WO2004071389A2

WO2004071389A2 - Non-steroidal infalmmation inhibitors

Info

Publication number: WO2004071389A2
Application number: PCT/EP2004/001507
Authority: WO
Inventors: Michael David Barker; Derek Anthony Demaine; David House; Graham George Adam Inglis; Michael John Johnston; Haydn Terence Jones; Simon John Fawcett Macdonald; Iain Mcfarlane Mclay; Stephen Shanahan; Philip Alan Skone; Maria Victoria Vinader
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 2003-02-15
Filing date: 2004-02-13
Publication date: 2004-08-26
Anticipated expiration: 2005-08-15
Also published as: WO2004071389A3

Abstract

A compound of formula (I) wherein: n represents an integer 0, 1 or 2; X represents, O, S, NR6a, or CHR6b; R1 represents hydrogen, halogen such as F, Cl or Br, NO2, hydroxy, cyano, -OC1-6 alkoxy such as methoxy, C1-6 alkyl such as methyl, NR8R9 such as NH2, NR8COR9 such as -NHCHO or -NHCOCH3, COOR7 or CONR8R9; R2 represents hydrogen, halogen such as F, Cl, Br, NO2, hydroxy, cyano, -OC1-6 alkoxy such as methoxy, C1-6 alkyl such as methyl, NR8R9 such as NH2, NR8COR9 such as -NHCHO or -NHCOCH3, COOR7 or CONR8R9; R3 represents hydrogen, halogen such as F, Cl, Br, NO2, hydroxy, cyano, -OC1-6 alkoxy such as methoxy, C1-6 alkyl such as methyl, NR8R9 such as NH2, NR8COR9 such as -NHCHO or -NHCOCH3, COOR7, CONR8R9; R4 represents hydrogen, halogen such as F, Cl, Br, NO2, hydroxy, cyano, -OC1-6 alkoxy such as methoxy, C1-6 alkyl such as methyl, NR8R9 such as NH2, NR8COR9 such as -NHCHO or -NHCOCH3, COOR7 or CONR8R9; R5 represents H, C1-6 alkyl, or C1-6 alkenyl; R6a represents hydrogen, C1-6 alkyl, CO2C1-3 alkyl, COC1-3 alkyl or SO2C1-3 alkyl; R6b represents hydrogen, or C1-6 alkyl; R7 represents hydrogen, C1-6 alkyl, C1-3 alkyleneSiC1-3 alkyl such as -CH2CH2Si(CH3)3; R8 and R9 independently represent hydrogen or C1-6 alkyl; including pharmaceutically acceptable esters, amides and carbamates thereof, salts thereof, solvates thereof, and solvates of such pharmaceutically acceptable esters, amides, carbamates and salts.

Description

Compounds

The present invention relates to non-steroidal compounds and their manufacture and preparation of compositions containing said compounds for treatment, particularly for the treatment of inflammation.

Nuclear receptors are a class of structurally related proteins involved in the regulation of gene expression. The steroid hormone receptors are a subset of this family whose natural ligands typically comprise endogenous steroids such as estradiol (estrogen receptor), progesterone (progesterone receptor) and cortisol (glucocorticoid receptor). Man-made ligands to these receptors play an important role in human health, in particular the use of glucocorticoid agonists to treat a wide range of inflammatory conditions.

Glucocorticoids exert their actions at the glucocorticoid receptor (GR) through at least two intracellular mechanisms, transactivation and transrepression (see references 1 , 2, 3).

Transactivation involves direct binding of the glucocorticoid receptor to distinct deoxyribonucleic acid (DNA) response elements (GREs) within gene promoters, usually but not always increasing the transcription of the downstream gene product. Recently, it has been shown that GR can also regulate gene expression through an additional pathway (transrepression) where GR does not bind directly to DNA. This mechanism involves interaction of GR with other transcription factors, in particular NF-kB and AP-1 , leading to inhibition of their pro-transcriptional activity (2,3). Many of the genes involved in the inflammatory response are transcriptionally activated through the NF-kB and AP-1 pathways and therefore inhibition of this pathway by glucocorticoids may explain their anti-inflammatory effect (4, 5).

Despite the effectiveness of glucocorticoids in treating a wide range of conditions, a number of side-effects are associated with pathological increases in endogenous cortisol or the use of exogenous, and particularly systemically administered, glucocorticoids. These include reduction in bone mineral density (6), slowing of growth (7), skin bruising (8), development of cataracts (9) and dysregulation of lipid and glucose metabolism (10, 11). The side-effects are serious enough often to limit the dose of glucocorticoid that can be used to treat the underlying pathology leading to reduced efficacy of treatment.

It has been suggested that excessive activation of the transactivation-GRE pathway may mediate some of these side-effects (see 1). Development of glucocorticoids that selectively modulate the transrepression pathway compared with the transactivation pathway may therefore have a superior anti-inflammatory to side-effect therapeutic index, allowing more effective and safer treatment of the patient. This new class of glucocorticoids could be used to treat more effectively and more safely the whole spectrum of disease currently treated by current glucocorticoids.

Current known glucocorticoids have proved useful in the treatment of inflammation, tissue rejection, auto-immunity, various malignancies, such as leukemias and lymphomas, Cushing's syndrome, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, immune proliferation/apoptosis, HPA axis suppression and regulation, hypercortisolemia, modulation of the Th1 Th2 cytokine balance, chronic kidney disease, stroke and spinal cord injury, hypercalcemia, hypergylcemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia and Little's syndrome.

Glucocorticoids are especially useful in disease states involving systemic inflammation such as inflammatory bowel disease, systemic lupus erythematosus, polyarteritis nodosa, Wegener's granulomatosis, giant cell arteritis, rheumatoid arthritis, osteoarthritis, seasonal rhinitis, allergic rhinitis, urticaria, angioneurotic edema, chronic obstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis, organ transplantation, hepatitis and cirrhosis. Glucocorticoids have also been used as immunostimulants and repressors and as wound healing and tissue repair agents.

Glucocorticoids have also found use in the treatment of diseases such as inflammatory scalp alopecia, panniculitis, psoriasis, discoid lupus erythemnatosus, inflamed cysts, atopic dermatitis, pyoderma gangrenosum, pemphigus vulgaris, bullous pemphigoid, systemic lupus erythematosus, dermatomyositis, herpes gestationis, eosinophilic fasciitis, relapsing polychondritis, inflammatory vasculitis, sarcoidosis, Sweet's disease, type 1 reactive leprosy, capillary hemangiomas, contact dermatitis, atopic dermatitis, lichen planus, exfoliative dermatitus, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiform, cutaneous T-cell lymphoma.

WO00/32584 discloses certain non-steroidal anti-inflammatories which claim a clear distinction between anti-inflammatory and metabolic effects. WO02/10143 discloses certain non-steroidal compounds with advantageous anti-inflammatory effects.

The present invention provides alternative anti-inflammatory compounds of formula (I)

wherein:

n represents an integer 0, 1 or 2;

X represents, O, S, NR^6a, or CHR^6b; R¹ represents hydrogen, halogen such as F, Cl or Br, NO₂, hydroxy, cyano, -Od.₆ alkoxy such as methoxy, C^e alkyl such as methyl, NR⁸R⁹ such as NH₂, NR⁸COR⁹ such as -NHCHO or -NHCOCH₃, COOR⁷ or CONR⁸R⁹;

R² represents hydrogen, halogen such as F, Cl, Br, NO₂, hydroxy, cyano, -Od.₆ alkoxy such as methoxy, d.₆ alkyl such as methyl, NR⁸R⁹ such as NH₂, NR⁸COR⁹ such as -NHCHO or -NHCOCH₃, COOR⁷ or CONR⁸R⁹;

R³ represents hydrogen, halogen such as F, Cl, Br, NO₂, hydroxy, cyano, -Od.₆ alkoxy such as methoxy, d-₆ alkyl such as methyl, NR⁸R⁹ such as NH₂, NR⁸COR⁹ such as -NHCHO or -NHCOCH₃, COOR⁷, CONR⁸R⁹;

R⁴ represents hydrogen, halogen such as F, Cl, Br, NO_2> hydroxy, cyano, -Od.₆ alkoxy such as methoxy, Cι-₆ alkyl such as methyl, NR⁸R⁹ such as NH₂₎ NR⁸COR⁹ such as -NHCHO or -NHCOCH₃, COOR⁷ or CONR⁸R⁹;

R⁵ represents H, d.₆ alkyl, or d-₆ alkenyl;

R^6a represents hydrogen, Cι.₆ alkyl, CO₂d.₃ alkyl, COd.₃ alkyl or SO₂C₁.₃ alkyl;

R^6b represents hydrogen, or d.₆ alkyl;

R⁷ represents hydrogen, d.₆ alkyl, d.₃ alkyleneSid-₃ alkyl such as -CH₂CH₂Si(CH₃)₃;

R⁸ and R⁹ independently represent hydrogen or d.₆ alkyl;

including pharmaceutically acceptable esters, amides and carbamates thereof, salts thereof, solvates thereof, and solvates of such pharmaceutically acceptable esters, amides, carbamates and salts.

When used herein "alkyl" includes branched as well as straight chain alkyl and may also include cycloalkyl when 3 or more carbon atoms are present.

The compounds of formula (I) may provide advantageous selectivity in respect of maintaining transrepression activity whilst reducing the transactivation activity thereby providing anti-inflammatory properties with fewer or less severe related side effects.

Preferably n represents 1 or 2, more preferably 1.

Preferably X represents O, S or CHR^6b, more preferably CHR^6b.

Preferably R¹ is hydrogen. Preferably R² is hydrogen. Preferably R³ is hydrogen.

Preferably R⁴ represents a halogen or Ci-₆ alkyl, more preferably F, Cl, Br or methyl. Alternatively, R⁴ preferably represents hydrogen.

In some preferred embodiments, two of R to R₄ independently represent a halogen atom, preferably selected from F or Cl. Particularly preferred are those in which R^ represents F or Cl and either R₃ or R₄ represents F or Cl

Preferably R⁵ represents H or a Cι_₆ alkyl group, more preferably a d.₆ alkyl group such as methyl ethyl propyl or butyl, still, more preferably a Ci-β straight chain alkyl group

More preferably R⁵ represents ethyl, propyl or butyl and particularly n-propyl or n-butyl.

In other preferred embodiments R⁵ represents H. Preferably R^6b represents hydrogen.

The compounds of formula (I) include all enantiomers and diastereoisomers as well as mixtures thereof in any proportions. One enantiomer may be preferred to others.

Salts and solvates of compounds of formula (I) which are suitable for use in medicine are those wherein the counter-ion or associated solvent is pharmaceutically acceptable. However, salts and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts, solvates, and physiologically functional derivatives.

References to 'alkyl' includes references to both straight chain and branched chain It will be appreciated that references to alkylene and alkoxy shall be interpreted similarly.

Ci-₆ alkenyl shall be interpreted to mean C₂.₆ alkenyl.

References to 'aryl' herein include references to monocyclic carbocyclic aromatic rings (e.g. phenyl) and bicyclic carbocyclic aromatic rings (e.g. naphthyl) and references to 'heteroaryl' include references to mono- and bicyclic heterocyclic aromatic rings containing 1-4 heteroatoms selected from nitrogen, oxygen and sulphur. Examples of monocyclic heterocyclic aromatic rings include e.g. pyridinyl, pyrimidinyl, thiophenyl, furanyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, uracil or imidazolyl. References to 'heterocyclyP include references to mono- and bicyclic heterocyclic rings containing 1-4 heteroatoms selected from nitrogen, oxygen and sulphur. Examples of monocyclic heterocyclic rings include morpholinyl, piperizinyl and piperidinyl, and examples of bicyclic heterocyclic aromatic rings include e.g. benzimidazolyl, quinolinyl, phthalimide or indolyl.

The invention includes physiologically functional derivatives of the compounds of formula (I). By the term "physiologically functional derivative" is meant a chemical derivative of a compound of formula (I) having the same physiological function as the free compound of formula (I), for example, by being convertible in the body thereto and includes any pharmaceutically acceptable esters, amides and carbamates, salts, solvates of compounds of formula (I) and solvates of any pharmaceutically acceptable esters, amides and carbamates or salts of compounds of formula (I), which, upon administration to the recipient, are capable of providing (directly or indirectly) compounds of formula (I) or active metabolite or residue thereof.

Suitable salts according to the invention include those formed with both organic and inorganic acids or bases. Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, triphenylacetic, sulphamic, sulphanilic, succinic, oxalic, fumaric, maleic, malic, glutamic, aspartic, oxaloacetic, methanesulphonic, ethanesulphonic, arylsulphonic (for example p-toluenesulphonic, benzenesulphonic, naphthalenesulphonic or naphthalenedisulphonic), salicylic, glutaric, gluconic, tricarballylic, cinnamic, substituted cinnamic (for example, phenyl, methyl , methoxy or halo substituted cinnamic, including 4-methyl and 4-methoxycinnamic acid), ascorbic, oleic, naphthoic, hydroxynaphthoic (for example 1 - or 3-hydroxy-2-naphthoic), naphthaleneacrylic (for example naphthalene-2-acrylic), benzoic, 4-methoxybenzoic, 2- or 4-hydroxybenzoic, 4-chlorobenzoic, 4-phenylbenzoic, benzeneacrylic (for example 1,4- benzenediacrylic) and isethionic acids. Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine.

The compounds of formula (I) have potentially beneficial anti-inflammatory or anti-allergic effects, particularly upon topical administration, demonstrated by, for example, their ability to bind to the glucocorticoid receptor and to illicit a response via that receptor. Hence, the compounds of formula (I) are useful in the treatment of inflammatory and/or allergic disorders.

Examples of disease states in which the compounds of the invention have utility include skin diseases such as eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis and hypersensitivity reactions; inflammatory conditions of the nose, throat or lungs such as asthma (including allergen-induced asthmatic reactions), rhinitis (including hayfever), nasal polyps, chronic obstructive pulmonary disease, interstitial lung disease, and fibrosis; inflammatory bowel conditions such as ulcerative colitis and Crohn's disease; and autoimmune diseases such as rheumatoid arthritis.

It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established conditions.

As mentioned above, compounds of formula (I) are useful in human or veterinary medicine, in particular as anti-inflammatory and anti-allergic agents. There is thus provided as a further aspect of the invention a compound of formula (I) or a physiologically acceptable salt or solvate thereof for use in human or veterinary medicine, particularly in the treatment of patients with inflammatory and/or allergic conditions, such as rheumatoid arthritis, asthma, allergy or rhinitis.

According to another aspect of the invention, there is provided the use of a compound of formula (I) or physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of patients with inflammatory and/or allergic conditions, such as rheumatoid arthritis, asthma, allergy or rhinitis.

According yet to another aspect of the invention, there is provided the use of a compound of formula (I) or physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of patients with skin disease such as eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis and hypersensitivity reactions.

In a further or alternative aspect, there is provided a method for the treatment of a human or animal subject with an inflammatory and/or allergic condition, which method comprises administering to said human or animal subject an effective amount of a compound of formula (I) or physiologically acceptable salt or solvate thereof.

In yet a further or alternative aspect, there is provided a method for the treatment of a human or animal subject with for skin diseases such as eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis and hypersensitivity reactions, which method comprises administering to said human or animal subject an effective amount of a compound of formula (I) or physiologically acceptable salt or solvate thereof.

The compounds according to the invention may be formulated for administration in any convenient way, and the invention therefore also includes within its scope pharmaceutical compositions comprising a compound of formula (I) or physiologically acceptable salt or solvate thereof together, if desirable, in admixture with one or more physiologically acceptable diluents or carriers.

Further, there is provided a process for the preparation of such pharmaceutical compositions which comprises mixing the ingredients.

The compounds according to the invention may, for example, be formulated for oral, buccal, sublingual, parenteral, local rectal administration or other local administration.

Local administration as used herein, includes administration by insufflation and inhalation. Examples of various types of preparation for local administration include ointments, lotions, creams, gels, foams, preparations for delivery by transdermal patches, powders, sprays, aerosols, capsules or cartridges for use in an inhaler or insufflator or drops (e.g. eye or nose drops), solutions/suspensions for nebulisation, suppositories, pessaries, retention enemas and chewable or suckable tablets or pellets (e.g. for the treatment of aphthous ulcers) or liposome or microencapsulation preparations. Ointments, creams and gels, may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agent and/or solvents. Such bases may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil, or a solvent such as polyethylene glycol. Thickening agents and gelling agents which may be used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols, woolfat, beeswax, carboxypolymethylene and cellulose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifying agents.

Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents or thickening agents.

Powders for external application may be formed with the aid of any suitable powder base, for example, talc, lactose or starch. Drops may be formulated with an aqueous or non- aqueous base also comprising one or more dispersing agents, solubilising agents, suspending agents or preservatives.

Spray compositions may for example be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant. Aerosol compositions suitable for inhalation can be either a suspension or a solution and generally contain a compound of formula (I) and a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, especially 1 ,1 ,1 ,2-tetrafluoroethane, 1 ,1 ,1 ,2,3,3,3-heptafluoro-n-propane or a mixture thereof. The aerosol composition may optionally contain additional formulation excipients well known in the art such as surfactants e.g. oleic acid or lecithin and cosolvents e.g. ethanol.

Advantageously, the formulations of the invention may be buffered by the addition of suitable buffering agents.

Capsules and cartridges for use in an inhaler or insufflator, of for example gelatine, may be formulated containing a powder mix for inhalation of a compound of the invention and a suitable powder base such as lactose or starch. Each capsule or cartridge may generally contain between 20μg-10mg of the compound of formula (I). Alternatively, the compound of the invention may be presented without excipients such as lactose.

The proportion of the active compound of formula (I) in the local compositions according to the invention depends on the precise type of formulation to be prepared but will generally be within the range of from 0.001 to 10% by weight. Generally, however for most types of preparations advantageously the proportion used will be within the range of from 0.005 to 1% and preferably 0.01 to 0.5%. However, in powders for inhalation or insufflation the proportion used will be within the range of from 0.1 to 5%. Aerosol formulations are preferably arranged so that each metered dose or "puff" of aerosol contains 20μg to 10mg preferably 20μg-2000μg, more preferably about 20μg- 500μg of a compound of formula (I). Administration may be once daily or several times daily, for example 2, 3, 4 or 8 times, giving for example 1 , 2 or 3 doses each time. The overall daily dose with an aerosol will be within the range 100μg-1 Omg preferably, 200μg- 2000μg. The overall daily dose and the metered dose delivered by capsules and cartridges in an inhaler or insufflator will generally be double that delivered with aerosol formulations.

The particle size of the particular (e.g., micronised) drug should be such as to permit inhalation of substantially all the drug into the lungs upon administration of the aerosol formulation and will thus be less than 100 microns, desirably less than 20 microns, and, in particular, in the range of 1-10 microns, such as 1 to 5 microns, more preferably 2 to 3 microns.

The formulations of the invention may be prepared by dispersal of the medicament and a compound of formula (I) in the selected propellant in an appropriate container, for example, with the aid of sonication or a high-shear mixer. The process is desirably carried out under controlled humidity conditions.

The chemical and physical stability and the pharmaceutical acceptability of the aerosol formulations according to the invention may be determined by techniques well known to those skilled in the art. Thus, for example, the chemical stability of the components may be determined by HPLC assay, for example, after prolonged storage of the product. Physical stability data may be gained from other conventional analytical techniques such as, for example, by leak testing, by valve delivery assay (average shot weights per actuation), by dose reproducibility assay (active ingredient per actuation) and spray distribution analysis.

The suspension stability of the aerosol formulations according to the invention may be measured by conventional techniques, for example, by measuring flocculation size distribution using a back light scattering instrument or by measuring particle size distribution by cascade impaction or by the "twin impinger" analytical process. As used herein reference to the "twin impinger" assay means "Determination of the deposition of the emitted dose in pressurised inhalations using apparatus A" as defined in British Pharmacopaeia 1988, pages A204-207, Appendix XVII C. Such techniques enable the "respirable fraction" of the aerosol formulations to be calculated. One method used to calculate the "respirable fraction" is by reference to "fine particle fraction" which is the amount of active ingredient collected in the lower impingement chamber per actuation expressed as a percentage of the total amount of active ingredient delivered per actuation using the twin impinger method described above.

MDI canisters generally comprise a container capable of withstanding the vapour pressure of the propellant used such as a plastic or plastic-coated glass bottle or preferably a metal can, for example, aluminium or an alloy thereof which may optionally be anodised, lacquer-coated and/or plastic-coated (e.g. incorporated herein by reference WO96/32099 wherein part or all of the internal surfaces are coated with one or more fluorocarbon polymers optionally in combination with one or more non-fluorocarbon polymers), which container is closed with a metering valve. The cap may be secured onto the can via ultrasonic welding, screw fitting or crimping. MDIs taught herein may be prepared by methods of the art (e.g., see Byron, above and WO/96/32099). Preferably the canister is fitted with a cap assembly, wherein a drug-metering valve is situated in the cap, and said cap is crimped in place.

The metering valves are designed to deliver a metered amount of the formulation per actuation and incorporate a gasket to prevent leakage of propellant through the valve. The gasket may comprise any suitable elastomeric material such as, for example, low density polyethylene, chlorobutyl, black and white butadiene-acrylonitrile rubbers, butyl rubber and neoprene. Suitable valves are commercially available from manufacturers well known in the aerosol industry, for example, from Valois, France (e.g. DF10, DF30, DF60), Bespak pic, UK (e.g. BK300, BK357) and 3M-Neotechnic Ltd, UK (e.g. SpraymiserTM).

A further aspect of this invention comprises a process for filling the said formulation into MDIs.

Conventional bulk manufacturing methods and machinery well known to those skilled in the art of pharmaceutical aerosol manufacture may be employed for the preparation of large-scale batches for the commercial production of filled canisters. Thus, for example, in one bulk manufacturing method a metering valve is crimped onto an aluminium can to form an empty canister. The particulate medicament is added to a charge vessel and liquefied propellant is pressure filled through the charge vessel into a manufacturing vessel, together with liquefied propellant containing the surfactant. The drug suspension is mixed before recirculation to a filling machine and an aliquot of the drug suspension is then filled through the metering valve into the canister.

In an alternative process, an aliquot of the liquefied formulation is added to an open canister under conditions which are sufficiently cold to ensure formulation does not vaporise, and then a metering valve crimped onto the canister.

Typically, in batches prepared for pharmaceutical use, each filled canister is check- weighed, coded with a batch number and packed into a tray for storage before release testing.

Topical preparations may be administered by one or more applications per day to the affected area; over skin areas occlusive dressings may advantageously be used. Continuous or prolonged delivery may be achieved by an adhesive reservoir system.

For internal administration the compounds according to the invention may, for example, be formulated in conventional manner for oral, parenteral or rectal administration. Formulations for oral administration include syrups, elixirs, powders, granules, tablets and capsules which typically, contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, wetting agents, suspending agents, emulsifying agents, preservatives, buffer salts, flavouring, colouring and/or sweetening agents as appropriate. Dosage unit forms are, however, preferred as described below.

The compounds according to the invention may in general may be given by internal administration in cases where systemic adreno-cortical therapy is indicated.

Slow release or enteric coated formulations may be advantageous, particularly for the treatment of inflammatory bowel disorders.

In some preferred embodiments, the compounds of formula (I) will be formulated for oral administration. In other preferred embodiments the compounds of formula (I) will be formulated for inhaled administration.

The pharmaceutical compositions according to the invention may also be used in combination with another therapeutically active agent, for example, a β₂ adrenoreceptor agonist, an anti-histamine or an anti-allergic. The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof together with another therapeutically active agent, for example, a β₂-adrenoreceptor agonist, an anti-histamine or an anti-allergic.

Examples of β₂-adrenoreceptor agonists include salmeterol (eg as racemate or a single enantiomer such as the R-enantiomer), salbutamol, formoterol, salmefamol, fenoterol or terbutaline and salts thereof, for example the xinafoate salt of salmeterol, the sulphate salt or free base of salbutamol or the fumarate salt of formoterol. Long-acting β₂- adrenoreceptor agonists are preferred, especially those having a therapeutic effect over a 24 hour period such as salmeterol or formoterol.

Preferred long acting β₂-adrenoreceptor agonists include those described in WO 02066422, WO02070490, WO02076933, WO03024439 and WO03072539.

Especially preferred long-acting β₂-adrenoreceptor agonists include compounds of formula(A):

or a salt or solvate thereof, wherein: m is an integer of from 2 to 8; n is an integer of from 3 to 11 , with the proviso that m + n is 5 to 19, R²¹ is -XSO₂NR²⁶R²⁷ wherein X is -(CH₂)_P- or C₂.₆ alkenylene;

R²⁶ and R²⁷ are independently selected from hydrogen, C_halky!, C₃.₇cycloalkyl,

C(O)NR²⁸R²⁹, phenyl, and phenyl (Cι.₄alkyl)-, or R²⁶ and R²⁷, together with the nitrogen to which they are bonded, form a 5-, 6-, or 7- membered nitrogen containing ring, and R²⁶ and R²⁷ are each optionally substituted by one or two groups selected from halo, d.₆alkyl, d.₆haloalkyl, d.₆alkoxy, hydroxy- substituted d.₆alkoxy, -CO₂R²⁸, -SO₂NR²⁸R²⁹, -CONR ⁸R²⁹, -NR²⁸C(O)R²⁹, or a 5-, 6- or

7-membered heterocylic ring;

R²⁸and R²⁹are independently selected from hydrogen, d-₆alkyl,

C₃-₆cycloalkyl, phenyl, and phenyl (d_₄alkyl)-; and p is an integer of from 0 to 6, preferably from 0 to 4;

R²² and R²³ are independently selected from hydrogen, d.₆alkyl, d^alkoxy, halo, phenyl, and d-ehaloalkyl; and

R²⁴ and R²⁵ are independently selected from hydrogen and d^alkyl with the proviso that the total number of carbon atoms in R²⁴ and R²⁵ is not more than 4.

Examples of anti-histamines include methapyrilene or loratadine.

Other suitable combinations include, for example, other anti-inflammatory agents eg. NSAIDs (eg. PDE4 inhibitors, leukotriene antagonists, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine 2a agonists)) or antiinfective agents (eg. antibiotics, antivirals).

Processes according to the invention for the preparation of compounds of formula (I) comprise treatment of a compound of formula (II)

wherein n, X, R¹, R², R³, R⁴ and R⁵ are as defined above for compounds of formula (I) with a trifluoromethylating agent of formula (III)

CF₃R 10 (III)

wherein R represents an activating group , for example, trimethylsilyl (TMS).

The reaction will generally be performed in the presence of an inert solvent, such as dimethylformamide (DMF) and a base , such as caesium carbonate (Cs₂CO₃) at a non- extreme temperature, for example, 0-120°C, and more suitably at room temperature. Where R¹⁰ represents a trialkylsilyl group the final step may include deprotection using a suitable reagent, for example, when R¹⁰ is TMS it may be removed by treatment with TBAF (tetrabutylammonium fluoride) in tetrahydrofuran.

Alternative conditions with PhSCF , Et₃GeNa in HMPA ( Yokoyama, Y. and Mochida, K. Syn. Lett. 1997, 907-8) may also be suitable. Further alternative reagents include CF₃H, CF₃I, PhSOCF₃ and PhSO₂CF₃. Alternative methods featuring trifluoromethylating reagents are described in Prakash, G.K.S.; Hu, J; Olah, G.A. Org. Lett. 2003, 5, 3253-6 and Caron, S.; Do, N.M.; Arpin, P.; Larivee, A. Synthesis, 2003, 1693-98; Langlois, B.R. et al Synthesis 2003, 185-194 and further methods cited in these papers.

Alternatively, in a more preferred process, the reaction of compound of formula (II) and a compound of formula (III) wherein R¹⁰ represents TMS may be effected in a solvent such as DMF in the presence of excess lithium fluoride (LiF) or caesium fluoride (CsF) at a non-extreme temperature, for example, between room temperature and 100°C , preferably at room temperature, wherein the compound of formula (III) is present in a large excess Compounds of formula (II) may be prepared from compounds of formula (IV)

wherein n, X, R¹, R²,R³, R⁴ and R⁵ are as defined above for compounds of formula (I) after activation and treatment with 6-amino-4-methyl-1 H-2,3-benzoxazin-1 -one.

The reaction is generally effected in the presence of a suitable solvent, for example, dimethylacetamide or dimethylformamide in the presence of thionyl chloride or phosphorus oxychloride at a non-extreme temperature. For example, the reaction may be carried out in dimethylacetamide in the presence of thionyl chloride at a temperature of - 15 to 25°C such as -5°C

Compounds of formula (IV) may prepared from the compounds of the formula (Va)

wherein n, X, R¹, R², R³, R⁴ and R⁵ are as defined above for compounds of formula (I) and R¹¹ represents C₁.3 alkyl, by known methods, for example, treatment with an aqueous base, for example an inorganic base such as potassium hydroxide in the presence of an organic co-solvent such as methanol or ethanol at a non-extreme temperature, for example, 0- 100°C, preferably at room temperature.

Compounds of formula (Va) may be prepared from compounds of formula (Via)

wherein n, X, R\ R ,R³,R⁴ and R⁵ are as defined above for compounds of formula (I) using a compound of formula (Vila)

wherein

R¹² represents d.₃ alkyl, such as methyl; R¹³ represents C₁.₃ alkyl, such as methyl; and Si represents silicon.

The process may be performed in a suitable solvent, for example, a chlorinated solvent such as dichloromethane or chloroform at a reduced temperature, such as 0° to -70°C, and preferably at -70°C in the presence of a Lewis acid such as tin tetrachloride.

Compounds of formula (Vila) may be prepared according to J. Org. Chem 1997, 62, 2462.

Certain compounds of formula (Via) wherein X is CH₂, n is 1 and R¹, R², R³, R⁴ are H and R⁵ is Me or ethyl, may be prepared by treatment of α-tetralone with methyllithium or ethyl lithium or the corresponding Grignard reagents and cerium chloride at a non-extreme temperature, for example, 0 to -70°C. Typically a temperature such as -65°C in a suitable solvent, for example, an ethereal solvent such as THF is used. The reaction may be quenched using aqueous acid such as aqueous acetic acid.

Other compounds of formula (Via) may be prepared by analogous methods.

When R⁵ is H, compounds of formula (IV) may be prepared from the compounds of the formula (Vb)

wherein n, X, R¹, R², R³ and R⁴ are as defined above for compounds of formula (I) and R¹⁴ represents d.₆ alkyl, by known methods and in a two stage process. The first stage for example, involves treatment with aqueous acid, for example, an inorganic acid such as hydrochloric acid, perchloric acid or sulphuric acid with an organic solvent such as methanol or ethanol. Preferably the compound of formula Vb will be prepared using an aqueous organic acid such as aqueous trifluoroacetic acid at a non- extreme temperature, for example, 0-100°C, preferably at room temperature. The second stage involves treatment with aqueous base, for example sodium, potassium or lithium hydroxide in a co- solvent such as methanol or ethanol at a non-extreme temperature, for example, 0-100°C, and preferably at room temperature.

Compounds of formula (Vb) may be prepared from compounds of formula (Vlb)

wherein n, X, R¹, R²,R³ and R⁴ are as defined above for compounds of formula (I) using a

Wadsworth Emmons reaction. The process may be performed, for example, by treatment with

(CH₃CH₂O)₂POCH(OCH₂CH3)CO₂CH₂CH₃in the presence of a strong sterically hindered base such as LDA (lithium diisopropylamide) in a suitable ethereal solvent, for example diethyl ether or more preferably anhydrous THF (tetrahydrofuran) at a non-extreme temperature, -10 to 65, such as -10°C and subsequent warming to room temperature.

Compounds of formula (Vlb) may be prepared from α-tetralone by, for example, treatment with (methoxymethyl)triphenylphosphonium chloride in the presence of sodium bis(trimethylsilyl)amide in the presence of suitable solvent, for example, dioxan at a non- extreme temperature, for example, -10 to 65°C such as room temperature. The subsequent treatment with a catalytic or stoichiometric amount of acid, for example stoichiometric perchloric acid, in diethylether at a non-extreme temperature, for example, 0 to 35°C such as room temperature yields the desired compound.

An alternative process for the preparation of compounds of formula (I) comprises reduction of a compound of formula (lib)

wherein

R¹, R², R³, R⁴, X and n are as defined above for compounds of formula (I).

Reduction of the double bond efficiently and selectively is difficult to effect by simple hydrogenation or similar standard methods due to the presence of incompatible functionality. Suitable reagents for the effecting the reduction are disclosed by D.J. Pasto and R.T. Taylor in Organic Reactions 1991 , 40, 91-155.

Preferably the reduction is performed using an excess, such as up to 6 molar equivalents, of an aryl sulphonyl hydrazide, for example, 1 ,3,5-triisopropylbenzene sulphonylhydrazide, 1 ,3,5-trimethylbenzene sulphonylhydrazide or tosyl hydrazide at an elevated temperature, for example 100 to 250°C such as 150°C for a short period, for example 5 to 10 minutes. The reaction may be effected using a microwave at 70 Watts for 5 to 10 minutes. The process is usually performed in the absence of a solvent or in the presence of a small quantity of /V-methyl pyrrolidinone (NMP).

Preferably the reaction is effected in the presence of an excess of tosyl hydrazide optionally in the presence of Λ/-methyl pyrrolidinone. Compounds of formula (lib) may be prepared from a compound of formula (VIII)

by treatment with a compound of formula (IX)

wherein R¹, R², R³, R⁴, X and n are as defined above for compounds of formula (I) and — - represents an endocyclic double bond or exocyclic double bond.

The reaction may be effected in the presence of a Lewis acid such as titanium (IV) chloride at a non-extreme temperature, for example, between -5 and 25°C such as -5°C in a suitable solvent such as chlorobenzene.

Alternatively the process may be performed at an elevated temperature, for example, in the temperature range 100 to 250°C in the presence or absence of p-toluene sulphonic acid, preferably in the absence, in a suitable solvent, for example, dimethylformamide, dimethylsulphoxide or Λ/-methylpyrrolidinone. Preferably the solvent is N- methylpyrrolidinone.

Another alternative preferred process is where the reaction is performed as a melt in the absence of additional solvent at a temperature in the range 100°C to 250°C and preferably 160 to 200°C, preferably using a non-microwave based heat source. This latter process may provide improved yields.

This process provides an efficient way to rapidly prepare a large variety of compounds of formula (I) via (lib), from compounds of formula (VIII) and (IX).

The preparation of compounds of formula (VIII) has been attempted unsuccessfully using a variety of conditions.

Surprisingly it has now been found that these compounds may be successfully prepared by reacting a compound of formula (X)

with a trifluoromethylacetylating agent.

Usually the reaction is performed at a non-extreme temperature, for example 0-40°C such as room temperature in the absence of additional solvent. Suitable trifluoromethyl acetylating reagents may include trifluoroacetyl chloride, trifluoromethyl acetate or trifluoroacetic anhydride. The reaction may be effected by stirring for approximately 8 to 46 hours.

Preferably trifluoroacetic anhydride is used.

The process provides an efficient method of preparing compounds of formula (VIII) despite the insolubility of the compound of formula (X). Furthermore, the said method provides (VIII) in good yields.

Compounds of formula (X) may be prepared by reacting 4-methyl-1 -oxo-1 H-2,3- benzoxazin-6-ylformamide with a dehydrating agent, for example, trifluoromethanesulphonic anhydride or phosphorus oxychloride in a suitable solvent, for example, dioxan, DCM or THF in the presence of a sterically hindered base, for example, pyridine, diisopropylethylamine or triethylamine and also usually in the presence of a solubilising agent such as DMPU at a non-extreme temperature, for example, 0 to 65°C, preferably room temperature.

Preferably the dehydrating agent is phosphorus oxychloride. Preferably the base is triethylamine.

4-Methyl-1 -oxo-1 H-2,3-benzoxazin-6-ylformamide may be prepared from 6-amino-4- methyl-1 H-2,3-benzoxazin-1 -one (as disclosed in WO9854159) by reaction with a formylating agent, for example, an anhydride such as formyl acetic anhydride in a suitable aprotic solvent, such as DCM or DMPU, at a non-extreme temperature, for example 0 to 65°C such as room temperature.

Compounds of type (IX) where the double bond is exocyclic may be prepared from a compound of formula (XI)

wherein R¹, R², R³, R⁴, X and n are as defined above for compounds of formula (I) using the Tebbe reagent (μ-chloro-μ- methyIene[bis(cyclopentadienyl)titanium]dimethylaluminium) as described by S.H. Pine, G.S. Shen, H. Hoang in Synthesis 1991 , 165-167. Compounds of type (IX) where the double bond is endocyclic may also be made in this fashion if the double bond migrates from exocyclic to endocyclic during the course of the reaction.

Alternatively the reaction may be effected in the presence of a phosphonium salt such as methyltriphenylphosphonium bromide in a suitable solvent, for example, in an ethereal solvent such as diethyl ether or THF under inert conditions such as a nitrogen atmosphere and preferably anhydrous conditions, at a reduced temperature such as -78 to 0°C such as -78°C using a strong base, for example, lithium diisopropylamide or butyl lithium.

Preferably the base used is lithium diisopropylamide.

Many compounds of formula (XI) are commercially available or may be prepared by interconverting from commercially available compounds by known methods. Other compounds of formula (XI) where X represents CH₂ may be prepared by cyclisation of a compound of formula (XII)

wherein R¹, R², R³, R⁴, X and n are as defined above for compounds of formula (I) except where R¹ to R⁴ independently represent Br, and R¹⁵ represents hydrogen or Ci-₆ alkyl.

Cyclisation may be effected by dehydration with a suitable dehydrating agent, such as Eaton's reagent (phosphorus pentoxide and methane sulphonic acid) or more preferably with polyphosphoric acid at a non-extreme temperature, for example room temperature to 120°C, such as 90°C.

For the cyclisation process, compounds of formula (XII) wherein R 15 represents hydrogen are preferred and processes using compounds of this particular formula are also preferred because the compounds may be readily purified, for example, by liquid phase extraction into a basic aqueous phase thus allowing non-basic impurities to be washed out with an organic solvent, and thereby minimising the number of impurities brought through to subsequent phases of the process.

Compounds of formula (XII) may be prepared by reaction of compounds of formula (XIII)

wherein:

R¹, R², R³ or R⁴ are as defined above for compounds of formula (I) except where R¹ to R⁴ independently represent Br and L¹ represents a halogen for example and preferably a bromine or iodine atom with a compound of formula (XIV)

wherein n is as defined above for compounds of formula (I), R ⁶ represents d.e alkyl and R¹⁷ represents MZnCH(R⁶ )-, -OH, -NHR^6a;

M represents a halogen (Cl, Br or I)

Zn represents zinc; and R^6a and R^6b are as defined above for compounds of formula (I).

Compounds of formula (XII) wherein X is CHR^6b may be prepared from compounds of formula (XIV) where R¹⁷ represents MZnCH(R^6b)- in the presence of a palladium catalyst. This process may be effected as described by L. Zhu, R.M. Wehmeyer, R.D. Rieke in J. Org. Chem. 1991 , 56, 1445-1453.

Suitable catalysts include palladium catalysts, for example, tetrakis(triphenylphosphine)- palladium-(O) or Fibrecat FC1001™ (a fibre supported palladium catalyst from Johnson Matthey) in a suitable solvent, such as THF, at a temperature, for example, in the range -78 to 65°C, such as room temperature.

Preferably the tetrakis(triphenylphosphine)palladium(0) catalyst is used.

Compounds of formula (XII) wherein X represents O, -NR^6a or S may be prepared by literature methods under conditions known to a person skilled in the art. Compounds of formula (XII) wherein R ⁵ represents H are prepared by subsequent hydrolysis of the ester product of the above process i.e. where R¹⁵ represents Cι-₆ alkyl, which may be typically performed in an alcoholic solvent, such as, methanol in the presence of a mineral base such as sodium hydroxide at a non-extreme temperature, for example 0 to 100°C, such as room temperature.

The alternative process proceeding through compounds of formula (lib) provides an efficient method for the preparation of compounds of formula (I) with fewer steps which is both time and cost efficient. It also enables compounds to be reliably prepared which are difficult to prepare by other methods.

Where R⁵ does not represent H, compounds of formula (IV) have proved difficult to synthesise. We have now provided a process which enables compounds with various R⁵ groups to be made.

In this alternative process, compounds of formula (IV) may be prepared by reaction of a compound of formula (XV)

wherein: n represents 0 or 1 and X represents O, NR^6a or CHR^6b, and R¹, R², R³, R⁴ and R⁵ R^6a and R^6b are as defined above for compounds of formula (I) and where A is a group selected from -CO-2-furanyl, -CO-ethynyl or -C(=CH₂)CO₂C₁.₆alkyl with a suitable oxidising agent. When A is -CO-2-furanyl or -C(=CH₂)CO₂C₁.₆alkyl, suitable oxidising agents include ozone, potassium permanganate or sodium periodate with a catalytic ruthenium salt. When A is a -CO-ethynyl group, suitable oxidising conditions include bromination followed by treatment with permanganate. Other suitable oxidising conditions include osmium tetroxide/te/f-butylhydroperoxide, osmium tetroxide/sodium periodate and MoOPH (oxodiperoxymolbdenum-pyridine-hexamethylphosphoric triamide) (as set out in, for example in Oxidations in Organic Chemistry, ACS Monograph 186, M. Hudlicky, 1990).

Ozonoiysis may be carried out in any suitable solvent, for example methanol or dichloromethane or mixtures of those solvents in a ratio between 100:0 and 0:100. The ozonoiysis may take place over a temperature range -78 °C to 0 °C. Optimally the ozonoiysis is carried out in methanol at -78 °C. A variety of work-up conditions may be used to decompose ozonide intermediates; those work-up conditions include treatment with Me₂S, Ph₃P or H₂O₂. In this case, dimethylsulphide is preferred. Compounds of formula (XV) may be prepared by reaction of a compound of formula (XVI)

wherein n represents 0 or 1 and X represents O, NR^6a or CHR^6b, R¹, R², R³, R⁴- R⁵ R^6a or R⁶ are as defined above for compounds of formula (I) except that R⁵ does not represent H and X' is selected from Br, I and OTf except that R¹ to R⁴ independently do not represent Br when X' represents Br, by reaction with Bu₃SnC(=CH₂)CO₂C₁.₆alkyl or Me₃SnC(=CH₂)CO₂d.₆alkyl or with carbon monoxide and a stannane such as tributylfuran-2-ylstannane, trimethylfuran-2-ylstannane, tributylethynylstannane, trimethylethynylstannane or a (l-alkoxyvinyl)trialkylstannane or carbon monoxide and a boronic acid such as furan-2-ylboronic acid in the presence of a source of Pd(0). The source of Pd(0) may for example be Pd(OAc)₂, PdCI₂(MeCN)₂, Pd(PPh₃) or Pd₂(dba)₃. Preferably, the reaction is carried out in the presence of a phosphine ligand, for example Ph₃P, (2-furyl)₃P or (o-tolyl)₃P. Preferably, the reaction is carried out at a temperature in the range of 25 °C to 140 °C. The reaction solvent is preferably an aprotic solvent and it may, for example, be selected from toluene, xylene, benzene or DMF. Most preferably, the reaction is carried out on a starting material with X'=l, and the reaction is with (2- furyl)tributylstannane and carbon monoxide in the presence of palladium acetate and triphenylphosphine in toluene at 110 °C. General conditions for reactions of this type are described in further detail in: J. K. Stille et al., J. Org. Chem., 1990, 55, 3114-3118 and R. Grigg et al., Tetrahedron, 2001, 57, 1347-1359.

OTF represents OSO CF₃, known as triflate.

Compounds of formula (XVI) may be prepared by reaction of a compound of formula (XVII)

wherein n represents 0 or 1 and X represents O, NR^6a or CHR^6b, R¹, R², R³, R⁴' R⁵ R^6a or R^6b R¹, R², R³, R⁴ and R⁵ are as defined above for compounds of formula (I) and X' is as defined above for compounds of formula (XVI) with a suitable olefinating reagent. Suitable olefinating reagents include Wittig reagents, for example methyltriphenylphosphonium salts. Peterson, Tebbe, Petasis and Lombardo reagents are also suitable. A Wittig reaction on compound (XVII) may suitably be carried out in a polar solvent, for example a solvent selected from diethylether, tetrahydrofuran, ethylene glycol dimethylether, diglyme or dioxane, in the presence of a strong base, for example n-BuLi, sec-BuLi, t-BuLi, LDA, LiHMDS, NaKHMDS, KHMDS, NaH or KO'Bu, at a temperature in the range of -78 °C to +70 °C. Preferably, a Wittig reaction is carried out using methyltriphenyphosphonium bromide in Et₂O as the solvent with n-BuLi as the base at a temperature of 0 °C warming to room temperature.

Compounds of formula (XVII) in which X is CH₂ may be prepared by reaction of a compound of formula (XVIII)

(XVIII)

wherein n represents 0 or I and R¹, R², R³ and R⁴ are as defined above for compounds of formula (I), X' is as defined above for compounds of formula (XVI) and M' is MgQ or ZnQ, where Q is Cl, Br or I with a compound of

in which R⁵ is as defined above for compounds of formula (I).

Preferably the reaction is carried out in a polar solvent, for example a solvent selected from tetrahydrofuran and diethylether at a temperature in the range of -78 °C to +25 °C. If M' is a magnesium halide, the reaction is preferably carried out in the presence of a copper(l) salt. In one embodiment, the reaction is preferably carried out with a magnesium bromide reagent in diethylether at -78 °C in the presence of a CuBr.Me₂S complex. The reaction is particularly suitable for use with compounds of formula (XVIII) in which X' is bromine atom and compounds of formula (XIX) in which R⁵ is a d.₆ alkyl group. If M' is a zinc halide, the reaction is preferably carried out in the presence of a complex of LiCI and CuCN. In one embodiment, the reaction is preferably carried out using a compound of formula (XVIII) in which M' is ZnQ where Q representsBr in the presence of a 2:1 LiCI:CuCN complex as well as one equivalent of TMSCI in THF at -78 °C. The reaction is particularly suitable for use with compounds of formula (XVIII) in which X' is a bromine or an iodine atom and compounds of formula (XIX) in which R⁵ is a d.₆ alkyl, an aryl, or a C-ι.₆ alkoxy.

In reactions in which compound (XVIII) includes protic groups in moieties R¹, R², R³ and R⁴, it is preferred for those protic R¹, R², R³ and R⁴ to be protected during the reaction to make compound (XVIII). Appropriate protecting groups compatible with this chemistry will be apparent to those skilled in the art and are described in T.W. Greene & P.G.M. Wuts "Protective Groups in Organic Synthesis" 3^rd Edition 1999 Wiley Interscience.

In a variation of the process, compounds of the formula (XVII) in which R⁵ is a Cι-₆ alkyl are particularly amenable to synthesis by reaction of (XX) where n, X, R¹, R², R³, and R⁴ are as defined above for compounds of formula (I) except that R^1"4 do not represent Br when X' represents Br and X' is as defined above for compounds of formula (XVI) and R^5' is a leaving group such as Cl, NMeOMe or

S-2-pyridyl with R⁵G where R⁵ is defined as for formula (I) and G is MgCI, MgBr or Mgl. Where R5' is Cl, the reaction can conveniently be catalysed using a manganese salt such as MnCI₄Li₂.

Compounds of formula (XX) where n, X, R¹, R², R³, and R⁴ are as defined above for compounds of formula (I) and X' is as defined above for compounds of formula (XVI) can readily be prepared by the methods described above from compounds (XVIII) and (XIX) where R⁵ = OCι_₆ alkyl followed by conversion into (XX) using standard methods (that is hydrolysis into the corresponding acid and derivation to the desired R^5' leaving group).

Certain compounds of formula (II), (lib), (IV), (Va), (Vb), (Via), (Vlb), (VIII), (IX), (X) and (XI), (XV), (XVI), (XVII), (XX) are new and form an aspect of the invention In addition processes for preparing formulations including one or more compounds of formula (I) form an aspect of this invention.

Compositions comprising compounds of formula (I) also constitute an aspect of the invention. REFERENCES

1 Schacke, H, Docke, W-D. & Asadullah, K (2002) Pharmacol and Therapeutics 96: 23- 43.

2. Ray, A., Siegel, M.D., Prefontaine, K.E. & Ray, P. (1995) Chest 107: 139S.

3. Konig, H., Ponta, H., Rahmsdorf, H.J. & Herriich, P. (1992) EMBO J 11 : 2241-2246.

4. Barnes, P. J. & Adcock, 1. (1993) Trend Pharmacol Sci 14: 436-441.

5. Cato, A.C. & Wade, E. (1996) Bioessays 18: 371 -378.

6. Wong, C.A., Walsh, L.J., Smith, C.J. et al. (2000) Lancet 355: 1399-1403.

7. Allen, D.B. (2000) Allergy 55: suppl 62, 15-18.

8. Pauwels, R.A., Lofdahl, C.G., Latinen, L.A. et al. (1999) N Engl J Med 340: 1948- 1953.

9. Gumming, R.G., Mitchell, P. & Leeder, S.R. (1997) N Engl J Med 337: 8-14.

10. Faul, J.L, Tormey, W. Tormey, V. & Burke, C. (1998) S/H7317: 1491.

11. Andrews, R.C. & Walker, B. R. (1999) Clin Sci 96: 513-523. The invention will now be illustrated by way of the following non-limiting examples.

Examples

Abbreviations

THF tetrahydrofuran RT room temperature

HCI hydrochloric acid EtOAc ethyl acetate

Et₂O diethyl ether SPE solid phase extraction

DCM dichloromethane CHCI₃ chloroform

DMF dimethylformamide TBAF tetrabutylammonium fluoride

EtOH ethanol NMP Λ/-methylpyrrolidinone

DMPU 1 ,3-dimethyl-3,4,5,6- Na₂SO₄ sodium sulphate tetrahydro -2(1 H)-pyrimidinone

MeCN acetonitrile DMA /V, /V-dimethylacetamide

TMSCF3 trifluoromethyltrimethylsilane TLC Thin Layer Chromatography

MeOH methanol

I PA isopropanol

AIBN 2,2'-azobisisobutyronitrile

General Experimental Conditions LC/MS:

Column: 3.3cm x 4.6mm ID, 3um ABZ+PLUS; Flow Rate: 3ml/min; Injection Volume: 5μl; Temp. RT; UV Detection Range: 215 to 330nm

Solvents: A: 0.1% Formic Acid + 10mMolar Ammonium Acetate. B: 95% Acetonitrile + 0.05% Formic Acid

Gradient: Time A% B% 0.00 100 0 0.70 100 0 4.20 0 100 5.30 0 100

5.50 100 0

LC/ S (Pink):

Mass Spectrometer - Platform LCT with electrospray source operating in positive ion mode. Waters 1525 lc plump running at 2.0 ml/min, HTS PAL autosampler, 200 μl/min split to the ESI source with inline Waters UV2488 Dual Wavelength UV detector at 254 nm and Sedex ELS detection.

Mobile Phase A) Water 0.1 % formic Acid B) Acetonitrile 0.1 % formic Acid

Gradient

Time flow %A %B

0.00 2.0 95 5

1.00 2.0 95 5 15.00 2.0 5 95

17.00 2.0 5 95

18.00 2.0 95 5

20.00 2.0 95 5

Column - Higgins Clipeus C18 5um 100 x 3.0mm

LC/MS System Orange:

Mass Spectrometer - Finnigan TSQ700 with electrospray source operating in positive or negative ion mode. HP1050 system running at 2.0 mLΛnin, 200 μL/min split to the ESI source with inline HP1050 Single Wavelength UV detector at 254 nm. Mobile Phase

A) Water 0.1 % formic Acid

B) Acetonitrile 0.1% formic Acid Gradient T Tiimmee ffllooww %%AA %B

0.00 2.0 95 5

1.00 2.0 95 5

15.00 2.0 5 95

17.00 2.0 5 95 1 188..0000 2 2..00 9955 5

20.00 2.0 95 5

Column - Hiqqins C

Mass Directed Chromatographv: Column 10cm x 21.3mm ID, 5μm SUPELCO; Flow Rate: 20mLJmin; Injection Volume: 500μL; Temp. RT; UV Detection Range: 200 to 320nm Solvents: A: Water + 0.1 % Formic Acid B: 60% Acetonitrile + 0.05% Formic Acid

Gradient: Time A% B%

0.00 40 60

1.00 40 60

10.00 35 65

13.50 1 99

14.90 1 99

15.00 40 60

Experimental Methods A and B Methods A and B are exemplified by the preparation of Examples 5 and 6 and describe the process of converting a carbonyl compound such as a chromanone, thiochromanone or a tetralone into the corresponding methylene derivative - the methylenation step - (as demonstrated by Intermediate 5 for the preparation of Example 5 and 6) followed by an ene reaction with Intermediate 8 (as demonstrated by Intermediate 9 for the preparation of Example 5 and 6) and finally followed by reduction with diimide (as demonstrated by the preparation of Example 5 and 6). Method A uses methyltriphenylphosphonium bromide for the methylenation step and Method B uses the Tebbe reagent (μ-chloro-μ- methylene[bis(cyclopentadienyl)titanium]dimethylaluminium) as described by S.H. Pine, G.S. Shen, H. Hoang Synthesis 1991 , 165-167.

Method C

Method C is a process for converting 4-ethoxy-4-oxobutylzinc bromide and a substituted bromobenzene into the correpsonding tetralone and is exemplified by the conversion of Intermediate 22 to Intermediate 24 via Intermediate 23.

Intermediate 1

1 ,2.3.4-tetrahvdro-1 -naphthaldehvde -Tetralone was converted into 1 ,2,3,4-tetrahydro-1 -naphthaldehyde according to the protocols described in J. Med. Chem. 1998, 41, 346.

Intermediate 2

Ethyl (2E/2Z)-2-ethoxy-3-(1 ,2,3,4-tetrahvdronaphthalen-1 -yl)prop-2-enoate n-Butyl lithium (1.6M in hexanes) (6.6mL) was added to diisopropylamine (1.49mL) in THF (15mL) at -10°C. After 15min triethyl phosphonoethoxyacetate (2.86g) was added followed 30min later by Intermediate 1 (1.71g). The mixture was allowed to warm to RT and stirred overnight. After quenching with brine (25mL) and 2M HCI (25mL), the mixture was extracted with EtOAc (2x50mL). The combined extracts were washed with brine, dried (MgSO₄) and concentrated. Purification by Biotage eluting with 49:1 cyclohexane:Et₂O gave the title product (2.27g) as a mixture of Eand Z isomers. LC/MS t_RET = 3.71 , 3.75 min, MH⁺ = 275.

Intermediate 3

2-Oxo-3-(1 ,2,3,4-tetrahvdronaphthalen-1 -vDpropanoic acid

Intermediate 2 (1.5g), trifluoroacetic acid (20mL) and water (15mL) were mixed at RT for

3h. The solvents were then removed in vacuo and the residue azeotroped with toluene (3 x 25mL) and dried in vacuo overnight to afford the title product (1.3g) as a crystalline solid.

LC/MS t_RET = 3.32 - 3.8 min, MH^" = 217.

Intermediate 4

Λ/-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)-2-oxo-3-(1 ,2,3,4-tetrahvdronaphthalen-1 - vDpropanamide

To Intermediate 3 (229mg) dissolved in dimethylacetamide (7.3mL) at -8°C was added thionyl chloride (0.117mL) in one portion. After raising the temperature to 0°C, 6-amino-4- methyl-2,3-benzoxazin-1 -one (129mg) was added and the mixture stirred for 3h warming to RT. After removing the solvents in vacuo, the residue was purified by silica SPE (1 Og) eluting with 20mL fractions of DCM (x 6), CHCI₃ (x 4) and Et₂O (x 2). The desired fractions were combined, concentrated and triturated with DCM to afford the title compound as a white solid (142mg). LC/MS t_RET = 3.60 min, MH⁺ = 377.

Intermediate 5

6.7.8.9-Tetrahvdro-5-methylene-5H-benzocvcloheptene Pre-dried methyltriphenylphosphonium bromide (17.88g) was suspended in dry THF (210mL) and cooled to -10°C under nitrogen. n-Butyl lithium (1.6M in hexanes) (30mL) was added dropwise over 10min. The mixture was stirred for 1 hr. A solution of 1- benzosuberone in THF (90mL) was added dropwise over 15min. The solution was allowed to warm to RT. The solution was poured onto water (500mL). The organic layer was separated and the aqueous layer was extracted with cyclohexane (3 x 200mL). The combined extracts were dried (MgSO₄) and concentrated. Purification on a 50g Si SPE cartridge, eluting with cyclohexane gave the title product (3.41 g). LC/MS t_RET =3.80 min.

Intermediate 6

6-Amino-4-methyl-t H-2.3-benzoxazin-1 -one

This material was prepared according to the method described in WO 9854159 (1998).

Intermediate 7 4-Methyl-1 -oxo-1 H-2,3-benzoxazin-6-ylformanπide

Formic acid (20.4mL) was added dropwise over 5 minutes to chilled (0°C) acetic anhydride (41.8mL). The mixture was warmed to 55°C and stirred for 2 hours. A suspension of Intermediate 6 (22.0g) in THF (500mL) under N₂ was prepared. To this, the first solution was added. The mixture was stirred under N₂ at RT for 72 hours, at which point the solvent was removed in vacuo to afford Intermediate 7 as a white solid (25.7g). LC/MS t_REτ = 2.17 min, MH⁺ = 205.

Intermediate 8

3.3.3-Trifluoro-2,2-dihydroxy-N-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)propanamide Intermediate 7 (12.4g) was partially dissolved in DMPU (73mL), then THF (182mL) was added to give a partial suspension. Triethylamine (25.3mL) followed by phosphorus oxychloride (6.63mL) was added, and the mixture was allowed to stir at RT under N₂ for 20 hours. The solvent was removed in vacuo and the residue was diluted with sodium bicarbonate (500mL, 5% aqueous solution) and extracted with EtOAc (3x500mL). The organic extracts were combined, washed with water (500mL), dried (Na₂SO₄), and the solvent was reduced in vacuo. The residue was triturated using DCM to give the isonitrile (7.97g) as a pale brown solid. LC/MS t_RET = 2.37 min.

The isonitrile (7.58g) was suspended in trifluoroacetic anhydride (143mL) and stirred at RT for 46 hours. The reaction mixture was cooled in an ice bath and quenched with methanol (143mL) and the solvent/reagent removed in vacuo. The remaining material was azeotroped with toluene. Purification by Si chromatography eluting with cyclohexane : EtOAc (gradient of 2:1 to 1 :5) afforded Intermediate 8 as an off-white solid. (8.2g) LC/MS t_RET = 2.53 min, MH⁺ = 319; MNH₄ ⁺ = 336.

Intermediate 9

2-(6J-Dihvdro-5H-benzo[a1cvclohepten-9-ylmethyl)-3.3.3-trifluoro-2-hvdroxy-N-(4-methyl- 1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide (racemic) Intermediate 8 (50mg) in a tapered glass vial was wetted with Intermediate 5 (50mg) and the vessel placed in an oil bath pre-heated to 200°C, for 10 min. The resultant was purified by silica SPE (10g) eluting with cyclohexane: EtOAc 2:1 , to give the title compound as a white, solidified foam (69.4mg). LC/MS t_RET=3.61 min, MH⁺=459.

Intermediate 10

1 -methyl-1.2,3.4-tetrahvdronaphthalen-1 -ol

Cerium chloride (25g) was suspended in anhydrous THF (100mL) at 5°C then stirred for

1.5h under nitrogen. The mixture was cooled to -70°C and methyl lithium (64mL of a 1.6M solution in Et₂O) was added over 15 minutes. When addition was complete, the mixture was stirred for 30 minutes then a solution of α-tetralone (9.85g) in THF (50mL) was added over 30 minutes and stirring at -65°C was continued for 2h. The ice bath was removed and the mixture was stirred at room temperature overnight, quenched with 5% acetic acid (100mL), filtered through Celite and extracted with EtOAc (400mL). The aqueous layer was further extracted with EtOAc (2x1 OOmL) and the combined extracts were washed with water (1x) and with brine (2x) then dried over magnesium sulphate and evaporated in vacuo to a brown solid (10.32g). Flash chromatography using cyclohexane: EtOAc 20:1 gave the product as a white solid (5g). TLC SiO₂ 18:2 cyclohexane: EtOAc R_f = 0.22. Intermediate 11

Methyl 3-(1 -methyl-1 ,2,3,4-tetrahvdronaphthalen-1 -yl)-2-oxopropanoate To Intermediate 10 (0.73g) and methyl 2-(trimethylsiloxy)acrylate (1.8g) (prepared according to J. Org. Chem. 1997, 62, 2462) in CHCI₃ (250mL) at -60°C was added tin tetrachloride (1 M in DCM) (3.4mL) dropwise over 30sec. After 5min the reaction was quenched with brine (50mL) and the organic layer separated, dried (MgSO₄) and concentrated in vacuo. This was purified on 3 x 50g SPE cartridges eluting with cyclohexane :EtOAc 50:0 to 35:15 in 1 mL increments to yield the title compound (0.196g). H-NMR (CDCI₃, 400MHz) δ 7.30 - 7.08 (m, 4H), 3.76 (s, 3H), 3.32 (d, J = 15Hz, 1 H), 3.16 (d, J = 15Hz, 1 H), 2.91 - 2.76 (m, 2H), 2.07 - 1.99 (m, 1 H), 1.95 - 1.67 (m, 3H), 1.47 (s, 3H).

Intermediate 12

3-(1 -Methyl-1.2.3.4-tetrahvdronaphthalen-1 -yl)-2-oxopropanoic acid Intermediate 11 (0.196g) was dissolved in methanol (28mL). To this was added solid potassium hydroxide (0.18g) and the mixture was stirred at RT for 2 hours. Volatiles were removed in vacuo and the residue was diluted with water then washed with Et₂O. The aqueous phase was acidified with 2M HCI and extracted with DCM. The combined extracts were dried and evaporated to yield the title compound as a gum (0.176g). ¹H-NMR (CDCI3, 400MHz) δ 7.32 - 7.05 (m, 4H), 3.50 (d, J = 15.5Hz, 1 H), 3.28 (d, J = 15.5Hz, 1 H), 2.95 - 2.78 (m, 2H), 2.10 - 2.00 (m, 1 H), 1.95 - 1.65 (m, 3H), 1.45 (s, 3H). LC/MS t_RET = 3.68 min, MH^" = 231.

Intermediate 13 Λ/-(4-Methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)-3-(1 -methyl-1.2.3.4-tetrahvdronaphthalen-1 - yl)-2-oxopropanamide

Intermediate 12 (0.156g) was azeotroped three times from toluene then dissolved in dimethylacetamide (5.5mL) at -5°C under nitrogen. To this was added thionyl chloride (74μL) and after 10 minutes the temperature was raised to +5°C. After 20 minutes 6- amino-4-methyl-2,3-benzoxazin-1 -one (0.108g) was added and the mixture was stirred for 3 hours at RT. Volatiles were removed in vacuo and the residue was purified by silica SPE (10g) eluting with 20mL fractions of DCM (x 4), Et₂O (x 4) and EtOAc (x 4). The desired fractions were combined and concentrated to afford the title compound as a white foam (0.178g). ¹H-NMR (CDCI3, 400MHz) δ 9.05 (s, 1 H), 8.34 (d, J = 8.57Hz, 1 H), 8.22 (s, 1 H), 7.78(m, 1 H), 7.28 (m, 1 H), 7.15 - 7.05 (m, 3H), 3.52 (d, J = 15.7Hz, 1 H), 3.38 (d, J = 15.7Hz, 1 H), 2.90 - 2.75 (m, 2H), 2.57 (s, 3H), 2.13 - 2.03 (m, 1 H), 1.95 - 1.67 (m, 3H), 1.45 (s, 3H). LC/MS t_RET = 3.62 min, MH⁺ = 391

Intermediate 14

1 -ethyl-1.2.3,4-tetrahvdronaphthalen-1 -ol

A solution of -tetralone (0.5g) in Et₂O (8.5mL) was cooled to -20°C and ethyl magnesium bromide (3.4mL of a 1 M solution in THF) was added over 10 minutes. The resulting mixture was allowed to come to room temperature then stirred for 1 hour and quenched with ammonium chloride solution. Extraction with EtOAc followed by drying and evaporation in vacuo of the combined extracts gave an oil (0.54g). Biotage purification using DCM gave the product as a yellow oil (128mg).

¹H-NMR (CDClg, 400MHz) δ 7.60 (m,1H), 7.33 - 7.10 (m,3H),2.82 (m,2H), 2.15 - 1.70 (m,6H), 0.95(t, J = 7.5Hz, 3H).

Intermediate 15

Methyl 3-(1 -ethyl-1 ,2,3,4-tetrahvdronaphthalen-1 -yl)-2-oxopropanoate Prepared similarly to the method for methyl 3-(1 -methyl-1 ,2,3,4-tetrahydronaphthalen-1- yl)-2-oxopropanoate (intermediate 11 ).

¹H-NMR(CDCI₃, 400MHz) δ 7.37 - 7.10(m,4H), 3.70(s,3H), 3.31 (d, J = 14.5Hz.1 H), 3.18(d, J = 14.5Hz,1 H), 2.86 (m,2H), 2.08 - 1.70(m,6H), 0.86(t, J = 7.3Hz,3H).

Intermediate 16 3-(1 -ethyl-1.2.3.4-tetrahvdronaphthalen-1 -yl)-2-oxopropanoic acid

Prepared similarly to the method for 3-(1 -methyl-1 ,2,3,4-tetrahydronaphthalen-1 -yl)-2- oxopropanoic acid (intermediate 12).

¹H-NMR(CDCI₃, 400MHz) δ 7.20 - 7.05(m,4H), 3.4(d, J = 15.8Hz, 1 H), 3.25(d, J = 15.8Hz,

1 H), 2.87 - 2.71 (m,2H),2.01 - 1.65(m,6H),1.81 (t, J = 7.2Hz,3H). LC/MS t_ret = 3.95 min, MH- = 245.

Intermediate d

N- (4-Methyl-1 -oxo-1 H-2. 3-benzoxazin-6-yl)-3-(1 -ethyl-1. 2.3.4-tetrahvdronaphthalen-1 - yl)-2-oxopropanamide Prepared similarly to the method for N- (4-Methyl-1 -oxo-1 H-2, 3-benzoxazin-6-yl)-3-(1 - methyl-1 , 2,3,4-tetrahydronaphthalen-1-yl)-2-oxopropanamide (intermediate 13). ¹H-NMR(CDCI₃, 400MHz) δ 8.95 (s, 1 H), 8.36 (d, J = 8.4Hz, 1H), 8.21 (s, 1H), 7.74 (m, 1 H), 7.20 (m, 1 H), 7.12 - 7.03 (m, 3H), 3.45 (d, J = 16Hz, 1 H), 3.35 (d, J = 16Hz, 1 H), 2.90 - 2.72 (m, 2H), 2.6 (s, 3H), 2.05 - 1.68 (m, 6H), 0.84 (t, J = 7.2Hz, 3H). LC/MS t_ret = 3.70 min, MH⁺ = 405, MH^" = 403.

Intermediate 18

7-Amino-1 -tetralone

To commercial 7-nitro-1 -tetralone (19.12g) in THF (400mL) was added solid tin (II) chloride dihydrate (112.8g). The temperature rose by ca. 2 degrees. After addition of the solid the mixture was stirred at room temperature for 5 minutes then at 50-60°C for ca. 1 hour. After cooling the mixture was diluted with ethyl acetate and taken to pH 5-6 with 8% aqueous sodium bicarbonate solution. The mixture was filtered and the aqueous layer was separated, extracted with ethyl acetate and the combined extracts were washed with brine, dried over magnesium sulphate and concentrated in vacuo to give a tan solid (14.2g). LC/MS t_RET = 1.75min, MH⁺ = 162.

intermediate 19 7-Bromo-1 -tetralone A mixture of copper (II) bromide (8.03g), f-butyl nitrite (5.35mL) and acetonitrile (120mL) was warmed to 60°C under nitrogen. To this was added Intermediate 18 (4.84g) as a solid portion-wise over 5-10 minutes. After 2 hours the reaction mixture was quenched with 2M HCI (250mL) and extracted with diethyl ether (2x200mL). The combined extracts were washed with brine and concentrated in vacuo to a brown/black solid. Purification was effected by Biotage chromatography eluting sequentially with cyclohexane/diethyl ether mixtures in the ratios 100:0, 19:1 , 18:2 and 17:3. The product was obtained as a pink solid (3g). LC/MS t_REτ = 3.14 min. ¹H-NMR(CDCI₃, 400MHz): 8.17 (s, 1 H), 7.58 (d, J = 8.2Hz, 1 H), 7.15 (d, J = 8.2Hz, 1 H), 2.94 (t, J = 6.0Hz, 2H), 2.65 (t, J = 6.6Hz, 2H), 2.15 (m, 2H).

Intermediate 20

7-Methyl-1 -tetralone To a mixture of Intermediate 19 (610mg), dichlorobis(triphenylphosphine) palladium(ll) (100mg) and DMF (4mL) was added tetramethylstannane (0.56mL). The mixture was heated at 100°C for 6 hours, further tetramethyl stannane (0.2mL) added and heating continued for a further 8 hours. Further tetramethylstannane (0.2mL) and catalyst (50mg) were added and heating continued for a further 6 hours. The reaction mixture was filtered and the filtrate was evaporated in vacuo. Flash chromatography of the residue using cyclohexane:EtOAc 4:1 and cyclohexane: EtOAc 6:1 gave the product (170mg). LC/MS t_RET = 2.94 min; MH⁺ = 161.

¹H-NMR(CDCI₃, 400MHz): 7.82 (1H, s), 7.28 (d, J = 7.9 Hz, 1H), 7.12 (d, J = 7.9Hz, 1H), 2.90 (m, 2H), 2.61 (m, 2H), 2.35 (s, 3H), 2.13 (m, 2H).

Intermediate 21

7-Fluoro-1 -tetralone

To a solution of Intermediate 18 (200mg) in hydrochloric acid (0.3mL) and water (0.55mL) was added a solution of sodium nitrite (90mg) in water (1.3mL) drop-wise keeping the temperature below 5°C. To this was added a solution of sodium tetrafluoroborate (200mg) in water (0.5mL) and the reaction mixture was stirred at 0°C for 40 minutes before cooling to -10°C, stirring for a further 15 minutes and filtering. The filtered solid was washed with ice-cold Et₂O, dried, dissolved in toluene (10mL) and the temperature was slowly raised to 110°C at which point nitrogen evolution began. Reflux was continued until gas evolution had ceased and for 1 hour thereafter. The hot solution was decanted from a quantity of precipitated oily material, washed with water, with 2M NaOH solution then dried and evaporated in vacuo to give the product as a red solid (98mg). LC/MS t_RET = 2.78 min. ¹H-NMR (CDCI₃, 400MHz): 7.72 (m, 1H); 7.21 (m, 2H); 2.97 (t, J = 5.5Hz, 2H); 2.77 (t, J = 6.1 Hz, 2H); 2.17 (m, 2H).

Intermediate 22

Ethyl 4-(5-chloro-2-fluorophenyl)butanoate To a stirred solution of 5-chloro-2-fluorobromobenzene (10.5g) and tetrakis(triphenylphosphine)palladium (2.90g) in THF (135mL), was added 0.5M 4-ethoxy- 4-oxobutylzinc bromide in THF solution (100mL), under N₂. After 18 hours the solution was poured into aqueous NH₄CI (500mL) and extracted with Et₂O (3 x 500mL). The organic layers were combined, dried (MgSO₄), and solvent reduced in vacuo to afford a crude oil. Purification by quad Biotage (4 x (40+M) Si cartridges), eluting with cyclohexane : EtOAc (20:1) afforded Intermediate 22 (4.95g).

¹H-NMR (CDCI₃, 400MHz), 1.27 (t, J = 7.2Hz, 3H), 1.95 (quintet, J = 7.5Hz, 2H), 2.34 (t, J = 7.4Hz, 2H), 2.67 (t, J = 7.7Hz, 2H), 4.14 (quartet, J = 7.0Hz, 2H), 6.96 (t, J = 9.0Hz, 1 H), 7.12-7.20 (m, 1 H), 7.28-7.39 (m, 1 H).

Intermediate 23

4-(5-Chloro-2-fluorophenyl)butanoic acid

To a stirred solution of Intermediate 22 (4.95g) in THF (70mL) and MeOH (70mL), was added aqueous 2M sodium hydroxide (150mL). After 5 hours the organic solvents were reduced in vacuo. The remaining aqueous solution was diluted with 2M sodium hydroxide

(300mL), and washed with Et₂O (2 x 300mL). The aqueous layer was acidified with cone.

HCI (aq) and extracted with ethyl acetate (3 x 300mL). The ethyl acetate layers were combined, dried (MgSO₄) and reduced in vacuo to afford Intermediate 23 as an oil (4.26g).

LC/MS t_RET = 3.08 min, MH- = 215, 217.

Intermediate 24

5-Fluoro-8-chloro-1 -tetralone A mixture of Intermediate 23 (4.26g) and polyphosphoric acid (excess) was stirred at 90°C for 2.5 hours. The reaction mixture was poured into water (300mL) and extracted with ethyl acetate (2 x 300mL). The organic layers were combined, dried (MgSO ) and reduced in vacuo. Purification by Si chromatography eluting with cyclohexane: EtOAc (gradient of 20:1 to 2:1 ) afforded Intermediate 24 as a solid (1.43g). LC/MS t_RET = 2.97 min, MH⁺ = 199, 201.

Intermediate 25

6-Fluoro-8-chloro-1 -tetralone and 6-Chloro-8-f luoro-1 -tetralone

Prepared via method C from 1-bromo-3-chloro-5-fluorobenzene and 4-ethoxy-4- oxobutylzinc bromide to afford Intermediate 25 as a mixture of positional isomers. LC/MS t_RET = 2.96 min, MH⁺ = 199, 201.

Intermediate 26

2-f(6-Chloro-8-fluoro-3. 4-dihvdro-1 -naphthalenyl) methvn-3.3.3-trifluoro-2-hvdroxy-N- (4- methyl-1 -oxo-1 H-2, 3-benzoxazin-6-yl) propanamide

1.6M Butyl lithium in hexane solution (17.9mL) was added drop-wise over 10 minutes to dried methyl triphenyl phosphonium bromide (10.8g) in THF (124mL) at -45°C under N₂. The mixture was stirred for 1 hour, at which point Intermediate 25 (3.7g) in THF (53mL) was added over 15 minutes. The resulting solution was allowed to warm to RT overnight. The reaction mixture was poured into water (500mL) and extracted with cyclohexane (2 x 500mL). The combined organic extracts were dried (MgSO₄), and reduced in vacuo. Purification with Si chromatography eluting with cyclohexane: EtOAc (gradient of 50:1 to 3:1) afforded a clear oil. Intermediate 8 (0.38g) and the purified material from above (0.28g) were heated in a tapered vial at 200°C for 10 minutes, after which time purification with Si chromatography eluting with cyclohexane: EtOAc (gradient of 2:1 to 1 :2) afforded a white solid. The material was purified further using a suitable HPLC gradient to afford Intermediate 26 (0.19g). LC/MS t_RET = 3.59 min, MH^' = 495, 497.

Intermediate 27

6-Fluoro-8-chloro-1 -tetralone

1.6M Butyl lithium in hexane solution (17.9mL) was added drop-wise over 10 minutes to dried methyl-triphenyl phosphonium bromide (10.8g) in THF (124mL) at -45°C under N₂. The mixture was stirred for 1 hour, at which point Intermediate 25 (3.7g) in THF (53mL) was added over 15 minutes. The resulting solution was allowed to warm to RT overnight. The reaction mixture was poured into water (500mL) and extracted with cyclohexane (2 x 500mL). The combined organic extracts were dried (MgSO₄), and reduced in vacuo. Purification with Si chromatography eluting with cyclohexane: EtOAc (gradient of 50:1 to 3:1) afforded a brown oil (1.74g).

1.6M Butyl lithium in hexanes solution (8.4mL) was added drop-wise over 10 minutes to dried methyl-triphenyl phosphonium bromide (5.1 g) in THF (58mL) at -45°C under N₂. The mixture was stirred for 1 hour, at which point the aforementioned brown oil (1.74g) in THF (25mL) was added over 15 minutes. The resulting solution was allowed to warm to RT overnight. The reaction mixture was poured into water (300mL) and extracted with cyclohexane (2 x 300mL). The combined organic extracts were dried (MgSO₄), and reduced in vacuo. Purification with Si chromatography eluting with cyclohexane: EtOAc (gradient of 50:1 to 1 :1) afforded Intermediate 27 as a yellow oil (1.2g). The repeated Wittig reaction on Intermediate 25 removed the 6-chloro-8-fluorotetralone to leave the other isomer, Intermediate 27, pure. LC/MS t_RET = 2.99 min, MH⁺ = 199, 201.

Intermediate 28 6-Chloro-1 -tetralone

To dried copper (II) chloride (1.61g) in dry MeCN was added f-butyl nitrite (1.78mL) and the mixture warmed to 60°C after which 6-aminotetralone (1.61g) was added. After 45min, the mixture was cooled and partitioned between 2M HCI (200mL) and Et₂O (200mL). The aqueous layer was re-extracted with Et₂O (100mL) and the combined organic extracts washed with water (200mL), brine (100mL), dried (MgSO₄) and concentrated in vacuo. The crude material was purified by Bond Elut (20g) eluting with 0- 100% EtOAc in cyclohexane to afford the Intermediate 28 (1.34g) as a yellow/orange oil. LC/MS t_RET = 3.07min, MH⁺ = 181. Intermediate 29

6-Fluoro-1 -tetralone

Intermediate 29 was similarly prepared to Intermediate 21 from 6-aminotetralone. LC/MS t_RET = 2.76min, MH⁺ = 165.

Intermediate 30

6-Bromo-1 -tetralone

Intermediate 30 was similarly prepared to Intermediate 19 from 6-aminotetralone. LC/MS t_RET = 3.16min, MH⁺ 225, 227.

intermediate 31

6-Methyl-1 -tetralone

Intermediate 30 (0.83g), potassium carbonate (1.5g), trimethylboroxine (0.58mL), palladium tetrakistriphenylphosphine (0.44g) and DMF were heated at 105°C for 4.5h.

After stirring for 13h at RT, further trimethylboroxine (0.58mL) and palladium tetrakistriphenylphosphine (0.22g) were added and the mixture heated at 105°C for 5h.

After filtration through Celite, the reaction mixture was diluted with Et₂O (250mL) and then washed with water (200mL), brine (200mL) and then dried (MgSO₄) and concentrated in vacuo. Purification by silica Bond Elut (20g) eluting with 0-100% EtOAc in cyclohexane gave Intermediate 31 (0.43g).

¹H-NMR (CDCI₃) δ 7.95 (d, 1H), 7.13 (d, 1H), 7.05 (s, 1 H), 2.92 (t, 2H), 2.64 (t, 2H), 2.37

(s, 3H), 2.13 (quintet, 2H).

Intermediate 32

6-Cvano-1 -tetralone

Intermediate 30 (0.26g), copper (I) cyanide (0.5g) and NMP (0.8mL) were heated in a microwave at 160°C for 30min. After dilution with DCM (50mL) and water (50mL), the aqueous layer was separated and re-extracted with further DCM (2 x 20mL). The combined organics were concentrated in vacuo and purified by Bond Elut (20g) eluting with 0-100% DCM in cyclohexane to afford Intermediate 32 as an off-white solid (0.162g). ¹H-NMR (CDCI3) δ 8.12 (d, 1 H), 7.60 (m, 2H), 3.02 (t, 2H), 2.72 (t, 2H), 2.18 (quintet, 2H).

Intermediate 33 8-Nitro-1 , 2,3,4-tetrahvdro-1 -naphthalenecarbaldehvde

5-Nitrotetralin (Kobe, K.A.; Doumaine, T.F. Org. Syn. Collect. Vol. Ill, 653) (5.1 g) and t- butoxybis(dimethylamino)methane (14.2g) were heated at 100°C for 17h. Further portions of t-butoxybis(dimethylamino)methane (7.37g, 12.1g, 4.5g) were added with heating at 100°C for a further 3 days. After cooling and concentration in vacuo, purification by flash chromatography eluting with 10-25% DCM in cyclohexane gave Intermediate 33 (4.48g) as a yellow solid. LC/MS t_RET = 2.91 min, MH⁺ = 206.

Intermediate 34 Ethyl (2E/2Z)-2-(ethyloxy)-3-(8-nitro-1 ,2,3.4-tetrahvdro-1 -naphthalenyl)-2-propenoate Intermediate 34 was similarly prepared to Intermediate 2 from Intermediate 33. LC/MS t_RET = 3.52 and 3.58min, MH⁺ = 320

Intermediate 35

3-(8-Nitro-1 ,2,34-tetrahvdro-1 -naphthalenyl)-2-oxopropanoic acid

Intermediate 35 was similarly prepared to Intermediate 3 (except the reaction mixture was heated at reflux for 5.5h) from Intermediate 34.

LC/MS t_RET = 3.40min, MH^' = 262

Intermediate 36

N-(4-Methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl -3-(8-nitro-1 ,2,3.4-tetrahvdro-1 -naphthalenvh- 2-oxopropanamide

Intermediate 36 was similarly prepared to Intermediate 4 from Intermediate 35 and 6- amino-4-methyl-2,3-benzoxazin-1 -one. LC/MS t_RET = 3.47min, MH⁺ = 422

Intermediate 37

5-Amino-1 -tetralone Similarly prepared to Intermediate 18, starting from 5-nitrotetralone (J. Med. Chem. 1989, 32, 2128).

¹H-NMR (CDCI3) δ 7.53 (d, 1 H), 7.15 (t, 1 H), 6.89 (dd, 1 H), 3.72 (br. s, 2H), 2.70 (t, 2H), 2.64 (t, 2H) and 2.18 (qn, 2H).

Intermediate 38

5-Chloro-1 -tetralone

Similarly prepared to Intermediate 28, starting from Intermediate 37.

¹H-NMR (CDCI3) δ 7.98 (d, 1 H), 7.57 (dd, 1 H), 7.27 (t, 1 H), 3.04 (t, 2H), 2.66 (t, 2H) and

2.17 (qn, 2H).

Intermediate 39

5-Fluoro-1 -tetralone

Similarly prepared to Intermediate 21 , starting from Intermediate 37.

¹H-NMR (CDCI3) δ 7.89 (d, 1H), 7.37-7.20 (m, 2H), 3.00 (t, 2H), 2.71 (t, 2H) and 2.20 (qn, 2H).

Intermediate 40

5-Bromo-1 -tetralone

_5-Bromo-1 -tetralone is commercially available.

Intermediate 41

5-Cvano-1 -tetralone

Similarly prepared to Intermediate 32, starting from 5-bromotetraIone (Intermediate 40). ¹H-NMR (CDCI3) δ 8.25 (d, 1 H), 7.80 (d, 1 H), 7.43 (t, 1 H), 3.19 (t, 2H), 2.70 (t, 2H) and 2.21 (qn, 2H).

Intermediate 42 5-Methyl-1 -tetralone

Similarly prepared to Intermediate 31 , starting from 5-bromotetralone (Intermediate 40). H-NMR (CDCI₃) δ 7.93 (d, 1 H), 7.36 (d, 1 H), 7.22 (t, 1 H), 2.87 (t, 2H), 2.65 (t, 2H), 2.32 (s, 3H) and 2.16 (qn, 2H).

Intermediate 43

1 -(2-lodophenyl)heptan-4-one

Tetrahydrofuran (25 ml) was added to anhydrous lithium chloride (2.2 g, 50 mmol) and copper (I) cyanide (2.24 g, 25 mmol) whilst stirring under an atmosphere of nitrogen at 25 °C. After stirring for 10 minutes this solution was cooled to -78 °C and 2-iodobenzylzinc bromide (50 ml, 0.5 M in THF, 25 mmol) was added. The solution was then warmed to - 15 °C for 20 minutes before re-cooling to -78 °C. Chlorotrimethylsilane (6.4 ml, 50 mmol) was added followed by propyl vinyl ketone (2.3 ml, 20 mmol) in anhydrous THF (5 ml). The reaction was maintained at -78 °C for 3 hours and then warmed to 25 °C. Stirring was continued for 1 hour. The reaction mixture was partitioned between water (150 ml) and diethyl ether (150 ml) and the aqueous layer was extracted with two further portions of ether (2 x 150 ml). The combined ether extracts were washed with brine and dried over magnesium sulphate. The solvent was removed to give the title compound as a colourless oil (6.1 g, 96%). ¹H-NMR: <5H (CDCI₃, 400 MHZ) 7.82 (d, J 7.8 Hz, 1 H, ArH), 7.28 (td, J 7.5 and 1.0 Hz, 1 H, ArH), 7.21 (dd, J 7.6 and 1.8 Hz, 1 H, ArH), 6.89 (td, J 7.5 and 1.7 Hz, 1 H, ArH), 2.73 (dd, J 7.8 and 7.6 Hz, 2H, ArCH₂), 2.48 (t, J 7.3 Hz, 2H, C^C^CO), 2.40 (t, J 7.3 Hz, 2H, CHaCHsCO), 1.94-1.84 (m, 2H, CH₂CH H₂), 1.62 (sx, J 7.3 Hz, 2H, CH₂CH^CH₃) and 0.92 (t, J7.2 Hz, 3H, CH₃).

Intermediate 44

1-lodo-2- (4-propylpent-4-enyl) benzene

Methyltriphenylphosphonium bromide (11.1 g, 31.1 mmol) was suspended in anhydrous diethyl ether (150 ml) and was cooled to 0 °C. n-Butyllithium (17 ml, 1.6 M solution in hexanes, 27.2 mmol) was added drop-wise over 10 minutes maintaining the temperature below 5 °C to give a bright yellow suspension. This suspension was left to stir for 30 minutes at 0 °C. The intermediate 43 (6.1 g, 19.4 mmol) in anhydrous ether (20 mL) was slowly added to the ylide solution, maintaining the solution below 5 °C. After stirring the reaction at 0 °C for 30 minutes the ice-bath was removed and the reaction warmed to room temperature. After a further 3 hours saturated NH₄CI solution (100 mL) was added and the reaction was partitioned between ether and water. The organic phase was separated and washed with 1 :1 saturated brine-saturated NH₄CI solution. The organic phase was dried over sodium sulphate and the solvent removed under vacuum to give a crude product consisting of an oil plus a solid. This product was suspended in cyclohexane and the solid was filtered off. The solid was washed with cyclohexane and the filtrate and wash were loaded onto a silica column and eluted with cyclohexane to give the title compound as a colourless liquid (5.2 g, 85%). LC/MS: t_ret 4.38 min (no significant mass ions)

¹H-NMR: <5H (CDCI₃, 400 MHz) 7.83 (d, 7.8 Hz, 1H, ArH), 7.29 (t, 7.3 and 1.2 Hz, 1H, ArH), 7.24 (dd, J 7.8 and 1.7 Hz, 1 H, ArH), 6.90 (td, J 7.5 and 1.8 Hz, 1 H, ArH), 4.78 (br. s, 1 H, C=CH_AH_B), 4.77 (br. s, 1 H, C=CH_AH_B), 2.72 (dd, J 8.1 and 7.9 Hz, 2H, ArCH₂), 2.13 (t, 7.6 Hz, 2H, CH₂CH₂C=CH₂), 2.05 (t, J 7.6 Hz, 2H, CH≥CH^CH;,), 1.80-1.71 (m, 2H, ArCH₂CH₂CH₂), 1.49 (sx, J7.6 Hz, 2H, C ₂CH H₃) and 0.93 (t, J7.3 Hz, 3H, CH₃).

Intermediate 45

(+/-)1-Furan-2-yl-2-(1 -propyl-1 ,2,3,4-tetrahvdronaphthalen-1 -vDethanone Palladium acetate (286 mg, 1.27 mmol) and triphenylphosphine (668 mg, 2.55 mmol) were dissolved in toluene (75 mL) and the intermediate 44 (2.0 g, 6.37 mmol) was added followed by (2-furyl)tributylstannane (2.2 mL, 7.0 mmol). The apparatus was evacuated and filled with carbon monoxide (3 times). The reaction mixture was then heated to 110 °C for 18 hours. The reaction was cooled to room temperature and was poured into water (100 mL). The aqueous layer was extracted with diethyl ether (50 mL) and the combined organic extracts were dried over magnesium sulphate. The solvent was evaporated to give a crude product. Purification was achieved on silica gel eluting with cyclohexane- DCM 1 :1 to give the title compound as an orange oil (1.2 g, 67%). LC/MS: 3.75 min; MH⁺ 283 , MNH₄ ⁺ 300

¹H-NMR: 4, (CDCI_3l 400 MHz) 7.52 (d, J 1.8 Hz, 1 H, Fur-H), 7.25 (br. d, J 6.7 Hz, 1 H, ArH), 7.12-7.02 (m, 3H, ArH), 7.03 (d, J 3.6 Hz, 1 H, Fur-H), 6.47 (dd, J 3.6 and 1.8 Hz, 1H, Fur-H), 3.16 (d, J 14.4 Hz, 1H, CH_ΛH_BCO), 3.10 (d, J 14.4 Hz, 1H, CH_Atf_sCO), 2.85- 2.65 (m, 2H, ArCH₂), 2.11-0.99 (m, 8H) and 0.84 (t, J7.3 Hz, 3H, CH₂CH₃).

Intermediate 46

(+/-)2-Oxo-3-(1-propyl-1 ,2,3.4-tetrahvdronaphthalen-1 -vDpropanoic acid

The intermediate 45 (200 mg, 0.71 mmol) was dissolved in methanol (20 mL) and the reaction was cooled to -70 °C (internal temperature). Ozone was bubbled through the solution until TLC indicated there was no starting material remaining. The ozone generator was switched off and oxygen was bubbled through the solution for 10 minutes, followed by nitrogen for 10 minutes. Dimethyl sulphide (2 mL, 27.2 mmol) was added and the reaction was allowed to warm to room temperature. The solvent was then removed to give a crude product. Potassium hydroxide pellets (0.46 g, 10 mmol) were then dissolved in methanol (20 mL) and added to the crude product. This solution was stirred for 2 hours and the methanol was removed by rotary evaporation. The residue was dissolved in 2 M potassium hydroxide solution (50 mL) and was washed with 1 :1 cyclohexane-diethyl ether (2 x 50 mL). The aqueous phase was then acidified to pH 1 (2 M HCI) and was extracted with DCM (2 x 50 mL). The DCM extracts were dried on magnesium sulphate and the solvent removed to give a crude product that was not purified further. The crude product consisted mainly of the required ketoacid and a carboxylic acid impurity (resulting from loss of the CO group) in a ratio of approximately 7:5 (185 mg). LCMS 4.30 min; MH^" 259 ¹H-NMR 5H (CDCI_3l 400 MHZ) 7.20-7.04 (m, 4H, ArH), 5.50 (v. broad s, 1 H, CO₂H), 3.42 (d, J 16.1 Hz, 1H, Ctf„H_BCO), 3.24 (d, J 16.1 Hz, 1 H, CH_Ar7_BCO), 2.87-2.68 (m, 2H, ArCH₂), 2.02-1.78 (m, 1 H), 1.35-1.07 (m, 7H) and 0.88 (t, J7.3 Hz, 3H, CH₂CH₃).

Intermediate 47

(+/-)Λ/-(4-Methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)-2-oxo-3-(1 -propyl-1.2.3.4- tetrahvdronaphthalen-1-yl propanamide

Thionyl chloride (80 μL, 1.09 mmol) was added to a solution of the intermediate 46 (156 mg, 0.60 mmol) in DMA (1 mL) cooled to -5 °C to give a yellow solution. After 30 minutes 6-amino-4-methyl-1 H-2,3-benzoxazin-1 -one (210 mg, 1.19 mmol) was added in dimethylacetamide (5 mL) and the solution became dark brown. The ice-methanol bath was removed and stirring continued for 3 hours. The reaction was then partitioned between 2 M HCI and DCM. The aqueous layer was then extracted with a further portion of DCM (10 mL). The combined organic extracts were dried over sodium sulphate and the solvent removed under vacuum to give a crude product. Purification was achieved on silica gel eluting with cyclohexane-ethyl acetate 9:1 to give the title compound as a white solid (175 mg, 70%).

LC/MS: t_ret 3.84 min MNH₄ ⁺ 436, MH^" 417 ¹H-NMR: δ (CDCI₃, 400 MHz) 8.96 (br. s, 1 H, NH), 8.36 (d, J 8.5 Hz, 1 H, ArH), 8.22 (d, J 2.0 Hz, 1 H, ArH), 7.75 (dd, 8.5 and 2.0 Hz, 1H, ArH), 7.23-7.19 (m, 1 H, ArH), 7.10-7.07 (m, 3H, ArH), 3.50 (d, J 16.1 Hz, 1 H, CH_ΛH_BCO), 3.35 (d, J 16.0 Hz, 1 H, CH_AH_sCO), 2.90- 2.71 (m, 2H, ArCH₂), 2.59 (s, 3H, CH₃), 2.05-1.95 (m, 1H), 1.95-1.80 (m, 4H), 1.70-1.60 (m, 1H), 1.40-1.10 (m, 2H) and 0.89 (t, J7.0 Hz, 3H, CH₂CH₃).

Intermediate 48

5-Ethyl-6.7.8.9-tetrahvdro-5/--benzocvclohepten-5-ol

Ethyl lithium was prepared from lithium wire (2.0g) and ethyl bromide (10mL) in Et₂O (25mL). The ethereal solution was added to anhydrous cerium (III) chloride (30.92g) in THF (105mL) drop-wise over 1 h and the mixture then aged for a further 45min. After cooling to -70°C, 1 -benzosuberone (13.4g) was then added over 35min. After 2h at - 70°C, the mixture was allowed to warm to -30°C when it was quenched with acetic acid (5mL) in H₂O (95mL). The product was extracted with Et₂O (4 x 100mL) and the combined extracts washed with brine, dried (MgSO₄) and concentrated in vacuo. Purification by chromatography on silica eluting with CHCI₃ gave the title compound (6.6g).

Tic SiO₂ CHCI₃ R_f = 0.17

Intermediate 49

Methyl 3-(5-ethyl-6,7.8,9-tetrahvdro-5 -/-benzocvclohepten-5-yl)-2-oxopropanoate Intermediate 48 (2.45g) and methyl 2-(trimethylsiloxy)acrylate (5.47g) were dissolved in dry DCM (330mL) and cooled to -70°C under nitrogen. Tin tetrachloride (1 M in DCM (9.8mL) was added over 100 seconds and then stirred for 5min when the reaction was quenched with brine (50mL). The aqueous phase was separated and extracted with DCM (2 x 75mL) and the combined organic extracts washed with water (2 x 50mL), brine (50mL) and dried (MgSO ). Solvent removal in vacuo and chromatography on silica eluting with CHCI₃ and 40-60 petrol (1 :2) followed by further chromatography on silica eluting with 5% EtOAc in 40-60 petrol gave the title product (0.73g) as a colourless oil. LC/MS t_RET = 3.66min, MH⁺ = 275

Intermediate 50

3-(5-Ethyl-6,7,8,9-tetrahvdro-5H-benzocvclohepten-5-yl)-2-oxopropanoic acid Intermediate 49 (0.72g), potassium hydroxide (0.6g) in MeOH (85mL) were stirred at RT for 18h. Water (200mL) was then added and the mixture washed with Et₂O (2 x 50mL). The aqueous layer was then acidified with 2M HCI and the product extracted with DCM (2 x 50mL). After drying (MgSO₄), the solvent was removed in vacuo to afford the title compound (0.72g). LC/MS t_RET = 4.21 min, MH^" = 260

Intermediate 51

3-(5-Ethyl-6.7.8.9-tetrahvdro-5H-benzocvclohepten-5-yl)-Λ/-(4-methyl-1 -oxo-1 H-2.3- benzoxazin-6-yl)-2-oxopropanamide

Intermediate 51 was similarly prepared to Intermediate 13 from Intermediate 50 and Intermediate 6. LC/MS t_RET = 4.21 min, MH⁺ = 419

Intermediate 52

3-(1 -Butyl-1 ,2,3,4-tetrahvdro-1 -naphthalenyl)-Λ/-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-vD- 2-oxopropanamide Intermediate 52 was similarly prepared to Intermediate 47. LC/MS t_RET = 4.04min, MH⁺ = 433, MH^" = 431

Examples 1-4 Example 1 (racemic diastereomer 1)

3.3.3-Trifluoro-2-hvdroxy-Λ/-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)-2-(1.2.3.4- tetrahvdronaphthalen-1 -ylmethyl) propanamide

Example 2 (racemic diastereomer 2) 3.3.3-Trif luoro-2-hvdroxy-Λ/-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)-2-(1.2.3.4- tetrahvdronaphthalen-1-ylmethyl)propanamide

Example 3 (diastereomer 2, enantiomer 1)

3.3.3-Trif luoro-2-hvdroxy-Λ/-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)-2-(1.2.3.4- tetrahvdronaphthalen-1-ylmethyl)propanamide

Example 4 (diastereomer 2, enantiomer 2)

3.3.3-Trifluoro-2-hvdroxy-Λ/-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)-2-(1.2.3.4- tetrahvdronaphthalen-1-ylmethyl)propanamide To Intermediate 4 (121mg) in DMF (5mL) at RT was added trimethylsilyltrifluoromethane

(0.248mL) and caesium carbonate (125mg). After stirring overnight TBAF (1.9mL of a

1 M solution in THF) was added. After 30min, the mixture was diluted with water (50mL) and extracted with EtOAc (2 x 50mL). The combined extracts were washed with water (100mL), dried (MgSO₄) and concentrated in vacuo. Purification by Biotage eluting with cyclohexane: EtOAc 4:1 gave the following:

Example 1 (15mg) diastereomer 1

Example 2 (18mg) diastereomer 2

LC/MS t_RET = 3.57min (diastereomer 2) and 3.61 min (diastereomer 1), both peaks MH⁺ = 447, MH^" = 445.

Example 2 was separated into its enantiomers using a 2 x 25cm Chiralpak AD column eluting with 10% EtOH in heptane with a flow rate of 15ml_/min. Example 3, (enantiomer

1 ) eluted after 14.1 min (6.2mg) and Example 4 (enantiomer 2) after 17.0min (5.9mg).

Analytical chiral HPLC (25 x 0.46cm Chiralpak AD column, 15% isopropanol in heptane eluting at 1 mL/min)

Example 3: 9.20min

LC/MS t_RET = 3.57min, MH⁺ = 447, MH^' = 445

Example 4: 10.88min

LC/MS t_RET = 3.57min, MH⁺ = 447, MH^' = 445

Example 5 (racemic diastereomer 1)

3.3,3-Trifluoro-2-hvdroxy-N-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)-2-(6.7.8.9- tetrahvdro-5H-benzora1cvcloheptan-5-ylmethyl)propanamide

Example 6 (racemic diastereomer 2)

3,3,3-Trifluoro-2-hvdroxy-N-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)-2-(6,7.8,9- tetrahvdro-5H-benzofa1cvcloheptan-5-ylmethyl)propanamide

To Intermediate 9 (0.060g) was added tosyl hydrazide (0.049g) and NMP (5 drops). This mixture was heated in a microwave (at 70W) to 150°C for 5min. Further tosyl hydrazide (0.049g) was added and the mixture heated in a microwave (at 70W) to 150°C for 5min. Further tosyl hydrazide (0.049g) was added and the mixture heated in a microwave (at 70W) to 150°C for 5min. The sample was then diluted with DCM (100mL) and washed with water (25mL). After drying (MgSO₄), the mixture was purified by Biotage (40S) eluting with cyclohexane : ethyl acetate using a gradient system from 95:5 to 80:20. The fractions containing desired material were isolated and further purified by reverse phase HPLC using 65-85% MeCN (0.05%TFA) gradient over 25min on a Supelcosil ABZ+ 40x21.2mm column with 4mL/min flow rate.

Example 5 (diasteromer 1 , 3mg) LC/MS t_RET = 3.55min, MH⁺ = 461 , MH^' = 459. Example 6 (diastereomer 2, 4mg) LC/MS t_RET = 3.67min, MH⁺ = 461 , MH^' = 459.

Example 7 (racemic diastereomer 1) 2-[(6-Chloro-3.4-dihvdro-2H-chromen-4-vπmethvn-3.3.3-trifluoro-2-hvdroxy-N-(4-methyl-1- oxo-1 H-2.3-benzoxazin-6-yl)propanamide

Example 8 (racemic diastereomer 2) 2-[(6-Chloro-3.4-dihvdro-2H-chromen-4-yl)methvn-3.3.3-trifluoro-2-hvdroxy-N-(4-methyl-1- oxo-1 H-2,3-benzoxazin-6-yl)propanamide Prepared from 6-chloro-4-chromanone according to Method B.

Example 7 Diastereomer 1 LC/MS (pink) t_RET = 9.91 min, MH⁺ = 483, 485. Example 8 Diastereomer 2 LC/MS (pink) t_RET = 10.49min, MH⁺ = 483, 485.

Example 9 (racemic diastereomer 1) 2-(3.4-Dihvdro-2H-1-benzothiopyran-4-ylmethyl)-3.3.3-trifluoro-2-hvdroxy-N-(4-methyl-1- oxo-1 H-2.3-benzoxazin-6-yl)propanamide

Example 10 (racemic diastereomer 2)

2-(3.4-Dihvdro-2H-1-benzothiopyran-4-ylmethyl)-3.3.3-trifluoro-2-hvdroxy-N-(4-methyl-1- oxo-1 H-2.3-benzoxazin-6-yl)propanamide

Prepared from 4-thiochromanone according to Method B.

Example 9 Diastereomer 1 LC/MS (pink) t_RET = 9.51 min, MH⁺ = 465. Example 10 Diastereomer 2

LC/MS (pink) t_RET = 10.38min, MH⁺ = 465.

Example 11 (racemic diastereomer 1)

3.3.3-Trifluoro-2-r(6-fluoro-3.4-dihvdro-2H-chromen-4-yl)methvn-2-hvdroxy-N-(4-methyl-1- oxo-1 H-2.3-benzoxazin-6-yl)propanamide

Example 12 (racemic diastereomer 2)

3.3.3-Trifluoro-2-r(6-fluoro-3.4-dihvdro-2H-chromen-4-yl)methyll-2-hvdroxy-N-(4-methyl-1 - oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 11-1 (diastereomer 1 , enantiomer 1)

3.3.3-Trifluoro-2-r(6-fluoro-3.4-dihvdro-2H-chromen-4-yl)methvn-2-hvdroxy-N-(4-methyl-1- oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 11-2 (diastereomer 1 , enantiomer 2)

3.3.3-Trifluoro-2-r(6-fluoro-3,4-dihvdro-2H-chromen-4-yl)methyll-2-hvdroxy-N-(4-methyl-1- oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Prepared from 6-fluoro-4-chromanone according to Method B.

Example 11 Diastereomer 1 LC/MS (orange) t_RET = 7.67min, MH^' = 465.

Example 12 Diastereomer 2

LC/MS (orange) t_RET = 8.27min, MH^" = 465.

Example 11 was separated into its enantiomers using a 2 x 25cm Chiralpak AS column eluting with 15% EtOH in heptane with a flow rate of 15mlJmin. Example 11-1 ,

(enantiomer 1) eluted around 12.5min and Example 11-2 (enantiomer 2) around 16.5min.

Analytical chiral HPLC (25 x 0.46cm Chiralpak AS column, 15% EtOH in heptane eluting at 1mL/min).

Example 11-1 : 8.93min

LC/MS (orange) t_RET = 7.67min, MH^" = 465

Example 11-2: 11.55minLC/MS (orange) t_RET = 7.67min, MH^" = 465

Example 13 (racemic diastereomer 1)

3.3,3-Trifluoro-2-hvdroxy-2-r(6-methyl-3.4-dihvdro-2H-chromen-4-yl)methvn-N-(4-methyl-

1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 14 (racemic diastereomer 2)

3.3.3-Trifluoro-2-hvdroxy-2-r(6-methyl-3.4-dihvdro-2H-chromen-4-yl)methyl1-N-(4-methyl- 1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide Prepared from 6-methyl-4-chromanone according to Method B.

Example 13 Diastereomer 1 LC/MS (orange) t_RET = 8.19min, MH^" = 461. Example 14 Diastereomer 2 LC/MS (orange) t_RET = 8.62min, MH^" = 461.

Example 15 (racemic diastereomer 2)

2-r(6-Chloro-3.4-dihvdro-2H-1-benzothiopyran-4-yl)methvπ-3.3.3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide Prepared from 6-chloro-4-thiochromanone according to Method B.

Example 15 Diastereomer 2

LC/MS (orange) ferr = 7.85min. MH^" = 497, 499.

Examples 16-21

Example 16 (racemic diastereomer 1)

3.3.3-Trifluoro-2-hvdroxy-/V-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)-2-r(1 -methyl-1.2.3.4- tetrahvdronaphthalen-1-yl)methyllpropanamide

Example 17 (racemic diastereomer 2)

3.3.3-Trif luoro-2-hvdroxy-Λ/-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)-2-lY1 -methyl-1.2.3.4- tetrahydronaphthalen-l-vDmethyllpropanamide

Example 18 (enantiomer 1 of diastereomer 1) 3.3.3-Trif luoro-2-hvdroxy-Λ/-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)-2-r(1 -methyl-1.2.3.4- tetrahvdronaphthalen-1-yl)methyl1propanamide

Example 19 (enantiomer 2 of diastereomer 1)

3.3,3-Trifluoro-2-hvdroxy-Λ/-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)-2-r(1 -methyl-1.2.3.4- tetrahvdronaphthalen-1-yl)methyllpropanamide

Example 20 (enantiomer 1 of diastereomer 2)

3,3.3-Trif luoro-2-hvdroxy-Λ/-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)-2-r(1 -methyl-1.2.3.4- tetrahvdronaphthalen-1-yl)methyllpropanamide

Example 21 (enantiomer 2 of diastereomer 2)

3.3,3-Trifluoro-2-hvdroxy-Λ/-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)-2-f(1 -methyl-1.2.3.4- tetrahvdronaphthalen-1-yl)methyllpropanamide

Intermediate 13 (0.15g) was dissolved in dry DMF (9.7mL) and cooled to 0°C. To this was added trimethylsilyltrifluoromethane (0.286mL) and cesium carbonate (0.158g). After stirring at RT for 3 hours TBAF (1.92mL of a 1 M solution in THF) was added. After 30 minutes the mixture was acidified with 1 M HCI (6.4mL) and extracted with EtOAc. The combined extracts were washed with brine, dried and concentrated in vacuo to a gum (0.27g). Purification by flash chromatography eluting with cyclohexane : EtOAc 7 : 3 followed by mass-directed chromatography gave the following:

Example 16 (2.0mg) diastereomer 1 LC/MS = 3.54 min, MH⁺ = 461 , MH^" = 459. Example 17 (2.4mg) diastereomer 2

LC/MS _t = 3.62 min, MH⁺ = 461 , MH^" = 459.

Example 16 (4.1 mg) was separated into its enantiomers using a 2 x 25cm Chiralpak AD column eluting with 10% EtOH in heptane with a flow rate of 15ml/min. Example 18 (enantiomer 1 ) eluted after 9.2 min (1.Omg) and Example 19 (enantiomer 2) after 13.4 min (1.1mg). Analytical chiral HPLC (25 x 0.46cm Chiralpak AD column, 10% EtOH in heptane eluting at 1 ml/min)

Example 18: 7.42min LC/MS = 3.54 min, MH⁺ = 461 , MH^" = 459. Example 19: 11.17min LC/MS _t = 3.54 min, MH⁺ = 461 , MH^" = 459.

Example 17 (2.5mg) was separated into its enantiomers using a 2 x 25cm Chiralpak AD column eluting with 10% EtOH in heptane with a flow rate of 15ml/min. Example 20 (enantiomer 1) eluted after 11.0 min ( 0.82mg) and Example 21 (enantiomer 2) after 14.4 min ( 0.92mg).

Analytical chiral HPLC (25 x 0.46cm Chiralpak AD column, 10% EtOH in heptane eluting at 1 ml/min) Example 20: 9.12min

LC/MS t_ret = 3.62 min, MH⁺ = 461 , MH^" = 459. Example 21 : 11.78min

LC/MS = 3.62 min, MH⁺ = 461 , MH^" = 459.

Examples 22- 27

Example 22 (racemic diastereomer 1)

3.3.3-Trif luoro-2-hvdroxy-Λ/-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)-2-IY1 -ethyl-1.2.3.4- tetrahydronaphthalen-l -vDmethyllpropanamide

Example 23 (racemic diastereomer 2)

3.3.3-Trif luoro-2-hvdroxy-A/-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)-2-r(1 -ethyl-1.2.3.4- tetrahydronaphthalen-l -vOmethyllpropanamide

Example 24 (enantiomer 1 of diastereomer 1)

3.3.3-Trif luoro-2-hvdroxy-/V-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)-2-IY1 -ethyl-1.2.3.4- tetrahydronaphthalen-1 -yl)methyllpropanamide

Example 25 (enantiomer 2 of diastereomer 1) 3,3.3-Trif luoro-2-hvdroxy-Λ/-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)-2-r(1 -ethyl-1.2.3.4- tetrahvdronaphthalen-1-yl)methyllpropanamide

Example 26 (enantiomer 1 of diastereomer 2)

3.3.3-Trif luoro-2-hvdroxy-Λ/-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)-2-r(1 -ethyl-1.2.3.4- tetrahydronaphthalen-l -vDmethyllpropanamide

Example 27 (enantiomer 2 of diastereomer 2)

3.3.3-Trifluoro-2-hvdroxy-Λ/-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)-2-lϊ1 -ethyl-1.2.3.4- tetrahydronaphthalen-1-yl)methyllpropanamide Intermediate 17 (0.57g) was dissolved in dry DMF (9mL). To this was added trimethysilyltrifluoromethane (1g) and cesium carbonate (0.55g). The mixture was stirred at RT for 1 hour after which time further trimethylsilyltrifluoromethane (0.4g) was added and stirring at RT was continued overnight. Volatiles were removed in vacuo and the residue was partitioned between water and DCM. The organic layer was dried and applied directly to a 50g Si SPE cartridge eluted with DCM and DCM:MeCN 10:1. Evaporation of the appropriate fractions in vacuo gave a mixture of diastereomers (0.32g). This was purified by reverse phase preparative HPLC using a 45-80% MeCN(0.05% TFA) gradient over 50 min on a Supelcosil ABZ+ 10cm x 21.2mm column with a 4mL/min flow rate. This gave the following:

Example 22 (110mg) diastereomer 1 LC/MS tret = 3.64 min, MH⁺ = 475, MH^" = 473. Example 23 (107mg) diastereomer 2 LC/MS tret = 3.72 min, MH⁺ = 475, MH^' = 473. Example 22 (110mg) was separated into its enantiomers using a 2 x 25cm Chiralcel ODH column eluting with 10% EtOH in heptane with a flow rate of 15ml/min. Example 24 (enantiomer 1) eluted after 15.0 min (28mg) and example 25 (enantiomer 2) eluted after 20.7 min (21 mg). Analytical chiral HPLC (25 x 0.46cm Chiralcel OD-H column, 10% EtOH in heptane eluting at 1 mL/min).

Example 24: 11.06 min

LC/MS = 3.65 min, MH⁺ = 475, MH^' = 473.

Example 25: 15.69 min. LC/MS _t = 3.65 min, MH⁺ = 475, MH^' = 473.

Example 23 (107mg) was separated into its enantiomers using a 2 x 25cm Chiralpak AS column eluting with 10% EtOH in heptane with a flow rate of 15 mL/min. Example 26

(enantiomer 1 ) eluted after 11.56 min (30mg) and Example 27 (enantiomer 2) eluted after

14.63 min (26mg) .Analytical chiral HPLC (25 x 0.46cm Chiralpak AS column, 10% EtOH in heptane eluting at 1 mlJmin).

Example 26: 9.07 min.

LC/MS tret = 3.72 min, MH⁺ = 475, MH^" = 473.

Circular Dichroism (MeCN, RT v = 350-190 nm)

203.0 nm (de = -10.42; E = 23414) 210.0 nm (de = -9.52; E = 16706)

243.0 nm (de = 10.35; E = 29387)

281.4 nm (de = 4.51 ; E = 14213)

Analytical chiral HPLC (25 x 0.46cm Chiralpak AS column, 10% EtOH in heptane eluting at 1 mL/min).

Example 27: 11.29 min.

LC/MS _t = 3.72 min, MH⁺ = 475, MH^' = 473.

Example 28 (racemic diastereomer 1) 3.3,3-Trifluoro-2-hvdroxy-N-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)-2-IY7-methyl-1.2.3.4- tetrahvdro-1-naphthalenyl)methvπpropanamide

Example 29 (racemic diastereomer 2)

3,3,3-Trifluoro-2-hvdroxy-N-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)-2-f(7-methyl-1.2.3.4- tetrahvdro-1-naphthalenyl)methvπpropanamide

Example 28 and example 29 were prepared according to Method A from intermediate 20 and purified using an appropriate reverse phase HPLC gradient.

Example 28 (diastereomer 1) LC/MS t_RET = 3.67 min; MNH₄ ⁺ = 478, MH^' = 459 Example 29 (diastereomer 2) LC/MS t_RET = 3.73 min; MNH₄ ⁺ = 478, MH^" = 459

Example 30 (racemic diastereomer 1) 3.3.3-Trifluoro-2-r(7-fluoro-1 ,2.3,4-tetrahvdro-1-naphthalenyl)methvn-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 31 (racemic diastereomer 2) 3,3,3-Trifluoro-2-r(7-fluoro-1 ,2,3,4-tetrahvdro-1-naphthalenyl)methvπ-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 30 and example 31 were prepared according to Method A from intermediate 21 and purified using an appropriate reverse phase HPLC gradient.

Example 30 (racemic diastereomer 1 )

LC/MS t_RET = 3.59 min, MH⁺ = 465, MH^' = 463. Example 31 (racemic diastereomer 2) LC/MS t_RET = 3.66 min, MH⁺ = 465, MH^' = 463.

Example 32 (racemic diastereomer 1 )

2-f(7-Bromo-1.2.3,4-tetrahvdro-1-naphthalenyl)methyll-3,3.3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-7-yl)propanamide

Example 33 (racemic diastereomer 2) 2-r(7-Bromo-1.2.3,4-tetrahvdro-1-naphthalenyl)methyll-3.3.3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-7-yl)propanamide

Example 34 (diastereomer 1, enantiomer 1)

2-r(7-Bromo-1.2.3.4-tetrahvdro-1-naphthalenyl)methvn-3,3,3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-7-yl)propanamide

Example 35 (diasteromer 1 enantiomer 2)

2-r(7-Bromo-1.2,3,4-tetrahvdro-1-naphthalenyl)methvn-3,3,3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-7-yl)propanamide Example 32 and Example 33 were prepared according to Method A from intermediate 19 and purified using an appropriate reverse phase HPLC gradient.

Example 32 (racemic diastereomer 1 )

LC/MS t_RET = 3.70 min; MH⁺ = 525, 527, MH^' = 523, 525.

Example 33 (racemic diastereomer 2) LC/MS t_RET = 3.82 min; MH⁺ = 525, 527, MH^' = 523, 525.

Example 32 was separated into its enantiomers using a 2 x 25cm Chiralcel OJ column eluting with 15% EtOH in heptane with a flow rate of 15mL/min. Example 34 (enantiomer

1 ) eluted after 18.65 min and example 35 (enantiomer 2) after 25.67 min.

Analytical chiral HPLC (25 x 0.46cm Chiralcel OJ column, 15% EtOH in heptane eluting at 1 mL min).

Example 34: 14.63 min

LC/MS t_RET = 3.70 min; MH⁺ = 525, 527, MH^' = 523, 525.

Example 35: 21.29 min LC/MS t_RET = 3.70 min; MH⁺ = 525, 527, MH^' = 523, 525.

Example 36 (racemic diastereomer 1)

3.3.3-Trifluoro-2-hvdroxy-N-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-vh-2-f(7-nitro-1.2.3.4- tetrahvdro-1-naphthalenyl)methvnpropanamide

Example 37 (racemic diastereomer 2)

3.3,3-Trifluoro-2-hvdroxy-N-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)-2-r(7-nitro-1.2.3.4- tetrahydro-l-naphthalenvDmethyllpropanamide Example 36 and example 37 were prepared according to Method A from 7-nitro-1- tetralone and purified using an appropriate reverse phase HPLC gradient. Example 36 (racemic diastereomer 1 ) LC/MS t_RET = 8.90 min; MH⁺ = 492

Example 37 (racemic diastereomer 2) LC/MS t_RET = 9.51 min; MH⁺ = 492

Examples 38-41

Example 38 (racemic diastereomer 1) 2-r(8-Chloro-5-fluoro-1.2.3.4-tetrahvdro-1-naphthalenyl)methvn-3.3.3-trifluoro-2-hvdroxy- N-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)propanamide

Example 39 (racemic diastereomer 2)

2-f(8-Chloro-5-fluoro-1.2.3.4-tetrahvdro-1-naphthalenyl)methyll-3,3.3-trifluoro-2-hvdroxy- N-f4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 40 (diastereomer 1, enantiomer 1)

2-r(8-Chloro-5-fluoro-1.2.3,4-tetrahvdro-1-naphthalenyl)methvn-3.3.3-trifluoro-2-hvdroxy-

N-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 41 (diastereomer 1, enantiomer 2)

2-r(8-Chloro-5-fluoro-1 ,2.3,4-tetrahvdro-1-naphthalenyl)methvn-3,3.3-trifluoro-2-hvdroxy-

N-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Examples 38 and 39 were similarly prepared to method A from Intermediate 24 and separated using Si chromatography eluting with cyclohexane : EtOAc (gradient of 30:1 to

1 :1). Example 38 was purified further using an appropriate reverse phase HPLC gradient.

Example 38 (10mg) diastereomer 1 LC/MS t_RET = 3.69min, MH⁺ = 499, 501. Example 39 (53mg) diastereomer 2

LC/MS t_RET = 3.79min MH⁺ = 499. 501.

Example 38 was separated into its enantiomers using a 25cm Chiralpak AS column eluting with 15% EtOH in heptane with a flow rate of 15mL per min. Example 40 (enantiomer 1),eluted after 8min and Example 41 (enantiomer 2) after 15min. Analytical chiral HPLC (25cm Chiralpak AS column, 15% EtOH in heptane, eluting at 1 mL/min).

Example 40: 8.29min LC/MS t_RET = 3.69min, MH⁺ = 499, 501. Example 41 : 11.86min LC/MS t_RET = 3.69min, MH⁺ = 499, 501.

Examples 42-47

Example 42 (racemic diastereomer 1)

2-|^"(8-Chloro-6-fluoro-1 ,2,3.4-tetrahvdro-1-naphthalenyl)methyl1-3,3,3-trifluoro-2-hvdroxy- N-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 43 (racemic diastereomer 2)

2-f(8-Chloro-6-fluoro-1 ,2,3.4-tetrahvdro-1-naphthalenyl)methvn-3,3.3-trifluoro-2-hvdroxy- N-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)propanamide

Example 44 (diastereomer 1, enantiomer 1) 2-r(8-Chloro-6-fluoro-1.2.3,4-tetrahvdro-1-naphthalenyl)methyll-3.3.3-trifluoro-2-hvdroxy- N-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)propanamide

Example 45 (diastereomer 1, enantiomer 2)

2-r(8-Chloro-6-fluoro-1 ,2,3,4-tetrahvdro-1-naphthalenyl)methyl^,|-3,3.3-trifluoro-2-hvdroxy- N-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 46 (diastereomer 2, enantiomer 1)

2-r(8-Chloro-6-fluoro-1 ,2,3,4-tetrahvdro-1-naphthalenyl)methvn-3.3.3-trifluoro-2-hvdroxy-

N-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 47 (diastereomer 2, enantiomer 2)

2-r(8-Chloro-6-fluoro-1 ,2,3.4-tetrahvdro-1-naphthalenyl)methvn-3.3.3-trifluoro-2-hvdroxy-

N-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)propanamide

Examples 42 and 43 were similarly prepared to method A from Intermediate 27 and separated using Si chromatography eluting with cyclohexane : EtOAc (gradient of 30:1 to

1:1).

Example 42 (23mg) diastereomer 1 LC/MS t_RET = 3.70min, MH⁺ = 499, 501. Example 43 (58mg) diastereomer 2

LC/MS t_RET = 3.77min, MH⁺ = 499, 501. Example 42 was separated into its enantiomers using a 2 x 25cm Chiralcel OJ column eluting with 15% EtOH in heptane with a flow rate of 15mL/min. Example 44 (enantiomer

1), eluted after 17.6min and Example 45 (enantiomer 2), after 26.0min.

Analytical chiral HPLC (25cm Chiralcel OJ column, 15% EtOH in heptane eluting at

1 mL/min).

Example 44: 15.97min

LC/MS t_RET = 3.70min, MH⁺ = 499, 501

Example 45 23.80min

LC/MS t_RET = 3.70min, MH⁺ = 499, 501

Examples 43 was separated into its enantiomers using a 2 x 25cm Chiralpak AS column eluting with 10% EtOH in heptane with a flow rate of 15mL/min. Example 46 (enantiomer 1), eluted after 12.3min and Example 47 (enantiomer 2), after 18.9min. Analytical chiral HPLC (25cm Chiralpak AS column, 10% EtOH in heptane eluting at 1 mL/min).

Example 46: 13.86min

LC/MS t_RET = 3.77min, MH⁺ = 499, 501

Example 47: 17.20min

LC/MS t_RET = 3.77min, MH⁺ = 499, 501

Examples 48-51

Example 48 (racemic diastereomer 1)

2-f(6-Chloro-8-fluoro-1.2,3,4-tetrahvdro-1-naphthalenyl)methvn-3.3.3-trifluoro-2-hvdroxy- N-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 49 (racemic diastereomer 2)

2-r(6-Chloro-8-fluoro-1 ,2,3.4-tetrahvdro-1-naphthalenyl)methvn-3.3.3-trifluoro-2-hvdroxy- N-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 50 (diastereomer 2, enantiomer 1)

2-r(6-Chloro-8-fluoro-1.2.3.4-tetrahvdro-1-naphthalenyl)methyll-3.3.3-trifluoro-2-hvdroxy- N-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 51 (diastereomer 2, enantiomer 2)

2-r(6-Chloro-8-fluoro-1 ,2,3,4-tetrahvdro-1-naphthalenyl)methyll-3,3,3-trifluoro-2-hvdroxy- N-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Intermediate 26 (0.08g), 4-methylbenzenesulfonyl hydrazide (0.06g), and 1-methyl-2- pyrrolidinone (5 drops), were heated in a tapered vial at 150°C for 4 minutes, after which time, more 4-methylbenzenesulfonyl hydrazide (0.06g) was added and the reaction heated at 150°C for a further 4 minutes. The residue was diluted with EtOAc (20mL), and washed with water (3 x 20mL). The organic layer was dried (MgSO₄) and reduced in vacuo. Purification using Si chromatography eluting with cyclohexane : EtOAc (gradient of 30:1 to 1 :1) afforded Examples 48 and 49. Example 48 (8mg) diastereomer 1

LC/MS t_RET = 3.71 min, MH⁺ = 499, 501

Example 49 (16mg) diastereomer 2

LC/MS t_RET 3.79min, MH⁺ = 499, 501

Example 49 was separated into its enantiomers using a 25cm Chiralpak AD column eluting with 15% isopropanol in heptane with a flow rate of 15mL/min. Example 50

(enantiomer 1) eluted after 12.0min and Example 51 (enantiomer 2) after 13.6min.

Analytical chiral HPLC (25cm Chiralpak AD column, 15% isopropanol in heptane eluting at 1 mL/min).

Example 50: 9.28min

LC/MS t_RET 3.79min, MH⁺ = 499, 501

Example 51 : 11.21 min

LC/MS t_RET 3.79min, MH⁺ = 499, 501

Example 52 (racemic diastereomer 1)

2-r(6-Chloro-1.2.3.4-tetrahvdro-1-naphthalenyl)methvn-3.3.3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 53 (racemic diastereomer 2)

Example 54 (diastereomer 1 , enantiomer 1) 2-r(6-Chloro-1.2.3.4-tetrahvdro-1-naphthalenyl)methvn-3.3.3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)propanamide

Example 55 (diastereomer 1, enantiomer 2)

2-r(6-Chloro-1.2,3.4-tetrahvdro-1-naphthalenyl)methvπ-3.3.3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Prepared from Intermediate 28 according to Method A and purified using an appropriate reverse phase HPLC gradient.

Example 52 Diastereomer 1

LC/MS t_RET = 3.75min, MH⁺ = 481 , 483, MH^" = 479, 481. Example 53 Diastereomer 2

LC/MS t_RET = 3.77min, MH⁺ = 481 , 483, MH^" = 479, 481.

Example 52 was separated into its enantiomers using a 2 x 25cm Chiralpak AS column eluting with 10% EtOH in heptane with a flow rate of 15ml_/min. Example 54, (enantiomer

1) eluted around 14.5min and Example 55 (enantiomer 2) between 22.5 - 25.5min. Analytical chiral HPLC (25 x 0.46cm Chiralpak AS column, 15% EtOH in heptane eluting at 1 mL min)

Example 54: 12.09min

LC/MS t_REτ = 3.75min, MH⁺ = 481 , 483, MH^" = 479, 481.

Example 55: 17.26min LC/MS t_RET = 3.75min, MH⁺ = 481 , 483, MH^" = 479, 481.

Example 56 (racemic diastereomer 1)

3.3.3-Trifluoro-2-f(6-fluoro-1 ,2,3,4-tetrahvdro-1-naphthalenyl)methvn-2-hydroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 57 (racemic diastereomer 2)

3,3.3-Trifluoro-2-r(6-fluoro-1.2.3.4-tetrahvdro-1-naphthalenyl)methvn-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 58 (diastereomer 1, enantiomer 1)

3.3.3-Trifluoro-2-r(6-fluoro-1.2.3.4-tetrahvdro-1-naphthalenyl)methvn-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 59 (diastereomer 1 , enantiomer 2)

Prepared from Intermediate 29 according to Method A and purified using an appropriate reverse phase HPLC gradient. Example 56 Diastereomer 1

LC/MS t_RET = 3.60min, MH⁺ = 465, MH^' = 463.

Example 57 Diastereomer 2

LC/MS t_RET = 3.62min, MH⁺ = 465, MH^' = 463.

Example 56 was separated into its enantiomers using a 2 x 25cm Chiralpak AD column eluting with 20% EtOH in heptane with a flow rate of 15ml_/min. Example 58, (enantiomer

1) eluted around 7min and Example 59 (enantiomer 2) around 8.5min.

Analytical chiral HPLC (25 x 0.46cm Chiralpak AD column, 20% EtOH in heptane eluting at 1 mL/min)

Example 58: 5.30min LC/MS t_RET = 3.60min, MH⁺ = 465, MH^' = 463.

Example 59: 6.52min

LC/MS t_RET = 3.60min, MH⁺ = 465, MH^' = 463.

Example 60 (racemic diastereomer 1) 2-r(6-Bromo-1.2.3,4-tetrahvdro-1-naphthalenyl)methvn-3.3.3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 61 (racemic diastereomer 2)

2-r(6-Bromo-1.2.3,4-tetrahvdro-1-naphthalenyl)methvn-3.3,3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 62 (diastereomer 1, enantiomer 1)

2-r(6-Bromo-1.2.3.4-tetrahvdro-1-na^phthalenyl)methyll-3.3.3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide Example 63 (diastereomer 1, enantiomer 2)

2-[(6-Bromo-1.2,3,4-tetrahvdro-1-naphthalenyl)methvn-3,3.3-trifluoro-2-hvdroχy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide Prepared from Intermediate 30 according to Method A and purified using an appropriate reverse phase HPLC gradient.

Example 60 Diastereomer 1

LC/MS t_RET = 3.76min, MH⁺ = 525, 527, MH^" = 523, 525.

Example 61 Diastereomer 2 LC/MS t_RET = 3.84min, MH⁺ = 525, 527, MH^" = 523, 525.

Example 60 was separated into its enantiomers using a 2 x 25cm Chiralpak AS column eluting with 10% EtOH in heptane with a flow rate of 15mL/min. Example 62, (enantiomer

1 ) eluted around 18.5min and Example 63 (enantiomer 2) around 26min.

Analytical chiral HPLC (25 x 0.46cm Chiralpak AS column, 10% EtOH in heptane eluting at 1 mL/min)

Example 62: 13.16min

LC/MS t_RET = 3.76min, MH⁺ = 525, 527, MH^" = 523, 525.

Example 63: 19.06min

LC/MS t_RET = 3.76min, MH⁺ = 525, 527, MH^" = 523, 525.

Example 64 (racemic diastereomer 1)

3.3.3-Trifluoro-2-hvdroxy-N-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)-2-r(6-methyl-1 ,2,3.4- tetrahydro-1-naphthalenyl)methyllpropanamide

Example 65 (racemic diastereomer 2)

3.3.3-Trif luoro-2-hvdroxy-N-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)-2-r(6-methyl-1.2.3.4- tetrahydro-l-naphthalenvOmethyllpropanamide

Example 66 (diastereomer 1, enantiomer 1) 3,3,3-Trifluoro-2-hvdroxy-N-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)-2-r(6-methyl-1.2.3.4- tetrahvdro-1-naphthalenyl)methvπpropanamide

Example 67 (diastereomer 1, enantiomer 2)

3,3,3-Trifluoro-2-hvdroxy-N-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)-2-r(6-methyl-1.2.3.4- tetrahydro-l-naphthalenvDmethyllpropanamide

Prepared from Intermediate 31 according to Method A and purified using an appropriate reverse phase HPLC gradient.

Example 64 Diastereomer 1

LC/MS t_RET = 3.70min, MH⁺ = 461 , MH^" = 459. Example 65 Diastereomer 2

LC/MS t_RET = 3.70min, MH⁺ = 461 , MH^" = 459.

Example 64 was separated into its enantiomers using a 2 x 25cm Chiralpak AS column eluting with 10% EtOH in heptane with a flow rate of 15mL/min. Example 66, (enantiomer

1) eluted around 15.5min and Example 67 (enantiomer 2) around 21 min. Analytical chiral HPLC (25 x 0.46cm Chiralpak AS column, 10% EtOH in heptane eluting at 1 mL/min) Example 66: 11.07min

LC/MS t_REτ = 3.70min, MH⁺ = 461 , MH^' = 459. Example 67: 14.96min

LC/MS t_RET = 3.70min, MH⁺ = 461 , MH^' = 459.

Example 68 (racemic diastereomer 1)

2-r(6-Cvano-1 ,2,3,4-tetrahvdro-1-naphthalenyl)methyll-3.3.3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 69 (racemic diastereomer 2)

2-r(6-Cvano-1.2.3.4-tetrahvdro-1-naphthalenyl)methvπ-3,3,3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide Prepared from Intermediate 32 according to Method A and purified using an SPE Bond

Elut with an appropriate cyclohexane/EtOAc gradient.

Example 68 Diastereomer 1

LC/MS t_RET = 3.44min, MH^' = 470.

Example 69 Diastereomer 2 LC/MS t_RET = 3.52min, MH^" = 470.

Example 70 (racemic diastereomer 1)

2-r(6-Methoxy-1.2.3.4-tetrahvdro-1-naphthalenyl)methyl1-3.3.3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 71 (racemic diastereomer 2)

2-r(6-Methoxy-1.2.3.4-tetrahvdro-1-naphthalenyl)methvn-3.3.3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Prepared from 6-methoxy-1 -tetralone according to Method A and purified using an SPE Bond Elut with an appropriate DCM/MeCN gradient and then by reverse phase HPLC using an appropriate gradient.

Example 70 Diastereomer 1

LC/MS t_RET = 3.51 min, MH^' = 475.

Example 71 Diastereomer 2 LC/MS t_RET = 3.57min, MH^" = 475.

Example 72 (racemic diastereomer 1)

3,3.3-Trif luoro-2-hvdroxy-N-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)-2-r(8-nitro-1 ,2.3.4- tetrahvdro-1-naphthalenyl)methyllpropanamide

Example 73 (racemic diastereomer 2)

3.3,3-Trifluoro-2-hvdroxy-N-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)-2-IY8-nitro-1.2.3.4- tetrahvdro-1-naphthalenyl)methvπpropanamide Intermediate 36 (0.449g) was azeotroped from PhMe three times and then dissolved in DMF (27mL). After cooling to 0°C, trimethylsilyltrifluoromethane (0.80mL) and caesium carbonate (0.431 g) were added. After warming to RT, further trimethylsilyltrifluoromethane (0.40mL) was added. After 45min, TBAF (1 M in THF) (5.5mL) was added. After 30min, 2M HCI (10mL) and water (10mL) were added and the mixture extracted with EtOAc (3 x 25mL). The combined extracts were washed with brine (25mL), dried (MgSO₄) and concentrated in vacuo. Purification by repeated flash column eluting with 1-1.5% MeOH in CHCI₃ gave Examples 72 (0.08g) and 73 (0.025g). Example 72 Diastereomer 1 LC/MS t_RET = 3.41 min, MH⁺ = 492, MH^" = 490. Example 73 Diastereomer 2 LC/MS t_RET = 3.52min, MH⁺ = 492, MH^" = 490.

Example 74 (racemic diastereomer 1) 2-f(8-Amino-1.2,3,4-tetrahvdro-1-naphthalenyl)methvn-3,3.3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 72 (0.145g), stannous chloride dihydrate (0.44g) and THF (2.5mL) were heated at 60°C for 3h. After cooling and concentration in vacuo, purification using an aminopropyl Bond Elut eluting with MeOH followed by a gravity column on SiO₂ eluting with 2.5% MeOH in CHCI₃ gave Example 74 (0.071 g). LC/MS t_RET = 3.37min, MH⁺ = 462, MH^' = 460.

Example 75 (racemic diastereomer 1)

3,3,3-Trifluoro-2-hvdroxy-2-r(8-iodo-1.2,3,4-tetrahvdro-1 -naphthalenyl)methyll-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 74 (0.07g), potassium iodide (0.051 g) and DMF were cooled to 0°C and t- butylnitrite (0.13mL) added. After warming to RT for 3h, the mixture was re-cooled to 0°C and further f-butyl nitrite (0.4mL) added. After stirring at RT for 18h, the mixture was concentrated in vacuo and purified twice by flash column eluting with 0-2% MeOH in CHCI₃ to afford Example 75 (0.059g).

LC/MS t_RET = 3.78min, MH⁺ = 573, MH^' = 571.

Example 76 (racemic diastereomer 1)

3,3,3-Trif luoro-2-hvdroxy-N-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)-2-IY8-methyl-1 ,2.3.4- tetrahydro-l-naphthalenvDmethyllpropanamide

Example 75 (0.03g), palladium chloride bistriphenylphosphine (0.003g), tetramethylstannane (0.04g) and PhMe (4mL) were heated at 112°C for 2h. Further catalyst (0.003g) and stannane (0.5mL) were then added. After 6h, the mixture was cooled, filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with 1-2% MeOH in CHCI₃ followed by reverse phase HPLC eluting with a 1 h gradient of 45-80% MeCN (0.05%TFA) gradient over 45min on a Supelcosil ABZ+ 40 x 21.2mm column with 4mLJmin flow rate to afford Example 76 (4.5mg). LC/MS t_RET = 3.65min, MH⁺ = 461 , MH^' = 459. Example 77 (racemic diastereomer 2)

2-r(8-Amino-1 ,2,3,4-tetrahvdro-1-naphthalenyl)methyll-3,3,3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide Example 77 was similarly prepared to Example 74 from Example 73. LC/MS t_RET = 3.52min, MH⁺ = 462, MH^' = 460.

Example 78 (racemic diastereomer 2)

3.3.3-Trifluoro-2-hvdroxy-2-r(8-iodo-1.2.3.4-tetrahvdro-1-naphthalenyl)methyll-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide Example 78 was similarly prepared to Example 75 from Example 77. LC/MS t_RET = 3.80min, MH⁺ = 573, MH^' = 571.

Example 79 (racemic diastereomer 2)

2-r(8-Chloro-1.2.3.4-tetrahvdro-1-naphthalenyl)methyl1-3,3.3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 80 (racemic diastereomer 2)

3.3,3-Trifluoro-2-r(8-fluoro-1.2.3.4-tetrahvdro-1-naphthalenyl)methvπ-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide Example 77 (30mg), DCM (0.2mL) and DMF (0.15mL) were cooled to -15°C and boron trifluoride diethyl etherate (0.030mL) added. f-Butylnitrite (0.025mL) in DCM (0.1 mL) was then added and after 15min, the mixture allowed to warm to 5°C. After adding hexane, the mixture was allowed to stand at RT for 2 days. After concentration in vacuo, the residue was purified by flash chromatography on silica eluting with 1 % MeOH in CHCI₃. The material from this column was then further purified by mass directed preparative HPLC to afford Example 79 (1.95mg) and Example 80 (5.6mg). It is probable that the chlorine atom was introduced into Example 79 not during this step but was a contaminant in the starting material Example 77 (prepared by treatment with stannous chloride dihydrate). Example 79

LC/MS t_RET = 3.68min, MH⁺ = 481 , 483, MH^' = 479, 481.

Example 80

LC/MS t_RET = 3.57min, MH⁺ = 465, MH^' = 463.

Example 81 (Racemic diastereomer 1)

2-r(8-Amino-5-bromo-1 ,2,3,4-tetrahvdro-1-naphthalenyl)methvn-3,3,3-trifluoro-2-hydroxy- N-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide.

To Example 74 (5mg) in chloroform (0.25mL) was added 1 M bromine in chloroform (11.9uL). After stirring at RT overnight, additional 1 M bromine in chloroform (10.8uL) was added. After 3hr, the reaction mixture was concentrated in vacuo. Mass directed chromatography gave the title product (1.5mg). LC/MS t_RET = 3.59min, MH⁺ = 540, 542, MH^' = 538, 540.

Example 82 (Racemic diastereomer 1) 2-r(8-Amino-5,7-dibromo-1 ,2.3.4-tetrahvdro-1-naphthalenyl)methyll-3.3,3-trifluoro-2- hvdroχy-N-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide. To Example 74 (5mg) in chloroform (0.25mL) was added N-bromosuccinimide (2.1 mg) and AIBN (0.5mg). After stirring at RT for 4 hr, the reaction mixture was diluted with chloroform (5mL) and washed with water (5mL). The organic layer was separated, dried (MgSO₄) and concentrated in vacuo. Mass directed chromatography gave the title product (2.6mg). LC/MS t_RET = 4.01 min, MH⁺ = 618, 620, 622, MH^' = 616, 618, 620.

Examples 83-87

Example 83 (Racemic diastereomer 1)

2-r(8-Amino-5-chloro-1 ,2.3.4-tetrahvdro-1-naphthalenyl)methvn-3.3.3-trifluoro-2-hvdroxy- N-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 84 (Racemic diastereomer 1 )

2-r(8-Amino-7-chloro-1 ,2,3,4-tetrahvdro-1-naphthalenyl)methvn-3,3,3-trifluoro-2-hvdroxy- N-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)propanamide

Example 85 (Racemic diastereomer 1) 2-r(8-Amino-5.7-dichloro-1.2.3.4-tetrahvdro-1-naphthalenyl)methyll-3.3,3-trifluoro-2- hvdroxy-N-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 86 (Diastereomer 1 , enantiomer 1)

2-r(8-Amino-5-chloro-1 ,2,3,4-tetrahvdro-1-naphthalenyl)methyll-3,3,3-trifluoro-2-hydroxy- N-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 87 (Diastereomer 1, enantiomer 2)

2-r(8-Amino-5-chloro-1 ,2.3,4-tetrahvdro-1-naphthalenyl)methvn-3,3,3-trifluoro-2-hvdroxy-

N-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide To Example 74 (53.8mg) in chloroform (1 mL) was added N-chlorosuccinimide (18.7mg) and AIBN (5mg). The mixture was heated at 60°C for 90 min. The reaction mixture was diluted with chloroform (5mL) and washed with water (5mL). The organic layer was separated, dried (MgSO ) and concentrated in vacuo. Purification on a Si preparative plate, eluting with 2.5 % MeOH/CHCI₃ (x4) gave Example 83 (racemic diastereomer 1) (12.5mg).

LC/MS t_RET = 3.64min, MH⁺ = 496, MH^' = 494.

Further purification of other bands from the preparative plate by mass directed chromatography gave the following:

Example 84 (1.9mg). LC/MS t_RET = 3.66min, MH⁺ = 496, MH^' = 494.

Example 85 (10.4mg)

LC/MS t_RET = 3.91 min, MH⁺ = 530, MH^' = 528. Example 83 was separated into its enantiomers using a 2 x 25cm Chiralpak AD column eluting with 20% IPA in heptane with a flow rate of 15mlJmin. Example 86, (enantiomer

1) eluted around 14.5min and Example 87 (enantiomer 2) around 20.5min.

Analytical chiral HPLC (25 x 0.46cm Chiralpak AD column, 30% IPA in heptane eluting at

1 mL/min):

Example 86: 5.24min

LC/MS t_RET = 3.64min, MH⁺ = 496, MH^" = 494.

Example 87: 8.06min

LC/MS t_RET = 3.64min, MH⁺ = 496, MH^" = 494.

Example 88 (racemic diastereomer 1)

3.3.3-Trifluoro-2-r(5-fluoro-1.2,3,4-tetrahvdro-1-naphthalenyl)methyll-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 89 (racemic diastereomer 2)

3.3.3-Trifluoro-2-r(5-fluoro-1 ,2,3,4-tetrahvdro-1-naphthalenyl)methyll-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 90 (diastereomer 1, enantiomer 1) 3.3.3-Trifluoro-2-r(5-fluoro-1 ,2,3,4-tetrahvdro-1-naphthalenyl)methvn-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 91 (diastereomer 1, enantiomer 2)

3.3.3-Trifluoro-2-r(5-fluoro-1.2.3.4-tetrahvdro-1-naphthalenyl)methvn-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 92 (diastereomer 2, enantiomer 1)

3,3.3-Trifluoro-2-r(5-fluoro-1.2.3.4-tetrahvdro-1-naphthalenyl)methvn-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 93 (diastereomer 2, enantiomer 2)

3.3.3-Trifluoro-2-r(5-fluoro-1 ,2,3.4-tetrahvdro-1-naphthalenyl)methyll-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Prepared from Intermediate 39 according to method A and purified using an appropriate reverse phase HPLC gradient.

Example 88 (diastereomer 1 )

LC/MS t_RET = 3.60 min, MH⁺ = 465, MH^" = 463.

Example 89 (diastereomer 2)

LC/MS t_RET = 3.65 min, MH⁺ = 465, MH^" = 463. Example 88 was separated into its enantiomers using a 25cm Chiralcel OD-H column eluting with 15% EtOH in heptane with a flow rate of 15mL/min. Example 90 (enantiomer

1) eluted around 13.8 min and example 91 (enantiomer 2) around 19 min. Analytical chiral HPLC (25 x 0.46cm Chiralcel OD-H column, 15% EtOH in heptane eluting at

I mlJmin). Example 90: 10.21 min

LC/MS t_RET = 3.60 min, MH⁺ = 465, MH^" = 463.

Example 91 : 14.28 min

LC/MS t_RET = 3.60 min, MH⁺ = 465, MH^" = 463.

Example 89 was separated into its enantiomers using a 25 cm Chiralcel OD-H column eluting with 30% EtOH in heptane with a flow rate of 15mL/min. Example 92 (enantiomer

1 ) eluted around 7.1 min and example 93 (enantiomer 2) around 14.3 min. Analytical chiral HPLC (25 x 0.46cm Chiralcel OD-H column, 30% EtOH in heptane eluting at I mLJmin).

Example 92: 5.44 min

LC/MS t_RET = 3.65 min, MH⁺ = 465, MH^" = 463.

Example 93: 10.31 min

LC/MS t_RET = 3.65 min, MH⁺ = 465, MH^" = 463.

Example 94 (racemic diastereomer 1)

2-r(5-Chloro-1.2.3.4-tetrahvdro-1-naphthalenyl)methvn-3.3.3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)propanamide

Example 95 (racemic diastereomer 2)

2-r(5-Chloro-1.2.3.4-tetrahvdro-1-naphthalenyl)methvn-3.3.3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 96 (diastereomer 1, enantiomer 1) 2-r(5-Chloro-1 ,2,3,4-tetrahvdro-1-naphthalenyl)methvn-3,3.3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 97 (diastereomer 1, enantiomer 2)

Example 98 (diastereomer 2, enantiomer 1)

2-r(5-Chloro-1.2.3,4-tetrahvdro-1-naphthalenyl)methyll-3.3.3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 99 (diastereomer 2, enantiomer 2)

2-r(5-Chloro-1 ,2,3.4-tetrahvdro-1-naphthalenyl)methvn-3,3,3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Prepared from intermediate 38 according to method A and purified using an appropriate reverse phase HPLC gradient.

Example 94 (diastereomer 1)

LC/MS t_RET = 3.74 min, MH⁺ = 481 , 483, MH^" = 479, 481.

Example 95 (diastereomer 2)

LC/MS t_RET = 3.81 min, MH⁺ = 481 , 483, MH^" = 479, 481. Example 94 was separated into its enantiomers using a 25 cm Chiralcel OD-H column eluting with 15% EtOH in heptane with a flow rate of 15mL/min. Example 96 (enantiomer 1) eluted around 14.1 min and example 97 (enantiomer 2) around 21.9 min. Analytical chiral HPLC (25 x 0.46cm Chiralcel OD-H column, 15% EtOH in heptane eluting at 1 mL/min). Example 96: 11.21 min

LC/MS t_RET = 3.74 min, MH⁺ = 481 , 483, MH^" = 479, 481. Example 97: 17.26 min LC/MS t_RET = 3.74 min, MH⁺ = 481 , 483, MH^" = 479, 481.

Example 95 was separated into its enantiomers using a 25 cm Chiralpak AD column eluting with 10% IPA in heptane with a flow rate of 15mLJmin. Example 98 (enantiomer 1) eluted around 22.6 min and example 99 (enantiomer 2) around 31.0 min. Analytical chiral HPLC (25 x 0.46cm Chiralpak AD column, 10% IPA in heptane eluting at 1 mL/min).

Example 98: 17.91 min

LC/MS t_RET = 3.81 min, MH⁺ = 481 , 483, MH^" = 479, 481. Example 99: 24.30 min

LC/MS t_RET = 3.81 min, MH⁺ = 481 , 483, MH^" = 479, 481.

Example 100 (racemic diastereomer 1)

2-r(5-Bromo-1 ,2,3,4-tetrahvdro-1-naphthalenyl)methvn-3,3.3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 101 (racemic diastereomer 2)

2-|^"(5-Bromo-1 ,2,3,4-tetrahvdro-1-naphthalenyl)methyl1-3,3,3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 102 (diastereomer 1, enantiomer 1)

2-r(5-Bromo-1 ,2.3,4-tetrahvdro-1-naphthalenyl)methvn-3.3,3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 103 (diastereomer 1 , enantiomer 2)

2-f(5-Bromo-1.2,3,4-tetrahvdro-1-naphthalenyl)methvn-3,3,3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 104 (diastereomer 2, enantiomer 1) 2-r(5-Bromo-1.2.3.4-tetrahvdro-1-naphthalenyl)methyl1-3.3.3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 105 (diastereomer 2, enantiomer 2) 2-[(5-Bromo-1 ,2.3.4-tetrahvdro-1-naphthalenyl)methvn-3.3.3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)propanamide

Prepared from 5-bromo-1 -tetralone (Intermediate 40) according to method A and purified using an appropriate reverse phase HPLC gradient. Example 100 (diastereomer 1 )

LC/MS t_Rετ = 3.78 min, MH⁺ = 525, 527, MH^" = 523, 525.

Example 101 (diastereomer 2)

LC/MS t_RET = 3.85 min, MH⁺ = 525, 527, MH^" = 523, 525.

Example 100 was separated into its enantiomers using a 25 cm Chiralcel OD-H column eluting with 15% EtOH in heptane with a flow rate of 15ml_/min. Example 102

(enantiomer 1) eluted around 10.6 min and example 103 (enantiomer 2) around 16.0 min.

Analytical chiral HPLC (25 x 0.46cm Chiralcel OD-H column, 15% EtOH in heptane eluting at 1 mL min). Example 102: 11.41 min

LC/MS t_RET = 3.78 min, MH⁺ = 525, 527, MH^" = 523, 525.

Example 103: 17.83 min

LC/MS t_RET = 3.78 min, MH⁺ = 525, 527, MH^" = 523, 525.

Example 101 was separated into its enantiomers using a 25 cm Chiralpak AD column eluting with 15% IPA in heptane with a flow rate of 15mL/min. Example 104 (enantiomer

1 ) eluted around 12.6 min and example 105 (enantiomer 2) around 15.7 min.

Analytical chiral HPLC (25 x 0.46cm Chiralpak AD column, 15% IPA in heptane eluting at

1 mL/min). Example 104: 9.55 min

LC/MS t_RET = 3.85 min, MH⁺ = 525, 527, MH^" = 523, 525.

Example 105: 11.80 min

LC/MS t_RET = 3.85 min, MH⁺ = 525, 527, MH^" = 523, 525.

Example 106 (racemic diastereomer 1)

3.3.3-Trifluoro-2-hvdroxy-N-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)-2-r(5-methyl-1.2.3.4- tetrahvdro-t-naphthalenyl)methvπpropanamide

Example 107 (racemic diastereomer 2) 3,3,3-Trif luoro-2-hvdroxy-N-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)-2-r(5-methyl-1.2.3.4- tetrahvdro-1-naphthalenyl)methvπpropanamide

Example 108 (diastereomer 1 , enantiomer 1)

3,3,3-Trif luoro-2-hvdroxy-N-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)-2-r(5-methyl-1.2.3.4- tetrahydro-l-naphthalenvDmethyllpropanamide

Example 109 (diastereomer 1, enantiomer 2)

3,3,3-Trif luoro-2-hvdroxy-N-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)-2-IY5-methyl-1.2.3.4- tetrahvdro-1-naphthalenyl)methyllpropanamide Prepared from Intermediate 42 according to method A and purified using an appropriate reverse phase HPLC gradient. Example 106 (diastereomer 1) LC/MS t_RET = 3.66 min, MH⁺ = 461 , MH^" = 459. Example 107 (diastereomer 2)

LC/MS t_RET = 3.71 min, MH⁺ = 461 , MH^" = 459.

Example 106 was separated into its enantiomers using a 25 cm Chiralcel OD-H column eluting with 10% EtOH in heptane with a flow rate of 15mlJmin. Example 108 (enantiomer 1 ) eluted around 25.9min and Example 109 (enantiomer 2) around 30.7min.

Analytical chiral HPLC (25 x 0.46cm Chiralcel OD-H column, 10% EtOH in heptane eluting at 1 mL/min)

Example 108: 21.01 min

LC/MS t_RET = 3.66 min, MH⁺ = 461 , MH^" = 459. Example 109: 25.34 min

LC/MS t_RET = 3.66 min, MH⁺ = 461 , MH^" = 459.

Example 110 (racemic diastereomer 1)

2-r(5-Cvano-1.2,3,4-tetrahvdro-1-naphthalenyl)methvn-3,3,3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 111 (racemic diastereomer 2)

2-r(5-Cvano-1 ,2,3,4-tetrahvdro-1-naphthalenyl)methvn-3,3,3-trifluoro-2-hydroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide Prepared from intermediate 41 according to method A and purified using an appropriate reverse phase HPLC gradient.

Example 110 (diastereomer 1 )

LC/MS t_RET = 3.45 min, MNH₄ ⁺ = 489, MH^" = 470.

Example 111 (diastereomer 2) LC/MS t_RET = 3.50 min, MNH₄ ⁺ = 489, MH^" = 470.

Example 112 (racemic diastereomer 1)

3,3,3-Trifluoro-2-hvdroxy-N-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)-2-(r5-(methyloxy)-

1 ,2,3.4-tetrahvdro-1 -naphthalenyllmethyllpropanamide

Example 113 (racemic diastereomer 2)

3,3,3-Trifluoro-2-hvdroxy-N-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)-2-{r5-(methyloxy)-

1 ,2,3,4-tetrahvdro-1 -naphthalenyllmethvDpropanamide

Prepared from 5-methoxy-1 -tetralone according to method A and purified using an appropriate reverse phase HPLC gradient.

Example 112 (diastereomer 1)

LC/MS t_RET = 3.56 min, MH⁺ = 477, MH^" = 475.

Example 113 (diastereomer 2)

LC/MS t_RET = 3.61 min, MH⁺ = 477, MH^" = 475. Example 114 (racemic diastereomer 1)

3.3,3-Trifluoro-2-hvdroxy-N-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)-2-r(5-nitro-1.2,3,4- tetrahvdro-1-naphthalenyl)methvnpropanamide

Example 115 (racemic diastereomer 2)

3.3.3-Trifluoro-2-hvdroxy-N-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)-2-r(5-nitro-1 ,2,3,4- tetrahvdro-1-naphthalenyl)methyllpropanamide

Prepared from 5-nitro-1 -tetralone (J. Med. Chem. 1989, 32, 2128) according to method A and purified using an appropriate reverse phase HPLC gradient.

Example 114 (diastereomer 1) LC/MS t_RET = 3.50 min, MH⁺ = 492, MH^' = 490. Example 115 (diastereomer 2) LC/MS t_RET = 3.56 min, MH⁺ = 492, MH^' = 490.

Examples 116-121

Example 116 (racemic diastereomer 1)

3.3.3-Trif luoro-2-hvdroxy-/V-(4-methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)-2-f (1 -propyl-1 ,2,3.4- tetrahydronaphthalen-1-yl)methyl]propanamide

Example 117 (racemic diastereomer 2)

3.3.3-Trif luoro-2-hvdroxy-Λ/-(4-methyl-1 -oxo-1 r/-2.3-benzoxazin-6-yl)-2-lY1 -propyl-1.2.3.4- tetrahydronaphthalen-l-vDmethyllpropanamide

Example 118 (enantiomer 1 of diastereomer 1)

3.3.3-Trifluoro-2-hvdroxy-Λ/-(4-methyl-1 -oxo-1 r/-2.3-benzoxazin-6-yl)-2-r(1 -propyl-1.2.3.4- tetrahvdronaphthalen-1 -yl)methyllpropanamide

Example 119 (enantiomer 2 of diastereomer 1)

3,3,3-Trifluoro-2-hvdroxy-Λ/-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)-2-r(1 -propyl-1.2.3.4- tetrahvdronaphthalen-1-yl)methyl1propanamide

Example 120 (enantiomer 1 of diastereomer 2) 3.3.3-Trif luoro-2-hvdroxy-Λ/-(4-methyl-1 -oxo-1 rt-2,3-benzoxazin-6-yl)-2-r(1 -propyl-1 ,2.3.4- tetrahvdronaphthalen-1-yl)methyl]propanamide

Example 121 (enantiomer 2 of diastereomer 2)

3,3,3-Trifluoro-2-hvdroxy-Λ/-(4-methyl-1 -oxo-1 ry-2,3-benzoxazin-6-yl)-2-f(1 -propyl-1.2.3.4- tetrahvdronaphthalen-1-yl)methyl propanamide

The intermediate 47 (175 mg, 418 μmol) was dissolved in anhydrous DMF (2.5 mL) and dried cesium carbonate (286 mg, 878 μmol) was added in one portion. The reaction mixture was cooled in an ice-bath and Me₃SiCF₃ (309 μL, 2.09 mmol) was added. The ice-bath was then removed. After approximately 2 hours stirring at 25 °C under nitrogen, the reaction was again cooled in an ice bath and a second portion of Me₃SiCF₃ (124 μL) was added. The reaction was allowed to warm to 25 °C and stirred until TLC (cyclohexane-20% ether) indicated there was no starting material remaining. TBAF (1 M solution in THF, 1 mL) was added to the reaction mixture and the reaction was stirred at 25 °C for 30 minutes. The mixture was then poured into 1 :1 :1 brine:saturated ammonium chloride:2 M HCI (10 mL) and extracted with ether (2 x 30 mL). The combined organic extracts were dried on magnesium sulphate and the solvent was evaporated. The reaction product was purified by chromatography on silica, eluting with cyclohexane-ethyl acetate 4:1 to give the title compound as a mixture of two diastereoisomers. This mixture of diastereomers was purified by reverse phase preparative HPLC using a 45-80% MeCN (0.05% TFA) gradient over 50 minutes on a Supelcosil ABZ+ 10 cm x 21.2 mm column with a 4 mL min flow rate. The purification gave the following:

Example 116 (12.6 mg, 7%) diastereomer 1 LC/MS: t_ret 3.77 min; (MNH₄)⁺ 506, MH^" 487

¹H-NMR: δπ (CDCI_3, 400 MHz) 8.33 (br. s, 1 H, NH), 8.31 (d, J 8.5 Hz, 1 H, ArH), 8.12 (d, J 1.8 Hz, 1 H, ArH), 7.45 (dd, J 8.7 and 2.0 Hz, 1 H, ArH), 7.22 (br. d, J 7.1 Hz, 1 H, ArH), 7.00 (br. d, J 6.5 Hz, 1 H, ArH), 6.93-6.85 (m, 2H, ArH), 3.18 (br. s, 1 H, OH), 2.93 (d, J 15.3 Hz, 1 H, CH_{A B}), 2.75 (br. t, J 6.5 Hz, 2H, ArCH₂), 2.60 (s, 3H, CH₃), 2.32 (d, J 15.6 Hz, 1 H, CH_AH_S), 2.02-1.62 (m, 6H), 1.41-1.26 (m, 1 H), 1.21-1.09 (m, 1 H) and 0.85 (t, J 7.3 Hz, 3H, CH₂CH₃)

Example 117 (8.5 mg, 5%) diastereomer 2

LC/MS: 3.86 min; MH⁺ 489 MNH₄ ⁺ 506, MH^' 487 ¹H-NMR: (CDCI_3, 400 MHz) 8.99 (br. s, 1 H, NH), 8.36 (d, J 8.6 Hz, 1 H, ArH), 8.32 (d, J

2.0 Hz, 1 H, ArH), 7.69 (dd, J 8.8 and 2.0 Hz, 1 H, ArH), 7.39 (d, J 7.8 Hz, 1 H, ArH), 7.33-

7.27 (m, 1 H, ArH), 7.24-7.15 (m, 2H, ArH), 3.01 (d, J 15.4 Hz, 1 H, CH_AH_B), 2.80-2.71 (m,

2H, ArCH₂), 2.79 (s, 1 H, OH), 2.69 (d, J 15.3 Hz, 1 H, CH_AH_S), 2.61 (s, 3H, CH₃), 1.90-

1.25 (m, 8H) and 0.88 (t, J7.0 Hz, 3H, CH₂CH₃)

Example 116 was separated into its enantiomers using a 25cm Chiralpak AD column eluting with 5% EtOH in heptane with a flow rate of 15mL/min. Example 118 (enantiomer

1 ) eluted around 17min and Example 119 (enantiomer 2) eluted around 25min.

Analytical chiral HPLC (25 x 0.46 cm Chiralpak AD column, 5% EtOH in heptane eluting at 1 mL/min)

Example 118: 15.8 min

LC/MS: t_ret 3.77 min; (MNH₄)⁺ 506, (MH)^" 487

Example 119: 23.9 min

LC/MS: 3.77 min; (MNH₄)⁺ 506, (M-H)^~ 487

Example 117 was separated into its enantiomers using a 25cm Chiralpak AD column eluting with 5% EtOH in heptane with a flow rate of 15mLJmin. Example 120 (enantiomer 1 ) eluted around 17.5min and Example 121 (enantiomer 2) eluted around 22.5min. Analytical chiral HPLC (25 x 0.46 cm Chiralpak AD column, 5% EtOH in heptane eluting at 1 mL min) Example 120: 17.5 min

LC/MS: 3.84 min; (MNH₄)⁺ 506, (M-H)^~ 487 Example 121 : 21.2 min

LC/MS: 3.84 min; (MNH₄)⁺ 506, (M-H)- 487

Example 122 - Example 127

Example 122 (racemic diastereomer 1 )

2-f(5-Ethyl-6.7,8,9-tetrahvdro-5H-benzocvclohepten-5-vπmethvn-3,3,3-trifluoro-2-hvdroxy- A/-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 123 (racemic diastereomer 2) 2-r(5-Ethyl-6,7,8.9-tetrahvdro-5H-benzocvclohepten-5-yl)methvn-3.3.3-trifluoro-2-hvdroxy- Λ/-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 124 (diastereomer 1 , enantiomer 1)

2-r(5-Ethyl-6,7,8,9-tetrahvdro-5ry-benzocvclohepten-5-yl)methvn-3,3,3-trifluoro-2-hvdroxy- Λ/-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 125 (diastereomer 1 , enantiomer 2)

2-r(5-Ethyl-6,7,8,9-tetrahvdro-5H-benzocvclohepten-5-yl)methyll-3,3,3-trifluoro-2-hvdroxy- A/-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 126 (diastereomer 2, enantiomer 1)

2-r(5-Ethyl-6,7,8,9-tetrahvdro-5 --benzocvclohepten-5-vπmethvn-3,3,3-trifluoro-2-hvdroxy- Λ/-(4-methyl-1 -oxo-1 r7-2,3-benzoxazin-6-yl)propanamide

Example 127 (diastereomer 2, enantiomer 2)

2-[(5-Ethyl-6,7,8,9-tetrahvdro-5H-benzocvclohepten-5-yl)methyll-3,3,3-trifluoro-2-hvdroxy- Λ/-(4-methyl-1 -oxo-1 -/-2,3-benzoxazin-6-yl)propanamide

To Intermediate 51 (0.94g) in dry DMF (15mL) was added caesium carbonate (0.87g) and trifluoromethyltrimethylsilane (0.66mL). After 3h, further trifluoromethyltrimethylsilane ((0.66mL) was added and after 18h, further trifluoromethyltrimethylsilane (0.5mL) and caesium carbonate (0.56g) were added. After 5h, the mixture was added to water (100mL) and the solid filtered off. The filtrate was extracted with CHCI₃ (2 x 50mL), filtered through a Teflon frit and concentrated in vacuo. Chromatography on silica eluting with CHCI₃ with 1 -2% MeOH removed un-reacted starting material. To the remainder of the material was added THF (10mL) and TBAF (1 M in THF) (3mL). After 45min, the mixture was added to 1.3M HCI (100mL) and CHCI₃ (25mL). The organic layer was separated using a Teflon frit, concentrated in vacuo and purified on a silica column eluting with 7:340-60 petrol: EtOAc to afford: Example 122 (racemic diastereomer 1 ) (58mg)

LC/MS t_RET = 3.77min, MH⁺ = 489

Example 123 (racemic diastereomer 2) (43mg)

LC/MS t_RET = 3.77min, MH⁺ = 489 Example 122 was separated into its enantiomers using 2 x 25cm Sumichiral OA-4900 column eluting with 15% EtOH in heptane with a flow rate of 15mL/min. Example 124

(enantiomer 1) eluted around 23min and Example 125 (enantiomer 2) eluted around

26min.

Analytical chiral HPLC (25 x 0.46cm Sumichiral OA-4900 column eluting with 15% EtOH in heptane with a flow rate of 1 mL/min)

Example 124: 18.16min

LC/MS t_RET = 3.77min, MH⁺ = 489

Example 125: 19.60min

LC/MS t_RET = 3.77min, MH⁺ = 489

Example 123 was separated into its enantiomers using 2 x 25cm Chiralpak AS column eluting with 15% EtOH in heptane with a flow rate of 15ml_/min. Example 126

(enantiomer 1) eluted around 7min and Example 127 (enantiomer 2) eluted around 12min.

Analytical chiral HPLC (25 x 0.46cm Chiralpak AS column eluting with 15% EtOH in heptane with a flow rate of 1 mLJmin)

Example 126: 5.59min

LC/MS t_RET = 3.77min, MH⁺ = 489

Example 127: 8.10min

LC/MS t_RET = 3.77min, MH⁺ = 489

Example 128 (racemic diastereomer 1)

2-K1 -Butyl-1 ,2.3,4-tetrahvdro-1 -naphthalenyl)methvn-3.3.3-trif luoro-2-hvdroxy-Λ/-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 129 (racemic diastereomer 2)

2-f(1 -Butyl-1 ,2,3,4-tetrahvdro-1 -naphthalenyl)methyll-3,3,3-trif luoro-2-hvdroxy-/V-(4- methyl-1 -oxo-1 /-/-2,3-benzoxazin-6-yl)propanamide

Example 130 (diastereomer 2, enantiomer 1) 2-f(1 -Butyl-1 ,2.3.4-tetrahvdro-1 -naphthalenyl)methvn-3,3.3-trif luoro-2-hvdroxy-/V-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide

Example 131 (diastereomer 2, enantiomer 2)

2-1(1 -Butyl-1 ,2.3.4-tetrahvdro-1 -naphthalenyl)methvn-3.3,3-trif luoro-2-hvdroxy-/V-(4- methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)propanamide

Intermediate 52 (30 mg, 69 μmol) was dissolved in anhydrous DMF (1 mL) and added to dried caesium fluoride (21 mg, 139 umol) in one portion. The reaction mixture was stirred under a nitrogen atmosphere and trifluoromethyltrimethylsilane (21 ul, 142 Emil) was added. After approximately 2 hours stirring at 25 °C, a second portion of trifluoromethyltrimethylsilane (32 ul) was added and reaction was left to stir for 24 h. The reaction mixture was diluted with DCM and washed with 1 M HCI. After drying the organic extract (Na₂SO ) the solvent was removed under vacuum. The residue was then re- dissolved in THF (3 mL), TBAF (1 M solution in THF, 350 ul) was added and the reaction was stirred at 25 °C for 1 hour. The mixture was then poured into 1 M HCI (10 mL) and extracted with DCM (2 x 30 mL). The combined organic extracts were dried on sodium sulphate and the solvent was evaporated. The reaction product was purified by chromatography on silica, eluting with cyclohexane - 15% ethyl acetate through to cyclohexane - 50% ethyl acetate to give Intermediate 52 (10.2 mg, 34%), Example 128, Example 129 and a further mixed batch of Examples 128 and 129 (2.1 mg, 6%). Example 128 (racemic diasteromer 1) (1.8mg) LC/MS t_RET = 3.89min, MH⁺ = 503, MH^' = 501 Example 129 (racemic diasteromer 2) (3.5mg) LC/MS t_RET = 3.95min, MH⁺ = 503, MH^' = 501

Example 129 was separated into its enantiomers using a 2 x 25cm Chiralpak AD column eluting with 5% EtOH in heptane with a flow rate of 15mLΛτιin. Example 130 (enantiomer

1) eluted around 17 min and Example 131 (enantiomer 2) around 19 min. Analytical chiral HPLC (25 x 0.46 cm Chiralpak AD column, 5% EtOH in heptane eluting at 1 mlJmin)

Example 130: 12.20 min

LC/MS t_RET = 3.95min, MH⁺ = 503, MH^' = 501

Example 131 : 14.32 min LC/MS t_RET = 3.95min, MH⁺ = 503, MH^' = 501

Preferred compounds of the invention being potent binders of the glucocorticoid receptor are Examples 2, 3, 6, 7, 9, 11 , 11-1 , 13, 15, 17,28,30, 32, 34, 36, 38, 42, 46, 49, 51 , 52, 56, 58, 60, 62, 64, 66, 68, 70, 78, 79, 84, 93, 97, 98, 100, 104, 106, 110, 112, 114, 115.

More preferred compounds of the invention being potent binders and agonists of the glucocorticoid receptor are Examples 5, 20, 26, 40, 41 , 44, 47, 50, 54, 73, 75, 76, 77, 81 , 82, 85, 87, 90, 94, 96, 102, 108, 121 , 126,130.

Biological Experimental

Glucocorticoid mediated Transrepression of NFkB activity.

Human A549 lung epithelial cells were engineered to contain a secreted placental alkaline phosphatase gene under the control of the distal region of the NFkB dependent ELAM promoter as previously described (12).

Compounds were solvated and diluted in DMSO, and transferred directly into assay plates such that the final concentration of DMSO was 0.7%. Following the addition of cells (40K per well), plates were incubated for 1 hr prior to the addition of 3ng/ml human recombinant TNFα. ~ Following continued incubation for 16hr, alkaline phosphatase activity was determined by measuring the change in optical density at 405nM with time following the addition of 0.7 volumes of assay buffer (1 mg/ml p-nitrophenylphosphate dissolved in 1 M diethanolamine, 0.28M NaCI, 0.5mM MgCI₂).

Glucocorticoid mediated Transactivation of MMTV driven gene expression

Human A549 lung epithelial cells were engineered to contain a renialla luciferase gene under the control of the distal region of the LTR from the mouse mammary tumour virus as previously described (13).

Compounds were solvated and diluted in DMSO, and transferred directly into assay plates such that the final concentration of DMSO was 0.7%. Following the addition of cells (40K per well), plates were incubated for 6hr. Luciferase activity was determined using the Firelight kit (Packard, Pangbourne, UK).

Glucocorticoid receptor binding assay

The ability of compounds to bind to the glucocorticoid receptor was determined by assessing their ability to compete with fluorescent-labelled glucocortioid using a kit supplied by Pan Vera (Madison, Wl, USA). Compounds were solvated and diluted in DMSO, and transferred directly into assay plates. Fluorescent glucocortioid and partially purified glucocorticoid receptor were added to the plates and incubated at 4°C for 16hrs in the dark. Binding of compound was assessed by analysing the displacement of fluorescent ligand by measuring the decrease in fluorescence polarisation signal from the mixture.

Reference

12. Ray KP. Farrow S. Daly M. Talabot F. Searle N. Induction of the E-selectin promoter by interleukin 1 and tumour necrosis factor alpha, and inhibition by glucocorticoids. Biochemical Journal. 1997 328 707- 15,

13. Austin RH, Maschera B, Walker A, Fairbaim L, Meldrum E, Farrow S, Uings IJ. Mometasone furoate is a less specific glucocortiocid than fluticasone propionate. European Respiratory Journal. 2002, 20, 1386-1392.

Claims

1. A compound of formula (I)

wherein:

n represents an integer 0, 1 or 2;

X represents, O, S, NR^6a, or CHR^6b;

R¹ represents hydrogen, halogen such as F, Cl or Br, NO₂, hydroxy, cyano, -Od.₆ alkoxy such as methoxy, d-₆ alkyl such as methyl, NR⁸R⁹ such as NH₂, NR⁸COR⁹ such as -NHCHO or -NHCOCH₃, COOR⁷ or CONR⁸R⁹;

R² represents hydrogen, halogen such as F, Cl, Br, NO₂, hydroxy, cyano, -OCι-₆ alkoxy such as methoxy, d.₆ alkyl such as methyl, NR⁸R⁹ such as NH₂, NR⁸COR⁹ such as -NHCHO or -NHCOCH₃, COOR⁷ or CONR⁸R⁹;

R³ represents hydrogen, halogen such as F, Cl, Br, NO₂, hydroxy, cyano, -Od.₆ alkoxy such as methoxy, Ci-₆ alkyl such as methyl, NR⁸R⁹ such as NH₂, NR⁸COR⁹ such as -NHCHO or -NHCOCHs, COOR⁷, CONR⁸R⁹;

R⁴ represents hydrogen, halogen such as F, Cl, Br, NO₂, hydroxy, cyano, d.₆ alkoxy such as methoxy, d.₆ alkyl such as methyl, NR⁸R⁹ such as NH₂, NR⁸COR⁹ such as -NHCHO or -NHCOCH₃, COOR⁷ or CONR⁸R⁹;

R⁵ represents H, d-e alkyl, or d.₆ alkenyl;

R^6a represents hydrogen, d.₆ alkyl, CO₂d.₃ alkyl, COd.₃ alkyl or SO₂d.₃ alkyl;

R^6b represents hydrogen, or d.₆ alkyl;

R⁷ represents hydrogen, d.₆ alkyl, C₁.₃ alkyleneSid.₃ alkyl such as -CH₂CH₂Si(CH₃)₃; R⁸ and R⁹ independently represent hydrogen or d.₆ alkyl; including pharmaceutically acceptable esters, amides and carbamates thereof, salts thereof, solvates thereof, and solvates of such pharmaceutically acceptable esters, amides, carbamates and salts.

2. A compound as claimed in claim 1 wherein R⁵ represents H, or a d-₆ alkyl group.

3. A compound as claimed in claim 2 wherein R⁵ represents methyl, ethyl, propyl or butyl.

4. A compound as claimed in claim 2 wherein R⁵ represents H.

5. A compound as claimed in any one of claims 1 to 4 wherein n represents 1.

6. A compound as claimed any one of claims 1 to 4 wherein X represents CH₂.

7. A compound as claimed in any one of claims 1 to 6 for use in human or veterinary medicine.

8. A compound as claimed in any one of claims 1 to 6 for use in the treatment of inflammatory and/or allergic conditions, such as rheumatoid arthritis, asthma, allergy or rhinitis.

9. A compound as claimed in any one of claims 1 to 6 for use in the treatment of patients with skin disease such as eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis and hypersensitivity reactions

10. Use of a compound as claimed in any one of claims 1 to 6 for the manufacture of a medicament for the treatment of patients with inflammatory and/or allergic conditions, such as rheumatoid arthritis, asthma, allergy or rhinitis.

11. Use of a compound as claimed in any one of claims 1 to 6 for the manufacture of a medicament for the treatment of patients with skin disease such as eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis and hypersensitivity reactions

12. A method for the treatment of a human or animal subject with an inflammatory and/or allergic condition, which method comprises administering to said human or animal subject an effective amount of a compound as claimed in any one of claims 1 to 6.

13. A method for the treatment of a human or animal subject with skin disease such as eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis and hypersensitivity reactions, which method comprises administering to said human or animal subject an effective amount of a compound as claimed in any one of claims 1 to 6.

14. A process for the preparation of a compound of formula (I) as claimed in claim 1 comprising treatment of a compound of formula (II)

wherein: n, X, R¹, R²,R³, R⁴ and R⁵ are as defined in claim 1 with a trifluoromethylating agent of formula (III)

CF₃R¹⁰ (III)

wherein R¹⁰ represents an activating group.

15. A compound of formula (II)

wherein n, X, R¹, R²,R³, R⁴ and R⁵ are as defined above for compounds of formula (I) in claim 1.

16. A process for the preparation of a compound of formula (II) as described in claim 15 comprising treatment of a compound of formula (IV):

wherein n, X, R¹, R²,R³, R⁴ and R⁵ are as defined above for compounds of formula (I) in claim 1 with an activating agent and 6-amino-4-methyl-1 H-2,3-benzoxazin-1 -one.

17. A compound of formula (I

18. A process for the preparation of a compound of formula (IV) as described in claim 17 comprising reaction of a compound of formula (XV)

wherein: n represents 0 or 1 and X represents O, NR^6a or CHR^6b, and R¹, R², R³, R⁴ and R⁵ R^6a and R^6b are as defined for compounds of formula (I) in claim 1 and where A is a group selected from -CO-2-furanyl, -CO-ethynyl or -C(=CH₂)CO₂d.₆alkyl with a suitable oxidising agent

19. A compound of formula (XV)

wherein: n represents 0 or 1 and X represents O, NR^6a or CHR⁶ , and R¹, R², R³, R⁴ and R⁵ R^6a and

R⁶ are as defined for compounds of formula (I) in claim 1.

20. A process for the preparation of a compound of formula (XV) as described in claim 19 comprising reaction of a compound of formula (XVI)

wherein n represents 0 or 1 and X represents O, NR^6a or CHR⁶ , R¹, R², R³, R⁴' R⁵ R^6a or R^6b are as defined above for compounds of formula (I) except that R⁵ does not represent H and X' is selected from Br, I and OTf except that R¹ to R⁴ independently do not represent Br when X' represents Br.by reaction with Bu₃SnC(=CH₂)CO₂C₁.₆alkyl or Me₃SnC(=CH₂)CO₂Ci.₆alkyI or with carbon monoxide and a stannane such as tributylfuran-2-ylstannane, trimethylfuran-2-ylstannane, tributylethynylstannane, trimethylethynylstannane or a (l-alkoxyvinyl)trialkylstannane or carbon monoxide and a boronic acid such as furan-2-ylboronic acid in the presence of a source of Pd(0).

21. A process for the preparation of a compound of formula (XVI) comprising reaction of compounds of formula (XVI) may be prepared by reaction of a compound of formula (XVII)

wherein: n represents 0 or 1 and X represents O, NR^6a or CHR^6b, R¹, R², R³, R^4, R⁵ R^6a or R^6b R¹, R², R³, R⁴ and R⁵ are as defined above for compounds of formula (I) and X' is as defined above for compounds of formula (XVI) with a suitable olefinating reagent.

22. A compound of formula (XVI)

wherein: n represents 0 or 1 and X represents O, NR^6a or CHR^6b, R¹, R², R³, R⁴' R⁵ R^6a or R^6b are as defined for compounds of formula (I) in claim 1 and X' is selected from Br, I and OTf

23. A compound of formula (XVII)

wherein n, X, R¹, R², R³, R⁴ and R⁵ are as defined for compounds of formula (I) in claim 1 and X' is as defined for compounds of formula (XVI) in claim 19.

24. A compound of formula (Va)

wherein: n, X, R¹, R², R3, R⁴ and R⁵ are as defined above for compounds of formula (I) in claim 1 and R¹¹ represents d.₃ alkyl.

25. A compound of formula (Via)

wherein: n, X, R¹, R², R³, R⁴ and R⁵ are as defined for compounds of formula (I) in claim 1.

26. A process for the preparation of a compound of formula (I) comprises reduction of a compound of formula (lib)

wherein R¹, R², R³, R⁴, X and n are as defined above for compounds of formula (I) in claim 1.

27. A process for the preparation of compounds of formula (lib)

wherein

R¹, R², R³, R⁴, X and n are as defined above for compounds of formula (I) in claim 1 prepared from a compound of formula (VIII)

by treatment with a compound of formula (IX)

wherein

R¹, R², R³, R⁴, X and n are as defined above for compounds of formula (I) and

— represents an endocyclic double bond or exocyclic double bond.

28. A process as claimed in claim 27 wherein the reaction is performed as a melt in the absence of additional solvent at a temperature in the range 100°C to 250°C.

29. A process for the preparation of a compound of formula (VIII) by reacting a compound of formula (X)

with a trifluoromethylacetylating agent