MXPA06009857A - Diaminopyrimidines as p2x3 and p2x2/3 antagonists - Google Patents

Abstract

Compounds and methods for treating diseases mediated by a P2X3 and/or a P2X2/3 receptor antagonists, the methods comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein D, X, Y, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined herein.

Description

DIAMINOPIRIMIDINAS AS ANTAGONISTS P2X3 AND P2X23 Description of the Invention This invention relates to compounds useful for the treatment of diseases associated with P2X purinergic receptors and more particularly to P2X3 and / or P2X2 / 3 antagonists which can be used for the treatment of diseases, conditions and genitourinary disorders and painful. The urinary bladder performs two important physiological functions: the storage of urine and the emptying of urine: (1) the bladder fills progressively until the tension in its walls increases until it exceeds a threshold level; and (2) then a nervous reflex is produced, called a micturition reflex, which empties the bladder or, if this is not done, produces at least a conscious desire to urinate. Although the micturition reflex is an autonomous reflex of the spinal cord, it can be inhibited or mediated also from centers in the cerebral cortex or the brain. Purines, which act by extracellular purinorreceptors, are involved, since they possess a wide variety of physiological and pathological roles. ATP, and to a lesser extent, adenosine can stimulate the sensory nerve terminals causing intense pain and a pronounced increase in sensory nerve discharge. REF: 175044 recipients of ATP have been classified into two main families, P2Y and P2X purinorreceptors, based on molecular structure, transduction mechanisms and pharmacological characterization. The P2Y purinorreceptors are receptors bound to the G protein, while the P2X purinorreceptors are a family of cationic channels regulated by ATP. It is known that purinergic receptors, in particular P2X receptors, form homomultimers or heteromultimers. To date, the cDNAs of several subtypes of P2X receptors have been cloned, including: six homomeric receptors: P2X ?; P2X2; P2X3; P2X; P2X5; and P2X7; and three heteromeric receptors: P2X2 / 3, P2X / 6 and P2X? / 5. The structure and chromosomal mapping of the genomic P2X3 receptor subunit of the mouse have also been described. "In vitro" requires the co-expression of P2X2 and P2X3 receptors to produce currents regulated by ATP, whose properties have been observed in some sensory neurons. Subunits of P2X receptors have been found in afferents of the urothelium of the bladder of rodents and humans. There are data suggesting that ATP can be released from the epithelial / endothelial cells of the urinary bladder or hollow organs, as a result of distention. ATP released in this way may take on the role of carrying information to sensory neurons located in subepithelial components, for example, the suburotial lamina propria. P2X receptors have been studied in a large number of neurons, including sensory, sympathetic, parasympathetic, mesenteric and central neurons. These studies indicate that purinergic receptors play a role in afferent neurotransmission from the bladder and that modulators of P2X receptors are potentially useful - for the treatment of bladder disorders and other genitourinary diseases and conditions. Recent findings also suggest a role for endogenous ATP and purinergic receptors in the nociceptive responses of mice. It has been found that ATP-induced activation of the P2X receptors of the nerve terminals of the spinal cord spinal ganglia stimulates the segregation of glutamate, a key neurotransmitter involved in nociceptive signaling. P2X3 receptors have been identified in nociceptive neurons in the dental pulp. Therefore, ATP released in damaged cells can lead to pain by activation of receptors containing P2X3 and / or P2X2 / 3 in the nociceptive sensing nerve terminals. This is consistent with the induction of pain by ATP applied intradermally in a basic human ampulla model. It has been found that P2X antagonists act as analgesics in animal models. This fact suggests that P2X2 and P2X3 are involved in nociception and that modulators of P2X receptors are potentially useful as analgesics.

There is, therefore, a need for methods of treating diseases, disease states and disorders mediated by P2X3 and / or P2X2 / 3 receptors as well as the need for compounds that act as modulators of P2X receptors, including antagonists of P2X3 receptors. P2X3 and P2X2 / 3 receivers. The present invention satisfies these and other needs. Many diaminopyrimidine compounds have been previously obtained, for example "ormetoprim" (US 2,658,897) and "trimethoprim" (US 2,909,522), and have been identified as antibacterial agents. However, diaminopyrimidines have not yet been identified as modulators of P2X receptors. The invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein: X is -CH2-; -0-; -CHOH-; -S (0) n-; or -NRC-, wherein n is a number from 0 to 2 and Rc is hydrogen or alkyl; And it's hydrogen; or -NRdRe in which one of Rd and Re is hydrogen and the other is hydrogen; I rent; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl; D is an optional oxygen; R1 is alkyl; alkenyl; cycloalkyl; cycloalkenyl; halogen; haloalkyl; hydroxyalkyl; or alkoxy; R2, R3, R4 and R5 independently of each other are hydrogen; I rent; alkenyl; Not me; halogen; amido; haloalkyl; alkoxy; hydroxy; haloalkoxy; nitro; Not me; hydroxyalkyl; alkoxyalkyl; hydroxyalkoxy; alkynylalkoxy; alkylsulfonyl; Aryisulfonyl; cyano; aril; heteroaryl; heterocyclyl; heterocyclylalkoxy; aryloxy; heteroaryloxy; aralkyloxy; heteroaralkyloxy; phenoxy optionally substituted; - (CH2) m- (Z) n- (C0) -Rf or - (CH2) m- (Z) nS02- (NRg) n -Rf, where m and n independently are 0 or 1, Z is O or NRg, Rf is hydrogen, alkyl, hydroxy, alkoxy, amino, hydroxyalkyl or alkoxyalkyl and each Rg independently of its appearance is hydrogen or alkyl; or R3 and R4 together can form a - alkylenedioxy; or R3 and R4 together with the atoms to which they are attached can form a five or six member ring optionally including one or two heteroatoms chosen from O, S and N; or R2 and R3 together can form an alkylenedioxy; or R2 and R3 together with the atoms to which they are attached can form a five or six member ring optionally including one or two heteroatoms chosen from 0, S and N; R6 is hydrogen; I rent; halogen; haloalkyl; Not me; or alkoxy; and one of R7 and R8 is hydrogen and the other is hydrogen; I rent; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl; with the proviso that, when X is -CH2- and R7, R8, Rd and Re are hydrogen, R1 is isopropyl, isopropenyl, cyclopropyl or iodo. In another embodiment, the present invention provides a method for treating a disease mediated by a P2X3 receptor antagonist, a P2X2 / 3 receptor antagonist or both, said method comprising administering to a subject in need thereof an effective amount of a compound of the formula (I *): or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: X is -CH2-; -0-; -C (0) -; -CHOH-; -S (0) n-; or -NRC-, wherein n is a number from 0 to 2 and Rc is hydrogen or alkyl; And it's hydrogen; or -NRdRe, in which one of Rd and Re is hydrogen and the other is hydrogen; I rent; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl; R1 is alkyl; alkenyl; cycloalkyl; cycloalkenyl; halogen; haloalkyl; or alkoxy; R2, R3, R4 and R5 independently of each other are hydrogen; I rent; Not me; amido; haloalkyl; alkoxy; alkylsulfonyl; Aryisulfonyl; sulfonamido; cyano; acetyl; heteroaryl; carboxylic acid; carboxylic acid amide; urea; carbamate; acetamido; or optionally substituted phenoxy; or R3 and R4 together can form an alkylene dioxy; or R3 and R4 together with the atoms to which they are attached can form a five or six member ring including one or two heteroatoms chosen from O, S and N; or R2 and R3 together can form an alkylenedioxy; or R2 and R3 together with the atoms to which they are attached can form a five or six member ring including one or two heteroatoms chosen from O, S and N; R6 is hydrogen; I rent; haloalkyl; Not me; or alkoxy; and one of R7 and R8 is "hydrogen and the other is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, acetyl, alkylsulfonyl, alkylsulfonylalkyl, aryl, aralkyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl, heterocyclyl, or heterocyclylalkyl. The invention also provides pharmaceutical compositions containing the compounds, methods for the use of the compounds and methods for obtaining the compounds.

Unless otherwise indicated, the following terms used in this application, including the description and the claims, have the meanings defined below. It should be noted that the singular forms "one", "one", "the" and "the", used in the description and appended claims, also include plural referents, unless the context clearly dictates otherwise. "Agonist" indicates a compound that enhances the activity of another compound or receptor site. "Antagonist" indicates a compound decreases or prevents the action of another compound or receptor site. "Alkyl" means a monovalent, straight or branched saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms and having one to twelve carbon atoms. "Lower alkyl" means an alkyl group of one to six carbon atoms, i.e., C 1 -C 6 alkyl. Examples of alkyl groups include, but are not limited to: methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like. "Alkylene" means a linear divalent saturated hydrocarbon radical, of one to six carbon atoms or a branched divalent saturated hydrocarbon radical of three to six carbon atoms, for example methylene, ethylene, 2,2-dimethyl-ethylene, propylene, -methylpropylene, butylene, pentylene and the like. "Alkoxy" means a moiety of the formula -OR, wherein R is an alkyl moiety, defined herein. Examples of alkoxy moieties include, but are not limited to: methoxy, ethoxy, isopropoxy and the like. "Alkoxyalkyl" means a radical of the formula Ra-0-Rb-, wherein Ra is alkyl and Rb is alkylene, defined herein. Representative alkoxyalkyl groups include, for example, 2-methoxyethyl, 3-methoxypropyl, 1-methyl-2-methoxyethyl, 1- (2-methoxyethyl) -3-methoxypropyl and 1- (2-methoxyethyl) -3-methoxypropyl. "Alkylcarbonyl" means a moiety of the formula -R'-R ", wherein R 'is oxo and R" is alkyl, defined herein.

"Alkylsulfonyl" means a moiety of the formula -R'-R ", wherein R 'is -S02- and R" is alkyl, defined herein. "Alkylsulfonylalkyl" means a radical of the formula -R'-R "-R" ', wherein R' is alkyl, R "is -S02- and R" 'is alkyl, defined herein. "Alkylamino" means a moiety of the formula -NR-R 'wherein R is hydrogen or alkyl and R' is alkyl, defined herein. "Alkoxyamino" means a moiety of the formula -NR-OR 'wherein R is hydrogen or alkyl and R' is alkyl, defined herein. "Alkylsulfanyl" means a radical of the formula -SR in which R is alkyl, defined herein. "Aminoalkyl" means a group -R-R 'wherein R' is amino and R is alkylene, defined herein. "Aminoalkyl" includes aminomethyl, aminoethyl, 1-aminopropyl, 2-aminopropyl and the like. The "aminoalkyl" amino moiety can be substituted once or twice by alkyl to give "alkylaminoalkyl" and "dialkylaminoalkyl", respectively. "Alkylaminoalkyl" includes methylaminomethyl, methylaminoethyl, methylaminopropyl, ethylaminoethyl and the like. "Dialkylaminoalkyl" includes dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, N-methyl-N-ethylaminoethyl, and the like.

"Aminoalkoxy" means a group -OR-R 'wherein R' is amino and R is alkylene, defined herein. "Alkylsulfonylamido" means a moiety of the formula -NR'S02-R wherein R is alkyl and R 'is hydrogen or alkyl. "Aryl" means a monovalent cyclic aromatic hydrocarbon residue, which has a mono-, bi- or tricyclic aromatic ring. The aryl group may be optionally substituted as defined herein. Examples of aryl moieties include, but are not limited to: optionally substituted phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylene diphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxyl, benzopyranyl , benzoxazinyl, benzoxazinonyl, benzopiperadinil, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl and the like, including the partially hydrogenated derivatives thereof. "Arylalkyl" and "aralkyl", which may be used interchangeably, mean a radical -RaRb in which R is an alkylene group and Rb is an aryl group, defined herein; Examples of arylalkyl are, for example, phenylalkyl such as benzyl, phenylethyl, 3- (3-chlorophenyl) -2-methylpentyl and the like. "Cyanoalkyl" means a moiety of the formula -R'-R ", wherein R 'is alkylene, defined herein and R" is cyano or nitrile. "Cycloalkyl" means a monovalent saturated carbocyclic moiety consisting of mono- or bicyclic rings. The cycloalkyl may be optionally substituted by one or more substituents, each substituent independently of its occurrence being hydroxy, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino or dialkylamino, unless otherwise specifically indicated. Examples of cycloalkyl moieties include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, including the partially hydrogenated derivatives thereof. "Cycloalkylalkyl" means a radical of the formula -R'-R ", wherein R 'is alkylene and R" is cycloalkyl, defined herein. "Heteroalkyl" means an alkyl moiety, defined herein, wherein one, two or three hydrogen atoms have been replaced by a chosen substituent independently of their occurrence from the group consisting of -0Ra, -NRbRc and -S ( 0) nRd (where n is an integer from 0 to 2), assuming that the point of attachment of the heteroalkyl moiety is a carbon atom, where Ra is hydrogen, acyl, alkyl, cycloalkyl or cycloalkylalkyl; Rb and Rc independently of each other are hydrogen, acyl, alkyl, cycloalkyl or cycloalkylalkyl; and, when n is 0, Rd is hydrogen, alkyl, cycloalkyl or cycloalkylalkyl and, when n is 1 or 2, Rd is alkyl, cycloalkyl, cycloalkylalkyl, amino, aeylamino, monoalkylamino or dialkylamino. Representative examples include, but are not limited to: 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2 -hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfo-nylmethyl, methylaminosulfonylethyl, methylaminosulfonylpropyl and the like. "Heteroaryl" means a monocyclic or bicyclic residue of 5 to 12 ring atoms, having at least one aromatic ring containing one, two or three heteroatoms in the ring, chosen from N, 0 and S, the other atoms of the ring are C, assuming that the point of attachment of the heteroaryl moiety can be in the aromatic ring. The heteroaryl ring may be optionally substituted as defined herein. Examples of heteroaryl moieties include, but are not limited to: imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuryl benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzo-oxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl optionally substituted and the like , including partially hydrogenated derivatives thereof. The terms "halo", "halogen1" and "halide", which can be used interchangeably, mean a fluorine, chlorine, bromine or iodine substituent. "Haloalkyl" means alkyl, defined herein, in which one or more hydrogens have been replaced by the same or different halogen atoms Examples of haloalkyls include -CH2C1, -CH2CF3, -CH2CC13, perfluoroalkyl (e.g.

-CF3) and similar. "Haloalkoxy" means a radical of the formula -OR, in which R is a haloalkyl radical, defined herein. An example of haloalkoxy is difluoromethoxy. "Heterocycloamino" means a saturated ring in which at least one of the ring atoms is N, NH or N-alkyl and the other ring atoms form an alkylene group. "Heterocyclyl" means a saturated monovalent radical, containing one to three rings and incorporating one, two or three or four heteroatoms (chosen from nitrogen, oxygen and sulfur). The heterocyclyl ring may be optionally substituted as defined herein. Examples of heterocyclyl moieties include, but are not limited to: piperidinyl, piperazinyl, homopiperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyridinyl, pyridazinyl, pyrimidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinuclidinyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolylidinyl, benzothiazolidinyl, benzoazolylidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dihydroquinolinyl, dihydrisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl optionally substituted and the like. "Heterocyclylalkyl" means a radical of the formula -R-R 'wherein R is alkylene and R' is heterocyclyl, defined herein. "Heterocyclyloxy" means a radical of the formula -OR in which R is heterocyclyl, defined herein. "Heterocyclylalkoxy" means a residue of the formula OR-R 'wherein R is alkylene and R' is heterocyclyl, defined herein. "Hydroxyalkoxy" means a radical of the formula -OR in which R is hydroxyalkyl, defined herein. "Hydroxyalkylamino" means a residue of the formula NR-R1 in which R is hydrogen or alkyl and R 'is hydroxyalkyl, defined herein. "Hydroxyalkylaminoalkyl" means a radical of the formula -R-NR'-R "in which R is alkylene, R1 is hydrogen or alkyl and R" is hydroxyalkyl, defined herein. "Hydroxyalkyl" means an alkyl moiety, defined herein, substituted by one or more hydroxy groups, preferably one, two or three, with the proviso that the same carbon atom carries no more than one hydroxy group. Representative examples include, but are not limited to: hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3 -dihydroxypropyl, 2-hydroxy-l-hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2- (hydroxymethyl) -3-hydroxypropyl. "Hydroxycycloalkyl" means a cycloalkyl moiety, defined herein, wherein one, two or three hydrogen atoms of the cycloalkyl moiety have been replaced by a hydroxy substituent. Representative examples include, but are not limited to: 2-, 3- or 4-hydroxycyclohexyl and the like. "Urea" or "ureido" means a group of the formula -NR'-C (0) -NR "R" ', wherein R', R "and R" 'independently of each other are hydrogen or alkyl.

"Carbamate" means a group of the formula -0-C (0) -NR'R ", wherein R 'and R" independently of each other are hydrogen or alkyl. "Carboxy" means a group of the formula -0-C (0) -OH; "Sulfonamido" means a group of the formula -S02-NR'R "in which R ', R" and R "' independently of each other are hydrogen or alkyl." Optionally substituted ", when used in association with" aryl " "phenyl", "heteroaryl", "cyclohexyl" or "heterocyclyl", means an aryl, phenyl, heteroaryl, cyclohexyl or heterocyclyl which is optionally substituted independently of its occurrence from one to four times by substituents, preferably by one or two substituents, chosen from alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyalkyl, halogen, nitro, cyano, hydroxy, alkoxy, amino, acylamino, monoalkylamino, dialkylamino, haloalkyl, haloalkoxy, heteroalkyl, -COR (where R is hydrogen, alkyl, phenyl or phenylalkyl), (CR1 R ") n-COOR (wherein n is an integer of 0 to 5, R 'and R "independently of each other are hydrogen or alkyl and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl) or - (CR' R") n-C0NRRb (wherein n is a integer from 0 to 5, R 'and R "independently of each other are hydrogen or alkyl and Ra and Rb independently of each other are hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl). "Leaving group" means the group having the meaning conventionally associated therewith in synthetic organic chemistry, ie, an atom or group displaceable under the conditions of substitution reaction. Examples of leaving groups include, but are not limited to: halogen, alkane- or arylenesulfonyloxy, for example methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy and thienyloxy, dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy, acyloxy and the like. "Modulator" means a molecule that interacts with a target. The interactions include, but are not limited to: agonist, antagonist and the like, defined herein. "Optional" or "optionally" means that the event or circumstance described below may occur but not necessarily and that the description includes the cases in which the event or circumstance occurs and the cases in which it does not occur. "Disease" and "pathological condition" means any disease, condition, symptom, disorder or indication. "Inert organic solvent" or "inert solvent" means that the solvent is inert under the conditions in which it performs the reaction described in combination therewith, includes for example benzene, toluene, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, chloroform , methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine and the like. Unless otherwise specified, the solvents used in the reactions of the present invention are inert solvents. "Pharmaceutically acceptable" means that it is useful for manufacturing a pharmaceutical composition, which is generally safe, non-toxic and non-disruptive in biological or other sense and includes that it is acceptable for "veterinary use and also for human pharmaceutical use. "Pharmaceutically acceptable salts" of a compound means salts that are pharmaceutically acceptable, as defined herein and that possess the desired pharmacological activity of the parent compound. Said salts include: acid addition salts, formed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; -or formed with organic acids, for example acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid and the like; or salts formed when an acid proton present in the original compound is replaced by a metal ion, for example an alkali metal ion, an alkaline earth metal ion or an aluminum ion; or it is coordinated with an organic or inorganic base. Acceptable organic bases - include diethanolamine, ethanolamine, N-methylglucamine,. triethanolamine, tromethamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide. Preferred pharmaceutically acceptable salts are the salts formed with acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc and magnesium. It is assumed that all references to pharmaceutically acceptable salts include the solvent addition forms (solvates) and the crystalline forms (polymorphs), as defined herein, of the same acid addition salt.

The terms "prodrug" and "pro-drug" refer to any compound that releases "in vivo" the original active drug of formula I when said prodrug is administered to a mammalian subject. The prodrugs of a compound of the formula I are obtained by modification of one or more functional groups present in the compound of the formula I in such a way that the modifications can be eliminated "in vivo" by releasing the original compound again. Prodrugs include compounds of formula I in which a hydroxy, amino or sulfhydryl group of a compound of formula I has been attached to any other group that can be removed "in vivo" to regenerate the free hydroxyl, amino or sulfhydryl group , respectively. Examples of prodrugs include, but are not limited to: esters (for example acetate, formate and benzoate derivatives), carbamates (for example N, N-dimethylaminocarbonyl) of hydroxy functional groups of compounds of formula I, N-acyl derivatives ( for example N-acetyl), N-bases of Mannich, Schiff bases and enaminones of amino functional groups, oximes, acetals, ketals and enol-esters of functional groups ketone and aldehyde of compounds of the formula I and the like, see Bundegaard, " Design of Prodrugs ", pl-92, Elsevier, New York-Oxford (1985) and the like. "Protective group" or "protecting group" means the group that selectively blocks a reactive site of a multifunctional compound, such that a chemical reaction can be performed selectively at another unprotected reactive site, in the sense conventionally associated therewith. in synthetic chemistry. Certain processes of this invention may be based on the fact that the protecting groups block a reactive nitrogen and / or oxygen atom present in the reagents. For example, the terms "amino protecting group" and "nitrogen protecting group" are used in the present description in an indistinct manner and indicate that these organic groups have the function of protecting the nitrogen atom from the annoying (undesirable) reactions that may occur during the synthesis procedures. Examples of nitrogen protecting groups include, but are not limited to: trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl (carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC) and the like. The person skilled in the art will know how to choose the group taking into account that it must be easy to eliminate later and that it must resist unaltered the reactions of the process. "Solvates" means solvent addition forms that contain stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to retain a fixed molar ratio of solvent molecules within their crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. The hydrates can be formed by combining one or more water molecules with one of the substances in which the water retains its molecular status of H20, such combination is capable of forming one or several hydrates.

"Subject" means mammals and not mammals. Mammals means any member of the group of mammals, including, but not limited to - "them: humans, non-human primates, eg chimpanzees and other species of apes and monkeys; livestock-interest animals, eg cows, horses, sheep, goats and pigs, domestic animals, for example rabbits, dogs and cats, and laboratory animals, including rodents, for example rats, mice and guinea pigs, and the like Examples of non-mammals include, but are not limited to: birds and the like The term "subject" does not denote a specific age or sex. "Urinary tract disorders" or "uropathy", which is used interchangeably with "urinary tract symptoms", means pathological changes of the urinary tract. Urinary tract disorders include, but are not limited to: incontinence, benign prostatic hyperplasia (BPH), prostatitis, detrusor hyperreflexia, obstruction of the exit, urinary frequency, nocturia, urgency, overactive bladder, pelvic hypersensitivity, urge incontinence, urethritis, prostatodynia , cystitis, idiopathic bladder hypersensitivity and the like. "Overactive bladder" or "detrusor overactivity" includes but is not limited to: changes manifested symptomatically such as urgency, frequency, altered bladder capacity, incontinence, threshold of urination, unstable bladder contractions, sphincter spasms, hyperreflexia of the detrusor (neurogenic bladder), detrusor instability and the like. "Output obstruction" includes but is not limited to: benign prostatic hypertrophy (BPH), urethral stricture disease, tumors, "small" jet, difficulty in initiating urination, urgency, suprapubic pain, and the like. "Evacuation failure" includes, but is not limited to: urethra hypermobility, intrinsic sphincter deficiency, mixed incontinence, stress incontinence and the like. "Pelvic hypersensitivity" includes, but is not limited to: pelvic pain, interstitial (cell) cystitis, prostatodynia, prostatitis , vulvadynia, urethritis, orchidalgia, overactive bladder and the like "" Therapeutically effective amount "means the amount of a compound that, when administered to a subject to treat a pathological condition, is sufficient to produce such treatment of the pathological condition. Therapeutically effective "will vary depending on the compound, the disease state being treated, the severity or the disease treated, of the age and of the relative health of the subject, of the route and form of administration, of the criterion of the medical or veterinary physician attending to the patient and of other factors. The terms "those defined above" and "those defined herein," when referring to a variable, incorporate by reference the broad definition of the variable as well as the preferred, highly preferred and especially preferred definitions, if any. "Treat" or "treatment" of a pathological state includes: (i) preventing the pathological state, that is, causing the clinical symptoms of the pathological state not to develop in a subject that may be exposed or predisposed to the pathological state, but that still does not experience or manifest the symptoms of the pathological state, (ii) inhibit the pathological state, that is, stop the development of that pathological state or its clinical symptoms, or (iii) alleviate the pathological state, that is, cause regression temporary or permanent of the pathological state or its clinical symptoms. The terms "treat", "contact" and "react", when referring to a chemical reaction, mean adding or mixing two or more reagents under the appropriate conditions to produce the indicated and / or desired product. It will be readily understood that the reaction generated by an indicated and / or desired product may not necessarily occur directly from the combination of the two reactants that are initially charged, that is, one or more intermediates may be generated within the mixture that finally it leads to the formation of the indicated and / or desired product. In general, the nomenclature used is this application is based on the AUTONOM ™ v. 4.0, a computerized system of the Beilstein Institute for the generation of the systematic nomenclature of the IUPAC. The chemical structures presented in this application are generated using the ISIS® version 2.2 program. Any open valence that appears in a carbon, oxygen or nitrogen atom of the structures represented indicates the presence of a hydrogen atom. All patents and publications identified in this description are incorporated therein in their entirety as references. In certain modalities of the formula (I), R5 and R6 are hydrogen. In certain embodiments of the formula (I), R2 is hydrogen. In certain embodiments of the formula (I), X is -CH2- or -0-. X is preferably 0. In certain embodiments of the formula (I), D is absent.

In certain embodiments of the formula (I), R 1 is alkyl, alkenyl or cycloalkyl. R1 is preferably ethyl, cyclopropyl, isopropenyl or isopropyl. R1 is more preferably isopropyl. In certain embodiments of the formula (I), one of R7 and R8 is hydrogen and the other is alkyl, cycloalkyl; cycloalkylalkyl; haloalkyl; hydroxyalkyl; alkoxyalkyl; alkylsulfonylalkyl; acetyl; alkylsulfonyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl. In certain embodiments of the formula (I), one of R7 and R8 is hydrogen and the other is alkyl, hydroxyalkyl or haloalkyl. In many modalities of the formula (I), Y is -NRdRe. In certain embodiments of formula (I), Y is -NRdRe and one of Rd and Re is hydrogen and the other is alkyl, cycloalkyl; cycloalkylalkyl; haloalkyl; hydroxyalkyl; alkoxyalkyl; alkylsulfonylalkyl; acetyl; alkylsulfonyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl. In certain embodiments of formula (I), Y is -NRdRe and one of Rd and Re is hydrogen and the other is alkyl, hydroxyalkyl or haloalkyl. In certain embodiments of the formula (I), R3 and R4 independently of one another are halogen, alkoxy, haloalkoxy or alkylsulfonyl. In certain embodiments of the formula (I), R3 is halogen, alkoxy, haloalkoxy or hydroxy. R3 is preferably methoxy, fluorine or chlorine. R3 is more preferably methoxy. In certain embodiments, R3 is hydroxy. In certain embodiments of the formula (I), R 4 is halogen, alkoxy, alkylsulfonyl or heteroaryl. R 4 is preferably methoxy, iodo, methanesulfonyl or heteroaryl. R 4 is more preferably methoxy, bromine, chlorine or iodine. In specific embodiments, R4 can be methoxy, while in other embodiments R4 can be iodine. In certain embodiments of the formula (I), R7, R8, Rd and Re are hydrogen. In certain embodiments of the formula (I), R 4 is heteroaryl. The heteroaryl may be, in certain embodiments, tetrazolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, thiophenyl, triazolyl, furanyl, isoxazolyl, oxadiazolyl, benzothiophenyl, pyridinyl or pyrrolyl. The heteroaryl may be more specifically tetrazol-5-yl, pyrazol-1-yl, 3-methylpyrazol-1-yl, oxazol-2-yl, oxazol-5-yl, imidazol-2-yl, thiazol-2-yl, thiazol-4-yl, thiophen-3-yl, 5-chloro-thiophen-2-yl, l-methyl-imidazol-2-yl, imidazol-1-yl, pyrazol-3-yl, 2-methyl-thiazole- 4-ilo,. furan-2-yl, 3,5-dimethyl-pyrazol-1-yl, 4,5-dihydrooxazol-2-yl, isoxazol-5-yl, [1, 2, 4] -oxadiazol-3-yl, benzo [ b] thiophen-3-yl, oxazol-4-yl, furan-3-yl, 4-methyl-thiophen-2-yl, thiazol-5-yl, tetrazol-1-yl, [1, 2, 4] triazole -1-yl, 2-methyl-thiazol-5-yl, 1-methyl-pyrazol-4-yl, 2-thiolyl-imidazol-1-yl, pyridin-2-yl or 2,5-dimethyl-pyrrole-1 -ilo. In certain embodiments of the formula (I), R3 and R4 together with the atoms to which they are attached can form a five or six member ring optionally including one or two heteroatoms. chosen from O, S and N. In many such embodiments, R3 and R4 together with the atoms to which they are attached can form: a five-membered aromatic ring with a nitrogen, for example a pyrrole ring; a five-membered aromatic ring with two nitrogens, for example a pyrazole or imidazole ring; a five-membered aromatic ring with a nitrogen and an oxygen, for example an oxazole or isoxazole ring; a five-membered aromatic ring with a nitrogen and a sulfur, for example a thiazole or isothiazole ring; a five-membered aromatic ring with an oxygen, for example a furanyl ring; or a five-membered aromatic ring with a sulfur, for example a thiophenyl ring. In certain embodiments of the formula (I), R2 and R3 together with the atoms to which they are attached can form a five or six member ring optionally including one or two heteroatoms chosen from 0, S and N. In many such embodiments, R3 and R4 together with the atoms to which they are attached can form: a five-membered aromatic ring with a nitrogen, for example a pyrrole ring; a five-membered aromatic ring with two nitrogens, for example a pyrazole or imidazole ring; a five-membered aromatic ring with a nitrogen and an oxygen, for example an oxazole or isoxazole ring; a five-membered aromatic ring with a nitrogen and a sulfur, for example a thiazole or isothiazole ring; a five-membered aromatic ring with an oxygen, for example a furanyl ring; or a five-membered aromatic ring with a sulfur, for example a thiophenyl ring. In a preferred embodiment of the formula (I), X is -O-, R1 is alkyl, alkenyl, cycloalkyl or halogen, R2 is hydrogen, R3 is alkoxy, hydroxy or halogen, R4 is alkoxy, halogen, alkenyl or heteroaryl selected from tetrazolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, thiophenyl, triazolyl, furanyl, isoxazolyl, oxadiazolyl, benzothiophenyl, pyridinyl and pyrrolyl and R5 and R6 are hydrogen.

In another preferred embodiment of formula (I), X is -0-, R1 is alkyl, alkenyl, cycloalkyl or halogen, R2 is hydrogen, R3 is alkoxy, hydroxy or halogen, R4 is alkoxy, halogen or alkenyl and R5 and R6 are hydrogen.

In another preferred embodiment of formula (I), X is -0-, R1 is alkyl, alkenyl, cycloalkyl or halogen, R2 is hydrogen, R3 is alkoxy, hydroxy or halogen, R4 is heteroaryl selected from tetrazolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, thiophenyl, triazolyl, furanyl, isoxazolyl, oxadiazoyl, benzothiophenyl, pyridinyl and pyrrolyl and R 5 and R 6 are hydrogen. In another preferred embodiment of the formula (I), X is -0-, R1 is alkyl, alkenyl, cycloalkyl or halogen, R2 is hydrogen, R3 is alkoxy, hydroxy or halogen, R4 is alkoxy, halogen or alkenyl, R5 and R6 they are hydrogen, R7 and R8 are hydrogen and one of Ra and Rb is hydrogen and the other is hydrogen, alkyl, hydroxyalkyl or haloalkyl. In another preferred embodiment of formula (I), X is -0-, R1 is alkyl, alkenyl, cycloalkyl or halogen, R2 is hydrogen, R3 is alkoxy, hydroxy or halogen, R4 is heteroaryl selected from tetrazolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, thiophenyl, triazolyl, furanyl, isoxazolyl, oxadiazolyl, benzothiophenyl, pyridinyl and pyrrolyl, R5 and R6 are hydrogen, R7 and R8 are hydrogen and one of Ra and Rb is hydrogen and the other is hydrogen, alkyl, acetyl, hydroxyalkyl or haloalkyl. In another preferred embodiment of the formula (I), X is -0- or -CH2-, R1 is isopropyl, isopropenyl, cyclopropyl or iodo, R2 is hydrogen, R3 is alkoxy, hydroxy or halogen, R4 is alkoxy or halogen and R5 is and R6 are hydrogen. In another preferred embodiment of the formula (I), X is -0- or -CH2-, R1 is isopropyl, isopropenyl, cyclopropyl or iodo, R2 is hydrogen, R3 is alkoxy, hydroxy or halogen, R4 is alkoxy or halogen, R5 and R6 are hydrogen, R7 and R8 are hydrogen and one of Ra and Rb is hydrogen and the other is hydrogen, alkyl, hydroxyalkyl or haloalkyl. In another preferred embodiment of the formula (I), X is -0- or -CH2-, R1 is isopropyl or iodine, R2 is hydrogen, R3 is methoxy, hydroxy, chlorine, bromine or iodine, R4 is methoxy, chlorine, bromine or iodine and R5 and R6 are hydrogen. In another preferred embodiment of the formula (I), X is -0- or -CH2-, R1 is isopropyl or iodo, R2 is hydrogen, R3 is methoxy, hydroxy, chloro, bromo or iodo, R4 methoxy, chloro, bromo or iodine, R5 and R6 are hydrogen, R7 and R8 are hydrogen and one of Ra and Rb is hydrogen and the other is hydrogen, alkyl, hydroxyalkyl or haloalkyl. In another preferred embodiment of formula (I), X is -0- or -CH2-, R1 is isopropyl, R2 is hydrogen, R3 is methoxy, hydroxy, chloro, bromo or iodo, R4 is methoxy, chloro, bromo or iodo and R5 and R6 are hydrogen. In another preferred embodiment of formula (I), X is -0- or -CH2-, R1 is isopropyl, R2 is hydrogen, R3 is methoxy, hydroxy, chloro, bromo or iodo, R4 methoxy, chloro, bromo or iodo, R5 and R6 are hydrogen, R7 and R6 are hydrogen and one of Ra and Rb is hydrogen and the other is hydrogen, alkyl, hydroxyalkyl or haloalkyl. The compounds of the invention in many embodiments can be of the formula (II) wherein: X is -CH2-; u -0-; R1 is alkyl; alkenyl; cycloalkyl; or cycloalkenyl; or halogen; R3 and R4 independently of each other are hydrogen; I rent; alkenyl; Not me; halogen; amido; haloalkyl; alkoxy; hydroxy; haloalkoxy; nitro; hydroxyalkyl; alkoxyalkyl; hydroxyalkoxy; alkynylalkoxy; alkylsulfonyl; Aryisulfonyl; cyano; aril; heteroaryl; heterocyclyl; heterocyclylalkoxy; aryloxy; heteroaryloxy; aralkyloxy; heteroaralkyloxy; phenoxy optionally substituted; - (CH2) m- (Z) n- (CO) -Rf or - (CH2) m- (Z) n-S02- (NRg) n -Rf, in which m and n independently are 0 or 1, Z is 0 or NRg, Rf is hydrogen, alkyl, hydroxy, alkoxy, amino, hydroxyalkyl or alkoxyalkyl and each Rg independently of its appearance is hydrogen or alkyl; or R3 and R4 together can form an alkylenedioxy; or R3 and R4 together with the atoms to which they are attached can form a five or six member ring optionally including one or two heteroatoms chosen from 0, S and N; one of R7 and R8 is hydrogen and the other is hydrogen; I rent; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl; and one of Rd and Re is hydrogen and the other is hydrogen; I rent; cycloalkyl; . cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl. In certain embodiments of the formula (II), R1 is alkyl, alkenyl or cycloalkyl. R1 is preferably ethyl, cyclopropyl, isopropenyl or isopropyl. R1 is more preferably isopropyl. In certain embodiments of the formula (II), one of R7 and R8 is hydrogen and the other is alkyl, cycloalkyl; cycloalkylalkyl; haloalkyl; hydroxyalkyl; alkoxyalkyl; alkylsulfonylalkyl; acetyl; alkylsulfonyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl. In certain embodiments of the formula (II), one of R7 and R8 is hydrogen and the other is alkyl, hydroxyalkyl or haloalkyl. In certain embodiments of the formula (II), one of Rd and Re is hydrogen and the other is alkyl, cycloalkyl; cycloalkylalkyl; haloalkyl; hydroxyalkyl; alkoxyalkyl; alkylsulfonylalkyl; acetyl; alkylsulfonyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl. In certain embodiments of the formula (II), one of Rd and Re is hydrogen and the other is alkyl, hydroxyalkyl or haloalkyl. In certain embodiments of the formula (II), R3 and R4 independently of each other are halogen, alkoxy, haloalkoxy or alkylsulfonyl. In certain embodiments of the formula (II), R3 is halogen, alkoxy, haloalkoxy or hydroxy. R3 is preferably methoxy, fluorine or chlorine. R3 is more preferably methoxy. In certain embodiments, R3 is hydroxy. In certain embodiments of the formula (II), R 4 is halogen, alkoxy, alkylsulfonyl or heteroaryl. R 4 is preferably methoxy, iodo, methanesulfonyl or heteroaryl. R 4 is more preferably methoxy, bromine, chlorine or iodine. In specific embodiments, R 4 can be methoxy, while in other embodiments R 4 can be iodine. In certain embodiments of the formula (II), R7, R8, Rd and Re are hydrogen. In certain embodiments of the formula (II), R 4 is heteroaryl. The heteroaryl may be, in certain embodiments, tetrazolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, thiophenyl, triazolyl, furanyl, isoxazolyl, oxadiazolyl, benzothiophenyl, pyridinyl or pyrrolyl. The heteroaryl may be more specifically tetrazol-5-yl, pyrazol-1-yl, 3-methyl-pyrazol-1-yl, oxazol-2-yl, oxazol-5- yl, imidazol-2-yl, thiazol-2-yl, thiazol-4-yl, thiophen-3- yl, 5-chloro-thiophen-yl 2-yl l-methyl-imidazol-2-, imidazol-1-IOI pyrazol-3-yl, 2-methyl-thiazole 4-yl, furan-2-yl, 3,5- 4, 5-dihydrooxazol-2-yl, isoxazol-5-yl, [1, 2, 4] -oxadiazol-3-yl, benzo [b] thiophene- 3-yl, oxazol-4-yl, furan-3-yl, 4-methyl-thiophen-2-yl yl tetrazol-1-, yl thiazol-5-, [1, 2, 4] triazol-1-yl , 2-methyl-thiazol-5-yl, l-methyl-pyrazol-4-yl, 2-thiolyl-imidazol-1-yl, pyridin-2-yl or 2,5-dimethyl-pyrrol-1-yl. In certain embodiments of formula (II), R3 and R4 together with the atoms to which they are attached can form a five or six member ring optionally including one or two heteroatoms chosen from 0, S and N. In many of such embodiments, R3 and R4 together with the atoms to which they are attached can form a five-membered aromatic ring with a nitrogen, for example a pyrrole ring; a five-membered aromatic ring with two nitrogens, for example a pyrazole or imidazole ring; a five-membered aromatic ring with a nitrogen and an oxygen, for example an oxazole or isoxazole ring; a five-membered aromatic ring with a nitrogen and a sulfur, for example a thiazole or isothiazole ring; a five-membered aromatic ring with an oxygen, for example a furanyl ring; or a five-membered aromatic ring with a sulfur, for example a thiophenyl ring. In a preferred embodiment of formula (II), X is -O-, R1 is alkyl, alkenyl, cycloalkyl or halogen, R3 is alkoxy, hydroxy or halogen and R4 is alkoxy, halogen, alkenyl or heteroaryl selected from tetrazolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, thiophenyl, triazolyl, furanyl, isoxazolyl, oxadiazolyl, benzothiophenyl, pyridinyl and pyrrolyl. In another preferred embodiment of formula (II), X is -O-, R1 is alkyl, alkenyl, cycloalkyl or halogen, R3 is alkoxy, hydroxy or halogen and R4 is alkoxy, halogen or alkenyl. In another preferred embodiment of formula (II), X is -O-, R1 is alkyl, alkenyl, cycloalkyl or halogen, R3 is alkoxy, hydroxy or halogen and R4 is heteroaryl selected from tetrazolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, thiophenyl, triazolyl, furanyl, isoxazolyl, oxadiazolyl, benzothiophenyl, pyridinyl and pyrrolyl. In another preferred embodiment of formula (II), X is 0-, R1 is alkyl, alkenyl, cycloalkyl or halogen, R3 is alkoxy, hydroxy or halogen, R4 is alkoxy, halogen or alkenyl, R7 and R8 are hydrogen and one of Ra and Rb is hydrogen and the other is hydrogen, alkyl, hydroxyalkyl or haloalkyl. In another preferred embodiment of formula (II), X is 0-, R1 is alkyl, alkenyl, cycloalkyl or halogen, R3 is alkoxy, hydroxy or halogen, R4 is heteroaryl selected from tetrazolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, thiophenyl, triazolyl, furanyl, isoxazolyl, oxadiazolyl, benzothiophenyl, pyridinyl and pyrrolyl, R7 and R8 are hydrogen and one of Ra and Rb is hydrogen and the other is hydrogen, alkyl, acetyl, hydroxyalkyl or haloalkyl. In another preferred embodiment of formula (II), X is -0- or -CH-, R1 is isopropyl, isopropenyl, cyclopropyl or iodo, R3 is alkoxy, hydroxy or halogen and R4 is alkoxy or halogen. In another preferred embodiment of formula (II), X is -0- or -CH2-, R1 is isopropyl, isopropenyl, cyclopropyl or iodo, R3 is alkoxy, hydroxy or halogen, R4 is alkoxy or halogen, R7 and R8 are hydrogen and one of Ra and Rb is hydrogen and the other is hydrogen, alkyl, hydroxyalkyl or haloalkyl.

In another preferred embodiment of formula (II), X is -0- or -CH2-, R1 is isopropyl or iodo, R3 is methoxy, hydroxy, chloro, bromo or iodo and R4 is methoxy, chloro, bromo or iodo. In another preferred embodiment of formula (II), X is O- or -CH 2 -, R 1 is isopropyl or iodine, R 3 is methoxy, hydroxy, chlorine, bromine or iodine, R 4 is methoxy, chlorine, bromine or iodine, R 7 and R8 are hydrogen and one of Ra and Rb is hydrogen and the other is hydrogen, alkyl, hydroxyalkyl or haloalkyl. In another preferred embodiment of formula (II), X is -0- or -CH2-, R1 is isopropyl, R3 is methoxy, hydroxy, chloro, bromo or iodo and R4 is methoxy, chloro, bromo or iodo. In another preferred embodiment of formula (II), X is -0- or -CH2-, R1 is isopropyl, R3 is methoxy, hydroxy, chlorine, bromine or iodine, R4 methoxy, chlorine, bromine or iodine, R7 and R8 are hydrogen and one of R and Rb is hydrogen and the other is hydrogen, alkyl, hydroxyalkyl or haloalkyl. The compounds of the invention in certain embodiments can be of the formula (III) wherein: R1 is isopropyl; isopropenyl; cyclopropyl; or iodine; R3 and R4 independently of each other are hydrogen; I rent; alkenyl; Not me; halogen; amido; haloalkyl; alkoxy; hydroxy; haloalkoxy; nitro; hydroxyalkyl; alkoxyalkyl; hydroxyalkoxy; alkynylalkoxy; alkylsulfonyl; Aryisulfonyl; cyano; aril; heteroaryl; heterocyclyl; heterocyclylalkoxy; aryloxy; heteroaryloxy; aralkyloxy; heteroaralkyloxy; phenoxy optionally substituted; - (CH2) m- (Z) n- (CO) -Rf or - (CH2) m- (Z) n-S02- (NRg) n -Rf, in which m and n independently are 0 or 1, Z is O or NRg, Rf is hydrogen, alkyl, hydroxy, alkoxy, amino, hydroxyalkyl or alkoxyalkyl and each Rg independently of its appearance is hydrogen or alkyl; or R3 and R4 together can form an alkylenedioxy; or R3 and R4 together with the atoms to which they are attached can form a five or six member ring optionally including one or two heteroatoms chosen from O, S and N; one of R7 and R8 is hydrogen and the other is hydrogen; I rent; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl; and one of Rd and Re is hydrogen and the other is hydrogen; I rent; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl. In other embodiments, the compounds in question may be of the formula (IV) wherein: R1 is alkyl; alkenyl; cycloalkyl; or cycloalkenyl; R3 and R4 independently of each other are hydrogen; I rent; alkenyl; Not me; halogen; amido; haloalkyl; alkoxy; hydroxy; haloalkoxy; nitro; hydroxyalkyl; alkoxyalkyl; hydroxyalkoxy; alkynylalkoxy; alkylsulfonyl; Aryisulfonyl; cyano; aril; heteroaryl; heterocyclyl; heterocyclylalkoxy; aryloxy; heteroaryloxy; aralkyloxy; heteroaralkyloxy; phenoxy optionally substituted; - (CH2) m- (Z) n- (CO) -Rf or - (CH2) m- (Z) n-S02- (NRg) n -Rf, in which m and n independently are 0 or 1, Z is 0 or NRg, Rf is hydrogen, alkyl, hydroxy, alkoxy, amino, hydroxyalkyl or alkoxyalkyl and each Rg independently of its appearance is hydrogen or alkyl; or R3 and R4 together can form an alkylenedioxy; or R3 and R4 together with the atoms to which they are attached can form a five or six member ring optionally including one or two heteroatoms chosen from 0, S and N; one of R7 and R8 is hydrogen and the other is hydrogen; I rent; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; "aminocarbonyloxyalkyl, hydroxycarbonylalkyl, hydroxyalkyloxycarbonylalkyl, aryl, aralkyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl, heterocyclyl, or heterocyclylalkyl, and one of Rd and Re is hydrogen and the other is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl. haloalkoxy, hydroxyalkyl, alkoxyalkyl, acetyl, alkylsulfonyl, alkylsulfonylalkyl, aminocarbonyloxyalkyl, hydroxycarbonylalkyl, hydroxyalkyloxycarbonylalkyl, aryl, aralkyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylsulphonyl, heterocyclyl, or heterocyclylalkyl, In certain embodiments of formula (IV), R1 is alkyl, alkenyl or cycloalkyl R1 is preferably ethyl, cyclopropyl, isopropenyl or isopropyl R1 is more preferably isopropyl In certain embodiments of formula (III) or formula (IV), one of R7 and R8 is hydrogen and the other is: alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl; hydroxyalkyl; alkoxyalkyl; alkylsulfonylalkyl; acetyl; alkylsulfonyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl. In certain embodiments of formula (III) or formula (IV), one of R7 and R8 is hydrogen and the other is alkyl, hydroxyalkyl or haloalkyl. In certain embodiments of formula (III) or formula (IV), one of Rd and Re is hydrogen and the other is alkyl, cycloalkyl; cycloalkylalkyl; haloalkyl; hydroxyalkyl; alkoxyalkyl; alkylsulfonylalkyl; acetyl; alkylsulfonyl; aril; aralkyl; Arylsulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl. In certain embodiments of formula (III) or formula (IV), one of Rd and Re is hydrogen and the other is alkyl, hydroxyalkyl or haloalkyl. In certain embodiments of the formula (III) or of the formula (IV), R3 and R4 independently of one another are halogen, alkoxy, haloalkoxy or alkylsulfonyl. In certain embodiments of the formula (III) or of the formula (IV), R3 is halogen, alkoxy, haloalkoxy or hydroxy. R3 is preferably methoxy, fluorine or chlorine. R3 is more preferably methoxy. In certain embodiments R3 is hydroxy. In certain embodiments of the formula (III) or the formula (IV), R 4 is halogen, alkoxy, alkylsulfonyl or heteroaryl. R 4 is preferably methoxy, iodo, methanesulfonyl or heteroaryl. R 4 is more preferably methoxy, bromine, chlorine or iodine. In specific embodiments, R4 can be methoxy, while in other embodiments R4 can be iodine. In certain embodiments of formula (III) or formula (IV), R7, R8, Rd and Re are hydrogen. In certain embodiments of the formula (III) or of the formula (IV), R4 is heteroaryl. Heteroaryl may be, in certain embodiments, tetrazolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, thiophenyl, triazolyl, furanyl, isoxazolyl, oxadiazolyl, benzothiophenyl, pyridinyl or pyrrolyl. The heteroaryl may be more specifically tetrazol-5-yl, pyrazol-1-yl, 3-methylpyrazol-1-yl, oxazol-2-yl, oxazol-5-yl, imidazol-2-yl, thiazol-2-yl, thiazol-4-yl, thiophen-3-yl, 5-chloro-thiophen-2-yl, l-methyl-imidazol-2-yl, imidazol-1-yl, pyrazol-3-yl, 2-methyl-thiazole- 4-yl, furan-2-yl, 3,5-dimethyl-pyrazol-1-yl, 4,5-dihydrooxazol-2-yl, isoxazol-5-yl, [1, 2, 4] -oxadiazol-3 ilo, benzo [b] thiophen-3-yl, oxazol-4-l-yl, furan-3-yl, 4-methylthiophen-2-yl, thiazol-5-yl, tetrazol-1-yl, [1, 2 , 4] triazol-1-yl, 2-methyl-thiazol-5-yl, l-methyl-pyrazol-4-yl, 2-thiolylimidazol-l-yl, pyridin-2-yl or 2,5-dimethyl-pyrrole -l-ilo. In certain embodiments of formula (III) or formula (IV), R3 and R4 together with the atoms to which they are attached can form a five or six member ring optionally including one or two heteroatoms chosen from 0, S and N. In many such embodiments, R3 and R4 together with the atoms to which they are attached can form: a five-membered aromatic ring with a nitrogen, for example a pyrrole ring; a five-membered aromatic ring with two nitrogens, for example a pyrazole or imidazole ring; a five-membered aromatic ring with a nitrogen and an oxygen, for example an oxazole or isoxazole ring; a five-membered aromatic ring with a nitrogen and a sulfur, for example a thiazole or isothiazole ring; a five-membered aromatic ring with an oxygen, for example a furanyl ring; or a five-membered aromatic ring with a sulfur, for example a thiophenyl ring. The compounds of the invention in certain embodiments can be of the formula (V) wherein: R3 and R4 independently of each other are hydrogen; I rent; alkenyl; Not me; halogen; amido; haloalkyl; alkoxy; hydroxy; haloalkoxy; nitro; hydroxyalkyl; alkoxyalkyl; hydroxyalkoxy; alkylsulfonyl; Aryisulfonyl; cyano; aril; heteroaryl; heterocyclyl; heterocyclylalkoxy; aryloxy; heteroaryloxy; aralkyloxy; heteroaralkyloxy; phenoxy optionally substituted; - (CH2) m- (Z) n- (CO) -Rf or - (CH2) m- (Z) n- S02- (NRg) n -Rf, in which m and n independently are 0 or 1, Z is 0 or NRg, Rf is hydrogen, alkyl, hydroxy, alkoxy, amino, hydroxyalkyl or alkoxyalkyl and each Rg independently of its appearance is hydrogen or alkyl; or R3 and R4 together can form an alkylenedioxy; or R3 and R4 together with the atoms to which they are attached can form a five or six member ring optionally including one or two heteroatoms chosen from O, S and N; one of R7 and R8 is hydrogen and the other is hydrogen; I rent; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfenyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl; and one of Rd and Re is hydrogen and the other is hydrogen; I rent; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl. In other embodiments, the compounds in question may be of the formula (VI) wherein: R3 and R4 independently of each other are hydrogen; I rent; alkenyl; Not me; halogen; amido; haloalkyl; alkoxy; hydroxy; haloalkoxy; nitro; hydroxyalkyl; alkoxyalkyl; 'hydroxyalkoxy; alkynylalkoxy; alkylsulfonyl; Aryisulfonyl; cyano; aril; heteroaryl; heterocyclyl; heterocyclylalkoxy; aryloxy; heteroaryloxy; aralkyloxy; heteroaralkyloxy; phenoxy optionally substituted; - (CH2) m- (Z) n- (C0) -Rf or - (CH2) m- (Z) n-S02- (NRg) n-Rf, in which m and n independently of each other are 0 or 1, Z is O or NRg, Rf is hydrogen, alkyl, hydroxy, alkoxy, amino, hydroxyalkyl or alkoxyalkyl and each Rg independently of its appearance is hydrogen or alkyl; or R3 and R4 together can form an alkylenedioxy; or R3 and R4 together with the atoms to which they are attached can form a five or six member ring optionally including one or two heteroatoms chosen from O, S and N; one of R7 and R8 is hydrogen and the other is hydrogen; I rent; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl; and one of Rd and Re is hydrogen and the other is hydrogen; I rent; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroaryl-alkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl. In certain embodiments of the formula (V) or of the formula (VI), one of R7 and R8 is hydrogen and the other is alkyl, cycloalkyl; cycloalkylalkyl; haloalkyl; hydroxyalkyl; alkoxyalkyl; alkylsulfonylalkyl; acetyl; alkylsulfonyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl. In certain embodiments of the formula (V) or of the formula (VI), one of R7 and R8 is hydrogen and the other is alkyl, hydroxyalkyl or haloalkyl. In certain embodiments of formula (V) or formula (VI), one of Rd and Re is hydrogen and the other is alkyl, cycloalkyl; cycloalkylalkyl; haloalkyl; hydroxyalkyl; alkoxyalkyl; alkylsulfonylalkyl; acetyl; alkylsulfonyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl. In certain embodiments of formula (V) or formula (VI), one of Rd and Re is hydrogen and the other is alkyl, hydroxyalkyl or haloalkyl. In certain modalities of formula (V) or formula (VI), R3 and R4 independently of each other are halogen, alkoxy, haloalkoxy or alkylsulfonyl. In certain modalities of formula (V) or formula (VI), R3 is halogen, alkoxy, haloalkoxy or hydroxy. R3 is preferably methoxy, fluorine or chlorine. R3 is more preferably methoxy. In certain embodiments, R3 is hydroxy. In certain embodiments of the formula (V) or of the formula (VI), R 4 is halogen, alkoxy, alkylsulfonyl or heteroaryl. R 4 is preferably methoxy, iodo, methanesulfonyl or heteroaryl. R 4 is more preferably methoxy, bromine, chlorine or iodine. In specific embodiments, R 4 can be methoxy, while in other embodiments R 4 can be iodine. In certain embodiments of the formula (V) or of the formula (V), R7, R8, Rd and Re are hydrogen. In certain embodiments of the formula (V) or of the formula (VI), R 4 is heteroaryl. The heteroaryl may be, in certain embodiments, tetrazolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, thiophenyl, triazolyl, furanyl, isoxazolyl, oxadiazolyl, benzothiophenyl, pyridinyl or pyrrolyl. Heteroaryl may be more specifically tetrazol-5-yl, pyrazol-1-yl, 3-methylpyrazolyl, oxazol-2-yl, oxazol-5-yl, imidazol-2-yl, thiazol-2-yl, thiazol-4-yl, thiophen-3-yl, 5-chloro-thiophen-2-yl, l-methyl-imidazol-2-yl, imidazol-1-yl, pyrazol-3-yl, 2-methylthiazole-4- ilo, furan-2-yl, 3,5-dimethyl-pyrazol-1-yl, 4,5-dihydrooxazol-2-yl, isoxazol-5-yl, [1,2,4] -oxadiazol-3-yl, benzp [b] thiophen-3-yl, oxazol-4-yl, furan-3-yl, 4-methylthiophen-2-yl, thiazol-5-yl, tetrazol-1-yl, [1,2,4] triazol-1-yl, 2-methyl-thiazol-5-yl, 1-methyl-pyrazol-4-yl, 2-thiolylimidazol-1-yl, pyridin-2 -yl or 2,5-dimethyl-pyrrol-1-yl. In certain embodiments of formula (V) or formula (VI), R3 and R4 together with the atoms to which they are attached can form a five or six member ring optionally including one or two heteroatoms chosen from O, S and N. In many such embodiments, R3 and R4 together with the atoms to which they are attached can form: a five-membered aromatic ring with a nitrogen, for example a pyrrole ring; a five-membered aromatic ring with two nitrogens, for example a pyrazole or imidazole ring; a five-membered aromatic ring with a nitrogen and an oxygen, for example an oxazole or isoxazole ring; a five-membered aromatic ring with a nitrogen and a sulfur, for example a thiazole or isothiazole ring; a five-membered aromatic ring with an oxygen, for example a furanyl ring; or a five-membered aromatic ring with a sulfur, for example a thiophenyl ring. In certain embodiments, the compounds of the invention may be of the formula (VII) wherein: X is -CH2-; u -O-; R1 is alkyl; alkenyl; cycloalkyl; or cycloalkenyl; or halogen; R2 is hydrogen; I rent; alkenyl; Not me; halogen; amido; haloalkyl; alkoxy; hydroxy; haloalkoxy; nitro; hydroxyalkyl; alkoxyalkyl; hydroxyalkoxy; alkynylalkoxy; alkylsulfonyl; Aryisulfonyl; cyano; aril; heteroaryl; heterocyclyl; heterocyclylalkoxy; aryloxy; heteroaryloxy; aralkyloxy; heteroaralkyloxy; phenoxy optionally substituted; or - (CH2) m- (Z) n- (CO) -Rf or - (CH2) m- (Z) nS02- (NRg) n -Rf, where m and n independently are 0 or 1, Z is 0 or NRg, Rf is hydrogen, alkyl, hydroxy, alkoxy, amino, hydroxyalkyl or alkoxyalkyl and each R2 independently of its appearance is hydrogen or alkyl; one of R7 and R8 is hydrogen and the other is hydrogen; I rent; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; .acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl; one of Rd and Re is hydrogen and the other is hydrogen; I rent; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl; Q is CR9, one of A and E is O, S or NR10 and the other is CR9 or N; or Q is N, one of A and E is NR10 and the other is CR9; each R9 independently of its appearance is hydrogen, alkyl, halogen or alkoxy; and R10 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, - (CH2) m (Z) n- (CO) -Rf or - (CH2) m- (Z) n-S02- (NR) n-Rf. In certain embodiments of the formula (VII), A is NR10 and Q and E are CR9. In certain embodiments of formula (VII), E is NR10 and A and Q are CR9. In certain embodiments of formula (VII), Q is NR10 and A and E are CR9. In certain embodiments of the formula (VII), A is 0, E is N and Q is CR9. In certain embodiments of the formula (VII), A is N, E is 0 and Q is CR9. In certain embodiments of the formula (VII), A is S, E is N and Q is CR9. In certain embodiments of the formula (VII), A is N, E is S and Q is CR9. In certain embodiments of the formula (VII), E is S and A and Q are CR9. In certain embodiments of formula (VII), E is 0 and A and Q are CR9. In certain embodiments of formula (VII), A is S and E and Q are CR9. In certain embodiments of formula (VII), A is O and E and Q are CR9. In certain embodiments of the formula (VII), A is NR10, Q is N and E is CR9.

In certain embodiments of formula (VII), E is NR10, Q is N and A is CR9. In certain embodiments of formula (VII), R2 is hydrogen. In certain embodiments of the formula (VII), X is -CH2- or -0-. X is preferably 0. In certain embodiments of the formula (VII), R1 is alkyl, alkenyl or cycloalkyl. R1 is preferably ethyl, cyclopropyl, isopropenyl or isopropyl. R1 is more preferably isopropyl. In certain embodiments of the formula (VII), one of R7 and R8 is hydrogen and the other is alkyl, cycloalkyl; cycloalkylalkyl; haloalkyl; hydroxyalkyl; alkoxyalkyl; alkylsulfonylalkyl; acetyl; alkylsulfonyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl. In certain embodiments of the formula (VII), one of R7 and R8 is hydrogen and the other is alkyl, hydroxyalkyl or haloalkyl. In certain embodiments of formula (VII), one of Rd and Re is hydrogen and the other is alkyl, cycloalkyl; cycloalkylalkyl; haloalkyl; hydroxyalkyl; alkoxyalkyl; alkylsulfonylalkyl; acetyl; alkylsulfonyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl. In certain embodiments of the formula (VII), one of Rd and Re is hydrogen and the other is alkyl, hydroxyalkyl or haloalkyl. In certain embodiments of the formula (VII), R7, R8, Rd and Re are hydrogen. In other embodiments of the invention, the compounds may be of the formula (VIII) wherein: X is -CH2-; u -O-; R1 is alkyl; alkenyl; cycloalkyl; or cycloalkenyl; or halogen; R4 is hydrogen; I rent; alkenyl; Not me; halogen; amido; haloalkyl; alkoxy; hydroxy; haloalkoxy; nitro; hydroxyalkyl; alkoxyalkyl; hydroxyalkoxy; alkynylalkoxy; alkylsulfonyl; Aryisulfonyl; cyano; aril; heteroaryl; heterocyclyl; heterocyclylalkoxy; aryloxy; heteroaryloxy; aralkyloxy; heteroaralkyloxy; phenoxy optionally substituted; or - (CH2) m- (Z) n- (CO) -Rf or - (CH2) m (Z) n-S02- (NRg) n-Rf, in which m and n independently are 0 or 1, Z is O or NR9, Rf is hydrogen, alkyl, hydroxy, alkoxy, amino, hydroxyalkyl or alkoxyalkyl and each Rg independently of its appearance is hydrogen or alkyl; one of R7 and R8 is hydrogen and the other is hydrogen; I rent; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl; one of Rd and Re is hydrogen and the other is hydrogen; I rent; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl; Q is CR9, one of A and E is 0, S or NR10 and the other is CR9 or N; or Q is N, one of A and E is NR10 and the other is CR9; each R9 independently of its appearance is hydrogen, alkyl, halogen or alkoxy; and R10 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, (CH2) m- (Z) n- (C0) -Rf or - (CH2) m- (Z) n-S02- (NRg) n-Rf. In certain embodiments of the formula (VIII), A is NR10 and Q and E are CRy In certain embodiments of the formula (VIII), E is NR and A and Q are CRa In certain embodiments of the formula (VIII), Q is NR10 and A and E are CR In certain embodiments of the formula (VIII), A is 0, E is N and Q is CR9. In certain embodiments of the formula (VIII), A is N, E is O and Q is CR9. In certain embodiments of formula (VIII), A is S, E is N and Q is CR9. In certain embodiments of the formula (VIII), - A is N, E is S and Q is CR9. In certain embodiments of formula (VIII), E is S and A and Q are CR9. In certain embodiments of the formula (VIII), E is 0 and A and Q are CR9. In certain embodiments of formula (VIII), A is S and E and Q are CR9. In certain embodiments of the formula (VIII), A is 0 and E and Q are CR9. In certain embodiments of the formula (VIII), A is NR10, Q is N and E is CR9. In certain embodiments of the formula (VIII), E is NR10, Q is N and A is CR9.

In certain embodiments of the formula (VIII), X is -CH2- or -0-. X is preferably 0. In certain embodiments of the formula (VIII), R1 is alkyl, alkenyl or cycloalkyl. R1 is preferably ethyl, cyclopropyl, isopropenyl or isopropyl. R1 is more preferably isopropyl. In certain embodiments of the formula (VIII), one of R7 and R8 is hydrogen and the other is alkyl, cycloalkyl; cycloalkylalkyl; haloalkyl; hydroxyalkyl; alkoxyalkyl; alkylsulfonylalkyl; acetyl; alkylsulfonyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl. In certain embodiments of the formula (VIII), one of R7 and R8 is hydrogen and the other is alkyl, hydroxyalkyl or haloalkyl. In certain embodiments of the formula (VIII), one of Rd and Re is hydrogen and the other is alkyl, cycloalkyl; cycloalkylalkyl; haloalkyl; hydroxyalkyl; alkoxyalkyl; alkylsulfonylalkyl; acetyl; alkylsulfonyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl. In certain embodiments of the formula (VIII), one of Rd and Re is hydrogen and the other is alkyl, hydroxyalkyl or haloalkyl. In certain embodiments of the formula (VIII), R7, R8, Rd and Re are hydrogen. In certain embodiments of the formula (VIII), R 4 is halogen, alkoxy, haloalkoxy or alkylsulfonyl. In certain embodiments of the formula (VIII), R 4 is halogen, alkoxy, alkylsulfonyl or heteroaryl. R 4 is preferably methoxy, iodo, methanesulfonyl or heteroaryl. R 4 is more preferably methoxy, bromine, chlorine or iodine. In specific embodiments, R4 can be methoxy, while in other embodiments R4 can be iodine. In certain embodiments of the formula R 4 is heteroaryl. The heteroaryl may be, in certain embodiments, tetrazolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, thiophenyl, triazolyl, furanyl, isoxazolyl, oxadiazolyl, benzothiophenyl, pyridinyl or pyrrolyl. Heteroaryl may be more specifically tetrazol-5-yl, pyrazol-1-yl, 3-methylpyrazol-1-yl, oxazol-2-yl, oxazol-5-yl, imidazol-2-yl, thiazole-2 ilo, thiazol-4-yl, thiophen-3-yl, 5-chloro-thiophen-2-yl, l-methyl-imidazol-2-yl, imidazol-1-yl, pyrazol-3-yl, 2-methyl- thiazol-4-yl, furan-2-yl, 3,5-dimethyl-pyrazol-l-yl, 4,5-dihydrooxazol-2-yl, isoxazol-5-yl, [1,2,4] -oxadiazole- 3-yl, benzo [b] thiophen-3-yl, oxazol-4-yl, furan-3-yl, 4-methyl-thiophen-2-yl, thiazol-5-yl, tetrazol-1-yl, [1 , 2,4] triazol-1-yl, 2-methyl-thiazol-5-yl, l-methyl-pyrazol-4-yl, 2-thiolyl-imidazol-1-yl, pyridin-2-yl or 2, 5 -dimethyl-pyrrol-1-yl. In embodiments of the invention, wherein any one of R7, R8, Rd or Re is heterocyclyl or a group including a heterocyclyl moiety, such a heterocyclyl or heterocyclyl moiety may be piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothiopyranyl or 1,1-dioxotetrahydrothiopyranyl . More preferably, such a heterocyclyl or heterocyclyl radical can be piperidin-4-yl, l-methyl-piperidin-4-yl, 1-methanesulfonyl-piperidin-4-yl, tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl or , l-dioxotetrahydrothiopyran-4-yl. When any one of R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R c, R r R, R f, R g or Rh is alkyl or contains an alkyl moiety, said alkyl is preferably lower alkyl, for example CI-CT alkyl and more preferably C? -C4 alkyl. The invention further provides methods for treating a disease mediated by a P2X3 receptor antagonist, a P2X2 / 3 receptor antagonist or both, the method comprising administering to a subject in need thereof an effective amount of a compound of any one of formulas from (I) to (VIII). The disease can be a genitourinary disease or a disease of the urinary tract. In other cases, the disease can be a disease associated with pain. Urinary tract disease can be: reduced capacity of the bladder; frequent urination; urgent incontinence; stress incontinence; bladder hyperreactivity; benign prostatic hypertrophy; prostatitis; detrusor hyperreflexia; urinary frequency; nocturia; urinary urgency; overactive bladder; pelvic hypersensitivity; urethritis; prostatitis; pelvic pain syndrome; prostatodynia; cystitis; or hypersensitivity of idiopathic bladder. The disease associated with pain may be: inflammatory pain; surgical pain; visceral pain; Dental pain; premenstrual pain; central pain; pain due to burns; migraine or periodic migrainous neuralgia; nerve injuries; neuritis; neuralgia; poisoning; Ischemic lesions; interstitial cystitis; cancerous pain; infection - viral, parasitic or bacterial; post-traumatic injury; or pain associated with irritable bowel syndrome. Table 1 shows representative compounds according to the methods of the invention. Table 1 Name N * 2 * -isopropyl-5- (2-isopropyl-4,5-dimethoxy-benzyl) -N * 4 * -methyl-pyrimidine-2,4-diamine 5- (2-isopropyl- 4,5-dimethoxy-phenoxy) -pyrimidine-2,4-diamine 5- (2-isopropyl-4,5-dimethoxy-benzyl) -N * 4 * -isoxazol-5-ylmethyl-pyrimidipa-2,4-diamine N * 2 * -isopropyl-5- (2-isopropyl-4,5-dimethoxy-benzyl) -pyrimidine-2,4-diamine 5- (2-isopropyl-4,5-dimethoxy-benzyl) -N * 4 * - (2-methoxy-benzyl) -pyrimidine-2,4-diamine n Name 5- (2-isopropyl-4,5-dimethoxy-benzyl) -N * 2 * - (2, 2, 2-trifluoride) -ethyl) -pyrimidine-2,4-diamine 3- [2-amino-5- (2-isopropyl-4,5-dimethoxy-benzyl) -pyridin-4-ylamino] -propane-1, 2- diol N- [4-amino-5- (2-isopropyl-4,5-dimethoxy-benzyl) -pyrimidin-2-yl] -acetamide - (2-isopropyl-4,5-dimethoxy-benzyl) -N * 4 * - (4-methoxy-benzyl) -pyrimidine-2,4-diamine 5- (2-isopropyl-4,5-dimethoxy-benzyl) -N * 4 * -phenyl-pyrimidine-2,4-diamine 11 5- (5-chloro-2-isopropyl-4-methoxy-benzyl) -N * 2 * -phenethyl-pyrimidine-2,4-diamine 12 5- (5-chloro-2-isopropyl-4-methoxy-benzyl) -pyrimidine-2, 4- diamine 13 N * 4 * -isobutyl-N * 2 * -isopropyl-5- (2-isopropyl-4,5-dimethoxy-benzyl) -pyrimidine-2,4-diamine 14 5- (2-isopropyl-4,5-dimethoxy-benzyl) -N * 2 * -phenyl-pyrimidine-2,4-diamine N * 2 *, N * 4 * -diisopropyl-5- (2-isopropyl-4,5-dimethoxy-benzyl) -pyrimidine-2,4-diamine 16 5- (5-chloro-2-isopropyl-4-methoxy-benzyl) -N * 2 * -isopropyl-pyrimidine-2,4-diamine 17 2- [2-amino-5- (2-isopropyl-4,5-dimethoxy-benzyl) -pyrimidin-4-ylamino] -ethanol Name 5- (2-isopropyl-5-methyl-phenoxy) -pyrimidine -2, 4-diamine - (5-chloro-2-isopropyl-4-methoxy-benzyl) -N * 2 * -methyl-pi-rimidine-2,4-diamine N * 2 * -benzyl-5 ~ (5-chloro-2- isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine 2- [2-isopropylamino-5- (2-isopropyl-4,5-dimethoxy-benzyl) pyrimidin-4-ylamino-ethanol - (5-chloro-2-isopropyl-4-methoxy-phenpxi) -N * 2 * - (tetrahi-dro-pyran-4-yl) -pyrimidine-2,4-diamine N * 2 * - (4-Chloro-phenyl) -5- (2-isopropyl-4,5-dimethoxy-benzyl) -pyrimidine-2,4-diamine - (2-isopropyl-phenoxy) -pyrimidine-2,4-diamine 5- (2-isopropyl-4,5-dimethoxy-benzyl) -N * 4 * -methyl-pyrimidine-2, 4-diamine - (5-chloro-2-isopropyl-4-methoxy-phenoxy) -N * 2 * -isopropyl-pyrimidine-2,4-diamine - (2-isopropyl-4,5-dimethoxy-benzyl) -N * 4 * - (2-methoxyethyl) pyrimidine-2, -diamine N * 2 * -isopropyl-5- (2-isopropyl-4,5-dimethoxy-f-enoxy) pyrimidine-2,4-diamine - (2-ethyl-4,5-dimethoxy-benzyl) -pyrimidine-2,4-diamine - (2-isopropyl-4,5-dimethoxy-f-enoxy) -N * 2 * -phenyl-pyrimidine-2,4-diamine n Name 92 (2,4-diamino-pyrimidin-5-yl) - (2-isopropyl-4,5-dimethoxyphenyl) -methanone 93 5- [5- (1H-imidazol-2-yl) -2-isopropyl-4-methoxy-phenoxy] -pyrimidine-2,4-diamine 94 (2,4-diamino-pyrimidin-5-yl) - (2-isopropyl-4,5-dimethoxy-phenyl) -methanol 95 5- (2-bromo-4,5-dimethoxy-benzyl) -pyrimidine-2,4-diamine 96 5- [5-chloro-2- (2-fluoro-l-methyl-ethyl) -4-methoxy-phenoxy] -pyrimidine-2,4-diamine 97 (5-chloro-2-isopropyl-4- methoxy-f-enyl) - (2,4-diamino-pyrimidin-5-yl) -methanol 98 2- [4-amino-5- (5-chloro-2-ethyl-4-methoxy-phenoxy) -pyrimidin-2-ylamino] -butan-1-ol 99 5- (5-chloro-2-isopropyl- 4-methoxy-phenoxy) -N * 2 * - (3-ethanesulfonyl-1-methyl-propyl) -pyrimidine-2,4-diamine 100 5- (5-bromo-2-ethyl-4-methoxy-phenoxy) ) -pyrimidine-2,4-di-amine 101 5- (5-Chloro-2-ethyl-4-methoxy-phenoxy) -pyrimidine-2,4-di-amine 102 5- (5-chloro-2-cyclopropyl-4-metho-phenoxy) -pyrimidine-2,4-diamine 103 (5- (5-Fluoro-2-isopropyl-4-methoxy-benzyl) -pyridine-2, 4- diamine 104 5- (2-ethyl-5-methanesulfonyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine 05 5- (2-allyl-4,5-dimethoxy-benzyl) -pyrimidine-2,4-diamine n Name 106 5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxybenzamide 107 5- (4,5-dimethoxy-2-vinyl-f-enoxy) -pyrimidine-2,4-diamine 108 5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-benzoic acid 109 5- (2-cyclopropyl-4, 5-dimethoxy-f-enoxy) -pyrimidine-2,4-diamine 110 5- [2-isopropyl-4-methoxy-5- (1H-tetrazol-5-yl) -phenoxy) ] - pyrimidine-2,4-diamine 111 5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-benzonitrile 112 4- [4-amino-5- (5-chloro-2-isopropyl-4-methoxy-f-enoxy) -pyrimidin-2-ylamino] -piperidine-1-carboxylate 113 [5- (2, -diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-enyl] -urea 114 5- (5-Chloro-2-isopropyl-4-methoxy-f-enoxy) -N * 2 * - (1-cyclopropyl-ethyl) -pyrimidine-2,4-diamine 115 5- (5-Chloro-4-difluoromethoxy-2-isopropyl-phenoxy) -pyrimidine-2,4-diamine 116 5- (5-amino-2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2, di amine 117 N * 4 * -isopropyl-5- (2-isopropyl-4,5-dimethoxy-benzyl) -N * 2 * -methyl-pyrimidine-2,4-diamine 118 N- [5- (2, 4-diamino -pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-phenyl] -acetamide 119 5- (2-isopropyl-4-methoxy-5-tetrazol-1-yl-phenoxy) -pyrimidine-2 , 4-diamine n Name 120 5- (2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine 121 5- (2-isopropyl-5-methanesulfonyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine 122 5- (5-chloro-4-ethoxy-2-isopropyl-benzyl) -pyrimidine-2 4- diamine 123 5- (2-isopropyl-4-methoxy-5-methyl-phenoxy) -N * 4 * -phenyl-pyrimidine-2,4-diamine 124 5- (5-chloro-2-isopropyl-4-methoxy -phenoxy) -N * 2 * - (1,1-dioxo-hexahydro-llambda * 6 * -thiopyran-4-yl) -pyrimidine-2,4-di-amine 125 Methyl-carbamic acid ester of 2- [ 4-amino-5- (5-chloro-2-isopropyl-4-methoxy-phenoxy) -pyrimidin-2-ylamino] -propyl 126 5- (4-chloro-2-isopropyl-5-methyl-phenoxy) -pyrimidine -2,4-diamine 127 5- (2-isopropyl-4,5-dimethoxy-f-enoxy) -6-methyl-pyrimidine-2,4-diamine 128 5- [4,5-dimethoxy-2- (1-) methyl-2-phenyl-ethyl) -benzyl] -pyrimidine-2,4-diamine 129 1- (4- { 2- [4-amino-5- (5-chloro-2-isopropyl-4-methoxy-phenoxy) -pyrimidin-2-ylamino] -propyl.} - piperazine- 1-il) -etanone 130 5- (5-chloro-2-isopropyl-4-methoxy-phenoxy) ~ N * 2 * - (1-methanesulfonyl-piperidin-4-yl) -pyrimidine-2, -diamine 131 2- [4-amino-5- (5-chloro-2-isopropyl-4-methoxy-phenoxy) -pyridinin-2-ylamino] - (R) -propan-1-ol 32 5- (2- ethyl-4, 5-dimethoxy-f-enoxy) -pyrimidine-2,4-di-amine Y Name 133 5- (2-isopropyl-5-methanesulfonyl-4-methoxy-phenoxy) -N '(tetrahydro-thiopyran-4-) il) -pyrimidine-2,4-diamine 134 5- (2-isopropyl-5-methanesulfonyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine 135 5- [5- (4,5-dihydro) -lH-imidazol-2-yl) -2-iso? ropil-4-methoxy-phenoxy] -pyrimidine-2,4-diamine 136 1- [5- (2, -diamino-pyrimidin-5-yloxy) -2-hydroxy-4-isopropyl-phenyl] -ethanone 137 5- (5-iodo-2-isopropyl-4-methoxy-phenoxy) - pyrimidine-2, 4- diamine 138 5- (2-iodo-4,5-dimethoxy-phenoxy) -pyrimidine-2,4-diamine 139 5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-benzenesulfonamide 140 4- (2,4-diamino-pyrimidin-5-yloxy) -2-iodo-5-isopropyl -f-nol 141 5- (2,5-diiodo-4-methoxy-phenoxy) -pyrimidine-2,4-diamine 142 3- [4-amino-5- (5-bromo-2-isopropyl-4-methoxy-phenoxy) -pyridin-2-ylamino] -pentane-1,5-diol 143 5- (2-ethyl-5-iodo-4-methoxy-phenoxy) -pyrimidine-2,4-diamine 144 5- (5-iodo-2-isopropyl-4-methoxy-f-enoxy) -1-oxy-pyrimidine-2,4-diamine 145 5- (2-isopropyl-4-methoxy-5-vinyl-phenoxy) - pyrimidine-2, 4- diamine 146 5- (5-iodo-2-isopropenyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine n Name 147 5- (2-isopropyl-4-methoxy-5-pyrazole -l-yl-phenoxy) -pyrimidine-2,4-diamine 148 5- (5-iodo-2-isopropyl-phenoxy) -pyrimidine-2,4-diamine 149 5- [2-isopropyl-4-methoxy-5- (3-methyl-pyrazol-1-yl) -phenoxy] -pyrimidine-2,4-diamine 150 4- (2,4-diamino-pyrimidin-5-ylmethyl) -2-iodo-5-isopropyl-phenol 151 5- (2-isopropyl-4-methoxy-5-oxazol-2-yl-phenoxy) -pyrimidi - na-2, 4-diamine 152 (S) -2- [4-amino-5- (5-bromo-2-isopropyl-4-methoxy-phenoxy) pyrimidin-2-ylamino] -butan-1-ol 5- (4-iodo-2-isopropyl-5-methoxy-phenoxy) -pyrimidine-2, 4- diamine 154 5- (4-bromo-2-isopropyl-5-methoxy-phenoxy) -pyrimidine-2, 4- diamine 155 5- (2-ethyl-5-iodo-phenoxy) -pyrimidine-2,4-diamine 156 5- (2-isopropyl-4-methoxy-5-trifluoromethyl-phenoxy) -pyrimidine-2, 4- diamine 157 5- (2-isopropyl-4-methoxy-5-thiazol-4-yl-phenoxy) -pyrimidine-2,4-diamine 158 [4- (2,4-diamino-pyrimidin-5-yloxy) - 2-iodo-5-isopropyl-phenoxy] -acetonitrile 159 5- (2-isopropyl-4-l-methoxy-5-thiophen-3-yl-phenoxy) -pyrimidine-2,4-diamine 160 (R) -2 - [4-amino-5- (2-isopropyl-5-methanesulfonyl-4-methoxy-phenoxy) -pyrimidin-2-ylamino] -butan-1-ol n "Name 161 5- (7-isopropyl-4-methyl) -benzooxazol-6-yloxy) -pyrimidine-2,4-diamine 162 (S) -2- [4-amino-5- (5-chloro-2-isopropyl-4-methoxy-phenoxy) -pyrimidine- 2-ylamino] -propionic 163 5- [5- (4, 5-dihydro-oxazol-2-yl) -2-isopropyl-4-methoxy-phenoxy] -pyrimidine-2,4-diamine 164 5- (8- bromo-5-ethyl-2, 3-dihydro-benzo [1,4] dioxin-6-yloxy) pyrimidine-2,4-diamine 165 5- (2-iodo-4,5-dimethoxy-phenoxy) -pyrimidine- 2, 4-diamine 166 5- (2-isopropyl-5-methanesulfonyl-4-methoxy-phenoxy) -N-2- (2,2, 2-trifluor-ethyl) -pyrimidine-2,4-diamine 167 5- (5-iodo- 2-isopropyl-4-methoxy-benzyl) -pyrimidine-2, 4- diamine 168 5- (5-bromo-2-cyclopropyl-4-methoxy-phenoxy) -pyrimidine2, 4- diamine 169 (S) propyl ester -2- [3-hydroxy-2-methyl-2-methyl-propyl] -3-amino-5- (5-chloro-2-isopropyl-4-methoxy-phenoxy) -pyrimidin-2-ylamino] -propionate 170 5- [5- (5-Chloro-thiophen-2-yl) -2-isopropyl-4-methoxy-phenoxy-pyrimidine-2,4-diamine-5- (2-ethyl-4-methoxy-5-trifluoromethyl) -phenoxy) -pyrimidine-2,4-diamine 172 5- [2-isopropyl-4-methoxy-5- (l-methyl-lH-imidazol-2-yl) -phenoxyl-pyrimidine-2,4-diamine 173 - [2-isopropyl-4-methoxy-5- (2H-pyrazol-3-yl) -phenoxy] -pyrimidine-2,4-diamine 174 5- (5-imidazol-1-yl-2-isopropyl- 4-methoxy-phenoxy) -pyrimidine-2,4-diamine n Name 189 5- [5- (3,5-dimethyl-pyrazol-1-yl) -2-isopropyl-4-methoxy-3-enoxy] - pyrimidine-2,4-diamine 190 N2-benzyl-5- (2-isopropyl-5-methanesulfonyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine 191 N2-eti1-5- (2-isopropyl-5 -methanesulfonyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine 192 5- (2-isopropyl-5-methanesulfonyl-4-methoxy-phenoxy) -N2- (1-methanesulfonyl-piperidin-4-yl) - pyrimidine-2,4-diamine 193 1- [4-amino-5- (2-isopropyl-4,5-dimethoxy-benzyl) -pyrimidin-2-ylamino] -2-methyl-propan-2-ol 194 N2-isobutyl-5- ( 2-isopropy1-5-methanesulfonyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine 195 5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-N-methyl -benzamide 196 5- (2,4-diamino-pyrimidin-5-yloxy) -6-isopropyl-l-methyl-indol-3-carboxylate 197 5- (2-isopropyl-5-isoxazole-5-) ethyl ester 11-4-methoxy-phenoxy) -pyrimidine-2,4-diamine 198 5- (4-ethyl-7-methyl-benzo [b] thiof-5-yloxy) -pyrimidine2., 4-diamine 199 N2 - (4-Fluoro-phenyl) -5- (2-isopropyl-5-methanesulfonyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine 200 5- (5-chloro-2-isopropyl-4- methoxy-benzyl) -N2- (2,2, 2-trifluoromethyl) -pyrimidine-2,4-diamine 201 5- (2-isopropyl-4-methoxy-5- [1,4] oxadiazole -3-yl-phenoxy) pyrimidine-2,4-diamine 202 5- (2-isopropyl-5-methanesulfonyl-4-methoxy-phenoxy) -N2- (tetrahydro-pyran-4-yl) -pyrimidine-2, 4 -diamine n Name 203 1- [5- (2, 4-diamino-pyrimidin-5-yloxy ) -4-isopropyl-2-methoxy-phenyl] -ethanol 204 5- (6-isopropyl-4-methyl-3, -dihydro-2H-benzo [1,4] oxazin-7-yloxy) -pyrimidine- 2, 4-diamine 205 5- (2,5-diisopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-di-amine 206 5- (5-benzo [b] thiophen-3-yl-2-isopropyl) 4-methoxy-phenoxy) pyrimidine-2,4-diamine 207 5- [2-isopropyl-4-methoxy-5- (1-methoxy-ethyl) -phenoxy] -pyrimidine-2, 4-diamine 208 5- (2-isopropyl-4-methoxy-5-oxazol-4-yl-f-enoxy) -pyrimidine-2,4-diamine 209 5- (4-ethyl-7-methyl-benzo [b] thiophen-5-yloxy) -pyrimidine-2,4-diamine 210 5- [5- (5-chloro-thiophen-2-yl) -2-isopropyl-4-methoxy-benzyl] pyrimidine-2, 4 -diamine 211 5- (2-isopropyl-4-methoxy-5-thiazol-2-yl-phenoxy) -pyrimidine-2,4-diamine 212 5- (2-isopropyl-4-methoxy-5-thiophene) 3-yl-benzyl) -pyrimidine-2,4-diamine 213 5- (5-furan-3-yl-2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine 214 5- ( 2-isopropyl-5-methoxy-f-enoxy) -pyrimidine-2,4-diamine 215 5- [5-iodo-2-isopropyl-4- (pyrimidin-2-ylmethoxy) -phenoxy] pyrimidine-2,4-diamine 216 5- (2-isopropyl-4,5-dimethoxy-benzyl) -N2- pyridin-2-yl-pyrimidine-2,4-diamine n Name 217 5- (1,3-dimethyl-6-trifluoromethyl-lH-indol-5-yloxy) -pyrimidine-2,4-diamine 218 5- (2-iso? Ropil-4-methoxy-5-thiophen-2-yl-phenoxy) -pyrimidine-2,4-diamine 219 1- [5- (2, 4-diamino-pyrimidine-5- iloxy) -4-isopropyl-2-methoxy-phenyl] -3-phenyl-urea 220 5- (5-chloro-2-isopropyl-4-methoxy-benzyl) - N - (2-methoxy-ethyl) - pyrimidine-2,4-diamine 221 5- (2,4-diamino-? irimidin-5-yloxy) -4-iso? ropil-2-methoxy-N-methyl-benzenesulfonamide 222 5- (2-isopropyl-5- methanesulfonyl-4-methoxy-phenoxy) -N-methyl-pyrimidine-2,4-diamine 223 5- [5-iodo-2-isopropyl-4- (pyridin-2-ylmethoxy) -phenoxy] -pyrimidine-2, 4-diamine 224 N- [2-acetylamino-5- (2-isopropyl-4-methoxy-5-methyl-benzyl) -pyrimidin-4-yl] -acetamide 225 5- [4- (2-f) -benzyloxy) -5-iodo-2-isopropyl-f-enoxy] -pyrimidine-2,4-diamine 226 5- (2-isopr opyl-4-methoxy-5-pyrrol-l-yl-phenoxy) -pyrimidine-2,4-diamine 227 5- (2-isopropyl-4-methoxy-5-trifluoromethoxy-phenoxy) -pyridine- 2,4-diamine 228 2- [4- (2, 4-diamino-pyrimidin-5-ylmethyl) -2-iodo-5-isopropyl-phenoxy] -ethanol 229 5- (6-isopropyl-1-methyl-1H -indazol-5-yloxy) -pyrimidine-2,4-diamine 230 5- [5- (4,5-dihydro-oxazol-2-yl) -2-isopropyl-4-methoxy-benzy] -pyrimidine- 2, 4-diamine n Name 259 5- (2-isopropyl-4-methoxy-5-nitro-phenoxy) -pyrimidine-2, 4- diamine 260 5- [5-iodo-2-isopropyl-4- (l- methyl-piperidin-2-ylmethoxy) phenoxy] -pyrimidine-2,4-diamine 261 5- [5-iodo-2-isopropyl-4- (tetrahydro-pyran-2-ylmethoxy) phenoxy] -pyrimidine-2, 4- diamine 262 5- (2-isopropyl-4-methoxy-5- [1,2,4] triazol-1-yl-phenoxy-pyrimidine-2,4-diamine 263 5- (2-isopropyl-4,5-dimethoxy-) f-enoxy) -N - (2-methoxy-ethyl-pyrimidine-2,4-diamine 264 5- (4-fluoro-4-isopropyl-6-methoxy-biphenyl-3-yloxy) -pyrimidine-2, 4- diamine 265 5- (5-chloro-2-isopropyl-4-methoxy-phenoxy) -N- (2,2, 2-tr i- fluor-ethyl) -pyrimidine-2,4-diamine 266 5- (2,4-diamino-pyrimidin-5-ylmethyl) -4-isopropyl-2-methoxy-benzonitrile 267 5- [2-isopropyl-4- methoxy-5- (2-methyl-thiazol-5-yl) -phenoxy] pyrimidine-2,4-diamine 268 5- (2-isopropyl-4-methoxy-6-methyl-phenoxy) -pyrimidine-2, 4- diamine 269 5- (5-ethanesulfonyl-2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine 270 5- (2-isopropyl-4-methoxy-5-thiazol-5-yl-benzyl) ) -pyrimidine- 2,4-diamine 271 1- [5- (2, 4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-phenyl] -lH-imidazole-2-thiol 272 5- [2-isopropyl-4-methoxy-5- (l-methyl-lH-pyrazol-4-yl) -phenoxy] -pyrimidine-2,4-diamine n Name 273 5- [5-iodo-2-isopropyl-4 - (pyridin-4-ylmethoxy) -phenoxy] -pyrimidine-2,4-diamine 274 5- (4-iodo-2-isopropyl-phenoxy) -pyrimidine-2,4-diamine 275 5- (5-iodo-4-isopropyl-2-methoxy-benzyl) -pyrimidine-2, 4-diamine 276 5- (5-fluoro-2-isopropyl-4-ethoxy-phenoxy) -pyrimidine-2, 4 - diamine 277 5- (4'-fluoro-5-isopropyl-2-methoxy-biphenyl-4-yloxy) -pyridimine-2,4-diamine 278 5- [4- (3-fluoro-benzyloxy) -5 -Iodo-2-isopropyl-phenoxy] -pyrimidine-2,4-diamine 279 5- (4-bromo-2-isopropyl-phenoxy) -pyrimidine-2,4-diamine 280 5- (4-furan-2-yl-2-isopropyl-5-methoxy-phenoxy) -pyrimidine-2,4-diamine 281 2- [5- (2,4-diamino-pyrimidin-5-yloxy) - 4-isopropyl-2-methoxy-phenyl] -propan-2-ol 282 5- (2,4-diamino-pyrimidin-5-yloxy) -6-isopropyl-1-methyl-1H-indole-3-carboxylic acid 283 5- [4- (2,6-difluor-benzyloxy) -5-iodo-2-isopropyl-phenoxy] -pyrimidine-2,4-diamine 284 5- (5-iodo-2-isopropyl-4-phenethyloxy-phenoxy) ) -pyrimidine2,4-diamine 285 5- (2-isopropyl-4-methoxy-5-pyridin-4-yl-phenoxy) -pyrimidine-2,4-diamine 286 5- (2-isopropyl-4,5-dimethoxy) -benzyl) -N- (1-methyl-piperidin-4-yl) -pyrimidine-2,4-diamine n Name 287 5- (2,4-diamino-pyrimidin-5-yloxy) -N-ethyl-4- isopropyl-2-methoxy-benzenesulfonamide 288 5- [2-isopropyl-5- (4-methanesulfonyl-piperazin-1-yl) -4-methoxy-phenoxy] -pyrimidine-2,4-diamiha 289 5- (2 -isopropyl-4-methoxy-5-pyridin-3-yl-phenoxy) -pyrimidine-2,4-diamine 290 5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxyN, N-dimethyl-benzamide 291 5- [5- (2, 5-dimethyl-pir rol-l-il) -2-isopropyl-4-methoxy-phenoxy] -pyrimidine-2,4-diamine 292 5- (2-ethyl-3-methoxy-benzyl) -pyrimidine-2,4-diamine 293 5- (2-bromo-4, 5-dimethoxy-phenoxy) -pyrimidine-2,4-diamine 294 6- (2, 4-diamino-pyrimidin-5-yloxy) 5-isopropyl-3-methyl-lH-indole-2-carboxylate ethyl ester The compounds of the present invention can be obtained by a large number of methods which are detailed in the illustrative schemes of synthetic reactions which are presented and described below. The starting materials and the reagents used for the synthesis of these compounds are in general commercial products supplied, for example, by the company Aldrich Chemical Co. or they can be obtained by methods that those skilled in the art already know and are described in the following references : Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, 1991, volumes 1-15; Rodd 's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, volumes 1-5 and supplements; and Organics Reactions, Wiley & Sons: New York, 1991, volumes 1-40. The following schemes of synthetic reactions are merely illustrative of some methods that allow the compounds of the present invention to be synthesized and various modifications can be introduced in these schemes of synthesis reactions that the person skilled in the art will intuit quickly in view of the description contained in this application. The starting materials and intermediates of the synthetic reaction schemes can be isolated and purified, if desired, by applying conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Said materials can be characterized by conventional methods, which include the determination of the physical constants and the spectral data. Unless indicated otherwise, the reactions described herein are preferably carried out in an atmosphere of inert gas, at atmospheric pressure and in a range of reaction temperatures between -78 ° C and 150 ° C, with greater preference between 0 ° C and 125 ° C and with special preference and conveniently around the ambient temperature (TA), for example around 20 ° C.

The following scheme A illustrates a synthetic process which can be used to obtain compounds of the formula (I), wherein X is methylene, Y is -NRdRe and R1, R2, R3, R4, R6, R6, R7, R8, Rd and Re have the meanings defined in the present description.

REACTION SCHEME A In stage 1 of scheme A, benzaldehyde a is rented with the Grignard reagent derived from 4-chloro-5-iodo-2-ethylsulfanyl-pyrimidine or a similar iodopyrimidine to obtain an alpha-hydroxybenzyl -pyrimidine c. The iodopyrimidine used in this step can be obtained according to the procedure described by Sakamoto et al., Chem. Pharm. Bull. 34: 2719 (1986). Numerous substituted benzaldehydes are commercial products or can be obtained easily by techniques well known to those skilled in the art. In many cases a "masked aldehyde", for example an imine or oxazoline, may be used to achieve the introduction of the desired functional groups into the benzaldehyde a, after which the masked aldehyde is protected to obtain the free aldehyde group again . Aldehyde protection schemes of this type are illustrated in the following experimental examples. The reaction of step 1 can be carried out in the presence of an alkylmagnesium bromide, in a dry polar aprotic solvent. In step 2, alpha-hydroxy-benzyl-pyrimidine c is reduced to obtain benzyl-pyrimidine d. The reduction of step 2 can be carried out using triethylsilane and trifluoroacetic acid (TFA) in a polar solvent. In step 3, a first amination by reaction of the amine e with the benzyl-pyrimidine d gives the benzyl aminopyrimidine f. The amine e can be any suitable primary or secondary amine, having functional groups R7 or R8 according to the invention. The amine e can be, for example, ammonia, methylamine, ethylamine, isopropylamine, aniline, benzylamine, phenylethylamine, cyclopropylamine, dimethylamine, aziridine, pyrrolidine, piperidine or the like. The amination of step 3 can be carried out by heating the benzyl-pyrimidine d in the presence of an excess of amine e under sealed conditions. In step 4, an oxidation of the methylsulfanyl group of the benzyl aminopyrimidine is carried out, obtaining the amino-methanesulfonyl-benzylpyrimidine a. The oxidation of step 4 can be carried out using metachloroperbenzoic acid (mCPBA), OXONE® or a similar oxidizing agent in a mild polar solvent. A second amination takes place in step 6 in which the amino-methanesulfonyl benzylpyrimidine g is treated with the amine h to displace the methanesulfonyl group and obtain the diamino-benzylpyrimidine i. The diamino-benzylpyrimidine i is a compound of the formula (I) and can be used in the methods of the invention. The amination of step 6 can be carried out by heating the amino-methanesulfonyl-benzylpyrimidine g in the presence of an excess of the amine h in a polar solvent and light pressure. Numerous variations of the above procedure are possible which will be apparent to those skilled in the art on their own after examining this description. For example, various pyrimidine reagents can be used in place of iodopyrimidine b in step 1. In such a variation, described in the following experimental examples, benzaldehyde a can be treated with 5-lithium-2,6-dimethoxypyrimidine [Mathson et al. col., JOC 55 (10): 3410-3412 (1990)] to form a dimethoxy-benzyl-pyrimidine-alcohol which is then oxidized with MnO2. The resulting ketone can then be amined to displace the methoxy groups and obtain a diamino-benzylpyrimidine according to the invention.

In the following reaction scheme B, another synthetic procedure is illustrated, which can be used to obtain specific compounds of the formula (I) above, in which X is 0, Y is -NRdRe, R7 and R8 are hydrogen and R1, R2, R3, R4, R5, Rd and Re have the meanings defined in the present description.

REACTION SCHEME B In stage 1 of scheme B, 0-alkylation is carried out by reaction of the phenol j with a haloacetonitrile, for example an iodoacetonitrile k, obtaining a cyano ether 1. Numerous substituted phenols are commercially available or they can be obtained by well-known chemistry techniques which can be applied to step 1. For example, the benzaldehydes substituted in reaction scheme A above can be converted into the corresponding phenols j by Baeyer-Villiger oxidation using a peracid, for example the mCPBA, as illustrated in the following experimental examples. The alkylation of step 1 can be carried out in the presence of a weak base and in a polar aprotic solvent. In step 2 a cyanoenol ether compound is formed by treating cyano ether 1 with a strong base, for example sodium hydride, and then introducing ester m to form an enolate, which is in turn alkylated by addition of iodomethane or other alkyl halide. This step can be carried out in a polar aprotic solvent. In step 3 the cyano-enol ether n is reacted with a guanidine compound or in the presence of a base, in a polar aprotic solvent, obtaining a diaminopyrimidine (SAW) . Diaminopyrimidine (VI) is a compound of the formula (I) usable in the methods of the invention. As in the case of the reaction scheme A discussed above, numerous variations of the reaction scheme procedure B are possible that will be readily apparent to those skilled in the art. For example, a selective amination of the -NH2 group of diaminopyrimidine p can be applied using the reductive amination technique or the like to introduce functional groups R7 and R8 according to formula (I). Another additional process that can be used to obtain the compounds in question is shown in scheme C, wherein R1, R2, R3, R4 and R5 have the meanings defined herein. In reaction scheme C, the well known synthesis of the antibacterial compounds "ormetoprim" and "trimethoprim" is presented. This synthesis procedure is described in Manchand et al., J. Org. Chem. 57: 3531-3535 (1992).

REACTION SCHEME C In the procedure of Scheme C, benzaldehyde a is treated with acrylonitrile in the presence of sodium methoxide in step 1 obtaining a phenyl-methoxymethylcinnamonitrile compound q, which is itself reacted with guanidine in step 2 to obtain the diaminopyrimidine r. The diamino-pyrimidine r is a compound of the formula (I) wherein X is -CH 2 -, Y is -NH 2 and R 6, R 7 and R 8 are hydrogen. The procedure of reaction scheme C can be used effectively when the benzaldehydes a have small R1 and R5 groups, so that the functional group aldehyde in stage 1 and the methoxymethyl-cynamonitrile functional group in stage 2 are relatively unimpeded spherically However, the introduction, for example, of R1 when it is an isopropyl group or a more bulky alkyl group reduces the yield of step 1 to a nominal value of zero. In the following table 2 the relative yields achieved in the reaction scheme C with the various benzaldehydes used as starting materials are shown. Table 2 The specific details for obtaining the compounds of the invention are described in the following section of the examples. The compounds of the invention can be used for the treatment of a wide range of diseases, pathological states and genitourinary disorders, including the pathological states of the urinary tract associated with obstruction of the exit of the bladder and urinary incontinence, for example reduced bladder capacity, frequency of urination, urge incontinence, stress incontinence, bladder hyperresponsiveness, benign prostatic hypertrophy (BPH), prostatitis, hyperreflexia of the detruSor, urinary frequency , nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity, urethritis, prostatitis, pelvic pain syndrome, prostatodynia, cystitis and idiopathic bladder hypersensitivity and other symptoms related to overactive bladder. It is expected that the compounds of the invention will find their utility as analgesics for the treatment of diseases and conditions associated with pain due to a wide variety of. causes, including, but not limited to: inflammatory pain, surgical pain, visceral pain, premenstrual pain, central pain, pain due to burns, migraine or periodic migrainous neuralgia, nerve injuries, neuritis , neuralgia, intoxication, ischemic lesions, interstitial cystitis, cancerous pain, viral, parasitic or bacterial infections, post-traumatic injuries (including fractures and injuries during sports) or pain associated with bowel syndrome irritable. The present invention includes pharmaceutical compositions containing at least one compound of the present invention or an individual isomer or a racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof, together with at least one pharmaceutically excipient. acceptable and optionally other therapeutic and / or prophylactic ingredients. In general, the compounds of the present invention will be administered in a therapeutically effective amount by any of the acceptable modes of administration for agents intended for similar purposes. Suitable dosing ranges are, for example, 1-500 mg per day, preferably 1-100 mg per day and with special preference 1-30 mg per day, depending on many factors, for example the severity of the disease. treat, the age and relative health of the subject, the potency of the compound used, the route and the form of administration, the indication to which the administration is directed and the preferences and experience of the physician attending to the patient. A person skilled in treating these diseases will be able to evaluate the therapeutically effective amount of the compounds of the present invention for a given disease, without having to experiment unnecessarily, based on his personal knowledge and the description of this application.

In general, the compounds of the present invention will be administered in the form of pharmaceutical formulations containing them and are suitable for oral (including buccal and sublingual), rectal, nasal, topical, pulmonary, vaginal or parenteral administration (including intramuscular administration). , intraarterial, intrathecal, subcutaneous and intravenous) or in a form suitable for administration by inhalation or insufflation. The preferred mode of administration is generally oral using a convenient regimen of daily doses that can be adjusted to the severity of the condition. A compound or compounds of the present invention, together with one or more conventional adjuvants, excipients or diluents, may be incorporated into the form of the pharmaceutical compositions and unit doses. The pharmaceutical compositions and dosage unit forms may contain conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient, in accordance with the desired daily dosage range. that will be applied. The pharmaceutical compositions may be administered in the form of solids, for example filled tablets or capsules, semi-solids, powders, persistent release formulations or liquids, for example solutions, suspensions, emulsions, elixirs or filled capsules for oral use; or in the form of suppositories for rectal or vaginal use; or in the form of sterile injectable solutions for parenteral use. Formulations containing one (1) milligram of active principle or, with greater amplitude, 0.01 to one hundred (100) milligrams per tablet, are therefore representative and suitable unit dosage forms. The compounds of the present invention can be formulated in a wide variety of dosage forms for oral administration. The pharmaceutical compositions and dosage forms may contain a compound or compounds of the present invention or pharmaceutically acceptable salts thereof as the active ingredient. The pharmaceutically acceptable excipients may be solid or liquid. Solid preparations include powders, tablets, pills, capsules, seals (hollow wafers), suppositories and dispersible granules. A solid excipient may further contain one or more substances that further act as diluents, flavors, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or an encapsulating material. In powders, the excipient is in general a finely divided solid, mixed with the finely divided active ingredient. In tablets, the active ingredient is usually mixed with the excipient which has a sufficient binding capacity in suitable proportions and is compacted to acquire the desired shape and size. The powders and tablets preferably contain one (1) to seventy (70) percent active ingredient. Suitable excipients include but are not limited to: magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting point wax, cocoa butter and the like . The term "preparation" designates the formulation of the active compound together with the encapsulating material as an excipient, giving rise to a capsule in which the active principle, with or without excipient, is enveloped by the excipient, which is associated therewith. . Seals (hollow wafers) and pills are also included. Tablets, powders, capsules, pills, seals (wafers) and pills can have solid forms suitable for oral administration. Other forms suitable for oral administration include preparations in liquid form, among which are emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions or solid form preparations which are intended to be converted into liquid form preparations immediately before use. Emulsions can be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents, for example lecithin, sorbitol monooleate or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers and thickeners. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with a viscous material, for example natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other known suspending agents. The solid form preparations include solutions, suspensions and emulsions and, in addition to the active component, may contain colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers and the like. The compounds of the present invention can be formulated for parenteral administration (for example by injection, for example bolus injection or continuous infusion) and can be presented in unit dosage forms in ampoules, pre-packaged syringes, small volume infusion containers or multi-dose containers, which also contain a preservative. The compositions can also take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or non-aqueous excipients, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (for example olive oil) and injectable organic esters (for example ethyl oleate) and may contain formulating agents, Examples are preservatives, wetting, emulsifying or suspending, stabilizing and / or dispersing agents. Alternatively, the active principle can be presented in powder form, obtained by aseptic isolation of sterile solid or by lyophilization of the solution for reconstitution before use in a suitable vehicle, for example sterile, pyrogen-free water.

The compounds of the present invention can also be formulated for topical administration on the epidermis in the form of ointments, creams or lotions or in the form of transdermal plaster (patch). The ointments and the creams can be formulated, for example, with an aqueous or oily base, by adding suitable thickeners and / or gelling agents. The lotions can be formulated on an aqueous or oily basis and will generally carry one or more emulsifying agents, stabilizers, dispersants, suspending agents, thickeners or colorants. Suitable formulations for topical administration in the mouth include lozenge-shaped lozenges containing an active ingredient in a flavored base, typically sucrose and acacia or tragacanth; the tablets containing the active ingredient in an inert base, for example gelatin and glycerin or sucrose and acacia; and oral lotions containing the active ingredient in a suitable liquid excipient. The compounds of the present invention can be formulated for administration in the form of suppositories. First a low melting point wax is melted, for example a mixture of fatty acid glycerides or cocoa butter and then the active ingredient is dispersed therein homogeneously, for example by stirring. The molten homogeneous mixture is then poured into molds of the appropriate volume, allowed to cool and solidify.

The compounds of the present invention can be formulated for vaginal administration. Pessaries, buffers, creams, gels, pastes, foams or sprays which contain, in addition to the active ingredient, suitable excipients are known as suitable in the art. The compounds of the present invention can be formulated for nasal administration. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with an eyedropper, a pipette or a nebulizer. The formulations can be administered in the form of single or multi-dose. In the latter case of an eyedropper or pipette, the use may be made by the same patient that a suitable predetermined volume of the solution or suspension is administered. In the case of the nebulizer, the use can be made for example by means of a spray pump that atomizes a fixed, calibrated quantity. The compounds of the present invention can be formulated for aerosol administration, especially for the respiratory tract, including intranasal administration. In general, the compound should have a small particle size, for example in the order of five (5) microns or less. Such a particle size can be obtained by means already known in the art, for example by micronization. The active ingredient is supplied in a pressurized container containing a suitable propellant, for example a chlorofluorinated hydrocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane or carbon dioxide or other suitable gas. Conveniently, the aerosol may also contain a surfactant, for example lecithin. The dose of drug can be controlled by a calibrated valve. Alternatively, the active ingredients may be supplied in the form of dry powder, for example a powdery mixture containing the compound in a suitable powder base, for example lactose, starch, starch derivatives, for example hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP). The powdery excipient will form a gel in the nasal cavity. The powder composition can be presented in unit dosage form, for example in capsules or cartridges for example of gelatin or in blister packs, from which the powder can be administered by means of an inhaler. If desired, the formulations can be manufactured with an enteric coating, adapted to the continued or controlled release of the active ingredient. For example, the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous in the case that a continuous delivery is necessary and when the submission or compliance of a treatment regime by the patient is crucial. The compounds of transdermal delivery systems are often incorporated into a solid support, adhesive on the skin. The compound of interest can be further combined with a penetration enhancer, for example azone (1-dodecylazacycloheptan-2-one). Delivery systems with continuous release are inserted subcutaneously into the subdermal layer by surgery or injection. The subdermal implants encapsulate the compound in a soluble lipid membrane, for example silicone rubber or a biodegradable polymer, for example polylactic acid. The pharmaceutical preparations are preferably present in unit dosage forms. In such forms the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged preparation, the package contains discrete quantities of the preparation, for example packaged tablets, capsules and powders in vials or ampoules. The unit dosage form can also be a capsule, a tablet, a stamp or even a tablet, or it can be an appropriate number of any of them in packaged form. Other pharmaceutically suitable excipients and their formulations are described in Remington: The Science and Practice of Pharmacy (1995), coordinated by Martin, Mack Publishing Company, 19"edition, Easton, Pa. In the following examples representative pharmaceutical formulations are described which They contain a compound of the present invention EXAMPLES The following embodiments and examples are provided to enable those skilled in the art to clearly understand and practice the present invention.They should not be taken as limiting the scope of the invention, but as examples merely illustrative and representative thereof Obtaining 1: N- (2- (R) -nidroxy-1-methyl-ethyl) -guanidine Stage 1: bis-benzyloxycarbonyl-N- (2- (R) -hydroxy-1- methyl-ethyl) -guanidine To a solution of R- (-) -2-amino-1-propanol (0.59 g, 8.0 mmol) in 50 ml of THF is added pyrazole carboxamidine (3.0 g, 8.0 mmol, obtained as described by Berbatowicz et al. ., Tetrahedron 34: 3389 (1993) After 16 hours the mixture is concentrated in vacuo, purification by flash chromatography (93: 7 mixture of ethyl acetate / CH2Cl2) yields bis-benzyloxycarbonyl-N- (2- (R ) -hydroxy-lmethyl-ethyl) -guanidine (3.0 g, 97%) as a white solid Step 2: N- (2- (R) -hydroxy-1-methyl-ethyl) -guanidine To a solution of bis-benzyloxycarbonyl-N- (2- (R) -hydroxy-1-methyl-ethyl) -guanidine in 75 ml of EtOH is added Pd-10. % on C (0.10 g). The mixture is stirred at a pressure of H2 of 1 atmosphere. After 16 hours the mixture was filtered through a pad of Celite and concentrated in vacuo, obtaining N- (2- (R) -hydroxy-1-methyl-ethyl) -guanidine (0.44 g, 69%). Using the appropriate amines in the above process, the following guanidine compounds can also be obtained: N- (3-ethanesulfonyl-1-methyl-propyl) -guanidine; 4-guanidino-piperidine-1-carboxylate ethyl ester; N- (1-cyclopropyl-ethyl) -guanidine; N- (tetrahydro-thiopyran-4-yl) -guanidine; N- [2- (4-acetyl-piperazin-1-yl) -1-methyl-ethyl] -guanidine; N- (1-hydroxymethyl-propyl) -guanidine; N- (1-methanesulfonyl-piperidin-4-yl) -guanidine; and N- [3-hydroxy-1- (2-hydroxy-ethyl) -propyl] -guanidine. Example 1: 5- [4,5-dimethoxy-2- (l-methyl-2-phenyl-ethyl) -benzyl] -pyrimidine-2,4-diamine The synthetic procedure applied in this example is presented in the reaction scheme D.

Reaction Scheme D Step 1. 2- [4,5-Dimethoxy-2- (1-methyl-2-phenyl-ethyl) -phenyl] -4,4-dimethyl-4,5-dihydro-oxazole The 4 is obtained, 4-dimethyl-2- (2,4,5-trimethoxy-phenyl) -4,5-dihydro-oxazole used in this step according to the procedure described by Meyers et al., J. Org. Chem. 43, 1372-1379 (1978). To a rapidly stirred suspension of magnesium chips (1.32 g, 54.5 moles) in 35 ml of tetrahydrofuran (THF) is added 1,2-dibromoethane (0.10 ml) in one portion. Add 2-bromo-1-phenylpropane (10.86 g, 54.5 mmol). at a speed that maintains the internal temperature at 40 ° C. After 2.5 hours, the turbid suspension is transferred to a solution of 4, -dimethyl-2- (2,4,5-trimethoxy-phenyl) -4,5-dihydro-oxazole (10,013 g, 36.4 mmol) via a cannula. 50 ml of THF. After 18 hours the solution is cooled to 0 ° C and the reaction is stopped by the slow addition of NHC1 of 10%. 500 ml of H20 are added and the mixture is extracted with ethyl acetate, washed with H20 and washed with brine. The organic phases are combined, dried over Na 2 SO 4, filtered and concentrated in vacuo to obtain a crude solid. Purification by flash chromatography (4: 1 mixture of hexane / ethyl acetate) gives 2- [4,5-dimethoxy-2- (1-methyl-2-phenyl-ethyl) -phenyl] -4,4-dimethyl. -4, 5-dihydro-oxazole in the form of transparent and viscous oil (7.833 g, 41%). Stage 2 . 2- [4,5-dimethoxy-2- (l-methyl-2-phenylethyl) -phenyl] -3,4,4-trimethyl-4,5-dihydro-oxazolium iodide To a solution of 2- [4, 5-dimethoxy-2- (1-methyl-2-phenyl-ethyl) -phenyl] -4,4-dimethyl-4,5-dihydro-oxazole (7.515 g, 21.3 mmol) in 50 ml of N02CH3 is added iodomethane (2.65 ml, 42.5 mmol). The solution is heated to 110 ° C. After 3 hours, the solution was cooled and concentrated in vacuo to give 2- [4,5-dimethoxy-2- (l-methyl-2-phenyl-ethyl) -phenyl] -3.4, 4- iodide. trimethyl-4,5-dihydrooxazolium (10.108 g) as an orange solid. Step 3. 4-5-dimethoxy-2- (l-methyl-2-phenyl-ethyl) -benzoate methyl ester To a solution of 2- [4,5-dimethoxy-2- (l-methyl- iodide 2-phenyl-ethyl) -phenyl] -3,4,4-trimethyl-4,5-dihydrooxazolium (5132 g, 10.4 mmol) in 52 ml of methanol is added 4 M NaOH (5.2 ml, 20.7 mmol) . The solution is heated to reflux. After 16 hours the solution is cooled to 0 ° C and acidified to pH = 1 with concentrated HCl. The mixture is extracted with ethyl acetate, wash with H20 and wash with brine. The organic phases are combined, dried over Na2SO4, filtered and concentrated in vacuo to give a crude acid (3.228 g). A portion of this acid (2.919 g, 9.73 mmol) is dissolved in a mixture of 70 ml of benzene and 20 ml of MeOH. Trimethylsilyldiazomethane (6.3 ml, 2.0 M in hexanes) is added dropwise. After 30 minutes, the solution was concentrated in vacuo to obtain the 4,5-dimethoxy-2- (l-methyl-2-phenyl-ethyl) -benzoate methyl ester in the form of oil (2886 g). Step 4. [4,5-Dimethoxy-2- (l-methyl-2-phenyl-ethyl) -phenyl] -methanol Diisobutyl aluminum hydride (22.9 ml, 1.0 M in THF) is added to a methyl ester solution. of 4,5-dimethoxy-2- (1-methyl-2-phenylethyl) -benzoate (2886 g, 9.2 mmol) in 100 ml of THF at -78 ° C for 10 min. The mixture is kept stirring for 1 h and heated to T.A. After 1.5 hours the reaction is stopped by the slow addition of 50 ml of a saturated solution of the Rochelle salt. After stirring rapidly for 30 minutes, the mixture is filtered through a pad of Celite and concentrated in vacuo. H20 is added and the suspension is extracted with ethyl acetate, washed with H20 and washed with brine. The organic phases are combined, dried over Na 2 SO 4, filtered and concentrated in vacuo to obtain a crude oil. Purification by flash chromatography (3: 1 mixture of hexane / ethyl acetate) gives [4,5-dimethoxy-2- (1-methyl-2-phenyl-ethyl) -phenyl] -methanol as a clear oil ( 1,269 g, 48%). Step 5. 4, 5-dimethoxy-2- (1-methyl-2 ^ -phenyl-ethyl) -benzaldehyde A solution of pyridinium chlorochromate (1253 g, 5.8 mmol) in 40 ml of CH2C12 is cooled to 0 ° C. [4,5-Dimethoxy-2- (1-methyl-2-phenyl-ethyl) -phenyl] -methanol (1110 g, 3.88 mmol) in 5.0 mL of CH2C12 is added dropwise and kept stirring for 45 minutes . The mixture is diluted in 200 ml of Et20, filtered through Celite and concentrated in vacuo to give a dark brown oil. Purification by flash chromatography (9: 1 mixture of hexane / ethyl acetate) gives 4,5-dimethoxy-2- (1-methyl-2-phenyl-ethyl) -benzaldehyde (0.840 g, 76%) as a transparent oil. Step 6. [4,5-Dimethoxy-2- (l-methyl-2-phenyl-ethyl) -phenyl] - (2, -dimethoxy-pyrimidin-5-yl) -methanol. 2, 2, 6 is dissolved, 6-tetramethyl-piperidine (0.85 ml, 5.0 mmol) freshly distilled in 20 ml of THF and cooled to 0 ° C. N-butyllithium (2.0 ml, 2.5 M in hexanes) is added dropwise over 5 minutes and the mixture is kept stirred for 30 minutes and then cooled to 78 ° C. 2,3-Dimethoxypyridine (0.353 g, 2.52 mmol) is added dropwise over 5 min. After 45 min. the solution is transferred by means of an ice-cold cannula to a solution of 4,5-dimethoxy-2- (l-methyl-2-phenyl-ethyl) -benzaldehyde (0.717 g, 2.52 mmol) in 20 ml of THF at -78. ° C. After stirring for 1 hour the solution is heated to T.A. and the reaction is interrupted by the slow addition of 50 ml of 10% NH 4 Cl. Then 100 ml of H20 is added, it is extracted • the mixture, with ethyl acetate, is washed with H20 and washed with brine. The organic phases are combined, dried with Na 2 SO 4, filtered and concentrated in vacuo to give an orange oil. fication by flash chromatography (3: 2 mixture of hexane / ethyl acetate) gives [4,5-dimethoxy-2- (1-methyl-2-phenyl-ethyl) -phenyl] - (2,4-dimethoxy-pyrimidin-5-yl) ) -methanol (0.551 g, 52%) in the form of a clear oil.

Step 7. [4,5-Dimethoxy-2- (l-methyl-2-phenyl-ethyl) -phenyl] - (2,4-dimethoxy-pyrimidin-5-yl) -methanone To a solution of [4, 5 -dimethoxy-2- (l-methyl-2-phenylethyl) -phenyl] - (2,4-dimethoxy-pyrimidin-5-yl) -methanol (0.418 g, 0.9 mmol) in 20 ml of toluene is added Mn02 ( 0.335 g, 4.7 mmol). The mixture is heated to reflux and the H20 is removed by a Dean-Stark trap. After 1 hour the mixture is cooled, filtered through a pad of Celite and concentrated in vacuo to obtain a crude oil. fication by flash chromatography (7: 3 mixture of hexane / ethyl acetate) gives [4,5-dimethoxy-2- (1-methyl-2-phenyl-ethyl) -phenyl] - (2,4-dimethoxy). pyrimidin-5-yl) -methanone (0.258 g, 62%) as a clear oil. Step 8. (2,4-diamino-pyrimidin-5-yl) - [4,5-dimethoxy-2- (1-methyl-2-phenyl-ethyl) -phenyl] -methanone A solution of [4, 5-dimethoxy-2- (1-methyl-2-phenyl-ethyl) -phenyl] - (2,4-dimethoxy-pyrimidin-5-yl) -methanone (0.212 g, 0.5 mmol) in 5.0 ml of MeOH over ammonia (15 ml, 7.0M in MeOH) in a sealed tube. The mixture is heated to 80 ° C. After 16 hours the solution is cooled and concentrated in vacuo to obtain a dark solid. fication by flash chromatography (95: 5 mixture of CH2Cl2 / MeC) H) gives (2,4-diamino-pyrimidin-5-yl) - [4,5-dimethoxy-2- (l-methyl-2-phenyl) ethyl) -phenyl] -methanone (0.162 g, 86%) as a white solid.

Step 9. 5- [4,5-dimethoxy-2- (1-methyl-2-phenyl-ethyl) -benzyl] -pyrimidine-2,4-diamine To a solution of (2,4-diamino-pyrimidine-5) -yl) - [4,5-dimethoxy-2- (l-methyl-2-phenyl-ethyl) -phenyl] -methanone (0.413 g, 0.4 mmol) in 10 ml of THF is added LiAlH4 (0.73 ml, 1.0 M in THF) for 5 min. Once the evolution of gas has ceased, the mixture is heated to reflux. After 3 h the mixture is cooled to 0 ° C and the reaction is interrupted by the Fieser method. After 30 min. The mixture is filtered through a pad of Celite and concentrated in vacuo to obtain a solid, white crude. To a solution of this solid in 5 ml of CH2C12 is added trifluoroacetic acid (TFA, 1.1 ml, 14.0 mmol) and then triethylsilane (0.4 ml, 2.8 mmol) is added. After 30 min, 50 ml of 10% K2CO3 is added and the mixture is extracted with ethyl acetate and washed with brine. The organic phases are combined, dried over Na 2 SO, filtered and concentrated in vacuo. fication by flash chromatography (95: 5 mixture of CH2C12) provides 5- [4,5-dimethoxy-2- (l-methyl-2-phenyl-ethyl) -benzyl] -pyrimidine-2,4-diamine (0.066 g , 58%) in the form of white foam; melting point (HCl salt) 227. l-227-4 ° C. Using the procedure just described of example 1, but replacing the 2-bromo-l-phenyl-propane from step 1 with 2-bromopropane or other alkyl bromides and replacing the ammonia from step 8 with several alkyl- or benzyl-amines , a large variety of compounds are obtained under reaction conditions that are essentially the same. Table 1 shows additional compounds obtained by applying the procedure described in Example 1. Example 2: 5- (5-bromo-2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine The synthesis procedure used in this example is described in the reaction scheme E.

Reaction Scheme E Step 1. 2-bromo-5-isopropyl-f-enol A solution of 3-isopropyl-phenol is cooled to -20 ° C. (4.975 g, 36.5 mmol) in 37 ml of CC14. Bromine dissolves (1.9 ml, 38.4 mmoles) in 5.0 ml of CC14 and added by dripping at a rate such that the internal temperature remains below -10 ° C. The mixture is allowed to warm to T.A. After 12 hours the mixture is collected in 100 ml of CH2C12, washed with H20 and then with brine. The organic phases are combined, dried over Na 2 SO 4, filtered and concentrated in vacuo to obtain 8,663 g of a 1: 1 mixture of 2-bromo-5-isopropyl-phenol and 4-bromo-5-isopropyl-phenol in the form of dark oil. These two isomers are inseparable and are used together in the next step 2. Step 2. l-Bromo-4-isopropyl-2-methoxy-benzene To a mixture of 2-bromo-5-isopropyl-phenol and 4-bromo-5 -isopropyl-phenol from step 1 (8.663 g, 40.3 mmol) and K2C03 (16.710 g, 120.9 mmol) in 50 ml of DMF was added iodo-methane (3.0 ml, 48.3 mmol) with mechanical stirring. The mixture is heated at 50 ° C for 4 hours. After cooling to T.A. 300 ml of H20 are added and the solution is extracted with diethyl ether (Et20), washed with H20 and washed with brine. The organic phases were combined, dried over MgSO4, filtered and concentrated in vacuo to give l-bromo-4-isopropyl-2-methoxy-benzene and l-bromo-2-isopropyl-4-methoxy-benzene ( 6.621 g, 72%) as an inseparable 1: 1 mixture in the form of a pale yellow oil. This mixture of regioisomers is used directly in the next step 3. Step 3. 5-bromo-2-isopropyl-4-methoxy-benzaldehyde To a solution of l-bromo-4-isopropyl-2-methoxy-benzene and l-bromine -2-isopropyl-4-methoxy-benzene from step 2 (6.621 g, 28.9 mmol) in 100 ml of 1,2-dichloroethane is added TiCl4 (6.3 ml, 57.8 mmol) at 0 ° C. After 10 minutes, dichloromethoxymethane (Cl 2 CHOMe) (2.6 ml, 28.9 mmol) was added and the mixture was heated to reflux. After 3 hours the mixture is cooled, poured on ice and acidified with 50 ml of 2M HCl. The resulting suspension is extracted with CH2C12 and washed with brine. The organic phases are combined, dried with MgSO, filtered and concentrated in vacuo to obtain a dark green oil. Purification by flash chromatography (96: 4 mixture of hexane / ethyl acetate) gives 5-bromo-2-iso-ro-pyl-4-methoxy-benzaldehyde and 5-bromo-4-isopropyl-2-methoxy-benzaldehyde ( 2.876 g, 39%, 6.621 g, 72%) as a 1: 1 mixture of inseparable isomers in the form of an orange oil, which is used directly in stage 4. Step 4. 5-bromo-2-isopropyl-4- methoxy-phenol To a solution of 5-bromo-2-isopropyl-4-methoxy-benzaldehyde and 5-bromo-4-isopropyl-2-methoxy-benzaldehyde from step 3 (2.87 g, 11.2 mmol) in 25 ml of CH2C12 mCPBA acid (2.31 g, 13.4 mmol) is added. After 16 hours the mixture is taken up in 150 ml of CH2C12 and washed with a saturated solution of NaHCO3 and then with brine. The organic phases are combined, dried over Na 2 SO 4, filtered and concentrated in vacuo to obtain an oil which is taken up in 50 ml of MeOH and 30 ml of 4M NaOH. After 2 hours the mixture is concentrated by evaporation, diluted with water and acidified to pH = 1 with concentrated HCl. The mixture is extracted with ethyl acetate (3 X 100 ml) and washed with 100 ml of brine. The organic phases are combined, dried over Na 2 SO 4, filtered and concentrated to obtain a mixture of 5-bromo-2-isopropyl-4-methoxy-phenol and 2-bromo-5-isopropyl-4-methoxy-phenol in the form of orange residue. These regio-isomers are separated by flash chromatography (gradient: hexane, hexane / CH2Cl2 = 7: 3, = 1: 1), obtaining 5-bromo-2-isopropyl-4-methoxy-phenol (0.929, 34%) in yellow oil form used in the next step and 2-bromo-5-isopropyl-4-methoxy-phenol (0.404 g, 15%) as a yellow solid. Step 5. (5-Bromo-2-isopropyl-4-methoxy-phenoxy) -acetonitrile To a mixture of 5-bromo-2-isopropyl-4-methoxy-phenol from step 4 (0.831 g, 3.4 mmol) and K2C03 (0.562 g, 4.1 mmol) in 17 ml of dimethylformamide (DMF) was added iodoacetonitrile (0.594 g, 3.6 mmol). The mixture is heated at 60 ° C for 30 minutes and then allowed to cool to T.A. After cooling to T.A. the mixture is taken up in 50 ml of H20 and extracted with a 1: 1 mixture of toluene / ethyl acetate, it is washed with H20 and then with brine. The organic phases are combined, dried over Na 2 SO 4, filtered and concentrated in vacuo to obtain a crude solid. Purification by flash chromatography (1: 1 mixture of hexane / CH2Cl2) gives (5-bromo-2-isopropyl-4-methoxy-phenoxy) -acetonitrile (0.611 g, 63%) as a white solid. Step 6. 2- (5-Bromo-2-isopropyl-4-methoxy-phenoxy) -3-methoxy-acrylonitrile The sodium hydride (0.122 g, 5.0 mmol, 60% w / w) is washed with dry hexanes and concentrated in a stream of nitrogen. 10 ml of THF are added and the mixture is cooled to 0 ° C.

Add (5-bromo-2-isopropyl-4-methoxy-phenoxy) -acetonitrile (0.577 g, 2.03 mmol) in portions. After 30 min, ethyl formate (4.9 ml, 60.9 mmol) is added and the solution is heated to 80 ° C. After 4.5 hours the mixture is cooled and 5.0 ml of iodomethane are added in one portion. After 16 hours the reaction is quenched with H20, concentrated in vacuo, extracted with ethyl acetate, washed with H20 and then washed with brine. The organic phases are combined, dried over Na 2 SO, filtered and concentrated in vacuo. Purification by flash chromatography (9: 1 mixture of hexane / ethyl acetate) gives the 2- (5-bromo-2-isopropyl-4-methoxy-phenoxy) -3-methoxy-acrylonitrile (0.319 g, 48%) in white solid form. Step 7. 5- (5-Bromo-2-lsopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine To a solution of 2- (5-bromo-2-isopropyl-4-methoxy-phenoxy) - 3-methoxy-acrylonitrile (0.282 g, 0.9 mmol) and guanidine carbonate (0.078 g, 0.4 mmol) in 10.0 ml of dimethyl sulfoxide (DMSO) is added with sodium methoxide (1.0 ml, 1.0M in MeOH). The mixture is heated to 120 ° C. The methanol is collected with a short path condenser. After 3 h the mixture is cooled and concentrated in vacuo to obtain a crude oil. Purification by flash chromatography (95: 5 mixture of CH2Cl2 / MeOH) gives compound 17 (0.246 g, 77%) as a pink solid; mass spectrum M + H = 352. The above procedure can be used with several different phenols in step 1 and / or guanidines substituted in step 7 under essentially identical reaction conditions to obtain additional compounds. Table 1 shows the additional compounds obtained according to the procedure described in Example 2. Example 3: N * 4 * -ethyl-5- (2-isopropyl-, 5-dimethoxy-benzyl) -pyrimidine-2, 4 -diamine The synthesis procedure used in this example is described in scheme F.

Reaction scheme F Stage 1. (l-isopropyl-2-methyl-propyl) - (2,4-, 5-trimethoxy-benzylidene) -amine To a solution of 2,4-trimethoxybenzaldehyde (20.10 g, 102.4 mmol) in 200 ml of toluene is added 2,4-dimethylpentyl-3-amine and p-toluenesulfonic acid (0.1 g). The mixture is heated to reflux. The generated H20 is removed with a Dean-Stark trap. After 3 h the solution is cooled, washed with 50 ml of a saturated solution of NaHCO 3, dried with Na 2 SO 4 and filtered. The solution is concentrated in vacuo to obtain a yellow syrup. Purification by means of a ball tube distillation (80 ° C, 200 Torr) provides (l-isopropyl-2-methyl-propyl) - (2,4,5-trimethoxy-benzylidene) -amine (28.70 g, 96% ) in the form of a pale yellow solid. Step 2. (2-isopropyl-4,5-dimethoxy-benzylidene) - (1-isopropyl-2-methyl-propyl) -amine To a solution of (l-isopropyl-2-methyl-propyl) - (2, 4 , 5-trimethoxy-benzylidene) -amine (1024 g, 3.5 mmol) in 35 ml of THF was added dropwise at -78 ° C for 5 minutes the isopropyl-lithium (6.0 ml, 0.7 M in pentane). The solution is maintained under stirring at -78 ° C for 30 min. After hea to T.A. for 45 minutes the reaction is stopped by the addition of 5 ml of NH 4 Cl 1 of 10% and concentrated in vacuo. 100 ml of H20 are added and the mixture is extracted with ethyl acetate, washed with H20 and then with brine. The organic phases are combined, dried over Na 2 SO 4, filtered and concentrated in vacuo to give (2-isopropyl-4,5-dimethoxy-benzylidene) - (1-isopropyl-2-methyl-propyl) -amine in the form of yellow oil. Step 3. 2-Isopropyl-4,5-dimethoxy-benzaldehyde The (2-isopropyl-4,5-dimethoxy-benzylidene) - (1-isopropyl-2-methyl-propyl) -amine is dissolved in 30 ml of THF. HCl is added (4.1 ml, 4 M) and the mixture is heated to reflux. After 3 hours the mixture is cooled and concentrated in vacuo. They are added 100 ml of H20 and the mixture is extracted with ethyl acetate, washed with H20 and then with brine. The organic phases are combined, dried over Na 2 SO, they are filtered and concentrated in vacuo, obtaining an orange oil. Purification by flash chromatography (85:15 mixture of hexane / ethyl acetate) gives 2-isopropyl-4,5-dimethoxybenzaldehyde (0.331g, 43%) as a clear oil. Step 4. (4-Chloro-2-methylsulfanyl-pyrimidin-5-yl) - (2-isopropyl-4,5-dimethoxy-phenyl) -methanol The 4-chloro-5-iodo-2-methylsulfanyl-pyrimidine used in this step is obtained according to the procedure described by Sakamoto et al., Chem. Pharm. Bull., 34: 2719 (1986). To a solution of 4-chloro-5-iodo-2-methylsulfanylpyrimidine (1.10 g, 3.9 mmoles). ) in 20 ml of THF is added isopropyl-magnesium bromide (2.3 ml, 2 M in THF) at -40 ° C for 5 minutes, after 30 minutes the 2-isopropyl-4,5-dimethoxy is added. benzaldehyde from step 3 (1.04 g, 4.6 mmol) and the solution is warmed to RT. The reaction is quenched by the addition of brine and extracted with CH2C12. The organic phases are combined, dried over Na2SO, filtered and concentrated with vacuum Purification by flash chromatography (ethyl acetate) gives (4-chloro-2-methylsulfanyl-pyrimidin-5-yl) - (2-isopropyl-4,5-dimethoxy-phenyl) -methanol (1168 g, 82%) in the form of solid slightly loves Step 5. 4-Chloro-5- (2-isopropyl-4,5-dimethoxy-benzyl) -2-methylsulfanyl-pyrimidine To a solution of (4-chloro-2-methylsulfanyl-pyrimidin-5-yl) - (2-isopropyl-4,5-dimethoxy-phenyl) -methanol (6.5 g, 17.6 mmol) in 200 ml of CH 2 C 12 is added triethylsilane (28.0 ml, 176 mmol) and TFA acid (70 ml, 881 mmol). After 2 hours the solution is concentrated in vacuo, 10% 2C03 is added and extracted with CH2C12. The organic phases are combined, washed with brine, dried over Na 2 SO 4, filtered and concentrated in vacuo. Purification by flash chromatography (4: 1 mixture of hexanes / ethyl acetate) gives 4-chloro-5- (2-isopropyl-4,5-dimethoxy-benzyl) -2-methylsulfanyl-pyrimidine (5.60 g, 91% ) in the form of transparent oil. Step 6. Ethyl- [5- (2-isopropyl-4,5-dimethoxy-benzyl) -2-methylsulfanyl-pyrimidin-4-yl] -amine In a pressure-resistant glass flask, containing 4-chloro- 5- (2-isopropyl-4,5-dimethoxy-benzyl) -2-methylsulfanyl-pyrimidine (0.212 g, 0.6 mmol), 5.0 ml of ethyl amine are introduced via a cold finger condenser. The flask is closed with a stopper and heated to 50 ° C. After 16 hours the solution is cooled to T.A., concentrated and taken up in H20. The mixture is extracted with ethyl acetate, washed with H20 and then washed with brine. HE. The organic phases are combined, dried over Na 2 SO 4, filtered and concentrated in vacuo. Purification by flash chromatography (4: 1 mixture of hexane / ethyl acetate) gives ethyl- [5- (2-isopropyl-4,5-dimethoxy-benzyl) -2-methylsulfanylpyridin-4-yl] -amine (0.136 g, 63%) as a white solid. Step 7. Ethyl- [5- (2-isopropyl-4,5-dimethoxybenzyl) -2-methanesulfonyl-pyrimidin-4-yl] -amine To a solution of ethyl- [5- (2-isopropyl-4, 5- dimethoxy-benzyl) -2-methylsulfanyl-pyrimidin-4-yl] -amine (0.129 g, 0.4 mmol) in 20 ml of a 1: 1 mixture of H20 / THF was added OXONE® (0.461 g, 0.8 mmol) in 4.0 ml of H20. After 2 hours 50 ml of H20 are added and the mixture is extracted with ethyl acetate, washed with H20 and washed with brine. The organic phases are combined, dried over Na 2 SO 4, filtered and concentrated in vacuo to give ethyl- [5- (2-isopropyl-4,5-dimethoxy-benzyl) -2-methanesulfonyl-pyrimidin-4-yl] -amine (0.131 g, 92%) as a white foam. Step 8. N * 4 * -ethyl-5- (2-isopropyl-4,5-dimethoxy-benzyl) -pyrimidine-2,4-diamine To ethyl- [5- (2-isopropyl-4,5-dimethoxy -benzyl) -2-methanesulfonyl-pyrimidin-4-yl] -amine (0.078 g, 0.2 mmol) in a vial for microwave reactor is added 2.0 ml of dimethoxy-ethane and 0.5 ml of concentrated NH0H. The vial is closed and placed in the microwave reactor. The internal temperature rises to 145 ° C. After 2 hours an additional 0.4 ml portion of concentrated NH0H is added and the mixture is heated for a further 2 hours. The mixture is cooled and concentrated in vacuo. Purification by flash chromatography (96: 4 mixture of CH2Cl2 / MeOH) gives N * 4 * -ethyl-5- (2-isopropyl-4), 5-dimethoxy-benzyl) -pyrimidine-2, 4-diamine (0.031 g, 47%) as a pale yellow solid; mass spectrum M + H = 329. The use of different alkyl lithium reagents in step 1 and / or different amines substituted in steps 6 and 8 of the above procedure provides additional compounds under identical or very similar reaction conditions. Table 1 lists additional compounds, obtained by the procedure described in example 3. Example 4: 2- [4-amino-5- (5-chloro-2-isopropyl-4-methoxy-phenoxy) -pyrimidin-2 -amino] - (R) -propan-1-ol The synthesis procedure used in this example is described in the reaction scheme G ..

Ethyl Reaction Scheme 6 Step 1. 2-Chloro-5-isopropyl-phenol A solution of 3-isopropyl-phenol (10.0 g, 73.4 mmol) in 350 ml of a 9: 1 mixture of benzene is cooled to 0 ° C. CHCl3. Tertbutyl hypochlorite (8.77 g, 80.8 mmol) was added dropwise over 5 minutes and the mixture was allowed to warm to T.A. After 16 h, the mixture is concentrated in vacuo to obtain a crude oil. Purification by flash chromatography provides 2-chloro-5-isopropyl-phenol and 4-chloro-3-isopropyl-phenol (6,540 g, 52%) as inseparable 7: 3 mixture of isomers in the form of a pale yellow oil. The combined regioisomers are used together in the next step. Step 2. l-Chloro-4-isopropyl-2-methoxy-benzene To a solution of 2-chloro-5-isopropyl-phenol and 4-chloro-3-isopropyl-phenol from step 1 (8.694 g, 47.1 mmol) in 50 ml of DME, K2C03 is added. The iodomethane (3.5 ml, 56.5 mmol) is added and the mixture is heated to 50 ° C. After 4 hours H20 is added. The mixture is extracted with ethyl acetate, washed with H20 and washed with brine. The organic phases were combined, dried over Na 2 SO, filtered and concentrated in vacuo to obtain l-chloro-4-isopropyl-2-methoxybenzene and l-chloro-2-isopropyl-4-methoxy-benzene (9,289 g. ) as an inseparable 7: 3 mixture in the form of pale yellow oil, which is used directly in the next step. Step 3. 5-chloro-2-isopropyl-4-methoxy-benzaldehyde. By applying the procedure of step 3 of example 2, the l-chloro-4-isopropyl-2-methoxy-benzene and the 1-chloro-2 are treated. -isopropyl-4-methoxy-benzene (3.715 g, 20.1 mmol) combined with TiCl and then with Cl2CHOMe, obtaining one. mixture of 5-chloro-2-isopropyl-4-methoxy-benzaldehyde and 5-chloro-4-isopropyl-2-methoxy-benzaldehyde as a yellow oil. Regioisomers were separated by flash chromatography (gradient: hexane, 7: 3 mixture and then 1: 1 hexane / CH2C12), yielding 5-chloro-2-isopropyl-4-methoxy-benzaldehyde (1269 g, 30%). in the form of a pale yellow solid. Step 4. 5-Chloro-2-isopropyl-4-methoxy-phenol Applying the procedure of step 4 of Example 2 described above, 5-chloro-2-isopropyl-4-methoxy-benzaldehyde (3.203 g, 15.1 mmoles) yields 5-chloro-2-isopropyl-4-methoxy-phenol (1768 g, 58%) as a clear oil. Step 5. (5-Chloro-2-isopropyl-4-methoxy-phenoxy) -acetonitrile To a solution of 5-chloro-2-isopropyl-4-methoxy-phenol (10.36 g, 51.6 mmol) in 40 ml of DMF was adds K2C03 (8.55 g, 62.0 mmol) and the mixture is heated to 65 ° C. After 15 minutes the iodoacetonitrile (9.05 g, 54.2 mmol) is added and the mixture is heated at 80 ° C for 1 hour. The mixture is cooled, poured onto an ice / H20 mixture and extracted with a 1: 1 mixture of toluene / hexane. The organic phases are combined, washed with brine, dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude product is purified by filtering through a small silica gel cartridge, thereby obtaining (5-chloro-2-isopropyl-4-methoxy-phenoxy) -acetonitrile (11.97 g, 97%) in the form of white solid. Step 6. 2- (5-Chloro-2-isopropyl-4-methoxy-phenoxy) -3-methoxy-acrylonitrile To a solution of (5-chloro-2-isopropyl-4-methoxy-phenoxy) -acetonitrile (1.44 g , 6.0 mmoles) and ethyl formate (2.2 g, 29. 2 mmole) in 7 ml of 1,2-dimethoxy-ethane is added at 5 ° C. 95% NaH (0.15 g, 6.0 mmol) in one portion. The mixture is heated to T.A. After 95 minutes, 95% NaH is addedVE. (0.15 g, mmoles) in one serving. After 1 hour, add 10 ml of iodomethane and keep the mixture under stirring for 16 hours. The mixture is concentrated in vacuo, added HCl IN and the mixture extracted with ethyl acetate. The organic phases are combined, washed with brine, dried with Na2SO, filter and concentrate with vacuum. Purification by flash chromatography (85/15 mixture of hexane / ethyl acetate) affords 2- (5-chloro-2-isopropyl-4-methoxy-phenoxy) -3-methoxy-acrylonitrile (1.41 g, 84%) in white solid form. Step 7. 2- [4-amino-5- (5-chloro-2-isopropyl-4-methoxy-phenoxy) -pyrimidin-2-ylamino] - (R) -propan-1-ol To a solution of 2- (5-chloro-2-isopropyl-4-methoxyphenoxy) -3-methoxy-acrylonitrile (0.20 g, 0.7 mmol) in 1 ml of DMSO is added with N- (2- (R) -hydroxy-1-methyl- ethyl) -guanidine from obtaining 1 (0.10 g, 0.8 mmol). The solution is heated to 120 ° C. After 45 minutes, the solution is cooled, taken up in H20 and extracted with ethyl acetate. The organic phases are combined, washed with H20, dried over NaSO4, filtered and concentrated in vacuo. Purification by flash chromatography (95: 5 mixture of CH2Cl2 / MeOH) affords 2- [4-amino-5- (5-chloro-2-isopropyl-4-methoxyphenoxy) -pyrimidin-2-ylamino] - (R) -propan-1-ol (0.128 g, 50%) as a solid; mass spectrum M + H = 366. Example 5: 2- [4-amino-5- (5-chloro-2-ethyl-4-methoxy-phenoxy) -pyrimidin-2-ylamino] -butan-1-ol To a solution of N- (2- (R) -hydroxy-1-methyl-ethyl) -guani-dine of the preparation 1 (0.15 g, 1.1 mmol) in 1 ml of dry DMSO is added the 2- (5 -chloro-2-isopropyl-7-methoxy-phenoxy) -3-methoxy-acrylonitrile (0.23 g, 0.9 mmol) from step 6 of Example 4. The mixture is heated at 120 ° C for 3.0 hours. The reaction mixture was cooled, 20 ml of water were added and it was extracted with EtOAc (2 X 50 ml). The organic solutions are then combined, washed with water (3 X 50 ml) and then with brine. The solution is dried with MgSO, filtered and concentrated. The compound is purified by column chromatography through silica gel using 2% MeOH in dichloromethane as eluent. The fractions containing product are combined and concentrated under reduced pressure, obtaining the crude product. This product is suspended in 2 ml of ether and 0.6 ml of 1M HCl in ether (1.5 eq.) Is added. After 30 minutes the solid was filtered and washed with ether, obtaining 160 mg of 2- [4-amino-5- (5-chloro-2-isopropyl-4-methoxy-phenoxy) -pyrimidin-2-ylamino] - ( R) -propan-1-ol in the form of a hydrochloride salt: mass spectrum M + H = '367; from p.f. 111.4-116.9 ° C. The above procedure is applied to several different phenols and amino guanidines under essentially identical reaction conditions to obtain additional compounds, which are listed in Table 1. Example 6: N * 2 * - (1, l-dioxo-hexahydro-llambda) * 6 * -thiopyran-4-yl) -5- (2-isopropyl-4,5-dimethoxy-phenoxy) -pyrimidine-2,4-diamine - (2-isopropyl-4,5-dimethoxy-phenoxy) -N * 2 * - (tetrahydro-thiopyran-4-yl) -pyrimidine-2,4-diamine is obtained according to the procedure of Example 5, using 2- (2-isopropyl-4,5-dimethoxy-phenoxy) -3-methoxy-acrylonitrile (obtained by the procedure of Example 4) together with "N- (tetrahydro-thiopyran-4-yl) -guanidine of the Obtaining 1. To a mixture of 5- (2-isopropyl-4,5-dimethoxy-phenoxy) -N * 2 * - (tetrahydro-thiopyran-4-yl) -pyrimidine-2,4-diamine (0.19 g, 0.46 g) mmoles) in 25 ml of methanol and 25 ml of water is added OXONE (1.73 g, 1.4 mmol) .This mixture is stirred at RT overnight The reaction mixture is diluted with water (50 ml) and extracted with EtOAc (3 X 50 ml) The organic solution is washed with brine and dried with MgSO 4 The solution is filtered and concentrated The residue is purified on a preparative TLC plate (20 x 40 cm) eluting with EtOAc. stir the product recovered with 1.5 eq of 1M HCl in ether, obtaining 25 mg of the N * 2 * - (1, 1-dioxo) -hexahydro-llambda * 6 * -thiopyran-4-yl) -5- (2-isopropyl-4,5-dimethoxy-phenoxy) -pyrimidine-2,4-diamine (HCl salt); MS (M + H) = 441; of pf. 255.1 - 257.8 ° C. Example 7: 2- [4-amino-5- (5-chloro-2-isopropyl-4-methoxy-phenoxy) -pyrimidin-2-ylamino] -propyl methyl-carbamic acid It is added to T.A. 1,1-carbonyldiimidazole (0.97 g, mmole) to a solution of 2- [4-amino-5- (5-chloro-2-isopropyl-4-methoxy-phenoxy) -pyrimidin-2-ylamino] - (R ) -propan-1-ol of example 4 (0.22 g, mmoles) in 20 ml of THF. The mixture is stirred for 2 hours and methylamine (3 ml, 2M / THF, 0.6 mmol) is added. The reaction mixture was stirred overnight and concentrated under reduced pressure, diluted with water (75 ml) and extracted with EtOAc (2 X 75 ml). The organic phase is washed with brine and dried with MgSO4. The solution is filtered and concentrated. The residue is purified on two preparative TLC silica gel plates (20 X 40 cm) eluting with 5% MeOH in dichloromethane, thereby obtaining 143 mg of 2- [4-amino-5- methyl-carbamate. (5-chloro-2-isopropyl-4-methoxy-phenoxy) -pyrimidin-2-ylamino] -propyl; MS (M + H) = 424; p.f. = 63.5 - 69.4 ° C. Example 8: 5- (4,5-dimethoxy-2-methyl-benzyl) -pyrimidine-2,4-diamine The synthesis procedure used in this example is described in the reaction scheme H.

Reaction Scheme H In this example the procedure described by Manchand et al., J. Org. Chem. 57: 3531-3535 (1992).

Briefly, in step 1, 4,5-dimethoxy-2-methylbenzaldehyde and sodium methoxide in cold methanol are dissolved and stirred under a nitrogen atmosphere at T.A. for 18 hours. The mixture is cooled to -15 ° C and 3- (4,5-dimethoxy-2-methyl-phenyl) -2-methoxymethyl-acrylonitrile is collected as filtrate. In step 2, 3- (4,5-dimethoxy-2-methyl-phenyl) -2-methoxymethyl-acrylonitrile and sodium methoxide are dissolved in dry DMSO and stirred for 3.5 hours at 85 ° C under a nitrogen atmosphere. Then guanidine carbonate is added to the stirring solution, after which the temperature is raised to 125 ° C for three hours, in this period the methanol is removed by a Dean-Stark trap. The solution is cooled to RT, diluted with water and the crude filtrate is recrystallized from DMF, yielding 5- (4,5-dimethoxy-2-methyl-benzyl) -pyrimidine-2,4-diamine in the form of solid white, from pf 232 ° C. Mass spectrum (M + H): 275. Table 1 lists additional compounds obtained by the procedure of example 8. Example 9: 5- (6-isopropyl-1,3-dimethyl-lH-indol-5-yloxy) ) -pyrimidine-2,4-diamine The synthesis procedure used in this example is described in reaction scheme I.

Reaction Scheme I The 5-benzyloxy-6-isopropyl-lH-indole used in step 1 of this example is obtained from l-. { 2 - [(5-benzyloxy) -4- (1-methylethyl) -2-nitrophenylhenyltenyl} -pyrrolidine according to the procedure described by Leonardi et al., Eur. J. Med. Chem. 29: 551-559 (1994). The methylation of the next step 3 is also carried out according to the procedure described by Leonardi et al. Step 1. 5-Benzyloxy-6-isopropyl-3-methyl-1H-indole The methylation carried out in this step is carried out according to the indole-alkylation process described by Marino et al., J. Am. Chem. Soc. 114: 5566-5572 (1992). The 5-benzyloxy-6-isopropyl-1H-indole (0.855 g, 3.22 mmol) is dissolved in 20 ml of dry THF and the resulting solution is cooled in an ice bath. Ethylmagnesium bromide (4.9 ml, 4.9 molar in ether) is added dropwise to the solution and then the solution is stirred for 4 hours at T.A. Then methyl iodide (1.42 g, 10 mmol) is added and stirring is continued for an additional 18 hours at T.A. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic phases are combined, washed with a saturated solution of ammonium chloride, dried (MgSO 4) and concentrated in vacuo. The resulting residue was purified by flash chromatography (ethyl acetate / hexanes = 1/9) to obtain 325 mg of 5-benzyloxy-6-isopropyl-3-methyl-1H-indole, mass spectrum (M + H): 280 Step 2. 5-Benzyloxy-6-isopropyl-1,3-dimethyl-1H-indole. 5-Benzyloxy-6-isopropyl-3-methyl-1H-indole is added. (0.320 g, 1.15 mmol), KOH (0.264 g, 4.7 mmol), benzyl tributylammonium chloride (0.071 g, 0.230 mmol) and methyl iodide (0.107 mL, 1.72 mmol) to 3 mL of toluene. The resulting mixture is stirred for 4 hours at 90 ° C, cooled to T.A., poured into water and extracted with ethyl acetate twice. The organic phases are combined, washed with water, dried (MgSO 4) and concentrated in vacuo to obtain a crude oil which is purified by flash chromatography (ethyl acetate / hexanes = 1/9).; yield: 270 mg of 5-benzyloxy-6-isopropyl-1,3-dimethyl-1H-indole.

Step 3. 6-Isopropyl-1,3-dimethyl-1H-indol-5-ol. 5-Benzyloxy-6-isopropyl-1,3-dimethyl-1H-indole (0.270 g, 1.30 mmol) and Pd were added. 10% on C (0.150 g) to 10 ml of methanol and the mixture is hydrogenated in a Paar apparatus for 1.5 hours with a hydrogen pressure of 55 psi, at RT The catalyst is removed by filtration and the solvent is removed in vacuo. The residue was purified by flash chromatography (5% ethyl acetate in hexanes) to obtain 210 mg of 6-isopropyl-1,3-dimethyl-1H-indol-5-ol. Step 4. (6-isopropyl-l, 3-dimethyl-lH-indol-5-yloxy) -acetonitrile Applying the procedure of step 5 of. In Example 2, (6-isopropyl-1,3-dimethyl-lH-indol-5-yloxy) -acetonitrile is obtained starting from 6-isopropyl-l, 3-dimethyl-lH-indol-5-ol by treatment with iodine acetonitrile. Step 5. 2- (6-isopropyl-1,3-dimethyl-lH-indol-5-ylpxi) -4-methoxy-but-2-enonitrile The 2- (6-isopropyl-1,3-dimethyl- lH-indol-5-yloxy) -4-methoxy-but-2-enonitrile from (6-isopropyl-1,3-dimethyl-lH-indole-5-yloxyHac- toonitrile by treatment with sodium hydride and methyl iodide applying the procedure of step 6 of the previous example 2. Step 6. 5- (6-isopropyl-1,3-dimethyl-lH-indol-5-yloxy) -pyrimidine-2,4-diamine The 5- (6- isopropyl-l, 3-dimethyl-lH-indol-5-yloxy) -pyrimidine-2,4-diamine from 2- (6-isopropyl-1,3-dimethyl-lH-indol-5-yloxy) -4 -methoxy-but-2-enonitrile by treatment with guanidine carbonate and sodium methoxide applying the procedure of step 7 of the previous example 2. This material is dissolved in 2.5 ml of absolute ethanol and 820 ml of 1 N HCl are added with stirring. in diethyl ether Diethyl ether is added slowly until small crystals form and then the solution is placed in a congel at -10 ° C for 18 hours. The solid that formed was collected by filtration, washed with diethyl ether and dried under vacuum at 45 ° C, obtaining 171 mg of the hydrochloride salt, of m.p. 185.1 ° C. 5- (d-isopropyl-l-methyl-lH-indol-S-yloxy) -pyrimidine-2,4-diamine is also obtained by applying the above procedure, but omitting 3-methylation from step 1. EM (M) + H): 298. Example 10: 5- (2-isopropyl-4-methoxy-5-methyl-phenoxy) -N * 4 * -phenyl-pyrimidine-2,4-diamine The synthesis procedure used in this example is described in the reaction scheme J.

Reaction Scheme J Stage 1. (Ethyl 2-isopropyl-4-methoxy-5-methyl-phenoxy) -acetate To a solution of 2-isopropyl-4-methoxy-5-methyl-phenol (3.933 g, 21.8 mmol) in acetone (100 ml) is added potassium carbonate (20 g, 145 mmol) and ethyl bromoacetate (5 ml, 45.1 mmol). The mixture is refluxed overnight and filtered through Celite. The filtrate is concentrated under reduced pressure and the residue is partitioned between ethyl acetate and water. The organic phase is washed with brine and dried with anhydrous sodium sulfate. After removing the dehydrating agent, the organic solution is concentrated under reduced pressure. The residue is purified by chromatography on silica gel (10% to 15% methylene chloride in hexane) to obtain ethyl (2-isopropyl-4-methoxy-5-methyl-phenoxy) -acetate in the form of solid white (4.78 g, 82%). Step 2. 2- (2-isopropyl-4-methoxy-5-methyl-phenoxy) -3-methoxy-acrylate acid ethyl ester To a solution of (2-isopropyl-4-methoxy-5-methyl) ethyl ester -phenoxy) -acetate (4.42 g, 16.6 mmol) in anhydrous 1,2-dimethoxyethane (60 ml) is added to TA sodium hydride (60% in mineral oil, 3.5 g, 87.5 mol). After stirring for 5 minutes, ethyl formate (40 ml, 495 mmoles) is added. The mixture is heated at 85 ° C for 7 hours. After cooling to T.A. the iodomethane is added and stirring is continued overnight. The solvent is evaporated under reduced pressure and the residue is partitioned between ethyl acetate and water. The organic phase is washed with brine and dried with anhydrous sodium sulfate. After removing the dehydrating agent, the organic solution is concentrated under reduced pressure. The residue is purified by chromatography on silica gel (10% to 30% ethyl acetate in hexane) to obtain 2- (2-isopropyl-4-methoxy-5-methyl-phenoxy) -3-methoxy- Ethyl acrylate in the form of pale yellow oil (1.19 g, 23%). Step 3. 2-amino-5- (2-isopropyl-4-methoxy-5-methyl-phenoxy) -3H-pyrimidin-4-one To a solution of NaOM'e [obtained from sodium (0.05 g, 2.17 mmoles) in anhydrous methanol (5 ml)] is added guanidine carbonate. After 5 minutes a solution of ethyl 2- (2-isopropyl-4-methoxy-5-methyl-phenoxy) -3-methoxy-acrylate (0.22 g, 0.713 mmol) in anhydrous DMSO (10 mL) is added. The mixture is heated at 120 ° C for 3 hours and cooled and partitioned between ethyl acetate and water. The organic phase is washed with brine and dried with anhydrous sodium sulfate. After removing the dehydrating agent, the organic solution is concentrated under reduced pressure. The residue is purified by chromatography on silica gel (5% methanol in methylene chloride / 0.1% concentrated NH40H), yielding 2-amino-5- (2-isopropyl-4-methoxy-5-methyl). phenoxy) -3H-pyrimidin-4-one as a pale yellow solid (0.045 g, 22%). MS M + H = 290. Step 4. 4-Chloro-5- (2-isopropyl-4-methoxy-5-methyl-phenoxy) -pyrimidin-2-ylamine A mixture of 2 is heated at 110 ° C for 40 minutes. -amino-5- (2-isopropyl-4-methoxy-5-methyl-phenoxy) -3H-pyrimidin-4-one and phosphorus oxychloride (5 ml) and stirred at RT during one night. The solvent is removed under reduced pressure and ice-water is added. The aqueous solution is basified with potassium carbonate to pH 9 and extracted with methylene chloride. The organic phase is washed with brine and dried with anhydrous sodium sulfate. After removing the dehydrating agent, the organic solution is concentrated under reduced pressure, obtaining 4-chloro-5- (2-isopropyl-4-methoxy-5-methyl-phenoxy) -pyridin-2-ylamine in the form of yellow solid (0.043 g, 88%). MS M + H = 308. Step 5. 5- (2-isopropyl-4-methoxy-5-methyl-phenoxy) -N * 4 * -phenyl-pyrimidine-2,4-diamine A suspension is introduced into a sealed tube. of 4-chloro-5- (2-isopropyl-4-methoxy-5-methyl-phenoxy) -pyrimidin-2-ylamine (0.043 g, 0.14 mmol) in aniline (4 ml) and heated at 100 ° C for 1 hour. night. Methylene chloride is added and the insoluble solid is removed by filtration through Celite. The methylene chloride filtrates are combined, washed with water and dried with anhydrous sodium sulfate. After removing the drying agent, the organic phase is concentrated under reduced pressure. The residue is purified by chromatography on silica gel (2% methanol in methylene chloride), obtaining a yellow oily residue, which is then purified by preparative TLC and HPLC (5 to 100% acetonitrile in water with 0.1% TFA), yielding 5- (2-isopropyl-4-methoxy-5-methylphenoxy) -N * 4 * -phenyl-pyrimidine-2,4-diamine, M + H: 365. Example 11: 5 - (2-cyclopropyl-4,5-dimethoxy-phenoxy) -pyrimidine-2,4-diamine Stage 1. 4-cyclopropyl-1,2-dimethoxy-benzene To a solution of zirconocene chloride (1.76 g, 6.02 mmol) in dry THF (25 ml) is slowly added at -78 ° C ethyl magnesium bromide (12 ml, 1 M in THF, 12 mmol). The green solution is stirred at -78 ° C for 15 minutes and then heated at 2 ° C until the color of the reaction mixture turns red (15 minutes). A solution of 3,4-di-ethoxy-benzaldehyde (1.00 g, 6.02 mmol) in dry THF (20 ml) is added and the reaction mixture is allowed to warm to T.A. for 1.5 hours. The solvent is removed under reduced pressure and dichloromethane (20 ml) is added. The reaction mixture was cooled to 0 ° C and titanium (IV) chloride (6 ml, 1M in dichloromethane, 6 - 'mmoles) was added. The reaction mixture is allowed to warm to T.A. for 30 minutes and the reaction is quenched with a saturated solution of ammonium chloride. The mixture is filtered through Celite and partitioned between dichloromethane and water. The dichloromethane phases are combined, washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium bicarbonate and brine. The organic phase is dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel (gradient: ethyl acetate of 8% to 30% in hexane), yielding 4-cyclopropyl-1,2-dimethoxy-benzene as an oily yellow residue ( 0.2 g, 19%). Ref: Vincent Gandon et al., Eur. J. Org. Chem. 2000, 3713. RMN-H1 (CDC13) d: 0.60-0.66 (, 2H), 0.87-0.92 (m, 2H), 1.81-1.91 (m, ÍH), 3.85 (s, 3H), 3.87 (s) , 3H), 6.62-6.79 (m, 3H). Step 2. 5- (2-Cyclopropyl-4,5-dimethoxy-f-enoxy) -pyrimidine-2, 4- diamine - (2-Cyclopropyl-4,5-dimethoxy-phenoxy) -pyrimidine-2,4-diamine is obtained from 4-cyclopropyl-1,2-dime-toxy-benzene according to the procedure of step 1 and steps 3-7 of the above example 2. Example 12: 5- (5-Chloro-2-cyclopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine Stage 1. l-chloro-4-cyclopropyl-2-methoxy-benzene To a solution of 4-bromo-l-chloro-2-methoxy-benzene (1.45 g, 6.55 mmol) in dry THF (10 ml) is added to T.A. he . { 1,3-bis (diphenylphosphino) -propane} dichloroniquel (II) and cyclopropyl magnesium bromide (46 ml, 0.5 M in THF, 23 mmol). The solution is stirred at T.A. for 2 hours and then heated at 65 ° C for 48 hours. An aqueous solution of hydrochloric acid (1 N, 20 ml) is added and then the mixture is cooled to T.A. and stirred for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water. The organic phases are combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (2% ethyl acetate in hexane) to obtain 1-chloro-4-cyclopropyl-2-methoxy-benzene as a yellow oily residue (0.81 g. 67%). NMR-H1 (CDC13) d: 0.65-0.70 (m, 2H), 0.94-1.00 (m, 2H), 1.85- 1.89 (m, 1H), 3.89 (s, 3H), 6.57 (dd, 1H, J = 8.1 Hz, 2.0 Hz), 7.21 (d, 1H, J = 8.1 Hz). Step 2. 5- (5-Chloro-2-cyclopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine - (5-Chloro-2-cyclopropyl-4-methoxyphenoxy) -pyrimidine-2,4-diamine is obtained from 4-cyclopropyl, 2-dimethoxy-benzene according to the procedure of step 1 and steps 3- 7 of the previous example 2.

Example 13: 5- (2-isopropyl-5-methanesulfonyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine To a mixture of 5- (2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine (0.32 g, 1.17 mmol), obtained according to Example 2 and methanesulfonic anhydride (0.81 g, 4.67 mmol) were add trifluoromethanesulfonic acid (0.45 g, 3.00 mmol) and heat the mixture at 80 ° C for 16 h. The reaction mixture was poured into ice water, basified with a saturated solution of NaHCO 3 and extracted with dichloromethane, which was dried over Na 2 SO 4, filtered and concentrated in vacuo. The residue was purified by flash chromatography through silica gel (3% CH3OH in CH2C12 with 0.1% NH4OH), yielding 5- (2-isopropyl-5-methanesulfonyl-4-methoxy-phenoxy) -pyrimidine- 2,4-diamine as a white solid (0.248 g, 90%, 0.107 g), MS (M + H): 353. Example 14: 5- [5- (2,3-dinidro-lH-tetrazole-5 -yl) -2-isopropyl-4-methoxy-phenoxy] -pyrimidine-2,4-diamine Step 1: 5- (5-iodo-2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2, -diamine To a solution of 5- (2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine (0.40 g, 1.44 mmole) in glacial acetic acid (4 ml) is added to T.A. a solution of iodine monochloride (0.28 g, 1.76 mmol) in glacial acetic acid (4 ml). Water (6 ml) is added and the reaction mixture is stirred for 16 hours, after which another portion of iodine monochloride (0.4 g, 2.47 mmol) in glacial acetic acid (4 ml) is added. The reaction mixture is stirred at T.A. for one more hour. The acid mixture is basified with a saturated solution of NaHCO 3 and extracted with dichloromethane. The organic phase is dried with Na 2 SO 4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (5% CH3OH in CH2C12 with 0.1% NHOH), yielding 5- (5-iodo-2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine in beige solid form (0.536 g, 92%). M + H 400. Stage 2. 5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-benzonitrile A mixture of 5- (5-iodo-2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine (0.37 g, 0.925 mmol) and CuCN (0.12 g) is heated at 120 ° C for 3 hours. 1.39 mmol) in DMF (5 ml).

Water (100 ml) is added and the precipitate is collected. The residue is triturated with methanolic dichloromethane (10% CH3OH in CH2C12 with 0.1% NH0H) to release the product from its copper complex and filtered. The filtrate was concentrated and purified by flash chromatography (3% CH3OH in CH2C12 with 0.1% NH40H), yielding 5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-. methoxy-benzonitrile as a white solid (0.12 g, 44%). M + H 300. Step 3. 5- [5- (2,3-dihydro-lH-tetrazol-5-yl) -2-isopropyl-4-methoxy-phenoxy] -pyrimidine-2,4-diamine "o '" TV "PCXNH» To a hot solution of 5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-benzonitrile (0.2 g, 0.67 mmole) in xylene (15 ml ) the azidotributyl tin (1.10 g, 0.67 mmol) was added at 120 ° C and the reaction mixture was heated for two hours, another portion of azidotributyltin (1.10 g, 3.34 mmol) was added and the mixture was heated during 5 hours more The reaction mixture is cooled to 0 ° C and HCl gas is bubbled through it for five minutes.

Collect the solid formed by filtration and wash with CH2C12 (3 x 5 ml). The purification of the solid by preparative HPLC (CH3CN from 15 to 95% in water, gradient of 10 minutes) provides 5- [5- (2,3-dihydro-lH-tetrazol-5-yl) -2-isopropyl-4-methoxy-phenoxy] -pyrimidine -2,4-diamine, HCl salt, as a white solid (62 mg, 25%). M + H 343. Example 15: 5- [5- (lH-imidazol-2-11) -2-isopropyl-4-methoxy-phenoxy] -pyrimidine-2,4-diamine Step 1. 5- [5- ( 4, 5-dihydro-lH-imidazol-2-yl) -2-isopropyl-4-methoxy-phenoxy] -pyrimidine-2,4-diamine HCl gas is bubbled through a cooled (0 ° C) suspension of 5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-benzonitrile (0.138 g, 0.461 mmol) in Dry methanol (15 ml) for 10 minutes and keep cooling overnight. The solvent is evaporated under reduced pressure, obtaining a yellow solid which is dissolved again in dry methanol (10 ml). Ethylene diamine (0.034 ml, 0.509 mmol) is added and the reaction mixture is boiled under reflux for 20 hours and concentrated under reduced pressure. The residue is purified by chromatography on silica gel (gradient: methanol of 7 to 50% in methylene chloride / 0.1% concentrated NHOH), yielding 5- [5- (4,5-dihydro-1H-imidazole -2-yl) -2-isopropyl-4-methoxyphenoxy] -pyrimidine-2,4-diamine which is crystallized from methanol / ethyl acetate / ether to obtain a white solid (0.053 g, 33%). 1 H-NMR (DMSO) delta: 1.26 (d, 6H, J = 6.9 Hz), 3.33-3.48 (, 5H), 3.85 (s, 3H), 5.83 (b, 2H), 6.30 (b, 2H), 6.56 (b, ÍH), 6.97 (s, ÍH), 7.19 (s, 1H), 7.33 (s, ÍH). M + H: 343. Step 2. 5- [5- (lH-imidazol-2-yl) -2-isopropyl-4-methoxy-enoxy] -pyrimidine-2,4-diamine To a solution of 5- [5- (4,5-dihydro-lH-imidazol-2-yl) -2-isopropyl-4-methoxy-phenoxy] -pyrimidine-2,4-diamine (0.033 g, 0.096 mmol) in dry methylene chloride (25 ml) is added barium manganate (0.4 g, 1.56 mmole). The reaction mixture is refluxed overnight, after which more barium manganate (0.1 g) is added and the mixture is refluxed for a further 6 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (8% methanol / methylene chloride / 0.1% concentrated ammonium hydroxide), yielding 5- [5- (lH-imidazol-2-yl) -2-isopropyl-4-methoxy). phenoxy] -pyrimidine-2,4-diamine as a pale yellow solid (0.026 g, 41%). 1 H-NMR (DMSO) delta: 1.29 (d, 6H, J = 6.9 Hz), 3.3-3.39 (m, HH), 3.94 (s, 3H), 5.53 (b, 2H), 6.00 (b, 2H), 7.01 (b, 3H), 7.36 (b, ÍH), 7.45 (s, 1H). M + H: 341, MH: 339. Example 16: 1- [5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-phenyl] -ethanone and 1- [5- (2,4-diamino-pyrimidin-5-yloxy) -2- hydroxy-4-isopropyl-phenyl] -ethanone - (2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine in anhydrous dichloroethane (20 ml) is added to TFA (0.06 ml, 0.77 mmol), acetyl chloride (0.31 ml, 4.37 mmol) ) and aluminum trichloride (583 mg, 4.37 mmol). After stirring for 22 hours at T.A. Water (1.2 ml) is added to the reaction mixture at 0 ° C. Dry the mixture using anhydrous sodium sulfate and concentrate in vacuo. Aqueous sodium hydroxide (OAM, 10 ml) is added to the residue and the mixture is heated at 100 ° C for 1 hour. After cooling, the reaction mixture was extracted with dichloromethane. The dichloromethane phase is dried using anhydrous magnesium sulfate, concentrated and purified by column chromatography through silica gel, eluting with a 96/4 / 0.1 mixture of dichloromethane / methanol / ammonium hydroxide, thereby obtaining 1- [5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-phenyl] -ethanone (72 mg, 31%) as a white off-white solid. MS (M + H) = 317, NMR-H1 (hydrochloride salt) - (DMSO-d6) d: 1.24 (d, 6H, J = 6.9 Hz), 2.51 (s, 3H), 3.19 (m, 1H, J = 6.9 Hz), 3.93 (s, 3H), 7.13 (s, lH), 7.18 (s, ÍH), 7.29 (s, ÍH), 7.62 (s, 2H), 8.30 (s, 1H), 8.60 (s) , 1H), 12.01 (s, ÍH). 1- [5- (2,4-diaminopyrimidin-5-yloxy) -2-hydroxy-4-isopropyl-phenyl] -ethanone (43 mg, 20%) is also obtained as a pale yellow solid, MS (M + H) = 303, NMR-H1 (hydrochloride salt) - (DMSO-d6) d: 1.18 (d, 6H, J = 6.9 Hz), 2.59 (s, 3H), 3.10 (m, ÍH, J = 6.9 H), 7.00 (s, 1H), 7.26 (s, 1H), 7.54 (s, ÍH), 7.60 (s, 2H), 8.32 (s, ÍH), 8.62 (s, ÍH), 11.75 (s, 1H), 12.05 (s, ÍH). Example 17: _ 5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-benzoic acid To a suspension of 5- (2, 4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-benzonitrile (50 mg, 0.17 mmol, from Example 15) in ethanol (1 mL) is added hydroxide sodium (174 mg, 4.34 mmol, dissolved in 1 ml of water). After refluxing overnight the reaction mixture is cooled in an ice bath. Aqueous hydrochloric acid (3M) is added until the pH of the reaction mixture is 7. The white solid precipitate is collected, washed with small amounts of water and dichloromethane and dried, yielding 5- (2,4-diamino) acid. -pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-benzoic acid: (51 mg, 96%, MS (M + H) = 319), which is converted to the hydrochloride salt: NMR-H1 - (DMSO- d6) d: 1.23 (d, 6H, J = 6.9 Hz), 3.17 (m, ÍH, J = 6.9 Hz), 3.85 (s, 3H), 7.08 (s, ÍH), 7.26 (s, 2H), 7.53 (s, 2H), 8.33 (s, 1H), 8.60 (s, ÍH), 11.65 (s, ÍH). Example 18: 5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxybenzamide To a suspension of 5- (2, 4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-benzonitrile (49 mg, 0.16 mmol, from Example 15) in ethanol (1 mL) is added hydroxide sodium (64 mg, 1.60 mmol, dissolved in 1 ml of water). The reaction was heated at 110 ° C for 5 hours, cooled and washed with dichloromethane (25 ml). The dichloromethane phase is concentrated and purified with preparative TLC plates (92/8 / 0.5 dichloromethane / methanol / ammonium hydroxide mixture), obtaining 5- (2,4-diamino-pyrimidin-5-yloxy) -4 -isopropyl-2-methoxy-benzamide as a white solid (9 mg, 17%, MS (M + H) = 318), which is converted to the hydrochloride salt: RMN-H1 - (DMS0-d6) d: 1.05 (d, 6H, J = 6.9 Hz), 3.00 (m, ÍH, J = 6.9 Hz), 3.75 (s, 3H), 6.91 (s, 1H), 7.07 (s, 1H), 7.21 (s, 1H) -, 7.37 (s, 2H), 7.44 (s, ÍH), 7.47 (s, 1H), 8.15 (s, ÍH), 8.43 (s, ÍH), 11.52 (s, 1H). Example 19: [5- (2, 4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-f-enyl] -urea Step 1. 5- (5-amino-2-isopropyl-4-methoxy -phenoxy) -pyrimidine-2,4-diamine To a suspension of 5- (2-isopropyl-4-methoxy-5-nitro-phenoxy) -pyrimidine-2,4-diamine (2.1 g, 6.58 mmol) in ethanol (150 ml) in a Paar pump is added palladium 10% on charcoal (210 mg). After hydrogenation in the Paar hydrogenator overnight with a hydrogen pressure of 35 psi, the reaction mixture is filtered through Celite. The Celite pad is washed with ethanol and ethyl acetate and the filtrate is concentrated. Purification by column chromatography through silica gel (92/8 / 0.1 mixture of dichloromethane / methanol / ammonium hydroxide) provides 5- (5-amino-2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2, 4-diamine as a pale orange solid (468 mg, 25%, (M + H) + = 290), which is converted to the hydrochloride salt. NMR-H1 - (DMS0-d6) d: 0.99 (d, 6H, J = 6.9 Hz), 2.92 (m, ÍH, J = 6.9 Hz), 3.66 (s, 3H), 6.64 (s, ÍH), 6.82 (s, 1H), 7.05 (s, ÍH), 7.40 (s, 2H), 8.10 (s, 1H), 8.42 (s, ÍH). Step 2. [5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-f-enyl] -urea To a suspension of 5- (5-amino-2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine (314 mg, 1.09 mmol) in water (3 ml) is added acetic acid (0.25 ml, 4.34 mmoles). Once all solids have dissolved, sodium cyanate (71 mg, 1.09 mmol, dissolved in 1.5 ml of water) is added dropwise. After 30 minutes the reaction mixture was concentrated and purified by column chromatography through silica gel eluting with a 92/8 / 0.1 mixture of dichloromethane / methanol / ammonium hydroxide, thereby obtaining [5- (2 , 4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-phenyl] -urea as a white-colored solid (244 mg, 68%, M + H + = 333), which becomes the hydrochloride salt: NMR-H1 - (DMSO-d6) d: 1.18 (d, 6H, J = 6.9 Hz), 3.02 (m, HI, J = 6.9 Hz), 3.89 (s, 3H), 6.94 (s, ÍH), 7.00 (s, ÍH), 7.54 (s, 2H), 7.85 (s, ÍH), 8.08 (s, 1H), 8.38 (s, 1H), 8.63 (s, ÍH), 11.61 (s, ÍH) ).

Example 20: N- [5- (2, 4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-me oxy-phenyl] -acetamide To a solution of 5- (5-amino-2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine (100 mg, 0.35 mmol, from Example 17) in anhydrous dichloromethane (10 mL) was added. add anhydrous pyridine (0.03 ml, 0.38 mmol). To this reaction mixture is added at 0 ° C acetyl chloride (0.03 ml, 0.38 mmol). After shaking at T.A. for - 1 hour the reaction mixture was concentrated and purified by preparative TLC (93/7 / 0.5 mixture of dichloromethane / methanol / ammonium hydroxide), yielding a matt white solid (74 mg, mixture of bis- and tris-acetylated compounds) . To this solid is added aqueous sodium hydroxide (0.2 M, 2 ml) and the mixture is refluxed for 1 hour, cooled and washed with dichloromethane (10 ml). The dichloromethane phase is dried using anhydrous magnesium sulfate and concentrated in vacuo to obtain N- [5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-phenyl] -acetamide in the form of white solid (53 mg, 46%, M + H + = 332), which is converted to the hydrochloride salt: RMN-H1 - (DMSO-d6) d: 1.21 (d, 6H, J = 6.9 Hz), 2.08 ( s, 3H), 3.09 (m, ÍH, J = 6.9 Hz), 3.88 (s, 3H), 7.00 (s, 1H), 7.09 (s, 1H), 7.57 (s, 2H), 7.74 (s, ), 8.36 (s, 1H), 8.63 (s, 1H), 9.26 (s, 1H), 11.75 (s, 1H). Example 21: 5- (2-isopropyl-4-methoxy-5-nitro-phenoxy) -pyrimidine-2,4-diamine The synthesis procedure used in this example is described in the reaction scheme K. stage 3 Tosyl Chloride Reaction scheme K Stage 1. 2- (1-hydroxy-1-methyl-ethyl) -4-methoxy-phenol To a solution of methylmagnesium bromide (221 ml, 665 mmol) in 800 ml of THF is added at 0 ° C 1- (2-hydroxy-5-methoxy-phenyl) -ethanone (20.21 g, 302 mmol) in portions over 30 min. The mixture is allowed to warm to T.A. After 16 h the reaction is stopped by the slow addition of 10% NH4CL, carefully acidified to pH = 1 (slow addition) with concentrated HCl and extracted with Et20. The organic phases are combined, washed with H20, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 2- (1-hydroxy-1-methyl-ethyl) -4-methoxyphenol (50.57 g). g, 100%) as a brown solid. Step 2. 2-isopropyl-4-methoxy-phenol To a solution of 2- (1-hydroxy-l-methyl-ethyl) -4-methoxy-phenol (50.57 g, 278 mmol) in 550 ml of AcOH is added 10% Pd on C (in suspension form in 20 ml of H20). The ammonium formate is added in portions (87.52 g, 1388 mol). The mixture is heated at 100 ° C for 1 hour, cooled and filtered through a pad of Celite. The Celite pad is washed with ethyl acetate. The mother liquor is mixed with H20 and extracted with ethyl acetate. The organic phases are combined, washed with H20, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give 2-isopropyl-4-methoxy-phenol (44.74, 97%) as an oil. pale yellow. Step 3. 2-isopropyl-4-methoxyphenyl toluene-4-sulfonate A solution of 2-isopropyl-4-methoxy-phenol (56.91 g, 342 mmol) and triethylamine (57.3.0 ml, 411 mmol) in 750 ml of CH2C12 is cooled to 0 ° C. The p-toluenesulfonyl chloride (68.54 g, 360 mmol) in 250 ml of CH2C12 is added dropwise at a rate which maintains the internal temperature < 10 ° C. The mixture is allowed to warm to T.A. After 16 h H20 is added and the mixture is extracted with CH2C12. The organic phases are combined, washed with brine, dried over Na 2 SO 4, filtered and concentrated in vacuo to obtain a crude solid. Recrystallization from hexanes affords 2-isopropyl-4-methoxy-phenyl toluene-4-sulfonate (81.67 g, 74%) as white needles. Step 4. 2-isopropyl-4-methoxy-5-nitro-phenyl toluene-4-sulfonate ester To a solution of 2-isopropyl-4-methoxy-phenyl toluene-4-sulfonate (19.00 g, 59 mmol) ) 236 ml of fuming HN03 are added in 118 ml of AcOH for 20 min After 16 h the solution is poured onto a stirred suspension with a speed of 2 1 of ice / H20, after 15 min the precipitate is filtered, washed with H20 and dried with vacuum (50 ° C), obtaining toluene-4-sulfonate of 2-isopropyl-4-methoxy-5-nitro-phenyl (21.27 g, 98%) and toluene-4- 2-isopropyl-4-methoxy-3-nitro-phenyl sulfonate as a pale yellow solid (inseparable 7: 1 mixture). Step 5. 2-isopropyl-4-methoxy-5-nitro-phenol A solution of toluene-4-sulfonate of 2-isopropyl-4-methoxy-5-nitro-phenyl and of 2-isopropyl-2-isopropyl is heated to 100 ° C. 4-methoxy-3-nitro-phenyl (21.20 g, 58 mmol) and 175 ml of 2M KOH in 350 ml of EtOH. After 45 minutes the mixture is cooled, concentrated and taken up in 1 liter of water. The solution is acidified to pH 1 with 12 M HCl and extracted with ethyl acetate. The organic phases are combined, washed with H20, brine, dried over Na2SO, filtered and concentrated in vacuo. The crude oil was purified by flash chromatography (gradient: from a 95: 5 to 4: 1 mixture of hexane / ethyl acetate), yielding 3-amino-2-isopropyl-5-nitro-phenol (10.03 g, 81%). %) as a yellow solid and 3-amino-2-isopropyl-3-nitro-phenol (1.32 g, 11%) as a yellow oil. Step 6. (2-isopropyl-4-methoxy-5-nitro-phenoxy) -acetonitrile A mixture of 3-amino-2-isopropyl-5-nitrophenol (9.94 g, 47 mol), K2C03 ( 13.00 g, 94 mmol) and cyanomethyl benzenesulfonate (10.93 g, 52 mmol) in 500 ml of DMF. After 16 h the mixture is cooled, poured into 500 ml of H20 and extracted with toluene / ethyl acetate (1: 1) The organic phases are combined, washed with H20, washed with brine, filtered and concentrated in vacuo. The crude solid was recrystallized from EtOH to give (2-isopropyl-4-methoxy-5-nitro-phenoxy) -acetonitrile (8.95 g, 76%) as a yellow crystalline solid. Step 7. 5- (2-isopropyl-4-methoxy-5-nitro-phenoxy) -pyrimidine-2,4-diamine A mixture of (2-isopropyl-4-ethoxy-5-nitro) is heated at 100 ° C. phenoxy) -acetonitrile (8.785 g, 35.5 mmol) and Brederick's reagent (14.6 mL, 70.9 mmol). After 45 min the mixture is concentrated by evaporation under reduced pressure (50 ° C, 50 mtorr), obtaining an orange solid. The solid is added to an aniline hydrochloride solution (9.19 g, 70.9 mmol) in 150 ml EtOH. The mixture is heated to reflux. After 16 h more aniline hydrochloride (4.596 g, 35.5 mmol) is added and the mixture is refluxed for 4 h. The solution is concentrated in vacuo and poured onto H20. The mixture was extracted with ethyl acetate, washed with H20, washed with brine, dried over Na2SO4 and concentrated in vacuo to give a yellow-green solid. This crude product is added to a mixture of 200 ml of NMP and guanidine carbonate (17.70 g, 98 mmol) and heated to 130 ° C. After 5 hours the mixture is cooled, then it is poured onto 2 1 of an ice / H20 mixture. The resulting precipitate is filtered, washed with H20 and dried under vacuum (50 ° C). The crude solid was recrystallized from EtOH, yielding 5- (2-isopropyl-4-methoxy-5-nitro-phenoxy) -pyridine-2,4-diamine (8.14 g, 63%, 3 steps) in the form of yellow crystalline solid (solvated 1: 1 with EtOH). (M + H) + = 320. EXAMPLE 22: 1- [5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-phenyl] -3-ethyl-urea Step 1. 5- (5-amino-2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine To a solution of 5- (2-isopropyl-4-methoxy-5-nitro-phenoxy) -pyrimidine-2,4-diamine (2953 g, 9.2 mmol) in 250 mL of EtOH and AcOH is added Pd at 10 ° C. % over C. The mixture is introduced into a hydrogenated Paar with a pressure of 50 psi of H2. After 2.5 h, the mixture is filtered through a pad of Celite. The bed is washed with ethyl acetate and the solution is partially concentrated in vacuo. The residue is taken up in 500 ml of H20 and cooled to 0 ° C. The solution is acidified slowly to pH = 12 with 50% NaOH and extracted with ethyl acetate. The organic phases were combined, washed with "H20, washed with brine, dried over Na2SO, filtered and concentrated in vacuo to give 5- (5-amino-2-isopropyl-4-methoxy-phenoxy) - pyrimidine-2,4-diamine (2156 g, 82%) as a dark orange solid, Step 2. 1- [5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2 -methoxy-phenyl] -3-ethyl-urea A solution of 5- (5-amino-2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine is heated in a sealed tube at 100 ° C. (0.117 g, 0.4 mmol) and ethyl isocyanate (0.034 g, 0.5 mmol) in 4 ml of toluene. After 5 h the solution is cooled and concentrated in vacuo to obtain a brown solid. Purification by flash chromatography (CH2Cl2 / MeOH = 97: 3) gives 1- [5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-phenyl] -3-ethyl- urea (0.120 g, 83%) as a white solid; (M + H) = 361. Example 23: 1- [5- (2, 4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-phenyl] -3-phenyl-urea In the manner described in the above procedure, 5- (5-amino-2-isopropyl-4-methoxy-phenoxy) -pyridine-2,4-diamine (0.309 g, 1.1 mol) in the 1- [[ 5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-phenyl-l-3-phenylurea (0.122 g, 28%) as a white solid; [MH] + = 408. Example 24: 5- (2-isopropyl-4-methoxy-5-pyrrol-1-yl-phenoxy) -pyrimidine-2,4-diamine To a solution of 5- (5-amino-2-isopropyl-4-methoxyphenoxy) -pyrimidine-2,4-diamine (0.303 g, 1.0 mmol) in 15 mL of AcOH is added 2,5-dimethoxy-pyran (0.152). g, 1.2 mmol). The solution is heated to reflux. After 2 h the solution is cooled and poured onto ice / H20. The solution is converted to pH = 8 with 50% NaOH and extracted with ethyl acetate (3 x 75 mL). The organic phases meet, they are washed with H20, washed with brine, dried with Na2SO4, filtered and concentrated in vacuo to obtain a brown solid. Purification by flash chromatography (CH2Cl2 / MeOH = 97: 3) gives 5- (2-isopropyl-4-methoxy-5-pyrrol-1-yl-phenoxy) -pyrimidine-2,4-diamine (0.244 g, 72 %) in the form of a pale yellow solid. (M + H) = 340. Similarly, from 5- (5-amino-2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine (0.313 g, 1.1 mmol) and from 2,5-hexanedione (0.14 mL, 1.2 mmol) gives 5- [5- (2,5-dimethyl-pyrrol-1-yl) -2-isopropyl-4-methoxy-phenoxy] -pyrimidine-2, 4-diamine, (0.259 g, 64%). (M + H) = 368. Example 25: 5- (2-isopropyl-4-methoxy-5- [1,2,3] riazol-1-yl-phenoxy) -pyrimidine-2,4-diamine According to the procedure described by Harada et al., Heterocycles 48: 695-702 (1998), to a solution of 5- (5-amino-2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine (0.400 g, 1. 8 mmoles) in 5 ml of methanol is added at 0 ° C trimethylamine (0.308 g, 3.0 mmol) and hydrazine X1 (0.388 g, 1.4 mmol). The solution is heated to 50 ° C. After 4 h the mixture is concentrated in vacuo and extracted with CH2C12. The organic phases are combined, washed with H20, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (94: 6 mixture of CH2Cl2 / MeOH) affords 5- (2-isopropyl-4-methoxy-5- [1,2,3] triazol-1-yl-phenoxy) -pyrimidine-2, 4-diamine (0.145 g, 31%) as a white solid; [MH] + = 342. EXAMPLE 26: 1- [5- (4-Amino-2-methyl-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-phenyl] -pyrrolidin-2-one Step 1. 4-Chloro-N- [5- (2, 4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-phenyl] -butyramide To a solution of 5- (5-amino-2-isopropyl-4-methoxyphenoxy) -pyrimidine-2,4-diamine (0.400 g, 1.4 mmol) in 15 ml of CHC13 and Na2HP0 (0.392 g, 2.8 mmol) was add 4-chlorobutyryl chloride (0.194 g, 1.4 mmol) dropwise. After 4.5 h, H20 and CH2C12 are added and the mixture is kept stirring for 15 min. The mixture is neutralized with 2N Na 2 CO 2 and extracted with CH 2 C 12. The organic phases are combined, washed with brine, dried over Na 2 SO, filtered and concentrated in vacuo to give 4-chloro-N- [5- (2,4-di-amino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-phenyl] -butyramide (0.495 g, 91%) as a brown foam; [MH] + = 394. Step 2. 1- [5- (4-amino-2-methyl-pyrimidin-5-yloxy) -4- isopropyl-2-methoxy-phenyl] -pyrrolidin-2-one To a solution of 5 ml of 1.9 M NaOMe in MeOH is added 4-chloroamide X (0.495 g, 1.3 mmoles). After 6 h the solution is concentrated in vacuo. The residue is taken up in ethyl acetate, washed with H20, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give 1- [5- (4-amino-2-methyl-pyrimidin- 5-yloxy) -4-isopropyl-2-methoxy-phenyl] -pyrrolidin-2-one (0.230 g, 47%) as a white solid; [MH] + = 358; p.f. (HCl salt) > 300 ° C. Example 27: 1- [5- (2, 4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-phenyl] -lH-imidazole-2-thiol Step 1. 5- (2-isopropyl- 5-isothiocyanato-4-methoxy-phenoxy) -pyrimidine-2,4-diamine To a solution of 5- (5-amino-2-isopropyl-4-methoxy-phe-noxy) -pyrimidine-2,4-diamine (0.100 g, 0.4 mmol) in 1 ml of H20 and TFA (0.040 g, 0.4 mmoles) is added thiophosgene (0.040 g, 0.4 mmol). After 1 h, the mixture is neutralized with 2M NaOH and extracted with CH2C12. The organic phases are combined, washed with brine, dried over NaSO4, filtered and concentrated in vacuo to give 5- (2-isopropyl-5-isothiocyanato-4-methoxy-phenoxy) -pyrimidine-2, 4- di-amine (0.042 g, 36%) as a brown foam; [MH] + = 334. Step 2. 1- [5- (2, 4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-phenyl] -lH-imidazole-2-thiol To an amino-acetal solution (0.173 g, 1.3 mol) in ml of EtOH is added a solution of thio-isocyanate (0.430 g, 1.3 mmol) in 2 ml of EtOH. The mixture is heated to reflux. After 30 min the mixture is cooled, concentrated in vacuo and suspended in 1M HCl and refluxed again for a further 30 min, the reaction mixture is neutralized with a saturated solution of NaHCO 3 and extracted with CH 2 C 12. The organic phases are combined, washed with brine, dried over Na 2 SO, filtered and concentrated in vacuo to give 1- [5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2. -methoxy-phenyl] -lH-imidazole-2-thiol (0.298 g, 50%) as a white solid; [MH] + = 373. Example 28: 5- (5-imidazol-1-yl-2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine A suspension of 5-iodo-diamino-pyrimidine (0.294 g, 0.74 mmol), imidazole (0.120 g, 1.8 mmol), Cul (0.070 g, 0.4 mmol) and Cs2C03 (0.616 g, 1.9 mmol) is heated at 100 ° C. in 4 ml of DMF. After 72 h. The mixture is cooled, diluted with H20 and extracted with ethyl acetate. The organic phases are combined, washed with brine, dried over Na 2 SO, filtered and concentrated in vacuo. Purification by preparative TLC (94: 6 mixture of CH2Cl2 / MeOH) affords 5- (5-imidazol-1-yl-2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine (0.020 g, 8%) in the form of white solid; [MH] + = 341. EXAMPLE 29: 2- [5- (2,4-Diaminopyrimidin-5-yloxy) -4-isopropyl-2-methoxy-phenyl] -propan-2-ol 1- (5- (2,4-diamino-pyrimidine) is added portionwise at 0 ° C to a solution of methylmagnesium bromide (83.4 mmol, 27.8 mL, 3.0 M in Et20) in 83 mL of THF. 5-yloxy) -4-isopropyl-2-methoxy-phenyl] -ethanone (2.523 g, 8.3 mmol, from Example 16). After 16 h the mixture is cooled to 0 ° C and the reaction is stopped by addition of 10% NHC1. H20 is added and the mixture is extracted with ethyl acetate. The organic phases are combined, washed with H20, washed with brine, dried with NaHCO3, filtered and concentrated in vacuo. The crude solid was purified by flash chromatography (94: 6 mixture of CH2Cl2 / MeOH), yielding acetophenone X (1.00 g, recovered by 40%) as a white solid and alcohol X (1.00 g, as a mixture). 1: 1 methylated / demethylated). The mixture of alcohols is taken up in 31 ml of DMF. K2C03 (0.65 g, 4.7 mmol) and iodomethane (0.098 ml, 1.6 mmol) are added and the mixture is heated to 50 ° C. Additional portions of iodomethane (0.019 ml, 0.6 mmol) are added after 1, 2 and 3 h. After 16 h the mixture is cooled and 10% NH 4 Cl is added and extracted with ethyl acetate. The organic phases are combined, washed with H20, washed with brine, dried over Na2SO, filtered and concentrated in vacuo to give 2- [5- (2,4-diaminopyrimidin-5-yloxy) -4- isopropyl-2-methoxy-phenyl] -propan-2-ol (yield: 0.711 g) as a white solid. [MH] + = 333.

Example 30: 5- (2,5-diisopropyl-methoxy-f-enoxy) -pyrimidine-2,4-diamine To a solution of 2- [5- (2, 4-diaminopyrimidin-5-yloxy) -4-isopropyl-2-methoxy-phenyl] -propan-2-ol (0.350 g, 1.1 mmol) in 10 mL of CH2C12 was add TFA (4.0 ml, 52.6 mmol) and triethylsilane (1.7 ml, 10.5 mmol). After 30 min a saturated solution of NaHCO 3 is added and the mixture is extracted with ethyl acetate. The organic phases are combined, washed with brine, dried over Na 2 SO 4, filtered and concentrated in vacuo to obtain a crude oil. Purification by flash chromatography (96: 4 mixture of CH2Cl2 / MeOH) gives 5- (2,5-diisopropyl-methoxy-phenoxy) -pyrimidine-2,4-diamine (0.225 g, 68%) as a white solid . [MH] + = 317. Example 31: 1- [5- (2, 4-diamino-pyrimidine-5-yloxy) -4-isopropyl-2-methoxy-phenyl] -ethanol To a solution of 1- [5- (2, 4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-phenyl-ethanone (2500 g, 8.3 mmol) in 100 mL of MeOH is added slowly at 0 ° C NaBH 4 (1566 g, 41.4 mmol). The solution is allowed to warm to T.A. After 20 h a saturated NH 4 Cl solution is added, the mixture is concentrated in vacuo and extracted with ethyl acetate. The organic phases are combined, washed with brine, dried over Na 2 SO 4, filtered and concentrated in vacuo. Purification by column chromatography through silica gel (9: 1 mixture of CH2Cl2 / MeOH) yields 1- [5- (2,4-diaminopyrimidine-5-yloxy) -4-isopropyl-2-methoxy-phenyl ] -ethanol (1613 g, 60%) as a white foam; [MH] + = 3_01. Example 32: 5- (2-isopropyl-4-methoxy-5-vinyl-phenoxy) -pyrimidine-2, 4-diamine and 5- [2-isopropyl-4-methoxy-5- (1-methoxy-ethyl) - phenoxy] - pyrimidine-2,4-diamine To a solution of 1- [5- (2, 4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-phenyl] -ethanol (1.613 g, 5.3 mmol) in 30 mL of CH2C12 is added at -78 ° C the trifluoride of (diethylamino) sulfur (DAST) (0.935 g, 5.8 mmol). After stirring for 1.5 h, a saturated solution of NaHCO 3 is added and the mixture is extracted with CH 2 C 12. The organic phases are combined, washed with brine and dried over Na 2 SO, filtered and concentrated in vacuo. Purification by chromatography on silica gel (95: 5 mixture of CH 2 Cl 2 / MeOH) gives the 5- ( 2-isopropyl-4-methoxy-5-vinyl-phenoxy) -pyrimidine-2,4-diamine (0.044 g, 3%) as a foam ([MH] + = 301) and 5- [2-isopropyl- 4-methoxy-5- (1-methoxy-ethyl) -phenoxy] -pyrimidine-2,4-diamine (0.075 g, 4%) as a foam; [MH] + = 303. Example 33: 5- (2-ethyl-3-methoxy-benzyl) -pyrimidine-2,4-diamine The synthesis procedure used in this example is described in the reaction scheme M.

Reaction Scheme M Step 1. Cyclohexyl- (3-methoxy-benzylidene) -amine By the method described in step 1 of Example 3, 3-methoxy-benzaldehyde (10.105 g, 74.2 mmol) is converted to cyclohexyl- (3 -methoxy-benzylidene) -amine (15.08 g, 94%) as a clear oil. Step 2. 2-Ethyl-3-methoxy-benzaldehyde To a solution of 2,2,6,6-tetramethylpiperidine (4.67 g, 33 mmoles) in 75 ml of THF is added dropwise at -15 ° C. - Butyllithium (12.6 ml, 32 mmol, 2.5 in hexanes), keeping the internal temperature below -10 ° C. After 15 min, a solution of cyclohexyl- (3-methoxybenzylidene) -amine (3.259 g, 15.0 mmol) in 5.0 ml of THF is added and the solution is maintained under stirring at -15 ° C. After 1 h the solution is cooled to -78 ° C. Iodoethane (11.9 ml, 150 mmol) is added in one portion and the solution is allowed to warm to T.A. for 45 min, it is poured onto NHC1 of 10% and extracted with Et20. The organic phases are combined, washed with H20, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to obtain a crude imine in the form of an oil. The oil is taken up in 90 ml of THF and HCl (22 ml, 89 mmol, 4.0 M) and heated to reflux. After 2 the solution is cooled. H20 is added and the mixture is extracted with ethyl acetate. The organic phases are combined, washed with H20, washed with brine, dried over Na2SO, filtered and concentrated in vacuo to obtain a crude oil. Purification by flash chromatography (98: 2 mixture of hexane / ethyl acetate) gives the 2-ethyl-3-methoxy benzaldehyde (1543 g, 63%, 2 steps) as a clear oil. Step 3. 5- (2-Ethyl-3-methoxy-benzyl) -pyrimidine-2,4-diamine According to the procedure of steps 4-8 of Example 3, 2-ethyl-3-methoxy benzaldehyde (1.025 g , 6.24 mmole) affords 5- (2-ethyl-3-methoxy-benzyl) -pyrimidine-2,4-diamine (0.154 g, 10%, 2 steps) as a pale yellow solid; [MH +] = 259. EXAMPLE 34: 5- (5-Chloro-2-isopropyl-4-methoxy-benzyl) -N2- (2,2,2-trifluor-ethyl) -pyrimidine-2,4-diamine The procedure The synthesis used in this example is described in the reaction scheme M.

Scheme of reaction Stage 1. 5- (5-Chloro-2-isopropyl-4-methoxy-benzyl) -2-methylsulfanyl-pyrimidin-4-ylamine To 25 ml of a saturated solution of NH3 in EtOH is added the 4-chloro -5- (5-Chloro-2-isopropyl-4-methoxy-benzyl) -2-methylsulfanyl-pyrimidine (0.580 g, 1.6 mmol). The solution is heated to 85 ° C in a sealed reactor flask. After 3 days the solution is cooled, concentrated in vacuo and suspended in CH2C12. The precipitate is filtered and the mother liquors are concentrated with vacuum. Purification by flash chromatography (7: 3 mixture of hexane / ethyl acetate) gives the 5- (5-chloro-2-isopropyl-4-methoxy-benzyl) -2-methylsulfanyl-pyrimidin-4-ylamine (0.504 g, 92%) in the form of white solid. Step 2. 5- (5-chloro-2-isopropyl-4-methoxy-benzyl) -2-methylsulfonyl-pyrimidine-4-ylamine To a solution of 4-chloro-5- (5-chloro-2-isopropyl-4) -methoxy-benzyl) -2-methylsulfanyl-pyrimidine (0.320 g, 0.9 mmol) in 15 ml of THF and 15 ml of H20 is added in portions the Oxone (1-.227 g, 2 mmol). After 16 h the solution is concentrated in vacuo and extracted with ethyl acetate. The organic phases are combined, washed with brine, dried over Na 2 SO 4, filtered and concentrated in vacuo. Purification by flash chromatography affords 5- (5-chloro-2-isopropyl-4-methoxy-benzyl) -2-methylsulfonyl-pyrimidine-4-ylamine (0.333, 96%) as a white solid. Step 3. 5- (5-chloro-2-isopropyl-4-methoxy-benzyl) -N2- (2,2,2-trifluor-ethyl) -pyrimidine-2,4-diamine To a solution of 5- (5 -chloro ~ 2-isopropyl-4-methoxybenzyl) -2-methylsulfonyl-pyrimidine-4-ylamine (0.050 g, 0.1 mmol) in 3 ml of dimethyl ether. ethylene glycol (DME) is added 0.5 ml of 2,2,2-trifluoroethylamine. The mixture is heated in. the microwave (130 ° C, 10 bar). After 22 h the mixture is concentrated in vacuo. Purification by preparative HPLC in reverse phase provides the TFA salt of 5- (5-chloro-2-isopropyl-4-methoxy-benzyl) -N2- (2,2,2-trifluoro-ethyl) -pyrimidine-2, 4-diamine (0.010 g, 19%) as a white solid); [MH] + = 389. Similarly, from 5- (5-chloro-2-isopropyl-4-methoxy-benzyl) -2-methylsulfonyl-pyrimidine-4-ylamine (0.100 g, 0.3 mmol) but using 2-methoxyethylamine, 5- (5-chloro-2-isopropyl-4-methoxy-benzyl) -N2- (2-methoxyethyl) -pyrimidine-2,4-diamine (0.068 g, 63%) is obtained in the form of white solid; [MH] + = 365. Example 35: 5- [5-chloro-2- (1-fluoro-l-methyl-ethyl) -4-methoxy-phenoxy] -pyrimidine-2,4-diamine The synthesis procedure used in this example it is described in the reaction scheme N.

Reaction Scheme N Step 1. 1- (4-Chloro-2-hydroxy-5-methoxy-phenol) -ethanone To a mixture of ALCL3 (8.89 g, 59 mmol) in CH2CL2 is added dropwise at -10 ° C acetyl chloride (4.1 ml, 58 mmol), keeping the internal temperature below 0 ° C.

After 20 min 2-chloro-l, 4-dimethoxybenzene is dissolved (10.0 g, 8.3 mmol) in 8 ml of CH2C12 and added dropwise to the previous solution, keeping the internal temperature below 0 ° C. After 20 min the mixture is heated to T.A. for 1 h and then heated to reflux. After 21 h the solution is cooled, poured onto a mixture of ice and concentrated HCl and extracted with dichloromethane. The organic phases were combined, concentrated in vacuo and recrystallized from H20 / EtOH, yielding 1- (4-chloro-2-hydroxy-5-methoxy-phenol) -ethanone (8.78 g, 85%) as a solid. . Step 2. 5-chloro-2- (1-hydroxy-1-methyl-ethyl) -4-methoxyphenol To a solution of 1- (4-chloro-2-hydroxy-5-methoxy-phenyl) -ethanone (9.80 g , 49 mmoles) in 90 ml of THF is added at 0 ° C methyl magnesium bromide (37 ml, 112 mmol, 3.0 M in Et20). After 2 h the reaction is stopped by the addition of NHC1 of 10%. The pH of the mixture is adjusted to 1 with 2M HCl and extracted with ethyl acetate. The organic phases are combined, washed with H20, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to obtain a crude solid. Purification by flash chromatography provides the alcohol 5-chloro-2- (1-hydroxy-1-methylethyl) -4-methoxy-phenol (11.85 g, more than 100%), in the form of a yellow solid. Step 3. [5-chloro-2- (1-hydroxy-l-methyl-ethyl) -4-methoxy-phenoxy] -pyrimidine-2,4-diamine To a mixture of 5-chloro-2- (1-hydroxy) -l-methyl-ethyl) -4-methoxy-phenol (2.00 g, 9 mmol) and K2CO3 (2.55 g, 19 mmol) in 50 ml of DES is added a tosylating reagent (2.34 g, 11 mmol). The mixture is kept stirred at T.A. After 16 h the mixture is poured into 200 ml of water and extracted with ethyl acetate. The organic phases are combined, washed with water, washed with brine, dried over Na 2 SO, filtered and concentrated in vacuo to obtain a crude solid. Purification by flash chromatography (7: 3 mixture of hexane / ethyl acetate) gives [5-chloro-2- (1-hydroxy-1-methyl-ethyl) -4-methoxy-phenoxy] -pyrimidine-2, 4 -diamine (1.62 g, 69%) as a white solid. Step 4. 5- [5-Chloro-2- (1-fluor-1-methyl-ethyl) -methoxy-phenoxy] -acetonitrile To a solution of [5-chloro-2- (1-hydroxy-1-methyl- ethyl) -4-methoxy-phenoxy] -pyrimidine-2,4-diamine (1432 g, 5.6 mmol) in 50 ml of CH2C12 is added dropwise at -78 ° C to DAST (0.77 ml, 5.9 mmol). After 1.5 the solution is heated to T.A. and the reaction is quenched by the addition of a saturated solution of NaHCO 3 and extracted with CH 2 Cl. The organic phases were combined, washed with brine, dried over Na 2 SO 4, filtered and concentrated in vacuo to obtain an inseparable mixture (9: 1) of 5- [5-chloro-2- (1-fluoromethyl) ethyl) -methoxy-phenoxy] -acetonitrile (1543 g) and (5-chloro-2-isopropenyl-4-methoxy-phenoxy) -acetonitrile as a pale brown oil. Step 5. 5- [5-Chloro-2- (1-fluor-l-methyl-ethyl) -methoxy-phenoxy] -pyrimidine-2,4-diamine As described in steps 6 and 7 of Example 2 it becomes 5- [5-chloro-2- (1-fluoro-1-methyl-ethyl) -methoxy-phenoxy] -acetonitrile (1447 g, 4.2 mmol) in 5- [5-chloro-2- (1- fluor. -1-methyl-ethyl) -methoxy-phenoxy] -pyrimidine-2,4-diamine (0.263 g, 10% three-step) as a yellow solid; p.f. = 220.1-220.6 ° C (HCl salt); [MH] + = 328. By a similar method, but starting with 3-fluor-1, 4-dimethoxybenzene and carrying out a hydrogenation with Pd / C in step 4 instead of DAST, 5- (5-fluorine is obtained -2- isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine (0.778 g, 42%); p. f. (HCl salt) = 239-241 ° C; [MH] + = 293. Example 36: 5- (8-bromo-5-ethyl-2,3-dihydro-benzo [1,4] dioxin-6-yloxy) -pyrimidine-2,4-diamine The synthesis procedure used in this example is described in the reaction scheme O.

Reaction scheme O Stage 1. 3-bromo-4,5-dihydroxy-benzaldehyde To a solution of 3,4-dihydoxy-benzaldehyde (15.48 g, 112 mmol) in 500 ml of AcOH is added bromine (6.1 ml). , 118 mmol) in 50 ml of AcOH for 10 min. After 4 h the mixture is poured on cold H20. The precipitate is filtered, washed with cold H20 and dried under vacuum, obtaining 3-bromo-4,5-dihydroxy-benzaldehyde (11.64 g, 48%) as a gray liquid. Stage 2 . 8-bromo-2, 3-dihydro-benzo [1,4] dioxin-6-carboxaldehyde XA a solution of 3-bromo-4,5-dihydroxy-benzaldehyde (20.78 g, 95 mmol) in 480 ml of DMF was add K2C03 (52.95 g, 383 mol) and then 1,2-dibromoethane (8.7 ml, 101 mmol). The mixture is heated to 100 ° C. After 18 h more 1,2-dibromoethane (1.0 ml) is added. After 2 h the mixture is poured into water and extracted with ethyl acetate. The organic phases are combined, washed with brine, dried over Na 2 SO, filtered and concentrated in vacuo. The crude solid was purified by flash chromatography (9: 1 mixture of hexane / ethyl acetate) to obtain 8-bromo-2,3-dihydro-benzo [1,4] dioxin-6-carboxaldehyde (15.82 g, 99%). %) in the form of a white solid. Step 3. (8-bromo-2,3-dihydro-benzo [1,4] dioxin-6-ylmethylene) -cyclohexyl-amine According to the procedure of example 3 (step 1), starting from 8-bromine -2, 3-dihydro-benzo [1,4] dioxine-6-carboxaldehyde (15.63 g, 64 mmol)) and cyclohexylamine (7.02 g, 71 mmol) yields 8-bromo-2,3-dihydro -benzo [1,4] dioxin-6-ylmethylene) -cyclohexyl-amine (24.2 g) as a viscous oil which is used in the next step without purification. Step 4. 8-Bromo-5-ethyl-2,3-dihydro-benzo [1,4] dioxine-6-carboxaldehyde According to the procedure of step 2 of example 33, starting with 8-bromo-2, 3-dihydro-benzo [1,4] dioxin-6-ylmethylene) -cyclohexyl-amine (23.09 g, 71 mmol) yields 8-bromo-5-ethyl-2,3-dihydro-benzo [1,4] dioxin-6-carboxaldehyde (3.67 g, 24%). Step 5. 8-Bromo-5-ethyl-2,3-dihydro-benzo [1,4] dioxin-6-ol Using the procedure described in Example 2 (step 4), 8-bromo-5-ethyl is converted -2, 3-dihydro-benzo- [1,4] dioxin-6-carboxaldehyde (3,674 g, 13.5 mmol) in 8-bromo-5-ethyl-2,3-dinidro-benzo [1,4] dioxin- 6-ol (3.182 g, 91%) as a white solid. Step 6. (8 ~ bromo-5-ethyl-2,3-dihydro-benzo [1,4] dioxin-6-yloxy) -acetonitrile As described in step 6 of Example 21, 8-bromo-5 is converted ethyl-2, 3-dihydro-benzo [1,4] dioxin-6-ol (3182 g, 12.3 mmol) in the cyanomethyl ether 8-bromo-5-ethyl-2,3-dihydro-benzo [1, 4] dioxin-6-yloxy) -acetonitrile (2.30 g, 63%).

Step 7. 5- (8-Bromo-5-ethyl-2,3-dihydro-benzo [1,4] dioxin-6-yloxy) -pyrimidine-2-diamine. Applying the procedure of steps 6 and 7 of the example 2 8-bromo-5-ethyl-2,3-dihydro-benzo [1,4] dioxin-6-yloxy) -acetonitrile (2.30 g, 8.7 mmol) is converted to 5- (8-bromo-5-) ethyl-2, 3-dihydro-benzo [1,4] dioxin-6-yloxy) -pyrimidine-2, 4-diamine (0.951 g, 32%) as a yellow solid; p.f. = 291-293 ° C; [MH] + = 368. Example 37: 5- (7-iodo-5-isopropyl-2,3-dihydro-benzo [1,4] dioxin-6-yloxy) -pyrimidine-2,4-diamine The process of Syntheses used in this example is described in the reaction scheme P.

Reaction scheme P Stage 1. 2, 3-dihydro-benzo [1,4] dioxin-6-ol To a solution of 2,3-dihydro-benzo [1,4] dioxin-6-carboxaldehyde (30.0 g, 183 mmoles) in 500 ml of CH2C12 is added mCPBA acid (37.85 g, 219 mmoles). The suspension is heated to 50 ° C. After 16 h a saturated solution of NaHCO 3 is added and the mixture is extracted with CH 2 Cl. The organic phases are combined, concentrated in vacuo and taken up in MeOH and 200 ml of 4 M NaOH are added. After 2 h the mixture is acidified with 4M HCl and extracted with ethyl acetate. The organic phases are combined, washed with a saturated solution of NaHCO 3, washed with brine, concentrated in vacuo and taken up in CH 2 C 12. The solution is filtered to separate the precipitate. The resulting solution is stirred with a saturated NaHCO 3 solution for 1 hit is separated, dried with MgSO, filtered and concentrated in vacuo to obtain 2,3-dihydro-benzo [1,4] dioxin-6-ol (26.92 g, 94%). Step 2. 6-methoxy-2,3-dihydro-benzo [1,4] dioxin To a mixture of K2C03 (47.54 g, 344 mmol) and Bu4NI (1.256 g, 3.4 mmol) in DMF is added 2.3 Dihydro-benzo [1,4] dioxin-6-ol (26.2 g, 172 mmol) and then iodomethane (16.1 ml, 258 mmol). After 16 hours the mixture is filtered. The solution is mixed with H20 and extracted with ethyl acetate. The organic phases are combined, washed with brine, dried with MgSO 4, filtered and concentrated in vacuo. Purification by flash chromatography (95: 5 hexane / ethyl acetate) gives the methyl compound, 6-methoxy-2,3-dihydro-benzo [1,4] dioxin (24.23 g, 85%) as clear oil . Step 3. 6-methoxy-2,3-dihydro-benzo [1,4] dioxin-5-yl-boronic acid To a solution of methyl ether X (10.0 g, 60 mmol) in 50 ml of THF is added drip at -78 ° C the n-butyllithium (36 ml, 90 immoles, 2.5 M in hexanes). After 1 h the solution is heated to T.A. After 1 h the solution is cooled to -78 ° C and trimethyl borate (13.6 ml, 120 mmol) is added. The solution is heated to T.A. After 16 h the reaction is quenched by the addition of water and the resulting mixture is acidified with AcOH and extracted with ethyl acetate. The organic phases are combined, washed with a saturated solution of NaHCO 3, dried with MgSO 4, filtered and concentrated in vacuo. The resulting oil is subjected to azeotropic distillation with toluene, obtaining 6-methoxy-2,3-dihydro-benzo [1,4] dioxin-5-yl-boronic acid (13.72 g, 98%) as an oil. Step 4. 5-isopropenyl-6-methoxy-2,3-dihydro-benzo [1,4] dioxin To a solution of 2-bromopropene (5.4 ml, 59 mmol) in 200 ml of DME is added Pd ( Ph3P) 4 (3.116, 2.8 mmol). After 30 min, 6-methoxy-2,3-dihydro-benzo [1,] dioxin-5-yl-boronic acid (13.320 g, 58.6 mol) and K2C03 (8.099 g, 58.6 mmol) are added. The mixture is heated to reflux. After 16 hours the mixture is cooled, filtered through a pad of Celite and concentrated in vacuo. The residue is dissolved in H20 and extracted with ethyl acetate. The organic phases are combined, washed with a saturated solution of NaHCO 3, dried with MgSO 4, filtered and concentrated in vacuo. Purification by flash chromatography affords isoprene 5-isopropenyl-6-methoxy-2,3-dihydro-benzo [1,4] dioxin (5,542 g, as an inseparable 1: 1 mixture of product / sm, as an oil. 5. 5-isopropyl-6-methoxy-2,3-dihydro-benzo [1,4] dioxin To a solution of 5-isopropenyl-6-methoxy-2,3-dihydro-benzo [1,4] dioxin (5.00) g, x mmoles) in 80 ml of MeOH is added 10% Pd on C (0.18 g) The mixture is subjected to a pressure of 50 psi of H. After 16 hours the mixture is filtered through a bed of Celite The solution is concentrated in vacuo Purification by flash chromatography (97: 3 mixture of hexane / ethyl acetate) yields isopropyl 5-isopropyl-6-methoxy-2,3-dihydro-benzo [1, 4] dioxin (2.458 g, 21% boronic acid) as a clear oil Step 6. 5-isopropyl-6-hydroxy-2,3-dihydro-benzo [1,4] dioxin -A solution of 5- isopropyl-6-methoxy-2,3-dihydro-benzo [1,4] dioxin (1011 g, 4.9 mmol) in 15 m BBr3 (7.3 ml, 7.3 mmol) is added to CH2C12 at -78 ° C. The solution is allowed to warm to T.A. After 16 hours the solution is cooled to -78 ° C, the reaction is stopped with H20, heated to T.A. and extracted with CH2C12. The organic phases are combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography (7: 3 mixture of hexane / ethyl acetate) gives the 5-isopropyl-6-hydroxy-2,3-dihydro-benzo [1,4] -dioxin (0.622 g, 63%) in the form of pale yellow oil. Step 7. 5-isopropyl-2,3-dihydro-benzo [1,4] dioxin-6-yl-oxy) acetonitrile As described in Example 2 (step 5), 5-isopropyl-6-hydroxy is converted 2, 3-dihydro-benzo [1,4] dioxin (0.622 g, 3.2 mmol) in 5-isopropyl-2,3-dihydro-benzo [1,4] dioxin-6-yloxy) acetonitrile (0.544 g, 72%) as a clear oil. Step 8. 5- (5-isopropyl-2,3-dihydro-benzo [1,4] dioxin-6-yloxy) -pyrimidine-2,4-diamine. As described in step 6 of Example 21, the -isopropyl-2, 3-dihydro-benzo [1,4] dioxin-6-yl-oxy) acetonitrile (0.544 g, 2.3 mmol) in 5- (5-isopropyl-2,3-dihydro-benzo [1, 4] dioxin-6-yloxy) -pyrimidine-2,4-diamine (0.560 g, 86%) as a yellow foam. Step 9. 5- (7-iodo-5-isopropyl-2,3-dihydro-benzo [1,4] -dioxin-6-yloxy) -pyrimidine-2,4-diamine and 5- (7,8-diiodo) -5-isopropyl-2, 3-dihydro-benzo [1,4] dioxin-6-yloxy) -pyrimidine2,4-diamine To a solution of 5- (5-isopropyl-2,3-dihydro-benzo- [1 , 4] dioxin-6-yloxy) -α-irimidine-2,4-diamine (250 mg, 0.83 mmole) in acetic acid (2 ml) is added the ICI (0.670 g, 4.13 mmol) in 3 ml of AcOH and 2 ml of H20. After 20 h the reaction mixture is neutralized with Na 2 CO 3 and extracted with CH 2 C 12. The organic phases are combined, washed with 10% NaHS03, washed with brine, dried over Na 2 SO, filtered and concentrated in vacuo, purification by flash chromatography (mixture of CH 2 Cl 2 / MeOH 97: 3). 5- (7,8-diiodo-5-isopropyl-2,3-dihydro-benzo [1,4] dioxin-6-yloxy) -pyrimidine-2,4-diamine (0.049 g, 10%) as a solid yellow ([MH] + = 555) and 5- (7-iodo-5-isopropyl-2,3-dihydro-benzo [1,4] dioxin-6-yloxy) -pyrimidine-2,4-diamine (0.050) g, 14%) in the form of foam; [MH] + = 429.

Example 38: 2- [2- (2, 4-diamino-pyrimidin-5-yloxy) -4-iodo-5-methoxyphenyl] -propan-1-ol The synthesis procedure used in this example is described in the scheme of Q reaction apa 3 icyfeiSHt " Reaction Scheme Q Step 1. 1- (2-hydroxy-4-iodo-5-methoxy-phenyl) -ethanone To a suspension of sodium hydride (0.044 g, 1.1 mmol, 60% in mineral oil) in 0.5 ml of DMF was added 5-iodo-2-acetyl-4-methoxyphenol sodium (0.292 g, 1 mmol, obtained as described in example 35) as a solution in 1.5 ml of DMF. After 10 minutes the chloromethoxy-methane is added (0.079 g, 1.0 immoles). After 30 minutes the mixture is extracted with CH2C12. The organic phases are combined, washed with brine, dried over Na 2 SO 4, filtered and concentrated in vacuo. Purification by flash chromatography (88:12 mixture of hexane / ethyl acetate) gives 1- (2-hydroxy-4-iodo-5-methoxy-phenol) -ethanone (0.314 g, 85%) as a yellow solid; [MH] + = 337. Step 2. l-Iodo-4-isoprenyl-2-methoxy-5-methoxymethoxybenzene To a suspension of methyl triphenylphosphonium bromide (0.457 g, 1.3 mmol) in 8 ml of THF is added the sodium hexamethyldisilazide (1.3 ml, 1.29 immoles, 1.0 M in THF). After 1.5 h, 1- (2-hydroxy-4-iodo-5-methoxy-phenyl) -ethanone (0.288 g, 0.9 mmol) as a solution in 8 ml of THF is added dropwise. After 20 h the mixture is filtered through a pad of Celite and extracted with CH2C12. The organic phases are combined, washed with brine, dried over Na 2 SO and concentrated in vacuo. Purification by flash chromatography (95: 5 mixture of hexane / ethyl acetate) gives l-iodo-4-isoprenyl-2-methoxy-5-methoxymethoxy-benzene (0.224 g, 78%) as a colorless liquid; [MH] + = 335. Step 3. 2- (2-hydroxy-1-methyl-ethyl) -5-iodo-4-methoxyphenol To a mixture of NaBH 4 (0.051 g, 1.3 mmol) in 4 ml of DME is add TiCl4 (0.67 ml, 0.67 mmol, 1.0 M in CH2C12). After 1 h, 2-methyl-l-iodo-4-isoprenyl-2-methoxy-5-methoxymethoxy-benzene (0.224 g, 0.7 mmol) in 4 ml of DME is added. After 20 h the reaction is quenched with H20 and the reaction mixture is extracted with ethyl acetate. The organic phases are combined, washed with brine, dried over Na 2 SO 4, filtered and concentrated in vacuo to obtain an oil. To a solution of this oil in 3 ml of isopropanol is added 3 ml of 6M HCl. After 3 h the mixture is neutralized with a saturated solution of NaHCO 3 and extracted with ethyl acetate. The organic phases are combined, washed with brine, dried over Na 2 SO 4, filtered and concentrated in vacuo to obtain an oil. Purification by preparative TLC (70:30 mixture of hexane / ethyl acetate) gives the 2- (2-hydroxy-1-methyl-ethyl) -5-iodo-4-methoxyphenol (0.080 g, 30%) as a transparent oil; [MH] + = 309. Step 4. [2- (2-hydroxy-methyl-ethyl) -5-iodo-4-methoxy-phenoxy] -acetonitrile As described in step 6 of example 21, the 2- is converted (2-hydroxy-1-methyl-ethyl) -5-iodo-4-methoxy-phenol (0.080 g, 0.3 mmol) in [2- (2-hydroxy-methyl-ethyl) -5-iodo-4-methoxy-phenoxy ] -acetonitrile (0.076 g, 84%). in the form of a white solid; [MH] + = 348. Step 5. 2- [2- (2,4-diaminopyrimidin-5-yloxy) -4-iodo-5-methoxy-phenyl] -propan-1-ol Applying the procedure, step 7 of Example 21 converts [2- (2-hydroxy-methyl-ethyl) -5-iodo-4-methoxy-phenoxy] -acetonitrile (0.488 g, 1.4 mmol) to 2- [2- (2.4 -diaminopyrimidin-5-yloxy) -4-iodo-5-methoxy-phenyl] -propan-1-ol (0.459 g, 79%) as a white solid; p.f. (HCl salt) = 290.1-292.2 ° C; [MH] + = 417.

Example 39: 5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-N-methyl-yl-benzene-sulfonamide Step 1. 5- (2,4-diamino-pyrimidine-5-chloride) -iloxy) -4- isopropyl-2-methoxy-benzenesulfonyl A mixture of pyrimidine (0.400 g, 1.5 mmol) in 2 ml of chlorosulfonic acid is kept under stirring for 20 min. Pour the mixture on ice. The precipitate is filtered, washed with cold H20 and dried under vacuum to obtain 5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopro-yl-2-methoxy-benzenesulfonyl chloride (0.515). g, 95%) as a white solid; [MH] + = 373. Step 2. 5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-N-methyl-benzenethylsulfonamide In a closed tube with a screw cap, 10 ml of methyl amine are introduced and 5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2- chloride is added at -78 ° C. methoxy-benzenesulfonyl (0.300 g, 0.8 mmol). The mixture is allowed to warm to T.A. After 20 hours the mixture is concentrated by evaporation, washed with H20 and dried under vacuum, obtaining 5- (2, 4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-N-methyl -benzeneomethylsulfonamide (0.170 g, 57%) as a white solid; p.f. (HCl salt) = 252.3-252.9 ° C; [MH] + = 367. Similarly, replacing methylamine with ethylamine yields 5- (2,4-diamino-pyrimidin-5-yloxy) -N-ethyl-4-isopropyl-2-methoxy-benzenesulfonamide (0.186 g, 61%) in white solid form; p.f. (HCl salt) = 260-265 ° C; [MH] + = 382. Example 40: 5- [2-isopropyl-4-methoxy-5- (1-methyl-1H-imidazol-2-yl) -phenoxy] -3,4-dihydro-pyrimidine-2, 4-diamine To a solution of 5- [5- (lH-imidazol-2-yl) -2-isopropyl-4-methoxy-phenoxy] -3,4-dihydro-pyrimidine-2,4-diamine (0.044 g, 0.129 mmol) and iodomethane (9 ul, 0.145 mmol) in acetone (5 ml) is added KOH (0.055 g, 0.98 mmol), the mixture is heated at 30 ° C for 20 min, the mixture is filtered through Celite, washed With CH2C1, the organic solutions are combined and concentrated in vacuo. The residue is purified on two preparative TLC silica gel plates, eluting four times with 5% MeOH in CH2C12 / NH40H, thereby obtaining 5- [2-isopropyl-4-methoxy-5- (l- methyl-lH-imidazol-2-yl) -phenoxy] -3,4-dihydro-pyrimidine-2,4-diamine (0.244 g, 52%).

Mass spectrum: M + H: 355. Example 41: 5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-N, N-dimethyl-benzamide To a suspension of 5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-benzoic acid (180 mg, 0.57 mmol, from Example 17) in anhydrous dichloromethane (5.6 mL) was added. add TFA (0.08 ml, 1.14 mmol) and then thionyl chloride (0.36 ml, 5.65 mmol). After 1 hour the reaction mixture is concentrated. Anhydrous dichloromethane is added to the residue (4.5 ml) and dimethylamine (2.84 ml of a 2M solution in THF, 5.65 mmol). After 2 hours of stirring at T.A. The reaction mixture is filtered and concentrated. Purification by column chromatography through silica gel eluting with a mixture of 95/5 / 0.1 to 93/7 / 0.1 dichloromethane / methanol / ammonium hydroxide provides 5- (2,4-diamino-pyrimidine) -5-yloxy) -4-isopropyl-2-methoxy-N, N-dimethyl-benzamide (40 mg, 20%) as a pale yellow solid, MS (M + H) = 346.

Similarly, using methylamine in place of dimethylamine, 5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-N-methyl-benzamide (23 mg, 15 mg) is obtained. %) as a pale yellow solid, MS (M + H) = 332. Example 42: 4- (2,4-diamino-pyrimidin-5-yloxy) -2-iodo-5-isopropylphenol To a cold suspension of 1 (0.21 g, 0.52 mmol) in dichloromethane (15 ml) is added at 0 ° C the BBr3 (0.26 g, 1.05 mmol). The reaction mixture is stirred at T.A. for 16 h, the reaction is quenched with water and the reaction mixture is basified with a saturated solution of NaHCO 3. The insoluble solid is collected by filtration. The filtered liquid is washed with water, dried with Na 2 SO, filtered and concentrated in vacuo. The residues are combined and the solid subjected to flash chromatography through silica gel (methane): 3 to 5% in dichloromethane with 0.1% NHOH), obtaining the desired product (0.174 g, 86%); M + l 387.

Example 43: 5- (5-iodo-2-isopropyl-4-prop-2-ynyloxy-phenoxy) -pyrimidine-2,4-diamine The 4- (2,4-diamino-pyrimidin-5-yloxy) -2-iodo-5-isopropyl-phenol (200 mg, 0.43 mmol) is dissolved in anhydrous N, N-dimethylformamide (2 mL), add anhydrous potassium carbonate (414 mg, 3.00 mmol) and propargyl chloride (0.03 ml, 0.43 mmol). After shaking at T.A. overnight the reaction mixture is extracted with dichloromethane, water and brine. The dichloromethane phase is dried using anhydrous magnesium sulfate, concentrated and purified by column chromatography through silica gel eluting with a 95/5 / 0.1 mixture of dichloromethane / methanol / ammonium hydroxide, thereby obtaining the (5-iodo-2-isopropyl-4-prop-2-ynyloxy-phenoxy) -pyrimidine-2,4-diamine as a white solid (131 mg, 71%), MS (M + H) = 425. Example 44: N- [2-acetylamino-5- (2-isopropyl-4-methoxy-5-methyl-benzyl) -pyrimidin-4-yl] -acetamide The 5- (2-isopropyl-4-methoxy-5-methyl-benzyl) -pyrimidine-2,4-diamine (30 mg, 0.10 mmol) is dissolved in anhydrous pyridine (1 mL) and acetyl chloride ( 0.04 ml, 0.44 mmole). After stirring 30 minutes at T.A. the reaction mixture is concentrated. The residue is dissolved in dichloromethane and washed with water. Purification of the concentrated dichloromethane phase using preparative TLC plates (95/5 dichloromethane / methanol mixture) yields N- [2- acetylamino-5- (2-isopropyl-methoxy-5-methyl-benzyl) -pyridi - din-4-yl] -acetamide (7 mg, 18%), MS (M + H) = 371. Example 45: 5- (2-isopropyl-5-isoxazol-5-yl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine The synthesis procedure used in this example is described in reaction scheme Q.

Scheme of reaction Step 1. N '- [5- [5- (3-dimethylamino-acryloyl) -2-isopropyl-4-methoxy-phenoxy] 4- (dimethylamino-methyleneamino) -pyrimidin-2-yl] -, - dimethyl-formamidine 1- [5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopro-yl-2-methoxy-phenyl] -ethanone is dissolved (100 mg, 0.32 mmol, from Example 16) in N, N-dimethylformamide anhydrous (0.6 ml), the dimethyl acetal of N, N-dimethylformamide (0.17 ml, 1.26 mmol) is added and the reaction mixture is heated at 114 ° C overnight. The concentration of the reaction mixture gives the N '- [5- [5- (3-dimethylamino-acryloyl) -2-iso? Ro-pil-4-methoxy-phenoxy] -4- (dimethylamino-methyleneamino) -pyrim -din-2-yl] -N, N-dimethyl-formamidine. Step 2. 1- [5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-phenyl] -3-dimethylamino-propenone The N '- [5- [5- (3-dimethylamino-acryloyl) -2-isopropyl-4-methoxy-phenoxy] -4- (dimethylamino-methyleneamino) -pi-rimidin-2-yl] -N, N-dimethyl-formamidine from step 1 in methanol ( 1 ml) and ammonium hydroxide (1 ml). After stirring 5 days at T.A. The reaction mixture was concentrated and purified with preparative TLC plates (92/8 / 0.5 dichloromethane / methanol / ammonium hydroxide mixture), yielding 1- [5- (2,4-diamino-pyrimidin-5-yloxy) - 4-isopropyl-2-methoxy-phenyl] -3-dimethylamino-propenyone (34 mg, 29%) as a white solid. Step 3. 5- (2-isopropyl-5-isoxazol-5-yl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine 1- [5- (2, 4-diamino-pyrimidine-5 is dissolved -iloxy) -4- isopropyl-2-methoxy-phenyl] -3-dimethylamino-propenyone (30 mg, 0. 08 mmoles) in a mixture of methanol (1.5 ml) and water (0.4 ml) and hydroxylamine hydrochloride (14 mg, 0. 20 mmol) and the reaction mixture is refluxed for 1 hour. Purification with preparative TLC plates (mixture 92/8 / 0.5 dichloromethane / methanol / ammonium hydroxide) affords 5- (2-isopropyl-5-isoxazol-5-yl-4-methoxy-pheno-xi) -pyrimidine-2,4-diamine (8 mg, 29%) as a white solid, MS (M + H) = 342. Example 46: 5- (2-isopropyl-4-methoxy-5-thiazol-5-yl-phenoxy) -pyrimidine-2, 4 -diamine The 5- (5-iodo-2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine (600 mg, 1.5 mmol, from example 14, step 1) is dissolved in N, N-dimethylacetamide (4.8 ml) and potassium acetate (221 mg, 2.24 mmole), thiazole (0.53 ml, 7.5 mmole) and tetrakis (triphenylphosphine) palladium (0) (70 mg, 0.06 mmole). Then it is heated at 115 ° C overnight. The cooled reaction mixture was extracted with dichloromethane (100 ml) and water (2 x 100 ml). The dichloromethane phase is dried with anhydrous sodium sulfate, concentrated and purified by column chromatography through silica gel eluting with a 95/5 / 0.1 mixture of "dichloromethane / methanol / ammonium hydroxide, thereby obtaining the - (2-isopropyl-4-methoxy-5-thiazol-5-yl-phenoxy) -pyrimidine-2,4-diamine (49 mg, 9%) as a pale yellow solid, MS (M + H) = 358. Example 47: 5- (2-isopropyl-3-methoxy-phenoxy) -pyrimidine-2,4-diamine ~~ - The synthesis procedure used in this example is described in reaction scheme R.

Scheme, Reaction R Stage 1. 2- (1-hydroxy-1-methyl-ethyl) -3-methoxy-phenol To a solution of methylmagnesium bromide (24 ml of a 3M solution in diethyl ether, 72.2 mmoles) in anhydrous THF (20 ml) is added at 0 ° C a solution of 2'-hydroxy6'-methoxyacetophenone (4 g, 24.1 mmoles) in anhydrous THF (40 ml), keeping the temperature below 11 ° C during the addition. After stirring for 1.5 hours at T.A. A 10% solution of ammonium chloride (30 ml) is added slowly, keeping the temperature below 22 ° C by using an ice bath. Water (300 ml) is added slowly and the reaction mixture is extracted twice with ethyl acetate. The combined ethyl acetate phases are washed with water, brine, dried over anhydrous sodium sulfate and concentrated to give 2- (1-hydroxy-1-methyl-ethyl) -3-methoxyphenol (4.52 g). in the form of a pale yellow solid. Step 2. 2-isopropyl-3-methoxy-phenol To a solution of 1 (material from step 1 above) in acetic acid (50 ml) is added 10% palladium on carbon (500 mg), water (6 ml) and ammonium formate (7.82 g, 124 mmol).

After maintaining the reaction mixture under reflux for 1 hour, it is cooled and filtered through Celite. The Celite pad is washed with ethyl acetate (500 ml). Water (300 ml) is added to the filtrate and the mixture is basified (pH = 8) with solid sodium bicarbonate. The ethyl acetate phase is collected and washed with water, brine, dried over anhydrous sodium sulfate and concentrated to give 2-isopropyl-3-methoxy-phenol (3.68 g, 92%) as a yellow solid. pale. Step 3. Using the 2-isopropyl-3-methoxy-phenol of the previous step 3 and according to the procedure of steps 5-7 of example 2, 5- (2-isopropyl-3-methoxy-phenoxy) - pyrimidine-2,4-diamine; MS (M + H) = 275.

Similarly, 5- (2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine; MS (M + H) = 275. Example 48: 5- (5-Ethanesulfonyl-2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine To a solution of sodium sulfite (541 mg, 4.29 mmol) in water (20 ml) is added 5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-benzenesulfonyl chloride. (400 mg, 1.07 mmol) and the reaction mixture is heated to 80 ° C for 1 hour. Sodium bicarbonate (361 mg, 4.29 mmol, dissolved in 5 ml of water), dioxane (20 ml) and ethyl iodide (0.10 ml, 1.29 mmol) are added and the reaction mixture is heated at 80 ° C for 2 hours. hours. The reaction mixture was concentrated, extracted with dichloromethane (150 ml) and water (20 ml). The dichloromethane phase is dried with anhydrous sodium sulfate, concentrated and purified by column chromatography through silica gel eluting with a 95/5 / 0.1 mixture of dichloromethane / methanol / ammonium hydroxide, thereby obtaining the (5-Ethanesulfonyl-2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine (77 mg, 20%) as a white solid, MS (M + H) = 367.

Example 49: 5- (2-isopropyl-4-methoxy-5-trifluoromethyl-phenoxy) -pyrimidine-2,4-diamine The synthesis procedure used in this example is described in the reaction scheme S. et Scheme of reaction S Stage 1. l-iodo-4-isopropyl-2-methoxy-5- (toluene-4-sulfonyl) -benzene To a solution of 2-isopropyl-4-methoxy-1- (toluene-4- sulfonyl) -benzene (10 g, 31.25 immoles) in HOAc (10 ml) is added one. ICI solution (9.6 g, 59.26 mmol) in HOAc (10 ml) and H20 (5 ml). The reaction mixture is stirred at T.A. for 16 h and basify with a saturated solution of NaHCO3. The aqueous solution is extracted with EtOAc, then washed with water, brine, dried with Na 2 SO 4, filtered and concentrated in vacuo to obtain l-iodo-4-isopropyl-2-methoxy-5- (toluene-4). sulfonyl) -benzene (12.35 g, 89%). Step 2. l-Isopropyl-5-methoxy-2- (toluene-4-sulfonyl) -4-trifluoromethyl-benzene To a hot mixture (temperature of the oil bath 120 ° C) of l-iodo-4-isopropyl-2 -methoxy-5- (toluene-4-sulfonyl) -benzene (0.5 g, 1.12 mmol), Cul, KF in anhydrous DMF (10 ml) was added trifluoromethyl iodide (0.64 g, 4.48 mmol) in portions over 30 min. The reaction mixture was heated for 4 h and poured into H20 (100 ml). The insoluble solid is collected by filtration, triturated with methylene chloride, filtered and concentrated to give 1-isopropyl-5-methoxy-2- (toluene-4-sulfonyl) -4-trifluoromethyl-benzene (0.45 g, 100%) in the form of a solid. Step 3. 2-isopropyl-4-methoxy-5-trifluoromethyl-phenol A solution of 1-iso-propyl-5-methoxy-2- (toluene-4-sulfonyl) -4- is heated at 90 ° C for 2 h. trifluoromethyl-benzene (0.40 g, 1.03 mmole) and NaOH (0.5 g, 12.5 mmole) in MeOH (5 ml) and H20 (5 ml). The reaction mixture was cooled, acidified with 3N HCl and extracted with methylene chloride. The organic extracts are combined, dried over Na 2 SO 4, filtered and concentrated to obtain the desired 2-isopropyl-4-methoxy-5-trifluoromethyl-phenol (0.194 g, 81%) as an oil. Step 4. 5- (2-isopropyl-4-methoxy-5-trifluoromethyl-phenoxy) -pyrimidine-2,4-diamine According to the procedure of example 2, steps 5-7 is converted to 2-isopropyl-4-methoxy -5-trifluoromethyl-phenol in 5- (2-isopropyl-4-methoxy-5-trifluoromethyl-phenoxy) -pyrimidine-2,4-diamine; M + H = 343.

Example 50: 5- (2-isopropyl-4-methoxy-5-thiazol-4-yl-phenoxy) -pyrimidine-2,4-diamine The synthesis procedure used in this example is described in the reaction scheme T.

Reaction scheme T Stage 1. 1- [4-isopro-yl-2-methoxy-5- (toluene-4-sulfonyl) -phenyl] -ethanone To a clear solution of 2-isopropyl-4-methoxy-1- ( toluene-4-sulfonyl) -benzene (5.3 g, 16.56 mmol) in DCE (50 ml) is added to T.A. acetyl chloride (2.0 g, 24.84 mmoles) and A1C13 (3.3 g, 24.84 mmoles). The reaction mixture is stirred at T.A. for 16 h and quench the reaction with H20 (10 ml). Ten minutes after such interruption, the aqueous solution is extracted with CH2C12. The organic extracts are combined, washed with H20, dried over Na2SO, filtered and concentrated. Flash chromatography through silica gel (0 to 30% EtOAc in hex) affords l- [4-isopropyl-2-methoxy-5- (toluene-4-sulfonyl) -phenyl] -ethanone (4.7 g, 79%) in the form of a white solid. Step 2. 2-Bromo-l- [4-isopropyl-2-methoxy-5- (toluene-4-sulfonyl) -phenyl] -ethanone To a warm mixture of CuBr2 (0.25 g, 1.10 mmol) in EtOAc (1 ml ) was added a solution of 1- [4-isopropyl-2-methoxy-5- (toluene-4-sulfonyl) -phenyl] -ethanone (0.2 g, 0.55 mmol) in CH3C1 (1 ml). The reaction mixture was refluxed for 16 h, filtered and concentrated, yielding 2-bromo-l- [4-isopropyl-2-methoxy-5- (toluens-4-sulfonyl) -phenyl] -ethanone (0.23 g). g, 95%) in the form of oil. Step 3. 4- [4-isopropyl-2-methoxy-5- (toluene-4-sulfonyl) -phenyl] -thiazole To a solution of 2-bromo-l- [4-isopropyl-2-methoxy-5- ( toluene-4-sulfonyl) -phenyl] -ethanone (0.23 g, 0.51 mmol) in anhydrous dioxane (5 ml) is added Na2CO3 (1.1 g, 10.12 mmol) and thioamide (5 ml, 0.31 g, 5.06 mmol) . The reaction mixture is refluxed for 3 h and partitioned between H20 and methylene chloride. The organic extracts are combined, dried over Na 2 SO 4, filtered and concentrated. Flash chromatography through silica gel (30% EtOAc in hex) affords 4- [4-isopropyl-2-methoxy5- (toluene-4-sulfonyl) -phenyl] -thiazole (0.19 g, 95%) in oil form. Step 4. 2-isopropyl-4-methoxy-5-thiazol-4-yl-phenol A mixture of 4- [4-isopropyl-2-methoxy-5- (toluene-4-sulfonyl) -phenyl] is refluxed. -thiazole (1.0 g, 2.27 mmol) and K2C03 (1.6 g, 11.34 mmol) "in anhydrous MeOH (10 mL) for 8 h.The solvent is removed in vacuo and the residue is partitioned between methylene chloride and water. The organic extracts are dried with Na 2 SO 4, filtered and concentrated to obtain 2-isopropyl-4-petoxy-5-thiazole-4-yl-phenol Step 5. (2-isopropyl-4-methoxy-5-thiazole) -4-yl-phenoxy) -acetonitrile The 2-isopropyl-4-methoxy-5-thiazol-4-yl-phenol from crude stage 4 and bromoacetonitrile (0.33 g) are heated at 60 ° C for 3 h. 2.72 mmol) together with K2C03 (0.94 g, 6.81 mmol) in anhydrous acetonitrile (30 ml) The reaction mixture was partitioned between EtOAc and water, the organic extracts were combined, dried over Na 2 SO, filtered and concentrated. Flash chromatography through silica gel (10 to 20% EtOAc in hexanes) gives (2-isopropyl-4-methoxy-5-thiazol-4-yl-phenoxy) -acetonitrile (0.47 g, 72%) as an oil. Step 6. 5- (2-isopropyl-4-methoxy-5-thiazol-4-yl-phenoxy) -pyrimidine-2,4-diamine A mixture of (2-isopropyl-4) is heated at 100 ° C for 2 h. -methoxy-5-thiazol-4-yl-phenoxy) -acetonitrile (0.27 g, 0.94 mmole) and Brederick's reagent (0.35 g, 2.01 mmol). The excess of the Brederick reagent is removed under reduced pressure. The residue is dissolved in anhydrous EtOH (10 ml) and aniline HCl (0.38 g, 2.93 mmol) is added. The reaction mixture was heated at 80 ° C for 18 h and partitioned between EtOAc and water. The organic extracts are combined, dried over Na 2 SO 4, filtered and concentrated. Add guanidine carbonate (0.27 g, 1.49 mmol) and NMP (10 ml) and heat at 120 ° C for 10 h. The reaction mixture was poured into water and extracted with EtOAc. The organic extracts are combined, dried over Na 2 SO 4, filtered and concentrated. Flash chromatography through silica gel (3% MeOH in methylene chloride with 0.1% NH4OH) gives 5- (2-isopropyl-4-methoxy-5-thiazol-4-yl-phenoxy) -pyrimidine -2,4-diamine (0.15 g, 68%) as a solid. M + H 358. Example 51: 5- [5- (- Allylidene-hydrazinomethyl) -2-isopropyl-4-methoxy-phenoxy] -pyrimidine-2,4-diamine To a solution of 1- [5- (2, 4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-phenyl] -3-dimethylamino-propenyone (0.25 g, 0.67 mmol) in EtOH (6 ml) hydrated hydrazine (0.076 g, 1.2 mmol) is added. The reaction mixture is stirred at T.A. for 16 h and concentrates. Recrystallization of the crude residue from EtOH / EtOAc gives 5- [5- (N1-allylidene-hydrazinomethyl) -2-isopropyl-4-methoxy-phenoxy] -pyrimidine-2,4-diamine (0.228 g, 100%); M + H 341. EXAMPLE 52: 2- [4- (2, 4-diamino-pyrimidin-5-yloxy) -2-iodo-5-isopropyl-phenoxy] -ethanol Step 1. 5- [5-iodo-2 -isopropyl-4- (2-trimethylsilanyloxyethoxy) -phenoxy] -pyrimidine-2,4-diamine A mixture of 4- (2,4-diamino-pyrimidin-5-yloxy) -2-iodo-5-isopropyl-phenol (0.3 g) is heated at 80 ° C. for 16 h. 0. 78 mmol), (2-bromoethoxy) -tert-butyl-dimethylsilane (0.28 g, 1.17 mmol) and K2CO3 (0.22 g, 1.56 mmol) in anhydrous DMF (5 ml). The solvent is removed with vacuum. The residue is partitioned between methylene chloride and water. The organic extracts are combined, washed with water, dried over Na 2 SO, filtered and concentrated. Flash chromatography through silica gel (3% MeOH in methylene chloride with 0.1% NH 4 OH) affords 5- [5-iodo-2-isopropyl-4- (2-tri-methylsilanyloxy-ethoxy) -phenoxy] -pyrimidine-2,4-diamine (0.38 g, 90%) as a solid. Step 2. 2- [4- (2,4-diamino-pyrimidin-5-yloxy) -2-iodo-5-isopropyl-phenoxy] -ethanol The 5- [5-iodo-2-isopropyl-4- (2-trimethylsilanyloxy-ethoxy) -phenoxy] -pyrimidine-2,4-diamine (0.38 g, 0.69 mmoles), dissolved in water, is heated at 65 ° C for 16 h. a mixture of HOAc / THF / H20 in proportion 3/1 / 1.95 ml). The pH of the reaction mixture is adjusted to 9 and extracted with methylene chloride. The extracts are combined, dried over Na 2 SO, filtered and concentrated. Flash chromatography through silica gel (5% MeOH in methylene chloride with 0.1% NH4OH) gives 2- [4- (2, 4-diamino-pyrimidin-5-yloxy) -2-iodo- 5-isopropyl-phenoxy] -ethanol (0.25 g, 86%) as a white solid; M + 'H 431. Example 53: 5- (4-amino-2-ethylamino-pyrimidin-5-yloxy) -4-isopropyl-2-me oxy-benzamide Step 1. 5- (4-amino-2-ethylamino- pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-benzonitrile To a solution of N * 2 * -ethyl-5- (5-iodo-2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine (1.65 g, 4.12 mmol) in anhydrous DMF (10 ml) CuCN is added and the reaction mixture is heated at 120 ° C for 3 h. The reaction mixture was poured into water (200 ml) and the insoluble portion was collected by filtration. The solid is triturated with a solution of 10% MeOH in methylene chloride and 0.1% NH4OH (100 ml) and filtered again. The filtrate is concentrated and subjected to flash chromatography through silica gel (3% MeOH in methylene chloride with 0.1% NH4OH), obtaining 5- (4-amino-2-ethylamino-pyrimidine-5). -yloxy) -4-isopropyl-2-methoxy-benzonitrile (0.87 g, 71%) as a white solid. Step 2. 5- (4-Amino-2-ethylamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-benzamide To a solution of 5- (4-amino-2-ethylamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-benzonitrile (0.3 g, 0.92 mmol) in EtOH / H20 (1: 1 mixture, 10 ml ) a solution of NaOH (0.37 g, 9.17 mmol) in H20 (1 mL). The mixture is heated reacting at 100 ° C for 24 h and neutralized with 3N HCl. The ethanol is removed in vacuo and the remaining aqueous solution is extracted with methylene chloride. The extracts are combined, washed with water, dried over Na 2 SO, filtered and concentrated. Flash chromatography through silica gel gel (3 to 8% EtOAc in hexanes) affords 5- (4-amino-2-ethylamino-pyrimidin-5-yloxy) -4-isopropyl-2-ethoxy-benzamide ( 0.086 g, 27%) as a white solid; M + H = 346.

Example 54: N * 2 * -ethyl-5- (2-isopropyl-5-methanesulfonyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine A mixture of N * 2 is heated at 70 ° C for two hours. * -ethyl-5- (2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine (0.30 g), 0.99 mmole), methanesulfonic anhydride (1.0 g, 5.96 mmole) and trifluoromethanesulfonic acid (0.37 g, 2.48 mmole). The hot reaction mixture was poured onto ice water and basified with a saturated solution of NaHCO 3. The aqueous solution is then extracted with methylene chloride. The organic extracts are combined, washed with H20, dried over Na2SO, filtered and concentrated. Flash chromatography through silica gel (1% MeOH in methylene chloride with 1% NH4OH) yields N * 2 * - ethyl-5- (2-isopropyl-5-methanesulfonyl-4-methoxy-phenoxy) ) -pyrimidine-2,4-diamine (87 mg, 23%) as a solid; M + H = 381. Example 55: 5- (2-isopropyl-4-methoxy-5-oxazol-4-yl-phenoxy) -pyrimidine-2,4-diamine Step 1. 2-bromo-l- [ 4-isopropyl-2-methoxy-5- (toluene-4-sulfonyl) -phenyl] -ethanone Stir at T.A. for 16 hours a mixture of 2-bromol- [4-isopropyl-2-methoxy-5- (toluene-4-sulfonyl) -phenyl] -ethanone (0.2 g, 0.45 mmol) and sodium formate (0.040 g, 0.60 mmol) in anhydrous DMF (3 ml). The reaction mixture was poured onto H20 and extracted with EtOAc. The organic extracts are combined, dried over Na 2 SO, filtered and concentrated to give 2-hromo-l- [4-isopropyl-2-methoxy-5- (toluene-4-sulfonyl) -phenyl] -ethanone. Stage 2 . 4- [4-isopropyl-2-methoxy-5- (toluene-4-sulfonyl) -phenyl] -oxazole A solution of crude 2-bromo-1- [4-isopropyl-2-methoxy-5- (toluene-4-sulfonyl) -phenyl] -ethanone from the previous section and ammonium acetate is heated at 100 ° C for 2 h. (0.17 g, 2.25 immoles) in HOAc (5 ml). The reaction mixture was partitioned between methylene chloride and a saturated solution of NaHCO 3. The organic extracts are combined, dried over Na 2 SO 4, filtered and concentrated. Flash chromatography through silica gel (30 to 50% EtOAc in hex) affords 4- [4-isopropyl-2-methoxy-5- (toluene-4-sulfonyl) -phenyl] -oxazole (25 mg, 14%) in the form of a white solid. Step 3. 5- (2-isopropyl-4-methoxy-5-oxazol-4-yl-phenoxy) -pyrimidine-2,4-di-amine Applying the procedure of steps 4-6 of example 49 becomes 4-. { 4-isopropyl-2-methoxy-5- (toluene-4-sulfonyl) -phenyl] -oxazole in 5- (2-i.sopropyl-4-methoxy-5-oxazol-4-yl-phenoxy) -pyrimidine -2, 4-diamine; M + H = 342. Example 56: 5- (2-isopropyl-4-methoxy-5-thiazol-2-yl-phenoxy) -pyrimidine-2,, -diamine Step 1. 5- (2,4-diamino- pyrimidin-5-yloxy) -4-iso-ropil-2-methoxy-thiobenzamide Stir at T.A. for 16 h a mixture of 5- (2,4-di-amino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-benzamide (0.25 g, 0.79 mmol), obtained according to the procedure of Example 52) and Lawesson's reagent (0.96 g, 2.37 mmol) in anhydrous THF (20 ml) and concentrated in vacuo. Flash chromatography through silica gel (5% CH3OH in methylene chloride with 1% NH4OH) gives 5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy -thiobenzamide (0.201 g, 76%) as a yellow solid.

Stage 2 . 5- (2-isopropyl-4-methoxy-5-thiazol-2-yl-phenoxy-pyrimidine-2,4-diamine To a solution of 5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-thiobenzamide (0.23 g, 0.69 mmol) in HOAc (5 ml) is added bromoacetaldehyde diethylacetal ( 0.18 g, 0.9 mmol) and TsOH (5 mg) as a catalyst. The reaction mixture was heated at 110 ° C for 16 h and basified with a saturated solution of NaHCO. The aqueous solution is extracted with methylene chloride. The organic extracts are combined, dried over Na 2 SO 4, filtered and concentrated. Flash chromatography through silica gel (5% MeOH in methylene chloride with 1% NH4OH) gives 5- (2-isopropyl-4-methoxy-5-thiazol-2-yl-phenoxy) -pyrimidine -2,4-diamine (0.070 g, 28%) as a yellow solid; M + H = 358 Example 57: 5- (4-Ethoxy-5-iodo-2-isopropyl-phenoxy) -pyrimidine-2,4-diamine To a solution of 4- (2,4-diamino-pyrimidin-5-yloxy) -2-iodo-5-isopropyl-phenol (0.2 g, 0.52 mmol) in anhydrous DMF (2 ml) is added in portions .tBr (57 mg, 0.52 mmol). The reaction mixture was partitioned between EtOAc and H20. Dry the organic extract with Na 2 SO 4, filter and concentrate. Flash chromatography through silica gel (3% MeOH in methylene chloride with 1% NH4OH) yields 5- (4-ethoxy-5-iodo-2-isopropyl-phenoxy) -pyrimidine-2, 4 -diamine (0.17 g, 28%) as a yellow solid. M + H = 415. Example 58: 5- (2-isopropyl-4-methoxy-5- [1,2,4] oxadiazol-3-yl-phenoxy) -pyrimidine-2,4-diamine The synthesis procedure used in this example it is described in the reaction scheme U.

Reaction scheme U The 5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-benzonitrile used in step 1 of this example is obtained by the method described in ' reaction scheme 1. Step 1: 5- (2,4-diamino-pyrimidin-5-yloxy) -N-hydroxy-4-isopropyl-2-methoxy-benzamidine The benzamidation carried out in this step is carried out according to the procedure described by Meyer et al., Synthesis 6: 899-905 (2003). To a stirred mixture of hydroxylamine hydrochloride (0.099 g, 1.43 mmol) and sodium hydrogen carbonate (0.119 g, 1.42 mmol) in ethanol (1.4 ml) and water (0.3 ml) is added 5- (2, 4- diamine-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-benzonitrile (0.385 g, 1.29 mmol) and the mixture is refluxed for 5 hours. A second portion of hydroxylamine hydrochloride (0.049 g, 0.71 mmol) and sodium hydrogen carbonate (0.060 g, 0.71 mmol) is added. After a further 2 hours the mixture is cooled, concentrated in vacuo, then diluted with water (10 ml) and extracted with ethyl acetate. The organic extracts are combined, washed with brine and then dried (MgSO), filtered and concentrated in vacuo to give 5- (2,4-diamino-pyrimidin-5-yloxy) -N-hydroxy-4-. isopropyl-2-methoxy-benzamidine (355 mg) as a yellow foam. This material is used directly without further purification. Step 2: N- [2-amino-5- (2-isopropyl-4-methoxy-5- [1, 2, 4] -oxadiazol-3-yl-phenoxy) -pyrimidin-4-11] formamide, N- [4-amino-5- (2-isopropyl-4-methoxy-5- [1, 2,] oxadiazol-3-yl-phenoxy) -pyridin-2-yl] formamide and N- [4-formylamino- 5- (2-isopropyl-4-me-toxy-5- [1,2,4] oxadiazol-3-yl-phenoxy) -pyrimidin-2-yl] -formamide. The formulation carried out in this step conforms to the procedure described by Kitamura et al., Chem. Pharm. Bull. 49: 268-277 (2001). Namely, to a suspension of 5- (2,4-diamino-pyrimidin-5-yloxy) -N-hydroxy-4-isopropyl-2-methoxy-benzamidine (0.350 g, 1.05 mmol) in trimethyl orthoformate (1.12 g) , 10.5 mmole) at TA and boron trifluoride diethyl ether is added under a nitrogen atmosphere (~ 1 drop) and then the mixture is refluxed for 1.5 hours The resulting mixture is cooled, diluted with dichloromethane (60 ml), then washed with water (20 ml), brine (20 ml) and then dried (MgSO 4), filtered and concentrated in vacuo to obtain a mixture of N- [2-amino-5- (2-isopropyl-4-methoxy-5- [1,2,4] oxadiazol-3-yl-pheno-xi) -pyrimidin-4-yl] formamide, N- [4 -amino-5- (2-isopropyl-4-methoxy-5- [1,2,4] oxadiazol-3-yl-phenoxy) -pyrimidin-2-yl] -formamide and N- [4-formylamino-5] - (2-isopropyl-4-methoxy-5- [1, 2, 4] oxa-diazol-3-yl-phenoxy) -pyrimidin-2-yl] -formamide as a yellow solid (260 mg). This material is used directly without further purification. Step 3: 5- (2-isopropyl-4-methoxy-5- [1, 2, 4] oxadiazol-3-yl-phenoxy) -pyrimidine-2,4-diamine.

A mixture of N- [2-amino-5- (2-isopropyl-4-methoxy-5- [1, 2, 4] oxa-diazol-3-yl-phenoxy) is kept under reflux for 24 h. pyrimidin-4-yl] formamide, N- [4-amino-5- (2-isopropyl-4-methoxy-5- [1,2,4] oxadiazol-3-yl-phenoxy) -pyrimidin-2- il] formamide and N- [4-formylamino-5- (2-isopropyl-4-methoxy-5- [1, 2, 4] oxadiazol-3-yl-phenoxy) -pyrimidin-2-yl] -formamide (0.164 g) in TFA (10 ml). The mixture is then cooled and concentrated in vacuo. The residue was purified by flash chromatography (0 to 5% methanol in dichloromethane), yielding 76 mg of 5- (2-isopropyl-4-methoxy-5- [1,4,2] oxadiazol-3-yl-phenoxy ) -pyrimidine-2,4-diamine in the form of its trifluoroacetic acid salt. M + H + = 343; p.f. 135-138.5 ° C; NMR-H1 - (CDC1) d: 1.27 (app d, 6H, J = 7.0 Hz), 3.11 (quintet, ÍH, J = 7.0 Hz), 4.04 (s, 3H), 6.02 - 6.24 (br D, 2H), 6.93 (s, ÍH), 7.02 (s, ÍH), 7.68 (s, ÍH), 8.74 (s, ÍH) . Example 59: 5- (6-isopropyl-4-methyl-3,4-dihydro-2H-benzo [1,4-oxazin-7-yloxy) -pyrimidine-2,4-diamine The synthesis procedure used in this example is described in the reaction scheme V.

Reaction Scheme V Stage 1. 2-chloro-N- (2,4-dimethoxy-phenyl) -acetamide A mixture of 2,4-dimethoxy aniline (30.6 g, 0.2 mol) is stirred at 0 ° C under nitrogen. and triethylamine (27.9 ml, 0.2 moles) in 600 ml of methylene chloride. Chloroacetyl chloride (16 ml, 0.2 mol) is added dropwise and the reaction mixture is stirred for 15 minutes at 0 ° C and then stirred for a further two hours, during this period the reaction mixture is allowed to warm to T.A. The reaction is quenched by the addition of 1N HCl and then a saturated aqueous solution of sodium bicarbonate. The aqueous mixture was partitioned with EtOAc, the organic phase was separated, dried (MgSO), filtered and concentrated under reduced pressure, obtaining 45.58 g of the 2-chloro-N- (2,4-dimethoxy-phenyl) - crude acetamide; MS (M + H) = 230. Step 2. 2-Chloro-N- (2-hydroxy-4-methoxy-phenyl) -acetamide Dissolve 2-chloro-N- (2,4-dimethoxy-phenyl) -acetamide (45.8 g, 0.2 mol) in 1000 ml of methylene chloride and the reaction mixture was stirred at 0 ° C under a nitrogen atmosphere. Aluminum trichloride (78.9 g, 0.6 mole) is added in portions over 30 minutes and the reaction mixture is kept stirring at T.A. for 17 hours. The reaction mixture was concentrated under reduced pressure to a volume of 200 ml and then poured on ice. The solids are separated by filtration and the liquid is taken up in EtOAc, washed with brine, dried (MgSO 4), filtered and concentrated under reduced pressure, obtaining 39.67 g of 2-chloro-N- (2-hydroxy). 4-methoxy-phenyl) -acetamide; MS (M + H) = 216. Step 3. 7-methoxy-4H-benzo [1,4] oxazin-3-one 2-chloro-N- (2-hydroxy-4-methoxy-phenyl) - acetamide (390.0 g, 0.18 moles) and potassium carbonate powder (27.6 g, 0.2 mol) was added to 1000 ml of acetone and the reaction mixture was boiled under reflux under nitrogen for eight hours. The reaction mixture was cooled, the solids were separated by filtration and the liquid was concentrated under reduced pressure, obtaining 32.56 g of crude 7-methoxy-4H-benzo [1,4] oxazin-3-one.; (M + H) = 180. Step 4. 7-methoxy-4-methyl-4H-benzo [1,4] oxazin-3-one. 7-methoxy-4H-benzo is stirred at 0 ° C under nitrogen. [1,4] oxazin-3-one (11.61 g, 0.065 mol) in 100 ml of dry DMF. Sodium hydride (60%, 2.85 g, 0.0713 mol) is added in portions over 30 minutes, then methyl iodide (4.44 ml, 0.071 mol) is added dropwise. The reaction mixture was stirred at 0 ° C for 2.5 hours, then poured into 1400 ml of water. The resulting aqueous mixture is extracted four times with 400 ml of EtOAc and the organic phases are combined, washed with water, then with brine, dried (MgSO.sub.4), filtered and concentrated under reduced pressure, obtaining 13.07 g. -methoxy-4-methyl-4H-benzo [1,4] oxa-zin-3-one. (M + H) = 194. Step 5. 7-Methoxy-4-methyl-3,4-dihydro-2H-benzo [1,4] oxazine 7-Methoxy-4-methyl-4H-benzo [1 is added , 4] oxazin-3-one (13.07 g, 0.68 mol) to 100 ml of dry THF and the reaction mixture is maintained under boiling under reflux under a nitrogen atmosphere. Borane-dimethyl sulfide (13.6 ml, 0.136 mol) is added dropwise over an hour and the reaction mixture is refluxed for two hours. The reaction mixture was cooled and the reaction was stopped by the addition of 50 ml of 10% HCl in water. The precipitate is separated by filtration and the liquid is concentrated under reduced pressure, obtaining 11.17 g of 7-methoxy-4-methyl-3,4-dihydro-2H-benzo [1,4] oxazine; (M + H) = 180. Step 6. 1- (7-methoxy-4-methyl-3,4-dihydro-2H-benzo [1,4] -oxazin-6-yl) -ethanone. It is stirred at 0 °. C under nitrogen atmosphere 7-methoxy-4-methyl-3,4-dihydro-2H-benzo [1,4] oxazine (11.17 g, 0.625 moles) in 400 ml of 1,2-dichloroethane. Aluminum trichloride (8.3 g, 0.625 mole) is added in portions and then acetyl chloride (4.9 ml, 0.678 mole) is added dropwise. The reaction mixture was stirred at 0 ° C for 2.5 hours. The aluminum trichloride (3 g) is added and the reaction mixture is stirred at T.A. for 24 hours. The reaction mixture was poured onto ice and added with 550 ml of 3N HCl. The aqueous mixture is extracted with methylene chloride, the organic phases are combined, dried (MgSO 4), filtered and concentrated under reduced pressure, obtaining 10.48 g of the l- (7- methoxy-4-methyl-3, 4 -dihydro-2H-benzo [1,4] oxazin-6-yl) -ethanone; (M + H) = 222. Step 7. 6-Isopropyl-7-methoxy-4-methyl-3,4-dihydro-2H-benzo [1,4] oxazine Dissolve 1- (7-methoxy-4- methyl-3, 4-dinidro-2H-benzo [1,4] oxazin-6-yl) -ethanone (10.48 g, 0.473 mol) in 25 ml of dry THF and the reaction mixture was stirred at 0 ° C in nitrogen atmosphere. Methyl magnesium bromide (22 ml of a 3M solution in Et20, 0.15 mol) is added dropwise and the reaction mixture is stirred at 0 ° C for two hours. The reaction is stopped by the dropwise addition of 50 ml of 10% ammonium chloride in water and then water. The aqueous mixture is extracted with EtOAc and the organic phases are combined, dried (MgSO), filtered and concentrated under reduced pressure. The residue is taken up in 95 ml of acetic acid and the reaction mixture is stirred at T.A. in a nitrogen atmosphere. Ammonium formate (14.92 g) and 10% palladium on activated carbon (1.0 g) are added and the reaction mixture is heated at 120 ° C for three hours. The reaction mixture is cooled, the solids are separated by filtration and the filtrate is diluted with water and neutralized by the addition of solid sodium bicarbonate. The resulting aqueous solution was extracted with EtOAc and the organic phases were combined, dried (MgSO), filtered and concentrated under reduced pressure to obtain 9.97 g of 6-isopropyl-7-methoxy-4-methyl-3, 4 -dihydro-2H-benzo [1,4] oxazine. Step 8. 5- (6-isopropyl-4-methyl-3,4-dihydro-2H-benzo- [1,4] oxazin-7-yloxy) -pyrimidine-2,4-diamine The 6-isopropyl- 7-methoxy-4-methyl-3, 4-dihydro-2H-benzo [1,4] oxazine (2.21 g, 0.01 mol) in 20 ml of methylene chloride and the reaction mixture was cooled to -65 ° C. Boron tribromide (12 ml of a 1M solution in methylene chloride) is added dropwise, 0.012 moles) for 15 minutes and the reaction mixture was stirred for 5.5 hours, during this period the reaction mixture was allowed to warm to 0 ° C. The reaction mixture is then maintained under stirring at T.A. for 24 hours. The reaction mixture was cooled to 0 ° C and methanol was slowly added until the exothermic reaction ceased. The reaction mixture was partitioned between water and methylene chloride and the organic phase was dried (MgSO), filtered and concentrated under reduced pressure, obtaining 1.38 g of the 5- (6-isopropyl-4-methyl-3, 4 -dihydro-2H-benzo [1,4] oxazin-7-yloxy) -pyrimidine-2, -diamine. (M + H) = 208. Step 9. 5- (6-isopropyl-4-methyl-3,4-dihydro-2H-benzo- (1,4] oxazin-7-yloxy) -pyrimidine-2, 4- diamine Applying the procedure of steps 4-6 of example 49 converts 5- (6-isopropyl-4-methyl-3,4-dihydro-2H-benzo [1,4] oxazin-7-yloxy) -pyrimidine- 2,4-diamine in 5- (6-isopropyl-4-methyl-3,4-dihydro-2H-benzo [1,4] oxazin-7-yloxy) -pyrimidine-2,4-diamine. (M + H) = 316; p.f. = 167.3-170.1 ° C. Example 60: 5- (5-furan-2-yl-2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine In a closed pressure flask with screw cap, 5- (5-iodo-2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine (400 mg, 1 mmol), furan- 2-boronic (285 mg, 1.5 mmol) and Pd (Ph3) 2 Cl2 (50 mg) in 13 ml of degassed dioxane. Sodium bicarbonate (2 ml of a 2M aqueous solution) is added and the reaction mixture is heated at 105 ° C for 40 hours. The reaction mixture was cooled and partitioned between water and ethyl acetate. The organic phase is separated, dried (MgSO), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (3% to 5% MeOH in methylene chloride with 1% ammonium hydroxide), obtaining 53 mg of the 5- (5-furan-2-yl-2-isopropyl-4- methoxy-phenoxy) -pyrimidine-2,4-diamine. (M + H) = 339; p.f. = 253.7 - 254.6 ° C. Example 61: 5- (5-furan-2-yl-2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine In a sealed pressure vial with a screw cap, 5- (5-iodo-2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine (400 mg, 1.0 mmol), potassium acetate, is introduced. (147 mg), Pd (Ph3) 2Cl2 (40 mg in 2 ml of dimethyl acetamide) and thiazole and heated at 155 ° C for 40 hours. The reaction mixture was cooled and partitioned between water and ethyl acetate. The organic phase is separated, dried (MgSO), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (3% to 5% MeOH in methylene chloride with 1% ammonium hydroxide), affording 61 mg of 5- (5-furan-2-yl-2-isopropyl-4- methoxy-phenoxy) -pyrimidine-2,4-di-amine. (M + H) = 356; p.f. = 199.1 - 203.3 ° C. Example 62: 5- [2-isopropyl-5- (4-methanesulfonyl-piperazin-1-yl) -4-me oxy-phenoxy] -pyrimidine-2,4-diamine Reaction Scheme W Stage 1. 1- [4- (4-benzyl-piperazin-1-yl) -2-hydroxy-5-methoxy-phenyl] -ethanone To a solution of 1- (2-benzyloxy-4-fluor) -5-methoxy-phenyl) -ethanone (4.25 g, 15.5 mmol) in 3 ml of DMF was added 1-benzyl-piperazine (5.4 ml, 30.9 mmol) and potassium carbonate (4.28 g, 30.9 mmol). The reaction mixture was heated under a nitrogen atmosphere at 130-140 ° C for 18 hours. The reaction mixture was cooled to T.A., poured onto ice-water and extracted with EtOAc. The organic phases are combined, washed with brine, dried (MgSO), filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography through silica gel (hexanes / ethyl acetate = 8.5 / 1.5), obtaining- 4.5 g (73%) of the 1- [4- (4-benzyl-piperazine-1- il) -2-hydroxy-5-methoxy-phenyl] -ethanone as a solid; p.f. = 90-92 ° C. Step 2. 2- [2-benzyloxy-4- (4-benzyl-piperazin-1-yl) -5-methoxyphenyl] -propan-2-ol 1- [4- (4-benzyl-piperazine-1) is dissolved -yl) -2-hydroxy-5-methoxy-phenyl] -ethanone (4.25 g, 11.3 mmol) in 100 ml of dry THF, the resulting solution is cooled to 0 ° C and stirred under a nitrogen atmosphere. Methyl magnesium bromide (5.6 ml, 16.9 mmol) was added dropwise and the reaction mixture was stirred for 30 minutes at 0 ° C. The reaction mixture is stirred at T.A. for an additional 12 hours, then it is poured onto ice-water and extracted with EtOAc. The organic phases are combined, washed with a saturated aqueous solution of ammonium chloride, dried (MgSO), filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography through silica gel (hexanes / ethyl acetate = 8/2), obtaining 4.73 g (94%) of 2- [2-benzyloxy-4- (4-benzyl-piperazine- 1-yl) -5-methoxy-phenyl] -propan2-ol as a solid; p.f. = 94-96 ° C.

Step 3. 2- (1-Hydroxy-1-methyl-ethyl) -4-methoxy-5-piperazin-1-yl-phenol Hydrogenate to T.A. for 12 hours a mixture of 2- [2-benzyloxy-4- (4-benzyl-piperazin-1-yl) -5-methoxy-phenyl] -propan-2-ol (2.01 g, 4.5 mmol) and Pd at 10 % on C (0.28 g) in EtOH (60 ml) with a hydrogen pressure of 50 psi. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated under reduced pressure, obtaining 1.1 g (92%) of 2- (1-hydroxy-l-methyl-ethyl) -4-methoxy-5-piperazine-1. -yl-phenol. Step 4. 2-isopropyl-4-methoxy-5-piperazin-1-yl-phenol To a suspension stirred under a nitrogen atmosphere at T.A. of 2- (1-hydroxy-l-methyl-ethyl) -4-methoxy-5-piperazin-1-ylphenol (0.5 g), 1.9 mmol) in dichloromethane was added TFA acid (7.2 ml, 93.86 mmol) and then triethylsilane (3.0 ml, 18.8 mmol). The reaction mixture is stirred at T.A. for 18 hours and then concentrated under reduced pressure. The residue is partitioned between dichloromethane and a saturated aqueous solution of potassium carbonate. The organic phase is separated, washed with water, dried (MgSO 4), filtered and concentrated under reduced pressure, obtaining 0.47 g (99%) of 2-isopropyl-4-methoxy-5-piperazin-1-yl- phenol in the form of oil. Step 5. 2-Isopropyl-5- (4-methanesulfonyl-piperazin-1-yl) -4-methoxy-phenol To a stirred solution at 0 ° C under nitrogen atmosphere of 2-isopropyl-4-methoxy-5-piperazine -l-yl-phenol (0.47 g, 1.88 mmol) in dichloromethane is added triethylamine (0.26 ml, 1.89 mmol) and then methanesulfonyl chloride (0.15 ml, 1.89 mmol). The reaction mixture was stirred at 0 ° C for five minutes and then allowed to warm to T.A. The reaction mixture was partitioned between dichloromethane and water and the organic phase was separated, washed with water, dried (MgSO 4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexanes / EtOAc = 3/2), obtaining 0.1 g (16%) of 2-isopropyl-5- (4-methanesulfonyl-piperazin-1-yl) -4-methoxy-phenol in the form of oil. Step 6. 5- [2-isopropyl-5- (4-methanesulfonyl-piperazin-1-yl) -4-methoxy-phenoxy] -pyrimidine-2,4-diamine Applying the procedure of steps 4-6 of example 49 2-isopropyl-5- (4-methanesulfonyl-piperazin-1-yl) -4-methoxy-phenol is converted to 5- [2-isopropyl-5- (4-methanesulfonyl-piperazin-1-yl) -4 -methoxy-phenoxy] -pyrimidine-2,4-diamine. (M + H) = 437; p.f. = 115-117 ° C. Example 63: 5- (4-ethyl-7-methyl-benzo [b] iofen-5-yloxy) -pyrimidine-2,4-diamine The synthesis procedure used in this example is described in reaction scheme X. et Anüi Reaction scheme X Stage 1: N-methoxy-N-methyl-butyramide Pyridine (100 ml) is cooled to 0 ° C and N, O-dimethylhydroxylamine hydrochloride (20.14 g, 206 g) is added with stirring. mmoles). This solution is stirred for 10 minutes and then a solution of butyryl chloride (19.5 ml, 20 g, 188 mmol) in 50 ml of methylene chloride is added through a loading funnel for 30 minutes. After 5 minutes, a precipitate forms. This suspension is stirred and allowed to warm to T.A. Stirring is continued for 2.0 hours, the reaction mixture is diluted with water and dried. extract twice with methylene chloride. The methylene chloride phases are combined and washed twice with 1 N HCl and once with brine. Diethyl ether (100 ml) is added to facilitate the separation of the emulsion, the organic phase is separated and washed with a saturated bicarbonate solution and with brine and dried with magnesium sulfate. The solution is filtered and the solvent is removed in vacuo, obtaining the N-methoxy-N-methyl-butyramide as an oil (22.1 g, 89%). Step 2. l-Thiophene-3-yl-butan-1-one Dissolve the 3-bromothiophene (11 g, 67 mmol) in hexanes (110 mL), cool to -20 ° C in an acetone bath. water and slowly added, in 10 min, n-BuLi (28 ml, 71 immoles, 2.5 n solution in hexanes), then stirred at -20 ° C for 10 min. In 5 min THF (10 ml) is added with rapid stirring. A precipitate is formed after 2/3 of the addition is completed. After all the THF had been added, the reaction mixture was stirred at -20 ° C for 20 min, 20 ml of hexanes were added and the reaction mixture was allowed to warm to 0 ° C. In 5 minutes, N-methoxy-N-methyl-butyramide (9.29 g, 71 mmol) dissolved in 20 ml of hexanes is added via cannula and the reaction mixture is stirred at 0 ° C for 1.5 hours. The reaction is quenched with water, then with 1N HCl (75 ml), the reaction mixture is extracted twice with ether, washed with 1 N HCl and with brine and dried with magnesium sulfate. The solvent is removed under reduced pressure, obtaining an oil which is purified by flash chromatography (5% EtOAc in hexanes), obtaining 6.7 g (64%) of l-thiophen-3-yl-butan-1-one in the form of oil. Step 3. 2-bromo-l-thiophen-3-yl-butan-1-one The l-thiophen-3-yl-butan-1-one (6.7 g, 43 mmol) in 210 ml is cooled to 0 ° C. of diethyl ether and 0.6 ml of glacial acetic acid are added dropwise, followed by bromine (2.26 ml, 46 mmol) per drop. The reaction mixture is allowed to warm to T.A. during hours. The reaction mixture was washed with water, a 1 N sodium thiosulfate solution, brine and then dried with magnesium sulfate. The solvent was removed under reduced pressure, obtaining an oil that was chromatographed (5% EtOAc in hexanes), obtaining 6.1 g of 2-bromo-l-thiophen-3-yl-butan-1-one (79%). ), in the form of oil. Step 4. 5-thiophene-3-yl-heptane-2,4-dione The EtMgBr (6.69 ml, 13 mmol, 2 M in ethyl ether) in benzene (10 ml) is cooled to 0 ° C and added to it. slowly the tBuOH (1.28 ml, 13 mmol). The reaction mixture was stirred at 0 ° C for 5 minutes, then acetone (530 ul, 7 mmol) was added, followed by a solution of 2-bromo-l-thiophen-3-yl-butan-1-one (1.3 g, 6 mmoles) in 3 ml of benzene through a cannula. The reaction mixture is heated under reflux for 1 hour and acetone (250 ul) is added. The reaction mixture was heated at reflux for a further 2 hours. The reaction mixture was cooled, the reaction was quenched with 1 N HCl (10 ml), the reaction mixture was extracted three times with diethyl ether, washed with brine and dried with magnesium sulfate. The solvent is removed in vacuo and the residue is chromatographed (5% ethyl acetate in hexanes) to obtain 247 mg of the starting material 2-bromo-l-thiophen-3-yl-butan-1-one and 520 mg of 5-thiophene-3-yl-heptane-2,4-dione (44%). Step 5. 4-Ethyl-7-methyl-benzo [b] thiophen-5-ol Dissolve 5-thiophen-3-yl-heptane-2, 4-dione (410 mg, 2 immoles) in 15 ml of benzene and p-toluenesulfonic acid monohydrate (408 mg, 2 mmol) is added. The reaction mixture is heated at reflux for 30 min, cooled, diluted with diethyl ether, washed with a saturated solution of sodium bicarbonate, water, brine and dried with magnesium sulfate. It is concentrated in the rotary evaporator, obtaining 370 mg of 4-ethyl-7-methyl-benzo [b] thiophen-5-ol, 98%, as a white solid. Step 6. (4-Ethyl-7-methyl-benzo [b] thiophen-5-yloxy) -acetonitrile Dissolve 4-ethyl-7-methyl-benzo [b] thiophen-5-ol (438 mg, 2 mmol ) in 10 ml of DMF and the reaction mixture was cooled to 0 ° C. Sodium hydride (66 mg, 3 mmol) is added and the reaction mixture is stirred at 0 ° C for 30 minutes. Bromoacetonitrile (170 DI, 3 mmol) is added and the reaction mixture is stirred at 0 ° C for 10 minutes, then allowed to warm to T.A. After 1 hour at T.A. the reaction is quenched with water, diluted with ethyl acetate, washed with water, brine and dried with magnesium sulfate. The solvent is removed in vacuo and the residue is chromatographed (10% ethyl acetate in hexanes) to obtain 422 mg of (4-ethyl-7-methyl-benzo [b] thiophen-5-yloxy) -acetonitrile in the form of oil, 80%. Step 7. 3, 3-bis-dimethylamino-2- (4-ethyl-7-methyl-benzo- [b] thiophen-5-yloxy) -propionitrile. 3,3-bis-dimethylamino-2- (4) is dissolved. -ethyl-7-methyl-benzo [b] thiophen-5-yloxy) -propionitrile (422 mg, 2 mmol) in 2.5 ml of tert-butoxy-bis (dimethylamino) methane and the reaction mixture was heated at 100 ° C for 1 hour. The reaction mixture was cooled to T.A. and its volume is reduced with a vacuum of 1 mm while heating to 60 ° C. The flask containing the residue is connected to a high vacuum pump for 1 hour, obtaining 3, 3-bis-dimethylamino-2- (4-ethyl-7-methyl-benzo [b] thiophen-5-yloxy) - propionitrile, 595 mg, 98%, in the form of oil. Step 8. 2- (4-Ethyl-7-methyl-benzo [b] thiophen-5-yloxy) -3-phenylamino-acrylonitrile The 3, 3-bis-dimethylamino-2 is kept at boiling under reflux for 2.0 hours. (4-ethyl-7-methyl-benzo [b] thiophen-5-yloxy) -propionitrile (590 mg, 2 mmol) and the aniline HCl (1.1 g, 9 mmol) in 5 ml of absolute ethanol. In a separate flask, guanidine HCl (0.850 mg, 9 mmol) and a solution of sodium methoxide (1.83 ml, 9 mmol, 4.9 molar solution in methanol) are mixed with 1 ml of ethanol. The guanidine solution is added with a pipette. to the reaction mixture and the reaction mixture is heated under reflux for 5 hours, then cooled. The solvent was removed in vacuo and the residue was chromatographed (5% MeOH in methylene chloride and 1% NH4OH) to obtain 368 mg of 2- (4-ethyl-7-methyl-benzo [b] thiophen-5 -yloxy) -3-phenylamino-acrylonitrile, 61%. 50 mg of 5- (4-ethyl-7-methyl-benzo [b] thiophen-5-yloxy) -pyrimidine-2,4-diamine, 9% are also present. Step 9: 2- (4-Ethyl-7-methyl-benzo [b] thiophen-5-yloxy) -3-phenylamino-acrylonitrile (360 mg, 1 mmol), guanidine HCl are maintained under reflux for 2 hours. (411 mg, 4 mmol) and sodium methoxide (880 ul, 4 mmol, 4.9 M solution in methanol) in 5 ml of absolute ethanol. The guanidine HCl (411 mg, 4 mmol) and sodium methoxide (880 ul, 4 mmol, 4.9 M solution in methanol) are mixed in 1 ml of EtOH and added by pipette and the reaction mixture is heated at reflux for 2 hours. . The reaction mixture was cooled, diluted with water, extracted twice with EtOAc, washed with brine and dried with magnesium sulfate. The solvent was removed in vacuo to obtain 241 mg of 5- (4-ethyl-7-methyl-benzo [b] thiophen-5-yloxy) -pyrimidine-2,4-diamine as a white solid (74%).; mass spectrum M + H = 301 p.f. = 181 ° C. Recrystallization of 175 mg of this product from MeOH and HCl / diethyl ether yields 98 mg of the corresponding HCl salt (49%), mass spectrum M + H = 301, m.p. > 300 ° C. Example 64: 5- (1,3-dimethyl-6-trifluoromethyl-lH-indol-5-yloxy) -pyrimidine-2,4-diamine The synthesis procedure used in this example is described in reaction scheme Y.

Reaction Scheme Y Stage 1. 4-methoxy-3-trifluoromethyl-phenylamine In a Paar apparatus, l-methoxy-4-nitro-2-trifluoromethyl-benzene (10 g, 45 mmol) is hydrogenated with a hydrogen pressure of 50 psi and with stirring for 4 hours, using 1 g of Pd at 10% by weight on C. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo, obtaining 8.6 g of the 4-methoxy-3-. trifluoromethyl-phenylamine, 99%, as a solid. Step 2. Ethyl 5-methoxy-3-methyl-6-trifluoromethyl-lH-indole-2-carboxylate. 4-methoxy-3-trifluoromethyl-phenylamine is cooled to -5 ° C. (5 g, 26 mmol) in 12 ml of water (ice / methanol bath). The conc. HCl is added dropwise. (7 ml) and the reaction mixture was stirred for five minutes. A solution of NaN02 (2.0 g, 29 mmol) in 3 ml of water is added dropwise over 10 minutes and the reaction mixture is stirred for 30 min. Sodium acetate (1.8 g, 22 mol) is then added and stirring is continued at -5 ° C. In a separate flask, the ethyl alpha-acetoacetate (4.55 g, 29 mmol) is stirred in 20 ml of absolute ethanol and KOH (1.6 g, 29 mmol) dissolved in 3 ml of water is added, followed by ice (30 g). ). The resulting diazonium salt is quickly added to the reaction mixture, rinsing with 5 ml of EtOH and the reaction mixture is stirred at 0 ° C for 3.5 hours, then stored at -10 ° C for 16 hours. The reaction mixture is heated to T.A. and extracted with ethyl acetate, washed with brine and dried with magnesium sulfate. The solvent is removed under reduced pressure, obtaining a liquid residue. In a separate flask, 100 ml of EtOH and 21 ml of acetyl chloride are mixed, cooling with an ice bath, then heated to 70 ° C. With a pipette, the liquid residue is added in 15 minutes to the acetyl chloride solution. This reaction mixture is heated to reflux for 2.5 hours, cooled, concentrated under reduced pressure. The residue was purified by column chromatography (10% ethyl acetate in hexane) to obtain 3.0 g of ethyl 5-methoxy-3-methyl-6-trifluoromethyl-1H-indole-2-carboxylate, 38%, of white solid and triturated with diethyl ether, yielding ethyl 5-methoxy-3-methyl-6-trifluoromethyl-lH-indole-2-carboxylate (1.0 g) as a white solid and 5-methoxy-3 ethyl-methyl-4-trifluoromethyl-lH-indole-2-carboxylate (13.9%) as a white solid. Step 3. 5-Methoxy-3-methyl-6-trifluoromethyl-1H-indole-2-carboxylic acid Dissolve 5-methoxy-3-methyl-6-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester (3.0 g , 10 mmol) in 10 ml of absolute ethanol and a solution of KOH (1.7 g, 30 mol) in 7 ml of water is added. The reaction mixture is heated at reflux for 2.5 hours, then cooled, acidified slowly with 6 N HCl to pH = 2 and extracted with ethyl acetate. The organic phases are combined, washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure, yielding 2.0 g (73%) of 5-methoxy-3-methyl-6-trifluoromethyl-1H-indole. -2-carboxylic. Step 4. 5-methoxy-3-methyl-6-trifluoromethyl-1H-indole To a solution of 5-methoxy-3-methyl-6-trifluor-methyl-1H-indole-2-carboxylic acid (2.0 g, 7 mmol) in 5 ml of quinoline, copper powder (50 mg) is added and the reaction mixture is heated at reflux for 1.5 hours. Copper powder (50 mg) is added and the reaction mixture is boiled at reflux for 1 hour. The reaction mixture was cooled, diluted with EtOAc, poured into 50 ml of 6 N HCl and extracted with EtOAc. The organic phases are combined, washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed (10% EtOAc in hexanes) to give 5-methoxy-3-methyl-6-trifluoromethyl-1H-indole (850 mg, 51%) as a solid. Step 5. 5-methoxy-1,3-dimethyl-6-trifluoromethyl-1H-indole A solution of 5-methoxy-3-methyl-6-trifluoromethyl-1H-indole (900 mg, 4 mmol) was cooled to 0 ° C. ) in 7 ml of DMF and sodium hydride (104 mg) is added., 4 immoles, 95% powder). The reaction mixture was stirred at 0 ° C for 15 minutes and iodomethane (270 ID, 4 mmol) was added. The reaction mixture was stirred for 1 hour and allowed to warm to T.A. The reaction mixture was then cooled to 0 ° C, the reaction was quenched by the addition of 1 N NH 4 Cl 1, diluted with water and extracted with EtOAc. The organic phases are combined, washed with water, brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain 5-methoxy-1,3-dimethyl-6-trifluoromethyl-1H-indole (725 mg. , 75%) in solid form. Step 6 The 5-methoxy-1,3-dimethyl-6-trifluoromethyl-1H-indole (725 mg, 3 mmol) in methylene chloride (15 ml) is cooled to 0 ° C and the BBr3 is added slowly with a syringe. (14.9 ml of a 1 N solution in methylene chloride). The reaction mixture was stirred at zero degrees for 15 minutes, then allowed to warm to T.A. for one hour with agitation. The reaction is stopped by slowly adding 75 ml of 1 N NaOH. The mixture is acidified to pH approx. With 1 N HCl, it is extracted with methylene chloride and the organic phases are combined, washed with water, brine and dried with magnesium sulfate. The solvent was removed under reduced pressure and the residue was chromatographed (20% EtOAc in hexanes) to obtain 235 mg (75%) of 1,3-dimethyl-6-trifluoromethyl-1H-indol-5-ol. Step 7: By applying the procedure of steps 6-9 of Example 62, 1,3-dimethyl-6-trifluoromethyl-1H-indol-5-ol is converted into 5- (1,3-dimethyl-6-trifluoromethyl-1H) -indol-5-yloxy) -pyrimidine-2, -diamine (70 mg). The corresponding hydrochloride salt is recrystallized from MeOH / diethyl ether; mass spectrum M + H = 338, p.f. = 256 ° C. Example 65: 6- (2,4-diamino-pyrimidin-5-yloxy) -5-isopropyl-3-methyl-1H-indole-2-carboxylic acid. The synthesis procedure used in this example is described in the Z reaction scheme. et Reaction Scheme Z Step 1. N- (4-Acetyl-3-methoxy-phenyl) -acetamide. N- (3-methoxy-phenyl) -acetamide (17.7 g, 107 mmol) in chloride is cooled to 0 ° C. of methylene and slowly added acetyl chloride (19.0 ml, 268 mmol) and then aluminum chloride (35.7 g, 268 mol) in small portions for 15 min. The reaction mixture was stirred at zero degrees for 15 minutes, then allowed to warm to T.A. with agitation. The reaction mixture was poured onto ice, stirred for 35 minutes and filtered. The solid is washed with water. The filtrate is extracted with EtOAc and the solvent is removed under reduced pressure. The solids were combined, yielding N- (4-acetyl-3-methoxyphenyl) -acetamide (16.5 g, 74%) as a solid. Step 2. N- [4- (1-Hydroxy-l-methyl-ethyl) -3-methoxy-phenyl] -acetamide. Methyl-magnesium chloride (49.9 ml, 150 ml, 3 M solution) is cooled to 0 ° C. in THF) in 100 ml of THF and N- (4-acetyl-3-methoxy-phenyl) -acetamide (14.1 g, 68 mmol) in 200 ml of THF is added in 25 minutes with a cannula. The reaction mixture was stirred and allowed to warm to T.A. for 2.5 hours. The reaction is quenched by the addition of 1 N NH 4 Cl and extracted with EtOAc. The organic phases were combined, washed with 1N ammonium chloride, brine, dried over MgSO4 and concentrated under reduced pressure, yielding N- [4- (l-hydroxy-1-methyl-ethyl) -3-methoxy- phenyl] -acetamide (16.4 g, 100%). Step 3. N- (4-isopropyl-3-methoxy-phenyl) -acetamide. N- [4- (1-hydroxy-l-methyl-ethyl) -3-methoxy-phenyl is stirred at room temperature under N2. ] -acetamide (16.4 g) in 100 ml of glacial acetic acid, 10% palladium on p. on activated carbon (3 g) and then 5 g of ammonium formate. The reaction mixture is heated to reflux. After 30 minutes, 5 g of ammonium formate are added and after another 45 minutes, an additional 8.5 g of ammonium formate is added. The reflux is maintained for a further hour, then the reaction mixture is cooled and filtered through Celite. The filtrate is diluted with water, extracted with EtOAc, the organic phases are combined, washed with brine and dried with magnesium sulfate. Concentration under reduced pressure affords N- (4-isopropyl-3-methoxyphenyl) -acetamide (15.1 g, 99%). Step 4. 4-Isopropyl-3-methoxy-phenylamine. The N- (4-isopropyl-3-methoxy-phenyl) -acetamide (14.5 g, 69.9 mmol) in 200 ml of 6 HCl is heated at 95 ° C for 3.0 hours. - N. The reaction mixture is cooled to RT and keeps T.A. for 72 hours, during this time crystals form. The reaction mixture was filtered and the crystals were washed with 1 N HCl and dried under vacuum, yielding 4-isopropyl-3-methoxy-phenylamine in the form of HCl salt (7.6 g, 60%). Step 5. Ethyl 5-isopropyl-6-methoxy-3-methyl-lH-indol-2-carboxylate The HCl salt of 4-isopropyl-3-methoxy is cooled to -5 ° C (ice bath / methanol) phenylamine (3.1 g, 19 mmol) and a mixture of 8 ml of water and 5 ml of concentrated HCl is added dropwise. The reaction mixture was stirred for five minutes and sodium nitrite (1.42 g, 21 mmol) dissolved in 3 ml of water was added dropwise in 10 minutes. The reaction mixture was stirred for 45 min, then sodium acetate (1.3 g, 16 mmol) was added. In a separate flask, to a stirred mixture of ethyl alpha-acetoacetate (3.26 g, 21 mmol) in 15 ml of absolute ethanol is added KOH (1.2 g, 21 mmol) dissolved in 3 ml of water and then ice is added. (10 g). This mixture is added to the diazonium salt and the reaction mixture is stirred at 0 ° C for 3.5 hours. The reaction mixture was stored at -10 ° C for 16 hours, then extracted with EtOAc. The organic phases are combined, washed with brine, dried with magnesium sulfate and concentrated under reduced pressure, obtaining a liquid residue. In a separate flask, 100 ml of EtOH are slowly mixed with 22 ml of acetyl chloride, cooling with an ice bath. The EtOH / acetyl chloride solution is heated to 70 ° C and the residue is added by pipette for 10 min. The reaction mixture is heated under reflux for 2.5 hours, cooled, concentrated under reduced pressure, obtaining a suspension; it is diluted with water (100 ml) and filtered. The solid is washed with water. The solid was triturated with hexanes to obtain ethyl 5-isopropyl-6-methoxy-3-methyl-1H-indole-2-carboxylate (1.7 g, 34%) as a solid. Step 6. Ethyl 6- (2, 4-diamino-pyrimidin-5-yloxy) -5-isopropyl-3-methyl-lH-indole-2-carboxylate Using the procedure of steps 5-9 of Example 62, it becomes ethyl 5-isopropyl-6-methoxy-3-methyl-lH-indole-2-carboxylate in 6- (2,4-diamino-pyrimidin-5-yloxy) -5-isopropyl-3-methyl-1H- ethyl indole-2-carboxylate; mass spectrum M + H = 370, p.f. = 188.2 ° C. The 6- (2,4-diamino-pyrimidin-5-yloxy) -5-isopropyl-3-methyl-1H-indole-2-carboxylic acid ethyl ester is converted to 6- (2,4-diamino-pyrimidin- 5-yloxy) -5-isopropyl-3-methyl-1H-indole-2-carboxylic acid by treatment with ethanolic potassium hydroxide; (91 mg, 76%); mass spectrum M + H = 342; p.f. > 300 ° C. Example 66: 5- (7-isopropyl-4-methyl-benzooxazol-6-yloxy) -pyrimidine-2,4-diamine Step 1. 7-isopropyl-4-methyl-benzooxazole-6-ol The 4-amino-2-isopropyl-5-methyl-benzene-1,3-diol (450 mg, 2.5 mmol) is charged in a flask (Treibs and Albrecht, Journal fuer praktische Chemie (1961), 13, 291-305 ), purged with argon, cooled to 0 ° C and the triethyl orthoformate (0.7 ml, 4.2 mmol), EtOH (4 ml) and a 10% H2SO4 solution v / v in. EtOH (40 ID). The reaction mixture was allowed to slowly warm to T.A., was stirred overnight, the reaction was quenched with a saturated solution of NaHCO 3 and the reaction mixture was concentrated. The residue is partitioned between water and methylene chloride. The organic phases were combined, dried over Na 2 SO 4 and concentrated, yielding 510 mg of 7-isopropyl-4-methyl-benzooxazol-6-ol. Step 2. 5- (7-isopropyl-4-methyl-benzooxazol-6-yloxy) -pyrimidine-2,4-diamine By applying the procedure of steps 5-7 of Example 2, 7-isopropyl-4-methyl-benzooxazol-6-ol is converted into the - (7-isopropyl-4-methyl-benzooxazol-6-yloxy) -pyrimidine-2,4-diamine. The hydrochloride salt is recrystallized from EtOH / diethyl ether. MS (M + H): 300. Example 67: 5- (7-isopropyl-2,4-dimethyl-benzooxazol-6-yloxy) -pyrimidine-2,4-diamine Step 1. 7-isopropyl-2, 4- dimethyl-benzooxazol-6-ol The 4-amino-2-isopropyl-5-methyl-benzene-1,3-diol (250 mg, 1.4 mmol) is charged in a flask [Treibs and Albrecht, Journal fuer praktische Chemie 13: 291-305 (1961)] , purge with argon, cool to 0 ° C and add triethyl orthoformate (0.53 ml, 4.2 mmol), MeOH (2.5 ml) and a 10% v / v H2SO4 solution in MeOH (25 DI). ). The reaction mixture was allowed to warm slowly to T.A., stirred overnight, the reaction was quenched with a saturated solution of NaHCO3 and concentrated. The residue is partitioned between water and methylene chloride. The organic phases are combined, dried over Na 2 SO and concentrated. Purification by flash chromatography provides 175 mg of 7-isopropyl-2,4-dimethyl-benzooxazol-6-ol. Step 2. 5- (7-isopropyl-2,4-dimethyl-benzooxazol-6-yloxy) -pyrimidine-2,4-diamine Applying the procedure of steps 5-7 of Example 2 converts 7-isopropyl-2,4-dimethyl-benzooxazol-6-ol to 5- (7-isopropyl-2,4-dimethyl-benzooxazol-6-yloxy) ) -pyrimidine-2,4-diamine. The hydrochloride salt is recrystallized from EtOH / diethyl ether. MS (M + H): 314, p.f. > 300 ° C. Example 68: 5- (5-iodo-2-isopropyl-4-methoxy-phenoxy) -1-oxy-pyrimidine-2,4-diamine To a solution of the compound 5- (5-iodo-2-isopropyl-4-methoxy-phenoxy) -pyrimidine-2,4-diamine (1.6 g, 4.0 mmol) in DMF / MeOH (30 ml / 10 ml) was added. add HF (48% solution in water, 0.3 ml, 8.3 mmol). After 3 minutes the m-chloroperoxybenzoic acid (80%, 2.16 g, 10.0 mmol) is added, the mixture is stirred at T.A. for an hour. A cold aqueous 1N NaOH solution is added and the reaction mixture is partitioned between ethyl acetate and water. The organic phase is washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (2% MeOH, 5%, 6%, 8% in CH2C12 with 0.1% NHOH), obtaining 5- (5-iodo-2-isopropyl-4) -methoxy-phenoxy) -l-oxy-pyrimidine-2, 4-diamine (0.2 g, 12%) as a yellow solid; M + H: 417. Example 69: Formulations Pharmaceutical preparations for administration by various routes are formulated as indicated in the tables. The term "active ingredient" or "active ingredient" used in the tables means one or more of the compounds of the formula I. Composition for oral administration Ingredient% p./p. active ingredient 20.0% lactose 79.5% magnesium stearate 0.5% The ingredients are mixed and packaged in capsules containing 100 mg each; The content of one capsule is approximately equivalent to the total daily dose. Composition for oral administration Ingredient% p./p. active substance 20.0% magnesium stearate 0.5% croscarmellose sodium 2.0% lactose 76.5% PVP (polyvinylpyrrolidone) 1.0% The ingredients are combined and granulated using a solvent, for example methanol. The formulation is then dried and pressed into tablets (each containing about 20 mg of the active ingredient) with a machine suitable for the manufacture of tablets. Composition for oral administration Ingredient quantity active ingredient 1.0 g fumaric acid 0.5 g sodium chloride 2.0 g methyl paraben 0.15 g propyl paraben 0.05 g granulated sugar 25.5 g sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 g aroma - 0.035 ml dye 0.5 mg distilled water, sufic amount. up to 100 ml The ingredients are mixed to form a suspension intended for oral administration. Parenteral formulation Ingredient% p./p. active ingredient 0.25 g sodium chloride, sufic. for isotonic water for injections 100 ml The active substance is dissolved in a portion of the water for injections. Then a sufficient amount of sodium chloride is added with stirring to make the solution isotonic. The solution is completed to the desired weight with the remaining water for injection, filtered through a 0.2 micron membrane filter and packaged under sterile conditions. Suppository formulation Ingredient% p./p. active ingredient 1.0% polyethylene glycol 1000 74.5% polyethylene glycol 4000 24.5% The ingredients are melted once, mixed on a steam bath.- and poured into molds, whose total capacity is 2.5 g.

Topical formulation Ingredients grams active principle 0.2-2 Span 60 2 Tween 60 2 mineral oil 5 petrolatum 10 methyl paraben 0.15 propyl paraben 0.05 BHA (butylated hydroxyanisole) 0.01 water, sufficient amount up to 100 All the ingredients are combined, except the water, and heat with agitation at 60 ° C. A sufficient amount of water with vigorous stirring is added at 60 ° C to emulsify the ingredients and then a sufficient amount of water is added to complete the 100 g. Nasal Spray Formulations Various aqueous suspensions containing 0.025 to 0.5 percent active substance are prepared as nasal spray formulations. The formulations optionally contain inactive ingredients, for example microcrystalline cellulose, sodium carboxymethylcellulose, dextrose, and the like. Hydrochloric acid is added to adjust the pH. The nasal spray formulations can be administered by a calibrated pump that delivers 50 to 100 microliters of formulation in each actuation. A typical dosing schedule would be 2 to 4 nebulizations every 4-12 hours. Example 70: FLIPR (Fluormetric Imaging Pye Reader) Assay of P2X3 / P2X2 / 3 CHO-K1 cells are transfected with subunits of rat P2X3 receptor or cloned P2X2 / human receptor and stored in flasks. 18-24 hours before the FLIPR assay, the cells are removed from their flasks, centrifuged and resuspended in a nutrient medium at 2.5 x 10 5 cells / ml. The cells are divided into aliquots in 96-well black bottom plates at a density of 50,000 cells / well and incubated at 37 ° C overnight at 5% C02. On the same day of the assay, the cells are washed with FLIPR buffer (Hank's balanced salt solution, calcium and magnesium free, 10 mM HEPES, 2 mM CaCl 2, 2. mM probenecid, FB). In each hole 100 μl of FB and 100 μl of fluorescent dye Fluo-3 AM [final concentration: 2 μM] are introduced. After 1 hour incubation at 37 ° C with the loaded dye the cells are washed 4 times with FB and a concentration of 75 μl / well of FB is left in each hole. The compounds to be tested are added to each well (dissolved in DMSO at a concentration of 10 mM and diluted in series with FB) or the vehicle (25 μl of a 4X solution) and allowed to equilibrate for 20 minutes at T.A. The plates are then placed in the FLIPR and a measurement of the base fluorescence (excitation at 488 nm and emission at 510-570 nm) is carried out for 10 seconds before the addition of 100 μl / hole of agonist or vehicle. The agonist is a 2X solution of a, ß-meATP that results in a final concentration of 1 μM (of P2X3) or 5 μM (of P2X2 / 3). Fluorescence is measured for 2 more minutes at 1 second intervals After addition of the agonist, a final addition of ionomycin (final concentration: 5 μM) is made to each well of the FLIPR assay plate to check the cell viability and the maximum fluorescence of the cytosolic calcium fixed on the dye. Fluorescence peak of the response to the addition of α, β - meATP (in the absence and presence of the test compounds) and inhibition curves are generated using a non - linear regression.The positive control is PPADS, a standard antagonist. of the P2X When the above procedure is applied, the compounds of the invention exhibit activity with respect to the P2X3 receptor.Applying the above test, the compound N * 2 * ~ isopropyl-5- (2-isopropyl-4,5-dimethoxy- benzyl) -pyrimidi-na-2,4-diamine p It is for example a pIC50 of about 7.54. Surprisingly and unexpectedly, the compounds of the formulas (I-IV), in which R1 is isopropyl, have a higher affinity with respect to P2X3 than the compounds in which R1 is any other alkyl or another substituent. In the following table 3 a comparison of the pICso data of several compounds with different substituents R1 is provided. TABLE 3 From the data in Table 3 it can be deduced that the compounds of the invention, wherein R1 is isopropyl, have better affinity to the P2X receptor than similar compounds having other alkyl substituents at the R1 site. The present invention has been described with reference to the specific forms of execution thereof, but it is assumed by those skilled in the art that various changes can be made and materials can be substituted by other equivalents without departing from the true spirit and scope of the invention. invention. In addition, many modifications can be introduced to adapt it to a particular situation, material, composition of matter, process, stage or process steps, to the spirit and objective scope of the present invention. All modifications are considered to be within the scope of the appended claims.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Claims (7)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A compound of the formula (I): or a pharmaceutically acceptable salt thereof, characterized in that: X is -CH2-; -0-; -CHOH-; -S (0) n-; or -NRC-, wherein n is a number from 0 to 2 and Rc is hydrogen or alkyl; And it's hydrogen; or -NRdRe in which one of Rd and Re is hydrogen and the other is hydrogen; I rent; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl; D is an optional oxygen; Ra is alkyl; alkenyl; cycloalkyl; cycloalkenyl; halogen; haloalkyl; hydroxyalkyl; or alkoxy; R2, R3, R4 and R5 independently of each other are hydrogen; I rent; alkenyl; Not me; halogen; amido; haloalkyl; alkoxy; hydroxy; haloalkoxy; nitro; Not me; hydroxyalkyl; alkoxyalkyl; hydroxyalkoxy; alkynylalkoxy; alkylsulfonyl; Aryisulfonyl; cyano; aril; heteroaryl; heterocyclyl; heterocyclylalkoxy; aryloxy; heteroaryloxy; aralkyloxy; heteroaralkyloxy; phenoxy optionally substituted; ~ (CH2) m- (Z) n- (CO) -Rf or - (CH2) m- (Z) nS02- (NRg) n -Rf, where m and n independently are 0 or 1, Z is 0 or NRg, Rf is hydrogen, alkyl, hydroxy, alkoxy, amino, hydroxyalkyl or alkoxyalkyl and each R9 independently of its appearance is hydrogen or alkyl; or R3 and R4 together can form an alkylenedioxy; or R3 and R4 together with the atoms to which they are attached can form a five or six member ring optionally including one or two heteroatoms chosen from O, S and N; or R2 and R3 together can form an alkylenedioxy; or R2 and R3 together with the atoms to which they are attached can form a five or six member ring optionally including one or two heteroatoms chosen from 0, S and N; R6 is hydrogen; I rent; halogen; haloalkyl; Not me; or alkoxy; and one of R7 and R8 is hydrogen and the other is hydrogen; I rent; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroaryl-alkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl; with the proviso that, when X is -CH2- and R7, R8, Rd and Re are hydrogen, R1 is isopropyl, isopropenyl, cyclopropyl or iodo.
2. 2. The compound according to claim 1, characterized in that it is (a) of the formula (II) wherein: X is -CH2-; u -O-; R1 is alkyl; alkenyl; cycloalkyl; or cycloalkenyl; or halogen; R3 and R4. independently of each other are hydrogen; I rent; alkenyl; Not me; halogen; amido; haloalkyl; alkoxy; hydroxy; haloalkoxy; nitro; hydroxyalkyl; alkoxyalkyl; hydroxyalkoxy; alkynylalkoxy; alkylsulfonyl; Aryisulfonyl; cyano; aril; heteroaryl; heterocyclyl; heterocyclylalkoxy; aryloxy; heteroaryloxy; aralkyloxy; heteroaralkyloxy; phenoxy optionally substituted; - (CH2) m- (Z) n- (CO) -Rf or '- (CH2) m- (Z) n- S02- (NRg) n-Rf, where m and n independently of each other are 0 or 1, Z is O or NRg, Rf is hydrogen, alkyl, hydroxy, alkoxy, amino, hydroxyalkyl or alkoxyalkyl and each Rg irrespective of its appearance is hydrogen or alkyl; or R3 and R4 together can form an alkylenedioxy; or R3 and R4 'together with the atoms to which they are attached can form a five or six member ring optionally including one or two heteroatoms chosen from 0, S and N; one of R7 and R8 is hydrogen and the other is hydrogen; I rent; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl; and one of Rd and Re is hydrogen and the other is hydrogen; I rent; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroaryl-alkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl; or (b) a compound of the formula (III) wherein: R1 is isopropyl; isopropenyl; cyclopropyl; or iodine; R3, R4, R7, R8, Rd and Re have the meanings defined in (a); or (c) a compound of the formula (IV) wherein: R1 is alkyl; alkenyl; cycloalkyl; or cycloalkenyl; R3, R4, R7, R8, Rd and Re have the meanings defined in (a); or (d) a compound of the formula (V) wherein: R3, R4, R7, R8, Rd and Re have the meanings defined in (a); or (e) a compound of the formula (VI) wherein: R3, R4, R7, R8, Rd and Re have the meanings defined in (a); or (f) a compound of the formula (VII) wherein: X is -CH2-; u -0-; R1 is alkyl; alkenyl; cycloalkyl; or cycloalkenyl; or halogen; R2 is hydrogen; I rent; alkenyl; Not me; halogen; amido; haloalkyl; alkoxy; hydroxy; haloalkoxy; nitro; hydroxyalkyl; alkoxyalkyl; hydroxyalkoxy; alkynylalkoxy; alkylsulfonyl; Aryisulfonyl; cyano; aril; heteroaryl; heterocyclyl; heterocyclylalkoxy; aryloxy; heteroaryloxy; aralkyloxy; heteroaralkyloxy; phenoxy optionally substituted; or - (CH2) m- (Z) n- (C0) -Rf or - (CH2) m- (Z) nS02- (NRg) n -Rf, where m and n independently are 0 or 1, Z is O or NRg, Rf is hydrogen, alkyl, hydroxy, alkoxy, amino, hydroxyalkyl or alkoxyalkyl and each R2 independently of its appearance is hydrogen or alkyl; one of R7 and R8 is hydrogen and the other is hydrogen; I rent; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl; one of Rd and Re is hydrogen and the other is hydrogen; I rent; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; acetyl; alkylsulfonyl; alkylsulfonylalkyl; aminocarbonyloxyalkyl; hydroxycarbonylalkyl; hydroxyalkyloxycarbonylalkyl; aril; aralkyl; Aryisulfonyl; heteroaryl; heteroarylalkyl; heteroarylsulfonyl; heterocyclyl; or heterocyclylalkyl; Q is CR9, one of A and E is O, S or NR10 and the other is CR9 or N; or Q is N, one of A and E is NR10 and the other is CR9; each R9 independently of its appearance is hydrogen, alkyl, halogen or alkoxy; and R10 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, - (CH2) m (Z) n- (CO) -Rf or - (CH2) m- (Z) n-S02- (NRg) n-Rf; or (g) a compound of the formula (VIII) wherein: X is -CH2-; u -O-; R1 is alkyl; alkenyl; cycloalkyl; or cycloalkenyl; or halogen; R2 is hydrogen; I rent; alkenyl; Not me; halogen; amido; haloalkyl; alkoxy; hydroxy; haloalkoxy; nitro; hydroxyalkyl; alkoxyalkyl; hydroxyalkoxy; alkynylalkoxy; alkylsulfonyl; Aryisulfonyl; cyano; aril; heteroaryl; heterocyclyl; heterocyclylalkoxy; aryloxy; heteroaryloxy; aralkyloxy; heteroaralkyloxy; phenoxy optionally substituted; or - (CH2) m- (Z) n- (CO) -Rf or - (CH2) m- (Z) nS02- (NRg) n -Rf, where m and n independently are 0 or 1, Z is 0 or NRg, Rf is hydrogen, alkyl, hydroxy, alkoxy, amino, hydroxyalkyl or alkoxyalkyl and each Rg is independent of hydrogen or alkyl; R7, R8, Rd and Re are as defined in (a); Q is CR9, one of A and E is O, S or NR10 and the other is CR9 or N; or Q is N, one of A and E is NR10 and the other is CR9; each R9 independently of its appearance is hydrogen, alkyl, halogen or alkoxy; and R10 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, ~ (CH2) m (Z) n- (CO) -Rf or - (CH2) m- (Z) n-S02- (NRg) n-Rf.
3. 3. A pharmaceutical composition, characterized in that it contains a pharmaceutically acceptable excipient and a compound of claim 1 according to claim 1.
4. A method for treating a disease mediated by a P2X3 or P2X2 / 3 receptor antagonist, characterized in that it consists in administering to a subject in need thereof an effective amount of a compound of the formula (I) according to claim 1.
5. 5. The method according to claim 4, characterized in that the disease is a genitourinary disease or a disease associated with pain.
6. 6. The method according to claim 5, characterized in that the genitourinary disease is a reduced capacity of the bladder; frequent urination; urgent incontinence; stress incontinence; bladder hyperreactivity; benign prostatic hypertrophy; prostatitis; detrusor hyperreflexia; urinary frequency; nocturia; urinary urgency; overactive bladder; pelvic hypersensitivity; urethritis; prostatitis; pelvic pain syndrome; prostatodynia; cystitis; or hypersensitivity of idiopathic bladder; and the disease associated with the pain may be: inflammatory pain; surgical pain; visceral pain; Dental pain; premenstrual pain; central pain; pain due to burns; migraine or periodic migrainous neuralgia; nerve injuries; neuritis; neuralgia; poisoning; Ischemic lesions; interstitial cystitis; cancerous pain; viral, parasitic or bacterial infection; post-traumatic injury; or pain associated with irritable bowel syndrome.
7. 7. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment of a disease mediated by the P2X3 or P2X / 3 receptor antagonist.