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AU2008313622A1 - Solid dispersion product of N-aryl urea-based drugs - Google Patents

Solid dispersion product of N-aryl urea-based drugs Download PDF

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AU2008313622A1
AU2008313622A1 AU2008313622A AU2008313622A AU2008313622A1 AU 2008313622 A1 AU2008313622 A1 AU 2008313622A1 AU 2008313622 A AU2008313622 A AU 2008313622A AU 2008313622 A AU2008313622 A AU 2008313622A AU 2008313622 A1 AU2008313622 A1 AU 2008313622A1
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phenyl
amino
alkyl
urea
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AU2008313622A
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Tanja Heitermann
Rudolf Schroeder
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Abbott GmbH and Co KG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Description

WO 2009/050291 PCT/EP2008/064076 1 Solid dispersion product of N-aryl urea-based drugs Many potent drugs belong to the class of compounds of N-aryl ureas and compounds of related structural types. Unfortunately, the crystalline forms of most N-aryl urea based active agents are characterized by poor solubility in aqueous liquids. 5 Drugs of low water solubility, for example those classified as "practically insoluble" or "insoluble" according to United States Pharmacopeia (USP) 24 (2000), p. 10, i. e., hav ing a solubility of less than about 1 part per 10,000 parts water (less than about 100 ig/ml) are notoriously difficult to formulate for oral delivery. Among other problems, 10 bioavailability of such drugs, when administered by the oral route, tends to be very low. A specific illustrative small-molecule drug of low water solubility is the compound N-[4 (3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea (ABT-869), a multi targeted protein tyrosine kinase (PTK) inhibitor. This compound, which has a molecular 15 weight of 375.4 g/mol, is disclosed in International Patent Publication No. WO 2004/113304 of Abbott Laboratories. For a variety of reasons, such as patient compliance and taste masking, a solid dosage form is usually preferred over a liquid dosage form. In most instances, however, oral 20 solid dosage forms of a drug provide a lower bioavailability than oral solutions of the drug. There remains a need in the pharmaceutical art for a novel solid formulation of N-aryl urea-based active agents of low water solubility such as ABT-869 that is suitable for 25 oral administration. More particularly and without limitation, there is a need for such a formulation having at least one of the following features, advantages or benefits: ac ceptably high concentration of the drug; and acceptable bioavailability when adminis tered orally. 30 The invention relates to a solid dispersion product comprising at least one pharmaceu tically active agent, obtained by a) preparing a liquid mixture containing the at least one active agent, at least one pharmaceutically acceptable matrix-forming agent, at least one pharmaceutically 35 acceptable surfactant and at least one solvent, and b) removing the solvent(s) from the liquid mixture to obtain the solid dispersion product. 40 The invention is particularly useful for water-insoluble or poorly water-soluble (or "hy drophobic" or "lipophilic") compounds. Compounds are considered water-insoluble or poorly water-soluble when their solubility in water at 25 'C is less than 1 g/1 00 ml, es pecially less than 0,1 g/100 ml.
WO 2009/050291 PCT/EP2008/064076 2 In the dosage forms of the invention, the active agent is present as a solid dispersion or, preferably, as a solid solution. The term "solid dispersion" defines a system in a solid state (as opposed to a liquid or gaseous state) comprising at least two compo nents, wherein one component is dispersed evenly throughout the other component or 5 components. For example, the active agent or combination of active agents is dis persed in a matrix comprised of the matrix-forming agent(s) and pharmaceutically ac ceptable surfactant(s). The term "solid dispersion" encompasses systems having small particles, typically of less than 1 ptm in diameter, of one phase dispersed in another phase. When said dispersion of the components is such that the system is chemically 10 and physically uniform or homogenous throughout or consists of one phase (as defined in thermodynamics), such a solid dispersion will be called a "solid solution" or a "glassy solution". A glassy solution is a homogeneous, glassy system in which a solute is dis solved in a glassy solvent. Glassy solutions and solid solutions are preferred physical systems. These systems do not contain any significant amounts of active agents in 15 their crystalline or microcrystalline state, as evidenced by thermal analysis (DSC) or X ray diffraction analysis (WAXS). In an embodiment of the invention, at least one filler is added to the liquid mixture be fore removing the solvent(s). It was found that incorporation of a filler into the liquid 20 mixture before removing the solvent(s) increases the brittleness of the solid dispersion product obtained. This allows the solid dispersion product to be subjected to a direct tabletting process. Preferably, the filler is essentially insoluble in the liquid mixture. 25 The choice of fillers is not particularly restricted. The filler may be suitably selected from inorganic particulate materials such as silica, calcium carbonate, calcium phos phates, titanium dioxide; natural and pre-gelatinized starches such as corn starch, ce real starch, potato starch; or the like. 30 However, the filler is preferably water-soluble. Useful fillers to that end may be selected from sugars such as lactose, sucrose; sugar alcohols such as mannitol, sorbitol, xylitol; or sugar alcohol derivatives. 35 The relative amounts of active agent, pharmaceutically acceptable matrix-forming agent and pharmaceutically acceptable surfactant are chosen with the following condi tions in mind: (1) Essentially all of the active agent should be dispersed evenly throughout the matrix comprised of the matrix-forming agent(s) and pharmaceutically acceptable surfactant(s). (2) The matrix should have sufficient mechanical integrity and 40 stability; in particular, the matrix should not exhibit cold flow. Generally, the mass ratio of active agent and pharmaceutically acceptable matrix-forming agent is from 0.01:1 to 1:3, preferably 0.05:1 to 0.2:1; generally the mass ratio of active agent and pharmaceu tically acceptable surfactant(s) is from 0.1:1 to 1:7, preferably 1:4 to 1:6.5. 45 Generally, the solid dispersion product comprises WO 2009/050291 PCT/EP2008/064076 3 from about 1 to 30 % by weight, preferably from about 4 to 15 % by weight, of said at least one pharmaceutically active agent, from about 15 to 70 % by weight, preferably from about 20 to 55 % by weight, of said at least one pharmaceutically acceptable matrix-forming agent, 5 from about 2 to 70 % by weight, preferably from about 5 to 55 % by weight, of said at least one surfactant, and from about 0 to 80 % by weight, preferably from about 0 to 60 % by weight, of additives such as fillers. 10 The matrix-forming agent may be any agent capable of embedding an active agent and/or being loaded with an active agent and stabilizing an essentially amorphous state of the active agent. Mixtures of matrix-forming agents can, of course, be used. The pharmaceutically acceptable matrix-forming agent is suitably selected from the 15 group consisting of cyclodextrines, pharmaceutically acceptable polymers, lipids or combinations of two or more thereof. Cyclodextrins for the purpose of the invention are cyclic oligo- or polysaccharides, for example so-called cycloamyloses or cycloglucans, and analogous cyclic carbohydrates 20 which are described, for example, in Angew. Chem. 92 (1980) p. 343 or F. V6gtle, Su pramolekulare Chemie, 2nd Edition, (1992). Suitable and preferred are those cyclodex trins which have a structure suitable for interactions with active agent molecules, in particular in the sense of host-guest systems. Particularly suitable cyclodextrins are those consisting of 6, 7, 8 or 9 a-1,4-glycosidically linked glucose units, which are 25 called a-, P-, y- or 6-cyclodextrins. Higher structures analogous to cyclodextrins and composed of a larger number of glucoses or similar sugars are also conceivable and suitable. Also suitable as cyclodextrins are modified cyclodextrins such as, for example, prod 30 ucts which can be prepared by reacting cyclodextrins with alkylene oxides, alkyl hal ides, acid chlorides, epihalohydrins, isocyanates or halogenated carboxylic acids. Thus, suitable examples are products of the reaction of cyclodextrins with alkylene ox ides such as ethylene oxide, propylene oxide, butylene oxide or styrene oxide. One, more than one or all hydroxyl groups in the cyclodextrin polyethers formed in this way 35 may be substituted. Depending on the degree of substitution or the chain lengths of the polyether units, the average molar degree of substitution, that is to say the number of moles of alkylene oxide with which one mole of cyclodextrin is reacted, is usually be tween 3 and 20,000, but there is in principle no upper limit. Particularly suitable exam ples are the products of the reaction of cyclodextrins with alkylating agents such as C 40 C 22 -alkyl halides, for example methyl chloride, ethyl chloride, isopropyl chloride, n-butyl chloride, isobutyl chloride, benzyl chloride, lauryl chloride, stearyl chloride, methyl bro mide, ethyl bromide, n-butyl bromide and dialkyl sulfates such as, for example, di methyl sulfate or diethyl sulfate. Reaction with alkylating reagents leads to cyclodextrin ethers in which one, more than one or all hydroxyl groups are substituted by alkyl ether 45 groups. With the cyclodextrins composed of glucose units, the average degree of eth- WO 2009/050291 PCT/EP2008/064076 4 erification per glucose unit is usually in the range from 0.5 to 3, preferably in the range from 0.1 to 2.5 and particularly preferably in the range from 1 to 2. Particular prefer ence is given to methylated, ethylated or propylated a-, P-, y-cyclodextrins with an av erage degree of etherification of from 1.5 to 2.2. Also suitable are cyclodextrin esters 5 which are obtainable by reacting cyclodextrins with acid chlorides such as carbonyl or sulfonyl chlorides. Particularly suitable are carbonyl chlorides such as acetyl chloride, acryloyl chloride, methacryloyl chloride or benzoyl chloride. Also suitable are polymer-modified cyclodextrins, that is to say cyclodextrins which are 10 incorporated into the main chain of polymers and/or cyclodextrins which have been attached to side chains of polymers or are themselves side chains of polymers. Poly mer-modified cyclodextrins in which the cyclodextrin units are arranged in the main chain of the polymer can be obtained, for example, by reacting cyclodextrins with or in the presence of suitable coupling or crosslinking reagents, for example as described in 15 Helv. Chim. Acta, Vol. 48, (1965), p. 1225. Polymer-modified cyclodextrins in which the cyclodextrin units are side chain constituents or act as side chains can be obtained, for example, by cyclodextrins modified with polymerizable groups being polymerized with other comonomers, for example by polymerizing cyclodextrin (meth)acrylates in the presence of other ethylenically unsaturated monomers or by free-radical grafting of 20 cyclodextrin (meth)acrylates onto polymers with free hydroxyl groups such as, for ex ample, polyvinyl alcohol. Another possibility for preparing polymer-modified cyclodex trins with the cyclodextrin units on side groups or as side groups of polymers is to react cyclodextrins, deprotonated cyclodextrins or their alkali metal salts with polymers which have complementary reactive groups such as, for example, anhydride, isocyanate, acid 25 halide or epoxy groups or halogens. Preferred cyclodextrines are hydroxyalkyl-cyclodextrines, such as hydroxypropyl-p cyclodextrin. 30 Suitable lipids may be selected from waxes, tri-, di-, and monoglycerides and phospholipids. The preferred matrix-forming agents are pharmaceutically acceptable polymers. 35 The pharmaceutically acceptable polymers may be selected from water-soluble poly mers, water-dispersible polymers or water-swellable polymers or any mixture thereof. Polymers are considered water-soluble if they form a clear homogeneous solution in water. When dissolved at 20 OC in an aqueous solution at 2 % (w/v), the water-soluble polymer preferably has an apparent viscosity of 1 to 5000 mPa.s, more preferably of 1 40 to 700 mPa.s, and most preferably of 5 to 100 mPa.s. Water-dispersible polymers are those that, when contacted with water, form colloidal dispersions rather than a clear solution. Upon contact with water or aqueous solutions, water-swellable polymers typi cally form a rubbery gel. Water-soluble polymers are preferred.
WO 2009/050291 PCT/EP2008/064076 5 Preferably, the pharmaceutically acceptable polymer employed in the invention has a Tg of at least 40'C, preferably at least +500C, most preferably from 80 to 180. OC. "Tg" means glass transition temperature. Methods for determining Tg values of the organic polymers are described in "Introduction to Physical Polymer Science", 2nd Edi 5 tion by L.H. Sperling, published by John Wiley & Sons, Inc., 1992. The Tg value can be calculated as the weighted sum of the Tg values for homopolymers derived from each of the individual monomers, i, that make up the polymer: Tg = E Wi Xi where W is the weight percent of monomer i in the organic polymer, and X is the Tg value for the ho mopolymer derived from monomer i. Tg values for the homopolymers may be taken 10 from "Polymer Handbook", 2nd Edition by J. Brandrup and E.H. Immergut, Editors, published by John Wiley & Sons, Inc., 1975. Various additives contained in the solid dispersion product or even the active ingredi ent(s) itself may exert a plasticizing effect on the polymer and thus depress the Tg of 15 the polymer such that the final solid dispersion product has a somewhat lower Tg than the starting polymer used for its preparation. In general, the final solid dispersion prod uct has a Tg of 10 OC or higher, preferably 15 OC or higher, more preferably 20 OC or higher and most preferred 30 OC or higher. 20 For example, preferred pharmaceutically acceptable polymers can be selected from the group comprising homopolymers and copolymers of N-vinyl lactams, especially homopolymers and co polymers of N-vinyl pyrrolidone, e.g. polyvinylpyrrolidone (PVP), copolymers of N-vinyl 25 pyrrolidone and vinyl acetate or vinyl propionate, cellulose esters and cellulose ethers, in particular methylcellulose and ethylcellulose, hydroxyalkylcelluloses, in particular hydroxypropylcellulose, hydroxyalkylalkylcellu loses, in particular hydroxypropylmethylcellulose, cellulose phthalates or succinates, in 30 particular cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate, hy droxypropylmethylcellulose succinate or hydroxypropylmethylcellulose acetate succi nate; high molecular polyalkylene oxides such as polyethylene oxide and polypropylene ox 35 ide and copolymers of ethylene oxide and propylene oxide, polyvinyl alcohol-polyethylene glycol-graft copolymers (available as Kollicoat@ IR from BASF AG, Ludwigshafen, Germany); 40 polyacrylates and polymethacrylates such as methacrylic acid/ethyl acrylate copoly mers, methacrylic acid/methyl methacrylate copolymers, butyl methacrylate/2-dimethyl aminoethyl methacrylate copolymers, poly(hydroxyalkyl acrylates), poly(hydroxyalkyl methacrylates), 45 polyacrylamides, WO 2009/050291 PCT/EP2008/064076 6 vinyl acetate polymers such as copolymers of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate (also referred to as partially saponified "polyvinyl alcohol"), 5 polyvinyl alcohol, oligo- and polysaccharides such as carrageenans, galactomannans and xanthan gum, or mixtures of one or more thereof. 10 Among these, homopolymers or copolymers of N-vinyl pyrrolidone, in particular a co polymer of N-vinyl pyrrolidone and vinyl acetate, are preferred. A particularly preferred polymer is a copolymer of 60 % by weight of the copolymer, N-vinyl pyrrolidone and 40 % by weight of the copolymer, vinyl acetate. 15 A further polymer which can be suitably used is Kollidon@ SR (available from BASF AG, Ludwigshafen, Germany) which comprises a mixture of PVP and polyvinylacetate. The term "pharmaceutically acceptable surfactant" as used herein refers to a pharma ceutically acceptable non-ionic surfactant. The surfactant may effectuate an instanta 20 neous emulsification of the active agent released from the dosage form and/or prevent precipitation of the active ingredient in the aqueous fluids of the gastrointestinal tract. A single surfactant as well as combinations of surfactants may be used. According to an embodiment of the invention, the solid dispersion product comprises a combination of two or more pharmaceutically acceptable surfactants. 25 Preferred surfactants are selected from sorbitan fatty acid esters, polyalkoxylated fatty acid esters such as, for example, polyalkoxylated glycerides, polyalkoxylated sorbitan fatty acid esters or fatty acid esters of polyalkylene glycols, polyalkoxylated ethers of fatty alcohols, tocopheryl compounds or mixtures of two or more thereof. A fatty acid 30 chain in these compounds ordinarily comprises from 8 to 22 carbon atoms. The polyal kylene oxide blocks comprise on average from 4 to 50 alkylene oxide units, preferably ethylene oxide units, per molecule. Suitable sorbitan fatty acid esters are sorbitan monolaurate, sorbitan monopalmitate, 35 sorbitan monostearate (Span@ 60), sorbitan monooleate (Span@ 80), sorbitan tristearate, sorbitan trioleate, sorbitan monostearate, sorbitan monolaurate or sorbitan monooleate. Examples of suitable polyalkoxylated sorbitan fatty acid esters are polyoxyethylene 40 (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethyl ene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate (Tween® 80), polyoxyethylene (20) sorbitan tristearate (Tween@ 65), polyoxyethylene (20) sorbi tan trioleate (Tween@ 85), polyoxyethylene (4) sorbitan monostearate, polyoxyethylene (4) sorbitan monolaurate or polyoxyethylene (4) sorbitan monooleate. 45 WO 2009/050291 PCT/EP2008/064076 7 Suitable polyalkoxylated glycerides are obtained for example by alkoxylation of natural or hydrogenated glycerides or by transesterification of natural or hydrogenated glyc erides with polyalkylene glycols. Commercially available examples are polyoxyethylene glycerol ricinoleate 35, polyoxyethylene glycerol trihyd roxystearate 40 (Cremophor@ 5 RH40, BASF AG) and polyalkoxylated glycerides like those obtainable under the pro prietary names Gelucire@ and Labrafil@ from Gattefosse, e.g. Gelucire@ 44/14 (lauroyl macrogol 32 glycerides prepared by transesterification of hydrogenated palm kernel oil with PEG 1500), Gelucire@ 50/13 (stearoyl macrogol 32 glycerides, prepared by trans esterification of hydrogenated palm oil with PEG 1500) or Labrafil M1944 CS (oleoyl 10 macrogol 6 glycerides prepared by transesterification of apricot kernel oil with PEG 300). A suitable fatty acid ester of polyalkylene glycols is, for example, PEG 660 hydroxy stearic acid (polyglycol ester of 12-hydroxystearic acid (70 mol%) with 30 mol% ethyl 15 ene glycol). Suitable polyalkoxylated ethers of fatty alcohols are, for example, PEG (2) stearyl ether (Brij@ 72), macrogol 6 cetylstearyl ether or macrogol 25 cetylstearyl ether. 20 In general, the tocopheryl compound corresponds to the formula below Z- O(CHR1-CHR 2 O)nH CH3 CH3CH3 CH3 CH3 3 3 H3C O CH3 CH3 wherein Z is a linking group, R 1 and R 2 are, independently of one another, hydrogen or 25 C1-C4 alkyl and n is an integer from 5 to 100, preferably 10 to 50. Typically, Z is the residue of an aliphatic dibasic acid such as glutaric, succinic, or adipic acid. Preferably, both R 1 and R 2 are hydrogen. The preferred tocopheryl compound is alpha tocopheryl polyethylene glycol succinate, 30 which is commonly abbreviated as vitamin E TPGS. Vitamin E TPGS is a water-soluble form of natural-source vitamin E prepared by esterifying d-alpha-tocopheryl acid succi nate with polyethylene glycol 1000. Vitamin E TPGS is available from Eastman Chemi cal Company, Kingsport, TN, USA and is listed in the US pharmacopoeia (NF). 35 It was found that surfactants or combination of surfactants having a defined HLB (hy drophilic lipophilic balance) value are preferred over other solubilizers.
WO 2009/050291 PCT/EP2008/064076 8 The HLB system (Fiedler, H.B., Encyclopedia of Excipients, 5 th ed., Aulendorf: ECV Editio-Cantor-Verlag (2002)) attributes numeric values to surfactants, with lipophilic substances receiving lower HLB values und hydrophilic substances receiving higher 5 HLB values. In preferred embodiments, the pharmaceutically acceptable surfactant comprises at least one surfactant having an H LB value of 10 or more. 10 Solubilizers having an HLB value of 10 or more may be selected from Gelucire@ 44/14 (H LB 14), Cremophor@ RH40 (H LB 13), Tween@ 65 (H LB 10.5), Tween@ 85 (H LB 11). Preferred high HLB solubilizers are tocopheryl compounds having a polyalkylene glycol moiety. 15 In a preferred embodiment, a combination of solubilizers is used which comprises (i) at least one tocopheryl compound having a polyalkylene glycol moiety, preferably alpha tocopheryl polyethylene glycol succinate, and (ii) at least one polyalkoxylated polyol fatty acid ester. The tocopheryl compound preferably is alpha tocopheryl polyethylene glycol succinate. The polyalkoxylated polyol fatty acid ester preferably is a polyalkoxy 20 lated glyceride. The mass ratio of tocopheryl compound and polyalkoxylated polyol fatty acid ester preferably is in the range of from 0.2:1 to 1:1. In an embodiment, the active agent is a N-aryl urea-based active agent. N-aryl urea based active agents are biologically active compounds which comprise at least one 25 urea moiety in their molecular structure wherein one or both nitrogen atoms are substi tuted by an aryl group, and which exert a local physiological effect, as well as those which exert a systemic effect, after oral administration. The aryl group may be a carbo cyclic or heterocyclic aromatic group or a fused carbocyclic or heterocyclic aromatic group. Attachment to the nitrogen atom is usually via a carbon atom of the aryl group. 30 A fused aromatic group may be linked to the nitrogen atom via an aromatic or non aromatic carbon atom. The aryl group may, of course, be substituted by further sub stituents. Generally, the N-aryl urea-based active agent is represented by the general formula 35 0 (Z)n G2 G1 N N H H wherein 40 WO 2009/050291 PCT/EP2008/064076 9 G' and G 2 are, independently from one another, a carbocyclic ring selected from phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, ben zocycloheptanyl, benzocycloheptenyl, indanyl and indenyl; 5 a ring system selected from benzoxazinyl, benzimidazolyl, indazolyl, benzo thiazolyl, benzooxazolyl, benzisoxazolyl, benzofuranyl, benzopyranyl, benzodi oxolyl, quinaldinyl, quinazolinyl, quinoxalinyl, isoquinolinyl, quinolinyl, indolyl, iso indolyl, indolinyl, purinyl, tetrahydroquinolinyl, indazolyl, imidazo-pyridinyl, pyra zolo-pyridinyl, pyrazolo-pyrimidinyl, pyrrolo-pyrimidinyl, pyrrolo-pyridinyl, pyrido 10 pyrazinyl, pyrido-pyrimidinyl, pyrido-oxazinyl, pyrido-thiazinyl, pyrido-oxazolyl, pyrido-thioxazolyl, pyrimido-pyrimidine, pteridinyl, cinnolinyl and naphthyridinyl; wherein G 1 or G2 or both may be substituted by one or more substituents selected from the group consisting of C1-6 branched or unbranched alkyl, C1.6 haloalkyl, C1.6 15 branched or unbranched acyl, C1.6 branched or unbranched alkoxy, halogen, C1.6 branched or unbranched alkyloxycarbonyl, hydroxy, amino, mono- or di-(C 1
.
4 al kyl)amino, mono- or di-(C 1
.
4 alkyl)amino-SO 2 , cyano, nitro or H 2
NSO
2 , Z is 1,4-phenylene, and 20 n is 0 or1, or the pharmaceutically acceptable salts, esters, isomers, hydrates or solvates thereof 25 In an embodiment, the active agent is represented by the formula (1)
R
3
R
4 A
H
2 N R5 N R1 R (I), 30 or a therapeutically acceptable salt thereof, wherein A is selected from the group consisting of indolyl, phenyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, and thienyl; X is selected from the group consisting of 0, S, and NR 9 ;
R
1 and R 2 are independently selected from the group consisting of hydrogen, 35 alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocycly lalkyl, heterocyclyloxyalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, (NRaRb)alkoxy, (NRaRb)alkenyl, (NRaRb)alkyl, (NRaRb)alkynyl, (NRaRb)carbonylalkenyl, and (NRaRb)carbonylalkyl; WO 2009/050291 PCT/EP2008/064076 10
R
3 , R 4 , and R 5 are each independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkyl, halo, haloalkoxy, haloalkyl, hydroxy, and LR 6 ; provided that at least two of R 3 , R 4 , and R 5 are other than LR 6 ; L is selected from the group consisting of (CH 2 )mN(R 7
)C(O)N(R
8
)(CH
2 )n and 5 CH 2 C(O)NR , wherein m and n are independently 0 or 1, and wherein each group is drawn with its left end attached to A;
R
6 is selected from the group consisting of hydrogen, aryl, cycloalkyl, heterocy clyl, and 1,3-benzodioxolyl wherein the 1,3-benzodioxolyl can be optionally substituted with one, two, or three substituents independently selected from the group consisting of 10 alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkoxy, arylal kyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second heterocy clyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NRcRd, and (NRcRd)alkyl;
R
7 and R3 are independently selected from the group consisting of hydrogen and alkyl; 15 R 9 is selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkyl, alkylcarbonyl, aryl, heterocyclylalkyl, hydroxyalkyl, and (NRaRb)alkyl; Ra and Rb are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylcarbonyl, arylsulfonyl, haloalkylsulfonyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, and heterocyclylsulfonyl; 20 and Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and hetero cyclylalkyl. In another embodiment, the active agent is a compound of formula (II)
R
4
H
2 N R 3 N 25 R 1
R
2 (II), or a therapeutically acceptable salt thereof, wherein X is selected from the group consisting of 0, S, and NR 9 ;
R
1 and R 2 are independently selected from the group consisting of hydrogen, 30 alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloal kyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocycly loxyalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, (NRaRb)alkoxy, (NRaRb)alkenyl, (NRaRb)alkyl, (NRaRb)carbonylalkenyl, and (NRaRb)carbonylalkyl;
R
3 and R 4 are independently selected from the group consisting of hydrogen, 35 alkoxy, alkyl, halo, haloalkoxy, haloalkyl, and hydroxy; WO 2009/050291 PCT/EP2008/064076 11 L is selected from the group consisting of (CH 2 )mN(R 7
)C(O)N(R
8
)(CH
2 )n and
CH
2 C(O)NR , wherein m and n are independently 0 or 1, and wherein each group is drawn with its left end attached to the ring substituted with R 3 and R 4 ;
R
7 and R3 are independently selected from the group consisting of hydrogen 5 and alkyl;
R
9 is selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkyl, alkylcarbonyl, aryl, heterocyclylalkyl, hydroxyalkyl, and (NRaRb)alkyl;
R
10 and R" are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, 10 haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NRcRd; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsul fonyl; and Rc and Rd are independently selected from the group consisting of hydrogen, 15 alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and hetero cyclylalkyl. In another embodiment, the present invention provides a compound of formula (1) wherein X is 0 and A, R 1 , R 2 , R 3 , R 4 , and R 5 are as defined in formula (1). 20 In another embodiment, the present invention provides a compound of formula (1) wherein A is phenyl; X is 0; R 5 is LR 6 ; R 6 is 1,3-benzodioxolyl optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkoxy, arylal kyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second heterocy 25 clyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NRcRd, and (NRcRd)alkyl; L is
(CH
2 )mN(R 7
)C(O)N(R)(CH
2 )n; and m, n, Rc, Rd, R 1 , R 2 , R 3 , R 4 , R 7 , and R3 are as de fined in formula (1). In another embodiment, the present invention provides a compound of formula (1) wherein A is phenyl; X is 0; R 5 is LR 6 ; R 6 is 1,3-benzodioxolyl optionally substituted 30 with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkoxy, arylal kyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second heterocy clyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NRcRd, and (NRcRd)alkyl; L is
(CH
2 )mN(R 7
)C(O)N(R)(CH
2 )n; m and n are 0; R 1 and R 2 are independently selected 35 from the group consisting of hydrogen and alkoxy; R 3 , R 4 , R 7 , and R 8 are hydrogen; and Rc and Rd are selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula (1) wherein A is phenyl; X is 0; R 5 is LR 6 ; R 6 is 1,3-benzodioxolyl; L is
(CH
2 )mN(R 7
)C(O)N(R)(CH
2 )n; m and n are 0; R 1 and R 2 are independently selected 40 from the group consisting of hydrogen and alkoxy; and R 3 , R 4 , R 7 , and R" are hydro gen. In another embodiment, the present invention provides a compound of formula (1) wherein X is S and A, R 1 , R 2 , R 3 , R 4 , and R 5 are as defined in formula (1). In another embodiment, the present invention provides a compound of formula 45 (1) wherein A is phenyl; X is S; R 5 is LR 6 ; R 6 is 1,3-benzodioxolyl optionally substituted WO 2009/050291 PCT/EP2008/064076 12 with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkoxy, arylal kyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second heterocy clyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NRcRd, and (NRcRd)alkyl; L is 5 (CH 2 )mN(R 7
)C(O)N(R)(CH
2 )n; and m, n, Rc, Rd, R 1 , R 2 , R 3 , R 4 , R 7 , and R 8 are as de fined in formula (1). In another embodiment, the present invention provides a compound of formula (1) wherein A is phenyl; X is S; R 5 is LR 6 ; R 6 is 1,3-benzodioxolyl optionally substituted with one, two, or three substituents independently selected from the group consisting of 10 alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkoxy, arylal kyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second heterocy clyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NRcRd, and (NRcRd)alkyl; L is
(CH
2 )mN(R 7
)C(O)N(R)(CH
2 )n; m and n are 0; R 1 and R 2 are independently selected from the group consisting of hydrogen and alkoxy; R 3 , R 4 , R 7 , and R 8 are hydrogen; 15 and Rc and Rd are selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula (1) wherein A is phenyl; X is S; R 5 is LR 6 ; R 6 is 1,3-benzodioxolyl; L is
(CH
2 )mN(R 7
)C(O)N(R)(CH
2 )n; m and n are 0; R 1 and R 2 are independently selected from the group consisting of hydrogen and alkoxy; and R 3 , R 4 , R 7 , and R 8 are hydro 20 gen. In another embodiment, the present invention provides a compound of formula (1) wherein X is NR 9 ; and A, R 1 , R 2 , R 3 , R 4 , R 5 , and R 9 are as defined in formula (1). In another embodiment, the present invention provides a compound of formula (1) wherein A is phenyl; X is NR 9 ; R 5 is LR 6 ; R 6 is 1,3-benzodioxolyl optionally substi 25 tuted with one, two, or three substituents independently selected from the group con sisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, ary lalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NRcRd, and (NRcRd)alkyl; L is (CH 2 )mN(R 7
)C(O)N(R)(CH
2 )n; and m, n, Rc, Rd, R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , 30 and R 9 are as defined in formula (1). In another embodiment, the present invention provides a compound of formula (1) wherein A is phenyl; X is NR 9 ; R 5 is LR 6 ; R 6 is 1,3-benzodioxolyl optionally substi tuted with one, two, or three substituents independently selected from the group con sisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, ary 35 lalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NRcRd, and (NRcRd)alkyl; L is (CH 2 )mN(R 7
)C(O)N(R)(CH
2 )n; m and n are 0; R 1 and R 2 are inde pendently selected from the group consisting of hydrogen and alkoxy; R 3 , R 4 , R 7 , and
R
8 are hydrogen; R 9 is selected from the group consisting of hydrogen and alkyl; and 40 Rc and Rd are selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula (1) wherein A is phenyl; X is NR 9 ; R 5 is LR 6 ; R 6 is 1,3-benzodioxolyl; L is
(CH
2 )mN(R 7
)C(O)N(R)(CH
2 )n; m and n are 0; R 1 and R 2 are independently selected from the group consisting of hydrogen and alkoxy; R 3 , R 4 , R 7 , and R 8 are hydrogen; 45 and R 9 is selected from the group consisting of hydrogen and alkyl.
WO 2009/050291 PCT/EP2008/064076 13 In another embodiment, the present invention provides a compound of formula (1) wherein A is phenyl; X is 0; R 5 is LR 6 ; R 6 is cycloalkyl optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, 5 haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NRcRd, (NRcRd)alkyl, and oxo; L is
(CH
2 )mN(R 7
)C(O)N(R)(CH
2 )n; and m, n, Rc, Rd, R 1 , R 2 , R 3 , R 4 , R 7 , and R3 are as de fined in formula (1). In another embodiment, the present invention provides a compound of formula (1) wherein A is phenyl; X is 0; R 5 is LR 6 ; R 6 is cycloalkyl wherein the cycloalkyl is se 10 lected from the group consisting of cyclobutyl, cyclopentyl, and cyclohexyl, wherein the cycloalkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, NRcRd, (NRcRd)alkyl, and oxo; L is (CH 2 )mN(R 7
)C(O)N(R)(CH
2 )n; m and n are 0; R 1 and 15 R 2 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkyl, halo, hydroxy, (NRaRb)alkoxy, (NRaRb)alkyl, and (NRaRb)carbonylalkenyl; R 3 and R 4 are independently selected from the group consist ing of hydrogen, alkyl, alkoxy, alkoxyalkoxy, halo, haloalkoxy, and hydroxy; R 7 and R 8 are hydrogen; R" and Rb are independently selected from the group consisting of hy 20 drogen and alkyl; and Rc and Rd are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula (1) wherein A is phenyl; X is 0; R 5 is LR 6 ; R 6 is cycloalkyl wherein the cycloalkyl is cyclopentyl; L is (CH 2 )mN(R 7
)C(O)N(R)(CH
2 )n; m and n are 0; R 1 and R 2 are independ 25 ently selected from the group consisting of hydrogen and alkoxy; and R 3 , R 4 , R 7 , and
R
8 are hydrogen. In another embodiment, the present invention provides a compound of formula (1) wherein A is phenyl; X is S; R 5 is LR 6 ; R 6 is cycloalkyl optionally substituted with one, two, or three substituents independently selected from the group consisting of 30 alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NRcRd, (NRcRd)alkyl, and oxo; L is
(CH
2 )mN(R 7
)C(O)N(R)(CH
2 )n; and m, n, Rc, Rd, R 1 , R 2 , R 3 , R 4 , R 7 , and R3 are as de fined in formula (1). In another embodiment, the present invention provides a compound of formula 35 (1) wherein A is phenyl; X is S; R 5 is LR 6 ; R 6 is cycloalkyl wherein the cycloalkyl is se lected from the group consisting of cyclobutyl, cyclopentyl, and cyclohexyl, wherein the cycloalkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, 40 NRcRd, (NRcRd)alkyl, and oxo; L is (CH 2 )mN(R 7
)C(O)N(R)(CH
2 )n; m and n are 0; R 1 and R2 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkyl, halo, hydroxy, (NRaRb)alkoxy, (NRaRb)alkyl, and (NRaRb)carbonylalkenyl; R 3 and R 4 are independently selected from the group consist ing of hydrogen, alkyl, alkoxy, alkoxyalkoxy, halo, haloalkoxy, and hydroxy; R 7 and R 8 45 are hydrogen; R" and Rb are independently selected from the group consisting of hy- WO 2009/050291 PCT/EP2008/064076 14 drogen and alkyl; and RC and Rd are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula (1) wherein A is phenyl; X is S; R 5 is LR 6 ; R 6 is cycloalkyl wherein the cycloalkyl is 5 cyclopentyl; L is (CH 2 )mN(R 7
)C(O)N(R)(CH
2 )n; m and n are 0; R 1 and R 2 are independ ently selected from the group consisting of hydrogen and alkoxy; and R 3 , R 4 , R 7 , and
R
8 are hydrogen. In another embodiment, the present invention provides a compound of formula (1) wherein A is phenyl; X is NR 9 ; R 5 is LR 6 ; R 6 is cycloalkyl optionally substituted with 10 one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NRcRd, (NRcRd)alkyl, and oxo; L is
(CH
2 )mN(R 7
)C(O)N(R)(CH
2 )n; and m, n, Rc, Rd, R 1 , R 2 , R 3 , R 4 , R 7 , R", and R 9 are as defined in formula (1). 15 In another embodiment, the present invention provides a compound of formula (1) wherein A is phenyl; X is NR 9 ; R 5 is LR 6 ; R 6 is cycloalkyl wherein the cycloalkyl is selected from the group consisting of cyclobutyl, cyclopentyl, and cyclohexyl, wherein the cycloalkyl is optionally substituted with one, two, or three substituents independ ently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, 20 alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NRcRd, (NRcRd)alkyl, and oxo; L is (CH 2 )mN(R 7
)C(O)N(R)(CH
2 )n; m and n are 0; R 1 and R 2 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkyl, halo, hydroxy, (NRaRb)alkoxy, (NRaRb)alkyl, and (NRaRb)carbonylalkenyl; R 3 and R 4 are independently selected from the group consist 25 ing of hydrogen, alkyl, alkoxy, alkoxyalkoxy, halo, haloalkoxy, and hydroxy; R 7 and R 8 are hydrogen; R 9 is selected from the group consisting of hydrogen and alkyl; R" and Rb are independently selected from the group consisting of hydrogen and alkyl; and Rc and Rd are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula 30 (1) wherein A is phenyl; X is NR 9 ; R 5 is LR 6 ; R 6 is cycloalkyl wherein the cycloalkyl is cyclopentyl; L is (CH 2 )mN(R 7
)C(O)N(R)(CH
2 )n; m and n are 0; R 1 and R 2 are independ ently selected from the group consisting of hydrogen and alkoxy; R 3 , R 4 , R 7 , and R 8 are hydrogen; and R 9 is selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula 35 (1) wherein A is phenyl; X is 0; R 5 is LR 6 ; R 6 is heterocyclyl optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NRcRd, (NRcRd)alkyl, and oxo; L is
(CH
2 )mN(R 7
)C(O)N(R)(CH
2 )n; and m, n, Rc, Rd, R 1 , R 2 , R 3 , R 4 , R 7 , and R3 are as de 40 fined in formula (1). In another embodiment, the present invention provides a compound of formula (1) wherein A is phenyl; X is 0; R 5 is LR 6 ; R 6 is heterocyclyl wherein the heterocyclyl is selected from the group consisting of furyl, isoxazolyl, isothiazolyl, oxazolyl, pyridinyl, thiazolyl, and thienyl, wherein the heterocyclyl is optionally substituted with one, two, or 45 three substituents independently selected from the group consisting of alkenyl, alkoxy, WO 2009/050291 PCT/EP2008/064076 15 alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NRcRd, (NRcRd)alkyl, and oxo; L is
(CH
2 )mN(R 7
)C(O)N(R)(CH
2 )n; m and n are 0; R 1 and R 2 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkyl, halo, hydroxy, 5 (NRaRb)alkoxy, (NRaRb)alkyl, and (NRaRb)carbonylalkenyl; R 3 and R 4 are independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkoxy, halo, haloalkoxy, and hydroxy; R 7 and R3 are hydrogen; R" and Rb are independently se lected from the group consisting of hydrogen and alkyl; and Rc and Rd are independ ently selected from the group consisting of hydrogen and alkyl. 10 In another embodiment, the present invention provides a compound of formula (1) wherein A is phenyl; X is 0; R 5 is LR 6 ; R 6 is heterocyclyl wherein the heterocyclyl is thienyl; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 1 and R 2 are independently selected from the group consisting of hydrogen and alkoxy; and R 3 , R 4 , R 7 , and R 8 are hydrogen. 15 In another embodiment, the present invention provides a compound of formula (1) wherein A is phenyl; X is S; R 5 is LR 6 ; R 6 is heterocyclyl optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NRcRd, (NRcRd)alkyl, and oxo; L is 20 (CH 2 )mN(R 7
)C(O)N(R)(CH
2 )n; and m, n, Rc, Rd, R 1 , R 2 , R 3 , R 4 , R 7 , and R 8 are as de fined in formula (1). In another embodiment, the present invention provides a compound of formula (1) wherein A is phenyl; X is S; R 5 is LR 6 ; R 6 is heterocyclyl wherein the heterocyclyl is selected from the group consisting of furyl, isoxazolyl, isothiazolyl, oxazolyl, pyridinyl, 25 thiazolyl, and thienyl, wherein the heterocyclyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NRcRd, (NRcRd)alkyl, and oxo; L is
(CH
2 )mN(R 7
)C(O)N(R)(CH
2 )n; m and n are 0; R 1 and R 2 are independently selected 30 from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkyl, halo, hydroxy, (NRaRb)alkoxy, (NRaRb)alkyl, and (NRaRb)carbonylalkenyl; R 3 and R 4 are independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkoxy, halo, haloalkoxy, and hydroxy; R 7 and R3 are hydrogen; R" and Rb are independently se lected from the group consisting of hydrogen and alkyl; and Rc and Rd are independ 35 ently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula (1) wherein A is phenyl; X is S; R 5 is LR 6 ; R 6 is heterocyclyl wherein the heterocyclyl is thienyl; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 1 and R 2 are independently selected from the group consisting of hydrogen and alkoxy; and R 3 , R 4 , R 7 , and R 8 are 40 hydrogen. In another embodiment, the present invention provides a compound of formula (1) wherein A is phenyl; X is NR 9 ; R 5 is LR 6 ; R 6 is heterocyclyl optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, 45 haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NRcRd, (NRcRd)alkyl, and oxo; L is WO 2009/050291 PCT/EP2008/064076 16
(CH
2 )mN(R 7
)C(O)N(R)(CH
2 )n; and m, n, Rc, Rd, R 1 , R 2 , R 3 , R 4 , R 7 , R", and R 9 are as defined in formula (1). In another embodiment, the present invention provides a compound of formula (1) wherein A is phenyl; X is NR 9 ; R 5 is LR 6 ; R 6 is heterocyclyl wherein the heterocyclyl 5 is selected from the group consisting of furyl, isoxazolyl, isothiazolyl, oxazolyl, pyridinyl, thiazolyl, and thienyl, wherein the heterocyclyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NRcRd, (NRcRd)alkyl, and oxo; L is 10 (CH 2 )mN(R 7
)C(O)N(R)(CH
2 )n; m and n are 0; R 1 and R 2 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkyl, halo, hydroxy, (NRaRb)alkoxy, (NRaRb)alkyl, and (NRaRb)carbonylalkenyl; R 3 and R 4 are independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkoxy, halo, haloalkoxy, and hydroxy; R 7 and R3 are hydrogen; R 9 is selected from the group con 15 sisting of hydrogen and alkyl; R" and Rb are independently selected from the group consisting of hydrogen and alkyl; and Rc and Rd are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula (1) wherein A is phenyl; X is NR 9 ; R 5 is LR 6 ; R 6 is heterocyclyl wherein the heterocyclyl 20 is thienyl; L is (CH 2 )mN(R 7
)C(O)N(R)(CH
2 )n; m and n are 0; R 1 and R 2 are independ ently selected from the group consisting of hydrogen and alkoxy; R 3 , R 4 , R 7 , and R 8 are hydrogen; and R 9 is selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a pharmaceutical com position comprising a compound of formula (1), or a therapeutically acceptable salt 25 thereof, in combination with a therapeutically acceptable carrier. In another embodiment, the present invention provides a method for inhibiting protein kinase in a patient in recognized need of such treatment comprising administer ing to the patient a therapeutically acceptable amount of a compound of formula (1), or a therapeutically acceptable salt thereof. 30 In another embodiment, the present invention provides a method for treating cancer in a patient in recognized need of such treatment comprising administering to the patient a therapeutically acceptable amount of a compound of formula (1), or a therapeutically acceptable salt thereof. In another embodiment, the present invention provides a compound of formula 35 (II) wherein L is CH 2 C(O)NR ; and X, R 1 , R 2 , R 3 , R 4 , R , R 1 0 , and R" are as defined in formula (II). In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 ; L is CH 2
C(O)NR
7 ; and R 1 , R 2 , R 3 , R 4 , R , R 9 , R 1 0 , and R" are as defined in formula (II). 40 In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 ; L is CH 2
C(O)NR
7 ; and R 1 , R 2 , R 3 , R 4 , R , R 9 , R 1 0 , and R" are as defined in formula (II). In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 ; L is CH 2
C(O)NR
7 ; R 1 , R 2 , R 3 , R 4 , and R 7 are hydrogen; R 9 is se 45 lected from the group consisting of hydrogen and alkyl; R 10 and R" are as defined in WO 2009/050291 PCT/EP2008/064076 17 formula (II). In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 ; L is CH 2
C(O)NR
7 ; R 1 , R 2 , R 3 , R 4 , and R 7 are hydrogen; R 9 is se lected from the group consisting of hydrogen and alkyl; R 10 and R" independently se 5 lected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NRcRd, and aryloxy wherein the aryloxy is phenoxy; and Rc and Rd are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula 10 (II) wherein X is NR 9 ; L is CH 2
C(O)NR
7 ; R 1 , R 2 , R 3 , R 4 , and R 7 are hydrogen; R 9 is se lected from the group consisting of hydrogen and alkyl; R 10 and R" independently se lected from the group consisting of hydrogen, alkyl, halo, and haloalkyl. In another embodiment, the present invention provides a compound of formula (II) wherein L is (CH 2 )mN(R 7
)C(O)N(R)(CH
2 )n; and m, n, X, R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 1 0 , 15 and R" are as defined in formula (II). In another embodiment, the present invention provides a compound of for mula(II) wherein X is NR 9 ; and L, R 1 , R 2 , R 3 , R 4 , R 9 , R 10 , and R" are as defined in for mula (II). In another embodiment, the present invention provides a compound of formula 20 (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; and m, n, R 1 , R 2 , R 3 , R 4 , R 7 , R", R 9 , R 1 0 , and R" are as defined in formula (II). In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 7 and R 8 are hydrogen; R 9 is selected from the group consisting of alkoxyalkyl, alkyl, alkylcarbonyl, 25 aryl, heterocyclylalkyl, hydroxyalkyl, and (NRaR )alkyl; and R", Rb, R 1 , R 2 , R 3 , R 4 , R 1 0 , and R" are as defined in formula (II). In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; and R 1 , R 2 , R 3 , R 4 , R 10 , and R" are as defined in formula 30 (II). In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; one of R 1 and R 2 is selected from the group consisting of hydrogen and halo and the other is selected from the group consisting of hydroxy, hy 35 droxyalkyl, and (NRaRb)alkyl; and R", Rb, R 3 , R 4 , R 10 , and R" are as defined in formula (II). In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; one of R 1 and R 2 is selected from the group consisting of 40 hydrogen and halo and the other is selected from the group consisting of hydroxy, hy droxyalkyl, and (NRaRb)alkyl; one of R 3 and R 4 is hydrogen and the other is selected from the group consisting of alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; R 10 and R" are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, 45 haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NRcRd; Ra and Rb are independently se- WO 2009/050291 PCT/EP2008/064076 18 lected from the group consisting of hydrogen and alkyl; and Rc and Rd are independ ently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 1 , R 2 , R 3 , R 7 , 5 R3, and R 9 are hydrogen; R 4 is selected from the group consisting of hydrogen and halo; R 10 and R" are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NRcRd; and Rc and Rd are in dependently selected from the group consisting of hydrogen and alkyl. 10 In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 1 , R 2 , R 3 , R 7 ,
R
8 , and R 9 are hydrogen; R 4 is selected from the group consisting of hydrogen and halo; R 10 and R" are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hy 15 droxyalkyl, nitro, -NRcRd, and aryloxy wherein the aryloxy is phenoxy; and Rc and Rd are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 1 , R 2 , R 3 , R 7 ,
R
8 , and R 9 are hydrogen; R 4 is selected from the group consisting of hydrogen and 20 halo; and R 1 0 and R" are independently selected from the group consisting of hydro gen, alkyl, halo, and haloalkyl. In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 1 , R 2 , R 3 , R 7 , and R3 are hydrogen; R 9 is alkyl; R 4 is selected from the group consisting of hydrogen 25 and halo; R 1 0 and R" are independently selected from the group consisting of hydro gen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NRcRd; and Rc and Rd are in dependently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula 30 (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 1 , R 2 , R 3 , R 7 , and R3 are hydrogen; R 9 is alkyl; R 4 is selected from the group consisting of hydrogen and halo; R 1 0 and R" are independently selected from the group consisting of hydro gen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NRcRd, and aryloxy wherein the aryloxy is phenoxy; and Rc and Rd 35 are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 1 , R 2 , R 3 , R 7 , and R3 are hydrogen; R 9 is alkyl; R 4 is selected from the group consisting of hydrogen and halo; and R 1 0 and R" are independently selected from the group consisting of hy 40 drogen, alkyl, halo, and haloalkyl. In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; one of R 1 and R 2 is hydrogen and the other is halo; and R 3
R
4 , R 1 0 , and R" are as defined in formula (II).
WO 2009/050291 PCT/EP2008/064076 19 In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; one of R 1 and R 2 is hydrogen and the other is halo; R 3 and R4 are independently selected from the group consisting of hydrogen, alkoxyalkoxy, 5 alkyl, halo, haloalkoxy, and hydroxy; R 1 0 and R" are selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NRcRd, and aryloxy wherein the aryloxy is phenoxy; and Rc and Rd are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula 10 (II) wherein X is NR 9 , L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n, m and n are 0, R 7 and R 8 are hydrogen, R 9 is hydrogen, one of R 1 and R 2 is hydrogen and the other is heterocycly lalkoxy; and R 3 , R 4 , R 1 0 , and R" are as defined in formula (II). In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 , L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n, m and n are 0, R 7 and R 8 are 15 hydrogen, R 9 is hydrogen, one of R 1 and R 2 is hydrogen and the other is heterocycly lalkoxy; R 3 and R 4 are independently selected from the group consisting of hydrogen, alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; R 10 and R" are selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NRcRd, and aryloxy wherein the 20 aryloxy is phenoxy; and Rc and Rd are independently selected from the group consist ing of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 , L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n, m and n are 0, R 7 and R 8 are hydrogen, R 9 is hydrogen, one of R 1 and R 2 is hydrogen and the other is heterocycly 25 lalkoxy wherein the heterocyclyl is selected from the group consisting of morpholinyl, piperidinyl, pyridinyl, pyrrolyl, pyrrolidinyl optionally substituted with oxo, and 3,4,4 trimethyl-2,5-dioxo-1-imidazolidinyl; R 3 and R 4 are independently selected from the group consisting of hydrogen, alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; R 10 and R" are selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, 30 alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NRcRd, and aryloxy wherein the aryloxy is phenoxy; and Rc and Rd are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 7 and R 8 are 35 hydrogen; R 9 is hydrogen; one of R 1 and R 2 is hydrogen and the other is selected from the group consisting of (NRaRb)carbonylalkenyl and (NRaRb)alkoxy; and R", Rb, R 3 , R 4 ,
R
1 0 , and R" are as defined in formula (II). In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 7 and R 8 are 40 hydrogen; R 9 is hydrogen; one of R 1 and R 2 is hydrogen and the other is selected from the group consisting of (NRaRb)carbonylalkenyl and (NRaRb)alkoxy; R 3 and R 4 are in dependently selected from the group consisting of hydrogen, alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; R 1 0 and R" are selected from the group consisting of hydro gen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, 45 hydroxyalkyl, nitro, -NRcRd, and aryloxy wherein the aryloxy is phenoxy; R" and Rb are WO 2009/050291 PCT/EP2008/064076 20 independently selected from the group consisting of hydrogen, alkyl, alkylsulfonyl, aryl sulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; and Rc and Rd are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula 5 (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; one of R 1 and R 2 is hydrogen and the other is selected from the group consisting of (NRaRb)carbonylalkenyl and (NRaRb)alkoxy; R 3 and R 4 are in dependently selected from the group consisting of hydrogen, alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; R 1 0 and R" are selected from the group consisting of hydro 10 gen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NRcRd, and aryloxy wherein the aryloxy is phenoxy; R" and Rb are independently selected from the group consisting of hydrogen, alkyl, alkylsulfonyl, aryl sulfonyl wherein the aryl is phenyl, haloalkylsulfonyl, and heterocyclylsulfonyl wherein the heterocyclyl is thienyl; and Rc and Rd are independently selected from the group 15 consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; one of R 1 and R 2 is hydrogen and the other is selected from the group consisting of aryloxyalkyl, heterocyclyl, heterocyclylalkyl and heterocycly 20 loxyalkyl; and R 3 , R 4 , R 10 , and R" are as defined in formula (II). In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; one of R 1 and R 2 is hydrogen and the other is selected from the group consisting of aryloxyalkyl, heterocyclyl, heterocyclylalkyl and heterocycly 25 loxyalkyl; R 3 and R 4 are independently selected from the group consisting of hydrogen, alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; R 10 and R" are selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NRcRd, and aryloxy wherein the aryloxy is phenoxy; and Rc and Rd are independently selected from the group consist 30 ing of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; one of R 1 and R 2 is hydrogen and the other is aryloxyalkyl wherein the aryl is phenyl optionally substituted with halo; R 3 and R 4 are independently 35 selected from the group consisting of hydrogen, alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; R 10 and R" are selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyal kyl, nitro, -NRcRd, and aryloxy wherein the aryloxy is phenoxy; and Rc and Rd are inde pendently selected from the group consisting of hydrogen and alkyl. 40 In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; one of R 1 and R 2 is hydrogen and the other is heterocyclyl wherein the heterocyclyl is selected from the group consisting of pyridinyl and thienyl;
R
3 and R 4 are independently selected from the group consisting of hydrogen, 45 alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; R 10 and R" are selected from the WO 2009/050291 PCT/EP2008/064076 21 group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NRcRd, and aryloxy wherein the aryloxy is phenoxy; and Rc and Rd are independently selected from the group consist ing of hydrogen and alkyl. 5 In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; one of R 1 and R 2 is hydrogen and the other is heterocycly lalkyl wherein the heterocyclyl is selected from the group consisting of morpholinyl and piperazinyl wherein the piperazinyl is optionally substituted with alkyl; R 3 and R 4 are 10 independently selected from the group consisting of hydrogen, alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; R 10 and R" are selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NRcRd, and aryloxy wherein the aryloxy is phenoxy; and Rc and Rd are independently selected from the group consisting of hydrogen and alkyl. 15 In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; one of R 1 and R 2 is hydrogen and the other is heterocycly loxyalkyl wherein the heterocyclyl is pyridinyl; R 3 and R 4 are independently selected from the group consisting of hydrogen, alkoxyalkoxy, alkyl, halo, haloalkoxy, and hy 20 droxy; R 10 and R" are selected from the group consisting of hydrogen, alkoxy, alkoxy carbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, ni tro, -NRcRd, and aryloxy wherein the aryloxy is phenoxy; and Rc and Rd are independ ently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula 25 (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; one of R 1 and R 2 is hydrogen and the other is selected from the group consisting of alkoxy, alkoxyalkoxy, and alkyl; and R 3 , R 4 , R 1 0 , and R" are as defined in formula (II). In another embodiment, the present invention provides a compound of formula 30 (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; one of R 1 and R 2 is hydrogen and the other is selected from the group consisting of alkoxy, alkoxyalkoxy, and alkyl; R 3 and R 4 are independently selected from the group consisting of hydrogen, alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; R 10 and R" are selected from the group consisting of hydrogen, alkoxy, 35 alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyal kyl, nitro, -NRcRd, and aryloxy wherein the aryloxy is phenoxy; and Rc and Rd are inde pendently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 7 and R 8 are 40 hydrogen; R 9 is hydrogen; R 1 and R 2 are hydrogen; and R 3 , R 4 , R 1 0 , and R" are as defined in formula (II). In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; R 1 and R 2 are hydrogen; one of R 3 and R 4 is hydrogen and WO 2009/050291 PCT/EP2008/064076 22 the other is selected from the group consisting of alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; and R 10 and R" are as defined in formula (II). In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 7 and R 8 are 5 hydrogen; R 9 is hydrogen; R 1 and R 2 are hydrogen; one of R 3 and R 4 is hydrogen and the other is selected from the group consisting of alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; and R 10 and R" are selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hy droxyalkyl, nitro, -NRcRd, and aryloxy wherein the aryloxy is phenoxy; and Rc and Rd 10 are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; R 1 and R 2 are hydrogen; R 3 and R 4 are hydrogen; and R 10 and R" are as defined in formula (II). 15 In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; R 1 and R 2 are hydrogen; R 3 and R 4 are hydrogen; and R 10 and R" are selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NRcRd, 20 and aryloxy wherein the aryloxy is phenoxy; and Rc and Rd are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; R 1 and R 2 are hydrogen; R 3 and R 4 are alkyl; and R 1 0 and 25 R" are selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NRcRd, and aryloxy wherein the aryloxy is phenoxy; and Rc and Rd are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula 30 (II) wherein R 1 and R 2 are independently selected from the group consisting of hydro gen, alkoxy, alkoxyalkoxy, alkoxyalkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, (NRaRb)alkoxy, (NRaRb)alkenyl, (NRaRb)alkyl, (NRaRb)carbonylalkenyl, and (NRaRb)carbonylalkyl; and X, L, Ra, Rb, R 3 , R 4 , R 1 0 , and R" are as defined in formula (II). 35 In another embodiment, the present invention provides a compound of for mula(II) wherein X is 0 and L, R 1 , R 2 , R 3 , R 4 , R 1 0 , and R" are as defined in formula (II). In another embodiment, the present invention provides a compound of formula (II) wherein X is 0; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; and m, n, R 1 , R 2 , R 3 , R 4 , R 7 , R 8 ,
R
1 0 , and R" are as defined in formula (II). 40 In another embodiment, the present invention provides a compound of formula (II) wherein X is 0; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 1 , R 2 , R 3 , R 4 , R 7 , and R3 are hydrogen; R 10 and R" are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NRaRb; and Ra 45 and Rb are independently selected from the group consisting of hydrogen and alkyl.
WO 2009/050291 PCT/EP2008/064076 23 In another embodiment, the present invention provides a compound of formula (II) wherein X is 0; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 1 , R 2 , R 3 , R 4 , R 7 , and R3 are hydrogen; R 10 and R" are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, 5 hydroxy, hydroxyalkyl, nitro, -NRaRb, and aryloxy wherein the aryloxy is phenoxy; and Ra and Rb are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula (II) wherein X is 0; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 1 is heterocycly lalkoxy; R 2 , R 3 , R 4 , R 7 , and R3 are hydrogen; R 10 and R" are independently selected 10 from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, ary loxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NRaRb; and Ra and Rb are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula 15 (II) wherein X is 0; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 1 is heterocycly lalkoxy wherein the heterocyclyl is morpholinyl; R 2 , R 3 , R 4 , R 7 , and R" are hydrogen;
R
1 0 and R" are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyal kyl, nitro, -NRaRb, and aryloxy wherein the aryloxy is phenoxy; and R" and Rb are inde 20 pendently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula (II) wherein X is 0; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 1 is selected from the group consisting of alkoxy, alkyl, halo, and haloalkoxy; R 2 , R 3 , R 4 , R 7 , and R" are hydrogen; R 10 and R" are independently selected from the group consisting of hy 25 drogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hy droxy, hydroxyalkyl, nitro, -NRaRb, and aryloxy wherein the aryloxy is phenoxy; and R" and Rb are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of for mula(II) wherein X is S and L, R 1 , R 2 , R 3 , R 4 , R 1 0 , and R" are as defined in formula (II). 30 In another embodiment, the present invention provides a compound of formula (II) wherein X is S; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; and m, n, R 1 , R 2 , R 3 , R 4 , R 7 , R 8 ,
R
1 0 , and R" are as defined in formula (II). In another embodiment, the present invention provides a compound of formula (II) wherein X is S; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 1 , R 2 , R 3 , R 4 , R 7 , 35 and R3 are hydrogen; R 10 and R" are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NRaRb; and Ra and Rb are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula 40 (II) wherein X is S; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 1 , R 2 , R 3 , R 4 , R 7 , and R3 are hydrogen; R 10 and R" are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NRaRb, and aryloxy wherein the aryloxy is phenoxy; and Ra and Rb are independently selected from the group consisting of hydrogen and alkyl..
WO 2009/050291 PCT/EP2008/064076 24 In another embodiment, the present invention provides a compound of formula (II) wherein X is S; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 1 , R 2 , R 3 , R 4 , R 7 , and R3 are hydrogen; and R 10 and R" are independently selected from the group con sisting of hydrogen, alkyl, halo, and haloalkyl. 5 In another embodiment, the present invention provides a compound of formula (II) wherein X is S; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 1 is heterocycly lalkoxy; R 2 , R 3 , R 4 , R 7 , and R3 are hydrogen; R 10 and R" are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, ary loxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, 10 and -NRaRb; and Ra and Rb are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula (II) wherein X is S; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 1 is heterocycly lalkoxy wherein the heterocyclyl is morpholinyl; R 2 , R 3 , R 4 , R 7 , and R" are hydrogen; 15 R 1 0 and R" are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyal kyl, nitro, -NRaRb, and aryloxy wherein the aryloxy is phenoxy; and R" and Rb are inde pendently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a compound of formula 20 (II) wherein X is S; L is (CH 2 )mN(R 7
)C(O)N(R")(CH
2 )n; m and n are 0; R 1 is selected from the group consisting of alkoxy, alkyl, halo, and haloalkoxy; R 2 , R 3 , R 4 , R 7 , and R" are hydrogen; R 1 0 and R" are independently selected from the group consisting of hy drogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hy droxy, hydroxyalkyl, nitro, -NRaRb, and aryloxy wherein the aryloxy is phenoxy; and R" 25 and Rb are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the present invention provides a pharmaceutical com position comprising a compound of formula (II), or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier. In another embodiment, the present invention provides a method for inhibiting 30 protein kinase in a patient in recognized need of such treatment comprising administer ing to the patient a therapeutically acceptable amount of a compound of formula (II), or a therapeutically acceptable salt thereof. In another embodiment, the present invention provides a method for treating cancer in a patient in recognized need of such treatment comprising administering to 35 the patient a therapeutically acceptable amount of a compound of formula (II), or a therapeutically acceptable salt thereof. As used in the present specification the following terms have the meanings indi cated: 40 The term "alkenyl," as used herein, refers to a straight or branched chain group of two to six carbon atoms containing at least one carbon-carbon double bond. The term "alkoxy," as used herein, refers to an alkyl group attached to the par ent molecular moiety through an oxygen atom. The term "alkoxyalkoxy," as used herein, refers to an alkoxy group attached to 45 the parent molecular moiety through another alkoxy group.
WO 2009/050291 PCT/EP2008/064076 25 The term "alkoxyalkyl," as used herein, refers to an alkyl group substituted with at least one alkoxy group. The term "alkoxycarbonyl," as used herein, refers to an alkoxy group attached to the parent molecular moiety through a carbonyl group. 5 The term "alkyl," as used herein, refers to a group derived from a straight or branched chain saturated hydrocarbon of one to six carbon atoms. Preferred alkyl groups of the present invention are of one to three carbon atoms. Most preferred alkyl groups are methyl and ethyl. The term "alkylcarbonyl," as used herein, refers to an alkyl group attached to 10 the parent molecular moiety through a carbonyl group. The term "alkylsulfonyl," as used herein, refers to an alkyl group attached to the parent molecular moiety through a sulfonyl group. The term "aryl," as used herein, refers to a phenyl group, or a bicyclic or tricyclic fused ring system wherein one or more of the fused rings is a phenyl group. Bicyclic 15 fused ring systems are exemplified by a phenyl group fused to a monocyclic cycloal kenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or another phenyl group. Tricyclic fused ring systems are exemplified by a bicyclic fused ring system fused to a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or another phenyl group. Aryl groups include, but 20 are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. The aryl groups of the present invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, 25 haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, NRcRd, (NRcRd)alkyl, and oxo; wherein the second aryl group, the aryl part of the ary lalkoxy, the arylalkyl, and the aryloxy, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl can be further optionally substituted with one, two, three, four, or five groups independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, 30 alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and oxo. The term "arylalkyl," as used herein, refers to an alkyl group substituted with at least one aryl group. The term "arylcarbonyl," as used herein, refers to an aryl group attached to the parent molecular moiety through a carbonyl group. 35 The term "arylalkoxy," as used herein, refers to an aryl group attached to the parent molecular moiety through an alkoxy group. The term "aryloxy," as used herein, refers to an aryl group attached to the par ent molecular moiety through an oxygen atom. The term "aryloxyalkyl," as used herein, refers to an aryloxy group attached to 40 the parent molecular moiety through an alkyl group. The term "arylsulfonyl," as used herein, refers to an aryl group attached to the parent molecular moiety through a sulfonyl group. The term "carbonyl," as used herein, refers to -C(0)-. The term "carboxy," as used herein, refers to -CO 2 H. 45 The term "cyano," as used herein, refers to -CN.
WO 2009/050291 PCT/EP2008/064076 26 The term "cycloalkenyl," as used herein, refers to a non-aromatic cyclic or bi cyclic ring system having three to ten carbon atoms and one to three rings, wherein each five-membered ring has one double bond, each six-membered ring has one or two double bonds, each seven- and eight-membered ring has one to three double 5 bonds, and each nine-to ten-membered ring has one to four double bonds. Examples of cycloalkenyl groups include, but are not limited to, cyclohexenyl, octahydronaphtha lenyl, and norbornylenyl. The term "cycloalkyl," as used herein, refers to a saturated monocyclic, bicyclic, or tricyclic hydrocarbon ring system having three to twelve carbon atoms. Examples of 10 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, bicyclo[3.1.1]heptyl, and adamantyl. The cycloalkyl groups of the present invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group con sisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, 15 cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NRcRd, (NRcRd)alkyl, and oxo. The terms "halo," and "halogen," as used herein, refer to F, Cl, Br, and I. The term "haloalkoxy," as used herein, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom. 20 The term "haloalkyl," as used herein, refers to an alkyl group substituted by one, two, three, or four halogen atoms. The term "haloalkylsulfonyl," as used herein, refers to a haloalkyl group at tached to the parent molecular moiety through a sulfonyl group. The term "heterocyclyl," as used herein, represents a monocyclic, bicyclic, or 25 tricyclic ring system wherein one or more rings is a four-, five-, six-, or seven membered ring containing one, two, or three heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Monocyclic ring systems are ex emplified by any 3- or 4-membered ring containing a heteroatom independently se lected from the group consisting of oxygen, nitrogen and sulfur; or a 5-, 6- or 7 30 membered ring containing one, two or three heteroatoms wherein the heteroatoms are independently selected from the group consisting of nitrogen, oxygen and sulfur. The 3- and 4-membered rings have no double bonds, the 5-membered ring has from 0-2 double bonds and the 6- and 7-membered rings have from 0-3 double bonds. Repre sentative examples of monocyclic ring systems include, but are not limited to, 35 azetidine, azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane, furan, imida zole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine, oxadiazole, oxadiazoline, oxadiazolidine, oxa zole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyra zoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, tet 40 rahydrofuran, tetrahydrothiophene, tetrazine, tetrazole, thiadiazole, thiadiazoline, thiadiazolidine, thiazole, thiazoline, thiazolidine, thiophene, thiomorpholine, thiomor pholine sulfone, thiopyran, triazine, triazole, and trithiane. Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to phenyl ring, a mono cyclic cycloalkyl group as defined herein, a monocyclic cycloalkenyl group, as defined 45 herein, or another monocyclic heterocyclyl ring system. Representative examples of WO 2009/050291 PCT/EP2008/064076 27 bicyclic ring systems include but are not limited to, benzimidazole, benzothiazole, ben zothiophene, benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxine, 1,3-benzodioxole, cinnoline, dihydrobenzimidazole, indazole, indole, indoline, indoliz ine, naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquino 5 line, phthalazine, pyranopyridine, quinoline, quinolizine, quinoxaline, quinazoline, tetra hydroisoquinoline, tetrahydroquinoline, and thiopyranopyridine. Tricyclic rings systems are exemplified by any of the above bicyclic ring systems fused to a phenyl ring, a monocyclic cycloalkyl group as defined herein, a monocyclic cycloalkenyl group as defined herein, or another monocyclic heterocyclyl ring system. Representative exam 10 ples of tricyclic ring systems include, but are not limited to, acridine, carbazole, car boline, dibenzofuran, dibenzothiophene, naphthofuran, naphthothiophene, oxanthrene, phenazine, phenoxathin, phenoxazine, phenothiazine, thianthrene, thioxanthene, and xanthene. Heterocyclyl groups can be attached to the parent molecular moiety through a carbon atom or a nitrogen atom in the group. 15 The heterocyclyl groups of the present invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, ary lalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NRcRd, 20 (NRcRd)alkyl, and oxo; wherein the aryl, the aryl part of the arylalkoxy, the arylalkyl, and the aryloxy, the second heterocyclyl group, and the heterocyclyl part of the heterocycly lalkyl can be further optionally substituted with one, two, three, four, or five groups in dependently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and oxo. 25 The term "heterocyclylalkenyl," as used herein, refers to an alkenyl group sub stituted with at least one heterocyclyl group. The term "heterocyclylalkoxy," as used herein, refers to a heterocyclyl group attached to the parent molecular moiety through an alkoxy group. The term "heterocyclylalkyl," as used herein, refers to an alkyl group substituted 30 with at least one heterocyclyl group. The term "heterocyclyloxy," as used herein, refers to a heterocyclyl group at tached to the parent molecular moiety through an oxygen atom. The term "heterocyclyloxyalkyl," as used herein, refers to an alkyl group substi tuted with at least one heterocyclyloxy group. 35 The term "heterocyclylsulfonyl," as used herein, refers to a heterocyclyl group attached to the parent molecular moiety through a sulfonyl group. The term "hydroxy," as used herein, refers to -OH. The term "hydroxyalkoxy," as used herein, refers to a hydroxy group attached to the parent molecular moiety through an alkoxy group. 40 The term "hydroxyalkyl," as used herein, refers to an alkyl group substituted with at least one hydroxy group. The term "nitro," as used herein, refers to -NO 2 . The term "-NRaR " as used herein, represents two groups, Ra and Rb, which are attached to the parent molecular moiety through a nitrogen atom. Ra and Rb are 45 independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcar- WO 2009/050291 PCT/EP2008/064076 28 bonyl, alkylsulfonyl, aryl, arylalkyl, arylcarbonyl, arylsulfonyl, haloalkylsulfonyl, cycloal kyl, heterocyclyl, heterocyclylalkyl, and heterocyclylsulfonyl, wherein the aryl, the aryl part of the arylalkyl and the arylcarbonyl, the heterocyclyl, the heterocyclyl part of the heterocyclylalkyl and the heterocyclylsulfonyl can be further optionally substituted with 5 one, two, three, four, or five substituents independently selected from the group con sisting of alkenyl, alkoxy, alkyl, cyano, halo, haloalkyl, haloalkoxy, nitro, and oxo. The term "(NRaRb)alkenyl," as used herein, represents an alkenyl group substi tuted with at least one -NRaRb group. The term "(NRaRb)alkoxy," as used herein, represents an -NRaRb group at 10 tached to the parent molecular moiety through an alkoxy group. The term "(NRaRb)alkyl," as used herein, represents an alkyl group substituted with at least one -NRaRb group. The term "(NRaRb)alkynyl," as used herein, represents an alkynyl group substi tuted with at least one -NRaRb group. 15 The term "(NRaRb)carbonyl," as used herein, represents an (NRaRb) group at tached to the parent molecular moiety through a carbonyl group. The term "(NRaRb)carbonylalkenyl," as used herein, represents an alkenyl group substituted with at least one (NRaRb)carbonyl group. The term "(NRaRb)carbonylalkyl," as used herein, represents an alkyl group 20 substituted with at least one (NRaRb)carbonyl group. The term "-NRcR," as used herein, represents two groups, Rc and Rd, which are attached to the parent molecular moiety through a nitrogen atom. Rc and Rd are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, wherein the 25 aryl, the aryl part of the arylalkyl, the heterocyclyl, and the heterocyclyl part of the het erocyclylalkyl can be further optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkyl, cyano, halo, haloalkyl, haloalkoxy, nitro, and oxo. The term "(NRcRd)alkyl," as used herein, represents an alkyl group substituted 30 with at least one -NRcRd group. The term "oxo," as used herein, refers to =0. The term "sulfonyl," as used herein, refers to -SO 2 . The compounds of the present invention can exist as therapeutically acceptable salts. The term "therapeutically acceptable salt," as used herein, represents salts or 35 zwitterionic forms of the compounds of the present invention which are water or oil soluble or dispersible, which are suitable for treatment of diseases without undue toxic ity, irritation, and allergic response; which are commensurate with a reasonable bene fit/risk ratio, and which are effective for their intended use. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting an 40 -NRaRb group with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, hep tanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2 hydroxyethansulfonate, lactate, maleate, mesitylenesulfonate, methanesulfonate, 45 naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, WO 2009/050291 PCT/EP2008/064076 29 persulfate, 3-phenylproprionate, picrate, pivalate, propionate, succinate, tartrate, tri chloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para toluenesulfonate, and undecanoate. Also, -NRaRb groups in the compounds of the present invention can be quaternized with methyl, ethyl, propyl, and butyl chlorides, 5 bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bro mides. Examples of acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. 10 The present compounds can also exist as therapeutically acceptable prodrugs. The term "therapeutically acceptable prodrug," refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use. The term "prodrug," refers to compounds 15 which are rapidly transformed in vivo to parent compounds of formula (1) or (II) for ex ample, by hydrolysis in blood. Representative compounds of formulas (1) and (II) are: N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea; 20 N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(3,5-dimethoxyphenyl)urea; N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea; N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea; N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea; N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea; 25 N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea; N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(3-bromo-4-methylphenyl)urea; N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(3-ethylphenyl)urea; N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-phenylurea; N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(3-fluoro-4-methylphenyl)urea; 30 N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(2-fluorophenyl)urea; N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(4-fluorophenyl)urea; N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea; N-{4-[3-amino-7-(4-morpholinylmethyl)-1 H-indazol-4-yl]phenyl}-N'-(3-fluorophenyl)urea; N-{4-[3-amino-7-(4-morpholinylmethyl)-1 H-indazol-4-yl]phenyl}-N'-(3 35 methylphenyl)urea; N-{4-[3-amino-7-(4-morpholinylmethyl)-1 H-indazol-4-yl]phenyl}-N'-[2-fluoro-5 (trifluoromethyl)phenyl]urea; N-{4-[3-amino-7-(4-morpholinylmethyl)-1 H-indazol-4-yl]phenyl}-N'-[4-fluoro-3 (trifluoromethyl)phenyl]urea; 40 N-{4-[3-amino-7-(4-morpholinylmethyl)-1 H-indazol-4-yl]phenyl}-N'-[3 (trifluoromethyl)phenyl]urea; N-(4-{3-amino-7-[(4-methyl-1 -piperazinyl)methyl]-1 H-indazol-4-yl}phenyl)-N'-(3 chlorophenyl)urea; N-(4-{3-amino-7-[(4-methyl-1 -piperazinyl)methyl]-1 H-indazol-4-yl}phenyl)-N'-(3 45 methylphenyl)urea; WO 2009/050291 PCT/EP2008/064076 30 N-(4-{3-amino-7-[(4-methyl-1 -piperazinyl)methyl]-1 H-indazol-4-yl}phenyl)-N'-(3 fluorophenyl)urea; N-(4-{3-amino-7-[(4-methyl-1 -piperazinyl)methyl]-1 H-indazol-4-yl}phenyl)-N'-[3 (trifluoromethyl)phenyl]u rea; 5 N-(4-{3-amino-7-[(4-methyl-1 -piperazinyl)methyl]-1 H-indazol-4-yl}phenyl)-N'-[2-fluoro-5 (trifluoromethyl)phenyl]u rea; N-(4-{3-amino-7-[(4-methyl-1 -piperazinyl)methyl]-1 H-indazol-4-yl}phenyl)-N'-(2-fluoro-5 methylphenyl)urea; N-[4-(3-amino-7-fluoro-1 H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea; 10 N-[4-(3-amino-7-fluoro-1 H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea; N-[4-(3-amino-7-fluoro-1 H-indazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea; N-[4-(3-amino-7-fluoro-1 H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea; N-[4-(3-amino-7-fluoro-1 H-indazol-4-yl)phenyl]-N'-(3-cyanophenyl)urea; N-(4-{3-amino-7-[(dimethylamino)methyl]-1 H-indazol-4-yl}phenyl)-N'-(2-fluoro-5 15 methylphenyl)urea; N-(4-{3-amino-7-[(dimethylamino)methyl]-1 H-indazol-4-yl}phenyl)-N'-(3 chlorophenyl)urea; N-(4-{3-amino-7-[(dimethylamino)methyl]-1 H-indazol-4-yl}phenyl)-N'-[3 (trifluoromethyl)phenyl]urea; 20 N-[4-(3-amino-1 -methyl-1 H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea; N-[4-(3-amino-1 -methyl-1 H-indazol-4-yl)phenyl]-N'-phenylurea; N-[4-(3-amino-1 -methyl-1 H-indazol-4-yl)phenyl]-N'-(2-methylphenyl)urea; N-[4-(3-amino-1 -methyl-1 H-indazol-4-yl)phenyl]-N'-(4-methylphenyl)urea; N-[4-(3-amino-1 -methyl-1 H-indazol-4-yl)phenyl]-N'-(3-methoxyphenyl)urea; 25 N-[4-(3-amino-1 -methyl-1 H-indazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea; N-[4-(3-amino-1 -methyl-1 H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea; N-[4-(3-amino-1 -methyl-1 H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea; N-[4-(3-amino-1 -methyl-1 H-indazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea; N-[4-(3-amino-1 -methyl-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea; 30 N-[4-(3-amino-1 H-indazol-4-yl)-2-fluorophenyl]-N'-(3-methylphenyl)urea; N-[4-(3-amino-1 H-indazol-4-yl)-2-fluorophenyl]-N'-(3-fluorophenyl)urea; N-[4-(3-amino-1 H-indazol-4-yl)-2-fluorophenyl]-N'-(3,5-dimethylphenyl)urea; N-[4-(3-amino-1 H-indazol-4-yl)-2-fluorophenyl]-N'-(3-ethylphenyl)urea; N-[4-(3-amino-1 H-indazol-4-yl)-2-fluorophenyl]-N'-(3-chloro-4-fluorophenyl)urea; 35 N-[4-(3-amino-1 H-indazol-4-yl)-2-fluorophenyl]-N'-(3-fluoro-4-methylphenyl)urea; N-[4-(3-amino-1 H-indazol-4-yl)-2-fluorophenyl]-N'-(3-chlorophenyl)urea; N-[4-(3-amino-7-bromo-1 H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea; N-{4-[3-amino-1 -(2-hydroxyethyl)-1 H-indazol-4-yl]phenyl}-N'-(3-methylphenyl)urea; 2-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N-phenylacetamide; 40 2-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N-(3-chlorophenyl)acetamide; 2-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N-(4-fluoro-3-methylphenyl)acetamide; 2-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N-[3-(trifluoromethyl)phenyl]acetamide; 2-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N-(3-methylphenyl)acetamide; N-[4-(3-amino-7-methoxy-1 H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea; WO 2009/050291 PCT/EP2008/064076 31 N-[4-(3-amino-7-methoxy-1 H-indazol-4-yl)phenyl]-N'-[2-fluoro-5 (trifluoromethyl)phenyl]urea; N-[4-(3-amino-7-methoxy-1 H-indazol-4-yl)phenyl]-N'-phenylurea; N-[4-(3-amino-7-methoxy-1 H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea; 5 N-[4-(3-amino-7-methoxy-1 H-indazol-4-yl)phenyl]-N'-(3-ethylphenyl)urea; N-[4-(3-amino-7-methoxy-1 H-indazol-4-yl)phenyl]-N'-(3-fluoro-4-methylphenyl)urea; N-[4-(3-amino-7-methoxy-1 H-indazol-4-yl)phenyl]-N'-[4-fluoro-3 (trifluoromethyl)phenyl]urea; N-[4-(3-amino-7-methoxy-1 H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea; 10 N-[4-(3-amino-7-methoxy-1 H-indazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea; N-[4-(3-amino-7-methoxy-1 H-indazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea; N-{4-[3-amino-7-(2-methoxyethoxy)-1 H-indazol-4-yl]phenyl}-N'-(3-methylphenyl)urea; N-{4-[3-amino-7-(2-methoxyethoxy)-1 H-indazol-4-yl]phenyl}-N'-phenylurea; N-{4-[3-amino-7-(2-methoxyethoxy)-1 H-indazol-4-yl]phenyl}-N'-(3-fluorophenyl)urea; 15 N-{4-[3-amino-7-(2-methoxyethoxy)-1 H-indazol-4-yl]phenyl}-N'-(3-bromophenyl)urea; N-{4-[3-amino-7-(2-methoxyethoxy)-1 H-indazol-4-yl]phenyl}-N'-(3-chlorophenyl)urea; N-{4-[3-amino-7-(2-methoxyethoxy)-1 H-indazol-4-yl]phenyl}-N'-[3 (trifluoromethyl)phenyl]urea; N-{4-[3-amino-7-(2-methoxyethoxy)-1 H-indazol-4-yl]phenyl}-N'-[2-fluoro-5 20 (trifluoromethyl)phenyl]urea; N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3 methylphenyl)urea; N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-phenylurea; N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3 25 fluorophenyl)urea; N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3 bromophenyl)urea; N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3 ethylphenyl)urea; 30 N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-[2-fluoro-5 (trifluoromethyl)phenyl]urea; N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-[4-fluoro-3 (trifluoromethyl)phenyl]urea; N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3 35 chlorophenyl)urea; N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-[3 (trifluoromethyl)phenyl]urea; (2E)-3-{3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1 H-indazol-7 yl}-NN-dimethylacrylamide; 40 (2E)-3-{3-amino-4-[4-({[(3-chlorophenyl)amino]carbonyl}amino)phenyl]-1 H-indazol-7 yl}-NN-dimethylacrylamide; (2E)-3-(3-amino-4-{4-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-1 H indazol-7-yl)-NN-dimethylacrylamide; N-(4-{3-amino-7-[2-(dimethylamino)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-phenylurea; WO 2009/050291 PCT/EP2008/064076 32 N-(4-{3-amino-7-[2-(dimethylamino)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3 bromophenyl)urea; N-(4-{3-amino-7-[2-(dimethylamino)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3 methylphenyl)urea; 5 N-(4-{3-amino-7-[2-(dimethylamino)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3 chlorophenyl)urea; N-(4-{3-amino-7-[2-(2-oxo-1 -pyrrolidinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3 methylphenyl)urea; 2-[4-(3-amino-1 -methyl-1 H-indazol-4-yl)phenyl]-N-(3-methylphenyl)acetamide. 10 N-[4-(3-amino-1 H-indazol-4-yl)-2-methylphenyl]-N'-(3-methylphenyl)urea; N-(4-{3-amino-7-[2-(2-oxo-1 -pyrrolidinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3 chlorophenyl)urea; N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methylphenyl)urea; N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-(trifluoromethyl)phenyl]urea; 15 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea; N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea; N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-fluoro-5 (trifluoromethyl)phenyl]urea; 20 N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methylphenyl)urea; N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-[3 (trifluoromethyl)phenyl]urea; N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea; N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(2-fluoro-5 25 methylphenyl)urea; N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-[2-fluoro-5 (trifluoromethyl)phenyl]urea; N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-[3 (trifluoromethyl)phenyl]urea; 30 N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3 chlorophenyl)urea; N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3 methylphenyl)urea; N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-(2-fluoro-5 35 methylphenyl)urea; N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3,5 dimethylphenyl)urea; N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3 phenoxyphenyl)urea; 40 N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3 bromophenyl)urea; N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-4-yl}phenyl)-N'-[3 (trifluoromethyl)phenyl]urea; N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-4-yl}phenyl)-N'-(2-fluoro-5 45 methylphenyl)urea; WO 2009/050291 PCT/EP2008/064076 33 N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-4-yl}phenyl)-N'-[2-fluoro-5 (trifluoromethyl)phenyl]urea; N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-4-yl}phenyl)-N'-(3 methylphenyl)urea; 5 N-{4-[3-amino-7-(2-methoxyethoxy)-1 H-indazol-4-yl]phenyl}-N'-(2-fluoro-5 methylphenyl)urea; N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(2-fluoro-5 methylphenyl)urea; N-{4-[3-amino-7-(methoxymethoxy)-1 H-indazol-4-yl]phenyl}-N'-(2-fluoro-5 10 methylphenyl)urea; N-[4-(3-amino-7-hydroxy-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea; N-[4-(3-amino-7-hydroxy-1 H-indazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea; N-[4-(3-amino-7-hydroxy-1 H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea; N-[4-(3-amino-7-hydroxy-1 H-indazol-4-yl)phenyl]-N'-(3-ethylphenyl)urea; 15 N-[4-(3-amino-7-hydroxy-1 H-indazol-4-yl)phenyl]-N'-[2-fluoro-5 (trifluoromethyl)phenyl]urea; N-[4-(3-amino-7-hydroxy-1 H-indazol-4-yl)phenyl]-N'-[4-fluoro-3 (trifluoromethyl)phenyl]urea; N-[4-(3-amino-7-hydroxy-1 H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea; 20 N-[4-(3-amino-7-hydroxy-1 H-indazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea; N-[4-(3-amino-7-hydroxy-1 H-indazol-4-yl)phenyl]-N'-phenylurea; N-(4-{3-amino-7-[2-(1 -pyrrolidinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-phenylurea; N-(4-{3-amino-7-[2-(1 -pyrrolidinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3 fluorophenyl)urea; 25 N-(4-{3-amino-7-[2-(1 -pyrrolidinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(2-fluoro-5 methylphenyl)urea; N-(4-{3-amino-7-[2-(1 -pyrrolidinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3 methylphenyl)urea; N-(4-{3-amino-7-[2-(1 -pyrrolidinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3 30 bromophenyl)urea; N-(4-{3-amino-7-[2-(1 -pyrrolidinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-[2-fluoro-5 (trifluoromethyl)phenyl]urea; N-(4-{3-amino-7-[2-(1 -pyrrolidinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3 chlorophenyl)urea; 35 N-(4-{3-amino-7-[2-(1 -pyrrolidinyl)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-[3 (trifluoromethyl)phenyl]urea; N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-phenylurea; N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3 fluorophenyl)urea; 40 N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(2-fluoro-5 methylphenyl)urea; N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3 methylphenyl)urea; N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3 45 bromophenyl)urea; WO 2009/050291 PCT/EP2008/064076 34 N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-[2-fluoro-5 (trifluoromethyl)phenyl]urea; N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-(3 chlorophenyl)urea; 5 N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1 H-indazol-4-yl}phenyl)-N'-[3 (trifluoromethyl)phenyl]urea; N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxo-1 -imidazolidinyl)ethoxy]-1 H-indazol-4 yl}phenyl)-N'-(3-methylphenyl)urea; N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxo-1 -imidazolidinyl)ethoxy]-1 H-indazol-4 10 yl}phenyl)-N'-(3-chlorophenyl)urea; N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxo-1 -imidazolidinyl)ethoxy]-1 H-indazol-4 yl}phenyl)-N'-(2-fluoro-5-methylphenyl)urea; N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxo-1 -imidazolidinyl)ethoxy]-1 H-indazol-4 yl}phenyl)-N'-[3-(trifluoromethyl)phenyl]urea; 15 N-[4-(3-amino-1 H-indazol-4-yl)-2-ethylphenyl]-N'-(2-fluoro-5-methylphenyl)urea; N-[4-(3-amino-1 H-indazol-4-yl)-2-ethylphenyl]-N'-[3-(trifluoromethyl)phenyl]urea; N-[4-(3-amino-7-fluoro-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea; N-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1 H-indazol-4-yl]phenyl}-N'-(2-fluoro-5 methylphenyl)urea; 20 N-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1 H-indazol-4-yl]phenyl}-N'-[3 (trifluoromethyl)phenyl]urea; N-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1 H-indazol-4-yl]phenyl}-N'-(3 chlorophenyl)urea; N-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1 H-indazol-4-yl]phenyl}-N'-(3 25 methylphenyl)urea; N-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1 H-indazol-4-yl]phenyl}-N'-(3 fluorophenyl)urea; N-(4-{3-amino-6-[(diethylamino)methyl]-7-fluoro-1 H-indazol-4-yl}phenyl)-N'-(2-fluoro-5 methylphenyl)urea; 30 N-(4-{3-amino-6-[(diethylamino)methyl]-7-fluoro-1 H-indazol-4-yl}phenyl)-N'-[3 (trifluoromethyl)phenyl]urea; N-(4-{3-amino-6-[(diethylamino)methyl]-7-fluoro-1 H-indazol-4-yl}phenyl)-N'-(3 chlorophenyl)urea; N-(4-{3-amino-6-[(diethylamino)methyl]-7-fluoro-1 H-indazol-4-yl}phenyl)-N'-(3 35 methylphenyl)urea; N-(4-{3-amino-7-[(3-pyridinyloxy)methyl]-1 H-indazol-4-yl}phenyl)-N'-[3 (trifluoromethyl)phenyl]urea; N-(4-{3-amino-1 -[2-(4-morpholinyl)ethyl]-1 H-indazol-4-yl}phenyl)-N'-(2-fluoro-5 methylphenyl)urea; 40 N-(4-{3-amino-1 -[2-(4-morpholinyl)ethyl]-1 H-indazol-4-yl}phenyl)-N'-(3 fluorophenyl)urea; N-(4-{3-amino-1 -[2-(4-morpholinyl)ethyl]-1 H-indazol-4-yl}phenyl)-N'-(3 chlorophenyl)urea; N-(4-{3-amino-1 -[2-(4-morpholinyl)ethyl]-1 H-indazol-4-yl}phenyl)-N'-[3 45 (trifluoromethyl)phenyl]urea; WO 2009/050291 PCT/EP2008/064076 35 N-(4-{3-amino-1 -[2-(4-morpholinyl)ethyl]-1 H-indazol-4-yl}phenyl)-N'-(3 methylphenyl)urea; N-[4-(3-amino-6-bromo-1 H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea; N-[4-(3-amino-4-bromo-1 H-indazol-6-yl)phenyl]-N'-(3-methylphenyl)urea; 5 N-(4-{3-amino-1 -[2-(dimethylamino)ethyl]-1 H-indazol-4-yl}phenyl)-N'-(2-fluoro-5 methylphenyl)urea; N-(4-{3-amino-1 -[2-(dimethylamino)ethyl]-1 H-indazol-4-yl}phenyl)-N'-(3 chlorophenyl)urea; N-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]-1 H 10 indazol-7-yl}oxy)ethyl]methanesulfonamide; 4-(1 H-indol-5-yl)-1 H-indazol-3-amine; N-{4-[3-amino-1 -(2-methoxyethyl)-1 H-indazol-4-yl]phenyl}-N'-(2-fluoro-5 methylphenyl)urea; N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1 -yl)ethoxy]-1 H 15 indazol-4-yl}phenyl)-N'-(3,5-dimethylphenyl)urea; N-[4-(3-amino-1 H-indazol-4-yl)-2,6-dimethylphenyl]-N'-(2-fluoro-5 methylphenyl)urea; N-[4-(3-amino-1 H-indazol-4-yl)-2,6-dimethylphenyl]-N'-[3 (trifluoromethyl)phenyl]urea; 20 N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(3-hydroxyphenyl)urea; N-[2-({3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1 H indazol-7-yl}oxy)ethyl]methanesulfonamide; N-{2-[(3-amino-4-{4-[({[2-fluoro-5 (trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-1 H-indazol-7 25 yl)oxy]ethyl}methanesulfonamide; N-[2-({3-amino-4-[4-({[(3-chlorophenyl)amino]carbonyl}amino)phenyl]-1 H indazol-7-yl}oxy)ethyl]methanesulfonamide; N-{2-[(3-amino-4-{4-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl} 1 H-indazol-7-yl)oxy]ethyl}methanesulfonamide; 30 N-[3-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea; N-[4-(3-amino-7-methyl-1 H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea; N-[4-(3-amino-7-methyl-1 H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea; N-[4-(3-amino-7-methyl-1 H-indazol-4-yl)phenyl]-N'-[3 (trifluoromethyl)phenyl]urea; 35 N-[4-(3-amino-7-methyl-1 H-indazol-4-yl)phenyl]-N'-[2-fluoro-5 (trifluoromethyl)phenyl]urea; N-[4-(3-amino-7-methyl-1 H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea; N-[4-(3-amino-7-methyl-1 H-indazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea; N-[4-(3-amino-7-methyl-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5 40 methylphenyl)urea; N-[4-(3-amino-7-methyl-1 H-indazol-4-yl)phenyl]-N'-(3-cyanophenyl)urea N-[4-(3-amino-1 H-indazol-4-yl)-2-(trifluoromethoxy)phenyl]-N'-(2-fluoro-5 methylphenyl)urea; N-[4-(3-amino-7-fluoro-1 H-indazol-4-yl)phenyl]-N'-[2-fluoro-5 45 (trifluoromethyl)phenyl]urea; WO 2009/050291 PCT/EP2008/064076 36 N-[4-(3-amino-7-fluoro-1 H-indazol-4-yl)phenyl]-N'-(4-fluorophenyl)urea; N-[4-(3-amino-7-fluoro-1 H-indazol-4-yl)phenyl]-N'-(2-fluorophenyl)urea; N-[4-(3-amino-7-fluoro-1 H-indazol-4-yl)phenyl]-N'-(3-fluoro-4 methylphenyl)urea; 5 N-[4-(3-amino-7-fluoro-1 H-indazol-4-yl)phenyl]-N'-phenylurea; N-[2-({3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1 H indazol-7-yl}oxy)ethyl]-1,1,1-trifluoromethanesulfonamide; N-[4-(3-amino-1 H-indazol-4-yl)-2-fluorophenyl]-N'-(2-fluoro-5 methylphenyl)urea; 10 N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-[4-fluoro-3 (trifluoromethyl)phenyl]urea; N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-[2-fluoro-3 (trifluoromethyl)phenyl]urea; N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(4-bromo-2-fluorophenyl)urea; 15 N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(5-fluoro-2-methylphenyl)urea; N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(4-fluoro-3-methylphenyl)urea; N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N' phenylurea; N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-(3 20 fluorophenyl)urea; N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-(2-fluoro 5-methylphenyl)urea; N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-(3 methylphenyl)urea; 25 N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-[2-fluoro 5-(trifluoromethyl)phenyl]urea; N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-(3 chlorophenyl)urea; N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-[3 30 (trifluoromethyl)phenyl]urea; N-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl] 1 H-indazol-7-yl}oxy)ethyl]-1,1,1 -trifluoromethanesulfonamide; N-[2-({3-amino-4-[4-({[(3-fluorophenyl)amino]carbonyl}amino)phenyl]-1 H indazol-7-yl}oxy)ethyl]-1,1,1-trifluoromethanesulfonamide; 35 N-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl] 1 H-indazol-7-yl}oxy)ethyl]benzenesulfonamide; N-{2-[(3-amino-4-{4-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl} 1 H-indazol-7-yl)oxy]ethyl}benzenesulfonamide; N-[2-({3-amino-4-[4-({[(3-fluorophenyl)amino]carbonyl}amino)phenyl]-1 H 40 indazol-7-yl}oxy)ethyl]benzenesulfonamide; N-[2-({3-amino-4-[4-({[(3-chlorophenyl)amino]carbonyl}amino)phenyl]-1 H indazol-7-yl}oxy)ethyl]benzenesulfonamide; N-(4-{3-amino-7-[(isopropylamino)methyl]-1 H-indazol-4-yl}phenyl)-N'-(2-fluoro 5-methylphenyl)urea; WO 2009/050291 PCT/EP2008/064076 37 N-(4-{3-amino-7-[(isopropylamino)methyl]-1 H-indazol-4-yl}phenyl)-N'-(3 chlorophenyl)urea; N-(4-{3-amino-7-[(isopropylamino)methyl]-1 H-indazol-4-yl}phenyl)-N'-[3 (trifluoromethyl)phenyl]urea; 5 N-(4-{3-amino-7-[(isopropylamino)methyl]-1 H-indazol-4-yl}phenyl)-N'-(3 methylphenyl)urea; N-(4-{3-amino-7-[(isopropylamino)methyl]-1 H-indazol-4-yl}phenyl)-N'-(4-fluoro 3-methylphenyl)urea; N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1 H-indazol-4-yl}phenyl)-N'-(2-fluoro 10 5-methylphenyl)urea; N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1 H-indazol-4-yl}phenyl)-N'-(3 chlorophenyl)urea; N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1 H-indazol-4-yl}phenyl)-N'-[3 (trifluoromethyl)phenyl]urea; 15 N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1 H-indazol-4-yl}phenyl)-N'-(3 methylphenyl)urea; N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1 H-indazol-4-yl}phenyl)-N'-(4-fluoro 3-methylphenyl)urea; N-(4-{3-amino-7-[3-(1 H-pyrrol-1 -yl)propoxy]-1 H-indazol-4-yl}phenyl)-N'-(2 20 fluoro-5-methylphenyl)urea; 4-(1 H-indol-5-yl)-7-[3-(1 H-pyrrol-1 -yl)propoxy]-1 H-indazol-3-amine; N-(4-{3-amino-7-[3-(1 H-pyrrol-1 -yl)propoxy]-1 H-indazol-4-yl}phenyl)-N'-(3 methylphenyl)urea; N-(4-{3-amino-7-[3-(1 H-pyrrol-1 -yl)propoxy]-1 H-indazol-4-yl}phenyl)-N'-(3 25 chlorophenyl)urea; N-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl] 1 H-indazol-7-yl}oxy)ethyl]thiophene-2-sulfonamide; N-[2-({3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1 H indazol-7-yl}oxy)ethyl]thiophene-2-sulfonamide; 30 N-(2-{[3-amino-4-(1 H-indol-5-yl)-1 H-indazol-7-yl]oxy}ethyl)thiophene-2 sulfonamide N-(4-{3-amino-7-[3-(diethylamino)propoxy]-1 H-indazol-4-yl}phenyl)-N'-(2-fluoro 5-methylphenyl)urea; N-(4-{3-amino-7-[3-(diethylamino)propoxy]-1 H-indazol-4-yl}phenyl)-N'-(3 35 chlorophenyl)urea; N-(4-{3-amino-7-[3-(diethylamino)propoxy]-1 H-indazol-4-yl}phenyl)-N'-[3 (trifluoromethyl)phenyl]urea; N-(4-{3-amino-7-[3-(diethylamino)propoxy]-1 H-indazol-4-yl}phenyl)-N'-(3 fluorophenyl)urea; 40 N-[4-(3-amino-1 H-indazol-4-yl)-2-fluorophenyl]-N'-[3-(trifluoromethyl) phenyl]urea; N-[4-(3-amino-1 H-indazol-4-yl)-2-fluorophenyl]-N'-[4-fluoro-3 (trifluoromethyl)phenyl]urea; N-[4-(3-amino-7-pyridin-3-yl-1 H-indazol-4-yl)phenyl]-N'-(4-fluoro-3 45 methylphenyl)urea; WO 2009/050291 PCT/EP2008/064076 38 N-[4-(3-amino-7-pyridin-3-yl-1 H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea; N-[4-(3-amino-7-pyridin-3-yl-1 H-indazol-4-yl)phenyl]-N'-[3 (trifluoromethyl)phenyl]urea; N-[4-(3-amino-7-pyridin-3-yl-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5 5 methylphenyl)urea; N-[4-(3-amino-7-pyridin-3-yl-1 H-indazol-4-yl)phenyl]-N'-[4-fluoro-3 (trifluoromethyl)phenyl]urea; N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1 H-indazol-4-yl}phenyl)-N'-(3 methylphenyl)urea; 10 N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1 H-indazol-4-yl}phenyl)-N'-(2 fluoro-5-methylphenyl)urea; N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1 H-indazol-4-yl}phenyl)-N'-(3 fluorophenyl)urea; N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1 H-indazol-4-yl}phenyl)-N'-(3 15 chlorophenyl)urea; N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1 H-indazol-4-yl}phenyl)-N'-[3 (trifluoromethyl)phenyl]urea; N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1 H-indazol-4-yl}phenyl)-N'-(4 fluoro-3-methylphenyl)urea; 20 N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-(3 bromophenyl)urea; N-[4-(3-amino-1 H-indazol-4-yl)-3-fluorophenyl]-N'-(3-methylphenyl)urea; N-[4-(3-amino-1 H-indazol-4-yl)-3-fluorophenyl]-N'-(2-fluoro-5 methylphenyl)urea; 25 N-[4-(3-amino-1 H-indazol-4-yl)-3-fluorophenyl]-N'-(3-chlorophenyl)urea; N-[4-(3-amino-1 H-indazol-4-yl)-3-fluorophenyl]-N'-(4-fluoro-3 methylphenyl)urea; N-[4-(3-amino-1 H-indazol-4-yl)-3-fluorophenyl]-N'-[2-fluoro-5 (trifluoromethyl)phenyl]urea; 30 N-[4-(3-amino-1 H-indazol-4-yl)-3-fluorophenyl]-N'-[4-fluoro-3 (trifluoromethyl)phenyl]urea; N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3,5-dimethylphenyl)urea; N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-phenylurea; N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(4-methylphenyl)urea; 35 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-cyanophenyl)urea; N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-fluoro-3 (trifluoromethyl)phenyl]urea; N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-bromophenyl)urea; N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea; 40 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-ethylphenyl)urea; N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-(trifluoromethyl)phenyl]urea; N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-fluoro-4-methylphenyl)urea; N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea; N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3,5-difluorophenyl)urea; 45 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methoxyphenyl)urea; WO 2009/050291 PCT/EP2008/064076 39 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(4-methoxyphenyl)u rea; N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]u rea; N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-n itrophenyl)u rea; N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(4-fluorophenyl)u rea; 5 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(2-fluorophenyl)u rea; N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-ch loro-4-fluorophenyl)u rea; N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-ch loro-4-methoxy phenyl)urea; N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-(d imethylamino)phenyl]u rea; 10 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-1,3-benzod ioxol-5-ylu rea; N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-(trifluoromethoxy) phenyl]urea; N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-(trifluoromethoxy) phenyl]urea; 15 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[3,5-bis(trifluoromethyl) phenyl]urea; N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-ch loro-4-methylphenyl)u rea; N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-[3,5 bis(trifluoromethyl)phenyl]urea; 20 N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-[4 (trifluoromethoxy)phenyl]u rea; N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea; N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methoxy phenyl)urea; 25 N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3,5-d ifl uorophenyl) urea; N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(4-methylphenyl) urea; N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-bromophenyl) 30 urea; N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3,5-di methyl phenyl)urea; N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-(d imethylamino) phenyl]urea; 35 N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-1,3-benzod ioxol-5 ylurea N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methylphenyl)u rea; N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-chlorophenyl)u rea; N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(2-fluoro-5 40 methylphenyl)urea; N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-fluoro-5 (trifluoromethyl)phenyl]u rea; N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-[3-(trifluoromethyl) phenyl]urea; WO 2009/050291 PCT/EP2008/064076 40 N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3,5-d imethyl phenyl)urea; N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-ethylphenyl)u rea; N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(4-methylphenyl)u rea; 5 N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-(trifluoro methoxy)phenyl]urea; N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-fluoro-4 methylphenyl)urea; N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methoxyphenyl) 10 urea; N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-phenylu rea; N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-[3,5-bis(trifluoro methyl)phenyl]urea; N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-bromophenyl)u rea; 15 N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea; N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-fluoro-3 (trifluoromethyl)phenyl]u rea; N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(4-fluoro-3 methylphenyl)urea; 20 N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-[3-(trifl uoromethyl) phenyl]urea; N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-ch lorophenyl)urea; N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-fluoro-3 (trifluoromethyl)phenyl]urea; 25 N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methylphenyl)u rea; N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-fluoro-5 (trifluoromethyl)phenyl]u rea; N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-(2-fluoro-5 methylphenyl)urea; 30 N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-[2-fluoro-5 (trifluoromethyl)phenyl]u rea; N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-[3 (trifluoromethyl)phenyl]u rea; N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-(2-fluoro-5 35 methylphenyl)urea; N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3 chlorophenyl)urea; N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3 bromophenyl)urea; 40 N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-[4-fluoro-3 (trifluoromethyl)phenyl]urea; N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-(4-fluoro-3 methylphenyl)urea; N-[4-(3-amino-1 ,2-benzisoth iazol-4-yl)phenyl]-N'-(3,5-d imethylphenyl)u rea; 45 N-[4-(3-amino-1 ,2-benzisoth iazol-4-yl)phenyl]-N'-(3-chlorophenyl)u rea; WO 2009/050291 PCT/EP2008/064076 41 N-[4-(3-amino-1,2-benzisoth iazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)u rea; N-[4-(3-amino-1,2-benzisoth iazol-4-yl)phenyl]-N'-(3-methylphenyl)urea; N-[4-(3-amino-1,2-benzisoth iazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea; N-[4-(3-amino-7-fluoro-1 H-indazol-4-yl)-2-fluorophenyl]-N'-(2-fluoro-5 5 methylphenyl)urea; N-[4-(3-amino-7-fluoro-1 H-indazol-4-yl)-2-fluorophenyl]-N'-(3-chlorophenyl)urea; N-(4-{3-amino-7-[(1 -methylpiperidin-4-yl)methoxy]-1 H-indazol-4-yl}-2 fluorophenyl)-N'-(2-fluoro-5-methylphenyl)urea; N-(4-{3-amino-7-[(1 -methylpiperidin-4-yl)methoxy]-1 H-indazol-4-yl}phenyl)-N' 10 (3-methylphenyl)urea; N-(4-{3-amino-7-[(1 -methylpiperidin-4-yl)methoxy]-1 H-indazol-4-yl}phenyl)-N' (3-chlorophenyl)urea; N-(4-{3-amino-7-[(1 -methylpiperidin-4-yl)methoxy]-1 H-indazol-4-yl}phenyl)-N' (4-fluoro-3-methylphenyl)urea; 15 N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-(3 chlorophenyl)urea; N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-(3 methylphenyl)urea; N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-[4-fluoro-3 20 (trifluoromethyl)phenyl]urea; N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-(4-fluoro-3 methylphenyl)urea; N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-(3-chloro-4 fluorophenyl)urea; 25 N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-[3 (trifluoromethyl)phenyl]urea; N-{4-[3-amino-7-(3-pyridin-4-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-(2-fluoro-5 methylphenyl)urea; N-{4-[3-amino-7-(3-pyridin-4-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-(3 30 methylphenyl)urea; N-{4-[3-amino-7-(3-pyridin-4-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-(3 chlorophenyl)urea; N-[4-(3-amino-1 H-indazol-4-yl)-2-(methoxymethoxy)phenyl]-N'-(2-fluoro-5 methylphenyl)urea; 35 N-[4-(3-amino-1 H-indazol-4-yl)-2-hydroxyphenyl]-N'-(2-fluoro-5 methylphenyl)urea; N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-[2-fluoro-5 (hydroxymethyl)phenyl]urea; N-[4-(3-amino-7-thien-3-yl-1 H-indazol-4-yl)phenyl]-N'-[3 40 (trifluoromethyl)phenyl]urea; N-[4-(3-amino-7-thien-3-yl-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5 methylphenyl)urea; N-[4-(3-amino-7-pyridin-4-yl-1 H-indazol-4-yl)phenyl]-N'-(4-fluoro-3 methylphenyl)urea; WO 2009/050291 PCT/EP2008/064076 42 N-[4-(3-amino-7-pyridin-4-yl-1 H-indazol-4-yl)phenyl]-N'-[3 (trifluoromethyl)phenyl]urea; N-[4-(3-amino-7-pyridin-4-yl-1 H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea; N-[4-(3-amino-7-pyridin-4-yl-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5 5 methylphenyl)urea; N-[4-(3-amino-7-pyridin-4-yl-1 H-indazol-4-yl)phenyl]-N'-[4-fluoro-3 (trifluoromethyl)phenyl]urea; N-[4-(3-amino-7-pyridin-4-yl-1 H-indazol-4-yl)phenyl]-N'-[2-fluoro-5 (trifluoromethyl)phenyl]urea; 10 N-[4-(3-amino-5-fluoro-1 H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea; N-[4-(3-amino-5-fluoro-1 H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea; N-[4-(3-amino-5-fluoro-1 H-indazol-4-yl)phenyl]-N'-phenylurea; N-[4-(3-amino-5-fluoro-1 H-indazol-4-yl)phenyl]-N'-[2-fluoro-3 (trifluoromethyl)phenyl]urea; 15 N-[4-(3-amino-5-fluoro-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5 methylphenyl)urea; N-[4-(3-amino-5-fluoro-1 H-indazol-4-yl)phenyl]-N'-[3 (trifluoromethyl)phenyl]urea; N-[4-(3-amino-5-fluoro-1 H-indazol-4-yl)phenyl]-N'-[4-fluoro-3 20 (trifluoromethyl)phenyl]urea; N-[4-(3-amino-5-fluoro-1 H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea; N-[4-(3-amino-5-fluoro-1 H-indazol-4-yl)phenyl]-N'-(4-fluoro-3 methylphenyl)urea; N-[4-(3-amino-5-fluoro-1 H-indazol-4-yl)phenyl]-N'-(3-chloro-4-fluorophenyl)urea; 25 N-[4-(3-amino-7-bromo-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5 methylphenyl)urea; 3-[({[4-(3-amino-1 H-indazol-4-yl)phenyl]amino}carbonyl)amino]-4-fluorobenzoic acid; methyl 3-[({[4-(3-amino-1 H-indazol-4-yl)phenyl]amino}carbonyl)amino]-4 30 fluorobenzoate; N-[4-(3-amino-1 H-indazol-6-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea N-[2-({3-amino-4-[4-({[(3-fluorophenyl)amino]carbonyl}amino)phenyl]-1 H indazol-7-yl}oxy)ethyl]methanesulfonamide; and N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1 H-indazol-4-yl}phenyl)-N'-[4 35 fluoro-3-(trifluoromethyl)phenyl]urea; N-[4-(1 -acetyl-3-amino-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5 methylphenyl)urea; N-[4-(3-amino-7-fluoro-1 H-indazol-4-yl)phenyl]-N'-(4-bromo-3 methylphenyl)urea; 40 N-[4-(3-amino-1 -phenyl-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5 methylphenyl)urea; N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1 H-indazol-4-yl]phenyl}-N'-(2-fluoro-5 methylphenyl)urea; N-[4-(3-amino-1 H-indazol-6-yl)phenyl]-N'-phenylurea; 45 N-[4-(3-amino-1 H-indazol-6-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea; WO 2009/050291 PCT/EP2008/064076 43 N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-thien-3-ylurea; and N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-cyclopentylurea. In an embodiment of the invention, the active agent is N-[4-(3-amino-1 H-indazol-4 5 yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea (ABT869) or salts or hydrates or solvates thereof. Compounds of formula (1) or (II) are useful for inhibiting protein tyrosine kinases. The solid dispersion product or dosage forms containing the solid dispersion product of the 10 invention are used in a method for treating cancer in a patient in recognized need of such treatment comprising administering to the patient a therapeutically acceptable amount of a compound. The solid dispersion product is prepared by a process which comprises 15 a) preparing a liquid mixture containing the at least one active agent, at least one pharmaceutically acceptable matrix-forming agent, at least one pharmaceutically acceptable surfactant and at least one solvent, and b) removing the solvent(s) from the liquid mixture to obtain the solid dispersion 20 product. As described above, at least one filler may advantageously be added to the liquid mix ture before removing the solvent(s). 25 Suitable solvents are those which are capable of dissolving or solubilising the matrix forming agent. Any such solvent may be used, however, pharmaceutically acceptable solvents are preferred because traces of solvent may remain in the dried solid disper sion product. Suitably, the solvent may be selected from the group consisting of alka nols, such as methanol, ethanol, isopropanol, n-propanol, isobutanol, n-butanol; hydro 30 carbons, such as pentane, hexane, cyclohexane, methylcyclohexane, toluene, xylene; halogenated hydrocarbons, such as dichloromethane, trichloromethane, dichloro ethane, chlorobenzene; ketones, such as acetone; esters, such as ethyl acetate; ethers, such as dioxane, tetrahydrofurane; and combinations of two or more thereof. Ethanol is particularly preferred due to its availability, dissolving power and pharmaceu 35 tical safeness. The liquid mixture may be prepared by any suitable method of contacting the essential ingredients thereof, i. e. the pharmaceutically acceptable matrix-forming agent, active agent, the pharmaceutically acceptable surfactant and the solvent or combination of 40 solvents. In an embodiment, the liquid mixture is prepared by dissolving the pharma ceutically acceptable matrix-forming agent to obtain a matrix-forming agent solution, and adding the active agent and the pharmaceutically acceptable surfactant to the so lution. The dissolved matrix-forming agent may exert an solubility-enhancing effect on the active agent; thus, the solubility of the active agent in the matrix-forming agent solu- WO 2009/050291 PCT/EP2008/064076 44 tion may be several times higher than its solubility in the solvent alone. Preferably, the active agent is essentially completely dissolved in the liquid mixture. The liquid mixture has a dry matter content of up to 90 % by weight, for example 0.5 to 5 90 % by weight, in most instances 2 to 60 % by weight, relative to the total weight of the liquid mixture. The solvent(s) may be removed by any suitable method known in the art, such as spray-drying, drum drying, belt drying, tray drying, fluid-bed drying or combinations of 10 two or more thereof. For example, the primary solid dispersion powder obtained by spray-drying may be further dried by tray drying (optionally under vacuum) or fluid-bed drying (optionally under vacuum). In an embodiment, removal of the solvent comprises a spray-drying step, optionally in combination with one or more drying steps other than spray-drying. 15 The residual solvent content in the final solid dispersion product is preferably 5% by weight or less, more preferably 1% by weight or less. In spray-drying, the liquid to be dried is suspended in a gas flow, e. g., air, i. e. the liq 20 uid is converted into a fog-like mist (atomized), providing a large surface area. The at omized liquid is exposed to a flow of hot gas in a drying chamber. The moisture evapo rates quickly and the solids are recovered as a powder consisting of fine, hollow spherical particles. Gas inlet temperatures of up to 250 OC or even higher may be used, due to the evaporation the gas temperature drops very rapidly to a temperature of 25 about 30 to 150 OC (outlet temperature of the gas). The principle of the drum drying process (roller drying) is that a thin film of material is applied to the smooth surface of a continuously rotating, heated metal drum. The film of dried material is continuously scraped off by a stationary knife located opposite the 30 point of application of the liquid material. The dryer consists of a single drum or a pair of drums with or without "satellite" rollers. The drum(s) may be located in a vacuum chamber. Conveniently, the solvent vapours are collected and the solvent is recovered and recycled. 35 In a belt dryer, the liquid is spread or sprayed onto a belt which passes over several heated plates underneath the belt. The material is heated by steam-heated or electri cally heated plates. The evaporation of the solvent can additionally be fostered by infra red radiators or microwave radiators located over the belt. Belt drying may be carried out in a vacuum chamber. 40 In tray drying, the liquid mixture (or a dispersion product that has been pre-dried by any other method) is distributed over a number of trays. These are placed in an oven, usu ally in a stream of hot gas, e. g. air. Vacuum may be applied additionally. 45 The dried solid dispersion product may then be grinded and/or classified (sieved).
WO 2009/050291 PCT/EP2008/064076 45 The dried solid dispersion product may then be filled into capsules or may be com pacted. Compacting means a process whereby a powder mass comprising the solid dispersion product is densified under high pressure in order to obtain a compact with 5 low porosity, e.g. a tablet. Compression of the powder mass is usually done in a tablet press, more specifically in a steel die between two moving punches. At least one additive selected from flow regulators, disintegrants, bulking agents and lubricants is preferably used in compacting the granules. Disintegrants promote a rapid 10 disintegration of the compact in the stomach and keep the liberated granules separate from one another. Suitable disintegrants are crosslinked polymers such as crosslinked polyvinyl pyrrolidone and crosslinked sodium carboxymethyl cellulose. Suitable bulking agents are selected from lactose, calcium hydrogenphosphate, microcrystalline cellu lose (Avicel@), magnesium oxide, natural or pre-gelatinized potato or corn starch, poly 15 vinyl alcohol. Suitable flow regulators are selected from highly dispersed silica (Aerosil@), and animal or vegetable fats or waxes. 20 A lubricant is preferably used in compacting the granules. Suitable lubricants are se lected from polyethylene glycol (e.g., having a Mw of from 1000 to 6000), magnesium and calcium stearates, sodium stearyl fumarate, talc, and the like. Various other additives may be used, for example dyes such as azo dyes, organic or 25 inorganic pigments such as aluminium oxide or titanium dioxide, or dyes of natural ori gin; stabilizers such as antioxidants, light stabilizers, radical scavengers, or stabilizers against microbial attack. In order to facilitate the intake of such a dosage form by a mammal, it is advantageous 30 to give the dosage form an appropriate shape. Large tablets that can be swallowed comfortably are therefore preferably elongated rather than round in shape. A film coat on the tablet further contributes to the ease with which it can be swallowed. A film coat also improves taste and provides an elegant appearance. If desired, the film 35 coat may be an enteric coat. The film coat usually includes a polymeric film-forming material such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, and acrylate or methacrylate copolymers. Besides a film-forming polymer, the film coat may further comprise a plasticizer, e.g. polyethylene glycol, a surfactant, e.g. a Tween@ type, and optionally a pigment, e.g. titanium dioxide or iron oxides. The film-coating may also 40 comprise talc as anti-adhesive. The film coat usually accounts for less than about 5 % by weight of the dosage form. The following examples will serve to further illustrate the invention without limiting it. 45 WO 2009/050291 PCT/EP2008/064076 46 Example 1: Preparation of Solid Dispersion Products Solid dispersion products wherein the matrix-forming agent is PVP are prepared ac cording to the following protocol: 5 (1) Dissolve PVP in ethanol. For PVP K30 prepare a 30 % (w/w) solution, for PVP K12 prepare a 50 % (w/w) solution. (2) Melt surfactants at 60 'C in an oven and mix in the ratio indicated. (3) Weigh PVP solution into amber glass bottle. 10 (4) Weigh active agent (ABT 869) and add to PVP solution; stir until dissolved. (5) Add surfactant and mix. If surfactant solidifies partially, warm again. (6) If solution is still turbid after one hour, add further ethanol and homogenize. Solid dispersion products wherein the matrix-forming agent is hydroxypropyl-p 15 cyclodextrin (HP-p-CD) are prepared according to the following protocol: (1) Weigh 8.5 g HP-p-CD and dissolve in 60 g ethanol (anhydrous). (2) Weigh active agent and dissolve in (1). (3) Melt surfactant and add to (2). 20 (4) If surfactant solidifies partially, warm again until a clear solution is obtained. Spray drying was performed using a BOchi B-191 lab scale spray dryer. The equipment was pre-heated before the spray cycle was started. After spraying a final drying was conducted for 10-20 minutes before the cooling cycle was initiated. For atomization of 25 the liquid a two-component nozzle (liquid plus air for atomization) has been used. Protocol for the oral bioavailability studies 30 For bioavailability evaluation, solid dispersion powder as obtained in example were screened and filled into capsules or compressed to tablets. The studies were run in a randomized cross-over study design. 35 Dogs (beagle dogs, mixed sexes, weighing approximately 10 kg) received a balanced diet with 27 % fat and were permitted water ad libitum (non-fasted) or were left without diet overnight and water ad libitum (fasted). Each dog received a 100 rig/kg subcuta neous dose of histamine approximately 30 minutes prior to dosing. A single dose of ABT 869 was administered to each dog. The dose was followed by approximately 10 40 milliliters of water. Blood samples were obtained from each animal prior to dosing and 0.25, 0.5, 1.0, 1.5, 2, 3, 4, 6, 9, 12 and 24 hours after drug administration. The plasma was separated from the red cells by centrifugation and frozen (-30 'C) until analysis. Concentrations of active ingredient were determined by reverse phase HPLC with low wavelength UV detection following liquid-liquid extraction of the plasma samples. The 45 area under the curve (AUC) was calculated by the trapezoidal method over the time WO 2009/050291 PCT/EP2008/064076 47 course of the study. Each dosage form was evaluated in a group containing 3-6 dogs; the values reported are averages for each group of dogs. Following the procedures above, an ABT 869 solid dispersion product having the fol 5 lowing composition was prepared: 6% ABT-869: 54.8% K30: 23.4% Gelucire 44/14: 15.6% Vitamin E TPGS. Bioavailability was tested as described above with 20 mg/dog. The studies were run with liquid clinical formulation as reference (4.0 % by weight ABT 869 in ethanol 10 surfactant solution) in a crossover study design. Each dosage form was evaluated in a group containing 5 dogs; the values reported are averages for each group of dogs. Cmax Tmax t1/ 2
AUC_
0 Cmax AUC (pg/ml) (hr) (hr) (pg-hr/ml) Pt. est. Pt. est. Clinical 0.35 1.2 0.7 0.62 Reference Solid Dis- 0.42 0.9 0.8 0.74 1.07 1.04 persion 15 Example 2: Following the procedures of Example 1 above, a liquid mixture is prepared, containing 20 56.13 % by weight of ethanol, 15.36 % of PVP K30, 3.56 % of Gelucire 44/14, 1.92 % of Vitamin E TPGS, 21.94 % of maltitol and 1.10 % of ABT-869. The liquid mixture is fed to a twin-drum dryer. This dryer comprises a pair of drums which are rotated in the opposite direction to each other. The drums are heated to a 25 temperature of about 60 'C by circulating thermal oil. The space between the drums forms a liquid pool into which the liquid mixture is introduced. The liquid mixture is be ing spread on the circumferential faces of the respective drums; the adjustable gap between the two drums acts as a means to control the film thickness. After travelling part of a revolution, the dried material is removed in the form of thin sheets by scraper 30 knifes. The drying drums are positioned in a vacuum chamber which is maintained at a pres sure of 50mbar (absolute pressure). The ethanol vapours are drawn off and con densed. 35

Claims (39)

1. A solid dispersion product comprising at least one pharmaceutically active agent, obtained by 5 a) preparing a liquid mixture containing the at least one active agent, at least one pharmaceutically acceptable matrix-forming agent, at least one phar maceutically acceptable surfactant and at least one solvent, and b) removing the solvent(s) from the liquid mixture to obtain the solid dispersion product. 10
2. The solid dispersion product of claim 1, wherein at least one filler is added to the liquid mixture before removing the solvent(s).
3. The solid dispersion product of claim 1, wherein the mass ratio of active agent 15 and pharmaceutically acceptable matrix-forming agent is from 0.01:1 to 1:3.
4. The solid dispersion product of claim 1, wherein the mass ratio of active agent and pharmaceutically acceptable surfactant is from 0.1:1 to 1:7. 20
5. The solid dispersion product of claim 1, wherein the pharmaceutically acceptable matrix-forming agent is selected from the group consisting of cyclodextrines, pharmaceutically acceptable polymers, lipids or combinations of two or more thereof. 25
6. The solid dispersion product of claim 1, wherein said pharmaceutically accept able matrix-forming agent is selected from the group consisting of cellulose es ters, cellulose ethers, maltodextrines, N-vinyl pyrrolidone homopolymers, N-vinyl pyrrolidone copolymers and combinations of two or more thereof. 30
7. The solid dispersion product of claim 1, wherein said pharmaceutically accept able matrix-forming agent is selected from the group consisting of poly N vinylpyrrolidones, copolymers of N-vinyl pyrrolidone and vinyl acetate and combi nations thereof. 35
8. The solid dispersion product of claim 1, wherein the pharmaceutically acceptable surfactant is selected from the group consisting of polyol fatty acid esters, polyalkoxylated polyol fatty acid esters, polyalkoxylated fatty alcohol ethers, to copheryl compounds or combinations of two or more thereof. 40
9. The solid dispersion product of claim 1, wherein the pharmaceutically acceptable surfactant comprises a combination of two or more pharmaceutically acceptable surfactants. WO 2009/050291 PCT/EP2008/064076 49
10. The solid dispersion product dispersion product of claim 1, wherein the pharma ceutically acceptable surfactant comprises at least one surfactant having an HLB value of 10 or more. 5
11. The solid dispersion product of claim 9 wherein the combination of pharmaceuti cally acceptable surfactants comprises (i) at least one tocopheryl compound hav ing a polyalkylene glycol moiety and (ii) at least one polyalkoxylated polyol fatty acid ester. 10
12. The solid dispersion product of claim 11, wherein the tocopheryl compound is alpha tocopheryl polyethylene glycol succinate.
13. The solid dispersion product of claim 11, wherein the polyalkoxylated polyol fatty acid ester is a polyalkoxylated glyceride. 15
14. The solid dispersion product of claim 11, wherein the mass ratio of tocopheryl compound and polyalkoxylated polyol fatty acid ester is in the range of from 0.2:1 to 1:1. 20
15. The solid dispersion product of claim 1, wherein the active agent is represented by the formula (1) R3 R4 A H 2 N R5 N V R 1 R 2 (1), 25 or a therapeutically acceptable salt thereof, wherein A is selected from the group consisting of indolyl, phenyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, and thienyl; X is selected from the group consisting of 0, S, and NR 9 ; 30 R 1 and R 2 are independently selected from the group consisting of hy drogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryl, arylalkyl, aryloxy, aryloxyal kyl, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocycly lalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxy, hydroxyalkoxy, hy droxyalkyl, (NRaRb)alkoxy, (NRaRb)alkenyl, (NRaRb)alkyl, (NRaRb)alkynyl, 35 (NRaRb)carbonylalkenyl, and (NRaRb)carbonylalkyl; R 3 , R 4 , and R 5 are each independently selected from the group consist ing of hydrogen, alkoxy, alkoxyalkoxy, alkyl, halo, haloalkoxy, haloalkyl, hydroxy, and LR 6 ; provided that at least two of R 3 , R 4 , and R 5 are other than LR 6 ; WO 2009/050291 PCT/EP2008/064076 50 L is selected from the group consisting of (CH 2 )mN(R 7 )C(O)N(R 8 )(CH 2 )n and CH 2 C(O)NR , wherein m and n are independently 0 or 1, and wherein each group is drawn with its left end attached to A; R 6 is selected from the group consisting of hydrogen, aryl, cycloalkyl, 5 heterocyclyl, and 1,3-benzodioxolyl wherein the 1,3-benzodioxolyl can be option ally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkyl carbonyl, aryl, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, hydroxy, 10 hydroxyalkyl, nitro, -NRcRd, and (NRcRd)alkyl; R 7 and R3 are independently selected from the group consising of hy drogen and alkyl; R 9 is selected from the group consisting of hydrogen, alkenyl, alkoxyal kyl, alkyl, alkylcarbonyl, aryl, heterocyclylalkyl, hydroxyalkyl, and (NRaRb)alkyl; 15 Ra and Rb are independently selected from the group consisting of hy drogen, alkenyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylcarbonyl, arylsulfonyl, haloalkylsulfonyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, and het erocyclylsulfonyl; and Rc and Rd are independently selected from the group consisting of hy 20 drogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, and heterocyclyl.
16. The solid dispersion product of claim 15, wherein the active agent is represented by the formula (II) R 4 H 2 N R 3 N / N x 25 R1 R2 (II), or a therapeutically acceptable salt thereof, wherein X is selected from the group consisting of 0, S, and NR 9 ; 30 R 1 and R 2 are independently selected from the group consisting of hy drogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, het erocyclylalkyl, heterocyclyloxyalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, (NRaRb)alkoxy, (NRaRb)alkenyl, (NRaRb)alkyl, (NRaRb)carbonylalkenyl, and 35 (NRaRb)carbonylalkyl; WO 2009/050291 PCT/EP2008/064076 51 R 3 and R 4 are independently selected from the group consisting of hy drogen, alkoxy, alkyl, halo, haloalkoxy, haloalkyl, and hydroxy; L is selected from the group consisting of (CH 2 )mN(R 7 )C(O)N(R)(CH 2 )n and CH 2 C(O)NR , wherein m and n are independently 0 or 1, and wherein each 5 group is drawn with its left end attached to the ring substituted with R 3 and R 4 ; R 7 and R3 are independently selected from the group consising of hy drogen and alkyl; R 9 is selected from the group consisting of hydrogen, alkenyl, alkoxyal kyl, alkyl, alkylcarbonyl, aryl, heterocyclylalkyl, hydroxyalkyl, and (NRaRb)alkyl; 10 R 1 0 and R" are independently selected from the group consisting of hy drogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NRcRd; Ra and Rb are independently selected from the group consisting of hy drogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and het 15 erocyclylsulfonyl; and Rc and Rd are independently selected from the group consisting of hy drogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocy clyl, and heterocyclylalkyl. 20
17. The solid dispersion product of claim 1, wherein the active agent is selected from the group consisting of N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5 methylphenyl)urea (ABT869) or salts or hydrates or solvates thereof.
18. A pharmaceutical dosage form, comprising the solid dispersion product of claim 25 1.
19. A process for preparing a solid dispersion product comprising at least one pharmaceutically active agent, which process comprises 30 a) preparing a liquid mixture containing the at least one active agent, at least one pharmaceutically acceptable matrix-forming agent, at least one phar maceutically acceptable surfactant and at least one solvent, and b) removing the solvent(s) from the liquid mixture to obtain the solid dispersion product. 35
20. The process of claim 19, wherein the liquid mixture is prepared by dissolving the pharmaceutically acceptable matrix-forming agent to obtain a matrix-forming agent solution, and adding the active agent and the pharmaceutically acceptable surfactant to the solution. 40
21. The process of claim 19, wherein the liquid mixture has a dry matter content of up to 90 % by weight. WO 2009/050291 PCT/EP2008/064076 52
22. The process of claim 19, wherein removing of the solvent is carried out by spray drying, drum drying, belt drying, tray drying or combinations of two or more thereof. 5
23. The process of claim 19, wherein the solvent is selected from the group consist ing of alkanols, hydrocarbons, halogenated hydrocarbons, ketons, esters, ethers and combinations of two or more thereof.
24. The process of claim 19, further comprising compressing the solid dispersion 10 product to obtain a tablet.
25. The process of claim 24, wherein at least one additive selected from flow regula tors, disintegrants, bulking agents and lubricants is added before compressing. 15
26. The process of claim 19, further comprising filling the solid dispersion product into capsules.
27. The process of claim 19, wherein at least one filler is added to the liquid mixture before removing the solvent(s). 20
28. The process of claim 19, wherein the mass ratio of active agent and pharmaceu tically acceptable matrix-forming agent is from 0.01:1 to 1:3.
29. The process of claim 19, wherein the mass ratio of active agent and pharmaceu 25 tically acceptable surfactant is from 0.1:1 to 1:7.
30. The process of claim 19, wherein the pharmaceutically acceptable matrix-forming agent is selected from the group consisting of cyclodextrines, pharmaceutically acceptable polymers, lipids or combinations of two or more thereof. 30
31. The process of claim 19, wherein said pharmaceutically acceptable matrix forming agent is selected from the group consisting of cellulose esters, cellulose ethers, maltodextrines, N-vinyl pyrrolidone homopolymers, N-vinyl pyrrolidone copolymers and combinations of two or more thereof. 35
32. The process of claim 19, wherein said pharmaceutically acceptable matrix forming agent is selected from the group consisting of poly N-vinylpyrrolidones, copolymers of N-vinyl pyrrolidone and vinyl acetate and combinations thereof. 40
33. The process of claim 19, wherein the pharmaceutically acceptable surfactant is selected from the group consisting of polyol fatty acid esters, polyalkoxylated polyol fatty acid esters, polyalkoxylated fatty alcohol ethers, tocopheryl com pounds or combinations of two or more thereof. WO 2009/050291 PCT/EP2008/064076 53
34. The process of claim 19, wherein the pharmaceutically acceptable surfactant comprises a combination of two or more pharmaceutically acceptable surfactants.
35. The process dispersion product of claim 19, wherein the pharmaceutically ac 5 ceptable surfactant comprises at least one surfactant having an HLB value of 10 or more.
36. The process of claim 34 wherein the combination of pharmaceutically acceptable surfactants comprises (i) at least one tocopheryl compound having a polyalkylene 10 glycol moiety and (ii) at least one polyalkoxylated polyol fatty acid ester.
37. The process of claim 36, wherein the tocopheryl compound is alpha tocopheryl polyethylene glycol succinate. 15
38. The process of claim 36, wherein the polyalkoxylated polyol fatty acid ester is a polyalkoxylated glyceride.
39. The process of claim 36, wherein the mass ratio of tocopheryl compound and polyalkoxylated polyol fatty acid ester is in the range of from 0.2:1 to 1:1 .
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