US 2012O31 6160A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0316160 A1 Taylor (43) Pub. Date: Dec. 13, 2012

(54) XINAFOATE SALT OF (60) Provisional application No. 60/970,030, filed on Sep. N4-(2,2-DIFLUORO-4H-BENZO1,4- 5, 2007. OXAZIN-3-ONE)-6-YL-5-FLUORO-N2-3- (METHYLAMINOCARBONYLMETHYL Publication Classification ENEOXY)PHENYL2.4- PYRIMDNEDLAMINE (51) Int. Cl. A6II 3/538 (2006.01) (75) Inventor: Stefan Colin John Taylor, A6IP II/06 (2006.01) Sandwich (GB) C07D 413/12 (2006.01) (73) Assignee: Rigel Pharmaceuticals, Inc. (52) U.S. Cl...... 514/230.5:544/105 (21) Appl. No.: 13/467,850 (22) Filed: May 9, 2012 (57) ABSTRACT The present invention relates to the Xinafoate salt of N4-(2, Related U.S. Application Data 2-difluoro-4H-benzo 1.4oxazin-3-one)-6-yl)-5-fluoro-N2 (63) Continuation of application No. 12/676,075, filed on 3-(methylaminocarbonylmethyleneoxy)phenyl-2,4-pyrim Mar. 2, 2010, now Pat. No. 8,193,181, filed as appli idinediamine. This compound is a Suitable drug Substance cation No. PCT/IB2008/002288 on Aug. 27, 2008. and is useful in the treatment of conditions including . Patent Application Publication Dec. 13, 2012 Sheet 1 of 6 US 2012/0316160 A1

Figure 1

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Figure 2 se towakebouwh-i-war endulative between weekskoolubleake

2OO Patent Application Publication Dec. 13, 2012 Sheet 2 of 6 US 2012/0316160 A1

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Reflectance/Wavenumber orn-1) Patent Application Publication Dec. 13, 2012 Sheet 3 of 6 US 2012/0316160 A1

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- - s:xxxas&x& & S. 2O). SOO 6OO OO 2O) OOO 3OO ReflectanceWavenumber (cm-) Figure 6

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Figure 7

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wrotes everyosaecessassissilewish asswissaloowo issues sawsary both sometownywherseyseriesissistewater. 200 18OO 600 1400 1200 1000 800 SO 40) 200 AbsorbanceWavenumber (cm-1} Patent Application Publication Dec. 13, 2012 Sheets of 6 US 2012/031616.0 A1

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180 I60 40 120 100 80 60 40 20 ppm Patent Application Publication Dec. 13, 2012 Sheet 6 of 6 US 2012/0316160 A1

Figure 9

---T------40 -60 -80 Ot) -120 -140 -160 -180 -200 ppm US 2012/031 6160 A1 Dec. 13, 2012

XNAFOATE SALT OF dependent on finding a form of the compound with a unique N4-(2,2-DIFLUORO-4H-BENZO14OXAZIN-3- combination of properties determined according to the ONE)-6-YL-5-FLUORO-N2-3-(METHYL intended route of administration. AMINOCARBONYLMETHYLENEOXY)- 0004. The free form of N4-(2,2-difluoro-4H-benzo[1,4] PHENYL2.4-PYRIMIDINEDIAMINE oxazin-3-one)-6-yl-5-fluoro-N2-3-(methylaminocarbonyl methyleneoxy)phenyl-2,4-pyrimidinediamine disclosed in WO-A-03/063794 is not suitable for commercialisation as a 0001. The present invention relates to the Xinafoate salt of drug since it is predominantly amorphous, or exists in a dis N4-(2,2-difluoro-4Hbenzo 1.4 oxazin-3-one)-6-yl-5- ordered crystalline form and is prone to hydration and Solva fluoro-N2-3-(methylaminocarbonylmethylene oxy)phe tion. There is therefore a need to provide a new form of nyl-2,4-pyrimidinediamine and to pharmaceutical composi N4-(2,2-difluoro-4Hbenzo 1.4 oxazin-3-one)-6-yl-5- tions comprising and to processes for making Such a fluoro-N2-3-(methylaminocarbonylmethyleneoxy)phenyl compound. The invention further relates to the use of the salt 2.4-pyrimidinediamine which has the required characteris and its compositions in the treatment of various conditions, tics. Salt formation is one possible avenue of enquiry, but the particularly in the treatment of inflammatory conditions such properties of salts are hard to predict and, worse still, the as asthma. compound will not form salts with many common pharma 0002 The compound N4-(2,2-difluoro-4H-benzo 1.4 ceutically acceptable acids. Many salt forms that do form, oxazin-3-one)-6-yl-5-fluoro-N2-3-(methylaminocarbonyl Such as the mesylate, fumarate, hemifumarate, hydrobro methyleneoxy)phenyl-2,4-pyrimidinediamine, having the mide, hydrochloride, D-tartrate, hemisulphate and isethion structural formula (I): ate salts, have one or more unsatisfactory properties such as poor crystallinity and the propensity to form hydrates and/or Solvates. (I) BRIEF DESCRIPTION OF THE DRAWINGS

F O C H 0005 FIG. 1 is a differential scanning calorimetry trace of O N N N-- O NS the Xinafoate salt. H H H 1. CH 0006 FIG. 2 is a powder X-ray diffraction pattern of the O Xinafoate salt. 0007 FIG. 3 is a simulated crystal X-ray analysis of the Xinafoate salt. is disclosed in WO-A-03/063794 as Example 7.3.907 on page 0008 FIG. 4 is a Fourier Transform IR spectrum of the 440. The compound, which is also known as 2-3-4-(2,2- Xinafoate salt. Difluoro-3-oxo-3,4-dihydro-2H-benzo14 oxazin-6- 0009 FIG. 5 is a fingerprint region of the FIRT spectrum ylamino)-5-fluoro-pyrimidin-2-ylaminolphenoxy-N-me of FIG. 4. thyl-acetamide, is one of a genus of compounds which are 0010 FIG. 6 is a Fourier transform Raman spectrum of the disclosed to be inhibitors of Sykkinase and therefore useful in Xinafoate salt. the treatment of inflammatory conditions such as chronic 0011 FIG. 7 is a fingerprint region of the Fourier Trans obstructive pulmonary disease (COPD). It is noted that the form Raman spectrum of FIG. 6. compounds can be formulated in a pharmaceutical composi (0012 FIG. 8 is a proton decoupled C'solid state NMR of tion in their free form or in the form of a hydrate, solvate, the Xinafoate salt. N-oxide orpharmaceutically acceptable salt (pages 70-71). A 0013 FIG.9 is a fluorine solid state NMR of the Xinafoate pharmaceutical composition Suitable for inhalation compris salt. ing one of the compounds and a suitable powder base. Such as 0014. As a result of extensive research, however, it has lactose or starch, is specifically mentioned (page 72). now been possible to design a form of N4-(2,2-difluoro-4H 0003) If a compound is to be developed as a drug, it is benzo 1,4-oxazin-3-one)-6-yl-5-fluoro-N2-3-(methylami important to provide a form of that compound (commonly nocarbonylmethyleneoxy)phenyl-2,4-pyrimidinediamine known as a drug Substance) which can be reliably prepared which has a unique set of characteristics making it ideal for and purified on a large scale, which is stable and which does administration in a dry powder formulation. The Xinafoate not degrade on Storage. Such characteristics are normally salt is highly crystalline, has a melting point of about 233°C., found in a drug Substance which is crystalline and of high is essentially non-hygroscopic and can be micronised by jet melting point; a high-melting point crystalline solid tends to milling without inducing any change in crystalline form. Fur be easy to purify by recrystallization and stable on storage. thermore, it shows good stability when blended with lactose Furthermore, the drug substance must be suitable for formu monohydrate and stored under aggressive conditions of heat lationina dosage form chosen according to the intended route and humidity and the lactose blend aerosolises well when of administration. For formulation as a dry powder suitable used in conjunction with standard dry powder inhalers. for inhalation, nonhygroscopicity is particularly important in 0015 The present invention therefore provides, in a first order to obtain good flow characteristics. Compatibility with aspect, the Xinafoate salt of N4-(2,2-difluoro-4H-benzo 1.4 conventional excipients such as lactose and starch is a further oxazin-3-one)-6-yl-5-fluoro-N2-3-(methylaminocarbonyl mandatory requirement. Further, the drug Substance will usu methyleneoxy)phenyl-2,4-pyrimidinediamine, having the ally require processing in order to achieve a particle size structure shown in Formula (II) below. Xinafoate is the com suitable for inhalation and any crystalline form must be stable mon name for 1-hydroxy-2-naphthoate. It should be noted during Such processing so that the properties of the final that this molecule can be depicted in several different tauto product are predictable and reliable. In short, whether or not meric forms depending on the location of the proton, all of a compound is Suitable for commercialisation as a drug is which are equivalent. US 2012/031 6160 A1 Dec. 13, 2012

(II) F O F OH 21 N F H CO N Na O N N NH- N O CH H H H O

0016. The invention further provides: the Xinafoate salt of methyl ethyl ketone (MEK), each optionally containing a N4-(2,2-difluoro-4Hbenzo 1.4 oxazin-3-one)-6-yl-5- small amount of water (e.g. less than 10%). Methyl ethyl fluoro-N2-3-(methylaminocarbonylmethyleneoxy)phenyl ketone is particularly suitable and is preferably used with 2.4-pyrimidinediamine for use as a medicament; the Xin about 5% by volume of water. The reactants are typically afoate salt of N4-(2,2-difluoro-4H-benzo 1.4 oxazin-3- dissolved in the solvent at a temperature higher than room one)-6-yl)-5-fluoro-N2-3-(methylaminocarbonyl temperature but below the boiling point of the solvent. methyleneoxy)phenyl-2,4-pyrimidinediamine for use in 0018 N4-(2,2-Difluoro-4H-benzo 1.4oxazin-3-one)-6- treating a condition for which a Syk kinase inhibitor is indi yl-5-fluoro-N2-3-(methylaminocarbonylmethyleneoxy) cated; the use of the Xinafoate salt of N4-(2,2-difluoro phenyl-2,4-pyrimidinediamine may be prepared by the gen 4Hbenzo 1.4oxazin-3-one)-6-yl)-5-fluoro-N2-3-(methy eral and specific methods disclosed in WO-A-03/063794. It laminocarbonylmethyleneoxy)phenyl-2,4- may, for example, be prepared by reacting a compound of pyrimidinediamine for the manufacture of a medicament to formula treat a disease for which a Syk kinase inhibitor is indicated; a pharmaceutical composition comprising the Xinafoate salt of N4-(2,2-difluoro-4H-benzo14 oxazin-3-one)-6-yl-5- (III) fluoro-N2-3-(methylaminocarbonylmethyleneoxy)phenyl 2.4-pyrimidinediamine and a pharmaceutically acceptable excipient; a pharmaceutical composition for the treatment of a disease for which a Syk kinase inhibitor is indicated com HN r YCH, prising the Xinafoate salt of N4-(2,2-difluoro-4H-benzo 1.4 oxazin-3-one)-6-yl-5-fluoro-N2-3-(methylaminocarbonyl O methyleneoxy)phenyl-2,4-pyrimidinediamine; and a method of treating a disease for which a Syk kinase inhibitor with a compound of formula is indicated in a mammal comprising administering to the mammal in need thereofatherapeutically effective amount of the Xinafoate salt of N4-(2,2-difluoro-4H-benzo 1.4 oxazin 3-one)-6-yl)-5-fluoro-N2-3-(methylaminocarbonylmethyl F eneoxy)phenyl-2,4-pyrimidinediamine. Preferred diseases O CCDCN N N-s, for which a Syk inhibitor is indicated are inflammatory res H H piratory diseases such as asthma, and COPD, particu larly asthma. 0017. The Xinafoate salt can be prepared by dissolving 0019. The reaction is typically carried out in a suitable N4-(2,2-difluoro-4H-benzo14 oxazin-3-one)-6-yl-5- Solvent, preferably an alcohol Such as isoamyl alcohol or fluoro-N2-3-(methylaminocarbonylmethyleneoxy)phenyl isopropyl alcohol, and in the presence of an acid catalyst Such 2.4-pyrimidinediamine and between 1 and 1.1 molar equiva as trifluoroacetic acid. The reaction is best carried out at an lents 1-hydroxy-2-naphthoic acid in the minimum amount of elevated temperature. If amyl alcohol is selected as the sol a suitable organic solvent and cooling the solution slowly, vent, for example, a temperature of about 100°C. is preferred. optionally with stirring, until the salt precipitates from the 0020. A compound of formula (III) may be prepared by Solution. Suitable solvents are acetone, acetonitrile and the route set out in Scheme 1 below.

Scheme 1

BrCHCO2H -e- NaOH, EtOH OH ON OH ON O~ O (VII) (VI)

CH3NH2-HCI TBTU, DIPEA, DMF US 2012/031 6160 A1 Dec. 13, 2012

-continued

H N H2, Pd/C HN O YCH, - " " - ON EtOH, EtOAc

0021. A compound of formula (III) may be prepared by 0025. A compound of formula (IV) may be prepared by reducing the nitro group in a compound of formula (V). In a reacting a compound of formula (VIII) with 5-fluoro-2,4- preferred procedure, hydrogenation is used. Typically, a solu dichloropyrimidine. In a typical procedure, a solution of the tion of the compound of formula (V) in a Suitable organic reactants in a suitable organic solvent, such as ethanol (EtOH) solvent, such as a mixture of ethanol (EtOH) and ethyl acetate (EtOAc), is treated with a hydrogenation catalyst, Such as or a mixture of ethanol and tetrahydrofuran (THF), is treated palladium on carbon, and exposed to hydrogen gas. The with a base Such as sodium hydrogencarbonate. hydrogen is usually applied at a pressure above atmospheric, 0026. A compound of formula (VIII) may be prepared by preferably at 30 pounds per square inch (psi). the reducing the nitro group in a compound of formula (IX). 0022. A compound of formula (V) may be prepared by In a preferred procedure, hydrogenation is used. Typically, a condensing the acid of formula (VI) with methylamine, or a solution of the compound of formula (IX) in a suitable salt thereof (such as the hydrochloride salt). Any condensing organic solvent, such as ethanol (EtOH), is treated with a agent suitable for the formation of amide bonds may be used hydrogenation catalyst, such as palladium on carbon, and in principle, but the use of 2-(1H-benzatriazole-1-yl)-1,1,3, exposed to hydrogen gas. The hydrogen is usually applied at 3-tetramethyluronium tetrafluoroborate (TBTU) is preferred. a pressure above atmospheric, preferably at 30 pounds per The condensation catalysed by TBTU is carried out in a square inch (psi). suitable organic solvent, such as N,N-dimethylformamide (DMF), and in the presence of a base such as N.Ndiisopro 0027. A compound of formula (IX) may be prepared by pylethylamine (DIPEA). the cyclisation of a compound of formula (X). In a typical 0023. A compound of formula (VI) may be prepared by procedure, a solution of a compound of formula (X) in a alkylating 3-nitrophenol (VII) with bromoacetic acid. The suitable organic solvent, such as N,N-dimethylformamide reaction is typically carried out in a Suitable solvent, such as (DMF) or isopropyl acetate, is treated with a base, such as water or aqueous ethanol (EtOH), in the presence of a base, potassium carbonate, and heated, for example at the reflux such as sodium hydroxide (NaOH), and at elevated tempera temperature of the solvent. When DMF is chosen as solvent, ture, e.g. at the reflux temperature of the chosen solvent. a temperature of about 120° C. is preferred. When isopropyl 0024. A compound of formula (IV) can be prepared by the acetate is chosen as solvent, a temperature of about 85°C. is route set out in Scheme 2 below. preferred.

Scheme 2 O F HO O BrFC ls C K2CO3 He F EtN DMF HN NO BrF2C NO O N NO DCM H (XI) (X) (IX)

H2, Pd/C EtOH F NaHCO3, F EtOHFTHF F e F O COON N N-- NN O NH2 H H N (IV) (VIII) C Nals C US 2012/031 6160 A1 Dec. 13, 2012

0028. A compound of formula (X) may be prepared by 0034) bronchial hyper-responsivity to environmental acylation of the aniline of formula (XI) with 2-bromo-2,2- agents: difluoroacetylchloride. The reaction is preferably carried out 0035 rhinitis or of whatever type, etiology, in a suitable organic solvent, such as dichloromethane (DCM) or pathogenesis, in particular seasonal allergic rhini or acetonitrile, in the presence of a base, such as triethy tis, perennial , perennial rhinitis, vaso lamine. The reaction is exothermic and cooling, for example to 0°C., may therefore be required. motor rhinitis, post-nasal drip, purulent or nonpuru 0029. The present invention includes all crystalline and lent sinusitis, acute or chronic sinusitis and ethmoid, pharmaceutically acceptable isotopically-labeled forms of frontal, maxillary, or sphenoid sinusitis; the Xinafoate salt of N4-(2,2-difluoro-4H-benzo 1.4 oxazin 0036 chronic obstructive pulmonary disease 3-one)-6-yl)-5-fluoro-N2-3-(methylaminocarbonylmethyl (COPD), chronic (COLD). eneoxy)phenyl-2,4-pyrimidinediamine. In an isotopically chronic obstructive airways disease (COAD) or small labeled form, one or more atoms are replaced by an atom or airways obstruction of whatever type, etiology, or atoms having the same atomic number, but an atomic mass or pathogenesis, in particular chronic , pulmo mass number different from the atomic mass or mass number nary emphysema, , , which predominates in nature. obliterans, bronchiolitis obliterans orga 0030) Suitable isotopes include isotopes of hydrogen, nizing (BOOP), chronic organizing pneu such as Hand H; carbon, such as 'C, 'Cand ''C; nitrogen, monia (COP), bronchiolitis fibrosa obliterans, folli such as 'N and 'N; oxygen, such as "O, O and 'O; and cular bronchiolitis or dyspnea associated therewith: sulphur, such as S. Certain isotopically-labeled com 0037 bronchitis of whatever type, etiology, or patho pounds, Such as those incorporating a radioactive isotope, are genesis, in particular , acute laryn useful in drug and/or substrate tissue distribution studies. The gotracheal bronchitis, arachidic bronchitis, catarrhal radioactive isotopes tritium, i.e. H, and carbon-14, i.e. ''C, bronchitis, croupus bronchitis, chronic bronchitis, dry are particularly useful for this purpose in view of their ease of bronchitis, infectious asthmatic bronchitis, produc incorporation and ready means of detection. Substitution tive bronchitis, staphylococcus or streptococcal bron with heavier isotopes such as deuterium, i.e. H. may afford chitis and vesicular bronchitis; certain therapeutic advantages resulting from greater meta 0038 bronchiectasis of whatever type, etiology, or bolic stability, for example, increased in vivo half-life or pathogenesis, in particular cylindric bronchiectasis, reduced dosage requirements, and hence may be preferred in sacculated bronchiectasis, fusiform bronchiectasis, Some circumstances. Substitution with positron emitting iso capillary bronchiectasis, cystic bronchiectasis, cystic topes, such as ''C, F, 'O, and 'N, can be useful in Positron fibrosis, Kartageners's syndrome, dry bronchiectasis Emission Topography (PET) studies for examining substrate or follicular bronchiectasis; receptor occupancy. Isotopically-labeled compounds can 0039 pulmonary eosinophilic syndromes of what generally be prepared by conventional techniques known to ever type, etiology, or pathogenesis, in particular those skilled in the art or by processes analogous to those acute (idiopathic or due to described in the accompanying Examples and Preparations drugs or parasites), simple pulmonary eosinophilia, using an appropriate isotopically-labeled reagent in place of Loeffler's syndrome, tropical pulmonary eosino the non-labeled reagent previously employed. philia, chronic eosinophilic pneumonia, allergic 0031 N4-(2,2-Difluoro-4H-benzo 1.4 oxazin-3-one)-6- bronchopulmonary mycosis, allergic bronchopulmo yl-5-fluoro-N2-3-(methylaminocarbonylmethyleneoxy) nary aspergillosis (ABPA), Churg-Strauss syndrome phenyl-2,4-pyrimidinediamine is a Syk kinase inhibitor and or idiopathic hypereosinophilic syndrome; is able to inhibit the degranulation of immune cells, such as 0040 interstitial lung diseases (ILD) or pulmonary mast, basophile, neutrophiland/or eosinophil cells. It may be fibrosis of whatever type, etiology, or pathogenesis, in useful, in the form of the Xinafoate salt disclosed by the particular idiopathic , crytogenic present invention and otherwise, in the treatment of the fol fibrosing alveolitis, fibrosing alveolitis, ILD or pull lowing conditions: monary fibrosis associated with connective tissue dis 0032 Treatable obstructive, restrictive or inflammatory ease (systemic lupus erythematosis, mixed connec airways diseases of whatever type, etiology, or patho tive tissue disease, polymyositis, dermatomyositis, genesis, in particular an obstructive, restrictive or Sjörgen’s syndrome, systemic sclerosis, Scleroderma, inflammatory airways disease Such as: rheumatoid arthritis), usual interstitial pneumonia 0033 asthma, in particular atopic asthma, allergic (UIP), descuamative interstitial pneumonia (DIP), asthma, atopic bronchial lgE-mediated asthma, non granulomatous lung disease, , Wegener's atopic asthma, bronchial asthma, non-allergic granulomatosis, histiocytosis X, Langerhan's cell asthma, essential asthma, true asthma, intrinsic granulomatosis, hypersensitivity , asthma caused by pathophysiologic disturbances, extrinsic allergic alveolitis, , chronic eosino essential asthma of unknown or inapparent cause, philic pneumonia, lymphangiolyomatosis, drug-in emphysematous asthma, exercise-induced asthma, duced ILD or pulmonary fibrosis, radiation-induced emotion-induced asthma, extrinsic asthma caused by ILD or pulmonary fibrosis, alveolar proteinosis, graft environmental factors, cold air induced asthma, occu Versus-host-disease (GVHD), lung transplant rejec pational asthma, infective asthma caused by or asso tion, ILD or pulmonary fibrosis due to environmental/ ciated with bacterial, fungal, protozoal, or viral infec occupational exposure, BOOP, COP bronchiolitis tion, incipient asthma, wheezy infant syndrome, fibrosa obliterans, follicular bronchiolitis, idiopathic bronchiolitis, cough variant asthma or drug-induced acute interstitial pneumonitis (Hamman Rich syn asthma; drome) or alveolar hemorrhage syndromes; US 2012/031 6160 A1 Dec. 13, 2012

0041 of whatever type, etiology, or 0051 autoimmune/inflammatory diseases of whatever pathogenesis, in particular or bauxite type, etiology, or pathogenesis, in particular autoim workers' disease, anthracosis or miners asthma, pro mune hematological disorders, hemolytic anemia, gressive massive fibrosis (PMF), or steam aplastic anemia, pure red cell anemia, idiopathic throm fitters asthma, chalicosis or flint disease, ptilosis bocytopenic purpura, rheumatoid arthritis, systemic caused by inhaling the dust from ostrich feathers, lupus erythematosus, Scleroderma, systemic sclerosis, caused by the inhalation of iron particles, oolymyalgia rheumatica, dermatomyositis, polymyosi silicosis or grinders disease, or cotton tis, polychondritis, Wegner's granulomatosis, chronic dust asthma or talc pneumoconiosis: active hepatitis, myasthenia gravis, Stevens-Johnson 0042 Acute Respiratory Distress Syndrome syndrome, idiopathic sprue, autoimmune inflammatory (ARDS), adult respiratory distress syndrome or acute bowel diseases, Crohn's disease, ulcerative colitis, lung injury of whatever type, etiology, or pathogen endocrine opthalmopathy, Grave's disease, sarcoidosis, esis; alveolitis, chronic hypersensitivity pneumonitis, pri 0043 aspiration disorders of whatever type, etiology, mary biliary cirrhosis,juvenile diabetes or diabetes mel or pathogenesis leading to aspiration pneumonitis or litus type I, keratoconjunctivitis sicca, epidemic kerato ; conjunctivitis, glomerulonephritis with or without 0044) alveolar hemorrhage of whatever type, etiol nephrotic syndrome, acute glomerulonephritis, idio ogy, or pathogenesis, in particular a member of the pathic nephrotic syndrome, minimal change nephropa group consisting of idiopathic pulmonary hemosid thy, autoimmune disorders associated with interstitial erosis, alveolar hemorrhage due to drugs or other lung disease and/or pulmonary fibrosis or autoimmune exogenous agents, alveolar hemorrhage associated or inflammatory skin disorders; with HIV or bone marrow transplant or autoimmune 0.052 inflammatory bowel disease (IBD) of whatever alveolar hemorrhage (e.g. associated with Systemic type, etiology, or pathogenesis, in particular collagenous lupus erythematosis, Goodpasture's syndrome, Wegener's granulomatosis, microscopic polyangiitis, colitis, colitis polyposa, transmural colitis, ulcerative Churg-Strauss syndrome, pauci-immune glomerulo colitis or Crohn's disease (CD); 0.053 of whatever type, etiol nephritis); ogy or pathogenesis including pulmonary arterial hyper 0045 acute or chronic or ; tension, pulmonary venous hypertension, pulmonary 0046 cough of whatever type, etiology, or pathogen hypertension associated with disorders of the respiratory esis in particularidiopathic cough or cough associated system and/or hypoxemia, pulmonary hypertension due with gastro-esophageal reflux disease (GERD), to chronic thrombotic and/or embolic disease and pull drugs, bronchial hyper-responsivity, asthma, COPD, monary hypertension due to disorders directly affecting COLD, COAD, bronchitis, bronchiectasis, pulmo the pulmonary vasculature; nary eosinophilic syndromes, pneumoconiosis, inter 0.054 arthritis of whatever type, etiology, or pathogen Stitial lung disease, pulmonary fibrosis, aspiration esis, in particular rheumatoid arthritis, osteorthritis, disorders, rhinitis, laryngitis or pharyngitis; gouty arthritis, pyrophosphate arthropathy, acute cal 0047 anaphylaxis and type 1 hypersensitivity reactions cific periarthritis, chronic inflammatory arthritis, arthri of whatever aetiology; tis associated with a connective tissue disorder (e.g. 0048 atopic, allergic, autoimmune or inflammatory systemic lupus erythematosis, polymyositis, dermato skin disorders of whatever type, etiology, or pathogen myositis, systemic Sclerosis, Scleroderma), sarcoidosis, esis, in particular atopic dermatitis, allergic dermatitis, polymyalgia rheumatica, degenerative arthritis, infec contact dermatitis, allergic or atopic eczema, lichen pla tious arthritis, Lyme arthritis, proliferative arthritis, pso nus, mastocytosis, erythema nodosum, erythema multi riatic arthritis, ankylosing spondylitis, cervical spondy forme, benign familial pemphigus, pemphigus erythe losis, vertebral arthritis, juvenile arthritis (Still's matosus, pemphigus foliaceus, and pemphigus Vulgaris, disease), amyloidosis, ankylosing vertebral hyperosto bullous pemphigoid, epidermolysis bullosa, dermatitis sis (Forrestier's disease), Behcet’s syndrome, drug-in hepetiformis, psoriasis, immune-mediated urticaria, duced arthritis, familial Mediterranean fever, hypermo complement-mediated urticaria, urticariogenic mate bility syndrome, osteochondritis dessicans, rial-induced urticaria, physical agent-induced urticaria, osteochondromatosis, palindromic rheumatism, pig stress-induced urticaria, idiopathic urticaria, acute urti mented villonodular synovitis, relapsing polychondritis, caria, chronic urticaria, angioedema, cholinergic urti temporomandibular pain dysfunction syndrome or caria, cold urticaria in the autosomal dominant form or arthritis associated with hyperlipidemia; in the acquired form, contact urticaria, giant urticaria or 0.055 an eosinophil-related disorder of whatever type, papular urticaria; etiology, or pathogenesis, in particular pulmonary eosi 0049 conjunctivitis of whatever type, etiology, or nophilic syndromes, aspergilloma, granulomas contain pathogenesis, in particular actinic conjunctivitis, acute ing eosinophils, allergic granulomatous angiitis or catarrhal conjunctivitis, acute contagious conjunctivitis, Churg-Strauss syndrome, polyarteritis nodosa (PAN) or allergic conjunctivitis, atopic conjunctivitis, chronic systemic necrotizing vasculitis; catarrhal conjunctivitis, purulent conjunctivitis or Vernal 0056 uveitis of whatever type, etiology, or pathogen conjunctivitis; esis, in particular inflammation of all or part of the uvea, 0050 multiple sclerosis of whatever type, etiology, or anterior uveitis, iritis, cyclitis, iridocyclitis, granuloma pathogenesis, in particular primary progressive multiple tous uveitis, nongranulomatous uveitis, phacoantigenic Sclerosis or relapsing remitting multiple Sclerosis; uveitis, posterior uveitis, choroiditis or chorioretinitis; US 2012/031 6160 A1 Dec. 13, 2012

0057 septic shock of whatever type, etiology, or patho emulsifying agents and/or Suspending agents. Liquid formu genesis; lations may also be prepared by the reconstitution of a solid, 0.058 disorders of bone deposition/resorption, includ for example, from a Sachet. ing osteoporosis and osteopenia; 0069. The compound of the invention may also be used in 0059 lymphoproliferative disorders (e.g. lymphoma, fast-dissolving, fast-disintegrating dosage forms such as myeloma); those described in Expert Opinion in Therapeutic Patents, 11 0060 HIV or AIDs related disorders: (6), 981-986, by Liang and Chen (2001). 0070 For tablet dosage forms, depending on dose, the 0061 infection, especially infection due to viruses compound of the invention may make up from 1 weight% to wherein such viruses increase the production of TNF-C. 80 weight% of the dosage form, more typically from 5 weight in their host, or wherein such viruses are sensitive to % to 60 weight% of the dosage form. upregulation of TNF-C. in their host so that their repli 0071. In addition, tablets generally contain a disintegrant. cation or other vital activities are adversely impacted, Examples of disintegrants include Sodium starch glycolate, including a virus which is a member selected from the Sodium carboxymethyl cellulose, calcium carboxymethyl group consisting of HIV-1, HIV-2, and HIV-3, cytome cellulose, croScarmellose sodium, crospovidone, polyvi galovirus (CMV), , adenoviruses and Herpes nylpyrrolidone, methyl cellulose, microcrystalline cellulose, viruses including Herpes Zoster and Herpes simplex; lower alkyl-substituted hydroxypropyl cellulose, starch, 0062 yeast and fungal infections wherein the yeast or pregelatinised starch and Sodium alginate. Generally, the dis fungus is sensitive to upregulation by TNF-C. or elicits integrant will comprise from 1 weight % to 25 weight %, TNF-C. production in the host, e.g., fungal meningitis, preferably from 5 weight % to 20 weight % of the dosage particularly when administered in conjunction with form. other drugs of choice for the treatment of systemic yeast 0072 Binders are also generally used to impart cohesive and fungus infections, including but are not limited to, qualities to a tablet formulation. Suitable binders include polymixins (e.g. Polymycin B), imidazoles (e.g. clotri microcrystalline cellulose, gelatin, Sugars, polyethylene gly mazole, econazole, miconazole, and ketoconazole), tria col, natural and synthetic gums, polyvinylpyrrolidone, prege Zoles (e.g. fluconazole and itranazole) and amphot latinised starch, hydroxypropyl cellulose and hydroxypropyl ericins (e.g. Amphotericin B and liposomal methylcellulose. Tablets may also contain diluents, such as Amphotericin B); and lactose (monohydrate, spray-dried monohydrate, anhydrous 006.3 Mycobacterial infections e.g. due to mycobacte and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, rium tuberculosis. microcrystalline cellulose, starch and dibasic calcium phos 0064. The Xinafoate salt of N4-(2,2-difluoro-4H-benzo phate dihydrate. 1,4-oxazin-3-one)-6-yl)-5-fluoro-N2-3-(methylaminocar 0073 Tablets may also optionally comprise surface active bonylmethyleneoxy)phenyl-2,4-pyrimidinediamine (hence agents, such as Sodium lauryl Sulfate and polysorbate 80, and forth referred to as the compound of the invention) may be glidants such as silicon dioxide and talc. When present, Sur administered alone but will generally be administered as a face active agents may comprise from 0.2 weight '% to 5 formulation in association with one or more pharmaceutically weight % of the tablet, and glidants may comprise from 0.2 acceptable excipients. The term excipient is used herein to weight% to 1 weight% of the tablet. describe any ingredient other than the compound of the inven 0074 Tablets also generally contain lubricants such as tion. The choice of excipient will to a large extent depend on magnesium Stearate, calcium Stearate, Zinc Stearate, sodium factors such as the particular mode of administration, the Stearyl fumarate, and mixtures of magnesium Stearate with effect of the excipient on solubility and stability, and the Sodium lauryl Sulphate. Lubricants generally comprise from nature of the dosage form. 0.25 weight% to 10 weight%, preferably from 0.5 weight% 0065. Pharmaceutical compositions suitable for the deliv to 3 weight% of the tablet. ery of the compound of the invention and methods for their 0075 Other possible tablet ingredients include anti-oxi preparation will be readily apparent to those skilled in the art. dants, colouring agents, flavouring agents, preservatives and Such compositions and methods for their preparation may be taste-masking agents. found, for example, in Remington's Pharmaceutical Sci 0076 Exemplary tablets contain up to about 80% drug, ences, 19th Edition (Mack Publishing Company, 1995). from about 10 weight % to about 90 weight % binder, from 0066. The compound of the invention may be adminis about 0 weight% to about 85 weight% diluent, from about 2 tered orally. Oral administration may involve Swallowing, so weight% to about 10 weight% disintegrant, and from about that the compound enters the gastrointestinal tract, or buccal 0.25 weight% to about 10 weight% lubricant. or Sublingual administration may be employed by which the (0077 Tablet blends may be compressed directly or by compound enters the blood stream directly from the mouth. roller compaction to form tablets. Tablet blends orportions of 0067. Formulations suitable for oral administration blends may alternatively be wet-, dry-, or melt-granulated, include solid formulations such as tablets, capsules contain melt congealed, or extruded before tabletting. The final for ing particulates, liquids, or powders, lozenges (including liq mulation may comprise one or more layers and may be coated uid-filled), chews, multi- and nano-particulates, gels, Solid or uncoated; it may even be encapsulated. Solution, liposome, films, ovules, sprays and liquid formula 0078. The formulation of tablets is discussed in Pharma tions. ceutical Dosage Forms: Tablets, Vol. 1, by H. Lieberman and 0068 Liquid formulations include suspensions, solutions, L. Lachman (Marcel Dekker, New York, 1980). syrups and elixirs. Such formulations may be employed as 007.9 The compound of the invention may also be orally fillers in Soft or hard capsules and typically comprise a carrier, administered in the form of a consumable oral film for human for example, water, ethanol, polyethylene glycol, propylene or veterinary use. Such a film is typically a pliable water glycol, methylcellulose, or a suitable oil, and one or more soluble or water-swellable thin film dosage form which may US 2012/031 6160 A1 Dec. 13, 2012 be rapidly dissolving or mucoadhesive and typically com implants, sponges, fibres, bandages and microemulsions. prises the compound of the invention, a film-forming poly Liposomes may also be used. Typical carriers include alco mer, a binder, a solvent, a humectant, a plasticiser, a stabiliser hol, water, mineral oil, liquid petrolatum, white petrolatum, or emulsifier, a viscosity-modifying agent and a solvent. glycerin, polyethylene glycol and propylene glycol. Penetra Some components of the formulation may perform more than tion enhancers may be incorporated—see, for example, J. one function. Pharm. Sci., 88 (10),955-958, by Finnin and Morgan (Octo 0080. The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids ber 1999). and is typically present in the range 0.01 to 99 weight%, more 0090. Other means oftopical administration include deliv typically in the range 30 to 80 weight%. ery by electroporation, iontophoresis, phonophoresis, Sono 0081. Other possible film ingredients include anti-oxi phoresis and microneedle or needle-free (e.g. PowderjectTM, dants, colouring agents, flavourings and flavour enhancers, BiojectTM) injection. preservatives, salivary stimulating agents, cooling agents, 0091 Formulations for topical administration may befor cosolvents (including oils), emollients, bulking agents, anti mulated to be immediate and/or modified release. Modified foaming agents, Surfactants and taste-masking agents. release includes delayed, Sustained, pulsed, controlled, tar 0082 Films in accordance with the invention are typically geted and programmed release. prepared by evaporative drying of thin aqueous films coated 0092. The compound of the invention can also be admin onto a peelable backing Support or paper. This may be done in istered intranasally or by inhalation, typically in the form of a a drying oven or tunnel, typically a combined coater dryer, or dry powder (either alone, as a mixture, for example, in a dry by freeze-drying or vacuum drying. blend with lactose, or as a mixed component particle, for 0083 Solid formulations for oral administration may be example, mixed with phospholipids, such as phosphatidyl formulated to be immediate and/or modified release. Modi choline) from a dry powder inhaler orasanaerosol spray from fied release includes delayed, Sustained, pulsed, controlled, a pressurised container, pump, spray, atomiser (preferably an targeted and programmed release. atomiser using electrohydrodynamics to produce a fine mist), 0084 Suitable modified release formulations for the pur poses of the invention are described in U.S. Pat. No. 6,106, or nebuliser, with or without the use of a suitable propellant, 864. Details of other suitable release technologies such as such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluo high energy dispersions and osmotic and coated particles are ropropane. For intranasal use, the powder may comprise a to be found in Pharmaceutical Technology On-line, 25(2), bioadhesive agent, for example, chitosan or cyclodextrin. 1-14, by Verma et al (2001). The use of chewing gum to Administration in the form of a dry powder from a dry powder achieve controlled release is described in WO-A-00/35298. inhaler is a particularly preferred form of delivery. 0085. The compound of the invention may also be admin 0093. The pressurised container, pump, spray, atomizer or istered directly into the blood stream, into muscle, or into an nebuliser contains a solution or Suspension of the compound internal organ. Such parenteral administration may be via the of the invention comprising, for example, ethanol, aqueous intravenous, intraarterial, intraperitoneal, intrathecal, intra ethanol or a suitable alternative agent for dispersing, solu Ventricular, intraurethral, intrasternal, intracranial, intramus bilising or extending release of the active, a propellant(s) as cular or subcutaneous route. Suitable devices for parenteral Solvent and an optional Surfactant. Such as Sorbitan trioleate, administration include needle (including microneedle) injec oleic acid or an oligolactic acid. tors, needle-free injectors and infusion techniques. I0086 Parenteral formulations are typically aqueous solu 0094 Prior to use in a dry powder or suspension formula tions which may contain excipients such as salts, carbohy tion, the drug product is micronised to a size Suitable for drates and buffering agents (preferably to a pH of from 3 to 9), delivery by inhalation (typically less than 5 microns). This but, for Some applications, they may be more Suitably formu may be achieved by any appropriate comminuting method, lated as a sterile non-aqueous solution or as a dried form to be Such as spiral jet milling, fluid bed jet milling, Supercritical used in conjunction with a suitable vehicle Such as sterile, fluid processing to form nanoparticles, high pressure pyrogen-free water. homogenisation or spray drying. 0087. The preparation of parenteral formulations under 0.095 Capsules (made, for example, from gelatin or sterile conditions, for example, by lyophilisation, may readily hydroxypropylmethylcellulose), blisters and cartridges for be accomplished using standard pharmaceutical techniques use in an inhaler or insufflator may be formulated to contain well known to those skilled in the art. a powder mix of the compound of the invention, a Suitable 0088 Formulations for parenteral administration may be powder base Such as lactose or starch and a performance formulated to be immediate and/or modified release. Modi modifier Such as 1-leucine, mannitol or magnesium Stearate. fied release includes delayed, Sustained, pulsed, controlled, The lactose may be anhydrous or in the form of the monohy targeted and programmed release. Thus compound of the drate, preferably the latter. Other suitable excipients include invention may be formulated as a solid, semi-solid or thixo dextran, glucose, maltose, Sorbitol. Xylitol, fructose, Sucrose tropic liquid for administration as an implanted depot provid and trehalose. ing modified release of the compound of the invention. 0096. A suitable solution formulation for use in an atom Examples of Such formulations include drug-coated Stents iser using electrohydrodynamics to produce a fine mist may and poly(dl-lactic-coglycolic)acid (PGLA) microspheres. contain from 1 Jug to 20 mg of the compound of the invention 0089. The compound of the invention may also be admin per actuation and the actuation Volume may vary from 1 Jul to istered topically to the skin or mucosa, i.e. dermally or trans 100 ul. A typical formulation may comprise a compound of dermally. Typical formulations for this purpose include gels, formula I, propylene glycol, sterile water, ethanol and sodium hydrogels, lotions, solutions, creams, ointments, dusting chloride. Alternative solvents which may be used instead of powders, dressings, foams, films, skin patches, wafers, propylene glycol include glycerol and polyethylene glycol. US 2012/031 6160 A1 Dec. 13, 2012

0097 Suitable flavouring agents, such as menthol and the corticoid receptor); (xi) monoclonal antibodies active levomenthol, or Sweeteners, such as saccharin or saccharin against endogenous inflammatory entities; (xii) anti-tumor sodium, may be added to those formulations of the invention necrosis factor (anti-TNF-C) agents; (xiii) adhesion molecule intended for inhaled/intranasal administration. inhibitors including VLA-4 antagonists; (xiv) kinin-B- and 0098. Formulations for inhaled/intranasal administration B-receptor antagonists; (XV) immunosuppressive agents; may be formulated to be immediate and/or modified release using, for example, PGLA. Modified release includes (xvi) inhibitors of matrix metalloproteases (MMPs); (xvii) delayed, Sustained, pulsed, controlled, targeted and pro tachykinin NK, NK and NK receptor antagonists; (xviii) grammed release. elastase inhibitors; (xix) adenosine A receptor agonists: 0099. In the case of dry powder inhalers and aerosols, the (XX) inhibitors of urokinase; (XXi) compounds that act on dosage unit may be determined by means of a valve which dopamine receptors, e.g. D2 agonists; (XXii) modulators of delivers a metered amount. The overall daily dose may be the NF pathway, e.g. IKK inhibitors; (xxiii) modulators of administered in a single dose or, more usually, as divided cytokine signaling pathways such as a p38 MAP kinase or doses throughout the day. JAK kinase inhibitor, (XXiv) agents that can be classed as 0100. The compound of the invention may be adminis mucolytics or anti-tussive: (XXV) antibiotics; (xxvi) HDAC tered rectally or vaginally, in the form, for example, of a inhibitors; (xxvii) PI3 kinase inhibitors; (xxviii) B2 agonists: Suppository, pessary or enema. Cocoa butter is a traditional and (XXiX) dual compounds active as Bagonists and musca Suppository base, but various alternatives may be used as rinic M receptor antagonists. Preferred examples of Such appropriate. The compound of the invention may also be therapeutic agents include: (a) glucocorticosteroids, in par administered by the ocular or aural route. 0101 The compound of the invention may be combined ticular inhaled glucocorticosteroids with reduced systemic with a soluble macromolecular entity, such as a cyclodextrin side effects, flunisolide, triamcinolone acetonide, beclom or a suitable derivative thereof or a polyethylene glycol-con ethasone dipropionate, budesonide, fluticasone propionate, taining polymer, in order to improve its solubility, dissolution ciclesonide, and mometasone furoate; (b) muscarinic M. rate, taste-masking, bioavailability and/or stability for use in receptor antagonists oranticholinergic agents including ipra any of the aforementioned modes of administration. tropium salts such as the bromide, tiotropium salts such as the 0102 Drug-cyclodextrin complexes, for example, are bromide, oxitropium salts such as the bromide, perenzepine found to be generally useful for most dosage forms and and telenzepine; and (c) 3 agonists including salbutamol. administration routes. Both inclusion and non-inclusion com terbutaline, bambuterol, fenoterol, salmeterol, formoterol, plexes may be used. As an alternative to direct complexation tulobuterol. Any of the agents specifically mentioned may with the drug, the cyclodextrin may be used as an auxiliary optionally be used in the form of a pharmaceutically accept additive, i.e. as a carrier, diluent, or solubiliser. Most com monly used for these purposes are alpha-, beta- and gamma able salt. cyclodextrins, examples of which may be found in WO-A- 01.06 Where it is desirable to administer a combination of 91/11172, WO-A-94/02518 and WO-A-98/55148. active compounds, two or more pharmaceutical composi 0103 For administration to human patients, the total daily tions, at least one of which contains the compound of the dose of the compound of the invention will typically be in the invention, may conveniently be combined in the form of a kit range 0.002 mg/kg to 100 mg/kg depending, of course, on the Suitable for co-administration. mode of administration. The total daily dose may be admin 0107 Such a kit comprises two or more separate pharma istered in single or divided doses and may, at the physician's ceutical compositions, at least one of which contains the discretion, fall outside of the typical range given herein. compound of the invention, and means for separately retain 0104 For the avoidance of doubt, references herein to “treatment include references to curative, palliative and pro ing said compositions. Such as a container, divided bottle, or phylactic treatment. divided foil packet. An example of such a kit is the familiar 0105 Syk kinase inhibitors, such as the compound of the blisterpack used for the packaging of tablets, capsules and the invention, may advantageously be administered in combina like. tion with one or more other therapeutic agents, particularly in 0.108 Such a kit is particularly suitable for administering the treatment of respiratory diseases such as asthma. different dosage forms, for example, oral and parenteral dos Examples of such further therapeutic agents include: (i) 5-li age forms, for administering the separate compositions at poxygenase (5-LO) inhibitors or 5-lipoxygenase activating different dosage intervals, or for titrating the separate com protein (FLAP) antagonists; (ii) leukotriene antagonists positions against one another. To assist compliance, the kit (LTRAS) including antagonists of LTB, LTC, LTD, and LTE, (iii) histamine receptor antagonists including H. H. typically comprises directions for administration and may be and H antagonists; (iv) C- and C2-adrenoceptor agonist provided with a so-called memory aid. vasoconstrictor sympathomimetic agents for nasal deconges tant use; (v) muscarinic M receptor antagonists or anticho PREPARATIVE EXAMPLE linergic agents; (vi) PDE inhibitors, e.g. PDE, PDE and PDEs inhibitors; (vii) theophylline; (viii) sodium cromogly 0109 The following example illustrates the preparation of cate; (ix) COX inhibitors both non-selective and selective the Xinafoate salt of N4-(2,2-difluoro-4H-benzo 1.4 oxazin COX-1 or COX-2 inhibitors (NSAIDs); (x) oral and inhaled 3-one)-6-yl)-5-fluoro-N2-3-(methylaminocarbonyl methyl glucocorticosteroids, such as DAGR (dissociated agonists of eneoxy)phenyl-2,4-pyrimidinediamine. US 2012/031 6160 A1 Dec. 13, 2012

'v O F NN Xinafoic acid OF N N Cas MEK/water H H H rs O F O F NN F l. O N NH NH-|- NH or N O OH CO

0110. A suspension of 2-3-4-(2,2-Difluoro-3-oxo-3,4- dihydro-2H-benzo 1.4 oxazin-6-ylamino)-5-fluoro-pyrimi TABLE 1 din-2-ylaminolphenoxy-N-methyl-acetamide (1.18 kg, 2.49 mmol. 1 equiv) in methyl ethyl ketone (MEK) (23.6 L. 20 Characteristic PXRD peaks ml/g) was heated to 55°C., whereupon water (1.18L, 1 ml/g) Angle 2-Theta Relative intensity was added, resulting in a solution. The solution was passed (degrees) (%) through a filter for clarification then held at 55° C. for 1 hour. 8.0 68.7 8.9 36.5 The subsequent addition of a pre-formed spec-free solution of 11.6 42.6 1-hydroxy-2-naphoic acid (515 g, 2.74 mol, 1.1 equiv) in 13.2 42.5 MEK (4.72 L, 4 ml/g) resulted in precipitation of a white solid 13.5 23.8 14.0 18.7 after ~10 mins. The reaction was cooled to ambient temp, 15.3 1S.O stirred overnight (18 hours) and then cooled to 5° C. for 2 15.6 17.4 hours before filtration. The filtered solid was washed with 16.1 445 16.4 20.1 MEK (2x2.36 L, 2x2 ml/g) and dried under reduced pressure 17.3 14.5 at 50° C. for 16 hours. The product, 2-3-4-(2,2-difluoro-3- 17.5 21.4 oxo-3,4-dihydro-2H-benzo 1.4oxazin-6-ylamino)-5- 17.8 30.3 19.0 28.9 fluoro-pyrimidin-2-ylaminolphenoxy-N-methyl-acetamide 19.8 54.0 1-hydroxy-2-naphoic acid salt, was isolated as a white Solid 2O.O 28.8 20.4 13.0 (1.32 kg, 80%). 22.1 1S.O 0111. When analysed by conventional proton NMR (300 22.4 16.5 23.0 24.1 MHz, d-DMSO), thexinafoate salt gives the following spec 23.2 19.9 trum: & 2.65 (d. J=4.5 Hz, 3H), 4.34, (s. 2H), 6.46-6.52 (m, 23.5 22.8 1H), 7.10 (t, J 8.0 Hz, 1H), 7.23-7.28 (m, 2H), 7.36-7.41 (m, 23.6 20.9 24.1 38.1 2H), 7.45-7.48 (m. 1H), 7.55-7.62 (m, 2H), 7.64-7.71 (m, 24.5 1OO.O 1H), 7.73-7.77 (m, 1H), 7.86-7.95 (m, 2H), 8.14 (d. J40 Hz, 24.7 20.6 1H), 8.26-8.32 (m, 1H), 9.14 (s, 1H), 9.56 (s, 1H), 11.90-11. 26.6 41.1 27.5 12.3 96 (m, 1H). 27.7 73.7 0112. When analysed by differential scanning calorimetry 28.1 14.1 29.3 16.6 (DSC) (8.588 mg of the sample was heated from 25 to 250° C. 29.5 11.4 at 20°C. per minute using a PerkinElmer Diamond DSC with 31.2 11.8 autosampler and a 4 hole side wall vented aluminum pan and 32.4 14.4 lid with nitrogen flow gas), the Xinafoate salt shows a sharp 33.4 22.5 endothermic melting peak at 233°C.2°C. The DSC trace is shown in FIG. 1. 0114. The powder X-ray diffraction pattern was deter 0113. When characterised by powder X-ray diffraction mined using a Bruker-AXS Ltd D4 powder X-ray diffracto (PXRD), the Xinafoate salt gives the pattern shown in FIG. 2. meter fitted with an automatic sample changer, a theta-theta The characteristic peaks are given in Table 1 below. The main goniometer, automatic beam divergence slit, and a PSD Van characteristic peaks are at 8.0, 8.9, 11.6, 24.5 and 27.7 tec-1 detector. The sample was prepared for analysis by degrees two theta (+0.1 degree). mounting on a low background silicon wafer specimen US 2012/031 6160 A1 Dec. 13, 2012

mount. The specimen was rotated whilst being irradiated with copper K-alpha 1 X-rays (wavelength=1.5406 Angstroms) TABLE 3 with the X-ray tube operated at 40 kV/30 mA. The analyses Characteristic FT-IR peaks were performed with the goniometer running in continuous Wavenumber (cm) mode set for a 0.2 second count per 0.018 step over a two 3230*(w) theta range of 2 to 55°. Peaks were selected manually using 3069 (w) Bruker-AXS Ltd evaluation software. The data were col 3015 (w) lected at 21°C. 717 (s) 669 (m) 0115. As will be appreciated by the skilled person, the 659 (m) 625 (m) relative intensities of the various peaks within Table 1 given 608 (m) below may vary due to a number of factors such as for 587 (im) example orientation effects of crystals in the X-ray beam or 569 (m) 523 (m) the purity of the material being analysed or the degree of 501 (w) crystallinity of the sample. The peak positions may also shift 455 (m) for variations in sample height but the peak positions will 431 (s) 407 (s) remain substantially as defined in given Table 1. The skilled 364 (w) person will also appreciate that measurements using a differ 331 (w) 316 (w) ent wavelength will result in different shifts according to the 283 (w) Bragg equation nu-2d sin 0. Such alternative PXRD pat 272 (w) terns generated by use of alternative wavelengths are never 228 (m) 212 (m) theless representations of the same material. 174 (m) 0116. The main PXRD peaks which have been simulated 161 (m) 152 (m) from a single crystal X-ray analysis are listed in Table 2 below 107 (w) and the corresponding simulated pattern is shown in FIG. 3. 078 (s) 020 (w) TABLE 2 928 (w) 888 (m) 877 (w) Characteristic simulated PXRD peaks 858 (s) Angle 2-Theta Relative intensity 823 (m) (degrees) (%) 810 (w) 796 (m) 8.0 72.5 764 (s) 8.9 41.3 747 (s) 9.4 O.S 734 (w) 11.4 1.5 721 (w) 11.6 43.0 683 (m) 13.5 6.6 653 (m) 14.0 9.2 15.3 3.3 15.7 O.2 0118. The FT-IR spectrum was acquired using a Ther 16.0 4.3 16.1 7.6 moNicolet Nexus FTIR spectrometer equipped with a 16.4 7.1 DurasamplIR single reflection ATR accessory (diamond 17.5 9.4 surface on Zinc selenide substrate) and d-TGS KBr detector. 17.9 20.3 18.9 1.7 The spectrum was collected at 2 cm' resolution and a co 19.0 3.2 addition of 256 scans for all compounds. Happ-Genzel 19.9 5.8 apodization was used. Because the FT-IR spectrum was 20.1 25.1 23.0 5.2 recorded using single reflection ATR, no sample preparation 23.2 1.5 was required. Using ATR FT-IR will cause the relative inten 23.5 O.2 sities of infrared bands to differ from those seen in a trans 23.6 2.1 mission FT-IR spectrum using KBr disc or nujol mull sample 24.1 28.5 24.4 4.1 preparations. Due to the nature of ATR FT-IR, the bands at 24.5 1OO.O lower wavenumber are more intense than those at higher 24.7 1.9 wavenumber. Experimental error, unless otherwise noted, 27.7 58.5 was+2cm. Peaks were picked using ThermoNicolet Omnic 6.0a Software. 0117. When characterised by Fourier Transform Infra-red 0119 When characterised by Fourier Transform Raman (FT-IR) spectroscopy, the Xinafoate salt gives the pattern spectroscopy, the Xinafoate Salt gives the pattern shown in shown in FIG. 4. The fingerprint region is shown in expanded FIG. 6. The fingerprint region is shown in greater detail in form in FIG. 5. The characteristic peaks are given in Table 3 FIG. 7. The characteristic peaks are given in Table 4 below below (w-weak, S=Strong, m medium). The main character (w—weak, S-strong, m medium). The main characteristic istic peaks are 1228 (m), 1152 (m), 1078 (s) and 858 (s). peaks are 1626 (m), 1205 (m), 998 (s), 156 (s) and 91 (s). US 2012/031 6160 A1 Dec. 13, 2012

0.122 Approximately 80 mg of sample were tightly TABLE 4 packed into a 4 mm ZrO spinner. The spectrum was collected at ambient conditions on a Bruker-Biospin 4 mm BL HFX Characteristic FT-Raman peaks CPMAS probe positioned into a wide-bore Bruker-Biospin Wavenumber Wavenumber Avance DSX 500 MHz NMR spectrometer. The sample was (cm) Wavenumber (cm) Wavenumber (cm) (cm) positioned at the magic angle and spun at 15.0 kHz. The fast spinning speed minimized the intensities of the spinning side 3092 (w) 1473 (w) 1253 (m) 332 (w) 3071 (w) 1465 (w) 1205 (m) 302 (w) bands. The number of scans was adjusted to obtain adequate 1679 (w) 1434 (m) 1162 (w) 286 (w) S/N. The C solid state spectrum was collected using a 1659 (m) 1414 (w) 1026 (w) 253 (w) proton decoupled cross-polarization magic angle spinning 1626 (m) 1379 (m) 998 (s) 221 (m) experiment (CPMAS). A proton decoupling field of approxi 1161 (w) 1365 (m) 879 (w) 192 (w) 1596 (w) 1353 (m) 726 (m) 156 (s) mately 85 kHz was applied. 656 scans were collected with the 1584 (w) 1333 (s) 542 (w) 130 (m) recycle delay adjusted to 80 seconds. The spectrum was ref 1574 (w) 1296 (m) 495 (w) 110 (s) erenced using an external standard of crystalline adamantane, 1525 (m) 1276 (w) 434 (w) 91 (s) setting its upfield resonance to 29.5 ppm. 1502 (m) 1260 (m) 352 (w) 62 (s) (0123. When characterised by fluorine solid state NMR, the Xinafoate salt gives the spectrum shown in FIG. 9. The 0120. The Raman spectrum was collected using a Bruker characteristic shifts are -69.2, -72.4 and -164.0 ppm. Inten Vertex.70 with Ram II module FT-Raman spectrometer sities can vary depending on the actual setup of the experi equipped with a 1064 nm NdYAG laser and LN-Germanium mental parameters and the thermal history of the sample and detector. The spectrum was recorded using 2 cm-1 resolution are not therefore necessarily quantitative. and Blackman-Harris 4-term apodization. Laser power was 0.124. The same apparatus was used to acquire the fluorine 300 mW and 2048 co-added scans were collected. Each NMR spectrum as that used to acquire the 'C spectrum. The sample was placed in a glass vial and exposed to the laser 'F solid state spectrum was collected using a proton radiation. The data is presented as intensity as a function of decoupled magic angle spinning (MAS) experiment. The pro Raman shift and is corrected for instrument response and ton decoupling field of approximately 85 kHz was applied frequency dependent scattering using a white light spectrum and 8 scans were collected. The recycle delay was set to 750 from a reference lamp. The Bruker Raman Correct function S to ensure acquisition of quantitative spectra. Proton longi was used to do the correction. (Bruker software OPUS 6.0). tudinal relaxation times (HT) were calculated based on a Experimental error, unless otherwise noted, was t2 cm-1. fluorine detected proton inversion recovery relaxation experi Peaks were picked using ThermoNicolet Omnic 6.0a soft ment. Fluorine longitudinal relaxation times (FT) were Ware calculated based on a fluorine detected fluorine inversion I0121) When characterised by proton decoupled 'C solid recovery relaxation experiment. The spectrum was refer state NMR, the Xinafoate salt gives the spectrum shown in FIG. 8. The characteristic shifts are given in Table 5 below. enced using an external sample of trifluoroacetic acid (50% The main characteristic shifts are 176.8, 159.4, 137.1, 118.2, by Volume in HO), setting its resonance to -76.54 ppm. 104.9 and 25.4 ppm. Intensities can vary depending on the actual setup of the experimental parameters and the thermal Stability Data history of the sample and are not therefore necessarily quan 0.125. In contrast to the free base, the Xinafoate salt of titative. N4-(2,2-difluoro-4H-benzo14 oxazin-3-one)-6-yl-5- TABLE 5 fluoro-N2-3-(methylaminocarbonylmethyleneoxy)phenyl 2.4-pyrimidinediamine is essentially non-hygroscopic. Characteristic C solid state NMR shifts Hygroscopicity was assessed using dynamic vapour sorption Chemical shift equipment (Surface Measurement Systems Ltd, model DVS (ppm) Intensity 1). The analysis was conducted at 30°C. with a nitrogen gas 76.8 6.48 flow of 200cc/min. Water sorption and desorption were deter 71.8 6.04 mined in the range 0 to 90% relative humidity (RH) using 59.4 10.46 15% RH intervals. Exposure was for a minimum of 2 hours at 57.5 4.33 each humidity or until the rate of weight change was less than SO.O 4.66 48.3 4.83 0.0003%/minute (averaged over 10 minutes). Sample weight 40.9 6.12 was 12.6 mg. The sample was weighed using a CAHND-200, 39.2 2.37 seven place digital recording balance, which is an integral 37.1 9.88 part of the equipment. The compound showed only 0.6% 34.4 6.97 33.1 6.41 water sorption at 90% RH. Furthermore, following microni 28.4 4.88 sation using jet milling, there was no change in Solid form, a 26.9 9.39 negligible decrease in the degree of crystallinity and no sig 25.8 1122 nificant change in hygroscopicity (0.9% water sorption at 23.0 6.03 21.6 9.38 90% relative humidity). 18.2 7.96 0.126 Furthermore, the Xinafoate salt does not show any 10.9 12 hydration or salvation. Solvation/Hydration was assessed by 09.0 437 thermogravimetric analysis (TGA) using a TA Instruments O4.9 3.99 69.3 4.01 Hi-Res TGA2950 instrument measuring the weight loss of a 25.4 6.37 8.8 mg sample in an open platinum pan. The sample was heated at 20° C./min from ambient to 300° C. utilizing a nitrogen furnace purge gas. Whereas a single form of the US 2012/031 6160 A1 Dec. 13, 2012

Xinafoate salt has hitherto been identified, the free base solid state NMR referenced to an external sample of trifluo hydrates to form a hemihydrate and formed a different sol roacetic acid (50% by volume in HO) assigned a resonance vated form in each of nine solvents tested. at -76.54 ppm. 0127. In order to test for solid state stability and excipient 15. The method of claim 13 wherein the disease is asthma. compatibility, a sample of the Xinafoate salt was micronised 16. A Xinafoate salt of N4-(2,2-difluoro-4H-benzo 1.4 by jet milling (particle size: D10-0.24 um, D50=1.15 um, oxazin-3-one)-6-yl-5-fluoro-N2-3-(methylaminocarbonyl D90=4.29 um) and the resulting powder was blended at a methyleneoxy)phenyl-2,4-pyrimidinediamine formulated 1:100 weight ratio with lactose monohydrate (Respitose for use as a medicament. 17. The salt of claim 16 formulated for treating a disease for grade SV008). Samples were stored for 12 weeks at 25° which a Syk inhibitor is indicated. C/60% relative humidity and 40° C./75% relative humidity 18. The salt of claim 16 formulated for treating asthma. and assayed for remaining drug content and impurities at 4, 8 19. A method for making a composition for treating a and 12 weeks. The results are shown in Table 6. A control disease for which a Syk kinase inhibitor is indicated, com sample was stored at 5°C/0% humidity. prising: providing axinafoate salt of N4-(2,2-difluoro-4H-benzo TABLE 6 1,4-oxazin-3-one)-6-yl)-5-fluoro-N2-3-(methylami nocarbonylmethyleneoxy)phenyl-2,4-pyrimidinedi Stability data amine; and making a composition comprising the Xinafoate salt of % main band remaining versus control N4-(2,2-difluoro-4H-benzo14 oxazin-3-one)-6-yl)- Sample 4 weeks 8 weeks 12 weeks 5-fluoro-N2-3-(methylaminocarbonylmethyleneoxy) phenyl-2,4-pyrimidinediamine. 25 C.60% RH 1OO.2 99.9 100.1 40° C.;75% RH 100.4 1OOO 1OOO 20. The method according to claim 19 where the disease is asthma. 21. A composition, comprising: 0128. The results show that lactose blends of the Xinafoate a Xinafoate salt of N4-(2,2-difluoro-4H-benzo 1.4 ox salt have good stability. During the experiment, no change in azin-3-one)-6-yl)-5-fluoro-N2-3-(methylaminocarbo physical form was detected and no significant degradation nylmethyleneoxy)phenyl-2,4-pyrimidinediamine; and was observed. a second pharmacologically active Substance. 22. The composition according to claim 21 formulated for 1-12. (canceled) treating a disease for which a Syk kinase inhibitor is indi 13. A method for treating a disease for which a Syk inhibi cated. tor is indicated in a mammal comprising administering to the 23. The composition according to claim 21 wherein the mammal in need thereofatherapeutically effective amount of second pharmacological Substance is useful for treating a the Xinafoate salt of N4-(2,2-difluoro-4H-benzo 1.4 oxazin disease for which a Syk kinase inhibitor is indicated. 3-one)-6-yl)-5-fluoro-N2-3-(methylaminocarbonylmethyl 24. The composition according to claim 22 wherein the eneoxy)phenyl-2,4-pyrimidinediamine. disease is asthma. 14. The Xinafoate salt of claim 13 having shifts at about -69.2, -72.4 and -164.0 ppm when characterized by fluorine