] (3) -(CR4R4)nC(=O)NRaRa,

[0056] (4) -(CR4R4)nNRaC(=O) C1-4 alkyl substituted with 0-5 Re,

[0057] (5) -(CR4R4)nNRaC(=O)(CR4R4)nOC1-4 alkyl substituted with 0-5 Re,

[0058] (6) -(CR4R4)n-R5,

[0059] (7) -(CR4R4)n- OR5 and

[0060] (8) -(CR4R4)nNRaC(=O)(CR4R4)nR5;

[0061] R4 is independently selected from: H, F, Cl, NRaRa, OC1-4 alkyl and C1-4 alkyl; or R4 and R4 together with the carbon atom to which they are both attached form C3-6 cycloalkyl substituted with 0-5 Re;

[0062] R5 is independently selected from: -(CH2)n-aryl, -(CH2)n-C3-6 cycloalkyl and -(CH2)n-heterocycle, each substituted with 0-3 R6;

[0063] R6 is independently selected from: H, F, Cl, Br, -ORb, =O, -(CH2)nC(=O)Rb, -(CH2)nC(=O)ORb, -(CH2)nNRaRa , CN, -(CH2)nC(=O)NRaRa, C1-4 alkyl substituted with 0-3 Re, (CH2)n-C3-6 carbocyclyl substituted with 0-3 Re and -(CH2)n-heterocyclyl substituted with 0-3 Re;

[0064] Ra is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re ; or Ra and Ra together with the nitrogen atom to which they are attached form a heterocyclic ring with 0-5 Re;

[0065] Rb is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, -(CH2)n-C3 -10carbocyclyl substituted with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re;

[0066] Re is independently selected from C1-6 alkyl substituted with 0-5 Rf, C2-6 alkenyl, C2-6 alkynyl, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl , -(CH2)n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H, -(CH2)nORf, S(O)pRf, C(=O)NRfRf , NRfC(=O)Rf, S(O)pNRfRf, NRfS(O)pRf, NRfC(=O)ORf, OC(=O)NRfRf and -(CH2)nNRfRf;

[0067] Rf is independently selected from H, F, Cl, Br, CN, OH, C1-5alkyl (optionally substituted with halogen and OH), C3-6 cycloalkyl and phenyl;

[0068] n is independently selected from zero, 1, 2 and 3; It is

[0069] p is independently selected from zero, 1 and 2.

[0070] In a third aspect, the present invention provides a compound of formula (III):

[0071] or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, within the scope of the first or second aspect in which:

[0072] R1 is independently selected from: F, Cl, OH and OC1-4 alkyl;

[0073] R1a is independently selected from: F, Cl and C1-2 alkyl;

[0074] R2 is independently selected from: C1-5 alkyl substituted with 0-3 Re; C1-5 alkenyl and C1-6 cycloalkyl and CH2O(CH2)1- 3CH3;

[0075] R3 is independently selected from:

[0076] (1) -(CR4R4)nC(=O)OC1-4 alkyl substituted with 0-5 Re,

[0077] (2) -(CR4R4)nNRaRa,

[0078] (3) -(CR4R4)nC(=O)NRaRa,

[0079] (4) -(CR4R4)nNRaC(=O) C1-4 alkyl substituted with 0-5 Re,

[0080] (5) -(CR4R4)nNRaC(=O)(CR4R4)nOC1-4 alkyl substituted with 0-5 Re,

[0081] (6) -(CR4R4)n-R5,

[0082] (7) -(CR4R4)n- OR5 and

[0083] (8) -(CR4R4)nNRaC(=O)(CR4R4)nR5;

[0084] R4 is independently selected from: H, F, Cl, NRaRa, OC1-4 alkyl and C1-4 alkyl; or R4 and R4 together with the carbon atom to which they are both attached form C3-6 cycloalkyl substituted with 0-5 Re;

[0085] R5 is independently selected from: -(CH2)n-aryl, -(CH2)n-C3-6 cycloalkyl and -(CH2)n-heterocycle, each substituted with 0-3 R6;

[0086] R6 is independently selected from: H, F, Cl, Br, -ORb, =O, -(CH2)nC(=O)Rb, -(CH2)nC(=O)ORb, -(CH2)nNRaRa , CN, -(CH2)nC(=O)NRaRa, C1-4 alkyl substituted with 0-3 Re, (CH2)n-C3-6 carbocyclyl substituted with 0-3 Re and -(CH2)n-heterocyclyl substituted with 0-3 Re;

[0087] Ra is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re ; or Ra and Ra together with the nitrogen atom to which they are attached form a heterocyclic ring with 0-5 Re;

[0088] Rb is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, -(CH2)n-C3 -10carbocyclyl substituted with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re;

[0089] Re is independently selected from C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, - (CH2)n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H; It is

[0090] n is independently selected from zero, 1, 2 and 3.

[0091] In a fourth aspect, the present invention provides a compound of formula (III), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, within the scope of any of the first, second and third aspects in which:

[0092] R3 is independently selected from:

[0093] (1) -(CR4R4)n-R5,

[0094] (2) -(CR4R4)n- OR5 and

[0095] (3) -(CR4R4)nNRaC(=O)(CR4R4)nR5;

[0096] R4 is independently selected from: H, F, Cl, N(CH3)2, OCH3 and CH3; or R4 and R4 together with the carbon atom to which they are both attached form cyclopropyl;

[0097] R5 is independently selected from:

[0098] R6 is independently selected from: H, F, Cl, Br, -OCH3, -OCF3, =O, CN, CH3, CF3 -(CH2)n-aryl, -(CH2)n-C3-6 substituted cycloalkyl with 0-3 Re and -(CH2)n-heterocyclyl substituted with 0-3 Re;

[0099] R6a is independently selected from: H, CH3, aryl substituted with 0-3 Re and heterocyclyl substituted with 0-3 Re;

[00100] Ra is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re ;

[00101] Re is independently selected from C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, - (CH2)n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H; It is

[00102] n is independently selected from zero, 1, 2 and 3.

[00103] In a fifth aspect, the present invention provides a compound of formula (III),

[00104] or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, within the scope of any of the first, second and third aspects in which:

[00105] R3 is independently selected from:

[00106] (1) -(CR4R4)nNRaRa,

[00107] (2) -(CR4R4)nC(=O)NRaRa,

[00108] R4 is independently selected from: H, F, Cl, N(CH3)2, OCH3 and CH3; or R4 and R4 together with the carbon atom to which they are both attached form C3-6 cycloalkyl substituted with 0-5 Re;

[00109] R6 is independently selected from: H, F, Cl, Br, -OCH3, -OCF3, =O, CN, CH3, CF3 -(CH2)n-aryl, -(CH2)n-C3-6 substituted cycloalkyl with 0-3 Re and -(CH2)n-heterocyclyl substituted with 0-3 Re;

[00110] R6a is independently selected from: H, CH3, aryl substituted with 0-3 Re and heterocyclyl substituted with 0-3 Re;

[00111] Ra and Ra together with the nitrogen atom to which they are attached form a heterocyclic ring with 0-5 Re in which the heterocyclic ring is selected from:

[00112] Re is independently selected from C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, - (CH2)n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H; It is

[00113] n is independently selected from zero, 1, 2 and 3.

[00114] In a sixth aspect, the present invention provides a compound of formula (III), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, within the scope of any of the first, second and third aspects in which:

[00115] R1 is independently selected from: F, Cl, OH and OC1-4 alkyl;

[00116] R1a is independently selected from: F, Cl and C1-2 alkyl;

[00117] R2 is independently selected from: C1-5 alkyl substituted with 0-3 Re; C1-5 alkenyl and C1-6 cycloalkyl; and CH2O(CH2)1- 3CH3;

[00118] R3 is independently selected from:

[00119] (1) -(CH2)nC(=O)OC1-4 alkyl substituted with 0-3 Re,

[00120] (2) -(CH2)nNRaRa,

[00121] (3) -(CH2)nC(=O)NRaRa,

[00122] (4) -(CH2)nNRaC(=O) C1-4 alkyl substituted with 0-3 Re and

[00123] (5) -(CH2)nNRaC(=O)(CR4R4)nOC1-4 alkyl substituted with 0-3 Re;

[00124] R4 is independently selected from: H, F, Cl, NRaRa, OC1-4 alkyl and C1-4 alkyl;

[00125] R5 is independently selected from: -(CH2)n-aryl, -(CH2)n-C3-6 cycloalkyl and -(CH2)n-heterocycle, each substituted with 0-3 R6;

[00126] R6 is independently selected from: H, F, Cl, Br, -OCH3, -OCF3, =O, CN, CH3, CF3 -(CH2)n-aryl, -(CH2)n-C3-6 substituted cycloalkyl with 0-3 Re and -(CH2)n-heterocyclyl substituted with 0-3 Re;

[00127] Ra is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re ;

[00128] Re is independently selected from C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, - (CH2)n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H; It is

[00129] n is independently selected from zero, 1, 2 and 3.

[00130] In a seventh aspect, the present invention provides a compound of formula (IV):

[00131] or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, within the scope of the first and second aspect in which:

[00132] R1 is independently selected from: -CH2OH, -OCH3, - OCF3, OCH2Ph, -C(=O)NRaRa, -NRaRa, CH3, CH2CH3, CH(CH3)2 and cyclopropyl;

[00133] R2 is independently selected from: C1-4 alkyl substituted with 0-3 Re; C2-4 alkenyl, C1-6 cycloalkyl and CH2O(CH2)1- 3CH3;

[00134] R3 is independently selected from:

[00135] (1) -(CR4R4)nC(=O)OC1-4 alkyl substituted with 0-3 Re,

[00136] (2) -(CR4R4)nNRaRa,

[00137] (3) -(CR4R4)nC(=O)NRaRa,

[00138] (4) -(CR4R4)nNRaC(=O) C1-4 alkyl substituted with 0-3 Re,

[00139] (5) -(CR4R4)nNRaC(=O)(CR4R4)nOC1-4 alkyl substituted with 0-3 Re,

[00140] (6) -(CR4R4)n-R5,

[00141] (7) -(CR4R4)n- OR5 and

[00142] (8) -(CR4R4)nNRaC(=O)(CR4R4)nR5;

[00143] R4 is independently selected from: H, F, Cl, NRaRa, OC1-4 alkyl and C1-4 alkyl;

[00144] R5 is independently selected from: aryl, C3-6 cycloalkyl and heterocycle, each substituted with 0-3 R6;

[00145] R6 is independently selected from: H, F, Cl, Br, -ORb, =O, -(CH2)nC(=O)Rb, -(CH2)nC(=O)ORb, -(CH2)nNRaRa , CN, -(CH2)nC(=O)NRaRa, C1-4 alkyl substituted with 0-3 Re, (CH2)n-C3-6 carbocyclyl substituted with 0-3 Re and -(CH2)n-heterocyclyl substituted with 0-3 Re;

[00146] Ra is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re ; or Ra and Ra together with the nitrogen atom to which they are attached form a heterocyclic ring with 0-5 Re;

[00147] Rb is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, -(CH2)n-C3 -10carbocyclyl substituted with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re;

[00148] Re is independently selected from C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, - (CH2)n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H; It is

[00149] n is independently selected from zero, 1, 2 and 3.

[00150] In an eighth aspect, the present invention provides a compound selected from the exemplified examples or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.

[00151] In another aspect, the present invention provides compounds of formula (I):

[00152] or enantiomeric stereoisomers, diastereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof in which:

[00153] alk is C1-6 alkyl substituted with 0-5 Re;

[00154] ring A is independently selected from:

[00155] ring B is independently selected from:

[00156] 'eh and 6-membered heteroaryl;

[00157] R1 is independently selected from: H, halogen, NO2, -(CH2)nORb, (CH2)nS(O)pRc, -(CH2)nC(=O)Rb, -(CH2)nNRaRa, -(CH2 )nCN, -(CH2)nC(=O)NRaRa, -(CH2)nNRaC(=O)Rb, -(CH2)nNRaC(=O)NRaRa, -(CH2)nNRaC(=O)ORb, -(CH2 )nOC(=O)NRaRa, -(CH2)nC(=O)ORb, -(CH2)nS(O)pNRaRa, -(CH2)nNRaS(O)pNRaRa, -(CH2)nNRaS(O)pRc, C1 -4 alkyl substituted with 0-3 Re, -(CH2)n-C3-6 carbocyclyl substituted with 0-3 Re and -(CH2)n-heterocyclyl substituted with 0-3 Re;

[00158] R2 is independently selected from: C1-5 alkyl substituted with 0-3 Re; C1-5 alkenyl substituted with 0-3 Re and C1-6 cycloalkyl substituted with 0-3 Re; provided that when R2 is C1-5 alkyl, the carbon atom other than that attached directly to the pyridine ring may be replaced by O, N and S;

[00159] R3 is independently selected from:

[00160] (1) -(CR4R4)rC(=O)OC1-4 alkyl substituted with 0-5 Re,

[00161] (2) -(CR4R4)rNRaRa,

[00162] (3) -(CR4R4)rC(=O)NRaRa,

[00163] (4) -(CR4R4)rNRaC(=O)C1-4 alkyl substituted with 0-5 Re,

[00164] (5) -(CR4R4)rNRaC(=O)(CR4R4 )nOC1-4 alkyl substituted with 0-5 Re,

[00165] (6) -(CR4R4)r-R5,

[00166] (7) -(CR4R4)r-OR5,

[00167] (8) -(CR4R4)rNRaC(=O)(CR4R4)nR5 and

[00168] (9) -(CR4R4)rC(=O)NRa(CR4R4)nR5;

[00169] R4 is independently selected from: H, halogen, NRaRa, OC1-4 alkyl and C1-4 alkyl; or R4 and R4 together with the carbon atom to which they are both attached form C3-6 cycloalkyl substituted with 0-5 Re;

[00170] R5 is independently selected from: -(CH2)n-C3-10 carbocycle and -(CH2)n-heterocycle, each substituted with 0-3 R6;

[00171] R6 is independently selected from: H, halogen, =O, -(CH2)nORb, (CH2)nS(O)pRc, -(CH2)nC(=O)Rb, -(CH2)nNRaRa, -( CH2)nCN, -(CH2)nC(=O)NRaRa, -(CH2)nNRaC(=O)Rb, -(CH2)nNRaC(=O)NRaRa, -(CH2)nNRaC(=O)ORb, -( CH2)nOC(=O)NRaRa, -(CH2)nC(=O)ORb, -(CH2)nS(O)pNRaRa, -(CH2)nNRaS(O)pNRaRa, -(CH2)nNRaS(O)pRc, C1-5 alkyl substituted with 0-3 Re, (CH2)n-C3-6 carbocyclyl substituted with 0-3 Re and -(CH2)n-heterocyclyl substituted with 0-3 Re;

[00172] Ra is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, -(CH2)n-C3 -10carbocyclyl substituted with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are attached form a heterocyclic ring with 0-5 Re;

[00173] Rb is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, -(CH2)n-C3 -10carbocyclyl substituted with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re;

[00174] Rc is independently selected from C1-6 alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, C3-6carbocyclyl and heterocyclyl;

[00175] Rd is independently selected from H and C1-4 alkyl substituted with 0-5 Re;

[00176] Re is independently selected from C1-6 alkyl substituted with 0-5 Rf, C2-6 alkenyl, C2-6 alkynyl, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl , -(CH2)n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H, -(CH2)nORf, S(O)pRf, C(=O)NRfRf , NRfC(=O)Rf, S(O)pNRfRf, NRfS(O)pRf, NRfC(=O)ORf, OC(=O)NRfRf and -(CH2)nNRfRf;

[00177] Rf is independently selected from H, F, Cl, Br, CN, OH, C1-5alkyl (optionally substituted with halogen and OH), C3-6 cycloalkyl and phenyl, or Rf and Rf together with the nitrogen atom at the which they are both linked to form a heterocyclic ring optionally substituted with C1-4 alkyl;

[00178] n is independently selected from zero, 1, 2 and 3;

[00179] r is independently selected from zero, 1, 2 and 3; It is

[00180] p is independently selected from zero, 1 and 2.

[00181] In another aspect, the present invention provides compounds of formula (I), or enantiomeric stereoisomers, diastereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof in which:

[00182] alk is C1-6 alkyl substituted with 0-5 Re;

[00183] ring A is independently selected from:

[00184] ring B is independently selected from:

[00185] , and 6-membered heteroaryl;

[00186] R1 is independently selected from: H, halogen, NO2, -(CH2)nORb, (CH2)nS(O)pRc, -(CH2)nC(=O)Rb, -(CH2)nNRaRa, -(CH2 )nCN, -(CH2)nC(=O)NRaRa, -(CH2)nNRaC(=O)Rb, -(CH2)nNRaC(=O)NRaRa, -(CH2)nNRaC(=O)ORb, -(CH2 )nOC(=O)NRaRa, -(CH2)nC(=O)ORb, -(CH2)nS(O)pNRaRa, -(CH2)nNRaS(O)pNRaRa, -(CH2)nNRaS(O)pRc, C1 -4 alkyl substituted with 0-3 Re, -(CH2)n-C3-6 carbocyclyl substituted with 0-3 Re and -(CH2)n-heterocyclyl substituted with 0-3 Re;

[00187] R2 is independently selected from: C1-5 alkyl substituted with 0-3 Re; C1-5 alkenyl substituted with 0-3 Re and C1-6 cycloalkyl substituted with 0-3 Re; provided that when R2 is C1-5 alkyl, the carbon atom other than that attached directly to the pyridine ring may be replaced by O, N and S;

[00188] R3 is independently selected from:

[00189] (1) -(CR4R4)rC(=O)OC1-4 alkyl substituted with 0-5 Re,

[00190] (2) -(CR4R4)rNRaRa,

[00191] (3) -(CR4R4)rC(=O)NRaRa,

[00192] (4) -(CR4R4)rNRaC(=O)C1-4 alkyl substituted with 0-5 Re,

[00193] (5) -(CR4R4)rNRaC(=O)(CR4R4 )nOC1-4 alkyl substituted with 0-5 Re,

[00194] (6) -(CR4R4)r-R5,

[00195] (7) -(CR4R4)r-OR5,

[00196] (8) -(CR4R4)rNRaC(=O)(CR4R4)nR5 and

[00197] (9) -(CR4R4)rC(=O)NRa(CR4R4)nR5;

[00198] R4 is independently selected from: H, halogen, NRaRa, OC1-4 alkyl and C1-4 alkyl; or R4 and R4 together with the carbon atom to which they are both attached form C3-6 cycloalkyl substituted with 0-5 Re;

[00199] R5 is independently selected from: -(CH2)n-C3-10 carbocycle and -(CH2)n-heterocycle, each substituted with 0-3 R6;

[00200] R6 is independently selected from: H, halogen, =O, -(CH2)nORb, (CH2)nS(O)pRc, -(CH2)nC(=O)Rb, -(CH2)nNRaRa, -( CH2)nCN, -(CH2)nC(=O)NRaRa, -(CH2)nNRaC(=O)Rb, -(CH2)nNRaC(=O)NRaRa, -(CH2)nNRaC(=O)ORb, -( CH2)nOC(=O)NRaRa, -(CH2)nC(=O)ORb, -(CH2)nS(O)pNRaRa, -(CH2)nNRaS(O)pNRaRa, -(CH2)nNRaS(O)pRc, C1-5 alkyl substituted with 0-3 Re, (CH2)n-C3-6 carbocyclyl substituted with 0-3 Re and -(CH2)n-heterocyclyl substituted with 0-3 Re;

[00201] Ra is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, -(CH2)n-C3 -10carbocyclyl substituted with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are attached form a heterocyclic ring with 0-5 Re;

[00202] Rb is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, -(CH2)n-C3 -10carbocyclyl substituted with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re;

[00203] Rc is independently selected from C1-6 alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re, C3-6carbocyclyl and heterocyclyl;

[00204] Rd is independently selected from H and C1-4 alkyl substituted with 0-5 Re;

[00205] Re is independently selected from C1-6 alkyl substituted with 0-5 Rf, C2-6 alkenyl, C2-6 alkynyl, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl , -(CH2)n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H, -(CH2)nORf, S(O)pRf, C(=O)NRfRf , NRfC(=O)Rf, S(O)pNRfRf, NRfS(O)pRf, NRfC(=O)ORf, OC(=O)NRfRf and - (CH2)nNRfRf;

[00206] Rf is independently selected from H, F, Cl, Br, CN, OH, C1-5alkyl (optionally substituted with halogen and OH), C3-6 cycloalkyl and phenyl, or Rf and Rf together with the nitrogen atom at the which they are both linked to form a heterocyclic ring optionally substituted with C1-4 alkyl;

[00207] n is independently selected from zero, 1, 2 and 3;

[00208] r is independently selected from zero, 1, 2 and 3; It is

[00209] p is independently selected from zero, 1 and 2.

[00210] In another aspect, the present invention provides compounds of formula (II):

[00211] or stereoisomers, enantiomers, diastereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof in which:

[00212] R1 is independently selected from: F, Cl, Br, NO2, -(CH2)nORb, -(CH2)nC(=O)Rb, -(CH2)nNRaRa, -(CH2)nC(=O)NRaRa , -(CH2)nNRaC(=O)Rb, C1-4 alkyl substituted with 0-3 Re and C3-6 cycloalkyl substituted with 0-3 Re;

[00213] R2 is independently selected from: C1-5 alkyl substituted with 0-3 Re; C1-5 alkenyl and C1-6 cycloalkyl; provided that when R2 is C1-5 alkyl, the carbon atom other than that attached directly to the pyridine ring may be replaced by O, N and S;

[00214] R3 is independently selected from:

[00215] (1) -(CR4R4)rC(=O)OC1-4 alkyl substituted with 0-5 Re,

[00216] (2) -(CR4R4)rNRaRa,

[00217] (3) -(CR4R4)rC(=O)NRaRa,

[00218] (4) -(CR4R4)rNRaC(=O)C1-4 alkyl substituted with 0-5 Re,

[00219] (5) -(CR4R4)rNRaC(=O)(CR4R4)nOC1-4 alkyl substituted with 0-5 Re,

[00220] (6) -(CR4R4)r-R5,

[00221] (7) -(CR4R4)r-OR5,

[00222] (8) -(CR4R4)rNRaC(=O)(CR4R4)nR5 and

[00223] (9) -(CR4R4)rC(=O)NRa(CR4R4)nR5;

[00224] R4 is independently selected from: H, F, Cl, NRaRa, OC1-4 alkyl and C1-4 alkyl; or R4 and R4 together with the carbon atom to which they are both attached form C3-6 cycloalkyl substituted with 0-5 Re;

[00225] R5 is independently selected from: -(CH2)n-aryl, -(CH2)n-C3-6 cycloalkyl and -(CH2)n-heterocycle, each substituted with 0-3 R6;

[00226] R6 is independently selected from: H, F, Cl, Br, -ORb, =O, -(CH2)nC(=O)Rb, -(CH2)nC(=O)ORb, -(CH2)nNRaRa , CN, - (CH2)nC(=O)NRaRa, -(CH2)nS(O)pNRaRa, C1-4 alkyl substituted with 0-3 Re, (CH2)n-C3-6 carbocyclyl substituted with 0-3 Re and -(CH2)n-heterocyclyl substituted with 0-3 Re;

[00227] Ra is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re ; or Ra and Ra together with the nitrogen atom to which they are attached form a heterocyclic ring with 0-5 Re;

[00228] Rb is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, -(CH2)n-C3 -10carbocyclyl substituted with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re;

[00229] Re is independently selected from C1-6 alkyl substituted with 0-5 Rf, C2-6 alkenyl, C2-6 alkynyl, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl , -(CH2)n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H, -(CH2)nORf, S(O)pRf, C(=O)NRfRf , NRfC(=O)Rf, S(O)pNRfRf, NRfS(O)pRf, NRfC(=O)ORf, OC(=O)NRfRf and -(CH2)nNRfRf;

[00230] Rf is independently selected from H, F, Cl, Br, CN, OH, C1-5alkyl (optionally substituted with halogen and OH), C3-6 cycloalkyl and phenyl;

[00231] n is independently selected from zero, 1, 2 and 3;

[00232] r is independently selected from 1, 2 and 3; It is

[00233] p is independently selected from zero, 1 and 2.

[00234] In another aspect, the present invention provides compounds of formula (III):

[00235] or stereoisomers, enantiomers, diastereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof in which:

[00236] R1 is independently selected from: F, Cl, OH and OC1-4 alkyl;

[00237] R1a is independently selected from: F, Cl and C1-2 alkyl;

[00238] R2 is independently selected from: C1-5 alkyl substituted with 0-3 Re; C1-5 alkenyl and C1-6 cycloalkyl and CH2O(CH2)1- 3CH3;

[00239] R3 is independently selected from:

[00240] (1) -(CR4R4)rC(=O)OC1-4 alkyl substituted with 0-5 Re,

[00241] (2) -(CR4R4)rNRaRa,

[00242] (3) -(CR4R4)rC(=O)NRaRa,

[00243] (4) -(CR4R4)rNRaC(=O) C1-4 alkyl substituted with 0-5 Re,

[00244] (5) -(CR4R4)rNRaC(=O)(CR4R4)nOC1-4 alkyl substituted with 0-5 Re,

[00245] (6) -(CR4R4)r-R5,

[00246] (7) -(CR4R4)r-OR5 and

[00247] (8) -(CR4R4)rNRaC(=O)(CR4R4)nR5 and

[00248] (9) -(CR4R4)rC(=O)NRa(CR4R4)nR5;

[00249] R4 is independently selected from: H, F, Cl, NRaRa, OC1-4 alkyl and C1-4 alkyl; or R4 and R4 together with the carbon atom to which they are both attached form C3-6 cycloalkyl substituted with 0-5 Re;

[00250] R5 is independently selected from: -(CH2)n-aryl, -(CH2)n-C3-6 cycloalkyl and -(CH2)n-heterocycle, each substituted with 0-3 R6;

[00251] R6 is independently selected from: H, F, Cl, Br, -ORb, =O, -(CH2)nC(=O)Rb, -(CH2)nC(=O)ORb, -(CH2)nNRaRa , CN, -(CH2)nC(=O)NRaRa, -(CH2)nS(O)pNRaRa, C1-4 alkyl substituted with 0-3 Re, (CH2)n-C3-6 carbocyclyl substituted with 0-3 Re and -(CH2)n-heterocyclyl substituted with 0-3 Re;

[00252] Ra is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re ; or Ra and Ra together with the nitrogen atom to which they are attached form a heterocyclic ring with 0-5 Re;

[00253] Rb is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, -(CH2)n-C3 -10carbocyclyl substituted with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re;

[00254] Re is independently selected from C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, - (CH2)n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H; It is

[00255] n is independently selected from zero, 1, 2 and 3; It is

[00256] r is independently selected from 1, 2 and 3.

[00257] In another aspect, the present invention provides compounds of formula (IIIa):

[00258] or stereoisomers, enantiomers, diastereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof in which:

[00259] R1 is independently selected from: F, Cl, OH and OC1-4 alkyl;

[00260] R1a is independently selected from: F, Cl and C1-2 alkyl;

[00261] R2 is independently selected from: C1-5 alkyl substituted with 0-3 Re; C1-5 alkenyl and C1-6 cycloalkyl and CH2O(CH2)1- 3CH3;

[00262] R3 is independently selected from:

[00263] (1) -(CR4R4)rC(=O)OC1-4 alkyl substituted with 0-5 Re,

[00264] (2) -(CR4R4)rNRaRa,

[00265] (3) -(CR4R4)rC(=O)NRaRa,

[00266] (4) -(CR4R4)rNRaC(=O) C1-4 alkyl substituted with 0-5 Re,

[00267] (5) -(CR4R4)rNRaC(=O)(CR4R4)nOC1-4 alkyl substituted with 0-5 Re,

[00268] (6) -(CR4R4)r-R5,

[00269] (7) -(CR4R4)r-OR5 and

[00270] (8) -(CR4R4)rNRaC(=O)(CR4R4)nR5 and

[00271] (9) -(CR4R4)rC(=O)NRa(CR4R4)nR5;

[00272] R4 is independently selected from: H, F, Cl, NRaRa, OC1-4 alkyl and C1-4 alkyl; or R4 and R4 together with the carbon atom to which they are both attached form C3-6 cycloalkyl substituted with 0-5 Re;

[00273] R5 is independently selected from: -(CH2)n-aryl, -(CH2)n-C3-6 cycloalkyl and -(CH2)n-heterocycle, each substituted with 0-3 R6;

[00274] R6 is independently selected from: H, F, Cl, Br, -ORb, =O, -(CH2)nC(=O)Rb, -(CH2)nC(=O)ORb, -(CH2)nNRaRa , CN, -(CH2)nC(=O)NRaRa, -(CH2)nS(O)pNRaRa, C1-4 alkyl substituted with 0-3 Re, (CH2)n-C3-6 carbocyclyl substituted with 0-3 Re and -(CH2)n-heterocyclyl substituted with 0-3 Re;

[00275] Ra is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re ; or Ra and Ra together with the nitrogen atom to which they are attached form a heterocyclic ring with 0-5 Re;

[00276] Rb is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, -(CH2)n-C3 -10carbocyclyl substituted with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re;

[00277] Re is independently selected from C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, - (CH2)n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H; d

[00278] n is independently selected from zero, 1, 2 and 3; It is

[00279] r is independently selected from 1, 2 and 3.

[00280] In another aspect, the present invention provides compounds of formula (III), or enantiomeric stereoisomers, diastereoisomers, tautomers, pharmaceutically acceptable salts, solvate, or prodrugs thereof in which:

[00281] R3 is independently selected from:

[00282] (1) -(CR4R4)r-R5,

[00283] (2) -(CR4R4)r-OR5,

[00284] (3) -(CR4R4)rNRaC(=O)(CR4R4)nR5 and

[00285] (4) -(CR4R4)rC(=O)NRa(CR4R4)nR5;

[00286] R4 is independently selected from: H, F, Cl, N(CH3)2, OCH3 and CH3; or R4 and R4 together with the carbon atom to which they are both attached form cyclopropyl;

[00287] R5 is independently selected from:

[00288] R6 is independently selected from: H, F, Cl, Br, -OCH3, -OCF3, =O, -NRaRa, CN, -S(O)2NH2, CH3, CF3 -(CH2)n-aryl, - (CH2)n-C3-6 cycloalkyl substituted with 0-3 Re and -(CH2)n-heterocyclyl substituted with 0-3 Re;

[00289] R6a is independently selected from: H, CH3, aryl substituted with 0-3 Re and heterocyclyl substituted with 0-3 Re;

[00290] Ra is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re ;

[00291] Re is independently selected from C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, - (CH2)n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H;

[00292] n is independently selected from zero, 1, 2 and 3;

[00293] r is independently selected from 1, 2 and 3; It is

[00294] other variables are as defined in formula (III).

[00295] In another aspect, the present invention provides compounds of formula (III), or enantiomeric stereoisomers, diastereoisomers, tautomers, pharmaceutically acceptable salts, solvate, or prodrugs thereof in which:

[00296] R3 is independently selected from:

[00297] (1) -(CR4R4)rNRaRa and

[00298] (2) -(CR4R4)rC(=O)NRaRa,

[00299] R4 is independently selected from: H, F, Cl, N(CH3)2, OCH3 and CH3; or R4 and R4 together with the carbon atom to which they are both attached form C3-6 cycloalkyl substituted with 0-5 Re;

[00300] R6 is independently selected from: H, F, Cl, Br, -OCH3, -OCF3, =O, CN, -NRaRa, -S(O)2NH2, -CH3, CF3 -(CH2)n-aryl, - (CH2)n-C3-6 cycloalkyl substituted with 0-3 Re and -(CH2)n-heterocyclyl substituted with 0-3 Re;

[00301] R6a is independently selected from: H, CH3, aryl substituted with 0-3 Re and heterocyclyl substituted with 0-3 Re;

[00302] Ra and Ra together with the nitrogen atom to which they are attached form a heterocyclic ring with 0-5 Re in which the heterocyclic ring is selected from:

[00303] Re is independently selected from C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, - (CH2)n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H;

[00304] n is independently selected from zero, 1, 2 and 3;

[00305] r is independently selected from 1, 2 and 3 and

[00306] other variables are as defined in formula (III).

[00307] In another aspect, the present invention provides compounds of formula (III), or enantiomeric stereoisomers, diastereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof in which:

[00308] R1 is independently selected from: F, Cl, OH and OC1-4 alkyl;

[00309] R1a is independently selected from: F, Cl and C1-2 alkyl;

[00310] R2 is independently selected from: C1-5 alkyl substituted with 0-3 Re; C1-5 alkenyl and C1-6 cycloalkyl; and CH2O(CH2)1- 3CH3;

[00311] R3 is independently selected from:

[00312] (1) -(CH2)rC(=O)OC1-4 alkyl substituted with 0-3 Re,

[00313] (2) -(CH2)rNRaRa,

[00314] (3) -(CH2)rC(=O)NRaRa,

[00315] (4) -(CH2)rNRaC(=O)C1-4 alkyl substituted with 0-3 Re and

[00316] (5) -(CH2)rNRaC(=O)(CR4R4)nOC1-4 alkyl substituted with 0-3 Re;

[00317] R4 is independently selected from: H, F, Cl, NRaRa, OC1-4 alkyl and C1-4 alkyl;

[00318] R5 is independently selected from: -(CH2)n-aryl, -(CH2)n-C3-6 cycloalkyl and -(CH2)n-heterocycle, each substituted with 0-3 R6;

[00319] R6 is independently selected from: H, F, Cl, Br, -OCH3, -OCF3, =O, CN, -NRaRa, -S(O)2NH2, CH3, CF3 -(CH2)n-aryl, - (CH2)n-C3-6 cycloalkyl substituted with 0-3 Re and -(CH2)n-heterocyclyl substituted with 0-3 Re;

[00320] Ra is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re ;

[00321] Re is independently selected from C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, - (CH2)n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H;

[00322] n is independently selected from zero, 1, 2 and 3; It is

[00323] r is independently selected from 1, 2 and 3; It is

[00324] other variables are as defined in formula (III).

[00325] In another aspect, the present invention provides compounds of formula (IVa):

[00326] or stereoisomers, enantiomers, diastereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof in which:

[00327] R1 is independently selected from: -CH2OH, -OCH3, - OCF3, OCH2Ph, -C(=O)NRaRa, -NRaRa, CH3, CH2CH3, CH(CH3)2 and cyclopropyl;

[00328] R2 is independently selected from: C1-4 alkyl substituted with 0-3 Re; C2-4 alkenyl, C1-6 cycloalkyl and CH2O(CH2)1- 3CH3;

[00329] R3 is independently selected from:

[00330] (1) -(CR4R4)rC(=O)OC1-4 alkyl substituted with 0-3 Re,

[00331] (2) -(CR4R4)rNRaRa,

[00332] (3) -(CR4R4)rC(=O)NRaRa,

[00333] (4) -(CR4R4)rNRaC(=O)C1-4 alkyl substituted with 0-3 Re,

[00334] (5) -(CR4R4)rNRaC(=O)(CR4R4)nOC1-4 alkyl substituted with 0-3 Re,

[00335] (6) -(CR4R4)r-R5,

[00336] (7) -(CR4R4)r-OR5,

[00337] (8) -(CR4R4)rNRaC(=O)(CR4R4)nR5 and

[00338] (9) -(CR4R4)rC(=O)NRa(CR4R4)nR5;

[00339] R4 is independently selected from: H, F, Cl, NRaRa, OC1-4 alkyl and C1-4 alkyl;

[00340] R5 is independently selected from: aryl, C3-6 cycloalkyl and heterocycle, each substituted with 0-3 R6;

[00341] R6 is independently selected from: H, F, Cl, Br, -ORb, =O, -(CH2)nC(=O)Rb, -(CH2)nC(=O)ORb, -(CH2)nNRaRa , CN, -(CH2)nC(=O)NRaRa, C1-4 alkyl substituted with 0-3 Re, (CH2)n-C3-6 carbocyclyl substituted with 0-3 Re and -(CH2)n-heterocyclyl substituted with 0-3 Re;

[00342] Ra is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re ; or Ra and Ra together with the nitrogen atom to which they are attached form a heterocyclic ring with 0-5 Re;

[00343] Rb is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, -(CH2)n-C3 -10carbocyclyl substituted with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re;

[00344] Re is independently selected from C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, - (CH2)n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H;

[00345] n is independently selected from zero, 1, 2 and 3; It is

[00346] r is independently selected from 1, 2 and 3.

[00347] In another aspect, the present invention provides compounds of formula (V):

[00348] or stereoisomers, enantiomers, diastereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof in which:

[00349] R1 is independently selected from: -CH2OH, -OCH3, - OCF3, CH3, CH2CH3, CH(CH3)2 and cyclopropyl;

[00350] R2 is independently selected from: C1-4 alkyl substituted with 0-3 Re; C2-4 alkenyl, C1-6 cycloalkyl and CH2O(CH2)1- 3CH3;

[00351] R3 is independently selected from:

[00352] (1) -CH2C(=O)OC1-4 alkyl substituted with 0-3 Re,

[00353] (2) -CH2NRaRa,

[00354] (3) -CH2C(=O)NRaRa,

[00355] (4) -CH2NHC(=O)C1-4 alkyl substituted with 0-3 Re,

[00356] (5) -CH2NRaC(=O)(CH2)0-2OC1-4 alkyl substituted with 0-3 Re,

[00357] (6) -CH2-R5,

[00358] (7) -CH2-OR5,

[00359] (8) -CH2NRaC(=O)(CH2)0-2R5 and

[00360] (9) -CH2C(=O)NRa(CH2)0-2R5;

[00361] R5 is independently selected from: aryl, C3-6 cycloalkyl and heterocycle, each substituted with 0-3 R6;

[00362] R6 is independently selected from: H, F, Cl, Br, -ORb, =O, -(CH2)nC(=O)Rb, -(CH2)nC(=O)ORb, -(CH2)nNRaRa , CN, -(CH2)nC(=O)NRaRa, -S(O)2NH2, C1-4 alkyl substituted with 0-3 Re, (CH2)n-C3-6 carbocyclyl substituted with 0-3 Re and -( CH2)n-heterocyclyl substituted with 0-3 Re;

[00363] Ra is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re ; or Ra and Ra together with the nitrogen atom to which they are attached form a heterocyclic ring with 0-5 Re;

[00364] Rb is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, -(CH2)n-C3 -10carbocyclyl substituted with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re;

[00365] Re is independently selected from C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, - (CH2)n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H;

[00366] n is independently selected from zero, 1, 2 and 3.

[00367] In another aspect, the present invention provides compounds of formula (V), or enantiomeric stereoisomers, diastereoisomers, tautomers, pharmaceutically acceptable salts, solvate, or prodrugs thereof in which:

[00368] R3 is independently selected from:

[00369] (1) -CH2-R5,

[00370] (2) -CH2-OR5,

[00371] (3) -CH2-NHC(=O)(CH2)0-1R5 and

[00372] (4) -CH2-C(=O)NH(CH2)0-1R5;

[00373] R5 is independently selected from:

[00374] R6 is independently selected from: H, F, Cl, Br, -OCH3, -OCF3, =O, CN, CH3, CF3 -(CH2)n-aryl, -(CH2)n-C3-6 substituted cycloalkyl with 0-3 Re and -(CH2)n-heterocyclyl substituted with 0-3 Re;

[00375] R6a is independently selected from: H, CH3, aryl substituted with 0-3 Re and heterocyclyl substituted with 0-3 Re;

[00376] Ra is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re ;

[00377] Re is independently selected from C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, - (CH2)n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H;

[00378] n is independently selected from zero, 1, 2 and 3.

[00379] In another aspect, the present invention provides compounds of formula (VI):

[00380] or stereoisomers, enantiomers, diastereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof in which:

[00381] R1 is independently selected from: F, Cl, Br, NO2, -(CH2)nORb, -(CH2)nC(=O)Rb, -(CH2)nNRaRa, -(CH2)nC(=O)NRaRa , -(CH2)nNRaC(=O)Rb, C1-4 alkyl substituted with 0-3 Re and C3-6 cycloalkyl substituted with 0-3 Re;

[00382] R2 is independently selected from: C1-5 alkyl substituted with 0-3 Re; C1-5 alkenyl and C1-6 cycloalkyl; wherein when R2 is independently selected from: C1-5 alkyl, the carbon atom except that directly linked to the pyridine ring may be replaced by O, N and S;

[00383] R3 is independently selected from:

[00384] (1) -CH2C(=O)OC1-4 alkyl substituted with 0-5 Re,

[00385] (2) -CH2NRaRa,

[00386] (3) -CH2C(=O)NRaRa,

[00387] (4) -CH2NRaC(=O)C1-4 alkyl substituted with 0-5 Re,

[00388] (5) -CH2NRaC(=O)( CH2)nOC1-4 alkyl substituted with 0-5 Re,

[00389] (6) -CH2-R5,

[00390] (7) -CH2-OR5,

[00391] (8) -CH2NRaC(=O)(CH2)nR5 and

[00392] (9) -CH2C(=O)NRa(CH2)nR5

[00393] R5 is independently selected from: -(CH2)n-aryl, -(CH2)n-C3-6 cycloalkyl and -(CH2)n-heterocycle, each substituted with 0-3 R6;

[00394] R6 is independently selected from: H, F, Cl, Br, -ORb, =O, -(CH2)nC(=O)Rb, -(CH2)nC(=O)ORb, -(CH2)nNRaRa , CN, -(CH2)nC(=O)NRaRa, C1-4 alkyl substituted with 0-3 Re, (CH2)n-C3-6 carbocyclyl substituted with 0-3 Re and -(CH2)n-heterocyclyl substituted with 0-3 Re;

[00395] Ra is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re ; or Ra and Ra together with the nitrogen atom to which they are attached form a heterocyclic ring with 0-5 Re;

[00396] Rb is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, -(CH2)n-C3 -10carbocyclyl substituted with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re;

[00397] Re is independently selected from C1-6 alkyl substituted with 0-5 Rf, C2-6 alkenyl, C2-6 alkynyl, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl , -(CH2)n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H, -(CH2)nORf, S(O)pRf, C(=O)NRfRf , NRfC(=O)Rf, S(O)pNRfRf, NRfS(O)pRf, NRfC(=O)ORf, OC(=O)NRfRf and -(CH2)nNRfRf;

[00398] Rf is independently selected from H, F, Cl, Br, CN, OH, C1-5alkyl (optionally substituted with halogen and OH), C3-6 cycloalkyl and phenyl;

[00399] n is independently selected from zero, 1, 2 and 3; It is

[00400] p is independently selected from zero, 1 and 2.

[00401] In a non-limiting modality, ring A is the or ring B is ; R1 is OC1-4 alkyl; R2 is independently selected from: C1-5 alkyl substituted with 0-3 Re; C1-5 alkenyl and C1-6 cycloalkyl; provided that when R2 is C1-5 alkyl, the carbon atom other than that attached directly to the pyridine ring may be replaced by O, N and S; R3 is CH2-R5; R5 is aryl, C3-6 cycloalkyl and heteroaryl, each substituted with 0-3 R6; R6 is independently selected from: H, F, Cl, Br, -ORb, =O, - (CH2)nC(=O)Rb, -(CH2)nC(=O)ORb, -(CH2)nNRaRa, CN, - (CH2)nC(=O)NRaRa, -S(O)2NH2, C1-4 alkyl substituted with 0-3 Re, (CH2)n-C3-6 carbocyclyl substituted with 0-3 Re and -(CH2)n -heterocyclyl substituted with 0-3 Re; Ra is independently selected from H, C16 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are attached form a heterocyclic ring with 0-5 Re; Rb is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, - (CH2)n-C3-10 substituted carbocyclyl with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re; Re is independently selected from C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6heterocyclyl, -(CH2)n -aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H; n is independently selected from zero, 1, 2 and 3.

[00402] In another non-limiting embodiment, ring A is ring B is R1 is OC1-4 alkyl; R2 is independently selected from C1-5 alkyl substituted with 0-3 Re; and C1-6 cycloalkyl; provided that when R2 is C1-5 alkyl, the carbon atom other than that attached directly to the pyridine ring may be replaced by O; R3 is CH2-R5; R5 is aryl, C3-6 cycloalkyl and heteroaryl, each substituted with 0-3 R6; R6 is independently selected from: H, F, Cl, Br, -ORb, =O, -(CH2)nC(=O)Rb, -(CH2)nC(=O)ORb, -(CH2)nNRaRa, CN, -(CH2)nC(=O)NRaRa, -S(O)2NH2, C1-4 alkyl substituted with 0-3 Re, (CH2)n-C3-6 carbocyclyl substituted with 0-3 Re and -(CH2)n -heterocyclyl substituted with 0-3 Re; Ra is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are attached form a heterocyclic ring with 0-5 Re; Rb is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, -(CH2)n-C3-10 substituted carbocyclyl with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re; Re is independently selected from C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6heterocyclyl, -(CH2)n -aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H; n is independently selected from zero, 1, 2 and 3.

[00403] In another non-limiting embodiment, ring A is ; ring B is ; R1 is OC1-4 alkyl; R2 is independently selected from: C1-4 alkyl substituted with 0-3 Re; C2-4 alkenyl, C1-6 cycloalkyl and CH2O(CH2)I-3CHS; R3 is CH2-R5; R5 is aryl or heteroaryl independently selected from: H, F, Cl, Br -OCH3, -OCF3, =O, CN, CH3, CF3 -(CH2)n-aryl, -(CH2)n-C3-6 substituted cycloalkyl with 0-3 Re and -(CH2)n-heterocyclyl substituted with 0-3 Re; R6a is independently selected from: H, CH3, Re is independently selected from C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, F, Cl, Br, CN, NO2; n is independently selected from zero, 1, 2 and 3.

[00404] In another non-limiting embodiment, ring A and ring B is R1 is OC1-4 alkyl; R2 is independently; o selected from: C1-4 alkyl substituted with 0-3 Re; C2-4 alkenyl, C1-6 cycloalkyl and CH2O(CH2)1-3CH3; R3 and CH2-R5; R5 is aryl or heteroaryl H, F, Cl, Br, -OCH3, -OCF3, =O, CN, CH3, CF3 -(CH2)n-aryl, -(CH2)n-C3-6 cycloalkyl substituted with 0-3 Re and -(CH2 )n-heterocyclyl substituted with 0-3 Re; R6a is independently selected from: H, CH3, Re is independently selected from C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, F, Cl, Br, CN, NO2; n is independently selected from zero, 1, 2 and 3.

[00405] In another non-limiting embodiment, ring A is ; ring B is ; R1 is OC1-4 alkyl; R2 is C1-4 alkyl or CH2O(CH2)I-3CH3; R3 is CH2-R5; R5 is aryl or heteroaryl selected from R6 is independently

[00406] The invention can be included in other specific forms without departing from the spirit or essential attributes thereof. This invention also encompasses all combinations of alternative aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be considered in conjunction with any other embodiment to describe additional embodiments of the present invention. Furthermore, any elements (including individual variable definitions) of an embodiment are intended to be combined with any and all other elements of any of the embodiments to describe additional embodiments. The present invention also provides a pharmaceutical composition comprising a compound of formula I, or an enantiomer, diastereomer, or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier thereof.

[00407] In another embodiment, compounds of the present invention have EC50 values < 10 µM, using the APJ hcAMP assay described herein, preferably, EC50 values < 5 µM, more preferably, EC50 values < 1 µM, even more preferably, EC50 values < 0.5 µM, even more preferably, EC50 values < 0.1 µM, even more preferably, EC50 values < 0.01 µM.

[00408] In another aspect, the present invention provides compounds selected from any subgroup list of compounds exemplified in the present application.

[00409] In another aspect, the present invention provides compounds selected from the subset in which the APJ hcAMP EC50 potency range is A.

[00410] In another aspect, the present invention provides compounds selected from the subset in which the APJ hcAMP EC50 potency range is B.

[00411] In another aspect, the present invention provides compounds selected from the subgroup in which the APJ hcAMP EC50 potency range is C.

[00412] In another aspect, the present invention provides a compound selected from

[00413] 3-(5-benzyl-1,3,4-oxadiazol-2-yl)-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,

[00414] 3-(5-benzyl-1,3,4-oxadiazol-2-yl)-6-butyl-5-(2,6-dimethoxy-4-methylphenyl)pyridine-2,4-diol,

[00415] 6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(pyridin-4-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,

[00416] 6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(2-phenylethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,

[00417] 6-butyl-3-{5-[(2-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol ,

[00418] 6-Butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(2-methoxyphenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol ,

[00419] 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(3-methoxyphenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol ,

[00420] 6-butyl-3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol ,

[00421] 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(4-methoxyphenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol ,

[00422] 6-butyl-3-[5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl]-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,

[00423] 6-butyl-3-[5-(2-chlorophenyl)-1,3,4-oxadiazol-2-yl]-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,

[00424] 6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(pyrazin-2-yl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,

[00425] 6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(1-phenylcyclopropyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,

[00426] 6-butyl-3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,

[00427] 6-Butyl-5-(2,6-dimethoxyphenyl)-3-[5-(2-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl]pyridine-2,4- diol,

[00428] 6-butyl-5-(2,6-dimethoxyphenyl)-3- [5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,

[00429] 6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(phenoxymethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,

[00430] 3-(5-benzyl-1,3,4-oxadiazol-2-yl)-6-(but-3-en-1-yl)-5-(2,6-dimethoxyphenyl)pyridine-2, 4-diol,

[00431] 6-Butyl-5-(2,6-dimethoxyphenyl)-3- [5-(5-methyl-1H-pyrazol-3-yl)- 1,3,4-oxadiazol-2-yl]pyridine- 2,4-diol,

[00432] 3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2, 4-diol,

[00433] 6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(pyrazin-2-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,

[00434] 6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(pyrimidin-5-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,

[00435] 6-butyl-3-{5-[(3-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol ,

[00436] 6-butyl-3-{5-[difluoro(phenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,

[00437] 3-[5-(1,3-benzoxazol-2-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2, 4-diol,

[00438] 3- [5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5- (2,6-dimethoxy-4-methylphenyl) pyridine-2,4-diol,

[00439] 3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-(but-3-en-1-yl)-5-( 2,6-dimethoxyphenyl)pyridine-2,4-diol,

[00440] 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5- [2-(5-phenyl-1,3-oxazol-2-yl)ethyl]-1,3,4-oxadiazole -2-yl}pyridine-2,4-diol,

[00441] 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5- [2-(1-methyl-1H-imidazol-2-yl)ethyl]-1,3,4-oxadiazol-2 -yl}pyridine-2,4-diol,

[00442] 6-butyl-3-{5-[(6-chloropyridin-3-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2 ,4-diol,

[00443] 6-butyl-3-{5-[2-(4-chlorophenyl)propan-2-yl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine -2,4-diol,

[00444] 6-Butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(4-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol ,

[00445] 6-butyl-3-{5-[(3,4-dichlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4 -diol,

[00446] 6-Butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[4-fluoro-3-(trifluoromethyl)phenyl]methyl}-1,3,4-oxadiazol-2-yl) pyridine-2,4-diol,

[00447] 6-butyl-3-{5-[(2,4-dichlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4 -diol,

[00448] 6-Butyl-5-(2,6-dimethoxyphenyl)-3-{5- [(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-1,3,4-oxadiazol-2 -yl}pyridine-2,4-diol,

[00449] 4-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )benzonitrile,

[00450] 6-butyl-3-{5-[(3,4-difluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4 -diol,

[00451] 6-butyl-3-(5-{ [2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}-1,3,4-oxadiazol-2-yl)-5- (2,6-dimethoxyphenyl)pyridine-2,4-diol,

[00452] 6-butyl-3-{5-[1-(4-chlorophenyl)ethyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4 -diol,

[00453] 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5- [(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-1,3,4-oxadiazole -2-yl}pyridine-2,4-diol,

[00454] 6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(4-fluorophenoxymethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,

[00455] 6-Butyl-5-(2,6-dimethoxyphenyl)-3- [5-(1H-indazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4- diol,

[00456] 4-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )-1,2-dihydrophthalazin-1-one,

[00457] 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[methoxy(phenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,

[00458] 6-Butyl-5-(2,6-dimethoxyphenyl)-3-{5- [(2-phenyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2 -yl}pyridine-2,4-diol,

[00459] 3-{5-[2-(1,3-benzoxazol-2-yl)ethyl]-1,3,4-oxadiazol-2-yl}-6-butyl-5-(2,6-dimethoxyphenyl )pyridine-2,4-diol,

[00460] 6-Butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(4-fluoro-3-methoxyphenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2 ,4-diol,

[00461] 6-butyl-5-(2,6-dimethoxyphenyl)-3- [5-(1,3-thiazol-5-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2, 4-diol,

[00462] 6-butyl-3-[5-(3,4-dichlorophenoxymethyl)-1,3,4-oxadiazol-2-yl]-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,

[00463] 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5- [(3-methyl-1,2-oxazol-5-yl)methyl]-1,3,4-oxadiazol-2 -yl}pyridine-2,4-diol,

[00464] 6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{2-[3-(pyrazin-2-yl)-1,2,4-oxadiazol-5-yl]ethyl} -1,3,4-oxadiazol-2-yl)pyridine-2,4-diol,

[00465] 6-butyl-3-[5-(4-chlorophenoxymethyl)-1,3,4-oxadiazol-2-yl]-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,

[00466] 6-Butyl-3-{5-[2-(4-chlorophenyl)-2-methylpropyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine- 2,4-diol,

[00467] 6-Butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-1 ,3,4-oxadiazol-2-yl)pyridine-2,4-diol,

[00468] 6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[4-(trifluoromethoxy)phenyl]methyl}-1,3,4-oxadiazol-2-yl)pyridine-2, 4-diol,

[00469] 6-Butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}-1,3,4-oxadiazol-2-yl) pyridine-2,4-diol,

[00470] 6-Butyl-5-(2,6-dimethoxyphenyl)-3-{5-[2-(1-methyl-1H-1,3-benzodiazol-2-yl)ethyl]-1,3,4 -oxadiazol-2-yl}pyridine-2,4-diol,

[00471] 6-butyl-3-{5-[(2-chloropyridin-4-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2 ,4-diol,

[00472] 6-Butyl-5-(2,6-dimethoxyphenyl)-3-(5-{2-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]ethyl}-1 ,3,4-oxadiazol-2-yl)pyridine-2,4-diol,

[00473] 6-Butyl-5-(2,6-dimethoxyphenyl)-3- [5-(1,2,3,4-tetrahydroisoquinolin-1-yl)-1,3,4-oxadiazol-2- yl]pyridine-2,4-diol,

[00474] 6-Butyl-3-{5-[2-(3,4-dichlorophenyl)propan-2-yl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl )pyridine-2,4-diol,

[00475] 6-Butyl-5-(2,6-dimethoxyphenyl)-3-{5- [(2-methyl-2H-1,2,3,4-tetrazol-5-yl)methyl]-1,3 ,4-oxadiazol-2-yl}pyridine-2,4-diol,

[00476] 6-Butyl-5-(2,6-dimethoxyphenyl)-3- [5-(2-methyl-1-phenylpropan-2-yl)- 1,3,4-oxadiazol-2-yl]pyridine- 2,4-diol,

[00477] 6-Butyl-5-(2,6-dimethoxyphenyl)-3-{5-[4-(trifluoromethyl)phenoxymethyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol ,

[00478] 6-Butyl-5-(2,6-dimethoxyphenyl)-3-{5- [(5-phenyl-4H-1,2,4-triazol-3-yl)methyl]-1,3,4 -oxadiazol-2-yl}pyridine-2,4-diol,

[00479] 6-butyl-3-[5-(cyclohexylmethyl)-1,3,4-oxadiazol-2-yl]-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,

[00480] 6-butyl-3-{5-[2-(4-chlorophenyl)ethyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4 -diol,

[00481] 6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(oxan-4-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,

[00482] 6-butyl-3-{5-[(3-chloro-4-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2 ,4-diol,

[00483] 6-butyl-3-{5-[(4-chloro-3-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2 ,4-diol,

[00484] 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[2-(1,3-thiazol-2-yl)ethyl]-1,3,4-oxadiazol-2-yl }pyridine-2,4-diol,

[00485] 6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[3-(trifluoromethyl)phenyl]methyl}-1,3,4-oxadiazol-2-yl)pyridine-2, 4-diol,

[00486] 6-butyl-3-{5-[2-(3,4-difluorophenyl)ethyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2 ,4-diol,

[00487] 6-Butyl-5-(2,6-dimethoxyphenyl)-3-(5-{2-[4-(trifluoromethyl)phenyl]ethyl}-1,3,4-oxadiazol-2-yl)pyridine- 2,4-diol,

[00488] 6-butyl-3-[5-(3,4-difluorophenoxymethyl)-1,3,4-oxadiazol-2-yl]-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,

[00489] 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[2-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl]-1,3,4 -oxadiazol-2-yl}pyridine-2,4-diol,

[00490] 6-Butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(1-phenyl-1H-pyrazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl }pyridine-2,4-diol,

[00491] 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5- [(2-methyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2 -yl}pyridine-2,4-diol,

[00492] 6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[4-(trifluoromethyl)phenyl]methyl}-1,3,4-oxadiazol-2-yl)pyridine-2, 4-diol,

[00493] 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[2-(pyrimidin-2-yl)ethyl]-1,3,4-oxadiazol-2-yl}pyridine-2 ,4-diol,

[00494] 3-{5-[2-(1,3-benzothiazol-2-yl)ethyl]-1,3,4-oxadiazol-2-yl}-6-butyl-5-(2,6-dimethoxyphenyl )pyridine-2,4-diol,

[00495] 6-Butyl-5-(2,6-dimethoxyphenyl)-3-(5-{2-[3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl]ethyl} -1,3,4-oxadiazol-2-yl)pyridine-2,4-diol,

[00496] 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5- [(5-methyl-2-phenyl-1,3-thiazol-4-yl)methyl]-1,3,4 -oxadiazol-2-yl}pyridine-2,4-diol,

[00497] 6-butyl-3-{5-[2-(3,4-dichlorophenyl)ethyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2 ,4-diol,

[00498] 3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5-(2,6-dichlorophenyl)pyridine-2, 4-diol,

[00499] 6-butyl-3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dichlorophenyl)pyridine-2,4-diol ,

[00500] 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(dimethylamino)(4-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2, 4-diol,

[00501] 3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)pyridine- 2,4-diol,

[00502] 3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)pyridine-2,4 -diol,

[00503] 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5- [(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]-1,3,4 -oxadiazol-2-yl}pyridine-2,4-diol,

[00504] 3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-cyclopropyl-5-(2,6-dimethoxyphenyl)pyridine-2, 4-diol,

[00505] 3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-6-cyclopropyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol ,

[00506] 6-cyclopropyl-5-(2,6-dimethoxyphenyl)-3-{5-[(2-methyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2 -yl}pyridine-2,4-diol,

[00507] 6-cyclopropyl-5-(2,6-dimethoxyphenyl)-3-(5-{[3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-1 ,3,4-oxadiazol-2-yl)pyridine-2,4-diol,

[00508] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}acetate ethyl,

[00509] 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5- [(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-1,3,4-oxadiazol-2 -yl}pyridine-2,4-diol,

[00510] 3-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )-1-methylimidazolidine-2,4-dione,

[00511] 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(3-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol ,

[00512] 6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(piperidin-1-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,

[00513] 6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl]methyl}-1 ,3,4-oxadiazol-2-yl)pyridine-2,4-diol,

[00514] 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(1-methyl-1H-pyrazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl }pyridine-2,4-diol,

[00515] 6-butyl-3-{5-[(4-chloro-2-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2 ,4-diol,

[00516] 6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl]methyl}-1 ,3,4-oxadiazol-2-yl)pyridine-2,4-diol,

[00517] 1-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )pyrrolidin-2-one,

[00518] 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-{5-[(2-methyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazole -2-yl}pyridine-2,4-diol,

[00519] 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-(5-{ [5-(pyridin-2-yl)- 1,2,4-oxadiazol-3-yl]methyl} -1,3,4-oxadiazol-2-yl)pyridine-2,4-diol,

[00520] 3-{5-[(3-benzyl-1,2,4-oxadiazol-5-yl)methyl]-1,3,4-oxadiazol-2-yl}-6-butyl-5-(2 ,6-dimethoxyphenyl)pyridine-2,4-diol,

[00521] 6-butyl-3-{5- [(3-cyclopropyl-1,2,4-oxadiazol-5-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2 ,6-dimethoxyphenyl)pyridine-2,4-diol,

[00522] 3-{5-[(6-chloropyridin-3-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)pyridine -2,4-diol,

[00523] 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5- [(3-phenyl-1,2,4-oxadiazol-5-yl)methyl]-1,3,4-oxadiazole -2-yl}pyridine-2,4-diol,

[00524] 1-({5-[5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl }methyl)pyrrolidin-2-one,

[00525] 3-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )imidazolidine-2,4-dione,

[00526] 1-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )-1,2-dihydropyridin-2-one,

[00527] 6-butyl-5-(2,6-dimethoxyphenyl)-3- [5-(1H-imidazol-1-ylmethyl)- 1,3,4-oxadiazol-2-yl]pyridine-2,4- diol,

[00528] 3-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )-1,3-oxazolidin-2-one,

[00529] 4-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )morpholin-3-one,

[00530] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}acetate tert-butyl,

[00531] 1-({5-[5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl }methyl)-1,2-dihydropyridin-2-one,

[00532] N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl ) tert-butyl carbamate,

[00533] N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl tert-butyl )-N-methylcarbamate,

[00534] 3-{5-[(4-chloro-3-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)pyridine -2,4-diol,

[00535] 3-{5-[(4-chloro-2-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)pyridine -2,4-diol,

[00536] 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-{5-[(5-fluoropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine -2,4-diol,

[00537] 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-[5-(1H-imidazol-1-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2, 4-diol,

[00538] 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-{5-[(3-fluoro-4-methylphenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine -2,4-diol,

[00539] 3-{5-[(5-chloropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)pyridine -2,4-diol,

[00540] 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-{5-[(3-phenyl-1H-pyrazol-1-yl)methyl]-1,3,4-oxadiazol-2 -yl}pyridine-2,4-diol,

[00541] 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-(5-{ [3-(trifluoromethyl)- 1H-pyrazol-1-yl]methyl}-1,3,4-oxadiazole -2-yl)pyridine-2,4-diol,

[00542] 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-{5-[(1-methyl-1H-pyrazol-4-yl)methyl]-1,3,4-oxadiazol-2 -yl}pyridine-2,4-diol,

[00543] 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-{5-[(6-fluoropyridin-3-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine -2,4-diol,

[00544] 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-[5-(1H-indazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2, 4-diol,

[00545] 3-[5-(1H-1,2,3-benzotriazol-1-ylmethyl)-1,3,4-oxadiazol-2-yl]-5-(2,6-dimethoxyphenyl)-6-( ethoxymethyl)pyridine-2,4-diol,

[00546] 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-[5-(1H-indazol-1-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2, 4-diol,

[00547] 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-{5-[(4-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4 -diol,

[00548] 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3- [5-(1H-indol-1-ylmethyl)- 1,3,4-oxadiazol-2-yl]pyridine-2, 4-diol,

[00549] 6-butyl-5-(3-ethylphenyl)-4-hydroxy-3-{5- [(2-methyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazole -2-yl}-1,2-dihydropyridin-2-one,

[00550] 3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5-phenylpyridine-2,4-diol,

[00551] 6-butyl-3-{5-[(3,4-difluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(3-methoxyphenyl)pyridine-2,4-diol ,

[00552] 6-butyl-3-{5-[(3,4-difluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(3-ethylphenyl)pyridine-2,4-diol ,

[00553] 6-butyl-3-{5-[(3,4-difluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-[3-(trifluoromethoxy)phenyl]pyridine-2, 4-diol,

[00554] 5-[3-(benzyloxy)phenyl]-6-butyl-3-{5-[(3,4-difluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2, 4-diol,

[00555] 6-butyl-3-{5-[(3,4-difluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-[3-(hydroxymethyl)phenyl]pyridine-2, 4-diol,

[00556] 6-butyl-5-(cyclohex-1-en-1-yl)-3-{5-[(3,4-difluorophenyl)methyl]-1,3,4-oxadiazol-2-yl }pyridine-2,4-diol,

[00557] 6-butyl-3-{5-[(3,4-difluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-[3-(propan-2-yl)phenyl] pyridine-2,4-diol,

[00558] 6-butyl-3-{5-[(3,4-difluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-[3-(methoxymethyl)phenyl]pyridine-2, 4-diol,

[00559] 3-(2-butyl-5-{5-[(3,4-difluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-4,6-dihydroxypyridin-3-yl )-N-(propan-2-yl)benzamide,

[00560] 6-butyl-4-hydroxy-3-{5- [(2-methyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}-5- [3-(propan-2-yl)phenyl]-1,2-dihydropyridin-2-one,

[00561] 3-(2-butyl-4-hydroxy-5-{5- [(2-methyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl} -6-oxo-1,6-dihydropyridin-3-yl)-N-(propan-2-yl)benzamide,

[00562] 6-butyl-5-(3-cyclopropylphenyl)-4-hydroxy-3-{5- [(2-methyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazole -2-yl}-1,2-dihydropyridin-2-one,

[00563] 6-butyl-4-hydroxy-5-(3-methoxyphenyl)-3-{5- [(2-methyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazole -2-yl}-1,2-dihydropyridin-2-one,

[00564] 6-butyl-4-hydroxy-5- [3-(hydroxymethyl)phenyl]-3-{5- [(2-methyl-1,3-thiazol-4-yl)methyl]-1,3, 4-oxadiazol-2-yl}-1,2-dihydropyridin-2-one,

[00565] 6-butyl-4-hydroxy-3-{5- [(2-methyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}-5- [3-(pyrrolidin-1-yl)phenyl]-1,2-dihydropyridin-2-one,

[00566] 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(methylamino)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,

[00567] N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )-N-methyl-2-phenylacetamide,

[00568] N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )-3-chloro-N-methylbenzamide,

[00569] N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )-N-methylpyridine-2-carboxamide,

[00570] N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )-2-methoxyacetamide,

[00571] N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )-N-methylpyridine-4-carboxamide,

[00572] N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )pyridine-3-carboxamide,

[00573] N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )-2-chloro-N-methylbenzamide,

[00574] N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )-3-chlorobenzamide,

[00575] N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )-4-chlorobenzamide,

[00576] N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )pyridine-4-carboxamide,

[00577] N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )-N-methylpyridine-3-carboxamide,

[00578] N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )-2-phenylacetamide,

[00579] N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )-2,2-dimethylpropanamide,

[00580] N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )pyridine-2-carboxamide,

[00581] N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )-N,2,2-trimethylpropanamide,

[00582] 3-[5-(aminomethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,

[00583] N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )benzamide,

[00584] N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )-N-methylbenzamide,

[00585] N-({5-[5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl }methyl)benzamide,

[00586] N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )-3-methylbutanamide,

[00587] N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )acetamide,

[00588] N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )-2,2,2-trifluoroacetamide,

[00589] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N ,N-diethylacetamide,

[00590] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N -(pyridin-2-ylmethyl)acetamide,

[00591] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N -methylacetamide,

[00592] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}acetamide,

[00593] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N -(propan-2-yl)acetamide,

[00594] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N ,N-dimethylacetamide,

[00595] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N -(4-methoxyphenyl)acetamide,

[00596] 4-(2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl }acetyl)piperazin-2-one,

[00597] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-1 -(4-methylpiperazin-1-yl)ethan-1-one,

[00598] N-Benzyl-2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2- yl}acetamide,

[00599] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N -ethylacetamide,

[00600] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N -cyclopropylacetamide,

[00601] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N -propylacetamide,

[00602] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N -(2-fluoroethyl)acetamide,

[00603] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N -(2,2-difluoroethyl)acetamide,

[00604] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N -(2,2,2-trifluoroethyl)acetamide,

[00605] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N -(2-methoxyethyl)acetamide,

[00606] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-1 -(pyrrolidin-1-yl)etan-1-one,

[00607] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-1 -(piperidin-1-yl)etan-1-one,

[00608] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-1 -(morpholin-4-yl)etan-1-one,

[00609] N-butyl-2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2- yl}acetamide,

[00610] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N -pentylacetamide,

[00611] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-1 -(3-fluoroazetidin-1-yl)ethan-1-one,

[00612] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-1 -(3,3-difluoroazetidin-1-yl)ethan-1-one,

[00613] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N -(1,3-thiazol-2-yl)acetamide,

[00614] 3-(3-benzyl-1,2,4-oxadiazol-5-yl)-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,

[00615] 6-butyl-3-{3-[(4-chlorophenyl)methyl]-1,2,4-oxadiazol-5-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol ,

[00616] 3-(5-benzyl-4H-1,2,4-triazol-3-yl)-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,

[00617] 6-butyl-3-(5-{ [5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3,4-oxadiazol-2-yl)- 5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,

[00618] 6-Butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl]methyl}-1 ,3,4-oxadiazol-2-yl)pyridine-2,4-diol,

[00619] 6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-1 ,3,4-oxadiazol-2-yl)pyridine-2,4-diol,

[00620] 6-Butyl-3-(5-{ [5-(2-chlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3,4-oxadiazol-2-yl)- 5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,

[00621] 3-{5-[(5-benzyl-1,3,4-oxadiazol-2-yl)methyl]-1,3,4-oxadiazol-2-yl}-6-butyl-5-(2 ,6-dimethoxyphenyl)pyridine-2,4-diol,

[00622] 6-butyl-3-(5-{ [5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3,4-oxadiazol-2-yl)- 5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,

[00623] 6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl]methyl}-1 ,3,4-oxadiazol-2-yl)pyridine-2,4-diol,

[00624] 1-({5-[6-(ethoxymethyl)-5-(4-fluoro-2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazole -2-yl}methyl)-1,2-dihydropyridin-2-one,

[00625] 3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-(ethoxymethyl)-5-(4-fluoro-2,6- dimethoxyphenyl)pyridine-2,4-diol,

[00626] 3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-6-(ethoxymethyl)-5-(4-fluoro-2,6-dimethoxyphenyl)pyridine -2,4-diol,

[00627] 1-({5-[6-(ethoxymethyl)-5-(4-fluoro-2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazole -2-yl}methyl)pyrrolidin-2-one,

[00628] 3-{5-[(6-chloropyridin-3-yl)methyl]-1,3,4-oxadiazol-2-yl}-6-(ethoxymethyl)-5-(4-fluoro-2,6 -dimethoxyphenyl)pyridine-2,4-diol,

[00629] 3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(3,5-dimethoxypyridin-4-yl)-6-(ethoxymethyl)pyridine -2,4-diol,

[00630] 6-butyl-3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(3-fluoro-2,6-dimethoxyphenyl)pyridine-2 ,4-diol,

[00631] 3- [5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5- (3-fluoro-2,6-dimethoxyphenyl) pyridine-2,4-diol,

[00632] 3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-6-(ethoxymethyl)- 5-(2-hydroxy-6-methoxyphenyl)pyridine-2 ,4-diol,

[00633] 3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5-(2,6-dimethylphenyl)pyridine-2, 4-diol,

[00634] 3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5-(2,4,6-trimethylphenyl)pyridine- 2,4-diol,

[00635] 3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5-(2,6-diethylphenyl)pyridine-2, 4-diol,

[00636] 6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{ [1,2]oxazolo [4,5-b]pyridin-3-ylmethyl}-1,3,4-oxadiazole -2-yl)pyridine-2,4-diol,

[00637] 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-(5-{ [1,2]oxazolo [4,5- b]pyridin-3-ylmethyl}-1,3,4 -oxadiazol-2-yl)pyridine-2,4-diol,

[00638] 3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dihydroxyphenyl)-6-(ethoxymethyl)pyridine-2 ,4-diol,

[00639] 3-{5- [(5-chloropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6- [(ethylamino) methyl]pyridine-2,4-diol,

[00640] 3-{5-[(1,2-benzoxazol-3-yl)methyl]-1,3,4-thiadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl )pyridine-2,4-diol,

[00641] 3-{5-[(5-chloropyridin-2-yl)methyl]-1,3,4-thiadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)pyridine -2,4-diol,

[00642] 3-{5-[(5-chloropyridin-2-yl)methyl]-1,3,4-thiadiazol-2-yl}-6-cyclopentyl-5-(2,6-dimethoxyphenyl)pyridine-2 ,4-diol,

[00643] 3-{5-[(4-chlorophenyl)methyl]-1,3,4-thiadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)pyridine-2,4 -diol,

[00644] N-({5-[5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-thiadiazol-2-yl }methyl)pyridine-2-carboxamide,

[00645] 6-Butyl-3-{5-[(5-chloro-3-fluoropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl )pyridine-2,4-diol,

[00646] 3-{5- [(5-chloro-3-fluoropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}- 5-(2,6-dimethoxyphenyl)-6- (ethoxymethyl)pyridine-2,4-diol,

[00647] 3-{5-[(5-chloropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}-6-cyclopentyl-5-(2,6-dimethoxyphenyl)pyridine-2 ,4-diol,

[00648] 3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-6-cyclopentyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol ,

[00649] 3-{5- [(5-chloropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6- [(2- methoxyethoxy)methyl]pyridine-2,4-diol,

[00650] 3-{5-[(1,2-benzoxazol-3-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-[( 2-methoxyethoxy)methyl]pyridine-2,4-diol,

[00651] 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-{5-[(phenylamino)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol ,

[00652] 3-{5- [(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6- [(2-methoxyethoxy)methyl] pyridine-2,4-diol,

[00653] N-({5-[6-butyl-5-(2,5-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )benzamide,

[00654] N- [(5-{6-butyl-2,4-dihydroxy-5- [2-methoxy-5-(propan-2-yl)phenyl]pyridin-3-yl}-1,3 ,4-oxadiazol-2-yl)methyl]benzamide,

[00655] 3-{5-[(1,2-benzoxazol-3-yl)methyl]-1,3,4-oxadiazol-2-yl}-6-(ethoxymethyl)-5-(2-methoxyphenyl)pyridine -2,4-diol,

[00656] 3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-6-(ethoxymethyl)-5-(2-methoxyphenyl)pyridine-2,4-diol ,

[00657] N-({5-[6-butyl-5-(2,3-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )benzamide,

[00658] N-({5-[6-(ethoxymethyl)-2,4-dihydroxy-5-(2-methoxyphenyl)pyridin-3-yl]-1,3,4-oxadiazol-2-yl} methyl)benzamide,

[00659] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N -(pyridin-3-yl)acetamide,

[00660] 2-{5-[5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl} -N-(1,3-thiazol-2-yl)acetamide,

[00661] N-[(1,3-benzothiazol-2-yl)methyl]-2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3- yl]-1,3,4-oxadiazol-2-yl}acetamide,

[00662] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N - [(pyridin-3-yl)methyl]acetamide,

[00663] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N - [(1,3-oxazol-2-yl)methyl]acetamide,

[00664] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N - [2-(4-sulfamoylphenyl)ethyl]acetamide,

[00665] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N - [2-(2-chlorophenyl)ethyl]acetamide,

[00666] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N - [(3-chlorophenyl)methyl]acetamide,

[00667] N-Benzyl-2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2- yl}-N-methylacetamide,

[00668] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N -methyl-N-(2-phenylethyl)acetamide,

[00669] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N -(prop-2-in-1-yl)acetamide,

[00670] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N -(3-methyl-1H-pyrazol-5-yl)acetamide,

[00671] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N - [(2-methylphenyl)methyl]acetamide,

[00672] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N - [(2-chlorophenyl)methyl]acetamide,

[00673] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N - [(4-chlorophenyl)methyl]acetamide,

[00674] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N - [2-(4-chlorophenyl)ethyl]acetamide,

[00675] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N - [(pyridin-4-yl)methyl]acetamide,

[00676] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N - [(4-methoxyphenyl)methyl]acetamide,

[00677] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N -{ [4-(dimethylamino)phenyl]methyl}acetamide,

[00678] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N - [(5-methyl-1,3,4-oxadiazol-2-yl)methyl]acetamide, 271

[00679] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N -{[3-(propan-2-yl)-1,2-oxazol-5-yl]methyl}acetamide,

[00680] 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N - [(4-sulfamoylphenyl)methyl]acetamide,

[00681] 3-{5-[(5-chloropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}-6-(ethoxymethyl)-5-(2-hydroxy-6-methoxyphenyl )pyridine-2,4-diol,

[00682] 3-{5-[(5-chloropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}-6-(ethoxymethyl)-5-(2-hydroxy-6-methoxyphenyl )pyridine-2,4-diol and

[00683] 3-{5-[(5-chloropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dihydroxyphenyl)-6-(ethoxymethyl )pyridine-2,4-diol, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.

II. OTHER EMBODIMENTS OF THE INVENTION

[00684] In another embodiment, the present invention provides a composition comprising at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.

[00685] In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.

[00686] In another embodiment, the present invention provides a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate of the same.

[00687] In another embodiment, the present invention provides a process for preparing a compound of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.

[00688] In another embodiment, the present invention provides an intermediate for preparing a compound of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.

[00689] The present invention provides a pharmaceutical composition also comprising additional therapeutic agent(s). In a preferred embodiment, the present invention provides pharmaceutical composition in which the additional therapeutic agent is, for example, angiotensin-converting enzyme (ACE) inhibitor, e-adrenergic receptor blocker, angiotensin II receptor blocker, diuretic, antagonist of aldosterone and digital compounds.

[00690] In another embodiment, the present invention provides a method for the treatment and/or prophylaxis of multiple diseases or disorders associated with APJ or apelin activity, comprising administering to a patient in need of such treatment and/or prophylaxis an amount therapeutically effective of at least one of the compounds of the present invention, alone, or, optionally in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

[00691] Examples of diseases or disorders associated with APJ and apelin activity that can be prevented, modulated, or treated in accordance with the present invention include, but are not limited to, heart failure such as acute decompensated heart failure (ADHF), atrial fibrillation, coronary artery disease, peripheral vascular disease, atherosclerosis, diabetes, metabolic syndrome, hypertension, pulmonary hypertension, cerebrovascular disorders and their sequelae, cardiovascular disorders, angina, ischemia, stroke, myocardial infarction, acute coronary syndrome , reperfusion injury, angioplastic restenosis, vascular complications of diabetes and obesity.

[00692] In another embodiment, the present invention provides a method for the treatment and/or prophylaxis of heart failure, coronary artery disease, peripheral vascular disease, atherosclerosis, diabetes, metabolic syndrome, hypertension, pulmonary hypertension, atrial fibrillation, angina, ischemia, stroke, myocardial infarction, acute coronary syndrome, reperfusion injury, angioplastic restenosis, vascular complications of diabetes, obesity, comprising administering to a patient in need of such treatment and/or prophylaxis a therapeutically effective amount of at least one of the compounds of the present invention, alone, or, optionally in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

[00693] In another embodiment, the present invention provides a method for the treatment and/or prophylaxis of heart failure such as ADHF, comprising administering to a patient in need of such treatment and/or prophylaxis a therapeutically effective amount of at least one of compounds of the present invention, alone, or, optionally in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

[00694] In another embodiment, the present invention provides a method for the treatment and/or prophylaxis of diabetes and obesity, comprising administering to a patient in need of such treatment and/or prophylaxis a therapeutically effective amount of at least one of the compounds of present invention, alone, or, optionally in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

[00695] In another embodiment, the present invention provides a method for the treatment and/or prophylaxis of hypertension, comprising administering to a patient in need of such treatment and/or prophylaxis a therapeutically effective amount of at least one of the compounds of the present invention , alone, or, optionally in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

[00696] In another embodiment, the present invention provides a method for the treatment and/or prophylaxis of pulmonary hypertension, comprising administering to a patient in need of such treatment and/or prophylaxis a therapeutically effective amount of at least one of the compounds of the present invention, alone, or, optionally in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

[00697] In another embodiment, the present invention provides a method for the treatment and/or prophylaxis of acute coronary syndrome and cardiac ischemia, comprising administering to a patient in need of such treatment and/or prophylaxis a therapeutically effective amount of at least one of the compounds of the present invention, alone, or, optionally in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

[00698] In another embodiment, the present invention provides a compound of the present invention for use in therapy.

[00699] In another embodiment, the present invention provides a compound of the present invention for use in therapy for the treatment and/or prophylaxis of multiple diseases or disorders associated with APJ and apelin.

[00700] In another embodiment, the present invention also provides the use of a compound of the present invention for the manufacture of a medicament for the treatment and/or prophylaxis of multiple diseases or disorders associated with APJ and apelin.

[00701] In another embodiment, the present invention provides a method for the treatment and/or prophylaxis of multiple diseases or disorders associated with APJ and apelin, comprising administering to a patient in need thereof a therapeutically effective amount of a first and second agent therapeutic agent wherein the first therapeutic agent is a compound of the present invention. Preferably, the second therapeutic agent, e.g., inotropic agent selected such as ß-adrenergic agonist (e.g., dobutamine).

[00702] In another embodiment, the present invention provides a combined preparation of a compound of the present invention and additional therapeutic agent(s) for simultaneous, separate or sequential use in therapy.

[00703] In another embodiment, the present invention provides a combined preparation of a compound of the present invention and additional therapeutic agent(s) for simultaneous, separate or sequential use in the treatment and/or prophylaxis of multiple diseases or disorders associated with APJ and apelin .

[00704] Where desired, the compound of the present invention can be in combination with one or more other types of cardiovascular agents and/or one or more other types of therapeutic agents that can be administered orally in the same dosage form in a dosage form separately or by injection. The other type of cardiovascular agents that may optionally be employed in combination with the APJ agonist of the present invention may be one, two, three or more cardiovascular agents administered orally in the same dosage form in a separate oral dosage form, or by injection. to produce an additional pharmacological benefit.

[00705] The compounds of the present invention can be employed in combination with additional therapeutic agent(s) selected from one or more, preferably one to three, of the following therapeutic agents: antihypertensive agents, ACE inhibitors, mineralocorticoid receptor antagonists , angiotensin receptor blockers, calcium channel blockers, e-adrenergic receptor blockers, diuretics, vasorelaxation agents such as nitrates, antiatherosclerotic agents, antidyslipidemic agents, antidiabetic agents, antihyperglycemic agents, antihyperinsulinemic agents, antithrombotic agents , antiretinopathic agents, neuropathic agents, antineuropathic agents, antiischemic agents, calcium channel blockers, antiobesity agents, antihyperlipidemic agents, antihypertriglyceridemic agents, antihypercholesterolemic agents, antirestenotic agents, antipancreatic agents, lipid lowering agents , anorectic agents, memory enhancing agents, antidementia agents, cognition promoting agents, appetite suppressants, agents for treating heart failure, agents for treating peripheral arterial disease, agents for treating malignant tumors, anti-inflammatory agents.

[00706] In another embodiment, additional therapeutic agent(s) used in combined pharmaceutical compositions or combined methods or combined uses, are selected from one or more, preferably one to three, of the following therapeutic agents in the treatment of heart failure: ACE inhibitors , ß-blockers, diuretics, mineralocorticoid receptor antagonists, renin inhibitors, calcium channel blockers, angiotensin II receptor antagonists, nitrates, digitalis compounds, inotropic agents.

[00707] The present invention can be incorporated in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be considered in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also understood that each individual element of the modalities is its own independent modality. Furthermore, any element of an embodiment is intended to be combined with any and all other elements of any embodiment to describe a further embodiment. III. CHEMICAL

[00708] Throughout the specification and the attached claims, a given formula or chemical name must encompass all stereo and optical isomers and racemates thereof where such isomers exist. Unless otherwise indicated, all chiral forms (enantiomeric and diasteremeric) and racemic forms are within the scope of the invention. Many geometric isomers of C=C double bonds, C=N double bonds, ring systems and the like may also be present in the compounds and all such stable isomers are contemplated in the present invention. Cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as isomeric forms. The present compounds can be isolated in optically active or racemic forms. Optically active forms can be prepared by resolution of racemic forms or by synthesis of optically active starting materials. All processes used to prepare the compounds of the present invention and intermediates made in this manner are considered to be part of the present invention. When enantiomeric or diastereomeric products are prepared they can be separated by conventional methods, for example, by fractional crystallization or chromatography. Depending on the process conditions, the final products of the present invention are obtained in free (neutral) or salt form. Both the free form and the salts of these end products are within the scope of the invention. If so desired, one form of a compound can be converted into another form. A free base or acid can be converted to a salt; a salt can be converted to the free compound or another salt; a mixture of isomeric compounds of the present invention can be separated into the individual isomers. The compounds of the present invention, free form and salts thereof, can exist in multiple tautomeric forms in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that all tautomeric forms, to the extent that they may exist, are included in the invention.

[00709] As used herein, the term "alkyl" or "alkylene" is intended to include both branched and straight chain aliphatic hydrocarbon groups having the specified number of carbon atoms. For examples, "C1 to C12 alkyl" or "C1-12 alkyl" (or alkylene), is intended to include groups C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, and C12 alkyl; "C4 to C18 alkyl" or "C4-18 alkyl" (or alkylene), is intended to include groups C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17 and C18 alkyl. Additionally, for example, "C1 to C6 alkyl" or "C1-6 alkyl" means alkyl having 1 to 6 carbon atoms. Alkyl group can be unsubstituted or substituted with at least one hydrogen being replaced by another chemical group. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), and pentyl (e.g., e.g. n-pentyl, isopentyl, neopentyl). When "C0 alkyl" or "C0 alkylene" is used, it is intended to mean a direct bond.

[00710] "Alkenyl" or "alkenylene" is intended to include hydrocarbon chains of linear or branched configuration having the specified number of carbon atoms and one or more, preferably one to two, carbon-carbon double bonds that may occur in any stable point along the chain. For example, "C2 to C6 alkenyl" or "C2-6 alkenyl" (or alkenylene), is intended to include C2, C3, C4, C5 and C6 alkenyl groups. Examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4- hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl.

[00711] "Alkynyl" or "alkynylene" is intended to include hydrocarbon chains of linear or branched configuration having one or more, preferably one to three, carbon-carbon triple bonds that can occur at any stable point along the chain. For example, "C2 to C6 alkynyl" or "C2-6 alkynyl" (or alkynylene), is intended to include C2, C3, C4, C5 and C6 alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl and hexinyl.

[00712] When the term "hydrocarbon chain" is used it is intended to include "alkyl", "alkenyl" and "alkynyl", unless otherwise specified.

[00713] The term "alkoxy" or "alkyloxy" refers to an -O-alkyl group. For example, "C1 to C6 alkoxy" or "C1-6 alkoxy" (or alkyloxy), is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy ethoxy, propoxy (e.g., n-propoxy and isopropoxy) and t-butoxy. Similarly, "alkylthio" or "thioalkoxy" represents an alkyl group as defined above with the indicated number of carbon atoms linked through a sulfur bridge; for example methyl-S- and ethyl-S-.

[00714] "Halo" or "halogen" includes fluorine, chlorine, bromine and iodine. "Haloalkyl" is intended to include both straight and branched chain aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl and heptachloropropyl. Examples of haloalkyl also include "fluoroalkyl" which is intended to include both straight and branched chain aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more fluorine atoms.

[00715] "Haloalkoxy" or "haloalkyloxy" represents a haloalkyl group as defined above with the indicated number of carbon atoms linked through an oxygen bridge. For example, "C16 haloalkoxy" is intended to include C1, C2, C3, C4, C5 and C6 haloalkoxy groups. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy and pentafluorothoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" represents a haloalkyl group as defined above with the indicated number of carbon atoms linked through a sulfur bridge; for example, trifluoromethyl-S- and pentafluoroethyl-S-.

[00716] The term "cycloalkyl" refers to cyclized alkyl groups, including mono-, bi- or polycyclic ring systems. For example, "C3 to C6 cycloalkyl" or "C3-6 cycloalkyl" is intended to include C3, C4, C5 and C6 cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and norbornyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". The term "cycloalkenyl" refers to cyclized alkenyl groups. C4-6 cycloalkenyl is intended to include C4, C5, and C6 cycloalkenyl groups. Examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl and cyclohexenyl.

[00717] As used herein, "carbocycle", "carbocyclyl", or "carbocyclic residue" is intended to mean any monocyclic or bicyclic hydrocarbon ring of stable 3-, 4-, 5-, 6-, 7-, or 8 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic hydrocarbon ring or ring, any of which may be saturated, partially unsaturated, unsaturated or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl , [3,3.0]bicyclooctane, [4.3.0]bicyclononane, [4,4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl and tetrahydronaphthyl ( tetralin). As shown above, bridged rings are also included in the carbocycle definition (e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, indanyl and tetrahydronaphthyl. When the term "carbocycle" is used it is intended to include "aryl." A bridged ring occurs when one or more, preferably one to three, carbon atoms link two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is observed that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, substituents recited for the ring may also be present on the bridge.

[00718] As used herein, the term "bicyclic carbocycle" or "bicyclic carbocyclic group" is intended to mean a stable 9 to 10 member carbocyclic ring system that contains two fused rings and consists of carbon atoms. Of the two fused rings, one ring is a benzo ring fused to a second ring; and the second ring is a 5- or 6-membered carbon ring that is saturated, partially unsaturated, or unsaturated. The bicyclic carbocyclic group can be attached to its pendant group on any carbon atom that results in a stable structure. The bicyclic carbocyclic group here can be substituted on any carbon if the resulting compound is stable. Examples of a bicyclic carbocyclic group are, but are not limited to, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl and indanyl.

[00719] "Aryl" groups refer to monocyclic or bicyclic aromatic hydrocarbons, including, for example, phenyl and naphthyl. Aryl moieties are well known and described, for example in Lewis, R.J. ed., Hawley's Condensed Chemical Dictionary, 15th Edition, John Wiley & Sons, Inc., New York (2007). "C6-10 aryl" refers to phenyl and naphthyl.

[00720] The term "benzyl", as used herein, refers to a methyl group in which one of the hydrogen atoms is replaced by a phenyl group.

[00721] As used herein, the term "heterocycle", "heterocyclyl", or "heterocyclic group" is intended to mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic ring or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered polycyclic heterocyclic that is saturated, partially unsaturated, or fully unsaturated and that contains carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S; and including any polycyclic group in which any of the above-described heterocyclic rings are fused to a benzene ring. Nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N^O and S(O)p where p is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted (i.e., N or NR where R is H or another substituent, if defined). The heterocyclic ring can be attached to its pendant group on any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described here can be substituted on the carbon or nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle can optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1 then these heteroatoms will not be adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not greater than 1. When the term "heterocycle" is used it is intended to include heteroaryl.

[00722] Examples of heterocycles include, but are not limited to, acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl , cromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl , imidazolopyridinyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1 ,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl, pyrimidinyl, phenantridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl , phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyrido-oxazolyl, pyridoimidazolyl, pyridothiazolyl, pyrid inyl, pyrimidinyl, pyrrolidinyl , pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thidiazinyl, 1 ,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl , 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

[00723] Examples of 5- to 10-membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl, benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazol yl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl, quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl and pyrazolopyridinyl.

[00724] Examples of 5- to 6-membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl and triazolyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

[00725] As used herein, the term "bicyclic heterocycle" or "bicyclic heterocyclic group" is intended to mean a stable 9- to 10-membered heterocyclic ring system that contains two fused rings and consists of carbon atoms and 1, 2 , 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S. Of the two fused rings, one ring is a 5- or 6-membered monocyclic aromatic ring comprising a 5-membered heteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, each fused to a second ring. The second ring is a 6-membered monocyclic ring that is saturated, partially unsaturated, or unsaturated and comprises a 5-membered heterocycle, a 6-membered heterocycle, or a carbocycle (provided that the first ring is not benzo when the second ring is a carbocycle).

[00726] The bicyclic heterocyclic group can be linked to its pendant group on any heteroatom or carbon atom resulting in a stable structure. The bicyclic heterocyclic group described here can be substituted on the carbon or nitrogen atom if the resulting compound is stable. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1 then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not greater than 1.

[00727] Examples of a bicyclic heterocyclic group are, but are not limited to, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1, 2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro-quinoxalinyl and 1,2,3,4-tetrahydro-quinazolinyl.

[00728] As used herein, the term "aromatic heterocyclic group" or "heteroaryl" is intended to mean monocyclic and polycyclic aromatic hydrocarbons that include at least one heteroatom ring member such as sulfur, oxygen, or nitrogen. Heteroaryl groups include, without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl , 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, benzodioxolanyl and benzodioxane. Heteroaryl groups are substituted or unsubstituted. The nitrogen atom is substituted or unsubstituted (i.e., N or NR where R is H or another substituent, if defined). Nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N^O and S(O)p where p is 0, 1 or 2).

[00729] Examples of 5- to 6-membered heteroaryls include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, imidazolyl, imidazolidinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolidinyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl and triazolyl.

[00730] Bridged rings are also included in the definition of heterocycle. A bridged ring occurs when one or more, preferably one to three, atoms (i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms. Examples of bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It is observed that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, substituents related to the ring may also be present on the bridge.

[00731] The term "counterion" is used to represent a negatively charged species such as chloride, bromide, hydroxide, acetate and sulfate or a positively charged species such as sodium (Na+), potassium (K+), ammonium (RnNHm+ where n= 0-4 and m=0-4) and similar.

[00732] When a dotted ring is used within a ring structure, this indicates that the ring structure can be saturated, partially saturated or unsaturated.

[00733] As used herein, the term "amine protecting group" means any group known in the art of organic synthesis for the protection of amine groups that is stable to an ester reducing agent, a disubstituted hydrazine, R4-M and R7-M, a nucleophile, a hydrazine reducing agent, an activator, a strong base, a hindered amine base, and a cyclizing agent. Such amine protecting groups that meet these criteria include those listed in Wuts, P.G.M. et al., Protecting Groups in Organic Synthesis, 4th Edition, Wiley (2007) and The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the description of which is hereby incorporated by reference . Examples of protecting groups include, but are not limited to, the following: (1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; (2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl and 9-fluorenylmethyloxycarbonyl (Fmoc); (3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc) ethoxycarbonyl, diisopropylmethoxycarbonyl and allyloxycarbonyl; (4) types of cyclic alkyl carbamate such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; (5) alkyl types such as triphenylmethyl and benzyl; (6) trialkylsilane such as trimethylsilane; (7) thiol-containing types such as phenylthiocarbonyl and dithiasuccinoyl; and (8) alkyl types such as triphenylmethyl, methyl and benzyl; and substituted alkyl types such as 2,2,2-trichloroethyl, 2-phenylethyl and t-butyl; and types of trialkylsilane such as trimethylsilane.

[00734] As noted herein, the term "substituted" means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that normal valences are maintained and that the substitution results in a stable compound. Ring double bonds, as used here, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[00735] In cases where there are nitrogen atoms (e.g., amines) in the compounds of the present invention, these can be converted into N-oxides by treatment with an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) to provide other compounds of this invention. Thus, the nitrogen atoms shown and claimed are considered to encompass both the nitrogen shown and its N-oxide derivative (N^O).

[00736] When any variable occurs more than once in any constituent or formula for a compound, its condition in each occurrence is independent of its definition in each other occurrence. Thus, for example, if a group is shown to be replaced with 0-3 R then said group can optionally be replaced with up to three R groups and in each occurrence R is selected independently of the definition of R.

[00737] When a bond to a substituent is shown to cross a bond that connects two atoms in a ring then such a substituent can be bonded to any atom in the ring. When a substituent is listed without indicating the atom at which such substituent is attached to the remainder of the compound of a given formula then such substituent may be attached through any atom in such substituent.

[00738] Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

[00739] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and/or dosage forms that are, within the scope of safe medical judgment, suitable for use in contact with the tissues of human beings. and animals without toxicity, irritation, allergic response and/or other problem or complication, commensurate with a reasonable risk/benefit ratio.

[00740] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the described compounds in which the parent compound is modified by preparing acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfamic, phosphoric and nitric; and prepared salts of organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pammoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, ethanedisulfonic, oxalic and isethionic methanesulfonic and similar.

[00741] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free base or acid forms of these compounds with a stoichiometric amount of the appropriate acid or base in water or an organic solvent, or in a mixture of the two; Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Allen, Jr., L.V. ed., Remington: The Science and Practice of Pharmacy, 22nd Edition, Pharmaceutical Press, London, United Kingdom (2012), the description of which is hereby incorporated by reference.

[00742] Furthermore, compounds of formula I may have prodrug forms. Any compound that will be converted in vivo to provide bioactive agent (i.e., a compound of formula I) is a prodrug within the scope and spirit of the invention. Various forms of prodrugs are well known in the art. For example of such prodrug derivatives, see: a) Bundgaard, H. ed., Design of Prodrugs elsevier (1985), and Widder, K. et al. eds., Methods in Enzymology, 112:309-396, Academic Press (1985); b) Bundgaard, H., Chapter 5, "Design and Application of Prodrugs", Krosgaard-Larsen, P. et al. eds., A Textbook of Drug Design and Development, pp. 113-191, Harwood Academic Publishers (1991); c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992); d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988); e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984); and f) Rautio, J. ed., Prodrugs and Targeted Delivery (Methods and Principles in Medicinal Chemistry), Vol. 47, Wiley-VCH (2011).

[00743] Compounds containing a carboxy group can form physiologically hydrolysable esters that function as prodrugs and are hydrolyzable in the body to produce compounds of formula I per se. Such drugs are preferably administered orally since hydrolysis in many cases occurs mainly under the influence of digestive enzymes. Parenteral administration may be used where the ester itself is active, or in those cases where hydrolysis occurs in the blood. Examples of physiologically hydrolyzable esters of compounds of formula I include C1-6 alkyl, C1-6 alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, C1-6 alkanoyloxy-C1-6alkyl (for example, acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl), C1-6alkoxycarbonyloxy-C1-6alkyl (e.g., methoxycarbonyloxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl) and other physiologically hydrolyzable esters used, for example, in penicillin and cephalosporin techniques. Such esters can be prepared by conventional techniques known in the art.

[00744] Preparation of prodrugs is well known in the art and described in, for example, King, F.D. ed., Medicinal Chemistry: Principles and Practice, The Royal Society of Chemistry, Cambridge, United Kingdom (2nd Edition, reproduced (2006)); Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C.G. ed., The Practice of Medicinal Chemistry, 3rd Edition, Academic Press, San Diego, CA (2008).

[00745] The present invention is intended to include all isotopes of atoms that occur in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13C and 14C. Isotopically labeled compounds of the invention can generally be prepared by techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically labeled reagent in place of the unlabeled reagent otherwise employed.

[00746] The term "solvate" means a physical association of a compound of this invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. The solvent molecules in the solvate can be present in a regular arrangement and/or an unordered arrangement. The solvate may comprise a stoichiometric or non-stoichiometric amount of the solvent molecules. "Solvate" encompasses both solution-phase and isolatable solvates. Exemplary solvates include, but are not limited to, ethanolate hydrates, methanolates, and isopropanolates. Solvation methods are generally known in the art.

[00747] Abbreviations as used herein are defined as follows: "1 x" for once, "2 x" for twice, "3 x" for three times, "°C" for degrees Celsius, "eq" for equivalent or equivalents, "g" for gram or grams, "mg" for milligram or milligrams, "L" for liter or liters, "mL" for milliliter or milliliters, "µL" for microliter or microliters, "N" for normal, "M" for molar, "mmol" for millimole or millimoles, "min" for minute or min, "h" for hour or h, "rt" for room temperature, "RT" for retention time, "atm" for atmosphere, "psi" for pounds per square inch, "conc." for concentrate, "aq" for aqueous, "sat" or "sat'd" for saturated, "MW" for molecular weight, "mp" for melting point, "MS" or "Mass Spec" for mass spectrometry. mass, "ESI" for electrospray ionization mass spectrometry, "HR" for high resolution, "HRMS" for high resolution mass spectrometry, "LCMS" for liquid chromatography mass spectrometry, "HPLC" for liquid chromatography high pressure, "RP HPLC" for reversed phase HPLC, "TLC" or "tlc" for thin layer chromatography, "NMR" for nuclear magnetic resonance spectroscopy, "nOe" for nuclear Overhauser spectroscopy, "1H" for proton, "d" for delta, "s" for singlet, "d" for doublet, "t" for triplet, "q" for quartet, "m" for multiplet, "br" for broad, "Hz" for hertz and "a", "ß", "R", "S", "E", "Z" and "ee" are stereochemical designations familiar to those skilled in the art.

[00748] The compounds of the present invention can be prepared in various ways known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon, as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. Reactions are carried out in a solvent or solvent mixture appropriate to the reagents and materials used and suitable for the transformations being carried out. It will be understood by those skilled in the technique of organic synthesis that the functionality present in the molecule must be consistent with the proposed transformations. This sometimes requires judgment to modify the order of synthetic steps or to select a particular process scheme over another in order to obtain a desired compound of the invention.

[00749] The new compounds of this invention can be prepared using the reactions and techniques described in this section. Furthermore, in the description of the synthetic methods described below, it should be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of experiments and preparation procedures, are chosen to be the conditions pattern for the reaction, which should be easily recognized by one skilled in the art. Restrictions on substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods should therefore be used.

SYNTHESIS

[00750] The compounds of formula (I) can be prepared by the exemplary processes described in the following preparation schemes and examples, as well as published literature procedures that are used by one skilled in the art. Exemplary reagents and procedures for these reactions appear here below and in the preparation examples. Protection and deprotection in the processes below can be carried out by procedures generally known in the art (see, for example, Wuts, P.G.M. et al., Protecting Groups in Organic Synthesis, 4th Edition, Wiley (2007)). General methods of organic synthesis and functional group transformations are found in: Trost, B.M. et al. eds., Comprehensive Organic Synthesis: Selectivity, Strategy & Efficiency in Modern Organic Chemistry, Pergamon Press, New York, NY (1991); Smith, M. B. et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure. 6th Edition, Wiley & Sons, New York, NY (2007); Katritzky, A. R. et al eds., Comprehensive Organic Functional Groups Transformations II, 2nd Edition elsevier Science Inc., Tarrytown, NY (2004); Larock, R.C., Comprehensive Organic Transformations, VCH Publishers, Inc., New York, NY (1999) and references therein.

[00751] Compounds of formula (I) can be prepared as described in Scheme 1. Scheme 1

[00752] Step 1 describes the preparation of compounds of formula G1b by condensing an ester of Formula G1a with an acid R2CO-LG, where LG represents a leaving group (such as halogens and the like). Preferred solvents are ethers (such as tetrahydrofuran, dioxane and the like) and polar aprotic solvents (such as N,N-dimethylformamide). Preferred bases are metal amides (such as lithium bis(trimethylsilyl)amide and lithium diisopropylamide and the like) and metal hydrides (such as sodium hydride and the like).

[00753] Step 2 describes the preparation of compounds of formula G1c by condensation of compounds of formula G1b with ammonia. Preferred sources of ammonia are ammonia (gas) or salts thereof (such as ammonium acetate, ammonium formate and the like). Preferred solvents are alcohols (such as methanol, ethanol and the like).

[00754] Step 3 describes the preparation of pyridine compounds of formula G1d from compounds of formula G1c by condensation with malonate derivatives RbOCOCH2CO-LG, where LG represents a leaving group (such as halogens or alkoxides such as ethoxide and the like) in the presence of base. The process can be carried out in one simple step, or in stages. Preferred solvents for the first step of the two-step process are halogenated solvents (such as DCM and the like), ethers (such as tetrahydrofuran, dioxane and the like) and water. Preferred bases for the first step of the two-step process are tertiary amines (such as TEA, DIEA and the like) and alkali metal carbonates, -bicarbonates, -hydroxides (such as sodium carbonate, sodium bicarbonate, sodium hydroxide and the like). ). Preferred solvents for the second step and single step process are alcohols (such as MeOH and EtOH and the like). Preferred bases for the second step and single step process are alkali metal alkoxide (such as sodium ethoxide and the like).

[00755] Step 4 describes the preparation of compounds of formula (I) by converting the ester of compounds of formula G1d into a heterocycle ®. The conversion of compounds of formula G1d into compounds of formula (I) can be carried out in one step or in several steps, depending on the heterocycle ®. The ester of formula G1d can be condensed pure with an N'-hydroxy imidamide to provide a 1,2,4-oxadiazole in one simple step. Alternatively, in the two-step process, the ester of Formula G1d can be condensed with hydrazine in the presence of alcohol solvents (such as methanol and the like) to form a hydrazide and then the hydrazide condensed with an acid in the presence of an alcohol reagent. dehydration (such as T3P® eDC and the like) and an inert solvent (such as dioxane etOAc and the like) to provide a 1,3,4-oxadiazole. Alternatively, the hydrazide can be condensed with an imidate in alcoholic solvents (such as isopropanol and the like) in the presence of tertiary amines (such as TEA, DIEA and the like) to provide 1,3,4-triazole.

[00756] Alternatively, compounds of formula (I) can be prepared as described in Scheme 2. Scheme 2

[00757] Step 1 describes the preparation of compounds of formula G2b from a compound of formula G2a (prepared as described in W2007/197478), where LG represents a leaving group (such as halogens, preferably bromine). Preferred agents for leaving group incorporation are bromine sources (such as elemental bromine and NBS and the like). Preferred solvents are halogenated solvents (such as DCM and the like).

[00758] Step 2 describes the preparation of a compound of formula G2c from a compound of formula G2b and is analogous to Step 4 in Scheme 1.

[00759] Step 3 describes the preparation of compounds of formula (I) by coupling an organometallic reagent M-(alk)o-2-®-(R1)i-4 with a compound of formula G2c. The organometallic reagent M- (alk)o—2-®-(R1)i-4 is preferably generated by reaction of an alkylboronic acid or ester B(OR)2-(alk)o-2-®-(R1)i -4, R = H or alkyl, with a transition metal catalyst (such as Pd(PPh3)4 and Pd(OAc)2 and the like). Preferred solvents are ethers (such as tetrahydrofuran, dioxane and the like), aprotic solvents (such as toluene and the like) and water. Preferred bases are alkali metal carbonates, bicarbonates (such as sodium carbonate, sodium bicarbonate and the like).

[00760] Alternatively, compounds of formula (I) can be prepared as described in Scheme 3. Scheme 3

[00761] Step 1 describes the preparation of compounds of formula G3b by bromination of ester of Formula G3a. Preferred sources of bromine are elemental bromine and NBS and the like. Preferred solvents are ethers (such as tetrahydrofuran, dioxane and the like). Preferred bases are metal amides (such as lithium bis(trimethylsilyl)amide and lithium diisopropylamide and the like) and metal hydrides (such as sodium hydride and the like).

[00762] Step 2 describes the preparation of compounds of formula G3c from compounds of formula G3b by means of condensation with nitrile R2-CN in the presence of a transition metal. The preferred transition metal is zinc and a cocatalyst (zinc oxide, alkyl sulfonic acid and the like) can be used. Inert solvents such as ethers (such as tetrahydrofuran, dioxane and the like) and aprotic solvents (such as toluene and the like) can be used. Preferably, the reaction is carried out under pure conditions.

[00763] Step 3 describes the preparation of a compound of formula G3d from a compound of formula G2c and is analogous to Step 3 in Scheme 1.

[00764] Step 3 describes the preparation of a compound of formula (I) from a compound of formula G3d and is analogous to Step 4 in Scheme 1.

IV. BIOLOGY

[00765] The APJ receptor was discovered in 1993 as an orphan G protein-coupled receptor (GPCR) and was subsequently discovered to recognize the apelin peptide as its endogenous ligand. It belongs to class A of GPCRs and has a classical 7-transmembrane domain structure exhibiting highest sequence homology to the AT1 angiotensin receptor (for review see Pitkin, S.L. et al., Pharmacol. Rev., 62(3):331- 342 (2010)). APJ is expressed in a wide variety of peripheral and CNS tissues and has relatively high expression in the placenta, myocardium, vascular endothelial cells, smooth muscle cells as well as cardiac myocytes (Kleinz, J.M. et al., Pharmacol. Ther., 107( 2):198- 211(2005)). Apelin peptide was originally identified in bovine stomach extract and remains to date the only known endogenous ligand and AJP receptor ligand (Tatemoto, K. et al., Biochem. Biophys. Res. Commun., 255:471-476 (1998)). Apelin gene tissue expression closely reflects the expression pattern of APJ and has been postulated to act in an autocrine or paracrine manner, often exemplified by reference to the "apelin-APJ system". The apelin gene encodes the 77 amino acid precursor peptide that is cleaved to form mature secreted peptide and undergoes further cleavage forming shorter C-terminal fragments. Apelin-36, -17 and -13 represent the main active forms with the pyroglutamated form of apelin-13 being the most stable form and the most abundant form present in cardiac tissue (Maguire, J.J. et al., Hypertension, 54(3) :598-604 (2009)). Apelin has a very short half-life in circulation estimated to be less than 5 minutes (Japp, A.G. et al., Circulation, 121(16):1818-1827 (2010)).

[00766] APJ receptor activation is known to inhibit forskolin-stimulated cyclic AMP (cAMP) levels in a pertussis toxin-sensitive manner, indicating coupling to Gi proteins. Apelin binding affinity and EC50 values in the cAMP assay are reported to be in the sub-nanomolar range (for review see Pitkin, S.L. et al., Pharmacol. Rev., 62(3):331-342(2010)). . In addition to cAMP inhibition, APJ receptor activation also induces ß-arrestin recruitment, receptor internalization, and activation of extracellular regulated kinases (ERKs) (for review see Kleinz, J.M. et al., Pharmacol. Ther.,107 (2):198-211 (2005)). Which of these signaling mechanisms contribute to the modulation of physiological effects downstream of apelin is currently unclear. The APJ receptor has been shown to interact with the AT1 receptor. Although apelin does not bind AT1 and angiotensin II does not bind APJ, it has been postulated that certain physiological actions of apelin are mediated, at least in part, through functional antagonism of the angiotensin II and AT1 receptor reaction series (Chun, A.J. et al., J. Clin. Invest., 118(10):3343-3354 (2008)).

[00767] It is also desirable and preferable to discover compounds with advantageous and improved characteristics compared to known HF treatment agents in one or more of the following categories which are provided as examples and are not intended to be limiting: (a) pharmacokinetic properties, including oral bioavailability, half-life and clearance; (b) pharmaceutical properties; (c) dosage requirements; (d) factors that decrease peak-to-trough characteristics of blood drug concentration; (e) factors that increase the concentration of active drug in the receptor; (f) factors that reduce the risk of clinical drug-drug interactions; (g) factors that decrease the potential for adverse side effects, including selectivity versus other biological targets; and (h) improved therapeutic index.

[00768] As used herein, the term "patient" encompasses all mammalian species.

[00769] As used herein, the term "subject" refers to any human or non-human organism that would potentially benefit from treatment with an APJ agonist. Exemplary individuals include humans of any age with risk factors for the development of heart failure and its sequelae, angina, ischemia, cardiac ischemia, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia, stroke, as well as atherosclerosis, coronary artery disease, acute coronary syndrome and/or dyslipidemias.

[00770] As used herein, "treat" or "treatment" encompasses the treatment of a disease state in a mammal, particularly a human, and includes: (a) inhibiting the disease state, that is, stopping development; and/or (b) alleviating the disease state, i.e., causing regression of the disease state.

[00771] As used herein, "prophylaxis" or "prevention" encompasses the preventative treatment of a subclinical disease state in a mammal, particularly in a human, aimed at reducing the likelihood of the occurrence of a clinical disease state. Patients are selected for preventive therapy based on factors that are known to increase the risk of suffering from clinical disease states compared to the general population. "Prophylaxis" therapies can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treatment in an individual who has not yet experienced a clinical disease state while secondary prevention is defined as prevention of a second occurrence of the same or similar clinical disease state.

[00772] As used herein, "risk reduction" encompasses therapies that decrease the incidence of developing a clinical disease state. As such, primary and secondary prevention therapies are examples of risk reduction.

[00773] "Therapeutically effective amount" is intended to include an amount of a compound of the present invention that is effective when administered alone or in combination to modulate APJ and/or prevent or treat the disorders listed herein. When applied to a combination, the term refers to the combined amounts of active ingredients that result in preventative or therapeutic effect, whether administered in combination, serially, or simultaneously.

A. TEST METHODS Intracellular cAMP Accumulation Assay

[00774] HEK293 cells stably expressing human APJ receptor were used to evaluate the activity of compounds. Cultured cells were separated and resuspended in Homogeneous cAMP Time-Resolved Fluorescence (HTRF) assay buffer (Cisbio cat; #62AM4PEJ). The assay was performed in 384-well assay plates (Perkin-Elmer; cat #6008289) according to the assay protocol provided by the manufacturer. Serial dilutions of a compound together with assay buffer containing 0.2nM IBMX and 2 µM forskolin were added to each well containing 5,000 cells and incubated for 30 minutes at room temperature. Subsequently, cAMP D2 reagent was added into the lysis buffer followed by EuK antibody (Cisbio; cat #62AM4PEJ) and incubated for 60 min. The fluorescence emission ratio was measured using fluorometer. Intracellular cAMP concentrations (compound-stimulated inhibition of forskolin-mediated cAMP production) were calculated by extrapolation of a standard curve using known cAMP concentrations. EC50 values were obtained by fitting the data to a sigmoidal concentration response curve with variable decline. The maximum obtainable inhibition of forskolin-induced cAMP levels (Ymax) for each compound was expressed as relative percentage of inhibition achieved using pyroglutamated apelin-13 peptide ((Pir1)apelin-13), which was set at 100%.

[00775] The examples described below were tested in the in vitro APJ assays described above and were found to have human APJ cyclic AMP (hcAMP) activity. The EC50 value of each compound is presented at the end of the example description.

[00776] The compounds of the present invention have activity as APJ receptor agonists and, therefore, can be used in the treatment of diseases associated with APJ activity. Accordingly, the compounds of the present invention can be administered to mammals, preferably humans, for the treatment of a variety of conditions and disorders, including, but not limited to, treating, preventing, or slowing the progression of heart failure, coronary artery disease, peripheral vascular disease, atherosclerosis, diabetes, metabolic syndrome and its sequelae, hypertension, pulmonary hypertension, cerebrovascular disorders, atrial fibrillation, angina, ischemia, stroke, myocardial infarction, acute coronary syndrome, reperfusion injury, angioplastic restenosis, vascular complications of diabetes and obesity.

[00777] The biological activity of the exemplified compounds of this invention determined by the assay described above is shown at the end of each example. APJ cAMP EC50 potency ranges are as follows: A = 0.01 - 10 nM; B = 10.01 - 100 nM; C = 100.01 - 300 nM.

V. PHARMACEUTICAL COMPOSITIONS, FORMULATIONS AND COMBINATIONS

[00778] The compounds of this invention may be administered for any of the uses described herein by any suitable methods, for example, orally, such as tablets, capsules (each of which include extended-release or time-release formulations), pills, powders, elixir granules, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups and emulsions; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (e.g., as sterile injectable aqueous or nonaqueous solutions or suspensions); nasally, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories. They may be administered alone, but will generally be administered with a pharmaceutical vehicle selected based on the chosen administration routine and standard pharmaceutical practice.

[00779] The term "pharmaceutical composition" means a composition comprising a compound of the invention in combination with at least one additional pharmaceutically acceptable carrier. A "pharmaceutically acceptable carrier" refers to means generally accepted in the art for delivering biologically active agents to animals, in particular mammals, including, i.e., adjuvant, excipient or carrier, such as diluents, preservatives, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispersing agents, depending on the nature of the mode of administration and forms dosage.

[00780] Pharmaceutically acceptable carriers are formulated according to several factors well within the competence of those skilled in the art. These include, without limitation: the type and nature of the active agent being formed; the individual to whom the agent-containing composition is to be administered; the intended routine of administration of the composition; and the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of semisolid dosage forms. Such carriers may include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, for example stabilization of the active agent, binders, well known to those skilled in the art. Descriptions of pharmaceutically acceptable carriers and factors involved in their selection are found in a variety of readily available sources such as, for example, Allen, Jr., L.V. et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press (2012).

[00781] The dosage regimen for the compounds of the present invention will certainly vary depending on known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and routine of administration; the species, age, sex, health, medical condition and weight of the recipient; the nature and extent of symptoms; the type of competing treatment; the frequency of treatment; the administration routine, the patient's kidney and liver function and the desired effect.

[00782] By way of general guidance, the daily oral dosage of each active ingredient, when used for its indicated effects, will range from about 0.001 to about 5000 mg per day, preferably from about 0.01 to about 1000 mg per day and more preferably between about 0.1 to about 250 mg per day. Intravenously, the most preferred doses will range from about 0.01 to about 10 mg/kg/minute during constant rate infusion. The compounds of this invention can be administered in a single daily dosage, or the total daily dosage can be administered in divided doses two, three, or four times daily.

[00783] The compounds are typically administered in admixture with diluents, excipients, or suitable pharmaceutical carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, for example, oral tablets, capsules, elixirs and syrups and consistent with practical conventional pharmaceuticals.

[00784] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 2000 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of about 0.195% by weight based on the total weight of the composition.

[00785] A typical capsule for oral administration contains at least one of the compounds of the present invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packaged in a No. 1 gelatin capsule.

[00786] A typical injectable preparation is produced by aseptically placing at least one of the compounds of the present invention (250 mg) in a vial, aseptically freezing drying and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline, to produce the injectable preparation.

[00787] The present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, a therapeutically effective amount of at least one of the compounds of the present invention, alone or in combination with a pharmaceutical carrier. Optionally, the compounds of the present invention may be used alone in combination with other compounds of the invention, or in combination with one or more other therapeutic agents, for example, agents used in the treatment of heart failure or other pharmaceutically acceptable material.

[00788] The compounds of the present invention can be employed in combination with other APJ agonists or one or more other suitable therapeutic agents useful in the treatment of the aforementioned disorders including: agents for treating heart failure, antihypertensive agents, antiatherosclerotic agents, antidyslipidemic agents, antidiabetic agents, antihyperglycemic agents, antihyperinsulinemic agents, antithrombotic agents, antiretinopathic agents, neuropathic agents, antineuropathic agents, antiischemic agents, antiobesity agents, antihyperlipidemic agents, antihypertriglyceridemic agents, antihypercholesterolemic agents , antirestenotic agents, antipancreatic agents, lipid-lowering agents, anorectic agents, memory-enhancing agents, anti-dementia agents, cognition-promoting agents, appetite suppressants, and agents for treating peripheral arterial disease.

[00789] The compounds of the present invention may be employed in combination with additional therapeutic agent(s) selected from one or more, preferably one to three, of the following therapeutic agents in the treatment of heart failure and coronary artery disease: ACE inhibitors, ß-blockers, diuretics, mineralocorticoid receptor antagonists, renin inhibitors, calcium channel blockers, angiotensin II receptor antagonists, nitrates, digital compounds, inotropic agents and ß-agonists receptor, antihyperlipidemic agents, plasma HDL increasing agents, antihypercholesterolemic agents, chlorsterol biosynthesis inhibitors (such as HMG CoA reductase inhibitors), LXR agonist, probucol, raloxifene, nicotinic acid, niacinamide, inhibitors cholesterol absorption agents, bile acid sequestrants (such as anion exchange resins, or quaternary animals (e.g., cholestyramine or colestipol), low-density lipoprotein receptor inducers, clofibrate, fenofibrate, benzofibrate, cipofibrate, gemfibrizole, vitamin B6, vitamin B12, antioxidant vitamins, antidiabetes agents, platelet aggregation inhibitors, fibronogen receptor antagonists, aspirin and fibric acid derivatives.

[00790] The compounds of the invention can be used in combination with one or more, preferably one to three, of the following antidiabetic agents depending on the desired target therapy. Studies indicate that the modulation of diabetes and hyperlipidemia can also be improved by adding a second agent to the therapeutic regimen. Examples of antidiabetic agents include, but are not limited to, sulfonylureas (such as chlorpropamide, tolbutamide, acetohexamide, tolazamide, glyburide, gliclazide, glinase, glimepiride and glipizide), biguanides (such as metformin), thiazolidinediones (such as ciglitazone, pioglitazone , troglitazone and rosiglitazone) and related insulin sensitizers, such as selective and non-selective activators of PPARa, PPARß and PPARγ; desdroepiandrosterone (also referred to as DHEA or its conjugated sulfate ester, DHEA-SO4); antiglucocorticoids; TNFa inhibitors; dipeptidyl peptidase IV (DPP4) inhibitor (such as sitagliptin, saxagliptin), GLP-1 agonists or analogues (such as exenatide), α-glucosidase inhibitors (such as acarbose, miglitol and voglibose), pramlintide (a synthetic analogue of human hormone amylin), other insulin secretagogues (such as repaglinide, gliquidone and nateglinide), insulin, as well as the therapeutic agents described above for the treatment of heart failure and atherosclerosis.

[00791] The compounds of the invention can be used in combination with one or more, preferably one to three, of the following anti-obesity agents selected from phenylpropanolamine, phentermine, diethylpropion, mazindol, fenfluramine, dexfenfluramine, phentyramine, e3-adrenergic receptor agonist agents ; sibutramine, gastrointestinal lipase inhibitors (such as orlistat) and leptins. Other agents used in the treatment of obesity or obesity-related disorders include neuropeptide Y enterostatin, cholecytokinin, bombesin, amylin, histamine H3 receptors, dopamine D2 receptor modulators, melanocyte-stimulating hormone, corticotropin-releasing factor, galanin, and acid gamma amino butyric acid (GABA).

[00792] The other therapeutic agents above, when employed in combination with the compounds of the present invention may be used, for example, in those amounts indicated in the Physicians' Desk Reference, as in the patents mentioned above, or as otherwise determined by one skilled in the art. in technique.

[00793] Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when the compound of the present invention and a second therapeutic agent are combined in a single dosage unit they are formulated so that although the active ingredients are combined in a single dosage unit, physical contact between the active ingredients is minimized (i.e. reduced). For example, an active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize contact between the combined active ingredients, but also to control the release of these components in the gastrointestinal tract so that one of these components is not released into the stomach, but is instead released in the intestines. One of the active ingredients may also be coated with a material that affects sustained release through the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the extended release component can be additionally enteric coated, so that the release of this component occurs only in the intestine. Yet another method would involve formulating a combination product in which one component is coated with a sustained-release and/or enteric polymer and the other component is also coated with a polymer such as low viscosity grade hydroxypropyl methylcellulose (HPMC). or other appropriate materials as known in the art, in order to also separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.

[00794] These, as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms, but at the same time in the same manner, will be readily apparent to those skilled in the art once armed with the present invention.

[00795] The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. By "administered in combination" or "combination therapy" is meant that the compound of the present invention and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination, each component may be administered at the same time or sequentially in any order at different points in time. In this way, each component will be administered separately, but sufficiently close in time, in order to provide the desired therapeutic effect.

[00796] The compounds of the present invention are also useful as standard or reference compounds, for example, as a control or quality standard in tests or assays involving the APJ receptor and apelin activity. Such compounds can be provided in a commercial kit, for example, for use in pharmaceutical research involving APJ and apelin or anti-heart failure activity. For example, a compound of the present invention would be used as a reference in an assay to compare its known activity to a compound with unknown activity. This would assure the experimenter that the assay was being properly performed and would provide a basis for comparison especially if the test compound was a derivative of the reference compound. When developing new assays or protocols, compounds according to the present invention would be used to test their effectiveness.

[00797] The compounds of the present invention can also be used in diagnostic assays involving APJ and apelin.

[00798] The present invention also encompasses an article of manufacture. As used herein, article of manufacture is intended to include, but not limited to, kits and packaging. The article of manufacture of the present invention comprises: (a) a first container; (b) a pharmaceutical composition located within the first container wherein the composition comprises a first therapeutic agent, comprising a compound of the present invention or a pharmaceutically acceptable salt form thereof; and, (c) a packaging insert indicating that the pharmaceutical composition can be used for the treatment and/or prophylaxis of multiple diseases or disorders associated with APJ and apelin (as previously defined). In another embodiment, the package insert states that the pharmaceutical composition can be used in combination (as previously defined) with a second therapeutic agent for the treatment and/or prophylaxis of multiple diseases or disorders associated with APJ and apelin. The article of manufacture may also comprise: (d) a second container wherein components (a) and (b) are located within the second container and component (c) is located inside or outside the second container. Located within the first and second containers means that the respective container keeps the item within its boundaries.

[00799] The first container is a receptacle used to hold a pharmaceutical composition. This container can be used for manufacturing, storage, shipping and/or individual/bulk sales. The first container is intended to line a bottle, jar, jar, vial, syringe, tube (e.g., for a crème preparation), or any other container used to manufacture, maintain, store, or distribute a pharmaceutical product.

[00800] The second container is the one used to hold the first container and, optionally, the packaging insert. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cardboard boxes, bags (e.g., paper or plastic bags), bags, and sacks. The package insert may be attached to the outside of the first container by means of tape, glue, staple, or other attachment method, or it may remain inside the second container without any physical methods of attachment to the first container. Alternatively, the packaging insert is located on the outside of the second container. When located on the outside of the second container, it is preferred that the packaging insert be physically attached by means of tape, glue, staple or other attachment method. Alternatively it may be adjacent to or touching the outside of the second container without being physically attached.

[00801] The packaging insert is a label, label, marker, etc. which recites information related to the pharmaceutical composition located within the first container. The information recited will generally be determined by the regulatory agency that regulates the area in which the article of manufacture is to be sold (for example, the United States Food and Drug Administration). Preferably, the package insert specifically recites the indications for which the pharmaceutical composition has been approved. The packaging insert may be made of any material on which a person can read the information contained in or on it. Preferably, the packaging insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper or plastic, etc.) on which the desired information has been formed (e.g., printed or applied).

[00802] Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are provided for illustration of the invention and are not intended to be limiting thereof.

SAW. EXAMPLES

[00803] The following Examples are offered as illustrative, as a partial scope and particular embodiments of the invention and are not intended to limit the scope of the invention. Chemical abbreviations and symbols have their usual and customary meanings unless otherwise noted. Unless otherwise indicated, the compounds described herein have been prepared, isolated and characterized using the schemes and other methods described herein or can be prepared using the same.

[00804] Since a person skilled in the art would be able to understand that pyridone in a molecule can tautomerize into its keto and enol forms, as shown in the following equation in which R1, R2, R3 and R4 are as defined above this The invention is intended to cover all possible tautomers, even when the structure describes only one of them.

Description of Analytical LCMS Methods:

[00805] Method A: Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 ACN:water with 10 mM NH4OAc; Mobile Phase B: 95:5 ACN:water with 10 mM NH4OAc; Temperature: 50°C; Gradient: 0-100% B for 3 minutes then a 0.75 minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.

[00806] Method B: Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 ACN:water with 0.1% TFA; Mobile Phase B: 95:5 ACN:water with 0.1% TFA; Temperature: 50°C; Gradient: 0-100% B for 3 minutes then a 0.75 minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.

[00807] Method C: Column: FENOMENEX® Luna 3 µm C18 (2.0 x 30 mm); Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA; Gradient: 0-100% B for 2 minutes then a 1 minute hold at 100% B; Flow: 1 mL/min; Detection: UV at 220 nm.

[00808] Method D: Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7 µm particle; Mobile Phase A: water with 0.1% TFA; Mobile Phase B: ACN with 0.1% TFA; Gradient: 2-98% B for 1 minute then retention of 0.5 to 98% B; Flow: 0.8 mL/min; Detection: UV at 220 nm.

[00809] Method E: Column: Fenomenex Luna 3u C18(2) 2.0 x 30 mm; Mobile Phase A: 10:90 MeOH:water with 10 mM NH4OAc; Mobile Phase B: 90:10 MeOH:water with 10 mM NH4OAc; Gradient: 0100% B for 2 minutes then a 1 minute hold at 100% B; Temperature: 40°C; Flow: 1.00 mL/min; Detection: UV at 220 nm. Example 1. 3-(5-benzyl-1,3,4-oxadiazol-2-yl)-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol Compound 1a. Ethyl 2-(2,6-dimethoxyphenyl)acetate

[00810] To a solution of 1,3-dimethoxybenzene (3.3 mL, 25 mmol) in THF (40 mL) was added dropwise 2.5M nBuLi in hexanes (10 mL, 25 mmol) over a period of 10 minutes then the mixture is stirred for 2 hours. Crushed copper(I) iodide (2.38 g, 12.5 mmol) was added slowly then the mixture was stirred for 1 hour, becoming homogeneous. The mixture was cooled to -78°C then ethyl bromoacetate (2.8 mL, 25 mmol) was added dropwise over 20 min. The cold bath was removed and the mixture allowed to warm to room temperature. The mixture was quenched by adding water then Et2O added and the mixture filtered through celite. The filtrate was diluted with 1.5N K2HPO4 and extracted with Et2O (2x). The extracts were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0 to 15% EtOAc/hexanes to provide compound 1a (4.8 g, 86% yield) as a light brown oil that solidified upon standing. MS m/z = 225.1 (M+H), 1H NMR (500MHz, CDCl3) d 7.23 (t, J=8.4 Hz, 1H), 6.58 (d, J=8.3 Hz , 2H), 4.17 (q, J=7.2 Hz, 2H), 3.83 (s, 6H), 3.71 (s, 2H), 1.27 (t, J=7.2 Hz , 3H). Compound 1b. Ethyl 2-(2,6-dimethoxyphenyl)-3-hydroxyhept-2-enoate

[00811] To a solution of compound 1a (1.50 g, 6.70 mmol) in THF (14 mL) at -78 °C was added dropwise 1.0M LiHMDS in THF (16.7 mL, 16 .7 mmol) and the mixture was stirred for 10 min then at room temperature for 1 hour. The mixture was cooled to -78°C then valeryl chloride (1.34 mL, 11.0 mmol) was added dropwise and the mixture allowed to warm to 0°C and stirred for 15 min. The mixture was quenched with saturated NH4Cl and extracted with EtOAc (3x). The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0 to 30% EtOAc/hexanes to provide an isomeric mixture of Compound 1b (1.81 g, 88% yield) as a clear colorless oil. MS m/z = 309.1 (M+H). 1H NMR of larger isomer (400MHz, CDCl3) d 13.22 (s, 1H), 7.26 - 7.22 (m, 1H), 6.56 (d, J=8.6 Hz, 2H), 4 .14 (q, J=7.0 Hz, 2H), 3.75 (s, 5H), 2.05 - 1.96 (m, 2H), 1.51 - 1.42 (m, 2H), 1.22 - 1.17 (m, 2H), 1.14 (t, J=7.2 Hz, 3H), 0.77 (t, J=7.3 Hz, 3H). Compound 1c. Ethyl 3-amino-2-(2,6-dimethoxyphenyl)hept-2-enoate

[00812] To the isomeric mixture of Compound 1b (1.8 g, 5.9 mmol) and ammonium formate (1.9 g, 29 mmol) in absolute ethanol (35 mL) molecular sieves were added, then the mixture was heated in reflux for 10h. The mixture was allowed to warm to room temperature then filtered and concentrated under reduced pressure. The residue was dissolved in water and extracted with EtOAc (3x). The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0 to 35% EtOAc/hexanes to provide compound 1c (1.2 g, 68% yield) as a clear colorless oil. MS m/z = 308.1 (M+H). 1H NMR (400MHz, CDCl3) d 7.21 (t, J=8.4 Hz, 1H), 6.55 (d, J=8.4 Hz, 2H), 4.05 (q, J=7, 0 Hz, 2H), 3.75 (s, 6H), 1.98 - 1.88 (m, 2H), 1.43 - 1.31 (m, 2H), 1.18 (dt, J=15 0, 7.5 Hz, 2H), 1.09 (t, J=7.0 Hz, 3H), 0.73 (t, J=7.4 Hz, 3H). Compound 1d. Ethyl 6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxynicotinate

[00813] To a solution of compound 1c (1.23 g, 4.00 mmol) in a mixture of DCM (20 mL) and 1N NaHCO3 (24 mL, 24 mmol) was added dropwise a solution of sodium chloride ethyl malonyl (1.54 mL, 12.0 mmol) in DCM (5 mL) and the mixture stirred vigorously for 10 min. The mixture was diluted with DCM, the layers separated and the aqueous layer extracted with DCM (2x). The combined extracts were washed with saturated NH4Cl and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was dissolved in absolute EtOH (20 mL) then 2.5M sodium ethoxide in ethanol (6.4 mL, 16 mmol) added and the mixture stirred for 24 hours, generating a precipitate. The mixture was evaporated to dryness then diluted with saturated NH4Cl and extracted with DCM (3x). The combined extracts were washed with brine, dried (Na2SO4), decanted and concentrated under reduced pressure in celite. The residue was purified by silica gel chromatography eluting with 5 to 75% EtOAc/DCM to provide compound 1d (0.52 g, 35% yield) as a white solid. MS m/z = 376.1 (M+H). 1H NMR (400MHz, DMSO-d6) d 7.33 (t, J=8.4 Hz, 1H), 6.70 (d, J=8.4 Hz, 2H), 4.30 (q, J= 6.8 Hz, 2H), 3.68 (s, 6H), 2.09 (t, J=7.2 Hz, 2H), 1.37 - 1.23 (m, 5H), 1.12 - 0.99 (m, 2H), 0.65 (t, J=7.4 Hz, 3H).

Compound 1e. 6-Butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxynicotinehydrazide

[00814] To a suspension of Compound 1d (50 mg, 0.13 mmol) in ethanol (0.75 mL) was added hydrazine (0.084 mL, 2.6 mmol) and the mixture stirred for 0.5h. The mixture was concentrated under reduced pressure to provide compound 1e (47 mg, 98% yield) as a white solid. MS m/z = 362.1 (M+H). 1H NMR (400MHz, DMSO-d6) d 15.52 (s, 1H), 11.78 (br, s., 1H), 10.89 (t, J=4.4 Hz, 1H), 7.34 (t, J=8.4 Hz, 1H), 6.71 (d, J=8.4 Hz, 2H), 4.72 (d, J=4.8 Hz, 2H), 3.68 (s , 6H), 2.18 - 2.09 (m, 2H), 1.32 (quin, J=7.5 Hz, 2H), 1.14 - 1.02 (m, 2H), 0.66 ( t, J=7.4 Hz, 3H).

Example 1. 3-(5-benzyl-1,3,4-oxadiazol-2-yl)-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol

[00815] To a solution of compound 1e (15 mg, 0.042 mmol) in dioxane (0.4 mL) was added phenylacetic acid (6.2 mg, 0.046 mmol) followed by a 50% solution of T3P® in acetate ethyl (0.075 mL, 0.13 mmol) and the mixture heated by microwave irradiation at 160 °C for 1 hour. The mixture was concentrated under reduced pressure then purified by preparative HPLC to provide Example 1 (14 mg, 72% yield). LCMS (Method A) Tr = 1.83 min, m/z = 462.1 (M+H). 1H NMR (500MHz, DMSO-d6) d 7.42 - 7.23 (m, 6H), 6.73 (d, J=8.2 Hz, 2H), 4.36 (s, 2H), 3.68 (s, 6H), 2.15 (t, J=7.3 Hz, 2H), 1.39 - 1.27 (m, 2H), 1.14 - 1.02 (m, 2H), 0.70 - 0 .60 (m, 3H). Human APJ cAMP EC50 potency range B.

[00816] Example 2 to Example 136 were prepared as described in the general procedure provided by example 1. Example 137. 6-Butyl-5-(3-ethylphenyl)-4-hydroxy-3-{5-[(2-methyl -1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}-1,2-dihydropyridin-2-one Compound 137b. Ethyl 5-bromo-6-butyl-2,4-dihydroxynicotinate

[00817] Bromine (0.55 mL, 11 mmol) was added to Compound 137a (1.7 g, 7.1 mmol; prepared as described in W2007/197478) in DCM (40 mL). After 15 minutes, the reaction mixture was concentrated and purified by silica gel chromatography eluting with 0 to 5% methanol/DCM to provide compound 137b (2.2 g, 99% yield) as a white solid. LCMS (Method D) Tr = 0.90 min, m/z = 320.0 [M+H]+. 1H NMR (500MHz, CDCl3) d 14.28 (s, 1H), 12.09 - 11.75 (m, 1H), 4.45 (q, J=7.0 Hz, 2H), 2.95 - 2.71 (m, 2H), 1.80 - 1.64 (m, 2H), 1.52 - 1.37 (m, 5H), 0.98 (t, J=7.4 Hz, 3H) . Compound 137c. 5-Bromo-6-butyl-2,4-dihydroxynicotinehydrazide

[00818] Hydrazine (0.77 mL, 25 mmol) was added to Compound 137b (750 mg, 2.47 mmol) in MeOH (20 mL). After 16 hours, the reaction mixture was concentrated under reduced pressure, suspended in Methanol (10 mL) and the solid collected via Buchner filtration to provide compound 137c (690 mg, 92% production) as a white solid. LCMS (Method D) Tr = 0.74 min, m/z = 305.9 [M+H]+. 1H NMR (500MHz, DMSO-d6) d 3.30 (s, 2H), 2.58 (br. s., 2H), 1.53 (d, J=7.,4 Hz, 2H), 1, 39 - 1.26 (m, 2H), 0.89 (t, J=7.4 Hz, 3H). Compound 137d. 5-Bromo-6-butyl-3-(5-((2-methylthiazol-4-yl)methyl)-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol

[00819] Compound 137d (190 mg, 45% production) was prepared from compound 137c as described by example 1. LCMS (Method D) Tr = 0.87, m/z = 426.9 [M+H ]+. 1H NMR (500MHz, DMSO-d6) d 12.09 - 11.87 (m, 1H), 7.43 (s, 1H), 4.43 (s, 2H), 2.72 - 2.64 (m , 2H), 2.62 (s, 3H), 1.62 - 1.51 (m, 2H), 1.40 - 1.30 (m, 2H), 0.91 (t, J=7.3 Hz, 3H).

Example 137. 6-Butyl-5-(3-ethylphenyl)-4-hydroxy-3-{5-[(2-methyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazole -2-yl}-1,2-dihydropyridin-2-one

[00820] Compound 137d (15 mg, 0.035 mmol), (3-ethylphenyl)boronic acid (7.9 mg, 0.053 mmol) and Pd(PPh3)4 (12.2 mg, 10.6 µmol) in dioxane (1 mL) / 2M Na2CO3 (0.5 mL) were purged with argon and then heated to 100°C. After 2 hours, the reaction mixture was filtered, concentrated, dissolved in DMF/methanol and purified by preparative HPLC to provide Example 137 (3.2 mg, 20% yield). LCMS (Method A) Tr = 1.88 min, m/z = 451.0. 1H NMR (500MHz, DMSO-d6) d 7.42 (s, 1H), 7.38 - 7.28 (m, 1H), 7.21 (d, J=7.3 Hz, 1H), 7, 14 - 6.99 (m, 2H), 4.43 (s., 2H), 2.72 - 2.58 (m, 5H), 2.28 (br, s., 2H), 1.50 - 1 .34 (m, 2H), 1.26 - 1.14 (m, 3H), 1.15 - 1.01 (m, 2H), 0.67 (t, J=7.3 Hz, 3H). Human AJP cAMP EC50 potency range B.

[00821] Example 138 to Example 153 were prepared as described in the general procedure provided by example 137. Example 154 and Example 155. 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(methylamino) methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol and N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-di- hydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)- N-methyl-2-phenylacetamide Example 154. 6-Butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(methylamino)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol

[00822] To a solution of Example 121 (450 mg, 0.88 mmol) in DCM (3 mL) was added TFA (3 mL) and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure to provide Example 154 (330 mg, 88% production). LCMS (Method C) Tr = 1.59 min, m/z = 415.1 (M+H), 1H NMR (500MHz, DMSO-d6) d 7.37 (t, J=8.4 Hz, 1H) , 6.75 (d, J=8.5 Hz, 2H), 4.06 (s, 2H), 3.71 (s, 6H), 2.45 - 2.36 (m, 3H), 2, 17 (t, J=7.4 Hz, 2H), 1.39 - 1.28 (m, 2H), 1.16 - 1.04 (m, 2H), 0.68 (t, J=7, 2Hz, 3H). Human AJP cAMP EC50 potency range B.

Example 155. N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )-N-methyl-2-phenylacetamide

[00823] To a solution of Example 154 (12 mg, 0.029 mmol) and 2-phenylacetic acid (4.7 mg, 0.035 mmol) in DMF (0.5 mL) was added BOP reagent (15 mg, 0.035 mmol) followed by triethylamine (0.020 mL, 0.15 mmol) and the mixture stirred for 1 hour. The reaction mixture was concentrated under reduced pressure then purified by preparative HPLC to provide Example 155 (13 mg, 83% yield). LCMS (Method C) Tr = 2.07 min, m/z = 533.2 (M+H). 1H NMR (500MHz, DMSO-d6) d 7.43 - 7.16 (m, 6H), 6.80 - 6.68 (m, 2H), 4.88 (s, 2H), 3.82 (s , 2H), 3.70 (s, 6H), 2.52 (br. s., 3H), 2.20 - 2.11 (m, 2H), 1.41 - 1.28 (m, 2H) , 1.18 - 1.02 (m, 2H), 0.67 (t, J=7.3 Hz, 3H). Human AJP cAMP EC50 potency range A.

[00824] Example 156 to Example 176 were prepared as described in the general procedure provided by example 155. Example 177. 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-di- hydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N,N-diethylacetamide Example 177. 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N ,N-diethylacetamide

[00825] To a solution of Example 118 (122 mg, 0.250 mmol) in DCM (2 mL) was added TFA (2 mL) and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to provide the intermediate acid (120 mg, 90% production). To the intermediate acid portion (10 mg, 0.023 mmol) in DMF (0.5 mL) was added diethylamine (0.003 mL, 0.05 mmol) followed by BOP reagent (12 mg, 0.028 mmol) and triethylamine (0.016 mL, 0.12 mmol) and the mixture stirred for 1 hour. The mixture was concentrated under reduced pressure then purified by preparative HPLC to provide Example 177 (4.0 mg, 34% yield). LCMS (Method C) Tr = 1.90 min, m/z = 485.1 (M+H), 1H NMR (500MHz, DMSO-d6) d 7.37 (t, J=8.3 Hz, 1H) , 6.74 (d, J=8.5 Hz, 2H), 4.27 (s, 2H), 3.70 (s, 6H), 2.56 (s, 6H), 2.17 (t, J=7.7 Hz, 2H), 1.34 (t, J=7.8 Hz, 2H), 1.20 (t, J=7.0 Hz, 2H), 1.12 - 1.03 ( m, 4H), 0.67 (t, J=7.3 Hz, 3H). Human AJP cAMP EC50 potency range A.

[00826] Example 178 to Example 201 were prepared as described in the general procedure provided by example 177. Example 202. 3-(3-benzyl-1,2,4-oxadiazol-5-yl)-6-butyl-5- (2,6-dimethoxyphenyl)pyridine-2,4-diol

Example 202. 3-(3-benzyl-1,2,4-oxadiazol-5-yl)-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol

[00827] A vial containing Compound 1d (25 mg, 0.067 mmol) and N'-hydroxy-2-phenylacetimidamide (50 mg, 0.33 mmol) was sealed and then stirred at 120 °C for 3 hours. The reaction mixture was purified by preparative HPLC to provide Example 202 (8.0 mg, 26% yield). LCMS (Method C) Tr = 2.17 min, m/z = 462.1 (M+H). 1H NMR (500MHz, DMSO-d6) d 7.48 - 7.32 (m, 5H), 7.31 - 7.23 (m, 1H), 6.73 (d, J=8.5 Hz, 2H ), 4.15 (s, 2H), 3.68 (s, 6H), 2.17 (t, J=7.7 Hz, 2H), 1.34 (t, J=7.7 Hz, 2H ), 1.15 - 1.02 (m, 2H), 0.67 (t, J=7.3 Hz, 3H). Human AJP cAMP EC50 potency range B.

[00828] Example 203 was prepared as described in the general procedure provided by example 202. Example 204. 3-(5-benzyl-4H-1,2,4-triazol-3-yl)-6-butyl-5-( 2,6-dimethoxyphenyl)pyridine-2,4-diol Example 204. 3-(5-benzyl-4H-1,2,4-triazol-3-yl)-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol

[00829] To a solution of compound 1e (6.0 mg, 0.017 mmol) and ethyl 2-phenylacetimidate (2.7 mg, 0.017 mmol) in 2-propanol (0.3 mL) was added DIEA (0.10 mL, 0.57 mmol) and the reaction mixture heated to 120 °C using microwave irradiation for 20 min. The reaction mixture was concentrated under reduced pressure then purified by preparative HPLC to provide Example 204 (5.3 mg, 56% yield). LCMS (Method C) Tr = 2.21 min, m/z = 461.2 (M+H). 1H NMR (500MHz, DMSO-d6) d 7.34 (t, J=8.4 Hz, 1H), 7.30 - 7.26 (m, 4H), 7.23 - 7.17 (m, 1H), 6.71 (d, J=8.6 Hz, 2H), 4.02 (s, 2H), 3.73 - 3.59 (m, 6H), 2.20 - 2.07 (m, 2H) , 1.33 (dt, J=15.3, 7.5 Hz, 2H), 1.08 (sxt, J=7.4 Hz, 2H), 0.66 (t, J=7.4 Hz, 3H). Potency range C of Human APJ cAMP EC50. Example 205. 6-Butyl-3-(5-{[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3,4-oxadiazol-2-yl)- 5-(2,6-dimethoxyphenyl)pyridine-2,4-diol Example 205. 6-Butyl-3-(5-{[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3,4-oxadiazol-2-yl)- 5-(2,6-dimethoxyphenyl)pyridine-2,4-diol.

[00830] To a solution of Example 96 (500 mg, 1.1 mmol) in ethanol (5 mL) was added hydrazine (0.35 mL, 11 mmol) and the mixture stirred for 1 hour. The mixture was concentrated under reduced pressure to provide the hydrazide intermediate (480 mg, 98% yield) as a white solid. MS m/z = 441.1 (M+H). A portion of the hydrazide intermediate (20 mg, 0.045 mmol) and 4-chlorobenzoic acid (8.5 mg, 0.054 mmol) were dissolved in dioxane (1 mL) then DIEA (0.020 mL, 0.11 mmol) added followed by a 50% solution of T3P® in ethyl acetate (0.067 mL, 0.11 mmol) and the mixture heated at 60 °C for 1 hour. To the reaction mixture, additional DIEA (0.020 mL, 0.11 mmol) and 50% solution of T3P® in ethyl acetate (0.067 mL, 0.11 mmol) were added and the reaction mixture was heated at 90 °C for 16 hours. The reaction mixture was concentrated under reduced pressure then purified by preparative HPLC to provide Example 205 (9.7 mg, 38% yield). LCMS (Method D) Tr = 0.97 min, m/z = 564.3 (M+H). 1H NMR (500MHz, DMSO-d6) d 8.03 (d, J=8.3 Hz, 2H), 7.70 (d, J=8.3 Hz, 2H), 7.35 (t, J= 8.5 Hz, 1H), 6.73 (d, J=8.5 Hz, 2H), 4.96 (s, 2H), 3.70 (s, 6H), 2.14 (t, J= 7.6 Hz, 2H), 1.41 - 1.26 (m, 2H), 1.16 - 1.01 (m, 2H), 0.67 (t, J=7.3 Hz, 3H). ). Human AJP cAMP EC50 potency range B.

[00831] Example 206 to Example 211 were prepared as described in the general procedure provided by example 205. Example 212. 1-({5-[6-(ethoxymethyl)-5-(4-fluoro-2,6-dimethoxyphenyl) -2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-1,2-dihydropyridin-2-one Compound 212a. 4-Fluoro-2,6-dimethoxybenzaldehyde

[00832] To a stirred solution of 1-fluoro-3,5-dimethoxybenzene (3.00 g, 19.2 mmol) in DCM (45 mL) was slowly added a 1.0 M solution of TiCk in DCM (38 .4 mL, 38.4 mmol) at 0°C for 15 minutes. The reaction mixture was cooled to -78 °C and treated with dichloro(methoxy)methane (2.26 mL, 25.0 mmol) dropwise. The reaction mixture was stirred at -78°C for 30 minutes and allowed to warm to 0°C. After 1 hour, the reaction mixture was poured into diluted HCl and extracted with ethyl acetate (2X). The combined organic fractions were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel chromatography eluting with 0% to 30% ACN/DCM to provide Compound 212a (1.60 g, 45%) as a white solid. MS m/z = 184.9 (M+H), 1H NMR (400MHz, CDCl3) d 10.42 (s, 1H), 6.34 (s, 1H), 6.31 (s, 1H), 3 .91 (s, 6H) Compound 212b. (4-Fluoro-2,6-dimethoxyphenyl)methanol

[00833] To a suspension of Compound 212a (2.52 g, 13.7 mmol) in ethanol (60 mL) at 0 °C was added sodium borohydride (0.35 g, 9.1 mmol). The ice bath was removed and stirring continued for 20 min. The reaction mixture was cooled to 0 °C then quenched by adding saturated ammonium chloride solution. The resulting suspension was concentrated and redissolved in an EtOAc/water mixture. The layers were separated and the organic fraction was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to provide compound 212b (2.3 g, 90%) as a white solid which was used without further purification. LCMS (Method C) Tr = 1.38 min. 1H NMR (400MHz, CDCl3) d 6.33 (s, 1H), 6.31 (s, 1H), 4.74 (m, 2H), 3.85 (s, 6H) Compound 212c. 4-Fluoro-2,6-dimethoxybenzyl methanesulfonate

[00834] To a solution of compound 212b (2.3 g, 13 mmol) in DCM (80 mL) was added TEA (3.5 mL, 25 mmol). The reaction mixture was cooled to 0 °C and treated with mesyl chloride (7.4 mL, 0.095 mol) in DCM (25 mL). After 30 min, the reaction mixture was diluted with DCM (100 mL) and washed with water (3 x 50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to provide compound 212c (2.7 g, 82%) which was used without further purification. LCMS (Method C) Tr = 1.64 min. 1H NMR (400MHz, CDCl3) d 6.23 (s, 1H), 6.20 (s, 1H), 4.64 (s, 2H), 3.78 (s, 6H) Compound 212d. 2-(4-Fluoro-2,6-dimethoxyphenyl)acetonitrile

[00835] To a solution of compound 212c (2.7 g, 10 mmol) in DMF (40 mL) was added sodium cyanide (1.0 g, 20 mmol) and the reaction mixture was stirred for 30 min. The reaction mixture was diluted with water (800 mL) and extracted with 30% ethyl acetate in hexane (3 x 200 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0 to 5% ethyl acetate in hexane to provide compound 212d (1.8 g, 88%). MS m/z = 196.0 (M+H). 1H NMR (400MHz, DMSO-d6) d 6.67 (s, 1H), 6.64 (s, 1H), 3.85 (s, 6H), 3.65 (s, 2H) Compound 212e. Ethyl 2-(4-fluoro-2,6-dimethoxyphenyl)acetate

[00836] To a solution of compound 212d (1.75 g, 8.97 mmol) in EtOH (40 mL) was bubbled HCl gas for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water (50 mL) and heated at 40 °C overnight. After allowing to cool to room temperature, the reaction mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give compound 212e (1.6 g, 76%), MS m/z = 243.1 (M+H), 1H NMR (400MHz, DMSO-d6 ) d 6.58 (s, 1H), 6.55 (s, 1H), 4.05 (q, J=7.0 Hz, 2H), 3.76 (s, 6H), 3.49 (s , 2H), 1.17 (t, J=7.2 Hz, 3H)

Example 212. 1-({5-[6-(ethoxymethyl)-5-(4-fluoro-2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazole -2-yl}methyl)-1,2-dihydropyridin-2-one

[00837] Example 212 was prepared from compound 212e as described in the general procedure by example 1 at 5% production. LCMS (Method C) Tr = 1.66 min, m/z = 499.1 (M+H), 1H NMR (400MHz, CDCl3) d 7.51 (m, 1H), 7.46 (m, 1H) , 6.72 (d, J=9.0 Hz, 1H), 6.42 (s, 1H), 6.40 (s, 1H), 6.38 - 6.33 (m, 1H), 5, 49 (s, 2H), 4.19 (s, 2H), 3.75 (s, 6H), 3.57 (m, 2H), 1.28 (t, J=6.9 Hz, 3H). Human AJP cAMP EC50 potency range B.

[00838] Example 213 to Example 216 were prepared as described in the general procedure provided by example 212. Example 217. 3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl} -5-(3,5-dimethoxypyridin-4-yl)-6-(ethoxymethyl)pyridine-2,4-diol Compound 217a. (3,5-Dimethoxypyridin-4-yl)methanol

[00839] To a suspension of 3,5-dimethoxy-isonicotinaldehyde (300 mg, 1.80 mmol) in ethanol (12 mL) at 0 °C was added sodium borohydride (45.2 mg, 1.20 mmol). The ice bath was removed and stirring continued for 20 minutes. The reaction mixture was cooled to 0 °C and quenched by adding saturated ammonium chloride. The resulting suspension was concentrated and redissolved in EtOAc/water. The reaction mixture was extracted with EtOAc and the organic extracts washed with brine, dried over MgSO4 and concentrated to provide compound 217a (0.30 g, 98%) as a clear oil. MS m/z = 170.0 (M+H). 1H NMR (400MHz, CDCl3) d 8.04 (s, 2H), 4.77 (s, 2H), 3.95 (s, 6H) Compound 217b. 2-(3,5-Dimethoxypyridin-4-yl)acetonitrile

[00840] To a solution of compound 217a (400 mg, 2.3 mmol) in DCM (14 mL) and TEA (0.49 mL, 3.6 mmol) at 0 °C was added dropwise a solution of mesyl chloride (7.4 mL, 0.095 mol) in DCM (25 mL). After 0.5h the mixture was diluted with DCM (100 mL) and washed with water (3 x 50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a light brown oil which was dissolved in DMF (10 mL) and treated with sodium cyanide (0.23 g, 4.7 mmol). The reaction mixture was stirred for 0.5h then diluted with water (80 mL) and extracted with 30% ethyl acetate in hexane (3 x 200 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0.65% ethyl acetate in hexane to provide compound 217b (200 mg, 47%) as a white solid. MS m/z = 179.0 (M+H).

Compound 217c. Ethyl 2-(3,5-dimethoxypyridin-4-yl)acetate

[00841] A solution of compound 217b (200 mg, 1.12 mmol) in EtOH (8 mL) was bubbled with HCl gas for 2h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water (15 mL) and heated at 40 °C for 14h. After allowing to cool to rt, the reaction mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0100% ethyl acetate in hexane to provide compound 217c (220 mg, 87%) as a clear oil. MS m/z = 226.0 (M+H). 1H NMR (400MHz, CDCl3) d 8.02 (br, s., 2H), 4.15 (q, J=7.1 Hz, 2H), 3.91 (s, 6H), 3.67 (s , 2H), 1.24 (t, J=7.0 Hz, 3H) Example 217. 3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5 -(3,5-dimethoxypyridin-4-yl)-6-(ethoxymethyl)pyridine-2,4-diol

[00842] Example 217 was prepared from compound 217c as described in the general procedure by example 1 in 1% production. LCMS (Method C) Tr = 1.67 min, m/z = 499.0 (M+H). 1H NMR (400MHz, CDCl3) d 8.16 (s, 2H), 7.33 (m, 4H), 4.30 (s, 2H), 4.12 (s, 2H), 3.89 (s, 6H), 3.53 (m, 2H), 1.25 (t, J=7.0 Hz, 3H). Human AJP cAMP EC50 potency range B. Example 218. 6-Butyl-3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(3-fluoro-2,6-dimethoxyphenyl)pyridine-2 ,4-diol (isomer 1) and Example 219. 6-butyl-3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(3-fluoro- 2,6-dimethoxyphenyl)pyridine-2,4-diol (isomer 2) Compound 218a. Ethyl 6-butyl-5-(3-fluoro-2,6-dimethoxyphenyl)-2,4-dihydroxynicotinate

[00843] To a solution of compound 1d (650 mg, 1.73 mmol) in DMF (7.5 mL) at 0 °C was slowly added Selectfluor™ (613 mg, 1.73 mmol). After stirring for one minute at 0°C, the ice bath was removed and stirring continued at room temperature for 16 h. The reaction mixture was diluted with EtOAc, washed with water (3X) then brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting solid was triturated with EtOAc (3X). The triturate was evaporated under reduced pressure and the residue purified by silica gel chromatography eluting with 0-100% ethyl acetate in hexane to give compound 218a (170 mg, 25%) as a white solid. MS m/z = 394.1.0 (M+H), 1H NMR (400MHz, CDCl3) d 7.10 (dd, J=11.2, 9.2 Hz, 1H), 6.69 - 6, 54 (m, 1H), 4.41 (q, J=7.0 Hz, 2H), 3.82 (m, 3H), 3.72 (s, 3H), 2.35 (t, J=7 .8 Hz, 2H), 1.52 (td, J=7.5, 2.5 Hz, 2H), 1.40 (t, J=7.0 Hz, 3H), 0.78 (t, J =7.3 Hz, 3H) Example 218. 6-Butyl-3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(3-fluoro-2 ,6-dimethoxyphenyl)pyridine-2,4-diol (isomer 1) and Example 219. 6-butyl-3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl} -5-(3-fluoro-2,6-dimethoxyphenyl)pyridine-2,4-diol (isomer 2)

[00844] Example 218 and Example 219 were prepared from Compound 218a as described in the general procedures by example 1. The atropisomers were separated using chiral SFC after the final step (instrument: Berger Multigram II SFC; column: Chirapak AD- H, 21 x 250 mm ID, 5 micron; flow rate: 45 mL/min, 100 bar, 40 °C; mobile phase: 20% isopropanol/80% CO2; wavelength: 220 nm) to deliver first elution of Example 218 (3 mg, 7%) as a white solid, analytical SFC Tr = 4.0 min (instrument: Aurora analytical SFC; column: Chirapak AD-H, 4.6 x 250 mm ID, 5 micron; rate flow rate: 2 mL/min, 150 bar, 35 °C; mobile phase: 25% isopropanol/75% CO2; 220 nm), LCMS (Method C) Tr = 2.20 min, m/z = 514, 0 (M+H), 1H NMR (400MHz, CDCl3) d 7.24 (m, 4H), 7.06 (m, 1H), 6.54 (m, 1H), 4.20 (s, 2H) , 4.01 - 3.91 (m, 2H), 3.74 (m, 3H), 3.64 (s, 3H), 3.42 (m, 2H), 0.71 (t, J=7.2 Hz, 3H), Human AJP cAMP EC50 Power Band B; and the second elution of Example 219 (3 mg, 7%) as a white solid, analytical SFC Tr = 5.2 min, LCMS (Method C) Tr = 2.20 min, m/z = 514.0 (M+ H), 1H NMR (400MHz, CDCl3) d 7.24 (m, 4H), 7.06 (m, 1H), 6.54 (m, 1H), 4.20 (s, 2H), 4.01 - 3.91 (m, 2H), 3.74 (m, 3H), 3.64 (s, 3H), 3.42 (m, 2H), 0.71 (t, J=7.2 Hz, 3H), Human AJP cAMP EC50 potency range A.

[00845] Example 220 and Example 221 were prepared as described in the general procedure provided by example 218 and Example 219. Example 222 and Example 223. 3-{5-[(4-chlorophenyl)methyl]-1,3,4 -oxadiazol- 2-yl}-6-(ethoxymethyl)-5-(2-hydroxy-6-methoxyphenyl)pyridine-2,4-diol (Isomer 1) and 3-{5- [(4-chlorophenyl)methyl] -1,3,4-oxadiazol-2-yl}-6-(ethoxymethyl)-5-(2-hydroxy-6-methoxyphenyl)pyridine-2,4-diol (Isomer 2)

[00846] To a solution of Example 90 (66 mg, 0.13 mmol) in DCM (2 mL) at -78°C was added BBR3 (1M in hexanes) (0.13 mL, 0.13 mmol) and the reaction mixture stirred for 15 min. The reaction mixture was cooled to 0 °C and stirred for 15 min. More BBR3 (1M in hexanes) (0.07 mL, 0.07 mmol) was added and the reaction mixture stirred for 15 min. The reaction mixture was diluted with water (5 mL) extracted with DCM (3 X 5 mL) and the combined organic portions dried over Na2SO4, filtered then concentrated under reduced pressure. The residue was purified by preparative HPLC then the atropisomers separated by chiral SFC (instrument: Berger Multigram II SFC; column: Chirapak AD-H, 21 x 250 mm ID, 5 micron; flow rate: 45 mL/min, 100 bar , 40 °C; mobile phase: 35% isopropanol/65% CO2; wavelength: 220 nm) to give Example 222 (11 mg, 16%) as isomer 1, analytical SFC Tr = 7.2 min (instrument : Aurora SFC analytical; column: Chirapak AD-H, 4.6 x 250 mm ID, 5 micron; flow rate: 2 mL/min, 150 bar, 35 °C; mobile phase: 35% isopropanol/65% CO2; 220 nm): LCMS (Method D) Tr = 0.90 min, m/z = 484.1 [M+H]+, 1H NMR (500MHz, CD3OD) d 7.47 - 7.31 (m, 4H) , 7.22 - 7.08 (m, 1H), 6.61 - 6.44 (m, 2H), 4.39 - 4.25 (m, 2H), 4.18 - 4.07 (m, 2H), 3.71 (s, 3H), 3.49 - 3.41 (m, 2H), 1.35 - 1.28 (m, 3H); Human AJP cAMP EC50 potency range A; and Example 223 (11 mg, 16%) as isomer 2, analytical SFC Tr = 12.6 min: LCMS (Method D) Tr = 0.90 min, m/z = 484.1 [M+H]+. 1H NMR (500MHz, CD3OD) d 7.47 - 7.31 (m, 4H), 7.22 - 7.08 (m, 1H), 6.61 - 6.44 (m, 2H), 4.39 - 4.25 (m, 2H), 4.18 - 4.07 (m, 2H), 3.71 (s, 3H), 3.49 - 3.41 (m, 2H), 1.35 - 1 .28 (m.3H); Human AJP cAMP EC50 potency range B. Example 224. 3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5-(2,6-dimethylphenyl)pyridine-2, 4-diol Compound 224a. Ethyl 2-bromo-2-(2,6-dimethylphenyl)acetate

[00847] To a solution of 1N LiHMDS in THF (4.4 mL, 4.4 mmol) in THF (7 mL) at -30 °C was added dropwise a solution of 2-(2,6-dimethylphenyl )ethyl acetate (800 mg, 4.2 mmol) in THF (7 mL) and the reaction mixture stirred for 15 min. A solution of bromine (0.21 mL, 4.2 mmol) in THF (7 mL) was added dropwise then the temperature was allowed to warm to -5°C over a period of 1 hour. The reaction mixture was quenched by addition of aqueous sodium thiosulfate then extracted with EtOAc. The organic extract was washed with saturated NH4Cl and brine then dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1 to 4% EtOAc/hexanes to provide compound 224a (740 mg, 2.7 mmol, 66% yield) as a clear colorless oil which solidified upon standing. MS m/z = 271.0 (M+H), 1H NMR (400MHz, CDCl3) d 7.16 - 7.09 (m, 1H), 7.06 - 7.01 (m, 2H), 5, 95 (s, 1H), 4.33 - 4.19 (m, 2H), 2.37 (s, 6H), 1.26 (t, J=7.2 Hz, 3H). Compound 224b. (Z)-ethyl 3-amino-2-(2,6-dimethylphenyl)hept-2-enoate

[00848] To a solution of compound 224a (130 mg, 0.47 mmol) in valeonitrile (0.50 mL, 4.7 mmol) activated zinc (46 mg, 0.71 mmol) was added followed by methanesulfonic acid (0 .61 µl, 9.4 µmol) and the reaction mixture stirred at 40 °C for 1.5 hours. The reaction mixture was allowed to warm to room temperature then diluted with EtOAc and filtered. The filtrate was poured into saturated NaHCO3 and extracted with EtOAc (3x). The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0 to 15% EtOAc/hexanes to provide compound 224b (74 mg, 0.27 mmol, 57% yield) as a clear oil, MS m/z = 276. 5 (M+H), 1H NMR (400MHz, CDCl3) d 7.11 - 6.99 (m, 3H), 4.06 (q, J=7.0 Hz, 2H), 2.12 (s, 6H), 1.88 - 1.78 (m, 2H), 1.40 - 1.28 (m, 2H), 1.23 - 1.13 (m, 2H), 1.10 (t, J= 7.2 Hz, 3H), 0.75 (t, J=7.3 Hz, 3H). Example 224. 3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5-(2,6-dimethylphenyl)pyridine-2, 4-diol

[00849] Example 224 was prepared from compound 224b as described in the general procedure provided by example 1 at 33% production. LCMS (Method A) Tr = 2.12 min, m/z = 471.1 (M+H). 1H NMR (500MHz, DMSO-d6)d 8.00 (d, J=7.6 Hz, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.72 (t, J= 7.2 Hz, 1H), 7.44 (t, J=6.7 Hz, 1H), 7.20 (d, J=7.3 Hz, 1H), 7.17 - 7.10 (m, 2H), 4.96 (s., 2H), 2.52 (br, s., 5H), 2.15 (br, s., 1H), 1.36 (br, s., 2H), 1, 12 (d, J=7.0 Hz, 2H), 0.69 (t, J=6.9 Hz, 3H). Human AJP cAMP EC50 potency range A.

[00850] Example 225 and Example 226 were prepared as described in the general procedure provided by example 224. Example 227. 6-Butyl-5-(2,6-dimethoxyphenyl)-3-(5-{ [1,2] oxazolo[4,5-b]pyridin-3-ylmethyl}-1,3,4-oxadiazol-2-yl)pyridin-2,4-diol Compound 227a. 2-(isoxazole [4,5-b]pyridin-3-yl)acetic acid

[00851] To a vial containing hydroxylamine hydrochloride (280 mg, 4.0 mmol) was added 10% aq sodium carbonate (1.5 mL, 1.5 mmol) and the mixture stirred for 10 min. The solution was added to a flask containing 4-hydroxy-2H-pyran[3,2-b]pyridin-2-one (130 mg, 0.79 mmol; prepared as described in DE2442666A1, 1975) and the reaction mixture stirred at 50°C for 16 hours. The reaction mixture was cooled to 10 °C then acidified to pH 2 with dilute HCl. The reaction mixture was stirred for 0.5h then filtered. The filtrate was purified by HPLC to provide compound 227a (80 mg, 0.45 mmol, 57% yield) as a light yellow solid. MS m/z = 179.0 (M+H). 1H NMR (500MHz, DMSO-d6) d 12.92 (br. s., 1H), 8.80 - 8.72 (m, 1H), 8.28 (dd, J=8.5, 1.1 Hz, 1H), 7.71 (dd, J=8.5, 4.4 Hz, 1H), 4.13 (s, 2H). Example 227. 6-Butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[1,2]oxazolo[4,5-b]pyridin-3-ylmethyl}-1,3,4-oxadiazole -2-yl)pyridine-2,4-diol

[00852] Example 227 was prepared from compound 227a and Compound 1e as described in the general procedure provided by example 1 at 68% production. LCMS (Method A) Tr = 1.56 min, m/z = 504.2 (M+H). 1H NMR (500MHz, DMSO-d6) d 8.77 (d, J=4.3 Hz, 1H), 8.34 (d, J=8.5 Hz, 1H), 7.75 (dd, J= 8.4, 4.4 Hz, 1H), 7.36 (t, J=8.4 Hz, 1H), 6.73 (d, J=8.5 Hz, 2H), 4.96 (s, 2H), 3.70 (s, 6H), 2.15 (t, J=7.5 Hz, 2H), 1.40 - 1.27 (m, 2H), 1.15 - 1.03 (m , 2H), 0.66 (t, J=7.3 Hz, 3H). Human AJP cAMP EC50 potency range A.

[00853] Example 228 was prepared as described in the general procedure provided by example 227. Example 229. 3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5- (2,6-dihydroxyphenyl)-6-(ethoxymethyl)pyridine-2,4-diol Example 229. 3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dihydroxyphenyl)-6-(ethoxymethyl)pyridine-2 ,4-diol

[00854] To a solution of Example 90 (86 mg, 0.17 mmol) in DCM (2 mL) at -78°C was added BBR3 (1.0M in hexanes) (0.17 mL, 0.17 mmol) and the reaction mixture stirred for 15 min. The reaction mixture was then placed in an ice bath and stirred for 15 minutes. More BBR3 (1.0M in hexanes) (0.09 mL, 0.09 mmol) was added and the reaction mixture stirred 15 minutes then diluted with water (5 mL) extracted with DCM (2 X 15 mL), dried over Na2SO4 is then concentrated under reduced pressure. The residue was purified by preparative HPLC to provide Example 229 (19 mg, 23% yield) as a white solid. LCMS (Method D) Tr = 0.81 min, m/z = 470.0 [M+H]+. 1H NMR (500MHz, CD3OD) d 7.46 - 7.30 (m, 4H), 7.13 - 6.97 (m, 1H), 6.50 - 6.32 (m, 2H), 4.41 - 4.31 (m, 2H), 4.28 - 4.22 (m, 2H), 3.51 - 3.46 (m, 2H), 1.24 - 1.12 (m, 3H).; Human APJ cAP EC50 potency range B. Example 230. 3-{5-[(5-chloropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-[(ethylamino) methyl]pyridine-2,4-diol

[00855] Compound 230a. tert-butyl (2-(1H-imidazol-1-yl)-2-oxoethyl)(ethyl)carbamate

[00856] To a solution of 2-((tert-butoxycarbonyl)(ethyl)amino)acetic acid (200 mg, 0.98 mmol) in THF (2 mL) was added CDI (180 mg, 1.1 mmol) and the reaction mixture was stirred for 18h. The reaction mixture was diluted with water and extracted with EtOAc (3x). The combined extracts were dried (MgSO4), filtered and concentrated under reduced pressure to give Compound 230a (220 mg, 0.87 mmol, 88% yield) as a yellow oil. LCMS (Method E) Tr = 1.58 min, m/z = 252.2 (M-H). Compound 230b. Ethyl 4-((tert-butoxycarbonyl)(ethyl)amino)-2-(2,6-dimethoxyphenyl)-3-oxobutanoate

[00857] To a solution of compound 1a (0.90 g, 4.0 mmol) in THF (5 mL) at -78 °C was added dropwise 1M LiHMDS in THF (5.6 mL, 5.6 mmol) and the reaction mixture stirred for 10 minutes then allowed to warm to room temperature and stirred for 1h. The reaction mixture was cooled again to -78 °C then a 2M solution of diethylzinc in hexane (2.8 mL, 5.6 mmol) was added dropwise. The reaction mixture was stirred for 10 minutes then allowed to warm to -20°C. A solution of compound 230a (1.2 g, 4.8 mmol) in THF (1 mL) was added dropwise and the reaction mixture stirred at -20 °C for 20 minutes then quenched by addition of 1N HCl. The reaction mixture was extracted with DCM (2x) and the organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0 to 30% EtOAc/hexanes to provide compound 230b (0.81g, 2.0 mmol, 49% yield) as a white solid. LCMS (Method E) Tr = 1.99 min, m/z = 410.3 (M+H). Compound 230c. N- [(5-{5- [(5-chloropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}- 3-(2,6-dimethoxyphenyl)-4,6-di tert-butyl-hydroxypyridin-2-yl)methyl]-N-ethylcarbamate

[00858] Compound 230c was prepared from compound 230b as described in the general procedure provided by example 1 at 5% total production. LCMS (Method A) Tr = 1.76 min, m/z = 598.4 (M+H), 1H NMR (500MHz, DMSO-d6) d 8.53 (s, 1H), 8.03 - 7, 87 (m, 1H), 7.54 (d, J=8.2 Hz, 1H), 7.33 (t, J=8.2 Hz, 1H), 6.70 (d, J=8.2 Hz, 2H), 4.54 (s, 2H), 3.95 (br, m, 1H), 3.72 (br,m,, 2H), 2.78 (br, m,, 2H), 2 .51 (br, s,, 6H), 1.26 (s, 4H), 1.30 (s, 5H), 0.77 (br, s,, 3H). Example 230. 3-{5-[(5-chloropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-[(ethylamino) methyl]pyridine-2,4-diol

[00859] To a solution of compound 230b (13 mg, 0.022 mmol) in DCM (1 mL) was added TFA (0.1 mL) and the reaction mixture was stirred for 24h. The reaction mixture was concentrated under reduced pressure and the residue purified by preparative HPLC to provide Example 230 (10 mg, 0.019 mmol, 85% yield) as a white solid. LCMS (Method A) Tr = 0.95 min, m/z = 498.1 (M+H). 1H NMR (500MHz, DMSO-d6) d 8.56 (s, 1H), 7.97 (d, J=6.8 Hz, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.37 (t, J=8.3 Hz, 1H), 6.74 (d, J=8.3 Hz, 2H), 4.56 (s, 2H), 2.55 (m, 8H), 2.47 (br. s., 2H), 0.89 (t, J=6.7 Hz, 3H). Human AJP cAMP EC50 potency range A. Example 231. 3-{5-[(1,2-benzoxazol-3-yl)methyl]-1,3,4-thiadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl )pyridine-2,4-diol Compound 231a. N'-(2-(benzo[d]isoxazol-3-yl)acetyl)-6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxynicotinehydrazide

[00860] A mixture of 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-2,4-dihydroxynicotinehydrazide (80 mg, 0.22 mmol, prepared by the general procedures provided by example 1) and 2-(benzo[d]isoxazol-3-yl)acetic acid (47 mg, 0.26 mmol) in DCM (1 mL) was added and Hunig's base (0.058 mL, 0.33 mmol) followed by a solution of 50% T3P® in ethyl acetate (0.20 mL, 0.33 mmol) and the reaction mixture was stirred at room temperature for 1.5h. The reaction mixture was concentrated under reduced pressure and the residue purified by preparative HPLC to provide compound 231a (82 mg, 0.16 mmol, 71% yield) as a white solid. LCMS (Method D) Tr = 0.82 min, m/z = 517.2 (M+H). Example 231. 3-{5-[(1,2-benzoxazol-3-yl)methyl]-1,3,4-thiadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl )pyridine-2,4-diol

[00861] To a solution of compound 231a (82 mg, 0.16 mmol) in THF (2 mL) was added Lawesson's reagent (64 mg, 0.16 mmol) and the mixture was heated at 75 oC for 1 hour. The mixture was allowed to warm to room temperature then concentrated under reduced pressure. The residue was dissolved in dioxane (1 mL) then Hunig's base (0.069 mL, 0.39 mmol) was added followed by a 50% solution of T3P® in ethyl acetate (0.23 mL, 0.39 mmol ) and the reaction mixture was heated at 90 oC for 0.5 hours. The reaction mixture was allowed to warm to room temperature then concentrated under reduced pressure and the residue purified by preparative HPLC to provide Example 231 (56 mg, 0.11 mmol, 69% yield) as a white solid. LCMS (Method A) Tr = 2.013 min, m/z = 521.0 (M+H). 1H NMR (500MHz, DMSO-d6) d 7.85 (d, J=7.9 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.69 (t, J= 7.6 Hz, 1H), 7.48 - 7.32 (m, 2H), 6.75 (d, J=8.5 Hz, 2H), 5.04 (s, 2H), 4.01 ( s, 2H), 3.69 (s, 6H), 3.28 (q, J=6.9 Hz, 2H), 1.00 (t, J=7.0 Hz, 3H). Human AJP cAMP EC50 potency range B.

[00862] Examples 232 - 235 were prepared by the general procedures provided by example 231.

[00863] Examples 236 - 245 were prepared by the general procedures provided by example 1.

[00864] Examples 246 - 251 were prepared by the general procedures provided by example 137.

[00865] Examples 252 - 273 were prepared by the general procedures provided by example 177.

[00866] Examples 274 - 276 were prepared by the general procedures provided by example 222.

Claims (23)

1. Compound, characterized by having formula (I): or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: alk is C1-6 alkyl substituted with 0-5 Re; ring A is independently selected from: ring B is independently selected from: R1 is independently selected from: H, halogen, NO2, -(CH2)nORb, (CH2)nS(O)pRc, -(CH2)nC(=O)Rb, -(CH2)nNRaRa, -(CH2)nCN, -(CH2)nC(=O)NRaRa, -(CH2)nNRaC(=O)Rb, - (CH2)nNRaC(=O)NRaRa, -(CH2)nNRaC(=O)ORb, -(CH2)nOC( =O)NRaRa, - (CH2)nC(=O)ORb, -(CH2)nS(O)pNRaRa, -(CH2)nNRaS(O)pNRaRa, - (CH2)nNRaS(O)pRc, C1-4 alkyl substituted with 0-3 Re, -(CH2)n-C3-6 carbocyclyl substituted with 0-3 Re and -(CH2)n-heterocyclyl substituted with 0-3 Re; R2 is independently selected from: C1-5 alkyl substituted with 0-3 Re; C2-5 alkenyl substituted with 0-3 Re and C3-6 cycloalkyl substituted with 0-3 Re; provided that when R2 is C1-5 alkyl, the carbon atom other than that attached directly to the pyridine ring may be replaced by O, N and S; R3 is independently selected from: (1) -(CR4R4)rC(=O)OC1-4 alkyl substituted with 0-5 Re, (2) -(CR4R4)rNRaRa, (3) -(CR4R4)rC(=O) NRaRa, (4) -(CR4R4)rNRaC(=O)C1-4 alkyl substituted with 0-5 Re, (5) -(CR4R4)rNRaC(=O)(CR4R4)nOC1-4 alkyl substituted with 0-5 Re , (6) -(CR4R4)r-R5, (7) -(CR4R4)r-OR5, (8) -(CR4R4)rNRaC(=O)(CR4R4)nR5 and (9) -(CR4R4)rC(= O)NRa(CR4R4)nR5; R4 is independently selected from: H, halogen, NRaRa, OC1-4 alkyl and C1-4 alkyl; or R4 and R4 together with the carbon atom to which they are both attached form C3-6 cycloalkyl substituted with 0-5 Re; R5 is independently selected from: -(CH2)n-C3-10 carbocycle and -(CH2)n-heterocycle, each substituted with 0-3 R6; R6 is independently selected from: H, halogen, =O, -(CH2)nORb, (CH2)nS(O)pRc, -(CH2)nC(=O)Rb, -(CH2)nNRaRa, -(CH2)nCN , -(CH2)nC(=O)NRaRa, -(CH2)nNRaC(=O)Rb, -(CH2)nNRaC(=O)NRaRa, -(CH2)nNRaC(=O)ORb, -(CH2)nOC (=O)NRaRa, -(CH2)nC(=O)ORb, -(CH2)nS(O)pNRaRa, -(CH2)nNRaS(O)pNRaRa, -(CH2)nNRaS(O)pRc, C1-5 alkyl substituted with 0-3 Re, (CH2)n-C3-6 carbocyclyl substituted with 0-3 Re and -(CH2)n-heterocyclyl substituted with 0-3 Re; Ra is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, -(CH2)n-C3-10 substituted carbocyclyl with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are attached form a heterocyclic ring with 0-5 Re; Rb is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, -(CH2)n-C3-10 substituted carbocyclyl with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re; Rc is independently selected from C1-6 alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re, C3-6carbocyclyl and heterocyclyl; Rd is independently selected from H and C1-4 alkyl substituted with 0-5 Re; Re is independently selected from C1-6 alkyl substituted with 0-5 Rf, C2-6 alkenyl, C2-6 alkynyl, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -( CH2)n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H, -(CH2)nORf, S(O)pRf, C(=O)NRfRf, NRfC( =O)Rf, S(O)pNRfRf, NRfS(O)pRf, NRfC(=O)ORf, OC(=O)NRfRf and -(CH2)nNRfRf; Rf is independently selected from H, F, Cl, Br, CN, OH, C1-5alkyl (optionally substituted with halogen and OH), C3-6 cycloalkyl and phenyl, or Rf and Rf together with the nitrogen atom to which they are attached. both linked form a heterocyclic ring optionally substituted with C1-4 alkyl; n is independently selected from zero, 1, 2 and 3; r is independently selected from zero, 1, 2 and 3; ep is independently selected from zero, 1 and 2. 2. Compound according to claim 1, characterized by the fact that it has formula (II): or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is independently selected from: F, Cl, Br, NO2, -(CH2)nORb, -(CH2)nC(=O)Rb, - (CH2)nNRaRa, -(CH2)nC(=O)NRaRa, -(CH2)nNRaC(=O)Rb, C1-4 alkyl substituted with 0-3 Re and C3-6 cycloalkyl substituted with 0-3 Re; R2 is independently selected from: C1-5 alkyl substituted with 0-3 Re; C2-5 alkenyl and C3-6 cycloalkyl; provided that when R2 is C1-5 alkyl, the carbon atom other than that attached directly to the pyridine ring may be replaced by O and S; R3 is independently selected from: (1) -(CR4R4)rC(=O)OC1-4 alkyl substituted with 0-5 Re, (2) -(CR4R4)rNRaRa, (3) -(CR4R4)rC(=O) NRaRa, (4) -(CR4R4)rNRaC(=O)C1-4 alkyl substituted with 0-5 Re, (5) -(CR4R4)rNRaC(=O)(CR4R4)nOC1-4 alkyl substituted with 0-5 Re , (6) -(CR4R4)r-R5, (7) -(CR4R4)r-OR5, (8) -(CR4R4)rNRaC(=O)(CR4R4)nR5 and (9) -(CR4R4)rC(= O)NRa(CR4R4)nR5; R4 is independently selected from: H, F, Cl, NRaRa, OC1-4 alkyl and C1-4 alkyl; or R4 and R4 together with the carbon atom to which they are both attached form C3-6 cycloalkyl substituted with 0-5 Re; R5 is independently selected from: -(CH2)n-aryl, -(CH2)n-C3-6 cycloalkyl and -(CH2)n-heterocycle, each substituted with 0-3 R6; R6 is independently selected from: H, F, Cl, Br, -ORb, =O, -(CH2)nC(=O)Rb, -(CH2)nC(=O)ORb, -(CH2)nNRaRa, CN, -(CH2)nC(=O)NRaRa, -(CH2)nS(O)pNRaRa, C1-4 alkyl substituted with 0-3 Re, (CH2)n-C3-6 carbocyclyl substituted with 0-3 Re and -( CH2)n-heterocyclyl substituted with 0-3 Re; Ra is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are attached form a heterocyclic ring with 0-5 Re; Rb is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, -(CH2)n-C3-10 substituted carbocyclyl with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re; Re is independently selected from C1-6 alkyl substituted with 0-5 Rf, C2-6 alkenyl, C2-6 alkynyl, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -( CH2)n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H, -(CH2)nORf, S(O)pRf, C(=O)NRfRf, NRfC( =O)Rf, S(O)pNRfRf, NRfS(O)pRf, NRfC(=O)ORf, OC(=O)NRfRf and -(CH2)nNRfRf; Rf is independently selected from H, F, Cl, Br, CN, OH, C1-5alkyl (optionally substituted with halogen and OH), C3-6 cycloalkyl and phenyl; n is independently selected from zero, 1, 2 and 3; r is independently selected from 1, 2 and 3; ep is independently selected from zero, 1 and 2. 3. Compound according to claim 1 or 2, characterized by the fact that it has formula (III): or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is independently selected from: F, Cl, OH and OC1-4 alkyl; R1a is independently selected from: F, Cl and C1-2 alkyl; cycle R2 is independently selected from: C1-5 alkyl substituted with 0-3 Re; C2-5 alkenyl, and C3-6 cycloalkyl and CH2O(CH2)1- 3CH3; R3 is independently selected from: (1) -(CR4R4)rC(=O)OC1-4 alkyl substituted with 0-5 Re, (2) -(CR4R4)rNRaRa, (3) -(CR4R4)rC(=O) NRaRa, (4) -(CR4R4)rNRaC(=O) C1-4 alkyl substituted with 0-5 Re, (5) -(CR4R4)rNRaC(=O)(CR4R4)nOC1-4 alkyl substituted with 0-5 Re , (6) -(CR4R4)r-R5, (7) -(CR4R4)r-OR5 and (8) -(CR4R4)rNRaC(=O)(CR4R4)nR5 and (9) -(CR4R4)rC(= O)NRa(CR4R4)nR5; R4 is independently selected from: H, F, Cl, NRaRa, OC1-4 alkyl and C1-4 alkyl; or R4 and R4 together with the carbon atom to which they are both attached form C3-6 cycloalkyl substituted with 0-5 Re; R5 is independently selected from: -(CH2)n-aryl, -(CH2)n-C3-6 cycloalkyl and -(CH2)n-heterocycle, each substituted with 0-3 R6; R6 is independently selected from: H, F, Cl, Br, -ORb, =O, -(CH2)nC(=O)Rb, -(CH2)nC(=O)ORb, -(CH2)nNRaRa, CN, -(CH2)nC(=O)NRaRa, -(CH2)nS(O)pNRaRa, C1-4 alkyl substituted with 0-3 Re, (CH2)n-C3-6 carbocyclyl substituted with 0-3 Re and -( CH2)n-heterocyclyl substituted with 0-3 Re; Ra is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are attached form a heterocyclic ring with 0-5 Re; Rb is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, -(CH2)n-C3-10 substituted carbocyclyl with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re; Re is independently selected from C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -(CH2) n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H; en is independently selected from zero, 1, 2 and 3; er is independently selected from 1, 2 and 3. 4. Compound according to any one of claims 1 to 3, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, characterized by the fact that: R3 is independently selected from: (1) -(CR4R4)r- R5, (2) -(CR4R4)r-OR5, (3) -(CR4R4)rNRaC(=O)(CR4R4)nR5 and (4) -(CR4R4)rC(=O)NRa(CR4R4)nR5; R4 is independently selected from: H, F, Cl, N(CH3)2, OCH3 and CH3; or R4 and R4 together with the carbon atom to which they are both attached form cyclopropyl; R5 is independently selected from: R6 is independently selected from: H, F, Cl, Br, -OCH3, -OCF3, =O, -NRaRa, CN, -S(O)2NH2, CH3, CF3 -(CH2)n-aryl, - (CH2) n-C3-6 cycloalkyl substituted with 0-3 Re and -(CH2)n-heterocyclyl substituted with 0-3 Re; R6a is independently selected from: H, CH3, aryl substituted with 0-3 Re and heterocyclyl substituted with 0-3 Re; Ra is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; Re is independently selected from C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -(CH2) n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H; n is independently selected from zero, 1, 2 and 3; er is independently selected from 1, 2 and 3. 5. Compound according to any one of claims 1 to 3, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, characterized by the fact that: R3 is independently selected from: (1) -(CR4R4)rNRaRa and (2) -(CR4R4)rC(=O)NRaRa, R4 is independently selected from: H, F, Cl, N(CH3)2, OCH3 and CH3; or R4 and R4 together with the carbon atom to which they are both attached form C3-6 cycloalkyl substituted with 0-5 Re; R6 is independently selected from: H, F, Cl, Br, -OCH3, -OCF3, =O, CN, -NRaRa, -S(O)2NH2, -CH3, CF3 -(CH2)n-aryl, - (CH2 )n-C3-6 cycloalkyl substituted with 0-3 Re and -(CH2)n-heterocyclyl substituted with 0-3 Re; R6a is independently selected from: H, CH3, aryl substituted with 0-3 Re and heterocyclyl substituted with 0-3 Re; Ra and Ra together with the nitrogen atom to which they are attached form a 0-5 Re substituted heterocyclic ring, wherein the heterocyclic ring is selected from: Re is independently selected from C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -(CH2) n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H; n is independently selected from zero, 1, 2 and 3; er is independently selected from 1, 2 and 3. 6. Compound according to any one of claims 1 to 3, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, characterized by the fact that: R1 is independently selected from: F, Cl, OH and OC1- 4 alkyl; R1a is independently selected from: F, Cl and C1-2 alkyl; R2 is independently selected from: C1-5 alkyl substituted with 0-3 Re; C2-5 alkenyl and C3-6 cycloalkyl; and CH2O(CH2)1- 3CH3; R3 is independently selected from: (1) -(CH2)rC(=O)OC1-4 alkyl substituted with 0-3 Re, (2) -(CH2)rNRaRa, (3) -(CH2)rC(=O) NRaRa, (4) -(CH2)rNRaC(=O)C1-4 alkyl substituted with 0-3 Re and (5) -(CH2)rNRaC(=O)(CR4R4)nOC1-4 alkyl substituted with 0-3 Re ; R4 is independently selected from: H, F, Cl, NRaRa, OC1-4 alkyl and C1-4 alkyl; R5 is independently selected from: -(CH2)n-aryl, -(CH2)n-C3-6 cycloalkyl and -(CH2)n-heterocycle, each substituted with 0-3 R6; R6 is independently selected from: H, F, Cl, Br, -OCH3, -OCF3, =O, CN, -NRaRa, -S(O)2NH2, CH3, CF3 -(CH2)n-aryl, - (CH2) n-C3-6 cycloalkyl substituted with 0-3 Re and -(CH2)n-heterocyclyl substituted with 0-3 Re; Ra is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; Re is independently selected from C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -(CH2) n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H; n is independently selected from zero, 1, 2 and 3; and r is independently selected from 1, 2 and 3. 7. Compound, according to claim 1 or 2, characterized by the fact that it has formula (IVa): or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is independently selected from: -CH2OH, -OCH3, -OCF3,OCH2Ph, -C(=O)NRaRa, -NRaRa, CH3, CH2CH3, CH(CH3)2 and cyclopropyl; R2 is independently selected from: C1-4 alkyl substituted with 0-3 Re; C2-4 alkenyl, C3-6 cycloalkyl and CH2O(CH2)1- 3CH3; R3 is independently selected from: (1) -(CR4R4)rC(=O)OC1-4 alkyl substituted with 0-3 Re, (2) -(CR4R4)rNRaRa, (3) -(CR4R4)rC(=O) NRaRa, (4) -(CR4R4)rNRaC(=O)C1-4 alkyl substituted with 0-3 Re, (5) -(CR4R4)rNRaC(=O)(CR4R4)nOC1-4 alkyl substituted with 0-3 Re , (6) -(CR4R4)r-R5, (7) -(CR4R4)r-OR5, (8) -(CR4R4)rNRaC(=O)(CR4R4)nR5 and (9) -(CR4R4)rC(= O)NRa(CR4R4)nR5; R4 is independently selected from: H, F, Cl, NRaRa, OC1-4 alkyl and C1-4 alkyl; R5 is independently selected from: aryl, C3-6 cycloalkyl and heterocycle, each substituted with 0-3 R6; R6 is independently selected from: H, F, Cl, Br, -ORb, =O, -(CH2)nC(=O)Rb, -(CH2)nC(=O)ORb, -(CH2)nNRaRa, CN, -(CH2)nC(=O)NRaRa, C1-4 alkyl substituted with 0-3 Re, (CH2)n-C3-6 carbocyclyl substituted with 0-3 Re and -(CH2)n-heterocyclyl substituted with 0-3 Re; Ra is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are attached form a heterocyclic ring with 0-5 Re; Rb is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, -(CH2)n-C3-10 substituted carbocyclyl with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re; Re is independently selected from C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -(CH2) n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H; n is independently selected from zero, 1, 2 and 3; er is independently selected from 1, 2 and 3. 8. Compound according to claim 1 or 2, characterized by the fact that it has formula (V): or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is independently selected from: -CH2OH, -OCH3, -OCF3, CH3, CH2CH3, CH(CH3)2 and cyclopropyl; R2 is independently selected from: C1-4 alkyl substituted with 0-3 Re; C2-4 alkenyl, C3-6 cycloalkyl and CH2O(CH2)1- 3CH3; R3 is independently selected from: (1) -CH2C(=O)OC1-4 alkyl substituted with 0-3 Re, (2) -CH2NRaRa, (3) -CH2C(=O)NRaRa, (4) -CH2NHC(= O)C1-4 alkyl substituted with 0-3 Re, (5) -CH2NRaC(=O)(CH2)0-2OC1-4alkyl substituted with 0-3 Re, (6) -CH2-R5, (7) -CH2 -OR5, (8) -CH2NRaC(=O)(CH2)0-2R5 and (9) -CH2C(=O)NRa(CH2)0-2R5; R5 is independently selected from: aryl, C3-6 cycloalkyl and heterocycle, each substituted with 0-3 R6; R6 is independently selected from: H, F, Cl, Br, -ORb, =O, -(CH2)nC(=O)Rb, -(CH2)nC(=O)ORb, -(CH2)nNRaRa, CN, -(CH2)nC(=O)NRaRa, -S(O)2NH2, C1-4 alkyl substituted with 0-3 Re, (CH2)n-C3-6 carbocyclyl substituted with 0-3 Re and -(CH2)n -heterocyclyl substituted with 0-3 Re; Ra is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are attached form a heterocyclic ring with 0-5 Re; Rb is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, -(CH2)n-C3-10 substituted carbocyclyl with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re; Re is independently selected from C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -(CH2) n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H; n is independently selected from zero, 1, 2 and 3. 9. Compound according to claim 8, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, characterized in that: R3 is independently selected from: (1) -CH2-R5, (2) - CH2-OR5, (3) -CH2-NHC(=O)(CH2)0-1R5 and (4) -CH2-C(=O)NH(CH2)0-1R5; R5 is independently selected from: ; R6 is independently selected from: H, F, Cl, Br, -OCH3, -OCF3, =O, CN, CH3, CF3 -(CH2)n-aryl, -(CH2)n-C3-6 0-substituted cycloalkyl 3 Re and -(CH2)n-heterocyclyl substituted with 0-3 Re; R6a is independently selected from: H, CH3, aryl substituted with 0-3 Re and heterocyclyl substituted with 0-3 Re; Ra is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; Re is independently selected from C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -(CH2) n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H; n is independently selected from zero, 1, 2 and 3. 10. Compound according to claim 1, characterized by the fact that it has formula (VI): (VI) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is independently selected from: F, Cl, Br, NO2, -(CH2)nORb, -(CH2)nC(=O) Rb, -(CH2)nNRaRa, -(CH2)nC(=O)NRaRa, -(CH2)nNRaC(=O)Rb, C1-4 alkyl substituted with 0-3 Re and C3-6 cycloalkyl substituted with 0-3 Re; R2 is independently selected from: C1-5 alkyl substituted with 0-3 Re; C2-5 alkenyl and C3-6 cycloalkyl; provided that when R2 is C1-5 alkyl, the carbon atom other than that attached directly to the pyridine ring may be replaced by O, N and S; R3 is independently selected from: (1) -CH2C(=O)OC1-4 alkyl substituted with 0-5 Re, (2) -CH2NRaRa, (3) -CH2C(=O)NRaRa, (4) -CH2NRaC(= O)C1-4 alkyl substituted with 0-5 Re, (5) -CH2NRaC(=O)( CH2)nOC1-4alkyl substituted with 0-5 Re, (6) -CH2-R5, (7) -CH2-OR5 , (8) -CH2NRaC(=O)(CH2)nR5 and (9) -CH2C(=O)NRa(CH2)nR5 R5 is independently selected from: -(CH2)n-aryl, -(CH2)n-C3 -6 cycloalkyl and -(CH2)n-heterocycle, each substituted with 0-3 R6; R6 is independently selected from: H, F, Cl, Br, -ORb, =O, -(CH2)nC(=O)Rb, -(CH2)nC(=O)ORb, -(CH2)nNRaRa, CN, -(CH2)nC(=O)NRaRa, C1-4 alkyl substituted with 0-3 Re, (CH2)n-C3-6 carbocyclyl substituted with 0-3 Re and -(CH2)n-heterocyclyl substituted with 0-3 Re; Ra is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are attached form a heterocyclic ring with 0-5 Re; Rb is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, -(CH2)n-C3-10 substituted carbocyclyl with 0-5 Re and -(CH2)n-heterocyclyl substituted with 0-5 Re; Re is independently selected from C1-6 alkyl substituted with 0-5 Rf, C2-6 alkenyl, C2-6 alkynyl, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -( CH2)n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H, -(CH2)nORf, S(O)pRf, C(=O)NRfRf, NRfC( =O)Rf, S(O)pNRfRf, NRfS(O)pRf, NRfC(=O)ORf, OC(=O)NRfRf and -(CH2)nNRfRf; Rf is independently selected from H, F, Cl, Br, CN, OH, C1-5alkyl (optionally substituted with halogen and OH), C3-6 cycloalkyl and phenyl; n is independently selected from zero, 1, 2 and 3; ep is independently selected from zero, 1 and 2. 11. Compound according to claim 1, characterized in that it is selected from the group consisting of: 3-(5-benzyl-1,3,4-oxadiazol-2-yl)-6-butyl-5-( 2,6-dimethoxyphenyl)pyridine-2,4-diol, 3-(5-benzyl-1,3,4-oxadiazol-2-yl)-6-butyl-5-(2,6-dimethoxy-4-methylphenyl )pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(pyridin-4-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine- 2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(2-phenylethyl)-1,3,4-oxadiazol- 2-yl]pyridine-2,4-diol , 6-butyl-3-{5-[(2-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 6 -butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(2-methoxyphenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, 6-butyl -5-(2,6-dimethoxyphenyl)-3-{5-[(3-methoxyphenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, 6-butyl-3 -{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 6-butyl-5-( 2,6-dimethoxyphenyl)-3-{5-[(4-methoxyphenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, 6-butyl-3-[5- (3-chlorophenyl)-1,3,4-oxadiazol-2-yl]-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 6-butyl-3-[5-(2-chlorophenyl) -1,3,4-oxadiazol-2-yl]-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-[5- (pyrazin-2-yl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(1- phenylcyclopropyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol, 6-butyl-3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-5-( 2,6-dimethoxyphenyl)pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(2-phenylpropan-2-yl)-1,3,4-oxadiazole -2-yl]pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3- [5-(pyridin-3-yl)-1,3,4-oxadiazole-2- yl]pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(phenoxymethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4 -diol, 3-(5-benzyl-1,3,4-oxadiazol-2-yl)-6-(but-3-en-1-yl)-5-(2,6-dimethoxyphenyl)pyridine-2, 4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3- [5-(5-methyl-1H-pyrazol-3-yl)- 1,3,4-oxadiazol-2-yl]pyridine -2,4-diol, 3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5-(2,6-dimethoxyphenyl) pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(pyrazin-2-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2 ,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(pyrimidin-5-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4- diol, 6-butyl-3-{5-[(3-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 6-butyl-3-{5-[difluoro(phenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 3-[ 5-(1,3-benzoxazol-2-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 3- [5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5-(2,6-dimethoxy-4-methylphenyl)pyridine-2,4 -diol, 3- [5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-(but-3-en-1-yl)-5-( 2,6-dimethoxyphenyl)pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[2-(5-phenyl-1,3-oxazol-2-yl )ethyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[2-(1-methyl -1H-imidazol-2-yl)ethyl]-1,3,4-oxadiazol-2-yl}pyridin-2,4-diol, 6-butyl-3-{5-[(6-chloropyridin-3-yl )methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 6-butyl-3-{5-[2-(4-chlorophenyl )propan-2-yl]-1,3,4-oxadiazol-2-yl}- 5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl )-3-{5-[(4-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, 6-butyl-3-{5- [(3,4 -dichlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)- 3-(5-{[4-fluoro-3-(trifluoromethyl)phenyl]methyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol, 6-butyl-3-{5- [(2,4-dichlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 6-butyl-5-(2, 6-dimethoxyphenyl)-3-{5-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, 4 -({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)benzonitrile, 6 -butyl-3-{5-[(3,4-difluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 6 -butyl-3-(5-{[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}-1,3,4-oxadiazol-2-yl)-5-(2,6 -dimethoxyphenyl)pyridine-2,4-diol, 6-butyl-3-{5-[1-(4-chlorophenyl)ethyl]-1,3,4-oxadiazol-2-yl}-5-(2,6 - dimethoxyphenyl)pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5- [(4-methyl-1,2,5-oxadiazol-3-yl)methyl] -1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(4-fluorophenoxymethyl)-1,3, 4-oxadiazol-2-yl]pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(1H-indazol-3-ylmethyl)-1,3,4 - oxadiazol-2-yl]pyridine-2,4-diol, 4-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]- 1 ,3,4-oxadiazol-2-yl}methyl)-1,2-dihydrophthalazin-1-one, 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[methoxy(phenyl) methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(2-phenyl-1, 3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, 3-{5-[2-(1,3-benzoxazol-2-yl) ethyl]-1,3,4-oxadiazol-2-yl}-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl) -3-{5-[(4-fluoro-3-methoxyphenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, 6-butyl-5-(2,6- dimethoxyphenyl)-3-[5-(1,3-thiazol-5-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol, 6-butyl-3-[5-( 3,4-dichlorophenoxymethyl)-1,3,4-oxadiazol-2-yl]-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl) -3-{5- [(3-methyl-1,2-oxazol-5-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, 6-butyl-5 -(2,6-dimethoxyphenyl)-3-(5-{2- [3-(pyrazin-2-yl)-1,2,4-oxadiazol-5-yl]ethyl}-1,3,4-oxadiazole -2-yl)pyridine-2,4-diol, 6-butyl-3-[5-(4-chlorophenoxymethyl)-1,3,4-oxadiazol-2-yl]-5-(2,6-dimethoxyphenyl) pyridine-2,4-diol, 6-butyl-3-{5-[2-(4-chlorophenyl)-2-methylpropyl]-1,3,4-oxadiazol-2-yl}-5-(2,6 -dimethoxyphenyl)pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[3-(pyridin-2-yl)-1,2,4-oxadiazole- 5-yl]methyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{ [4- (trifluoromethoxy)phenyl]methyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{ [3 -fluoro-5-(trifluoromethyl)phenyl]methyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-{ 5-[2-(1-methyl-1H-1,3-benzodiazol-2-yl)ethyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, 6-butyl-3 -{5- [(2-chloropyridin-4-yl)methyl]-1,3,4-oxadiazol-2-yl}-5- (2,6-dimethoxyphenyl)pyridine-2,4-diol, 6-butyl -5-(2,6-dimethoxyphenyl)-3-(5-{2- [3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]ethyl}-1,3,4-oxadiazole -2-yl)pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3- [5-(1,2,3,4-tetrahydroisoquinolin-1-yl)- 1,3,4-oxadiazol-2-yl]pyridine-2,4-diol, 6-butyl-3-{5-[2-(3,4-dichlorophenyl)propan-2-yl]-1,3, 4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(2-methyl -2H-1,2,3,4-tetrazol-5-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, 6-butyl-5-(2,6 -dimethoxyphenyl)-3-[5-(2-methyl-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol, 6-butyl-5-( 2,6-dimethoxyphenyl)-3-{5-[4-(trifluoromethyl)phenoxymethyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, 6-butyl-5-(2, 6-dimethoxyphenyl)-3-{5-[(5-phenyl-4H-1,2,4-triazol-3-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4 -diol, 6-butyl-3-[5-(cyclohexylmethyl)-1,3,4-oxadiazol-2-yl]-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 6- butyl-3-{5-[2-(4-chlorophenyl)ethyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 6- butyl-5-(2,6-dimethoxyphenyl)-3-[5-(oxan-4-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol, 6-butyl-3 -{5- [(3-chloro-4-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}- 5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 6-butyl -3-{5-[(4-chloro-3-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 6 -butyl-5-(2,6-dimethoxyphenyl)-3-{5-[2-(1,3-thiazol-2-yl)ethyl]-1,3,4-oxadiazol-2-yl}pyridine-2 ,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[3-(trifluoromethyl)phenyl]methyl}-1,3,4-oxadiazol-2-yl)pyridine- 2,4-diol, 6-butyl-3-{5-[2-(3,4-difluorophenyl)ethyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl) pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{2-[4-(trifluoromethyl)phenyl]ethyl}-1,3,4-oxadiazole-2 -yl)pyridine-2,4-diol, 6-butyl-3- [5-(3,4-difluorophenoxymethyl)-1,3,4-oxadiazol-2-yl]-5- (2,6-dimethoxyphenyl) pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[2-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl]- 1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(1-phenyl-1H-pyrazol-4 - yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(2-methyl -1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3- (5-{[4-(trifluoromethyl)phenyl]methyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3 -{5- [2-(pyrimidin-2-yl)ethyl]-1,3,4- oxadiazol-2-yl}pyridine-2,4-diol, 3-{5- [2-(1,3- benzothiazol-2-yl)ethyl]-1,3,4-oxadiazol-2-yl}-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 6-butyl-5-( 2,6-dimethoxyphenyl)-3-(5-{2- [3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl]ethyl}-1,3,4-oxadiazol-2 -yl)pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5- [(5-methyl-2-phenyl-1,3-thiazol-4-yl) methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, 6-butyl-3-{5-[2-(3,4-dichlorophenyl)ethyl]-1,3,4 -oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol- 2-yl]-6-butyl-5-(2,6-dichlorophenyl)pyridine-2,4-diol, 6-butyl-3-{5-[(4-chlorophenyl)methyl]-1,3,4- oxadiazol-2-yl}-5-(2,6-dichlorophenyl)pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(dimethylamino)(4- fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, 3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol- 2-yl]-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)pyridine-2,4-diol, 3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazole- 2-yl}-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5- [(5 -methyl-2-phenyl-1,3-oxazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, 3-[5-(1,2- benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-cyclopropyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 3-{5-[(4- chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-6-cyclopropyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 6-cyclopropyl-5-(2,6- dimethoxyphenyl)-3-{5-[(2-methyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, 6-cyclopropyl -5-(2,6-dimethoxyphenyl)-3-(5-{[3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-1,3,4-oxadiazole -2-yl)pyridine-2,4-diol, 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3, Ethyl 4-oxadiazol-2-yl}acetate, 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5- [(1,3-dimethyl-1H-pyrazol-5-yl)methyl]- 1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, 3-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3 -yl]-1,3,4-oxadiazol-2-yl}methyl)-1-methylimidazolidine-2,4-dione, 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5- [( 3-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridin-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(piperidin-1 -ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{ [3-(pyridin- 3-yl)-1,2,4-oxadiazol-5-yl]methyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol, 6-butyl-5-(2,6 -dimethoxyphenyl)-3-{5- [(1-methyl-1H-pyrazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, 6-butyl- 3-{5-[(4-chloro-2-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 6- butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl]methyl}-1,3,4- oxadiazol-2-yl)pyridine-2,4-diol, 1-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1, 3,4-oxadiazol-2-yl}methyl)pyrrolidin-2-one, 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-{5-[(2-methyl-1,3-thiazole -4-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-(5-{ [5-(pyridin-2-yl)-1,2,4-oxadiazol-3-yl]methyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol, 3-{5 - [(3-benzyl-1,2,4-oxadiazol-5-yl)methyl]-1,3,4-oxadiazol-2-yl}-6-butyl-5-(2,6-dimethoxyphenyl)pyridine- 2,4-diol, 6-butyl-3-{5-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl)methyl]-1,3,4-oxadiazol-2-yl}-5 -(2,6-dimethoxyphenyl)pyridine-2,4-diol, 3-{5-[(6-chloropyridin-3-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-( 2,6-dimethoxyphenyl)-6-(ethoxymethyl)pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(3-phenyl-1,2,4 -oxadiazol-5-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, 1-({5-[5-(2,6-dimethoxyphenyl)-6-( ethoxymethyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)pyrrolidin-2-one, 3-({5-[6-butyl-5-( 2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)imidazolidine-2,4-dione, 1-({5-[6 -butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-1,2-dihydropyridin-2 -one, 6-butyl-5-(2,6-dimethoxyphenyl)-3- [5-(1H-imidazol-1-ylmethyl)- 1,3,4-oxadiazol-2-yl]pyridine-2,4- diol, 3-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl) -1,3-oxazolidin-2-one, 4-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]- 1,3,4 -oxadiazol-2-yl}methyl)morpholin-3-one, 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1, tert-butyl 3,4-oxadiazol-2-yl}acetate, 1-({5-[5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-2,4-dihydroxypyridin-3-yl ]-1,3,4-oxadiazol-2-yl}methyl)-1,2-dihydropyridin-2-one, N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)- tert-butyl 2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)carbamate, N-({5-[6-butyl-5-(2,6 tert-butyl-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-N-methylcarbamate, 3-{5-[(4- chloro-3-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)pyridine-2,4-diol, 3-{5- [(4-chloro-2-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)pyridine-2,4-diol, 5 -(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-{5-[(5-fluoropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4 -diol, 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-[5-(1H-imidazol-1-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2, 4-diol, 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-{5-[(3-fluoro-4-methylphenyl)methyl]-1,3,4-oxadiazol-2-yl} pyridine-2,4-diol, 3-{5-[(5-chloropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6 -(ethoxymethyl)pyridine-2,4-diol, 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-{5- [(3-phenyl-1H-pyrazol-1-yl)methyl]- 1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-(5-{ [3-(trifluoromethyl)- 1H -pyrazol-1-yl]methyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol, 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-{5 - [(1-methyl-1H-pyrazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, 5-(2,6-dimethoxyphenyl)-6- (ethoxymethyl)-3-{5-[(6-fluoropyridin-3-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, 5-(2,6-dimethoxyphenyl )-6-(ethoxymethyl)-3-[5-(1H-indazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol, 3-[5-(1H -1,2,3-benzotriazol-1-ylmethyl)-1,3,4-oxadiazol-2-yl]-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)pyridine-2,4-diol, 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-[5-(1H-indazol-1-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol , 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-{5-[(4-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol , 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3- [5-(1H-indol-1-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4- diol, 6-butyl-5-(3-ethylphenyl)-4-hydroxy-3-{5- [(2-methyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazole- 2-yl}-1,2-dihydropyridin-2-one, 3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl -5- phenylpyridine-2,4-diol, 6-butyl-3-{5-[(3,4-difluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(3-methoxyphenyl )pyridine-2,4-diol, 6-butyl-3-{5-[(3,4-difluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(3-ethylphenyl)pyridine -2,4-diol, 6-butyl-3-{5-[(3,4-difluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-[3-(trifluoromethoxy)phenyl] pyridine-2,4-diol, 5-[3-(benzyloxy)phenyl]-6-butyl-3-{5-[(3,4-difluorophenyl)methyl]-1,3,4-oxadiazol-2-yl }pyridine-2,4-diol, 6-butyl-3-{5- [(3,4-difluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5- [3-(hydroxymethyl) phenyl]pyridine-2,4-diol, 6-butyl-5-(cyclohex-1-en-1-yl)-3-{5-[(3,4-difluorophenyl)methyl]- 1,3, 4-oxadiazol-2-yl}pyridine-2,4-diol, 6-butyl-3-{5-[(3,4-difluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5 - [3-(propan-2-yl)phenyl]pyridine-2,4-diol, 6-butyl-3-{5-[(3,4-difluorophenyl)methyl]-1,3,4-oxadiazol-2 -yl}-5- [3-(methoxymethyl)phenyl]pyridine-2,4-diol, 3-(2-butyl-5-{5-[(3,4-difluorophenyl)methyl]-1,3,4 -oxadiazol-2-yl}-4,6-dihydroxypyridin-3-yl)-N-(propan-2-yl)benzamide, 6-butyl-4-hydroxy-3-{5-[(2-methyl -1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-[3-(propan-2-yl)phenyl]-1,2-dihydropyridin- 2-one, 3-(2-butyl-4-hydroxy-5-{5- [(2-methyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl }-6-oxo-1,6-dihydropyridin-3-yl)-N-(propan-2-yl)benzamide, 6-butyl-5-(3-cyclopropylphenyl)-4-hydroxy-3-{5 - [(2-methyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}-1,2-dihydropyridin-2-one, 6-butyl-4 -hydroxy-5-(3-methoxyphenyl)-3-{5- [(2-methyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}-1, 2-dihydropyridin-2-one, 6-butyl-4-hydroxy-5- [3-(hydroxymethyl)phenyl]-3-{5- [(2-methyl-1,3-thiazol-4-yl) methyl]-1,3,4-oxadiazol-2-yl}-1,2-dihydropyridin-2-one, 6-butyl-4-hydroxy-3-{5-[(2-methyl-1,3 -thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-[3-(pyrrolidin-1-yl)phenyl]-1,2-dihydropyridin-2-one, 6-Butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(methylamino)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, N-({ 5-[6-Butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-N-methyl-2 -phenylacetamide, N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )-3-chloro-N-methylbenzamide, N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]- 1,3,4- oxadiazol-2-yl}methyl)-N-methylpyridine-2-carboxamide, N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl] - 1,3,4-oxadiazol-2-yl}methyl)-2-methoxyacetamide, N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3 -yl]-1,3,4-oxadiazol-2-yl}methyl)-N-methylpyridine-4-carboxamide, N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2, 4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)pyridine-3-carboxamide, N-({5-[6-butyl-5-(2,6-dimethoxyphenyl )-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-2-chloro-N-methylbenzamide, N-({5-[6-butyl-5 -(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]- 1,3,4-oxadiazol-2-yl}methyl)-3-chlorobenzamide, N-({5-[6- butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-4-chlorobenzamide, N-({5- [6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)pyridine-4-carboxamide, N- ({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-N-methylpyridine -3-carboxamide, N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]- 1,3,4-oxadiazol-2-yl }methyl)-2-phenylacetamide, N-({5- [6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]- 1,3,4-oxadiazol- 2-yl}methyl)-2,2-dimethylpropanamide, N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]- 1,3 ,4-oxadiazol-2-yl}methyl)pyridine-2-carboxamide, N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl] - 1,3,4-oxadiazol-2-yl}methyl)-N,2,2-trimethylpropanamide, 3-[5-(aminomethyl)-1,3,4-oxadiazol-2-yl]-6-butyl- 5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl] - 1,3,4-oxadiazol-2-yl}methyl)benzamide, N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl] - 1,3,4-oxadiazol-2-yl}methyl)-N-methylbenzamide, N-({5-[5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-2,4-dihydroxypyridine -3-yl]-1,3,4-oxadiazol-2-yl}methyl)benzamide, N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridine -3-yl]-1,3,4-oxadiazol-2-yl}methyl)-3-methylbutanamide, N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4- dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide, N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4- dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-2,2,2-trifluoroacetamide, 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl )-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N,N-diethylacetamide, 2-{5-[6-butyl-5-(2,6 -dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-(pyridin-2-ylmethyl)acetamide, 2-{5-[6-butyl -5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-methylacetamide, 2-{5-[6-butyl -5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]- 1,3,4-oxadiazol-2-yl}acetamide, 2-{5-[6-butyl-5- (2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-(propan-2-yl)acetamide, 2-{5- [6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N,N-dimethylacetamide, 2-{ 5- [6-Butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]- 1,3,4-oxadiazol-2-yl}-N-(4-methoxyphenyl) acetamide, 4-(2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]- 1,3,4-oxadiazol-2-yl} acetyl)piperazin-2-one, 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2 -yl}-1-(4-methylpiperazin-1-yl)ethan-1-one, N-benzyl-2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-di -hydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}acetamide, 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin- 3-yl]-1,3,4-oxadiazol-2-yl}-N-ethylacetamide, 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin- 3-yl]-1,3,4-oxadiazol-2-yl}-N-cyclopropylacetamide, 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin- 3-yl]-1,3,4-oxadiazol-2-yl}-N-propylacetamide, 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin- 3-yl]-1,3,4-oxadiazol-2-yl}-N-(2-fluoroethyl)acetamide, 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4 -dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-(2,2-difluoroethyl)acetamide, 2-{5-[6-butyl-5-(2,6 -dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-(2,2,2-trifluoroethyl)acetamide, 2-{5-[6 -butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-(2-methoxyethyl)acetamide, 2- {5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-1-(pyrrolidin-1 -yl)ethan-1-one, 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]- 1,3,4-oxadiazole- 2-yl}-1-(piperidin-1-yl)ethan-1-one, 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3- yl]-1,3,4-oxadiazol-2-yl}-1-(morpholin-4-yl)ethan-1-one, N-butyl-2-{5-[6-butyl-5-(2, 6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}acetamide, 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl )-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-pentylacetamide, 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl )-2,4-dihydroxypyridin-3-yl]- 1,3,4-oxadiazol-2-yl}-1-(3-fluoroazetidin-1-yl)ethan-1-one, 2-{5- [6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]- 1,3,4-oxadiazol-2-yl}-1-(3,3-difluoroazetidin- 1-yl)ethan-1-one, 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]- 1,3,4-oxadiazole -2-yl}-N-(1,3-thiazol-2-yl)acetamide, 3-(3-benzyl-1,2,4-oxadiazol-5-yl)-6-butyl-5-(2, 6-dimethoxyphenyl)pyridine-2,4-diol, 6-butyl-3-{3-[(4-chlorophenyl)methyl]-1,2,4-oxadiazol-5-yl}-5-(2,6- dimethoxyphenyl)pyridine-2,4-diol, 3-(5-benzyl-4H-1,2,4-triazol-3-yl)-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2,4 -diol, 6-butyl-3-(5-{[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3,4-oxadiazol-2-yl)- 5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[5-(pyridin-4-yl)-1, 3,4-oxadiazol-2-yl]methyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-( 5-{[5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol, 6 -butyl-3-(5-{[5-(2-chlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3,4-oxadiazol-2-yl)-5-(2 ,6-dimethoxyphenyl)pyridine-2,4-diol, 3-{5- [(5-benzyl-1,3,4-oxadiazol-2-yl)methyl]-1,3,4-oxadiazol-2-yl }-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 6-butyl-3-(5-{ [5-(3-chlorophenyl)-1,3,4-oxadiazole- 2-yl]methyl}-1,3,4-oxadiazol-2-yl)-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl) -3-(5-{[5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl]methyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4 -diol, 1-({5-[6-(ethoxymethyl)-5-(4-fluoro-2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazole -2-yl}methyl)-1,2-dihydropyridin-2-one, 3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]- 6-(ethoxymethyl)-5-(4-fluoro-2,6-dimethoxyphenyl)pyridine-2,4-diol, 3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2 -yl}-6-(ethoxymethyl)- 5-(4-fluoro-2,6-dimethoxyphenyl)pyridine-2,4-diol, 1-({5-[6-(ethoxymethyl)-5-(4-fluoro -2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)pyrrolidin-2-one, 3-{5- [(6- chloropyridin-3-yl)methyl]-1,3,4-oxadiazol-2-yl}-6-(ethoxymethyl)-5-(4-fluoro-2,6-dimethoxyphenyl)pyridin-2,4-diol, 3 -{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(3,5-dimethoxypyridin-4-yl)-6-(ethoxymethyl)pyridine-2,4 -diol, 6-butyl-3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(3-fluoro-2,6-dimethoxyphenyl)pyridine-2 ,4-diol, 3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5-(3-fluoro-2,6- dimethoxyphenyl)pyridine-2,4-diol, 3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-6-(ethoxymethyl)- 5-(2-hydroxy- 6-methoxyphenyl)pyridine-2,4-diol, 3- [5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5- (2 ,6-dimethylphenyl)pyridine-2,4-diol, 3- [5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5- ( 2,4,6-trimethylphenyl)pyridine-2,4-diol, 3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl- 5-(2,6-diethylphenyl)pyridine-2,4-diol, 6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{ [1,2]oxazole [4,5-b] pyridin-3-ylmethyl}-1,3,4-oxadiazol-2-yl)pyridin-2,4-diol, 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-(5-{ [ 1,2]oxazolo [4,5- b]pyridin-3-ylmethyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol, 3-{5- [(4-chlorophenyl) methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dihydroxyphenyl)-6-(ethoxymethyl)pyridine-2,4-diol, 3-{5- [(5- chloropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-[(ethylamino)methyl]pyridin-2,4-diol, 3- {5-[(1,2-benzoxazol-3-yl)methyl]-1,3,4-thiadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)pyridine-2, 4-diol, 3-{5-[(5-chloropyridin-2-yl)methyl]-1,3,4-thiadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl) pyridine-2,4-diol, 3-{5-[(5-chloropyridin-2-yl)methyl]-1,3,4-thiadiazol-2-yl}-6-cyclopentyl-5-(2,6- dimethoxyphenyl)pyridine-2,4-diol, 3-{5-[(4-chlorophenyl)methyl]-1,3,4-thiadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-( ethoxymethyl)pyridine-2,4-diol, N-({5-[5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-2,4-dihydroxypyridin-3-yl]-1,3, 4-thiadiazol-2-yl}methyl)pyridine-2-carboxamide, 6-butyl-3-{5-[(5-chloro-3-fluoropyridin-2-yl)methyl]-1,3,4-oxadiazol- 2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 3-{5-[(5-chloro-3-fluoropyridin-2-yl)methyl]-1,3,4- oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)pyridine-2,4-diol, 3-{5-[(5-chloropyridin-2-yl)methyl]-1, 3,4-oxadiazol-2-yl}-6-cyclopentyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 3-{5-[(4-chlorophenyl)methyl]-1,3, 4-oxadiazol-2-yl}-6-cyclopentyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol, 3-{5-[(5-chloropyridin-2-yl)methyl]-1, 3,4-oxadiazol-2-yl}-5-(2,6- dimethoxyphenyl)-6- [(2-methoxyethoxy)methyl]pyridine-2,4-diol, 3-{5- [(1,2- benzoxazol-3-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-[(2-methoxyethoxy)methyl]pyridine-2,4-diol, 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-{5-[(phenylamino)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol, 3- {5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-[(2-methoxyethoxy)methyl]pyridine-2,4 -diol, N-({5-[6-butyl-5-(2,5-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl )benzamide, N- [(5-{6-butyl-2,4-dihydroxy-5- [2-methoxy-5-(propan-2-yl)phenyl]pyridin-3-yl}-1,3 ,4-oxadiazol-2-yl)methyl]benzamide, 3-{5-[(1,2-benzoxazol-3-yl)methyl]-1,3,4-oxadiazol-2-yl}-6-(ethoxymethyl )-5-(2-methoxyphenyl)pyridine-2,4-diol, 3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-6-(ethoxymethyl)- 5-(2-methoxyphenyl)pyridine-2,4-diol, N-({5-[6-butyl-5-(2,3-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]- 1 ,3,4-oxadiazol-2-yl}methyl)benzamide, N-({5-[6-(ethoxymethyl)-2,4-dihydroxy-5-(2-methoxyphenyl)pyridin-3-yl]- 1,3,4-oxadiazol-2-yl}methyl)benzamide, 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]- 1 ,3,4-oxadiazol-2-yl}-N-(pyridin-3-yl)acetamide, 2-{5-[5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-2,4-di -hydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-(1,3-thiazol-2-yl)acetamide, N-[(1,3-benzothiazol-2-yl) methyl]-2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}acetamide, 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-[( pyridin-3-yl)methyl]acetamide, 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazole -2-yl}-N-[(1,3-oxazol-2-yl)methyl]acetamide, 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-di- hydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-[2-(4-sulfamoylphenyl)ethyl]acetamide, 2-{5-[6-butyl-5-(2,6 -dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]- 1,3,4-oxadiazol-2-yl}-N-[2-(2-chlorophenyl)ethyl]acetamide, 2-{5-[ 6-Butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-[(3-chlorophenyl)methyl] acetamide, N-benzyl-2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl }-N-methylacetamide, 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl }-N-methyl-N-(2-phenylethyl)acetamide, 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1, 3,4-oxadiazol-2-yl}-N-(prop-2-yn-1-yl)acetamide, 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4- dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-(3-methyl-1H-pyrazol-5-yl)acetamide, 2-{5-[6-butyl-5 -(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]- 1,3,4-oxadiazol-2-yl}-N- [(2-methylphenyl)methyl]acetamide, 2-{ 5-[6-Butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-[(2-chlorophenyl )methyl]acetamide, 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl} -N- [(4-chlorophenyl)methyl]acetamide, 2-{5- [6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]- 1,3, 4-oxadiazol-2-yl}-N-[2-(4-chlorophenyl)ethyl]acetamide, 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin -3-yl]- 1,3,4-oxadiazol-2-yl}-N- [(pyridin-4-yl)methyl]acetamide, 2-{5- [6-butyl-5-(2,6- dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-[(4-methoxyphenyl)methyl]acetamide, 2-{5-[6-butyl -5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]- 1,3,4-oxadiazol-2-yl}-N-{[4-(dimethylamino)phenyl]methyl} acetamide, 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N- [(5-methyl-1,3,4-oxadiazol-2-yl)methyl]acetamide, 271 2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridine -3-yl]- 1,3,4-oxadiazol-2-yl}-N-{ [3-(propan-2-yl)-1,2-oxazol-5-yl]methyl}acetamide, 2-{ 5-[6-Butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-[(4-sulfamoylphenyl )methyl]acetamide, 3-{5-[(5-chloropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}-6-(ethoxymethyl)-5-(2-hydroxy-6 -methoxyphenyl)pyridine-2,4-diol, 3-{5-[(5-chloropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}-6-(ethoxymethyl)-5- (2-hydroxy-6-methoxyphenyl)pyridine-2,4-diol and 3-{5- [(5-chloropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}-5- (2,6-dihydroxyphenyl)-6-(ethoxymethyl)pyridine-2,4-diol. 12. Compound, according to claim 1, characterized by the fact that it has the structure: or a pharmaceutically acceptable salt thereof. 13. Compound, according to claim 1, characterized by the fact that it has the structure: or a pharmaceutically acceptable salt thereof. 14. Compound, according to claim 1, characterized by the fact that it has the structure: or a pharmaceutically acceptable salt thereof. 15. Compound, according to claim 1, characterized by the fact that it has the structure: or a pharmaceutically acceptable salt thereof. 16. Compound, according to claim 1, characterized by the fact that it has the structure: or a pharmaceutically acceptable salt thereof. 17. Compound, according to claim 1, characterized by the fact that it has the structure: or a pharmaceutically acceptable salt thereof. 18. Compound, according to claim 1, characterized by the fact that it has the structure: or a pharmaceutically acceptable salt thereof. 19. Compound, according to claim 1, characterized by the fact that it has the structure: or a pharmaceutically acceptable salt thereof. 20. Compound, according to claim 1, characterized by the fact that it has the structure: or a pharmaceutically acceptable salt thereof. 21. Compound, according to claim 1, characterized by the fact that it has the structure: or a pharmaceutically acceptable salt thereof. 22. Pharmaceutical composition, characterized by the fact that it comprises a pharmaceutically acceptable carrier and compound as defined in any one of claims 1 to 21, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof. 23. Use of a compound, as defined in any one of claims 1 to 21, characterized by the fact that it is for preparing a composition or medicine for the treatment of cardiovascular diseases, wherein said cardiovascular diseases are coronary heart disease, stroke cerebral, heart failure, systolic heart failure, diastolic heart failure, diabetic heart failure, heart failure with preserved ejection fraction, cardiomyopathy, myocardial infarction, left ventricular dysfunction, left ventricular dysfunction after myocardial infarction, cardiac hypertrophy, myocardial remodeling, remodeling myocardium after infarction or after cardiac surgery and valvular heart disease.