Technical field

The present invention generally relates to rhenium complexes that are useful in the treatment of cancer. The present invention also relates to processes for preparing the rhenium complexes .

Background

It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art, in Australia or any other country.

Cancer is one of the leading causes of death and, as such, the drive to discover new anti-cancer drugs is an expanding area of research.

One class of frontline anti-cancer agents are the platinum-based drugs cisplatin, carboplatin, and

oxaliplatin. These agents are extremely effective at eradicating cancer cells (either alone or in combination with other treatments, but suffer from severe side-effects and poor activity against platinum-resistant cancers.

Other organometallic and inorganic complexes have been studied extensively as anti-cancer agents as an alternative to organic-based drugs. In this context, gold, platinum, and ruthenium, have attracted considerable attention and have been shown to be particularly

effective, often targeting mitochondria or DNA.

Organometallic complexes of rhenium that contain the robust Re (CO) 3 fragment have recently shown potential as cytotoxic agents, but they have been far less studied. All the reported cytotoxic rhenium complexes contain bidentate or tridentate ligands of nitrogen, oxygen, and phosphorous donors, a chemical design that seems to be predominantly inspired by the use of these species as luminescent cellular markers . Other rare examples include rhenium complexes bearing cyclopentadienyl ligands. However, the mechanism of action of these rhenium complexes has not been established in detail yet, which hinders the

systematic design and investigation of targeted rhenium complexes as anti-cancer agents .

There is therefore a need for new alternative therapeutic agents for treating cancer.

Summary

The present invention relates to rhenium complexes, more specifically rhenium complexes bound to C-donor N- heterocyclic carbene (NHC) ligands and their use in treating of cancer and inhibiting Aurora kinase

phosphorylation .

Accordingly, in one aspect of the present invention provides a method for treatment or prophylaxis of a cancer comprising administering an effective amount of a rhenium complex of formula (I) to a subject in need thereof:

wherein

ring A is selected from one of the following

structures :

Y is CR ₆ or N;

Z is CR ₇ or N;

Ri is selected from halo, thiocyanate, isothiocyanate , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , aryl, heterocyclyl , heteroaryl, -Ci-6alkylaryl , -Ci- ₆ alkylheteroaryl, -C ₂ - ₆ alkenylaryl, C ₂ - ₆ alkenylheteroaryl, -C2-6alkynylaryl and -C2-6alkynylheteroaryl ;

R ₂ and R ₃ are independently selected from H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy and acyl;

or R2 and R3 together with the carbon atoms to which they are attached form an optionally substituted

cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl ring;

R4 is selected from alkyl, alkenyl, alkynyl,

cycloalkyl, cycloalkenyl, aryl, heteroaryl, -Ci-6alkylNRsR9 , -Ci- ₆ alkylORio and -Ci- ₆ alkylP (R13) _m ;

each of Rs _a , Rsb, Rsc and Rsd is independently selected from H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy or acyl;

R6 and R7 are independently selected from H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy and acyl;

or R2 and R7 together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl, cycloalkenyl , aryl, heterocyclyl or heteroaryl ring;

one of R.8 and Rg is H and the other is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl and -C (O) Rn;

Rio is selected from alkyl, alkenyl, alkynyl,

cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl and -C (O) Rn;

Rn is selected from alkyl, alkenyl, alkynyl,

-C0-4alkylcycloalkenyl , -Co- ₄ alkylaryl ,

-Co- ₄ alkylheterocyclyl and Co- ₄ alkylheteroaryl ;

each Ri3 is independently selected from alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl; and

in is 2 or 3;

wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl group may be optionally substituted.

In another aspect, the present invention provides use of a rhenium complex of formula (I) as defined above in the manufacture of a medicament for treatment or

prophylaxis of a cancer.

A further aspect of the present invention provides a method for treatment or prophylaxis of a disease

associated with Aurora kinase activity comprising

administering an effective amount of a rhenium complex of formula (I) as defined above to a subject in need thereof.

In another aspect, there is provided use of a rhenium complex of formula (I) as defined above in the manufacture of a medicament for treatment or prophylaxis a disease associated with Aurora kinase activity.

A further aspect of the present invention provides an Aurora kinase phosphorylation inhibitor comprising a rhenium complex of formula (I) as defined above.

Another further aspect of the present invention provides a method of inhibiting Aurora kinase

phosphorylation comprising exposing a cell comprising an Aurora kinase to a rhenium complex of formula (I) as defined above.

Another yet further aspect of the present invention provides a pharmaceutical composition comprising a rhenium complex of formula (I) as defined above and a

pharmaceutically acceptable carrier.

Another still further aspect of the present invention provides a rhenium complex of formula (la) :

wherein

ring A is selected from one of the following

structures :

Y is CR ₆ or N; Z is CR ₇ or N;

Ri is selected from halo, thiocyanate, isothiocyanate , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , aryl, heterocyclyl , heteroaryl, -Ci-6alkylaryl ,

-Ci-6alkylheteroaryl , -C ₂ -6alkenylaryl ,

C ₂ -6alkenylheteroaryl, -C ₂ -6alkynylaryl and

-C ₂ -6alkynylheteroaryl ;

R ₂ and R ₃ are independently selected from H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy and acyl;

or R ₂ and R ₃ together with the carbon atoms to which they are attached form an optionally substituted

cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl ring;

R4 is selected from alkyl, alkenyl, alkynyl,

cycloalkyl, cycloalkenyl, aryl, heteroaryl, -Ci-ealkylNRsRg,

-Ci-ealkylORio, -Ci- ₆ alkylP ( R13 ) _m ;

Rsa, R5b, R5c and Rsd are each independently selected from H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy or acyl;

R6 and R7 are independently selected from H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy and acyl;

or R ₂ and R7 together with the carbon atoms to which they are attached form an optionally substituted

cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl ring;

one of Re and Rg is H and the other is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl and -C (O) Rn;

Rio is selected from alkyl, alkenyl, alkynyl,

cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl and -C (O) Rn;

Rn is selected from alkyl, alkenyl, alkynyl,

-Co-4alkylcycloalkenyl , -Co-4alkylaryl , -Co- 4alkylheterocyclyl and Co-4alkylheteroaryl ; and

each Ri3 is independently selected from alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl; and

is is 2 or 3;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl,

cycloalkenyl , aryl, heterocyclyl and heteroaryl group may be optionally substituted;

with the following provisos:

(i) when ring B is pyridyl, pyrimidyl, quinolinyl or

quinoxyl, ring A is R.4 is phenyl, Ri is not CI or Br;

(ii) when ring B is pyridyl, ring A is nd

R ₄ is n-butyl or mesityl, Ri is not CI o

(iii) when ring B is pyrimidyl, ring A i

and R4 is mesityl, Ri is not CI or Br;

(iv) when ring B is pyridyl or pyrimidyl, ring A is

, and R4 is mesityl, Ri is not

B is pyridyl, ring A is

, Rsa, R5b, R5c, R5d are each hydrogen and R ₄ is butyl, Ri is not CI or Br, Detailed description

Definitions

Unless defined otherwise, all technical and

scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are described. For the purposes of the present invention, the following terms are defined below.

The articles "a" and "an" are used herein to refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

Throughout this specification, unless the context requires otherwise, the words "comprise", "comprises" and "comprising" will be understood to imply the inclusion of a stated step or element or group of steps or elements but not the exclusion of any other step or element or group of steps or elements.

As used herein, the term "alkyl" refers to a straight chain or branched saturated hydrocarbon group having 1 to 15 carbon atoms. Where appropriate, the alkyl group may have a specified number of carbon atoms. For example,

Ci-6alkyl, which includes alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement. Examples of suitable alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl , 4-methylbutyl, n-hexyl, 2-methylpentyl, 3-methylpentyl , 4-methylpentyl , 5-methylpentyl, 2-ethylbutyl ,

3-ethylbutyl , heptyl, octyl, nonyl, decyl, undecyl and dodecyl .

As used herein, the term "alkenyl" refers to a straight chain or branched hydrocarbon group having one or more double bonds between carbon atoms and having 2 to 15 carbon atoms. Where appropriate, the alkenyl group may have a specified number of carbon atoms. For example, C ₂ -C6 as in "C ₂ -C ₆ alkenyl" includes groups having 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement. Examples of suitable alkenyl groups include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl and dodecenyl.

As used herein, the term "alkynyl" refers to a straight chain or branched hydrocarbon group having one or more triple bonds and having 2 to 15 carbon atoms . Where appropriate, the alkynyl group may have a specified number of carbon atoms. For example, C ₂ -C6 as in "C ₂ -C ₆ alkynyl" includes groups having 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement. Examples of suitable alkynyl groups include, but are not limited to ethynyl, propynyl, butynyl, pentynyl and hexynyl .

As used herein, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon. The cycloalkyl ring may include a specified number of carbon atoms. For example, a 3- to 8-membered cycloalkyl group includes a ring having 3, 4, 5, 6, 7 or 8 carbon atoms. Examples of suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

cycloheptyl and cyclooctyl .

As used herein, the term "cycloalkenyl" refers to an unsaturated cyclic hydrocarbon. The cycloalkenyl ring may include a specified number of carbon atoms. For example, a 5- to 8-membered cycloalkenyl group includes 5, 6, 7 or 8 carbon atoms. The cycloalkenyl group has one or more double bonds and when more than one double bond is present, the double bonds may be unconjugated or

conjugated, however the cycloalkenyl group is not

aromatic. Examples of suitable cycloalkenyl groups include, but are not limited to, cyclopentenyl ,

cyclohexenyl , cyclohexadienyl , cycloheptenyl ,

cycloheptadienyl , cycloheptatrienyl, cyclooctenyl , cyclooctadienyl and cyclooctatrienyl.

As used herein, the term "aryl" is intended to mean any stable, substituted or unsubstituted monocyclic, bicyclic or tricyclic carbon ring system of up to 7 atoms in each ring, wherein at least one ring is aromatic.

Examples of such aryl groups include, but are not limited to, phenyl, mesityl, naphthyl, tetrahydronaphthyl , indanyl, fluorenyl, phenanthrenyl, biphenyl and

binaphthyl .

As used herein, the term "alkoxy" refers to an alkyl group with an oxygen atom bonded anywhere along the hydrocarbon chain, especially where the oxygen atom is bonded at the beginning of the hydrocarbon chain. Examples include methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, t- butoxy and pentoxy.

As used herein, the term "acyl" refers to the group -C(0)R, where R is hydrogen or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or aryl. Examples of suitable acyl groups include formyl, acetyl, propionyl, benzoyl and acryloyl .

As used herein, the term "halogen" or "halo" refers to bromine (bromo) , chlorine (chloro), iodine (iodo) and fluorine (fluoro).

The term "heterocyclic" or "heterocyclyl" as used herein, refers to a cyclic hydrocarbon in which 1 to 4 carbon atoms have been replaced by heteroatoms

independently selected from the group consisting of N, N(R), S, S(O), S(0)2 and O. A heterocyclic ring may be saturated or unsaturated but not aromatic. Examples of suitable heterocyclyl groups include, but are not limited to, azetidine, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl , 2-oxopyrrolidinyl , pyrrolinyl, pyranyl, dioxolanyl, piperidinyl, 2-oxopiperidinyl, pyrazolinyl, imidazolinyl , thiazolinyl, dithiolyl, oxathiolyl,

dioxanyl, dioxinyl, dioxazolyl, oxathiozolyl , oxazolonyl, piperazinyl, morpholino, thiomorpholinyl, 3- oxomorpholinyl , dithianyl, trithianyl and oxazinyl. The term "heteroaryl" as used herein, represents a stable monocyclic, bicyclic or tricyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic and at least one ring contains from 1 to 4 heteroatoms selected from the group consisting of 0, N and S .

Heteroaryl groups within the scope of this definition include, but are not limited to, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl , quinazolinyl, pyrazolyl, indolyl, isoindolyl, 1H, 3H-l-oxoisoindolyl,

benzotriazolyl , furanyl, thienyl, thiophenyl,

benzothienyl , benzofuranyl , benzodioxane, benzodioxin, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl,

imidazolyl, pyrazinyl, pyridazinyl, pyridyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinolinyl, thiazolyl, isothiazolyl , 1 , 2 , 3-triazolyl , 1, 2 , -triazolyl,

1, 2, -oxadiazolyl, 1, 2, 4-thiadiazolyl, 1, 3, 5-triazinyl, 1, 2, 4-triazinyl, 1, 2, 4, 5-tetrazinyl and tetrazolyl.

Particular heteroaryl groups have 5- or 6-membered rings, such as pyrazolyl, furanyl, thienyl, oxazolyl, indolyl, isoindolyl, 1H, 3H-l-oxoisoindolyl, isoxazolyl, imidazolyl, pyrazinyl, pyridazinyl, pyridyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, isothiazolyl, 1 , 2 , 3-triazolyl,

1, 2, 4-triazolyl and 1 , 2 , 4-oxadiazolyl and

1,2, 4-thiadiazolyl .

The term "phosphonium" as used herein, refers to a positively charged phosphorous atom.

The terms "organophosphorous", "organophosphonium", and "organophosphine" as used herein, refer to a

phosphorous atom in the appropriate oxidation state that is covalently bonded to at least one carbon atom.

Each of the above groups may be optionally

substituted. Unless otherwise defined, the term

"optionally substituted" or "optional substituent" as used herein refers to a group which may or may not be further substituted with one or more groups selected from

-Ci- ₆ alkyl, -C ₂ - ₆ alkenyl, -C ₂ - ₆ alkynyl, -aryl, -aldehyde, oxo, halo, nitro, cyano, haloCi- ₆ alkyl-, haloC ₂ - ₆ alkenyl- , haloC ₂ - ₆ alkynyl-, haloaryl-, -hydroxy, -Ci- ₆ alkylhydroxy, Ci- ₆ alkoxy-, -OCi- ₆ alkylhydroxy, -OCi- ₆ alkylCi- ₆ alkoxy,

C ₂ - ₆ alkenyloxy- , aryloxy-, benzyloxy-, haloCi- ₆ alkoxy-, haloC2-6alkenyloxy-, haloaryloxy-, -amino, Ci-6alkylamino-, Ci- ₆ dialkylamino- , C ₂ - ₆ alkenylamino- , C ₂ - ₆ alkynylamino-, arylamino-, diarylamino- , benzylamino-, dibenzylamino-, -acyl, -Ci- ₆ alkylacyl, C ₂ - ₆ alkenylacyl-, C ₂ - ₆ alkynylacyl-, arylacyl-, acylamino-, diacylamino-, acyloxy-,

alkylsulphonyloxy-, arylsulphenyloxy-, -heterocyclyl, - heterocycloxy, heterocyclamino- , haloheterocyclyl-, heteroaryl-, heteroaryloxy-, -heteroarylamino,

haloheteroaryl-, alkylsulphenyl-, arylsulphenyl-, - mercapto, Ci- ₆ alkylthio-, benzylthio- and acylthio-.

Preferred substituents of groups include, but are not limited to, Ci-6alkyl, especially methyl, Ci-6alkoxy, especially methoxy, aryl, especially phenyl, and acyl, especially phenylC( O ) - , optionally further substituted with halo .

The complexes of the invention may be in the form of pharmaceutically acceptable salts. It will be appreciated however that non-pharmaceutically acceptable salts also fall within the scope of the invention since these may be useful as intermediates in the preparation of

pharmaceutically acceptable salts or may be useful during storage or transport.

Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically

acceptable inorganic acids such as hydrochloric,

sulphuric, phosphoric, nitric, carbonic, boric, sulfamic and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic,

benezenesulphonic, salicylic sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids. Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium.

Basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others .

The salts may also include a non-coordinating anion such as hexafluorophosphate, tetrafluoroborate ,

tetraphenylborate and perchlorate salts . Triflate salts are also included. Such salts may not be suitable as pharmaceutically acceptable salts, however may be useful for synthesis and/or purification processes.

Phosphorous-containing groups may be present in a number of different stable oxidation states in the

complexes disclosed herein, including -3, +3 and +5. The phosphorous-containing compounds of the invention

generally comprise phosphorous in a +3 oxidation state.

Phosphorous-containing groups may comprise an

organophosphine (e.g. a complex of formula (I) wherein R ₄ is -Ci- ₆ alkylP ( Ri3 ) and m is 2) . Organophosphines may be prone to oxidation under mild conditions, and therefore the present compounds may also include corresponding phosphine oxides (e.g. a compound of formula (I) wherein R ₄ is -Ci- ₆ alkylP(0) (Ris ) .

Phosphorous-containing compounds of the invention may comprise a phosphonium atom. Due to the positive charge on the phosphonium atom, phosphonium-containing complexes are typically provided in the form of a salt. Phosphonium compounds of the invention may be provided as any suitable salt form, for example, selected from any of the above salts, and preferably in the form of a salt comprising a non-coordinating anion.

Some organophosphonium compounds (such as an

alkylphosphonium compound) may form a phosphorous ylid upon exposure to a base. The term "phosphorous ylid" as used herein, refers to a neutral dipolar molecule

containing an atom with formal negative charge bonded to a phosphorous atom with a formal positive charge, where both atoms have full octets of electrons. It will be

appreciated therefore that a reference to -Ci-6alkylP ⁺ (R13) 3 also includes a reference to its corresponding phosphorous ylid, which may be denoted as -Ci-5alkylCH ^" P ⁺ (R13) 3 or -Ci- ₅ alkylCH=P (R13) 3.

It will also be recognised that the rhenium complexes of the invention may possess asymmetric centres and are therefore capable of existing in more than one

stereoisomeric form. The invention thus also relates to rhenium complexes in substantially pure isomeric form at one or more asymmetric centres, e.g., greater than about 90% ee, such as about 95% or 97% ee, or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof. Such isomers may be prepared by asymmetric synthesis, for example using chiral intermediates, or by chiral resolution.

Methods of treatment

The rhenium complexes of the present invention are inhibitors of Aurora kinase phosphorylation, and therefore useful as therapeutic agents for the treatment of a variety of cancers.

There are three subtypes of Aurora kinase, namely Aurora A, Aurora B and Aurora C. Therefore, in some embodiments, Aurora kinase is Aurora A, Aurora B or Aurora C.

Aurora A plays a crucial role in mitotic entry and G2 checkpoint control. Dysregulation of Aurora A induces abnormal G2-M transition in mammalian cells leading to chromosome instability and eventually in the development and progression of malignant tumors. Several studies have also shown amplification and overexpression of Aurora kinase A gene (AURKA) in several cancers. Increasing evidence demonstrates that Aurora A plays a key role in regulating cell cycle and mitosis, as well as a number of important oncogenic signaling pathways.

Without wishing to be bound by theory, it is thought that a rhenium complex of formula (I) acts as a cytostatic drug by inducing a cell cycle arrest at the G ₂ /M phase associated with inhibition of the phosphorylation of Aurora A kinase.

Accordingly, in one aspect of the invention there is provided a method for treatment or prophylaxis of a cancer comprising administering an effective amount of a rhenium complex of formula (I) to a subject in need thereof:

wherein

ring A is selected from one of the following

structures :

Y is CR ₆ or N;

Z is CR ₇ or N;

Ri is selected from halo, thiocyanate, isothiocyanate , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , aryl, heterocyclyl , heteroaryl, -Ci-6alkylaryl,

-Ci-6alkylheteroaryl , -C2-6alkenylaryl ,

C ₂ -6alkenylheteroaryl, -C ₂ -6alkynylaryl and

-C2-6alkynylheteroaryl ;

R ₂ and R ₃ are independently selected from H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy and acyl;

or R2 and R3 together with the carbon atoms to which they are attached form an optionally substituted

cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl ring;

R4 is selected from alkyl, alkenyl, alkynyl,

cycloalkyl, cycloalkenyl, aryl, heteroaryl, -Ci- 6al kylNRsR9 , -Ci- ₆ alkylORio and -Ci- ₆ alkylP (R13 ) _m ;

each of Rs _a , Rsb, Rsc and Rsd is independently selected from H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy or acyl;

R6 and R7 are independently selected from H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy and acyl;

or R2 and R7 together with the carbon atoms to which they are attached form an optionally substituted

cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl ring;

one of Re and Rg is H and the other is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , aryl, heterocyclyl, heteroaryl and -C (O) Rn;

Rio is selected from alkyl, alkenyl, alkynyl,

cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl and -C (O) Rn;

Rn is selected from alkyl, alkenyl, alkynyl,

-C0-4alkylcycloalkenyl , -Co- ₄ alkylaryl ,

-Co- ₄ alkylheterocyclyl and Co- ₄ alkylheteroaryl ;

each Ri3 is independently selected from alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl; and

is is 2 or 3;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl group may be optionally substituted.

In some embodiments, the carbene ligand is normal, abnormal or a mixture thereof. In a particular embodiment, the carbene ligand is normal.

In some embodiments, ring A is selected from one of the following structures :

In some embodiments, ring A has the following structure :

In some embodiments, R ₂ and R ₃ are each H; or R ₂ and R ₃ together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl, cycloalkenyl , aryl, heterocyclyl or heteroaryl ring. In a particular embodiment, R ₂ and R ₃ together with the carbon atoms to which they are attached form an optionally substituted aryl, especially a phenyl group.

In some embodiments, the ring B is selected from one of the following structures:

In one particular embodiment, the rhenium complex of formula (I) is a rhenium complex of formula (II) :

wherein

Y is CR ₆ or N;

Z is CR ₇ or N;

Ri is selected from halo, thiocyanate, isothiocyanate , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, -Ci-6alkylaryl ,

-Ci- ₆ alkylheteroaryl , -C ₂ - ₆ alkenylaryl , C ₂ - ₆ alkenylheteroaryl, -C ₂ - ₆ alkynylaryl and

-C ₂ - ₆ alkynylheteroaryl ;

R ₂ and R3 are each H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , aryl, heterocyclyl, heteroaryl, alkoxy or acyl;

or R. ₂ and R3 together with the carbon atoms to which they are attached form an optionally substituted

cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl ring;

R4 is selected from alkyl, alkenyl, alkynyl,

cycloalkyl, cycloalkenyl, aryl, heteroaryl, -Ci-ealkylNRsRg , -Ci- ₆ alkylORio and -Ci- ₆ alkylP (R13 ) _m ;

R6 and R7 are independently selected from H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy and acyl;

or R ₂ and R7 together with the carbon atoms to which they are attached form an optionally substituted

cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl ring;

one of Re and Rg is H and the other is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl and -C (O) Rn;

Rio is selected from alkyl, alkenyl, alkynyl,

cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl and -C (O) Rn;

Rn is selected from alkyl, alkenyl, alkynyl,

-C0-4alkylcycloalkenyl , -Co-4alkylaryl ,

-Co- ₄ alkylheterocyclyl and Co- ₄ alkylheteroaryl ;

each Ri3 is independently selected from alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl; and

is is 2 or 3;

wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl group may be optionally substituted.

In another particular embodiment, the rhenium complex of formula (I) is a rhenium complex of formula (III) :

wherein

one of Wi and W2 is N and the other is CR12 , wherein

R12 is H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , aryl, heterocyclyl, heteroaryl, alkoxy or acyl;

Y is CR ₆ or N;

Z is CR ₇ or N;

Ri is selected from halo, thiocyanate, isothiocyanate , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, -Ci- ₆ alkylaryl ,

-Ci- ₆ alkylheteroaryl , -C2- ₆ alkenylaryl ,

C2- ₆ alkenylheteroaryl, -C2- ₆ alkynylaryl and

-C2- ₆ alkynylheteroaryl ;

R2 and R ₃ are each H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy or acyl;

or R2 and R ₃ together with the carbon atoms to which they are attached form an optionally substituted

cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl ring;

R4 is selected from alkyl, alkenyl, alkynyl,

cycloalkyl, cycloalkenyl, aryl, heteroaryl, -Ci-ealkylNRsRg, -Ci- ₆ alkylORio and -Ci- ₆ alkylP (R13 ) _m ;

R6 and R ₇ are independently selected from H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy and acyl;

or R2 and R ₇ together with the carbon atoms to which they are attached form an optionally substituted

cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl ring;

one of R.8 and Rg is H and the other is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , aryl, heterocyclyl, heteroaryl and -C (O) Rn;

Rio is selected from alkyl, alkenyl, alkynyl,

cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl and -C (O) Rn;

Rn is selected from alkyl, alkenyl, alkynyl,

-Co- ₄ alkylcycloalkenyl , -Co- ₄ alkylaryl ,

-Co- ₄ alkylheterocyclyl and Co- ₄ alkylheteroaryl ;

each Ri3 is independently selected from alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl; and

is is 2 or 3;

wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl group may be optionally substituted.

In one embodiment, Ri is selected from halo,

especially Br, CI and I, or is thiocyanate and

isothiocyanate . In another embodiment, Ri is optionally substituted and selected from C ₂ - ₆ alkynylaryl and

heteroaryl. The C ₂ - ₆ alkynylaryl may be -ethynylphenyl . The heteroaryl may be 5- or 6-membered ring, such as pyridyl, tetrazolyl and imidazolyl, each of which may be optionally substituted with alkyl or aryl. In this embodiment, Ri may be pyridyl, phenyltetrazolyl or 3-methyl-l-imidazolyl .

In one embodiment, R4 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, -Ci- ealkylNRsRg and -Ci- ₆ alkylORio .

In one embodiment, R4 is optionally substituted and selected from alkyl, aryl, -Ci-6alkylNRsRg, -Ci-6alkylORio or -Ci-6alkylP (R13) The alkyl may be Ci-isalkyl, especially ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl . The aryl may be phenyl or substituted phenyl such as mesityl. A particular

substituent is methoxy. With -Ci-6al kylNRsRg and -Ci- 6al kylORio , Rg and Rio may be -C(0)Rn, where Rn may be a substituted Co- ₄ alkylheteroaryl . In some embodiments, R ₄ is propyl indomethacin, propyl indomethacinamide or propyl acetamide .

In one embodiment, ring A is ; Y is CR.6 ; Z is CR7; Ri is halo; R2 and R3 are each H, or R2 and R3 together with the carbon atoms to which they are attached form an aryl ring; R ₄ is selected from alkyl, aryl, propyl

indomethacin and -C1-C6P ( R13 ) m! R6 and R7 are each H; each Ri3 is independently selected from alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl; and m is 2 or 3.

In particular embodiments, the rhenium complex of formula (I) is:

Particular rhenium complexes of formula (II) include Rhenium Complexes 5, 6, 9, 10, 12, 14, 15, 16, 17, 18, 19,

20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,

34, 35, 36, 37 and 38, especially Rhenium Complexes 9, 10,

12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 25, 26, 27, 29,

30, 31, 32, 33, 34, 35, 36, 37 and 38. In one embodiment, the complex is selected from Rhenium Complexes 9, 21, 26,

27, 37 and 38.

Particular rhenium complexes of formula (III) include Rhenium Complexes 1, 2, 3, 4, 7 and 8, especially Rhenium Complexes 1, 2, 3 and 4. In another aspect, the present invention provides use of a rhenium complex of formula (I) as defined above in the manufacture of a medicament for treatment or prophylaxis of a cancer.

A further aspect of the present invention provides a method for treatment or prophylaxis of a disease

associated with Aurora kinase activity comprising

administering an effective amount of a rhenium complex of formula (I) as defined above to a subject in need thereof.

In another aspect, there is provided use of a rhenium complex of formula (I) as defined above in the manufacture of a medicament for treatment or prophylaxis a disease associated with Aurora kinase activity.

A further aspect of the present invention provides an Aurora kinase phosphorylation inhibitor comprising a rhenium complex of formula (I) as defined above. Another further aspect of the present invention provides a method of inhibiting Aurora kinase

phosphorylation comprising exposing a cell comprising an Aurora kinase to a rhenium complex of formula (I) as defined above. In some embodiments, the cell is in vivo. In other embodiments, the cell is in vitro.

In some embodiments, the cancer may be a blood cancer or bone marrow cancer. In other embodiments, the cancer is a solid tumour cancer.

In some embodiments, the cancer is leukemia such as acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia or chronic myelogenous leukemia. In some embodiments, the cancer is a lymphoma such as Hodgkin' s disease, non-Hodgkin' s lymphoma or AIDs- associated lymphoma. In some embodiments, the cancer is a myeloma such as multiple myeloma.

In some embodiments, the cancer is a solid tumour cancer, for example, bladder cancer, brain tumour, spinal tumour, breast cancer, cervical cancer, colon cancer, rectal cancer, esophageal cancer, Ewing' s sarcoma, head or neck cancer, oral cancer, ovarian cancer, endometrial cancer, uterine cancer, kidney cancer, adrenal cancer, liver cancer, skin cancer such as melanoma, osteosarcoma, bone cancer, pancreatic cancer, prostate cancer,

testicular cancer, thyroid cancer, biliary tract cancer, pharyngeal cancer and nerve cancer.

In particular embodiments, the cancer is a cancer associated with Aurora kinase activity such as a blood cancer, breast cancer, uterine cancer, cervical cancer, pancreatic cancer, prostate cancer, bladder cancer, kidney cancer, stomach cancer, esophageal cancer, liver cancer, colon cancer, rectal cancer, biliary tract cancer, lung cancer, cancer of the oral cavity, bone cancer such as osteosarcoma, pharyngeal cancer, melanoma, a brain tumour such as a brain neoplasm or a nerve cancer such as neuroblastoma .

In one embodiment, the cancer is pancreatic cancer. In another embodiment, the cancer is neuroblastoma.

In some embodiments, the cancer is associated with a KRAS mutation. KRAS is a protooncogene . The presence of KRAS-mut in cancerous tissue may be detected by any means known in the art, for example therascreen KRAS test (QUIAGEN) .

It is also noted that, in some embodiments, the rhenium complexes are cytostatic agents, while in other embodiments, the rhenium complexes are cytotoxic agents.

The subjects (or individuals or patients) to be treated are vertebrate subjects, such as a mammalian subject or a fish subject. Mammalian subjects include but are not limited to humans, primates, livestock animals such as sheep, cattle, pigs, horses, donkeys and goats; laboratory test animals such as mice, rats, rabbits and guinea pigs; companion animals such as cats and dogs or captive wild animals such as those kept in zoos. In a particular embodiment, the subject is a human. Fish subjects include but are not limited to zebrafish.

An "effective amount" means an amount necessary to at least partly attain the desired response, or to delay the onset or inhibit progression or halt altogether, the onset or progression of a particular disease being treated. The amount varies depending upon the health and physical condition of the subject to be treated, the taxonomic group of subject to be treated, the degree of protection desired, the formulation of the rhenium complex, the assessment of the medical situation, and other relevant factors . It is expected that the amount will fall in a relatively broad range that can be determined through routine trials . An effective amount in relation to a human subject, for example, may lie in the range of about 0.1 ng per kg of body weight to 1 g per kg of body weight per dosage. The dosage is preferably in the range of 1 pq to 1 g per kg of body weight per dosage, such as in the range of 1 mg to 1 g per kg of body weight per dosage. In one embodiment, the dosage is in the range of 1 mg to 500 mg per kg of body weight per dosage. In another embodiment, the dosage is in the range of 1 mg to 250 mg per kg of body weight per dosage. In yet another embodiment, the dosage is in the range of 1 mg to 100 mg per kg of body weight per dosage, such as up to 50 mg per kg of body weight per dosage. In yet another embodiment, the dosage is in the range of 1 pq to 1 mg per kg of body weight per dosage .

Dosage regimes may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily, weekly, monthly or other suitable time intervals, or the dose may be proportionally reduced as indicated by the exigencies of the situation.

Reference herein to "treatment" and "prophylaxis" is to be considered in its broadest context. The term

"treatment" does not necessarily imply that a subject is treated until total recovery. "Treatment" may reduce the severity of an existing condition. The term "prophylaxis" does not necessarily mean that the subject will not eventually contract a disease condition. The term

"prophylaxis" may be considered to include delaying the onset of a particular condition. Accordingly, treatment and prophylaxis include amelioration of the symptoms of a particular condition or preventing or otherwise reducing the risk of developing a particular condition.

In some embodiments, the rhenium complex of formula (I) may be administered together with another therapy. Administration may be in a single composition or in separate compositions simultaneously or sequentially such that both are active at the same time in the body.

In some embodiments, the rhenium complex of formula (I) is administered together with another therapy, especially another therapy to treat cancer, for example radiotherapy or in combination with a second anti-cancer drug. In such embodiments, the amount of the second anticancer drug may be reduced when administration is together with a rhenium complex of formula (I) . The second anti-cancer drug may be a known anticancer drug. These known anti-cancer agents include the following: oestrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, anti-proliferative agents, and further angiogenesis inhibitors.

"Oestrogen receptor modulators" refers to compounds which interfere with or inhibit the binding of oestrogen to the receptor, regardless of mechanism. Examples of oestrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381, LY 117081, toremifene, fulvestrant, 4- [7- ( 2 , 2-dimethyl-l-oxopropoxy- -methyl-2- [4- [2- (1- piperidinyl ) ethoxy] phenyl ] -2H-1- benzopyran-3-yl] phenyl 2 , 2-dimethylpropanoate, 4,4'- dihydroxybenzophenone-2 , 4-dinitrophenylhydrazone and SH646.

"Androgen receptor modulators" refers to compounds which interfere with or inhibit the binding of androgens to the receptor, regardless of mechanism. Examples of androgen receptor modulators include finasteride and other 5ot-reductase inhibitors, nilutamide, flutamide,

bicalutamide , liarozole and abiraterone acetate.

"Retinoid receptor modulators" refers to compounds which interfere with or inhibit the binding of retinoids to the receptor, regardless of mechanism. Examples of such retinoid receptor modulators include bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,

ot-difluoromethylornithine, ILX23-7553, trans-N-(4'- hydroxyphenyl ) retinamide and N-4-carboxyphenylretinamide .

"Cytotoxic agents" refers to compounds which result in cell death primarily through direct action on the cellular function or inhibit or interfere with cell myosis, including alkylating agents, tumour necrosis factors, intercalators , microtubulin inhibitors and topoisomerase inhibitors . Examples of cytotoxic agents include, but are not limited to, tirapazimine, sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine, prednimustine , dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide , heptaplatin, estramustine , improsulfan tosylate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin,

cisplatin, irofulven, dexifosfamide, cis-aminedichloro ( 2- methylpyridine ) platinum, benzylguanine, glufosfamide, GPX100 , (trans , trans , trans ) bis-mu- (hexane-1 , 6-diamine ) -mu- [diamineplatinum ( II ) ] bis [diamine ( chloro ) platinum ( II ) ] tetrachloride, diarisidinylspermine, arsenic trioxide, 1- ( 11-dodecylamino-lO-hydroxyundecyl ) -3 , 7-dimethyl- xanthine, zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone , pirarubicin, pinafide, valrubicin,

amrubicin, antineoplaston, 3 ' -deamino-3 ' -morpholino- 13-deoxo-lO-hydroxycarminomycin, annamycin, galarubicin, elinafide, MEN10755 and 4-demethoxy-3-deamino-3-azirid- inyl-4-methylsulfonyldaunorubicin (see WO 00/50032) .

Examples of microtubulin inhibitors include

paclitaxel, vindesine sulfate, 3 ' , 4 ' -didehydro-4 ' -deoxy- 8 ' -norvincaleukoblastine , docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin, 2,3,4,5,6- pentafluoro-N- ( 3-fluoro-4-methoxyphenyl )

benzenesulfonamide, anhydrovinblastine, N, -dimethyl-L- valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t- butylamide, TDX258 and BMS188797.

Topoisomerase inhibitors are, for example, topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl- 3 ' , 4 ' -O-exobenzylidenechartreusin, 9-methoxy-N, -dimethyl- 5-nitropyrazolo [3,4,5-kl]acridine-2-(6H) -propanamine, l-amino-9-ethyl-5-fluoro-2 , 3-dihydro-9-hydroxy-4-methyl- 1H, 12H-benzo [de] pyrano [3 ' , 4 ' :b, 7] indolizino [1, 2b]

quinoline-10, 13 ( 9H, 15H) -dione, lurtotecan, 7-[2-(N- isopropylamino ) ethyl] - (20S) -camptothecin, BNP1350,

BNPI1100, BN80915, BN80942, etoposide phosphate,

teniposide, sobuzoxane, 2 ' -dimethylamino-2 ' - deoxyetoposide , GL331, N- [2- (dimethylamino) ethyl] -9- hydroxy-5 , 6-dimethyl-6H-pyrido [ , 3-b] carbazole-l-carbox- amide, asulacrine, (5a, 5aB, 8aa, 9b) -9- [2- [N- [2- (di- methylamino) ethyl] -N-methylamino] ethyl] -5- [4-hydroxy-3, 5- dimethoxyphenyl] -5, 5a, 6, 8, 8a, 9-hexohydro- furo ( 3 ' , 4 ' : 6 , 7 ) naphtho ( 2 , 3-d) -1 , 3-dioxol-6-one , 2,3-

(methylenedioxy) -5-methyl-7-hydroxy-8-methoxybenzo [c] phen- anthridinium, 6, 9-bis [ (2-aminoethyl) amino] benzo [g] isoquinoline-5,10-dione, 5- ( 3-aminopropylamino ) -7 , 10- dihydroxy-2- (2-hydroxyethylaminomethyl) -6H-pyrazolo [4,5,1- de ] acridin-6-one , N- [ 1- [ 2 ( diethylamino ) ethylamino ] -7- methoxy-9-oxo-9H-thioxanthen-4-ylmethyl] formamide, N- (2- (dimethylamino ) ethyl) acridine-4-carboxamide, 6- [ [2- ( dimethylamino ) ethyl] amino ] -3-hydroxy-7H-indeno [2 , 1-c] - quinolin-7-one and dimesna.

"Anti-proliferative agents" include antisense RNA and

DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and INX3001 and antimetabolites such as

enocitabine, carmofur, tegafur, pentostatin, doxifluri- dine, trimetrexate, fludarabine, capecitabine,

galocitabine , cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2 ' -deoxy- 2 ' -methylidenecytidine, 2 ' -fluoromethylene-2 ' - deoxycytidine, N- [5- (2, 3-dihydrobenzofuryl ) sulfonyl] -N' - (3, 4-dichlorophenyl) urea, N6- [4-deoxy-4- [N2- [2 (E) , 4 (E) - tetradecadienoyl ] glycylamino] -L-glycero-B-L-mannohepto- pyranosyl] adenine, aplidine, ecteinascidin, troxacitabine, 4- [2-amino-4-oxo-4 , 6,7, 8-tetrahydro-3H-pyrimidino [5 , 4-b] - 1, 4-thiazin-6-yl- (S) -ethyl ] -2 , 5-thienoyl-L-glutamic acid, aminopterin, 5-fluorouracil, alanosine, ll-acetyl-8-

( carbamoyloxymethyl ) -4-formyl-6-methoxy-14-oxa-l, 11-diaza- tetracyclo (7.4.1.0.0) tetradeca-2, 4, 6-trien-9-ylacetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase, 2 ' -cyano-2 ' -deoxy-N4-palmitoyl-l-B-D-arabinofuranosyl cytosine and 3-aminopyridine-2-carboxaldehyde thiosemi- carbazone. "Antiproliferative agents" also include monoclonal antibodies to growth factors other than those listed under "angiogenesis inhibitors", such as

trastuzumab, and tumour suppressor genes, such as p53, which can be delivered via recombinant virus-mediated gene transfer (see US Patent No. 6,069,134, for example) .

The rhenium complexes of the present invention may also be suitable for administration at the same time as radiotherapy, alone or in combination with one or more anti-cancer drugs.

Pharmaceutical compositions

While it is possible that, for use in therapy, a rhenium complex may be administered as a neat chemical, it is generally preferable that it is formulated in a pharmaceutical composition.

Thus, in another aspect of the present invention there is provided a pharmaceutical composition comprising a rhenium complex of formula (I) as defined above and a pharmaceutically acceptable carrier.

It is possible that the pharmaceutical composition may be in any suitable form suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration.

In a one embodiment, the pharmaceutical composition is in a form suitable for oral administration. In another embodiment, the pharmaceutical composition is in a form suitable for parenteral administration. In this

embodiment, the pharmaceutical composition may be in a form suitable for intravenous administration, for example, an injectable composition.

The pharmaceutical composition for oral

administration may be in the form of capsule or tablet. The oral composition may also comprise conventional excipients such as starch, lactose, talc, magnesium stearate and so on. The oral composition may also comprise other excipients known in the art for oral compositions, including for example, a diluent, a binder, a lubricant, a fluidizing agent, and an adhesion inhibitor. The pharmaceutical composition for parenteral administration, more specifically, for intravenous administration, may be in form of an injectable

composition. The injectable composition may comprise conventional excipients such as a solvent (such as an alcohol including ethanol or benzylalcohol,

propyleneglycol, glycerine, a higher fatty acid ester such as ethyl oleinate) , a diluent (such as a phosphate buffer saline (PBS) or saline), and an antiseptic (such as sodium benzoate, methylparaben and propylparaben). The injectable composition may also comprise other excipients known in the art for such kinds of compositions.

The injectable composition can also be freeze-dried to be in the form of a powder. The powder would then be dissolved in a suitable solvent such as an alcohol, and diluted with a phosphate buffer saline (PBS) or saline, before administration to a subject.

Rhenium complexes

Some of the rhenium complexes of formula (I) are new.

Therefore, in another aspect of the present invention there is provided a rhenium complex of formula (la) :

wherein

ring A is selected from one of the following

structures :

Y is CR ₆ or N;

Z is CR ₇ or N;

Ri is selected from halo, thiocyanate, isothiocyanate , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , aryl, heterocyclyl , heteroaryl, -Ci-6alkylaryl ,

-Ci-6alkylheteroaryl , -C2-6alkenylaryl ,

C2-6alkenylheteroaryl, -C2-6alkynylaryl and

-C2-6alkynylheteroaryl ;

R2 and R ₃ are independently selected from H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy and acyl;

or R2 and R3 together with the carbon atoms to which they are attached form an optionally substituted

cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl ring;

R4 is selected from alkyl, alkenyl, alkynyl,

cycloalkyl, cycloalkenyl, aryl, heteroaryl, -Ci-6alkylNRsR9 , -Ci- ₆ alkylORio and -Ci- ₆ alkylP (R13 ) _m ;

Rsa, R5b, R5c and Rsd are each independently selected from H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy or acyl;

R6 and R7 are independently selected from H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, alkoxy and acyl; or R.2 and R7 together with the carbon atoms to which they are attached form an optionally substituted

cycloalkyl, cycloalkenyl , aryl, heterocyclyl or heteroaryl ring;

one of R.8 and Rg is H and the other is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl and -C (O) Rn;

Rio is selected from alkyl, alkenyl, alkynyl,

cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl and -C (O) Rn;

Rn is selected from alkyl, alkenyl, alkynyl,

-C0-4alkylcycloalkenyl , -Co- ₄ alkylaryl ,

-Co- ₄ alkylheterocyclyl and Co- ₄ alkylheteroaryl ;

each Ri3 is independently selected from alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl; and

is is 2 or 3;

wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl group may be optionally substituted;

with the following provisos:

(i) when ring B is pyridy pyrimidyl, quinolinyl or

quinoxyl, ring A is and R4 is phenyl,

and R.4 is mesityl, Ri is not CI or Br;

B is pyridyl or pyrimidyl, ring A is

is mesityl, Ri is not

B is pyridyl, ring

, Rsa, R5b, R5c, R5d are each hydrc and R4 is butyl, Ri is not CI or Br

(vi) when ring B is pyrimidyl, ring A is

and R4 is n-butyl, Ri is not CI or Br.

In particular embodiments, the rhenium complex of formula (la) is:

Synthesis of Rhenium Complexes

The following is a description of a synthesis method for preparing the rhenium complexes described above.

Methods of making pyridyl, pyrimidyl, quinoxylyl, quinolinyl and isoquinolinyl imidazolium salts are known in the art, for example, by the methods described by Loch et al. Organometallics (2002) 21:700-706; Kaufhold et al. J. Organometallic Chem. (2008) 693:3435-3440 and Vaughan et al. Inorganic Chemistry (2014) 53, 3629-3641.

In general, the rhenium complexes may be synthesised by reaction of a pyridyl, pyrimidyl, quinoxyl, quinolinyl or isoquinolinyl derivative of an imidazolium salt, thiazolium salt, oxazolium salt, benzimidazolium salt, benzothiazolium salt or benzoxazolium salt with Re(CO)5X complexes in the presence of a solvent, such as toluene or dichloromethane, at reflux and in the presence of a base, such as triethylamine as shown in Scheme 1.

This method is particularly useful in preparing rhenium complexes in which the group X is a halide such as a chloride or bromide. However, the group X, when it is a halide such as chloride or bromide, may be readily replaced by reaction with a sodium salt in the presence of silver triflate to produce a rhenium complex where X is other than chloride or bromide, as shown in Scheme 2.

14 (56%, X I)

Scheme 2

In some embodiments, when the reaction of Scheme 1 is undertaken, the resulting product may be a functionalised normal carbene or an abnormal carbene as shown in Scheme 3.

Scheme 3

It is preferred that all reactions are carried out under an atmosphere of 2 and that all reactions are carried out in the dark where possible.

Brief description of the figures

The examples will be described with reference to the accompanying figures in which:

Figure 1 is a graphical representation showing the activity of rhenium complexes 9 (yellow diamond) , 10 (blue square) and 21 (red triangle) against pancreatic cancer cells AsPCl (a), CFPAC (b) and HPAF (c) . The results are shown as cell counts as a percent of control.

Figure 2 provides a graphical representation of a cell cycle analysis of AsPCl cells exposed to rhenium complexes 9, 10 and 21 and controls gemcitabine,

Nocodazole (a positive G2/M blocker) and DMSO vehicle control. The left hand blue panel shows the G0/G1 gated population, the central red panel shows the S gated population and the right hand green panel shows the G2/M gated population together with the relative abundances in percent .

Figure 3 provides graphical representations of the apoptotic index and cytotoxicity index for Rhenium Complex 9 (a and b) , Rhenium Complex 21 (c and d) and Rhenium Complex 10 (e and f ) .

Figure 4 is a Western blot analysis of activated phosphor-Aurora A (Threonine 288) in AsPCl cells treated for 24 hours with Rhenium Complexes 9, 10 and 21. Samples were analysed for Aurora A phosphorylation (Th-288), Total Aurora A protein (Aurora-A) and α-Actinin. The same blot used for phosphor-Aurora A was stripped and then reprobed with Anti-Aurora A antibody. Results are representative of three independent experiments .

Figure 5 is a graphical representation showing the activity of Rhenium Complex 9 against neuroblastoma cancer cell line SHSY5. The results are shown as cell counts as a percent of control.

Figure 6 is a graphical representation showing the activity of Rhenium Complexes 10, 21, 26 and 27 against neuroblastoma cancer cell line SHSY5. The results are shown as cell counts as a percent of control.

Figure 7 is a series of images showing the activity of Rhenium Complex 21 compared to a dimethylsulphoxide (DMSO) control in primary cells derived from KPC mice primary pancreatic tumour.

Figure 8 is a dose response curve for the activity of Rhenium Complex 21 against primary cells derived from KPC mice primary pancreatic tumour (p<0.0001; one-way ANOVA) .

Figure 9 is a series of graphical representations of zebrafish hatching counts at various time points after treatment with DMSO (negative control) , Rhenium Complex 21, Rhenium Complex 37 or cisplatin (positive control).

Figure 10 is a series of graphical representations of zebrafish mortality rates at various time points after treatment with DMSO (negative control) , Rhenium Complex 21, Rhenium Complex 37 or cisplatin (positive control).

Figure 11 is a graphical representation of zebrafish heartbeats following treatment with various doses of Rhenium Complex 21 compared to a DMSO control.

Examples

Various embodiments/aspects of the present invention will now be described with reference to the following non- limiting examples.

General methods and reagents

All reagents and solvents were purchased from Sigma Aldrich, Strem, or Alfa Aesar and used as received without further purification. All reactions were conducted under an atmosphere of 2. All reactions and subsequent

manipulations were performed in the dark where possible. 1- ( 2-pyridyl ) imidazole, 1- ( 2-pyridyl ) -1, 2 , -triazole, 4- (2-pyridyl) -1, 2, -triazole, 4- ( 2 , 6-pyrimidyl ) -1 , 2 , 4- triazole, l-(2, 4-pyrimidyl ) -4 -butyl-1 , 3-imidazolium hexafluorophosphate , N- (3-bromopropyl) acetamide, Rhenium Complexes 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 36 and Re (phen) (C0)3C1 were prepared according to

previously published procedures (e.g. Inorganic Chemistry 2011, 50, 1229; Dalton Transactions 2013, 42, 14100 and Inorganic Chemistry 2014, 53, 3629). Nuclear magnetic resonance spectra were recorded using a Bruker Avance 400 spectrometer (400.1 MHz for ¹ H; 100 MHz for ¹³ C; 162 MHz for ³¹ P) at 300 K. All the NMR spectra were calibrated to residual solvent signals . Infrared spectra were recorded using an attenuated total reflectance Perkin Elmer

Spectrum 100 FT-IR with a diamond stage. IR spectra were recorded from 4000 to 650 cm ^-1 . The intensities of the IR bands are reported as strong (s), medium (m) , or weak (w) , with broad (br) bands also specified. Elemental analyses were obtained at Curtin University using a Thermo Finnigan EA 1112 Series Flash. Synthesis of Azolium Salts

Example 1

A mixture of 4-bromobutane (76 μΐ,, 0.70 mmol) and

1- (2-pyridyl) -1, 2, 4-triazole (103 mg, 0.70 mmol) in acetonitrile (2 mL) was heated in a sealed tube at 120 °C for 2 days. The solution was cooled and then filtered through Celite into stirring diethyl ether. The resulting solid was collected, washed with diethyl ether (3 x 3 mL) and dried to afford the product as a hygroscopic white powder. Yield: 118.2 mg, 60%. Anal. calc. for

CiiHi ₅ BrN ₄ .1.25 (H ₂ 0) : C 43.22, H 5.77, N 18.33; found: C 42.82, H 5.32, N 18.19. FT-IR (ATR) Vmax/cm ^"1 : 3372 br w, 2958 w, 1570 m, 1469 m, 1195 m, 972 m. ^! H-NMR δ/ppm

(de-DMSO) : 11.13 (1H, m, H5 ) , 9.59 (1H, s, H3), 8.74 (1H, ddd, ³ JH, H = 4.8 Hz, ⁴ JH, H = 1.9 Hz, ⁵ J ^" _H , H = 0.8 Hz, H6') , 8.29 (1H, ddd, ³ JH, H = 8.2 Hz, ³ J ^" _H , H = 7.5 Hz, ⁴ J ^" _H , H = 1.9 Hz, H4') , 8.09 (1H, ddd, ^{3 H} - ^li = 8.2 Hz, ⁴ JH, H = 1.0 Hz, ⁵ J ^H - ^H = 0.8 Hz, H3') , 7.76 (1H, ddd, ³ JH, H = 7.5 Hz, ³ JH, H = 4.8 Hz, ⁴ JH, H = 1.0 Hz, H5') , 4.41 (2H, t, ³ JH, H = 7.3 Hz, NCH ₂ ), 1.96 (2H, m, NCH ₂ CH ₂ ), 1.40 (2H, m, NCH ₂ CH ₂ CH ₂ ), 0.98 (3H, t, ³ JH, H = 7.4 Hz, CH ₃ ) . ¹³ C-NMR δ/ppm (d ₆ -DMSO) : 149.2 (C6') , 147.0 (C2'), 145.4 (C3), 141.4 (C5), 141.0 (C4') , 126.1 (C5') , 113.8 (C3') , 47.8 (NCH ₂ ), 30.7 (NCH ₂ CH ₂ ), 18.8 (NCH ₂ CH ₂ CH ₂ ) , 13.3 (CH ₃ ) .

Example 2

A mixture of 4-bromobutane (300 μL, 2.74 mmol) and

4- (2-pyridyl) -1, 2, 4-triazole (400 mg, 2.74 mmol) in acetonitrile (8 mL) was heated in a sealed tube at 120 °C for 2 days. The solution was cooled, concentrated to 3 mL and then filtered through Celite into stirring diethyl ether. The resulting solid was collected, washed with diethyl ether (3 x 3 mL) and dried to afford the product as a hygroscopic white powder. Yield: 590 mg, 76%. Anal. calc. for CiiHi ₅ BrN ₄ .0.3 (H ₂ 0) : C 45.50, H 5.48, N 19.29;

found: C 45.34, H 5.12, N 19.43. FT-IR (ATR) Vmax/cm ^"1 : 3490 br w, 2961 m, 1560 s, 1472 m, 1340 m, 1100 m, 992 m. ^X H-NMR δ/ppm (de-DMSO) : 11.13 (1H, m, H5), 10.07 (1H, s, H3), 8.73 (1H, ddd, ³ JH, H = 4.8 Hz, ⁴ J ^" _H , H = 1.8 Hz, ⁵ J ^" _H , H = 0.8 Hz, H6') , 8.32 (1H, ddd, ³ J ^" _H , H = 8.2 Hz, ³ J ^" _H , H = 7.5 Hz, ⁴ J ^" _H , H = 1.8 Hz, H4') , 8.13 (1H, ddd, ³ JH, H = 8.2 Hz, ⁴ JH, H = 0.9 Hz, ⁵ JH, H = 0.8 Hz, H3') , 7.75 (1H, ddd, ³ J ^" _H , H = 7.5 Hz, ³ J ^" _H , H = 4.8 Hz, ⁴ JH, H = 0.9 Hz, H5') , 4.52 (2H, t, ³ JH, H = 7.0 Hz, NCH ₂ ), 1.97 (2H, m, NCH ₂ Cfi ₂ ), 1.42 (2H, m, NCH ₂ CH ₂ Cfi ₂ ) , 0.98 (3H, t, ³ JH, H = 7.4 Hz, CH ₃ ) . ¹³ C-NMR δ/ppm (d ₆ -DMSO) : 149.3 (C6') , 144.8 (C2') , 141.6 (C3), 140.7 (C5), 140.6 (C4') , 125.8 (C5'), 115.1 (C3') , 51.7 (NCH ₂ ), 29.9 (NCH ₂ CH ₂ ), 18.7

(NCH ₂ CH ₂ CH ₂ ) , 13.3 (CH ₃ ) .

Example 3

A mixture of 4-bromobutane (295 μL, 2.72 mmol) and

4- (2, 4-pyrimidyl) -1, 2, 4-triazole (400 mg, 2.72 mmol) in acetonitrile (8 mL) was heated in a sealed tube at 120 °C for 2 days. The solution was cooled and the resulting solid dissolved by addition of methanol (5 mL) and then dried. Acetone (5 mL) was added to the residue and the resulting solid was collected, washed with cold acetone (3 x 3 mL) and diethyl ether (3 x 3 mL) and dried to afford the product as a hygroscopic white powder. Yield: 580 mg, 75%. Anal. calc. for CioHi ₄ BrN ₅ . ( H ₂ 0 ) : C 39.75, H 5.34, N 23.18; found: C 39.90, H 5.12, N 23.14. FT-IR (ATR)

Vmax/cm ^"1 : 3469 br m, 2966 m, 1557 s, 1439 s, 1397 s, 1346 m, 1101 m, 985 m. ^X H-NMR δ/ppm (d ₆ -DMSO) : 11.13 (1H, m,

H5), 10.08 (1H, s, H3), 9.15 (2H, d, ³ JH, H = 4.9 Hz, Η4'/6') , 7.88 (1H, d, ³ JH,H = 4.9 Hz, H5') , 4.54 (2H, t, ³ JH,H = 7.0 Hz, NCH ₂ ), 1.96 (2H, m, NCH ₂ C¾), 1.40 (2H, m, NCH ₂ CH ₂ C¾ ) , 0.97 (3H, t, ³ JH,H = 7.4 Hz, CH ₃ ) . ¹³ C-NMR δ/ppm (d ₆ -DMSO): 160.2 (C4'/6'), 151.0 (C2') , 141.9 (C3), 141.4 (C5), 123.0 (C5') , 51.7 (NCH ₂ ), 30.0 (NCH ₂ CH ₂ ), 18.6 (NCH ₂ CH ₂ CH ₂ ) , 13.2 (CH ₃ ) .

Example 4

A mixture of N- ( 3-bromopropyl ) acetamide (303 mg, 1.69 mmol) and 1- ( 2 ' -pyridyl ) imidazole (246 mg, 1.69 mmol) in acetonitrile (5 mL) was heated in a sealed tube at 120 °C for 2 days. The solution was cooled and the solvent was removed in vacuo. The resulting oil was triturated with diethyl ether (3 x 10 mL) then dissolved in methanol/water (50/50, 2 mL) and dropped into a stirring solution of excess NaBPti ₄ in a methanol/water solution (50/50, 2 mL) . The resulting solid was stirred for 20 min and then collected, washed with water (5 x 3 mL) , dried, then diethyl ether (2 x 3 mL) and dried. The solid was then subjected to column chromatography on silica (gradient elution using dichloromethane/methanol ) . The fractions containing the product were dried, then dissolved in a minimum amount of dichloromethane and filtered through a 0.2 μπι PTFE membrane directly into diethyl ether. The resulting gum was triturated with diethyl ether (5 x 3 mL) and dried in vacuo, affording the product as a hygroscopic fluffy white solid, which was ca 90 - 95% pure by ^! H-NMR, and was used without further purification in the following step. Yield: 400 mg, 42%. ^! H-NMR δ/ppm (d ₆ -DMSO) : 10.10 (1H, m, H2), 8.69 (1H, ddd, ³ JH,H = 4.7 Hz, ⁴ JH,H = 1.8 Hz, ⁵ JH,H = 0.8 Hz, H6') , 8.56 (1H, m, H4 ) , 8.25 (1H, ddd, ³ JH,H = 8.2 Hz, ³ JH,H = 7.5 Hz, ⁴ JH,H = 1.8 Hz, H4') , 8.09 (1H, m, H5), 8.05 (1H, ddd, ³ J ^" _H ,H = 8.2 Hz, ⁴ J ^" _H ,H = 0.9 Hz, ⁵ J ^" _H ,H = 0.8 Hz, H3') , 8.00 (1H, app t, NH), 7.68 (1H, ddd, ³ J ^" _H ,H = 7.5 Hz, ³ JH,H = 4.7 Hz, ⁴ J ^" _H ,H = 0.9 Hz, H5') , 7.22 (8H, m, BPh ₄ Ar CH), 6.96 (8H, m, BPh ₄ Ar CH) , 6.83 (4H, m, BPh ₄ Ar CH), 4.32 (2H, t, ³ JH,H = 6.9 Hz, NCH ₂ ), 3.14 (2H, m,

CONHCH ₂ ) , 2.06 (2H, m, NCH ₂ Cfi ₂ ) , 1.86 (3H, s, CH ₃ ).

Example 5

A solution of ( 3-bromopropyl ) triphenylphosphonium bromide

(0.75 g, 1.62 mmol) in a mixture of CHaCN/MeOH (9:1, 10 mL) was added dropwise to a refluxing solution of l-(2- pyridyl) imidazole (0.28 g, 1.94 mmol) in CH3CN (10 mL) and the resulting solution stirred at reflux for 2 d. The resulting colourless solution was concentrated to dryness and the residue was triturated with diethyl ether (3 5 mL) . The resulting clear gum was purified by column chromatography eluting with a gradient of

dichloromethane/methanol to obtain the pure product as a bromide salt. The bromide salt was dissolved in a minimal amount of water and treated with a solution of KPF6 in water (lg, 5.43 mmol) . The resulting precipitate was collected, washed with water (3 x 5 mL) , dried, and then washed with diethyl ether (3 x 5 mL) , to afford the product as a slightly hydroscopic white powder. Yield:

0.71 g, 59%. Anal. calc. for C29H28 F12N3P3 . (H2O) : C 45.98, H 3.99, N 5.55; found: C 46.11, H 4.08, N 5.52. FT-IR (ATR) Vmax/cm ^"1 : 3164 w (H ₂ 0) , 1545 m, 1477 m, 1441 s, 1211 m, 1113 s, 1083 m. ¹ H-NMR δ/ppm (DMSO-d ₆ ) : 10.15 (1H, s, H2 ) , 8.71 (1H, ddd, ³ JH,H = 4.9 Hz, ⁴ JH,H = 1.8 Hz, ⁵ JH,H = 0.8 Hz, H6') , 8.60 (1H, m, H4), 8.28 (1H, ddd, ³ JH,H = 8.3 Hz, ³ JH,H = 7.5 Hz, ⁴ JH,H = 1.8 Hz, H4') , 8.07 (1H, ddd, ³ JH,H = 8.3 Hz, ³ JH,H = 4.9 Hz, ⁴ JH,H = 4.8 Hz, H5') , 8.04 (1H, m, H5), 7.96 (3H, m, Ar CH) , 7.79 - 7.85 (2 x6H, 2 x m, 2 x Ar CH) , 7.70 (1H, ddd, ³ JH,H = 7.5 Hz, ⁴ JH,H = 4.8 Hz, ⁵ J ^" _H ,H = 0.8 Hz, H3') , 4.49 (2H, m, NC¾), 3.69 (2H, m, CH ₂ P) , 2.27 (2H, m, NCH ₂ C¾) . ¹³ C-NMR δ/ppm (DMSO-d ₆ ) : 149.3 (C6') , 146.3 (py quat . C) , 140.7 (C4') , 135.6 (C2), 135.1 (d, ³ J _C , _P = 10.1 Hz, Ar CH) , 133.6 (d, ⁴ JC,P = 3.1 Hz, Ar CH) , 130.3 (d, ² J ^" _C ,P = 12.5 Hz, Ar CH), 125.3 (C5), 123.5 (C5') , 119.3 (C4), 118.0 (d, ¹ J _c ,v = 86.4 Hz, Ar C) , 114.0 (C3') , 49.3 (d, ³ Jc,p = 20.5 Hz,

NCH ₂ ), 22.4 (NCH ₂ CH ₂ ), 17.8 (d, ¹ J,v = 52.9 Hz, CH ₂ P) . ³¹ P- NMR δ/ppm (DMSO-d ₆ ) : -24.0 (CH ₂ PPh ₃ ), -144.2 (PF ₆ ) .

Synthesis of Rhenium Complexes

Example 6 : Rhenium Complex 1

Triethylamine (1.03 mL, 7.40 mmol) was added to a mixture of 1- (2-pyridyl) -4-butyl-l, 2, 4-triazolium bromide (210 mg, 0.74 mmol) and Re(CO) ₅ Br (301 mg, 0.74 mmol) in toluene (10 mL) and then heated at reflux for 2 days. The yellow solution was decanted off and the remaining residue washed with toluene (2 x 5 mL) , and the combined organic

fractions dried in vacuo. The resulting residue was dissolved in dichloromethane (~10 mL) and washed with water (2 x 10 mL) , then dried over MgS0 ₄ . The residue was dissolved in a minimum amount of dichloromethane and filtered through a plug of acidic alumina (Brockmann grade II), eluting with dichloromethane until the eluent was colourless. The solution was dried concentrated to ~3 mL and filtered through a plug of Celite into stirring pentane (~5 mL) . The resulting solid was collected, washed with pentane (3 x 5 mL) and dried to afford the product as a yellow powder. Yield: 184.5 mg, 45%. Anal. calc. for Ci4Hi ₄ Br 40 ₃ Re: C 30.44, H 2.55, N 10.14; found: C 30.90, H 2.44, N 10.06. FT-IR (ATR) Vmax/cm ^"1 : 2013 s (CO), 1910 s

(CO), 1882 s (CO), 1621 m, 1483 m, 1392 w, 1349 w, 1075 w. ^! H-NMR δ/ppm (CDCI3) : 8.55 (1H, ddd, ³ JH,H = 5.6 Hz, ⁴ J ^" _H ,H = 1.6 Hz, ⁵ JH,H = 0.8 Hz, H6') , 8.10 (1H, s, H3), 8.08 (1H, ddd, ³ JH,H = 8.3 Hz, ³ JH,H = 7.2 Hz, ⁴ J ^" _H ,H = 1.6 Hz, H4') , 8.04 (1H, ddd, ³ JH,H = 8.3 Hz, ⁴ JH,H = 1.6 Hz, ⁵ JH,H = 0.8 Hz, H3') , 7.39 (1H, ddd, ³ J ^" _H ,H = 7.2 Hz, ³ J ^" _H ,H = 5.6 Hz, ⁴ J ^" _H ,H = 1.6 Hz, H5') , 4.36 (2H, m, NCH ₂ ), 2.02 (2H, m, NCH ₂ Cfi ₂ ), 1.49 (2H, m, Cfi ₂ CH ₃ ) , 1.02 (3H, apparent t, ³ JH,H = 7.4 Hz, CH ₃ ).

1 ³ C-NMR δ/ppm ( CDCI ₃ ) : 199.4 (CO), 196.3 (CO), 195.9 (C5), 186.8 (CO), 153.5 (C6') , 152.3 (C2') , 143.4 (C3), 141.1

(C4'), 124.5 (C5') , 113.4 (C3') , 50.0 (NCH ₂ ), 32.9 (NCH ₂ CH ₂ ), 19.9 (CH ₂ CH ₃ ) , 13.7 (CH ₃ ) .

Example 7 : Rhenium Complex 2

A saturated aqueous solution of potassium

hexafluorophosphate was added to an aqueous solution of azolium salt prepared in Example 1 until precipitation ceased. The resulting solid was collected, dried, and used in the following reaction without further purification.

Triethylamine (0.66 mL, 4.70 mmol) was added to a mixture of 1- (2-pyridyl) -4-butyl-l, 2, -triazolium hexafluoro- phosphate (164 mg, 0.47 mmol) and Re(CO) ₅ Cl (171 mg, 0.47 mmol) in toluene (7 mL) and then heated at reflux for 3 days. The yellow solution was decanted off and the remaining residue washed with toluene (2 x 5 mL) , and the combined organic fractions dried in vacuo. The resulting residue was dissolved in dichloromethane (~10 mL) and washed with water (2 x 10 mL) , then dried over MgS04. The residue was dissolved in a minimum amount of

dichloromethane and filtered through a plug of acidic alumina (Brockmann grade II), eluting with dichloromethane until the eluent was colourless . The solution was dried concentrated to ~3 mL and filtered through a plug of

Celite into stirring pentane (~5 mL) . The resulting solid was collected, washed with pentane (3 x 5 mL) and dried to afford a yellow powder. Recrystallisation by vapour diffusion from deuterated chloroform/petroleum spirits afforded the product as yellow microcrystals . Yield: 43.1 mg, 18%. Anal. calc. for Ci4Hi ₄ Cl 40 ₃ Re : C 33.10, H 2.78, N 11.03; found: C 33.05, H 2.45, N 11.06. FT-IR (ATR)

Vmax/cm ^"1 : 2012 s (CO), 1905 s (CO), 1869 s (CO), 1620 m, 1482 m, 1392 w, 1349 w, 1074 w. ^X H-NMR δ/ppm (CDCI3) : 8.85 (1H, ddd, ³ JH,H = 5.6 Hz, ⁴ J ^" _H ,H = 1.6 Hz, ⁵ J ^" _H ,H = 0.8 Hz, H6') , 8.10 (1H, ddd, ³ J ^" _H ,H = 8.3 Hz, ³ J ^" _H ,H = 7.2 Hz, ⁴ J ^" _H ,H = 1.6 Hz, H4') , 8.09 (1H, s, H3 ) , 8.04 (1H, ddd, ³ JH,H = 8.3 Hz, ⁴ JH,H = 1.6 Hz, ⁵ JH,H = 0.8 Hz, H3') , 7.41 (1H, ddd, ³ J ^" _H ,H = 7.2 Hz, ³ JH,H = 5.6 Hz, ⁴ JH,H = 1.6 Hz, H5') , 4.35 (2H, m, NCH ₂ ), 2.01 (2H, m, NCH ₂ Cfi ₂ ), 1.49 (2H, m, Cfi ₂ CH ₃ ), 1.02 (3H, apparent t, ³ JH,H = 7.4 Hz, CH ₃ ) . ¹³ C-NMR δ/ppm (CDCI3) : 197.0 (CO), 196.9 (CO), 196.6 (C5), 187.3 (CO), 153.3 (C6'), 152.3 (C2'), 143.4 (C3), 141.2 (C4') , 124.6 (C5') , 113.4 (C3') , 50.0 (NCH ₂ ), 33.1 (NCH ₂ CH ₂ ), 19.9 (CH ₂ CH ₃ ), 13.7 (CH ₃ ). Example 8 : Rhenium Complex 3

Triethylamine (0.99 mL, 7.06 mmol) was added to a mixture of l-butyl-4- (2-pyridyl) -1, 2, -triazolium bromide from Example 2 (200 mg, 0.71 mmol) and Re(CO) ₅ Br (287 mg, 0.71 mmol) in toluene (7 mL) and then heated at reflux for 3 days. The yellow solution was decanted off and the remaining residue washed with toluene (2 x 5 mL) , and the combined organic fractions dried in vacuo. The resulting residue was dissolved in dichloromethane (~10 mL) and washed with water (3 x 10 mL) , then dried over MgS04. The resulting residue was subjected to column chromatography on acidic alumina (Brockmann grade II, gradient elution using petroleum spirits/dichloromethane ) . The purified fractions were combined, dried in vacuo, then dissolved in dichloromethane (2 mL) and precipitated with pentane. The resulting solid was collected, washed with pentane ( x 3 mL) , and dried to afford the product as a yellow solid. Yield: 77.1 mg, 20%. Anal. calc. for Ci4Hi ₄ Br 40 ₃ Re : C

30.44, H 2.55, N 10.14; found: C 30.45, H 2.12, N 10.11. FT-IR (ATR) Vmax/cm ^"1 : 2018 s (CO), 1931 s (CO), 1889 s (CO), 1614 m, 1488 s, 1333 m, 1249 w. ^! H-NMR δ/ppm (CDCls): 8.94 (1H, ddd, ³ J ^" _H ,H = 5.6 Hz, ⁴ J ^" _H ,H = 1.6 Hz, ⁵ J ^" _H ,H = 0.8 Hz, H6') , 8.70 (1H, s, H3 ) , 8.06 (1H, ddd, ³ JH,H = 8.2 Hz, ³ JH,H = 7.6 Hz, ⁴ JH,H = 1.6 Hz, H4') , 8.04 (1H, ddd, ³ J ^" _H ,H = 8.2 Hz, ⁴ JH,H = 1.2 Hz, ⁵ JH,H = 0.8 Hz, H3') , 7.40 (1H, ddd, ³ JH,H = 7.6 Hz, ³ JH,H = 5.6 Hz, ⁴ J ^" _H ,H = 1.2 Hz, H5') , 4.49 (2H, m, NCH ₂ ), 2.03 (2H, m, NCH ₂ Cfi ₂ ), 1.50 (2H, m, C¾CH ₃ ), 1.01 (3H, apparent t, ³ J ^" _H , _H = 7.4 Hz, CH ₃ ) . ¹³ C-NMR δ/ppm (CDCI3) : 196.5 (CO), 196.4 (CO), 190.9 (C5), 187.4 (CO), 154.4 - si - i c e' ) , 150.3 (C2') , 141.3 (C4') , 137.1 (C3), 124.7 (C5') , 112.4 (C3') , 53.8 (NCH ₂ ), 32.2 (NCH ₂ CH ₂ ), 19.9 (CH ₂ CH ₃ ), 13.7 (CH ₃ ) .

Example 9 : Rhenium Complex 4

A saturated aqueous solution of potassium

hexafluorophosphate was added to an aqueous solution of the complex prepared in Example 2 until precipitation ceased. The resulting solid was collected, dried, and used in the following reaction without further purification.

Triethylamine (0.80 mL, 5.74 mmol) was added to a mixture of l-butyl-4- (2-pyridyl) -1,2, 4-triazolium

hexafluorophosphate (200 mg, 0.57 mmol) and Re(CO) ₅ Cl (208 mg, 0.57 mmol) in toluene (8 mL) and then heated at reflux for 2 days. The yellow solution was decanted off and the remaining residue washed with toluene (2 x 5 mL) , and the combined organic fractions dried in vacuo. The resulting residue was dissolved in dichloromethane (~10 mL) and washed with water (3 x 10 mL) , then dried over MgS04. The resulting residue was subjected to column chromatography on acidic alumina (Brockmann grade II, gradient elution using petroleum spirits/dichloromethane ) . The purified fractions were combined, dried in vacuo, then dissolved in dichloromethane (2 mL) and precipitated with pentane. The resulting solid was collected, washed with pentane (4 x 3 mL) , and dried to afford a yellow solid. Recrystallisation by vapour diffusion from methanol/diethyl ether afforded the product as yellow microcrystals . Yield: 59.7 mg, 21%. Anal. calc. for Ci4Hi4ClN ₄ 0 ₃ Re : C 33.10, H 2.78, N 11.03; found: C 33.09, H 2.29, N 10.89. FT-IR (ATR) Vmax/cm ^"1 : 2017 s (CO), 1929 s (CO), 1880 s (CO), 1614 m, 1487 s, 1334 m, 1249 w. ^! H- MR δ/ppm (CDCI ₃ ) : 8.93 (1H, ddd, ³ J ^" _H , _H = 5.5 Hz, ⁴ JH,H = 1.7 Hz, ⁵ JH,H = 0.8 Hz, H6') , 8.72 (1H, s, H3 ) , 8.04 (1H, ddd, ³ JH,H = 8.2 Hz, ³ J ^" _H ,H = 7.6 Hz, ⁴ J ^" _H ,H = 1.7 Hz, H4') , 7.77 (1H, ddd, ³ JH,H = 8.2 Hz, ⁴ JH,H = 1.2 Hz, ⁵ JH,H = 0.8 Hz, H3') , 7.40 (1H, ddd, ³ JH,H = 7.6 Hz, ³ JH,H = 5.5 Hz, ⁴ JH,H = 1.2 Hz, H5') , 4.49 (2H, m, NCH ₂ ) , 2.03 (2H, m, NCH ₂ C¾), 1.50 (2H, m, Cfi ₂ CH ₃ ) , 1.02 (3H, apparent t, ³ J _H , _H = 7.4 Hz, CH ₃ ) . ¹³ C-NMR δ/ppm (CDCI ₃ ) : 197.1 (CO), 197.0 (CO), 191.7 (C5), 187.9 (CO), 154.2 (C6') , 150.3 (C2') , 141.4 (C4') , 137.2 (C3), 124.8 (C5') , 112.5 (C3') , 53.9 (NCH ₂ ), 32.3 (NCH ₂ CH ₂ ), 19.8 (CH ₂ CH ₃ ), 13.8 (CH ₃ ).

Example 10: Rhenium Complex 5

Triethylamine (0.80 mL, 5.74 mmol) was added to a mixture of 1- ( 2 , 6-pyrimidyl ) -3-butyl-imidazolium

hexafluorophosphate (200 mg, 0.57 mmol) and Re(CO)5Br (233 mg, 0.57 mmol) in toluene (8 mL) and then heated at reflux for 2 days. The yellow solution was decanted off and the remaining residue washed with toluene (2 x 5 mL) , and the combined organic fractions dried in vacuo. The resulting residue was dissolved in dichloromethane (~10 mL) and washed with water (3 x 10 mL) , then dried over MgS04. The resulting residue was subjected to column chromatography on acidic alumina (Brockmann grade II, gradient elution using petroleum spirits/dichloromethane ) . The purified fractions were combined, dried in vacuo, then dissolved in dichloromethane (2 mL) and precipitated with pentane. The resulting solid was collected, washed with pentane (4 x 3 mL) , and dried to afford the product as a yellow solid. Yield: 38.0 mg, 12%. Anal. calc. for Ci4Hi ₄ Br 40 ₃ Re : C 30.44, H 2.55, N 10.14; found: C 30.49, H 2.36, N 10.09.

FT-IR (ATR) Vmax/cm ^"1 : 2016 s (CO), 1914 s (CO), 1871 s (CO), 1593 m, 1473 s, 1364 m, 1249 w. ^! H-NMR δ/ppm (CDCI3) : 9.08 (1H, dd, ³ Jk,H = 5.5 Hz, ⁴ Jk,H = 2.3 Hz, H6') , 8.84 (1H, dd, ³ JH,H = 4.8 Hz, ⁴ JH,H = 2.3 Hz, H4'), 7.89 (1H, d, ³ JH,H = 2.2 Hz, H4), 7.32 (1H, dd, ³ J ^" _H ,H = 5.5 Hz, ³ J ^" _H ,H = 4.8 Hz, H5') , 7.05 (1H, d, ³ JH,H = 2.2 Hz, H5 ) , 4.28 (2H, m, NCH ₂ ), 1.98 (2H, m, NCH ₂ C¾), 1.50 (2H, m, Cfi ₂ CH ₃ ), 1.01 (3H, apparent t, ³ JH,H = 7.4 Hz, CH ₃ ) . ¹³ C-NMR δ/ppm (CDCI3) :

197.0 (CO), 196.3 (CO), 191.5 (C2), 187.4 (CO), 162.2

(C4'), 159.9 (C6') , 158.6 (C2') , 123.0 (C5), 119.2 (C5') , 117.8 (C4), 52.2 (NCH ₂ ), 33.2 (NCH ₂ CH ₂ ), 20.0 (CH ₂ CH ₃ ), 13.8 (CH ₃ ) .

Example 11: Rhenium Complex 6

Triethylamine (0.80 mL, 5.74 mmol) was added to a mixture of 1- ( 2 , 6-pyrimidyl ) -3-butyl-imidazolium

hexafluorophosphate (200 mg, 0.57 mmol) and Re(CO) ₅ Cl (208 mg, 0.57 mmol) in toluene (8 mL) and then heated at reflux for 2 days. The yellow solution was decanted off and the remaining residue washed with toluene (2 x 5 mL) , and the combined organic fractions dried in vacuo. The resulting residue was dissolved in dichloromethane (~10 mL) and washed with water (3 x 10 mL) , then dried over MgS04. The resulting residue was subjected to column chromatography on acidic alumina (Brockmann grade II, gradient elution using petroleum spirits/dichloromethane ) . The purified fractions were combined, dried in vacuo, then dissolved in dichloromethane (2 mL) and precipitated with pentane. The resulting solid was collected, washed with pentane (4 x 3 mL) , and dried to afford the product as a yellow solid. Yield: 75.2 mg, 26%. Anal. calc. for Ci4Hi ₄ Cl 40 ₃ Re : C

33.10, H 2.78, N 11.03; found: C 33.11, H 2.57, N 10.98. FT-IR (ATR) Vmax/cm ^"1 : 2012 s (CO), 1910 s (CO), 1880 s (CO), 1597 m, 1474 s, 1363 m, 1249 w. ^! H-NMR δ/ppm (CDCls): 9.07 (1H, dd, ³ JH,H = 5.5 Hz, ⁴ JH,H = 2.2 Hz, H6') , 8.85 (1H, dd, ³ JH,H = 4.8 Hz, ⁴ JH,H = 2.2 Hz, H4'), 7.88 (1H, d, ³ JH,H = 2.1 Hz, H4), 7.34 (1H, dd, ³ J ^" _H ,H = 5.5 Hz, ³ J ^" _H ,H = 4.8 Hz, H5') , 7.05 (1H, d, ³ JH,H = 2.1 Hz, H5 ) , 4.27 (2H, m, NCH ₂ ), 1.96 (2H, m, NCH ₂ C¾), 1.49 (2H, m, Cfi ₂ CH ₃ ), 1.01 (3H, apparent t, ³ JH,H = 7.4 Hz, CH ₃ ) . ¹³ C-NMR δ/ppm (CDCI3) :

197.6 (CO), 196.9 (CO), 192.4 (C2), 187.9 (CO), 162.1 (C4'), 160.0 (C6') , 158.7 (C2') , 122.9 (C5), 119.9 (C5') , 117.8 (C4), 52.2 (NCH ₂ ), 33.3 (NCH ₂ CH ₂ ), 20.0 (CH ₂ CH ₃ ), 13.8 (CH ₃ ) .

Example 12: Rhenium Complex 7

Triethylamine (0.98 mL, 7.04 mmol) was added to a mixture of l-butyl-4- (2, 6-pyrimidyl) -1, 2, 4-triazolium bromide (200 mg, 0.70 mmol) and Re(CO)5Br (286 mg, 0.70 mmol) in toluene (10 mL) and then heated at reflux for 3 days. The yellow solution was decanted off and the remaining residue washed with toluene (2 x 5 mL) , and the combined organic

fractions dried in vacuo. The resulting residue was dissolved in dichloromethane (~10 mL) and washed with water (3 x 10 mL) , then dried over MgS04. The resulting residue was subjected to column chromatography on acidic alumina (Brockmann grade II, gradient elution using petroleum spirits/dichloromethane ) . The purified fractions were combined, dried in vacuo, then dissolved in

dichloromethane (2 mL) and precipitated with pentane. The resulting solid was collected, washed with pentane ( x 3 mL) , and dried to afford the product as a yellow solid. Yield: 187.7 mg, 48%. Anal. calc. for CisHisBrNsOsRe : C 28.22, H 2.37, N 12.66; found: C 28.19, H 2.12, N 12.76. FT-IR (ATR) Vmax/cm ^"1 : 2020 s (CO), 1932 s (CO), 1890 s

(CO), 1594 m, 1475 s, 1385 m, 1329 m. ^! H-NMR δ/ppm (CDCI3) : 9.13 (1H, dd, ³ JH,H = 5.6 Hz, ⁴ JH,H = 2.2 Hz, H6') , 8.90 (1H, dd, ³ JH,H = 4.8 Hz, ⁴ JH,H = 2.2 Hz, H4'), 8.90 (1H, s, H3), 7.45 (1H, dd, ³ JH,H = 5.6 Hz, ³ JH,H = 4.8 Hz, H5') , 4.48 (2H, apparent t, ³ JH,H = 7.3 Hz, NCH ₂ ) , 2.04 (2H, m, NCH ₂ Cfi ₂ ),

1.50 (2H, m, Cfi ₂ CH ₃ ) , 1.01 (3H, apparent t, ³ JH,H = 7.4 Hz, CH ₃ ) . ¹³ C-NMR δ/ppm (CDCI3) : 196.0 (CO), 195.7 (CO), 189.0 (C5), 186.7 (CO), 162.6 (C4') , 160.1 (C6') , 156.5 (C2') , 138.8 (C3), 121.0 (C5') , 53.5 (NCH ₂ ), 32.1 (NCH ₂ CH ₂ ), 19.8 (CH ₂ CH ₃ ) , 13.7 (CH ₃ ) .

Example 13: Rhenium Complex 8

A saturated aqueous solution of potassium

hexafluorophosphate was added to an aqueous solution of the complex prepared in Example 3 until precipitation ceased. The resulting solid was collected, dried, and used in the following reaction without further purification. Triethylamine (0.52 mL, 3.72 mmol) was added to a mixture of l-butyl-4- (2, 6-pyrimidyl) -1, 2, 4-triazolium

hexafluorophosphate (130 mg, 0.37 mmol) and Re(CO)5Cl (135 mg, 0.37 mmol) in toluene (10 mL) and then heated at reflux for 3 days. The mixture was dried, and the

resulting residue was subjected to column chromatography on acidic alumina (Brockmann grade II, gradient elution using petroleum spirits/dichloromethane ) . The purified fractions were combined, dried in vacuo, then dissolved in dichloromethane (2 mL) and precipitated with pentane. The resulting solid was collected, washed with pentane ( x 3 mL) , and dried to afford the product as a yellow solid. Yield: 82.8 mg, 44%. Anal. calc. for CisHisCl sOsRe : C

30.68, H 2.57, N 13.76; found: C 30.60, H 2.34, N 13.71. FT-IR (ATR) Vmax/cm ^"1 : 2020 s (CO), 1930 s (CO), 1886 s (CO), 1595 m, 1473 s, 1385 m, 1329 m. ^X H-NMR δ/ppm (CDCI3) : 9.12 (1H, dd, ³ JH,H = 5.6 Hz, ⁴ JH,H = 2.2 Hz, H6') , 8.92 (1H, dd, ³ JH,H = 4.8 Hz, ⁴ JH,H = 2.2 Hz, H4'), 8.87 (1H, s, H3),

7.46 (1H, dd, ³ JH,H = 5.6 Hz, ³ JH,H = 4.8 Hz, H5') , 4.49 (2H, m, NCH ₂ ) , 2.03 (2H, m, NCH ₂ Cfi ₂ ) , 1.49 (2H, m, Cfi ₂ CH ₃ ), 1.01 (3H, apparent t, ³ J ^" _H , _H = 7.4 Hz, CH ₃ ) . ¹³ C-NMR δ/ppm (CDCI3) : 196.5 (CO), 196.4 (CO), 189.8 (C5), 187.3 (CO), 162.4 (C4'), 160.2 (C6') , 156.6 (C2') , 138.9 (C3), 121.1 (C5') , 53.6 (NCH ₂ ), 32.2 (NCH ₂ CH ₂ ), 19.8 (CH ₂ CH ₃ ), 13.7 (CH ₃ ).

Example 14: Rhenium Complex 14

Silver triflate (14 mg, 0.054 mmol) was added to a mixture of Rhenium Complex 27 (28 mg, 0.045 mmol) in

tetrahydrofuran (10 mL) and the mixture heated at reflux for 20 h. An additional portion of silver triflate (6 mg) was added and heating continued for 3 h. The mixture was cannula filtered into another Schlenk flask. Sodium iodide (20 mg, 0.14 mmol) was added to the resulting solution, which was then heated at 50 °C for 20 h. The solution was dried in vacuo, and the resulting residue dissolved in dichloromethane and washed with water (3 x 10 mL) then died over MgS04. The residue was dissolved in

dichloromethane (2 mL) and precipitated with diethyl ether/petroleum spirits (50/50) . The resulting solids was collected, washed with diethyl ether/petroleum spirits (50/50, x 3 mL) , and dried to afford Rhenium Complex 14 as a yellow solid. Yield: 17 mg, 56%. Anal. calc. for C ₂ iHi3l 30 ₃ Re : C 37.73, H 1.96, N 6.29; found: C 37.40, H 1.63, N 6.20. FT-IR (ATR) Vmax/cm ^"1 : 2008 s (CO), 1884 s (CO), 1864 s (CO), 1599 w, 1514 w, 1426 m. ^X H-NMR δ/ppm (CDCls) : 8.81 (1H, m, H8') , 8.49 (1H, m, H4') , 7.99 (1H, m, H6') , 7.93 (1H, m, H5') , 7.88 (1H, d, ³ JH,H = 2.2 Hz, H4 ) , 7.74 (1H, m, H3') , 7.72 (2H, m, Ar CH) , 7.71 (1H, m, H7') ,

7.62 (1H, m, Ar CH) , 7.61 (2H, m, Ar CH), 7.35 (1H, d, ³ J _H , _H = 2.2 Hz, H5). ¹³ C-NMR δ/ppm (CDCI ₃ ) : 195.9 (CO), 194.4 (CO), 193.1 (C2), 187.6 (CO), 153.5 (Ar C), 147.4 (Ar C), 142.4 (C4') , 139.4 (Ar C), 133.2 (C6') , 130.7 (Ar CH) , 130.2 (Ar CH) , 130.1 (C8') , 128.9 (C5') , 128.1 (C7') , 126.9 (Ar C) , 126.9 (Ar CH), 125.0 (C5), 116.8 (C4), 110.12 (C3') . Example 15: Rhenium Complex 15

Silver triflate (11 mg, 0.044 mmol) was added to a mixture of Rhenium Complex 27 (21 mg, 0.034 mmol) in

tetrahydrofuran (10 mL) and the mixture heated at reflux for 20 h. An additional portion of silver triflate (5 mg) was added and heating continued for 3 h. The mixture was cannula filtered into another Schlenk flask. Sodium thiocyanate (8 mg, 0.10 mmol) was added to the resulting solution, which was then heated at 50 °C for 20 h. The solution was dried in vacuo, and the resulting residue dissolved in dichloromethane and washed with water (3 x 10 mL) then died over MgS04. The residue was dissolved in dichloromethane (2 mL) and precipitated with diethyl ether/petroleum spirits (50/50) . The resulting solids was collected, washed with diethyl ether/petroleum spirits (50/50, x 3 mL) , and dried to afford Rhenium Complex 15 as a yellow solid. Yield: 12.4 mg, 61%. Anal. calc. for C ₂₂ Hi ₃ 40 ₃ SRe: C 44.07, H 2.19, N 9.34; found: C 43.65, H 1.93, N 9.28. FT-IR (ATR) Vmax/cm ^"1 : 2090 s (NCS), 2018 s (CO), 1921 s (CO), 1903 s (CO), 1596 w, 1514 w, 1496 w, 1429 m. ^! H- MR δ/ppm (CDCI ₃ ) : 8.73 (1H, H8') , 8.58 (1H, m, H4'), 8.01 (1H, m, H6') , 7.97 (1H, m, H5') , 7.88 (1H, d, ³ JH,H = 2.2 Hz, H4), 7.78 (1H, d, ³ JH,H = 8.7 Hz, H3') , 7.75 (1H, m, H7') , 7.70 (2H, m, Ar CH) , 7.65 (2H, m, Ar CH), 7.62 (1H, m, Ar CH) , 7.37 (1H, d, ³ J ^" _H ,H = 2.2 Hz, H5 ) . ¹³ C-NMR δ/ppm (CDCI3) : 195.7 (CO), 193.0 (CO), 192.1 (C2), 190.6 (CO), 153.8 (Ar C) , 147.0 (Ar C), 143.3 (C4'), 139.0 (Ar C) , 133.7 (C6'), 130.5 (Ar CH) , 130.3 (Ar CH) , 130.3 (C8') , 129.0 (C5') , 128.4 (C7') , 127.3 (Ar C) , 126.6 (Ar CH) , 124.9 (C5) , 117.1 (C4) , 110.0 (C3') .

Example 16: Rhenium Complexes 12 and 13

Triethylamine (0.50 mL, 3.55 mmol) was added to a mixture of l-propylacetamide-4- (2-pyridyl) -imidazolium

tetraphenylborate prepared in Example 4 (200 mg, 0.35 mmol) and Re(CO)sBr (144 mg, 0.35 mmol) in toluene (7 mL) and then heated at reflux for 2 days. The mixture was concentrated in vacuo and the resulting residue was subjected to column chromatography on acidic alumina

(Brockmann grade II, gradient elution using

dichloromethane/methanol ) . Two main fractions were

obtained, the first being Rhenium Complex 12 and the second being Rhenium Complex 13. The purified fractions were dried in vacuo, then dissolved in dichloromethane (2 mL) and precipitated with diethyl ether/petroleum spirits (50/50). The resulting solids was collected, washed with diethyl ether/petroleum spirits (50/50, x 3 mL) , and dried to afford Rhenium Complex 12 as a pale yellow solid, and Rhenium Complex 13 as a yellow solid that rapidly became an oily gum in air. Yield: Rhenium Complex 12: 12.7 mg, 6%; Rhenium Complex 13: 7.1 mg, 3%. Rhenium Complex 12: Anal. calc. for

Ci6Hi ₆ Br 40 ₄ Re.0.1 (C4H10O) : C 32.73, H 2.85, N 9.31; found: C 32.86, H 2.63, N 9.20. FT-IR (ATR) Vmax/cm ^"1 : 2016 s (CO), 1888 br s (2 x CO) , 1667 m, 1619 w, 1494 m. ^X H-NMR δ/ppm (CDCI3) : 8.92 (1H, ddd, ³ JH,H = 5.6 Hz, ⁴ JH,H = 1.7 Hz, ⁵ JH,H = 0.8 Hz, H6') , 7.63 (1H, d, ³ J ^" _H ,H = 2.2 Hz, H4), 8.06 (1H, ddd, ³ Jk,H = 8.3 Hz, ³ Jk,H = 7.5 Hz, ⁴ JH,H = 1.7 Hz, H4') , 7.58 (1H, ddd, ³ JH,H = 8.3 Hz, ⁴ J ^" _H ,H = 1.1 Hz, ⁵ J ^" _H ,H = 0.8 Hz, H3') , 7.35 (1H, ddd, ³ J ^" _H ,H = 7.5 Hz, ³ J ^" _H ,H = 5.6 Hz, ⁴ J ^" _H ,H = 1.1 Hz, H5') , 7.23 (1H, d, ³ JH,H = 2.2 Hz, H5 ) , 6.70 (1H, apparent t, NH), 4.63 (1H, m, NCfffl) , 4.20 (1H, m, NCHfi) , 3.47 (1H, m, NCH ₂ CfiH), 3.03 (1H, m, NCH ₂ CHfi) , 2.40 (1H, m, CONHCfffl) , 2.18 (1H, m, CONHCHfi) , 1.92 (3H, s, CH ₃ ) . ¹³ C-NMR δ/ppm (CDCI3) : 197.6 (CO), 196.4 (CO), 192.8 (C2), 187.7 (CO), 170.4 (NHCO) , 154.0 (C6') , 152.9 (C2') , 141.1 (C4') , 123.6 (C5), 122.8 (C5') , 116.5 (C4), 111.6 (C3') , 49.1 (NCH ₂ ), 36.0 (CONHCH2), 29.2 (NCH ₂ CH ₂ ), 23.4 (CH ₃ ) .

Rhenium Complex 13: FT-IR (ATR) Vmax/cm ^"1 : 2004 s (CO), 1861 br s (2 x CO) , 1647 w, 1611 w, 1473 m. ^X H-NMR δ/ppm

(CDCls) : 9.87 (1H, d, ⁴ Jk,H = 1.1 Hz, H5 ) , 8.97 (1H, ddd, ³ JH,H = 5.6 Hz, ⁴ JH,H = 1.7 Hz, ⁵ J ^" _H ,H = 0.7 Hz, H6') , 8.02 (1H, ddd, ³ JH,H = 8.3 Hz, ³ JH,H = 7.5 Hz, ⁴ J ^" _H ,H = 1.7 Hz, H4') , 7.94 (1H, ddd, ³ JH,H = 8.3 Hz, ⁴ J ^" _H ,H = 1.2 Hz, ⁵ J ^" _H ,H = 0.7 Hz, H3') , 7.34 (1H, ddd, ³ J ^" _H ,H = 7.5 Hz, ³ J ^" _H ,H = 5.6 Hz, ⁴ J ^" _H ,H = 1.2 Hz, H5') , 6.85 (1H, d, ⁴ JH,H = 1.1 Hz, H3 ) , 6.49 (1H, apparent t, NH), 4.12 (2H, m, NCH ₂ ), 3.25 (2H, m, NCH ₂ Cfi ₂ ), 2.05 (2H, m, CONHC¾), 2.04 (3H, s, CH ₃ ). ¹³ C-NMR δ/ppm ( CDCI3 ) : 199.2 (CO), 198.7 (CO), 191.8 (CO), 171.8 (NHCO), 168.6 (C2), 154.0 (C6') , 152.3 (C2') , 141.0 (C4') , 132.6 (C5), 126.1 (C3), 124.3 (C5') , 113.0 (C3') , 46.0 (NCH ₂ ),

(CONHCH ₂ ), 30.1 ( NCH2 CH2 ) , 8.8 (CH ₃ ).

Example 17: Rhenium Complex 9

a) 3- ( Bromopropyl ) indomethacin ester. Potassium

carbonate (1.55 g, 11.18 mmol) was added to a suspension of indomethacin (2.00 g, 5.59 mmol) and 1 , 3-dibromopropane (5.7 mL, 55.90 mmol) in acetone (100 mL) and the mixture heated at reflux for 20 h. The mixture was filtered and the filtrate dried in vacuo. The resulting yellow oil was triturated with petroleum spirits (4 ^χ 10 mL) and then subjected to column chromatography (silica gel, gradient elution using dichloromethane/petroleum spirits). The purified fractions were combined and dried in vacuo, affording a yellow oil that solidified upon cooling in the fridge overnight. Yield: 1.82 g, 68%. Anal. calc. for C22H ₂ iBrClN0 ₄ : C 55.19, H 4.42, N 2.93; found: C 55.10, H 4.18, N 2.94. FT-IR (ATR) Vmax/cm ^"1 : 1721 s, 1680 s, 1601 m, 1478 m. ^! H- MR δ/ppm (CDCI3) : 7.66 (2H, d, ³ J ^" _H ,H = 8.5 Hz, Hll), 7.47 (2H, d, ³ Jk,H = 8.5 Hz, H12), 6.95 (1H, d, ⁴ JH,H = 2.5 Hz, H4), 6.87 (1H, d, ³ JH,H = 9.0 Hz, H7 ) , 6.67 (1H, dd, ³ Jk,H = 9.0 Hz, ⁴ Jk,H = 2.5 Hz, H6), 4.25 (2H, m, OCH ₂ ), 3.84 (3H, s, OCH3) , 3.67 (2H, s, CH2CO2CH2 ) , 3.36 (2H, m, CH ₂ Br) , 2.39 (3H, s, CCHs), 2.15 (2H, m, CH2CH2CH2 ) . ¹³ C-NMR δ/ppm (CDCls) : 170.7 ( CH2CO2CH2 ) , 168.3 (CO), 156.1 (C5), 139.3 (CIO), 135.9 (C2), 133.9 (C13), 131.2 (Cll), 130.8 (C8), 130.5 (C9), 129.1 (C12), 115.0 (C7), 112.4 (C3), 111.7 (C6), 101.2 (C4), 62.7 (CH ₂ C0 ₂ CH ₂ ), 55.7 (OCH ₃ ), 31.5

(CH ₂ Br), 30.3 ( CH2CO2CH2 ) , 29.1 ( CH2CH2 ) , 13.3 (CCH3) .

b) Azolium salt l.Br. A solution of l-(2- pyridyl ) imidazole ) (139 mg, 0.95 mmol) and 3- (bromopropyl ) indomethacin ester from a) (457 mg, 0.95 mmol) in

acetonitrile (4 mL) was heated at 130 °C in a sealed tube for 2 d. The solution was concentrated to ca 2 mL and dropped into diethyl ether (10 mL) . The resulting gum slowly solidified with stirring (30 min) and was

collected, washed with diethyl ether (4 4 mL) , and dried to afford the product as a white, hygroscopic powder.

Yield: 402 mg, 68%. Anal. calc. for C ₃ oH28BrCl ₄ 04 : C 57.75, H 4.52, N 8.98; found: C 57.31, H 4.38, N 9.08. FT-IR (ATR) Vmax/cm ^"1 : 1734 s, 1662 s, 1599 s, 1542 m, 1478 s. ^X H- NMR δ/ppm (d ₆ -DMSO) : 10.15 (H2), 8.68 (1H, ddd, ³ J _H , _H = 4.9 Hz, ⁴ JH, H = 1.9 Hz, ⁵ JH, H = 0.9 Hz, H6'), 8.58 (1H, m, H4), 8.26 (1H, ddd, ³ J ^" _H , H = 8.2 Hz, ³ J ^" _H , H = 7.6 Hz, ⁴ J ^" _H , H = 1.9 Hz, H4 ' ) , 8.07 (1H, m, H5 ) , 8.06 (1H, m, H3 ' ) , 7.68 (1H, m, H5'), 7.70 (2H, m, Hll''), 7.69 (2H, m, H12 ' ' ) , 7.07 (1H, d, ⁴ Jk, H = 2.5 Hz, H4 ' ' ) , 6.95 (1H, d, ³ Jk, H = 9.0 Hz, H7 ' ' ) , 6.76 (1H, dd, ³ JH, H = 9.0 Hz, ⁴ JH, H = 2.5 Hz, H6 ' ' ) , 4.43 (2H, d, ³ JH, H = 6.9 Hz, OCH ₂ ), 4.19 (2H, d, ³ J ^" _H , H = 6.2 Hz, NCH ₂ ), 3.80 (2H, s, CH ₂ C0 ₂ CH ₂ ), 3.79 (3H, s, OCH ₃ ), 2.30 (2H, m, CH ₂ CH ₂ CH ₂ ), 2.44 (3H, s, CCH ₃ ). ¹³ C-NMR δ/ppm (d ₆ - DMSO) : 170.9 (CH ₂ C0 ₂ CH ₂ ), 168.5 (C=0) , 156.0 (C5 ' ' ) , 149.7 (C6'), 146.3 (C2'), 140.6 (C4 ' ) , 137.7 (CIO''), 135.5 (C2''), 135.3 (C2), 134.0 (C13 ' ' ) , 131.2 (Cll''), 130.5 (C8''), 130.2 (C9''), 129.1 (C12 ' ' ) , 125.2 (C5'), 123.6 (C5), 119.3 (C4), 114.6 (C7 ' ' ) , 114.2 (C3'), 112.5 (C3 ' ' ) , 111.3 (C6''), 101.8 (C4''), 61.4 (CH ₂ C0 ₂ CH ₂ ), 55.4 (OCH ₃ ), 46.9 (NCH ₂ ), 29.2 (CH ₂ C0 ₂ CH ₂ ), 28.3 (NCH ₂ CH ₂ ), 13.2 (CCH ₃ ) .

c) Rhenium complex 9. Triethylamine (0.45 mL, 3.19 mmol) was added to a mixture of azolium salt from b) (199 mg, 0.32 mmol) and Re(CO)5Br (130 mg, 0.32 mmol) in toluene (10 mL) and then heated at reflux for 2 d. The yellow solution was decanted off and the remaining residue washed with toluene (2 ^χ 5 mL) , and the combined organic

fractions dried in vacuo. The resulting residue was dissolved in dichloromethane (~10 mL) and washed with water (3 ^χ 10 mL) , then dried over MgS04. The resulting residue was purified by repeated precipitation from dichloromethane and methanol ( ^χ 3) . On the final

precipitation, the solid was collected, washed with methanol (3 3 mL) , then diethyl ether (1 x 3 mL) , and dried to afford the product as a pale yellow solid. Yield: 112.6 mg, 39%. Anal. calc. for : C 44.38, H 3.05, N 6.27; found: C 44.18, H 2.62, N 6.17. FT-IR (ATR) Vmax/cm ^"1 : 2015 s (CO), 1915 s (CO), 1875 s (CO), 1732 m, 1670 m, 1591 w, 1479 s. ^X H-NMR δ/ppm (CDCI3) : 8.89 (1H, ddd, ³ Jk,H = 5.6 Hz, ⁴ Jk,H = 1.6 Hz, ⁵ JH,H = 0.8 Hz, H6 ' ) ,

8.01 (1H, ddd, ³ J ^" _H ,H = 8.3 Hz, ³ J ^" _H ,H = 7.6 Hz, ⁴ J ^" _H ,H = 1.6 Hz, H4'), 7.67 (2H, d, ³ JH,H = 8.6 Hz, Hll''), 7.54 (1H, ddd, ³ Jk,H = 8.3 Hz, ⁴ Jk,H = 1.1 Hz, ⁵ JH,H = 0.8 Hz, H3 ' ) , 7.48 (2H, d, ³ JH,H = 8.6 Hz, H12 ' ' ) , 7.46 (1H, d, ³ JH,H = 2.2 Hz, H4), 7.32 (1H, ddd, ³ JH,H = 7.6 Hz, ³ JH,H = 5.6 Hz, ⁴ JH,H =

1.1 Hz, H5'), 7.02 (1H, d, ⁴ JH,H = 2.5 Hz, H4 ' ' ) , 6.91 (1H, d, ³ Jk,H = 9.0 Hz, H7 ' ' ) , 6.70 (1H, dd, ³ JH,H = 9.0 Hz, ⁴ JH,H = 2.5 Hz, H6''), 6.68 (1H, d, ³ JH,H = 2.2 Hz, H5), 4.10-4.29 (2 x 2H, 2 x m, NCH ₂ , OCH ₂ ), 3.85 (3H, s, OCH ₃ ), 3.74 (2H, s, CH2CO2CH2), 2.41 (3H, s, CCH3), 2.33 (2H, m, CH ₂ CH ₂ CH ₂ ) . ¹³ C-NMR δ/ppm (CDCI3): 198.1 (CO), 197.3 (CO), 194.3 (C2), 188.4 (CO), 170.8 (CH ₂ C0 ₂ CH ₂ ), 168.5 (C=0) , 156.3 (C5 ' ' ) , 153.9 (C6'), 152.9 (C2 ' ) , 141.1 (C ' ) , 139.7 (CIO''), 136.2 (C2''), 133.9 (C13 ' ' ) , 131.4 (Cll ' ' ) , 131.0 (C8 ' ' ) , 130.7 (C9''), 129.4 (C12 ' ' ) , 123.6 (C5 ' ) , 123.4 (C5), 115.9 (C4), 115.2 (C7''), 112.7 (C3 ' ' ) , 111.9 (C6 ' ' ) , 111.7 (C3'), 101.6 (C4 ' ' ) , 61.5 (CH ₂ C0 ₂ CH ₂ ), 56.0 (OCH ₃ ), 49.2 (NCH ₂ ), 30.6 (CH ₂ C0 ₂ CH ₂ ), 30.5 (NCH ₂ CH ₂ ), 13.5 (CCH ₃ ) . Example 18: Rhenium Complexes 10 and 11

a) 3- ( Bromopropyl ) indomethacin amide. Triethylamine

(0.6 mL, excess) was added to a suspension of indomethacin (0.5 g, 1.40 mmol) and 3-bromopropylamine hydrobromide (0.31 g, 1.54 mmol) in acetonitrile, forming a light yellow solution. HBTU (0.61 g, 1.61 mmol) was added portionwise and the solution stirred for 20 h. Copious amounts of solid precipitated. A brine solution was added to the resulting mixture, which was stirred for an

additional 10 min and the solid then collected, washed with water (4 χ 4 mL) , dried, washed with diethyl

ether/petroleum spirits (50/50, 4 χ 4 mL) , and dried to afford the product as a pale yellow/green solid. Yield: 0.39 g, 60%. Anal. calc. for C ₂₂ H ₂₂ BrClN ₂ 0 ₃ : C 55.31, H 4.64, N 5.86; found: C 55.10, H 4.26, N 5.84. FT-IR (ATR) Vmax/cm ^"1 : 3309 w, 1676 s, 1634 m, 1596 m, 1477 m. ^! H-NMR δ/ppm (CDCls): 7.67 (2H, d, ³ JH,H = 8.7 Hz, Hll), 7.49 (2H, d, ³ JH,H = 8.5 Hz, H12), 6.87 (1H, d, ⁴ J ^" _H ,H = 2.5 Hz, H4), 6.86 (1H, d, ³ JH,H = 9.0 Hz, H7), 6.70 (1H, dd, ³ Jk,H = 9.0 Hz, ⁴ JH,H = 2.5 Hz, H6) , 5.77 (1H, app t, NH), 3.82 (3H, s, OCHs), 3.64 (2H, s, CH ₂ CONHCH ₂ ), 3.36 (2H, q, ³ Jk,H = 6.5 Hz, NHCH ₂ ) , 3.30 (2H, t, ³ J ^" _H ,H = 6.4 Hz, CH ₂ Br) , 2.40 (3H, s,

CCHs), 2.01 (2H, m, CH ₂ CH ₂ CH ₂ ) . ¹³ C-NMR δ/ppm (CDCls) : 170.3 (CONH), 168.5 (CO), 156.5 (C5), 139.8 (CIO), 136.5 (C2), 133.7 (C13), 131.3 (Cll), 131.1 (C8), 130.3 (C9), 129.4 (C12), 115.3 (C7), 112.8 (C3), 112.6 (C6), 100.8 (C4), 55.9 (OCHs), 38.5 (CONHCH ₂ ), 32.4 ( CH ₂ CONHCH ₂ ) , 32.1

(CH2CH2) , 30.8 (CH ₂ Br) , 13.4 (CCH3).

b) Azolium salt 2. BPh ₄ A solution of l-(2- pyridyl ) imidazole ) (81 mg, 0.56 mmol) and 3- (bromopropyl ) indomethacin amide from a) (259 mg, 0.56 mmol) in

acetonitrile (5 mL) was heated at 130 °C in a sealed tube for 2 d. The solution was dried in vacuo and triturated with diethyl ether (4 ^χ 4 mL) . The resulting oil was dissolved in water/methanol (5:1, 3 mL) and added to a water/methanol (3:1) solution of excess NaBPh ₄ . The resulting solid was collected and washed with water (3 ^χ 4 mL) , water/methanol (7:3, 1 ^χ 4 mL) , methanol (1 4 mL) , diethyl ether (2 x 4 mL) , and then dried, affording the product as a hygroscopic white solid. Yield: 294 mg, 62%. Anal. calc. for C54H49BCIN5O3 : C 75.22, H 5.73, N 8.12;

found: C 74.77, H 5.67, N 7.95. FT-IR (ATR) Vmax/cm ^"1 : 1659 m, 1600 s, 1444 s. ^! H-NMR δ/ppm (d ₆ -DMSO) : 10.07 (H2), 8.69 (1H, ddd, ³ JH,H = 4.8 Hz, ⁴ J ^" _H ,H = 1.8 Hz, ⁵ J ^" _H ,H = 0.8 Hz, H6'), 8.56 (1H, m, H4 ) , 8.25 (1H, ddd, ³ JH,H = 8.3 Hz, ³ Jk,H = 7.6 Hz, ⁴ JH,H = 1.8 Hz, H4 ' ) , 8.19 (1H, apparent t, NH) , 8.06 (1H, m, H5), 8.03 (1H, m, H3 ' ) , 7.72 (2H, d, ³ Jk,H = 8.8 Hz, Hll''), 7.69 (2H, d, ³ JH,H = 8.8 Hz, H12 ' ' ) , 7.68 (1H, m, H5 ' ) , 7.21 (8H, m, BPh ₄ Ar CH) , 7.15 (1H, d, ⁴ J ^" _H ,H = 2.5 Hz, H4''), 6.97 (1H, d, ⁴ JH,H = 9.0 Hz, H7 ' ' ) , 6.96 (8H, m, BPh ₄ Ar CH), 6.82 (4H, m, BPh ₄ Ar CH), 6.75 (1H, dd, ³ Jk,H = 9.0 Hz, ⁴ Jk,H = 2.5 Hz, H6 ' ' ) , 4.32 (2H, t, ³ JH,H =

6.8 Hz, NCH ₂ ), 3.79 (3H, s, OCH ₃ ), 3.56 (2H, s, CH ₂ CONHCH ₂ ), 3.17 (1H, m, CONHCH2), 2.27 (3H, s, CCH ₃ ), 2.08 (2H, m, CH2CH2CH2) . ¹³ C-NMR δ/ppm (d ₆ -DMSO) : 169.8 (CONH), 167.8 (C=0) , 164.1 (Ar C), 155.5 (C5 ' ' ) , 149.2 (C6 ' ) , 146.4 (C2'), 140.6 (C4'), 135.5 (Ar CH) , 137.6 (C2 ' ' ) , 135.5 (C2), 135.2 (CIO''), 134.2 (C13 ' ' ) , 131.1 (Cll ' ' ) , 130. (C8''), 130.3 (C9''), 129.0 (C12 ' ' ) , 125.3 (Ar CH), 125 (C5'), 123.5 (C5), 121.5 (Ar CH), 119.2 (C4), 114.1 (C7''), 114.0 (C3'), 112.1 (C3 ' ' ) , 111.1 (C6 ' ' ) , 101.9 (C4''), 55.4 ( OCH3 ) , 47.4 (NCH ₂ ), 35.5 ( CONHCH2 ) , 31.2 ( CH2CONHCH2 ) , 29.5 ( NCH2CH2 ) , 13.4 ( CCH3 ) .

10 11

c) Rhenium complexes 10 and 11. Triethylamine (0.18 mL, 1.80 mmol) was added to a mixture of azolium salt from b) (154 mg, 0.18 mmol) and Re(CO) ₅ Br (74 mg, 0.18 mmol) in toluene (8 mL) and then heated at reflux for 2 d. The mixture was concentrated in vacuo and the resulting residue was subjected to column chromatography on acidic alumina (Brockmann grade II, gradient elution using dichloromethane/methanol). Two main fractions were obtained, the first being 10 and the second being 11. The purified fractions were dried in vacuo, then dissolved in dichloromethane (2 mL) and precipitated with diethyl ether/petroleum spirits (50/50) . The resulting solid was collected, washed with diethyl ether/petroleum spirits (50/50, 4 x 3 mL) , and dried to afford 10 and 11 as pale yellow, and yellow solids, respectively. Yield: 10 18.7 mg, 12%; 11 27.1 mg, 17%. 10: Anal. calc. for

C ₃₃ H ₂₈ BrCl ₅ 0 ₆ Re : C 44.43, H 3.16, N 7.85; found: C 44.22, H 2.80, N 7.63. FT-IR (ATR) Vmax/cm ^"1 : 2012 s (CO), 1910 s (CO), 1877 s (CO), 1667 m, 1616 w, 1489 m, 1255 m. ¹ H-NMR δ/ppm (CDCls) : 8.90 (1H, ddd, ³ J ^" _H ,H = 5.6 Hz, ⁴ J ^" _H ,H = 1.7 Hz, ⁵ JH,H = 0.8 Hz, H6'), 8.04 (1H, ddd, ³ JH,H = 8.3 Hz, ³ JH,H =

7.5 Hz, ⁴ JH,H = 1.7 Hz, H4 ' ) , 7.65 (2H, d, ³ J ^" _H ,H = 8.6 Hz, Hll''), 7.56 (1H, ddd, ³ JH,H = 8.3 Hz, ⁴ JH,H = 1.1 Hz, ⁵ JH,H = 0.8 Hz, H3 ' ) , 7.48 (1H, d, ³ J ^" _H ,H = 2.2 Hz, H4), 7.46 (2H, d, ³ JH,H = 8.6 Hz, H12''), 7.32 (1H, ddd, ³ JH,H = 7.5 Hz, ³ JH,H =

5.6 Hz, ⁴ JH,H = 1.1 Hz, H5 ' ) , 7.13 (1H, d, ³ J ^" _H ,H = 2.2 Hz, H5), 6.97 (1H, d, JH,H = 2.6 Hz, H4 ' ' ) , 6.95 (1H, d, ³ JH,H =

9.0 Hz, H7 ' ' ) , 6.68 (1H, dd, ³ J ^" _H ,H = 9.0 Hz, ⁴ J ^" _H ,H = 2.6 Hz, H6''), 6.65 (1H, apparent t, NH) , 4.57 (1H, m, NCHHCH ₂ ),

4.18 (1H, m, NCHHCH ₂ ), 3.82 (3H, s, OCH ₃ ), 3.57 (2H, m, CH2CONH ) , 3.44 (1H, m, CONHCHH) , 3.16 (1H, m, CONHCHH), 2.34 (1H, m, CH ₂ CHHCH ₂ ), 2.31 (3H, s, CCH ₃ ), 2.17 (2H, m, CH2CHHCH2 ) . ¹³ C-NMR δ/ppm (CDCI3) : 197.9 (CO), 196.5 (CO), 192.7 (C2), 187.7 (CO), 171.3 (CONH) , 168.6 (C=0) , 156.3 (C5''), 153.9 (C6'), 152.9 (C2 ' ) , 141.1 (C4 ' ) , 139.3

(CIO''), 136.3 (C2''), 134.0 (C13 ' ' ) , 131.4 (Cll ' ' ) , 131.1 (C8''), 130.9 (C9''), 129.3 (C12 ' ' ) , 123.6 (C5'), 122.7 (C5), 116.4 (C4), 115.2 (C7 ' ' ) , 113.4 (C3''), 112.1

(C6''), 111.7 (C3'), 101.5 (C4 ' ' ) , 56.1 (OCH ₃ ), 50.2

(NCH ₂ ) , 36.7 ( CONHCH2 ) , 32.5 ( CH2CONHCH2 ) , 29.7 (NCH ₂ CH ₂ ), 13.9 ( CCH3 ) . 4b: Anal. calc. for Css^sBrClNsOeRe .0.8 (C ₃ H ₆ 0) : C 45.30, H 3.52, N 7.46; found: C 45.40, H 3.25, N 7.85. FT-IR (ATR) Vmax/cm ^"1 : 2005 s (CO), 1868 br s (CO), 1666 m, 1612 w, 1516 m, 1475 m, 1257 m. ¹ H-NMR δ/ppm ( CDCI3 ) : 9.57 (1H, d, ⁴ JH,H = 1.3 Hz, H5), 8.95 (1H, ddd, ³ JH,H = 5.6 Hz, ⁴ JH,H = 1.7 Hz, ⁵ JH,H = 0.8 Hz, H6 ' ) , 7.98 (1H, ddd, ³ JH,H = 8.3 Hz, ³ JH,H = 7.5 Hz, ⁴ J ^" _H ,H = 1.7 Hz, H4 ' ) , 7.81 (1H, ddd, ³ JH,H = 8.3 Hz, ⁴ JH,H = 1.1 Hz, ⁵ J ^" _H ,H = 0.8 Hz, H3 ' ) , 7.67 (2H, d, ³ JH,H = 8.6 Hz, Hll' '), 7.48 (2H, d, ³ J ^" _H ,H = 8.6 Hz, H12''), 7.32 (1H, ddd, ³ JH,H = 7.5 Hz, ³ JH,H = 5.6 Hz, ⁴ JH,H =

1.1 Hz, H5'), 6.95 (1H, d, JH,H = 2.5 Hz, H4 ' ' ) , 6.89 (1H, d, ³ JH,H = 9.0 Hz, H7 ' ' ) , 6.77 (1H, d, ³ JH,H = 1.3 Hz, H3 ) , 6.70 (1H, dd, ³ JH,H = 9.0 Hz, ⁴ JH,H = 2.5 Hz, H6 ' ' ) , 6.32 (1H, apparent t, NH) , 3.97 (2H, m, NCH ₂ CH ₂ ), 3.81 (3H, s, OCHs), 3.67 (2H, m, CH2CONHCH2 ) , 3.19 (2H, m, CONHCH2 ) , 2.41 (3H, s, CCH3) , 1.95 (2H, m, CH ₂ CH ₂ CH ₂ ). ¹³ C-NMR δ/ppm

(CDCI3) : 199.3 (CO), 198.8 (CO), 191.8 (CO), 171.7 (CONH), 168.8 (C2), 168.6 (C=0) , 156.4 (C5 ' ' ) , 154.1 (C6'), 152.4 (C2'), 141.1 (C4'), 139.9 (CIO''), 136.8 (C2 ' ' ) , 133.6 (C13''), 132.2 (C5), 131.5 (Cll ' ' ) , 131.2 (C8 ' ' ) , 130.5 (C9''), 129.4 (C12''), 126.3 (C3), 124.4 (C5 ' ) , 115.4 (C7''), 113.0 (C3'), 112.8 (C3 ' ' ) , 111.8 (C6 ' ' ) , 101.8 (C4''), 56.2 (OCH3) , 46.4 (NCH ₂ ), 36.0 (CONHCH ₂ ), 32.4 (CH ₂ CONHCH ₂ ) , 30.1 (NCH ₂ CH ₂ ), 13.6 (CCH ³ ).

Example 19: Rhenium Complex 17

[Re (PylmPh) (CO) ₃ Br] (52 mg, 0.092 mmol) was added to AgOTf (29 mg, 0.11 mmol) in DCM. This mixture was heated at reflux under nitrogen, whilst stirring in darkness for 4 hours. The resulting AgBr precipitate was filtered off and the resulting filtrate was concentrated under reduced pressure to afford yellow residue. This residue was dissolved in pyridine (ca. 2 mL) and heated at reflux under nitrogen overnight. After cooling down at room temperature, pyridine was removed in vacuo to afford dark orange residue. To this residue was added minimal DCM and then diethyl ether was added to re-precipitate the

compound. This was filtered under vacuum to afford beige- yellow powder. Finally, this was dissolved in MeOH and then saturated solution of KPF6 was added to afford dull yellow precipitate (45 mg, 86%); m.p. 210-213°C. v _max (ATR- FTIR, solid) /cm ^"1 : 3124 w, 2022 s (CO, A'(l)), 1926 sh (CO, A' (2)), 1909 s (CO, A"), 1617 m, 1486 m, 1258 m, 1029 m, 758 w, 695 w. ^X H NMR (δ, ppm, acetone-d ₆ ) : 9.27 (1H, d, J = 5.6 Hz, pyridyl CH) , 8.59 (1H, sharp d, J = 2.2 Hz, imidazoyl CH) , 8.49-8.38 (4H, m, 4 ^χ pyridyl CH) , 7.99

(1H, app t, J = 8.0 Hz, pyridine solvate), 7.96 (1H, sharp d, imidazoyl CH) , 7.83-7.71 (6H, m, 5 ^χ phenyl CH and pyridyl CH) , 7.48 (2H, app t, J = 4.0 Hz, pyridine solvate). ¹³ C NMR (δ, ppm, acetone-d ₆ ): 197.7 (CO), 195.8 (CO), 191.9 (CO), 191.3 (NCN) , 155.0 (pyridyl CH) , 154.8 (pyridyl CH) , 154.7 (pyridyl quat . C) , 144.4 (imidazoyl CH), 140.4 (phenyl CH) , 140.1 (pyridine solvate CH) , 131.2 (phenyl CH) , 127.8 (pyridine solvate CH) , 127.4 (phenyl quat. C), 127.0 (pyridine solvate CH) , 126.4 (phenyl CH) , 119.6 (pyridyl CH) , 114.9 (pyridyl CH) . Elemental

Analysis; Calc for C ₂ 3Hi6 406F ₃ SiRe · 0.5 H ₂ 0 0.5 DCM; C

(36.60%), H (2.35%), N (7.27%); found: C (37.35%), H

(2.12%) , N (7.17%) .

Example 20: Rhenium Complex 19

[Re (PylmPh) (CO) ₃ Br] (44 mg, 0.08 mmol) and phenyl tetrazole ligand (16 mg, 0.11 mmol) were combined with triethylamine (20 L, 0.14 mmol) and MeCN/MeOH (4:1) in a microwave vial. This mixture was heated in a Biotage microwave reactor for 60 min reaching a maximum of 130 °C. After the reaction mixture cooled down to room temperature,

deionised water (ca. 10 mL) was added to the orange solution and extracted with dichloromethane (3 ^χ 10 mL) . The organic extracts were combined, dried (MgSO and concentrated under reduced pressure to afford fluffy yellow solid (45 mg, 94%); m.p. 208°C (dec) . v _max (ATR- FTIR, acetone solution) /cm ^"1 : 2021 s (CO, A'(l)), 1906 s (CO, A") cm-1. ^X H NMR (400 MHz, acetone-d ₆ ) : δ 9.08 (1H, d, J = 8 Hz, pyridyl CH) , 8.50 (1H, sharp d, J = 4 Hz, imidazolyl CH) , 8.30 (1H, t, J = 8 Hz, pyridyl CH) , 8.22 (1H, d, J = 12 Hz, pyridyl CH) , 7.93-7.90 (2H, m, phenyl CH), 7.86-7.82 (3H, m, imidazolyl and phenyl CH) , 7.63- 7.60 (3H, m, phenyl CH) , 7.59-7.53 (1H, app . t, J = 16 Hz, pyridyl CH) , 7.36-7.29 (3H, m, phenyl CH) ppm; ¹³ C NMR (100 MHz, acetone-d6) : δ 198.7 (CO), 196.9 (CO), 193.9 (CO), 192.6 (NCN) , 164.1 (CN4-C ₆ H ₅ ), 154.9 (pyridyl C) , 154.7 (pyridyl quat . C) , 143.1 (pyridyl C) , 140.8 (phenyl quat . C) , 131.6 (phenyl quat. C) , 130.6 (phenyl C) , 130.5

(phenyl C) , 129.2 (phenyl C) , 128.9 (phenyl C) , 127.4 (phenyl C) , 126.8 (phenyl C) , 126.1 (imid. C) , 124.9 (pyridyl C) , 118.5 (imid. C) , 113.6 (pyridyl C) ppm.

Example 21: Rhenium Complex 18

Pentacarbonylrhenium bromide (55 mg, 0.135 mmol) was added to a mixture of [QuImPhOMe] [PF ₆ ] salt (50 mg, 0.112 mmol) and triethylamine (85 L, 0.615 mmol) in toluene (ca. 10 mL) . The reaction mixture was heated to reflux under nitrogen for 2 days. Over time, yellow precipitate formed. After heating was stopped and reaction left to cool down at room temperature, the mixture was washed with water and extracted with DCM. The dark yellow organic extracts were dried (MgS04) and concentrated under reduced pressure to afford orange-grey solid (101 mg, 90%). M.p. 258°C (dec). max (ATR-IR) /cm ^-1 (solid state): 2015 s (CO, A'(l)), 1943 s (CO), 1907 s (CO), 1882 s (CO, A") . ^X H NMR (δ, ppm, DMSO- d ₆ ) : 8.98 (1H, d, J = 8.9 Hz, quinolinyl CH) , 8.81 (1H, app s , J = 1.7 Hz, imid. CH) , 8.59 (1H, d, J = 8.8 Hz, quinolinyl CH) , 8.51 (1H, d, J = 8.9 Hz, quinolinyl CH) , 8.22 (1H, d, J = 8.2 Hz, quinolinyl CH) , 8.09 (1H, app . t, J = 8.0 Hz, quinolinyl CH) , 7.98 (1H, d, J = 2.1 Hz, imid. CH), 7.82 (1H, app. t, J = 8.0 Hz, quinolinyl CH) , 7.61 (2H, d, J = 8.9 Hz, phenyl CH) , 7.20 (2H, d, J = 8.9 Hz, phenyl CH) , 3.85 (3H, s, OCH ₃ ) . ¹³ C NMR (δ, ppm, DMSO-d ₆ ) : 197.8 (CO), 194.6 (CO), 192.0 (NCN) , 188.9 (CO), 160.0 (phenyl quat . C) , 154.4 (quinolyl quat . C) , 145.7

(quinolyl quat. C) , 143.6 (quinolyl CH) , 132.9 (quinolyl CH), 132.2 (OCH3 quat. C), 129.5 (quinolyl CH) , 128.9 (quinolyl CH) , 127.7 (phenyl quat. C) , 127.6 (quinolyl CH), 126.9 (quinolyl CH) , 125.9 (imid. CH) , 118.7 (imid. CH), 114.8 (phenyl CH) , 111.9 (quinolyl CH) , 55.7 (OCH ₃ ) . Elemental Analysis; Calc for BrC22Hi5 ₃ 0 ₄ Re ; C (40.58%), H (2.32%), N (6.45%); found: C (40.65%), H (1.98%), N

(6.31%) .

Example 22: Rhenium Complex 34

Silver triflate (25 mg, 0.091 mmol) was added to a suspension of Rhenium Complex 21 (50 mg, 0.091 mmol) in pyridine (3 mL) and stirred at reflux for 2.5 h.

Dichloromethane (10 mL) was added and the suspension was filtered through a 0.2 \im PTFE membrane directly into rapidly stirring diethyl ether. The resulting oil was washed by trituration with diethyl ether (3 ^χ 5 mL) . The oil was then dissolved in methanol (2 mL) and dropped into a H4PF6 solution in methanol/water (1:1, 10 mL) . The resulting solid was collected, washed with water (3 ^χ 5 mL) , methanol/water (1:1, 3 ^χ 5mL) , diethyl ether (3 5 mL) , and dried to afford the product as a pale yellow solid. Yield: 26 mg, 41%. Anal. calc. for

C ₂ oH ₂ oF _{6 4} 0 ₃ PRe .0.4 (H ₂ 0) .0.5 CH ₂ C1 ₂ : C 33.04, H 2.95, N 7.52; found: C 32.69, H 2.34, N 7.57. FT-IR (ATR) Vmax/cm ^"1 : 2021 s (CO), 1925 s (CO), 1905 s (CO), 1620 w, 1490 m. ^X H-NMR δ/ppm (d6~acetone) : 9.23 (1H, ddd, ³ JH, H = 5.6 Hz, ⁴ JH, H = 1.6 Hz, ⁵ JH, H = 0.8 Hz, H6'), 8.58 (2H, dt, ³ JH, H = 4.9 Hz, ⁴ JH, H = 1.5 Hz, H2 ' ' ) , 8.45 (1H, ddd, ³ J ^" _H , H = 8.3 Hz, ³ J ^" _H , H = 7.6 Hz, ⁴ JH, H = 1.6 Hz, H4 ' ) , 8.39 (1H, d, ³ J ^" _H , H = 2.2 Hz, H4), 8.26 (1H, ddd, ³ J ^" _H , H = 8.3 Hz, ⁴ J ^" _H , H = 1.2 Hz, ⁵ J ^" _H , H = 0.8 Hz, H3 ' ) , 8.01 (1H, tt, ³ JH, H = 7.8 Hz, ⁴ JH, H = 1.5 Hz, H4 ' ' ) , 7.83 (1H, d, ³ J ^" _H , H = 2.2 Hz, H5), 7.65 (1H, ddd, ³ JH, H = 7.6 Hz, ³ JH, H = 5.6 Hz, ⁴ J ^" _H , H = 1.2 Hz, H5 ' ) , 7.47 (2H, dt, 3JH,H = 7.8 Hz, ³ JH, H = 4.9 Hz, H3 ' ' ) , 4.58 (2H, m, NCH ₂ ), 2.00 (2H, m, NCH ₂ CH ₂ ), 1.48 (2H, m, NCH ₂ CH ₂ CH ₂ ), 0.97 (3H, t, ³ JH, H = 7.4 Hz, CH ₃ ) . ¹³ C-NMR δ/ppm ( d ₆ -acetone ) : 197.9 (CO), 197.7 (CO), 191.7 (C2), 189.8 (CO), 155.0 (C2 ' ' ) , 154.8 (C6'), 154.5 (C2 ' ) , 144.3 (C4 ' ) , 140.5 (C4''), 127.8 (C3''), 126.0 (C5), 125.7 (C5 ' ) , 119.3 (C4), 114.5 (C3 ' ) , 52.9 (NCH ₂ ), 34.0 (NHCH ₂ CH ₂ ), 20.4 (NCH ₂ CH ₂ CH ₂ ) , 13.9 (CH ₃ ). ³¹ P-NMR δ/ppm ( d ₆ -acetone ) : -144.2.

Example 23: Rhenium Complex 35

Silver triflate (28.0 mg, 0.11 mmol) was added to a suspension of Rhenium Complex 21 (50.7 mg, 0.092 mmol) in THF (10 mL) and stirred at reflux for 20 h. The suspension was filtered by cannula filtration into another Schlenk flask. 2 Methylimidazole (73 L, 9.19 mmol) was added and the solution was heated at 60 °C for 20 h. The solution was dried then dissolved in methanol (1 mL) and dropped into a H4PF6 solution in methanol/water (5:1, 5 mL) . Water was slowly added to the solution until the solution became cloudy and an oil formed. The suspension was stirred rapidly for 20 min and the resulting solid was collected, washed with water (3 ^χ 5 mL) , methanol/water (1:1, 2 ^χ

5mL) , diethyl ether (4 * 5 mL) , and dried to afford the product as a pale yellow solid. Yield: 32.5 mg, 51%. Anal, calc. for Ci ₉ H ₂ iF ₆ N ₅ 0 ₃ PRe : C 32.67, H 3.03, N 10.03; found: C 32.61, H 2.84, N 9.94. FT-IR (ATR) Vmax/cm ^"1 : 2019 s (CO), 1915 s (CO), 1881 s (CO), 1617 w, 1488 m. ^X H-NMR δ/ppm (de- acetone): 9.08 (1H, ddd, ³ JH,H = 5.6 Hz, ⁴ JH,H = 1.6 Hz, ⁵ JH,H = 0.8 Hz, H6'), 8.41 (1H, ddd, ³ J ^" _H ,H = 8.3 Hz, ³ J ^" _H ,H = 7.6 Hz, ⁴ JH,H = 1.6 Hz, H4 ' ) , 8.39 (1H, d, ³ JH,H = 2.2 Hz, H4 ) , 8.25 (1H, ddd, ³ J ^" _H ,H = 8.3 Hz, ⁴ J ^" _H ,H = 1.2 Hz, ⁵ J ^" _H ,H = 0.8 Hz, H3 ' ) , 7.84 (1H, s, H2 ' ' ) , 7.79 (1H, d, ³ JH,H = 2.2 Hz, H5 ) , 7.65 (1H, ddd, ³ J ^" _H ,H = 7.6 Hz, ³ J ^" _H ,H = 5.6 Hz, ⁴ J ^" _H ,H = 1.2 Hz, H5 ' ) , 7.12 (1H, m, H4 ' ' or H5 ' ' ) , 6.68 (1H, m, H4 ' ' or H5 ' ' ) , 4.45 (2H, m, NCH ₂ ) , 3.69 (3H, s, NCH ₃ ), 1.97 (2H, m, NCH2CH2) , 1.47 (2H, m, NCH ₂ CH ₂ CH ₂ ), 0.97 (3H, t, ³ JH,H = 7.4 Hz, CH ₃ ) . ¹³ C-NMR δ/ppm (d ₆ -acetone) : 198.0 (CO), 197.6 (CO), 192.0 (C2), 189.2 (CO), 154.6 (C6 ' ) , 154.3 (C2 ' ) , 144.0 (C4'), 143.2 (C2 ' ' ) , 131.7 (C4 ' ' or C5 ' ' ) , 125.7 (C5), 125.6 (C5'), 123.9 (C4 ' ' or C5 ' ' ) , 119.0 (C4), 114.2 (C3'), 52.8 (NCH ₂ ), 34.7 (NCH ₃ ), 34.0 (NHCH ₂ CH ₂ ), 20.3 (NCH ₂ CH ₂ CH ₂ ) , 13.9 (CH ₃ ). ³¹ P-NMR δ/ppm (d ₆ -acetone) : -144.2. Example 24: Rhenium Complex 36

Silver triflate (27.0 mg, 0.11 mmol) was added to a suspension of Rhenium Complex 21 (49.0 mg, 0.089 mmol) in THF (10 mL) and stirred at reflux for 20 h. The suspension was filtered by cannula filtration into another Schlenk flask. Imidazole (210 mg, 3.08 mmol) was added and the solution was heated at 60 °C for 20 h. The solution was dried then dissolved in methanol (1 mL) and dropped into a H4PF6 solution in methanol/water (5:1, 5 mL) . Water was slowly added to the solution until the solution became cloudy and an oil formed. The suspension was stirred rapidly for 20 min and then extracted with dichloromethane (3 x 10 mL) . The dichloromethane fraction was dried and the resulting oil was triturated with diethyl ether (2 ^χ 5 mL) , petroleum spirits (3 ^χ 5 mL) and dried overnight to afford the product as a flaky pale yellow solid. Yield: 15.0 mg, 25%. Anal. calc. for CisHigFeNsOsPRe : C 31.58, H 2.80, N 10.23; found: C 32.13, H 2.78, N 10.14. FT-IR (ATR) Vmax/cm ^"1 : 3411 br w, 2019 s (CO), 1888 s (CO), 1618 w, 1489 m. ^! H- MR δ/ppm (d6-acetone) : 9.10 (1H, ddd, ³ J ^" _H , _H = 5.7 Hz, ⁴ JH,H = 1.5 Hz, ⁵ J ^" _H ,H = 0.6 Hz, H6'), 8.40 (1H, ddd, ³ JH,H = 8.3 Hz, ³ JH,H = 7.5 Hz, ⁴ J ^" _H ,H = 1.5 Hz, H4 ' ) , 8.38 (1H, d, ³ JH,H = 2.2 Hz, H4), 8.25 (1H, ddd, ³ JH,H = 8.3 Hz, ⁴ JH,H = 1.2 Hz, ⁵ JH,H = 0.6 Hz, H3 ' ) , 7.82 (1H, s, H2 ' ' ) ,

7.79 (1H, d, ³ JH,H = 2.2 Hz, H5), 7.64 (1H, ddd, ³ JH,H = 7.5 Hz, ³ JH,H = 5.7 Hz, ⁴ JH,H = 1.2 Hz, H5 ' ) , 7.16 (1H, br s, H4 ' ' or H5 ' ' ) , 6.75 (1H, br s, H4 ' ' or H5 ' ' ) , 4.50 (2H, m, NCH ₂ ), 1.97 (2H, m, NCH ₂ CH ₂ ), 1.47 (2H, m, NCH ₂ CH ₂ CH ₂ ), 0.96 (3H, t, ³ JH,H = 7.4 Hz, CH ₃ ) . ¹³ C-NMR δ/ppm ( d ₆ -acetone ) : 198.2 (CO), 197.7 (CO), 192.1 (C2), 189.4 (CO), 154.6 (C6'), 154.3 (C2'), 144.0 (C4 ' ) , 141.7 (C2 ' ' ) , 131.2 (C4 ' ' or C5 ' ' ) , 125.6 (C5), 125.5 (C5'), 120.4 (C4 ' ' or C5 ' ' ) , 119.0 (C4), 114.2 (C3'), 52.8 (NCH ₂ ), 34.0 (NHCH ₂ CH ₂ ), 20.3 (NCH ₂ CH ₂ CH ₂ ) , 13.9 (CH ₃ ). ³¹ P-NMR δ/ppm (d ₆ -acetone) : -144.2. xample 25: Rhenium complex 37

Triethylamine (0.26 mL, 1.87 mmol) was added to a mixture of the azolium salt of Example 5 (138.5 mg, 0.19 mmol) and Re(CO)5Br (76 mg, 0.19 mmol) in toluene (7 mL) and the resulting mixture was heated at reflux for 3 d. The yellow toluene solution of the crude product was decanted, and the residue rinsed with toluene (3 mL) . The combined toluene fractions were concentrated in vacuo. The

resulting residue was dissolved in dichloromethane (10 mL) and washed with water (3 x 8 mL) , then concentrated to dryness without drying over MgS04. The resulting residue was subjected to column chromatography on acidic alumina (Brockmann grade II, gradient elution using

dichloromethane/methanol ) . The purified fractions were combined, dried in vacuo, then dissolved in

dichloromethane (2 mL) and precipitated with diethyl ether. The resulting solid was collected, washed with diethyl ether ( x 3 mL) , and dried to afford the product as a pale yellow solid. Yield: 32.7 mg, 19%) . Anal. calc. for C32H27BrF6 ₃ 0 ₃ P2Re : C 40.73, H 2.88, N 4.45; found: C 40.71, H 2.88, N 4.41. FT-IR (ATR) Vmax/cm ^"1 : 2014 s (CO), 1913 s (CO), 1873 s (CO), 1619 w, 1489 m, 1438 m, 1331 w, 1270 w. ^! H- MR δ/ppm (CDCI ₃ ) : 8.83 (1H, ddd, ³ J ^" _H , _H = 5.6 Hz, ⁴ Jk,H = 1.7 Hz, ⁵ Jk,H = 0.7 Hz, H6'), 8.04 (1H, ddd, ³ Jk,H =

8.3 Hz, ³ JH,H = 7.6 Hz, ⁴ J ^" _H ,H = 1.7 Hz, H4') , 7.81 (3H, m, Ar CH), 7.72 (6H, m, Ar CH) , 7.66 (1H, ddd, ³ JH,H = 8.3 Hz, ⁴ Jk,H = 1.1 Hz, ⁵ Jk,H = 0.7 Hz, H3') , 7.65 (6H, m, Ar CH), 7.62 (1H, d, ³ JH,H = 2.2 Hz, H4), 7.57 (1H, d, ³ J ^" _H ,H = 2.2 Hz, H5), 7.30 (1H, ddd, ³ J ^" _H ,H = 7.6 Hz, ³ J ^" _H ,H = 5.6 Hz, ⁴ J ^" _H ,H = 1.1 Hz, H5') , 4.64 - 4.48 (2 x 1H, 2 x m, NC¾), 3.37 - 3.22 (2 x 1H, 2 x m, CH ₂ P) , 2.51 (1H, m, NCffflCffe), 2.36 (1H, m, NCHHZH ₂ ) . ¹³ C-NMR δ/ppm (CDCls) : 198.9 (CO), 196.7 (CO), 192.4 (C2), 187.5 (CO), 153.6 (C6') , 153.1 (py quat. C) , 141.3 (C4'), 135.5 (d, ³ J _C ,P = 10.1 Hz, Ar CH), 133.7 (d, ⁴ JC,P = 3.0 Hz, Ar CH), 130.9 (d, ² J ^" _C ,P = 12.7 Hz, Ar CH), 124.8 (C5), 123.5 (C5') , 117.4 (d, ¹ J _c ,v = 86.7 Hz, Ar C) , 116.6 (C4), 112.2 (C3') , 51.3 (d, ³ J _C ,P = 21.1 Hz, NCH ₂ ), 24.1 (d, ² JC,P = 3.2 Hz, NCH ₂ CH ₂ ), 20.6 (d, ¹ J,v = 54.7 Hz, CH ₂ P) . ³¹ P-NMR δ/ppm ( CDCI3 ) : -24.0 (CH ₂ PPh ₃ ), -144.2 (PF ₆ ) . Example 26: Rhenium complex 38

Triethylamine (0.38 mL, 2.70 mmol) was added to a mixture of the azolium salt of Example 5 (200.0 mg, 0.27 mmol) and

Re(CO) ₅ Cl (98 mg, 0.27 mmol) in toluene (8 mL) and the resulting mixture was heated at reflux for 3 d. The yellow toluene solution of the crude product was decanted, and the residue rinsed with toluene (3 mL) . The combined toluene fractions were concentrated in vacuo. The

resulting residue was dissolved in dichloromethane (10 mL) and washed with water (3 x 8 mL) , then concentrated to dryness without drying over MgS04. The resulting residue was subjected to column chromatography on acidic alumina (Brockmann grade II, gradient elution using

dichloromethane/methanol ) . The purified fractions were combined, dried in vacuo, then dissolved in

dichloromethane (2 mL) and precipitated with diethyl ether. The resulting solid was collected, washed with diethyl ether ( x 3 mL) , and dried to afford the product as a pale yellow solid. Yield: 79.6 mg, 33%) . Anal. calc. for C ₃₂ H ₂₇ ClF _{6 3} 0 ₃ P2Re . (H ₂ 0) : C 41.90, H 3.19, N 4.58; found: C 41.65, H 3.18, N 4.48. FT-IR (ATR) Vmax/cm ^"1 : 2012 s (CO), 1911 s (CO), 1872 s (CO), 1619 w, 1489 m, 1438 m, 1332 w, 1270 w. ^! H- MR δ/ppm (CDCI ₃ ) : 8.82 (1H, ddd, ³ J ^" _H ,H = 5.6 Hz, ⁴ JH,H = 1.6 Hz, ⁵ JH,H = 0.8 Hz, H6') , 8.06 (1H, ddd, ³ JH,H = 8.3 Hz, ³ JH,H = 7.6 Hz, ⁴ J ^" _H ,H = 1.7 Hz, H4') , 7.80 (3H, m, Ar CH), 7.72 (6H, m, Ar CH) , 7.69 (1H, ddd, ³ J ^" _H ,H = 8.3 Hz, ⁴ JH,H = 1.1 Hz, ⁵ JH,H = 0.8 Hz, H3') , 7.67 (1H, d, ³ JH,H = 2.2 Hz, H4), 7.65 (6H, m, Ar CH) , 7.53 (1H, d, ³ JH,H = 2.2 Hz, H5), 7.31 (1H, ddd, ³ J ^" _H ,H = 7.5 Hz, ³ J ^" _H ,H = 5.6 Hz, ⁴ J ^" _H ,H = 1.1 Hz, H5') , 4.63 - 4.49 (2 x 1H, 2 x m, NCi¾), 3.41 - 3.18 (2 x 1H, 2 x m, CH ₂ P) , 2.47 (1H, m, NCffflC^), 2.36 (1H, m, NCHHZH2) . ¹³ C-NMR δ/ppm (CDCI3) : 199.4 (CO), 197.4 (CO), 193.1 (C2), 188.1 (CO), 153.3 (C6') , 153.1 (py quat. C) , 141.6 (C4'), 135.5 (d, ³ J _C ,P = 10.0 Hz, Ar CH), 133.7 (d, ⁴ JC,P = 3.1 Hz, Ar CH), 130.9 (d, ² J ^" _C ,P = 12.7 Hz, Ar CH), 124.4 (C5), 123.6 (C5') , 117.4 (d, ¹ J _c ,v = 86.6 Hz, Ar C) , 116.9 (C4), 112.4 (C3') , 51.3 (d, ³ J _C ,P = 20.5 Hz, NCH ₂ ), 24.3 (NCH2CH2) , 20.4 (d, ^! JCP = 54.6 Hz, CH ₂ P) . ³¹ P-NMR δ/ppm (CDCI3) : -23.9 (CH ₂ PPh ₃ ), -144.2 (PF ₆ ).

Biological Examples

Example 27: Activity against pancreatic cell lines

The activity of Rhenium Complexes 9, 10 and 21 were tested against a panel of human pancreatic cell lines comprising HPAF-11, AsPCl and CFPAC. Control cells used were healthy human embryonic kidney 293T cells (HEK293T) .

For cell counting, cells were seeded in 12 well plates and grown in cell culture medium supplemented with 10% FBS for the indicated times. When necessary, cells were treated with Rhenium Complexes. For the dose treatments

experiments, 50,000 cells per well of AsPCl, HPAF-II, CFPAC or HEK-293T were seeded into 12 well plates. After an overnight incubation, the complete media was replaced with fresh one containing DMSO 0.1%, 0.5 μΜ, 1 μΜ, 2.5 μΜ, 5 μΜ and 10 μΜ of Rhenium Complexes 9, 10 and 21. After 72 Hours of incubation at 37°C/5% CO ₂ , cells were washed once in warm PBS, and detached with Tripsyn-EDTA 0.25% at 37°C/5% CO ₂ . When a complete cell detachment was achieved, the proteasic activity was stopped with one volume of complete media. The total number of cells per each well was quantified by manual cell counting under bright field microscopy using Neubauer or Burker chambers . Table 1 displays experimental IC ₅₀ S as averages (2-4 replicates) + Standard Error of the Mean.

Table 1 : IC ₅₀ (μΜ) values for Rhenium Complexes 9, 10 and 21 against pancreatic cancer cell lines

Figure 1 shows the cell number as a percent of control where AsPCl, HPAFII and CFPAC cells were treated with Rhenium Complexes 9, 10 and 21 at concentrations of 0.5 μΜ, 1 μΜ, 2.5 μΜ, 5 μΜ and 10 μΜ. The results show that

Rhenium Complexes 9, 10 and 21 significantly decreased the percentage of viable pancreatic cancer cells .

Example 28: Cell Cycle Analysis

Exponentially growing AsPCl cells were cultured in a T75 flask at a seeding density of 20,000 cells per cm ² in complete media. After an overnight incubation media was changed and cells were treated with Gemcitabine, Rhenium Complexes 9, 10 and 21 at 10 μΜ. Vehicle-control was treated with DMSO 0.1% and the G ₂ /M cell cycle arrest positive control with Nocodazole 200 ng/mL. After 24 hours of treatment cell were washed in PBS and trypsinized, resuspended again in PBS and counted. An equal amount of cells per each condition was then pelleted and fixed in cold Ethanol 70% on ice for at least 30 minutes. Samples were spun down, and cells washed once with PBS, pelleted and resuspended in 100 of Propidium Iodide 10 μg/mL, RnaseA 100 μg/mL and TritonX-100 0.1% v/v in PBS. After ca . 20 minutes of incubation on ice in the dark, cells were analyzed by flow cytometry with a BD FACSCanto-II . At least 10,000 events are displayed for each condition. All the centrifugation steps were operated at 300g for 5 minutes .

The results are shown in Figure 2. The results show a significant decrease in the number of cells at Gi with high percentage of cells that were arrested in G ₂ /M phase.

Example 29: Apoptosis Assay

AsPCl cells were cultured in a 96 wells plate, 2,000 were seeded per well in triplicate for each condition. After an overnight incubation, cells were exposed to new complete media additioned with 5 μΜ IncuCyte Caspase 3/7 probe

[Essenbioscience ] , IncuCyte Cytotox Red 250 nM

[Essenbioscience ] and increasing amounts of Rhenium

Complexes 9, 10, or 21. Cells were incubated at 37°C/5% CO2 and images were collected every two hours in the bright field, green and red fluorescent channels up to 72 hours with a 4x magnification objective. Apoptotic index, is herein defined as the ratio between Caspase 3 or 7

positive nuclei, and the corresponding cellular

confluence. Nuclei positive for active Caspase 3 or 7 were quantified with a DEVD peptide that upon a specific cleavage by Caspase 3 or 7 , intercalates nuclear DNA and emits green fluorescence. Cellular confluence in the bright field, and fluorescent green or red nuclei in the respective channels were simultaneously quantified with the IncuCyte ZOOM built in 2016A software of

EssenBioscience . Cytotoxicity Index, is defined as the ratio between red fluorescent cells and cellular

confluence, and quantitatively reflects a pathological alteration of the cellular membrane permeability.

The results are shown in Figure 3. Rhenium Complexes 9 and 21, although cytostatic, did not induce apoptosis, when compared to the control. In contrast, Rhenium Complex 10 (Figures 3e and 3f) induced apoptosis.

Example 30: Inhibition of Aurora A in pancreatic cells

300,000 AsPCl cells per well were seeded into 6-well plate, after an overnight incubation for cell attachment, they were treated for 24 hours at 37°C/5% CO ₂ with the Rhenium Complexes 9, 10, 21, Gemcitabine at 10 μΜ or Nocodazole 300ng/mL as phospho-Aurora inducer control. DMSO 0.1% was used for the vehicle control. Cells were washed once with sterile PBS and protein lysates collected by scraping on ice in 100 μΐ of RIPA buffer additioned with Halt™ Protease and Phosphatase inhibitor cocktail lx [Thermo Scientific] . Lysates were sonicated at 4°C, 10 times for 10 seconds, with 10 seconds of cooling period between each cycle, and cellular debries spun down at 14,000rpm for 15 minutes at 4°C with a table top

microcentrifuge. Protein content was evaluated via IR spectrometry [Direct Detect® Assay-free Cards - Millipore] , and 30 g resuspended in Laemmli Buffer lx and loaded in each lane. Proteins were separated with a 10 % polyacrylamide gel following a classic SDS-PAGE protocol. Lysates were resolved at 130V for 75 minutes ca. and blotted onto a nitrocellulose membrane with a Trans-Blot Turbo Transfer System, following proprietary

recommendations [Biorad] . Each membrane was briefly rinsed in dH ₂ 0 and Tris Buffer Solution, before proceeding with the blocking in BSA 3% [Bovogen] in TBS-Tween20 0.05% for 1 hour at room temperature. Lysates were then probed with specific primary antibodies overnight at 4°C [Cell signaling p-Aurora #2914, total-Aurora #3092, Actinin #3134], washed three times in TBS-Tween20 0.05% for 5 minutes and incubated for 1 hour at RT with a secondary, HRP fused, anti-rabbit antibody diluted 1:40,000 in BSA 0.75% TBS-Tween20 0.05%. After three further washings of 5 minutes in TBS-Tween 0.05%, Immunodetection was performed with Clarity™ Western ECL Substrate [Biorad] .

As evidenced by Figure 4, Rhenium Complexes 9, 10 and 21 completely inhibited the phosphorylation of Aurora A.

Example 31: Activity against neuroblastoma cells

Rhenium Complexes 10, 21, 26, 27 and 9 were tested against neuroblastoma cells (SHSY5) at concentrations of 0.5 μΜ, 1 μΜ, 2.5 μΜ, 5 μΜ and 10 μΜ. Control cells used were healthy human embryonic kidney 293T cells (HEK293T) .

For cell counting, cells were seeded in 12 well plates and grown in cell culture medium supplemented with 10% FBS for the indicated times. When necessary, cells were treated with rhenium complexes. For the dose treatments

experiments, 50,000 cells per well of SHSY5 or HEK-293T cells were seeded into 12 well plates. After an overnight incubation, the complete media was replaced with fresh one containing DMSO 0.1%, 0.5 μΜ, 1 μΜ, 2.5 μΜ, 5 μΜ and 10 μΜ of Rhenium Complexes 9, 10, 21, 26 and 27. After 72 Hours of incubation at 37°C/5% CO ₂ , cells were washed once in warm PBS, and detached with Tripsyn-EDTA 0.25% at 37°C/5% CO ₂ . When a complete cell detachment was achieved, the proteasic activity was stopped with one volume of complete media. The total number of cells per each well was quantified by manual cell counting under bright field microscopy using Neubauer or Burker chambers . Table 2 displays experimental IC ₅₀ S as averages (3-4 replicates) ± Standard Error of the Mean (SEM) .

Table 2 : IC ₅₀ (μΜ) values for Rhenium Complexes 9, 21, 26 and 27 against neuroblastoma cancer cell line SHSY5

Figures 5 and 6 show the cell counts as a percentage of control cells at concentrations of 0.1%, 0.5 μΜ, 1 μΜ, 2.5 μΜ, 5 μΜ and 10 μΜ of Rhenium Complex 9 (Figure 5) and 10, 21, 26 and 27 (Figure 6) . The results show that the rhenium complexes significantly decreased the percentage of viable neuroblastoma cells, especially Rhenium Complex 9.

Example 32: Activity of Rhenium Complexes 37 and 38 against various cell lines (cancerous and non-cancerous) and comparison of efficacy with carboplatin.

The activity of Rhenium Complexes 37 and 38 was tested against HPAF and AsPCl pancreatic cancer cell lines. These results are compared with published results for

carboplatin in the same cell lines .

These results were obtained by following the procedure described above in Example 27 for the equivalent cell lines .

Table 3. IC50 values (μΜ) for Rhenium Complexes 37 and 38, and carboplatin on cancerous and healthy cell lines.

SI refers to the selectivity index derived from dividing the corresponding IC50 against healthy RC-124 by the IC50 against the corresponding cancer cell line.

b Carboplatin used as controls for pancreatic cancer cell lines. Values obtained from E. Ratzon, Y. Najajreh, R. Salem, H. Khamaisie, .

Ruthardt, J. ahajna, BMC Cancer 2016, 16, 140.

The results in Table 3 show that Rhenium Complexes 37 and 38 have some efficacy against HPAF and AsPCl pancreatic cancer cell lines.

Example 33: Activity in the KPC mouse model

The KPC mouse model ( KrasLSL . G12D/+; p53R172H/+;

PdxCretg/+) is a well validated genetically engineered mouse model (GEMM) for human pancreatic ductal

adenocarcinoma (PDAC) . Briefly, KPC mice have mutated KRAS and p53 in the pancreas, and develop an array of premalignant lesions that progress to PDAC with 100% penetrance with characteristics very similar to human PDAC. Cells were isolated from primary tumours in KPC mice and cultured. In culture, KPC primary cells show some "islet" of epithelioid-like cells interconnected by a matrix of fibroblast-like cells . Figure 7 shows that treatment with Rhenium Complex 21 significantly reduces the growth of KPC primary cells . Figure 7 also shows that both the epithelioid-like cells and the fibroblast-like cells are affected by Rhenium Complex 21 treatment. Figure 8 shows that this growth reduction proceeds in a dose dependent manner.

Example 34: In vivo toxicity

Toxicity has been tested using a zebrafish model. Embryos were treated 24 hours post fertilization (hpf ) , hatching and mortality rate were scored as indexes of toxicity. Dimethylsulphoxide (DMSO) and Cisplatin (drug of reference as standard of therapy) were used as controls.

Considering the hatching, Figure 9 shows that Rhenium Complex 21 has lower toxicity compared to cisplatin and that Rhenium Complex 37 has similar toxicity to the cisplatin control.

Considering the mortality rate, Figure 10 shows that Rhenium Complex 21 has lower toxicity compared to

cisplatin for concentrations up to 500μΜ and that Rhenium Complex 37 has similar toxicity to cisplatin, for

concentrations up to 500μΜ.

In addition, Figure 11 shows that Rhenium Complex 21 surprisingly did not have an effect on the heart rate of the zebrafish compared to the DMSO control.