PYRIMDINE COMPOUNDS USEFUL AS KINASE INHIBITORS

Field of the Invention

The present invention relates to mono-anilino pyrimidine derivatives, compositions and medicaments containing the same, as well as processes for the preparation and use of such compounds, compositions and medicaments. Such mono-anilino pyrimidine derivatives are of potential therapeutic benefit in the treatment of diseases and conditions associated with inappropriate Syk activity, in particular in the treatment of inflammatory and allergic diseases.

Background to the Invention

Spleen Tyrosine Kinase (Syk) is a protein tyrosine kinase which has been described as a key mediator of immunoreceptor signalling in a host of inflammatory cells including mast cells, B-cells, macrophages and neutrophils.

These immunoreceptors, including Fc receptors and the B-cell receptor, are important for both allergic diseases and antibody-mediated autoimmune diseases and thus pharmacologically interfering with Syk could conceivably treat these disorders.

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 (FcεRl) and IgG (FcεRl) 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 FcεRl

and or FcεRl receptors, and is positioned early in the signalling cascade. In mast cells, for example, the early sequence of FcεRl signalling following allergen cross-linking of receptor-IgE complexes involves first Lyn (a Src family tyrosine kinase) and then Syk. Inhibitors of Syk 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 et al 2004, Expert Opin. Investig. Drugs (2004) 13 (7) 743-762).

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. CW. 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 Spleen Tyrosine Kinase (Syk) have demonstrated a non-redundant role of this kinase in B cell function. The deficiency in syk 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 (Kurasaki et al 2000, Immunol. Rev. 176:19-29), demonstrate that Syk is required for the differentiation and activation of B cells. Hence, inhibition of Syk in RA patients, is likely block B cell function and hence to reduce Rheumatoid Factor production. In addition to the role of Syk in B cell function, of relevance to the treatment of RA, is the requirement for syk activity in Fc receptor (FcR) signalling. FcR activation by immune commplexes in RA has been suggested to contribute to the release of multiple pro-inflammatory mediators.

The contribution of Syk dependent processes to the pathology of RA has been reviewed in Wong et al (2004, Expert Opin Investig Drugs 13:743-762).

WO 2003/063794, WO 2004/014382, WO 2005/012294, and WO 2005/16893 (Rigel Pharmaceuticals Inc) describes a series of 2,4-pyrimidine diamine compounds which inhibit Syk Kinase, for use in treating autoimmune diseases.

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

The present invention relates to novel mono-anilino pyrimidine compounds, which are inhibitors of kinase activity. Such mono aniline pyrimidine derivatives therefore have potential therapeutic benefit in the treatment of disorders associated with inappropriate kinase, in particular inappropriate Syk activity, in particular in the treatment and prevention of disease states mediated by kinase mechanisms, particularly those diseases mediated by Syk including inflammatory, allergic and autoimmune diseases including asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), ulcerative colitis, Crohns disease, bronchitis, dermatitis, allergic rhinitis, psoriasis, scleroderma, urticaria, rheumatoid arthritis, multiple sclerosis, cancer, HIV and lupus.

Brief Summary of the Invention

In one aspect of the present invention there is provided a compound of formula (I) or a salt or solvate thereof H _? CH(R ² )-R ³

H

(1 ) wherein^ -

R ¹ is H or Ci-3 alkyl;

R ² is H, OH, Ci-3 alkyl or Cr ₃ hydroxyalkyl;

R ³ is pyridyl or phenyl (wherein the phenyl group is optionally substituted by one or more substituents independently selected from halogen, C1-3 haloalkyl, C1-3 alkyl, C1-3 alkoxy);

R ⁴ is

(i) a bicyclic heteroaryl group having 9-14 ring members optionally substituted by one or more substituents independently selected from -halogen, -C1-3 alkyl, oxo, - (CH ₂ ) 1-3 NR ^a R ^b ,), where R ^a and R ^b are independently H or C1-3 alkyl; or

(ii) phenyl (optionally substituted by one or more substituents independently selected from CN, -halogen, C1-3 alkyl, -C1-3 haloalkyl,

-Ci-3 alkoxy, -Ci-3 -haloalkoxy, -COOH, -CH ₂ SO ₂ C1-3 alkyl, -XNR ^c R ^d , a 5 membered hereroaryl group (optionally substituted by -C1-3 alkyl),

-phenyl (optionally substituted by CH ₂ NR ^e R ^f ),"CO-phenyl, or a group

X represents a bond (ie is absent), -NHCOCH ₂ -, -NHCOCH ₂ CH ₂ -, CH ₂ NHCOCH ₂ -, OCH ₂ CO-, SO ₂ , CH ₂ -, CH ₂ CH ₂ -, OCH ₂ CH ₂ -, -OCH ₂ CH ₂ CH ₂ -, CO-, or -CH ₂ SO ₂ -;

R ^c and R ^d independently represent H, -C1-3 alkyl, -(C1-3 alkylene) NRsR ^h , a 6 membered heterocyclic group optionally substituted by C1-3 alkyl, or R ^c and R ^d together with the nitrogen to which they are joined form a 5 or 6 membered heterocyclic group (optionally containing a further heteroatom selected from O or N and optionally substituted by one or more substituentsl

Rs and R ^h independently represent H, C1-3 alkyl or R ⁹ and R ^h together with the nitrogen to which they are joined form a 5 or 6 membered heterocyclic group, optionally containing a further heteroatom selected from 0 or s and optionally substituted by C1-3 alkyl; and

R ^e and R ^f are independently H, C1-3 alkyl, (C1-3 alkylene)-pyridyl

In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I), or a salt or solvate, thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients.

In a further aspect of the present invention, there is provided a compound of formula (I), or a salt or solvate, thereof for use in therapy.

In a further aspect of the present invention, there is provided a compound of formula (I) or a salt or solvate thereof for use in the treatment of a disease or condition mediated by inappropriate Syk activity, particularly inflammatory, allergic and autoimmune diseases.

In a further aspect of the present invention, there is provided a method of treating a disease or condition mediated by inappropriate Syk activity particularly inflammatory, allergic and autoimmune diseases in a mammal comprising

administering to said mammal a compound of formula (I) or a salt or solvate thereof.

In a further aspect of the present invention there is provided the use of a compound of formula (I) or a salt or solvate thereof in the manufacture of a medicament for use in the treatment of a disease or condition mediated by inappropriate Syk activity particularly inflammatory, allergic and autoimmune diseases.

Detailed Description of the Invention

As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

As used herein the term "alkyl" refers to a straight- or branched-chain hydrocarbon radical having the specified number of carbon atoms. As used herein, the terms "C1-C3 alkyl" and "Ci-Cβ alkyl" refer to an alkyl group, as defined above, containing at least 1, and at most 3 or 6 carbon atoms respectively. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, and the like.

As used herein, the term "alkylene" refers to a straight or branched chain divalent hydrocarbon radical having the specified number of carbon atoms. As used herein, the terms "C1-C3 alkylene" and "Ci-Cβ alkylene" refer to an alkylene group, as defined above, which contains at least 1, and at most 3 or 6, carbon atoms respectively. Examples of "alkylene" as used herein include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, and the like.

As used herein, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) and the term "halo" refers to the halogen radicals^ fluoro ("F), chloro (-Cl), bromo(-Br), and iodo(-l).

As used herein, the term "haloalkyl" refers to an alkyl group as defined above, substituted with at least one halo group, halo being as defined herein. Examples of such branched or straight chained haloalkyl groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl substituted independently with one or more halos, e.g., fluoro, chloro, bromo and iodo.

As used herein, the term "heterocyclic" or the term "heterocyclyl" refers to a non-aromatic heterocyclic ring, being saturated or having one or more degrees of unsaturation, containing one or more heteroatom substitutions selected from S, S(O), S(O)2, O, or N, and having the specified number of ring members.

As used herein, the term "alkoxy" refers to the group RaO", where Ra is alkyl as defined above and the terms "C1-C3 alkoxy" and "Ci-Cβ alkoxy" refer to an alkoxy group as defined herein wherein the alkyl moiety contains at least 1, and at most 3 or 6, carbon atoms. Exemplary "C1-C3 alkoxy" and "Ci-Cβ alkoxy" groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and t-butoxy.

As used herein, the term "haloalkoxy" refers to the group RaO", where Ra is haloalkyl as defined above and the term "Ci-Cβ haloalkoxy" refers to a haloalkoxy group as defined herein wherein the haloalkyl moiety contains at least 1, and at most 6, carbon atoms. Exemplary Ci-Cβ haloalkoxy groups useful in the present invention include, but are not limited to, trifluoromethoxy.

As used herein the term "hydroxy" refers to the group —OH.

The term "heteroaryl", unless otherwise specified, refers to an aromatic

monocyclic 5-7 monitored ring group and fused bicyclic rings, having at least one aromatic ring and having the specified number of ring members (e.g. carbon and heteratoms N, O, and/or S) and containing 1, 2, 3 or 4 heteroatoms selected from N, O and S. Examples of particular heteroaryl groups include, but are not limited to, furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiopene, benzazepine, benzimidazole, benzoimidazole, indole, oxindole and indazole.

As used herein, the term "hydroxyalkyl" refers to an alkyl group as defined above substituted with at least one hydroxy, hydroxy being as defined herein. Examples of branched or straight chained "CrCβ hydroxyalkyl" groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl substituted independently with one or more hydroxy groups.

As used herein, the term "optionally" means that the subsequently described event(s) may or may not occur, and includes both event(s), which occur, and events that do not occur.

As used herein, the term "substituted" refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.

The term "Syk inhibitor", is used to mean a compound which inhibits the Syk receptor respectively.

The term "Syk mediated disease" or a "disorder or disease or condition mediated by inappropriate Syk activity" is used to mean any disease state mediated or modulated by Syk kinase mechanisms, in particular inflammatory, allergic and autoimmune diseases including asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDs), ulcerative colitis, Crohns

disease, bronchitis, dermatitis, allergic rhinitis, psorasis, scleroderma, urticaria, rheumatoid arthritis, multiple sclerosis, cancer, HIV and lupus.

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.

As used herein, "a compound of the invention" means a compound of formula (I) or a salt, or solvate thereof.

Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a complex with water is known as "hydrate". Solvates of the compound of the invention are within the scope of the invention.

As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I), or a salt thereof) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, acetone, methanol, ethanol and acetic acid.

Preferably the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include water, ethanol and acetic acid. Most preferably the solvent is water.

The compounds of formula (I) including salts and solvates thereof may have the ability to crystallize in more than one form, a characteristic, which is known as polymorphism, and it is understood that such polymorphic forms ("polymorphs") are within the scope of formula (I). 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 polymorphs. 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, diasteroisomers, 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 our (l) 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 in the compound of the present invention whether such tautomers exist in equilibrium or predominately in one form.

In one embodiment, R ¹ is H or -CH3. In a further embodiment R ¹ is H.

In one embodiment R ² is "OH, -CH3 or -CH2OH. In a further embodiment R ² is -OH.

In one embodiment, R ³ is phenyl (optionally substituted one or more times by substituents independently selected from -CH3, "F, -CF3, -OCH3) or R ³ is

In a further embodiment, R ³ is phenyl (monsubstituted in the ortho, para or meta position by -CH ₃ , -F, -CH ₃ or -OCH ₃ ) or R ³ is

In one embodiment, R ⁴ is a bicyclic heteroaryl group having 9-14 ring members (optionally substituted by one or more substituents independently selected from F,

-CH ₃ , = O, -(CH ₂ ) ₂ N(CH ₃ ) ₂ . In a further embodiment, R ⁴ is

In an embodiment, R ⁴ is phenyl (optimally substituted by, one or more substituents independently selected from

-Cl, -CN, -CH ₃ , -CH2SO2CH3, -OCH3, F, -COOH, -CO-phenyl,

or a group -XNR ^c R ^d wherein X is as described herein above and NR ^c R ^d represents -NH ₂ , -N(CHa) ₂ , -NH(CH ₃ ), -NH(CH ₂ ) ₃ , N(CHa) ₂ ,

In a further embodiment, R ⁴ is phenyl which is mono substituted.

While the embodiments for each variable have generally been listed above separately for each variable this invention includes those compounds in which several or each embodiment in formula (I) is selected from each of the embodiments listed above. Therefore, this invention is intended to include all combinations of embodiments for each variable.

Specific examples of compounds of the present invention include Examples 1 — 284 as described in the Examples section below.

The compounds of the present invention may be in the form of and/or may be administered as a pharmaceutically acceptable salt. For a review on suitable salts see Berge et al, J. Pharm. Sci. 1977, 66, 1-19.

Typically, the salts of the present invention are pharmaceutically acceptable salts.

As used herein, the term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal un desired 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.

Suitable pharmaceutically acceptable salts can include acid or base additions salts.

A pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamaic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic such as 2 -naphthalene sulfonic, or hexanoic acid), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration. A pharmaceutically acceptable acid addition salt of a compound of formula (I) can comprise or be for example a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formarate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethane sulfonate, naphthalenesulfonate (e.g.

2-naphthalenesulfbnate) or hexanoate salt.

A pharmaceutically acceptable base addition salt may, where there is a suitable acidic group, be formed by reaction of a compound of formula (I) with a suitable inorganic or organic base (e.g. triethylamine, ethanolamine, triethanolamine, choline, arginine, lysine or histidine), optionally in a suitable solvent such as an organic solvent, to give the base addition salt which is usually isolated for example by crystallisation and filtration.

Other suitable pharmaceutically acceptable salts include pharmaceutically acceptable metal salts, for example pharmaceutically acceptable alkali-metal or alkaline-earth-metal salts such as sodium, potassium, calcium or magnesium salts; in particular pharmaceutically acceptable metal salts of one or more carboxylic acid moieties that may be present in the compound of formula (I).

Other non-pharmaceutically acceptable salts, e.g. oxalates or trifluoroacetates, may be used, for example in the isolation of compounds of the invention, and are included within the scope of this invention.

The invention includes within its scope all possible stoichiometric and non- stoichiometric forms of the compounds of formula (I).

The compounds of formula (I) and salts and solvates thereof are believed to be inhibitors of Syk activity, and thus be potentially useful in the treatment of diseases and conditions associated with inappropriate Syk activity.

The invention thus provides compounds of formula (I) and salts and solvates thereof for use in therapy, and particularly in the treatment of diseases and conditions mediated by inappropriate Syk activity.

While it is possible that, for use in therapy, a compound of formula (I), as well as salts and solvates thereof, may be administered as the raw chemical, it is possible to present the active ingredient as a pharmaceutical composition. Accordingly,

the invention further provides a pharmaceutical composition, which comprises a compound of formula (I) and salts and solvates thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The compounds of the formula (I) and salts and solvates thereof, are as described above. The carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical composition including admixing a compound of the formula (I), or salts and solvates thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.

Pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, for example, 5μg to Ig, preferably lmg to 700mg, more preferably 5mg to lOOmg of a compound of the formula (I), depending on the condition being treated, the route of administration and the age, weight and condition of the patient. Such unit doses may therefore be administered more than once a day. Preferred unit dosage compositions are those containing a daily dose or sub- dose (for administration more than once a day), as herein above recited, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical compositions may be prepared by any of the methods well known in the pharmacy art.

Pharmaceutical compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, inhaled, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).

Pharmaceutical compositions adapted for oral administration may be presented as discrete units such as capsules or tablets! powders or granules! solutions or

suspensions in aqueous or non-aqueous liquids! edible foams or whips! or oiHn-water liquid emulsions or water-in-oil liquid emulsions.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.

Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as

bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.

Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.

Where appropriate, dosage unit compositions for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.

The compounds of formula (I), and salts, solvates and physiological functional derivatives thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids,

such as cholesterol, stearylamine or phosphatidylcholines.

The compounds of formula (I) and salts, solvates and physiological functional derivatives thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.

Pharmaceutical compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

For treatments of the eye or other external tissues, for example mouth and skin, the compositions are preferably applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oiHn-water cream base or a water-in-oil base.

Pharmaceutical compositions adapted for topical administrations to the eye

include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical compositions adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.

Pharmaceutical compositions adapted for rectal administration may be presented as suppositories or as enemas.

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

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 Lrleucine 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 ™ 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.

The compound of formula (I) or pharmaceutically acceptable salts or solvates thereof may be formulated as a fluid formulation for delivery from a fluid dispenser, for example 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. A fluid dispenser of the aforementioned type is described and illustrated in WOA-2005/044354, the entire content of which is hereby incorporated herein by reference. 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.

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.

Pharmaceutical compositions adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered, dose pressurised aerosols, nebulizers or insufflators.

Pharmaceutical compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

Pharmaceutical compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti- oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

It should be understood that in addition to the ingredients particularly mentioned

above, the compositions may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.

A therapeutically effective amount of a compound of the present invention will depend upon a number of factors including, for example, the age and weight of the animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian However, an effective amount of a compound of formula (I) for the treatment of diseases or conditions associated with inappropriate Syk activity, will generally be in the range of 5μg to 100 mg/kg body weight of recipient (mammal) per day and more usually in the range of 5μg to 10 mg/kg body weight per day. This amount may be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same. An effective amount of a salt or solvate, thereof, may be determined as a proportion of the effective amount of the compound of formula (I) per se.

The compounds of the present invention and their salts and solvates, and physiologically functional derivatives thereof, may be employed alone or in combination with other therapeutic agents for the treatment of diseases and conditions associated with inappropriate tyrosine and serine/threonine kinase activity. Combination therapies according to the present invention thus comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, and the use of at least one other pharmaceutically active agent. Preferably, combination therapies according to the present invention comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, and at least one other pharmaceutically active agent. The compound(s) of formula (I) and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately this may occur simultaneously or sequentially in any order. The amounts of the compound(s) of

formula (I) and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.

The compounds of formula (I) and salts, solvates and physiological functional derivatives thereof, are believed to have therapeutic potential particularly in inflammatory, allergy and autoimmune diseases as a result of inhibition of the protein kinase Syk.

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

The present invention also provides compounds of formula (I) and pharmaceutically acceptable salts or solvates thereof, or physiologically functional derivatives thereof for use in the treatment of disorders mediated by inappropriate Syk activity.

The inappropriate Syk activity referred to herein is any Syk activity that deviates from the normal Syk activity expected in a particular mammalian subject. Inappropriate Syk activity may take the form of, for instance, an abnormal increase in activity, or an aberration in the timing and or control of Syk activity. Such inappropriate activity may result then, for example, from overexpression or mutation of the protein kinase leading to inappropriate or uncontrolled activation.

The present invention is directed to methods of regulating, modulating, or inhibiting Syk for the prevention and/or treatment of disorders related to unregulated Syk activity.

A further aspect of the invention provides a method of treatment of a mammal suffering from a disorder mediated by Syk activity, which includes administering to said subject a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or a physiologically functional derivative thereof.

A further aspect of the present invention provided the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, in the preparation of a medicament for the treatment of a disorder mediated by Syk activity.

The compounds of the present invention and their salts and solvates, and physiologically functional derivatives thereof, may be employed alone or in combination with other therapeutic agents. Combination therapies according to the present invention thus comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and the use of at least one other pharmaceutically active agent. Preferably, combination therapies according to the present invention comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and at least one other pharmaceutically active agent. The compound(s) of formula (I) and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately this may occur simultaneously or sequentially in any order. The amounts of the compound(s) of formula (I) and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. Thus in a further aspect, the present invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and a further therapeutic agent, pharmaceutical compositions containing said combination and use of such combinations and compositions in therapy.

Compounds of the present invention may also be used in combination with other classes of therapeutic agents which are known in the art. Representative classes of agents for use in such combinations include, for treating asthma, anti-inflammatory steroids (in particular corticosteroids), anticholinergic agents, 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 Hl 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 Al (Glaxo Group Ltd), in particular, the compounds of Example 1 ( 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-llβ-hydroxy- 16α-methyl-3-oxo-andr osta-l,4-diene-17β-carbothioic acid _* S ^L fluoromethyl ester) and Example 41 (6α,9α-difluoro-llβ-hydroxy-16α-methyl-17α-[(4-methyM,3 -thiazole-5-carbonyl)o xy]-3-oxo-androsta-l,4-diene-17β-carbothioic acid AS'-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 antihistamines include methapyrilene, olopatadine, or loratadine, cetirizine, desloratadine or fexofenadine.

Examples of anticholinergic compounds include muscarinic (M) receptor antagonists, in particular Mi, M2, M1M2, 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 Al and US 2002/052312 Al. 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).

It will be clear to a person skilled in the art that, where appropriate, the other therapeutic ingredient(s) may be used in the form of salts, for example as alkali metal or amine salts or as acid addition salts, or prodrugs, or as esters, for example lower alkyl esters, or as solvates, for example hydrates, to optimise the activity and/or stability and/or physical characteristics, such as solubility, of the therapeutic ingredient. It will be clear also that, where appropriate, the therapeutic ingredients may be used in optically pure form.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical composition and thus pharmaceutical compositions comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention. These combinations are of particular interest in respiratory diseases and are conveniently adapted for inhaled or intranasal delivery.

Rheumatoid arthritis (RA) is a further inflammatory disease where combination therapy may be contemplated. Thus in a further aspect, the present invention provides a compound of formula (I) or a salt or solvate thereof in combination with a further therapeutic agent useful in the treatment of rheumatoid arthritis, said combination being useful for the treatment of rheumatoid arthritis.

The compound and pharmaceutical compositions according to the invention may be used in combination with or include one or more other therapeutic agents, for example selected from NSAIDS, corticosteroids, COX-2 inhibitors, cytokine inhibitors, anti-TNF agents, inhibitors of oncostatin M, antimalarials, immunosuppressivess and cytostatics

Two classes of medication are contemplated for the treatment of RA, these may be

classified as "fast acting" and "slow acting" or "second line" drugs (also referred to as Disease Modifying Antirheumatic Drugs or DMARDS). The first line drugs such as typical NSAIDs (e.g. aspirin, ibuprofen, naproxen, etodolac), corticosteroids (e.g. prednisone). Second line drugs include COX-2 inhibitors and anti-TNF agents. Examples of COX-2 inhibitors are celecoxib (Celebrex), etoricoxib and rofecoxib (Vioxx).

Anti-TNF agents include infliximab (Remicade), etanercept (Enbrel) and adalimumab (Humira). Other "biological" treatments include anakinra (Kineret), Rituximab, Lymphostat-B, BAFF/APRIL inhibitors and CTLA-4-Ig or mimetics thereof. Other cytokine inhibitors include leflunomide (Arava). Further second line drugs include gold preparations (Auranofin (Ridaura tablets) or Aurothiomalate (Myocrisin injection)), medicines used for malaria: (Hydroxychloroquine (Plaquenil)), medicines that suppress the immune system (Azathioprine (Imuran, Thioprine), methotrexate (Methoblastin, Ledertrexate, Emthexate), cyclosporin (Sandimmun, Neoral)), Cyclophosphamide (Cycloblastin), Cytoxan, Endoxan), D-Penicillamine (D-Penamine), Sulphasalazine (Salazopyrin), nonsteroidal anti inflammatory drugs (including aspirin and ibuprofen).

The present invention also provides for so-called "triple" 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 described above and/or as described in WO 03/030939 Al. 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.

The individual compounds of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical compositions. Preferably, the individual compounds will be administered

simultaneously in a combined pharmaceutical composition. Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.

The compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the Working Examples.

Compounds of general formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthesis schemes. In all of the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of Formula (I). Those skilled in the art will recognize if a stereocenter exists in compounds of Formula (I). Accordingly, the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. When a compound is desired as a single enantiomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wileylnterscience, 1994).

SCHEME 1

O OTMS OH

FT' TMS-CN, NH ₉

FT CN LAH, ether R neat, N ₉ reflux, 3 h

Intermediates 3a-12a

SCHEME 2

EXAMPLES

As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of

Biological Chemistry. Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the Lrconfiguration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification:

g (grams);

1 (liters); μl (microliters);

M (molar);

MHz (megahertz); mmol (millimoles); min (minutes); Rt (retention time);

MeOH (methanol);

TFA (trifluoroacetic acid);

THF (tetrahydrofuran);

DMSO (dimethylsulfoxide); DCM (dichloromethane);

DMF (λζN-dimethylformamide);

Ac (acetyl);

TMS (trimethylsilyl);

DMAP (4-dimethylaminopyridine); ATP (adenosine triphosphate);

DMEM (Dulbecco's modified Eagle medium);

HPLC (high pressure liquid chromatography);

TBAF (tetra-irbutylammonium fluoride);

HBTU(O-Benzotriazole-l-yl-λ^λ^λ/ ^" ^λ/ ^"i tetramethyluroniumhexafluoro phosphate).

HEPES (4-(2-hydroxyethyl)-l-piperazine ethane sulfonic acid);

DPPA (diphenylphosphoryl azide);

EDTA (ethylenediaminetetraacetic acid);

TMEDA (λ^λζ^NHetramethyl-l^-ethanediamine);

NBS (jV-bromosuccinimide);

HATU (O-(7azabenzobenzotriazol-l-yl)-AfAfA/ ^" 'A^etramethyluronium hexafluorophosphate) ; DIPEA (diisopropylethylamine); dppf (l,l'-bis(diphenylphosphino)ferrocene);

NIS (λ^iodsuccinimide);

PTFE ((poly)tetrafluoroethylene);

LC/MS (liquid chromatography - mass spectrometry); mg (milligrams); ml (milliliters); psi (pounds per square inch); mM (millimolar); rt (room temperature); h (hours);

IPA (isopropanol); atm (atmosphere);

BSA (bovine serum albumin)

HRP (horseradish peroxidase);

All references to ether are to diethyl ether; brine refers to a saturated aqueous solution of NaCl. Unless otherwise indicated, all temperatures are expressed in °C (degrees Centigrade). All reactions are conducted under an inert atmosphere at room temperature unless otherwise noted.

¹ H NMR spectra were recorded using a Bruker DPX 400MHz, Bruker DPX

250MHz or a Bruker DRX 600MHz machine referenced to tetramethylsilane.

LC/MS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm x 4.6 mm ID) eluting with 0.1% HCO2H and 0.01M 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"4.2min 100%B, 4.2-5.3min 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

or a Waters ZQ spectrometer using electrospray positive and negative mode (ES+ve and ES- ve).

"Mass directed autoprep" / "preparative mass directed HPLC" was conducted on a system such as; a Waters FractionLynx system comprising of a Waters 600 or a Waters 2525 pump with extended pump heads, Waters 2700 or Waters 2767 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 recorded on a Micromass ZMD or a Waters ZQ mass spectrometer using electrospray positive and negative mode, alternate scans. The software used was MassLynx 3.5 with OpenLynx and FractionLynx options or using equivalent alternative systems.

Method A refers to use of a water / acetonitrile gradient containing 0.1% formic acid. Method B refers to use of a water / acetonitrile gradient containing 0.1% trifluoroacetic acid.

"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.

Flash silica chromatography techniques include either automated (Flashmaster/ISCO SQ16X) techniques or manual chromatography on pre-packed cartridges (SPE/Redisep) or manually-packed flash columns.

The ISCO SQ16X is an automated multi-user flash chromatography system, available from Presearch, which utilises disposable, normal phase, Redisep™ cartridges (4 g to 33Og). 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

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 Examples have been obtained using the compound naming programme "ACD Name Pro 6.02".

Intermediate 1

2- [(2-chloro-4-pyrimidinyl)amino] - 1 -phenylethanol

2-amincrl-phenylethanol (3.Og, 21.9mmol) and triethylamine (2.18g, 3mL, 21.6mmol) were added to a solution of 2,4-dichloropyrimidine (3.1g, 20.8mmol) in

THF (lOOmL). The mixture was left stirring at room temperature under a nitrogen atmosphere for 16 hours. After filtering through a glass sinter, the filtrate was pre-absorbed under vacuum onto diatomaceous earth. Purification was achieved using flash silica chromatography on an ISCO SQ16X machine, eluting with an ethyl acetate/cyclohexane gradient. Concentration of the relevant fractions afforded the title compound as a white solid (3.5g, 13.9mmol).

IH NMR (400 MHz, DMSOD6) δ ppm 3.27-3.37 (m, 1 H) 3.48-3.56 (m, 1 H) 4.67-4.77 (m, 1 H) 5.6 (d, J=A Hz, 1 H) 6.52 (d, J=G Hz, 1 H) 7.25 (t, J=I Hz, IH) 7.3-7.4 (m, 4 H) 7.87 (d, J=6 Hz, 1 H) 8.04 (bt, J=5 Hz, 1 H). MS m/z 250/252 (3:1 ratio) (M+ 1) ⁺

Intermediate 2 2-chlorcr.λK2-phenvlethvl)-4-pvrimidinamine

A mixture of 2,4-dichloropyrimidine (l.OOg, 6.71mmol), (2-phenethyl)amine (0.885mL, 7.05mmol), triethylamine (0.983mL, 7.05mmol) and absolute ethanol

(2OmL) was stirred at ambient temperature for 18 hours. The volatiles were removed under vacuum and the residue partitioned between ethyl acetate^water.

The phases were separated and the aqueous phase extracted with ethyl acetate.

The combined organic phase was dried with magnesium sulfate and evaporated under vacuum to give an amber oil.

Purification was achieved using flash silica chromatography on an ISCO

Combiflash ^® , eluting with an ethyl acetate/hexanes gradient. Concentration of the relevant fractions afforded the title compound as a white solid (l.04g,

4.45mmol). IH NMR (400 MHz, DMSOD6) 8 ppm 2.80 (t, 2 H) 3.46-3.51 (m, 2 H) 6.42 (d, J=6

Hz, 1 H) 7.17-7.3 (m, 5 H) 7.86 (d, J=6 Hz, 1 H) 7.98 (br s, 1 H). MS m/z 234

(M+l) ⁺

Intermediate 3a 2-amino-l-(2-methylphenyl)ethanol

Universal Organics (Durham, NC)

The title compound was synthesized using the procedure recited for Intermediate 6a, except 2-methylbenzaldehyde was used. The product was converted to the hydrochloride salt by dissolving the free base in ethanol and adding cone.

hydrochloric acid followed by co-evaporation with ethanol. MS m/z 134 (M-17) ⁺

Intermediate 3b

2~ [(2'chloro'4-pyrimidinyl)amino] ~ 1 '(2τnethylphenyl)ethanol u21946/19/l

A mixture of 2,4-dichloropyrimidine (l-OOg, 6.71mmol),

2-amino"l"(2-methylphenyl)ethanol hydrochloride (l.32g, 7.05mmol), triethylamine (l.97mL, 14.1mmol) and absolute ethanol (2OmL) was stirred at ambient temperature for 2.5 days. The reaction mixture was pre-adsorbed to silica gel (5g) by removing the volatiles under vacuum. Purification was achieved using flash silica chromatography on an ISCO Combiflash ^® , eluting with an ethyl acetate/hexanes gradient. Concentration of the relevant fractions afforded the title compound as a white solid (0.98g, 3.7mmol).

IH NMR (400 MHz, DMSOD6) δ ppm 2.35 (s, 3 H) 3.05-3.11/3.49-3.53 (m, 2 H) 4.91-4.93 (m, 1 H) 5.42 (d, 1 H) 6.48 (d, J=5.8 Hz, 1 H) 7.10-7.18 (m, 3 H) 7.45 (d, J=T.3 Hz, 1 H) 7.85 (d, J=5.8 Hz, 1 H) 8.17 (br t, 1 H). MS m/z 264 (M+l) ⁺

Intermediate 4a

2'amino' 1 '(3τnethylphenyl)ethanol

Universal Organics (Durham, NC)

The title compound was synthesized using the procedure recited for Intermediate 3a, except 3-methylbenzaldehyde was used. MS m/z 134 (M- 17) ⁺

Intermediate 4b 2- [(2-chloro-4-pyrimidinyl)amino] - 1 -(3-methylphenyl)ethanol

A mixture of 2,4-dichloropyrimidine (0.541g, 3.63mmol),

2-amino"l"(3"methylphenyl)ethanol hydrochloride (0.715g, 3.81mmol), triethylamine (l.OδmL, 7.62mmol) and absolute ethanol (2OmL) was stirred at ambient temperature for 2.5 days. The reaction mixture was pre-adsorbed to silica gel (5g) by removing the volatiles under vacuum. Purification was achieved using flash silica chromatography on an ISCO Combiflash ^® , eluting with an ethyl acetate/hexanes gradient. Concentration of the relevant fractions afforded the title compound as a white solid (0.707g, 2.68mmol). IH NMR (400 MHz, DMSOD6) δ ppm 2.27 (s, 3 H) 3.24-3.31/3.45-3.49 (m, 2 H) 4.66 (m, 1 H) 5.50 (d, 1 H) 6.49 (d, J=6 Hz, 1 H) 7.03 (d, 1 H) 7.11-7.20 (m, 3 H) 7.84 (d, J=6 Hz, 1 H) 7.99 (br t, 1 H). MS m/z 264 (M+l) ⁺

Intermediate 5a

2'amino' 1 -(4-methylphenyl)ethanol

Universal Organics (Durham, NC)

The title compound was synthesized using the procedure recited for Intermediate 3a, except 4-methylbenzaldehyde was used. MS m/z 134 (M-17) ⁺

Intermediate 5b 2~ [(2'chloro'4-pyrimidinyl)amino] ~ 1 -(4-methylphenyl)ethanol

The title compound was synthesized using the procedure recited for Intermediate 3, except 2-amino-l-(4-methylphenyl)ethanol hydrochloride (l.32g, 7.05mmol) was used to give solid (0.99g, 3.8mmol). IH NMR (400 MHz, DMSOD6) 8 ppm 2.31 (s, 3 H) 3.29-3.38/3.47-3.54 (m, 2 H) 4.72 (m, 1 H) 5.54 (d, 1 H) 6.55 (d, J=Q Hz, 1 H) 7.23 (AB q, 4 H) 7.90 (d, J=6 Hz, 1 H) 8.03 (br t, 1 H). MS m/z 264 (M+ 1) ⁺

Intermediate 6a 2-amino-l-(2-fluorophenvl)ethanol

Trimethylsilylcyanide (l5.6mL, 117mmol) was added to neat 2-fluorobenzaldehyde (4.24mL, 40.3mmol) under a flow of nitrogen. A catalytic amount of zinc iodide (0.154g, 0.484mmol) was added in one portion to the stirring mixture (exothermic) and the reaction was stirred overnight for 18 hours. The volatiles were removed under vacuum at 7O ⁰ C. The residual oil was dissolved in ether (3OmL) and the TMS-protected cyanohydrin/ether solution added to IM lithium aluminum hydride in ether (l22mL) over 20 minutes, maintaining mild reflux. After three hours reflux, the reaction was cooled to ambient temperature. Using the Fieser workup procedure (ref. l), excess LAH was quenched by dropwise addition of H2O (4.6mL), then with 15% aqueous NaOH (4.6mL), followed by addition of H2O (l3.9mL). The aluminum salts were removed by filtration and the solids were washed with warm EtOAc (3x15OmL). The combined EtOAc extract was dried over sodium sulfate, filtered, and the volatiles removed under vacuum to give the title compound (5.46g, 35.2mmol) as a red-amber oil. IH NMR (300 MHz, DMSO-D6) δ ppm 1.65 (br s, 2H), 2.62 (m, 2H), 4.72 (m, IH), 5.38 (br s, IH), 7.06-7.30 (m, 3H), 7.47 (m, IH). MS m/z 156 (M+l) ⁺

Intermediate 6b

2~ [(2'chloro'4-pyrimidinyl)amino] ~ 1 '(2'fluorophenyl)ethanol

The title compound was synthesized using the procedure recited for Intermediate 3, except 2-amino-l-(2-fluorophenyl)ethanol (l.09g, 7.03mmol) and triethylamine (0.98OmL, 7.03mmol) was used to give solid (0.571g, 2.13mmol). IH NMR (300 MHz, DMSO-D6) δ ppm 2.31 (s, 3 H) 3.25-3.55 (m, 2 H) 5.07 (m, 1 H) 5.72 (d, 1 H) 6.52 (d, J=Q Hz, 1 H) 7.11-7.37 (m, 3 H) 7.48-7.59 (m, 1 H) 7.89 (d,

J=6 Hz, 1 H) 8.08 (br t, 1 H). MS m/z 268 (M+l) ⁺

Intermediate 7a 2-amino-l-(3-fluorophenyl)ethanol

The title compound was synthesized using the procedure recited for Intermediate 3a, except 3-fluorobenzaldehyde was used and the free base was isolated. MS m/z 156 (M+l) ⁺

Intermediate 7b

2~ [(2'chloro'4-pyrimidinyl)amino] ~ 1 '(3'fluorophenyl)ethanol

The title compound was synthesized using the procedure recited for Intermediate 6, except 2-amino-l-(3-fluorophenyl)ethanol (l.09g, 7.03mmol) was used to give solid (0.852g, 3.18mmol).

IH NMR (300 MHz, DMSOD6) δ ppm 3.33-3.45/3.51-3.59 (m, 2 H) 4.79 (m, 1 H) 5.75 (d, 1 H) 6.55 (d, J=G Hz, 1 H) 7.07-7.14 (m, 1 H) 7.21-7.39 (m, 2 H) 7.41-7.44 (m, 1 H) 7.90 (d, J=6 Hz, 1 H) 8.06 (br t, 1 H). MS m/z 268 (M+l) ⁺

Intermediate 8a

2'amino' 1 ~ [3'(methyloxy)phenyl]ethanol

Universal Organics (Durham, NC)

The title compound was synthesized using the procedure recited for Intermediate 3a, except 3-methoxybenzaldehyde was used. MS m/z 168 (M+ 1) ⁺

Intermediate 8b

2- [(2-chloro-4-pyrimidinyl)amino] - 1 - [3-(methyloxy)phenyl] ethanol u21946/19/8

The title compound was synthesized using the procedure recited for Intermediate 3, except 2-amino-l-[3-(methyloxy)phenyl]ethanol hydrochloride (l.44g, 7.07mmol) was used to give solid (l.41g, 5.04mmol).

IH NMR (300 MHz, DMSOD6) δ ppm 2.31 (s, 3 H) 3.32-3.40/3.51-3.64 (m, 2 H) 3.78 (s, 3 H) 4.74 (m, 1 H) 5.61 (d, 1 H) 6.56 (d, J=6 Hz, 1 H) 6.83-6.87 (m, 1 H) 6.96-6.98 (m, 1 H) 7.25-7.30 (m, 1 H) 7.90 (d, J=6 Hz, 1 H) 8.05 (br t, 1 H). MS m/z 280 (M+l) ⁺

Intermediate 9a

2'amino' 1 ~ [2 '(trifluoromethyl)phenyl] ethanol

Universal Organics (Durham, NC)

The title compound was synthesized using the procedure recited for Intermediate 3a, except 2-(trifluoromethyl)benzaldehyde was used. MS m/z 206 (M+l) ⁺

Intermediate 9b 2- [(2-chloro-4-pyrimidinyl)amino] - 1 - [2-(trifluoromethyl)phenyl] -ethanol

The title compound was synthesized using the procedure recited for Intermediate 3, except 2-amino"l"[2-(trifluoromethyl)phenyl]ethanol hydrochloride (l.70g, 7.04mmol) was used to give solid (l.66g, 5.23mmol).

IH NMR (300 MHz, DMSOD6) δ ppm 3.42-3.56 (m, 2 H) 5.09 (m, 1 H) 5.89 (d, 1 H) 6.53 (d, J=G Hz, 1 H) 7.49-7.54 (m, 1 H) 7.69-7.75 (m, 2 H) 7.86-7.91 (m, 2 H) 8.14 (br s, I H). MS m/z 318 (M+l) ⁺

Intermediate IQa

2-amino- 1 - [3-(trifluoromethyl)phenyl] ethanol

Universal Organics (Durham, NC)

The title compound was synthesized using the procedure recited for Intermediate 3a, except 3-(trifluoromethyl)benzaldehyde was used. MS m/z 206 (M+l) ⁺

Intermediate IQb

2- [(2-chloro-4-pvrimidinvl)amino] " 1 " [3-(trifluoromethvl)phenvll -ethanol

The title compound was synthesized using the procedure recited for Intermediate 3, except 2-amino-l-[3-(trifluoromethyl)phenyl]ethanol hydrochloride (l.70g, 7.04mmol) was used to give solid (l.l4g, 3.59mmol).

IH NMR (300 MHz, DMSOD6) δ ppm 3.43-3.59 (m, 2 H) 4.88 (m, 1 H) 5.84 (d, 1 H) 6.54 (d, J=6 Hz, 1 H) 7.57-7.75 (m, 4 H) 7.89 (d, J=Q Hz, 1 H) 8.08 (br s, 1 H). MS m/z 318 (M+l) ⁺

Intermediate 11a

2-amino- 1 - [4-(trifluoromethyl)phenyl] ethanol

Universal Organics (Durham, NC)

The title compound was synthesized using the procedure recited for Intermediate

3a, except 4-(trifluoromethyl)benzaldehyde was used and the free base was isolated.

MS m/z 206 (M+l) ⁺

Intermediate lib

2- [(2-chloro-4-pyrimidinyl)amino] - 1 - [4-(trifluoromethyl)phenyl] -ethanol

The title compound was synthesized using the procedure recited for Intermediate

6, except 2-amino-l-[4-(trifluoromethyl)phenyl]ethanol hydrochloride (l.44g, 7.02mmol) was used to give solid (l.02g, 3.21mmol).

IH NMR (300 MHz, DMSOD6) δ ppm 3.40-3.57 (m, 2 H) 4.86 (m, 1 H) 5.83 (d, 1 H) 6.54 (d, J=6 Hz, 1 H) 7.61-7.63 (m, 2 H) 7.72-7.75 (m, 2 H) 7.91 (d, J=Q Hz, 1 H) 8.07 (br s, 1 H). MS m/z 318 (M+l) ⁺

Intermediate 12a

2'amino' 1 ~(2 -pyridinyl)ethanol

The title compound was synthesized using the procedure recited for Intermediate 3a, except 2-pyridinecarbaldehyde was used. MS m/z 139 (M+l) ⁺

Intermediate 12b 2- [(2-chloro-4-pyrimidinyl)amino] - 1 -(2-pyridinyl)ethanol

The title compound was synthesized using the procedure recited for Intermediate 3, except 2-amino-l-(2-pyridinyl)ethanol hydrochloride (l.23g, 7.04mmol) was used to give solid (l.l7g, 4.67mmol).

IH NMR (300 MHz, DMSOD6) δ ppm 3.20-3.48/3.79-3.84 (m, 2 H) 4.80 (m, 1 H) 5.82 (d, 1 H) 6.56 (d, J=Q Hz, 1 H) 7.29-7.33 (m, 1 H) 7.53-7.58 (m, 1 H) 7.80-7.90 (m, 2 H) 8.05 (br s, 1 H) 8.54 (d, 1 H). MS m/z 251 (M+l) ⁺

Intermediate 13 ffi(3-nitrophenyl) - 1 -pyrrolidinecarboxamide

Pyrrolidine (5.08mL, 60.9mmol) was added dropwise to a stirring solution of l-isocyanato-3-nitrobenzene (lO.Og, 60.9mmol) and tetrahydrofuran (l25mL) over 15 minutes. The reaction was stirred at ambient temperature for 18 hours and concentrated to dryness. The residue was dissolved in EtOAc

(60OmL) and washed with 0.1N hydrochloric acid (2x50mL), then with water

(5OmL) and saturated brine (5OmL). The organic layer was dried over sodium sulfate, filtered, and the volatiles removed under reduced pressure to give the title compound (13. Ig, 55.7mmol) as a solid.

IH NMR (400 MHz, DMSOD6) δ ppm 1.82-1.85 (m, 4H) 3.34-3.37 (m, 4H) 7.48 (t, ,7=8.2 Hz, IH) 7.73 (dd, ,7=7.9 Hz, IH) 7.93 (dd, J=8.2 Hz, IH) 8.52 (dd, J=2.2 Hz, IH) 8.61 (s, IH). MS m/z 236 (M+l) ⁺

Intermediate 14

■λK3-aminophenyl) ' 1 'Pyrrolidinecarboxamide

A mixture of Intermediate 13 (13. Og, 55.3mmol), 10% palladium on carbon (0.65g) and EtOH (225mL) was shaken on a Parr apparatus under a hydrogen atmosphere 4 hours. The reaction mixture was filtered through Celite and the pad rinsed with EtOH. The combined filtrates were concentrated to an oil

(lθ.8g). The residue was dissolved in EtOH (lOmL) with warming and sonication, then ether (40OmL) was added to the solution and stirred for 18 hours at ambient temperature. The solids were collected by filtration and dried to give the title compound (lO.Og, 48.7mmol) as a tan solid. IH NMR (300 MHz, DMSO-D6) δ ppm 1.81-1.90 (m, 4H) 3.34-3.38 (m, 4H) 4.90

(br s, 2H) 6.17 (dd, J=I. S Hz, IH) 6.64 (d, ,7=7.9 Hz, IH) 6.82-6.90 (m, 2H) 7.77 (s, IH). MS m/z 206 (M+l) ⁺

Intermediate 17 Preparation of 5-amino-2-(2-dimethylamino-ethyl)isoindole-l,3-dione

a. 5-nitro-2-(2-dimethylamino-ethyl)isoindole-l,3-dione monohydrochloride

The reaction was carried out in a 6 L 3-necked RB flask, equipped with a mechanical stirrer, thermometer, condenser and CaCb tube.

λ^λ^dimethylethylenediamine (234.8 g, 2.59 mol) was added to a stirred suspension of 4-nitro-phthalic anhydride (500 g, 2.66 mol) in glacial acetic acid (3,383 ml) over 30 minutes. The temperature rose from 15 to 32°C during this addition. The resulting solution was heated to reflux (ca. 112°C) for 48 hours. The reaction mixture was then allowed to cool to room temperature and filtered. The filtrate was concentrated to ca. 2 L and filtered again. The resulting latter filtrate was concentrated to dryness. The solid residue was taken up in methanol (250 ml) and Et2θ (2,250 ml), and treated with methanolic HCl (from MeOH (500 ml) and AcCl (160 ml)). The precipitated salt was collected by filtration, dried and recrystallised from MeOH (3 1) to give a cream coloured solid (254 g, 33 % theory).

b. 5-amino-2-(2-dimethylamino-ethyl)isoindole-l,3-dione monohydrochloride

The reduction was carried out in a 2 1 3-necked flask provided with magnetic stirring.

To a warm solution (35°C) of the nitro compound (105 g, 0.35 mol) in methanol

(1,575 ml), purged with N2, was added 5-10% Pd on C (21 g, water wet). The reaction mixture was stirred magnetically and purged with H2. A modest exotherm maintained the temperature at 33"37 ^O C, and theoretical uptake of hydrogen occurred in 5 hours.

This reaction was repeated for a second batch under identical conditions.

The two reaction mixtures were then combined, heated to ca. 50 ⁰ C and filtered hot through Celite. The cake was washed further with MeOH (6 L, and the combined mother and wash liquors concentrated to dryness, giving a bright yellow

solid (160 g).

The filter cake was again washed with further hot methanol (1.5 L, 50 ⁰ C) and the filtrate used to slurry wash the crude product.

Filtration gave the target compound as a bright yellow solid of m.p 248.8-249.9°C (156 g, 82% theory).

IH NMR (300 MHz, DMSOdδ) δ ppm 10.41 (br s, IH), 7.52 (d, IH, J = 8.2), 6.98 (s, IH), 6.85 (dd, IH, J = 8.2, 2), 6.6 (br s, 2H), 3.88 (t, 2H, J = 6.2), 3.34 (t, 2H, J = 5.9), 2.83 (s, 6H)

Example Y-

2 - [2 - (dimethylamino)ethyl] - 5 -({4- [(2 -hydroxy-2 -phenylethyl) amino] -2 -pyrimidinyl }amino)-l.ffisoindole-l,3(2.fl!)-dione

2-[(2-chloro"4-pyrimidinyl)amino]"l"phenylethanol (37mg, O.lδmmol) and 5-amino-2-[2-(dimethylamino)ethyl]-lH-isoindole-l,3(2H)-dion e (78mg,

0.30mmol) were combined with isopropanol (2mL) and cone, hydrochloric acid (75μL, 0.9mmol). The mixture was heated to 17O ⁰ C for 20 minutes in a

Personal Chemistry SmithSynthesizer ^® microwave instrument. Triethylamine (l39μL, l.Ommol) was added and volatiles removed under vacuum with heating at 75 ⁰ F. The compound was purified by mass- directed ηPLC. Concentration of the relevant fractions afforded the title compound as a solid (I9mg, 0.043mmol).

MS m/z 447 (M+l) ⁺

Example 2:

2-{[2-({3-[2-(4-morpholinyl)ethyl]phenyl}amino)-4-pyrimid inyl]amino}-l-phenylet hanol

The title compound was synthesized using the procedure recited in Example 1, except 3" [2-(4-morpholinyl)ethyl] aniline (57mg, 0.30mmol) was used to give solid

(38mg, 0.092mmol). MS m/z 420 (M+l) ⁺

Example 3: 4-[3'({4-[(2'hvdroxy2'phenylethyl)amino]'2'Pyrimidinyl}amino )phenyl]'5'methyl' 2.4-dihvdro-3,ffl.2.4-triazol-3-one

The title compound was synthesized using the procedure recited in Example 1, except 4-(3"aminophenyl)-5"methyl-2,4-dihydro"3H"l,2,4-triazol"3"θ ne (57mg, 0.30mmol) was used to give solid (25mg, 0.063mmol).

MS m/z 404 (M+l) ⁺

Example 4:

4-[4-({4-[(2'hvdroxy2'phenylethyl)amino]'2'pyrimidinyl}am ino)phenyl]'5'methyl' 2,4-dihvdro-3,ffl,2,4-triazol-3-one

The title compound was synthesized using the procedure recited in Example 1, except 4-(4-aminophenyl)-5"methyl-2,4-dihydro"3H"l,2,4-triazol"3"θ ne (55mg, 0.30mmol) was used to give solid (l9mg, 0.046mmol). MS m/z 404 (M+l) ⁺

Example 5:

■λ^[4-({4-[(2'hvdroxy2'phenylethyl)amino]'2'pyrimidiny l}amino)phenyl]'3'(l'pipe ridinvOpropanamide

The title compound was synthesized using the procedure recited in Example 1, except AK4-aminophenyl)-3-(l-piperidinyl)propanamide (70mg, 0.30mmol) was used to give solid (27mg, 0.059mmol). MS m/z 461 (M+l) ⁺

Example 6:

2'({2'[(3'{[3'(4-morpholinyl)propyl]oxy}phenyl)amino]'4-p yrimidinyl}amino)'l'phe nylethanol

The title compound was synthesized using the procedure recited in Example 1, except 3-{[3-(4-morpholinyl)propyl]oxy}aniline (71mg, 0.30mmol) was used to give solid (48mg, O.llmmol). MS m/z 450 (M+l) ⁺

Example 7: l-[4-({4-[(2'hvdroxy2'phenylethyl)amino]'2'Pyrimidinyl}amino )phenyl]'4-(l-meth ylethyl)-2-piperazinone

The title compound was synthesized using the procedure recited in Example 1, except l-(4-aminophenyl)-4-(l-methylethyl)-2-piperazinone (66mg, 0.30mmol) was used to give solid (I8mg, 0.040mmol). MS m/z 447 (M+l) ⁺

Example 8:

1 ~ [3~({4- [(2 'hvdroxy2 'phenylethvOamino] ~2 'pyrimidinyl}amino)phenyl] ~4-(l -meth ylethyl)-2-piperazinone

The title compound was synthesized using the procedure recited in Example 1, except l-(3"aminophenyl)-4-(l-methylethyl)-2-piperazinone (64mg, 0.30mmol) was used to give solid (32mg, 0.071mmol).

MS m/z 447 (M+ 1) ⁺

Example 9:

2-{[2-({4- [(4-methyl- 1 -piperazinyl)carbonyl]phenyl}amino)-4-pyrimidinyl] amino}- 1 -phenylethanol

The title compound was synthesized using the procedure recited in Example 1, except 4- [(4-methyl-l-piperazinyl)carbonyl] aniline (61mg, 0.30mmol) was used to give solid (23mg, 0.054mmol). MS m/z 433 (M+l) ⁺

Example IQ:

■λ^'[4-({4-[(2'hvdroxy'2'phenylethv0amino]'2'pyrimidin yl}amino)phenyl]'.λ^..λ^'di methylglvcinamide

The title compound was synthesized using the procedure recited in Example 1, except j?V ¹ -(4-aminophenyl)-λ ² ,λ ² -dimethylglycinamide (52mg, 0.30mmol) was used to give solid (8.8mg, 0.022mmol). MS m/z 407 (M+l) ⁺

Example 11-

2-({2-[(3-{[4-(methylsulfonyl)-l-piperazinyl]methyl}pheny l)amino]-4-pyrimidinyl}a mino) - 1 -phenylethanol

The title compound was synthesized using the procedure recited in Example 1, except 3-{[4-(methylsulfonyl)-l-piperazinyl]methyl}aniline (77mg, 0.30mmol) was used to give solid (28mg, 0.059mmol). MS m/z 483(M+l) ⁺

Example 12:

■λ^[4-({4-[(2'hvdroxy'2'phenylethyl)amino]'2'pyrimidin yl}amino)phenyl]'3'(4-met hyl- 1 -piperazinvDpropanamide

The title compound was synthesized using the procedure recited in Example 1, except jV-(4-aminophenyl)-3"(4-methyl-l-piperazinyl)propanamide (74mg, 0.30mmol) was used to give solid (llmg, 0.023mmol). MS m/z 476 (M+l) ⁺

Example 13:

2-{[2-({4'-[(dimethylamino)methyl]-3-biphenylyl}amino)-4- pyrimidinyl] amino}- 1-p henylethanol

The title compound was synthesized using the procedure recited in Example 1, except 4'-[(dimethylamino)methyl]-3-biphenylamine (86mg, 0.30mmol) was used to give solid (21mg, 0.049mmol).

MS m/z 440 (M+l) ⁺

Example 14:

2'({2'[(2'methyl'4-{[2'(l'piperidinyl)ethyl]oxy}phenyl)am ino]'4-pyrimidinyl}amin o) - 1 -phenylethanol

The title compound was synthesized using the procedure recited in Example 1, except 4-{[2-(diethylamino)ethyl]oxy}"2-methylaniline (70mg, 0.30mmol) was used to give solid (39mg, 0.088mmol). MS m/z 448 (M+ 1) ⁺

Example 15:

2'[(2'{[3'(4-methyl'l'piperazinyl)phenyl] amino}'4-pyrimidinyl) amino] 'l'phenylet hanol

The title compound was synthesized using the procedure recited in Example 1, except 3-(4-methyl-l-piperazinyl)aniline (64mg, 0.30mmol) was used to give solid (25mg, O.Oδlmmol). MS m/z 405 (M+l) ⁺

Example 16: N- [4-({4- [(2 -hvdroxy-2 -phenylethvOamino] -2 -pyrimidinyl}amino)phenyl] -2 -(I -pipe ridinyl) acetamide

The title compound was synthesized using the procedure recited in Example 1, except 7V ^: (4-aminophenyl)-2-(l-piperidinyl)acetamide (66mg, 0.30mmol) was used to give solid (23mg, O.Oδlmmol).

MS m/z 447 (M+l) ⁺

Example 17:

4-({4-[(2-hvdroxy-2-phenylethyl)amino]-2-pyrimidinyl}amin o)-.^[2-(4-morpholinyl )eth yl] benzamide

The title compound was synthesized using the procedure recited in Example 1, except 4-amino"jV-[2-(4-morpholinyl)ethyl]benzamide (72mg, 0.30mmol) was used

to give solid (32mg, 0.070mmol). MS m/z 463 (M+l) ⁺

Example 18: 2-{[2-({4'-[(dimethylamino)methyl]-4-biphenylyl}amino)-4-pyr imidinyl] amino}- 1-p henylethanol

The title compound was synthesized using the procedure recited in Example 1, except 4'-[(dimethylamino)methyl]-4-biphenylamine (62mg, 0.30mmol) was used to give solid (I3mg, 0.030mmol).

MS m/z 440 (M+l) ⁺

Example 19: l'phenyl'2'{[2'(l.2.3.4-tetrahvdro'7'isoquinolinylamino)'4-p yrimidinyl]amino}eth anol

Example 19: l-Phenyl-2-{[2-(l,2,3,4-tetrahydro-7-isoquinolinylamino)-4-p yrimidinyl]amino}eth anol

2-[(2-Chloro-4-pyrimidinyl)amino]-l-phenylethanol (163 mg, 0.65 mmol) and 2-(trifluoroacetyl)-l,2,3,4-tetrahydro-7-isoquinolinamine (160 mg, 0.65 mmol) were combined with isopropanol (6 mL) and cone, hydrochloric acid (75μL, 0.9mmol). The mixture was heated to 85 ⁰ C for 160 minutes in an oil bath. Ethyl acetate (10 mL) and hexanes (20 mL) were added and the mixture was purified by trituration to yield the desired solid (270 mg). This material was dissolved in THF (10 mL). LiOH (120 mg, 2.8 mmol) was then added in water (2 mL). The reaction was stirred at RT for 60 minutes. Ethyl acetate (100 mL) and aqueous NaHCθ3 (20 mL), and brine (10 mL) were added and the organic layer dried with MgSθ4. The mixture was filtered through Celite and the concentrate (oil) was purified by trituration with ethyl acetate and hexanes to yield the desired material (55 mg, 0.15 mmol). IH NMR (400 MHz, DMSOD6) δ ppm 2.59 (t, J = 6 Hz, 2 H), 2.92 (t, J = 6 Hz, 2 H), 3.21-3.27 (m, 3H), 3.61 (m, 2 H), 4.71-4.73 (m, 1 H), 5.46 (bs, 1 H), 5.94 (d, J = 6 Hz, 1 H), 6.86 (d, J = 8 Hz, 1 H), 7.23-7.24 (m, 2H), 7.29-7.34 (m, 4 H), 7.36-7.43 (m, 2 H), 8.73 (s, IH). MS m/z 362 (M+ 1) ⁺

Example 2Q: 2'{[2'({3''[(dimethylamino)methyl]'4-biphenylyl}amino)'4-pyr imidinyl] amino}' I-P henylethanol

The title compound was synthesized using the procedure recited in Example 1, except 3' "[(dimethylamino) methyl] -4-biphenylamine (65mg, 0.30mmol) was used to give solid (31mg, 0.070mmol). MS m/z 439 (M+l) ⁺

Example 21:

2-{[2-({3-chloro-4-[(l-methyl-4-piperidinyl)oxy]phenyl}am ino)-4-pyrimidinyl]amin o} - 1 -phenylethanol

The title compound was synthesized using the procedure recited in Example 1, except 3-chloro-4-[(l-methyl-4-piperidinyl)oxy]aniline (66mg, 0.30mmol) was used to give solid (45mg, 0.099mmol).

MS m/z 454 (M+l) ⁺

Example 22:

2'{[2'({4-[2'(4-morpholinyl)ethyl]phenyl}amino)'4-pyrimid inyl]amino}'l'phenylet hanol

The title compound was synthesized using the procedure recited in Example 1, except 4-[2-(4-morpholinyl)ethyl]aniline (57mg, 0.30mmol) was used to give solid (I3mg, 0.032mmol). MS m/z 420 (M+l) ⁺

Example 23:

2'({2'[(4-{[2'(4-morpholinyl)ethyl]oxy}phenyl) amino] '4-pyrimidinyl}amino)'l'phen ylethanol

The title compound was synthesized using the procedure recited in Example 1, except 4-{[2-(4-morpholinyl)ethyl]oxy}aniline (65mg, 0.30mmol) was used to give solid (37mg, 0.085mmol). MS m/z 436 (M+l) ⁺

Example 24:

2-[(2-{[2-methyl-5-(4-morpholinylmethyl)phenyl]amino}-4-p yrimidinyl) amino] -1-p henylethanol

The title compound was synthesized using the procedure recited in Example 1, except 2-methyl-5-(4-morpholinylmethyl)aniline (59mg, 0.30mmol) was used to give solid (32mg, 0.076mmol). MS m/z 420 (M+l) ⁺

Example 25:

2'({2'[(4-{[4-(methylsulfonyl)'l'piperazinyl]methyl}pheny l)amino]'4-pyrimidinyl}a mino) - 1 -phen ylethanol

The title compound was synthesized using the procedure recited in Example 1, except 4-({4-[methyl(methylidene)oxidθ"l ⁴ "Sulfanyl]-l-piperazinyl}methyl)aniline (74mg, 0.30mmol) was used to give solid (l3mg, 0.027mmol).

MS m/z 483 (M+l) ⁺

Example 26:

3-({4- [(2 -hydroxy-2 -phenylethyl)amino] -2 -pyrimidinyl} amino) -ffi (3-pyridinylmeth vObenzamide

The title compound was synthesized using the procedure recited in Example 1, except 3"amino"jV-(3"pyridinylmethyl)benzamide (66mg, 0.30mmol) was used to give solid (25mg, 0.056mmol). MS m/z 441 (M+l) ⁺

Example 27: iV ^L '{[4-({4-[(2-hvdroxy-2-phenylethyl)amino]-2-pyrimidinyl}amin o)phenyl]methyl}

'■λ^.-λ^'dimethylglvcinamide

The title compound was synthesized using the procedure recited in Example 1, except λ ^α -[(4-aminophenyl)methyl]-λ ² ,λ ² -dimethylglycinamide (60mg, 0.30mmol) was used to give solid (22mg, O.Oδlmmol).

MS m/z 421 (M+l) ⁺

Example 28:

1 ~ [3~({4- [(2 'hvdroxy2 'phenylethvOamino] ~2 'pyrimidinyl}amino)phenyl] '4-methyl'

2-piperazinone

The title compound was synthesized using the procedure recited in Example 1, except l-(3"aminophenyl)-4-methyl-2-piperazinone (57mg, 0.30mmol) was used to give solid (I4mg, 0.033mmol). MS m/z 419 (M+l) ⁺

Example 29:

4-({4-[(2-hvdroxy-2-phenylethyl)amino]-2-pyrimidinyl}amin o)-.^methyl-.^(l-met hyl-4-piperidinyl)benzamide

The title compound was synthesized using the procedure recited in Example 1, except 4-amino-λ^methyl-λKl-methyl-4-piperidinyl)benzamide (69mg, 0.30mmol) was used to give solid (35mg, 0.076mmol). MS m/z 461 (M+l) ⁺

Example 3Q:

3-[4-({4-[(2-hvdroxy-2-phenylethyl)amino]-2-pyrimidinyl}a mino)phenyl]-2.4-imida zolidinedione

The title compound was synthesized using the procedure recited in Example 1, except 3-(4-aminophenyl)-2,4-imidazolidinedione (55mg, 0.30mmol) was used to give solid (8.2mg, 0.020mmol).

MS m/z 405 (M+l) ⁺

Example 31:

3'[3'({4-[(2'hvdroxy2'phenylethyl)amino]'2'Pyrimidinyl}am ino)phenyl]'2.4-imida zolidinedione

The title compound was synthesized using the procedure recited in Example 1, except 3"(3"aminophenyl)-2,4-imidazolidinedione (56mg, 0.30mmol) was used to give solid (24mg, O.OβOmmol). MS m/z 405 (M+l) ⁺

Example 32: iV ^L -[3-({4-[(2-hvdroxy-2-phenylethyl)amino]-2-pyrimidinyl}amino )phenyl]-.λ^..λ^-di methylglycinamide

The title compound was synthesized using the procedure recited in Example 1, except A^3-aminophenyl)-A^,A^-dimethylglycinamide (59mg, 0.30mmol) was used to give solid (l7mg, 0.041mmol).

MS m/z 407 (M+l) ⁺

Example 33: 2'({2~ [(4-{[(4-methyl- l'piperazinvQsulfonyl] methyl}phenyl)amino] '4-pyrimidinyl}a mino) - 1 -phenylethanol

The title compound was synthesized using the procedure recited in Example 1, except 4-{[(4-methyl-l-piperazinyl)sulfonyl]methyl}aniline (83mg, 0.30mmol) was used to give solid (8.2mg, 0.017mmol).

MS m/z 483 (M+l) ⁺

Example 34:

2~{[2'({4- [(4-methyl' 1 'piperazinvϋmethyl]phenyl}amino)'4-pyrimidinyl] amino}' 1 ~ phenylethanol

The title compound was synthesized using the procedure recited in Example 1, except 4- [(4-methyl-l-piperazinyl)methyl] aniline (64mg, 0.30mmol) was used to give solid (5.3mg, 0.013mmol). MS m/z 419 (M+l) ⁺

Example 35:

■^[3-(dimethylamino)propyl]-3-({4-[(2-hvdroxy-2-phenyle thyl)amino]-2-pyrimidin yl}amino)benzenesulfonamide

The title compound was synthesized using the procedure recited in Example 1, except 3-amino-A^[3-(dimethylamino)propyl]benzenesulfonamide (80mg, 0.30mmol) was used to give solid (21mg, 0.045mmol). MS m/z 471 (M+l) ⁺

Example 36: ■λ^[4-({4-[(2'hvdroxy2'phenylethyl)amino]'2'pyrimidinyl}a mino)phenyl]'2'(4-mor pholinvDacetamide

The title compound was synthesized using the procedure recited in Example 1, except jV-(4-aminophenyl)-2-(4-morpholinyl)acetamide (71mg, 0.30mmol) was used to give solid (llmg, 0.024mmol). MS m/z 449 (M+l) ⁺

Example 37:

3'[3'({4-[(2'phenylethyl)amino]'2'Pyrimidinyl}amino)pheny l]'2.4-imidazolidinedio ne

A mixture of 2-chloro-7V ^: (2-phenylethyl)-4-pyrimidinamine (35mg, O.lδmmol),

3"(3"aminophenyl)-2,4-imidazolidinedione (57mg, 0.30mmol), cone, hydrochloric acid (75DL, 0.90mmol) and isopropanol (2.OmL) was heated at 17O ⁰ C for 20 minutes in a Personal Chemistry SmithSynthesizer ^® microwave instrument. Triethylamine (l39μL, l.Ommol) was added and the volatiles removed under vacuum with heating at 75 ⁰ F. Purification was achieved using flash silica chromatography on an ISCO Combiflash ^® , eluting with an ethyl acetate/hexanes gradient. Concentration of the relevant fractions afforded the title compound as a white solid (47mg, 0.12mmol).

MS m/z 389 (M+ 1) ⁺

Example 38:

3-[4-({4-[(2-phenylethyl)amino]-2-pyrimidinyl}amino)pheny l]-2.4-imidazolidinedio ne

The title compound was synthesized using the procedure recited in Example 37, except 3-(4-aminophenyl)-2,4-imidazolidinedione (57mg, 0.30mmol) was used to give solid (l2mg, 0.031mmol). MS m/z 389 (M+ 1) ⁺

Example 39:

JV ^L -{3-[(4-{[2-hvdroxy-2-(4-methylphenyl)ethyl]amino}-2-pyrimid inyl)amino]phenv l}-.λft,.λft-dimethylglvcinamide

The title compound was synthesized using the procedure recited in Example 1, except Intermediate 5b

(2-[(2-chloro-4-pyrimidinyl)amino]-l-(4-methylphenyl)etha nol) (40mg, O.lδmmol) and λ^-(3-aminophenyl)-λ^,λ^-dimethylglycinamide (58mg, 0.30mmol) was used to give solid (5mg, 0.012mmol).

MS m/z 42l (M+l) ⁺

Example 4Q: iV ^L -(3-{[4-({2-hvdroxy-2-[3-(methyloxy)phenyl]ethyl}amino)-2-py rimidinyl]amino}p henyl)-.λ^..λ^'dimethylglvcinamide

The title compound was synthesized using the procedure recited in Example 1, except Intermediate 8b

(2-[(2-chloro"4-pyrimidinyl)amino]"l"[3"(methyloxy)phenyl]et hanol) (42mg, O.lδmmol) and AM3-aminophenyl)-A^,A^-dimethylglycinamide (58mg, 0.30mmol) was used to give solid (22mg, O.OδOmmol). MS m/z 437 (M+l) ⁺

Example 4V- iV ^L -(3-{[4-({2-hvdroxy-2-[2-(trifluoromethyl)phenyl]ethyl}amino )-2-pyrimidinyl]am ino}phenyl)-.rø..λft-dimethylglvcinamide

The title compound was synthesized using the procedure recited in Example 1, except Intermediate 9b (2-[(2-chloro-4-pyrimidinyl)amino]-l-[2-(trifluoromethyl)phe nyl]-ethanol) (48mg, O.lδmmol) and λ^-(3-aminophenyl)-λ^,λ^-dimethylglycinamide (58mg, 0.30mmol) was used to give solid (I8mg, 0.038mmol). MS m/z 475 (M+l) ⁺

Example 42: iV ^L -(3-{[4-({2-hvdroxy-2-[3-(trifluoromethyl)phenyl]ethyl}amino )-2-pyrimidinyl]am ino}phenyl)-.rø,.λft-dimethylglvcinamide

The title compound was synthesized using the procedure recited in Example 1, except Intermediate 10b

(2-[(2-chloro"4-pyrimidinyl)amino]"l"[3"(trifluoromethyl) phenyl]-ethanol) (48mg, O.lδmmol) and A^-(3-aminophenyl)-A^,A^-dimethylglycinamide (58mg, 0.30mmol) was used to give solid (lδmg, 0.032mmol).

MS m/z 475 (M+l) ⁺

Example 43: iV ^L -(3-{[4-({2-hvdroxy-2-[4-(trifluoromethyl)phenyl]ethyl}amino )-2-pyrimidinyl]am ino}phenyl)-.λ^..λ^'dimethylglvcinamide

The title compound was synthesized using the procedure recited in Example 1, except Intermediate lib

(2-[(2-chloro"4-pyrimidinyl)amino]"l"[4-(trifluoromethyl)phe nyl]-ethanol) (48mg, O.lδmmol) and AM3-aminophenyl)-A^,A^-dimethylglycinamide (58mg, 0.30mmol) was used to give solid (26mg, 0.055mmol). MS m/z 475 (M+l) ⁺

Example 44: iV ^L -{3-[(4-{[2-hvdroxy-2-(2-pyridinyl)ethyl]amino}-2-pyrimidiny l)amino]phenyl}-.λ^ .■λE-dimethylglvcinamide

The title compound was synthesized using the procedure recited in Example 1, except Intermediate 12b (2-[(2-chloro-4-pyrimidinyl)amino]-l-(2-pyridinyl)ethanol) (38mg, O.lδmmol) and λ^-(3-aminophenyl)-λ^,λ^-dimethylglycinamide (58mg, 0.30mmol) was used to give solid (8mg, 0.020mmol). MS m/z 408 (M+l) ⁺

Example 45:

2-({2-[(4-methylphenyl)amino]-4-pyrimidinyl} amino)- 1-phenylethanol

The title compound was synthesized using the procedure recited in Example 1, except Intermediate 1 (2- [(2-chloro-4-pyrimidinyl)amino]- 1-phenylethanol) (37mg, O.lδmmol) and 4-methylaniline (32mg, 0.30mmol) was used to give solid (22mg, 0.069mmol). IH NMR (400 MHz, DMSOD6) δ ppm 2.21 (s, 3 H) 3.19-3.23/3.60-3.75 (m, 2 H) 4.72-4.7δ (m, 1 H) δ.48 (d, 1 H) δ.96 (d, J=δ.6 Hz, 1 H) 6.98/7.61 (AB q, 4 H) 7.23-7.39 (m, 6 H) 7.74 (m, 1 H) 8.79 (s, 1 H). MS m/z 321

(M+l) ⁺

Example 46:

2-({2-[(4-{[3-(dimethylamino)propyl]amino}-3-fluorophenyl )amino]-4-pyrimidinyl} amino) ~ 1 'phenylethanol

2-[(2-Chloro-4-pyrimidinyl)amino]-l-phenylethanol (169 mg, 0.68 mmol) and (4-amino-2-fluorophenyl)[3-(dimethylamino)propyl] amine (443 mg, 0.68 mmol) were combined with isopropanol (8 mL) and cone, hydrochloric acid (75μL, 0.9mmol). The mixture was heated to 85 ⁰ C for 60 minutes in an oil bath. Ethyl acetate (100 mL) and aqueous NaHCθ3 (20 mL), and brine (10 mL) were added and the organic layer dried with MgSCh. The mixture was filtered through Celite and the concentrated compound (oil) was purified by trituration with ethyl acetate followed by hexanes to yield the desired material (35 mg, 0.08 mmol). IH NMR (400 MHz, DMSOD6) δ ppm 1.65-1.68 (m, 2 H), 2.13 (s, 6 H), 2.27-2.31 (m, 2 H), 3.03-3.04 (m, 2 H), 3.18-3.21 (m, 2 H), 4.70-4.74 (m, 1 H), 5.01 (bs, 1 H), 5.47 (d, J = 4 Hz, 1 H), 5.92 (d, J = 6 Hz, 1 H), 6.56 (t, J = 9 Hz, 1 H), 7.22-7.25 (m, 3 H), 7.30-7.38 (m, 5 H), 7.55 (d, J = 14 Hz, 1 H), 7.71 (d, J = 5 Hz, 1 H), 8.65 (s, 1 H). MS m/z 425 (M+l) ⁺ Aniline Synthesis:

Step A: jV-(2-Fluoro-4-nitrophenyl)-N,N-dimethyl-l,3-propanediamine[ 3-(dimethylamino) propyl] (2-fluoro-4-nitrophenyl)amine

To a solution of l,2-difluoro-4-nitrobenzene (l g, 6.28 mmol) in 62 mL of THF was added Et3N (l.58g, 15.7mmol) followed by λζjV-dimethyM,3-propanediamine (0.77g, 7.54mmol). The resulting reaction was stirred at rt for 18 hours. The reaction was diluted with EtOAc, and quenched with sat aq. NaHCθ3. Following extraction with EtOAc, the organics were combined, filtered over MgSθ4, and reduced in vacuo onto silica gel. Purification via ISCO chromatography

(hexanes: EtOAc) afforded a yellow solid as the desired product. LRMS calculated for C11H17FN3O2 [M+H] ⁺ 242, found 242.

Step B:

N- [3-(3-{2-[(4-{[3-(Dimethylamino)propyl]amino}-3-fluorophenyl ) amino] -4-pyrimid inyl}pyrazolo[l,5"a]pyridin-2-yl)phenyl]-2,6"difluorobenzami de.

(Dimethylamino)propyl](2-fluoro-4-nitrophenyl)amine (0.72 g, 2.9 mmol) was dissolved in EtOAc (50 niL) and Pd/C (10%, 0.16g, O.lδmmol) was added. The reaction was then placed under 1 atmosphere of H2. The reaction was allowed to stir for 24 h. The reaction was treated with Celite, and the resulting slurry was filtered over Celite. The filtrate was reduced in vacuo to afford the intermediate aniline as a dark-red oil that was used without further purification.

Example 47:

2-{[2-({4-[(methylsulfonyl)methyl]phenyl}amino)-4-pyrimid inyl] amino}- 1-phenylet hanol

2-[(2-Chloro"4-pyrimidinyl)amino]"l"phenylethanol (250 mg, 1.0 mmol) and- [(methylsulfonyl)methyl] aniline (185 mg, 1.0 mmol) were combined with isopropanol (6 mL) and cone, hydrochloric acid (75μL, 0.9mmol). The mixture was heated to 85 ⁰ C for 4 hours in an oil bath. Ethyl acetate (lOO mL) and aqueous NaHCθ3 (20 mL), and brine (10 mL) were added and the organic layer dried with MgSθ4. The mixture was filtered through Celite and the concentrated compound (oil) was purified by trituration with ethyl acetate followed by hexanes to yield a solid which was further purified by column chromatography (1-6% MeOH/CHaCla) to yield the desired material (350 mg, 0.87 mmol). IH NMR (400 MHz, DMSO-D6) δ ppm 2.85 (s, 3 H), 3.23 (m, 1 H), 3.7 (bs,

1 H), 4.35 (s, 2 H), 4.74-4.76 (m, 1 H), 5.50 (d, J = 4 Hz, 1 H), 6.01 (d, J = 6 Hz, 1 H), 7.21-7.34 (m, 3 H), 7.35-7.40 (m, 5 H), 7.77-7.79 (m, 3 H), 9.05 (s, 1 H). MS

m/z 399 (M+ 1) ⁴

Example 48: l'phenyl'2'[(2'{[3.4.5'tris(methyloxy)phenyl]amino}'4-pyrimi dinyl)amino]ethanol

The title compound was synthesized using the procedure recited in Example 1, except 3,4,5-tris(methyloxy)aniline (55mg, 0.30mmol) was used to give solid (38mg, 0.095mmol). MS m/z 397 (M+l) ⁺

Example 49: 3-({4-[(2-hvdroxy-2-phenylethyl)amino]-2-pyrimidinyl}amino)b enzonitrile

The title compound was synthesized using the procedure recited in Example 1, except 3-aminobenzonitrile (35mg, 0.30mmol) was used to give solid (30mg, 0.090mmol).

MS m/z 332 (M+l) ⁺

Example 5Q:

2~ [(2'{[3'(2-methyl' 1.3'thiazol-4-yl)phenyl] amino}'4-pyrimidinyl)amino] ~ 1 'phenyl ethanol

The title compound was synthesized using the procedure recited in Example 1, except 3"(2-methyl-l,3"thiazol"4-yl)aniline (57mg, 0.30mmol) was used to give solid (40mg, 0.098mmol).

MS m/z 404 (M+ 1) ⁺

Example 51:

2-({2-[(2-methylphenyl)amino]-4-pyrimidinyl} amino)- 1-phenylethanol

The title compound was synthesized using the procedure recited in Example 1, except 2-methylaniline (32mg, 0.30mmol) was used to give solid (22mg, 0.068mmol). MS m/z 32l (M+l) ⁺

Example 52: 2-({2-[(3-methylphenyl)amino]-4-pyrimidinyl}amino)-l-phenyle thanol

The title compound was synthesized using the procedure recited in Example 1, except 3-methylaniline (32mg, 0.30mmol) was used to give solid (23mg, 0.071mmol).

MS m/z 321 (M+l) ⁺

Example 53: 2-[(2-{[4-(methyloxy)phenyl1aniino}-4-pyrimidinyl)amino]-l-p henylethanol

The title compound was synthesized using the procedure recited in Example 1, except 4-(methyloxy)aniline (37mg, 0.30mmol) was used to give solid (32mg, 0.096mmol). MS m/z 337 (M+l) ⁺

Example 54: 2-({2-[(2-chlorophenyl)amino1'4-pyrimidinyl}amino)-l-phenyle thanol

The title compound was synthesized using the procedure recited in Example 1, except 2-chloroaniline (38mg, 0.30mmol) was used to give solid (I7mg, O.Oδlmmol).

MS m/z 341 (M+l) ⁺

Example 55: 2-({2-[(3-chlorophenyl)amino1'4-pyrimidinyl}amino)-l-phenyle thanol

The title compound was synthesized using the procedure recited in Example 1, except 3-chloroaniline (38mg, 0.30mmol) was used to give solid (31mg, 0.091mmol). MS m/z 341 (M+l) ⁺

Example 56:

2'({2'[(4-chlorophenyl)amino1'4-pyrimidinyl}amino)'l'phen ylethanol

The title compound was synthesized using the procedure recited in Example 1, except 4-chloroaniline (38mg, 0.30mmol) was used to give solid (28mg, 0.083mmol).

MS m/z 341 (M+l) ⁺

Example 57:

1 -phenvl-2 -{[2 ^■ (phenvlamino) ^-pvrimidinvl] aminolethanol

The title compound was synthesized using the procedure recited in Example 1, except aniline (28mg, 0.30mmol) was used to give solid (32mg, O.lOδmmol). MS m/z 307 (M+l) ⁺

Example 58: l-(2-methylphenyl)-2-{[2-({4-[(methylsulfonyl)methyl]-phenyl }amino)-4-pyrimidin yl] aminolethanol

The title compound was synthesized using the procedure recited in Example 1, except Intermediate 3b (2-[(2-chloro-4-pyrimidinyl)amino]-l-(2-methylphenyl)ethanol ) (40mg, O.lδmmol) and 4- [(methylsulfonyl)methyl] -aniline (56mg, 0.30mmol) was used to give solid (I6mg, 0.038mmol). MS m/z 413 (M+l) ⁺

Example 59: l'(2'methylphenyl)'2'[(2'{[3.4.5'tris(methyloxy)phenyl]amino }'4-pyrimidinyl)ami no]ethanol

The title compound was synthesized using the procedure recited in Example 58, except 3,4,5"tris(methyloxy)aniline (55mg, 0.30mmol) was used to give solid (21mg, O.Oδlmmol). MS m/z 411 (M+ 1) ⁺

Example 6Q:

4- [(4- {[2 'hvdrox v2 ~ (2 ~ methylphenvOethyl] amino} ~2 ~p yrimidinyl) amino] benzonitri Ie

The title compound was synthesized using the procedure recited in Example 58, except 4-aminobenzonitrile (35mg, 0.30mmol) was used to give solid (l3mg, 0.037mmol). MS m/z 346 (M+l) ⁺

Example 61: l-(2-methylphenyl)-2-[(2-{[3-(2-methyl-1.3-thiazol-4-yl)phen yl]amino}-4-pyrimidi nvDamino] ethanol

The title compound was synthesized using the procedure recited in Example 58, except 3"(2-methyl-l,3"thiazol"4-yl)aniline (57mg, 0.30mmol) was used to give solid (I4mg, 0.034mmol). MS m/z 418 (M+l) ⁺

Example 62: l-(2-methylphenyl)-2-({2-[(2-methylphenyl)amino]-4-pyrimidin yl}amino)ethanol

The title compound was synthesized using the procedure recited in Example 58, except 2-methylaniline (32mg, 0.30mmol) was used to give solid (l2mg, 0.035mmol).

MS m/z 335 (M+l) ⁺

Example 63: l-(2-methylphenyl)-2-({2-[(3-methylphenyl)amino]-4-pyrimidin yl}amino)ethanol

The title compound was synthesized using the procedure recited in Example 58, except 3-methylaniline (32mg, 0.30mmol) was used to give solid (l6mg,

0.048mmol).

MS m/z 335 (M+l) ⁺

Example 64: l'(2'methylphenyl)'2'({2'[(4'methylphenyl)amino]'4'pyrimidin yl}amino)ethanol

The title compound was synthesized using the procedure recited in Example 58, except 4-methylaniline (32mg, 0.30mmol) was used to give solid (l5mg, 0.044mmol). MS m/z 335 (M+l) ⁺

Example 65:

2-[(2-{[2-(methyloxy)phenyl]aniino}-4-pyrimidinyl) amino] -l-(2-methylphenyl)etha nol

The title compound was synthesized using the procedure recited in Example 58, except 2-(methyloxy)aniline (37mg, 0.30mmol) was used to give solid (l4mg, 0.041mmol).

MS m/z 351 (M+l) ⁺

Example 66:

2-[(2-{[3-(methyloxy)phenyl]aniino}-4-pyrimidinyl) amino] -l-(2-methylphenyl)etha nol

The title compound was synthesized using the procedure recited in Example 58, except 3-(methyloxy)aniline (37mg, 0.30mmol) was used to give solid (9.8mg,

0.028mmol).

MS m/z 351 (M+l) ⁺

Example 67:

2-[(2-{[4-(methyloxy)phenyl]amino}-4-pyrimidinyl) amino] -l-(2-methylphenyl)etha nol

The title compound was synthesized using the procedure recited in Example 58, except 4-(methyloxy)aniline (37mg, 0.30mmol) was used to give solid (6.7mg,

0.019mmol).

MS m/z 351 (M+l) ⁺

Example 68: 2'({2'[(2'chlorophenyl)amino1'4-pyrimidinyl}amino)'l'(2'meth ylphenyl)ethanol

The title compound was synthesized using the procedure recited in Example 58, except 2-chloroaniline (38mg, 0.30mmol) was used to give solid (lOmg,

0.028mmol).

MS m/z 355 (M+l) ⁺

Example 69: 2-({2-[(3-chlorophenvl)amino]-4-pvrimidinvl}amino)-l-(2-meth vlphenvl)ethanol

The title compound was synthesized using the procedure recited in Example 58, except 3-chloroaniline (38mg, 0.30mmol) was used to give solid (5.6mg, O.Olβmmol). MS m/z 355 (M+ 1) ⁺

Example 7Q:

2-({2-[(4-chlorophenyl)amino1'4-pyrimidinyl}amino)-l-(2-m ethylphenyl)ethanol

The title compound was synthesized using the procedure recited in Example 58, except 4-chloroaniline (38mg, 0.30mmol) was used to give solid (7.4mg, 0.021mmol).

MS m/z 355 (M+ 1) ⁺

Example 11-

l-(2-methylphenyl)-2-{[2-(phenylamino)-4-pyrimidinyl]amin o}-ethanol

The title compound was synthesized using the procedure recited in Example 58, except aniline (28mg, 0.30mmol) was used to give solid (2.6mg, 0.0081mmol). MS m/z 32l (M+l) ⁺

Example 72: l-(3-methylphenyl)-2-{[2-({4-[(methylsulfonyl)methyl]phenyl} -amino)-4-pyrimidin yl] aminolethanol

The title compound was synthesized using the procedure recited in Example 1, except Intermediate 4b (2-[(2-chloro-4-pyrimidinyl)amino]-l-(3-methylphenyl)ethanol ) (40mg, O.lδmmol) and 4- [(methylsulfonyl)methyl] -aniline (56mg, 0.30mmol) was used to give solid (I7mg, 0.042mmol). MS m/z 413 (M+l) ⁺

Example 73:

3'[(4-{[2'hvdroxy2'(3'methylphenyl)ethyl]amino}'2'Pyrimid inyl)amino]benzenes ulfonamide

The title compound was synthesized using the procedure recited in Example 72, except 3-aminobenzenesulfonamide (52mg, 0.30mmol) was used to give solid (I8mg, 0.046mmol). MS m/z 400 (M+l) ⁺

Example 74:

I'(3'methylphenyl)'2'[(2'{r3.4.5'tris(methyloxy)phenyl]am ino}'4-pyrimidinyl)ami nolethanol

The title compound was synthesized using the procedure recited in Example 72, except 3,4,5-tris(methyloxy)aniline (55mg, 0.30mmol) was used to give solid (21mg, 0.052mmol). MS m/z 411 (M+ 1) ⁺

Example 75:

3-[(4-{[2-hvdroxy-2-(3-methylphenyl)ethyl]amino}-2-pyrimi dinyl)amino]benzonitri

Ie

The title compound was synthesized using the procedure recited in Example 72, except 3-aminobenzonitrile (35mg, 0.30mmol) was used to give solid (l5mg,

0.044mmol).

MS m/z 346 (M+l) ⁺

Example 76: l-(3-methylphenyl)-2-[(2-{r3-(2-methyl-1.3-thiazol-4-yl)phen yl]amino}-4-pyrimidi nypamino] ethanol

The title compound was synthesized using the procedure recited in Example 72, except 3-(2-methyl-l,3-thiazol-4-yl)aniline (57mg, 0.30mmol) was used to give solid (I7mg, 0.041mmol). MS m/z 418 (M+l) ⁺

Example IT- l"(3"methvliDhenvl)"2"({2"r(2"methvliDhenvl)aminol"4-τ)vrim idinvl}amino)ethanol

The title compound was synthesized using the procedure recited in Example 72, except 2-methylaniline (32mg, 0.30mmol) was used to give solid (l8mg, 0.054mmol). MS m/z 335 (M+l) ⁺

Example 78: l-(3-methylphenyl)-2-({2-[(3-methylphenyl)amino]-4-pyrimidin yl}amino)ethanol

The title compound was synthesized using the procedure recited in Example 72, except 3-methylaniline (32mg, 0.30mmol) was used to give solid (l7mg, O.Oδlmmol).

MS m/z 335 (M+l) ⁺

Example 79:

l-(3-methylphenyl)-2-({2-[(4-methylphenyl)amino]-4-pyrimi dinyl}amino)ethanol

The title compound was synthesized using the procedure recited in Example 72, except 4-methylaniline (32mg, 0.30mmol) was used to give solid (l4mg, 0.042mmol). MS m/z 335 (M+l) ⁺

Example 8Q: 2-[(2-{[2-(methyloxy)phenyl]aniino}-4-pyrimidinyl)amino]-l-( 3-methylphenyl)etha nol

The title compound was synthesized using the procedure recited in Example 72, except 2-(methyloxy)aniline (37mg, 0.30mmol) was used to give solid (l4mg, 0.041mmol).

MS m/z 351 (M+l) ⁺

Example 81:

2-[(2-{[3-(methyloxy)phenyl]aniino}-4-pyrimidinyl) amino] -l-(3-methylphenyl)etha nol

The title compound was synthesized using the procedure recited in Example 72, except 3-(methyloxy)aniline (37mg, 0.30mmol) was used to give solid (l5mg, 0.042mmol). MS m/z 351 (M+l) ⁺

Example 82:

2-[(2-{[4-(methyloxy)phenyl]amino}-4-pyrimidinyl) amino] -l-(3-methylphenyl)etha nol

The title compound was synthesized using the procedure recited in Example 72, except 4-(methyloxy)aniline (37mg, 0.30mmol) was used to give solid (20mg, 0.058mmol). MS m/z 351 (M+l) ⁺

Example 83: 2-({2-[(2-chlorophenvl)amino]-4-pvrimidinvl}amino)-l-(3-meth vlphenvl)ethanol

The title compound was synthesized using the procedure recited in Example 72, except 2-chloroaniline (38mg, 0.30mmol) was used to give solid (l2mg,

0.034mmol).

MS m/z 355 (M+l) ⁺

Example 84: 2-({2-[(3-chlorophenvl)amino]-4-pvrimidinvl}amino)-l-(3-meth vlphenvl)ethanol

The title compound was synthesized using the procedure recited in Example 72, except 3-chloroaniline (38mg, 0.30mmol) was used to give solid (l7mg, 0.048mmol). MS m/z 355 (M+l) ⁺

Example 85:

2-({2-[(4-chlorophenyl)amino]'4-pyrimidinyl}amino)-l-(3-m ethylphenyl)ethanol

The title compound was synthesized using the procedure recited in Example 72, except 4-chloroaniline (38mg, 0.30mmol) was used to give solid (l4mg, 0.041mmol).

MS m/z 355 (M+l) ⁺

Example 86:

l-(3-methylphenyl)-2-{[2-(phenylamino)-4-pyrimidinyl]amin o}ethanol

The title compound was synthesized using the procedure recited in Example 72, except aniline (28mg, 0.30mmol) was used to give solid (l4mg, 0.045mmol). MS m/z 32l (M+l) ⁺

Example 87: l-(4-methylphenyl)-2-{[2-({4-[(methylsulfonyl)methyl]-phenyl }amino)-4-pyrimidin yl] aminolethanol

The title compound was synthesized using the procedure recited in Example 1, except Intermediate 5b (2-[(2-chloro-4-pyrimidinyl)amino]-l-(4-methylphenyl)ethanol ) (40mg, O.lδmmol) and 4-[(methylsulfonyl)-methyl]aniline (56mg, 0.30mmol) was used to give solid (3.3mg, 0.008mmol). MS m/z 413 (M+l) ⁺

Example 88: l'(4-methylphenyl)'2'[(2'{[3.4.5'tris(methyloxy)phenyl]amino }'4-pyrimidinyl)ami no]ethanol

The title compound was synthesized using the procedure recited in Example 87, except 3,4,5-tris(methyloxy)aniline (55mg, 0.30mmol) was used to give solid (9.9mg, 0.024mmol). MS m/z 411 (M+ 1) ⁺

Example 89:

3'[(4-{[2'hvdroxy2'(4-methylphenyl)ethyl]amino}'2'pyrimid inyl)amino]benzonitri

Ie

The title compound was synthesized using the procedure recited in Example 87, except 3-aminobenzonitrile (35mg, 0.30mmol) was used to give solid (6.9mg,

0.020mmol).

MS m/z 346 (M+l) ⁺

Example 9Q: l'(4-methylphenyl)'2'[(2'{[3'(2'methyl'1.3'thiazol-4-yl)phen yl]amino}'4-pyrimidi nypamino] ethanol

The title compound was synthesized using the procedure recited in Example 87, except 3"(2-methyl-l,3"thiazol"4-yl)aniline (57mg, 0.30mmol) was used to give

solid (5.7mg, 0.014mmol). MS m/z 418 (M+l) ⁺

Example 9V- l"(4-methvli3henvl)"2"({2"r(2"methvliDhenvl)aminol"4-τ)vrim idinvl}amino)ethanol

The title compound was synthesized using the procedure recited in Example 87, except 2-methylaniline (32mg, 0.30mmol) was used to give solid (3.8mg,

O.Ollmmol).

MS m/z 335 (M+l) ⁺

Example 92: l"(4-methvli3henvl)"2"({2"r(3"methvliDhenvl)aminol"4-τ)vrim idinvl}amino)ethanol

The title compound was synthesized using the procedure recited in Example 87, except 3-methylaniline (32mg, 0.30mmol) was used to give solid (7.4mg, 0.022mmol). MS m/z 335 (M+l) ⁺

Example 93: l-(4-methylphenyl)-2-({2-[(4-methylphenyl)amino]-4-pyrimidin yl}amino)ethanol

The title compound was synthesized using the procedure recited in Example 87, except 4-methylaniline (32mg, 0.30mmol) was used to give solid (4.6mg, 0.014mmol).

MS m/z 335 (M+l) ⁺

Example 94:

2-[(2-{[2-(methyloxy)phenyl]aniino}-4-pyrimidinyl) amino] -l-(4-methylphenyl)etha nol

The title compound was synthesized using the procedure recited in Example 87, except 2-(methyloxy)aniline (37mg, 0.30mmol) was used to give solid (5.2mg, O.Olδmmol). MS m/z 351 (M+l) ⁺

Example 95:

2-[(2-{[3-(methyloxy)phenyl]amino}-4-pyrimidinyl) amino] -l-(4-methylphenyl)etha nol

The title compound was synthesized using the procedure recited in Example 87, except 3-(methyloxy)aniline (37mg, 0.30mmol) was used to give solid (4.5mg, 0.013mmol).

MS m/z 351 (M+l) ⁺

Example 96:

2'[(2'{[4-(methyloxy)phenyl1amino}'4-pyrimidinyl)amino]'l '(4-methylphenyl)etha nol

The title compound was synthesized using the procedure recited in Example 87, except 4-(methyloxy)aniline (37mg, 0.30mmol) was used to give solid (5.9mg,

0.017mmol).

MS m/z 351 (M+l) ⁺

Example 97: 2-({2-[(2-chlorophenvl)amino]-4-pvrimidinvl}amino)-l-(4-meth vlphenvl)ethanol

The title compound was synthesized using the procedure recited in Example 87, except 2-chloroaniline (38mg, 0.30mmol) was used to give solid (3.0mg, 0.0085mmol). MS m/z 355 (M+ 1) ⁺

Example 98:

2-({2-[(3-chlorophenyl)amino]'4-pyrimidinyl}amino)-l-(4-m ethylphenyl)ethanol

The title compound was synthesized using the procedure recited in Example 87, except 3-chloroaniline (38mg, 0.30mmol) was used to give solid (β.Omg, 0.017mmol). MS m/z 355 (M+l) ⁺

Example 99:

l-(4-methylphenyl)-2-{[2-(phenylamino)-4-pyrimidinyl]amin o}ethanol

The title compound was synthesized using the procedure recited in Example 87, except aniline (28mg, 0.30mmol) was used to give solid (6.3mg, 0.020mmol). MS m/z 321 (M+l) ⁺

Example IQQ: l-(2-fluorophenvl)-2-({2-[(2-methvlphenvl) amino] ^■ 4-pvrimidinvl}amino)ethanol

The title compound was synthesized using the procedure recited in Example 1, except Intermediate 6b

(2-[(2-chloro-4-pyrimidinyl)amino]-l-(2-fluorophenyl)ethanol ) (40mg, O.lδmmol) and 2-methylaniline (32mg, 0.30mmol) was used to give solid (9.9mg, 0.029mmol). MS m/z 339 (M+l) ⁺

Example 101: 2-({2-[(3-chlorophenyl)amino]-4-pyrimidinyl}amino)-l-(2-fluo rophenyl)ethanol

The title compound was synthesized using the procedure recited in Example 100, except 3-chloroaniline (38mg, 0.30mmol) was used to give solid (lOmg,

0.028mmol).

MS m/z 359 (M+l) ⁺

Example 102:

I'(3'fluorophenyl)'2'{[2'({4'[(methylsulfonv0methyl]pheny l}'amino)'4'pyrimidinv 1] aminolethanol

The title compound was synthesized using the procedure recited in Example 1, except Intermediate 7b

(2-[(2-chloro-4-pyrimidinyl)amino]-l-(3-fluorophenyl)ethanol ) (40mg, O.lδmmol) and 4-[(methylsulfonyl)-methyl]aniline (56mg, 0.30mmol) was used to give solid (30mg, 0.071mmol). MS m/z 417 (M+l) ⁺

Example 103:

3-[(4-{[2-(3-fluorophenyl)-2-hvdroxyethyl]amino}-2-pyrimi dinyl)amino]benzenesul fonamide

The title compound was synthesized using the procedure recited in Example 102, except 3-aminobenzenesulfonamide (52mg, 0.30mmol) was used to give solid

(37mg, 0.092mmol).

MS m/z 404 (M+ 1) ⁺

Example 104: l'(3'fluorophenyl)'2'[(2'{[3.4.5'tris(methyloxy)phenyl]amino }'4-pyrimidinyl)amin o]ethanol

The title compound was synthesized using the procedure recited in Example 102, except 3,4,5"tris(methyloxy)aniline (55mg, 0.30mmol) was used to give solid (23mg, 0.056mmol). MS m/z 415 (M+l) ⁺

Example 105:

3'[(4-{[2'(3'fluorophenyl)'2'hvdroxyethyl]amino}'2'Pyrimi dinyl)'amino]benzonitri

Ie

The title compound was synthesized using the procedure recited in Example 102, except 3-aminobenzonitrile (35mg, 0.30mmol) was used to give solid (26mg,

0.074mmol).

MS m/z 350 (M+l) ⁺

Example 106: l'(3'fluorophenyl)'2'[(2'{[3'(2'methyl'1.3'thiazol-4-yl)phen yl]amino}'4-pyrimidin vDamino] ethanol

The title compound was synthesized using the procedure recited in Example 102, except 3"(2-methyl-l,3"thiazol"4-yl)aniline (57mg, 0.30mmol) was used to give solid (35mg, 0.084mmol). MS m/z 422 (M+l) ⁺

Example 107:

3'{3'[(4-{[2'(3'fluorophenyl)'2'hvdroxyethyl]amino}'2'Pyr imidinyl)amino]phenyl}' 2.4-imidazolidinedione

The title compound was synthesized using the procedure recited in Example 102, except 3"(3"aminophenyl)-2, 4-imidazolidinedione (57mg, 0.30mmol) was used to give solid (26mg, O.Oβlmmol). MS m/z 423 (M+l) ⁺

Example 108: l'(3'fluorophenyl)'2'({2'[(2'methylphenyl) amino] '4-pyrimidinyl}amino)ethanol

The title compound was synthesized using the procedure recited in Example 102, except 2-methylaniline (32mg, 0.30mmol) was used to give solid (25mg, 0.074mmol).

MS m/z 339 (M+l) ⁺

Example 109: l-(3-fluorophenyl)-2-({2-[(3-methylphenyl) amino] -4-pyrimidinyl}amino)ethanol

The title compound was synthesized using the procedure recited in Example 102, except 3-methylaniline (32mg, 0.30mmol) was used to give solid (7.8mg,

0.023mmol).

MS m/z 339 (M+l) ⁺

Example HQ: l-(3-fluorophenyl)-2-({2-[(4-methylphenyl) amino] -4-pyrimidinyl}-amino)ethanol

The title compound was synthesized using the procedure recited in Example 102, except 4-methylaniline (32mg, 0.30mmol) was used to give solid (25mg,

0.075mmol).

MS m/z 339 (M+l) ⁺

Example 111: l-(3-fluorophenyl)-2-[(2-{[2-(methyloxy)phenyl]amino}-4-pyri midinyl)amino]ethan ol

The title compound was synthesized using the procedure recited in Example 102, except 2-(methyloxy)aniline (37mg, 0.30mmol) was used to give solid (36mg, O.lOmmol).

MS m/z 355 (M+l) ⁺

Example 112:

I'(3'fluorophenyl)'2'[(2'{r3'(methyloxy)phenyl]amino}'4-p yrimidinyl)amino]ethan ol

The title compound was synthesized using the procedure recited in Example 102, except 3-(methyloxy)aniline (37mg, 0.30mmol) was used to give solid (33mg,

0.092mmol).

MS m/z 355 (M+ 1) ⁺

Example 113: l-(3-fluorophenyl)-2-[(2-{[4-(methyloxy)phenyl]amino}-4-pyri midinyl)amino]ethan ol

The title compound was synthesized using the procedure recited in Example 102, except 4-(methyloxy)aniline (37mg, 0.30mmol) was used to give solid (34mg, 0.095mmol).

MS m/z 355 (M+ 1) ⁺

Example 114: 2'({2'[(2'chlorophenyl)amino1'4'pyrimidinyl}amino)'l'(3'fluo rophenyl)ethanol

The title compound was synthesized using the procedure recited in Example 102, except 2-chloroaniline (38mg, 0.30mmol) was used to give solid (23mg,

0.064mmol).

MS m/z 359 (M+ 1) ⁺

Example 115^ 2-({2-[(3-chlorophenyl)amino1'4-pyrimidinyl}amino)-l-(3-fluo rophenyl)ethanol

The title compound was synthesized using the procedure recited in Example 102, except 3-chloroaniline (38mg, 0.30mmol) was used to give solid (l5mg, 0.041mmol). MS m/z 359 (M+l) ⁺

Example 116: 2-({2-[(4-chlorophenvl)amino]-4-pvrimidinvl}amino)-l-(3-fluo rophenvl)ethanol

The title compound was synthesized using the procedure recited in Example 102, except 4-chloroaniline (38mg, 0.30mmol) was used to give solid (26mg, 0.074mmol). MS m/z 359 (M+ 1) ⁺

Example 117:

1 -(3-fluorophenyl) - 2 -{ [2 - (phenylamino) - 4-p yrimidinyl] amino} -ethanol

The title compound was synthesized using the procedure recited in Example 102, except aniline (28mg, 0.30mmol) was used to give solid (28mg, 0.085mmol). MS m/z 325 (M+l) ⁺

Example 118: l-[3-(methyloxy)phenyl]-2-{r2-({4-[(methylsulfonyl)methyl] -phenyl} amino) -4-pyri

midinyl] amino}ethanol

The title compound was synthesized using the procedure recited in Example 1, except Intermediate 8b

(2-[(2-chloro-4-pyrimidinyl)amino]-l-[3-(methyloxy)phenyl ]ethanol) (42mg,

O.lδmmol) and 4-[(methylsulfonyl)-methyl]aniline (56mg, 0.30mmol) was used to give solid (29mg, 0.068mmol). MS m/z 429 (M+ 1) ⁺

Example 119:

3'{[4-({2'hvdroxy2'[3'(methyloxy)phenyl]ethyl}amino)'2'Py rimidinyl]amino}benz enesulfonamide

The title compound was synthesized using the procedure recited in Example 118, except 3-aminobenzenesulfonamide (52mg, 0.30mmol) was used to give solid (42mg, O.lOmmol). MS m/z 416 (M+l) ⁺

Example 12Q: l-[3-(methyloxy)phenyl]-2-[(2-{[3,4,5-tris(methyloxy)phenyl] amino}-4-pyrimidinyl

)amino]ethanol

The title compound was synthesized using the procedure recited in Example 118, except 3,4,5-tris(methyloxy)aniline (55mg, 0.30mmol) was used to give solid (48mg, O.llmmol). MS m/z 427 (M+l) ⁺

Example 121:

3-{[4-({2-hvdroxy-2-[3-(methyloxy)phenyl]ethyl}amino)-2-p yrimidinyl]amino}benz onitrile

The title compound was synthesized using the procedure recited in Example 118, except 3-aminobenzonitrile (35mg, 0.30mmol) was used to give solid (36mg,

O.lOmmol).

MS m/z 362 (M+l) ⁺

Example 122: l-[3-(methyloxy)phenyl]-2-[(2-{[3-(2-methyl-1.3-thiazol-4-yl )phenyl]amino}-4-pyri midinvϋamino] ethanol

The title compound was synthesized using the procedure recited in Example 118, except 3"(2-methyl-l,3"thiazol"4-yl)aniline (57mg, 0.30mmol) was used to give solid (43mg, 0.099mmol). MS m/z 434 (M+l) ⁺

Example 123:

3'(3'{[4-({2'hvdroxy2'[3'(methyloxy)phenyl]ethyl}amino)'2 'Pyrimidinyl]amino}ph envl)-2,4-imidazolidinedione

The title compound was synthesized using the procedure recited in Example 118, except 3-(3-aminophenyl)-2,4-imidazolidinedione (57mg, 0.30mmol) was used to give solid (55mg, 0.13mmol). MS m/z 435 (M+l) ⁺

Example 124: l-[3-(methyloxy)phenyl]-2-({2-[(2-methylphenyl) amino] -4-pyrimidinyl}amino)etha nol

The title compound was synthesized using the procedure recited in Example 118, except 2-methylaniline (32mg, 0.30mmol) was used to give solid (29mg,

0.082mmol).

MS m/z 351 (M+l) ⁺

Example 125:

I'[3'(methyloxy)phenyl1'2'({2'[(3'methylphenyl) amino] '4-pyrimidinyl}amino)etha nol

The title compound was synthesized using the procedure recited in Example 118, except 3-methylaniline (32mg, 0.30mmol) was used to give solid (36mg, O.lOmmol).

MS m/z 351 (M+l) ⁺

Example 126: l-[3-(methyloxy)phenyl]-2-({2-[(4-methylphenyl) amino] -4-pyrimidinyl}amino)etha nol

The title compound was synthesized using the procedure recited in Example 118,

except 4-methylaniline (32mg, 0.30mmol) was used to give solid (32mg,

0.092mmol).

MS m/z 351 (M+l) ⁺

Example 127: l-[3-(methyloxy)phenyl]-2-[(2-{[2-(methyloxy)phenyl]amino}-4 -pyrimidinyl)amino ]ethanol

The title compound was synthesized using the procedure recited in Example 118, except 2-(methyloxy)aniline (37mg, 0.30mmol) was used to give solid (39mg, O.llmmol).

MS m/z 367 (M+l) ⁺

Example 128: l-[3-(methyloxy)phenyl]-2-[(2-{[3-(methyloxy)phenyl]amino}-4 -pyrimidinyl)amino ]ethanol

The title compound was synthesized using the procedure recited in Example 118, except 3-(methyloxy)aniline (37mg, 0.30mmol) was used to give solid (35mg, 0.096mmol).

MS m/z 367 (M+l) ⁺

Example 129: l-[3-(methyloxy)phenyl]-2-[(2-{[4-(methyloxy)phenyl]amino}-4 -pyrimidinyl)amino ]ethanol

The title compound was synthesized using the procedure recited in Example 118, except 4-(methyloxy)aniline (37mg, 0.30mmol) was used to give solid (45mg, 0.12mmol).

MS m/z 367 (M+ 1) ⁺

Example 13Q:

2'({2~ [(2'chlorophenyl)amino1 '4-pyrimidinyl}amino)' 1 ~ [3'(methyloxy)phenyl] etha nol

The title compound was synthesized using the procedure recited in Example 118, except 2-chloroaniline (38mg, 0.30mmol) was used to give solid (27mg,

0.072mmol).

MS m/z 371 (M+l) ⁺

Example 131:

2-({2- [(3-chlorophenyl)amino1 -4-pyrimidinyllamino)- 1 - [3-(methyloxy)phenyl] etha

nol

The title compound was synthesized using the procedure recited in Example 118, except 3-chloroaniline (38mg, 0.30mmol) was used to give solid (20mg, 0.054mmol). MS m/z 371 (M+ 1) ⁺

Example 132: 2-({2- [(4-chlorophenyl)amino] -4-pyrimidinyl}amino)- 1 - [3-(methyloxy)phenyl] etha nol

The title compound was synthesized using the procedure recited in Example 118, except 4-chloroaniline (38mg, 0.30mmol) was used to give solid (31mg, 0.084mmol). MS m/z 371 (M+l) ⁺

Example 133:

l-[3-(methyloxy)phenyl]-2-{[2-(phenylamino)-4-pyrimidinyl ]amino}ethanol

The title compound was synthesized using the procedure recited in Example 118, except aniline (28mg, 0.30mmol) was used to give solid (39mg, 0.12mmol). MS m/z 337 (M+l) ⁺

Example 134:

2'{[2'({4-[(methylsulfonyl)methyl]phenyl}amino)'4-pyrimid inyl] amino}' I- [2'(triflu oromethyl)phenyl] ethanol

The title compound was synthesized using the procedure recited in Example 1, except Intermediate 9b

(2- [(2-chloro-4-pyrimidinyl)amino]-l-[2-(trifluoromethyl)phenyl ] -ethanol) (48mg, O.lδmmol) and 4-[(methylsulfonyl)-methyl]aniline (56mg, 0.30mmol) was used to give solid (66mg, 0.14mmol). MS m/z 467 (M+l) ⁺

Example 135: 3-{[4-({2-hvdroxy-2-[2-(trifluoromethyl)phenyl]ethyl}amino)- 2-pyrimidinyl] amino} benzenesulfonamide

The title compound was synthesized using the procedure recited in Example 134, except 3-aminobenzenesulfonamide (52mg, 0.30mmol) was used to give solid (66mg, 0.14mmol). MS m/z 454 (M+l) ⁺

Example 136: l-[2-(trifluoromethyl)phenyl]-2-[(2-{[3,4,5-tris(methyloxy)p henyl]amino}-4-pyrimi dinvOamino] ethanol

The title compound was synthesized using the procedure recited in Example 134, except 3,4,5-tris(methyloxy)aniline (55mg, 0.30mmol) was used to give solid (51mg, O.llmmol). MS m/z 465 (M+l) ⁺

Example 137:

3-{[4-({2-hvdroxy-2-[2-(trifluoromethyl)phenyl]ethyl}amin o)-2-pyrimidinyl] amino} benzonitrile

The title compound was synthesized using the procedure recited in Example 134, except 3-aminobenzonitrile (35mg, 0.30mmol) was used to give solid (44mg, O.llmmol).

MS m/z 400 (M+l) ⁺

Example 138:

2'[(2'{[3'(2'methyl'1.3'thiazol'4-yl)phenyl]amino}'4-pyri midinyl) amino] 'I- [2'(trifl uoromethvQphenyl] ethanol

The title compound was synthesized using the procedure recited in Example 134, except 3-(2-methyl-l,3-thiazol-4-yl)aniline (57mg, 0.30mmol) was used to give solid (58mg, 0.12mmol). MS m/z 472 (M+l) ⁺

Example 139:

3'(3'{[4-({2'hvdroxy2'[2'(trifluoromethyl)phenyl]ethyl}am ino)'2'Pyrimidinyl]ami nolphenyl) - 2.4-imidazolidinedione

The title compound was synthesized using the procedure recited in Example 134, except 3"(3"aminophenyl)-2, 4-imidazolidinedione (57mg, 0.30mmol) was used to give solid (60mg, 0.13mmol). MS m/z 473 (M+l) ⁺

Example 14CK

2~({2 ~ [(2 τnethylphenyl)amino] '4-pyrimidinyl}amino) ~ 1 ~ [2 '(trifluoromethyl)phenyl

]ethanol

The title compound was synthesized using the procedure recited in Example 134, except 2-methylaniline (32mg, 0.30mmol) was used to give solid (37mg, 0.095mmol).

MS m/z 389 (M+ 1) ⁺

Example 141:

2-({2 - [(3-methylphenyl)amino] -4-pyrimidinyllamino) - 1 - [2 -(trifluoromethyl)phenyl

]ethanol

The title compound was synthesized using the procedure recited in Example 134, except 3-methylaniline (32mg, 0.30mmol) was used to give solid (43mg, O.llmmol).

MS m/z 389 (M+l) ⁺

Example 142:

2-({2 - [(4-methylphenyl)amino] -4-pyrimidinyl}amino) - 1 - [2 -(trifluoromethyl)phenyl ]ethanol

The title compound was synthesized using the procedure recited in Example 134, except 4-methylaniline (32mg, 0.30mmol) was used to give solid (47mg, 0.12mmol).

MS m/z 389 (M+l) ⁺

Example 143:

2'[(2'{[2'(methyloxy)phenyl1amino}'4-pyrimidinyl)amino]'l '[2'(trifluoromethyl)p henyl] ethanol

The title compound was synthesized using the procedure recited in Example 134, except 2-(methyloxy)aniline (37mg, 0.30mmol) was used to give solid (44mg,

O.llmmol).

MS m/z 405 (M+l) ⁺

Example 144:

2'[(2'{[3'(methyloxy)phenyl1amino}'4-pyrimidinyl)amino]'l '[2'(trifluoromethyl)p henyl] ethanol

The title compound was synthesized using the procedure recited in Example 134, except 3-(methyloxy)aniline (37mg, 0.30mmol) was used to give solid (45mg, O.llmmol).

MS m/z 405 (M+l) ⁺

Example 145:

2-[(2-{[4-(methyloxy)phenyl1aniino}-4-pyrimidinyl)amino]- l-[2-(trifluoromethyl)p henyl]ethanol

The title compound was synthesized using the procedure recited in Example 134, except 4-(methyloxy)aniline (37mg, 0.30mmol) was used to give solid (40mg,

0.099mmol).

MS m/z 405 (M+l) ⁺

Example 146:

2'({2'[(2'chlorophenyl)amino1'4-pyrimidinyl}amino)'l'[2'( trifluoromethyl)phenyl] ethanol

The title compound was synthesized using the procedure recited in Example 134, except 2-chloroaniline (38mg, 0.30mmol) was used to give solid (36mg,

0.088mmol).

MS m/z 409 (M+ 1) ⁺

Example 147:

2'({2'[(3'chlorophenyl)amino1'4-pyrimidinyl}amino)'l'[2'( trifluoromethyl)phenyl] ethanol

The title compound was synthesized using the procedure recited in Example 134, except 3-chloroaniline (38mg, 0.30mmol) was used to give solid (44mg, O.llmmol). MS m/z 409 (M+ 1) ⁺

Example 148:

2'({2'[(4-chlorophenyl)amino1'4-pyrimidinyl}amino)'l'[2'( trifluoromethyl)phenyl] ethanol

The title compound was synthesized using the procedure recited in Example 134, except 4-chloroaniline (38mg, 0.30mmol) was used to give solid (52mg, 0.13mmol). MS m/z 409 (M+ 1) ⁺

Example 149:

2 -{ [2 - (phenylamino) - 4-p yrimidinyl] amino} - 1 - [2 -(trifluoromethyl) -phenyl] ethanol

The title compound was synthesized using the procedure recited in Example 134, except aniline (28mg, 0.30mmol) was used to give solid (38mg, O.llmmol). MS m/z 375 (M+l) ⁺

Example 15Q:

2-{[2-({4-[(methylsulfonyl)methyl]phenyl}amino)-4-pyrimid inyl] amino}- l-[3-(triflu

oromethyQphenyl] ethanol

The title compound was synthesized using the procedure recited in Example 1, except Intermediate 10b

(2-[(2-chloro-4-pyrimidinyl)amino]-l-[3-(trifluoromethyl)phe nyl]ethanol) (48mg, O.lδmmol) and 4-[(methylsulfonyl)-methyl]aniline (56mg, 0.30mmol) was used to give solid (48mg, O.lOmmol). MS m/z 467 (M+l) ⁺

Example 151-

3'{[4-({2'hvdroxy2'[3'(trifluoromethyl)phenyl]ethyl}amino )'2'Pyrimidinyl] amino} benzenesulfonamide

The title compound was synthesized using the procedure recited in Example 150, except 3-aminobenzenesulfonamide (52mg, 0.30mmol) was used to give solid (54mg, 0.12mmol). MS m/z 454 (M+l) ⁺

Example 152: l-[3-(trifluoromethyl)phenyl]-2-[(2-{[3,4,5-tris(methyloxy)p henyl]amino}-4-pyrimi dinvDamino] ethanol

The title compound was synthesized using the procedure recited in Example 150, except 3,4,5-tris(methyloxy)aniline (55mg, 0.30mmol) was used to give solid (43mg, 0.093mmol). MS m/z 465 (M+l) ⁺

Example 153:

3-{[4-({2-hvdroxy-2-[3-(trifluoromethyl)phenyl]ethyl}amin o)-2-pyrimidinyl] amino} benzonitrile

The title compound was synthesized using the procedure recited in Example 150, except 3-aminobenzonitrile (35mg, 0.30mmol) was used to give solid (38mg, 0.096mmol).

MS m/z 400 (M+l) ⁺

Example 154:

2'[(2'{[3'(2'methyl'1.3'thiazol'4-yl)phenyl]amino}'4-pyri midinyl) amino] 'I- [3'(trifl uoromethvQphenyl] ethanol

The title compound was synthesized using the procedure recited in Example 150, except 3-(2-methyl-l,3-thiazol-4-yl)aniline (57mg, 0.30mmol) was used to give solid (40mg, 0.085mmol). MS m/z 472 (M+l) ⁺

Example 155:

3'(3'{[4-({2'hvdroxy2'[3'(trifluoromethyl)phenyl]ethyl}am ino)'2'Pyrimidinyl]ami nolphenyl) ~ 2.4'imidazolidinedione

The title compound was synthesized using the procedure recited in Example 150, except 3-(3-aminophenyl)-2,4-imidazolidinedione (57mg, 0.30mmol) was used to give solid (43mg, 0.091mmol). MS m/z 473 (M+l) ⁺

Example 156:

2-({2 - [(2 -methylphenvOamino] -4-pyrimidinyllamino) - 1 - [3-(trifluoromethyl)phenyl

]ethanol

The title compound was synthesized using the procedure recited in Example 150, except 2-methylaniline (32mg, 0.30mmol) was used to give solid (32mg,

0.083mmol).

MS m/z 389 (M+ 1) ⁺

Example 157:

2-({2-[(3-methylphenyl)amino]-4-pyrimidinyl}amino)-l-[3-( trifluoromethyl)phenyl

]ethanol

The title compound was synthesized using the procedure recited in Example 150, except 3-methylaniline (32mg, 0.30mmol) was used to give solid (27mg,

0.070mmol).

MS m/z 389 (M+ 1) ⁺

Example 158:

2-({2-[(4-methylphenyl)amino]-4-pyrimidinyl}amino)-l-[3-( trifluoromethyl)phenyl

]ethanol

The title compound was synthesized using the procedure recited in Example 150, except 4-methylaniline (32mg, 0.30mmol) was used to give solid (32mg,

0.082mmol).

MS m/z 389 (M+l) ⁺

Example 159:

2'[(2'{[2'(methyloxy)phenyl1amino}'4-pyrimidinyl)amino]'l '[3'(trifluoromethyl)p henyl] ethanol

The title compound was synthesized using the procedure recited in Example 150, except 2-(methyloxy)aniline (37mg, 0.30mmol) was used to give solid (35mg,

0.086mmol).

MS m/z 405 (M+l) ⁺

Example 16Q:

2-[(2-{[3-(methyloxy)phenyl1aniino}-4-pyrimidinyl)amino]- l-[3-(trifluoromethyl)p henyl] ethanol

The title compound was synthesized using the procedure recited in Example 150, except 3-(methyloxy)aniline (37mg, 0.30mmol) was used to give solid (35mg,

0.087mmol).

MS m/z 405 (M+l) ⁺

Example 161:

2-[(2-{[4-(methyloxy)phenyl1aniino}-4-pyrimidinyl)amino]- l-[3-(trifluoromethyl)p henyl]ethanol

The title compound was synthesized using the procedure recited in Example 150, except 4-(methyloxy)aniline (37mg, 0.30mmol) was used to give solid (42mg,

O.lOmmol).

MS m/z 405 (M+l) ⁺

Example 162:

2-({2-[(2-chlorophenyl)amino]'4-pyrimidinyl}amino)-l-[3-( trifluoromethyl)phenyl] ethanol

The title compound was synthesized using the procedure recited in Example 150, except 2-chloroaniline (38mg, 0.30mmol) was used to give solid (30mg,

0.074mmol).

MS m/z 409 (M+l) ⁺

Example 163:

2-({2-[(3-chlorophenyl)amino]'4-pyrimidinyl}amino)-l-[3-( trifluoromethyl)phenyl] ethanol

The title compound was synthesized using the procedure recited in Example 150, except 3-chloroaniline (38mg, 0.30mmol) was used to give solid (42mg, O.lOmmol). MS m/z 409 (M+l) ⁺

Example 164:

2-({2-[(4-chlorophenyl)amino]'4-pyrimidinyl}amino)-l-[3-( trifluoromethyl)phenyl] ethanol

The title compound was synthesized using the procedure recited in Example 150, except 4-chloroaniline (38mg, 0.30mmol) was used to give solid (38mg,

0.092mmol).

MS m/z 409 (M+l) ⁺

Example 165:

2 -{ [2 - (phenylamino) - 4-pyrimidinyl] amino} - 1 - [3 -(trifluoromethyl) -phenyl] ethanol

The title compound was synthesized using the procedure recited in Example 150, except aniline (28mg, 0.30mmol) was used to give solid (22mg, O.OβOmmol).

MS m/z 375 (M+ 1) ⁺

Example 166:

2-{[2-({4-[(methylsulfonyl)methyl]phenyl}amino)-4-pyrimid inyl] amino}- l-[4-(triflu oromethyl)phenyl] ethanol

The title compound was synthesized using the procedure recited in Example 1, except Intermediate lib

(2- [(2-chloro-4-pyrimidinyl)amino]-l-[4-(trifluoromethyl)phenyl ] -ethanol) (48mg, O.lδmmol) and 4-[(methylsulfonyl)-methyl]aniline (56mg, 0.30mmol) was used to give solid (53mg, O.llmmol). MS m/z 467 (M+l) ⁺

Example 167:

3 - { [4 ~ ({2 'hydroxy 2 ~ [4 ~ (trifluor ometh yl) phenyl] ethyl} amino) ~ 2 ~ p yrimidin yl] amino}

benzenesulfonamide

The title compound was synthesized using the procedure recited in Example 166, except 3-aminobenzenesulfonamide (52mg, 0.30mmol) was used to give solid (34mg, 0.075mmol). MS m/z 454 (M+l) ⁺

Example 168: l'[4-(trifluoromethyl)phenyl]'2'[(2'{[3.4.5'tris(methyloxy)p henyl]amino}'4-pyrimi dinvOamino] ethanol

The title compound was synthesized using the procedure recited in Example 166, except 3,4,5"tris(methyloxy)aniline (55mg, 0.30mmol) was used to give solid (32mg, 0.070mmol). MS m/z 465 (M+l) ⁺

Example 169:

3 - { [4 ~ ({2 'hydroxy 2 ~ [4 ~ (trifluor ometh yl) phenyl] ethyl} amino) ~ 2 ~ p yrimidin yl] amino} benzonitrile

The title compound was synthesized using the procedure recited in Example 166, except 3-aminobenzonitrile (35mg, 0.30mmol) was used to give solid (27mg,

0.068mmol).

MS m/z 400 (M+l) ⁺

Example 17Q:

2-[(2-{[3-(2-methyl-1.3-thiazol-4-yl)phenyl]amino}-4-pyri midinyl) amino] -l-[4-(trifl uoromethypphenyl] ethanol

The title compound was synthesized using the procedure recited in Example 166, except 3"(2-methyl-l,3"thiazol"4-yl)aniline (57mg, 0.30mmol) was used to give solid (35mg, 0.074mmol). MS m/z 472 (M+l) ⁺

Example 171:

3'(3'{[4-({2'hvdroxy2'[4-(trifluoromethyl)phenyl]ethyl}am ino)'2'Pyrimidinyl]ami nolphenyl) - 2.4-imidazolidinedione

The title compound was synthesized using the procedure recited in Example 166, except 3"(3"aminophenyl)-2, 4-imidazolidinedione (57mg, 0.30mmol) was used to give solid (38mg, 0.080mmol). MS m/z 473 (M+l) ⁺

Example 172:

2~({2 ~ [(2 τnethylphenyl)amino] '4-pyrimidinyl}amino) ~ 1 ~ [4-(trifluoromethyl)phenyl

]ethanol

The title compound was synthesized using the procedure recited in Example 166, except 2-methylaniline (32mg, 0.30mmol) was used to give solid (25mg, 0.064mmol). MS m/z 389 (M+l) ⁺

Example 173:

2'({2'[(3'methylphenyl)amino]'4-pyrimidinyl}amino)'l'[4-( trifluoromethyl)phenyl

]ethanol

The title compound was synthesized using the procedure recited in Example 166, except 3-methylaniline (32mg, 0.30mmol) was used to give solid (26mg,

0.066mmol).

MS m/z 389 (M+l) ⁺

Example 174:

2~({2 ~ [(4-methylphenyl)amino] '4-pyrimidinyl}amino) ~ 1 ~ [4-(trifluoromethyl)phenyl

]ethanol

The title compound was synthesized using the procedure recited in Example 166, except 4-methylaniline (32mg, 0.30mmol) was used to give solid (26mg,

0.067mmol).

MS m/z 389 (M+l) ⁺

Example 175:

2-[(2-{[2-(methyloxy)phenyl1aniino}-4-pyrimidinyl)amino]- l-[4-(trifluoromethyl)p henyl]ethanol

The title compound was synthesized using the procedure recited in Example 166, except 2-(methyloxy)aniline (37mg, 0.30mmol) was used to give solid (23mg,

0.056mmol).

MS m/z 405 (M+l) ⁺

Example 176:

2'[(2'{[3'(methyloxy)phenyl1amino}'4-pyrimidinyl)amino]'l '[4-(trifluoromethyl)p henyl] ethanol

The title compound was synthesized using the procedure recited in Example 166, except 3-(methyloxy)aniline (37mg, 0.30mmol) was used to give solid (30mg,

0.075mmol).

MS m/z 405 (M+l) ⁺

Example 177:

2-[(2-{[4-(methyloxy)phenyl1aniino}-4-pyrimidinyl)amino]- l-[4-(trifluoromethyl)p henyl] ethanol

The title compound was synthesized using the procedure recited in Example 166, except 4-(methyloxy)aniline (37mg, 0.30mmol) was used to give solid (l2mg,

0.029mmol).

MS m/z 405 (M+l) ⁺

Example 178:

2-({2-[(2-chlorophenyl)amino1'4-pyrimidinyl}amino)-l-[4-( trifluoromethyl)phenyl] ethanol

The title compound was synthesized using the procedure recited in Example 166, except 2-chloroaniline (38mg, 0.30mmol) was used to give solid (l9mg,

0.046mmol).

MS m/z 409 (M+l) ⁺

Example 179:

2'({2'[(3'chlorophenyl)amino]'4-pyrimidinyl}amino)'l'[4-( trifluoromethyl)phenyl] ethanol

The title compound was synthesized using the procedure recited in Example 166, except 3-chloroaniline (38mg, 0.30mmol) was used to give solid (27mg,

0.066mmol).

MS m/z 409 (M+l) ⁺

Example 18Q:

2'({2'[(4-chlorophenyl)amino]'4-pyrimidinyl}amino)'l'[4-( trifluoromethyl)phenyl] ethanol

The title compound was synthesized using the procedure recited in Example 166, except 4-chloroaniline (38mg, 0.30mmol) was used to give solid (27mg,

0.067mmol).

MS m/z 409 (M+l) ⁺

Example 181:

2 ~{ [2 ~ (phenylamino) ~ 4~p yrimidinyl] amino} ^• ! ^• [4-(trifluoromethyl) 'phenyl] ethanol

The title compound was synthesized using the procedure recited in Example 166, except aniline (28mg, 0.30mmol) was used to give solid (21mg, 0.055mmol).

MS m/z 375 (M+ 1) ⁺

Example 182:

2-{[2-({4-[(methylsulfonyl)methyl]phenyl}amino)-4-pyrimid inyl]-amino}-l-(2-pyrid invOethanol

The title compound was synthesized using the procedure recited in Example 1, except Intermediate 12b

(2-[(2-chloro-4-pyrimidinyl)amino]-l-(2-pyridinyl)ethanol ) (38mg, O.lδmmol) and 4- [(methylsulfonyl) -methyl] aniline (56mg, 0.30mmol) was used to give solid (24mg, 0.061mmol).

MS m/z 400 (M+ 1) ⁺

Example 183: l-(2-pyridinyl)-2-[(2-{[3,4,5-tris(methyloxy)phenyl]amino}-4 -pyrimidinyl)amino]et hanol

The title compound was synthesized using the procedure recited in Example 182, except 3,4,5-tris(methyloxy)aniline (55mg, 0.30mmol) was used to give solid (27mg, 0.068mmol). MS m/z 398 (M+l) ⁺

Example 184: 3-[(4-{[2-hvdroxv-2-(2-pvridinvl)ethvl]amino}-2-pvrimidinvl) -aminolbenzonitrile

The title compound was synthesized using the procedure recited in Example 182, except 3-aminobenzonitrile (35mg, 0.30mmol) was used to give solid (21mg, 0.063mmol). MS m/z 333 (M+l) ⁺

Example 185:

2-[(2-{[3-(2-methyl-l,3-thiazol-4-yl)phenyl]amino}-4-pyri midinyl)-amino]-l-(2-pyri dinvDethanol

The title compound was synthesized using the procedure recited in Example 182, except 3"(2-methyl-l,3"thiazol"4-yl)aniline (57mg, 0.30mmol) was used to give solid (32mg, 0.079mmol).

MS m/z 405 (M+l) ⁺

Example 186:

3-{3-[(4-{[2-hvdroxy-2-(2-pyridinyl)ethyl]amino}-2-pyrimi dinyl)-amino]phenyl}-2,4

'imidazolidinedione

The title compound was synthesized using the procedure recited in Example 182, except 3-(3-aminophenyl)-2,4-imidazolidinedione (57mg, 0.30mmol) was used to give solid (28mg, 0.070mmol). MS m/z 406 (M+l) ⁺

Example 187:

The title compound was synthesized using the procedure recited in Example 182, except 2-methylaniline (32mg, 0.30mmol) was used to give solid (l8mg, 0.057mmol). MS m/z 322 (M+l) ⁺

Example 188:

2-({2-[(3-methylphenyl)amino]-4-pyrimidinyl}amino)-l-(2 -pyridinvOethanol

The title compound was synthesized using the procedure recited in Example 182, except 3-methylaniline (32mg, 0.30mmol) was used to give solid (25mg, 0.078mmol). MS m/z 322 (M+l) ⁺

Example 189:

2-({2-[(4-methylphenyl)amino]-4-pyrimidinyl}amino)-l-(2-p yridinyl)ethanol

The title compound was synthesized using the procedure recited in Example 182, except 4-methylaniline (32mg, 0.30mmol) was used to give solid (25mg, 0.079mmol). MS m/z 322 (M+l) ⁺

Example 19Q: 2- [(2 -{[2 -(methyloxy)phenyl] amino} -4-pyrimidinyl)amino] - 1 -(2 -pyridinvDethanol

The title compound was synthesized using the procedure recited in Example 182, except 2-(methyloxy)aniline (37mg, 0.30mmol) was used to give solid (22mg, 0.065mmol).

MS m/z 338 (M+l) ⁺

Example 191:

2- [(2 -{[3-(methyloxy)phenyl1 amino} -4-pyrimidinyl)amino] - 1 -(2 -pyridinvOethanol

The title compound was synthesized using the procedure recited in Example 182, except 3-(methyloxy)aniline (37mg, 0.30mmol) was used to give solid (l7mg, O.OδOmmol).

MS m/z 338 (M+l) ⁺

Example 192:

The title compound was synthesized using the procedure recited in Example 182, except 4-(methyloxy)aniline (37mg, 0.30mmol) was used to give solid (25mg,

0.073mmol).

MS m/z 338 (M+l) ⁺

Example 193:

2'({2'[(2'chlorophenyl)amino1'4'pyri mi dinyllamino)'! ~(2 'PyridinvOethanol

The title compound was synthesized using the procedure recited in Example 182, except 2-chloroaniline (38mg, 0.30mmol) was used to give solid (l7mg,

0.049mmol).

MS m/z 342 (M+l) ⁺

Example 194: 2-({2-[(3-chlorophenvl)amino]-4-pvrimidinvl}amino)-l-(2-pvri dinvl)ethanol

The title compound was synthesized using the procedure recited in Example 182, except 3-chloroaniline (38mg, 0.30mmol) was used to give solid (l6mg, 0.047mmol). MS m/z 342 (M+l) ⁺

Example 195:

2-({2-[(4-chlorophenyl)amino]'4-pyrimidinyl}amino)-l-(2-p yridinyl)ethanol

The title compound was synthesized using the procedure recited in Example 182, except 4-chloroaniline (38mg, 0.30mmol) was used to give solid (26mg, 0.077mmol). MS m/z 342 (M+l) ⁺

Example 196:

2 -{ [2 - (phenylamino) - 4-p yrimidinyl] amino} - 1 -(2 -pyridinyl)ethanol

The title compound was synthesized using the procedure recited in Example 182, except aniline (28mg, 0.30mmol) was used to give solid (l6mg, 0.053mmol).

MS m/z 308 (M+l) ⁺

Example 197:

2-({2-[(4-{[3-(dimethylamino)propyl]amino}-3-fluorophenyl )amino]-4-pyrimidinyl} amino) -1-phenylethanol

2-[(2-Chloro"4-pyrimidinyl)amino]"l"phenylethanol (169 mg, 0.68 mmol) and (4-amino-2-fluorophenyl)[3-(dimethylamino)propyl] amine (443 mg, 0.68 mmol) were combined with isopropanol (8 mL) and cone, hydrochloric acid (75μL, 0.9mmol). The mixture was heated to 85 ⁰ C for 60 minutes in an oil bath. Ethyl acetate (100 mL) and aqueous NaHCθ3 (20 mL), and brine (10 mL) were added and the organic layer dried with MgSCh. The mixture was filtered through Celite and the concentrated compound (oil) was purified by trituration with ethyl

acetate followed by hexanes to yield the desired material (35 mg, 0.08 mmol). IH NMR (400 MHz, DMSOD6) δ ppm 1.65-1.68 (m, 2 H), 2.13 (s, 6 H), 2.27-2.31 (m, 2 H), 3.03-3.04 (m, 2 H), 3.18-3.21 (m, 2 H), 4.70-4.74 (m, 1 H), 5.01 (bs, 1 H), 5.47 (d, J = 4 Hz, 1 H), 5.92 (d, J = 6 Hz, 1 H), 6.56 (t, J = 9 Hz, 1 H), 7.22-7.25 (m, 3 H), 7.30-7.38 (m, 5 H), 7.55 (d, J = 14 Hz, 1 H), 7.71 (d, J = 5 Hz, 1 H), 8.65 (s, 1 H). MS m/z 425 (M+l) ⁺

Aniline Synthesis^

Step A: jV-(2-Fluoro-4-nitrophenyl)-N,N-dimethyl-l,3-propanediamine[ 3-(dimethylamino) propyl] (2-fluoro-4-nitrophenyl)amine

To a solution of l,2-difluoro-4-nitrobenzene (l g, 6.28 mmol) in 62 mL of THF was added Et3N (l.58g, 15.7mmol) followed by λζjV-dimethyl-l,3-propanediamine (θ.77g, 7.54mmol). The resulting reaction was stirred at rt for 18 hours. The reaction was diluted with EtOAc, and quenched with sat aq. NaHCθ3. Following extraction with EtOAc, the organics were combined, filtered over MgSθ4, and reduced in vacuo onto silica gel. Purification via ISCO chromatography (hexanes: EtOAc) afforded a yellow solid as the desired product. LRMS calculated for C11H17FN3O2 [M+H] ⁺ 242, found 242.

Step B:

7V ^: [3-(3-{2-[(4-{[3-(Dimethylamino)propyl]amino}-3-fluorophenyl )-amino]-4-pyrimi dinyl}pyrazolo[l,5"a]pyridin-2-yl)phenyl]-2,6"di£luoro"benz amide.

(Dimethylamino)propyl](2-fluoro-4-nitrophenyl)amine (0.72 g, 2.9 mmol) was dissolved in EtOAc (50 niL) and Pd/C (10%, 0.16g, O.lδmmol) was added. The reaction was then placed under 1 atmosphere of H2. The reaction was allowed to stir for 24 h. The reaction was treated with Celite, and the resulting slurry was filtered over Celite. The filtrate was reduced in vacuo to afford the intermediate aniline as a dark-red oil that was used without further purification.

Example 198: l-Phenyl-2-{[2-(l,2,3,4-tetrahydro-7-isoquinolinylamino)-4-p yrimidinyl]amino}eth anol

2-[(2-Chloro-4-pyrimidinyl)amino]-l-phenylethanol (163 mg, 0.65 mmol) and 2-(trifluoroacetyl)-l,2,3,4-tetrahydro"7"isoquinolinamine (160 mg, 0.65 mmol) were combined with isopropanol (6 mL) and cone, hydrochloric acid (75μL, 0.9mmol). The mixture was heated to 85 ⁰ C for 160 minutes in an oil bath. Ethyl acetate (10 mL) and hexanes (20 mL) were added and the mixture was purified by trituration to yield the desired solid (270 mg). This material was dissolved in THF (10 mL). LiOH (120 mg, 2.8 mmol) was then added in water (2

niL). The reaction was stirred at RT for 60 minutes. Ethyl acetate (100 mL) and aqueous NaHCθ3 (20 mL), and brine (10 mL) were added and the organic layer dried with MgSθ4. The mixture was filtered through Celite and the concentrate (oil) was purified by trituration with ethyl acetate and hexanes to yield the desired material (55 mg, 0.15 mmol). IH NMR (400 MHz, DMSOD6) δppm 2.59 (t, J = 6 Hz, 2 H), 2.92 (t, J = 6 Hz, 2 H), 3.21-3.27 (m, 3H), 3.61 (m, 2 H), 4.71-4.73 (m, 1 H), 5.46 (bs, 1 H), 5.94 (d, J = 6 Hz, 1 H), 6.86 (d, J = 8 Hz, 1 H), 7.23-7.24 (m, 2H), 7.29-7.34 (m, 4 H), 7.36-7.43 (m, 2 H), 8.73 (s, IH). MS m/z 362 (M+l) ⁺

Aniline Synthesis^

Step A: 2,2,2-TrIfIuOrO-N- [2-(4-nitrophenyl)ethyl]acetamide

A solution of 4-nitrophenethylamine hydrochloride (4.05 g, 20 mmol) in pyridine (80 mL) was cooled to O ⁰ C. To this solution, trifluoroacetic anhydride (3.11 mL,

22 mmol) was added dropwise. The reaction mixture was stirred for 30 min at

O ⁰ C. The mixture was poured into 5% NaHCθ3 aq and extracted with EtOAc.

The organic layer was combined, washed with brine and dried (NaaSCh). The solvent was reduced under pressure. The residue was recrystalized with Hex/EtOAc to give the amide (5.56 g) as white solid.

Step B: 7-Nitro-2-(trifluoroacetyl)-l,2,3,4-tetrahydroisoquinoline

A mixture of 2,2,2-trifluoro-N[2-(4-nitrophenyl)ethyl]acetamide (2.5 g, 9.54 mmol) and paraformaldehyde (447 mg, 14.3 mmol) was added to a solution of acetic acid (10 mL) in sulfuric acid (15 mL) at rt. After stirring for 16 h the reaction mixture was poured into ice-HaO. The gummy residue was extracted with EtOAc and the organic layer was washed with sat. NaHCθ3, brine, dried

(MgaSOj and evaporated. The residue was chromatographed on silica gel (Hex/EtOAc = 20-50%) to afford the cyclic amide (2.47 g).

Step C: 2-(Trifluoroacetyl)-l,2,3,4-tetrahydro-7-isoquinolinamine

A mixture of 2-(trifluoroacetyl)- 1,2,3, 4-tetrahydro-7-isoquinolinamine (2.45 g) and 10% Pd/C (200 mg) in EtOH (90 niL) was stirred for 16 h under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was evaporated in vacuo. Chromatography on silica gel eluting with Hex/EtOAc gradient (50-100%) gave the desired aniline (1.95 g).

Example 199:

2-{[2-({4-[(methylsulfonyl)methyl]phenyl}amino)-4-pyrimid inyl]-amino}-l-phenyle thanol

2-[(2-Chloro"4-pyrimidinyl)amino]"l"phenylethanol (250 mg, 1.0 mmol) and- [(methylsulfonyl)methyl] aniline (ref.2) (185 mg, 1.0 mmol) were combined with isopropanol (6 mL) and cone, hydrochloric acid (75μL, 0.9mmol). The mixture was heated to 85 ⁰ C for 4 hours in an oil bath. Ethyl acetate (100 mL) and aqueous NaHCθ3 (20 mL), and brine (10 mL) were added and the organic layer dried with MgSθ4. The mixture was filtered through Celite and the concentrated compound (oil) was purified by trituration with ethyl acetate followed by hexanes to yield a solid which was further purified by column chromatography (1-6% MeOH/CH ₂ Cl2) to yield the desired material (350 mg, 0.87 mmol). IH NMR (400 MHz, DMSOD6) δ ppm 2.85 (s, 3 H), 3.23 (m, 1 H), 3.7 (bs, 1 H), 4.35 (s, 2 H), 4.74-4.76 (m, 1 H), 5.50 (d, J = 4 Hz, 1 H), 6.01 (d, J = 6 Hz, 1

H), 7.21-7.34 (m, 3 H), 7.35-7.40 (m, 5 H), 7.77-7.79 (m, 3 H), 9.05 (s, 1 H). MS m/z 399 (M+ 1) ⁺

Further intermediates and Examples are described below

Intermediate A

2~ [(2'chloro'4-pyrimidinyl)amino] ~ 1 'phenylethanol

R12581/77/1 (GSK621591A)

2-amino-l-phenylethanol (3.Og, 21.9mmol) and triethylamine (2.18g, 3mL, 21.6mmol) were added to a solution of 2,4-dichloropyrimidine (3.1g, 20.8mmol) in THF (lOOmL). The mixture was left stirring at room temperature under a nitrogen atmosphere for 16 hours. After filtering through a glass sinter, the filtrate was pre-absorbed under vacuum onto diatomaceous earth. Purification was achieved using flash silica chromatography on an ISCO SQ16X machine, eluting with an ethyl acetate/cyclohexane gradient. Concentration of the relevant fractions afforded the title compound as a white solid (3.5g, 13.9mmol). IH NMR (400 MHz, DMSOD6) 8 ppm 3.27-3.37 (m, 1 H) 3.48-3.56 (m, 1 H) 4.67-4.77 (m, 1 H) 5.6 (d, J=A Hz, 1 H) 6.52 (d, J=G Hz, 1 H) 7.25 (t, J=I Hz, IH) 7.3-7.4 (m, 4 H) 7.87 (d, J=6 Hz, 1 H) 8.04 (bt, J=δ Hz, 1 H). MS m/z 250/252 (3:1 ratio) (M+ 1) ⁺

Intermediate B 2-bromo-2,2-difluoro-ffi(2-hvdroxy-5-nitrophenyl)acetamide

Triethylamine (l.97g, 19.46mmol) was added to an ice-cooled solution of

2-amino-4-nitrophenol (3g, 19.46mmol) in THF (30ml).

Bromodifluoroacetylbromide (2.48ml, 19.46mmol) was added dropwise to the solution and the mixture stirred at O ⁰ C for 45min. The reaction was quenched with water and extracted with ethyl acetate (3x 50ml). The combined organic extracts were washed with brine, dried (magnesium sulphate) and reduced to dryness under vacuum to give

2-bromo"2,2-difluoro"jV-(2-hydroxy"5"nitrophenyl)acetamid e (7.09g) as a brown solid.

LC/MS: Rt 3.09min, [M-H]- 311/309.

Intermediate C

2,2-difluoro-6-nitro-2.ff l,4-benzoxazin-3(4.fl!)-one

2-bromo-2,2-difluoro-jV-(2-hydroxy-5-nitrophenyl)acetamide (5.6g, 18mmol) and potassium carbonate (7.46g, 54mmol) in DMF (50ml) were stirred for 18hrs at 5O ⁰ C. The reaction was filtered and the filtrate reduced to dryness under vacuum. The residue was partitioned between ethyl acetate and water and the aqueous layer extracted with ethyl acetate (x3). The combined organic phases were washed with a little water and the solvent evaporated under vacuum to give 2,2-difluoro-6-nitro-2H-l,4-benzoxazin-3(4H)-one as a sticky yellow solid, which was used without further purification. LC/MS: Rt 2.86min, [M-H]- 229.

Intermediate D: 6-amino-2,2-difluoro-2-ffl,4-benzoxazin-3(4 _J fift-one

2,2-difluoro-6-nitro-2H-l,4-benzoxazin-3(4H)-one (2.87g, 12.47mmol) and palladium on carbon (10%, 650mg) in ethyl acetate (lOOml) were hydrogenated under hydrogen for 5hrs. The reaction was filtered through celite, the residue washed with ethyl acetate and the filtrate and washings reduced to dryness under vacuum. The crude product was purified by chromatography on a Flashmaster cartridge (Si, 7Og), eluting with a MeOη/DCM/triethylamine gradient (0-15% MeOH, 1% triethylamine) and then washing the column with further MeOη/DCM/triethylamine (10% MeOH, 1% triethylamine. The product fractions were reduced to dryness under vacuum to give 6-amino-2,2-difluoro-2H-l,4-benzoxazin-3(4H)-one (857mg) as a brown solid. LC/MS: Rt 2.25min, [M-H]- 199.

Example 200

2.2-difluoro-6-({4-[(2-hvdroxy-2-phenylethyl)amino]-2-pyr imidinyl}amino)-2.ff 1.4- benzoxazin-3(4.fl!)-one trifluoroacetate salt

2-[(2-chloro-4-pyrimidinyl)amino]-l-phenylethanol (O.lmmol, 24.9mg) was added to a solution of 6"amino"2,2-difluoro"2H-l,4-benzoxazin-3(4H)-one (O.lδmmol,

30mg) in acetone (lmL), water (l.δmL) and 2N hydrochloric acid (20μL). The mixture was allowed to stir at 7O ⁰ C for 16 hours. The mixture was concentrated under vacuum and purified using SCX SPE (lg). The crude was loaded in methanol (δOOμL) and eluted with methanol (lδOOμL x 2) and 2.0M Nη3/MeOη (lδOO μL). The ammonia fraction was concentrated and further purified by mass directed HPLC. The product containing fractions were concentrated to give title compound. (0.09g, 0.017mmol).

IH NMR (2δO MHz, DMSOD6) δ ppm 3.66-3.78 (m, 1 H) 4.69-4.76 (dd, J=3.δ Hz 1 H) 6.27-6.30 (d, J=7 Hz, 1 H) 7.26-7.28 (m, 6 H) 7.3δ (bs, 1 H) 7.77-7.79 (d, «/=6.91 Hz, 1 H) 9.04 (bs, 1 H) 10.33 (bs, 1 H) 12.05 (bs, 1 H). MS m/z 414 (M+ 1) ⁺

Example 201

4-({4- [(2 'hvdroxy2 'phenylethvOamino] ~2 'pyrimidinyll amino) benzenesulfonamide formate salt

2-[(2-chloro-4-pyrimidinyl)amino]-l-phenylethanolphenylet hanol (30mg,

0.12mmol) and 4-aminobenzenesulfonamide (23mg, 0.13mmol) were combined with acetone (ImL) water (l.δmL) and cone. Hydrochloric acid (20μL). The mixture was heated to 14O ⁰ C for 15 minutes in a Biotage microwave. Solvent was removed under vacuum and the compound purified by mass directed HPLC using an acetonitrile/water (modified with formic acid) gradient as the eluent.

Concentration of the relevant fractions afforded the title compound as a white solid (28mg, 0.07mmol).

IH NMR (400 MHz, DMSOD6) δ ppm 3.3 (Jam, 1 H) 3.7 (Jam, 1 H) 4.77 (dd, J=S & 4 Hz, 1 H) 5.3-5.7 (bs, 1 H) 6.09 (d, J=Q Hz, 1 H) 7.11 (s, 2 H) 7.27 (tt, J=I & 2

Hz, 1 H) 7.3-7.4 (m, 5 H) 7.65 (d, J=9 Hz, 2 H) 7.84 (bd, J=4.5 Hz, 1 H) 7.92 (d, J=9

Hz, 2 H) 8.16 (s, 1 H) 9.36 (s, 1 H). MS m/z 386 (M+l) ⁺

Example 202

4-({4-[(2-hvdroxy-2-phenylethyl) amino] -2-pyrimidinyl}amino)benzenesulfonamide trifluoroacetate salt

The title compound was synthesized using the procedure recited in Example 200, except 4-aminobenzenesulfonamide was used. IH NMR (600MHz DMSOD6) δ ppm 3.42-3.47 (m, 1 H) 3.68-3.72 (m, 1 H) 4.79 (dd, J= 7.5 & 4 Hz, 1 H) 6.33 (d, J=I Hz, 1 H) 7.26-7.29 (m, 1 H) 7.34 (s, 1 H) 7.35-7.37 (m, 5 H) 7.76 (d, J=S Hz, 2 H) 7.81 (d, J=Q Hz, 2 H) 7.85 (d, J=I. h Hz, 1 H). MS m/z 386 (M+ 1) ⁺

Example 203

3~({4- [(2 'hvdroxy2 'phenylethvOamino] ~2 'pyrimidinyll amino) benzenesulfonamide formate salt

The title compound was synthesized using the procedure recited in Example 201, except 3-aminobenzenesulfonamide was used.

IH NMR (400 MHz, DMSOD6) δ ppm 3.4 (bm, 1 H) 3.6 (bs, 1 H) 4.78 (dd, J=I.5 & 4 Hz, 1 H) 5.35-5.6 (bs, 1 H) 6.07 (d, J=G Hz, 1 H) 7.2-7.4 (m, 10 H) 7.81 (bs, 1 H) 7.98 (d, J=S Hz, 1 H) 8.14 (s, 1 H) 8.30 (s, 1 H) 9.24 (s, 1 H). MS m/z 386 (M+ 1) ⁺

Intermediate E 2-methyl-5-nitrobenzenesulfonamide

To a solution of 2-methyl-5-nitrobenzenesulfonyl chloride (6Og, 0.255mol) in diethyl ether (191OmL) was added aqueous ammonia solution (35% solution, 255mL) dropwise over 20 minutes keeping the temperature below 25°C. The mixture was stirred at ambient temperature for 60 hours. The reaction mixture was filtered under vacuum and the aqueous layer of the filtrate extracted with ethyl acetate, dried over magnesium sulfate and evaporated under vacuum to give 1.9g of the title compound. The ether layer from the reaction mixture was

washed with water, separated, dried over magnesium sulfate, filtered and evaporated under vacuum to give 14.7g of the title compound. The residue from the filtration of the reaction mixture was dissolved in ethyl acetate, filtered, washed with water, separated, dried over magnesium sulfate, filtered and evaporated under vacuum to give 34.2g of the title compound. A representative NMR is given below.

IH NMR (400 MHz, DMSOD6) δ ppm 2.71 (s, 3 H) 7.70 (s, 1 H) 7.77 (s, 2 H) 8.34 (dd, J=8.δ & 1.5 Hz, 1 H) 8.6 (d, J=I Hz, 1 H).

Intermediate F

6-nitro-1.2-benzisothiazol-3(2.fl!)-one 1.1-dioxide

To a solution of chromium trioxide (40.7g, 0.407mol) in water (30OmL) was added concentrated sulphuric acid (374mL) dropwise over 30 minutes keeping the temperature below 45°C. 2-methyl-5-nitrobenzenesulfonamide (2Og, 92.5mmol) was added and the mixture stirred at room temperature for 18.5 hours. The mixture was filtered through a sinter funnel and the residue washed with water, dissolved in sodium bicarbonate solution and filtered under vacuum. The reaction filtrate was acidified with concentrated hydrochloric acid and a precipitate collected by filtration. This was dried under vacuum at 40°C to give 5.37g of the title compound. The residue from the basic filtration was washed with water and dried at 50°C for 12 hours. The filtrates from the basification and acidification were combined and a precipitate filtered off and the filtrate evaporated under vacuum to give a solid. The residue, precipitate and solid were combined, washed with acetone and filtered. The filtrate was evaporated under vacuum to give 6g of the title compound. A representative NMR is given below. IH NMR (400 MHz, DMSOD6) δ ppm 7.97 (d, ,7=8 Hz, 1 H) 8.51 (dd, J=S & 2 Hz, 1 H) 8.64 (d, J=I.5 Hz, 1 H). MS m/z 227 (M- 1)

Intermediate G

6-amino- 1.2 -benzisothiazol-3(2.fl!)-one 1.1 dioxide

Platinum oxide (0.76g, 3.4mmol) and 6"nitro"l,2-benzisothiazol"3(2H)-one l,l"dioxide (5.96g, 26.2mmol) were dissolved in ethanol (l54mL) and dimethylformamide (l2mL) and the reaction stirred under an atmosphere of hydrogen for 19 hours. The mixture was filtered through celite and the filtrate evaporated under vacuum. The residue was triturated with toluene and the solvent removed under vacuum. The residue was re-dissolved in ethanol and evaporated under vacuum to give 4.78g of crude title compound. This crude compound (4.78g) was re-dissolved in ethanol (l54mL) and platinum oxide (0.54g) added. The reaction was stirred at room temperature for 3.75 hours under an atmosphere of hydrogen. The catalyst was filtered off and the filtrate evaporated to dryness to give 3.12g of the title compound.

1η NMR (400 MHz, DMSOD6) δ ppm 6.6-6.9 (bs, 2 H) 6.88 (d, J=8.δ & 2 Hz, 1 H) 6.93 (d, J=I.5 Hz, 1 H) 7.58 (d, J=8.δ Hz, 1 H).

Intermediate H 2,3-dihvdro-l,2-benzisothiazol-6-amine 1.1 -dioxide

To a suspension of 6-amino-l,2-benzisothiazol-3(2H)-onel,ldioxide

(6.37g, 32.1mmol, made using a similar method to the one described for intermediate G) was added zinc dust (18.9g, 0.289mol) over half an hour with cooling in an ice bath. The reaction was then stirred at room temperature for 3 hours. The mixture was basified with saturated sodium bicarbonate solution and solid sodium bicarbonate carefully over a one hour period. The mixture was filtered and the filtrate extracted with ethyl acetate. The organic layer was washed with brine solution, dried over magnesium sulfate and evaporated under vacuum to give 1.55g of the title compound. The residue from the filtration was triturated with ethyl acetate, filtered and the filtrate evaporated under vacuum to give 1.8g of the title compound. The residue from the trituration was triturated with ethyl acetate, filtered and the filtrate evaporated under vacuum to give 0.36g of the title compound. The 3 batches of product were combined, dissolved in methanol and evaporated under vacuum to give 3.15g of the title compound. 1η NMR (400 MHz, DMSOD6) δ ppm 4.17 (d, J=δ Hz, 2 H) 5.6 (s, 2 H) 6.78 (d, «£=1.5 Hz, 1 H) 6.82 (dd, J=8 & 2 Hz, 1 H) 7.14 (d, J=S Hz, 1 H) 7.54 (t, ,7=4.5 Hz, 1 H).

Example 204

2-({2-[(l.l-dioxido-2.3-dihvdro-1.2-benzisothiazol-6-yl)a mino]-4-pyrimidinyl}amin o)-l-phenylethanol formate salt.

The title compound was synthesized using the procedure recited in Example 201 except 2,3-dihydro-l,2-benzisothiazol-6-amine 1,1-dioxide was used. IH NMR (400 MHz, DMSOD6) δ ppm 3.6 (bs, 1 H) 4.3 (d, J=3 Hz, 2 H) 4.76 (dd, J=S & 4 Hz, 1 H) 5.3-5.6 (bs, 1 H) 6.1 (d, J=G Hz, 1 H) 7.25 (t, J=I Hz, 1 H) 7.3-7.4 (m, 3 H) 7.41 (d, J=I Hz, 2 H) 7.68 (bs, 1 H) 7.85 (bs, 1 H) 7.94 (dd, J=S.h & 2 Hz, 1 H) 8.15 (s, 1 H) 8.31 (s, 1 H) 9.32 (s, 1 H). MS m/z 398 (M+ 1) ⁺

Example 205

2-({2-[(l.l-dioxido-2.3-dihvdro-1.2-benzisothiazol-6-yl)a mino]-4-pyrimidinyl}amin o)-l-phenylethanol trifluoroacetate salt

The title compound was synthesized using the procedure recited in Example 200, except 2,3"dihydro"l,2-benzisothiazol"6"amine 1,1-dioxide was used. IH NMR (600MHz, DMSOD6) δ ppm 3.46-3.52 (m, 1 H) 3.62-3.67 (m, 1 H) 4.40 (bs, 2 H) 4.75 (m, 1 H) 6.33 (d, J=7.5 Hz, 1 H) 7.22-7.25 (m, 1 H) 7.27-7.34 (m, 5 H) 7.53 (d, J=8 Hz, 1 H) 7.79 (d, J=8 Hz, 1 H) 7.82 (d, J=H Hz, 1 H) 7.89 (bs, 1 H) 7.95 (bs, IH). MS m/z 398 (M+l) ⁺

Example 206

5-({4-[(2-hvdroxy-2φhenylethyl)amino]-2-pyrimidinyl}amin o)-1.3-dihvdro-2.ffben zimidazol-2-one formate salt

The title compound was synthesized using the procedure recited in Example 201 except 5-amino-l,3-dihydro-2H-benzimidazol-2-one was used. IH NMR (400 MHz, DMSOD6) δ ppm 3.25 (Jam, 1 H) 3.65 (bs, 1 H) 4.75 (dd, J=S & 4 Hz, 1 H) 5.98 (d, J=G Hz, 1 H) 6.76 (d, ,7=8.5 Hz, 1 H) 7.2-7.4 (m, 7 H) 7.45 (s, 1 H) 7.76 (d, J=h Hz, 1 H) 8.2 (s, 1 H) 8.8 (s, 1 H) 10.3 (s, 1 H) 10.4 (s, 1 H). MS m/z 363 (M+ 1) ⁺

Example 207

2-{[2-(l.ffindazol-6-ylamino)-4-pyrimidinyl]amino}-l-phen ylethanol formate salt

The title compound was synthesized using the procedure recited in Example 201 except lH-indazol"5"amine was used.

IH NMR (400 MHz, DMSOD6) δ ppm 3.3 (Jam, 1 H) 3.7 (bs, 1 H) 4.78 (dd, J=S & 4 Hz, 1 H) 6.06 (d, J=G Hz, 1 H) 7.2-7.4 (m, 6 H) 7.53 (d, J=Q Hz, 1 H) 7.84 (d, J=A.h Hz, 1 H) 7.88 (s, 1 H) 8.2 (s, 1 H) 9.0 (s, 1 H). MS m/z 347 (M+l) ⁺

Example 208

2~{[2'(l.ffindazol-6'ylamino)'4-pyrimidinyl]amino}'l'phen ylethanol trifluoroacetate salt

The title compound was synthesized using the procedure recited in Example 200, except lH-indazol"6"amine was used.

IH NMR (600MHz, DMSOD6) δ ppm 3.34-3.38 (m, 1 H) 3.67-3.70 (m, 1 H) 4.73-4.75 (dd, 2 H) 6.31 (d, J=IKz, 1 H) 7.18-7.25 (m, 8 H) 7.70 (bs, IH) 7.76 (s, 1 H) 7.77-7.79 (m, 2 H) 8.10 (s, 1 H) 9.21 (bs, 1 H) 10.61 (bs, 1 H). MS m/z 347

(M+l) ⁺

Example 209

2~{[2'(l.ff 1.2.3'benzotriazol-5'ylamino)'4-pyrimidinyl]amino}'l'phenyle thanol trifluoroacetate salt

The title compound was synthesized using the procedure recited in Example 201 except lH-l,2,3-benzotriazol-5-amine was used and the product was purified using mass directed ηPLC where the solvents were modified with trifluoroacetic acid instead of formic acid.

1η NMR (400 MHz, DMSOD6) δ ppm 3.4 (bm, 1 H) 3.6 (bs, 1 H) 4.72 (dd, ,7=8 & 4 Hz, 1 H) 5.6 (bs, 1 H) 6.3 (d, J=I Hz, 1 H) 7.21 (bs, 5 H) 7.49 (d, J=I Hz, 1 H) 7.78 (d, J=I Hz, 1 H) 7.9 (bm, 1 H) 8.1 (bs, 1 H) 9.0 (bs, 1 H) 10.39 (s, 1 H). MS m/z 348 (M+l) ⁺

Example 210

2-{[2-(lH- 1.2.3-benzotriazol-5-ylamino)-4-pyrimidinyl]amino}-l-phenyle thanol trifluoroacetate salt

The title compound was synthesized using the procedure recited in Example 200, except lH-l,2,3-benzotriazol-5-amine was used.

IH NMR (600MHz, DMSOD6) δ ppm 3.34-3.36 (bm, 1 H) 3.65-3.70 (bm, 1 H)

4.72-4.74 (bm, 1 H) 6.33 (d, J=I Hz, 1 H) 7.18-7.22 (m, 5 H) 7.51 (d, J=S Hz, 1 H)

7.81 (d, J=I Hz, 1 H) 7.95 (bs, 1 H) 9.22 (bs, 1 H) 10.70 (bs,l H). MS m/z 348

(M+l) ⁺

Example 211

2-({2-[(3-chlorophenyl)amino]-4-pyrimidinyl}amino)-l-phen ylethanol trifluoroacetate salt

The title compound was synthesized using the procedure recited in Example 201 except 3-chloroaniline was used and the product was purified using mass directed HPLC where the solvents were modified with trifluoroacetic acid instead of formic

acid.

IH NMR (400 MHz, DMSOD6) δ ppm 3.6-3.7 (Jam, 1 H) 4.76 (dd, J=S & 4 Hz, 1 H) 5.6-5.7 (bs, 1 H) 6.31 (d, J=I Hz, 1 H) 7.3-7.4 (m, 8 H) 7.47 (d, ,7=8 Hz, 1 H) 7.76 (s, 1 H) 7.80 (d, J=7 Hz, 1 H) 9.0 (bs, 1 H) 10.2 (bs, 1 H). MS m/z 341 (M+l) ⁺

Example 212 iV ^L -[3-({4-[(2-hvdroxy-2-phenylethyl)amino]-2-pyrimidinyl}amino )phenyl]-.λ^,.λ^-di methylglvcinamide formate salt

The title compound was synthesized using the procedure recited in Example 201 except λ^-tø-aminophenyO-λ^λ^-dimethylglycinamide was used. The product obtained after initial purification was re-purified using an HPLC system. IH NMR (400 MHz, DMSOD6) δ ppm 2.4 (s, 6 H) 3.68 (bs, 1 H) 4.46 (dd, ,7=8 & 4 Hz, 1 H) 6.0 (d, J=G Hz, 1 H) 7.1-7.4 (m, 8 H) 7.47 (d, J=S Hz, 1 H) 7.78 (d, J=h Hz, 1 H) 7.97 (s, 1 H) 8.14 (s, 1 H) 8.94 (s, 1 H) 9.74 (s, 1 H). MS m/z 407 (M+ 1) ⁺

Intermediate I (l-S)-2-[(2-chloro-4-pvrimidinvl)amino]-l-phenvlethanol

(li?)-2-amino"l"phenylethanol (3.Og, 21.9mmol) and triethylamine (2.18g, 3mL, 21.6mmol) were added to a solution of 2,4-dichloropyrimidine (3.1g, 20.8mmol) in THF (lOOmL). The mixture was left stirring at room temperature under a nitrogen atmosphere for 16 hours. After filtering through a glass sinter, the filtrate was pre-absorbed under vacuum onto diatomaceous earth. Purification was achieved using flash silica chromatography on an ISCO SQ16X machine, eluting with an ethyl acetate/cyclohexane gradient. Concentration of the relevant fractions afforded the title compound as a white solid (3.1g, 12.4mmol). IH NMR (400 MHz, DMSOD6) δ ppm 3.31 (m, 1 H) 3.49-3.57 (m, 1 H) 4.7 (m, 1 H) 5.6 (d, J=A Hz, 1 H) 6.5 (d, J=G Hz, 1 H) 7.25 (t, J=I Hz, IH) 7.3-7.4 (m, 4 H) 7.87 (d, J=6 Hz, 1 H) 8.04 (bt, J=5 Hz, 1 H). MS m/z 250/252 (3:1 ratio) (M+ 1) ⁺

Example 213

4-[(4-{[(2itj)-2-hvdroxy-2-phenylethyl]amino}-2-pyrimidin yl)amino]benzenesulfona mide trifluoracetate salt

(li?)-2-[(2-chloro"4-pyrimidinyl)amino]"l"phenylethanol (30mg, 0.12mmol) and 4-aminobenzenesulfonamide (23mg, 0.13mmol) were combined with acetone (ImL) water (l.δmL) and cone. Hydrochloric acid (20μL). The mixture was heated to 14O ⁰ C for 15 minutes in a Biotage microwave. Solvent was removed under vacuum and the compound purified by mass directed HPLC using an acetonitrile/water (modified with trifluoroacetic acid) gradient as the eluent. Concentration of the relevant fractions afforded the title compound as a white solid (28mg, 0.07mmol). IH NMR (400 MHz, DMSOD6) 8 ppm 3.65-3.75 (bm, 1 H) 4.77 (dd, J=S & 4 Hz, 1 H) 5.6-5.8 (bs, 1 H) 6.32 (d, J=I Hz, 1 H) 7.25-7.35 (m, 7 H) 7.75-7.84 (m, 5 H) 8.96 (bs, 1 H) 10.42 (bs, 1 H). MS m/z 386 (M+l) ⁺

Example 214

3'[(4-{[(2.i'-j)'2'hvdroxy2'phenylethyl]amino}'2'Pyrimidi nyl)amino]benzenesulfona mide trifluoroacetate salt

The title compound was synthesized using the procedure recited in Example 213, except 3-aminobenzenesulfonamide was used.

IH NMR (400 MHz, DMSOD6) δ ppm 3.6 (bm, 1 H) 4.75 (dd, J=T.5 & 4 Hz, 1 H) 5.6-5.7 (bs, 1 H) 6.30 (d, J=I Hz, 1 H) 7.2-7.3 (m, 5 H) 7.4 (s, 2 H) 7.5 (t, J=S Hz, 1 H) 7.6 (d, J=I. h Hz, 1 H) 7.78 (d, J=I Hz, 1 H) 7.83 (d, ,7=8 Hz, 1 H) 8.0 (bs, 1 H) 8.95 (bs, 1 H) 10.41 (bs, 1 H). MS m/z 386 (M+l) ⁺

Example 215

(l./-!)'2'({2'[(l.l'dioxidθ'2.3'dihvdro'1.2'benzisothiaz ol'6'yl) amino] '4'pyrimidinyl} amino)- 1-phenylethanol trifluoroacetate salt

The title compound was synthesized using the procedure recited in Example 213 except 2,3"dihydro"l,2-benzisothiazol"6"amine 1,1-dioxide was used. IH NMR (400 MHz, DMSOD6) δ ppm 3.5 (Jam, 1 H) 3.6 (Jam, 1 H) 4.4 (d, J=4 Hz, 2 H) 4.7 (dd, J=7.δ & 4 Hz, 1 H) 5.5-5.7 (bs, 1 H) 6.3 (d, J=I Hz, 1 H) 7.2-7.35 (m, 5 H) 7.5 (d, J=8.5 Hz, 1 H) 7.78-7.85 (m, 4 H) 7.97 (s, 1 H) 8.9 (bs, 1 H) 10.3 (bs, 1 H). MS m/z 398 (M+ 1) ⁺

Example 216

5-[(4-{[(2itj)-2-hvdroxy-2-phenylethyl]amino}-2-pyrimidin yl)amino]-1.3-dihvdro-2 ■ffbenzimidazol-2-one formate salt

The title compound was synthesized using the procedure recited in Example 213 except 5-amino-l,3-dihydro-2H-benzimidazol-2-one was used. The product obtained after initial purification was also re-purified using an HPLC system with formic acid as the solvent modifier.

IH NMR (400 MHz, DMSOD6) δ ppm 3.6-3.7 (bm, 1 H) 4.73 (m, 1 H) 5.5 (bs, 1 H) 6.1 (d, J=6.5 Hz, 1 H) 6.83 (d, ,7=8 Hz, 1 H) 7.13 (d, ,7=8 Hz, 1 H) 7.2-7.3 (m, 5 H) 7.7 (d, J=G Hz, 1 H) 8.0-8.25 (bs, 1 H) 8.13 (s, 1 H) 9.2-9.4 (bs, 1 H) 10.49 (s, 1 H) 10.53 (s, 1 H). MS m/z 363 (M+l) ⁺

Example 217

(llft-2-{[2-(lH- indazol-6-ylamino)-4-pyrimidinyl] amino}- 1-phenylethanol formate salt

The title compound was synthesized using the procedure recited in Example 213 except lH-indazol-5-amine was used. The product obtained after initial purification was also re-purified using an HPLC system with formic acid as the solvent modifier.

IH NMR (400 MHz, DMSOD6) δ ppm 3.6-3.7 (Jam, 1 H) 4.7-4.8 (Jam, 1 H) 5.5-5.6 (bs, 1 H) 6.14 (d, J=G Hz, 1 H) 7.2-7.35 (m, 6 H) 7.61 (d, J=Q Hz, 1 H) 7.81 (bd, J=A.h Hz, 1 H) 7.95 (s, 1 H) 8.03 (bs, 1 H) 8.13 (s, 1 H) 9.4-9.6 (bs, 1 H) 12.7-12.9 (bs, 1 H). MS m/z 347 (M+l) ⁺

Example 218

(litj)-2-{[2-(l.3-benzothiazol-6-ylamino)-4-pyrimidinyl]a mino}-l-phenylethanol formate salt

The title compound was synthesized using the procedure recited in Example 213 except l,3-benzothiazol-6-amine was used. The product obtained after initial purification was also re-purified using an HPLC system with formic acid as the solvent modifier.

IH NMR (400 MHz, DMSOD6) δ ppm 3.3 (Jam, 1 H) 3.7 (Jam, 1 H) 4.77 (dd, J=S & 4 Hz, 1 H) 6.07 (d, J=G Hz, 1 H) 7.25-7.4 (m, 6 H) 7.7 (dd, J=Q & 2 Hz, 1 H) 7.84 (m, 1 H) 7.89 (d, J=Q Hz, 1 H) 8.2 (s, 1 H) 8.75 (bs, 1 H) 9.13 (s, 1 H) 9.24 (s, 1 H). MS m/z 364 (M+ 1) ⁺

Example 219

4-[(4-{[(2itj)-2-hvdroxy-2-phenylethyl]amino}-2-pyrimidin yl)amino]benzamide formate salt

The title compound was synthesized using the procedure recited in Example 213 except l,3"benzothiazol"6"amine was used and the product was purified using mass directed HPLC where the solvents were modified with formic acid instead of trifluoroacetic acid.

IH NMR (400 MHz, DMSOD6) δ ppm 3.4-3.5 (Jam, 1 H) 3.6-3.7 (Jam, 1 H) 4.77 (dd, J=S & 4 Hz, 1 H) 5.6-5.8 (bs, 1 H) 6.33 (d, J=I Hz, 1 H) 7.2-7.4 (m, 6 H) 7.62 (d, J=S Hz, 2 H) 7.84 (d, J=I Hz, 1 H) 7.90 (d, J=S.h Hz, 2 H) 7.95 (bs, 1 H) 9.2 (bs, 1 H) 10.7 (s, 1 H). MS m/z 350 (M+ 1) ⁺

Example 220

(llft-2-{[2-(lH- 1.2.3-benzotriazol-5-ylamino)-4-pyrimidinyl]amino}-l-phenyle than ol trifluoroacetate salt

The title compound was synthesized using the procedure recited in Example 213 except lH-l,2,3-benzotriazol-5-amine was used.

IH NMR (400 MHz, DMSOD6) δ ppm 3.4 (bm, 1 H) 3.6 (bs, 1 H) 4.72 (dd, ,7=8 & 3.5 Hz, 1 H) 5.6 (bs, 1 H) 6.3 (d, J=I Hz, 1 H) 7.2 (bs, 5 H) 7.5 (d, J=8.5 Hz, 1 H) 7.79 (d, J=6.5 Hz, 1 H) 7.9 (bs, 1 H) 8.1 (bs, 1 H) 9.0 (bs, 1 H) 10.34 (s, 1 H). MS m/z 348 (M+ 1) ⁺

Example 221

(litj)-2-({2-[(3-chlorophenyl) amino] -4-pyrimidinyl}amino)-l-phenylethanol

The title compound was synthesized using the procedure recited in Example 213 except 3"chloroaniline was used. The product obtained after initial purification was also re-purified using an HPLC system with formic acid as the solvent modifier.

IH NMR (400 MHz, DMSOD6) δ ppm 3.6-3.7 (bm, 1 H) 4.75 (dd, J=S & 3.5 Hz, 1 H) 5.7 (bs, 1 H) 6.2 (d, J=6.δ Hz, 1 H) 7.0 (d, J=7.δ Hz, 1 H) 7.2-7.4 (m, 6 H) 7.65 (d, J=T.5 Hz, 1 H) 7.80 (d, J=6 Hz, 1 H) 7.86 (s, 1 H) 8.13 (s, 1 H) 8.25 (bs, 1 H) 9.7 (bs, 1 H). MS m/z 341 (M+ 1) ⁺

Example 222

N ¹ -^- [(4-{[(2R)-2-hvdroxy-2-phenylethyl]amino}-2-pyrimidinyl)amin o]phenyl}-N ² . N ² -dimethylglycinamide formate salt

The title compound was synthesized using the procedure recited in Example 213 except AM3-aminophenyl)-A^,A£-dimethylglycinamide was used. The product obtained after initial purification was re-purified using an HPLC system with formic acid as the solvent modifier.

IH NMR (400 MHz, DMSOD6) δ ppm 2.24 (s, 6 H) 2.99 (s, 2 H) 3.2-3.3 (Jam, 1 H) 3.6-3.7 (Jam, 1 H) 4.75 (dd, J=S & 4 Hz, 1 H) 6.0 (d, J=Q Hz, 1 H) 7.1 (t, J=S Hz, 1 H) 7.2-7.4 (m, 7 H) 7.44 (d, ,7=8.5 Hz, 1 H) 7.78 (d, J=h Hz, 1 H) 7.97 (s, 1 H) 8.29 (s, 2 H) 8.88 (s, 1 H) 9.48 (s, 1 H). MS m/z 407 (M+l) ⁺

Intermediate J

(-.$ ^■ 2- [(2-chloro-4-nvrimidinvl)aminol " l'Phenvlethanol

(l _* S)-2-amino"l"phenylethanol (3.Og, 21.9mmol) and triethylamine (2.18g, 3mL, 21.6mmol) were added to a solution of 2,4-dichloropyrimidine (3.1g, 20.8mmol) in THF (lOOmL). The mixture was left stirring at room temperature under a nitrogen atmosphere for 16 hours. After filtering through a glass sinter, the filtrate was pre-absorbed under vacuum onto diatomaceous earth. Purification was achieved using flash silica chromatography on an ISCO SQ16X machine, eluting with an ethyl acetate/cyclohexane gradient. Concentration of the relevant fractions afforded the title compound as a white solid (3.6g, 14.3mmol). IH NMR (400 MHz, DMSOD6) δ ppm 3.31 (m, 1 H) 3.49-3.57 (m, 1 H) 4.7 (m, 1 H) 5.6 (d, J=A Hz, 1 H) 6.5 (d, J=G Hz, 1 H) 7.25 (t, J=I Hz, IH) 7.3-7.4 (m, 4 H) 7.87 (d, J=6 Hz, 1 H) 8.04 (bt, J=5 Hz, 1 H). MS m/z 250/252 (3:1 ratio) (M+ 1) ⁺

Example 223

4-[(4-{[(2-^>-2-hvdroxy-2-phenylethyl]amino}-2-pyrimid inyl)amino]benzenesulfona mide trifluoracetate salt

The title compound was synthesized using the procedure recited in Example 213, except (l$-2-amino-l-phenylethanol was used.

IH NMR (400 MHz, DMSOD6) δ ppm 3.65-3.75 (bm, 1 H) 4.77 (dd, J=S & 4 Hz, 1 H) 5.6-5.75 (bs, 1 H) 6.32 (d, J=I Hz, 1 H) 7.25-7.35 (m, 7 H) 7.75-7.84 (m, 5 H) 8.95 (bs, 1 H) 10.4 (bs, 1 H). MS m/z 386 (M+ 1) ⁺

Example 224

3'[(4-{[(2-^>'2'hvdroxy2'phenylethyl]amino}'2'pyrimidi nyl)amino]benzenesulfona mide trifluoroacetate salt

The title compound was synthesized using the procedure recited in Example 213, except 3-aminobenzenesulfonamide and (l$-2-amino-l-phenylethanol were used. IH NMR (400 MHz, DMSOD6) δ ppm 3.5 (bm, 1 H) 3.6 (bm, 1 H) 4.75 (dd, J=I.5 & 4 Hz, 1 H) 5.6-5.75 (bs, 1 H) 6.30 (d, J=I Hz, 1 H) 7.2-7.33 (m, 5 H) 7.38 (s, 2 H) 7.53 (t, J=S Hz, 1 H) 7.6 (d, J=I .h Hz, 1 H) 7.78 (d, J=I Hz, 1 H) 7.83 (d, ,7=8 Hz, 1 H) 8.0 (bs, 1 H) 8.95 (bs, 1 H) 10.42 (bs, 1 H). MS m/z 386 (M+ 1) ⁺

Example 225

(l-^>'2'({2'[(l.l'dioxidθ'2.3'dihvdro'1.2'benzisothia zol-6'yl)amino]'4-pyrimidinyl} amino)- 1-phenylethanol trifluoroacetate salt

The title compound was synthesized using the procedure recited in Example 213, except 2,3-dihydro-l,2-benzisothiazol-6-amine 1,1-dioxide and

(l _* S?)-2-amino- 1-phenylethanol were used.

IH NMR (400 MHz, DMSOD6) δ ppm 3.5 (bm, 1 H) 3.6 (bm, 1 H) 4.4 (d, J=4 Hz, 2 H) 4.7 (dd, J=7.δ & 4 Hz, 1 H) 5.5-5.7 (bs, 1 H) 6.3 (d, J=I Hz, 1 H) 7.2-7.35 (m, 5 H) 7.5 (d, J=8.5 Hz, 1 H) 7.78-7.85 (m, 4 H) 7.97 (s, 1 H) 8.9 (bs, 1 H) 10.3 (bs, 1 H). MS m/z 398 (M+ 1) ⁺

Example 226

δ-^-l^-^^-hvdroxy^-phenylethyllaminol^-pyrimidinvOaminol -l.δ-dihvdro^-fir -benzimidazol-2 -one

The title compound was synthesized using the procedure recited in Example 213, except 5-amino-l,3-dihydro-2H-benzimidazol-2-one and

(l$-2-amino-l-phenylethanol were used. IH NMR (400 MHz, DMSOD6) δ ppm 3.6-3.7 (bm, 1 H) 4.73 (m, 1 H) 5.5 (bs, 1 H) 6.1 (d, J=6.5 Hz, 1 H) 6.84 (d, J=S Hz, 1 H) 7.1 (d, J=S Hz, 1 H) 7.2-7.3 (m, 5 H) 7.7 (d, J=5.5 Hz, 1 H) 8.05-8.3 (bs, 1 H) 8.13 (bs, 1 H) 9.4 (bs, 1 H) 10.51 (s, 1 H) 10.55 (s, 1 H). MS m/z 363 (M+ 1) ⁺

Example 227

(l-^>-2-{[2-(l.3-benzothiazol-6-ylamino)-4-pyrimidinyl ]amino}-l-phenylethanol formate salt

The title compound was synthesized using the procedure recited in Example 213, except l,3-benzothiazol-6-amine and (l$-2-amino-l-phenylethanol were used. IH NMR (400 MHz, DMSOD6) δ ppm 3.4 (bm, 1 H) 3.6 (bm, 1 H) 4.74 (dd, ,7=8.5 & 4 Hz, 1 H) 5.55-5.75 (bs, 1 H) 6.31 (d, J=I Hz, 1 H) 7.25 (s, 5 H) 7.6 (dd, J=Q & 2 Hz, 1 H) 7.80 (d, J=I Hz, 1 H) 8.07 (d, J=Q Hz, 1 H) 8.43 (s, 1 H) 9.05 (bs, 1 H) 9.35 (s, 1 H) 10.45 (bs, 1 H). MS m/z 364 (M+ 1) ⁺

Example 228

4- [(4- {[(2.Sj> - 2 -h vdroxy-2 -phenylethyl] amino} -2 -pyrimidinvOamino] benzamide

The title compound was synthesized using the procedure recited in Example 213 except 4-aminobenzamide and (l$-2-amino-l-phenylethanol were used and the product was purified using an HPLC system where the solvents were modified with formic acid instead of trifluoroacetic acid.

IH NMR (400 MHz, DMSOD6) δ ppm 3.4-3.5 (Jam, 1 H) 3.6-3.7 (Jam, 1 H) 4.77 (dd, J=S & 4 Hz, 1 H) 5.6-5.8 (bs, 1 H) 6.33 (d, ,7=7.5 Hz, 1 H) 7.2-7.35 (m, 6 H) 7.62 (d, J=8.5 Hz, 2 H) 7.84 (d, J=H Hz, 1 H) 7.90 (d, J=8.5 Hz, 2 H) 7.95 (bs, 1 H) 9.2 (bs, 1 H) 10.65 (bs, 1 H). MS m/z 350 (M+ 1) ⁺

Example 229

(l-^>-2-{[2-(l.ff 1.2.3-benzotriazol-5-ylamino)-4-pyrimidinyl] amino}- 1-phenylethan ol formate salt

The title compound was synthesized using the procedure recited in Example 213 except lH-l,2,3-benzotriazol-5-amine and (l$-2-amino-l-phenylethanol were used. The product obtained after initial purification was re-purified using an HPLC system with formic acid as the solvent modifier.

IH NMR (400 MHz, DMSOD6) δ ppm 3.6 (bs, 1 H) 4.74 (m, 1 H) 5.6 (bs, 1 H) 6.2 (d, J=6 Hz, 1 H) 7.2-7.35 (m, 5 H) 7.52 (d, J=8.5 Hz, 1 H) 7.8 (bm, 1 H) 7.9 (bs, 1 H) 8.1-8.4 (bs, 1 H) 9.6-10.0 (bs, 1 H). MS m/z 348 (M+l) ⁺

Example 230

(l-^>-2-({2-[(3-chlorophenyl)amino]-4-pyrimidinyl}amin o)-l-phenylethanol trifluoroacetate salt

The title compound was synthesized using the procedure recited in Example 213 except 3-chloroaniline and (l$-2-amino-l-phenylethanol were used. IH NMR (400 MHz, DMSOD6) δ ppm 3.3-3.45 (Jam, 1 H) 3.6-3.7 (Jam, 1 H) 4.75 (dd, ,7=8.5 & 4 Hz, 1 H) 5.65 (bs, 1 H) 6.3 (d, J=I Hz, 1 H) 7.2-7.4 (m, 8 H) 7.46 (d, J=I. h Hz, 1 H) 7.76 (s, 1 H) 7.80 (d, J=I Hz, 1 H) 8.13 (s, 1 H) 9.0 (bs, 1 H) 10.3 (bs, 1 H). MS m/z 341 (M+ 1) ⁺

Example 231

iV ^L -{3-[(4-{[(2-^>-2-hvdroxy-2-phenylethyl]amino}-2-pyrimidi nyl)amino]phenyl}-.^. ■λE-dimethylglycinamide trifluoroacetate salt

The title compound was synthesized using the procedure recited in Example 213 except AM3-aminophenyl)-A^,A^-dimethylglycinamide and

(l _* S)"2-amino"l"phenylethanol were used. IH NMR (400 MHz, DMSOD6) 8 ppm 2.81 (s, 6H) 3.3-3.4 (bm, 1 H) 3.65-3.75 (bm, IH) 4.04 (d, J=16 Hz, 1 H) 4.08 (d, J=16 Hz, 1 H) 4.75 (dd, J=8.δ & 3.5 Hz, 1 H) 5.6 (bs, 1 H) 6.28 (d, J=I Hz, 1 H) 7.2-7.37 (m, 7 H) 7.4 (m, 1 H) 7.82 (d, J=I Hz, 1 H) 7.87 (s, 1 H) 9.03 (bs, 1 H) 10.45 (bs, 1 H) 10.63 (s, 1 H). MS m/z 407 (M+ 1) ⁺

Intermediate K 2'chloro'.λK2'phenylpropyl)'4-pyrimidinamine

2-phenyl-l-propanamine (3.Og, 3.2mL, 22.2mmol) and triethylamine (2.18g, 3mL, 21.6mmol) were added to a solution of 2,4-dichloropyrimidine (3.15g, 21.1mmol) in THF (lOOmL). The mixture was left stirring at room temperature under a nitrogen atmosphere for 16 hours. After filtering through a glass sinter, the filtrate was pre-absorbed under vacuum onto diatomaceous earth. Purification was achieved using flash silica chromatography on an ISCO SQ16X machine, eluting with an ethyl acetate/cyclohexane gradient. Concentration of the relevant fractions afforded the title compound as a white solid (3.3g, 13.3mmol). IH NMR (400 MHz, DMSOD6) δ ppm 1.23 (d, J=7 Hz, 3 H) 2.95-3.05 (m, 1 H) 3.45-3.5 (m, 1 H) 3.5-3.55 (m, 1 H) 6.4-6.5 (m, 1 H) 7.18-7.32 (m, 5 H) 7.84-8.04 (m, 2 H). MS m/z 248/250 (3:1 ratio) (M+l) ⁺

Example 232

4-({4- [(2 -phenylpropyOamino] -2 -pyrimidinyl}amino)benzenesulfonamide trifluoracetate salt

The title compound was synthesized using the procedure recited in Example 213, except 2-chloro-AK2-phenylpropyl)-4-pyrimidinamine was used. IH NMR (400 MHz, DMSOD6) δ ppm 1.26 (d, J=7 Hz) 3.05-3.11 (q, J=7 Hz, 1 H) 3.4-3.6 (m, 2 H) 6.20 (d, J=6.5 Hz, 1 H) 7.20-7.35 (m, 7 H) 7.75-7.82 (m, 5 H) 8.71 (bs, 1 H) 10.42 (bs, 1 H). MS m/z 384 (M+ 1) ⁺

Example 233

3~({4- [(2 'phenylpropyOamino] ~2 'pyrimidinyl}amino)benzenesulfonamide trifluoroacetate salt

The title compound was synthesized using the procedure recited in Example 213, except 3-aminobenzenesulfonamide and

2-chloro-7V ^: (2-phenylpropyl)-4-pyrimidinamine were used.

IH NMR (400 MHz, DMSOD6) δ ppm 1.24 (d, J=I Hz, 3 H) 3.03 (q, J=I Hz, 1 H) 3.6-3.7 (bm, 2 H) 6.19 (d, J=I Hz, 1 H) 7.2-7.3 (m, 5 H) 7.38 (s, 2 H) 7.54 (t, ,7=8 Hz, 1 H) 7.6 (d, J=I Hz, 1 H) 7.78 (m, 2 H) 8.16 (bs, 1 H) 8.8 (bs, 1 H) 10.48 (bs, 1 H). MS m/z 384 (M+ 1) ⁺

Example 234

■λ^-(l.l-dioxido-2.3-dihvdro-1.2-benzisothiazol-6-yl)- .^-(2-phenylpropyl)-2.4-pyri midinediamine trifluoroacetate salt

The title compound was synthesized using the procedure recited in Example 213, except 2,3-dihydro-l,2-benzisothiazol-6-amine 1,1-dioxide and

2-chloro-7V ^: (2-phenylpropyl)-4-pyrimidinamine were used.

IH NMR (400 MHz, DMSOD6) δ ppm 1.26 (d, J=I Hz, 3 H) 3.03 (q, J=I Hz, 1 H) 4.4 (d, J=A Hz, 2 H) 6.18 (d, J=I Hz, 1 H) 7.15-7.3 (m, 5 H) 7.53 (d, J=8.5 Hz, 1 H) 7.72 (d, J=I Hz, 1 H) 7.78 (d, ,7=8 Hz, 1 H) 7.85 (s, 1 H) 8.18 (s, 1 H) 8.75 (bs, 1 H) 10.45 (bs, 1 H). MS m/z 396 (M+l) ⁺

Example 235

5-({4-[(2-phenylpropyl)amino]-2-pyrimidinyl}amino)-1.3-di hvdro-2.ffbenzimidazol -2-one

The title compound was synthesized using the procedure recited in Example 213, except 5-amino-l,3-dihydro-2H-benzimidazol-2-one and

2-chloro-7V ^: (2-phenylpropyl)-4-pyrimidinamine were used and the product was purified using an HPLC system where the solvents were modified with formic acid instead of trifluoroacetic acid.

IH NMR (400 MHz, DMSOD6) δ ppm 1.21 (d, J=7 Hz, 3 H) 3.04 (q, J=7 Hz, 1 H) 3.35-3.42 (bm, 1 H) 3.45-3.55 (bm, 1 H) 6.0 (d, J=6.5 Hz, 1 H) 6.83 (d, J=S Hz, 1 H) 7.15-7.3 (m, 7 H) 7.70 (d, J=6 Hz, 1 H) 7.95-8.15 (bs, 1 H) 9.45 (bs, 1 H) 10.48 (s, 1 H) 10.56 (s, 1 H). MS m/z 361 (M+l) ⁺

Example 236

■λE- IH- indazol-6-yl-ffi-(2-phenylpropyQ-2.4-pyrimidinediamine formate salt

The title compound was synthesized using the procedure recited in Example 213 except lH-indazol-5-amine and 2-chloro-AK2-phenylpropyl)-4-pyrimidinamine were used. The product obtained after initial purification was also re-purified using an HPLC system with formic acid as the solvent modifier.

IH NMR (400 MHz, DMSOD6) δ ppm 1.26 (d, J=I Hz, 3 H) 3.05-3.11 (q, J=I, 1 H) 5.97 (d, J=G Hz, 1 H) 7.15-7.30 (m, 6 H) 7.38 (dd, J=Q & 1 Hz) 7.53 (d, J=S.δ Hz, 1 H) 7.82 (d, J=4.δ Hz, 1 H) 7.88 (s, 1 H) 8.03 (bs, 1 H) 8.17 (s, 1 H) 8.21 (s, 1 H) 9.0 (bs, 1 H) 12.5-12.8 (bs, 1 H). MS m/z 345 (M+l) ⁺

Example 237

.λ^'1.3'benzothiazol-6'yl'.λ^'(2'phenylpropyl)'2.4-pyri midinediamine trifluroacetate salt

The title compound was synthesized using the procedure recited in Example 213, except l,3-benzothiazol-6-amine and

2-chloro-7V ^: (2-phenylpropyl)-4-pyrimidinamine were used.

IH NMR (400 MHz, DMSOD6) δ ppm 1.23 (d, J=I Hz, 3 H) 3.02-3.08 (q, J=I, 1 H) 3.53 (m, 2 H) 6.19-6.21 (d, J=G Hz, 1 H) 7.15-7.3 (m, 6 H) 7.62 (dd, J=Q & 2 Hz, 1 H) 7.78 (d, J=Q Hz, 1 H) 8.08 (d, J=Q Hz, 1 H) 8.46 (s, 1 H) 8.9 (bs, 1 H) 9.34 (s, 1 H) 10.45 (bs, 1 H). MS m/z 362 (M+ 1) ⁺

Example 238

4-({4-[(2-phenylpropyl)amino]-2-pyrimidinyl}amino)benzami de

The title compound was synthesized using the procedure recited in Example 213 except 4-aminobenzamide and 2-chloro-AK2-phenylpropyl)-4-pyrimidinamine were used and the product was purified using an HPLC system where the solvents were modified with formic acid instead of trifluoroacetic acid. IH NMR (400 MHz, DMSOD6) δ ppm 1.27 (d, J=I Hz, 3 H) 3.05-3.11 (q, J=I Hz, 1 H) 3.45-3.6 (bm, 2 H) 6.13 (d, J=6.5 Hz, 1 H) 7.2-7.35 (m, 6 H) 7.74 (d, J=Q Hz, 2 H) 7.78-7.88 (m, 4 H) 8.25-8.45 (bs, 1 H) 9.95-10.05 (bs, 1 H). MS m/z 348 (M+ 1) ⁺

Example 239

N^λH- 1.2.3-benzotriazol-5-yl-ffi-(2-phenylpropyl)-2.4-pyrimidined iamine

The title compound was synthesized using the procedure recited in Example 213 except 1H-I,2,3"benzotriazol"5"amine and

2-chloro-7V ^: (2-phenylpropyl)-4-pyrimidinamine were used. The product obtained after initial purification was re-purified using an HPLC system with formic acid as the solvent modifier.

IH NMR (400 MHz, DMSOD6) δ ppm 1.24 (d, J=7 Hz, 3 H) 3.04-3.09 (q, J=I Hz, 1 H) 3.4-3.6 (bm, 1 H) 6.09 (d, J=Q Hz, 1 H) 7.15-7.3 (bs, 5 H) 7.56 (d, J=l.h Hz, 1 H) 7.7-7.9 (m, 2 H) 8.1 (bs, 1 H) 8.3 (bs, 1 H) 9.7 (bs, 1 H). MS m/z 346 (M+l) ⁺

Example 240

■λ^-(3-chlorophenyl)-.^-(2-phenylpropyl)-2.4-pyrimidin ediamine

The title compound was synthesized using the procedure recited in Example 213 except 3"chloroaniline and 2-chloro"jV-(2-phenylpropyl)"4-pyrimidinamine were used.

IH NMR (400 MHz, DMSOD6) δ ppm 1.27 (d, J=7 Hz, 3 H) 3.03-3.08 (q, J=I Hz,

1 H) 3.5-3.6 (bm, 2 H) 6.19 (d, J=I Hz, 1 H) 7.2-7.3 (m, 6 H) 7.37 (t, J=S Hz, 1 H)

7.46 (d, ,7=8 Hz, 1 H) 7.79 (d, J=I Hz, 1 H) 7.87 (s, 1 H) 8.85 (bs, 1 H) 10.35 (bs, 1

H). MS m/z 339 (M+ 1) ⁺

Example 241

■λE.-λft-dimethyl-iV ¹ - [3-({4- [(2-phenylpropyl)amino] -2-pyrimidinyl}amino)phenyl] gl ycinamide

The title compound was synthesized using the procedure recited in Example 213 except AM3-aminophenyl)-A^,A^-dimethylglycinamide and

2-chloro-7V ^: (2-phenylpropyl)-4-pyrimidinamine were used and the product was purified using an HPLC system where the solvents were modified with formic acid instead of trifluoroacetic acid.

IH NMR (400 MHz, DMSOD6) δ ppm 1.21 (d, J=7 Hz, 3 H) 3.02-3.08 (q, J=I Hz, 1 H) 3.35-3.45 (bm, 1 H) 3.45-3.55 (bm, IH) 4.13 (s, 2 H) 6.23 (d, J=7.δ Hz, 1 H) 7.15-7.41 (m, 8 H) 7.51 (d, ,7=7.5 Hz, 1 H) 7.83 (d, J=I Hz, 1 H) 7.87 (s, 1 H) 9.15 (bs, 1 H) 10.7 (s, 1 H) 11.0 (s, 1 H). MS m/z 405 (M+l) ⁺

Intermediate L 2-chloro-J\^[(2-S)-2-phenvlpropvl]-4-pvrimidinamine

(2i?)-2-phenyl-l-propanamine (3.Og, 3.2mL, 22.2mmol) and triethylamine (2.18g, 3mL, 21.6mmol) were added to a solution of 2,4-dichloropyrimidine (3.15g, 21.1mmol) in THF (lOOmL). The mixture was left stirring at room temperature under a nitrogen atmosphere for 16 hours. After filtering through a glass sinter, the filtrate was pre-absorbed under vacuum onto diatomaceous earth. Purification was achieved using flash silica chromatography on an ISCO SQ16X machine, eluting with an ethyl acetate/cyclohexane gradient. Concentration of the relevant fractions afforded the title compound as a white solid (4.Og, 15.9mmol). IH NMR (400 MHz, DMSOD6) δ ppm 1.23 (d, J=H Hz, 3 H) 2.95-3.05 (m, 1 H) 3.3-3.4 (m, 1 H) 3.4-3.5 (m, 1 H) 6.4-6.5 (m, 1 H) 7.18-7.32 (m, 5 H) 7.84-8.04 (m, 2 H). MS m/z 248/250 (3:1 ratio) (M+ 1) ⁺

Example 242

4-[(4-{[(2itj)-2-phenylpropyl]amino}-2-pyrimidinyl)amino] benzenesulfonamide trifluoracetate salt

The title compound was synthesized using the procedure recited in Example 213, except 2-chloro-A^[(2i?)-2-phenylpropyl]-4-pyrimidinamine was used. IH NMR (250 MHz, DMSOD6) δ ppm 1.26 (d, J=I Hz, 3 H) 3.04-3.12 (q, J=I Hz, 1 H) 3.5-3.6 (m, 2 H) 6.21 (d, J=I Hz, 1 H) 7.20-7.35 (m, 7 H) 7.75-7.85 (m, 5 H) 8.87 (bs, 1 H) 10.49 (bs, 1 H). MS m/z 384 (M+l) ⁺

Example 243

3'[(4-{[(2.i'-j)'2'phenylpropyl]amino}'2'Pyrimidinyl)amin o]benzenesulfonamide trifluoroacetate salt

The title compound was synthesized using the procedure recited in Example 213, except 3-aminobenzenesulfonamide and

2-chloro-A^[(2i?)-2-phenylpropyl]-4-pyrimidinamine were used. IH NMR (250 MHz, DMSOD6) δ ppm 1.24 (d, J=I Hz, 3 H) 2.98-3.07 (q, J=I Hz, 1 H) 3.5-3.6 (bm, 2 H) 6.18 (d, J=I Hz, 1 H) 7.15-7.3 (m, 5 H) 7.38 (s, 2 H) 7.5-7.6 (m, 2 H) 7.78 (m, 2 H) 8.16 (bs, 1 H) 8.8 (bs, 1 H) 10.48 (bs, 1 H). MS m/z 384 (M+l) ⁺

Example 244

■λ^-(lJ-dioxido-2.3-dihvdro-1.2-benzisothiazol-6-yl)-iV ^g -r(2.-^-2-phenylpropyl1-2.4- pyrimidinediamine trifluoroacetate salt

The title compound was synthesized using the procedure recited in Example 213, except 2,3-dihydro-l,2-benzisothiazol-6-amine 1,1-dioxide and

2-chloro-A^[(2i?)-2-phenylpropyl]-4-pyrimidinamine were used. IH NMR (250 MHz, DMSOD6) δ ppm 1.26 (d, J=I Hz, 3 H) 3-3.07 (q, J=I Hz, 1 H) 4.39 (d, J=4.5 Hz, 2 H) 6.18 (d, J=I Hz, 1 H) 7.15-7.3 (m, 5 H) 7.53 (d, J=8.5 Hz, 1 H) 7.7-7.9 (m, 3 H) 8.18 (d, J=2 Hz, I H) 8.75 (bs, 1 H) 10.44 (bs, 1 H). MS m/z 396 (M+l) ⁺

Example 245

5-[(4-{[(2itj)-2-phenylpropyl] amino}-2-pyrimidinyl) amino] -1.3-dihvdro-2.ffbenzimi dazol-2-one

The title compound was synthesized using the procedure recited in Example 213, except 5-amino-l,3-dihydro-2H-benzimidazol-2-one and

2-chloro-A^[(2i?)-2-phenylpropyl]-4-pyrimidinamine were used and the product was purified using an HPLC system where the solvents were modified with formic acid instead of trifluoroacetic acid.

IH NMR (250 MHz, DMSOD6) δ ppm 1.21 (d, J=7 Hz, 3 H) 2.98-3.07 (q, J=7 Hz, 1 H) 3.35-3.55 (bm, 2 H) 6.02 (d, ,7=6.5 Hz, 1 H) 6.83 (d, ,7=8.5 Hz, 1 H) 7.15-7.3 (m, 7 H) 7.70 (d, J=6 Hz, 1 H) 7.95-8.15 (bs, 1 H) 9.4 (bs, 1 H) 10.48 (s, 1 H) 10.56 (s, 1 H). MS m/z 361 (M+ 1) ⁺

Example 246

■λ^-lH-indazol-6-yl-iV ^g -[(2i-j)-2-phenylpropyl]-2.4-pyrimidinediamine formate salt

The title compound was synthesized using the procedure recited in Example 213 except lH-indazol"5"amine and

2-chloro-A^[(2i?)-2-phenylpropyl]-4-pyrimidinamine were used. The product obtained after initial purification was also re-purified using an HPLC system with formic acid as the solvent modifier.

IH NMR (400 MHz, DMSOD6) δ ppm 1.26 (d, J=7 Hz, 3 H) 3.05-3.12 (q, J=I Hz, 1 H) 5.97 (d, J=G Hz, 1 H) 7.15-7.30 (m, 6 H) 7.37 (dd, J=8.5 & 1.5 Hz, 1 H) 7.53 (d, J=S Hz, 1 H) 7.81 (d, J=4.δ Hz, 1 H) 7.88 (s, 1 H) 8.14 (s, 1 H) 8.21 (s, 1 H) 9.0 (s, 1 H) 12.5-12.8 (bs, 1 H). MS m/z 345 (M+ 1) ⁺

Example 247

i\^-1.3-benzothiazol-6-yl-.^-[(2i-j)-2-phenylpropyl]-2.4- pyrimidinediaminetrifluroa cetate salt

The title compound was synthesized using the procedure recited in Example 213, except l,3-benzothiazol-6-amine and

2-chloro"jV-[(2i?)-2-phenylpropyl]"4-pyrimidinamine were used. IH NMR (250 MHz, DMSOD6) δ ppm 1.23 (d, J=I Hz, 3 H) 3.01-3.09 (q, J=I, 1 H) 3.5 (bm, 2 H) 6.2 (d, J=I Hz, 1 H) 7.15-7.3 (m, 6 H) 7.62 (dd, J=Q & 2 Hz, 1 H) 7.79 (d, J=I Hz, 1 H) 8.07 (d, J=Q Hz, 1 H) 8.47 (s, 1 H) 8.9 (bs, 1 H) 9.34 (s, 1 H) 10.49 (bs, 1 H). MS m/z 362 (M+l) ⁺

Example 248

4-[(4-{[(2itj)-2-phenylpropyl]amino}-2-pyrimidinyl)amino] benzamide formate salt

The title compound was synthesized using the procedure recited in Example 213 except 4-aminobenzamide and

2-chloro-A^[(2i?)-2-phenylpropyl]-4-pyrimidinamine were used and the product was purified using an HPLC system where the solvents were modified with formic acid instead of trifluoroacetic acid.

IH NMR (400 MHz, DMSOD6) δ ppm 1.27 (d, J=7 Hz, 3 H) 3.04-3.13 (q, J=I Hz, 1 H) 3.2-3.4 (bm, 1 H) 3.4-3.54 (bm, 1 H) 5.98 (d, J=G Hz, 1 H) 7.1 (s, 1 H) 7.2-7.35 (m, 6 H) 7.73-7.86 (m, 6 H) 8.15 (s, 1 H) 9.21 (s, 1 H). MS m/z 348 (M+ 1) ⁺

Example 249

N^λH- 1.2.3-benzotriazol-5-yl-.^-[(2i-j)-2-phenylpropyl]-2.4-pyrim idinediamine formate salt

The title compound was synthesized using the procedure recited in Example 213 except lH-l,2,3-benzotriazol-5-amine and

2-chloro-A^[(2i?)-2-phenylpropyl]-4-pyrimidinamine were used and the product was purified using an HPLC system where the solvents were modified with formic acid instead of trifluoroacetic acid.

IH NMR (250 MHz, DMSOD6) δ ppm 1.27 (d, J=I Hz, 3 H) 3.04-3.13 (q, J=I Hz, 1 H) 3.4-3.6 (bm, 2 H) 5.99 (d, J=G Hz, 1 H) 7.17-7.3 (m, 6 H) 7.61 (dd, J=Q & 2 Hz, 1 H) 7.76 (d, J=Q Hz, IH) 7.83 (d, J=5.5 Hz, 1 H) 8.22 (bs, 1 H) 8.48 (bs, 1 H) 9.21 (bs, 1 H). MS m/z 346 (M+l) ⁺

Example 250

■λ^'(3-chlorophenyl)'.λ^'[(2.-'-j)'2'phenylpropyl]'2. 4-pyrimidinediamine trifluoroacetate salt.

The title compound was synthesized using the procedure recited in Example 213 except 3-chloroaniline and 2-chloro-A^[(2i?)-2-phenylpropyl]-4-pyrimidinamine was used.

IH NMR (250 MHz, DMSOD6) δ ppm 1.26 (d, J=7 Hz, 3 H) 3.01-3.10 (q, J=I Hz, 1 H) 3.5-3.6 (bm, 2 H) 6.20 (d, J=I Hz, 1 H) 7.18-7.47 (m, 8 H) 7.79 (d, J=I Hz, 1 H) 7.86 (s, 1 H) 8.85 (bs, 1 H) 10.35 (bs, 1 H). MS m/z 339 (M+ 1) ⁺

Example 251

.λ^..λ^-dimethyl-.^-{3-[(4-{[(2./-j)-2-phenylpropyl]ami no}-2-pyrimidinyl)amino]phen yllglycinamide formate salt

The title compound was synthesized using the procedure recited in Example 213 except AM3-aminophenyl)-A^,A^-dimethylglycinamide and

2-chloro-A^[(2i?)-2-phenylpropyl]-4-pyrimidinamine were used and the product was purified using an HPLC system where the solvents were modified with formic acid instead of trifluoroacetic acid.

IH NMR (250 MHz, DMSOD6) δ ppm 1.23 (d, J=7 Hz, 3 H) 3.0-3.08 (q, J=I Hz, 1 H) 5.95 (d, J=G Hz, 1 H) 7.1-7.35 (m, 9 H) 7.53 (d, J=S Hz, 1 H) 7.77 (d, J=5.5 Hz, 1 H) 7.95 (s, 1 H) 8.14 (s, 1 H) 9.01 (s, 1 H) 10.0 (s, 1 H). MS m/z 405 (M+ 1) ⁺

Intermediate M 2-chloro-.λP[(2$-2-phenvlpropvl]-4-pvrimidinamine

(2^)-2-phenyl-l-propanamine (3.Og, 3.2mL, 22.2mmol) and triethylamine (2.18g, 3mL, 21.6mmol) were added to a solution of 2,4-dichloropyrimidine (3.15g, 21.1mmol) in THF (lOOmL). The mixture was left stirring at room temperature under a nitrogen atmosphere for 16 hours. After filtering through a glass sinter, the filtrate was pre-absorbed under vacuum onto diatomaceous earth. Purification was achieved using flash silica chromatography on an ISCO SQ16X machine, eluting with an ethyl acetate/cyclohexane gradient. Concentration of the relevant fractions afforded the title compound as a white solid (3.6g, 14.3mmol). IH NMR (400 MHz, DMSOD6) δ ppm 1.23 (d, J=H Hz, 3 H) 3-3.05 (q, J=H Hz, 1 H) 3.3-3.5 (bm, 2 H) 6.38-6.52 (m, 1 H) 7.18-7.32 (m, 5 H) 7.81-8.01 (m, 2 H). MS m/z 248/250 (3:1 ratio) (M+l) ⁺

Example 252

4- [(4- {[(2.Sj> - 2 -phenylprop yl] amino} -2 -p yrimidinyl) amino] benzenesulfonamide trifluoracetate salt

The title compound was synthesized using the procedure recited in Example 213, except 2-chloro-A^[(2$-2-phenylpropyl]-4-pyrimidinamine was used. IH NMR (250 MHz, DMSOD6) δ ppm 1.27 (d, J=I Hz, 3 H) 3.04-3.12 (q, J=I, 1 H) 3.45-3.65 (m, 2 H) 6.22 (d, J=I Hz, 1 H) 7.20-7.35 (m, 8 H) 7.73-7.87 (m, 5 H) 8.86 (bs, 1 H) 10.49 (bs, 1 H). MS m/z 384 (M+l) ⁺

Example 253

3~ [(4- {[(2 S) - 2 'phenylprop yl] amino} ~2 ~p yrimidinyl) amino] benzenesulfonamide trifluoroacetate salt

The title compound was synthesized using the procedure recited in Example 213, except 3-aminobenzenesulfonamide and

2-chloro-A^[(2$-2-phenylpropyl]-4-pyrimidinamine were used. IH NMR (250 MHz, DMSOD6) δ ppm 1.24 (d, J=I Hz, 3 H) 2.98-3.07 (q, J=I Hz, 1 H) 6.19 (d, J=I Hz, 1 H) 7.15-7.3 (m, 5 H) 7.38 (s, 2 H) 7.5-7.6 (m, 2 H) 7.7-7.85 (m, 2 H) 8.16 (bs, 1 H) 8.8 (bs, 1 H) 10.45 (bs, 1 H). MS m/z 384 (M+l) ⁺

Example 254

iV ^g -(l.l-dioxido-2.3-dihvdro-1.2-benzisothiazol-6-yl)-iV ^g -r(2-g>-2-phenylpropyn-2.4- pyrimidinediamine trifluoroacetate salt.

The title compound was synthesized using the procedure recited in Example 213, except 2,3-dihydro-l,2-benzisothiazol-6-amine 1,1-dioxide and

2-chloro-A^[(2$-2-phenylpropyl]-4-pyrimidinamine were used. IH NMR (250 MHz, DMSOD6) δ ppm 1.26 (d, J=I Hz, 3 H) 2.98-3.07 (q, J=I Hz, 1 H) 3.54-3.59 (m, 2 H) 4.35 (d, J=A Hz, 2 H) 6.18 (d, J=I Hz, 1 H) 7.15-7.3 (m, 5 H) 7.53 (d, ,7=8.5 Hz, 1 H) 7.72 (d, ,7=8.5 Hz, 1 H) 7.79 (d, J=I Hz, 1 H) 7.85 (m, 1 H) 8.18 (d, J=1.5 Hz, 1 H) 8.77 (bs, 1 H) 10.45 (bs, 1 H). MS m/z 396 (M+l) ⁺

Example 255

5-[(4-{[(2-^>-2-phenylpropyl]amino}-2-pyrimidinyl)amin o]-1.3-dihvdro-2.ffbenzimi dazol-2-one formate salt

The title compound was synthesized using the procedure recited in Example 213, except 5-amino-l,3-dihydro-2H-benzimidazol-2-one and

2-chloro-A^[(2$-2-phenylpropyl]-4-pyrimidinamine were used and the product was purified using an HPLC system where the solvents were modified with formic acid instead of trifluoroacetic acid.

IH NMR (250 MHz, DMSOD6) δ ppm 1.23 (d, J=I Hz, 3 H) 3.0-3.1 (q, J=I Hz, 1 H) 3.4-3.55 (bm, 2 H) 5.9 (d, J=G Hz, 1 H) 6.75 (d, ,7=8.5 Hz, 1 H) 7.15-7.3 (m, 7 H) 7.42 (s, 1 H) 7.73 (d, J=6 Hz, 1 H) 8.14 (s, 1 H) 8.81 (bs, 1 H) 10.32 (s, 1 H) 10.42 (s, 1 H). MS m/z 361 (M+ 1) ⁺

Example 256

■λ^-lH-indazol-6-yl-iV ^g -[(2-^>-2-phenylpropyl]-2.4-pyrimidinediamine trifluoroacetate salt.

The title compound was synthesized using the procedure recited in Example 213 except lH-indazol"5"amine and 2-chloro-A^[(2$-2-phenylpropyl]-4-pyrimidinamine were used.

IH NMR (250 MHz, DMSOD6) δ ppm 1.26 (d, J=7 Hz, 3 H) 3.0-3.09 (q, J=7 Hz, 1 H) 3.4-3.6 (bm, 2 H) 6.19 (d, J=<6 Hz, 1 H) 7.1-7.3 (m, 6 H) 7.7-7.8 (m, 3 H) 8.07 (s, 1 H) 8.9 (bs, 1 H) 10.4 (s, 1 H) 13.0 (bs, 1 H). MS m/z 345 (M+l) ⁺

Example 257

■λ^-1.3-benzothiazol-6-yl-.^-[(2-^>-2-phenylpropyl] -2.4-pyrimidinediamine trifluroacetate salt

The title compound was synthesized using the procedure recited in Example 213, except l,3-benzothiazol-6-amine and

2-chloro-λ^[(2$-2-phenylpropyl]-4-pyrimidinamine were used. IH NMR (400 MHz, DMSOD6) δ ppm 1.23 (d, J=7 Hz, 3 H) 3.03-3.08 (q, J=7 Hz, 1 H) 3.5 (m, 2 H) 6.21 (d, J=I Hz, 1 H) 7.15-7.3 (m, 6 H) 7.62 (dd, J=8.5& 2 Hz, 1 H) 7.79 (d, J=ZHz, 1 H) 8.07 (d, J=8.5 Hz, 1 H) 8.46 (s, 1 H) 8.95 (bs, 1 H) 9.35 (s, 1 H) 10.5 (bs, 1 H). MS m/z 362 (M+l) ⁺

Example 258

4- [(4- {[(2.Sj> - 2 -phenylprop yl] amino} -2 -pyrimidinvOamino] benzamide formate salt

The title compound was synthesized using the procedure recited in Example 213 except 4-aminobenzamide and

2-chloro-A^[(2$-2-phenylpropyl]-4-pyrimidinamine were used and the product was purified using an HPLC system where the solvents were modified with formic acid instead of trifluoroacetic acid.

IH NMR (250 MHz, DMSOD6) δ ppm 1.27 (d, J=7 Hz, 3 H) 3.04-3.13 (q, J=7 Hz, 1 H) 3.4-3.55 (bm, 2 H) 6.02 (d, J=6 Hz, 1 H) 7.0-7.15 (bs, 1 H) 7.15-7.35 (m, 6 H) 7.5-7.7 (bs, 1 H) 7.75-7.84 (m, 6 H) 8.13 (s, 1 H) 9.4 (bs, 1 H). MS m/z 348 (M+l) ⁺

Example 259

N^λH- 1.2.3-benzotriazol-5-yl-.^-[(2-^>-2-phenylpropyl]-2.4-pyr imidinediamine trifluoroacetate salt

The title compound was synthesized using the procedure recited in Example 213 except lH-l,2,3-benzotriazol-5-amine and

2-chloro-A^[(2$-2-phenylpropyl]-4-pyrimidinamine were used. IH NMR (250 MHz, DMSOD6) δ ppm 1.23 (d, J=I Hz, 3 H) 3.0-3.08 (q, J=I Hz, 1 H) 3.4-3.6 (bm, 2 H) 6.20 (d, J=Q Hz, 1 H) 7.1-7.25 (bs, 5 H) 7.52 (dd, J=I.5 & 1 Hz, 1 H) 7.78 (d, J=I.5 Hz, 1 H) 7.85-7.95 (m, 1 H) 8.15 (bs, 1 H) 8.9 (bs, 1 H) 10.4 (bs, 1 H). MS m/z 346 (M+l) ⁺

Example 260

■λ^-(3-chlorophenyl)-.^-[(2-^>-2-phenylpropyl]-2.4- pyrimidinediamine trifluoroacetate salt

The title compound was synthesized using the procedure recited in Example 213 except 3-chloroaniline and 2-chloro-A^[(2$-2-phenylpropyl]-4-pyrimidinamine were used.

IH NMR (250 MHz, DMSOD6) δ ppm 1.26 (d, J=I Hz, 3 H) 3.01-3.1 (q, J=I Hz, 1 H) 3.5-3.6 (bm, 2 H) 6.20 (d, J=I Hz, 1 H) 7.18-7.3 (m, 7 H) 7.37 (t, J=S Hz, 1 H) 7.46 (d, ,7=8 Hz, 1 H) 7.79 (d, J=I Hz, 1 H) 7.86 (s, 1 H) 8.85 (bs, 1 H) 10.35 (bs, 1 H) MS m/z 339 (M+ 1) ⁺

Example 261

.λ^..λ^-dimethyl-.^-{3-[(4-{[(2-^-2-phenylpropyl]amino} -2-pyrimidinyl)amino]phen yllglvcinamide formate salt

The title compound was synthesized using the procedure recited in Example 213 except AM3-aminophenyl)-A£,A£-dimethylglycinamide and 2-chloro-λ^[(2$-2-phenylpropyl]-4-pyrimidinamine were used and the product was purified using an HPLC system where the solvents were modified with formic acid instead of trifluoroacetic acid.

IH NMR (250 MHz, DMSOD6) δ ppm 1.23 (d, J=I Hz, 3 H) 3.01-3.10 (q, J=I Hz,

1 H) 3.3-3.5 (bm, 2H) 3.55 (s, 1 H) 4.13 (s, 2 H) 5.95 (d, J=Q Hz, 1 H) 7.1-7.35 (m, 9 H) 7.53 (d, ,7=8 Hz, 1 H) 7.77 (d, J=Q Hz, 1 H) 7.95 (s, 1 H) 8.14 (s, 1 H) 9.0 (s, 1 H)

10.0 (s, 1 H). MS m/z 405 (M+ 1) ⁺

Intermediate N

2-chloro-ffi(2-phenylethyl)-4-pyrimidinamine

2-phenylethanamine (2.95g, 3.05mL, 24.4mmol) and triethylamine (2.18g, 3mL, 21.6mmol) were added to a solution of 2,4-dichloropyrimidine (3.1g, 20.8 nimol) in THF (lOOmL). The mixture was left stirring at room temperature under a nitrogen atmosphere for 16 hours. After filtering through a glass sinter, the filtrate was pre-absorbed under vacuum onto diatomaceous earth. Purification was achieved using flash silica chromatography on an ISCO SQ16X machine, eluting with an ethyl acetate/cyclohexane gradient. Concentration of the relevant fractions afforded the title compound as a white solid (3.2g, 13.6mmol). IH NMR (400 MHz, DMSOD6) 8 ppm 2.8 (t, J=7.5 Hz, 2 H) 3.4-3.6 (m, 2 H) 6.4-6.5 (m, 1 H) 7.2-7.3 (m, 5 H) 7.8-8.0 (m, 2 H). MS m/z 234/236 (3:1 ratio) (M+l) ⁺

Example 262

4-({4- [(2 -phenylethvOamino] -2 -pyrimidinyl}amino)benzenesulfonamide trifluoroacetate salt

The title compound was synthesized using the procedure recited in Example 213, except 2-chloro-AK2-phenylethyl)-4-pyrimidinamine was used. IH NMR (250 MHz, DMSOD6) δ ppm 2.84-2.90 (t, J=I Hz, 2 H) 3.5-3.7 (m, 2 H) 6.23 (d, J=I Hz, 1 H) 7.20-7.35 (m, 7 H) 7.79-7.85 (m, 5 H) 8.88 (bs, 1 H) 10.45 (bs, 1 H). MS m/z 370 (M+ 1) ⁺

Example 263

3-({4- [(2 -phenylethvOamino] -2 -pyrimidinyl}amino)benzenesulfonamide trifluoroaceate salt

The title compound was synthesized using the procedure recited in Example 213, except 3-aminobenzenesulfonamide and

2-chloro"jV-(2-phenylethyl)-4-pyrimidinamine were used.

IH NMR (250 MHz, DMSOD6) δ ppm 2.83-2.90 (t, J=I Hz, 2 H) 3.6-3.7 (m, 2 H) 6.21 (d, J=I Hz, 1 H) 7.16-7.30 (m, 5 H) 7.38 (s, 2 H) 7.51-7.61 (m, 2 H) 7.79 (t, J=I Hz, 2 H) 8.19 (s, 1 H) 8.87 (bs, 1 H) 10.48 (bs, 1 H). MS m/z 370 (M+ 1) ⁺

Example 264

■λ^-(l.l-dioxido-2.3-dihvdro-1.2-benzisothiazol-6-yl)- .^-(2-phenylethyl)-2.4-pyrimi dinediaminetrifluoroacetate salt

The title compound was synthesized using the procedure recited in Example 213, except 2,3-dihydro-l,2-benzisothiazol-6-amine 1,1-dioxide and

2-chloro-7V ^: (2-phenylethyl)-4-pyrimidinamine were used.

IH NMR (250 MHz, DMSOD6) δ ppm 2.83-2.89 (t, J=I, 2 H) 3.5-3.7 (m, 2 H) 4.39 (d, J=A Hz, 1 H) 6.20 (d, J=I Hz, 1 H) 7.16-7.31 (m, 5 H) 7.38 (s, 2 H) 7.53 (d, J=8.5 Hz, 1 H) 7.72-7.84 (m, 3 H) 8.16 (d, J=2 Hz, 1 H) 8.81 (bs, 1 H) 10.43 (bs, 1 H). MS m/z 382 (M+ 1) ⁺

Example 265

5~({4-[(2 'phenylethyl) amino! '2'pyrimidinyl}amino)'1.3'dihvdro'2.ffbenzimidazol- 2 -one trifluoroacetate salt

The title compound was synthesized using the procedure recited in Example 213, except 5-amino-l,3-dihydro-2H-benzimidazol-2-one and

2-chloro-7V ^: (2-phenylethyl)-4-pyrimidinamine were used. IH NMR (250 MHz, DMSOD6) δ ppm 2.81 (t, J=I Hz, 2 H) 3.51-3.59 (q, J=6.5 Hz, 2 H) 6.14 (d, J=I Hz, 1 H) 6.95 (d, J=S.h, 1 H) 7.02 (dd, J=S.h & 2 Hz, IH) 7.1-7.3 (m, 6 H) 7.68 (d, J=I. h Hz, 1 H) 8.9 (bs, 1 H) 10.15 (bs, 1 H) 10.67 (s, 1 H) 10.72 (s, 1 H) 11.7-12.0 (bs, 1 H). MS m/z 347 (M+ 1) ⁺

Example 266

.λE- IH- indazol-6-yl-.^-(2-phenylethyl)-2.4-pyrimidinediamine formate salt

The title compound was synthesized using the procedure recited in Example 213 except lH-indazol-5-amine and 2-chloro-AK2-phenylethyl)-4-pyrimidinamine were used. The product obtained after initial purification was also re-purified using an HPLC system with formic acid as the solvent modifier. IH NMR (400 MHz, DMSOD6) δ ppm 2.87 (t, J=7.δ, 2 H) 3.5-3.65 (m, 2 H) 6.06 (d, J=6 Hz, 1 H) 7.19-7.30 (m, 6 H) 7.62 (d, J=8.5 Hz) 7.81 (bd, J=5 Hz, 1 H) 7.95 (s, 1 H) 8.11 (s, 1 H) 8.13 (s, 1 H) 9.5 (bs, 1 H) 12.8 (bs, 1 H). MS m/z 331 (M+ 1) ⁺

Example 267

■λ^-1.3-benzothiazol-6-yl-.^-(2-phenylethyl)-2.4-pyrim idinediamine trifluroacetate salt

The title compound was synthesized using the procedure recited in Example 213, except l,3"benzothiazol"6"amine and

2-chloro-7V ^: (2-phenylethyl)-4-pyrimidinamine were used.

IH NMR (250 MHz, DMSOD6) δ ppm 2.84 (t, J=I .h Hz, 2 H) 3.56-3.64 (q, J=I.5, 2 H) 6.22 (d, J=I Hz, 1 H) 7.13-7.25 (m, 5 H) 7.62 (dd, J=Q & 2 Hz, 1 H) 7.80 (d, J=I Hz, 1 H) 8.08 (d, J=Q Hz, 1 H) 8.43 (s, 1 H) 9.0 (bs, 1 H) 9.35 (s, 1 H) 10.51 (bs, 1 H). MS m/z 348 (M+ 1) ⁺

Example 268

4-({4- [(2 ^■ phnvlethvDamino] "2 ^■ pvrimidinvl}amino)benzamide

The title compound was synthesized using the procedure recited in Example 213 except 4-aminobenzamide and 2-chloro-jV-(2-phenylethyl)-4-pyrimidinamine were used and the product was purified using an HPLC system where the solvents were modified with formic acid instead of trifluoroacetic acid. IH NMR (250 MHz, DMSOD6) δ ppm 1.27 (d, J=7.5 Hz, 2 H) 3.55-3.65 (m, 1 H) 6.13 (d, J=6.5, IH) 6.49 (bs, 1 H) 7.18-7.35 (m, 6 H) 7.72-7.85 (m, 6 H) 8.2-8.4 (bs, 1 H) 9.85-10.05 (bs, 1 H). MS m/z 334 (M+l) ⁺

Example 269

M-IH- 1.2.3-benzotriazol-5-yl'-^-(2-phenylethyl)-2.4-pyrimidinedia mine trifluoroacetate salt

The title compound was synthesized using the procedure recited in Example 213 except lH ^" -l,2,3-benzotriazol-5-amine and

2-chloro"jV-(2-phenylethyl)-4-pyrimidinamine were used. 1η NMR (250 MHz, DMSOD6) δ ppm 2.84 (t, J=7 Hz, 2 H) 3.55-3.7 (m, 2 H) 6.22 (d, J=I Hz, 1 H) 7.1-7.3 (m, 5 H) 7.5 (d, J=Q Hz, 1 H) 7.8 (d, J=I Hz, 1 H) 7.86-7.99 (m, 1 H) 8.1-8.3 (bs, 1 H) 8.84-9.03 (bs, 1 H) 10.4-10.5 (bs, 1 H). MS m/z 332 (M+l) ⁺

Example 270

■λ^'(3-chlorophenyl)'.λ^'(2'phenylethyl)'2.4-pyrimidi nediaminetrifluoroacetate salt

The title compound was synthesized using the procedure recited in Example 213 except 3"chloroaniline and 2-chloro"jV-(2-phenylethyl)-4-pyrimidinamine were used.

IH NMR (250 MHz, DMSOD6) δ ppm 2.86 (t, J=7 Hz, 2 H) 3.58-3.66 (q, J=6.5

Hz, 2 H) 6.21 (d, J=I Hz, 1 H) 7.18-7.3 (m, 6 H) 7.38 (t, J=S Hz, 1 H) 7.47 (d, J=8

Hz, 1 H) 7.75-7.85 (m, 2 H) 8.90 (bs, 1 H) 10.35 (bs, 1 H). MS m/z 325 (M+ 1) ⁺

Intermediate O

3~ [(4-QXQ- 1.4-dihvdro'2'pyrimidinyl)amino]benzoic acid

A suspension of 2-(methylthio)-4(lH)-pyrimidinone (6.54g, 46mmol) and 3-aminobenzoic acid (6.31g, 46mmol) in diethylene glycol dimethyl ether was heated at reflux for 16 hours. Diethylether (20OmL) was added and a solid collected by filtration. This was washed with water and then dried under vacuum for five hours to give 7.3g (31.6mmol) of the title compound.

IH NMR (400 MHz, DMSOD6) δ ppm 5.87 (bs, 1 H) 6.09 (bs, 1 H) 7.42 (t, J=S Hz, 1 H) 7.59 (d, J=S Hz, 1 H) 7.75-7.95 (bs, 2 H) 8.23 (s, 1 H). MS m/z 230

Intermediate P

3-[(4-chloro-2-pyrimidinyl)amino]benzamide

3"[(4-oxθ"l,4-dihydro"2-pyrimidinyl)amino]benzoic acid (3.5g, 15.5mmol) was heated under reflux in phosphoryl oxychloride for 6 hours. The mixture was cooled and evaporated under vacuum. Toluene was added to the residue and then removed under vacuum, this was repeated three times. Toluene was added again and the resultant black oil added to a rapidly stirring solution of 0.5M ammonia in dioxane (20OmL). The suspension was stirred for 30 minutes and then concentrated under vacuum. The residue was suspended in water, filtered and washed with water and sodium bicarbonate solution. The product was dried to give 3.2g (I2.9mmol) of the title compound.

IH NMR (400 MHz, DMSOD6) δ ppm 7.0 (d, J=I Hz, 1 H) 7.34 (bs, 1 H) 7.37 (t, J=S Hz, 1 H) 7.49 (d, J=I. h Hz, 1 H) 7.84 (dd, J=S & 2 Hz, 1 H) 7.88-7.95 (bs, 1 H) 8.16 (s, I H) 8.47 (d, J=5 Hz, 1 H) 10.14 (s, 1 H). MS m/z 249/251 (3:1 ratio)

Example 271

3-({4-[(2-hvdroxy-2-phenylethyl)amino]-2-pyrimidinyl}amin o)benzamide.

3-[(4-chloro-2-pyrimidinyl)amino]benzamide (25mg, O.lmmol) and

2-amincrl-phenylethanol (82mg, O.δmmol) were added to a mixture of 1.2mL of acetone, 1.8mL of water and 24μL cone. Hydrochloric acid. The mixture was heated at 17O ⁰ C for 45 minutes in a Biotage microwave. The crude reaction mixture was evaporated to dryness under vacuum and then purified by HPLC using an acetonitrile/water (modified with formic acid) gradient as the eluent. Concentration of the relevant fractions afforded the title compound as a white solid (I7mg, 0.049mmol). IH NMR (400 MHz, DMSOD6) δ ppm 3.5-3.7 (bm, 2 H) 4.77 (m, 1 H) 5.3-5.65 (bs, 1 H) 6.03 (d, ,7=5.5 Hz, 1 H) 7.2-7.4 (m, 8 H) 7.81 (s, 2 H) 7.92 (d, J=S Hz, 1 H) 8.16 (s, 1 H) 8.20 (s, 1 H) 9.0 (s, 1 H). MS m/z 350 (M+ 1) ⁺

Example 272

3-({4- [(2 -phenylpropyl)amino] -2 -pyrimidinyllamincObenzamide.

The title compound was synthesized using the procedure recited in Example 271, except 2-phenyM-propanamine (81mg/86μL, 0.68mmol) was used. IH NMR (400 MHz, DMSOD6) δ ppm 1.23 (d, J=I Hz, 3H) 2.95-3.09 (m, 1 H) 3.45-3.6 (m, 2 H) 6.04 (d, ,7=6.5 Hz, 1 H) 7.15-7.35 (m, 7 H) 7.48 (d, J=I. h Hz, 1 H) 7.75-7.8 (m, 4 H) 8.19 (s, 1 H) 9.5 (bs, 1 H). MS m/z 348 (M+ 1) ⁺

Example 273

3-[(4-{[(2-^>-2-hvdroxy-2-phenylethyl]amino}-2-pyrimid inyl)amino]benzamide

The title compound was synthesized using the procedure recited in Example 271, except (l _* S)-2-amino"l"phenylethanol was used.

IH NMR (400 MHz, DMSOD6, spectra collected at 80 ⁰ C) δ ppm 3.35-3.45 (bm, 1 H) 3.55-3.65 (bm, 1 H) 4.77 (dd, ,7=7.5 & 4 Hz, 1 H) 5.15-5.4 (bs, 1 H) 6.07 (d, J=6 Hz, 1 H) 7.2-7.4 (m, 6 H) 7.42 (d, J=H Hz, 1 H) 7.78 (d, J=6 Hz, 1 H) 7.85 (m, 1 H) 8.13 (s, 1 H) 8.98 (bs, 1 H). MS m/z 350 (M+l) ⁺

Example 274

3-[(4-{[(2itj)-2-hvdroxy-2-phenylethyl]amino}-2-pyrimidin yl)amino]benzamide

The title compound was synthesized using the procedure recited in Example 271, except (li?)-2-amino"l"phenylethanol was used.

IH NMR (400 MHz, DMSOD6) δ ppm 3.5-3.7 (bm, 2 H) 4.74-4.82 (m, 1 H) 5.45-5.55 (bs, 1 H) 6.03 (d, J=6 Hz, 1 H) 7.2-7.4 (m, 9 H) 7.75-7.85 (m, J=H Hz, 2 H) 7.92 (d, J=π.h Hz, 1 H) 8.20 (s, 1 H) 9.04 (s, 1 H). MS m/z 350 (M+ 1) ⁺

Example 275

3-[(4-{[(2-^>-2-phenylpropyl]amino}-2-pyrimidinyl)amin o]benzamide

The title compound was synthesized using the procedure recited in Example 271, except (25)-2-phenyl-l-propanamine (81mg/86μL, 0.68mmol) was used. IH NMR (400 MHz, DMSOD6) δ ppm 1.23 (d, J=7 Hz, 3 H) 3.0-3.1 (m, 1 H) 3.45-3.6 (bm, 2 H) 6.02 (d, J=6.5 Hz, 1 H) 7.17-7.31 (m, 7H) 7.45 (d, J=7.5 Hz, 1 H) 7.72-7.93 (m, 4 H) 8.15-8.25 (bs, 1 H) 9.4-9.5 (bs, 1 H). MS m/z 348 (M+ 1) ⁺

Example 276

3-[(4-{[(2itj)-2-phenylpropyl]amino}-2-pyrimidinyl)amino] benzamide

The title compound was synthesized using the procedure recited in Example 271, except (2i?)-2-phenyl-l-propanamine (81mg/86μL, 0.68mmol) was used. IH NMR (400 MHz, DMSOD6) δ ppm 1.23 (d, J=7 Hz, 3 H) 3.0-3.1 (m, 1 H) 3.4-3.6 (bm, 2 H) 5.99 (d, J=6 Hz, 1 H) 7.15-7.3 (m, 7 H) 7.42 (d, J=7.5 Hz, 1 H) 7.59-7.93 (m, 4 H) 8.2-8.3 (bs, 1 H) 9.25-9.35 (bs, 1 H). MS m/z 348 (M+l) ⁺

Example 277

3-({4-[(3-hvdroxy-2-phenylpropyl) amino] -2-pyrimidinyl}amino)benzamide

The title compound was synthesized using the procedure recited in Example 271, except 3-amino-2-phenyM-propanol (90mg, 0.59mmol) was used. IH NMR (400 MHz, DMSOD6) δ ppm 2.99-3.06 (m, 1 H) 3.56-3.75 (bm, 4 H) 4.6-4.7 (bs, 1 H) 5.94 (d, J=Q Hz, 1 H) 7.2-7.3 (m, 8 H) 7.36 (d, ,7=7.5 Hz, 1 H) 7.7-7.8 (bs, IH) 7.8 (s, 1 H) 7.93 (d, J=G.b Hz, 1 H) 8.18-8.25 (bs, 1 H) 9.08-9.16 (bs, 1 H). MS m/z 364 (M+ 1) ⁺

Example 278

3-({4-[(2 ^■ phenvlethvl) amino] -2-pvrimidinyl}amino)benzamide

The title compound was synthesized using the procedure recited in Example 271, except 2-phenylethanamine (96.5mg, lOOμL, 0.80mmol) was used. IH NMR (400 MHz, DMSOD6) δ ppm 2.84 (t, J=I Hz, 2 H) 5.95 (d, ,7=5.5 Hz, 1 H) 7.2-7.35 (m, 9 H) 7.75-7.85 (m, 2 H) 7.92 (d, J=S Hz, 1 H) 8.2 (s, 1 H) 9.05 (s, 1 H). MS m/z 334 (M+ 1) ⁺

Example 279

4-({4-[(2-hvdroxy-2-phenylethyl)amino]-2-pyrimidinyl}amin o)benzoic acid trifluoroacetate salt

The title compound was synthesized using the procedure recited in Example 200, except 4-aminobenzoic acid was used.

IH NMR (600MHz, DMSO D-6) δ ppm 3.40-3.46 (m, 1 H) 3.68-3.73 (m, 1 H) 4.78 (dd, J=7.5 & 4 Hz, 1 H) 6.33 (d, J=7 Hz, 1 H) 7.26-7.29 (m, 1 H) 7.30-7.36 (m, 4 H) 7.72 (d, J=8.5 Hz, 2 H) 7.85 (d, J=7 Hz, 1 H) 7.94 (d, J=8.5 Hz, 2 H) 9.15 (bs, 1 H) 10.73 (bs, 1 H). MS m/z 351 (M+ 1) ⁺

Example 280

7-({4-[(2-hvdroxy-2-phenylethyl)amino]-2-pyrimidinyl}amin o)-4-methyl-2(l-fi&-qui nolinone trifluoroacetate salt

The title compound was synthesized using the procedure recited in Example 200, except 7"amino"4-methyl-2(lH)-quinolinone was used.

1η NMR (600MHz, DMSOD6) δ ppm 2.40 (s, 3 H) 3.34-3.39 (m, 1 H) 3.80-3.85 (m, 1 H) 4.74-4.77 (m, 1 H) 6.33 (d, J=7 Hz, 1 H) 6.34 (s, 1 H) 7.21 (m, 3 H) 7.26 (m, 2 H) 7.40 (d, J=9.5 Hz, 1 H) 7.56 (s, 1 H) 7.66 (d, J=8.5 Hz, 1 H) 7.85 (d, J=H Hz, 1 H) 9.18 (bs, 1 H) 10.78 (bs, 1 H) 10.64 (s, 1 H). MS m/z 388 (M+l) ⁺

Example 281

2 -{ [2 - ({3 - [( 1 - methylethvOoxy] phenyl} amino) -4-pyrimidinyl] amino} - 1 -phenylethan ol trifluoroacetate salt

The title compound was synthesized using the procedure recited in Example 200, except {3"[(l"methylethyl)oxy]phenyl}amine was used. IH NMR (600MHz, DMSO-D6) 8 ppm 1.18 (m, 6 H) 3.66-3.71 (m, 1 H) 4.51 (q, 1 H) 4.77 (dd, J=S & 4 Hz, IH) 6.31 (d, J=I Hz, 1 H) 6.74 (d, J=I. h Hz 1 H) 7.07 (d, J=8.5 Hz, 1 H) 7.15 (s, 1 H) 7.25 (t, 1 H) 7.25-7.28 (m, 1 H) 7.33-7.34 (m, 4 H) 7.79 (d, J=I Hz, 1 H) 9.14 (bs, 1 H) 10.45 (bs, 1 H). MS m/z 365 (M+ 1) ⁺

Example 282

l-phenyl-2-[(2-{[4-(l.fftetrazol-5-yl)phenyl]amino}-4-pyr imidinyl)amino]ethanol trifluoroacetate salt

The title compound was synthesized using the procedure recited in Example 200, except [4-(lH-tetrazol"5-yl)phenyl] amine was used.

1η NMR (600MHz DMSOD6) δ ppm 3.43-3.48 (m, 1 H) 3.69-3.73 (m, 1 H) 4.79 (dd, J=π.h & 4 Hz, 1 H) 6.35 (d, J=H Hz, 1 H) 7.24-7.27 (m, 1 H) 7.31 (t, J=H Hz, 2 H) 7.34 (s, 1 H) 7.35 (d, J=H Hz, 1 H) 7.80 (d, J=8.5 Hz, 2 H) 7.86 (d, J=H Hz, 1 H) 8.06 (d, J=8.5, 2 H) 9.24 (m, 1 H) 10.81 (m, 1 H). MS m/z 375 (M+l) ⁺

Example 283

2- [(2 -{[4-(dimethylamino)phenyl] amino} -4-pyrimidinyl)amino] - 1 -phenylethanol trifluoroacetate salt

2-[(2-chloro"4-pyrimidinyl)amino]"l"phenylethanol (O.lmmol, 24.9mg) was added to a solution of N,N- dimethyl- 1,4-benzenediamine (O.lδmmol, 20.4mg) in acetone (ImL), water (l.δmL) and 2N HCl (20μL). The mixture was allowed to stir at 7O ⁰ C for 40 hours. The mixture was concentrated under a reduced atmosphere and purified using SCX SPE (lg). The crude was loaded in methanol (δOOμL) and eluted with methanol (lδOOμL x 2) and 2.0M NH3/MeOH (lδOOμL). The ammonia fraction was concentrated and further purified by mass directed HPLC. The product containing fractions were concentrated to give title compound. (0.0025g, O.OOδmmol).

IH NMR (600MHz DMSOD6) δ ppm 2.93 (s, 6 H) 4.72-4.74 (m, 1 H) 6.23 (d, J=7 Hz, 1 H) 6.78 (d, «/=8.5, 2 H) 7.27-7.33 (m, 7 H) 10.07 (s, 1 H). MS m/z 3δO (M+ 1) ⁺

Intermediate Q ethyl [(3-nitrophenyl)oxy] acetate

A mixture of 3-nitrophenol (6.37g, 45.8mmol), ethyl bromoacetate (6.09ml, 54.96ml) and potassium carbonate (12.7g, 91.6mmol) in DMF (40ml) were stirred for 3hrs at 7O ⁰ C. The reaction was filtered and the filtrate reduced to dryness under vacuum. The residue was partitioned between ethyl acetate and water and the aqueous extracted with ethyl acetate. The combined organic phases were washed with a little water and the solvent evaporated under vacuum. The residue was purified by chromatography on a flashmaster cartridge (Si, 10Og) eluting with an ethyl acetate / cyclohexane gradient (0-50%). The product fractions were reduced to dryness under vacuum to give ethyl [(3-nitrophenyl)oxy] acetate (9.63g) as a yellow oil. LC/MS: Rt 2.95min, MH+ not observed.

Intermediate R ffimethyl-2-[(3-nitrophenyl)oxy]acetamide

Ethyl [(3-nitrophenyl)oxy] acetate (4g, 17.76mmol) and methylamine in methanol (2M, 54ml) was stirred at room temperature overnight. The reaction was filtered, the solid washed with methanol and dried to give A^methyl-2-[(3-nitrophenyl)oxy]acetamide (l.76g) as a white solid. Evaporation of the filtrate and trituration of the residue with a minimal quantity of methanol gave a further 1.3 Ig of the desired product. LC/MS: Rt 2.28min, MH+ 211.

Intermediate S

2- [(3-aminophenyl)oxy] -ffimethylacetamide

jV-methyl-2-[(3"nitrophenyl)oxy]acetamide (3.07g, 14.6mmol), and palladium on carbon (10%, 700mg) in ethanol (lOOml) were hydrogenated under hydrogen for 5hrs. The reaction was filtered through celite, the residue washed with ethyl acetate and the filtrate and washings reduced to dryness under vacuum to give 2-[(3-aminophenyl)oxy]-jty-methylacetamide as a grey/white solid (2.62g). LC/MS: Rt 0.86min, MH+ 181.

Example 284

2-{[3-({4-[(2-hvdroxy-2-phenylethyl) amino] -2-pyrimidinyl}amino)phenyl]oxy}-ffim ethylacetamide trifluoroacetate salt

2-[(2-chloro-4-pyrimidinyl)amino]-l-phenylethanol (O.lmmol, 24.9mg) was dissolved in acetone (l.δmL), water (ImL) and 2N HCl (20μL). The resulting mixture was treated with 2-[(3-aminophenyl)oxy]-7V ^: methylacetamide (O.lδmmol, 27mg) and allowed to stir at 7O ⁰ C for 88hours. The mixture was concentrated

under a reduced atmosphere and purified using SCX SPE (lg). The crude was loaded in methanol (500μL) and eluted with methanol (lδOOμL x 2) and 2.0M NH3/MeOH (lδOOμL). The ammonia fraction was concentrated and further purified by mass directed HPLC. The product containing fractions were concentrated to give title compound (0.025mg, 0.049mmol).

IH NMR (400MHz DMSOD6) δ ppm 2.64 (d, J=4.5 Hz, 3 H) 3.35-3.42 (m, 1 H) 4.43 (s, 2 H) 4.76 (dd, J=S & 4 Hz, 1 H) 6.31 (d, J=I Hz, 1 H) 6.82 (dd, J=S & 1.5 Hz, IH) 7.13-7.19 (m, 2 H) 7.24-7.29 (m, 2 H) 7.30-7.33 (bm, 6 H) 7.78 (d, J=I Hz, 1 H) 8.02 (m, 1 H) 9.23 (bs, 1 H) 10.41 (s, 1 H). MS m/z 394 (M+ 1) ⁺

References^

1. Fieser and Fieser, "Reagents for Organic Synthesis", vol.l, p.584 cites a useful procedure for quenching excess LAH and easy filtration of the resulting lithium aluminum hydroxide salts. See V. M. Micovic and M. L J. Mihailovic, J. Org. Chem., 1 8, 1 1 90 (1 953).

2. Literature compound (CAS#24176-70-3).

Biological test methods

Compounds of the invention may be tested for in vitro activity in accordance with the following or similar assays^

1. Enzyme Assay - Timeτesolved 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 MgCl ₂ (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 NaCl, 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 30 mins in the presence of 16.6mM MgCl ₂ , 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 MgCl ₂ (1OmM final) in 4OmM HEPES pH 7.4, 0.01% BSA, were added to wells containing O.lμl 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 NaCl, 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 ICso values less than lOμM.

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

Cells are plated at a density of lxlO ⁵ /well in a volume of 200μL growth medium (DMEM containing 10% heat inactivated foetal calf serum, 1% Lrglutamine, 400μg/ml geneticin and 400μg/ml zeocin) in 96 well Collagen 1 coated tissue culture plates. Following incubation at 37 ⁰ C, 10% CO2, 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 ⁰ C. After removal of the supernatant, the cells are washed with cold PBS and lysed with lOOμl lysis buffer for 4h at 4 ⁰ 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 16h at 4 ⁰ C. The plate is washed and a biotinylated anti-phosphotyrosine detection antibody added (lOOμl/well) for 2h at room temperature. This is removed and replaced with lOOμl Streptavidin-HRP for 30min. Captured phosphorylated SYK is visualised using lOOμL TMB substrate. The reaction is terminated with 50μl IM 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 IxIO ^"5 to 1.54xlO ^"n M. Compound dilutions are prepared using the Biomek 2000 or Biomek Nx automated robotic pipetting systems.

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^