The present invention relates to dispiro tetraoxane compounds, particularly but not exclusively, for use in the treatment of malaria and/or cancer, and methods for producing such compounds.

Malaria remains a risk to nearly half of the world population a century and over since it was established to be a parasitic disease. The risk is greatest among young children, pregnant women and visitors from non-endemic areas. Artemisinin derivatives (1) are currently the most effective drugs and are recommended by the World Health Organization for use with other antimalarials such as amodiaquine, lumefantrine, mefloquine, sulfadoxime / pyrimethamine and primaquine. However, they are expensive and are not affordable to majority of those needing treatment.

R = OC(O)CH ₂ CH ₂ CO ₂ H, artesunate Amodiaquine series Isoquine Pyronaridine R = OCH ₂ Ph(CO ₂ H)-P -artelinic acid R = N(CH ₂ J ₄ SO ₂ , artemisone

Reports of inadequate supply coupled with the observation of clinical resistance to the artemisinins calls for alternative new chemical entities for malaria chemotherapy. Our quest to find purely synthetic antimalarial agents, made from cheap and commercially available starting materials, that contain the peroxide entity found in the artemisinins led to the synthesis of a wide range of 1 ,2,4,5-tetraoxanes as described in the applicant's co-pending International Patent Application WO 2008/038030. Most of these agents displayed remarkable activity, superior to the clinically used artemisinins and chloroquine.

Amodiaquine (2), isoquine (3), and pyronaridine (4) all contain a Mannich base side-chain and a phenolic hydroxyl group. The basic side-chain has been shown to be critical for antimalarial activity since it is necessary for accumulation in the acidic digestive vacuole of the malaria parasite. In addition to this feature the phenolic Mannich side-chain of these drugs has been shown to be important for binding to the carboxylic acid residues in hematin. This has been demonstrated for both isoquine and the amodiaquine analogue tebuquine. All of these Mannich base antimalarials demonstrate excellent antiplasmodial activity against both chloroquine sensitive and resistance strains of the malaria parasite.

An object of the present invention is to develop new chemical entities for the treatment of malaria.

According to the first aspect of the present invention there is provided a compound having the formula (VII)

(VII) wherein

R ³ = -(CH ₂ J _n -R ⁵ in which n is an integer greater than or equal to 0, and R ⁵ = H, substituted or unsubstituted amino;

R ⁴ = -(CH ₂ ) _m -R ⁶ in which m is an integer greater than or equal to 0, and R ⁶ = H, halo, saturated or unsaturated substituted or unsubstituted alkyl, saturated or unsaturated substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted amino, saturated or unsaturated substituted or unsubstituted carbocyclic ring, saturated or unsaturated substituted or unsubstituted heterocyclic ring, or any combination;

R ¹ and R ² are each individually selected from the group consisting of H, saturated or unsaturated substituted or unsubstituted alkyl, substituted or unsubstituted aryl, saturated or unsaturated substituted or unsubstituted carbocyclic ring, saturated or unsaturated substituted or unsubstituted heterocyclic ring, or any combination thereof; or

R ¹ and R ² are linked so as to form part of a substituted or unsubstituted monocyclic or multicyclic ring system;

R ¹¹ is H, saturated or unsaturated substituted or unsubstituted alkyl, saturated or unsaturated substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted amino, substituted or unsubstituted amido, saturated or unsaturated substituted or unsubstituted carbocyclic ring, saturated or unsaturated substituted or unsubstituted heterocyclic ring, or any combination.

According to a first preferred embodiment of the first aspect of the present invention there is provided a compound having the formula (I)

(I) wherein

R ³ = -(CH ₂ ) _n -R ⁵ in which n is an integer greater than or equal to 0, and R ⁵ = substituted or unsubstituted amino;

R ⁴ = -(CH ₂ J _m -R ⁶ in which m is an integer greater than or equal to 0, and R ⁶ = H, halo, saturated or unsaturated substituted or unsubstituted alkyl, saturated or unsaturated substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted amino, saturated or unsaturated substituted or unsubstituted carbocyclic ring, saturated or unsaturated substituted or unsubstituted heterocyclic ring, or any combination;

R ¹ and R ² are each individually selected from the group consisting of H, saturated or unsaturated substituted or unsubstituted alkyl, substituted or unsubstituted aryl, saturated or unsaturated substituted or unsubstituted carbocyclic ring, saturated or unsaturated substituted or unsubstituted heterocyclic ring, or any combination thereof; or

R ¹ and R ² are linked so as to form part of a substituted or unsubstituted monocyclic or multicyclic ring system.

A second preferred embodiment of the first aspect of the present invention provides a compound of general formula (VIII)

(VIII) wherein

R ¹ , R ² , R ³ and R ⁴ are defined as in the first aspect of the present invention, L is a linker group, p is an integer greater than or equal to O, and A is a nitrogen-containing group.

In the second preferred embodiment, the nitrogen-containing group, A, is or comprises a substituted or unsubstituted amino group or a substituted or unsubstituted amido group. In either case, the amino or amido group may incorporate any desirable type of substituent group or groups. For example, the nitrogen atom of the amino or amido group may be bonded to none, one or two hydrogen atoms. When the nitrogen atom of group A is bonded to no hydrogen atoms the nitrogen atom may be symmetrically substituted with two identical but separate chemical groups, such as saturated or unsaturated substituted or unsubstituted alkyl or alkoxyl groups, or the nitrogen atom may be asymmetrically substitited with two different chemical groups, or the nitrogen atom may form part of a heterocyclic ring structure of any desirable size and incorporating any desirable number of carbon and non-carbon (e.g. O, S, N) atoms. Exemplary ring structures incorporating the nitrogen atom, which may be substituted or unsubstituted, include pyrrolidyl, piperidyl, morpholinyl, thiomorpholinyl and thiomorpholinyl sulfone. Heterocyclic ring substituents include halo groups, saturated or unsaturated substituted or unsubstituted alkyl groups, alkoxyl groups, carbocyclic rings and heterocyclic rings (such as those listed above), and substituted or unsubstituted aryl, amino and amido groups.

In embodiments in which the nitrogen atom of group A is bonded to a single hydrogen atom, the other substituent on the nitrogen atom may be halo, saturated or unsaturated substituted or unsubstituted alkyl, saturated or unsaturated substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted amino, saturated or unsaturated substituted or unsubstituted carbocyclic ring, saturated or unsaturated substituted or unsubstituted heterocyclic ring, or any combination thereof. Exemplary carbocyclic and heterocyclic rings include 3, 4, 5, 6, 7 or more ring atoms, and may incorporate mono- or polycyclic ring systems in which adjacent rings are bridged, fused or linked via a spiro arrangement. Preferred carbocyclic ring structures include cyclopropane, cyclobutane, cyclopentane and cyclohexane, each of which may be subsituted or unsubstituted with further groups selected from the above list, such as one or halogen atoms (e.g. F, Cl, Br, I). Preferred heterocyclic ring structures include substituted or unsubstituted pyrrolidyl, piperidyl, morpholinyl, thiomorpholinyl and thiomorpholinyl sulfone groups.

It will be appreciated that in formula (VIII) when p = 0 there is no linker group present such that the group A is bonded directly to the oxo group connected to the aryl group. When p > 0, i.e. when p = 1 , 2, 3 or more, the appropriate number of linker groups, L, are present in between the group A and the oxo group. It is preferred that p = 1 , but any appropiate number may be chosen to suit a particular application. L may be any suitable divalent atom or chemical group. By way of example, L may be an oxygen or sulfur atom. By way of further example, L may be chosen from the group consisting of saturated or unsaturated substituted or unsubstituted alkyl, saturated or unsaturated substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted amino, saturated or unsaturated substituted or unsubstituted carbocyclic ring, saturated or unsaturated substituted or unsubstituted heterocyclic ring, or any combination thereof. A preferred linker group, L, is an alkyl group, such as a short chain C _1-6 alkyl group, which may be straight or branched. Particularly preferred linker groups are methyl, ethyl, propyl and butyl. A preferred compound according to the second preferred embodiment of the first aspect of the present invention has general formula (IX)

(IX) wherein R ¹² is a substituted or unsubstituted amino group.

It will be appreciated that compound (IX) represents a preferred embodiment of compound (VIII) in which the linker group, L, is a propyl group connected to the aryl oxo group and the carbonyl carbon atom via the central carbon atom of the propyl group, p = 1 , and group A is an amido group of formula -C(O)R ¹² . The R ¹² amino group may be a primary, secondary or tertiary amino group. It is preferred that R ¹² is -NR ¹³ R ¹⁴ wherein R ¹³ and R ¹⁴ are each separately selected from the group consisting of H, saturated or unsaturated substituted or unsubstituted alkyl, substituted or unsubstituted aryl, saturated or unsaturated substituted or unsubstituted carbocyclic ring, saturated or unsaturated substituted or unsubstituted heterocyclic ring, or any combination thereof; or R ¹³ and R ¹⁴ are linked so as to form part of a substituted or unsubstituted monocyclic or multicyclic ring system, which may incorporate one or more carbocyclic or heterocyclic rings. In particularly preferred embodiments of compound (IX) R ¹³ and R ¹⁴ are linked so as to define a substituted or unsubstitued hetrocyclic ring selected from the group consisting of pyrrolidyl, piperidyl, morpholinyl, thiomorpholinyl and thiomorpholinyl sulfone.

In compound (VIII) representing the second preferred embodiment, while one or both of R ³ and R ⁴ may be hydrogen atoms, it is preferred that R ³ and R ⁴ are both hydrogen atoms.

Compounds of the present invention incorporate a Mannich side chain within a tetraoxane template in order to: (a) provide functional groups suitable for formulation as water soluble salts: (b) enhance drug accumulation within acidic compartments of the malaria parasite; and (c) enhance interactions with the propionate groups of hematin. While the inventors do not wish to be bound by any particular theory, the design of molecules containing features of an endoperoxide coupled with a Mannich base antimalarial may provide an additional advantage in terms of mechanism, in the sense that these molecules may have a dual mechanism of action: i.e. inhibition of hematin crystallisation and alkylation of proteins/hematin after reductive bioactivation.

Preferred compounds in accordance with the first aspect of the present invention have unprecedented in vitro and in vivo levels of antimalarial activity for a tetraoxane-based drug.

A second aspect of the present invention provides a method for the production of a compound according to the first preferred embodiment of the first aspect of the present invention, wherein the method comprises reacting a bishydoperoxide compound having formula (IA) with a ketone having formula (IB)

Compound (IA) is preferably prepared by oxidising an appropriate starting material using a suitable oxidising agent. Compound (IA) may be isolated from any excess unreacted oxidising agent prior to reacting compound (IA) with compound (IB).

A preferred oxidising agent is hydrogen peroxide.

Oxidation of said appropriate starting material may be carried out at a temperature of up to around room temperature. Particularly preferred temperatures are around 0 ⁰ C and 20-25 ^C C.

Oxidation of said appropriate starting material may be catalyzed, for example, by effecting oxidation in the presence of a Lewis acid or Bronsted Lewis acid, such as formic acid.

Oxidation of said appropriate starting material may be carried out in any suitable solvent. Preferably oxidation is effected in the presence of acetonitrile.

It is preferred that said appropriate starting material has the formula (IC)

(IC) wherein

R ³ and R ⁴ are as defined herein in respect of the first preferred embodiment of the first aspect of the present invention.

A third aspect of the present invention provides a method for the production of a compound according to the first preferred embodiment of the first aspect of the present invention in which n = 0 and R ⁵ = -NR ⁷ R ⁸ , where R ⁷ and R ⁸ are each separately H or an organic group, the method comprising a Mannich reaction between formaldehyde, NHR ⁷ R ⁸ and a compound having formula (V)

(V)

Compound (V), in which m = 1 and R ⁶ = -NR ⁹ R ¹⁰ , where R ⁹ and R ¹⁰ are each separately H or an organic group, may be prepared using a method comprising a Mannich reaction between formaldehyde, NHR ⁹ R ¹⁰ and a compound having formula (Vl)

(Vl)

One or more of R ⁹ and R ¹⁰ may be the same type of chemical group as R ⁷ and/or R ⁸ .

Where it is desired to prepare a compound according to the first preferred embodiment of the first aspect of the present invention having formula (I) incorporating symmetrically substituted groups at the ortho positions to the phenolic hydroxyl group, m = 1 and R ⁹ = R ⁷ and R ¹⁰ = R ⁸ .

In the methods forming the second and third aspects of the present invention it will be appreciated that each functional group, such as R ¹ and R ² , may take any of the options set out herein in relation to the first aspect of the present invention.

In a preferred embodiment, R ¹ and R ² both contain carbonyl groups. The ring system incorporating R ¹ and R ² may comprise one or more substituted or unsubstituted carbocyclic ring and/or substituted or unsubstituted heterocyclic ring. One of said carbocyclic ring(s) or said heterocyclic ring(s) may contain one or more double bond, or may be aromatic. Said ring system incorporating R ¹ and R ² may be a substituted or unsubstituted mono- or polycyclic alkyl ring.

Said ring system incorporating R ¹ and R ² may contain 3 to 30 carbon atoms, more preferably

5 to 15 carbon atoms. Still more preferably the R ¹ / R ² -containing ring system comprises 6, 8, 10 or 12 carbon atoms.

It is preferred that said ring system incorporating R ¹ and R ² is a substituted or unsubstituted ring selected from the group consisting of a cyclopentyl ring, a cyclohexyl ring, a cyclododecanyl ring, and an adamantyl group.

In preferred embodiments, R ¹ and R ² are linked to form part of a substituted or unsubstituted cyclohexyl, mentholidine or adamantyl group.

With regard to the above defined aspects of the present invention, concerning the functional groups at the ortho position relative to the phenolic oxo group (R ³ and R ⁴ ) it is particularly preferred that n = 0 and m = 0 or 1.

In one preferred embodiment, at least one of R ⁵ and R ⁶ = -NR ⁷ R ⁸ in which R ⁷ = H and R ⁸ = an alkyl group substituted with a group selected from the group consisting of an ester group, an amino group or an amido group.

The alkyl group may contain any desirable number of carbon atoms, but it is preferably a Ci-

₆ alkyl group, which may be straight or branched and contain any desirable level of unsaturation. It is particularly preferred that the alkyl group is an ethyl group.

The amino group substituent may be any desirable type of amino group, such as a secondary or tertiary amino group, in which the amino substituents may be aliphatic, alicyclic, aromatic or may be connected such that the amino group forms part of a heterocyclic group. In a preferred embodiment, the amino group is a diethylaminoethyl group.

The ester group substituent may take any suitable structure, such as an alkyl or aryl ester. A preferred ester is a C^ alkyl ester, for example, a methylester group. In another preferred embodiment at least one of R ⁵ and R ⁶ = -NR ⁷ R ⁸ in which R ⁷ = H and R ⁸ contains a saturated or unsaturated substituted or unsubstituted carbocyclic ring and/or a saturated or unsaturated substituted or unsubstituted heterocyclic ring.

Preferably R ⁸ contains two or more of said rings, i.e. two or more carbocyclic rings, two or more heterocyclic rings or a combination of carbocyclic and heterocyclic rings. Zero, one or more methylene radicals may be provided in between, and thus link, the or each pair of adjacent rings.

In this preferred embodiment, said carbocyclic ring is preferably a substituted or unsubstituted mono- or poly-cyclic cycloalkyl group containing any desirable number of carbon atoms. For example, the cycloalkyl group may contain 3 to 20 carbon atoms, more preferably 4 to 15, and most preferably 5 to 8 carbon atoms.

Also in this preferred embodiment, said heterocyclic ring may be a substituted or unsubstituted mono- or poly-cyclic heterocyclic group containing any desirable number of carbon atoms in addition to the one or more heteroatoms (e.g. nitrogen, sulfur or oxygen atoms). By way of example, the heterocyclic group preferably contains 3 to 11 carbon atoms, more preferably 4 to 7 carbon atoms. The heterocyclic group may incorporate a total (i.e. heteroatom(s) plus carbon atoms) of 3 to 20 atoms, more preferably 4 to 15 atoms and most preferably 5 to 8 atoms.

It is preferred that said heterocyclic group contains one or more heteroatoms, the or each heteroatom being separately selected from the group consisting of nitrogen, oxygen and sulfur.

Said heterocyclic ring, which may be substituted or unsubstituted, is selected from the group consisting of a pyrrolidyl group, a piperidyl group, a morpholinyl group, a thiomorpholinyl group and a thiomorpholinyl sulfone group.

Preferably said carbocyclic ring is bonded directly to the nitrogen atom of the R ⁵ and/or R ⁶ group, alternatively, said heterocyclic ring may be linked to the nitrogen atom of the R ⁵ and/or R ⁶ group via one or more, preferably two, methylene radicals. Where R ⁵ and R ⁶ are different functional groups but both groups contain at least one carbocyclic ring and at least one heterocyclic ring, it will be appreciated that one of R ⁵ and R ⁶ may have a structure where the carbocyclic ring is bonded directly to the nitrogen atom of that R group and the other of R ⁵ and R ⁶ may have a structure where the heterocyclic ring is bonded directly to the nitrogen atom of that particular R group.

It will be appreciated that any reference herein to polycyclic rings is intended to encompass ring systems which contain more than one ring system which may be "fused", where adjacent rings share two adjacent carbon atoms, may be "bridged", where the rings are defined by at least two common carbon atoms (bridgeheads) and at least three acyclic chains (bridges) connecting the common carbon atoms, or may be "spiro" compounds where adjacent rings are linked by a single common carbon atom.

In a further preferred embodiment, at least one of R ⁵ and R ⁶ = -NR ⁷ R ⁸ in which R ⁷ and R ⁸ are linked so as to form part of a substituted or unsubstituted heterocyclic ring. Said heterocyclic ring is preferably a substituted or unsubstituted mono- or poly-cyclic heterocyclic group containing 3 to 11 carbon atoms. The heterocyclic group may contain one or more heteroatoms other than the nitrogen atom of the -NR ⁷ R ⁸ group, the or each heteroatom being separately selected from the group consisting of nitrogen, oxygen and sulfur. The heterocyclic ring contains a substituted or unsubstituted mono- or poly-cyclic heterocyclic group selected from the group consisting of a piperazinyl group, pyrrolidyl group, a piperidyl group, a morpholinyl group, a thiomorpholinyl group and a thiomorpholinyl sulfone group.

With regard to the various preferred embodiments set out above, it is preferable that R ⁶ = H or R ⁵ . Alternatively, R ⁶ may be selected from the group consisting of a halo group, an alkyl group (e.g. C _1-6 , preferably methyl) substituted with one or more halo groups, and an alkoxy group (e.g. Ci _-6 , preferably methoxy). The halo group(s) may be fluoride, chloride, bromide or iodide, but is preferably fluoride.

Another aspect of the present invention provides a compound having the formula (II), which is denoted compound 29 in the following examples.

(II)

Another aspect of the present invention provides a compound having the formula (III), which is denoted compound 30 in the following examples.

(III)

A further aspect of the present invention provides a compound having the formula (IV), which is denoted compound 42 in the following examples.

A further aspect of the present invention provides a compound having the formula (X), which is denoted compound 50 in the following examples.

(X)

A further aspect of the present invention provides a compound having the formula (Xl), which is denoted compound 53 in the following examples.

A further aspect of the present invention provides a compound having the formula (XII), which is denoted compound 54 in the following examples.

Preferred compounds of general formula (I) according to the first preferred embodiment of the first aspect of the present invention are represented below in Tables 1 and 2.

(I)

Table 1

Table 2

Preferred compounds of general formula (IX) according to the first aspect of the present invention are represented below in Table 3.

(IX)

Further preferred compounds according to the first aspect of the present invention include amino anologues of the compounds shown above in Table 3, i.e. compounds in which the terminal -C(O)R ¹² amido group of Formula (IX) is replaced with a terminal -R ¹² amino group. In the amino analogues the propyl group linking the R ¹² group to the aryl oxo group may be present or may be replaced with any other suitable divalent linker group, such as a different type of alkyl group, such as methyl or ethyl.

It will be appreciated from the foregoing discussion of the first and second preferred embodiments of compounds according to the first aspect of the present invention that the first preferred embodiment focusses upon phenolic derivatives of compound (VII) in which the aromatic group is substituted with an alkyl-amino group of varying chemical structure, and the second preferred embodiment focusses upon oxo derivatives of compound (VII) in which the oxo group is connected to nitrogen-containing group of varying chemical structure, notably including various amido and amino structures. Where chemically feasible it is envisaged that any structural modification to the first preferred embodiment described above can be applied to the second preferred embodiment. That is, any structural modification to any one or more of groups R ¹ to R ⁴ described above in relation to the first preferred embodiment can be applied to the second preferred embodiment.

A further aspect of the present invention provides a salt, preferably a pharmaceutial salt, of the compound according to the first aspect of the present invention. Said salt may be an acid addition salt produced by reacting a suitable compound according to the first aspect of the present invention with an appropriate acid, such as an organic acid or mineral acid.

The present invention further provides a pharmaceutical composition comprising a compound according to the first aspect of the present invention and a pharmaceutically acceptable excipient.

There is still further provided a pharmaceutical composition comprising a compound according to the first aspect of the present invention and a pharmaceutically acceptable excipient for the treatment of malaria.

A further aspect of the present invention provides use of a compound according to the first aspect of the present invention in the preparation of a medicament for the treatment of malaria.

Another aspect of the present invention provides a method of treating malaria in a human or animal patient comprising administering to said patient a therapeutically effective amount of a compound according to the first aspect of the present invention. A yet further aspect of the present invention provides a pharmaceutical composition for the treatment of a cancer comprising a compound according to the first aspect of the present invention and a pharmaceutically acceptable excipient.

There is further provides use of a compound according to the first aspect of the present invention in the preparation of a medicament for the treatment of cancer.

A still further aspect of the present invention provides a method of treating a cancer in a human or animal patient comprising administering to said patient a therapeutically effective amount of a compound according to the first aspect of the present invention.

The compound of the first aspect of the present invention may take a number of different forms depending, in particular on the manner in which the compound is to be used. Thus, for example, the compound may be provided in the form of a powder, tablet, capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray, micelle, transdermal patch, liposome or any other suitable form that may be administered to a person or animal. It will be appreciated that the vehicle of the compound of the invention should be one which is well tolerated by the subject to whom it is given and enables delivery of the compound to the required location.

The compound may be administered orally either in liquid or solid composition form. Compositions suitable for oral administration include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.

The compound of the invention may be used in a number of ways. For instance, systemic administration may be required in which case the compound may, for example, be ingested orally in the form of a tablet, capsule or liquid. Alternatively the compound may be administered by injection into the blood stream. Injections may be intravenous (bolus or infusion) or subcutaneous (bolus or infusion). The compounds may be administered by inhalation (e.g. intranasally).

The compound may also be administered centrally by means of intrathecal delivery.

The compound may also be incorporated within a slow or delayed release device. Such devices may, for example, be inserted on or under the skin and the compound may be released over weeks or even months. The devices may be particularly advantageous when a compound is used which would normally require frequent administration (e.g. at least daily ingestion of a tablet or daily injection).

It will be appreciated that the amount of a compound required is determined by biological activity and bioavailability which in turn depends on the mode of administration, the physicochemical properties of the compound employed and whether the compound is being used as a monotherapy or in a combined therapy. The frequency of administration will also be influenced by the above mentioned factors and particularly the half-life of the compound within the subject being treated.

Optimal dosages of the compound to be administered may be determined by those skilled in the art, and will vary with the particular compound in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and time of administration.

Known procedures, such as those conventionally employed by the pharmaceutical industry (e.g. in vivo experimentation, clinical trials, etc.), may be used to establish specific formulations of compounds and compositions and precise therapeutic regimes (such as daily doses of the compounds and the frequency of administration).

Generally, a daily dose of between 0.01 μg/kg of body weight and 1.0 g/kg of body weight of the inventive compound may be used depending upon which specific compound is used. More preferably, the daily dose is between 0.01 mg/kg of body weight and 100 mg/kg of body weight.

Daily doses may be given as a single administration (e.g. a daily tablet for oral consumption or as a single daily injection). Alternatively, the compound used may require administration twice or more times during a day. As an example, patients may be administered as two or more daily doses of between 25 mgs and 5000 mgs in tablet form. A patient receiving treatment may take a first dose upon waking and then a second dose in the evening (if on a two dose regime) or at 3 or 4 hourly intervals thereafter. Alternatively, a slow release device may be used to provide optimal doses to a patient without the need to administer repeated doses. This invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention and, preferably, a pharmaceutically acceptable vehicle. In the subject invention a "therapeutically effective amount" is any amount of a compound or composition which, when administered to a subject suffering from a disease against which the compounds are effective, causes reduction, remission, or regression of the disease. A "subject" is a vertebrate, mammal, domestic animal or human being. In the practice of this invention the "pharmaceutically acceptable vehicle" is any physiological vehicle known to those of ordinary skill in the art useful in formulating pharmaceutical compositions.

In one embodiment, the amount of the compound in the composition according to the the present invention is an amount from about 0.01 mg to about 800 mg. In another embodiment, the amount of the compound is an amount from about 0.01 mg to about 500 mg. In another embodiment, the amount of the compound is an amount from about 0.01 mg to about 250 mg. In another embodiment, the amount of the compound is an amount from about 0.1 mg to about 60 mg. In another embodiment, the amount of the compound is an amount from about 1 mg to about 20 mg.

In one embodiment, the pharmaceutical vehicle employed in the composition of the present invention may be a liquid and the pharmaceutical composition would be in the form of a solution. In another embodiment, the pharmaceutically acceptable vehicle is a solid and the composition is in the form of a powder or tablet. In a further embodiment, the pharmaceutical vehicle is a gel and the composition is in the form of a suppository or cream. In a further embodiment the compound or composition may be formulated as a part of a pharmaceutically acceptable transdermal patch.

A solid vehicle employed in the composition according to the present invention can include one or more substances which may also act as flavouring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders, the vehicle is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a vehicle having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid vehicles include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. Liquid vehicles may be used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions according to the present invention. The compound of the first aspect of the present invention can be dissolved or suspended in a pharmaceutically acceptable liquid vehicle such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.

The liquid vehicle can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid vehicles for oral and parenteral administration of the compound forming the first aspect of the present invention include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the vehicle can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid vehicles are useful in sterile liquid form compositions for parenteral administration. The liquid vehicle for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellent.

The compound forming the first aspect of the present invention can be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents (for example, enough saline or glucose to make the solution isotonic), bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by for example, intramuscular, intrathecal, epidural, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The inventive compounds may be prepared as a sterile solid composition according to the present invention which may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium. Vehicles are intended to include necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.

The compound forming part of the present invention is eminently suitable for use in prophylactic treatment. By the term "prophylactic treatment" we include any treatment applied to prevent, or mitigate the effect of a disorder. The prophylactic treatment may be given, for example, periodically to a person who is of a predetermined minimum age or who is genetically predisposed to a disorder. Alternatively the prophylactic treatment may be given on an ad hoc basis to a person who is to be subjected to conditions which might make the onset of a disorder more likely.

The invention will be further described by way of example only with reference to the following non-limiting Examples and Figure 1 , which shows the relative remaining concentrations of compound 29 in incubations of varying time period both with and without cofactors (initial substrate concentration was 10 μM; cofactors = NADPH and UDPGA).

EXAMPLES

Example 1

Exemplary compounds of formula (I) were prepared in which R ¹ , R ² and R ³ were varied and R ⁴ = H. An initial target molecule was prepared by the following method (Scheme 1 ) in which 4-(4-Hydroxyphenyl)cyclohexanone and carbonyl compounds were allowed to react in a two step sequence.

6, > 80% 7, R ¹ and R ² = (CH ₂ ) _S , 60%

8, R ¹ and R ² = L-Menthonylidene, 43%

9, R ¹ and R ² = Adamantylidene, 60%

10-35, R = Various amines

Scheme 1: Synthesis of compounds 7 to 35, 46 and 47: Reagents: a) 50% H ₂ O ₂ , CH ₃ CN, HCOOH, O ⁰ C, 30 min. b) R ¹ R ² C=O, DCM, Re ₂ O ₇ , rt. 1hr. c) EtOH, 12O ⁰ C, 24 hrs, HNR ⁷ R ⁸ , formaldehyde.

4-(4-Hydroxyphenyl)cyclohexanone 5 was treated with 30% H ₂ O ₂ in acetonitrile catalysed by formic acid to give gemdihydroperoxide 6. Condensation of 6 with cyclohexanone or L- menthone catalysed by either HBF ₄ or Re ₂ O ₇ gave tetraoxanes 7 and 8. Repeating the condensation reaction but with using 2-adamantanone instead gave compound 9 in reasonable yield.

The initial difficulty using HBF ₄ for the condensation of 6 with substrates such as 2- adamantanone was overcome by using Re ₂ O ₇ . Small amounts of the usual impurities such as the 1 ,2,4,5,7,8-hexaoxonane, a symmetrical tetraoxane and Baeyer-Villiger rearranged products were isolated. Refluxing 7 to 9 with 1.1 equivalents of various amines and 38% formaldehyde in ethanol for 24 hours provided the mono-Mannich base analogues 10 to 35, 46 and 47. The yields obtained are presented below in Table 4.

Table 4

Example 2

Exemplary compounds of formula (I) were prepared in which R ¹ , R ² , R ³ and R ⁴ were varied, with R ⁴ ≠ H. An initial target molecule was prepared by the following method (Scheme 2) in which 4-(4-Hydroxyphenyl)cyclohexanone and the carbonyl compounds were allowed to react in a two step sequence.

6, > 80% 7, R ¹ and R ² = (CH ₂ ) _S , 60%

9, R ¹ and R ² = Adamantylidene, 60%

36-45, R = Various amines Scheme 2: Synthesis of compounds 7, 9 and 36 to 45-: Reagents: a) 50% H ₂ O ₂ , CH ₃ CN, HCOOH, O ⁰ C, 30 min. b) R ¹ R ² C=O, DCM, Re ₂ O ₇ , rt. 1hr. c) EtOH, 12O ⁰ C, 24 hrs, HNR ⁷ R ⁸ and/or HNR ⁹ R ¹⁰ , formaldehyde.

4-(4-Hydroxyphenyl)cyclohexanone 5 was treated with 30% H ₂ O ₂ in acetonitrile catalysed by formic acid to give gemdihydroperoxide 6. Condensation of 6 with cyclohexanone or L- menthone catalysed by either HBF ₄ or Re ₂ O ₇ gave tetraoxanes 7 and 8. Repeating the condensation reaction but with using 2-adamantanone instead gave compound 9 in reasonable yield.

Refluxing 7 or 9 with 2.2 equivalents of various amines (e.g. HNR ⁷ R ⁸ ) and 38% formaldehyde in ethanol for 24 hours provided the symmetrical bis-Mannich base analogues, while the mixed bis-mannich base analogues were prepared by carrying out a first Mannich base reaction using a first amine (e.g. HNR ⁷ R ⁸ ) to produce a mono-substituted compound and then repeating the Mannich chemistry on the mono-substituted compound with a different amine (e.g. HNR ⁹ R ¹⁰ ). The yields obtained are presented below in Table 5.

Table 5

Example 3

Exemplary compounds of general formula (IX) according to the second preferred embodiment of the first aspect of the present invention were prepared in which R ¹ and R ² were linked to form part of an adamantylidene group, R ³ and R ⁴ were hydrogen and R ¹² was varied.

(IX)

This class of compounds were prepared according to Scheme 3 by treatment of the phonol 9 with Methyl-α-bromoisobutyrate ⁵ in acetone to afford the ester 48 which was hydrolysed to the carboxylic acid 49 under basic conditions ⁶ . Reaction of 48 in the presence of N- methylmorpholine (NMM), 1-hydroxy-benzotriazole (HOBt) and /V-(3-dimethylaminopropyl)- Λ/'-ethylcarbodiimide hydrochloride (EDAC) ⁷ gave 50-56 in moderate to good yields (Table 6).

49, 84%

50-56, R ¹³ and R ¹⁴ = various

Scheme 3: Synthesis of compound 48-56; Conditions: (a) Acetone, K ₂ CO ₃ , 36 hr, reflux, (b)(i) NaOH ₁ , MeOH, 1hr, 7O ⁰ C, (ii)DCM, H ₂ O, HCI, (c) (i)DCM, O ⁰ C, NMM, NR ¹³ R ¹⁴ (ii) EDAC, HOBt, rt,12hr

Table 6

The skilled person will appreciate from the foregoing and in view of his common general knowledge in the art how analogues of compounds 50 to 56 could be synthesised in which the terminal amido group is replaced with a terminal amino group.

Example 4 Biological activity

The antiplasmodial potentials of mannich base tetraoxanes of the present invention were explored by subjecting them to in vitro screening by measuring the IC50 values against the 3D7 Chloroquine-sensitive strain of the P. falciparum parasite. The results obtained are presented in Tables 7A and 7B.

Table 7A:/n Vitro Activities vrs the 3D7 Chloroquine-sensitive strain of P. falciparum * ^{b a} See experimental section for the description of the assays. ^b IC50 values were averaged values determined by at least three independent experiments. ND = Not Determined

Table 7B: In Vitro Activities vrs the 3D7 Chloroquine-sensitive strain of

P. falciparum ¹ ** as well as calculated LogP and LogS. aSee Experimental section for the description of the assays. ^b IC50 values were averaged values determined by at least three independent experiments. ND = Not Determined

Next, a series of in vivo activity analyses of a selection of the preferred compounds were performed for comparison to existing compounds. First, 4 day Peter's ¹ tests were performed using a 30 mg/kg oral (p.o) dose followed by a full dose response to determine the ED50 and ED90 against the P. berghei ANKA. The results obtained are presented in Table 8.

Table 8: 4 Day Peter's Suppressive Test and Dose response against P. berghei ANKA in Mice ^a .

In another experiment, a single oral dose of 30 mg/kg were performed v P. berghei GFP MRA-865 and then three oral doses of 10 mg/kg were performed v P. berghei GFP MRA- 865. The results are summarised in Table 9 below. Blood parasitemia levels as well as duration of animal survival compared to survival time of animals receiving no drug were determined in this experiment.

Table 9: Parasitaemia was determined by microscopic examination of Giemsa stained blood films taken on day 4. Microscopic counts of blood films from each mouse were processed using

MICROSOFT@EXCEL spreadsheet (Microsoft Corp.) and expressed as percentage of inhibition from the arithmetic mean parasitaemias of each group in relation to the untreated group, (ie 97% = 97% clearance of parasites compared with control group). Antimalarial activity using 3 x 10 mg/kg and 1 x

30 mg/kg dose regimens vrs P. berghei GFP MRA-865. NB For compound 35 2/3 mice were cured with a 66% cure rate for a 3 x 10mg/kg dosage regimen.

The results obtained in this experiment showed that the Mannoxanes tested at the two dose regiments of 30 mg/kg single dose and 3 x10mg/kg exhibited superior activities than the clinically used artesunate. Both the percentage activity and average mice survival were better than the results obtained for the clinically used artesunate.

Further experiments investigated the metabolic stability and metabolite formation in human liver microsomes in vitro as well as permeation across CACO-2 cell line of 29 using a concentration of 10 μM followed by LC/TOF-MS and LC/MS/MS analyses. With initial concentration of 5 μM, about half of 29 were remaining after 60 min incubation with human liver microsomes suggesting moderate metabolic stability. Fourteen metabolites were detected, with the main biotransformation reactions being several hydroxylation reactions (76%). In addition, dehydrogenation and glucuronide conjugation were observed.

In addition, the disappearance of 29 was investigated, and pharmacokinetic calculations performed. Figure 1 shows the relative remaining concentrations for 29 (denoted "RKA213" in Figure 1 ) in 0, 10, 30 and 60 min incubations, with and without cofactors. Initial substrate concentration was 10 μM. Cofactors = NADPH, UDPGA. As can be seen in Figure 1 , the remaining relative abundance of 29 after 60 min incubation time was 49 %. The disappearance was cofactor (thus metabolism) dependent.

Calculations of pharmacokinetic (PK) parameters on the basis of substrate depletion for 29 in human liver microsomes have been determined and are shown in Table 10.

Table 10: Kinetic in vitro clearance, T _1/2 and liver intrinsic clearance of the study compounds Intrinsic clearance = CL _int (microsomal incubation), in vitro half-life = t _1/2 , Intrinsic clearance (whole liver) = CL _{int h}

The in vitro disappearance rate falls into typical intermediate clearance range of such experiments (Zn vitro half life 20 to 60 min) ² . Therefore, it is expected that first-pass metabolism will reduce bioavailability but not to a very high degree. Similarly, half-life in the body should be intermediate. However, plasma protein binding and ultimate in vivo volume of distribution dictates the eventual plasma kinetics of the molecules.

Antimalarial Activity Assays

The parasites were maintained in continuous culture using the method of Jensen and Trager ³ . Cultures were grown in flasks containing human erythrocytes (2-5%) with parasitemia in the range of 1% to 10% suspended in RPMI 1640 medium supplemented with 25 mM HEPES and 32 mM NaHCO3, and 10% human serum (complete medium). Cultures were gassed with a mixture of 3% 02, 4% CO2 and 93% N2- Antimalarial activity was assessed with an adaption of the 48-h sensitivity assay of Desjardins et al. ⁴ using [ H]- hypoxanthine incorporation as an assessment of parasite growth. Stock drug solutions were prepared in 100 % dimethylsulphoxide (DMSO) and diluted to the appropriate concentration using complete medium. Assays were performed in sterile 96-well microtitre plates, each plate contained 200 μl of parasite culture (2 % parasitemia, 0.5 % haematocrit) with or without 10 μl drug dilutions. Each drug was tested in triplicate and parasite growth compared to control wells (which constituted 100 % parasite growth). After 24-h incubation at 37 ⁰ C, 0.5 μCi hypoxanthine was added to each well. Cultures were incubated for a further 24 h before they were harvested onto filter-mats, dried for 1 h at 55 ⁰ C and counted using a Wallac 1450 Microbeta Trilux Liquid scintillation and luminescence counter. IC50 values were calculated by interpolation of the probit transformation of the log dose - response curve. In vivo Antimalarial Screening

In vivo data was determined using 30 mg/kg oral (p.o) and subcutaneous (sc) doses in a 4 - days Peter's test. For subcutaneous administration, compounds were dissolved in 10%dimethylsulfoxide (DMSO) 0.05% Tween 80 (Sigma, Dorset, UK) in distilled water. For oral administration, compounds were dissolved in standard suspending vehicle (SSV) [0.5 % sodium carboxymethylcellulose, 0.5 % benzyl alcohol, 0.4 % Tween 80, 0.9 %NaCI (all Sigma)]. Subcutaneous (s.c) or oral (p.o) treatment was done with 0.2ml of a solution of the test compound two hours (day 0) and on days 1 , 2, and 3 post infections. Parasitaemia was determined by microscopic examination of Giemsa stained blood films taken on day 4. Microscopic counts of blood films from each mouse were processed using MICROSOFT@EXCEL spreadsheet (Microsoft Corp.) and expressed as percentage of inhibition from the arithmetic mean parasitaemias of each group in relation to the untreated group.

Experimental Preparation of Inventive Compounds

General procedure for the preparation of bishydroperoxides 6

A stirred solution of 4-(4-Hydroxyphenyl)cyclohexanone [0.4M] in formic acid/acetonitrile (1 :1 ) was added 30% aqueous hydrogen peroxide (2 equiv) and the mixture was stirred at room temperature for 30 minutes. The mixture was then poured into ice-cold water and the organic products were extracted in DCM. After conventional workup, the residue was concentrated in vacuo to give the bishydroperoxide 6 in over 80%.

General procedure for the preparation of the 1,2,4,5-tetraoxane

Preparation of tetraoxane 7

A stirred solution of cyclohexanone (carbonyl compound) [0.50M] in DCM was added to a solution of 4-(4,4-dihydroperoxycyclohexyl)phenol 6 [0.13M] in DCM and Re ₂ O ₇ (2mol%) and stirred for 1 hr at room temperature. The crude reaction mixture was filtered through a plug of silica and concentrated. Purification by flash column chromatography gave the product in 60%. General procedure for the Mannich Base tetraoxane (Mannoxane) reaction

38% Formaldehyde (1.4 equiv) and the amine (1.4 equiv) mixture were preformed and added to a solution of the tetraoxane compound (1 equiv, 0.1 M) in Ethanol. The resulting mixture was refluxed at 12O ⁰ C for 24 hours. The solution was cooled, concentrated in vacuo and dissolved in ethyl acetate. The organic layer was washed with brine, dried over MgSO ₄ and concentrated. The residue was purified by flash column chromatography on silica gel to give the required Mannich compound.

Preparation of 4-(7,8,15,16-tetraoxadispiro[5.2.5.2]hexadec-3-yl)phenol 7

This product was isolated in 60% according to the general procedure for the preparation of the 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using Hex/EtOAc (9:1 , v/v, Rf = 0.6) as eluent.

Preparation of 4-[( 10S, 13R)-10-isopropyl-13-methyl-7,8, 15,16- tetraoxadispiro[5.2.5.2]hexa-dec-3-yl]phenol 8

This product was isolated in 43% according to the general procedure for the preparation of the 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using Hex/EtOAc (9:1 , v/v, Rf = 0.6) as eluent.

Preparation of 4-(dispiro[cyclohexane-1 ,3'-[1 ,2,4,5]tetroxane-6',2"- tricyclo[3.3.1.13,7]decan]-4-yl)phenol 9

This product was isolated in 60% according to the general procedure for the preparation of the 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using Hex/EtOAc (9:1 , v/v, Rf = 0.5) as eluent. Preparation of 2-[(diethylamino)methyl]-4-(7,8, 15,16-tetraoxadispiro[5.2.5.2] hexadec-3- yl)phenol 10

This product was isolated in 45% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using Hex/EtOAc (1 :1, v/v, Rf = 0.6) as eluent.

Preparation of 2-[(tert-butylamino)methyl]-4-(7,8,15,16-tetraoxadispiro[5.2 .5.2]hexadec- 3-yl)phenol 11

This product was isolated in 17% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using DCM/MeOH (9:1 , v/v, Rf = 0.3) as eluent.

Preparation of 2-{[4-(4-fluorophenyl)piperazin-1-yl]methyl}-4-(7, 8,15,16- tetraoxadispiro[5.2.5.2]hexadec-3-yl)phenol 12

This product was isolated in 42% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using DCM/MeOH (9:1 , v/v, Rf = 0.7) as eluent.

Preparation of 2-(piperidin-1-ylmethyl)-4-(7,8,15,16-tetraoxadispiro[5.2.5. 2]hexadec-3- yl)phenol 13.

This product was isolated in 49% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using DCM/MeOH (9:1 , v/v, Rf = 0.7) as eluent.

Preparation of 2-(pyrrolidin-1-ylmethyl)-4-(7,8,15,16-tetraoxadispiro[5.2.5 .2]hexadec-3- yl)phenol 14

This product was isolated in 35% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using DCM/MeOH (9:1 , v/v, Rf = 0.5) as eluent.

Preparation of 2-{[4-(pyrimidin-2-yl)piperazin-1-yl]methyl}-4-(7,8,15,16- tetraoxadispiro[5.2.5.2]hexadec-3-yl)phenol 15

This product was isolated in 49% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using Hex/e (1 :1 , EtOAc/v, Rf = 0.4) as eluent.

Preparation of 2-{[4-(morpholin-4-yl)piperidin-1-yl]methyl}-4-(7,8,15,16- tetraoxadispiro[5.2.5.2]hexadec-3-yl)phenol 16

This product was isolated in 66% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using DCM/MeOH (9:1 , v/v, Rf = 0.6) as eluent.

Preparation of 2-(1,4 ^l -bipiperidin-1 ^l -ylmethyl)-4-(7,8,15,16- tetraoxadispiro[5.2.5.2]hexadec-3-yl)phenol 17

This product was isolated in 56% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using DCM/MeOH (1 :1 , v/v, Rf = 0.3) as eluent.

Preparation of 2-(morpholin-4-ylmethyl)-4-(7,8,15,16-tetraoxadispiro[5.2.5. 2]hexadec-3- yl)phenol 18

This product was isolated in 53% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using Hex/EtOAc (1 :1 , v/v, Rf = 0.5) as eluent.

Preparation of 2-{[4-(4-methylpiperazin-1-yl)piperidin-1-yl]methyl}-4-(7,8, 15,16- tetraoxadispiro[5.2.5.2]hexadec-3-yl)phenol 19

This product was isolated in 49% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using DCM/MeOH (9:1 , v/v, Rf = 0.2) as eluent.

Preparation of 4-[(10S,13R)-10-isopropyl-13-methyl-7,8,15,16- tetraoxadispiro[5.2.5.2]hexadec-3-yl]-2-(morpholin-4-ylmethy l)phenol 20

This product was isolated in 48% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using Hex/EtOAc (1 :1 , v/v, Rf = 0.5) as eluent. Preparation of 4-[(10S,13R)-10-isopropyl-13-methyl-7,8,15,16- tetraoxadispiro[5.2.5.2]hexadec-3-yl]-2-(piperidin-1-ylmethy l)phenol 21

This product was isolated in 57% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using DCM/EtOAc (1 :1 , v/v, Rf = 0.1 ) as eluent.

Preparation of 4-[(10S,13R)-10-isopropyl-13-methyl-7,8,15,16- tetraoxadispiro[5.2.5.2]hexadec-3-yl]-2-[(4-methylpiperazin- 1-yl)methyl]phenol 22

This product was isolated in 36% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using DCM/MeOH (9:1 , v/v, Rf = 0.7) as eluent.

Preparation of 4-[(10S,13R)-10-isopropyl-13-methyl-7,8,15,16- tetraoxadispiro[5.2.5.2]hexa-dec-3-yl]-2-(pyrrolidin-1-ylmet hyl)phenol 23

This product was isolated in 43% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using DCM/EtOAc (1 :1 , v/v, Rf = 0.2) as eluent

Preparation of 4-(dispiro[cyclohexane-1,3 ^I -[1,2,4,5]tetroxane-6',2"- tricyclop.S.I.ISJldecanl^-yO^-^-isobutylpiperazin-i-ylJmethy llphenol 24

This product was isolated in 60% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using DCM/MeOH (9:1 , v/v, Rf = 0.4) as eluent.

Preparation of 4-(dispiro[cyclohexane-1 ,3'-[1 ,2,4,5]tetroxane-6',2"- tricyclo[3.3.1.13,7]decan]-4-yl)-2-{[4-(pyrimidin-2-yl)piper azin-1-yl]methyl}phenol 25

This product was isolated in 53% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using DCM/EtOAc (1 :1 , v/v, Rf = 0.6) as eluent.

Preparation of 2-(1,4'-bipiperidin-1 ^l -ylmethyl)-4-(dispiro[cyclohexane-1,3 ¹ - [1,2,4,5]tetroxane-6 ^l ,2"-tricyclo[3.3.1.13,7]decan]-4-yl)phenol 26

This product was isola ed in 46% according to the general pro-cedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using DCM/EtOAC (1 :1 , v/v, Rf = 0.2) as eluent.

Preparation of 4-(dispiro[cyclohexane-1 ,3'-[1 ,2,4,5]tetroxane-6',2"- tricyclotS.S.I.ISJldecanJ^-yO^-^-tpyrrolidin-i-yOpiperidin-i -yllmethy^phenol 27

This product was isolated in 53% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using DCM/MeOH (1 :1 , v/v, Rf = 0.1 ) as eluent.

Preparation of 4-(dispiro[cyciohexane-1 ,3'-[1 ,2,4,5]tetroxane-6',2"- tricyclo[3.3.1.13,7]decan]-4-yl)-2-({[2-(morpholin-4-yl)ethy l]amino}methyl)phenol 28

This product was isolated in 56% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using DCM/MeOH (9:1 , v/v, Rf = 0.7) as eluent

Preparation of 4-(dispiro[cyclohexane-1 ,3'-[1 ,2,4,5]tetroxane-6',2"- tricydo[3.3.1.13,7]decan]-4-yl)-2-(morpholin-4-ylmethyl)phen ol 29

This product was isolated in 42% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using DCIWEtOAc (9:1 , v/v, Rf = 0.5) as eluent.

Preparation of 4-(dispiro[cyclohexane-1 ,3'-[1 ,2,4,5]tetroxane-6',2"- tricyclo[3.3.1.13,7]decan]-4-yl)-2-{[4-(4-methylpiperazin-1- yl)piperidin-1- yl]methyl}phenol 30

This product was isolated in 43% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using DCM/MeOH (9:1 , v/v, Rf = 0.1 ) as eluent.

Preparation of 4-(dispiro[cyclohexane-1 ,3'-[1 ,2,4,5]tetroxane-6',2"- tricycloβ.S.I.ISJldecanH-yl^-fpyrrolidin-i-ylmethyOphenol 31

This product was isolated in 32% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using DCM/MeOH (1 :1 , v/v, Rf = 0.3) as eluent. Preparation of 4-(dispiro[cyclohexane-1 ,3'-[1 ,2,4,5]tetroxane-6',2"- tricyclo[3.3.1.13,7]decan]-4-yl)-2-(piperidin-1-ylmethyl)phe nol 32

This product was isolated in 55% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using DCM/EtOAc (1:1 , v/v, Rf = 0.3) as eluent.

Preparation of 4-(dispiro[cyclohexane-1 ,3'-[1 ,2,4,5]tetroxane-6',2"- tricycloβ.S.I.ISJldecanM-yl^-l^-methylpiperazin-i-yOmethyll phenol 33

This product was isolated in 61% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using DCM/MeOH (1 :1 , v/v, Rf = 0.6) as eluent.

Preparation of 4-(dispiro[cyclohexane-1 ,3'-[1 ,2,4,5]tetroxane-6',2"- tricycloIS.S.I.ISJldecanJ^-ylJ^^^-tmorpholin^-ylJpiperidin-i -ylJmethy^phenol 34

This product was isolated in 48% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using DCM/MeOH (9:1 , v/v, Rf = 0.4) as eluent.

Preparation of 2-[(diethylamino)methyl]-4-(dispiro[cyclohexane-1 ,3'-[1 ,2,4,5]tetroxane- 6',2"-WCyCIo[S-S-1.13,7]decan]-4-yl)phenol 35

This product was isolated in 55% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using Hex/EtOAc (3:2, v/v, Rf = 0.3) as eluent.

Preparation of 4-(dispiro[cyclohexane-1 ,3'-[1 ,2,4,5]tetroxane-6',2"- tricyclo[3.3.1.13,7]decan]-4-yl)-2-{[4-(2-methoxyphenyl)pipe razin-1-yl]methyl}phenol

46

This product was isolated in 54% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using dDCM/EtOAc (1 :1 , v/v, Rf = 0.5) as eluent.

Preparation of 4-(dispiro[cyclohexane-1 ,3'-[1 ,2,4,5]tetroxane-6',2"- tricyclo[3.3.1.13,7]decan]-4-yl)-2-{[4-(1-methylpiperidin-4- yl)piperazin-1- yl]methyl}phenol 47

This product was isolated in 56% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using DCM/MeOH (9:1 , v/v, Rf = 0.23) as eluent.

Preparation of 2,6-bis(pyrrolidin-1-ylmethyl)-4-(7,8,15,16- tetraoxadispiro[5.2.5.2]hexadec-3-yl)phenol 36

This product was isolated in 69% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using DCM/MeOH (9:1 v/v, Rf = 0.1 ) as eluent. Preparation of 37

This product was isolated in 50% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using DCM/MeOH (9:1 v/v, Rf = 0.2) as eluent.

Preparation of 2,6-bis(piperidin-1-ylmethyl)-4-(7,8,15,16- tetraoxadispiro[5.2.5.2]hexadec-3-yl)phenol 38

This product was isolated in 17% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using DCM/MeOH (9:1 v/v, Rf = 0.01 ) as eluent.

Preparation of 2,6-bis[(diethylamino)methyl]-4-(7,8,15,16- tetraoxadispiro[5.2.5.2]hexadec-3-yl)phenol 39

This product was isolated in 28% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using Hex/EtOAC (1 :1 , v/v, Rf = 0.1 ) as eluent.

Preparation of 2-(morpholin-4-ylmethyl)-6-(piperidin-1-ylmethyl)-4-(7,8,15, 16- tetraoxadispiro[5.2.5.2]hexadec-3-yl)phenol 40

This product was isolated in 50% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using DCM/MeOH (1 :1 , v/v, Rf = 0.5) as eluent.

Preparation of 2-(piperidin-1-ylmethyl)-6-(pyrrolidin-1-ylmethyl)-4-(7,8,15 ,16- tetraoxadispiro[5.2.5.2]hexadec-3-yl)phenol 41

This product was isolated in % according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using Hex/EtOAC (1 :1 , v/v, Rf = 0.5) as eluent.

Preparation of 4-(dispiro[cyclohexane-1 ,3'-[1 ,2,4,5]tetroxane-6',2"- tricyclo[3.3.1.13,7]decan]-4-yl)-2,6-bis(pyrrolidin-1-ylmeth yl)phenol 42

This product was isolated in 36% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using Hex/EtOAc (2:3, v/v, Rf = 0.1 ) as eluent.

Preparation of 4-(dispiro[cyclohexane-1 ,3'-[1 ,2,4,5]tetroxane-6',2"- tricycloIS.S.I.IS.yidecanl^-ylJ^.Θ-bistpiperidin-i-ylmethyl Jphenol 43

This product was isolated in according to the general p for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using Hex/EtOAc (3:2, v/v, Rf = 0.1 ) as eluent.

Preparation of 4-(dispiro[cyclohexane-1 ,3'-[1 ,2,4,5]tetroxane-6',2"- tricyclo[3.3.1.13,7]decan]-4-yl)-2,6-bis(morpholin-4-ylmethy l)phenol 44

This product was isolated in 22% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using Hex/EtOAc (3:2, v/v, Rf = 0.1 ) as eluent.

Preparation of 4-(dispiro[cyclohexane-1 ,3'-[1 ,2,4,5]tetroxane-6',2"- tricyclo[3.3.1.13,7]decan]-4-yl)-2-(piperidin-1-ylmethyl)-6- (pyrrolidin-1-ylmethyl)phenol

45

This product was isolated in 26% according to the general procedure for the preparation of the mannich base 1 ,2,4,5-tetraoxane. This product was purified by flash column chromatography using Hex/EtOAc (1 :1 , v/v, Rf = 0.1 ) as eluent. Experimental Preparation of Compounds According to General Formula (VIII)

(VIII)

General Procedure For The Preparation Of The Tetraoxane Ester

Methyl-α-bromoisobutyrate (13.4mmol) and K ₂ CO ₃ (10.7 mmol) were added to a stirred solution of compound 9 (5.5 mmol.) and acetone (20 ml_). The solution was refluxed at 85°C for 36 hr. The acetone was removed at reduced pressure and the resulting powder was dissolved in EtOAc and washed with water and brine. The EtOAc was removed at reduced pressure and the crude product was purified by flash column chromatography on silica gel.

General Procedure For The Preparation Of The Tetraoxane Carboxylic Acid

Sodium hydroxide (15.9 mmol) was dissolved in water (3 mL) and added to a stirred solution of the ester (3.2mmol) in methanol (20 mL) and this solution was refluxed at 75 - 80 ⁰ C for 1 hour. DCM was added to the cooled solution and the salt intermediate was extracted with water. The aqueous extract was acidified with concentrated HCI (3 mL) and the crude product was extracted with DCM (3 x 10 mL). The organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography on silica gel.

General Procedure For Preparation Of Tetraoxane Amides Of Formula (VIII)

NMM (1.96 mmol) and an amine (0.79 mmol) were added to a stirred solution of comound 49 (0.65 mmol) in dry DCM (2OmL) at O ⁰ C. HOBt (0.79 mmol) and EDAC (0.79 mmol) were then added and the mixture was allowed to warm up to room temperature and stirred overnight. DCM (10 mL) was added and the solution was washed with 2.0 M HCI (5 mL), saturated aq. NaHCO ₃ (5 mL) and brine (5 mL). The organic phase was dried over MgSO ₄ , filtered and the solvent was removed at reduced pressure to give the crude product. This was purified by flash column chromatography on silica gel.

General Procedure For Preparation of Tetroxane Amines Of Formula (VIII)

The skilled person using his common general knowledge in the art will appreciate how to synthesise compounds according to Formula (VIII) in which group A is a substituted or unsubstituted amino group. Preparation of Methyl-2-(4-spiro[adamantane-1 ',3-(1 ,2,4,5-tetraoxaspiro[5.5]undecan-9- yl)]phenoxy)-2-methylpropanoate 48

This product was isolated in 31% as white powder according to the general procedure for the preparation of the tetraoxane ester.

Preparation of 2-(4-spiro[adamantane-1 ',3-(1 ,2,4,5-tetraoxaspiro[5.5]undecan-9- yl)]phenoxy)-2-methylpropanoic acid 49

This product was isolated in 84% as white powder according to the general procedure for the preparation of the tetraoxane ester.

Preparation of 2-(4-spiro[adamantane-1 ',3-(1 ,2,4,5-tetraoxaspiro[5.5]undecan-9- yl)]phenoxy)-2-methyl-1-morpholinopropan-1-one 50

This product was isolated in 29% as white powder according to the general procedure for the preparation of the tetraoxane amides.

Preparation of 2-(4-spiro[adamantane-1 ',3-(1 ,2,4,5-tetraoxaspiro[5.5]undecan-9- yl)]phenoxy)-2-methyl-1-(4-methylpiperazin-1-yl)propan-1-one 51

This product was isolated in 21% as a yellow brown powder according to the general procedure for the preparation of the tetraoxane amides.

Preparation of 2-(4-spiro[adamantane-1 ',3-(1 ,2,4,5-tetraoxaspiro[5.5]undecan-9- yl)]phenoxy)-2-methyl-1-(4-morpholinopiperidin-1-yl)propan-1 -one 52

This product was isolated in 40% as a white powder according to the general procedure for the preparation of the tetraoxane amides.

Preparation of 2-(4-spiro[adamantane-1 ',3-(1 ,2,4,5-tetraoxaspiro[5.5]undecan-9- yl)]phenoxy)-N-(4,4-difluorocyclohexyl)-2-methylpropanamide 53

This product was isolated in 25% as a white powder according to the general procedure for the preparation of the tetraoxane amides.

Preparation of 2-(4-spiro[adamantane-1 ',3-(1 ,2,4,5-tetraoxaspiro[5.5]undecan-9- yl)]phenoxy)-2-methyl-1-(4-(4-methylpiperazin-1-yl)piperidin -1-yl)propan-1-one 54

This product was isolated in 26% as an orange-brown powder according to the general procedure for the preparation of the tetraoxane amides.

Preparation of 1-([1,4'-bipiperidin]-1'-yl)-2-(4-spiro[adamantane-1',3-(1, 2,4,5- tetraoxaspiro[5.5]undecan-9-yl)]phenoxy)-2-methylpropan-1-on e 55

This product was isolated in 41% as a yellow-brown powder according to the general procedure for the preparation of the tetraoxane amides.

Preparation of 2-(4-spiro[adamantane-1 ',3-(1 ,2,4,5-tetraoxaspiro[5.5]undecan-9- yl)]phenoxy)-N-cyclopropyl-2-methylpropanamide 56

This product was isolated in 50% as a yellow powder according to the general procedure for the preparation of the tetraoxane amides.

APPENDIX 1 Characterization data

¹ H NMR (400MHz, CDCI ₃ ) δ _H 1.43-1.92(m, 16H, cyclohexyl), 2.21-2.45 (m, 2H, cyclohexyl), 2.51-2.59 (m, 1 H, CH), 4.83 (s, 1 H, OH), 6.77 (d, 2H, J = 8.5 Hz, Ar), 7.09 (d, 2H, J = 8.5 Hz, Ar). ¹³ C NMR (100MHz, CDCI ₃ ), δ _c 21.4, 25.0, 25.9, 28.7, 34.6, 43.1 , 108.1 , 108.8, 115.6, 128.2, 138.3, 154.6,

4-[(10S,13R)-10-isopropyl-13-methyl-7,8,15,16-tetraoxadis piro[5.2.5.2]hexa-dec-3- yl]phenol 8

¹ H NMR (400MHz, CDCI ₃ ) δ _H 0.85 (dd, 6H, J = 2.4 Hz, 6.8 Hz, CH ₃ ), 0.94 (dd, 3H, J = 6.8 Hz, 9.1 Hz, CH ₃ ), 1.6-2.0 (m, 15H, CH/CH ₂ ), 2.50-2.59 (m, 1 H, CH), 3.20 (dt, 2H, J = 13.4 Hz, CH), 6.19 (s, 1 H, OH), 6.80 (dd, 2H, J = 2.4 Hz, 8.6 Hz, Ar), 7.10 (dd, 2H, J = 2.4 Hz, 8.6Hz, Ar) ¹³ C NMR (100MHz, CDCI ₃ ), δ _c 19.2, 22.3, 23.5, 24.9, 29.9, 30.2, 30.7, 32.4, 35.0, 43.1 , 50.4, 108.0, 111.6, 115.7, 128.1 , 138.1 , 154.9

4-(dispiro[cyclohexane-1,3'-[1,2,4,5]tetroxane-6',2"-tric yclo[3.3.1.13,7]decan]-4- yl)phenol 9

(White powder, 60%) Mpt. 149-151 ⁰ C ¹ H NMR (400MHz, CDCI ₃ ) δ _H 1.58-2.11(m, 22H), 2.50-2.52 (m, 1H, CH), 4.58 (s, 1 H, OH), 6.75 (d, 2H, J = 8.6 Hz, Ar), 7.09 (d, 2H, J = 8.6 Hz, Ar) ¹³ C NMR (100MHz, CDCI ₃ ), δ _c 27.5, 33.6, 37.4, 39.7, 43.2, 47.4, 108.0, 110.9, 115.6, 128.3, 138.6, 154.3 MS (ES+), [M + H] ⁺ (100), HRMS calculated for C ₂₈ H ₄₇ O ₅ N ₂ , found 491.3488.

2-[(tert-butylamino)methyl]-4-(7,8,15,16-tetraoxadispiro[ 5.2.5.2]hexadec-3-yl)phenol 11

(White powder, 17%) ¹ H NMR (400 MHz, CDCI ₃ ) δ _H 1.20 (s, 9H), 2.03-1.40 (m, 16H), 2.25 (s, 1 H), 2.37 (s, 1 H), 2.49 (m, 1 H), 3.25 (s, 1 H), 3.90 (s, 2H, ArCH ₂ ), 6.74 (d, J = 8.2 Hz, 1 H, Ar), 6.85 (d, J = 2.0 Hz, 1 H, Ar), 6.99 (dd, J = 8.2 Hz, 2.1 Hz, 1 H, Ar), ¹³ C NMR (101 MHz, CDCI ₃ ) δ _c 22.3, 22.7, 25.8, 29.0, 30.1 , 32.3, 43.2, 46.6, 51.4, 108.2, 108.8, 116.7, 123.7, 126.6, 127.3, 136.7, 157.1. MS (ES+), [M + H] ⁺ (IOO), 406.3 HRMS calculated for 406.2593 C ₂₃ H ₃₆ O ₅ N, found 406.2599. Elemental analysis C: 68.09, H: 8.71 , N: 3.51 (required values C: 68.12, H: 8.70, N: 3.45).

2-{[4-(4-fluorophenyl)piperazin-1 -yl]methyl}-4-(7, 8,15,16- tetraoxadispiro[5.2.5.2]hexadec-3-yl)phenol 12

(White powder, 42%) Mpt. 138-140 °C ¹ H NMR (400MHz, CDCI ₃ ) δ _H 1.42-1.91 (m, 16H, cyclohexyl), 2.20-2.44 (m, 2H, cyclohexyl), 2.47-2.56 (m, 1 H, CH), 2.62-2.81 (m, 4H, NCH ₂ ), 3.04-3.32 (m, 4H, CH ₂ N), 3.73 (s, 2H, ArCH ₂ ), 6.76 (d, 2H, J = 8.3 Hz, Ar), 6.85-6.91 (m, 3H, Ar), 6.93-7.00 (m, 2H, Ar), 7.32 (dd, 1 H, J = , 8.3Hz, 2.3 Hz, Ar), 10.5 (bs, 1 H, OH) ¹³ C NMR (100MHz, CDCI ₃ ), δ _c 22.3, 22.6, 25.8, 30.0, 32.3, 43.1 , 50.6, 53.0, 62.0, 108.1 , 108.8, 115.9, 116.1 , 118.6, 121.2, 127.3, 127.7, 137.1 , 147.9, 156.3, 159.0 MS (ES+), [M + H] ⁺ (100), 513.3 HRMS calculated for 513.2765 C ₂₉ H ₃₈ O ₅ N ₂ F, found 513.2776. Elemental analysis C: 68.12, H: 7.30, N: 3.73 (required values C: 67.95, H: 7.28, N: 3.71 ).

2-(piperidin-1-ylmethyl)-4-(7,8,15,16-tetraoxadispiro[5.2 .5.2]hexadec-3-yl)phenol 13.

¹ H NMR (400 MHz, CDCI ₃ ) δ _H , 2.05 - 1.35 (m, 22H), 2.80-2.10 (m, 7H), 3.23 (s, 1 H), 3.61 (s, 2H), 6.73 (d, J = 8.2 Hz, 1 H), 6.80 (d, J = 2.1 Hz, 1 H), 6.99 (dd, J = 8.2 Hz, 2.2 Hz, 1 H), ¹³ C NMR (100 MHz, CDCI ₃ ) δ _c 22.4, 22.7, 24.2, 25.8, 26.3, 30.0, 32.2, 43.2, 54.3, 62.7, 108.2, 108.8, 116.2, 121.9, 127.0, 127.2, 136.7, 156.8 MS (ES+), [M + H] ⁺ (100418.3 HRMS calculated for 418.2593 C ₂₄ H ₃₆ O ₅ N, found 418.2599. Elemental analysis C: 69.10, H: 8.26, N: 3.39 (required values C: 69.04, H: 8.45, N: 3.35).

2-(pyrrolidin-1-ylmethyl)-4-(7,8,15,16-tetraoxadispiro[5. 2.5.2]hexadec-3-yl)phenol 14

¹ H NMR (400 MHz, CDCI ₃ ) δ _H 2.03 - 1.35 (m, 20H), 2.26 (s, 1 H), 2.38 (s, 1 H), 2.49 (tt, J = 11.6 Hz, 3.6 Hz, 1H), 2.62 (s, 4H), 3.26 (s, 1 H), 3.77 (s, 2H), 6.73 (d, J = 8.2 Hz, 1 H), 6.82 (d, J = 1.7 Hz, 1H), 6.99 (dd, J = 8.2Hz, 2.1 Hz, 1 H). ¹³ C NMR (100 MHz, CDCI ₃ ) δ _c 22.3, 22.6, 24.1 , 25.8, 30.0, 32.3, 43.1 , 54.0, 59.4, 77.1 , 77.4, 77.7, 108.2, 108.8, 116.1 , 122.7, 126.4, 127.4, 136.6, 156.7 MS (ES+), [M + H] ⁺ (100), 404.3 HRMS calculated for 404.2437 C ₂₃ H ₃₄ O ₅ N, found 404.2445. Elemental analysis C: 68.47, H: 8.30, N: 3.48 (required values C: 68.46, H: 8.24, N: 3.47).

2-{[4-(pyrimidin-2-yl)piperazin-1-yl]methyl}-4-(7,8,15,16 - tetraoxadispiro[5.2.5.2]hexadec-3-yl)phenol 15

(White powder, 49%) Mpt. 162-164 ⁰ C ¹ H NMR (400MHz, CDCI ₃ ) δ _H 1.41-1.91(m, 16H, cyclohexyl), 2.20-2.45 (m, 2H, cyclohexyl), 2.46-2.74 (m, 9H, CH ₂ /CH), 3.7 (s, 2H, ArCH ₂ ), 3.90 (bs, 1 H, OH), 6.61 (t, 1 H, J = 4.8 Hz, Ar), 6.78 (d, 1 H, J = 8.4Hz, Ar), 6.83 (d, 1 H, J = 2.2Hz, Ar), 7.02 (dd, 1 H, J = 8.4 Hz, Ar), 8.31 (d, 2H, J = 4.8 Hz, Ar) ¹³ C NMR (100MHz, CDCI ₃ ), δ _c 22.3, 25.8, 30.1 , 32.4, 43.1 , 43.9, 52.9, 62.2, 108.1 , 108.8, 110.7, 116.4, 121.2, 127.3, 127.7, 137.1 , 156.3, 158.2, 161.9 MS (ES+), [M + H] ⁺ (IOO), 497.2 HRMS calculated for 497.2764 C ₂₇ H ₃₇ O ₅ N ₄ , found 497.2776. Elemental analysis C: 65.29, H: 7.33, N: 11.31 (required values C: 65.30, H: 7.31 , N: 11.28).

2-{[4-(morpholin-4-yl)piperidin-1-yl]methyl}-4-(7,8,15,16 - tetraoxadispiro[5.2.5.2]hexadec-3-yl)phenol 16

(White powder, 66%) Mpt. 158-160 ⁰ C ¹ H NMR (400MHz, CDCI ₃ ) δ _H 1.42-1.92 (m, 22H, CH ₂ ), 2.08 (t, 2H, J = 11.8 Hz, CH ₂ ), 2.21-2.30 (m, 2H, CH), 2.54 (t, 4H, J = 4.7 Hz, NCH ₂ ), 3.04 (dt, 2H, J = 11.8 Hz, CH ₂ ), 3.63 (s, 2H, ArCH ₂ ), 3.72 (t, 4H ₁ J = 4.7 Hz, CH ₂ O), 6.73 (d, 1 H, J = 8.3 Hz, Ar), 6.80 (d, 1H, J = 2.3 Hz, Ar), 7.01 (dd, 1 H, J =8.3 Hz, 2.3 Hz, Ar) ¹³ C NMR (100MHz, CDCI ₃ ), δ _c 22.7, 25.8, 28.5, 30.0, 32.2, 33.6, 41.8, 43.1 , 50.2, 52.8, 62.0, 67.7, 108.1 , 108.8, 116.2, 121.7, 127.0, 127.4, 136.8, 142.9, 156.6 MS (ES+), [M + H] ⁺ (100), 503.1 HRMS calculated for 503.3121 C ₂₈ H ₄₃ O ₆ N ₂ , found 503.3112. Elemental analysis C: 66.89, H: 8.45, N: 5.56 (required values C: 66.91 , H: 8.42, N: 5.57).

2-(1,4 ^l -bipiperidin-1'-ylmethyl)-4-(7,8,15,16-tetraoxadispiro [5.2.5.2]hexadec-3-yl)phenol 17

(White powder, 56%) Mpt. 148-150 ⁰ C ¹ H NMR (400MHz, CDCI ₃ ) δ _H 1.41-1.90 (m, 24H, CH ₂ ), 1.99 (d, 2H, J = 12.2Hz, CH ₂ ), 2.21 (t, 2H, J = 11.7 Hz, CH ₂ ), 2.20-2.44 (m, 2H, CH ₂ ), 2.45-2.55 (m, 2H, CH), 2.68 (bs, 4H, NCH ₂ ), 3.09(dt, 2H, J = 12.2 Hz, CH ₂ ), 3.64 (s, 2H, ArCH ₂ ), 6.73 (d, 1 H, J = 8.3 Hz, Ar), 6.80 (d, 1 H, J = 2.2 Hz, Ar), 7.01 (dd, 1 H, J = 8.3 Hz, Ar) ¹³ C NMR (100MHz, CDCI ₃ ), δ _c 22.5, 24.5, 25.7, 25.9, 27.6, 30.0, 32.2, 43.1 , 50.5, 52.9, 61.8,63.1 , 108.1 , 108.8, 116.3, 121.5, 127.1 , 127.5, 137.0, 156.4 MS (ES+), [M + H] ⁺ (100), 501.3 HRMS calculated for 501.3328 C ₂₉ H ₄₅ O ₅ N ₂ , found 501.3317. Elemental analysis C: 69.72, H: 8.88, N: 5.69 (required values C: 69.57, H: 8.86, N: 5.60).

2-(morpholin-4-ylmethyl)-4-(7,8,15,16-tetraoxadispiro[5.2 .5.2]hexadec-3-yl)phenol 18

(White powder, 53%) Mpt. 136-138 ⁰ C ¹ H NMR (400MHz, CDCI ₃ ) δ _H 1.42-1.90 (m, 16H, cyclohexyl), 2.20-2.43 (m, 2H, cyclohexyl), 2.45-2.64 (m, 5H, NCH ₂ /CH), 3.66 (s, 2H, ArCH ₂ ), 3.75 (bs, 4H, CH ₂ O), 6.75 (d, 1 H, J = 8.3 Hz, Ar), 6.84 (s, 1 H, Ar), 7.02 (dd, 1 H ₁ J = 2.3 Hz, 8.3 Hz, Ar), 10.3 (bs, 1 H, OH) ¹³ C NMR (100MHz, CDCI ₃ ), δ _c 22.3, 25.8, 30.0, 32.3, 43.1 , 53.4, 62.4, 67.2, 108.1 , 108.8, 116.3, 120.9, 127.4, 127.7, 137.2, 156.2 MS (ES+), [M + H] ⁺ (100), 420.3 HRMS calculated for 420.2386 C ₂₃ H ₃₄ O ₆ N, found 420.2404. Elemental analysis C: 66.03, H: 8.04, N: 3.33 (required values C: 65.85, H: 7.93, N: 3.34). 2-{[4-(4-methylpiperazin-1-yl)piperidin-1-yl]methyl}-4-(7, 8,15,16- tetraoxadispiro[5.2.5.2]hexadec-3-yl)phenol 19

(White powder, 49%) 138-140 ⁰ C ¹ H NMR (400MHz, CDCI ₃ ) δ _H 1.43-1.98 (m, 28H ₁ CH ₂ ), 2.28 (s, 3H, CH ₃ ), 2.45-2.76 (m, 6H, CH/CH ₂ ), 2.9 (dt, 2H, J = 12.1 Hz, CH ₂ ), 3.63 (s, 2H, ArCH ₂ ), 6.73 (d, 1 H, J = 8.3 Hz, Ar), 6.82 (d, 1 H, J = 2.2 Hz, Ar), 7.01 (dd, 1 H, J = 8.3 Hz, 2.2Hz, Ar) ¹³ C NMR (100MHz, CDCI ₃ ), δ _c 25.8, 28.5, 30.1 , 32.3, 43.1 , 46.5, 49.3, 53.3, 55.8, 61.9, 108.1 , 108.8, 116.2, 121.4, 127.2, 127.4, 136.9, 156.4 MS (ES+), [M + H] ⁺ (100), 516.3 HRMS calculated for 516.3437 C ₂₉ H ₄₆ O ₅ N ₃ , found 516.3433. Elemental analysis C: 68.20, H: 8.71 , N: 2.92 (required values C: 68.18, H: 8.69, N: 2.94).

4-[(10S,13R)-10-isopropyl-13-methyl-7,8,15,16-tetraoxadis piro[5.2.5.2]hexadec-3-yl]-2- (morpholin-4-ylmethyl)phenol 20

(White foam, 48%) Mpt. 58-60 ⁰ C ¹ H NMR (400MHz, CDCI ₃ ) δ _H 0.92 (dd, 6H, J = 7.2 Hz, CH ₃ ), 0.98 (dd, 3H, J = 3.4 Hz, 6.4Hz, 14.4Hz, CH ₃ ), 1.40-1.91 (m, 15H, CH ₂ /CH), 2.30-2.40 (m, 1 H, CH), 2.58 (t, 4H, J = 3.8 Hz, morpholinyl), 3.18-3.24 (m, 2H, CH), 3.67 (s, 2H, ArCH ₂ ), 3.75 (t, 4H, J = 3.8 Hz, CH ₂ O), 6.75 (dd, 1 H, J = 2.1 Hz, 8.3 Hz, Ar), 6.84 (pseudo t, 1 H, J = 2.3 Hz, Ar), 7.01 (dd, 1 H, J = 2.1 Hz, 8.3 Hz, Ar), 10.2 (bs, 1H, OH) ¹³ C NMR (100MHz, CDCI ₃ ), δ _c 25.0, 29.4, 29.9, 30.3, 30.7, 32.4, 35.0, 39.5, 43.0, 50.4, 53.4, 62.4, 67.2, 108.0, 111.7, 116.3, 127.4, 127.7, 137.2, 156.2 MS (ES+), [M + H] ⁺ (100), 476.4 HRMS calculated for 476.3012 C ₂₇ H ₄₂ O ₆ N, found 476.2966. Elemental analysis C: 68.21 , H: 8.77, N: 3.01 (required values C: 68.18, H: 8.69, N: 2.94).

4-[(10S,13R)-10-isopropyl-13-methyl-7,8,15,16-tetraoxadis piro[5.2.5.2]hexadec-3-yl]-2- (piperidin-i-ylmethyl)phenol 21

(White powder, 57%) Mpt. 56-58 ⁰ C ¹ H NMR (400MHz, CDCI ₃ ) δ _H 0.92 (dd, 6H, J = 7.6 Hz, 15.1 Hz, CH ₃ ), 0.98 (dd, 3H, J = 3.4 Hz, 6.6 Hz, CH ₃ ), 1.40-1.91 (m, 23H), 2.30-2.43 (m, 1 H, CH), 2.50-2.60 (m, 2H ₁ piperidinyl), 3.17-3.28 (m, 2H, CH), 3.63 (s, 2H, ArCH ₂ ), 6.73 (dd, 1 H, J = 2.10Hz, 8.3 Hz, Ar), 6.81 (pseudo t, 1 H, J = 2.4 Hz, Ar), 7.0 (dd, 1 H, J = 2.0 Hz, 8.3Hz, Ar), 7.7 (bs, 1 H, OH) ¹³ C NMR (100MHz, CDCI ₃ ), δ _c 19.3, 21.9, 24.4, 26.3, 29.4, 30.1 , 32.4, 35.0, 39.5, 43.1 , 50.4, 62.7, 108.0, 111.7, 116.2, 121.8, 127.0, 127.2, 136.7, 156.7 MS (ES+), [M + H] ⁺ (100), 474.3 HRMS calculated for 474.3219 C ₂₈ H ₄₄ O ₅ N, found 474.3206. Elemental analysis C: 69.98, H: 9.16, N: 3.01 (required values C: 71.00, H: 9.15, N: 2.96).

4-[(10S,13R)-10-isopropyl-13-methyl-7,8,15,16-tetraoxadis piro[5.2.5.2]hexadec-3-yl]-2- [(4-methylpiperazin-1-yl)methyl]phenol 22

(White powder, 36%) Mpt. 56-58 ⁰ C ¹ H NMR (400MHz, CDCI ₃ ) δ _H 0.91 (dd, 6H, J = 7.5 Hz, 15.0Hz, CH ₃ ), 0.97 (dd, 3H, J = 3.2 Hz, 6.5Hz, CH ₃ ), 1.40-1.91 (m, 15H, CH/CH ₂ ), 2,31 (s, 3H, NCH ₃ ), 2.45-2.90 (m, 9H, CH/CH ₂ ), 3.16-3.28 (m, 2H, CH) ₁ , 3.68 (s, 2H, ArCH ₂ ), 6.74 (dd, 1 H, J = 2.2 Hz, 8.3Hz, Ar), 6.84 (pseudo t, 1 H, 2.4 Hz, Ar), 7.01 (dd, 1 H, J = 2.0Hz, 8.3 Hz, Ar) ¹³ C NMR (100MHz, CDCI ₃ ), δ _c 19.3, 21.9, 22.3, 24.9, 25.0, 29.4, 32.4, 35..0, 39.5, 43.0, 46.3, 50.3, 52.9, 55.3, 62.0,108.8, 11.7, 116.2, 121.4, 127.3, 127.5, 137.0, 156.3 MS (ES+), [M + H] ⁺ (100), 489.3 HRMS calculated for 489.3328 C ₂₈ H ₄₅ O ₅ N ₂ , found 489.3353. Elemental analysis C: 69.03, H: 9.10, N: 5.72 (required values C: 68.82, H: 9.08, N: 5.73).

4-[(10S,13R)-10-isopropyl-13-methyl-7,8,15,16-tetraoxadis piro[5.2.5.2]hexa-dec-3-yl]-2- (pyrrolidin-i-ylmethyl)phenol 23

(White powder, 43%) Mpt. 52-54 ⁰ C ¹ H NMR (400MHz, CDCI ₃ ) δ _H 0.92 (dd, 6H, J = 6.5 Hz, 15.3Hz, CH ₃ ), 0.98 (dd, 3H, J = 3.4 Hz, 6.6 Hz, CH ₃ ), 1.40-1.82(m, 15H, CH/CH ₂ ), 1.86 (bs, 4H, pyrrolidinyl), 2.44-2.55 (m, 1 H, CH), 2.62 (bs, 4H, pyrrolidinyl), 3.18-3.24 (m, 2H, CH) ₁ , 3.80 (s, 2H, ArCH ₂ ), 6.74 (dd, 1 H, J = 2.0Hz, 8.3H, Ar, 6.83 (pseudo t, 1 H, J = 2.4 Hz, Ar), 7.0 (dd, 1 H, J = 2.0 Hz, 8.3 Hz, Ar) ¹³ C NMR (100MHz, CDCI ₃ ), δ _c 19.3, 21.9, 22.3, 24.0, 25.0, 29.5, 32.4, 35.0, 39.5, 43.0, 50.3, 53.9, 59.3, 108.0, 111.7, 116.2, 122.6, 126.5, 127.3, 136.6, 156.6. MS (ES+), [M + H] ⁺ (100), 460.2 HRMS calculated for 460.3063 C ₂₇ H ₄₂ O ₅ N, found 460.3062. Elemental analysis C: 70.57, H: 9.12, N: 3.10 (required values C: 70.56, H: 8.99, N: 3.05).

4-(dispiro[cyclohexane-1,3'-[1,2,4,5]tetroxane-6',2"-tric yclo[3.3.1.13,7]decan]-4-yl)-2- [(4-isobutylpiperazin-1-yl)methyl]phenol 24

(White powder, 60%) Mpt. 74-76 ⁰ C ¹ H NMR (400MHz, CDCI ₃ ) δ _H 0.89 (d, 6H, J = 6.6 Hz, CH ₃ ), 1.5602.07 (m, 23H), 2.09 (d,, 2H, J =7.4 Hz, NCH ₂ ), 2.30-2.73 (m, 9H, CH/piperazinyl), 3.66 (S, 2H, ArCH ₂ ), 6.73 (d, 1 H, J = 8.3 Hz, Ar), 6.73 (d, 1H, J =2.1 Hz, Ar), 7.01 (dd, 1 H, J = 2.1 Hz, , 8.3Hz, Ar) ¹³ C NMR (100MHz, CDCI ₃ ), δ _c 21.3, 25.8, 27.5, 30.4, 33.6, 37.4, 43.2, 53.0, 53.7, 62.0, 67.1 , 108.0, 110.9, 116.2, 121.5, 127.2, 127.4, 136.9, 156.5. MS (ES+), [M + H] ⁺ (100), 527.4 HRMS calculated for 527.3485 C ₃₁ H ₄₇ O ₅ N ₂ , found 527.3485. Elemental analysis C: 70.71 , H: 8.82, N: 5.54 (required values C: 70.69, H: 8.80, N: 5.32).

4-(dispiro[cyclohexane-1 ,3'-[1 ,2,4,5]tetroxane-6',2"-tricyclo[3.3.1.13,7]decan]-4-yl)-2- {[4-(pyrimidin-2-yl)piperazin-1-yl]methyl}phenol 25

(White powder, 53%) Mpt. 78-80 ⁰ C ¹ H NMR (400MHz, CDCI ₃ ) δ _H 1.55-2.06 (m, 22H), 2.45- 2.90 (m, 9H, CH/piperazinyl), 3.72 (s, 2H, ArCH ₂ ), 6.53 (t, 1H, J = 4.8 Hz, Ar), 6.78 (d, 1 H, J = 8.3 Hz, Ar), 6.87 (d, 1H, J = 1.6 Hz, Ar), 7.01 (dd, 1H, J = 1.6Hz, 8.3Hz, Ar), 8.3 (d, 2H, J = 4.8 Hz, Ar), 10.4 (bs, 1 H, OH) ¹³ C NMR (100MHz, CDCI ₃ ), δ _c 27.5, 30.1 , 33.6, 37.4, 43.2, 43.9, 52.9, 54.9, 62.2, 108.0, 110.6, 111.0, 116.4, 121.2, 127.3, 127.7, 137.2, 156.3, 158.2, 161.9. MS (ES+), [M + H] ⁺ (100), 549.4 HRMS calculated for549.3077 C _3I H ₄₁ O ₅ N ₄ , found549.3090. Elemental analysis C: 67.87, H: 7.37, N: 10.23 (required values C: 67.86, H: 7.35, N: 10.21 ).

2-(1,4'-bipiperidin-1 ^l -ylmethyl)-4-(dispiro[cyclohexane-1,3 ^l -[1,2,4,5]tetroxane-6 ^l ,2"- tricyclo[3.3.1.13,7]decan]-4-yl)phenol 26

(White powder, 46%) Mpt. 76-78 ⁰ C ¹ H NMR (400MHz, CDCI ₃ ) δ _H 1.40-2.11 (m, 32), 2.30- 2.40(m, 2H, CH), 2.45-2.58(m, 6H, CH ₂ ), 3.05(dt, 2H, J = 11.6 Hz, CH ₂ ), 3.62(s, 2H ₁ ArCH ₂ ), 6.73 (d, 1H, J = 8.3 Hz, Ar), 6.81 (d, 1H, J = 2.2 Hz, Ar), 7.0 (dd, 1H, J = 8.3 Hz, 2.2 Hz, Ar) ¹³ C NMR (100MHz, CDCI ₃ ), δ _c 25.1 , 26.7, 27.5, 28.2, 30.1 , 33.6, 37.4, 43.2, 50.6, 53.3, 62.0, 62.7, 108.0, 110.9, 116.2, 121.8, 127.0, 127.4, 136.8, 156.6 MS (ES+), [M + H] ⁺ (IOO), 553.4 HRMS calculated for 553.3641 C ₃₃ H ₄₉ O ₅ N ₂ , found 553.3656. Elemental analysis C: 71.70, H: 8.76, N: 5.09 (required values C: 71.71 , H: 8.75, N: 5.07).

4-(dispiro[cyclohexane-1,3'-[1,2,4,5]tetroxane-6',2"-tric yclo[3.3.1.13,7]decan]-4-yl)-2- {[4-(pyrrolidin-1-yl)piperidin-1-yl]methyl}phenol 27

(White powder, 52%) Mpt. 86-88 ⁰ C ¹ H NMR (400MHz, CDCI ₃ ) δ _H 1.56 -2.77 (m, 32H), 2.45- 2.54 (m, 2H, CH) ₁ 2.65 (bs, 4H ₁ CH ₂ ), 3.0 (dt, 2H, J = 11.3 Hz, CH ₂ ), 3.64 (s, 2H ₁ ArCH ₂ ), 6.73 (d, 1 H, J = 8.3 Hz, Ar), 6.81 (d, 1 H, J = 2.0 Hz, Ar), 7.01 (dd, 1 H, J = 8.3 Hz ₁ Ar) ¹³ C NMR (100MHz ₁ CDCI ₃ ), δ _c 23.7, 27.5, 30.1 , 31.1 , 33.6, 37.4, 43.2, 51.6, 62.0, 108.0, 110.9, 116.3, 121.7, 127.0, 127.4, 136.8, 156.6 MS (ES+), [M + H] ⁺ (IOO) ₁ 539.3 HRMS calculated for 539.3485 C ₃₂ H ₄₇ O ₅ N ₂ , found 539.3475. Elemental analysis C: 71.38, H: 8.59, N: 5.18 (required values C: 71.34, H: 8.61 , N: 5.20).

4-(dispiro[cyclohexane-1 ,3'-[1 ,2,4,5]tetroxane-6',2"-tricyclo[3.3.1.13,7]decan]-4-yl)-2- ({[2-(morpholin-4-yl)ethyl]amino}methyl)phenol 28

(White foam, 56%) Mpt. 60-62 ⁰ C ¹ H NMR (400MHz, CDCI ₃ ) δ _H 1.56-2.20 (m, 22H), 2.50 (t, 4H, J = 4.6 Hz, morpholinyl), 2.60 (t, 2H ₁ J = 6.7 Hz, CH ₂ N) ₁ 2.93 (t, 2H, J = 6.7 Hz, NCH ₂ ), 3.06-3.11 (m, 1 H, CH) ₁ 3.72 (t, 4H ₁ J = 4.6 Hz ₁ morpholinyl), 4.10 (s, 2H, NCH ₂ ), 6.75 (d, 1 H, J = 8.4 Hz, Ar), 6.81 (d, 1 H, J = 2.1 Hz ₁ Ar), 7.0 (dd, 1 H, J = 2.1 Hz ₁ 8.4 Hz, Ar) ¹³ C NMR (100MHz ₁ CDCI ₃ ), δ _c 26.2, 27.5, 31.3, 33.6, 36.2, 41.6, 48.6, 54.4, 67.2, 107.9, 110.9, 116.6, 120.3, 126.0, 126.6, 138.5, 152.9 MS (ES+), [M + H] ⁺ (100), 515.4 HRMS calculated for 515.3121 C ₂₉ H ₄₃ O ₆ N ₂ , found 515.3098. Elemental analysis C: 67.70, H: 8.22, N: 5.43 (required values C: 67.68, H: 8.23, N: 5.44). 4-(dispiro[cyclohexane-1 ,3'-[1 ,2,4,5]tetroxane-6 ^l ,2"-tricyclo[3.3.1.13,7]decan]-4-yl)-2- (morpholin-4-ylmethyl)phenol 29

(White powder, 42%) Mpt. 176-178 ⁰ C ¹ H NMR (400MHz, CDCI ₃ ) δ _H 1.58-2.09 (m, 22H), 2.44-2.62 (m, 5H, CH/CH ₂ ), 3.66 (s, 2H, ArCH ₂ ), 3.74 (bs, 4H, CH ₂ O), 6.76 (d, 1 H, J = 8.3 Hz, Ar), 7.03 (dd, 1 H, J = 2.1 Hz, 8.3 Hz, Ar), 10.40 (bs, 1 H, OH) ¹³ C NMR (100MHz, CDCI ₃ ), δ _c 27.5, 30.4, 33.6, 34.7, 37.4, 43.1, 53.4, 62.4, 67.2, 108.0, 110.9, 116.3, 120.9, 127.4, 127.7, 137.2, 156.1 MS (ES+), [M + H] ⁺ (IOO), 472.3 HRMS calculated for 472.2699 C ₂₇ H ₃₈ O ₆ N, found 472.271. Elemental analysis C: 68.82, H: 7.97, N: 2.90 (required values C: 68.77, H: 7.91 , N: 2.97).

^(dispiroIcyclohexane-i.r-II^.^Sltetroxane-e'^'^tricycloi a.a.i.iSJldecanl-A-yl)^- {[4-(4-methylpiperazin-1-yl)piperidin-1-yl]methyl}phenol 30

(White powder, 43%) Mpt. 118-120 ⁰ C ¹ H NMR (400MHz, CDCI ₃ ) δ _H 1.53-2.13 (m, 30H), 2.31 (s, 3H, NCH ₃ ), 2.44-2.55 (m, 4H, CH/CH ₂ ), 2.62 (bs, 4H, CH ₂ N), 3.04 (dt, 2H, J = 12.1 Hz, CH ₂ ), 3.64 (s, 2H, ArCH ₂ ), 6.72 (d, 1 H, J = 8.3 Hz, Ar), 6.79 (d, 1 H, J = 2.2 Hz, Ar), 7.0 (dd, 1 H, J = 8.3Hz, 2.2 Hz, Ar) ¹³ C NMR (100MHz, CDCI ₃ ), δ _c 27.5, 28.6, 33.6, 37.4, 43.2, 46.3, 49.3, 53.0, 55.7, 61.9, 108.0, 110.9, 116.2, 121.7, 127.0, 127.4, 136.9, 156.6. MS (ES+), [M + H] ⁺ (100), 568.5 HRMS calculated for 568.3726 C ₃₃ H ₅₀ O ₅ N ₃ , found 568.3728. Elemental analysis C: 69.83, H: 8.72, N: 7.39 (required values C: 69.81 , H: 8.70, N: 7.40).

4-(dispiro[cyclohexane-1,3 ^l -[1,2,4,5]tetroxane-6 ^l ,2"-tricyclo[3.3.1.13,7]decan]-4-yl)-2- (pyrrolidin-i-ylmethyl)phenol 31

(White powder, 32%) Mpt. 144-146 ⁰ C ¹ H NMR (400MHz, CDCI ₃ ) δ _H 1.56-2.09 (m, 26H), 2.45-2.55 (m, 1 H, CH), 2.65 (bs, 4H, NCH ₂ ), 3.80 (s, 2H, ArCH ₂ ), 4.70 (s, 1 H, OH), 6.75 (d, 1 H, J = 8.3 Hz, Ar), 6.84 (d, 1 H, J = 2.2 Hz, Ar), 7.01 (dd, 1 H, J = 8.3Hz, 2.2 Hz, Ar) ¹³ C NMR (100MHz, CDCI ₃ ), δ _c 24.0, 27.5, 30.1 , 33.6, 36.2, 37.4, 43.2, 53.9, 59.0, 108.0, 110.8, 116.4, 122.3, 127.7, 127.6, 136.8, 156.6 MS (ES+), [M + H] ⁺ (IOO), 456.3 HRMS calculated for 456.2750 C ₂₇ H ₃₈ O ₅ N, found 456.2758. Elemental analysis C: 71.20, H: 8.22, N: 3.08 (required values C: 71.18, H: 8.19, N: 3.07).

4-(dispiro[cyclohexane-1,3 ^l -[1,2,4,5]tetroxane-6 ^l ,2"-tricyclo[3.3.1.13,7]decan]-4-yl)-2- (piperidin-i-ylmethyl)phenol 32

(White powder, 55%) Mpt. 158-160 ⁰ C ¹ H NMR (400MHz, CDCI ₃ ) δ _H 1.42-2.10 (m, 32H), 2.45-2.55 (m, 1 H, CH), 3.62 (s, 2H, ArCH ₂ ), 6.72 (d, 1H ₁ J = 8.3Hz, Ar), 6.81 ( d, 1 H, J = 2.2 Hz, Ar), 6.99 (dd, 1 H, J = 8.3Hz, 2.2 Hz, Ar) ¹³ C NMR (100MHz, CDCI ₃ ), δ _c 19.51 , 22.48, 24.3, 25.6, 28.4, 31.6, 35.5, 41.3, 58.9, 60.8, 106.1 , 108.9, 114.9, 125.1 , 125.3, 134.8, 154.8 MS (ES+), [M + H] ⁺ (100),470.3 HRMS calculated for470.2906 C ₂₈ H ₄₀ O ₅ N, found470.2904. Elemental analysis C: 71.62, H: 8.38, N: 3.01 (required values C: 71.61 , H: 8.37, N: 2.98).

4-(dispiro[cyclohexane-1,3'-[1,2,4,5]tetroxane-6 ^I ,2"-tricyclo[3.3.1.13,7]decan]-4-yl)-2- [(4-methylpiperazin-1-yl)methyl]phenol 33

(White powder, 61%) Mpt. 154-156 ⁰ C ¹ H NMR (400MHz, CDCI ₃ ) δ _H 1.56-2.10 (m, 30H), 2.30(s, 3H, CH ₃ ), 2.44-2.55(m , 1 H, CH), 3.68 (s, 2H, ArCH ₂ ), 6.73 (d, 1H, J = 28.3Hz, Ar), 6.84 (d, 1 H, J = 2.2Hz, Ar), 7.10 (dd, 1 H, J = 8.3 Hz, 2.2 Hz, Ar) ¹³ C NMR (100MHz, CDCI ₃ ), δ _c 27.1 , 29.7, 32.0, 33.2, 37.0, 42.8, 45.8, 52.5, 54.9, 55.2, 61.5107.6, 110.5, 115.8, 120.9, 126.8, 127.1 , 136.6, 155.9 MS (ES+), [M + H] ⁺ (IOO), 485.3 HRMS calculated for 485.3015 C ₂₈ H ₄ i0 ₅ N ₂ , found 485.3010. Elemental analysis C: 69.42, H: 8.34, N: 5.79 (required values C: 69.39, H: 8.32, N: 5.78).

4-(dispiro[cyclohexane-1,3 ^l -[1,2,4,5]tetroxane-6',2"-tricyclo[3.3.1.13,7]decan]-4 -yl)-2- {[4-(morpholin-4-yl)piperidin-1-yl]methyl}phenol 34

(White powder, 48%) Mpt. 140-142 ⁰ C ¹ H NMR (400MHz, CDCI ₃ ) δ _H 1.52-2.13 (m, 28H), 2.21-2.30 (m, 1 H, CH) ₁ 2.45-2.51 (m, 1 H, CH), 2.54 (t, 4H, J = 4.8 Hz, NCH ₂ ), 3.04 (dt, 2H, J = 11.3 Hz, CH ₂ ), 3.64 (s, 2H, ArCH ₂ ), 3.72 (t, 4H, J = 4.8 Hz, CH ₂ O) ₁ 6.73 (d, 1 H, J = 8.3 Hz, Ar), 6.81 (d, 1 H, J = 2.2 Hz, Ar), 7.01 (dd, 1 H, J = 8.3 Hz, Ar) ¹³ C NMR (100MHz, CDCI ₃ ), δ _c 27.1 , 28.1 , 29.9, 33.2, 37.0, 42.8, 49.8, 52.5, 61.6, 67.3, 107.6, 110.5, 115.8, 121.3, 126.6, 127.1 , 136.8, 156.2. MS (ES+), [M + H] ⁺ (100), 555.4 HRMS calculated for 555.3434 C ₃₂ H ₄₇ O ₆ N ₂ , found 555.3431. Elemental analysis C: 69.32, H: 8.37, N: 5.07 (required values C: 69.29, H: 8.36, N: 5.05).

2-[(diethylamino)methyl]-4-(dispiro[cyclohexane-1,3'-[1,2 ,4,5]tetroxane-6',2"- tricyclo[3.3.1.13,7]decan]-4-yl)phenol 35

(White powder, 55%) ¹ H NMR (400 MHz, CDCI ₃ ) δ _H 1.23 - 1.00 (m, 6H), 2.22 - 1.40 (m, 21 H), 2.55-2.40 (m, 1 H), 2.60 (q, J = 7.1 Hz, 4H), 3.43 - 3.04 (m, 2H), 3.72 (s, 2H, ArCH ₂ ), 6.71 (d, J = 8.2 Hz, 1 H, Ar), 6.82 (s, 1 H, Ar), 6.99 (dd, J = 8.2 Hz, 1 H, Ar), ¹³ C NMR (100 MHz, CDCI ₃ ) δ _c 11.6, 27.5, 30.2, 32.3, 33.6, 34.7, 37.4, 43.2, 46.7, 57.5, 77.10, 77.4, 77.7, 108.0, 110.9, 116.2, 122.3, 126.9, 127.2, 136.6, 157.0. MS (ES+), [M + H] ⁺ (100), 458.2 HRMS calculated for 458.2906 C ₂₇ H ₄₀ O ₅ N, found 458.2927.

4-(dispiro[cyclohexane-1,3 ^l -[1,2,4,5]tetroxane-6',2"-tricyclo[3.3.1.13,7]decan]-4 -yl)-2- {[4-(2-methoxyphenyl)piperazin-1-yl]methyl}phenol 46

4-(dispiro[cyclohexane-1,3'-[1,2,4,5]tetroxane-6',2"-tric yclo[3.3.1.13,7]decan]-4-yl)-2- {[4-(1-methylpiperidin-4-yl)piperazin-1-yl]methyl}phenol 47

¹ H NMR (400MHz, CDCI ₃ ) δ _H , 1.36-2.09 (m, 30H), 2.28 (s, 3H, CH ₃ ), 2.46-2.76 (m, 8H, NCH ₂ /CH ₂ N), 2.93 (dt, 2H, J = 11.8 Hz, CH), 3.66 (s, 2H, ArCH ₂ ), 6.72 (d, 1 H, J = 8.3 Hz, Ar) ₁ 6.84 (d, 1 H, J = 2.1 Hz, Ar), 7.01 (dd, 1 H, J = 2.1 Hz, 8.3 Hz, Ar)n ¹³ C NMR (100MHz, CDCI ₃ ), δ _c 27.5, 28.4, 33.6, 37.4, 43.2, 46.4, 49.3, 53.3, 55.7, 61.9, 108.0, 110.9, 116.2, 121.4, 127.2, 127.5, 137.0, 156.4 MS (ES+), [M + H] ⁺ (100) 568.2, HRMS calculated for 568.3750 C ₃₃ H ₅₀ O ₅ N ₃ , found 568.3724. Elemental analysis C: 69.32, H: 8.37, N: 5.07 (required values C: 69.29, H: 8.36, N: 5.05).

2,6-bis(pyrrolidin-1-ylmethyl)-4-(7,8,15,16-tetraoxadispi ro[5.2.5.2]hexadec-3-yl)phenol 36

¹ H NMR (400 MHz, CDCI ₃ ) δ _H 2.04 - 1.35 (m, 24H), 2.27 (s, 1 H), 2.39 (s, 1 H), 2.49 (m, 1 H), 2.62 (s, 8H), 3.25 (s, 1H), 3.73 (s, 4H, ArCH ₂ ), 6.90 (s, 2H), ¹³ C NMR (100 MHz, CDCI ₃ ) δ _c 22.2, 22.6, 24.0, 25.8, 30.0, 32.3, 43.1 , 54.1 , 56.8, 77.1 , 77.4, 77.8, 108.2, 108.7, 123.3, 127.1 , 136.1 , 155.0. MS (ES+), [M + H] ⁺ (100487.3 HRMS calculated for 487.3172 C ₂₈ H ₄₃ O ₅ N ₂ , found 487.3179. Elemental analysis C: 69.02, H: 8.68, N: 5.92 (required values C: 69.11, H: 8.70, N: 5.76).

Comopund 37

¹ H NMR (400 MHz, CDCI ₃ ) δ _H 2.01 - 1.39 (m, 16H), 2.26 (s, 1 H), 2.39 (s, 1 H), 2.50 (s, 9H), 3.26 (s, 1 H), 3.60 (s, 4H, ArCH ₂ ), 3.96 - 3.69 (m, 8H), 6.90 (s, 2H, Ar), ¹³ C NMR (101 MHz, CDCI ₃ ) δ _c 22.3, 22.7, 25.8, 30.1 , 32.3, 43.1 , 53.6, 59.9, 67.3, 77.1 77.4, 77.7, 108.1 , 108.8, 122.4, 127.9, 136.5, 154.8 MS (ES+), [M + H] ⁺ (IOO), 519.3 HRMS calculated for 519.3070 C ₂₈ H ₄₃ O ₇ N ₂ , found 519.3049. Elemental analysis C: 65.02, H: 8.27, N: 5.52 (required values C: 64.84, H: 8.16, N: 5.40).

2,6-bis(piperidin-1-ylmethyl)-4-(7,8,15,16-tetraoxadispir o[5.2.5.2]hexadec-3-yl)phenol 38

¹ H NMR (400 MHz, CDCI ₃ ) δ _H 2.00 - 1.60 (m, 28H), 2.25 (s, 1 H), 2.46 (s, 10H), 3.22 (s, 1 H), 3.55 (s, 4H, ArCH ₂ ), 6.78 (s, 2H, Ar), ¹³ C NMR (100 MHz, CDCI ₃ ) δ _c 22.2, 22.6, 24.6, 25.8, 26.3, 30.1 , 32.2, 43.2, 54.6, 60.2, 108.2, 108.7, 123.1 , 127.2, 135.8, 155.2. MS (ES+), [M + H] ⁺ (100), 515.4 HRMS calculated for 515.3485 C ₃₀ H ₄₇ O ₅ N ₂ , found 515.3506. Elemental analysis C: 69.98, H: 8.97, N: 5.51 (required values C: 70.01 , H: 9.01 , N: 5.44).

2,6-bis[(diethylamino)methyl]-4-(7,8,15,16-tetraoxadispir o[5.2.5.2]hexadec-3-yl)phenol 39

¹ H NMR (400 MHz, CDCI ₃ ) δ _H 1.25 (t, 12H, J = 7.2 Hz, CH ₃ ), 1.43-1.91 (m, 18H, CH ₂ ), 2.86 (q, 8H, J = 7.2 Hz, NCH ₂ ), 2.96-3.04 (m, 1H, CH), 3.98 (s, 4H, ArCH ₂ ), 6.96 (bs, 1 H, OH), 7.20 (s, 2H, Ar) ¹³ C NMR (100 MHz, CDCI ₃ ) δ _c , 10.3, 25.8, 30.0, 42.6, 46.3, 53.3, 53.8, 108.1 , 108.7, 129.9, 137.2, 156.4 MS (ES+), [M + H] ⁺ (100), 491.3 HRMS calculated for 491.3485 C ₂₈ H ₄₇ O ₅ N ₂ , found 491.3488.

2-(morpholin-4-ylmethyl)-6-(piperidin-1-ylmethyl)-4-(7,8, 15,16- tetraoxadispiro[5.2.5.2]hexadec-3-yl)phenol 40

¹ H NMR (400 MHz, CDCI ₃ ) δ _H 2.01 - 1.32 (m, 22H), 2.72 - 2.08 (m, 11H), 3.26 (s, 1 H), 3.55(s, 2H), 3.69 (s, 2H) ₁ 3.89 - 3.68 (m, 4H, ArCH ₂ ), 6.79 (d, J = 1.5 Hz, 1 H, Ar), 6.97 (d, J = 1.9 Hz, 1 H, Ar), ¹³ C NMR (100 MHz, CDCI ₃ ) δ _c 22.3, 22.6, 24.4, 25.8, 26.2, 30.0, 32.3, 43.1 , 53.9, 54.3, 58.3, 61.8, 67.4, 77.1 , 77.5, 77.8, 108.2, 108.8, 122.1 , 123.2, 126.7, 128.4, 136.0, 155.3. MS (ES+), [M + H] ⁺ (IOO), 517.3 HRMS calculated for 517.3278 C ₂₉ H ₄₅ O ₆ N ₂ , found 517.3276. Elemental analysis C: 66.98, H: 8.63, N: 5.56 (required values C: 67.41 , H: 8.58, N: 5.42). 4-(dispiro[cyclohexane-1,3 ^l -[1,2,4,5]tetroxane-6',2"-tricyclo[3.3.1.13,7]decan]-4 -yl)-2,6- bis(pyrrolidin-1-ylmethyl)phenol 42

¹ H NMR (400 MHz, CDCI ₃ ) δ _H 2.20-1.10 (m, 29H), 2.49 (m, 1 H), 2.70 (s, 8H), 3.21 (s, 1 H), 3.25 (s, 1H), 3.79 (s, 4H, ArCH ₂ ), 6.95 (s, 2H, Ar), ¹³ C NMR (100MHz ₁ CDCI ₃ ) δ _c 24.0, 27.5, 30.2, 32.4, 33.6, 34.7 37.4, 43.2, 54.1, 56.8, 108.1, 110.8, 123.3, 127.1, 136.1, 155.0. MS (ES+), [M + H] ⁺ (100), 539.4 HRMS calculated for 539.3485 C ₃₂ H ₄₇ O ₆ N ₂ , found 539.3470. Elemental analysis C: 71.30, H: 8.74, N: 5.22 (required values C: 71.34, H: 8.61 , N: 5.20).

4-(dispiro[cyclohexane-1 ,3'-[1 ,2,4,5]tetroxane-6\2"-tricyclo[3.3.1.13,7]decan]-4-yl)-2,6- bis(piperidin-1 -ylmethyl)phenol 43

¹ H NMR (400 MHz, CDCI ₃ ) δ _H 2.14 - 1.34 (m, 34H), 2.80-2.17 (m, 8H), 3.21 (s, 1 H), 3.25 (s, 1 H), 3.68 (S, 4H, ArCH ₂ ), 6.97 (s, 2H, Ar), ¹³ C NMR (100 MHz, CDCI ₃ ) δ _c 24.1 , 25.7, 27.5, 30.1 , 32.3, 33.6, 34.7, 37.4, 43.0, 54.1 , 59.5, 77.1 , 77.4, 77.8, 108.0, 110.9, 128.4, 136.4, 155.7. MS (ES+), [M + H] ⁺ (100), 567.4 HRMS calculated for 567.3798 C ₃₄ H _5I O ₅ N ₂ , found 567.3826. Elemental analysis C: 72.32, H: 8.76, N: 5.05 (required values C: 72.05, H: 8.89, N: 4.94).

4-(dispiro[cyclohexane-1 ,3'-[1 ,2,4,5]tetroxane-6\2"-tricyclo[3.3.1.13,7]decan]-4-yl)-2,6- bis(morpholin-4-ylmethyl)phenol 44

¹ H NMR (400 MHz, CDCI ₃ ) δ _H 1.82 (m, 20H), 2.54 (s, 10H), 3.21 (s, 1 H) ₁ 3.27 (s, 1H), 3.61 (s, 4H), 3.84 - 3.69 (m, 8H), 6.92 (s, 2H, Ar), ¹³ C NMR (101 MHz, CDCI3) δ _c 27.5, 30.2, 32.0, 33.6, 34.7, 37.4, 43.2, 53.6, 59.8, 67.2, 77.1 , 77.4, 77.7, 108.0, 110.9, 128.1 , 136.6, 154.8. MS (ES+), [M + H] ⁺ (IOO), 571.4 HRMS calculated for 571.3383 C ₃₂ H ₄₇ O ₇ N ₂ , found 571.3371. Elemental analysis C: 67.49, H: 8.33, N: 5.03 (required values C: 67.34, H: 8.12, N: 4.91 ).

4-(dispiro[cyclohexane-1,3 ^l -[1,2,4,5]tetroxane-6 ^> ,2"-tricyclo[3.3.1.13,7]decan]-4-yl)-2- (piperidin-1-ylmethyl)-6-(pyrrolidin-1-ylmethyl)phenol 45

¹ H NMR (400 MHz, CDCI ₃ ) δ _H 2.20 - 1.19 (m, 30H), 2.50 (m, 5H), 2.64 (s, 4H), 3.21 (s, 1 H), 3.25 (s, 1H), 3.60 (s, 2H, ArCH ₂ ), 3.73 (s, 2H, ArCH ₂ ), 6.82 (s, 1 H, Ar), 6.99 (s, 1 H, Ar), ¹³ C NMR (100 MHz, CDCI ₃ ) δ _c 23.9, 24.4, 26.1 , 27.5, 30.1 , 32.3, 33.6, 34.7, 37.4, 43.2, 54.2, 54.4, 55.6, 61.2, 108.1 , 110.9, 122.1 , 123.9, 126.9, 128.0, 136.1 , 155.1. MS (ES+), [M + H] ⁺ (100), 553.3 HRMS calculated for 553.3641 C ₃₃ H ₄₉ O ₅ N ₂ , found 553.3658. Elemental analysis C: 71.83, H: 8.83, N: 5.10 (required values C: 71.71 , H: 8.75, N: 5.07).

APPENDIX Il

Characterization Data For Tetroxane Amides Of General Formula (VIII)

Methyl-2-(4-spiro[adamantane-1',3-(1,2,4,5-tetraoxaspiro[ 5.5]undecan-9-yl)]phenoxy)- 2-methylpropanoate 48

¹ H NMR (400 MHz, CDCI ₃ ) δ ^~ _H , 0.9 - 2.10 (m, 28H), 2.52 - 2.58 (s, 1 H, CH), 3.77 (s, 3H, OCH ₃ ), 6.75 (d, 2H, J = 8.6 Hz, Ar), 7.08 (d, 2H, J = 8.6 Hz, Ar); ¹³ C NMR (100 MHz, CDCI ₃ ) δ _c 25.8, 27.6, 30.1 , 32.0, 33.6, 37.4, 39.7, 43.2, 47.4, 52.8, 79.4, 107.9, 110.9, 119.5, 127.8, 140.1 , 154.0, 175.4, MS (ES+), 495 [M + Na] ⁺ (100), HRMS calculated for 495.2359 C ₂₇ H ₃₆ O ₇ Na, found 495.2376.

2-(4-spiro[adamantane-1',3-(1,2,4,5-tetraoxaspiro[5.5]und ecan-9-yl)]phenoxy)-2- methylpropanoic acid 49

¹ H NMR (400 MHz, CDCI ₃ ) δ _H (ppm), 1.26 - 2.55 (m, 28H), 2.69 - 2.78 (m, 1 H, CH), 6.67 (d, 2H, J = 8.6 Hz Ar), 6.94 (d, 2H ₁ J = 8.6 Hz, Ar); (MS (ES+), 481.2 [M + Na] ⁺ (100), HRMS calculated for 481.2202 C ₂₆ H ₃₄ O ₇ Na, found 481.2217.

2-(4-spiro[adamantane-1',3-(1,2,4,5-tetraoxaspiro[5.5]und ecan-9-yl)]phenoxy)-2- methyl-1-morpholinopropan-1-one 50

¹ H NMR (400 MHz, CDCI ₃ ) δ _H , 1.54 - 2.56 (m, 28H), 2.54 - 2.56 (m, 1 H, CH), 2.58 (bs, 4H, morpholine), 3.64 (bs, 4H, morpholine), 6.75 (d, 2H, J 8.6 Hz, Ar), 7.08 (d, 2H, J 8.6 Hz, Ar); ¹³ C NMR (100 MHz, CDCI ₃ ) δ _c 23.1 , 26.5, 27.6, 32.0, 33.6, 37.4, 39.7, 43.1 , 47.4, 64.0, 81.0, 107.9, 110.9, 117.3, 128.0, 143.0, 152.7, 175.0; MS (ES+), 550.3 [M + Na] ⁺ (100), HRMS calculated for 550.2792 C ₃₀ H ₄₁ NO ₇ Na, found 550.2781.

2-(4-spiro[adamantane-1',3-(1,2,4,5-tetraoxaspiro[5.5]und ecan-9-yl)]phenoxy)-2- methyl-1-(4-methylpiperazin-1-yl)propan-1-one 51

¹ H NMR (400 MHz, CDCI ₃ ) δ _H , 1.55 - 2.05 (m, 28H), 2.15 (bs, 3H, NCH ₃ ), 2.25 - 2.33 (m, 4H, CH ₂ N), 2.50 - 2.60 (m, 1 H, CH), 3.66 (bs, 2H, NCH ₂ ), 3.85 (bs, 2H, NCH ₂ ), 6.74(d, 2H, J = 8.6 Hz, Ar), 7.07 (d, 2H, J = 8.6 Hz, Ar); ¹³ C NMR (100 MHz, CDCI ₃ ) δ _c 26.5, 27.5, 30.1 , 32.3, 33.6, 39.7, 43.2, 46.2, 53.8, 55.1 , 81.1 , 107.9, 110.9, 117.4, 128.0, 139.4 154.1 , 172.1 MS (ES+), 541.2 [M + H] ⁺ (100), HRMS calculated for 541.3278 C ₃₁ H ₄₅ N ₂ O ₆ , found 541.3268.

2-(4-spiro[adamantane-1',3-(1,2,4,5-tetraoxaspiro[5.5]und ecan-9-yl)]phenoxy)-2- methyl-1-(4-morpholinopiperidin-1-yl)propan-1-one 52

¹ H NMR (400 MHz, CDCI ₃ ) δ _H , 1.25 - 2.40 (m, 32H), 2.40 - 2.55 (m, 2H, CH), 2.87 - 2.93 (m, 4H, NCH ₂ ), 3.19 - 3.26 (m, 4H, NCH ₂ ), 4.70 - 4.77 (m, 4H, OCH ₂ ), 6.82 (d, 2H, J = 8.5 Hz, Ar), 7.12 (d, 2H, J = 8.5 Hz, Ar); ¹³ C NMR (100 MHz, CDCI ₃ ) δ _c , 26.8, 27.5, 27.8, 30.1 , 33.6, 36.7, 37.4, 39.7, 43.1 , 47.4, 49.7, 81.0, 107.9, 110.9, 117.3, 128.0, 139.2, 171.9, 219.0 MS (ES+), 611.5 [M + H] ⁺ (100), HRMS calculated for 611.3696 C ₃₅ H _5I N ₂ O ₇ , found 611.3687.

2-(4-spiro[adamantane-1',3-(1,2,4,5-tetraoxaspiro[5.5]und ecan-9-yl)]phenoxy)-N-(4,4- difluorocyclohexyl)-2-methylpropanamide 53

¹ H NMR (400 MHz, CDCI ₃ ) δ _H , 1.26 - 2.10 (m, 36H), 2.55 - 2.64 (m, 1 H, CH), 3.87- 3.99 (m, 1 H, CH), 6.64 (bs, 1 H, NH), 6.82 (d, 2H, J = 8.5 Hz, Ar), 7.12 (d, 2H, J = 8.5 Hz, Ar). ¹³ C NMR (100 MHz, CDCI ₃ ) δ _c , 23.1 , 25.3, 25.5, 27.5, 28.9, 31.9, 33.6, 37.4, 39.7, 43.2, 47.4, 81.7, 107.9, 110.9, 121.7, , 127.9, , 143.0, 152.7, 174.4, MS (ES+), 598.3 [M + Na] ⁺ (100), HRMS calculated for 598.2956 C ₃₂ H ₄₂ F ₂ NO ₆ Na, found 598.2960.

2-(4-spiro[adamantane-1',3-(1,2,4,5-tetraoxaspiro[5.5]und ecan-9-yl)]phenoxy)-2- methyl-1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)propan-1- one 54

¹ H NMR (400 MHz, CDCI ₃ ) δ _H , 0.86 - 2.17 (m, 32H), 2.34 (s, 3H, NCH ₃ ), 2.87 - 2.90 (m, 2H, CH), 3.49 (s, 8H, NCH ₂ ), 4.72 - 4.74 (m, 4H, NCH ₂ ), 6.77 (d, 2H, J = 8.6 Hz, Ar), 7.09 (d, 2H, J = 8.6 Hz, Ar); ¹³ C NMR (100 MHz, CDCI ₃ ) <5 _C , 23.1 , 27.5, 30.1 , 32.0, 33.6, 37.4, 42.9, 45.8, 48.5, 55.3, 61.9, 82.4, 107.9, 110.9, 117.3, 124.6, 127.9, 154.3, 171.9; MS (ES+), 624.4 [M + H] ⁺ (100), HRMS calculated for 624.4013 C ₃₆ H ₅₄ N ₃ O ₆ , found 624.3996.

1-([1,4'-bipiperidin]-1'-yl)-2-(4-spiro[adamantane-1',3-( 1, 2,4,5- tetraoxaspiro[5.5]undecan-9-yl)]phenoxy)-2-methylpropan-1-on e 55

¹ H NMR (400 MHz, CDCI ₃ ) δ _H , 1.26 - 2.30 (m,38H), 2.43 - 2.73 (m, 2H, CH), 2.81 - 2.92 (m, 4H, NCH ₂ ), 3.73 (t, 4H, J = 5 Hz, NCH ₂ ), 6.75 (d, 2H, J = 8.6 Hz, Ar), 7.08 (d, 2H, J = 8.6 Hz, Ar); ¹³ C NMR (100 MHz, CDCI ₃ ) δ _c , 23.1 , 25.9, 32.0, 33.5, 37.3, 42.9, 50.0, 51.2, 55.8, 63.5, 67.3, 80.9, 107.8, 110.9, 117.2, 128.0, 139.2, 154.3, 172.0; MS (ES+), 609.5 [M + H] ⁺ (100), HRMS calculated for 609.3904 C ₃₆ H ₅₃ N ₂ O ₆ , found 609.3921. 2-(4-spiro[adamantane-r,3-(1,2,4,5-tetraoxaspiro[5.5]undecan -9-yl)]phenoxy)-N- cyclopropyl-2-methylpropanamide 56

¹ H NMR (400 MHz ₁ CDCI ₃ ) δ _H , 0.40 - 0.47 (m, 2H, cyclopropyl), 0.69 - 2.72 (m, 2H, cyclopropyl), 1.14-2.16 (m, 28H), 2.47 - 2.53 (m, 1 H, CH), 2.68 - 2.72 (m, 1 H, CH), 6.69 (bs, 1H, NH), 6.74 (d, 2H, J = 8.6 Hz, Ar), 7.04(d, 2H, J = 8.6 Hz, Ar); ¹³ C NMR (100 MHz, CDCI ₃ ) δ _c , 6.8, 22.9, 25.4, 27.5, 27.8, 33.6, 39.7, 47.4, 53.8, 81.8, 107.9, 110.9, 121.7, 127.9, 141.3, 152.8, 176.7; MS (ES+), 520.4 [M + Na] ⁺ (100), HRMS calculated for 520.2675 C ₂₉ H ₃₉ NO ₆ Na, found 520.2667.

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