Novel spirocyclic compounds

Field of the invention

The present invention relates to new spirocyclic compounds that may be useful as anticancer and anti-microbial agents, to the preparation of the compounds, and to compositions including the compounds. The present invention also relates to the use of the compounds, as well as compositions including the compounds, in treating or preventing cancer, and treating or preventing microbial infections.

Background of the invention

Numerous structurally-interesting and biologically-useful compounds have been isolated from marine organisms. In 2004, a number of intriguing new alkaloids were isolated from the Leucetta sponge, including one (spiroleucettadine) which was found to possess anti-bacterial activity.

The total synthesis of spiroleucettadine has proved to be challenging, and was hampered for many years due to an initial incorrect structure assignment. Therefore, there is a need for an efficient and enantioselective synthesis of spiroleucettadine, and analogues thereof. There is also a need for new analogues of spiroleucettadine, which may possess improved biological activity.

Reference to any prior art in the specification is not an acknowledgment or suggestion that this prior art forms part of the common general knowledge in any jurisdiction or that this prior art could reasonably be expected to be understood, regarded as relevant, and/or combined with other pieces of prior art by a skilled person in the art.

Summary of the invention

In a first aspect, the present invention relates to a compound of formula (I):

(I) or a pharmaceutically acceptable salt or prodrug thereof, wherein: R ¹ and R ² are each independently selected from H, OH, O-alkyl, NH ₂ , NH-alkyl, N(alkyl) ₂ , alkyl, N0 ₂ and halogen;

R ³ is selected from H, OC(0)-alkyl, NH-alkyl, N(alkyl) ₂ and S-alkyl;

R ⁴ and R ⁶ are each independently selected from H, alkyl and heteroalkyl;

R ⁵ is selected from O, NH, N-alkyl and N-heteroalkyl;

m is 0, 1 , 2, 3, 4, 5 or 6; and

R ⁷ is selected from alkyl, aryl and heteroaryl, which groups are optionally substituted, wherein the compound of formula (I) is not spiroleucettadine:

In a second aspect, the present invention relates to a compound of formula (I):

(I) or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R ¹ and R ² are each independently selected from H, OH, O-alkyl, NH ₂ , NH-alkyl, N(alkyl) ₂ , alkyl, N0 ₂ and halogen;

R ³ is selected from H, OC(0)-alkyl, NH-alkyl, N(alkyl) ₂ and S-alkyl;

R ⁴ and R ⁶ are each independently selected from H, alkyl and heteroalkyl;

R ⁵ is selected from NH, N-alkyl and N-heteroalkyl;

m is 0, 1 , 2, 3, 4, 5 or 6; and

R ⁷ is selected from alkyl, aryl and heteroaryl, which groups are optionally substituted. In a third aspect, the present invention relates to a compound of formula (I):

(I) or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R ¹ and R ² are each independently selected from H, OH, O-alkyl, NH ₂ , NH-alkyl, N(alkyl) ₂ , alkyl, N0 ₂ and halogen;

R ³ is selected from H, OC(0)-alkyl, NH-alkyl, N(alkyl) ₂ and S-alkyl;

R ⁴ and R ⁶ are each independently selected from H, alkyl and heteroalkyl;

R ⁵ is selected from O, NH, N-alkyl and N-heteroalkyl;

m is 0, 1 , 2, 3, 4, 5 or 6; and

R ⁷ is selected from alkyl, aryl and heteroaryl, which groups are optionally substituted.

R ¹ and R ² may both be H. The halogen may be bromine or chlorine.

R ³ may be H. R ³ may be OC(0)-alkyl (e.g. OC(O)-methyl). R ³ may be NH-alkyl (e.g. NH- methyl).

R ⁴ and R ⁶ may both be alkyl (e.g. methyl).

R ⁵ may be NH.

m may be 1 .

R ⁷ may be an aryl group. The aryl group may be substituted. The substituent may be heteroalkyl (e.g. methoxy).

The compound may be a compound of formula (III):

(III) wherein m, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined herein. In a fourth aspect, the present invention relates to a pharmaceutical composition including a compound of formula (I) (according to the first, second or third aspect of the invention) together with a pharmaceutically acceptable carrier, diluent or excipient.

Compounds and pharmaceutical compositions according to the present invention may be suitable for treating and/or preventing cancer, and microbial infections. Accordingly, in another aspect, the present invention relates to a method of treating and/or preventing cancer or microbial infection in a subject, the method including administering to the subject an effective amount of a compound of formula (I) according to the first, second or third aspect of the invention or a pharmaceutical composition according to the fourth aspect of the invention.

In a further aspect the present invention relates to the use of a compound of formula (I) according to the first, second or third aspect of the invention or a pharmaceutical composition according to the fourth aspect of the invention in the manufacture of a medicament for treating and/or preventing cancer or microbial infection.

In a further aspect the present invention relates to the use of a compound of formula (I) according to the first, second or third aspect of the invention or a pharmaceutical composition according to the fourth aspect of the invention for the treatment and/or prevention of cancer or microbial infection in a subject.

In a further aspect the present invention relates to a compound of formula (I) according to the first, second or third aspect of the invention or a pharmaceutical composition according to the fourth aspect of the invention for use in the treatment and/or prevention of cancer or microbial infection in a subject.

The compounds of formula (I) may be used in therapy alone or in combination with one or more other therapeutic agents, for example, as part of a combination therapy.

In a further aspect, the present invention relates to a process for making a compound of formula (I):

(I)

harmaceutically acceptable salt or prodrug thereof, wherein R ¹ and R ² are each independently selected from H, OH, O-alkyl, NH ₂ , NH-alkyl, N(alkyl) ₂ , alkyl, N0 ₂ and halogen;

R ³ is selected from H, OC(0)-alkyl, NH-alkyl, N(alkyl) ₂ and S-alkyl;

R ⁴ and R ⁶ are each independently selected from H, alkyl and heteroalkyl;

R ⁵ is selected from O, NH, N-alkyl and N-heteroalkyl;

m is 0, 1 , 2, 3, 4, 5 or 6; and

R ⁷ is selected from alkyl, aryl and heteroaryl, which groups are optionally substituted, the process including treating a compound of formula (II):

(II)

with a hypervalent iodine reagent to produce a spirocyclic compound of formula (III):

(Ml)

In a further aspect, the present invention relates to a process for making a compound of formula (I):

(I)

or a pharmaceutically acceptable salt or prodrug thereof, wherein: R ¹ and R ² are each independently selected from H, OH, O-alkyl, NH ₂ , NH-alkyl, N(alkyl) ₂ , alkyl, N0 ₂ and halogen;

R ³ is selected from H, OC(0)-alkyl, NH-alkyl, N(alkyl) ₂ and S-alkyl;

R ⁴ and R ⁶ are each independently selected from H, alkyl and heteroalkyl;

R ⁵ is selected from O, NH, N-alkyl and N-heteroalkyl;

m is 0, 1 , 2, 3, 4, 5 or 6; and

R ⁷ is selected from alkyl, aryl and heteroaryl, which groups are optionally substituted, the process including treating a compound of formula (II):

with a hypervalent iodine reagent to produce a spirocyclic compound of formula (III):

(Ml) wherein the compound of formula (I) is not spiroleucettadine:

In a further aspect, the present invention relates to a process for making a compound of formula (I):

(I)

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R ¹ and R ² are each independently selected from H, OH, O-alkyl, NH ₂ , NH-alkyl, N(alkyl) ₂ , alkyl, N0 ₂ and halogen;

R ³ is selected from H, OC(0)-alkyl, NH-alkyl, N(alkyl) ₂ and S-alkyl;

R ⁴ and R ⁶ are each independently selected from H, alkyl and heteroalkyl;

R ⁵ is selected from NH, N-alkyl and N-heteroalkyl;

m is 0, 1 , 2, 3, 4, 5 or 6; and

R ⁷ is selected from alkyl, aryl and heteroaryl, which groups are optionally substituted, the process including treating a compound of formula (II):

with a hypervalent iodine reagent to produce a spirocyclic compound of formula (III):

(III)

The hypervalent iodine reagent may be selected from an organic iodine (III) compound, such as an aryliodine(lll) carboxylate (e.g. phenyliodine{ 11 l)-bis{trif luoroacetate) (PIFA) or phenyliodine(lll)-difluoroacetate (PIDA)). The process may include the further step of treating the compound of formula (III) with a hypervalent iodine reagent to produce a compound of formula (IV):

(IV)

The hypervalent iodine reagent may be selected from an organic iodine (V) compound, such as a periodinane (e.g. Dess-Martin periodinane), PIFA or PIDA.

Further aspects of the present invention and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, given by way of example.

Detailed description of the embodiments

Compounds are generally described herein using standard nomenclature. The compounds of formulae (I) and (IV) are also intended to include the other cis isomer (i.e. their enantiomer):

(I) and (IV)

Therefore, a person skilled in the art will understand that the compound of formula (III) also intended to include its enantiomer:

(III) For compounds also having other asymmetric centres (e.g. where R\ R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and/or R ⁷ include one or more chiral centres), it will be understood that, unless otherwise specified, all of the optical isomers and mixtures thereof are encompassed. Compounds with two or more asymmetric elements can also be present as mixtures of diastereomers. In addition, compounds with carbon-carbon double bonds may occur in Z and E forms, with all isomeric forms of the compounds being included in the present invention unless otherwise specified. Where a compound exists in various tautomeric forms, a recited compound is not limited to any one specific tautomer, but rather is intended to encompass all tautomeric forms. Recited compounds are further intended to encompass compounds in which one or more atoms are replaced with an isotope, i.e., an atom having the same atomic number but a different mass number. By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include ¹¹ C, ¹³ C, and ¹⁴ C.

Compounds according to the formula provided herein, which have one or more stereogenic centres, have an enantiomeric excess of at least 50%. For example, such compounds may have an enantiomeric excess of at least 60%, 70%, 80%, 85%, 90%, 95%, or 98%. Some embodiments of the compounds have an enantiomeric excess of at least 99%. It will be apparent that single enantiomers (optically active forms) can be obtained by asymmetric synthesis, synthesis from optically pure precursors, biosynthesis or by resolution of the racemates, for example, enzymatic resolution or resolution by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral HPLC column.

Certain compounds are described herein using a general formula that includes variables such as R ¹ , R ² and R ³ . Unless otherwise specified, each variable within such a formula is defined independently of any other variable, and any variable that occurs more than one time in a formula is defined independently at each occurrence. Therefore, for example, if a group is shown to be substituted with 0, 1 or 2 R ^* , the group may be unsubstituted or substituted with up to two R ^* groups and R ^* at each occurrence is selected independently from the definition of R ^* . Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds, i.e., compounds that can be isolated, characterized and tested for biological activity.

A "pharmaceutically acceptable salt" of a compound disclosed herein is an acid or base salt that is generally considered in the art to be suitable for use in contact with the tissues of human beings or animals without excessive toxicity or carcinogenicity, and preferably without irritation, allergic response, or other problem or complication. Such salts include mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids.

Suitable pharmaceutically acceptable salts include, but are not limited to, salts of acids such as hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic, sulfanilic, formic, toluenesulfonic, methanesulfonic, benzenesulfonic, ethane disulfonic, 2- hydroxyethylsulfonic, nitric, benzoic, 2-acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic, succinic, fumaric, maleic, propionic, hydroxymaleic, hydroiodic, phenylacetic, alkanoic (such as acetic, HOOC-(CH ₂ )n-COOH where n is any integer from 0 to 6, i.e., 0, 1 , 2, 3, 4, 5 or 6), and the like. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. A person skilled in the art will recognize further pharmaceutically acceptable salts for the compounds provided herein. In general, a pharmaceutically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Generally, the use of nonaqueous media, such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, is preferred.

It will be apparent that each compound of formula (I) may, but need not, be present as a hydrate, solvate or non-covalent complex. In addition, the various crystal forms and polymorphs are within the scope of the present invention, as are prodrugs of the compounds of formula (I) provided herein.

A "prodrug" is a compound that may not fully satisfy the structural requirements of the compounds provided herein, but is modified in vivo, following administration to a subject or patient, to produce a compound of formula (I) provided herein. For example, a prodrug may be an acylated derivative of a compound as provided herein. Prodrugs include compounds wherein hydroxy, carboxy, amine or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy, carboxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein. Prodrugs of the compounds provided herein may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved in vivo to generate the parent compounds.

A "substituent" as used herein, refers to a molecular moiety that is covalently bonded to an atom within a molecule of interest. For example, a "ring substituent" may be a moiety such as a halogen, alkyl group, heteroalkyi group, haloalkyi group or other substituent described herein that is covalently bonded to an atom, preferably a carbon or nitrogen atom, that is a ring member. The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated substituents, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound, i.e., a compound that can be isolated, characterized and tested for biological activity. When a substituent is oxo, i.e., =0, then two hydrogens on the atom are replaced. An oxo group that is a substituent of an aromatic carbon atom results in a conversion of -CH- to - C(=0)- and a loss of aromaticity. For example a pyridyl group substituted by oxo is a pyridone. Examples of suitable substituents are alkyl (including haloalkyi e.g., CF ₃ ), heteroalkyi (e.g. OMe), halogen (for example, fluorine, chlorine, bromine or iodine atoms), C(0)OH, C(0)H, OH, =0, SH, S0 ₃ H, NH ₂ , NH-alkyl, N(alkyl) ₂ , =NH, N ₃ and N0 ₂ groups. Other suitable substituents include aryl (e.g. phenyl), heteroaryl (e.g. pyridine), alkyl-aryl (e.g. benzyl), and alkyl-heteroaryl (e.g. CH ₂ -pyridine). The term "alkyl" refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, for example a n-octyl group, especially from 1 to 6, i.e., 1 , 2, 3, 4, 5, or 6, carbon atoms. Specific examples of alkyl groups are methyl, ethyl, propyl, / ^' so-propyl, n-butyl, / ^' so-butyl, sec-butyl, ferf-butyl, n-pentyl, iso- pentyl, n-hexyl and 2,2-dimethylbutyl. The term "heteroalkyi" refers to an alkyl group as defined above that contains one or more heteroatoms selected from oxygen, nitrogen and sulphur (especially oxygen and nitrogen). Specific examples of heteroalkyi groups are methoxy, trifluoromethoxy, ethoxy, n- propyloxy, / ^' so-propyloxy, butoxy, ferf-butyloxy, methoxymethyl, ethoxymethyl, -CH ₂ CH ₂ OH, - CH ₂ OH, methoxyethyl, 1 -methoxyethyl, 1 -ethoxyethyl, 2-methoxyethyl or 2-ethoxyethyl, methylamino, ethylamino, propylamino, / ^' so-propylamino, dimethylamino, diethylamino, iso- propyl-ethylamino, methylamino methyl, ethylamino methyl, di-/so-propylamino ethyl, methylthio, ethylthio, / ^' so-propylthio, enol ether, dimethylamino methyl, dimethylamino ethyl, acetyl, propionyl, butyryloxy, acetyloxy, methoxycarbonyl, ethoxycarbonyl, propionyloxy, acetylamino, propionylamino, carboxymethyl, carboxyethyl, carboxypropyl, A/-ethyl-A/-methylcarbamoyl and A/-methylcarbamoyl. Further examples of heteroalkyi groups are nitrile, / ^' so-nitrile, cyanate, thiocyanate, / ^' so-cyanate, / ^' so-thiocyanate and alkylnitrile groups.

The term "aryl" refers to an aromatic group that contains one or more rings containing from 6 to 14 ring carbon atoms, preferably from 6 to 10 (especially 6) ring carbon atoms. Examples are phenyl, naphthyl and biphenyl groups. The term "heteroaryl" refers to an aromatic group that contains one or more rings containing from 5 to 14 ring atoms, preferably from 5 to 10 (especially 5 or 6) ring atoms, where one or more of the ring atoms are replaced with one or more (preferably 1 , 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N). Examples are pyridine, imidazole, thiazole, / ^' so-thiazole, 1 ,2,3-triazole, 1 ,2,4-triazole, oxadiazole, thiadiazole, indole, indazole, tetrazole, pyrazine, pyrimidine, pyridazine, oxazole, isoxazole, triazole, tetrazole, isoxazole, indazole, benzimidazole, benzoxazole, benzisoxazole, benzthiazole, pyridazine, quinoline, isoquinoline, pyrrole, purine, carbazole, acridine, and / ^' so-quinoline groups.

The expression "halogen" or "halogen atom" as used herein means fluorine, chlorine, bromine, or iodine. Preferably, the halogen is chlorine or bromine.

The term "optionally substituted" refers to a group in which one, two, three or more hydrogen atoms have been replaced independently of each other by, for example, halogen (for example, fluorine, chlorine, bromine or iodine atoms), C(0)OH, C(0)H, OH, =0, SH, =S, S0 ₃ H, NH ₂ , NH-alkyl, N(alkyl) ₂ , =NH, N ₃ or N0 ₂ groups. This expression also refers to a group that is substituted by one, two, three or more alkyl or heteroalkyl (e.g. OMe) groups. These groups may themselves be substituted. For example, an alkyl group substituent may be substituted by one or more halogen atoms {i.e., may be a haloalkyl group).

As used herein a wording defining the limits of a range of length such as, for example, "from 1 to 5" means any integer from 1 to 5, i. e. 1 , 2, 3, 4 and 5. In other words, any range defined by two integers explicitly mentioned is meant to comprise and disclose any integer defining said limits and any integer comprised in said range.

As discussed above, the present invention relates to a compound of formula (I):

(I) or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R ¹ and R ² are each independently selected from H, OH, O-alkyl, NH ₂ , NH-alkyl, N(alkyl) ₂ , alkyl, N0 ₂ and halogen; Ft ³ is selected from H, OC(0)-alkyl, NH-alkyl, N(alkyl) ₂ and S-alkyl;

R ⁴ and R ⁶ are each independently selected from H, alkyl and heteroalkyi;

R ⁵ is selected from O, NH, N-alkyl and N-heteroalkyl;

m is 0, 1 , 2, 3, 4, 5 or 6; and

R ⁷ is selected from alkyl, aryl and heteroaryl, which groups are optionally substituted, wherein the compound of formula (I) is not spiroleucettadine:

The present invention also relates to a compound of formula (I):

(I) or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R ¹ and R ² are each independently selected from H, OH, O-alkyl, NH ₂ , NH-alkyl, N(alkyl) ₂ , alkyl, N0 ₂ and halogen;

R ³ is selected from H, OC(0)-alkyl, NH-alkyl, N(alkyl) ₂ and S-alkyl;

R ⁴ and R ⁶ are each independently selected from H, alkyl and heteroalkyi;

R ⁵ is selected from NH, N-alkyl and N-heteroalkyl;

m is 0, 1 , 2, 3, 4, 5 or 6; and

R ⁷ is selected from alkyl, aryl and heteroaryl, which groups are optionally substituted. The present invention also relates to a compound of formula (I):

(I) or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R ¹ and R ² are each independently selected from H, OH, O-alkyl, NH ₂ , NH-alkyl, N(alkyl) ₂ , alkyl, N0 ₂ and halogen;

R ³ is selected from H, OC(0)-alkyl, NH-alkyl, N(alkyl) ₂ and S-alkyl;

R ⁴ and R ⁶ are each independently selected from H, alkyl and heteroalkyl;

R ⁵ is selected from O, NH, N-alkyl and N-heteroalkyl;

m is 0, 1 , 2, 3, 4, 5 or 6; and

R ⁷ is selected from alkyl, aryl and heteroaryl, which groups are optionally substituted.

R ¹ and R ² may both be H. The halogen may be bromine or chlorine.

R ³ may be H. R ³ may be OC(0)-alkyl (e.g. OC(O)-methyl). R ³ may be NH-alkyl (e.g. NH- methyl).

R ⁴ and R ⁶ may both be alkyl (e.g. methyl).

R ⁵ may be NH.

m may be 1 .

R ⁷ may be an aryl group. The aryl group may be substituted. The substituent may be heteroalkyl (e.g. methoxy).

The compound may be a compound of formula (III):

(III) wherein m, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined herein. The compounds of the present invention can be synthesised by any suitable method known to a person skilled in the art. Two examples of general syntheses that may be followed are given below in Schemes 1 and 2. The dashed arrows in Scheme 1 indicate proposed synthetic steps.

Scheme 1

Scheme 2

The present inventors have developed a synthetic procedure that is efficient (having less steps than previously-reported syntheses of the related natural product spiroleucettadine), can be used for a number of different analogues, and utilises a readily-available starting material ((L)- tyrosine).

As mentioned above, the present invention also relates to a process for making a compound of formula (I):

(I)

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R ¹ and R ² are each independently selected from H, OH, O-alkyl, NH ₂ , NH-alkyl, N(alkyl) ₂ , alkyl, N0 ₂ or halogen;

R ³ is selected from NH-alkyl, N(alkyl) ₂ and S-alkyl;

R ⁴ and R ⁶ are each independently selected from H, alkyl and heteroalkyl; R ⁵ is selected from O, NH, N-alkyl and N-heteroalkyl;

m is 0, 1 , 2, 3, 4, 5 or 6; and

R ⁷ is selected from alkyl, aryl and heteroaryl, which groups are optionally substituted, the process including treating a compound of formula (II):

with a hypervalent iodine reagent to produce a spirocyclic compound of formula (III):

(Ml)

The present invention also relates to a process for making a compound of formula (I):

(I)

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R ¹ and R ² are each independently selected from H, OH, O-alkyl, NH ₂ , NH-alkyl, N(alkyl) ₂ , alkyl, N0 ₂ and halogen;

R ³ is selected from H, OC(0)-alkyl, NH-alkyl, N(alkyl) ₂ and S-alkyl;

R ⁴ and R ⁶ are each independently selected from H, alkyl and heteroalkyl;

R ⁵ is selected from O, NH, N-alkyl and N-heteroalkyl;

m is 0, 1 , 2, 3, 4, 5 or 6; and R ⁷ is selected from alkyl, aryl and heteroaryl, which groups are optionally substituted, the process including treating a compound of formula (II):

(N)

with a hypervalent iodine reagent to produce a spirocyclic compound of formula (III):

wherein the compound of formula (I) is not spiroleucettadine:

The present invention also relates to a process for making a compound of formula (I):

(I)

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R ¹ and R ² are each independently selected from H, OH, O-alkyl, NH ₂ , NH-alkyl, N(alkyl) ₂ , alkyl, N0 ₂ and halogen;

R ³ is selected from H, OC(0)-alkyl, NH-alkyl, N(alkyl) ₂ and S-alkyl; R ⁴ and R ⁶ are each independently selected from H, alkyl and heteroalkyl;

R ⁵ is selected from NH, N-alkyl and N-heteroalkyl;

m is 0, 1 , 2, 3, 4, 5 or 6; and

R ⁷ is selected from alkyl, aryl and heteroaryl, which groups are optionally substituted, the process including treating a compound of formula (II):

(II)

with a hypervalent iodine reagent to produce a spirocyclic compound of formula (III):

(Hi)

The compound of formula (II) is in equilibrium with the compound of formula ( I la) shown below.

The compound of formula (I la) is the compound that cyclises to give the compound of formula (III) under the oxidative conditions.

The hypervalent iodine reagent that may be used to convert the compound of formula (II) into the corresponding spirocyclic compound may be an organic iodine compound that acts as a selective oxidizing agent. Suitable agents in this regard would be known to a person skilled in the art and include iodine (III) compounds, such as (difluoroiodo)arenes, (dichloroiodo)arenes, iodosylarenes, [bis(acyloxy)iodo]arenes, aryliodine(lll) organosulfonates, and five-membered iodine heterocylces (e.g. benziodoxoles and benziodazoles). Preferred agents are [bis(acyloxy)iodo]arenes, or aryliodine(lll) carboxylates, such as (diacetoxyiodo)benzene (also referred to as phenyliodine diacetate or PI DA) and [bis(trifluoroacetoxy)iodo]benzene (also referred to as phenyliodine bis(trifluoroacetate) or PIFA).

The reaction may be performed under any suitable conditions known to the person skilled in the art. Preferably, the reaction is carried out in a dry atmosphere, at room temperature in the presence of diethylisopropylamine, and in an acetonitrile/CF ₃ CH20H solvent mixture. The process may include the further step of treating the compound of formula (III) with a hypervalent iodine reagent to produce a compound of formula (IV):

(IV)

The hypervalent iodine reagent that may be used to convert the compounds of formula (III) into the corresponding acylated compound may be an organic iodine compound that acts as a selective oxidizing agent. Suitable agents in this regard would be known to a person skilled in the art and include iodine (V) compounds, such as periodinanes (e.g. Dess-Martin periodinane or 2-iodoxybenzoic acid), or iodine (III) compounds, such as PIDA or PIFA. The preferred reagent is Dess-Martin periodinane.

The reaction may be performed under any suitable conditions known to the person skilled in the art. Preferably, the reaction is carried out in a dry atmosphere and in a halogenated solvent.

The therapeutic use of compounds of formula (I), their pharmaceutically acceptable salts, solvates or hydrates and also formulations and pharmaceutical compositions (including mixtures of the compounds of formula (I)) are within the scope of the present invention. Accordingly, the present invention also relates to pharmaceutical compositions including a therapeutically effective amount of the compounds of formula (I), or its pharmaceutically acceptable salt, prodrug, solvate or hydrate thereof, and one or more pharmaceutically acceptable excipients, carriers or diluents. Pharmaceutical compositions may be formulated for any appropriate route of administration including, for example, topical (for example, transdermal or ocular), oral, buccal, nasal, vaginal, rectal or parenteral administration. The term parenteral as used herein includes subcutaneous, intradermal, intravascular (for example, intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial and intraperitoneal injection, as well as any similar injection or infusion technique. Suitable oral forms include, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.

Aqueous suspensions contain the active ingredient(s) in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as naturally-occurring phosphatides (for example, lecithin), condensation products of an alkylene oxide with fatty acids such as polyoxyethylene stearate, condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadecaethyleneoxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol mono-oleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate. Aqueous suspensions may also comprise one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and/or flavoring agents may be added to provide palatable oral preparations. Such suspensions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweetening, flavouring and colouring agents, may also be present.

Pharmaceutical compositions may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as olive oil or arachis oil, a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifying agents include naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides such as sorbitan monoleate, and condensation products of partial esters derived from fatty acids and hexitol with ethylene oxide such as polyoxyethylene sorbitan monoleate. An emulsion may also comprise one or more sweetening and/or flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also comprise one or more demulcents, preservatives, flavouring agents and/or colouring agents.

A composition may further include one or more components adapted to improve the stability or effectiveness of the applied formulation, such as stabilizing agents, suspending agents, emulsifying agents, viscosity adjusters, gelling agents, preservatives, antioxidants, skin penetration enhancers, moisturizers and sustained release materials. Examples of such components are described in Martindale - The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Martin (ed.), Remington's Pharmaceutical Sciences. Formulations may comprise microcapsules, such as hydroxymethylcellulose or gelatin-microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles or nanocapsules.

A pharmaceutical composition may be formulated as inhaled formulations, including sprays, mists, or aerosols. For inhalation formulations, the compounds provided herein may be delivered via any inhalation methods known to a person skilled in the art. Such inhalation methods and devices include, but are not limited to, metered dose inhalers with propellants such as CFC or HFA or propellants that are physiologically and environmentally acceptable. Other suitable devices are breath operated inhalers, multidose dry powder inhalers and aerosol nebulizers. Aerosol formulations for use in the subject method typically include propellants, surfactants and co-solvents and may be filled into conventional aerosol containers that are closed by a suitable metering valve.

Inhalant compositions may comprise liquid or powdered compositions containing the active ingredient that are suitable for nebulization and intrabronchial use, or aerosol compositions administered via an aerosol unit dispensing metered doses. Suitable liquid compositions comprise the active ingredient in an aqueous, pharmaceutically acceptable inhalant solvent such as isotonic saline or bacteriostatic water. The solutions are administered by means of a pump or squeeze-actuated nebulized spray dispenser, or by any other conventional means for causing or enabling the requisite dosage amount of the liquid composition to be inhaled into the patient's lungs. Suitable formulations, wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.

Pharmaceutical compositions may also be prepared in the form of suppositories such as for rectal administration. Such compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.

Pharmaceutical compositions may be formulated as sustained release formulations such as a capsule that creates a slow release of modulator following administration. Such formulations may generally be prepared using well-known technology and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site. Carriers for use within such formulations are biocompatible, and may also be biodegradable. Preferably, the formulation provides a relatively constant level of modulator release. The amount of modulator contained within a sustained release formulation depends upon, for example, the site of implantation, the rate and expected duration of release and the nature of the condition to be treated or prevented.

For the treatment of the conditions discussed herein, the dose of the biologically active compound according to the invention may vary within wide limits and may be adjusted to individual requirements. Active compounds according to the present invention are generally administered in a therapeutically effective amount. Preferred doses range from about 0.1 mg to about 140 mg per kilogram of body weight per day {e.g., about 0.5 mg to about 7 g per patient per day). The daily dose may be administered as a single dose or in a plurality of doses. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between about 1 mg to about 500 mg of an active ingredient.

However, it will be understood, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination (i.e., other drugs being used to treat the patient), and the severity of the particular disorder undergoing therapy.

The terms "therapeutically effective amount" or "effective amount" refer to an amount of the compound of formula (I) that results in an improvement or remediation of the disorder. Preferred compounds of the invention will have certain pharmacological properties. Such properties include, but are not limited to oral bioavailability, such that the preferred oral dosage forms discussed above can provide therapeutically effective levels of the compound in vivo.

The compounds of the present invention are preferably administered to a patient (for example, a human) orally, and are present within at least one body fluid or tissue of the patient. Accordingly, the present invention further provides methods for treating and/or preventing cancer, and methods for treating and/or preventing microbial infections.

As used herein, the term "treatment" encompasses both disorder-modifying treatment and symptomatic treatment. It refers to therapeutic treatment, i.e., after the onset of symptoms, in order to reduce the severity and/or duration of symptoms, and/or to cure the condition or disorder. As used herein, the term "prevention" encompasses prophylactic treatment, i.e., before the onset of symptoms, in order to prevent, delay or reduce the severity of symptoms and/or the condition or disorder. Patients may include but are not limited to primates, especially humans, domesticated companion animals such as dogs, cats, horses, and livestock such as cattle, pigs, sheep, and poultry, with dosages as described herein.

Compounds of the present invention may be useful for the treatment and/or prevention of cancer, and for the treatment and/or prevention of microbial infections, in a subject. Accordingly, the present invention also relates to a method of treating or preventing cancer, or treating or preventing microbial infection, in a patient including administration to the patient of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt, solvate or hydrate thereof. The present invention also relates to the use of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt, solvate or hydrate thereof, for treating or preventing cancer, or treating or preventing microbial infection. The present invention also provides a pharmaceutical composition for use in treating or preventing cancer, or treating or preventing microbial infection, in any of the embodiments described in the specification. The present invention also relates to the use of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, for the manufacture of a medicament for treating or preventing cancer, or treating or preventing microbial infection.

The present invention also relates to a compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, when used in a method of treating or preventing cancer, or treating or preventing microbial infection. The present invention also relates to a composition having an active ingredient for use in treating or preventing cancer, or treating or preventing microbial infection, wherein the active ingredient is a compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof. The present invention also relates to the use of a pharmaceutical composition containing a compound of the formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, in treating or preventing cancer, or treating or preventing microbial infection, such as described above. In one embodiment, the compound of formula (I) is essentially the only active ingredient of the composition.

It is also within the present invention that the compounds according to the invention are used as or for the manufacture of a diagnostic agent, whereby such diagnostic agent is for the diagnosis of the disorders and conditions which can be addressed by the compounds of the present invention for therapeutic purposes as disclosed herein.

For various applications, the compounds of the invention can be labelled by isotopes, fluorescence or luminescence markers, antibodies or antibody fragments, any other affinity label like nanobodies, aptamers, peptides etc., enzymes or enzyme substrates. These labelled compounds of this invention are useful for mapping the location of receptors in vivo, ex vivo, in vitro and in situ such as in tissue sections via autoradiography and as radiotracers for positron emission tomography (PET) imaging, single photon emission computerized tomography (SPECT) and the like, to characterize those receptors in living subjects or other materials. The labelled compounds according to the present invention may be used in therapy, diagnosis and other applications such as research tools in vivo and in vitro, in particular the applications disclosed herein.

It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.

Examples

Synthesis of compounds The synthesis of a compound of the present invention was carried out by following the general procedure depicted in Schemes 1 or 2 above, as follows.

Compound 1 : The procedure for synthesising this compound is given in Aberle, N. S. et al (2006) Org. Lett, vol. 8(3), pages 419-21 .

Compound 2: Mel (270 4.3 mmol) was added to NBoc-Tyr(Bzl)-OH (200 mg, 0.54 mmol) dissolved in 1 .6 mL of dry THF. At 0°C, NaH (74 mg of 60% dispersion in oil) was added in one portion. The reaction was stirred under nitrogen atmosphere for 24 hrs. The reaction was then diluted with 5 mL of AcOEt and 5 mL of water. The mixture was concentrated to dryness. The residue was partitioned between Et ₂ 0 and water. The organic layer was washed twice with a saturated aqueous solution of NaHC0 ₃ . The combined aqueous layers were acidified to pH 3 with 5% citric acid. The aqueous phase was extracted twice with EtOAc. The combined organic layers were washed with water, 5% aqueous Na ₂ S ₂ 03 and water. The organic phase was then dried over MgS0 ₄ and concentrated. A white semi-solid was obtained (m = 148 mg, 70%) and used in the next step without further purification. ¹ H NMR (CDCI ₃ , ppm): appears as two conformers, D zTl .34 and 1 .39 (2 s, 9H), 2.68 and 2.74 (2 s, 3H), 2.97- 3.25 (m, 2H), 4.54 and 4.79 (2 m, 1 H), 5.03 (s, 2H), 6.88-6.91 (m, 2H), 7.07-7.10 (m, 2H), 7.30-7.42 (m, 5H). MS m/z: 384.5 (M-H). Compound 3: Compound 2 (3.52 g, 9.12 mmol) was dissolved in 40 mL of CH ₂ CI ₂ . At

0°C, this solution was treated successively with diethylisopropylamine (2.4 mL, 13.8 mmol) and DAST (0.77 mL, 10.9 mmol). The reaction was stirred at 0°C for 15 minutes. Separately, Ν,Ο- dimethylhydroxylamine.HCI (1 .34 g, 13.7 mmol) was dissolved in 20 mL of CH ₂ CI ₂ . The solution was cooled to 0°C and treated with Diethylisopropylamine (3.65 mL, 20.95 mmol), stirred 15 minutes at 0°C and added dropwise to the solution of compound 2. The combined reaction was stirred for a further 15 minutes at 0°C and then 3 hours at room temperature. After that time, the reaction was diluted with CH ₂ CI ₂ and washed successively with saturated aqueous NaHC0 ₃ , saturated aqueous NH ₄ CI and brine. The organic phase was then dried over MgS0 ₄ and concentrated. The residue was then purified by flash chromatography on Si0 ₂ (CH ₂ CI ₂ /MeOH, 100:0 to 90:10). Compound 3 was obtained (3.36 g, 86%). Ή NMR (CDCI ₃ , ppm): D D 1 .26 and 1 .36 (2 s, 9H), 2.84 (s, 3H), 2.88-3.14 (m, 2H), 3.16 and 3.18 (2 s, 3H), 3.61 and 3.63 (2 s, 3H), 5.03 (s, 2H), 5.22 and 5.48 (2 br s, 1 H), 6.87-6.90 (m, 2H), 7.07-7.17 (m, 2H), 7.30-7.43 (m, 5H). MS m/z: 451 .3 (M+Na ⁺ ).

Compound 4: Compound 3 (2.9 g, 6.8 mmol) was dissolved in 27 mL of dry THF. 50 mL of a 0.2 M solution of 4-methoxybenzylmagnesium chloride (10 mmol) was added dropwise over a 15 minute period. The reaction was then cooled to 0°C and quenched with 20 mL of saturated aqueous NH ₄ CI. The resulting solids were dissolved with water. The layers were separated and the aqueous layer was extracted 3 times with Et ₂ 0. The combined organic layers were washed with brine, dried over MgS0 ₄ and concentrated. The residue was purified by flash chromatography on Si0 ₂ (Petroleum ether/AcOEt, 4:1 ). Compound 4 was obtained as a clear oil that crystallised upon standing (2.1 g, 62%). ¹ H NMR (CDCI3, ppm): appears as two conformers, □ 1 .36 and 1 .44 (2 s, 9H), 2.54 and 2.60 (2s, 3H), 2.77-2.85 (m, 1 H), 3.09-3.15 (m, 1 H), 3.67 (s, 3H), 3.80 (s, 3H), 4.31 -4.35 and 4.72-4.75 (2 m, 1 H), 5.03 (s, 1 H), 6.83-6.88 (m, 4H), 7.01 -7.1 1 (m, 4H), 7.30-7.44 (m, 5H). MS m/z: 512 (M+Na ⁺ ). Compound 5: Compound 4 (1 .28 g, 2.6 mmol) was treated with 2.5 mL of 4 M HCI in Et ₂ 0. The reaction was stirred at room temperature for 1 .5 hr. It was then concentrated to dryness. 20 mL of Et ₂ 0 was added. A white precipitated appeared. It was collected by filtration and washed with cold Et ₂ 0 and dried. Compound 5 was obtained as white solid (0.95 g, 85%). Compound 6: Compound 5 (876 mg, 2.1 mmol) was dissolved in a mixture of 25.4 mL of acetonitrile and 12.7 mL of MeOH. Diethylisopropylamine (4.2 mL) was then added followed by A/-methyl-A/-Boc-S-Me-thiourea (1 mL). A solution of AgN0 ₃ (2.34 g) in 6.3 mL of acetonitrile was then added dropwise over 30 minutes. All solutions were kept in the dark during the addition. The reaction was then stirred for 17 hours in the dark. It was then filtered through a plug of silica and washed through with MeOH. The filtrate was concentrated. The residue was purified by flash chromatography on Si0 ₂ (petroleum ether/ AcOEt, 3:1 ). A pale orange foamy solid was obtained (902 mg, 80%). Ή NMR (CDCI ₃ , ppm): □ 1 .5 (s, 9H), 2.54-2.59 (m, 1 H), 2.49-2.80 (m, 1 H), 2.59 (s, 3H), 2.75-3.00 (m, 2H), 2.96 (s, 3H), 3.43-3.47 (m, 1 H), 3.78 (s, 3H), 5.08 (s, 2H), 6.75-6.79 (m, 4H), 6.92-6.94 (m, 2H), 7.09-7.12 (m, 2H), 7.30-7.49 (m, 5H). Compound 7: Compound 6 (49 mg, 0.090 mmol) was dissolved in 7 mL of MeOH. 10%

Pd/C (8 mg) followed by ammonium formate (50 mg, 0.8 mmol) were added to this solution. The reaction was then stirred at 75°C for 3 hours. As reaction was not completed, a further 34 mg of 10% Pd/C and 100 mg of ammonium formate were added. The reaction was stirred for another 2 hours at 75°C. The reaction was cooled down and filtered through celite. The celite was washed with MeOH. The filtrate was concentrated. The product was used in the next step without further purification (40 mg, quantitative). Ή NMR (MeOD-c/ ₄ , ppm):□ 1 .44 (s, 9H), 2.43 (s, 3H), 2.53 (d, J = 14.5 Hz, 1 H), 2.75-2.84 (m, 1 H), 2.92, (s, 3H), 2.98 (d, J = 14.4 Hz, 1 H), 3.50 (t, J = 6.9 Hz, 1 H), 3.73 (s, 3H), 6.73 (d, J = 8.7 Hz, 2H), 6.79 (d, J= 9 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H). MS (+ve): 456.1 (M+H ⁺ ). Compound 8: Compound 7 (39 mg, 0.086 mmol) and diethylisopropylamine (44 DL,

0.25 mmol) were dissolved in a mixture of acetonitrile and CF ₃ CH ₂ OH (1 .5 mL and 200 D L, respectively). PIFA (84 mg, 0.2 mmol) was then added to this reaction. After 10 minutes, all starting material had been consumed (as shown by TLC). The reaction was quenched with aqueous NaHC0 ₃ and extracted 3 times with ethyl acetate. The combined organic layers were washed with brine and dried over MgS0 ₄ . The residue was purified by flash chromatography using Si0 ₂ (AcOEt, 100%). Compound 8 was obtained as a clear oil (20 mg, 51 %). Ή NMR (MeOD-cfc, ppm):□ 1 .49 (9H), 1 .60-1 .69 (m, 1 H), 2.17 (d, J = 15 Hz, 1 H), 2.79 (d, J= 9 Hz, 1 H), 3.30-3.36 (m, 1 H), 2.85 (s, 3H), 2.97 (s, 3H), 3.80 (s, 3H), 4.33 (d, J = 6 Hz, 1 H), 6.04-6.13 (m, 2H), 6.48 (dd, J = 10.0, 3.0 Hz, 1 H), 6.81 (dd, J = 9.0, 3.0 Hz, 1 H), 6.94 (d, J = 9.0 Hz, 2H), 7.28 (d, J = 9.0 Hz, 2H). MS (+ve): 454.0 (M+H ⁺ ).

Compound 12 was prepared according to a literature procedure (Ko et al. (201 1 ) Org. Lett., pages 980-983). Compound 13: A solution of Weinreb amide 12 (1 .489 g, 3.59 mmol) in THF (15 mL) was stirred at 0°C, to which was added a solution of 4-methoxybenzylmagnesium chloride (10.8 mmol, 0.36 M) dropwise over 10 min. The resulting solution was stirred at room temperature until the observed disappearance of starting material as monitored by TLC. The solution was cooled to 0°C, and quenched with sat. NH ₄ CI and partitioned between EtOAc (45 mL) and distilled water (30 mL). The aqueous layer was extracted with EtOAc (3 x 45 mL) and the combined organic layers were washed with brine, dried over MgS0 ₄ , filtered and concentrated in vacuo. The title compound was obtained as white solid following purification by column chromatography using EtOAc/40:60 petroleum ether as eluent (1 .143 g, 67%). [a] ²⁵ _D = +18.6 (c = 1 .93, CHCI ₃ ). White solid M.P. 103-104°C. ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.44-7.29 (m, 5H), 7.02 (m, 4H), 6.90 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 5.08 (d, J = 7.7 Hz, 1 H), 5.04 (s, 2H), 4.58 (m, 1 H), 3.79 (s, 3H), 3.62 (ABq, Δδ _ΑΒ = 25.6 Hz, J = 16.4 Hz), 2.95 (m, 2H), 1 .43 (s, 9H). ¹³ C NMR (100 MHz, CDCI ₃ ): δ 207.2, 158.8, 157.9, 155.3, 137.1 , 130.7, 130.4, 128.7, 128.5, 128.1 , 127.6, 125.2, 1 15.1 , 1 14.2, 80.0, 70.1 , 59.6, 55.4, 47.2, 37.2, 28.4. v _ma x (ATR-IR) cm ^"1 3351 , 3033, 2996, 2980, 2928, 2907, 2879, 2831 , 1718, 1688, 1613, 1512, 1383, 1243, 1 164, 1082, 1040, 1026, 696. HRMS-ESI: calcd. CsgHasNNaOs [M + Na ⁺ ]: 498.2251 , found 498.2251 .

Compound 14: A suspension of benzyl ether 13 (1 .143 g, 2.40 mmol) and Pd/C 5% (1 14 mg, 10% wt) in 3:1 MeOH/EtOAc (12 mL) was stirred under an atmosphere of H ₂ until the disappearance of starting material was observed by TLC analysis. The mixture was filtered through a plug of celite and concentrated in vacuo to yield the title compound as a colourless semi solid (778 mg, 84%). [a] ²⁶ _D = +24.3 (c = 1 .07, CHCI ₃ ). Colourless semi-solid. ¹ H NMR (400 MHz, CDCI3): 7.00 (d, J = 8.3 Hz, 2H), 6.95 (d, J = 8.2 Hz), 6.82 (d, J = 8.2 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.3 Hz, 2H), 6.08 and 5.69 (2 x br s, 1 H), 5.13 (d, J = 6.7 Hz, 0.82H), 4.87 (br s, 0.14H), 4.59 (app q, J = 7.2, 6.6 Hz, 0.80H), 4.34 (br s, 0.15H), 3.78 (s, 3H), 3.61 (2H), 2.92 (1 .81 H), 2.75 (br s, 0.18H), 1 .42 (s, 9H). ¹³ C NMR (100 MHz, CDCI ₃ ): J 207.4, 158.8, 155.1 , 130.8, 130.6, 128.0, 125.2, 1 15.7, 1 14.3, 80.3, 59.7, 55.4, 47.3, 37.3, 29.8, 28.5. v _max (ATR-IR) cm ^"1 3386, 3012, 2958, 2926, 2852, 1684, 1613, 1512, 1441 , 1392, 1367, 1301 , 1246, 1 162, 1 132, 1 105, 1072, 1029, 909. HRMS-ESI: calcd. C22H ₂ 7NNa0 ₅ [M + Na ⁺ ]: 408.1781 , found 408.1755. Compound 15: To a stirred solution of Boc-protected amino ketone 14 (778 mg, 2.02 mmol) in DCM (8 mL) at 0°C was added TFA (1 .55 mL, 20.2 mmol). The reaction was monitored by TLC analysis until the disappearance of starting material was observed. The solution was concentrated in vacuo and the residue was triturated with Et ₂ 0 to yield a beige solid (749 mg, 93%). [a] ²⁵ _D = +68.9 (c = 1 .26, MeOH). Beige solid M.P.: 144-145°C. ¹ H NMR (400 MHz, DMSO-de): 9.48 (s, 1 H), 8.08 (br s, 3H), 7.08 (d, J = 8.5 Hz, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.08 (d, J = 8.7 Hz, 2H), 7.75 (d, J = 8.5 Hz, 2H), 4.38 (t, J = 6.8 Hz, 1 H), 3.83 and 3.69 (ABq, JAB = 17.2 Hz, 2H), 3.73 (s, 3H), 3.08 and 2.96 (ABX, JAB = 14.2, J _AX = 6.5 Hz, 2H). ¹³ C NMR (100 MHz, DSMO-d ₆ ): 204.5, 158.2, 156.7, 130.8, 130.5, 124.5, 124.5, 1 15.6, 1 13.8, 58.7, 55.1 , 45.4, 34.7. v _max (ATR-IR) cm ¹ 3385, 3109, 3066, 3054, 2987, 1726, 1654, 1613, 1597, 1515, 1 198, 1019, 744, 551 , 517, 481 . HRMS-ESI: calcd. for C17H20NO3 [M - TFA]: 286.1443; found 286.1 143.

Compound 17: To a solution of A/-methylcarbamoyl imidazole (704 mg, 5.63 mmol) and Et ₃ N (785 μΐ, 5.63 mmol) in THF (6 mL) was added the TFA salt 15 (749 mg, 1 .88 mmol) in THF (21 mL) dropwise over 20 min and the resulting solution was stirred at room temperature overnight. The mixture was partitioned between EtOAc (60 mL) and H ₂ 0 (30 mL) and the aqueous layer extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (30 mL), dried over MgS0 ₄ and concentrated in vacuo. The crude residue (compound 16) was taken up in 2,2,2-trifluoroethanol (10 mL) and cooled to 0°C. PIDA (604 mg, 1 .88 mmol) was added and the solution was stirred at 0°C for 15 min. The reaction was quenched with Na ₂ S ₂ 0 ₃ (1 M) and partitioned between EtOAc (20 mL) and H ₂ 0 (10 mL). The aqueous layer extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (30 mL), dried over MgS0 ₄ and concentrated in vacuo. Colum chromatography using EtOAc as eluent followed by recrystallization from EtOAc yielded the title compound as a white crystalline solid (105 mg, 17%). Yield 33% over two steps. [a] ²⁴ _D = -37.3 (c = 0.533, MeOH). White crystalline solid M. P.: 122-123°C. Ή NMR (400 MHz, CDCI ₃ ): £ 7.19 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.5 Hz, 2H), 6.84 (dd, J = 10.3, 3.0 Hz, 1 H), 6.34 (dd, J = 10.1 , 3.0 Hz, 1 H), 6.12 (dd, J = 10.1 , 3 Hz, 1 H), 6.09 (br s, 1 H), 6.06 (dd, J = 10.1 , 3.0 Hz, 1 H), 4.24 (dd, J = 6.5, 1 .5 Hz, 1 H), 3.82 (s, 3H), 3.36 and 2.84 (abq, J = 14.1 , 2H), 2.93 (s, 3H), 1 .83 (d, J = 13.8 Hz, 1 H), 1 .45 (dd, J = 13.8, 6.8 Hz, 1 H). ¹³ C NMR (100 MHz, CDCI ₃ ): £ 185.0, 159.5, 159.1 , 149.2, 148.8, 131 .8, 129.0, 127.3, 126.1 , 1 13.9, 102.7, 79.7, 58.3, 55.4, 44.8, 41 .1 , 25.1 . v _max (ATR-IR) cnr ¹ 3277, 2956, 2851 , 1697, 1670, 1631 , 1513, 1440, 1400, 1302, 1 172, 1067, 1030, 943, 827. HRMS- ESI: calcd. for Ci ₉ H ₂ oN ₂ Na0 ₄ [M + Na ⁺ ]: 363.1315; found 363.1342.

Compound 18: To a solution of spiro compound 17 (39 mg, 0.1 15 mmol) in fluorobenzene (4 mL) was added Dess-Martin periodinane (98 mg, 0.230 mmol) and the solution was heated to 60°C. The reaction was monitored by TLC analysis and upon consumption of starting material was cooled to room temperature. The reaction was quenched with solid NaHC0 ₃ and filtered through a plug of silica and purified by column chromatography to yield the title compound as a colourless foam (34 mg, 0.086 mmol, 75%). Compound may be acid sensitive and moisture/nucleophiles may result in OAc substituted for OH/Nu. [a] ²⁵ _D = +37.8 (c = 1 .083, CHCI ₃ ). Colourless foam. ¹ H NMR (400 MHz, CDCI ₃ ): 7.31 (d, J = 8.5 Hz, 2H), 7.25 (m, 1 H), 6.88 (d, J = 8.5 Hz, 2H), 6.87 (m, 3H), 3.83 (s, 1 H), 3.35 and 3.14 (abq, J = 14.5 Hz, 2H), 2.92 (s, 3H), 2.81 and 1 .87 (abq, J = 13.6, 2H), 2.2 (s, 3H). ¹³ C NMR (100 MHz, CDCI ₃ ): δ 184.7, 170.2, 160.0, 156.6, 148.1 , 147.4, 133.1 , 129.3, 127.9, 126.3, 1 13.5, 102.0, 95.1 , 78.1 , 55.4, 47.8, 38.2, 25.6, 21 .6. v _max (ATR-IR) cm ¹ 3260, 3012, 2960, 2929, 2838, 1716, 1671 , 1632, 161 1 , 1513, 1397, 1370, 1244, 1 176, 1014, 747, 713, 691 , 554. HRMS-ESI: calcd. for C2i + Na ⁺ ]: 421 .1370; found 421 .1377.

Compound 19, spiroleucettadine: The OAc substituted spiro 18 (13 mg, 0.0327 mmol) compound was dissolved in THF (2 ml_), to which was added methylamine hydrochloride (22.1 mg, 0.327 mmol) and Et ₃ N (45 μΙ_, 0.327 mmol) and the reaction was monitored by TLC analysis. Upon consumption of starting material the mixture was diluted with EtOAc (5 mL) and washed with distilled H ₂ 0 (5 mL), brine (5 mL), dried over MgS0 ₄ and concentrated in vacuo. Column chromatography using EtOAc/MeOH as eluent yielded the spiroleucettatadine (1 1 mg, 92%). Colourless solid. ¹ H NMR (400 MHz, CDCI ₃ ) δ: 7.40 (d, J = 8.5 Hz, 2H), 7.05 (dd, J = 10.2, 3.0 Hz, 1 H), 6.88 (d, J = 8.5 Hz, 2H), 6.02 (three dd, J = 10.1 , 3.0 Hz, 3H), 5.56 (s, 1 H), 3.84 (s, 3H), 3.12 and 3.22 (abq, J = 14.5 Hz, 2H), 2.91 (s, 3H), 2.48 (s, 3H), 2.15 and 1 .97 (abq, J = 13.2 Hz, 2H). ¹³ C NMR (100 MHz, MeOH-ck): S 186.9, 161 .2, 160.2, 152.5, 151 .5, 134.2, 129.0, 128.4, 127.4, 1 14.2, 104.0, 84.0, 78.6, 55.7, 49.0, 38.6, 29.0, 26.2. v _max (ATR-IR) cm ^"1 3293, 3057, 2928, 2853, 2837, 2809, 1699, 1669, 1629, 1610, 151 1 , 1437, 1393, 1329, 1300, 1246, 1 177, 1 158, 1031 , 1013, 733, 500, 585. HRMS-ESI: calcd. for C2oH ₂ 3N ₃ Na04 [M + Na ⁺ ]: 392.1581 ; found 392.1592.