TREA

Aryl and heteroaryl compounds and methods to modulate coagulation

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  • Patent Application
  • 20040110832
  • Publication Number
    20040110832
  • Date Filed
    August 08, 2003
    21 years ago
  • Date Published
    June 10, 2004
    20 years ago
Information
Abstract
This invention provides certain compounds, methods of their preparation, pharmaceutical compositions comprising the compounds, and their use in treating human or animal disorders. The compounds of the invention are useful as antagonists, or more preferably, partial antagonist of factor IX and thus, may be used to inhibit the intrinsic pathway of blood coagulation. The compounds are useful in a variety of applications including the management, treatment and/or control of diseases caused in part by the intrinsic clotting pathway utilizing factor IX. Such diseases or disease states include stroke, myocardial infarction, aneurysm surgery, and deep vein thrombosis associated with surgical procedures, long periods of confinement, and acquired or inherited pro-coagulant states.
Description


FIELD OF THE INVENTION

[0002] This invention relates to compounds which are antagonists of the intrinsic clotting pathway by binding to and inhibiting the function of factor IX.


BACKGROUND OF THE INVENTION

[0003] Hemostasis, the arrest of bleeding from an injured blood vessel, requires the concerted activity of vascular, platelet, and plasma factors to eventually form a hemostatic seal or a blood clot. In normal hemostasis, the combined activity of these factors is counterbalanced by regulatory mechanisms to limit the accumulation of platelets and fibrin in the area of injury.

[0004] Upon injury to a blood vessel, vascular factors reduce blood flow from the blood vessel by local vasoconstriction and compression of injured vessels. At the same time, platelets adhere to the site of vessel wall injury and form aggregates called hemostatic plugs, which form the first key element of the hemostatic seal. Platelets also release factors that provide surface membrane sites and components for the formation of enzyme/cofactor complexes in blood coagulation reactions. Through a series of interacting and propagating zymogen activations, the activated form of one plasma factor catalyzes the activation of the next plasma factor. This cascade of blood coagulation reactions eventually forms a fibrin clot. The fibrin clot, an insoluble fibrin matrix that radiates from and anchors the hemostatic plug, is the second key element of the hemostatic seal

[0005] Specifically, the cascade of blood coagulation reactions discussed involvse two interdependent pathways, an intrinsic pathway and an extrinsic pathway. Each pathway ultimately catalyzes the proteolytic activation of factor X to factor Xa.

[0006] Damage to the blood vessel or a negatively charged surface initiates blood clotting by the intrinsic pathway. As seen in FIG. 1, the major components of the intrinsic pathway include factor VIII, a non-enzymatic co-factor, and factors IX and XI, zymogen serine proteases. The initiation of the intrinsic pathway results in the activation of factor XI to XIa. Factor XIa, as well as the presence of the factor VIIa/tissue factor complex involved in the extrinsic pathway, catalyzes the activation of factor IX to factor IXa. The presence of factor IXa, in combination with the activated form of factor VIII on an appropriate phospholipid

[0007] surface, results in the formation of a tenase complex (10). The tenase complex catalyzes the formation of factor Xa from its zymogen, factor X.

[0008] Exposure of blood to injured tissue initiates blood clotting by the extrinsic pathway. As is shown in FIG. 1, the major components of the extrinsic pathway are factor VII, a zymogen serine protease, and tissue factor, a membrane bound protein. Tissue factor serves as the requisite non-enzymatic co-factor for factor VII. The initiation of the extrinsic pathway is thought to be an autocatalytic event resulting from the activation of factor VII by trace levels of activated factor VII (factor VIIa), both of which are bound to newly exposed tissue factor on membrane surfaces at sites of vascular damage (20). The factor VIIa/tissue factor complex directly catalyzes the formation of factor Xa from factor X.

[0009] Once the initial intrinsic or extrinsic cascade results in the activation of factor X, factor Xa catalyzes the penultimate step in the blood coagulation cascade, the formation of serine protease thrombin. As seen in FIG. 2, thrombin formation occurs when a prothrombinase complex, comprising of factor Xa, the non-enzymatic co-factor Va and the substrate prothrombin, is assembled on an appropriate phospholipid surface (30). Once formed, thrombin functions as part of a feedback loop, controlling the activation of factors V and VIII. It additionally catalyzes both the activation of factor VIII and the conversion of fibrinogen to fibrin. Finally, the factor VIIIa interacts with fibrin to catalyze the formation of a thrombus, or crosslinked fibrin clot.

[0010] In normal hemostasis, the process of clot formation (blood coagulation) and clot dissolution (fibrinolysis) is delicately balanced. A slight imbalance between the processes of clot formation and dissolution can lead to excessive bleeding or thrombosis. Many significant disease states are related to abnormal hemostasis. With respect to the coronary arterial vasculature, abnormal thrombus formation due to the rupture of an established atherosclerotic plaque is the major cause of acute myocardial infarction and unstable angina. Moreover, treatment of an occlusive coronary thrombus by either thrombolytic therapy or percutaneous transluminal coronary angioplasty (PTCA) is often accompanied by an acute thrombotic reclosure of the affected vessel which requires immediate resolution. With respect to the venous vasculature, a high percentage of patients undergoing major surgery in the lower extremities or the abdominal area suffer from thrombus formation in the venous vasculature which can result in reduced blood flow to the affected extremity and a predisposition to pulmonary embolism. Disseminated intravascular coagulopathy commonly occurs within both vascular systems during septic shock, certain viral infections and cancer and is characterized by the rapid consumption of coagulation factors and systemic coagulation which results in the formation of life-threatening thrombi occurring throughout the vasculature leading to widespread organ failure.

[0011] Pathogenic thrombosis in the arterial vasculature is a major clinical concern in today's medicine. It is the leading cause of acute myocardial infarction which is one of the leading causes of death in the western world. Recurrent arterial thrombosis also remains one of the leading causes of failure following enzymatic or mechanical recanalization of occluded coronary vessels using thrombolytic agents or percutaneous transluminal coronary angioplasty (PTCA), respectively (Ross, A. M., Thrombosis in Cardiovascular Disorder, p. 327, W. B. Saunders Co. (Fuster, V. and Verstraete, M. edit. 1991); Califf, R. M. and Willerson, J. T., Id. at p 389]. In contrast to thrombotic events in the venous vasculature, arterial thrombosis is the result of a complex interaction between fibrin formation resulting from the blood coagulation cascade and cellular components, particularly platelets, which make up a large percentage of arterial thrombi. Heparin, the most widely used clinical anticoagulant administered intravenously, has not been shown to be universally effective in the treatment or prevention of acute arterial thrombosis or rethrombosis [Prins, M. H. and Hirsh, J., J. Am. Coll. Cardiol., 67: 3A (1991)].

[0012] Besides the unpredictable, recurrent thrombotic reocclusion which commonly occurs following PTCA, a profound restenosis of the recanalized vessel occurs in 30 to 40% of patients 1 to 6 months following this procedure [Califf, R. M. et al., J. Am. Coll. Cardiol., 17: 2B (1991)]. These patients require further treatment with either a repeat PTCA or coronary artery bypass surgery to relieve the newly formed stenosis. Restenosis of a mechanically damaged vessel is not a thrombotic process but instead is the result of a hyperproliferative response in the surrounding smooth muscle cells which over time results in a decreased luminal diameter of the affected vessel due to increased muscle mass. Id. As for arterial thrombosis, there is currently no effective pharmacologic treatment for the prevention of vascular restenosis following mechanical recanalization.

[0013] Numerous strategies have been developed for the treatment of thrombotic disorders. Many antithrombotic therapies are based on interference in the hemostatic system. This approach carries the inherent risk of bleeding, since the hemostatic system is no longer fully responsive to potential injury. Therefore, antithrombotic benefits are normally associated with antihemostatic risks. In attempts to improve the benefit-to-risk ratio, antithrombotic agents are continuously being developed. Various antithrombotic strategies include administering general inhibitors of thrombin formation such as heparin or vitamin K antagonists; administering specific thrombin inhibitors; administering specific factor Xa inhibitors; and administering inhibitors of platelet activation and adhesion.

[0014] Evaluation of current antithrombotic strategies in terms of antithrombotic benefits versus antihemostatic risks reveals that the benefit-to-risk ratio tends to be more favorable for strategies that interfere with one specific step rather than in a more general phase of the hemostatic system [L. A. Harker, Biomedical Progress vol 8, 1995, 17-26]. For example, the development of inhibitors specific for factor Xa is an improvement from general and specific thrombin inhibitors. But, this approach still blocks the common (intrinsic and extrinsic) pathway of thrombin generation (see FIG. 1), and thereby thrombin-dependent platelet activation. Thus, a need exists for more specific antithrombotic agents that selectively inhibit one single hemostatic pathway, while leaving other pathways unaffected.


SUMMARY OF THE INVENTION

[0015] The present invention provides compositions and methods for the treatment of cardiovascular diseases. More particularly, the present invention relates to modifying thrombus formation and growth by administering an agent or agents that inhibit the clotting activity of factor IX in the intrinsic clotting pathway. Embodiments of the present invention provide compounds of Formula (I) as depicted below. Embodiments of the present invention also provide methods for the preparation of compounds of Formula (I); pharmaceutical compositions comprising compounds of Formula (I); and methods for the use of compounds of Formula (I) and pharmaceutical compositions comprising compounds of Formula (I) in treating human or animal disorders. Compounds of Formula (I) are useful as modulators of the intrinsic clotting pathway by inhibiting the biological activity of factor IX. Compounds of Formula (I) are useful in a variety of applications including management, treatment, control, and/or as an adjunct of diseases in humans caused in part by the intrinsic clotting pathway utilizing factor IX. Such diseases or disease states include cardiopulmonary bypass, stroke, myocardial infarction, deep vein thrombosis associated with surgical procedures or long periods of confinement, acute and chronic inflammation and clotting associated with hemodialysis.






BRIEF DESCRIPTION OF THE FIGURES

[0016] The present invention will be described with reference to the accompanying drawings, wherein:

[0017]
FIG. 1 is a diagram depicting the steps involved in the intrinsic and extrinsic blood clotting cascades, from time of trauma to the activation of factor X.

[0018]
FIG. 2 is a diagram depicting the steps following initial intrinsic and extrinsic blood clotting cascades, beginning with the formation of Xa and culminating in the formation of a thrombus.






DETAILED DESCRIPTION

[0019] Two blood coagulation pathways are associated with normal hemostasis: intrinsic and extrinsic. These two coagulation pathways converge in the formation of factor Xa. But, these two coagulation pathways are interdependent because complete elimination of the intrinsic pathway leads to uncontrolled bleeding. For example, Type B hemophiliacs completely lack factor IX or factor IX function and have a phenotype characterized by a severe bleeding disorder. Thus, the direct factor VIIa/tissue factor activation of factor X, which bypasses the need for factor VIII and factor IX, is insufficient for normal hemostasis. Conversely, formation of the factor VIIIa/IXa phospholipid factor X activator (tenase complex) (20) is essential for normal hemostasis.

[0020] Selective inhibition of the intrinsic pathway of coagulation with a factor IX antagonist can provide a method to inhibit the clotting cascade associated with some surgery, stroke, myocardial infarction and hemodialysis while leaving the clotting pathway associated with external lesions such as trauma or abscess intact. Factor IX is primarily associated with the intrinsic clotting pathway. A specific antagonist of factor IX should have a therapeutic benefit in diseases associated with intrinsic pathway clotting by inhibiting intravascular thrombosis. Also, a specific antagonist of factor IX should not have the side effect of unwanted or uncontrollable bleeding by impairing extravascular hemostasis associated with wound healing.

[0021] Some point mutations in factor IX partially inhibit its function and result in a mild or moderate phenotype manifested as a non-life threatening bleeding disorder [Bowen, D. J., J. Clin. Pathol: Mol. Pathol. 55:1-18 (2002)]. These point mutations cause factor IX to behave as if it were subject to a partial antagonist. In the presence of a partial antagonist, factor IX should maintain some activity, even at saturation levels of the partial antagonist. As a result of the point mutations in factor IX, its activity is reduced along with clotting associated with the intrinsic pathway, but some residual activity remains that leaves the extrinsic pathway intact.

[0022] The present invention provides compositions and methods that inhibit the clotting activity of factor IX. Inhibition of hemostasis with agents that selectively inhibit the intrinsic pathway of factor X activation should leave the extrinsic pathway intact and allow the formation of small, but hemostatically important amounts of factor Xa and thrombin.

[0023] Embodiments of the present invention provide compounds of Formula (I) as depicted below. Embodiments of the present invention also provide methods of the preparation of compounds of Formula (I); pharmaceutical compositions comprising compounds of Formula (I); and methods for the use of compounds of Formula (I) and pharmaceutical compositions comprising compounds of Formula (I) in treating human or animal disorders. Compounds of the Formula (I) are useful as modulators of the intrinsic clotting pathway by inhibiting the biological activity of factor IX. Compounds of Formula (I) are useful in a variety of applications including management, treatment, control, and/or as an adjunct of diseases in humans caused in part by the intrinsic clotting pathway utilizing factor IX. Such diseases or disease states include cardiopulmonary bypass, stroke, myocardial infarction, deep vein thrombosis associated with surgical procedures or long periods of confinement, acute and chronic inflammation and clotting associated with hemodialysis.

[0024] In a first aspect, the present invention provides a compound comprising at least one moiety of the formula I. Such compounds are useful in a variety of applications including for the management, treatment, control, and/or as an adjunct of diseases in humans caused in part by the intrinsic clotting pathway utilizing factor IX, will be discussed in more detail below.

[0025] In one aspect, the present invention provides compounds which are represented by Formula I:
1

[0026] wherein c is equal to 0, 1, or 2; wherein the values of 0, 1, and 2 comprise a direct bond, —CH2—, and —CH2—CH2—, optionally substituted 1 to 4 times with a substituent group, wherein said substituent group(s) or the term substituted refers to groups comprising: -alkyl, -aryl, -alkylene-aryl, -arylene-alkyl, -alkylene-arylene-alkyl, —O-alkyl, —O-aryl, or hydroxyl. In preferred embodiments, c is equal to 0 or 1. In especially preferred embodiments, c is equal to 0.

[0027] G comprises: -hydrogen, —CO2R1, —CH2OR1, —C(O)—R1, —C(R1)═N—O—R2, or an acid isostere; wherein R1 and R2 independently comprise: -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or -alkylene-arylene-alkyl. In preferred embodiments, G comprises: -hydrogen or —CO2R1; wherein R1 comprises: -hydrogen, -alkyl, or -aryl. In especially preferred embodiments, G comprises: -hydrogen or —CO2H.

[0028] V comprises: (CH2)b—O—(CH2)a—, —(CH2)b—N(R7)(CH2)a, —(CH2)b—O—, —(CH2)b—N(R7), —(CH2)a—, or a direct bond; in which a is equal to 0, 1, or 2, b is equal to 1 or 2, and R7 comprises: -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or -alkylene-arylene-alkyl; wherein the values of 0, 1, and 2 comprise a direct bond, —CH2—, and —CH2—CH2—, optionally substituted 1 to 4 times with a substituent group, wherein said substituent group(s) or the term substituted refers to groups comprising: -alkyl, -aryl, -alkylene-aryl, -arylene-alkyl, -alkylene-arylene-alkyl, —O-alkyl, —O-aryl, or -hydroxyl. In preferred embodiments, V comprises: —(CH2)a—, —(CH2)b—O—(CH2)a—, or a direct bond, wherein a is equal to 1 or 2, and b is equal to 1. In especially preferred embodiments, V comprises: —(CH2)a— or a direct bond, wherein a is equal to 1.

[0029] X comprises: —N(R8)—, —CON(R8)—, —N(R8)CO—, —N(R8)CON(R9)—, —OC(O)N(R8)—, —SO2N(R8)—, or —N(R8)SO2N(R9)—; wherein R8 and R9 independently comprise: -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, -alkylene-arylene-alkyl, -alkylene-cycloalkylene-C(O)-alkylene-aryl, -alkylene-heterocyclylene-C(O)-alkylene-aryl, -alkylene-C(H)(R10)(R11), or -alkylene-N—(R10)(R11),

[0030] wherein R10 comprises H, alkyl, alkylene-aryl, alkylene-heteroaryl, aryl, or heteroaryl, and R11 comprises H, -alkyl, -alkylene-aryl, -alkylene-heteroaryl, -aryl, -heteroaryl, —C(O)—O-alkyl, —C(O)—O-alkylene-aryl, —C(O)—O-alkylene-heteroaryl, —C(O)-alkyl, —C(O)-alkylene-aryl, —C(O)-alkylene-heteroaryl, —S(O)2-alkyl, —S(O)2-aryl, , —S(O)2-heteroaryl, —S(O)2-alkylene-aryl, —S(O)2-alkylene-heteroaryl, —S(O)2—NH-alkyl, —S(O)2—NH-alkylene-aryl, —S(O)2—NH-alkylene-heteroaryl, —S(O)2—NH-aryl, or —S(O)2—NH-heteroaryl;

[0031] R10 and R11 may be taken together to form a ring having the formula —(CH2)m-Z-(CH2)n-bonded to the nitrogen or carbon atom to which R10 and R11 are attached, wherein m and n are, independently, 1, 2, 3, or 4; Z independently comprises —CH2—, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O2)—, —CON(H)—, —NHC(O)—, —NHC(O)N(H)—, —NH(SO2)—, —S(O2)N(H)—, —(O)CO—, —NHS(O2)NH—, —OC(O)—, —N(R12)—, —N(C(O)R12)—, —N(C(O)NHR12)—, —N(S(O2)NHR12)—, —N(SO2R12)—, or —N(C(O)OR12)—; or

[0032] R10 and R11 may be taken together, with the nitrogen or carbon atom to which they are attached, to form a heterocyclyl or heteroaryl ring.

[0033] R12 comprises hydrogen, aryl, alkyl, or alkylene-aryl;

[0034] In preferred embodiments, X comprises: —N(R8)—, —CON(R8)—, —N(R8)CO—, or —N(R8)CON(R9)—, wherein R8 and R9 independently comprise: -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or -alkylene-arylene-alkyl. In especially preferred embodiments, X comprises: —N(R8)—, —CON(R8)—, or —N(R8)CO—, wherein R8 comprises: -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or -alkylene-arylene-alkyl.

[0035] Ar1 comprises an aryl, heteroaryl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl, or fused heterocyclylheteroaryl group optionally substituted 1 to 7 times. In preferred embodiments, Ar1 comprises a mono- or bicyclic aryl or heteroaryl group optionally substituted 1 to 7 times. In especially preferred embodiments, Ar1 comprises a phenyl group having 1 to 5 substituents, wherein the substituents independently comprise:

[0036] a) -fluoro;

[0037] b) -chloro;

[0038] c) -bromo;

[0039] d) -iodo;

[0040] e) -cyano;

[0041] f) -nitro;

[0042] g) -perfluoroalkyl;

[0043] h) -D1-R13;

[0044] i) -alkyl;

[0045] j) -aryl;

[0046] k) -heteroaryl;

[0047] l) -heterocyclyl;

[0048] m) -cycloalkyl;

[0049] n) -alkylene-aryl;

[0050] o) -alkylene-heteroaryl;

[0051] p) -alkylene-arylene-D1-R13;

[0052] q) -alkylene-heteroarylene-D1-R13;

[0053] r) -alkylene-arylene-aryl;

[0054] s) -alkylene-heteroarylene-aryl;

[0055] t) -alkylene-arylene-heteroaryl

[0056] u) -alkylene-arylene-arylene-D1-R13;

[0057] v) -alkylene-arylene-alkyl;

[0058] w) -alkylene-heteroarylene-alkyl;

[0059] x) -arylene-alkyl;

[0060] y) -arylene-cycloalkyl;

[0061] z) -heteroarylene-alkyl;

[0062] aa) -arylene-arylene-alkyl;

[0063] bb) -D1-alkyl;

[0064] cc) -D1-aryl;

[0065] dd) -D1-heteroaryl;

[0066] ee) -D1-arylene-D2-R14;

[0067] ff) -D1-heteroarylene-D2-R14;

[0068] gg) -D1-alkylene-heteroaryl;

[0069] hh) -D1-alkylene-aryl;

[0070] ii) -D1-alkylene-arylene-D2-R14

[0071] jj) -D1-alkylene-heteroarylene-D2-R14

[0072] kk) -D1-arylene-alkyl;

[0073] ll) -D1-heteroarylene-alkyl;

[0074] mm) -D1-alkylene-arylene-aryl;

[0075] nn) -D1-alkylene-heteroarylene-aryl;

[0076] oo) -D1-arylene-arylene-aryl;

[0077] pp) -D1-alkylene-arylene-alkyl;

[0078] qq) -D1-alkylene-heteroarylene-alky

[0079] ss) -alkylene-D1-alkylene-aryl;

[0080] tt) -alkylene-D1-alkylene-arylene-D2-R14

[0081] uu) -arylene-D1-alkyl;

[0082] vv) -arylene-D1-cycloalkyl;

[0083] ww) -arylene-D1-heterocyclyl;

[0084] xx) -alkylene-D1-aryl;

[0085] yy) -alkylene-D1-heteroaryl;

[0086] zz) -alkylene-D1-arylene-D2-R14

[0087] aaa) -alkylene-D1-heteroarylene-D2-R14

[0088] bbb) -alkylene-D1-heteroaryl;

[0089] ccc) -alkylene-D1-cycloalkyl;

[0090] ddd) -alkylene-D1-heterocyclyl;

[0091] eee) -alkylene-D1-arylene-alkyl;

[0092] fff) -alkylene-D1-heteroarylene-alkyl;

[0093] ggg) -alkylene-D1-alkylene-arylene-alkyl;

[0094] hh) -alkylene-D1-alkylene-heteroarylene-alkyl;

[0095] iii) -alkylene-D1-alkyl;

[0096] jjj) -alkylene-D1-R13;

[0097] kkk) -arylene-D1-R13;

[0098] lll) -heteroarylene-D1-R13; or

[0099] mmm) -hydrogen;

[0100] wherein D1 comprises —CH2—, -alkylene-, -alkenylene-, -alkylene-S—, —S-alkylene-, -alkylene-O—, —O-alkylene-, -alkylene-S(O)2—, —S(O)2-alkylene,

[0101] —O—, —N(R15)—, —C(O)—, —CON(R15)—, —N(R15)C(O)—, —N(R15)CON(R16)—, —N(R15)C(O)O—, —OC(O)N(R15)—, —N(R15)SO2—, —SO2N(R15)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O2)—, —N(R15)SO2N(R16)—,
2

[0102] and wherein R13, R15, R16, and R17 independently comprise: -hydrogen, -alkyl, -aryl, -heteroaryl, -arylene-alkyl, -heteroarylene-alkyl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene-arylene-alkyl, or -alkylene-heteroarylene-alkyl.

[0103] D2 comprises —CH2—, -alkylene-, -alkenylene-, -alkylene-S—, —S-alkylene-, -alkylene-O—, —O-alkylene-, -alkylene-S(O)2—, —S(O)2-alkylene, —O—, —N(R25)—, —C(O)—, —CON(R25)—, —N(R18)C(O)—, —N(R18)CON(R19)—, —N(R18)C(O)O—, —OC(O)N(R18)—, —N(R18)SO2—, —SO2N(R18)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O2)—, —N(R18)SO2N(R19)—, and wherein R18 and R19 independently comprise: -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or -alkylene-arylene-alkyl.

[0104] R14 comprises -hydrogen, -alkyl, -aryl, -heteroaryl, -arylene-alkyl, -heteroarylene-alkyl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene-arylene-alkyl, or -alkylene-heteroarylene-alkyl.

[0105] The most preferred embodiments of Ar1 are those in which Ar1 comprises a monosubstituted phenyl group wherein the substituent comprises: -aryl, -arylene-alkyl, -D1-aryl, -D1-alkylene-arylene-alkyl, or -arylene-D1-alkyl; wherein D1 comprises —O—, —N(R15)—, CON(R15)—, or —N(R15)C(O)—, and wherein R15 comprises: -hydrogen; -alkyl; or -aryl.

[0106] Ar2 comprises an aryl or heteroaryl group optionally substituted 1 to 7 times. In preferred embodiments, Ar2 comprises a phenyl, naphthyl, pyridyl, isoquinolyl, pyrimidyl or quinazolyl group optionally substituted 1 to 7 times. In especially preferred embodiments, Ar2 comprises a substituted phenyl, 2-naphthyl, 2-pyridyl, 3-isoquinolyl, 2-pyrimidyl or 2-quinazolyl group having 1 to 5 substituents wherein the substituents independently comprise:

[0107] a) -fluoro;

[0108] b) -chloro;

[0109] c) -bromo;

[0110] d) -iodo;

[0111] e) -cyano;

[0112] f) -nitro;

[0113] g) -perfluoroalkyl;

[0114] h) -T1-R20;

[0115] i) -alkyl;

[0116] j) -aryl;

[0117] k) -heteroaryl;

[0118] l) -heterocyclyl;

[0119] m) -cycloalkyl;

[0120] n) -alkylene-aryl;

[0121] o) -alkylene-arylene-aryl;

[0122] p) -alkylene-arylene-alkyl;

[0123] q) -arylene-alkyl;

[0124] r) -arylene-aryl;

[0125] s) -arylene-heteroaryl;

[0126] t) -heteroarylene-aryl;

[0127] u) -heteroarylene-heteroaryl;

[0128] v) -heteroarylene-heterocyclyl

[0129] w) -arylene-heterocyclyl

[0130] x) -arylene-arylene-alkyl;

[0131] y) -T1-alkyl;

[0132] z) -T1-aryl;

[0133] aa) -T1-alkylene-aryl;

[0134] bb) -T1-alkenylene-aryl;

[0135] cc) -T1-alkylene-heteroaryl;

[0136] dd) -T1-alkenylene-heteroaryl;

[0137] ee) -T1-cycloalkylene-aryl;

[0138] ff) -T1-cycloalkylene-heteroaryl;

[0139] gg) -T1-heterocyclylene-aryl;

[0140] hh) -T1-heterocyclylene-heteroaryl;

[0141] ii) -T1-arylene-alkyl;

[0142] jj) -T1-arylene-alkenyl;

[0143] kk) -T1-alkylene-arylene-aryl;

[0144] ll) -T1-arylene-T2-aryl;

[0145] mm) -T1-arylene-arylene-aryl;

[0146] nn) -T1-alkylene-arylene-alkyl;

[0147] oo) -alkylene-T1-alkylene-aryl;

[0148] pp) -arylene-T1-alkyl;

[0149] qq) -arylene-T1-alkylene-aryl;

[0150] rr) -T1-alkylene-T2-aryl;

[0151] ss) -T1-alkylene-aryl;

[0152] tt) -alkylene-T1-heteroaryl;

[0153] uu) -alkylene-T1-cycloalkyl;

[0154] vv) -alkylene-T1-heterocyclyl;

[0155] ww) -alkylene-T-arylene-alkyl;

[0156] xx) -alkylene-T1-alkylene-arylene-alkyl;

[0157] yy) -alkylene-T1-alkyl;

[0158] zz) -alkylene-T1-R20;

[0159] aaa) -arylene-T1-R20; or

[0160] bbb) -hydrogen;

[0161] wherein T1 comprises —CH2—, —O—, —N(R21)—, —C(O)—, —CON(R21)—, —N(R21)C(O)—, —N(R21)CON(R22)—, —N(R21)C(O)O—, —OC(O)N(R21)—, —N(R21)SO2—, —SO2N(R21)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O2)—, —N(R21)SO2N(R22)—,
3

[0162] and wherein R20, R21, R22 and R23, independently comprise: -hydrogen, -alkyl, -alkenyl, -alkylene-cycloalkyl, -alkynene-heterocyclyl, -aryl, -heteroaryl, -arylene-alkyl, -alkylene-aryl, -alkylene-arylene-alkyl, -alkylene-arylene-aryl, -alkylene-arylene-alkylene-aryl, -alkylene-arylene-O-arylene, or alkylene-arylene-O-alkylene-aryl; and

[0163] wherein T2 comprises a direct bond, —CH2—, —O—, —N(R24)—, —C(O)—, —CON(R24)—, —N(R24)C(O)—, —N(R24)CON(R25)—, —N(R24)C(O)O—, —OC(O)N(R24)—, —N(R24)SO2—, —SO2N(R24)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O2)—, —N(R24)SO2N(R25)—, wherein R24 and R25 independently comprise; -hydrogen, -alkyl, -alkenyl, -alkylene-cycloalkyl, alkynene-heterocyclyl, -aryl, -heteroaryl, -arylene-alkyl, -alkylene-aryl, and -alkylene-arylene-alkyl.

[0164] The most preferred embodiments of Ar2 are those in which Ar2 comprises a substituted phenyl, 2-naphthyl, 2-pyridyl, 3-isoquinolyl, 2-pyrimidyl or 2-quinazolyl group having 1 to substituents independently comprising:

[0165] a) -fluoro;

[0166] b) -chloro;

[0167] c) -bromo;

[0168] d) -iodo;

[0169] e) -cyano;

[0170] f) -nitro;

[0171] g) -perfluoroalkyl;

[0172] h) -T1-R20;

[0173] i) -alkyl;

[0174] j) -aryl;

[0175] k) -arylene-alkyl;

[0176] l) -T1-alkyl;

[0177] m) -T1-alkylene-aryl;

[0178] n) -T1-alkylene-arylene-aryl;

[0179] o) -T1-alkylene-arylene-alkyl;

[0180] p) -arylene-T1-alkyl; or

[0181] q) -hydrogen;

[0182] wherein T1 comprises —CH2—, —O—, —N(R21)—, —CON(R21)—, or —N(R21)C(O)—; wherein R20 and R21 independently comprise: -hydrogen, -alkyl, or -aryl.

[0183] The alkyl, aryl, heteroaryl, alkylene, and arylene groups in Ar1, Ar2, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, and R23 may be optionally substituted 1 to 4 times with a substituent group, wherein said substituent group(s) or the term substituted refers to groups comprising:

[0184] a) -hydrogen;

[0185] b) -fluoro;

[0186] c) -chloro;

[0187] d) -bromo;

[0188] e) -iodo;

[0189] f) -cyano;

[0190] g) -nitro;

[0191] h) -perfluoroalkyl;

[0192] i) -Q-perfluoroalkyl

[0193] j) -Q-R24;

[0194] k) -Q-alkyl;

[0195] l) -Q-aryl;

[0196] m) -Q-alkylene-aryl;

[0197] n) -Q-alkylene-NR25R26; or

[0198] o) -Q-alkyl-W—R27;

[0199] wherein Q and W independently comprise: —CH2—, —O—, —N(R28)—, —C(O)—, —CON(R28)—, —N(R28)C(O)—, —N(R28)CON(R29)—, —N(R28)C(O)O—, —OC(O)N(R28)—, —N(R28)SO2—, —SO2N(R28)—, —C(O)—O—, —O—C(O)—, or —N(R28)SO2N(R29)—, wherein R24, R25, R26, R27, R28, and R29 independently comprise: -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or -alkylene-arylene-alkyl.

[0200] Also included within the scope of the invention are the individual enantiomers of the compounds represented by Formula (I) above as well as any wholly or partially racemic mixtures thereof. The present invention also covers the individual enantiomers of the compounds represented by formula above as mixtures with diastereoisomers thereof in which one or more stereocenters are inverted.

[0201] In one group of particularly preferred embodiments, the compounds are represented by Formula (I), in which c is equal to 0; G comprises: -hydrogen or —CO2H; V comprises: —CH2— or a direct bond; X comprises: —CON(R8)—, or —N(R8)CO— wherein R8 comprises: -hydrogen; Ar1 comprises a mono-substituted phenyl group wherein the substituent comprises: -aryl, -arylene-alkyl, -D1-aryl -D1-alkylene-arylene-alkyl, or -arylene-D1-alkyl, wherein D1 comprises —O—, or —N(R15)—, wherein R15 comprises: -hydrogen, -alkyl, or -aryl; and Ar2 comprises a substituted phenyl, 2-naphthyl, 2-pyridyl, 3-isoquinolyl, 2-pyrimidyl or 2-quinazolyl group having 1 to 5 substituents independently comprising: -hydrogen, -fluoro, -chloro, -bromo, iodo, -cyano, -nitro, -perfluoroalkyl, -T1-R14, -alkyl, -aryl, -arylene-alkyl, -T1-alkyl, -T1-alkylene-aryl, -T1-alkylene-arylene-aryl, -T1-alkylene-arylene-alkyl, or -arylene-T1-alkyl; wherein T1 comprises —CH2—, —O—, —N(R21)—, —CON(R21)—, or —N(R21)C(O)—; wherein R21 comprises: -hydrogen, -alkyl, or -aryl. The alkyl, aryl, alkylene, and arylene groups in Ar1, and Ar2 may be optionally substituted 1 to 4 times with a substituent group, wherein said substituent group(s) or the term substituted refers to groups comprising: -hydrogen, -fluoro, -chloro, -bromo, iodo, cyano, -nitro, or -perfluoroalkyl.

[0202] Compounds of the present invention having biological activity are listed below in Table 1.

[0203] Unless indicated otherwise, the structures of Examples of compounds of Formula (I) in Table 1 and elsewhere having vacant connectivity for heteroatoms, such as oxygen and nitrogen, are assumed to have a hydrogen atom attached thereto.
1TABLE 1ExampleStructureName143-Biphenyl-4-yl-(2S)- [(isoquinoline-3-carbonyl)- amino]-propionic acid25(2S)-[(Isoquinoline-3- carbonyl)-amino]-3-(4′- trifluoromethyl-biphenyl-4- yl)-propionic acid36(2S)-[(Isoquinoline-3- carbonyl)-amino]-3-(3;5′- bistrifluoromethyl-biphenyl-4- yl)-propionic acid47(2S)-[(Isoquinoline-3- carbonyl)-amino]-3-(4′- methoxy-biphenyl-4-yl)- propionic acid583-[4-(4′-Cyano-phenoxy)- phenyl]-(2S)-[(isoquinoline-3- carbonyl)-amino]-propionic acid693-[4-(4′-Nitro-phenoxy)- phenyl]-(2S)-[(isoquinoline- carbonyl)-amino]-propionic acid7103-(3′-Chloro-4′-fluoro- biphenyl-4-yl)-(2S)- [(isoquinoline-3-carbonyl)- amino]-propionic acid8113-(4′-Cyano-biphenyl-4-yl)- (2S)-[(isoquinoline-3- carbonyl)-amino]-propionic acid912(2S)-[(Isoquinoline-3- carbonyl)-amino]- 3-(3′-trifluoromethyl- biphenyl-4-yl)-propionic acid1013(2S)-[(Isoquinoline-3- carbonyl)-amino]- 3-(3′-nitro-biphenyl-4-yl)- propionic acid11143-Biphenyl-4-yl-(2S)-[(7- bromo-isoquinoline-3- carbonyl)-amino]-propionic acid12153-Biphenyl-4-yl-(2S)-{[7-(4- trifluoromethyl-phenyl)- isoquinoline-3-carbonyl]- amino}-propionic acid13163-Biphenyl-4-yl-(2S)-{[7-(3- chloro-4-fluoro-phenyl)- isoquinoline-3-carbonyl]- amino}-propionic acid14172-Biphenyl-4-yl-N-(1-bromo- isoquinolin-3-yl)-acetamide15182-Biphenyl-4-yl-N-[1(4- trifluoromethyl-phenyl)- isoquinolin-3-yl]-acetamide1619N-[1(4-aminomethyl-phenyl)- isoquinolin-3-yl]-2-biphenyl- 4-yl-acetamide17203-Biphenyl-4-yl-(2S)-{[4-(2- biphenyl-4-yl-ethylamino)- quinazoline-2-carbonyl]- amino}-propionic acid18213-Biphenyl-4-yl-(2S)-{[4-tert- butyl-benzylamino)- quinazoline-2-carbonyl]- amino}-propionic acid19223-Biphenyl-4-yl-(2S)-{[6-(3- chloro-4-fluoro-phenyl)- pyridine-2-carbonyl]-amino}- propionic acid20233-Biphenyl-4-yl-(2S)-{[6-(3- chloro-4-fluoro-phenyl)- pyridine-2-carbonyl]-amino}- propionic acid21243-Biphenyl-4-yl-(2S)-{[6-(4- trifluoromethoxy-phenyl)- pyridine-2-carbonyl]-amino}- propionic acid22253-Biphenyl-4-yl-(2S)-{[6-(4- fluoro-3-methyl-phenyl)- pyridine-2-carbonyl]- amino}-propionic acid2326(2S){[6-(4-Amino-phenyl)- pyridine-2-carbonyl]-amino}- 3-biphenyl-4-yl-propionic acid24273-Biphenyl-4-yl-(2S)-{[6-(3- cyano-phenyl)-pyridine-2- carbonyl]-amino}-propionic acid25283-Biphenyl-4-yl-(2S)-{[6-(4- methanesulfonyl-phenyl)- pyridine-2-carbonyl]- amino}-propionic acid26293-Biphenyl-4-yl-(2S)-{[6-(4- methoxy-phenyl)-pyridine-2- carbonyl]-amino}-propionic acid27303-Biphenyl-4-yl-(2S)-{[6-(3- carboxamidinoyl-phenyl)- pyridine-2-carbonyl]-amino}- propionic acid28313-Biphenyl-4-yl-(2S)-{[6-(4- phenoxy-phenyl)-pyridine-2- carbonyl]-amino}-propionic acid29323-Biphenyl-4-yl-(2S)-{[6-(4- tert-butyl-phenyl)-pyridine-2- carbonyl]-amino}-propionic acid30333-Biphenyl-4-yl-(2S)-{[5-(3- chloro-4-fluoro-phenyl)-pyridine-2-carbonyl]-amino}- propionic acid31343-Biphenyl-4-yl-(2S)-{[5-(4- rifluoromethyl-phenyl)- pyridine-2-carbonyl]- amino}-propionic acid32353-Biphenyl-4-yl-(2S)-{[5-(4- methoxy-phenyl)-pyridine-2- carbonyl]-amino}-propionic acid33363-Biphenyl-4-yl-(2S)-{[4-(3- chloro-4-fluoro-phenyl)- pyridine-2-carbonyl]-amino}- propionic acid34373-Biphenyl-4-yl-(2S)-{[4-(4- methoxy-phenyl)-pyridine-2- carbonyl]-amino}-propionic acid35383-Biphenyl-4-yl-(2S)-{[4-(4- trifluoromethyl-phenyl)- pyridine-2-carbonyl]- amino}-propionic acid36393-Biphenyl-4-yl-(2S)-{[4-(3- trifluoromethyl-phenyl)- pyridine-2-carbonyl]- amino}-propionic acid37403-Hydroxy-napthalene-2- carboxylic acid (2-biphenyl- 4-yl-ethyl)-amide38413-[(3′-Chloro-4′-fluoro)- biphenyl-4-yl]-(2S)-[(3- hydroxy-naphthalene-2- carbonyl)-amino]-propionic acid39423-(Biphenyl-4-yl)-(2S)-[(3- hydroxy-napthalene-2- carbonyl)-amino]-propionic acid4043(2S)-[(3-Hydroxy- napthalene-2-carbonyl)- amino]-3-[(3′-nitro)-biphenyl- 4-yl]-propionic acid41443-(Biphenyl-4-yl)-(2S)-[(3′- chloro-4′-fluoro-4-hydroxy- biphenyl-3-carbonyl)-amino]- propionic acid methyl ester42453-(Biphenyl-4-yl)-(2S)-[(4′- trifluoromethyl-4-hydroxy- biphenyl-3-carbonyl)-amino]- propionic acid methyl ester4346(2S)-[(3′-Chloro-4′-fluoro-4- bydroxy-biphenyl-3- carbonyl)-amino]-3-(3′- trifluoromethyl-biphenyl-4- yl)-propionic acid methyl ester44473-(4′-Nitro-biphenyl-4-yl)- (2S)-[(4′-trifluoromethyl-4- hydroxy-biphenyl-3- carbonyl)-amino]-propionic acid methyl ester45483-(3′-Trifluoromethyl- biphenyl-4-yl)-(2S)-[(4′- trifluoromethyl-4-hydroxy- propionic acid methyl ester46493-(4′-Trifluoromethyl- biphenyl-4-yl)-(2S)-[(4′- trifluoromethyl-4-hydroxy- biphenyl-3-carbonyl)-amino]- propionic acid methyl ester47503-Biphenyl-4-yl-(2S)-[(2′,4′- difluoro-4-hydroxy-biphenyl- 3-carbonyl)-amino]-propionic acid48513-Biphenyl-4-yl-(2S)-[(4′- chloro-3′-fluoro-4-hydroxy- biphenyl-3-carbonyl)-amino]- propionic acid methyl ester49523-Biphenyl-4-yl-(2S)-[(3′- chloro-4′-fluoro-4-hydroxy- biphenyl-3-carbonyl)-amino]- propionic acid50533-Biphenyl-4-yl-(2S)-[(4- hydroxy-3′-nitro-bipheny-3- carbonyl)-amino]-propionic acid methyl ester51543-Biphenyl-4-yl-(2S)-[(4- hydroxy-4′-trifluoromethoxy- biphenyl-3-carbonyl)-amino]- propionic acid methyl ester5255(2S)-[(4-Hydroxy-4′- trifluoromethyl-biphenyl-3- carbonyl)-amino]-3-(3′-nitro- biphenyl-4-yl)-propionic acid5356(2S)-[(4-Hydroxy-4′- trifluoromethyl-biphenyl-3- carbonyl)-amino]-3-(3′-nitro- biphenyl-4-yl)-propionic acid methyl ester5457(2S)-[(3′-Chloro-4′-fluoro-4- hydroxy-biphenyl-3- carbonyl)-amino]-3-(3′-nitro- biphenyl-4-yl)-propionic acid methyl ester55583-Biphenyl-4-yl-(2S)-[(4′- fluoro-4-hydroxy-biphenyl-3- carbonyl)-amino]-propionic acid methyl ester56593-Biphenyl-4-yl-(2S)-[(4- hydroxy-4′-methoxy- biphenyl-3-carbonyl)-amino]- propionic acid methyl ester57603-Biphenyl-4-yl-(2S)-[(4′-tert- butyl-4-hydroxy-biphenyl-3- carbonyl)-amino]-propionic acid methyl ester5861(2S)-[(4-Hydroxy-3′-nitro- biphenyl-3-carbonyl)-amino]- 3-(3′-trifluoromethyl- biphenyl-4-yl)-propionic acid methyl ester59623-(3′-Chloro-4′-fluoro-biphenyl-4-yl-(2S)-[(4- hydroxy-3′-nitro-biphenyl- 3-carbonyl)-amino]-propionic acid methyl ester6063(2S)-[(4′-Amino-4-hydroxy- biphenyl-3-carbonyl)-amino]- 3-biphenyl-4-yl-propionic acid methyl ester6164(2S)-[(3′-Amino-4-hydroxy- biphenyl-3-carbonyl)-amino]- 3-biphenyl-4-yl-propionic acid methyl ester62653-Biphenyl-4-yl-(2S)-[(5′- fluoro-4-hydroxy-2′-methoxy- biphenyl-3-carbonyl)-amino]- propionic acid methyl ester63663-Biphenyl-4-yl-(2S)-[(3′- fluoro-4-hydroxy-biphenyl-3- carbonyl)-amino]-propionic acid methyl ester64673-Biphenyl-4-yl-(2S)-[(4- hydroxy-3′-trifluoromethyl- biphenyl-3-carbonyl)- amino]-propionic acid methyl ester65683-Biphenyl-4-yl-(2S)-[(4- hydroxy-3′,5′-bis- trifluoromethyl-biphenyl-3- carbonyl)-amino]-propionic acid methyl ester66693-Biphenyl-4-yl-(2S)-[(3′- chloro-4-hydroxy-biphenyl-3- carbonyl)-amino]-propionic acid methyl ester67703-Biphenyl-4-yl-(2S)-[(4′- chloro-4-hydroxy-biphenyl-3- carbonyl)-amino]-propionic acid methyl ester68713-Biphenyl-4-yl-(2S)-[(3′,5′- difluoro-4-hydroxy-biphenyl- 3-carbonyl)-amino]-propionic acid methyl ester69723-Biphenyl-4-yl-(2S)-[(4′- fluoro-4-hydroxy-3′-methyl- biphenyl-3-carbonyl)-amino]- propionic acid methyl ester7073(2S)-[(3′-Chloro-4′-fluoro-4- hydroxy-biphenyl-3- carbonyl)-amino]-3-(4′- trifluoromethyl-biphenyl-4- yl)-propionic acid methyl ester7174(2S)-[(3′-Chloro-4′-fluoro-4- hydroxy-biphenyl-3- carbonyl)-amino]-3-(4′- methoxy-biphenyl-4-yl)- propionic acid methyl ester72753-Biphenyl-4-yl-(2S)-[(4- hydroxy-4′-trifluoromethoxy- biphenyl-3-carbonyl)- amino]-propionic acid73763-Biphenyl-4-yl-(2S)-[(4′-tert- butyl-4-hydroxy-biphenyl-3- carbonyl)-amino]-propionic acid74773-Biphenyl-4-yl-(2S)-[(4- hydroxy-3′.4′-dimethoxy- biphenyl-3-carbonyl)-amino]- propionic acid methyl ester7578(2S)-(5-Benzo[1,3]dioxol-5- yl-2-hydroxy-benzoylamino)- 3-biphenyl-4-yl-propionic acid methyl ester76793-(3′-Chloro-4′-fluoro- biphenyl-4-yl-(2S)-[(4- hydroxy-4′-trifluoromethyl- biphenyl-3-carbonyl)-amino]- propionic acid methyl ester77803-Biphenyl-4-yl-(2S)-[(4- hydroxy-4′-methanesulfonyl- biphenyl-3-carbonyl)- amino]-propionic acid methyl ester7881(2S)-[(3′-Amino-4-hydroxy- biphenyl-3-carbonyl)-amino]- 3-(3′-trifluoromethyl- biphenyl-4-yl-propionic acid methyl ester79823-(3′,5′-Bis-trifluoromethyl- biphenyl-4-yl)-(2S)-[(3′- chloro-4′-fluoro-4-hydroxy- biphenyl-3-carbonyl)-amino]- propionic acid methyl ester80833-(3′,5′-Bis-trifluoromethyl- biphenyl-4-yl)-(2S)-[(4′- fluoro-4-hydroxy-biphenyl-3- carbonyl)-amino]-propionic acid methyl ester81843-(3′,5′-Bis-trifluoromethyl- biphenyl-4-yl)-(2S)-[(4- hydroxy-4′-trifluoromethyl- biphenyl-3-carbonyl)-amino]- propionic acid methyl ester8285(2S)-[(3′-Chloro-4′-fluoro-4- hydroxy-biphenyl-3 carbonyl)-amino]-3-(3′- trifluoromethyl-biphenyl-4- yl)-propionic acid8386(2S)-[(4-Hydroxy-4′- trifluoromethyl-biphenyl-3- carbonyl)-amino]-3-(3′- trifluoromethoxy-biphenyl-4- yl)-propionic acid methyl ester8487(2S)-[(4-Hydroxy-3′- trifluoromethyl-biphenyl-3- carbonyl)-amino]-3-(3′- trifluoromethyl-biphenyl-4- yl)-propionic acid methyl ester85884′-{(2S)-[(4-Hydroxy-4′- trifluoromethyl-biphenyl-3- carbonyl)-amino]-2- methoxycarbonyl-ethyl}-5- nitro biphenyl-3-carboxylic acid methyl ester8689(2S)-[(4-Hydroxy-4′- trifluoromethyl-biphenyl-3- carbonyl)-amino]-3-(3′,4′,5′- trimethoxy-biphenyl-4-yl)- propionic acid methyl ester8790(2S)-[(3′-Chloro-4′-fluoro-4- hydroxy-biphenyl-3- carbonyl)-amino]-3-(3′- trifluoromethoxy-biphenyl-4- yl)-propionic acid methyl ester88913-Biphenyl-4-yl-(2S)-[(4- hydroxy-4′-trifluoromethyl- biphenyl-3-carbonyl)- amino]-propionic acid8992(2S)-[(4-Hydroxy-2′- trifluoromethyl-biphenyl-3- carbonyl)-amino]-3-(2′- trifluoromethyl-biphenyl-4- yl)-propionic acid methyl ester90933-(3′-Chloro-4′-fluoro- biphenyl-4-yl)-(2S)-[(3′- chloro-4′-fluoro-4-hydroxy- biphenyl-3-carbonyl)-amino]- propionic acid methyl ester9194(2S)-[(4-Hydroxy-3′-nitro- biphenyl-3-carbonyl)-amino]- 3-(3′-nitro-biphenyl-4-yl)- propionic acid methyl ester9295(2S)-[(4-Hydroxy-3′- trifluoromethyl-biphenyl-3- carbonyl)-amino]-3-(3′-nitro- biphenyl-4-yl)-propionic acid methyl ester9396(2S)-[(4-Hydroxy-3′- trifluoromethyl-biphenyl-3- carbonyl)-amino]-3-(4′- trifluoromethyl-biphenyl-4- yl)-propionic acid methyl ester94973-(3′-Chloro-4′-fluoro- biphenyl-4-yl)-(2S)-[(4- hydroxy-3′-trifluoromethyl- biphenyl-3-carbonyl)-amino]- propionic acid methyl ester95983-Biphenyl-4-yl-(2S)-[(4- hydroxy-2′-trifluoromethyl- biphenyl-3-carbonyl)- amino]-propionic acid methyl ester96993-(3′,5′-Bis-trifluoromethyl- biphenyl-4-yl)-(2S)-[(4- hydroxy-3′-trifluoromethyl- biphenyl-3-carbonyl)-amino]- propionic acid methyl ester97100(2S)-[(4-Hydroxy-3′- trifuloromethyl-biphenyl-3- carbonyl)-amino]-3-(2′- trifluoromethyl-biphenyl-4- yl)-propionic acid methyl ester98101(2S)-[2-(4-Benzyloxy- benzyloxy)-5-bromo- benzoylamino]-3-biphenyl-4- yl-propionic acid991023-Biphenyl-4-yl-2S-{[4-(4- tert-butyl-benzyloxy)-3′- chloro-4′-fluoro-biphenyl-3- carbonyl]-amino}-propionic acid100103(2S)-[5-Bromo-2-(4- trifluoromethyl-benzyloxy)- benzoylamino]-3-(2′-phenoxy- biphenyl-4-yl)-propionic acid101104(2S)-(5-Bromo-2-heptyloxy- benzoylamino)-3-[2′-(4- trifluoromethyl-phenoxy)- biphenyl-4-yl]-propionic acid102105(2S)-(5-Chloro-2-heptyloxy- benzoylamino)-3-(4′- trifluoromethoxy-biphenyl- 4-yl)-propionic acid1031063-Biphenyl-4-yl-(2S)-[2-(3,4- bis-benzyloxy-benzyloxy)-5- bromo-benzoylamino]- propionic acid methyl ester1041073-Biphenyl-4-yl-(2S)-[2-(3,4- bis-benzyloxy-benzyloxy)-5- bromo-benzoylamino]- propionic acid105108(2S)-[2-(4- Benzyloxybenzyloxy)-5- bromo-benzoylamino]-3- biphenyl-4-yl-propionic acid methyl ester1061093-Biphenyl-4-yl-(2S)-[5- bromo-2-(4-bromo- benzyloxy)-benzoylamino]- propionic acid methyl ester1071103-Biphenyl-4-yl-(2S)-[5- bromo-2-(4-bromo- benzyloxy)-benzoylamino]- propionic acid1081113-Biphenyl-4-yl-(2S)-[5- bromo-2-(4-tert-butyl- benzyloxy)-benzoylamino]- propionic acid methyl ester1091123-Biphenyl-4-yl-(2S)-[4- bromo-2-(4-tert-butyl- benzyloxy)-benzoylamino]- propionic acid1101133-Biphenyl-4-yl-(2S)-[2- (biphenyl-4-ylmethoxy)-5- bromo-benzoylamino]- propionic acid1111143-Biphenyl-4-yl-(2S)-(5- chloro-2-methoxy- benzoylamino)-propionic acid1121153-Biphenyl-4-yl-(2S)-[2-(4- tert-butyl-benzyloxy)-5- chloro-benzoylamino]- propionic acid1131163-Biphenyl-4-yl-(2S)-[2-(4- tert-butyl-benzyloxy)-5-(4- trifluoromethylphenyl)- benzoylamino]-propionic acid114117(2S)-[5-Bromo-2-(3-methyl- benzyloxy)-benzoylamino]-3- (2′-phenoxy-biphenyl-4-yl)- propionic acid methyl ester115118(2S)-[5-Bromo-2-(4-methyl- benzyloxy)-benzoylamino]-3- (2′-phenoxy-biphenyl-4-yl)- propionic acid116119(2S)-[5-Bromo-2-(3-methyl- benzyloxy)-benzoylamino]-3- (2′-phenoxy-biphenyl-4-yl)- propionic acid117120(2S)-[5-Bromo-2-(4-carboxy- benzyloxy)-benzoylamino]-3- (2′-phenoxy-biphenyl-4-yl)- propionic acid118121(2S)-[5-Bromo-2-(4- trifluoromethyl-phenoxy)- benzoylamino[-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid119122(2S)-[5-Bromo-2-heptyloxy- benzoylamino-3-(2′-phenoxy- biphenyl-4-yl)-propionic acid methyl ester1201233-Biphenyl-4-yl-(2S)-(5- bromo-2-heptyloxy- benzoylamino)-propionic acid methyl ester1211243-Biphenyl-4-yl-(2S)-(5- bromo-2-heptyloxy- benzoylamino)-propionic acid122125(2S)-(5-Bromo-2-heptyloxy- benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid1231263-Biphenyl-4-yl-(2S)-[5- chloro-2-(4-pyrazol-1-yl- benzyloxy)-benzoylamino]- propionic acid124127(2S)-[5-Bromo-2-(4-tert- butyl-benzyloxy)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid125128(2S)-(2-Benzyloxy-5-bromo- benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester126129(2S)-(2-Benzyloxy-5-bromo- benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid127130(2S)-[5-Bromo-2-(4-bromo- benzyloxy)-benzoylamino]-3- (2′-phenoxy-biphenyl- 4-yl-propionic acid128131(2S)-(5-Bromo-2-propoxy- benzoylamino)- 3-2′-phenoxy-biphenyl-4-yl)- propionic acid129132(2S)-[(5-Bromo-2,3-dihydro- benzofuran- 7-carbonyl)-amino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid130133(2S)-[5-Bromo-2-(3-phenyl- allyloxy)-benzoylamino]-3- (2′-phenoxy-biphenyl- 4-yl)-propionic acid methyl ester131134(2S)-[5-Bromo-2-(3-phenyl- allyloxy)-benzoylamino]-3- (2′-phenoxy-biphenyl- 4-yl)-propionic acid132135(2S)-[5-Bromo-2-(4- methanesulfonyl-benzyloxy)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester133136(2S)-[5-Bromo-2-(4- methanesulfonyl-benzyloxy)- benzoylamino]-3-(2′-phenoxy- biphenyl-4-yl)-propionic acid134137(2S)-]5-Bromo-2-(3-methyl- butoxy)-benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester135138(2S)-[5-Bromo-2-(3-methyl- butoxy)-benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid136139(2S)-[2-(Biphenyl-4- ylmethoxy)-5-bromo- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester137140(2S)-[2-(Biphenyl-4- ylmethoxy)-5-bromo- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid138141(2S)-[5-Bromo-2-(4-methoxy- phenoxy)-benzoylamino]-3- (2′-phenoxy-biphenyl-4-yl)- propionic acid139142(2S)-[5-Bromo-2-(4-phenoxy- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid140143(2S)-[5-Bromo-2-(1-methyl- butoxy)-benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester141144(2S)-[5-Bromo-2-(1-methyl- butoxy)-benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid142145(2S)-(5-Bromo-2-isopropoxy- benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid143146(2S)-[5-Bromo-2-(3- trifluoromethyl-phenoxy)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid144147(2S)-(5-Bromo-2-heptyloxy- benzoylamino)-3-[2′-(4- methoxy-phenoxy)-biphenyl- 4-yl]-propionic acid145148(2S)-[5-Bromo-2-(2- morpholin-4-yl-ethoxy)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester146149(2S)-{5-Bromo-2-[2-(2- methoxy-ethoxy)- ethoxy]-benzoylamino}-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester147150(2S)-(5-Bromo-2-{2-[2-(2- methoxy-ethoxy)-ethoxy]- ethoxy}-benzoylamino)-3- (2′-phenoxy-biphenyl-4-yl)- propionic acid methyl ester148151(2S)-(5-Bromo-2-{2-[2-(2- methoxy-ethoxy)-ethoxy]- ethoxy}-benzoylamino)-3- (2′-phenoxy-biphenyl-4-yl)- propionic acid methyl ester149152(2S)-{5-Bromo-2-[2-(2-oxo- pyrrolidin-1-yl)-ethoxy]- benzoylamino}-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester150153(2S)-[5-Bromo-2-(2-phenyl- cyclopropylmethoxy)- benzoylamino]-3-(2′-phenoxy- biphenyl-4-yl)-propionic acid151154(2S)-(5-Bromo-2-sec-butoxy- benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl- propionic acid152155(2S)-(5-Chloro-2-heptyloxy- benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester153156(2S)-(5-Chloro-2-heptyloxy- benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid154157(2S)-(5-Bromo-2-isobutoxy- benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester155158(2S)-(5-Bromo-2-isobutoxy- benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid156159(2S)-(5-Bromo-2- ethoxycarbonyloxy- benzoylamino)-3-(2′- phenoxy-biphenyl-4- yl)-propionic acid methyl ester157160(2S)-(5-Bromo-2- dimethylcarbamoyloxy- benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester158161(2S)-{5-Bromo-2-[2-(2- methoxy-ethoxy)- ethoxy]-benzoylamino}-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid159162(2S)[5-Bromo-2-(4-phenyl- butoxy)-benzoylamino]-3-(2′- phenoxy-biphenyl-4- yl)-propionic acid160163(2S)-[5-Bromo-2-(5-phenyl- pentyloxy)-benzoylamino]-3- (2′-phenoxy-biphenyl-4-yl)- propionic acid161164(2S)-[5-Bromo-2-(6-phenyl- hexyloxy)-benzoylamino]-3- (2′-phenoxy-biphenyl- 4-yl)-propionic acid162165(2S)-(5-Bromo-2-heptyloxy- benzoylamino)-3-[2′-(4- trifluoromethoxy-phenoxy)- biphenyl-4-yl]-propionic acid163166(2S)-(5-Bromo-2-{2-[2-(2- methoxy-ethoxy)-ethoxy]- ethoxy}-benzoylamino)-3- (2′-phenoxy-bipheny-4-yl)- propionic acid164167(2S)-[5-Bromo-2-(2-piperidin- 1-yl-ethoxy)-benzoylamino]- 3-(2′-phenoxy-biphenyl-4-yl)- propionic acid165168(2S)-(5-Bromo-2-heptyloxy- benzoylamino)-3-[2′-(4-tert- butyl-phenoxy)-biphenyl-4- yl]-propionic acid166169(2S)-(5-Chloro-2-heptyloxy- benzoylamino)-3-(4′- trifluoromethyl-biphenyl-4- yl)-propionic acid1671703-(3′-Chloro-4′-fluoro- biphenyl-4-yl)-(2S)-(5-chloro- 2-heptyloxy-benzoylamino)- propionic acid168171(2S)-[5-Bromo-2-(3-phenyl- propoxy)-benzoylamino]-3- (2′-phenoxy-biphenyl-4-yl)- propionic acid169172(2S)-{5-Bromo-2-[3-(3,4- dimethoxy-phenyl)-propoxy]- benzoylamino}-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid170173(2S)-[5-Bromo-2-(3-pyridin- 3-yl-propoxy)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid171174(2S)-[5-Bromo-2-(3-pyridin- 4-yl-propoxy)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid172175(2S)-(5-Bromo-2- dimethylcarbamoyloxy- benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid173176(2S)-[5-Bromo-2-(3- morpholin-4-yl-propoxy)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid174177(2S)-[5Bromo-2-(4,4,4- trifluoro-butoxy)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid175178(2S)-(5-Chloro-2-heptyloxy- benzoylamino)-3-(4′- cyclohexyl-biphenyl-4-yl)- propionic acid176179(2S)-(5-Chloro-2-heptyloxy- benzoylamino)-3-(3′,4′- dichloro-biphenyl-4-yl)- propionic acid177180(2S)-(5-Bromo-2-butoxy- benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)-propionic acid178181(2S)-[5-Bromo-2-(2-methyl- butoxy)-benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid179182(2S)-(5-Bromo-2- cyclopropylmethoxy- benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester180183(2S)-(5-Bromo-2- cyclopropylmethoxy- benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid181184(2S)-[5-Bromo-2-(4- [1,2,4]triazol-1-yl-benzyloxy)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid182185(2S)-[5-Bromo-2- (isoquinolin-1-ylmethoxy)- benzoylamino[-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid183186(2S)-[2-(3-Benzyloxy- benzyloxy)-5-bromo- benzoylamino]-3-(4′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester184187(2S)-[2-(3-Benzyloxy- benzyloxy)-5-bromo- benzoylamino]-3-(4′- phenoxy-biphenyl-4-yl)- propionic acid185188(2S)-[5-Bromo-2-(4- trifluoromethoxy-benzyloxy)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester186189(2S)-[5-Bromo-2-(4- trifluoromethoxy-benzyloxy)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid187190(2S)-[5-Bromo-2-(4-phenyl- butoxy)-benzoylamino]-3-(4′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester188191(2S)-[5-Bromo-2-(6-phenyl- hexloxy)-benzoylamino]-3- (4′-phenoxy-biphenyl-4-yl)- propionic acid methyl ester189192(2S)-(5-Chloro-2-heptyloxy- benzoylamino)-3-(4′- dimethylamino-biphenyl-4- yl)-propionic acid190193(2S)-[5-Bromo-2-(4-phenyl- butoxy)-benzoylamino]-3-(4′- phenoxy-biphenyl-4-yl)- propionic acid191194(2S)-[5-Bromo-2-(6-phenyl- hexyloxy)-benzoylamino]-3- (4′-phenoxy-biphenyl-4-yl)- propionic acid192195(2S)-[5-Bromo-2-(2- cyclohexyl-ethoxy)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester193196(2S)-[5-Bromo-2-(2- cyclohexyl-ethoxy)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid194197(2S)-(5-Bromo-2- cyclohexylmethoxy- benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid195198(2S)-(5-Bromo-2- cyclohexyloxy- benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester196199(2S)-(5-Bromo-2- cyclohexyloxy- benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid197200N-[2-Hydroxy-4-(4- trifluoromethyl-phenoxy)- phenyl]-2-(3′-methoxy- biphenyl-4-yl)-acetamide198201N-[2-Hydroxy-4-(3,4- dichloro-phenoxy)-phenyl]-2- (4′-trifluoromethyl-biphenyl- 4-yl)-acetamide199202N-[2-Hydroxy-4-(2,4- dichloro-6-methyl-phenoxy)- phenyl]-2-(4′-trifluoromethyl- biphenyl-4-yl)-acetamide200203N-[2-Hydroxy-4-(2,4- dichloro-6-methyl-phenoxy)- phenyl]-2-(3′-trifluoromethyl- biphenyl-4-yl)-acetamide2012043-(3′-Chloro-4′-fluoro- biphenyl-4-yl)-N-[4-(2,4- dichloro-6-methyl-phenoxy)- 2-hydroxy-phenyl]- propionamide202205N-[4-(2-Fluoro-6-methoxy- phenoxy)-2-hydroxy-phenyl]- 3-(3′-methoxy-biphenyl-4-yl)- propionamide203206N-[4-(2,4-Dichloro-6-methyl- phenoxy)-2-hydroxy-phenyl]- 2-(4′-methoxy-biphenyl-4-yl- acetamide2042072-(3′-Chloro-4′-fluoro- biphenyl-4-yl)-N-[4-(2,4- dichloro-6-methyl-phenoxy)- 2-hydroxy-phenyl]-acetamide2052082-Biphenyl-4-yl-N-[2- hydroxy-4-)4′- methoxy-biphenyl-4-yloxy)- phenyl]-acetamide2062092-Biphenyl-4-yl-N-[2- hydroxy-4-(4′-trifluoromethyl- biphenyl-4-yloxy)-phenyl]-acetamide207210N-[4-(3,4-Dichloro-phenoxy)- 2-hydroxy-phenyl]-2-(3′-nitro- biphenyl-4-yl)-acetamide208211N-[5-(3-Chloro-phenyl)- pyridin-2-yl]-2-[4-(3-hydroxy- 4-nitro-phenoxy)-phenyl]- acetamide209212N-[5-(3,4-Dichloro-phenyl)- pyridin-2-yl]-2-[4-(3-hydroxy- 4-nitro-phenoxy)-phenyl]- acetamide210213N-[5-(3-Trifluromethyl- phenyl)-pyridin-2-yl]-2-[4-(3- hydroxy-4-nitro-phenoxy)- phenyl]-acetamide211214N-[5-(4-Methoxy-phenyl)- pyridin-2-yl]-2-[4-(3-hydroxy- 4-nitro-phenoxy)-phenyl]- acetamide2122153-Biphenyl-4-yl-(2S)-[(4′- trifluoromethyl-bipheynl-4- carbonyl)-amino]-propionic acid2132163-Biphenyl-4-yl-(2S)-[(3′- chloro-4′-fluoro-biphenyl-4- carbonyl)-amino]-propionic acid2142173-Biphenyl-4-yl-(2S)-[(4′- trifluoromethoxy-biphenyl-4- carbonyl)-amino]-propionic acid2152183-Biphenyl-4-yl-(2S)-[(4′- ethyl-biphenyl-4-carbonyl)- amino]-propionic acid2162193-Biphenyl-4-yl-(2S)-[(3′- ethyl-biphenyl-3-carbonyl)- amino]-propionic acid2172203-Biphenyl-4-yl-(2S)-[(4′-tert- butylbiphenyl-3-carbonyl)- amino]-propionic acid2182213-Biphenyl-4-yl-(2S)-[(4′- methoxy-biphenyl-3- carbonyl)-amino]-propionic acid2192223-Biphenyl-4-yl-(2S)-[(4′- methane-sulfonyl-biphenyl- 3-carbonyl)-amino]-propionic acid2202233-Biphenyl-4-yl-(2S)-[(4′-tert- butyl-4-chloro-biphenyl-3- carbonyl)-amino]-propionic acid221224(2S)-[(4-Chloro-4′- trifluoromethyl-biphenyl-3- carbonyl)-amino]-3-(4′- trifluoromethyl-biphenyl-4- yl)-propionic acid222225(2S)-[(-4′-Methoxy-biphenyl- 3-carbonyl)-amino]-3-(4′- methoxyl-biphenyl-4-yl)- propionic acid2232263-Biphenyl-4-yl-(2S)-[3-nitro- 4-(3-trifluoromethyl- phenoxy)-benzoylamino]- propionic acid2242273-(4′-Trifluoromethyl- biphenyl-4-yl)-(2S)-[4-(4- trifluoromethyl-phenoxy)- benzoylamino]-propionic acid2252283-(4′-Trifluoromethyl- biphenyl-4-yl)-(2S)-[4-(5- trifluoromethyl-pyridin-2- yloxy)-benzoylamino]- propionic acid2262293-[4-(4-Trifluoromethyl- phenoxy)-phenyl]-(2S)-[(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid2272303-[4-(4-Cyano-phenoxy)- phenyl]-(2S)-[(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid2282312S-(4-Benzyloxy- benzoylamino)-3-biphenyl-4- yl-propionic acid2292323-Biphenyl-4-yl-(2S)-[(4′- trifluoromethyl-biphenyl-3- carbonyl)-amino]-propionic acid2302333-Biphenyl-4-yl-(2S)-[(3- chloro-4′-trifluoromethyl- biphenyl-4-carbonyl)-amino]- propionic acid2312343-Biphenyl-4-yl-(2S)-[4-(4- nitro phenoxy)- benzoylamino]- propionic acid2322353-Biphenyl-4-yl-(2S)-[4-(3,4- dimethyl-phenoxy)-3-nitro- benzoylamino]-propionic acid2332363-Biphenyl-4-yl-(2S)-[(3′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid2342373-Biphenyl-4-yl-(2S)-[(3′,5′- bis-trifluoromethyl-biphenyl- 4-carbonyl)-amino]-propionic acid2352383-Biphenyl-4-yl-(2S)-[4′-tert- butyl-biphenyl-4-carbonyl)- amino]-propionic acid2362393-Biphenyl-4-yl-(2S)-[(4′- dimethylamino-biphenyl-4- carbonyl)-amino]-propionic acid2372403-Biphenyl-4-yl-(2S)-[(4′- methoxy-biphenyl-4- carbonyl)-amino]-propionic acid2382413-Biphenyl-4-yl-2-[(3′,4′- dichloro-biphenyl-4- carbonyl)-amino]-propionic acid2392423-Biphenyl-4-yl-(2S)-[(5′- chloro-2′-methoxy-biphenyl- 4-carbonyl)-amino]-propionic acid240243(2S)-[(3′-Amino-biphenyl-4- carbonyl)-amino]-3-biphenyl- 4-yl-propionic acid241244(2S)-[(4′-Trifluoromethoxy- biphenyl-4-carbonyl)-amino]- 3-(4′-trifluoromethyl- biphenyl-4-yl)-propionic acid2422453-(4′-Trifluoromethoxy- biphenyl-4-yl)-(2S)-[(4′- trifluoromethyl-biphenyl- 4-carbonyl)-amino]-propionic acid2432463-(4-Pyridin-4-yl-phenyl)- (2S)-[(4′-trifluormethyl- biphenyl-4-carbonyl)-amino]- propionic acid2442473-Biphenyl-4-yl-(2S)-[4-(5- trifluoromethyl-pyridin-2-yl)- benzoylamino]-propionic acid2452483-(4-Pyridin-4-yl-phenyl)- (2S)-[4-(5-trifluoromethyl- pyridin-2-yl-)benzoylamino]- propionic acid2462493-(4′-Methanesulfonylamino- biphenyl-4-yl)-(2S)-[(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid2472503-(3′-Chloro-4′-fluoro- biphenyl-4-yl)-(2S)-[(′- trifluoromethyl-biphenyl- 4-carbonyl)-amino]-propionic- acid2482513-(4′-Cyano-biphenyl-4-yl)- (2S)-[(4′-trifluoromethyl- biphenyl-4-carbonyl)- amino]-propionic acid2492523-(5-Phenyl-pyridin-2-yl)-2- [(4′-trifluoromethoxy- biphenyl-4-carbonyl)- amino]-propionic acid2502533-(4′-Amino-biphenyl-4-yl)- (2S)-[(4′-trifluoromethyl- biphenyl-4-carbonyl)-amino]- propionic acid2512543-(4′-Dimethylamino- biphenyl-4-yl)-(2S)-[(4′- trifluoromethyl-biphenyl-4- carbonyl-amino]-propionic acid2522553-(4′-Trifluoromethoxy- biphenyl-4-yl)-(2S)-[4-(5- trifluoromethyl-pyridin-2-yl)- benzoylamino]-propionic acid2532563-(4′-Tribluoromethyl- biphenyl-4-yl)-(2S)-[4-(5- trifluoromethyl-pyridin-2- yl)-benzoylamino]-propionic acid2542573-(4′-Trifluoromethoxy- biphenyl-4-yl)-(2S)-[4-(4- trifluoromethyl-phenoxy)- benzoylamino]-propionic acid2552583-Biphenyl-4-yl-(2S)-[4-(4- trifluoromethyl-phenoxy)- benzoylamino]-propionic acid2562593-Biphenyl-4-yl-(2S)-[4-(4- formyl-phenoxy)- benzoylamino]-propionic acid2572603-(5′-Chloro-2′-methoxy- biphenyl-4-yl)-(2S)-[(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid2582613-(4′-Chloro-biphenyl-4-yl)- (2S)-[(4′-trifluoromethyl- biphenyl-4-carbonyl)-amino]- propionic acid2592623-Biphenyl-4-yl-(2R)-[(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid2602633-(5-Phenyl-pyridin-2-yl)-2- [(4′-trifluoromethyl-biphenyl- 4-carbonyl)-amino]-propionic acid2612643-(3′-Acetylamino-biphenyl- 4-yl)-(2S)-[(4′-trifluoromethyl- biphenyl-4-carbonyl)-amino]- propionic acid2622653-(3′,4′-Dichloro-biphenyl-4- yl)-(2S)-[(4′-trifluoromethyl- biphenyl-4-carbonyl)-amino]- propionic acid2632663-(5′-Fluoro-2′-methoxy- biphenyl-4-yl)-(2S)-[(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid2642673-[4′-(Acetylamino-methyl)- biphenyl-4-yl]-(2S)-[(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid2652683-(4′-Trifluoromethoxy- biphenyl-4-yl)-(2S)-[4-(5- trifluoromethyl-pyridin-2- yloxy)-benzoylamino]- propionic acid2662693-Biphenyl-4-yl-(2S)-[4-(5- trifluoromethyl-pyridin-2- yloxy)-benzoylamino]- propionic acid2672703-[4-(4-Nitro-phenoxy)- phenyl]-(2S)-[(4- trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid2682713-[4-(4-Formyl-phenoxy)- phenyl]-(2S)-[(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid2692723-(4-Thiophen-3-yl-phenyl)- (2S)-[(4′-trifluoromethyl- biphenyl-4-carbonyl)-amino]- propionic acid2702733-(4-Thiophen-3-yl-phenyl)- (2S)-[(4′-trifluoromethoxy- biphenyl-4-carbonyl)-amino]- propionic acid271274(2S0-(4-Benzyloxy- benzoylamino)-3-(4′- trifluoromethoxy-biphenyl-4- yl)-propionic acid2722753-(2′-Phenoxy-biphenyl-4-yl)- (2S)-[(4′-trifluoromethyl- biphenyl-4-carbonyl)-amino]- propionic acid2732763-(4′-Phenoxy-biphenyl-4-yl)- (2S)-[(4′-trifluoromethyl- biphenyl-4-carbonyl)-amino]- propionic acid2742773-Biphenyl-4-yl-(2S)-[2-(4- tert-butyl-benzoylamino)-5- iodo-benzoyl-amino]- propionic acid2752783-Biphenyl-4-yl-(2S)-{[4-(4- tert-butyl-benzoylamino)-3′- trifluoromethyl-biphenyl-3- carbonyl]-amino}-propionic acid2762793-Biphenyl-4-yl-(2S0-{[4-(4- tert-butyl-benzoylamino)-4′- nitro-iphenyl-3-carbonyl]- mino}-propionic acid2772803-Biphenyl-4-yl-(2S)-{[4-(4- tert-butyl-benzoylamino)-3′- chloro-4′-fluoro-biphenyl-3- carbonyl]-amino}-propionic acid2782813-Biphenyl-4-yl-(2S)-[4-(4- tert-butyl-benzoylamino)-5- (4-chloro-3-trifluromethyl- phenoxy)-benzoylamino]- propionic acid2792823-Biphenyl-4-yl-(2S)-[2-(3,5- bis-trifluoromethyl- benzoylamino)-5-bromo- benzoylamino]-propionic acid280283(2S)-[5-bromo-2-(2- cyclopentyl-acetylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid281284(2S)-[5-Bromo-2(3,3,5- trimethyl-hexanoylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid282285(2S)-[5-Chloro-2-(4-phenoxy- benzoylamino)- benzoylamino]-3-(2′- isopropoxy-biphenyl-4-yl)- propionic acid2832863-Biphenyl-4-yl-(2S)-[2-(4- tert-butyl-benzoylamino)- benzoylamino]- propionic acid2842873-Biphenyl-4-yl-(2S)-[5- chloro-2-(2,4-dichloro- benzoylamino)- benzoylamino]- propionic acid285288(2S)-({4-[(Biphenyl-4- carbonyl)-amino]-3′-chloro- 4′-fluoro-biphenyl-3- carbonyl}-amino)-3-biphenyl- 4-yl-propionic acid286289(2S)-{2-[Biphenyl-4- carbonyl)-amino]- benzoylamino}-3-(3′-chloro- 4′-fluoro-biphenyl-4-yl)- propionic acid287290(2S)-[2-(4-tert-Butyl- benzoylamino)- benzoylamino]-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)- propionic acid2882913-Biphenyl-4-yl-(2S)-[5- bromo-2-(4-tert-butyl- benzoylamino)- benzoylamino]- propionic acid2892923-Biphenyl-4-yl-(2S)-{[4-(4- tert-butyl-benzoylamino)-4′- cyano-biphenyl-3-carbonyl]- amino}-propionic acid290293(2S)-{[4′-Amino-4-(4-tert- butyl-benzoylamino)- biphenyl-3-carbonyl]-amino}- 3-biphenyl-4-yl-propionic acid2912943-Biphenyl-4-yl-(2S)-{[4-(4- tert-butyl-benzoylamino)-3′- cyano-biphenyl-3-carbonyl]- amino}-propionic acid292295(2S)-({3-[(Biphenyl-4- carbonyl)-amino]- naphthalene-2-carbonyl}- amino)-3-(3′-chloro-4′-fluoro- biphenyl-4-yl)-propionic acid293296(2S)-{[3-(4-tert-Butyl- benzoylamino)-naphthalene- 2-carbonyl]-amino}-3-(3′- chloro-4′-fluoro-biphenyl-4- yl)-propionic acid294297(2S)-{[3′-Aminomethyl-4-(4- tert-butyl-benzoylamino)- biphenyl-3-carbonyl]-amino}- 3-biphenyl-4-yl-propionic acid2952983-Biphenyl-4-yl-(2S)-{[4-(4- tert-butyl-benzoylamino)-4′- carbamimidoyl-biphenyl-3- carbonyl]-amino}-propionic acid2962993-Biphenyl-4-yl-(2S)-[2-(4- tert-butyl-benzoylamino)-5- (4-nitro-phenoxy)- benzoylamino]-propionic acid297300(2S)-{[4-(4-tert-Butyl- benzoylamino)-3′- trifluoromethyl-biphenyl-3- carbonyl]-amino}-3-(3′- trifluoromethyl-biphenyl-4- yl)-propionic acid298301(2S)-{[4-(4-tert-Butyl- benzoylamino)-3′-chloro-4′- fluoro-biphenyl-3-carbonyl]- amino}-3-(3′-chloro-4′-fluoro- biphenyl-4-yl)-propionic acid299302(2S)-{[4-(4-tert-Butyl- benzoylamino)-4′- trifluoromethyl-biphenyl-3- carbonyl]-amino}-3-(4′- trifluoromethyl-biphenyl-4- yl)-propionic acid3003033-Biphenyl-4-yl-(2S)-[5- bromo-2-(3-phenyl- acryloylamino)- benzoylamino]-propionic acid3013043-Biphenyl-4-yl-(2S)-{5- bromo-2-[(naphthalene-2- carbonyl)-amino]- benzoylamino}-propionic acid3023053-Biphenyl-4-yl-(2S)-[5-bromo-2-(2-cyclopentyl- acetylamino)-benzoylamino]- propionic acid3033063-Biphenyl-4-yl-(2S)-[5- bromo-2-(4-trifluoromethoxy- benzoylamino)-benzoylamino]- propionic acid3043073-Biphenyl-4-yl-(2S)-[5- bromo-2-(4-phenoxy- butyrylamino)- benzoylamino]-propionic acid3053083-Biphenyl-4-yl-(2S)-(5- bromo-2-[2-(4- tert-butyl-phenoxy)- acetylamino]-benzoylamino)- propionic acid306309(2S)-[2-(4-tert-Butyl- benzoylamino)-5- chloro-benzoylamino]-3-(4′- phenoxy-biphenyl-4-yl)- propionic acid3073102-[5-Bromo-(2S)-(4-tert- butyl-benzoylamino)- benzoylamino]-3-(4′- phenoxy-biphenyl-4-yl)- propionic acid3083113-Biphenyl-4-yl-(2S)-[4- chloro-2-(4-trifluoromethyl- benzoylamino)-benzoylamino]- propionic acid3093123-Biphenyl-4-yl-(2S)-[2-(4- tert-butyl-benzoylamino)-5- (4-trifluoromethyl-phenoxy)- benzoylamino]-propionic acid3103133-Biphenyl-4-yl-(2S)-[2-(4- trifluoromethyl- benzoylamino)-5-(4- trifluoromethyl-phenoxy)- benzoylamino]-propionic acid3113143-Biphenyl-4-yl-(2S)-[2-(4- tert-butyl-benzoylamino)-4- (4-trifluoromethyl-phenoxy)- benzoylamino]-propionic acid312315(2S)-[2-(4-tert-Butyl- benzoylamino)-5- chloro-benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid313316(2S)-[5-Chloro-2-(4-phenoxy- benzoylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid314317(2S)-[2-(4-Benzyloxy- benzoylamino)-5-chloro- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid315318(2S)-(5-Bromo-2- phenylacetylamino- benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid316319(2S)-[5-Bromo-2-(4-bromo- benzoylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid317320(2S)-{5-Bromo-2-[2-(4-fluoro- phenyl)-acetylamino]- benzoylamino}-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid3183212-{5-Bromo-(2S)- [(naphthalene-2-carbonyl)- amino]-benzoylamino}-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid319322(2S)-{5-Bromo-2- [(naphthalene-1-carbonyl)- amino]-benzoylamino}-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid320323(2S)-[5-Chloro-2-(3-phenoxy- benzoylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid321324-S-[2-(3-Benzyloxy- benzoylamino)-5-chloro- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid322325(2S)-[5-Bromo-2-(4-phenoxy- benzoylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid323326(2S)-[5-Bromo-2-(4-hexyl- benzoylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid324327(2S)-[5-Bromo-2-(4-fluoro- benzoylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid325328(2S)-{5-Bromo-2- [(thiophene-2-carbonyl)- amino]-benzoylamino}-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid326329(2S)-[5-Bromo-2-(2- thiophen-2-yl-acetylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid327330(2S)-[5-Bromo-2- (cyclopropanecarbonyl- amino)-benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid328331(2S)-[5-Bromo-2- (cyclobutanecarbonyl- amino)-benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid329332(2S)-{5-Bromo-2- (cyclopentanecarbonyl- amino)-benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid330333(2S)-[5-Bromo-2-(2-propyl- pentanoylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid331334(2S)-[5-Bromo-2-(2-phenoxy- propionylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid332335(2S)-[2-(3,5-Bis- rifluoromethyl- benzoylamino)-5-chloro- benzoylamino]-3-(3′- phenoxy-biphenyl-4-yl)- propionic acid333336(2S)-[5-Bromo-2-(3,4,5- trimethoxy-benzoylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid334337(2S)-{2-[(Adamantane-1- carbonyl)-amino]-5-bromo- benzoylamino}-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid335338(2S)-(5-Bromo-2-{[1-(4- chloro-phenyl)- cyclopropanecarbonyl]- amino}-benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid336339(2S)-(5-Bromo-2-{[1-(2,4- dichloro-phenyl)- cyclopropanecarbonyl]- amino}-benzoylamino)-3-(2′- phenoxy-biphenyl- 4-yl)-propionic acid337340(2S)-{5-Bromo-2-[(2,2- dichloro-1-methyl- cyclopropanecarbonyl)- amino]-benzoylamino}-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid338341(2S)-{5-Chloro-2-[(6-chloro- pyridine-3-carbonyl)-amino]- benzoylamino}-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid339342(2S)-(5-Chloro-2-{[1-(4- trifluoromethyl-pyrimidin-2- yl)-piperidine-4-carbonyl]- amino}-benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid340343(2S)-{5-Bromo-2-[(1-phenyl- cyclopropanecarbonyl)- amino]-benzoylamino}-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid341344(2S)-{5-Bromo-2-[(2-phenyl- cyclopropanecarbonyl)- amino]-benzoylamino}-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid342345(2S)-[5-Chloro-2-(2-phenoxy- benzoylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid3433463-(2′-Benzyloxy-biphenyl-4-yl)-(2S)-[2-(3,5-bis- trifluoromethyl- benzoylamino)-5-chloro- benzoylamino]-propionic acid344347(2S)-{5-Chloro-2-[(6- phenoxy-pyridine-3- carbonyl)-amino]- benzoylamino{-3- (2′-phenoxy-biphenyl-4-yl)- propionic acid345348(2S)-[5-Chloro-2-(4-phenoxy- benzoylamino)- benzoylamino]-3-(2′- cyclopentyloxy-biphenyl-4- yl)-propionic acid346349(2S)-[5-Chloro-2-(4-phenoxy- benzoylamino)- benzoylamino]-3-[2′-(4- trifluoromethyl-benzyloxy)- biphenyl-4-yl]-propionic acid3473503-[2′-(4-tert-Butyl-benzyloxy)- biphenyl-4-yl]-(2S)-[5-chloro- 2-(4-phenoxy- benzoylamino)- benzoylamino]-propionic acid348351(2S)-[5-Chloro-2-(4- [1,2,3]thiadiazol-4-yl- benzoylamino)benzoylamin]- 3-(2′-phenoxy-biphenyl-4-yl)- propionic acid349352(2S)-{5-Chloro-2-[4-(pyridin- 4-ylmethoxy)-benzoylamino]- benzoylamino}-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid350353(2S)-(5-Chloro-2-{[1-(4- chloro-phenyl)-5- trifluoromethyl-1H-pyrazole- 4-carbonyl]-amino}- benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid351354(2S)-(5-Chloro-2-{[1-(4- chloro-phenyl)-5-propyl-1H- pyrazole-4-carbonyl]-amino}- benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid352355(2S)-[5-Bromo-2-(3-phenyl- propionylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid353356(2S)-[2-(3,5-Bis- trifluoromethyl- benzoylamino)-5-chloro- benzoylamino]-3- [2′-(4-pentyl-phenoxy)- biphenyl-4-yl]-propionic acid354357(2S)-{2-[(Benzofuran-2- carbonyl)-amino]-5-bromo- benzoylamino}-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid355358(2S)-{2-[(Benzo[b]thiophene- 2-carbonyl)-amino]-5-bromo- benzoylamino}-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid356359(2S)-{5-Bromo-2-[(3-chloro- benzo[b]thiophene-2- carbonyl)-amino]- benzoylamino}-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid357360(2S)-{2-[(3,5-Bis- trifluoromethyl-benzoyl)- pentyl-amino]-5-chloro- benzoylamino}-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid358361(2S)-{2-[(Biphenyl-4- carbonyl)-(4-methyl-benzyl)- amino]-5-chloro- benzoylamino}-3-biphenyl-4- yl)-propionic acid3593623-Biphenyl-4-yl-(2S){5- chloro-2-[(3,5-dichloro- benzoyl)-(4-methyl-benzyl)- amino]-benzoylamino}- propionic acid360363(2S)-{2-[(Biphenyl-4- carbonyl)-(3-phenyl-propyl)- amino]-5-chloro- benzoylamino}-3-biphenyl-4- yl-propionic acid3613643-Biphenyl-4-yl-(2S)-{5- chloro-2-[(2,4-dichloro- benzoyl)-(3-phenyl-propyl)- amino]-benzoylamino}- propionic acid362365(2S)-{2-[(Biphenyl-4- carbonyl)-biphenyl-4- ylmethyl-amino]-5-chloro- benzoylamino}-3-biphenyl-4- yl-propionic acid3633663-Biphenyl-4-yl-(2S)-{2- [biphenyl-4-ylmethyl-(2,4- dichloro-benzoyl)-amino]-5- chloro-benzoylamino}- propionic acid364367(2S)-{2[(Biphenyl-4- carbonyl)-(4-isopropyl- benzyl)-amino]-5-chloro- benzoylamino}-3-biphenyl-4- yl-propionic acid365368(2S)-{2-[(Biphenyl-4- carbonyl)-(4-isopropoxy- benzyl)-amino]-5-chloro- benzoylamino}-3-biphenyl-4- yl-propionic acid366369(2S)-{5-Bromo-2-[(2-methyl- butyl)-(4-phenoxy-benzoyl)- amino]-benzoylamino}-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid367370(2S)-[5-Chloro-2-(5- dibutylamino-naphthalene-1- sulfonylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester368371(2S)-[5-Bromo-2-(4-tert- butyl- benzenesulfonylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid369372(2S)-[5-Bromo-2-(4-tert- butyl- benzenesulfonylamino)- benzoylamino]-3-(4′- phenoxy-biphenyl-4-yl)- propionic acid3703733-Biphenyl-4-yl-(2S)-[2-(3,4- dichloro- benzenesulfonylamino)-5- iodo-benzoylamino]- propionic acid371374(2S)-{2-[(Biphenyl-4- sulfonyl)-(4-methyl-benzyl)- amino]-5-chloro- benzoylamino}-3-biphenyl-4- yl-propionic acid372375(2S)-[2-(Biphenyl-4- sulfonylamino)-5-chloro- benzoylamino]-3-biphenyl-4- yl-propionic acid3733763-Biphenyl-4-yl-(2S)[2-(4- tert-butyl- benzenesulfonylamino)-5- propionic acid3743773-Biphenyl-4-yl-(2S){[4-(4- tert-butyl- benzenesulfonylamino)-3′- chloro-4′- fluoro-biphenyl-3-carbonyl]- amino}-propionic acid3753783-Biphenyl-4-yl-(2S)[5-iodo- 2-(2,4,5-trichloro- benzenesulfonylamino)- benzoylamino]-propionic acid3763793-Biphenyl-4-yl-(2S)-[2-(2,5- dichloro- benzenesulfonylamino)-5- iodo-benzoylamino]- propionic acid3773803-Biphenyl-4-yl-(2S)-[2-(2,4- difluoro- benzenesulfonylamino)-5- iodo-benzoylamino]- propionic acid3783813-Biphenyl-4-yl-(3S)-[5-iodo- 2-(4-propyl- benzenesulfonylamino)- benzoylamino]-propionic acid3793823-Biphenyl-4-yl-(2S)-(5-iodo- 2- pentamethylbenzenesulfonyl- amino-benzoylamino)- propionic acid3803833-Biphenyl-4-yl-(2S)-[5-iodo- 2-(toluene-4-sulfonylamino)- benzoylamino]-propionic acid3813843-Biphenyl-4-yl-(2S)-[2-(4- bromo- benzenesulfonylamino)-5- iodo-benzoylamino]- propionic acid3823853-Biphenyl-4-yl-(2S)-[5-iodo- 2-(naphthalene-2- sulfonylamino)- benzoylamino]-propionic acid3833863-Biphenyl-4-yl-(2S)-[5- bromo-2-(4-tert-butyl- benzenesulfonylamino)- benzoylamino]-propionic acid3843872-[5-Acetylamino-(2S)-(4- tert-butyl- benzenesulfonylamino)- benzoylamino]-3-biphenyl-4- yl-propionic acid3853883-Biphenyl-4-yl-(2R)-[5- bromo-2-(4-tert-butyl- benzenesulfonylamino)- benzoylamino]-propionic acid methyl ester3863893-Biphenyl-4-yl-(2S)-[5- bromo-2-(6-morpholin-4-yl- pyridine-3-sulfonylamino)- benzoylamino]propionic acid3873903-Biphenyl-4-yl-(2S)-[5- bromo-2-(4-vinyl- benzenesulfonylamino)- benzoylamino]-propionic acid3883913-Biphenyl-4-yl-(2S)-[5- bromo-2-(3,4-dichloro- benzenesulfonylamino)- benzoylamino]-propionic acid3893923-Biphenyl-4-yl-(2S)-[5- bromo-2-(4-nitro- bensenesulfonylamino)- benzoylamino]-propionic acid3903933-Biphenyl-4-yl-(2S)-[5- bromo-2-(2-phenyl- ethenesulfonylamino)- benzoylamino]-propionic acid3913943-Biphenyl-4-yl-(2S)-{5- bromo-2-[5-(5- trifluoromethyl-isoxazol-3-yl)- thiophene-2-sulfonylamino]- benzoylamino}-propionic acid3923953-Biphenyl-4-yl-(2S)-[5- bromo-2-(4-bromo- benzenesulfonylamino)- benzoylamino]-propionic acid3933963-Biphenyl-4-yl-(2S)-[5- bromo-2-(3,4-dimethoxy- benzenesulfonylamino)- benzoylamino]-propionic acid394397(2S)-[2-(4-Acetylamino- benzenesulfonylamino)-5- bromo-benzoylamino]-3- biphenyl-4-yl-propionic acid3953983-Biphenyl-4-yl-(2S)-[5- bromo-2-(4-isopropyl- benzenesulfonylamino)- benzoylamino]-propionic acid3963993-Biphenyl-4-yl-(2S)-[5- bromo-2-(2,5-dichloro- benzenesulfonylamino)- benzoylamino]-propionic acid3974003-Biphenyl-4-yl-(2S)-[5- bromo-2-(2-rifluoromethoxy- benzenesulfonylamino)- benzoylamino]-propionic acid398401(2S)-[5-Bromo-2-(5- dibutylamino-naphthalene-1- sulfonylamino)- benzoylamino]-3-(4′- phenoxy-biphenyl-4-yl)- propionic acid399402(2S)-[5-Chloro-2-(5- dibutylamino-naphthalene-1- sulfonylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid400403(2S)-[5-Chloro-2-(5- dimethylamino-naphthalene- 1-sulfonylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester401404(2S)-[5-Bromo-2-(5- dimethylamino-naphthalene- 1-sulfonylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester402405(2S)-[5-Chloro-2-(5- dimethylamino-naphthalene- 1-sulfonylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid403406(2S)-[5-Bromo-2-(5- dimethylamino-naphthalene- 1-sulfonylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid404407(2S)-[5-Bromo-2-(5- dibutylamino-naphthalene-1- sulfonylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid405408(2S)-(2- Benzenesulfonylamino-5- chloro- benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester406409(2S)-(2- Benzenesulfonylamino-5- chloro- benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid407410(2S)-[5-Chloro-2- (naphthalene-1- sulfonylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester408411(2S)-[5-Chloro-2- (naphthalene-1- sulfonylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid409412(2S)-[5-Chloro-2- (naphthalene-2- sulfonylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester410413(2S)-[5-Chloro-2- (naphthalene-2- sulfonylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid411414(2S)-[2-(4-tert-Butyl- benzenesulfonylamino)-5- chloro-benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester412415(2S)-[2-(4-tert-Butyl- benzenesulfonylamino)-5- chloro-benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid413416(2S)-[2-(Biphenyl-4- sulfonylamino)-5-chloro- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester414417(2S)-[2-(Biphenyl-4- sulfonylamino)-5-chloro- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid415418(2S)-[5-Chloro-2-(quinoline- 8-sulfonylamino)- benzoylamino]-3-(2′- phenoxy- biphenyl-4-yl)-propionic acid methyl ester416419(2S)-[5-Chloro-2-(quinoline- 8-sulfonylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid417420(2S)-[5-Chloro-2-(5-chloro- 1,3-dimethyl-1H-pyrazole-4- sulfonylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4- yl)-propionic acid418421(2S)-[5-Chloro-2-(1-methyl- 1H-imidazole-4- sulfonylamino)- benzoylamino]-3- (2′-phenoxy-biphenyl-4-yl)- propionic acid419422(2S)-[5-Chloro-2-(6-phenoxy- pyridine-3-sulfonylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid420423(2S)-[5-Chloro-2-(4-pyrazol- 1-yl-benzenesulfonylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid421424(2S)-[5-Chloro-2-(5-chloro- 1,3-dimethyl-1H-pyrazole-4- sulfonylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4- yl)-propionic acid methyl ester422425(2S)-{5-Chloro-2-[3-(5- methyl-[1,3,4]oxadiazol-2-yl)- benzenesulfonylamino]- benzoylamino}-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester423426(2S)-[5-Chloro-2-(6-phenoxy- pyridine-3-sulfonylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester424427(2S)-[5-Chloro-2-(4-pyrazol- 1-yl-benzenesulfonylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester425428(2S)-[5-Chloro-2-(1-methyl- 1H-imidazole-4- sulfonylamino)- benzoylamino]-3- (2′-phenoxy-biphenyl-4-yl)- propionic acid methyl ester426429(2S)-[5-Chloro-2-(3,5- dimethyl-isoxazole-4- sulfonylamino)- benzoylamino]-3- (2′-phenoxy-biphenyl-4-yl)- propionic acid methyl ester427430(2S)-[5-Chloro-2-(6- morpholin-4-yl-pyridine-3- sulfonylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester428431(2S)-[5-Chloro-2-(6- morpholin-4-yl-pyridine-3- sulfonylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid429432(2S)-{5-Chloro-2-[5-(2- methylsulfanyl- pyrimidin-4-yl)-thiophene-2- sulfonylamino]- benzoylamino}-3-(2′-phenoxy- biphenyl-4-yl)-propionic acid methyl ester430433(2S)-{5-Chloro-2-[5-(2- methylsulfanyl- pyrimidin-4-yl)-thiophene-2- sulfonylamino]- benzoylamino}-3-(2′-phenoxy- biphenyl-4-yl)-propionic acid431434(2S)-{5-Chloro-2-[4-(5- methyl-[1,3,4]oxadiazol-2-yl)- benzenesulfonylamino]- benzoylamino}-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid4324353-Biphenyl-4-yl-(2S)-[2-(2,5- dichloro- benzenesulfonylamino)-5- iodo-benzoylamino]- propionic acid methyl ester4334363-Biphenyl-4-yl-(2S)-[2-(4- bromo- benzenesulfonylamino)-5- iodo-benzoylamino]-propionic acid methyl ester4344373-Biphenyl-4-yl-(2S)-[2-(3,5- bis-trifluoromethyl- benzenesulfonylamino)-5- chloro-benzoylamino]-propionic acid435438(2S)-[5-Chloro-2-(4-oxazol-5- yl-benzenesulfonylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester436439(2S)-[5-Chloro-2-(4-oxazol-5- yl-benzenesulfonylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid437440(2S)-[5-Chloro-2-(4-phenoxy- benzenesulfonylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester438441(2S)-[5-Chloro-2-(4-phenoxy- benzenesulfonylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid439442(2S)-[5-Chloro-2-(3-nitro- benzenesulfonylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid440443(2S)-[2-(3,5-Bis- trifluoromethyl- benzenesulfonylamino)-5- chloro-benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester441444(2S)-[2-(3,5-Bis- trifluoromethyl- benzenesulfonylamino)-5- chloro-benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid442445(2S)-[2-(3-Amino- benzenesulfonylamino)-5- chloro-benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester443446(2S)-{5-Chloro-2-[5-(2- methyl-5-trifluoromethyl-2H- pyrazol-3-yl)-thiophene-2- sulfonylamino]- benzoylamino}-3- (2′-phenoxy-biphenyl-4-yl)- propionic acid methyl ester444447(2S)-{5-Chloro-2-[5-(2- methyl-5-trifluoromethyl-2H- pyrazol-3-yl)-thiophene-2- sulfonylamino]- benzoylamino}-3- (2′-phenoxy-biphenyl-4-yl)- propionic acid4454483-Biphenyl-4-yl-(2S)-[5- chloro-2-(5-dibutylamino- naphthalene-1- sulfonylamino)- enzoylamino]-propionic acid methyl ester4464493-Biphenyl-4-yl-(2S)-[5- chloro-2-(5-dibutylamino- naphthalene-1- sulfonylamino)- benzoylamino]-propionic acid447450(2S)-[5-Bromo-2-(4-tert- butyl- benzenesulfonylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester448451(2S)-[5-Bromo-2-(4-tert- butyl- benzenesulfonylamino)- benzoylamino]-3-(4′- phenoxy-biphenyl-4-yl)- propionic acid methyl ester4494523-Biphenyl-4-yl-(2S)-{5- chloro-2-[naphthalene-1- ylmethyl-(4-nitro- benzenesulfonyl)-amino]- benzoylamino}-propionic acid450453(2S)-{2-[(Biphenyl-4- sulfonyl)-(3-methyl-thiophen- 2-ylmethyl)-amino]-5-chloro- benzoylamino}-3-biphenyl-4- yl-propionic acid451454(2S)-{2-[(Biphenyl-4- sulfonyl)-(3phenyl-propyl)- amino]-5-chloro- benzoylamino}-3-biphenyl-4- yl-propionic acid452455(2S)-{2-[(Biphenyl-4- sulfonyl)-biphenyl-4- ylmethyl-amino]-5-chloro- benzoylamino}-3-biphenyl-4- yl-propionic acid453456(2S)-{2-[(Biphenyl-4- sulfonyl)-naphthalen-1- ylmethyl-amino]-5-chloro- benzoylamino}-3-biphenyl-4- yl-propionic acid454457(2S)-{2-[(Biphenyl-4- sulfonyl)-(4-isopropyl- benzyl)-amino]-5-chloro- benzoylamino}-3-biphenyl-4- yl-propionic acid4554583-Biphenyl-4-yl-(2S)-{2- [biphenyl-4-ylmethyl-(2,4- dichloro-benzenesulfonyl)- amino]-5-chloro- benzoylamino}-propionic acid456459(2S)-{2-[(Biphenyl-4- sulfonyl)-ethyl-amino]-5- chloro-benzoylamino}-3- biphenyl-4-yl-propionic acid457460(2S)-{2-[(Biphenyl-4- sulfonyl)-ethyl-amino]-5- iodo-benzoylamino}-3- biphenyl-4-yl-propionic acid4584612-{5-Chloro-2-[(naphthalen- 1-ylmethyl)-amino]- benzoylamino}-3-(4′- trifluoromethyl-biphenyl-4- yl)-propionic acid459462(S)-2-{2-[3-(4-tert-Butyl- phenoxy)-benzylamino]-5- chloro-benzoylamino}-3-(4′- cyclohexyl-biphenyl-4-yl)- propionic acid460463(2S)-{5-Chloro-2- [(naphthalen-1-ylmethyl)- amino]-benzoylamino}-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid461464(2S)-{5-Chloro-2- [(naphthalen-2-ylmethyl)- amino]-benzoylamino}-3-(2′- piperidin-1-ylmethyl- biphenyl-4-yl)-propionic acid4624652S-[5-Chloro-2-(2-methyl- butylamino)-benzoylamino]- 3-(2′-phenoxy-biphenyl-4-yl)- propionic acid4634663-Biphenyl-4-yl-2S-{5-chloro- 2-[(naphthalen-1-ylmethyl)- amino]-benzoylamino}- propionic acid4644673-(4′-tert-Butyl-biphenyl-4- yl)-(2S)-{5-chloro-2- [(naphthalen-1-ylmethyl)- amino]-benzoylamino}- propionic acid465468(2S)-{5-Chloro-2- [(naphthalen-1-ylmethyl)- amino]-benzoylamino}-3-(4′- methanesulfonyl-biphenyl-4- yl)-propionic acid466469(2S)-(5-Chloro-2- hexylamino-benzoylamino)- 3-(4′-trifluoromethyl- biphenyl-4-yl)-propionic acid467470(2S)-(5-Chloro-2- hexylamino-benzoylamino)- 3-(4′-dimethylamino- biphenyl-4-yl)-propionic acid468471(2S)-[2-(4-tert-Butyl- benzylamino)-5-chloro- benzoylamino]-3-(4′- dimethylamino-biphenyl-4- yl)-propionic acid469472(2S)-{2-[3-(4-tert-Butyl- phenoxy)-benzylamino]-5- chloro-benzoylamino}-3-(4′- dimethylamino-biphenyl-4- yl)-propionic acid470473(2S)-{5-Chloro-2- [(naphthalen-1-ylmethyl)- amino]-benzoylamino}-3-(4′- phenoxy-biphenyl-4-yl)- propionic acid471474(2S)-[2-(4-tert-Butyl- benzylamino)-5-chloro-benzoylamino]-3-)4′- cyclohexyl-biphenyl-4-yl)- propionic acid472475(2S)-(5-Chloro-2- heptylamino-benzoylamino)- 3-(4′-phenoxy-biphenyl-4-yl)- propionic acid473476(2S)-(5-Chloro-2- heptylamino-benzoylamino)- 3-(4′-cyclohexyl-biphenyl-4- yl)-propionic acid474477(2S)-{5-Chloro-2- [(naphthalen-1-ylmethyl)- amino]-benzoylamino}-3-(4′- cyclohexyl-biphenyl-4-yl)- propionic acid475478(2S)-{5-Chloro-2- [(naphthalen-1-ylmethyl)- amino]-benzoylamino}-3-(4′- pentyl-biphenyl-4-yl)- propionic acid476479(2S)-[2-(4-tert-Butyl- benzylamino)-5-iodo- benzoylamino]-3-(4′- phenoxy-biphenyl-4-yl)- propionic acid4774803-(4′-Amino-biphenyl-4-yl)- 2S)-{5-chloro-2- [(naphthalen-1-ylmethyl)- amino]-benzoylamino}- propionic acid4784813-Biphenyl-4-yl-2S-[2-(4-tert- butyl-benzylamino)-5-(3,4- dichloro-phenoxy)- benzoylamino]-propionic acid4794823-Biphenyl-4-yl-2S-[2-(4-tert- butyl-benzylamino)-5-(3- chloro-4-fluoro-phenoxy)- benzoylamino]-propionic acid4804833-Biphenyl-4-yl-(2S)-[2-(4- tert-butyl-benzylamino)-5-(3- trifluoromethyl-phenoxy)- benzoylamino]-propionic acid4814843-Biphenyl-4-yl-(2S)-[2-(4- tert-butyl-benzylamino)-5- (2,3,4-trichloro-phenoxy)- benzoylamino]- propionic acid4824853-Biphenyl-4-yl-(2S)-[2-(4- tert-butyl-benzylamino)-4- chloro-benzoylamino]- propionic acid4834863-Biphenyl-4-yl-(2S)-[2-(4- tert-butyl-benzylamino)-5-(4- chloro-phenoxy)- benzoylamino]- propionic acid4844873-Biphenyl-4-yl-2S-[2-(4-tert- butyl-benzylamino)-5-(4- chloro-3-fluoro-phenoxy)- benzoylamino]- propionic acid4854883-Biphenyl-4-yl-(2S)-[2-(4- tert-butyl-benzylamino)-5- (3,4-dimethoxy-phenoxy)- benzoylamino]-propionic acid4864893-(2′-Benzyloxy-biphenyl-4- yl)-(2S)-{5-chloro-2- [(naphthalen-1-ylmethyl)- amino]-benzoylamino}- propionic acid4874903-(3′-Benzyloxy-biphenyl-4- yl)-(2S)-{5-chloro-2- [(naphthalen-1-ylmethyl)- amino]-benzoylamino}- propionic acid488491(2S)-{5-Chloro-2- [(naphthalen-1-ylmethyl)- amino]-benzoylamino}-3-(2′- trifluoromethyl-biphenyl-4- yl)-propionic acid489492(2S)-{2-[3-(4-tert-Butyl- phenoxy)-benzylamino]-5- chloro-benzoylamino}-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid490493(2S)-[2-(4-tert-Butyl- benzylamino)-5-chloro- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid491494(2S)-[5-Bromo-2-(4-tert- butyl-benzylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid492495(2S)-[5-Bromo-2-(2-methyl- pentylamino)-benzoylamino]- 3-(2′-phenoxy-biphenyl-4-yl)- propionic acid4934963-Biphenyl-4-yl-(2S)-{5- chloro-2-[(piperidin-4- ylmethyl)-amino]- benzoylamino}-propionic acid4944973-(2′-Benzyloxy-biphenyl-4- yl)-(2S)-{2-]3-(4-tert-butyl- phenoxy)-benzylamino]-5- chloro-benzoylamino}- propionic acid4954983-(2′-Benzyloxy-biphenyl-4- yl)-(2S)-[2-(4-tert-butyl- benzylamino)-5-chloro-benzoylamino]-propionic acid496499(2S)-[5-Chloro-2-(3-phenoxy- benzylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid497500(2S)-[2-(3,5-Bis- trifluoromethyl-benzylamino)- 5-chloro-benzoylamino]-3- (2′-phenoxy-biphenyl-4-yl)- propionic acid498501(2S)-[5-Chloro-2-(4-phenoxy- benzylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid499502(2S)-[2-(4-Benzyloxy- benzylamino)-5-chloro- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid5005033-Biphenyl-4-yl-(2S)-[5-(2- chloro-4-trifluoromethyl- phenoxy)-2-(2-methyl- butylamino)-benzoylamino]- propionicacid501504(2S)-[3,5-Dichloro-2-(2- methyl-butylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid502505(2S)-[5-Bromo-2- (cyclohexylmethyl-amino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid503506(2S)-(5-Chloro-2- pentylamino-benzoylamino)- 3-(2′-phenoxy-biphenyl-4-yl)- propionic acid504507(2S)-{2-[3-(4-tert-Butyl- phenoxy)-benzylamino]-5- chloro-benzoylamino}-3-(2′- hydroxy-biphenyl-4-yl)- propionic acid505508(2S)-(5-Chloro-2-hexa-2,4- dienylamino- benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid506509(2S)-[5-Chloro-2-(3-phenyl- propylamino)-benzoylamino]- 3-(2′-phenoxy-biphenyl-4-yl)- propionic acid507510(2S)-(5-Chloro-2-octylamino- benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid508511(2S)-(5-Chloro-2- hexylamino-benzoylamino)- 3-(2′-phenoxy-biphenyl-4-yl)- propionic acid509512(2S)-[5-Chloro-2-(2,2- dimethyl-propylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid510513(2S)-[5-Chloro-2-(2-methyl- pent-2-enylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid511514(2S)-(5-Chloro-2-ethylamino-benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid512515:(2S)-(5-Chloro-2- diethylamino-benzoylamino)- 3-(2′-phenoxy-biphenyl-4-yl)- propionic acid5135162-(5-Chloro-2-diethylamino- benzoylamino)-3-[3′-(4- trifluoromethyl-phenoxy)- biphenyl-4-yl]-propionic acid514517(2S)-[5-Chloro-2-(3,5- dimethyl-piperidin-1-yl)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid5155183-Biphenyl-4-yl-(2S)-{2-[bis- (4-benzyloxy-benzyl)-amino]- 5-chloro-benzoylamino}- propionic acid5165193-Biphenyl-4-yl-(2S)-[2-(bis- naphthalen-1-ylmethyl- amino)-5-chloro- benzoylamino]-propionic acid5175203-Biphenyl-4-yl-(2S)-[2-(bis- biphenyl-4-methyl-amino)- 5-chloro-benzoylamino]- propionic acid518521(2S)-(5-Bromo-2- dibutylamino-benzoylamino)- 3-(2′-phenoxy-biphenyl-4-yl)- propionic acid519522(2S)-(5-Bromo-2- dihexylamino- benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid520523(2S)-(5-Chloro-2- dipentylamino- benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid521524(2S)-(5-Chloro-2-piperidin-1- yl-benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid522525(2S)-(5-Bromo-2- diethylamino-benzoylamino)- 3-(2′-phenoxy-biphenyl-4-yl)- propionic acid523526(2S)-(5-Chloro-2- diethylamino-benzoylamino)- 3-[3′-(3-chloro-4- fluorophenoxy)-biphenyl-4- yl]-propionic acid524527(2S)-(5-Bromo-2-piperidin-1- yl-benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid525528(2S)-(5-Chloro-2- diethylamino-benzoylamino)- 3-[3′-(4-methoxy-phenoxy)- biphenyl-4-yl]-propionic526529(2S)-(5-Chloro-2- diethylamino-benzoylamino)- 3-[3′-(4-trifluoromethoxy- phenoxy)-biphenyl-4-yl]- propionic acid5275303-[3′-(4-tert-Butyl-phenoxy)- biphenyl-4-yl]-(2S)-(5-chloro- 2-diethylamino- benzoylamino)-propionic acid528531(2S)-(5-Bromo-2- diethylamino-benzoylamino)- 3-[3′-(4-trifluoromethyl- phenoxy)-biphenyl-4-yl]- propionic acid529532(2S)-(5-Bromo-2- diethylamino-benzoylamino)- 3-[3′-(3-fluoro-phenoxy)- biphenyl-4-yl]-propionic acid530533(2S)-(5-Bromo-2-pyrrolidin-1- yl-benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid531534(2S)-[5-Chloro-2-(4-methyl- piperazin-1-yl)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid532535(2S)-[5-Chloro-2-(4-phenyl- piperazin-1-yl)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid533536(2S)-[5-Chloro-2-(3,4- dihydro-1H-isoquinolin-2-yl)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid534537(2S)-(5-Chloro-2-morpholin- 4-yl-benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid535538(2S)-(2-Azepin-1-yl-5-chloro- benzoylamino)-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid536539(2S)-[5-Chloro-2-(4- trifluoromethyl-piperidin-1- yl)-benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid537540(2S)-[5-Chloro-2-(4- methylsulfanyl- phenylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid538541(2S)-[5-Chloro-2-(3-chloro-4- fluoro-phenylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid539542(2S)-[5-Bromo-2-(4- trifluoromethyl- phenylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid540543(2S)-(5-Bromo-2- phenylamino-benzoylamino)- 3-(2′-phenoxy-biphenyl-4-yl)- propionic acid541544(2S)-(5-Chloro-2- phenylamino-benzoylamino)- 3-(2′-phenoxy-biphenyl-4-yl)- propionic acid542545(2S)-[5-Chloro-2-(4- trifluoromethyl- phenylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid543546(2S)-[5-Chloro-2-(3,5- dimethyl-phenylamino)- benzoylamino]3-(2′- phenoxy-biphenyl-4-yl)- propionic acid544547(2S)-[5-Chloro-2-(3- trifluoromethyl- phenylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid545548(2S)-[5-Chloro-2-(4-methoxy- phenylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid546549(2S)-[2-(4-tert-Butyl- phenylamino)-5-chloro- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid547550(2S)-[5-Chloro-2-(3,4- difluoro-phenylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid548551(2S)-[5-Chloro-2-(4-fluoro-3- methyl-phenylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid549552(2S)-[5-Chloro-2-(3,4- dichloro-phenylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid550553(2S)-[5-Chloro-2-(4- trifluoromethoxy- phenylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid551554(2S)-[5-Chloro-2-(4- methanesulfonyl- phenylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid552555(2S)-[2-(4-Benzyloxy- phenylamino)-5-chloro- benzoylamino[-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid553556(2S)-[5-Chloro-2- (naphthalen-1-ylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid554557(2S)-[5-Chloro-2- (naphthalen-2-ylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid555558(2S)-[2-(3,5-Bis- trifluoromethyl- phenylamino)-5-chloro- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid556559(2S)-[5-Chloro-2-(4- cyclohexyl-phenylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid557560(2S)-[2-(Biphenyl-4-ylamino)- 5-chloro- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid558561(2S)-[2-(3-Butoxy- phenylamino)-5-chloro- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid559562(2S)-[5-Chloro-2-(4-ethoxy- phenylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid560563(2S)-[5-Chloro-2-(4-fluoro-3- methoxy-phenylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid561564(2S)-[5-Chloro-2-(4-chloro- phenylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid562565(2S)-[5-Chloro-2-(3-chloro- phenylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid563566(2S)-[5-Chloro-2-(2,4- dichloro-phenylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid564567(2S)-[2-(benzo[1,3]dioxol-5- ylamino)-5-chloro- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid565568(2S)-[5-Chloro-2-(4-cyano- phenylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid566569(2S)-[5-Chloro-2-(4-methoxy- 3-methyl-phenylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid567570(2S)-[5-Chloro-2-(3- isopropyl-phenylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid568571(2S)-[5-Chloro-2-(4-nitro- phenylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid569572(2S)-[5-Chloro-2-(4-methyl- 3-nitro-phenylamino)- benzoylamino]-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid570573(2S)-{[(2-Biphenyl-4-yl- methoxycarbonyl-ethyl)-(4′- trifluoromethyl-biphenyl- carbonyl)-amino]-methyl}- (2S)-pyrrolidine-1-carboxylic acid tert-butyl ester571574(2S)-(2-{[(2-Biphenyl-4-yl-1- methoxycarbonyl-ethyl)-(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-methyl}- (2S)-pyrrolidine-1-sulfonyl)- benzoic acid methyl ester5725753-Biphenyl-4-yl-(2S)-[[(2R)- 1-(2-thiophen-2-yl-acetyl)- pyrrolidine-2-methyl]-(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid573576(2S)-[[2-(2-Acetylamino-4- methyl-thiazole-5- sulfonylamino)-ethyl]-(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-3-biphenyl- 4-yl-propionic acid methyl ester574577(2S)-[(Biphenyl-4-carbonyl)- (2-hydroxy-benzyl)-amino]-3- biphenyl-4-yl-propionic acid575578(2S)-[(Biphenyl-4-carbonyl)- (4-isopropyl-benzyl)-amino]- 3-biphenyl-4-yl-propionic acid5765793-Biphenyl-4-yl-(2S)-[(4- isopropyl-benzyl)- (naphthalene-2-carbonyl)- amino]-propionic acid5775803-Biphenyl-4-yl-(2S)-[(4-tert- butyl-benzoyl)-(4-isopropyl- benzyl)amino]- propionic acid5785813-Biphenyl-4-yl-(2S)-[(3,4- dichloro-benzoyl)-(4- isopropyl-benzyl)-amino]- propionic acid579582(2S)-[(Biphenyl-4-carbonyl)- naphthalen-1-ylmethyl- amino]-3-biphenyl-4-yl- propionic acid5805833-Biphenyl-4-yl-(2S)- [(naphthalene-2-carbonyl)- naphthalen-1-ylmethyl- amino]-propionic acid5815843-Biphenyl-4-yl-(2S)-[(4-tert- butyl-benzoyl)-naphthalen-1- ylmethyl-amino]-propionic acid5825853-Biphenyl-4-yl-(2S)-[(3,5- dichloro-benzoyl)- naphthalen-1-ylmethyl- amino]-propionic acid5835863-Biphenyl-4-yl-(2S)- [(naphthalene-1-carbonyl)- naphthalen-1-ylmethyl- amino]-propionic acid5845873-Biphenyl-4-yl-(2S)-[(3,4- dichloro-benzoyl)- naphthalen-1-ylmethyl- amino]-propionic acid5855883-Biphenyl-4-yl-(2S)-[(4- methyl-benzoyl)-naphthalen- 1-ylmethyl-amino]-propionic acid5865893-Biphenyl-4-yl-(2S)-[(2,4- dichloro-benzoyl)- naphthalen-1-ylmethyl- amino]-propionic acid5875903-Biphenyl-4-yl-(2S)- [naphthalen-1-yl-methyl-(4- nitro-benzoyl)-amino]- propionic acid5885913-Biphenyl-4-yl-(2S)-[(4- chloro-benzoyl)-naphthalen- 1-ylmethyl-amino]-propionic acid589592(2S)-[(Biphenyl-4-carbonyl)- (4-chloro- benzyl)-amino]-3-biphenyl-4- yl-propionic acid5905933-Biphenyl-4-yl-(2S)-[(4- chloro-benzyl)-(3,5-dichloro- benzoyl)-amino]-propionic acid591594(2S)-[(Biphenyl-4-carbonyl)- (5-tert-butyl-2-hydroxy- benzyl)-amino]-3-biphenyl-4- yl-propionic acid592595Biphenyl-4-carboxylic acid (2S)-{[(biphenyl-4-carbonyl)- (2-biphenyl-4-yl- 1-carboxy-ethyl)-amino]- methyl}-4-tert-butyl-phenyl ester5935963-Biphenyl-4-yl-(2S)-[(4- bromo-benzoyl)-(2-tert- butoxycarbonylamino-ethyl)- amino]-propionic acid5945973-Biphenyl-4-yl-(2S)-[(2-tert- butoxycarbonylamino-ethyl)- (4′-trifluoromethoxy-biphenyl- 4-carbonyl)-amino]-propionic acid595598(2S)-[(2-Amino-ethyl)-(4- bromo-benzoyl)-amino]-3- biphenyl-4-yl-propionic acid methyl ester596599(2S)-[(2-Amino-ethyl)-(4- bromo-benzoyl)-amino]-3- biphenyl-4-yl-propionic acid5976003-Biphenyl-4-yl-(2S)-[(4- chloro-benzyl)-(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid598601(2S)-{2-[(2-Biphenyl-4-yl-1- carboxy-ethyl)-(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]- ethylsulfamoyl}-benzoic acid5996023-Biphenyl-4-yl-(2S)-[[2-(2- methanesulfonyl- benzenesulfonylamino)- ethyl]- (4′-trifluoromethyl-biphenyl- 4-carbonyl)-amino]-propionic acid600603(2S)-{[(2-Biphenyl-4-yl-1- methoxycarbonyl-ethyl)-(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-methyl}- (2R)-pyrrolidine-1-carboxylic acid tert-butyl ester601604(2S)-{2-[(2-Biphenyl-4-yl-1- methoxycarbonyl-ethyl)-(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]- ethylsulfamoyl}-benzoic acid methyl ester6026053-Biphenyl-4-yl-(2S)-[[2-(2- methanesulfonyl- benzenesulfonylamino)- ethyl]- (4′-trifluoromethyl-biphenyl- 4-carbonyl)-amino]-propionic acid methyl ester6036063-Biphenyl-4-yl-(2S)-[[2-(4- methanesulfonyl- benzenesulfonylamino)- ethyl]-(4′-trifluoromethyl- biphenyl-4-carbonyl)-amino]- propionic acid methyl ester6046073-Biphenyl-4-yl-(2S)-[[1-(2- methanesulfonyl- benzenesulfonyl)-(2S)- pyrrolidin-2-ylmethyl]-(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid methyl ester6056083-Biphenyl-4-yl-(2S)-[[1-(4- methanesulfonyl- benzenesulfonyl)-(2S)- pyrrolidin-2-ylmethyl]-(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid methyl ester606609(2S)-{[(2-Biphenyl-4-yl-1- carboxy-ethyl)-(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-methyl}- (2S)-pyrrolidine-1-carboxylic acid tert-butyl ester607610(2S)-{[(2-Biphenyl-4-yl-1- carboxy-ethyl)-(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-methyl}- (2R)-pyrrolidine-1-carboxylic acid tert-butyl ester608611(2S)-(2-{[(2-Biphenyl-4-yl-1- carboxy-ethyl)-(4′- trifluoromethyl-biphenyl- 4-carbonyl)-amino]-methyl}- (2S)-pyrrolidine-1-sulfonyl)- benzoic acid methylester6096123-Biphenyl-4-yl-(2S)-[[1-(2- methanesulfonyl- benzenesulfonyl)-(2S)- pyrrolidin-2-ylmethyl]-(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid6106133-Biphenyl-4-yl-(2S)-[[1-(4- methanesulfonyl- benzenesulfonyl)-(2S)- pyrrolidin-2-ylmethyl]-(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid611614(2S)-(2-{[(2-Biphenyl-4-yl-1- methoxycarbonyl-ethyl)-(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-methyl}- (2R)- pyrrolidine-1-sulfonyl)- benzoic acid methyl ester6126153-Biphenyl-4-yl-(2S)-[[1-(2- methanesulfonyl- benzenesulfonyl)-(2R)- pyrrolidin-2-ylmethyl]-(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid methyl ester6136163-Biphenyl-4-yl-(2S)-[[1-(4- methanesulfonyl- benzenesulfonyl)-(2R)- pyrrolidin-2-ylmethyl]-(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid methyl ester6146173-Biphenyl-4-yl-(2S)-[[1-(2- thiophen-2-yl-acetyl)-(2R)- pyrrolidin-2-ylmethyl]- (4′-trifluoromethyl-biphenyl- 4-carbonyl)-amino]-propionic acid methyl ester615618(2S)-(2-{[(2-Biphenyl-4-yl-1- carboxy-ethyl)-(4′- trifluoromethyl-biphenyl- 4-carbonyl)-amino]-methyl}- (2R)-pyrrolidine-1-sulfonyl)- benzoic acid methyl ester6166193-Biphenyl-4-yl-(2S)-[[1-(2- methanesulfonyl- benzenesulfonyl)-(2R)- pyrrolidin-2-ylmethyl]-(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid6176203-Biphenyl-4-yl-(2S)-[(1- cyclopentanecarbonyl-(2S)- pyrrolidin-2-ylmethyl)-(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid methyl ester6186213-Biphenyl-4-yl-(2S)-[(1- cyclopropanecarbonyl-(2R)- pyrrolidin-2-ylmethyl)-(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid methyl ester6196223-Biphenyl-4-yl-(2S)-[[1-(4- methanesulfonyl- benzenesulfonyl)-(2R)- pyrrolidin-2-ylmethyl]-(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid620623(2S)-[(1-Acetyl-(2S)- pyrrolidin-2-ylmethyl)-(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-3-biphenyl- 4-yl-propionic acid6216243-Biphenyl-4-yl-(2S)-[[1-(2,2- dimethyl-propionyl)-(2S)- pyrrolidin-2-ylmethyl]- (4′-trifluoromethyl-biphenyl- 4-carbonyl)-amino]-propionic acid6226253-Biphenyl-4-yl-(2S)-[(1- cyclopentanecarbonyl-(2S)- pyrrolidin-2-ylmethyl)-(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid623626(2S)-[(1-Acetyl-(2R)- pyrrolidin-2-ylmethyl)-(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-3-biphenyl- 4-yl-propionic acid6246273-Biphenyl-4-yl-(2S)-[(1- cyclopropanecarbonyl-(2R)- pyrrolidin-2-ylmethyl)-(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid625628(2S)-[[2-(2-Acetylamino-4- methyl-thiazole-5- sulfonylamino)-ethyl]-(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-3-biphenyl- 4-yl-propionic acid6266293-Biphenyl-4-yl-(2S)-[[2-(5- chloro-1,3-dimethyl-1H- pyrazole-4-sulfonylamino)- ethyl]-(4′-trifluoromethyl- biphenyl-4-carbonyl)-amino]- propionic acid6276303-Biphenyl-4-yl-(2S)-[[2-(3,5- dimethyl-isoxazole-4- sulfonylamino)-ethyl]- (4′-trifluoromethyl-biphenyl- 4-carbonyl)-amino]-propionic acid6286313-Biphenyl-4-yl-(2S)-[[2-(1,2- dimethyl-1H-imidazole-4- sulfonylamino)-ethyl]-(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid6296323-Biphenyl-4-yl-(2S)-[[2-(3,5- dimethyl-isoxazole-4- sulfonylamino)-ethyl]- (4′-trifluoromethyl-biphenyl- 4-carbonyl)-amino]-propionic acid methyl ester6306333-Biphenyl-4-yl-(2S)-[[2-(1,2- dimethyl-1H-imidazole-4- sulfonylamino)-ethyl]-(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]- propionic acid methyl ester6316343-Biphenyl-4-yl-(2S)-[[2-(5- chloro-1,3-dimethyl-1H- pyrazole-4-sulfonylamino)- ethyl]-(4′-trifluoromethyl- biphenyl-4-carbonyl)-amino]- propionic acid methyl ester6326353-Biphenyl-4-yl-(2S)-[[2-(1- methyl-1H- imidazole-4-sulfonylamino)- ethyl]-(4′-trifluoromethyl- biphenyl-4-carbonyl)-amino]- propionic acid6336363-Biphenyl-4-yl-(2S)-[[2-(2,4- dimethoxy-benzylamino)- ethyl]-(4′-trifluoromethyl- biphenyl-4-carbonyl)-amino]- propionic acid6346373-Biphenyl-4-yl-(2S)-[(2-tert- butoxycarbonylamino-ethyl)- (4′-trifluoromethyl- biphenyl-4-carbonyl)- amino]-propionic acid6356382-{[1-(4-Fluoro-phenyl)-5- trifluoromethyl-1H-pyrazole- 4-carbonyl]-amino}-3-(4′- trifluoromethoxy-biphenyl-4- yl)-propionic acid6366392-{[1-(4-Fluoro-phenyl)-5- trifluoromethyl-1H-pyrazole- 4-carbonyl]-amino}-3-(4′- trifluoromethyl-biphenyl-4- yl)-propionic acid6376403-Biphenyl-4-yl-2-{[1-(4- fluoro-phenyl)-5- trifluoromethyl-1H-pyrazole- 4-carbonyl]-amino}-propionic acid638641(2S)-{[1-(4-Chloro-phenyl)-5- trifluoromethyl-1H-pyrazole- 4-carbonyl]-amino}-3-(4′- trifluoromethyl-biphenyl-4- yl)-propionic acid6396423-Biphenyl-4-yl-(2S)-{[1-(4- chloro-phenyl)-5- trifluoromethyl-1H-pyrazole- 4-carbonyl]-amino}-propionic acid640643(2S)-{[1-(4-Chloro-phenyl)-5- trifluoromethyl-1H-pyrazole- 4-carbonyl]-amino}-3-(4′- trifluoromethoxy-biphenyl-4- yl)-propionic acid6416442-{[1-(4-Fluoro-phenyl)-5- trifluoromethyl-1H-pyrazole- 4-carbonyl]-amino}-3-(6- phenyl-pyridin-3-yl)-propionic acid642645(2S)-{[1-(4-Nitro-phenyl)-5- trifluoromethyl-1H-pyrazole- 4-carbonyl]-amino}-3-(4′- trifluoromethoxy-biphenyl-4- yl)-propionic acid643646(2S)-{[1-(4-tert-Butyl-phenyl)- 5-trifluoromethyl-1H- pyrazole-4-carbonyl]- amino}-3-(4′- trifluoromethoxy-biphenyl-4- yl)-propionic acid644647(2S)-[(1-p-Tolyl-5- trifluoromethyl-1H- pyrazole-4-carbonyl)-amino]- 3-(4′-trifluoromethoxy- biphenyl-4-yl)-propionic acid645648(2S)-{[1-(6-Methoxy- pyridazin-3-yl)-5- trifluoromethyl-1H-pyrazole- 4-carbonyl]-amino}-3-(4′- trifluoromethoxy- biphenyl-4-yl)-propionic acid646649(2S)-[(5-Methyl-1-phenyl-1H- pyrazole-4-carbonyl)-amino]- 3-(4′-trifluoromethoxy- biphenyl-4-yl)-propionic acid647650(2S)-{[1-(4-Chloro-phenyl)-5- trifluoromethyl-1H-pyrazole- 4-carbonyl]-amino}-3-(4′- trifluoromethoxy-biphenyl- 4-yl)-propionic acid6486513-(4′-Trifluoromethoxy- biphenyl-4-yl)-(2S)-{[1-(4- trifluoromethoxy-phenyl)-5- trifluoromethyl-1H-pyrazole- 4-carbonyl]-amino}-propionic acid649652(2S)-{[1-(3-Chloro-4-fluoro- phenyl)-5- trifluoromethyl-1H-pyrazole- 4-carbonyl]-amino}-3-(4′- trifluoromethoxy- biphenyl-4-yl)-propionic acid650653(2S)-{[1-(4-Chloro-phenyl)- 1H-pyrazole-4-carbonyl]- amino}-3-(4′- trifluoromethoxy-biphenyl-4- yl)-propionic acid651654(2S)-[(1-Phenyl-5- trifluoromethyl-1H-pyrazole- 4-carbonyl)-amino]-3-(4′- trifluoromethoxy-biphenyl-4- yl)-propionic acid652655(2S)-[(1-Phenyl-5- trifluoromethyl-1H-pyrazole- 4-carbonyl)-amino]-3-(4′- trifluoromethyl-biphenyl-4- yl)-propionic acid6536563-Biphenyl-4-yl-(2S)-[(1- phenyl-5-trifluoromethyl-1H- pyrazole-4-carbonyl)-amino]- propionic acid654657(2S)-{[1-(4-Chloro-phenyl)-5- propyl-1H-pyrazole-4- carbonyl]-amino}-3-(2′- phenoxy-biphenyl-4-yl)- propionic acid6556583-(Biphenyl-4-ylmethoxy)- (2S)-[(4′-trifluoromethyl- biphenyl-4-carbonyl)-amino]- propionic acid6566593-[(Biphenyl-4-ylmethyl)- amino]-(2S)-[(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid.6576603-(Biphenyl-4-ylmethyl- methyl-amino)-(2S)-[(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid:6586613-(Biphenyl-4-ylmethyl- pyridin-4-ylmethyl-amino)- (2S)-[(4′-trifluoromethyl- biphenyl-4-carbonyl)-amino]- propionic acid:6596623-(Biphenyl-4-ylmethyl-furan- 2-ylmethyl-amino)-(2S)-[(4′- trifluoromethyl- biphenyl-4-carbonyl)-amino]- propionic acid:6606633- (Biphenyl-4- carbonyl)-amino]-(2S)-[(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid:661664(2S), 3-Bis-[(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]- propionic acid:6626653-(Biphenyl-4- sulfonylamino)-(2S)-[(4′- trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid:


[0204] In another aspect, the present invention comprises a pharmaceutical composition comprising the compound of Formula (I) and one or more pharmaceutically acceptable carriers, excipients, or diluents.

[0205] As used herein, the term “lower” refers to a group having between one and six carbons.

[0206] As used herein, the term “alkyl” refers to a straight or branched chain hydrocarbon having from one to ten carbon atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such an “alkyl” group may containing one or more O, S, S(O), or S(O)2 atoms. Examples of “alkyl” as used herein include, but are not limited to, methyl, n-butyl, t-butyl, n-pentyl, isobutyl, and isopropyl, and the like.

[0207] As used herein, the term “alkylene” refers to a straight or branched chain divalent hydrocarbon radical having from one to ten carbon atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such an “alkylene” group may containing one or more O, S, S(O), or S(O)2 atoms. Examples of “alkylene” as used herein include, but are not limited to, methylene, ethylene, and the like.

[0208] As used herein, the term “alkenyl” refers to a hydrocarbon radical having from two to ten carbons and at least one carbon-carbon double bond, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such an “alkenyl” group may containing one or more O, S, S(O), or S(O)2 atoms.

[0209] As used herein, the term “alkenylene” refers to a straight or branched chain divalent hydrocarbon radical having from two to ten carbon atoms and one or more carbon-carbon double bonds, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such an “alkenylene” group may containing one or more O, S, S(O), or S(O)2 atoms. Examples of “alkenylene” as used herein include, but are not limited to, ethene-1,2-diyl, propene-1,3-diyl, methylene-1,1-diyl, and the like.

[0210] As used herein, the term “alkynyl” refers to a hydrocarbon radical having from two to ten carbons and at least one carbon-carbon triple bond, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such an “alkynyl” group may containing one or more O, S, S(O), or S(O)2 atoms.

[0211] As used herein, the term “alkynylene” refers to a straight or branched chain divalent hydrocarbon radical having from two to ten carbon atoms and one or more carbon-carbon triple bonds, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such an “alkynylene” group may containing one or more O, S, S(O), or S(O)2 atoms. Examples of “alkynylene” as used herein include, but are not limited to, ethyne-1,2-diyl, propyne-1,3-diyl, and the like.

[0212] As used herein, “cycloalkyl” refers to a alicyclic hydrocarbon group optionally possessing one or more degrees of unsaturation, having from three to twelve carbon atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. “Cycloalkyl” includes by way of example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and the like.

[0213] As used herein, the term “cycloalkylene” refers to an non-aromatic alicyclic divalent hydrocarbon radical having from three to twelve carbon atoms and optionally possessing one or more degrees of unsaturation, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of “cycloalkylene” as used herein include, but are not limited to, cyclopropyl-1,1-diyl, cyclopropyl-1,2-diyl, cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl, cyclohexyl-1,4-diyl, cycloheptyl-1,4-diyl, or cyclooctyl-1,5-diyl, and the like.

[0214] As used herein, the term “heterocyclic” or the term “heterocyclyl” refers to a three to twelve-membered heterocyclic ring optionally possessing one or more degrees of unsaturation, containing one or more heteroatomic substitutions selected from S, SO, SO2, O, or N, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such a ring may be optionally fused to one or more of another “heterocyclic” ring(s) or cycloalkyl ring(s). Examples of “heterocyclic” include, but are not limited to, tetrahydrofuran, 1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine, morpholine, piperazine, and the like.

[0215] As used herein, the term “heterocyclylene” refers to a three to twelve-membered heterocyclic ring diradical optionally having one or more degrees of unsaturation containing one or more heteroatoms selected from S, SO, SO2, O, or N, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such a ring may be optionally fused to one or more benzene rings or to one or more of another “heterocyclic” rings or cycloalkyl rings. Examples of “heterocyclylene” include, but are not limited to, tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl, pyran-2,4-diyl, 1,4-dioxane-2,3-diyl, 1,3-dioxane-2,4-diyl, piperidine-2,4-diyl, piperidine-1,4-diyl, pyrrolidine-1,3-diyl, morpholine-2,4-diyl, piperazine-1,4-dyil, and the like.

[0216] As used herein, the term “aryl” refers to a benzene ring or to an optionally substituted benzene ring system fused to one or more optionally substituted benzene rings, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, di(lower alkyl)aminoalkyl, aminoalkyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acylamino, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of aryl include, but are not limited to, phenyl, 2-naphthyl, 1-naphthyl, 1-anthracenyl, and the like.

[0217] As used herein, the term “arylene” refers to a benzene ring diradical or to a benzene ring system diradical fused to one or more optionally substituted benzene rings, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, di(lower alkyl)aminoalkyl, aminoalkyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acylamino, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of “arylene” include, but are not limited to, benzene-1,4-diyl, naphthalene-1,8-diyl, and the like.

[0218] As used herein, the term “heteroaryl” refers to a five- to seven-membered aromatic ring, or to a polycyclic heterocyclic aromatic ring, containing one or more nitrogen, oxygen, or sulfur heteroatoms, where N-oxides and sulfur monoxides and sulfur dioxides are permissible heteroaromatic substitutions, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. For polycyclic aromatic ring systems, one or more of the rings may contain one or more heteroatoms. Examples of “heteroaryl” used herein are furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, quinazoline, benzofuran, benzothiophene, indole, and indazole, and the like.

[0219] As used herein, the term “heteroarylene” refers to a five- to seven-membered aromatic ring diradical, or to a polycyclic heterocyclic aromatic ring diradical, containing one or more nitrogen, oxygen, or sulfur heteroatoms, where N-oxides and sulfur monoxides and sulfur dioxides are permissible heteroaromatic substitutions, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. For polycyclic aromatic ring system diradicals, one or more of the rings may contain one or more heteroatoms. Examples of “heteroarylene” used herein are furan-2,5-diyl, thiophene-2,4-diyl, 1,3,4-oxadiazole-2,5-diyl, 1,3,4-thiadiazole-2,5-diyl, 1,3-thiazole-2,4-diyl, 1,3-thiazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,3-diyl, pyridine-2,5-diyl, pyrimidine-2,4-diyl, quinoline-2,3-diyl, and the like.

[0220] As used herein, the term “fused cycloalkylaryl” refers to a cycloalkyl group fused to an aryl group, the two having two atoms in common, and wherein the aryl group is the point of substitution. Examples of “fused cycloalkylaryl” used herein include 5-indanyl, 5,6,7,8-tetrahydro-2-naphthyl,
666

[0221] and the like.

[0222] As used herein, the term “fused cycloalkylarylene” refers to a fused cycloalkylaryl, wherein the aryl group is divalent. Examples include
667

[0223] and the like.

[0224] As used herein, the term “fused arylcycloalkyl” refers to an aryl group fused to a cycloalkyl group, the two having two atoms in common, and wherein the cycloalkyl group is the point of substitution. Examples of “fused arylcycloalkyl” used herein include 1-indanyl, 2-indanyl, 1-(1,2,3,4-tetrahydronaphthyl),
668

[0225] and the like.

[0226] As used herein, the term “fused arylcycloalkylene” refers to a fused arylcycloalkyl, wherein the cycloalkyl group is divalent. Examples include
669

[0227] and the like.

[0228] As used herein, the term “fused heterocyclylaryl” refers to a heterocyclyl group fused to an aryl group, the two having two atoms in common, and wherein the aryl group is the point of substitution. Examples of “fused heterocyclylaryl” used herein include 3,4-methylenedioxy-1-phenyl,
670

[0229] and the like

[0230] As used herein, the term “fused heterocyclylarylene” refers to a fused heterocyclylaryl, wherein the aryl group is divalent. Examples include
671

[0231] and the like.

[0232] As used herein, the term “fused arylheterocyclyl” refers to an aryl group fused to a heterocyclyl group, the two having two atoms in common, and wherein the heterocyclyl group is the point of substitution. Examples of “fused arylheterocyclyl” used herein include 2-(1,3-benzodioxolyl),
672

[0233] and the like.

[0234] As used herein, the term “fused arylheterocyclylene” refers to a fused arylheterocyclyl, wherein the heterocyclyl group is divalent. Examples include
673

[0235] and the like.

[0236] As used herein, the term “fused cycloalkylheteroaryl” refers to a cycloalkyl group fused to a heteroaryl group, the two having two atoms in common, and wherein the heteroaryl group is the point of substitution. Examples of “fused cycloalkylheteroaryl” used herein include 5-aza-6-indanyl,
674

[0237] and the like.

[0238] As used herein, the term “fused cycloalkylheteroarylene” refers to a fused cycloalkylheteroaryl, wherein the heteroaryl group is divalent. Examples include
675

[0239] and the like.

[0240] As used herein, the term “fused heteroarylcycloalkyl” refers to a heteroaryl group fused to a cycloalkyl group, the two having two atoms in common, and wherein the cycloalkyl group is the point of substitution. Examples of “fused heteroarylcycloalkyl” used herein include 5-aza-1-indanyl,
676

[0241] and the like.

[0242] As used herein, the term “fused heteroarylcycloalkylene” refers to a fused heteroarylcycloalkyl, wherein the cycloalkyl group is divalent. Examples include
677

[0243] and the like.

[0244] As used herein, the term “fused heterocyclylheteroaryl” refers to a heterocyclyl group fused to a heteroaryl group, the two having two atoms in common, and wherein the heteroaryl group is the point of substitution. Examples of “fused heterocyclylheteroaryl” used herein include 1,2,3,4-tetrahydro-beta-carbolin-8-yl,
678

[0245] and the like.

[0246] As used herein, the term “fused heterocyclylheteroarylene” refers to a fused heterocyclylheteroaryl, wherein the heteroaryl group is divalent. Examples include
679

[0247] and the like.

[0248] As used herein, the term “fused heteroarylheterocyclyl” refers to a heteroaryl group fused to a heterocyclyl group, the two having two atoms in common, and wherein the heterocyclyl group is the point of substitution. Examples of “fused heteroarylheterocyclyl” used herein include -5-aza-2,3-dihydrobenzofuran-2-yl,
680

[0249] and the like.

[0250] As used herein, the term “fused heteroarylheterocyclylene” refers to a fused heteroarylheterocyclyl, wherein the heterocyclyl group is divalent. Examples include
681

[0251] and the like.

[0252] As used herein, the term “acid isostere” refers to a substituent group which will ionize at physiological pH to bear a net negative charge. Examples of such “acid isosteres” include but are not limited to heteroaryl groups such as but not limited to isoxazol-3-ol-5-yl, 1H-tetrazole-5-yl, or 2H-tetrazole-5-yl. Such acid isosteres include but are not limited to heterocyclyl groups such as but not limited to imidazolidine-2,4-dione-5-yl, imidazolidine-2,4-dione-1-yl, 1,3-thiazolidine-2,4-dione-5-yl, or 5-hydroxy-4H-pyran-4-on-2-yl.

[0253] As used herein, the term “direct bond”, where part of a structural variable specification, refers to the direct joining of the substituents flanking (preceding and succeeding) the variable taken as a “direct bond”.

[0254] As used herein, the term “alkoxy” refers to the group RaO—, where Ra is alkyl.

[0255] As used herein, the term “alkenyloxy” refers to the group RaO, where Ra is alkenyl.

[0256] As used herein, the term “alkynyloxy” refers to the group RaO, where Ra is alkynyl.

[0257] As used herein, the term “alkylsulfanyl” refers to the group RaS—, where Ra is alkyl.

[0258] As used herein, the term “alkenylsulfanyl” refers to the group RaS—, where Ra is alkenyl.

[0259] As used herein, the term “alkynylsulfanyl” refers to the group RaS—, where Ra is alkynyl.

[0260] As used herein, the term “alkylsulfenyl” refers to the group RaS(O)—, where Ra is alkyl.

[0261] As used herein, the term “alkenylsulfenyl” refers to the group RaS(O)—, where Ra is alkenyl.

[0262] As used herein, the term “alkynylsulfenyl” refers to the group RaS(O)—, where Ra is alkynyl.

[0263] As used herein, the term “alkylsulfonyl” refers to the group RaSO2—, where Ra is alkyl.

[0264] As used herein, the term “alkenylsulfonyl” refers to the group RaSO2—, where Ra is alkenyl.

[0265] As used herein, the term “alkynylsulfonyl” refers to the group RaSO2—, where Ra is alkynyl.

[0266] As used herein, the term “acyl” refers to the group RaC(O)—, where Ra is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or heterocyclyl.

[0267] As used herein, the term “aroyl” refers to the group RaC(O)—, where Ra is aryl.

[0268] As used herein, the term “heteroaroyl” refers to the group RaC(O)—, where Ra is heteroaryl.

[0269] As used herein, the term “alkoxycarbonyl” refers to the group RaOC(O)—, where Ra is alkyl.

[0270] As used herein, the term “acyloxy” refers to the group RaC(O)O—, where Ra is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or heterocyclyl.

[0271] As used herein, the term “aroyloxy” refers to the group RaC(O)O—, where Ra is aryl.

[0272] As used herein, the term “heteroaroyloxy” refers to the group RaC(O)O—, where Ra is heteroaryl.

[0273] As used herein, the term “optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s) which occur and events that do not occur.

[0274] As used herein, the term “substituted” refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.

[0275] As used herein, the terms “contain” or “containing” can refer to in-line substitutions at any position along the above defined alkyl, alkenyl, alkynyl or cycloalkyl substituents with one or more of any of O, S, SO, SO2, N, or N-alkyl, including, for example, —CH2—O—CH2—, —CH2—SO2—CH2—, —CH2—NH—CH3 and so forth.

[0276] Whenever the terms “alkyl” or “aryl” or either of their prefix roots appear in a name of a substituent (e.g. arylalkoxyaryloxy) they shall be interpreted as including those limitations given above for “alkyl” and “aryl”. Alkyl or cycloalkyl substituents shall be recognized as being functionally equivalent to those having one or more degrees of unsaturation. Designated numbers of carbon atoms (e.g. C1-10) shall refer independently to the number of carbon atoms in an alkyl, alkenyl or alkynyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which the term “alkyl” appears as its prefix root.

[0277] As used herein, the term “oxo” shall refer to the substituent ═O.

[0278] As used herein, the term “halogen” or “halo” shall include iodine, bromine, chlorine and fluorine.

[0279] As used herein, the term “mercapto” shall refer to the substituent —SH.

[0280] As used herein, the term “carboxy” shall refer to the substituent —COOH.

[0281] As used herein, the term “cyano” shall refer to the substituent —CN.

[0282] As used herein, the term “aminosulfonyl” shall refer to the substituent —SO2NH2.

[0283] As used herein, the term “carbamoyl” shall refer to the substituent —C(O)NH2.

[0284] As used herein, the term “sulfanyl” shall refer to the substituent —S—.

[0285] As used herein, the term “sulfenyl” shall refer to the substituent —S(O)—.

[0286] As used herein, the term “sulfonyl” shall refer to the substituent —S(O)2—.

[0287] The compounds can be prepared readily according to the following reaction Schemes (in which variables are as defined before or are defined) using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail.

[0288] The present invention also provides a method for the synthesis of compounds useful as intermediates in the preparation of compounds of Formula (I) along with methods for the preparation of compounds of Formula (I).

[0289] Scheme I describes the synthesis of an intermediate of structure (4).

[0290] Ar3 and Ar4 are, independently, groups such as, but not limited to, a heteroaryl, heteroarylene, arylene, or aryl ring system.

[0291] As shown in Scheme I, in one embodiment, bromo- or iodo-substituted aryl alanine methyl ester (or amino acid esterified in linkage to Wang resin) (1) is treated with a carboxylic acid in the presence of a coupling reagent, such as, but not limited to, diisopropyl carbodiimide (DIC) to form the amide (2). The resulting amide is then subjected to coupling with an arylboronic acid in the presence of a catalyst such as but not limited to tetrakis(triphenylphosphine)palladium (0), in the presence of base such as, but not limited to, sodium carbonate to form compound (3). The methyl ester (3) is hydrolyzed using a base such as, but not limited to, LiOH to provide the free carboxylic acid (4), where Ar1 and Ar2 are as defined for Formula (1).
682

[0292] Scheme II describes the preparation of a compound of structure (4).

[0293] Ar3 and Ar4 are, independently, groups such as but not limited to a heteroaryl, heteroarylene, arylene, or aryl ring system.

[0294] As shown in Scheme II, in another embodiment, an aryl hydroxy amino acid methyl ester (or amino acid esterified in linkage to Wang resin) (5) is treated with a carboxylic acid Ar2—CO2H in the presence of a coupling reagent such as, but not limited to, diisopropyl carbodiimide (DIC) to form the amide (6). The resulting amide is then subjected to: 1) nucleophilic substitutions with an optionally substituted electron-deficient fluoroaromatic or fluoroheteroaromatic in the presence of base such as, but not limited to, potassium carbonate; or 2) coupling with an aryl bromide, or heteroaryl bromide, and copper iodide in the presence of a base including, but not limited to, cesium carbonate to form compound (7). The methyl ester in (7) is hydrolyzed using a base such as LiOH to provide the free carboxylic acid (4), where Ar1 and Ar2 are as defined for Formula (I)
683

[0295] Scheme III describes the preparation of a compound of formula (4).

[0296] Ar5 and Ar6 are, independently, groups such as but not limited to a heteroaryl, heteroarylene, arylene, or aryl ring system.

[0297] As shown in Scheme III, in another embodiment, an amino acid methyl ester (or, alternately, an amino acid esterified in linkage to Wang resin) (8) is treated with a bromo-substituted aryl carboxylic acid in the presence of a coupling reagent such as, but not limited to, diisopropyl carbodiimide (DIC) to form the amide (9). The resulting amide then is subjected to coupling with an arylboronic acid or heteroarylboronic acid in the presence of a catalyst such as but not limited to tetrakis(triphenylphosphine)palladium(0), in the presence of base such as, but not limited to, sodium carbonate to form compound (10). The methyl ester (10) is hydrolyzed using a base such as, but not limited to, LiOH to provide the free carboxylic acid (4), where Ar1 and Ar2 are as defined for Formula (I)
684

[0298] Scheme IV describes the synthesis of a compound of formula (4).

[0299] Ar3, Ar7, Ar5 and Ar6 are, independently, groups such as but not limited to a heteroaryl, heteroarylene, arylene, or aryl ring system.

[0300] As shown in Scheme IV, in another embodiment, a bromo or iodo aryl alanine methyl ester (or amino acid esterified in linkage to Wang resin) (11) is subjected to coupling with an arylboronic acid in the presence of a catalyst such as but not limited to tetrakis(triphenylphosphine)palladium(0), in the presence of base such as but not limited to sodium carbonate to form compound (12). The resulting compound is treated with a bromo- or iodo-substituted aryl carboxylic acid in the presence of a coupling reagent such as, but not limited to, diisopropyl carbodiimide (DIC) to form the amide (13). The resulting amide is then subjected to coupling with a arylboronic acid or heteroarylboronic acid in the presence of a catalyst such as but not limited to tetrakis(triphenylphosphine)plladium(0), in the presence of base such as, but not limited to, sodium carbonate, and the product methyl ester is hydrolyzed using a base such as LiOH to provide the free carboxylic acid (4), where Ar1 and Ar2 are as defined for Formula (I).
685

[0301] Scheme V describes the preparation of a compound of formula (16).

[0302] Ar3 and Ar7 are, independently, groups such as but not limited to a heteroaryl, heteroarylene, arylene, or aryl ring system.

[0303] Pol is a functionalized polymeric support, such as but not limited to Wang Resin.

[0304] As shown in Scheme V, in another embodiment, a hydroxy aryl ester loaded onto the Wang Bromo resin or Merrifield resin using base such as, but not limited to, sodium methoxide in DMA, and hydrolyzed to give (14), is coupled with a bromo- or iodo-subsituted aryl amino acid methyl ester (11) in the presence of a coupling reagent such as, but not limited to, diisopropyl carbodiimide (DIC) to give the amide (15). The resulting amide (15) is then subjected to a coupling with an arylboronic acid or heteroarylboronic acid in the presence of a catalyst such as but not limited to tetrakis(triphenylphosphine)palladium(0), in the presence of base such as, but not limited to, sodium carbonate followed by cleavage from the resin with TMSBr/TFA/DCM (1:1:1) or a similar suitable cleavage cocktail to yield the desired product (16), where Ar1 and Ar2 are as defined for Formula (I)
686

[0305] Scheme VI describes the preparation of a compound of formula (19).

[0306] Ar6 and Ar8 are, independently, groups such as but not limited to a heteroaryl, heteroarylene, arylene, or aryl ring system.

[0307] Pol is a functionalized polymeric support, such as but not limited to Wang Resin.

[0308] As shown in Scheme VI, in another embodiment, a hydroxy aryl ester loaded onto the Wang Bromo resin, Merrifiend resin, or other suitable support using base such as, but not limited to, sodium methoxide in DMA, is hydrolyzed to give (17), and is coupled with an amino acid methyl ester (8) in the presence of a coupling reagent such as, but not limited to, diisopropyl carbodiimide (DIC) to give the amide (18). The resulting amide (18) is then subjected to a coupling with an arylboronic acid or heteroarylboronic acid in the presence of a catalyst such as but not limited to tetrakis(triphenylphosphine)palladium(0), in the presence of base such as, but not limited to, sodium carbonate, and is then cleaved from the resin with TMSBr/TFA/DCM (1:1:1) or a similar suitable cleavage cocktail to yield the desired product (19), where Ar1 and Ar2 are as defined for Formula (I).
687

[0309] Scheme VII describes the synthesis of a compound of formula (23).

[0310] Ar3, Ar7, and Ar6 are, independently, groups such as but not limited to a heteroaryl, heteroarylene, arylene, or aryl ring system.

[0311] Pol is a functionalized polymeric support, such as but not limited to Wang Resin.

[0312] As shown in Scheme VII, in another embodiment, a bromo hydroxy aryl ester (20) loaded onto Wang Bromo resin, Merrifield resin, or other suitable support using base such as, but not limited to, sodium methoxide in DMF, is then subjected to a coupling with an arylboronic acid or heteroarylboronic acid in the presence of a catalyst such as but not limited to tetrakis(triphenylphosphine)plladium(0), in the presence of base such as, but not limited to, sodium carbonate, followed by hydrolysis of the product ester to yield the acid (21). The resulting carboxylic acid (21) is then subjected to coupling with a bromo- or iodo-substituted aryl amino acid methyl ester (11) in the presence of a coupling reagent such as, but not limited to, diisopropyl carbodiimide (DIC) to give the amide (22). The resulting amide (22) is then subjected to a coupling with an arylboronic acid or heteroaryl boronic acid in the presence of a catalyst such as but not limited to tetrakis(triphenylphosphine)plladium(0), in the presence of base such as, but not limited to, sodium carbonate followed by cleavage from the resin with TMSBr/TFA/DCM (1:1:1) or a similar cleavage cocktail to yield the desired product (23), where Ar1 and Ar2 are as defined for Formula (I).
688

[0313] Scheme VIII describes the preparation of a compound of formula (29).

[0314] Ar7, Ar9, Ar10, and Ar11 are, independently, groups such as but not limited to a heteroaryl, heteroarylene, arylene, or aryl ring system.

[0315] As shown in Scheme VIII, in another embodiment, a fluoro nitro phenol (24) loaded onto a polymer such as Wang Bromo resin using base such as, but not limited to, sodium methoxide in DMA, is then treated with a hydroxy aryl compound (25) in the presence of base, followed by reduction of the nitro group to give the free amine (26). The resulting amine (26) is then subjected to coupling with a bromo- or iodo-substituted aryl acid (27) in the presence of a coupling reagent such as, but not limited to, diisopropyl carbodiimide (DIC) to give the amide (28). The resulting amide (28) is then subjected to a coupling with an arylboronic acid or heteroarylboronic acid in the presence of a catalyst such as but not limited to tetrakis(triphenylphosphine)palladium(0), in the presence of base such as, but not limited to, sodium carbonate followed by cleavage from the resin with TMSBr/TFA/DCM (1:1:1) or a similar suitable cleavage cocktail to yield the desired product (29), where Ar1 and Ar2 are as defined for Formula (I).
689

[0316] Scheme IX describes the preparation of a compound of formula (32).

[0317] Ar6, Ar12, and Ar13 are, independently, groups such as but not limited to a heteroaryl, heteroarylene, arylene, or aryl ring system.

[0318] PG1 is an amino protecting group such as allyloxycarbonyl or tert-butoxycarbonyl.

[0319] As shown in Scheme IX, In another embodiment, an aryl amino acid methyl ester (8) is reacted with an iodo-subsituted aryl amino carboxylic acid (the amino group of which may be protected with an amino protecting group PG1) in the presence of a coupling reagent such as, but not limited to, diisopropyl carbodiimide (DIC) giving the amide (30). The amino group of the amide (30) may be then deprotected, if desired, by treatment with, in the case of PG1 as tert-butoxycarbonyl, TFA, and is then treated with an aroyl chloride in the presence of a base such as pyridine or TEA to give the iodo amide (31). The amide (31) is subjected to coupling with an arylboronic acid or heteroaryl boronic acid in the presence of a catalyst such as but not limited to tetrakis(triphenylphosphine)palladium(0), in the presence of base such as, but not limited to, sodium carbonate. Hydrolysis of the product methyl ester with an alkaline reagent such as LiOH provides compound (32), where Ar1 and Ar2 are as defined for Formula (I).
690

[0320] In Scheme X, in another embodiment, a beta ketoester (33) may be treated with a reagent such as triethyl orthoformate of triethyl orthoacetate in the presence of acetic anhydride and heat to afford the ethoxy olefin derivative (34). R41 is a group such as but not limited to aryl, heteroaryl, or alkyl. The derivative (34) may be treated with a hydrazine derivative (35) to afford the pyrazole (36). Hydrolysis of the ester of (36) with aqueous alkali and mild acidification with a weak acid such as aqueous citric acid affords (37).
691

[0321] In Scheme XI, in another embodiment, is described the derivitization of aniline and amine nitrogen atoms. L1 is either a direct bond or a group such as an alkylene group. An amide derivative (38) may be prepared substantially in like manner as (30) and may be deprotected to afford (39). For example, where PG1 is a tert-butoxycarbonyl group, treatment of (38) with TFA followed by neutralization affords (39). (39) may be treated with R44—C(O)OH in the presence of a coupling agent such as HBTU or DCC to afford (40), or R44—COCl in the presence of a weak base such as triethylamine, to afford (40). (39) may be treated with an aldehyde or ketone and a reducing agent such as sodium cyanoborohydroide or sodium triacetoxyborohydride to afford (42). (39) may be treated with a sulfonyl chloride R44SO2Cl in the presence of a weak base such as triethylamine or pyridine to afford (43). (39) may also be treated with an activated aromatic halide such as 4-fluorobenzonitrile in the presence of a weak base such as DIEA, in a solvent such as DMF, at a temperature of from 25° C. to 120° C., to afford the product of ipso halide displacement (41). Other activated or electron-deficient heteroaryl or aryl groups may be employed in this reaction. Alternately, where L1 is a direct bond, the aniline may be arylated by treatment of (39) with cuprous acetate and Ar14—B(OH)2, and a weak base such as triethylamine, in a solvent such as DCM or 1,2-dichloroethane, to afford (41).

[0322] The derivative (42) may be reductively aminated a second time in the manner described above. (42) may also be acylated or sulfenylated as described above to afford (45) and (46), respectively.
692

[0323] Scheme XII describes an additional embodiment. In Scheme XII, an amino ester and a protected phenolic aryl carboxylic acid or similar species are coupled as in Scheme 1. The protecting group PG2 is removed, where PG2 is a hydroxyl or alcohol protecting group. For example, where PG2 is a tert-butyldimethylsilyl group, treatment of (49) with tetrabutylammonium fluoride in THF affords (50). (50) may be treated with a reagent such as but not limited to potassium carbonate and an alkyl halide R47—X, where R47 is a group such as alkyl or substituted alkyl and X is a group such as bromo or iodo, to afford (51). Alternately, where R47 is an activated or unactivated aromatic or heteroaromatic ring system and X is fluoro, treatment of (50) with R47—X in the presence of a base such as but not limited to potassium carbonate in a solvent such as DMF, at a temperature of 25° C. to 120° C., affords (51). Hydrolysis of the ester as described previously affords (52).
693

[0324] Scheme XIII describes another embodiment. L3 is a group such as -alkylene-. The amino ester (53) may be coupled with a carboxylic acid as described in Scheme I to afford 54. The protecting group PG3 may be removed. Where J is NH and PG3 is, for example, a tert-butoxycarbonylamino group, treatment of (54) with TFA or HCl in dioxane solvent affords the amine salt (55). Where J is O and PG3 is, for example, a benzyl group, treatment of (54) with a reagent such as but not limited to palladium on carbon in a solvent such as methanol or ethanol under a hydrogen atmosphere affords (55). Where J is S and PG3 is, for example, a trityl group, treatment of (54) with catalytic HCl or other acid in a solvent such as methanol under a nitrogen atmosphere affords (55). (55) where J is O or S may be alkylated with a reagent R48—X, where R48 is (un)substituted alkyl and X is bromo or iodo or chloro, by reacting (55) with a base such as sodium hydride in a solvent such as THF or DMF and treating the reaction mixture with R48—X. The resulting compounds (56) and (57) may be processed on to compounds of formula (I). Additionally, (56) may be oxidized to the sulfoxide or sulfone, respectively, by treatment with one or two equivalents of an oxidizing agent such as m-chloroperbenzoic acid in a solvent such as DCM or 1,2-dichloroethane. (55) may be treated with a carboxylic acid R49—COOH and a coupling agent such as DCC under conditions described previoulsy to afford (59), where L4 is —C(O)—. Alternately, (55) may be treated with a sulfonyl chloride R49—SO2Cl in the presence of a base such as TEA or pyridine to afford (59), where L4 is —SO2—. The amine (55) may be reductively aminated employing a ketone or aldehyde under conditions described previously to afford (58), and (58) may be reductively aminated with a ketone or aldehyde to afford (60). Alternately, the amine (58) may be sulfenylated or acylated as described above to afford (61), where L4 is —SO2— or —C(O)—.
694

[0325] The term “amino protecting group” as used herein refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups on the compound. Examples of such amino-protecting groups include the formyl group, the trityl group, the phthalimido group, the trichloroacetyl group, the chloroacetyl, bromoacetyl and iodoacetyl groups, urethane-type blocking groups such as benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxy-carbonyl, 2-(4-xenyl)iso-propoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl, 2(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl, 9-fluorenylmethoxycarbonyl (“FMOC”), t-butoxycarbonyl (“BOC”), 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl, isobornyloxycarbonyl, 1-piperidyloxycarbonyl and the like; the benzoylmethylsulfonyl group, the 2-(nitro)phenylsulfenyl group, the diphenylphosphine oxide group and like amino-protecting groups. The species of amino-protecting group employed is not critical so long as the derivatized amino group is stable to the condition of subsequent reaction(s) on other positions of the compound of Formula (I) and can be removed at the desired point without disrupting the remainder of the molecule. Preferred amino-protecting groups are the allyloxycarbonyl, the t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, and the trityl groups. Similar amino-protecting groups used in the cephalosporin, penicillin and peptide art are also embraced by the above terms. Further examples of groups referred to by the above terms are described by J. W. Barton, “Protective Groups In Organic Chemistry”, J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, and T. W. Greene, “Protective Groups in Organic Synthesis”, John Wiley and Sons, New York, N.Y., 1981. The related term “protected amino” or “protected amino group” defines an amino group substituted with an amino-protecting group discussed above.

[0326] The term “hydroxyl protecting group” as used herein refers to substituents of the alcohol group commonly employed to block or protect the alcohol functionality while reacting other functional groups on the compound. Examples of such alcohol -protecting groups include the 2-tetrahydropyranyl group, 2-ethoxyethyl group, the trityl group, the trichloroacetyl group, urethane-type blocking groups such as benzyloxycarbonyl, and the trialkylsilyl group, examples of such being trimethylsilyl, tert-butyldimethylsilyl, phenyldimethylsilyl, triiospropylsilyl and thexyldimethylsilyl. The choice of of alcohol-protecting group employed is not critical so long as the derivatized alcohol group is stable to the condition of subsequent reaction(s) on other positions of the compound of the formulae and can be removed at the desired point without disrupting the remainder of the molecule. Further examples of groups referred to by the above terms are described by J. W. Barton, “Protective Groups In Organic Chemistry”, J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, and T. W. Greene, “Protective Groups in Organic Synthesis”, John Wiley and Sons, New York, N.Y., 1981. The related term “protected hydroxyl” or “protected alcohol” defines a hydroxyl group substituted with a hydroxyl-protecting group as discussed above.

[0327] The term “carboxyl protecting group” as used herein refers to substituents of the carboxyl group commonly employed to block or protect the —OH functionality while reacting other functional groups on the compound. Examples of such alcohol -protecting groups include the 2-tetrahydropyranyl group, 2-ethoxyethyl group, the trityl group, the allyl group, the trimethylsilylethoxymethyl group, the 2,2,2-trichloroethyl group, the benzyl group, and the trialkylsilyl group, examples of such being trimethylsilyl, tert-butyldimethylsilyl, phenyldimethylsilyl, triiospropylsilyl and thexyldimethylsilyl. The choice of carboxyl protecting group employed is not critical so long as the derivatized alcohol group is stable to the condition of subsequent reaction(s) on other positions of the compound of the formulae and can be removed at the desired point without disrupting the remainder of the molecule. Further examples of groups referred to by the above terms are described by J. W. Barton, “Protective Groups In Organic Chemistry”, J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, and T. W. Greene, “Protective Groups in Organic Synthesis”, John Wiley and Sons, New York, N.Y., 1981. The related term “protected carboxyl” defines a carboxyl group substituted with a carboxyl-protecting group as discussed above.

[0328] The general procedures used in the methods of the present invention are described below.

[0329] General Experimental:

[0330] LC-MS data was obtained using gradient elution on a Waters 600 controller equipped with a 2487 dual wavelength detector and a Leap Technologies HTS PAL Autosampler using an YMC Combiscreen ODS-A 50×4.6 mm column. A three minute gradient was run from 25% B (97.5% acetonitrile, 2.5% water, 0.05% TFA) and 75% A (97.5% water, 2.5% acetonitrile, 0.05% TFA) to 100% B. The mass spectrometer used was a Micromass ZMD instrument. All data was obtained in the positive mode unless otherwise noted. 1H NMR data was obtained on a Varian 400 MHz spectrometer.

[0331] Common names and definitions for resin reagents used in the disclosure are;
2Merrifieldp-Chloromethyl polystyreneHydroxy-Merrifieldp-Hydroxymethyl polystyreneWang(4-Hydroxymethyl)phenoxymethyl polystyreneWang carbonate4-(p-nitrophenyl carbonate)phenoxymethyl polystyreneRink Resin4-(2′,4′-Dimethoxyphenyl-Fmco-aminomethyl)-phenoxypolystyrene resinWang Bromo Resin(4-Bromomethyl)phenoxymethyl polystyreneTHP Resin3,4-Dihydro-2H-pyran-2-ylmethoxymethylpolystyrene


[0332] Aldehyde resin can refer to the following:

[0333] 4-Benzyloxybenzaldehyde polystyrene

[0334] 3-Benzyloxybenzaldehyde polystyrene

[0335] 4-(4-Formyl-3-methoxyphenoxy)butyryl-aminomethyl polystyrene

[0336] 2-(4-Formyl-3-methoxyphenoxy)ethyl polystyrene

[0337] 2-(3,5-dimethoxy-4-formylphenoxy)ethoxy-methyl polystyrene

[0338] 2-(3,5-dimethoxy-4-formylphenoxy)ethoxy polystyrene

[0339] (3-Formylindolyl)acetamidomethyl polystyrene

[0340] (4-Formyl-3-methoxyphenoxy) grafted (polyethyleneglycol)-polystyrene; or

[0341] (4-Formyl-3-methoxyphenoxy)methylpolystyrene.

[0342] Abbreviations used in the Examples are as follows:

[0343] APCI=atmospheric pressure chemical ionization

[0344] BOC=tert-butoxycarbonyl

[0345] BOP=(1-benzotriazolyloxy)tris(dimethylamino)phosphonium hexafluorophosphate

[0346] d=day

[0347] DIAD=diisopropyl azodicarboxylate

[0348] DCC=dicyclohexylcarbodiimide

[0349] DCE=1,2-dichloroethane

[0350] DCM=dichloromethane

[0351] DIC=diisopropylcarbodiimide

[0352] DIEA=diisopropylethylamine

[0353] DMA=N,N-dimethylacetamide

[0354] DMAP=dimethylaminopyridine

[0355] DME=1,2 dimethoxyethane

[0356] DMF=N,N-dimethylformamide

[0357] DMPU=1,3-dimethypropylene urea

[0358] DMSO=dimethylsulfoxide

[0359] EDC=1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride

[0360] EDTA=ethylenediamine tetraacetic acid

[0361] ELISA=enzyme-linked immunosorbent assay

[0362] ESI=electrospray ionization

[0363] ether=diethyl ether

[0364] EtOAc=ethyl acetate

[0365] FBS=fetal bovine serum

[0366] g=gram

[0367] h=hour

[0368] HBTU=O-benzotriazol-1-yl-N ,N,N′,N′-tetramethyluronium hexafluorophosphate

[0369] HMPA=hexamethylphosphoric triamide

[0370] HOBt=1-hydroxybenzotriazole

[0371] Hz=hertz

[0372] i.v.=intravenous

[0373] kD=kiloDalton

[0374] L=liter

[0375] LAH=lithium aluminum hydride

[0376] LDA=lithium diisopropylamide

[0377] LPS=lipopolysaccharide

[0378] M=molar

[0379] m/z=mass to charge ratio

[0380] mbar=millibar

[0381] MeOH=methanol

[0382] mg=milligram

[0383] min=minute

[0384] mL=milliliter

[0385] mM=millimolar

[0386] mmol=millimole

[0387] mol=mole

[0388] mp=melting point

[0389] MS=mass spectrometry

[0390] N=normal

[0391] NMM=N-methylmorpholine, 4-methylmorpholine

[0392] NMR=nuclear magnetic resonance spectroscopy

[0393] p.o.=per oral

[0394] PBS=phosphate buffered saline solution

[0395] PMA=phorbol myristate acetate

[0396] ppm=parts per million

[0397] psi=pounds per square inch

[0398] Rf=relative TLC mobility

[0399] rt=room temperature

[0400] s.c.=subcutaneous

[0401] SPA=scintillation proximity assay

[0402] TEA=triethylamine

[0403] TFA=trifluoroacetic acid

[0404] THF=tetrahydrofuran

[0405] THP=tetrahydropyranyl

[0406] TLC=thin layer chromatography

[0407] TMSBr=bromotrimethylsilane, trimethylsilylbromide

[0408] Tr=retention time

[0409] Thus, in an embodiment, the following compounds were synthesized according to the Schemes described herein.

[0410] General Procedure A:

[0411] To a solution of a carboxylic acid (1.0-1.5 mmol) in DMF (6 mL) was added an amino acid methyl ester (1.0-1.5 mmol), HBTU (1.0-1.5 mmol), and DIEA (2.0-3.0 mmol) and the mixture was stirred overnight. After completion of the reaction, sufficient amount of water was added and the mixture was extracted with ethyl acetate (3×15 ml). The combined organic layer was washed with water and brine, and then dried over sodium sulfate. The solvent was removed in vacuum to afford the amide, which was used for further transformation without further purification or purified by flash chromatography.

[0412] General Procedure B:

[0413] To a mixture of phenol and the aryl fluoride (2 eq) in DMF was added solid potassium carbonate (10 eq), and the mixture was heated at 80° C. for 12 h. After completion of the reaction, sufficient amount of water was added, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over sodium sulfate. The solvent was removed in vacuum and the crude material obtained was purified by flash chromatography to afford the desired aryl ethers.

[0414] General Procedure C:

[0415] To a solution of ester in THF, CH3OH (4:1), 2N-lithium hydroxide solution (5 eq) was added, and the resulting reaction mixture was stirred at 0° C. for 30 minutes and then warmed to room temperature. After completion of the reaction, 2N HCl was used to neutralize the base, extracted with ethyl acetate, the organic layer was washed with brine, dried over sodium sulfate, and the solvent was removed in vacuum to afford the product.

[0416] General Procedure D:

[0417] To a solution of phenyl bromide in DME or Toluene were added corresponding boronic acid (5 eq), Pd (PPh3)4 (0.5% eq), 2N Na2CO3 solution (5 eq). The mixture was heated at 75° C. for 12 h. After completion of the reaction, solvent was evaporated in vacuo. During the reaction, most of the ester was hydrolyzed to the corresponding acid. Therefore, crude product so obtained was re-esterfied by dissolving it in CH3OH containing 1% of HCl. The mixture was refluxed for 6 h and after the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica, CH2Cl2) to provide the desired ester. The resulting ester was hydrolyzed as described in procedure C yielding the acid.

[0418] General Procedure E:

[0419] To a solution of an aniline (1.0 mmol) in DCE (10 mL) was added an aldehyde (2.0-2.2 mmol), acetic acid (3.0 mmol) and sodium triacetoxyborohydride (2.5 mmol) or sodium cyanoborohydride and the mixture was stirred overnight. After completion of the reaction, 50 mL of DCM was added and the organic layer was washed with saturated sodium bicarbonate solution and brine, and then dried over sodium sulfate. The solvent was removed in vacuum to afford the amine, which was purified by flash chromatography.

[0420] General Procedure F:

[0421] To a solution of an aniline (1.0 mmol) in DCM (10 mL) was added a sulfonyl chloride (1.0 mmol), and pyridine (10.0 mmol) and the mixture was stirred overnight. After completion of the reaction, 50 mL of DCM was added and the organic layer was washed with 1 N HCl, saturated sodium bicarbonate solution and brine, and then dried over sodium sulfate. The solvent was removed in vacuum to afford the sulfonamide, which was purified by flash chromatography.

[0422] General Procedure G:

[0423] A flask is charged with phenol or aniline (1.0 equiv), Cu(OAc)2 (1.0 equiv), arylboronic acid (1.0-3.0), and powdered 4 A0 molecular sieves. The reaction mixture is diluted with CH2Cl2 to yield a solution approximately 0.1 M in phenol or aniline, and the Et3N (5.0 equiv) is added. After stirring the colored heterogeneous reaction mixture for 24 h at 25° C. under ambient atmosphere, the resulting slurry is filtered and the diaryl ether or diaryl amine is isolated from the organic filtrate by flash chromatography.

[0424] General Procedure H:

[0425] To a solution of a phenol (1.0 mmol) in DMF (5 mL) was added an alkyl halide (1.2 mmol) (a catalytic amount of NaI is added for alkyl chlorides), and potassium carbonate (2.5 mmol) and the mixture heated at 70° C. overnight. After completion of the reaction, 5 mL of ethyl acetate and 5 mL of water was added. The organic layer was washed with water, and then dried over sodium sulfate. The solvent was removed in vacuum to afford the ether, which was purified by flash chromatography.

[0426] General Procedure I:

[0427] To a solution of ester in THF was added lithium hydroxide (3-4 eq), water, and methanol. The ratio of THF/water/methanol is 4:1:1. The reaction mixture was stirred at RT for 1-1.5 h. A 10% solution of citric acid was added to adjust the pH between 6-7. Ethyl acetate was added and the organic layer is separated. The aqueous layer was extracted with ethyl acetate twice. The combined organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure to give the product.

[0428] General Procedure J:

[0429] To a stirring solution of an aniline (2 mmol) dissolved in DCM containing pyridine (4 mmol ) was added acid chloride (2.5 mmol) at 0° C. The reaction mixture was stirred at rt for 3 h, extracted with DCM, washed with 1 M HCl and brine evaporation followed by column chromatography purification gave amide.

[0430] The above general methods are for illustration only; Alternative conditions that may optionally be used include: Use of alternative solvents, alternative stoichiometries of reagents, alternative reaction temperatures and alternative methods of purification.

[0431] Synthesis of 4′-Trifluoromethyl-biphenyl-4-carboxylic Acid
695

[0432] The title compound was made as described in general procedure D using 4-bromo benzoic acid (10 g, 49.4 mmol), 4-trifluoromethyl phenylboronic acid (14.17 g, 74.61 mmol), palladium tetrakis-triphenylphosphine (5.7 g, 4.974 mmol) and 2N Na2CO3 aq. solution (150 mL, 149.2 mmol) in 500 ml of Toluene. After the reaction is complete, the reaction mixture was neutralized with 2N HCl then filtered. The resulting solid was dissolved in ethyl acetate then passed through a short column of silica gel giving 9.7 g (75%) of the compound as a white solid.

[0433] Synthesis of Amino Acids:

[0434] (2S)-Amino-3-(2′-phenoxy-biphenyl-4-yl)-propionic Acid Methyl Ester
696

[0435] The title compound was prepared following the procedure D using (L)-4-bromophenylalanine (8.55 g, 35.0 mmol), 2-phenoxyphenyl boronic acid (10.00 g, 46.73 mmol), and palladium tetrakis-triphenylphosphine (4.0 g, 10% mmol)) and 2N Na2CO3 aq. solution (70 mL, 140 mmol) in 140 ml of DME. After removal of solvents, the solid was washed with ether to afford the title compound as the HCl salt (10.0 g, 26.20 mmol, 75% yield).

[0436] (2S)-Amino-3-(4′-trifluoromethoxy-biphenyl-4-yl)-propionic Acid Methyl Ester
697

[0437] The title compound was prepared following the procedure D using (L)-4-bromophenylalanine (8.0 g, 32.7 mmol), 4-trifluoromethoxybenzene boronic acid (10.1 g, 49.1 mmol), palladium tetrakis-triphenylphosphine (3.7 g, 3.2 mmol), and Na2CO3 (2.0 N, 80.0 mL, 160 mmol) in DME (300 mL). After removal of solvent, the solid was washed with ether to afford the title compound as the HCl salt (10.8 g, 28.7 mmol, 88% yield).

[0438] (2S)-Amino-3-(4′-trifluoro-biphenyl-4-yl)-propionic Acid Methyl Ester
698

[0439] The title compound was prepared exactly following the procedure D using (L)-4-bromophenylalanine (9.0 g, 36.8 mmol), 4-trifluoromethylbenzene boronic acid(10.48 g, 55.2 mmol), palladium tetrakis-triphenylphosphine (4.25 g, 3.6 mmol), and aqueous Na2CO3 (2.0 N, 90.0 mL, 185 mmol) in DME (300 mL). After removal of solvent, the solid was washed with ether to afford the title compound as the HCl salt (10.5 g, 29.2 mmol, 79% yield).


EXAMPLE 1

[0440] 3-Biphenyl-4-yl-(2S)-[(isoquinoline-3-carbonyl)-amino]-propionic Acid

[0441] 2-L-amino-3-biphenyl-4-yl-propionic acid methyl ester (100 mg, 0.1 mmol) was reacted with isoquinoline-3-carboxylic acid (78 mg, 0.5 mmol) as described in general procedure A. The resulting compound was hydrolyzed according to general procedure C to afford the title product (132 mg, 81%) as a white solid.

[0442]

1
H-NMR (400 MHz, CD3COCD3): 3.38 (dd, 1H), 3.47 (dd, 1H), 5.09 (m, 1H), 7.32 (m, 1H), 7.42 (m, 4H), 7.60 (m, 4H), 7.82 (m, 1H), 7.89 (m, 1H), 8.17 (m, 1H), 8.23 (m, 1H), 8.58 (s, 1H), 8.76 (m, 1H), 9.30 (d, 1H); LC/MS (m/z): 397 (M+1)+.


EXAMPLE 2

[0443] (2S)-[(Isoquinoline-3-carbonyl)-amino]-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic Acid

[0444] 3-(4-Bromo-phenyl)-(2S)-[(isoquinoline-3-carbonyl)-amino]-propionic acid methyl ester (720 mg, 90%) was prepared starting from 2-L-amino-3-(4-bromo-phenyl)propionic acid methyl ester (500 mg, 1.9 mmol) and isoquinoline -3-carboxylic acid (400 mg, 2.3 mmol) according to general procedure A.

[0445] The resulting amide (100 mg, 0.24 mmol) was reacted with 4-trifluoromethylphenyl boronic acid (95 mg, 0.5 mmol) as described in general procedure D yielding the title compound (80 mg, 80%) as a white solid.

[0446]

1
H-NMR(400 MHz, CDCl3): 3.33 (m, 2H), 5.08 (m, 1H), 7.11 (d, 1H ), 7.36 (t, 2H), 7.49 (m, 1H), 7.61 (s, 2H), 7.77 (m, 3H), 8.00 (m, 3H), 8.60 (d, 1H), 8.75 (m, 1H), 9.16 (s, 1H); LC/MS (m/z): 465 (M+1)+.


EXAMPLE 3

[0447] (2S)-[(Isoquinoline-3-carbonyl)-amino]-3-(3;5′-bistrifluoromethyl-biphenyl-4-yl)-propionic Acid

[0448] 3-(4-Bromo-phenyl-(2S)-[(isoquinoline-3-carbonyl)-amino]-propionic acid methyl ester (100 mg, 0.24 mmol) prepared as in example 2 was reacted with 3,5-bis(trifluoromethyl)phenyl boronic acid (129 mg, 0.5 mmol) as described in general procedure D to afford the title compound (100 mg, 79%) as a white solid.

[0449]

1
H-NMR(400 MHz, CDCl3): 3.36 (dd, 1H), 3.48 (dd, 1H), 5.18 (m, 1H), 7.40 (d, 2H), 7.51 (d, 2H), 7.74 (m, 2H), 7.79 (m, 1H), 7.94 (m, 2H), 8.00 (m, 2H), 8.59 (s, 1H), 8.74 (d, 1H), 9.14 (s, 1H); LC/MS (m/z): 533 (M++1)+.


EXAMPLE 4

[0450] (2S)-[(Isoquinoline-3-carbonyl)-amino]-3-(4′-methoxy-biphenyl-4-yl)-propionic Acid

[0451] 3-(4-Bromo-phenyl-(2S)-[(isoquinoline-3-carbonyl)-amino]-propionic acid methyl ester (100 mg, 0.24 mmol) prepared as in example 2 was reacted with 4-methoxyphenyl boronic acid (76 mg, 0.5 mmol) as described in general procedure D yielding the title compound (84 mg, 82%) as a white solid.

[0452]

1
H-NMR(400 MHz, CDCl3): 3.32 (m, 2H), 3.81 (s, 3H), 5.12 (m, 1H), 6.91 (m , 1H), 7.11 (d, 1H), 7.26 (m, 2H), 7.32 (m, 2H), 7.46 (m, 2H), 7.74 (m , 3H), 7.98 (m, 2H), 8.59 (d, 1H), 8.74 (m, 1H), 9.14 (s, 1H); LC/MS (m/z): 427 (M+1)+.


EXAMPLE 5

[0453] 3-[4-(4′-Cyano-phenoxy)-phenyl]-(2S)-[(isoquinoline-3-carbonyl)-amino]-propionic Acid

[0454] 3-(4-Hydroxyphenyl)-(2S)-[(isoquinoline-3-carbonyl)-amino]-propionic acid methyl ester (807 mg, 90%) was prepared from (2S)-amino-3-(4-hydroxy-phenyl)-propionic acid methyl ester (500 mg, 3.0 mmol) and isoquinoline -3-carboxylic acid (530 mg, 2.3 mmol) according to general procedure A.

[0455] The resulting amide (100 mg, 0.28 mmol) was reacted with 4-cyano fluorobenzene (36 mg, 0.30 mmol) as described in general procedure B. The resulting aryl ether was hydrolyzed as described in general procedure C yielding the title compound (47 mg, 72%) as a white solid.

[0456]

1
H-NMR(400 MHz, CDCl3): 3.30 (dd, 1H), 3.44 (dd, 1H), 5.10 (m, 1H), 6.96 (m, 3H), 7.27 (m, 1H), 7.31 (d, 2H), 7.53 (d, 2H), 7.77 (m, 2H), 7.99 (d, 1H), 8.05 (d, 1H), 8.59 (s, 1H), 8.70 (d, 1H), 9.15 (s, 1H); LC/MS (m/z): 438(M+1)+.


EXAMPLE 6

[0457] 3-[4-(4′-Nitro-phenoxy)-phenyl]-(2S)-[(isoquinoline-3-carbonyl)-amino]-propionic Acid

[0458] 3-(4-Hydroxy-phenyl)-(2S)-[(isoquinoline-3-carbonyl)-amino]-propionic acid methyl ester (50 mg, 0.15 mmol) prepared as in example 5 was reacted with 4-nitrofluorobenzene (42 mg, 0.30 mmol) as described in general procedure B and hydrolyzed as described in general procedure C yielding the title compound (49 mg, 71%) as a light yellow solid. LC/MS (m/z): 456 (M+1)+

[0459] By analogous methods to those described above the following Examples were synthesized.
3EX-AMPLENAMELC/MS(m/z)73-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-(2S)-449[(isoquinoline-3-carbonyl)-amino]-propionic acid83-(4′-Cyano-biphenyl-4-yl)-(2S)-[(isoquinoline-4223-carbonyl)-amino]-propionic acid9(2S)-[(Isoquinoline-3-carbonyl)-amino]-3-(3′-465trifluoromethyl-biphenyl-4-yl)-propionic acid10(2S)-[(Isoquinoline-3-carbonyl)-amino]-3-(3′-442nitro-biphenyl-4-yl)-propionic acid



EXAMPLE 11

[0460] 3-Biphenyl-4-yl-(2S)-[(7-bromo-isoquinoline-3-carbonyl)-amino]-propionic Acid

[0461] To a solution of 4-bromophthalic acid (3.0 g, 12.24 mmol) in 30 mL of THF was added a solution of borane-THF complex (1.0M) dropwise at 0° C. The solution was warmed to rt and stirred for 3 h. The reaction mixture was quenched by addition of HCl (2N) at 0° C. The product was extracted with ethyl acetate and washed with sat. NaCl, dried over Na2SO4, and concentrated under reduced pressure to afford 2.8 g (100%) of 4-bromo-2-hydroxymethylbenzyl alcohol as a colorless oil. 1H NMR (CDCl3) 7.28 (m, 2H), 7.26 (m, 1H), 4.69 (s, 4H), 2.80 (bs, 2H).

[0462] To a solution of oxalyl chloride (2.37 mL, 4.607 mmol) in DCM (20 mL) was added dropwise DMSO (1.95 mL) at −78° C. The mixture was stirred at −78° C. for 30 min and a solution of the diol (1.00 g, 4.607 mmol) was added dropwise. The reaction mixture was stirred for 2 hr and TEA (11.5 mL) was added. The reaction mixture was warmed to rt and water was added. The organic layer was separated and washed with sat. NaCl, dried over Na2SO4, and concentrated under reduced pressure to give 4-bromo-benzene-1,2-dicarbaldehyde as a yellow oil (0.450 g, 46%).

[0463] A mixture of 4-bromo-benzene-1,2-dicarbaldehyde (0.450 g, 2.137 mmol), diethylamino malonate (0.452 g, 2.137 mmol), and sodium ethoxide (0.218 g, 3.20 mmol) in anhydrous ethanol (15 mL) was refluxed for 4 hr. The solution was cooled to rt and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (silica gel, 0.5% MeOH in CHCl3) to obtain 0.460 g (78%) of the 7-bromo-isoquinoline-3-carboxylic acid ethyl ester which was hydrolyzed according to general procedure C yielding the 0.350 g (85%) of 7-bromo-isoquinoline-3-carboxylic acid as a white solid. LC/MS (m/z): 253 (M+1)+.

[0464] (2S)-amino-3-biphenyl-4yl-propionic acid methyl ester (340 mg, 13.9 mmol) was reacted with 7-bromo-isoquinoline-3-carboxylic acid (350 mg, 13.9 mmol) as described in general procedure A. The resulting compound was hydrolyzed by following general procedure C yielding the title compound (132 mg, 81%) as a white solid.


EXAMPLE 12

[0465] 3-Biphenyl-4-yl-(2S)-{[7-(4-trifluoromethyl-phenyl)-isoquinoline-3-carbonyl]-amino}-propionic Acid

[0466] Example 11 (50 mg, 0.1 mmol) was reacted with 4-trifluoromethylphenyl boronic acid (42.5 mg, 0.3 mmol) as described in general procedure D yielding the title compound (45 mg, 80%) as a white solid.

[0467]

1
H-NMR (400 MHz, CDCl3): 8.94 (s, 1H), 8.75 (3s, 1H), 8.67 (m, 1H), 8.47 (m, 1H), 7.82 (m, 2H), 7.51 (m, 12H), 5.07 (m, 1H), 3.28 (m, 2H); LC/MS (m/z): 541 (M+1)+.


EXAMPLE 13

[0468] 3-Biphenyl-4-yl-(2S)-{[7-(3-chloro-4-fluoro-phenyl)-isoquinoline-3-carbonyl]-amino}-propionic Acid

[0469] Example 11 (50 mg, 0.1 mmol) was reacted with 3-chloro-4-fluoro-phenyl boronic acid (109 mg, 0.3 mmol) as described in general procedure D yielding the title compound (45 mg, 80%) as a white solid.

[0470]

1
H-NMR (400 MHz, CDCl3): 9.11 (s, 1H), 8.74 (s, 1H), 8.58 (m, 1H), 8.01 (m, 1H), 7.82-7.26 (m, 13H), 5.13 (m, 1H), 3.44 (m, 2H); LC/MS (m/z): 541 (M+1)+.


EXAMPLE 14

[0471] 2-Biphenyl-4-yl-N-(1-bromo-isoquinolin-3-yl)-acetamide

[0472] To a solution of 4-biphenylacetic acid (1.0 g, 4.7 mmol) in 10 ml of anhydrous DMF was added HBTU (2.1 g, 5.7 mmol) and 1.0 ml of DIEA. The mixture was stirred at room temperature for 10 min, and then 1-bromo-3-isoquinolinamine (0.68 g, 4.7 mmol) was added. After stirring over night, the mixture was poured into water, acidified with 10% citric acid, and extracted with ethyl acetate. The organic extracts were washed with water and brine, dried over Na2SO4. After the condensation of the solvent, the residue was purified by flash column chromatography (SiO2, 1:1 hexane:ethyl aceate) to provide the title compound (1.7 g, 86%) as a light yellow solid.

[0473]

1
H-NMR (400 MHz, CDCl3): 3.83 (s, 3H), 7.33-7.37 (m, 1H), 7.42-7.48 (m, 4H), 7.52-7.58 (m, 1H), 7.60-7.64 (m, 4H), 7.65-7.70 (m, 1H), 7.80 (d, 1H,), 7.61 (s, 1H), 8.18 (d, 1H), 8.56 (s, 1H); LC/MS (m/z): 418 (M+1)+.


EXAMPLE 15

[0474] 2-Biphenyl-4-yl-N-[1 (4-trifluoromethyl-phenyl)-isoquinolin-3-yl]-acetamide

[0475] A mixture of Example 14 (0.1 g, 0.24 mmol), 3-trifluoromethylphenylboronic acid (0.14 g, 0.72 mmol), Pd (PPh3)4 (0.028 g, 0.024 mmol) and 2N Na2CO3 solution (0.1 ml) in DME was heated at 75° C. for 12 h under nitrogen. The reaction mixture was cooled, and the solvent was evaporated. The resulting residue was purified by flash column chromatography (SiO2, 10% ethyl acetate in hexane) to provide the title compound (0.1 g, 87%) as a light yellow solid.

[0476]

1
H-NMR(400 MHz, CDCl3): 3.85 (s, 3H), 7.34-7.39 (m, 1H), 7.42-7.46 (m, 5H), 7.56-7.67 (m, 6H), 7.77 (d, 1H), 7.8 (d, 1H), 7.85-7.91 (m, 3H), 8.15 (s, 1H), 8.65 (s, 1H); LC/MS (m/z): 483 (M+1)+.


EXAMPLE 16

[0477] N-[1 (4-aminomethyl-phenyl)-isoquinolin-3-yl]-2-biphenyl-4-yl-acetamide

[0478] The title compound was prepared (0.1 g, 85%) from Example 14 (0.1 g, 0.24 mmol) employing 4-amino methyl phenylboronic acid (0.1 g, 0.72 mmol) as described in Example 15. LC/MS (m/z): 444 (M+1)+.


EXAMPLE 17

[0479] 3-Biphenyl-4-yl-(2S)-{[4-(2-biphenyl-4-yl-ethylamino)-quinazoline-2-carbonyl]-amino}-propionic Acid

[0480] 2.18 g (10 mmol) of 2-ethoxycarbonylquinazolin-4-one was suspended in 20 ml of phosphorus oxychloride. The mixture was refluxed for one hour, and the solvent was removed by rotary evaporation. The resulting residue was dissolved in ethyl acetate, and the obtained solution was washed with saturated sodium bicarbonate solution three times, dried over anhydrous sodium sulfate, filtered, and evaporated to give 2.13 g (90% mmol) of 2-ethoxycarbonyl-4-chloroquinazoline as a pale-yellow solid. LC/MS (m/z) 237 (M+1)+.

[0481] 236 mg (1.0 mmol) of 2-ethoxycarbonyl-4-chloroquinazoline obtained above, 210 mg (1.05 mmol) of biphenylethylamine and 1.0 ml (5.74 mmol) of diisopropylethylamine were mixed with 10 ml of isopropyl alcohol. The mixture was refluxed for 12 hours. The residue obtained after removing the solvent was purified by chromatography (5% ethyl acetate in DCM) to give 360 mg (0.9 mmol) of 2-ethoxycarbonyl-4-biphenylethylaminoquinazoline as a white solid. The ethyl ester was hydrolyzed according to general procedure C yielding the 295 mg (90%) of 4-biphenylethylaminoquinazoline-2-carboxylic acid as a white solid. LC/MS (m/z): 398 (M+1)+.

[0482] To 200 mg (−0.2 mmol) of Wang resin (1.1 mmol/g) loaded with L-4-biphenylalanine were added 220 mg of (0.6 mmol) 4-biphenylethylaminoquinazoline-2-carboxylic acid, 0.6 mL (0.6 mmol) of 1.0 M DIC in DMF, 0.6 mL (0.6 mmol) of 1.0 M HOBt in DMF, and a catalytic amount of DMAP. The resulting mixture was left on shaker overnight. The resin was washed with DMF, MeOH, DCM three times of each and cleaved with 20% TFA in DCM. The residue obtained after removing the solvent was purified by chromatography (10% methanol in DCM) to give 72 mg (60%) of the title compound.

[0483]

1
H NMR (400 MHz, CD3OD): 2.91 (t, 2H), 3.30-3.36 (m, 2H), 3.90-4.00 (m, 2H), 4.98 (t, 1H), 7.06 (d, 2H), 7.12-7.21 (m, 4H), 7.22-7.31 (m, 9H), 7.33-7.38 (m, 3H), 7.72 (td, 1H), 7.90-7.96 (m, 2H), 8.22 (d, 1H); LC/MS (m/z): 593 (M+1)+.


EXAMPLE 18

[0484] 3-Biphenyl-4-yl-(2S)-{[4-tert-butyl-benzylamino)-quinazoline-2-carbonyl]-amino}-propionic Acid

[0485] 4-tert-butyl benzyl aminoquinazoline-2-carboxylic acid (290 mg, 90%) was synthesized from 236 mg (1.0 mmol) of 2-ethoxycarbonyl-4-chloroquinazoline, 210 mg (1.05 mmol) of 4-tert-butyl benzylamine and 1.0 ml (5.74 mmol) of diisopropylethylamine as described in Example 17.

[0486] 4-tert-butyl benzyl aminoquinazoline-2-carboxylic acid (290 mg, 0.6 mmol) so obtained was reacted with 200 mg (−0.2 mmol) of Wang resin (1.1 mmol/g) loaded with L-4-biphenylalanine as described in Example 17 yielding the title compound (70 mg, 60%). LC/MS (m/z) 559 (M+1)+.


EXAMPLE 19

[0487] 3-Biphenyl-4-yl-(2S)-{[6-(3-chloro-4-fluoro-phenyl)-pyridine-2-carbonyl]-amino}-propionic Acid

[0488] 3-Biphenyl-4-yl-(2S)-[(6-bromo-pyridine-2-carbonyl)-amino]-propionic acid methyl ester (1.5 g, 90%) was prepared by following general procedure A from commercially available 5-bromo picolinic acid (0.95 g, 4.7 mmol) and (2S)-amino-3-biphenyl-4-yl-propionic acid methyl ester (1.0 g, 3.9 mmol).

[0489] The above compound (80 mg, 0.20 mmol) was reacted with 3-chloro-4-fluoro phenylboronic acid (87 mg, 0.5 mmol) as described in general procedure D yielding 3-Biphenyl-4-yl-2-{[6-(3-chloro-4-fluoro-phenyl)-pyridine-2-carbonyl]-amino}-propionic Acid (75 mg, 79%) as a light yellow solid. LC/MS (m/z): 475 (M+1)+.


EXAMPLE 20

[0490] 3-Biphenyl-4-yl-(2S)-{[6-(3-chloro-4-fluorophenyl)-pyridine-2-carbonyl]-amino}-propionic Acid

[0491] 3-Biphenyl-4-yl-(2S)-[(6-bromo-pyridine-2-carbonyl)-amino]-propionic acid methyl ester (80 mg, 0.20 mmol) was reacted with 4-trifluoro methyl phenylboronic acid (87 mg, 0.5 mmol) as described in general procedure D to afford the title compound (75 mg, 79%) as a light yellow solid. LC/MS (m/z): 475 (M+1)+.

[0492] By analogous methods to those described above the following compounds were synthesized.
4EX-AMPLENAMELC/MS(m/z)213-Biphenyl-4-yl-(2S)-{[6-(4-trifluoromethoxy-507phenyl)-pyridine-2-carbonyl]-amino}-propionicacid223-Biphenyl-4-yl-(2S)-{[6-(4-fluoro-3-methyl-455phenyl)-pyridine-2-carbonyl]-amino}-propionic acid23(2S){[6-(4-Amino-phenyl)-pyridine-2-carbonyl]-438amino}-3-biphenyl-4-yl-propionic acid243-Biphenyl-4-yl-(2S)-{[6-(3-cyano-phenyl)-448pyridine-2-carbonyl]-amino}-propionic acid253-Biphenyl-4-yl-(2S)-{[6-(4-methanesulfonyl-501phenyl)-pyridine-2-carbonyl]-amino}-propionic acid263-Biphenyl-4-yl-(2S)-{[6-(4-methoxy-phenyl)-453pyridine-2-carbonyl]-amino}-propionic acid273-Biphenyl-4-yl-(2S)-{[6-(3-carbamimidoyl-465phenyl)-pyridine-2-carbonyl]-amino}-propionicacid283-Biphenyl-4-yl-(2S)-{[6-(4-phenoxy-phenyl)-515pyridine-2-carbonyl]-amino}-propionic acid293-Biphenyl-4-yl-(2S)-{[6-(4-tert-butyl-phenyl)-479pyridine-2-carbonyl]-amino}-propionic acid



EXAMPLE 30

[0493] 3-Biphenyl-4-yl-(2S)-{[5-(3-chloro-4-fluoro-phenyl)-pyridine-2-carbonyl]-amino}-propionic Acid

[0494] 3-Biphenyl-4-yl-(2S)-[(5-bromo-pyridine-2-carbonyl)-amino]-propionic acid methyl ester (1.5 g, 90%) was prepared by following general procedure A from commercially available 5-bromo picolinic acid (0.9 g, 4.7 mmol) and (2S)-amino-3-biphenyl-4-yl-propionic acid methyl ester (1.0 g, 3.9 mmol).

[0495] The above compound (80 mg, 0.20 mmol) was reacted with 3-chloro-4-fluoro phenylboronic acid (87 mg, 0.5 mmol) as described in general procedure D yielding the title compound (75 mg, 79%) as a light yellow solid. LC/MS (m/z): 475 (M+1)+.

[0496] By analogous methods to those described above the following compounds were synthesized.
5EX-AMPLENAMELC/MS(m/z)313-Biphenyl-4-yl-(2S)-{[5-(4-trifluoromethyl-491phenyl)-pyridine-2-carbonyl]-amino}-propionic acid323-Biphenyl-4-yl-(2S)-{[5-(4-methoxy-phenyl)-453pyridine-2-carbonyl]-amino}-propionic acid



EXAMPLE 33

[0497] 3-Biphenyl-4-yl-(2S)-{[4-(3-chloro-4-fluoro-phenyl)-pyridine-2-rarbonyl]-amino}-propionic Acid

[0498] 3-Biphenyl-4-yl-(2S)-[(4-chloro-pyridine-2-carbonyl)-amino]-propionic acid methyl ester (1.26 g, 85%) was prepared by following general procedure A from commercially available 4-chloro picolinic acid (0.7 g, 4.4 mmol) and (2S)-amino-3-biphenyl-4-yl-propionic acid methyl ester (1.0 g, 3.9 mmol).

[0499] The above compound (80 mg, 20 mmol) was reacted with 3-chloro 4-fluoro phenylboronic acid (70 mg, 0.40 mmol) as described in general procedure D yielding the title compound (48 mg, 51%) as a white solid. LC/MS (m/z): 475 (M+1)+.


EXAMPLE 34

[0500] 3-Biphenyl-4-yl-(2S)-{[4-(4-methoxy-phenyl)-pyridine-2-carbonyl]-amino}-propionic acid 3-Biphenyl-4-yl-(2S)-[(4-chloro-pyridine-2-carbonyl)-amino]-propionic acid methyl ester (80 mg, 0.20 mmol) was reacted with 4-methoxy phenylboronic acid (61 mg, 0.40 mmol) as described in general procedure D to afford the title compound (42 mg, 46%) as a light yellow solid. LC/MS (m/z): 453 (M+1)+.

[0501] By analogous methods to those described above the following compounds were synthesized
6EXAMPLENAMELC/MS (m/z)353-Biphenyl-4-yl-(2S)-{[4-491(4-trifluoromethyl-phenyl)-pyridine-2-carbonyl]-amino}-propionic acid363-Biphenyl-4-yl-(2S)-{[4-491(3-trifluoromethyl-phenyl)-pyridine-2-carbonyl]-amino}-propionic acid



EXAMPLE 37

[0502] 3-Hydroxy-naphthalene-2-carboxylic acid (2-biphenyl-4yl-ethyl)-amide

[0503] To 40.40 g (200 mmol) of Methyl 3-hydroxy-2-naphthoate, 11.0 g (220 mmol) of sodium methoxide in 500 mL of anhydrous DMA was added 13.30 g (71 mmol) of Merrifield resin. The mixture was heated at 110° C. overnight. The resin was washed with H2O, DMF, MeOH, DCM three times each, and dried. The resulting resin-bound methyl naphthoate was hydrolyzed with LiOH/H2O/THF/ethanol at rt for 3 days.

[0504] To 1.0 g (2.5 mmol) of above resulting resin-bound naphthoic acid was added mixture of 1.5 g (7.5 mmol) of 4-bromophenethylamine, 7.5 mL (7.5 mmol) of 1.0 M DIC in DMF, 7.5 mL (7.5 mmol) of 1.0 M HOBt in DMF, and a catalytic amount of DMAP. The resulting mixture was left on a shaker overnight. The resin was washed with DMF, MeOH, DCM three times of each to give the resin-bound N-2-(4-bromophenyl)ethyl-3 hydroxyl-2-naphthamide.

[0505] To 0.05 g (0.1 mmol) of above resin-bound N-2-(4-Bromophenyl)ethyl-3 hydroxyl-2-naphthamide in 2.0 mL of DME were added 36.6 mg (0.3 mmol) of phenylboronic acid, 30 mg (0.03 mmol) of Pd(PPh3)4, and 0.3 mL (0.6 mmol) of 2N Na2CO3 solution. The mixture was heated to 80° C. for 12 h. The resin was washed with H2O, DMF, MeOH, DCM three times of each and cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue obtained after removing the solvent was purified by chromatography (100% methylene chloride) to give 22 mg (60%) of the title compound.

[0506]

1
H NMR (400 MHz, CDCl3): 3.04 (t, 2H), 3.82 (dd, 2H), 6.60 (m, 1H), 7.28-7.38 (m, 5H), 7.43-7.49 (m, 3H), 7.59-7.61 (m, 4H), 7.67-7.70 (m, 2H), 7.81 (s, 1H), 11.75 (s, 1H); LC/MS (m/z): 368 (M+1)+.


EXAMPLE 38

[0507] 3-[(3′-Chloro-4′-fluoro)-biphenyl-4-yl]-(2S)-[(3-hydroxy-naphthalene-2-carbonyl)-amino]-propionic Acid

[0508] To 1.0 g (2.5 mmol) of resin-bound naphthoic acid obtained in Example 37 was added 1.95 g (7.5 mmol) of L-4-bromophenylalanine methyl ester, 7.5 mL (7.5 mmol) of 1.0 M DIC in DMF, 7.5 mL (7.5 mmol) of 1.0 M HOBt in DMF, and a catalytic amount of DMAP. The resulting mixture was left on a shaker overnight. The resin was washed with DMF, MeOH, DCM three times of each to give resin-bound 3-(4-bromophenyl) ethyl-2-[3-(hydroxy-napthalene-2-carbonyl)amino]-propionic acid methyl ester.

[0509] To 0.05 g (0.1 mmol) of the above resin-bound 3-(4-bromophenyl)ethyl-(2S)-[3-(hydroxy-napthalene-2-carbonyl)-amino]-propionic acid methyl ester in 2.0 mL of DME were added 52.0 mg (0.3 mmol) of 3-chloro-4-fluorophenylboronic acid, 30 mg (0.03 mmol) of Pd(PPh3)4, and 0.3 mL (0.6 mmol) of 2N Na2CO3 solution. The mixture was heated to 80° C. for 12 h. The resin was washed with H2O, DMF, MeOH, DCM three times of each and cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue obtained after removing the solvent was purified by chromatography (DCM) to give 30 mg (60%) of 3-[(3′-Chloro-4′-fluoro)-biphenyl-4-yl]-(2S)-[(3-hydroxy-napthalene-2-carbonyl)-amino]-propionic acid methyl ester which was hydrolyzed as described in general procedure C yielding the title compound (28.5 mg, 100%). LC/MS (m/z) 464 (M+1)+.


EXAMPLE 39

[0510] 3-(Biphenyl-4-yl)-(2S)-[(3-hydroxy-napthalene-2-carbonyl)-amino]-propionic Acid

[0511] The title compound (26 mg, 65%) was prepared from 0.05 g (0.1 mmol) of resin-bound 3-(4-bromophenyl)ethyl-(2S)-[3-(hydroxy-napthalene-2-carbonyl)-amino]-propionic acid methyl ester and 36.0 mg (0.3 mmol) of phenyl boronic acid as described in Example 38. LC/MS (m/z): 412 (M+1)+.


EXAMPLE 40

[0512] (2S)-[(3-Hydroxy-napthalene-2-carbonyl)-amino]-3-[(3′-nitro)-biphenyl-4-yl]-propionic Acid

[0513] The title compound (27 mg, 60%) was prepared from 0.05 g (0.1 mmol) of resin-bound 3-(4-bromophenyl)ethyl-(2S)-[3-(hydroxy-napthalene-2-carbonyl)-amino]propionic acid methyl ester and 50.0 mg (0.3 mmol) of 3-nitro-phenyl boronic acid as described in Example 38. LC/MS (m/z): 457 (M+1)+.


EXAMPLE 41

[0514] 3-(Biphenyl-4-yl)-(2S)-[(3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic Acid Methyl Ester

[0515] To 1.0 g (2.5 mmol) of resin-bound 5-bromo-2-hydroxy-benzoic acid obtained by a similar procedure as in Example 37 were added 1.92 g (7.5 mmol) of (2S)-amino-3-biphenyl-4yl-propionic acid methyl ester, 7.5 mL (7.5 mmol) of 1.0 M DIC in DMF, 7.5 mL (7.5 mmol) of 1.0 M HOBt in DMF, and a catalytic amount of DMAP. The resulting mixture was left on a shaker overnight. The resin was washed with DMF, MeOH, DCM three times of each to give resin-bound 3-(biphenyl-4-yl)-(2S)-(5-bromo-4-hydroxy-benzoylamino)-propionic acid methyl ester.

[0516] To 0.05 g (0.1 mmol) of above resin-bound 3-(biphenyl-4-yl)-(2S)-(5-bromo-4-hydroxy-benzoylamino)-propionic acid methyl ester in 2.0 mL of DME were added 52.0 mg (0.3 mmol) of 3-chloro-4-fluorophenylboronic acid, 30 mg (0.03 mmol) of Pd(PPh3)4, and 0.3 mL (0.6 mmol) of 2N Na2CO3 solution. The mixture was heated to 80° C. for 12 h. The resin was washed with H2O, DMF, MeOH, DCM three times of each and cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue obtained after removing the solvent was purified by chromatography (DCM) to give 35 mg (70%) of title compound LC/MS (m/z): 490 (M+1)+.


EXAMPLE 42

[0517] 3-(Biphenyl-4-yl)-(2S)-[(4′-trifluoromethyl-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic Acid Methyl Ester

[0518] The resin-bound 3-(biphenyl-4-yl)-(2S)-(5-bromo-4-hydroxy-benzoyl-amino)propionic acid methyl ester (50 mg, 0.1 mmol) obtained as in Example 37 was reacted with 4-trifluoromethyl phenyl boronic acid (56.7 mg, 0.3 mmol) as generally described in Example 41 to provide the title compound (36 mg, 70%) as a white solid. LC/MS (m/z): 520 (M+1)+.


EXAMPLE 43

[0519] (2S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionic Acid Methyl Ester

[0520] To 2.50 g (5.0 mmol) of resin-bound methyl 5-bromo-2-hydroxy-benzoate obtained by a similar procedure as in Example 37 in 30 mL of DME were added 2.60 g (15 mmol) of 3-chloro-4-fluorophenylboronic acid, 1.12 g (1.0 mmol) of Pd(PPh3)4, and 15 mL (30.0 mmol) of 2N Na2CO3 solution. The mixture was heated to 80° C. for 12 h. The resin was washed with H2O, DMF, MeOH, DCM three times of each, and was hydrolyzed by LiOH/H2O/THF/ethanol at rt for 3 days to give the resin-bound 3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carboxylic acid.

[0521] To 1.5 g (2.5 mmol) of above resin-bound 3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carboxylic acid were added 1.95 g (7.5 mmol) of L-4-bromophenylalanine methyl ester, 7.5 mL (7.5 mmol) of 1.0 M DIC in DMF, 7.5 mL (7.5 mmol) of 1.0 M HOBt in DMF, and catalytic amount of DMAP. The resulting mixture was left on a shaker overnight. The resin was washed with DMF, MeOH, DCM three times of each to give resin-bound 3-(4-bromo-phenyl)-2-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester.

[0522] To 0.05 g (0.1 mmol) of above resin-bound 3-(4-bromo-phenyl)-(2S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester in 2.0 mL of DME were added 58.0 mg (0.3 mmol) of 3-(trifluoromethyl)phenylboronic acid, 30 mg (0.03 mmol) of Pd(PPh3)4, and 0.3 mL (0.6 mmol) of 2N Na2CO3 solution. The mixture was heated at 80° C. for 12 h. The resin was washed with H2O, DMF, MeOH, DCM three times of each and cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue obtained after removing the solvent was purified by chromatography (100% DCM) to give 29 mg (50%) of the title compound. LC/MS (m/z): 572 (M+1)+.


EXAMPLE 44

[0523] 3-(4′-Nitro-biphenyl-4-yl)-(2S)-[(4′-trifluoromethyl-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic Acid Methyl Ester

[0524] The resin-bound 3-(4-bromo-phenyl)-(2S)-[(4′-trifluoromethyl-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester (50 mg, 0.1 mmol) prepared as generally described in Example 37 was reacted with 4-nitro-phenyl boronic acid (50.1 mg, 0.3 mmol) by adapting the procedure as described in Example 43 to give title compound (28.2 mg, 50%). LC/MS (m/z): 565 (M+1)+.


EXAMPLE 45

[0525] 3-(3′-Trifluoromethyl-biphenyl-4-yl)-(2S)-[(4′-trifluoromethyl-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic Acid Methyl Ester

[0526] The resin-bound 3-(4-bromo-phenyl)-(2S)-[(4′-trifluoromethyl-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester (50 mg, 0.1 mmol) prepared as described in above Example 44 was reacted with 3-trifluoromethyl-phenyl boronic acid (57.2 mg, 0.3 mmol) by following as generally described in Example 44 to give title compound (29.2 mg , 50%). LC/MS (m/z): 588 (M+1)+.


EXAMPLE 46

[0527] 3-(4′-Trifluoromethyl-biphenyl-4-yl)-(2S)-[(4′-trifluoromethyl-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic Acid Methyl Ester

[0528] The resin-bound 3-(4-bromo-phenyl)-(2S)-[(4′-trifluoromethyl-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester (50 mg, 0.1 mmol) prepared as generally described in Example 37 was reacted with 4-trifluoromethyl-phenyl boronic acid (57.2 mg, 0.3 mmol) by adapting the procedure in Example 45 to give the title compound (29.2 mg, 50%).

[0529]

1
H NMR (400 MHz, CDCl3): 3.30-3.42 (m, 2H), 3.84 (s, 3H), 5.11 (dd, 1H), 6.82 (d, 1H), 7.10 (d, 1H), 7.43-7.45 (m, 2H), 7.53-7.57 (m, 4H), 7.60-7.70 (m, 6H); LC/MS (m/z): 588 (M+1)+.

[0530] By analogous methods to those described above the following Examples were synthesized;
7EX-LC/MSAMPLENAME(m/z)473-Biphenyl-4-yl-(2S)-[(2′,4′-difluoro-4-hydroxy-488biphenyl-3-carbonyl)-amino]-propionic acid483-Biphenyl-4-yl-(2S)-[(4′-chloro-3′-fluoro-4-504hydroxy-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester493-Biphenyl-4-yl-(2S)-[(3′-chloro-4′-fluoro-4-490hydroxy-biphenyl-3-carbonyl)-amino]-propionic acid503-Biphenyl-4-yl-(2S)-[(4-hydroxy-3′-nitro-499biphenyl-3-carbonyl)-amino]-propionic acidmethyl ester513-Biphenyl-4-yl-(2S)-[(4-hydroxy-4′-536trifluoromethoxy-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester52(2S)-[(4-Hydroxy-4′-trifluoromethyl-biphenyl-5533-carbonyl)-amino]-3-(3′-nitro-biphenyl-4-yl)-propionic acid53(2S)-[(4-Hydroxy-4′-trifluoromethyl-biphenyl-5663-carbonyl)-amino]-3-(3′-nitro-biphenyl-4-yl)-propionic acid methyl ester54(2S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-5513-carbonyl)-amino]-3-(3′-nitro-biphenyl-4-yl)-propionic acid methyl ester553-Biphenyl-4-yl-(2S)-[(4′-fluoro-4-hydroxy-470biphenyl-3-carbonyl)-amino]-propionic acidmethyl ester563-Biphenyl-4-yl-(2S)-[(4-hydroxy-4′-methoxy-482biphenyl-3-carbonyl)-amino]-propionic acidmethyl ester573-Biphenyl-4-yl-(2S)-[(4′-tert-butyl-4-hydroxy-508biphenyl-3-carbonyl)-amino]-propionic acidmethyl ester58(2S)-[(4-Hydroxy-3′-nitro-biphenyl-3-567carbonyl)-amino]-3-(3′-rifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester593-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-(2S)-[(4-551hydroxy-3′-nitro-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester60(2S)-[(4′-Amino-4-hydroxy-biphenyl-3-467carbonyl)-amino]-3-biphenyl-4-yl-propionicacid methyl ester61(2S)-[(3′-Amino-4-hydroxy-biphenyl-3-467carbonyl)-amino]-3-biphenyl-4-yl-propionicacid methyl ester623-Biphenyl-4-yl-(2S)-[(5′-fluoro-4-hydroxy-2′-500methoxy-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester633-Biphenyl-4-yl-(2S)-[(3′-fluoro-4-hydroxy-470biphenyl-3-carbonyl)-amino]-propionic acidmethyl ester643-Biphenyl-4-yl-(2S)-[(4-hydroxy-3′-520trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester653-Biphenyl-4-yl-(2S)-[(4-hydroxy-3′,5′-bis-588trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester663-Biphenyl-4-yl-(2S)-[(3′-chloro-4-hydroxy-486biphenyl-3-carbonyl)-amino]-propionic acidmethyl ester673-Biphenyl-4-yl-(2S)-[(4′-chloro-4-hydroxy-486biphenyl-3-carbonyl)-amino]-propionic acidmethyl ester683-Biphenyl-4-yl-(2S)-[(3′,5′-difluoro-4-hydroxy-488biphenyl-3-carbonyl)-amino]-propionic acidmethyl ester693-Biphenyl-4-yl-(2S)-[(4′-fluoro-4-hydroxy-3′-483methyl-biphenyl-3-carbonyl)-amino]-propionicacid methyl ester70(2S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-5723-carbonyl)-amino]-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester71(2S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-5343-carbonyl)-amino]-3-(4′-methoxy-biphenyl-4-yl)-propionic acidmethyl ester723-Biphenyl-4-yl-(2S)-[(4-hydroxy-4′-522trifluoromethoxy-biphenyl-3-carbonyl)-amino]-propionic acid733-Biphenyl-4-yl-(2S)-[(4′-tert-butyl-4-hydroxy-494biphenyl-3-carbonyl)-amino]-propionic acid743-Biphenyl-4-yl-(2S)-[(4-hydroxy-3′,4′-512dimethoxy-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester75(2S)-(5-Benzo[1, 3]dioxol-5-yl-2-hydroxy-496benzoylamino)-3-biphenyl-4-yl-propionic acidmethyl ester763-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-(2S)-[(4-572hydroxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester773-Biphenyl-4-yl-(2S)-[(4-hydroxy-4′-530methanesulfonyl-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester78(2S)-[(3′-Amino-4-hydroxy-biphenyl-3-535carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester793-(3′,5′-Bis-trifluoromethyl-biphenyl-4-yl)-(2S)-640[(3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester803-(3′,5′-Bis-trifluoromethyl-biphenyl-4-yl)-(2S)-606[(4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester813-(3′,5′-Bis-trifluoromethyl-biphenyl-4-yl)-(2S)-656[(4-hydroxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester82(2S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-5583-carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionic acid83(2S)-[(4-Hydroxy-4′-trifluoromethyl-biphenyl-6043-carbonyl)-amino]-3-(3′-trifluoromethoxy-biphenyl-4-yl)-propionic acid methyl ester84(2S)-[(4-Hydroxy-3′-trifluoromethyl-biphenyl-5883-carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester854′-{(2S)-[(4-Hydroxy-4′-trifluoromethyl-623biphenyl-3-carbonyl)-amino]-2-methoxycarbonyl-ethyl}-5-nitro-biphenyl-3-carboxylic acid methyl ester86(2S)-[(4-Hydroxy-4′-trifluoromethyl-biphenyl-6103-carbonyl)-amino]-3-(3′,4′,5′-trimethoxy-biphenyl-4-yl)-propionic acid methyl ester87(2S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-5883-carbonyl)-amino]-3-(3′-trifluoromethoxy-biphenyl-4-yl)-propionic acid methyl ester883-Biphenyl-4-yl-(2S)-[(4-hydroxy-4′-506trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionic acid89(2S)-[(4-Hydroxy-2′-trifluoromethyl-biphenyl-5883-carbonyl)-amino]-3-(2′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester903-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-(2S)-[(3′-556chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester91(2S)-[(4-Hydroxy-3′-nitro-biphenyl-3-542carbonyl)-amino]-3-(3′-nitro-biphenyl-4-yl)-propionic acid methyl ester92(2S)-[(4-Hydroxy-3′-trifluoromethyl-biphenyl-5653-carbonyl)-amino]-3-(3′-nitro-biphenyl-4-yl)-propionic acid methyl ester93(2S)-[(4-Hydroxy-3′-trifluoromethyl-biphenyl-5883-carbonyl)-amino]-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester943-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-(2S)-[(4-572hydroxy-3′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester953-Biphenyl-4-yl-(2S)-[(4-hydroxy-2′-520trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester963-(3′,5′-Bis-trifluoromethyl-biphenyl-4-yl)-(2S)-656[(4-hydroxy-3′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester97(2S)-[(4-Hydroxy-3′-trifluoromethyl-biphenyl-5883-carbonyl)-amino]-3-(2′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester



EXAMPLE 98

[0531] (2S)-[2-(4-Benzyloxy-benzyloxy)-5-bromo-benzoylamino]-3-biphenyl-4-yl-propionic Acid

[0532] 3-Biphenyl-4-yl-(2S)-(5-bromo-2-hydroxy-benzoylamino)-propionic acid methyl ester (2.75 g, 35%) was prepared from (2S)-amino-3-biphenyl-4-yl-propionic acid methyl ester-hydrochloride (5.0 g, 17.2 mmol), 5-bromo-2-hydroxy-benzoic acid (3.7 g, 17.2 mmol) as described in general procedure A except for an adapted work-up. After reaction completion, the reaction mixture was poured onto 150 mL of 1 N HCl and 150 mL of EtOAc. The organic layer was washed with 1 N HCl, saturated sodium bicarbonate, dried over sodium sulfate and evaporated. The crude material was purified over silica gel (7:3, DCM-hexanes).

[0533] (2S)-[2-(4-Benzyloxy-benzyloxy)-5-bromo-benzoylamino]-3-biphenyl-4-yl-propionic acid methyl ester (302 mg, 50%) was prepared from (2S)-3-Biphenyl-4-yl-2-(5-bromo-2-hydroxy-benzoylamino)-propionic acid methyl ester (400 mg, 0.92 mmol) and 4-benzyloxybenzyl chloride (256 mg, 0.39) as described in general procedure H and purified over silica gel (8:2, DCM-hexanes).

[0534] (2S)-[2-(4-Benzyloxy-benzyloxy)-5-bromo-benzoylamino]-3-biphenyl-4-yl-propionic acid methyl ester (60 mg, 0.092 mmol) was dissolved in 5 mL of THF-MeOH (4-1), cooled to 0° C. and 1.1 equiv of 2 N LiOH added. After 30 minutes, 2.2 additional equiv of 2N LiOH was added and the reaction stirred for 30 minutes. The reaction was worked up according to general procedure C to give (2S)-[2-(4-Benzyloxy-benzyloxy)-5-bromo-benzoylamino]-3-biphenyl-4-yl-propionic acid (35 mg, 60%).

[0535]

1
H-NMR(400 MHz, DMSO-d6): 2.90 (m, 1H), 3.17 (m, 1H), 4.69 (m, 1H), 4.98 (s, 2H), 5.18 (s, 2H), 6.92 (m, 2H), 7.21 (m, 3H), 7.33 (m, 10H), 7.53 (d, 2H), 7.61 (m, 3H), 7.84 (d, 1H), 8.51 (d, 1H); LC/MS (m/z): 638.1 (M+2)+.


EXAMPLE 99

[0536] 3-Biphenyl-4-yl-(2S)-{[4-(4-tert-butyl-benzyloxy)-3′-chloro-4′-fluoro-biphenyl-3-carbonyl]-amino}-propionic Acid

[0537] 5-Bromo-2-(4-t-butyl-benzyloxy)-benzoic acid methyl ester (338 mg, 90%) was made from 5-bromosalicilic acid methyl ester (230 mg, 1.0 mmol) and t-butyl-benzyl bromide (226 mg, 1.0 mmol) following general procedure H, then hydrolyzed as in general procedure C to give the corresponding acid (310 mg, 95%). The above acid (40 mg, 0.11 mmol) was reacted with biphenyl alanine methyl ester (44 mg, 0.15 mmol) as described in general procedure A to give 3-biphenyl-4-yl-(2S)-[2-(4-t-butyl-benzyloxy)-5-bromo-benzoylamino]-propionic acid methyl ester. The methyl ester (60 mg, 0.1 mmol) so obtained was reacted with 3-chloro-4-fluorophenyl boronic acid (35 mg, 0.2 mmol) as described in general procedure D to provide the (2S)-[(3′-chloro-4′-fluoro-4-tert-butyl-benzyloxy-biphenyl-3-carbonyl)-amino]-3-biphenyl-4-yl-propionic acid methyl ester (52 mg, 80%). The ester was hydrolyzed following general procedure C to give the title compound (48 mg, 95%).

[0538]

1
H NMR (400 MHz, CDCl3): 1.27 (s, 9H), 2.89 (m, 1H), 3.30 (m , 1H), 4.93 (m, 1H), 5.11 (m, 2H), 7.00 (m, 2H), 7.26-7.60 (m, 17H), 8.41 (d, 1H), 8.58 (d, 1H); LC/MS (m/z): 636 (M+1)+.


EXAMPLE 100

[0539] (2S)-[5-Bromo-2-(4-trifluoromethylbenzyloxy)-benzoylamine]-3-(2′-phenoxybiphenyl-4-yl)-propionic Acid

[0540] 5-Bromo-salicylic acid (2.16 g, 10 mmol) was first transformed into 2-acetyl-5-bromo-salicylic acid (252 g, 98%) with acetyl chloride (2.34 g, 30 mmol) and pyridine (3.95 g, 50 mmol) in DCM. The above acid (1.29 g, 5.0 mmol) was converted into acid chloride by using oxyl chloride (1.97 g, 15 mmol) and catalytic amount of DMF in DCM, then 2-phenoxy-biphenyl alanine (1.45 g, 5.0 mmol) and DIEA (0.77 g, 6.0 mmol) were added to the acid chloride to form (2S)-[5-Bromo-2-hydroxybenzoylamine]-3-(2′-phenoxybiphenyl-4-yl)-propionic acid methyl ester (1.92 g, 85%). The above methyl ester (50 mg, 0.092 mmol) was reacted with 4-trifluoromethyl benzyl bromide (44 mg, 0.18 mmol) as described in general procedure H to provide (2S)-[5-Bromo-2-(4-trifluoromethylbenzyloxy)-benzoylamine]-3-(2′-phenoxybiphenyl-4-yl)-propionic acid methyl ester (55 mg, 85%). The ester was hydrolyzed following general procedure C to give the title compound (52 mg, 96%).

[0541]

1
H NMR (400 MHz, CDCl3): 3.03, 3.22 (ABX, 2H), 4.92 (m, 3H), 6.64 (d, 1H), 6.76 (m, 2H), 6.85 (dd, 1H), 6.93 (m, 2H), 7.00 (d, 2H), 7.07-7.24 (m, 7H), 7.39 (m, 4H), 8.22 (d, 1H), 8.26 (d, 1H); LC/MS (m/z): 690 (M+1)+.


EXAMPLE 101

[0542] (2S)-(5-Bromo-2-heptyloxy-benzoylamino)-3-[2′-(4-trifluoromethyl-phenoxy) -biphenyl-4-yl]-propionic Acid

[0543] 5-Bromo-2-heptyloxy-benzoic acid was prepared by reacting 5-bromo-2-hydroxy-benzoic acid methyl ester (1.0 g, 4.32 mmol) with iodoheptane (1.46 g, 6.49 mmol) as per general procedure H with potassium carbonate (1.5 g, 10.8 mmol) added. The ester thus obtained was subjected to hydrolysis as per general procedure C to yield the 5-Bromo-2-heptyloxy-benzoic acid (0.950 gm, 70%).

[0544] (2S)-Amino-3-(2′-hydroxy-biphenyl-4-yl)-propionic acid was prepared from 4-bromophenylalanine (5.0 g, 20.48 mmol), 2-hydroxyphenylboronic acid (4.23 g, 30.72 mmol) and Pd (PPh3)4 (2.36 g, 2.038 mmol) as per procedure D to yield the corresponding amino acid which was further esterified with methanolic solution of anhydrous HCl to yield the corresponding HCl salt of the (2S)-Amino-3-(2′-hydroxy-biphenyl-4-yl)-propionic acid methyl ester (5.0 g, 90% crude yield).

[0545] 5-Bromo-2-heptyloxy-benzoic acid (0.231 g, 0.738 mmol) and the (2S)-amino-3-(2′-hydroxy-biphenyl-4-yl)-propionic acid methyl ester (0.200 g, 0.738 mmol) were then combined as per general procedure A with HBTU (0.335 g, 0.885 mmol) and diisopropylethylamine (0.285 g, 2.21 mmol) to yield the (2S)-(5-bromo-2-heptyloxy-benzoylamino)-3-(2′-hydroxy-biphenyl-4-yl)-propionic acid methyl ester (0.200 g, 50%).

[0546] The title compound was the prepared from (2S)-(5-bromo-2-heptyloxybenzoylamino)-3-(2′-hydroxy-biphenyl-4-yl)-propionic acid methyl ester (0.080 g, 0.140 mmol) and 4-trifluoromethylphenylboronic acid (0.050 g, 0.281 mmol) as per general procedure G to give (2S)-(5-bromo-2-heptyloxy-benzoylamino)-3-[2′-(4-trifluoromethyl-phenoxy)-biphenyl-4-yl]-propionic acid methyl ester which was further hydrolyzed as per general procedure C to give the title compound (0.020 g, 30% yield).

[0547]

1
H-NMR(400 MHz, CDCl3): 1.14 (t, 3H), 1.53 (m, 8H), 1.92 (m, 2H), 3.6 (m, 2H), 4.21 (m, 2H), 5.21 (m, 1H), 7.12 (d, 1H), 7.22 (m, 2H), 7.36 (d, 1H), 7.5 (d, 2H), 7.58 (m, 2H), 7.66 (m, 1H), 7.78 (m, 6H), 8.62 (S, 1H), 8.9 (bs, 1H). LC/MS (m/z): 700.2 (M+2).


EXAMPLE 102

[0548] 2S-(5-Chloro-2-heptyloxy-benzoylamino)-3-(4′-trifluoromethoxy-biphenyl-4-yl)-propionic Acid

[0549] 5-Chloro-2-hydroxy-benzoic acid (2.5 g, 28.97 mmol) was coupled with 2-amino-3-(4-bromo-phenyl)-propionic acid methyl ester hydrochloride (4.26 g, 28.96 mmol) with HBTU (6.59 g, 34.76 mmol) and diisopropylethylamine (8 ml, 86.91 mmol) as per general procedure A to yield the corresponding 3-(4-Bromo-phenyl)-(2S)-(5-chloro-2-hydroxy-benzoylamino)-propionic acid methyl ester in 50% yield.

[0550] The above hydroxy compound (0.500 g, 1.21 mmol) was then alkylated with heptyliodide (0.410 g, 1.815 mmol) and potassium carbonate (0.050 g, 3.025 mmol) as per general procedure H to yield the 3-(4-bromo-phenyl)-(2S)-(5-chloro-2-heptyloxy-benzoylamino)-propionic acid methyl ester (0.500 g, 80%)

[0551] The title compound was then prepared from 3-(4-bromo-phenyl)-(2S)-(5-chloro-2-heptyloxy-benzoylamino)-propionic acid methyl ester (0.090 g, 0.176 mmol) and trifluoromethyl boronic acid (0.067 g, 0.352 mmol) with Pd (PPh3) (0.020 g, 0.0176 mmol) and 2 N Na2CO3 (0.528 ml, 0.528 mmol) as per general procedure D to yield the (2S)-(5-chloro-2-heptyloxy-benzoylamino)-3-(4′-trifluoromethoxy-biphenyl-4-yl)-propionic acid methyl ester which was further hydrolyzed as per general procedure C to give the title compound (0.050 g, 50%)%). 1H-NMR(400 MHz, CDCl3): 1.11 (t, 3H), 1.44 (m, 8H), 1.87 (m, 2H), 3.65 (dddd, 2H), 4.27 (m, 2H), 5.50 (m, 1H), 7.18 (m, 2H), 7.4 (d, 1H), 7.57 (m, 4H), 7.68-7.85 (m, 4H), 8.52 (S, 1H), 8.98 (bs, 1H). LC/MS (m/z): 578.2(M+2).

[0552] By analogous methods to those described above the following compounds were synthesized.
8EX-LC/MSAMPLENAME(m/z)1033-Biphenyl-4-yl-(2S)-[2-(3,4-bis-benzyloxy-757benzyloxy)-5-bromo-benzoylamino]-propionic acidmethyl ester1043-Biphenyl-4-yl-(2S)-[2-(3,4-bis-benzyloxy743benzyloxy)-5-bromo-benzoylamino]-propionic acid105(2S)-[2-(4-Benzyloxybenzyloxy)-5-bromo651benzoylamino]-3-biphenyl-4-yl-propionicacid methyl ester1063-Biphenyl-4-yl-(2S)-[5-bromo-2-(4-bromo-624benzyloxy)-benzoylamino]-propionic acid methylester1073-Biphenyl-4-yl-(2S)-[5-bromo-2-(4-bromo-610benzyloxy)-benzoylamino]-propionic acid1083-Biphenyl-4-yl-(2S)-[5-bromo-2-(4-tert-butyl-601benzyloxy)-benzoylamino]-propionic acid methylester1093-Biphenyl-4-yl-(2S)-[5-bromo-2-(4-tert-butyl-587benzyloxy)-benzoylamino]-propionic acid1103-Biphenyl-4-yl-(2S)-[2-(biphenyl-4-ylmethoxy)-5-607bromo-benzoylamino]-propionic acid1113-Biphenyl-4-yl-(2S)-(5-chloro-2-methoxy-benzoyl410amino)-propionic acid1123-Biphenyl-4-yl-(2S)-[2-(4-tert-butyl-benzyloxy)-5-542chloro-benzoylamino]-propionic acid1133-Biphenyl-4-yl-(2S)-[2-(4-tert-butyl-benzyloxy)-5-636(4-trifluoromethylphenyl)-benzoylamino]-propionicacid114(2S)-[5-Bromo-2-(3-methyl-benzyloxy)-652benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester115(2S)-[5-Bromo-2-(4-methyl-benzyloxy)-637benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid116(2S)-[5-Bromo-2-(3-methyl-benzyloxy)-637benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid117(2S)-[5-Bromo-2-(4-carboxy-benzyloxy)-667benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid118(2S)-[5-Bromo-2-(4-trifluoromethyl-phenoxy)-677benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid119(2S)-(5-Bromo-2-heptyloxy-benzoylamin-3-(2′-645phenoxy-biphenyl-4-yl)-propionic acid methyl ester1203-Biphenyl-4-yl-(2S)-(5-bromo-2-heptyloxy-553benzoylamino)-propionic acid methyl ester1213-Biphenyl-4-yl-(2S)-(5-bromo-2-heptyloxy-539benzoylamino)-propionic acid122(2S)-(5-Bromo-2-heptyloxy-benzoylamino)-3-(2′-631phenoxy-biphenyl-4-yl)-propionic acid1233-Biphenyl-4-yl-(2S)-[5-chloro-2-(4-pyrazol-1-yl-552benzyloxy)-benzoylamino]-propionic acid124(2S)-[5-Bromo-2-(4-tert-butyl-benzyloxy)-679benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid125(2S)-(2-Benzyloxy-5-bromo-benzoylamino)-3-(2′-637phenoxy-biphenyl-4-yl)-propionic acid methyl ester126(2S)-(2-Benzyloxy-5-bromo-benzoylamino)-3-(2′-623phenoxy-biphenyl-4-yl)-propionic acid127(2S)-[5-Bromo-2-(4-bromo-benzyloxy)-702benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid128(2S)-(5-Bromo-2-propoxy-benzoylamino)-5753-(2′-phenoxy-biphenyl-4-yl)-propionic acid129(2S)-[(5-Bromo-2,3-dihydro-benzofuran-5597-carbonyl)-amino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid130(2S)-[5-Bromo-2-(3-phenyl-allyloxy)-663benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester131(2S)-[5-Bromo-2-(3-phenyl-allyloxy)-649benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid132(2S)-[5-Bromo-2-(4-methanesulfonyl-benzyloxy)-715benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester133(2S)-[5-Bromo-2-(4-methanesulfonyl-benzyloxy)-701benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid134(2S)-[5-Bromo-2-(3-methyl-butoxy)-benzoylamino]-6173-(2′-phenoxy-biphenyl-4-yl)-propionic acid methylester135(2S)-[5-Bromo-2-(3-methyl-butoxy)-benzoylamino]-6033-(2′-phenoxy-biphenyl-4-yl)-propionic acid136(2S)-[2-(Biphenyl-4-ylmethoxy)-5-bromo-713benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester137(2S)-[2-(Biphenyl-4-ylmethoxy)-5-bromo-699benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid138(2S)-[5-Bromo-2-(4-methoxy-phenoxy)-639benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid139(2S)-[5-Bromo-2-(4-phenoxy-benzyloxy)-715benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid140(2S)-[5-Bromo-2-(1-methyl-butoxy)-benzoylamino]-6173-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester141(2S)-[5-Bromo-2-(1-methyl-butoxy)-benzoylamino]-6033-(2′-phenoxy-biphenyl-4-yl)-propionic acid142(2S)-(5-Bromo-2-isopropoxy-benzoylamino)-3-(2′-575phenoxy-biphenyl-4-yl)-propionic acid143(2S)-[5-Bromo-2-(3-trifluoromethyl-phenoxy)-677benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid144(2S)-(5-Bromo-2-heptyloxy-benzoylamino)-6613-[2′-(4-methoxy-phenoxy)-biphenyl-4-yl]-propionicacid145(2S)-[5-Bromo-2-(2-morpholin-4-yl-ethoxy)-660benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester146(2S)-{5-Bromo-2-[2-(2-methoxy-ethoxy)-649ethoxy]-benzoylamino}-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester147(2S)-(5-Bromo-2-{2-[-(2-methoxy-ethoxy)-ethoxy]-693ethoxy}-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methylester148(2S)-(5-Bromo-2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-658ethoxy}-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methylester149(2S)-{5-Bromo-2-[2-(2-oxo-pyrrolidin-1-658yl)-ethoxy]-benzoylamino}-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester150(2S)-[5-Bromo-2-(2-phenyl-cyclopropylmethoxy)-663benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid151(2S)-(5-Bromo-2-sec-butoxy-benzoylamino)-3-(2′-589phenoxy-biphenyl-4-yl)-propionic acid152(2S)-(5-Chloro-2-heptyloxy-benzoylamino)-3-(2′-600phenoxy-biphenyl-4-yl)-propionic acid methyl ester153(2S)-(5-Chloro-2-heptyloxy-benzoylamino)-3-(2′-586phenoxy-biphenyl-4-yl)-propionic acid154(2S)-(5-Bromo-2-isobutoxy-benzoylamino)-3-(2′-603phenoxy-biphenyl-4-yl)-propionic acid methyl ester155(2S)-(5-Bromo-2-isobutoxy-benzoylamino)-3-(2′-588phenoxy-biphenyl-4-yl)-propionic acid156(2S)-(5-Bromo-2-ethoxycarbonyloxy-619benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester157(2S)-(5-Bromo-2-dimethylcarbamoyloxy-618benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester158(2S)-{5-Bromo-2-[2-(2-methoxy-ethoxy)-635ethoxy]-benzoylamino}-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid159(2S)[5-Bromo-2-(4-phenyl-butoxy)-benzoylamino]-6653-(2′-phenoxy-biphenyl-4-yl)-propionic acid160(2S)-[5-Bromo-2-(5-phenyl-pentyloxy)-679benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid161(2S)-[5-Bromo-2-(6-phenyl-hexyloxy)-693benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid162(2S)-(5-Bromo-2-heptyloxy-benzoylamino)-3-[2′-(4-715trifluoromethoxy-phenoxy)-biphenyl-4-yl]-propionic acid163(2S)-(5-Bromo-2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-679ethoxy}-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid164(2S)-[5-Bromo-2-(2-piperidin-1-yl-ethoxy)-644benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid165(2S)-(5-Bromo-2-heptyloxy-benzoylamino)-3-[2′-(4-687tert-butyl-phenoxy)-biphenyl-4-yl]-propionic acid166(2S)-(5-Chloro-2-heptyloxy-benzoylamino)-3-(4′-562trifluoromethyl-biphenyl-4-yl)-propionic acid1673-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-(2S)-(5-chloro-5462-heptyloxy-benzoylamino)-propionic acid168(2S)-[5-Bromo-2-(3-phenyl-propoxy)-651benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid169(2S)-{5-Bromo-2-[3-(3,4-dimethoxy-phenyl)-711propoxy]-benzoylamino}-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid170(2S)-[5-Bromo-2-(3-pyridin-3-yl-propoxy)-652benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid171(2S)-[5-Bromo-2-(3-pyridin-4-yl-propoxy)-652benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid172(2S)-(5-Bromo-2-dimethylcarbamoyloxy-604benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid173(2S)-[5-Bromo-2-(3-morpholin-4-yl-propoxy)-660benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid174(2S)-[5-Bromo-2-(4,4,4-trifluoro-butoxy)-643benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid175(2S)-(5-Chloro-2-heptyloxy-benzoylamino)-3-(4′-576cyclohexyl-biphenyl-4-yl)-propionic acid176(2S)-(5-Chloro-2-heptyloxy-benzoylamino)-3-(3′,4′-562dichloro-biphenyl-4-yl)-propionic acid177(2S)-(5-Bromo-2-butoxy-benzoylamino)-3-(2′-589phenoxy-biphenyl-4-yl)-propionic acid178(2S)-[5-Bromo-2-(2-methyl-butoxy)-benzoylamino]-6033-(2′-phenoxy-biphenyl-4-yl)-propionic acid179(2S)-(5-Bromo-2-cyclopropylmethoxy-601benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester180(2S)-(5-Bromo-2-cyclopropylmethoxy-587benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid181(2S)-[5-Bromo-2-(4-[1,2,4]triazol-1-yl-benzyloxy)-690benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid182(2S)-[5-Bromo-2-(isoquinolin-1-ylmethoxy)-674benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid183(2S)-[2-(3-Benzyloxy-benzyloxy)-5-bromo-743benzoylamino]-3-(4′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester184(2S)-[2-(3-Benzyloxy-benzyloxy)-5-bromo-728benzoylamino]-3-(4′-phenoxy-biphenyl-4-yl)-propionic acid185(2S)-[5-Bromo-2-(4-trifluoromethoxy-benzyloxy)-721benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester186(2S)-[5-Bromo-2-(4-trifluoromethoxy-benzyloxy)-707benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid187(2S)-[5-Bromo-2-(4-phenyl-butoxy)-benzoylamino]-6793-(4′-phenoxy-biphenyl-4-yl)-propionic acid methylester188(2S)-[5-Bromo-2-(6-phenyl-hexyloxy)-707enzoylamino]-3-(4′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester189(2S)-(5-Chloro-2-heptyloxy-benzoylamino)-3-(4′-537dimethylamino-biphenyl-4-yl)-propionic acid190(2S)-[5-Bromo-2-(4-phenyl-butoxy)-benzoylamino]-6653-(4′-phenoxy-biphenyl-4-yl)-propionic acid191(2S)-[5-Bromo-2-(6-phenyl-hexyloxy)-693benzoylamino]-3-(4′-phenoxy-biphenyl-4-yl)-propionic acid192(2S)-[5-Bromo-2-(2-cyclohexyl-ethoxy)-657benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester193(2S)-[5-Bromo-2-(2-cyclohexyl-ethoxy)-643benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid194(2S)-(5-Bromo-2-cyclohexylmethoxy-629benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid195(2S)-(5-Bromo-2-cyclohexyloxy-benzoylamino)-3-629(2′-phenoxy-biphenyl-4-yl)-propionic acid methylester196(2S)-(5-Bromo-2-cyclohexyloxy-benzoylamino)-3-615(2′-phenoxy-biphenyl-4-yl)-propionic acid



EXAMPLE 197

[0553] N-[2-Hydroxy-4-(4-trifluoromethyl-phenoxy)-phenyl]-2-(3′-methoxy-biphenyl-4-yl)-acetamide

[0554] To 4.0 g (4.0 mmol) of resin-bound 5-fluoro-2-nitro-phenol obtained by a similar procedure as in Example 37 in 8.0 mL of DMF were added 1.31 g (8.0 mmol) of 4-hydroxybenzotrifluoride, and 1.20 g (8.0 mmol) of K2CO3. The mixture was heated to 110° C. for 12 h. The resin was washed with H2O, DMF, MeOH, DCM three times of each, and was reduced by SnCl2 hydrate in NMP at rt for 4 h to give the resin-bound 2-amino-5-(4-trifluoromethyl-phenoxy)-phenol.

[0555] To 3.0 g (2.5 mmol) of above resin-bound 2-amino-5-(4-trifluoromethyl-phenoxy)-phenol were added 1.62 g (7.5 mmol) of 4-bromophenylacetic acid, 7.5 mL (7.5 mmol) of 1.0 M DIC in DMF, 7.5 mL (7.5 mmol) of 1.0 M HOBt in DMF, and a catalytic amount of DMAP. The resulting mixture was left on a shaker overnight. The resin was washed with DMF, MeOH, DCM three times of each to give resin-bound 2-(4-bromo-phenyl)-N-[2-Hydroxy-4-(4-trifluoromethyl-phenoxy)-phenyl]-acetamide.

[0556] To 120 mg (0.1 mmol) of above resin-bound 2-(4-bromo-phenyl)-N-[2-Hydroxy-4-(4-trifluoromethyl-phenoxy)-phenyl]-acetamide in 2.0 mL of DME were added 46.0 mg (0.3 mmol) of 3-methoxyphenylboronic acid, 30 mg (0.03 mmol) of Pd(PPh3)4, and 0.3 mL (0.6 mmol) of 2N Na2CO3 solution. The mixture was heated to 80° C. for 12 h. The resin was washed with H2O, DMF, MeOH, DCM three times of each and cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue obtained after removing the solvent was purified by chromatography (100% methylene chloride) to give 25 mg (50%) of the title compound. LC/MS (m/z) 494 (M+1)+.


EXAMPLE 198

[0557] N-[2-Hydroxy-4-(3,4-dichloro-phenoxy)-phenyl]-2-(4′-trifluoromethyl-biphenyl-4-yl)-acetamide

[0558] The resin-bound 2-(4-bromo-phenyl)-N-[2-Hydroxy-4-(3,4-dichloro-phenoxy)phenyl]-acetamide (120 mg, 0.1 mmol) prepared as described in Example 197 was reacted with 4-trifluoromethyl-phenyl boronic acid (56.7 mg, 0.3 mmol) as generally described in Example 197 to afford (26.9 mg, 50%) the title compound.

[0559]

1
H NMR (400 MHz, CDCl3): 3.88 (s, 2H), 6.48 (dd, 1H), 6.66 (d, 1H), 6.79-6.85 (m, 2H), 7.05 (d, 1H), 7.36 (d, 2H), 7.46-7.48 (m, 2H), 7.66-7.68 (m, 2H), 7.71 (m, 4H), 8.92 (s, 1H); LC/MS (m/z): 532 (M+1)+.


EXAMPLE 199

[0560] N-[2-Hydroxy-4-(2,4-dichloro-6-methyl-phenoxy)-phenyl]-2-(4′-trifluoromethyl-biphenyl-4-yl)-acetamide

[0561] The resin-bound 2-(4-bromo-phenyl)-N-[2-Hydroxy-4-(3,4-dichloro-6-methyl-phenoxy)-phenyl]-acetamide (120 mg, 0.1 mmol) prepared as described in Example 197 was reacted with 4-trifluormethyl-phenyl boronic acid (56.7 mg, 0.3 mmol) as generally described in Example 197 to afford (27.5 mg, 50%) of title compound.

[0562]

1
H NMR (400 MHz, CDCl3): 2.13 (s, 3H), 3.86 (s, 2H), 6.33 (dd, 1H), 6.36 (d, 1H), 6.69 (d, 1H), 7.15 (d, 1H, 7.29 (d, 1H), 7.45 (d, 2H), 7.64-7.71 (m, 6H), 8.92 (s, 1H); LC/MS (m/z): 546 (M+1)+.

[0563] N-[2-Hydroxy-4-(2,4-dichloro-6-methyl-phenoxy)-phenyl]-2-(3′-trifluoromethyl-biphenyl-4-yl)-acetamide

[0564] The resin-bound 2-(4-bromo-phenyl)-N-[2-Hydroxy-4-(3,4-dichloro-6-methyl-phenoxy)-phenyl]-acetamide (120 mg, 0.1 mmol) prepared as described in Example 197 was reacted with 3-trifluormethyl-phenyl boronic acid (56.7 mg, 0.3 mmol) as generally described in Example 197 to afford (27.5 mg, 50%) of title compound.

[0565]

1
H NMR (400 MHz, CDCl3): 2.13 (s, 1H), 3.86 (s, 2H), 6.33 (dd, 1H), 6.37 (d, 1H), 6.69 (d, 1H), 7.15 (m, 1H), 7.30 (d, 1H), 7.45 (dd, 2H), 7.59-7.65 (m, 4H), 7.78 (m, 1H), 7.84 (s, 1H), 8.84 (s, 1H); LC/MS (m/z): 546 (M+1)+.

[0566] By analogous methods to those described above the following compounds were synthesized
9LC/MSEXAMPLENAME(m/z)2013-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-N-[4-(2,4-544dichloro-6-methyl-phenoxy)-2-hydroxy-phenyl]-propionamide202N-[4-(2-Fluoro-6-methoxy-phenoxy)-2-hydroxy-488phenyl]-3-(3′-methoxy-biphenyl-4-yl)-propionamide203N-[4-(2,4-Dichloro-6-methyl-phenoxy)-2-508hydroxy-phenyl]-2-(4′-methoxy-biphenyl-4-yl)-acetamide2042-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-N-[4-(2,4-530dichloro-6-methyl-phenoxy)-2-hydroxy-phenyl]-acetamide2052-Biphenyl-4-yl-N-[2-hydroxy-4-(4′-502methoxy-biphenyl-4-yloxy)-phenyl]-acetamide2062-Biphenyl-4-yl-N-[2-hydroxy-4-(4′-540trifluoromethyl-biphenyl-4-yloxy)-phenyl]-acetamide207N-[4-(3,4-Dichloro-phenoxy)-2-hydroxy-phenyl]-5082-(3′-nitro-biphenyl-4-yl)-acetamide



EXAMPLE 208

[0567] N-[5-(3-Chloro-phenyl)-pyridin-2-yl]-2-[4-(3-hydroxy-4-nitro-phenoxy)-phenyl]-acetamide

[0568] To 4.0 g (4.0 mmol) of resin-bound 5-fluoro-2-nitro-phenol prepared as generally described in Example 37 in 8.0 mL of DMF were added 1.34 g (8.0 mmol) of methyl 4-hydroxyphenylacetate, and 1.20 g (8.0 mmol) of K2CO3. The mixture was heated to 110° C. for 12 h. The resin was washed with H2O, DMF, MeOH, DCM three times of each, and was hydrolyzed by LiOH/H2O/THF/ethanol at rt for 12 h to give the resin-bound [4-(3-hydroxy-4-nitro-phenoxy)-phenyl]-acetic acid.

[0569] To 3.0 g (2.5 mmol) of above resin-bound [4-(3-hydroxy-4-nitro-phenoxy)phenyl]-acetic acid were added 1.30 g (7.5 mmol) of 2-amino-5-bromopyridine, 7.5 mL (7.5 mmol) of 1.0 M DIC in DMF, 7.5 mL (7.5 mmol) of 1.0 M HOBt in DMF, and catalytic amount of DMAP. The resulting mixture was left on a shaker overnight. The resin was washed with DMF, MeOH, DCM three times of each to give resin-bound N-(5-bromo-pyridin-2-yl)-2-[4-(3-hydroxy-4-nitro-phenoxy)-phenyl]-acetamide

[0570] To 120 mg (0.1 mmol) of above resin-bound bound N-(5-bromo-pyridin-2-yl)-2-[4(3-hydroxy-4-nitro-phenoxy)-phenyl]-acetamide in 2.0 mL of DME were added 48.0 mg (0.3 mmol) of 3-chlorophenylboronic acid, 30 mg (0.03 mmol) of Pd(PPh3)4, and 0.3 mL (0.6 mmol) of 2N Na2CO3 solution. The mixture was heated to 80° C. for 12 h. The resin was washed with H2O, DMF, MeOH, DCM three times of each and cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue obtained after removing the solvent was purified by chromatography (silica gel, DCM) to give 20 mg (40%) of the title compound.

[0571]

1
H NMR (400 MHz, CDCl3): 3.81 (s, 2H), 6.51-6.55 (m, 1H), 6.60-6.63 (m, 1H), 7.11-7.13 (m, 2H), 7.26-7.45 (m, 5H), 7.52 (m, 1H), 7.91 (dd, 1H), 8.08 (m, 1H), 8.34 (d, 1H), 8.43 (m, 1H), 10.89 (s, 1H); LC/MS (m/z): 476 (M+1)+.


EXAMPLE 209

[0572] N-[5-(3,4-Dichloro-phenyl)-pyridin-2-yl]-2-[4-(3-hydroxy-4-nitro-phenoxy)-phenyl]-acetamide

[0573] The resin-bound N-(5-bromo-pyridin-2-yl)-2-[4-(3-hydroxy-4-nitro-phenoxy)phenyl]-acetamide (120 mg, 0.1 mmol) was reacted with 3,4-dichloro-phenyl boronic acid (57 mg, 0.3 mmol) as described in example 208 to afford 25 mg (45%) of the title compound. LC/MS (m/z): 510 (M+1)+.


EXAMPLE 210

[0574] N-[5-(3-Trifluromethyl-phenyl)-pyridin-2-yl]-2-[4-(3-hydroxy-4-nitro-phenoxy)-phenyl]-acetamide

[0575] The resin-bound N-(5-bromo-pyridin-2-yl)-2-[4-(3-hydroxy-4-nitro-phenoxy)phenyl]-acetamide (120 mg, 0.1 mmol) was reacted with 3-trifluoromethyl-phenyl boronic acid (57 mg, 0.3 mmol) as described in example 208 to afford 22.9 mg (45%) of the title compound.

[0576]

1
H NMR (400 MHz, CDCl3): 3.72 (s, 2H), 3.89 (s, 3H), 6.52 (m, 1H), 6.58-6.63 (m, 1H), 7.07-7.11 (m, 2H), 7.48-7.50 (m, 2H), 7.66-7.78 (m, 4H), 8.06-8.09 (m, 1H), 8.25 (dd, 1H), 8.43 (dd, 1H), 8.72 (d, 1H), 10.90 (s, 1H); LC/MS (m/z): 510 (M+1)+.


EXAMPLE 211

[0577] N-[5-(4-Methoxy-phenyl)-pyridin-2-yl]-2-[4-(3-hydroxy-4-nitro-phenoxy)-phenyl]-acetamide

[0578] The resin-bound N-(5-bromo-pyridin-2-yl)-2-[4-(3-hydroxy-4-nitro-phenoxy)-phenyl]-acetamide (120 mg, 0.1 mmol) was reacted with 4-methoxy-phenyl boronic acid (45 mg, 0.3 mmol) as described in example 208 to afford 21.2 mg (45%) of the title compound.

[0579]

1
H NMR (400 MHz, CDCl3): 3.87 (s, 3H), 3.88 (s, 2H), 6.52 (d, 1H), 6.61 (dd, 1H), 7.01-7.03 (m , 2H), 7.08-7.10 (m, 2H), 7.46-7.50 (m, 4H), 8.08 (d, 1H), 8.16 (dd, 1H), 8.36 (dd, 1H), 8.62 (d, 1H), 10.89 (s, 1H); LC/MS (m/z): 472 (M+1)+.


EXAMPLE 212

[0580] 3-Biphenyl-4-yl-(2S)-[(4′-trifluoromethyl -biphenyl-4-carbonyl)-amino]-propionic Acid

[0581] (2S)-Amino-3-biphenyl-4-yl-propionic acid methyl ester (1.00 g mg, 4.1 mmol) was reacted with 4-bromo-benzoic acid (1.07 g mg, 5.3 mmol) as described in general procedure A yielding 3-biphenyl-4-yl-(2S)-[(5-bromo-benzoyl-amino)-propionic acid (1.48 g, 85%).

[0582] 3-Biphenyl-4-yl-(2S)-[(5-bromo-benzoylamino)-propionic acid (100 mg, 0.23 mmol) was reacted with 4-trifluoromethyl phenyl boronic acid (0.133 mg, 0.69 mmol) by following general procedure D yielding the title compound (98 mg, 85%) as a white solid.

[0583]

1
H-NMR(400 MHz, DMSO-d6): 3.07-3.25 (m, 2H), 4.63-4.69 (m, 1H), 7.26-7.32 (m, 1H), 7.39-7.42 (m, 4H), 7.56-7.62 (m, 4H), 7.1-7.84 (m, 4H), 7.81-7.84 (m, 4H), 7.92-7.95 (m, 4H), 8.86 (d, 1H); LC/MS (m/z): 490 (M+1)+.


EXAMPLE 213

[0584] 3-Biphenyl-4-yl-(2S)-[(3′-chloro-4′-fluoro-biphenyl-4-carbonyl)-amino]-propionic Acid

[0585] 3-Biphenyl-4-yl-(2S)-[(5-bromo-benzoyl-amino)-propionic acid (100 mg, 0.23 mmol) was reacted with 3-chloro-4-fluoro-phenyl boronic acid (0.123 mg, 0.69 mmol) by following general procedure D to afford title compound (89 mg, 80%) as a white solid. 1H NMR (400 MHz, CD3COCD3): 4.05 (dd, 2H), 5.00 (m, 1H), 7.32 (m, 1H), 7.44 (m, 4H), 7.62 (m, 4H), 7.71 (m, 1H), 7.74 (m, 2H), 7.84 (m, 1H), 7.96 (m, 3H). LC/MS (m/z): 474 (M+1)+.


EXAMPLE 214

[0586] 3-Biphenyl-4-yl-(2S)-[(4′-trifluoromethoxy-biphenyl-4-carbonyl)-amino]-propionic Acid

[0587] 3-Biphenyl-4-yl-(2S)-[(5-bromo-benzoyl-amino)-propionic acid (100 mg, 0.23 mmol) was reacted with 4-trifluoromethoxyphenylboronic acid (0.145 mg, 0.69 mmol) by following general procedure D yielding the title compound (101 mg, 85%) as a white solid:

[0588]

1
H-NMR(400 MHz, DMSO-d6): 3.08-3.15 (m, 1H), 3.20-3.25 (m, 1H), 4.62-4.68 (m, 1H), 7.28-7.32 (m, 1H ), 7.39-7.46 (m, 6H), 7.55-7.61 (m, 4H), 7.77 (d, 2H), 7.82 (d, 2H), 7.92 (d, 2H), 8.84 (d, 1H); LC/MS (m/z): 524 (M+1)+.


EXAMPLE 215

[0589] 3-Biphenyl-4-yl-(2S)-[(4′-ethyl-biphenyl-4-carbonyl)-amino]-propionic Acid

[0590] 3-Biphenyl-4-yl-(2S)-[(5-bromo-benzoyl-amino)-propionic acid (100 mg, 0.23 mmol) was reacted with 4-ethyl phenyl boronic acid (0.145 mg, 0.69 mmol) by following general procedure D yielding the title compound (101 mg, 85%) as a white solid. LC/MS (m/z): 450 (M+1)+.


EXAMPLE 216

[0591] 3-Biphenyl-4-yl-(2S)-[(3′-ethyl-biphenyl-3-carbonyl)-amino]-propionic Acid

[0592] (2S)-amino-3-biphenyl-4yl-propionic acid methyl ester (1.0 g mg, 4.1 mmol) was reacted with 3-bromo-benzoic acid (1.07 g mg, 5.3 mmol) as described in general procedure A yielding 3-biphenyl-4-yl-(2S)-(3-bromo-benzoylamino)-propionic acid (1.48 g, 85%).

[0593] 3-Biphenyl-4-yl-(2S)-[(3-bromo-benzoyl-amino)-propionic acid (100 mg, 0.23 mmol) was reacted with 4-ethyl phenyl boronic acid (0.145 mg, 0.69 mmol) by following general procedure D yielding the title compound (101 mg, 85%) as a white solid.

[0594]

1
H-NMR(400 MHz, DMSO-d6): 1.22 (t, 3H), 2.61 (q, 2H), 3.25-3.30 (m, 1H), 3.37-3.39 (m, 1H), 5.06-5.08 (m, 1H), 6.75 (d, 1H, J=6.4 Hz), 7.15 (d, 2H), 7.24-7.26 (m, 2H), 7.30-7.33 (m, 1H), 7.36-7.43 (m, 5H), 7.49 (t, 4H), 7.60 (d, 1H), 7.64 (d, 1H ), 7.85 (s, 1H); LC/MS (m/z): 450 (M+1)+.


EXAMPLE 217

[0595] 3-Biphenyl-4-yl-(2S)-[(4′-tert-butyl-biphenyl-3-carbonyl)-amino]-propionic Acid

[0596] 3-Biphenyl-4-yl-(2S)-[(3-bromo-benzoyl-amino)-propionic acid (100 mg, 0.23 mmol) was reacted with 4-tert-butyl phenyl boronic acid (0.125 mg, 0.69 mmol) by following general procedure D yielding the title compound (95 mg, 85%) as a white solid.

[0597]

1
H-NMR(400 MHz, DMSO-d6): 1.31 (s, 9H), 3.34-3.42 (m, 1H), 3.42-3.46 (m, 1H), 5.10-5.14 (m, 1H), 6.62 (bs, 1H), 7.25 (s, 1H), 7.28 (d, 1H), 7.31-7.35 (m, 1H), 7.37-7.43 (m, 4H), 7.44-7.49 (m, 3H), 7.52-7.56 (m, 4H), 7.64 (d, 1H), 7.70-7.72 (m, 1H,), 7.4 (s, 1H); LC/MS (m/z): 478 (M+1)+.


EXAMPLE 218

[0598] 3-Biphenyl-4-yl-(2S)-[(4′-methoxy-biphenyl-3-carbonyl)-amino]-propionic Acid

[0599] 3-Biphenyl-4-yl-(2S)-[(3-bromo-benzoyl-amino)-propionic acid (100 mg, 0.23 mmol) was reacted with 4-methoxy-phenyl boronic acid (0.106 mg, 0.69 mmol) by following general procedure D yielding the title compound (85 mg, 80%) as a white solid.

[0600]

1
H-NMR(400 MHz, DMSO-d6): 3.26-3.31 (m, 1H), 3.39-3.40 (m, 1H), 3.77 (s, 3H), 5.02-5.04 (m, 1H), 6.73 (bs, 1H), 6.85 (d, 1H), 7.79 (m, 17H); LC/MS (m/z): 452 (M+1)+.


EXAMPLE 219

[0601] 3-Biphenyl-4-yl-(2S)-[(4′-methane-sulfonyl-biphenyl-3-carbonyl)-amino]-propionic Acid

[0602] 3-Biphenyl-4-yl-(2S)-[(3-bromo-benzoyl-amino)-propionic acid (100 mg, 0.23 mmol) was reacted with 4-methanesulfonyl-phenyl boronic acid (0.141 mg, 0.69 mmol) by following general procedure D yielding the title compound (102 mg, 87%) as a light yellow solid.

[0603]

1
H-NMR(400 MHz, CDCl3): 3.11-3.17 (m, 1H), 3.26-3.30 (m, 1H,), 4.69-4.74 (m, 1H), 7.30-7.34 (m, 1H), 7.58-7.63 (m, 5H), 7.87-7.93 (m, 2H), 7.98-8.05 (m, 4H), 8.14 (s, 1H), 8.97 (d, 1H); LC/MS (m/z): 500 (M+1)+.


EXAMPLE 220

[0604] 3-Biphenyl-4-yl-(2S)-[(4′-tert-butyl-4-chloro-biphenyl-3-carbonyl)-amino]-propionic Acid

[0605] (2S)-Amino-3-biphenyl-4yl-propionic acid methyl ester (1.0 g mg, 4.1 mmol) was reacted with 5-bromo-2-chloro-benzoic acid (1.07 g mg, 5.3 mmol) as described in general procedure A yielding 3-biphenyl-4-yl-(2S)-(5-bromo-2-chloro-benzoyl-amino)-propionic acid (1.5 g, 85%) as white solid.

[0606] 3-Biphenyl-4-yl-(2S)-[(2-chloro-5-bromo-benzoyl-amino)-propionic acid (100 mg, 0.23 mmol) was reacted with 4-trifluoromethyl-phenyl boronic acid (0.141 mg, 0.69 mmol) by following general procedure D yielding the title compound (114 mg, 75%) as a white solid.

[0607]

1
H-NMR(400 MHz, DMSO-d6): 2.98-3.02 (m, 1H), 3.24-3.28 (m, 1H), 4.71-4.73 (m, 1H), 7.25 (d, 1H), 7.31-7.34 (m, 1H), 7.38-7.41 (m, 4H), 7.56-7.60 (m, 5H), 7.70 (d, 2H), 7.74-7.77 (m, 3H), 8.9 (d, 1H); LC/MS (m/z): 524 (M+1)+.


EXAMPLE 221

[0608] (2S)-[(4-Chloro-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic Acid

[0609] (2S)-Amino-3-(4-bromo-phenyl)-propionic acid methyl ester (1.0 g mg, 3.8 mmol) was reacted with 5-bromo-2-chloro-benzoic acid (1.09 g mg, 4.5 mmol) as described in general procedure A yielding (2S)-(5-bromo-2-chloro-benzoyl-amino)-3-(4-bromophenyl)-propionic acid (1.35 g, 75%).

[0610] (2S)-(5-Bromo-2-chloro-benzoyl-amino)-3-(4-bromo-phenyl)-propionic acid (100 mg, 0.21 mmol) was reacted with 4-trifluoromethyl-phenyl-boronic acid (243 mg, 1.2 mmol) by following general procedure D yielding the title compound (114 mg, 75%) as a light yellow solid.

[0611]

1
H-NMR(400 MHz, DMSO-d6): 3.01-3.04 (m, 1H), 3.27-3.29 (m, 1H), 4.74-4.76 (m, 1H), 7.17 (d, 1H), 7.46 (d, 2H), 7.57 (d, 1H ), 7.64 (d, 2H, J=8 Hz), 7.67-7.82 (m, 9H), 8.91 (d, 1H, J=8.4 Hz); LC/MS (m/z): 592 (M+1)+.


EXAMPLE 222

[0612] (2S)-[(-4′-Methoxy-biphenyl-3-carbonyl)-amino]-3-(4′-methoxy]-biphenyl-4-yl)-propionic Acid

[0613] (2S)-Amino-3-(4-bromo-phenyl)-propionic acid methyl ester (1.0 g, 3.8 mmol) was reacted with 3-bromo-benzoic acid (0.91 g , 4.5 mmol) as described in general procedure A yielding (2S)-(3-bromo-benzoyl-amino)-3-(4-bromo-phenyl)-propionic acid methyl ester (1.38 g, 81%).

[0614] (2S)-(3-Bromo-benzoyl-amino)-3-(4-bromo-phenyl)-propionic acid methyl ester (100 mg, 0.22 mmol) was reacted with 4-methoxy-phenyl-boronic acid (204 mg, 1.4 mmol) according to general procedure D yielding the title compound (90 mg, 83%) as a white solid.

[0615]

1
H-NMR (400 MHz, DMSO-d6): 3.08 (m, 1H), 3.22 (m, 1H), 3.74 (s, 3H), 3.76 (s, 3H), 4.38 (m, 1H), 6.96-7.01 (m, 3H), 7.25 (d, 2H), 7.43-7.48 (m, 3H), 7.52 (d, 2H), 7.62-7.07 (m, 3H), 7.70 (d, 1H), 7.87 (s, 1H), 8.10 (d, 1H); LC/MS (m/z): 482 (M+1)+.


EXAMPLE 223

[0616] 3-Biphenyl-4-yl-(2S)-[3-nitro-4-(3-trifluoromethyl-phenoxy)-benzoylamino]-propionic Acid
699

[0617] 3-Nitro-4-(3-trifluoromethyl-phenoxy)-benzoic acid (530 mg, 81%) was prepared from 4-fluoro-3-nitro-benzoic acid (370 mg, 2.0 mmol) and 3-trifluoromethyl phenol (324 mg, 2.0 mmol) as in general procedure B. To Wang resin (60 mg, 0.06 mmol, 1.1 mmol/g) loaded with 4-L-biphenylalanine were added 82 mg of (0.25 mmol) 3-nitro-4-(3-trifluoromethyl-phenoxy)-benzoic acid (82 mg, 0.25 mmol), 1.0 M DIC (1.5 mL, 1.5 mmol) in DMF, 1.0 M HOBt (1.5 mL, 1.5 mmol) in DMF, and a catalytic amount of DMAP. The resulting mixture was left on shaker overnight. The resin was washed with DMF, MeOH, DCM three times of each and cleaved with 20% TFA in DCM. The residue obtained after removing the solvent was purified by chromatography to give the title compound (26 mg, 79%).

[0618]

1
H NMR (400 MHz, CDCl3): 3.35, 3.40 (ABX, 2H), 5.18 (dd, 1H), 6.64 (d, 1H), 7.03 (dd, 2H), 7.28 (m, 1H), 7.34 (m, 2H), 7.42 (m, 2H), 7.55 (m, 5H), 7.91 (dd, 1H), 8.21 (dd, 1H), 8.36 (d, 1H), 8.69 (d, 1H); LC/MS (m/z): 551 (M+1)+.


EXAMPLE 224

[0619] 3-(4′-Trifluoromethyl-biphenyl-4-yl)-(2S)-[4-(4-trifluoromethyl-phenoxy)-benzoylamino]-propionic Acid
700

[0620] 4-(4-Trifluoromethyl-phenoxy)benzoic acid (474 mg, 80%) was prepared from 1-fluoro-4-trifluoromethyl benzene (328 mg, 2.0 mmol) and 4-hydroxy benzoic acid methyl ester (304 mg, 2.0 mmol) following general procedure B, then hydrolyzed following general procedure C to give the corresponding acid (450 mg, 80%). 3-(4′Trifluoromethyl-biphenyl-4-yl)-(2S)-[4-(4-trifluoromethyl-phenoxy)-benzoylamino]-propionic acid methyl ester (121 mg, 82%) was prepared starting from the above acid (70 mg, 0.25 mmol) and 2-amino-3-(4′-trifluoromethyl-biphenyl-4-yl)-(2S)-propionic acid methyl ester (108 mg, 0.30 mmol) according to general procedure A. The ester was hydrolyzed following general procedure C to give the title compound (105 mg, 89%)

[0621]

1
H NMR (400 MHz, CDCl3): 3.40 (m, 2H), 5.10 (m, 1H), 6.58 (m, 1H), 7.08 (m, 4H), 7.33 (m, 2H), 7.64 (m, 10H); LC/MS (m/z): 574 (M+1)+.


EXAMPLE 225

[0622] 3-Biphenyl-4-yl-(2S)-[4-(5-trifluoromethyl-pyridin-2-yloxy)-benzoylamino]-propionic Acid

[0623] 5-(Trifluoromethyl)-2-pyridinol (1.63 g, 10 mmol) was reacted with 4-fluorobenzaldehyde (1.24 g, 10 mmol) as described in general procedure B. The resulting compound was oxidized by AgNO3 (20 mmol) in 2N NaOH aq. solution (20 mL, 40 mmol) to afford 4-(5-(trifluoromethyl-pyridin-2-yloxy)-benzoic acid (5.10 g, 80%) as a white solid.

[0624] 2-L-amino-3-biphenyl-4-yl-propionic acid methyl ester (128 mg, 0.5 mmol) was reacted with above 4-(5-(trifluoromethyl-pyridin-2-yloxy)-benzoic acid (142 mg, 0.5 mmol) as described in general procedure A. The resulting compound was hydrolyzed according to general procedure C to afford the title product (225 mg, 80%) as a white solid. 1H-NMR(400 MHz, CDCl3): 3.21 (dd, 1H), 3.36 (dd, 1H), 5.02 (dd, 1H), 6.74 (d, 1H), 7.39-7.27 (m, 8H), 7.56-7.48 (m, 5H), 7.67 (s, 1H), 7.79 (d, 2H); LC/MS (m/z): 507(M+1)+


EXAMPLE 226

[0625] 3-[4-(4-Trifluoromethyl-phenoxy)-phenyl]-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic Acid

[0626] 3-(4-Hydroxy-phenyl)-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester (664 mg, 75%) was prepared starting from 4′-trifluoromethyl-biphenyl-4-carboxylic acid (532 mg, 2.0 mmol) and tyrosine methyl ester (462 mg, 2.0 mmol) according to general procedure A. The above compound (443 mg, 1.0 mmol) was treated with 1-fluoro-4-trifluorobenzene (246 mg, 1.5 mmol) following general procedure B to give 3-[4-(4-trifluoromethyl-phenoxy)-phenyl]-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester (305 mg, 52%). The ester was hydrolyzed following general procedure C to give the title compound (296 mg, 99%). 1H NMR (400 MHz, CDCl3): 3.22, 3.36 (ABX, 2H), 5.04 (dd, 1H), 6.56 (d, 1H), 6.94 (m, 4H), 7.17 (m, 2H), 7.49 (d, 2H), 7.63 (m, 6H), 7.76 (d, 2H); LC/MS (m/z): 574 (M+1)+.


EXAMPLE 227

[0627] 3-[4-(4-Cyano-phenoxy)-phenyl]-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic Acid

[0628] 3-(4-Hydroxy-phenyl)-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester (664 mg, 75%) was prepared starting from 4′-trifluoromethyl-biphenyl-4-carboxylic acid (532 mg, 2.0 mmol) and tyrosine methyl ester (462 mg, 2.0 mmol) according to general procedure A. The above compound (443 mg, 1.0 mmol) was treated with 1-fluoro-4-cyanobenzene (181 mg, 1.5 mmol) following general procedure B to give 3-[4-(4-cyano-phenoxy)-phenyl]-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester (360 mg, 66%). The ester was hydrolyzed following general procedure C to give the title compound (345 mg, 99%)

[0629]

1
H NMR (400 MHz, CDCl3): 3.28, 3.44 (ABX, 2H), 5.12 (dd, 1H), 6.65 (d, 1H), 6.99 (m, 4H), 7.28 (m, 2H), 7.58 (d, 2H), 7.69 (m, 6H), 7.84 (d, 2H); LC/MS (m/z): 530 (M+1)+.


EXAMPLE 228

[0630] (2S)-(4-Benzyloxy-benzoylamino)-3-biphenyl-4-yl-propionic Acid

[0631] 2-L-amino-3-biphenyl-4-yl-propionic acid methyl ester (255 mg, 1.0 mmol) was reacted with 4-(benzyloxy)-benzoic acid (228 mg, 1.0 mmol) as described in general procedure A. The resulting compound was hydrolyzed according to general procedure C to afford the title product (370 mg, 82%) as a white solid. 1H-NMR(400 MHz, CDCl3): 3.31 (dd, 1H), 3.40 (dd, 1H), 5.09-5.05 (m, 3H), 6.56 (d, 1H), 6.96 (d, 2H), 7.27 (d, 2H), 7.36-7.32 (m, 2H), 7.43-7.38 (m, 6H), 7.57-7.52 (m, 4H), 7.67 (d, 2H); LC/MS (m/z): 452 (M+1)+.

[0632] By analogous methods to those described above the following compounds were synthesized
10LC/MSEXAMPLENAME(m/z)2293-Biphenyl-4-yl-(2S)-[(4′-trifluoromethyl-490biphenyl-3-carbonyl)-amino]-propionic acid2303-Biphenyl-4-yl-(2S)-[(3-chloro-4′-524trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid2313-Biphenyl-4-yl-(2S)-[4-(4-nitro-phenoxy)-483benzoylamino]-propionic acid2323-Biphenyl-4-yl-(2S)-[4-(3,4-dimethyl-511phenoxy)-3-nitro-benzoylamino]-propionicacid2333-Biphenyl-4-yl-(2S)-[(3′-trifluoromethyl-490biphenyl-4-carbonyl)-amino]-propionic acid2343-Biphenyl-4-yl-(2S)-[(3′,5′-bis-trifluoromethyl-558biphenyl-4-carbonyl)-amino]-propionic acid2353-Biphenyl-4-yl-(2S)-[(4′-tert-butyl-biphenyl-4-478carbonyl)-amino]-propionic acid2363-Biphenyl-4-yl-(2S)-[(4′-dimethylamino-465biphenyl-4-carbonyl)-amino]-propionic acid2373-Biphenyl-4-yl-(2S)-[(4′-methoxy-biphenyl-4-452carbonyl)-amino]-propionic acid2383-Biphenyl-4-yl-2-[(3′,4′-dichloro-biphenyl-4-490carbonyl)-amino]-propionic acid2393-Biphenyl-4-yl-(2S)-[(5′-chloro-2′-methoxy-486biphenyl-4-carbonyl)-amino]-propionic acid240(2S)-[(3′-Amino-biphenyl-4-carbonyl)-amino]-4373-biphenyl-4-yl-propionic acid241(2S)-[(4′-Trifluoromethoxy-biphenyl-4-574carbonyl)-amino]-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid2423-(4′-Trifluoromethoxy-biphenyl-4-yl)-(2S)-574[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid2433-(4-Pyridin-4-yl-phenyl)-(2S)-[(4′-491trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid2443-Biphenyl-4-yl-(2S)-[4-(5-trifluoromethyl-491pyridin-2-yl)-benzoylamino]-propionic acid2453-(4-Pyridin-4-yl-phenyl)-(2S)-[4-(5-492trifluoromethyl-pyridin-2-yl)-benzoylamino]-propionic acid2463-(4′-Methanesulfonylamino-biphenyl-4-yl)-583(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid2473-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-(2S)-[(4′-542trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid2483-(4′-Cyano-biphenyl-4-yl)-(2S)-[(4′-515trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid2493-(5-Phenyl-pyridin-2-yl)-2-[(4′-507trifluoromethoxy-biphenyl-4-carbonyl)-amino]-propionic acid2503-(4′-Amino-biphenyl-4-yl)-(2S)-[(4′-505trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid2513-(4′-Dimethylamino-biphenyl-4-yl)-(2S)-[(4′-533trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid2523-(4′-Trifluoromethoxy-biphenyl-4-yl)-(2S)-[4-575(5-trifluoromethyl-pyridin-2-yl)-benzoylamino]-propionic acid2533-(4′-Trifluoromethyl-biphenyl-4-yl)-(2S)-[4-(5-559trifluoromethyl-pyridin-2-yl)-benzoylamino]-propionic acid2543-(4′-Trifluoromethoxy-biphenyl-4-yl)-(2S)-[4-590(4-trifluoromethyl-phenoxy)-benzoylamino]-propionic acid2553-Biphenyl-4-yl-(2S)-[4-(4-trifluoromethyl-506phenoxy)-benzoylamino]-propionic acid2563-Biphenyl-4-yl-(2S)-[4-(4-formyl-phenoxy)-466benzoylamino]-propionic acid2573-(5′-Chloro-2′-methoxy-biphenyl-4-yl)-(2S)-554[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid2583-(4′-Chloro-biphenyl-4-yl)-(2S)-[(4′-524trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid2593-Biphenyl-4-yl-(2R)-[(4′-trifluoromethyl-490biphenyl-4-carbonyl)-amino]-propionic acid2603-(5-Phenyl-pyridin-2-yl)-2-[(4′-trifluoromethyl-491biphenyl-4-carbonyl)-amino]-propionic acid2613-(3′-Acetylamino-biphenyl-4-yl)-(2S)-[(4′-547trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid2623-(3′,4′-Dichloro-biphenyl-4-yl)-(2S)-[(4′-558trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid2633-(5′-Fluoro-2′-methoxy-biphenyl-4-yl)-(2S)-538[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid2643-[4′-(Acetylamino-methyl)-biphenyl-4-yl]-561(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid2653-(4′-Trifluoromethoxy-biphenyl-4-yl)-(2S)-[4-591(5-trifluoromethyl-pyridin-2-yloxy)-benzoylamino]-propionic acid2663-Biphenyl-4-yl-(2S)-[4-(5-trifluoromethyl-507pyridin-2-yloxy)-benzoylamino]-propionic acid2673-[4-(4-Nitro-phenoxy)-phenyl]-(2S)-[(4′-553trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid2683-[4-(4-Formyl-phenoxy)-phenyl]-(2S)-[(4′-534trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid2693-(4-Thiophen-3-yl-phenyl)-(2S)-[(4′-496trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid2703-(4-Thiophen-3-yl-phenyl)-(2S)-[(4′-512trifluoromethoxy-biphenyl-4-carbonyl)-amino]-propionic acid271(2S)-(4-Benzyloxy-benzoylamino)-3-(4′-536trifluoromethoxy-biphenyl-4-yl)-propionic acid2723-(2′-Phenoxy-biphenyl-4-yl)-(2S)-[(4′-537trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid2733-(4′-Phenoxy-biphenyl-4-yl)-(2S)-[(4′-582trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid



EXAMPLE 274

[0633] 3-Biphenyl-4-yl-(2S)-[2-(4-tert-butyl-benzoylamino)]-propionic Acid

[0634] (2S)-(2-Amino-5-iodo-benzoyl-amino)-3-biphenyl-4-yl-propionic acid methyl ester (1.53 g, 80%) was prepared from (2S)-amino-3-biphenyl-4-yl-propionic acid methyl ester (1.0 g, 4.1 mmol), 5-iodo-2-amino-benzoic acid (1.23 g, 4.9 mmol) as described in general procedure A.

[0635] 3-Biphenyl-4-yl-(2S)-[2-(4-tert-butyl-benzoylamino)-5-iodo-benzoyl-amino]-propionic acid methyl ester was prepared as a white solid from (2S)-(2-amino-5-iodo-benzoyl-amino)-3-biphenyl-4-yl-propionic acid methyl ester (1.0 g, 2 mmol) prepared above, pyridine (1.58 g, 4 mmol ), t-butyl-benzoyl chloride (1.20 g, 2.5 mmol) as described in general procedure K. The title compound (1.23 g, 100%) as a white solid ((1.23 g, 100%) was obtained after hydrolysis according to general procedure C

[0636]

1
H-NMR(400 MHz, DMSO-d6): 1.26 (s, 9H), 3.09-3.19 (m, 1H), 3.21-3.29 (m, 1H), 4.74-4.76 (m, 1H), 7.27-7.29 (m, 1H ), 7.42-7.39 (m, 4H), 7.44-7.57 (m, 7H), 7.67-7.77 (m, 3H), 7.99 (s, 1H), 8.54 (d, 1H), 9.32 (d, 1H), 11.98 (s, 1H); LC/MS (m/z): 647 (M+1)+.


EXAMPLE 275

[0637] 3-Biphenyl-4-yl-(2S)-{[4-(4-tert-butyl-benzoylamino)-3′-trifluoromethyl-biphenyl-3-carbonyl]-amino}-propionic Acid

[0638] Example 274 (100 mg, 0.15 mmol) was reacted with 3-trifluoromethyl phenyl boronic acid (87.5 mg, 4.5 mmol) as described in general procedure D yielding the title compound (92 mg, 90%) as white solid. LC/MS (m/z): 665 (M+1)+.


EXAMPLE 276

[0639] 3-Biphenyl-4-yl-(2S)-{[4-(4-tert-butyl-benzoylamino)-4′-nitro-biphenyl-3-carbonyl]-amino}-propionic Acid

[0640] Example 274 (100 mg, 0.15 mmol) was reacted with 4-nitro-phenyl boronic acid (77 mg, 4.5 mmol) as described in general procedure D yielding the title compound (92 mg, 90%) as white solid. LC/MS (m/z): 642 (M+1)+.


EXAMPLE 277

[0641] 3-Biphenyl-4-yl-(2S)-{[4-(4-tert-butyl-benzoylamino)-3′-chloro-4′-fluoro-biphenyl-3-carbonyl]-amino}-propionic Acid

[0642] Example 274 (100 mg, 0.15 mmol) was reacted with 3-chloro-4-fluoro-phenyl boronic acid (80 mg, 4.5 mmol) as described in general procedure D yielding the title compound (95 mg, 95%) as a white solid.

[0643]

1
H-NMR(400 MHz, DMSO-d6): 1.28 (s, 9H), 3.09-3.19 (m, 1H), 3.21-3.29 (m, 1H), 4.74-4.76 (m, 1H), 7.27-7.29 (m, 1H ), 7.32-7.44 (m, 6H), 7.44-7.57 (m, 7H), 7.50-7.59 (m, 2H), 7.71-7.77 (m, 2H), 7.80-7.86 (m, 2H), 7.88-7.90 (m, 3H), 8.3 (s, 2H), 8.7 (d, 1H), 9.38 (d, 1H), 12.00 (s, 1H); LC/MS (m/z): 647 (M+1)+.


EXAMPLE 278

[0644] 3-Biphenyl-4-yl-(2S)-[4-(4-tert-butyl-benzoylamino)-5-(4-chloro-3-trifluromethyl-phenoxy)-benzoylamino)-propionic Acid

[0645] Example 274 (100 mg, 0.15 mmol), 4-chloro-3-trifluoromethyl phenol (60.4 mg, 0.3 mmol), cesium carbonate (0.3 mmol), CuI (0.15 mmol) were added to 10 mL of toluene containing 4 Å molecular sieves. The mixture was degassed and filled with nitrogen three times. This mixture was then heated to reflux under nitrogen and followed by HPLC until completion of the reaction. The reaction with diluted with toluene and filtered. The toluene was evaporated, and the residue was dissolved in ethyl acetate washed with 2M HCl and then saturated NaCl. The title compound (70 mg, 65%) was isolated by flash chromatography (silica, 1% MeOH in DCM) as a white solid. 1H-NMR (400 MHz, CDCl3): 1.35 (s, 9H), 3.22-3.27 (m, 1H), 3.32-3.37 (m, 1H, 5.03-5.13 (m, 1H), 6.69 (d, 1H), 6.98-7.01 (m, 1H ), 7.13-7.18 (m, 4H), 7.28-7.53 (m, 10H), 7.93 (d, 1H), 8.85 (d, 1H), 11.72 (s, 1H); LC/MS (m/z): 715 (M+1)+.


EXAMPLE 279

[0646] 3-Biphenyl-4-yl-(2S)-[2-(3,5-bis-trifluoromethyl-benzoylamino)-5-bromo-benzoylamino]-propionic Acid

[0647] To a solution of fmoc-L-biphenylalanine (40.0 mmol) in DMF (40 mL) was added Wang resin (16.0 mmol), HOBt (40.0 mmol) in DMF (40 mL), DIC (40.0 mmol) in DMF (40 mL) and DMAP (0.40 mmol) and the mixture was shaken overnight. The reaction mixture was drained and the resin washed with DMF, methanol and DCM (3×150 mL each solvent).

[0648] The resulting resin-bound fmoc-L-biphenylalanine was deprotected with 20% piperidine in DMF (150 mL) for 2 hours. The reaction mixture was drained and washed with DMF, methanol and DCM (3×150 mL each solvent).

[0649] To the resin-bound L-biphenylalanine (12 mmol), a solution of 2-amino-5-bromobenzoic acid (30 mmol) in DMF (30 mL), HOBt (30 mmol) in DMF (30 mL) and DIC (30 mmol) in DMF (30 mL) were added and the mixture was shaken overnight. The reaction mixture was drained and washed with DMF, methanol and DCM (3×150 mL each solvent).

[0650] To the resin-bound (S)-2-(2-amino-5-bromo-benzoylamino)-3-biphenyl-4-yl-propionic acid (0.12 mmol) was added a solution of 3,5-bis-(trifluoromethyl)benzoyl chloride (0.3 mmol) and pyridine (0.3 mmol) and the mixture agitated for 72 hours. The reaction mixture was drained and washed with DMF, methanol and DCM (3×5 mL each solvent).

[0651] Resin bound (S)-3-biphenyl-4-yl-2-[2-(3,5-bistrifluoromethyl-benzoylamino)-5-bromo-benzoylamino] propionic acid was treated with 20% TFA in DCM (2 mL) for 1 hour. The filtrate was collected and evaporated to give (S)-3-biphenyl-4-yl-2-[2-(3,5-bis(trifluoromethyl)-benzoylamino)-5-bromo-benzoylamino] propionic acid (0.0412 g, 50%). The product was purified via chromatography (silica, DCM/ethyl acetate). LC/MS (m/z): 680 (M+1)+.


EXAMPLE 280

[0652] (2S)-[5-Bromo-(2S)-(2-cyclopentyl-acetylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic Acid

[0653] (S)-(2-Amino-5-bromo-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester (1.53 g, 80%) was prepared from (2S)-Amino-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester HCl salt (1.0 g, 2.6 mmol, 5-bromo-2-amino-benzoic acid (0.5 g, 2.9 mmol) as described in general procedure A.

[0654] (S)-(2-Amino-5-bromo-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester (0.2 g, 0.04 mmol) in 5 ml of DCM was reacted with cyclopentyl acetyl chloride (82.6 mg, 0.06 mmol) and pyridine (60 mg, 0.08 mmol) as described in general procedure K. The resulting ester was hydrolyzed according to the general procedure C to afford the title compound (0.2 g, 83.3%) as a white solid. LCMS: 642 (M+1)+. 1H NMR (CDCl3): 1.1-1.26 [m, 3H], 1.5-1.75 [m, 3H], 1.8-1.90 [m, 2H], 2.2-2.41 [m, 2H], 2.48 [d, 1H], 3.1-3.4 (m, 2H], 5.0-5.1 [m, 1H], 6.6 [d, 1H], 6.89-6.97 [m, 4H], 7.18-7.26 [m, 6H], 7.43-7.52 [m, 5H], 8.48 (d, 1), 10.73 (s, 1H).


EXAMPLE 281

[0655] (2S)-[5-Bromo-2-(3,3,5-trimethyl-hexanoylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic Acid

[0656] A solution of (2S)-(2-amino-5-bromo-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester (54.5 mg, 0.10 mmol) from example 294 in 1 mL dry CH2Cl2 was treated with 3,5,5-trimethylhexanoyl chloride(1.2 eq., 23 microL, 0.12 mmol) and pyridine (1.5 eq., 12 microL, 0.15 mmol) in succession and stirred under an atmosphere of dry N2 for one hour, then concentrated in vacuo. The crude residue was purified by flash column chromatography (hexanes, EtOAc) to afford the desired amide, (2S)-[5-Bromo-2-(3,3,5-trimethyl-hexanoylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester, in quantitative yield (68 mg, 100%). The methyl ester (20 mg, 29 micromol) was dissolved in 2.0 mL THF and 0.5 mL MeOH and saponified with 2N aqueous LiOH solution (0.25 mL), as described in general procedure C, to afford the title compound, (2S)-[5-Bromo-2-(3,3,5-trimethyl-hexanoylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid (20 mg, 100%), as a white solid. LCMS 673 (M+1)+. 1H NMR (400 MHz, CDCl3) 10.74 [s, 1H], 8.51 [d, 1H], 7.51 [m, 3H], 7.43 [m, 2H], 7.27-7.30 [m, 2H], 7.16-7.26 [m, 5H], 6.98 [d, 2H], 6.88 [d, 2H], 6.59 [d, 1H], 5.03 [dd, 1H], 3.28 [dq, 2H], 2.36 [m, 1H], 2.14 [m, 1H], 1.11-1.25 [m, 3H], 1.00 [s, 3H], 0.92 [s, 3H], 0.91 [d, 6H].


EXAMPLE 282

[0657] (2S)-[5-Chloro-2-(4-phenoxy-benzoylamino)-benzoylamino]-3-(2′-isopropoxy-biphenyl-4-yl)-propionic Acid

[0658] 2-Amino-5-chloro-benzoic acid (0.702 g, 4.09 mmol) was coupled with 2-Amino-3-(4-bromo-phenyl)-propionic acid methyl ester hydrochloride (1 g, 4.09 mmol) using HBTU (1.86 g, 4.908 mmol) and diisopropylethylamine (1.32 ml, 10.22 mmol) as per general procedure A to yield the 2-(2-amino-5-chloro-benzoylamino)-3-(4-bromo-phenyl)-propionic acid methyl ester in 60% yield.

[0659] The above compound (0.500 g, 1.21 mmol) was reacted with 4-phenoxy-benzoyl chloride (0.337 g, 1.45 mmol) in dry dichloromethane at 0° C. as described in general procedure J to get 3-(4-Bromo-phenyl)-2-[5-chloro-2-(4-phenoxy-benzoylamino)benzoylamino]-propionic acid methyl ester (0.590 g, 80%).

[0660] The above compound (0.100 g, 0.164 mmol) was then subjected to Suzuki coupling with 2-isopropoxyphenylboronic acid (0.059 g, 0.328 mmol) and with Pd (PPh3) (0.018 g, 0.016 mmol) and 2N Na2CO3 (0.410 ml, 0.410 mmol) as per general procedure D to yield (2S)-[5-chloro-2-(4-phenoxy-benzoylamino)-benzoylamino]-3-(2′-isopropoxy-biphenyl-4-yl)-propionic acid methyl ester which was further hydrolyzed as per general procedure C to give the title compound (0.050 g, 50%)%). 1H-NMR(400 MHz, CDCl3): 1.56 (d, 6H), 3.65 (dddd, 2H), 4.76 (m, 1H), 5.42 (m, 1H), 7.30-7.38 (m, 6H), 7.39-7.58 (m, 8H), 7.59-7.83 (m, 6H), 8.27 (m, 2H), 9.01 (d, 1H). LC/MS (m/z): 649(M+1).

[0661] By analogous methods to those described above the following compounds were synthesized.
11LC/MSEXAMPLENAME(m/z)2833-Biphenyl-4-yl-(2S)-[2-(4-tert-butyl-521benzoylamino)-benzoylamino]-propionic acid2843-Biphenyl-4-yl-(2S)-[5-chloro-2-(2,4-dichloro-567benzoylamino)-benzoylamino]-propionic acid285(2S)-({4-[(Biphenyl-4-carbonyl)-amino]-3′-669chloro-4′-fluoro-biphenyl-3-carbonyl}-amino)-3-biphenyl-4-yl-propionic acid286(2S)-{2-[(Biphenyl-4-carbonyl)-amino]-593benzoylamino}-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionic acid287(2S)-[2-(4-tert-Butyl-benzoylamino)-573benzoylamino]-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionic acid2883-Biphenyl-4-yl-(2S)-[5-bromo-2-(4-tert-butyl-600benzoylamino)-benzoylamino]-propionic acid2893-Biphenyl-4-yl-(2S)-{[4-(4-tert-butyl-622benzoylamino)-4′-cyano-biphenyl-3-carbonyl]-amino}-propionic acid290(2S)-{[4′-Amino-4-(4-tert-butyl-benzoylamino)-612biphenyl-3-carbonyl]-amino}-3-biphenyl-4-yl-propionic acid2913-Biphenyl-4-yl-(2S)-{[4-(4-tert-butyl-622benzoylamino)-3′-cyano-biphenyl-3-carbonyl]-amino}-propionic acid292(2S)-({3-[(Biphenyl-4-carbonyl)-amino]-643naphthalene-2-carbonyl}-amino)-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionic acid293(2S)-{[3-(4-tert-Butyl-benzoylamino)-623naphthalene-2-carbonyl]-amino}-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionic acid294(2S)-{[3′-Aminomethyl-4-(4-tert-butyl-626benzoylamino)-biphenyl-3-carbonyl]-amino}-3-biphenyl-4-yl-propionic acid2953-Biphenyl-4-yl-(2S)-{[4-(4-tert-butyl-639benzoylamino)-4′-carbamimidoyl-biphenyl-3-carbonyl]-amino}-propionicacid2963-Biphenyl-4-yl-(2S)-[2-(4-tert-butyl-658benzoylamino)-5-(4-nitro-phenoxy)-benzoylamino]-propionic acid297(2S)-{[4-(4-tert-Butyl-benzoylamino)-3′-733trifluoromethyl-biphenyl-3-carbonyl]-amino}-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionic acid298(2S)-{[4-(4-tert-Butyl-benzoylamino)-3′-chloro-4-701fluoro-biphenyl-3-carbonyl]-amino}-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionic acid299(2S)-{[4-(4-tert-Butyl-benzoylamino)-4′-733trifluoromethyl-biphenyl-3-carbonyl]-amino}-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid3003-Biphenyl-4-yl-(2S)-[5-bromo-2-(3-phenyl-570acryloylamino)-benzoylamino]-propionic acid3013-Biphenyl-4-yl-(2S)-{5-bromo-2-[(naphthalene-5942-carbonyl)-amino]-benzoylamino}-propionicacid3023-Biphenyl-4-yl-(2S)-[5-bromo-2-(2-cyclopentyl-550acetylamino)-benzoylamino]-propionic acid3033-Biphenyl-4-yl-(2S)-[5-bromo-2-(4-628trifluoromethoxy-benzoylamino)-benzoylamino]-propionic acid3043-Biphenyl-4-yl-(2S)-[5-bromo-2-(4-phenoxy-602butyrylamino)-benzoylamino]-propionic acid3053-Biphenyl-4-yl-(2S)-{5-bromo-2-[2-(4-630tert-butyl-phenoxy)-acetylamino]-benzoylamino}-propionic acid306(2S)-[2-(4-tert-Butyl-benzoylamino)-5-647chloro-benzoylamino]-3-(4′-phenoxy-biphenyl-4-yl)-propionic acid3072-[5-Bromo-(2S)-(4-tert-butyl-benzoylamino)-692benzoylamino]-3-(4′-phenoxy-biphenyl-4-yl)-propionic acid3083-Biphenyl-4-yl-(2S)-[4-chloro-2-(4-567trifluoromethyl-benzoylamino)-benzoylamino]-propionic acid3093-Biphenyl-4-yl-(2S)-[2-(4-tert-butyl-681benzoylamino)-5-(4-trifluoromethyl-phenoxy)-benzoylamino]-propionic acid3103-Biphenyl-4-yl-(2S)-[2-(4-trifluoromethyl-693benzoylamino)-5-(4-trifluoromethyl-phenoxy)-benzoylamino]-propionic acid3113-Biphenyl-4-yl-(2S)-[2-(4-tert-butyl-681benzoylamino)-4-(4-trifluoromethyl-phenoxy)-benzoylamino]-propionic acid312(2S)-[2-(4-tert-Butyl-benzoylamino)-5-647chloro-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid313(2S)-[5-Chloro-2-(4-phenoxy-benzoylamino)-683benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid314(2S)-[2-(4-Benzyloxy-benzoylamino)-5-chloro-697benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid315(2S)-(5-Bromo-2-phenylacetylamino-650benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid316(2S)-[5-Bromo-2-(4-bromo-benzoylamino)-715benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid317(2S)-{5-Bromo-2-[2-(4-fluoro-phenyl)-668acetylamino]-benzoylamino}-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid3182-{5-Bromo-(2S)-[(naphthalene-2-carbonyl)-686amino]-benzoylamino}-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid319(2S)-{5-Bromo-2-[(naphthalene-1-carbonyl)-686amino]-benzoylamino}-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid320(2S)-[5-Chloro-2-(3-phenoxy-benzoylamino)-683benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid321-S-[2-(3-Benzyloxy-benzoylamino)-5-chloro-697benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid322(2S)-[5-Bromo-2-(4-phenoxy-benzoylamino)-728benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid323(2S)-[5-Bromo-2-(4-hexyl-benzoylamino)-720benzoylamino]-3-(2′-henoxy-biphenyl-4-yl)-propionic acid324(2S)-[5-Bromo-2-(4-fluoro-benzoylamino)-654benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid325(2S)-{5-Bromo-2-[(thiophene-2-carbonyl)-642amino]-benzoylamino}-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid326(2S)-[5-Bromo-2-(2-thiophen-2-yl-acetylamino)-656benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid327(2S)-[5-Bromo-2-(cyclopropanecarbonyl-amino)-600benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid328(2S)-[5-Bromo-2-(cyclobutanecarbonyl-amino)-614benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid329(2S)-[5-Bromo-2-(cyclopentanecarbonyl-628amino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid330(2S)-[5-Bromo-2-(2-propyl-pentanoylamino)-658benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid345(2S)-[5-Bromo-2-(2-phenoxy-propionylamino)-680benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid332(2S)-[2-(3,5-Bis-rifluoromethyl-benzoylamino)-5-727chloro-benzoylamino]-3-(3′-phenoxy-biphenyl-4-yl)-propionicacid333(2S)-[5-Bromo-2-(3,4,5-trimethoxy-726benzoylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid334(2S)-{2-[(Adamantane-1-carbonyl)-amino]-5-694bromo-benzoylamino}-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid335(2S)-(5-Bromo-2-{[1-(4-chloro-phenyl)-710cyclopropanecarbonyl]-amino}-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid336(2S)-(5-Bromo-2-{[1-(2,4-dichloro-phenyl)-744cyclopropanecarbonyl]-amino}-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid337(2S)-{5-Bromo-2-[(2,2-dichloro-1-methyl-682cyclopropanecarbonyl)-amino]-benzoylamino}-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid338(2S)-{5-Chloro-2-[(6-chloro-pyridine-3-carbonyl)-626amino]-benzoylamino}-3-(2′-phenoxy-biphenyl-4-yl)-propionicacid339(2S)-(5-Chloro-2-{[1-(4-trifluoromethyl-744pyrimidin-2-yl)-piperidine-4-carbonyl]-amino}-enzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid340(2S)-{5-Bromo-2-[(1-phenyl-676cyclopropanecarbonyl)-amino]-benzoylamino}-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid341(2S)-{5-Bromo-2-[(2-phenyl-676cyclopropanecarbonyl)-amino]-benzoylamino}-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid342(2S)-[5-Chloro-2-(2-phenoxy-benzoylamino)-683benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid3433-(2′-Benzyloxy-biphenyl-4-yl)-(2S)-[2-(3,5-bis-741trifluoromethyl-benzoylamino)-5-chloro-benzoylamino]-propionic acid344(2S)-{5-Chloro-2-[(6-phenoxy-pyridine-3-684carbonyl)-amino]-benzoylamino}-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid345(2S)-[5-Chloro-2-(4-phenoxy-benzoylamino)-675benzoylamino]-3-(2′-cyclopentyloxy-biphenyl-4-yl)-propionic acid346(2S)-[5-Chloro-2-(4-phenoxy-benzoylamino)-765benzoylamino]-3-[2′-(4-trifluoromethyl-benzyloxy)-biphenyl-4-yl]-propionic acid3473-[2′-(4-tert-Butyl-benzyloxy)-biphenyl-4-753yl]-(2S)-[5-chloro-2-(4-phenoxy-benzoylamino)-benzoylamino]-propionic acid348(2S)-[5-Chloro-2-(4-[1,2,3]thiadiazol-4-yl-675benzoylamino)benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid349(2S)-{5-Chloro-2-[4-(pyridin-4-ylmethoxy)-698benzoylamino]-benzoylamino}-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid350(2S)-(5-Chloro-2-{[1-(4-chloro-phenyl)-5-759trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid351(2S)-(5-Chloro-2-{[1-(4-chloro-phenyl)-5-propyl-7331H-pyrazole-4-carbonyl]-amino}-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid352(2S)-[5-Bromo-2-(3-phenyl-propionylamino)-664benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid353(2S)-[2-(3,5-Bis-trifluoromethyl-benzo796ylamino)-5-chloro-benzoylamino]-3-[2′-(4-pentyl-phenoxy)-biphenyl-4-yl]-propionic acid354(2S)-{2-[(Benzofuran-2-carbonyl)-amino]-5-676bromo-benzoylamino}-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid355(2S)-{2-[(Benzo[b]thiophene-2-carbonyl)-amino]-6925-bromo-benzoylamino}-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid356(2S)-{5-Bromo-2-[(3-chloro-benzo[b]thiophene-2-726carbonyl)-amino]-benzoylamino}-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid



EXAMPLE 357

[0662] (2S)-{2-[(3,5-Bis-trifluoromethyl-benzoyl)-pentyl-amino]-5-chloro-benzoylamino}-3-(2′-phenoxy-biphenyl-4-yl)-propionic Acid

[0663] (2S)-amino-3-(2′-phenoxy-biphenyl-4-yl-propionic acid methyl ester (192 mg, 0.5 mmol), which was prepared in the general section of syntheses of amino acids, was reacted with 5-bromoanthranilic acid (90 mg, 0.5 mmol) as described in general procedure A. The resulting crude compound was alkylated by valeraldehyde (86 mg, 1.0 mmol) as described in general reductive amination procedure E. The purified compound was reacted with 3,5-bis(trifluoromethyl)benzoyl chloride (210 mg, 0.75 mmol) as described in general procedure F. The resulting compound was hydrolyzed according to general procedure C to afford the title product (200 mg, 50%) as a white solid. 1H-NMR(400 MHz, CDCl3): 0.86 (t, 3H), 3.71-2.91 (m, 8H), 4.29-4.23 (m, 1H), 4.85 (broad, 1H), 5.09-4.99 (m, 1H), 6.91-6.87 (m, 2H), 7.03-6.96 (m, 2H), 7.30-7.15 (m, 8H), 7.59-7.35 (m, 4H), 8.11-7.91 (m, 2H), 8.52 (s, 1H)

[0664] LC/MS (m/z): 797(M+1)+.


EXAMPLE 358

[0665] (2S)-(2-[(Biphenyl-4-carbonyl)-(4-methyl-benzyl)-amino]-5-chloro-benzoylamino)-3-biphenyl-4-yl-propionic Acid

[0666] To the resin-bound L-biphenylalanine (1.2 mmol) which was made in example 279, a solution of 2-amino-5-chloro benzoic acid (3.0 mmol), HOBt (30 mmol), DIC (30 mmol) and DMAP (0.03 mmol) in DMF (30 mL) were added and the mixture was shaken overnight. The reaction mixture was drained and washed with DMF, methanol and DCM (3×150 mL each solvent).

[0667] To the resin-bound (2S)-(2-amino-5-chloro-benzoylamino)-3-biphenyl-4-yl-propionic acid (0.12 mmol) synthesized above was suspended in DCE (5 mL) was added 4-methyl benzaldehyde (0.6 mmol), acetic acid (0.6 mmol) and sodium cyanoborohydride (1.2 mmol) and the mixture was shaken overnight. Upon completion of the reaction, the reaction mixture was drained and washed with DMF, methanol and DCM (3×5 mL each solvent).

[0668] To the resin-bound 3-Biphenyl-4-yl-(2S)-[5-chloro-2-(4-methyl-benzylamino)-benzoylamino]-propionic acid (0.12 mmol) was added a solution of Biphenyl-4-carbonyl chloride (0.3 mmol) and pyridine (0.3 mmol) and the mixture agitated for 24 hours. The reaction mixture was drained and washed with DMF, methanol and DCM (3×5 mL each solvent).

[0669] Resin bound 2S-{2-[(Biphenyl-4-carbonyl)-(4-methyl-benzyl)-amino]-5-chloro-benzoylamino}-3-biphenyl-4-yl-propionic acid was treated with 20% TFA in DCM (2 mL) for 1 hour. The filtrate was collected and evaporated to give 10 mg of the title compound with 95% purity. LC/MS (m/z): 679 (m+1)+

[0670] By analogous methods to those described above the following Examples were synthesized.
12LC/MSEXAMPLENAME(m/z)3593-Biphenyl-4-yl-(2S){5-chloro-2-[(3,5-dichloro-671benzoyl)-(4-methyl-benzyl)-amino]-benzoylamino}-propionic acid360(2S)-{2-[(Biphenyl-4-carbonyl)-(3-phenyl-693propyl)-amino]-5-chloro-benzoylamino}-3-biphenyl-4-yl-propionic acid3613-Biphenyl-4-yl-(2S)-{5-chloro-2-[(2,4-685dichloro-benzoyl)-(3-phenyl-propyl)-amino]-benzoylamino}-propionic acid362(2S)-{2-[(Biphenyl-4-carbonyl)-biphenyl-4-741ylmethyl-amino]-5-chloro-benzoylamino}-3-biphenyl-4-yl-propionic acid3633-Biphenyl-4-yl-(2S)-{2-[biphenyl-4-ylmethyl-733(2,4-dichloro-benzoyl)-amino]-5-chloro-benzoylamino}-propionic acid364(2S)-{2-[(Biphenyl-4-carbonyl)-(4-isopropyl-707benzyl)-amino]-5-chloro-benzoylamino}-3-biphenyl-4-yl-propionicacid365(2S)-{2-[(Biphenyl-4-carbonyl)-(4-isopropoxy-723benzyl)-amino]-5-chloro-benzoylamino}-3-biphenyl-4-yl-propionic acid366(2S)-{5-Bromo-2-[(2-methyl-butyl)-(4-798phenoxy-benzoyl)-amino]-benzoylamino}-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid



EXAMPLE 367

[0671] (2S)-[5-Chloro-2-(5-dibutylamino-naphthalene-1-sulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic Acid Methyl Ester

[0672] A solution of 2-(2-amino-5-chloro-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid (0.05 g, 0.1 mmol) [prepared by reacting (2S)-amino-3-(2′-phenoxy-biphenyl-4-yl) propionic acid methyl ester hydrochloride salt and 2-amino-5-chlorobenzoic acid by general procedure A] in CH2Cl2 was treated with (0.035 g, 0.1 mmol) of bansyl chloride according to the general procedure F. Product was purified by flash column chromatography on silicagel using ethyl acetate hexanes to give product as pale yellow solid (0.06 g, 74.0% yield).

[0673]

1
HNMR (400 MHz, CDCl3): 0.8 (t, 6H), 1.14-1.28 (m, 4H), 1.34-1.44 (m, 4H), 2.98-3.11 (m, 5H), 3.16 (dd, 1H), 3.73 (s, 3H), 4.91 (dd, 1H), 6.42 (d, 1H), 6.88 (d, 2H), 6.93-7.20 (m, 4H), 7.16-7.32 (m, 7H ), 7.40-7.47 (m, 4H), 7.54-7.61 (m, 2H), 8.24-8.29 (m, 1H), 8.35 (d, 1H), 8.56 (d, 1H), 11.11 (s, 1H).

[0674] LC/MS (m/z): 818.3 (M+1)+.


EXAMPLE 368

[0675] (2S)-[5-Bromo-2-(4-tert-butyl-benzenesulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic Acid

[0676] A solution of 2-(2-amino-5-bromo-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid (0.06 g, 0.11 mmol) [prepared by reacting (2S)-amino-3-(2′-phenoxy-biphenyl-4-yl) propionic acid methyl ester hydrochloride salt and 2-amino-5-bromobenzoic acid by general procedure A]] in CH2Cl2 was treated with of 4-tert-butylbenzenesulfonyl chloride (0.025 g, 0.11 mmol) according to the general procedure F. Product was purified by flash column chromatography on silicagel using ethyl acetate hexanes to give product as white solid (0.065 g, 79.6% yield).

[0677] 2-[5-Bromo-2-(4-t-butyl-benzenesulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl) propionic acid methyl ester (0.04 g, 0.054 mmol ) was treated with LiOH (2 eq, 1 N aqueous solution) according to the general procedure C to give 0.034 g (87.0%) of 2-[5-Bromo-2-(4-t-butyl-benzenesulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl) propionic acid.

[0678]

1
HNMR (400 MHz, DMSO-d6): 1.2 (s, 9H) 3.04 (dd, 1H), 3.21 (dd, 1H), 4.58-4.70 (m, 1H), 6.83-6.87 (m, 2H), 6.94-6.99 (m, 2H), 7.20-7.39 (m, 6H), 7.42-7.49 (m, 4H), 7.51-7.56 (m, 2H), 7.64-7.72 (m, 3H), 7.86 (d, 1H), 9.29 (d, 1H), 11.38 (s, 1H), 13.06 (s, 1H)

[0679] LC/MS (m/z): 727.1 (M+1)+.


EXAMPLE 369

[0680] (2S)-[5-Bromo-2-(4-tert-butyl-benzenesulfonylamino)-benzoylamino]-3-(4′-phenoxy-biphenyl-4-yl)-propionic Acid

[0681] To a mixture of (L)-4-bromophenylalanine (8.55, 35.0 mmol), 2-phenoxyphenyl boronic acid (10.00 g, 46.73 mmol), and palladium tetrakis-triphenylphosphine (4.0 g, 10% mmol) were added DME (140 mL) and 2N Na2CO3 aq. solution (70 mL, 140 mmol). The resulting mixture was heated at 90° C. under N2 for 20 h. While the reaction solution was hot, the aqueous layer was removed and the top organic layer was concentrated. The residue was neutralized with HCl and washed with diethyl ether, and then was dissolved in methanol and the insoluble solid was removed by filtration. The methanol filtrate was refluxed with HCl/Ether for 6 h. After removal of solvents, the solid was washed with ether to afford (2S)-amino-3-(4′-phenoxy-biphenyl-4-yl-propionic acid methyl ester in HCl salt form (11.0 g, 28.65 mmol, 82% yield).

[0682] (2S)-amino-3-(4′-phenoxy-biphenyl-4-yl-propionic acid methyl ester (192 mg, 0.5 mmol) was reacted with 5-bromoanthranilic acid (110 mg, 0.5 mmol) as described in general procedure A. The resulting crude compound was sulfonylated by 4-tert-butylbenzenesulfonyl chloride (175 mg, 0.75 mmol) as described in general procedure F. The resulting compound was hydrolyzed according to general procedure C to afford the title product (219 mg, 60%) as a white solid. 1H-NMR(400 MHz, CDCl3): 1.25 (s, 9H), 3.25 (dd, 1H), 3.35 (dd, 1H), 5.01 (dd, 1H), 6.62 (d, 1H), 7.05-7.03 (m, 4H), 7.12 (t, 1H), 7.21 (d, 2H), 7.45-7.33 (m, 6H), 7.54-7.49 (m, 5H), 7.60 (d, 2H), 10.61 (s, 1H)

[0683] LC/MS (m/z): 727(M+1)+.


EXAMPLE 370

[0684] 3-Biphenyl-4-yl-(2S)-[2-(3,4-dichloro-benzenesulfonylamino)-5-iodo-benzoylamino]-propionic Acid

[0685] To the resin-bound L-biphenylalanine (1.2 mmol) which was made in example 279, a solution of 2-amino-5-iodo benzoic acid (3.0 mmol), HOBt (30 mmol), DIC (30 mmol) and DMAP (0.03 mmol) in DMF (30 mL) were added and the mixture was shaken overnight. The reaction mixture was drained and washed with DMF, methanol and DCM (3×150 mL each solvent).

[0686] To the resin-bound (2S)-(2-amino-5-iodo-benzoylamino)-3-biphenyl-4-yl-propionic acid (0.12 mmol) was added a solution of 3,4-dichloro benzenesulfonyl chloride (0.3 mmol) and pyridine (0.3 mmol) in 5 ml of DCM and the mixture agitated for 24 hours. The reaction mixture was drained and washed with DMF, methanol and DCM (3×5 mL each solvent).

[0687] Resin bound 3-Biphenyl-4-yl-(2S)-[2-(3,4-dichloro-benzenesulfonylamino)-5-iodobenzoylamino]-propionic acid was treated with 20% TFA in DCM (2 mL) for 1 hour. The filtrate was collected and evaporated to give 10 mg of the title compound with 95% purity. LC/MS (m/z): 695 (m+1)+


EXAMPLE 371

[0688] (2S)-(2-[(Biphenyl-4-sulfonyl)-(4-methyl-benzyl)-amino]-5-chloro-benzoylamino)-3-biphenyl-4-yl-propionic Acid

[0689] To the resin-bound 3-Biphenyl-4-yl-(2S)-[5-chloro-2-(4-methyl-benzylamino)-benzoylamino]-propionic acid (0.12 mmol) prepared in example 358 was added a solution of biphenyl-4-sulfonyl chloride (0.3 mmol) and pyridine (0.3 mmol) and the mixture agitated for 72 hours. The reaction mixture was drained and washed with DMF, methanol and DCM (3×5 mL each solvent).

[0690] Resin bound (2S)-{2-[(biphenyl-4-sulfonyl)-(4-methyl-benzyl)-amino]-5-chloro-benzoylamino}-3-biphenyl-4-yl-propionic acid was treated with 20% TFA in DCM (2 mL) for 1 hour. The filtrate was collected and evaporated to give 10 mg of the title compound with 95% purity. LC/MS (m/z): 715 (m+1)+

[0691] By analogous methods to those described above the following compounds were synthesized.
13LC/MSEXAMPLENAME(m/z)372(2S)-[2-(Biphenyl-4-sulfonylamino)-5-611chloro-benzoylamino]-3-biphenyl-4-yl-propionic acid3733-Biphenyl-4-yl-(2S)[2-(4-tert-butyl-683benzenesulfonylamino)-5-iodo-benzoylamino]-propionic acid3743-Biphenyl-4-yl-(2S){[4-(4-tert-butyl-685benzenesulfonylamino)-3′-chloro-4′-fluoro-biphenyl-3-carbonyl]-amino}-propionic acid3753-Biphenyl-4-yl-(2S)[5-iodo-2-(2,4,5-729trichloro-benzenesulfonylamino)-benzoylamino]-propionic acid3763-Biphenyl-4-yl-(2S)-[2-(2,5-dichloro-695benzenesulfonylamino)-5-iodo-benzoylamino]-propionic acid3773-Biphenyl-4-yl-(2S)-[2-(2,4-difluoro-663benzenesulfonylamino)-5-iodo-benzoylamino]-propionic acid3783-Biphenyl-4-yl-(2S)-[5-iodo-2-(4-propyl-benzenesulfonylamino)-benzoylamino]-propionic acid3793-Biphenyl-4-yl-(2S)-(5-iodo-2-697pentamethylbenzenesulfonylamino-benzoylamino)-propionic acid3803-Biphenyl-4-yl-(2S)-[5-iodo-2-(toluene-4-sulfonylamino)-benzoylamino]-propionicacid3813-Biphenyl-4-yl-(2S)-[2-(4-bromo-706benzenesulfonylamino)-5-iodo-benzoylamino]-propionic acid3823-Biphenyl-4-yl-(2S)-[5-iodo-2-677(naphthalene-2-sulfonylamino)-benzoylamino]-propionic acid3833-Biphenyl-4-yl-(2S)-[5-bromo-2-(4-tert-636butyl-benzenesulfonylamino)-benzoylamino]-propionic acid3842-[5-Acetylamino-(2S)-(4-tert-butyl-614benzenesulfonylamino)-benzoylamino]-3-biphenyl-4-yl-propionic acid3853-Biphenyl-4-yl-(2R)-[5-bromo-2-(4-tert-650butyl-benzenesulfonylamino)-benzoylamino]-propionic acid methyl ester3863-Biphenyl-4-yl-(2S)-[5-bromo-2-(6-665morpholin-4-yl-pyridine-3-sulfonylamino)-benzoylamino]-propionic acid3873-Biphenyl-4-yl-(2S)-[5-bromo-2-(4-vinyl-606benzenesulfonylamino)-benzoylamino]-propionic acid3883-Biphenyl-4-yl-(2S)-[5-bromo-2-(3,4-648dichloro-benzenesulfonylamino)-benzoylamino]-propionic acid3893-Biphenyl-4-yl-(2S)-[5-bromo-2-(4-nitro-625benzenesulfonylamino)-benzoylamino]-propionic acid3903-Biphenyl-4-yl-(2S)-[5-bromo-2-(2-phenyl-608ethenesulfonylamino)-benzoylamino]-propionic acid3913-Biphenyl-4-yl-(2S)-{5-bromo-2-[5-(5-721trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonylamino]-benzoylamino}-propionicacid3923-Biphenyl-4-yl-(2S)-[5-bromo-2-(4-bromo-659benzenesulfonylamino)-benzoylamino]-propionic acid3933-Biphenyl-4-yl-(2S)-[5-bromo-2-(3,4-640dimethoxy-benzenesulfonylamino)-benzoylamino]-propionic acid394(2S)-[2-(4-Acetylamino-637benzenesulfonylamino)-5-bromo-benzoylamino]-3-biphenyl-4-yl-propionicacid3953-Biphenyl-4-yl-(2S)-[5-bromo-2-(4-622isopropyl-benzenesulfonylamino)-benzoylamino]-propionic acid3963-Biphenyl-4-yl-(2S)-[5-bromo-2-(2,5-648dichloro-benzenesulfonylamino)-benzoylamino]-propionic acid3973-Biphenyl-4-yl-(2S)-[5-bromo-2-(2-664rifluoromethoxy-benzenesulfonylamino)-benzoylamino]-propionic acid398(2S)-[5-Bromo-2-(5-dibutylamino-849naphthalene-1-sulfonylamino)-benzoylamino]-3-(4′-phenoxy-biphenyl-4-yl)-propionic acid399(2S)-[5-Chloro-2-(5-dibutylamino-804naphthalene-1-sulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid400(2S)-[5-Chloro-2-(5-dimethylamino-734naphthalene-1-sulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester401(2S)-[5-Bromo-2-(5-dimethylamino-780naphthalene-1-sulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester402(2S)-[5-Chloro-2-(5-dimethylamino-720naphthalene-1-sulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid403(2S)-[5-Bromo-2-(5-dimethylamino-765naphthalene-1-sulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid404(2S)-[5-Bromo-2-(5-dibutylamino-849naphthalene-1-sulfonylamino)benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid405(2S)-(2-Benzenesulfonylamino-5-chloro-641benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester406(2S)-(2-Benzenesulfonylamino-5-chloro-627benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid407(2S)-[5-Chloro-2-(naphthalene-1-691sulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acidmethyl ester408(2S)-[5-Chloro-2-(naphthalene-1-677sulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid409(2S)-[5-Chloro-2-(naphthalene-2-691sulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acidmethyl ester410(2S)-[5-Chloro-2-(naphthalene-2-677sulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid411(2S)-[2-(4-tert-Butyl-697benzenesulfonylamino)-5-chloro-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acidmethyl ester412(2S)-[2-(4-tert-Butyl-683benzenesulfonylamino)-5-chloro-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid413(2S)-[2-(Biphenyl-4-sulfonylamino)-5-c717hloro-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methylester414(2S)-[2-(Biphenyl-4-sulfonylamino)-5-703chloro-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid415(2S)-[5-Chloro-2-(quinoline-8-692sulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acidmethyl ester416(2S)-[5-Chloro-2-(quinoline-8-678sulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid417(2S)-[5-Chloro-2-(5-chloro-1,3-dimethyl-1H-679pyrazole-4-sulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid418(2S)-[5-Chloro-2-(1-methyl-1H-imidazol631e-4-sulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid419(2S)-[5-Chloro-2-(6-phenoxy-pyridine-3-720sulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid420(2S)-[5-Chloro-2-(4-pyrazol-1-yl-693benzenesulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid421(2S)-[5-Chloro-2-(5-chloro-1,3-dimethyl-1H693pyrazole-4-sulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester422(2S)-{5-Chloro-2-[3-(5-methyl-[1,3,4]oxadiazol-7232-yl)-benzenesulfonylamino]-benzoylamino}-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester423(2S)-[5-Chloro-2-(6-phenoxy-pyridine-3-734sulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acidmethyl ester424(2S)-[5-Chloro-2-(4-pyrazol-1-yl-707benzenesulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acidmethyl ester425(2S)-[5-Chloro-2-(1-methyl-1H-imidazole-4-645sulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acidmethyl ester426(2S)-[5-Chloro-2-(3,5-dimethyl-isoxazole-4-660ulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid ethylester427(2S)-[5-Chloro-2-(6-morpholin-4-yl-pyridine-7273-sulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acidmethyl ester428(2S)-[5-Chloro-2-(6-morpholin-4-yl-pyridine7133-sulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid429(2S)-{5-Chloro-2-[5-(2-methylsulfanyl-771pyrimidin-4-yl)-thiophene-2-sulfonylamino]-benzoylamino}-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester430(2S)-{5-Chloro-2-[5-(2-methylsulfanyl-757pyrimidin-4-yl)-thiophene-2-sulfonylamino]-benzoylamino}-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid431(2S)-{5-Chloro-2-[4-(5-methyl-709[1,3,4]oxadiazol-2-yl)-benzenesulfonylamino]-benzoylamino}-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid4323-Biphenyl-4-yl-(2S)-[2-(2,5-dichloro-709benzenesulfonylamino]-5-iodo-benzoylamino)-propionic acid methyl ester4333-Biphenyl-4-yl-(2S)-[2-(4-bromo-720benzenesulfonylamino)-5-iodo-benzoylamino]-propionic acid methyl ester4343-Biphenyl-4-yl-(2S)-[2-(3,5-bis-671trifluoromethyl-benzenesulfonylamino)-5-chloro-benzoylamino]-propionic acid435(2S)-[5-Chloro-2-(4-oxazol-5-yl-708benzenesulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acidmethyl ester436(2S)-[5-Chloro-2-(4-oxazol-5-yl-694benzenesulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid437(2S)-[5-Chloro-2-(4-phenoxy-733benzenesulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acidmethyl ester438(2S)-[5-Chloro-2-(4-phenoxy-719benzenesulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid439(2S)-[5-Chloro-2-(3-nitro-672benzenesulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid440(2S)-[2-(3,5-Bis-trifluoromethyl-777benzenesulfonylamino)-5-chloro-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester441(2S)-[2-(3,5-Bis-trifluoromethyl-763benzenesulfonylamino)-5-chloro-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid442(2S)-[2-(3-Amino-benzenesulfonylamino)-6565-chloro-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester443(2S)-{5-Chloro-2-[5-(2-methyl-5-795trifluoromethyl-2H-pyrazol-3-yl)-thiophene-2-sulfonylamino]-benzoylamino}-3-(2′-phenoxy-biphenyl-4-yl)-propionic acidmethyl ester444(2S)-{5-Chloro-2-[5-(2-methyl-5-781trifluoromethyl-2H-pyrazol-3-yl)-thiophene-2-sulfonylamino]-benzoylamino}-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid4453-Biphenyl-4-yl-(2S)-[5-chloro-2-(5-726dibutylamino-naphthalene-1-sulfonylamino)-enzoylamino]-propionic acid methylester4463-Biphenyl-4-yl-(2S)-[5-chloro-2-(5-712dibutylamino-naphthalene-1-sulfonylamino)-benzoylamino]-propionic acid447(2S)-[5-Bromo-2-(4-tert-butyl-742benzenesulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acidmethyl ester448(2S)-[5-Bromo-2-(4-tert-butyl-benzenes742ulfonylamino)-benzoylamino]-3-(4′-phenoxy-biphenyl-4-yl)-propionic acidmethyl ester4493-Biphenyl-4-yl-(2S)-{5-chloro-2-720[naphthalen-1-ylmethyl-(4-nitro-benzenesulfonyl)-amino]-benzoylamino}-propionic acid450(2S)-{2-[(Biphenyl-4-sulfonyl)-(3-methyl-721thiophen-2-ylmethyl)-amino]-5-chloro-benzoylamino}-3-biphenyl-4-yl-propionicacid451(2S)-{2-[(Biphenyl-4-sulfonyl)-(3-phenyl-729propyl)-amino]-5-chloro-benzoylamino}-3-biphenyl-4-yl-propionic acid452(2S)-{2-[(Biphenyl-4-sulfonyl)-biphenyl-4-777ylmethyl-amino]-5-chloro-benzoylamino}-3-biphenyl-4-yl-propionic acid453(2S)-{2-[(Biphenyl-4-sulfonyl)-naphthalen-1-751ylmethyl-amino]-5-chloro-benzoylamino}-3-biphenyl-4-yl-propionic acid454(2S)-{2-[(Biphenyl-4-sulfonyl)-(4-isopropyl-753benzyl)-amino]-5-chloro-benzoylamino}-3-biphenyl-4-yl-propionic acid4553-Biphenyl-4-yl-(2S)-{2-[biphenyl-4-769ylmethyl-(2,4-dichloro-benzenesulfonyl)-amino]-5-chloro-benzoylamino}-propionicacid456(2S)-{2-[(Biphenyl-4-sulfonyl)-ethyl-amino]-6395-chloro-benzoylamino}-3-biphenyl-4-yl-propionic acid457(2S)-{2-[(Biphenyl-4-sulfonyl)-ethyl-amino]-7315-iodo-benzoylamino}-3-biphenyl-4-yl-propionic acid



EXAMPLE 458

[0692] 2-{5-Chloro-2-[(naphthalen-1-ylmethyl)-amino]-benzoylamino}-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic Acid

[0693] A solution of 2-amino-5-chlorobenzoic acid (0.58 g, 3.37 mmol) in DMF (7.0 mL) was reacted with (L)-4-bromophenylalanine methyl ester hydrochloride (1.00 g, 3.37 mmol), HBTU (1.20 g, 3.37 mmol), and DIEA (1.80 mL, 10.13 mmol) by the general procedure A. The crude product was purified by flash column chromatography on silica gel using DCM(+50% hexane) followed by DCM to give 0.890 g (64%) of 2-(2-amino-5-chloro-benzoylamino)-3-(4-bromo-phenyl)-propionic acid methyl ester as a white solid. A solution of 2-(2-amino-5-chloro-benzoylamino)-3-(4-bromo-phenyl)-propionic acid methyl ester (0.600 g, 1.45 mmol) in DME (10.0 mL) was reacted with 4-trifluoromethylbenzene boronic acid (0.55 g, 2.91 mmol), Pd(PPh3)4 (0.70 g, 0.14 mmol), and Na2CO3 (2.0 N, 3.50 mL, 3.64 mmol) by the general procedure D to form 0.850 g of 2-(2-amino-5-chloro-benzoylamino)-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester as a brown oil.

[0694] A solution of 2-(2-amino-5-chloro-benzoylamino)-3-(4-bromo-phenyl)-propionic acid methyl ester (0.830 g, 1.74 mol) in DCE (15 mL) was reacted with 1-naphthaldehyde (0.244 g, 3.50 mmol), sodium triacetoxyborohydride (0.553 g, 2.61 mmol), and acetic acid/DCM(1.0 M, 2.0 mL) by the general procedure E. The crude product was purified by flash column chromatography on silica gel using DCM (+35% hexane) to give 0.580 g (54%) of 2-{5-Chloro-2-[(naphthalen-1-ylmethyl)-amino]-benzoylamino}-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester as a colorless oil. This ester was treated with LiOH (0.123 g, 2.92 mmol) by the general procedure J to give 0.405 g (92%) of the title compound. 2-{5-chloro-2-[(naphthalen-1-ylmethyl)-amino]-benzoylamino}-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid as a white solid. LCMS 603 (M+1)+. 1H NMR (DMSO-d6) 8.62 [d, 1H], 8.10 [m, 1H], 8.03 [m, 1H], 7.92 [m, 1H], 7.81 [m, 2H], 7.72 [m, 2H], 7.59 [m, 3H], 7.50 [m, 2H], 7.38 [m, 3H], 7.23 [dd, 1H], 6.67 [d, 1H], 4.47 [m, 1H], 3.25 [dd, 1H], 3.16 [s, 2H], 3.07 [m, 1H].


EXAMPLE 459

[0695] (2S)-{2-[3-(4-tert-Butyl-phenoxy)-benzylamino]-5-chloro-benzoylamino}-3-(4′-cyclohexyl-biphenyl-4-yl)-propionic Acid

[0696] (2S)-(2-Amino-5-chloro-benzoylamino)-3-biphenyl-4-yl-propionic acid methyl ester was prepared following General Procedure A using 2-amino-5-chloro-benzoic acid (1.751 g, 98%, 10 mmol), (S)-2-amino-3-(4-bromo-phenyl)-propionic acid methyl ester hydrochloride salt (2.95 g, 10 mmol), HBTU (4.55 g, 12 mmol) and DIEA (6.33 mL, 99%, 36 mmol) in DMF (60 mL). Purification by flash chromatography (ethyl acetate/hexanes 1:3, 1:2, 1:1.5) gave solid (3.48 g, 8.45 mmol, 85% yield).

[0697] (2S)-(2-Amino-5-chloro-benzoylamino)-3-(4′-cyclohexyl-biphenyl-4-yl)propionic acid methyl ester compound was prepared following General Procedure D using (S)-2-(2-amino-5-chloro-benzoylamino)-3-(4-bromo-phenyl)-propionic acid methyl ester (1.803 g, 4.38 mmol), 4-cyclohexyl-benzene boronic acid (1.61 g, 98%, 7.88 mmol), palladium tetrakis-triphenylphosphine (0.462 g, 0.4 mmol), and aqueous Na2CO3 (2.0 N, 16 mL, 32 mmol) in DME (32 mL). The mixture was heated at 80° C. for 14 h. Purification by flash chromatography (ethyl acetate/hexanes 1:3, 1:2) gave product as a red solid (2.01 g, 4.09 mmol, 93% yield).

[0698] Reductive amination was carried out using (2S)-(2-amino-5-chloro-benzoylamino)-3-(4′-cyclohexyl-biphenyl-4-yl)propionic acid methyl ester (123 mg, 0.25 mmol), 3-(4-tert-butyl-phenoxy)-benzaldehyde (130 mg, 98%, 0.5 mmol), acetic acid (0.7 mmol), sodium triacetoxyborohydride (131 mg, 97%, 0.6 mmol) and DCE (2.5 mL). The mixture was stirred for 7 h. Purification by flash chromatography (ethyl acetate/hexanes 1:9) gave the title compound as colorless oil (139 mg, 0.19 mmol, 76% yield).

[0699] The title compound was prepared following General Procedure C using (S)-2-{2-[3-(4-tert-Butyl-phenoxy)-benzylamino]-5-chloro-benzoylamino}-3-(4′-cyclohexyl-biphenyl-4-yl)-propionic acid methyl ester (135 mg, 0.19 mmol), LiOH(aq) (2.0 N, 0.22 mL, 0.44 mmol), THF (4 mL) and MeOH (1 mL). The mixture was stirred at 0° C. for 12 h. The product was obtained as off-white solid (115 mg, 0.16 mmol, 84% yield).

[0700]

1
H-NMR (400 MHz, DMSO-d6): 12.82 (s, 1H), 8.77 (d, 1H), 8.06 (t, 1H), 7.62 (d, 1H), 6.75-7.54 (m, 17H), 6.54 (d, 1H), 4.59 (ddd, 1H), 4.33 (d, 2H), 3.08-3.31 (m, 3H), 1.33-1.79 (m, 10H), 1.24 (s, 9H); LC-MS m/z: 715 (M+1)+.


EXAMPLE 460

[0701] (2S)-{5-Chloro-2-[(naphthalen-1-ylmethyl)-amino]-benzoylamino}-3-(2′-phenoxy-biphenyl-4-yl)-propionic Acid

[0702] 2-Amino-5-chlorobenzoic acid methyl ester (1.85 g, 10.0 mmol) was treated with 1-napthaldehyde (1.56 g, 10.0 mmol) and sodium triacetoxyborohydride (4.23 g, 20.0 mmol) in 1,2-dichloroethane as described in general procedure E to give 5-chloro-2-[(napthalen-1yl-methyl)-amino]-benzoic acid methyl ester (2.54 g, 78%). This methyl ester (2.0 g, 6.13 mmol) was treated with LiOH (2 eq, 1 N aqueous solution) according to the general procedure C gave 5-chloro-2-[(napthalen-lyl-methyl)-amino]-benzoic acid (1.64 g, 86.0%).

[0703] 5-Chloro-2-[(napthalen-1-yl-methyl)-amino]-benzoic acid (0.1 g, 0.32 mmol) was treated with (2S)-amino-3-(2′-phenoxy-biphenyl-4-yl) propionic acid methyl ester hydrochloride salt (0.123 g, 0.32 mmol) according to the general procedure A to give 2-{5-Chloro-2-[(naphthalene-1-yl-methyl)-amino]-3-(2′phenoxy-biphenyl-4-yl)-propionic acid methyl ester (0.155 g, 75.6%). This methyl ester (0.15 g, 0.23 mmol) was treated with LiOH (2 eq, 1 N aqueous solution) according to the general procedure C to give 2-{5-chloro-2-[(naphthalene-1-yl-methyl)-amino]-3-(2′phenoxy-biphenyl-4-yl)-propionic acid (0.13 g, 90.0%) as white solid. 1HNMR (400 MHz, DMSO-d6): 3.36 (dd, 1H), 3.46 (dd, 1H), 4.79-4.88 (m, 1H), 5.10 (d, 2H), 7.01 (d, 1H), 7.18 (d, 2H), 7.26 (d, 1H), 7.33 (t, 1H), 7.50-7.90 (m, 14H), 7.96 (d, 1H), 8.10-8.20 (m, 1H), 8.22-8.30 (m, 1H), 8.32-8.48 (m, 2H), 9.07 (d, 1H), 13.10 (s, 1H). LC/MS (m/z): 627.2 (M+1)+.


EXAMPLE 461

[0704] (2S)-{5-Chloro-2-[(naphthalen-2-ylmethyl)-amino]-benzoylamino}-3-(2′-piperidin-1-ylmethyl-biphenyl-4-yl)-propionic Acid

[0705] The (2S)-(2-Amino-5-chloro-benzoylamino)-3-(4-bromo-phenyl)-propionic acid methyl ester (0.400 g, 0.972 mmol) was made according to the procedure for Example 282 and this was subjected to reductive amination with naphthalene-2-carbaldehyde (0.227 g, 1.45 mmol) and sodium triacetoxyborohydride (0.515 g, 2.43 mmol) as per general procedure E to yield the 3-(4-Bromo-phenyl)-2-{5-chloro-2-[(naphthalen-2-ylmethyl)-amino]-benzoylamino}-propionic acid methyl ester (0.428 g, 80%).

[0706] The above compound (0.360 g, 0.653 mmol) was then subjected to Suzuki coupling with 2-(formylphenyl) boronic acid (0.195 g, 1.306 mmol) and Pd (PPh3) (0.075 g, 0.0653 mmol) and 2N Na2CO3 (2.0 ml, 1.956 mmol) as per general procedure D to yield (2S)-{5-Chloro-2-[(naphthalen-2-ylmethyl)-amino]-benzoylamino}-3-(2′-formyl-biphenyl-4-yl)-propionic acid methyl ester (0.244 g, 65%).

[0707] The title compound was hen prepared by reductive amination on (2S)-{5-chloro-2-[(naphthalen-2-ylmethyl)-amino]-benzoylamino}-3-(2′-formyl-biphenyl-4-yl)-propionic acid methyl ester (0.100 g, 0.173 mmol) with piperidine (0.0345 g, 0.347 mmol) as per general procedure E to give the (2S)-{5-chloro-2-[(naphthalen-2-ylmethyl)-amino]-benzoylamino}-3-(2′-piperidin-4-ylmethyl-biphenyl-4-yl)-propionic acid methyl ester which was further hydrolyzed as per general procedure C to give the title compound (0.56 g, 50%). LC/MS (m/z): 632 (M+1).

[0708] By analogous methods to those described above the following compounds were synthesized.
14LC/MSEXAMPLENAME(m/z)4622S-[5-Chloro-2-(2-methyl-butylamino)-557benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid4633-Biphenyl-4-yl-2S-{5-chloro-2-535[(naphthalen-1-ylmethyl)-amino]-benzoylamino}-propionic acid4643-(4′-tert-Butyl-biphenyl-4-yl)-(2S)-{5-591chloro-2-[(naphthalen-1-ylmethyl)-amino]-benzoylamino}-propionic acid465(2S)-{5-Chloro-2-[(naphthalen-1-613ylmethyl)-amino]-benzoylamino}-3-(4′-methanesulfonyl-biphenyl-4-yl)-propionicacid466(2S)-(5-Chloro-2-hexylamino-547benzoylamino)-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid467(2S)-(5-Chloro-2-hexylamino-522benzoylamino)-3-(4′-dimethylamino-biphenyl-4-yl)-propionic acid468(2S)-[2-(4-tert-Butyl-benzylamino)-5-584chloro-benzoylamino]-3-(4′-dimethylamino-biphenyl-4-yl)-propionicacid469(2S)-{2-[3-(4-tert-Butyl-phenoxy)-676benzylamino]-5-chloro-benzoylamino}-3-(4′-dimethylamino-biphenyl-4-yl)-propionicacid470(2S)-{5-Chloro-2-[(naphthalen-1-627ylmethyl)-amino]-benzoylamino}-3-(4′-phenoxy-biphenyl-4-yl)-propionic acid471(2S)-[2-(4-tert-Butyl-benzylamino)-5-623chloro-benzoylamino]-3-(4′-cyclohexyl-biphenyl-4-yl)-propionic acid472(2S)-(5-Chloro-2-heptylamino-585benzoylamino)-3-(4′-phenoxy-biphenyl-4-yl)-propionic acid473(2S)-(5-Chloro-2-heptylamino-575benzoylamino)-3-(4′-cyclohexyl-biphenyl-4-yl)-propionic acid474(2S)-{5-Chloro-2-[(naphthalen-1-617ylmethyl)-amino]-benzoylamino}-3-(4′-cyclohexyl-biphenyl-4-yl)-propionic acid475(2S)-{5-Chloro-2-[(naphthalen-1-605ylmethyl)-amino]-benzoylamino}-3-(4′-pentyl-biphenyl-4-yl)-propionic acid476(2S)-[2-(4-tert-Butyl-benzylamino)-5-iodo-725benzoylamino]-3-(4′-phenoxy-biphenyl-4-yl)-propionic acid4773-(4′-Amino-biphenyl-4-yl)-2S)-{5-chloro-5502-[(naphthalen-1-ylmethyl)-amino]-benzoylamino}-propionic acid4783-Biphenyl-4-yl-2S-[2-(4-tert-butyl-667benzylamino)-5-(3,4-dichloro-phenoxy)-benzoylamino]-propionic acid4793-Biphenyl-4-yl-2S-[2-(4-tert-butyl-651benzylamino)-5-(3-chloro-4-fluoro-phenoxy)-benzoylamino]-propionic acid4803-Biphenyl-4-yl-(2S)-[2-(4-tert-butyl-667benzylamino)-5-(3-trifluoromethyl-phenoxy)-benzoylamino]-propionic acid4813-Biphenyl-4-yl-(2S)-[2-(4-tert-butyl-701benzylamino)-5-(2,3,4-trichloro-phenoxy)-benzoylamino]-propionic acid4823-Biphenyl-4-yl-(2S)-[2-(4-tert-butyl-541benzylamino)-4-chloro-benzoylamino]-propionic acid4833-Biphenyl-4-yl-(2S)-[2-(4-tert-butyl-633benzylamino)-5-(4-chloro-phenoxy)-benzoylamino]-propionic acid4843-Biphenyl-4-yl-2S-[2-(4-tert-butyl-651benzylamino)-5-(4-chloro-3-fluoro-phenoxy)-benzoylamino]-propionic acid4853-Biphenyl-4-yl-(2S)-[2-(4-tert-butyl-659benzylamino)-5-(3,4-dimethoxy-phenoxy)-benzoylamino]-propionic acid4863-(2′-Benzyloxy-biphenyl-4-yl)-(2S)-{5-641chloro-2-[(naphthalen-1-ylmethyl)-amino]-benzoylamino}-propionic acid4873-(3′-Benzyloxy-biphenyl-4-yl)-(2S)-{5-641chloro-2-[(naphthalen-1-ylmethyl)-amino]-benzoylamino}-propionic acid488(2S)-{5-Chloro-2-[(naphthalen-1-603ylmethyl)-amino]-benzoylamino}-3-(2′-trifluoromethyl-biphenyl-4-yl)-propionicacid489(2S)-{2-[3-(4-tert-Butyl-phenoxy)-725benzylamino]-5-chloro-benzoylamino}-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid490(2S)-[2-(4-tert-Butyl-benzylamino)-5-633chloro-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid491(2S)-[5-Bromo-2-(4-tert-butyl-678benzylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid492(2S)-[5-Bromo-2-(2-methyl-pentylamino)-616benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid4933-Biphenyl-4-yl-(2S)-{5-chloro-2-492[(piperidin-4-ylmethyl)-amino]-benzoylamino}-propionic acid4943-(2′-Benzyloxy-biphenyl-4-yl)-(2S)-{2-[3-739(4-tert-butyl-phenoxy)-benzylamino]-5-chloro-benzoylamino}-propionic acid4953-(2′-Benzyloxy-biphenyl-4-yl)-(2S)-[2-(4-647tert-butyl-benzylamino)-5-chloro-benzoylamino]-propionic acid496(2S)-[5-Chloro-2-(3-phenoxy-669benzylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid497(2S)-[2-(3,5-Bis-trifluoromethyl-713benzylamino)-5-chloro-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid498(2S)-[5-Chloro-2-(4-phenoxy-669benzylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid499(2S)-[2-(4-Benzyloxy-benzylamino)-5-683chloro-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid5003-Biphenyl-4-yl-(2S)-[5-(2-chloro-4-625trifluoromethyl-phenoxy)-2-(2-methyl-butylamino)-benzoylamino]-propionicacid501(2S)-[3,5-Dichloro-2-(2-methyl-591butylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid502(2S)-[5-Bromo-2-(cyclohexylmethyl-628amino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid503(2S)-(5-Chloro-2-pentylamino-557benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid504(2S)-{2-[3-(4-tert-Butyl-phenoxy)-649benzylamino]-5-chloro-benzoylamino}-3-(2′-hydroxy-biphenyl-4-yl)-propionic acid505(2S)-(5-Chloro-2-hexa-2,4-dienylamino-567benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid506(2S)-[5-Chloro-2-(3-phenyl-propylamino)-605benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid507(2S)-(5-Chloro-2-octylamino-599benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid508(2S)-(5-Chloro-2-hexylamino-571benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid509(2S)-[5-Chloro-2-(2,2-dimethyl-557propylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid510(2S)-[5-Chloro-2-(2-methyl-pent-2-569enylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid511(2S)-(5-Chloro-2-ethylamino-515benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid



EXAMPLE 512

[0709] (2S)-(5-Chloro-2-diethylamino-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic Acid

[0710] (2S)-(2-Amino-5-chloro-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester was prepared (0.6 g, 80%) from (2S)-Amino-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester (0.5 g, 1.5 mmol), 5-chloro-2-amino-benzoic acid (0.28 g, 1.65 mmol) as desribed in general procedure A.

[0711] (2S)-(2-Amino-5-chloro-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester (0.5 g, 1.0 mmol), was reacted with acetaldehyde (0.175 g, 3.0 mmol), sodium cyanoboro hydride (10 ml 1.0M solution in THF, 10 mmol), in DCM (50 ml) as described in the general procedure E. The crude product was purified by flash column chromatography on silica gel using DCM as an eluent to give ester wich was hydrolyzed by following the general procedure I to give 0.4 g (69% of over all) of the title compound. LCMS: 543 (M+1)+. 1H NMR (CDCl3) [t, 6H], 2.88 [q, 4H], 3.45 [m, 1H], 3.58 [m, 1H], 5.12 [m, 1H], 7.17-7.7 [m, 16H], 8.48 [d, 1H], 11.57 [s, 1H].


EXAMPLE 513

[0712] 2-(5-Chloro-2-diethylamino-benzoylamino)-3-[3′-(4-trifluoromethyl-phenoxy)-biphenyl-4-yl]-propionic Acid

[0713] A solution of (L)-4-bromophenylalanine (7.0 g, 28.6 mmol) in DME(100 mL) was reacted with 3-hydroxyphenyl boronic acid(5.14 g, 37.2 mmol), palladium tetrakis-triphenylphosphine (3.3 g, 2.8 mmol), and Na2CO3(2.0 N, 43.0 mL, 86 mmol) by the general procedure D. After removal of solvent, the solid was washed with ether and DCM to afford 2-amino-3-(3′-hydroxy-biphenyl-4-yl)propionic acid methyl ester in HCl salt form (8.20 g, 31.9 mmol, 93% yield).

[0714] A solution of 2-amino-5-chloro-benzoic acid (1.95 g, 11.38 mmol) in DMF (10.0 mL) was reacted with 2-amino-3-(3′-hydroxy-biphenyl-4-yl)propionic acid methyl ester (3.50 g, 11.38 mmol), HBTU (3.98 g, 10.50 mmol), and DIEA (6.08 mL, 34.15 mmol) by the general procedure A. The crude product was purified by flash column chromatography on silical gel using DCM (+15% hexane) and increasing the gradient to DCM and finally DCM (+0.25% methanol) to give 1.75 g, (36%) of 2-(2-amino-5-chloro-benzoylamino)-3-(3′-hydroxy-biphenyl-4-yl)-propionic acid methyl ester as a white solid. LCMS: 425 (M+1)+.

[0715] A solution 2-(2-amino-5-chloro-benzoylamino)-3-(3′-hydroxy-biphenyl-4-yl)-propionic acid methyl ester (0.850 g, 2.00 mmol) was reacted with acetaldehyde (0.350 g, 6.01 mmol), sodium triacetoxyborohydride (0.850 g, 4.00 mmol), and acetic acid/DCM (1.0 M, 3.00 mL) by the general procedure E. The crude product was purified by flash column chromatography on silica gel using DCM (+15% hexane) and increasing the gradient to DCM and finally DCM (+0.25% methanol) to give 0.540 g, (56%) of the phenolic etser.

[0716] A solution of this phenolic ester (0.240 g, 0.49 mmol) in DCM (5.0 mL) was reacted with copper acetate (0.100 g, 0.54 mmol), and 4-trifluoromethylbenzene boronic acid (0.236 g, 1.24 mmol), and triethyl amine (0.350 mL) by the general procedure G. The crude product was purified by the flash column chromatography on silica gel using DCM (+5% hexane) to give 0.133 g, (43%) of 2-(5-Chloro-2-diethylamino-benzoylamino)-3-[3′-(4-trifluoromethyl-phenoxy)-biphenyl-4-yl]-propionic acid methyl ester. This ester (0.110 g, 0.17 mmol) was reacted with LiOH (0.030 g, 0.70 mmol) by the general procedure J to give 0.095 g (89%) of 2-(5-Chloro-2-diethylamino-benzoylamino)-3-[3′-(4-trifluoromethyl-phenoxy)-biphenyl-4-yl]-propionic acid as a white solid. LCMS: 612 (M+1)+. 1H NMR (CDCl3) 11.56 [s, 1H], 8.28 [d, 1H], 7.59 [d, 2H], 7.42 [dd, 1H], 7.35 [dd, 1H], 7.28 [m, 4H], 7.19 [t, 1H], 7.15 [d, 1H], 7.09 [d, 1H], 7.02 [dd, 1H], 7.00 [dd, 1H], 5.05 [m, 1H], 3.32 [m, 2H], 2.79 [q, 4H], 0.69 [t, 6H].


EXAMPLE 514

[0717] To a solution of 5-chloro-2-fluoro-benzonitrile (0.700 g, 4.499 mmol) in anhydrous DMF (8.0 mL) was added 3,5-dimethylpiperdine (0.713 g, 6.299 mmol) and cesium carbonate (4.30 g, 13.497 mmol). The reaction mixture was heated at 80 C for 2 h. Upon cooling to rt, water and ethylacetate was added. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. To the combined organic layer was added ether and the organic layer was washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure to give 1.15 g (96%) of 5-chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzonitrile as solid. LCMS 249(M+1)+. The compound was >98% purity and was hence used directly for the next step

[0718] To a solution of 5-chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzonitrile (1.05 g, 4.220 mmol) in Diethylene glycol monomethyl ether (2.50 mL) was added KOH (0.947 g, 16.883 mmol) and water (0.750 ml). The reaction was heated at 130-135° C. overnight. Upon cooling to rt, water and ethyl acetate was added the organic layer was discarded and the aqueous layer is acidified to pH 6-7. The aqueous layer was then extracted with ethyl acetate three times. The combined organic layer was washed with water, brine, dried (Na2SO4), and concentrated to give required 5-chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzoic acid (0.850 g, 75%) as an off white solid. LCMS 268 (M+1)+.

[0719] A solution of 5-chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzoic acid (0.250 g, 0.933 mmol) in DMF (4.0 mL) was reacted with (2S)-amino-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester hydrochloride (0.360 g, 0.933 mmol), HBTU (0.355 g, 0.933 mmol), and DIEA (0.500 mL, 2.800 mmol) by the general procedure A. The crude product was purified by flash column chromatography on silica gel using DCM(+20% hexane) to give 0.435 g (62%) of 2-[5-Chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester. A solution of this ester (0.200 g, 0.334 mmol) in THF (4.0 mL) was reacted with LiOH (0.050 g, 1.172 mmol) by the general procedure I to give 0.182 g (93%) of 2-[5-Chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid as a white solid. LCMS: 584 (M+1)+. 1H NMR (CDCl3) 11.20 [d, 1H], 8.21 [d, 1H], 7.45 [m, 2H], 7.39 [m, 2H], 7.23 [m, 8H], 7.02 [m, 2H], 6.86 [m, 2H], 4.90 [m, 1H], 3.38 [dd, 5.60 Hz, 1H], 3.26 [dd, 1H], 2.80 [m, 2H], 2.16 [t, 1H], 2.04 [t, 1H], 1.70 [m, 2H], 1.43 [m, 1H], 0.76 [m, 6H], 0.58 [m, 1H].

[0720] By analogous methods to those described above the following compounds were synthesized.
15LC/MSEXAMPLENAME(m/z)5153-Biphenyl-4-yl-(2S)-{2-[bis-(4-benzyloxy-787benzyl)-amino]-5-chloro-benzoylamino}-propionic acid5163-Biphenyl-4-yl-(2S)-[2-(bis-naphthalen-1-675ylmethyl-amino)-5-chloro-benzoylamino]-propionic acid5173-Biphenyl-4-yl-(2S)-[2-(bis-biphenyl-4-727ylmethyl-amino)-5-chloro-benzoylamino]-propionic acid518(2S)-(5-Bromo-2-dibutylamino-644benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid519(2S)-(5-Bromo-2-dihexylamino-700benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid520(2S)-(5-Chloro-2-dipentylamino-627benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid521(2S)-(5-Chloro-2-piperidin-1-yl-benzoylamino)-5553-(2′-phenoxy-biphenyl-4-yl)-propionic acid522(2S)-(5-Bromo-2-diethylamino-benzoylamino)-5883-(2′-phenoxy-biphenyl-4-yl)-propionicacid523(2S)-(5-Chloro-2-diethylamino-benzoylamino)-5953-[3′-(3-chloro-4-fluoro-phenoxy)-biphenyl-4-yl]-propionic acid524(2S)-(5-Bromo-2-piperidin-1-yl-600benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid525(2S)-(5-Chloro-2-diethylamino-573benzoylamino)-3-[3′-(4-methoxy-phenoxy)-biphenyl-4-yl]-propionic acid526(2S)-(5-Chloro-2-diethylamino-627benzoylamino)-3-[3′-(4-trifluoromethoxy-phenoxy)-biphenyl-4-yl]-propionic acid5273-[3′-(4-tert-Butyl-phenoxy)-biphenyl-4-yl]-599(2S)-(5-chloro-2-diethylamino-benzoylamino)-propionic acid528(2S)-(5-Bromo-2-diethylamino-656benzoylamino)-3-[3′-(4-trifluoromethyl-phenoxy)-biphenyl-4-yl]-propionic acid529(2S)-(5-Bromo-2-diethylamino-606benzoylamino)-3-[3′-(3-fluoro-phenoxy)-biphenyl-4-yl]-propionic acid530(2S)-(5-Bromo-2-pyrrolidin-1-yl-586benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid531(2S)-[5-Chloro-2-(4-methyl-piperazin-1-yl)-570benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid532(2S)-[5-Chloro-2-(4-phenyl-piperazin-1-yl)-632enzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid533(2S)-[5-Chloro-2-(3,4-dihydro-1H-603isoquinolin-2-yl)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid534(2S)-(5-Chloro-2-morpholin-4-yl-557benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid535(2S)-(2-Azepan-1-yl-5-chloro-569benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid536(2S)-[5-Chloro-2-(4-trifluoromethyl-623piperidin-1-yl)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid



EXAMPLE 537

[0721] (2S)-[5-Chloro-2-(4-methylsulfanyl-phenylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic Acid

[0722] A solution of (2S)-(2-amino-5-chloro-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid (0.154 g, 0.307 mmol), prepared by reacting (2S)-amino-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester and 2-amino-5-chlorobenzoic acid by the general procedure A) was reacted with 4-(methylthio)phenylboronic acid (0.130 g, 0.768 mmol), copper acetate (0.084 g, 0.460 mmol), and triethyl amine (0.215 mL, 1.535 mmol) by the general procedure G. The crude product was purified by flash column chromatography on silica gel using DCM (+25% hexane) to give 0.075 g (39%) of 2-[5-chloro-2-(4-methylsulfanyl-phenylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester as a colorless oil. This ester was treated with LiOH (0.019 g, 0.441 mmol) by the general procedure I to give 0.049 g (92%) of 2-[5-chloro-2-(4-methylsulfanyl-phenylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid. LCMS: 610 (M+1)+. 1H NMR (CDCl3) 8.94 [bs, 1H], 7.49 [d, 2H], 7.47 [d, 1H], 7.22 [m, 10H], 7.06 [d, 2H], 6.99 [d, 2H], 6.88 [d, 2H], 6.50 [d, 1H], 4.99 [m, 1H], 3.30 [m, 2H], 2.45 [s, 3H].


EXAMPLE 538

[0723] 2S-[5-Chloro-2-(3-chloro-4-fluoro-phenylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic Acid

[0724] (2S)-(2-amino-5-chloro-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid (0.154 g, 0.307 mmol) prepared above was reacted with 3-Cl, 4-F-phenyl boronic acid (0.13 g, 0.77 mmol), copper acetate (0.084 g, 0.460 mmol), and triethyl amine (0.215 mL, 1.535 mmol) as described in the general procedure G. The crude product was purified by column chromatography using DCM as an eluent then hydrolyzed as described in the general proceudure I to get the title compound (20 mg, 10%) as a light yellow solid. LCMS: 615 (M+1)+. 1H NMR (CDCl3) 3.12 [m, 1H], 3.39 [m, 1H], 4.84 [m, 1H], 6.61 [m, 1H], 6.79-7.58 [m, 19H], 8.88 [s, 1H].

[0725] By analogous methods to those described above the following compounds were synthesized.
16LC/MSEXAMPLENAME(m/z)539(2S)-[5-Bromo-2-(4-trifluoromethyl-676phenylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid540(2S)-(5-Bromo-2-phenylamino-benzoylamino)-6083-(2′-phenoxy-biphenyl-4-yl)-propionic acid541(2S)-(5-Chloro-2-phenylamino-benzoylamino)-5633-(2′-phenoxy-biphenyl-4-yl)-propionic acid542(2S)-[5-Chloro-2-(4-trifluoromethyl-631phenylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid543(2S)-[5-Chloro-2-(3,5-dimethyl-phenylamino)-591benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid544(2S)-[5-Chloro-2-(3-trifluoromethyl-631phenylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid545(2S)-[5-Chloro-2-(4-methoxy-phenylamino)-593benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid546(2S)-[2-(4-tert-Butyl-phenylamino)-5-chloro-619benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid547(2S)-[5-Chloro-2-(3,4-difluoro-phenylamino)-599benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid548(2S)-[5-Chloro-2-(4-fluoro-3-methyl-595phenylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid549(2S)-[5-Chloro-2-(3,4-dichloro-phenylamino)-631benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid550(2S)-[5-Chloro-2-(4-trifluoromethoxy-647phenylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid551(2S)-[5-Chloro-2-(4-methanesulfonyl-641phenylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid552(2S)-[2-(4-Benzyloxy-phenylamino)-5-chloro-669benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid553(2S)-[5-Chloro-2-(naphthalen-1-ylamino)-613benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid554(2S)-[5-Chloro-2-(naphthalen-2-ylamino)-613benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid555(2S)-[2-(3,5-Bis-trifluoromethyl-phenylamino)-5-699chloro-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid556(2S)-[5-Chloro-2-(4-cyclohexyl-phenylamino)-645benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid557(2S)-[2-(Biphenyl-4-ylamino)-5-chloro-639benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid558(2S)-[2-(3-Butoxy-phenylamino)-5-chloro-635benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid559(2S)-[5-Chloro-2-(4-ethoxy-phenylamino)-607benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid560(2S)-[5-Chloro-2-(4-fluoro-3-methoxy-611phenylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid561(2S)-[5-Chloro-2-(4-chloro-phenylamino)-597benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid562(2S)-[5-Chloro-2-(3-chloro-phenylamino)-597benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid563(2S)-[5-Chloro-2-(2,4-dichloro-phenylamino)-631benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid564(2S)-[2-(Benzo[1,3]dioxol-5-ylamino)-5-chloro-607benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid565(2S)-[5-Chloro-2-(4-cyano-phenylamino)-588benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid566(2S)-[5-Chloro-2-(4-methoxy-3-methyl-607phenylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid567(2S)-[5-Chloro-2-(3-isopropyl-phenylamino)-605benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid568(2S)-[5-Chloro-2-(4-nitro-phenylamino)-608benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid569(2S)-[5-Chloro-2-(4-methyl-3-nitro-622phenylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid



EXAMPLE 570

[0726] (2S)-{[(2-Biphenyl-4-yl-methoxycarbonyl-ethyl)-(4′-trifluoromethyl-biphenyl-carbonyl)-amino]-methyl}-(2S)-pyrrolidine-1-carboxylic Acid Tert-Butyl Ester

[0727] To a solution of 2-biphenyl-4-yl-(1S)-(methoxycarbonyl)ethylammonium chloride (1.337 g, 4.58 mmol) and (2S)-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 eq., 913 mg, 4.58 mmol) in a mixture of 25 mL methanol and 25 mL THF was added glacial acetic acid (1.5 eq., 0.40 mL, 6.87 mmol) and the mixture was stirred at ambient temperature for ten minutes. To this was added a 1.0 N solution of NaCNBH3 in THF (1.5 eq., 6.87 mL, 6.87 mmol) in small portions and the reaction mixture was stirred at r.t. overnight. The solvent was removed and the residue was dissolved in water and DCM and partitioned. The organic portion was dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography (2:1 EtOAc;Hexanes, EtOAc) to provide (2S)-[(2-biphenyl-4-yl-(1S)-1-methoxycarbonyl-ethylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.440 g, 72%) as a clear colorless oil.

[0728] A portion of the product (584 mg, 1.33 mmol), dissolved in 13 mL dry CH2Cl2, was subsequently condensed with 4′-trifluoromethyl-biphenyl-4-carbonyl chloride (1.2 eq., 455 mg, 1.60 mmol) (synthesized from 4′-trifluoromethyl-biphenyl-4-carboxylic acid by heating at reflux in a neat solution of thionyl chloride, followed by removal of excess reagent and volatiles in vacuo) in dry CH2Cl2 (13 mL), in the presence of triethylamine (3.0 eq., 3.99 mmol, 0.56 mL) at 0° C. The reaction was stirred at that temperature and gradually allowed to warm to ambient temperature until the reaction was shown to be complete by TLC. The solvent was removed and the crude residue was purified by flash column chromatography (1:1 EtOAc:hexanes) to afford the title compound, (2S)-{[(2-biphenyl-4-yl-(1S)-methoxycarbonyl-ethyl)-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-methyl}-(2S)-pyrrolidine-1-carboxylic acid tert-butyl ester (600 mg, 76%), as a white solid. LCMS 687 (M+1)+.


EXAMPLE 571

[0729] (2S)-(2-{[(2-Biphenyl-4-yl-1-methoxycarbonyl-ethyl)-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-methyl}-(2S)-pyrrolidine-1-sulfonyl)-benzoic Acid Methyl Ester

[0730] Into a dry flask was placed 2-(2S)-{[(2-biphenyl-4-yl-(1S)-methoxycarbonyl-ethyl)-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (333 mg, 0.485 mmol) (for preparation, see Example 570), and the flask was capped and purged with dry N2. The flask was then charged with 5 mL of 4N HCl/dioxane and stirred at rt for about one hour. The solvent was removed and the crude product was rinsed with ether and dried in vacuo to afford 302 mg (100%) of the desired product, (2S)-{[(2-biphenyl-4-yl-(1S)-methoxycarbonyl-ethyl)-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-methyl}-pyrrolidinium; chloride, which was used without further purification.

[0731] The amine hydrochloride (40 mg, 64 micromol) was dissolved in anhydrous acetonitrile (2 mL) and to this was added 2-chlorosulfonyl-benzoic acid methyl ester (3.0 eq., 50 mg, 0.193 mmol), pyridine (0.2 mL) and DMAP (0.1 eq., 0.8 mg, 6.4 micromol) and the reaction carried out as described in general procedure F. The crude product was purified by flash column chromatography to afford 40 mg (79%) of the title compound, 2-(2S)-{[(2-Biphenyl-4-yl-(1S)-methoxycarbonyl-ethyl)-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-methyl}-pyrrolidine-1-sulfonyl)-benzoic acid methyl ester. LC/MS 785 (M+1)+.


EXAMPLE 572

[0732] 3-Biphenyl-4-yl-(2S)-[[(2R)-1-(2-thiophen-2-yl-acetyl)-pyrrolidine-2-methyl]-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic Acid

[0733] The synthesis of the title compound proceeds through the intermediacy of (2S)-{[(2-biphenyl-4-yl-(1S)methoxycarbonyl-ethyl)-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-methyl}-(2R)-pyrrolidinium chloride, similar in all respects to the intermediate in the synthesis of Example 570, (2S)-{[(2-biphenyl-4-yl-(1S)-methoxycarbonyl-ethyl)-(4′ trifluoromethyl-biphenyl-4-carbonyl)-amino]-methyl}-(2S)-pyrrolidinium chloride, in all respects except for the stereochemical orientation at the 2-position of the pyrrolidine ring. Thus, the synthesis of this intermediate proceeds as described in Examples 570 and 571 with the exception that (2S)-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester is replaced with (2R)-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester in the first step of the sequence.

[0734] To a solution of (2S)-{[(2-biphenyl-4-yl-(1S)methoxycarbonyl-ethyl)-(4′trifluoromethyl-biphenyl-4-carbonyl)-amino]-methyl}-(2R)-pyrrolidinium chloride (15 mg, 24 micromol) in dry CH2Cl2 under dry N2 at 0° C. was added 2-thiophene acetyl chloride (3.0 eq., 72 μmol, 8.9 μL) followed by triethylamine (5.0 eq., 0.12 mmol, 17 μL) and the mixture was stirred at 0° C. for one hour, then the solvent was removed. The residue was purified by flash column chromatography (4:1 EtOAc:hexanes) to yield the purified amide, 3-biphenyl-4-yl-(2S)-[[1−(2-thiophen-2-yl-acetyl)-pyrrolidin-(2R)-ylmethyl]-(4′trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester (17 mg, 100%). The ester was saponified according to general procedure C. Thus, 3-biphenyl-4-yl-(2S)-[[1-(2-thiophen-2-yl-acetyl)-pyrrolidin-(2R)-ylmethyl]-(4′trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester (16 mg, 23 μmol) was dissolved in 1 mL of a 4:1 mixture of THF and methanol and cooled to 0° C. for the addition of 0.1 mL of 2N aq. LiOH. The reaction furnished the title compound, 3-Biphenyl-4-yl-(2S)-[[1-(2-thiophen-2-yl-acetyl)-pyrrolidin-(2R)-ylmethyl]-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]propionic acid (14 mg, 100%) LCMS: 697 (M+1)+.


EXAMPLE 573

[0735] (2S)-[[2-(2-Acetylamino-4-methyl-thiazole-5-sulfonylamino)-ethyl]-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-3-biphenyl-4-yl-propionic Acid Methyl Ester

[0736] To a solution of 2-biphenyl-4-yl-(1S)-methoxycarbonyl-ethyl-ammonium chloride (1.833 g, 6.28 mmol) and (2-oxo-ethyl)-carbamic acid tert-butyl ester (1.0 eq., 1.00 g, 6.28 mmol), dissolved in a mixture of 25 mL each of THF and methanol, was added glacial acetic acid (2.0 eq., 0.72 mL, 12.56 mmol), and after stirring for 10 minutes, NaCNBH3 in small portions. The reaction mixture was stirred overnight at rt then the volatiles were removed in vacuo. The crude residue was purified by flash column chromatography (3:2 EtOAc:hexanes) to afford the desired secondary amine, 3-Biphenyl-4-yl-(2S)-(2-tert-butoxycarbonylamino-ethylamino)-propionic acid methyl ester (775 mg, 31%).

[0737] This secondary amine (803 mg, 2.02 mmol) was reacted with 4′-rifluoromethyl-biphenyl-4-carbonyl chloride (1.24 eq., 713 mg, 2.50 mmol) (see Example 591 for preparation) in 40 mL anhydrous CH2Cl2 in the presence of triethylamine (3.0 eq., 0.84 mL, 6.06 mmol) at 0° C. for one hour, then the mixture was allowed to warm to ambient temperature and stirred overnight. The volatiles were removed in vacuo and the residue was purified by flash column chromatography (1:1 EtOAc:hexanes) to afford 3-biphenyl-4-yl-(2S)-[(2-tert-butoxycarbonylamino-ethyl)-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester (996 mg, 76%). A portion of this compound (395 mg, 0.61 mmol) was placed in a dry flask, capped with a septum and purged with dry N2. The flask was charged with 10 mL of 4N HCl/dioxane solution and stirred at r.t. for 1 hour, at which point the reaction was shown to be complete by TLC. The volatiles were removed and the residue was dissolved in ether and triturated with hexanes. The crude product, 2-[(2-biphenyl-4-yl-(1S)-methoxycarbonyl-ethyl)-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-ethyl-ammonium chloride (356 mg, 100%) was used without further purification.

[0738] To a mixture of 2-[(2-biphenyl-4-yl-(1S)-methoxycarbonyl-ethyl)-(4′-trifluoro-methyl-biphenyl-4-carbonyl)-amino]-ethyl-ammonium chloride (40 mg, 69 mmol) and 2-acetyl-amino-4-methyl-thiazole-5-sulfonyl chloride (3.0 eq., 52.4 mg, 0.21 mmol), in 2 mL anhydrous CH2Cl2 at 0° C., was added pyridine (5.0 eq., 28 μL, 0.34 mmol) and DMAP (0.1 eq., 0.8 mg, 6.9 μmol) and the mixture was allowed to gradually warm to ambient temperature and stirred overnight. The solvent was removed and the residue was purified by flash column chromatography (EtOAc) to afford the title compound, (2S)-[[2-(2-Acetylamino-4-methyl-thiazole-5-sulfonylamino)-ethyl]-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-3-biphenyl-4-yl-propionic acid methyl ester (42 mg, 80%). LCMS 765 (M+1)+.

[0739] By analogous methods to those described above the following compounds were synthesized.
17LC/MSEXAMPLENAME(m/z)574(2S)-[(Biphenyl-4-carbonyl)-(2-hydroxy-528benzyl)-amino]-3-biphenyl-4-yl-propionic acid575(2S)-[(Biphenyl-4-carbonyl)-(4-554isopropyl-benzyl)-amino]-3-biphenyl-4-yl-propionic acid5763-Biphenyl-4-yl-(2S)-[(4-isopropyl-528benzyl)-(naphthalene-2-carbonyl)-amino]-propionic acid5773-Biphenyl-4-yl-(2S)-[(4-tert-butyl-534benzoyl)-(4-isopropyl-benzyl)amino]-propionic acid5783-Biphenyl-4-yl-(2S)-[(3,4-dichloro-546benzoyl)-(4-isopropyl-benzyl)-amino]-propionic acid579(2S)-[(Biphenyl-4-carbonyl)-naphthalen-5621-ylmethyl-amino]-3-biphenyl-4-yl-propionic acid5803-Biphenyl-4-yl-(2S)-[(naphthalene-2-536carbonyl)-naphthalen-1-ylmethyl-amino]-propionic acid5813-Biphenyl-4-yl-(2S)-[(4-tert-butyl-542benzoyl)-naphthalen-1-ylmethyl-amino]-propionic acid5823-Biphenyl-4-yl-(2S)-[(3,5-dichloro-554benzoyl)-naphthalen-1-ylmethyl-amino]-propionic acid5833-Biphenyl-4-yl-(2S)-[(naphthalene-1-536carbonyl)-naphthalen-1-ylmethyl-amino]-propionic acid5843-Biphenyl-4-yl-(2S)-[(3,4-dichloro-554benzoyl)-naphthalen-1-ylmethyl-amino]-propionic acid5853-Biphenyl-4-yl-(2S)-[(4-methyl-500benzoyl)-naphthalen-1-ylmethyl-amino]-propionic acid5863-Biphenyl-4-yl-(2S)-[(2,4-dichloro-554benzoyl)-naphthalen-1-ylmethyl-amino]-propionic acid5873-Biphenyl-4-yl-(2S)-[naphthalen-1-yl-531methyl-(4-nitro-benzoyl)-amino]-propionic acid5883-Biphenyl-4-yl-(2S)-[(4-chloro-520benzoyl)-naphthalen-1-ylmethyl-amino]-propionic acid589(2S)-[(Biphenyl-4-carbonyl)-(4-chloro-546benzyl)-amino]-3-biphenyl-4-yl-propionic acid5903-Biphenyl-4-yl-(2S)-[(4-chloro-benzyl)-538(3,5-dichloro-benzoyl)-amino]-propionicacid591(2S)-[(Biphenyl-4-carbonyl)-(5-tert-butyl-5842-hydroxy-benzyl)-amino]-3-biphenyl-4-yl-propionic acid592Biphenyl-4-carboxylic acid (2S)-764{[(biphenyl-4-carbonyl)-(2-biphenyl-4-yl-1-carboxy-ethyl)-amino]-methyl}-4-tert-butyl-phenyl ester5933-Biphenyl-4-yl-(2S)-[(4-bromo-568benzoyl)-(2-tert-butoxycarbonylamino-ethyl)-amino]-propionic acid5943-Biphenyl-4-yl-(2S)-[(2-tert-649butoxycarbonylamino-ethyl)-(4′-trifluoromethoxy-biphenyl-4-carbonyl)-amino]-propionic acid595(2S)-[(2-Amino-ethyl)-(4-bromo-482benzoyl)-amino]-3-biphenyl-4-yl-propionic acid methyl ester596(2S)-[(2-Amino-ethyl)-(4-bromo-468benzoyl)-amino]-3-biphenyl-4-yl-propionic acid5973-Biphenyl-4-yl-(2S)-[(4-chloro-benzyl)-614(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid598(2S)-{2-[(2-Biphenyl-4-yl-1-carboxy-717ethyl)-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-ethylsulfamoyl}-benzoic acid5993-Biphenyl-4-yl-(2S)-[[2-(2-751methanesulfonyl-benzenesulfonylamino)-ethyl]-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid600(2S)-{[(2-Biphenyl-4-yl-1-687methoxycarbonyl-ethyl)-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylicacid tert-butyl ester601(2S)-{2-[(2-Biphenyl-4-yl-1-methoxycarbonyl-745ethyl)-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-ethylsulfamoyl}-benzoic acid methyl ester6023-Biphenyl-4-yl-(2S)-[[2-(2-765methanesulfonyl-benzenesulfonylamino)-ethyl]-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester6033-Biphenyl-4-yl-(2S)-[[2-(4-765methanesulfonyl-benzenesulfonylamino)-ethyl]-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester6043-Biphenyl-4-yl-(2S)-[[1-(2-805methanesulfonyl-benzenesulfonyl)-pyrrolidin-2-ylmethyl]-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionicacid methyl ester6053-Biphenyl-4-yl-(2S)-[[1-(4-methanesulfonyl-805benzenesulfonyl)-pyrrolidin-2-ylmethyl]-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methylester606(2S)-{[(2-Biphenyl-4-yl-1-carboxy-ethyl)-673(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylicacid tert-butyl ester607(2S)-{[(2-Biphenyl-4-yl-1-carboxy-ethyl)-673(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylicacid tert-butyl ester608(2S)-(2-{[(2-Biphenyl-4-yl-1-carboxy-771ethyl)-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-methyl}-pyrrolidine-1-sulfonyl)-benzoic acid methylester6093-Biphenyl-4-yl-(2S)-[[1-(2-791methanesulfonyl-benzenesulfonyl)-pyrrolidin-2-ylmethyl]-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionicacid6103-Biphenyl-4-yl-(2S)-[[1-(4-791methanesulfonyl-benzenesulfonyl)-pyrrolidin-2-ylmethyl]-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionicacid611(2S)-(2-{[(2-Biphenyl-4-yl-1-785methoxycarbonyl-ethyl)-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-methyl}-pyrrolidine-1-sulfonyl)-benzoic acidmethyl ester6123-Biphenyl-4-yl-(2S)-[[1-(2-805methanesulfonyl-benzenesulfonyl)-pyrrolidin-2-ylmethyl]-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionicacid methyl ester6133-Biphenyl-4-yl-(2S)-[[1-(4-805methanesulfonyl-benzenesulfonyl)-pyrrolidin-2-ylmethyl]-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionicacid methyl ester6143-Biphenyl-4-yl-(2S)-[[1-(2-thiophen-2-711yl-acetyl)-pyrrolidin-2-ylmethyl]-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester615(2S)-(2-{[(2-Biphenyl-4-yl-1-carboxy-771ethyl)-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-methyl}-pyrrolidine-1-sulfonyl)-benzoic acid methyl ester6163-Biphenyl-4-yl-(2S)-[[1-(2-791methanesulfonyl-benzenesulfonyl)-pyrrolidin-2-ylmethyl]-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionicacid6173-Biphenyl-4-yl-(2S)-[(1-683cyclopentanecarbonyl-pyrrolidin-2-ylmethyl)-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methylester6183-Biphenyl-4-yl-(2S)-[(1-655cyclopropanecarbonyl-pyrrolidin-2-ylmethyl)-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methylester6193-Biphenyl-4-yl-(2S)-[[1-(4-791methanesulfonyl-benzenesulfonyl)-pyrrolidin-2-ylmethyl]-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionicacid620(2S)-[(1-Acetyl-pyrrolidin-2-ylmethyl)-615(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-3-biphenyl-4-yl-propionic acid6213-Biphenyl-4-yl-(2S)-[[1-(2,2-dimethyl-657propionyl)-pyrrolidin-2-ylmethyl]-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid6223-Biphenyl-4-yl-(2S)-[(1-669cyclopentanecarbonyl-pyrrolidin-2-ylmethyl)-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid623(2S)-[(1-Acetyl-pyrrolidin-2-ylmethyl)-615(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-3-biphenyl-4-yl-propionic acid6243-Biphenyl-4-yl-(2S)-[(1-641cyclopropanecarbonyl-pyrrolidin-2-ylmethyl)-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid625(2S)-[[2-(2-Acetylamino-4-methyl-751thiazole-5-sulfonylamino)-ethyl]-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-3-biphenyl-4-yl-propionic acid6263-Biphenyl-4-yl-(2S)-[[2-(5-chloro-1,3-725dimethyl-1H-pyrazole-4-sulfonylamino)-ethyl]-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid6273-Biphenyl-4-yl-(2S)-[[2-(3,5-dimethyl-692isoxazole-4-sulfonylamino)-ethyl]-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid6283-Biphenyl-4-yl-(2S)-[[2-(1,2-dimethyl-6911H-imidazole-4-sulfonylamino)-ethyl]-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid6293-Biphenyl-4-yl-(2S)-[[2-(3,5-dimethyl-706isoxazole-4-sulfonylamino)-ethyl]-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester6303-Biphenyl-4-yl-(2S)-[[2-(1,2-dimethyl-7051H-imidazole-4-sulfonylamino)-ethyl]-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester6313-Biphenyl-4-yl-(2S)-[[2-(5-chloro-1,3-739dimethyl-1H-pyrazole-4-sulfonylamino)-ethyl]-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methylester6323-Biphenyl-4-yl-(2S)-[[2-(1-methyl-1H-677imidazole-4-sulfonylamino)-ethyl]-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid6333-Biphenyl-4-yl-(2S)-[[2-(2,4-dimethoxy-683benzylamino)-ethyl]-(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionicacid6343-Biphenyl-4-yl-(2S)-[(2-tert-633utoxycarbonylamino-ethyl)-(4′-rifluoromethyl—biphenyl-4-carbonyl)-amino]-propionic acid



EXAMPLE 635

[0740] 2-{[1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-3-(4′-trifluoromethoxy-biphenyl-4-yl)-propionic Acid

[0741] A solution of hydrazine (1.00 mmol), ethyl 2-(ethoxymethylene)-4,4,4-trifluoroacetoacetate (1.00 mmol), and DIEA (1.00 mmol) in anhydrous acetonitrile was stirred at rt or 2 h. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography to give the desired ester as a white solid. This ester was then hydrolyzed by general procedure J to give the desired 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid as a white solid.

[0742] A solution of above acid in DMF (3.0 mL) was reacted with (2S)-amino-3-(4′-trifluoromethoxy-biphenyl-4-yl)-propionic acid methyl ester Hydrochloride (0.300 g, 0.797 mmol), HBTU (0.300 g, 0.797 mmol), and DIEA (0.425 mL, 2.40 mmol) as described in general procedure A. The crude compound was purified by flash column chromatography on silica gel using CHCl3 as the mobile phase to give 0.290 g (61%) of 2-{[1−(4-fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-3-(4′trifluoromethoxy-biphenyl-4-yl)-propionic acid methyl ester. A solution of this ester (0.140 g, 0.235 mmol) in THF (4.0 mL) was treated with LiOH (0.035 g) by general procedure I to afford (0.125 g, 92%) of the title compound 2-{[1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid as a white solid. LCMS: 582 (M+1)+. 1H NMR (DMSO-d6) 8.94 [d, 1H], 8.07 [s, 1H], 7.76 [m, 2H], 7.57 [m, 4H], 7.42 [m, 6H], 4.64 [m, 1H], 3.22 [m, 1H], 3.05 [m, 1H].


EXAMPLE 636

[0743] 2-{[1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic Acid

[0744] A solution of 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (0.300 g, 1.097 mmol, prepared in example 635) in DMF (4.0 mL) was reacted with (2S)-amino-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester Hydrochloride (0.394 g, 1.097 mmol), HBTU (0.416 g, 1.097 mmol), and DIEA (0.585 mL, 3.29 mmol) as described in general procedure A. The crude compound was purified by washing with ethyl ether to give 0.300 g (47%) of 2-{[1−(4-Fluoro-phenyl)-5-trifluoromethyl-1 H-pyrazole-4-carbonyl]-amino}-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester. A solution of this ester (0.125 g, 0.215 mmol) in THF (4.0 mL) was treated with LiOH (0.031 g) by general procedure I to afford (0.105 g, 87%) the title compound 2-{[1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid as a white solid. LCMS: 565 (M+1)+. 1H NMR (DMSO-d6) 8.92 [d, 1H], 8.39 [s, 1H], 8.18 [d, 2H], 8.09 [d, 2H], 7.96 [d, 2H], 7.87 [m, 2H], 7.71 [m, 4H], 4.83 [m, 1H], 3.58 [m, 1H], 3.36 [m, 1H].


EXAMPLE 637

[0745] (2S)-{[1−(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic Acid

[0746] A solution of 1-(4-fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (0.200 g, 0.731 mmol, prepared in example 635) in DMF (4.0 mL) was reacted with 2-L-amino-3-biphenyl-4-yl-propionic acid methyl ester hydrochloride (0.213 g, 0.731 mmol), HBTU (0.277 g, 0.731 mmol), and DIEA (0.450 mL, 2.566 mmol) as described in general procedure A. The crude compound was purified by flash column chromatography on silica gel using CHCl3 (+10% hexane) to give 0.150 g (41%) of 3-biphenyl-4-yl-2-{(1-(4-fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-propionic acid methyl ester. A solution of this ester (0.085 g, 0.166 mmol) in THF (3.0 mL) was treated with LiOH (0.025 g) by general procedure I to afford (0.070 g, 85%) of the title compound 3-Biphenyl-4-yl-2-{[1-(4-fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-propionic acid as a white solid. LCMS: 498 (M+1)+. 1H NMR (DMSO-d6) 8.94 [d, 1H], 8.08 [s, 1H], 7.58 [m, 6H], 7.42 [m, 7H], 4.63 [m, 1H], 3.22 [m, 1H], 3.04 [m, 1H].

[0747] 3-Biphenyl-4-yl-(2S)-{[1−(4-fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-propionic Acid

[0748] By analogous methods to those described above the following compounds were synthesized.
18LC/MSEXAMPLENAME(m/z)638(2S)-{[1-(4-Chloro-phenyl)-5-582trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid6393-Biphenyl-4-yl-(2S)-{[1-(4-chloro-phenyl)-5145-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-propionic acid640(2S)-{[1-(4-Chloro-phenyl)-5-598trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-3-(4′-trifluoromethoxy-biphenyl-4-yl)-propionic acid6412-{[1-(4-Fluoro-phenyl)-5-trifluoromethyl-4991H-pyrazole-4-carbonyl]-amino}-3-(6-phenyl-pyridin-3-yl)-propionic acid642(2S)-{[1-(4-Nitro-phenyl)-5-rifluoromethyl-6091H-pyrazole-4-carbonyl]-amino}-3-(4′-trifluoromethoxy-biphenyl-4-yl)-propionic acid643(2S)-{[1-(4-tert-Butyl-phenyl)-5-620trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-3-(4′-trifluoromethoxy-biphenyl-4-yl)-propionic acid644(2S)-[(1-p-Tolyl-5-trifluoromethyl-1H-578pyrazole-4-carbonyl)-amino]-3-(4′-trifluoromethoxy-biphenyl-4-yl)-propionicacid645(2S)-{[1-(6-Methoxy-pyridazin-3-yl)-5-596trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-3-(4′-trifluoromethoxy-biphenyl-4-yl)-propionic acid646(2S)-[(5-Methyl-1-phenyl-1H-pyrazole-4-510carbonyl)-amino]-3-(4′-trifluoromethoxy-biphenyl-4-yl)-propionic acid647(2S)-{[1-(4-Chloro-phenyl)-5-598trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-3-(4′-trifluoromethoxy-biphenyl-4-yl)-propionic acid6483-(4′-Trifluoromethoxy-biphenyl-4-yl)-(2S)-648{[1-(4-trifluoromethoxy-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-propionic acid649(2S)-{[1-(3-Chloro-4-fluoro-phenyl)-5-616trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-3-(4′-trifluoromethoxy-biphenyl-4-yl)-propionic acid650(2S)-{[1-(4-Chloro-phenyl)-1H-pyrazole-4-530carbonyl]-amino}-3-(4′-trifluoromethoxy-biphenyl-4-yl)-propionic acid651(2S)-[(1-Phenyl-5-trifluoromethyl-1H-564pyrazole-4-carbonyl)-amino]-3-(4′-trifluoromethoxy-biphenyl-4-yl)-propionicacid652(2S)-[(1-Phenyl-5-trifluoromethyl-1H-548pyrazole-4-carbonyl)-amino]-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionicacid6533-Biphenyl-4-yl-(2S)-[(1-phenyl-5-480trifluoromethyl-1H-pyrazole-4-carbonyl)-amino]-propionic acid654(2S)-{[1-(4-Chloro-phenyl)-5-propyl-1H-580pyrazole-4-carbonyl]-amino}-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid



EXAMPLE 655

[0749] 3-(Biphenyl-4-ylmethoxy)-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic Acid

[0750] To a solution of 2-tert-Butoxycarbonylamino-3-hydroxy-propionic acid methyl ester (0.400 g, 1.82 mmol) in dimethylformamide (15 ml) was added sodium hydride (65%)(0.145 g, 3.64 mmol) at 0° C. after the evolution of hydrogen gas ceased, the freshly distilled benzyl bromide (0.449 g, 1.82 mmol) was added to the solution. The reaction mixture was stirred at 25-30° C. for 5 hr to give a clear solution The solvent was then removed under reduced pressure below 40° C. The residue was dissolved in water (30 ml) and the solution extracted with ethyl acetate (two 20 ml portions). The combined organic layers were further washed with brine and dried over anhydrous sodium sulfate. The ethyl acetate was then removed under reduced pressure to give the 3-(biphenyl-4-ylmethoxy)-(2S)-tert-butoxycarbonylamino-propionic acid methyl ester as colorless oil (0.421 g, 60%). LC/MS (m/z): 386 (M+1).

[0751] To 3-(Biphenyl-4-ylmethoxy)-(2S)-tert-butoxycarbonylamino-propionic acid methyl ester (0.421 gms, 1.1 mmol) was added 2 ml of 4M HCl in dioxane (8.8 mmol) and stirred for 30 min. The HCl was then removed under reduced pressure and the residue was then triturated with dichloromethane and hexane for 2-3 times and the solvents were removed under reduced pressure to yield the HCl salt of the compound (2S)-amino-3-(biphenyl-4-ylmethoxy)-propionic acid methyl ester hydrochloride as a white solid (0.300 g, 90%). LC/MS (m/z): 286 (M+1).

[0752] (2S)-Amino-3-(biphenyl-4-ylmethoxy)-propionic acid methyl ester hydrochloride (0.150 g, 0.483 mmol) was reacted with 4′-trifluoromethyl-biphenyl-4-carboxylic acid (0.136 g, 0.483 mmol) as described in general procedure A yielding the 3-(biphenyl-4-ylmethoxy)-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester. The resulting compound was then hydrolyzed by following the general procedure C to yield the title compound (0.200 g, 80%).

[0753]

1
H-NMR(400 MHz, CDCl3): 4.2 (m, 2H), 4.9 (S, 2H), 5.1 (m, 1H), 7.72 (m, 1H), 7.74 (m, 4H), 7.94 (m, 4H), 8.17 (m, 4H), 8.28 (d, 2H), 8.34 (d, 2H), 8.62 (S, 1H), 9.3 (d, 1H); LC/MS (m/z): 520.2 (M+1)+.


EXAMPLE 656

[0754] 3-[(Biphenyl-4-ylmethyl)-amino]-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic Acid.

[0755] (2S)-amino-3-tert-butoxycarbonylamino-propionic acid methyl ester hydrochloride (0.200 g, 0.785 mmol) was reacted with 4′-trifluoromethyl-biphenyl-4-carboxylic acid (0.208 g, 0.785 mmol) as described in general procedure A yielding 3-tert-butoxycarbonylamino-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester (0.313 g, 85%). LC/MS (m/z): 367 (M+1).

[0756] To 3-tert-butoxycarbonylamino-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)amino]-propionic acid methyl ester (0.313 g, 0.671 mmol) was added 2 ml of 4M HCl in dioxane (3.3 mmol) and stirred for 30 min. The HCl was then removed under reduced pressure and the residue was then triturated with dichloromethane and hexane for 2-3 times and the solvents were removed under reduced pressure to yield the HCl salt of the compound 3-amino-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester hydrochloride as a white solid (0.300 g, 90%). LC/MS (m/z): 267 (M+1).

[0757] 3-Amino-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester hydrochloride (0.200 g, 0.493 mmol) was subjected to reductive amination as per general procedure E with biphenyl-4-carbaldehyde (0.080 g, 0.444 mmol) and sodium triacetoxyborohydride (0.208 g, 0.986 mmol) to yield the 3-[(biphenyl-4-ylmethyl)-amino]-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester which was further hydrolyzed as per general procedure C to yield 3-[(biphenyl-4-ylmethyl)-amino]-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]propionic acid (0.190 g, 70%).

[0758]

1
H-NMR(400 MHz, DMSOd6): 3.9 (m, 2H) 4.6 (m, 2H), 5.2 (m, 1H), 7.72 (m, 1H), 7.78 (m, 2H), 7.98 (m, 4H), 8.05 (bd, 2H), 8.19 (m, 4H), 8.27 (d, 2H), 8.40 (d, 2H), 8.7 (S, 1H), 9.5 (d, 1H); LC/MS (m/z): 519.3 (M+1).


EXAMPLE 657

[0759] 3-(Biphenyl-4-ylmethyl-methyl-amino)-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic Acid:

[0760] 3-[(Biphenyl-4-ylmethyl)-amino]-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)amino]-propionic acid methyl ester (0.050 g, 0.093 mmol) prepared as per the above listed example 656 was subjected to reductive amination as per procedure E with formaldehyde (0.010 ml, 0.093 mmol) and sodium triacetoxyborohydride (0.039 gms, 0.186 mmol) to yield the corresponding 3-(Biphenyl-4-ylmethyl-methyl-amino)-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester which was then hydrolyzed as per general procedure C to yield the title compound (0.040 g, 80%). 1H-NMR (400 MHz, DMSOd6): 3.17 (s, 3H), 3.9 (m, 2H), 4.76 (m, 2H), 5.31 (s, 1H), 7.69 (m, 1H), 7.77 (m, 2H), 7.97 (m, 4H), 8.05 (bd, 2H), 8.19 (m, 4H), 8.27 (d, 2H), 8.40 (d, 2H), 9.5 (s, 1H); LC/MS (m/z): 533.3 (M+1).


EXAMPLE 658

[0761] 3-(Biphenyl-4-ylmethyl-pyridin-4-ylmethyl-amino)-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic Acid:

[0762] 3-[(Biphenyl-4-ylmethyl)-amino]-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester (0.050 g, 0.093 mmol) prepared as per the above listed example 656 was subjected to reductive amination as per procedure E with 4-pyridine carbaldehyde (0.010 ml, 0.093 mmol) and sodium triacetoxyborohydride (0.039 gms, 0.186 mmol) to yield the corresponding 3-(Biphenyl-4-ylmethyl-pyridin-4-yl methyl-amino)-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester which was then hydrolyzed as per general procedure C to yield the title compound (0.040 g, 80%). 1H-NMR(400 MHz, DMSOd6): 3.3 (m, 2H), 4.001 (s, 4H), 5.18 (m, 1H), 7.62-7.75 (m, 8H), 7.8-7.93 (m, 4H), 8.17 (m, 4H), 8.27 (m, 4H), 8.77 (d, 2H), 9.1 (d, 1H), 8.7 (S, 1H); LC/MS (m/z): 610.4 (M+1).


EXAMPLE 659

[0763] 3-(Biphenyl-4-ylmethyl-furan-2-ylmethyl-amino)-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic Acid:

[0764] 3-[(Biphenyl-4-ylmethyl)-amino]-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester (0.050 g, 0.093 mmol) prepared as per the above listed example 657 and was subjected to reductive amination as per procedure E with furan-2-carbaldehyde (0.009 g, 0.093 mmol) and sodium triacetoxyborohydride (0.039 gms, 0.186 mmol) to yield the corresponding 3-(biphenyl-4-ylmethyl-furan-2-ylmethyl-amino)-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester which was then hydrolyzed as per general procedure C to yield the title compound (0.030 g, 60%). 1H-NMR(400 MHz, DMSOd6): 3.21 (m, 2H), 4.0 (m, 3H), 6.7 (d, 1H), 7.6 (m, 2H), 7.8 (m, 8H), 8.24 (m, 8H); LC/MS (m/z): 599.3 (M+1).


EXAMPLE 660

[0765] 3-[(Biphenyl-4-carbonyl)-amino]-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic Acid:

[0766] The 3-amino-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester hydrochloride (0.100 g, 0.273 mmol) prepared as per the above listed Example 656 was reacted with biphenylcarboxylic acid as per general procedure A to yield the corresponding 3-[(biphenyl-4-carbonyl)-amino]-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester which was then hydrolyzed as per general procedure C to yield the title compound (0.095 g, 65%). 1H-NMR(400 MHz, DMSOd6): 4.16 (m, 2H), 4.98 (m, 1H), 7.71 (m, 2H), 7.79 (m, 2H), 8.08 (dd, 4H), 8.2-8.4 (m, 9H), 9.16 (m, 1H), 9.2 (d, 1H); LC/MS (m/z): 533.2 (M+1).


EXAMPLE 661

[0767] (2S)-2,3-Bis-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic Acid:

[0768] (2S)-2,3-Diamino-propionic acid methyl ester (0.080 g, 0.421 mmol) was reacted with 4′-trifluoromethyl-biphenyl-4-carboxylic acid (0.224 g, 0.841 mmol) as described in general procedure A yielding the corresponding (2S)-3-bis-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester which was then hydrolyzed as per general procedure C to yield the title compound (0.150 g, 60%). 1H-NMR(400 MHz, DMSOd6): 4.16 (m, 2H), 5.0 (m, 1H), 8.17 (m, 8H), 8.28 (m, 8H), 9.18 (m, 1H), 9.21 (d, 1H); LC/MS (m/z): 601.2 (M+1).


EXAMPLE 662

[0769] 3-(Biphenyl-4-sulfonylamino)-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic Acid:

[0770] To 3-amino-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester hydrochloride (0.100 g, 0.273 mmol) prepared as per the above listed example 656 was added dry dichloromethane (10 ml) followed by diisopropylethylamine (0.095 g, 0.738 mmol) and stirred for 10 min. To this mixture at 0° C. was added Biphenyl-4-sulfonyl chloride (0.062 g, 0273 mmol) and the reaction was stirred at ambient temperature. After 2 hrs the reaction mixture was diluted with dichloromethane and washed with water (20 ml) followed by brine (20 ml). The organic layers were collected and dried over sodium sulfate and concentrated under reduced pressure to yield the 3-(Biphenyl-4-sulfonylamino)-2-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester which was then hydrolyzed as per procedure C to yield the title compound (0.045 g, 50%). 1H-NMR(400 MHz, DMSOd6): 3.65 (m, 2H), 4.85 (m, 1H), 7.78 (m, 4H), 8.02 (d, 2H), 8.17 (m, 7H), 8.27 (m, 4H), 8.62 (S, 1H), 8.9 (bs, 1H). LC/MS (m/z): 569.1 (M+1).

[0771] Bi Logical Assay

[0772] The following assay methods are utilized to identify compounds of Formula (I) that are effective in antagonizing the function of factor IX. Compounds of Formula (I) are effective in antagonizing the function of factor IX and are useful as inhibitors of the intrinsic clotting pathway.

[0773] General Assay Procedure

[0774] Factor IXa Florescence Based Molecular Assay:

[0775] Method where a Fluorescent product is generated based on factor IXa cleaving the substrate CH3SO2-(D)-CHG-Gly-Arg-AMC AcOH (methyl sulfonyl-D-cyclohexylglycylglycyl-arginine-7-amino-4-methylcoumarid monoacetate) available from Centerchem, Inc.

[0776] 12 μL of 4× compound dilutions (final 1% DMSO) is incubated for 10 min at room temp with 24 μL FIXa (HCIXA-0050 Haemotologic Technologies Inc. Essex Junction, Vt.) 3.9 units/mL in Buffer containing 80% Ethylene glycol, 10 mM CaCl2, 200 mM NaCl, and 100 mM Tris (pH 7.4). The reaction is started by the addition of 12 μL of 0.5 mM FIXa substrate (Pefa-10148 from Pentapharm Basel, Switzerland). After incubating the reaction for 10 min at room temp, the plate is read in a Spectromax Gemini fluorescence plate reader with and exitation wavelenth of 340 nm and an emmision wavelength of 440 nm. From the varying concentrations of test compound, IC50's are then calculated. The Examples in Table 1 inhibit Factor IX in this assay with IC50 of less than 30 micromolar.

[0777] Factor IXa In Vitro Clotting Assay:

[0778] Method where Inhibition of Clotting Using Citrated Human Plasma with Exogenous Human Factor IXa is Measured by Turbidity.

[0779] Potential inhibitors of factor IX are added to a mixture of citrated human plasma, Cephalin, and human factor IX to give a final concentration of 0.8 U/ml. The mixture is allowed to incubate at 37° C. for 10 minutes. Clotting is initiated by the addition of 10 mM CaCl2. The optical density is measured at 405 nm for 5 minutes. Relative IC50's as well as maximum efficacy are calculated.

[0780] A first control assay is performed using a mixture of citrated human plasma, Cephalin, and human factor IX. A second control assay is performed using a mixture of citrated human plasma and Cephalin. Clotting for the two control assays is initiated by the addition of CaCl2, and the optical density is measured at 405 nm for 5 minutes.

[0781] Analysis of graphs of optical denisty versus time for the two control assays and various concentrations of compounds of Formula (I) demonstrates that factor IX decreases the time for Ca+2 induced clotting of human serum. Analysis also demonstrates that compounds of Formula (I) prolong the Ca+2 induced clotting time in the presence of factor IX.

[0782] Factor Xa in vitro clotting assays were performed using compounds of Formula (I) under the same or similar conditions as the factor IXa in vitro clotting assay. These data demonstrate that compounds of Formula (I) are partial inhibitors or partial antagonists of factor IX. For example, where a range of concentrations of a compound of Formula (I) in the presence of factor IX prolong the Ca+2 induced clotting time from 700 seconds to 1500 seconds, the same range of concentrations of a compound of Formula (I) in the presence of factor Xa did not alter the Ca+2 induced clotting time from 200 seconds.

[0783] The invention further provides pharmaceutical compositions comprising the factor IX modulating compounds of the invention. The term “pharmaceutical composition” is used herein to denote a composition that may be administered to a mammalian host, e.g., orally, topically, parenterally, by inhalation spray, or rectally, in unit dosage formulations containing conventional non-toxic carriers, diluents, adjuvants, vehicles and the like. The term “parenteral” as used herein, includes subcutaneous injections, intravenous, intramuscular, intracisternal injection, or by infusion techniques.

[0784] The term “factor IX” is used herein to refer to blood coagulation factor IX, including both activated and non-activated forms thereof.

[0785] The term “therapeutically effective amount” is used herein to denote that amount of a drug or pharmaceutical agent that will elicit the therapeutic response of an animal or human that is being sought.

[0786] The pharmaceutical compositions containing a compound of the invention may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous, or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any known method, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically-acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Pat. Nos. 4,356,108; 4,166,452; and 4,265,874, to form osmotic therapeutic tablets for controlled release.

[0787] Formulations for oral use may also be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or a soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

[0788] Aqueous suspensions may contain the active compounds in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide such as lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyl-eneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0789] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as a liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alchol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

[0790] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active compound in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring, and coloring agents may also be present.

[0791] The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example a liquid paraffin, or a mixture thereof. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

[0792] Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectible aqueous or oleaginous suspension. This suspension may be formulated according to the known methods using suitable dispersing or wetting agents and suspending agents described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conveniently employed as solvent or suspending medium. For this purpose, any bland fixed oil may be employed using synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0793] The compositions may also be in the form of suppositories for rectal administration of the compounds of the invention. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will thus melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols, for example.

[0794] For topical use, creams, ointments, jellies, solutions of suspensions, etc., containing the compounds of the invention are contemplated. For the purpose of this application, topical applications shall include mouth washes and gargles. The compounds of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes may be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines. Also provided by the present invention are prodrugs of the invention.

[0795] Pharmaceutically-acceptable salts of the compounds of the present invention, where a basic or acidic group is present in the structure, are also included within the scope of the invention. The term “pharmaceutically acceptable salts” refers to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid or by reacting the acid with a suitable organic or inorganic base. Representative salts include the following salts: Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium Edetate, Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrocloride, Hydroxynaphthoate, Iodide, Isethionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Methanesulfonate, Methylbromide, Methylnitrate, Methylsulfate, Monopotassium Maleate, Mucate, Napsylate, Nitrate, N-methylglucamine, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate, Phosphate/diphosphate, Polygalacturonate, Potassium, Salicylate, Sodium, Stearate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate, Triethiodide, Trimethylammonium and Valerate. When an acidic substituent is present, such as-COOH, there can be formed the ammonium, morpholinium, sodium, potassium, barium, calcium salt, and the like, for use as the dosage form. When a basic group is present, such as amino or a basic heteroaryl radical, such as pyridyl, an acidic salt, such as hydrochloride, hydrobromide, phosphate, sulfate, trifluoroacetate, trichloroacetate, acetate, oxlate, maleate, pyruvate, malonate, succinate, citrate, tartarate, fumarate, mandelate, benzoate, cinnamate, methanesulfonate, ethanesulfonate, picrate and the like, and include acids related to the pharmaceutically-acceptable salts listed in the Journal of Pharmaceutical Science, 66, 2 (1977) p. 1-19.

[0796] Other salts which are not pharmaceutically acceptable may be useful in the preparation of compounds of the invention and these form a further aspect of the invention.

[0797] In addition, some of the compounds of Formula (I) may form solvates with water or common organic solvents. Such solvates are also encompassed within the scope of the invention.

[0798] Thus, in another aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug therof, and one or more pharmaceutically acceptable carriers, excipients, or diluents. In an embodiment of the pharmaceutical composition, the compound of Formula (I) is an antagonist of factor IX activity. In another embodiment of the pharmaceutical composition, the compound of Formula (I) is a partial antagonist of factor IX activity, wherein a partial antagonist comprises a compound that inhibits less than complete activity at a physiologically tolerable dose. In another embodiment of the pharmaceutical composition, the compound of Formula (I) is a partial antagonist of factor IX activity, wherein the compound of Formula (I) inhibits up to 95% of factor IX activity. In another embodiment of the pharmaceutical composition, the compound of Formula (I) is a partial antagonist of factor IX activity, wherein the compound of Formula (I) inhibits up to 80% of factor IX activity. In another embodiment of the pharmaceutical composition, the compound of Formula (I) is a partial antagonist of factor IX activity, wherein the compound of Formula (I) inhibits up to 50% of factor IX activity. In another embodiment of the pharmaceutical composition, the compound of Formula (I) antagonizes blood clotting mediated by factor IX.

[0799] In another aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I),

[0800] or a pharmaceutically acceptable salt, solvate, or prodrug therof, and one or more pharmaceutically acceptable carriers, excipients, or diluents, wherein said therapeutically effective amount of Formula (I) preferentially inhibits the intrinsic clotting cascade as compared to the extrinsic clotting cascade. In an embodiment of the pharmaceutical composition, said therapeutically effective amount of Formula (I) inhibits the intrinsic clotting cascade by greater than 80% and inhibits the extrinsic clotting cascade by less than 50%. In another embodiment of the pharmaceutical composition, said therapeutically effective amount of Formula (I) comprises an amount sufficient to achieve and maintain a sustained blood level that at least partially antagonizes factor IX biological activity. Preferably, said sustained blood level comprises a concentration ranging from about 0.01 μM to 2 mM, more preferably from about 1 μM to 300 μM, and even more preferably from about 20 μM to about 100 μM.

[0801] In another aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug therof, and one or more pharmaceutically acceptable carriers, excipients, or diluents, wherein said therapeutically effective amount comprises a sufficient amount of the compound of Formula (I) to at least partially inhibit the biological activity of factor IX in a subject, a sufficient amount of the compound of Formula (I) for at least partial amelioration of at least one factor IX-mediated disease, or a sufficient amount of the compound of Formula (I) to at least partially inhibit the intrinsic clotting cascade in a subject. In an embodiment of the pharmaceutial composition, said factor IX-mediated disease comprises stroke. In another embodiment of the pharmaceutial composition, said factor IX-mediated disease comprises deep vein thrombosis. In another embodiment of the pharmaceutial composition, said factor IX-mediated disease comprises deep vein thrombosis, wherein said thrombosis is associated with surgical procedures, long periods of confinement, acquired or inherited pro-coagulant states including anti-phospholipid antibody syndrome, protein C deficiency and protein S deficiency, or acute and chronic inflammation including recurrent miscarriage or Systemic Lupus Erythmatosis (SLE). In another embodiment, said factor IX-mediated disease comprises excessive clotting associated with the treatment of kidney diseases by hemodialysis and/or venous hemofiltration. In another embodiment, said factor IX-mediated disease comprises cardiovascular disease. In another embodiment, said factor IX-mediated disease comprises cardiovascular disease, wherein said cardiovascular disease comprises myocardial infarction, arrhythmia, or aneurysm.

[0802] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of Formula (1), and one or more pharmaceutically acceptable carriers, excipients, or diluents, wherein said pharmaceutical composition is used to replace or supplement compounds that reduce clotting.

[0803] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of Formula (I), and one or more pharmaceutically acceptable carriers, excipients, or diluents, further comprising one or more therapeutic agents.

[0804] In another aspect, the present invention provides a method for the inhibition of the normal biological function of factor IX comprising administering to a subject in need thereof a compound of Formula (1). In embodiment of the method, said compound of Formula (I) is an antagonist of factor IX activity. In another embodiment of the method, said compound of Formula (I) antagonizes blood clotting mediated by factor IX. In another embodiment of the method, said compound of Formula (I) is administered in an amount sufficient to partially antagonize the biological activity of factor IX in said subject. In another embodiment of the method, said compound of Formula (I) is an antagonist of factor IX activity. In another embodiment of the method, said compound of Formula (I) antagonizes blood clotting mediated by factor IX. In another embodiment of the method, said compound of Formula (I) is administered in an amount sufficient to partially antagonize the biological activity of factor IX in said subject. In another embodiment of the method, said pharmaceutical composition is administered in the form of an oral dosage or parenteral dosage unit. In another embodiment of the method, said compound of Formula (I) is administered as a dose in a range from about 0.01 to 1,000 mg/kg of body weight per day. In another embodiment of the method, said compound of Formula (I) is administered as a dose in a range from about 0.1 to 100 mg/kg of body weight per day. In another embodiment of the method, said compound of Formula (I) is administered as a dose in a range from about 0.5 to 10 mg/kg of body weight per day. In another embodiment, said compound of Formula (I) is used to replace or supplement compounds that reduce clotting.

[0805] In another aspect, the present invention provides a method for the inhibition of the normal biological function of factor IX comprising administering to a subject in need thereof a compound of Formula (I), wherein said compound of Formula (I) is administered to said subject as a pharmaceutical composition comprising a therapeutically effective amount of said compound of Formula (I) and one or more pharmaceutically acceptable carriers, excipients, or diluents. In an embodiment of the method, said therapeutically effective amount of the compound of Formula (I) comprises a sufficient amount of the compound of Formula (I) to at least partially inhibit the intrinsic clotting cascade in said subject. In another embodiment of the method, said therapeutically effective amount of Formula (I) preferentially inhibits the intrinsic clotting cascade as compared to the extrinsic clotting cascade. In another embodiment of the method, said therapeutically effective amount of Formula (I) inhibits the intrinsic clotting cascade by greater than 80% and inhibits the extrinsic clotting cascade by less than 50%. In another embodiment of the method, said therapeutically effective amount of the compound of Formula I comprises an amount sufficient to achieve and maintain a sustained blood level that at least partially antagonizes factor IX biological activity. Preferably, said sustained blood level comprises a concentration ranging from about 0.01 μM to 2 mM, more preferably from about 1 μM to 300 μM, and even more preferably from about 20 μM to about 100 μM. In another embodiment of the method, said pharmaceutical composition further comprises one or more therapeutic agents.

[0806] In another aspect, the present invention provides a method for the inhibition of the normal biological function of factor IX comprising administering to a subject in need thereof a compound of Formula (I), wherein said compound of Formula (I) is a partial antagonist of factor IX, wherein a partial antagonist comprises a compound that inhibits less than complete activity at a physiologically tolerable dose. In an embodiment of the method, said compound of Formula (I) inhibits up to 95% of factor IX activity. In another embodiment of the method, said compound of Formula (I) inhibits up to 80% of factor IX activity. In another embodiment of the method, said compound of Formula (I) inhibits up to 50% of factor IX activity.

[0807] In another aspect, the present invention provides a method for the inhibition of the normal biological function of factor IX comprising administering to a subject in need thereof a compound of Formula (I), wherein said compound of Formula (I) is administered to said subject as a pharmaceutical composition comprising a therapeutically effective amount of said compound of Formula (I) and one or more pharmaceutically acceptable carriers, excipients, or diluents, wherein said therapeutically effective amount of the compound of Formula (I) comprises a sufficient amount of the compound of Formula (I) for treatment or prevention of factor IX-mediated diseases. In an embodiment of the method, said factor IX-mediated disease comprises stroke. In another embodiment of the method, said factor IX-mediated disease comprises deep vein thrombosis. The thrombosis may be associated with surgical procedures, long periods of confinement, acquired or inherited pro-coagulant states including anti-phospholipid antibody syndrome, protein C deficiency and protein S deficiency, or acute and chronic inflammation including recurrent miscarriage or Systemic Lupus Erythmatosis (SLE). In another embodiment of the method, said factor IX-mediated disease comprises clotting associated with the treatment of kidney disease by hemodialysis and/or venous hemofiltration. In another embodiment of the method, said factor IX-mediated disease comprises cardiovascular disease. The cardiovascular disease may be associated myocardial infarction, arrhythmia, or aneurysm.

[0808] In a further aspect of the present invention, the factor IXa modulators of the invention are utilized in adjuvant therapeutic or combination therapeutic treatments with other known therapeutic agents.

[0809] The term “treatment” as used herein, refers to the full spectrum of treatments for a given disorder from which the patient is suffering, including alleviation of one, most of all symptoms resulting from that disorder, to an outright cure for the particular disorder or prevention of the onset of the disorder.

[0810] The following is a non-exhaustive listing of adjuvants and additional therapeutic agents which may be utilized in combination with the factor IXa antagonists of the present invention:

[0811] 1. Analgesics: Aspirin

[0812] 2. NSAIDs (Nonsteroidal anti-inflammatory drugs): Ibuprofen, Naproxen, Diclofenac

[0813] 3. DMARDs (Disease-Modifying Antirheumatic drugs): Methotrexate, gold preparations, hydroxychloroquine, sulfasalazine

[0814] 4. Biologic Response Modifiers, DMARDs: Etanercept, Infliximab Glucocorticoids

[0815] In a further preferred embodiment, the present invention provides a method of treating or preventing a factor IXa mediated diseases, the method comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula (I) alone or in combination with therapeutic agents selected from the group consisting of antibiotics, hormones, biologic response modifiers, analgesics, NSAIDs, DMARDs, glucocorticoids, thrombolytic agents, antidepressants, and anticonvulsants.

[0816] Generally speaking, the compound of the present invention, preferably Formula (I), is administered at a dosage level of from about 0.01 to 1000 mg/kg of the body weight of the subject being treated, with a preferred dosage range between 0.01 and 100 mg/kg, most preferably 0.5 to 10 mg/kg of body weight per day. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for oral administration to humans may contain 1 mg to 2 grams of a compound of Formula (I) with an appropriate and convenient amount of carrier material which may vary from about 5 to 95 percent of the total composition. Dosage unit forms will generally contain between from about 5 mg to about 500 mg of active ingredient. This dosage has to be individualized by the clinician based on the specific clinical condition of the subject being treated. Thus, it will be understood that the specific dosage level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

[0817] While the invention has been described and illustrated with reference to certain preferred embodiments therof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages other than the preferred dosages as set forth herein may be applicable as a consequence of variations in the responsiveness of the mammal being treated for factor IXa-mediated disease(s). Likewise, the specific pharmacological responses observed may vary according to and depending on the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention.

Claims
  • 1. The compound of Formula (I):
  • 29. The compound of Formula (I) in claim 1,
  • 2. The compound of Formula (I) in claim 1, wherein c is equal to 0 or 1.
  • 3. The compound of Formula (I) in claim 1, wherein c is equal to 0.
  • 4. The compound of Formula (I) in claim 1, wherein G comprises: -hydrogen or —CO2R1; wherein R1 comprises: -hydrogen, -alkyl, and -aryl.
  • 5. The compound of Formula (I) in claim 1, wherein c is equal to 0 and G comprises: -hydrogen or —CO2H.
  • 6. The compound of Formula (I) in claim 1, wherein V comprises —(CH2)a—, —(CH2)b—O—(CH2)a—, or a direct bond, wherein a is equal to 1 or 2 and b is equal to 1.
  • 7. The compound of Formula (I) in claim 1, wherein V comprises —(CH2)a— or a direct bond, wherein a is equal to 1.
  • 8. The compound of Formula (I) in claim 1, wherein X comprises —N(R8)—, —CON(R8)—, —N(R8)CO—, or —N(R8)CON(R9)—, wherein R8 and R9 independently comprise: -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or -alkylene-arylene-alkyl.
  • 9. The compound of Formula (I) in claim 1, wherein X comprises —N(R8)—, —CON(R8)—, or —N(R8)CO—, wherein R8 comprises: -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or -alkylene-arylene-alkyl.
  • 10. The compound of Formula (I) in claim 1, wherein Ar1 comprises a mono- or bicyclic aryl or heteroaryl group optionally substituted 1 to 7 times.
  • 11. The compound of Formula (I) in claim 1, wherein Ar1 comprises a phenyl group having 1 to 5 substituents, wherein the substituents independently comprise: a) -fluoro; b) -chloro; c) -bromo; d) -iodo; e) -cyano; f) -nitro; g) -perfluoroalkyl; h) -D1-R13; i) -alkyl; j) -aryl; k) -heteroaryl; l) -heterocyclyl; m) -cycloalkyl; n) -alkylene-aryl; o) -alkylene-heteroaryl; p) -alkylene-arylene-D1-R13; q) -alkylene-heteroarylene-D1-R13; r) -alkylene-arylene-aryl; s) -alkylene-heteroarylene-aryl; t) -alkylene-arylene-heteroaryl u) -alkylene-arylene-arylene-DI-R13; v) -alkylene-arylene-alkyl; w) -alkylene-heteroarylene-alkyl; x) -arylene-alkyl; y) -arylene-cycloalkyl; z) -heteroarylene-alkyl; aa) -arylene-arylene-alkyl; bb) -D1-alkyl; cc) -D1-aryl; dd) -D1-heteroaryl; ee) -D1-arylene-D2-R14; ff) -D1-heteroarylene-D2-R14; gg) -D1-alkylene-heteroaryl; hh) -D1-alkylene-aryl; ii) -D1-alkylene-arylene-D2-R14 jj) -D1-alkylene-heteroarylene-D2-R14 kk) -D1-arylene-alkyl; ll) -D1-heteroarylene-alkyl; mm) -D1-alkylene-arylene-aryl; nn) -D1-alkylene-heteroarylene-aryl; oo) -D1-arylene-arylene-aryl; pp) -D1-alkylene-arylene-alkyl; qq) -D1-alkylene-heteroarylene-alky ss) -alkylene-D1-alkylene-aryl; tt) -alkylene-D1-alkylene-arylene-D2-R14 uu) -arylene-D1-alkyl; vv) -arylene-D1-cycloalkyl; ww) -arylene-D1-heterocyclyl; xx) -alkylene-D1-aryl; yy) -alkylene-D1-heteroaryl; zz) -alkylene-D1-arylene-D2-R14 aaa) -alkylene-D1-heteroarylene-D2-R14 bbb) -alkylene-D1-heteroaryl; ccc) -alkylene-D1-cycloalkyl; ddd) -alkylene-D1-heterocyclyl; eee) -alkylene-D1-arylene-alkyl; fff) -alkylene-D1-heteroarylene-alkyl; ggg) -alkylene-D1-alkylene-arylene-alkyl; hh) -alkylene-D1-alkylene-heteroarylene-alkyl; iii) -alkylene-D1-alkyl; jjj) -alkylene-D1-R13; kkk) -arylene-D1-R13; lll) -heteroarylene-D1-R13; or mmm) -hydrogen;  wherein D1 comprises —CH2—, -alkylene-, -alkenylene-, -alkylene-S—, —S-alkylene-, -alkylene-O—, —O-alkylene-, -alkylene-S(O)2—, —S(O)2-alkylene, —O—, —N(R15)—, —C(O)—, —CON(R15)—, —N(R15)C(O)—, —N(R15)CON(R16)—, —N(R15)C(O)O—, —OC(O)N(R15)—, —N(R15)SO2—, —SO2N(R15)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O2)—, —N(R15)SO2N(R16)—, 704 wherein R13, R15, R16, and R17 independently comprise: -hydrogen, -alkyl, -aryl, -heteroaryl, -arylene-alkyl, -heteroarylene-alkyl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene-arylene-alkyl, or -alkylene-heteroarylene-alkyl; D2 comprises —CH2—, -alkylene-, -alkenylene-, -alkylene-S—, —S-alkylene-, -alkylene-O—, —O-alkylene-, -alkylene-S(O)2—, —S(O)2-alkylene, —O—, —N(R25)—, —C(O)—, —CON(R25)—, —N(R18)C(O)—, —N(R18)CON(R19)—, —N(R18)C(O)O—, —OC(O)N(R18)—, —N(R18)SO2—, —SO2N(R18)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O2)—, —N(R18)SO2N(R19)—, and  wherein R18 and R19 independently comprise: -hydrogen, -alkyl, -aryl, arylene-alkyl, -alkylene-aryl, or -alkylene-arylene-alkyl; and R14 comprises -hydrogen, -alkyl, -aryl, -heteroaryl, -arylene-alkyl, -heteroarylene-alkyl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene-arylene-alkyl, or -alkylene-heteroarylene-alkyl.
  • 12. The compound of Formula (I) in claim 1, wherein Ar1 comprises a monosubstituted phenyl group wherein the substituent comprises: -aryl, -arylene-alkyl, -D1-aryl, -D1-alkylene-arylene-alkyl, or -arylene-D1-alkyl; wherein D1 comprises —O—, —N(R11)—, —CON(R11)—, or —N(R11)C(O)—, and wherein R11 comprises: -hydrogen; -alkyl; or -aryl.
  • 13. The compound of Formula (I) in claim 1, wherein Ar2 comprises a phenyl, naphthyl, pyridyl, isoquinolyl, pyrimidyl or quinazolyl group optionally substituted 1 to 7 times.
  • 14. The compound of Formula (I) in claim 1, wherein Ar2 comprises a substituted phenyl, 2-naphthyl, 2-pyridyl, 3-isoquinolyl, 2-pyrimidyl or 2-quinazolyl group having 1 to 5 substituents wherein the substituents independently comprise: a) -fluoro; b) -chloro; c) -bromo; d) -iodo; e) -cyano; f) -nitro; g) -perfluoroalkyl; h) -T1-R20; i) -alkyl; j) -aryl; k) -heteroaryl; l) -heterocyclyl; m) -cycloalkyl; n) -alkylene-aryl; o) -alkylene-arylene-aryl; p) -alkylene-arylene-alkyl; q) -arylene-alkyl; r) -arylene-aryl; s) -arylene-heteroaryl; t) -heteroarylene-aryl; u) -heteroarylene-heteroaryl; v) -heteroarylene-heterocyclyl w) -arylene-heterocyclyl x) -arylene-arylene-alkyl; y) -T1-alkyl; z) -T1-aryl; aa) -T1-alkylene-aryl; bb) -T1-alkenylene-aryl; cc) -T1-alkylene-heteroaryl; dd) -T1-alkenylene-heteroaryl; ee) -T1-cycloalkylene-aryl; ff) -T1-cycloalkylene-heteroaryl; gg) -T1-heterocyclylene-aryl; hh) -T1-heterocyclylene-heteroaryl; ii) -T1-arylene-alkyl; jj) -T1-arylene-alkenyl; kk) -T1-alkylene-arylene-aryl; ll) -T1-arylene-T2-aryl; mm) -T1-arylene-arylene-aryl; nn) -T1-alkylene-arylene-alkyl; oo) -alkylene-T1-alkylene-aryl; pp) -arylene-T1-alkyl; qq) -arylene-T1-alkylene-aryl; rr) -T1-alkylene-T2-aryl; ss) -T1-alkylene-aryl; tt) -alkylene-T1-heteroaryl; uu) -alkylene-T1-cycloalkyl; vv) -alkylene-T1-heterocyclyl; ww) -alkylene-T-arylene-alkyl; xx) -alkylene-T1-alkylene-arylene-alkyl; yy) -alkylene-T1-alkyl; zz) -alkylene-T1-R20; aaa) -arylene-T1-R20; or bbb) -hydrogen;  wherein T1 comprises —CH2—, —O—, —N(R21)—, —C(O)—, —CON(R21)—, —N(R21)C(O)—, —N(R21)CON(R22)—, —N(R21)C(O)O—, —OC(O)N(R21)—, —N(R21)SO2—, —SO2N(R21)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O2)—, —N(R21)SO2N(R22)—, 705 and  wherein R20, R21, R22 and R23, independently comprise: -hydrogen, -alkyl, -alkenyl, -alkylene-cycloalkyl, -alkynene-heterocyclyl, -aryl, -heteroaryl, -arylene-alkyl, -alkylene-aryl, -alkylene-arylene-alkyl, -alkylene-arylene-aryl, -alkylene-arylene-alkylene-aryl, -alkylene-arylene-O-arylene, or alkylene-arylene-O-alkylene-aryl; and T2 comprises a direct bond, —CH2—, —O—, —N(R24)—, —C(O)—, —CON(R24)—, —N(R24)C(O)—, —N(R24)CON(R25)—, —N(R24)C(O)O—, —OC(O)N(R24)—, —N(R24)SO2—, —SO2N(R24)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O2)—, —N(R24)SO2N(R25)—,  wherein R24 and R25 independently comprise; -hydrogen, -alkyl, -alkenyl, -alkylene-cycloalkyl, alkynene-heterocyclyl, -aryl, -heteroaryl, -arylene-alkyl, -alkylene-aryl, and -alkylene-arylene-alkyl.
  • 15. The compound of Formula (I) in claim 1, wherein Ar2 comprises a substituted phenyl, 2-naphthyl, 2-pyridyl, 3-isoquinolyl, 2-pyrimidyl or 2-quinazolyl group having 1 to 5 substituents independently comprising: a) -fluoro; b) -chloro; c) -bromo; d) -iodo; e) -cyano; f) -nitro; g) -perfluoroalkyl; h) -T1-R20; i) -alkyl; j) -aryl; k) -arylene-alkyl; l) -T1-alkyl; m) -T1-alkylene-aryl; n) -T1-alkylene-arylene-aryl; o) -T1-alkylene-arylene-alkyl; p) -arylene-T1-alkyl; or q) -hydrogen;  wherein T1 comprises —CH2—, —O—, —N(R21)—, —CON(R21)—, or —N(R21)C(O)—; wherein R20 and R21 independently comprise: -hydrogen, -alkyl, or -aryl.
  • 16. The compound of Formula (I) in claim 1,
  • 17. The compound of Formula (I) in claim 1, wherein Ar1 comprises: 2′-phenoxy-biphenyl-4-yl, 2′-(4-methoxy-phenoxy)-biphenyl-4-yl, 2′-(4-pentyl-phenoxy)-biphenyl-4-yl, 2′-(4-tert-butyl-phenoxy)-biphenyl-4-yl, 2′-(4-trifluoromethoxy-phenoxy)-biphenyl-4-yl, 2′-Benzyloxy-biphenyl-4-yl, 2-Biphenyl-4-yl, 2′-cyclopentyloxy-biphenyl-4-yl, 2′-hydroxy-biphenyl-4-yl, 2′-isopropoxy-biphenyl-4-yl, 2′-phenoxy-biphenyl-4-yl, 2′-piperidin-1-ylmethyl-biphenyl-4-yl, 2′-trifluoromethyl-biphenyl-4-yl, 3′,4′,5′-trimethoxy-biphenyl-4-yl, 3′,4′-dichloro-biphenyl-4-yl, 3′,5′-Bis-trifluoromethyl-biphenyl-4-yl, 3′-Chloro-4′-fluoro-biphenyl-4-yl, 3′-methoxy-biphenyl-4-yl, 3′-nitro)-biphenyl-4-yl], 3′-trifluoromethyl-biphenyl-4-yl, 3′-Acetylamino-biphenyl-4-yl, 3′-Benzyloxy-biphenyl-4-yl, Biphenyl-4-yl, 3′-Chloro-4′-fluoro-biphenyl-4-yl, 3-chloro-4-fluorophenoxy-biphenyl-4-yl, 3-fluoro-phenoxy-biphenyl-4-yl, 3-hydroxy-4-nitro-phenoxy, 3-hydroxy-4-nitro-phenoxy-phenyl, 3′-methoxy-biphenyl-4-yl, 3′-nitro-biphenyl-4-yl, 3′-phenoxy-biphenyl-4-yl, 3′-trifluoromethyl-biphenyl-4-yl, 4-(4′-Cyano-phenoxy)-phenyl, 4-(4′-Nitro-phenoxy)-phenyl, 4-(4-Trifluoromethyl-phenoxy)-phenyl, 4′-(Acetylamino-methyl)-biphenyl-4-yl, 4′-cyclohexyl-biphenyl-4-yl, 4′-methoxy-biphenyl-4-yl, 4′-Nitro-biphenyl-4-yl, 4′-trifluoromethyl-biphenyl-4-yl, 4′-Trifluoromethyl-biphenyl-4-yl, 4′-Amino-biphenyl-4-yl, 4′-Chloro-biphenyl-4-yl, 4-Cyano-phenoxy)-phenyl, 4′-cyclohexyl-biphenyl-4-yl, 4′-Dimethylamino-biphenyl-4-yl, 4-Formyl-phenoxy)-phenyl, 4′-Methanesulfonylamino-biphenyl-4-yl, 4′-methoxy-biphenyl-4-yl, 4-methoxy-phenoxy)-biphenyl-4-yl, 4′-pentyl-biphenyl-4-yl, 4′-phenoxy-biphenyl-4-yl, 4-Pyridin-4-yl-phenyl, 4-tert-Butyl-benzyloxy)-biphenyl-4-yl, 4′-tert-Butyl-biphenyl-4-yl, 4-tert-Butyl-phenoxy)-biphenyl-4-yl, 4-Thiophen-3-yl-phenyl, 4′-trifluoromethoxy-biphenyl-4-yl, 4-trifluoromethyl-phenoxy)-biphenyl-4-yl, 4-trifluoromethyl-phenoxy)-biphenyl-4-yl, 5′-Chloro-2′-methoxy-biphenyl-4-yl, 5′-Fluoro-2′-methoxy-biphenyl-4-yl, 5-nitro-biphenyl-3-carboxylic acid methyl ester, or 5-Phenyl-pyridin-2-yl, 6-phenyl-pyridin-3-yl, 4′-cyano-biphenyl-4-yl.
  • 18. The compound of Formula (I) in claim 1, wherein X comprises —CON(R8)— or —N(R8)CO— wherein R8 comprises hydrogen, (1−Acetyl-(2R)-pyrrolidin-2-yl)-methyl, (1-cyclopentanecarbonyl-(2S)-pyrrolidin-2-yl)-methyl, (biphenyl-4-carbonyl)-(2-biphenyl-4-yl-1-carboxy)-ethyl, 1-(2-methanesulfonyl-benzenesulfonyl)-(2R)-pyrrolidin-2-ylmethyl, 2-(1-methyl-1H-imidazole-4-sulfonylamino)-ethyl, 1-(2,2-dimethyl-propionyl)-(2S)-pyrrolidin-2-ylmethyl, 2-methanesulfonyl-benzenesulfonyl, 1-(2-thiophen-2-yl-acetyl)-(2R)-pyrrolidin-2-ylmethyl, 4-methanesulfonyl-benzenesulfonyl, 1-(4-methanesulfonyl-benzenesulfonyl)-(2R)-pyrrolidin-2-ylmethyl), 2-(1,2-dimethyl-1H-imidazole-4-sulfonylamino)-ethyl, 1-Acetyl-(2S)-pyrrolidin-2-ylmethyl, 1-cyclopentanecarbonyl-(2S)-pyrrolidin-2-ylmethyl, 2-(2-Acetylamino-4-methyl-thiazole-5-sulfonylamino)-ethyl, 2-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonylamino)-ethyl, 2-(2-methanesulfonyl-benzenesulfonylamino)-ethyl, 2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-ethyl, 2-(4-methanesulfonyl-benzenesulfonylamino)-ethyl, 2-(5-chloro-1,3-di methyl-1H-pyrazole-4-sulfonylamino)-ethyl, 2-(2,4-dimethoxy-benzylamino)-ethyl, 2-Amino-ethyl, 2-hydroxy-benzyl, (2-methanesulfonyl-benzenesulfonylamino)-ethyl, 2-tert-butoxycarbonylamino-ethyl, (2-thiophen-2-yl-acetyl)-pyrrolidine-2-methyl, 4-chloro-benzyl, 4-isopropyl-benzyl, 5-tert-butyl-2-hydroxy-benzyl, naphthalen-1-yl-methyl.
  • 19. The compound of Formula (I) in claim 1 comprising (2S)-[(Isoquinoline-3carbonyl)-amino]-3-(3;5′-bistrifluoromethyl-biphenyl-4-yl)-propionic acid.
  • 20. The compound of Formula (I) in claim 1 comprising 3-Biphenyl-4-yl-(2S)-{[7-(3-chloro-4-fluoro-phenyl)-isoquinoline-3-carbonyl]-amino}-propionic acid.
  • 21. The compound of Formula (I) in claim 1 comprising 3-Biphenyl-4-yl-(2S)-{[6-(3-chloro-4-fluoro-phenyl)-pyridine-2-carbonyl]-amino}-propionic acid.
  • 22. The compound of Formula (I) in claim 1 comprising 3-Hydroxy-napthalene-2carboxylic acid (2-biphenyl-4-yl-ethyl)-amide.
  • 23. The compound of Formula (I) in claim 1 comprising (2S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester.
  • 24. The compound of Formula (I) in claim 1 comprising (2S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester.
  • 25. The compound of Formula (I) in claim 1 comprising (2S)-[5-Bromo-2-(4-trifluoromethyl-benzyloxy)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid.
  • 26. The compound of Formula (I) in claim 1 comprising 3-Biphenyl-4-yl-(2S)-[5-bromo-2-(4-tert-butyl-benzyloxy)-benzoylamino]-propionic acid.
  • 27. The compound of Formula (I) in claim 1 comprising (2S)-[5-Bromo-2-(4-phenyl-butoxy)-benzoylamino]-3-(4′-phenoxy-biphenyl-4-yl)-propionic acid.
  • 28. The compound of Formula (I) in claim 1 comprising 3-Biphenyl-4-yl-(2S)-[(4′-trifluoromethyl -biphenyl-4-carbonyl)-amino]-propionic acid.
  • 29. The compound of Formula (I) in claim 1 comprising 3-Biphenyl-4-yl-(2S)-[(3′-chloro-4′-fluoro-biphenyl-4-carbonyl)-amino]-propionic acid.
  • 30. The compound of Formula (I) in claim 1 comprising 3-Biphenyl-4-yl-(2S)-[(4′-trifluoromethoxy-biphenyl-4-carbonyl)-amino]-propionic acid.
  • 31. The compound of Formula (I) in claim 1 comprising 3-Biphenyl-4-yl-(2S)-[(4′-tert-butyl-4-chloro-biphenyl-3-carbonyl)-amino]-propionic acid.
  • 32. The compound of Formula (I) in claim 1 comprising 3-(4′-Trifluoromethyl-biphenyl-4-yl)-(2S)-[4-(4-trifluoromethyl-phenoxy)-benzoylamino]-propionic acid.
  • 33. The compound of Formula (I) in claim 1 comprising (2S)-[(4′-Trifluoromethoxy-biphenyl-4-carbonyl)-amino]-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid.
  • 34. The compound of Formula (I) in claim 1 comprising 3-(4′-Trifluoromethoxy-biphenyl-4-yl)-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid.
  • 35. The compound of Formula (I) in claim 1 comprising 3-Biphenyl-4-yl-(2S)-{[4-(4-tert-butyl-benzoylamino)-3′-chloro-4′-fluoro-biphenyl-3-carbonyl]-amino}-propionic acid.
  • 36. The compound of Formula (I) in claim 1 comprising 3-Biphenyl-4-yl-(2S)-[5-bromo-2-(4-tert-butyl-benzenesulfonylamino)-benzoylamino]-propionic acid.
  • 37. The compound of Formula (I) in claim 1 comprising (2S)-{5-Chloro-2-[(naphthalen-1-ylmethyl)-amino]-benzoylamino}-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid.
  • 38. The compound of Formula (I) in claim 1 comprising 2S-[5-Chloro-2-(2-methyl-butylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid.
  • 39. The compound of Formula (I) in claim 1 comprising (2S)-[5-Chloro-2-(3-chloro-4-fluoro-phenylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid.
  • 40. A pharmaceutical composition comprising a therapeutically effective amount of the compound of Formula (I) as claimed in claim 1, and one or more pharmaceutically acceptable carriers, excipients, or diluents.
  • 41. The pharmaceutical composition of claim 40, wherein the compound of Formula (I) is an antagonist of factor IX activity.
  • 42. The pharmaceutical composition of claim 41, wherein the compound of Formula (I) is a partial antagonist of factor IX activity, wherein a partial antagonist comprises a compound that inhibits less than complete activity at a physiologically tolerable dose.
  • 43. The pharmaceutical composition of claim 42, wherein the compound of Formula (I) inhibits up to 95% of factor IX activity.
  • 44. The pharmaceutical composition of claim 42, wherein the compound of Formula (I) inhibits up to 80% of factor IX activity.
  • 45. The pharmaceutical composition of claim 42, wherein the compound of Formula (I) inhibits up to 50% of factor IX activity.
  • 46. The pharmaceutical composition of claim 41, wherein the compound of Formula (I) antagonizes blood clotting mediated by factor IX.
  • 47. The pharmaceutical composition of claim 40, wherein said therapeutically effective amount comprises a sufficient amount of the compound of Formula (I) to at least partially inhibit the biological activity of factor IX in a subject.
  • 48. The pharmaceutical composition of claim 40 wherein said therapeutically effective amount of Formula (I) comprises a sufficient amount of the compound of Formula (I) to at least partially inhibit the intrinsic clotting cascade in a subject.
  • 49. The pharmaceutical composition of claim 48, wherein said therapeutically effective amount of Formula (I) preferentially inhibits the intrinsic clotting cascade as compared to the extrinsic clotting cascade.
  • 50. The pharmaceutical composition of claim 48, wherein said therapeutically effective amount of Formula (I) inhibits the intrinsic clotting cascade by greater than 80% and inhibits the extrinsic clotting cascade by less than 50%.
  • 51. The pharmaceutical composition of claim 40, wherein said therapeutically effective amount of Formula (I) comprises a sufficient amount of the compound of Formula (I) for at least partial amelioration of at least one factor IX-mediated disease.
  • 52. The pharmaceutical composition of claim 40 in the form of an oral dosage or parenteral dosage unit.
  • 53. The pharmaceutical composition of claim 40, wherein said compound of Formula (I) is administered as a dose in a range from about 0.01 to 1,000 mg/kg of body weight per day.
  • 54. The pharmaceutical composition of claim 40, wherein said compound of Formula (I) is administered as a dose in a range from about 0.1 to 100 mg/kg of body weight per day.
  • 55. The pharmaceutical composition of claim 40, wherein said compound of Formula (I) is administered as a dose in a range from about 0.5 to 10 mg/kg of body weight per day.
  • 56. The pharmaceutical composition of claim 51, wherein said factor IX-mediated disease comprises stroke.
  • 57. The pharmaceutical composition of claim 51, wherein said factor IX-mediated disease comprises deep vein thrombosis.
  • 58. The pharmaceutical composition of claim 57, wherein said thrombosis is associated with surgical procedures, long periods of confinement, acquired or inherited pro-coagulant states including anti-phospholipid antibody syndrome, protein C deficiency and protein S deficiency, or acute and chronic inflammation including recurrent miscarriage or Systemic Lupus Erythmatosis (SLE).
  • 59. The pharmaceutical composition of claim 51, wherein said factor IX-mediated disease comprises excessive clotting associated with the treatment of kidney diseases by hemodialysis and/or venous hemofiltration.
  • 60. The pharmaceutical composition of claim 51, wherein said factor IX-mediated disease comprises cardiovascular disease.
  • 61. The pharmaceutical composition of claim 40, wherein said cardiovascular disease comprises myocardial infarction, arrhythmia, or aneurysm.
  • 62. The pharmaceutical composition of claim 40, wherein said composition is used to replace or supplement compounds that reduce clotting.
  • 63. The pharmaceutical composition of claim 40 further comprising one or more therapeutic agents.
  • 64. A method for the inhibition of the normal biological function of factor IX comprising administering to a subject in need thereof a compound of Formula (I) as claimed in claim 1.
  • 65. The method of claim 64, wherein said compound of Formula (I) is administered to said subject as a pharmaceutical composition comprising a therapeutically effective amount of said compound of Formula (I) and one or more pharmaceutically acceptable carriers, excipients, or diluents.
  • 66. The method of claim 64, wherein the compound of Formula (I) is an antagonist of factor IX activity.
  • 67. The method of claim 64, wherein said compound of Formula (I) is a partial antagonist of factor IX, wherein a partial antagonist comprises a compound that inhibits less than complete activity at a physiologically tolerable dose.
  • 68. The method of claim 67, wherein said compound of Formula (I) inhibits up to 95% of factor IX activity.
  • 69. The method of claim 67, wherein said compound of Formula (I) inhibits up to 80% of factor IX activity.
  • 70. The method of claim 67, wherein said compound of Formula (I) inhibits up to 50% of factor IX activity.
  • 71. The method of claim 64, wherein the compound of Formula (I) antagonizes blood clotting mediated by factor IX.
  • 72. The method of claim 64, wherein said compound of Formula (I) is administered in an amount sufficient to partially antagonize the biological activity of factor IX in said subject.
  • 73. The method of claim 65, wherein said therapeutically effective amount of the compound of Formula (I) comprises a sufficient amount of the compound of Formula (I) to at least partially inhibit the intrinsic clotting cascade in said subject.
  • 74. The method of claim 65, wherein said therapeutically effective amount of Formula (I) preferentially inhibits the intrinsic clotting cascade as compared to the extrinsic clotting cascade.
  • 75. The method of claim 65, wherein said therapeutically effective amount of Formula (I) inhibits the intrinsic clotting cascade by greater than 80% and inhibits the extrinsic clotting cascade by less than 50%.
  • 76. The method of claim 65, wherein said therapeutically effective amount of the compound of Formula (I) comprises a sufficient amount of the compound of Formula (I) for treatment or prevention of factor IX-mediated diseases.
  • 77. The method of claim 64, wherein said pharmaceutical composition is administered in the form of an oral dosage or parenteral dosage unit.
  • 78. The method of claim 64, wherein said compound of Formula (I) is administered as a dose in a range from about 0.01 to 1,000 mg/kg of body weight per day.
  • 79. The method of claim 64, wherein said compound of Formula (I) is administered as a dose in a range from about 0.1 to 100 mg/kg of body weight per day.
  • 80. The method of claim 64, wherein said compound of Formula (I) is administered as a dose in a range from about 0.5 to 10 mg/kg of body weight per day.
  • 81. The method of claim 76, wherein said factor IX-mediated disease comprises stroke.
  • 82. The method of claim 76, wherein said factor IX-mediated disease comprises deep vein thrombosis.
  • 83. The method of claim 82, wherein said thrombosis is associated with surgical procedures, long periods of confinement, acquired or inherited pro-coagulant states including anti-phospholipid antibody syndrome, protein C deficiency and protein S deficiency, or acute and chronic inflammation including recurrent miscarriage or Systemic Lupus Erythmatosis (SLE).
  • 84. The method of claim 76, wherein said factor IX-mediated disease comprises clotting associated with the treatment of kidney disease by hemodialysis and/or venous hemofiltration.
  • 85. The method of claim 76, wherein said factor IX-mediated disease comprises cardiovascular disease.
  • 86. The method of claim 85, wherein said cardiovascular disease comprises myocardial infarction, arrhythmia, or aneurysm.
  • 87. The method of claim 64, wherein said compound of Formula (I) is used to replace or supplement compounds that reduce clotting.
  • 88. The method of claim 65, wherein said pharmaceutical composition further comprises one or more therapeutic agents.
STATEMENT OF RELATED APPLICATION

[0001] The present application claims priority under 35 USC 119 from the following US Provisional Application: Serial No. 60/402,272, filed Aug. 9, 2002, entitled “Aryl and Heteroaryl Compounds and Methods to Modulate Coagulation,” the entirety of which is herein incorporated by reference.

Provisional Applications (1)
Number Date Country
60402272 Aug 2002 US