HK1115751A

HK1115751A - 2-[isoquinolin-s-carbonyl) amino] -propionic acid derivatives as inhibitors of factors xi and ix for the treatment of thrombosis

Info

Publication number: HK1115751A
Application number: HK08105883.1A
Authority: HK
Inventors: Adnan M.M. Mjalli; Devi Reddy Gohimmukkula; Sameer Tyagi
Original assignee: Transtech Pharma, Inc.
Priority date: 2005-03-01
Filing date: 2006-02-23
Publication date: 2008-12-05

Description

2- [ isoquinoline-S-carbonyl ] amino ] -propionic acid derivatives as inhibitors of factors XI and IX for the treatment of thrombosis

Statement of related application

This application is a partial continuation of U.S. application No.10/913,168 filed on 6.8.2004, which in turn claims priority from the following U.S. provisional patent applications, under section 119 of U.S. code 35: an application entitled "aryl and heteroaryl compounds as antiviral agents" filed 8/2003, serial No.60/493,879; an application entitled "aryl and heteroaryl compounds and methods of modulating red blood cell production" filed on 8/2003, serial No.60/493,878; an application entitled "aryl and heteroaryl compounds and methods for regulating coagulation" filed on 8/2003, serial No.60/493,903, which is incorporated herein by reference in its entirety.

Technical Field

The present invention relates to aryl and heteroaryl compounds and compositions that are antagonists of the intrinsic coagulation pathway due to binding to and inhibiting the function of factor XI or factor XI and IX, as well as methods of using these compounds and compositions.

Background

Hemostasis, which is the prevention of bleeding from injured blood vessels, requires synergistic efforts of blood vessels, platelets, and plasma factors to eventually form a hemostatic seal or clot. In normal hemostasis, the collective activity of these factors is balanced by regulatory mechanisms to limit the aggregation of platelets and fibrin in the damaged area.

After vascular injury, vascular factors reduce blood flow to the vessel by local constriction and compression of the injured vessel. At the same time, platelets adhere to the site of vessel wall injury and form aggregates known as tampons, which form the first key element of a hemostatic closure. Platelets also release factors, providing surface membrane sites and components for the formation of enzyme/cofactor complexes in the clotting reaction. Through a series of interactions and the propagation of zymogen activation, the activated form of one plasma factor catalyzes the activation of the next. This coagulation cascade ultimately forms a fibrin clot. The fibrin clot, the insoluble fibrin matrix that is released from and anchors the hemostatic plug, is the second key element of the hemostatic closure.

In particular, the coagulation cascade in question comprises two interdependent pathways, the intrinsic and extrinsic pathways. Both pathways ultimately catalyze the proteolytic activation of factor X to factor Xa conversion.

Damage to blood vessels or negatively charged surfaces initiates coagulation through the intrinsic pathway. As seen in fig. 1, the major components of the endogenous pathway include factor VIII (non-enzymatic cofactor) and factors IX and XI (zymogen serine proteases). Initiation of the endogenous pathway leads to activation of factor XI to factor XIa. The presence of factor XIa, and a factor vila/tissue factor complex associated with 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 the surface of the appropriate phospholipid, results in the formation of the X enzyme complex (10). The enzyme X complex catalyzes the conversion of factor Xa from the zymogen factor X.

Blood contact with injured tissue initiates coagulation by an extrinsic pathway. As seen in fig. 1, the main components of the exogenous pathway are factor VII (zymogen serine protease) and tissue factor (membrane bound protein). Tissue factor functions as a non-enzymatic cofactor essential for factor VII. Initiation of the extrinsic pathway is thought to be an autocatalytic event resulting from trace levels of activated factor VII (factor VIIa) activation of factor VII, both of which bind to newly exposed tissue factor on the membrane surface at the site of vascular injury (20). The factor VIIa/tissue factor complex directly catalyzes the formation of factor X into factor Xa.

Once the initial endogenous or exogenous cascade results in the activation of factor X, factor Xa catalyzes the penultimate step of the coagulation cascade, i.e., the formation of the serine protein thrombin. As seen in fig. 2, thrombin formation occurs when a prothrombinase complex, including factor Xa, non-enzyme cofactor Va and the substrate prothrombin, is assembled on a suitable phospholipid surface (30).

Once formed, thrombin acts as part of a feedback loop, controlling the activation of factors V and VIII. In addition, thrombin also catalyzes the activation of factor VIII and the conversion of fibrinogen to fibrin. Finally, factor VIIIa interacts with fibrin to catalyze the formation of a thrombus or cross-linked fibrin clot.

In normal hemostasis, the processes of clot formation (coagulation) and clot dissolution (fibrinolysis) are subtly balanced. A slight imbalance between the process of clot formation and dissolution can lead to excessive bleeding or thrombosis. Many significant disease states are associated with abnormal hemostasis. In the case of coronary vessels, abnormal thrombosis resulting from rupture of an established atherosclerotic plaque is a major cause of acute myocardial infarction and unstable angina. Furthermore, treatment of coronary thrombotic occlusions with thrombolytic therapy or Percutaneous Transluminal Coronary Angioplasty (PTCA) is often accompanied by acute thrombotic reclosure of the diseased vessel, which needs to be addressed immediately. In the case of venous vessels, patients undergoing major surgery in the lower limb or abdominal region suffer from a high proportion of venous vessel thrombosis, which can lead to reduced blood flow in the diseased limb and is a cause of pulmonary embolism. Disseminated intravascular coagulopathy commonly occurs in both vascular systems during septic shock, certain viral infections and cancer, and is characterized by rapid consumption of coagulation factors and by systemic coagulation, which leads to fatal thrombus formation throughout the vascular system, resulting in extensive organ failure.

Pathogenic thrombi in arterial vessels are a major clinical problem of modern medical concern. It is one of the leading causes of acute myocardial infarction, one of the causes of death in the western world. Recurrent arterial Thrombosis also remains one of the leading causes of failure of the occluded coronary vessels following enzymatic or mechanical recanalization with thrombolytic agents or Percutaneous Transluminal Coronary Angioplasty (PTCA), respectively [ Ross, a.m., Thrombosis in Cardiovascular disease Disorder, p.327, w.b. saunders Co. (fuse, v.and Verstraete, m.edit.1991); califf, r.m. and Willerson, j.t., id.atpp389 ]. In contrast to thrombotic events of venous vessels, arterial thrombi are the result of complex interactions between fibrin formation and cellular components, especially platelets, which form a large number of arterial thrombi, resulting from the coagulation cascade. Heparin, the most widely used clinically intravenously administered anticoagulant, has not shown universal effectiveness in treating or preventing acute arterial thrombosis or thrombosis reoccurrence [ Prins, m.h. and Hirsh, j., j.am.coll.cardiol., 67: 3A (1991) ].

In addition to unpredictable recurrent thrombotic reocclusion that typically occurs after PTCA, 1-6 months after this procedure, 30-40% of patients develop deep restenosis of the recanalization vessel [ Califf, r.m.et al, j.am.col.cardiol., 17: 2B (1991) ]. These patients need further treatment with repeated PTCA or coronary bypass surgery to relieve the newly formed stenosis. Restenosis of mechanically damaged vessels is not a process of thrombosis, but rather a result of a hyper-proliferative response of surrounding smooth muscle cells, which over time results in a decrease in the vessel lumen diameter of the diseased vessel due to the increased muscle mass. As for arterial thrombosis, there is currently no effective pharmacological therapy for preventing restenosis of the vessel after mechanical recanalization.

Many strategies have been developed for the treatment of thrombotic disorders. Many antithrombotic therapies are based on interference with the hemostatic system. Such methods have an inherent bleeding risk as the hemostatic system is no longer adequately responsive to the underlying injury. Thus, antithrombotic benefits are often associated with the risk of hemostasis. In an attempt to improve the benefit-to-risk ratio, antithrombotic agents are continually being developed. Different antithrombotic strategies include administration of universal inhibitors of thrombin formation, such as heparin or vitamin K antagonists; administering a specific thrombin inhibitor; administering a specific factor Xa inhibitor; and administering a platelet activation and adhesion inhibitor.

Evaluation of existing antithrombotic strategies in terms of antithrombotic benefit versus antithrombogenic risk ratio shows that the benefit-risk ratio tends to be better by interfering with the strategy at one particular step of the hemostatic system rather than at the more general stage [ L a. harker, Biomedical Progress vol8, 1995, 17-26 ]. For example, the development of specific inhibitors of factor Xa is an improvement over the general and specific thrombin inhibitors. However, this approach blocks the common (endogenous and exogenous) pathway of thrombin generation (see fig. 1), thereby blocking thrombin-dependent platelet activation. Thus, there is a need for more specific antithrombotic agents that selectively inhibit one hemostatic pathway by a single agent, while leaving the other pathway unaffected.

Summary of The Invention

The present invention provides compounds of formula (I or X), pharmaceutical compositions and methods of treating cardiovascular diseases. Embodiments of the invention provide compounds of formula (I or X) depicted below. Embodiments of the invention also provide methods of preparing compounds of formula (I or X) and pharmaceutical compositions comprising compounds of formula (I or X).

In another embodiment, the invention provides the use of compounds of formula (I or X) and pharmaceutical compositions comprising compounds of formula (I or X) in disorders of the human or animal body. .

By inhibiting the physiological activity of factor XI and/or factor IX and factor XI, compounds of formula (I or X) may be used as modulators of the intrinsic coagulation pathway. The compounds of formula (I or X) may be used in a variety of applications, including the treatment, control and/or as an adjunct to human diseases caused in part by the intrinsic coagulation pathway using factor XI/IX. These diseases or conditions include cardiopulmonary bypass, stroke, myocardial infarction, deep vein thrombosis associated with surgical procedures or long-term restriction, acute and chronic inflammation, and hemodialysis-related coagulation.

Brief Description of Drawings

The invention will be described with reference to the accompanying drawings, in which:

figure 1 depicts the intrinsic and extrinsic coagulation cascades, including the steps from time of injury to factor X activation.

FIG. 2 depicts the steps from formation of Xa to final thrombus formation after the initial intrinsic and extrinsic coagulation cascades.

Detailed Description

Normal hemostasis is associated with two coagulation pathways: endogenous and exogenous. These two coagulation pathways meet at the point of factor Xa formation (fig. 1 and 2). However, these two coagulation pathways are interdependent in that complete elimination of the intrinsic pathway can lead to uncontrolled bleeding. For example, hemophilia B completely lacks factor IX or factor IX function and has a phenotype characterized by severe bleeding disorders. Thus, direct factor VIIa/tissue factor directly activated factor X, which bypasses the need for factor VIII and factor IX, is not sufficient for normal hemostasis. In contrast, the formation of factor VIIIa/IXa phospholipid factor X activator (enzyme X complex) (20) is essential for normal hemostasis.

Selective inhibition of the intrinsic coagulation pathway with a factor XI antagonist or a double factor XI/IX antagonist may provide a means to inhibit the coagulation cascade associated with some surgeries, stroke, myocardial infarction, and hemodialysis, while preserving the coagulation pathway associated with external injury, such as trauma or intact abscess. Factors XI and IX are primarily involved in the intrinsic coagulation pathway. Antagonists that are active on factor XI or dual active on factor XI/IX may have therapeutic benefit in diseases associated with the intrinsic coagulation pathway by inhibiting intravascular thrombosis. In addition, antagonists of factor XI or dual antagonists of factor XI/IX do not have the deleterious or uncontrollable bleeding side effects by impairing extravascular hemostasis associated with healing wounds.

Some point mutations in factor IX partially inhibit its function and result in a mild or moderate phenotype that manifests as a non-fatal bleeding disorder [ Bowen, d.j., j.clin.pathol: mol. Pathol.55: 1-18(2002)]. These point mutations result in factor IX behaving as if it were subjected to partial antagonists. Factor IX should retain some activity in the presence of site antagonists, even partial antagonists at saturating levels. As a result of the point mutation of factor IX, its activity is reduced along with intrinsic pathway-associated coagulation, but some residual activity remains, leaving the extrinsic pathway intact. Furthermore, antibodies against the gamma-carboxyglutamic acid domain of factor XI have shown efficacy in animal models of thrombosis without an increase in bleeding time. [ Refino, CJ., et. alpha.l.TlimombHaemost82 (3)1188-1195(1999) ].

The present invention provides compounds of formula (I or X), pharmaceutical compositions and methods of inhibiting coagulation activity of factor XI and/or factor IX and factor XI. Inhibition of hemostasis by agents that selectively inhibit the endogenous pathway of factor X activation can leave the extrinsic pathway intact and allow the formation of small but hemostatic-important amounts of factor Xa and thrombin.

Embodiments of the invention provide compounds of formula (I or X) depicted below. Embodiments of the invention also provide methods of preparing compounds of formula (I or X) and pharmaceutical compositions comprising compounds of formula (I or X).

In another embodiment, the invention provides the use of compounds of formula (I or X) and pharmaceutical compositions comprising compounds of formula (I or X) for the treatment of disorders in humans or animals. By inhibiting the biological activity of factor XI and/or factor IX and factor XI, compounds of formula (I or X) may be used as modulators of the intrinsic coagulation pathway. The compounds of formula (I or X) may be used in a variety of applications, including the treatment, control and/or as an adjunct to human diseases caused in part by the intrinsic coagulation pathway using factor XI/IX. These diseases or disease states include cardiopulmonary bypass, stroke, myocardial infarction, deep vein thrombosis associated with surgical procedures or long-term restriction, acute and chronic inflammation, and hemodialysis-related coagulation.

In a first aspect, the present invention provides compounds comprising at least one moiety of formula (I or X).

In one aspect, the invention provides a compound represented by formula I:

Ar₂-K

(I)

wherein the content of the first and second substances,

Ar₂including aryl, heteroaryl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl or fused heterocyclylheteroaryl optionally substituted 1-7 times. In one embodiment, Ar₂Including aryl, heteroaryl or fused arylheterocyclyl optionally substituted 1-7 times. In another embodiment, Ar₂Including optionally substituted 1-7 times phenyl, naphthyl, pyridyl, indolyl, isoquinolinyl, pyrimidinyl, tetrahydroisoquinolinyl, quinoxazoyl, or quinazolinyl. In another embodiment, Ar₂Including substituted phenyl, 2-naphthyl, 2-pyridyl, 3-isoquinolinyl, 2-pyrimidinyl, 2-quinazolinyl, or 3-tetrahydroisoquinolinyl having 1-5 substituents, wherein the substituents independently include:

a) -fluorine;

b) -chlorine;

c) -bromine;

d) -iodine;

e) -a cyano group;

f) -a nitro group;

g) -a perfluoroalkyl group;

h)-T₁-R₂₀；

i) -an alkyl group;

j) -an aryl group;

k) -a heteroaryl group;

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-alkyl;

y)-T₁-an alkyl group;

z)-T₁-an aryl group;

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-an aryl group;

mm)-T₁-arylene-aryl;

nn)-T₁-alkylene-arylene-alkyl;

oo) -alkylene-T₁-alkylene-aryl;

pp) -arylene-T₁-an alkyl group;

qq) -arylene-T₁-alkylene-aryl;

rr)-T₁-alkylene-T₂-an aryl group;

ss)-T₁-alkylene-aryl;

tt) -alkylene-T₁-a heteroaryl group;

uu) -alkylene-T₁-a cycloalkyl group;

vv) -alkylene-T₁-a heterocyclic group;

ww) -alkylene-T-arylene-alkyl;

xx) -alkylene-T₁-alkylene-arylene-alkyl;

yy) -alkylene-T₁-an alkyl group;

zz) -alkylene-T₁-R₂₀；

aaa) -arylene-T₁-R₂₀；

bbb) -alkylene-cycloalkyl;

ccc)-T₁-arylene-T₂-alkylene-aryl;

ddd)-T₁-arylene-aryl;

eee)-T₁-alkylene-cycloalkyl;

fff)-T₁-a cycloalkyl group;

ggg)-T₁-heterocyclyl-T₂-an aryl group;

hhh)-T₁-an alkynyl group;

iii)-T₁-alkylene-T₂-an alkyl group; or

jjj) -hydrogen;

wherein T is₁comprising-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)-、

Or

And wherein R₂₀、R₂₁、R₂₂And R₂₃Independently comprising: -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 is

Wherein T is₂Comprising 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 R₂₄And R₂₅Independently comprising: -hydrogen, -alkyl, -alkenyl, -alkylene-cycloalkyl, alkynene-heterocyclyl, -aryl, -heteroaryl, -arylene-alkyl, -alkylene-aryl, and-alkylene-arylene-alkyl.

In another embodiment, Ar₂Including substituted phenyl, 2-naphthyl, 2-pyridyl, 3-isoquinolinyl, 2-pyrimidinyl, or 2-quinazolinyl having 1-5 substituents independently including:

a) -fluorine;

b) -chlorine;

c) -bromine;

d) -iodine;

e) -a cyano group;

f) -a nitro group;

g) -a perfluoroalkyl group;

h)-T1-R20；

i) -an alkyl group;

j) -an aryl group;

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 T is₁comprising-CH₂-、-O-、-N(R₂₁)-、-CON(R₂₁) -or-N (R)₂₁) C (O) -; wherein R is₂₀And R₂₁Independently comprising: -hydrogen, -alkyl or-aryl.

K comprises a group of the formula:

wherein the content of the first and second substances,

c is equal to 0, 1 or 2; wherein the values of 0, 1 and 2 include a direct bond, -CH optionally substituted 1-4 times by a substituent₂-and-CH₂-CH₂-, wherein said substituents or term substitution is meant to include: -alkyl, -aryl, -alkylene-aryl, -arylene-alkyl, -alkylene-arylene-alkyl, -O-aryl, or-hydroxy. In one embodiment, c is equal to 0 or 1. In another embodiment, c is equal to 0.

G comprises: -hydrogen, -CO₂R₁、-CH₂OR₁、-C(O)-R₁、-C(R₁)＝N-O-R₂、-C(O)N(R₁)(R₂)、-C(O)-NH-NH₂Acid isostere or ester isostere, wherein R₁And R₂Independently comprising: -hydrogen, -alkyl, alkoxy, alkylhydroxy, alkyl-N, N' -dialkyl-amino, alkyl-amino-acyl, -aryl, -arylene-alkyl, -alkylene-aryl, -alkylene-arylene-alkyl, or when R is₁And R₂When bonded to the nitrogen group in G, R₁And R₂Can be combined to form a compound having the formula- (CH)₂)_m-Z₂-(CH₂)_nWherein m and n are independently 1, 2, 3 or 4; z₂comprising-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(R₂₄)-、-N(C(O)R₂₄)-、-N(C(O)NHR₁₂)-、-N(S(O₂)NHR₂₄)-、-N(SO₂R₂₄) -OR-N (C (O) OR)₂₄) -; wherein R is₂₄Including hydrogen, aryl, alkyl or alkylene-aryl. In one embodiment, G comprises: -hydrogen, -CO₂R₁、-CH₂OR₁、-C(O)-R₁、-C(R₁)＝N-O-R₂Or an acidic isostere; wherein R is₁And R₂Independently comprising: -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl or-alkylene-arylene-alkyl. In another embodiment, G comprises: -hydrogen or-CO₂R₁(ii) a Wherein R is₁The method comprises the following steps: -hydrogen, -alkyl or-aryl. In another embodiment, G comprises: -hydrogen or-CO₂H. In another embodiment, G comprises: -CO₂R₁Or an ester isostere wherein R₁Including-alkyl, -alkylene-aryl or-aryl.

R₃The method comprises the following steps: hydrogen, -alkyl, alkylene-aryl, or-alkylene-cycloalkyl. In one embodiment, R₃The method comprises the following steps: and (3) hydrogen. In another embodiment, R₃The method comprises the following steps: -alkyl, alkylene-aryl or-alkylene-cycloalkyl.

R₄The method comprises the following steps: hydrogen, -alkyl, -alkylene-cycloalkyl or-alkylene-heterocyclyl, -alkylene.

R₅The method comprises the following steps: hydrogen, -alkyl, -alkylene-cycloalkyl, -alkylene-heterocyclyl, -alkoxy, alkylhydroxy, alkyl-N, N' -dialkyl-amino or-alkyl-amino-acyl. In one embodiment, R₄The method comprises the following steps: hydrogen, and R₅The method comprises the following steps: alkyl, -alkoxy, alkylhydroxy or-alkylene-cycloalkyl.

J₁、J₂、J₃、J₄、J₅Independently comprise-C (R)₂₅)(R₂₆) -or a direct bond, wherein R₂₅And R₂₆Independently include hydrogen, -alkyl, -aryl, -alkylene-aryl, alkoxy, alkylhydroxy, alkylene-O-alkyl, alkylene-O-alkylene-aryl, -CO₂H. alkylene-CO₂H、-CO₂-alkyl or-alkylene-CO₂-alkyl, -acid isostere or-ester isostere and wherein the ring comprises nitrogen, J₁-J₅Containing at least 4 carbon atoms, J₁-J₅At least 1 of which is-CO₂H. alkylene-CO₂H、-CO₂-alkyl or-alkylene-CO₂-alkyl, -acidic isostere or-ester isostere substitution.

Z₁comprising-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(R₆)-、-N(C(O)R₆)-、-N(C(O)NHR₆)-、-N(S(O₂)NHR₆)-、-N(SO₂R₆) -OR-N (C (O) OR)₆) -; wherein R is₆The method comprises the following steps: -hydrogen, alkyl, aryl or alkylene-aryl. In one embodiment, Z₁comprising-CH₂-、-O-、-N(H)-、-S-、-S(O₂)-、-N(R₆) -OR-N (C (O) OR)₆) -, wherein R₆Including alkyl or alkylene-aryl.

V includes: - (CH)₂)_b-S-(CH₂)_a-、-(CH₂)_b-S-、-S-(CH₂)_a-、-(CH₂)_b-S(O₂)-(CH₂)_a-、-(CH₂)_b-S(O₂)-、-S(O₂)-(CH₂)_a-、-(CH₂)b-O-(CH₂)_a、-(CH₂)_b-N(R₇)-(CH₂)_a、-(CH₂)_b-O-、-(CH₂)_b-N(R₇)、-(CH₂)_a-or a direct bond; wherein a is equal to 0, 1 or 2, b is equal to 1 or 2, and R₇The method comprises the following steps:-hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or-alkylene-arylene-alkyl; wherein the values of 0, 1 and 2 include a direct bond, -CH optionally substituted 1-4 times by a substituent₂-and-CH₂-CH₂-, wherein said substituents or term substitution is meant to include: -alkyl, -aryl, -alkylene-aryl, -arylene-alkyl, -alkylene-arylene-alkyl, -O-aryl, or-hydroxy. In one embodiment, V comprises: - (CH)₂)_b-O-(CH₂)_a-、-(CH₂)_b-N(R₇)-(CH₂)_a-、-(CH₂)_b-O-、-(CH₂)_b-N(R₇)、-(CH₂)_a-or a direct bond; wherein a is equal to 0, 1 or 2, b is equal to 1 or 2, and R₇The method comprises the following steps: -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or-alkylene-arylene-alkyl; wherein the values of 0, 1 and 2 include a direct bond, -CH optionally substituted 1-4 times by a substituent₂-and-CH₂-CH₂-, wherein said substituents or term substitution is meant to include: -alkyl, -aryl, -alkylene-aryl, -arylene-alkyl, -alkylene-arylene-alkyl, -O-aryl, or-hydroxy. In another embodiment, V comprises: - (CH)₂)_a-、-(CH₂)_b-O-(CH₂)_a-or a direct bond, wherein a equals 1 or 2 and b equals 1. In another embodiment, V comprises: - (CH)₂)_a-or a direct bond, wherein a equals 1.

X comprises: -N (R)₈)-、-CON(R₈)-、-N(R₈)CO-、-N(R₈)CON(R₉)-、-OC(O)N(R₈)-、-SO₂N(R₈) -or-N (R)₈)SO₂N(R₉) -; wherein R is₈And R₉Independently comprising: -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) -yaalkyl-N- (R)₁₀)(R₁₁) Or an-alkylene-cycloalkyl group, or a-alkylene-cycloalkyl group,

wherein R is₁₀Including H, alkyl, alkylene-aryl, alkylene-heteroaryl, aryl, or heteroaryl, and R₁₁Including 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)₂Alkylene-aryl radicals, -S (O)₂Alkylene-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;

R₁₀and R₁₁Can be combined to form₁₀And R₁₁Bound to a nitrogen or carbon atom of the formula- (CH)₂)_m-Z₂-(CH₂)_n-wherein m and n are independently 1, 2, 3 or 4; z₂Independently comprise-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) OR)₁₂) -; or

R₁₀And R₁₁May form a heterocyclyl or heteroaryl ring with the nitrogen or carbon atom to which it is attached.

R₁₂Including hydrogen, aryl, alkyl, or alkylene-aryl;

in one embodiment, X comprises: -N (R)₈)-、-CON(R₈)-、-N(R₈) CO-or-N (R)₈)CON(R₉) -, wherein R₈And R₉Independently comprising: -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl or-alkylene-arylene-alkyl. In another embodiment, X comprises: -N (R)₈)-、-CON(R₈) -or-N (R)₈) CO-, wherein R₈The method comprises the following steps: -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl or-alkylene-arylene-alkyl. In another embodiment, X comprises-CON (R)₈) -, wherein R₈Including-hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, -alkylene-arylene-alkyl, or-alkylene-cycloalkyl.

Ar₁Including aryl, heteroaryl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl or fused heterocyclylheteroaryl optionally substituted 1-7 times. In one embodiment, Ar₁Including monocyclic or bicyclic aryl or heteroaryl optionally substituted 1-7 times. In another embodiment, Ar₁Including optionally substituted 1-7 times phenyl, pyridyl, indolyl, naphthyl, thiophenyl, thiazole, or benzothiazole. In another embodiment, Ar₁Including phenyl having 1-5 substituents, wherein the substituents independently include:

a) -fluorine;

b) -chlorine;

c) -bromine;

d) -iodine;

e) -a cyano group;

f) -a nitro group;

g) -a perfluoroalkyl group;

h)-D₁-R₁₄；

i) -an alkyl group;

j) -an aryl group;

k) -a heteroaryl group;

l) -heterocyclyl;

m) -cycloalkyl;

n) -alkylene-aryl;

o) -alkylene-heteroaryl;

p) -alkylene-arylene-D₁-R₁₄；

q) -alkylene-heteroarylene-D₁-R₁₄；

r) -alkylene-arylene-aryl;

s) -alkylene-heteroarylene-aryl;

t) -alkylene-arylene-heteroaryl;

u) -alkylene-arylene-D₁-R₁₄；

v) -alkylene-arylene-alkyl;

w) -alkylene-heteroarylene-alkyl;

x) y) -arylene-cycloalkyl;

z) -heteroarylene-alkyl;

aa) -arylene-alkyl;

bb)-D₁-an alkyl group;

cc)-D₁-an aryl group;

dd)-D₁-a heteroaryl group;

ee)-D₁-arylene radical-D₂-R₁₄；

ff)-D₁-heteroarylene-D₂-R₁₄；

gg)-D₁-alkylene-heteroaryl;

hh)-D₁-alkylene-aryl;

ii)-D₁alkylene-arylene-D₂-R₁₄；

jj)-D₁alkylene-heteroarylene-D₂-R₁₄；

kk)-D₁-arylene-alkyl;

ll)-D₁-heteroarylene-alkyl;

mm)-D₁-alkylene-arylene-aryl;

nn)-D₁-alkylene-heteroarylene-aryl;

oo)-D₁-arylene-aryl;

pp)-D₁-alkylene-arylene-alkyl;

qq)-D₁-alkylene-heteroarylene-alkyl;

ss) -alkylene-D₁-alkylene-aryl;

tt) -alkylene-D₁alkylene-arylene-D₂-R₁₄；

uu) -arylene-D₁-an alkyl group;

vv) -arylene-D₁-a cycloalkyl group;

ww) -arylene-D₁-a heterocyclic group;

xx) -alkylene-D₁-an aryl group;

y) -alkylene-D₁-a heteroaryl group;

zz) -alkylene-D₁-arylene radical-D₂-R₁₄；

aaa) -alkylene-D₁-heteroarylene-D₂-R₁₄；

bbb) -alkylene-D₁-a heteroaryl group;

ccc) -alkylene-D₁-a cycloalkyl group;

ddd) -alkylene-D₁-a heterocyclic group;

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-an alkyl group;

jjj) -alkylene-D₁-R₁₄；

kkk) -arylene-D₁-R₁₄；

lll) -heteroarylene-D₁-R₁₄；

mmm)-D₁-an alkynyl group;

nnn)-D₁-alkylene-cycloalkyl;

ooo) -arylene-D₁-arylene radical-D₂-R₁₄(ii) a Or

ppp) -hydrogen;

wherein D₁comprising-CH₂-, - (alkylene-) -, - (alkenylene-) -, - (alkylene-S-) -, - (S-alkylene-) -, - (alkylene-O-) -, - (O-alkylene-) -, - (alkylene-S-) - (O)₂-、-S(O)₂Alkylene, -O-, -N (R)₁₅)-、-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)-、

Or

And wherein R₁₄、R₁₅、R₁₆And R₁₇Independently comprising: -hydrogen, -alkyl, -aryl, -heteroaryl, -arylene-alkyl, -heteroarylene-alkyl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene-arylene-alkyl, or-alkylene-heteroarylene-alkyl.

D₂comprising-CH₂-, - (alkylene-) -, - (alkenylene-) -, - (alkylene-S-) -, - (S-alkylene-) -, - (alkylene-O-) -, - (O-alkylene-) -, - (alkylene-S-) - (O)₂-、-S(O)₂Alkylene, -O-, -N (R)₁₈)-、-C(O)-、-CON(R₁₈)-、-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 R₁₈And R₁₉Independently comprising: -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl or-alkylene-arylene-alkyl.

In another embodiment, Ar₁Including mono-substituted phenyl, wherein the substituents include: -aryl, -arylene-alkyl, -D₁-aryl, -D₁Alkylene-arylene-alkyl or-arylene-D₁-an alkyl group; wherein D₁comprising-O-, -N (R)₁₅)-、-CON(R₁₅) -or-N (R)₁₅) C (O) -, and wherein R₁₅The method comprises the following steps: -hydrogen, -alkyl or-aryl.

In another embodiment, Ar₁Comprising a phenyl group substituted with at least one of the following substituents:

-D₁-R₁₄；

-an alkyl group;

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-arylene-alkyl;

-D₁-an alkyl group;

-D₁-an aryl group;

-D₁-a heteroaryl group;

-D₁-arylene radical-D₂-R₁₄；

-D₁-alkylene-heteroaryl;

-D₁-alkylene-aryl;

-D₁alkylene-arylene-D₂-R₁₄

-arylene radical-D₁-an alkyl group;

alkylene-D₁-an alkyl group;

alkylene-D₁-R₁₄；

-arylene radical-D₁-R₁₄；

-D₁-an alkynyl group;

-D₁-alkylene-cycloalkyl;

-arylene radical-D₁-arylene radical-D₂-R₁₄

Wherein the content of the first and second substances,

D₁and D₂Independently comprising: -O-or-S (O)₂) -, and

R₁₄including hydrogen, -alkyl-aryl, -arylene-aryl, -alkylene-aryl.

In another embodiment, Ar₁Including unsubstituted phenyl or biphenyl.

Ar₁、Ar₂、R₁-R₂₆The alkyl, aryl, heteroaryl, alkylene and arylene groups in (a) may be optionally substituted 1-4 times with a substituent, wherein the substituent or term substituted refers to a group comprising the following substituents:

a) -hydrogen;

b) -fluorine;

c) -chlorine;

d) -bromine;

e) -iodine;

f) -a cyano group;

g) -a nitro group;

h) -a perfluoroalkyl group;

i) -Q-perfluoroalkyl;

j)-Q-R27；

k) -Q-alkyl;

l) -Q-aryl;

m) -Q-alkylene-aryl;

n) -Q-alkylene-NR₂₇R₂₈(ii) a Or

o) -Q-alkyl-W-R₂₈；

Wherein Q and W independently comprise: -CH₂-、-O-、-N(R₂₉)-、-C(O)-、-CON(R₂₉)-、-N(R₂₉)C(O)-、-N(R₂₉)CON(R₃₀)-、-N(R₂₉)C(O)O-、-OC(O)N(R₂₉)-、-N(R₂₉)SO₂-、-SO₂N(R₂₉) -, -C (O) -O-, -O-C (O) -or-N (R)₂₉)SO₂N(R₃₀) -, wherein R₂₇、R₂₈、R₂₉And R₃₀Independently comprising: -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl or-alkylene-arylene-alkyl.

In another embodiment, the compounds are represented by formula (I), wherein c is equal to 0; g comprises: -hydrogen or-CO₂H; v includes: -CH₂-or a direct bond; x comprises: -CON (R)₈) -or-N (R)₈) CO-, wherein R₈The method comprises the following steps: -hydrogen; ar (Ar)₁Including mono-substituted phenyl, wherein the substituents include: -aryl, -arylene-alkyl, -D₁-aryl, -D₁Alkylene-arylene-alkyl or-arylene-D₁-alkyl, wherein D₁comprising-O-or-N (R)₁₅) -, wherein R₁₅The method comprises the following steps: -hydrogen, -alkyl or-aryl; and Ar₂Including substituted phenyl, 2-naphthyl, 2-pyridyl, 3-isoquinolinyl, 2-pyrimidinyl, or 2-quinazolinyl having 1-5 substituents independently including: -hydrogen, -fluoro, -chloro, -bromo, iodo, -cyano, -nitro, -perfluoroalkyl, -T₁-R₁₄-alkyl, -aryl, -arylene-alkyl, -T₁-alkyl, -T₁-alkylene-aryl, -T₁Alkylene-arylene-aryl, -T₁Alkylene-arylene-alkyl or-arylene-T₁-an alkyl group; wherein T is₁comprising-CH₂-、-O-、-N(R₂₁)-、-CON(R₂₁) -or-N (R)₂₁) C (O) -; wherein R is₂₁The method comprises the following steps: -hydrogen, -alkyl or-aryl. Ar (Ar)₁And Ar₂The alkyl, aryl, alkylene and arylene groups in (a) may be optionally substituted 1-4 times with a substituent, wherein said substituent or term substituted is meant to include: -hydrogen, -fluoro, -chloro, -bromo, iodo, -cyano, -nitro or-perfluoroalkyl.

In another embodiment, the present invention relates to a compound of formula (X), or a pharmaceutically acceptable salt, ester, or prodrug thereof:

wherein the content of the first and second substances,

R₁₀₁is selected from-H or-CH₂-thienyl, wherein-CH₂The thienyl group of the-thienyl group being optionally substituted by-Br or-CH₃Substitution;

R₁₀₂selected from the group consisting of-C (O) OH, -C (O) OCH₃-C (O) O-tert-butyl, -C (O) NH-OCH₂-phenyl, -C (O) NHOH and-C (O) NHSO₂CH₃；

R₁₀₃Is selected from-H, -CH₂-thienyl, -CH₂-phenyl, -CH₂-furyl, -thienyl and benzothienyl, wherein R₁₀₃Each of the above possibilities except-H is optionally substituted with one or more members selected from the group consisting of:

-H、-CH₃、-CF₃、-Cl、-Br、-F、-C(O)CH₃、-CH₂CH₃、-CH＝CH₂、-CH₂OH、-CH(CH₃)₂、-CH₂CH₂CH₃、

-propenyl, -3, 3-dimethyl-butenyl, -isopropenyl, -phenyl, -phenylene-methyl, -phenylene-propyl, -phenylene-trifluoromethyl, -phenylene-chloride, -cyclopentyl, -cyclopentenyl and-furanyl;

R₁₀₄selected from the group consisting of-O-cyclohexylidene-ethyl, -O-cyclohexylidene-tert-butyl, -O-cyclohexylidene-isopropyl, -O-phenylene-tert-butyl, and-c (O) -phenylene-tert-butyl;

and Y is selected from the group consisting of-H, -methylene-cyclopentyl, -amino-cyclohexyl, -methylene-thienylene-methyl, methylene-thienylene-bromide, and tetrahydrop-pyranyl.

wherein the content of the first and second substances,

R₁₀₃Is selected from-H, -CH₂-thienyl, -CH₂-phenyl, -CH₂-furyl, thienyl and benzothienyl, wherein R is other than-H₁₀₃Each of the above possibilities of (a) is optionally substituted with one or more members selected from the group consisting of:

-propenyl, -3, 3-dimethyl-butenyl, -isopropenyl, -phenyl, -phenylene-methyl, phenylene-trifluoromethyl, -phenylene-chloride, cyclopentyl, cyclopentenyl and furanyl;

and Y is selected from the group consisting of-H, -methylene-cyclopentyl, -amino-cyclohexyl, -methylene-thienylene-methyl, methylene-thienylene-bromide, and tetrahydropyranyl.

The present invention also relates to compounds of formula (X), or a pharmaceutically acceptable salt, ester, or prodrug thereof:

wherein R is₁₀₁Is selected from-H or-CH₂-thienyl, wherein-CH₂The thienyl group of the-thienyl group being optionally substituted by-Br or-CH₃Substitution;

R₁₀₃Is selected from-H, -CH₂-thienyl, -CH₂-phenyl, -CH₂-furyl, thienyl and benzothienyl, wherein R₁₀₃Each of the above possibilities, except-H, is optionally substituted with one or more members selected from the group consisting of: -H, -CH₃、-CF₃、-Cl、-Br、-F、-C(O)CH₃、-CH₂CH₃、-CH＝CH₂、-CH₂OH、-CH(CH₃)₂、-CH₂CH₂CH₃、

R₁₀₄Selected from the group consisting of:

and Y is selected from the following groups: -a source of hydrogen (H),

another embodiment are where R is₁₀₄Is thatAnd R is₁₀₃Is that

Optionally substituted-CH₂-2-yl-thienyl or optionally substituted-CH₂-phenyl compounds. Furthermore, another embodiment relates to wherein R₁₀₁A compound which is-H and a compound wherein Y is selected from the group consisting of:

in another embodiment, Y is-methylene-cyclopentyl.

In another embodiment, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (X), or a pharmaceutically acceptable salt, ester, or prodrug thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents:

R₁₀₃Is selected from-H, -CH₂-thienyl, -CH₂-phenyl, -CH₂-furyl, thiopheneA group and a benzothienyl group, wherein R₁₀₃Each of the above possibilities, except-H, is optionally substituted with one or more members selected from the group consisting of: -H, -CH₃、-CF₃、-Cl、-Br、-F、-C(O)CH₃、-CH₂CH₃、-CH＝CH₂、-CH₂OH、-CH(CH₃)₂、-CH₂CH₂CH₃、

R₁₀₄Selected from the group consisting of:

and Y is selected from the following groups: -a source of hydrogen (H),

and

other embodiments are wherein R₁₀₄Is thatAnd wherein R₁₀₃Is optionally substituted-CH₂-2-yl-thienyl or optionally substituted-CH₂-a phenyl group.

In another embodiment, R₁₀₃Is optionally substituted-CH₂-2-yl-thienyl.

Other embodiments are pharmaceutical compositions of compounds having the formula (X) above, wherein R₁₀₁Is H, or Y is selected from the following groups:

more particularly Y is-methylene-cyclopentyl.

The present invention also relates to a method of inhibiting the normal biological function of factor IX comprising administering to a subject a compound of formula (X), or a pharmaceutically acceptable salt, ester or prodrug thereof:

R₁₀₃Is selected from-H, -CH₂-thienyl, -CH₂-phenyl, -CH₂-furyl, thienyl and benzothienyl, wherein R₁₀₃Each of the above possibilities except-H is optionally substituted with one or more members selected from the group consisting of: -H, -CH₃、-CF₃、-Cl、-Br、-F、-C(O)CH₃、-CH₂CH₃、-CH＝CH₂、-CH₂OH、-CH(CH₃)₂、-CH₂CH₂CH₃、

R₁₀₄Selected from the group consisting of:

and Y is selected from the following groups: -a source of hydrogen (H),

in another embodiment, the invention relates to a method of inhibiting the normal biological function of factor IX, wherein the compound of formula (X) is delivered as part of a pharmaceutical composition.

In another embodiment, the method of inhibiting the normal biological function of factor IX uses a compound of formula (X), wherein R₁₀₄Is thatOr, wherein R₁₀₃Is optionally substituted-CH₂-2-yl-thienyl or optionally substituted-CH₂-phenyl.

Another embodiment is a method of inhibiting the normal biological function of factor IX, wherein a compound of formula (X) is administered, and R₁₀₁is-H. Or wherein Y is selected from the group consisting of:

another method of inhibiting the normal biological function of factor IX is to administer a compound in which Y is-methylene-cyclopentyl.

In another embodiment, the invention includes a method of treating stroke, myocardial infarction, aneurysm, or thrombosis comprising administering to a subject a compound of formula (X), or a pharmaceutically acceptable salt, ester, or prodrug thereof:

And Y is selected from the following groups: -H and

in another embodiment, a method of treating a disease listed above comprises administering a compound of formula (X) as part of a pharmaceutical composition.

In another embodiment, a method of treating a disease listed above comprises administering a compound of formula (X), wherein R is₁₀₄Is thatOr wherein R is₁₀₃Is optionally substituted-CH₂-2-yl-thienyl or optionally substituted-CH₂-phenyl. The method according to claim 30, wherein R₁₀₁is-H.

A method of treating the diseases listed above uses a compound selected from the group consisting of:

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-phenyl-thiophen-2-yl) -propionic acid;

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- [5- (4-trifluoromethyl-phenyl) -thiophen-2-yl ] -propionic acid;

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-cyclopent-1-enyl-thiophen-2-yl) -propionic acid methyl ester;

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-cyclopent-1-enyl-thiophen-2-yl) -propionic acid;

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-cyclopentyl-thiophen-2-yl) -propionic acid methyl ester;

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-cyclopentyl-thiophen-2-yl) -propionic acid;

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-furan-3-yl-thiophen-2-yl) -propionic acid;

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- [5- (4-isopropyl-phenyl) -thiophen-2-yl ] -propionic acid;

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-vinyl-thiophen-2-yl) -propionic acid;

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-p-tolyl-thiophen-2-yl) -propionic acid;

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- [5- (4-chloro-phenyl) -thiophen-2-yl ] -propionic acid;

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-ethyl-thiophen-2-yl) -propionic acid;

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3-furan-2-yl-propionic acid;

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (2-trifluoromethyl-phenyl) -propionic acid;

{ (5-bromo-thiophen-2-ylmethyl) - [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -acetic acid tert-butyl ester;

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (3, 5-difluorophenyl) -propionic acid;

[ [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] - (5-methyl-thiophen-2-ylmethyl) -amino ] -acetic acid;

{ (5-bromo-thiophen-2-ylmethyl) - [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -acetic acid methyl ester;

{ (4-bromo-thiophen-2-ylmethyl) - [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -acetic acid;

{ (5-bromo-thiophen-2-ylmethyl) - [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -acetic acid;

benzo [ b ] thiophen-3-yl- { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -acetic acid;

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (4-fluoro-phenyl) -propionic acid;

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-propenyl-thiophen-2-yl) -propionic acid;

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-propyl-thiophen-2-yl) -propionic acid;

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- [5- (3, 3-dimethyl-but-1-enyl) -thiophen-2-yl ] -propionic acid;

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-hydroxymethyl-thiophen-2-yl) -propionic acid methyl ester;

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-hydroxymethyl-thiophen-2-yl) -propionic acid;

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-methyl-thiophen-2-yl) -propionic acid;

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-isopropenyl-thiophen-2-yl) -propionic acid;

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-isopropylthiophen-2-yl) -propionic acid;

3- (5-bromo-thiophen-2-yl) -2(R) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -propionic acid;

2(R) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-chloro-thiophen-2-yl) -propionic acid;

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-chloro-furan-2-yl) -propionic acid;

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (2, 5-dichloro-thiophen-3-yl) -propionic acid;

(5-bromo-thiophen-2-yl) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -acetic acid;

3- (5-bromo-furan-2-yl) -2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -propionic acid;

3- (5-bromo-thiophen-2-yl) -2(S) - { [7- (4-trans-tert-butyl-cyclohexyloxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -propionic acid;

3- (5-bromo-thiophen-2-yl) -2(S) - { [6- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -propionic acid;

2(S) - { [7- (4-trans-tert-butyl-cyclohexyloxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-isopropenyl-thiophen-2-yl) -propionic acid;

2(S) - { [7- (4-trans-tert-butyl-cyclohexyloxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid;

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-furan-2-yl) -propionic acid;

2(S) - { [ 1-cyclopentylmethyl-7- (4-isopropyl-cyclohexyloxy) -isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid;

2(R) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid;

2(S) - { [7- (4-tert-butyl-phenoxy) -isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid;

2(S) - { [ 1-cyclopentylmethyl-7- (4-trans-ethyl-cyclohexyloxy) -isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid;

2(S) - { [ 1-cyclopentylmethyl-7- (4-isopropyl-phenoxy) -isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid;

2(S) - { [7- (4-tert-butyl-phenoxy) -1- (tetrahydro-pyran-4-yl) -isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid;

2(S) - { [6- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid;

2(S) - { [7- (4-tert-butyl-phenyl) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid;

2(S) - { [7- (4-tert-butyl-benzoyl) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid;

3- (5-acetyl-thiophen-2-yl) -2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -propionic acid;

7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carboxylic acid [1- (5-isopropyl-thiophen-2-ylmethyl) -2(R) -methanesulfonylamino-2-oxy-ethyl ] -amide;

7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carboxylic acid [1- (5-isopropyl-thiophen-2-ylmethyl) -2(S) -methanesulfonylamino-2-oxy-ethyl ] -amide;

7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carboxylic acid [ 1-benzyloxycarbamoyl-2- (5-isopropyl-thiophen-2-yl) -ethyl ] -amide; and

7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carboxylic acid [ 1-hydroxycarbamoyl-2- (5-isopropyl-thiophen-2-yl) -ethyl ] -amide.

In another embodiment, a method of treating a disease listed above comprises the administration of formula (X), wherein Y is selected from the group consisting of:

in another embodiment, a method of treating a disease listed above comprises administering a compound of formula (X), wherein Y is-methylene-cyclopentyl,

also included within the scope of the present invention are the individual enantiomers of the compounds represented by formula (I or X) above, as well as the fully or partially racemic mixtures thereof. The invention also encompasses mixtures of individual enantiomers of the compounds represented by the above formula and diastereomers thereof in which one or more chiral centers are inverted.

The compounds of the present invention are listed in table 1 below.

TABLE 1

In the chemical structures listed in Table 1, the unused valences of heteroatoms, such as oxygen and nitrogen, are each assumed to be depleted in hydrogen atoms.

In another aspect, the invention includes a pharmaceutical composition comprising a compound of formula (I or X) and one or more pharmaceutically acceptable carriers, excipients or diluents.

The term "lower" as used herein refers to groups containing between 1 and 6 carbons.

The term "alkyl" as used herein"refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms, optionally substituted with a substituent selected from the group consisting of: halogen, lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, oxygen, hydroxy, mercapto, amino optionally substituted with alkyl, carboxy, carbamoyl optionally substituted with alkyl, aminosulfonyl optionally substituted with alkyl, siloxy optionally substituted with alkoxy, alkyl or aryl, silyl optionally substituted with alkoxy, alkyl or aryl, nitro, cyano, halogen or lower perfluoroalkyl, allowing various degrees of substitution. Such "alkyl" groups may contain one or more of O, S, S (O) or S (O)₂An atom. Examples of "alkyl" as used herein include, but are not limited to, methyl, n-butyl, t-butyl, n-propyl, isobutyl, isopropyl, and the like.

The term "alkylene" as used herein refers to a straight or branched chain divalent hydrocarbon radical containing from 1 to 10 carbon atoms, optionally substituted with a substituent selected from the group consisting of: halogen, lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, oxygen, hydroxy, mercapto, amino optionally substituted with alkyl, carboxy, carbamoyl optionally substituted with alkyl, aminosulfonyl optionally substituted with alkyl, siloxy optionally substituted with alkoxy, alkyl or aryl, silyl optionally substituted with alkoxy, alkyl or aryl, nitro, cyano, halogen or lower perfluoroalkyl, allowing various degrees of substitution. Such "alkylene" may comprise one or more of O, S, S (O) or S (O)₂An atom. Examples of "alkylene" as used herein include, but are not limited to, methylene, ethylene, and the like.

The term "alkenyl" as used herein refers to a hydrocarbon group containing 2 to 10 carbons and at least 1 carbon-carbon double bond, which is optionally substituted with a substituent selected from the group consisting of: lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted with alkyl, carboxy, carbamoyl optionally substituted with alkylSubstituted aminosulfonyl, siloxy optionally substituted with alkoxy, alkyl or aryl, silyl optionally substituted with alkoxy, alkyl or aryl, nitro, cyano, halogen or lower perfluoroalkyl, allowing a variety of degrees of substitution. Such "alkenyl" groups may comprise one or more of O, S, S (O) or S (O)₂An atom.

The term "alkenylene" as used herein refers to a straight or branched chain divalent hydrocarbon radical containing 2 to 10 carbon atoms and one or more carbon-carbon double bonds, optionally substituted with a substituent selected from the group consisting of: halogen, lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, oxygen, hydroxy, mercapto, amino optionally substituted with alkyl, carboxy, carbamoyl optionally substituted with alkyl, aminosulfonyl optionally substituted with alkyl, siloxy optionally substituted with alkoxy, alkyl or aryl, silyl optionally substituted with alkoxy, alkyl or aryl, nitro, cyano, halogen or lower perfluoroalkyl, allowing various degrees of substitution. Such "alkenylene" may contain one or more of O, S, S (O) or S (O)₂An atom. Examples of "alkenylene" as used herein include, but are not limited to, ethylene-1, 2-diyl, propylene-1, 3-diyl, methylene-1, 1-diyl, and the like.

The term "alkynyl" as used herein refers to a hydrocarbon group containing 2 to 10 carbons and at least one carbon-carbon triple bond, which is optionally substituted with a substituent selected from the group consisting of: halogen, lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, oxygen, hydroxy, mercapto, amino optionally substituted with alkyl, carboxy, carbamoyl optionally substituted with alkyl, aminosulfonyl optionally substituted with alkyl, siloxy optionally substituted with alkoxy, alkyl or aryl, silyl optionally substituted with alkoxy, alkyl or aryl, nitro, cyano, halogen or lower perfluoroalkyl, allowing various degrees of substitution. Such "alkynyl" groups may contain one or more of O, S, S (O) or S (O)₂An atom.

As used hereinBy the term "alkynylene" is meant a straight or branched chain divalent hydrocarbon radical containing 2 to 10 carbon atoms and one or more carbon-carbon triple bonds, optionally substituted with substituents selected from the group consisting of: halogen, lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, oxygen, hydroxy, mercapto, amino optionally substituted with alkyl, carboxy, carbamoyl optionally substituted with alkyl, aminosulfonyl optionally substituted with alkyl, siloxy optionally substituted with alkoxy, alkyl or aryl, silyl optionally substituted with alkoxy, alkyl or aryl, nitro, cyano, halogen or lower perfluoroalkyl, allowing various degrees of substitution. Such "alkynylene" may comprise one or more of O, S, S (O) or S (O)₂An atom. Examples of "alkynylene" as used herein include, but are not limited to, acetylene-1, 2-diyl, propyne-1, 3-diyl, and the like.

As used herein, "cycloalkyl" refers to an alicyclic hydrocarbon group optionally having one or more unsaturations and containing from 3 to 12 carbon atoms, which is optionally substituted with a substituent selected from the group consisting of: halogen, lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, oxygen, hydroxy, mercapto, amino optionally substituted with alkyl, carboxy, carbamoyl optionally substituted with alkyl, aminosulfonyl optionally substituted with alkyl, nitro, cyano, halogen or lower perfluoroalkyl, allowing various degrees of substitution. "cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

The term "cycloalkylene" as used herein refers to a non-aromatic divalent alicyclic hydrocarbon group containing from 3 to 12 carbon atoms, and optionally having one or more degrees of unsaturation, which is optionally substituted with a substituent selected from the group consisting of: halogen, lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, oxygen, hydroxy, mercapto, amino optionally substituted with alkyl, carboxy, carbamoyl optionally substituted with alkyl, aminosulfonyl optionally substituted with alkyl, nitro, cyano, halogen or lower perfluoroalkyl, allowing various degrees of substitution. 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, cyclooctyl-1, 5-diyl, and the like.

The term "heterocycle" or the term "heterocyclyl" as used herein means optionally having one or more unsaturations and comprising one or more substituents selected from S, SO₂A heteroatom-substituted 3-12 membered heterocycle of O or N, optionally substituted with a substituent selected from the group consisting of: halogen, lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, oxygen, hydroxy, mercapto, amino optionally substituted with alkyl, carboxy, carbamoyl optionally substituted with alkyl, aminosulfonyl optionally substituted with alkyl, nitro, cyano, halogen or lower perfluoroalkyl, allowing various degrees of substitution. Such rings may optionally be fused to one or more other "heterocyclic" or cycloalkyl rings. Examples of "heterocycle" include, but are not limited to, tetrahydrofuran, 1, 4-dioxane, 1, 3-dioxane, piperidine, pyrrolidine, morpholine, piperazine and the like.

The term "heterocyclylene" as used herein means optionally having one or more unsaturations and comprising one or more substituents selected from S, SO₂3-12 membered heterocydic diradicals of heteroatoms of O or N, optionally substituted with substituents selected from the group consisting of: halogen, lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, oxygen, hydroxy, mercapto, amino optionally substituted with alkyl, carboxy, carbamoyl optionally substituted with alkyl, aminosulfonyl optionally substituted with alkyl, nitro, cyano, halogen or lower perfluoroalkyl, allowing various degrees of substitution. Such rings may optionally be fused to one or more benzene rings or one or more other "heterocyclic" 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-24-diyl, piperidine-2, 4-diyl, piperidine-1, 4-diyl, pyrrolidine-1, 3-diyl, morpholine-2, 4-diyl, piperazine-1, 4-diyl, and the like.

The term "aryl" as used herein refers to a phenyl ring or an optionally substituted phenyl ring system fused to one or more optionally substituted phenyl rings, which are optionally substituted with a substituent selected from the group consisting of: halogen, lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, di (lower alkyl) aminoalkyl, oxygen, 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, siloxy optionally substituted by alkoxy, alkyl or aryl, silyl optionally substituted by alkoxy, alkyl or aryl, nitro, cyano, halogen or lower perfluoroalkyl, allowing a variety of degrees of substitution. Examples of aryl groups include, but are not limited to, phenyl, 2-naphthyl, 1-anthracenyl, and the like.

The term "arylene" as used herein refers to a phenyl ring diradical or a phenyl ring system diradical fused to one or more optionally substituted phenyl rings, which is optionally substituted with a substituent selected from the group consisting of: halogen, lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, di (lower alkyl) aminoalkyl, oxygen, 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, siloxy optionally substituted by alkoxy, alkyl or aryl, silyl optionally substituted by alkoxy, alkyl or aryl, nitro, cyano, halogen or lower perfluoroalkyl, allowing a variety of degrees of substitution. Examples of "arylene" include, but are not limited to, benzene-1, 4-diyl, naphthalene-1, 8-diyl, and the like.

The term "heteroaryl" as used herein refers to a 5-7 membered aromatic or polycyclic aromatic ring containing one or more nitrogen, oxygen or sulfur heteroatoms, wherein N-oxides and sulfur monoxide and sulfur dioxide are permissible heteroaryl substitutes, which are optionally substituted with substituents selected from the group consisting of: halogen, lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, oxygen, hydroxy, mercapto, amino optionally substituted with alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted with alkyl, aminosulfonyl optionally substituted with alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, siloxy optionally substituted with alkoxy, alkyl or aryl, silyl optionally substituted with alkoxy, alkyl or aryl, nitro, cyano, halogen or lower perfluoroalkyl, allowing various degrees of substitution. For polycyclic aromatic ring systems, one or more of the rings may contain one or more heteroatoms. Examples of "heteroaryl" as 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.

The term "heteroarylene" as used herein refers to a 5-7 membered aromatic or polycyclic aromatic ring diradical containing one or more nitrogen, oxygen or sulfur heteroatoms, wherein N-oxides and sulfur monoxide and sulfur dioxide are permissible heteroaryl substitutes, which are optionally substituted with substituents selected from the group consisting of: halogen, lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, oxygen, hydroxy, mercapto, amino optionally substituted with alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted with alkyl, aminosulfonyl optionally substituted with alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, siloxy optionally substituted with alkoxy, alkyl or aryl, silyl optionally substituted with alkoxy, alkyl or aryl, nitro, cyano, halogen or lower perfluoroalkyl, allowing various degrees of substitution. For a diradical of a polycyclic aromatic ring system, one or more of the rings may contain one or more heteroatoms. Examples of "heteroarylene" as 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.

The term "fused cycloalkylaryl" as used herein means a cycloalkyl fused to an aryl, both moieties sharing two atoms, and wherein aryl is the point of substitution. Examples of "fused cycloalkylaryl" as used herein include 5-indanyl, 5, 6, 7, 8-tetrahydro-2-naphthyl,and the like.

The term "fused cycloalkylarylene" as used herein refers to fused cycloalkylaryl groups in which the aryl group is divalent. Examples includeAnd the like.

The term "fused arylcycloalkyl" as used herein means an aryl fused to a cycloalkyl, both moieties sharing two atoms, and wherein cycloalkyl is the point of substitution. Examples of "fused arylcycloalkyl" as used herein include 1-indanyl, 2-indanyl, 1- (1, 2, 3, 4-tetrahydronaphthyl),And the like.

The term "fused arylcycloalkylene" as used herein refers to a fused arylcycloalkyl group, wherein the cycloalkyl group is divalent. Examples includeAnd the like.

The term "fused heterocyclylaryl" as used herein means that a heterocyclyl is fused to an aryl, both moieties share two atoms, and wherein aryl is the point of substitution. Examples of "fused heterocyclylaryl" as used herein include 3, 4-methylenedioxy-1-phenyl, and,And the like.

The term "fused heterocyclylarylene" as used herein refers to a fused heterocyclylaryl group in which the aryl group is divalent. Examples includeAnd the like.

The term "fused arylheterocyclyl" as used herein means that an aryl group is fused to a heterocyclyl group, both moieties sharing two atoms, and wherein the heterocyclyl group is the point of substitution. Examples of "fused arylheterocyclyl" as used herein include 2- (1, 3-benzodioxolyl)And the like.

The term "fused arylheterocyclylene" as used herein refers to a fused arylheterocyclyl group, wherein the heterocyclyl group is divalent. Examples includeAnd the like.

The term "fused cycloalkylheteroaryl" as used herein means a cycloalkyl group fused to a heteroaryl group, both moieties sharing two atoms, and wherein the heteroaryl group is the point of substitution. Examples of "fused cycloalkylheteroaryl" as used herein include 5-aza-6-indanyl,and the like.

The term "fused cycloalkylheteroarylene" as used herein refers to a fused cycloalkylheteroaryl group, wherein the heteroaryl group is divalent. Examples includeAnd the like.

The term "fused heteroarylcycloalkyl" as used herein means that a heteroaryl is fused to a cycloalkyl, both moieties sharing two atoms, and wherein cycloalkyl is the point of substitution. Examples of "fused heteroarylcycloalkyl" as used herein include 5-aza-1-indanyl,and the like.

The term "fused heteroarylcycloalkylene" as used herein refers to a fused heteroarylcycloalkyl group, wherein the cycloalkyl group is divalent. Examples includeAnd the like.

The term "fused heterocyclylheteroaryl" as used herein means that a heterocyclyl is fused to a heteroaryl, both moieties sharing two atoms, and wherein heteroaryl is the point of substitution. Examples of "fused heterocyclylheteroaryl" as used herein include 1, 2, 3, 4-tetrahydro-beta-carbolin-8-yl, and,And the like.

The term "fused heterocyclylheteroarylene" as used herein refers to a fused heterocyclylheteroaryl group, wherein the heteroaryl group is divalent. Examples includeAnd the like.

The term "fused heteroarylheterocyclyl" as used herein means that the heteroaryl is fused to a heterocyclyl, and the two moieties share two common moietiesAnd wherein heterocyclyl is a point of substitution. Examples of "fused heteroarylheterocyclyl" as used herein include 5-aza-2, 3-dihydrobenzofuran-2-yl,And the like.

The term "fused heteroarylheterocyclylene" as used herein refers to a fused heteroarylheterocyclyl group, wherein the heterocyclyl group is divalent. Examples includeAnd the like.

The term "acidic isostere" as used herein refers to a substituent which is ionized at physiological pH to have a net negative charge. Examples of such "acidic isosteres" include, but are not limited to, heteroaryl groups such as, but not limited to, isoxazol-3-ol-5-yl, 1H-tetrazol-5-yl, or 2H-tetrazol-5-yl. The acidic isostere includes, but is not limited to, a heterocyclic group such as, but not limited to, imidazolidin-2, 4-dione-5-yl, imidazolidin-2, 4-dione-1-yl, 1, 3-thiazolidine-2, 4-dione-5-yl, or 5-hydroxy-4H-pyran-4-one-2-yl, 1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide-4-yl, or 1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide-5-yl.

The term "ester isostere" as used herein refers to a substituent that is metabolically stable and can maintain the selectivity and affinity of the corresponding ester for the target protein. Examples of such "ester isosteres" include, but are not limited to, heteroaryl groups such as, but not limited to, 1, 3-oxazol-5-yl, 1, 3-oxazol-2-yl, 1, 2, 3-oxadiazol-5-yl, 1, 2, 4-oxadiazol-5-yl, 1, 3, 4-oxadiazol-5-yl, 1, 2, 3-thiadiazol-5-yl, 1, 2, 4-thiadiazol-5-yl, 1, 3, 4-thiadiazol-5-yl, 5-alkyl-1, 3-oxazol-2-yl, 2-alkyl-1, 3-oxazol-5-yl, 4-alkyl-1, 2, 3-oxadiazol-5-yl, 2-oxadiazol-5-yl, 3-alkyl-1, 2, 4-oxadiazol-5-yl, 2-alkyl-1, 3, 4-oxadiazol-5-yl, 4-alkyl-1, 2, 3-thiadiazol-5-yl, 3-alkyl-1, 2, 4-thiadiazol-5-yl, 2-alkyl-1, 3, 4-thiadiazol-5-yl, 1, 2, 4-triazol-1-yl, 3-alkyl-1, 2, 4-triazol-1-yl, tetrazol-1-yl and 1-alkyl-tetrazol-5-yl; aryl groups such as, but not limited to, 3, 5-difluoro-4-alkoxyphenyl; and heterocyclic groups such as, but not limited to, 1-alkyl-imidazolidin-2, 4-dione-5-yl, imidazolidin-2, 4-dione-1-yl, 3-alkyl-1, 3-thiazolidine-2, 4-dione-5-yl, and 5-alkoxy-4H-pyran-4-one-2-yl. The alkyl groups in the heterocyclic, aryl and heteroaryl groups of the ester isostere may be replaced with phenyl or alkylphenyl groups.

The term "direct bond" as used herein as part of a description of a structural variable means that the substituent is attached directly to the side (front and back) of the variable as a "direct bond".

The term "alkoxy" as used herein refers to the group R_aO-, wherein R_aIs an alkyl group.

The term "alkenyloxy" as used herein refers to the group R_aO-, wherein R_aIs an alkenyl group.

The term "alkynyloxy" as used herein refers to the group R_aO-, wherein R_aIs an alkynyl group.

The term "alkylsulfanyl" as used herein refers to the group R_aS-, wherein R_aIs an alkyl group.

The term "alkenylsulfanyl" as used herein refers to the group R_aS-, wherein R_aIs an alkenyl group.

The term "alkynylsulfanyl" as used herein refers to the group R_aS-, wherein R_aIs an alkynyl group.

The term "alkylsulfinyl" as used herein refers to the group R_aS (O) -, wherein R_aIs an alkyl group.

The term "alkenylsulfinyl" as used herein refers to the group R_aS (O) -, wherein R_aIs an alkenyl group.

The term "alkynylsulfinyl" as used herein refers to the group R_aS (O) -, wherein R_aIs an alkynyl group.

The term "alkylsulfonyl" as used herein refers to the group R_aSO₂-, wherein R_aIs an alkyl group.

The term "alkenylsulfonyl" as used herein refers to the group R_aSO₂-, wherein R_aIs an alkenyl group.

The term "alkynylsulfonyl" as used herein refers to the group R_aSO₂-, wherein R_aIs an alkynyl group.

The term "acyl" as used herein refers to the group R_aC (O) -, wherein R_aIs alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or heterocyclyl.

The term "aroyl" as used herein refers to the group R_aC (O) -, wherein R_aIs an aryl group.

The term "heteroaroyl" as used herein refers to the group R_aC (O) -, wherein R_aIs a heteroaryl group.

The term "alkoxycarbonyl" as used herein refers to the group R_aOC (O) -, wherein R_aIs an alkyl group.

The term "acyloxy", as used herein, refers to the group R_aC (O) O-, wherein R_aIs alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or heterocyclyl.

The term "aroyloxy" as used herein refers to the group R_aC (O) O-, wherein R_aIs an aryl group.

The term "heteroaroyloxy" as used herein refers to the group R_aC (O) O-, wherein R_aIs a heteroaryl group.

The term "optionally" is used herein to indicate that the subsequently described event may or may not occur, and includes both occurring and non-occurring events.

The term "substituted" as used herein means substituted with the specified substituent or substituents, and, unless otherwise specified, allows for a variety of degrees of substitution.

The term "comprising" as used herein may refer to O, S, SO₂Any one or more of N or N-alkyl groups may be insertionally substituted at any position within the alkyl, alkenyl, alkynyl or cycloalkyl substituents defined hereinbefore, including, for example, -CH₂-O-CH₂-、-CH₂-SO₂-CH₂-、-CH₂-NH-CH₃And the like.

The term "solvate" as used herein is a complex of variable stoichiometry formed by a solute (in the present invention a compound of formula (X or XI)) and a solvent. Such solvents, which are consistent with the object of the present invention, do not substantially interfere with the biological activity of the solute. The solvent may be, for example, water, ethanol or acetic acid.

The term "biohydrolyzable ester" as used herein is an ester of a drug substance (in the present invention a compound of formula (X or XI)) which either a) does not interfere with the biological activity of the parent substance but confers on the substance advantageous in vivo properties, such as duration of action, onset of action, etc., or b) is biologically inactive but is readily converted in the subject to the biologically active ingredient. Advantageously, the biohydrolyzable ester is absorbed from the intestinal tract after oral administration and converted in the plasma to the formula (X or XI), for example. Many examples of such are well known in the art and include, for example, lower alkyl esters (e.g., C1-C4), lower acyloxyalkyl esters, lower alkoxyacyloxyalkyl esters, alkoxyacyloxy esters, alkylamidoalkyl esters, and choline esters.

The term "biohydrolyzable amide" as used herein is an amide of a drug substance (in the present invention, a compound of formula (I or X)) which either a) does not interfere with the biological activity of the parent substance but confers on the substance advantageous in vivo properties, such as duration of action, onset of action, etc., or b) is biologically inactive but is readily converted in vivo in a subject to the biologically active ingredient. The advantage is, for example, that the biohydrolyzable amide is absorbed from the intestinal tract after oral administration and converted in the plasma to the formula (I or X). Many examples of such are well known in the art and include, for example, lower alkyl amides, alpha-amino acid amides, alkoxy amides, and alkyl amino alkyl carbonyl amides.

The term "prodrug" as used herein includes biohydrolyzable amides and biohydrolyzable esters and includes a) compounds wherein the biohydrolyzable functionality of such a prodrug is included in the compounds of formula (I or X), and b) compounds that are biooxidizable or reducible at a specified functional group to produce a drug substance of formula (I or X). Examples of such functional groups include, but are not limited to, 1, 4-dihydropyridine, N-alkylcarbonyl-1, 4-dihydropyridine, 1, 4-cyclohexadiene, t-butyl, and the like.

When the term "alkyl" or "aryl" or any of their prefixes appears in the name of a substituent (e.g., arylalkoxyaryloxy), it should be construed to include those definitions given above for "alkyl" and "aryl". Specified number of carbon atoms (e.g., C)_1-10) Independently, the number of carbon atoms in the alkyl, alkenyl or alkynyl group or cycloalkyl moiety, or the number of carbon atoms in the alkyl moiety of the bulky substituent in which the term "alkyl" appears in its prefix.

The term "oxygen" as used herein shall mean the substituent ═ O.

The term "halogen" as used herein shall include iodine, bromine, chlorine and fluorine.

As used herein, the term "mercapto" shall refer to the substituent-SH.

The term "carboxy" as used herein shall mean the substituent-COOH.

The term "cyano" as used herein shall mean the substituent-CN.

The term "aminosulfonyl" as used herein shall mean the substituent-SO₂NH₂。

As used herein, the term "carbamoyl" shall mean the substituent-C (O) NH₂。

The term "thioalkyl" as used herein shall mean the substituent-S-.

The term "sulfinyl", as used herein, shall mean the substituent-S (O) -.

The term "sulfonyl", as used herein, shall mean the substituent-S (O)₂-。

The compounds may be prepared according to the following reaction schemes (wherein the variables are in accordance with the foregoing definitions or defined below), using readily available starting materials, reagents and conventional synthetic procedures. In these reactions, it is likewise possible to use variants which are known to the person skilled in the art themselves, but are not mentioned in more detail.

The invention also provides methods for the synthesis of compounds useful as intermediates in the preparation of compounds of formula (I or X), and methods for preparing compounds of formula (I or X).

Scheme XIV describes the synthesis of a compound of formula (66). R₈₅And R₈₆May be a group such as, but not limited to, hydrogen, alkyl or-alkylene-aryl. R₈₁May be, for example, a group of a side chain of a natural or unnatural amino acid. R₈₂There may be groups such as aryl, heteroaryl, alkyl or cycloalkyl. R₈₄Groups such as, but not limited to, alkyl, aryl, heteroaryl, cycloalkyl, -alkylene-cycloalkyl, or-alkylene-aryl may be used.

Compound (62) represents a nitrogen-containing fused heterocyclyl aryl ring system which may be synthesised by methods known in the art, for example, the corresponding amino acid with carbonyl compound R₈₅C(O)R₈₆Acid catalyzed condensation is performed followed by protection at the nitrogen with a protecting group such as, but not limited to, BOC. Treatment of (62) with a peptide coupling agent, such as DIC or HBTU, and an amino ester, such as (63), in the presence or absence of a base, such as DIEA, in a solvent, such as DMF or DCM, affords (64). An amine having a structure similar to (63) may also be used to provide (64) without methoxycarbonyl functionality. (64) By di-alkyl of azodicarboxylic acids at a temperature of-20 ℃ to 25 ℃ in a solvent such as THF, with primary or secondary alcoholsEster and triphenylphosphine treatment (64) to obtain a compound in which R is₈₂Is alkyl, substituted alkyl or cycloalkyl (65). Treatment of (64) with an aryl or heteroaryl boronic acid and copper (II) acetate may also be used to provide compounds in which R is₈₂Is aryl or heteroaryl (65). PG of optional general formula (65)₁Removing groups; thus free nitrogen is represented by R₈₃Functionalizing it, wherein R₈₃Represents a group such as, but not limited to, alkylsulfinyl, alkoxycarbonyl or acyl or alkanoyl. Removal of the methyl ester of the intermediate by treatment with, for example, lithium hydroxide in THF-methanol in water at a temperature of 0 deg.C to 25 deg.C gives (66).

Scheme XIV

Scheme XV depicts the synthesis of a compound of formula (70). R₈₅、R₈₂And R₈₁Having the meaning described in scheme XIV. The phenol functionality of (67) can be functionalized according to the method in scheme XIV to remove PG with reagents such as TFA₁A protecting group, wherein PG₁Is tBOC. Treatment (68) with a reagent such as dichlorodicyanoquinone (DDQ) in a solvent such as toluene at a temperature of 25 ℃ to 110 ℃ gives the acid (69) after hydrolysis of the ester with a reagent such as lithium hydroxide in a solvent such as aqueous THF. Acid (69) is coupled to an amino ester or other amine by a method similar to that described in scheme XIV, and the ester, if present, is hydrolyzed with aqueous base to provide (70).

Flow chart XV

Scheme XVI describes the synthesis of intermediates and other compounds of formula I. Coupling of the acid (69) with a functionalized bromoaryl alanine ester or other similar brominated aromatic substituted amine under the conditions previously described affords (71). (71) is converted to (72) using the conditions described in scheme II. Similarly, (69) coupling with a hydroxyaryl alanine ester or other similar hydroxyaryl or hydroxyheteroaryl substituted amine affords (73), which is functionalized according to the methods described in scheme III to afford (74).

Scheme XVI

Scheme XVII describes the synthesis of a compound of formula (79). R₈₅、R₈₂And R₈₁Have the meaning described for scheme XIV. PG (Picture experts group)₂Represents a hydroxyl protecting group. Treatment of the N-acylated amino acid ester (75) with a reagent such as oxalyl chloride in a solvent such as DCM at a temperature of 0 deg.C to 25 deg.C to give an imidoyl chloride intermediate which is first treated with a reagent such as, but not limited to FeCl₃Is treated with a solution of sulfuric acid in methanol to give the cyclized product; concomitant PG generation₂(wherein PG₂Is t-butyl or benzyl) to yield (76). PG during these steps₂When not removed, it can be removed by treatment with TFA or HCl in dioxane, where PG is present₂Is a tert-butyl group. (76) Dehydrogenation was carried out by treatment with Pd/C in xylene at a temperature of 25-130 deg.C, or with ketoacetate (II) in DCM to give (77). Functionalizing the phenol functionality of (77) according to scheme XIV; likewise, the product (78) after ester hydrolysis is coupled with an amine or amino acid ester to yield the acid (79) after hydrolysis.

Scheme XVII

The term "amino protecting group" as used herein refers to a substituent of an amino group that is typically used to block or protect the amino functionality when other functional groups of the compound are reacted. Examples of such amino-protecting groups include formyl, trityl, phthalimidyl, trichloroacetyl, chloroacetyl, bromoacetyl and iodoacetyl groups, urethane-based protecting groups such as benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2, 4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, 2- (4-biphenyl) isopropoxycarbonyl, 1-diphenyleth-1-yloxycarbonyl, 1, 1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2- (p-toluyl) prop-2-yloxycarbonyl, cyclopentyloxycarbonyl, 1-methylcyclopentyloxycarbonyl, cyclohexyloxycarbonyl, 1-methylcyclohexyloxycarbonyl, 2- (4-toluoylsulfonyl) ethoxycarbonyl, 2- (methylsulfonyl) ethoxycarbonyl, 2- (triphenylphosphino) ethoxycarbonyl, 9-fluorenylmethoxycarbonyl ("FMOC"), tert-butoxycarbonyl ("BOC"), 2- (trimethylsilyl) ethoxycarbonyl, allyloxycarbonyl, 1- (trimethylsilylmethyl) prop-1-enyloxycarbonyl, N-phenyloxycarbonyl, 5-bezisoxalyl methoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2, 2, 2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4- (decyloxy) benzyloxycarbonyl, isobornyloxycarbonyl, 1-piperidinyloxycarbonyl and the like; amino protecting groups such as phenacylmethylsulfonyl, 2- (nitro) phenylsulfinyl, and diphenylphosphineoxide. The type of amino protecting group used is not critical as long as the derivatized amino group is stable to the conditions of subsequent reactions occurring elsewhere in the compound of formula (I or X) and can be removed at the target site without destroying the rest of the molecule. Commonly used amino protecting groups are allyloxycarbonyl, tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl and trityl. Similar amino protecting groups used in the cephalosporin, penicillin and peptide arts are also encompassed within the above terms. The relative term "protected amino" refers to an amino group substituted with an amino protecting group as discussed above.

The term "hydroxyl protecting group" as used herein refers to a substituent of an alcohol group that is typically used to block or protect the alcohol functionality upon reaction of other functional groups of the compound. Examples of such alcohol protecting groups include 2-tetrahydropyranyl, 2-ethoxyethyl, trityl, trichloroacetyl, urethane protecting groups such as benzyloxycarbonyl and trialkylsilyl groups, and examples of the trialkylsilyl groups include trimethylsilyl, t-butyldimethylsilyl, phenyldimethylsilyl, triisopropylsilyl and thexyldimethylsilyl. The choice of alcohol protecting group used is not critical as long as the alcohol group after derivatization is stable to the conditions of the reactions that take place later on in other positions of the compound of the formula and can be removed at the target site without damaging the rest of the molecule. The relative terms "protected hydroxy" or "protected alcohol" refer to a hydroxy group substituted with a hydroxy protecting group as discussed above.

The term "carboxy protecting group" as used herein refers to a substituent of a carboxy group that is typically used to block or protect the-OH functionality when other functional groups of the compound are reacted. Examples of such alcohol protecting groups include 2-tetrahydropyranyl, 2-ethoxyethyl, trityl, allyl, trimethylsilylethoxymethyl, 2, 2, 2-trichloroethyl, benzyl and trialkylsilyl groups, examples of which are trimethylsilyl, t-butyldimethylsilyl, phenyldimethylsilyl, triisopropylsilyl and thexyldimethylsilyl. The choice of carboxyl protecting group used is not critical as long as the alcohol group after derivatization is stable to the conditions of the reactions that take place later on in other positions of the compound of the formula and can be removed at the target site without damaging the rest of the molecule. The relative term "protected carboxy" refers to carboxy substituted with a carboxy protecting group as discussed above.

Barton, "Protective Groups In Organic Chemistry", j.g.w.mcmoie, 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 describe other examples of pro-Groups (progroups) to which the above terms relate.

The invention further provides pharmaceutical compositions comprising a factor XI or factor IX/XI dual factor modulating compound of the invention. The term "pharmaceutical composition" as used herein refers to a composition which may be administered to a mammalian host, for example, orally, topically, parenterally, by inhalation spray, rectally, or the like, in the form of unit dose formulations including 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.

The term "factor IX" as used herein refers to coagulation factor IX, including activated or unactivated forms thereof.

The term "therapeutically effective amount" as used herein refers to an amount of a drug or agent that will elicit the therapeutic response sought in an animal or human.

The pharmaceutical compositions containing the compounds of the present invention may be in a form suitable for oral administration, for example, as tablets, 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 ingredients selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may comprise the active ingredient in admixture with pharmaceutically acceptable non-toxic 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, such as corn starch or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as 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 using techniques described in U.S. Pat. Nos. 4,356,108, 4,166,452 and 4,265,874 to form controlled release therapeutic osmotic tablets.

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

Aqueous suspensions may include the active compound 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 naturally occurring phosphatides, for example 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-ethyleneoxycetanol (heptadecadecadecaethyl-ethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids with hexitol(s), for example polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids with hexitol anhydrides (partial esters), for example polyethylene sorbitan monooleate. The aqueous suspension may also include one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

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 liquid paraffin. Oily suspensions may include a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. 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 antioxidant such as ascorbic acid.

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 mentioned above as examples. Other excipients, for example sweetening, flavouring and colouring agents, may likewise be present.

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

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also include a demulcent (demulcent), a preservative and flavouring and colouring agents. The pharmaceutical compositions may be in the form of sterile injectable aqueous or oleaginous suspensions. Such suspensions may be formulated in accordance with known procedures using suitable dispersing or wetting agents and suspending agents as described hereinbefore. The sterile injectable preparation may likewise be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example 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 (fixed oils) are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oils (fixed oils) of synthetic mono-or diglycerides may be used. In addition, the use of fatty acids such as oleic acid in the preparation of injectables has been found.

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 therefore melt in the rectum to release the drug. Such materials include, for example, cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, suspensions, etc., containing the compounds of the present invention are contemplated. For the purposes of this application, topical application shall include mouth washes and throat rinses.

The compounds of the invention may also be administered in the form of liposomal delivery systems, such as small unilamellar liposomes, large unilamellar liposomes and multilamellar liposomes. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

The invention also provides prodrugs of the invention.

Pharmaceutically acceptable salts of the compounds of the present invention having basic or acidic groups in the structure are also included within the scope of the present invention. The term "pharmaceutically acceptable salt" refers to non-toxic salts of the compounds of the present invention, which are typically prepared by reacting the free base with a suitable organic or inorganic acid, or by reacting an acid with a suitable organic or inorganic base. Representative salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, etonate, ethylsulfonate (Egylate), fumarate, glucoheptonate (gluceptate), gluconate, glutamate, glycollylate, hexylresorcinate, halate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactylate, laurate, malate, maleate, mandelate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, monopotassium maleate, mucate, naphthalenesulfonate, nitrate, N-methylglucamine, N-methylgluconate, D-camphorsulfonate, D-camphorate, D-methyl-salicylate, D-methyl-tartrate, D-methyl-ethyl-propyl-, Oxalate, pamoate (embonate), palmitate, pantothenate, phosphoric acid/diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate, succinate, tannate, tartrate, 8-chlorophate, tosylate, triethyliodide, trimethylammonium salt, and valerate. When an acidic substituent such as-COOH is present, ammonium, morpholine, sodium, potassium, barium, calcium salts, and the like may be formed for use as dosage forms. When a basic group, such as amino or a basic heteroaryl group, such as pyridyl, is present, acidic salts include, for example, hydrochloride, hydrobromide, phosphate, sulfate, trifluoroacetate, trichloroacetate, acetate, oxalate, maleate, pyruvate, malonate, succinate, citrate, tartrate, fumarate, mandelate, benzoate, cinnamate, methanesulfonate, ethanesulfonate, picrate, and the like, and include acids associated with the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2(1977) p.1-19.

Other non-pharmaceutically acceptable salts may be used in the preparation of the compounds of the invention and these form a further aspect of the invention.

In addition, some compounds of formula (I or X) may form solvates with water or common organic solvents. Such solvates are also included within the scope of the present invention.

Accordingly, another aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I or X), or a pharmaceutically acceptable salt, solvate or prodrug thereof, and one or more pharmaceutically acceptable carriers, excipients or diluents. In one embodiment of the pharmaceutical composition, the compound of formula (I or X) is an antagonist of factor XI or an antagonist of factor IX/XI activity. In another embodiment of the pharmaceutical composition, the compound of formula (I or X) is a partial antagonist of factor XI activity or factor IX/XI activity, wherein a partial antagonist comprises a compound that inhibits incomplete activity at a physiologically tolerable dose. In another embodiment of the pharmaceutical composition, the compound of formula (I or X) is a partial antagonist of factor XI activity or factor IX/XI activity, wherein the compound of formula (I or X) inhibits up to 95% of factor XI or factor IX/XI activity. In another embodiment of the pharmaceutical composition, the compound of formula (I or X) is a partial antagonist of factor XI activity or factor IX/XI activity, wherein the compound of formula (I or X) inhibits factor XI or factor IX/XI activity by up to 80%. In another embodiment of the pharmaceutical composition, the compound of formula (I or X) is a partial antagonist of factor XI activity or factor IX/XI activity, wherein the compound of formula (I or X) inhibits factor XI or factor IX/XI activity by up to 50%. In another embodiment of the pharmaceutical composition, the compound of formula (I or X) antagonizes factor XI or IX/XI mediated coagulation.

Another aspect of the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I or X), or a pharmaceutically acceptable salt, solvate or prodrug thereof, and one or more pharmaceutically acceptable carriers, excipients or diluents, wherein the therapeutically effective amount of formula (I or X) preferentially inhibits the intrinsic coagulation cascade when compared to the extrinsic coagulation cascade. In one embodiment of the pharmaceutical composition, the therapeutically effective amount of formula (I or X) inhibits more than 80% of the intrinsic coagulation cascade and less than 50% of the extrinsic coagulation cascade. In another embodiment of the pharmaceutical composition, a therapeutically effective amount of said formula (I or X) includes an amount sufficient to achieve and maintain a sustained blood level that at least partially antagonizes the biological activity of factor XI or factor IX/XI. In another embodiment, the sustained blood level comprises a concentration ranging from about 0.01 μ M to 2 mM. In another embodiment, the sustained blood level comprises a concentration ranging from about 0.05 μ Μ to 100 μ Μ. In another embodiment, the sustained blood concentration includes a concentration ranging from about 0.1 μ Μ to about 30 μ Μ.

Another aspect of the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I or X), or a pharmaceutically acceptable salt, solvate or prodrug thereof, and one or more pharmaceutically acceptable carriers, excipients or diluents, wherein the therapeutically effective amount comprises an amount of a compound of formula (I or X) sufficient to at least partially inhibit factor XI or factor IX/XI biological activity in a subject, an amount of a compound of formula (I or X) sufficient to at least partially ameliorate at least one factor XI or factor IX/XI mediated disease, or an amount of a compound of formula (I or X) sufficient to at least partially inhibit the endogenous coagulation cascade of a subject. In one embodiment of the pharmaceutical composition, the factor XI or factor IX/XI mediated disease comprises stroke. In another embodiment of the pharmaceutical composition, the factor XI or factor IX/XI mediated disease comprises deep vein thrombosis. In another embodiment of the pharmaceutical composition, the factor XI or factor IX/XI mediated disease comprises deep vein thrombosis, wherein the thrombosis is associated with a surgical procedure, long term restriction, acquired or inherited procoagulant state including antiphospholipid antibody syndrome, protein C deficiency and protein S deficiency, or acute or chronic inflammation including recurrent abortion or Systemic Lupus Erythematosus (SLE). In another embodiment, the factor XI or factor IX/XI mediated disease comprises excessive coagulation associated with hemodialysis and/or venous hemofiltration treatment of renal disease. In another embodiment, the factor XI or factor IX/XI mediated disease comprises cardiovascular disease. In another embodiment, the factor XI or factor IX/XI mediated disease comprises a cardiovascular disease, wherein the cardiovascular disease comprises myocardial infarction, arrhythmia, or aneurysm.

In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I or X), and one or more pharmaceutically acceptable carriers, excipients or diluents, wherein the pharmaceutical composition is used in place of or in addition to a compound that reduces blood coagulation.

In another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I or X), and one or more pharmaceutically acceptable carriers, excipients or diluents, which further comprise one or more therapeutic agents.

In another aspect, the invention provides a method of inhibiting normal biological function of factor XI or factor IX/XI comprising administering to a subject in need thereof a compound of formula (I or X). In embodiments of the methods, the compound of formula (I or X) is an antagonist of factor XI or factor IX/XI activity. In another embodiment of the method, the compound of formula (I or X) antagonizes factor XI or factor IX/XI mediated coagulation. In another embodiment of the method, the compound of formula (I or X) is administered in an amount sufficient to partially antagonize the biological activity of factor XI or factor IX/XI in the subject. In another embodiment of the method, the compound of formula (I or X) is an antagonist of factor XI or factor IX/XI activity. In another embodiment of the method, the compound of formula (I or X) antagonizes factor XI or factor IX/XI mediated coagulation. In another embodiment of the method, the compound of formula (I or X) is administered in an amount sufficient to partially antagonize the biological activity of factor XI or factor IX/XI in the subject. In another embodiment of the method, the pharmaceutical composition is administered in the form of an oral dosage unit or a parenterally used dosage unit. In another embodiment of the method, the compound of formula (I or X) is administered at a dose ranging from about 0.01 to 1,000mg/kg body weight/day. In another embodiment of the method, the compound of formula (I or X) is administered in a dose ranging from about 0.1 to 100mg/kg body weight/day. In another embodiment of the method, the compound of formula (I or X) is administered in a dose ranging from about 0.5 to 10mg/kg body weight/day. In another embodiment, the compound of formula (I or X) is used in place of or in addition to a compound that reduces blood coagulation.

In another aspect, the present invention provides a method of inhibiting the normal biological function of factor XI or factor IX/XI comprising administering to a subject in need thereof a compound of formula (I or X), wherein said compound of formula (I or X) is administered to said subject in the form of a pharmaceutical composition comprising a therapeutically effective amount of said compound of formula (I or X), and one or more pharmaceutically acceptable carriers, excipients, or diluents. In one embodiment of the method, the therapeutically effective amount of a compound of formula (I or X) comprises an amount of a compound of formula (I or X) sufficient to at least partially inhibit the intrinsic coagulation cascade in the subject. In another embodiment of the method, the therapeutically effective amount of formula (I or X) preferentially inhibits the intrinsic coagulation cascade when compared to the extrinsic coagulation cascade. In another embodiment of the method, the therapeutically effective amount of formula (I or X) inhibits more than 80% of the intrinsic coagulation cascade and less than 50% of the extrinsic coagulation cascade. In another embodiment of the method, a therapeutically effective amount of the compound of formula (I or X) includes an amount sufficient to achieve and maintain sustained blood levels, at least partially antagonize the biological activity of factor XI or factor IX/XI. In another embodiment, the sustained blood level comprises a concentration ranging from about 0.01 μ M to 2 mM. In another embodiment, the sustained blood level comprises a concentration ranging from about 0.05 μ Μ to 100 μ Μ. In another embodiment, the sustained blood level comprises a concentration ranging from about 0.1 μ Μ to about 30 μ Μ. In another embodiment of the method, the pharmaceutical composition further comprises one or more therapeutic agents.

In another aspect, the invention provides a method of inhibiting the normal biological function of factor XI or factor IX/XI comprising administering to a subject in need thereof a compound of formula (I or X), wherein the compound of formula (I or X) is a partial antagonist of factor XI or factor IX/XI, wherein a partial antagonist comprises a compound that inhibits incomplete activity at a physiologically tolerable dose. In one embodiment of the method, the compound of formula (I or X) inhibits up to 95% of factor XI or factor IX/XI activity. In another embodiment of the method, the compound of formula (I or X) inhibits factor XI or factor IX/XI activity by up to 80%. In another embodiment of the method, the compound of formula (I or X) inhibits factor XI or factor IX/XI activity by up to 50%.

In another aspect, the invention provides a method of inhibiting the normal biological function of factor XI or factor IX/XI comprising administering to a subject in need thereof a compound of formula (I or X), wherein said compound of formula (I or X) is administered to said subject in the form of a pharmaceutical composition comprising a therapeutically effective amount of said compound of formula (I or X), and one or more pharmaceutically acceptable carriers, excipients, or diluents, wherein said therapeutically effective amount of the compound of formula (I or X) comprises an amount of the compound of formula (I or X) sufficient to treat or prevent a factor XI or factor IX/XI mediated disease. In one embodiment of the method, the factor XI or factor IX/XI mediated disease comprises stroke. In another embodiment of the method, the factor XI or factor IX/XI mediated disease comprises deep vein thrombosis. Thrombi may be associated with surgical procedures, long-term restriction, acquired or inherited procoagulant states including antiphospholipid antibody syndrome, protein C deficiency and protein S deficiency, or acute and chronic inflammation including recurrent abortion or Systemic Lupus Erythematosus (SLE). In another embodiment of the method, the factor XI or factor IX/XI mediated disease comprises coagulation associated with hemodialysis and/or venous hemofiltration treatment of renal disease. In another embodiment of the method, the factor XI or factor IX/XI mediated disease comprises cardiovascular disease. Cardiovascular disease may be associated with myocardial infarction, arrhythmia or aneurysm.

In another aspect of the invention, the factor XI or IX/XI dual factor modulators of the invention are used in adjuvant therapy or in combination therapy with other known therapeutic agents.

The term "treatment" as used herein refers to the full spectrum of treatment of a particular condition from which a patient suffers, including the alleviation of one or most of all the symptoms contributed by that condition, up to the complete cure or prevention of the onset of that condition for that particular condition.

The following is a non-exhaustive list of adjuvants and other therapeutic agents that may be used in combination with factor IXa antagonists of the present invention:

1. analgesic agents: aspirin

2. Non-steroidal anti-inflammatory drugs (NSAIDs): ibuprofen, naproxen and diclofenac

3. Disease modifying antirheumatic drugs (DMARDs): methotrexate, gold preparations, hydroxychloroquine, sulfasalazine

4. Biological response modifiers, DMARDs: etanercept, infliximab, glucocorticoid

In another embodiment, the invention provides a method of treating or preventing a factor IXa-mediated disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I or X), alone or in combination with a therapeutic agent selected from the group consisting of antibiotics, hormones, biological response modifiers, analgesics, NSAIDs, DMARDs, glucocorticoids, thrombolytic agents, antidepressants, and anticonvulsants.

The compounds of formula (I or X) of the present invention may be administered at dosage levels of from about 0.01 to 1000mg/kg body weight of the subject being treated. In another embodiment, the compounds of formula (I or X) of the present invention may be administered in a dosage range of 0.01 to 100 mg/kg. In another embodiment, the compounds of formula (I or X) of the present invention may be administered in a dosage range of 0.5 to 10mg/kg body weight/day. The amount of active ingredient that is combined with the carrier materials to produce a single dose 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 1mg to 2g of a compound of formula (I or X) and an appropriate and convenient amount of carrier material which may vary from about 5% to 95% of the total composition. Dosage unit forms typically contain from about 5mg to about 500mg of the active ingredient. The dose may be individualized by the clinician depending on the particular clinical condition of the subject being treated. It will be understood, therefore, that the specific dose 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.

The general procedure for the method of the invention is described below.

The generic name and definition of resinous reagents used in this disclosure is:

merrifield: p-chloromethyl polystyrene

Hydroxyl Merrifield: para hydroxymethyl polystyrene

Wang: (4-hydroxymethyl) phenoxymethyl polystyrene

Wang carbonate: 4- (p-nitrophenylcarbonate) phenoxymethyl polystyrene

Rink resin: 4- (2 ', 4' -dimethoxyphenyl-Fmco-aminomethyl) -phenoxy polystyrene resin

Wang bromine resin: (4-bromomethyl) phenoxymethyl polystyrene

THP resin: 3, 4-dihydro-2H-pyran-2-ylmethoxymethyl-polystyrene

The polyaldehyde resin may refer to the following resins:

4-benzyloxybenzaldehyde polystyrene

3-benzyloxybenzaldehyde polystyrene

4- (4-formyl-3-methoxyphenoxy) butyryl-aminomethyl polystyrene

2- (4-formyl-3-methoxyphenoxy) ethyl polystyrene

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

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

(3-Formylindolyl) acetamidomethyl polystyrene

(4-formyl-3-methoxyphenoxy) graft (polyethylene glycol) -polystyrene; or

(4-formyl-3-methoxyphenoxy) methyl polystyrene

Abbreviations used in the examples are as follows:

APCI-atmospheric pressure chemical ionization

BOC ═ tert-butoxycarbonyl

BOP (1-benzotriazolyloxy) tris (dimethylamino) phosphine hexafluorophosphate

d is day

DIAD (diisopropyl azodicarboxylate)

DCC-dicyclohexylcarbodiimide

DCE ═ 1, 2-dichloroethane

DCM ═ dichloromethane

DIC ═ diisopropylcarbodiimide

DIEA is diisopropylethylamine

DMA ═ N, N-dimethylacetamide

DMAP ═ dimethylaminopyridine

DME ═ 1, 2-dimethoxyethane

DMF ═ N, N-dimethylformamide

DMPU ═ 1, 3-dimethylpropyleneurea

DMSO ═ dimethyl sulfoxide

EDC ═ 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride

EDTA-EDTA

ELISA ═ enzyme-linked immunosorbent assay

ESI-electrospray ionization

ether ═ diethyl ether

EtOAc ═ ethyl acetate

FBS (fetal bovine serum)

g is g ═ g

h is hour

HBTU ═ O-benzotriazol-1-yl-N, N' -tetramethyluronium hexafluorophosphate

HMPA (hexamethylphosphoric triamide)

HOBt ═ 1-hydroxybenzotriazole

Hz-Hz

i.v. ═ intravenous

kD ═ kilodaltons

L is liter

LAH ═ lithium aluminum hydride

Lithium Diisopropylamide (LDA)

LPS ═ lipopolysaccharide

M is molar

m/z mass to charge ratio

mbar (mbar) ═ mbar

MeOH ═ methanol

mg ═ mg

min is minutes

mL to mL

millimolar mM

mmol ═ mmol

mol to mol

mp is melting point

MS mass spectrum

Normal (N ═ normal)

NMM ═ N-methylmorpholine, 4-methylmorpholine

NMR spectrum

p.o. ═ oral

PBS (phosphate buffered saline)

PMA myristoyl phorbol ethyl ester

ppm to parts per million

psi pounds per square inch

R_fTLC shift value

rt-room temperature

s.c. subcutaneous ═ s

SPA ═ proximity scintillation assay

TEA ═ triethylamine

TFA ═ trifluoroacetic acid

THF ═ tetrahydrofuran

THP-tetrahydropyranyl group

TLC ═ thin layer chromatography

TMSBr ═ bromotrimethylsilane, trimethylsilyl bromide

T_rRetention time ═ retention time

General procedure A

To a solution of carboxylic acid (1.0mmol) in DMF was added the amino acid methyl ester (1.2mmol), HBTU (1.1mmol) and DIEA (4.0mmol) and the mixture was stirred overnight. After completion of the reaction, a sufficient amount of water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, brine and dried (Na)₂SO₄) And concentrated under reduced pressure to give the amide. The crude product was purified by flash chromatography (silica gel, hexanes: EtOAc) to afford the pure product.

General procedure B

To a mixture of phenol (1mmol) and aryl or heteroaryl fluoride (2mmol) in DMF was added solid potassium carbonate (5mmol) and the mixture was heated at 80 ℃ for 12 h. After completion of the reaction, a sufficient amount of water was added, and the mixture was extracted with ethyl acetate. After the reaction is complete, a sufficient amount of water is added and the mixture is treated with acetic acidAnd (5) extracting with ethyl ester. The organic layer was washed with water, brine and dried (Na)₂SO₄) And concentrating under reduced pressure to obtain a crude product. The crude material obtained was purified by flash chromatography (silica gel, hexane: EtOAc) to afford the desired ether.

General procedure C

To esters in THF-CH₃To a solution of OH (4: 1) was added 2N lithium hydroxide solution (5 equivalents), and the resulting reaction mixture was stirred at 0 ℃ for 30 minutes and then warmed to room temperature. After completion of the reaction, the mixture was acidified with 2N HCl and extracted with ethyl acetate, the organic layer was washed with brine and dried (Na)₂SO₄) And removing the solvent under reduced pressure to obtain the product.

General procedure D

To a solution of aryl bromide or heteroaryl bromide (1mmol) in DME or toluene was added boric acid (2 equiv.), Pd (PPh)₃)₄(about 10 mol%), 2N Na₂CO₃Solution (3 mmol). The mixture was heated at 75 ℃ for 12 h. After the reaction is finished, the solvent is evaporated by decompression, and the residue is purified by column chromatography to obtain the target ester. The resulting ester was hydrolyzed according to the procedure described in procedure C to produce the acid.

General procedure E

To a solution of aniline or amine (1.0mmol) in DCE (10mL) was added aldehyde (2.0-2.2mmol), acetic acid (3.0mmol) and sodium triacetoxyborohydride (2.5mmol) or sodium cyanoborohydride and the mixture was stirred overnight. After completion of the reaction, 50mL DCM was added and the organic layer was washed with saturated sodium bicarbonate solution and brine, then over Na₂SO₄And drying. The solvent was removed under vacuum and the resulting product was purified by flash chromatography.

General procedure F

To a solution of aniline or amine (1.0mmol) in DCM (10mL) was added sulfonyl chloride (1.0mmol), pyridine (10.0mmol), and the mixture was stirred overnight. After completion of the reaction, 50ml of lcm was added and the organic layer was washed with 1N HCl, saturated sodium bicarbonate solution and brine, then over Na₂SO₄And drying. The solvent was removed under vacuum and the resulting sulfonamide was purified by flash chromatography.

General procedure G

The flask was charged with phenol or aniline (1.0 eq.), Cu (OAc)₂(1.0 equiv.), arylboronic acid (1.0-3.0) and powdered 4A molecular sieve. Reaction mixture with CH₂Cl₂Diluting to give an about 0.1M solution in phenol or aniline, adding Et₃N (5.0 equiv.). After stirring the colored heterogeneous reaction mixture at 25 ℃ for 24h at ambient atmosphere, the resulting slurry was filtered and the diaryl ether or diaryl amine was separated from the organic filtrate by flash chromatography.

General procedure H

To a solution of phenol (1.0mmol) in DMF (5mL) was added an alkyl halide (1.2mmol) (alkyl chloride then catalytic amount of NaI) and potassium carbonate (2.5mmol), and the mixture was heated at 70 ℃ overnight. After the reaction was complete, 5mL of ethyl acetate and 5mL of water were added. The organic layer was washed with water and then Na₂SO₄And (5) drying. The solvent was removed under vacuum and the ether obtained was purified by flash chromatography.

General procedure I

To a solution of the ester in THF was added lithium hydroxide (3-4 equivalents), water and methanol. The THF/water/methanol ratio was 4: 1. The reaction mixture was stirred at room temperature for 1-1.5 h. Adding 10% citric acid solution, and adjusting pH to 6-7. Ethyl acetate was added and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried (Na)₂SO₄) And concentrating under reduced pressure to obtain the product.

General procedure J

To a stirred solution of aniline (2mmol) dissolved in pyridine (4mmol) in DCM at 0 deg.C was added acid chloride (2.5 mmol). The reaction mixture was stirred at room temperature for 3h, extracted with DCM, washed with 1M HCl and brine, evaporated and then purified by column chromatography to give the amide.

General procedure K

To a stirred solution of amine or aniline (1mmol) dissolved in triethylamine (4mmol) in DCM at room temperature was added chloroformate (1.5 mmol). The reaction mixture was stirred for 1-1.5 h. The reaction mixture was concentrated and purified by chromatography to give a carbamate salt.

General procedure L

To a stirred solution of amine or aniline (1mmol) dissolved in DIEA (4mmol) in DCM at room temperature was added isocyanate (1.5 mmol). The reaction mixture was stirred for 1-1.5 h. The reaction mixture was concentrated and purified by chromatography to give urea.

General procedure M

By introducing N into the solution₂Gas 10min, aryl or heteroaryl bromide (1mmol) and Pd (PPh)₃)₄(10 mol%) A solution in anhydrous dioxane was degassed. To this solution was added tin alkenyl (1.2mmol), the solution was degassed for a further 10min and then in N₂The mixture was heated at 80 ℃ overnight. The reaction was cooled to room temperature, KF solution was added and the reaction mixture was stirred for 30 min. The precipitated solid was filtered and the solid residue on the filter funnel was washed with a large amount of ethyl acetate to wash out the product. The filtrate was concentrated and purified by flash column chromatography (silica gel, hexane: EtOAc) to afford the corresponding coupled product. The product was hydrolyzed as described in general procedure C to give the acid.

General procedure N

Pd/C (10 wt%) is added to a solution of olefin in anhydrous methanol or ethyl acetate, and the reaction is stirred under an atmosphere of hydrogen (1atm) for 2-18 h. For some olefin substrates, the reaction is carried out under 3-4 atmospheres of hydrogen. The reaction mixture was filtered over a pad of celite, washing with methanol. The filtrate was concentrated under reduced pressure to give the desired reduced product.

The general methods described above are for illustration only. Other conditions that may optionally be used include: other solvents, stoichiometries for alternative reagents, alternative reaction temperatures and alternative purification methods are used.

Examples

In a parallel MUX running 4 Waters1525 binary HPLC pumps, equipped with a Mux-UV2488 multichannel UV-Vis detector (recorded at 215 and 254 nM) and a Leap technologies HTS PAL autosampler^TMOn the system, gradient elution was performed with a Sepax GP-C18 column (4.6X 50mm) to obtain LC-MS data. 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 system was connected to a Waters Micromass ZQ mass spectrometer using electrospray ionization. All MS data were obtained in positive ion mode unless otherwise stated. 1HNMR data were obtained on a Varian400MHz spectrometer.

Example E-1

7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carboxylic acid

To a stirred solution of 0 deg.C H-Tyr (O-tert-Bu) -OMe HCl (15g, 52.1mmol), NEt₃

(13.1g, 129.7mmol) to a solution of 400mL DCM was added cyclopentylacetyl chloride (8.4g, 57.3 mmol). The reaction mixture was warmed to room temperature and stirred for an additional 45 min. The organic layer was then washed with water, 1.0N HCl and brine, then over Na₂SO₄And drying. The solvent was evaporated to dryness to afford 19g of amide, which was used in the next step without purification.

LCMS：438(M+1)⁺

To a stirred solution of the above amide (19g, 52.1mmol) in 400mL dry DCM at 0 deg.C was added oxalyl chloride (7.9g, 63.1 mmol). The reaction mixture was allowed to return to room temperature and stirring was continued for 1 h. The reaction mixture was then cooled to-10 ℃ and anhydrous FeCl was added thereto in portions₃(10.1g, 62.3 mmol). Stirring was continued at room temperature for 12h and the reaction mixture was treated with 200mL of 2.0M HCl for 2 h. The organic layer was separated, washed with water and brine, over Na₂SO₄Dried and concentrated under reduced pressure. To the foamy residue were added methanol (400mL) and concentrated H₂SO₄(10mL), the reaction was heated to reflux for 12h, the methanol was evaporated to dryness and the crude product was extracted with ethyl acetate (2X 100 mL). Aqueous layer with NH4OH (pH)>9) Basified and extracted with DCM (2 × 100 mL). The organic layer was washed with water and brine, over Na₂SO₄The solvent was dried to dryness to give 7.0g of 1-cyclopentylmethyl-7-hydroxy-3, 4-dihydro-isoquinoline-3-carboxylic acid methyl ester.

LCMS：288(M+1)⁺

The above compound (7g, 24.3mmol) was dissolved in 200mL DCM, and then 8.8g (48.6mmol) copper (II) acetate and 12.3g (121mmol) NEt were added₃. The resulting mixture was stirred at room temperature for 2.0h, filtered, and the filtrate was concentrated and then eluted by column chromatography using ethyl acetate and hexane to give 6.6g 1-cyclopentylmethyl-7-hydroxy-isoquinoline-3-carboxylic acid methyl ester.

LCMS：286(M+1)⁺

3.0g (10.5mmol) of the above phenol, 2.7g (15.7mmol) of 4-tert-butylphenyl-boronic acid, 1.9g (10.5mmol) of the ketone (II) acetate and 1g of the finely divided 4A molecular sieve are introduced into 115ml of LPCM. To the stirred solution was added 5.3g (115mmol) NEt₃Stirring was continued for 12 h. Filtration and evaporation of the solvent followed by column chromatography with hexane and ethyl acetate as eluent gave 1.5g7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carboxylic acid methyl ester.

LCMS：418(M+1)⁺

To a stirred solution of 1.5g (3.6mmol) of the ester in 9.0mL THF and 2.16mL MeOH at room temperature was added 2.16mL 2 NLiOH. Stirring was continued for 30min, and the mixture was acidified with 1.0N HCl (pH about 3) and extracted with 2X 25mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 1.37g of the title compound as a pale yellow solid.

¹H-NMR(400MHZ，CDCl₃)：δ8.47(s，1H)，7.98(d，1H)，7.59(s，1H)，7.53(dd，1H)，7.46(d，2H)，7.05(d，2H)，3.15(d，2H)，2.35(m，1H)，1.67(m，4H)，1.53(m，2H)，1.36(s，9H)，1.30(m，2H).LCMS：404(M+1)⁺

Example E-2

3- (5-bromo-thiophen-2-yl) -2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -propionic acid methyl ester

Compound E-1 was prepared according to general procedure a by treating compound E-1 with commercially available (2S) -amino-3- (5-bromo-thiophen-2-yl) -propionic acid methyl ester HCl prepared from (2S) -amino-3- (5-bromo-thiophen-2-yl) -propionic acid.

Example E-3

7- (trans-4-tert-butyl-cyclohexyloxy) -1-cyclopentylmethyl-isoquinoline-3-carboxylic acid

0.7g (2.5mmol) of methyl 1-cyclopentylmethyl-7-hydroxy-isoquinoline-3-carboxylate (prepared as in example E-1), 3.0g (5.0mmol) of triphenylphosphine polystyrene resin (1.10mmol/g) and 0.42g (2.7mmol) of cis-4-tert-butylcyclohexanol are placed in 25mL of DCM. DIAD (0.6g, 3.0mmol) was added thereto at 0 ℃. The reaction mixture was shaken for 2 h. Filtration and evaporation of the solvent followed by column chromatography with hexane/ethyl acetate gave 0.75g of product which was hydrolyzed as described in general procedure C to give 669mg of the title compound as a pale yellow solid.

LCMS：410(M+1)⁺

Example E-4

6- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carboxylic acid

12.5g (54.3mmol) of methyl 2-amino-3- (3-hydroxy-phenyl) -propionate was reacted with cyclopentylacetic acid (6.97g, 54.3mmol) as described in general procedure A. The compound was purified by gradient elution with ethyl acetate in hexane to give 9.1g of methyl 2- (2-cyclopentyl-acetylamino) -3- (3-hydroxy-phenyl) -propionate.

LCMS307(M+1)⁺.

A portion of the starting material from the previous step (4.0g, 13.1mmol) was dissolved in 120mL of anhydrous DCM to which was added 4-tert-butylphenyl boronic acid (2.0 equiv., 26.2mmol, 4.66g), ketone (II) acetate (1.1 equiv., 14.4mmol, 2.62g) and 2.0g of powdered 4A molecular sieve. To the stirred mixture was added triethylamine (3.0 eq, 39.3mmol, 5.5mL) and the reaction was carried out according to general procedure G. Purification by chromatography eluting with ethyl acetate in hexane on silica gel afforded 2.50g of 3- [3- (4-tert-butyl-phenoxy) -phenyl ] -2- (2-cyclopentyl-acetylamino) -propionic acid methyl ester.

LCMS：439(M+1)⁺.

1.77g (4.07mmol) of methyl 3- [3- (4-tert-butyl-phenoxy) -phenyl ] -2- (2-cyclopentyl-acetylamino) -propionate are dissolved in 40mL of anhydrous toluene, phosphorus oxychloride is added, and the mixture is heated at 90 ℃ for several hours and then cooled. The solvent and excess reagents were removed and the residue was purified by silica gel column chromatography eluting with 20-30% ethyl acetate in hexane to give 380mg of the cyclised product, methyl 6- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-3, 4-dihydro-isoquinoline-3-carboxylate.

LCMS421(M+1)⁺.

The product of the previous reaction (380mg, 0.91mmol) was dissolved in 9mL of dry DCM, triethylamine (5.0 eq., 4.53mmol, 0.63mL) and ketone (II) acetate (2.2 eq., 1.99mmol, 362mg) were added, and the mixture was stirred at room temperature for several hours. The solution was concentrated and purified by silica gel column chromatography eluting with ethyl acetate/hexane to give 378mg of 6- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carboxylic acid methyl ester.

LCMS419(M+1)⁺.

The entire amount of the above starting material (378mg, 0.905mmol) was taken and hydrolyzed according to general procedure C to give the title compound (365mg) as a white solid.

LCMS405(M+1)⁺.

Example E-5

2(R) -amino-3- (5-isopropyl-thiophen-2-yl) -propionic acid methyl ester HCl

To a suspension of (2R) -amino-3- (5-bromo-thiophen-2-yl) -propionic acid methyl ester HCl (14.0g, 46.59mmol) (prepared with commercially available (2R) -amino-3- (5-bromo-thiophen-2-yl) -propionic acid) in DCM (250mL) was added NaHCO₃(9.78g, 116.49mmol), water (100 mL). The solution was stirred for 10min and tert-butyloxycarbonyl anhydride (Boc-anhydride) (12.20g, 55.91mmol) was added. The reaction was stirred overnight. The organic layer was separated, washed with brine and dried (Na)₂SO₄) And concentrated under reduced pressure to give 17.0g of 3- (5-bromo-thiophen-2-yl) -2(R) -tert-butoxycarbonylamino-propionic acid methyl ester.

As described in general procedure M, with tributyl-isopropenyl-stannane (17.88g, 54.07mmol) and Pd (PPh)₃)4(4.8g, 4.15mmol) 15.0g (41.17mmol) of 3- (5-bromo-thiophen-2-yl) -2(R) -tert-butoxycarbonylamino-propionic acid methyl ester were treated to give 8.50g of 2(R) -tert-butoxycarbonylamino-3- (5-isopropenyl-thiophen-2-yl) -propionic acid methyl ester.

Following general procedure N, 8.50g2(R) -tert-butoxycarbonylamino 3- (5-isopropenyl-thiophen-2-yl) -propionic acid methyl ester was treated with Pd/C and H₂Gas (1atm) treatment gave 8.20g of methyl 2(R) -tert-butoxycarbonylamino-3- (5-isopropyl-thiophen-2-yl) -propionate. The ester was treated with HCl/dioxane (4.0M) to give 7.10g of the title compound.

Example E-6

2(S) -amino-3- (5-isopropyl-thiophen-2-yl) -propionic acid methyl ester HCl

The title compound was prepared by a similar procedure as used for the preparation of compound E-5.

Example E to 7

7- (4-tert-butyl-phenoxy) -1- (tetrahydro-pyran-4-yl) -isoquinoline-3-carboxylic acid

The title compound was synthesized by a similar procedure used to prepare compound E-1, except that tetrahydro-pyran-4-carbonyl chloride was used instead of cyclopentylacetyl chloride.

Examples E to 8

1-cyclopentylmethyl-7- (4-isopropyl-cyclohexyloxy) -isoquinoline-3-carboxylic acid

To a 0 deg.C solution of compound E-1(1.0mmol) in THF was added 4-isopropylcyclohexanol (1.5mmol), triphenylphosphine polystyrene resin (1.10mmol/g, 2.50mmol) and DIAD (2 mmol). The reaction was warmed to room temperature and stirred for 4 h. The reaction mixture was filtered and concentrated. The crude product was purified by flash column chromatography (silica gel, hexanes/EtOAc) to afford 1-cyclopentylmethyl-7- (4-isopropyl-cyclohexyloxy) -isoquinoline-3-carboxylic acid methyl ester. The ester was hydrolyzed in general procedure C to give the title compound.

Examples E to 9

1-cyclopentylmethyl-7- (4-trans-ethyl-cyclohexyloxy) -isoquinoline-3-carboxylic acid

The title compound was prepared by a similar procedure as used for the preparation of compound E-8, except that 4-cis-4-ethyl-cyclohexanol was used.

Examples E to 10

7- (4-tert-butylphenoxy) -isoquinoline-3-carboxylic acid

To a solution of (3S) -7-hydroxy-3, 4-dihydro-1H-isoquinoline-2, 3-dicarboxylic acid 2-tert-butyl ester (1.47g, 5.0mmol) in dry DMF (25mL) at ambient temperature was added methyl iodide (1.2 equiv., 6.0mmol, 0.37mL) followed by diisopropylethylamine (1.5 equiv., 7.5mmol, 1.31mL) and the reaction mixture stirred at room temperature for 3-4H at which time LC/MS analysis indicated the presence of product. The reaction mixture was poured into 50mL of water, extracted with DCM (3X 50mL), and the combined DCM extracts were washed with water (3X 50mL) and brine (50mL) over Na₂SO₄Dried, filtered and concentrated under reduced pressure. Purifying the crude product by silica gel flash column chromatography (ethyl acetate/hexane) to obtain (3S) -7-hydroxy-3, 4-dihydro-1H-isoquinoline-2, 3-Dicarboxylic acid 2-tert-butyl ester 3-methyl ester (1.13 g).

LCMS：308(M+1)⁺.

The above phenol (1.20G, 3.91mmol) was reacted with 4- (tert-butyl) phenylboronic acid (1.6 equiv., 6.26mmol, 1.11G), ketone (II) acetate (1.0 equiv., 3.91mmol, 710mg) as described in general procedure G. Flash column chromatography over silica gel (EtOAc/hexane) afforded 750mg of the title product, (3S) -7- (4-tert-butylphenoxy) -3, 4-dihydro-1H-isoquinoline-2, 3-dicarboxylic acid 2-tert-butyl 3-methyl ester.

LCMS：440(M+1)⁺

A portion of the above starting material (400mg, 0.91mmol) was placed in a dry 4 dram vial containing a magnetic rotor and treated with a 4N solution of anhydrous HCl in 1, 4-dioxane (1.0mL, 4.0mmol, 4.4 equiv.). The reaction was stirred at ambient temperature for 1h until TLC indicated completion of the reaction. The solvent and residual HCl were removed under vacuum and the crude (3S) -7- (4-tert-butylphenoxy) -1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid methyl ester hydrochloride was used without further purification.

LCMS：340(M+1)⁺

The crude product was dissolved in 18mL of dry toluene and DDQ (3.0 eq, 2.73mmol, 620mg) was added in one portion. The mixture was heated to reflux for 2h, then cooled to room temperature and concentrated under reduced pressure. The crude residue was placed directly on top of a silica gel column and eluted with a mixture of ethyl acetate and hexane to give 229mg of 7- (4-tert-butylphenoxy) -isoquinoline-3-carboxylic acid methyl ester. A portion of the ester (208mg, 0.62mmol) was hydrolyzed as described in general procedure C to give 199mg of the title compound as a white solid.

¹H-NMR(400MHZ，CDCl₃)：δ8.47(s，1H)，7.98(d，1H)，7.59(s，1H)，7.53(dd，1H)，7.46(d，2H)，7.05(d，2H)，3.15(d，2H)，2.35(m，1H)，1.67(m，4H)，1.53(m，2H)，1.36(s，9H)，1.30(m，2H).LCMS：322(M+1)⁺.

Examples E to 11

[ (5-bromo-thiophen-2-ylmethyl) -amino ] -acetic acid tert-butyl ester

The title compound was prepared by treating 5-bromo-thiophene-2-carbaldehyde with tert-butyl amino-acetate according to general procedure E.

Examples E to 12

[ (5-bromo-thiophen-2-ylmethyl) -amino ] -acetic acid methyl ester

The title compound was prepared according to general procedure E by treating 5-bromo-thiophene-2-carbaldehyde with amino-acetic acid methyl ester.

Examples E to 13

[ (4-bromo-thiophen-2-ylmethyl) -amino ] -acetic acid methyl ester

The title compound was prepared according to general procedure E by treating 4-bromo-thiophene-2-carbaldehyde with amino-acetic acid methyl ester.

Examples E to 14

[ (5-methyl-thiophen-2-ylmethyl) -amino ] -acetic acid methyl ester

The title compound was prepared according to general procedure E by treating 5-methyl-thiophene-2-carbaldehyde with amino-acetic acid methyl ester.

Example 1

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-phenylthiophen-2-yl) -propionic acid

The title compound was prepared according to general procedure D by treating compound E-2 with phenylboronic acid to give 2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-phenylthiophen-2-yl) -propionic acid methyl ester. The ester was hydrolyzed in general procedure C to give the title compound.

LCMS：624(M+1)⁺

Example 2

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- [5- (4-trifluoromethyl-phenyl) thiophen-2-yl ] -propionic acid

The title compound was prepared according to general procedure D by treatment of compound E-2 with 4-trifluorophenylboronic acid to give 2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- [5- (4-trifluoromethyl-phenyl) thiophen-2-yl ] -propionic acid methyl ester. The ester was hydrolyzed in general procedure C to give the title compound.

LCMS：702(M+1)⁺

Example 3

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-cyclopent-1-enyl-thiophen-2-yl) -propionic acid methyl ester

The title compound was prepared according to general procedure D by treating compound E-2 with cyclopenten-1-ylboronic acid.

LCMS：638(M+1)⁺

Example 4

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-cyclopent-1-enyl-thiophen-2-yl) -propionic acid

Example 3 was hydrolyzed by general procedure C to give the title compound.

LCMS：624(M+1)⁺

Example 5

2- (S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-cyclopentyl-thiophen-2-yl) -propionic acid methyl ester

According to general procedure N, by using Pd/C and H₂Example 3 was treated with gas (1 atmosphere) to prepare the title compound.

LCMS：640(M+1)⁺

Example 6

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-cyclopentyl-thiophen-2-yl) -propionic acid

The title compound was prepared by hydrolysis of example 5 according to general procedure C.

LCMS：626(M+1)⁺

Example 7

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-furan-3-yl-thiophen-2-yl) -propionic acid

The title compound was prepared by treating compound E-2 with furan-3-boronic acid to give 2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-furan-3-yl-thiophen-2-yl) -propionic acid methyl ester. The ester was hydrolyzed by general procedure C to give the title compound.

LCMS：624(M+1)⁺

Example 8

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- [5- (4-isopropylphenyl) -thiophen-2-yl ] propionic acid

The title compound was prepared by treating compound E-2 with 4-isopropylphenylboronic acid to give methyl 2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- [5- (4-isopropylphenyl) -thiophen-2-yl ] propanoate. The ester was hydrolyzed by general procedure C to give the title compound.

LCMS：676(M+1)⁺

Example 9

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-vinyl-thiophen-2-yl) -propionic acid

The title compound was prepared according to general procedure M using tributylvinylstannane and Pd (PPh)₃)₄Treatment of Compound E-2 to give 2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino } -3- (5-vinylthiophen-2-yl) -propionic acid methyl ester. The ester was hydrolyzed by general procedure C to give the title compound.

LCMS：584(M+1)⁺

Example 10

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-p-tolyl-thiophen-2-yl) -propionic acid

The title compound was prepared according to general procedure D by treating compound E-2 with 4-methylphenylboronic acid to give 2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-p-tolyl-thiophen-2-yl) -propionic acid methyl ester. The ester was hydrolyzed by general procedure C to give the title compound.

LCMS：648(M+1)⁺

Example 11

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- [5- (4-chloro-phenyl) -thiophen-2-yl ] -propionic acid

The title compound was prepared according to general procedure D by treating compound E-2 with 4-chlorophenylboronic acid to give 2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- [5- (4-chloro-phenyl) -thiophen-2-yl ] -propionic acid methyl ester. The ester was hydrolyzed by general procedure C to give the title compound.

LCMS：668(M+1)⁺

Example 12

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-ethyl-thiophen-2-yl) -propionic acid

According to general procedure N, by using Pd/C and H₂Example 9 was treated (1 atmosphere) to prepare the title compound.

LCMS：586(M+1)⁺

Example 13

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3-furan-2-yl-propionic acid

As described in general procedure A, compound E-1(0.050g, 0.012mmol) was reacted with (2S) -amino-3-furan-2-yl-propionic acid methyl ester hydrochloride (0.038g, 0.018mmol, prepared from commercially available (2S) -amino-3-furan-2-yl-propionic acid) to give 0.066g of 2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3-furan-2-yl-propionic acid methyl ester.

The resulting ester was hydrolyzed by general procedure C to give 0.060g of the title compound.

LCMS：542(M+1)⁺

Example 14

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (2-trifluoromethyl-phenyl) -propionic acid

The title compound was prepared by a similar procedure used to prepare example 13, except using 2(S) -amino-3- (2-trifluoromethyl-phenyl) -propionic acid methyl ester hydrochloride (prepared with commercially available 2(S) -amino-3- (2-trifluoromethyl-phenyl) -propionic acid).

The resulting ester was hydrolyzed by general procedure C to give the title compound.

LCMS：620(M+1)⁺

Example 15

{ (5-bromo-thiophen-2-ylmethyl) - [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -acetic acid tert-butyl ester

Compound E-11(0.060g, 0.195mmol) was treated with compound E-1(0.079g, 0.195mmol) according to general procedure A to give 36mg of the title compound.

LCMS：693(M+1)⁺

Example 16

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (3, 5-difluorophenyl) -propionic acid

The title compound was prepared by a similar procedure used to prepare example 13, except using methyl 2(S) -amino-3- (3, 5-difluorophenyl) -propionate hydrochloride (prepared with commercially available 2(S) -amino-3- (3, 5-difluorophenyl) -propionic acid).

LCMS：588(M+1)⁺

Example 17

[ [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] - (5-methyl-thiophen-2-ylmethyl) -amino ] -acetic acid

Compound E-14 was treated with compound E-1 according to general procedure a to give [ [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] - (5-methyl-thiophen-2-ylmethyl) -amino ] -acetic acid methyl ester, which after hydrolysis according to general procedure C gives the title compound.

LCMS：572(M+1)⁺

Example 18

{ (5-bromo-thiophen-2-ylmethyl) - [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -acetic acid methyl ester

Compound E-12 was treated with compound E-1 according to general procedure E to give the title compound.

LCMS：651(M+1)⁺

Example 19

{ (4-bromo-thiophen-2-ylmethyl) - [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -acetic acid

Compound E-13 was treated with compound E-1 according to general procedure a to give { (4-bromo-thiophen-2-ylmethyl) - [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -acetic acid methyl ester, which upon hydrolysis by general procedure C gives the title compound.

LCMS：637(M+1)⁺

Example 20

{ (5-bromo-thiophen-2-ylmethyl) - [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -acetic acid

Example 18 was hydrolyzed according to general procedure C to give the title compound.

LCMS：637(M+1)⁺

Example 21

Benzo [ b ] thiophen-3-yl- { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -acetic acid

The title compound was prepared by a similar procedure used for the preparation of example 13, except using amino-benzo [ b ] thiophen-3-yl-acetic acid methyl ester hydrochloride (obtained from commercially available amino-benzo [ b ] thiophen-3-yl-acetic acid).

LCMS：594(M+1)⁺

Example 22

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (4-fluoro-phenyl) -propionic acid

The title compound was prepared by a similar procedure used to prepare example 13, except using 2(S) -amino-3- (4-fluoro-phenyl) -propionic acid methyl ester hydrochloride (obtained from commercially available 2(S) -amino-3- (4-fluoro-phenyl) -propionic acid).

LCMS：570(M+1)⁺

Example 23

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-propenylthion-2-yl) -propionic acid

Compound E-2 was treated with tributyl-propenyl-stannane according to general procedure M to give 2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-propenylthion-2-yl) -propionic acid methyl ester. The ester was hydrolyzed by general procedure C to give the title compound.

LCMS：598(M+1)⁺

Example 24

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-propylthiophen-2-yl) -propionic acid

The title compound is prepared byAccording to general procedure N, with Pd/C and H₂(1atm) treatment of 2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino } -3- (5-propenylthion-2-yl) -propionic acid methyl ester (prepared in example 23) to give 2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino } -3- (5-propylthiophen-2-yl) -propionic acid methyl ester. The ester was hydrolyzed by general procedure C to give the title compound.

LCMS：600(M+1)⁺

Example 25

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5- (3, 3-dimethyl-but-1-enyl) -thiophen-2-yl) -propionic acid

Compound E-2 was treated with tributyl- (3, 3-dimethyl-but-1-enyl) -stannane according to general procedure M to give 2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5- (3, 3-dimethyl-but-1-enyl) -thiophen-2-yl) -propionic acid methyl ester. The ester was hydrolyzed by general procedure C to give the title compound.

LCMS：640(M+1)⁺

Example 26

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- [5- (hydroxymethylthiophen-2-yl))) -propionic acid methyl ester (example 26):

to 2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl]To a solution of-amino } -3- (5-vinylthiophen-2-yl) -propionic acid methyl ester (prepared in example 9) (0.650g, 1.09mmol) in acetone: water was added methylmorpholine-N-oxide (0.340mL) and osmium tetroxide (2 particles crystals). The solution was stirred at 0 ℃ for 1.5 h. Adding ethyl acetate and adding Na₂S₂O₄(saturated) solution, brine extraction, drying (Na)₂SO₄) And concentrated under reduced pressure to give 0.600g of 2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino } -3- [5- (1, 2-dihydroxy-ethyl) -thiophen-2-yl]-methyl propionate.

To a solution of the methyl ester (0.600g, 0.954mmol) in THF/water (1: 1, 7mL) at 0 deg.C was added NaIO₄(0.816g, 3.817 mmol). The reaction was stirred at 0 ℃ for 1.5 h. EtOAc was added, the organic layer was separated and washed with brine and dried (Na)₂SO₄) And concentrating under reduced pressure to obtain an oily product. The crude product was purified by flash column chromatography (silica gel, hexane: EtOAc) to give 0.220g of 2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino } -3- [5- (formyl-thiophen-2-yl)]-methyl propionate.

To a solution of the methyl ester (0.060g, 0.100mmol) in dry methanol (1.5mL) at 0 deg.C was added NaBH₄(15 mg). The reaction was stirred at 0 ℃ for 20 min. LCMS showed about 25% of the ester groups in the target product were reduced to alcohol. The reaction mixture was concentrated and purified by flash column chromatography (silica gel, hexane: EtOAc) to give 22mg of 2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino } -3- [5- (hydroxymethylthiophen-2-yl)]-methyl propionate (example 26).

Example 26-LCMS: 602(M +1)⁺

Example 27

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- [5- (hydroxymethylthiophen-2-yl ] -propionic acid

The title compound was obtained by hydrolysis of example 26 according to general procedure C.

LCMS：588(M+1)⁺

Example 28

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- [5- (methyl-thiophen-2-yl))) -propanoic acid

To the solution of example 26(0.060g, 0.100mmol) was added 4 Å MS and TMSCl (0.076 mL). To which NaBH was added at 0 deg.C₃CN (0.038g, 0.601 mmol). Heating of the solutionBrought to room temperature and stirred for 18 h. The crude reaction mixture was purified by flash column chromatography (silica gel, hexane: EtOAc) to give 8.5mg of 2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino } -3- [ 5-methyl-thiophen-2-yl]-methyl propionate. The ester was hydrolyzed by general procedure C to give 5.0mg of the title compound.

LCMS：572(M+1)⁺

Example 29

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-isopropenylthiophen-2-yl) -propionic acid

The title compound was prepared as described in general procedure M using tributyl-isopropenyl-stannane and Pd (PPh)₃)₄Treatment of Compound E-2 to give 2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino } -3- (5-isopropenylthiophen-2-yl) -propionic acid methyl ester. The ester was hydrolyzed by general procedure C to give the title compound.

LCMS：598(M+1)⁺

Example 30

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-isopropylthiophen-2-yl) -propionic acid

The title compound was prepared according to general procedure N, 2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino } -3- (5-isopropenylthiophen-2-yl) -propionic acid methyl ester (prepared in example 29) with Pd/C and H₂Gas (1atm) treatment to give 2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino } -3- (5-isopropylthiophen-2-yl) -propionic acid methyl ester. The ester was hydrolyzed by general procedure C to give the title compound.

LCMS：600(M+1)⁺

Example 31

3- (5-bromo-thiophen-2-yl) -2(R) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -propionic acid

As described in general procedure A, compound E-1(0.150g, 0.37mmol) was reacted with (2R) -amino-3- (5-bromo-thiophen-2-yl) -propionic acid methyl ester HCl (0.145g, 0.482mmol) (prepared with commercially available (2R) -amino-3- (5-bromo-thiophen-2-yl) -propionic acid) to give 0.180g3- (5-bromo-thiophen-2-yl) -2(R) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -propionic acid methyl ester. The resulting ester was hydrolyzed by general procedure C to give 0.158g of the title compound.

LCMS：637(M+1)⁺

Example 32

2(R) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-chloro-thiophen-2-yl) -propionic acid

Compound E-1 was treated with 2(R) -amino-3- (5-chloro-thiophen-2-yl) -propionic acid methyl ester (obtained from commercially available 2(R) -amino-3- (5-chloro-thiophen-2-yl) -propionic acid) according to general procedure a to give 2(R) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-chloro-thiophen-2-yl) -propionic acid methyl ester. The ester was hydrolyzed by general procedure C to give the title compound.

LCMS：592(M+1)⁺

Example 33

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-chloro-furan-2-yl) -propionic acid

Compound E-1 was treated with 2(S) -amino-3- (5-chloro-furan-2-yl) -propionic acid methyl ester hydrochloride (obtained from commercially available 2(S) -amino-3- (5-chloro-furan-2-yl) -propionic acid) according to general procedure a to give 2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-chloro-furan-2-yl) -propionic acid methyl ester. The ester was hydrolyzed by general procedure C to give the title compound.

LCMS：576(M+1)⁺

Example 34

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (2, 5-dichloro-thiophen-3-yl) -propionic acid

Compound E-1 was treated with 2(S) -amino-3- (2, 5-dichloro-thiophen-3-yl) -propionic acid methyl ester HCl (obtained from commercially available 2(S) -amino-3- (2, 5-dichloro-thiophen-3-yl) -propionic acid) according to general procedure a to give 2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (2, 5-dichloro-thiophen-3-yl) -propionic acid methyl ester. The ester was hydrolyzed by general procedure C to give the title compound.

LCMS：626(M+1)⁺

Example 35

(5-bromo-thiophen-2-yl) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -acetic acid

Compound E-1 was treated with amino- (5-bromo-thiophen-2-yl) -acetic acid methyl ester (obtained from commercially available amino- (5-bromo-thiophen-2-yl) -acetic acid) according to general procedure a to give (5-bromo-thiophen-2-yl) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -acetic acid methyl ester. The ester was hydrolyzed by general procedure C to give the title compound.

LCMS：622(M+1)⁺

Example 36

3- (5-bromo-furan-2-yl) -2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -propionic acid

Compound E-1 was treated with 2(S) -amino- (5-bromo-furan-2-yl) -propionic acid methyl ester hydrochloride (obtained from commercially available 2(S) -amino- (5-bromo-furan-2-yl) -propionic acid) according to general procedure a to give 3- (5-bromo-furan-2-yl) -2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -propionic acid methyl ester. The ester was hydrolyzed by general procedure C to give the title compound.

LCMS：620(M+1)⁺

Example 37

3- (5-bromo-thiophen-2-yl) -2(S) - { [7- (4-trans-tert-butyl-cyclohexyloxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -propionic acid

Compound E-3 was treated with (2S) -amino-3- (5-bromo-thiophen-2-yl) -propionic acid methyl ester hydrochloride (prepared with commercially available (2S) -amino-3- (5-bromo-thiophen-2-yl) -propionic acid) according to general procedure a to give 3- (5-bromo-thiophen-2-yl) -2(S) - { [7- (4-trans-tert-butyl-cyclohexyloxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -propionic acid methyl ester. The ester was hydrolyzed by general procedure C to give the title compound.

LCMS：642(M+1)⁺

Example 38

3- (5-bromo-thiophen-2-yl) -2(S) - { [6- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -propionic acid

Compound E-4 was treated with (2S) -amino-3- (5-bromo-thiophen-2-yl) -propionic acid methyl ester hydrochloride (prepared with commercially available (2S) -amino-3- (5-bromo-thiophen-2-yl) -propionic acid) according to general procedure a to give 3- (5-bromo-thiophen-2-yl) -2(S) - { [6- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -propionic acid methyl ester. The ester was hydrolyzed by general procedure C to give the title compound.

LCMS：636(M+1)⁺

Example 39

2(S) - { [7- (4-trans-tert-butyl-cyclohexyloxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-isopropenyl-thiophen-2-yl) -propionic acid

Following general procedure M, 3- (5-bromo-thiophen-2-yl) -2(S) - { [7- (4-trans-tert-butyl-cyclohexyloxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl]Methyl-amino } -propionate (prepared in example 37) was prepared with tributyl-isoPropenyl-stannane and Pd (PPh)₃)₄Treatment to give 2(S) - { [7- (4-trans-tert-butyl-cyclohexyloxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino } -3- (5-isopropenyl-thiophen-2-yl) -propionic acid methyl ester. The ester was hydrolyzed by general procedure C to give the title compound.

LCMS：604(M+1)⁺

Example 40

2(S) - { [7- (4-trans-tert-butyl-cyclohexyloxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid

Following general procedure N, 2(S) - { [7- (4-trans-tert-butyl-cyclohexyloxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino } -3- (5-isopropenyl-thiophen-2-yl) -propionic acid methyl ester (prepared in example 39) with Pd/C and H₂(1atm) to give 2(S) - { [7- (4-trans-tert-butyl-cyclohexyloxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid methyl ester. The ester was hydrolyzed by general procedure C to give the title compound.

LCMS：606(M+1)⁺

EXAMPLE 41

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-furan-2-yl) -propionic acid

Following general procedure a, a solution of compound E-1(1mmol) in DMF was treated with 2(S) -amino-3- (5-bromo-furan-2-yl) -propionic acid methyl ester hydrochloride (1.2mmol, prepared with commercially available 2(S) -amino-3- (5-bromo-furan-2-yl) -propionic acid) to give 3- (5-bromo-furan-2-yl) -2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -propionic acid methyl ester.

Following general procedure M, the above bromide (1mmol) was reacted with tributyl-isopropenyl-stannane (1.5mmol) and Pd (PPh)₃)₄(10 mol%) to give 2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino groupMethyl } 3- (5-isopropenyl-furan-2-yl) -propionate.

The above olefin was reduced according to general procedure N to give 2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-furan-2-yl) -propionic acid methyl ester. The ester was hydrolyzed by general procedure C to give the title compound.

LCMS：584(M+1)⁺

Example 42

2(S) - { [ 1-cyclopentylmethyl-7- (4-isopropyl-cyclohexyloxy) -isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid

The title compound was prepared according to general procedure A by treating E-8(1mmol) with E-6(1.20mmol) to give 2(S) - { [ 1-cyclopentylmethyl-7- (4-isopropyl-cyclohexyloxy) -isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid methyl ester. The ester was hydrolyzed by general procedure C to give the title compound.

LCMS：592(M+1)⁺

Example 43

2(R) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-isopropylthiophen-2-yl) -propionic acid

According to general procedure M, 0.370g (0.570mmol)3- (5-bromo-thiophen-2-yl) -2(R) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl]Methyl-amino } -propionate (prepared in example 31) with tributyl-isopropenyl-stannane (0.330g, 0.997mmol) and Pd (PPh)₃)₄(65mg, 0.057mmol) to yield 0.295g of coupled olefin product. The resulting alkene (95mg) was reduced as described in general procedure N to give 84mg2(R) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino } -3- (5-isopropylthiophen-2-yl) -propionic acid methyl ester. This ester (75mg) was hydrolyzed by general procedure C to give 65mg of the title compound as a white solid. 1H-NMR (400MHz, CDC 13): Δ 8.85(d, 1H), 8.32(s, 1H), 7.78(d，1H)，7.39(m，3H)，7.00(d，2H)，6.67(s，1H)，6.48(s，1H)，4.93(d，1H)，3.45(d，2H)，2.97(m，3H)，2.27(m，1H)，1.58(m，6H)，1.34(m，9H)，1.21(m，8H).LCMS：600(M+2)⁺.

LCMS：600(M+1)⁺

Example 44

2(S) - { [7- (4-tert-butyl-phenoxy) -isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid

The title compound was prepared according to general procedure a by treating compound E-10(1mmol) with compound E-6(1.2mmol) to give 2(S) - { [7- (4-tert-butyl-phenoxy) -isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid methyl ester. The ester was hydrolyzed by general procedure C to give the title compound.

LCMS：517(M+1)⁺

Example 45

2(S) - { [ 1-cyclopentylmethyl-7- (4-trans-ethyl-cyclohexyloxy) -isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid

The title compound was prepared according to general procedure a by treating compound E-9(1mmol) with compound E-6(1.20mmol) to give 2(S) - { [ 1-cyclopentylmethyl-7- (4-ethyl-cyclohexyloxy) -isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid methyl ester. The ester was hydrolyzed by general procedure C to give the title compound.

LCMS：578(M+1)⁺

Example 46

2(S) - { [ 1-cyclopentylmethyl-7- (4-isopropyl-phenoxy) -isoquinoline-3-carbonyl-amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid

Following general procedure G, methyl 1-cyclopentylmethyl-7-hydroxy-isoquinoline-3-carboxylate (prepared in example E-1) is treated with 4-isopropylphenylboronic acid to give methyl 7- (4-isopropyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carboxylate. This ester was hydrolyzed by general procedure C to give 7- (4-isopropyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carboxylic acid. This acid was coupled with compound E-6 by general procedure a to give 2(S) - { [ 1-cyclopentylmethyl-7- (4-isopropyl-phenoxy) -isoquinoline-3-carbonyl-amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid methyl ester. The ester was hydrolyzed by general procedure C to give the title compound.

LCMS：586(M+1)⁺

Example 47

2(S) - { [7- (4-tert-butyl-phenoxy) -1- (tetrahydro-pyran-4-yl) -isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid

It is prepared by treating compound E-7 with compound E-6 to give 2(S) - { [7- (4-tert-butyl-phenoxy) -1- (tetrahydro-pyran-4-yl) -isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid methyl ester. The ester was hydrolyzed by general procedure C to give the title compound.

LCMS：602(M+1)⁺

Example 48

2(S) - { [6- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid

3- (5-bromo-thiophen-2-yl) -2(S) - { [6- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl]Methyl-amino } -propionate (prepared in example 38) was prepared with tributyl-isopropenyl-stannane and Pd (PPh)₃)₄Treatment to give 2(S) - { [6- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino } -3- (5-isopropenyl-thiophen-2-yl) -propionic acid methyl ester. It was treated with Pd/C and H according to general procedure N₂(1atm) to give 2(S) - { [6- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid methyl ester. The ester was hydrolyzed by general procedure C to give the title compound。

LCMS：600(M+1)⁺

Example 49

2(S) - { [7- (4-tert-butyl-phenyl) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid

1-Cyclopentylmethyl-7-hydroxy-isoquinoline-3-carboxylic acid methyl ester (prepared in example E-1) is hydrolyzed by general procedure C to give 1-cyclopentylmethyl-7-hydroxy-isoquinoline-3-carboxylic acid. This acid (1mmol) was coupled with compound E-6 to give 2(S) - [ (1-cyclopentylmethyl-7-hydroxy-isoquinoline-3-carbonyl) amino ] -3- (5-isopropyl-thiophen-2-yl) -propionic acid methyl ester.

Et was added to a stirred solution of the above phenol (1mmol) at 0 deg.C₃N (2mmol) and DMAP (cat.) in DCM, then excess trifluoromethanesulfonic anhydride (2mmol) was added at 0 ℃. The reaction was stirred at room temperature for 30 min. The organic layer was separated, washed with citric acid, water and brine, and dried (Na)₂SO₄) And concentrated under reduced pressure to give the desired trifluoride, which is used directly in the next step without further purification.

The above-mentioned trifluoride (1mmol) was reacted with 4-tert-butylphenyl-boronic acid (2mmol), Pd (PPh) according to general procedure D₃)₄(0.05mmol) and 2N Na₂CO₃(3mmol) to give 2(S) - { [7- (4-tert-butyl-phenyl) -1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid methyl ester. The ester was hydrolyzed by general procedure C to give the title compound.

LCMS：584(M+1)⁺

Example 50

2(S) - { [7- (4-tert-butyl-benzoyl) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid

Into a direct fire dried flask was added the trifluoride (1mmol) of example 49, 4-tert-butylphenyl boronic acid (1.40mmol), PdCl₂(dppf) (10 mol%), potassium carbonate (3mmol) and comminuted NaI (3 mmol). The flask was charged with CO gas, and then anisole was added. The mixture was heated at 80 ℃ for 48h under a CO atmosphere. The reaction mixture was cooled to rt, filtered, and washed with EtOAc. The organic layer was washed with water, brine, dried and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, hexanes: EtOAc) to afford pure 2(S) - { [7- (4-tert-butyl-benzoyl) -1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid methyl ester. The ester was hydrolyzed by general procedure C to give the title compound.

LCMS：612(M+1)⁺

Example 51

3- (5-acetyl-thiophen-2-yl) -2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -propionic acid

Following general procedure M, compound E-2(1.0g, 1.53mmol) was reacted with tributyl- (1-ethoxy-vinyl) -stannane (0.83g, 2.3mmol) and Pd (PPh)₃)₄(0.177g, 0.15mmol) to yield 0.600g of 3- (5-acetyl-thiophen-2-yl) -2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino } -propionic acid methyl ester. The ester (20mg) was hydrolyzed by general procedure C to give the title compound.

LCMS：600(M+1)⁺

Example 52

7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carboxylic acid [1- (5-isopropyl-thiophen-2-ylmethyl) - (2R) -methanesulfonylamino-2-oxo-ethyl ] -amide

To a solution of example 43(0.150g, 0.250mmol) in DCM was added oxalyl chloride (0.063g, 0.50mmol) and the solution was stirred for 45 min. The solution was concentrated and the solid was dried under vacuum. The solid was dissolved in DCM, methanesulfonamide (0.070g, 0.750mmol) was added, followed by NEt₃(0.100mL, 0.750mmol) and the reaction stirred for 2 h. The solution was concentrated and purified by flash chromatography (silica gel, DCM: MeOH)To yield 7mg of the title compound.

LCMS：677(M+1)⁺

Example 53

7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carboxylic acid [1- (5-isopropyl-thiophen-2-ylmethyl) - (2S) -methanesulfonylamino-2-oxo-ethyl ] -amide

To a solution of example 30(0.105g, 0.17mmol) in THF was added CDI (0.085g, 0.526mmol) and the reaction was stirred at room temperature for 6 h. To this was added methanesulfonamide (0.035g, 0.36mmol) and DBU (0.040g, 0.26mmol) in THF, and the reaction was heated at 60 ℃ for 3h and stirred at room temperature for 3 h. The solution was concentrated under reduced pressure, and the crude product was purified by the same procedure as used in example 52 to give 8mg of the title compound.

LCMS：677(M+1)⁺

Example 54

7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carboxylic acid [ 1-benzyloxycarbamoyl-2- (5-isopropyl-thiophen-2-yl) -ethyl ] -amide

A solution of example 43(0.090g, 0.150mmol) in DMF was treated with o-benzylhydroxylamine hydrochloride (27mg, 0.165mmol), HBTU (0.063g, 0.165mmol) and DIEA (0.150mL, 0.829mmol) according to general procedure A. The crude product was purified by flash chromatography (silica gel, hexane: EtOAc) to give 74mg of the title compound.

LCMS：705(M+1)⁺

Example 55

7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carboxylic acid [ 1-hydroxycarbamoyl-2- (5-isopropyl-thiophen-2-yl) -ethyl ] -amide

Example 54(68mg, 0.09mmol) was reacted with H according to general procedure N₂(1 atmosphere) and Pd/C treatment. Subjecting the crude product to flash chromatography (silica gel, CH)₂Cl₂∶CH₃OH) to yield 6mg of the title compound.

LCMS：615(M+1)⁺

Biological analysis

The following assay may be used to identify compounds of formula (I or X) that are effective in antagonizing the function of factor IX. Compounds of formula (I or X) that are effective in antagonizing the function of factor IX may be inhibitors of the intrinsic coagulation pathway.

Total analysis program

Fluorescence-based molecular analysis of factor IXa:

for determining the IC of a compound of formula (I or X) in relation to factor IXa₅₀mu.L of solutions of compounds of formula (I or X) at different concentrations (2% DMSO final concentration) were incubated for 10min at room temperature with 24. mu.L of a solution of FIXa (HCIXA-0050 Haemotologic Technologies Inc. Essexjunction, VT; 3.9 units/mL) in a buffer containing 80% ethylene glycol, 10mM CaCl₂200mM NaCl and 100mM Tris (pH7.4), wherein a 24. mu.L solution of FIXa has an activity of 3.9 units/mL. The reaction was initiated by the addition of 12. mu.L of 0.5mM FIXa substrate (Pefa-10148 from Pentapharm Basel, Switzerland; methanesulfonyl-D-cyclohexylglycyl-glycyl-arginine-7-amino-4-methylcoumarid monoacetate, available from Centerchem, Inc.). After incubation at room temperature for 10min, the plates were read in a Spectromax Gemini fluorescence plate reader at an excitation wavelength of 340nm and an emission wavelength of 440 nm. IC was then calculated from the different concentrations of test compound₅₀。

Color-based molecular analysis of factor XIa:

for determining the IC of a compound of formula (I or X) in relation to factor IXa₅₀mu.L solutions of compounds of formula (I or X) at different concentrations (2% DMSO final concentration) were incubated for 10min at room temperature with 10. mu.L of FIXa (HCXIA-0160 from Haemotology Technologies Inc. Essex Junction, VT) in buffer (containing 50mM Tris (pH7.4) and 150mM NaCl) and 150. mu.L of buffer, where 10. mu.L of FXIa solution had 2 mono-moleculesbit/mL activity. The reaction was initiated by the addition of 20. mu.L of 10mM FXIa substrate (Pefa-3371 from Pentapharm Basel, Switzerland; Pyr-Phg-Arg-pNA monoacetate from Centerchem, Inc.). After incubation of the reaction at room temperature for 10min, plates were read at 405nm in a Spectromax UV/vis plate reader.

In vitro coagulation assay for FIXa

The inhibitory effect of the compound of formula (I or X) of the present invention on plasma coagulation with exogenous factor IXa added was evaluated. mu.L of solutions of compounds of formula (I or X) at different concentrations containing 2% DMSO were incubated for 10min at 37 ℃ with 30. mu.L of 3.2 units/mL FIXa (HCXIA-0160 from Haemotological Technologies Inc. Essex Junction, VT) in assay buffer containing 20mM HEPES (pH7.4) and 150mM NaCl, 50. mu.L of 64-fold dilution of ALEXIN (trinity biosciences) with assay buffer containing 20mM HEPES and 50. mu.L of recombinant human citrated plasma (Sigma). By adding 50. mu.L of 40mM CaCl₂The assay buffer solution of (a) initiates the reaction. Immediately after calcium addition the plates were read in kinetic mode at 405nm at 37 ℃. Plates were read on a Spectromax UV/vis plate reader for 5-10min at 10 second intervals (depending on clotting time).

In vitro coagulation assay of FXIa:

the inhibitory effect of the compound of formula (I or X) of the present invention on plasma coagulation with exogenous factor XI added was evaluated. mu.L of a solution of compounds of formula (I or X) at different concentrations containing 2% DMSO for 10min at 37 ℃ were incubated with 30. mu.L of 0.4 units/mL FIXa (HCXIA-0160 from Haemotological Technologies Inc. Essex Junction, VT) in assay buffer containing 20mM HEPES (pH7.4) and 150mM NaCl, 50. mu.L of 64-fold ALEXIN (trinity biosciences) diluted with assay buffer containing 20mM HEPES (pH7.4) and 50. mu.L of recombinant human citrated plasma (Sigma). By adding 50. mu.L of 40mM CaCl₂The assay buffer solution initiates the reaction. Immediately after calcium addition the plates were read in kinetic mode at 405nm at 37 ℃. Plates were read on a Spectromax UV/vis plate reader for 5-10min at 10 second intervals (depending on clotting time).

The examples in Table 1 are shown with IC's of less than 30. mu.M₅₀Or inhibiting factor IX in a factor IXa fluorescence assay, inhibiting factor XI in a factor XIa chromogenic assay, inhibiting factor IX in an factor IXa in vitro coagulation assay, or inhibiting factor XI in an in vitro coagulation assay. Various embodiments in Table 1 may also have an IC of less than 30 μ M in more than one of the above assays₅₀。

While the invention has been described and illustrated with reference to certain preferred embodiments thereof, 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, for IXa mediated diseases, effective dosages other than the preferred dosages as set forth herein can be employed as a result of different responses in the treated mammal. Likewise, the particular pharmacological responses observed may vary depending upon and upon the particular active compound selected, or whether a pharmaceutically acceptable carrier is present, 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. Moreover, all compounds set forth in the written description are contemplated as being potentially suitable for any of the described methods, processes, compositions, and/or compounds presented in the written description and appended claims.

Claims

1. A compound of formula (X), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein the content of the first and second substances,

R₁₀₁is selected from-H or-CH₂-thienyl, wherein-CH₂Thienyl of-thienyl by-Br or-CH₃Optionally substituted;

R₁₀₃Is selected from-H, -CH₂-thienyl, -CH₂-phenyl, -CH₂-furyl, thienyl and benzothienyl, wherein R₁₀₃Each of the above possibilities, except-H, is optionally substituted with one or more members selected from the group consisting of:

-H、-CH₃、-CF₃、-Cl、-Br、-F、-C(O)CH₃、-CH₂CH₃、-CH＝CH₂、-CH₂OH、-CH(CH₃)₂、-CH₂CH₂CH₃-propenyl, -3, 3-dimethyl-butenyl, -isopropenyl, -phenyl, -phenylene-methyl, -phenylene-propyl, -phenylene-trifluoromethyl, -phenylene-chloride, -cyclopentyl, -cyclopentenyl and-furyl;

2. A compound of formula (X), or a pharmaceutically acceptable salt, ester or prodrug thereof:

wherein R is₁₀₁Is selected from-H or-CH₂-thienyl, wherein-CH₂Thienyl of-thienyl by-Br or-CH₃Optionally substituted;

-H，-CH₃，-CF₃，-Cl，-Br，-F，-C(O)CH₃，-CH₂CH₃，-CH＝CH₂，-CH₂OH，-CH(CH₃)₂，-CH₂CH₂CH₃，

R₁₀₄selected from the following groups:

and Y is selected from the following groups: h, performing a chemical reaction on the mixture of the hydrogen peroxide and the nitrogen peroxide,

3. a compound according to claim 2, wherein R₁₀₄Is that

4. A compound according to claim 2, wherein R₁₀₃Is optionally substituted-CH₂-2-yl-thienyl or optionally substituted-CH₂-phenyl.

5. A compound according to claim 2, wherein R₁₀₃Is optionally substituted-CH₂-2-yl-thienyl。

6. A compound according to claim 3, wherein R₁₀₁is-H.

7. A compound according to claim 3, wherein Y is selected from the group consisting of:

8. a compound according to claim 2, wherein the compound of formula (X) is selected from:

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-phenyl-thiophen-2-yl) -propionic acid,

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- [5- (4-trifluoromethyl-phenyl) -thiophen-2-yl ] -propionic acid,

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-cyclopent-1-enyl-thiophen-2-yl) -propionic acid methyl ester,

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-cyclopent-1-enyl-thiophen-2-yl) -propionic acid,

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-cyclopentyl-thiophen-2-yl) -propionic acid methyl ester,

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-cyclopentyl-thiophen-2-yl) -propionic acid,

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-furan-3-yl-thiophen-2-yl) -propionic acid,

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- [5- (4-isopropyl-phenyl) -thiophen-2-yl ] -propionic acid,

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-vinyl-thiophen-2-yl) -propionic acid,

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-p-tolyl-thiophen-2-yl) -propionic acid,

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- [5- (4-chloro-phenyl) -thiophen-2-yl ] -propionic acid,

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-ethyl-thiophen-2-yl) -propionic acid,

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3-furan-2-yl-propionic acid,

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (2-trifluoromethyl-phenyl) -propionic acid,

{ (5-bromo-thiophen-2-ylmethyl) - [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -acetic acid tert-butyl ester,

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (3, 5-difluorophenyl) -propionic acid,

[ [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] - (5-methyl-thiophen-2-ylmethyl) -amino ] -acetic acid,

{ (5-bromo-thiophen-2-ylmethyl) - [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -acetic acid methyl ester,

{ (4-bromo-thiophen-2-ylmethyl) - [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -acetic acid,

{ (5-bromo-thiophen-2-ylmethyl) - [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -acetic acid,

benzo [ b ] thiophen-3-yl- { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -acetic acid,

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (4-fluoro-phenyl) -propionic acid,

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-propenyl-thiophen-2-yl) -propionic acid,

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-propyl-thiophen-2-yl) -propionic acid,

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- [5- (3, 3-dimethyl-but-1-enyl) -thiophen-2-yl ] -propionic acid,

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-hydroxymethyl-thiophen-2-yl) -propionic acid methyl ester,

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-hydroxymethyl-thiophen-2-yl) -propionic acid,

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-methyl-thiophen-2-yl) -propionic acid,

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-isopropenyl-thiophen-2-yl) -propionic acid,

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-isopropylthiophen-2-yl) -propionic acid,

3- (5-bromo-thiophen-2-yl) -2(R) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -propionic acid,

2(R) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-chloro-thiophen-2-yl) -propionic acid,

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-chloro-furan-2-yl) -propionic acid,

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (2, 5-dichloro-thiophen-3-yl) -propionic acid,

(5-bromo-thiophen-2-yl) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -acetic acid,

3- (5-bromo-furan-2-yl) -2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -propionic acid,

3- (5-bromo-thiophen-2-yl) -2(S) - { [7- (4-trans-tert-butyl-cyclohexyloxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -propionic acid,

3- (5-bromo-thiophen-2-yl) -2(S) - { [6- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -propionic acid,

2(S) - { [7- (4-trans-tert-butyl-cyclohexyloxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-isopropenyl-thiophen-2-yl) -propionic acid,

2(S) - { [7- (4-trans-tert-butyl-cyclohexyloxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid,

2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-furan-2-yl) -propionic acid,

2(S) - { [ 1-cyclopentylmethyl-7- (4-isopropyl-cyclohexyloxy) -isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid,

2(R) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid,

2(S) - { [7- (4-tert-butyl-phenoxy) -isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid,

2(S) - { [ 1-cyclopentylmethyl-7- (4-trans-ethyl-cyclohexyloxy) -isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid,

2(S) - { [ 1-cyclopentylmethyl-7- (4-isopropyl-phenoxy) -isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid,

2(S) - { [7- (4-tert-butyl-phenoxy) -1- (tetrahydro-pyran-4-yl) -isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid,

2(S) - { [6- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid,

2(S) - { [7- (4-tert-butyl-phenyl) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid,

2(S) - { [7- (4-tert-butyl-benzoyl) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -3- (5-isopropyl-thiophen-2-yl) -propionic acid,

3- (5-acetyl-thiophen-2-yl) -2(S) - { [7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carbonyl ] -amino } -propionic acid,

7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carboxylic acid [1- (5-isopropyl-thiophen-2-ylmethyl) -2(R) -methanesulfonylamino-2-oxo-ethyl ] -amide,

7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carboxylic acid [1- (5-isopropyl-thiophen-2-ylmethyl) -2(S) -methanesulfonylamino-2-oxy-ethyl ] -amide,

7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carboxylic acid [ 1-benzyloxycarbamoyl-2- (5-isopropyl-thiophen-2-yl) -ethyl ] -amide, and

9. A compound according to claim 2, wherein Y is-methylene-cyclopentyl.

10. A pharmaceutical composition comprising a compound of formula (X), or a pharmaceutically acceptable salt, ester, or prodrug thereof:

R₁₀₃Is selected from-H, -CH₂-thienyl, -CH₂-phenyl, -CH₂-furyl, thienyl and benzothienyl, wherein R₁₀₃Each of the above possibilities, except-H, is optionally substituted with one or more members selected from the group consisting of: -H, -CH₃，-CF₃，-Cl，-Br，-F，-C(O)CH₃，-CH₂CH₃，-CH＝CH₂，-CH₂OH，-CH(CH₃)₂，-CH₂CH₂CH₃，

R₁₀₄Selected from the following groups:

and Y is selected from: h, performing a chemical reaction on the mixture of the hydrogen peroxide and the nitrogen peroxide,

11. the pharmaceutical composition according to claim 10, wherein R is₁₀₄Is that

12. The pharmaceutical composition according to claim 10, wherein R is₁₀₃Is optionally substituted-CH₂-2-yl-thienyl or optionally substituted-CH₂-phenyl.

13. The pharmaceutical composition according to claim 10, wherein R is₁₀₃Is optionally substituted-CH₂-2-yl-thienyl.

14. The pharmaceutical composition according to claim 13, wherein R is₁₀₁Is H.

15. The pharmaceutical composition according to claim 10, wherein Y is selected from the group consisting of:

16. the pharmaceutical composition according to claim 10, wherein Y is-methylene-cyclopentyl.

17. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is prepared in a dosage range of about 0.01 to 1,000mg/kg body weight/day.

18. The pharmaceutical composition of claim 10, wherein the compound of formula (X) is an antagonist of factor XI or factor IX/XI activity.

19. The pharmaceutical composition of claim 18 wherein the compound of formula (X) is a partial antagonist of factor XI and factor XI/IX activity, wherein a partial antagonist comprises a compound that inhibits incomplete activity at physiological doses.

20. The pharmaceutical composition of claim 18, comprising a therapeutically effective amount of a compound of formula (X), wherein the therapeutically effective amount of formula (X) preferentially inhibits the intrinsic coagulation cascade when compared to the extrinsic coagulation cascade.

21. The pharmaceutical composition of claim 20, wherein the therapeutically effective amount of formula (X) comprises an amount sufficient to achieve and maintain sustained blood levels that at least partially antagonize the biological activity of factor XI or factor IX/XI.

22. The pharmaceutical composition of claim 10, wherein the compound of formula (X) is an antagonist of factor IX activity.

23. The pharmaceutical composition of claim 22, wherein the compound of formula (X) is a partial antagonist of factor IX activity, wherein a partial antagonist comprises a compound that inhibits incomplete activity at physiological doses.

24. The pharmaceutical composition of claim 10, comprising a therapeutically effective amount of a compound of formula (X), wherein the therapeutically effective amount comprises an amount of the compound of formula (X) sufficient to at least partially inhibit the biological activity of factor IX in a subject.

25. The pharmaceutical composition of claim 10, comprising a therapeutically effective amount of a compound of formula (X), wherein the therapeutically effective amount comprises an amount of the compound of formula (X) sufficient to at least partially inhibit the biological activity of factor IX in a subject.

26. The pharmaceutical composition of claim 25, wherein the therapeutically effective amount of formula (X) preferentially inhibits the intrinsic coagulation cascade when compared to the extrinsic coagulation cascade.

27. The pharmaceutical composition of claim 10, wherein the therapeutically effective amount of formula (X) comprises an amount of the compound of formula (X) sufficient to at least partially alleviate at least one factor IX-mediated disease.

28. The pharmaceutical composition of claim 10 in the form of an oral dose or a parenteral dosage unit.

29. A method comprising administering to a subject a compound of formula (X):

R₁₀₄Selected from the following groups:

30. the method according to claim 29, wherein the compound of formula (X) is delivered as part of a pharmaceutical composition comprising a therapeutically effective amount of said compound of formula (X) and one or more pharmaceutically acceptable carriers, excipients or diluents.

31. The method according to claim 29, wherein R₁₀₄Is that

32. The method according to claim 31, wherein R₁₀₁is-H.

33. The method according to claim 29, wherein R₁₀₃Is optionally substituted-CH₂-2-yl-thienyl or optionally substituted-CH₂-phenyl.

34. The method according to claim 29, wherein Y is selected from the group consisting of:

35. the method according to claim 29, wherein Y is-methylene-cyclopentyl.

36. The method according to claim 29, wherein the compound of formula (X) is selected from the following compounds:

7- (4-tert-butyl-phenoxy) -1-cyclopentylmethyl-isoquinoline-3-carboxylic acid [1- (5-isopropyl-thiophen-2-ylmethyl) -2(R) -methanesulfonylamino-2-oxo-ethyl ] -amide, and,

37. A method according to claim 29, wherein the compound of formula (X) inhibits factor IX activity by up to 95%.

38. A method of treating stroke, myocardial infarction, aneurysm, or thrombosis comprising the method of claim 29.

39. The method of claim 29, wherein the compound of formula (X) is an antagonist of factor IX activity.

40. The method of claim 29 wherein the compound of formula (X) is a partial antagonist of factor IX, wherein a partial antagonist comprises a compound that inhibits incomplete activity at physiological doses.

41. The method of claim 29, wherein the compound of formula (X) antagonizes factor IX-mediated coagulation.

42. The method of claim 29, wherein the compound of formula (X) is administered in an amount sufficient to partially antagonize the biological activity of factor IX in the subject.

43. The method of claim 30, wherein the therapeutically effective amount of the compound of formula (X) comprises an amount of the compound of formula (X) sufficient to at least partially inhibit the intrinsic coagulation cascade in the subject.

44. The method of claim 30, wherein the therapeutically effective amount of formula (X) preferentially inhibits the intrinsic coagulation cascade when compared to the extrinsic coagulation cascade.

45. The method of claim 30, wherein the therapeutically effective amount of the compound of formula (X) comprises an amount of the compound of formula (X) sufficient to treat or prevent a factor IX mediated disease.

46. The method of claim 29, wherein the pharmaceutical composition is administered in the form of an oral dose or a parenteral dosage unit.

47. The method of claim 29 wherein said compound of formula (X) is administered in a dosage range of about 0.01 to 1,000mg/kg body weight/day.

48. The method of claim 45, wherein said factor IX mediated disease comprises stroke.

49. The method of claim 45, wherein said factor IX mediated disease comprises deep vein thrombosis.

50. The method of claim 49, wherein the thrombus is associated with a surgical procedure, long-term restriction, acquired or inherited procoagulant state including antiphospholipid antibody syndrome, protein C deficiency and protein S deficiency, or acute or chronic inflammation including recurrent abortion or Systemic Lupus Erythematosus (SLE).

51. The method of claim 45, wherein said factor IX mediated disease comprises coagulation associated with hemodialysis and/or venous hemofiltration treatment of a renal disease.

52. The method of claim 45, wherein said factor IX mediated disease comprises a cardiovascular disease.

53. The method of claim 52, wherein the cardiovascular disease comprises myocardial infarction, arrhythmia, or aneurysm.

54. The method of claim 29, wherein the compound of formula (X) is used in place of or in addition to a compound that reduces blood coagulation.

55. The method of claim 30, wherein the pharmaceutical composition further comprises one or more therapeutic agents.

56. A method of inhibiting normal biological function of factor XI or factor IX/XI comprising the method of claim 29.

57. A method of inhibiting blood coagulation comprising the method of claim 29.