MX2008009610A - Thieno-pyridine derivatives as mek inhibitors - Google Patents

Abstract

A series of thieno[2,3-b]pyridine derivatives which are substituted in the 2- position by a substituted anilino moiety, being selective inhibitors of human MEK (MAPKK) enzymes, are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, proliferative (including oncological) and nociceptive conditions.

Description

DERIVATIVES OF TIENO-PIRIDINA AS MEK INHIBITORS FIELD OF THE INVENTION The present invention relates to a class of thieno-pyridine derivatives and to their use in therapy. More particularly, the invention relates to thieno derivatives [2, 3-¿> ] pyridine which are substituted in the 2-position with a substituted anilino residue. These compounds are selective inhibitors of MEK enzymes (MAPKK), and are therefore beneficial as pharmaceutical agents, especially in the treatment of adverse inflammatory, autoimmune, cardiovascular, proliferative (including oncological) and nociceptive adverse conditions). BACKGROUND OF THE INVENTION MEK enzymes are involved in a variety of physiological and pathological functions that are believed to be involved in a number of human diseases. These functions are summarized in paragraphs [0004] and [0005] of US 2005/0049276 Al. The compounds of use in the present invention, being potent and selective inhibitors of MEK, are therefore beneficial in the treatment and / or the prevention of various human ailments. These include autoimmune and inflammatory disorders such as rheumatoid arthritis, osteoarthritis, multiple sclerosis, asthma, inflammatory bowel disease, psoriasis and rejection of transplants; disorders REF. : 194552 cardiovascular which include thrombosis, cardiac hypertrophy, hypertension, and irregular heart contractility (e.g., during heart failure); proliferative disorders such as restenosis, and oncological conditions including leukemia, glioblastoma, lymphoma, melanoma, and human cancers of the liver, bone, skin, brain, pancreas, lung, breast, stomach, colon, rectum, prostate, ovary, and cervix; as well as pain and nociceptive disorders, which include chronic pain and neuropathic pain. Additionally, the compounds of use in the present invention may be beneficial as pharmacological standards for use in the development of new biological tests and in the investigation of new pharmacological agents. Thus, the compounds of use in this invention may be useful as radioligands in assays for detection of compounds capable of binding to human MEK enzymes. MEK inhibitors based on a bicyclic aromatic ring system linked to a substituted anilino moiety are known in the art. Examples of relevant publications include WO 2005/051906, WO 2005/023251, US-A-2005/0049276, WO 2005/009975, WO 03/077914 and WO 03/077855. WO 2005/023818 discloses an extensive range of compounds based on a bicyclic condensed aromatic ring system, which generically encompasses thieno-pyridine derivatives linked to a substituted anilino moiety, but does not specifically describe any particular compound of this type. No discrete pharmacological activity is ascribed, in terms of an identifiable pharmacological mechanism, to the compounds described in said document, but it is nevertheless stated that they are useful inter alia in the treatment of proliferative cellular diseases such as cancer. US-A-2003/0220365 is also relevant in a related context. However, nowhere in the prior art is the precise description of a class of thieno [2,3-jb] pyridine derivatives linked at position 2 to a substituted anilino moiety. It has now been found that such compounds are particularly valuable as selective inhibitors of MEK enzymes. The compounds of the present invention are potent and selective inhibitors of MEK having a binding affinity (CI5o) for the enzyme MEK1 and / or human MEK2 of 50 μ? or less, generally 20 μ? or less, usually 5 μ? or less, typically 1 μ? or less, conveniently 500 nM or less, ideally 100 nM or less, and preferably 20 nM or less (the skilled person will appreciate that a lower IC50 figure designates a more active compound). The compounds of the invention may possess at least a 10-fold selective affinity, typically at least a 20-fold selective affinity, conveniently at least a 50-fold selective affinity, and ideally at least a 100-fold selective affinity, for the human MEK-1 and / or MEK-2 enzyme relative to other kinases human BRIEF DESCRIPTION OF THE INVENTION The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, solvate or N-oxide thereof: 0) wherein R1 represents hydrogen, halogen or Ci-6 alkyl, "R2 represents halogen or Ci-β alkyl, R3 represents hydrogen, cyano, -C02Ra, -CONRbRc or CON (ORb) Rc, Ra represents Ci_6 alkyl, Rb represents hydrogen; or Ci-6 alkyl, C3_7 cycloalkyl, C3-7 cycloalkyl (Ci-6) alkyl, aryl, aryl (Ci-6) alkyl, C3_7 heterocycloalkyl, C3_7 heterocycloalkyl (Ci-6) alkyl, heteroaryl or heteroaryl-alkyl (Ci- 6), wherein any of said groups optionally substituted with one or more substituents, and Rc represents hydrogen or Ci_6 alkyl (optionally substituted with hydroxy), or Rb and Rc, when taken together with the nitrogen atom which are both bonded, represent azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperidinyl, homomorpholinyl or homopiperazinyl, wherein any of said groups may be optionally substituted with one or more substituents DETAILED DESCRIPTION OF THE INVENTION ION The present invention also provides a compound of formula (I) as described above, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein R1 and R2 are as defined above; R3 represents cyano, -C02Ra, -CONRbRc or -CON (ORb) Rc; Ra represents Ci- 6 alkyl, "Rb represents hydrogen, or Ci_6 alkyl, cycloalkyl C3-7, C3-7-cycloalkyl-C1-6alkyl, aryl, aryl-alkyl (Ci_6), C3_7 heterocycloalkyl, C3_7-heterocycloalkyl- (Ci- 6) alkyl, heteroaryl or heteroaryl- (Ci_6) alkyl, any of said groups optionally substituted with one or more substituents; and R c represents hydrogen or Ci-6 alkyl; or Rb and Rc, when considered together with the nitrogen atom to which both are attached, represent azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperidinyl or homomorpholinyl, wherein any of said groups may be optionally substituted with one or more substituents . For use in medicine, the salts of the compounds of formula (I) will be pharmaceutically acceptable salts. However, other salts may be useful in the preparation of the compounds of the invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which can, for example, be formed by mixing a solution of the compound of the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid or phosphoric acid. Additionally, in cases where the compounds of the invention carry an acidic moiety, e.g. carboxy, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts. The present invention includes within its scope solvates of the compounds of the formula (I) above. Such solvates can be formed with common organic solvents, e.g. hydrocarbon solvents such as benzene or toluene; chlorinated solvents such as chloroform or dichloromethane; alcohol solvents such as methanol, ethanol or isopropanol; ethereal solvents such as diethyl ether or tetrahydrofuran; or ester type solvents such as ethyl acetate. Alternatively, the solvates of the compounds of formula (I) can be formed with water, in which case they will be hydrates. Suitable alkyl groups which may be present in the compounds of the invention include straight chain and branched Ci_6 alkyl groups, for example Ci-4 alkyl groups. Typical examples include methyl and ethyl groups, and straight chain or branched propyl, butyl and pentyl groups. Particular alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tere-butyl and 2,2-dimethylpropyl. Derivative expressions such as "Ci-6 alkoxy", "Ci_6 alkylthio", "Ci_6 alkylsulfonyl" and "Ci-6 alkylamino" must be construed in accordance with the foregoing. Specific C3-7 cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Suitable aryl groups include phenyl and naphthyl, preferably phenyl. Suitable aryl-alkyl groups (Ci_6) include benzyl, phenylethyl, phenylpropyl and naphthylmethyl. Suitable heterocycloalkyl groups, which may comprise benzocondensate analogs thereof, include azetidinyl, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, indolinyl, imidazolidinyl, tetrahydropyranyl, piperidinyl, 1,2,4,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, piperazinyl. , morpholinyl and thiomorpholinyl. Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl groups. , pyrimidinyl and pyrazinyl. The term "halogen", as used herein, is intended to include fluorine, chlorine, bromine and iodine atoms. When the compounds of formula (I) have one or more asymmetric centers, they can accordingly exist as enantiomers. When the compounds of the invention possess two or more asymmetric centers, they may additionally exist as diastereoisomers. It should be understood that the invention extends to all such enantiomers and diastereomers, and to mixtures thereof in any proportion, including racemates. The formula (I) and the formulas represented later in this specification are intended to represent all individual stereoisomers and all possible mixtures thereof, unless otherwise stated or indicated. Additionally, the compounds of formula (I) can exist as tautomers, for example keto tautomers (CH2C = 0) -enol (CH = CHOH). The formula (I) and the formulas represented later in this specification are intended to represent the totality of the individual tautomers and all possible mixtures thereof, unless otherwise stated or stated. In one embodiment, R1 represents hydrogen. In another embodiment, R1 represents halogen, particularly fluorine or chlorine, especially fluoro. In a further embodiment, R1 represents Ci_6 alkyl, especially methyl. Typically, R1 is fluoro. In one embodiment, R 2 represents halogen, especially bromine or iodine. In another embodiment, R2 represents Ci_6 alkyl, especially methyl. In a specific embodiment, R2 is bromine. In another specific embodiment, R2 is iodine. Suitably, Ra represents methyl or ethyl, especially ethyl. Favorably, Rb represents hydrogen; or Ci-6 alkyl, C3_7 cycloalkyl- (Ci-6) alkyl, C3_7 heterocycloalkyl or C3-7 heterocycloalkyl- (Ci_6) alkyl, any of said groups being optionally substituted with one or more substituents. Conveniently, Rb represents hydrogen; or Ci-6 alkyl, aryl, aryl (Ci_6) alkyl, C3-7 heterocycloalkyl, C3_7 heterocycloalkyl (CI-E), heteroaryl or heteroaryl (Ci-6) alkyl, any of said groups being optionally substituted with one or more substituents. Conveniently, the group Rb, or the cyclic moiety NRbRc, may be unsubstituted, or substituted with one or more substituents, typically with one or two substituents. In one embodiment, the Rb group, or the cyclic moiety -NRbRc, is unsubstituted. In another embodiment, the Rb group, or the cyclic moiety -NRbRc, is monosubstituted. In a further embodiment, the Rb group, or the cyclic moiety -NRbRc, is disubstituted. Examples of typical substituents on Rb, or on the cyclic moiety -NRbRc, include Ci_6 alkyl, Ci-6 alkoxy, hydroxy, hydroxy-alkyl (Ci_6), amino-alkyl (Ci-6), (amino) (hydroxy) -alkyl (Ci-6), halogen, oxo, C2-6 alkylcarbonyl, carboxy, C2_6 alkoxycarbonyl, di-alkyl (d-6) -hydrazinylcarbonyl, amino, Ci_6 alkylamino, di-alkylamino (Ci-6), C2_6 alkylcarbonylamino, aminocarbonylamino, aminocarbonyl, C 1-6 alkyl-aminocarbonyl, di-alkyl (Ci 6) aminocarbonyl, aminosulfonyl, Ci_6 alkylsulfonyl and Ci_6-aminocarbonyl-Ci_6 alkyl. Additional examples include C 1-6 alkoxy (Ci-6) alkyl, carboxy-alkyl (Ci-6), C 2-6 alkoxycarbonyl (Ci-6), C 2-6 alkoxycarbonylamino and C 2-6 alkoxycarbonylamino (Ci_6) · Examples of particular substituents in Rb, or in the cyclic moiety -NRbRc, include methyl, methoxy, hydroxy, hydroxymethyl, 2-hydroxyethyl, aminomethyl, 2-amino-3-hydroxypropyl, fluoro, oxo, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, dimethylhydrazinylcarbonyl , amino, methylamino, 1,3-dimethylbutylamino, dimethylamino, acetylamino, aminocarbonylamino, aminocarbonyl, ethylaminocarbonyl, di-ethylaminocarbonyl, aminosulfonyl, methylsulfonyl and methylaminocarbonylmethyl. Additional examples include methoxymethyl, carboxymethyl, ethoxycarbonylmethyl, tert-butoxycarbonylamino and tert-butoxycarbonylaminomethyl. Examples of preferred substituents on Rb, or on the cyclic moiety -NRbRc, include Ci-6 alkyl, Ci-6 alkoxy (Ci_6) alkyl, hydroxy, hydroxy (Ci-6) alkyl, amino, amino-alkyl (Ci-6) 6) carboxymethyl, C 2-6 alkoxycarbonyl, C 2-6 alkoxycarbonyl (Ci_6), di-alkylamino (Ci_6), C2-6 alkoxycarbonylamino, and C2-6 alkoxycarbonylamino- (C6-6) alkyl. Examples of specific substituents in Rb, or in the cyclic moiety -NRbRc, include methyl, methoxymethyl, hydroxy, hydroxymethyl, 2-hydroxyethyl, amino, aminomethyl, carboxymethyl, tert-butoxycarbonyl, ethoxycarbonylmethyl, dimethylamino, tert-butoxycarbonylamino and tert-butoxycarbonylaminomethyl. Preferred values of Rb include hydrogen, methyl, ethyl, propyl, cyclopropylmethyl, azetidinyl, pyrrolidinyl, piperidinyl, azetidinylmethyl, dioxolanylmethyl, pyrrolidinylmethyl, morpholinylethyl, and morpholinylpropyl, wherein any such group may be optionally substituted with one or more substituents. Preferred substituents in this context include C 1-6 alkyl (especially methyl), hydroxy, amino, C 2-6 alkoxycarbonyl (especially tert-butoxycarbonyl) and di-C 1-6 alkylamino (especially dimethylamino). Specific values of Rb include hydrogen, methyl, 2-hydroxyethyl, 3-hydroxypropyl, l-hydroxyprop-2-yl, 2,3-dihydroxypropyl, 2-amino-2-methylpropyl, 2,2-dimethyl-3- (dimethylamino. ) propyl, cyclopropylmethyl, 1-tert-butoxycarbonylazetidin-3-yl, pyrrolidin-3-yl, 1-tert-butoxycarbonylpyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, 1-methylpiperidin-4-yl , 1-tert-butoxycarbonylpiperidin-3-yl, 1-tert-butoxy-carbonyl-piperidin-4-yl, 1-tert-butoxycarbonyl-azetidin-3-ylmethyl, 2,2-dimethyl- [1, 3] dioxolan- 4-ylmethyl, pyrrolidin-2-ylmethyl, 2- (morpholin-4-yl) ethyl and 3- (morpholin-4-yl) propyl. Typically, Rb represents hydrogen; or Ci_6 alkyl, optionally substituted with one or more, preferably one or two, hydroxy groups. Typical values of Rb include hydrogen, methyl, hydroxypropyl and dihydroxypropyl. In one embodiment, Rb represents hydrogen. In another embodiment, Rb represents methyl. In a further embodiment, Rb represents hydroxypropyl, especially 3-hydroxypropyl. In a further embodiment, Rb represents dihydroxypropyl, especially 2,3-dihydroxypropyl. In one embodiment, R ° is hydrogen. In another embodiment, Rc represents Ci-6 alkyl, especially methyl. In a further embodiment, Rc represents hydroxy-alkyl (Ci-6), e.g. hydroxyethyl (especially 2-hydroxyethyl). Alternatively, the -NRbRc moiety may conveniently represent azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl or homomorpholin-4-yl, wherein any of said groups may be optionally substituted with one or more substituents. The residue -NRbRc may also represent optionally substituted homopiperazin-1-yl. Particular values for the cyclic moiety -NRbRc include azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl and homopiperazin-1-yl, any of which may be groups optionally substituted with one or more substituents. Specific values of the cyclic moiety -NRbRc include 3-hydroxyazetidin-1-yl, 3-aminoazetidin-1-yl, 3- (aminomethylazetidin-1-yl, 3- (tert-butoxycarbonyl-amino) azetidin-1-yl, 3- (erc-butoxycarbonylamino-methyl) azetidin-1-yl, pyrrolidin-1-yl, 2- (methoxy-methyl) pyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl, 3-aminopyrrolidin-1-yl, 3- (tert-butoxycarbonyl-amino) pyrrolidin-1-yl, 2- (hydroxymethylperidin-1-yl, 4-aminopiperidin-1-yl, 4- (tert-butoxycarbonyl-amino) piperidin-1-yl, morpholin-4-yl 2- (hydroxymethyl) morpholin-4-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, 2- (hydroxymethyl) -piperazin-1-yl, 4- (2-hydroxyethyl-piperazin-1-yl) 4- (carboxymethyl-piperazin-1-yl) 4- (tere-butoxycarbonyl) -2- (hydroxy-methylpiperazin-1-yl) 4- (ethoxycarbonylmethyl) -piperazin-1-yl and homopiperazin-1-yl. , the cyclic moiety -NRbRc may be substituted with alkyl-, especially methyl, Particular values of -R ^ include pyrrolidin-1-yl, morpholin-4-yl, and 4-methylpiperazin-1-yl. Typically, R3 represents cyano, -C < ¾Ra, -CONR ^, or -CON (ORb) Rc, where Ra, R13 and Rc are as defined above. Conveniently, R3 represents cyano, -C02Ra or -CONR1 ^, especially cyano or -CONR'fc0, in which Ra, Rb and R ° are as defined above. Conveniently, R3 represents -CON (ORb) Rc, wherein R13 and Rc are as defined above. In one embodiment, R3 represents cyano. In another embodiment, R3 represents -C (¾Ra, where Ra is as defined above.In a further embodiment, R3 represents -CONR ^ 0, wherein Rb and Rc are as defined above In a further embodiment, R3 represents -CON (ORb) Rc, wherein Rb and Rc are as defined above In a further embodiment, R3 represents hydrogen A particular subgroup of compounds according to the invention is represented by the compounds of formula (II), and salts , solvates and ??? pharmaceutically acceptable oxides thereof: (?) wherein R 12 represents halogen; and R3 is as defined above. In a specific embodiment, R12 is bromine. In another specific embodiment R12 is iodine. Specific novel compounds according to the present invention include each of the compounds whose preparation is described in the accompanying examples, and pharmaceutically acceptable salts and solvates thereof.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, in association with one or more pharmaceutically acceptable carriers. The pharmaceutical compositions according to the invention may have a convenient form for oral, buccal, parenteral, nasal, topical, ophthalmic or rectal administration, or a convenient form for administration by inhalation or insufflation. For oral administration, the pharmaceutical compositions may be in the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium glycolate); or wetting agents (e.g., sodium lauryl sulfate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, and non-aqueous vehicles or preservatives. The preparations may also contain buffer salts, flavoring agents, coloring agents, or sweetening agents, as appropriate. Preparations for oral administration can be conveniently formulated to provide a controlled release of the active compound. For buccal administration, the compositions may have the form of tablets or lozenges formulated in a conventional manner. The compounds of formula (I) can be formulated for parenteral administration by injection, e.g. by bolus injection or infusion. Formulations for injection may be presented in unit dosage form, e.g. in glass ampoules or multi-dose containers, e.g. glass vials The compositions for injection may have forms such as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending agents, stabilizers, preservatives and / or dispersants. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use. In addition to the formulations described above, the compounds of formula (I) can also be formulated as a deposit type preparation. Such long-acting formulations can be administered by implantation or by intramuscular injection. For nasal administration or administration by inhalation, the compounds according to the present invention can be conveniently delivered in the form of an aerosol spray presentation for pressurized containers or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or gas mixture (a).

The compositions may, if desired, be presented in a pack or dispensing device which may contain one or more unit dosage forms containing the active ingredient. The package or dispensing device may be accompanied by instructions for administration.

For topical administration, the compounds according to the present invention can conveniently be formulated in a suitable ointment containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Particular vehicles include, for example, mineral oil, liquid petroleum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water. Alternatively, the compounds according to the present invention can be formulated in a suitable lotion containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Particular vehicles include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, benzyl alcohol, 2-octyldodecanol and water. For ophthalmic administration, the compounds according to the present invention can conveniently be formulated as micronized suspensions in isotonic and sterile saline adjusted in pH, either with or without a preservative such as a bactericidal or fungicidal agent, for example phenyluric nitrate, benzylalkonium or chlorhexidine acetate. Alternatively, for ophthalmic administration the compounds can be formulated into an ointment such as petrolatum. For rectal administration, the compounds according to the present invention can conveniently be formulated as suppositories. These can be prepared by mixing the active component with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the active component. Materials of this type include, for example, cocoa butter, beeswax and polyethylene glycols. The amount of a compound of the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound selected and the condition of the patient to be treated. In general, however, daily doses may comprise from about 10 ng / kg to 1000 mg / kg, typically from 100 ng / kg to 100 mg / kg, e.g. about 0.01 mg / kg to 40 mg / kg of body weight, for oral or buccal administration, from about 10 ng / kg to 50 mg / kg of body weight for parenteral administration, and from about 0.05 mg to around 1000 mg, vg from about 0.5 mg to about 1000 mg, for nasal administration or administration by inhalation or insufflation. The compounds of formula (I) above, and the N-oxides thereof, can be prepared by a process comprising reacting a compound of formula (III) or a W-oxide thereof, with a compound of formula (IV) ) (MY V) wherein R1, R2 and R3 are as defined above, and L1 represents a suitable leaving group. The leaving group L1 is typically a halogen atom, e.g. chlorine. The reaction is conveniently carried out, at a high temperature if necessary, in a suitable solvent, e.g. dimethylsulfoxide, typically under basic conditions, e.g. in the presence of an inorganic base such as sodium hydride. The intermediates of the formula (IV) above can be prepared by reaction of a compound of the formula (V): (V) wherein R1 and R2 are as defined above, with thiophosgene. The reaction is conveniently carried out in a suitable solvent, typically a mixture of chloroform and water. In another method, the compounds of formula (I) above wherein R3 represents -CONRbRc or -CON (ORb) Rc, and the N-oxides thereof, can be prepared by a process comprising reacting a compound of formula H -NRbRc or HN (ORb) Rc with a compound of formula (VI), or an N-oxide thereof: (VD where R1, R2, Rb and Rc are as defined above, in the presence of a condensing agent.) A suitable condensing agent is 1- (3-dimetho-1-aminoprop-1-yl) -3-carbodiimide hydrochloride ( EDC), in which case the reaction is conveniently carried out in the presence of 1-hydroxybenzotriazole (HOBT) and W-methylmorphine (NMM) The compounds of formula (VI) above can be prepared by reaction of the compound of formula (VII): (VH) with a compound of formula (V) as defined above.

The reaction can be conveniently carried out by treating the compound (V) with a base, e.g. lithium bis (trimethylsilyl) amide, in a suitable solvent, e.g. tetrahydrofuran, followed by the addition of the compound (VII). The Intermediate Compound of formula (VII) above can be prepared from a compound of formula (VIII): (vm) where Ra is as defined above; by saponification of the ester residue followed by oxidation of the methylsulfañyl group. The saponification of the ester residue -C02Ra in the compound (VIII) can be carried out by treatment with an alkaline base, e.g. sodium hydroxide, in a suitable solvent, e.g. an aqueous mixture of a lower alkanol such as methanol and a cyclic ether such as tetrahydrofuran. Oxidation of the methylsulfañyl group in the resulting compound can then be effected by treatment with a suitable oxidizing agent, e.g. Oxone® (potassium peroxymonosulfate), in an appropriate solvent, e.g. aqueous methanol. Intermediates of formula (VIII) above can be prepared by reaction of a compound of formula (III), wherein R3 is -C02Ra as defined above, with carbon disulfide, followed by treatment with a methyl halide such as Iodomethane. The reaction is conveniently carried out in a suitable solvent, e.g. dimethyl sulfoxide, in the presence of a base such as sodium hydride. In cases where they are not commercially available, the starting materials of formula (III) and (V) can be prepared by methods analogous to those described in the accompanying exas, or by standard methods well known in the art. It will be understood that any compound of formula (I) obtained initially by any of the above processes can, if appropriate, be subsequently processed into a further compound of formula (I) by methods well known in the art. By way of exa, a compound of formula (I) wherein R3 represents -C02Ra can be converted into the corresponding compound wherein R3 represents -CONH2 by treatment with ammonia, typically in a lower alkanol solvent, e.g. ethanol, at elevated temperature and pressure. Alternatively, a compound of formula (I) wherein R3 represents -C02Ra can be converted to the corresponding compound wherein R3 represents -CONRbRc by treatment with the appropriate amine of formula H-NRbRc in the presence of trimethylaluminum. A compound of formula (I) wherein R3 represents -C02Ra can be converted into the corresponding compound wherein R3 represents hydrogen by treatment with an alkaline reagent such as lithium hydroxide under forced conditions, e.g. by heating to reflux in a mixture of ethanol and water. A compound of formula (I) wherein R3 contains a 2,2-dimethyl- [1, 3] dioxolan-4-ylmethyl moiety can be converted into the corresponding compound wherein R3 contains a 2,3-dihydroxypropyl moiety by treatment with a mineral acid such as hydrochloric acid. A compound of formula (I) wherein R3 contains a nitrogen atom to which a tert-butoxycarbonyl group (BOC) is attached can be converted to the corresponding compound wherein R3 contains an N-H functionality by treatment with an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid. A compound of formula (I) wherein R3 contains an N-H functionality can be converted into the corresponding compound wherein R3 contains a nitrogen atom to which an ethoxycarbonylmethyl group is attached by treatment with ethyl chloroacetate, typically in the presence of triethylamine; the resulting compound can then be converted into the corresponding compound wherein R3 contains a nitrogen atom to which a carboxymethyl group is attached by treatment with an alkaline acid such as sodium hydroxide, typically in an aqueous solution of a lower alkanol such as ethanol. The pyridine N-oxide derivative of a compound of formula (I) can be converted to the corresponding compound of formula (I) by treatment with triphenylphosphine and phosphorus trichloride. In the case where a mixture of products is obtained from any of the processes described above for the preparation of compounds according to the invention, the desired product can be separated from it in an appropriate step by conventional methods such as preparative HPLC; or column chromatography using, for example, silica and / or alumina in association with an appropriate solvent system. Where the processes described above for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers can be separated by conventional techniques. In particular, where it is desired to obtain a particular enantiomer of a compound of formula (I), it can be produced from a corresponding mixture of enantiomers using any conventional method suitable for resolving enantiomers. Thus, for example, the diastereomeric derivatives, e.g. salts, can be produced by reaction of a mixture of enantiomers of formula (I), e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base. The diastereoisomers can then be separated by any convenient means, for example by crystallization, and the desired enantiomer can be recovered, e.g. by treatment with an acid in the case where the diastereomer is a salt. In another resolution process, a racemate of formula (I) can be separated using chiral HPLC. In addition, if desired, a particular enantiomer can be obtained by using an appropriate chiral Intermediate Compound in one of the processes described above. Alternatively, a particular enantiomer can be obtained by performing a specific enzymatic biotransformation of enantiomers, e.g. a hydrolysis of esters using an esterase, and subsequent purification only of the enantiomerically pure hydrolyzed acid from the unreacted antipoded ester. Chromatography, recrystallization and other conventional separation methods can also be used with intermediates or final products in cases where it is desired to obtain a particular geometric isomer of the invention.

During any of the above synthesis sequences it may be necessary and / or desirable to protect sensitive or reactive groups in any of the molecules in question. This can be done by means of conventional protecting groups, such as those described in Protectíve Groups in Organic Chemistry, compiler J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G. . Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3rd edition, 1999. Protective groups can be removed at any convenient later stage using methods known in the art. The following examples illustrate the preparation of the compounds according to the invention. The compounds according to this invention strongly inhibit the activity of the human MEK enzyme. MEK in vitro assay The activity of MEK 1 was measured in a cascade assay initiated by active Raf, by activation of MEK, Erk2 and subsequent phosphorylation of the fluorescein-labeled Erk-tide substrate in a fluorescence polarization-based assay (IMAP). . The assay was carried out in 20 mM Tris + 5 mM MgCl2 + 2 mM DL-dithiothreitol + 0.01% Tween 20, pH 7.2, containing 1.5 nM deactivated MEK, 100 nM deactivated Erk and Erk -turns 200 nM (all concentrations are final concentrations). Compounds, or DMSO controls, were tested at a final concentration of 2% DMSO, and the assay was initiated in the presence of 5 μM ATP. by adding 1.25 nM active Raf in assay buffer. After 20 minutes at room temperature, stop solution followed by IMAP binder beads was added, the test mixture was then incubated for 90 min at room temperature (with shaking) and then read on a LJL HT reader from Molecular Devices. When tested in the above assay, it was found that all the compounds of the accompanying examples inhibit the human MEK enzyme with IC5 values of 10 μ? or better. EXAMPLES Abbreviations utili EtOAc - Ethyl acetate DMSO - Dimethylsulfoxide THF - Tetrahydrofuran DCM - Dichloromethane Ether - diethyl ether CDC13 - Deuteriochloroform MeOH - Methanol MeCN - Acetonitrile EtOH - Ethanol ES - Electrospray DMF - N, N - HOBT - 1 - dimethylformamide hydroxybenzotriazole Si02 - Silica NMM - N-methylmorpholine h - hour (s) min - minute (s) t. to . - temperature aq - aqueous sat. - saturated RT - retention time BOC - tert-LiHMDS butoxycarbonyl bis (trimethylsilyl) lithium amide MCPBA - 3-chloroperoxybenzoic acid EDC - 1- (3-dimethylaminopropyl) -3-carbodiimide hydrochloride All NMR spectra were obtained at 300 MHz or 400 MHz. The compounds were named with the help of the ACD Labs Nomenclature (v. 7.0) supplied by Advanced Chemical Development, Toronto, Canada. LCMS Standard Method The LC-MS system used comprises a Waters Alliance 2795 HT quaternary HPLC detector, a Waters 996 photodiode network (PDA) detector and a Waters ZQ 4000 single-quadrupole mass spectrometer. The ZQ instrument can acquire data simultaneously in ionization modes by positive and negative electrospray.

Mass spectrometer ZQ Capillary 3.5 kV Cone 50 V Extractor 2 V Temp. Source 80 ° C Temp. of 200 ° C Gas cone 150 1 / h desolvation Gas 250 1 / h Multiplier 650 V desolvation The data were acquired in a full scan from 100 to 1000 m / z. Sweep duration 0.80 s Intervalled delay 0.20 s HPLC Analytical reverse phase separation was performed on a Phenex C18 Gemini instrument 50 x 4.6 mm with 5 um silica. Injection volume 5 μ? UV data 240 at 400 nm Sample temperature 20 ° C Column temperature 30 ° C Flow rate 0.9 ml / min Division for ZQ -0.40 ml / min Solvent A: 90% NH4C02 10 mM in water / 0, 1% formic acid / 10% CH3CN Solvent B: 90% CH3CN / 0.1% formic acid / 10% NH4C02 10 mM in water Solvent C: 90% NH4C02 10 mM in water / 0.1% ammonia / 10% CH3CN Solvent D: CH3CN / 10% NH4C02 10 mM in water / 0.1! ammonia Gradient program For the method 5 95 pH 3 Time (min) A% B% Flow rate Curve 0, 00 95, 0 5,0 0, 900 1 2, 00 5, 0 95, 0 0, 900 6 4, 00 5.0 95, 0 0, 900 6 5, 00 95, 0 5.0 0, 900 For the method 5_95_pH 10 Time (min) A% Flow Rate Curve 0.00 95.0 5, 0 0.900 1 2.00 5.0 95, 0 0, 900 6 4.00 5.0 95, 0 0, 900 6 5.00 95.0 5, 0 0.900 6 Preparative UV-HPLC The LC system comprises a Waters 2525 quaternary pump, a Waters 996 photodiode system detector (PDA), a Waters 2700 sample manager, a Fluidics Column organizer and a Waters fraction collector that operates in reverse phase in one of two pH systems. Low pH system (approximately pH 3.2) Reverse phase separation was performed on a Luna C18 instrument of Phenomenex 100 x 21.2 mm with silica of 5 μp ?. Injection volume 500 μ? UV data 254 nm Flow rate 20 ml / min Solvent A 90% water / 10% CH3CN / 0.1% formic acid Solvent B 90% CH3CN, 10% water / 0.1% formic acid High pH system (approximately pH 9.5) Reverse phase separation was carried out on a Phenomenex C18 Gemini instrument 150 x 21.2 mm with silica of 10 μp ?.

Injection volume 500 μ? UV data 254 nm Flow rate 20 ml / min Solvent C 90% NH4HCO2 10 mM in water / 0.1% ammonia / 10% CH3CN Solvent D 90% CH3CN / 10% NH4HC02 10 mM in water / 0.1% ammonia Typical gradient profiles are described below: Gradient Program for the pH Method Low Time Á% B% C% D% Flow Ci 0.9 95.0 5.0 0.0 0.0 20 1 9.00 5.0 95.0 0.0 0.0 20 6 11.00 5.0 95.0 0.0 0.0 20 6 11.50 95.0 5.0 0.0 0.0 20 6 12.00 95.0 5.0 0.0 0.0 20 6 Gradient Program for the pH Method High Time Time A% B% C% D% Flow C 0.00 0.0 0.0 95.0 5.0 20 1 9.00 0.0 0.0 5.0 95.0 20 6 11.00 0.0 0.0 5.0 95.0 20 6 11.50 0.0 0.0 95.0 5.0 20 6 12.00 0.0 0.0 95.0 5.0 20 6 INTERMEDIATE COMPOUND 1 2-Fluoro-4-iodo-l-isothiocyanatobenzene Thiophosgene (3.55 ml, 46.4 mmol) was added to a rapidly stirred mixture of 2-fluoro-4-iodoaniline (10.0 g, 42.2 mmol) in CHC13 (200 ml) and water (100 ml). The mixture was stirred at t.a. for 16 h. The organic phase was dried (Na2SO4) and concentrated in vacuo to give the title compound as an off-white crystalline solid (11.8 g, quantitative). d? (DMSO-dg) 7.87 (1H, dd, J = 1.8, 9.5 Hz), 7.63 (1H, ddd, J 1.0, 1.8, 8.4 Hz), 7, 25 (1H, dd, J 8.2, 8.4 Hz). INTERMEDIATE COMPOUND 2 2- [(4-Bromo-2-fluorophenyl) amino] thieno [2,3-d] pyridine-3-carboxylic acid ethyl ester Prepared from (2-chloropyridine-3-yl) ethyl acetate ( DH Bremner et al., Synthesis, 1997, 949) (500 mg, 2.5 mmol) and 4-bromo-2-fluorophenyl isothiocyanate (580 mg, 2.5 mmol) by the method of Example 1. The compound of title was obtained as an off-white solid (390 mg, 40%). d? (DMSO-d6) 10.37 (1H, br s), 8.25 (1H, dd, J 1.4, 8.1 Hz), 8.19 (1H, d, J 4.8 Hz), 7 , 69 (1H, dd, J l, 8, 10.2 Hz), 7, 56-7, 45 (2H, m), 7.32 (1H, dd, J 4.5, 8.1 Hz), 4.35 (2H, q, J 7.1 Hz), 1.37 (3H, t, J 7.1 Hz), LCMS (ES +) RT 4.66 minutes, 395 ((79Br) + H) +. INTERMEDIATE COMPOUND 3 3- (tert-Butyldimethylsilanyloxy) propylamine To a solution of N- (3-hydroxypropyl) phthalimide (5.25 g, 24.36 mmol) in DMF (20 mL) was added imidazole (16.6 g, 240 mmole) and tert-butyl chloride were added if 1 i (19 g, 120 mmol). The reaction mixture was stirred at room temperature for 18 hours before volatile matter was removed in vacuo and a portion of the crude product was subjected to column chromatography (SiO2, 1: 1 DCM / hexanes) to give 2 - [3- (t erc-but ildimet i 1 silanyl-oxy) propyl] isoindol-1,3-dione as a clear oil (5 g). 2 - [3- (tert-Butyldimethyl-lysilanyloxy) -propyl] -isoindole-1,3-dione (5 g, 26.4 mmol) was dissolved in ethanol (50 mL) and methylahydrazine (2, 94 ml, 55.4 mmol). The reaction mixture was heated at 75 ° C for 8 hours before performing the concentration in vacuo. The crude residue was triturated with a mixture of diethyl ether (150 ml) and hexanes (50 ml) and the resulting solid was removed by filtration. The solvents were removed in vacuo to give the title compound as a pale yellow oil (1.8 g, 61%). d? (DMSO-d6) 4.58 (2H, br. S), 3.63-3.58 (2H, m), 2.67-2.62 (2H, m), 1.60-1.55 (2H, m), 0.83 (9H, d, J 1 , 1 Hz), 0.00 (6H, d, J 1.2 Hz), LCMS (ES +) RT 1.77 minutes, 190 (M + H) +. INTERMEDIATE COMPOUND 4 2-Methylsulfanylthieno [2,3-b] pyridine-3-carboxylic acid ethyl ester To a solution of ethyl (2-chloropyridin-3-yl) acetate (DH Bremner et al., Synthesis, 1997, 949 ) (8.0 g, 40.0 mmol) and carbon disulfide (3.18 g, 42.0 mmol) in DMSO (100 mL) was added portionwise sodium hydride (2.4 g, 60.0 mmol). ). After 60 minutes of stirring at room temperature, the mixture was heated at 80 ° C for 2 hours. After this time, the reaction mixture was allowed to cool to room temperature and methyl iodide (7.6 g, 54.0 mmol) was added. After 18 hours ice (50 ml) was added and a yellow precipitate formed which was isolated by filtration to give the title compound as a gray solid (7.95 g, 78%). d? (DMSO-d6) 8.60 (1H, dd, J 1.6, 8.2 Hz), 8.46, (1H, dd, J 1.6, 4.6 Hz), 7.35 (1H, dd, J 4.6, 8.2 Hz), 4.48 (2H, q, J l, 1 Hz), 2.71, (3H, s), 1.49 (3H, t, J 7, l Hz). INTERMEDIATE COMPOUND 5 2-Methylsulfanylthieno [2, 3-b] pyridine-3-carboxylic acid A mixture of Intermediate 4 (12.5 g, 50.0 mmol) in THF (200 mL) and MeOH (50 mL) was treated with sodium hydroxide solution (10% solution in water, 50 ml) and stirred at room temperature for 18 h. After this time, the reaction mixture was reduced in vacuo to one third of its volume. Water (50 ml) was then added before adding 10% HC1 until a white precipitate formed. This was filtered to give the title compound as a white crystalline solid (10.6 g, 95%). d? (DMSO-d6) 13.50-13.20 (1H br s), 8.55 (1H, dd, J 1.2, 8.2 Hz), 8.48 (1H, dd, J 1.3, 4.5 Hz), 7.49 (1H, dd, J, 6, 8.2 Hz), 3.25 (3H, s). INTERMEDIATE COMPOUND 6 2-Methanesulfinyl-thieno [2,3-b] pyridine-3-carboxylic acid oxone (14.5 g, 24.0 mmol) dissolved in water (25 ml) was added to a rapidly stirred mixture of Intermediate Compound 5 (10.6 g, 47 mmol) in eOH (250 mL). The mixture was stirred at room temperature for 4 h. The reaction mixture was separated between DCM (300 ml) and water (200 ml). The organic layer was dried (Na2SO4) and concentrated in vacuo to give the title compound as a white crystalline solid (10.0 g, 88%). d? (DMSO-d6) 14.20-13.80 (1H, br s), 8.73 (1H, dd, J 1.7, 8.3 Hz), 8.69 (1H, J 1.7, 4 , 6 Hz), 7.61 (1H, dd, J 4.6, 8, 3 Hz), 3.05 (3H, s). INTERMEDIATE COMPOUND 7 2- [(2-Fluoro-4-iodophenyl) amino] thieno [2, 3-b] -pyridine-2-carboxylic acid To a stirred solution of 2-fluoro-4-iodoaniline (6.0 g, 25 mmol) in THF (100 mL) at 0 ° C (ice bath) was added LiHMDS (1.0 solution in THF, 20.0 mL, 20.0 mmol) slowly. The mixture was allowed to stir at room temperature for 30 minutes before cooling to 0 ° C, and Intermediate 6 (2.00 g, 8.3 mmol) was added in portions. The mixture was stirred at room temperature for 1 hour. After this time, the reaction mixture was poured into ice and when it was at room temperature citric acid was added until a precipitate formed. The mixture was filtered to give the title compound as a light brown crystalline solid (2.9 g, 84%). d? (DMSO-d6) 14, 00-13.00 (1H, br s), 10.80 (1H, s), 8.36 (1H, dd, J 1.3, 8.1 Hz), 8.32 (1H, dd, J, 1.3, 4.8 Hz), 7.84 (1H, dd, J 1.8, 10.1 Hz), 7.69 (1H, d, J 8.3 Hz) , 7.54 (1H, m), 7.42 (1H, dd, J 8, 3, 4.8 Hz). INTERMEDIATE COMPOUND 8 4-Iodo-1-isothiocyanato-2-methylbenzene To a stirred solution of 4-iodo-2-methylaniline (1.0 g, 4.2 mmol) in DCM (50 mL) was added water (20 mL). ) followed by thiophosgene (490 mg, 4.2 mmol). The reaction mixture was stirred overnight before the layers were separated and the organic layer was dried (Na2SC >.4) and evaporated in vacuo to give the desired product as a brown solid (1.05 g, 89%). d? (CDC13) 7.75 (1H, d, J 1.2 Hz), 7.62 (1H, dd, J 1.2, 8.3 Hz)., 7.15 (1H, d, J8.3 Hz ), 2.20 (3H, s). INTERMEDIATE COMPOUND 9 2-Chloro-4-iodo-l-isothiocyanatobenzene To a stirred solution of 2-chloro-4-iodoaniline (1.0 g, 3.9 mmol) in CCM (50 mL) was added water (20 mL) followed by thiophosgene (476 mg, 4.1 mmol). The reaction mixture was stirred overnight before the layers were separated and the organic layer was dried (Na2SO4) and evaporated in vacuo to give the desired product as a brown solid (1.0 g, 86%). d? (CDC13) 7.79 (1H, d, J 1.9 Hz), 7.58 (1H, dd, J 1.9, 8.4 Hz), 6.97 (1H, d, J 8.4 Hz) ). INTERMEDIATE COMPOUND 10 (2R) -2- [(. {2- [(2-Fluoro-4-iodophenyl) amino) thieno [2, 3-b] pyridine-3-carbonyl tert -butyl ester} amino) methyl] pyrrolidine-l-carboxylic acid 1- (3-Dimethylaminopropyl) -3-carbodiimide hydrochloride (13.9 mg, 0.72 mmol) was added to a solution of Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole (98 mg, 0.72 mmol), N-methylmorpholine (0.11 ml, 0.99 mmol) and (R) -2- (aminomethyl) -1-BOC-pyrrolidine (144 mg, 0.72 mmol) in N, N-dimethylformamide (5 ml). The reaction mixture was stirred at t.a. for 20 h, and then poured into EtOAc (25 mL). The organic solution was washed with saturated brine (3 x 25 mL), dried (Na2SO, j), filtered and concentrated in vacuo to give a brown solid. The crude product was subjected to column chromatography (Si02, 4: 1 hexanes / EtOAc) to give the title compound, which was evaporated in ether to give a hard foam (135 mg, 63%). d? (CDC13) 11.67 (1H, s), 8, 35-8, 33 (2H, m), 8.04 (1H, br s), 7, 54-7, 43 (3H, m), 7, 32-7.30 (1H, m), 4.19 (1H, m), 3, 82-3, 78 (1H, m), 3, 53-3, 35 (3H, m), 2.18- 1.86 (3H, m), 1.78 (1H, m), 1.45 (9H, s). INTERMEDIATE COMPOUND 11 (2S) -2- [(. {2- [(2-Fluoro-4-iodophenyl) amino] thieno [2, 3-b] pyridine-3-carbonyl) tert-butyl ester. amino) -methyl] pyrrolidine-l-carboxylic acid was prepared from Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole (98 mg, 0.78 mmol), N-methylmorpholine (0.11 ml, 0.99 mmol), l- (3-dimethylaminopropyl) -3-carbodiimide hydrochloride (139 mg , 0.72 mmol) and (S) -2- (aminomethyl) -1-BOC-pyrrolidine (144 mg, 0.72 mmol, by the method of Intermediate Compound 10. The title compound was evaporated in ether to give a colorless hard foam (139 mg, 64%) d? (CDC13) 11.67 (1H, s), 8, 35-8, 33 (2H, m), 8.04 (1H, br s), 7, 54-7, 43 (3H, m), 7, 32-7, 30 (1H, m), 4.19 (1H, m), 3.82-3.78 (1H, m), 3.53- 3.35 (3H, m), 2.18-1.86 (3H, m), 1.78 (1H, m), 1.45 (9H, s) INTERMEDIATE COMPOUND 12 Acid (2-chloropyridin-3) -yl) acetic acid 2-Chloro-3- (cyanomethyl) pyridine (DH Bremner et al., Syn.thesis, 1997, 949) (10.3 g, 67.1 mmol) in concentrated HC1 (100 ml) was refluxed. ) for 3 h.The reaction mixture was concentrated in vacuo and the residue was suspended in water.The white solid was recrystallized by filtration and washed with water, after which it was dried at room temperature. providing the required product (11.15 g). d? (DMSO-de) 12.60 (1H, br s), 8.32 (1H, dd, J 4.7, 1.9 Hz), 7.86 (1H, dd, J 7.5, 1.9 Hz), 7.40 (1H, dd, J 7.5, 4.7 Hz), 3.75 (2H, s), LCMS (ES +) RT 1.85 minutes, 174 (M + H) +. INTERMEDIATE COMPOUND 13 (2-Chloropyridin-3-yl) acetic acid methyl ester To a suspension of Intermediate 12 (3.88 g, 22.6 mmol) in methanol was added acetyl chloride (1.8 ml, 24.9 mmol) and the mixture was heated at 70 ° C for 18 hours. The solvents were removed in vacuo to give the title compound as a light brown oil (4.63 g, quantitative). d? (DMSO-de) 8.35 (1H, dd, J 4.7, 1.9 Hz), 7.88 (1H, dd, J 8.5, 1.9 Hz), 7.43 (1H, dd) , J 8.5, 4.7 Hz), 3.80 (2H, s), 3.65 (3H, s), LCMS (ES +) RT 2.40 minutes, 186 (M + H) +. INTERMEDIATE COMPOUND 14 2- [(2-Fluoro-4-iodophenyl) -amino] thieno [2, 3-b] pyridine-3-carboxylic acid methyl ester To a solution of Intermediate 13 (4.1 g, 22, 1 mmol) and Intermediate 1 (6.16 g, 22.1 mmol) in dry DMSO under nitrogen was added sodium hydride (1.05 g, 24.3 mmol, 60% by weight dispersion in mineral oil). The mixture was stirred at room temperature for 15 minutes and then heated at 90 ° C for 3 hours. The reaction mixture was cooled, and then poured into ice water (200 ml). The aqueous phase was extracted with EtOAc (3 x 200 mL), the combined organic extracts were washed with brine, dried (MgSO 4), filtered and the solvents were removed in vacuo. The sticky yellow solid was triturated with ethanol to give a fine yellow solid which was collected by filtration, washed with diethyl ether and dried under suction to give the title compound as a pale yellow solid (1.73 g). d? (DMSO-d6) 10.30 (1H, s), 8.36-8.31 (2H, m), 7.87 (1H, dd, J 1.9, 10.0 Hz), 7.70 ( 1H, d, J6.6 Hz), 7.51 (1H, t, J 8.5 Hz), 7.42 (1H, dd, J 5.7, 8.1 Hz), 3.94 (3H , s), LCMS (ES +) RT 4.00 minutes, 429 (M + H) +.

INTERMEDIATE CO 2 2- (2-Chloropyridin-3-yl) -N-methoxy-N-methylacetamide Intermediate 12 (500 mg, 2.9 mmol) in dichloroethane (20 mL) with N, O-dimethylhydroxylamine (300 mg, 3.04 mmol), EDC (583 mg, 3.04 mmol) and N-methyl-morpholine (0.98 mL, 8.70 mmol) were stirred at rt. for 18 h. The reaction mixture was washed with 2M HC1, and the organic phase was dried (magnesium sulfate) and concentrated in vacuo. Chromatography (Si02; 1: 1 ethyl acetate: DCM) afforded the title compound (320 mg) as a white solid. d? (DMSO-d6) 8.31 (1H, dd, J 4.7, 1.9 Hz), 7.81 (1H, dd, J 7.5, 1.9 Hz), 7.40 (1H, dd) , J 7.5, 4.7 Hz), 3.93 (2H, s), 3.76 (3H, s), 3.15 (3H, s), LCMS (ES +) RT 2.22 minutes, 215 / 217 (M + H) +. INTERMEDIATE COMPOUND 16 2- (2-Chloro-1-oxypyridin-3-yl) -N-methoxy-N-methylacetamide Intermediate 15 (270 mg, 1.25 mmol) was dissolved in DCM (5 mL) and treated with mCPBA (324 mg, 1.88 mmol). After stirring at a.t. for 3 days, the reaction mixture was poured directly into a flash column and chromatographed (Si02; ethyl acetate: 5% methanol in ethyl acetate), yielding the required product (265 mg), as a white solid. d? (DMS0-d6) 8.39 (1H, dd, J 5.4, 2.5 Hz), 7.37-7.35 (2H, m), 3.98 (2H, s), 3.76 ( 3H, s), 3.15 (3H, s), LCMS (ES +) RT 1.81 minutes, 231/233 (M + H) +.

EXAMPLE 1 2- [(2-Fluoro-4-iodophenyl) amino] thieno [2,3- £ > ] ethyl pyridine-3-carboxylate Sodium hydride (650 mg of a 60% dispersion in mineral oil, 16.2 mmol) was added portionwise over 10 min to a mixture of Intermediate Compound 1 (3.75 g, , 5 mmol) and ethyl (2-chloropyridin-3-yl) acetate (DH Bremner et al., Synthesis, 1997, 949) (2.7 g, 13.5 mmol) in DMSO (25 mL). When the evolution of gas had ceased, the mixture was heated to 70 ° C for 3 h and then left at t.a. during one night. Water (150 ml) was added and the resulting solid liquid was decanted. The solid mass was treated with ethanol (40 ml) to give a fine white suspension which was separated by filtration, washed with ethanol (10 ml) and ether (2 x 15 ml) and dried in vacuo at 40 ° C. to give the title compound as a white solid (2.90 g, 48%). d? (DMSO-d6) 10.40 (1H, s), 8, 40-8, 30 (2H, m), 7.85 (1H, dd, J 1.9, 10.1 Hz), 7.70 ( 1H, d, J 8.5 Hz), 7, 55-7, 49 (1H, m), 7.43 (1H, dd, J 4.9, 8.0 Hz), 4.43 (2H, q , J 7.9 Hz), 1.41 (3H, t, J1.9 Hz), LCMS (ES +) RT 5.27 minutes, 443 (M + H) +. EXAMPLE 2 2- [(2-Fluoro-4-iodophenyl) amino] -A / -methylthieno [2,3-b] pyridine-3-carboxamide Trimethylaluminum (1.5 ml of a 2M solution in hexane, 3, 0 mmol) was added to a solution of methylamine (1.5 ml of a 2M solution in THF, 3.0 mmol) in toluene (5 ml). After 5 min, Example 1 (250 mg, 0.60 mmol) was added and the mixture was heated at 100 ° C for 4 h. After cooling, the reaction mixture was quenched with saturated solution of ammonium chloride (75 ml) and HC1 (10 ml, 2M) and then extracted with EtOAc (80 ml). The organic phase was dried (Na2SO4) and concentrated in vacuo to give a solid. Trituration with ether (30 mL) and filtration gave the title compound as an off-white solid (138 mg, 57%). d? (CDC13) 11.13 (1H, br s), 8.25 (1H, dd, J 1.4, 4.7 Hz), 7.80 (1H, dd, J 1.4, 8.2 Hz) , 7.46-7.42 (2H, m), 7.33 (1H, dd, J 8, 3, 8.3 Hz), 7.21 (1H, dd, J 4.7, 8.2 Hz) ), 5.82 (1H, br s), 3.00 (3H, d, J 4.8 Hz), LCMS (ES ") RT 3.63 minutes, 426 (MH) ~ EXAMPLE 3 2- [( 2-Fluoro-4-iodophenyl) amino] -A7 A7-dimethylthieno [2, 3-b] pyridine-3-carboxamide Prepared from Example 1 (100 mg, 0.23 mmol) and dimethylamine (0.35 ml) of a 2.0M solution in THF, 0.7 mmol) by the method of Example 2. The title compound was obtained as a white solid (21 mg, 20%) d (DMSO-d6) 9.12 ( 1H, s), 8.35 (1H, dd, J 1.6, 4.7 Hz), 7.77 (1H, dd, J 1.6, 8.1 Hz), 7.67 (1H, dd , J 1.9, 10.6 Hz), 7.48 (1H, dd, J 1.1, 1.9 Hz), 7.35 (1H, dd, J 4.7, 8.0 Hz), 7.15-7.10 (1H, m), 2.87 (6H, s), LCMS (ES +) RT 3.29 minutes, 442 (M + H) +.

EXAMPLE 4 N- (2-Fluoro-4-iodophenyl) -3- (morpholin-4-ylcarbonyl) -thieno [2, 3-b] pyridin-2-amine Prepared from Example 1 (250 mg, 0, 60 mmol) and morpholine (0.26 ml, 3 mmol) by the method of Example 2. The title compound was obtained as a white solid (215 mg, 78%). d? (DMSO-d6) 9.22 (1H, br s), 8.34 (1H, dd, J 1.4, 4.6 Hz), 7.81 (1H, dd, J 1.4, 8.0 Hz), 7.68 (1H, dd, J 1.9, 10.5 Hz), 7.50-7.46 (1H, m), 7.35 (1H, dd, J 4.6, 8, 0 Hz), 7.13 (1H, dd, J 8.6, 8.6 Hz), 3.54-3.48 (4H, m), 3.43-3.39 (4H, m), LCMS (ES +) RT 3.17 minutes, 484 (M + H) +. EXAMPLE 5 N- (2-Fluoro-4-iodophenyl) -3- [(4-methylpiperazin-1-yl) -carbonyl] thieno [2, 3-b] pyridin-2-amine Trimethylaluminum (1.5 ml. from a 2M solution in hexane, 3.0 mmol) to a solution of 1-methylpiperazine (0.333 mL, 3.0 mmol) in toluene (5 mL). After 10 min, Example 1 (250 mg, 0.60 mmol) and toluene (2 mL) were added and the mixture was heated at 90 ° C for 6 h. After cooling, the mixture was quenched with NaOH (50 ml, 1) and extracted with EtOAc (50 ml plus 25 ml). The combined organic extracts were washed with saturated brine (50 ml), dried (Na 2 SO 4) and concentrated in vacuo to give a yellow solid. Trituration with hexane / ether (10: 1, 30 mL) and filtration gave the title compound as a pale yellow solid (245 mg, 87%). d? (DMSO-d6) 9, 13 (1H, br s), 8.37 (1H, br d, J 4.4 Hz), 7.79 (1H, br d, J 7.8 Hz), 7.67 (1H, br d, J 10.4 Hz), 7.47 (1H, br d, J 8.4 Hz), 7.37 (11-1, dd, J 4.7, 8.1 Hz), 7.10 (1H, m), 3.30 (4H, br s), 2.21 (4H, br s), 2.14 (3H, s), LCMS (ES) RT 2.09 minutes, 497 (M + H) +. EXAMPLE 6 2- [(4-Bromo-2-fluorophenyl) amino] -N- (2,3-dihydroxy-propyl) thieno [2,3-b] pyridine-3-carboxamide. Trimethylaluminum (0.95 ml. a 2M solution in hexane, 1.90 mmol) was added to a solution of 2,2-dimethyl-1,3-dioxolane-4-methanamine (249 mg, 1.9 mmol) in toluene (4 mL). After 2 minutes, Intermediate 2 (150 mg, 0.38 mmol) was added and the mixture was heated at 90 ° C for 4 h. After cooling, the reaction mixture was quenched with saturated solution of ammonium chloride (5 mL) and HC1 (5 mL, 2M), stirred, and then extracted with EtOAc (2 x 25 mL) and DC (25 mL). ). The organic phase was dried (Na2SO4) and concentrated in vacuo to give a solid. Trituration with ether / hexane (1: 3, 10 mL) and filtration gave the title compound as a white solid (95 mg, 57%). d? (DMSO-d6) 10.64 (1H, br s), 8.36 (111, dd, J 1.4, 4.7 Hz), 8.20 (1H, dd, J 1.4, 8.2 Hz), 7.89 (1H, dd, J 8.8, 8.8 Hz), 7.69 (1H, dd, J 2.1, 10.6 Hz), 7.58 (1H, dd, J 8.8, 8.8 Hz), 7.48-7.41 (2H, m), 4.86 (1H, d, J 5.0 Hz), 4.64 (1H, t, J 5.7 Hz), 3.72-3.66 (1H, m), 3.52-3.36 (3H, m), 3.31-3.22 (1H, m), LCMS (ES +) RT 2.80 minutes, 440 (M (79Br) + H) +. EXAMPLE 7 2- [(2-Fluoro-4-iodophenyl) amino] -N- (2,3-dihydroxy-propyl) thieno [2, 3-b] pyridine-3-carboxamide Prepared from Example 1 (150 mg, 0.34 mmol) and 2,2-dimethyl-1,3-dioxolane-4-methanamine (0.14 mL, 1.0 mmol) by the method of Example 6. The title compound was obtained as a solid. pale yellow (94 mg, 57%). d? (DMSO-d6) 10.68 (1H, s), 8, 36-8, 35 (1H, m), 8.20 (1H, dd, J 1.2, 8.2 Hz), 7, 90- 7, 87 (1H, m), 7.76 (1H, dd, J 1.7, 10.4 Hz), 7, 62-7, 59 (1H, m), 7, 45-7, 40 (2H , m), 4.86 (1H, d, J 5.0 Hz), 4.64 (1H, t, J 5.7 Hz), 3.72-3.64 (1H, m), 3.51 -3.41 (3H, m), 3.40-3.34 (1H, m), LC S (ES +) RT 2.91 minutes, 488 (M + H) +. EXAMPLE 8 2- [(2-Fluoro-4-iodophenyl) amino] thieno [2, 3-b] pyridine-3-carboxylate-7-ethyl oxide It was prepared from Intermediate 1 (2.38 g, 8 , 58 mmol) and ethyl (2-chloro-l-oxidopyridin-3-yl) acetate (DH Bremner, et al., Synthesis, 1997, 949) (1.85 g, 8.58 mmol) by the method of Example 1. The title compound was obtained as a pale yellow solid (3.10 g, 79%). d? (DMSO-de) 10.31 (1H, br s), 8.20 (1H, d, J 5.9 Hz), 7.94 (1H, d, J 7.8 Hz), 7.89 (1H , dd, J 1.8, 10.0 Hz), 7.72 (1H, d, J 8.4 Hz), 7.55-7.46 (2H, m), 4.41 (2H, q, J 8.4 Hz), 1.40 (3H, t, J 7, l Hz), LCMS (ES +) RT 3.44 minutes, 459 (M + H) +. EXAMPLE 9 N-2, 3-Dihydroxypropyl) -2- [(2-fluoro-4-iodophenyl) amino] -thieno [2, 3-b] pyridine-3-carboxamide-7-oxide. Prepared from Example 8 (200 mg, 0.43 mmol) and 2, 2-dimethyl-1,3-dioxolane-4-methanamine (0.18 ml, 1.3 mmol) by the method of Example 6. The title compound was obtained as a white solid mg, 15%). d? (DMSO-d6) 10.60 (1H, s), 8.22 (11-1, m), 7.90 (1H, s), 7, 84-7, 76 (2H, m), 7.64. -7, 60 (1H, m), 7, 45-7, 40 (2H, m), 4.78 (11-1, d, J 4.9 Hz), 4.64 (1H, t, J 5 , 6 Hz), 3.70-3.60 (1H, m), 3.50-3.15 (4H, m), LCMS (ES) RT 2.37 minutes, 502 (MH) ~. EXAMPLE 10 2- [(2-Fluoro-4-iodophenyl) amino] thieno [2, 3-¿> ] pyridine-3-carbonitrile To a solution of (2-chloropyridin-3-yl) acetonitrile (DH Bremner et al., Synthesis, 1997, 949) (700 mg, 4.59 mmol) and Intermediate 1 (1.28) g, 4.60 mmol) in dry DMSO (15 mL) was added sodium hydride (202 mg, 60% in mineral oil, 5.06 mmol). The mixture was stirred at room temperature for 15 minutes before heating at 90 ° C for 4 hours. The reaction mixture was poured into water (80 ml) and the precipitated solid was filtered and washed with water / ethanol (2: 1, 50 ml mixture) followed by diethyl ether / hexane (1: 1, 20 ml mixture). . The solid was dried in a vacuum oven and recrystallized from ethanol / water to give the title compound as a light brown solid. (800 mg, 45%). d? (DMS0-d6) 10.40 (1H, s), 8.37 (1H, dd, J 1.3, 4.6 Hz), 7.83-7.81 (2H, m), 7.64 ( 1H, d, J 8.3 Hz), 7.44 (1H, dd, J 4.7, 8.0 Hz), 7.33 (1H, dd, J 8.3, 8.3 Hz), LC S RT 3.08 minutes, (ES ") 394 (MH) ~, (ES +) 396 (M + H) + EXAMPLE 11 2- [(2-Fluoro-4-iodophenyl) amino] thieno- acid amide [ 2, 3-j] pyridine-3-carboxylic acid A solution of Example 1 (250 mg, 0.56 mmol) in ethanol (5 mL) was added to liquid ammonia (15 mL) and the mixture was heated on a Parr apparatus. at 95 ° C and 800 psi (54.4 atm) for 18 hours.The volatiles were removed in vacuo to give a brown oily residue The repeated trituration with ethanol and DCM gave the title compound as a white solid (18 mg ) d? (DMSO-d6) 11.20 (1H, bs), 8.34 (1H, d, J 3, 4 Hz), 8.20 (1H, dd, J 8.2, 1.3 Hz) , 7.76 (1H, dd, J 10.4, 1.8 Hz), 7.62 (1H, d, J 8.2 Hz), 7.57 (2H, br s), 7, 49-7 , 39 (2H, m), LCMS (ES +) RT 3.11 minutes, 412 (M + H) + EXAMPLE 12 [2- [(2-Fluoro-4-iodophenyl) amino] thieno [2, 3- j] pyridin-3-yl] (pyrrolidin-1-yl) methanone Prepared from Example 1 (250 mg, 0.60 mmol) and pyrrolidine (0.25 mL, 3 mmol) by the method of Example 2. obtained the title compound as a pale yellow solid (136 mg, 51%). d? (DMSO-d6) 9.21 (1H, br s), 8.35 (1H, dd, J 1.6, 4.7 Hz), 7.81 (1H, dd, J 1.6, 8.1 Hz), 7.67 (1H, dd, J 1.9, 10.5 Hz), 7.50-7.46 (1H, m), 7.35 (1H, dd, J 4.7, 8, 1 Hz), 7.13 (1H, dd, J 8.6, 8.6 Hz), 3.32-3, 30 (4H, m), 1.78-1.73 (4H, m), LCMS (ES +) RT 3.32 minutes, 468 (M + H) +. EXAMPLE 13 2- [(2-Fluoro-4-iodo-phenyl) amino] thieno [2, 3-jb] pyridine-3-carboxylic acid (3-hydroxypropyl) amide Example 1 (500 mg, 1, 13 mmol) in dry toluene (6 ml) under nitrogen. To this solution was added trimethylaluminum (2.83 ml of a 2M solution in hexane, 5.66 mmol) for 5 minutes. After 10 minutes, a solution of Intermediate 3 (1.07 g, 5.66 mmol) in dry toluene (5 mL) was added and the reaction mixture was heated at 100 ° C for 6 hours. The reaction mixture was allowed to cool to room temperature and treated with 2M HC1 (10 mL) and water (30 mL). The mixture was extracted with ethyl acetate (3 x 50 mL), then the organic phases were dried over Na2SO4 and filtered, after which the solvents were removed in vacuo. The crude residue was dissolved in methanol (30 mL), treated with 2M HC1 (20 mL) and stirred at room temperature for 18 hours. The mixture was concentrated in vacuo, treated with NaOH 2 (20 mL) and extracted with ethyl acetate (3 x 50 mL). The organic phases were dried over Na 2 SO 4, filtered, and volatiles were removed in vacuo. The residual solid was triturated with diethyl ether (10 mL) and dried in a vacuum oven to give the title compound as a pale yellow solid (100 mg, 19%). d? (DMSO-d6) 10.75 (1H, br s), 8.35 (1H, m), 8.17 (1H, d, J 7.9 Hz), 8.01 (1H, br s), 7 , 75 (1H, d, J 10.1 Hz), 7.59 (1H, d, J 8.1 Hz), 7.44-7.41 (2H, m), 4.55 (1H, t, J 5, l Hz), 3.54-3, 48 (2H, m), 3.41-3.34 (2H, m), 1.75-1.67 (2H, m), LCMS (ES +) RT 3.22 minutes, 472 (M + H) +. EXAMPLE 14 2- [(2-Fluoro-4-iodophenyl) amino] thieno [2- (2), 3-dihydroxypropyl) -amide.;] pyridine-3-carboxylic acid Prepared from Example 1 (1.0 g, 2.26 mmol) and (S) - (2,2-dimethyl-1,3-dioxolan-4-yl) methylamine (1, 48 g, 11.3 mmol) by the method of Example 6. The title compound was obtained as a white solid (425 mg, 39%). d? (DMSO-d6) 10.67 (1H, bs), 8.36 (1H, d, J 3.8 Hz), 8.20 (1H, d, J 8.5 Hz), 7.88 (1H, bs), 7.76 (1H, d, J 10.5 Hz), 7.61 (1H, d, J 8.5 Hz), 7, 46-7, 40 (2H, m), 4.86 ( 1H, d, J 5.0 Hz), 4.64 (1H, t, J 5.7 Hz), 3.72-3.67 (1H, m), 3.52-3.38 (3H, m ), 3.30-3.22 (1H, m), LCMS (ES +) RT 2.91 minutes, 488 (M + H) +.

EXAMPLE 15 2- [(2-Fluoro-4-iodophenyl) amino] thieno [2, 3-b] pyridine-3-carboxylic acid 2 (R), 3-Dihydroxypropyl) -amide Prepared from Example 1 (500 mg, 1.13 mmol) and (R) - (2,2-dimethyl-1,3-dioxolan-4-yl) methylamine (655 g, 4.52 mmol) by the method of Example 6. The compound was obtained of the title as a white solid (100 mg, 18%). d? (DMSO-d6) 10.67 (1H, bs), 8.36 (1H, d, J 3.8 Hz), 8.20 (1H, d, J 8.5 Hz), 7.88 (1H, bs), 7.76 (1H, d, J 10.5 Hz), 7.61 (1H, d, J 8.5 Hz), 7, 46-7, 40 (2H, m), 4.86 ( 1H, d, J 5.0 Hz), 4.64 (1H, t, J 5.7 Hz), 3, 72-3, 67 (1H, m), 3.52-3, 38 (3H, m ), 3.30-3.22 (1H, m), LCMS (ES +) RT 2.91 minutes, 488 (+ H) +. EXAMPLE 16 2- [(4-Bromo-2-fluorophenyl) amino] -thieno [2,3-b] pyridine-3-carboxylic acid methylamide Prepared from Intermediate 2 (150 mg, 0.38 mmol) and a 2M solution of methylamine in THF (0.95 mL, 1.9 mmol) was obtained by the method of Example 2. The title compound was obtained as a white solid (125 mg, 87%). d? (DMSO-de) 10.83 (1H, bs), 8.35 (1H, dd, J 1.4, 4.6 Hz), 8.18 (1H, dd, J 1.4, 8.2 Hz ), 7.92 (1H, bs), 7.69 (1H, dd, J 2.1, 10.6 Hz), 7.59 (1H, dd, J 8.8, 8.8 Hz), 7 , 48-7, 43 (1H, m), 7.42 (1H, dd, J 8.2, 4.6 Hz), 2.83 (3H, d, J 4.5 Hz), LCMS (ES +) RT 3.45 minutes, 380/382 [Br79 / Br81] (M + H) +.

EXAMPLE 17 2- [(4-Iodophenyl) amino] thieno- [2, 3-b] pyridine-3-carboxylic acid ethyl ester Prepared from ethyl (2-chloropyridin-3-yl) acetate (DH Bremner et al., Synthesis, 1997, 949) (750 mg, 3.8 mmol) and 4-iodophenyl isothiocyanate (1.0 g, 3.8 mmol) by the method of Example 1. The title compound was obtained as a whitish solid (800 (800 mg, 50%) d? (DMSO-d6) 10.34 (1H, br s), 8, 33-8, 30 (2H, m), 7.79 (2H, dt , J 2.0, 6.7 Hz), 7.43-7.31 (3H, m), 4.40 (2H, q, J 7.1 Hz), 1.40 (3H, t, J 7 , 1 Hz), LCMS (ES +) RT 4.31 minutes, 425 (M + H) + EXAMPLE 18 2- [(4-Yodo-2-methylphenyl) amino] thieno [2, 3-b] pyridine-3 -carbonitrile To a stirred solution of Intermediate 8 (429 mg, 3.28 mmol) and (2-chloropyridin-3-yl) acetonitrile (DH Bremner et al., Synthesis, 1997, 949) (500 mg, 3.28 mmol) in DMSO (20 mL) was added sodium hydride (164 mg, 4.1 mmol). When the evolution of gases had ceased, the reaction mixture was heated for a period of time. e 3 hours at 80 ° C. After this time, the reaction mixture was poured onto ice and extracted into DCM (2 x 50 mL). The organic components were dried (Na 2 SO 4) and then evaporated in vacuo to give a brown residue. Column chromatography (Si02, 5: 1 hexane: EtOAc) gave the title compound as a yellow powder (198 mg, 15%). d? (DMSO-d6) 10.11 (1H, s), 8.29 (1H, dd, J 1.5, 4.7 Hz), 7.75 (2H, m), 7.63 (1H, dd, J 1.7, 8.1 Hz), 7.39 (1H, dd, J 8.1, 4.8 Hz), 7.19 (1H, d, J 8.3 Hz), 2.24 (3H , s), LCMS (ES +) RT 3.68 minutes, 392 (M + H) +. EXAMPLE 19 2- [(4-Bromo-2-fluorophenyl) amino] thieno [2, 3-b] pyridine-3-carbonitrile 4-Bromo-2-fluoro-l-isothiocyanatobenzene (250 mg, 1.08 mmol) and (2-chloropyridin-3-yl) acetonitrile (DH Bremner et al., Synthesis, 1997, 949) (165 mg, 1.08 mmol) was stirred in DMSO (20 mL) and sodium hydride was added in portions (52 mg, 1.3 mmol). After the evolution of gases had ended, the reaction mixture was heated for 4 hours at 80 ° C. After this time, the reaction mixture was added to ice (50 ml) and a precipitate formed. This was filtered and purified by preparative HPLC (pH 10, 2-3 min) to give the title compound as a white powder ((30 mg, 9%) d? (DMSO-d6) 10.45 (1H, s), 8.31 (1H, d, J 3.9 Hz), 7.75 (2H, m), 7.51-7.38 (3H, m), LCMS (ES +) RT 3.49 minutes, 350 (M + H) + EXAMPLE 20 2- [(2-Chloro-4-iodophenyl) amino] thieno [2,3-j] pyridine-3-carbonitrile Intermediate 9 (300 mg, 1.01 mmol) and (2-c lor opi ri di n-3-i 1) ace t on itri 1 o (DH Bremner et al., Synthesis, 1997, 949) (165 mg, 1.01 mmol) were shaken together in DMSO ( 20 ml) and sodium hydride (48 mg) was added in portions, 1.21 mmol). After the evolution of gases had been completed, the reaction mixture was heated for 4 h at 80 ° C. After this time, the reaction mixture was added to ice (50 ml) and then extracted into DCM (2 x 50 ml), dried (Na 2 SO 4) and evaporated in vacuo to give a yellow residue. This residue was subjected to column chromatography (Si02, 1: 4 E t OAc: hexane) to give the title compound as a yellow powder (118 mg, 28%). d? (DMSO-d6) 10.38 (1H, s), 8.35 (1H, dd, J 1.5, 4.8 Hz), 8.00 (1H, d, J 1.9 Hz), 7, 80 (2H, m), 7.42 (1H, dd, J 8.0, 4.8 Hz), 7.35 (1H, d, J 8.3 Hz), LCMS, (ES +) RT 3, 70 minutes, 412 (M + H) +. EXAMPLE 21 2- [(2-Fluoro-4-iodophenyl) amino] thieno [2, 3-b] pyridine-3-carboxylic acid (2-amino-2-methylpropyl) -amide. mi from a 2M solution in hexane, 5.7 mmol) was added to a solution of 1,2-diamino-2-methylpropane (498 mg, 5.7 mmol) in toluene (5 mL). After 10 minutes, Example 1 (500 mg, 1.13 mmol) was added and the mixture was heated at 100 ° C for 4 h. After cooling, the reaction mixture was quenched with 10% sodium hydroxide solution (75 ml) and extracted with EtOAc (100 ml). The organic phase was dried (Na2SO4) and concentrated in vacuo to give a solid. Trituration with hexanes (30 mL) and filtration gave the title compound as a yellow solid (248 mg, 45%). d? (DMSO-d6) 10.72 (1H, m), 8.43 (1H, dd, J 1.7, 8.0 Hz), 7.84 (1H, dd, J 1.7, 4.7 Hz ), 7.80-7.40 (2H, s), 7.46-7.35 (2H, m), 7.21 (1H, m), 7.00 (1H, dd, J 4.7, 8.0 Hz), 3.40 (2H, d, J 5.7 Hz), 1.25 (6H, s), LCMS (ES +) RT 2.23 minutes, 501 (M + H) +. EXAMPLE 22 2- [(2-Fluoro-4-iodophenyl) amino] thieno [2, 3-b] 2- [(2-fluoro-4-iodophenyl) amino] thieno [2-4 dimethyl- [1,3-] dioxolan-4-ylmethoxy] amide] pyridin-3-carboxylic acid 1- (3-dimethylaminopropyl) -3-carbodiimide hydrochloride (131 mg, 0.68 mmol) was added to a solution of Intermediate 7 (142 mg, 0.34 mmol), 1- hydroxybenzotriazole (93 mg, 0.68 mmol), N-methylmorpholine (0.10 ml, 0.94 mmol) and (4R) -2, 2-dimethyl- [1, 3] dioxolan-4-ylmethoxylamine (WO document) 02/006213) (101 mg, 0.68 mmol) in N, N-dimethylformamide (5 mL). The reaction mixture was stirred at t.a. for 20 h, and then poured into EtOAc (25 mL). The organic solution was washed with saturated brine (2 x 25 mL), then dried (Na2SO4), filtered and concentrated in vacuo to give a brown solid. The crude product was subjected to column chromatography (SiO2, 2: 1 hexanes / EtOAc) to give the title compound as a pale yellow powder (135 mg, 95%). d? (DMSO-d6) 10.98 (1H, s), 8.74 (1H, s), 8.28-8.26 (1H, m), 7.94-7.91 (1H, m), 7 , 48-7, 46 (2H, m), 7, 37-7, 32 (1H, m), 7.23 (1H, dd, J 4.8, 8.2 Hz), 4.46-4, 40 (1H, m), 4.17 (1H, dd, J 3.8, 11.7 Hz), 4.11-4.01 (2H, m), 3.79 (1H, dd, J 7, 0, 8.3 Hz), 1.15 (3H, s), 1.10 (3H, s), LCMS RT 3.38 minutes, (ES ") 542 (MH)", (ES +) 544 (M + H) +. EXAMPLE 23 [. { 2R) -2- [(2-fluoro-4-iodophenyl) amino] thieno [2, 3-jb] pyridine-3-carboxylic acid 2, 3-Dihydroxypropoxy] amide A solution of Example 22 (125 mg, 0, 23 mmol) in methanol (5 mL) and THF (5 mL) was treated with 10% aqueous HC1 (5 mL). The reaction mixture was stirred for 3.5 h at t.a., and then diluted with EtOAc (25 mL). The organic solution was washed with saturated brine (2 x 25 mL), then dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a white powder, which was washed with EtOAc, then with hexanes, and dried under suction (76 mg, 66%). d? (DMSO-d6) 11.31 (1? S), 10.33 (1H, s), 8.34-8.33 (1H, m), 8.12-8.09 (1H, m), 7, 79-7, 76 (1H, m), 7.63-7.60 (1H, m), 7, 45-7, 40 (2H, m), 4, 89-4, 88 (1H, m ), 4, 62-4.59 (1H, m), 3.99-3, 97 (1H, m), 3, 85-3, 80 (2H, m), 3.43 (2H, m), LCMS RT 3.38 minutes, (ES ") 502 (MH)", (ES +) 504 (M + H) +.

EXAMPLE 24 (1- {2 - [(2-Fluoro-4-iodophenyl) amino] thieno [2, 3-b] pyridine-3-carbonyl} -piper-idin-4-tert-butyl ester. il) carbamic It was prepared from Intermediate Compound 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole (98 mg, 0.72 mmol), N-methylmorpholine (0.11 mL, 0.99 mmol), l- (3-dimethylaminopropyl) -3-carbodiimide hydrochloride (139 mg , 0.72 mmol) and 4- (BOC-amino) -piperidine (145 mg, 0.72 mmol) by the method of Example 22. The title compound was evaporated in ether to give a hard, colorless foam (111 mg, 51%). d? (CDCI3, contains rotamers) 9.17 (0.64H, s), 8.90 (0.36H, s), 8.39-8.37 (1H, m), 7, 75-7, 73 (0, 36H, m), 7, 66- 7, 63 (0.64H, m), 7.53-7.50 (2H, m), 7, 44-7, 39 (1H, m), 7.31-7.28 (1H, m), 4.57 (0.36H, m), 4.40 (0.64H, m), 4, 20-4, 15 (1, 28H, m), 4.03-3.98 (0.72H, m ), 3.72 (1H, m), 3.16-3.08 (2H, m), 2.05-2, 00 (2H, m), 1.47 (3.2H, s), 1, 44 (5.8H, s), 1, 36-1.28 (2H, m), LCMS RT 3.36 minutes, (ES ") 595 (MH)", (ES +) 597 (M + H) +. EXAMPLE 25 2- [(2-Fluoro-4-iodophenyl) amino] thieno [2, 3-b] pyridine-3-carboxylic acid (4-aminopiperidin-1-yl) -amide A solution of Example 24 (99 mg, 0.17 mmol) in methanol (2 mL) was treated with 4M HC1 in 1,4-dioxane (5 mL) and stirred at rt. for 3 h. The reaction mixture was concentrated in vacuo to give a yellow gum, which was dissolved in water (25 ml). The aqueous solution was washed with ether (2 x 25 mL), and then evaporated in vacuo. The resulting gum was triturated with ether to give the title compound as a yellow powder (89 mg, 94%). d? (DMSO-d6, contains rotamers) 9.24 (0.5H, s), 9.14 (0.5H, s), 8.38-8.37 (1H, m), 8.13 (3H, br s), 7.82-7.75 (1H, m), 7.72-7, 66 (1H, m), 7, 55-7, 47 (1H, m), 7.38 (1H, dd, J 4.7, 8.1 Hz), 7.23-7.10 (1H, m), 4.02 (2H, br m), 3.25 (1H, br m), 3, 06-2, 98 (1H, m), 2.88-2.81 (1H, m), 1.93-1, 89 (2H, m), 1.43 (2H, br m), LCMS RT 2.86 minutes, (ES +) 497 (M + H) +. EXAMPLE 26 2- [(2-Fluoro-4-iodophenyl) amino] thieno [2,3-b] pyridine-3-carboxylic acid (2-hydroxy-l-methylethyl) amide was prepared from Intermediate 7 ( 150 mg, 0.36 mmol), 1-hydroxybenzotriazole (98 mg, 0.72 mmol), N-methylmorpholine (0.11 mL, 0.99 mmol), l- (3-dimethylaminopropyl) -3-carbodiimide hydrochloride (139 mg, 0.72 mmol) and 2-aminopropanol (0.06 ml, 0.72 mmol), by the method of Example 22. The crude product was subjected to column chromatography (SiO2, 1: 1 hexanes / EtOAc ) to give the title compound, which was recrystallized from EtOAc / hexanes to give a beige powder (56 mg, 33%). d? (DMSO-d6) 10.45 (1H, s), 8, 37-8, 36 (1H, m), 8.16-8.13 (1H, m), 7.76-7.71 (2H, m), 7, 60-7, 57 (1H, m), 7, 46-7, 36 (2H, m), 4.78 (1H, t, J 5, 6 Hz), 4.10-4, 03 (1H, m), 3.52-3, 35 (2H, m), 1.13 (3H, d, J 6.7 Hz), LCMS RT 3.46 minutes, (ES +) 472 (M + H ) + EXAMPLE 27 3- [(. {2- 2- [(2-Fluoro-4-iodophenyl) amino] thieno [2, 3-b] pyridine-3-carbonyl} -amino) methyl tert-butyl ester] -zetidine-l-carboxylic acid It was prepared from Intermediate Compound 7 (150 mg, 0. 36 mmol), 1-hydroxybenzotriazole (98 mg, 0.72 mmol), N-methylmorpholine (0.11 mL, 0.99 mmol), l- (3-dimethylaminopropyl) -3-carbodiimide hydrochloride (139 mg, , 72 mmol) and 1-BOC-3- (aminomethyl) azetidine (135 mg, 0.72 mmol) by the method of Example 22. The crude product was subjected to column chromatography (SiO2, 3: 2 hexanes / EtOAc) to give the title compound, which was recrystallized from ether / hexanes to give a cream colored powder (116 mg, 55%). d? (CDC13) 8.37 (1H, dd, J 1.3, 4.7 Hz), 7.84 (1H, dd, J 1.3, 8.2 Hz), 7, 56-7, 53 (2H , m), 7.46-7.41 (1H, m), 7.32 (1H, dd, J 4.7, 8.2 Hz), 6.08 (1H, m), 4.14-4 , 09 (2H, m), 3, 77-3, 73 (4H, m), 2, 94-2, 92 (11-1, m), 1.46 (9H, s), LCMS RT 3.68 minutes, (ES ") 581 (MH)", (ES +) 583 (M + H) +. EXAMPLE 28 (l-. {2- 2- [(2-Fluoro-4-iodo-phenyl) amino] thieno [2, 3-b] pyridine-3-carbonyl} azetidin-3-butyl ester. ilmethyl) carbamic was prepared from Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole (98 mg, 0.72 mmol), N-methylmorpholine (0.11 mL, 0.99 mmol), l- (3-dimethylaminopropyl) -3-carbodiimide hydrochloride (139 mg, 0.72 mmol) and 3- (BOC-aminomethyl) -azetidine (135 mg, 0.72 mmol), by the method of Example 22. The title compound was evaporated in ether to give a hard, colorless foam (75 mg). mg, 36%). d? (CDC13) 8.25 (1H, dd, J 1.5, 4.7 Hz), 7.67 (1H, dd, J 1.5, 8.1 Hz), 7.46-7.41 (214 , m), 7.38-7, 33 (1H, m), 7.22 (1H, dd, J 4.7, 8.1 Hz), 4.59 (1H, br s), 4.15- 4.09 (2H, m), 3, 80-3, 75 (2H, m), 3.32 (2H, m), 2, 78-2, 74 (1H, m), 1.35 (9H, s), LCMS RT 3.41 minutes, (ES ") 581 (MH) ~, (ES +) 583 (M + H) + EXAMPLE 29 Tert-Butyl Ester of 3- (. {2- (2 Fluoro-4-iodo-phenyl) amino] thieno [2, 3-b] pyridine-3-carbonyl} amino (aze-tidine-1-carboxylic acid) Prepared from Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole (98 mg, 0.72 mmol), N-methylmorpholine (0.11 mL, 0.99 mmol), l- (3-dimethylaminopropyl) -3-carbodiimide hydrochloride (139 mg , 0.72 mmol) and 1-B0C-3-aminoazetidine (125 mg, 0.72 mmol), by the method of Example 22. The title compound was recrystallized from ether / hexanes to give a cream-colored powder (116 mg, 57%). d? (CDC13) 8.38 (1H, dd, J 1.2, 4.7 Hz), 7.90 (1H, dd, J 1.2, 8.1 Hz), 7, 56-7, 53 (2H , m), 7, 45-7, 40 (1H, m), 7.35 (1H, dd, J 4.7, 8.1 Hz), 6.19 (1H, d, J 6.9 Hz) , 4, 89-4, 84 (1H, m), 4, 44-4, 38 (2H, m), 3, 93-3, 88 (2H, m), 1.48 (9H, s), LCMS RT 3.66 minutes, (ES ") 567 (MH)", (ES) 569 (M + H) +. EXAMPLE 30 [3- (Aminomethyl) azetidin-1-yl] -. { 2- [(2-Fluoro-4-iodo-phenyl) amino] thieno [2, 3-b] pyridin-3-yl} -metanone A solution of Example 28 (65 mg, 0.11 mmol) in DCM (7 ml) was treated with trifluoroacetic acid (3 ml) and stirred for 1 h at RT. The reaction mixture was concentrated in vacuo to give a yellow gum, which was dissolved in water (25 ml) and basified to pH 10 with sodium carbonate. The aqueous solution was extracted with 5% methanol in DCM (4 x 25 mL), and the extracts were combined, dried (Na2SC>), filtered and concentrated in vacuo. The crude product was subjected to column chromatography (Si02, 4: 1 DCM / methanol) to give the title compound as a gummy solid which was triturated in ether to give a cream-colored powder (34 mg, 63%). d? (DMSO-de) 8.31 (1H, m), 7.93 (1H, m), 7.72 (1H, dd, J 1.5, 10.5 Hz), 7.55 (1H, m) , 7.37 (1H, dd, J 4.6, 8.1 Hz), 7.29-7.24 (1H, m), 4.88 (2H, br s), 4.03-3.97 (2H, m), 3.71-3.67 (2H, m), 2.65 (1H, m), 2.70-2, 68 (2H, m), LCMS RT 2.93 minutes, (ES ") 481 (MH) ", (ES +) 483 (M + H) +. EXAMPLE 31 [. { 2R [2-Fluoro-4-chlorophenyl] amino] thieno [2,3-b] pyridine-3-carboxylic acid 2R-pyrrolidin-2-ylmethyl] amide A solution of Intermediate 10 (135 mg, , 23 mmol) in methanol (2 mL) was treated with 4M HC1 in 1,4-dioxane (5 mL) and stirred at rt. for 30 minutes. The reaction mixture was concentrated in vacuo to give a yellow gum, which was dissolved in water (25 ml). The aqueous solution was washed with ether (2 x 25 mL), and then basified to pH 11 with 25% aqueous ammonium hydroxide. The aqueous solution was extracted with DCM (2 x 25 mL), and the organic extracts were combined, dried (Na2SC > 4), filtered and concentrated in vacuo. The crude product was subjected to column chromatography (Si02, 91: 8: 1 DCM / methanol / 25% aqueous ammonium hydroxide) to give the title compound, which was lyophilized overnight in acetonitrile / water to give a powder Cream colored (73 mg, 65%). d? (DMSO-d6) 10.63 (1H, s), 9.12 (1H, br s), 8.37 (1H, dd, J 2.7, 8.0 Hz), 7.84 (1H, dd, J 1.7, 4.7 Hz), 7.47 (1H, dd, J 2.0, 10.4 Hz), 7.42-7.38, (1H, m), 7.17-7.11, (1H, m), 7.00 (1H, dd, J 4.7, 8.0 Hz), 3.68-3.61, (1H, m), 3.51-3.49, (2H, m), 3.17-3.12, (2H, m), 2.28-1, 62 (4H, m). LCMS RT 2.42 minutes, (ES ") 495 (MH) ~, (ES +) 497 (M + H) + EXAMPLE 32 [(2S) -Pyrrolidin-2-ylmethyl] 2- [(2- fluoro-iodophenyl) amino] thieno [2,3-b] pyridine-3-carboxylic acid. Prepared from Intermediate 11 (139 mg, 0.23 mmol) by the method of Example 31. The title compound was obtained as a cream-colored powder (81 mg, 70%) d? (DMSO-d6) 10.63 (1H, s), 9.12 (1H, br s), 8.37 (1H, dd, J 1.7, 8.0 Hz), 7.84 (1H, dd, J 1.7, 4.7 Hz), 7.47 (1H, dd, J 2.0, 10.4 Hz), 7.42-7.38 (1H, m), 7.17-7.11 (1H, m), 7.00 (1H, dd, J 4.7, 8.0 Hz), 3.68-3.61 (1H, m), 3.51-3.49 (2H, m), 3.17-3.12 (2H, m), 2.28-1.62 (4H, m) LCMS RT 2.42 minutes, (ES) 495 (MH), (ES +) 497 (M + H) + EXAMPLE 33 (35) -3- (. {2- [(2-fluoro-4-iodo-phenyl) amino] tert-butyl ester] thieno [2, 3-b] pyridine-3-carbonyl.} amino) -piperidine-1-carboxylic acid. Prepared from Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole (98 mg, , 72 mm ol), N-methylmorpholine (0.11 ml, 0.99 mmol), l- (3-dimethylaminopropyl) -3-carbodiimide hydrochloride (139 mg, 0.72 mmol) and (S) -l-BOC-3-aminopiperidine (145 mg, 0.72 mmol) by the method of Example 22. The title compound was obtained as a yellow gummy solid (131 mg, 61%). %). d? (CDC13) 11.34 (1H, s), 8.36-8.34 (1H, m), 7.90-7.88 (1H, m), 7.55-7.52 (2H, m), 7.45-7.42 (1H, m), 7.32-7.29 ( 1H, m), 5.32 (1H, br s), 4.31 (1H, m), 3.83-3.78 (2H, m), 3.46-3.42 (1H, m), 3.17 (1H, m), 1.89-1.73 (2H , m), 1.67 (2H, m), 1.47 (9H, s). LCMS RT 4.04 minutes, (ES +) 597 (M + H) +. EXAMPLE 34 (3i¾) -3- (. {2- [(2-Fluoro-4-iodophenyl) amino] thieno tert -butyl ester [2, 3-¿>];] pyridine-3-carbonyl] amino) -piperidine-l-carboxylic acid. Prepared from Intermediate 7 (150 mg, 0.86 mmol), 1-hydroxybenzotriazole (98 mg, 0.72 mmol), N-methylmorpholine (0.11 ml, 0.99 mmol), l- (3-dimethylaminopropyl) -3-carbodiimide hydrochloride (139 mg, 0.72 mmol) and (R) -l-BOC-3-aminopiperidine (145 mg, 0.72 mmol) was added by the method of Example 22. The title compound was obtained as a pale pink gummy solid (136 mg, 63%). d? (CDC13) 11.34 (1H, s), 8.36-8.34 (1H, m), 7.90-7.88 (1H, m), 7.55-7.52 (2H, m), 7.45-7.42 (1H, m), 7.32- 7.29 (1H, m), 5.32 (1H, br s), 4.31 (1H, m), 3.83-3.78 (2H, m), 3.46-3.42 (1H, m), 3.17 (1H, m), 1.89-1.73 (2H, m), 1.67 (2H, m), 1.47 (9H, s). LCMS RT 4.03 minutes, (ES +) 597 (M + H) +. EXAMPLE 35 [2- (2-Fluoro-4-iodophenyl) amino] thieno [2,3-b] piperidine-3-carboxylic acid [(3S) -piperidin-3-yl] amide dihydrochloride A solution of Example 33 (120 mg, 0.20 mmol) in methanol (2 ml) was treated with 4M HC1 in 1,4-dioxane (5 ml) and stirred at rt. for 3 h. The reaction mixture was evaporated in vacuo to give the title compound as a yellow gummy solid, which was triturated in ether to give a yellow powder (112 mg, 98%). d? (D SO-d6) 10.38 (1H, s), 9.04-8.92 (2H, m), 8.38 (1H, dd, J 1. 3, 4.6 Hz), 8.17-8.14 (2H, m), 7.75 (1H, dd, J 1.8, 10.4 Hz), 7.61-7.58 (1H, m), 7.44 (1H, dd, J.6, 8.2 Hz), 7.42-7.36 (1H, m), 4.09 (1H, m), 3.34- 3.31 (1H, m), 3.21-3.17 (1H, m), 2.94-2.79 (2H, m), 1.91 (2H, m), 1.74-1.61 (2H, m). LC S RT 2.38 minutes, (ES +) 497 (M + H) +. EXAMPLE 36 2- [(2-Fluoro-4-iodophenyl) amino] thieno [2,3-b] pyridine-3-carboxylic acid [(3R) -piperidin-3-yl] -hydrochloride was prepared from Example 34 (126 mg, 0.21 mmol) by the method of Example 35. The title compound was obtained as a yellow powder (115 mg, 96%). d? (DMSO-d6) 0.38 (1H, s), 9.04-8.92 (2H, m), 8.38 (1H, dd, J 1.3, 4.6 Hz), 8.17-8.14 (2H, m), 7.75 (1H, dd, J 1.8, 10.4 Hz), 7.61-7.58 (1H, m), 7.44 (1H, dd, J 4.6, 8.2 Hz), 7.42-7.36 (1H, m), 4.09 (1H, m), 3.34-3.31 (1H, m), 3.21-3.17 (1H, m), 2.94-2.79 (2H, m), 1.91 (2H, m), 1.74-1.61 (2H, m). LCMS RT 2.38 minutes, (ES +) 497 (M + H) +. EXAMPLE 37 (1- {2 - [(2-Fluoro-4-iodophenyl) amino] thieno [2, 3-j] pyridine-3-carbonyl] - (3.R) tert -butyl ester. pyrrolidin-3-yl) carbamic was prepared from Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole (98 mg, 0.72 mmol), N-methylmorpholine (0.11 mL, 0.99 mmol), l- (3-dimethylaminopropyl) -3-carbodiimide hydrochloride (139 mg , 0.72 mmol) and (R) -3- (BOC-amino) -pyrrolidine (186 mg, 0.72 mmol), by the method of Example 22. The crude product was subjected to column chromatography (Si02, 3). : 2 hexanes: EtOAc) to give the title compound, which was evaporated in ether to give a hard, colorless foam (110 mg, 52%). d? (CDC13) 9.03 (1H, s), 8.28 (1H, dd, J 1.5, 4.7 Hz), 7.56 (1H, dd, J 1.5, 8.1 Hz), 7.43-7.39 (2H, m), 7.34-7.29 (1H , m), 7.22-7.18 (1H, m), 4.50 (1H, br s), 4.16-4.14 (1H, m), 3.71 (1H, dd, J 6.2, 11.8 .Hz), 3.63-3.56 (2H, m), 3.30 (1H, dd, J 5 .1, 11.8 Hz), 2.19-2.12 (1H, m), 1.86-1.77 (1H, m), 1.35 (9H, s). LCMS RT 3.33 minutes, (ES ") 581 (M-H +), (ES +) 583 (M + H) + EXAMPLE 38 Tetrabutyl ester of (1-. {2- [(2-fluoro-4) -iodophenyl) amino] thieno [2,3-b] pyridine-3-carbonyl- (3S) -pyrrolidin-3-yl) -carbamic acid. Prepared from Intermediate 7 (150 mg, 0.36 mmol), 1- hydroxybenzotriazole (98 mg, 0.72 mmol), N-methylmorpholine (0.11 ml, 0.99 mmol), l- (3-dimethylaminopropyl) -3-carbodiimide hydrochloride (139 mg, 0.72 mmol) and ( S) -3- (BOC-amino) -pyrrolidine (186 mg, 0.72 mmol), by the method of Example 37. The title compound was obtained as a hard, colorless foam (125 mg, 59%). (CDC13) 9.03 (1H, s), 8.28 (1H, dd, J 1.5, 4.7 Hz), 7.56 (1H, dd, J 1.5, 8.1 Hz), 7.43-7.39 (2H, m), 7.34-7.29 (1H , m), 7.22-7.18 (1H, m), 4.50 (1H, br s), 4.16-4.14 (1H, m), 3.71 (1H, dd, J 6.2, 11.8 Hz), 3.63-3.56 (2H, m ), 3.30 (1H, dd, J 5.1, 11.8 Hz), 2.19-2.12 (1H, m), 1.86-1.77 (1H, m), 1.35 (9H, s) LCMS RT 3.33 minutes, (ES ") 581 (MH) ", (ES +) 583 (M + H) +. JEMPLO 39 Tert-butyl ester of the acid (1-. { 2- [(2-Fluoro-4-iodophenyl) amino] thieno [2, 3-b] pyridine-3-carbonyl} azeti-din-3-yl) -carbamic acid. Prepared from Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole (98 mg, 0.72 mmol), N-methylmorpholine (0.11 ml, 0.99 .mmol), l- (3-dimethylaminopropyl) -3-carbodiimide hydrochloride (139 mg, 0.72 mmol) and 3- (BOC-amino) azetidine (125 mg, 0.72 mmol), by Method of Example 22. The crude product was subjected to column chromatography (SiO2, 3: 1 hexanes / EtOAc) to give the title compound, which was evaporated in ether to give a cream colored powder (100 mg, 49%) . d? (CDC13) 10.11 (1H, s), 8.35 (1H, dd, J 1.5, 4.7 Hz), 7.76 (1H, dd, J 1.5, 8.1 Hz), 7.55-7.51 (2H, m), 7.47-7.41 (1H , m), 7.31 (1H, dd, J 4.7.- 8.1 Hz), 4.95 (1H, br s), 4.52 (1H, br s), 4.46-4.40 (2H, m), 4.01-3.96 (2H, m ). , 1.45 (9H, s). LCMS RT 3.47 minutes, (ES ") 567 M-H)", (ES +) 569 (M + H) +. EXAMPLE 40 4- (. {2- [(2-Fluoro-4-iodo-enyl) amino] thieno tert -butyl ester [2, 3-¿>;] pyridine-3-carbonyl} amino) pipe-idine-1-carboxylic acid It was prepared from Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole (98 mg, 0.72 mmol), N-methylmorpholine (0.11 ml, , 99 mmol), l- (3-dimethylaminopropyl) -3-carbodiimide hydrochloride (139 mg, 0.72 mmol) and 4-amino-1-BOC-piperidine (145 mg, 0.72 mmol) by the method of Example 22. The crude product was adsorbed on Si02 and subjected to column chromatography (SiO2, 2: 1 hexanes / EtOAc) to give the title compound, which was evaporated in ether to give cream-colored flakes (97 mg, %). d? (CDC13) 11.18 (1H, s), 8.36 (1H, dd, J 1.4, 4.7 Hz), 7.81 (1H, dd, J 1.4, 8.2 Hz), 7.55-7.53 (2H, m), 7.46-7.41 (1H , m), 7.32 (1H, dd, J 4.7, 8.2 Hz), 5.74 (1H, d, J 7.6 Hz), 4.27-4.20 (1H, m), 4.15-4.11 (2H, m), 3.03-2.96 ( 2H, m), 2.15-2.10 (2H, m), 1.50 (9H, s), 1.45 (2H, m). LC S RT 3.95 minutes, (ES ") 567 (MH), (ES +) 569 (M + H) + EXAMPLE 41 [(3R) -3-Aminopyrrolidin-1-yl] - { 2- [(2 -fluoro-4-iodo-phenyl) mino] thieno [2, 3-b] pyridin-3-yl.}. -methanone Prepared from Example 37 (100 mg, 0.17 mmol) following the method of Example 35 The title compound was obtained as a yellow powder (100 mg, quant.) D? (DMSO-d6) 9.29 (1H, s), 8.36 (1H, dd, J 1.5, 4.7 Hz), 8.29 (3H, s), 7.91-7.89 (1H, m), 7.72 (1H, dd, J 1.8, 10.4 Hz), 7.55-7.52 (1H, m), 7.37 (1H, dd, J 4.7, 8.1 Hz), 7.24-7.19 (1H, m), 3.79-3.72 (1H, m), 3.70-3.58 (2H, m), 3.51-3.38 (2H, m), 2.20-2.13 (1H, m), 2.01-1.97 (1H, m) LCMS RT 2.24 minutes, (ES ") 481 (MH"), (ES +) 483 (M + H) +.

EXAMPLE 42 [(35) -3-Aminopyrrolidin-1-yl] -. { 2- [(2-Fluoro-4-iodo-phenyl) amino] thieno [2, 3-b] pyridin-3-yl} methanone Prepared from Example 38 (115 mg, 0.20 mmol) following the method of Example 35. The title compound was obtained as a yellow powder (109 mg, 99%). d? (D SO-d6) 9.29 (1H, s), 8.36 (1H, dd, J 1.5, 4.7 Hz), 8.29 (3H, s), 7.91-7.89 (1H, m), 7.72 (1H, dd, J 1.8 , 10.4 Hz), 7.55-7.52 (1H, m), 7.37 (1H, dd, J 4.7, 8.1 Hz), 7.24-7.19 (1H, m), 3.79-3.72 (1H, m), 3.70-3.58 (2H , m), 3.51-3.38 (2H, m), 2.20-2.13 (1H, m), 2.01-1.97 (1H, m). LCMS RT 2.24 minutes, (ES ") 481 (MH) ~, (ES +) 483 (M + H) + EXAMPLE 43 (Piperidin-4-yl) 2 - [(2-fluoro-4-iodophenyl)) amide -amino] thieno [2,3-b] pyridine-3-carboxylic acid Prepared from Example 40 (87 mg, 0.15 mmol) following the method of Example 35. The title compound was obtained as a yellow powder (80 mg, 96%) d? (DMSO-d6) 10.31 (1H, s), 8.84 (1H, m), 8.68 (1H, m), 8.38 (1H, dd, J 1.3, 4.6 Hz), 8.24 (1H , d, J 7.5 Hz), 8.09 (1H, dd, J 1.3, 8.2 Hz), 7.74 (1H, dd, J 1.8, 10.5 Hz), 7.59-7.57 (1H, m), 7.44 (1H, dd, J 4.7, 8.2 Hz), 7.39-7.34 (1H, m), 4.05-3.97 (1H, m), 3.32-3.27 (2H, m), 3.03-2.87 (2H, m), 2.00-1.97 (2H, m) , 1.82-1.71 (2H, m) LCMS RT 2.40 minutes, (ES ") 495 (MH)", (ES +) 497 (M + H) +.

EXAMPLE 44 3-Aminoazetictin-1-yl) -. { 2- [(2-Fluoro-4-iodophenyl) amino] -thieno [2,3-j] pyridin-3-yl] -methanone Prepared from Example 39 (90 mg, 0.16 mmol) by the method of Example 30. The reaction mixture was concentrated in vacuo to give a yellow gum, which was dissolved in methanol (5 ml) and water (5 ml) and basified to pH 10 with ammonium hydroxide aq. to 25%. The aqueous solution was concentrated in vacuo over SiO2, and the crude product was subjected to column chromatography (Si02, 95: 4: 1 DCM / methanol / ammonium hydroxide aq. to 25%). The title compound was lyophilized overnight in acetonitrile / methanol / water to give a cream-colored powder (31 mg) 42%). d? (DMSO-d6) 8.33 (1H, dd, J 1.5, 4.7 Hz), 7.94 (1H, dd, J 1.5, 8.1 Hz), 7.73 (1H, dd, J 1.9, 10.5 Hz), 7.54 (1H, ddd, J 0.9, 0.9, 8.4 Hz), 7.38 (1H, dd, J 4.7, 8.1 Hz), 7.31-7.26 (1H, m), 4.23-4.11 (2H, m), 3.72-3.59 (3H, m). LCMS RT 3.00 minutes, (ES ") 467 (mH) ~, (ES +) 469 (M + H) + EXAMPLE 45 Bis (2-hydroxyethyl) amide of 2- [(2-fluoro-4-iodo-phenyl)] ) amino] thieno [2, 3-b] pyridine-3-carboxylic acid Prepared from Intermediate 7 (150 mg, 136 mmol), 1-hydroxybenzotriazole (98 mg, 0.72 mmol), N-methylmorpholine (0, 11 ml, 0.99 mmol), l- (3-dimethylaminopropyl) -3-carbodiimide hydrochloride (139 mg, 0.72 mmol) and diethanolamine (76 mg, 0.72 mmol) by the method of Example 22. The crude product was subjected to column chromatography (S1O2, EtOAc, 2 times) to give the title compound, which was lyophilized overnight in acetonitrile / water to give a cream-colored powder (62 mg, 34%) d ( DMS0-d6) 8.79 (1H, br s), 8.38 (1H, dd, J 1.5, 4.7 Hz), 7.77 (1H, dd, J 1.5, 8.1 Hz), 7.67 (1H, dd, J 1.9, 10.5 Hz) , 7.69-7.46 (1H, m), 7.38 (1H, dd, J 4.7, 8.1 Hz), 7.18-7.12 (1H, m), 4.83 (2H, br s), 3.30 (8H, s) LCMS RT 3.01 minutes, (ES +) 502 (M + H) +. EXAMPLE 46 { 2- [(2-Fluoro-4-y odophenyl) amino] thieno [2,3-j] pyridin-3-yl} - (3-hydroxyazetidin-1-yl) -methanone Prepared from Intermediate 7 (225 mg, 0.54 mmol), 1-hydroxybenzotriazole (147 mg, 1.08 mmol), N-methylmorpholine (0.16 ml) 1.48 mmol), l- (3-dimethylaminopropyl) -3-carbodiimide hydrochloride (208 mg, 1.08 mmol) and 3-hydroxyazetidine hydrochloride (120 mg, 1.08 mmol) by the method of Example 22 After chromatography, the title compound was recrystallized from methanol / ether to give a white powder (125 mg, 49%). 29 (DMSO-d6) 9.60 (1H, s), 8.35-8.34 (1H, m), 7.94 (1H, dd, J 1.4, 8.1 Hz), 7.75-7.71 (1H, m), 7.57-7.54 (1H, m), 7.41-7.37 (1H, m), 7.31-7.25 (1H, m), 5.68 (1H, d, J 6.0 Hz), 4.47-4.44 (1H, m), 4.21-4.16 (2H, m), 3.79-3.74 (2H, m). LCMS RT 3.31 minutes, (ES +) 470 (M + H) +.

EXAMPLE 47 { 2 - [(2-Fluoro-iodophenyl) amino] thieno [2, 3-Jb] pyridin-3-yl} - [(3R) -3-hydroxypyrrolidin-1-yl] -methanone Prepared from Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole (98 mg, 0.72 mmol), N-methylmorpholine ( 0.11 ml, 0.99 mmol), l- (3-dimethylaminopropyl) -3-carbodiimide hydrochloride (139 mg, 0.72 mmol) and (R) -3-hydroxypyrrolidine (63 mg, 0.72 mmol) by the method of Example 22. After chromatography, the title compound was lyophilized overnight in acetonitrile / water to give a cream-colored powder (116 mg, 66%). d? (DMSO-d6) 9.20 (1H, s), 8.35 (1H, dd, J 1.5, 4.7 Hz), 7.81 (1H, dd, J 1.5, 8.1 Hz), 7.67 (1H, dd, J 1.9, 10.5 Hz) , 7.50-7.47 (1H, m), 7.36 (1H, dd, J 4.7, 8.1 Hz), 7.17-7.11 (1H, m), 4.91 (1H, s), 4.22 (1H, s), 3.54-3.30 ( 3H, m), 3.21-3.17 (1H, m), 1.90-1.74 (2H, m). LCMS RT 3.18 minutes, (ES +) 484 (M + H) +. EXAMPLE 48 { 2- [(2-Fluoro-4-iodophenyl) amino] thieno [2,3-b] pyridin-3-yl} - [(35) -3-hydroxypyrrolidin-1-yl] -methanone Prepared from Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole (98 mg, 0.72 mmol), N-methylthio-1-naphthyl ester (0.11 mL, 0.99 mmol), hydrochloride of 1 - (3 -dime ti 1 aminopr op i 1) - 3 -carbodiimide (139 mg, 0.72 mmol) and (S) -3-hydroxypropyl ether (63 mg, 0.72 mmol, by the method of Example 47. The title compound was obtained as a cream-colored powder (105 mg, 60%) d? (D SO-d6) 9.20 (1H, s), 8.35 (1H, dd, J 1.5, 4.7 Hz) , 7.81 (1H, dd, J 1.5, 8.1 Hz), 7.67 (1H, dd, J 1.9, 10.5 Hz), 7.50-7.47 (1H, m), 7.36 (1H, dd, J 4.7, 8.1 Hz), 7.17 -7.11 (1H, m), 4.91 (1H, s), 4.22 (1H, s), 3.54-3.30 (3H, m), 3.21-3.17 (1H, m), 1.90-1.74 (2H, m). RT 3.17 minutes, (ES +) 484 (M + H) +, EXAMPLE 49. {2- 2- [(2-Fluoro-4-iodophenyl) amino] thieno [2,3-jb] pyridin-3-yl}. - [2- (hydroxymethyl) -piperidin-1-yl] -methanone Prepared from Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole (98 mg, 0.72 mmol), N-methylmorpholine ( 0.11 ml, 0.99 mmol), hydrochloride of l- (3-dimethylaminopropyl) -3-carbodiimide (139 mg, 0.72 mmol) and 2-piperidinemethanol (83 mg, 0.72 mmol), by the method of Example 22. After chromatography, the compound was recrystallized of the title in EtOAc / hexanes to give a pale yellow powder (44 mg, 24%). d? (DMSO-d6, 130 ° C) 8.38 (1H, dd, J 1.5, 4.7 Hz), 7.83 (1H, dd, J 1.5, 8.0 Hz), 7.59 (1H, dd, J 1.9, 10.5 Hz), 7.47 ( 1H, d, J 8.5 Hz), 7.35 (1H, dd, J 4.7, 8.0 Hz), 7.16 (1H, dd, J 8.8, 8.8 Hz), 4.30 (1H, br s), 4.21 (1H, m), 3.89 (1H, m), 3.65-3.60 (1H, m), 3.51-3.47 (1H, m), 3.03-2.97 (1H, m), 1.74-1.72 (1H, m), 1.65-1.56 (4H, m ), 1.37 (1H, m). LCMS RT 2.86 minutes, (ES ") 510 (M-H)", (ES +) 512 (M + H) +. EXAMPLE 50 { 2- [(2-Fluoro-4-iodophenyl) amino] thieno [2, 3-b] pyridin-3-yl} - [(35) -3- (Hydroxymethyl) morpholin-4-yl] -methanone Prepared from Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole (98 mg, 0.72 mmol), N-methylmorpholine (0.11 mL, 0.99 mmol), l- (3-dimethylaminopropyl) -3-carbodiimide hydrochloride (139 mg , 0.72 mmol) and (3S) -3- (hydroxymethyl) morpholine (85 mg, 0.72 mmol), by the method of Example 22. After chromatography, the title compound was lyophilized overnight in acetonitrile. water to give a cream-colored powder (81 mg, 44%). d? (DMSO-d6, 120 ° C) 8.37-8.36 (1H, m), 7.85-7.83 (1H, m), 7.60 (1H, dd, J 1.8, 10.5 Hz), 7.49-7.47 (1H, m), 7.35 (1H, dd, J 4.7, 8.0 Hz), 7.15 (1H, dd, J 8.7, 8.7 Hz), 3.99 (1H, m), 3.85 (1H, d, J 11.6 Hz), 3.80-3.77 (1H, m ), 3.70-3.67 (1H, m), 3.65-3.56 (2H, m), 3.48-3.45 (1H, m), 3.34 (1H, m), 3.27-3.21 (1H, m). LCMS RT 2.60 minutes, (ES ") 512 (MH) ~, (ES +) 514 (M + H) + EXAMPLE 51 4- ({2- (2-fluoro-4-iodine) tert-butyl ester phenyl) amino] thieno [2, 3-b] pyridine-3-carbonyl.} - (3R) -3- (hydroxymethyl) piperazine-1-carboxylic acid Prepared from Intermediate 7 (150 mg, 0, 36 mmol), 1-hydroxybenzotriazole (98 mg, 0.72 mmol), N-methylmorpholine (0.11 mL, 0.99 mmol), l- (3-dimethylaminopropyl) -3-carbodiimide hydrochloride (139 mg, 0.72 mmol) and. { 2R) -4-BOC-2- (hydroxymethyl) piperazine (157 mg, 0.72 mmol), by the method of Example 22. The crude product was subjected to column chromatography (SiO2, 1: 1 hexanes / EtOAc) for give the title compound, which was evaporated in ether to give a pale pink hard foam (95 mg, 43%). d? (D SO-d6, 120 ° C) 8.53 (1H, br s), 8.38-8.37 (1H, m), 7.86-7.84 (1H, m), 7.60 (1H, dd, J 1.7, 10.5 Hz), 7.49 (111, d, J 8.5 Hz), 7.36 (1H, dd, J 4.7, 8.0 Hz), 7.19-7.15 (1H, dd, J 8.5, 8.7 Hz), 4.52 (1H, br s), 4.16 (11- 1, m), 3.95 (1H, d, J 13.5 Hz), 3.88-3.81 (2H, m), 3.49-3.43 (2H, m), 3.14-3.10 (1H, m), 3.02-2.95 (1H, m ), 1.43 (9H, s). LCMS RT 2.98 minutes, (ES +) 613 (M + H) +. EXAMPLE 52 2- [(2-Fluoro-4-iodophenyl) amino] thieno [2, 3-j] pyridine-7-oxide Example 8 (250 mg, 0.55 mmol) was suspended in a mixture of ethanol (20 mg). ml) and water (10 ml). Lithium hydroxide hydrate (24.0 mg, 0.57 mmol) was added and the mixture was heated to reflux for 24 hours. After concentration and lyophilization, the mixture was purified by chromatography (silica, dichloromethane and then 2% MeOH in dichloromethane). The title compound was obtained as an off-white solid (50 mg, 24%). d? (DMSO-d6) 9.42 (1H, br s), 8.13 (1H, dd, J 0.7, 6.2 Hz), 7.69 (1H, dd, J 1.9, 10.7 Hz), 7.54-7.51 (2H, m), 7.39- 7.32 (2H, m), 6.73 (1H, s). LCMS (ES +) RT 2.84 minutes, 387 (M + H) +. EXAMPLE 53 2- [(2-Fluoro-4-iodophenyl) amino] -N- [2- (morpholin-4-yl) -ethyl] thieno [2,3-¿>;] pyridine-3-carboxamide Prepared from Example 1 (250 mg, 0.56 mmol) and 4- (2-aminoethyl) morpholine (292 mg, 2.24 mmol) by the method of Example 5. After chromatography (5% methanol, 95% dichloromethane) the title compound was obtained as an off-white solid (140 mg, 47%). d? (CDC13) 11.43 (1H, br s), 8.36 (1H, dd, J 1 .4, 4.7 Hz), 8.03 (1H, dd, J 1.4, 8.2 Hz), 7.55-7.51 (2H, m), 7.44 ( 1H, dd, J 8 .2, 8.2 Hz), 7.32 (1H, dd, J 4.7, 8.2 Hz), 6.84 (1H, br s), 3.80-3.77 (4H, m), 3.67-3.62 (2H, m ), 2.73-2.69 (2H, m), 2.62-2.59 (4H, m). LCMS (ES +) RT 2.37 minutes, 527 (M + H) +. EXAMPLE 54 2- [4- ( { 2- [(2-Fluoro-4-iodophenyl) amino] thieno [2, 3-bjpiri-din-3-yl.] .carbonyl) piperazine-1-yl] ethanol Prepared from Example 1 (250 mg, 0.56 mmol) and N- (2-hydroxyethyl) piperazine (292 mg, 2.24 mmol) by the method of Example 5. After chromatography (5% methanol, 95% dichloromethane) the title compound was obtained as a white solid (86 mg, 29%). d? (DMSO-d6) 9.13 (1H, br s), 8.36 (1H, dd, J 1.5, 4.7 Hz), 7.80 (1H, dd, J 1.5, 8.1 Hz), 7.68 (1H, dd, J 1.9, 10.5 Hz ), 7.49-7.45 (1H, m), 7.37 (1H, dd, J 4.7, 8.1 Hz), 7.10 (1H, dd, J 8.7, 8.7 Hz), 4.37 (1H, t, J 5.4 Hz), 3.50- 3.40 (6H, m), 2.37-2.33 (6H, m). LCMS (ES +) RT 2. 16 minutes, 527 (M + H) +. EXAMPLE 55 3- (1, 4-Diazepan-1-ylcarbonyl) -N- (2-fluoro-4-iodophenyl) -thieno [2, 3-j] pyridin-2-amine Prepared from Example 1 (250 mg , 0.56 mmol) and homopiperazine (224 mg, 2.24 mmol) by the method of Example 5. After chromatography (10-15% methanol in dichloromethane) the title compound was obtained as a pale yellow solid (180 mg). mg, 64%). d? (CDC13) 8.99 (1H, br s), 8.34 (1H, dd, J 1.6, 4.7 Hz), 7.74 (1H, dd, J 1.6, 8.1 Hz), 7.47-7.43 (2H, m), 7.35 (1H, dd, J 8.5, 8.5 Hz), 7.28-7.22 (1H, m), 4.30-4.10 (1H, br m), 3.95-3.80 (1H, br m), 3.39-2.86 (6H, br m), 2.17- 1.77 (3H, br m). LCMS (ES +) RT 2. 17 minutes, 497 (M + H) +. EXAMPLE 56 N- [3- (Dimethylamino) -2,2-dimethylpropyl] -2- [(2-fluoro-4-iodophenyl) amino] thieno [2, 3-b] pyridine-3-carboxamide Prepared from Example 1 (250 mg, 0.56 mmol) and N, N, 2, 2 - 1 etr ame ti 1 - 1, 3 -pr opanodi amine (292 mg, 2.24 mmol) by the method of Example 5. After chromatography (5% methanol, 95% dichloromethane) the title compound was obtained as a pale yellow solid (60 mg, 20%). d? (DMSO-d6) 10.81 (1H, br s), 9.10 (1H, br s), 8.24-8.21 (2H, m), 7.69-7.65 (1H, m), 7.55-7.52 (1H, m), 7.37- 7.31 (2H, m), 3.29-3.27 (2H, m), 2.50-2.37 (8H, br m), 0.96 (6H, s). LCMS (ES +) RT 2.39 minutes, 527 (M + H) +. EXAMPLE 57 2- [(2-Fluoro-4-iodophenyl) amino] -N- [3- (morpholin-4-yl) -propyl] thieno [2, 3-b] pyridine-3-carboxamide Prepared from Example 1 (250 mg, 0.56 mmol) and 4- (3-aminopropyl) morpholine (323 mg, 2.24 mmol) by the method of Example 5. After chromatography (5% methanol, 95% dichloromethane) the Compound the title as a pale yellow solid (115 mg, 38%). d? (CDC13) 11.29 (1H, br s), 8.36 (1H, dd, J 1.4, 4.7 Hz), 7.99 (1H, dd, J 1.4, 8.2 Hz), 7.63-7.51 (2H, m), 7.47-7.41 ( 1H, m), 7.33-7.29 (1H, m), 7.12 (1H, br s), 3.70-3.64 (2H, m), 3.60-3.56 (4H, m), 2.58-2.54 (2H, m), 2.49 -2.46 (4H, m), 1.90-1.82 (2H, m). LCMS (ES +) RT 2.34 minutes, 541 (M + H) +. EXAMPLE 58 N- (2-Fluoro-4-iodophenyl) -3- (piperazin-1-ylcarbonyl) -thieno [2, 3-J] pyridin-2-amine Piperazine (3.90 g, 45.2 mmol) was dissolved. ) in dry toluene (100 ml) under nitrogen. The mixture was placed in a water bath at 20 ° C and trimethylaluminum (2.0M in toluene, 22.6 ml, 45.2 mmol) was slowly added. After 10 minutes, Example 1 (4.00 g, 0.56 mmol) was added. The mixture was heated at 100 ° C under nitrogen for 6 hours. After cooling to room temperature, the mixture was poured onto a slurry of silica (100 g) in chloroform (400 ml) and methanol (200 ml). After stirring for 10 minutes, the mixture was allowed to stand overnight. Filtration, and concentration of the organic solvent in vacuo, gave a crude material, which was purified by trituration with diethyl ether (50 ml), filtration and washing with diethyl ether (20 ml). The title compound was isolated as a yellow solid (3.56 g, 82%), which could be used for further chemical processes. The dihydrochloride salt of the title compound was prepared by dissolving the free base (1.60 g, 3.32 mmol) in dichloromethane (30 mL) and methanol (5 mL). HC1 in ether (2.0M, 3.34 mL, 6.70 mmol) was added and the mixture was concentrated in vacuo. Trituration with diethyl ether (40 mL) and filtration gave the dihydrochloride salt of the title compound (1.80 g, 98%). d? (DMS0-d6) 9.75 (0.25H, br s), 9.43 (1.75H, br s), 9.30 (1H, s), 8.36 (1H, dd, J 1.6, 4.7 Hz), 7.87 (1H, dd, J 1.6, 8.1 Hz), 7.72 (1H, dd, J 1.9, 10.6 Hz), 7.53 (1H, m), 7.39 (1H, dd, J 4.7, 8.1 Hz), 7.22 (1H, dd, J 8.5, 8.5 Hz ), 3.75-3.58 (4H, m), 3.17-3.06 (4H, m). LCMS (ES +) RT 2.19 minutes, 483 (M + H) +.

EXAMPLE 59 [4- ( { 2- [(2-Fluoro-4-iodophenyl) amino] thieno [2,3-j] pyridin-3-yl.} Carbonyl) -piperazin-1-yl] acetate ethyl Example 58 (300 mg, 0.62 mmol) was dissolved in dichloromethane (10 ml) and triethylamine (94 μl, 0.65 mmol) and ethyl chloroacetate (56 μl, 0.65 mmol) were added. The mixture was refluxed for 12 hours. After cooling and partition between dichloromethane and water (25 ml each), the organic layer was dried (Na 2 SO 4) and concentrated in vacuo. Purification by chromatography (silica, 3% methanol, 97% dichloromethane) gave the product as an oil, which was dissolved in diethyl ether (5 ml) and concentrated in high vacuum to give the title compound as a white solid ( 240 mg, 68%). d? (CDC13) 9.11 (1H, br s), 8.37 (1H, dd, J 1.5, 4.7 Hz), 7.71 (1H, dd, J 1.5, 8.1 Hz), 7.53-7.49 (214, m), 7.40 (1H, dd, J 8.4, 8.4 Hz), 7.32-7.28 (1H, m), 4.21 (2H, q, J 7 .1 Hz), 3.75-3.61 (4H, m), 3.31 (2H, s), 2.79-2.62 (4H, m), 1.29 (3H, t, J 7.1 Hz). LCMS (ES +) RT 3.26 minutes, 569 (M + H) +. EXAMPLE 60 [4- ( { 2- [(2-Fluoro-4-iodophenyl) amino] thieno [2,3-, 3-pyridin-3-yl.] Carbonyl) piperazin-1-yl] acetic acid Example 59 (213 mg, 0.375 mmol) was dissolved in ethanol (7 mL) and water (7 mL). Sodium hydroxide (15.0 mg, 0.375 mmol) was added and the mixture was stirred at room temperature for 18 hours. Lyophilization gave the title compound as its sodium salt (200 mg, 99%). d? (D SO-d6) 9.29 (1H, br s), 8.22-8.17 (1H, br m), 7.68 (1H, br d, J 8.0 Hz), 7.56 (1H, br d, J 10.4 Hz), 7.40 ( 1H, br d, J 8.6 Hz), 7.28-7.20 (1H, br m), 7.07 (1H, dd, J 8.6, 8.6 Hz), 3.42-3.38 (4H, m), 2.65 (2H, s), 2.37 -2.35 (4H, m). LCMS (ES +) RT 2.64 minutes, 541 (M + H) +. EXAMPLE 61 (3i) -3- [( {2- [(2-Fluoro-4-iodophenyl) amino] -thieno [2, 3-j] pyridin-3-yl}. Carbonyl) amino] pyrrolidine- tere-butyl l-carboxylate Prepared from Example 1 (250 mg, 0.56 mmol) and (R) -3-amino-1-tert-butoxycarbonylpyrrolidine (417 mg, 2.24 mmol) by the method of Example 5. After chromatography (25% ethyl acetate, 75% dichloromethane) the title compound was obtained as an off-white solid (45 mg, 13%). d? (DMSO-d6) 10.27 (1H, br s), 8.35 (1H, dd, J 1.4, 4.7 Hz), 8.23 (1H, br d, J 6.5 Hz), 8.06 (1H, dd, J 1.4, 8.2 Hz) , 7.74 (1H, dd, J 1.9, 10.5 Hz), 7.57 (1H, d, J 8.5 Hz), 7.43 (1H, dd, J 4.7, 8.2 Hz), 7.36 (1H, dd, J 8.6, 8.6 Hz) , 4.46-4.40 (1H, br in), 3.57-3.54 (1H, m), 3.52-3.30 (3H, m), 2.15-2.05 (1H, br m), 1.95-1.85 (1H, br m), 1.41 (9H, s). LCMS (ES +) RT 3.70 minutes, 583 (M + H) +.

EXAMPLE 62 (3S) -3- [( { 2- [(2-Fluoro-4-iodophenyl) amino] thieno [2, 3-b] -pyridin-3-yl] .carbonyl) amino] pyrrolidine tere-butyl carboxylate was prepared from Example 1 (250 mg, 0.56 mmol) and (S) -3-amino-l-tert-butoxycarbonylpyrrolidine (417 mg, 2.24 mmol) by the method of Example 5. After chromatography (25% ethyl acetate, 75% dichloromethane) the title compound was obtained as a whitish solid (190 mg, 58%). d? (DMSO-de) 10.27 (1H, br s), 8.35 (1H, dd, J 1.4, 4.7 Hz), 8.23 (1H, br d, J 6.5 Hz), 8.06 (1H, dd, J 1.4, 8.2 Hz) , 7.74 (1H, dd, J 1.9, 10.5 Hz), 7.57 (1H, d, J 8.5 Hz), 7.43 (1H, dd, J 4.7, 8.2 Hz), 7.36 (1H, dd, J 8.6, 8.6 Hz) , 4.46-4.40 (1H, br m), 3.57-3.54 (1H, m), 3.52-3.30 (3H, m), 2.15-2.05 (1H, br m), 1.95-1.85 (1H, br m), 1.41 (9H, s). LCMS (ES +) RT 3.70 minutes, 583 (M + H) +. EXAMPLE 63 2- [(2-Fluoro-4-iodophenyl) amino] -N- [. { 3R) -pyrrolidin-3-yl] thieno [2, 3-b] pyridine-3-carboxamide. Example 61 (40 mg, 0.069 mmol) was dissolved in dichloromethane (3 mL) and HC1 in dioxane (4.0M) was added. 1.0 mL, 4.0 mmol). The mixture was stirred at room temperature for 18 hours. The resulting solid was separated by filtration and dried under vacuum at 40 ° C to give the dihydrochloride salt of the title compound (28 mg, 73%). d? (DMSO-d6) 10.44 (1H, br s), 9.25 (2H, br m), 8.37-8.31 (2H, m), 8.21 (1H, dd, J 1.3, 8.2 Hz), 7.76 (1H, dd, J 1.8, 10.4 Hz), 7.61 (1H, d, J 8.5 Hz), 7.45-7.39 (2H, m), 4.61-4.57 (1H, m), 3.45-3.23 (4H, m), 2.27-2.15 (1H, m), 2.09-1.98 (1H, m). LCMS (ES +) RT 2.30 minutes, 483 (M + H) +. EXAMPLE 64 2- [(2-Fluoro-4-iodophenyl) amino] -N- [(35) -pyrrolidin-3-yl] thieno [2,3-¿>;] pyridine-3-carboxamide Example 62 (170 mg, 0.069 mmol) was dissolved in dichloromethane (4 mL) and HC1 in dioxane (4.0M, 4.0 mL, 16.0 mmol) was added. The mixture was stirred at room temperature for 18 hours. The resulting solid was separated by filtration and dried under vacuum at 40 ° C to give the dihydrochloride salt of the title compound (150 mg, 92%). d? (DMSO-de) 10.44 (1H, br s), 9.25 (2H, br m), 8.37-8.31 (2H, m), 8.21 (1H, dd, J 1.3, 8.2 Hz), 7.76 (1H, dd, J 1.8, 10.4 Hz), 7.61 (1H, d, J 8.5 Hz), 7.45-7.39 (2H, m), 4.61-4.57 (1H, m), 3.45-3.23 (4H, m), 2.27-2.15 (1H, m), 2.09-1.98 (1H, m). LCMS (ES +) RT 2.30 minutes, 483 (M + H) +. EXAMPLE 65 2- [(2-Fluoro-4-iodophenyl) amino] -N- (1-methylpiperidin-4-yl) thieno [2 3-¿> ] pyridine-3-carboxamide Prepared from Example 1 (250 mg, 0.56 mmol) and 4-amino-1-methylpiperidine (255 mg, 2.24 mmol) by the method of Example 5. After chromatography % methanol, 90% dichloromethane) the crude material was dissolved in dichloromethane (2 ml) and HC1 2, OM in diethyl ether (2 ml) was added. The resulting solid was separated by filtration to give the dihydrochloride salt of the title compound as a yellow solid (145 mg, 44%). d? (DMSO-d6) 10.62 (1H, br s), 10.37 (0.8H, s), 10.26 (0.2H, s), 8.40-8.36 (1H, m), 8.31-8.28 (0.8H, m), 8.22- 8.20 (0.2H, m), 8.19-8.16 (0.2H, m), 8.10-8.07 (0.8H, m), 7.75-7.71 (11-1, m), 7.59-7.56 (1H, m), 7.47- 7.31 (2H, m), 4.05 (1H, br m), 3.45-3.05 5H, m), 2.70 (3H, d, J 6.0 Hz), 2.03-1.85 (4H, m). LCMS (ES +) RT 2.34 minutes, 511 (M + H) +. EXAMPLE 66 { 2- [(2-Fluoro-4-iodophenyl) amino] thieno [2, 3-¿> ] pyridin-3-yl} - [(2R) -2- (methoxymethyl) pyrrolidin-1-yl] -methanone Prepared from Intermediate 14 (285 mg, 0.66 mmol), 2M trimethylaluminum in hexane (1.6 ml, 3.30 g. mmol) and (R) -2- (methoxymethyl) pyrrolidine (383 mg, 3.30 mmol) by the method of Example 5, to give the title compound (17 mg). d? (DMSO-d6) 9.17 (1H, br s), 8.37 (1H, dd, J 4.6, 1.3 Hz), 7.78 (1H, d, J 7.7 Hz), 7.76 (1H, dd, J 10.6, 1.8 Hz), 7.46 (1H, d, J 8.5 Hz), 7.37 (1H, d, J 8.0, 4.6 Hz), 7.05 (1H, t, J 8.5 Hz), 4.10-4.00 (1H, br m), 3.33-3.01 (7H , br m), 1.90-1.64 (4H, br m). LCMS (ES +) RT 3.27 minutes, 215 (M + H) +.

EXAMPLE 67 2- [(2-Fluoro-iodo-phenyl) amino [thieno [2, 3-Jb] pyridine-3-carboxylic acid cyclopropylmethyl) amide was prepared from Intermediate 14 (450 mg, 1, 05 mmol), 2M trimethylaluminum in hexane (2.6 ml, 5.26 mmol) and (aminomethyl) cyclopropane (374 mg, 5.26 mmol) by the method of Example 5, to give the title compound (250 mg) . d? (DMSO-d6) 10.68 (1H, br s), 8.36 (1H, d, J 3.8 Hz), 8.17 (1H, d, J 8.1 Hz), 8.15-8.00 (1H, br m), 7.75 (1H, d , J 10.4 Hz), 7.60 (1H, d, J 1 .6 Hz), 7.47-7.38 (2H, br m), 3.18 (2H, t, J 6.2 Hz), 1.10-1.03 (1H, br m), 0.47-0.41 (2H, br m), 0.28-0.23 (2H, br m). LCMS (ES +) RT 3.54 minutes, 468 (+ H) +. EXAMPLE 68 2- [(2-Fluoro-4-iodo-phenyl) amino] -7-oxitiene [2-, 3-α] -amido-2- (2-fluoro-4-yl) amide. ] pyridine-3-carboxylic acid To a solution of Intermediate 16 (260 mg, 1.12 mmol) in DMSO was added sodium hydride (50 mg, 1.23 mmol), and the reaction mixture was stirred for 10 minutes. Intermediate 1 (328 mg, 1.18 mmol) was added and the reaction mixture was stirred for a further 1 hour at room temperature. The reaction mixture was poured into water and extracted into ethyl acetate. The organic phase was washed with brine, dried (magnesium sulfate) and concentrated in vacuo. The crude product was purified by chromatography (SiO2, 10% methanol in ethyl acetate) to give the required product as a pale yellow solid (64 mg). d? (DMSO-d6) 9.41 (1H, s), 8.20 (1H, dd, J 5.9, 1.0 Hz), 7.74 (1H, dd, J 10.3, 1.9 Hz), 7.57-7.54 (1H, m), 7.48-7.38 (2H, m), 7.22 (1H, t, J 8.6 Hz), 3.47 (3H, s), 3.17 (3H, s). LC S (ES +) RT 2.70 minutes, 474 (M + H) +. EXAMPLE 69 2- [(2-Fluoro-4-iodo-phenyl) amino] thieno [2,3-2 [alpha] 2-pyridine-3-carboxylic acid (2- (2-fluoro-4-iodo-phenyl) amino acid) Example 68 (64 mg) was heated , 0.13 mmol) and triphenylphosphine (177 mg, 0.68 mmol) in THF (1 mL) at 65 ° C overnight. Phosphorus trichloride (34 mg, 0.39 mmol) was added and the reaction mixture was stirred at room temperature for 90 minutes. The reaction was quenched with sodium hydrogencarbonate solution, and the product was extracted into DCM, dried (magnesium sulfate) and concentrated in vacuo. After preparative HPLC, the required product (10 mg) was obtained as an off-white solid. d? (DMSO-d6) 9.23 (1H, s), 8.35 (1H, dd, J 4.7, 1.6 Hz), 7.84 (1H, dd, J 8.1, 1.6 Hz), 7.70 (1H, dd, J 10 .3, 1.9 Hz), 7.53 (1H, d, J 8.4 Hz), 7.37 (1H, dd, J 8.1, 4.7 Hz), 7.22 (1H, t, J 8.6 Hz), 3.47 (3H, s), 3.20 (3H, s ). LCMS (ES +) RT 3.23 minutes, 458 (M + H) +.

EXAMPLE 70 { 2- [(2-Fluoro-4-iodophenyl) amino] thieno [2, 3-Jb] pyridin-3-yl} - [(2R) -2- (hydroxymethyl) -piperazin-1-yl] -methanone A solution of Example 51 (80 mg, 0.13 mmol) in methanol (2 mL) was treated with 4M HC1 in 1.4- dioxane (5 ml) and stirred at rt for 3 h. The reaction mixture was concentrated in vacuo to give a yellow gum, which was dissolved in methanol (20 ml) and water (5 ml), and then made basic to pH 11 with ammonium hydroxide aq. to 25%. The aqueous solution was extracted with DCM (3 x 25 mL), and the organic extracts were combined, dried (N a 2 S O 4), filtered and concentrated in vacuo. The crude product was subjected to column chromatography (Si02, 95: 4: 1 DCM / methanol / 25% aq. Ammonium hydroxide) to give the title compound as a mixture of two rotamers, which were lyophilized overnight in acetonitrile / water to give a cream-colored powder (63 mg, 94%). d? (DMS0-d6, 120 ° C, contains rotamers) 8.37-8.36 (1H, m), 8.29-8.28 (0.44H, m), 8.33 (0.56H, dd, J 1.4, 8.0 Hz), 7.75 (0.44H, dd, J 1.8, 10.0 Hz), 7.68-7.66 (0.44H, m), 7.58 (0.56H, dd, J 1.9, 10.5 Hz), 7.48-7.44 (1H, m), 7.39-7.33 (1H, m) , 7.17-7.13 (0.56H, m), 4.31-4.29 (1H, m), 4.00 (1H, m), 3.74-3.60 (2H, m), 3.10-2.83 (3H, m), 2.76-2.65 (2H , m), 2.60-2.53 (1H, m). LCMS RT 2.07 and 1.95 minutes, (ES +) 513 (M + H) +. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (10)

1. CLAIMS Having described the invention as above, it is claimed com property contained in the following claims: 1. A compound of formula (I), or a pharmaceutically acceptable salt, solvate or N-oxide thereof: characterized in that R1 represents hydrogen, halogen or Ci-s alkyl; R2 represents halogen or Ci-6 alkyl, "R3 represents hydrogen, cyano, -C02Ra, -CONRbRc or CON (ORb) Rc, Ra represents Ci-6 alkyl, Rb represents hydrogen, or Ci-6 alkyl, C3-7 cycloalkyl , C3_7-cycloalkyl- (C1-6) alkyl, aryl, aryl- (C6) alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl- (Ci-6) alkyl, heteroaryl or heteroaryl- (C1-6) alkyl, any of said groups optionally substituted with one or more substituents, and Rc represents hydrogen or Ci-6 alkyl (optionally substituted with hydroxy), or Rb and Rc, when considered together with the nitrogen atom to which both are attached, represent azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperidinyl, homomorpholinyl or homopiperazinyl, wherein any of said groups may be optionally substituted with one or more substituents
2. 2. A compound according to claim 1, characterized in that Rb represents hydrogen; or Ci-6 alkyl, C3_7 cycloalkyl (Ci_6) alkyl, C3-7 heterocycloalkyl or C3_7 heterocyclocycloalkyl (Ci-6) alkyl, any of said groups being optionally substituted with one or more substituents.
3. 3. A compound according to claim 1, characterized in that the cyclic moiety -NRbRc represents azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl or homopiperazin. -l-ilo, which may be any of said groups optionally substituted with one or more substituents.
4. 4. A compound according to any one of the preceding claims, characterized in that the substituents on Rb, or on the cyclic moiety -NRbRc, are selected from Ci-6 alkyl, Ci-6-alkoxy (Ci_6) alkoxy, hydroxy, hydroxy -alkyl (Ci_6), amino, amino-alkyl (Ci-6), carboxymethyl, alkoxycarbonyl C2_6, alkoxycarbonylC2-6alkyl (Ci_6), di-alkylamino (Ci-6), alkoxycarbonylaminoC2-6 and alkoxycarbonylaminoC2_6-alkyl (C1-6) ·
5. 5. A compound according to claim 1, represented by the formula (II), and pharmaceutically acceptable salts, solvates and N-oxides thereof: (?) characterized in that R12 represents halogen; and R3 is as defined in claim 1.
6. 6. A compound according to claim 5, characterized in that R12 represents bromine or iodine.
7. 7. A compound according to claim 1, characterized in that it is specifically described herein in any of the examples.
8. 8. A pharmaceutical composition characterized in that it comprises a compound of formula (I) as defined according to claim 1, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, in association with a pharmaceutically acceptable carrier.
9. 9. The use of a compound of formula (I) as defined according to claim 1, or a pharmaceutically acceptable salt, solvate or N-oxide thereof, for the manufacture of a medicament for the treatment and / or prevention of disorders for which administration of a selective MEK inhibitor is indicated.
10. 10. A method for the treatment and / or prevention of disorders for which the administration of a selective inhibitor of MEK is indicated, characterized in that it comprises administering to a patient in need of said treatment an effective amount of a compound of formula (I) as defined in accordance with claim 1, or a pharmaceutically acceptable salt, solvate or N-oxide thereof.