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Title:
RADIOACTIVE LIGANDS FOR CARDIAC BETA1 ADRENORECEPTOR FOR IMAGING CONGESTIVE HEART FAILURE
Document Type and Number:
WIPO Patent Application WO/2008/083054
Kind Code:
A2
Abstract:
Novel β1 adrenoreceptor ligands that find use as imaging agents within nuclear medicine applications (e.g., PET imaging and SPECT imaging) are provided. Methods of imaging, including methods of imaging congestive heart failure, are also provided. The novel compounds may exhibit high affinity and selectivity, minimal metabolism, minimal non-specific binding and have a favorable log P value (< 0). In some instances, β1-AR selective ligands are conjugated to an imaging moiety in such a way that it does not impact the antagonist affinity and their use. In other instances, the conjugation may be directly to the antagonist at several sites that will not impact affinity. In further instances, the conjugation may be by means of a linking group, which can be used to alter the pharmacokinetics and clearance of the complex.

Inventors:
PUROHIT AJAY (US)
HARRIS THOMAS D (US)
ROBINSON SIMON P (US)
YALAMANCHILI PADMAJA (US)
AZURE MICHAEL T (US)
CASEBIER DAVID S (US)
Application Number:
US2007/088495
Publication Date:
July 10, 2008
Filing Date:
December 21, 2007
Export Citation:
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Assignee:
BRISTOL MYERS SQUIBB PHARMA CO (US)
PUROHIT AJAY (US)
HARRIS THOMAS D (US)
ROBINSON SIMON P (US)
YALAMANCHILI PADMAJA (US)
AZURE MICHAEL T (US)
CASEBIER DAVID S (US)
International Classes:
A61K51/04; C07C275/34; C07D213/75; A61K101/02
Other References:
KOPKA K ET AL: "Non-invasive molecular imaging of [beta]-adrenoceptors in vivo: Perspectives for PET-radioligands" CURRENT MEDICINAL CHEMISTRY 2005 NL, vol. 12, no. 18, 2005, pages 2057-2074, XP002544584 ISSN: 0929-8673
WAGNER, STEFAN ET AL: "Synthesis of an 18F-labeled high affinity .beta.1-adrenoceptor PET radioligand based on ICI 89,406" JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS , 49(2), 177-195 CODEN: JLCRD4; ISSN: 0362-4803, 2006, XP002544585
Attorney, Agent or Firm:
LEVIS, John F. et al. (P.O. Box 4000Princeton, NJ, US)
Download PDF:
Claims:

What is claimed is:

1. A compound having the structure as follows:

wherein A, Z, K, Y, L, U are selected from the group consisting of a bond, H, R, OR, ROR, NH, NHR, CO 2 R, CONHR, SO 2 R, CN, F, Cl, Br, I, and an imaging moiety Im; m is O, 1 or 2;

G is selected from the group consisting of a bond, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, NH, NR, C=O, C=S, and oxalyl;

J and V are selected from the group consisting of H, R, O, S, OR, NHR, and NRiR 2 , wherein Ri and R 2 may form a cyclic structure as defined by -CHR 3 -CHR 3 - , -CHR 3 -CHR 3 -CHR 3 -, -CR 3 =CR 3 -, -Q=CR 3 -, -Q-CR 3 =CR 3 -, -Q-Q-, -Q-CHR 3 -, or - Q-CHR 3 -CHR 3 -, wherein Q is selected from the group consisting of O, NR, N=, and S, and wherein R 3 is a suitable R;

X is selected from the group consisting of an Im, a bond, H, R, NH, NR, O, and S;

T is selected from the group consisting of O, S, and NH; and

R is selected from the group consisting of a bond, H, Cl - C3 alkyl, Cl - C3 alkenyl, dialkyl ether, alkylaryl ether, aryl, methyl and heteroaryl.

2. The compound of claim 1, wherein the Im is selected from the group consisting Of 18 F, 76 Br, 124 1, 125 I, and 131 I.

3. The compound of claim 1, further comprising an Im on the R group, wherein Im is selected from the group consisting of 18 F, 76 Br, 124 I, 125 I, and 131 I.

4. The compound of claim 2, wherein K, Y and L are H;

U is CN;

m G is 1 ; G is a bond; J is NH; niτ is 1 ; T is O;

V is NH;

A is a pyridine ring; Z is a bond; and X is 18 F.

5. The compound of claim 2, wherein K, Y and L are H;

U is CN; m G is 1 ; G is a C2 alkyl; J is NH; rriτ is 1 ; T is O;

V is NH;

A is a pyridine ring; Z is a bond; and X is 76 Br.

6. The compound of claim 3, wherein K and L are H;

U is CN;

V is R a ORb, wherein R a is Cl alkyl, and Rb is C2 alkyl including an imaging moiety, specifically 18 F; m G is 1 ; G is a bond; J is NH; rriτ is 1 ; T is O;

V is NH;

A is a pyridine ring;

Z is wherein R c is a bond; and

X is H.

7. The compound of claim 3, wherein K and L are H;

U is a nitrile, CN;

V is R a OR b , wherein R a is Cl alkyl, and Rb is C2 alkyl including an imaging moiety, specifically 18 F; m G is 1 ; G is a bond; J is NH; m τ is 1 ; T is O;

V is NH;

A is a phenyl ring;

Z is wherein R c is a bond; and

X is H.

8. The compound of claim 3, wherein K, L, and U are H;

V is OR, wherein R is C2 dialkyl ether with an imaging moiety, 18 F; mG is 1 ;

G is a C2 alkyl; J is NH; m τ is 1 ; T is O;

V is NH;

A is a phenyl ring;

Z is a heteroaryl ring, specifically tetrazole; and

X is H.

9. The compound of claim 3, wherein K and L are H;

U is CN;

Y is R a OR b , wherein R a is Cl alkyl, and Rb is C2 alkyl including an imaging moiety, 18 F; m G is 1 ; G is a bond; J is NH; m τ is 1 ; T is O;

V is NH;

A is a heteroaryl ring, specifically imidazole; Z is a bond; and X is H.

10. The compound of claim 3, wherein K, L, and U are H;

Y is OR, wherein R is C2 dialkyl ether including an imaging moiety, specifically 18 F; m G is 1 ;

G is a C2 alkyl;

J is NH; m τ is 1 ;

T is O;

V is NH;

A is a bond;

Z is a heteroaryl unit, specifically indazole; and

X is H.

11. The compound of claim 1, wherein K, Y and L are H;

U is CN; m G is 1 ;

G is a C2 alkyl;

J is NH; niτ is 1 ;

T is O;

V is NH;

A is a phenyl ring;

Z is OR, wherein R is C3 alkyl; and

X is an imaging moiety, specifically 18 F.

12. A compound having the structure as follows:

13. A compound having the structure as follows:

14. A method of imaging cardiac heart failure comprising the steps of: administering an effective amount of the compound of claim 13 to a patient; detecting gamma radiation emitted by said compound; and forming an image therefrom.

Description:

LIGANDS FOR CARDIAC β x ADRENOCEPTOR FOR IMAGING CONGESTIVE HEART FAILURE

FIELD OF THE INVENTION [0001] The present invention provides novel βi adrenoreceptor selective ligands that find use as imaging agents within nuclear medicine applications (e.g., PET imaging and SPECT imaging). The present invention also provides methods of imaging, including methods of imaging congestive heart failure.

BACKGROUND OF THE INVENTION

[0002] Heart Failure (HF) is a condition that afflicts increasingly more people each year. It is defined as the inability of the heart to supply peripheral organs with sufficient amounts of blood. This condition is the common end-stage of many cardiac diseases (e.g. myocardial infarction, pressure overload, volume overload, viral myocarditis, toxic cardiomyopathy), and is characterized by relentless progression. The resultant myocardial damage from such events in conjunction with neurohormonal and cytokine activation, is suspect for chamber remodeling of the heart, an initial phase of HF. This remodeling results in decreased efficiency and eventually HF. To date, no cure for HF exists. Early diagnosis is a key factor in achieving a good prognosis and management of this disease. An imaging agent that identifies patients in early HF would enable immediate treatment and life-style improvements for those living with the disease.

[0003] Myocardial β-adrenergic receptors (ARs) play a critical role in heart efficiency, specifically, regulation of the heart rate and myocardial contractility, and are present in the atria and the ventricles. There are four different types of β-ARs namely β 1; β2, β3 and β 4 , but only the β 1; β2 and β3-ARs have received considerable attention. The βi and β 2 receptors are the two main ARs that control the adrenergic functionality in the heart. In the normal heart the βi/β 2 ratio is approximately 4: 1 and the average receptor density (B max ) is 70-100 fmol/mg protein. The β-AR density is altered in various pathophysiological conditions like heart failure, myocardial ischemia, hypertrophic and dilated cardiomyopathy. The loss of receptors can be global (the βi and β 2 being equally affected) or subtype selective (βi being lowered but β 2 remaining unchanged). For example in dilated cardiomyopathy, the ratio of

βi/β 2 adrenoceptors is shifted from 4: 1 to 1.5: 1 while the receptor density drops to 30-50 fmol/mg protein. Biopsies and postmortem results indicate that the down regulation of βi-AR density is proportionally greater than that of β 2 It is, therefore, of great clinical interest to be able to quantitatively image the βi-AR's using a suitable imaging technique as the information obtained would be very valuable in diagnosing early stage congestive HF.

[0004] As set forth in United States Patent Application Publication No. 20060127309 (herein incorporated by reference in its entirety), medical radionuclide imaging (e.g., Nuclear Medicine) is a key component of modern medical practice. This methodology involves the administration, typically by injection, of tracer amounts of a radioactive substance (e.g., radiotracer agents, radiotherapeutic agents, and radiopharmaceutical agents), which subsequently localize in the body in a manner dependent on the physiologic function of the organ or tissue system being studied. The radiotracer emissions, most commonly gamma photons, are imaged with a detector outside the body, creating a map of the radiotracer distribution within the body. When interpreted by an appropriately trained physician, these images provide information of great value in the clinical diagnosis and treatment of disease. Typical applications of this technology include detection of coronary artery disease (e.g., thallium scanning) and the detection of cancerous involvement of bones (e.g., bone scanning). The overwhelming bulk of clinical radionuclide imaging is performed using gamma emitting radiotracers and detectors known as "gamma cameras."

[0005] Recent advances in diagnostic imaging, such as magnetic resonance imaging (MRI), computerized tomography (CT), single photon emission computerized tomography (SPECT), and positron emission tomography (PET) have made a significant impact in cardiology, neurology, oncology, and radiology. Although these diagnostic methods employ different techniques and yield different types of anatomic and functional information, this information is often complementary in the diagnostic process. Generally speaking, PET uses imaging agents labeled with the positron-emitters such as 18 F, 11 C, 13 N and 15 0, 75 Br, 76 Br and 124 I. SPECT uses imaging agents labeled with the single-photon-emitters such as 201 Tl, 99 Tc, 123 I, and 131 I.

[0006] Glucose-based and amino acid-based compounds have also been used as imaging agents. Amino acid-based compounds are more useful in analyzing tumor cells, due to their faster uptake and incorporation into protein synthesis. Of the amino acid-based compounds, 11 C- and 18 F -containing compounds have been used with success. λ ^-containing radiolabeled amino acids suitable for imaging include, for example, L-[l- π C]leucine, L-[l- π C]tyrosine, L-[methyl- π C]methionine and L- [l- π C]methionine.

[0007] PET scans involve the detection of gamma rays in the form of annihilation photons from short-lived positron emitting radioactive isotopes including, but not limited to 18 F with a half-life of approximately 110 minutes, 11 C with a half-life of approximately 20 minutes, 13 N with a half-life of approximately 10 minutes and 15 O with a half-life of approximately 2 minutes, using the coincidence method. For PET imaging studies of cardiac sympathetic innervation, carbon- 11 ( 11 C) labeled compounds such as [ u C]meta-hydroxyephedrine (HED) are frequently used at major PET centers that have in-house cyclotrons and radiochemistry facilities. Recently the nuclear medicine market has seen a substantial increase in stand-alone PET imaging centers that do not have cyclotrons. These satellite-type facilities typically use 2- [ 18 F]fluoro-2-deoxy-D-glucose (FDG) for PET imaging of cancerous tumors. [0008] SPECT, on the other hand, uses longer-lived isotopes including but not limited to 99m Tc with a half-life of approximately 6 hours and 201 Tl with a half-life of approximately 74 hours. The resolution in present SPECT systems, however, is lower than that presently available in PET systems.

[0009] There are five selective PET ligands illustrated below that are available for the visualization of the β-adrenoreceptors.

Examples of β-AR selective PET ligands

(S)-[ 11 C]CGP 12177 (S)-[ 1B F]Fluorocarazolol

(S)-[ 11 C]CGP 12388 (S)-I 1 OJCarazolol

[0010] Of the five ligands shown above, only CGP 26505 shows both high affinity and selectivity for the βi-AR ex vivo, however, in vivo experiments showed uptake of this ligand did not reflect binding to βi-AR. The remaining four, CGP 12177, Fluorocarazolol, Carazolol and CGP 12388 show high affinity but poor selectivity for the βi-AR and have been used for imaging the cardiac β-AR density in various species including humans.

[0011] Several high affinity and highly selective βi-AR ligands have been reported, as illustrated below, for example. Some of these agents are based on ICI 89,406, an 125 I radiolabeled tracer that has been successfully used as a SPECT agent. And, other example structures are hybrid ligands incorporating features of zatebradine, a bradycardic agent.

Known βi-AR Selective Ligands

Structure of ICI 89,406:

ICI 89,406

Derivatives of ICI 89,406 - Structures I-V:

Structure I

Structure II Structure III

Structure IV

Derivatives of ICI 89,406 - Structures I-V - continued:

LK 204-545

Structure V

Structure of Zatebradine:

Zatebradine Derivative - Structure VI:

Structure VI

[0012] The ligands based on ICI 89,406, Structures I-V, show specific heart uptake but show unfavorable log P values and rapid metabolism, both undesirable features for βi-AR radioligands. The zatebradine-based ligands, Structure VI for example, have not yet been made in the radioligand form and hence there is no imaging data available. An analysis of β-ARs suggests selectivity for the βi-AR is enhanced by para arene substitution on the phenoxypropanolamine moiety, and receptor affinity is enhanced by substitution at this para arene position by either an aliphatic or aromatic ring at the end of a short linking group, as shown in Structure V, an analog of ICI 89,406. It has also been suggested that planar aliphatic or aromatic

structures attached to the nitrogen of the phenoxypropanolamine group provide the highest receptor affinity, as illustrated in Structure VI, a zatebradine derivative. [0013] There is, therefore, a clear need to design and synthesize new βi-AR ligands that will show high affinity and selectivity, minimal metabolism, minimal non-specific binding and have a favorable log P value (< 0).

SUMMARY OF THE INVENTION

[0014] The present invention provides βi adrenoreceptor selective ligands that find use as imaging agents within nuclear medicine applications (e.g., PET imaging and SPECT imaging). The present invention also provides methods of imaging, including methods of imaging congestive heart failure. The novel compounds may exhibit high affinity and selectivity, minimal metabolism, minimal non-specific binding and/or have a favorable log P value (< 0). In some embodiments of the present invention, βi-AR selective ligands are conjugated to an imageable entity in such a way that it does not impact the antagonist affinity and their use. In other embodiments, the conjugation may be directly to the antagonist at several sites that will not impact affinity. In alternative embodiments, the conjugation may be by means of a linking group, which can be used to alter the pharmacokinetics and clearance of the complex. In a further alternative embodiment, methods of using the ligands to image congestive heart failure, are provided. [0015] In certain embodiments, the present invention provides a βi-AR selective ligand having General Structure - Structure VII as follows:

wherein m G and m τ may be 0, 1 or 2, such that when m G is 0, G is absent, and when m τ is 0, T is absent; A, Z, K, Y, L, U are independently selected from the group consisting of a bond, H, R, OR, ROR, NH, NHR, CO 2 R, CONHR, SO 2 R, CN, F, Cl, Br, I, and an imaging moiety Im; G is a bond, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, NH, NR, C=O, C=S, oxalyl or absent; J and V are independently selected from the group consisting of H, R, O, S, OR, NHR, and NRiR 2 , wherein Ri and R 2

may form a cyclic structure as defined by -CHR 3 -CHR 3 -, -CHR 3 -CHR 3 -CHR 3 - , -CR 3 =CR 3 -, -Q=CR 3 -, -Q-CR 3 =CR 3 -, -Q-Q-, -Q-CHR 3 -, or -Q-CHR 3 -CHR 3 -, wherein Q is selected from the group consisting of O, NR, N=, and S, wherein R 3 can be a suitable R, or absent; X is selected from the group consisting of an Im, a bond, H, R, NH, NR, O, and S or absent; T is selected from the group consisting of O, S, and NH; R is selected from the group consisting of a bond, H, Cl - C3 alkyl or alkenyl, dialkyl ether, alkylaryl ether, aryl, methyl and heteroaryl, and may additionally include an Im; and Im (Imageable entity) is 18 F, /b Br, 124 I, 123 I, " 1 I, metal chelator or metal-chelate complex for a MRI, a ligand for the complexation of a metal for SPECT, a lipid for incorporation into a liposome, or the liposome itself. [0016] In certain other embodiments, the present invention provides a βi-AR selective ligand having Structure VIII:

which is derived from General Structure VII as follows: K and L are H; U is a nitrile, CN; Y is an imaging moiety, specifically 18 F; m G is 1; G is a C2 alkyl; J is NH; m τ is 1; T is O; V is NH; A is a phenyl ring; Z is CO 2 R, wherein R is H; and X is absent.

[0017] In certain other embodiments, the present invention provides a βi-AR selective ligand having Structure IX:

which is derived from General Structure VII as follows: K and L are H; U is a nitrile, CN; Y is an imaging moiety, specifically 18 F; mG is 1; G is a bond; J is NH; nix is 1; T is O; V is NH; A is a pyridine ring; Z is CO 2 R, wherein R is H; and X is absent.

[0018] In certain other embodiments, the present invention provides a βi-AR selective ligand having Structure X:

which is derived from General Structure VII as follows: K, Y and L are H; U is a nitrile, CN; m G is 1; G is a bond; J is NH; m τ is 1; T is O; V is NH; A is a pyridine ring; Z is a bond; and X is an imaging moiety, specifically 18 F. [0019] In certain other embodiments, the present invention provides a βi-AR selective ligand having Structure XI:

which is derived from General Structure VII as follows: K, Y and L are H; U is a nitrile, CN; m G is 1; G is a C2 alkyl; J is NH; m τ is 1; T is O; V is NH; A is a pyridine ring; Z is a bond; and X is an imaging moiety, specifically 76 Br. [0020] In certain other embodiments, the present invention provides a βi-AR selective ligand having Structure XII:

which is derived from General Structure VII: wherein K and L are H; U is a nitrile, CN; Y is R a ORb, wherein R 3 is Cl alkyl, and Rb is C2 alkyl including an imaging moiety, specifically 18 F; m G is 1; G is a bond; J is NH; m τ is 1; T is O; V is NH; A is a pyridine ring; Z is CChRc, wherein R c is a bond; and X is H.

[0021] In certain other embodiments, the present invention provides a βi-AR selective ligand having Structure XIII:

which is derived from General Structure VII as follows: K and L are H; U is a nitrile, CN; Y is R a ORb, wherein R a is C 1 alkyl, and Rb is C2 alkyl including an imaging moiety, specifically 18 F; m G is 1; G is a bond; J is NH; m τ is 1; T is O; V is NH; A is a phenyl ring; Z is CO 2 R 0 wherein R c is a bond; and X is H. [0022] In certain other embodiments, the present invention provides a βi-AR selective ligand having Structure XIV:

which is derived from General Structure VII as follows: K, L, and U are H; Y is OR, wherein the R is C2 dialkyl ether including imaging moiety, specifically 18 F; mo is 1; G is a C2 alkyl; J is NH; rriτ is 1; T is O; V is NH; A is a phenyl ring; Z is a heteroaryl ring (tetrazole); and X is H.

[0023] In certain other embodiments, the present invention provides a βi-AR selective ligand having Structure XV:

which is derived from General Structure VII as follows: K and L are H; U is a nitrile, CN; Y is R a ORb, wherein R a is Cl alkyl, and Rb is C2 alkyl including an imaging moiety, specifically 18 F; m G is 1; G is a bond; J is NH; m τ is 1; T is O; V is NH; A is a heteroaryl ring (imidazole); Z is a bond; and X is H. [0024] In certain other embodiments, the present invention provides a βi-AR selective ligand having Structure XVI:

which is derived from General Structure VII as follows: K, L, and U are H; Y is OR, wherein the R is C2 dialkyl ether with an imaging moiety, specifically 18 F; mo is 1; G is a C2 alkyl; J is NH; m τ is 1; T is O; V is NH; A is a bond; Z is a heteroaryl unit (indazole); and X is H.

[0025] In certain other embodiments, the present invention provides a βi-AR selective ligand having Structure XVII:

which is derived from General Structure VII as follows: K, L, and U are H; Y is OR, wherein R is C2 alkylarene ether with an imaging moiety, specifically 18τ F; mo

is zero; J is NH; niτ is zero; V is absent; A is a phenyl ring; Z is OR, wherein R is methyl; and X is absent.

[0026] In another preferred embodiment, the present invention provides a βi-AR selective ligand having Structure XVIII:

which is derived from General Structure VII as follows: K, Y and L are H; U is a nitrile, CN; m G is 1; G is a C2 alkyl; J is NH; m τ is 1; T is O; V is NH; A is a phenyl ring; Z is OR, wherein R is C3 alkyl; and X is an imaging moiety, specifically

18 P

[0027] In a further embodiment of the invention, there is the proviso that none of the compounds hereinafter described and set forth have the following structure:

[0028] An alternative embodiment describes a method of imaging congestive heart failure comprising the steps of: administering an effective amount of the compounds disclosed above, to a patient; detecting gamma radiation emitted by said compound; and forming an image therefrom.

[0029] The present invention is directed to these, as well as other important ends, hereinafter described.

DETAILED DESCRIPTION OF THE EMBODIMENTS Definitions

[0030] Unless otherwise indicated, the terms "alkyl" and "alk" as may be employed herein alone or as part of another group includes both straight and branched chain hydrocarbons containing 1 to 20 carbons, preferably 1 to 10 carbons, more preferably 1 to 8 carbons, in the normal chain, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl,

octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, and the like as well as such groups including 1 to 4 substituents such as halo, for example F, Br, Cl or I or CF 3 , alkyl, alkoxy, aryl, aryloxy, aryl(aryl) or diaryl, arylalkyl, arylalkyloxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkyloxy, hydroxy, hydroxyalkyl, acyl, alkanoyl, heteroaryl, heteroaryloxy, cycloheteroalkyl, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, alkylamido, alkylamino, alkanoylamino, arylcarbonylamino, nitro, cyano, thiol, haloalkyl, trihaloalkyl and/or alkylthio. [0031] Unless otherwise indicated, the term "cycloalkyl" as may be employed herein alone or as part of another group includes saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, any one of which may optionally be a spiro substituted cycloalkyl, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, preferably 3 to 10 carbons, forming the ring and which may be fused to 1 or 2 aromatic rings as described for aryl, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl,

any of which groups may be optionally substituted with 1 to 4 substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl, arylcarbonylamino, nitro, cyano, thiol and/or alkylthio and/or any of the alkyl substituents. [0032] The term "heterocyclo", "heterocycle", "heterocyclyl" or "heterocyclic ring", as may be used herein and unless otherwise described, represents an unsubstituted or substituted stable 4 to 7-membered monocyclic ring system which may be saturated or unsaturated, and which consists of carbon atoms, with one to four heteroatoms selected from nitrogen, oxygen or sulfur, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heterocyclic ring may be attached at any heteroatom

or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic groups include, but is not limited to, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, pyrrolyl, pyrrolidinyl, furanyl, thienyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, thiadiazolyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, oxadiazolyl and other heterocycles described in Katritzky, A. R. and Rees, C. W., eds. Comprehensive Heterocyclic Chemistry: The Structure, Reactions, Synthesis and Uses of Heterocyclic Compounds 1984, Pergamon Press, New York, NY; and Katritzky, A. R., Rees, C. W., Scriven, E. F., eds. Comprehensive Heterocyclic Chemistry II: A Review of the Literature 1982-1995 1996, Elsevier Science, Inc., Tarrytown, NY; and references therein. [0033] Unless otherwise indicated, the term "aryl" or "Aryl" as may be employed herein alone or as part of another group refers to monocyclic and bicyclic aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or naphthyl including 1-naphthyl and 2-naphthyl) and may optionally include one to three additional rings fused to a carbocyclic ring or a heterocyclic ring (such as aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings). For example

and may be optionally substituted through available carbon atoms with 1, 2, or 3 groups selected from hydrogen, halo, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkyl-alkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, alkoxycarbonyl, arylcarbonyl, arylalkenyl,

aminocarbonylaryl, arylthio, arylsulfinyl, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro, cyano, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino and arylsulfonaminocarbonyl and/or any of the alkyl substituents set out herein.

[0034] Unless otherwise indicated, the term "heteroaryl" as may be used herein alone or as part of another group refers to a 5- or 6- membered aromatic ring which includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygen or sulfur. Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl and include possible N- oxides as described in Katritzky, A. R. and Rees, C. W., eds. Comprehensive Heterocyclic Chemistry: The Structure, Reactions, Synthesis and Uses of Heterocyclic Compounds 1984, Pergamon Press, New York, NY; and Katritzky, A. R., Rees, C. W., Scriven, E. F., eds. Comprehensive Heterocyclic Chemistry II: A

Review of the Literature 1982-1995 1996, Elsevier Science, Inc., Tarrytown, NY; and references therein. Further, "heteroaryl", as defined herein, may optionally be substituted with one or more substituents such as the substituents included above in the definition of "substituted alkyl" and "substituted aryl". Examples of heteroaryl groups include the following:

( li_S-/ , ( V_S_/ . , ( ϊ—S 1 J , , * N=>N • λ N _ N _

and the like.

[0035] Several new βi adrenoreceptor selective ligands, which may be used for imaging the βi-AR and relate to antagonists of the βi-AR, have been developed in an attempt to address the limitations of prior βi-AR selective ligands. Specifically, these ligands may exhibit high affinity and selectivity, minimal metabolism, minimal nonspecific binding and/or have a favorable log P value (< 0). In some embodiments of the present invention, βi-AR selective ligands are conjugated to an imageable entity in such a way that it does not impact the antagonist affinity and their use. In certain embodiments, the imageable entity may be a radioisotope for nuclear medicine imaging, a paramagnetic species for use in MRI imaging, an echogenic entity for use in ultrasound imaging, a fluorescent entity for use in fluorescence imaging, or a light- active entity for use in optical imaging. In certain other embodiments the conjugation may be directly to the antagonist at several sites that will not impact affinity. In alternative embodiments, the conjugation may be by means of a linking group, which can be used to alter the pharmacokinetics and clearance of the complex. In further alternative embodiments, methods of using the ligands to image congestive heart failure, are provided. Several such ligands and a general structure are illustrated below.

General Structure and Example Structures of βi-ARs

General Structure - Structure VII:

[0036] One embodiment of the present invention provides a βi-AR as illustrated in the above General Structure, Structure VII. The symbols in the general structure independently have the following meaning: m = 0, 1 or 2; A, Z, K, Y, L, U are independently selected from the group consisting of a bond, H, R, OR, ROR, NH,

NHR, CO 2 R, CONHR, SO 2 R, CN, F, Cl, Br, I, and Im; G is a bond, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, NH, NR, C=O, C=S, oxalyl or absent; J and V are independently selected from the group consisting of H, R, O, S, OR, NHR, and NRiR 2 , wherein Ri and R 2 may form a cyclic structure as defined by -CHR 3 -CHR 3 - , -CHR 3 -CHR 3 -CHR 3 -, -CR 3 =CR 3 -, -Q=CR 3 -, -Q-CR 3 =CR 3 -, -Q-Q-, -Q-CHR 3 -, or - Q-CHR 3 -CHR 3 -, wherein Q is selected from the group consisting of O, NR, N=, and S, wherein R 3 can be a suitable R, or absent; X is selected from the group consisting of an Im, a bond, H, R, NH, NR, O, and S or absent; T is selected from the group consisting of O, S, and NH; R is selected from the group consisting of a bond, H, Cl - C3 alkyl or alkenyl, dialkyl ether, alkylaryl ether, aryl, methyl and heteroaryl, and may additionally include an imaging moiety Im; wherein Im is 18 F, 76 Br, 124 I, 125 I, 131 I, metal chelator or metal-chelate complex for a MRI, a ligand for the complexation of a metal for SPECT, a lipid for incorporation into a liposome or the liposome itself.

Structure VIII:

[0037] Another embodiment provides a βi-AR as illustrated in Structure VIII, which is derived from the General Structure, Structure VII, wherein K and L are H; U is a nitrile, CN; Y is an imaging moiety, specifically 18 F; m G is 1; G is a C2 alkyl; J is NH; m τ is 1; T is O; V is NH; A is a phenyl ring; Z is CO 2 R, wherein R is H; and X is absent.

Structure IX:

[0038] A further embodiment provides a βi-AR as illustrated in Structure IX, which is derived from the General Structure, Structure VII, wherein K and L are H; U is a nitrile, CN; Y is an imaging moiety, specifically 18 F; mo is 1; G is a bond; J is NH; m τ is 1; T is O; V is NH; A is a pyridine ring; Z is CO 2 R, wherein R is H; and X is absent.

Structure X:

[0039] Another further embodiment provides a βi-AR as illustrated in Structure X, which is derived from the General Structure, Structure VII, wherein K, Y and L are H; U is a nitrile, CN; m G is 1; G is a bond; J is NH; m τ is 1; T is O; V is NH; A is a pyridine ring; Z is a bond; and X is an imaging moiety, specifically 18 F.

Structure XI:

[0040] Another further embodiment provides a βi-AR as illustrated in Structure XI, which is derived from the General Structure, Structure VII, wherein K, Y and L are H; U is a nitrile, CN; m G is 1; G is a C2 alkyl; J is NH; m τ is 1; T is O; V is NH; A is a pyridine ring; Z is a bond; and X is an imaging moiety, specifically 76 Br.

Structure XII:

[0041] Another further embodiment provides a βi-AR as illustrated in Structure XII, which is derived from the General Structure, Structure VII, wherein K and L are H; U is a nitrile, CN; Y is R a OR b , wherein R a is Cl alkyl, and R b is C2 alkyl including an imaging moiety, specifically 18 F; rriG is 1; G is a bond; J is NH; mr is 1; T is O; V is NH; A is a pyridine ring; Z is wherein R 0 is a bond; and X is H.

Structure XIII:

[0042] Another further embodiment provides a βi-AR as illustrated in Structure XIII, which is derived from the General Structure, Structure VII, wherein K and L are H; U is a nitrile, CN; Y is R a OR b , wherein R a is Cl alkyl, and R b is C2 alkyl including an imaging moiety, specifically 18 F; m G is 1; G is a bond; J is NH; m τ is 1; T is O; V is NH; A is a phenyl ring; Z is CChRc, wherein R c is a bond; and X is H.

Structure XIV:

[0043] Another further embodiment provides a βi-AR as illustrated in Structure XIV, which is derived from the General Structure, Structure VII, wherein K, L, and U are H; Y is OR, wherein the R is C2 dialkyl ether with an imaging moiety, specifically 18 F; m G is 1; G is a C2 alkyl; J is NH; m τ is 1; T is O; V is NH; A is a phenyl ring; Z is a heteroaryl ring (tetrazole); and X is H.

Structure XV:

[0044] Another further embodiment provides a βi-AR as illustrated in Structure XV, which is derived from the General Structure, Structure VII, wherein K and L are H; U is a nitrile, CN; Y is R a OR b , wherein R a is Cl alkyl, and R b is C2 alkyl including an imaging moiety, specifically 18 F; mG is 1; G is a bond; J is NH; mr is 1; T is O; V is NH; A is a heteroaryl ring (imidazole); Z is a bond; and X is H.

Structure XVI:

[0045] Another further embodiment provides a βi-AR as illustrated in Structure XVI, which is derived from the General Structure, Structure VII, wherein K, L, and U are H; Y is OR, wherein the R is C2 dialkyl ether with an imaging moiety, specifically 18 F; m G is 1; G is a C2 alkyl; J is NH; m τ is 1; T is O; V is NH; A is a bond; Z is a heteroaryl unit (indazole); and X is H.

Structure XVII:

[0046] Another further embodiment provides a βi-AR as illustrated in Structure XVII, which is derived from the General Structure, Structure VII, wherein K, L, and U are H; Y is OR, wherein R is C2 alkylarene ether with an imaging moiety, specifically 18 F; m G is zero; J is NH; m τ is zero; V is absent; A is a phenyl ring; Z is OR, wherein R is methyl; and X is absent.

Structure XVIII:

[0047] Another embodiment which is particularly preferred provides a βi-AR as illustrated in Structure XVIII, which is derived from the General Structure, Structure VII, wherein K, Y and L are H; U is a nitrile, CN; m G is 1; G is a C2 alkyl; J is NH; m τ is 1; T is O; V is NH; A is a phenyl ring; Z is OR, wherein R is C3 alkyl; and X is an imaging moiety, specifically 18 F. This compound provides enhanced performance characteristics over certain other compounds available in the art.

[0048] In a further embodiment of the invention, there is the proviso that none of the foregoing compounds herein set forth have the following structure:

[0049] A further embodiment describes a method of imaging congestive heart failure comprising the steps of: administering an effective amount of one or more of the compounds disclosed above, to a patient; detecting gamma radiation emitted by said compound(s); and forming an image therefrom.

[0050] Another embodiment of the invention involves imaging for congestive heart failure utilizing one or more of the compounds herein described with PET perfusion scanning or SPECT imaging techniques available to the skilled artisan, or other methods which may be employed. In this regard, the procedures described in the aforementioned US Patent Appn. No. 20060127309 may be useful.

[0051] There is also provided a composition useful in medical imaging which comprises one or more of the compounds hereinabove set forth, together with one or more excipients. [0052] The compounds hereinabove described may be synthesized by methods available to the skilled artisan, which are in part further exemplified by the non- limiting Examples below.

EXAMPLES

[0053] The following examples are provided to demonstrate and further illustrate certain preferred embodiments of the present invention and are not to be construed as limiting the scope thereof:

[0054] General Experimental. 1 H NMR spectra were recorded on a Bruker Avance DRX 600 MHz spectrometer or on a Bruker Avance 300 MHz spectrometer. Chemical shifts are reported in ppm from tetramethylsilane with the residual solvent resonance resulting from incomplete deuteration as the internal standard (CDCI3: δ 7.25 ppm, CD 3 CN: δ 1.94 ppm, DMSO-fife: δ 2.50 ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, b or br = broad, m = multiplet), coupling constants, and integration. 13 C NMR spectra were recorded on a Bruker Avance DRX 150 MHz or on a Bruker Avance 75 MHz spectrometer with complete proton decoupling. Chemical shifts are

reported in ppm from tetramethylsilane with the solvent as the internal reference (CDCl 3 : δ 77.0 ppm, CD 3 CN: δ 118.1 ppm, DMSO-^ 6 : δ 39.5 ppm). 19 F NMR spectra were recorded on a Bruker Avance DRX 565 MHz spectrometer. Chemical shifts are reported in ppm relative to an external standard (CCl 3 F; δ = 0.00 ppm). [0055] Low-resolution mass spectrometry was performed on an Agilent

Technologies 1100 Series LC/MS ESI-MS (positive mode). High-resolution mass spectrometry was performed on an Ionspec Ultima FTMS; ESI-MS (positive mode), or on an Agilent MSD-TOF; ESI-MS (positive mode). Melting points were determined using a Thomas-Hoover melting point apparatus and are uncorrected. [0056] Unless otherwise stated, all reactions were conducted under an inert atmosphere of dry nitrogen. Indicated temperatures refer to those of the reaction bath, while ambient laboratory temperature is noted as 22 °C. Anhydrous dimethylformamide (DMF), acetonitrile (ACN), pyridine, triethylamine (TEA), and diisopropylethylamine (DIEA) were obtained from Aldrich in SURESEAL ® bottles. Absolute ethanol was obtained from Quantum Chemical Corp. Merck silica gel, grade 9385, 230^00 mesh, 60 A was used for flash chromatography. Ethyl acetate (EtOAc), chloroform (CHCI3), methanol (MeOH), acetonitrile (ACN), dichloromethane (DCM), ethyl ether, acetone, sodium hydroxide (NaOH), and hydrochloric acid (HCl) were obtained from Baker. (5)-(+)-Glycidyl 3- nitrobenzenesulfonate was purchased from Acros Organics. 5-Amino-2- fluoropyridine and 2-(2-fluorophenoxy)-l-ethanamine were purchased from Matrix Scientific. 2-( 1H-Benzotriazol- 1 -yl)- 1 , 1 ,3,3 -tetramethyluronium hexafluorophosphate (HBTU), benzotriazol- 1 -yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBOP), and Boc-β-alanine were purchased from Advanced ChemTech. Cloned β-adrenoreceptor subtype 1 (human) produced in sf9 cells, cloned β-adrenoreceptor subtype 2 (human) produced in sf9 cells, and [ H]CGP 12177 were obtained from Perkin Elmer (Boston, MA). Polyethyleneimine and ICI 118,551 hydrochloride were purchased from Sigma (St. Louis, MO). Other reagents were obtained from Lancaster Synthesis, Inc., Aldrich Chemical Co., or Fluka Chemical Corp.

Example 1

Synthesis of iV-(2-(3-(4-Carboxyphenyl)ureido)ethyl)-3-(2-chloro-5- methylphenoxy)-2-hydroxypropan-l-aminium 2,2,2-Trifluoroacetate

Part A - Preparation of Ethyl 4-(3-(2-(tert-

H H Boc ^ N M

H o ^ . butoxycarbonylamino)ethyl)ureido)benzoate c ° 2Et

[0057] Tert-bvAyl 2-aminoethylcarbamate (2.00 g, 12.48 mmol) was added to a flame dried 15 mL round bottom flask, followed by 12.5 mL of dichloromethane. Ethyl 4-isocyanatobenzoate (2.38 g, 12.48 mmol) was then added to the flask and the reaction mixture stirred for 30 minutes under nitrogen. The reaction mixture was then filtered and the white solid obtained was washed with dichloromethane (10 mL) and ether (30 mL). The solid was dried to obtain 4.32 g (100%) of the title compound as a colorless solid. 1 H NMR (600 MHz, DMSO-d 6 ): δ 8.90 (s, IH), 7.82 (d, 2H, J = 8.4 Hz), 7.51 (d, 2H, J= 8.4 Hz), 6.82 (br t, IH), 6.29 (br t, IH), 4.25 (q, 2H, J= 12 Hz), 3.14 (dd, 2H, J= 6.6, 7.2 Hz), 3.01 (dd, 2H, J= 6 Hz) 1.37 (s, 9H), 1.29 (t, 3H, J= 7.2 Hz).

Part B - Preparation of Ethyl 4-(3-(2-Aminoethyl)ureido)benzoate

Hydrochloride

[0058] The product of Part A (2.0 g, 5.69 mmol) was charged to a 25 mL round bottom flask. 11.3 mL of 4 M HCl was added in dioxane drop-wise while cooling the flask in an ice bath. After addition was complete the ice bath was removed and the reaction mixture allowed to stir for 15 minutes after which it was filtered. The white solid obtained was washed with ether and dried to obtain 0.82 g (100%) of the title compound. 1 H NMR (D 2 O, 600 MHz): δ 8.08 (d, 2H, J= 9.0 Hz), 7.55 (d, 2H, J

= 9.0 Hz), 4.48 (q, 2H, J= 7.2 Hz), 3.66 (t, 2H, J= 5.4 Hz), 3.30 (t, 2H, J= 5.4 Hz), 1.49 (t, 3H, J= 7.2 Hz).

Part C - Preparation of 2-((2-Chloro-5-methylphenoxy)methyl)oxirane

[0059] A 50 mL flame dried round bottom flask was charged with 2-chloro-5- methylphenol (1.0 g, 7.01 mmol), glycidol (0.62 g, 8.41 mmol) and triphenylphosphine (2.2 g, 8.41 mmol). Tetrahydrofuran (20 mL) was then added to this mixture and it was allowed to dissolve after which the solution was cooled in an ice bath. Diisopropylazodicarboxylate (1.701 g, 8.41 mmol) was then added drop- wise via syringe to this solution and the reaction allowed to stir at room temperature for 16 hours. All volatiles were then removed and the crude brown oil obtained was subjected to silica gel flash chromatography (9: 1 hexanes: ether) to obtain 1.22 g (87%) of the title compound as a colorless oil. 1 H NMR (300 MHz, CDCl 3 ): δ 7.21 (d, IH, J= 6.0 Hz), 6.76-6.70 (m, 2H), 4.26 (dd, IH, J = 12.0, 3.0 Hz), 4.03 (dd, IH, J = 12.0, 6.0 Hz), 3.40-3.35 (m, IH), 2.90 (dd, IH, J = 6, 3 Hz), 2.80 (dd, IH, J = 6, 3 Hz), 2.30 (s, 3H). 13 C NMR (75.4 MHz, CDCl 3 ): δ 153.73, 137.91, 129.98, 121.75, 120.12, 115.08, 69.67, 50.06, 45.67, 44.65, 21.26.

Part D - Preparation of 7V-(2-(3-(4-Carboxyphenyl)ureido)ethyl)-3-(2-chloro-5- methylphenoxy)-2-hydroxypropan-l-aminium 2,2,2-Trifluoroacetate [0060] The product of Part C (38 mg, 0.194 mmol) and the product of Part B (56 mg, 0.194 mmol) were added to a flame dried flask. To this mixture isopropanol (2.0 mL) was added followed by diisopropylethylamine amine (75.49 mg, 0.58 mmol), after which the flask was immersed in an oil bath and heated to 50 0 C for 6 hours. The solution was then cooled to room temperature and 1 N NaOH solution (0.584 mL) was added to it. The flask was then re-immersed in the oil bath and heated to 50 0 C for 3 hours after which all volatiles were removed on a rotary evaporator. The crude mixture was then dissolved in water and subjected to preparative HPLC purification (0-90% B over 30 min; Mobile phase A = O.1% TFA in water and B =

0.1% TFA in 90% water) to obtain 30 mg (37%) of the title compound as a colorless solid. 1 H NMR (600 MHz, CD 3 CNiD 2 O, 1 :3): δ 7.76 (d, 2H, J = 9.0 Hz), 7.24 (d, 2H, J = 8.4 Hz), 7.07 (d, 2H, J = 7.8 Hz), 6.79 (s, IH), 6.60 (d, IH), 4.31-4.29 (m, IH), 4.12^.08 (m, 2H), 3.58-3.53 (m, IH), 3.48-3.42 (m, 2H), 3.35-3.32 (m, IH), 3.28-3.25 (m, IH), 3.20-3.16 (m, IH), 2.15 (s, 3H). 13 C NMR (150 MHz,

CD 3 CNiD 2 O 1 :3): δ 171.01, 163.87, 158.69, 154.23, 145.28, 140.57, 132.39, 131.03, 124.76, 118.99, 116.38, 72.84, 66.23, 51.73, 50.23, 37.33, 21.81.

Example 2

Synthesis of (5)-3-(2-Cyanophenoxy)-iV-(3-(6-fluoropyridin-3-ylamino)-3- oxopropyl)-2-hydroxypropan-l-aminium Formate

Part A - Preparation of (5)-2-(Oxiran-2-ylmethoxy)benzonitrile

[0061] A solution of 2-cyanophenol (5.00 g, 0.0420 mol) in DMF (20 mL) was treated with a slurry of NaH (1.17 g, 0.0488 mol) in DMF (20 mL). The mixture was stirred at ambient temperatures until the cessation of gas evolution, treated with a solution of (S)-(+)-glycidy/?-toluenesulphonate (9.58 g, 0.0420 mol) in DMF (30 mL), and stirred for an additional six days. The mixture was treated with saturated NH 4 Cl (50 mL), and extracted with EtOAc (200 mL). The organic phase was washed with H 2 O (3 x 200 mL), dried (MgSO 4 ), and concentrated to give a yellow solid.

Purification by flash chromatography (CHCl 3 ) gave the title compound as a colorless solid (2.87 g, 39.0%), MP 84-85 0 C. 1 H NMR (600 MHz, CDCl 3 ): δ 7.56 (dd, J= 1.8, 7.8 Hz, IH), 7.53-7.49 (m, IH), 7.04-6.99 (m, 2H), 4.36 (dd, J= 3.0, 11.4 Hz, IH), 4.11 (dd, J= 5.4, 11.4 Hz, IH), 3.41-3.36 (m, IH), 2.92 (t, J= 4.8 Hz, IH), 2.83 (dd, J= 3.0, 4.8 Hz, IH); 13 C NMR (150 MHz, CDCl 3 ): δ 160.11, 134.31, 133.84, 121.39, 116.18, 112.72, 102.44, 69.41, 49.81, 44.55. MS (ESI): 351.2 (2M+H, 76),

193.2 (M+NH 4 , 100), 176.2 (M+H, 96); HRMS: Calculated for Ci 0 H 9 NaNO 2 (M+Na): 198.0526; Found: 198.0523.

Part B - Preparation of tert-Butyl 3-(6-fluoropyridin-3-ylamino)-3- oxop ropylcarb amate

[0062] A solution of Boc-β-alanine (945 mg, 5.00 mmol), 5-amino-2- fluoropyridine (560 mg, 5.00 mmol), DIEA (1.74 mL, 10 mmol), and PyBOP (2.86 g, 5.50 mmol) in DMF (10 mL) was stirred at ambient temperatures for 4 hours and concentrated to give an amber oil. This oil was taken up in EtOAc (150 mL), and washed consecutively with 10% citric acid (50 mL), 0.5 N NaOH (2 x 50 mL), H 2 O (50 mL), and saturated NaCl (50 mL). The organic phase was dried (MgSO 4 ) and concentrated to give an amber oil, which solidified upon standing overnight. Recrystallization from i-PrOH gave a colorless solid (1.00 g, 70.6%), MP 149.0- 150.5 0 C. 1 H NMR (300 MHz, CDCl 3 ): δ 9.60 (bs, IH), 8.16 (s, IH), 8.07-7.96 (m, IH), 6.67 (dd, J= 3.0, 9.0 Hz, IH), 5.38 (bs, IH), 3.31-3.19 (m, 2H), 2.40 (t, J= 6.0 Hz, 2H), 1.23 (s, 9H); 13 C NMR (75 MHz, CDCl 3 ): δ 170.17, 158.80 (d, J= 234.0), 155.65, 137.92 (d, J= 15.0), 133.29 (d, J= 4.5 Hz), 132.28 (d, J= 7.5 Hz), 108.44 (d, J= 38.2 Hz), 78.60, 36.46, 36.09, 27.95. MS (ESI): 306.3 (M+Na, 8), 228.2 (M+H-?Bu, 12), 184.2 (M+H-Boc, 100); HRMS: Calculated for Ci 3 H 18 NaN 3 O 3 F (M+Na): 306.1224; Found: 306.1219.

Part C - Preparation of (5)-3-(2-Cyanophenoxy)-iV-(3-(6-fluoropyridin-3- ylamino)-3-oxopropyl)-2-hydroxypropan-l-aminium Formate

[0063] The product of Part B (210 mg, 0.741 mmol) was dissolved in anhydrous dioxane (2.0 mL) and treated with 4 N HCl/dioxane (5.0 mL). A solid ppt began to form within 5 minutes. The reaction mixture was stirred at ambient temperatures for 30 minutes. The solid was collected by filtration, washed with dioxane, and dried in vacuo for 18 hours to give a colorless solid (140 mg). A mixture of this solid (135 mg, 0.616 mmol), the product of Part A (175 mmol, 1.00 mmol), and DIEA (215 μL, 1.23 mmol) in i-PrOH (2.0 mL) was heated briefly at 80 0 C to dissolve the reactants. The solution was treated with LiBr (8.0 mg, 0.092 mmol) and heating was continued

for 6 hours. The solution was concentrated and the residue was purified by HPLC on a Phenomenex Luna C18(2) column (21.2 x 250 mm) using a 0.9%/min gradient of 9-36% ACN containing 15 mmol NH 4 OAc at a flow rate of 20 mL/min. The main product peak eluting at 23 minutes was lyophilized to give 64 mg (25%) of the title compound as the TFA salt, which was very hygroscopic. A portion of this salt (22.0 mg) was dissolved in 1 : 1 ACN:H 2 O (1.0 mL) and treated with Bio-Rad AG 1-X8 ion exchange resin, formate form (1.0 mL bed volume). The resin was washed with 1 : 1 ACN:H 2 O (3 x 1.0 mL). The combined washes were lyophilized to give the title compound as a nonhygroscopic colorless solid (15 mg, 80%). 1 H NMR (600 MHz, 1 :3 CD 3 CN:D 2 O): δ 8.35 (s, IH), 8.16 (d, J= 3.0 Hz, IH), 7.96-7.90 (m, IH), 7.57- 7.50 (m, 2H), 7.04 (d, J= 9.0 Hz, IH), 7.00 (t, J= 7.5 Hz, IH), 6.97 (dd, J= 2.4, 9.0 Hz, IH), 4.12^.03 (m, 3H), 2.95-2.86 (m, 2H), 2.81 (dd, J= 4.5, 12.6 Hz, IH), 2.75 (dd, J= 6.6, 12.6 Hz, IH), 2.59-2.51 (m, 2H); 13 C NMR (150 MHz, 1 :3 CD 3 CN:D 2 O): δ 174.25, 171.51, 161.29, 160.63 (d, J= 235.6 Hz), 139.83 (d, J= 13.6 Hz), 136.49, 136.08 (d, J= 8.1 Hz), 134.76, 133.63 (d, J= 4.2 Hz), 122.42,

118.29, 1 13.82, 1 10.84 (d, J= 37.4), 101.29, 71.93, 68.97, 51.40, 45.50, 36.56. MS (ESI): 359.4 (M+H, 100); HRMS calculated for Ci 8 H 20 FN 4 O 3 (M+H): 359.1514; Found: 359.1508.

Example 3

Synthesis of (S)-3-(2-Cyanophenoxy)-7V-(2-(2-fluorophenoxy)ethyl)-2- hydroxypropan-1-aminium Trifluoroacetate

[0064] To a solution of the product of Example 2, Part A (100 mg, 0.53 mmol) dissolved in isopropanol (5.3 mL) was added 2-(2-fluorophenoxy)-l-ethanamine (82.1 mg, 0.53 mmol). After completion of addition the reaction was heated at 65 0 C overnight. The next day, the reaction mixture was cooled to room temperature and concentrated. The crude yellow oil was purified by HPLC using a Phenomenex Luna C18(2) column (10 μ, 21.2 x 250 mm, gradient method of 20-80% B over 30 min, where %B = 90% ACN in water using 0.1% TFA as a modifier and %A= water using

0.1%TFA as a modifier) to afford the title compound (76 mg, 43% yield). (DMSO- d 6 , 600 MHz): δ 7.75 (m, IH), 7.68 (m, IH), 7.22 (m, 5H), 7.01 (m, IH), 6.01 (br s, IH), 4.36 (m, IH), 4.29 (m, IH), 4.18 (m, 2H), 3.47 (m, 2H), 3.35 (m, IH), 3.18 (m, IH).

Example 4

Synthesis of (5)-3-(2-Bromophenoxy)-iV-(2-(3-(4-carboxyphenyl)ureido)ethy l)-2- hydroxypropan-1-aminium Acetate

Part A - Preparation of (5)-2-((2-Bromophenoxy)methyl)oxirane

[0065] A mixture of 2-bromophenol and CsF in DMF (10 mL) was stirred at ambient temperatures for 1.5 hours and treated with a solution of («S)-glycidyl 3- nitrobenzene-sulfonate in DMF (5.0 mL). The reaction mixture was stirred for an additional 18 hours, diluted with H 2 O (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried (MgSO 4 ) and concentrated. The resulting residue was purified by flash chromatography (7: 1 hexanes: EtOAc) to give the title compound as a colorless oil (1.404 g, 90.8%). 1 H NMR (CDCl 3 , 600 MHz): δ 7.53 (dd, J= 1.2, 7.8 Hz, IH), 7.27-7.22 (m, IH), 6.92 (dd, J= 1.2, 7.8 Hz, IH), 6.85 (dt, J= 1.2, 7.8 Hz, IH), 4.28 (dd, J= 3.0, 11.4 Hz, IH), 4.06 (dd, J= 5.1, 11.4 Hz, IH), 3.41-3.37 (m, IH), 2.91 (t, J= 5.1 Hz, IH), 2.84 (dd, J= 2.7, 5.1 Hz, IH); 13 C NMR (CDCl 3 , 150 MHz): δ 154.95, 133.48, 128.46, 122.54, 113.92, 112.49, 69.59, 50.20, 44.65. MS (ESI): HRMS calculated for C 9 H 9 BrNaO 2 (N+Na): 250.9678; Found: 250.9679.

Part B - Preparation of (S>3-(2-Bromophenoxy)-iV-(2-(3-(4- carboxyphenyl)ureido)ethyl)-2-hydroxypropan-l-aminium Acetate

[0066] A mixture of the product of Part A (84 mg, 0.368 mmol), the product of Example 1 Part B (106 mg, 0.368 mmol), Yt(OTf) 3 (4.6 mg. 0.0074 mmol), DEMB 5 (48 mg, 0.48 mmol), and DIEA (128 uL, 0.736 mmol) in ACN (2.0 mL) was heated at 80 0 C for 4 hours and cooled to ambient temperature. The reaction mixture was treated with 1 N NaOH (2.0 mL), ACN (1.0 mL), and i-PrOH (1.0 mL) and stirring was continued at ambient temperatures for 18 hours and at 50 0 C for an additional 4 hours. The reaction was adjusted to pH 6 with 1 N HCl and partially concentrated to 0 remove the organic solvents. The resulting mixture was purified by HPLC on a Phenomenex Luna C 18(2) column (21.2 x 250 mm) using a 0.9%/min gradient of 1.8-28.8% ACN containing 15 mmol NH 4 OAc at a flow rate of 20 mL/min. The main product peak eluting at 25 minutes was lyophilized to give the title compound as a colorless solid (48 mg, 25%). 1 H NMR (2:3 CD 3 CNiD 2 O, 600 MHz): δ 7.75- 5 7.70 (m, 2H), 7.49 (dd, J= 1.8, 7.8 Hz), 7.30-7.26 (m, IH), 7.26-7.22 (m, 2H), 6.99 (dd, J= 1.8, 8.4 Hz), 6.85 (dt, J= 1.2, 7.8 Hz), 4.30^.26 (m, IH), 4.10-4.04 (m, 2H), 3.56-3.42 (m, 2H), 3.34-3.25 (m, 2H), 3.25-3.14, (m, 2H), 1.81 (s, 3H); 13 C NMR (2:3 CD 3 CN:D 2 O, 150 MHz): δ 180.60, 174.38, 158.36, 155.36, 142.30, 134.17, 131.57, 131.22, 130.17, 123.93, 119.24, 115.05, 112.40, 71.79, 66.01, 51.14, 0 49.74, 37.30, 23.98. MS (ESI): 452.1 (M+H, 100); HRMS calculated for Ci 9 H 23 BrN 3 O 5 (M+H): 452.0816; Found: 452.0807.

Example 5

Synthesis of (5)-3-(2-Carbamoylphenoxy)-iV-(2-(3-(6-fluoropyridin-3- yl)ureido)ethyl)-2-hydroxypropan-l-aminium Acetate

Part A - Preparation of (5)-2-(Oxiran-2-ylmethoxy)benzamide

[0067] A mixture of CsF (997 mg, 6.56 mmol) and salicylamide (300 mg, 2.19 mmol) in DMF (2.0 mL) was stirred at ambient temperatures for 2 hours and treated with (5)-glycidyl 3-nitrobenzene-sulfonate (567 mg, 2.19 mmol) in DMF (2.0 mL). Stirring was continued for 72 hours. The mixture was diluted with H 2 O and extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried (MgSO 4 ) and concentrated. The resulting amber oil was purified by flash chromatography (1 :3 hexanes: EtOAc) to give the title compound as a colorless solid (265 mg, 62.7%). 1 H NMR (2:3 CDCl 3 , 300 MHz): δ 8.21 (dd, J= 1.5, 7.5 Hz, IH), 7.74 (bs, IH), 7.48 (dt, J= 1.5, 8.5 Hz, IH), 7.13 (t, J= 7.5 Hz, IH), 6.98 (d, J= 9.0 Hz, IH), 5.82 (bs, IH), 4.47 (dd, J= 3.0, 10.5 Hz, IH), 4.13 (dd, J= 6.0, 9.0 Hz, IH), 3.46-3.39 (m, IH), 2.97 (t, J= 6.0 Hz, IH), 2.86 (dd, J= 3.0, 6.0 Hz, IH). MS (ESI): 216.2 (M+Na, 25), 194.3 (M+H, 100); HRMS calculated for C 10 H 11 NaNO 3 (M+Na): 216.0631; Found: 216.0629.

Part B - Preparation of l-(2-Aminoethyl)-3-(6-fluoropyridin-3-yl)urea

Hydrochloride

[0068] A solution of 5-amino-2-fluoropyridine (598 mg, 5.33 mmol) and DIEA (935 μL, 5.38 mmol) in THF (20 mL) was added drop-wise with stirring over 1 hour to a solution of triphosgene (531 mg, 1.79 mmol) in THF (5.0 mL). Immediately after addition was complete the reaction was treated with a solution of tert-butyl 2- aminoethylcarbamate (850 mg, 5.33 mmol) and DIEA (935 μL, 5.38 mmol) in THF (5.0 mL). The reaction was stirred an additional 18 hours, diluted with H 2 O (20 mL), and extracted with EtOAc (40 mL). The organic extract was washed with saturated NaCl (30 mL), dried (Na2SO 4 ), and concentrated. The resulting residue was purified by flash chromatography (1 : 1 hexanes: EtOAc) to give the Boc -protected intermediate as a colorless oily solid. This solid was treated with 4 N HCl in dioxane (16 mL) and

the resulting suspension was stirred at ambient temperatures for 30 minutes. The solid was collected by filtration, taken up in H2O (30 mL), and refiltered. The filtrate was lyophilized to give the title compound as a pale yellow solid (304 mg, 24.3%). 1 H NMR (1 : 1 CD 3 CNiD 2 O, 600 MHz): δ 8.10 (s, IH), 7.93-7.85 (m, IH), 7.02-6.96 (m, IH), 3.40 (t, J= 5.7 Hz, 2H), 3.04 (t, J= 5.7 Hz, 2H). MS (ESI): 199.3 (M+H, 100); HRMS calculated for C 8 H 12 FN 4 O (M+H): 199.0990; Found: 199.0985.

Part C - Preparation of (5)-3-(2-Carbamoylphenoxy)-iV-(2-(3-(6-fluoropyridin- 3-yl)ureido)ethyl)-2-hydroxypropan-l-aminium Acetate

[0069] A mixture of the product of Part A (76 mg, 0.394 mmol), the product of Part B (92 mg, 0.934 mmol), DIEA (138 μL, 0.79 mmol), DEMB (51 mg, 0.51 mmol), and Yt(OTf) 3 (4.9 mg, 0.0079 mmol) in 1: 1 ACNa-PrOH (2.0 mL) was heated at 80 0 C for 24 hours. The mixture was cooled to ambient temperature, treated with concentrated HCl (2 drops) and MeOH (1.0 mL), and heated at 50 0 C for 30 minutes. The mixture was partially concentrated to remove volatile organics and purified by HPLC on a Phenomenex Luna C 18(2) column (21.2 x 250 mm) using a 0.9%/min gradient of 1.8-28.2% ACN containing 15 mmol NH 4 OAc at a flow rate of 20 mL/min. The main product peak eluting at 20 minutes was lyophilized to give the title compound as a colorless solid (31.2 mg, 17.6%). 1 H NMR (1 :2 CD 3 CN:D 2 O, 600 MHz): δ 8.00 (d, J= 3.0 Hz, IH), 7.82-7.77 (m, IH), 7.68 (dd, J= 1.8, 7.8 Hz, IH), 7.47-7.42 (m, IH), 7.05-7.00 (m, 2H), 6.94 (dd, J= 2.4, 9.0 Hz, IH), 4.30 (quin, J= 4.2 Hz, IH), 4.18-4.11 (m, 2H), 3.52-3.40 (m, 2H), 3.26-3.10 (m, 4H), 1.79 (s, 3H); 13 C NMR (1 :2 CD 3 CN:D 2 O, 150 MHz): δ 181.37, 171.21, 159.96 (d, J = 233.55 Hz), 158.43, 157.25, 138.66 (d, J= 13.5 Hz), 135.09 (d, J= 7.65 Hz), 134.81, 134.64, 131.45, 122.61, 114.36, 110.62 (d, J= 37.5 Hz), 71.70, 66.03, 50.77, 49.33, 37.19, 24.26; 19 F NMR (1:2 CD 3 CN:D 2 O, 565 MHz): δ -77.43. MS (ESI): 392.3 (M+H, 100); HRMS calculated for Ci 8 H 23 FN 5 O 4 : 392.1729; Found: 392.1728.

Example 6

Synthesis of (S)-3-(2-Cyano-3-fluorophenoxy)-iV-(2-(3-(4- ethoxyphenyl)ureido)ethyl)-2-hydroxypropan-l-aminium Trifluoroacetate

O

Part A - Preparation of (5)-2-Fluoro-6-(oxiran-2-ylmethoxy)benzonitrile

[0070] CsF (2.80 g, 18.17 mmol) was added to a solution of 2-fluoro-6- hydroxybenzonitrile (0.83 g, 6.06 mmol) dissolved in anhydrous DMF (4.0 mL). The resulting suspension stirred at room temperature for 2 hours, before the addition of (25)-(+)-glycidol nosylate (1.57 g, 6.06 mmol). After completion of addition the reaction continued to stir at room temperature overnight. The next day, the reaction mixture was diluted with water and a white precipitate formed. The white solid was collected via filtration and washed with water to afford the title compound (0.96 g, 82%) in good yield. 1 H NMR (DMSO-Cl 6 , 300 MHz): δ 7.77-7.68 (m, IH), 7.14- 7.06 (m, 2H), 4.59 (dd, J= 3.0, 12.0 Hz, IH), 4.08 (dd, J= 6.0, 9.0 Hz, IH), 3.39 (m, IH), 2.88 (t, J= 6.0 Hz, IH), 2.76 (dd, J= 3.0, 6.0 Hz, IH).

Part B - Preparation of tert-Butyl 2-(3-(4-Ethoxyphenyl)ureido)ethylcarbamate

[0071] A solution of N-(2-aminoethyl) carbonic acid tert-butyl ester (1.47 g, 9.2 mmol) dissolved in anhydrous THF (10.20 mL) was cooled to 0 0 C in an ice bath. 4- Ethoxyphenylisocyanate (1.50 g, 9.2 mmol) was added drop-wise to the cooled stirring reaction mixture. After completion of addition the ice bath was removed and the reaction mixture continued to stir overnight. A white precipitate formed, which was collected via filtration. The solid was washed with cold THF and dried under vacuum to afford the title compound (2.11 g, 71%). 1 H νMR (DMSOd 6 , 300 MHz):

δ 8.28 (s, IH), 7.25 (d, J= 9.0 Hz, 2H), 6.80 (m, IH), 6.78 (d, J= 9.0 Hz, 2H), 6.03 (m, IH), 3.94 (q, J= 6.0 Hz, 2H), 3.11-7.07 (m, 2H), 2.98 (m, 2H), 1.37 (s, 9H), 1.29 (t, J= 6.0 Hz, 3H).

Part C - Preparation of 2-(3-(4-Ethoxyphenyl)ureido)ethanaminium Chloride

[0072] A 1.0 M solution of HCl in 1,4-dioxane (1.50 mL) was added to the product of Part B (150 mg, 0.46 mmol). The suspension was stirred at room temperature overnight. The next day, a white precipitate was collected via filtration. The white solid was washed with 1,4-dioxane to obtain the title compound (98 mg, 82% yield), which was taken on to the next step without further purification. 1 H NMR (DMSO-d 6 , 600 MHz): δ 8.70 (s, IH), 7.92 (br s, 2H), 7.28 (m, 2H), 6.80 (m, 2H), 6.46 (br s, IH), 3.94 (q, J= 7.2 Hz, 2H), 3.31 (m, 2H), 2.87 (m, 2H), 1.29 (t, J= 6.6 Hz, 3H).

Part D - Preparation of (S)-3-(2-Cyano-3-fluorophenoxy)-iV-(2-(3-(4- ethoxyphenyl)ureido)ethyl)-2-hydroxypropan-l-aminium Trifluoroacetate

[0073] Diisopropylethylamine (94 μL, 0.54 mmol) was added to a suspension of the product of Part C (70 mg, 0.27 mmol) in isopropanol (1.40 mL). After completion of addition, the reaction mixture was heated to 74 0 C. When the reaction mixture turned clear, diethylmethoxyborane (46 μL, 0.35 mmol), ytterbium triflate (3.30 mg, 0.054 mmol), and the product of Part A (52 mg, 0.27 mmol) were added. The reaction stirred at 74 0 C and was monitored by TLC (90:9: 1 DCM:MeOH:NH 3 OH (28% ammonia in water)). After 30 minutes the reaction mixture was cooled to room temperature and concentrated to dryness. Purification by HPLC using a Phenomenex Luna C- 18 (2) column (10 μ, 250 x 21.2 mm, gradient method of 20-80% B over 30 min, where %B = 90% ACN in water using 0.1% TFA as a modifier and %A= water using 0.1% TFA as a modifier) with a flow rate of 20 mL/min afforded the title compound (34.7 mg, 31% yield). 1 H NMR (CD 3 CN:D 2 O 2: 1, 600 MHz): δ 7.63-7.59 (m, IH), 7.18-7.16 (m, 2H), 6.94 (d, J= 8.4 Hz, IH), 6.89 (t, J= 8.4 Hz, IH), 6.80-6.78 (m, 2H), 4.31-4.28 (m, IH), 4.16 (d, J= 4.8 Hz,

2H), 3.97 (q, J= 7.2 Hz, 2H), 3.45 (m, 2H), 3.29-3.14 (m, 4H), 1.30 (t, J= 6.6 Hz, 3H); 19 F NMR (CD 3 CNiD 2 O 2: 1, 565 MHz:): δ -108.00 (m). HRMS calculated for C 2I H 25 FN 4 O 4 : 439.1752; Found: 439.1757.

Example 7

Synthesis of (5)-l-(2-Chlorophenoxy)-3-(l-(6-chloropyridazin-3-yloxy)-2- methylpropan-2-ylamino)propan-2-ol

Part A - Preparation of (5')-2-((2-chlorophenoxy)methyl)oxirane

[0074] 2-chlorophenol (9.5 g, 74.1 mmol) was added to a 500 mL flame dried round bottom flask followed by (R)-glycidol (6.58 g, 88.8 mmol) and triphenylphosphine (23.3 g, 88.8 mmol). Tetrahydrofuran (370 mL) was then added to the above mixture and the contents were stirred to dissolve the solids. The flask was then cooled in an ice bath and diisopropylazodicarboxylate (22.4 g, 111 mmol) was added drop-wise to the above solution. The solution was stirred at room temperature under nitrogen for 16 hours after which it was concentrated and the crude oil subjected to silica gel flash chromatography (9: 1 pentane:ether) to obtain the desired product (9.85 g, 72%) as a white solid. 1 H NMR (300 MHz, CDCl 3 ): δ 7.38 (dd, IH, J = 3, 9 Hz) , 7.22 (ddd, IH, J = 1.5, 3, 12 Hz), 6.95 (m, 2H), 4.30 (dd, IH, J = 1.5, 6 Hz), 4.08 (dd, IH, J = 3, 6 Hz), 3.39-3.37 (m, IH), 2.93 (dd, IH, J= 1.5, 3 Hz), 2.83 (dd, IH, 3, 6 Hz).

Part B - Preparation of l-(6-Chloropyridazin-3-yloxy)-2-methylpropan-2-amine

[0075] A 50 mL round bottom flask was flame dried and a stir bar was placed in it and cooled under a stream of nitrogen. This flask was then charged with 3, 6- dichloropyridazine (5.0 g, 33.6 mmol) and sodium hydride (967 mg, 40.3 mmol). Toluene (25 mL) was then added to this mixture and the flask cooled to 0 0 C. 2- Amino-2-methyl-l-propanol (3.15 g, 35.3 mmol) dissolved in 5 mL toluene was then added drop-wise to the above at such a rate so as to keep gas evolution under control. The reaction mixture was then stirred for 30 minutes at room temperature after which it was filtered and the solid was washed with toluene (20 mL) and dichloromethane (20 mL). The filtrates were combined and concentrated under reduced pressure. The mixture so obtained was purified by silica gel flash chromatography (9:0.9:0.1 dichloromethane:methanol:NH 3 ) to obtain the title compound (5.86 g, 86%) as a semi-solid. 1 H NMR (600 MHz, OMSO-d 6 ): δ 7.77 (d, IH, J = 9.0 Hz), 7.47 (d, IH, J = 9.0 Hz), 4.10 (s, 2H), 1.10 (s, 6H).

Part C - Preparation of (5)-l-(2-Chlorophenoxy)-3-(l-(6-chloropyridazin-3- yloxy)-2-methylpropan-2-ylamino)propan-2-ol

[0076] Product from Part A (0.35 g, 1.9 mmol), product from Part B (0.38 g, 1.9 mmol), ytterbium triflate (23.6 mg, 38 μmol) and diethylmethoxyborane (0.2 g, 2.0 mmol) were placed in a 50 mL flame-dried round bottom flask under nitrogen.

Isopropanol (20 mL) was then added to it and the flask immersed in an oil bath and heated to 70 0 C for 9 hours after which it was cooled to room temperature. All volatiles were then removed under reduced pressure and the crude oil obtained was subjected to purification using flash chromatography (9.0:0.9:0.1 dichloromethane:methanol:NH 3 ) to obtain the desired product (625 mg, 85%). 1 H NMR (600 MHz, CD 3 CN): δ 7.48 (d, IH, J= 9.0 Hz), 7.36 (dd, IH, J= 1.8, 7.8 Hz), 7.26 (ddd, IH, J= 1.2, 7.2, 7.8), 7.06 (d, IH, J= 9.0 Hz), 7.04 (dd, IH, J= 1.2, 8.4 Hz), 6.93 (dt, IH, J= 1.2, 7.8 Hz), 4.26 (s, 2H), 4.04 (dd, IH, J= 4.2, 13.8 Hz), 4.01 (dd, IH, J= 5.4 10.2 Hz), 3.90-3.85 (m, IH), 2.85 (dd, IH, J= 9.6, 5.4 Hz), 2.72 (dd,

IH, J= 6.6, 12 Hz), 1.18 (s, 6H). 13 C NMR (150 MHz, ACN-(I 3 ): δ 166, 155.4, 151.98, 132.2, 131.1, 129.2, 123.1, 122.5, 121.5, 115.2, 74.3, 72.6, 71.1, 69.9, 53.3, 45.2, 44.8, 24.8.

Example 8

Synthesis of (5)-3-(2-Cyanophenoxy)-iV-(2-(2-(4-fluorophenyl)acetamido)et hyl)- 2-hydroxypropan-l-aminium Trifluoroacetate

Part A - Preparation of tert-Butyl 2-(2-(4- Fluorophenyl)acetamido)ethylcarbamate

[0077] 4-fluoro-phenylacetyl chloride (500 μL, 3.65 mmol) and diisopropylethylamine (1.30 mL, 7.30 mmol) was added to a solution of tert-butyl 2- aminoethylcarbamate (584 mg, 3.65 mmol) dissolved in anhydrous DCM (15 mL). After stirring at room temperature for 1 hour, formation of a precipitate was observed and the reaction mixture was diluted with ethyl acetate. The organic layer was separated and washed with 5% Na2CO3 (2x), H2O (2x), and brine (Ix), dried over Na 2 SO 4 , and concentrated to obtain a yellow solid (998 mg, 92 % yield). The solid was taken directly to the next step without further purification. 1 H NMR (DMSO-fi? < $, 600 MHz): δ 8.02 (br s, IH), 7.27 (m, 2H), 7.10 (m, 2H), 6.78 (br s, IH), 3.38 (s, 2H), 3.06 (m, 2H), 2.97 (m, 2H), 1.37 (s, 9H); 19 F NMR (OMSO-d 6 , 565 MHz): δ - 117.16-117.21 (m).

Part B - Preparation of 2-(2-(4-Fluorophenyl)acetamido)ethanaminium

Chloride

[0078] A 4.0 M solution of HCl in 1,4-dioxane (2.2 mL) was added to the product of Part A (200 mg, 0.68 mmol). The resulting suspension was stirred at room temperature overnight. The next day, a precipitate was collected via filtration. The white solid was washed with 1,4-dioxane to obtain the title compound (158 mg, 100% yield) which was taken to the next step without further purification. 1 H NMR (DMSO-Cl 6 , 600 MHz): δ 8.49 (br s, IH), 8.14 (br s, 2H), 7.30 (m, 2H), 7.11 (m, 2H), 3.45 (s, 2H), 3.30 (q, J= 6 Hz , 2H), 2.85 (q, J= 6.6 Hz , 2H); 19 F NMR (DMSO-Cl 6 , 565 MHz) -117.02-1 17.07 (m).

Part C - Preparation of (S)-3-(2-Cyanophenoxy)-7V-(2-(2-(4- fluorophenyl)acetamido)ethyl)-2-hydroxypropan-l-aminium Trifluoroacetate

[0079] Diisopropylethylamine (105 μL, 0.60 mmol) was added to a suspension of the product of Part B (70 mg, 0.30 mmol) in isopropanol (1.50 mL). After completion of addition the reaction mixture was heated to 74 0 C. When the reaction mixture turned clear, diethylmethoxyborane (51 μL, 0.39 mmol), ytterbium triflate (3.70 mg, 0.006 mmol), and the product of Example 2, Part A (53 mg, 0.30 mmol) were added. The reaction stirred at 74 0 C for 1.5 hours and was then concentrated to dryness. Purification by HPLC (gradient method of 20-80% B over 30 minutes, where %B = 90% ACN in water using 0.1% TFA as a modifier and %A= water using 0.1% TFA as a modifier) afforded the desired product as a TFA salt (32.3 mg, 23% yield). 1 H NMR (CD 3 CNiD 2 O 2: 1, 600 MHz): δ 7.62 (m, 2H), 7.26 (m, 2H), 7.11 (m, 2H), 7.02 (m, 2H), 4.27 (m, IH), 4.12 (d, J= 4.8 Hz, 2H), 3.52 (s, 2H), 3.45 (m, 2H), 3.18 (m, 4H); 19 F NMR (CD 3 CN:D 2 O 2: 1, 565 MHz): δ -107.98 (m). HRMS calculated for C 20 H 22 FN 3 O 3 : 372.1718; Found: 372.1717.

Example 9

Synthesis of (S>iV-(2-(3-(2-Fluorophenoxy)-2- hydroxypropylamino)ethyl)morpholine-4-carboxamide

Part A - Preparation of (5)-2-((2-Fluorophenoxy)inethyl)oxirane

[0080] 2-fluorophenol (3.00 g, 26.77 mmol) was added to a 100 mL flame-dried round bottom flask followed by (R)-glycidol (2.00 g, 17.8 mmol) and triphenylphosphine (5.61 g, 21.4 mmol). Tetrahydrofuran (90 mL) was the added to the above mixture and the contents were stirred to dissolve. The flask was then cooled in an ice bath and diisopropylazodicarboxylate (5.4 g, 26.7 mmol) was added drop-wise to the above mixture. The solution was stirred at room temperature under nitrogen for 16 hours after which it was concentrated and the crude oil subjected to silica gel flash chromatography (9: 1 pentane: ether) to obtain the title compound (1.95 g, 65%) as a white solid. 1 H NMR (600 MHz, CDCl 3 ): δ 7.09-6.98 (m, 3H), 6.93-6.90 (m, IH), 4.26 (dd, IH, J = 11.4, 3.0 Hz), 4.03 (dd, IH, J = 11.1, 6.0 Hz), 3.37-3.35 (m, IH), 2.89 (dd, IH. J= 3.6, 5.1 Hz), 2.75 (dd, IH, J = 3.6, 5.1 Hz); 13 C NMR (150 MHz, CDCl 3 ): δ 154.5, 151.2, 146.6, 124.3, 122.01, 116, 70.46, 50.0, 44.6.

Part B - Preparation of iV-(2-Aminoethyl)morpholine-4-carboxamide

[0081] Morpholine-4-carbonyl chloride (1.5 g, 10.0 mmol) was dissolved in dichloromethane (10 mL) in a 25 mL round bottom flask and to this was added 2- aminoethyl carbamic acid benzyl ester hydrochloride (2.54 g, 11.0 mmol) followed by diisopropylethylamine amine (2.59 g, 20.0 mmol). This mixture was stirred for 45 minutes after which the mixture was poured into a separatory funnel and washed with water (10 mL) and brine (10 mL), and dried (MgSO 4 ). After filtration the dichloromethane was removed under reduced pressure. The resulting crude residue was the dissolved in methanol (50 mL) and to this solution was added 10% Pd/C

(1.06 g). The mixture was then stirred under a hydrogen atmosphere (introduced via a balloon) for 1 hour. The reaction mixture was then filtered through a pad of

CELITE ® and concentrated to obtain the desired product (1.7 g, 98%) as a clear, colorless oil. 1 H NMR (600 MHz, D 2 O): δ 3.60 (t, 4H, J = 6 Hz), 3.29-3.25 (m, 4H), 3.17 (t, 2H, J = 6 Hz), 2.69 (t, 2H, J = 6 Hz).

Part C - Preparation of (S)-7V-(2-(3-(2-Fluorophenoxy)-2-hydroxypropylamino)- ethyl)morpholine-4-carboxamide

[0082] The product of Part A (43.4 mg, 0.258 mmol) was added to a 15 mL flame dried round bottom flask followed by the product of Part B (54 mg, 0.311 mmol). Ytterbium triflate (3.2 mg, 5.16 μmol), diethylmethoxyborane (28.4 mg, 0.284 mmol), and diisopropylethylamine amine (66.7 mg, 0.516 mmol) were added in succession. Finally isopropanol (2.6 mL) was added to the above mixture and the flask was heated to 75 0 C for 6 hours. The reaction mixture was cooled to room temperature and the mixture concentrated under reduced pressure. The crude oil obtained was dissolved in 1 : 1 ACN:water and subjected to purification by silica gel flash chromatography (9.0:0.9:0.1 dichloromethane:methanol:NH 3 ) to obtain the title compound (35 mg, 40%). 1 H NMR (600 MHz, CDCl 3 ): δ 7.07-7.02 (m, 2H), 6.97- 6.95 (m, IH), 6.93-6.89 (m, IH), 5.28 (br t, IH), 4.19-4.14 (m, IH), 4.07^.02 (m, 2H), 3.64 (t, 4H, J = 4.8 Hz), 3.41 (dd, 2H, J = 5.4 Hz), 3.33 (t, 4H, J = 4.8 Hz), 2.98-2.89 (m, 4H).

Example 10

Synthesis of (5)-3-(2-Acetamidophenoxy)-iV-(2-(3-(6-fluoropyridin-3- yl)ureido)ethyl)-2-hydroxypropan-l-aminium Acetate

Part A - Preparation of (5')-iV-(2-(Oxiran-2-ylmethoxy)phenyl)acetamide

[0083] A mixture of 2-acetamidophenol (300 mg, 1.98 mmol) and CsF (904 mg, 5.95 mmol) in DMF (2.0 mL) was stirred at ambient temperatures for 2 hours and treated with a solution of («S)-glycidyl 3-nitrobenzene-sulfonate (514 mg, 1.98 mmol) in DMF (2.0 mL). Stirring was continued at ambient temperatures for 4 days. The mixture was diluted with H 2 O (25 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extracts were dried (Na 2 SO 4 ) and concentrated to give a yellow oil. The oil was purified by flash chromatography (hexanes: EtOAc 3: 1, then 2: 1) to give the title compound as a colorless solid (290 mg, 71%). 1 H NMR (CDCl 3 , 600 MHz): δ 8.38-8.33 (m, IH), 7.87 (bs, IH), 7.04-6.96 (m, 2H), 6.92-6.86 (m, IH), 4.34 (dd, J= 2.4, 11.4 Hz, IH), 3.95 (dd, J= 6, 11.4 Hz, IH), 3.38-3.35 (m, IH), 2.94 (t, J= 4.8 Hz, IH), 2.78 (dd, J= 3.0, 4.8 Hz, IH), 2.20 (s, 3H); 13 C NMR (CDCl 3 , 75 MHz): δ 168.29, 146.66, 128.49, 123.59, 122.27, 120.28, 112.50, 70.11, 50.05, 44.55, 24.88. MS (ESI): 230.2 (M+Na, 12), 208.2 (M+H, 100); HRMS calculated for C H H I4 NO 3 (M+H): 208.0968; Found: 208.0972.

Part B - Preparation of (5)-3-(2-Acetamidophenoxy)-iV-(2-(3-(6-fluoropyridin-3- yl)ureido)ethyl)-2-hydroxypropan-l-aminium Acetate

[0084] A mixture of the product of Part A (78.4 mg, 0.378 mmol), the product of Example 5 Part B (88.8 mg, 0.378 mmol), DEMB (49 mg, 0.49 mmol), DIEA (132 μL, 0.757 mmol), and Yt(OTf) 3 (4.7 mg, 0.008 mmol) in 1 : 1 ACNa-PrOH (2.0 mL) was heated at 80 0 C for 26 hours and cooled to ambient temperature. The mixture was treated with concentrated HCl (2 drops) and MeOH (1.0 mL) and heated at 50 0 C for 30 minutes. The mixture was concentrated in vacuo and the resulting residue was purified by HPLC on a Phenomenex Luna C 18(2) column (21.2 x 250 mm) using a 0.9%/min gradient of 1.8-28.2% ACN containing 15 mmol NH 4 OAc at a flow rate of 20 mL/min. The main product peak eluting at 18.5 minutes was lyophilized to give the title compound as a colorless solid (12 mg, 5.7%). 1 H NMR (1:2 CD 3 CN:D 2 O, 600 MHz): δ 8.04 (d, J= 2.4 Hz, IH), 7.86-7.80 (m, IH), 7.62 (dd, J= 1.5, 2.4 Hz,

IH), 7.15-7.10 (m, IH), 7.01-6.92 (m, 3H), 4.28-4.21 (m, IH), 4.07-3.98 (m, 2H), 3.45 (t, J= 5.7 Hz, 2H), 3.24-3.08 (m, 4H), 2.10 (s, 3H), 1.79 (s, 3H); 13 C NMR (1:2 CD 3 CNiD 2 O, 75 MHz): δ 181.55, 173.18, 160.03 (d, J= 234.0 Hz), 158.56, 157.70, 138.89 (d, J= 13.5 Hz), 135.36 (d, J= 8.25 Hz), 134.78 (d, J= 4.5 Hz), 127.42, 127.07, 125.00, 122.44, 113.85, 110.67 (d, J= 37.5 Hz), 71.24, 66.63, 50.69, 49.39, 37.54, 24.32, 23.88; 19 F NMR (1:2 CD 3 CN:D 2 O, 565 MHz): δ -77.26. MS (ESI): 406.2 (M+H,100); HRMS calculated for Ci 9 H 25 FN 5 O 4 : 406.1885; Found: 406.1881.

Example 11

Synthesis of (5)-l-(2-(3-(2-Aminophenoxy)-2-hydroxypropylamino)ethyl)-3-( 6- fluoropyridin-3-yl)urea Bis(2,2,2-trifluoroacetate)

[0085] A solution of the product of Example 10 Part B ( 66 mg, 0.142 mmol) in 1: 1 ACN:H 2 O (1.0 mL) and concentrated HCl (0.5 mL) was stirred at ambient temperatures for 5 days. The solution was concentrated and the residue was purified by HPLC on a Phenomenex Luna Cl 8(2) column (21.2 x 250 mm) using a 0.9%/min gradient of 1.8-28.2% ACN containing 0.1% TFA at a flow rate of 20 mL/min. The main product peak eluting at 23 minutes was lyophilized to give the title compound as a colorless solid (12.0 mg, 14.3%). 1 H NMR (2: 1 CD 3 CN:D 2 O, 600 MHz): δ 8.12-8.08 (m, IH), 7.89-7.88 (m, IH), 7.39-7.33 (m, IH), 7.30 (dd, J= 1.2, 7.8 Hz, IH), 7.08 (dd, J= 0.6, 8.4 Hz, IH), 7.03 (dt, J= 0.6, 7.8 Hz, IH), 6.95 (dd, J= 2.4, 9.0 Hz, IH), 4.35-4.28 (m, IH), 4.15-4.09 (m, 2H), 3.54-3.45 (m, 2H), 3.32-3.15 (m, 4H); 13 C NMR (2: 1 CD 3 CN:D 2 O, 75 MHz): δ 162.45 (q, J= 44.1 Hz), 160.03 (d, J= 233.6 Hz), 158.52, 151.95, 138.98 (d, J= 14.2 Hz), 135.07 (d, J= 4.5 Hz), 134.88 (d, J= 7.5 Hz), 130.77, 124.67, 122.76, 121.28, 119.77 (q, J= 283.5) 114.04, 110.52 (d, J= 38.2 Hz). 19 F NMR (2: 1 CD 3 CN:D 2 O, 565 MHz): δ -75.92 (s, 6H), - 77.72 (s, IH). MS (ESI): 364.2 (M+H, 100), 182.7 (47); HRMS calculated for Ci 7 H 22 FN 5 O 3 : 364.1779; Found: 364.1778.

Example 12

l-{2-[3-(2-Cyano-phenoxy)-2-hydroxy-propylamino]-ethyl}-3 -[4-(3- fluoropropoxy)-phenyl]-urea

[0086] To a solution of the product of Example 2, Part A (100 mg, 0.53 mmol) dissolved in isopropanol (5.3 mL) is added l-(2-aminoethyl)-3-[4-(2-fluoropropoxy)- phenyl]-urea (128 mg, 0.53 mmol). After completion of addition the reaction is heated at 65 0 C overnight. The next day, the reaction mixture is cooled to room temperature and concentrated. The crude oil is purified by HPLC using a Phenomenex Luna C 18(2) column (10 μ, 21.2 x 250 mm, gradient method of 20- 80% B over 30 min, where %B = 90% ACN in water using 0.1% TFA as a modifier and %A= water using 0.1%TFA as a modifier) to afford the title compound.

Example 13 Radioligand Binding Assay

[0087] Radioligand binding studies were performed in an incubation buffer containing 75 mM Tris-HCl (pH 7.4), 12.5 mM MgCl 2 , 2 mM EDTA containing 1 unit of membrane with either βi or β 2 adrenoceptor in a volume of 1.05 mL and a final concentration of 0.14 nM [ 3 H] CGP12177. Each unit of membrane is defined as the quantity of receptor protein that will yield specific binding of approximately 1,000 dpm at a final concentration of 0.14 nM [ 3 H] CGP12177. Competition studies with ICI 118, 551 used various concentrations of the cold compound (0-31.75 nM). Competition studies with test compounds used various concentrations of test compounds between 0-50 nM for βi adrenoceptor assay and between 0-500 nM for β 2 adrenoceptor assay. The binding reaction was incubated at 27 0 C for 60 minutes and terminated by filtration through a 96 well Whatman GF/C filters coated with 0.3% polyethylenimine and washed 3 times with incubation buffer. The filters were punched and placed in scintillation fluid. The radioactivity on the filter was counted

on a beta counter. Nonspecific binding was determined in the absence of membrane. The radioligand binding data obtained from competition curves were analyzed by nonlinear regression analysis to determine IC50 and K 1 values using PRISM software (GraphPad Software Inc., San Diego, CA). Receptor affinity data is shown below.

βi and β 2 Receptor Affinity

General Procedure for the Radiosynthesis of F-18 labeled βi-Adrenoreceptor

Ligands

Reaction Schematic

Na 1 1 8 8 F EI UtiOn » K 1 1 8 8 F OTs

K 2 CO 3 MW 100W 3 min. AcCN

Ion Capture Resin

Typical RCP>90%

[0088] A 1000 mCi sample of aqueous F-18 was prepared by the 18 O(p,n) 18 F reaction and applied to a previously activated MPl anion exchange resin (BioRad) cartridge contained within a remote control radiosynthesis system. The 18 F radioactivity was eluted from the cartridge and collected into a 25 ml conical bottom silanized pear shaped flask by the addition of 1 ml of the following stock solution: Ten mg of potassium carbonate (K 2 CO3) dissolved in 5 mL of distilled/deionized H 2 O. The solution solvent was then evaporated by applying a gentle stream of heated He (g ) and applied vacuum. After the H 2 O was removed, the contents of the pear shaped flask were reconstituted with 0.5 mL of CH3CN. The CH3CN was removed by heated He (g ) and applied to vacuum to eliminate residual H 2 O (azeotropic evaporation). A 900 μL aliquot of a prepared solution of 22.5 mg of 4,7,13, 16,21,24- Hexaoxa-l,10-diazabicyclo [8.8.8]hexacosane (KRYPTOFIX™; abbreviated as K222) was added and the constituents (K, CO3 2" , K222) were transferred to a conical bottomed 5mL WHEATON™ vial containing 3.0 mg of 1,3 -propanediol bis-(p- toluenesulfonate, MW 370) dissolved in 0.1 ml of CH3CN. The vial was positioned

inside a microwave cavity and subjected to microwave radiation for 3 minutes at a power setting of 100 watts. The contents of the microwave reaction vial were then filtered through an anion exchange resin to remove residual 18 F " and the eluate was collected in a conical bottomed 5mL WHEATON™ vial reaction vial. The stoichiometry of the 1,3-propanediol bis -(p-toluenesulfonate) and phenolic precursor were maintained such that there was always an excess of the phenolic precursor starting material to consume unreacted 1,3-propanediol bis-(p-toluenesulfonate). This approach obviated the need for a preliminary purification of the l-(3- [ 18 F]fluoropropyl) tosylate, which in routine use is typically problematic. [0089] The l-(3-[ 18 F]fluoropropyl) tosylate is transferred to a conical bottomed 5mL WHEATON™ vial reaction vial containing 4 mg of phenolic precursor dissolved in 300 μL of DMSO. The contents of the vial are heated at 85°C for 30 minutes. After the 30 minute heating cycle is completed the heat source is eliminated and 1.5 mL of trifluoroacetic acid (TFA) is transferred to the reaction vial containing the reaction constituents. The solution is stirred for 30 minutes at ambient temperature to complete the deprotection. The solution is transferred to a clean 25 mL pear shaped flask and diluted with 18.5 mL of H 2 O. The contents of the flask are passed through a Sep Pak™ Cl 8 cartridge and rinsed with 5 ml H 2 O. The aqueous eluate is directed to waste. The desired product is coordinated to the resin in the Sep Pak™ Cl 8 cartridge. The Sep Pak™ Cl 8 cartridge is eluted with 3 ml of CH 3 CN to remove the product and the product is collected in a conical bottomed 5mL WHEATON™ vial and the column dried with N 2(g ). The 3 mL is transferred to the injector of a purification HPLC fitted with a Phenomenex LUNA C- 18 column 250 x 10 mm, 5 micron particle size, lOOAngstrom pore size. The mobile phases are A: 0.1% Formic Acid in H 2 O and B: 0.1% formic acid in CH 3 CN. The gradient is 0- 100/20 sustained at 100% B to 20 minutes. The flow rate is 2 mL/minute. The 18 F- radiolabeled compound eluted from the column is collected into a pear shaped flask. The solvent is then evaporated using a heat assisted vacuum device. After all of the solvent had been removed the contents of the flask are reconstituted with a 10% ethanol solution for biological study. The final product yield is ~50 mCi, with a radiosynthesis and purification time of -120 min.

[0090] All publications and patents mentioned in the above specification are herein incorporated by reference. Although the invention has been described in

connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the relevant fields are intended to be within the scope of the following claims.