WO2007085540A1

WO2007085540A1 - 1h-indaz0l-4-yl-2 , 4-pyrimidinediamine derivatives

Info

Publication number: WO2007085540A1
Application number: PCT/EP2007/050309
Authority: WO
Inventors: Francis Louis Atkinson; Sebastien Andre Campos; Lee Andrew Harrison; Nigel James Parr; Vipulkumar Kantibhai Patel; Giovanni Vitulli
Original assignee: Glaxo Group Limited
Priority date: 2006-01-27
Filing date: 2007-01-12
Publication date: 2007-08-02

Abstract

Compounds of formula (I): or a salt or solvate, preferably a pharmaceutically acceptable salt or solvate, thereof; are useful as inhibitors of Syk kinase and thus useful in treating diseases resulting from inappropriate mast cell activation, for instance allergic and inflammatory diseases.

Description

1H-INDAZ0L-4-YL-2, 4-PYRIMIDINEDIAMINE DERIVATIVES

The present invention relates to novel chemical compounds which have activity against the spleen tyrosine kinase (Syk kinase), processes for their preparation, pharmaceutically acceptable formulations containing them and their use in therapy.

Allergic rhinitis and asthma are diseases associated with hypersensitivity reactions and inflammatory events involving a multitude of cell types including mast cells, eosinophils, T cells and dendritic cells. Following exposure to allergen, high affinity immunoglobulin receptors for IgE (FcεRI) and IgG (FcγRI) become cross-linked and activate downstream processes in mast cells and other cell types leading to the release of pro-inflammatory mediators and airway spasmogens. In the mast cell, for example, IgE receptor cross-linking by allergen leads to release of mediators including histamine from pre-formed granules, as well as the synthesis and release of newly synthesised lipid mediators including prostaglandins and leukotrienes.

Syk kinase is a non-receptor linked tyrosine kinase which is important in transducing the downstream cellular signals associated with cross-linking FcεRI and or FcγRI receptors, and is positioned early in the signalling cascade. In mast cells, for example, the early sequence of FcεRI signalling following allergen cross-linking of receptor-lgE complexes involves first Lyn (a Src family tyrosine kinase) and then Syk kinase. Inhibitors of Syk kinase activity would therefore be expected to inhibit all downstream signalling cascades thereby alleviating the immediate allergic response and adverse events initiated by the release of pro-inflammatory mediators and spasmogens (Wong, B., Grossbard, E. B. Payan, D. G & Masuda, E. S. Expert Opin. Investig. Drugs (2004) 13 (7) 743-762).

Rigel have shown that the Syk kinase inhibitor R112 dosed intranasally in a phase I/I I study for the treatment of allergic rhinitis, gave a statistically significant decrease in

PGD₂, a key immune mediator that is highly correlated with improvements in allergic rhinorrhea, as well as being safe across a range of indicators, thus providing the first evidence for the clinical safety and efficacy of a topical Syk kinase inhibitor. (Guyer

B, Shimamoto S, Bradhurst A et al, J Allergy Clin Immunol., (2004) 113(2):S28-29). In a more recent phase Il clinical trial for allergic rhinitis (Clinical Trials.gov Identifier

NCT0015089), R112 was however shown as having a lack of efficacy versus placebo.

Rheumatoid Arthritis (RA) is an auto-immune disease affecting approximately 1 % of the population. It is characterised by inflammation of articular joints leading to debilitating destruction of bone and cartilage. Recent clinical studies with Rituximab, which causes a reversible B cell depletion, (J. C. W. Edwards et al 2004, New Eng. J. Med. 350: 2572-2581 ) have shown that targeting B cell function is an appropriate therapeutic strategy in auto-immune diseases such as RA. Clinical benefit correlates with a reduction in auto-reactive antibodies (or Rheumatoid Factor) and these studies suggest that B cell function and indeed auto-antibody production are central to the ongoing pathology in the disease.

Studies using cells from mice deficient in the Syk kinase have demonstrated a non- redundant role of this kinase in B cell function. The deficiency in Syk kinase is characterised by a block in B cell development (M. Turner et al 1995 Nature 379: 298-302 and Cheng et al 1995, Nature 378: 303-306). These studies, along with studies on mature B cells deficient in Syk kinase (Kurasaki et al 2000, Immunol. Rev. 176:19-29), demonstrate that Syk kinase is required for the differentiation and activation of B cells. Hence, inhibition of Syk kinase in RA patients is likely to block B cell function and hence to reduce Rheumatoid Factor production. In addition to the role of Syk kinase in B cell function, of relevance to the treatment of RA, is the requirement for Syk kinase activity in Fc receptor (FcR) signalling. FcR activation by immune complexes in RA has been suggested to contribute to the release of multiple pro-inflammatory mediators.

The contribution of Syk kinase dependent processes to the pathology of RA has been reviewed in Wong et al (2004, ibid).

WO 03/057695 (Boehringer lngelheim Pharmaceuticals, Inc.) describes substituted [1 ,6]-naphthyridines that inhibit Syk kinase.

WO2003/063794, WO2004/014382, WO2005/012294 and WO2005/16893 (Rigel Pharmaceuticals, Inc) describes a series of 2,4-pyrimidinediamine compounds which inhibit Syk kinase, for use in treating autoimmune diseases.

WO2005/026158 (Novartis AG) describes 2,4-di (hetero)-arylamino-pyrimidine derivatives which have ZAP-70 and/or Syk inhibitory activities.

WO 04/035604 discloses the structural co-ordinates of the human Syk protein.

There remains however the need to identify further compounds which are inhibitors of Syk kinase.

Thus, in a first aspect invention, the present invention provides a compound of formula (I):

in which:

R¹ is hydrogen or a halogen;

R² and R³ is each independently selected from hydrogen, halogen, -C₀-₆alkylenehydroxy, -C_1-6 alkyl, -NR⁵R⁶, -CN, -C₀-₃ alkylene-CO₂H, OC(O)C_1-6 alkyl, C(O)C_1-6 alkoxy, -C_1-2 alkyl substituted by 1 or more fluorine atoms, -C_1-6alkoxy, - C(O)NR⁵R⁶, -OCH₂C(O)NR⁵R⁶, -NR⁵C(O)R⁶, -SC_1-6alkyl, -S(O)C_1-6alkyl, -S(O)₂C_1-6alkyl, -NHS(O)₂R⁷, -S(O)₂NR⁵R⁶ or -S(O)₂NR⁵R⁸; or

one of R² and R³ is hydrogen and the other is a 5- or 6-membered heteroaryl ring comprising from 1 to 3 heteroatoms selected from O, N and S bonded to the phenyl ring through a ring carbon atom and which heteroaryl ring is unsubstituted or substituted on one or more ring carbon atoms by C_1-6alkyl or oxo (=0), or on a ring nitrogen atom by C_1-6alky!; or

R² and R³ are joined and together form, in combination with the carbon atoms on the phenyl group to which they are attached, a 5- or 6-membered ring wherein: the ring is heterocyclic and comprises one heteroatom selected from O, N or S, the ring is heteroaryl or heterocyclic and comprises two heteroatoms selected from O, N or S, which maybe the same or different, and excluding two S atoms, the ring is heteroaryl and comprises three heteroatoms of which two are N atoms and the third is nitrogen or oxygen, which ring may be unsubstituted or substituted on: one or more ring carbon atoms which each may be independently substituted by oxo (=0) or by 1 or 2 substituents which may be the same or different selected from C_1-6 alkyl, hydroxyl, or halo, one or more ring nitrogen atoms by C_1-6 alkyl, CH₂C_3-7cycloalkyl or C_1-6 alkylcarbonyl, C_2-4alkylenehydroxy and a ring sulphur atom by (O)₂; and

R⁴ is C₂_₅alkyl substituted by hydroxy, C_1-3alkoxy, amino, C_1-3alkylamino, di-(C_1-3alkyl)amino, C_1-3alkylcarbonylamino, C_1-3alkylsulphonylamino; C_1-4alkyl substituted by carboxy, C_1-3alkylcarboxy, aminocarbonyl, C_1-3alkylaminocarbonyl; trifluoromethyl; CH₂CH(OH)CH₂OH; or

R⁴ is CH₂R⁹ wherein R⁹ is a heterocyclyl ring comprising 5 or 6 atoms comprising one heteroatom selected from N or O, bonded through a ring carbon and optionally substituted on N by C_1-3alkylcarbonyl; R⁵ and R⁶ is each independently hydrogen or C_1-6alkyl, or R⁵ and R⁶ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring which may comprise a second heteroatom selected from O, S or N and which may be substituted on the second N, if present, by C_1-6alkyl, and which may be substituted on a ring carbon by oxo (=0), C_1-6alkyl, di-Ci_₆alkyl (which may be the same or different), or halogen;

R⁷ is C_1-6 alkyl or phenyl optionally substituted by Ci_-6alkyl;

R⁸ is C₃.₇cycloalkyl, C_1-6alkyl (optionally terminally substituted with hydroxyl or tetrahydrofuranyl); or

a salt or solvate, preferably a pharmaceutically acceptable salt or solvate, thereof.

Compounds of the present invention are useful as inhibitors of Syk kinase and thus useful in treating diseases resulting from in appropriate mast cell activation, for instance allergic and inflammatory diseases.

In a further embodiment, representative values of R¹ include hydrogen and fluoro.

In a further embodiment, representative values of R² and R³ include hydrogen, halogen, -C(O)NR⁵R⁶, -S(O)₂C_1-6alkyl, -S(O)₂NR⁵R⁶; in particular, hydrogen, -CONH₂, -SO₂NH₂, and -SO₂CH₃; for instance, R² is hydrogen and R³ is -CONH₂, -SO₂NH₂, and -SO₂CH_{3 ,}

In a further embodiment, a representative example of R² is hydrogen and a representative example of R³ is a 5- or 6-membered heteroaryl ring as hereinbefore defined, in particular R² is hydrogen and R³ is:

In a further embodiment, representative examples of the 5- or 6- membered saturated or unsaturated ring formed by R² and R³, fused with the phenyl ring, include:

In a further embodiment, representative examples of the 5- or 6- membered saturated or unsaturated ring formed by R² and R³, fused with the phenyl ring, and including any substituents which may be present, include:

In a further embodiment, the 5- or 6- membered saturated or unsaturated ring formed by R² and R³, fused with the phenyl ring, is selected from:

In a further embodiment, representative examples of R⁴ include -(CH₂)_nOH where n is 2, 3 or 4; -(CH₂)_nOCi.₃alkyl where n is 2 or 3; -(CH₂)_nNH₂ where n is 2, 3, 4 or 5; -(CH₂)₃N(C_1-3alkyl)₂; -(CH₂)_nNHCOC_1-3alkyl where n is 3, 4 or 5; -(CH₂)_nNHSO₂C_1-3alkyl where n is 3, 4 or 5; -(CH₂)_nCOOH where n is 3 or 4; -(CH₂)_nCOOC_1-3alkyl where n is 3 or 4; -CH₂CONH₂; -CH₂CONHMe; -CH₂CH(OH)CH₂OH; -CH₂CF₃; -CH₂tetrahydrofuran-3-yl; -CH₂piperidin-4-yl; and -CH₂(I -acetyl)piperidin-4-yl.

In a further embodiment, R⁴ is C_2-3alkyl substituted by hydroxy or C_1-3alkoxy.

In a further embodiment, representative examples of R⁴ include -(CH₂)₃OH and -(CH₂)₃OCH₃, in particular -(CH₂)₃OCH₃.

In a further embodiment, representative examples of R⁵ and R⁶ include: H.

In a further embodiment, representative examples of R⁹ include tetrahydrofuran-3-yl, piperidin-4-yl and i-acetylpiperidin-4-yl.

In a further aspect, the present invention provides for compounds of formula (IA):

in which:

R¹⁰ and R¹¹ is each independently hydrogen, C_1-6alkyl or CH₂C₃.₇cycloalkyl; R¹² is C₂.₃alkyl substituted by hydroxy or Ci_-3alkoxy; and X¹ is halogen; or a salt or solvate, preferably a pharmaceutically acceptable salt or solvate, thereof.

Representative examples of R and R include hydrogen.

Representative examples of R¹² include -(CH₂)₃OH and -(CH₂)₃OCH₃ Representative examples of X¹ include fluorine.

In an embodiment, representative examples of compounds of formula (I) include those described hereinafter as Examples 1 to 97

In a further embodiment, representative examples of compounds of formula (I) include:

3-[{2-[(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)amino]-4-pyrimidinyl}(1 /-/- indazol-4-yl)amino]-1 -propanol;

Λ/⁴-(3-aminopropyl)-Λ/²-(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)-/V⁴-1H- indazol-4-yl-2,4-pyrimidinediamine;

Λ/-[4-(1 H-indazol-4-yl{2-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)amino]-4- pyrimidinyl}amino)butyl]acetamide; 5-[{2-[(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)amino]-4-pyrimidinyl}(1 /-/- indazol-4-yl)amino]pentanoic acid;

N²-( 1,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)-5-fluoro-N⁴-1H-indazol-4yl-Λ/⁴-[3-

(methyloxy)propyl]-2,4-pyrimidinediamine;

2-[[2-(1 H-1 ,2,3-benzotriazol-5-ylamino)-4-pyrimidinyl](1 H-indazol-4-yl)amino]ethanol; 3-[{2-[(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)amino]-4-pyrimidinyl}(1 /-/- indazol-4-yl)amino]-1 -propanol; and

3-[{5-fluoro-2-[(1 -methyl-1 H-indazol-6-yl)amino]-4-pyrimidinyl}(1 H-indazol-4- yl)amino]-1 -propanol; or a salt or solvate thereof, in particular, a pharmaceutically acceptable salt or solvate thereof.

It will be understood that compounds of formula (I) may exist in alternative tautomeric forms, for example when R² represents a non-hydrogen substituent on the nitrogen atom in the 2-position.

When used herein, and unless otherwise indicated, the term "heteroaryl" includes single or fused rings comprising up to four hetero-atoms in the ring selected from oxygen, nitrogen and sulphur and optionally substituted with up to three substituents. Representative heteroaryl rings comprise from 4 to 7, preferably 5 or 6, ring atoms. A fused heteroaryl ring system may include carbocyclic rings and need only include one heterocyclic ring.

When used herein, and unless otherwise indicated, the term "heterocyclic" includes non-aromatic single or fused rings comprising up to four hetero-atoms in the ring selected from oxygen, nitrogen and sulphur and optionally substituted with up to three substituents. Representative heterocyclic rings comprise from 4 to 7, preferably 5 to 6, ring atoms. A fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring.

Examples of substituents for such heteroaryl and heterocyclic rings include C_1-6 alkyl, halogen, C_1-6 alkoxy, cyano, hydroxy, nitro, amino, -N(CH₃)₂, -NHC(O)C_1-6 alkyl, - CF₃, -C(O)OC_1-6 alkyl, -C(O)NR¹⁹R²⁰ (wherein R¹⁹ and R²⁰ independently represent hydrogen or C_1-6 alkyl, e.g., methyl), -S(O)₂N(CH₃)₂, or -S(O)₂CH₃, and, for heterocyclic, oxo (=0).

Examples of "-C_1-2 alkyl substituted by 1 or more fluorine atoms" include, but is not restricted to, -CF₃.

References to alkyl include references to both straight chain and branched chain aliphatic isomers of the corresponding alkyl. It will be appreciated that references to alkylene and alkoxy shall be interpreted similarly.

References to C_3-7 cycloalkyl include references to all alicyclic (including branched) isomers of the corresponding alkyl.

When used herein, and unless otherwise indicated, the term "carbocyclic" refers to rings which may be saturated or unsaturated but which are not aromatic, may be branched, which contain 5-7 carbon atoms and which may be optionally substituted with up to three substituents.

Examples of substituents for such carbocyclic rings include those previously mentioned for heteroaryl and heterocyclic.

When used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio. The skilled artisan will appreciate that pharmaceutically acceptable salts of the compound of the present invention may be prepared. As used herein, the term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively. Indeed, in certain embodiments of the invention, pharmaceutically acceptable salts may be preferred over the respective free base or free acid because such salts impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage form. In certain embodiments, the compound of the present invention may contain one or more acidic functional groups. Suitable pharmaceutically acceptable salts include salts of such acidic functional groups. Representative salts include pharmaceutically acceptable metal salts such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc salts; carbonates and bicarbonates of a pharmaceutically- acceptable metal cation such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc; pharmaceutically acceptable organic primary, secondary, and tertiary amines including aliphatic amines, aromatic amines, aliphatic diamines, and hydroxy alkylamines such as methylamine, ethylamine, 2-hydroxyethylamine, diethylamine, thethylamine, ethylenediamine, ethanolamine, diethanolamine, and cyclohexylamine.

Compounds of the present invention are basic and accordingly generally capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid. Suitable acids include pharmaceutically acceptable inorganic acids and pharmaceutically acceptable organic acids. Representative pharmaceutically acceptable acid addition salts include hydrochloride, hydrobromide, nitrate, methylnitrate, sulfate, bisulfate, sulfamate, phosphate_i acetate, hydroxyacetate, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, p-aminosalicyclate, glycollate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, tannate, formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate, glutamate, estolate, methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate, benzenesulfonate (besylate), p-aminobenzenesulfonate, p-toluenesulfonate (tosylate), and napthalene-2-sulfonate.

As used herein, the term "compound" refers to one or more compounds. Similarly, the term "a compound of the present invention" refers to one or more compounds of the present invention.

The compound of the present invention may exist in solid or liquid form. In the solid state, the compound of the present invention may exist in crystalline or non- crystalline form, or as a mixture thereof. For a compound of the present invention that is in crystalline form, the skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve non-aqueous solvents such as, but not limited to, ethanol, isopropanol, n-butanol, i-butanol, acetone, tetrahydrofuran, dioxane, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent incorporated into the crystalline lattice are typically referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.

The skilled artisan will further appreciate that certain compounds of the invention that exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs." The invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymophs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.

The compound of the present invention may contain one or more asymmetric centers (also referred to as a chiral centre) and may, therefore, exist as individual enantiomers, diastereoisomers, or other stereoisomeric forms, or as mixtures thereof. Chiral centers, such as chiral carbon atoms, may also be present in a substituent such as an alkyl group. Where the stereochemistry of a chiral centre is not specified the structure is intended to encompass any stereoisomer and all mixtures thereof. Thus, the compound of the present invention containing one or more chiral centres may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers. Generally it is preferred to use a compound of formula (I) in the form of a purified single enantiomer.

Individual stereoisomers of a compound according to Formula (I) which contain one or more asymmetric centre may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1 ) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent. The skilled artisan will appreciate that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired form. Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.

The compound of the present invention may also contain double bonds or other centres of geometric asymmetry. Where the stereochemistry of a centre of geometric asymmetry is not specified, the structure is intended to encompass the trans (E) geometric isomer, the cis (Z) geometric isomer, and all mixtures thereof. Likewise, all tautomeric forms are also included the compound of the present invention whether such tautomers exist in equilibrium or predominately in one form.

Compounds of the present invention, as well as salts and solvates thereof, may be prepared by one or more of the general synthetic schemes described hereinafter.

Scheme 1 A

Scheme 1C

in which schemes R¹, R², R³ and R⁴ are as hereinbefore defined and Pr is a protecting group such as 2-(trimethylsilyl)ethoxymethyl or 1 ,1- d imethylethylcarboxylate .

Accordingly, in a further aspect, the present invention provides a process for preparing a compound of formula (I), or a salt or solvate thereof, which process comprises:

reacting a compound of formula (II):

or a protected derivative thereof wherein L¹ represents a suitable leaving group, with a compound of formula (III)

or a protected derivative thereof, wherein R¹, R², R³ and R⁴ are as defined above.

The process may be performed in the presence of a solvent (for example, aqueous acetone or propan-2-ol), in the presence of concentrated hydrochloric acid, at a suitable temperature, preferably in the range of 0-170° C.

Alternatively, with a 2-(trimethylsilyl)ethoxymethyl protecting group, the process may be performed in the presence of a solvent such as 2-propanol, and hydrogen chloride in ether, at a suitable temperature, preferably in the range of 0-100° C, preferably under a nitrogen atmosphere.

Alternatively, with a 1 ,1-dimethylethylcarboxylate protecting group, the process may be performed in the presence of a solvent such as 2-propanol, and a dilute acid such as dilute hydrochloric acid, at a suitable temperature, preferably in the range of 0- 100° C.

Examples of suitable leaving groups (L¹) include a halide such as chloride, bromide or iodide. Other leaving groups include, but are not restricted to, an alkyl and aryl sulfide, an alkyl and aryl sulfinyl, an alkyl and aryl sulfonyl, and an alcohol derived leaving group (such as triflate, mesylate, methylsulfonate or tosylate).

Alternatively the process may be performed in the presence of a non-nucleophilic base such as triethylamine or di-isopropylethylamine, as a melt, at a suitable temperature, preferably in the range of 0-180° C.

Examples of protecting groups and the means for their removal can be found in T. W. Greene 'Protective Groups in Organic Synthesis' (J. Wiley and Sons, 1991 ). Suitable amine protecting groups include, but are not restricted to, sulphonyl (such as tosyl), acyl (such as benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (such as benzyl), which may be removed by hydrolysis or hydrogenolysis as appropriate. Other suitable amine protecting groups include trifluoroacetyl (-C(O)CF₃), which may be removed by base catalysed hydrolysis, or a solid phase resin bound benzyl group, such as a Merrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker) which may be removed by acid catalysed hydrolysis (using, for example, trifluoroacetic acid). Compounds of formula (II) may be prepared from the corresponding compound of formula (IV):

wherein L¹ and R¹ are as hereinbefore defined, or a protected derivative thereof, by reacting with sodium hydride in DMF, followed by adding alkylbromide R⁴Br, at a temperature of about 0⁰C, under a nitrogen atmosphere.

Compounds of formula (IV) may be prepared by reacting a corresponding (protected) indazole-4-amine with a pyrimidine compound of formula (V):

in which L² is a leaving group such as chloro and L¹ and R¹ are as hereinbefore defined; in a solvent such as propan-2-ol or acetone in the presence or a base such as di-isopropylethylamine, and at a temperature in the range 120-180⁰C.

Compounds of formula (II) may also be prepared by reacting a compound of formula (Vl):

in which R¹, R⁴, and L¹ are as hereinbefore defined, or a protected derivative thereof, with an organic nitrite derivative, such as, but not limited to, tert-butyl nitrite. This reaction is preferably performed in the presence of an acid, such as acetic acid or hydrochloric acid.

The aforementioned reaction may be performed in the presence of acetic anhydride to yield a product in which an indazolyl nitrogen atom is protected.

Compounds of formula (Vl) may be prepared from the corresponding compound of formula (VII):

in which R¹ and L¹ are as hereinbefore defined, or a protected derivative thereof, with an alkylbromide R⁴Br in the presence of a base such as potassium carbonate, in an aprotic solvent such as DMF.

Compounds of formula (VII) may be prepared reacting the corresponding optionally protected aniline with a pyrimidine compound of formula (VIII):

in which L¹, L² and R¹ are as hereinbefore defined, in aqueous methanol, at a temperature of about 7O⁰C.

Compounds of formula (III) are either obtainable from commercial sources, known in the art or may be prepared from the corresponding nitro compound using conventional reducing conditions for such a transformation, for example sodium dithionite, hydrogen gas in the presence of palladium, or iron metal with hydrochloric acid.

Compounds of formula (II) in which the leaving group represents other than halogen, may be obtained via the corresponding halogen by conventional methods. Certain compounds of formula (II) and are new and form a further aspect of the invention.

Compounds of the present invention are useful as inhibitors of Syk and thus useful in treating diseases resulting from in appropriate mast cell activation, for instance allergic and inflammatory diseases.

Thus, in a further aspect, the present invention provides for a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.

In a further embodiment, the present invention provides for a method of treating of treating inappropriate mast cell activation which method comprises administering to a patient in need thereof an effective compound of formula I, or a or a pharmaceutically acceptable salt or solvate thereof.

In a further aspect, the present invention provides a method comprising administering to a patient in need thereof an effective compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, to inhibit a Syk kinase.

In a further aspect, the present invention provides a method of treating an inflammatory disease which comprises administering to a patient in need thereof an effective compound of formula I, or a pharmaceutically acceptable salt or solvate thereof.

In a further aspect, the present invention provides a method of treating an allergic disorder which comprises administering to a patient in need thereof an effective compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

Diseases and pathological conditions thought to be mediated by Syk kinase include inflammatory and allergic disorders involving mast cell activation, such as chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), asthma, ulcerative colitis, Crohn's Disease, bronchitis, conjunctivitis, psoriasis, sclerodoma, urticaria, dermatitis, and allergic rhinitis. They also include inflammatory conditions which involve B cells, for instance lupus and rheumatoid arthritis.

Compounds of the present invention may also be used in combination with other classes of therapeutic agents which are known in the art. Representative clases of agents for use in such combinations include, for treating asthma, anti-inflammatory steroids (in particular corticosteroids), topical glucocorticoid agonists, PDE4 inhibitors, IKK2 inhibitors, A2a agonists, β₂-adrenoreceptor agonists (including both slow acting and long acting β₂-adrenoreceptor agonists), alpha 4 integrin inhibitors, and anti-muscarinics, and, for treating allergies, the foregoing agents, as well as H1 and H1/H3 antagonists. Representative agents for use in combination therapy for treating severe asthma include topically acting p38 inhibitors, and IKK2 inhibitors. Anti-inflammatory corticosteroids are well known in the art. Representative examples include fluticasone propionate (e.g. see US patent 4,335,121 ), beclomethasone 17- propionate ester, beclomethasone 17,21-dipropionate ester, dexamethasone or an ester thereof, mometasone or an ester thereof (e.g. mometasone furoate), ciclesonide, budesonide, and flunisolide. Further examples of anti-inflammatory corticosteroids are described in WO 02/12266 A1 (Glaxo Group Ltd), in particular, the compounds of Example 1 ( 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11 β-hydroxy- 16α-methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester) and Example 41 (6α,9α-difluoro-11 β-hydroxy-16α-methyl-17α-[(4-methyl-1 ,3-thiazole-5- carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester), or a pharmaceutically acceptable salt thereof.

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

Examples of anti-histamines include methapyrilene, or loratadine, cetirizine, desloratadine or fexofenadine.

Examples of anticholinergic compounds include muscarinic (M) receptor antagonists, in particular M-| , M2, M-1/M2, or M3 receptor antagonists, in particular a (selective)

M3 receptor antagonist. Examples of anticholinergic compounds are described in

WO 03/011274 A2 and WO 02/069945 A2 / US 2002/0193393 A1 and US 2002/052312 A1. Examples of muscarinic M3 antagonists include ipratropium bromide, oxitropium bromide or tiotropium bromide.

Representative PDE4 or mixed PDE3/4 inhibitors that may be used in combination with compounds of the invention include AWD-12-281 (Elbion), PD-168787 (Pfizer), roflumilast, and cilomilast (GlaxoSmithKline)

The present invention also provides for so-called "triple combination" therapy, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with β₂-adrenoreceptor agonist and an anti-inflammatory corticosteroid.

Preferably this combination is for treatment and/or prophylaxis of asthma, COPD or allergic rhinitis. The β₂-adrenoreceptor agonist and/or the anti-inflammatory corticosteroid can be as described above and/or as described in WO 03/030939 A1. A representative example of such a "triple" combination comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, salmeterol or a pharmaceutically acceptable salt thereof (e.g. salmeterol xinafoate) and fluticasone propionate. Preferred compounds of formula (I) for use as inhibitors of Syk kinase are those which exhibit selectivity for the Syk kinase against other key kinases such as Aurora A, Aurora B, Zap 70, JNK3, for instance at least 10x (based on either pKi or plC₅₀ values for the enzymes)

The compound of the present invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically acceptable excipient.

The pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the patient, such as with powders or syrups. Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the invention. When prepared in unit dosage form, the pharmaceutical compositions of the invention typically contain from about 0.1 to 99.9 wt.%, depending on the nature of the formulation.

The pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments the pharmaceutical compositions of the invention contain two compounds of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds.

As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled, such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and would result in pharmaceutically unacceptable compositions are avoided. In addition, each excipient must of course be of sufficiently high purity to render it pharmaceutically acceptable.

The compound of the invention and the pharmaceutically acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration. For example, dosage forms include those adapted for (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration, such as transdermal patches; (4) rectal administration, such as suppositories; (5) inhalation, such as aerosols and solutions; (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels and (7) intranasal administration, such as solutions or sprays. Preferred dosage forms are those adapted for inhalation and intranasal administration.

Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the carrying or transporting the compound of the present invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.

Suitable pharmaceutically acceptable excipients include the following types of excipients: Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate that certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), Remington: The Science and Practice of Pharmacy, (Lippincott Williams & Wilkins), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

Oral solid dosage forms such as tablets will typically comprise one or more pharmaceutically acceptable excipients, which may for example help impart satisfactory processing and compression characteristics, or provide additional desirable physical characteristics to the tablet. Such pharmaceutically acceptable excipients may be selected from diluents, binders, glidants, lubricants, disintegrants, colorants, flavorants, sweetening agents, polymers, waxes or other solubility- modulating materials.

Dosage forms for parenteral administration will generally comprise fluids, particularly intravenous fluids, i.e., sterile solutions of simple chemicals such as sugars, amino acids or electrolytes, which can be easily carried by the circulatory system and assimilated. Such fluids are typically prepared with water for injection USP. Fluids used commonly for intravenous (IV) use are disclosed in Remington, The Science and Practice of Pharmacy [full citation previously provided]. The pH of such IV fluids may vary, and will typically be from 3.5 to 8 as known in the art.

Dosage forms for nasal or inhaled administration may conveniently be formulated as aerosols, solutions, drops, gels or dry powders.

Dosage forms for topical administration to the nasal cavity (nasal administration) include pressurised aerosol formulations and aqueous formulations administered to the nose by pressurised pump. Formulations which are non-pressurised and adapted for nasal administration are of particular interest. Suitable formulations contain water as the diluent or carrier for this purpose. Aqueous formulations for administration to the nose may be provided with conventional excipients such as buffering agents, tonicity modifying agents and the like. Aqueous formulations may also be administered to the nose by nebulisation.

In a further embodiment, dosage forms for nasal administration are provided in a metered dose device. The dosage form may be provided as a fluid formulation for delivery from a fluid dispenser having a dispensing nozzle or dispensing orifice through which a metered dose of the fluid formulation is dispensed upon the application of a user-applied force to a pump mechanism of the fluid dispenser. Such fluid dispensers are generally provided with a reservoir of multiple metered doses of the fluid formulation, the doses being dispensable upon sequential pump actuations. The dispensing nozzle or orifice may be configured for insertion into the nostrils of the user for spray dispensing of the fluid formulation into the nasal cavity. In one embodiment, the fluid dispenser is of the general type described and illustrated in WO-A-2005/044354. The dispenser has a housing which houses a fluid discharge device having a compression pump mounted on a container for containing a fluid formulation. The housing has at least one finger-operable side lever which is movable inwardly with respect to the housing to cam the container upwardly in the housing to cause the pump to compress and pump a metered dose of the formulation out of a pump stem through a nasal nozzle of the housing. A particularly preferred fluid dispenser is of the general type illustrated in Figures 30-40 of WO-A- 2005/044354.

For compositions suitable and/or adapted for inhaled administration, it is preferred that the compound or salt of formula (I) is in a particle-size-reduced form, and more preferably the size-reduced form is obtained or obtainable by micronisation. The preferable particle size of the size-reduced (e.g. micronised) compound or salt or solvate is defined by a D50 value of about 0.5 to about 10 microns (for example as measured using laser diffraction).

Aerosol formulations, e.g. for inhaled administration, can comprise a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or non-aqueous solvent. Aerosol formulations can be presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device or inhaler. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve (metered dose inhaler) which is intended for disposal once the contents of the container have been exhausted.

Where the dosage form comprises an aerosol dispenser, it preferably contains a suitable propellant under pressure such as compressed air, carbon dioxide or an organic propellant such as a hydrofluorocarbon (HFC). Suitable HFC propellants include 1 ,1 ,1 ,2,3,3,3-heptafluoropropane and 1 ,1 ,1 ,2-tetrafluoroethane. The aerosol dosage forms can also take the form of a pump-atomiser. The pressurised aerosol may contain a solution or a suspension of the active compound. This may require the incorporation of additional excipients e.g. co-solvents and/or surfactants to improve the dispersion characteristics and homogeneity of suspension formulations. Solution formulations may also require the addition of co-solvents such as ethanol. Other excipient modifiers may also be incorporated to improve, for example, the stability and/or taste and/or fine particle mass characteristics (amount and/or profile) of the formulation.

For pharmaceutical compositions suitable and/or adapted for inhaled administration, it is preferred that the pharmaceutical composition is a dry powder inhalable composition. Such a composition can comprise a powder base such as lactose, glucose, trehalose, mannitol or starch, the compound of formula (I) or salt or solvate thereof (preferably in particle-size-reduced form, e.g. in micronised form), and optionally a performance modifier such as L-leucine or another amino acid, cellobiose octaacetate and/or metals salts of stearic acid such as magnesium or calcium stearate. Preferably, the dry powder inhalable composition comprises a dry powder blend of lactose and the compound of formula (I) or salt thereof. The lactose is preferably lactose hydrate e.g. lactose monohydrate and/or is preferably inhalation- grade and/or fine-grade lactose. Preferably, the particle size of the lactose is defined by 90% or more (by weight or by volume) of the lactose particles being less than 1000 microns (micrometres) (e.g. 10-1000 microns e.g. 30-1000 microns) in diameter, and/or 50% or more of the lactose particles being less than 500 microns (e.g. 10-500 microns) in diameter. More preferably, the particle size of the lactose is defined by 90% or more of the lactose particles being less than 300 microns (e.g. 10- 300 microns e.g. 50-300 microns) in diameter, and/or 50% or more of the lactose particles being less than 100 microns in diameter. Optionally, the particle size of the lactose is defined by 90% or more of the lactose particles being less than 100-200 microns in diameter, and/or 50% or more of the lactose particles being less than 40- 70 microns in diameter. Most importantly, it is preferable that about 3 to about 30% (e.g. about 10%) (by weight or by volume) of the particles are less than 50 microns or less than 20 microns in diameter. For example, without limitation, a suitable inhalation-grade lactose is E9334 lactose (10% fines) (Borculo Domo Ingredients, Hanzeplein 25, 8017 JD Zwolle, Netherlands).

Optionally, in particular for dry powder inhalable compositions, a pharmaceutical composition for inhaled administration can be incorporated into a plurality of sealed dose containers (e.g. containing the dry powder composition) mounted longitudinally in a strip or ribbon inside a suitable inhalation device. The container is rupturable or peel-openable on demand and the dose of e.g. the dry powder composition can be administered by inhalation via the device such as the DISKUS TM device, marketed by GlaxoSmithKline. The DISKUS TM inhalation device is for example described in GB 2242134 A, and in such a device at least one container for the pharmaceutical composition in powder form (the container or containers preferably being a plurality of sealed dose containers mounted longitudinally in a strip or ribbon) is defined between two members peelably secured to one another; the device comprises: a means of defining an opening station for the said container or containers; a means for peeling the members apart at the opening station to open the container; and an outlet, communicating with the opened container, through which a user can inhale the pharmaceutical composition in powder form from the opened container.

A composition of the present invention, for intranasal administration, may also be adapted for dosing by insufflation, as a dry powder formulation.

It will be appreciated that when the compound of the present invention is administered in combination with other therapeutic agents normally administered by the inhaled, intravenous, oral or intranasal route, that the resultant pharmaceutical composition may be administered by the same routes.

The compound of the present invention may conveniently be administered in amounts of, for example, 0.001 to 500mg/kg body weight. The precise dose will of course depend on the age and condition of the patient and the particular route of administration chosen.

Biological test methods

Compounds of the invention may be tested for in vitro activity in accordance with the following assays:

1. Enzyme Assay - Time-resolved fluorescence resonance energy transfer kinase assay

Recombinant human Syk was expressed as a His-tagged protein^*. The activity of Syk was assessed using a time-resolved fluorescence resonance energy transfer (TR-FRET) assay.

Version A - 3μl of substrate reagent containing biotinylated peptide, Biotin- AAAEEIYGEI (0.5μM final), ATP (30μM final) and MgCI₂ (1OmM final) in HEPES pH

7.4, (4OmM final), were added to wells containing 0.2μl of various concentrations of compound or DMSO vehicle (3.3% final) in Greiner low volume 384 well black plate.

The reaction was initiated by the addition of 3μl of Syk (2OnM final) in HEPES pH 7.4

(4OmM final). The reaction was incubated for 40min at room temperature, then terminated by the addition of 3μl of read reagent containing 60 mM EDTA, 15OmM

NaCI, 5OnM Streptavidin APC (Prozyme, San Leandro, California, USA), 0.5nM antiphosphotyrosine antibody labelled with W-1024 europium chelate (Wallac OY,

Turku, Finland) in 4OmM HEPES pH 7.4, 0.03% BSA. The reaction was further incubated for 60min at room temperature. The degree of phosphorylation of Biotin- AAAEEIYGEI was measured using a BMG Rubystar plate reader (BMG

LabTechnologies Ltd, Aylesbury, UK) as a ratio of specific 665 nm energy transfer signal to reference europium 620 nm signal.

Version B - Syk was pre-activated at room temperature for 30mins in the presence of 16.6mM MgCI₂, 8.3mM ATP and then diluted to 4nM in 4OmM Hepes pH 7.4, 0.01 % BSA. 3μl of substrate reagent containing biotinylated peptide, Biotin-AAAEEIYGEI (0.5μM final), ATP (30μM final) and MgCI₂ (1OmM final) in 4OmM HEPES pH 7.4, 0.01% BSA, were added to wells containing 0.1 μl of various concentrations of compound or DMSO vehicle (1.7% final) in Greiner low volume 384 well black plate. The reaction was initiated by the addition of 3μl of diluted Syk (2nM final). The reaction was incubated for 60min at room temperature, then terminated by the addition of 3μl of read reagent containing 60 mM EDTA, 15OmM NaCI, 5OnM Streptavidin APC (Prozyme, San Leandro, California, USA), 0.5nM antiphosphotyrosine antibody labelled with W-1024 europium chelate (Wallac OY, Turku, Finland) in 4OmM HEPES pH 7.4, 0.03% BSA. The reaction was further incubated for 45min at room temperature. The degree of phosphorylation of Biotin- AAAEEIYGEI was measured using a BMG Rubystar plate reader (BMG LabTechnologies Ltd, Aylesbury, UK) as a ratio of specific 665 nm energy transfer signal to reference europium 620 nm signal. Compounds according to the present invention were assayed in this, or a similar Time-resolved fluorescence resonance energy transfer kinase assay, and gave IC₅O values less than 10μM.

^* Preparation of Recombinant Human Full Length Spleen Tyrosine Kinase (Syk)Svk

Full length human Syk was expressed with a 6His tag on the N-terminal using the baculovirus system (Invitrogen, Paisley, Scotland). The cells were disrupted by dounce homogenisation, the debris removed by centrifugation and the lysate contacted with NiNTA Superflow (Qiagen, Crawley, UK). The NiNTA was packed into a column and eluted using 10 column volumes each of buffer (2OmM Tris pHδ.O, 30OmM NaCI, 1 OmM βMcEtOH, 10% glycerol), buffer + 1 M NaCI, buffer + 2OmM Imidazole and buffer + 30OmM imidazole. The 30OmM Imidazole fractions were pooled buffer exchanged using G25M (Amersham Biosciences, Buckinghamshire, UK) into 2OmM MES pH 6.0, 2OmM NaCI, 1OmM βMcEtOH,10% glycerol. The buffer exchanged 6His-Syk was loaded onto a Source15S column (Amersham Biosciences, Buckinghamshire, UK) and the column eluted using a NaCI gradient 0-50OmM over 50 column volumes. The 6His-Syk containing fractions were pooled and concentrated by ultra-filtration. The identity of 6His-Syk was confirmed by peptide mass finger printing and intact LC-MS.

2. Whole Cell Assay - cFms assay

Principle of the assay

Cells of the mouse fibroblast cell line NIH-3T3 are stably transfected with a cFms- SYK chimera. Addition of the ligand (MCSF) produces dimerisation of the chimera resulting in autophosphorylation of the SYK kinase domain. Following cell lysis phosphorylated SYK is detected by ELISA.

Stimulation of cFms-SYK cells with MCSF Version A

Cells are plated at a density of 1x10⁵/well in a volume of 200μl growth medium

(DMEM containing 10% heat inactivated foetal calf serum, 1 % L-glutamine, 400μg/ml geneticin and 400μg/ml zeocin) in 96 well Collagen 1 coated tissue culture plates. Following incubation at 37⁰C, 10% CO_2, for 2Oh, the cell supernatant is removed and replaced with 200μl DMEM containing 1 % penicillin/streptomycin (serum free DMEM). The cells are incubated for one hour under the conditions described above. The medium is removed, 50μl appropriately diluted compound solution added and the plate incubated for a further hour. Cells are stimulated with 25μl MCSF (0.66μg/ml final) for 20min at 37°C. After removal of the supernatant, the cells are washed with cold PBS and lysed with 100μl lysis buffer for 4h at 4⁰C.

Stimulation of cFms-SYK cells with MCSF Version B Cells are plated at a density of 1x105/well in a volume of 200μl growth medium (DMEM containing 10% heat inactivated foetal calf serum, 1 % L-glutamine, 400μg/ml geneticin and 400μg/ml zeocin) in 96 well Collagen 1 coated tissue culture plates. Following incubation at 37⁰C, 10% CO2, for 2Oh the cell supernatant is removed and 50μl appropriately diluted compound solution added and the plate incubated for an hour. Cells are stimulated with 25μl MCSF (0.66μg/ml final) for 20min at 37°C. After removal of the supernatant, the cells are washed with cold PBS and lysed with 100μl lysis buffer for 4h at 4°C.

cFms ELISA

85μl cell lysate is transferred to a 96 well ELISA plate coated with goat anti human M-CSF R capture antibody and incubated for 16 hours at 4°C. The plate is washed and a biotinylated anti-phosphotyrosine detection antibody added (100μl/well) for 2h at room temperature. This is removed and replaced with 100μl Streptavidin-HRP for 30min. Captured phosphorylated SYK is visualised using 100μl TMB substrate. The reaction is terminated with 50μl 1 M sulphuric acid and the absorbance measured at 450nm.

Compound Preparation Compound is prepared as a 1OmM stock in DMSO and a dilution series prepared in DMSO using 9 successive 5-fold dilutions. This dilution series is diluted a further 1 :333 with serum free DMEM to give the concentration range to be tested of 1x10^'5 to 1.54x10^"11M. Compound dilutions are prepared using the Biomek 2000 or Biomek Nx automated robotic pipetting systems.

3. B Cell Proliferation Assay

Background The population of B cells observed in this assay are the naϊve mature IgM/lgD expressing population. These form at least 70% of the purified B cell population (the rest being isotype switched memory B cells) and are the only cells that proliferate as the cells are stimulated with anti-lgM.

Anti-lgM drives signalling through the B cell receptor which is Syk dependant. Proliferation is a functional measure of B cell signalling that can be measured by observing the incorporation of tritiated methyl thymidine into the cells.

Protocol Purified human tonsillar B cells are resuspended in Buckleys* medium at a concentration of 1.25 x 10⁶ ml. 160μl of cells re-suspended in Buckley's medium is added to the compound and control wells of a 96 well plate. The control wells are located on column 11 and 12 of the 96 well plate. The background wells are located in column 12 and 20μl of 10μM control is added to provide an appropriate background control. 20μl of 1% DMSO is added to the wells in column 11 for the stimulated control.

The compound titrations are located between columns 1 and 10. Three compounds are run in duplicate on each plate and row A and B are used for the control compound titration.

The final concentration of DMSO is 0.1% in the assay. The cells are left for 45min, after 45min the proliferative stimulus is added to the first 11 wells of the 96 well plate and 20μl of medium is added to column 12. F(ab')2 fragments of a polyclonal goat anti-sera raised to human IgM is used at a final concentration of 15μg/ ml to stimulate the cells. (Biosource. Cat no: AMI 4601 ).

Tritiated methyl thymidine is added to the cells at a concentration of 1 μCi per well. (Amersham, TRK 758). The radioactivity is added 65 hours after the initial stimulus and is left on the cells for 6 to 8 hours. After pulsing with methyl thymidine the cells are harvested on a Skatron 96 well cell harvester onto glass fibre mats. Once these have dried these are counted on a Wallac 1450 Microbeta scintillation counter.

Data is downloaded as an XL file and IC50's determined using Activity base.

* Buckleys Medium: 450 ml Iscoves (Sigma I 3390), 50ml FCS, 2.5 g BSA, 5ml Pen/ strep, 5ml Glutamine (20OmM), 500μl Apo transferrin (50mg/ml) Sigma (T 1147), 100μl Bovine Insulin (10mg/ml) Sigma (I 1882).

Compound Preparation Compound is prepared as a 1OmM stock in DMSO and a dilution series prepared in DMSO using 9 successive 3-fold dilutions. This dilution series is diluted a further 1 :100 with Buckleys medium to give the concentration range to be tested of 100μM to 5nM. This is added as 20μl to 96 well plates in duplicate to generate two IC50's for each compound tested. Each plate is run in the presence of a control compound, which acts as an internal standard.

4. LAD2 Assay

Principle of the assay

LAD2 is a stem cell factor (SCF)-dependent human mast cell line that was established by the NIH from bone marrow aspirates from a patient with mast cell sarcoma/leukaemia. LAD2 cells resemble CD34+-derived human mast cells and express functional FcεRI. The FcεRI is up-regulated in the presence of IL-4, SCF and IgE, subsequent cross linking of cell-bound IgE results in degranulation which can be measured as hexosaminidase release.

Priming LAD2 cells to up-regulate FcεRI LAD2 cells are re-suspended at 1x10⁵/ml in complete stem pro-34SFM (Gibco Cat 10640-019 media containing Stem Pro-34 nutrient supplement (1 :40), glutamine (2mM), penicillin (100μg/ml), streptomycin (100μg/ml)) with additional supplements of human recombinant SCF (100ng/ml; R&D systems), human recombinant Interleukin- 4 (6ng/ml; R&D Systems) and IgE (100μg/ml; Calbiochem). Cells are then maintained for 5 days at 37°C, 5% CO2 in a humidified atmosphere.

Compound Preparation

Compounds are titrated from a 2mM stock in 100% DMSO to give 9 successive 1 :3 dilutions (V 96-well Nunc; Biomek 2000). From this master plate 3μl is dispensed into a daughter plate (flat 96-well NuncBiomek Fx) which is then diluted 1 :40 in RPMI with 2mM glutamine, and 20μl of the diluted compound transferred into the Greiner cell plate. Therefore the final compound concentration range is 1x10^"5M to 5x10^'10M in a constant 0.5% DMSO. Control wells are treated with 0.5% DMSO.

Activation of LAD2 cells with anti-lgE Version A

Primed LAD2 cells are centrifuged (30Og, 5min), the supernatant discarded and the cell pellet re-suspended at 1x10⁴ cells/ml in RPMI supplemented with glutamine (2mM). Following a further centrifugation (30Og, 5min) the cells are re-suspended in fresh RPMI with glutamine (2mM), adjusted to a density of 2.85x10⁵/ml, and pipetted into sterile V-well plates (70μl/well; Greiner) containing 20μl diluted compound (prepared as detailed above). Cells are then incubated for 1 h (37⁰C, 5% CO₂ in a humidified atmosphere) before activating with a sub-maximal concentration of anti- lgE (10μl volume to give a final assay dilution of 1 :2700; Sigma). Following a 40min incubation (37⁰C, 5% CO₂ in a humidified atmosphere), plates are centrifuged (120Og, 10min, 4°C) and the supernatant removed for hexosaminidase assay. The cell pellet is lysed in 100μl/well thton-X (0.5% in RPMI 2mM glutamine) at 37°C for 30min.

Activation of LAD2 cells with anti-lgE Version B Primed LAD2 cells are centrifuged (400g, 5min), the supernatant discarded and the cell pellet re-suspended at 1x10⁴ cells/ml in RPMI supplemented with glutamine (2mM). Following a further centrifugation (40Og, 5min) the cells are re-suspended in fresh RPMI with glutamine (2mM), adjusted to a density of 5.7 x10⁵/ml, and pipetted into sterile V-well plates (70μl/well; Greiner) containing 20μl diluted compound (prepared as detailed above). Cells are then incubated for 1 h (37°C, 5% CO₂ in a humidified atmosphere) before activating with a sub-maximal concentration of anti- lgE (10μl volume to give a final assay dilution of 1 :2700; Sigma). Following a 40min incubation (37°C, 5% CO₂ in a humidified atmosphere), plates are centrifuged (120Og, 10min, 4°C) and the supernatant removed for hexosaminidase assay. The cell pellet is lysed in 100μl/well triton-X (0.5% in RPMI 2mM glutamine) at 37⁰C for 30min.

Beta-hexosaminidase assay Beta-hexosaminidase activity is measured by the conversion of 4-methylumbelliferyl N-acetyl-ε-D glucosaminide (Sigma) to a fluorescent product.

Supernatant or lysate (25μl) is incubated with an equal volume of 4- methylumbelliferyl N-acetyl-ε-D glucosaminide (500μM in 0.2M sodium citrate buffer, pH 4.5) in black 96-well plate (Nunc) for 1 h at 37°C. The reaction is then terminated by addition of Trizma pH9 (90μl) and the fluorescent product measured using excitation 356nm and emission 450nm (Tecan Safire)

A useful screening strategy comprises assay 1 (enzyme assay (pKi), assay 2 and then assay 3 (B Cell Proliferation) or assay 4 (LAD2).

The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the following claims:

Intermediates and Examples

General

All temperatures are in ⁰C.

DCM refers to dichloromethane

DMSO refers to dimethylsulfoxide.

DMF refers to Λ/,Λ/-dimethylformamide

IPA refers to propan-2-ol THF refers to tetrahydrofuran.

HPLC refers to high performance liquid chromatography.

ADDP refers to 1 ,1'(azodicarbonyl)dipiperidine

SPE refers to solid phase extraction cartridges marketed by lsolute

TBTU refers to O-benzotriazol-1-yl-Λ/,Λ/,Λ/',Λ/',-bis(tetramethylene)uronium tetrafluoroborate

HOBt refers to N-hydroxybenzotriazole hydrate

¹H NMR spectra were recorded using a Bruker DPX 400MHz, referenced to tetramethylsilane. LCMS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm x 4.6 mm ID) eluting with 0.1 % HCO2H and 0.01 M ammonium acetate in water (solvent A) and 0.05% HCO2H 5% water in acetonitrile (solvent B), using the following elution gradient 0.0-7min 0%B, 0.7-4.2 min 100%B, 4.2-5.3 min 0%B, 5.3-5.5min 0%B at a flow rate of 3ml/min. The mass spectra were recorded on a Fisons VG Platform spectrometer using electrospray positive and negative mode (ES+ve and ES-ve).

"Mass directed autoprep" / "preparative mass directed HPLC" / "Mass directed HPLC" was conducted on a system such as; a Waters FractionLynx system comprising of a Waters 600 pump with extended pump heads, Waters 2700 autosampler, Waters 996 diode array and Gilson 202 fraction collector on a 10 cm 2.54 cm ID ABZ+ column, eluting with either 0.1% formic acid or trifluoroacetic acid in water (solvent A) and 0.1% formic or trifluoroacetic acid in acetonitrile (solvent B) using the appropriate elution gradient. Mass spectra were recored on Micromass ZMD mass spectrometer using electrospray positive and negative mode, alternate scans. The software used was MassLynx 3.5 with OpenLynx and FractionLynx optio or using equivalent alternative systems.

"Hydrophobic frits" refers to filtration tubes sold by Whatman. SPE (solid phase extraction) refers to the use of cartridges sold by International Sorbent Technology Ltd.

The Flashmaster Il is an automated multi-user flash chromatography system, available from Argonaut Technologies Ltd, which utilises disposable, normal phase, SPE cartridges (2 g to 100 g). It provides quaternary on-line solvent mixing to enable gradient methods to be run. Samples are queued using the multi-functional open access software, which manages solvents, flow-rates, gradient profile and collection conditions. The system is equipped with a Knauer variable wavelength uv-detector and two Gilson FC204 fraction-collectors enabling automated peak cutting, collection and tracking.

Silica chromatography techniques include either automated (Flashmaster) techniques or manual chromatography on pre-packed cartridges (SPE) or manually- packed flash columns.

Microwave chemistry was typically performed in sealed vessels, irradiating with a suitable microwave reactor system, such as a Biotage Initiator™ Microwave Synthesiser.

When the name of a commercial supplier is given after the name of a compound or a reagent, for instance "compound X (Aldrich)" or "compound X / Aldrich", this means that compound X is obtainable from a commercial supplier, such as the commercial supplier named.

Similarly, when a literature or a patent reference is given after the name of a compound, for instance compound Y (EP 0 123 456), this means that the preparation of the compound is described in the named reference.

The names of the Intermediates and Examples mentioned herein have been obtained using the compound naming programme "ACD Name Pro 6.02".

Example 1 Λ/²-1 H- 1.2.3-benzotriazol-5-yl-5-fluoro-Λ/⁴-1 H-indazol-4-yl-N⁴ [3- (methyloxy)propyπ-2.4-pyhmidinediamine trifluoroacetate

Λ/-(2-Chloro-5-fluoro-4-pyrimidinyl)-Λ/-[3-(methyloxy)propyl]-1/-/-indazol-4-amine (33.5mg) was taken up in water (1.5ml), acetone (1 ml) and hydrochloric acid (20μl, 2N) the mixture was placed in a microwave vial and treated with I H-1 ,2,3- benzotriazol-5-amine (20.4mg, Lancaster). The vial was sealed and the reaction irradiated in a biotage microwave at 160⁰C for 2x 30min. The reaction mixture was concentrated and the residue purified using SCX SPE (500mg) by loading the residue in methanol and eluting with methanol then ammonia in methanol. The ammonia fraction was concentrated and the residue dissolved in 1 :1 DMSO : methanol and purified using Mass Directed HPLC. The product fractions were concentrated and purified again using SCX SPE (500mg) loading in methanol and eluting with methanol then ammonia in methanol. The ammonia fraction was concentrated and the residue dissolved in 1 :1 DMSO : methanol and re-purified using Mass Directed HPLC. The fractions containing product were evaporated to dryness to give the title compound (7.8mg) LC/MS; Rt 2.86min, MH⁺ 434.

Similarly prepared were the following:

Intermediate 1 Λ/-(2-chloro-5-fluoro-4-pyrimidinyl)-Λ/-[3-(methyloxy)propyl]-1H- indazol-4-amine

/v-(2-chloro-5-fluoro-4-pyrimidinyl)-Λ/-[3-(methyloxy)propyl]-1-({[2- (trimethylsilyl)ethyl]oxy}methyl)-1/-/-indazol-4-amine (1.87 g) was treated with a mixture of hydrochloric acid (5N) and IPA (2:1 , 45ml). The mixture was stirred at 55°C for 5.5h, allowed to cool to room temperature and the solvents evaporated in vacuo. The residue was basified with saturated sodium carbonate solution (50ml) and extracted with ethyl acetate (3 x 50ml). The combined organic extracts were dried (MgSO₄), filtered and the solvent evaporated in vacuo. The residue was purified by chromatography on a silica cartridge (10Og) eluting with a methanol / DCM gradient (0-50%) over 60min. Fractions containing the product were combined and reduced to dryness in vacuo. The residue was dissolved in IPA, treated with hydrochloric acid (5N, 9ml) and concentrated in vacuo. The residue was left to stand at room temperature for 3 days, basified with saturated sodium carbonate (25ml) and extracted with ethyl acetate (2 x 25ml). The combined organic phases were dried (MgSO₄) and concentrated in vacuo. The residue was purified by chromatography on a silica cartridge (10Og) eluting with an ethyl acetate / cyclohexane gradient (0- 100%) over 60min to afford the title compound (220mg). LC/MS; Rt 2.95min, MH⁺ 336/338.

Additional impure product fractions were further purified by chromatography on silica, eluting with an ethyl acetate / cyclohexane gradient (0 - 50%) to afford another batch of the title compound (140mg). LC/MS; Rt 2.94min, MH⁺ 336. The remaining impure product fractions were purified by mass-directed autoprep to afford the title compound (129mg). LC/MS; Rt 3.04min, MH⁺ 335.99.

Intermediate Λ/-(2-chloro-5-fluoro-4-pyrimidinyl)-Λ/-[3-(methyloxy)propyl]-1-({[2-

(trimethylsilyl)ethyl]oxy}methyl)-1H-indazol-4-amine

N-(2-chloro-5-fluoro-4-pyrimidinyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 H-indazol- 4-amine (2g) was dissolved in DMF (20ml) and the mixture cooled to 0⁰C in an ice- water bath, under nitrogen. Sodium hydride (60% in mineral oil, 244mg) was added and stirring continued for 15min. 1-Bromo-3-(methyloxy)propane (0.93g) was added and the reaction mixture allowed to warm to room temperature and stirred under a nitrogen atmosphere for 3 days. Saturated ammonium chloride solution (5ml) was added to the reaction. The mixture was transferred to a larger flask using a minimum of chloroform and concentrated in vacuo. The residue was partitioned between ethyl acetate (25ml) and water (15ml). The organic phase was washed with water (3 x 15ml) and concentrated in vacuo. The residue was purified by chromatography on a silica cartridge (100g), eluting with an ethyl acetate / cyclohexane gradient (0-50%) over 60min to afford, after evaporation of the solvents, the title compound (1.87g). LC/MS; Rt 3.91 min, MH⁺ 466.

Intermediate 3 Λ/-(2-chloro-5-fluoro-4-pyrimidinyl)-1 -({[2- (trimethylsilyl)ethyl]oxy}methyl)-1H-indazol-4-amine

To a stirred solution of a mixture of 2-({[2-(trimethylsilyl)ethyl]oxy}methyl)-2/-/-indazol- 4-amine and 1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1/-/-indazol-4-amine (isomeric mixture, 20.4g) in N,N-diisopropylethylamine (155ml) was added 2,4-dichloro-5- fluoropyrimidine (13.6g, Aldrich). The mixture was heated under nitrogen at reflux for 3h. Further 2,4-dichloro-5-fluoropyrimidine (0.97g) was added over 1h before the mixture was allowed to cool. The volatile components were evaporated in vacuo and the residue was re-dissolved in dichloromethane and divided into 2 portions of approximately 1 :2 ratio. The first portion was absorbed onto a silica cartridge (33Og) before being purified using a CombiFlash^® Companion™ system eluting with a gradient of ethyl acetate in cyclohexane (0-100%). The required pure fractions were combined and the solvent was evaporated in vacuo to give the Λ/-(2-chloro-5-fluoro- 4-pyrimidinyl)-1 -({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 /-/-indazol-4-amine as an orange/brown solid (4.99g). LC/MS; Rt 3.57min, MH⁺ 394/396.

The second portion was absorbed onto a 75Og silica cartridge before being purified using a CombiFlash^® Companion™ system eluting with a gradient of ethyl acetate in cyclohexane (0-100%). The required pure fractions were combined and the solvent was evaporated in vacuo to give a further quantity of the Λ/-(2-chloro-5-fluoro-4- pyrimidinyl)-1 -({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 /-/-indazol-4-amine as an orange/brown solid (10.96g). LC/MS; Rt 3.57min, MH⁺ 394/396. Intermediate 4 1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 H-indazol-4-amine and 2-({[2- (trimethylsilyl)ethyl]oxy}methyl)-2H-indazol-4-amine (isomeric mixture)

Two vigorously stirred solutions, each containing 4-nitro-1-({[2- (trimethylsilyl)ethyl]oxy}methyl)-1 H-indazole mixture with 4-nitro-2-({[2- (trimethylsilyl)ethyl]oxy}methyl)-2H-indazole (21.17g) in ethanol (150ml), were hydrogenated at room temperature and 1atm. of pressure using 10% palladium on carbon catalyst (2.65g) for 1.5h. The mixtures were both filtered through Celite and the filter cakes were washed with portions of ethanol. The combined ethanol filtrates and washings from both reactions were evaporated in vacuo to give 1-({[2- (trimethylsilyl)ethyl]oxy}methyl)-1 H-indazol-4-amine mixture with 2-({[2- (trimethylsilyl)ethyl]oxy}methyl)-2H-indazol-4-amine as a brown oil (36.83g). LC/MS; Rt 3.14 and 3.35min, MH⁺ 264.

Intermediate 5 4-nitro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 H-indazole mixture with 4-nitro-2-({[2-(trimethylsilyl)ethyl]oxy}methyl)-2H-indazole

To a stirred solution of 4-nitroindazole (24.Og, Bionet Research Intermediates Catalogue) in dry tetrahydrofuran (380ml), stirred under nitrogen and cooled using an ice bath was added portion wise sodium-tert-butoxide (14.85g) followed after 5min by 2-(trimethylsilyl)ethoxymethylchloride (28.2ml). After removal of the cooling bath, the mixture was stirred at room temperature for 3h. Methanol (240ml) was added to the mixture and the solvent was evaporated in vacuo. The residue was partitioned between chloroform (300ml) and water (200ml), the phases were separated and the aqueous phase was extracted with chloroform (3x100ml). The combined organic phases were dried (MgSO₄), filtered and the solvent evaporated in vacuo to give 4- nitro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 H-indazole mixture with 4-nitro-2-({[2- (trimethylsilyl)ethyl]oxy}methyl)-2H-indazole as a orange/brown oil (42.34g). LC/MS; Rt 3.68 and 3.77min, MH⁺ 294.

Intermediate 6 2,3-dihydro-1 ,2-benzisothiazol-6-amine 1 ,1 -dioxide

To a suspension of 6-amino-2-benzisothiazol-3(2H)-one 1 ,1-dioxide (6.37g, Bull Chem Soc Jpn 1982 55(12) 3824-7) in cone, hydrochloric acid (79.6ml) was added zinc dust (18.9g) in portions over 30min, cooling with an ice bath when necessary (maximum temperature 7O⁰C). The reaction was stirred at room temperature for 3h. The mixture was basified with a solution of saturated NaHCO₃ (50ml), then with solid NaHCO₃. The mixture was filtered and the filtrate was extracted with ethyl acetate (3x 150ml). The organic phases were combined, dried (brine and magnesium sulphate), filtered and concentrated under vacuum to give a pale yellow solid (1.548g). The residue from filtration of the basified reaction was triturated with ethyl acetate (500ml) and filtered. The orange filtrate was concentrated under vacuum to give an orange solid (1.789g). The residue obtained from filtration was triturated again with ethyl acetate (250ml), filtered and concentrated under vacuum to give a pale orange solid (0.357g). All the solids were dissolved in methanol, combined and then concentrated to give the desired product as a beige solid (3.15g). LC/MS; Rt 0.83min.

Example 8 6-[(5-fluoro-4-{1 H-indazol-4-yl[3-(methyloxy)propyl]amino}-2- pyrimidinyl)amino]-1 ,4-dihydro-2H-3, 1 -benzoxazin-2-one

Λ/-(2-Chloro-5-fluoro-4-pyhmidinyl)-Λ/-[3-(methyloxy)propyl]-1H-indazol-4-amine (33.5mg) was taken up in water (1.5ml), acetone (1 ml) and hydrochloric acid (20μl, 2N), the mixture was placed in a microwave vial and treated with 6-amino-1 ,4- dihydro-2/-/-3,1 -benzoxazin-2-one (24.6mg, Key Organics). The vial was sealed and the reaction was irradiated in a biotage microwave at 160⁰C for 2x 30min. The reaction was concentrated and applied to an SCX SPE (500mg), eluting with methanol and ammonia in methanol. The ammonia fraction was concentrated and the residue dissolved in 1 :1 DMSO : methanol and purified using Mass Directed HPLC. The product fractions were concentrated and again purified using SCX SPE (500mg), eluting with methanol and ammonia in methanol. The ammonia fraction was concentrated to dryness to give the title compound (9.9mg). LC/MS; Rt 2.77min, MH⁺ 464.

Similarly prepared were the following:

Example 1 1 3-[[2-(1 H- 1 ,2,3-benzotriazol-5-ylamino)-5-fluoro-4-pyrimidinyl](1 H- indazol-4-yl)amino]-1-propanol trifluoroacetate (salt)

3-[(2-Chloro-5-fluoro-4-pyrimidinyl)(1 H-indazol-4-yl)amino]-1 -propanol (32.2mg) was taken up in water (1.5ml), acetone (1 ml) and hydrochloric acid (20μl, 2N), the mixture was placed in a microwave vial and treated with 1 H-1 ,2,3-benzotriazol-5-amine (20.1 mg, Lancaster) The vial was sealed and the reaction was irradiated in a biotage microwave at 160⁰C for 2x 30min. The reaction was concentrated and applied to an SCX SPE (500mg), eluting with methanol then ammonia in methanol. The ammonia fraction was concentrated and the residue dissolved in 1 :1 DMSO : methanol and purified using Mass Directed HPLC, the fractions from the MDAP were basified with ammonia in methanol (750μl) prior to concentration. The resulting crude was again purified using SCX SPE (500mg), eluting with methanol then ammonia in methanol. The ammonia fraction was concentrated and the residue dissolved in 1 :1 DMSO : methanol and purified using Mass Directed HPLC. The fractions containing product were evaporated to dryness to give the title compound (2mg). LC/MS; Rt 2.58min, MH⁺ 420.

Intermediate 7 3-[(2-chloro-5-fluoro-4-pyrimidinyl)(1 H-indazol-4-yl)amino]-1 -propanol

Λ/-(2-chloro-5-fluoro-4-pyrimidinyl)-Λ/-(3-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}propyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H- indazol-4-amine (1.3 g) was treated with a mixture of hydrochloric acid (5N) and IPA (2:1 , 25 ml). The mixture was stirred at 55°C for 5.5h, allowed to cool to room temperature and concentrated in vacuo. The residue was basified with saturated sodium carbonate solution (30ml), extracted with ethyl acetate (3 x 30ml). The combined organic phases were dried (MgSO₄), filtered and the solvent evaporated in vacuo. The residue was purified by chromatography on a silica cartridge (10Og), eluting with a methanol / DCM gradient (0-50%) over 60min. Fractions containing the product were combined and reduced to dryness in vacuo. The residue was dissolved in IPA, treated with hydrochloric acid (5N, 5ml) and concentrated in vacuo. The residue was left to stand at room temperature for 3 days, basified with saturated sodium carbonate (15ml) and extracted with ethyl acetate (2 x 15ml). The combined organic phases were dried (MgSO₄) and the solvents evaporated in vacuo. The residue was purified by chromatography on a silica cartridge (100g), eluting with an ethyl acetate / cyclohexane gradient (0-100%) over 60min, to afford, after evaporation of the solvents, the title compound (212mg). LC/MS; Rt 2.67min, MH⁺ 322/324.

Intermediate 8 Λ/-(2-chloro-5-fluoro-4-pyhmidinyl)-Λ/-(3-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}propyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 H- indazol-4-amine

Λ/-(2-chloro-5-fluoro-4-pyrimidinyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-indazol- 4-amine (2g) was dissolved in DMF (20 ml) and the solution cooled to 0°C in an ice- water bath, under nitrogen. Sodium hydride (60% in mineral oil, 244mg) was added and stirring continued for 15min. [(3-Bromopropyl)oxy](1 ,1- dimethylethyl)dimethylsilane (1.54g) was added, the reaction mixture allowed to warm to room temperature and left to stir under nitrogen for 3 days. Saturated ammonium chloride solution (5ml) was added to the reaction mixture. The mixture was transferred to a larger flask using a minimum of chloroform and concentrated in vacuo. The residue was partitioned between ethyl acetate (25ml) and water (15ml). The organic phase was washed with water (3 x 15ml) and reduced to dryness in vacuo. The residue was purified by chromatography on a silica cartridge (100g), eluting with an ethyl acetate / cyclohexane gradient (0-50%) over 60min, to afford, after evaporation of the solvents, the title compound (1.3g). LC/MS; Rt 4.51 min, MH⁺ 566.

Example 12 3-[{5-fluoro-2-[(1 -methyl-1 /-/-indazol-6-yl)amino]-4-pyrimidinyl}(1 H- indazol-4-yl)amino]-1-propanol trifluoroacetate (salt)

3-[(2-Chloro-5-fluoro-4-pyrimidinyl)(1/-/-indazol-4-yl)amino]-1-propanol (32.2mg) was taken up in water (1.5ml), acetone (1 ml) and hydrochloric acid (20μl, 2N), the mixture was placed in a microwave vial and treated with 1 H-1 ,2,3-benzotriazol-5- amine (20.1mg, Lancaster) The vial was sealed and the reaction was irradiated in a biotage microwave at 160⁰C for 2x 30min. The reaction was concentrated and purified using SCX SPE (500mg), loading in methanol and eluting with methanol then ammonia in methanol. The ammonia fraction was concentrated and the residue dissolved in 1 :1 DMSO : methanol and purified using Mass Directed HPLC, the fractions from the MDAP were basified with ammonia in methanol (750μl) prior to being concentrated. The resulting crudes were again purified using SCX SPE (500mg), loading in methanol and eluting with methanol then ammonia in methanol. The ammonia fraction was concentrated to dryness to give the title compound (43mg). LC/MS; Rt 2.74min, MH⁺ 433.

Similarly prepared were the following:

Example 16 Λ/²-(1 ,1-dioxido-2, 3-di hydro- 1 ,2-benzisothiazol-6-yl)-5-fluoro- N⁴-1H- indazol-4-yl-/V⁴-[3-(methyloxy)propyl]-2,4-pyrimidinediamine

Λ/-(2-Chloro-5-fluoro-4-pyrimidinyl)-Λ/-[3-(methyloxy)propyl]-1H-indazol-4-amine (167.5mg) was taken up in water (3ml), acetone (2ml) and hydrochloric acid (40μl, 2N), the mixture was treated with 2,3-dihydro-1 ,2-benzisothiazol-6-amine 1 ,1-dioxide (138mg, Manchester Organics). The mixture was placed into a microwave vial, the vial sealed and the reaction irradiated in a biotage microwave at 160⁰C for 1 h. The reaction was treated with 2,3-dihydro-1 ,2-benzisothiazol-6-amine 1 ,1-dioxide (92mg, Manchester Organics) and irradiated in a biotage microwave at 160⁰C for a further 2x 30min. The reaction was concentrated and applied to an SCX SPE (10g), eluting with methanol (50ml) and ammonia in methanol (50ml). The ammonia fraction was concentrated and absorbed onto flurosil (3g). The solid was applied to a silica cartridge (2Og) and the cartridge eluted with an ethyl acetate : cyclohexane gradient (0-100%) over 30min. The product fractions were evaporated to dryness to give the title compound. (125mg). LC/MS; Rt 2.88min, MH⁺ 484.

Example 17 3-[(5-fluoro-2-{[3-(methylsulfonyl)phenyl]amino}-4-pyrimidinyl)(1H- indazol-4-yl)amino]-1-propanol trifluoroacetate (salt)

3-[(2-Chloro-5-fluoro-4-pyrimidinyl)(1 H-indazol-4-yl)amino]-1 -propanol (32.2mg) was taken up in water (1.5ml), acetone (1ml) and hydrochloric acid (20μl, 2N), the mixture was placed in a microwave vial and treated with [3-(methylsulfonyl)phenyl]amine (25.6mg, Acros). The vial was sealed and the reaction irradiated in a microwave at 160°C for 1 h. The reaction was concentrated and purified using SCX SPE (500mg), eluting with methanol then ammonia in methanol. The ammonia fraction was concentrated and the residue dissolved in 1 :1 DMSO : methanol and purified using Mass Directed HPLC. The fractions containing product were concentrated to dryness to give the title compound (25mg). LC/MS; Rt 2.80min, MH⁺ 456.9

Example 18 N²-(1 ,1-dioxido-2,3-dihydro-1,2-benzisothiazol-6-yl)-5-fluoro-N⁴-1H- indazol-4-yl-Λ/⁴-[3-(methyloxy)propyl]-2,4-pyrimidinediamine hydrochloride

Λ/²-(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)-5-fluoro-N⁴ -1H-indazol-4-yl-N ⁴-[3- (methyloxy)propyl]-2,4-pyrimidinediamine (50mg) was taken up in a minimal amount of methanol and treated with HCI in ethanol (1 M, 520μl) the mixture was allowed to stir at room temperature for IOmins and evaporated to dryness to give title compound (53mg)

LC/MS; Rt 2.92min, MH⁺ 484. NMR; [D₆-DMSO] δH 10.04,(1 H, bs), 8.22,(1 H, d), 8.06,(1 H, d), 7.99,(1 H, d), 7.83,(1 H, dd), 7.53,(1H, d), 7.43-7.36,(2H, m), 7.10,(1 H, d), 4.34,(2H, s), 4.11 ,(2H, m), 3.34,(2H₁ 1), 3.08,(3H, s), 1.88,(2H₁ m).

Example 19 3-[{5-fluoro-2-[(1 -methyl- 1 H-indazol-6-yl)amino]-4-pyrimidinyl}(1 H- indazol-4-yl)amino]-1 -propanol hydrochloride

HCl

3-[{5-fluoro-2-[(1-methyl-1/-/-indazol-6-yl)amino]-4-pyrimidinyl}(1H -indazol-4- yl)amino]-1 -propanol (10.5mg) was taken up in a minimal volume of methanol and treated with HCI in ethanol (1 M, 100μl) the mixture was allowed to stir at room temperature for 8mins and evaporated to dryness to give title compound (13.5mg). LC/MS; Rt 2.84min, MH⁺ 432.98. NMR; [D₆-DMSO] δH 10.36,(1 H, bs), 8.12,(1 H, d), 8.04,(1H, s), 7.96,(1 H, s), 7.88,(1 H, s), 7.67,(1 H, d), 7.56,(1 H, d), 7.39,(1 H, t), 7.28,(1 H, d), 7.13,(1 H, d), 4.14,(2H partially obscured by water, m + bs), 3.96,(3H, s), 3.33,(2H, t), 1.75,(2H, m). Example 20 3-[6-({5-Fluoro-4-[(3-hydroxypropyl)(1 H-indazol-4-yl)amino]-2- pyrimidinyl}amino)-3-methyl-1 H-indazol-1 -yl]-1 -propanol trifluoroacetate (salt)

3-[(2-Chloro-5-fluoro-4-pyrimidinyl)(1H-indazol-4-yl)amino]-1 -propanol (95mg), 1-(3- {[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-3-methyl-1 H-indazol-6-amine (100mg), and cone, hydrochloric acid (150μl) in isopropanol (4ml) was heated in a sealed vessel at 150⁰C for 60min. using a microwave. The reaction mixture was diluted with methanol and loaded onto a SCX-2 cartridge (5g). The cartridge was washed with methanol and the product was eluted with 2N ammonia in methanol. The appropriate ammonical fractions were combined and evaporated in vacuo. The residue was purified further by flash chromatography on a silica cartridge (5g), eluting with a gradient (1% triethylamine in Methanol) / DCM (0 to 5%). The appropriate fractions were combined and the solvent evaporated in vacuo. The residue was the purified by mass directed HPLC to give the title compound (40mg). LC/MS; Rt 2.72min, MH⁺ 491. NM R; [MeOD] δH 8.05,(1 H, s), 7.84,(1 H, d), 7.72-7.70,(2H, m), 7.63,(1 H, d), 7.46,(1 H, m), 7.24,(1 H, d), 7.18,(1 H, d), 4.43-4.40,(2H, t), 4.27-4.23,(2H, t), 3.53- 3.47,(4H, m), 2.54,(3H, s), 2.10-2.04,(2H, m), 1.93-1.87,(2H, m).

Intermediate 9 1-(3-{[(1 ,1-Dimethylethyl)(dimethyl)silyl]oxy}ρropyl)-3-methyl-1 H- indazol-6-amine

1-(3-{[(1 ,1-Dimethylethyl)(dimethyl)silyl]oxy}propyl)-3-methyl-6-nitro-1 H-indazole (6.4g) in absolute ethanol (150ml) was added to Palladium on carbon catalyst (10%, 650mg) and stirred under 1Atm. of hydrogen for 4h. The mixture was filtered through celite and evaporated in vacuo. The residue was purified by flash chromatography on a silica cartridge (100g), eluting with an ethyl acetate / cyclohexane gradient (0 to 100%) over 40min. to give the title compound (5.17g). LC/MS; Rt 3.53min.

Intermediate 10 1-(3-{[(1 ,1-Dimethylethyl)(dimethyl)silyl]oxy}propyl)-3-methyl-6-nitro- 1 H-indazole

3-Methyl-6-nitro-1 H-indazole (WO 2002059110 A1 ), (5g) was dissolved in dry DMF (40ml) and stirred under nitrogen. The solution was cooled in an ice/ water bath to ~5°C, and sodium hydride (60% in mineral oil; 1.13g) was added portionwise. The mixture was stirred with ice/ water cooling for a further 30min. [(3- Bromopropyl)oxy](1 ,1-dimethylethyl)dimethylsilane (6.72ml, Aldrich) in dry DMF (5ml) was added dropwise. The mixture was then allowed to warm up to room temperature and stirred for 18h under nitrogen. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phases were combined, dried (MgSO₄), and the solvent evaporated in vacuo. The residue was purified by flash chromatography on a silica cartridge (100g), eluting with an ethyl acetate / cyclohexane gradient (0 to 50%) over 40min. to give, after evaporation of the solvents a mixture of mono N-alkylation products (9.07g). This material was dissolved in cyclohexane (minimum volume) and loaded onto a silica SPE cartridge (100g). The cartridge was eluted with cyclohexane (200ml), 10% ethyl acetate / cyclohexane (200ml), and then 30% ethyl acetate / cyclohexane collecting 50ml fractions. The appropriate pure fractions of each isomer were combined and the solvent removed in vacuo from each sample.

NOE's (Nuclear Overhauser Enhancement) of each positional isomer determined which the desired isomer was. The less polar isomer by tic (1 :2 ethyl acetate- cyclohexane) was the title compound (6.4g). LC/MS; Rt 4.24min. N MR; [CDCI₃] δH 8.40, (1 H , s) , 7.98-7.95,( 1 H, d), 7.74-7.72, ( 1 H , d), 4.54-4.51 , (2H , t), 3.58-3.55, (2H , t), 2.62, (3H , s), 2. 14-2. 1 1 , (2H , m), 0.92,(6H , s), 0.04, (9H , s). Example 21 3-{6-[(5-Fluoro-4-{1 H-indazol-4-yl[3-(methyloxy)propyl]amino}-2- pyrimidinyl)amino]-3-methyl-1 H-indazol-1-yl}-1-propanol trifluoroacetate (salt)

N-(2-Chloro-5-fluoro-4-pyrimidinyl)-N-[3-(methyloxy)propyl]-1 H-indazol-4-amine (100mg), 1-(3-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-3-methyl-1 H-indazol-6- amine (100mg), and cone, hydrochloric acid (150μl) in isopropanol (4ml) was irradiated by microwave in a sealed vessel at 150⁰C for 60min. The reaction mixture was diluted with methanol and loaded onto a SCX-2 cartridge (5g). The cartridge was washed with methanol and the product eluted with 2N ammonia in methanol. The appropriate ammonical fractions were combined and evaporated in vacuo. The residue was purified further by flash chromatography on a silica cartridge (5g), eluting with a (1 %triethylamine in Methanol) / DCM gradient (0 to 5%). The appropriate fractions were combined and the solvents evaporated in vacuo. The residue was the purified by mass directed autoprep to give the title compound (46mg). LC/MS; Rt 2.98min, MH⁺ 505. N M R; [MeOD] δH 8.06,(1 H, s), 7.86,(1 H, d), 7.74-7.71 , (2H, m), 7.63,(1 H, d), 7.48-7.44,(1 H, m), 7.21-7.16,(2H, m), 4.45-4.41 , (2H, t), 4.24-4.20,(2H, t), 3.53-3.50,(2H, t), 3.25-3.22,(2H, t), 3.06,(3H, s), 2.55,(3H, s), 2.10-2.04,(2H, m), 1.94-1.87,(2H, m).

Example 22 N2-(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)-N4-1 H-indazol-4- yl-N4-[3-(methyloxy)propyl]-2,4-pyrimidinediamine trifluoroacetate

A mixture of Λ/-(2-chloro-4-pyrimidinyl)-Λ/-[3-(methyloxy)propyl]-1/-/-indazol-4-amine (32mg) and 2,3-dihydro-1 ,2-benzisothiazol-6-amine 1 ,1 -dioxide (28mg) in acetone : water : 2M hydrochloric acid (1 ml:1.5ml:20μl) was stirred and heated under reflux for 16h. The solvent was evaporated under a stream of nitrogen. The residue was dissolved in methanol and loaded onto an SCX SPE. The cartridge was washed with methanol and the product was eluted from the column using 10% ammonia in methanol. After concentration under a stream of nitrogen, the product was purified by mass directed HPLC to give the title compound (15mg). LC/MS; Rt 2.24min MH⁺ 465.8.

Similarly prepared were the following:

Ul

Intermediate 11 Λ/-(2-chloro-4-pyrimidinyl)-Λ/-[3-(methyloxy)propyl]-1 H-indazol-4- amine

A stirred solution of Λ/-(2-chloro-4-pyrimidinyl)-Λ/-[3-(methyloxy)propyl]-1-({[2- (trimethylsilyl)ethyl]oxy}methyl)-1H-indazol-4-amine (446mg) in 2-propanol (4ml) and aqueous hydrochloric acid (5M, 4ml) was heated at 65°C for 4.5h. The solvents were evaporated from the mixture in vacuo and the residue was basified with saturated aqueous sodium carbonate solution (5ml). The mixture was extracted with ethyl acetate (10ml), the phases separated and the aqueous phase extracted with further ethyl acetate (3x 5ml). The organic phases were combined, washed with brine (10ml), dried (MgSO₄), filtered, and the solvents evaporated in vacuo. The residue was purified by chromatography on a silica cartridge (2Og) eluting with a methanol / DCM gradient (0-50%) over 30min. The required fractions were combined and the solvent was evaporated in vacuo to give the title compound (214mg). LC/MS; Rt 2.75min, MH⁺ 318, 320.

Intermediate 12 Λ/-(2-chloro-4-pyrimidinyl)-Λ/-[3-(methyloxy)propyl]-1 -({[2-

(trimethylsilyl)ethyl]oxy}methyl)-1 H-indazol-4-amine and Λ/-(2-chloro-4-pyrimidinyl)-Λ/- [3-(methyloxy)propyl]-2-({[2-(trimethylsilyl)ethyl]oxy}methyl)-2/-/-indazol-4-amine

A portion (4ml) of a solution of Λ/-(2-chloro-4-pyrimidinyl)-2-({[2- (trimethylsilyl)ethyl]oxy}methyl)-2 H-indazol-4-amine and Λ/-(2-chloro-4-pyrimidinyl)-1- ({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 H-indazol-4-amine (isomeric mixture 4.3g) in DMF (48ml) was stirred under nitrogen. Sodium hydride (60% in mineral oil, 46mg) was added to the mixture followed by further DMF (1 ml), and after 5min, 1-bromo-3- methoxypropane (176mg). The mixture was stirred at room temperature for 40h and saturated aqueous ammonium chloride solution (1 ml) added to the mixture. The volatile components were evaporated in vacuo, water (5ml) added to the residue and the mixture extracted with chloroform (8ml). The phases were separated, the organic phase dried (MgSO₄), filtered, and the solvent evaporated in vacuo to give the title compound, containing a small quantity of DMF, as a brown gum (446mg). LC/MS; Rt 3.65 and 3.77min, MH⁺ 448, 450.

Intermediate 13 N-(2-chloro-4-pyrimidinyl)-1 -({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 H- indazol-4-amine mixture with N-(2-chloro-4-pyrimidinyl)-2-({[2-

(trimethylsilyl)ethyl]oxy}methyl)-2H-indazol-4-amine

To a stirred solution of 1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 H-indazol-4-amine mixture with 2-({[2-(trimethylsilyl)ethyl]oxy}methyl)-2H-indazol-4-amine (35.Og) in N,N-diisopropylethylamine (200ml) was added 2,4-dichloropyrimidine (29.75g). The mixture was heated under nitrogen at 15O⁰C for 3h before being allowed to cool and evaporation of the volatile components in vacuo. The residue was re-dissolved in DCM and the solvent again evaporated in vacuo. The residue was purified by chromatography; dissolved in DCM absorbed onto a silica cartridge (80Og) and the cartridge eluted with ethyl acetate / cyclohexane (35:65). The required pure fractions were combined and the solvent was evaporated in vacuo to give the title compounds as an orange/brown gum (16.11g). LC/MS; Rt 3.51 and 3.70min, MH⁺ 376, 378.

Intermediate 14 3-[(2-chloro-4-pyrimidinyl)(1 H-indazol-4-yl)amino]-1 -propanol

A stirred solution of Λ/-(2-chloro-4-pyrimidinyl)-Λ/-(3-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}propyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H- indazol-4-amine and Λ/-(2-chloro-4-pyrimidinyl)-N-(3-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}propyl)-2-({[2-(trimethylsilyl)ethyl]oxy}methyl)-2/-/- indazol-4-amine (isomeric mixture 549.5mg) in 2-propanol (4ml) and aqueous hydrochloric acid (5M, 4ml) was heated at 65°C for 4.5h. The solvents were evaporated in vacuo and the residue was basified with saturated aqueous sodium carbonate solution (5ml). The mixture was extracted with ethyl acetate (10ml), the phases separated and the aqueous phase extracted with further ethyl acetate (3x 5ml). The organic phases were combined, washed with brine (10ml), dried (MgSO₄), filtered, and the solvents evaporated in vacuo. The residue was purified by column chromatography on a silica cartridge (2Og), eluting with a methanol / DCM gradient (0-50%) over 30min. The required fractions were combined and the solvent was evaporated in vacuo to give the title compound (207mg). LC/MS; Rt 2.39min, MH⁺ 304, 306.

Intermediate 15 Λ/-(2-chloro-4-pyrimidinyl)-Λ/-(3-{[(1 , 1 - dimethylethyl)(dimethyl)silyl]oxy}propyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H- indazol-4-amine and Λ/-(2-chloro-4-pyrimidinyl)-Λ/-(3-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}propyl)-2-({[2-(trimethylsilyl)ethyl]oxy}methyl)-2/-/- indazol-4-amine (isomeric mixture)

A portion (4ml) of a solution of Λ/-(2-chloro-4-pyrimidinyl)-2-({[2- (trimethylsilyl)ethyl]oxy}methyl)-2 H-indazol-4-amine and Λ/-(2-chloro-4-pyrimidinyl)-1- ({[2-(tπmethylsilyl)ethyl]oxy}methyl)-1 H-indazol-4-amine (isomeric mixture, 4.3g) in DMF (48ml) was stirred under nitrogen. Sodium hydride (60% in mineral oils, 46mg) was added to the mixture followed by further DMF (1 ml), and after 5min, (3- bromopropoxy)-tert-butyl-dimethylsilane (266μl). The mixture was stirred at room temperature for 4Oh and saturated aqueous ammonium chloride solution (1 ml) was added to the mixture. The volatile components were evaporated in vacuo, water (5ml) was added to the residue and the mixture extracted with chloroform (8ml). The phases were separated, the organic phase dried (MgSO₄), filtered, and the solvent evaporated in vacuo to give the title compound, containing a small quantity of DMF, as a brown gum (549.5mg). LC/MS; Rt 4.48 and 4.56min, MH⁺ 548, 550.

Intermediate 16 Λ/-(2-chloro-4-pyrimidinyl)-Λ/-[2-(methyloxy)ethyl]-1 H-indazol-4- amine

An aliquot (4.5ml) from a solution of Λ/-(2-chloro-4-pyrimidinyl)-2-({[2- (trimethylsilyl)ethyl]oxy}methyl)-2/-/-indazol-4-amine and Λ/-(2-chloro-4-pyrimidinyl)-1 - ({[2-(trimethylsilyl)ethyl]oxy}methyl)-1/-/-indazol-4-amine (isomeric mixture, 920mg) in DMF (18ml) was stirred in a boiling tube under nitrogen. Sodium hydride (60% in mineral oils, 29.4mg) was added to the solution followed by 2-bromoethyl methylether (86μl). The mixture was stirred at room temperature for 22h. Saturated aqueous ammonium chloride solution (1 ml) was added to the mixture and the volatile components were evaporated in vacuo. The residue was partitioned between water (5ml) and chloroform (8ml) and the phases were separated. The organic phase was dried (MgSO₄), filtered, and the solvent evaporated in vacuo to give an orange/brown gum. The gum was stirred with 2-propanol (1 ml) and aqueous hydrochloric acid (5M, 4ml) and heated at 65°C for 3h. The solvents were evaporated in vacuo and the residue was then left to stand overnight before being partitioned between ethyl acetate (15ml) and saturated aqueous sodium carbonate solution (10ml). The phases were separated and the aqueous phase was further extracted with ethyl acetate (3x 10ml). The combined organic phases were washed with brine (10ml), dried (MgSO₄), filtered and the solvents evaporated in vacuo. The residue was purified by chromatography on a silica cartridge (2Og), eluting with an ethyl acetate / cyclohexane gradient (0-100%), then methanol / DCM (0-20%). The required fractions were combined and the solvent was evaporated in vacuo to give the title compound as a colourless gum (135.7mg). LC/MS; Rt 2.82min, MH⁺ 304, 306.

Intermediate 17 Λ/-(2-chloro-4-pyrimidinyl)-Λ/-(2,2,2-trifluoroethyl)-1H-indazol-4- amine

An aliquot (4.5ml) from a solution of Λ/-(2-chloro-4-pyrimidinyl)-2-({[2- (trimethylsilyl)ethyl]oxy}methyl)-2/-/-indazol-4-amine and Λ/-(2-chloro-4-pyrimidinyl)-1 - ({[2-(trimethylsilyl)ethyl]oxy}methyl)-1/-/-indazol-4-amine (isomeric mixture, 920mg) in DMF (18ml) was stirred in a boiling tube under nitrogen. Sodium hydride (60% in mineral oils, 29.4mg) was added to the solution followed by 2-iodo-1 ,1 ,1- thfluoroethane (108μl). The mixture was stirred at room temperature for 22h. The mixture was heated at 80⁰C for 1.5 days before cooling to room temperature. Further sodium hydride (60% in mineral oils, 29mg) was added to the mixture, which was heated at 80⁰C for a further 5h. Saturated aqueous ammonium chloride solution (1 ml) was added to the mixture and the volatile components were evaporated in vacuo. The residue was partitioned between water (5ml) and chloroform (8ml) and the phases were separated. The organic phase was dried (MgSO₄), filtered, and the solvent evaporated in vacuo to give a residue which was purified by chromatography on a silica cartridge (2Og) eluting with an ethyl acetate / cyclohexane gradient (0- 50%) over 20min. The required fractions were combined and the solvent was evaporated in vacuo to give a colourless gum. The gum was stirred with 2-propanol (1 ml) and aqueous hydrochloric acid (5M, 4ml) and heated at 65°C for 2h. The mixture had the solvents evaporated in vacuo and was then left to stand in a fridge for 4 days before being partitioned between ethyl acetate (15ml) and saturated aqueous sodium carbonate solution (10ml). The phases were separated and the aqueous phase was further extracted with ethyl acetate (3x 10ml). The combined organic phases were washed with brine (10ml), dried (MgSO₄), filtered and the solvents evaporated in vacuo. The residue was purified by chromatography on a silica cartridge (2Og), eluting with a methanol / DCM gradient (0-50%). The required fractions were combined and the solvent was evaporated in vacuo to give the crude product, which was further purified on a second silica cartridge (10g). The cartridge was eluted with an ethyl acetate / cyclohexane gradient (0-100%) over 30min, the required fractions were combined and the solvent was evaporated in vacuo to give the title compound as a colourless gum (25.3mg). LC/MS; Rt 3.12min, MH⁺ 328, 330.

Example 41 2-[{2-[(1 , 1 -dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)amino]-4- pyrimidinyl}(1 H-indazol-4-yl)amino]ethanol

A mixture of 2-[(2-chloro-4-pyrimidinyl)(1/-/-indazol-4-yl)amino]ethanol (29mg) and 2,3-dihydro-1 ,2-benzisothiazol-6-amine 1 ,1-dioxide (28mg) in acetone : water : 2M hydrochloric acid (1 ml:1.5ml:20μl) was stirred and heated under reflux for 16h. The solvent was evaporated under a stream of nitrogen. The residue was diluted in methanol and applied to an SPE cartridge (SCX). The column was washed with methanol and the product was released from the column using 10% ammonia in methanol. After concentration of the basic fraction under a stream of nitrogen, the product was purified by mass directed HPLC. The product fractions were reduced to dryness, the residue dissolved in methanol and filtered through an SPE cartridge (aminopropyl). After concentration of the filtrate under a stream of nitrogen, the title compound was obtained (6.8mg). LC/MS; Rt 2.03min, MH⁺ 438.

Similarly prepared were the following:

^* Compound was further purified by a second MDAP prior to aminopropyl SPE

Intermediate 18 2-[(2-chloro-4-pyrimidinyl)(1 /-/-indazol-4-yl)amino]ethanol

A portion (4ml) of a solution of Λ/-(2-chloro-4-pyrimidinyl)-2-({[2- (trimethylsilyl)ethyl]oxy}methyl)-2H-indazol-4-amine and Λ/-(2-chloro-4-pyrimidinyl)-1- ({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 /-/-indazol-4-amine (isomeric mixture, 4.3g) in DMF (48ml) was stirred under nitrogen. Sodium hydride (60% in mineral oils, 46mg) was added to the mixture followed by further DMF (1 ml), and after 5min, cyclobutylbromide (109μl). The mixture was stirred at room temperature for 68h and then heated at 65°C for 3h. After standing at room temperature for 4 days, further sodium hydride (60% in mineral oils, 46mg) was added to the mixture followed by further cyclobutylbromide (109μl). The mixture was heated at 65°C for a total of 2Oh before being left to stand at room temperature for 3 weeks. Saturated aqueous ammonium chloride solution (1ml) was added to the mixture, the volatile components were evaporated in vacuo, water (5ml) added to the residue and the mixture extracted with chloroform (8ml). The phases were separated, the organic phase dried (MgSO₄), filtered, and the solvent evaporated in vacuo. The residue was absorbed onto a silica cartridge (2Og) which had been pre-washed with cyclohexane and was eluted using an ethyl acetate / cyclohexane gradient (0-50%). The required fractions were combined and the solvent was evaporated in vacuo to give a residue which was further purified by chromatography on a silica cartridge (1Og, pre-washed with cyclohexane) eluting with an ethyl acetate / cyclohexane gradient (0-50%). The required fractions were combined and the solvent was evaporated in vacuo. The residue was re-dissolved in DMF (4ml) and was stirred under nitrogen. Sodium hydride (60% in mineral oils, 46mg) was added to the mixture followed by further DMF (1 ml), and after 5min, (2-bromoethoxy)-tert-butyldimethylsilane (247μl). The mixture was stirred at room temperature for 2h, then left to stand at room temperature for 18h. Saturated aqueous ammonium chloride solution (1 ml) was added to the mixture. The volatile components were evaporated in vacuo, water (5ml) added to the residue and the mixture extracted with chloroform (8ml). The phases were separated, the organic phase dried (MgSO₄), filtered, and the solvent evaporated in vacuo to give a brown gum. The residue was heated in 2-propanol (1 ml) and aqueous hydrochloric acid (5M, 5ml) at 60⁰C for 3h, then allowed to stand at room temperature for 16h. The solvents were evaporated in vacuo and saturated aqueous sodium carbonate solution (6ml) was added to the residue. The mixture was extracted with ethyl acetate (4x 10ml), the combined organic phases were dried (MgSO₄), filtered, and the solvent evaporated in vacuo. The residue was absorbed onto the top of a silica cartridge (2Og) and was purified by chromatography (mass directed) eluting with an ethyl acetate / cyclohexane gradient (20-100%) over 20min. The required fractions were combined and the solvent was evaporated in vacuo to give the title compound as a colourless gum (59mg). LC/MS; Rt 2.36min, MH⁺ 290, 292.

Intermediate 19 4-[(2-chloro-4-pyrimidinyl)(1 H-indazol-4-yl)amino]-1 -butanol

An aliquot (4.5ml) from a solution of Λ/-(2-chloro-4-pyrimidinyl)-2-({[2- (trimethylsilyl)ethyl]oxy}methyl)-2H-indazol-4-amine and Λ/-(2-chloro-4-pyrimidinyl)-1 - ({[2-(trimethylsilyl)ethyl]oxy}methyl)-1/-/-indazol-4-amine (isomeric mixture, 920mg) in DMF (18ml) and was stirred in a boiling tube under nitrogen. Sodium hydride (60% in mineral oils, 29.4mg) was added to the solution followed by tert-butyl-(4- iodobutoxy)dimethylsilane (238μl). The mixture was stirred at room temperature for 22h. Saturated aqueous ammonium chloride solution (1 ml) was added to the mixture and the volatile components were evaporated in vacuo. The residue was partitioned between water (5ml) and chloroform (8ml) and the phases were separated. The organic phase was dried (MgSO₄), filtered, and the solvent evaporated in vacuo to give an orange/brown viscous oil. The oil was stirred with 2-propanol (1 ml) and aqueous hydrochloric acid (5M, 4ml) at 65°C for 3h. The solvents were evaporated in vacuo, the residue was then left to stand overnight before partitioning between ethyl acetate (15ml) and saturated aqueous sodium carbonate solution (10ml). The phases were separated and the aqueous phase was further extracted with ethyl acetate (3x 10ml). The combined organic phases were washed with brine (10ml), dried (MgSO₄), filtered and the solvents evaporated in vacuo. The residue was purified by chromatography on a silica cartridge (2Og) eluting with an ethyl acetate / cyclohexane gradient (0-100%), then with methanol / DCM (0-20%). The required fractions were combined and the solvent was evaporated in vacuo to give the title compound as a colourless gum (129.6mg). LC/MS; Rt 2.59min, MH⁺ 318, 320.

Example 58 (2R)-3-[{2-[(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)amino]-4- pyrimidinyl}(1 H-indazol-4-yl)amino]-1 ,2-propanediol

A mixture of (2R)-3-[(2-chloro-4-pyrimidinyl)(1 H-indazol-4-yl)amino]-1 ,2-propanediol (33mg) and 2,3-dihydro-1 ,2-benzisothiazol-6-amine 1 ,1 -dioxide (28mg) in acetone / water / 2M hydrochloric acid (1ml:1.5ml:20μl) was stirred and heated under reflux for 16h. The solvent was evaporated under a stream of nitrogen. The residue was diluted in methanol and applied to an SCX SPE cartridge. The cartridge was washed with methanol and the product released from the column by elution with 10% ammonia in methanol. After concentration under a stream of nitrogen, the product was purified by mass directed HPLC. After evaporation of the solvent from the desired fractions, the residue was dissolved in methanol and eluted through an aminopropyl column. The filtrate was concentrated under a stream of nitrogen, to give the title compound. (33mg). LC/MS; Rt 2.03min, MH⁺ 468.

Intermediate 20 (2R)-3-[(2-chloro-4-pyrimidinyl)(1 H-indazol-4-yl)amino]-1 ,2- propanediol

A mixture of N-(2-chloro-4-pyrimidinyl)-N-{[(4R)-2,2-dimethyl-1 ,3-dioxolan-4- yl]methyl}-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 H-indazol-4-amine (185mg) in hydrochloric acid (5M, 2ml) and propanol (1 ml) was heated at 55°C for 3h. The solvent was then evaporated under vacuum and the residue was left dry at room temperature for 2Oh. The product was then purified by mass directed HPLC. After evaporation of the solvents from the desired fractions, the residue was dissolved in methanol and eluted through an aminopropyl SPE cartridge. After concentration under a stream of nitrogen, the title compound was obtained (34mg). LC/MS; Rt 2.21 min, MH⁺ 320.

Intermediate 21 N-(2-chloro-4-pyrimidinyl)-N-{[(4R)-2,2-dimethyl-1 ,3-dioxolan-4- yl]methyl}-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 H-indazol-4-amine \ /

Si--

A mixture of N-(2-chloro-4-pyrimidinyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 H- indazol-4-amine (360mg) was stirred in DMF (4ml) under an atmosphere of nitrogen. Sodium hydride (60% in mineral oil, 46mg) was added to the mixture followed by (4S)-4-(chloromethyl)-2,2-dimethyl-1 ,3-dioxolane (181 mg, Aldrich). The reaction mixture was stirred at room temperature for 2Oh under nitrogen. The mixture was then heated at 50°C for 4h then at 100⁰C for 2Oh. Sodium hydride (60% in mineral oil, 46mg) and (4R)-4-(chloromethyl)-2,2-dimethyl-1 ,3-dioxolane (181mg) were both added and the reaction mixture stirred at 100⁰C under nitrogen for further 2Oh. Once again sodium hydride (60% in mineral oil, 46mg) and (4R)-4-(chloromethyl)-2,2- dimethyl-1 ,3-dioxolane (181mg) were added and the reaction mixture stirred at 100⁰C under nitrogen for further 2Oh. The mixture was cooled down and saturated ammonium chloride (2ml) was added and the solvents were removed under vacuum. The residues were partitioned between ethyl acetate / chloroform (1 :1 ,10ml) and water (10ml). The phases were separated and the water layer was extracted once again with ethyl acetate / chloroform (1 :1 , 10ml). The organic phases were combined, dried through a hydrophobic frit and concentrated under vacuum. The product was then purified by chromatography on a silica column, eluting with a cyclohexane / ethyl acetate gradient (0-100%), to give, after evaporation of the solvents in vacuo, the desired product (185mg). LC/MS; Rt 3.82min, MH⁺ 490.

Example 59 4-[[2-(1 H-1 ,2,3-benzotriazol-5-ylamino)-4-pyrimidinyl](1 H-indazol-4- yl)amino]-1 -butanol hydrochloride

A mixture of 4-[(2-chloro-4-pyrimidinyl)(1/-/-indazol-4-yl)amino]-1-butanol (22mg) and 1 H-1 ,2,3-benzotriazol-5-amine (20mg) in acetone / water / 2M hydrochloric acid (1 ml:1.5ml:20μl) was stirred and heated under reflux for 16h. The solvent was evaporated under a stream of nitrogen. The residue was dissolved in methanol and applied to an SCX SPE. The cartridge was washed with methanol and the product eluted using 10% ammonia in methanol. After concentration of the basic fractions under a stream of nitrogen, theresidue was purified by mass directed HPLC. After evaporation of the solvents from the desired fractions, the residue was dissolved in methanol and applied to an aminopropyl SPE. The product was released from the column using 10% HCI in methanol. The acidic fractions were concentrated under a stream of nitrogen to give the title compound (14mg). LC/MS; Rt 2.19min, MH⁺ 416.

Example 60 5-({4-[[(1-acetyl-4-piperidinyl)methyl](1/-/-indazol-4-yl)amino]-2- pyrimidinyl}amino)-1 ,3-dihydro-2/-/-benzimidazol-2-one

Acetyl chloride (3.4μl) was added to a solution of 5-({4-[1H-indazol-4-yl(4- pipehdinylmethyl)amino]-2-pyrimidinyl}amino)-1 ,3-dihydro-2/-/-benzimidazol-2-one (21 mg) in DMF (0.5ml). The mixture was stirred at room temperature for 1 h, further acetyl chloride (3.4μl) was added followed by N,N-diethylisopropylamine (8.4μl). The mixture was stirred at room temperature for 1 h, pyridine (8μl) was added. Acetyl chloride (6.8μl) was added to the mixture followed by pyridine (16μl). The mixture was stirred at 5O⁰C for one day before a small quantity of polystyrene-supported benzaldehyde resin was added. The mixture was filtered and the solvent evaporated in vacuo to give a residue which was purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated in vacuo to give the title compound (1.85mg) as a clear gum. LC/MS; Rt 2.21 min, MH⁺ 498.

Example 61 5-({4-[1H-indazol-4-yl(4-piperidinylmethyl)amino]-2-pyrimidinyl}amino)- 1 ,3-dihydro-2/-/-benzimidazol-2-one

To a suspension of phenylmethyl 4-[(1/-/-indazol-4-yl{2-[(2-oxo-2,3-dihydro-1H- benzimidazol-5-yl)amino]-4-pyrimidinyl}amino)methyl]-1-piperidinecarboxylate (0.256g) in ethanol (20ml) was added glacial acetic acid (2ml). This was hydrogenated over palladium on carbon (0.02g, wet, 10%) under an atmosphere of hydrogen at room temperature for 16h. The mixture was filtered through a celite pad, and concentrated in vacuo. The crude product was dissolved in DCM and purified by chromatography on a silica cartridge (2Og), eluting with a (10% ammonia in methanol) / DCM gradient (0%, 5%, 10%, 15%, 20%, 40% and 50%). The appropriate fraction was concentrated in vacuo to yield the title compound as a white solid (0.07g). LC/MS; Rt 1.89min; MH⁺ 456.

Intermediate 22 phenylmethyl 4-[(1H-indazol-4-yl{2-[(2-oxo-2,3-dihydro-1H- benzimidazol-5-yl)amino]-4-pyrimidinyl}amino)methyl]-1-piperidinecarboxylate

A solution of Phenylmethyl 4-{[(2-chloro-4-pyrimidinyl)(1 /-/-indazol-4- yl)amino]methyl}-1-piperidinecarboxylate (0.215g) and 5-aminobenzimidazolone (0.1g) in acetone (9.5ml) / water (5.5ml) / aqueous hydrochloric acid (2M, 0.6ml) was heated in a sealed vessel using a microwave at 120°C for 10min. Further 5- aminobenzimidazolone (0.04g) was added and the reaction heated at 120⁰C for a further 8min before concentrating in vacuo. The crude product was dissolved in methanol, diisopropylethylamine (0.17g) added, the mixture concentrated in vacuo. The residue was redissolved in methanol and pre-adsorbed onto silica. The pre- adsorbed compound was loaded onto a silica cartridge (2Og) and this was eluted with a (10% ammonia in methanol) / dichloromethane gradient (0%, 5%, 10%, 20%, and 35%). Appropriate fractions were combined and concentrated in vacuo to give the title compound as a cream gummy solid (0.26g). LC/MS; Rt 2.59min, MH⁺ 590. Intermediate 23 Phenylmethyl 4-{[(2-chloro-4-pyrimidinyl)(1 /-/-indazol-4- yl)amino]methyl}-1-piperidinecarboxylate

To a solution of phenylmethyl 4-({(2-chloro-4-pyrimidinyl)[1-({[2- (trimethylsilyl)ethyl]oxy}methyl)-1/-/-indazol-4-yl]amino}methyl)-1- piperidinecarboxylate and phenylmethyl 4-({(2-chloro-4-pyrimidinyl)[2-({[2- (trimethylsilyl)ethyl]oxy}methyl)-2H-indazol-4-yl]amino}methyl)-1- pipehdinecarboxylate (isomeric mixture, 0.635g) in IPA (10ml) was added aqueous hydrochloric acid (5M, 16ml). This was heated at 55°C for 7h before cooling. The reaction mixture was concentrated in vacuo and basified with aqueous sodium hydroxide. It was extracted with ethyl acetate (150ml, 100ml, and 100ml) and the combined organics were washed with brine (100ml) and concentrated in vacuo. The crude product was dissolved in DCM and purified by chromatography on a silica SPE cartridge (2Og), eluting with ethyl acetate in DCM (0%, 5%, 10%, 20%, 50%, and 100%) and then methanol in ethyl acetate (25%, 50%). Appropriate fractions were combined and concentrated in vacuo to give the title compound as white foam (0.235g). LC/MS: Rt 3.41 min

Intermediate 24 Phenylmethyl 4-({(2-chloro-4-pyrimidinyl)[1-({[2- (trimethylsilyl)ethyl]oxy}methyl)-1H-indazol-4-yl]amino}rnethyl)-1- piperidinecarboxylate mixture with phenylmethyl 4-({(2-chloro-4-pyrimidinyl)[2-({[2- (trimethylsilyl)ethyl]oxy}methyl)-2H-indazol-4-yl]amino}methyl)-1- piperidinecarboxylate

To a solution of N-(2-chloro-4-pyrimidinyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 H- indazol-4-amine and N-(2-chloro-4-pyrimidinyl)-2-({[2-(trimethylsilyl)ethyl]oxy}methyl)- 2H-indazol-4-amine (isomeric mixture, 0.775g) in DMF (12ml) at 4°C was added sodium hydride (60% in mineral oil, 0.087g). After 10min phenylmethyl 4- (bromomethyl)-i-piperidinecarboxylate (0.643g) was added and this was warmed to room temperature and stirred for 18h. The reaction mixture was quenched with ammonium chloride and concentrated in vacuo. The crude product was purified by partitioning between DCM (30ml) and aqueous ammonium chloride (50ml). The organics were purified by chromatography on a silica SPE (5Og), eluting with ethyl acetate in DCM (0%, 2.5%, 5%, 7.5%, 10%, 20%, 50%). Appropriate fractions were combined and concentrated in vacuo to give the title compound as orange/yellow oil (0.726g). LC/MS: Rt 4.10min

Example 62 N-[4-(1 H-indazol-4-yl{2-[(2-oxo-2,3-dihydro-1 H-benzimidazol-5- yl)amino]-4-pyrimidinyl}amino)butyl]methanesulfonamide

Methanesulphonyl chloride (4.6μl) was added to a solution of 5-({4-[(4- aminobutyl)(1H-indazol-4-yl)amino]-2-pyrimidinyl}amino)-1 ,3-dihydro-2H- benzimidazol-2-one (23.9mg) in DMF (0.5ml). The mixture was stirred at room temperature for 1 h, further methanesulphonyl chloride (4.6μl) was added followed by N,N-diethylisopropylamine (9.4μl). A small quantity of polystyrene-supported benzaldehyde resin was added and the mixture left for 1 h. The reaction was filtered and the filtrate concentrated in vacuo to give a residue which was purified by mass- directed HPLC. The required fractions were combined and the solvent evaporated in vacuo to give residues which were further purified by mass-directed auto preparative HPLC. The required fractions were combined and the solvent evaporated in vacuo to give the title compound (1.14mg) as a colourless gum. LC/MS; Rt 2.15min, MH⁺ 508.

Example 63 N-[5-(1 H-indazol-4-yl{2-[(2-oxo-2,3-dihydro-1 H-benzimidazol-5- yl)amino]-4-pyrimidinyl}amino)pentyl]methanesulfonamide

Methanesulphonyl chloride (2μl) was added to a solution of 5-({4-[(5- aminopentyl)(1 /-/-indazol-4-yl)amino]-2-pyrimidinyl}amino)-1 ,3-dihydro-2/-/- benzimidazol-2-one (10.7mg) in DMF (0.5ml). The mixture was stirred at room temperature for 1 h, further methanesulphonyl chloride (2μl) was added followed by N,N-diethylisopropylamine (4.2μl). A small quantity of polystyrene-supported benzaldehyde resin was added and the mixture left for 1 h before being filtered and the filtrate concentrated in vacuo to give a residue which was purified by mass- directed HPLC. The required fractions were combined and the solvent evaporated in vacuo to give residues which were further purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated in vacuo to give the title compound (0.4mg) as a colourless gum. LC/MS; Rt 2.23min, MH⁺ 522.

Example 64 N-[3-(1 H-indazol-4-yl{2-[(2-oxo-2,3-dihydro-1 H-benzimidazol-5- yl)amino]-4-pyrimidinyl}amino)propyl]methanesulfonamide formate

Methanesulphonyl chloride (9.3μl) was added to a solution of 5-({4-[(3- aminopropyl)(1H-indazol-4-yl)amino]-2-pyrimidinyl}amino)-1 ,3-dihydro-2/-/- benzimidazol-2-one (25mg) in pyridine (0.5ml). The mixture was stirred at room temperature for 2Oh and further methanesulphonyl chloride (4.65μl) was added. The mixture was stirred at room temperature for 1 h before the volatiles were evaporated in vacuo to give a residue which was purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated in vacuo to give the title compound (7.6mg). LC/MS; Rt 2.17min, MH⁺ 494.

Example 65 3-({4-[[3-(diethylamino)propyl](1 H-indazol-4-yl)amino]-2- pyrimidinyl}amino)benzenesulfonamide formate

Cone, hydrochloric acid (20μl) was added to a mixture of Λ/-(2-chloro-4-pyrimidinyl)- N',N'-diethyl-N -1H-indazol-4-yl-1 ,3-propanediamine (37.5mg) and 3- aminobenzenesulphonamide (52mg) in acetone (1.5ml) and water (1 ml) and the reaction heated at 70⁰C for 18h. The solvent was evaporated in vacuo and the residue was purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated in vacuo to give a residue, which was triturated with ether and dried to give the title compound as a white solid (40.7mg). LC/MS; Rt 1.94min, MH⁺ 495.

Intermediate 25 N-(2-chloro-4-pyrimidinyl)-N',N'-diethyl-N-1 H-indazol-4-yl-1 ,3- propanediamine

A solution of N-(2-chloro-4-pyrimidinyl)-N',N'-diethyl-N-[1-({[2-

(trimethylsilyl)ethyl]oxy}methyl)-1 H-indazol-7-yl]-1 ,3-propanediamine and N-(2- chloro-4-pyrimidinyl)-N',N'-diethyl-N-[2-({[2-(thmethylsilyl)ethyl]oxy}methyl)-2H- indazol-7-yl]-1 ,3-propanediamine (isomeric mixture, 96.2mg) in 2-propanol (2ml) and aqueous hydrochloric acid (5M, 4.6ml) was heated at 55°C for 2.5h. The solvents were evaporated in vacuo and aqueous sodium hydroxide solution (2M) was added to the residue until the pH of the solution was 14. The mixture was extracted with ethyl acetate (30ml), the phases separated and the aqueous phase extracted with further ethyl acetate (2x1 OmI). The organic phases were combined, washed with water (10ml), dried, filtered, and the solvents evaporated in vacuo. The residue was purified by chromatography on a silica cartridge (5g), eluting with an ethyl acetate / cyclohexane gradient (0-100%) over 20min, followed by a methanol / DCM gradient (0-25%) over 15min. The required fractions were combined and the solvent was evaporated in vacuo to give the title compound as a white solid (37.5mg). LC/MS; Rt 2.08min, MH⁺ 359, 361.

Intermediate 26 N-(2-chloro-4-pyrimidinyl)-N',N'-diethyl-N-[1-({[2-

(trimethylsilyl)ethyl]oxy}methyl)-1 H-indazol-7-yl]-1 ,3-propanediamine mixture with N- (2-chloro-4-pyrimidinyl)-N',N¹-diethyl-N-[2-({[2-(trimethylsilyl)ethyl]oxy}methyl)-2H- indazol-7-yl]-1 ,3-propanediamine

A stirred solution of N-(2-chloro-4-pyrimidinyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)- 1 H-indazol-4-amine and N-(2-chloro-4-pyrimidinyl)-2-({[2-

(trimethylsilyl)ethyl]oxy}methyl)-2H-indazol-4-amine (isomeric mixture, 1.Og) in DMF (12ml) under nitrogen was cooled using an ice bath before sodium hydride (60% in mineral oil, 128mg) was added to the mixture followed 10min later by 3- diethylaminopropylchloride hydrochloride (480mg). The cooling bath was removed and the mixture allowed to stir at room temperature for 2 days before further sodium hydride (60% in mineral oil, 128mg) was added to the mixture. The mixture was stirred at room temperature for one day, further sodium hydride (60% in mineral oil, 52mg) was added and the mixture stirred for 2 days. Saturated aqueous ammonium chloride solution (10ml) was added to the mixture followed by chloroform (20ml) and the phases were separated (hydrophobic frit). The volatile components were evaporated from the organic phase in vacuo and the residue was purified by dissolving in methanol and applying to a SCX SPE cartridge. The cartridge was washed with methanol and the product eluted with 10% 0.880 ammonia solution in methanol. The ammonia fractions were evaporated in vacuo to give an oily residue which was further purified by chromatography on a silica cartridge (5Og) using a gradient of (1 % triethylamine in methanol) / DCM (0-15%). The required fractions were combined and the solvent evaporated in vacuo to give the title compound as a brown oil (650mg). LC/MS; Rt 2.75 and 2.82min, MH⁺ 489/491.

Example 66 Λ/⁴-[3-(diethylamino)propyl]-Λ/²-(1 , 1 -dioxido-2,3-dihydro-1 ,2- benzisothiazol-5-yl)-N⁴-1H-indazol-4-yl-2,4-pyrimidinediamine formate

OH

Cone, hydrochloric acid (20μl) was added to a mixture of Λ/-(2-chloro-4-pyrimidinyl)- Λ/',Λ/^'-diethyl-Λ/-1 /-/-indazol-4-yl-1 ,3-propanediamine (20mg) and 2,3-dihydro-1 ,2- benzisothiazol-5-amine 1 ,1 -dioxide (26mg) in acetone (1.5ml) and water (1 ml) and the mixture heated at 70°C overnight. The solvent was evaporated in vacuo and the residue was purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated in vacuo to give the title compound as a colourless gum (14mg). LC/MS; Rt 2.00min, MH⁺ 507.

Intermediate 27 2,3-dihydro-1 ,2-benzisothiazol-5-amine 1 ,1 -dioxide

Zinc dust (2.4g) was added portion wise to a stirred suspension of 5-amino-1 ,2- benzisothiazol-3(2H)-one 1 ,1-dioxide (820mg) in concentrated hydrochloric acid (10ml). The mixture was stirred at room temperature for 2Oh before saturated aqueous sodium hydrogen carbonate solution was added to the mixture until the pH of the solution was 8. The mixture was filtered and extracted with ethyl acetate (4x 150ml). The combined organic phases were dried (MgSO₄), filtered and the solvents evaporated in vacuo to give the title compound as a yellow solid (230mg). LC/MS; Rt 0.82min, MH⁺ 185.

Example 67 Λ/⁴-[3-(diethylamino)propyl]-N ²-(1 ,1-dioxido-2,3-dihydro-1 ,2- benzisothiazol-6-yl)-N⁴-1H-indazol-4-yl-2,4-pyrimidinediamine formate

OH

Cone, hydrochloric acid (20μl) was added to a mixture of Λ/-(2-chloro-4-pyrimidinyl)- N',N'-diethyl-N-1 H-indazol-4-yl-1 ,3-propanediamine

(2-chloro-4-pyrimidinyl)[3-(diethylamino)propyl]1H-indazol-4-ylamine (20mg) and 2,3- dihydro-1 ,2-benzisothiazol-6-amine 1 ,1-dioxide (26mg) in acetone (1.5ml) and water (1 ml) and the mixture heated at 7O⁰C for 2h. The solvent was evaporated in vacuo and the residue was purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated in vacuo to give the title compound as a colourless gum (20mg). LC/MS; Rt 2.00min, MH⁺ 507. Example 68 methyl 4-[{2-[(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)amino]-4- pyrimidinyl}(1H-indazol-4-yl)amino]butanoate

2,3-Dihydro-1 ,2-benzisothiazol-6-amine 1 ,1-dioxide (9.2mg), water (350μl) and cone, hydrochloric acid (7.1 μl) were added in turn to a solution of methyl 4-[(2-chloro-4- pyrimidinyl)(1/-/-indazol-4-yl)amino]butanoate (7.5mg) in acetone (0.5ml). The mixture was irradiated in a sealed vessel at 130°C using a microwave reactor for 10min. The solvent was evaporated in vacuo and the residue was dissolved in a small volume of methanol and cone, hydrochloric acid (50μl) added. The mixture was stirred before being left to stand overnight. The solvent was evaporated in vacuo and the residue was purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated in vacuo to give the title compound as a white solid (12.6mg). LC/MS; Rt 2.34min, MH⁺ 494.

Intermediate 28 methyl 4-[(2-chloro-4-pyhmidinyl)(1 H-indazol-4-yl)amino]butanoate

To a solution of 4-[(2-chloro-4-pyrimidinyl)(1 H-indazol-4-yl)amino]butanoic acid (26.3mg) in methanol (10ml) was added cone, hydrochloric acid (1 OOμl). The mixture was stirred at room temperature for 2h. The volatiles were evaporated in vacuo to give a residue which was purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated in vacuo to give the title compound (7.5mg). LC/MS; Rt 2.77min, MH⁺ 346, 348. Intermediate 29 4-[(2-chloro-4-pyrimidinyl)(1 H-indazol-4-yl)amino]butanoic acid

Λ/-(2-chloro-4-pyrimidinyl)-2-({[2-(trimethylsilyl)ethyl]oxy}methyl)-2/-/-indazol-4-amine and Λ/-(2-chloro-4-pyrimidinyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1/-/-indazol-4- amine (isomeric mixture, 1.Og) was dissolved in dry DMF (12ml) and was stirred under nitrogen whilst cooling (ice bath). Sodium hydride (60% in mineral oils, 127.2mg) was added to the solution followed after 10min by ethyl-4-bromobutyrate (455μl). The mixture was allowed to warm to room temperature and stirred for 3.5h. Saturated aqueous ammonium chloride solution (10ml) was added and the mixture was partitioned between water (60ml) and ethyl acetate (100ml). The phases were separated and the organic phase was dried (MgSO₄), filtered, and the solvent evaporated in vacuo to give a brown oil. The oil was stirred with 2-propanol (35ml) and aqueous hydrochloric acid (5M, 80.5ml) at 55°C for 2.5h. The 2-propanol was evaporated in vacuo and the resultant mixture was adjusted to pH7 and then partitioned between ethyl acetate (400ml) and water. The phases were separated and the aqueous phase was further washed with ethyl acetate (200ml). The aqueous phase was adjusted to pH2 and again extracted with ethyl acetate before being adjusted to pH6 and the water evaporated in vacuo. The residue was applied to an aminopropyl SPE cartridge pre-washed with methanol, and was eluted with methanol then 10% acetic acid in methanol and appropriate fractions were combined and the solvents evaporated in vacuo. The residue was dissolved in methanol and pre- absorbed onto silica. The silica was applied to the top of a silica cartridge (100g, pre- washed with DCM). The cartridge was eluted using a methanol / DCM gradient (0- 25%), the required fractions were combined and the solvent was evaporated in vacuo to give the title compound as a pale yellow solid (284.8mg). LC/MS; Rt 2.57min, MH⁺ 332, 334.

Example 69 methyl 5-[{2-[(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)amino]- 4-pyrimidinyl}(1/-/-indazol-4-yl)amino]pentanoate

Hydrochloric acid (0.5ml, 5M) was added to a solution of 5-[{2-[(1 ,1-dioxido-2,3- dihydro-1 ,2-benzisothiazol-6-yl)amino]-4-pyrimidinyl}(1/-/-indazol-4- yl)amino]pentanoic acid (9.5mg) in methanol (6ml). The mixture was stirred at room temperature for 2.5h and the solvent was evaporated in vacuo to give a residue which was purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated in vacuo to give the title compound (5.1 mg). LC/MS; Rt 2.45min, MH⁺ 508.

Intermediate 30 5-[{2-[(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)amino]-4- pyhmidinyl}(1 /-/-indazol-4-yl)amino]pentanoic acid

A solution of methyl 5-{(2-chloro-4-pyrimidinyl)[1-({[2-(trimethylsilyl)ethyl]oxy}methyl)- 1H-indazol-4-yl]amino}pentanoate (50mg) in acetone (2ml) was added to 2,3- dihydro-1 ,2-benzisothiazol-6-amine 1 ,1-dioxide (43.8mg) followed by water (2ml) and cone, hydrochloric acid (34μl). The mixture was heated at 130⁰C in a sealed vessel using a microwave reactor for 10min. Further cone, hydrochloric acid (100μl) was added and the mixture heated at 130⁰C in a microwave reactor for a further 15min. The solvent was evaporated in vacuo and the residue was dissolved in a small volume of methanol and applied to an aminopropyl SPE cartridge (10g) which had been pre-washed with methanol. The cartridge was eluted with methanol (3 column volumes) followed by 10% cone, hydrochloric acid in methanol (3 column volumes), and then further cone, hydrochloric acid in methanol solution (2 column volumes). The solvent was evaporated in vacuo and the residue was purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated in vacuo to give the title compound (9.5mg).

Intermediate 3J. methyl 5-{(2-chloro-4-pyrimidinyl)[1-({[2-

(trimethylsilyl)ethyl]oxy}methyl)-1H-indazol-4-yl]amino}pentanoate

N-(2-chloro-4-pyrimidinyl)-2-({[2-(trimethylsilyl)ethyl]oxy}methyl)-2/-/-indazol-4-amine and Λ/-(2-chloro-4-pyrimidinyl)-1 -({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 H-indazol-4- amine (isomeric mixture, 500mg) was dissolved in DMF (12ml) and was stirred under nitrogen whilst cooling (ice bath). Sodium hydride (60% in mineral oils, 63.6mg) was added to the solution followed after 30min by methyl-5-bromovalerate (227.4μl). The mixture was allowed to warm to room temperature and stirred for 19h. Saturated aqueous ammonium chloride solution (5ml) was added and the mixture was partitioned between water (50ml) and ethyl acetate (50ml). The phases were separated and the aqueous phase was extracted with further ethyl acetate (30ml). The combined organic phases were dried (MgSO₄), filtered, and the solvent evaporated in vacuo. The residue was absorbed onto a silica cartridge (5Og, pre- washed with cyclohexane) and was then eluted using an ethyl acetate / cyclohexane gradient (0-100%). The required fractions were combined and the solvent was evaporated in vacuo to give the title compound as a pale yellow oil (234.5mg). LC/MS; Rt 3.78min, MH⁺ 490, 492.

Example 70 4-[{2-[(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)amino]-4- pyrimidinyl}(1 H-indazol-4-yl)amino]butanoic acid

Acetone (10ml), water (7ml) and cone, hydrochloric acid (142.2μl) were added to a mixture of 4-[(2-chloro-4-pyrimidinyl)(1H-indazol-4-yl)amino]butanoic acid (142.4mg) and 2,3-dihydro-1 ,2-benzisothiazol-6-amine 1 ,1 -dioxide (184.8mg). The mixture was heated at 70°C for 17h, the solvent was evaporated in vacuo and the residue purified by dissolving in methanol and applying the solution to a aminopropyl SPE cartridge (10g) which had been pre-washed with methanol. The cartridge was washed with methanol and the product then eluted using a solution of 10% cone, hydrochloric acid in methanol. The required fractions were combined and the solvent evaporated in vacuo to give a residue which was further purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated in vacuo to give the title compound as a white solid (29.3mg). LC/MS; Rt 2.20min, MH⁺ 480.

Example 71 5-[{2-[(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)amino]-4- pyrimidinyl}(1 H-indazol-4-yl)amino]pentanoic acid trifluoroacetate

Acetone (2ml), water (2ml) and cone, hydrochloric acid (100μl) were added to a mixture of methyl 5-{(2-chloro-4-pyrimidinyl)[1-({[2-(trimethylsilyl)ethyl]oxy}methyl)- 1H-indazol-4-yl]amino}pentanoate (100mg) and 2,3-dihydro-1 ,2-benzisothiazol-6- amine 1 ,1-dioxide (87.6mg). The mixture was heated in a sealed vessel at 130⁰C in a microwave reactor for 15min. The solvent was evaporated in vacuo and the residue was purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated in vacuo to give a residue which was triturated with DCM before being further purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated in vacuo to give the title compound as a white solid (6.2mg). LC/MS; Rt 2.26min, MH⁺ 494.

Example 72 Λ/⁴-(3-aminopropyl)-Λ/²-(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)- N⁴-1H-indazol-4-yl-2,4-pyrimidinediamine

Methanol (1 ml) and methylamine (40% aqueous, 1 ml) were added to 2-{3-[{2-[(1 ,1- dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)amino]-4-pyrimidinyl}(1H-indazol-4- yl)amino]propyl}-1H-isoindole-1 ,3(2 H)-dione (8.5mg). The mixture was stirred under nitrogen for 1 h and the solvent was evaporated in vacuo. The white residue was purified by dissolving in methanol and applying the solution to a SCX SPE cartridge which had been pre-washed with methanol. The cartridge was washed with methanol (2x5ml) and the product then eluted using a solution of 10% 0.880 ammonia in methanol. The required fractions were combined and the solvent evaporated in vacuo to give the title compound as a white solid (6.4mg). LC/MS; Rt 1.88min, MH⁺ 451.

Intermediate 32 2-{3-[{2-[(1 , 1 -dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)amino]-4- pyrimidinyl}(1 H-indazol-4-yl)amino]propyl}-1 H-isoindole-1 ,3(2/-/)-dione

2-(3-{(2-chloro-4-pyrimidinyl)[1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-indazol-4- yl]amino}propyl)-1 H -isoindole-1 ,3(2 H)-dione (34.4mg) and 2,3-dihydro-1 ,2- benzisothiazol-6-amine 1 ,1 -dioxide (22.4mg) were stirred in a mixture of acetone (1.5ml), water (1ml) and cone, hydrochloric acid (40μl). The mixture was heated at 130⁰C in a sealed vessel using a microwave reactor for 10min. The solvent was evaporated in vacuo and the residue was purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated in vacuo to give the title compound as a yellow solid (1.9mg). LC/MS; Rt 2.52min, MH⁺ 581.

Intermediate 33 2-(3-{(2-chloro-4-pyrimidinyl)[1-({[2-(trimethylsilyl)ethyl]oxy}methyl)- 1 H-indazol-4-yl]amino}propyl)-1 H-isoindole-1 ,3(2/-/)-dione

(trimethylsilyl)ethyl]oxy}methyl)-2H-indazol-4-amine (isomeric mixture, 800mg) in DMF (8ml) under nitrogen was cooled using an ice bath before sodium hydride (60% in mineral oil, 80mg) was added to the mixture followed 10min later by N-(3- bromopropyl)phthalimide (858mg). The cooling bath was removed and the mixture allowed to stir at room temperature for 3h before saturated aqueous ammonium chloride solution (3ml) was added to the mixture followed by chloroform (5ml). The volatile components were evaporated in vacuo, water (15ml) was added to the residue and the mixture extracted with ethyl acetate (25ml). The phases were separated and the organic phase was washed with water (3x 15ml), dried (MgSO₄), filtered, and the solvent evaporated in vacuo to give an oily residue which was further purified by chromatography on a silica cartridge (5Og), eluting with an ethyl acetate / cyclohexane gradient (0-100%) over 40min. The required fractions were combined and the solvent evaporated in vacuo to give the title compound as a brown oil (757mg). LC/MS; Rt 3.83min, MH⁺ 563/565.

Example 73 Λ/⁴-(5-aminopentyl)-Λ/²-(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)- N⁴-1H-indazol-4-yl-2,4-pyrimidinediamine

Methanol (1 ml) and methylamine (40% aqueous, 1 ml) were added to 2-{5-[{2-[(1 ,1- dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)amino]-4-pyrimidinyl}(1H-indazol-4- yl)amino]pentyl}-1/-/-isoindole-1 ,3(2H)-dione (5.6mg). The mixture was stirred under nitrogen for 1 h and the solvent was evaporated in vacuo. The white residue was purified by dissolving in methanol and applying the solution to a SCX SPE cartridge which had been pre-washed with methanol. The cartridge was washed with methanol (2x5ml) and the product then eluted using a solution of 10% 0.880 ammonia in methanol. The required fractions were combined and the solvent evaporated in vacuo to give the title compound as a white solid (6.3mg). LC/MS; Rt 2.00min, MH⁺ 479.

Intermediate 34 2-{5-[{2-[(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)amino]-4- pyrimidinyl}(1 H-indazol-4-yl)amino]pentyl}-1 H-isoindole-1 ,3(2 H)-dione

Acetone (3ml), water (2ml) and cone, hydrochloric acid (80μl) were added to a mixture of 2-(5-{(2-chloro-4-pyrimidinyl)[1 -({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 H- indazol-4-yl]amino}pentyl)-1H-isoindole-1 ,3(2H)-dione (200mg) and 2,3-dihydro-1 ,2- benzisothiazol-6-amine 1 ,1-dioxide (124.5mg). The mixture was heated at 13O⁰C in a sealed vial using a microwave reactor for 10min. The solvent was evaporated in vacuo and the residue was pre-absorbed onto Florisil. The pre-absorbed solid was applied to the top of a silica SPE cartridge (2Og) and a frit placed on top. The cartridge was eluted with a methanol / DCM gradient (0-50%) over 30min. The required fractions were combined and the solvent evaporated in vacuo to give a brown oil which was further purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated in vacuo to give the title compound as a yellow solid (7.4mg). LC/MS; Rt 2.68min, MH⁺ 609.

Intermediate 35 2-(5-{(2-chloro-4-pyrimidinyl)[1-({[2-(trimethylsilyl)ethyl]oxy}methyl)- 1 /-/-indazol-4-yl]amino}pentyl)-1 H-isoindole-1 ,3(2/-/)-dione

(trimethylsilyl)ethyl]oxy}methyl)-2H-indazol-4-amine (isomeric mixture, 800mg) in DMF (8ml) under nitrogen was cooled using an ice bath before sodium hydride (60% in mineral oil, 80mg) was added to the mixture followed 10min later by N-(5- bromopentyl)phthalimide (1.2g). The cooling bath was removed and the mixture allowed to stir at room temperature for 3h before saturated aqueous ammonium chloride solution (3ml) was added to the mixture followed by chloroform (5ml). The volatile components were evaporated in vacuo and water (15ml) added to the residue. The mixture was extracted with ethyl acetate (25ml). The phases were separated and the organic phase was washed with water (3x 15ml), dried (MgSO₄), filtered, and the solvent evaporated in vacuo to give an oily residue which was further purified by chromatography on a silica cartridge (5Og), eluting with an ethyl acetate / cyclohexane gradient (0-100%) over 40min. The required fractions were combined and the solvent evaporated in vacuo to give the title compound as a brown oil (568mg). LC/MS; Rt 3.99min, MH⁺ 591/593.

Example 74 5-({4-[(3-aminopropyl)(1 H-indazol-4-yl)amino]-2-pyrimidinyl}amino)-1 ,3- dihydro-2H-benzimidazol-2-one

Methanol (14ml) and methylamine (40% aqueous, 14ml) were added to 2-[3-(M-I- indazol-4-yl{2-[(2-oxo-2,3-dihydro-1 H-benzimidazol-5-yl)amino]-4- pyrimidinyl}amino)propyl]-1/-/-isoindole-1 ,3(2/-/)-dione trifluoroacetate (320mg). The mixture was stirred under nitrogen for 1 h and the solvent evaporated in vacuo. The residue was dissolved in methanol and applied to a SCX SPE cartridge (2Og). The cartridge was washed with methanol (3x) and the product eluted using a solution of 10% 0.880 ammonia in methanol. The required fractions were combined and the HHlvent evaporated in vacuo. The residue was further purified by dissolving in methanol and pre-absorbing the solution onto Florisil. The pre-absorbed solid was applied to a silica SPE cartridge (5Og) and a frit placed on top. The cartridge was eluted with a gradient of (1% triethylamine in methanol) / DCM (0-15%) over 30min followed by 50% methanol / DCM. The required fractions were combined and the solvent evaporated in vacuo to give the title compound (69mg). LC/MS; Rt 1.77min, MH⁺ 416.

Intermediate 36 2-[3-(1 H-indazol-4-yl{2-[(2-oxo-2,3-dihydro-1 H-benzimidazol-5- yl)amino]-4-pyrimidinyl}amino)propyl]-1 H-isoindole-1 ,3(2H)-dione trifluoroacetate

IPA (5ml) and aqueous hydrochloric acid (5M, 10ml) were added to 2-(3-{(2-chloro-4- pyrimidinyl)[1 -({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 H-indazol-4-yl]amino}propyl)-1 H- isoindole-1 ,3(2H)-dione (757mg). The mixture was heated at 55°C for 5.5h and the solvents were evaporated in vacuo. Acetone (3ml), water (2ml) and cone, hydrochloric acid (80μl) were added to the residue, followed by 5- aminobenzimidazole (296mg). The mixture was heated at 130°C in a sealed vial using a microwave reactor for 10min and the solvents were evaporated in vacuo. The residue was dissolved in methanol and pre-absorbed onto Florisil, the pre- absorbed solid was applied to the top of a silica SPE cartridge (10Og) and a frit placed on top. The cartridge was eluted with a methanol / DCM gradient (0-50%). The required fractions were combined and the solvent evaporated in vacuo to give a yellow solid. A portion of the solid (20mg) was further purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated in vacuo to give the title compound (13.4mg). LC/MS; Rt 2.36min, MH⁺ 546.

Example 75 5-({4-[(4-aminobutyl)(1 H-indazol-4-yl)amino]-2-pyrimidinyl}amino)-1 ,3- dihydro-2H-benzimidazol-2-one

Methanol (14ml) and methylamine (40% aqueous, 14ml) were added to 2-[4-(1/-/- indazol-4-yl{2-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)amino]-4- pyrimidinyl}amino)butyl]-1 /-/-isoindole-1 ,3(2H)-dione trifluoroacetate (280mg). The mixture was stirred under nitrogen for 1 h, and the solvent evaporated in vacuo. The residue was dissolved in methanol and applied to a SCX SPE cartridge(20g) that had been pre-washed with methanol. The cartridge was washed with methanol and the product then eluted using a solution of 10% 0.880 ammonia in methanol. The required fractions were combined and the solvent evaporated in vacuo. The residue was dissolved in methanol and pre-absorbed onto Florisil. The pre-absorbed solid was applied to the top of a silica SPE cartridge (5Og) and a frit placed on top. The cartridge was eluted with a methanol / DCM gradient (0-50%) over 30min, followed by 50% methanol / DCM and then methanol. The required fractions were combined and the solvent evaporated in vacuo to give the title compound (78mg). LC/MS; Rt 1.78min, MH⁺ 430.

Intermediate 37 2-[4-(1 H-indazol-4-yl{2-[(2-oxo-2,3-dihydro-1 H-benzimidazol-5- yl)amino]-4-pyrimidinyl}amino)butyl]-1 H-isoindole-1 ,3(2/-/)-dione trifluoroacetate

IPA (5ml) and aqueous hydrochloric acid (5M₁ 10ml) were added to 2-(4-{(2-chloro-4- pyrimidinyl)[1 -({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 H-indazol-4-yl]amino}butyl)-1 H- isoindole-1 ,3(2/-/)-dione (687mg). The mixture was heated at 55°C for 5.5h before the solvents were evaporated in vacuo. Acetone (3ml), water (2ml) and cone, hydrochloric acid (80μl) were added to the residue, followed by 5- aminobenzimidazole (263mg). The mixture was heated at 130⁰C in a sealed vial using a microwave reactor for 10min and the solvents were evaporated in vacuo. The residue was dissolved in methanol and pre-absorbed onto Florisil. The pre- absorbed solid was applied to the top of a silica SPE cartridge (100g) and a frit placed on top. The cartridge was eluted with a methanol / DCM gradient (0-50%). The required fractions were combined and the solvent evaporated in vacuo to give a yellow solid. A portion of the solid (20mg) was further purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated in vacuo to give the title compound (12mg). LC/MS; Rt 2.40min, MH⁺ 560.

Intermediate 38 2-(4-{(2-chloro-4-pyrimidinyl)[1-({[2-(trimethylsilyl)ethyl]oxy}methyl)- 1 H-indazol-4-yl]amino}butyl)-1 H-isoindole-1 ,3(2/-/)-dione

(trimethylsilyl)ethyl]oxy}methyl)-2H-indazol-4-amine (isomeric mixture, 800mg) in DMF (8ml) under nitrogen was cooled using an ice bath before sodium hydride (60% in mineral oil, 80mg) was added to the mixture followed 10min later by N-(4- bromobutyl)phthalimide (902mg). The cooling bath was removed and the mixture allowed to stir at room temperature for 3h before saturated aqueous ammonium chloride solution (3ml) was added to the mixture followed by chloroform (5ml). The volatile components were evaporated in vacuo, water (15ml) added to the residue and the mixture extracted with ethyl acetate (25ml). The phases were separated and the organic phase was washed with water (3x 15ml), dried (MgSO₄), filtered, and the solvent evaporated in vacuo to give an oily residue which was further purified by chromatography on a silica cartridge (5Og), eluting with a gradient of ethyl acetate / cyclohexane (0-100%) over 40min. The required fractions were combined and the solvent evaporated in vacuo to give the title compound as a brown oil (687mg). LC/MS; Rt 3.91 min, MH⁺ 577/579.

Example 76 5-({4-[(5-aminopentyl)(1 H-indazol-4-yl)amino]-2-pyrimidinyl}amino)-1 ,3- dihydro-2H-benzimidazol-2-one

Methanol (14ml) and methylamine (40% aqueous, 14ml) were added to 2-[5-(1H- indazol-4-yl{2-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)amino]-4- pyrimidinyl}amino)pentyl]-1/-/-isoindole-1 ,3(2/-/)-dione trifluoroacetate (150mg). The mixture was stirred under nitrogen for 1 h and the solvent evaporated in vacuo. The residue was dissolved in methanol and the solution applied to a SCX SPE cartridge (2Og) that had been pre-washed with methanol. The cartridge was washed with methanol and the product then eluted using a solution of 10% 0.880 ammonia in methanol. The required fractions were combined and the solvent evaporated in vacuo. The residue was dissolved in methanol and pre-absorbed onto Florisil. The pre-absorbed solid was applied to the top of a silica SPE cartridge (5Og) and a frit placed on top. The cartridge was eluted with a methanol / DCM gradient (0-50%) over 30min, followed by 50% methanol / DCM and then methanol. The required fractions were combined and the solvent evaporated in vacuo to give the title compound (27mg). LC/MS; Rt 1.85min, MH⁺ 444.

Intermediate 39 2-[5-(1 H-indazol-4-yl{2-[(2-oxo-2,3-dihydro-1 H-benzimidazol-5- yl)amino]-4-pyrimidinyl}amino)pentyl]-1 /-/-isoindole-1 ,3(2/-/)-dione trifluoroacetate

IPA (5ml) and aqueous hydrochloric acid (5M, 10ml) were added to 2-(5-{(2-chloro-4- pyrimidinyl)[1 -({[2-(trimethylsilyl)ethyl]oxy}methyl)-1 H-indazol-4-yl]amino}pentyl)-1 H- isoindole-1 ,3(2H)-dione (568mg). The mixture was heated at 55°C for 5.5h and the solvents were evaporated in vacuo. Acetone (3ml), water (2ml) and cone, hydrochloric acid (80μl) were added to the residue, followed by 5- aminobenzimidazole (215mg). The mixture was heated at 130°C in a sealed vial using a microwave reactor for 10min and the solvents were evaporated in vacuo. The residue was dissolved in methanol and pre-absorbed onto Florisil. The pre- absorbed solid was applied to the top of a silica SPE cartridge (100g) and a frit placed on top. The cartridge was eluted with a methanol / DCM gradient (0-50%). The required fractions were combined and the solvent evaporated in vacuo to give a yellow solid. A portion of the solid (20mg) was further purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated in vacuo to give the title compound (11.4mg). LC/MS; Rt 2.52min, MH⁺ 574.

Example 77 N-[3-(1 H-indazol-4-yl{2-[(2-oxo-2,3-dihydro-1 H-benzimidazol-5- yl)amino]-4-pyrimidinyl}amino)propyl]acetamide formate

Acetyl chloride (4.3μl) was added to a solution of 5-({4-[(3-aminopropyl)(1H-indazol- 4-yl)amino]-2-pyrimidinyl}amino)-1 ,3-dihydro-2/-/-benzimidazol-2-one (25mg) in DMF (0.5ml). The mixture was stirred at room temperature for 1.5h, further acetyl chloride (4.3μl) added and the mixture stirred at room temperature for 1.5 days. N,N- Diethylisopropylamine (10.5μl) was added to the mixture and stirring continued for 30min. A small quantity of polystyrene-supported benzaldehyde resin was added. The mixture was filtered and the filtrate concentrated in vacuo to give a residue which was purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated in vacuo to give the title compound (4.5mg). LC/MS; Rt 2.04min, MH⁺ 458.

Example 78 N-[4-(1 H-indazol-4-yl{2-[(2-oxo-2,3-dihydro-1 H-benzimidazol-5- yl)amino]-4-pyrimidinyl}amino)butyl]acetamide formate

OH

Acetyl chloride (7.4μl) was added to a solution of 5-({4-[(4-aminobutyl)(1H-indazol-4- yl)amino]-2-pyhmidinyl}amino)-1 ,3-dihydro-2/-/-benzimidazol-2-one (20.1 mg) in DMF (0.5ml). The mixture was stirred at room temperature for 1 h, the solvent evaporated in vacuo and the resulting residue was purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated in vacuo to give the title compound (1.0mg). LC/MS; Rt 2.12min, MH⁺ 472. Example 79 N-[5-(1 H-indazol-4-yl{2-[(2-oxo-2,3-dihydro-1 H-benzimidazol-5- yl)amino]-4-pyrimidinyl}amino)pentyl]acetamide formate

Acetyl chloride (4μl) was added to a solution of 5-({4-[(5-aminopentyl)(1 H-indazol-4- yl)amino]-2-pyrimidinyl}amino)-1 ,3-dihydro-2/-/-benzimidazol-2-one (10.7mg) in DMF (0.5ml). The mixture was stirred at room temperature for 1 h, the solvent evaporated in vacuo and the resulting residue purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated in vacuo to give the title compound (2.4mg). LC/MS; Rt 2.16min, MH⁺ 486.

Example 80 5-({4-[[3-(diethylamino)propyl](1 H-indazol-4-yl)amino]-2- pyrimidinyl}amino)-1 ,2-benzisothiazol-3(2H)-one 1 ,1 -dioxide formate

OH

Cone, hydrochloric acid (20μl) was added to a mixture of Λ/-(2-chloro-4-pyrimidinyl)- N',N'-diethyl-N-1H-indazol-4-yl-1 ,3-propanediamine (20mg) and 5-amino-1,2- benzisothiazol-3(2H)-one 1 ,1 -dioxide (28mg) in acetone (1.5ml) and water (1ml) and the mixture heated at 70⁰C overnight. 5-Amino-1 ,2-benzisothiazol-3(2H)-one 1 ,1- dioxide (28mg) and cone, hydrochloric acid (20μl) were added to the mixture which was subsequently heated in a sealed vessel at 15O⁰C in a microwave reactor for 10min. The solvent was evaporated in vacuo and the residue was purified by mass- directed HPLC. The required fractions were combined and the solvent evaporated in vacuo to give the title compound as a yellow solid (3.4mg). LC/MS; Rt 2.00min, MH⁺ 521.

Intermediate 40 5-amino-1 ,2-benzisothiazol-3(2H)-one 1 ,1-dioxide

A vigorously stirred solution of 5-nitro-1 ,2-benzisothiazol-3(2H)-one 1 ,1-dioxide (Journal of Heterocyclic Chemistry 1986, 23(4), 1253-5, 1.99g) in ethanol (80ml) was hydrogenated at room temperature and 1 atmosphere of pressure using palladium on carbon catalyst (400mg) for 2 days. The mixture was filtered and the solvent was evaporated in vacuo, the residue was re-dissolved in ethanol (80ml) and was hydrogenated at room temperature and 1 atmosphere of pressure using palladium on carbon catalyst (400mg) for a further one day. The mixture was filtered and the solvent was evaporated in vacuo, the residue was dissolved in a small quantity of methanol, and pre-absorbed onto silica. The solid was placed onto the top of a silica cartridge (5Og) and a frit was placed onto the top of the solid before the cartridge was eluted using a (1 % triethylamine in methanol) / DCM gradient (0-15%). The required fractions were combined and the solvent was evaporated in vacuo to give 5-amino- 1 ,2-benzisothiazol-3(2H)-one 1 ,1-dioxide as a brown oil (603mg). LC/MS; Rt 1.68min, [M-HV 197.

Example 81 Λ/²-{2-[(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)amino]-5-fluoro- 4-pyrimidinyl}-/v²-1H-indazol-4-yl-Λ/¹-methylglycinamide trifluoroacetate

From a solution of Λ/-(2-chloro-5-fluoro-4-pyrimidinyl)-1-({[2-

(thmethylsilyl)ethyl]oxy}methyl)-1 H-indazol-4-amine (1.9g) in DMF (38ml) a 4ml aliquot was placed into a boiling tube and cesium carbonate (216mg) was added to it followed by 2-chloro-Λ/-methylacetamide (65.7mg). The mixture was heated at 80⁰C under nitrogen for 48h, further 2-chloro-Λ/-methylacetamide (66 mg) was added and heating continued for 3 days. After cooling, the solvent was evaporated from the mixture under a stream of nitrogen. The residue was partitioned between 10% aqueous sodium bicarbonate solution (5ml) and chloroform (6ml). The phases were separated and the organic layer was dried (MgSO₄), filtered, and the solvent evaporated under a stream of nitrogen. The residue was purified by mass-directed normal phase preparative chromatography on a silica cartridge (2Og) eluting with an ethyl acetate / cyclohexane gradient (5-70%) over 20min. The required fractions were combined and the solvent was evaporated under a stream of nitrogen. The residue (11 1 mg) was dissolved in IPA (4ml) and the solution divided into two equal parts. To one half was added cone, hydrochloric acid (100μl) and 2,3-dihydro-1 ,2- benzisothiazol-6-amine 1 ,1-dioxide (26.4mg) and the mixture was heated in a sealed vessel using a microwave reactor for 30min at 160⁰C. The solvent was evaporated under a stream of nitrogen and the residue was purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated under a stream of nitrogen to give a residue which was further purified by reverse phase HPLC. The required fractions were again combined and the solvent evaporated under a stream of nitrogen to give the title compound (5.3mg). LC/MS; Rt 2.50min, MH⁺ 483.

Example 82 (±)-A/²-(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)-5-fluoro-A/⁴-1H- indazol-4-yl-Λ/⁴-(tetrahydro-2-furanylmethyl)-2,4-pyrimidinediamine trifluoroacetate

From a solution of N-(2-chloro-5-fluoro-4-pyrimidinyl)-1-({[2-

(trimethylsilyl)ethyl]oxy}methyl)-1 H-indazol-4-amine (1.9g) in DMF (38ml) a 4ml aliquot was placed into a boiling tube and cesium carbonate (216mg) was added to it followed by racemic 2-(bromomethyl)tetrahydrofuran (100.8mg). The mixture was heated at 80⁰C under nitrogen for 48h. After cooling, the solvent was evaporated from the mixture under a stream of nitrogen. The residue was partitioned between 10% aqueous sodium bicarbonate solution (5ml) and chloroform (6ml). The phases were separated and the organic layer was dried (MgSO₄), filtered, and the solvent evaporated under a stream of nitrogen. The residue was purified by mass-directed normal phase preparative chromatography on a silica cartridge (2Og) eluting with an ethyl acetate / cyclohexane gradient (0-50%) over 20min. The required fractions were combined and the solvent was evaporated under a stream of nitrogen. The residue (207mg) was dissolved in IPA (4ml) and the solution divided into two equal parts. To one part was added cone, hydrochloric acid (100μl) and 2,3-dihydro-1 ,2- benzisothiazol-6-amine 1 ,1-dioxide (48.0mg) and the mixture was heated in a sealed vessel using a microwave reactor for 30min at 160⁰C. The solvent was evaporated under a stream of nitrogen and the residue was purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated under a stream of nitrogen to give a residue which was further purified by reverse phase HPLC. The required fractions were again combined and the solvent evaporated under a stream of nitrogen to give the title compound (13.4mg). LC/MS; Rt 2.87min, MH⁺ 496.

Example 83 /V⁴-(2-aminoethyl)-Λ/²-(1 ,1-dioxido-2,3-dihydro-1-benzothien-6-yl)-5- fluoro-N⁴-1H-indazol-4-yl-2,4-pyrimidinediamine trifluoroacetate

From a solution of N-(2-chloro-5-fluoro-4-pyrimidinyl)-1-({[2-

(trimethylsilyl)ethyl]oxy}methyl)-1 H-indazol-4-amine (1.9g) in DMF (38ml) a 4ml aliquot was placed into a boiling tube and cesium carbonate (216mg) was added to it followed by 1 ,1-dimethylethyl (2-bromoethyl)carbamate (136.9mg). The mixture was heated at 8O⁰C under nitrogen for 48h before further 1 ,1-dimethylethyl (2- bromoethyl)carbamate (137 mg) was added and heating continued for 3 days. After cooling, the solvent was evaporated from the mixture under a stream of nitrogen. The residue was partitioned between 10% aqueous sodium bicarbonate solution (5ml) and chloroform (6ml). The phases were separated and the organic layer was dried (MgSO₄), filtered, and the solvent evaporated under a stream of nitrogen. The residue was purified by mass-directed normal phase preparative chromatography on a silica cartridge (2Og) eluting with an ethyl acetate / cyclohexane gradient (0-50%) over 20min. The required fractions were combined and the solvent was evaporated under a stream of nitrogen. The residue (48mg) was dissolved in IPA (4ml) and the solution divided into two equal parts. To one part was added cone, hydrochloric acid (100μl) and (1 ,1-dioxido-2,3-dihydro-1-benzothien-6-yl)amine (9.6mg) and the mixture was heated in a microwave reactor for 30min at 160⁰C. The solvent was evaporated under a stream of nitrogen and the residue was purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated under a stream of nitrogen to give a residue which was further purified by reverse phase HPLC. The required fractions were again combined and the solvent evaporated under a stream of nitrogen to give the title compound (2.1 mg). LC/MS; Rt 2.30min, MH⁺ 454. Example 84 Λ/⁴-(3-aminopropyl)-Λ/²-(1 ,1-dioxido-2,3-dihydro-1-benzothien-6-yl)-5- fluoro-Λ/⁴-1 /-/-indazol-4-yl-2,4-pyrimidinediamine trifluoroacetate

From a solution of N-(2-chloro-5-fluoro-4-pyrimidinyl)-1-({[2-

(trimethylsilyl)ethyl]oxy}methyl)-1 H-indazol-4-amine (1.9g) in DMF (38ml) a 4ml aliquot was placed into a boiling tube and cesium carbonate (216mg) was added to it followed by 1 ,1-dimethylethyl (3-bromopropyl)carbamate (145.4mg). The mixture was heated at 80°C under nitrogen for 3h. After cooling, the solvent was evaporated from the mixture under a stream of nitrogen. The residue was partitioned between 10% aqueous sodium bicarbonate solution (5ml) and chloroform (6ml). The phases were separated and the organic layer was dried (MgSO₄), filtered, and the solvent evaporated under a stream of nitrogen. The residue was purified by mass-directed normal phase preparative chromatography on a silica cartridge (2Og) eluting with an ethyl acetate / cyclohexane gradient (0-50%) over 20min. The required fractions were combined and the solvent was evaporated under a stream of nitrogen. The residue (235mg) was dissolved in IPA (4ml) and the solution divided into two equal parts. To one part was added cone, hydrochloric acid (100μl) and (1 ,1-dioxido-2,3- dihydro-1-benzothien-6-yl)amine (47.2mg) and the mixture was heated in a sealed vessel using a microwave reactor for 30min at 160⁰C. The solvent was evaporated under a stream of nitrogen and the residue was purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated under a stream of nitrogen to give a residue which was further purified by reverse phase HPLC. The required fractions were again combined and the solvent evaporated under a stream of nitrogen to give the title compound (8.1 mg). LC/MS; Rt 2.31 min, MH⁺ 468.

Example 85 Λ/²-{2-[(1 ,1-dioxido-2,3-dihydro-1-benzothien-6-yl)amino]-5-fluoro-4- pyrimidinyl}-Λ/²-1 /-/-indazol-4-yl-Λ/¹-methylglycinamide trifluoroacetate

From a solution of N-(2-chloro-5-fluoro-4-pyrimidinyl)-1-({[2-

(trimethylsilyl)ethyl]oxy}methyl)-1 H-indazol-4-amine (1.9g) in DMF (38ml) a 4ml aliquot was placed into a boiling tube and cesium carbonate (216mg) was added to it followed by 2-chloro-Λ/-methylacetamide (65.7mg). The mixture was heated at 80⁰C under nitrogen for 48h, further 2-chloro-Λ/-methylacetamide (66 mg) was added and heating continued for 3 days. After cooling, the solvent was evaporated from the mixture under a stream of nitrogen. The residue was partitioned between 10% aqueous sodium bicarbonate solution (5ml) and chloroform (6ml). The phases were separated and the organic layer was dried (MgSO₄), filtered, and the solvent evaporated under a stream of nitrogen. The residue was purified by mass-directed normal phase preparative chromatography on a silica cartridge (2Og) eluting with an ethyl acetate / cyclohexane gradient (5-70%) over 20min. The required fractions were combined and the solvent was evaporated under a stream of nitrogen. The residue (11 1 mg) was dissolved in IPA (4ml) and the solution divided into two equal parts. To one part was added cone, hydrochloric acid (100μl) and (1 ,1-dioxido-2,3- dihydro-1-benzothien-6-yl)amine (26.3mg) and the mixture was heated in a sealed vessel using a microwave reactor for 30min at 160⁰C. The solvent was evaporated under a stream of nitrogen and the residue was purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated under a stream of nitrogen to give a residue which was further purified by reverse phase HPLC. The required fractions were again combined and the solvent evaporated under a stream of nitrogen to give the title compound (6.4mg). LC/MS; Rt 2.26min, MH⁺ 482.

Example 86 (±)-N²-(1,1-dioxido-2,3-dihydro-i-benzothien-6-yl)-5-fluoro-N⁴-1H- indazol-4-yl-Λ/⁴-(tetrahydro-2-furanylmethyl)-2,4-pyrimidinediamine trifluoroacetate

From a solution of N-(2-chloro-5-fluoro-4-pyrimidinyl)-1-({[2-

(trimethylsilyl)ethyl]oxy}methyl)-1 H-indazol-4-amine (1.9g) in DMF (38ml) a 4ml aliquot was placed into a boiling tube and cesium carbonate (216mg) was added to it followed by racemic 2-(bromomethyl)tetrahydrofuran (100.8mg). The mixture was heated at 80⁰C under nitrogen for 48h. After cooling, the solvent was evaporated from the mixture under a stream of nitrogen. The residue was partitioned between 10% aqueous sodium bicarbonate solution (5ml) and chloroform (6ml). The phases were separated and the organic layer was dried (MgSO₄), filtered, and the solvent evaporated under a stream of nitrogen. The residue was purified by mass-directed normal phase preparative chromatography on a silica cartridge (2Og) eluting with an ethyl acetate / cyclohexane gradient (0-50%) over 20min. The required fractions were combined and the solvent was evaporated under a stream of nitrogen. The residue (207mg) was dissolved in IPA (4ml) and the solution divided into two equal parts. To one part was added cone, hydrochloric acid (100μl) and (1 ,1-dioxido-2,3- dihydro-1-benzothien-6-yl)amine (47.7mg) and the mixture was heated in a sealed vessel using a microwave reactor for 30min at 160⁰C. The solvent was evaporated under a stream of nitrogen and the residue was purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated under a stream of nitrogen to give a residue which was further purified by a reverse phase HPLC. The required fractions were again combined and the solvent evaporated under a stream of nitrogen to give the title compound (1.5mg). LC/MS; Rt 2.93min, MH⁺ 495.

Example 87 (±)-Λ/²-(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)-5-fluoro-N⁴-1H- indazol-4-yl-Λ/⁴-(tetrahydro-3-furanylmethyl)-2,4-pyrimidinediamine trifluoroacetate

From a solution of Λ/-(2-chloro-5-fluoro-4-pyrimidinyl)-1-({[2-

(trimethylsilyl)ethyl]oxy}methyl)-1/-/-indazol-4-amine (2.1 g) in DMF (42ml) a 4ml aliquot was placed into a boiling tube and cesium carbonate (216mg) was added to it followed by racemic tetrahydro-3-furanylmethyl methanesulfonate (1 10.1 mg, WO 2004096813 A1). The mixture was heated at 80⁰C under nitrogen for 48h, further tetrahydro-3-furanylmethyl methanesulfonate (110 mg) was added and heating continued for 3 days. After cooling, the solvent was evaporated from the mixture under a stream of nitrogen. The residue was partitioned between 10% aqueous sodium bicarbonate solution (5ml) and chloroform (6ml). The phases were separated and the organic layer was dried (MgSO₄), filtered, and the solvent evaporated under a stream of nitrogen. The residue was purified by mass-directed normal phase preparative chromatography on a silica cartridge (2Og) eluting with an ethyl acetate / cyclohexane gradient (0-50%) over 20min. The required fractions were combined and the solvent was evaporated under a stream of nitrogen. The residue (165mg) was dissolved in IPA (4ml) and the solution divided into two equal parts. To one part was added cone, hydrochloric acid (100μl) and 2,3-dihydro-1 ,2-benzisothiazol-6- amine 1 ,1 -dioxide (38.2mg) and the mixture was heated in a microwave reactor for 30min at 160°C. The solvent was evaporated under a stream of nitrogen and the residue was purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated under a stream of nitrogen to give a residue which was further purified by reverse phase HPLC. The required fractions were again combined and the solvent evaporated under a stream of nitrogen to give the title compound (6.5mg). LC/MS; Rt 2.80min, MH⁺ 496.

Example 88 Λ/²-{2-[(1 ,1-dioxido-2,3-dihydro-1-benzothien-6-yl)amino]-5-fluoro-4- pyhmidinyl}-Λ/²-1 H-indazol-4-ylglycinamide thfluoroacetate

From a solution of Λ/-(2-chloro-5-fluoro-4-pyrimidinyl)-1-({[2-

(trimethylsilyl)ethyl]oxy}methyl)-1 /-/-indazol-4-amine (2.1g) in DMF (42ml) a 4ml aliquot was placed into a boiling tube and cesium carbonate (216mg) was added to it followed by 2-chloroacetamide (57.1 mg). The mixture was heated at 80°C under nitrogen for 48h, further 2-chloroacetamide (57 mg) was added and heating continued for 3 days. After cooling, the solvent was evaporated from the mixture under a stream of nitrogen. The residue was partitioned between 10% aqueous sodium bicarbonate solution (5ml) and chloroform (6ml). The phases were separated and the organic layer was dried (MgSO₄), filtered, and the solvent evaporated under a stream of nitrogen. The residue was purified by mass-directed normal phase preparative chromatography on a silica cartridge (2Og) eluting with an ethyl acetate / cyclohexane gradient (5-70%) over 20min. The required fractions were combined and the solvent was evaporated under a stream of nitrogen. The residue was dissolved in IPA (2ml), cone, hydrochloric acid (100μl) and (1 ,1-dioxido-2,3-dihydro- 1-benzothien-6-yl)amine (5.9mg) were added and the mixture was heated in a sealed vessel using a microwave reactor for 30min at 160⁰C. The solvent was evaporated under a stream of nitrogen and the residue was purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated under a stream of nitrogen to give a residue which was further purified by reverse phase HPLC. The required fractions were again combined and the solvent evaporated under a stream of nitrogen to give the title compound (1.8mg). LC/MS; Rt 2.50min, MH⁺ 468.

Example 89 2-[{2-[(1 ,1-dioxido-2,3-dihydro-1-benzothien-6-yl)amino]-5-fluoro-4- pyrimidinyl}(1 H-indazol-4-yl)amino]ethanol trifluoroacetate

From a solution of N-(2-chloro-5-fluoro-4-pyrimidinyl)-1-({[2-

(trimethylsilyl)ethyl]oxy}methyl)-1 H-indazol-4-amine (1.9g) in DMF (38ml), a 4ml aliquot was placed into a boiling tube and cesium carbonate (216mg) was added to it followed by 2-chloroethanol (41 μl). The mixture was heated at 80°C under nitrogen for 18h and then allowed to stand at room temperature for 9 days before sodium iodide (152mg) was added and heating at 80°C continued for a further 5h. [(2- bromoethyl)oxy](1 ,1-dimethylethyl)dimethylsilane (131 μl) was added to the mixture which was heated at 80⁰C under nitrogen for 1 h and then allowed to stand at room temperature overnight. The mixture was heated for a further 8h and then allowed to stand at room temperature overnight. Further [(2-bromoethyl)oxy](1 ,1- dimethylethyl)dimethylsilane (131 μl) was added to the mixture which was heated at 8O⁰C under nitrogen for a further two days After cooling, the solvent was evaporated from the mixture under a stream of nitrogen. The residue was partitioned between 10% aqueous sodium bicarbonate solution (5ml) and chloroform (6ml). The phases were separated and the organic layer was dried (MgSO₄), filtered, and the solvent evaporated under a stream of nitrogen. The residue was purified by chromatography on a silica cartridge (2Og), eluting with an ethyl acetate / cyclohexane gradient (0- 50%) over 20min, using mass directed fraction collection. The required fractions were combined and the solvent was evaporated under a stream of nitrogen. The residue (140mg) was dissolved in IPA (4ml) and the solution divided into two equal parts. To one part was added cone, hydrochloric acid (100μl) and (1 ,1-dioxido-2,3- dihydro-1-benzothien-6-yl)amine (27.9mg) and the mixture was heated in a sealed vial using a microwave reactor for 30min at 160°C. The solvent was evaporated under a stream of nitrogen and the residue was purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated under a stream of nitrogen to give a residue which was further purified by reverse phase HPLC. The required fractions were again combined and the solvent evaporated under a stream of nitrogen to give the title compound (1.7mg). LC/MS; Rt 2.47min, MH⁺ 455.

Example 90 3-[{2-[(1 ,1-dioxido-2,3-dihydro-1-benzothien-6-yl)amino]-5-fluoro-4- pyrimidinyl}(1H-indazol-4-yl)amino]-1-propanol trifluoroacetate

From a solution of N-(2-chloro-5-fluoro-4-pyrimidinyl)-1-({[2-

(trimethylsilyl)ethyl]oxy}methyl)-1 H-indazol-4-amine (1.9g) in DMF (38ml), a 4ml aliquot was placed into a boiling tube and cesium carbonate (216mg) was added to it followed by 3-chloro-1-propanol (44μl). The mixture was heated at 80°C under nitrogen for 18h and then allowed to stand at room temperature for 9 days before sodium iodide (152mg) was added and heating at 80⁰C continued for a further 5h. [(3-bromopropyl)oxy](1 ,1-dimethylethyl)dimethylsilane (141 μl) was added to the mixture which was heated at 8O⁰C under nitrogen for 1 h and then allowed to stand at room temperature overnight. The mixture was heated for a further 8h and then allowed to stand at room temperature overnight. Further [(3-bromopropyl)oxy](1 ,1- dimethylethyl)dimethylsilane (141 μl) was added to the mixture which was heated at 80⁰C under nitrogen for a further two days After cooling, the solvent was evaporated from the mixture under a stream of nitrogen. The residue was partitioned between 10% aqueous sodium bicarbonate solution (5ml) and chloroform (6ml). The phases were separated and the organic layer was dried (MgSO₄), filtered, and the solvent evaporated under a stream of nitrogen. The residue was purified by chromatography on a silica cartridge (2Og), eluting with an ethyl acetate / cyclohexane gradient (0- 50%) over 20min, using mass directed fraction collection. The required fractions were combined and the solvent was evaporated under a stream of nitrogen. The residue (168mg) was dissolved in IPA (4ml) and the solution divided into two equal parts. To one part was added cone, hydrochloric acid (100μl) and (1 ,1-dioxido-2,3- dihydro-1-benzothien-6-yl)amine (32.6mg) and the mixture was heated in a sealed vial using a microwave reactor for 30min at 16O⁰C. The solvent was evaporated under a stream of nitrogen and the residue was purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated under a stream of nitrogen to give a residue which was further purified by reverse phase HPLC. The required fractions were again combined and the solvent evaporated under a stream of nitrogen to give the title compound (11.5mg). LC/MS; Rt 2.27min, MH⁺ 469.

Example 91 4-[{2-[(1 ,1-dioxido-2,3-dihydro-1-benzothien-6-yl)amino]-5-fluoro-4- pyrimidinyl}(1 /-/-indazol-4-yl)amino]-1-butanol trifluoroacetate

From a solution of N-(2-chloro-5-fluoro-4-pyrimidinyl)-1-({[2-

(trimethylsilyl)ethyl]oxy}methyl)-1 H-indazol-4-amine (1.9g) in DMF (38ml), a 4ml aliquot was placed into a boiling tube and cesium carbonate (216mg) was added to it followed by 4-chloro-1-butanol (61 μl). The mixture was heated at 80°C under nitrogen for 18h and then allowed to stand at room temperature for 9 days before sodium iodide (152mg) was added and heating at 80°C continued for a further 5h. [(4-chlorobutyl)oxy](1 ,1-dimethylethyl)dimethylsilane (156μl) was added to the mixture which was heated at 8O⁰C under nitrogen for 1 h and then allowed to stand at room temperature overnight. The mixture was heated for a further 8h and then allowed to stand at room temperature overnight. Further [(4-chlorobutyl)oxy](1 ,1- dimethylethyl)dimethylsilane (156μl) was added to the mixture which was heated at 80⁰C under nitrogen for a further two days After cooling, the solvent was evaporated from the mixture under a stream of nitrogen. The residue was partitioned between 10% aqueous sodium bicarbonate solution (5ml) and chloroform (6ml). The phases were separated and the organic layer was dried (MgSO₄), filtered, and the solvent evaporated under a stream of nitrogen. The residue was purified by chromatography on a silica cartridge (2Og), eluting with an ethyl acetate / cyclohexane gradient (0- 50%) over 20min, using mass directed fraction collection. The required fractions were combined and the solvent was evaporated under a stream of nitrogen. The residue (234mg) was dissolved in IPA (4ml) and the solution divided into two equal parts. To one part was added cone, hydrochloric acid (100μl) and (1 ,1-dioxido-2,3- dihydro-1-benzothien-6-yl)amine (44.3mg) and the mixture was heated in a microwave reactor for 30min at 160⁰C. The solvent was evaporated under a stream of nitrogen and the residue was purified by mass-directed HPLC. The required fractions were combined and the solvent evaporated under a stream of nitrogen to give a residue which was further purified by reverse phase HPLC. The required fractions were again combined and the solvent evaporated under a stream of nitrogen to give the title compound (14.9mg). LC/MS; Rt 2.72min, MH⁺ 483.

Example 92 3-[{5-fluoro-2-[(1 -methyl-1 /-/-indazol-6-yl)amino]-4-pyrimidinyl}(1 H- indazol-4-yl)amino]-1-propanol

To a mixture of 1-acetyl-Λ/-(2-chloro-5-fluoro-4-pyrimidinyl)-Λ/-(3-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}propyl)-1 /-/-indazol-4-amine (7.89g) in 2-propanol (33ml), was added 1 -methyl-1 H-indazol-6-amine (2.67g, AsinEx Limited) and hydrochloric acid (2M, 6.6ml). The resulting mixture was heated at 95⁰C (reflux conditions) under nitrogen for ~25h. The reaction mixture was allowed to cool to room temperature. Water (70 ml) was added and the product precipitated. The dark red suspension was then cooled with a water-ice bath and stirred for 30min. The solid was isolated by filtration, washed with water and the resulting brown solid then dried in vacuo. This residue was partially dissolved in a methanol / chloroform / ethyl acetate mixture and applied to an SPE cartridge (aminopropyl, 7Og). The column was washed with methanol (9x 40ml) to elute the product. After concentration of the methanolic fractions in vacuo, the material was purified by column chromatography (silica, 12Og) eluting with 5% methanol, 1 % triethylamine, in DCM. Appropriate product containing fractions were combined and concentrated in vacuo. Removal of residual solvent under high vacuum for 26h afforded the title compound as an orange/brown gum (3.2g). LC/MS; Rt 2.74min, MH⁺ 433. NMR; [D₆-DMSO] δH 13.29,(11-1, bs), 9.53,(1 H s), 8.10,(1 H, s), 7.99,(1 H, d), 7.91 ,(H, s), 7.89,(1 H₁ s), 7.58,(1 H, d), 7.50,(1 H₁ d), 7.38,(1 H, m), 7.33,(1 H, dd), 7.07,(1 H, d), 4.46,(1H, t), 4.18,(2H, m), 3.93,(3H, s), 3.44,(2H, m), 1.81 , (2H, m).

Intermediate 41 1-acetyl-Λ/-(2-chloro-5-fluoro-4-pyrimidinyl)-Λ/-(3-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}propyl)-1/-/-indazol-4-amine

To a mixture of Λ/-{3-[(2-chloro-5-fluoro-4-pyrimidinyl)(3-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}propyl)amino]-2-methylphenyl}acetamide (7.705g), in chloroform (50ml) was added potassium acetate (1.7Og), acetic acid (1.09g, 1.04ml) acetic anhydride (1.7Og, 1.57ml) and tert-butylnitrite (3.88g, 90% w/w). The resulting yellow suspension was heated at 6O⁰C under nitrogen overnight. The reaction mixture was allowed to cool to room temperature. Aqueous potassium carbonate solution (1 M, 100ml) was added to the mixture followed by chloroform (50ml). The phases were separated and the aqueous phase extracted with chloroform (2x 50ml). The combined organic phases were dried (hydrophobic frit) and concentrated in vacuo to give the title compound as a brown oil (7.93g). LC/MS; Rt 4.19min, MH⁺ 478.

Intermediate 42 Λ/-{3-[(2-chloro-5-fluoro-4-pyrimidinyl)(3-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}propyl)amino]-2-methylphenyl}acetamide

To a stirred solution of of Λ/-{3-[(2-chloro-5-fluoro-4-pyrimidinyl)amino]-2- methylphenyl}acetamide (5.Og), in DMF (50ml), was added potassium carbonate (2.82g) and [(3-bromopropyl)oxy](1 ,1-dimethylethyl)dimethylsilane (4.74g, Aldrich). The resulting mixture was heated at 5O⁰C under nitrogen for 90min and then at 6O⁰C under nitrogen overnight. The reaction mixture was allowed to cool to room temperature and concentrated under vacuum. The resulting residue was partitioned between ethyl acetate (50ml) and water (50ml). The aqueous phase was extracted with ethyl acetate (2 x25ml). The combined organic phases were dried (hydrophobic frit) and concentrated in vacuo. The resulting residue was dried in vacuo, to give title compound (7.705g). LC/MS; Rt 3.75min, MH⁺ 467.

Intermediate 43 Λ/-{3-[(2-chloro-5-fluoro-4-pyrimidinyl)amino]-2- methylphenyl}acetamide

A mixture of 3-acetylamino-2-methylaniline (EP425345A1 , 7.72g) and 2,4-dichloro-5- fluoropyrimidine (7.84g) in methanol : water (1 :3, 188ml) was stirred at 70⁰C for 1 h. The reaction mixture was cooled and then filtered. The residue was washed with ice cold methanol / water (1 :3) and the solid dried in vacuo at 50°C and then at 65°C to give the title compound as a white solid (6.9g). LC/MS; Rt 2.24min, MH⁺ 295 / 297.

Example 93 Λ/²-(1 ,1-dioxido-2,3-dihydro- 1 ,2-benzisothiazol-6-yl)-5-fluoro-Λ/⁴- 1 H- indazol-4-yl-Λ/⁴-[3-(methyloxy)propyl]-2,4-pyrimidinediamine

To a mixture of 1-acetyl-Λ/-(2-chloro-5-fluoro-4-pyrimidinyl)-Λ/-[3-(methyloxy)propyl]- 1H-indazol-4-amine (6.23 g) in IPA (33ml) was added 2,3-dihydro-1 ,2-benzisothiazol- 6-amine 1 ,1 -dioxide (3.41 g) and hydrochloric acid (2M, 6.6ml). The resulting mixture was heated at reflux for ~25h. The IPA was evaporated in vacuo and water (30 ml) and ethyl acetate (50 ml) added to the residue. Saturated aqueous solution of sodium hydrogen carbonate was added and the resulting mixture was further diluted with water and ethyl acetate / DCM (1 :1 ) so that 250ml of aqueous layer and 250ml of organic layer were obtained. The phases were separated and the aqueous phase was extracted with DCM (4x 100ml). The combined organics, which contained some of brown solid, were concentrated in vacuo to give a yellow-brown solid (8.175g). 0.985g of this residue was adsorbed onto florisil and purified by chromatography on a silica cartridge, eluting with a (methanol + 1% triethylamine) / DCM gradient (0-30%), to give, after evaporation of the solvents in vacuo the desired product as a yellow- orange solid (0.365g). LC/MS; Rt 2.90min, MH⁺ 484 (76% purity by HPLC). A further 5.87g of the residue was dissolved in methanol and applied to an SCX SPE cartridge. The cartridge was washed with methanol and the product was eluted from the column with 2M ammonia in methanol. The appropriate fractions were combined and the solvent was evaporated in vacuo to leave a yellow-orange residue. The residue was adsorbed onto florisil and purified by chromatography on a silica cartridge, eluting with a (methanol + 1% triethylamine) / DCM gradient (0-30%), to give, after evaporation of the solvents in vacuo, the title compound as a orange solid (2.87g). LC/MS; Rt 2.86 min, MH⁺ 484 (77% purity by HPLC). The combined solids (3.235g) were applied to a silica column (100g), and the column eluted with a mixture of methanol, DCM and triethylamine (5:94:1 ) and then methanol. Appropriate fractions were combined and evaporated in vacuo. Portions of approximately 130mg, 250mg and 5 x 500mg were each dissolved in DMF (5ml) and trifluoroacetic acid (0.5ml) and injected in turn onto the HPLC column of 7micron Kromasil C8 (25 x 5cm), with a gradient of 0 to 40%B (where A is water +0.25% TFA and B is acetonitrile +0.25% TFA), at a flow of 80ml/min. The peaks between retention times 38.5 - 41.5min of mass 484 (MH⁺) were bulked from all the chromatographic separations. The bulked fractions were divided into 3 portions and diluted with water (2 volumes). Each portion was applied to an Amberchrom CG161 column (25cm x 2cm) to adsorb the compound. The columns were washed in turn with ammonium hydroxide (0.2M, 300ml), water (500ml), and then the compound eluted with acetone (250ml). The acetone elution samples were bulked and dried to afford the title compound (1.8g). LC/MS; Rt 2.82min, MH⁺ 484. NMR; [D₆-DMSO] δH 13.29,(br. s, 1 H), 9.76,(s, 1 H), 8.26,(s, 1 H), 8.00,(d, 1 H), 7.93,(s, 1 H), 7.85,(dd, 1 H), 7.76,(m, 1 H), 7.51 , (d, 1 H), 7.38,(m, 2H), 7.07,(d, 1 H), 4.32,(m, 2H), 4.11 ,(m, 2H), 3.37,(t, 2H), 3.09,(s, 3H), 1.90,(m, 2H)

Intermediate 44 1-acetyl-Λ/-(2-chloro-5-fluoro-4-pyrimidinyl)-Λ/-[3-(methyloxy)propyl]- 1 H-indazol-4-amine

To a solution of Λ/-(3-{(2-chloro-5-fluoro-4-pyrimidinyl)[3-(methyloxy)propyl]amino}-2- methylphenyl)acetamide (6.045g) in chloroform (50ml) were added potassium acetate (1.7Og), acetic acid (1.09g, 1.04ml) and acetic anhydride (1.7Og, 1.57ml). tert-Butylnitrite (90% w/w, 4.48ml) was added slowly to the reaction mixture. The resulting yellow solution was heated at 6O⁰C under nitrogen overnight. The reaction mixture was allowed to cool to room temperature, aqueous potassium carbonate (1 M, 100ml) was added to the mixture, followed by chloroform (70ml). The phases were separated and the aqueous phase extracted with chloroform (2x 30ml). The combined organic phases were dried (hydrophobic frit) and concentrated in vacuo to give the title compound (6.23 g). LC/MS; Rt 3.26min, MH⁺ 378.

Intermediate 45 N -(3-((2-chloro-5-fluoro-4-pvrimidinvl)f3-(methvloxv)propvl]amino}-2- methylphenyl)acetamide

To a stirred solution of of Λ/-{3-[(2-chloro-5-fluoro-4-pyrimidinyl)amino]-2- methylphenyl}acetamide (5.Og), in dry DMF (50ml) under nitrogen, was added potassium carbonate (2.82g) and 1 -bromo-3-(methyloxy)propane (2.86g). The resulting mixture was heated at 5O⁰C under nitrogen for 30min, then stirred at room temperature under nitrogen overnight. 1-Bromo-3-(methyloxy)propane (520mg) was added and the resulting mixture was stirred at room temperature under nitrogen for 1 h, then heated at 4O⁰C under nitrogen for 1 h. Further 1-bromo-3- (methyloxy)propane (520mg) was added and the resulting mixture was heated at 6O⁰C under nitrogen for 90min. The reaction mixture was allowed to cool to room temperature and diluted with water (50ml). The solvents were evaporated in vacuo and the residue partitioned between water (50ml) and ethyl acetate (50ml). The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried (hydrophobic frit) and concentrated in vacuo to give the title compound as a yellow solid (6.045g). LC/MS; Rt 2.78min, MH⁺ 367.

Example 94 - Λ/²-(1 ,1-dioxido-2,3-dihvdro-1 ,2-benzisothiazol-6-yl)-5-fluoro-Λ/⁴-1H- indazol-4-yl-Λ/⁴-r3-(methyloxy)propyll-2,4-pyrimidinediamine trifluoroacetate

Λ/-(2-Chloro-5-fluoro-4-pyrimidinyl)-Λ/-[3-(methyloxy)propyl]-1H-indazol-4-amine (33.5mg) was taken up in water (1.5ml), acetone (1 ml) and hydrochloric acid (20μl, 2N) the mixture was placed in a microwave vial and treated with 2,3-dihydro-1 ,2- benzisothiazol-6-amine 1 ,1-dioxide (27.6mg). The vial was sealed and the reaction irradiated in a biotage microwave at 160⁰C for 2x 30min. The reaction mixture was concentrated and the residue purified using SCX SPE (500mg) by loading the residue in methanol and eluting with methanol then ammonia in methanol. The ammonia fraction was concentrated and the residue dissolved in DMSO / methanol (1 :1 ) and purified using Mass Directed HPLC. The product fractions were concentrated and purified again using SCX SPE (500mg) loading in methanol and eluting with methanol then ammonia in methanol. The ammonia fraction was concentrated and the residue dissolved in DMSO / methanol (1 :1 ) and re-purified using Mass Directed HPLC. The fractions containing product were evaporated to dryness to give the title compound (9.2mg): LC/MS; Rt 2.84min, MH⁺ 484.

Intermediate 46 - Λ/-(2-chloro-5-fluoro-4-pyrimidinyl)-Λ/-r3-(methyloxy)propyl1-1 /-/- indazol-4-amine

Λ/-(2-chloro-5-fluoro-4-pyrimidinyl)-Λ/-[3-(methyloxy)propyl]-1-({[2- (trimethylsilyl)ethyl]oxy}methyl)-1H-indazol-4-amine (1.87 g) was treated with a mixture of hydrochloric acid (5N) and IPA (2:1 , 45ml). The mixture was stirred at 55°C for 5.5h, allowed to cool to room temperature and the solvents evaporated in vacuo. The residue was basified with saturated sodium carbonate solution (50ml) and extracted with ethyl acetate (3x 50ml). The combined organic extracts were dried (MgSO₄), filtered and the solvent evaporated in vacuo. The residue was purified by chromatography on a silica cartridge (10Og) eluting with a methanol / DCM gradient (0-50%) over 60min. Fractions containing the product were combined and reduced to dryness in vacuo. The residue was dissolved in IPA, treated with hydrochloric acid (5N, 9ml) and concentrated in vacuo. The residue was left to stand at room temperature for 3 days, basified with saturated sodium carbonate (25ml) and extracted with ethyl acetate (2x 25ml). The combined organic phases were dried (MgSO₄) and concentrated in vacuo. The residue was purified by chromatography on a silica cartridge (10Og) eluting with an ethyl acetate / cyclohexane gradient (0- 100%) over 60min to afford the title compound (220mg). LC/MS; Rt 2.95min, MH⁺ 336, 338.

Intermediate 47 - Λ/-(2-chloro-5-fluoro-4-pyrimidinyl)-Λ/-F3-(methyloxy)propyπ-1-({[2- (trimethylsilvl)ethyl1oxy}methyl)-1H-indazol-4-amine

Λ/-(2-chloro-5-fluoro-4-pyrimidinyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-indazol- 4-amine (2g) was dissolved in DMF (20ml) and the mixture cooled to 0⁰C in an ice- water bath, under nitrogen. Sodium hydride (60% in mineral oil, 244mg) was added and stirring continued for 15min. 1 -Bromo-3-(methyloxy)propane (0.93g) was added and the reaction mixture allowed to warm to room temperature and stirred under a nitrogen atmosphere for 3 days. Saturated ammonium chloride solution (5ml) was added to the reaction. The mixture was transferred to a larger flask using a minimum of chloroform and concentrated in vacuo. The residue was partitioned between ethyl acetate (25ml) and water (15ml). The organic phase was washed with water (3x 15ml) and concentrated in vacuo. The residue was purified by chromatography on a silica cartridge (100g), eluting with an ethyl acetate / cyclohexane gradient (0-50%) over 60min to afford, after evaporation of the solvents, the title compound (1.87g). LC/MS; Rt 3.91 min, MH⁺ 466. Example 95 - N²-(1,1-dioxido-2,3-dihvdro- 1,2-benzisothiazol-6-yl)-5-fluoro-N⁴1H - indazol-4-yl-Λ/⁴-f3-(methyloxy)propyn-2,4-pyrimidinediamine

To 1 -acetyl-Λ/-(2-chloro-5-fluoro-4-pyrimidinyl)-Λ/-[3-(methyloxy)propyl]-1 H-indazol-4- amine (25.14g) in IPA (140ml) stirring at room temperature under nitrogen was added 2,3-dihydro-1 ,2-benzisothiazol-6-amine 1 ,1 -dioxide (13.51g). The resulting mixture was treated with hydrochloric acid (2M, 26ml). The mixture was heated to reflux and maintained at reflux overnight. The suspension was cooled to room temperature and the solid was collected by filtration, and washed with IPA. The solid was then dried in vacuo at 45°C, before suspending in methanol (460ml). To the stirring mixture was added water (153ml), the resulting mixture was heated to 65°C and treated with sodium hydroxide (2M, 30ml). The solution was allowed to cool to room temperature, the resulting precipitate collected by filtration, and washed with methanol / water (1 :1), then water. The solid was dried in vacuo at 40⁰C. The solid was divided into 1.5g portions, each portion dissolved in DMF (10ml) and purified by preparative HPLC on a 2" x 25cm column packed with Kromasil C8 10μm RP and eluting with a gradient of 10 -100% of (70:30 acetonitrile / 0.1 M ammonium dihydrogenphosphate, adjusted to pH 2.6 with phosphoric acid) in (0.1 M ammonium dihydrogenphosphate, adjusted to pH 2.6 with phosphoric acid) over 21.5mins (flow rate 100ml/min). Material eluting in a broad peak at ~13mins was collected from each run, the fractions from the separate runs combined and the acetonitrile evaporated in vacuo. The residual aqueous was basified to pH 8.5 with 0.880 ammonia and the precipitated solid isolated by filtration. The residue was washed with water, then resuspended in water and freeze-dhed to yield the title compound (17g). LC/MS; MH⁺ 484, Rt 2.85min.

Example 96 - N ² ( 1,1dioxido-2,3-dihvdro-1.2-benzisothiazol-6-yl)-5-fluoro-N ⁴-1H- indazol-4-yl-Λ/⁴-r3-(methyloxy)propyll-2,4-Pyrimidinediamine

N²-(1,1-dioxido-2,3-dihydro- 1,2-benzisothiazol-6-yl)-5-fluoro-N⁴-1 H-indazol-4-yl-A/⁴-[3- (methyloxy)propyl]-2,4-pyrimidinediamine (0.5g) was dissolved in DMSO (0.5g), filtered, and methanol (1Og) was added to the filtrate. The solution was seeded with Λ/²-(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)-5-fluoro-Λ/⁴-1 H-indazol-4-yl-/V⁴-[3- (methyloxy)propyl]-2,4-pyrimidinediamine (1 mg) and allowed to crystallise overnight at 5°C. The crystallised solid was filtered off, washed with methanol (4x 0.5ml), water (2x 0.5ml) and dried for 16h under vacuum at 9O⁰C, to give the title compound (0.43g) as a tan solid. LC/MS; MH⁺ 484.

Intermediate 48 - 1-acetyl-Λ/-(2-chloro-5-fluoro-4-pyrimidinyl)-/v-F3-(methyloxy)propyπ- 1/-/-indazol-4-amine

To Λ/-(3-{(2-chloro-5-fluoro-4-pyrimidinyl)[3-(methyloxy)propyl]amino}-2- methylphenyl)acetamide (34.11g) dissolved in anhydrous chloroform (250ml) was added potassium acetate (9.6Og), followed by glacial acetic acid (5.97ml) and acetic anhydride (8.89ml). The resulting mixture was stirred under a nitrogen atmosphere at room temperature and t-butyl nitrite (22.83ml) added drop-wise over 10min. The mixture was heated to 60⁰C and maintained at 60°C overnight. The mixture was allowed to cool to room temperature, potassium carbonate (1 M, 250ml) added and the phases separated. The aqueous phase was extracted with chloroform, the combined organics washed with water then brine and dried (magnesium sulphate). The solvent was evaporated, the resulting brown oil was dissolved in ether (50ml) and cyclohexane was added (150ml) to the solution. The resulting solid precipitate was collected by filtration and was washed with cyclohexane / ether (3:1). The solid was dried in vacuo at 35⁰C to yield the title compound (26.4g). LC/MS; MH⁺ 378, 380, Rt 3.22min.

Intermediate 49 - Λ/-(3-{(2-chloro-5-fluoro-4-pyrimidinyl)[3-(methyloxy)propyllamino}- 2-methylphenyl)acetamide

To Λ/-{3-[(2-chloro-5-fluoro-4-pyrimidinyl)amino]-2-methylphenyl}acetamide (3Og) in DMF (150ml) was added potassium carbonate (16.8g). The resulting mixture was then heated to 50°C under nitrogen and 1-bromo-3-(methyloxy)propane (17.1g) added. The reaction was stirred overnight at 50⁰C under nitrogen, poured onto ice/water (450ml) and extracted with methyl-tert-butyl ether. The aqueous was re- extracted with methyl-tert-butyl ether, the combined organics were washed sequentially with lithium chloride solution (10%) and brine then dried (magnesium sulphate). The solvent was evaporated to yield the title compound as a yellow foam (34.11g) LC/MS; MH⁺ 367, 369, Rt 2.75min.

Intermediate 50 - 1-bromo-3-(methyloxy)propane

Triphenyl phosphine (138.7g) was added to a solution of 3-methoxy-1-propanol (47.6g) in anhydrous DCM (500ml). The resulting mixture was stirred under nitrogen and cooled to 0°C, N-bromosuccinimide (94.13g) was added portion-wise keeping the internal temperature under 20°C during the addition. The mixture was stirred overnight at room temperature, then, quenched by addition of sodium metabisulfite solution (5%). The phases were separated, the organic phase washed sequentially with sodium hydroxide (0.5M) then brine and dried (magnesium sulphate). The resulting green residue was triturated with hexane and the resulting solid collected by filtration and washed with hexane. The filtrate contained solid so it was re-filtered to remove the solid. The filtrate was concentrated to leave a pale brown oil that was distilled under reduced pressure (~112mbar). The second boiling fraction (bp=68°C) was collected to give the title compound as a colourless oil (33.66g). NMR; [CDCI₃] δH, 3.52-3.49,(4H, m), 3.35,(3H₁ s), 2.1 1-2.08,(2H, m).

indazol-4-yl-/v⁴-[3-(methyloxy)propyn-2,4-pyrimidinediamine

To 1 -acetyl-Λ/-(2-chloro-5-fluoro-4-pyrimidinyl)-Λ/-[3-(methyloxy)propyl]-1 H-indazol-4- amine (443.6g) in IPA (2500ml) stirring at room temperature was added 2,3-dihydro- 1 ,2-benzisothiazol-6-amine 1 ,1 -dioxide (238.4g). The resulting mixture was treated with hydrochloric acid (2M, 458.8ml). The mixture was heated to reflux under nitrogen and maintained at reflux overnight. The suspension was allowed to cool to room temperature and the solid was collected by filtration, and washed with IPA. The solid was dried in vacuo at 45°C.

The solid was divided into 2 portions. The first portion (284.13g) was suspended in methanol (4260ml) and water (1420ml), the mixture was heated to 65⁰C and treated with sodium hydroxide (2M, 290ml). The resulting solution was seeded with a pure sample of Λ/²-(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)5-fluoro-N⁴-1H- indazol-4-yl-Λ/⁴-[3-(methyloxy)propyl]-2,4-pyrimidinediamine and cooled to 40°C and maintained at 40⁰C for 1 h. The precipitate was collected by filtration, washed with methanol / water (1 :1 ) and the solid dried in vacuo at 40⁰C to give the title compound (201.59g). NMR; [D₆-DMSO] δH 13.28,(1 H, bs), 9.75,(1 H, s), 8.26,(1 H, s), 8.00,(1 H, d), 7.93,(1 H₁ s), 7.85,(1 H, d), 7.74,(1 H, bs), 7.51 , (1 H, d), 7.39-7.35,(2H, m), 7.07,(1 H, d), 4.32,(2H, s), 4.1 1 ,(2H, t), 3.39-3.34(2H, obscured by water), 3.09,(3H, s), 1.90,(2H, m).

The second portion (274.71 g) was suspended in methanol (4120ml) and water (1370ml), the mixture was heated to 65°C and treated with sodium hydroxide (2M, 280ml). The resulting solution was seeded with a pure sample of Λ/²-(1 ,1-dioxido-2,3- dihydro-1 ,2-benzisothiazol-6-yl)-5-fluoro-/V⁴-1 /-/-indazol-4-yl-Λ/⁴-[3-(methyloxy)propyl]- 2,4-pyrimidinediamine and cooled to 40⁰C and maintained at 40⁰C for 1 h. The precipitate was collected by filtration, washed with methanol / water (1 :1 ) and the solid dried in vacuo at 40°C to give the title compound (189.58g). NMR; [D₆-DMSO] δH 13.28,(1 H, bs), 9.75,(1 H, s), 8.27,(1 H, s), 8.00,(1 H, d), 7.93,(1 H, s), 7.86,(1 H₁ d), 7.74,(1 H₁ bs), 7.51 ,(1 H, d), 7.39-7.35,(2H, m), 7.07,(1 H, d), 4.33,(2H, s), 4.12,(2H, t), 3.39-3.36(2H, t), 3.10,(3H, s), 1.91 ,(2H₁ m).

N²-(1 ,1-dioxido-2,3-dihydro-1,2-benzisothiazol-6-yl)-5-fluoro-N⁴-1H-indazol-4-yl-N⁴-[3- (methyloxy)propyl]-2,4-pyrimidinediamine (380.28g, from combining the product from the above two portions) was further purified by suspending in DMSO (380ml) and heating to 40⁰C. Methanol (4940ml) was added over 35min, maintaining the temperature at 40±2°C. The mixture was heated to reflux, maintained at this temperature for 1 h, then cooled to 60⁰C and filtered under reduced pressure. The residue was washed with methanol (3800ml) and dried in vacuo at 50⁰C to room temperature overnight and then for a further 3 days under vacuum at room temperature to give the title compound (333.9g).

Intermediate 51 - 1-acetyl-Λ/-(2-chloro-5-fluoro-4-pyrimidinyl)-Λ/-[3-(methyloxy)propyll- 1 /-/-indazol-4-amine

To Λ/-(3-{(2-chloro-5-fluoro-4-pyrimidinyl)[3-(methyloxy)propyl]aπnino}-2- methylphenyl)acetamide (297.81 g) dissolved in anhydrous chloroform (2100ml) was added potassium acetate (83.8g), followed by glacial acetic acid (52ml) and acetic anhydride (77.6ml). The mixture was stirred under a nitrogen atmosphere at room temperature and t-butyl nitrite (199ml) added drop-wise over 10min. The mixture was heated to 60⁰C and maintained at 60⁰C overnight. The reaction was cooled to room temperature and aqueous potassium carbonate (1 M, 2100ml) added portionwise. The phases were separated, the aqueous extracted with chloroform, and the combined organic phases washed with water, brine and dried (magnesium sulphate). The solvent was evaporated in vacuo, the residual oil dissolved in ether (200ml) and cyclohexane (700ml) added to the solution in 100ml portions. Scratching of the flask initialled precipitation. The precipitate was isolated by filtration, washed with ether / cyclohexane (1 :4) and dried in vacuo at 40°C to give the title compound (246.28g). NMR; [D₆-DMSO] δH 8.51 , (1 H, s), 8.31 , (1 H, d), 8.18,(1 H, d), 7.68,(1 H, t), 7.46,(1 H, d), 4.08,(2H, t), 3.35-3.32,(2H, obscured by water), 3.14,(3H, s), 2.73,(3H, s), 1.82,(2H, m).

Intermediate 52 - Λ/-(3-{(2-chloro-5-fluoro-4-pyrimidinyl)[3-(methyloxy)propyπamino)- 2-methylphenyl)acetamide

To Λ/-{3-[(2-chloro-5-fluoro-4-pyrimidinyl)amino]-2-nnethylphenyl}acetamide (278.65g) in DMF (1393ml) was added potassium carbonate (157g). The mixture was heated to 50⁰C and 1-bromo-3-(methyloxy)propane (159g) added. The reaction was stirred overnight at 50°C, poured into water (4179ml) and extracted with methyl-tert-butyl ether. The aqueous was re-extracted with methyl-tert-butyl ether, the combined organics washed sequentially with aqueous lithium chloride solution (10%, 500ml) and brine (500ml) and dried (magnesium sulphate). The solvent was evaporated to yield the title compound as a yellow solid (298.72g). NMR; [D₆-DMSO] δH 9.41 ,(1 H, s), 8.12,(1 H, d), 7.47,(1 H, d), 7.22,(1 H, t), 7.14,(1 H, d), 4.14-4.06,(1 H, m), 3.53- 3.47,(1 H, m), 3.38-3.31 , (2H, partially obscured by water), 3.19,(3H, s), 2.06,(3H, s), 2.02,(3H, s), 1.92-1.74,(2H, m).

Claims

1. A compound of formula (I):

in which:

R¹ is hydrogen or a halogen;

R² and R³ is each independently selected from hydrogen, halogen, -Co-₆alkylenehydroxy, -C_1-6 alkyl, -NR⁵R⁶, -CN, -Co-₃alkylene-C0₂H, OC(O)C_1-6 alkyl, C(O)C_1-6 alkoxy, -C_1-2 alkyl substituted by 1 or more fluorine atoms, -C_1-6aIkOXy, - C(O)NR⁵R⁶, -OCH₂C(O)NR⁵R⁶, -NR⁵C(O)R⁶, -SC_1-6alkyl, -S(O)C_1-6alkyl, -S(O)₂C_1-6alkyl, -NHS(O)₂R⁷, -S(O)₂NR⁵R⁶ or -S(O)₂NR⁵R⁸; or

one of R² and R³ is hydrogen and the other is a 5- or 6-membered heteroaryl ring comprising from 1 to 3 heteroatoms selected from O, N and S bonded to the phenyl ring through a ring carbon atom and which heteroaryl ring is unsubstituted or substituted on one or more ring carbon atoms by C_1-6alkyl or oxo (=0), or on a ring nitrogen atom by C_1-6alkyl; or

R⁴ is C_2-5alkyl substituted by hydroxy, C_1-3alkoxy, amino, Ci.₃alkylamino, di-(C_1-3alkyl)amino, C_1-3alkylcarbonylamino, C_1-3alkylcarbony-N-C_1-3alkylamino, C_1-3alkylsulphonylamino; C_1-4alkyl substituted by carboxy, C_1-3alkylcarboxy, aminocarbonyl, C_1-3alkylaminocarbonyl; trifluoromethyl; CH₂CH(OH)CH₂OH; or R⁴ is CH₂R⁹ wherein R⁹ is a heterocyclyl ring comprising 5 or 6 atoms comprising one heteroatom selected from N or O, bonded through a ring carbon and optionally substituted on N by C_1-3alkylcarbonyl;

R⁵ and R⁶ is each independently hydrogen or C_1-6alkyl, or R⁵ and R⁶ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring which may comprise a second heteroatom selected from O, S or N and which may be substituted on the second N, if present, by C_1-6alkyl, and which may be substituted on a ring carbon by oxo (=0), C_1-6alkyl, di-Ci_-6alkyl (which may be the same or different), or halogen;

R⁷ is C_1-6alkyl or phenyl optionally substituted by C_1-6alkyl;

R⁸ is C_3-7cycloalkyl, C_1-6alkyl (optionally terminally substituted with hydroxyl or tetrahydrofuranyl); or

2. A compound of formula (I) as claimed in claim 1 in which R¹ is hydrogen or fluoro.

3. A compound of formula (I) as claimed in claim 1 or 2 in which R² and R³ is selected form: hydrogen, halogen, -C(O)NR⁵R⁶, -S(O)₂C_1-6alkyl, -S(O)₂NR⁵R⁶; in particular, hydrogen, -CONH₂, -SO₂NH₂, and -SO₂CH₃; for instance, R² is hydrogen and R³ is -CONH₂, -SO₂NH₂, and -SO₂CH_{3 ,} or

R² is hydrogen and R³ is a 5- or 6-membered heteroaryl ring.

4. A compound of formula (I) as claimed in any one of claim 1 to 3 in which as R² is hydrogen and R³ is:

5. A compound of formula (I) as claimed in any one of claim 1 to 3 in which the 5- or 6- membered saturated or unsaturated ring formed by R² and R³, fused with the phenyl ring, is:

6. A compound of formula (I) as claimed in any one of claim 1 to 3 in which the 5- or 6- membered saturated or unsaturated ring formed by R² and R³, fused with the phenyl ring, is selected from:

; and

7. A compound of formula (I) as claimed in any one of claim 1 to 6 in which R⁴ include -(CH₂)_nOH where n is 2, 3 or 4; -(CH₂)_nOC_1-3alkyl where n is 2 or 3; - (CH₂)_nNH₂ where n is 2, 3, 4 or 5; -(CH₂)₃N(C_1-3alkyl)₂; -(CH₂)_nNHCOC_1-3alkyl where n is 3, 4 or 5; -(CH₂)_nNHSO₂C_1-3alkyl where n is 3, 4 or 5; -(CH₂)_nCOOH where n is 3 or 4; -(CH₂)_nCOOC_1-3alkyl where n is 3 or 4; -CH₂CONH₂; -CH₂CONHMe; -CH₂CH(OH)CH₂OH; -CH₂CF₃; -CH₂tetrahydrofuran-3-yl; -CH₂piperidin-4-yl; and -CH₂(I -acetyl)piperidin-4-yl.

8. A compound of formula (I) as claimed in any one of claim 1 to 6 in which R⁴ is C_2-3alkyl substituted by hydroxy or C_1-3aIkOXy.

9. A compound of formula (I) as claimed in claim 1 in which the compound of formula (I) is a compound of the formula (IA):

in which:

R¹⁰ and R¹¹ is each independently hydrogen, C_1-6alkyl or CH₂C₃.₇cycloalkyl;

R¹² is C₂.₃alkyl substituted by hydroxy or C_1-3alkoxy; and

X¹ is halogen; or a salt or solvate, preferably a pharmaceutically acceptable salt or solvate, thereof.

10. A process for preparing a compound of formula (I), or a salt or solvate thereof, as defined in claim 1 , which process comprises reacting a compound of formula (II):

or a protected derivative thereof, wherein R¹, R², R³ and R⁴ are as defined for formula (I) in claim 1.

11. A compound of formula (I) or a salt or solvate thereof, selected from the group consisting of:

Λ/²-1 H- 1 ,2,3-benzotriazol-5-yl-5-fluoro-Λ/⁴-1 H-indazol-4-yl-/v⁴-[3-(methyloxy)propyl]-

2,4-pyrimidinediamine;

N²-(1.1-dioxido-2,3-dihydro-1,2-benzisothiazol-6-yl)-5-fluoro-N⁴-1H-indazol-4-yl-Λ/⁴-[3-

(methyloxy)propyl]-2,4-pyrimidinediamine; 5-[(5-fluoro-4-{1/-/-indazol-4-yl[3-(methyloxy)propyl]amino}-2-pyrimidinyl)amino]-1 ,3- dihydro-2/-/-benzimidazol-2-one;

5-fluoro-N⁴-1 H-indazol-4-yl-Λ/²-(1 -methyl-1 H-indazol-6-yl)-N⁴[3-(methyloxy)propyl]- 2,4-pyrimidinediamine; 3-[(5-fluoro-4-{1/-/-indazol-4-yl[3-(methyloxy)propyl]amino}-2- pyrimidinyl)amino]benzamide;

5-fluoro-N⁴-1H-indazol-4-yl-Λ/²-[3-(4-methyl-1 ,3-oxazol-5-yl)phenyl]-Λ/⁴-[3- (methyloxy)propyl]-2,4-pyrimidinediamine;

5-fluoro-Λ/⁴-1 H-indazol-4-yl-Λ/⁴-[3-(methyloxy)propyl]-Λ/²-[3-(methylsulfonyl)phenyl]- 2,4-pyrimidinediamine;

6-[(5-fluoro-4-{1H-indazol-4-yl[3-(methyloxy)propyl]amino}-2-pyrimidinyl)amino]-1 ,4- dihydro-2H-3,1-benzoxazin-2-one;

5-fluoro-Λ/⁴-1 H-indazol-4-yl-Λ/²-(1 -methyl-1 H-indazol-5-yl)-N⁴-[3-(methyloxy)propyl]-

2,4-pyrimidinediamine; -[(5-fluoro-4-{1 /-/-indazol-4-yl[3-(methyloxy)propyl]amino}-2- pyrimidinyl)annino]benzenesulfonamide;

3-[[2-(1 /-/-1 ,2,3-benzotriazol-5-ylamino)-5-fluoro-4-pyrimidinyl](1 H-indazol-4- yl)amino]-1 -propanol;

3-[{5-fluoro-2-[(1 -methyl-1 H-indazol-6-yl)amino]-4-pyrimidinyl}(1 H-indazol-4- yl)amino]-1 -propanol;

3-({5-fluoro-4-[(3-hydroxypropyl)(1H-indazol-4-yl)amino]-2- pyrimidinyl}amino)benzamide;

3-({5-fluoro-4-[(3-hydroxypropyl)(1 H-indazol-4-yl)amino]-2- pyrimidinyl}amino)benzenesulfonamide; 5-({5-fluoro-4-[(3-hydroxypropyl)(1 /-/-indazol-4-yl)amino]-2-pyrimidinyl}amino)-1 ,3- dihydro-2/-/-benzimidazol-2-one;

3-[(5-fluoro-2-{[3-(methylsulfonyl)phenyl]amino}-4-pyrimidinyl)(1/-/-indazol-4- yl)amino]-1 -propanol;

3-[6-({5-Fluoro-4-[(3-hydroxypropyl)(1 H-indazol-4-yl)amino]-2-pyrimidinyl}amino)-3- methyl-1 H-indazol-1-yl]-1 -propanol;

3-{6-[(5-Fluoro-4-{1 H-indazol-4-yl[3-(methyloxy)propyl]amino}-2-pyrimidinyl)amino]-3- methyl-1 H-indazol-1-yl}-1 -propanol; N2-(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)-N4-1 H-indazol-4-yl-N4-[3-

(methyloxy)propyl]-2,4-pyrimidinediamine; 3-[(4-{1 /-/-indazol-4-yl[3-(methyloxy)propyl]amino}-2-pyrimidinyl)amino]benzamide;

/V⁴-1H-indazol-4-yl-Λ/⁴-[3-(methyloxy)propyl]-Λ/²-[3-(methy!sulfonyl)phenyl]-2,4- pyrimidinediamine; 6-[(4-{1 H-indazol-4-yl[3-(methyloxy)propyl]amino}-2-pyrimidinyl)amino]-1 ,4-dihydro-

2H-3, 1 -benzoxazin-2-one;

5-[(4-{1H-indazol-4-yl[3-(methyloxy)propyl]amino}-2-pyrimidinyl)amino]-1 ,3-dihydro-

2H-benzimidazol-2-one; Λ/²-1 H- 1 ,2,3-benzotriazol-5-yl-Λ/⁴-1 H-indazol-4-yl-Λ/⁴-[3-(methyloxy)propyl]-2,4- pyrimidinediamine;

5-({4-[(3-hydroxypropyl)(1H-indazol-4-yl)amino]-2-pyrimidinyl}amino)-1 ,3-dihydro-2H- benzimidazol-2-one;

3-({4-[(3-hydroxypropyl)(1/-/-indazol-4-yl)amino]-2-pyrimidinyl}amino)benzamide; 6-({4-[(3-hydroxypropyl)(1 H-indazol-4-yl)amino]-2-pyrimidinyl}amino)-1 ,4-dihydro-2H-

3,1 -benzoxazin-2-one;

3-[[2-(1 H-1 ,2,3-benzotriazol-5-ylamino)-4-pyrimidinyl](1 H-indazol-4-yl)amino]-1 - propanol;

3-[{2-[(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)amino]-4-pyrimidinyl}(1H- indazol-4-yl)amino]-1 -propanol;

N²-(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)-N⁴-1H-indazol-4-yl-Λ/⁴-[2-

(methyloxy)ethyl]-2,4-pyrimidinediamine;

Λ/⁴-1 H-indazol-4-yl-Λ/²-(1 -methyl-1 H-indazol-6-yl)-/V⁴-[2-(methyloxy)ethyl]-2,4- pyrimidinediamine; 3-[(4-{1 H-indazol-4-yl[2-(methyloxy)ethyl]amino}-2- pyrimidinyl)amino]benzenesulfonamide;

Λ/²-1 H-1 ,2,3-benzotriazol-5-yl-Λ/⁴-1 H-indazol-4-yl-/V⁴-[2-(methyloxy)ethyl]-2,4- pyrimidinediamine;

Λ/*-1 H-indazol-4-yl-Λ/²-(1 -methyl-1 H-indazol-5-yl)-/V⁴-[2-(methyloxy)ethyl]-2,4- pyrimidinediamine;

N⁴-1 H-indazol-4-yl-Λ/²-[3-(4-methyl-1 ,3-oxazol-5-yl)phenyl]-N⁴-[2-(methyloxy)ethyl]-

2,4-pyrimidinediamine;

Λ/²-(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)-Λ/⁴-1H-indazol-4-yl-Λ/⁴-(2,2,2- trifluoroethyl)-2,4-pyrimidinediamine; Λ/²-(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)-/V⁴-1 H-indazol-4-yl-Λ/⁴-(2,2,2- trifluoroethyl)-2,4-pyhmidinediamine;

2-[{2-[(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)amino]-4-pyrimidinyl}(1 H- indazol-4-yl)amino]ethanol;

3-({4-[(2-hydroxyethyl)(1H-indazol-4-yl)amino]-2-pyrimidinyl}amino)benzamide;

2-[1 H-indazol-4-yl(2-{[3-(methylsulfonyl)phenyl]amino}-4-pyrimidinyl)amino]ethanol; 6-({4-[(2-hydroxyethyl)(1H-indazol-4-yl)amino]-2-pyrimidinyl}amino)-1 ,4-dihydro-2 H-

3,1 -benzoxazin-2-one;

2-[[2-(1 H-1 ,2,3-benzotriazol-5-ylamino)-4-pyrimidinyl](1 H-indazol-4-yl)amino]ethanol;

3-[{2-[(1 , 1 -dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)annino]-4-pyrimidinyl}(1 H- indazol-4-yl)amino]-1 -propanol;

5-({4-[(3-hydroxypropyl)(1 H-indazol-4-yl)amino]-2-pyrimidinyl}amino)-1 ,3-dihydro-2/-/- benzimidazol-2-one;

3-(1H-indazol-4-yl{2-[(1-methyl-1 H-indazol-6-yl)amino]-4-pyrimidinyl}amino)-1- propanol; 3-({4-[(3-hydroxypropyl)(1 H-indazol-4-yl)amino]-2- pyrimidinyl}amino)benzenesulfonamide;

3-[1 H-indazol-4-yl(2-{[3-(4-methyl-1 ,3-oxazol-5-yl)phenyl]amino}-4- pyrimidinyl)amino]-1 -propanol;

3-(1 H-indazol-4-yl{2-[(1-methyl-1 H-indazol-5-yl)amino]-4-pyrimidinyl}amino)-1- propanol;

4-[{2-[(1 ,1-dioxido-2_l3-dihydro-1 ,2-benzisothiazol-6-yl)amino]-4-pyrimidinyl}(1H- indazol-4-yl)amino]-1 -butanol;

4-(1H-indazol-4-yl{2-[(1-methyl-1 H-indazol-6-yl)amino]-4-pyrimidinyl}amino)-1- butanol; 3-({4-[(4-hydroxybutyl)(1 H-indazol-4-yl)amino]-2- pyrimidinyl}amino)benzenesulfonamide;

4-(1H-indazol-4-yl{2-[(1-methyl-1 H-indazol-5-yl)amino]-4-pyrimidinyl}amino)-1- butanol;

4-[1/-/-indazol-4-yl(2-{[3-(4-methyl-1 ,3-oxazol-5-yl)phenyl]amino}-4- pyrimidinyl)amino]-1 -butanol;

3-[1H-indazol-4-yl(2-{[3-(methylsulfonyl)phenyl]amino}-4-pyrimidinyl)amino]-1- propanol;

(2R)-3-[{2-[(1 , 1 -dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)amino]-4-pyrimidinyl}(1 H- indazol-4-yl)amino]-1 ,2-propanediol; 4-[[2-(1 H-1 ,2,3-benzotriazol-5-ylamino)-4-pyrimidinyl](1 H-indazol-4-yl)amino]-1- butanol hydrochloride;

5-({4-[[(1-acetyl-4-piperidinyl)methyl](1H-indazol-4-yl)amino]-2-pyrimidinyl}amino)-

1 ,3-dihydro-2H-benzimidazol-2-one;

5-({4-[1H-indazol-4-yl(4-piperidinylmethyl)amino]-2-pyrimidinyl}amino)-1 ,3-dihydro- 2/-/-benzimidazol-2-one; N-[4-(1 H-indazol-4-yl{2-[(2-oxo-2,3-dihydro-1 H-benzimidazol-5-yl)amino]-4- pyrimidinyl}amino)butyl]methanesulfonamide;

N-[5-(1 H-indazol-4-yl{2-[(2-oxo-2,3-dihydro-1 H-benzimidazol-5-yl)amino]-4- pyrimidinyl}amino)pentyl]methanesulfonamide; N-[3-(1 H-indazol-4-yl{2-[(2-oxo-2,3-dihydro-1 H-benzimidazol-5-yl)amino]-4- pyrimidinyl}amino)propyl]methanesulfonamide formate;

3-({4-[[3-(diethylamino)propyl](1 H-indazol-4-yl)amino]-2- pyrimidinyl}amino)benzenesulfonamide;

Λ/⁴-[3-(diethylamino)propyl]-Λ/²-(1 , 1 -dioxido-2,3-dihydro- 1,2-benzisothiazol-5-yl)-Λ/⁴- 1 H-indazol-4-yl-2,4-pyrimidinediamine;

Λ/⁴-[3-(diethylamino)propyl]-Λ/²-(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)-Λ/⁴-

1/-/-indazol-4-yl-2,4-pyrimidinediamine; methyl 4-[{2-[(1 ,1 -dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)amino]-4- pyrimidinyl}(1H-indazol-4-yl)amino]butanoate; methyl 5-[{2-[(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)amino]-4- pyrimidinyl}(1 H-indazol-4-yl)amino]pentanoate;

4-[{2-[(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)amino]-4-pyrimidinyl}(1 H- indazol-4-yl)amino]butanoic acid;

5-[{2-[(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)amino]-4-pyrimidinyl}(1 H- indazol-4-yl)amino]pentanoic acid;

N⁴-(3-aminopropyl)-N²-(1,1-dioxido-2,3-dihydro-1,2-benzisothiazol-6-yl)-Λ/⁴-1H- indazol-4-yl-2,4-pyrimidinediamine;

Λ/⁴-(5-aminopentyl)-Λ/²-(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)-/V⁴-1H- indazol-4-yl-2,4-pyrimidinediamine; 5-({4-[(3-aminopropyl)(1 H-indazol-4-yl)amino]-2-pyrimidinyl}amino)-1 ,3-dihydro-2H- benzimidazol-2-one;

5-({4-[(4-aminobutyl)(1 H-indazol-4-yl)amino]-2-pyrimidinyl}amino)-1 ,3-dihydro-2H- benzimidazol-2-one;

5-({4-[(5-aminopentyl)(1 H-indazol-4-yl)amino]-2-pyrimidinyl}amino)-1 ,3-dihydro-2H- benzimidazol-2-one;

N-[3-(1 H-indazol-4-yl{2-[(2-oxo-2,3-dihydro-1 H-benzimidazol-5-yl)amino]-4- pyrimidinyl}amino)propyl]acetamide;

N-[4-(1 H-indazol-4-yl{2-[(2-oxo-2,3-dihydro-1 H-benzimidazol-5-yl)amino]-4- pyrimidinyl}amino)butyl]acetamide; N-[5-(1 H-indazol-4-yl{2-[(2-oxo-2,3-dihydro-1 H-benzimidazol-5-yl)amino]-4- pyrimidinyl}amino)pentyl]acetamide; 5-({4-[[3-(diethylamino)propyl](1 H-indazol-4-yl)amino]-2-pyrimidinyl}amino)-1 ,2- benzisothiazol-3(2H)-one 1 ,1 -dioxide;

Λ/²-{2-[(1 , 1 -dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)amino]-5-fluoro-4-pyrimidinyl}-

Λ/²-1H-indazol-4-yl-Λ/¹-methylglycinamide; (±)-Λ/²-(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)-5-fluoro-N⁴-1H-indazol-4-yl-

N⁴-(tetrahydro-2-furanylmethyl)-2,4-pyrimidinediamine;

Λ/⁴-(2-aminoethyl)-Λ/²-(1 ,1-dioxido-2,3-dihydro-1-benzothien-6-yl)-5-fluoro-Λ/⁴-1 H- indazol-4-yl-2,4-pyrimidinediamine;

Λ/⁴-(3-aminopropyl)-Λ/²-(1 ,1-dioxido-2,3-dihydro-1-benzothien-6-yl)-5-fluoro-Λ/⁴-1H- indazol-4-yl-2,4-pyrimidinediamine;

Λ/²-{2-[(1 ,1-dioxido-2,3-dihydro-1-benzothien-6-yl)amino]-5-fluoro-4-pyrimidinyl}-Λ/²-

1/-/-indazol-4-yl-Λ/¹-methylglycinamide;

(±)-Λ/²-(1 ,1-dioxido-2,3-dihydro-1-benzothien-6-yl)-5-fluoro-Λ/⁴-1 H-indazol-4-yl-Λ/⁴-

(tetrahydro-2-furanylmethyl)-2,4-pyrimidinediamine; (±)-N2-(1 , 1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)-5-fluoro-Λ/⁴-1H-indazol-4-yl-

N⁴-(tetrahydro-3-furanyl methyl )-2,4-pyrimidinediamine;

1 H-indazol-4-ylglycinamide;

2-[{2-[(1 ,1-dioxido-2,3-dihydro-1-benzothien-6-yl)amino]-5-fluoro-4-pyrimidinyl}(1H- indazol-4-yl)amino]ethanol;

3-[{2-[(1 ,1-dioxido-2,3-dihydro-1-benzothien-6-yl)amino]-5-fluoro-4-pyrimidinyl}(1H- indazol-4-yl)amino]-1 -propanol;

4-[{2-[(1 ,1-dioxido-2,3-dihydro-1-benzothien-6-yl)amino]-5-fluoro-4-pyrimidinyl}(1H- indazol-4-yl)amino]-1 -butanol; and 3-[{5-fluoro-2-[(1-methyl-1H-indazol-6-yl)amino]-4-pyrinnidinyl}(1/-/-indazol-4- yl)amino]-1 -propanol.

12. A compound of formula (I) or a salt or solvate thereof, selected from the group consisting of: 3-[{2-[(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)amino]-4-pyrimidinyl}(1H- indazol-4-yl)amino]-1 -propanol;

N⁴-(3-anninopropyl)-Λ/²-1 ,1-dioxido-2,3-dihydro- 1 ,2-benzisothiazol-6-yl)-N⁴-1 H- indazol-4-yl-2,4-pyrimidinediamine;

Λ/-[4-(1/-/-indazol-4-yl{2-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)amino]-4- pyrimidinyl}amino)butyl]acetamide;

5-[{2-[(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)amino]-4-pyrimidinyl}(1H- indazol-4-yl)amino]pentanoic acid; N²-(i .i-dioxido-2,3-dihydro-1,2-benzisothiazol-6-yl)-5-fluoro-N⁴-1 H-indazol-4-yl-Λ/⁴-[3- (methyloxy)propyl]-2,4-pyrimidinediamine;

2-[[2-(1 H- 1 ,2,3-benzotriazol-5-ylamino)-4-pyrimidinyl](1 /-/-indazol-4-yl)amino]ethanol; 3-[{2-[(1 ,1-dioxido-2,3-dihydro-1 ,2-benzisothiazol-6-yl)amino]-4-pyrinnidinyl}(1 /-/- indazol-4-yl)amino]-1-propanol; and

3-[{5-fluoro-2-[(1-methyl-1H-indazol-6-yl)amino]-4-pyrimidinyl}(1H- indazol-4- yl)amino]-1-propanol; or a salt or solvate thereof, in particular, a pharmaceutically acceptable salt or solvate thereof.

13. A compound of formula (I) selected from the group consisting of: N²-( 1,1-dioxido-2,3-dihydro- 1,2-benzisothiazol-6-yl)-5-fluoro-N⁴-1 H-indazol-4-yl-Λ/⁴-[3- (methyloxy)propyl]-2,4-pyrimidinediamine; or a salt or solvate thereof, in particular, a pharmaceutically acceptable salt or solvate thereof.

14. A pharmaceutical formulation comprising a compound of formula (I), or a salt or solvate thereof, as defined in claim 1 , and pharmaceutically acceptable excipients.

15. A compound of formula (I) or a salt or solvate thereof as defined in claim 1 for use in therapy.

16. The use of a compound of formula (I) or a salt or solvate thereof as defined in claim 1 in the manufacture of a medicament for treating a disease associated with inappropriate mast cell activation

17. The use of a compound of formula (I) or a salt or solvate thereof as defined in claim 1 in the manufacture of a medicament to inhibit a Syk kinase.

18. The use of a compound of formula (I) or a salt or solvate thereof as defined in claim 1 in the manufacture of a medicament for of treating an inflammatory disease

19. The use of a compound of formula (I) or a salt or solvate thereof as defined in claim 1 in the manufacture of a medicament for treating an allergic disorder.

20. The use of a compound of formula (I) or a salt or solvate thereof as defined in claim 1 in the manufacture of a medicament for treating rhinitis.