Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/02—Nasal agents, e.g. decongestants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/08—Bronchodilators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• Benzoxazinone derivatives acting as beta2-adrenoreceptor agonist for the treatment of respiratory disorders Benzoxazinone derivatives acting as beta2-adrenoreceptor agonist for the treatment of respiratory disorders.
• the present invention relates to benzoxazinone derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
• Adrenoceptors are a group of G-protein coupled receptors divided into two major subfamilies, ⁇ and ⁇ . These sub-families are further divided into sub-types of which the ⁇ subfamily has at least 3 members: ⁇ l, ⁇ 2 and ⁇ 3. ⁇ 2 adrenoceptors (henceforth referred to as ⁇ 2 receptors) are mainly expressed on smooth muscle cells.
• ⁇ 2 agonists act as functional antagonists to all bronchoconstrictor substances such as the naturally-occurring histamine and acetylcholine as well as the experimental substances methacholine and carbachol.
• ⁇ 2 agonists are widely used to treat airways diseases including asthma and chronic obstructive pulmonary disease (COPD), and this has been extensively reviewed in the literature and incorporated into national guidelines for the treatment of these diseases (British Guideline on the Management of Asthma, NICE guideline No. 12 on the Management of COPD).
• ⁇ 2 agonists are classed either as short-acting or long-acting.
• Short-acting ⁇ 2 agonists such as salbutamol have a duration of action of 2-4 h. They are suitable for rescue medication during a period of acute bronchoconstriction but are not suitable for continuous medication because the beneficial effect of these drugs wears off during the night.
• Long-acting ⁇ 2 agonists currently have a duration of action of about 12 h and are administered twice daily to provide continuous bronchodilatation. They are particularly effective when administered in combination with inhaled corticosteroids. This benefit is not seen when inhaled corticosteroids are combined with SABAs (Kips and Pauwels, Am. J. Respir.
• LABAs are recommended as add-on therapy to patients already receiving inhaled corticosteroids for asthma to reduce nocturnal awakening and reduce the incidence of exacerbations of the disease. Corticosteroids and LABAs are conveniently co-administered in a single inhaler to improve patient compliance.
• Salmeterol a commonly used LABA
• Salmeterol also has a long onset of action which precludes its use as both a rescue and a maintenance therapy.
• All current LABAs are administered twice daily and there is a medical need for once daily treatments to improve treatment and patient compliance. Such once daily compounds, co-administered with corticosteroids, will become the mainstay of asthma treatment (Barnes, Nature Reviews, 2004, 3_, 831-844).
• W is CH 2 substituted by 0, 1 or 2 CH 3 groups
• R 1 is cyclopentyl, cyclohexyl, cycloheptyl or CH(CH3)(Ci_6 alkyl);
• R 2 is a 5-membered, nitrogen-containing heteroaryl that optionally has a ring oxygen atom, and R 2 is optionally substituted by Ci_6 alkyl (itself optionally substituted by Ci_6 alkoxy or C 3 _ 6 cycloalkyl);
• R 3 is hydrogen, halogen, Ci_4 alkyl, CF 3 , Ci_4 alkoxy, OCF 3 or cyano; or a pharmaceutically acceptable salt thereof.
• Alkyl, or the alkyl moiety of alkoxy is linear or branched and is, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl.
• CH(CH 3 )(CL 6 alkyl) is, for example, CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH(CH 3 )(CH 2 ) 2 CH 3 , CH(CH 3 )CH(CH 3 ) 2 , CH(CH 3 )(CH 2 ) 3 CH 3 or CH(CH 3 )C(CH 3 ) 3 .
• Halogen is, for example, fluorine, chlorine or bromine.
• a 5-membered, nitrogen-containing heteroaryl that optionally has a ring oxygen atom is, for example, a 5-membered ring comprising two, three or four (such as two or three) ring- heteroatoms atoms. It is, for example, oxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, 1,2,4-triazolyl or tetrazolyl.
• the compounds of the invention are selective ⁇ 2 receptor agonists and possess properties that make them suitable for fast onset of activity, once-a-day administration and minimal systemic exposure.
• all compounds of the invention are at least 10-fold more potent at the ⁇ 2 receptor compared to the ⁇ l , ⁇ 1 , or dopamine (D2) receptors.
• Certain compounds are also notable for having a fast onset of action, that is, the time interval between administration of a compound of the invention to a patient and the compound providing symptomatic relief.
• Onset can be predicted in vitro using isolated trachea from guinea pig or human.
• Certain compounds have been optimised to have appropriate duration in man. Duration can be predicted from pharmokinetic half lives in mammalian systems, or a pharmacodynamic model in a mammalian system.
• Certain compounds have reduced CYP (for example CYP3A4) inhibition.
• Certain compounds of the invention are also characterised as having a high plasma protein binding, meaning that there is less free compound in the plasma leading to a reduction in systemic side-effects (for example tremor or hypokalemia).
• the present invention provides a compound of formula (I) wherein: W is CH 2 substituted by O, 1 or 2 CH 3 groups; R 1 is cyclopentyl, cyclohexyl, cycloheptyl or CH(CH3)(Ci_6 alkyl); R 2 is a 5-membered, nitrogen-containing heteroaryl that optionally has a ring oxygen atom, and R 2 is optionally substituted by Ci_6 alkyl; R 3 is hydrogen, halogen, Ci_ 4 alkyl, CF 3 , Ci_ 4 alkoxy, OCF 3 or cyano; or a pharmaceutically acceptable salt thereof.
• a compound of formula (I) can form a salt with a pharmaceutically acceptable acid the ionic nature of the salt ranging from full proton transfer (for example with a strong acid) to being a co-crystal (where the compound of formula (I) is associated with a weak acid).
• the present invention encompases all such physical forms.
• a suitable pharmaceutically acceptable salt is, for example, an acid addition salt such as a chloride (for example a monochloride or a dichloride), bromide (for example a monobromide or a dibromide), trifluoroacetate (for example a mono-trifluoroacetate or a di-trifluoroacetate), sulphate, phosphate, acetate, fumarate (for example a hemifumaric acid salt), maleate, tartrate (such as L-(+) tartrate), lactate, citrate, pyruvate, succinate, oxalate, methanesulphonate, />toluenesulphonate, bisulphate, benzenesulphonate, ethanesulphonate, malonate, xinafoate, ascorbate, oleate, nicotinate, saccharinate, adipate, formate, glycolate, L-lactate, D-lactate, aspartate
• a suitable pharmaceutically acceptable salt is, for example, an acid addition salt such as a chloride (for example a monochloride or a dichloride), bromide (for example a monobromide or a dibromide), trifluoroacetate (for example a mono- trifluoroacetate or a di-trifluoroacetate), sulphate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulphonate, p- toluenesulphonate, bisulphate, benzenesulphonate, ethanesulphonate, malonate, xinafoate, ascorbate, oleate, nicotinate, saccharinate, adipate, formate, glycolate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate,
• the compounds of formula (I), and their pharmaceutically acceptable salts might exist as solvates (such as hydrates) and the present invention encompasses all such solvates in any proportion.
• the present invention provides a compound of formula (I) wherein R 1 is cyclohexyl.
• the present invention provides a compound of formula (I) wherein R 1 is CH(CH 3 )(CL 6 alkyl) (for example, CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH(CH 3 )(CH 2 ) 2 CH 3 , CH(CH 3 )CH(CH 3 ) 2 , CH(CH 3 )(CH 2 ) 3 CH 3 or CH(CH 3 )C(CH 3 ) 3 ).
• R 1 is CH(CH 3 )(CL 6 alkyl) (for example, CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH(CH 3 )(CH 2 ) 2 CH 3 , CH(CH 3 )CH(CH 3 ) 2 , CH(CH 3 )(CH 2 ) 3 CH 3 or CH(CH 3 )C(CH 3 ) 3 ).
• the present invention provides a compound of formula (I) wherein R 1 is CH(CH 3 )CH(CH 3 ) 2 or CH(CH 3 )(CH 2 ) 3 CH 3 .
• the present invention provides a compound of formula (I) wherein W is unsubstituted CH 2 .
• the present invention provides a compound of formula (I) wherein R 2 is a 5-membered, nitrogen-containing heteroaryl optionally substituted by Ci_ 6 alkyl.
• R 2 is a C-linked, 5-membered, nitrogen-containing heteroaryl (for example comprising two, three or four (such as two or three) ring-nitrogen atoms) carrying a Ci_ 6 alkyl group on a ring- nitrogen.
• Ci_ 6 alkyl group such as methyl or ethyl
• the alkyl group is methyl, ethyl, n-propyl or iso-propyl.
• the alkyl group is methyl.
• the present invention provides a compound of formula (I) wherein R 2 is C-linked pyrazolyl carrying a methyl on a ring nitrogen.
• the present invention provides a compound of formula (I) wherein R 3 is hydrogen.
• Trifluoroacetic Acid Salt N-Cyclohexyl-3-(3-fluoro-5-(l-methyl-lH-pyrazol-4-yl)phenethoxy)-N-(2-(2-(5-hydroxy-
• Trifluoroacetic Acid Salt N-Cyclopentyl-N-(2-(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazin-8- yl)ethylamino)ethyl)-3 -(3 -( 1 -propyl- 1 H-pyrazol-4-yl)phenethoxy)propanamide
• Trifluoroacetic Acid Salt N-Cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazin-8- yl)ethylamino)ethyl)-3 -(3 -( 1 -(2-methoxyethyl)- 1 H-pyrazol-4-yl)phenethoxy)propanamide
• the present invention provides each individual compound: N-Cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazin-8- yl)ethylamino)ethyl)-3 -(3 -( 1 -methyl- 1 H-pyrazol-4-yl)phenethoxy)propanamide; N-Cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazin-8- yl)ethylamino)ethyl)-3 -(3 -( 1 -methyl- 1 H-pyrazol-5 -yl)phenethoxy)propanamide; N-Cyclohexyl-3-(3-(l-ethyl-lH-l,2,3-triazol-4-yl)
• the present invention provides N-Cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo- 3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)-3-(3-(l-methyl-lH-pyrazol-4- yl)phenethoxy)propanamide or a pharmaceutically acceptable salt thereof (for example a Hemi-Fumaric Acid Salt).
• the present invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above.
• a compound of formula (I) can be prepared by adaptation of synthetic methods known in the literature, by using or adapting the synthetic methods described hereinbelow, or by using (when W in formula (I) is CH 2 ) or adapting the methods presented in Routes A, B, C and D below in which the following abbreviations are used:
• Triton B B enzy ltrimethy lammonium Hydroxide
• HATU (2-(7-Aza- 1 H-benzotriazole- 1 -yl)- 1 , 1 ,3 ,3 -tetramethyluronium hexafluorophosphate)
• a compound of formula (I) above can be converted to a pharmaceutically acceptable salt thereof by use or adaptation of methods used in the Examples or of methods described in the art.
• respiratory tract obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NS AID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vascula
• osteoarthritides associated with or including osteoarthritis/osteoarthrosis both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis, and low back and neck pain; osteoporosis; rheumatoid arthritis and Still's disease; seronegative spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated spondarthropathy; septic arthritis and other infection-related arthopathies and bone disorders such as tuberculosis, including Potts' disease and Poncet's syndrome; acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, and calcium apatite related tendon, bursal and synovial inflammation; Behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythemato
• arthitides for example rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy
• other joint disease such as intervertebral disc degeneration or temporomandibular joint degeneration
• bone remodelling disease such as osteoporosis, Paget's disease or osteonecrosis
• polychondritits such as osteoporosis, Paget's
• skin psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis; cutaneous lymphomas, non-melanom
• eyes blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; ulceris; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial; 6.
• gastrointestinal tract glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis (including ulcerative colitis, microscopic colitis and indeterminant colitis) proctitis, pruritis ani, coeliac disease, irritable bowel disorder, irritable bowel syndrome, non-inflammatory diarrhoea, and food- related allergies which may have effects remote from the gut (for example migraine, rhinitis or eczema); 7. abdominal: hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic;
• nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvo- vaginitis; Peyronie's disease; erectile dysfunction (both male and female);
• allograft rejection acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease;
• CNS Alzheimer's disease and other dementing disorders including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; myasthenia gravis; acute and chronic pain (acute, intermittent or persistent, whether of central or peripheral origin) including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post-herpetic, and HIV-associated neuropathies; neurosarcoidosis; central and peripheral nervous system complications of malignant, infectious or autoimmune processes; 11.
• cardiovascular atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis , inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infective (for example syphilitic); vasculitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins; and,
• oncology treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes.
• the present invention provides a compound of formula (I) or a pharmaceutically- acceptable salt thereof as hereinbefore defined for use in therapy.
• the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined in the manufacture of a medicament for use in therapy.
• the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
• the terms “therapeutic” and “therapeutically” should be construed accordingly.
• Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question.
• Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
• the invention still further provides a method of treating, or reducing the risk of, an inflammatory disease or condition (including a reversible obstructive airways disease or condition) which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.
• the compounds of this invention may be used in the treatment of adult respiratory distress syndrome (ARDS), pulmonary emphysema, bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), asthma and rhinitis.
• ARDS adult respiratory distress syndrome
• COPD chronic obstructive pulmonary disease
• the daily dosage of the compound of the invention if inhaled, may be in the range from 0.05 micrograms per kilogram body weight ( ⁇ g/kg) to 100 micrograms per kilogram body weight ( ⁇ g/kg).
• the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight ( ⁇ g/kg) to 100 milligrams per kilogram body weight (mg/kg).
• the compounds of formula (I) and pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
• a pharmaceutically acceptable adjuvant diluent or carrier.
• Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals-The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.
• the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
• the present invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
• the invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
• compositions may be administered topically (e.g. to the skin or to the lung and/or airways) in the form, e.g., of creams, solutions, suspensions, heptafluoroalkane (HFA) aerosols and dry powder formulations, for example, formulations in the inhaler device known as the Turbuhaler ® ; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of solutions or suspensions; or by subcutaneous administration; or by rectal administration in the form of suppositories; or transdermally.
• HFA heptafluoroalkane
• Dry powder formulations and pressurized HFA aerosols of the compounds of the invention may be administered by oral or nasal inhalation.
• the compound is desirably finely divided.
• the finely divided compound preferably has a mass median diameter of less than 10 ⁇ m, and may be suspended in a propellant mixture with the assistance of a dispersant, such as a Cg-C 2O fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
• a dispersant such as a Cg-C 2O fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
• the compounds of the invention may also be administered by means of a dry powder inhaler.
• the inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.
• a carrier substance for example, a mono-, di- or polysaccharide, a sugar alcohol, or another polyol.
• Suitable carriers are sugars, for example, lactose, glucose, raffmose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch.
• the finely divided compound may be coated by another substance.
• the powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound.
• This spheronized powder may be filled into the drug reservoir of a multidose inhaler, for example, that known as the Turbuhaler ® in which a dosing unit meters the desired dose which is then inhaled by the patient.
• a multidose inhaler for example, that known as the Turbuhaler ® in which a dosing unit meters the desired dose which is then inhaled by the patient.
• the active ingredient with or without a carrier substance, is delivered to the patient.
• the compound of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets.
• an adjuvant or a carrier for example, lactose, saccharose, sorbitol, mannitol
• a starch for example, potato starch, corn starch or amylopectin
• a cellulose derivative for example, gelatine or polyvinylpyrrolidone
• a lubricant for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax
• the cores may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
• a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
• the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
• the compound of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol.
• Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets.
• liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules.
• Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
• Such liquid preparations may contain colouring agents, flavouring agents, saccharine and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
• the compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions.
• the invention therefore further relates to combination therapies wherein a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed.
• NSAIDs non-steroidal anti-inflammatory agents
• COX-I / COX-2 inhibitors whether applied topically or systemically
• piroxicam diclofenac
• propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen
• fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin
• selective COX-2 inhibitors such as
• the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a cytokine or agonist or antagonist of cytokine function, (including agents which act on cytokine signalling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma- interferons; insulin- like growth factor type I (IGF-I); interleukins (IL) including ILl to 17, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF- ⁇ ) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and CDP-870) and TNF receptor antagonists including immunoglobulin molecules (such as etanercept) and low-molecular-weight agents such as pentoxyfylline.
• a cytokine or agonist or antagonist of cytokine function including agents which act on cytokine signal
• the invention relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a monoclonal antibody targeting B- Lymphocytes (such as CD20 (rituximab), MRA-aIL16R) or T-Lymphocytes (CTLA4-Ig, HuMax 11-15).
• B- Lymphocytes such as CD20 (rituximab), MRA-aIL16R) or T-Lymphocytes (CTLA4-Ig, HuMax 11-15).
• the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a modulator of chemokine receptor function such as an antagonist of CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRl 1 (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX 3 CRl for the C-X 3 - C family.
• a modulator of chemokine receptor function such as an antagonist of CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRl 1 (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X
• the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an inhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP-I), collagenase-2 (MMP-8), collagenase-3 (MMP- 13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-IO), and stromelysin-3 (MMP- 11) and MMP-9 and MMP-12, including agents such as doxycycline.
• MMPs matrix metalloprotease
• the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a leukotriene biosynthesis inhibitor, 5 -lipoxygenase (5-LO) inhibitor or 5 -lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a N-(5-substituted)-thiophene-2-alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2- cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, M
• the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4.
• a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4 selected from the group consisting of the phenothiazin-3-ls such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.
• the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5.
• PDE phosphodiesterase
• the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally.
• a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine
• the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist.
• a proton pump inhibitor such as omeprazole
• a gastroprotective histamine type 2 receptor antagonist such as a gastroprotective histamine type 2 receptor antagonist.
• the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an antagonist of the histamine type 4 receptor.
• the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride.
• an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochlor
• the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an anticholinergic agents including muscarinic receptor (Ml, M2, and M3) antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
• Ml, M2, and M3 antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
• the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a chromone, such as sodium cromoglycate or nedocromil sodium.
• a chromone such as sodium cromoglycate or nedocromil sodium.
• the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
• a glucocorticoid such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
• the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an agent that modulates a nuclear hormone receptor such as PPARs.
• the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).
• an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).
• the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and another systemic or topically-applied anti- inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
• another systemic or topically-applied anti- inflammatory agent such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
• the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and combinations of aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.
• aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine
• immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.
• the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta-lactam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfmavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcripta
• the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent such as a statin or a fibrate; a modulator of blood cell morphology such as pentoxyfylline; thrombolytic, or an anticoagulant such as a platelet aggregation inhibitor.
• a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist
• ACE angiotensin-converting enzyme
• angiotensin-2 receptor antagonist angiotensin-2 receptor antagonist
• a lipid lowering agent such as a statin or a fibrate
• a modulator of blood cell morphology such as
• the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dopa, ropinirole, pramipexole, a MAOB inhibitor such as selegine and rasagiline, a comP inhibitor such as tasmar, an A-2 inhibitor, a dopamine reuptake inhibitor, an NMDA antagonist, a nicotine agonist, a dopamine agonist or an inhibitor of neuronal nitric oxide synthase), or an anti- Alzheimer's drug such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor, propentofylline or metrifonate.
• a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dop
• the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an agent for the treatment of acute or chronic pain, such as a centrally or peripherally-acting analgesic (for example an opioid or derivative thereof), carbamazepine, phenytoin, sodium valproate, amitryptiline or other anti-depressant agent-s, paracetamol, or a non-steroidal anti-inflammatory agent.
• analgesic for example an opioid or derivative thereof
• carbamazepine for example an opioid or derivative thereof
• phenytoin for example an opioid or derivative thereof
• sodium valproate for example an opioid or derivative thereof
• amitryptiline or other anti-depressant agent-s sodium valproate
• paracetamol paracetamol
• non-steroidal anti-inflammatory agent for example an opioid or derivative thereof
• the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
• a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
• a compound of the present invention, or a pharmaceutically acceptable salt thereof can also be used in combination with an anti-osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.
• the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a: (i) tryptase inhibitor; (ii) platelet activating factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) adhesion molecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example Gef ⁇ tinib or Imatinib mesylate), a serine / threonine kinase (such as an inhibitor of a MAP kinase such as p38, JNK, protein kinase A, B or C, or IKK), or a kinase involved in cell cycle regulation (such as a cylin dependent kinas
• -receptor antagonist for example colchicine
• anti-gout agent for example colchicine
• xanthine oxidase inhibitor for example allopurinol
• uricosuric agent for example probenecid, sulfinpyrazone or benzbromarone
• growth hormone secretagogue for example transforming growth factor (TGF ⁇ );
• PDGF platelet-derived growth factor
• fibroblast growth factor for example basic fibroblast growth factor (bFGF);
• GM-CSF granulocyte macrophage colony stimulating factor
• capsaicin cream for example tachykinin NK.subl.
• NKP-608C SB-233412 (talnetant) or D-4418
• elastase inhibitor such as UT-77 or ZD-0892
• TACE TNF-alpha converting enzyme inhibitor
• iNOS induced nitric oxide synthase
• chemoattractant receptor-homologous molecule expressed on TH2 cells such as a CRTH2 antagonist
• inhibitor of P38 agent modulating the function of Toll-like receptors (TLR),
• agent modulating the activity of purinergic receptors such as P2X7
• inhibitor of transcription factor activation such as NFkB, API or STATS
• a glucocorticoid receptor GR-receptor
• the present invention provides a combination (for example for the treatment of COPD, asthma or allergic rhinitis) of a compound of formula (I) and one or more agents selected from the list comprising: o a non-steroidal glucocorticoid receptor (GR-receptor) agonist; o a PDE4 inhibitor including an inhibitor of the isoform PDE4D; o a muscarinic receptor antagonist (for example a Ml, M2 or M3 antagonist, such as a selective M3 antagonist) such as ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine; o a modulator of chemokine receptor function (such as a CCRl receptor antagonist); o a steroid (such as budesonide); or, o an inhibitor of a kinase function (for example IKK2 or p38).
• GR-receptor non-steroidal gluco
• the invention provides a kit comprising a preparation of a first active ingredient which is a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, and a preparation of a second active ingredient which is: o a non-steroidal glucocorticoid receptor (GR-receptor) agonist; o a PDE4 inhibitor including an inhibitor of the isoform PDE4D; o a muscarinic receptor antagonist (for example a Ml, M2 or M3 antagonist, such as a selective M3 antagonist) such as ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine; o a modulator of chemokine receptor function (such as a CCRl receptor antagonist); o a steroid (such as budesonide); or, o an inhibitor of a kinase function (for example IKK2 or p38). and instructions
• a compound of the invention, or a pharmaceutically acceptable salt thereof, can also be used in combination with an existing therapeutic agent for the treatment of cancer, for example suitable agents include:
• an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology such as an alkylating agent (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan or a nitrosourea); an antimetabolite (for example an antifolate such as a fluoropyrimidine like 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin or mithramycin); an antimitotic agent (for example a vinca alkaloid such as vincri
• a cytostatic agent such as an antioestrogen (for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene), an oestrogen receptor down regulator (for example fulvestrant), an antiandrogen (for example bicalutamide, flutamide, nilutamide or cyproterone acetate), a LHRH antagonist or LHRH agonist (for example goserelin, leuprorelin or buserelin), a progestogen (for example megestrol acetate), an aromatase inhibitor (for example as anastrozole, letrozole, vorazole or exemestane) or an inhibitor of 5 ⁇ -reductase such as finasteride; (iii) an agent which inhibits cancer cell invasion (for example a metalloproteinase inhibitor like marimastat or an inhibitor of urokinase plasm
• an antiangiogenic agent such as one which inhibits the effects of vascular endothelial growth factor (for example the anti-vascular endothelial cell growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or a compound that works by another mechanism (for example linomide, an inhibitor of integrin ⁇ v ⁇ 3 function or an angiostatin); (vi) a vascular damaging agent such as combretastatin A4, or a compound disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213; (vii) an agent used in antisense therapy, for example one directed to one of the targets listed above, such as ISIS 2503, an anti-ras antisense;
• vascular endothelial growth factor for example the anti-vascular endothelial
• an agent used in a gene therapy approach for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; or (ix) an agent used in an immunotherapeutic approach, for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
• GDEPT gene-directed enzyme pro-drug therapy
• Flash chromatography was carried out on silica causing Biotage FLASHTM or equivalent, for example Biotage FlashmasterTM or Isolute columns. Unless stated otherwise, starting materials were commercially available. All solvents and commercial reagents were of laboratory grade and were used as received.
• Preparative HPLC was carried out using either a Phenomenex Gemini C 18 5 ⁇ m, a Waters Xterra C 8 5 ⁇ m or a Waters Xbridge C 8 5 ⁇ m using aceonitrile in either aqueous ammonia or aqueous trifluoroacetic acid; or a Waters Sunfire Cl 8 5 ⁇ m using acetonitrile in aqueous trifluoroacetic acid.
• XRPD was carried out on PANalytical CubiX PRO machine in 0 - 0 configuration over the scan range 2° to 40° 20 with 100-second exposure per 0.02° increment.
• the X-rays were generated by a copper long-fine focus tube operated at 45kV and 4OmA.
• the wavelength of the copper X-rays was 1.5418 A .
• the Data was collected on zero background holders on which ⁇ 2mg of the compound was placed.
• the holder was made from a single crystal of silicon, which had been cut along a non-diffracting plane and then polished on an optically flat finish.
• the X-rays incident upon this surface were negated by Bragg extinction.
• DSC thermograms were measured using a TA QlOOO Differential Scanning Calorimeter, with aluminium pans and pierced lids. The sample weights varied between 0.3 to 5mg. The procedure was carried out under a flow of nitrogen gas (50ml/min) and the temperature studied from 25 to 300 0 C at a constant rate of temperature increase of 10 0 C per minute.
• Triton B B enzy ltrimethy lammonium Hydroxide
• HATU (2-(7-Aza- 1 H-benzotriazole- 1 -yl)- 1 , 1 ,3 ,3 -tetramethyluronium hexafluorophosphate)
• Lithium tert-butoxide (4.06 g) was added to a stirred solution of l-(2,4-dihydroxy-3- nitrophenyl)ethanone (10 g) in DMF (100 mL), under nitrogen, whilst maintaining the internal temperature below 30 0 C. After stirring for a further 10 min at ambient temperature, benzyl bromide (6.03 mL) was added and the mixture stirred for a further 20 h. Further benzyl bromide (3 mL) was added and the mixture stirred for 24 h.
• the reaction was quenched with water (300 mL), IM aqueous sodium hydroxide (50 mL) was added and the mixture was washed with ether (2 x 300 mL), filtering through Celite to aid separation.
• the basic solution was cooled in ice/water, acidified with ice cold 2M hydrochloric acid (200 mL) and the resulting precipitate filtered off, washed with water and dried to afford a light brown solid.
• the solid was slurried with ethanol (100 mL) for 1 h and the solid filtered off, washed with cold ethanol (20 mL), and dried under vacuum at 40 0 C to afford the subtitled compound as a light brown solid (6.8 g).
• Zinc dust (5.5 g) was added portionwise to a suspension of l-(4-(benzyloxy)-2-hydroxy-3- nitrophenyl)ethanone (5.5 g) in acetic acid (55 niL) over 15 min, whilst maintaining the internal temperature below 40 0 C with an ice bath. The mixture was allowed to attain ambient temperature and stirred for a further 2 h. The mixture was filtered through Celite (caution gets hot, do not allow to dry), washed with acetic acid, and the filtrate poured onto ice/water (500 mL). The resulting precipitate was filtered off, washed with water, and dried under vacuum at 40 0 C to afford the subtitled compound as a light brown solid (4.8 g).
• Benzyltrimethylammonium dichloroiodate 14.17 g was added to a stirred solution of 8- acetyl-5-(benzyloxy)-2H-benzo[b][l,4]oxazin-3(4H)-one (5.5 g) in a mixture of dichloromethane (100 niL), acetic acid (33 mL) and water (5.5 rnL) and the reaction mixture stirred at 65°C for 20 h. The reaction was cooled to ambient temperature, treated with aqueous sodium bisulphite (5.78 g in 100 mL) and stirred for a further 30 min.
• Acetic acid 45 mL
• concentrated hydrochloric acid (10.2 mL)
• water 45 mL
• 8-(2-azidoacetyl)-5-(benzyloxy)-2H- benzo[b][l,4]oxazin-3(4H)-one 5 g
• 10% palladium on carbon 2.5 g
• the mixture was hydrogenated at 4.7 bar and 25°C for 2h 20min to give a partial solution.
• the extraction solvent can be changed from diethyl ether to di-isopropyl ether.
• diethyl ether di-isopropyl ether.
• the aqueous phase was washed with di-isopropylether (200 mL). The aqueous phase was removed and heated to 50 0 C. 3 M aqueous hydrogen chloride (467.5mL) was charged and the mixture cooled to 20 0 C. The suspension was filtered, washed with water (50 mL) and dried under vacuum to yield the title compound (31.14g).
• the aqueous phase may added to an identical quantity of pre- heated (50 0 C) 3 M aqueous hydrogen chloride. On cooling to 20 0 C the suspension may be filtered to yield the sub-titled compound.
• Acetonitrile (700 mL) was added to the product of Preparation 2 Step i) (100 g) and sodium bicarbonate (49.0 g). The mixture was heated to 60 0 C and benzyl bromide (75.62 mL) added. The mixture was heated to reflux. After 6.5 h the mixture was cooled to 60 0 C and water (450 mL) added. The mixture was cooled to below 45°C and methyl tert-butyl ether (450 mL) added. The mixture was cooled to 20 0 C and stirred for at least 1.5 hours. The suspension was filtered and washed with water (250 mL) then ethanol (250 mL) to yield the title compound as a damp solid, 155.65g. Alternatively the material can be dried under vacuum.
• Step iii) l-(3-Amino-4-(benzyloxy)-2-hydroxyphenyl)ethanone
• the reduction conditions can be changed from using zinc dust in acetic acid to a catalytic hydrogenation in tetrahydrofuran using platinum-on-charcoal catalyst.
• Tetrahydrofuran (1000 mL) and triethylamine (9.70 mL) were added to the product of Preparation 2 Step ii) (100 g) and platinum on carbon (1%; Johnson-Matthey Type 18MA) (6 g).
• the mixture was hydrogenated at 50 0 C and 4 barg until complete then cooled to 20 0 C and filtered.
• the mixture was concentrated under vacuum to approximately half the initial volume then methyl isobutyl ketone (500 mL) was charged.
• the mixture was concentrated under vacuum to half the initial volume then methyl isobutyl ketone (500 mL) was charged.
• the resulting mixture can be directly used in the next step or evaporated to dryness to afford the sub-titled compound as a brown solid.
• the base can be changed from using cesium carbonate and sodium bicarbonate to only potassium bicarbonate. With this procedure the solvent is changed from dimethylformamide to 2-methyl pentan-4-one/water leading to the product precipitating directly rather then needing an extractive work-up.
• Step iii) (62.69 g, prepared as in Step iii), in methyl iso- butyl ketone 414 rnL) was charged methyl isobutyl ketone (150 mL).
• the solvent can be changed from DMF to NMP.
• Step vii) 8-(2-Aminoethyl)-5-hydroxy-2H-benzo[b][l,4]oxazin-3(4H)-one hydrochloride The ratio of acetic acid to water can be changed from 6:1 to 2: 1 or 1 :1. With this procedure the water is added at the start and the catalyst is charged in one portion.
• the product can be crystallised from n-butane/water. For example:
• Procedure B A solution of 2-(3-bromophenyl)ethanol (5 g) was stirred in toluene (30 mL) followed by the addition of Triton-B in methanol (0.57 mL). The volatiles were removed until ⁇ 10 mL remained. To this solution was added tert-butyl acrylate (3.94 mL) and the mixture was left to stir for 24 h. The solvent was evaporated and the residue was purified on silica eluting with isohexane-10% ethyl acetate/isohexane. The solvent was evaporated to afford the sub- titled compound as a colourless oil (6.7 g).
• Procedure A p-Toluenesulfonic acid acid monohydrate (9.2 g) was added to the solution of tert-butyl 3- (3-bromophenethoxy)propanoate (132 g, prepared as in Pereparation 3, Step I), Procedure A) in toluene (-590 mL) from the previous Step. The solution was heated to reflux and at reflux for 1.5h then allowed to cool to 20 0 C. 2-Methyltetrahydrofuran (197.8 mL) was added and the solution extracted with water (194.4 mL) and IM sodium hydroxide (725.3 mL).
• the separated aqueous layer was diluted with 2-methyltetrahydrofuran (593.4 mL), extracted with 3M hydrochloric acid (483.5 mL) and the layers separated.
• the separated organic layer can be evaporated to dryness to afford the sub-titled compound as a colourless oil (99.6 g) or the solution used directly in the next Step.
• Procedure B To tert-butyl 3-(3-bromophenethoxy)propanoate (6.7 g, prepared as in Preparation 3, Step i), Procedure B) in DCM (10 rnL) was added TFA (10 mL). The mixture was stirred overnight before the solvent was evaporated under vacuum. The residue was azeotroped twice with toluene to afford a colourless oil (5.63 g). This material was used in the next step directly.
• N-Cyclohexyl-N-(2,2-dimethoxyethyl)-3-(3-(l-methyl-lH-pyrazol-4- yl)phenethoxy)propanamide (0.5 g) was stirred in DCM (10 rnL) followed by the addition of p-toluenesulfonic acid monohydrate (0.43 g). The mixture was stirred for 1 h. Ethyl acetate was added followed by sodium hydrogen carbonate solution. The aqueous phase was removed and the remaining organic phase washed once with water, once with brine, dried over sodium sulphate, filtered and the solvent removed to afford the desired material as an oil (0.48 g). This material was used in the next step directly.
• N-cyclohexyl-3-(3-(l-methyl-lH-pyrazol-4-yl)phenethoxy)-N-(2- oxoethyl)propanamide (448 mg) in NMP (10 mL) and water (0.5 mL) was added 8-(2- aminoethyl)-5-hydroxy-2H-benzo[b][l,4]oxazin-3(4H)-one hydrochloride (303 mg) and sodium bicarbonate (104 mg). The mixture was stirred for 5 min before the addition of sodium triacetoxyborohydride (358 mg). The reaction was stirred overnight before the addition of sodium hydrogen carbonate solution, which was extracted three times with DCM.
• the vial was sealed and heated at HO 0 C within a Discover microwave for 40 min with stirring.
• the reaction was cooled followed by the addition of ethyl acetate, which was washed once with water, once with brine, dried over sodium sulphate and the solvent removed.
• the residue was purified on silica using neat ethyl acetate to afford the protected product (250 mg).
• This material was taken up in DCM followed by the addition of 4M hydrochloric acid in dioxane and stirred overnight.
• the solvent was removed under vacuum to afford of crude material (330 mg). This was basified with sodium hydrogen carbonate solution, which was extracted three times with DCM.
• the pooled organics were acidified with 0.5 mL of TFA and the solvent removed to afford the titled compound as a TFA salt.
• the solution was partially evaporated under vacuum to give a solution measuring 49OmL and split into 2 portions. Firstly half of the solution was cooled to 20 0 C and added to dibutyl ether (400 mL) at 20 0 C to give a precipitate which was stirred at 20 0 C for 2 h. The suspension was filtered, washed with dibutyl ether (100 mL) and dried at 50 0 C under vacuum to afford the sub-titled compound (34.1 g). The second half of the solution was added to dibutyl ether (400 mL) at 65°C to give a precipitate which was maintained at 65°C for 10 min then cooled to 15°C and stirred for 1 h. The suspension was filtered, washed with dibutyl ether (100 mL) and dried at 50°C under vacuum to afford the subtitled compound as a white solid (30.5 g).
• a line wash of tetrahydrofuran (50.3 mL) was then added and the solution stirred at ambient temperature for 1 h before being added to a solution of sodium hydroxide (19.6 g) and sodium chloride (100.6 g) in water (502.9 mL) at ⁇ 5°C.
• a line wash of tetrahydrofuran (25.1 mL) was then added and the solution warmed to 20 0 C.
• 1- Butanol (100.6 mL) was added and the layers separated. The separated organic layer can be evaporated to dryness to afford the sub-titled compound as an orange/brown oil or the solution used directly in the next Step.
• p-Toluenesulfonic acid monohydrate (5.31 g) was added in one portion to N-cyclohexyl-N- (2,2-dimethoxyethyl)-3-(3-(l-methyl-lH-pyrazol-4-yl)phenethoxy)propanamide (7.74 g, prepared as in Example 2a, Step ii)) in tetrahydrofuran (60 mL). The resulting solution was stirred at 20 0 C for 30 min.
• Solvents ethanol, acetonitrile, tetrahydrofuran, dichloromethane, 2-propanol, nitromethane, ethyl acetate, 1,4-dioxane; 1 mL each
• solvents ethanol, acetonitrile, tetrahydrofuran, dichloromethane, 2-propanol, nitromethane, ethyl acetate, 1,4-dioxane; 1 mL each
• Ethyl iodide (0.216 mL) was added in one portion to a mixture of tert-butyl 3-(3- ethynylphenethoxy)propanoate [Example 4, Step ii)] (564 mg), sodium azide (160 mg) tert-butanol (0.25 mL), water (1 mL) and copper (I) iodide (39 mg) and sealed into a microwave tube.
• the reaction was heated to 70 0 C, over a period of 6 h in a microwave reactor.
• the reaction mixture was diluted with ethyl acetate and 35% ammonia was added. The mixture was stirred for 30 min and separated.
• the reaction mixture was diluted with ethyl acetate (50 mL), and washed with saturated sodium hydrogen carbonate (20 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0-70% ethyl acetate in isohexane to afford the subtitled compound (0.46 g).
• Step vi) tert-Butyl 2-(5-(tert-butoxycarbonyloxy)-3-oxo-3,4-dihydro-2H- benzo[b][l,4]oxazin-8-yl)ethyl(2-(N-cyclohexyl-3-(3-(l-ethyl-lH-l,2,3-triazol-4- yl)phenethoxy)propanamido)ethyl)carbamate
• Step vii) N-Cyclohexyl-3-(3-(l-ethyl-lH-l,2,3-triazol-4-yl)phenethoxy)-N-(2-(2-(5- hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)propanamide Trifluoroacetic Acid Salt
• the crude product was purified by preparative HPLC on a Phenomenex Gemini column using a 15-60% gradient of aqueous 0.1% trifluoroacetic acid in acetonitrile as eluent to afford the titled compound as a white solid (62.3 mg).
• Methyl iodide (0.20 mL) was added in one portion to a mixture of tert-butyl 3-(3- ethynylphenethoxy)propanoate [Example4, Step ii)] (682 mg), sodium azide (194 mg), tert-butanol (0.750 mL), water (3 mL) and copper (I) iodide (47 mg) and sealed into a microwave tube. The reaction was heated to 70 0 C, over a period of 2 h in the microwave reactor. The reaction mixture was diluted with ethyl acetate and 35% ammonia was added. The mixture was stirred for 30 min and separated.
• the reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated sodium hydrogen carbonate (20 mL). The organic was dried over magnesium sulfate, filtered and evaporated to afford crude product.
• the crude product was purified by flash silica chromatography, elution gradient 20 to 100% ethyl acetate in isohexane then elution gradient 0-10% methanol in ethyl acetate to afford the subtitled compound (0.59 g).
• the crude product was purified by preparative HPLC on a Phenomenex Gemini column using a 15-60% gradient of aqueous 0.1% trifluoroacetic acid in acetonitrile as eluent to afford the titled compound as a white solid (94 mg).
• the reaction mixture was diluted with ethyl acetate (100 mL), and washed with saturated sodium hydrogen carbonate (50 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0-70% ethyl acetate in isohexane to afford the subtitled compound (0.51 g).
• Step ii) tert-Butyl 2-(5-(tert-butoxycarbonyloxy)-3-oxo-3,4-dihydro-2H- benzo[b][l,4]oxazin-8-yl)ethyl(2-(N-cycloheptyl-3-(3-(l-methyl-lH-l,2,3-triazol-4- yl)phenethoxy)propanamido)ethyl)carbamate
• the crude product was purified by preparative HPLC on a Phenomenex Gemini column using a 15-60% gradient of aqueous 0.1% trifluoroacetic acid in acetonitrile as eluent to afford the titled compound as a white solid (84 mg).
• Triethylamine hydrochloride (2.09 g) was added in one portion to a mixture of tert-butyl 3- (3-cyanophenethoxy)propanoate [Example7, Step i)] (1.74 g), sodium azide (0.99 g) and tert-butanol (12.64 mL), and sealed into a microwave tube.
• the reaction was heated to 140 0 C, over a period of 2 h in the microwave reactor.
• the reaction mixture was diluted with water and acidified with 2M hydrochloric acid (5 mL).
• the mixture was extracted with DCM and the organic layer was dried over magnesium sulfate, filtered and evaporated to afford crude product.
• the crude product was purified by flash silica chromatography, elution gradient 20-100% ethyl acetate in isohexane, then elution gradient 0-10% methanol in DCM to afford the subtitled compound (1.77 g).
• Trimethylsilyldiazomethane (4.5 mL) in diethyl ether was added to an ice-bath cooled solution of tert-butyl 3-(3-(2H-tetrazol-5-yl)phenethoxy)propanoate [Example7, Step ii)] (0.72 g) in DCM (5 mL) and methanol (5 mL). The mixture was stirred for 15 min and concentrated under vacuum. The crude product was purified by flash silica chromatography, elution gradient 10-100% ethyl acetate in isohexane to afford the subtitled compound as a gum (0.51 g).
• the reaction mixture was diluted with ethyl acetate (50 mL), and washed with saturated sodium hydrogen carbonate (20 rnL). The organic layer was dried over magnesium sulfate, filtered and evaporated to afford crude product.
• the crude product was purified by flash silica chromatography, elution gradient 20-100% ethyl acetate in isohexane, then elution gradient 0-10% methanol in ethyl acetate to afford the subtitled compound (0.66 g).
• reaction mixture was neutralised with saturated sodium hydrogen carbonate and extracted into DCM.
• the solvent was evaporated and the residue was treated with ethyl acetate (5 mL) and saturated sodium hydrogen carbonate (10 mL).
• a solution of BOC anhydride (0.53 mL, 2.29 mmol) in ethyl acetate (5 mL) was added.
• the resulting mixture was stirred at 25°C for 1 h.
• the reaction mixture was diluted with ethyl acetate (50 mL), and washed 3 times with water (50 rnL). The organic layer was dried over magnesium sulfate, filtered and evaporated to afford crude product.
• the crude product was purified by flash silica chromatography, elution gradient 20-100% ethyl acetate in isohexane and pure fractions were evaporated to dryness. The residue was treated with DCM (5 mL) and TFA (2 mL) and the mixture was stirred for 30 min, and then concentrated. The crude product was purified by preparative HPLC on a Phenomenex Gemini column using a gradient of aqueous 0.1% trifluoroacetic acid in acetonitrile as eluent to afford the titled compound as a white solid (36.9 mg).
• the reaction mixture was diluted with ethyl acetate (50 mL), and washed with saturated sodium hydrogen carbonate (20 mL). The organic was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20-100% ethyl acetate in isohexane to afford the subtitled compound (0.10 g).
• reaction mixture was neutralised with saturated sodium hydrogen carbonate and extracted into DCM.
• the solvent was evaporated and the residue was treated with Ethyl acetate (2 mL) and saturated sodium hydrogen carbonate (10 mL).
• a solution of BOC anhydride (0.14 mL) in ethyl acetate (3 mL) was added.
• the resulting mixture was stirred at 25°C for 30 min.
• the reaction mixture was diluted with ethyl acetate (50 mL), and washed 3 times with water (50 mL). The organic was dried over magnesium sulfate, filtered and evaporated to afford crude product.
• the crude product was purified by flash silica chromatography, elution gradient 20-100% ethyl acetate in isohexane. Pure fractions were evaporated to dryness. The residue was treated with DCM (2 mL) and TFA (1 mL) and the mixture was stirred for 30 min, then concentrated. The crude product was purified by preparative HPLC on a Phenomenex Gemini column using a gradient of aqueous 0.1% trifluoroacetic acid in acetonitrile as eluent to afford the titled compound as a white solid (14 mg).
• the reaction mixture was diluted with ethyl acetate (50 mL), and washed with saturated sodium hydrogen carbonate (20 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to afford crude product.
• the crude product was purified by flash silica chromatography, elution gradient 0-100% ethyl acetate in isohexane, then elution gradient 5-10% methanol in ethyl acetate to afford the subtitled compound as a gum (210 mg).
• Step ii) 3-(3-(l ,2,4-Oxadiazol-3-yl)phenethoxy)-N-cyclohexyl-N-(2,2- dimethoxyethyl)propanamide
• Examplel l, Step i) To N-cyclohexyl-N-(2,2-dimethoxyethyl)-3-(3-(N- hydroxycarbamimidoyl)phenethoxy)propanamide [Examplel l, Step i)] (530 mg) in a 10 mL microwave vial was added trimethyl orthoformate (1 mL), sealed and heated at 100 0 C for 20 min. The vial was then heated to 12O 0 C for 3 h before the addition of p-toluenesulfonic acid (3 mg) and then heated to 120 0 C for a further 60 min. Ethanol was added (30 mL) and the solvent was evaporated to afford the sub-titled compound (500 mg).
• 2-Iodopropane (0.168 niL) was added in one portion to a mixture tert-butyl 3-(3- ethynylphenethoxy)propanoate [Example 4, Step ii)] (383 mg), sodium azide (109 mg), tert-butanol (0.75 mL), water (3 mL) and copper(I) iodide (26.6 mg) and sealed into a microwave tube.
• the reaction was heated to 80 0 C, over a period of 3 h in the microwave reactor.
• the reaction mixture was diluted with ethyl acetate and 35% ammonia (1 mL) and ethyl acetate (2 mL) were added. The mixture was stirred for 30 min.
• the subtitled compound (777 mg) was prepared from tert-butyl 3-(3-(l-isopropyl-lH- l,2,3-triazol-4-yl)phenethoxy)propanoate [Examplel2, Step i)] using a similar method to that described in Example 4, Step iv).
• the subtitled compound (230 mg) was prepared from 3-(3-(l-isopropyl-lH-l,2,3-triazol-4- yl)phenethoxy)propanoic acid [Example 12, Step ii)] and N-(2,2- dimethoxyethyl)cyclohexanamine using a similar method to that described in Example 4, Step v) and the elution gradient to 0 to 100% ethyl acetate in isohexane.
• the organic was washed with a 1 : 1 mixture of water and saturated brine (2 x 10 ml). The organic was dried over magnesium sulfate, filtered and evaporated to afford crude product.
• the crude product was purified by flash silica chromatography, elution gradient 0 to 10% methanol in dichloromethane and repurified by preparative HPLC on a Phenomenex Gemini column using aqueous 0.1% trifluoroacetic acid in acetonitrile as eluent to afford the titled compound (175 mg).
• Pd-118 (0.201 g) was dissolved in acetonitrile (20 mL) and stirred for 5 min before addition of potassium carbonate (5.34 g), water (20 mL) and l-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (2.95 g). The mixture was stirred for a further 5 min then methyl 2-(3-bromo-4-fluorophenyl)acetate [Examplel3, Step i)] (3.18 g) in MeCN (2 mL) added and the reaction was heated at the heating block (80 0 C) for 25 min. The mixture was cooled and extracted into DCM (100 mL).
• Triton-B (0.4 ml, 0.88 mmol) was added to a stirred mixture of 2-(4-fluoro-3-(l-methyl- lH-pyrazol-4-yl)phenyl)ethanol [Examplel3, Step iii)] (1.7 g) and tert-butyl acrylate (8 mL). The mixture was stirred at room temperature over 1 h.
• the subtitled compound (4.32 g) was prepared from tert-butyl 3-(4-fluoro-3-(l-methyl-lH- pyrazol-4-yl)phenethoxy)propanoate [Examplel3, Step iv)] using a similar method to that described in Example 4, Step iv).
• the subtitled compound (3.3 g) was prepared from 3-(4-fluoro-3-(l-methyl-lH-pyrazol-4- yl)phenethoxy)propanoic acid [Example 13, Step v)] and N-(2,2- dimethoxyethyl)cyclohexanamine using a similar method to that described in Example 12, Step iii).
• Step vii) N-Cyclohexyl-3-(4-fluoro-3 -(I -methyl- lH-pyrazol-4-yl)phenethoxy)-N-(2-(2-(5- hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)propanamide Trifluoroacetic Acid Salt
• Cyclopropyl bromide (0.177 mL) was added in one portion to a mixture tert-butyl 3-(3- ethynylphenethoxy)propanoate [Example4, Step ii)] (506 mg), sodium azid e(144 mg), tert-butanol (0.5 mL), water (2 mL) and copper(I) iodide (35.1 mg) and sealed into a microwave tube. The reaction was heated to 70 0 C, over a period of 3 h in the microwave reactor. The reaction mixture was diluted with ethyl acetate and 35% ammonia (1 mL) and ethyl acetate (2 mL) were added. The mixture was stirred for 30 min.
• the subtitled compound (713 mg) was prepared from tert-butyl 3-(3-(l-allyl-lH-l,2,3- triazol-4-yl)phenethoxy)propanoate [Example 14, Step i)] using a similar method to that described in Example 4, Step iv).
• the subtitled compound (584 mg) was prepared from tert-butyl 3-(3-( 1 -allyl- IH- 1 ,2,3- triazol-4-yl)phenethoxy)propanoate [Ex 4, Step iii)] and N-(2,2- dimethoxyethyl)cyclohexanamine using a similar method to that described in Example 12, Step iii) the elution gradient 20 to 100% ethyl acetate in isohexane.
• the reaction was heated to 100 0 C, over a period of 90 min in the microwave reactor. After cooling to room temperature, TFA (1 mL) was added and the mixture was stirred for 30 min, then concentrated.
• the crude product was purified by preparative HPLC on a Phenomenex Gemini column using a gradient of aqueous 0.1% trifluoroacetic acid in acetonitrile as eluent to afford the titled compound (63.5 mg) as a solid.
• the subtitled compound (500 mg) was prepared from tert-butyl 3-(3-(2-allyl-2H-tetrazol- 5-yl)phenethoxy)propanoate using a similar method to that described in Example 4, Step iv).
• the subtitled compound (450 mg) was prepared from 3-(3-(2-allyl-2H-tetrazol-5- yl)phenethoxy)propanoic acid [Example 7, Step ii)] and N-(2,2- dimethoxyethyl)cyclohexanamine using a similar method to that described in Example 14, Step iii).
• the reaction was heated to 100 0 C, over a period of 30 min in the microwave reactor. After cooling to rt, TFA (1 mL) was added and the mixture stirred for 30 min. The mixture was concentrate in vacuo do give a crude product.
• the crude product was purified by preparative HPLC on a Phenomenex Gemini column using a gradient of aqueous 0.1% trifluoroacetic acid in acetonitrile as eluent to afford the titled compound (41.8 mg) as a solid.
• Methanesulfonic acid (0.4 mL) was added to a mixture of l-bromo-2-fluoro-3-(2- methoxyvinyl)benzene [Example 16, Step i)] (1.8 g), tetrahydrofuran (15 mL) and water (1.5 mL) and sealed into a microwave tube. The reaction was heated to 80 0 C, over a period of 90 min in the microwave reactor. Sodium bicarbonate (654 mg) was added portionwise and the mixture was stirred for 10 min. Sodium borohydride (295 mg) was added portionwise (gas evolution) and the mixture was stirred for 30 min. The reaction mixture was poured into saturated sodium hydrogen carbonate solution and extracted with DCM (3 x 30 mL).
• the subtitled compound (1.99 g) was prepared from 2-(3-bromo-2-fluorophenyl)ethanol [Example 16, Step ii)] using a similar method to that described in Example 13, Step iv) and elution gradient 0-10% ethyl acetate in isohexane.
• Pd-118 (104 mg) was dissolved in acetonitrile (10 mL) and stirred for 5 min before addition of potassium carbonate (2.364 g), water (10 mL) and l-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (1.305 g). The mixture was stirred for a further 5 min then tert-butyl 3-(3-bromo-2-fluorophenethoxy)propanoate [Example 16, Step iii)] (1.98 g) added and the reaction was heated at the heating block (80 0 C) for 2 h.
• the subtitled compound (2.45 g) was prepared from tert-butyl 3-(2-fluoro-3-(l-methyl-lH- pyrazol-4-yl)phenethoxy)propanoate [Example 16, Step iv)] using a similar method to that described in Example 4, Step iv).
• the subtitled compound (1.6 g) was prepared from 3-(2-fluoro-3-(l-methyl-lH-pyrazol-4- yl)phenethoxy)propanoic acid [Example 16, Step v)] and N-(2,2- dimethoxyethyl)cyclohexanamine using a similar method to that described in Example 12, Step iii).
• Step vii) N-Cyclohexyl-3-(2-fluoro-3 -(I -methyl- 1 H-pyrazol-4-yl)phenethoxy)-N-(2-(2-(5 - hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)propanamide Trifluoroacetic Acid Salt
• Step i) Methyl 2-(3-bromo-5-fluorophenyl)acetate
• the subtitled compound (1.0 g) was prepared from 2-(3-bromo-5-fluorophenyl)acetic acid using a similar method to that described in Example 13 Step i).
• the subtitled compound (1.09 g) was prepared from methyl 2-(3-bromo-5- fluorophenyl)acetate [Example 17, Step i)] using a similar method to that described in Example 13 Step ii).
• the subtitled compound (0.98 g) was prepared from methyl 2-(3-fluoro-5 -(I -methyl- IH- pyrazol-4-yl)phenyl)acetate [Example 17, Step ii)] using a similar method to that described in Example 13 Step iii).
• the subtitled compound (1.05 g) was prepared from 2-(3-fluoro-5 -(I -methyl- lH-pyrazol- 4-yl)phenyl)ethanol [Example 17, Step iii)] using a similar method to that described in Example 13 Step iv).
• the subtitled compound (1.05 g) was prepared from tert-butyl 3-(3-fluoro-5-(l -methyl- IH- pyrazol-4-yl)phenethoxy)propanoate [Example 17, Step vi)] using a similar method to that described in Example 4, Step iv).
• the subtitled compound (3.3 g) was prepared from 3 -(3 -fluoro-5 -(I -methyl- lH-pyrazol-4- yl)phenethoxy)propanoic acid [Example 17, Step v)] and N-(2,2- dimethoxyethyl)cyclohexanamine using a similar method to that described in Example 12, Step iii).
• Step vii) N-Cyclohexyl-3 -(3 -fluoro-5 -(I -methyl- 1 H-pyrazol-4-yl)phenethoxy)-N-(2-(2-(5 - hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)propanamide Trifluoroacetic Acid Salt
• the titled compound (345 mg) was prepared from N-cyclohexyl-N-(2,2-dimethoxyethyl)- 3 -(3 -fluoro-5 -(I -methyl- lH-pyrazol-4-yl)phenethoxy)propanamide [Example 17, Step vi)] using a similar method to that described in Example 12, Step iv).
• Pd-118 (51.7 mg) was dissolved in acetonitrile (8 mL) and stirred for 5 min before addition of potassium carbonate (1.1 g), water (8 mL) and a solution of l-propyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (750 mg) in MeCN (1 mL). The mixture was stirred for a further 5 min then a solution of tert-butyl 3-(3- bromophenethoxy)propanoate (870 mg, prepared as in Preparation 3, Step i)) was added and the reaction was heated at the heating block (80 0 C) for 30 min.
• the subtitled compound (1.65 g) was prepared from tert-butyl 3-(3-(l-propyl-lH-pyrazol- 4-yl)phenethoxy)propanoate [Example 18, Step i)] using a similar method to that described in Example 4, Step iv).
• the organic was filtered through a phase separator cartridge and evaporated to afford crude product.
• the crude product was purified by flash silica chromatography using elution gradient 0 to 100% ethyl acetate in isohexane to the subtitled compound (150 mg) as an oil.
• Step i) 1 -(Cyclopropylmethyl)-4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 H- pyrazole
• Pd-118 (28.6 mg) was dissolved in acetonitrile (6 niL) and stirred for 5 min before addition of potassium carbonate (606 mg), water (6 mL) and a solution of 1- (cyclopropylmethyl)-4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazole [Example 19, Step i)] (435 mg) in MeCN (1 mL).
• the subtitled compound (0.65 g) was prepared from tert-butyl 3 -(3-(I- (cyclopropylmethyl)-lH-pyrazol-4-yl)phenethoxy)propanoate [Example 19, Step ii)] using a similar method to that described in Example 4, Step iv).
• the subtitled compound (246 mg) was prepared from 3-(3-(l-(cyclopropylmethyl)-lH- pyrazol-4-yl)phenethoxy propanoic acid [Example 19, Step iii)] and N-(2,2- dimethoxyethyl)cyclopentanamine, prepared as in Preparation 9 using a similar method to that described in Example 18, Step iii).
• Step i) 1 -Isopropyl-4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazole
• the subtitled compound (1.03 g) was prepared from tert-butyl 3-(3- bromophenethoxy)propanoate [Preparation 3, Step i)] and l-isopropyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole [Example 20, Step i)] using a similar method to that described in Example 18, Step i).
• the subtitled compound (1.84 g) was prepared from tert-butyl 3-(3-(l-isopropyl-lH- pyrazol-4-yl)phenethoxy)propanoate [Example 20, Step ii)] using a similar method to that described in Example 4, Step iv).
• the subtitled compound (105 mg) was prepared from 3-(3-(l-isopropyl-lH-pyrazol-4- yl)phenethoxy)propanoic acid [Example 20, Step iii)] and (R)-N-(2,2-dimethoxyethyl)-3- methylbutan-2-amine, prepared as in Preparation 4 using a similar method to that described in Example 18, Step iii).
• the organic was washed with a 1 : 1 mixture of water and saturated brine (3 mL). The organic was dried over magnesium sulfate, filtered and evaporated to afford crude product.
• the crude product was purified by flash silica chromatography, elution gradient 0 to 15% methanol in dichloromethane and repurified by preparative HPLC on a Phenomenex Gemini column using aqueous 0.1% trifluoroacetic acid in methanol as eluent to afford the titled compound (40.4 mg) as a white solid.
• the subtitled compound (100 mg) was prepared from 3 -(3 -(I -isopropyl- lH-pyrazol-4- yl)phenethoxy)propanoic acid [Example 20 Step iii)] and ((R)-N-(2,2- dimethoxyethyl)pentan-2-amine [Preparation 10] using a similar method to that described in Example 18, Step iii).
• the subtitled compound (140 mg) was prepared from 3-(3-(l-isopropyl-lH-pyrazol-4- yl)phenethoxy)propanoic acid [Example 20 Step iii)] and N-(2,2- dimethoxyethyl)cyclopentanamine [Preparation 9] using a similar method to that described in Example 18, Step iii).
• the subtitled compound (0.64 g) was prepared from tert-butyl 3-(3- bromophenethoxy)propanoate [Preparation 3, Step i)] and l-ethyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazole using a similar method to that described in Example 18, Step i).
• MS [M+H-C4H8]+ 289 (MultiMode+)
• the subtitled compound (1.12 g) was prepared from tert-butyl 3-(3-(l-ethyl-lH-pyrazol-4- yl)phenethoxy)propanoate [Example 23, Step i)] using a similar method to that described in Example 4, Step iv).
• the subtitled compound (133 mg) was prepared from 3-(3-(l-ethyl-lH-pyrazol-4- yl)phenethoxy)propanoic acid [Example 23, Step ii)] and N-(2,2- dimethoxyethyl)cyclopentanamine [Preparation 4] using a similar method to that described in Example 18, Step iii) extending the reaction time to 2 h.
• the titled compound (31 mg) was prepared from (R)-N-(2,2-dimethoxyethyl)-3-(3-(l- ethyl- lH-pyrazol-4-yl)phenethoxy)-N-(3-methylbutan-2-yl)propanamide [Example 23, Step iii)] using a similar method to that described in Example 20, Step v).
• the subtitled compound (138 mg) was prepared from 3-(3-(l-ethyl-lH-pyrazol-4- yl)phenethoxy)propanoic acid [Example 23 Step ii)] and N-(2,2- dimethoxyethyl)cyclopentanamine [Preparation 9] using a similar method to that described in Example 18, Step iii), extending the reaction time to 1 h.
• the titled compound (33 mg) was prepared from (R)-N-(2,2-dimethoxyethyl)-N-(3,3- dimethylbutan-2-yl)-3 -(3 -( 1 -ethyl- 1 H-pyrazol-4-yl)phenethoxy)propanamide [Example 25 , Step i)] using a similar method to that described in Example 20, Step v).
• the titled compound (81 mg) was prepared from (R)-N-(2,2-dimethoxyethyl)-N-(3,3- dimethylbutan-2-yl)-3 -(3 -( 1 -methyl- 1 H-pyrazol-4-yl)phenethoxy)propanamide [Example 26, Step i)] using a similar method to that described in Example 20, Step v).
• the subtitled compound (100 mg) was prepared using a similar method to that described in Example 11 Step ii) using 1,1,1-trimethoxy ethane. After the addition of p-toluenesulfonic acid monohydrate (3 mg) the reaction was heated to 120 0 C for 30 min. The crude product was purified by flash silica chromatography, eluting with 40% ethyl acetate in isohexane to afford the subtitled compound.
• the subtitled compound (1.11 g) was prepared using a similar method to that described in Example 1 Step i) using l-ethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole. The reaction was heated to 100 0 C for 25 min. The crude product was purified by flash silica chromatography, eluting with 60% ethyl acetate in isohexane.
• Step ii) N-Cyclohexyl-3-(3-(l-ethyl-lH-pyrazol-4-yl)phenethoxy)-N-(2-(2-(5-hydroxy-3- oxo-3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)propanamide
• the titled compound (98 mg) was prepared from N-cyclohexyl-N-(2,2-dimethoxyethyl)-3- (3-(l-ethyl-lH-imidazol-2-yl)phenethoxy)propanamide [Example 29, Step i)] using a similar method to that described in Example 27 Step ii).
• the THF solution was stirred for 9 h before the NMP solution was added.
• the reaction mixture was stirred for 4 h after the addition of sodium triacetoxyborohydride.
• the subtitled compound (234 mg) was prepared using a similar method to that described in Preparation 3 Step iii) from 3-(3-(l-methyl-lH-pyrazol-4-yl)phenethoxy)propanoic acid [Example 2a, Step i)] and (R)-N-(2,2-dimethoxyethyl)hexan-2-amine [Preparation 13] and the reaction mixture was stirred for 2 h.
• the elution gradient used was 30-50% ethyl acetate in isohexane.
• the titled compound (150 mg) was prepared from (R)-N-(2,2-dimethoxyethyl)-N-(hexan- 2-yl)-3-(3-(l-methyl-lH-pyrazol-4-yl)phenethoxy)propanamide [Example 30, Step i)] using a similar method to that described in Example 27 Step ii).
• the THF solution was stirred for 2 h before the NMP solution was added.
• the mixture was stirred overnight after the addition of sodium triacetoxyborohydride, then diluted with water.
• the subtitled compound (1.2 g) was prepared from 3-(3-(l-methyl-lH-pyrazol-4- yl)phenethoxy)propanoic acid [Example 2a, Step i)] and N-(2,2- dimethoxyethyl)cycloheptanamine [Preparation 6], using a similar method to that described in Preparation 3 Step iii) and the elution gradient used was 50-80% ethyl acetate in isohexane.

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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
• Plural Heterocyclic Compounds (AREA)

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• 2009
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