HK1178511B - N-alkoxyamide conjugates as imaging agents - Google Patents

Description

N-alkoxyamide conjugates as imaging agents

Technical Field

The present invention relates to compounds and diagnostic agents and related methods.

Background

Cardiovascular disease is the leading cause of death in the united states, resulting in over 1 million deaths each year. In western countries, atherosclerosis is a major contributing factor to coronary heart disease and a major cause of unanticipated deaths. Much effort has been devoted to determining the etiology and potential treatment of atherosclerosis and its consequences, including myocardial infarction, angina pectoris, organ failure, and stroke. Despite these efforts, there are many unresolved issues, including how and when atherosclerotic lesions become vulnerable and life threatening, the best point of intervention, and how to discover and monitor the progress of the lesion.

Over the past 20 years, a number of radiotracers have been developed based on several molecules and cell types involved in atherosclerosis. Generally, radiolabeled proteins and platelets have shown some clinical potential as imaging agents for atherosclerosis, but due to poor target/background and target/blood ratios, these are not ideal imaging agents for coronary or even carotid lesions. Radiolabeled peptides, antibody fragments and metabolic tracers such as Fluorodeoxyglucose (FDG) have been shown to provide new opportunities for nuclear scintigraphy for the non-invasive imaging of atherosclerotic thrombosis. However, there is a need for non-invasive methods of diagnosing and monitoring various cardiovascular diseases.

Summary of The Invention

The present invention relates to compounds of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

x is a heteroatom;

R¹is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, alkylarylalkyl, alkoxyalkyl, heteroalkyl, or heterocyclylalkyl;

R²and R³Which may be the same or different, is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, or carbonyl; and

R⁴is alkyl, alkenyl, alkynyl, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl or heterocyclylalkyl,

wherein each R¹、R²、R³And R⁴Unsubstituted or substituted with one or more of the following groups: alkyl, alkenyl, alkynyl, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, or heterocyclylalkyl, -NR¹⁹R²⁰、-SH、-OH、-PR¹⁹R²⁰、-P(O)R²¹R²²、-CO₂H. = O, halo, trifluoromethyl, -CF₂H、-CH₂F. Cyano, -CO₂R²⁴、-C(＝O)R²⁴、-C(＝O)N(R²⁴)₂、-CHO、-CH₂OR²⁴、-OC(＝O)R²⁴、-OC(＝O)OR²⁴、-OR²⁴、-OC(＝O)N(R²⁴)₂、-NR²⁴C(＝O)R²⁴、-NR²⁴C(＝O)OR²⁴、-NR²⁴C(＝O)N(R²⁴)₂、-NR²⁴SO₂N(R²⁴)₂、-NR²⁴SO₂R²⁴、-SO₃H、-SO₂R²⁴、-SR²⁴、-S(＝O)R²⁴、-SO₂N(R²⁴)₂、-N(R²⁴)₂、-NHC(＝S)NHR²⁴、＝NOR²⁴、NO₂、-C(＝O)NHOR²⁴、-C(＝O)NHNR²⁴R²⁴、-OCH₂CO₂H. 2- (1-morpholino) ethoxy or chelator moiety;

R¹⁹and R²⁰Each independently selected from hydrogen, by 0-3R²³Substituted C_1-10Alkyl, by 0-3R²³Substituted aryl radicals, substituted by 0-3R²³Substituted C_3-10Cycloalkyl, by 0-3R²³Substituted heterocyclyl-C_1-10Alkyl, by 0-3R²³Substituted C_6-10aryl-C_1-10Alkyl and substituted by 0-3R²³A substituted heterocyclic group;

R²¹and R²²Each independently selected from-OH, by 0-3R²³Substituted C_1-10Alkyl, by 0-3R²³Substituted aryl radicals, substituted by 0-3R²³Substituted C_3-10Cycloalkyl, by 0-3R²³Substituted heterocyclyl-C_1-10Alkyl, by 0-3R²³Substituted C_6-10aryl-C_1-10Alkyl and substituted by 0-3R²³A substituted heterocyclic group;

each R²³Independently selected from ═ O, halo, trifluoromethyl, -CF₂H、-CH₂F. Cyano, -CO₂R²⁴、-C(＝O)R²⁴、-C(＝O)N(R²⁴)₂、-CHO、-CH₂OR²⁴、-OC(＝O)R²⁴、-OC(＝O)OR²⁴、-OR²⁴、-OC(＝O)N(R²⁴)₂、-NR²⁴C(＝O)R²⁴、-NR²⁴C(＝O)OR²⁴、-NR²⁴C(＝O)N(R²⁴)₂、-NR²⁴SO₂N(R²⁴)₂、-NR²⁴SO₂R²⁴、-SO₃H、-SO₂R²⁴、-SR²⁴、-S(＝O)R²⁴、-SO₂N(R²⁴)₂、-N(R²⁴)₂、-NHC(＝S)NHR²⁴、＝NOR²⁴、-NO₂、-C(＝O)NHOR²⁴、-C(＝O)NHNR²⁴R²⁴、-OCH₂CO₂H. 2- (1-morpholino) ethoxy, C_1-5Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl radical, C_3-6Cycloalkyl methyl, C_2-6Alkoxyalkyl, substituted by 0-2R²⁴Substituted aryl and heterocyclic groups;

each R²⁴Independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, carbonyl, or a protecting group; and

n' is an integer of from 0 to 4,

wherein the compound comprises at least one chelator moiety.

In some embodiments, X is nitrogen. In some embodiments, X is oxygen. In some embodiments, X is sulfur. In some embodiments, X is phosphorus.

In some embodiments, n' is an integer from 0 to 3.

In some embodiments, each R is²⁴Independently of each other is hydrogen, C_1-6Alkyl, phenyl, benzyl or C_1-6An alkoxy group.

In one set of embodiments, the first and second sets of embodiments,

x is nitrogen;

R¹is hydrogen, alkyl, arylalkyl or alkylarylalkyl;

R²and R³Which may be the same or different, is hydrogen, alkyl, alkylaryl, aryl, arylalkyl, alkylarylalkyl or heterocyclylalkyl;

R⁴is alkyl, alkylaryl, aryl, arylalkyl or alkylarylalkyl,

wherein R is¹、R²、R³And R⁴At least one of which is substituted with a chelator moiety.

In any of the embodiments above, R²Or R³May comprise the following structure(s),

wherein

n is 0 to 6; and

R^zselected from the group consisting of alkyl, aryl, cycloalkenyl, cycloalkyl, heteroaryl, and heterocyclyl.

In any of the embodiments above, R²Or R³It is also possible to include the following structure,

wherein

n is 0 to 6;

R^yselected from hydrogen, alkenyl, alkynyl and alkyl; and

R^zselected from the group consisting of alkyl, aryl, cycloalkenyl, cycloalkyl, heteroaryl, and heterocyclyl.

In one set of embodiments, the first and second sets of embodiments,

n is 1 or 2;

R^yis hydrogen; and

R^zselected from alkyl, aryl, cycloalkyl and heteroaryl.

In some embodiments, R¹Comprising the at least one chelator moiety. In some embodiments, R²Or R³Comprising the at least one chelator moiety. In some embodiments, R⁴Comprising the at leastA chelator moiety.

In one set of embodiments, the compounds have the structure of formula (II):

or a pharmaceutically acceptable salt thereof; wherein

R⁴Is alkyl, alkenyl, alkynyl, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, or heterocyclylalkyl substituted with the at least one chelating agent moiety;

n is 0 to 6;

R^yselected from hydrogen, alkenyl, alkynyl and alkyl; and

R^zselected from the group consisting of alkyl, aryl, cycloalkenyl, cycloalkyl, heteroaryl, and heterocyclyl.

In another set of embodiments, the compound has the structure of formula (III):

or a pharmaceutically acceptable salt thereof, wherein

R²And R³Which may be the same or different, is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, heterocyclylalkyl or carbonyl, R²And R³Is substituted with the at least one chelating agent moiety; and

R⁴is alkyl or arylalkyl.

In another set of embodiments, the compounds have the structure of formula (IV):

or a pharmaceutically acceptable salt thereof; wherein

R¹Is alkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, alkoxyalkyl, heteroalkyl, or heterocyclylalkyl substituted with the at least one chelating agent moiety;

n is 0 to 6;

R^zselected from alkyl, aryl, cycloalkenyl, cycloalkyl, heteroaryl, and heterocyclyl; and

R⁴is alkyl or arylalkyl.

In any of the embodiments above, R¹、R²、R³And R⁴Has the structure:

wherein n is 0 or greater than 0, m is 0 or greater than 0, and R^cIs a chelator moiety. In some embodiments, n is an integer between 0 and 12, including 0 and 12. In some embodiments, n is an integer between 0 and 6, including 0 and 6. In some embodiments, m is an integer between 0 and 12, including 0 and 12. In some embodiments, m is an integer between 0 and 6, including 0 and 6.

In some embodiments, R¹、R²、R³And R⁴At least one of the (b) has a structure,

wherein n is 0 or greater than 0; m is 0 or greater than 0; and R^cIs a chelator moiety. In some embodiments, n is an integer between 0 and 12, including 0 and 12. In some embodiments, n is an integer between 0 and 6, including 0 and 6. In some embodiments, m is an integer between 0 and 12, including 0 and 12. In some embodiments, is an integer between 0 and 6, including 0 and 6.

In some embodiments, R¹、R²、R³And R⁴Has a structure

Wherein R is^cIs a chelator moiety. In some embodiments, R¹Has the structure that the utility model has the advantages that,

wherein R is^cIs a chelator moiety. In some embodiments, R⁴Has the structure that the utility model has the advantages that,

wherein R is^cIs a chelator moiety.

In any of the preceding embodiments, the chelator moiety has a structure,

wherein X' is carbon, nitrogen or phosphorus; o is an integer between 0 and 12, including 0 and 12; and D¹And D²May be the same or different and is hydrogen, alkyl, heteroalkyl, alkylcarbonyl or carbonyl, or, D¹And D²Can be combined to form a ring.

In some embodiments, the chelator moiety has a structure,

wherein o is an integer between 0 and 12, including 0 and 12; and D¹And D²May be the same or different and is hydrogen, alkyl, heteroalkyl, acyl, carboxylate alkyl, carbonylalkyl, alkylcarbonyl or carbonyl, or D¹And D²Can be combined to form a ring.

In some embodiments, the chelator moiety has a structure,

wherein D¹And D²May be the same or different and is hydrogen, alkyl, heteroalkyl, acyl, carboxylate alkyl, carbonylalkyl, alkylcarbonyl or carbonyl, or D¹And D²Can be combined to form a ring. In some embodiments, D¹And D²At least one of which is hydrogen.

In some embodiments, the chelator moiety may be selected from,

wherein R' may be any group capable of coordinating a metal ion, including O^-、OH、N(R”’)₂、NHR”’、OPO₃ ^2-OR OR '"where R" and R' "are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkylarylA group, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, or substituted derivatives thereof; o, p, q, r, s, t and u are each independently 1-6; and v, w, x and y are each independently 1 to 3. In some embodiments, o, r, s, t, and u are each 1; and p and q are each 2. In some embodiments, o, r, s, t, v, w, x, and y are each 1.

In some embodiments, the chelator moiety may be selected from,

wherein o, p, q, r, s, t and u are each independently 1 to 6; and v, w, x and y are each independently 1 to 3. In some embodiments, o, r, s, t, and u are each 1; and p and q are each 2. In some embodiments, o, r, s, t, v, w, x, and y are each 1.

In some embodiments, the chelator moiety comprises one of the following structures,

wherein R' may be any group capable of coordinating a metal ion, including O^-、OH、N(R”’)₂、NHR”’、OPO₃ ^2-OR '", wherein R" and R' "are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, OR substituted derivatives thereof; o and p eachIndependently 0 to 5; and q, r, s, t, u, v, w, x and y are each independently 1 to 6. In some embodiments, R' is-CO₂H. In some embodiments, the chelator moiety comprises one of the following structures,

wherein R' may be any group capable of coordinating a metal ion, including O^-、OH、N(R”’)₂、NHR”’、OPO₃ ^2-OR '", wherein R" and R' "are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, OR substituted derivatives thereof. In some embodiments, R' is-CO₂H. In some embodiments, R' is-CO₂ ^-。

In some embodiments, D¹And D²One is hydrogen and the other has the structure,

in one embodiment, the compound has the structure,

in another embodiment, the compound has the structure,

in one aspect of the disclosure, there is provided a compound of formula (I-A),

or a pharmaceutically acceptable salt thereof; wherein

A is a D-amino acid residue or a peptide consisting of a D-amino acid residue and a second D-amino acid;

D¹and D²Independently selected from hydrogen, a chelator moiety, and an imaging moiety; and

L¹is a linker; or

L¹And D²Together with the nitrogen atom to which they are attached, form a 5-7 membered ring.

In a first embodiment of the first aspect, L¹Is a linker selected from the group consisting of alkenylene, alkylenearylalkyl, alkylene, arylenealkyl, heteroalkylene, and heterocyclylene. In a second embodiment of the first aspect, L¹Is an alkylene group. In a third embodiment of the first aspect, L¹Is an arylenealkyl group. In a fourth embodiment of the first aspect, L¹Is an alkylene arylalkyl group.

In a fifth embodiment of the first aspect, A is a D-amino acid residue. In a sixth embodiment of the first aspect, a is

Wherein

n is 0 to 6;

R^yselected from hydrogen, alkenyl, alkynyl and alkyl; and

R^zselected from the group consisting of alkyl, aryl, cycloalkenyl, cycloalkyl, heteroaryl, and heterocyclyl. In a seventh embodiment of the first aspect, n is 1 or 2; r^yIs hydrogen; r^zSelected from alkyl, aryl, cycloalkyl and heteroaryl.

In an eighth embodiment of the first aspect, the present disclosure provides compounds wherein D¹And D²One of which is hydrogen and the other of which is a chelator moiety. In a ninth embodiment of the first aspect, D¹And D²One of which is hydrogen and the other is a chelator moiety selected from

Wherein

o, p, q, r, s, t and u are each independently 1 to 6; and

v, w, x and y are each independently 1-3.

In a tenth embodiment, o, r, s, t and u are each 1; p and q are each 2.

In an eleventh embodiment, o, r, s, t, v, w, x and y are each 1.

The present invention also provides a diagnostic agent comprising a compound as described in any of the aspects and embodiments above; and an imaging agent bound to the at least one chelator moiety. In some embodiments, the imaging agent is an echo generator, an optical indicator (reporter), a boron neutron absorber, a paramagnetic metal ion, a ferromagnetic metal, a gamma-emitting radioisotope, a positron-emitting radioisotope, orx-ray absorber. In one set of embodiments, the imaging agent is a paramagnetic metal ion. In a specific embodiment, the paramagnetic metal ion is gd (iii). In another set of embodiments, the imaging agent is a gamma-emitting radioisotope or a positron-emitting radioisotope selected from¹¹¹In、⁶²Cu、⁶⁴Cu、⁶⁷Ga、⁶⁸Ga and¹⁵³Gd。

in one embodiment, the diagnostic agent has the structure,

in a second aspect, the present disclosure provides a diagnostic agent comprising:

a. a compound of the formula (I-B)

Or a pharmaceutically acceptable salt thereof; wherein

A is a D-amino acid residue or a peptide consisting of a D-amino acid residue and a second D-amino acid;

D¹and D²Independently selected from hydrogen and a chelator moiety;

L¹is a linker; or

L¹And D²Together with the nitrogen atom to which they are attached, form a 5-7 membered ring; and

b. imaging agents conjugated to compounds (e.g. Gd)³⁺)。

In some embodiments, the imaging agent is bound to the diagnostic agent through a chelator moiety.

In a first embodiment of the second aspect, the imaging agent is an echo-generator, an optical indicator, a boron neutron absorber, a paramagnetic metal ion, a ferromagnetic metal, a gamma-emitting radioisotope, a positron-emitting radioisotope, or an x-ray absorber. In a second embodiment of the second aspect, the imaging agent is a paramagnetic metal ion. In a third embodiment of the second aspect, the paramagnetic metal ion is gd (iii).

In a fourth embodiment of the second aspect, the imaging agent is a gamma-emitting radioisotope or a positron-emitting radioisotope selected from¹¹¹In、⁶²Cu、⁶⁴Cu、⁶⁷Ga、⁶⁸Ga and¹⁵³Gd。

in a third aspect, the present disclosure provides a compound selected from

Or a pharmaceutically acceptable salt thereof.

In a fourth aspect, the present disclosure provides a method selected from

The compound of (1).

In a fifth aspect, the present disclosure provides a method of detecting, imaging and/or monitoring elastin rich tissue in a patient, comprising the steps of:

a. administering to a patient a diagnostic agent comprising:

1. a compound of the formula (I-B)

Or a pharmaceutically acceptable salt thereof; wherein

A is a D-amino acid residue or a peptide consisting of a D-amino acid residue and a second D-amino acid;

D¹and D²Independently selected from hydrogen and a chelator moiety;

L¹is a linker; or

L¹And D²Together with the nitrogen atom to which they are attached, form a 5-7 membered ring; and

2. an imaging agent bound to the compound; and

b. images of the location of the compound in the patient are obtained by diagnostic imaging techniques.

In a first embodiment of the fifth aspect, the elastin rich tissue is an arterial wall, uterus, lung, skin, and/or ligaments.

In a sixth aspect, the present disclosure provides a method of detecting, imaging and/or monitoring the presence of coronary plaque, carotid plaque, iliac/femoral plaque, aortic plaque, renal artery plaque, plaque of any arterial vessel, aneurysm, vasculitis, other diseases of the arterial wall, arterio-venous malformations, and/or lesions or structural changes in ligaments, uterus, lungs or skin in a patient comprising the steps of:

a. administering to a patient a diagnostic agent comprising:

1. a compound of the formula (I-B)

Or a pharmaceutically acceptable salt thereof; wherein

A is a D-amino acid residue or a peptide consisting of a D-amino acid residue and a second D-amino acid;

D¹and D²Independently selected from hydrogen and a chelator moiety;

L¹is a linker; or

L¹And D²Together with the nitrogen atom to which they are attached, form a 5-7 membered ring; and

2. an imaging agent bound to the compound; and

b. images of the location of the concentration of the compound in the patient are obtained by diagnostic imaging techniques.

The invention also provides compounds of formula (V),

or a pharmaceutically acceptable salt thereof; wherein

R^pIs hydrogen or an amino protecting group;

R²and R³Which may be the same or different, is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, or carbonyl; and

R⁴is hydrogen, alkyl, alkylaryl or alkylarylalkyl,

wherein each R²、R³And R⁴Unsubstituted or substituted with one or more of the following groups: alkyl, alkenyl, alkynyl, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, or heterocyclylalkyl, -NR¹⁹R²⁰、-SH、-OH、-PR¹⁹R²⁰、-P(O)R²¹R²²、-CO₂H. = O, halo, trifluoromethyl, -CF₂H、CH₂F. Cyano, -CO₂R²⁴、-C(＝O)R²⁴、-C(＝O)N(R²⁴)₂、-CHO、-CH₂OR²⁴、-OC(＝O)R²⁴、-OC(＝O)OR²⁴、-OR²⁴、-OC(＝O)N(R²⁴)₂、-NR²⁴C(＝O)R²⁴、-NR²⁴C(＝O)OR²⁴、-NR²⁴C(＝O)N(R²⁴)₂、-NR²⁴SO₂N(R²⁴)₂、-NR²⁴SO₂R²⁴、-SO₃H、-SO₂R²⁴、-SR²⁴、-S(＝O)R²⁴、-SO₂N(R²⁴)₂、-N(R²⁴)₂、-NHC(＝S)NHR²⁴、＝NOR²⁴、NO₂、-C(＝O)NHOR²⁴、-C(＝O)NHNR²⁴R²⁴、-OCH₂CO₂H. 2- (1-morpholino) ethoxy or chelator moiety;

R¹⁹and R²⁰Each independently selected from hydrogen, by 0-3R²³Substituted C_1-10Alkyl, by 0-3R²³Substituted aryl radicals, substituted by 0-3R²³Substituted C_3-10Cycloalkyl, by 0-3R²³Substituted heterocyclyl-C_1-10Alkyl, by 0-3R²³Substituted C_6-10aryl-C_1-10Alkyl and substituted by 0-3R²³A substituted heterocyclic group;

R²¹and R²²Each independently selected from-OH, by 0-3R²³Substituted C_1-10Alkyl, by 0-3R²³Substituted aryl radicals, substituted by 0-3R²³Substituted C_3-10Cycloalkyl, by 0-3R²³Substituted heterocyclyl-C_1-10Alkyl, by 0-3R²³Substituted C_6-10aryl-C_1-10Alkyl and substituted by 0-3R²³A substituted heterocyclic group;

each R²³Independently selected from ═ O, halo, trifluoromethyl, -CF₂H、CH₂F. Cyano, -CO₂R²⁴、-C(＝O)R²⁴、-C(＝O)N(R²⁴)₂、-CHO、-CH₂OR²⁴、-OC(＝O)R²⁴、-OC(＝O)OR²⁴、-OR²⁴、-OC(＝O)N(R²⁴)₂、-NR²⁴C(＝O)R²⁴、-NR²⁴C(＝O)OR²⁴、-NR²⁴C(＝O)N(R²⁴)₂、-NR²⁴SO₂N(R²⁴)₂、-NR²⁴SO₂R²⁴、-SO₃H、-SO₂R²⁴、-SR²⁴、-S(＝O)R²⁴、-SO₂N(R²⁴)₂、-N(R²⁴)₂、-NHC(＝S)NHR²⁴、＝NOR²⁴、-NO₂、-C(＝O)NHOR²⁴、-C(＝O)NHNR²⁴R²⁴、-OCH₂CO₂H. 2- (1-morpholino) ethoxy, C_1-5Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl radical, C_3-6Cycloalkyl methyl, C_2-6Alkoxyalkyl, substituted by 0-2R²⁴Substituted aryl and heterocyclic groups; and

each R²⁴Independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, carbonyl, or a protecting group.

In some embodiments, each R is²⁴Independently of each other is hydrogen, C_1-6Alkyl, phenyl, benzyl or C_1-6An alkoxy group.

In some embodiments, R^pIs hydrogen, Boc or Fmoc; r⁴Is hydrogen, alkyl or alkylarylalkyl wherein the alkyl or alkylarylalkyl group is substituted with an amino group. For example, R⁴Can be

In one group of embodiments, the compounds have the structure of formula (VI),

or a pharmaceutically acceptable salt thereof; wherein R is²、R³And R⁴As defined herein.

In another set of embodiments, the compounds have the structure of formula (VII),

or a pharmaceutically acceptable salt thereof; wherein R is²And R³As defined herein.

In another set of embodiments, the compound has the structure of formula (VIII)

Or a pharmaceutically acceptable salt thereof; wherein R is⁴As defined herein.

In one embodiment, the compound has the structure,

in another embodiment, the compound has the structure,

in any of the aspects and embodiments above, the alkyl group may be C_1-20Alkyl radical, C_1-10Alkyl radical, C_1-6Alkyl or C_1-5An alkyl group; cycloalkyl may be C_1-16A cycloalkyl group, a,C_3-14Cycloalkyl radical, C_3-10Cycloalkyl or C_3-6A cycloalkyl group; the alkylaryl group may be C_1-10alkyl-C_6-10An aryl group; the alkenyl group may be C_2-4An alkenyl group; alkynyl may be C_2-4An alkynyl group; aryl may be C_6-10An aryl group; the arylalkyl group may be C_6-10aryl-C_1-10An alkyl group; the alkoxy group may be C_1-6An alkoxy group; the alkoxyalkyl group may be C_2-6An alkoxyalkyl group; heterocyclyl may be a 5-, 6-or 7-membered ring; the heterocyclylalkyl group may be heterocyclyl-C_1-10An alkyl group.

In any of the aspects and embodiments described above, the pharmaceutically acceptable salt can be any salt listed on pages 44-45 of the specification or otherwise disclosed herein.

In any of the aspects and embodiments described above, the diagnostic agent may be provided in the absence of a counter ion (e.g., as a free base or as a free acid).

The present invention also provides a method of synthesizing any of the compounds described above according to the methods described herein. In some embodiments, the method may comprise reacting the compound with an imaging agent to form a diagnostic agent. In another embodiment, the method may comprise reacting an intermediate molecule to prepare a compound of the invention. In some embodiments, the method may further comprise isolating and/or purifying the compound and/or the diagnostic agent. The method may further comprise characterizing the compound and/or the diagnostic agent.

The invention also provides methods of treating a patient. The method may comprise administering to the patient a diagnostic agent, such as any of the diagnostic agent embodiments described above; and acquiring an image of the location of the diagnostic agent in the patient by a diagnostic imaging technique. In some embodiments, treating may include detecting, imaging, and/or monitoring elastin rich tissue of the patient. The elastin rich tissue may be located within an arterial wall, uterus, lung, skin, and/or ligaments. In some embodiments, treatment may include detecting, imaging and/or monitoring the presence and/or amount of coronary plaque, carotid plaque, iliac/femoral plaque, aortic plaque, renal artery plaque, plaque of any arterial vessel, aneurysm, vasculitis, other diseases of the arterial wall, and/or damage or structural changes to ligaments, uterus, lungs or skin in a patient.

The invention also provides the use of a diagnostic agent in the manufacture of a medicament. In some embodiments, there is provided a use of a diagnostic agent as in any one of the preceding diagnostic agent embodiments in the preparation of a medicament for treating a patient, wherein the use comprises obtaining an image of a site in the patient where the diagnostic agent is concentrated by a diagnostic imaging technique. In some embodiments, the use comprises detecting, imaging, and/or monitoring elastin rich tissue in a patient. In some embodiments, the elastin rich tissue is within an arterial wall, uterus, lung, skin, and/or ligament. In some embodiments, the use comprises detecting, imaging, and/or monitoring the presence of coronary plaque, carotid plaque, iliac/femoral plaque, aortic plaque, renal artery plaque, plaque of any arterial vessel, aneurysm, vasculitis, other diseases of the arterial wall, and/or damage or structural changes to ligaments, uterus, lungs, or skin in a patient.

The present invention also provides a diagnostic agent as in any one of the aforementioned diagnostic agent embodiments for use in obtaining an image of the location of a concentration of the diagnostic agent in a patient by diagnostic imaging techniques. In some embodiments, the use comprises detecting, imaging, and/or monitoring elastin rich tissue in a patient. In some embodiments, the elastin rich tissue is within an arterial wall, uterus, lung, skin, and/or ligament. In some embodiments, the use comprises detecting, imaging, and/or monitoring the presence of coronary plaque, carotid plaque, iliac/femoral plaque, aortic plaque, renal artery plaque, plaque of any arterial vessel, aneurysm, vasculitis, other diseases of the arterial wall, and/or damage or structural changes to ligaments, uterus, lungs, or skin in a patient.

Other aspects of the invention may include suitable combinations of the embodiments and aspects disclosed herein.

Brief Description of Drawings

Figure 1 shows a transaxial MR image of rabbit abdominal aorta imaged with an imaging agent described herein.

Other aspects, embodiments and features of the present invention will become apparent from the following detailed description when considered in conjunction with the accompanying drawings. The figures are schematic and not drawn to scale. For purposes of clarity, not every component is labeled in every drawing, nor is every component of every embodiment of the invention shown where illustration is not necessary to allow those of ordinary skill in the art to understand the invention. All patent applications and patents incorporated by reference herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

Detailed Description

The present disclosure relates to compounds, diagnostic agents, and related methods. In some embodiments, methods of synthesizing compounds and/or diagnostic agents are provided. In some embodiments, methods of treating a patient are provided. For example, compounds, diagnostic agents, compositions and kits are provided for detecting and/or imaging and/or monitoring diseases associated with coronary plaque, carotid plaque, iliac/femoral plaque, aortic plaque, renal artery plaque, plaque of arterial vessels, aneurysms, vasculitis, other diseases of the arterial wall, and/or damage or structural changes to ligaments, uterus, lungs or skin. In addition, the present disclosure provides methods of detecting and/or imaging and/or monitoring arterial wall changes, including dilating and constrictive remodeling, total vessel wall area, lumen size, and external artery circumference. Other aspects and embodiments will be found in the description provided herein.

Unless specifically indicated otherwise herein, the terms listed below will have the following definitions.

In some instances, the number of carbon atoms in any particular group is indicated before the group is recited. For example, the term "C_6-10Aryl "denotes a packageAryl having 6 to 10 carbon atoms, the term "C_6-10aryl-C_1-10Alkyl "refers to an aryl group of 6 to 10 carbon atoms attached to the parent molecular moiety through an alkyl group of 1 to 10 carbon atoms. When such designations are present, they replace all other definitions contained herein.

As used herein, the singular forms "a," "an," and "the" include the plural reference unless the context clearly dictates otherwise.

The term "acyl" as used herein refers to a compound having the formula-C (═ O) R^A、-C(＝O)OR^A、-C(＝O)-O-C(＝O)R^A、-C(＝O)SR^A、-C(＝O)N(R^A)₂、-C(＝S)R^A、-C(＝S)N(R^A)₂and-C (═ S) S (R)^A)、-C(＝NR^A)R^A、-C(＝NR^A)OR^A、-C(＝NR^A)SR^Aand-C (═ NR)^A)N(R^A)₂Wherein R is^AIs hydrogen; halogen; substituted or unsubstituted hydroxy; a substituted or unsubstituted mercapto group; a substituted or unsubstituted amino group; a substituted or unsubstituted acyl group, a cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic group; a cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphatic oxy, heteroaliphatic oxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphatic sulfoxy (thioaxy), heteroaliphatic sulfoxy, alkylsulfoxy, heteroalkylsulfoxy, arylsulfenoxy, heteroarylsulfoxy, mono-or di-aliphatic amino, mono-or di-heteroaliphatic amino, mono-or di-alkylamino, mono-or di-heteroalkylamino, mono-or di-arylamino, or mono-or di-heteroarylamino; or two R^AThe groups are joined together to form a 5-to 6-membered heterocyclic ring. Examples of acyl groups include aldehydes (-CHO), carboxylic acids (-CO)₂H) Ketones, acid halides, esters, acid amidesAmines, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thioxo (thioxo), cyano, isocyano, amino, azido, nitro, hydroxyl, mercapto, halo, aliphatic amino, heteroaliphatic amino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphatic oxy, heteroaliphatic oxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphatic thioxo, heteroaliphatic thioxo, alkylthioxo, heteroalkylthioxo, arylthioxo, heteroarylthioxo, acyloxy, and the like, each of which may or may not be further substituted).

The term "alkenyl" as used herein refers to a straight or branched chain hydrocarbon of 2 to 14 carbon atoms containing at least one carbon-carbon double bond.

The term "alkenylene" as used herein refers to a divalent group derived from a straight or branched chain hydrocarbon of 2 to 14 carbon atoms containing at least one carbon-carbon double bond.

The term "alkoxy" as used herein refers to an alkyl group attached to the parent molecular moiety through an oxygen atom.

The term "alkoxyalkyl" as used herein refers to an alkoxy group attached to a parent molecular moiety through an alkyl group.

The term "alkoxycarbonyl" as used herein refers to an alkoxy group attached to the parent molecular moiety through a carbonyl group.

The term "alkyl" as used herein refers to a group derived from a straight or branched chain saturated hydrocarbon.

The term "alkylaryl" as used herein refers to an alkyl group attached to the parent molecular moiety through an aryl group.

The term "alkylcarbonyl" as used herein refers to an alkyl group attached to the parent molecular moiety through a carbonyl group.

The term "alkylene" as used herein refers to a divalent group derived from a straight or branched chain saturated hydrocarbon of 1 to 14 carbon atoms.

The term "alkynyl" as used herein refers to a straight or branched chain hydrocarbon of 2 to 14 carbon atoms containing at least one carbon-carbon triple bond.

As used herein, the phrase "amino acid residue" refers to a residue consisting of a residue containing an amino group (-NH)₂) A carboxylic acid group (-COOH) and any of a variety of pendant groups, particularly 20 moieties of the basic formula NH₂Any compound of chrooh linked together by peptide bonds to form a protein or to function as a chemical messenger or metabolic intermediate. For example, in the compound X

In the above, the molecular moiety represented by "A" is the residue of the amino acid D-leucine.

The term "aryl" as used herein refers to a phenyl group or a bicyclic fused ring system wherein one or more rings are phenyl. The bicyclic fused ring system consists of a phenyl fused to a monocyclic cycloalkenyl, a monocyclic cycloalkyl or another phenyl. The aryl groups of the present invention may be attached to the parent molecular moiety through any substitutable carbon atom in the group. Representative examples of aryl groups include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.

The term "arylalkyl" as used herein refers to an aryl group attached to the parent molecular moiety through an alkyl group.

The term "heteroarylalkyl" as used herein refers to a divalent arylalkyl group wherein the points of attachment to the parent molecular moiety are located one in the aryl moiety and the other in the alkyl moiety.

The term "alkylarylalkyl" as used herein refers to an alkylaryl group attached to the parent molecular moiety through an alkyl group.

The term "arylene" as used herein refers to a divalent aryl group.

The term "cycloalkyl" as used herein refers to a saturated monocyclic, bicyclic or tricyclic hydrocarbon ring system having 3-14 carbon atoms and 0 heteroatoms. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, bicyclo [3.1.1] heptyl, and adamantyl.

The term "cycloalkylene" as used herein refers to a divalent cycloalkyl group.

The term "cycloalkylmethyl" as used herein refers to a compound through-CH₂-a cycloalkyl group attached to the parent molecular moiety.

The term "heteroalkyl" as used herein refers to an alkyl group wherein 1 to 7 carbon atoms are replaced with a heteroatom selected from O, NH and S.

The term "heteroalkylene" as used herein refers to an alkylene group wherein 1 to 7 carbon atoms are replaced by a heteroatom selected from O, NH and S.

The term "heterocyclyl" as used herein refers to a 5-, 6-or 7-membered ring containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. The 5-membered ring has 0-2 double bonds, and the 6-and 7-membered rings have 0-3 double bonds. The term "heterocyclyl" also includes bicyclic groups in which a heterocyclyl ring is fused to a phenyl, a monocyclic cycloalkenyl, a monocyclic cycloalkyl, or another monocyclic heterocyclyl. The heterocyclic groups of the present invention may be attached to the parent molecular moiety through a carbon or nitrogen atom in the group. Examples of heterocyclic groups include, but are not limited to, benzothienyl, furyl, imidazolyl, indolinyl, indolyl, isothiazolylAzolyl, morpholinyl, oxazolyl, morpholinyl, oxazolyl, oxazol,Oxazolyl, piperazinyl, piperidinyl, pyrazolyl, pyridyl, pyrrolidinyl, pyrrolopyridyl, pyrrolyl, thiazolyl, thienyl and thiomorpholinyl.

The term "heterocyclylalkyl" as used herein refers to a heterocyclyl group attached to the parent molecular moiety through an alkyl group.

The term "heterocyclylalkyl" as used herein refers to a divalent heterocyclylalkyl group in which the points of attachment to the parent molecular moiety are one on the heterocyclyl portion and the other on the alkyl portion.

The term "heterocyclylene" as used herein refers to a divalent heterocyclic group.

The term "halo" as used herein refers to Br, Cl, F or I.

The term "carbonyl" as used herein refers to-C (O) -.

The term "carboxylate" as used herein refers to the acid form-CO₂H or salt form-CO₂ ^-。

The term "cyano" as used herein refers to-CN.

The term "amino" as used herein refers to-NR¹⁹R²⁰Wherein R is¹⁹And R²⁰As defined herein.

As used herein, the phrase "donor atom" refers to an atom that is directly attached to a metal by a chemical bond.

The term "linker" as used herein refers to a portion of a molecule comprising carbon, nitrogen, oxygen, sulfur, and/or phosphorus atoms that serves as a spacer between two other portions of the molecule. For example, the linker can serve as a spacer between the chelating moiety and the amino acid residue. The linker may also serve other functions as described herein. In some embodiments, the linker may be an alkyl, alkenyl, alkynyl, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, or heterocyclylalkyl group, any of which may be substituted or unsubstituted.

The term "protecting group" as used herein refers to a temporary substituent that protects a potentially reactive functional group (e.g., O, S)Or N) to avoid undesirable chemical changes. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. In some embodiments, the protecting groups are selectively reacted in good yield to give a protected substrate that is stable to the intended reaction; the protecting group should be selectively removed after easily obtaining good yields, preferably non-toxic reactants that do not attack other functional groups; protecting group formation derivatives that are easily isolated (more preferably without formation of new stereocenters); and protecting groups have minimal additional functionality to avoid more reactive sites. As detailed herein, oxygen, sulfur, nitrogen, and carbon protecting groups may be used. Hydroxy protecting groups include methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl) methoxymethyl (SMOM), Benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy) methyl (p-AOM), Guaiacolmethyl (GUM), t-butoxymethyl, 4-Pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2, 2, 2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl, 2- (trimethylsilyl) ethoxymethyl (SEMOR), Tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-Methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S, S-dioxide, 1- [ (2-chloro-4-methyl) phenyl]-4-methoxypiperidin-4-yl (CTMP), 1, 4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2, 3, 3a, 4, 5, 6, 7, 7 a-octahydro-7, 8, 8-trimethyl-4, 7-methylenebenzofuran-2-yl, 1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2, 2, 2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylhydrogenselenyl) ethyl, tert-butyl, tert-butylthio, methyl-2-ethylthio-benzofuranyl-2-yl, 1-methyl-1-benzyloxy-fluoroethyl, 2, 2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenyl, Allyl, p-chlorophenyl, p-methoxyphenyl, 2, 4-dinitrophenyl, benzyl, p-methoxybenzyl, 3, 4-dimethoxybenzyl, o-nitrobenzyl, p-halobenzyl, 2, 6-dichlorobenzyl, p-chlorobenzyl-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p '-dinitrobenzhydryl, 5-dibenzocycloheptyl, triphenylmethyl, α -naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di (p-methoxyphenyl) phenylmethyl, tris (p-methoxyphenyl) methyl, 4- (4' -bromobenzoylmethoxyphenyl) diphenylmethyl, 4 ', 4 ″ -tris (4, 5-dichlorophthalimidophenyl) methyl, 4', 4 ″ -tris (oxypentanoyloxyphenyl) methyl, 4 ', 4 ″ -tris (benzoyloxyphenyl) methyl, p-tolylbenzyl, p-nitrophenyl, p-naphthyldiphenylmethyl, p-methoxyphenyl diphenylmethyl, 4- (4' -bromobenzoylmethoxyphenyl) methyl, 4, 3- (imidazol-1-yl) bis (4 ', 4 "-dimethoxyphenyl) methyl, 1-bis (4-methoxyphenyl) -1' -pyrenylmethyl, 9-anthryl, 9- (9-phenyl) xanthenyl, 9- (9-phenyl-10-oxo) anthryl, 1, 3-benzodithiolan-2-yl, benzisothiazolyl S, S-dioxide, Trimethylsilyl (TMS), Triethylsilyl (TES), Triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), Diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, tert-butyldimethylsilyl (DMS), tert-butyldiphenylsilyl (TBDPS), tribenzylsilyl (IPDMS), Tri-p-xylylsilyl, triphenylsilyl, Diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate ester, benzoylformate ester, acetate ester, chloroacetate ester, dichloroacetate ester, trichloroacetate ester, trifluoroacetate ester, methoxyacetate ester, triphenylmethoxyacetate ester, phenoxyacetate ester, p-chlorophenoxyacetate ester, 3-phenylpropionate ester, 4-oxopentanoate ester (levulinic acid), 4- (ethylenedithio) pentanoate ester (oxypentanoyl dithioacetal), pivalate ester (pivaloate), adamantanate ester (adamantoate), crotonate ester, 4-methoxycrotonate ester, benzoate ester, p-phenylbenzoate ester, 2,4, 6-trimethylbenzoate (mesitate), Alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2, 2, 2-trichloroethyl carbonate (Troc), 2- (trimethylsilyl) ethyl carbonate (TMSEC), 2- (phenylsulfonyl) ethyl carbonate (Psec), 2- (triphenylphosphine)Yl) ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3, 4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl) benzoate, 2-formylbenzenesulfonate, 2- (methylthiomethoxy) ethyl, 4- (methylthiomethoxy) butyrate, di (methylthio) methyl-ethyl-carbonate, di (methylthio) methyl-carbonate, di (thio) methyl, 2- (methylthiomethoxymethyl) benzoate, 2, 6-chloro-4-methylphenoxyacetate, 2, 6-dichloro-4- (1, 1, 3, 3-tetramethylbutyl) phenoxyacetate, 2, 4-bis (1, 1-dimethylpropyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinate, (E) -2-methyl-2-butenoate, o- (methoxycarbonyl) benzoate, α -naphthoate, nitrate, alkyl N, N, N ', N' -tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2, 4-dinitrophenylsulfenamic acid (sulfenate), sulfate ester, Methane sulfonate (mesylate), benzyl sulfonate and toluene sulfonate (Ts). For the protection of 1, 2-or 1, 3-diols, the protective groups include methylene acetal, ethylene acetal, 1-tert-butylethylene ketal, 1-phenylethylene ketal, (4-methoxyphenyl) ethylene acetal, 2, 2, 2-trichloroethylene acetal, acetonide, cyclopentylene ketal, cyclohexylene ketal, cycloheptylene ketal, benzylidene acetal, p-methoxybenzylidene acetal, 2, 4-dimethoxybenzylidene ketal, 3, 4-dimethoxybenzylidene acetal, 2-nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethylene orthoester, 1-methoxyethylidene orthoester, 1-ethoxyethylidene orthoester, 1, 2-dimethoxyethylidene orthoester, 1, 3-dimethoxyethylidene orthoester, 1-nitrobenzylidene acetal, and the like, Alpha-methoxybenzylidene orthoester, 1- (N, N-dimethylamino) ethylene derivative, alpha-methoxybenzylidene orthoester, alpha-methoxybenzylidene derivative, 1- (N, N-dimethylamino) ethylene derivative, alpha-methoxybenzylidene,α - (N, N' -dimethylamino) benzylidene derivatives, 2-oxacyclopentylidene orthoester, di-tert-butylsilylene (DTBS), 1, 3- (1, 1, 3, 3-tetraisopropyldisiloxanylidene) derivatives (TIPDS), tetra-tert-butoxydisiloxane-1, 3-diylidene derivatives (TBDS), cyclic carbonates, cyclic borates (boronates), ethylborates and phenylboronates. Amino-protecting groups include methylcarbamate, ethylcarbamate (carbamante), 9-fluorenylmethylcarbamate (Fmoc), 9- (2-sulfo) fluorenylmethylcarbamate, 9- (2, 7-bromo) fluorenyl (fluoroenyl) methylcarbamate, 2, 7-di-tert-butyl- [9- (10, 10-dioxo-10, 10, 10, 10-tetrahydrothioxanthene (tetrahydrothioxanthyl))]Methyl carbamate (DBD-Tmoc), 4-methoxybenzoyl methyl carbamate (Phenoc), 2, 2, 2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1- (1-adamantyl) -1-methylethyl carbamate (Adpoc), 1-dimethyl-2-haloethylcarbamate, 1-dimethyl-2, 2-dibromoethylcarbamate (DB-tert-BOC), 1-dimethyl-2, 2, 2-Trichloroethylcarbamate (TCBOC), 1-methyl-1- (4-biphenylyl) ethylcarbamate (Bpoc), 1- (3, 5-di-tert-butylphenyl) -1-methylethylcarbamate (t-Bumeoc), 2- (2 '-and 4' -pyridyl) ethylcarbamate (Pyoc), 2- (N, N-dicyclohexylcarboxamido) ethylcarbamate, tert-Butylcarbamate (BOC), 1-adamantylcarbamate (Adoc), vinylcarbamate (Voc), allylcarbamate (Alloc), 1-isopropylallylcarbamate (Ipaoc), cinnamylcarbamate (Coc), 4-nitrocinnamylcarbamate (Noc), 8-quinolinylcarbamate, N-hydroxypiperidinylcarbamate, alkyldithiocarbamate, benzylcarbamate (Cbz), P-methoxybenzylcarbamate (Moz), p-nitrobenzylcarbamate, p-bromobenzylcarbamate, p-chlorobenzylcarbamate, 2, 4-dichlorobenzylcarbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethylcarbamate, diphenylmethylcarbamate, 2-methylthiomethylcarbamateEthylcarbamate, 2-methylsulfonylethylcarbamate, 2- (p-toluenesulfonyl) ethylcarbamate, [2- (1, 3-dithianyl)]Methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2, 4-dimethylthiophenyl carbamate (Bmpc), 2-phosphorusEthyl carbamate (Peoc), 2-triphenyl phosphineTriisopropylcarbamate (Ppoc), 1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acyloxybenzylcarbamate, p- (dihydroxyboryl) benzylcarbamate, 5-benzisothiazolylmethylcarbamate, 2- (trifluoromethyl) -6-chromonyl (chromonyl) methylcarbamate (Tcroc), m-nitrophenylcarbamate, 3, 5-dimethoxybenzylcarbamate, o-nitrobenzylcarbamate, 3, 4-dimethoxy-6-nitrobenzylcarbamate, phenyl (o-nitrophenyl) methylcarbamate, phenothiazinyl- (10) -carbonyl derivative, N ' -p-toluenesulfonylcarbonyl derivative, N ' -carboxymethylcarbonyl derivative, N ' -chlorobutylthiocarbamate derivative, N-chlorobutylcarbamate, N-butylthiocarbamate derivative, N-butylthiocarbamate, N-butylthiocarb, N' -phenylaminothiocarbonyl derivative, t-pentylcarbamate, S-benzylthiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexylcarbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzylcarbamate, 2-dimethoxycarbonylvinylcarbamate, o- (N, N-dimethylcarboxamido) benzylcarbamate, 1-dimethyl-3- (N, N-dimethylcarboxamido) propylcarbamate, 1-dimethylpropynyl (propylyl) carbamate, bis (2-pyridyl) methylcarbamate, 2-furylmethyl carbamate, 2-iodoethylcarbamate, methyl-2-iodocarbamate, methyl-2-dimethylcarbamato, methyl-2-dimethylcarbam, Isobornyl (isobornyl) carbamate, isobutyl carbamate, isonicotinyl carbamate, p- (p' -methoxyphenylazo) benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate1-methyl-1- (3, 5-dimethoxyphenyl) ethylcarbamate, 1-methyl-1- (p-phenylazophenyl) ethylcarbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1- (4-pyridyl) ethylcarbamate, phenylcarbamate, p- (phenylazo) benzylcarbamate, 2,4, 6-tri-tert-butylphenyl carbamate, 4- (trimethylammonium) benzylcarbamate, 2,4, 6-trimethylbenzylcarbamate, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, picolinamide, pyridinamide, and the like, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitro (nito) phenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N' -dithiobenzyloxycarbonylamino) acetamide, 3- (p-hydroxyphenyl) propionamide, 3- (o-nitrophenyl) propionamide, 2-methyl-2- (o-nitrophenoxy) propionamide, 2-methyl-2- (o-phenylazoylphenoxy) propionamide, 4-chlorobutyramide, 3-methyl-3-nitrobutyramide, o-nitrocinnamamide, N-acetylmethionine derivative, o-nitrobenzamide, N-acetylbutyrylamide, N-nitrobenzamide, N, O- (benzoyloxymethyl) benzamide, 4, 5-diphenyl-3-Oxazoline-2-ones, N-phthalimides, N-dithiasuccinimides (Dts), N-2, 3-diphenylmaleimides, N-2, 5-dimethylpyrroles, N-1, 1, 4, 4-tetramethyldisilylazacyclopentane adducts (STABASE), 5-substituted 1, 3-dimethyl-1, 3, 5-triazacyclohexan-2-ones, 5-substituted 1, 3-dibenzyl-1, 3, 5-triazacyclohexan-2-ones, 1-substituted 3, 5-dinitro-4-pyridones, N-methylamine, N-allylamine, N- [2- (trimethylsilyl) ethoxy.]Methylamine (SEM), N-3-acetoxypropylamine, N- (1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl) amine, quaternary ammonium salt, N-benzylamine, N-bis (4-methoxyphenyl) methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N- [ (4-methoxyphenyl) diphenylmethyl]Amines (MMTr), N-9-phenylfluorenamines (PhF), N-2, 7-dichloro-9-fluorenesMethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-pyridylmethylamino N' -oxide, N-1, 1-dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N- [ (2-pyridyl)Base of]Methyleneamine, N- (N ', N ' -dimethylaminomethylene) amine, N ' -isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylidene amine, N-5-chlorosalicylideneamine, N- (5-chloro-2-hydroxyphenyl) phenylmethylidene, N-cyclohexylidene amine, N- (5, 5-dimethyl-3-oxo-1-cyclohexyl) amine, N-borane derivatives, N-diphenylboronic acid (borinic acid) derivatives, N- [ phenyl (chromium or tungsten pentacarbonyl) carbonyl]Amines, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosamines, amine N-oxides, diphenylphosphinamides (Dpp), dimethylthiophosphamides (Mpt), diphenylphosphinamides (Ppt), dialkylaminophosphates, dibenzylphosphoramidates, diphenylphosphoramidates, benzenesulfenamides, o-nitrobenzenesulfinamides (Nps), 2, 4-dinitrobenzenesulfenamides, pentachlorobenzenesulfinamides, 2-nitro-4-methoxybenzsulfenamides, triphenylmethylsulfinamides, 3-nitropyridine sulfenamides (Npys), p-toluenesulfonamides (Ts), benzenesulfonamides, 2, 3, 6, -trimethyl-4-methoxybenzenesulfonamides (Mtr), 2,4, 6-trimethoxybenzenesulfonamides (Mtb), 2, 6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2, 3, 5, 6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4, 6-trimethylbenzenesulfonamide (Mts), 2, 6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2, 5, 7, 8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β -trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4- (4 ', 8' -dimethoxynaphthylmethyl) benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide and phenacylsulfonamide. Exemplary protecting groups are described in detail herein, however, it is to be understood that the invention is not intended to be limited to such protecting groups; instead, various other equivalent protecting groups can be readily identified using the above criteria and used in the methods of the present invention. Others of protecting groupsExamples can be found in Greene, T, w.; wuts, p.g.m. Protective groups in organic synthesis (Protective groups in organic synthesis), second edition; wiley: new York, 1991, the contents of which are incorporated herein by reference.

The terms "chelator" and "chelator moiety" as used herein refer to a moiety or group on a molecule that is bound to a metal ion through one or more coordinating atoms. Chelating agent through linker L²Optionally attached to a parent molecular moiety. Suitably L²Examples of groups include, but are not limited to, -C (O) CH₂-Ar-CH₂Nhc (o) -, wherein Ar is arylene; -c (o) -; -c (o) -Het-nhch (o) -, wherein Het is heteroarylene; -CH₂-Ar-CH₂-, wherein Ar is arylene; -c (o) -Het-; and other groups disclosed herein. In certain embodiments of the disclosed compounds and/or diagnostic agents, the chelating agent is a surfactant capable of forming lipid globules or microbubbles filled with echogenic species.

In certain other embodiments, the chelator moiety has a formula selected from

Wherein

Each A¹Independently selected from-NR¹⁹R²⁰、-N(R²⁶)₂、-SH、-OH、-PR¹⁹R²⁰、-P(O)R²¹R²²、-CO₂H. Bond to parent molecular moiety and²a bond of (a);

each A²Is independently selected from N (R)²⁶)、N(R¹⁹)、S、O、P(R¹⁹) and-OP (O) (R)²¹)O-；

A³Is N;

A⁴selected from OH and OC (═ O) C_1-20An alkyl group;

A⁵is OC (═ O) C_1-20An alkyl group;

each E is independently selected from the group consisting of 0-3R²³Substituted C_1-16Alkylene, by 0-3R²³Substituted C_6-10Arylene radical, substituted by 0-3R²³Substituted C_3-10Cycloalkylene radical, with 0-3R²³Substituted heterocyclylene-C_1-10Alkyl, by 0-3R²³Substituted sub-C_6-10aryl-C_1-10Alkyl, by 0-3R²³Substituted sub-C_1-10alkyl-C_6-10Aryl and substituted by 0-3R²³A substituted heterocyclylene group;

E¹selected from the group consisting of a bond and E;

each E²Independently selected from 0-3R²³Substituted C_1-16Alkyl, by 0-3R²³Substituted C_6-10Aryl radical, substituted by 0-3R²³Substituted C_3-10Cycloalkyl, by 0-3R²³Substituted heterocyclyl-C_1-10Alkyl, by 0-3R²³Substituted C_6-10aryl-C_1-10Alkyl, by 0-3R²³Substituted C_1-10alkyl-C_6-10Aryl and substituted by 0-3R²³A substituted heterocyclic group;

E³is substituted by 1-3R³²Substituted C_1-10An alkylene group;

R¹⁹and R²⁰Each independently selected from the group consisting of²A bond with a parent molecular moiety, hydrogen, by 0-3R²³Substituted C_1-10Alkyl, by 0-3R²³Substituted aryl radicals, substituted by 0-3R²³Substituted C_3-10Cycloalkyl, by 0-3R²³Substituted heterocyclyl-C_1-10Alkyl, by 0-3R²³Substituted C_6-10aryl-C_1-10Alkyl and substituted by 0-3R²³A substituted heterocyclic group;

R²¹and R²²Each independently selected from the group consisting of²A bond to a parent molecular moiety, -OH, is substituted by 0-3R²³Substituted C_1-10Alkyl, by 0-3R²³Substituted aryl radicals, substituted by 0-3R²³Substituted C_3-10Cycloalkyl, by 0-3R²³Substituted heterocyclyl-C_1-10Alkyl, by 0-3R²³Substituted C_6-10aryl-C_1-10Alkyl and substituted by 0-3R²³A substituted heterocyclic group;

each R²³Independently selected from the group consisting of²A bond with the parent molecular moiety, ═ O, halo, trifluoromethyl, -CF₂H、-CH₂F. Cyano, -CO₂R²⁴、-C(＝O)R²⁴、-C(＝O)N(R²⁴)₂、-CHO、-CH₂OR²⁴、-OC(＝O)R²⁴、-OC(＝O)OR²⁴、-OR²⁴、-OC(＝O)N(R²⁴)₂、-NR²⁴C(＝O)R²⁴、-NR²⁴C(＝O)OR²⁴、-NR²⁴C(＝O)N(R²⁴)₂、-NR²⁴SO₂N(R²⁴)₂、-NR²⁴SO₂R²⁴、-SO₃H、-8O₂R²⁴、-SR²⁴、-S(＝O)R²⁴、-SO₂N(R²⁴)₂、-N(R²⁴)₂、-NHC(＝S)NHR²⁴、＝NOR²⁴、-NO₂、-C(＝O)NHOR²⁴、-C(＝O)NHNR²⁴R²⁴、-OCH₂CO₂H. 2- (1-morpholino) ethoxy, C_1-5Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl radical, C_3-6Cycloalkyl methyl, C_2-6Alkoxyalkyl, substituted by 0-2R²⁴Substituted aryl and heterocyclic groups;

each R²⁴Independently selected from the group consisting of²A bond to the parent molecular moiety, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, carbonyl, or a protecting group;

each R²⁶Independently is a coordination bond to a metal or hydrazine protecting group;

each R³²Is selected from R³⁴、＝O、-CO₂R³³、-C(＝O)R³³、-C(＝O)N(R³³)₂、-CH₂OR³³、-OR³³、-N(R³³)₂、C₂-C₄Alkenyl and C_2-4An alkynyl group;

each R³³Independently selected from R³⁴Hydrogen, C₁-C₆Alkyl, phenyl, benzyl and trifluoromethyl; and

R³⁴is and L²A bond of (a);

wherein A is¹、R¹⁹、R²⁰、R²¹、R²²、R²³、R²⁴And R³⁴Is at least one of²Or a bond of a parent molecular moiety.

In some embodiments, each R is²⁴Independently of each other is hydrogen, C_1-6Alkyl, phenyl, benzyl or C_1-6An alkoxy group.

In embodiments of the present disclosure, the chelator moiety has the formula:

wherein

A^1cIs and L²A bond of (a);

A^1a、A^1b、A^1dand A^1eEach is-CO₂H；

A^3a、A^3bAnd A^3cEach is N;

E^band E^cIs C₂An alkylene group; and

E^a、E^d、E^e、E^fand E_gIs CH₂。

In another embodiment of the present disclosure, the chelator moiety has the formula:

wherein:

A^3a、A^3b、A^3cand A^3dEach is N;

A^1ais and L²A bond of (a);

A^1b、A^1cand A^1dEach is-CO₂H；

E^a、E^c、E^gAnd E^eEach is CH₂(ii) a And

E^b、E^d、E^fand E^hEach is C₂An alkylene group.

In another embodiment of the present disclosure, the chelator moiety has the formula:

wherein

A^1ais-N (R)²⁶)₂；

A^1bIs NHR¹⁹；

E is a bond;

R¹⁹is and L²A bond of (a); and

each R²⁶Is a coordinate bond to a metal.

In some embodiments, the chelator moiety has a structure,

wherein X is carbon, nitrogen or phosphorus; o is an integer between 0 and 12, including 0 and 12; and D¹And D²May be the same or different and is hydrogen, alkyl, heteroalkyl, acyl, carboxylate alkyl, carbonylalkyl, alkylcarbonyl or carbonyl, or, D¹And D²The binding forms a ring.

In some embodiments, the chelator moiety has a structure,

wherein D¹And D²May be the same or different and is hydrogen, alkyl, heteroalkyl, acyl, carboxylate alkyl, carbonylalkyl, alkylcarbonyl or carbonyl, or, D¹And D²The binding forms a ring.

In some embodiments, the chelator moiety has a structure,

wherein D¹And D²May be the same or different and is hydrogen, alkyl, heteroalkyl, acyl, carboxylate alkyl, carbonylalkyl, alkylcarbonyl or carbonyl, or, D¹And D²The binding forms a ring. In some embodiments, D¹And D²At least one of which is hydrogen.

In some embodiments, the chelator moiety may be selected from,

or a pharmaceutically acceptable salt thereof,

wherein R' may be any group capable of coordinating a metal ion, including O^-、OH、N(R”’)₂、NHR”’、OPO₃ ^2-OR '", wherein R" and R' "are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, OR substituted derivatives thereof; o, p, q, r, s, t and u are each independently 1-6; and v, w, x and y are each independently 1 to 3. In some embodiments, o, r, s, t, and u are each 1; and p and q are each 2. In some embodiments, o, r, s, t, v, w, x, and y are each 1.

In some embodiments, the chelator moiety may be selected from,

or a pharmaceutically acceptable salt thereof,

wherein o, p, q, r, s, t and u are each independently 1 to 6; and v, w, x and y are each independently 1 to 3. In some embodiments, o, r, s, t, and u are each 1; and p and q are each 2. In some embodiments, o, r, s, t, v, w, x, and y are each 1.

In some embodiments, the chelator moiety comprises one of the following structures,

or a pharmaceutically acceptable salt thereof,

wherein R' may be any group capable of coordinating a metal ion, including O^-、OH、N(R”’)₂、NHR”’、OPO₃ ^2-OR '", wherein R" and R' "are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, OR substituted derivatives thereof; o and p are each independently 0 to 5 and q, r, s, t, u, v, w, x and y are each independently 1 to 6. In some embodiments, R' is-CO₂H。

In some embodiments, the chelator moiety comprises one of the following structures,

or a pharmaceutically acceptable salt thereof,

wherein R' may be any group capable of coordinating a metal ion, including O^-、OH、NHR”’、OPO₃ ^2-OR '", wherein R" and R' "are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, OR substituted derivatives thereof. In some embodiments, R' is-CO₂H. In some embodiments, R' is-CO₂ ^-。

In some embodiments, D¹And D²One is hydrogen, and the other has a structure,

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound comprises one of the following structures,

or a pharmaceutically acceptable salt thereof.

As used herein, the terms "adjuvant" and "co-ligand" refer to a ligand that completes the radionuclide coordination sphere with the chelator of the reagent (reagent). For radiopharmaceuticals comprising a binary ligand system, the radionuclide coordination sphere comprises one or more chelators of one or more reagents and one or more adjuvants or co-ligands, provided that there are a total of two types of ligands or chelators. For example, a radiopharmaceutical comprising a chelating agent for one agent and two identical adjuvants or co-ligands and a radiopharmaceutical comprising two chelating agents for one or both agents and an adjuvant or co-ligand are considered to comprise a binary ligand system. For radiopharmaceuticals comprising a three-way ligand system, the radionuclide coordination sphere comprises one or more chelators of one or more reagents and one or more of two different types of adjuvants or co-ligands, provided that there are a total of three types of ligands or chelators. For example, a radiopharmaceutical comprising a chelator of one agent and two different adjuvants or co-ligands is considered to comprise a ternary ligand system.

Adjuvants or co-ligands useful for the preparation of radiopharmaceuticals and diagnostic kits for the preparation of said radiopharmaceuticals comprise one or more oxygen, nitrogen, carbon, sulfur, phosphorus, arsenic, selenium and tellurium coordinating atoms. The ligand may act as a transport ligand in the synthesis of the radiopharmaceutical and may also act as an adjuvant or co-ligand to another radiopharmaceutical. Ligands are referred to as transport (transfer) ligands or as adjuvants or co-ligands, depending on whether the ligand remains within the radionuclide coordination layer of the radiopharmaceutical, as determined by the coordination chemistry of the radionuclide and reagent chelator.

As used herein, the term "diagnostic agent" refers to a compound that can be used to detect, image, and/or monitor the presence and/or progression of a disease, disorder, and/or condition. It is understood that all compounds of the invention comprising an imaging agent are diagnostic agents. For example, where D¹And D²Compounds of formula (I-A), one of which is an imaging agent, are diagnostic agents.

The term "diagnostic imaging technique" as used herein refers to a process for detecting a diagnostic agent.

The terms "diagnostic kit" and "kit" as used herein refer to a collection of components in one or more vials for use by a professional end user in a clinical or pharmacy setting for the synthesis of a diagnostic agent. The kit provides a solution of all the necessary components (except for those typically available to the professional end user such as water for injection or saline) to synthesize and use the diagnostic, such as the imaging agent or its precursors, the equipment used for heating during synthesis of the diagnostic, the equipment necessary to administer the diagnostic to the patient such as syringes and shielding (if needed), and the imaging equipment.

The term "imaging moiety" as used herein refers to a portion or portions of a molecule comprising an imaging agent. The term "imaging agent" as used herein refers to an element or functional group in a diagnostic agent that allows for the detection, imaging and/or monitoring of the presence and/or progression of a disease, disorder and/or condition. The imaging agent may be bound to the diagnostic agent by a bond such as a covalent bond, an ionic bond, a hydrogen bond, a dative bond (e.g., complexation or chelation between a metal ion and a monodentate ligand or a polydentate ligand), and the like. For example, imaging agentsCan be a paramagnetic metal ion that is bound to the diagnostic agent by chelation of the metal ion with a monodentate ligand or a multidentate ligand (e.g., chelating moiety) of the diagnostic agent. The imaging moiety may comprise a linker L³And linking the developer to the parent molecule moiety. Suitably L³Examples of groups include straight or branched chain alkylene, -C (O) -and the like.

The imaging agent may be an echo-generator (liquid or gas), a non-metallic isotope, an optical indicator, a boron neutron absorber, a paramagnetic metal ion, a ferromagnetic metal, a gamma-emitting radioisotope, a positron-emitting radioisotope, or an x-ray absorber.

Suitable echo producing gases include sulfur hexafluoride or perfluorocarbon gases such as perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoropentane or perfluorohexane.

Suitable non-metallic isotopes include¹¹C、¹⁴C、¹³N、¹⁸F、¹²³I、¹²⁴I and¹²⁵I。

suitable optical indicators include fluorescent indicators and chemiluminescent groups.

Suitable radioisotopes include^99mTc、⁹⁵Tc、¹¹¹In、⁶²Cu、⁶⁴Cu、⁶⁷Ga、⁶⁸Ga and¹⁵³gd. In particular embodiments of the present disclosure, suitable radioisotopes include¹¹¹In、⁶²Cu、⁶⁴Cu、⁶⁷Ga、⁶⁸Ga and¹⁵³Gd。

suitable paramagnetic metal ions include: gd (III), Dy (III), Fe (III) and Mn (II).

Suitable X-ray absorbers include: re, Sm, Ho, Lu, Pm, Y, Bi, Pd, Gd, La, Au, Yb, Dy, Cu, Rh, Ag, Ir and I.

As used herein, the term "metallodrug" refers to a drug comprising a metal. Metals are the source of the imageable signal in diagnostic applications and the source of cytotoxic radiation in radiotherapy applications.

The term "radiopharmaceutical" is used herein to refer to a metal drug in which the metal is a radioisotope.

As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, diagnostic agents, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The compounds and/or diagnostic agents of the present disclosure may exist as pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" as used herein refers to a water-or oil-soluble or dispersible salt or zwitterionic form of a compound and/or diagnostic agent of the present disclosure that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, and effective for its intended use. Salts may be prepared during the final isolation and purification of the compound and/or diagnostic agent or prepared separately by reacting the appropriate nitrogen atom with an appropriate acid. Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, mesitylene sulfonate, methanesulfonate, naphthalenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate (palmoate), pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Examples of acids which may be used to form pharmaceutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acids, and organic acids such as oxalic, maleic, succinic and citric acids.

Base addition salts can be prepared during the final isolation and purification of the compounds and/or diagnostic agents by reacting the carboxyl groups with a suitable base, such as the hydroxide, carbonate or bicarbonate of a metal cation, or with ammonia or an organic primary, secondary or tertiary amine. Cations of pharmaceutically acceptable salts include lithium, sodium, potassium, calcium, magnesium and aluminum, and non-toxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N-dibenzylphenethylamine and N, N' -dibenzylethylenediamine. Other representative organic amines useful for forming base addition salts include ethylenediamine, ethanolamine, diethanolamine, meglumine, piperidine, and piperazine.

In some embodiments, the compounds and/or diagnostic agents described herein may be provided in the absence of a counter ion (e.g., as a free base).

As used herein, the term "agent" refers to a compound of the present disclosure that is capable of direct conversion to a diagnostic agent of the present disclosure. The reagents may be used directly to prepare the diagnostic agents of the present disclosure or may be components of the kits of the present disclosure.

As used herein, the term "lyophilization aid" refers to a component having physical properties (e.g., glass transition temperature) that facilitate lyophilization that is added to a formulation to improve the physical properties of all lyophilized formulation component combinations.

As used herein, the phrase "solubilizing aid" is a component that improves the solubility of one or more other components in the medium required for formulation.

As used herein, the phrase "stabilizing aid" refers to a component that is added to a metallic drug or diagnostic kit to stabilize the metallic drug or extend the shelf life of the kit before it must be used. The stabilizing aid may be an antioxidant, reducing agent or free radical scavenger, and may provide improved stability by reacting with substances that degrade other components or metallic drugs.

The term "stable" as used herein refers to compounds and/or diagnostic agents that possess the ability to permit manufacture and maintain their integrity for a sufficient time to be useful for the purposes detailed herein. Typically, the compounds and/or diagnostic agents of the present disclosure are stable for at least 1 week at temperatures of 40 ℃ or less in the absence of moisture or other chemical reaction conditions.

The term "buffer" as used herein refers to a substance that maintains the pH of the reaction mixture at about 3 to about 10.

The term "sterile" as used herein refers to being free or kept free of pathogenic microorganisms using methods.

As used herein, the term "bacteriostatic agent" refers to a component that inhibits the growth of bacteria in a formulation during storage prior to use of the formulation or after synthesis of the diagnostic with a diagnostic kit.

The term "carrier" as used herein refers to an adjuvant or vehicle which may be administered to a patient with a compound and/or diagnostic agent of the present disclosure and which does not destroy the activity thereof, and which is non-toxic when administered in a dosage sufficient to deliver an effective amount of the diagnostic agent and/or compound.

Asymmetric centers are present in the compounds and/or diagnostic agents of the present invention. These centers are designated by the symbols "R" or "S", depending on the configuration of the substituents around the chiral carbon atom. It is to be understood that the invention includes all stereochemically isomeric forms, or mixtures thereof, of the compounds and/or diagnostic agents of the present invention, unless otherwise specifically indicated. Individual stereoisomers of the compounds and/or diagnostic agents may be prepared either synthetically from commercially available starting materials containing chiral centers or by preparation of enantiomeric product mixtures followed by separation, e.g. conversion to diastereomeric mixtures, followed by separation or recrystallization, chromatographic techniques or direct separation of the enantiomers on a chiral chromatographic column. Starting compounds of specific stereochemistry are either commercially available or can be prepared and resolved by techniques known in the art.

Any of the compounds and reagents described herein may contain one or more deuterium atoms. For example, one or more hydrogen atoms of the compounds and reagents may be replaced with deuterium atoms. It is to be understood that the invention includes other isotopically enriched derivatives of the compounds/reagents described herein.

Certain compounds and/or diagnostic agents of the present disclosure may also exist in different isolated stable conformational forms. Torsional asymmetry due to limited rotation about asymmetric single bonds, for example because of steric hindrance or ring strain (ring strain), may allow separation of different conformers. The present disclosure includes each conformational isomer of these compounds and/or diagnostic agents and mixtures thereof.

When any variable occurs more than one time in any substituent or any formula, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if the radical is shown to be substituted by 0 to 2R²³Substituted, then said group may optionally be substituted with up to 2R²³Substituted, R²³Independently at each occurrence from the explicitly listed possible R²³. Also, for example, for the group-N (R)²⁴)₂2R on nitrogen²⁴Each substituent is independently selected from the explicitly listed possible R²⁴. Combinations of substituents and/or variables are permitted only if such combinations result in stable compounds and/or diagnostic agents. When a bond to a substituent is shown across the bond connecting 2 atoms in the ring, then such substituent may be bonded to any atom on the ring.

When the imaging agent is a radioisotope, the compound may further comprise a first adjuvant ligand and a second adjuvant ligand capable of stabilizing the radioisotope. Many ligands can serve as adjuvants or co-ligands, the choice of which depends on factors such as the ease of synthesis of the radiopharmaceutical, the chemical and physical properties of the adjuvant ligand, the rate of formation, yield and number of isomeric forms of the resulting radiopharmaceutical, the ability of the adjuvant or co-ligand to not produce an adverse physiological response to a patient following administration of the adjuvant or co-ligand to the patient, and the compatibility of the ligand in lyophilized kit formulations. The charge and lipophilicity of the adjuvant ligand will affect the charge and lipophilicity of the radiopharmaceutical. For example, 4, 5-dihydroxy-1, 3-benzenedisulfonate is used to produce radiopharmaceuticals with 2 additional anionic groups, since the sulfonic acid group will be anionic under physiological conditions. The use of N-alkyl substituted 3, 4-hydroxypyridones results in radiopharmaceuticals that are lipophilic to varying degrees (depending on the size of the alkyl substituent).

It is also understood that the compounds and/or diagnostic agents of the present disclosure may take a variety of conformational and ionic forms in solution, pharmaceutical compositions, and in vivo. Although specific compounds and/or diagnostic agents of the present disclosure are described herein in specific conformational and ionic forms, those descriptions contemplate and include those compounds and/or diagnostic agents in other conformational and ionic forms.

Pharmaceutically acceptable carriers, adjuvants, and vehicles that may be used in the pharmaceutical compositions of the disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffers such as phosphate, glycine, sorbic acid, potassium sorbate, TRIS (hydroxymethyl) aminomethane, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block copolymers, polyethylene glycol, and wool fat.

In accordance with the present disclosure, the pharmaceutical compositions may take the form of sterile injectable preparations, such as sterile injectable aqueous or oleaginous suspensions. Such suspensions may be formulated with suitable dispersing or wetting agents and suspending agents according to techniques known in the art. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Recognized vehicles and solvents that may be employed include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any bland fixed oil may be employed for such purpose including synthetic mono-or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as well as the natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant.

In some cases, depending on the injection dose and rate, the prodrug and the activated agent may saturate the binding sites on the plasma proteins. This results in a reduced fraction of protein binding agent, which can impair its half-life or tolerance as well as the efficacy of the drug. In these cases, it is desirable to inject the prodrug in conjunction with sterile albumin or plasmapheresis. Alternatively, a device/syringe containing a contrast agent may be used, which mixes the contrast agent with blood drawn into the syringe; and then re-injected into the patient.

The compounds, diagnostic agents and pharmaceutical compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, orally, vaginally or via an implanted reservoir in dosage forms containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.

When administered orally, the pharmaceutical compositions of the present disclosure may be administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents such as magnesium stearate are also typically added. In the case of an oral administration capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

Alternatively, when administered rectally in the form of suppositories, the pharmaceutical compositions of the present disclosure may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

As noted above, the pharmaceutical compositions of the present disclosure may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including the eye, skin or lower intestinal tract. Suitable topical formulations for use in various of these areas or organs are readily prepared.

Topical administration to the lower intestinal tract may be accomplished by rectal suppositories (see above) or suitable enemas. Topical-transdermal patches may also be used.

For topical administration, the pharmaceutical compositions may be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds and/or diagnostic agents of the present disclosure include, but are not limited to, mineral oil, liquid paraffin, white soft paraffin, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, and water. Alternatively, the pharmaceutical compositions may be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or as solutions in isotonic, pH adjusted sterile saline, with or without preservatives such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated as an ointment such as a wax.

For administration by nasal aerosol or inhalation, the pharmaceutical compositions of the present disclosure may be prepared according to techniques well known in the art of pharmaceutical formulation, and may be prepared as a saline solution, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and/or other conventional solubilizing or dispersing agents.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Typically the formulation will contain from about 5% to about 95% active compound (w/w). Typically, such formulations comprise from about 20% to about 80% active compound.

For intravenous and other types of administration, acceptable dosages range from about 0.001 to about 1.0mmol/kg body weight, with typical dosages of the active ingredient compound being from about 0.001 to about 0.5mmol/kg body weight. Even more typically from about 0.01 to about 0.1mmol/kg, and the most typical dose of the active ingredient compound is from about 0.0001 to about 0.05 mmol/kg.

As the skilled person will appreciate, lower or higher doses than the above ranges may be required. The specific dosage regimen 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, rate of excretion, drug combination and the judgment of the attending physician.

Buffers used in the preparation of diagnostic agents and kits thereof include, but are not limited to, phosphates, citrates, sulfosalicylates, and acetates. A more comprehensive list can be found in the United states pharmacopoeia.

Lyophilization aids for the preparation of diagnostic agents and kits thereof include, but are not limited to, mannitol, lactose, sorbitol, dextran, Ficoll, and polyvinyl pyrrolidine (PVP).

Stabilizing aids for the preparation of diagnostic agents and kits thereof include, but are not limited to, ascorbic acid, cysteine, monothioglycerol, sodium bisulfite, sodium metabisulfite, gentisic acid and inositol.

Solubilizing aids for use in the preparation of diagnostic agents and kits thereof include, but are not limited to, ethanol, glycerol, polyethylene glycol, propylene glycol, polyoxyethylene sorbitan monooleate, polysorbate, poly (oxyethylene) poly (oxypropylene) poly (oxyethylene) block copolymers (Pluronics), and lecithin. Typical solubilizing aids are polyethylene glycol and Pluronics copolymers.

Bacteriostatic agents useful in the preparation of diagnostic agents and kits thereof include, but are not limited to, benzyl alcohol, benzalkonium chloride, chlorobutanol, and methyl, propyl, or butyl parabens.

The components of the diagnostic kit may also serve more than one function. The reducing agent may also act as a stabilizing aid, the buffer may also act as a transport ligand, the lyophilization aid may also act as a transporter (transfer), adjuvant or co-ligand, and the like.

The predetermined amounts of the various components in the formulation will be determined by a variety of factors, sometimes with respect to that component, and sometimes depending on the amount of the other component or the presence and amount of the optional component. Generally, the minimum amount of each component that will produce the desired effect of the formulation is used. The desired effect of the formulation is that the professional end user can synthesize the diagnostic agent, and it is well established that the diagnostic agent can be safely injected into a patient and will provide diagnostic information about the disease state of the patient.

The diagnostic kit of the present disclosure may also contain instructions for the professional end-user to follow to synthesize the diagnostic agent. These instructions may be attached to one or more vials or to a container in which the one or more vials are packed for transport, or may be separate instructions, referred to as package instructions.

X-ray contrast agents, ultrasound contrast agents and metal drugs, which are used as contrast agents for magnetic resonance imaging, are provided to the end user in their final form, which is a formulation, usually contained in one vial, as a lyophilized solid or an aqueous solution. The end user reconstitutes the lyophilized solid with water or saline, withdraws the patient dose, or simply withdraws the dose from the provided aqueous solution formulation.

These diagnostic agents, whether used in gamma scintigraphy, positron emission tomography, MRI, ultrasound or x-ray image enhancement, are useful, inter alia, for detecting and monitoring changes in cardiovascular disease over time.

Also provided are methods of synthesizing the compounds and diagnostic agents described herein. In some cases, the methods may comprise reacting a compound and/or intermediate described herein to prepare a compound and/or diagnostic agent of the invention. For example, the method can comprise reacting the compound with an imaging agent to form a diagnostic agent, as described herein. In another example, a method may comprise reacting an intermediate molecule to prepare a compound of the invention. In some cases, the intermediate molecule may be a compound comprising hydroxylamine derivatives, hydroxamic acids, hydroxamates, amines, and the like. Other intermediate molecules are described herein, including the examples. The methods may further comprise isolating and/or purifying the compound and/or diagnostic agent, for example, by chromatography (e.g., column chromatography, HPLC), crystallization, filtration, solvent extraction, and the like. The method may further comprise characterizing the compound and/or diagnostic agent by mass spectrometry, NMR, or the like.

The compounds and/or diagnostic agents of the present disclosure may be prepared according to the procedures described herein. In some cases, compounds and/or diagnostic agents may be synthesized by coupling a hydroxylamine derivative with a carbonyl group, such as a carboxylic acid, an acyl halide, an ester, and the like, to form an hydroxamate. For example, scheme 1 shows carboxylic acid moieties with hydroxylamine derivatives (e.g., H)₂NOR⁴) Condensation to form the hydroxamate. In some cases, the hydroxylamine derivative may be partially substituted with a chelating agent.

Scheme 1

In some embodiments, compounds and/or diagnostic agents may be synthesized by coupling hydroxylamine to a carbonyl group to form hydroxamic acid, which may be further substituted with, for example, a chelating agent moiety. As shown in scheme 2, the carboxylate moiety is reacted with hydroxylamine to form hydroxyamido acid (hydroxyamic acid), which is then reacted on oxygen with a leaving group-containing species, Y-R⁴Substitution wherein Y is a leaving group, R⁴Comprising a chelator moiety.

Scheme 2

In some cases, the chelator moiety may be coupled to the compounds and diagnostic agents described herein using the methods and compounds described in international publication No. WO2003/011115, the contents of which are incorporated herein by reference in their entirety.

The compounds and diagnostic agents described herein can also be synthesized by a variety of methods known in the art that can form carbon-carbon bonds, carbon-heteroatom bonds, and the like. For example, moieties of the compound and the diagnostic agent may be bonded to each other through amino, ether, thioether, ester, thioester, amide, thiourea, or other linkages. In some cases, the chelator moiety can be bonded to the compound or diagnostic agent through an amide bond.

The skilled person will be able to select a suitable method of synthesizing a compound or diagnostic agent having a particular bond. For example, methods of coupling amino acids or peptides (as described more fully below) may be used in the context of the present invention to form amide bonds between moieties of a compound or diagnostic agent. In some cases, alkylation with an alcohol or a thiol may form an ether or a thioether, respectively. For example, reacting a thiol with an alkyl species containing a leaving group (e.g., halo, tosyl, mesyl, etc.) can form a bond between the thioether and the alkyl group, i.e., the thioether. In some embodiments, the compound or diagnostic agent may comprise a thiourea linkage, which may be formed by various methods known in the art, including an acylation reaction between an amine moiety and an isothiocyanate moiety.

In some cases, Mitsunobu reactions can be used to form a variety of linkages, including esters, phenyl ethers, thioethers, and the like, by reacting a nucleophile, such as an acidic nucleophile, with a primary or secondary alcohol in the presence of diethyl azodicarboxylate (DEAD). One skilled in the art will be able to select the appropriate nucleophile as appropriate for a particular use. For example, reaction of an alcohol with a phenol under Mitsunobu conditions can produce an aryl ether, while reaction of an alcohol or thiol with a carboxylic acid under Mitsunobu conditions can produce an ester or thioester, respectively.

The compounds and diagnostic agents described herein may also comprise phosphonate linkages. In some embodiments, phosphonates may be synthesized by coupling phosphonic acids with alcohols, for example, in the presence of DEAD or bicyclic carbodiimide (DCC). Other methods of synthesizing phosphonates are described, for example, in Savignac, p.et al, Modern phosphate Chemistry, CRC Press: new York, 2003, the contents of which are incorporated herein by reference.

Other methods of forming carbon-carbon bonds may be used to synthesize the compounds or diagnostic agents described herein, such as olefin metathesis. As used herein, "metathesis" or "olefin metathesis" has its general meaning in the art and refers to a chemical reaction in which two reactants exchange partners (partner) in the presence of a transition metal catalyst, a carbon-carbon double bond is formed between the two reactants, ethylene being a byproduct, according to the formula shown in scheme 3. Examples of different types of metathesis reactions include cross metathesis, ring-closing metathesis, ring-opening metathesis, acyclic diene metathesis, alkyne metathesis, enyne metathesis, and the like. Typically, the metathesis reaction is carried out in the presence of a metathesis catalyst, which may comprise ruthenium, molybdenum or tungsten (e.g., Grubbs ' first generation catalysts, Grubbs ' second generation catalysts, Schrock's catalysts).

Scheme 3

Metal catalyzed cross-coupling reactions are also useful for the synthesis of compounds and diagnostic reagents. For example, aryl halides can be reacted with various species in the presence of a metal catalyst to form bonds including biaryl ethers, acetylenes, alkenyl aryl groups (such as styrene and styrene derivatives), arenes, and the like. Examples of cross-coupling reactions suitable for use in the present invention include Ullmann, Sonogashira/Castro-Stevens, Heck, Stille, Suzuki and other related reactions. One skilled in the art will be able to select the appropriate reactants, catalysts and reaction conditions for synthesizing a particular desired compound or diagnostic agent.

Cycloaddition chemistry can also be used to synthesize the compounds and diagnostic agents described herein. For example, "click" chemistry may be used, wherein a [3+2] cycloaddition between an azide-containing species and an alkyne-containing species may form a triazole linkage between the two species. Such reactions can be carried out under mild conditions, with high tolerance for a variety of functional groups.

In some cases, a compound or diagnostic agent may include a peptide, polypeptide, and/or peptidomimetic (peptidomimetic), which may be synthesized using various known methods. In general, the α -amines of the C-terminal residues can be deprotected by the methods described, and coupled by peptide bonds to the next appropriately protected amino acid to extend peptides, polypeptides and peptidomimetics. This deprotection and coupling procedure is repeated until the desired sequence is obtained. This coupling can be carried out in a stepwise manner with the constituent amino acids, or by fragment (two to several amino acids) condensation, or a combination of the two methods, or by solid phase peptide synthesis according to the method described initially in J.Am.chem.Soc, 1963, 85, 2149-2154.

Peptides, polypeptides and peptidomimetics can also be synthesized using automated synthesis equipment. In addition to the above methods, procedures for synthesizing peptides, polypeptides and peptidomimetics are described in Stewart and Young, Solid phase peptide Synthesis, 2nd Ed., Pierce Chemical Co., Rockford, IL (1984); gross, Meienhofer, Udenfriend, eds., The Peptides: analysis, Synthesis, Biology, Vol.1, 2, 3, 5, and 9, Academic Press, New York, (1980-; bodanszky, Peptide Chemistry: a Practical Textbook, Springer-Verlag, New York (1988); and Bodanszky et al, The Practice of peptide Synthesis (handbook of peptide Synthesis), Springer-Verlag, New York (1984).

Coupling between two amino acid derivatives, an amino acid and a peptide, polypeptide or peptidomimetic, two peptides, polypeptides or peptidomimetic fragments, or cyclizing a peptide, polypeptide or peptidomimetic can be carried out using standard coupling procedures, such as, for example, the azide method, the mixed carbonic anhydride (isobutyl chloroformate) method, the carbodiimide (dicyclohexylcarbodiimide, diisopropylcarbodiimide or water-soluble carbodiimide) method, the active ester (p-nitrophenyl ester, N-hydroxysuccinimide ester) method, the Woodward reagent K method, the carbonyldiimidazole method, phosphorous reagents such as BOP-Cl or oxidation-reduction methods. Some of these processes (especially carbodiimides) can be facilitated by the addition of 1-hydroxybenzotriazole or 1-hydroxy-7-azabenzotriazole. These coupling reactions can be carried out in solution (liquid phase) or in solid phase, e.g. polystyrene or a suitable resin (see below).

The functional groups of the constituent amino acids or pseudo-amino acids are generally protected during the coupling reaction to avoid the formation of unwanted bonds. Protecting groups that can be used are described in Greene, protective groups in Organic Synthesis, John Wiley & Sons, New Jersey (2007) and The Peptides: analysis, Synthesis, Biology, Vol.3, Academic Press, New York (1981).

The α -carboxy group of the C-terminal residue may be protected with an ester, which is cleavable to give a carboxylic acid.

These protecting groups include:

(1) alkyl esters such as methyl ester and t-butyl ester;

(2) aryl esters such as benzyl and substituted benzyl esters, or

(3) Esters such as trichloroethyl and phenacyl which may be cleaved by mild base treatment or by mild reduction.

In the case of a solid phase, the C-terminal amino acid is attached to an insoluble support (usually polystyrene). These insoluble carriers contain groups that will react with the carboxyl groups to form bonds that are stable under extension conditions but that are later easily cleaved. Examples include: oxime resins (DeGrado and Kaiser (1980) J.org.chem.45, 1295-1300) chloro-or bromomethyl resins, hydroxymethyl resins and aminomethyl resins. Many of these resins are commercially available, already containing the desired C-terminal amino acid.

The alpha-amino group of each amino acid is typically protected, for example, by an alpha-amino protecting group. Any protecting group known in the art may be used. These examples are:

(1) acyl types such as formyl, trifluoroacetyl, phthaloyl and p-toluenesulfonyl;

(2) aromatic carbamates such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyl, 1- (p-biphenylyl) -1-methylethoxycarbonyl and 9-fluorenyl-methoxycarbonyl (Fmoc);

(3) aliphatic urethane types such as t-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl and allyloxycarbonyl;

(4) cycloalkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl;

(5) alkyl types such as triphenylmethyl and benzyl;

(6) trialkylsilanes such as trimethylsilyl; and

(7) mercapto-containing types such as phenylthiocarbonyl and dithiasuccinoyl.

Representative alpha-amino protecting groups are Boc or Fmoc. Many appropriately protected amino acids or pseudo-amino acid derivatives for peptide synthesis are commercially available.

The alpha-amino protecting group is isolated prior to coupling with the next amino acid. When using a Boc group, the method of choice is trifluoroacetic acid (neat or in dichloromethane) or HCl/dioxane. The resulting ammonium salt is then neutralized with a basic solution such as an aqueous buffer or a tertiary amine/dichloromethane or dimethylformamide either prior to coupling or in situ. When the Fmoc group is used, the reagent of choice is piperidine or substituted piperidine/dimethylformamide, but any secondary amine or basic aqueous solution can be used. Deprotection is carried out at a temperature of 0 ℃ to room temperature.

Amino acids or pseudo-amino acids bearing side chain functionality are typically protected with any of the groups described above during the preparation of the peptide. Those skilled in the art will appreciate that the selection and use of suitable protecting groups for these side chain functionalities will depend on the amino acid or pseudo-amino acid and other protecting groups present in the peptide, polypeptide or peptidomimetic. The choice of such a protecting group is important because it must not be removed during deprotection and coupling of the alpha-amino group.

For example, when Boc is selected for α -amine protection, the following protecting groups may be accepted: p-toluenesulfonyl (tosyl) moiety and nitro for arginine; benzyloxycarbonyl, substituted benzyloxycarbonyl, tosyl or trifluoroacetyl for lysine; benzyl or alkyl esters such as cyclopentyl for glutamic acid and aspartic acid; benzyl ethers for serine and threonine; benzyl ether, substituted benzyl ether or 2-bromobenzyloxycarbonyl for tyrosine; p-methylbenzyl, p-methoxybenzyl, acetamidomethyl, benzyl or tert-butylsulfonyl for cysteine; the indole of tryptophan may remain unprotected or protected with a formyl group.

When Fmoc is selected for alpha-amine protection, a t-butyl protecting group is typically accepted. For example, Boc can be used for lysine, tert-butyl ether for serine, threonine and tyrosine, and tert-butyl ester for glutamic acid and aspartic acid.

Once the extension of the peptide, polypeptide or peptidomimetic, or the extension and cyclization of the cyclic peptide or peptidomimetic is complete, all protecting groups are removed. For liquid phase synthesis, the protecting group is removed in any manner depending on the protecting group selected. These processes are well known to those skilled in the art.

When synthesizing cyclic peptides or peptidomimetics using solid phase synthesis, the peptide or peptidomimetic should be removed from the resin without simultaneously removing protecting groups for functional groups that may interfere with the cyclization process. Thus, if the peptide or peptidomimetic is to be cyclized in solution, it is necessary to select cleavage conditions that yield a free α -carboxylic acid group and a free α -amino group without simultaneously removing additional protecting groups. Alternatively, the resin peptide or peptidomimetic can be removed by hydrazinolysis and then coupled by azide. Another very convenient method involves the synthesis of peptides or peptidomimetics on oxime resins, followed by nucleophilic displacement from the resin molecule to yield cyclic peptides or peptidomimetics (Tetrahedron Letters, 1990, 43, 6121-. When oxime resins are used, a Boc protection scheme is usually chosen. Typical methods for removing side chain protecting groups then generally involve treatment with anhydrous HF containing additives such as dimethyl sulfide, anisole, thioanisole or p-cresol at 0 ℃. Cleavage of the peptide or peptidomimetic may also be accomplished by other acid agents such as a triflic acid/trifluoroacetic acid mixture.

Unusual amino acids for use in The present disclosure can be synthesized by standard methods familiar to those skilled in The art (The Peptides: Analysis, Synthesis, Biology, Vol.5, pp.342-449, Academic Press, New York (1981)). N-alkyl amino acids can be prepared by methods previously described (Cheung et al, Can.J.Chem., 1977, 55, 906; Freidinger et al.J.Org.Chem., 1982, 48, 77).

The chelating agent is selected so as to form a stable complex with the metal ion selected for the particular application. The chelating agent of the diagnostic radiopharmaceutical is selected so as to form a stable complex with a radioisotope having an imageable gamma-ray or positron emission, such as¹¹¹In、⁶²Cu、⁶⁰Cu、⁶⁴Cu、⁶⁷Ga、⁶⁸Ga、⁸⁶Y、¹⁵³Gd。

The chelating agent for the copper and gallium isotopes is selected from the group consisting of diaminedimercapto, monoamine-monoamidedimercapto, triamide-monomercapto, monoamine-diamide-monomercapto, diaminedioxime, and hydrazine. The chelating agent is typically tetradentate, with the coordinating atoms selected from nitrogen, oxygen and sulfur. The mercapto-sulfur atom and hydrazine can carry a protecting group which can be exchanged in situ prior to or more commonly during the synthesis of the radiopharmaceutical with the reagent.

Exemplary thiol protecting groups include those listed in Greene and Wuts, protective groups in Organic Synthesis, John Wiley & Sons, New Jersey (2007). Any thiol protecting group known in the art may be used. Examples of thiol protecting groups include, but are not limited to, the following: acetamidomethyl, benzoylaminomethyl, 1-ethoxyethyl, benzoyl and triphenylmethyl.

Such metals as indium (e.g. indium)¹¹¹In), yttrium (e.g. In)⁸⁶Y and⁹⁰y) and lanthanides (e.g., Eu (III), Gd (III), and Dy (III)) and chelating agent moieties selected from cyclic and acyclic polyaminocarboxylates such as DTPA, DOTA, DO3A, 2-benzyl-DOTA, α - (2-phenylethyl) 1, 4, 7, 10-tetraazacyclododecane-1-acetic acid-4, 7, 10-tris (methylethyl) acid, 2-benzyl-cyclohexyldiethylenetriamine pentaacetic acid, 2-benzyl-6-methyl-DTPA, and 6,6 "-bis [ N, N, N" -tetrakis (carboxymethyl) aminomethyl) -4 '- (3-amino-4-methoxyphenyl) -2, 2': 6', 2 "-tripyridine. Other chelating agents suitable for use in the present invention are described in U.S. patent No. 5,362,475, U.S. patent No. 6,676,929, and U.S. patent No. 7,060,250, each of which is incorporated herein by reference in its entirety. Methods for the synthesis of these non-commercially available chelating agents can be found in j.chem.soc.perkin trans, 1992, 1, 1175; bioconjugate chem., 1991, 2, 187; med, 1990, 31, 473; U.S. patent nos. 5,064,956; and U.S. patent No. 4,859,777, each of which is incorporated herein by reference in its entirety.

The coordination sphere of the metal ion includes all ligands or groups that bind to the metal. As for the stable transition metal complex, it generally has a coordination number (number of coordination atoms) of an integer of 4 or more and 8 or less; i.e., 4-8 atoms bound to the metal, is said to have an intact coordination sphere. With regard to the lanthanide or actinide metal complexes, the metal generally has a coordination number (number of coordination atoms) which is an integer greater than or equal to 4 and less than or equal to 10; i.e., 4-10 atoms bound to the metal, is said to have an intact coordination sphere. The number of coordination necessary for a stable metal drug complex is determined by the nature of the element, its oxidation state, and the type of coordinating atom. If the chelating agent does not provide all the atoms necessary to stabilize the metal complex by completing its coordination sphere, the coordination sphere is completed by the coordinating atoms of other ligands (which may also be terminal or chelating) called adjuvants or co-ligands.

Adjuvant ligand A_L1Containing one or more hard (hard) coordinating atoms, e.g. oxygen and amine nitrogen (sp)³Hybridization). The coordinating atom being radioactiveAt least one site of a nuclide metal coordination sphere; adjuvant ligand A_L1Acting as one ligand in a ligand system. Adjuvant ligand A_L1Examples of (a) include, but are not limited to, water, dioxyligands, and functionalized aminocarboxylates. A large number of such ligands are commercially available.

The adjuvant dioxygen ligand includes a ligand that coordinates to the metal ion through at least two oxygen coordinating atoms. Examples include, but are not limited to: glucoheptonate, gluconate, 2-hydroxyisobutyrate, lactate, tartrate, mannitol, glucarate, maltitol, kojic acid, 2-bis (hydroxymethyl) propionic acid, 4, 5-dihydroxy-1, 3-benzenedisulfonate, or substituted or unsubstituted 1, 2-or 3, 4-hydroxypyridone. (the ligand names in these examples refer to either the protonated or unprotonated forms of the ligand.)

The functionalized aminocarboxylate includes a ligand having a combination of amine nitrogen and oxygen coordinating atoms. Examples include, but are not limited to: iminodiacetic acid, 2, 3-diaminopropionic acid, nitrilotriacetic acid, N, N ' -ethylenediaminediacetic acid, N, N, N ' -ethylenediaminetriacetic acid, hydroxyethylethylenediaminetriacetic acid and N, N ' -ethylenediaminebis-hydroxyphenylglycine. (the ligand names in these examples refer to either the protonated or unprotonated forms of the ligand.)

Chelating agents for magnetic resonance imaging contrast agents are selected to form stable complexes with paramagnetic metal ions such as gd (iii), dy (iii), fe (iii) and mn (ii), selected from cyclic and acyclic polyaminocarboxylates such as DTPA, DOTA, DO3A, 2-benzyl-DOTA, α - (2-phenylethyl) 1, 4, 7, 10-tetraazacyclododecane-1-ethane-4, 7, 10-tris (methylethyl) acid, 2-benzyl-cyclohexyldiethylenetriaminepentaacetic acid, 2-benzyl-6-methyl-DTPA and 6,6 "-bis [ N, N" -tetrakis (carboxymethyl) aminomethyl) -4 '- (3-amino-4-methoxyphenyl) -2, 2': 6', 2 "-tripyridine.

As described above, methods of treating a patient are provided. The method can comprise administering a compound or diagnostic agent as described herein to a patient and obtaining an image of the location of the concentration of the diagnostic agent in the patient by a diagnostic imaging technique. Treatment may include detecting, imaging, and/or monitoring elastin rich tissue of the patient, including elastin rich tissue located within the arterial wall, uterus, lung, skin, and/or ligament. In some cases, treatment includes detecting, imaging and/or monitoring the presence and/or amount of coronary plaque, carotid plaque, iliac/femoral plaque, aortic plaque, renal artery plaque, plaque of any arterial vessel, aneurysm, vasculitis, other disease of the arterial wall, and/or damage or structural change of ligaments, uterus, lungs or skin in a patient.

Blood clearance is particularly important for cardiac imaging procedures because the cardiac blood pool is large compared to the lesion that needs to be imaged. For effective arterial wall imaging agents, the target to background ratio (lesion: blood and lesion: muscle) is typically greater than or equal to about 1.5, typically greater than or equal to about 2.0, and more typically even greater. Certain drugs of the present disclosure have a blood clearance rate of less than about 5% i.d./g 1 hour after injection when measured in a mouse model. In one embodiment, the diagnostic agents of the present disclosure have a blood clearance rate of less than about 2% i.d./g 1 hour after injection when measured in a mouse model.

The indium, copper, gallium and yttrium diagnostic agents of the present disclosure can be readily prepared by mixing a salt of a radionuclide with the reagent of the present disclosure in an aqueous solution at a temperature of about 0 ℃ to about 100 ℃. These radionuclides are usually obtained as dilute aqueous solutions in mineral acids such as hydrochloric acid, nitric acid or sulfuric acid. The radionuclide is combined with 1 to about 1000 equivalents of a reagent of the present disclosure dissolved in an aqueous solution. The pH of the reaction mixture is typically maintained at about 3 to about 10 with a buffer.

The gadolinium, dysprosium, iron, and manganese diagnostic agents of the present disclosure can be readily prepared by mixing a salt of a paramagnetic metal ion with a reactant of the present disclosure in an aqueous solution at a temperature of about 0 ℃ to about 100 ℃. These paramagnetic metal ions are generally commercially available as their oxides, chlorides or nitrates. Paramagnetic metal ions are combined with 1 to about 1000 equivalents of a reactant of the present disclosure dissolved in an aqueous solution. The pH of the reaction mixture is typically maintained at about 3 to about 10 with a buffer.

The total preparation time will vary depending on the metal ion characteristics, the nature and amount of the reactants, and the process used for preparation. The preparation may be completed in about 1 minute or may take longer to complete, resulting in greater than about 80% yield of the radiopharmaceutical. If a higher purity of the metallopharmaceutical is required or desired, the product may be purified by any method known to those skilled in the art, such as liquid chromatography, solid phase extraction, solvent extraction, dialysis or ultrafiltration.

Diagnostic radiopharmaceuticals are typically administered by intravenous injection in saline solution at a dose of about 1 to about 100mCi per 70kg body weight, or typically at a dose of about 5 to about 50 mCi. The visualization is performed using known procedures.

Diagnostic agents of the present disclosure containing magnetic resonance imaging contrast components may be used by methods similar to other MRI agents, as described in US-A-5,155,215; US-A-5,087,440; magnetic. Radiology, 1988, 166, 835; and Radiology, 1988, 166, 693. Typically, a sterile aqueous solution of the contrast agent is administered intravenously to the patient at a dosage of about 0.01 to about 1.0mmoles per kg body weight.

For use as an X-ray contrast agent, the diagnostic agents of the present disclosure should generally have a heavy atom concentration of from about 1mM to about 5M, typically from about 0.1M to about 2M. The dose administered by intravenous injection will generally be from about 0.5mmol/kg to 1.5mmol/kg, usually from about 0.8mmol/kg to 1.2 mmol/kg. Visualization is carried out by known techniques, typically X-ray computed tomography.

The diagnostic agents of the present disclosure containing an ultrasound contrast component are administered intravenously in an amount of about 10 to about 30 μ L echo generating gas per kg body weight or by infusion at a rate of about 3 μ L/kg/min. Visualization is performed using known ultrasound techniques.

Other features of the present disclosure will become apparent in the following description of exemplary embodiments, which are given for the purpose of illustrating the present disclosure and are not limiting of the present disclosure. The disclosure will now be explained by reference to the following specific, non-limiting examples. One skilled in the art of organic synthesis may know that there are other routes to synthesize the disclosed compounds and/or diagnostic agents. Reactants and intermediates used herein are either commercially available or prepared according to standard literature procedures unless otherwise described.

The present disclosure is contemplated to include compounds of formula (I) prepared by synthetic processes or by metabolic processes, including processes occurring in the human or animal body (in vivo) or in vitro. For example, compounds of the present disclosure can be synthesized or produced in vivo by cleaving larger sequences (e.g., peptides consisting of 3 amino acids and a D-amino acid residue), where A is a peptide consisting of a D-amino acid residue and a second D-amino acid.

Example 1

2- { [2- ({ [ N- ({4- [ ((2R) -2-amino-4-phenylbutylaminooxy) methyl ] phenyl } methyl) carbamoyl ] methyl } {2- [ bis (carboxymethyl) amino ] ethyl } amino) ethyl ] (carboxymethyl) amino } acetic acid, trifluoroacetic acid salt

Preparation of part A-N- (1- (N-hydroxycarbamoyl) (1R) -3-phenylpropyl) (tert-butoxy) -carboxamide

(trimethylsilyl) diazomethane (6.00 mmol; 3.00mL in Et) was added dropwise over 0.25 h at 22 deg.C₂2.0M solution in O) Boc-DHfe-OH (1.40g, 5.00mmol) was treated in 4: 1CH₂Cl₂Solution in MeOH (25.0 mL). Note that: a large amount of gas is evolved. The resulting yellow solution was stirred for an additional 0.25 h to ensure complete methylation (R in 1: 1 EtOAc/hexane)_f0.7). Glacial AcOH was added dropwise to deplete the excess (trimethylsilyl) diazomethane and all volatiles were removed in vacuo. The crude ester was redissolved in MeOH (25.0mL),cooling to 0 ℃ with H prepared beforehand₂Suspension treatment of NOH & HCl (1.04g, 15.0mmol) and KOH (1.68g, 30.0mmol) in MeOH (25.0 mL); large bore trocars are required for transfer. Then along with the ice bath melting, the obtained suspension is slowly heated to 22 ℃ over 3.5 hours; the suspension was stirred at 22 ℃ at 0.75 hour intervals. The suspension was acidified to pH 4-5 with concentrated HCl and then all volatiles were removed in vacuo. The solid was triturated with several portions of hot EtOAc (5X 10mL) and filtered off using a medium porosity sintered (screened) glass funnel. The combined filtrates were collected and concentrated in vacuo to an off-white powder (at 9: 1 CH)₂Cl₂R in MeOH_f0.7). Purification by recrystallization from hot EtOAc (150mL) afforded a white microcrystalline solid (0.893g, 3.03 mmol; 60.6%).

Mp 165.5-166.0℃.¹H NMR(DMSO-d₆，300MHz)：10.5(1H，brs)，8.79(1H，brs)，7.30-7.25(2H，m)，7.19-7.14(3H，m)，6.96(1H，brd，J＝8.1Hz)，3.82(1H，dt，J＝7.5，7.5Hz)，2.66-2.45(2H，m)，1.87-1.74(2H，m)，1.39(9H，s).¹³C NMR(DMSO-d₆，75MHz)：168.8，155.2，141.3，128.3，128.2，125.7，77.9，51.8，33.8，31.6，28.2.

C₁₅H₂₂N₂O₄HRMS calcd for (M + Na): 317.1472. measured value: 317.1466. the optical purity of the product was determined by chiral GLC analysis (99.9% D-homophenylalanine). Moiety B-N- { [4- (hydroxymethyl) phenyl]Preparation of methyl-prop-2-enyloxycarboxamide

A suspension of methyl 4- (aminomethyl) benzoate hydrochloride (1.01g, 5.00mmol) in THF (50.0mL) was treated with i-Pr₂NEt (2.09mL, 12.0mmol) and then cooled to 0 ℃. Allyl chloroformate (638. mu.L, 6.00mmol) was then added over 10 minutes, and the resulting suspension was stirred at 0 ℃ for 50 minutes. Subjecting the reaction mixture to hydrogenation with H₂Diluted with O (50mL) and the layers were combinedSeparating with Et₂The aqueous layer was washed with O (3X 50 mL). Combine THF and Et₂The O solution is MgSO₄Dried, filtered and concentrated in vacuo to a white solid (R in 1: 1 hexane/EtOAc)_f0.5), the solid was used in the next reduction step without further purification.

The crude ester (theoretically 5.00mmol) was dissolved in anhydrous THF (20.0mL), cooled to 0 deg.C, and LiAlH was added dropwise over 0.25 h using a syringe pump₄(5.00 mmol; 5.00mL of a 1M THF solution). The resulting solution was stirred at 0 ℃ for 0.25 h to ensure complete reduction. Carefully add H₂O (200 μ L) depleted excess LiAlH₄. The resulting white suspension was washed with 15% aqueous NaOH (200. mu.L) followed by H₂O (600. mu.L) and then stirred for 0.25 hours to a fine white slurry. The resulting mixture was filtered through a pad of celite and concentrated in vacuo. With 1: 1 hexane/EtOAc (R)_f0.3) silica (40 × 185mm) the crude oil was chromatographed. The main product eluted between 430 and 680mL was collected and concentrated to give a white crystalline solid (0.923g, 4.17 mmol; 83.4% over two steps).

Mp 80.0-81.0℃.¹H NMR(CDCl₃，300MHz)：7.32(2H，AB，J_AB＝8.2Hz)，7.26(2H，AB，J_AB＝8.2Hz)，5.91(1H，ddt，J＝17.2，10.4，5.6Hz)，5.30(1H，dq，J＝17.2，1.4Hz)，5.20(1H，dq，J＝10.5，1.3Hz)，4.65(2H，s)，4.58(2H，brdt，J＝5.6，1.3Hz)，4.34(2H，brd，J＝5.7Hz)，1.85(1H，s).¹³C NMR(CDCl₃，75MHz)：156.3，140.3，137.8，132.8，127.7，127.3，117.7，65.7，64.9，44.8.

C₁₂H₁₅NO₃HRMS calcd for (M + H): 222.1125. measured value: 222.1124. moiety C-N- { [4- (bromomethyl) phenyl]Preparation of methyl-prop-2-enyloxycarboxamide

Reacting the part 1B product(0.664g, 3.00mmol) and CBr₄(1.19g, 3.60mmol) in anhydrous CH₂Cl₂(30.0mL) the solution was cooled to 0 ℃ and PPh was added portionwise over 5 minutes₃(0.905g, 3.45 mmol). After 10 minutes at 0 ℃, the solution was warmed to 22 ℃, stirred for 20 minutes, and then concentrated in vacuo. With 3: 2 hexane/EtOAc (R in 1: 1 hexane/EtOAc)_fThe crude residue was chromatographed on 0.6) silica (25 × 170 mm). The major product, which eluted between 95-185mL, was collected and concentrated to give a white crystalline solid (0.738g, 2.60 mmol; 86.6%).

Mp 80.0-82.0℃.¹H NMR(CDCl₃，300MHz)：7.36(2H，AA’BB’.J_AB＝8.2Hz，J_AA’＝1.9Hz)，7.26(2H，AB，J_AB＝8.1Hz)，5.92(1H，ddt，J＝17.2，10.4，5.6Hz)，5.30(1H，brd，J＝17.0Hz)，5.21(1H，dq，J＝10.4，1.3Hz)，4.59(2H，brdt，J＝5.6，1.2Hz)，4.47(2H，s)，4.36(2H，d，J＝6.1Hz).¹³C NMR(CDCl₃，75MHz)：156.2，138.9，137.1，132.8，129.4，127.9，117.8，65.8，44.7，33.1.

C₁₂H₁₄BrNO₂HRMS calcd for (M + H): 284.0281. measured value: 284.0280. moiety D- (2R) -N- { [4- (aminomethyl) phenyl]Methoxy } -2- [ (tert-butoxy) carbonyl-amino]Preparation of (E) -4-phenylbutanamide, trifluoroacetate salt

A solution of the product of part 1A (0.662g, 2.25mmol) in anhydrous DMF (9.00mL) was taken with K₂CO₃(0.373g, 2.70mmol) and cooled to 0 ℃. Then part 1C (0.256g, 0.900mmol) was added in one portion and the resulting suspension was slowly warmed to 22 ℃ overnight as the ice bath thawed. After a total of 13 hours, the reaction mixture was partitioned between EtOAc (150mL) and H₂O(50mL) Between, transfer to a separatory funnel. The layers were separated and the EtOAc layer was washed with saturated aqueous NaCl (3X 50mL) and then MgSO₄Dried, filtered and concentrated in vacuo to a white powder which was used in the next deprotection step without further purification (R in 1: 1 hexane/EtOAc)_f＝0.4)。

The crude oximinomate (0.900 mmol theoretically) was dissolved in 2: 1MeCN/H at 22 deg.C₂O (9.00mL) was added 51.2mg of TPPTS (90.0. mu. mol; 10 mol%) followed by Et₂NH (233. mu.L, 2.25mmol) and 10.1mg Pd (OAc)₂(45.0. mu. mol; 5 mol%). Complete deprotection was seen within 0.5 h. The amber solution was filtered through a 0.45 μm Acrodisk and then directly purified by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 1%/min gradient, 0-40% MeCN, 0.1% TFA, 10% H₂O, 20 mL/min. The main product peak eluted at 32 min was collected and lyophilized as a white powder (158mg, 0.300 mmol; 33.3%).

¹HNMR(DMSO-d₆，600MHz)：11.25(1H，brs)，8.20(3H，brs)，7.44(4H，brs)，7.27(2H，dd，J＝7.6，7.6Hz)，7.17(1H，t，J＝7.3Hz)，7.15(2H，d，J＝7.3Hz)，7.08(1H，brd，J＝7.6Hz)，4.78(2H，brs)，4.02(2H，brs)，3.76(1H，dt，J＝7.3，7.1Hz)，2.60-2.55(1H，m)，2.50-2.45(1H，m)，1.81-1.77(2H，m)，1.39(9H，s).¹³C NMR(DMSO-d₆，151MHz)：169.0，157.8(q，J＝31.1Hz)，155.2，141.2，136.3，133.8，128.8，128.7，128.2，125.8，117.2，(q，J＝300Hz)，78.1，76.3，51.9，42.0，33.5，31.5，28.2.

C₂₃H₃₁N₃O₄HRMS calcd for (M + H): 414.2387. measured value: 414.2392.

preparation of the moiety E-2- { [2- ({ [ N- ({4- [ ((2R) -2-amino-4-phenylbutylaminooxy) methyl ] -phenyl } methyl) carbamoyl ] methyl } {2- [ bis (carboxymethyl) amino ] ethyl } amino) ethyl ] - (carboxymethyl) amino } acetic acid, trifluoroacetate

2- { bis [2- (bis { [ (tert-butyl) oxy) carbonyl ] at 22 deg.C]Methyl } amino) ethyl]Amino } acetic acid (24.2mg, 39.2 μmol; see: a) Williams, M.A., for the main literature on the synthesis and characterization of DTPA and related analogs; rapoport, h.j.org.chem.1993, 58, 1151.b) Anelli, p.l.; fedeli, f.; gazzotti, o.; lattuada, l.; lux, g.; rebast, F.bioconjugate chem.1999, 10, 137.) solutions in anhydrous DMF (3.27mL) were treated with HOBt (6.0mg, 39. mu. mol), i-Pr₂NEt (14. mu.L, 78. mu. mol) and HBTU (14.9mg, 39.2. mu. mol). After 0.25 h, the solution was transferred by catheter to portion 1D product (15.0mg, 32.7 μmol) and the resulting solution was stirred for 0.25 h. To complete the transformation, the solution was further treated with HBTU (7.43mg, 19.6. mu. mol) and i-Pr₂NEt (28.0. mu.L, 161. mu. mol), stirred for 0.25 h, then partitioned between EtOAc and 0.1M citric acid (30mL each) and transferred to a separatory funnel. The layers were separated and the aqueous layer was washed with EtOAc (2X 30 mL). The combined EtOAc layer was washed with 0.1M citric acid followed by NaHCO₃And NaCl saturated aqueous solution (3X 30mL each), followed by MgSO₄Dried, filtered and concentrated in vacuo to a colorless oil which was used in the next deprotection step without further purification (in 9: 1 CH)₂Cl₂R in MeOH_f＝0.4)。

The protected conjugate (theoretically 32.7. mu. mol) was dissolved in dioxane (650. mu.L) at 22 ℃ followed by H₂O (3. mu.L) and HCl (2.60 mmol; 0.650mL of 4M dioxane solution). The resulting pale yellow solution was stirred and monitored for 4 hours during which time a large amount of white precipitate formed. After complete deprotection at N₂Volatiles were removed under a stream of gas and the white solid residue was redissolved in H containing 0.1% TFA₂O (8.50mL), then purified directly by HPLC on a Phenomenex Luna C18 column (21.2X250mm) usingGradient 1%/min, 0-40% MeCN, 0.1% TFA, 10% H₂O, 20 mL/min. The main product peak eluted in 25 min was collected and lyophilized as a white powder (22.8mg, 22.1. mu. mol; 67.6%).

¹H NMR(DMSO-d₆，300MHz)：11.77(1H，brs)，8.95(1H，brt，J＝4.9Hz)，8.35(3H，brs)，7.40(2H，AB，J_AB＝8.0Hz)，7.32-7.27(4H，m)，7.20(1H，dd，J＝7.4，7.4Hz)，7.13(2H，AB，J_AB＝7.2Hz)，4.84(2H，AB，J＝11.6Hz)，4.34(2H，brd，J＝5.6Hz)，4.25(2H，s)，3.64(1H，brs)，3.50(8H，s)，3.38(4H，brt，J＝5.6Hz)，3.05(4H，brt，J＝5.7Hz)，2.55-2.50(2H，m)，1.97-1.90(2H，m).¹³C NMR(DMSO-d₆，151MHz)：172.7，165.3，164.8，158.0(q，J＝32.4Hz)，140.2，138.7，134.3，129.0，128.5，128.1，127.3，126.2，116.8(q，J＝298Hz)，76.9，54.3，53.9，52.2，50.3，48.6，42.1，32.8，30.3.C₃₂H₄₄N₆O₁₁HRMS calcd for (M + Na): 711.2960, found: 711.2964. the optical purity of the product was determined by chiral GLC analysis (99.8% D-homophenylalanine).

Example 2

2- (7- { [ N- ({4- [ ((2R) -2-amino-4-phenylbutylaminooxy) methyl ] phenyl } methyl) carbamoyl ] methyl } -1, 4, 7, 10-tetraaza-4, 10-bis (carboxymethyl) cyclododecyl) acetic acid, trifluoroacetic acid salt

2- (1, 4, 7, 10-tetraaza-4, 7, 10-tris { [ (tert-butyl) oxycarbonyl) at 22 ℃]A solution of methyl } -cyclododecyl) acetic acid (109mg, 0.190mmol) in anhydrous DMF (10.0mL) was treated with HOBt (29.0mg, 0.190mmol), HBTU (71.9mg, 0.190mmol) and i-Pr₂NEt (40.8. mu.L, 0.234 mmol). 0After 25 h, the solution was treated with part of the 1D product (0.158 mmol; 5.80mL of 0.027M DMF solution) and the resulting solution was stirred for 3 h. To complete the conversion, the solution was further treated with 30 mol% active ester, stirred for 0.25 h, then diluted with EtOAc (75mL) and transferred to a separatory funnel. The EtOAc solution was washed with 0.1M citric acid (3X 75mL) followed by NaHCO₃And NaCl saturated aqueous solution (3X 75mL each), followed by MgSO₄Dried, filtered and concentrated in vacuo to a colorless oil which was used for the next deprotection step without further purification.

The protected conjugate (theoretically 0.158mmol) was dissolved in dioxane (3.16mL) at 22 ℃ followed by H₂O (15. mu.L) and HCl (12.6 mmol; 3.16mL of 4M dioxane solution). The resulting pale yellow solution was stirred for 16 hours, during which time a large amount of white precipitate formed. After complete deprotection at N₂Removing volatiles under a stream of air to redissolve the white solid residue in H₂O (8.00mL) and then directly purified by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 1%/min gradient, 0-40% MeCN, 0.1% TFA, 10% H₂O, 20 mL/min. The main product peak eluted in 25 min was collected and lyophilized as a white powder (43.0mg, 41.3. mu. mol; 26.1%).

¹H NMR(DMSO-d₆，600MHz)：9.04(1H，brt，J＝6.0Hz)，7.46(2H，AB，J_AB＝8.0Hz)，7.38(2H，AB，J_AB＝8.0Hz)，7.28-7.25(3H，m)，7.20-7.16(3H，m)，5.01(2H，AB，J_AB＝11.6Hz)，4.47(2H，brd，J＝5.7Hz)，4.13(1H，t，J＝6.6Hz)，3.86(4H，s)，3.85(2H，s)，3.73(2H，s)，3.16(10H，brs)，3.08(2H，brs)，2.81-2.76(2H，m)，2.30-2.21(2H，m).¹³C NMR(DMSO-d₆，151MHz)：171.5，165.3，157.8(q，J＝31.4Hz)，140.2，138.8，134.3，128.9，128.5，128.0，127.4，126.2，117.1(q，J＝299Hz)，76.9，54.8，54.0，53.1，50.6，50.4，50.2，48.8，42.0，32.8，30.3.

C₃₄H₄₉N₇O₉(M+H) HRMS calculated of (a): 700.3665. measured value: 700.3659.

example 3

2- { [2- ({ [ N- ({4- [ ((2S) -2-amino-4-phenylbutylaminooxy) methyl ] -phenyl } methyl) carbamoyl ] methyl } {2- [ bis (carboxymethyl) amino ] ethyl } amino) ethyl ] - (carboxymethyl) amino } acetic acid, trifluoroacetic acid salt

Preparation of part A-N- (1- (N-hydroxycarbamoyl) (1S) -3-phenylpropyl) (tert-butoxy) -carboxamide

H-Hfe-OH (1.79g, 10.0mmol) in 2: 1 THF/H at 22 deg.C₂Suspension in O (50.0mL) over Na₂CO₃(2.54g, 24.0mmol) followed by a one-time Boc treatment₂O (2.62g, 12.0 mmol). After 1 hour the concentrated suspension was acidified to pH3-4 with 0.1M HCl and the resulting homogeneous solution was transferred to a separatory funnel and washed with EtOAc (4X 50 mL). The combined EtOAc washes over MgSO₄Dried, filtered and concentrated in vacuo to a colorless oil which was used for the next reaction without further purification.

(trimethylsilyl) diazomethane (12.0 mmol; 6.00mL of 2.0M Et was added dropwise over 0.25 h at 22 ℃₂O solution) treatment of crude Boc-Hfe-OH (theoretically 10.0mmol) in 4: 1CH₂Cl₂Solution in MeOH (50.0 mL). Note that: a large amount of gas is evolved. The resulting yellow solution was stirred for an additional 0.25 hours to ensure complete methylation. Glacial AcOH was added dropwise to deplete the excess (trimethylsilyl) diazomethane and all volatiles were removed in vacuo. The crude ester was redissolved in MeOH (50.0mL), cooled to 0 deg.C,with H prepared beforehand₂Suspension treatment of NOH & HCl (2.08g, 30.0mmol) and KOH (3.37g, 60.0mmol) in MeOH (50.0 mL); large bore trocars are required for transfer. The resulting suspension was then slowly warmed to 22 ℃ overnight with ice bath thawing. After 14 h, the suspension was acidified to pH 4-5 with concentrated HCl, and then all volatiles were removed in vacuo. The solid was triturated with a few portions of hot EtOAc (5X 10mL) and removed by filtration through a medium porosity sintered glass funnel. The combined filtrates were collected and concentrated in vacuo to an off-white powder. Purification by recrystallization from hot EtOAc (200mL) afforded a white microcrystalline solid (1.47g, 4.99 mmol; 49.9%). The spectral data obtained for this material is consistent with that described for the part 1A product.

Preparation of the part B- (2S) -N- { [4- (aminomethyl) phenyl ] methoxy } -2- [ (tert-butoxy) carbonyl-amino ] -4-phenylbutanamide, formate salt

Adding K at 22 DEG C₂CO₃(0.207g, 1.50mmol) in H₂A solution in O (3.00mL) was diluted with anhydrous EtOH (7.00mL) and then treated with a portion of the product 3A (0.442g, 1.50mmol) in one portion. After complete dissolution (10-15min), add part of the 1C product (0.284g, 1.00mmol) in one portion and stir the resulting suspension vigorously; a rapid stirring rate is required to ensure complete dissolution of the bromide. Within 25 minutes the solution became cloudy and a large amount of white precipitate formed; the reaction was completed in 1 hour. Then using H₂The resulting suspension was diluted with O (40mL) and the solid was collected on a medium porosity sintered glass funnel. The solid is further treated with H₂O and Et₂O (5X 20mL each) was washed and then dried in vacuo to a white powder which was used for the next deprotection step without further purification.

Hydroxamate (0.337g, 0.677mmol) was dissolved in 2: 1MeCN/H at 22 deg.C₂O (6.77mL) was treated with 15.4mg of TPPTS (27.1. mu. mol; 4 mol%) followed by Et₂NH (175. mu.L, 1.69mmol) and 3.0mg Pd (OAc)₂(13.5μmol；2mol％)And (6) processing. Complete deprotection was seen within 1 hour. The amber solution was diluted with 0.1% HCO₂H of H₂O was diluted to 14mL and then filtered with 0.45 μm Acrodisk and purified by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 1%/min gradient, 10-50% MeCN containing 0.1% HCO₂H，10％H₂O, 20 mL/min. The main product peak eluted in 17 min was collected and lyophilized as a white powder (0.229g, 0.498 mmol; 49.8%). The spectral data obtained for this material is consistent with that described for the part 1B product.

Preparation of the partial C-2- { [2- ({ [ N- ({4- [ ((2S) -2-amino-4-phenylbutylaminooxy) methyl ] -phenyl } methyl) carbamoyl ] methyl } {2- [ bis (carboxymethyl) amino ] ethyl } amino) ethyl ] - (carboxymethyl) amino } acetic acid, trifluoroacetate salt

HOBt (68.9mg, 0.450mmol) and i-Pr were sequentially added at 22 deg.C₂NEt (131. mu.L, 0.750mmol) and HBTU (0.171g, 0.450mmol) treated 2- { bis [2- (bis { [ (tert-butyl) oxycarbonyl ] oxy]Methyl } amino) ethyl]A solution of amino } acetic acid (0.278g, 0.450mmol) in anhydrous DMF (3.00 mL). After 0.25 h, the solution was transferred by catheter to portion 3B product (0.138g, 0.300 mmol). The resulting solution was stirred for 0.5 h, then partitioned between EtOAc and 0.1M citric acid (50mL each) and transferred to a separatory funnel. The layers were separated and the aqueous layer was washed with EtOAc (2X 50 mL). The combined EtOAc layer was washed with 0.1M citric acid followed by NaHCO₃And NaCl saturated aqueous solution (3X 50mL each) and then MgSO₄Dried, filtered and concentrated in vacuo to a colorless oil which was used for the next deprotection step without further purification.

The protected conjugate (theoretically 0.300mmol) was dissolved in dioxane (3.00mL) at 22 ℃ followed by H₂O (27. mu.L) and HCl (12.0 mmol; 3.00mL of 4M dioxane solution). The resulting pale yellow solution was stirred for 15 hours, during which time a large amount of white precipitate formedA compound (I) is provided. After complete deprotection, volatiles were removed in vacuo and the white solid residue redissolved in H containing 0.1% TFA₂O (8.00mL) and then directly purified by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 1%/min gradient, 0-40% MeCN, 0.1% TFA, 10% H₂O, 20 mL/min. The main product peak eluted in 25 min was collected and lyophilized as a white powder (0.181g, 0.176 mmol; 58.5%).

¹H NMR(DMSO-d₆，600MHz)：11.79(1H，brs)，8.96(1H，brt，J＝5.9Hz)，8.37(3H，brs)，7.39(2H，AB，J_AB＝8.1Hz)，7.32-7.29(4H，m)，7.20(1H，brdd，J＝7.3，7.3Hz)，7.13(2H，AB，J_AB＝7.1Hz)，4.84(2H，AB，J_AB＝11.8Hz)，4.34(2H，brd，J＝5.8Hz)，4.25(2H，brs)，3.65(1H，brs)，3.50(8H，s)，3.38(4H，brt，J＝5.8Hz)，3.05(4H，brt，J＝5.9Hz)，2.54-2.50(2H，m)，1.96-1.91(2H，m).¹³C NMR(DMSO-d₆，151MHz)：172.7，165.3，164.8，158.1(q，J＝32.2Hz)，140.2，138.7，134.3，128.9，128.5，128.1，127.3，126.2，116.9(q，J＝299Hz)，76.9，54.3，53.9，52.2，50.2，48.7，42.1，32.8，30.3.C₃₂H₄₄N₆O₁₁HRMS calcd for (M + H): 689.3141. measured value: 689.3147. the optical purity of the product (99.0% L-homophenylalanine) was determined by chiral GLC analysis.

Example 4

2- ({2- [ ({ N- [6- ((2R) -2-amino-4-methylpentanoylaminooxy) hexyl ] carbamoyl } methyl) {2- [ bis (carboxymethyl) amino ] ethyl } (carboxymethyl) amino) acetic acid, trifluoroacetate salt

Preparation of part A-6- (prop-2-enyloxycarbonylamino) hexyl methanesulfonate

N- (6-hydroxyhexyl) prop-2-enyloxycarboxamide (2.55g, 12.7 mmol; Charreyre, M.T.; Boullanger, P.; Pichot, C; Delair, T.; Mandrand, B.; Llauro, M.F. Mak chem.1993, 194(1), 117-35.) in anhydrous CH₂Cl₂(30.0mL) in Et₃N (4.06mL, 29.1mmol) and then cooled to 0 ℃. To this solution MsCl (15.2 mmol; 20.0mL of 0.76M CH) was transferred with a catheter₂Cl₂Solution); complete conversion was achieved at the same time as transfer was completed. The resulting solution was warmed to 22 ℃ and then treated with 2M NH₄Treated with Cl (50mL) and transferred to a separatory funnel. The layers are separated by CH₂Cl₂The aqueous layer was washed (3X 50 mL). The combined washes were washed with 20% aqueous NaCl and then MgSO₄Dried, filtered and concentrated in vacuo to a pale yellow oil (3.2g) which was used in the next alkylation step without further purification.

¹H NMR(CDCl₃，300MHz)：5.90(1H，ddt，J＝17.2，10.4，5.6Hz)，5.29(1H，dq，J＝17.2，1.6Hz)，5.19(1H，dq，J＝10.4，1.3Hz)，4.71(1H，brs)，4.54(2H，brd，J＝5.5Hz)，4.20(2H，t，J＝3.17(2H，brs)，2.98(3H，s)，1.79-1.69(2H，m)，1.55-1.29(6H，m).

Preparation of a partial B-N- {6- [ (tert-butoxy) carbonylaminooxy ] hexyl } prop-2-enyloxycarboxamide

N-Boc hydroxylamine (2.37g, 17.8mmol) in anhydrous Et₂A solution in O (5.00mL) was treated with DBU (2.85mL, 19.1mmol) and then cooled to 0 ℃. To this mixture was transferred with a catheter a portion of the 4A product (12.7 mmol; 5.00mL of 2.53M Et₂O solution). The resulting solution was slowly warmed to 22 ℃ overnight with ice bath melting. After 17 hours, at N₂Removal of Et under gas stream₂O, the resulting thick oil was stirred for 16 hours to ensure complete conversion. The solution was then treated with Et₂Diluted O (20mL), transferred to a separatory funnel, followed by 2M NH₄Cl (30mL) and 20% aqueous NaCl (2X 30 mL). The obtained Et₂The O solution is MgSO₄Dried, filtered and concentrated in vacuo to a pale yellow oil which was purified over silica (3: 1 hexane/EtOAc; R in 2: 1 hexane/EtOAc)_f0.5) to give a colorless oil (2.61g, 8.25 mmol; 65.1%).

¹H

NMR(CDCl₃，600MHz)：7.14(1H，brs)，5.91(1H，ddt，J＝17.2，10.5，5.7Hz)，5.29(1H，dq，J＝17.2，1.6Hz)，5.19(1H，dq，J＝10.5，1.4Hz)，4.77(1H，brs)，4.55(2H，brd，J＝5.0Hz)，3.83(2H，t，J＝6.5Hz)，3.17(2H，dt，J＝6.7，6.4Hz)，1.63-1.59(2H，m)，1.52-1.47(2H，m)，1.47(9H，s)，1.42-1.31(4H，m).

Preparation of a portion of C-N- [6- (aminooxy) hexyl ] prop-2-enyloxycarboxamide, hydrochloride

With HCl (16.0 mmol; 8.00mL of 2M Et₂O solution) portion 4B product (2.61g, 8.25mmol) was treated and the resulting solution was stirred at 22 ℃ for 5 hours. The large amount of white precipitate formed was collected on a sintered glass funnel and then treated with Et₂O (3X 8mL) and dried under vacuum to constant weight (1.02g, 4.04 mmol; 48.9%). The obtained substance does not need to be addedAnd (5) external purification.

¹H NMR(DMSO-d₆，600MHz)：10.95(3H，brs)，7.15(1H，brt，J＝5.5Hz)，5.89(1H，ddt，J＝17.2，10.5，5.2Hz)，5.25(1H，dq，J＝17.2，1.8Hz)，5.15(1H，dq，J＝10.5，1.6Hz)，4.43(2H，brd，J＝5.5Hz)，3.98(2H，t，J＝6.5Hz)，(2H，m)，1.57-1.53(2H，m)，1.38(2H，tt，J＝7.1，7.1Hz)，1.31-1.22(4H，m).¹³C NMR(DMSO-d₆，151MHz)：155.8，133.8，116.7，73.9，64.0，40.0，29.2，27.0，25.7，24.7.

C₁₀H₂₀N₂O₃HRMS calcd for (M + Na): 239.1366. measured value: 239.1363.

preparation of the partial D- (2R) -N- (6-aminohexyloxy) -2- [ (tert-butoxy) carbonylamino ] -4-methylpentanamide, trifluoroacetate salt

HOBt (0.153g, 1.00mmol), i-Pr were used successively at 22 deg.C₂NEt (174. mu.L, 1.00mmol) and HBTU (0.379g, 1.00mmol) treated a solution of Boc-DLeu-OH (0.231g, 1.00mmol) in MeCN (4.00 mL). After 0.25 h, the solution was treated once with part 4C product (0.210g, 0.831 mmol). The resulting solution was stirred for 1 hour and then partitioned in CH₂Cl₂And 0.1M citric acid (50mL each) was transferred to a separatory funnel. Separating the layers to obtain CH₂Cl₂The solution was treated with 0.1M citric acid (2X 50mL) followed by NaHCO₃(3X 50mL) and NaCl (50mL) in saturated aqueous solution, and washed with MgSO₄Dried, filtered and concentrated in vacuo to a colorless oil which was used for the next deprotection step without further purification.

The crude oximinomate (0.831 mmol, theoretically) was dissolved in 2: 1MeCN/H at 22 deg.C₂O (3.00mL) was treated with 18.9mg of TPPTS (33.2. mu. mol; 4 mol%) followed by Et₂NH (216. mu.L, 2.09mmol) and 3.7mg Pd (OAc)₂(16.5. mu. mol; 2 mol%). Complete deprotection was seen within 0.5 h. The amber solution was filtered through a 0.45 μm Acrodisk followed by direct HPLC purification on a Phenomenex Luna C18 column (21.2X250mm) using a 1%/min gradient, 0-40% MeCN, 0.1% TFA, 10% H₂O, 20 mL/min. The main product peak eluted at 34 min was collected and lyophilized as a white powder (0.190g, 0.413 mmol; 49.8%).

Preparation of the partial E-2- ({2- [ ({ N- [6- ((2R) -2-amino-4-methylpentanoylaminooxy) -hexyl ] carbamoyl } methyl) {2- [ bis (carboxymethyl) amino ] ethyl } (carboxymethyl) -amino) acetic acid, trifluoroacetate salt

HOBt (18.4mg, 0.120mmol), i-Pr were applied sequentially at 22 deg.C₂NEt (35. mu.L, 0.20mmol) and HBTU (45.5mg, 0.120mmol) treated 2- { bis [2- (bis { [ (tert-butyl) oxycarbonyl ] oxy]Methyl } amino) ethyl]A solution of amino } acetic acid (74.0mg, 0.120mmol) in anhydrous DMF (1.00 mL). After 0.25 h, the solution was treated with part of the 4D product (46.0mg, 0.100mmol) in one portion. The resulting solution was stirred for 0.5 h, then diluted with EtOAc (50mL), washed with saturated aqueous solution of 0.1M citric acid (3X 30mL), 0.1M NaOH (3X 30mL), and NaCl (30mL), then MgSO₄Dried, filtered and concentrated in vacuo to a colorless oil which was used for the next deprotection step without further purification.

The protected conjugate (theoretically 0.100mmol) was dissolved in dioxane (0.500mL) at 22 ℃ followed by H₂O (2. mu.L) and HCl (2.00 mmol; 0.500mL of 4M dioxane solution). The resulting pale yellow solution was stirred for 15 hours, during which time a large amount of white precipitate formed. After complete deprotection at N₂The volatiles were removed under a stream of gas and the white solid residue was directly subjected to HPLC on PhenoPurification on a menex Luna C18 column (21.2X250mm) using a 1%/min gradient, 0-40% MeCN, 0.1% TFA, 10% H₂O, 20 mL/min. The major product peak eluted at 20 min was collected and lyophilized as a white powder (52.0mg, 0.054 mmol; 54.0%).

¹H NMR(DMSO-d₆，600MHz)：11.68(1H，brs)，8.43(1H，brt，J＝5.5Hz)，8.26(2H，brs)，4.13(2H，s)，3.79(2H，t，J＝6.6Hz)，3.53(1H，brs)，3.49(8H，s)，3.34(4H，brt，J＝5.5Hz)，3.11(2H，td，J＝6.9，5.7Hz)，3.03(4H，brt，J＝5.9Hz)，1.60-1.50(5H，m)，1.43(2H，tt，J＝7.2，7.2Hz)，1.36-1.26(4H，m)，0.89(3H，d，J＝6.3Hz)，0.87(3H，d，J＝6.0Hz).¹³C NMR(DMSO-d₆，151MHz)：172.7，165.4，164.4，157.9(q，J＝31.8Hz)，117.1(q，J＝300Hz)，75.3，54.3，53.9，52.1，48.9，48.6，40.0，38.7，28.7，27.4，26.1，24.9，23.7，22.2，22.0.

C₂₆H₄₈N₆O₁₁HRMS calcd for (M + H): 621.3454. measured value: 621.3462.

example 5

2- [ (2- { [ (N- {6- [ (2R) -2-amino-3- (4-phenylphenyl) propionylaminoxy ] hexyl } carbamoyl) methyl ] {2- [ bis (carboxymethyl) amino ] ethyl } amino } ethyl) (carboxymethyl) amino ] acetic acid, trifluoroacetate salt

Preparation of part of A- (2R) -N- (6-aminohexyloxy) -2- [ (tert-butoxy) carbonylamino ] -3- (4-phenylphenyl) propanamide, trifluoroacetate

A solution of Boc-DBip-OH (0.231g, 1.00mmol) in MeCN (4.00mL) was treated with HOBt (0.153g, 1.00mmol), i-Pr sequentially at 22 deg.C₂NEt (174. mu.L, 1.00mmol) and HBTU (0.379g, 1.00 mmol). After 0.25 h, the solution was treated once with part 4C product (0.210g, 0.831 mmol). The resulting solution was stirred for 1 hour, then partitioned between EtOAc and 0.1M citric acid (50mL each) and transferred to a separatory funnel. The layers were separated and the EtOAc solution was treated with 0.1M citric acid (2X 50mL) followed by NaHCO₃(3X 50mL) and NaCl (50mL) in saturated aqueous solution, and washed with MgSO₄Dried, filtered and concentrated in vacuo to a white solid which was used for the next deprotection step without further purification.

The crude oximinomate (0.831 mmol, theoretically) was dissolved in 2: 1MeCN/H at 22 deg.C₂O (3.00mL) was treated with 18.9mg of TPPTS (33.2. mu. mol; 4 mol%) followed by Et₂NH (216. mu.L, 2.09mmol) and 3.7mg Pd (OAc)₂(16.5. mu. mol; 2 mol%). Complete deprotection was seen within 0.5 h. The amber solution was filtered through a 0.45 μm Acrodisk and then directly purified by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 1%/min gradient, 10-50% MeCN, 0.1% TFA, 10% H₂O, 20 mL/min. The main product peak eluted at 35 min was collected and lyophilized as a white powder (0.140g, 0.246 mmol; 29.6%).

¹H NMR(DMSO-d₆，600MHz)：11.06(1H，brs)，7.70-7.60(4H，m)，7.56(2H，AB，J_AB＝8.0Hz)，7.44(2H，dd，J＝8.0，7.4Hz)，7.33(1H，brt，J＝7.4Hz)，7.31(2H，AB，J_AB＝8.0Hz)，7.06(1H，brd，J＝8.2Hz)，4.02-3.99(1H，m)，3.68-3.59(2H，m)，2.88(2H，ABX，J_AB＝13.5Hz，J_AX＝6.1Hz，J_BX＝9.3Hz)，2.73(2H，brs)，1.52-1.42(4H，m)，1.31(9H，s)，1.30-1.25(4H，m).

Preparation of the moiety B-2- [ (2- { [ (N- {6- [ (2R) -2-amino-3- (4-phenylphenyl) propionylaminoxy ] -hexyl } carbamoyl) methyl ] {2- [ bis (carboxymethyl) amino ] ethyl } amino } ethyl) (carboxymethyl) -amino ] acetic acid, trifluoroacetate

HOBt (18.4mg, 0.120mmol), i-Pr were applied sequentially at 22 deg.C₂NEt (35. mu.L, 0.20mmol) and HBTU (45.5mg, 0.120mmol) treated 2- { bis [2- (bis { [ (tert-butyl) oxycarbonyl ] oxy]Methyl } amino) ethyl]A solution of amino } acetic acid (74.0mg, 0.120mmol) in anhydrous DMF (1.00 mL). After 0.25 h, the solution was treated once with part 5A product (57.0mg, 0.100 mmol). The resulting solution was stirred for 0.5 h, then diluted with EtOAc (50mL), washed with 0.1M citric acid (3X 30mL), 0.1M NaOH (3X 30mL), and saturated aqueous NaCl (30mL), followed by MgSO₄Dried, filtered and concentrated in vacuo to a colorless oil which was used for the next deprotection step without further purification.

The protected conjugate (theoretically 0.100mmol) was dissolved in dioxane (0.500mL) at 22 ℃ followed by H₂O (2. mu.L) and HCl (2.00 mmol; 0.500mL of 4M dioxane solution). The resulting pale yellow solution was stirred for 15 hours, during which time a large amount of white precipitate formed. After complete deprotection at N₂Volatiles were removed under a gas stream and the white solid residue was purified directly by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 1%/min gradient, 10-40% MeCN with 0.1% TFA, 10% H₂O, 20 mL/min. The major product peak eluted in 10 minutes was collected and lyophilized as a white powder (35.0mg, 32.6. mu. mol; 32.6%).

¹H NMR(DMSO-d₆，600MHz)：11.47(1H，brs)，8.43(2H，brs)，8.40(1H，brd，J＝5.5Hz)，7.64-7.63(4H，m)，7.47-7.44(2H，m)，7.37-7.34(1H，m)，7.30(2H，AB，J_AB＝7.8Hz)，4.13(2H，s)，3.79(1H，brs)，3.63(1H，ABX，J_AB＝9.7Hz，J_AX＝6.8Hz)，3.53(1H，ABX，J_AB＝9.7Hz，J_BX＝6.6Hz)，3.49(8H，s)，3.45(4H，brt，J＝5.8Hz)，3.09-2.99(4H，m)，3.03(4H，brt，J＝6.0Hz)，1.37-1.32(4H，m)，1.23-1.16(4H，m).¹³C NMR(DMSO-d₆，151MHz)：172.7，164.3，164.2，157.9(q，J＝31.8Hz)，139.6，139.0，133.9，130.0，128.9，127.4，126.7，126.4，116.9(q，J＝299Hz)，75.3，54.3，53.8，52.1，51.5，48.6，38.7，36.5，28.6，27.3，26.0，24.8.

C₃₅H₅₀N₆O₁₁HRMS calcd for (M + H): 731.3610. measured value: 731.3612.

example 6

2- ({2- [ ({ N- [6- ((2R) -2-amino-3-cyclohexylpropionylaminoalkoxy) hexyl ] carbamoyl } methyl) {2- [ bis (carboxymethyl) amino ] ethyl } (carboxymethyl) amino) acetic acid, trifluoroacetate salt

Preparation of part of A- (2R) -N- (6-aminohexyloxy) -2- [ (tert-butoxy) carbonylamino ] -3-cyclohexylpropionamide, trifluoroacetate

HOBt (55.1mg, 0.360mmol), i-Pr were sequentially added at 22 deg.C₂NEt (125. mu.L, 0.720mmol) and HBTU (0.137g, 0.360mmol) treated Boc-DCha-OH (0.163g, 0.360mmol) in CH₂Cl₂(3.00 mL). After 0.25 h, the solution was treated with part 4C product (75.8mg, 0.300mmol) in one portion. The resulting solution was stirred for 1 hour, then all volatiles were removed in vacuo. The crude hydroxamate is redissolved in 2: 1 MeCN-H₂O (3.00mL), followed by 17.1mg TPPTS (30.0. mu. mol; 10 mol%), Et₂NH (78. mu.L, 0.75mmol) and 3.4mg Pd (OAc)₂(15. mu. mol; 5 mol%). Complete deprotection was seen within 1 hour. The resulting yellow solution was washed with H containing 0.1% TFA₂O (5.00mL) was diluted and then filtered with 0.45 μm Acrodisk and purified directly by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 1%/min gradient, 10-50% MeCN with 0.1% TFA, 10% H₂O, 20 mL/min. The main product peak eluting at 38 min was collected and lyophilized as a white powder (77.7mg, 0.156 mmol; 51.8%). In that¹Small amounts of TPPTS could be detected in the H NMR spectrum.

¹H NMR(DMSO-d₆，600MHz)：11.04(1H，brs)，7.71(3H，brs)，6.84(1H，brd，J＝8.1Hz)，3.83-3.80(1H，m)，3.73-3.67(2H，m)，2.79-2.73(2H，m)，1.87-1.45(9H，m)，1.42-1.27(5H，m)，1.36(9H，s)，1.25-1.07(4H，m)，0.87-0.78(2H，m).¹³C NMR(DMSO-d₆，151MHz)：169.1，158.0(q，J＝31.8Hz)，155.1，117.0(q，J＝300Hz)，77.9，74.7，49.7，38.7，33.5，32.8，32.0，28.1，27.4，26.8，26.0，25.8，25.6，25.5，24.8.

C₂₀H₃₉N₃O₄HRMS calcd for (M + H): 386.3013. measured value: 386.3016.

preparation of part B-2- ({2- [ ({ N- [6- ((2R) -2-amino-3-cyclohexylpropionylaminoxy) hexyl ] -carbamoyl } methyl) {2- [ bis (carboxymethyl) amino ] ethyl } (carboxymethyl) -amino) acetic acid, trifluoroacetate salt

Using i-Pr at 22 deg.C₂NEt (10. mu.L, 6. mu. mol) and HBTU (11.4mg, 30.0. mu. mol) treated 2- { bis [2- (bis { [ (tert-butyl) oxycarbonyl ] oxy]Methyl } amino) ethyl]Amino } acetic acid (18.5mg, 30.0. mu. mol), HOBt (4.6mg, 30.0. mu. mol) and part of the 6A product (R) ((R))12.5mg, 25.0. mu. mol) in anhydrous DMF (1.00 mL). The resulting solution was stirred for 0.25 h, then partitioned between EtOAc and 0.1M citric acid (30mL each) and transferred to a separatory funnel. The layers were separated, the aqueous layer was washed with EtOAc (2X 30mL), and the combined EtOAc layers were washed with 0.1M citric acid followed by NaHCO₃And NaCl saturated aqueous solution (3X 30mL each) and MgSO₄Dried, filtered and concentrated in vacuo to a colorless oil which was used for the next deprotection step without further purification.

The protected conjugate (theoretically 25.0. mu. mol) was dissolved in dioxane (0.500mL) at 22 ℃ followed by H₂O (3. mu.L) and HCl (2.00 mmol; 0.500mL of 4M dioxane solution). The resulting pale yellow solution was stirred for 18 hours, during which time a large amount of white precipitate formed. After complete deprotection, volatiles were removed in vacuo and the white solid residue redissolved in H containing 0.1% TFA₂O (8.20mL) and then directly purified by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 1%/min gradient, 0-40% MeCN, 0.1% TFA, 10% H₂O, 20 mL/min. The main product peak eluted at 28 min was collected and lyophilized as a white powder (7.3mg, 7.3. mu. mol; 29%).

¹H NMR(DMSO-d₆，600MHz)：11.60(1H，brs)，8.40(1H，brs)，8.19(3H，brs)，4.11(2H，brs)，3.81-3.76(2H，m)，3.55(1H，brs)，3.49(8H，s)，3.33(4H，brs)，3.11(2H，td，J＝7.0，6.0Hz)，3.02(4H，brt，J＝5.8Hz)，1.72(1H，brd，J＝13.1Hz)，1.67-1.49(8H，m)，1.43(2H，tt，J＝7.6，7.1Hz)，1.37-1.24(5H，m)，1.19-1.10(3H，m).¹³C NMR(DMSO-d₆，151MHz)：172.7，165.4，157.7(q，J＝30.7Hz)，117.2(q，J＝300Hz)，75.3，54.3，53.8，52.1，48.7，48.4，40.0，38.7，38.4，32.8，32.3，32.2，28.7，27.4，26.1，25.7，25.5，25.4，24.9.

C₂₉H₅₂N₆O₁₁HRMS calcd for (M + H): 661.3767. measured value: 661.3766.

example 7

2- { [2- ({ [ N- ({4- [3- ((2R) -2-amino-3-indol-3-ylpropanoylaminooxy) propyl ] phenyl } methyl) carbamoyl ] methyl } {2- [ bis (carboxymethyl) amino ] ethyl } amino) ethyl ] (carboxymethyl) amino } acetic acid, trifluoroacetic acid salt

Preparation of part of A-3- {4- [ (prop-2-enyloxycarbonylamino) methyl ] phenyl } propanoic acid

(2E) -3- (4-cyanophenyl) prop-2-enoic acid (4.33g, 25.0mmol) in 2: 1 MeOH/28% NH at 22 deg.C₃The solution in water (300mL) was charged to a 500mL Parr bottle and then treated once with Raney Ni (5.00 g). Subjecting the resulting suspension to H₂Bubbling, then pressurizing to 50psi, and maintaining for 5 hours; at this time 2 equivalents of H were consumed₂. N for container₂Purged and charged with additional Raney Ni (2.5 g). To produce H again₂Atmosphere and maintaining until gas absorption stops; a total of 135psi was consumed. N for container₂Purge, filter with Celite to remove the catalyst. The filter cake was washed with 1: 1 MeOH/H₂O (4X 50mL) was washed thoroughly and the combined filtrates were concentrated in vacuo to a white solid.

The crude amino acid (theoretically 25.0mmol) was suspended in anhydrous THF (250mL) and then treated with i-Pr₂NEt (5.23mL, 30.0 mmol). Allyl chloroformate (3.19mL, 30.0mmol) was then added over 10 minutes and the resulting suspension was stirred at 22 ℃ for 1.5 hours. The now homogeneous solution was treated with 0.1M HCl (250mL), then diluted with EtOAc (100mL) and transferred to a separatory funnel. The layers were separated, the aqueous layer was washed with EtOAc (2X 100mL), and the combined EtOAc layers were MgSO₄Drying, filtering and vacuum concentrating to obtain colorless oil, and mixing the oil with 95: 5 CH₂Cl₂/MeOH(R_f0.4) purification by chromatography on silica (40X 280 mm). The main product eluted at 320-420mL was collected and concentrated to give a white powder (2.93g, 11.1 mmol; 44.5%).

Mp 109.5-110.5℃.¹H NMR(CDCl₃，600MHz)：7.20(2H，AB，J_AB＝7.7Hz)，7.16(2H，AB，J_AB＝8.0Hz)，5.91(1H，ddt，J＝17.0，10.7，5.5Hz)，5.29(1H，brd，J＝17.0Hz)，5.20(1H，d，J＝10.2Hz)，5.11(1H，brs)，4.58(2H，brd，J＝4.5Hz)，4.32(2H，brd，J＝5.7Hz)，2.93(2H，t，J＝7.7Hz)，2.64(2H，t，J＝7.7Hz).¹³C NMR(CDCl₃，151MHz)：178.2，156.3，139.5，136.5，132.8，128.5，127.7，117.7，65.7，44.8，35.5，30.2.C₁₄H₁₇NO₄HRMS calcd for (M + Na): 286.1050. measured value: 286.1041. moiety B-N- { [4- (3-hydroxypropyl) phenyl]Preparation of methyl-prop-2-enyloxycarboxamide

A solution of the product of part 7A (1.32g, 5.00mmol) in anhydrous THF (25.0mL) was cooled to 0 deg.C and LiAlH was added dropwise over 20 minutes with a syringe pump₄(10.0 mmol; 10.0mL of 1MTHF solution). The suspension was stirred at 0 ℃ for 0.5 h, then warmed to 22 ℃ for 2.5 h. After cooling to 0 ℃ H was carefully added₂O (400 μ L) depleted excess LiAlH₄The resulting white suspension was washed with 15% aqueous NaOH (400. mu.L) followed by H₂O (1.20mL), followed by stirring for 0.5 h to give a fine white slurry. The solid was removed by filtration through Celite, washed with THF (5X 20mL), and the combined filtrates concentrated in vacuo. The crude oil was taken up in 1: 1 pentane/EtOAc (R)_f0.2) silica chromatography (40 × 260 mm). The major product eluted between 600 and 800mL was collected and concentrated to give a white crystalline solid (0.795g, 3.19 mmol; 63.8%).

Mp

51.5-53.5℃.¹H NMR(CDCl₃，600MHz)：7.18(2H，AB，J_AB＝7.9Hz)，7.14(2H，AB，J_AB＝8,2Hz)，5.90(1H，ddt，J＝17.2，10.4，5.7Hz)，5.28(1H，brd，J＝17.0Hz)，5.19(1H，dq，J＝10.5，1.2Hz)，4.57(2H，brd，J＝4.9Hz)，4.31(2H，brd，J＝5.8Hz)，3.63(2H，t，J＝6.4Hz)，2.66(2H，dd，J＝7.7，7.7Hz)，1.87-1.82(3H，m).¹³C NMR(CDCl₃，151MHz)：156.3，141.1，135.9，132.8，128.6，127.5，117.6，65.6，62.0，44.7，34.1，31.6.

C₁₄H₁₉NO₃HRMS calcd for (M + Na): 272.1257. measured value: 272.1263. part of C-N- ({4- [3- (aminooxy) propyl)]Preparation of phenyl } methyl) prop-2-enyloxycarboxamide, hydrochloride

A solution of the product of part 7B (1.25g, 5.00mmol), 2-hydroxyisoindoline-1, 3-dione (0.979g, 6.00mmol) and PPh3(1.64g, 6.25mmol) in dry THF (50.0mL) was cooled to 0 deg.C and treated dropwise with DEAD (0.236mL, 1.50mmol) so that there was no persistent orange color. The solution was then warmed to 22 ℃ and the remainder of DEAD (0.709mL, 4.50mmol) was treated dropwise over 0.75 h. The pale yellow solution thus obtained was concentrated in vacuo and purified directly by chromatography on silica using a gradient elution of 3: 2 → 1: 1 pentane/EtOAc (R in 1: 1 pentane/EtOAc)_f0.5). Fractions containing product were combined and concentrated to a white crystalline solid which was further purified by recrystallisation from EtOAc/pentane to give fine colourless needles (1.37 g). Despite these efforts, the material still had ethoxy-N- (ethoxycarbonylamino) formamide contamination and was therefore used directly in the next deprotection step.

Crude phthalimide (1.18g) was dissolved in 9: 1 CHCl at 22 deg.C₃In MeOH (30.0mL), then treated with hydrazine (0.530mL, 9.00mmol) in one portion. A white precipitate formed within 5 minutes; the reaction was complete after 0.25 hours. The suspension was concentrated in vacuo and the resulting solid was taken up in Et₂O (5X 20mL) was triturated and then removed by filtration on a sintered glass funnel. The filtrate was then treated with HCl (8.00 mmol; 2.00mL of 4M dioxane solution) and the resulting precipitate was collected. The crystals were further treated with H₂O and Et₂O (3X 30mL each) was washed and then dried under vacuum to constant weight (0.345g, 1.15 mmol; 95.3%).

Mp187℃(dec).¹H NMR(DMSO-d₆，600MHz)：11.03(2H，brs)，7.72(1H，brt，J＝5.8Hz)，7.16(4H，s)，5.90(1H，dddd，J＝17.0，10.6，5.4，5.1Hz)，5.27(1H，brdd，J＝17.2，1.3Hz)，5.16(1H，brd，J＝10.2Hz)，4.47(2H，dt，J＝5.1，1.5Hz)，4.14(2H，d，J＝6.1Hz)，4.00(2H，t，J＝6.5Hz)，2.61-2.58(2H，m)，1.89-1.84(2H，m).¹³C NMR(DMSO-d₆，151MHz)：156.1，139.4，137.4，133.7，128.2，127.0，116.9，73.4，64.2，43.4，30.6，28.9.

C₁₄H₂₀N₂O₃HRMS calcd for (M + H): 265.1547. measured value: 265.1550.

preparation of the fraction D- (2R) -N- {3- [4- (aminomethyl) phenyl ] propoxy } -2- [ (tert-butoxy) -carbonylamino ] -3-indol-3-ylpropanamide, trifluoroacetate

HOBt (55.1mg, 0.360mmol), i-Pr were sequentially added at 22 deg.C₂NEt (125. mu.L, 0.720mmol) and HBTU (0.137g, 0.360mmol) treated Boc-DTrp-OH (0.110g, 0.360mmol) in CH₂Cl₂(3.00 mL). After 0.25 h, the solution was treated once with the product of part 7C (90.2mg, 0.300 mmol). The resulting solution was stirred for 1 hour, then all volatiles were removed in vacuo. Redissolving the crude hydroxamate at 22 deg.CAt 2: 1MeCN/H₂O (3.00mL) was added with 17.1mg of TPPTS (30.0. mu. mol; 10 mol%) and Et₂NH (78. mu.L, 0.75mmol) and 3.4mg Pd (OAc)₂(15. mu. mol; 5 mol%). Complete deprotection was seen within 1 hour. The resulting yellow solution was washed with H containing 0.1% TFA₂O (5.00mL) was diluted and then filtered with 0.45 μm Acrodisk and purified directly by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 1%/min gradient, 20-60% MeCN with 0.1% TFA, 10% H₂O, 20 mL/min. The main product peak eluted in 25 min was collected and lyophilized as a white powder (28.7mg, 49.4. mu. mol; 16.5%).

¹H NMR(DMSO-d₆，600MHz)：11.10(1H，brs)，10.81(1H，brs)，8.13(3H，brs)，7.57(1H，d，J＝7.7Hz)，7.36(2H，AB，J_AB＝8.0Hz)，7.32(1H，d，J＝8.0Hz)，7.26(2H，AB，J_AB＝8.0Hz)，7.13(1H，brs)，7.06(1H，ddd，J＝7.2，7.0，0.8Hz)，6.98(1H，dd，J＝7.5，7.2Hz)，6.93(1H，brd，J＝7.7Hz)，4.02(1H，td，J＝8.0，6.5Hz)，4.01-3.98(2H，m)，3.70-3.59(2H，m)，3.00(1H，ABX，J_AB＝14.1Hz，J_AX＝6.1Hz)，2.90(1H，ABX，J_AB＝14.5Hz，J_BX＝8.5Hz)，2.66-2.60(2H，m)，1.73(2H，brs)，1.33(9H，s).¹³C NMR(DMSO-d₆，151MHz)：168.6，155.0，142.1，136.0，131.3，128.8，128.6，127.2，123.7，120.8，118.4，118.1，111.2，109.8，78.0，74.0，52.9，42.1，31.0，29.3，28.1，27.6.

C₂₆H₃₄N₄O₄HRMS calcd for (M + H): 467.2653. measured value: 467.2649.

preparation of the moiety E-2- { [2- ({ [ N- ({4- [3- ((2R) -2-amino-3-indol-3-ylpropanoylaminooxy) -propyl ] phenyl } methyl) carbamoyl ] methyl } {2- [ bis (carboxymethyl) amino ] ethyl } amino) -ethyl ] (carboxymethyl) amino } acetic acid, trifluoroacetate

Using i-Pr at 22 deg.C₂NEt (10. mu.L, 6. mu. mol) and HBTU (11.4mg, 30.0. mu. mol) treated 2- { bis [2- (bis { [ (tert-butyl) oxycarbonyl ] oxy]Methyl } amino) ethyl]Amino } acetic acid (18.5mg, 30.0. mu. mol), HOBt (4.6mg, 30.0. mu. mol) and a solution of part 7D product (14.5mg, 25.0. mu. mol) in anhydrous DMF (1.00 mL). The resulting solution was stirred for 0.25 h, then partitioned between EtOAc and 0.1M citric acid (30mL each) and transferred to a separatory funnel. The layers were separated, the aqueous layer was washed with EtOAc (2X 30mL), and the combined EtOAc layers were washed with 0.1M citric acid followed by NaHCO₃And NaCl saturated aqueous solution (3X 30mL each), followed by MgSO₄Dried, filtered and concentrated in vacuo to a colorless oil which was used for the next deprotection step without further purification.

The protected conjugate (theoretically 25.0. mu. mol) was dissolved in dioxane (0.500mL) at 22 ℃ followed by H₂O (3. mu.L) and HCl (2.00 mmol; 0.500mL of 4M dioxane solution). The resulting pale yellow solution was stirred for 18 hours, during which time a large amount of white precipitate formed. After complete deprotection, volatiles were removed in vacuo and the white solid residue redissolved in H containing 0.1% TFA₂In O (8.00mL), purified directly by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 1%/min gradient, 10-50% MeCN, with 0.1% TFA, 10% H₂O, 20 mL/min. The major product peak eluted at 19 min was collected and lyophilized as a white powder (3.4mg, 3.1. mu. mol; 12.5%).

¹H NMR(DMSO-d₆，600MHz)：11.50(1H，brs)，11.01(1H，brs)，8.87(1H，brs)，8.26(3H，brs)，7.59(1H，d，J＝7.8Hz)，7.36(1H，d，J＝8.1Hz)，7.19(2H，AB，J_AB＝8.1Hz)，7.14(2H，AB，J_AB＝8.0Hz)，7.09(1H，dd，J＝7.6，7.4Hz)，7.01(1H，dd，J＝7.5，7.3Hz)，6.50(1H，brs)，4.31(2H，brd，J＝5.4Hz)，4.19(2H，brs)，3.73(1H，brs)，3.64(1H，ABXY，J_AB＝9.6Hz，J_AX＝6.6Hz，J_AY＝6.4Hz)，3.57(1H，ABXY，J_AB＝9.6Hz，J_BX＝6.4Hz，J_BY＝6.3Hz)，3.49(8H，s)，3.35(4H，brs)，3.17(1H，ABX，J_AB＝14.3Hz，J_AX＝7.2Hz)，3.09(1H，ABX，J_AB＝14.3Hz，J_BX＝6.8Hz)，3.03(4H，brt，J＝5.2Hz)，2.55(2H，dd，J＝7.7，7.6Hz)，1.70-1.63(2H，m).¹³C NMR(DMSO-d₆，151MHz)：172.7，165.0，157.7(q，J＝30.7Hz)，140.2，136.2，135.7，128.3，127.4，126.8，124.6，121.2，118.5，118.2，117.2(q，J＝301Hz)，111.5，106.7，74.6，54.3，53.9，52.2，51.0，48.7，42.1，30.8，29.1，27.2.

C₃₅H₄₇N₇O₁₁HRMS calcd for (M + H): 742.3406. measured value: 742.3401.

example 8

2- { [2- ({ [ N- ({4- [3- ((2R) -2-amino-4-phenylbutylaminooxy) propyl ] phenyl } methyl) carbamoyl ] methyl } {2- [ bis (carboxymethyl) amino ] ethyl } amino) ethyl ] (carboxymethyl) amino } acetic acid, trifluoroacetate salt

Preparation of the moiety A- (2R) -N- {3- [4- (aminomethyl) phenyl ] propoxy } -2- [ (tert-butoxy) carbonylamino ] -4-phenylbutanamide, trifluoroacetate

HOBt (55.1mg, 0.360mmol), i-Pr were sequentially added at 22 deg.C₂NEt (125. mu.L, 0.720mmol) and HBTU (0.137g, 0.360mmol) treated Boc-DHfe-OH (0.101g, 0.360mmol) in CH₂Cl₂(3.00 mL). After 0.25 hour, the solution was divided into two portionsThe 7C product (90.2mg, 0.300mmol) was processed in one portion. The resulting solution was stirred for 1 hour, then all volatiles were removed in vacuo. Redissolving the crude hydroxamate in 2: 1MeCN/H at 22 deg.C₂O (3.00mL) was added with 17.1mg of TPPTS (30.0. mu. mol; 10 mol%) and Et₂NH (78. mu.L, 0.75mmol) and 3.4mg Pd (OAc)₂(15. mu. mol; 5 mol%). Complete deprotection was seen within 1 hour. The resulting yellow solution was washed with H containing 0.1% TFA₂O (5.00mL) was diluted and then filtered with 0.45 μm Acrodisk and purified directly by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 1%/min gradient, 30-70% MeCN with 0.1% TFA, 10% H₂O, 20 mL/min. The main product peak eluted at 25 min was collected and lyophilized as a white powder (48.2mg, 86.8. mu. mol; 28.9%).

¹H NMR(DMSO-d₆，600MHz)：11.11(1H，brs)，8.12(3H，brs)，7.34(2H，AB，J_AB＝8.1Hz)，7.28-7.25(4H，m)，7.18-7.16(3H，m)，7.06(1H，brd，J＝7.8Hz)，4.00-3.96(2H，m)，3.77-3.70(3H，m)，2.67(2H，t，J＝7.6Hz)，2.62-2.57(1H，m)，2.52-2.47(1H，m)，1.83-1.78(4H，m)，1.38(9H，s).¹³C NMR(DMSO-d₆，75MHz)：168.8，155.3，142.1，141.2，131.4，128.8，128.6，128.3，125.8，76.1，74.2，51.9，42.0，33.5，31.5，31.0，29.4，28.1.C₂₅H₃₅N₃O₄HRMS calcd for (M + H): 442.2700. measured value: 442.2698.

preparation of part B-2- { [2- ({ [ N- ({4- [3- ((2R) -2-amino-4-phenylbutylaminooxy) -propyl ] phenyl } methyl) carbamoyl ] methyl } {2- [ bis (carboxymethyl) amino ] ethyl } amino) -ethyl ] (carboxymethyl) amino } acetic acid, trifluoroacetate salt

Using i-Pr at 22 deg.C₂NEt (10. mu.L, 6. mu. mol) and HBTU (11.4mg, 30.0. mu. mol) treated 2- { bis [2- (bis { [ (tert-butyl) oxy ] oxyCarbonyl radical]Methyl } amino) ethyl]Amino } acetic acid (18.5mg, 30.0. mu. mol), HOBt (4.6mg, 30.0. mu. mol) and a solution of the part 8A product (13.9mg, 25.0. mu. mol) in anhydrous DMF (1.00 mL). The resulting solution was stirred for 0.25 h, then partitioned between EtOAc and 0.1M citric acid (30mL each) and transferred to a separatory funnel. The layers were separated, the aqueous layer was washed with EtOAc (2X 30mL), and the combined EtOAc layers were washed with 0.1M citric acid followed by NaHCO₃And NaCl saturated aqueous solution (3X 30mL each), followed by MgSO₄Dried, filtered and concentrated in vacuo to a colorless oil which was used for the next deprotection step without further purification.

The protected conjugate (theoretically 25.0. mu. mol) was dissolved in dioxane (0.500mL) at 22 ℃ followed by H₂O (3. mu.L) and HCl (2.00 mmol; 0.500mL of 4M dioxane solution). The resulting pale yellow solution was stirred for 18 hours, during which time a large amount of white precipitate formed. After complete deprotection, volatiles were removed in vacuo and the white solid residue redissolved in H containing 0.1% TFA₂O (8.00mL) and then directly purified by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 1%/min gradient, 10-50% MeCN, with 0.1% TFA, 10% H₂O, 20 mL/min. The main product peak eluted at 21 min was collected and lyophilized as a white powder (10.5mg, 9.92. mu. mol; 39.7%).

¹H NMR(DMSO-d₆，600MHz)：11.74(1H，brs)，8.89(1H，brt，J＝5.8Hz)，8.35(3H，brs)，7.30(2H，dd，J＝7.6，7.3Hz)，7.22-7.16(8H，m)，4.30(2H，brd，J＝5.5Hz)，4.22(2H，s)，3.83(2H，dd，J＝6.4，6.1Hz)，3.67(1H，brs)，3.49(8H，s)，3.37(4H，brt，J＝5.5Hz)，3.04(4H，brt，J＝5.7Hz)，2.66(2H，dd，J＝7.9，7.6Hz)，2.58(2H，dd，J＝8.4，8.2Hz)，2.01-1.92(2H，m)，1.87-1.82(2H，m).¹³C NMR(DMSO-d₆，151MHz)：172.7，165.1，164.6，157.9(q，J＝31.7Hz)，140.3，140.2，135.8，128.5，128.3，128.0，127.4，126.2，117.0(q，J＝299Hz)，74.8，54.3，53.9，52.2，50.3，48.6，42.1，32.8，30.9，30.4，29.4.

C₃₄H₄₈N₆O₁₁HRMS calcd for (M + H): 717.3454. measured value: 717.3446.

example 9

2- ({2- [ ({ N- [6- ((2R) -2-amino-4-phenylbutylaminooxy) hexyl ] carbamoyl } methyl) {2- [ bis (carboxymethyl) amino ] ethyl } (carboxymethyl) amino) acetic acid, trifluoroacetate salt

Preparation of part A- (2R) -N- (6-aminohexyloxy) -2- [ (tert-butoxy) carbonylamino ] -4-phenylbutanamide, trifluoroacetate

HOBt (55.1mg, 0.360mmol), i-Pr were sequentially added at 22 deg.C₂NEt (125. mu.L, 0.720mmol) and HBTU (0.137g, 0.360mmol) treated Boc-DHfe-OH (0.101g, 0.360mmol) in CH₂Cl₂(3.00 mL). After 0.25 h, the solution was treated with part 4C product (75.8mg, 0.300mmol) in one portion. The resulting solution was stirred for 1 hour, then all volatiles were removed in vacuo. Redissolving the crude hydroxamate in 2: 1MeCN/H at 22 deg.C₂O (3.00mL) was added with 17.1mg of TPPTS (30.0. mu. mol; 10 mol%) and Et₂NH (78. mu.L, 0.75mmol) and 3.4mg Pd (OAc)₂(15. mu. mol; 5 mol%). Complete deprotection was seen within 1 hour. The resulting yellow solution was washed with H containing 0.1% TFA₂O (5.00mL) was diluted and then filtered with 0.45 μm Acrodisk and purified directly by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 1%/min gradient, 10-50% MeCN with 0.1% TFA, 10% H₂O, 20 mL/min. The main product peak eluted at 32 min was collected and lyophilized to a white powderAs (37.8mg, 74.5. mu. mol; 24.8%). In that¹Small amounts of TPPTS could be detected in the H NMR spectrum.

¹H NMR(DMSO-d₆，600MHz)：11.07(1H，brs)，7.77(3H，brs)，7.26(2H，dd，J＝7.6，7.6Hz)，7.18-7.15(3H，m)，7.04(1H，brd，J＝7.6Hz)，3.77-3.70(3H，m)，2.78-2.73(2H，m)，2.62-2.57(1H，m)，2.52-2.47(1H，m)，1.82-1.75(2H，m)，1.54-1.49(4H，m)，1.38(9H，s)，1.38-1.27(4H，m).¹³C NMR(DMSO-d₆，151MHz)：168.7，158.2(q，J＝32.0Hz)，155.2，141.23，128.3，128.2，125.8，116.9(q，J＝293Hz)，78.0，74.8，51.9，38.7，33.6，31.5，28.1，27.2，26.8，25.5，24.8.

C₂₁H₃₅N₃O₄HRMS calcd for (M + H): 394.2700. measured value: 394.2698.

preparation of part B-2- ({2- [ ({ N- [6- ((2R) -2-amino-4-phenylbutylaminooxy) hexyl ] -carbamoyl } methyl) {2- [ bis (carboxymethyl) amino ] ethyl } (carboxymethyl) -amino) acetic acid, trifluoroacetate salt

Using i-Pr at 22 deg.C₂NEt (10. mu.L, 6. mu. mol) and HBTU (11.4mg, 30.0. mu. mol) treated 2- { bis [2- (bis { [ (tert-butyl) oxycarbonyl ] oxy]Methyl } amino) ethyl]Amino } acetic acid (18.5mg, 30.0. mu. mol), HOBt (4.6mg, 30.0. mu. mol) and a solution of the partial 9A product (12.7mg, 25.0. mu. mol) in anhydrous DMF (1.00 mL). The resulting solution was stirred for 0.25 h, then partitioned between EtOAc and 0.1M citric acid (30mL each) and transferred to a separatory funnel. The layers were separated, the aqueous layer was washed with EtOAc (2X 30mL), and the combined EtOAc layers were washed with 0.1M citric acid followed by NaHCO₃And NaCl saturated aqueous solution (3X 30mL each), followed by MgSO₄Dried, filtered and concentrated in vacuo to a colorless oil which was used for the next deprotection step without further purification.

The protected conjugate (theoretically 25.0. mu. mol) was dissolved in dioxane (0.500mL) at 22 ℃ followed by H₂O (3. mu.L) and HCl (2.00 mmol; 0.500mL of 4M dioxane solution). The resulting pale yellow solution was stirred for 18 hours, during which time a large amount of white precipitate formed. After complete deprotection, volatiles were removed in vacuo and the white solid residue redissolved in H containing 0.1% TFA₂O (8.00mL) and then directly purified by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 1%/min gradient, 0-40% MeCN, 0.1% TFA, 10% H₂O, 20 mL/min. The main product peak eluted at 27 min was collected and lyophilized as a white powder (10.4mg, 10.3. mu. mol; 41.2%).

¹H NMR(DMSO-d₆，600MHz)：11.64(1H，brs)，8.41(1H，brt，J＝5.3Hz)，8.31(2H，brs)，7.30(2H，dd，J＝7.6，7.5Hz)，7.21(1H，dd，J＝7.4，7.4Hz)，7.18(2H，d，J＝7.2Hz)，4.13(2H，brs)，3.84-3.76(2H，m)，3.64(1H，brs)，3.49(8H，s)，3.34(4H，brt，J＝4.9Hz)，3.10(2H，td，J＝6.8，6.0Hz)，3.03(4H，brt，J＝5.7Hz)，2.58(2H，dd，J＝8.4，8.0Hz)，2.01-1.93(2H，m)，1.59-1.54(2H，m)，1.45-1.40(2H，m)，1.38-1.25(4H，m).¹³C NMR(DMSO-d₆，151MHz)：172.7，165.0，164.3，157.7(q，J＝31.4Hz)，140.1，128.5，128.0，126.2，117.0(q，J＝300Hz)，75.4，54.3，53.9，52.1，50.2，48.6，38.7，32.8，30.3，28.7，27.4，26.1，24.9.C₃₀H₄₈N₆O₁₁HRMS calcd for (M + H): 669.3454. measured value: 669.3446.

example 10

2- [ (2- { [ (N- { [4- ((2R) -2-amino-4-methylpentanoylaminooxy) phenyl ] methyl } carbamoyl) methyl ] {2- [ bis (carboxymethyl) amino ] ethyl } amino } ethyl) (carboxymethyl) amino ] acetic acid, trifluoroacetate salt

Preparation of part A-N- { [4- (aminooxy) phenyl ] methyl } prop-2-enyloxy-carboxamide, hydrochloride

Reacting N- [ (4-hydroxyphenyl) methyl]Prop-2-alkenyloxycarboxamide (2.07g, 10.0 mmol; Imamuura, H.; Ohtake, N.; Shimizu, A.; Jona, H.; Sato, H.; Nagano, R.; Ushijima, R.; Yamada, K.; Hashizume, T.; Morishima, H.Bioorg. MedChem.Lett.2000, 10 (2); 109) 113.) in dry MeOH (20.1mL) was cooled to 0 deg.C and treated with KOt-Bu (1.12g, 10.0mmol) in one portion. The resulting light pink solution was stirred for 0.25 h, then warmed to 22 ℃ for 0.25 h, and concentrated in vacuo. Redissolving the solid in DMF (13.0mL), cooling to 0 deg.C, and then adding dropwise freshly prepared amino 2,4, 6-trimethylbenzenesulfonate (10.0 mmol; 6.00mL of 1.67M DMF solution; (a) Carpino, L.A.J.Am.chem.Soc.1960, 82, 3133.(b) Krause, J.G.Synthesis 1972, 3, 140.(c) Suits, J.Z.; Applequist, D.E.; Swart, D.J.J.J.J.Org.chem.1983, 48, 5120.) over 5 minutes; quantitative transfer was performed with additional DMF (2X 0.50 mL). After 0.5 hour, the resulting solution was taken up with H₂Diluted O (100mL), transferred to a separatory funnel and then treated with Et₂O (5X 50 mL). The combined Et was washed at 22 deg.C₂Washing with O over MgSO₄Dried, filtered and then treated with HCl (4.00 mmol; 1.00mL of 4M dioxane solution). The resulting plate crystals were collected on a fine porosity sintered glass funnel and used for Et₂O and pentane (5X 20mL each) were washed and then dried on the funnel to constant weight (0.597g, 2.31 mmol; 23.1%).

¹H NMR(DMSO-d₆，300MHz)：7.74(1H，brt，J＝6.0Hz)，7.25(2H，AA’BB’，J_AB＝8.8Hz，J_AA’＝2.5Hz)，7.14(2H，AA’BB’，J_AB＝8.8Hz，J_BB’＝2.5Hz)，5.90(H，ddt，J＝17.2，10.5，5.4Hz)，5.26(1H，dq，J＝17.3，1.5Hz)，5.16(1H，dq，J＝10.4，1.4Hz)，4.47(2H，dt，J＝5.3，1.5Hz)，4.13(2H，brd，J＝6.1Hz).¹³C NMR(DMSO-d₆，151MHz)：156.1，156.0，135.3，133.7，128.2，116.9，114.3，64.3，43.1.

C₁₁H₁₄N₂O₃HRMS calcd for (M + H): 223.1077. measured value: 223.1079. part B- (2R) -N- [4- (aminomethyl) phenoxy]-2- [ (tert-butoxy) carbonylamino]Preparation of (E) -4-methylpentanamide, trifluoroacetic acid salt

Using i-Pr at 22 deg.C₂A solution of Boc-DLeu-OH (0.139g, 0.600mmol) and HOBt (91.9mg, 0.600mmol) in DMF (5.00mL) was treated with NEt (209. mu.L, 1.20mmol) and HBTU (0.228g, 0.600 mmol). After 10 minutes, the solution was treated once with a portion of the 10A product (0.129g, 0.500 mmol). The resulting solution was stirred for 17 hours and then treated with additional HBTU (56.9mg, 0.150mmol) to complete the conversion. After 1 hour, the solution was partitioned between EtOAc and 0.1M citric acid (30mL each) and then transferred to a separatory funnel. The layers were separated, the aqueous solution was washed with EtOAc (2X 30mL), and the combined EtOAc layers were washed with 0.1M citric acid followed by NaHCO₃And NaCl saturated aqueous solution (3X 30mL each), followed by MgSO₄Dried, filtered and concentrated in vacuo to a colorless oil which was used without further purification, i.e. in the next deprotection step.

The crude oximinomate (0.500 mmol theoretically) was dissolved in 2: 1MeCN/H at 22 deg.C₂O (5.00mL) was added 28.4mg of TPPTS (50.0. mu. mol; 10 mol%) followed by Et₂NH (129. mu.L, 1.25mmol) and 5.6mg Pd (OAc)₂(25.0. mu. mol; 5 mol%). Within 0.5 hourComplete deprotection was seen. The resulting amber solution was washed with H containing 0.1% TFA₂O (3.00mL) was diluted and then filtered with 0.45 μm Acrodisk and purified directly by HPLC on a Phenomenex LunaC18 column (21.2X250mm) using a 1%/min gradient, 10-40% MeCN with 0.1% TFA, 10% H₂O, 20 mL/min. The main product peak eluted at 23 min was collected and lyophilized as a white powder (71.3mg, 0.153 mmol; 30.6%).

¹H NMR(DMS0-d₆，300MHz)：12.11(1H，brs)，8.10(3H，brs)，7.36(2H，AB，J_AB＝8.5Hz)，7.171(1H，brd，J＝7.8Hz)，7.05(2H，AB，J_AB＝8.6Hz)，4.00-3.90(3H，m)，1.66-1.36(3H，m)，1.41(9H，s)，0.90(3H，d，J＝6.4Hz)，0.86(3H，d，J＝6.5Hz).¹³C NMR(DMSO-d₆，75MHz)：169.8，159.6，155.5，130.2，127.6，112.8，78.2，50.7，41.7，28.1，24.2，22.6，21.7.

C₁₈H₂₉N₃O₄(M+H-NH₃) HRMS calculated of (a): 335.1965. measured value: 335.1969. part of C-2- [ (2- { [ (N- { [4- ((2R) -2-amino-4-methylpentanoylaminooxy) -phenyl]Methyl } carbamoyl) methyl]{2- [ bis (carboxymethyl) amino group]Ethyl } amino } -ethyl) (carboxymethyl) amino]Preparation of acetic acid, trifluoroacetic acid salt

Using i-Pr at 22 deg.C₂NEt (38. mu.L, 0.22mmol) and HBTU (41.7mg, 0.110mmol) treated 2- { bis [2- (bis { [ (tert-butyl) oxycarbonyl ] oxy]Methyl } amino) ethyl]A solution of amino } acetic acid (67.9mg, 0.110mmol), HOBt (16.8mg, 0.110mmol) and the fraction 10B product (46.5mg, 0.100mmol) in anhydrous DMF (2.00 mL). The resulting solution was stirred for 0.5 h, then partitioned between EtOAc and 0.1M citric acid (30mL each) and transferred to a separatory funnel. The layers were separated, the aqueous layer was washed with EtOAc (2X 30mL), and the combined EtOAc layers were washed with 0.1M citric acid followed by NaHCO₃And saturation with NaClAqueous solutions (3X 30mL each) were washed, then MgSO₄Dried, filtered and concentrated in vacuo to a colorless oil which was used without further purification, i.e. in the next deprotection step.

The protected conjugate (theoretically 0.110mmol) was dissolved in dioxane (1.00mL) at 22 ℃ followed by H₂O (10. mu.L) and HCl (4.00 mmol; 1.00mL of 4M dioxane solution). The resulting pale yellow solution was stirred for 15 hours, during which time a large amount of white precipitate formed. After complete deprotection, volatiles were removed in vacuo and the white solid residue redissolved in H containing 0.1% TFA₂O (6.00mL) and then directly purified by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 1%/min gradient, 0-22% MeCN, 0.1% TFA, 10% H₂O, 20 mL/min. The main product peak eluted at 18 min was collected and lyophilized as a white powder (30.8mg, 31.8. mu. mol; 31.8%).

¹H NMR(DMSO-d₆，600MHz)：12.70(1H，brs)，8.90(1H，brs)，8.41(3H，brs)，7.26(2H，AB，J_AB＝8.4Hz)，7.03(2H，AB，J_AB＝8.1Hz)，4.30(2H，brd，J＝5.2Hz)，4.20(2H，s)，3.81(1H，brs)，3.50(8H，s)，3.36(4H，brt，J＝5.4Hz)，3.04(4H，brt，J＝5.8Hz)，1.64(3H，brs)，0.95(3H，brd，J＝5.5Hz)，0.92(3H，brd，J＝5.5Hz).¹³C NMR(DMSO-d₆，151MHz)：172.7，166.4，164.7，158.2，158.0(q，J＝30.7Hz)，132.8，128.7，117.1(q，J＝300Hz)，113.0，54.3，53.9，52.2，49.0，48.7，41.7，40.0，23.8，22.2，22.0.C₂₇H₄₂N₆O₁₁HRMS calcd for (M + H): 627.2986. measured value: 627.2989.

example 11

2- [ (2- { [ (N- { [4- ((2R) -2-amino-4-phenylbutylaminooxy) phenyl ] methyl } carbamoyl) methyl ] {2- [ bis (carboxymethyl) amino ] ethyl } amino } ethyl) (carboxymethyl) amino ] acetic acid, trifluoroacetate salt

Preparation of the moiety A- (2R) -N- [4- (aminomethyl) phenoxy ] -2- [ (tert-butoxy) carbonylamino ] -4-phenylbutanamide, trifluoroacetate

Using i-Pr at 22 deg.C₂NEt (209. mu.L, 1.20mmol) and HBTU (0.228g, 0.600mmol) treated a solution of Boc-DHfe-OH (0.168g, 0.600mmol) and HOBt (91.9mg, 0.600mmol) in DMF (5.00 mL). After 10 minutes, the solution was treated once with a portion of the 10A product (0.129g, 0.500 mmol). The resulting solution was stirred for 17 hours, then partitioned between EtOAc and 0.1M citric acid (30mL each) and transferred to a separatory funnel. The layers were separated, the aqueous solution was washed with EtOAc (2X 30mL), and the combined EtOAc layers were washed with 0.1M citric acid followed by NaHCO₃And NaCl saturated aqueous solution (3X 30mL each), followed by MgSO₄Dried, filtered and concentrated in vacuo to a colorless oil which was used without further purification, i.e. in the next deprotection step.

The crude oximinomate (0.500 mmol theoretically) was dissolved in 2: 1MeCN/H at 22 deg.C₂O (5.00mL) was added 28.4mg of TPPTS (50.0. mu. mol; 10 mol%) followed by Et₂NH (129. mu.L, 1.25mmol) and 5.6mg Pd (OAc)₂(25.0. mu. mol; 5 mol%). Complete deprotection was seen within 0.5 h. The resulting amber solution was washed with H containing 0.1% TFA₂Diluted with O (3.00mL) and then lyophilized. Redissolving the solid in 10: 1H₂O/MeCN (8.00ml), filtered with 0.45 μm Acrodisk, purified directly by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 1%/min gradient, 20-50% MeCN with 0.1% TFA, 10% H₂O, 20 mL/min. The main product peak eluted in 17 min was collected and lyophilized as a white powder (0.157g, 0.305 mmol; 61.0%).

¹H NMR(DMSO-d₆，600MHz)：12.11(1H，brs)，8.10(3H，brs)，7.36(2H，AB，J_AB＝8.5Hz)，7.34(1H，brd，J＝7.5Hz)，7.28(2H，dd，J＝7.7，7.5Hz)，7.20(2H，AB，J_AB＝7.5Hz)，7.18(1H，t，J＝7.2Hz)，7.06(2H，AB，J_AB＝8.5Hz)，3.96(2H，brd，J＝5.1Hz)，3.90-3.87(1H，m)，2.70-2.65(1H，m)，2.59-2.54(1H，m)，1.93-1.87(2H，m)，1.43(9H，s).¹³C NMR(DMSO-d₆，151MHz)：169.6，159.6，155.5，141.0，130.2，128.3，127.7，125.9，112.8，78.3，52.2，41.6，32.8，31.5，28.2.

C₂₂H₂₉N₃O₄HRMS calcd for (M + H): 400.2231. measured value: 400.2241. part B-2- [ (2- { [ (N- { [4- ((2R) -2-amino-4-phenylbutylaminooxy) -phenyl]Methyl } carbamoyl) methyl]{2- [ bis (carboxymethyl) amino group]Ethyl } amino } -ethyl) (carboxymethyl) amino]Preparation of acetic acid, trifluoroacetic acid salt

Using i-Pr at 22 deg.C₂NEt (25. mu.L, 0.14mmol) and EDC (13.6mg, 71.1. mu. mol) treatment of 2- { bis [2- (bis { [ (tert-butyl) oxycarbonyl ] oxy]Methyl } amino) ethyl]Amino } acetic acid (47.9mg, 77.6. mu. mol), HOBt (10.9mg, 71.1. mu. mol) and a solution of the part 11A product (33.2mg, 64.7. mu. mol) in anhydrous DMF (1.29 mL). The resulting solution was stirred for 20 hours, then partitioned between EtOAc and 0.1M citric acid (30mL each) and transferred to a separatory funnel. The layers were separated, the aqueous layer was washed with EtOAc (2X 30mL), and the combined EtOAc layers were washed with 0.1M citric acid, 0.1M NaOH, and saturated aqueous NaCl solution (3X 30mL each), followed by MgSO₄Dried, filtered and concentrated in vacuo to a colorless oil which was used without further purification, i.e. in the next deprotection step.

The protected conjugate (theoretically 64.7. mu. mol) was dissolved in dioxane (0.650mL) at 22 ℃ followed by H₂O (6. mu.L) and HCl (2.60 mmol; 0.650mL of 4M dioxane solution). The resulting pale yellow solution was stirred for 18.5 hours, during which time a large amount of white precipitate formed. After complete deprotection at N₂Volatiles were removed under a stream of gas and the white solid residue was redissolved in H containing 0.1% TFA₂O (8.00mL) and then directly purified by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 1%/min gradient, 0-30% MeCN, 0.1% TFA, 10% H₂O, 20 mL/min. The main product peak eluted at 23 min was collected and lyophilized as a white powder (29.4mg, 28.9. mu. mol; 44.7%).

¹HNMR(DMSO-d₆，600MHz)：12.79(1H，brs)，8.92(1H，brs)，8.56(3H，brs)，7.32(2H，dd，J＝7.8，7.1Hz)，8.27(2H，AB，J_AB＝8.4Hz)，7.23-7.21(3H，m)，7.06(2H，d，J＝7.6Hz)，4.31(2H，brd，J＝5.0Hz)，4.23(2H，s)，3.50(8H，s)，3.38(4H，brs)，3.05(4H，brt，J＝5.4Hz)，2.67(2H，brs)，2.09(2H，brs).¹³C NMR(DMSO-d₆，151MHz)：172.7，166.1，164.6，158.3，158.2(q，J＝32.9Hz)，140.2，132.8，128.7，128.6，128.1，126.3，116.9(q，J＝299Hz)，113.0，54.3，53.9，52.2，50.4，48.7，41.8，32.9，30.5.C₃₁H₄₂N₆O₁₁HRMS calcd for (M + H): 675.2984. measured value: 675.2997.

example 12

2- [ (2- { [ (N- { [4- ((2R) -2-amino-3- (2-naphthyl) propionylaminoxy) phenyl ] methyl } carbamoyl) methyl ] {2- [ bis (carboxymethyl) amino ] ethyl } amino } ethyl) (carboxymethyl) amino ] acetic acid, trifluoroacetate salt

Preparation of part of A- (2R) -N- [4- (aminomethyl) phenoxy ] -2- [ (tert-butoxy) carbonylamino ] -3- (2-naphthyl) propionamide, trifluoroacetate

Using i-Pr at 22 deg.C₂NEt (209. mu.L, 1.20mmol) and HBTU (0.228g, 0.600mmol) treated a solution of Boc-DNal-OH (0.189g, 0.600mmol) and HOBt (91.9mg, 0.600mmol) in DMF (5.00 mL). After 10 minutes, the solution was treated once with a portion of the 10A product (0.129g, 0.500 mmol). The resulting solution was stirred for 17 hours and then treated with additional HBTU (56.9mg, 0.150mmol) to complete the conversion. After 1 hour, the solution was partitioned between EtOAc and 0.1M citric acid (30mL each) and then transferred to a separatory funnel. The layers were separated, the aqueous solution was washed with EtOAc (2X 30mL), and the combined EtOAc layers were washed with 0.1M citric acid followed by NaHCO₃And NaCl saturated aqueous solution (3X 30mL each), followed by MgSO₄Dried, filtered and concentrated in vacuo to a colorless oil which was used without further purification, i.e. in the next deprotection step.

The crude oximinomate (0.500 mmol theoretically) was dissolved in 2: 1MeCN/H at 22 deg.C₂O (5.00mL) was added 28.4mg of TPPTS (50.0. mu. mol; 10 mol%) followed by Et₂NH (129. mu.L, 1.25mmol) and 5.6mg Pd (OAc)₂(25.0. mu. mol; 5 mol%). Complete deprotection was seen within 0.5 h. The resulting amber solution was washed with H containing 0.1% TFA₂Diluted with O (3.00mL) and then lyophilized. Redissolving the solid in 1: 1H₂O/MeCN (8.00ml), filtered with 0.45 μm Acrodisk, purified directly by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 1%/min gradient, 30-60% MeCN with 0.1% TFA, 10% H₂O, 20 mL/min. The main product peak eluting for 12 min was collected and lyophilized as a white powder (0.115g, 0.209 mmol; 41.9%).

¹H NMR(DMSO-d₆，600MHz)：12.08(1H，s)，8.10(3H，brs)，7.89(1H，d，J＝7.5Hz)，7.86(1H，d，J＝8.5Hz)，7.83(1H，d，J＝7.5Hz)，7.76(1H，s)，7.51-7.47(2H，m)，7.45(1H，d，J＝8.0Hz)，7.40(1H，brd，J＝7.7Hz)，7.21(2H，AB，J_AB＝8.3Hz)，6.86(2H，AB，J_AB＝8.5Hz)，4.28-4.24(1H，m)，3.92(2H，brs)，3.14(1H，ABX，J_AB＝13.6Hz，J_AX＝6.7Hz)，3.06(1H，ABX，J_AB＝13.3Hz，J_BX＝8.8Hz)，1.35(9H，s).¹³C NMR(DMSO-d₆，151MHz)：168.8，159.4，155.3，135.1，132.9，131.9，130.1，127.6，127.6，127.6，127.5，127.4，126.0，125.5，112.7，78.3，53.8，41.6，36.9，28.1.

C₂₅H₂₉N₃O₄(M+H-NH₃) HRMS calculated of (a): 419.1965. measured value: 419.1967.

preparation of part B-2- [ (2- { [ (N- { [4- ((2R) -2-amino-3- (2-naphthyl) propionylaminoxy) -phenyl ] methyl } carbamoyl) methyl ] {2- [ bis (carboxymethyl) amino ] ethyl } amino } -ethyl) (carboxymethyl) amino ] acetic acid, trifluoroacetate

Using i-Pr at 22 deg.C₂NEt (38. mu.L, 0.22mmol) and HBTU (41.7mg, 0.110mmol) treated 2- { bis [2- (bis { [ (tert-butyl) oxycarbonyl ] oxy]Methyl } amino) ethyl]A solution of amino } acetic acid (67.9mg, 0.110mmol), HOBt (16.8mg, 0.110mmol) and the part 12A product (54.9mg, 0.100mmol) in anhydrous DMF (2.00 mL). The resulting solution was stirred for 0.5 h, then partitioned between EtOAc and 0.1M citric acid (30mL each) and transferred to a separatory funnel. The layers were separated, the aqueous layer was washed with EtOAc (2X 30mL), and the combined EtOAc layers were washed with 0.1M citric acid followed by NaHCO₃And NaCl saturated aqueous solution (3X 30mL each), followed by MgSO₄Dried, filtered and concentrated in vacuo to a colorless oil which was used without further purification, i.e. in the next deprotection step.

The protected conjugate (theoretically 0.100mmol) was dissolved in dioxane (1.00mL) at 22 ℃ followed by H₂O (10. mu.L) and HCl (4.00 mmol; 1.00mL of 4M dioxane solution). The resulting pale yellow solution was stirred for 15 hours, during which time a large amount of white precipitate formed. After complete deprotection at N₂Volatiles were removed under a stream of gas and the white solid residue was redissolved in H containing 0.1% TFA₂O (8.00mL) and then directly purified by HPLC on a Phenomenex Lura C18 column (21.2X250mm) using a 1%/min gradient, 5-30% MeCN with 0.1% TFA, 10% H₂O, 20 mL/min. The major product peak eluted at 20 min was collected and lyophilized as a white powder (40.5mg, 38.5. mu. mol; 38.5%).

¹H NMR(DMSO-d₆，600MHz)：12.49(1H，brs)，8.84(1H，brt，J＝5.1Hz)，8.63(2H，brs)，7.98-7.95(2H，m)，7.89-7.86(1H，m)，7.77(1H，brs)，7.57-7.54(2H，m)，7.45(1H，brs)，6.85(2H，AB，J_AB＝8.2Hz)，6.50(2H，AB，J_AB＝7.6Hz)，4.20(2H，s)，4.21-4.15(3H，m)，3.51(8H，s)，3.38(4H，brt，J＝5.5Hz)，3.35-3.31(1H，m)，3.26-3.22(1H，m)，3.05(4H，brt，J＝5.7Hz).¹³C NMR(DMSO-d₆，151MHz)：172.7，156.2，164.6，158.1(q，J＝31.8Hz)，157.8，133.0，132.4，132.3，132.2，128.4，128.3，128.3，127.6，127.6，127.3，126.3，126.0，117.1(q，J＝299Hz)，112.6，54.3，53.8，52.2，51.6，48.7，41.7，37.0.C₃₄H₄₂N₆O₁₁HRMS calcd for (M + H): 711.2986. measured value: 711.2985.

example 13

2- { [2- ({ [ N- ({4- [2- ((2R) -2-amino-4-methylpentanoylaminooxy) ethyl ] phenyl } methyl) carbamoyl ] methyl } {2- [ bis (carboxymethyl) amino ] ethyl } amino) ethyl ] (carboxymethyl) amino } acetic acid, trifluoroacetic acid salt

Preparation of part A-N-methoxy-N-methyl (4- { [ (phenylmethoxy) carbonylamino ] -methyl } phenyl) carboxamide

Using i-Pr at 22 deg.C₂Treatment of 4- { [ (Phenylmethoxy) carbonylamino with NEt (4.87mL, 28.0mmol) and EDC (3.22g, 16.8mmol)]A solution of methyl } benzoic acid (3.99g, 14.0 mmol; Groves, K.; Wilson, A.J.; Hamilton, A.D.J.am.chem.Soc.2004, 126(40), 12833-12842.) and HOBt (2.57g, 16.8mmol) in anhydrous DMF (70.0 mL). After 0.25 h, the solution was treated once with methoxymethylammonium hydrochloride (1.64g, 16.8 mmol). The resulting mixture was stirred for 1 hour, then partitioned between EtOAc and 0.1M citric acid (100mL each) and transferred to a separatory funnel. The layers were separated, the aqueous layer was washed with EtOAc (2X 50mL), and the combined EtOAc layers were washed with 0.1M citric acid, 0.1M NaOH, and saturated aqueous NaCl solution (3X 50mL each), followed by MgSO₄Dried, filtered and concentrated in vacuo. Purification by silica chromatography (40X 250mm) using a gradient elution of 1: 1 → 3: 7 pentane/EtOAc (R in 1: 1 hexane/EtOAc)_f0.3) gave pure material as a colorless oil (3.94g, 12.0 mmol; 85.9%).

¹H NMR(CDCl₃，300MHz)：7.63(2H，AA’BB’，J_AB＝8.3Hz，J_AA’＝1.9Hz)，7.36-7.27(7H，m)，5.20(1H，brs)，5.13(2H，s)，4.40(2H，brd，J＝6.0Hz)，3.52(3H，s)，3.33(3H，s).¹³C NMR(CDCl₃，75MHz)：169.5，156.4，141.1，136.4，133.2，128.6，128.5，128.1，128.1，126.9，66.9，61.0，44.8，33.7.

C₁₈H₂₀N₂O₄HRMS calculated of (a): 329.1496. measured value: 329.1497. part of B-N- [ (4-acetylphenyl) methyl]Preparation of (phenylmethoxy) carboxamides

A solution of the product of part 13A (3.28g, 10.0mmol) in dry THF (100mL) was cooled to 0 deg.C and MeLi (30.0 mmol; 10.2mL of 2.94M Et was added dropwise over 0.25 h₂O solution) treatment; during the dropwise addition, a large amount of white precipitate formed. After 0.5 h, the resulting suspension was treated with concentrated HCl in anhydrous EtOH (5: 95 v/v; 100mL) followed by Et₂O and saturated aqueous NaCl solution (100mL each) were diluted and transferred to a separatory funnel. The layers were separated and Et₂The aqueous layer was washed with O (2X 50mL) and the combined Et₂The O layer was further washed with saturated aqueous NaCl (3X 100mL) and MgSO₄Dried, filtered and concentrated in vacuo. The crude material was purified by 1: 1 hexane/EtOAc silica chromatography (40X 300 mm). The major product eluted between 300-500mL was collected and concentrated to an amorphous white powder which was isolated from Et₂Recrystallization from O/pentane gave fine colorless needles (1.57g, 5.54 mmol; 55.6%).

Mp 101.0-103.0℃.¹H NMR(CDCl₃，300MHz)：7.90(2H，AB，J_AB＝8.3Hz)，7.34(7H，brs)，5.22(1H，brs)，5.13(2H，s)，4.40(2H，brd，J＝6.2Hz)，2.57(3H，s).¹³C NMR(DMSO-d₆，151MHz)：197.6，156.4，143.9，136.4，136.3，128.7，128.5，128.2，128.1，127.4，67.0，44.7，26.6.

C₁₇H₁₇NO₃HRMS calcd for (M + H): 284.1281. measured value: 284.1280.

preparation of part of methyl C-2- (4- { [ (phenylmethoxy) carbonylamino ] methyl } phenyl) acetate

With AgNO at 22 ℃ in succession₃(1.56g, 9.18mmol) and I₂(1.17g，4.61mmol) portion 13B product (1.24g, 4.38mmol) in 3: 1 MeOH/HC (OMe)₃(28.0 mL). The resulting solution was warmed to 68 ℃ and maintained under reflux for 2 hours. After cooling to 22 ℃ the suspension was filtered through a sintered glass funnel and the filtrate was partitioned in Et₂O and H₂Between O (50mL each), transfer to separatory funnel. The layers were separated and Et₂The aqueous layer was washed with O (2X 50mL) and the combined Et₂The O layer is MgSO₄Dried, filtered and concentrated in vacuo to a white solid which was used for the next reduction step without further purification.

¹H NMR(CDCl₃300 MHz): 7.87-7.80(5H, m), 7.23(4H, s), 5.13(2H, s), 5.04(1H, brs), 4.36(2H, brd, J ═ 5.9Hz), 3.68(3H, s), 3.60(2H, s) moieties D-N- { [4- (2-hydroxyethyl) phenyl]Preparation of methyl } (phenylmethoxy) carboxamide

A solution of the product of part 13C (1.20g, 3.83mmol) in dry THF (38.3mL) was cooled to 0 deg.C and LiAlH was added dropwise over 10 minutes₄(3.83 mmol; 3.83mL of a 1M THF solution). The resulting solution was stirred at 0 ℃ for 0.25 h to ensure complete reduction. Carefully add H₂O (145. mu.L) to deplete excess LiAlH₄. The resulting white suspension was washed with 15% aqueous NaOH (145. mu.L) followed by H₂O (435. mu.L) and then stirred for 0.25 hours to a fine white slurry. The resulting mixture was filtered through a pad of Celite and concentrated in vacuo. The crude oil was purified by 1: 1 hexane/EtOAc silica chromatography to give a white solid (0.670g, 2.35 mmol; 61.3%).

¹H NMR(CDCl₃，600MHz)：7.36-7.29(5H，m)，7.23(2H，AB，J_AB＝7.3Hz)，7.19(2H，AB，J_AB＝7.7Hz)，5.13(2H，s)，5.03(1H，brs)，4.36(2H，brd，J＝5.5Hz)，3.84(2H，t，J＝6.6Hz)，2.85(2H，t，J＝6.6Hz)，1.46(1H，

C₁₇H₁₉NO₃HRMS calcd for (M + Na): 308.1257. measured value: 308.1257.

preparation of a fraction of E-N- ({4- [2- (1, 3-dioxoisoindolin-2-yloxy) ethyl ] phenyl } methyl) - (phenylmethoxy) carboxamide

Portion 13D product (0.300g, 1.05mmol), 2-hydroxyisoindoline-1, 3-dione (0.206g, 1.26mmol), and PPh₃A solution of (0.414g, 1.58mmol) in dry THF (10.5mL) was cooled to 0 deg.C and treated dropwise with DEAD (0.224mL, 1.42mmol) so that there was no persistent orange color. The pale yellow solution thus obtained was immediately warmed to 22 ℃ and concentrated in vacuo and purified directly by chromatography on silica using a gradient elution of 2: 1 → 1: 1 hexane/EtOAc (R in 1: 1 hexane/EtOAc)_f0.5). Fractions containing product were combined and concentrated to a white crystalline solid (0.354g, 0.822 mmol; 78.2%).

¹H NMR(CDCl₃，600MHz)：7.83-7.80(2H，m)，7.74-7.72(2H，m)，7.36-7.29(5H，m)，7.26(2H，AB，J_AB＝8.0Hz)，7.21(2H，AB，J_AB＝7.5Hz)，5.13(2H，s)，4.98(1H，brs)，4.42(2H，t，J＝7.3Hz)，4.33(2H，brd，J＝5.5Hz)，3.12(2H，t，J＝7.3

C₂₅H₂₂N₂O₅HRMS calcd for (M + Na): 453.1421. measured value: 453.1425. part of F-N- ({4- [2- (aminooxy) ethyl)]Preparation of phenyl } methyl) (phenylmethoxy) carboxamide, hydrochloride

A portion of the 13E product (0.341g, 0.792mmol) was treated in one portion with hydrazine hydrate (0.190mL, 3.92mmol) at 22 deg.C in 9: 1 CHCl₃Solution in MeOH (8.00 mL). A white precipitate formed within 5 minutes; the reaction was complete after 1 hour. The suspension was filtered through a plug of silica (25g) followed by 9: 1CH₂Cl₂MeOH (750mL) and concentrated in vacuo to a white solid. Using the solid with Et₂The O was ground and then removed by filtration through a sintered glass funnel. The filtrate was further treated with HCl (0.8 mmol; 0.2mL of 4M dioxane solution), and the resulting precipitate was collected and treated with Et₂O (10X 5mL) and dried under vacuum to constant weight (0.220g, 0.653; 82.5%).

¹H NMR(DMSO-d₆，600MHz)：10.94(2H，brs)，7.78(1H，brt，J＝5.8Hz)，7.37-7.28(5H，m)，7.20(2H，AB，J_AB＝8.4Hz)，7.18(2H，AB，J_AB＝8.4Hz)，5.03(2H，s)，4.20(2H，t，J＝6.6Hz)，4.16(2H，brd，J＝6.0Hz)，2.90(2H，t，J＝6.5Hz).

C₁₇H₂₀N₂O₃HRMS calcd for (M + H): 301.1547. measured value: 301.1550.

preparation of the moiety G- (2R) -N- {2- [4- (aminomethyl) phenyl ] ethoxy } -2- [ (tert-butoxy) carbonyl-amino ] -4-methylpentanamide, trifluoroacetate

HOBt (30.0mg, 0.196mmol) and i-Pr were added sequentially at 22 deg.C₂A solution of Boc-DLeu-OH (49.0mg, 0.197mmol) in DMF (1.00mL) was treated with NEt (51. mu.L, 0.293mmol) and HBTU (75.0mg, 0.198 mmol). After 0.25 h, the solution was treated with part 13F product (55.0mg, 0.163mmol) in one portion. The resulting solution was stirred for 0.5 hThen diluted with EtOAc (25mL) and transferred to a separatory funnel. The EtOAc solution was treated with 0.1M citric acid (3X 30mL) followed by NaHCO₃(3X 30mL) and NaCl (30mL) in saturated aqueous solution, followed by MgSO₄Dried, filtered and concentrated in vacuo to a colorless oil which was used without further purification, i.e. in the next deprotection step.

The crude oximatoxidate (0.163 mmol theoretically) was dissolved in MeOH (1.00mL) at 22 deg.C and treated once with 10% Pd on carbon (17.4mg, 16.3. mu. mol; 10 mol%). Subjecting the resulting suspension to 1atm of H₂Bubbling was carried out for 1 hour. With N₂After purging the vessel, the suspension was filtered through 0.45 μm Acrodisk and then concentrated in vacuo. Redissolving the residue in 1: 1MeCN/H₂O (3.00mL) and then directly purified by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 1%/min gradient, 15-45% MeCN with 0.1% TFA, 10% H₂O, 20 mL/min. The major product peak eluted at 20 min was collected and lyophilized as a white powder (61.2mg, 0.124 mmol; 75.9%).

¹H NMR(DMSO-d₆，600MHz)：11.15(1H，brs)，8.12(2H，brs)，7.36(2H，AB，J_AB＝8.1Hz)，7.33(2H，AB，J_AB＝8.1Hz)，6.91(1H，brd，J＝7.6Hz)，3.99(2H，brs)，3.98-3.89(2H，m)，3.82-3.78(1H，m)，2.87(2H，brt，J＝6.2Hz)，1.58-1.52(1H，m)，1.46-1.40(1H，m)，1.36(9H，s)，1.36-1.31(1H，m)，0.87(3H，d，J＝6.5Hz)，0.84(3H，d，J＝6.5Hz).

C₂₀H₃₃N₃O₄HRMS calcd for (M + H): 380.2544. measured value: 380.2548.

preparation of part H- - { [2- ({ [ N- ({4- [2- ((2R) -2-amino-4-methylpentanoylaminooxy) ethyl ] -phenyl } methyl) carbamoyl ] methyl } {2- [ bis (carboxymethyl) amino ] ethyl } amino) -ethyl ] (carboxymethyl) amino } acetic acid, trifluoroacetate

Using i-Pr at 22 deg.C₂NEt (21. mu.L, 120. mu. mol) and HBTU (31.4mg, 82.8. mu. mol) treated 2- { bis [2- (bis { [ (tert-butyl) oxycarbonyl ] oxy]Methyl } amino) ethyl]Amino } acetic acid (51.1mg, 82.7. mu. mol), HOBt (12.7mg, 82.9. mu. mol) and a solution of part of the 13G product (34.0mg, 68.9. mu. mol) in anhydrous DMF (2.00 mL). The resulting solution was stirred for 1 hour, then diluted with EtOAc (15mL), followed by 0.1M citric acid (3X 10mL) and NaHCO₃(3X 10mL) and NaCl (10mL) in saturated aqueous solution, followed by MgSO₄Dried, filtered and concentrated in vacuo to a colorless oil which was used without further purification, i.e. in the next deprotection step.

The protected conjugate (theoretically 68.9. mu. mol) was dissolved in dioxane (0.500mL) at 22 ℃ followed by H₂O (2. mu.L) and HCl (2.00 mmol; 0.500mL of 4M dioxane solution). The resulting pale yellow solution was stirred for 18 hours, during which time a large amount of white precipitate formed. After complete deprotection at N₂Volatiles were removed under a stream of gas and the white solid residue was redissolved in H containing 0.1% TFA and 10% MeCN₂O (3.00mL) and then directly purified by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 1%/min gradient, 2-24% MeCN with 0.1% TFA, 10% H₂O, 20 mL/min. The major product peak eluted at 19 min was collected and lyophilized as a white powder (54.4mg, 54.5. mu. mol; 79.2%).

¹H NMR(DMSO-d₆，600MHz)：11.80(1H，brs)，8.92(1H，brt，J＝5.7Hz)，8.28(2H，brs)，7.24(2H，AB，J_AB＝8.4Hz)，7.21(2H，AB，J_AB＝8.4Hz)，4.32(2H，brd，J＝5.6Hz)，4.23(2H，s)，4.00(2H，ABXY，J_AB＝9.6Hz，J_AX＝J_AY＝7.0Hz，J_BX＝J_BY＝6.7Hz)，3.66(1H，brs)，3.50(8H，s)，3.38(4H，brt，J＝5.7Hz)，3.05(4H，brt，J＝5.7Hz)，2.87(2H，ABXY，J_AX＝J_AY＝7.0Hz，J_BX＝J_BY＝6.7Hz)，1.60-1.50(3H，m)，0.90(3H，d，J＝6.1Hz)，0.88(3H，d，J＝6.1Hz).¹³C NMR(DMSO-d₆，151MHz)：172.7，165.5，164.6，158.0(q，J＝31.8Hz)，136.8，136.2，128.8，127.4，116.9(q，J＝299Hz)，75.9，54.3，53.8，52.2，48.9，48.6，42.1，40.0，33.4，23.8，22.2，22.0.C₂₉H₄₆N₆O₁₁HRMS calcd for (M + H): 655.3297. measured value: 655.3291.

example 142- { [2- ({ [ N- ({4- [2- ((2R) -2-amino-4-phenylbutylaminooxy) ethyl]Phenyl } methyl) carbamoyl]Methyl } {2- [ bis (carboxymethyl) amino]Ethyl } amino) ethyl](carboxymethyl) amino } acetic acid, trifluoroacetate salt

Preparation of the moiety A- (2R) -N- {2- [4- (aminomethyl) phenyl ] ethoxy } -2- [ (tert-butoxy) carbonyl-amino ] -4-phenylbutanamide, trifluoroacetate

HOBt (30.0mg, 0.196mmol) and i-Pr were added sequentially at 22 deg.C₂NEt (51. mu.L, 0.293mmol) and HBTU (75.0mg, 0.198mmol) treated a solution of Boc-DHfe-OH (55.0mg, 0.197mmol) in DMF (1.00 mL). After 0.25 h, the solution was treated with part 13F product (55.0mg, 0.163mmol) in one portion. The resulting solution was stirred for 0.5 h, then diluted with EtOAc (25mL) and transferred to a separatory funnel. The EtOAc solution was treated with 0.1M citric acid (3X 30mL) followed by NaHCO₃(3X 30mL) and NaCl (30mL) in saturated aqueous solution, followed by MgSO₄Dried, filtered and concentrated in vacuo to a colorless oil which was used without further purification, i.e. in the next deprotection step.

Crude oximinomate (theoretically 0.163mmol) was dissolved in MeOH (1.00mL) at 22 ℃ and 10% Pd/mL was takenCarbon (17.4mg, 16.3. mu. mol; 10 mol%) was treated in one portion. Subjecting the resulting suspension to 1atm of H₂Bubbling was carried out for 1 hour. With N₂After purging the vessel, the suspension was filtered through 0.45 μm Acrodisk and then concentrated in vacuo. Redissolving the residue in 1: 1MeCN/H₂O (3.00mL) and then directly purified by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 1%/min gradient, 25-51% MeCN, with 0.1% TFA, 10% H₂O, 20 mL/min. The main product peak eluted in 17 minutes was collected and lyophilized as a white powder (25.0mg, 46.2. mu. mol; 28.3%).

¹H NMR(DMSO-d₆，600MHz)：11.14(1H，brs)，8.11(2H，brs)，7.36(2H，AB，J_AB＝8.2Hz)，7.33(2H，AB，J_AB＝8.2Hz)，7.26(2H，dd，J＝7.7，7.4Hz)，7.18-7.16(3H，m)，708(1H，brd，J＝7.4Hz)，3.98(2H，s)，3.97-3.91(2H，m)，3.75(1H，brs)，2.88(2H，brdd，J＝6.6，6.1Hz)，2.63-2.58(1H，m)，2.53-2.47(1H，m)，1.82-1.78(2H，m)，1.38(9H，s).

C₂₄H₃₃N₃O₄HRMS calcd for (M + H): 428.2544. measured value: 428.2542.

preparation of part B-2- { [2- ({ [ N- ({4- [2- ((2R) -2-amino-4-phenylbutylaminooxy) ethyl ] -phenyl } methyl) carbamoyl ] methyl } {2- [ bis (carboxymethyl) amino ] ethyl } amino) -ethyl ] (carboxymethyl) amino } acetic acid, trifluoroacetate salt

Using i-Pr at 22 deg.C₂NEt (13. mu.L, 75. mu. mol) and HBTU (19.3mg, 50.9. mu. mol) treated 2- { bis [2- (bis { [ (tert-butyl) oxycarbonyl ] oxy]Methyl } amino) ethyl]A solution of amino } acetic acid (31.5mg, 51.0. mu. mol), HOBt (7.8mg, 51. mu. mol) and the product of part 14A (23.0mg, 42.5. mu. mol) in anhydrous DMF (2.00 mL). The resulting solution was stirred for 1 hour, then diluted with EtOAc (15mL), followed by 0.1M citrateCitric acid (3X 10mL) and NaHCO₃(3X 10mL) and NaCl (10mL) in saturated aqueous solution, followed by MgSO₄Dried, filtered and concentrated in vacuo to a colorless oil which was used without further purification, i.e. in the next deprotection step.

The protected conjugate (theoretically 42.5. mu. mol) was dissolved in dioxane (0.500mL) at 22 ℃ followed by H₂O (2. mu.L) and HCl (2.00 mmol; 0.500mL of 4M dioxane solution). The resulting pale yellow solution was stirred for 18 hours, during which time a large amount of white precipitate formed. After complete deprotection at N₂Volatiles were removed under a stream of gas and the white solid residue was redissolved in H containing 0.1% TFA and 10% MeCN₂O (3.00mL) and then directly purified by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 1%/min gradient, 7-29% MeCN with 0.1% TFA, 10% H₂O, 20 mL/min. The main product peak eluted at 16 min was collected and lyophilized as a white powder (13.3mg, 12.7. mu. mol; 30.0%).

¹H NMR(DMSO-d₆，600MHz)：11.78(1H，brs)，8.90(1H，brt，J＝5.6Hz)，8.35(2H，brs)，7.30(2H，dd，J＝7.6，7.6Hz)，7.25(2H，AB，J_AB＝7.9Hz)，7.21(2H，AB，J_AB＝7.9Hz)，7.18(2H，d，J＝7.3Hz)，7.21-7.17(1H，m)，4.31(2H，brd，J＝5.2Hz)，4.23(2H，s)，4.03(2H，ABXY，J_AB＝9.7Hz，J_AX＝J_AY＝7.0Hz，J_BX＝J_BY＝6.7Hz)，3.68(1H，brs)，3.49(8H，s)，3.38(4H，brt，J＝5.5Hz)，3.04(4H，brt，J＝5.8Hz)，2.89(2H，ABXY，J_AX＝J_BX＝J_AY＝J_BY＝6.7Hz)，2.59(2H，dd，J＝8.5，8.2Hz)，2.03-1.93(2H，m).¹³C NMR(DMSO-d₆，151MHz)：172.7，165.2，164.6，157.9(q，J＝31.8Hz)，140.2，136.8，136.2，128.8，128.5，128.0，127.4，126.2，116.9(q，J＝299Hz)，76.0，54.3，53.8，52.2，50.3，48.6，42.1，33.4，32.7，30.4.

C₃₃H₄₆N₆O₁₁HRMS calcd for (M + H): 703.3297. measured value: 703.3289.

example 15

2- { [2- ({ [ N- ({4- [2- ((2R) -2-amino-3- (2-naphthyl) propionylaminoxy) ethyl ] phenyl } methyl) carbamoyl ] methyl } {2- [ bis (carboxymethyl) amino ] ethyl } amino) ethyl ] (carboxymethyl) amino } acetic acid, trifluoroacetic acid salt

Preparation of the part A- (2R) -N- {2- [4- (aminomethyl) phenyl ] ethoxy } -2- [ (tert-butoxy) carbonyl-amino ] -3- (2-naphthyl) propionamide, trifluoroacetate

HOBt (30.0mg, 0.196mmol) and i-Pr were added sequentially at 22 deg.C₂NEt (51. mu.L, 0.293mmol) and HBTU (75.0mg, 0.198mmol) treated a solution of Boc-DNal-OH (62.0mg, 0.197mmol) in DMF (1.00 mL). After 0.25 h, the solution was treated with part 13F product (55.0mg, 0.163mmol) in one portion. The resulting solution was stirred for 0.5 h, then diluted with EtOAc (25mL) and transferred to a separatory funnel. The EtOAc solution was treated with 0.1M citric acid (3X 30mL) followed by NaHCO₃(3X 30mL) and NaCl (30mL) in saturated aqueous solution, followed by MgSO₄Dried, filtered and concentrated in vacuo to a colorless oil which was used without further purification, i.e. in the next deprotection step.

The crude oximatoxidate (0.163 mmol theoretically) was dissolved in MeOH (1.00mL) at 22 deg.C and treated once with 10% Pd on carbon (17.4mg, 16.3. mu. mol; 10 mol%). Subjecting the resulting suspension to 1atm of H₂Bubbling and maintaining for 2 hours; after 1 hour, an additional 0.2 equivalent of Pd was added to ensure complete conversion. With N₂After purging the vessel, the suspension was treated with 0.45 μm Acrodisk filtered and then concentrated in vacuo. Redissolving the residue in 1: 1MeCN/H₂O (3.00mL) and then directly purified by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 1%/min gradient, 25-51% MeCN, with 0.1% TFA, 10% H₂O, 20 mL/min. The main product peak eluting at 18 min was collected and lyophilized as a white powder (60.8mg, 0.105 mmol; 64.5%).

¹H NMR(DMSO-d₆，600MHz)：11.14(1H，brs)，8.11(2H，brs)，7.85(1H，d，J＝7.3Hz)，7.82(1H，d，J＝8.4Hz)，7.80(1H，d，J＝7.6Hz)，7.71(1H，s)，7.48-7.44(2H，m)，7.41(1H，d，J＝8.1Hz)，7.33(2H，AB，J_AB＝7.8Hz)，7.21(2H，AB，J_AB＝7.3Hz)，7.14(1H，brd，J＝7.8Hz)，4.13-4.09(1H，m)，3.98(2H，s)，3.86-3.82(1H，m)，3.76-3.72(1H，m)，3.40(1H，ABXY，J_AB＝13.3Hz，J_AX＝J_AY＝6.5Hz)，2.97(1H，ABXY，J_AB＝13.5Hz，J_BX＝J_BY＝8.7Hz)，2.71(2H，brs)，1.29(9H，s).

C₂₇H₃₃N₃O₄HRMS calcd for (M + H): 464.2544. measured value: 464.2538. part B-2- { [2- ({ [ N- ({4- [2- ((2R) -2-amino-3- (2-naphthyl) propionylaminoxy) -ethyl]Phenyl } methyl) carbamoyl]Methyl } {2- [ bis (carboxymethyl) amino]Ethyl } amino) -ethyl]Preparation of (carboxymethyl) amino } acetic acid, trifluoroacetate salt

Using i-Pr at 22 deg.C₂NEt (19. mu.L, 110. mu. mol) and HBTU (28.4mg, 74.9. mu. mol) treated 2- { bis [2- (bis { [ (tert-butyl) oxycarbonyl ] oxy]Methyl } amino) ethyl]Amino } acetic acid (46.2mg, 74.8. mu. mol), HOBt (11.5mg, 75.1. mu. mol) and a solution of part 15A product (36.0mg, 62.3. mu. mol) in anhydrous DMF (2.00 mL). The resulting solution was stirred for 1 hour, then diluted with EtOAc (15mL) followed by 0.1M citric acid (3X 10mL) and NaHCO₃(3X 10mL) and NaCl (10mL) in saturated aqueous solution, followed by MgSO₄Dried, filtered and concentrated in vacuo to a colorless oil which was used without further purification, i.e. in the next deprotection step.

The protected conjugate (theoretically 62.3. mu. mol) was dissolved in dioxane (0.500mL) at 22 ℃ followed by H₂O (2. mu.L) and HCl (2.00 mmol; 0.500mL of 4M dioxane solution). The resulting pale yellow solution was stirred for 18 hours, during which time a large amount of white precipitate formed. After complete deprotection at N₂Volatiles were removed under a stream of gas and the white solid residue was redissolved in H containing 0.1% TFA and 10% MeCN₂O (3.00mL) and then directly purified by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 1%/min gradient, 12-32% MeCN with 0.1% TFA, 10% H₂O, 20 mL/min. The major product peak eluted in 20 min was collected and lyophilized as a white powder (36.5mg, 33.8. mu. mol; 54.2%).

¹H NMR(DMSO-d₆，600MHz)：11.55(1H，brs)，8.90(1H，brt，J＝5.7Hz)，8.47(2H，brs)，7.90-7.87(2H，m)，7.84-7.81(1H，m)，7.72(1H，s)，7.50-7.46(2H，m)，7.38(1H，brd，J＝8.3Hz)，7.14(2H，AB，J_AB＝8.0Hz)，7.00(2H，AB，J_AB＝8.0Hz)，4.29(2H，brd，J＝5.5Hz)，4.23(2H，s)，3.90(1H，brs)，3.79(1H，ABXY，J_AB＝10.0Hz，J_AX＝J_AY＝7.0Hz)，3.64(1H，ABXY，J_AB＝10.0Hz，J_BX＝J_BY＝6.8Hz)，3.50(8H，s)，3.38(4H，brt，J＝5.6Hz)，3.22(1H，ABX，J_AB＝13.2Hz，J_AX＝5.6Hz)，3.16(1H，ABX，J_AB＝13.2Hz，J_BX＝8.6Hz)，3.05(4H，brt，J＝5.7Hz)，2.56(2H，ABXY，J_AX＝J_BX＝J_AY＝J_BY＝6.9Hz).¹³C NMR(DMSO-d₆，151MHz)：172.7，164.6，164.4，158.0(q，J＝32.9Hz)，136.6，136.1，132.9，132.3，132.2，128.7，128.1，127.5，127.4，127.4，127.3，126.2，125.9，116.7(q，J＝297Hz)，75.7，54.3，53.8，52.2，51.5，48.6，42.1，37.0，33.1.

C₃₆H₄₆N₆O₁₁HRMS calcd for (M + H): 739.3297. measured value: 739.32.

example 16

2- {7- [ (N- { [4- ({ [ (1R) -1- (N-methoxycarbamoyl) -3-phenylpropyl ] amino } methyl) phenyl ] methyl } carbamoyl) methyl ] -1, 4, 7, 10-tetraaza-4, 10-bis (carboxymethyl) cyclododecyl } acetic acid, trifluoroacetic acid salt

Preparation of part A- (2R) -2-amino-N-methoxy-4-phenylbutanamide

A solution of Boc-DHfe-OH (1.40g, 5.00mmol) and HOBt (0.919g, 6.00mmol) in anhydrous DMF (25.0mL) was treated with i-Pr at 22 deg.C₂NEt (2.09mL, 12.0mmol) and HBTU (2.28g, 6.00mmol) were treated and then stirred for 0.25 h. Applying the obtained solution to MeONH₂HCl (0.501g, 6.00mmol) was treated in one portion for 0.5 h, then partitioned between EtOAc and 0.1M HCl (50mL each) and transferred to a separatory funnel. The layers were separated, the aqueous layer was washed with EtOAc (2X 50mL), the combined EtOAc washes were washed with 0.1M HCl, 0.1M NaOH, and saturated aqueous NaCl solution (3X 50mL each), followed by MgSO₄Dried, filtered and concentrated in vacuo to a white solid (R in 1: 1 hexane/EtOAc)_f＝0.2)。

The crude methyl hydroxamate was redissolved in dioxane (75.0mL) at 22 ℃ followed by Et followed by₃SiH (799. mu.L, 5.00mmol) and HCl (0.100 mol; 25.0mL of a 4.0M dioxane solution). The resulting solution was stirred for 12.5 hours, then neutralized with 1.0M NaOH (100mL), diluted with EtOAc (100mL) and transferred to a separatory funnel. The layers were separated, the aqueous layer was washed thoroughly with EtOAc (6X 50mL), and the combined EtOAc layers were MgSO₄Drying, filtration and concentration in vacuo to a colourless oil which is purified by chromatography on silica (40X 210mm) using 9: 1CH₂Cl₂MeOH (containing 1.0% Et)₃N) (in 9: 1CH₂Cl₂R in MeOH_f0.1). The major product eluted between 300 and 420mL was collected and concentrated to give an amorphous white powder (0.659g, 3.16 mmol; 63.3%).

¹HNMR(DMSO-d₆，300MHz)：7.30-7.14(5H，m)，3.58(3H，s)，3.02(1H，dd，J＝7.5，6.0Hz)，2.69-2.50(2H，m)，1.80(1H，dddd，J＝13.2，10.1，6.2，6.2Hz)，1.64(1H，dddd，J＝13.4，10.0，7.8，5.8Hz).¹³C NMR(DMSO-d₆，75MHz)：171.6，141.8，128.2，128.2，125.7，63.0，52.4，36.8，31.4.

C₁₁H₁₆N₂O₂HRMS calcd for (M + H): 209.1285. measured value: 209.1288. part of B-N- [ (4-formylphenyl) methyl]Preparation of prop-2-enyloxycarboxamides

Portion 1B product (2.21g, 10.0mmol) was treated in one portion with Dess-Martin periodinane (5.09g, 12.0mmol) in anhydrous CH at 22 deg.C with Dess-Martin oxidant (5.09g, 12.0mmol)₂Cl₂(50.0 mL). Within 1 minute, rapid dissolution of the oxidant was seen; resulting in a slight reflux of the reaction mixture. After 5min complete oxidation was seen with Et₂The resulting suspension was diluted with O (50 mL). The solid was removed by filtration through a pad of Celite and Et₂Thoroughly washing a filter cake; the final filtrate volume was 500 mL. The combined filtrates were concentrated in vacuo to a pale yellow oil, which was then purified by silica chromatography (40X 265mm) using a step gradient of 3: 2 → 2: 3 hexanealkane/EtOAc (R in 1: 1 hexane/EtOAc)_f0.5) to give the pure product as a colorless oil (2.15g, 9.81 mmol; 98.1%).

¹H NMR(CDCl₃，600MHz)：10.01(1H，s)，7.86(2H，AB，J_AB＝8.1Hz)，7.47(2H，AB，J_AB＝7.9Hz)，5.59(1H，ddt，J＝16.9，10.7，5.6Hz)5.33(1H，d，J＝17.0Hz)，5.24(1H，d，J＝10.4Hz)，5.22(1H，brs)，4.62(2H，dt，J＝5.7，1.5Hz)，4.47(2H，d，J＝6.1Hz).¹³C NMR(CDCl₃，151MHz)：191.8，156.3，145.5，135.7，132.6，130.1，127.8，117.9，65.9，44.7.

C₁₂H₁₃NO₃HRMS calcd for (M + H): 220.0968. measured value: 220.0967.

preparation of the hydrochloride salt of the moiety C- (2R) -N-methoxy-4-phenyl-2- [ ({4- [ (prop-2-enyloxycarbonylamino) methyl ] phenyl } methyl) amino ] butanamide

A solution of the fractions 16A (0.177g, 0.850mmol) and 16B (0.186g, 0.850mmol) in dry MeOH (8.50mL) was cooled to 0 deg.C, then treated with NaCNBH₃(0.160g, 2.55mmol) was treated in one portion. After 1 hour, glacial AcOH (0.048mL, 0.850mmol) was added to the reaction mixture; a sharp increase in conversion was seen. The AcOH treatment was repeated 2 more times over the next 2 hours, each time with 1 hour intervals. After 4 hours total reaction time, the resulting solution was partitioned between EtOAc and saturated NaHCO₃The aqueous solutions (50mL each) were transferred to a separatory funnel. The layers were separated, the aqueous layer was washed with EtOAc (2X 50mL), and the combined EtOAc layers were MgSO₄Dried, filtered and concentrated in vacuo to a pale yellow oil. Purification by 98: 2 EtOAc/MeOH silica chromatography (40X 260mm) afforded the pure product as a colorless oil. The oil was then redissolved in anhydrous Et at 22 deg.C₂O (100mL) in HCl (4.00 mmol; 1.00mL of 4.0M dioxygenHexacyclic ring solution). The resulting suspension was filtered through a medium porosity sintered glass funnel and the collected solid was treated with Et₂O was washed thoroughly and then dried in vacuo to an amorphous white powder (0.253g, 0.564 mmol; 66.3%).

¹H NMR(DMSO-d₆，600MHz)：12.20(1H，s)，10.16(1H，brs)，9.53(1H，brs)，7.83(1H，brt，J＝6.1Hz)，7.51(2H，AB，J_AB＝8.1Hz)，7.31-7.27(4H，m)，7.22-7.18(3H，m)，5.91(1H，ddt，J＝17.1，10.6，5.4Hz)，5.28(1H，dq，J＝17.2，1.7Hz)，5.18(1H，dq，J＝10.5，1.5Hz)，4.49(2H，dt，J＝5.4，1.5Hz)，4.20(2H，d，J＝6.2Hz)，4.13-3.99(2H，m)，3.68(3H，s)，3.47(1H，brs)，2.63(2H，ABXY，J_AB＝13.6Hz，J_AX＝J_BX＝10.9Hz，J_AY＝J_BY＝5.9Hz)2.24-2.16(1H，m)，2.10(1H，dddd，J＝13.5，10.8，8.6，6.3Hz).¹³C NMR(DMSO-d₆，151MHz)：163.5，156.2，140.8，140.2，133.7，130.3，129.7，128.4，128.1，127.0，126.2，116.9，64.4，63.6，56.7，48.6，43.4，31.3，30.4.

Preparation of the partial D-2- {7- [ (N- { [4- ({ [ (1R) -1- (N-methoxycarbamoyl) -3-phenylpropyl ] amino } methyl) phenyl ] methyl } carbamoyl) methyl ] -1, 4, 7, 10-tetraaza-4, 10-bis (carboxymethyl) cyclododecyl } acetic acid, trifluoroacetate

Part 16C product (112mg, 0.250mmol) was dissolved in 2: 1MeCN/H at 22 deg.C₂O (5.00mL) was added 14.2mg of TPPTS (25.0. mu. mol; 10 mol%) followed by Et₂NH (129. mu.L, 1.25mmol) and 2.8mg Pd (OAc)₂(12.5. mu. mol; 5 mol%). Complete deprotection was seen within 0.25 h. The resulting amber solution was then freeze dried to remove all volatile components.

The solid thus obtained is brought to 22 DEG CRedissolved in DMF and then treated with HOBt (45.9mg, 0.300mmol), 2- (1, 4, 7, 10-tetraaza-4, 7, 10-tris { [ (tert-butyl) oxy) carbonyl]Methyl } -cyclododecyl) acetic acid (172mg, 0.300mmol), i-Pr₂NEt (105. mu.L, 0.600mmol) and HBTU (114mg, 0.300 mmol). After 0.25 hours, complete acylation was seen; only traces of regioisomer and dimer products were formed. The resulting solution was partitioned between EtOAc and H₂Between O (50mL each), transfer to separatory funnel. The layers were separated and the aqueous layer was washed with EtOAc (2X 50 mL). The EtOAc solution was further washed with 0.1M NaOH (3X 50mL) and saturated aqueous NaCl solution (3X 50mL each), then MgSO₄Dried, filtered and concentrated in vacuo to a pale yellow oil which was used for the next deprotection step without further purification.

The protected conjugate (theoretically 0.250mmol) was dissolved in dioxane (2.50mL) at 22 ℃ followed by H₂O (23. mu.L) and HCl (10.0 mmol; 2.50mL of 4M dioxane solution). The resulting pale yellow solution was stirred for 17 hours, during which time a large amount of white precipitate formed. After complete deprotection at N₂Volatiles were removed under a stream of gas and the white solid residue was redissolved in H containing 0.1% TFA₂O (8.00mL), then partially purified by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 2%/min gradient, 0-60% MeCN, 0.1% TFA, 10% H₂O, 20 mL/min. The main product peak eluted at 22 minutes was collected and lyophilized as a white powder. The final purification was performed using the same column and method. The main product peak was collected and lyophilized as a white powder (99.0mg, 93.8. mu. mol; 37.5%).

¹H NMR (methanol-d)₄，600MHz)：7.44(2H，AB，J_AB＝8.3Hz)，7.41(2H，AB，J_AB＝8.3Hz)，7.31-7.27(2H，m)，7.20(3H，m)，4.40(2H，s)，4.16(2H，ABq，J_AB＝13.0Hz)，3.84-3.74(9H，brm)，3.78(3H，s)，3.35(8H，brs)，3.25(8H，brs)，2.72-2.62(2H，m)，2.24-2.13(2H，m).¹³CNMR (methanol-d)₄，151MHz)：165.7，163.0(q，J_CF＝34.6Hz)，142.0，141.1，131.7，130.8，129.9，129.8，129.4，127.8，118.3(q，J_CF＝293Hz)，65.0，59.1，56.2，55.6(br)，55.1(br)，51.5(br)，51.1，51.0(br)44.0，33.5，32.2.

C₃₅H₅₁N₇O₉HRMS calcd for (M + H): 714.3821. measured value: 714.3819.

example 17

2- (7- { [ N- ({4- [ ({ (1R) -3-phenyl-1- [ N- (phenylmethoxy) carbamoyl ] propyl } amino) methyl ] phenyl } methyl) carbamoyl ] methyl } -1, 4, 7, 10-tetraaza-4, 10-bis (carboxymethyl) cyclododecyl) acetic acid, trifluoroacetic acid salt

Preparation of moiety A- (2R) -2-amino-4-phenyl-N- (phenylmethoxy) butanamide

A solution of Boc-DHfe-OH (1.40g, 5.00mmol) and HOBt (0.919g, 6.00mmol) in anhydrous DMF (25.0mL) was treated with i-Pr at 22 deg.C₂NEt (2.09mL, 12.0mmol) and HBTU (2.28g, 6.00mmol) were treated and then stirred for 0.25 h. Subjecting the obtained solution to BnONH₂HCl (0.958g, 6.00mmol) was treated in one portion for 0.5 h, then partitioned between EtOAc and 0.1M HCl (50mL each) and transferred to a separatory funnel. The layers were separated, the aqueous layer was washed with EtOAc (2X 50mL), the combined EtOAc washes were washed with 0.1M HCl, 0.1M NaOH, and saturated aqueous NaCl solution (3X 50mL each), followed by MgSO₄Dried, filtered and concentrated in vacuo to a white solid (R in 1: 1 hexane/EtOAc)_f＝0.5)。

The crude benzyl hydroxamate was redissolved in dioxane (75.0mL) at 22 ℃ followed by Et followed by₃SiH (799. mu.L, 5.00mmol) and HCl (0.100 mol; 25.0mL of a 4.0M dioxane solution). The resulting solution was stirred for 12.5 hours, then neutralized with 1.0M NaOH (100mL), diluted with EtOAc (100mL) and transferred to a separatory funnel. The layers were separated, the aqueous layer was washed thoroughly with EtOAc (3X 50mL), and the combined EtOAc layers were MgSO₄Drying, filtration and concentration in vacuo to a colourless oil which is purified by chromatography on silica (50X 170mm) using 9: 1CH₂Cl₂MeOH (containing 1.0% Et)₃N) (in 9: 1CH₂Cl₂R in MeOH_f0.3). The major product eluted between 320 and 480mL was collected and concentrated to give an amorphous white powder (1.19g, 4.18 mmol; 83.7%).

¹H NMR(DMSO-d₆，600MHz)：7.41-7.32(5H，m)，7.28-7.25(2H，m)，7.17-7.15(3H，m)，4.81(2H，s)，3.02(1H，dd，J＝7.3，6.1Hz)，2.55(2H，ABXY，J_AB＝13.7Hz，J_AX＝J_BX＝10.3Hz，J_AY＝5.6Hz，J_BY＝6.2Hz)，1.78(1H，ddt，J＝13.2，10.2，6.1Hz)，1.63(1H，dddd，J＝13.1，10.2，7.5，5.6Hz).¹³C NMR(DMSO-d₆，151MHz)：171.9，141.8，136.1，128.7，128.2，128.1，125.6，76.6，52.4，36.9，31.4.

C₁₇H₂₀N₂O₂HRMS calcd for (M + H): 285.1598. measured value: 285.1596. part B- (2R) -4-phenyl-N- (phenylmethoxy) -2- [ ({4- [ (prop-2-enyloxycarbonylamino) methyl)]Phenyl } methyl) amino]Preparation of butanamide, hydrochloride

A solution of part 17A (0.270g, 0.950mmol) and 16B (0.208g, 0.950mmol) products in dry MeOH (8.50mL) was cooled to 0 deg.C, then treated with NaCNBH₃(0.179g, 2.85mmol) was treated in one portion. After 1 hour, glacial AcOH (0.054mL, 0.950mmol) was added to the reaction mixture; a sharp increase in conversion was seen. AcO was added over the next 2 hoursThe H treatment process was repeated 2 more times, each at 1 hour intervals. After 4 hours total reaction time, the resulting solution was partitioned between EtOAc and saturated NaHCO₃The aqueous solutions (50mL each) were transferred to a separatory funnel. The layers were separated, the aqueous layer was washed with EtOAc (2X 50mL), and the combined EtOAc layers were MgSO₄Dried, filtered and concentrated in vacuo to a pale yellow oil. Purification by 98: 2 EtOAc/MeOH silica chromatography (40X 250mm) afforded the pure product as a colorless oil. The oil was then redissolved in anhydrous Et at 22 deg.C₂O (100mL) was treated with HCl (4.00 mmol; 1.00mL of 4.0M dioxane solution). The resulting suspension was filtered through a medium porosity sintered glass funnel and the collected solid was treated with Et₂The O was thoroughly washed and then dried in vacuo to an amorphous white powder (0.330g, 0.629 mmol; 66.2%).

¹H NMR(DMSO-d₆，600MHz)：12.11(1H，s)，10.14(1H，brs)，9.52(1H，brs)，7.83(1H，brt，J＝6.1Hz)，7.49-7.44(4H，m)，7.40-7.37(2H，m)，7.36-7.33(1H，m)，7.30-7.27(4H，m)，7.21-7.18(1H，m)，7.14-7.12(2H，m)，5.92(1H，ddt，J＝17.2，10.6，5.4Hz)，5.29(1H，dq，J＝17.2，1.7Hz)，5.18(1H，dq，J＝10.5，1.5Hz)，4.94(2H，s)，4.49(2H，dt，J＝5.4，1.5Hz)，4.20(2H，d，J＝6.2Hz)，4.02-3.90(2H，m)，3.42(1H，brs)，2.50(2H，ABXY，J_AB＝13.8Hz，J_AX＝J_BX＝10.9Hz，J_AY＝J_BY＝5.8Hz)，2.17-2.11(1H，m)，2.05(1H，dddd，J＝13.4，11.1，8.7，6.0Hz).¹³C NMR(DMSO-d₆，151MHz)：163.7，156.2，140.8，140.2，135.6，133.7，130.3，129.6，128.8，128.4(2)，128.3，128.1，127.0，126.1，116.9，77.1，64.4，56.7，48.5，43.4，31.3，30.3.

Preparation of the moiety C-2- (7- { [ N- ({4- [ ({ (1R) -3-phenyl-1- [ -N- (phenylmethoxy) carbamoyl ] propyl } amino) methyl ] phenyl } methyl) carbamoyl ] methyl } -1, 4, 7, 10-tetraaza-4, 10-bis (carboxymethyl) cyclododecyl) acetic acid, trifluoroacetate

Part 17B product (131mg, 0.250mmol) was dissolved in 2: 1MeCN/H at 22 deg.C₂O (5.00mL) was added 14.2mg of TPPTS (25.0. mu. mol; 10 mol%) followed by Et₂NH (129. mu.L, 1.25mmol) and 2.8mg Pd (OAc)₂(12.5. mu. mol; 5 mol%). Complete deprotection was seen within 0.25 h. The resulting amber solution was then freeze dried to remove all volatile components.

The solid thus obtained was redissolved in DMF at 22 ℃ followed by HOBt (45.9mg, 0.300mmol), 2- (1, 4, 7, 10-tetraaza-4, 7, 10-tris { [ (tert-butyl) oxycarbonyl]Methyl } -cyclododecyl) acetic acid (172mg, 0.300mmol), i-Pr₂NEt (105. mu.L, 0.600mmol) and HBTU (114mg, 0.300 mmol). After 0.25 hours, complete acylation was seen; only traces of regioisomer and dimer products were formed. The resulting solution was partitioned between EtOAc and H₂Between O (50mL each), transfer to separatory funnel. The layers were separated and the aqueous layer was washed with EtOAc (2X 50 mL). The EtOAc solution was further washed with 0.1M NaOH (3X 50mL) and saturated aqueous NaCl solution (3X 50mL each), then MgSO₄Dried, filtered and concentrated in vacuo to a pale yellow oil which was used for the next deprotection step without further purification.

The protected conjugate (theoretically 0.250mmol) was dissolved in dioxane (2.50mL) at 22 ℃ followed by H₂O (23. mu.L) and HCl (10.0 mmol; 2.50mL of 4M dioxane solution). The resulting pale yellow solution was stirred for 17 hours, during which time a large amount of white precipitate formed. After complete deprotection at N₂Volatiles were removed under a stream of gas and the white solid residue was redissolved in H containing 0.1% TFA₂O (8.00mL), then partially purified by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 2%/min gradient, 0-60% MeCN, 0.1% TFA, 10% H₂O, 20 mL/min. Main part eluted in 21 minutesThe product peak was collected and lyophilized as a white powder. The final purification was performed using the same column and method. The main product peak was collected and lyophilized as a white powder (0.110g, 97.3. mu. mol; 38.9%).

¹H NMR (methanol-d)₄，600MHz)：7.50-7.48(2H，m)，7.42-7.35(6H，m)，7.34-7.30(1H，m)，7.28-7.24(2H，m)，7.21-7.17(1H，m)，7.12-7.09(2H，m)，4.98(2H，ABq，J_AB＝11.6Hz)，4.20(2H，ABq，J_AB＝15.4Hz)，3.99(2H，ABq，J_AB＝12.9Hz)，3.84(7H，brs)，3.68(1H，dd，J＝8.5，5.1Hz)，3.33(8H，brs)，3.28(8H，brs)，2.63(2H，ABXY，J_AB＝13.8Hz，J_AX＝J_BX＝10.0Hz，J_AY＝J_BY＝7.1Hz)2.17-2.03(2H，m).¹³C NMR (methanol-d)₄，151MHz)：165.6，162.93(q，J_CF＝34.7Hz)，141.9，141.1，136.9，131.7，130.8，130.5，130.1，129.8，129.8，129.7，129.4，127.7，118.3(q，J_CF＝293Hz)，79.3，59.3，56.1，55.3(br)，55.0(br)，51.4(br)，51.1，44.0，33.5，32.1.

C₄₁H₅₅N₇O₉HRMS calcd for (M + H): 790.4134. measured value: 790.4129.

example 18

2- (4- { [ N- ({4- [ (2R) -2-amino-2- (N-methoxycarbamoyl) ethyl ] phenyl } methyl) carbamoyl ] methyl } -1, 4, 7, 10-tetraaza-7, 10-bis (carboxymethyl) cyclododecyl) acetic acid, trifluoroacetic acid salt

Preparation of part of A- (2R) -3- [4- (aminomethyl) phenyl ] -2- [ (tert-butoxy) carbonyl-amino ] propionic acid, trifluoroacetate salt

Reacting (2R) -2- [ (tert-butoxy) carbonylamino]-3- (4-cyanophenyl) propionic acid (0.581g, 2.00mmol) dissolved in 28% aqueous NH₃In a solution of/MeOH (1: 2 v/v; 24mL) then in N₂Carefully treated under an atmosphere with 0.6g Raney Ni 2800. Using Parr apparatus, with H₂A250 mL reactor headspace was bubbled repeatedly, then pressurized to 50psi, and shaken at 22 ℃ for 4 hours. After complete conversion, the headspace is evacuated and then treated with N₂Bubbling was repeated. The resulting suspension was filtered through a pad of Celite and the filter cake (added to the reactor) was washed with a small 1: 1MeCN/H portion₂Thoroughly washing O; 100mL final wash volume. The filtrate was neutralized with glacial AcOH and then with H₂Diluted with O (100mL) and partially concentrated in vacuo; 175mL final volume. The solution was freeze-dried to give the crude product as a white solid, suitable for the next coupling step. If desired, the crude material can be purified by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 1%/min gradient, 0-40% MeCN, 0.1% TFA, 10% H₂O, 20 mL/min. The main product peak eluting at 24 min was collected and lyophilized as a white microcrystalline solid. All spectral data for this material are consistent with published reports.

Preparation of part B-2- (4- { [ N- ({4- [ (2R) -2-amino-2- (N-methoxycarbamoyl) ethyl ] phenyl) methyl) carbamoyl ] methyl } -1, 4, 7, 10-tetraaza-7, 10-bis (carboxymethyl) cyclododecyl) acetic acid, trifluoroacetate

2- (1, 4, 7, 10-tetraaza-4, 7, 10-tris { [ (tert-butyl) oxy-carbonyl) is treated with HOBt (18.4mg, 0.120mmol) and EDC (22.9mg, 0.120mmol) at 22 ℃ in succession]Methyl } -cyclododecyl) acetic acid (68.7mg, 0.120mmol) in dry DMF (1.00 mL). After 0.5 h, the solution was treated with the product of part 18A (40.8mg, 0.100mmol)The resulting mixture was stirred for 0.5 hour. The intermediate conjugate thus obtained was activated once more with EDC (22.9mg, 0.120mmol) and then stirred for 0.5 h, followed by MeONH₂HCl (10.0mg, 0.120mmol) final treatment. After 1h, the resulting mixture was diluted with EtOAc (100mL) and then transferred to a separatory funnel, washed with 0.1M NaOH followed by saturated aqueous NaCl solutions (3X 25mL each). The EtOAc solution is extracted with MgSO₄Dried, filtered and concentrated in vacuo to a colorless oil which was used for the next deprotection step without further purification.

The protected conjugate (theoretically 0.120mmol) was dissolved in dioxane (1.00mL) at 22 ℃ followed by H₂O (9. mu.L) and HCl (4.00 mmol; 1.00mL of 4M dioxane solution). The resulting pale yellow solution was stirred for 14 hours, during which time a large amount of white precipitate formed. After complete deprotection at N₂Volatiles were removed under a stream of gas and the white solid residue was redissolved in H containing 0.1% TFA₂O (8.00mL) and then directly purified by HPLC on a Phenomenex Luna C18 column (21.2X250mm) with a gradient of 1%/min, 0-30% MeCN, 0.1% TFA, 10% H₂O, 20 mL/min. The main product peak eluted at 11.5 min was collected and lyophilized as a white powder (12.8mg, 13.4. mu. mol; 13.4%).

¹H NMR (methanol-d)₄，600MHz)：7.33(2H，AB，J_AB＝8.0Hz)，7.22(2H，AB，J_AB＝8.1Hz)，4.36(2H，brs)，3.84(5H，brs)，3.75-3.66(4H，brm)，3.57(3H，s)，3.37(8H，brs)，3.31(8H，brs)，3.14-3.06(2H，m).

C₂₇H₄₃N₇O₉HRMS calcd for (M + H): 610.3195. measured value: 610.3199.

example 19

2- [7- ({ N- [ (4- { (2R) -2-amino-2- [ N- (phenylmethoxy) carbamoyl ] ethyl } phenyl) methyl ] carbamoyl } methyl) -1, 4, 7, 10-tetraaza-4, 10-bis (carboxymethyl) cyclododecyl ] acetic acid, trifluoroacetic acid salt

2- (1, 4, 7, 10-tetraaza-4, 7, 10-tris { [ (tert-butyl) oxy-carbonyl) is treated with HOBt (18.4mg, 0.120mmol) and EDC (22.9mg, 0.120mmol) at 22 ℃ in succession]A solution of methyl } -cyclododecyl) acetic acid (68.7mg, 0.120mmol) in anhydrous DMF (1.00 mL). After 0.5 h, the solution was treated with part 18A product (40.8mg, 0.100mmol) and the resulting mixture was stirred for 0.5 h. The intermediate conjugate thus obtained was activated once more with EDC (22.9mg, 0.120mmol) and then stirred for 0.5 h, followed by BnONH₂HCl (19.2mg, 0.120mmol) final treatment. After 1h, the resulting mixture was diluted with EtOAc (100mL) and then transferred to a separatory funnel, washed with 0.1M NaOH followed by saturated aqueous NaCl solutions (3X 25mL each). The EtOAc solution is extracted with MgSO₄Dried, filtered and concentrated in vacuo to a colorless oil which was used for the next deprotection step without further purification.

The protected conjugate (theoretically 0.120mmol) was dissolved in dioxane (1.00mL) at 22 ℃ followed by H₂O (9. mu.L) and HCl (4.00 mmol; 1.00mL of 4M dioxane solution). The resulting pale yellow solution was stirred for 14 hours, during which time a large amount of white precipitate formed. After complete deprotection at N₂Volatiles were removed under a stream of gas and the white solid residue was redissolved in H containing 0.1% TFA₂O (8.00mL), then partially purified by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 1%/min gradient, 0-40% MeCN, 0.1% TFA, 10% H₂O, 20 mL/min. The main product peak eluted at 21 minutes was collected and lyophilized as a white powder. Final purification was performed on the same column using a 1%/min gradient, 0-50% MeCN, with 0.1% HCO₂H，10％ H₂O, 20 mL/min. The major product peak eluted at 14 min was collected and lyophilized as a white powder (8.2mg, 10.0. mu. mol; 10.0%).

¹H NMR (methanol-d)₄，600MHz)：7.39(2H，AB，J_AB＝7.7Hz)，7.37-7.28(5H，m)，7.19(2H，AB，J_AB＝8.0Hz)，4.70(2H，ABq，J_AB＝11.0Hz)，4.41(2H，ABq，J_AB＝14.8Hz)，3.84(1H，brt，J＝6.8Hz)，3.66-3.36(16H，m)，3.11-2.91(11H，m).

C₃₃H₄₇N₇O₉HRMS calcd for (M + H): 686.3508. measured value: 686.3518.

example 20

2- { [2- ({ [ N- ({4- [ ((2R) -2-amino-4-methylpentanoylaminooxy) methyl ] phenyl } methyl) carbamoyl ] methyl } {2- [ bis (carboxymethyl) amino ] ethyl } amino) ethyl ] (carboxymethyl) amino } acetic acid, trifluoroacetic acid salt

Preparation of a partial A-N- ({4- [ (1, 3-dioxoisoindolin-2-yloxy) methyl ] phenyl } methyl) prop-2-enyloxycarboxamide

N-Hydroxyphthalimide (3.32g, 20.3mmol), part 1B product (3.00g, 13.6mmol) and PPh₃A solution of (5.33g, 20.3mmol) in dry THF (100mL) was cooled to 0 deg.C while under N₂Stirring the mixture. ADDP (5.13g, 20.3mmol) was added in one portion and the resulting yellow solution was warmed to ambient temperature. The solution was stirred for 23 hours and then heated to 50 ℃ for 5 hours. After cooling to 22 ℃ THF was removed in vacuo and the residue was partitioned in Et₂O and saturated NaHCO₃Aqueous solution (500 mL each). Adding Et₂The O layer was treated with additional NaHCO₃Wash with solution (2X 500mL)Then with Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product as a yellow solid (7.3g) which was used for the next deprotection step without further purification. LRMS: 389.2(100, M + Na), 367.2(100), 323.2(25).

Preparation of part B-N- ({4- [ (aminooxy) methyl ] phenyl } methyl) prop-2-enyloxy-carboxamide

A portion of the 20A product (1g) was dissolved in MeOH (40.0mL) at 22 deg.C and hydrazine hydrate (105mg, 3.3mmol) was added in one portion. The mixture was heated to reflux for 0.5 hour, then cooled to 0 ℃ with an ice water bath for 2 hours. The white solid precipitate was removed by filtration through a sintered glass funnel, and the filtrate was concentrated to give a pale yellow solid crude product (794mg) having a purity suitable for the next coupling reaction.

¹H NMR(DMSO-d₆，600MHz)：8.1(1H，brs)，7.24(4H，ABq，J_AB＝8.0Hz)，6.00(2H，brs)，5.91(1H，ddt，J＝17.4，10.2，5.4Hz)，5.28(1H，d，J＝17.4Hz)，5.17(1H，d，J＝10.2Hz)，4.53(2H，s)，4.49(2H，dt，J＝5.3，1.5Hz)，4.18(2H，d，6.2Hz).

C₁₂H₁₆N₂O₃HRMS calcd for (M + H): 237.1234. measured value: 237.1238.

preparation of the moiety C- (2R) -2- [ (tert-butoxy) carbonylamino ] -4-methyl-N- ({4- [ (prop-2-enyloxycarbonylamino) methyl ] phenyl } methoxy) pentanamide

A portion of the 20B product (0.200g, 0.846mmol) was added to Boc-DLeu-OH (254mg, 1.10mmol), HOBt (168mg, 1.10mmol), HBTU (417mg, 1.10mmol) at 22 deg.C) And i-Pr₂NEt (678. mu.L, 3.89mmol) in a stirred mixture of DMF. The resulting mixture was stirred overnight, then concentrated in vacuo, and the residue was dissolved in EtOAc. The EtOAc solution was treated with 0.1N HCl followed by 5% NaHCO₃The aqueous solution and saturated aqueous NaCl solution were washed, followed by Na₂SO₄Dried, filtered and concentrated in vacuo. The crude material was purified by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 2%/min gradient, 40-80% MeCN, containing 0.1% HCO₂H，10％ H₂O, 20 mL/min. The fractions containing the product were pooled and lyophilized to a white microcrystalline powder (224mg, 0.498 mmol; 58.9%).

¹H NMR(DMSO-d₆，300MHz)：11.15(1H，s)，8.04(1H，t，J＝6.9)，7.29(4H，ABq，J_AB＝8.0Hz)，6.86(1H，d，J＝7.8Hz)，5.91(1H，ddt，J＝17.4，10.6，5.4Hz)，5.28(1H，d，J＝16.3Hz)，5.17(1H，d，J＝10.7Hz)，4.73(2H，s)，4.49(2H，dt，J＝5.4，1.4Hz)，4.19(2H，d，J＝6.2)，3.81(1H，AB，J_AB＝7.9Hz)，1.60-1.25(3H，m)，1.37(9H，s)，0.84(3H，d，J＝6.9Hz)，0.81(3H，d，J＝6.9Hz).

C₂₃H₃₅N₃O₆HRMS calcd for (M + Na): 472.2418. measured value: 472.2415.

preparation of the partial D- (2R) -N- { [4- (aminomethyl) phenyl ] methoxy } -2- [ (tert-butoxy) carbonylamino ] -4-methylpentanamide, formate salt

Part of the 20C product (0.200g, 0.445mmol) was dissolved in 2: 1MeCN/H at 22 deg.C₂O (8.00mL), 25.3mg of TPPTS (44.5. mu. mol; 10 mol%) followed by Et₂NH (116. mu.L, 1.11mmol) and 5.00mg Pd (OAc)₂(22.3. mu. mol; 5 mol%). The resulting yellow solution was stirred for 0.5 h, then filtered with 0.45 μm Acrodisk and directly HPLC on Phenomenex Luna C1Purification on 8 columns (21.2X250mm) using a 1%/min gradient, 12-37% MeCN, containing 0.1% HCO₂H，10％H₂O, 20 mL/min. Fractions containing the product were pooled and lyophilized to give a white microcrystalline powder (113mg, 0.275 mmol; 61.7%).

¹H NMR(DMSO-d₆，600MHz)：8.32(1H，s)，7.37(4H，ABq，J_AB＝8.4Hz)，6.90(1H，d，J＝7.9Hz)，4.75(2H，s)，3.85(2H，s)，3.82(1H，AB，J_AB＝8.4Hz)，1.46-1.56(1H，m)，1.38(9H，s)，1.46-1.36(1H，m)，1.36-1.26(1H，m)，0.85(3H，d，J＝6.5Hz)，0.82(3H，d，J＝6.2Hz).LRMS：366.2(100，M+H)，731.5(25).

Preparation of the fraction tert-butyl E-2- [ (2- { [ (N- { [4- ({ (2R) -2- [ (tert-butoxy) carbonylamino ] -4-methylpentanoylaminooxy } methyl) phenyl ] methyl } carbamoyl) methyl ] [2- (bis { [ (tert-butyl) oxycarbonyl ] methyl } amino) ethyl ] amino } ethyl) { [ (tert-butyl) oxycarbonyl ] methyl } amino ] acetate

Using i-Pr at 22 deg.C₂NEt (115. mu.L, 0.662mmol) and HBTU (63.0mg, 0.166mmol) treated 2- { bis [2- (bis { [ (tert-butyl) oxycarbonyl ] oxy]Methyl } amino) ethyl]Amino } acetic acid (102mg, 0.166mmol), HOBt (22.4mg, 0.166mmol) and a solution of the fraction 20D product (55.0mg, 0.150mmol) in dry DMF (2.00 mL). The resulting solution was stirred for 18 hours, then heated to 50 ℃ for 0.5 hour. After cooling to 22 ℃, all volatiles were removed in vacuo and the residue was redissolved in EtOAc. The EtOAc solution was treated with 0.1N HCl followed by NaHCO₃And NaCl saturated aqueous solution, followed by Na₂SO₄Dried, filtered and concentrated in vacuo to a pale yellow oil which was used for the next deprotection step without further purification. LRMS: 966.0(100, M + H), 433.6(60).

Preparation of part of F-2- { [2- ({ [ N- ({4- [ ((2R) -2-amino-4-methylpentanoylaminooxy) methyl ] phenyl } methyl) carbamoyl ] methyl } {2- [ bis (carboxymethyl) amino ] ethyl } amino) ethyl ] (carboxymethyl) amino } ethanoic acid, trifluoroacetate

Part of the 20E product (theoretically 0.150mmol) was dissolved in 3: 2TFA/CH at 22 deg.C₂Cl₂(3.00mL) and then stirred overnight. After complete deprotection, all volatiles were removed in vacuo and the residue was purified by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 2%/min gradient, 0-30% MeCN with 0.1% TFA, 10% H₂O, 20 mL/min. Fractions containing the product were pooled and lyophilized to give a white microcrystalline powder (85.0mg, 86.5. mu. mol; 57.7%).

¹H NMR(DMSO-d₆，600MHz)11.76(1H，s)，8.97(1H，t，J＝5.7Hz)，8.25(3H，brs)，7.35(4H，ABq，J_AB＝8.1Hz)，4.82(2H，s)，4.37(2H，d，J＝5.7Hz)，4.27(2H，s)，3.50(9H，brs)，3.38(4H，t，J＝5.6Hz)，3.06(4H，t，J＝5.8Hz)，1.54-1.47(3H，m)，0.85(6H，d，J＝5.5Hz).¹³C NMR(DMSO-d₆，151MHz)：172.5，165.4，164.6，138.5，134.0，128.8，127.0，76.7，54.1，53.6，52.0，48.7，48.4，41.8，23.4，22.0，21.8.C₂₈H₄₄N₆O₁₁HRMS calcd for (M + H): 641.3141. measured value: 641.3450.

example 21

2- { [2- ({ [ N- ({4- [ ((2R) -2-amino-3- (2-naphthyl) propionylaminoxy) methyl ] phenyl } methyl) carbamoyl ] methyl } {2- [ bis (carboxymethyl) amino ] ethyl } amino) ethyl ] (carboxymethyl) amino } acetic acid, trifluoroacetic acid salt

Preparation of the moiety A- (R) -4- (9, 9-dimethyl-5- (naphthalen-2-ylmethyl) -4, 7-dioxo-2, 8-dioxa-3, 6-diazadecyl) benzylcarbamic acid allyl ester

Prepared as described in section 20C using Boc-DNal-OH (126mg, 0.235 mmol; 27.8%).

¹H NMR(DMSO-d₆，600MHz)：11.20(1H，s)，7.86(1H，d，J＝8.3Hz)，7.81(2H，t，J＝7.2Hz)，7.75(1H，t，J＝5.7Hz)，7.71(1H，s)，7.44-7.50(2H，m)，7.41(1H，d，J＝8.6Hz)，7.22(4H，ABq，J_AB＝8.1Hz)，7.10(1H，d，J＝8.2Hz)，5.91(1H，ddd，J＝17.4，10.7，5.5Hz)，5.28(1H，d，J＝17.3Hz)，5.17(1H，d，J＝10.3Hz)，4.62(2H，ABq，J_AB＝11.1Hz)，4.49(2H，d，J＝5.3Hz)，4.18(2H，d，J＝6.2Hz)，4.11(1H，ABq，J_AB＝8.4Hz)，2.99(2H，AB，J_AB＝7.8Hz)，1.29(9H，s).¹³C NMR(DMSO-d₆，151MHz)：168.3，156.1，155.1，139.9，135.4，133.7，132.9，131.8，128.8，127.7，127.5，127.4，127.3，126.8，125.9，125.4，116.9，78.0，76.5，64.3，53.5，43.5，37.7，28.1.

C₃₀H₃₅N₃O₆HRMS calcd for (M + H): 556.2418. measured value: 556.2410.

preparation of part of B- (2R) -N- { [4- (aminomethyl) phenyl ] methoxy } -2- [ (tert-butoxy) carbonylamino ] -3- (2-naphthyl) propionamide, formate salt

Prepared as described in section 20D (69.0mg, 0.139 mmol; 60.3%).

When in use¹HNMR(DMS0-d₆，600MHz)：8.33(1H，s)，7.86(1H，d，J＝7.8Hz)，7.82(1H，t，J＝8.3Hz)，7.72(1H，s)，7.44-7.50(2H，m)，7.42(1H，d，J＝8.2Hz)，7.31(4H，ABq，J_AB＝7.9Hz)，7.12(1H，d，J＝7.1Hz)，4.62(2H，ABq，J_AB＝10.8Hz)，4.12(1H，m)，3.82(2H，s)，2.91-3.06(2H，m)，1.29(9H，s).LRMS：450.6(100，M+H).

Preparation of a fraction of tert-butyl C-2- [ (2- { [ (N- { [4- ({ (2R) -2- [ (tert-butoxy) carbonylamino ] -3- (2-naphthyl) propionylamino } methyl) phenyl ] methyl } carbamoyl) methyl ] [2- (bis { [ (tert-butyl) oxycarbonyl ] methyl } amino) ethyl ] amino } ethyl) { [ (tert-butyl) oxycarbonyl ] methyl } amino ] acetate

Prepared as described in section 20E. LRMS: 1050.0(100, M + H), 618.8(80), 475.6(45).

Preparation of the partial D-2- { [2- ({ [ N- ({4- [ ((2R) -2-amino-3- (2-naphthyl) propionylaminoxy) methyl ] phenyl } methyl) carbamoyl ] methyl } {2- [ bis (carboxymethyl) amino ] ethyl } amino) ethyl ] (carboxymethyl) amino } acetic acid, trifluoroacetate

Prepared as described in section 20F (35.0mg, 32.81. mu. mol; 43.2%).

¹H NMR(DMSO-d₆，300MHz)：11.62(1H，s)，8.95(1H，t，J＝5.6Hz)，8.44(3H，brs)，7.82-7.95(3H，m)，7.74(1H，s)，7.56-7.47(2H，m)，7.37(1H，d，J＝8.8Hz)，7.17(4H，ABqJ_AB＝8.1Hz)，4.55(2H，AB，J_AB＝11.0Hz)，4.33(2H，d，J＝5.7Hz)，4.26(2H，s)，3.83-3.94(1H，m)，3.51(8H，s)，3.39(4H，t，J＝5.1Hz)，3.18(2H，d，J＝7.2Hz)，3.06(4H，t，J＝4.9Hz).¹³C NMR(DMSO-d₆，151MHz)：172.7，164.8，164.7，138.7，134.1，132.9，132.3，132.2，128.9，128.2，128.1，127.6，127.5，127.4，127.2，126.3，125.9，113.8，77.0，54.3，53.9，52.2，51.6，48.6.

C₃₅H₄₄N₆O₁₁HRMS calcd for (M + H): 725.3141. measured value: 725.3141.

example 22

2- { [2- ({ [ N- ({4- [ ((2R) -2-amino-3-phenylpropionylaminoxy) methyl ] phenyl } methyl) carbamoyl ] methyl } {2- [ bis (carboxymethyl) amino ] ethyl } amino) ethyl ] (carboxymethyl) amino } acetic acid, trifluoroacetic acid salt

Preparation of part of A- (2R) -2- [ (tert-butoxy) carbonylamino ] -3-phenyl-N- ({4- [ (prop-2-enyloxycarbonylamino) methyl ] phenyl } methoxy) propionamide

Prepared as described in section 20C, using Boc-DPhe-OH (88.0mg, 0.182 mmol; 21.5%).

¹H NMR(DMSO-d₆，60011.19(1H，s)，7.76(1H，t，J＝4.2Hz)，7.32-7.16(9H，m)，7.02(1H，d，J＝8.3Hz)，5.91(1H，ddd，J＝17.5，10.5，5.4Hz)，5.28(1H，d，J＝17.1Hz)，5.17(2H，d，J＝11.5Hz)，4.65(2H，ABq，J_AB＝10.7Hz)，4.49(2H，d，J＝5.3Hz)，4.19(2H，d，J＝6.2Hz)，4.00(1H，ABq，J_AB＝8.7Hz)，2.74-2.87(2H，m)，1.32(9H，s).

C₂₆H₃₃N₃O₆HRMS calcd for (M + H): 506.2262. measured value: 506.2254.

preparation of part B- (2R) -N- { [4- (aminomethyl) phenyl ] methoxy } -2- [ (tert-butoxy) carbonylamino ] -3-phenylpropanamide, formate salt

Prepared as described in section 20D (45.0mg, 0.101 mmol; 57.3%).

¹H NMR(DMSO-d₆，600MHz)：8.33(1H，s)，7.35(4H，ABq，J_AB＝8.3Hz)，7.30-7.17(5H，m)，7.03(1H，d，J＝8.4Hz)，4.66(2H，ABq，J_AB＝10.6Hz)，3.98-4.04(1H，m)，3.83(2H，s)，2.85(1H，dd，J＝13.7，5.8Hz)，2.78(1H，dd，J＝13.4，9.5Hz)，1.32(9H，s).LCMS：400.5(100，M+H).

Preparation of the fraction C-tert-butyl 2- [ (2- { [ (N- { [4- ({ (2R) -2- [ (tert-butoxy) carbonylamino ] -3-phenylpropionylaminoxy } methyl) phenyl ] methyl } carbamoyl) methyl ] [2- (bis { [ (tert-butyl) oxycarbonyl ] methyl } amino) ethyl ] amino } ethyl) { [ (tert-butyl) oxycarbonyl ] methyl } amino ] acetate

Prepared as described in section 20E. LRMS: 1000.0(100, M + H).

Preparation of the fraction D-2- { [2- ({ [ N- ({4- [ ((2R) -2-amino-3-phenylpropanoylamino-oxy) methyl ] phenyl } methyl) carbamoyl ] methyl } {2- [ bis (carboxymethyl) amino ] ethyl } amino) ethyl ] (carboxymethyl) amino } acetic acid, trifluoroacetate

Prepared as described in section 20F (60.0mg, 59.0. mu. mol; 59.7%).

¹H NMR(DMSO-d₆，300MHz)：11.62(1H，s)，8.98(1H，t，J＝5.8Hz)，8.43(3H，brs)，7.38-7.19(9H，m)，4.60(2H，ABq，J_AB＝10.9Hz)，4.36(2H，d，J＝5.6Hz)，4.27(2H，s)，3.84(1H，m)，3.51(8H，s)，3.39(4H，t，J＝5.1Hz)，3.06(4H，t，J＝6.0Hz)，3.01(2H，d，J＝6.7Hz).¹³C NMR(DMSO-d₆，151MHz)：172.7，164.8，164.6，138.7，134.7，134.1，129.4，129.0，128.6，127.3，77.0，54.3，53.9，52.2，51.5，48.7，42.0，38.6.C₃₁H₄₂N₆O₁₁HRMS calcd for (M + Na): 697.2804. measured value: 697.2824.

example 23

2- (7- { [ N- ({4- [ ((2R) -2-amino-4-methylpentanoylaminooxy) methyl ] phenyl } methyl) carbamoyl ] methyl } -1, 4, 7, 10-tetraaza-4, 10-bis (carboxymethyl) cyclododecyl) acetic acid, trifluoroacetic acid salt

Preparation of fraction A-tert-butyl 2- {7- [ (N- { [4- ({ (2R) -2- [ (tert-butoxy) carbonylamino ] -4-methylpentanoylaminooxy } methyl) phenyl ] methyl } carbamoyl) methyl ] -1, 4, 7, 10-tetraaza-4, 10-bis { [ (tert-butyl) oxycarbonyl ] methyl } cyclododecyl } acetate

HOBt (30.3mg, 0.224mmol), HBTU (84.9mg, 0.224mmol) and i-Pr were used sequentially at 22 deg.C₂NEt (146. mu.L, 0.840mmol) treated 2- (1, 4, 7, 10-tetraaza-4, 7, 10-tris { [ (tert-butyl) oxycarbonyl)]A solution of methyl } -cyclododecyl) acetic acid (128mg, 0.224mmol) in anhydrous DMF (5.00 mL). After 0.25 h, the solution was taken up with part 20D product (55.0mg, 0.134mmol) and i-Pr₂NEt (146. mu.L, 0.840mmol) and then stirred overnight. After 24 hours, the reaction was heated to 50 ℃ for 5 hours, then concentrated in vacuo to dissolve the residue in EtOAc. The EtOAc solution was treated with 0.1N HCl followed by NaHCO₃And NaCl saturated aqueous solution, followed by Na₂SO₄Dried, filtered and concentrated in vacuo to a pale yellow oil which was used for the next deprotection step without further purification.

LRMS：921.0(100，M+H)，411.2(65).

Preparation of part B-2- (7- { [ N- ({4- [ ((2R) -2-amino-4-methylpentanoylaminooxy) methyl ] phenyl } methyl) carbamoyl ] methyl } -1, 4, 7, 10-tetraaza-4, 10-bis (carboxymethyl) cyclododecyl) acetic acid, trifluoroacetate

Part 23A product (theoretically 0.134mmol) was dissolved in dioxane (3.00mL) at 22 deg.C, followed by H₂O (14. mu.L) and HCl (12.0 mmol; 3.00mL of 4M dioxane solution). The resulting pale yellow solution was stirred overnight, all volatiles were removed under reduced pressure, and the residue was purified directly by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 0.875%/min gradient, 0-35% MeCN, 0.1% TFA, 10% H₂O, 20 mL/min. The product-containing fractions were pooled and lyophilized to a white microcrystalline powder(63.0mg，63.4μmol；47.3％)。

¹H NMR(DMSO-d₆，600MHz)：9.01(1H，t，J＝5.4Hz)，7.42(4H，ABq，J_AB＝8.0Hz)，4.98(2H，s)，4.49(2H，d，J＝5.1Hz)，3.95(1H，t，J＝6.7Hz)，3.81(4H，s)，3.80(2H，s)，3.63(2H，s)，3.15(12H，s)，2.99(4H，s)，1.80-1.66(3H，m)，0.87(3H，d，J＝6.1Hz)，0.85(3H，d，J＝6.1Hz).

C₃₀H₄₉N₇O₉HRMS calcd for (M + H): 652.3665. measured value: 652.3669.

example 24

2- (7- { [ N- ({4- [ ((2R) -2-amino-3- (2-naphthyl) propionylaminoxy) methyl ] phenyl } methyl) carbamoyl ] methyl } -1, 4, 7, 10-tetraaza-4, 10-bis (carboxymethyl) cyclododecyl) acetic acid, trifluoroacetic acid salt

Preparation of part A tert-butyl 2- {7- [ (N- { [4- ({ (2R) -2- [ (tert-butoxy) carbonylamino ] -3- (2-naphthyl) propionylaminoxy } methyl) phenyl ] methyl } carbamoyl) methyl ] -1, 4, 7, 10-tetraaza-4, 10-bis { [ (tert-butyl) oxycarbonyl ] methyl } cyclododecyl } acetate

Prepared as described in section 23A. LRMS: 1005.0(60, M + H), 453.2(100). preparation of part B-2- (7- { [ N- ({4- [ ((2R) -2-amino-3- (2-naphthyl) propionylaminoxy) methyl ] phenyl } methyl) carbamoyl ] methyl } -1, 4, 7, 10-tetraaza-4, 10-bis (carboxymethyl) cyclododecyl) acetic acid, trifluoroacetate

Prepared as described in part 23B (28.6mg, 26.5. mu. mol; 39.9%).

¹H NMR(DMSO-d₆，600MHz)：8.98(1H，t，J＝5.8Hz)，7.89-7.79(5H，m)，7.52(2H，d，J＝8.6Hz)，7.53-7.49(2H，m)，7.33-7.20(4H，m)，4.79(2H，ABq，J_AB＝11.6Hz)，4.45(2H，s)，4.38(2H，s)，3.80-3.78(4H，m)，3.59(1H，s)，3.44(2H，d，J＝7.1Hz)，3.20-3.09(12H，m)，2.96(4H，s).

C₃₇H₄₉N₇O₉HRMS calcd for (M + H): 736.3665. measured value: 736.3663.

example 25

2- { [2- ({ [ N- ({4- [ ((2R) -2-amino-3-indol-2-ylpropanoylaminooxy) methyl ] phenyl } methyl) carbamoyl ] methyl } {2- [ bis (carboxymethyl) amino ] ethyl } amino) ethyl ] (carboxymethyl) amino } acetic acid, trifluoroacetic acid salt

Preparation of part of A- (2R) -2- [ (tert-butoxy) carbonylamino ] -3-indol-2-yl-N- ({4- [ (prop-2-enyloxycarbonylamino) methyl ] phenyl } methoxy) propionamide

Prepared as described in section 20C using Boc-DTrp-OH. LRMS: 423.5(100, M + H-Boc), 545.5(15, M + Na).

Preparation of part B- (2R) -N- { [4- (aminomethyl) phenyl ] methoxy } -2- [ (tert-butoxy) carbonylamino ] -3-indol-2-ylpropanamide, formate salt

Prepared as described in section 20D (154mg, 0.318 mmol; 43.4%).

¹H NMR(DMSO-d₆，600MHz)：11.22(1H，brs)，10.80(1H，s)，8.26(1H，s)，7.58(1H，d，J＝7.7Hz)，7.36(1H，d，J＝8.0Hz)，7.31(4H，ABq，J_AB＝8.3Hz)，7.12(1H，s)，7.05(1H，t，J＝7.5Hz)，6.97(1H，t，J＝7.5Hz)，6.91(1H，d，J＝8.1Hz)，4.64(2H，ABq，J_AB＝11.0Hz)，4.04(1H，AB，J_AB＝7.9Hz)，3.84(2H，s)，2.99(1H，dd，J＝14.3，5.9Hz)，2.90(1H，dd，J＝14.4，8.8Hz)，1.33(9H，s).

C₂₄H₃₀N₄O₄HRMS calcd for (M + Na): 461.259. measured value: 461.259.

preparation of a fraction of tert-butyl C-2- [ (2- { [ (N- { [4- ({ (2R) -2- [ (tert-butoxy) carbonylamino ] -3-indol-2-ylpropanoylaminooxy } methyl) phenyl ] methyl } carbamoyl) methyl ] [2- (bis { [ (tert-butyl) oxycarbonyl ] methyl } amino) ethyl ] amino } ethyl) { [ (tert-butyl) oxycarbonyl ] methyl } amino ] acetate

Prepared as described in section 20E to give the crude product which was used in the next step without further purification.

LRMS(m/z)：1039.0(100％，[M+H]⁺)

Preparation of the fraction D-2- { [2- ({ [ N- ({4- [ ((2R) -2-amino-3-indol-2-ylpropanoylaminooxy) methyl ] phenyl } methyl) carbamoyl ] methyl } {2- [ bis (carboxymethyl) amino ] ethyl } amino) ethyl ] (carboxymethyl) amino } acetic acid, trifluoroacetate

Prepared as described in section 20F (47.7mg, 45.2. mu. mol; 26.1%).

¹H NMR(DMSO-d₆，600MHz)：11.63(1H，s)，11.02(1H，s)，8.95(1H，t，J＝5.6Hz)，8.28(2H，brs)，7.60(1H，d，J＝7.9Hz)，7.38(1H，d，J＝8.1Hz)，7.25(4H，ABq，J_AB＝8.1Hz)，7.12(1H，s)，7.10(1H，t，J＝7.4Hz)，6.91(1H，t，J＝7.5Hz)，4.60(2H，ABq，J_AB＝10.9Hz)，4.36(2H，d，J＝4.7Hz)，4.26(2H，s)，3.78-3.72(1H，m)，3.51(8H，s)，3.38(4H，t，J＝5.3Hz)，3.18(1H，dd，J＝14.4，7.2Hz)，3.10(1H，dd，J＝14.4，7.4Hz)，3.01(4H，t，J＝5.4Hz).

C₃₃H₄₃N₇O₁₁HRMS calcd for (M + H): 714.3093. measured value: 714.3089.

example 26

2- (4- { [ N- ({4- [ ((2R) -2-amino-3-indol-2-ylpropanoylaminooxy) methyl ] phenyl } methyl) carbamoyl ] methyl } -1, 4, 7, 10-tetraaza-7, 10-bis (carboxymethyl) cyclododecyl) acetic acid, trifluoroacetic acid salt

Preparation of fraction A-tert-butyl 2- {10- [ (N- { [4- ({ (2R) -2- [ (tert-butoxy) carbonylamino ] -3-indol-2-ylpropanoylaminooxy } methyl) phenyl ] methyl } carbamoyl) methyl ] -1, 4, 7, 10-tetraaza-4, 7-bis { [ (tert-butyl) oxycarbonyl ] methyl } cyclododecyl } acetate

Prepared as described in section 23A. LRMS: 994.0(100, M + H), 589.7(50), 447.6(100).

Preparation of part B- (2- (4- { [ N- ({4- [ ((2R) -2-amino-3-indol-2-ylpropanoylaminooxy) methyl ] phenyl } methyl) carbamoyl ] methyl } -1, 4, 7, 10-tetraaza-7, 10-bis (carboxymethyl) cyclododecyl) acetic acid, trifluoroacetate

Prepared as described in part 23B (13mg, 11. mu. mol; 8.4%).

¹H NMR(DMSO-d₆，600MHz)：11.63(1H，s)，11.03(1H，s)，8.95(1H，brs)，8.31(2H，brs)，7.60(1H，d，J＝7.9Hz)，7.38(1H，d，J＝8.1Hz)，7.25(4H，ABq，J_AB＝7.9Hz)，7.20(1H，s)，7.10(1H，t，J＝7.5Hz)，7.02(1H，t，J＝7.5Hz)，4.60(2H，ABq，J_AB＝10.9Hz)，4.36(2H，d，J＝4.5Hz)，3.75(1H，t，J＝6.4Hz)，3.63(4H，s)，3.35(12H，brs)，3.17(1H，dd，J＝14.4，7.2Hz)，3.10(1H，dd，J＝14.5，7.5Hz)，3.04(8H，brs).

C₃₅H₄₈N₈O₉HRMS calcd for (M + H): 725.3617. measured value: 725.3627.

example 27

2- ({2- [ ({ N- [ (4- { [ (2R) -2-amino-3- (4-hydroxyphenyl) propionylaminoxy ] methyl } phenyl) methyl ] carbamoyl } methyl) {2- [ bis (carboxymethyl) amino ] ethyl } (carboxymethyl) amino) acetic acid, trifluoroacetate salt

Preparation of part of A- (2R) -2- [ (tert-butoxy) carbonylamino ] -3- (4-hydroxyphenyl) -N- ({4- [ (prop-2-enyloxycarbonylamino) methyl ] phenyl } methoxy) propionamide

Prepared as described in section 20C, using Boc-DTyr-OH (33mg, 66. mu. mol; 7.8%).

¹H NMR(DMSO-d₆，600MHz)：11.14(1H，s)，9.14(1H，s)，7.76(1H，t，J＝6.0Hz)，7.27(4H，ABq，J_AB＝7.9Hz)，7.00(2H，d，J＝8.2Hz)，6.93(1H，d，J＝8.5Hz)，6.64(2H，d，J＝8.3Hz)，5.91(1H，ddt，J＝17.5，10.4，5.1Hz)，5.28(1H，dd，J＝17.2，1.3Hz)，5.17(1H，dd，J＝10.7，1.0Hz)，4.64(2H，ABq，J_AB＝10.9Hz)，4.49(2H，dt，J＝5.5，1.3Hz)，4.19(2H，d，J＝6.2)，3.91(1H，AB，J_AB＝8.4Hz)，2.62-2.76(2H，m)，1.33(9H，s).C₂₆H₃₃N₃O₇HRMS calcd for (M + H): 522.2211. measured value: 522.2203. moiety B- (2R) -N- { [4- (aminomethyl) phenyl]Methoxy } -2- [ (tert-butoxy) carbonylamino group]Preparation of (E) -3- (4-hydroxyphenyl) propionamide, formate

Prepared as described in section 20D (16.9mg, 36.6. mu. mol; 59.0%).

¹H NMR(DMSO-d₆，600MHz)：8.36(1H，brs)，7.52(1H，dt，J＝7.6，2.8Hz)，7.40(4H，ABq，J_AB＝7.7Hz)，7.00(2H，d，J＝8.1Hz)，6.93(1H，d，J＝8.3Hz)，6.64(2H，d，J＝7.9Hz)，4.68(2H，ABq，J_AB＝10.9Hz)，3.97(2H，s)，3.91(1H，AB，J_AB＝8.0Hz)，2.73(1H，dd，J＝13.7，5.9Hz)，2.66(1H，dd，J＝13.3，9.2Hz)，1.33(9H，s).

C₂₂H₂₉N₃O₅HRMS calcd for (M + H): 416.2180. measured value: 416.2183.

preparation of a fraction of tert-butyl C-2- [ (2- { [ (N- { [4- ({ (2R) -2- [ (tert-butoxy) carbonylamino ] -3- (4-hydroxyphenyl) propionylamino } methyl) phenyl ] methyl } carbamoyl) methyl ] [2- (bis { [ (tert-butyl) oxycarbonyl ] methyl } amino) ethyl ] amino } ethyl) { [ (tert-butyl) oxycarbonyl ] methyl } amino ] acetate

Prepared as described in section 20E. LRMS: 1016.0(45, M + H), 458.6(30, (M-Boc) +2H).

Preparation of part of D-2- ({2- [ ({ N- [ (4- { [ (2R) -2-amino-3- (4-hydroxyphenyl) propionylaminoxy ] methyl } phenyl) methyl ] carbamoyl } methyl) {2- [ bis (carboxymethyl) amino ] ethyl } (carboxymethyl) amino) acetic acid, trifluoroacetate salt

Prepared as described in section 20F.

¹H NMR(DMSO-d₆，600MHz)：11.54(1H，s)，9.37(1H，brs)，8.95(1H，t，J＝5.3Hz)，8.32，(1H，brs)，8.28(1H，brs)，7.30(4H，ABq，J_AB＝8.2Hz)，7.00(2H，d，J＝8.2Hz)，6.72(2H，d，J＝8.6Hz)，4.64(2H，ABq，J_AB＝10.9Hz)，4.36(2H，d，J＝5.9Hz)，4.26(2H，s)，3.66(2H，brs)，3.66-3.39(9H，m)，3.41-3.36(4H，m)，3.06(4H，t，J＝5.6Hz)，2.88(2H，d，J＝7.6Hz).

C₃₁H₄₂N₆O₁₂HRMS calcd for (M + H): 691.2936. measured value: 691.2944.

example 28

2- { [2- ({ [ N- ({4- [ ((2R) -2-amino-3- (3-pyridyl) propionylaminoxy) methyl ] phenyl } methyl) carbamoyl ] methyl } {2- [ bis (carboxymethyl) amino ] ethyl } amino) ethyl ] (carboxymethyl) amino } acetic acid, trifluoroacetic acid salt

Preparation of part of A- (2R) -2- [ (tert-butoxy) carbonylamino ] -N- ({4- [ (prop-2-enyloxycarbonylamino) methyl ] phenyl } methoxy) -3- (3-pyridyl) propionamide

Prepared as described in section 20C using Boc-DPya-OH. LRMS: 485.6(100, M + H).

Preparation of part of B- (2R) -N- { [4- (aminomethyl) phenyl ] methoxy } -2- [ (tert-butoxy) carbonylamino ] -3- (3-pyridyl) propionamide, formate salt

Prepared as described in part 20D (151mg, 0.338 mmol; 79.9%). LRMS: 401.6(100, M + H).

Preparation of a fraction of tert-butyl C-2- [ (2- { [ (N- { [4- ({ (2R) -2- [ (tert-butoxy) carbonylamino ] -3- (3-pyridyl) propionylamino } methyl) phenyl ] methyl } carbamoyl) methyl ] [2- (bis { [ (tert-butyl) oxycarbonyl ] methyl } amino) ethyl ] amino } ethyl) { [ (tert-butyl) oxycarbonyl ] methyl } amino ] acetate

Prepared as described in section 20E. LRMS: 1001.0(75, M + H), 501.2(100, M +2H).

Preparation of the partial D-2- { [2- ({ [ N- ({4- [ ((2R) -2-amino-3- (3-pyridyl) propionylaminoxy) methyl ] phenyl } methyl) carbamoyl ] methyl } {2- [ bis (carboxymethyl) amino ] ethyl } amino) ethyl ] (carboxymethyl) amino } acetic acid, trifluoroacetate salt

Prepared as described in section 20F (3.3mg, 3.2. mu. mol; 1.8%).

¹H NMR(DMSO-d₆，600MHz)：11.64(1H，s)，8.95(1H，t，J＝5.8Hz)，8.52(1H，d，J＝5.0Hz)，8.38(2H，brs)，7.81-7.76(1H，m)，7.38-7.26(6H，m)，4.69(2H，ABq，J_AB＝11.6Hz)，4.37(2H，d，J＝4.7Hz)，4.27(2H，s)，4.07(1H，t，J＝5.9Hz)，3.64(8H，brs)，3.39(4H，t，J＝5.7Hz)，3.19(2H，d，J＝7.1Hz)，3.06(4H，t，J＝5.9Hz).

C₃₀H₄₁N₇O₁₁HRMS calcd for (M + H): 676.2937. measured value: 676.2940.

examples 29 to 36

Synthesis of gadolinium complexes

The following procedure is a representative manner of preparing the gadolinium complex of the above examples. Yield and characterization data are provided in table 1.

Using GdCl at 22 ℃₃(7.4mg, 28. mu. mol) the product of example 2 (24.3mg, 23.3. mu. mol) was treated in Milli-Q H in one portion₂Solution in O (466 μ L). Adjusting the pH of the solution to 5-6 with aqueous NaOH solution (933 μ L of 0.1M solution); HPLC analysis directly against the reaction mixture with pH 7 flow indicated that the complexation was complete. The solution was treated with 15mM NH₄OAc (5mL) was diluted and purified directly by HPLC on a Phenomenex Luna C18 column (21.2X250mm) using a 1.0%/min gradient, 0-30% MeCN at a flow rate of 20 mL/min; using 5mM NH₄OAc as the aqueous component. The main product peak eluting over 19 minutes was collected and lyophilized to give the title compound as a microcrystalline solid (15.5mg, 18.2. mu. mol; 77.8%).

TABLE 1 characterization data for examples 29-36

Examples 37 to 64

[¹⁵³Gd]Synthesis of gadolinium complexes

The following procedure is a representative manner of preparing the gadolinium complex of the above examples. The radiochemical purity values for each complex are provided in table 2.

Using a lead-shielded bottle, at 22 ℃¹⁵³Gd]GdCl₃(75. mu.L of 12.5 mCi/. mu.L solution in 0.5N HCl) the product of example 2 (0.350mg, 0.336. mu. mol) was treated in one portion with 0.5M NH₄Solution in OAc (0.850 mL). The vial was capped with a rubber stopper, secured with an aluminum crimp ring (crimp ring), and then heated to 95 deg.C (H)₂O bath) for 20 minutes. After cooling to 22 ℃, a 25 μ L aliquot was taken and analyzed by HPLC to determine complete conversion. The crude reaction mixture was then purified by HPLC on a Phenomenex Cosmosil C18 column (4.6X 250mm)Using a 6.7%/min gradient, 0-100% MeCN, 1mL/min, with inline (inline) INUS β -Ram and PDA (220nm) components; with 25mM NH₄OAc as the aqueous component. Fractions containing the product were collected, concentrated under reduced pressure, and analyzed by the methods described above to determine radiochemical purity.

TABLE 2 characterization data for examples 37-64

Example 65

Ex vivo vascular binding assays

Atherosclerotic plaque-bearing aorta was obtained from New Zealand white rabbits that were balloon stripped along the abdominal aorta (balloon stripped), high fat diet (0.5% cholesterol) for 16-22 weeks. Vascular lesions were created along the abdominal aorta and right iliac-femoral artery with a 4-F Fogarty catheter. This procedure accelerates the appearance of complex lesions in rabbits, the lipid-rich core of which is covered by a fibrous cap. Collected aortic sections (0.5cm) were cut at 37 ℃ with 0.135. mu. Ci diluted in phosphate buffered saline (450. mu.L)¹⁵³Gd-labelled compounds were incubated for 2 hours. The supernatant was removed and analyzed by HPLC to determine compound stability. The tissue sections were then washed with phosphate buffered saline (3X 10mL), followed by resuspension (10mL) and further incubation at 37 ℃ for 1 hour. The supernatant was then removed and the washing process repeated, finally the tissues were counted on a gamma counter. The amount of compound bound to the tissue was determined as the initial percent activity according to the following formula:

％＝————————————×100

data for percent compound bound to plaque-bearing aorta is collected in table 3.

Table 3: ex vivo vascular binding data

Example 66

In vivo ApoE mouse aortic absorption study

Apolipoprotein e (apoe) knockout mice are a model of hypercholesterolemia with atherosclerotic lesions in the brachiocephalic trunk, aortic arch and abdominal aorta. Mice were fed a high fat diet to accelerate plaque formation and compounds were tested in mice on a high fat diet for 35-42 weeks. The test compounds were administered to anesthetized mice at 0.3-0.4mCi/kg via the tail vein in a single bolus injection. Tail blood samples were collected for pharmacokinetic analysis 0-30 minutes after injection with CO at 60 minutes₂Mice were sacrificed to collect tissue. First, the aorta is flushed with saline through the left ventricle, draining it from the femoral vein, and then the portion of the aorta that branches off from the heart to the kidneys is removed; other biological samples (blood, muscle, liver, kidney, bile, urine, heart, femur, genitalia, lung, spleen and innominate artery) were also collected. All samples were weighed and radioactivity determined; absorption is expressed as percent injected dose per gram of tissue (% ID/g). Aortic absorption, aortic to blood ratio and aortic to heart ratio are shown in table 4.

TABLE 4 aortic absorption, aortic to heart and aortic to blood ratios of ApoE mice

Example 67

In vivo rabbit aortic absorption study

Atherosclerosis was induced in New Zealand White male rabbits (3kg) with aortic balloon endothelial injury (see above) followed by a 0.5% cholesterol diet for 22 weeks. The test compounds were administered to anesthetized rabbits at 0.01-0.05mCi/kg via the marginal vein of the ear in a single bolus injection. Blood samples of the middle ear artery were collected at 0,2, 5, 7, 10, 15, 30 and 60 minutes post injection, respectively. Rabbits were sacrificed 60 minutes after injection to collect tissues (blood, muscle, bile, urine, kidney, liver, spleen, heart, lung, colon, small intestine, stomach, testis, sometimes sternum, ligament and right ear). The abdominal aorta (superior, middle and inferior) and the left and right femoral arteries were also collected. All samples were weighed and radioactivity determined; absorption is expressed as percent injected dose per gram of tissue (% ID/g). Aortic absorption, aortic to blood ratio and aortic to heart ratio are shown in table 5; comparative analysis between plaque-bearing and non-plaque-bearing rabbits is also provided.

TABLE 5 Rabbit aortic absorption, aortic to cardiac and aortic to blood ratio

Example 68

In vivo rabbit aorta MR imaging

Atherosclerosis was induced in New Zealand White male rabbits (3kg) with aortic balloon endothelial injury (see above) followed by a 0.5% cholesterol diet for 22 weeks. A set of pre-injection images is acquired. Rabbits were then injected with test compound (i.e., example 31) at 0.1mmol/kg via the auricular vein and images were taken at specific time intervals. All images were acquired with a black blood (black blood), flow suppressed spin echo method with an 8.5cm field of view, 256 × 256 matrix at 4.7T. A significant increase in relative image intensity in the aorta (annular structure) was seen shortly after injection; the sample image is shown in figure 1.

Example 69

The compounds of examples 1-28 can also be synthesized using methods known in the art to include a DTPA derivative as the chelator moiety. As the embodiments illustrate, scheme 4 shows the reaction between (i) a hydroxyamide (hydroxamide) compound and a carboxylic acid-DTPA derivative, which can be carried out using standard peptide coupling techniques as described herein, followed by (ii) metal-complexing the resulting ligand with, for example, gadolinium using the general methods described in examples 29-36. In some embodiments, carboxylic acid-DTPA derivatives can be synthesized by oxidizing the corresponding hydroxymethyl DTPA derivative;

scheme 4

It will be clear to those skilled in the art that the present disclosure is not limited to the embodiments illustrated above, but that it can be embodied in other specific forms without departing from the essential attributes thereof. It is therefore intended that the embodiments be considered as illustrative and not restrictive, reference being made to the appended claims rather than to the foregoing embodiments, and all changes which come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims (16)

1. A compound of the formula (I),

or a pharmaceutically acceptable salt thereof, wherein:

x is nitrogen;

R¹is hydrogen, C_1-6Alkyl radical, C_6-10aryl-C_1-10Alkyl radical, C_1-6alkyl-C_6-10aryl-C_1-6Alkyl radical, C_2-6Alkoxyalkyl or C_1-6A heteroalkyl group;

R²and R³May be the same or different and is hydrogen, C_1-6Alkyl radical, C_3-10Cycloalkyl radical, C_1-6alkyl-C_6-10Aryl radical, C_6-10Aryl radical, C_6-10aryl-C_1-10Alkyl radical, C_1-6alkyl-C_6-10aryl-C_1-6Alkyl, heterocyclyl or heterocyclyl-C_1-10An alkyl group; and

R⁴is C_1-6Alkyl radical, C_1-6alkyl-C_6-10Aryl radical, C_6-10Aryl radical, C_6-10aryl-C_1-10Alkyl radical, C_1-6alkyl-C_6-10aryl-C_1-6Alkyl or C_1-6A heteroalkyl group is, for example,

wherein each R¹、R²、R³And R⁴Unsubstituted or substituted with one or more of the following groups: c_1-6Alkyl radical, C_3-10Cycloalkyl radical, C_1-6alkyl-C_6-10Aryl radical, C_6-10Aryl radical, C_6-10aryl-C_1-10Alkyl radical, C_1-6alkyl-C_6-10aryl-C_1-6Alkyl radical, C_1-6Heteroalkyl, heterocyclyl, -NR¹⁹R²⁰、-OH、＝O、-OR²⁴、-NR²⁴C(＝O)R²⁴、-N(R²⁴)₂A chelator moiety; or

Wherein R is¹、R²、R³And R⁴Has the following structure:

wherein n is an integer between 0 and 12, including 0 and 12, m is an integer between 0 and 12, including 0 and 12, and R^cIs a chelator moiety;

R¹⁹and R²⁰Each independently of the other being hydrogen or substituted by 0 to 3R²³Substituted C_1-10An alkyl group;

each R²³Independently selected from ═ O and-CO₂R²⁴、-OR²⁴and-N (R)²⁴)₂；

Each R²⁴Independently of each other is hydrogen, C_1-6Alkyl or C_1-6A heteroalkyl group; and

n' is an integer of from 0 to 3,

wherein the compound comprises a chelator moiety, and wherein said chelator moiety comprises the structure,

wherein:

each R' is O^-OH or NHR'; and

r 'and R' are each independently hydrogen, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-10Cycloalkyl radical, C_1-6alkyl-C_6-10Aryl radical, C_1-6Alkylcarbonyl group, C_6-10Aryl radical, C_6-10aryl-C_1-6Alkyl radical, C_1-6alkyl-C_6-10aryl-C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6alkoxy-C_1-6Alkyl radical, C_1-6Alkoxycarbonyl group, C_1-6Heteroalkyl, heterocyclic or heterocyclic C_1-10An alkyl group;

and wherein, unless otherwise specified:

heterocyclyl is a 5-, 6-or 7-membered ring containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and

heteroalkyl is an alkyl in which 1 to 7 carbon atoms are replaced by a heteroatom selected from O, NH and S.

2. The compound of claim 1, wherein:

each R¹Independently of each other is hydrogen, C_1-6Alkyl radical, C_6-10aryl-C_1-10Alkyl or C_1-6alkyl-C_6-10Aryl radicals-C_1-6An alkyl group;

R²and R³May be the same or different and is hydrogen, C_1-6Alkyl radical, C_1-6alkyl-C_6-10Aryl radical, C_6-10Aryl radical, C_6-10aryl-C_1-10Alkyl radical, C_1-6alkyl-C_6-10aryl-C_1-6Alkyl or heterocyclyl-C_1-10An alkyl group; and

R⁴is C_1-6Alkyl radical, C_1-6alkyl-C_6-10Aryl radical, C_6-10Aryl radical, C_6-10aryl-C_1-10Alkyl or C_1-6alkyl-C_6-10aryl-C_1-6An alkyl group, a carboxyl group,

wherein R is¹、R²、R³And R⁴One of which is substituted with a chelator moiety.

3. The compound of claim 1, wherein R²Or R³Comprises the following structures according to the formula,

wherein

n is 0 to 6; and

R^zis C_1-6Alkyl radical, C_6-10Aryl radical, C_3-10Cycloalkyl or heterocyclyl.

4. The compound of claim 1, wherein R¹Comprising said chelator moiety; or, optionally, the combination of the two,

wherein R is²Or R³Comprising said chelator moiety; or, optionally, the combination of the two,

wherein R is⁴Comprising said chelator moiety.

5. The compound of claim 1, wherein the compound has the structure of formula (II),

or a pharmaceutically acceptable salt thereof; wherein

R⁴Is C_1-6Alkyl radical, C_1-6alkyl-C_6-10Aryl radical, C_6-10Aryl radical, C_6-10aryl-C_1-10Alkyl radical, C_1-6alkyl-C_6-10aryl-C_1-6Alkyl or C_1-6A heteroalkyl group substituted with the chelator moiety;

n is 0 to 6;

R^yselected from hydrogen and C_1-6An alkyl group; and

R^zis selected from C_1-6Alkyl radical, C_6-10Aryl radical, C_3-10Cycloalkyl radical, C_5-10Heteroaryl and heterocyclyl groups;

or, optionally, the combination of (a) and (b),

wherein the compound has a structure of formula (III),

or a pharmaceutically acceptable salt thereof; wherein

R²And R³May be the same or different and is hydrogen, C_1-6Alkyl radical, C_1-6alkyl-C_6-10Aryl radical, C_6-10Aryl radical, C_6-10aryl-C_1-0Alkyl radical, C_1-6alkyl-C_6-10aryl-C_1-6Alkyl, heterocyclyl or heterocyclyl-C_1-10Alkyl, and R²And R³Is substituted with the chelator moiety; and

R⁴is C_1-6Alkyl or C_6-10aryl-C_1-10An alkyl group;

or optionally

Wherein the compound has a structure of a formula (IV),

or a pharmaceutically acceptable salt thereof; wherein

R¹Is C_1-6Alkyl radical, C_6-10aryl-C_1-10Alkyl radical, C_1-6alkyl-C_6-10aryl-C_1-6Alkyl or C_2-6An alkoxyalkyl group substituted with the chelator moiety;

n is 0 to 6;

R^zis selected from C_1-6Alkyl radical, C_6-10Aryl radical, C_3-10Cycloalkyl radical, C_5-10Heteroaryl and heterocyclyl groups; and

R⁴is C_1-6Alkyl or C_6-10aryl-C_1-10An alkyl group.

6. The compound of claim 1, wherein R¹、R²、R³And R⁴One of the two has a structure that,

wherein n is an integer between 0 and 12, including 0 and 12, m is an integer between 0 and 12, including 0 and 12, and R^cIs a chelator moiety;

or, optionally, the combination of the two,

wherein R is¹、R²、R³And R⁴One of the two has a structure that,

wherein n is an integer between 0 and 12, including 0 and 12, m is an integer between 0 and 12, including 0 and 12, and R^cIs a chelator moiety;

or, optionally, the combination of the two,

wherein R is¹、R²、R³And R⁴One of the two has a structure that,

wherein R is^cIs a chelator moiety.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound comprises the structure,

or, optionally, the combination of the two,

wherein the compound has the structure (I) or (II),

8. a diagnostic agent comprising:

a compound according to any one of claims 1 to 7; and

an imaging agent bound to the chelator moiety;

wherein the imaging agent is a paramagnetic metal ion; a ferromagnetic metal; a gamma-emitting radioisotope; positron emitting radioisotopes or x-ray absorbers.

9. The diagnostic agent of claim 8, wherein the paramagnetic metal ion is gd (iii).

10. The diagnostic agent of claim 8, wherein the imaging agent is selected from¹¹¹In、⁶²Cu、⁶⁴Cu、⁶⁷Ga、⁶⁸Ga and¹⁵³gamma-emitting radioisotopes or positron-emitting radioisotopes of Gd.

11. The diagnostic agent of claim 8, wherein the diagnostic agent has the structure,

12. use of a diagnostic agent according to any one of claims 8 to 11 in the manufacture of a medicament for administration to a patient for obtaining an image of the location of a concentration of the diagnostic agent in the patient by means of a diagnostic imaging technique.

13. Use of a diagnostic agent according to any one of claims 8 to 11 in the manufacture of a medicament for detecting, imaging and/or monitoring the presence of coronary plaques, carotid plaques, iliac/femoral plaques, aortic plaques, renal artery plaques, aneurysms, vasculitis, other diseases of the arterial wall and/or damage or structural changes to ligaments, uterus, lungs or skin in a patient.

14. Use of a diagnostic agent according to any one of claims 8 to 11 in the manufacture of a medicament for detecting, imaging and/or monitoring elastin rich tissue in a patient.

15. Use of a diagnostic agent of any one of claims 8-11 in the manufacture of a medicament for detecting, imaging and/or monitoring elastin rich tissue in a patient, wherein the elastin rich tissue is within an arterial wall, uterus, lung, skin, and/or ligament.

16. Use of a diagnostic agent according to any one of claims 8 to 11 in the manufacture of a medicament for detecting, imaging and/or monitoring the presence of plaque from any arterial blood vessel in a patient.