ES2234433A1 - 2,6 Bisheteroaryl-4-Aminopyrimidines as Adenosine Receptor Antagonists - Google Patents

Abstract

2,6-Bisheteroaryl-4-aminopyrimidine compounds (I) and their salts are new. 2,6-Bisheteroaryl-4-aminopyrimidine compounds of formula (I) and their salts are new. R 1>, R 2> : monocyclic or polycyclic heteroaryl (optionally substituted by lower alkyl, lower alkoxy, lower alkylthio (all optionally substituted), halo, cycloalkyl, OH, -SH, CN, -NR-aR-b or -CO 2R-a; either R-a, R-b : H or lower alkyl (optionally substituted); or NR-a+R-b : cyclic group; R 3> : -COR 4>, -CON(R 4>)R 5>, -COOR 4> or R 6>; R 4>, R 6> : H, lower alkyl (optionally substituted by halo, cycloalkyl, OH, lower alkoxy, lower alkylthio, NH 2, mono- or dialkylamino, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl or nitrile) or alkenyl derivative of formula (2); m, o, p : 0-1; n, q : 0-6; G : cycloalkyl or (hetero)aryl (both optionally substituted by halo atoms or cycloalkyl, lower (halo)alkyl, OH, lower alkoxy, lower alkylthio, NH 2, mono- or dialkylamino, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl or nitrile); and either R 5> : H or lower alkyl, cycloalkyl or benzyl; or NR 4>R 5> : optionally saturated ring (optionally substituted by lower alkyl, cycloalkyl or benzyl). Provided that the compound is not one of 2,6-dipyridin-4-ylpyrimidin-4-amine, 4-(3-methoxyanilino)-2,6-di(2-pyridinyl)pyrimidine, 4-(2,5-dimethoxyanilino)-2,6-di(2-pyridinyl)pyrimidine, 4-(5-methoxy-2-methylanilino)-2,6-di(2-pyridinyl)pyrimidine, 4-(2-methoxy-5-methylanilino)-2,6-di(2-pyridinyl)pyrimidine, 4-(2-chloro-5-methoxyanilino)-2,6-di(2-pyridinyl)pyrimidine or 4-(2,5-dimethylanilino)-2,6-di(2-pyridinyl)pyrimidine. An independent claim is also included for a combination product comprising (I) and another compound (L-DOPA, dopamine antagonists, inhibitors of dopamine decarboxylase, catechol-O-methyltransferase inhibitors or inhibitors of monoamine oxidase) for simultaneous, separate or sequential use. [Image] ACTIVITY : Vasotropic; Antiarrhythmic; Nephrotropic; Cardiant; Antiallergic; Antiinflammatory; Dermatological; Antiarthritic; Immunosuppressive; Gastrointestinal-Gen.; Antiasthmatic; Antidiabetic; Anorectic; Antiparkinsonian; Nootropic; Neuroprotective; Muscular-Gen. MECHANISM OF ACTION : Adenosine-2A receptor antagonist. (I) were tested for their adenosine-2A receptor antagonistic activity using biological assays. The results showed that the median inhibitory concentration of (I) was less than 0.25 mu M.

Description

4-Aminopyrimidines as adenosine receptor antagonists.

The present invention relates to new adenosine receptor antagonists, in particular antagonists of the A2A subtype of adenosine receptor, to the use of said compounds in the treatment of diseases and disorders likely to improve by receptor antagonism of adenosine, in particular diseases and disorders of the system central nervous susceptible to improving by using A 2A adenosine receptor antagonists, plus specifically movement disorders such as disease of Parkinson's, restless legs syndrome, and the dyskinesia and pharmaceutical compositions comprising said compounds.

The effects of adenosine are mid to through at least four specific membrane receptors that are classified as receivers A 1, A 2 A, A 2 B and A 3 and they belong to the family of G protein-coupled receptors. The A 1 and A 3 receptors decrease cAMP levels cell by coupling to the G i proteins that inhibit adenylate cyclase. In contrast, the A 2A receptors, and A 2B are coupled to the G_ {s} proteins that activate the adenylate cyclase and increase intracellular cAMP levels. TO through these receptors, adenosine regulates a wide range of physiological functions.

Thus, in the cardiovascular system the activation of the A 1 receptors protects the cardiac tissues from the effects of ischemia and hypoxia. A similar protective effect is produced by the antagonism of the A 2A receptors that improves the adrenergic responses induced by the A 1 receptors and may be useful in the treatment of acute myocardial ischemia and supraventricular arrhythmias (Norton GR et al . Am J Physiol . 1999 ; 276 (2 Pt2): H341-9; Auchampach JA, Bolli R. Am J Physiol . 1999 ; 276 (3 Pt 2): H1113-6). In addition, the A2B subtype adenosine receptors (Feoktistov, I. et al . Phamacol. Rev. 1997 , 49, 381-402) appear to be involved in the control of vascular tone and in the regulation of smooth muscle growth vascular.

In the kidney, adenosine exerts a biphasic action, inducing vasodilation at high concentrations and vasoconstriction at low concentrations. Therefore, adenosine plays a role in the pathogenesis of some forms of acute renal failure that can be improved by antagonism of the A 1 receptors (Costello-Boerrigter LC, et al . Med Clin North Am . 2003 Mar; 87 ( 2): 475-91; Gottlieb SS., Drugs 2001 ; 61 (10): 1387-93).

Adenosine is also involved in the pathophysiology of the immune system. It can induce degranulation of human mast cells through the A 2b and / or receptors A_ {3}. Therefore, the A 2b and / or receptor antagonists A_ {3} prevent mast cell degranulation and are, as Consequently, useful in the treatment, prevention and suppression of diseases induced by receptor activation A_ {2b} and / or A3 {and by mast cell degranulation. Such diseases include, but are not limited to, asthma, damage from Myocardial reperfusion, allergic reactions including but not limited to rhinitis, urticaria, scleroderma arthritis, others autoimmune diseases and inflammatory diseases Intestinal

In addition, in the respiratory system adenosine induces bronchoconstriction, modulates inflammation of the pathways respiratory and promotes chemotaxis of neutrophils. By Thus, adenosine antagonists would be particularly useful. in the treatment of asthma.

In the gastrointestinal and metabolic system, the A 2B subtype receptors (Feoktistov, I. et al . Phamacol. Rev. 1997 , 49, 381-402) appear to be involved in the) regulation of hepatic glucose production, in the modulation of the intestinal tone as well as in the intestinal secretion. Therefore, A2B receptor antagonists may also be useful in the treatment of diabetes mellitus and obesity.

In the central nervous system adenosine is a powerful endogenous neuromodulator that controls release presynaptic of many neurotransmitters and that is why it is involved in motor function, sleep, anxiety, pain and psychomotor activity All receptor subtypes of adenosine are present in the brain, the receptors being A_ {1} and A_ {2A} selectively distributed. The first ones found predominantly in the hippocampus and the cortex, while than the seconds) are found mainly in the striatum. The A 2A adenosine receptors modulate GABA release in the striatum, which possibly regulates the activity of the spiny interneurons

Therefore, A 2A receptor antagonists can be a useful treatment of neurodegenerative movement disorders such as Parkinson's disease and Huntington's disease (Truite P, et al . J. Expert Opin Investig Drugs . 2003 ; 12 : 1335-52; Popoli P. et al . J. Neurosci . 2002; 22 : 196775), dystonia such as restless legs syndrome (Happe S, et al . Neuropsychobiology 2003 : 48: 82-6) and dyskinesias such such as those caused by prolonged use of neuroleptic and / or dopaminergic medications (Jenner P. J. Neurol . 2000 ; 247 Suppl. 2: 1143-50).

In the treatment of Parkinson's disease A 2A antagonists can be useful not only in monotherapy but also administered in combination with L-DOPA and / or one or more of the following medications: dopamine antagonists, dopamine inhibitors decarboxylase inhibitors catechol-O-methyltransferase e monoamine oxidase inhibitors.

Additionally, A 2A antagonists may have therapeutic potential as neuroprotectors (Stone TW. Et al . Drug Dev. Res . 2001 ; 52: 323-330) and in the treatment of sleep disorders (Dunwiddie TV et al ., Ann. Rev. Neurosci . 2001 ; 24: 31-55).

It has now been discovered that certain derivatives of 4-aminopyrimidine are potent new antagonists and selective of the adenosine A2A receptor and can be used, therefore, in the treatment or prevention of diseases susceptible of improvement by antagonism of the A 2A receptor of the adenosine

Other objectives of the present invention are provide a process for preparing said compounds; pharmaceutical compositions comprising an effective amount of said compounds; the use of compounds in the manufacture of a medicine to treat pathological conditions or diseases that they can improve by antagonism of an adenosine receptor, in particularly by antagonism of the A2A receptor; of adenosine, treatment procedures for pathological conditions or diseases that can improve by antagonism of a receptor adenosine, in particular by A 2A receptor antagonism of adenosine comprising the administration of the compounds of the invention to a subject in need of treatment and combinations of said compounds with one or more of the following medications: L-DOPA dopamine antagonists, inhibitors of dopamine decarboxylase inhibitors catechol-O-methyltransferase e monoamine oxidase inhibitors.

Therefore, the present invention relates to new 4-aminopyrimidine derivatives of formula (I)

one

in the that

R 1 and R 2 represent, independently, a monocyclic or polycyclic heteroaryl group optionally substituted by one or more selected substituents from the group consisting of halogen atoms, lower alkyl, linear or branched, optionally substituted, cycloalkyl, hydroxy, lower alkoxy, linear or branched, substituted optionally, -SH, lower alkyl, linear or branched, optionally substituted, cyano, -NR'R '', -CO_ {R}, in which R 'and R' 'each independently represent an atom of hydrogen or a lower alkyl group, linear or branched, optionally substituted or R 'and R' 'together with the nitrogen atom to which they are attached form a cyclic group;

R 3 represents a group selected from -COR 4, -CON (R 4) R 5, -COOR 4 and -R 4 in the that R 4 represents a group selected from:

?

hydrogen atoms,

?

a lower alkyl group, linear or branched, which is optionally substituted by one or more halogen atoms or by one or more cycloalkyl groups, hydroxy, lower alkoxy, lower alkylthio, amino, mono- or dialkylamino, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl and nitrile;

?

a group of formula:

2

in the that:

m, o and p are, independently, 0 or 1;

n and q are independently selected from integers from 0 to 6;

R a and R b are independently an atom of hydrogen or a lower alkyl group;

G is a group selected from groups cycloalkyl, arite or heteroaryl which are substituted optionally by one or more halogen atoms or by one or more lower alkyl, cycloalkyl, lower haloalkyl groups, hydroxy, lower alkoxy, lower alkylthio, amino, mono- or dialkylamino, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl and nitrile;

and R 5 represents a hydrogen atom or a lower alkyl, cycloalkyl or benzyl group; or

R 4 and R 5 together with the nitrogen atom to which they are attached form a saturated or unsaturated ring that is optionally substituted by one or more lower alkyl groups, cycloalkyl or benzyl;

or pharmaceutically acceptable salts of the themselves;

with the proviso that the compound is not 2,6-dipyridin-4-ylpyrimidin-4-amine.

Other aspects of the present invention are: a) pharmaceutical compositions comprising an effective amount of said compounds, b) the use of said compounds in the preparation of a medicine to treat diseases that can be improved by antagonism of an adenosine receptor, in particular by A 2A receptor antagonism; of adenosine, c) procedures of treatment of diseases that can be improved by antagonism of an adenosine receptor, in particular by antagonism of the A 2A adenosine receptor; comprising said procedures administration of the compounds of the invention to a subject that need treatment and (e) combinations of said compounds with one or more of the following medications: L-DOPA dopamine antagonists, dopamine inhibitors decarboxylase inhibitors catechol-O-methyltransferase e monoamine oxidase inhibitors.

As used herein descriptively, the term lower alkyl includes linear radicals or branched, optionally substituted, having 1 to 8, preferably from 1 to 6 and more preferably from 1 to 4 atoms of carbon.

Examples include methyl, ethyl, n -propyl, i -propyl, n -butyl, sec -butyl and tert -butyl, n -pentyl, 1-methylbutyl, 2-methylbutyl, isopentyl, 1-ethylpropyl, 1,1- radicals dimethylpropyl, 1,2-dimethylpropyl, n-hexyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 2-methylpentyl, 3-methylpentyl and iso- hexyl.

As used herein descriptively, the term lower alkoxy includes radicals that contain the oxy group, linear or branched, substituted optionally, each having alkyl parts of 1 to 8, preferably from 1 to 6 and more preferably from 1 to 4 atoms of carbon.

Preferred alkoxy radicals include methoxy, ethoxy, n -propoxy, i -propoxy, n -butoxy, sec -butoxy, t -butoxy, trifluoromethoxy, difluoromethoxy, hydroxymethoxy, 2-hydroxyethoxy or 2-hydroxypropoxy.

As used herein descriptively, the term lower alkylthio includes radicals that contain optionally substituted, linear or radical alkyl radicals branched from 1 to 8, preferably from 1 to 6 and more preferably 1 to 4 carbon atoms.

Preferred, optionally substituted alkylthio radicals include methylthio, ethylthio, n -propylthio, i -propylthio, n -butylthio, sec -butylthio, t -butylthio, trifluoromethylthio, difluoromethylthio, hydroxymethylthio, 2-hydroxyethylthio or 2-hydroxypropyl.

As used herein descriptive, the term cyclic group includes, unless specify otherwise, carbocyclic and heterocyclic radicals. Cyclic radicals may contain one or more rings. The carbocyclic radicals can be aromatic or alicyclic, for example cycloalkyl radicals. Heterocyclic radicals they also include heteroaryl radicals.

As used herein descriptively, the term aromatic group typically includes a 5 to 14 member aromatic ring system, such as a 5 or 6 member ring that may contain one or more heteroatoms selected from O, S and N. When no heteroatoms are present, the radical is called the aryl radical and when there is at least a heteroatom, is called a heteroaryl radical. The radical aromatic can be monocyclic or polycyclic, such as phenyl or naphthyl. When an aromatic radical or moiety carries 2 or more substituents, the substituents may be the same or different.

As used herein descriptively, the term aryl radical typically includes a C 5 -C 14 monocyclic aryl radical or polycyclic such as phenyl or naphthyl, anthranyl or phenanthryl Preferred is phenyl. When an aryl radical carries 2 or more substituents, the substituents may be the same or different.

As used herein descriptively, the term heteroaryl radical typically includes a 5 to 14 member ring system comprising at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N. A heteroaryl radical can be a single ring or two or more condensed rings, containing the minus one ring a heteroatom.

Examples include pyridyl radicals, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, oxadiazolyl, oxazolyl, imidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, pyridinyl, benzothiazolyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, quinolizinyl, cinnolinyl, triazolyl, indolizinyl, indolinyl, isoindolinyl, isoindolyl, imidazolidinyl, pteridinyl and pyrazolyl. Preferred radicals they are thienyl, furanyl, pyrazolyl, pyridazinyl, pyrimidinyl and quinolyl

When a heteroaryl radical carries 2 or more substituents, the substituents may be the same or different.

As used herein descriptive, some of the atoms, radicals, moieties, chains or cycles present in the general structures of the invention are "optionally substituted". This means that these atoms, radicals, residues, chains or cycles may be unsubstituted or substituted in any position by one or more, for example 1, 2, 3 or 4 substituents, in which hydrogen atoms attached to atoms, radicals, moieties, chains or unsubstituted cycles are substituted by atoms, radicals, residues, chains or cycles Chemically acceptable. When two 5 or more are present substituents, each substituent may be the same or different.

As used herein Descriptively, the term halogen atom includes chlorine atoms, fluorine, bromine or iodine, typically a fluorine, chlorine or bromine atom, more preferably chlorine or fluorine. The term halo, when used As a prefix it has the same meaning.

As used herein Descriptively, the term pharmaceutically acceptable salt encompasses salts with a pharmaceutically acceptable acid or base. Acids Pharmaceutically acceptable include inorganic acids, by example hydrochloric, sulfuric, phosphoric, diphosphoric acid, hydrobromic, hydroiodic and nitric and organic acids, for example citric acid, maleic, malic, mandelic, ascorbic, oxalic, succinic, tartaric, acetic, methanesulfonic, ethanesulfonic, benzenesulfonic or p-toluenesulfonic. The bases Pharmaceutically acceptable include metal hydroxides alkaline (for example, sodium or potassium) and alkaline earth metals (for example, calcium or magnesium) and organic bases, for example alkylamines, arylalkylamines and heterocyclic amines.

Other preferred salts according to the invention are quaternary ammonium compounds in which a equivalent of an anion (X-) with the positive charge of the N atom. X- can be an anion of various mineral acids such as,  chloride, bromide, iodide, sulfate, nitrate, phosphate or an anion of an organic acid, such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulfonate and p-toluenesulfonate. X- is preferably an anion selected from chloride, bromide, iodide, sulfate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. Plus preferably X- is chloride, bromide, trifluoroacetate or methanesulfonate

As used herein Descriptively, an N-oxide is formed from amines or imines tertiary basic present in the molecule, using an agent convenient oxidant.

According to an embodiment of the present invention in the compounds of formula (I), R 1 represents a group monocyclic heteroaryl selected from the group consisting of furyl, thienyl, thiazolyl, oxazolyl, pyrazinyl groups, pyrazolyl, pyridazinyl, imidazolyl, triazolyl, pyrimidinyl and pyridyl; said groups are optionally substituted by one or more substituents selected from the group consisting of atoms of halogen and lower alkyl, linear or branched, substituted optionally

According to a preferred embodiment of the present invention, in the compounds of formula (I), R 1 represents a monocyclic heteroaryl group selected from the group constituted by furyl, thienyl, pyrazolyl, triazolyl, thiazolyl and pyridyl; said groups are optionally substituted by one or more substituents selected from the group consisting of atoms of halogen and lower alkyl, linear or branched, substituted optionally

According to another embodiment of the present invention, in the compounds of formula (I), R2 represents a group monocyclic heteroaryl selected from the group consisting of pyrazolyl, furyl, thiazolyl, oxazolyl, pyridyl groups, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, imidazolyl and triazolyl; said groups are optionally substituted by one or more substituents selected from the group consisting of atoms of halogen and lower alkyl, linear or branched, substituted optionally

According to another preferred embodiment of the present invention, in the compounds of formula (I), R2 represents a monocyclic heteroaryl group selected from the group constituted by pyrazolyl, furyl, thiazolyl, pyridyl, thienyl and triazolyl; said groups are optionally substituted by one or more substituents selected from the group consisting of atoms of halogen and lower alkyl, linear or branched, substituted optionally

Still according to another embodiment of the present invention, in the compounds of formula (I), R 4 represents a group selected from:

?

hydrogen atoms,

?

a lower alkyl group, linear or branched, which is optionally substituted by one or more halogen atoms;

?

a group of formula:

3

in the that:

o and p are independently 0 or 1;

n and q are independently selected from integers from 0 to 6;

R a and R b are independently an atom of hydrogen or a lower alkyl group;

G is a group selected from groups cycloalkyl, aryl or heteroaryl which are substituted optionally by one or more halogen atoms or by one or more lower alkoxy groups;

and R 5 represents a hydrogen atom.

Still according to another preferred embodiment of the present invention, in the compounds of formula (I), R 4 represents a group selected from:

?

hydrogen atoms,

?

a lower alkyl group, linear or branched, which is optionally substituted by one or more halogen atoms;

?

a group selected from cycloalkylalkyl, phenylalkyl, heteroarylalkyl groups, phenoxyalkyl and heteroaryloxyalkyl; these groups are optionally substituted by one or more halogen atoms or by one or more lower alkoxy groups;

and R 5 represents a hydrogen atom.

Still according to another preferred embodiment of the present invention, in the compounds of formula (I), R1 is a 2-furyl group and R2 is a pyrazolyl group that is optionally substituted by one or more alkyl groups lower.

Individual individual compounds of the invention include:

2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-ylamine

N- [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] acetamide

N - [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide

N - [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] isobutyramide

N - [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] tert -butyramide

[2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] amide of cyclopropanecarboxylic acid

[2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] amide of cyclobutanecarboxylic acid

[2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] amide of cyclohexanecarboxylic acid

3-Cyclopentyl- N - [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide

N - [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -2- (4-methoxyphenyl) -acetamide

2- (3,4-Dimethoxyphenyl) - N - [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] acetamide

N - [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl) -3-phenyl-propionamide

E -2-Phenylcyclopropanecarboxylic acid [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] amide

3, 3, 3-Trifluoro- N - [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide

3- (3,4-Dimethoxyphenyl) - N - [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide

N - [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -2-methyl-3-phenylpropionamide

N - [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3-phenoxy-propionamide

N - [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3- (pyridin-3-yl) -propionamide

N - [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3- (pyridin-3-yl) acetamide

E -3- (3,4-Dimethoxyphenyl) - N - [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] acrylamide

2- (Furan-2-yl) -6- (3,5-dimethylpyrazol-1-yl) pyrimidin-4-ylamine

N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] acetamide

N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] propionamide

N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] isobutyramide

N - [6- (3, 5-Dimethylpyrazol-1-yl) -2- (furan-2-i [) pyrimidin-4-yl] tert -butyramide

[6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] amide of cyclopropanecarboxylic acid

3-Cyclopentyl-N- [6- (3,5-dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] propionamide

N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] -2- (4-methoxyphenyl) acetamide

2- (3,4-Dimethoxyphenyl) -N- [6- (3, 5-dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] acetamide

N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] -3-phenyl-propionamide

N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] -3,3,3-trifluoropropionamide

3- (3,4-Dimethoxyphenyl) -N- [6- (3, 5-dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] propionamide

N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] -3-phenoxy propionamide

N - [6- (3, 5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) -pyrimidin-4-yl] -2- (pyridin-3-yl) acetamide

N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) -pyrimidin-4-yl] -2- (pyridin-3-yl) propionamide

2- (Furan-2-yl) -6- (4-methylpyrazol-1-yl) pyrimidin-4-ylamine

N - [2- (Furan-2-yl) -6- (4-methylpyrazol-1-yl) -pyrimidin-4-yl] propionamide

2- (Furan-2-yl) -6- (3-methylpyrazol-1-yl) pyrimidin-4-ylamine

N - [2- (Furan-2-yl) -6- (3-methylpyrazol-1-yl) -pyrimidin-4-yl] propionamide

2- (Furan-2-il) -6- (3- trifluoromethylpyrazol-1-yl) pyrimidin-4-ylamine

N- [2- (Furan-2-yl) -6- (3-trifluoromethylpyrazol-1-yl) pyrimidin-4-yl] propionamide

2- (Furan-2-yl) -6- (5-methyl-3-trifluoromethylpyrazol-1-yl) pyrimidin-4-ylamine

N- [2- (Furan-2-yl) -6- (5-methyl-3-trifluoromethylpyrazol-1-yl) pyrimidin-4-yl] propionamide

2- (Furan-2-yl) -6 - [[1,2,4] triazol-1-yl] pyrimidin-4-ylamine

N- [2- (Furan-2-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-yl] acetamide

N- [2- (Furan-2-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-yl] propionamide

3, 3, 3-Trifluoro-N- [2- (furan-2-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-yl) -propionamide

2- (5-Bromofuran-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-ylamine

N- [2- (5-Bromofuran-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide

2- (5-Chlorofuran-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-ylamine

N- [2- (5-Chlorofuran-2-yl) -6- (pyrazole-1 -yl) pyrimidin-4-yl] propionamide

2- (5-Methylfuran-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-ylamine

N- [2- (5-Methylfuran-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide

N- [2- (Furan-2-yl) -6- (pyridin-3-yl) pyrimidin-4-yl] propionamide

2- (Furan-2-yl) -6- (pyridin-3-yl) pyrimidin-4-yl] amide

6- (Pirazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-ylamine

N- [6- (Pirazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] acetamide

N- [6- (Pirazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] propionamide

3-Cyclopentyl-N- [6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl) propionamide

3-Phenyl-N- [6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] propionamide

3,3,3-Trifluoro-N- [6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] propionamide

3- (3,4-Dimethoxyphenyl) -N- [6- (pyrazol-1-yl) -2- (thiophene-2-yl) pyrimidin-4-yl) propionamide

3-Phenoxy-N- [6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] propionamide

N- [6- (Pirazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] -2- (pyridin-3-yl) acetamide

N- [6- (Pirazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] -3- (pyridin-3-yl) propionamide

E-3- (3,4-Dimethoxyphenyl) -N- [6- (pyrazol-1-yl) -2- (thiophene-2-yl) pyrimidin-4-yl) acrylamide

6- (3,5-Dimethylpyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-ylamine

N- [6- (3,5-Dimethylpyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] acetamide

N- [6- (3,5-dimethylpyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] propionamide

N- [6- (3, 5-Dimethylpyrazol-1-yl) -2- (thiophen-2-yl) pyrim idin-4-il] -3, 3, 3-trifluoropropionamide

2- (Thiophen-2-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-ylamine

N- [2- (Thiophen-2-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-yl] acetamide

N- [2- (Thiophen-2-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-yl] propionamide

3,3,3-Trifluoro-N- [2- (thiophen-2-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-yl] propionamide

N- [2- (3-Methylthiophene-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide

6- (Furan-2-yl) -2- (pyrazol-1-yl) pyrimidin-4-ylamine

N- [6- (Furan-2-yl) -2- (pyrazol-1-yl) pyrimidin-4-yl] acetamide

N- [6- (Furan-2-yl) -2- (pyrazol-1-yl) pyrimidin-4-yl] propionamide

3,3,3-Trifluoro-N- [6- (furan-2-yl) -2- (pyrazol-1-yl) pyrimidin-4-yl] propionamide

2- (3, 5-Dimethylpyrazol-1-yl) -6- (furan-2-yl) pyrimidin-4-ylamine

N- [2- (3,5-Dimethylpyrazol-1-yl) -6- (furan-2-yl) pyrimidin-4-yl] propionamide

N- [2- (3, 5-Dimethylpyrazol-1-yl) -6- (furan-2-yl) pyrimidin-4-yl] -2- (4-methoxyphenyl) acetamide

6- (Furan-2-yl) -2 - ([1,2,4] triazol-1-yl) pyrimidin-4-ylamine

N- [6- (Furan-2-yl) -2 - ([1,2,4] triazol-1-yl) pyrimidin-4-yl] propionamide

2- (Pirazol-1-yl) -6- (pyridin-2-yl) pyrimidin-4-ylamine

N- [2- (Pirazol-1-yl) -6- (pyridin-2-yl) pyrimidin-4-yl] propionamide

2- (3,5-Dimethylpyrazol-1-yl) -6- (pyridin-2-yl) pyrimidin-4-ylamine

N- [2- (3,5-Dimethylpyrazol-1-yl) -6- (pyridin-2-yl) pyrimidin-4-yl] propionamide

N- [2- (3,5-Dimethylpyrazol-1-yl) -6- (pyridin-2-yl) pyrimidin-4-yl] -2- (4-methoxyphenyl) acetamide.

2- (Pirazol-1-yl) -6- (pyridin-3-yl) pyrimidin-4-ylamine

N- [2- (Pirazol-1-yl) -6- (pyridin-3-yl) pyrimidin-4-yl] propionamide

2- (3,5-Dimethylpyrazol-1-yl) -6- (pyridin-3-yl) pyrimidin-4-ylamine

N- [2- (3,5-Dimethylpyrazol-1-yl) -6- (pyridin-3-yl) pyrimidin-4-yl] propionamide

N- [2- (3, 5-Dimethylpyrazol-1-yl) -6- (pyridin-3-yl) pyrimidin-4-yl] -2- (4-methoxyphenyl) acetamide

2- (Pirazol-1-yl) -6- (pyridin-4-yl) pyrimidin-4-ylamine

N- [2- (Pirazol-1-yl) -6- (pyridin-4-yl) pyrimidin-4-yl] propionamide

6- (Furan-2-yl) -2- (pyridin-2-yl) pyrimidin-4-ylamine

N- [6- (Furan-2-yl) -2- (pyridin-2-yl) pyrimidin-4-yl] propionamide

2- (3-Methylpyridin-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-ylamine

N- [2- (3-methylpyridin-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide

6- (Pirazol-1-yl) -2- (pyridin-3-yl) pyrimidin-4-ylamine

N- [6- (Pirazol-1-yl) -2- (pyridin-3-yl) pyrimidin-4-yl] acetamide

N- [6- (Pirazol-1-yl) -2- (pyridin-3-yl) pyrimidin-4-yl] propionamide

6- (3,5-Dimethylpyrazol-1-yl) -2- (pyridin-3-yl) pyrimidin-4-ylamine

N- [6- (3,5-Dimethylpyrazol-1-yl) -2- (pyridin-3-yl) pyrimidin-4-yl] acetamide

N- [6- (3,5-Dimethylpyrazol-1-yl) -2- (pyridin-3-yl) pyrimidin-4-yl] propionamide

N- [6- (3,5-Dimethylpyrazol-1-yl) -2- (pyridin-3-yl) pyrimidin-4-yl] -3,3,3-trifluoropropionamide

2- (Pyridin-3-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-ylamine

3,3,3-Trifluoro-N- [2- (pyridin-3-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-yl] propionamide

6- (Furan-2-yl) -2- (pyridin-3-yl) pyrimidin-4-ylamine

N- [6- (Furan-2-yl) -2- (pyridin-3-yl) pyrimidin-4-yl] propionamide

N- [6- (3,5-Dimethylpyrazol-1-yl) -2- (pyridin-4-yl) pyrimidin-4-yl] propionamide

6- (3, 5-dimethylpyrazol-1-yl) -2- (pyridin-4-yl) pyrimidin-4-ylamine

6- (Furan-2-yl) -2- (pyridin-4-yl) pyrimidin-4-ylamine

N- [6- (Furan-2-yl) -2- (pyridin-4-yl) pyrimidin-4-yl] propionamide

6- (Furan-2-yl) -2- (thiazol-2-yl) pyrimidin-4-ylamine

N- [6- (Furan-2-yl) -2- (thiazol-2-yl) pyrimidin-4-yl] propionamide

2- (4-Fluorophenyl) -N- [6- (furan-2-yl) -2- (thiazol-2-yl) pyrimidin-4-yl] acetamide

N- (Cyclopropylmethyl) -2- (2-furyl) -6- (pyrazol-1-yl) pyrimidin-4-amine

(2R) -2 - {[2- (2-Furil) -6- (pyrazol-1-yl) pyrimidin-4-yl] amino} propan-1-ol

3 - {[2- (2-Furil) -6- (pyrazol-1-yl) pyrimidin-4-yl] amino} propan-1-ol

N- [2- (2-Furil) -6- (pyrazol-1-yl) pyrimidin-4-yl] ethane-1,2-diamine

2- (2-Furil) -N- [2- (4-methoxyphenyl) ethyl] -6- (pyrazol-1-yl) pyrimidin-4-amine

N- [2- (3,4-Dimethoxyphenyl) ethyl] -2- (2-furyl) -6- (pyrazol-1-yl) pyrimidin-4-amine

2- (2-Furil) -6- (pyrazol-1-yl) -N- [2- (pyridin-2-yl) ethyl] pyrimidin-4-amine

2- (2-Furil) -6- (pyrazol-1-yl) -N- [2- (pyridin-3-yl) ethyl] pyrimidin-4-amine

2- (2-Furil) -N- (3-phenylpropyl) -6- (pyrazol-1-yl) pyrimidin-4-amine

2- (2-Furil) -N- [3- (imidazol-1-yl) propyl] -6- (pyrazol-1-yl) pyrimidin-4-amine

N- (Cyclopropylmethyl) -6- (pyrazol-1-yl) -2- (tien-2-yl) pyrimidin-4-amine

(2R) -2 - {[6- (Pirazol-1-yl) -2- (tien-2-yl) pyrimidin-4-yl] amino} propan-1-ol

3 - {[6- (Pirazol-1-yl) -2- (tien-2-yl) pyrimidin-4-yl] amino} propan-1-ol

N- (2-Aminoethyl) -N- [6- (pyrazol-1-yl) -2- (tien-2-yl) pyrimidin-4-yl] amine

N- [2- (4-Methoxyphenyl) ethyl] -6- (pyrazol-1-yl) -2- (tien-2-yl) pyrimidin-4-amine

N- [2- (3,4-Dimethoxyphenyl) ethyl] -6- (pyrazol-1-yl) -2- (tien-2-yl) pyrimidin-4-amine

6- (Pirazol-1-yl) -N- [2- (pyridin-2-yl) ethyl] -2- (tien-2-yl) pyrimidin-4-amine

6- (Pirazol-1-yl) -N- [2- (pyridin-3-yl) ethyl] -2- (tien-2-yl) pyrimidin-4-amine

N- (3-Phenylpropyl) -6- (pyrazol-1-yl) -2- (tien-2-yl) pyrimidin-4-amine

N- [3- (Imidazol-1-yl) propyl] -6- (pyrazol-1-yl) -2- (tien-2-yl) pyrimidin-4-amine

Ethyl 6- (pyrazol-1-yl) -2- (tien-2-yl) pyrimidin-4-ylcarbamate

1- [2- (Furan-2-il) -6- (pyrazole- 1 -il) p irimidin-4-yl] -3- (2-phenyl-cyclopropyl) urea

1- [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3-propylurea

1- [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3-isopropylurea

one -Cyclopentyl-3- [2- (furan-2-il) -6- (pyrazole- one -il) pyrimidin-4-yl] urea

1- [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3- (4-methoxy-phenyl) urea

1- [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3-phenethylurea

1-Benzyl-3- [2- (furan-2-il) -6- (pyrazole- one -il) pyrimidin-4-yl] urea

Of exceptional interest are:

2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-ylamine

N- [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] acetamide

N- [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] tert -butyramide

N- [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -2- (4-methoxyphenyl) -acetamide

2- (3,4-Dimethoxyphenyl) -N- [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] acetamide

3,3,3-Trifluoro-N- [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide

N- [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3- (pyridin-3-yl) -propionamide

N- [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3- (pyridin-3-yl) acetamide

N- [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] tert -butyramide

3-Cyclopentyl-N- [6- (3,5-dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] propionamide

N- [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] -2- (4-methoxyphenyl) acetamide

2- (3,4-Dimethoxyphenyl) -N- [6- (3,5-dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] acetamide

N- [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] -3-phenyl propionamide

N- [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) -pyrimidin-4-yl] -2- (pyridin-3-yl) acetamide

N- [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) -pyrimidin-4-yl] -2- (pyridin-3-yl) propionamide

2- (Furan-2-yl) -6- (3-trifluoromethylpyrazol-1-yl) pyrimidin-4-ylamine

The compounds of the present invention can be prepare by any of the procedures described to continuation.

The compounds of formula (I) and in particular the of formulas (VIIIa) or (IXa) in which R1 is a group monocyclic or polycyclic heteroaryl attached to the pyrimidine ring by a carbon atom and R2 is a heteroaryl group monocyclic or polycyclic attached to the pyrimidine ring by a nitrogen atom, can be obtained as shown in the Scheme one.

Scheme one

4

       \ newpage
    

The carboxyamidines of formula (II), in which R1 is a monocyclic or polycyclic heteroaryl group attached to the carboxyamidine group by a carbon atom, can be obtain by reacting a nitrile of formula (XXI) with trimethylaluminum and ammonium chloride, in a solvent as per example benzene, toluene or xylene, at a temperature of 80º to 120º. They can also be obtained by reacting a nitrile of the formula (XXXI) with sodium methoxide in methanol at room temperature, followed by reaction with ammonium chloride thereto temperature.

The carboxyamidines of formula (II) can be reacted with diethyl malonate in a solvent such as methanol, ethanol, isopropyl alcohol, butyl alcohol or tetrahydrofuran, in the presence of a base, such as sodium methoxide, sodium ethoxide or tert - potassium butoxide and at a temperature of room temperature at the boiling point of the solvent giving the pyrimidine-4,6-diols of formula (III).

The pyrimidine-4,6-diols resulting from formula (III) can be reacted with a chlorinating agent, such as phosphorus oxychloride, phosphorus pentachloride or a mixture thereof, in a solvent such as phosphorus oxychloride, benzene or toluene, at a temperature of room temperature at the boiling point of the solvent giving the 4,6-dichloropyrimidine compounds of formula (IV). Optionally, the presence of a base, such as for example dimethylaminoaniline, triethylamine or diisopropyl-ethylamine, at this stage of the reaction.

The reaction of the compounds 4,6-dichloropyrimidine of formula (IV) with hydroxide of ammonium in a solvent, such as methanol, ethanol, isopropyl alcohol or tetrahydrofuran, at a temperature of 80º to 140º produces the 6-chloropyrimidin-4-amines of formula (V).

The 6-chloropyrimidin-4-amines resulting from formula (V) are reacted with a compound of formula R 2 -H in which R 2 is a group monocyclic or polycyclic heteroaryl attached to the carboxyamidine group by a nitrogen atom, giving the compounds of formula (VIIIa), which is a particular case of the compounds of formula (I) according to the invention. The reaction is carried out in a solvent, such as dimethylformamide, dimethylacetamide or dimethylsulfoxide, in the presence of a base, such as hydride sodium, potassium carbonate or cesium carbonate, at a temperature from 60º to 140ºC.

The compounds of formula (VIIIa) can be acylate by an acid chloride and a base, such as pyridine, triethylamine or diisopropylethylamine, in a solvent such as tetrahydrofuran, methylene chloride, chloroform or  pyridine, at a temperature of room temperature to the point of boiling the solvent giving the compounds of formula (IXa), which is a particular case of the compounds of formula (I) according to the invention. The compounds of formula (IXa) can be prepared also by reacting the amine (VIIIa) with an anhydride, to a temperature from 80º to 160ºC.

The compounds 4,6-dichloropyrimidine of formula (IV) can be also transform into the 4-chloropyrimidines of formula (Xa) by reaction with a compound of formula R2 -H in which R2 is a heteroaryl group monocyclic or polycyclic bound to the carboxyamidine group by a nitrogen atom The reaction is carried out in a solvent, such as dimethylformamide, dimethylacetamide or dimethylsulfoxide, in the presence of a base, such as sodium hydride, potassium carbonate or cesium carbonate, at a temperature from 60º to 140ºC.

4-chloropyrimidines resulting from formula (Xa) can then be transformed into compounds of formula (VIIIa) according to the invention by reaction with ammonium hydroxide in a solvent, such as methanol, ethanol, isopropyl alcohol or tetrahydrofuran, at a temperature from 80 ° C to 140 ° C.

Alternatively, the compounds of formula (VIIIa) according to the invention can also be obtained from the compounds of formula (IXa) by reaction with a mineral acid, such as hydrochloric acid or sulfuric acid, in a solvent such as water, methanol, ethanol or alcohol isopropyl, at a temperature of room temperature to the point of boiling solvent.

The compounds of formula (IXa) according to the invention can be obtained by reacting the compounds of formula (XII) with compounds of formula R 2 H in which R 2 It is as defined above. The reaction takes conducted in a solvent, such as dimethylformamide, dimethylacetamide or dimethylsulfoxide, in the presence of a base, such as for example sodium hydride, potassium carbonate or carbonate of cesium, at a temperature of 60º to 140ºC.

The compounds of formula (XII) can be obtained from the compounds 6-aminopyrimidin-4-ol of formula (VI) by reaction with a carboxylic acid of formula R 4 COOH, in which R 4 is as defined previously in the presence of a chlorinating agent, such as phosphorus oxychloride, phosphorus pentachloride or chloride thionyl, at a temperature of 60 ° to 120 ° C.

The 6-aminopyrimidin-4-ol compounds of formula (VI) are, in turn, obtained by reaction of the carboxyamidines of formula (II) with ethyl cyanoacetate. The reaction is carried out in a solvent such as methanol, ethanol, isopropyl alcohol, butyl alcohol or tetrahydrofuran, in the presence of a base, such as sodium methoxide, sodium ethoxide or potassium tert -butoxide at room temperature at boiling point of the solvent.

The compounds of formula (I) and in particular the of formulas (VIIIb) or (IXb) in which R1 is a group monocyclic or polycyclic heteroaryl attached to the pyrimidine ring by a nitrogen atom and R2 is a heteroaryl group monocyclic or polycyclic attached to the pyrimidine ring by a carbon atom, can be obtained as shown in the Scheme 2.

Scheme 2

5

Aminonitriles of formula (XIV) can be obtained by reacting nitriles of formula (XII) in which R2 is as defined above and acetonitrile, in the presence of a base, preferably lithium or tert- diisopropylamide - potassium peroxide, in a solvent such as benzene, toluene or xylene, at a temperature from room temperature to the boiling point of the solvent.

The resulting aminonitriles (XIV) are reacted with thiourea, in a solvent such as methanol, ethanol, isopropyl alcohol, butyl alcohol or tetrahydrofuran, in the presence of a base such as sodium methoxide, sodium ethoxide or potassium tert -butoxide, a a temperature of 60 ° to 140 ° C giving 4-aminopyrimidine-2-thiols of formula (XV).

The 4-aminopyrimidine-2-thiols of formula (XV) can be reacted in a solvent as for example water, methanol, ethanol, dimethylformamide or dimethylsulfoxide, with methyl iodide or dimethyl sulfate, in presence of a base such as sodium hydroxide, carbonate sodium, potassium carbonate or sodium hydride, and at a temperature of room temperature at 80 ° C giving 2- (methylthio) pyrimidin-4-amines of formula (XVI).

The 2- (methylthio) pyrimidin-4-amines of formula (XVI) can be reacted with an oxidizing agent, preferably m-chloroperbenzoic acid, oxone or magnesium monoperoxyphthalate, in a solvent such as methanol, ethanol, acetone, methylene chloride or chloroform, and at a temperature from 0º to 70ºC giving 2- (methylsulfonyl) pyrimidin-4-amines of formula (XVII) or, alternatively, can be acylated with a acid chloride and a base, such as pyridine, triethylamine or diisopropylethylamine, in a solvent such as tetrahydrofuran, methylene chloride, chloroform or pyridine, at one room temperature temperature to the boiling point of solvent giving the 2- (methylthio) pyrimidin-4-amides of formula (XXI).

The 2- (methylsulfonyl) pyrimidin-4-amines of formula (XVII) can be transformed into compounds (VIIIb) according to the present invention by reaction with compounds of formula R 1 -H, in which R 1 is a group monocyclic or polycyclic heteroaryl attached to the pyrimidine ring by a nitrogen atom. The reaction is carried out in a solvent such as dimethylformamide, dimethylacetamide or dimethylsulfoxide, in the presence of a base, preferably hydride sodium, potassium carbonate or cesium carbonate, and at a temperature from 60º to 160ºC. Similarly the 2- (methylsulfonyl) pyrimidin-4-amides of formula (XXII) can be transformed into compounds (IXb) according to the present invention following the same procedure.

The 2- (methylthio) pyrimidin-4-amides of formula (XXI) can be reacted with an oxidizing agent, preferably m-chloroperbenzoic acid, oxone or magnesium monoperoxyphthalate, in a solvent such as methanol, ethanol, acetone, methylene chloride or chloroform, and at a temperature from 0º to 70ºC giving the 2- (methylsulfonyl) pyrimidin-4-amides of formula (XXII).

Finally, the compounds (VIIIb) according to the invention can be transformed into compounds (IXb) also according to the invention by reaction with an acid chloride and a base, such as pyridine, triethylamine or diisopropylethylamine, in a solvent such as tetrahydrofuran, chloride methylene, chloroform or pyridine, at a temperature of temperature ambient to the boiling point of the solvent. The compounds of formula (IXb) can also be prepared by reaction of the amine (VIIIb) with an anhydride, at a temperature of 80 ° to 160 ° C.

The reverse operation by which the compounds of formula (IXb) are transformed into compounds of formula (VIIIb) is also possible, and can be carried out by reaction with a mineral acid, such as hydrochloric acid or acid sulfuric acid, in a solvent such as water, methanol, ethanol or isopropyl alcohol, at a room temperature temperature at  boiling point of the solvent.

The compounds of formula (I) and in particular the of formulas (VIIIc) or (IXc) in which R1 is a group monocyclic or polycyclic heteroaryl attached to the pyrimidine ring by a carbon atom and R2 is a heteroaryl group monocyclic or polycyclic attached to the pyrimidine ring by a Carbon atom can be obtained as shown in the Scheme 3.

Scheme 3

6

The reaction between methyl ketones of formula (XXIII), in which R2 is a monocyclic heteroaryl group or polycyclic attached to the pyrimidine ring by an atom of carbon and diethyl carbonate, can be carried out in the presence of a base, preferably sodium hydride, in a solvent such as for example benzene, toluene, ethyl ether, tetrahydrofuran or dioxane, and at a temperature of 40º to 120ºC giving Ethyl 3-oxo-propanoates Substitutes of formula (XXIV).

The pyrimidin-4-ol compounds of formula (XXV) can be obtained from the substituted ethyl 3-oxo-propanoates of formula (XXIV) by reaction with carboxyamidines of formula (II) in a solvent such as methanol, ethanol , isopropyl alcohol, butyl alcohol or tetrahydrofuran, in the presence of a base, such as sodium methoxide, sodium ethoxide or potassium tert -butoxide and at a temperature of room temperature at the boiling point of the solvent.

The compounds pyrimidin-4-ol of formula (XXV) is they can react with a chlorinating agent such as phosphorus oxychloride, phosphorus pentachloride or a mixture of themselves, in a solvent such as phosphorus oxychloride, benzene or toluene, at a room temperature temperature at boiling point of the solvent giving the 4-chloropyrimidines of formula (Xb). Optionally the presence of a base may be necessary as for example dimethylaminoaniline, triethylamine or diisopropyl-ethylamine at this stage of reaction.

The compounds of formula (VIIIc) according to the The present invention can be prepared from 4-chloropyrimidines of formula (Xb) by reaction with ammonium hydroxide in a solvent such as methanol, ethanol, isopropyl alcohol or tetrahydrofuran, at a temperature from 80 ° C to 140 ° C.

Finally, the compounds of formula (IXc) according to the present invention can be prepared from the compounds of formula (VIIIc) by acylation with an acid chloride and a base, such as pyridine, triethylamine or diisopropylethylamine, in a solvent as per example tetrahydrofuran, methylene chloride, chloroform or pyridine, at a temperature from room temperature to the boiling point of the solvent. The compounds of formula (IXc) can also be prepared by reacting the amine (VIIIc) with an anhydride, at a temperature of 80 ° to
160 ° C.

The compounds of formula (VIIIc) can be also obtained from compounds of formula (IXc) by reaction with a mineral acid, such as hydrochloric acid or sulfuric acid, in a solvent such as water, methanol, ethanol or isopropyl alcohol, at a temperature temperature ambient to the boiling point of the solvent.

The compounds of formulas (VIIIc) and (IXc) in the that R1 is a monocyclic or polycyclic heteroaryl group attached to the pyrimidine ring by a carbon atom and R2 is a monocyclic or polycyclic heteroaryl group attached to the ring of pyrimidine by a carbon atom can also be obtained as shown in Scheme 4.

Scheme 4

7

\hbox{paladio(0),}

como por ejemplo tetrakis(trifenilfosfina)paladio(0).The Suzuki reaction between the 4-aminopyrimidines of formulas (IV), (V) or (XII) and the boronic acid of formula (XXIX), wherein R 2 is a monocyclic or polycyclic heteroaryl group attached to the ring of pyrimidine by means of a carbon atom, it is preferably carried out in an organic solvent, such as methanol, ethanol, acetonitrile, dioxane, tetrahydrofuran, dimethoxyethane, benzene or toluene, optionally in the presence of water, at a temperature between 60 ° and 120 ° C, with a base such as sodium or potassium carbonate and a catalyst of

 \ hbox {palladium (0),} 

such as tetrakis (triphenylphosphine) palladium (0).

The Stille reaction reaction between 4-aminopyrimidines of formulas (IV), (V) or (XII) and the organotin derivative of formula (XXX), in which R2 is a monocyclic or polycyclic heteroaryl group attached to the ring of pyrimidine by a carbon atom, is carried out, preferably, in an organic solvent, such as methanol, ethanol, acetonitrile, dioxane, tetrahydrofuran, dimethoxyethane, benzene or toluene, optionally in the presence of water, at a temperature between 60º and 120ºC, with a base as per example sodium or potassium carbonate and a catalyst of palladium (0), such as tetrakis (triphenylphosphine) palladium (0).

The compounds of 4-chloropyrimidine of formula (Xb) can be transform into the compounds of formula (VIIIc) by reaction with ammonium hydroxide in a solvent, such as methanol, ethanol, isopropyl alcohol or tetrahydrofuran, at a temperature from 80º to 140ºC.

Finally, the compounds of formula (IXc) according The present invention can be prepared from the compounds of formula (VIIIc) by acylation with an acid chloride and a base, such as pyridine, triethylamine or diisopropylethylamine, in a solvent such as tetrahydrofuran, chloride methylene, chloroform or pyridine, at a temperature of temperature ambient to the boiling point of the solvent. The compounds of formula (IXd) can also be prepared by reaction of the amine (VIIIc) with an anhydride, at a temperature of 80 ° to 160 ° C.

The compounds of formula (VIIIc) can be also obtained from compounds of formula (IXc) by reaction with a mineral acid, such as hydrochloric acid or sulfuric acid, in a solvent such as water, methanol, ethanol or isopropyl alcohol, at a temperature temperature ambient to the boiling point of the solvent.

The compounds of formulas (VIIId) and (IXd) in the that R1 is a monocyclic or polycyclic heteroaryl group attached to the pyrimidine ring by a carbon atom and R2 is a substituted cyclic heterogroup, can be obtained as shown in Scheme 5.

Scheme 5

8

The substituted 4-chloro-2- (2-heteroaryl) pyrimidines of formula (Xd) can be obtained by reaction of the corresponding unsubstituted 4-chloro-2- (2-heteroaryl) pyrimidines of formula (Xc). When the heteroaryl group is a furyl group, the reaction is preferably carried out with N- chlorosuccinimide (X = chlorine) or N- bromosuccinimide (X = bromine), with a solvent, such as dimethylformamide or dimethyl sulfoxide, at a temperature from 40º to 100ºC. Alternatively, a halogenating agent may be selected from the group consisting of Cl 2, Br 2, SOCl 2 and SOBr 2.

4-chloropyrimidine compounds of formula (Xd) can then be transformed into the compounds of formula (VIIId) by reaction with ammonium hydroxide in a solvent such as methanol, ethanol, isopropyl alcohol or tetrahydrofuran, at a temperature of 80 ° to 140 ° C.

Finally, the compounds of formula (IXd) according The present invention can be prepared from the compounds of formula (VIIId) by acylation with an acid chloride and a base, such as pyridine, triethylamine or diisopropylethylamine, in a solvent such as tetrahydrofuran, chloride methylene, chloroform or pyridine, at a temperature of temperature ambient to the boiling point of the solvent. The compounds of formula (IXd) can also be prepared by reaction of the amine (VIIId) with an anhydride, at a temperature of 80 ° to 160 ° C.

The compounds of formula (VIIId) can be also obtained from compounds of formula (IXd) by reaction with a mineral acid, such as hydrochloric acid or sulfuric acid, in a solvent such as water, methanol, ethanol or isopropyl alcohol, at a temperature temperature ambient to the boiling point of the solvent.

The carbamates of formula (XXVI) and ureas of formula (XX) can be synthesized as summarized in the Scheme 6.

Scheme 6

9

The carbamates of formula (XXVI) are obtained by reaction of a compound of formula (VIII) with a compound of formula Z-COOR 4, in which Z represents a leaving group, such as a halogen atom, preferably chlorine or a group selected from ethoxy, methoxy, p-nitrophenoxy and imidazolyl. The reaction takes conducted in a solvent, such as tetrahydrofuran, chloroform, methylene chloride or dimethylformamide, in the presence of a base, preferably triethylamine, diisopropylethylamine, potassium carbonate or sodium hydroxide, at a temperature of -70º to 100 ° C

The compounds of formula (VIII) can be also transform into ureas of formula (XX) in which R 5 it is a hydrogen atom by reaction with an isocyanate of formula R 4 -N = C = O in a solvent such as benzene, toluene or xylene, at a temperature of temperature ambient at 140 ° C.

The synthesis of amines of formula (XXVII) can be Prepare following Scheme 7.

Scheme 7

       \ vskip1.000000 \ baselineskip
    

10

       \ vskip1.000000 \ baselineskip
    

When R 1 represents a monocyclic or polycyclic heteroaryl group attached to the pyrimidine ring by a carbon atom, the compounds of formula (XXVII) can be obtained from the compounds of formulas (Xa and Xb) by reaction with a amine of formula R 4 NH 2. The reaction is carried out in a solvent such as methanol, ethanol, isopropanol, butanol, pentanol, tetrahydrofuran or dimethylformamide, in the presence of a base such as an excess of the reactive amine R 4 NH 2 or potassium carbonate, sodium carbonate, triethylamine or diisopropylethylamine, and at a temperature between room temperature and the boiling point of
solvent

When the R 1 to R 5 groups already defined they may undergo a chemical reaction under the conditions of procedures described herein above descriptive or incompatible with such procedures, it they can use conventional protecting groups according to practice habitual; see, for example T. W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry", 3rd Edition, John Wiley & Sons (1999). The check-out may be the last stage of the synthesis of the compounds of formula (I).

The compounds of formulas (XIII), (XXIII), (XXIX), (XXX) and (XXXI), are known compounds, or can be prepare by analogy with known procedures.

In particular, the compounds of formulas (XXIX) and (XXXI) can be prepared by the procedures described in Tyrrell, E .; Brookes, P; Synthesis, 2003, 4, 469-483; Condret, C. Synthetic Communications 1996, 26 (19), 3543-3547 and Handbook of Organopalladium Chemistry for Organic Synthesis, set of two volumes edited by Ei-ichi Negishi. John Wiley and Sons, 2002.

Pharmacological activity Competitive radioligand binding assay of the subtypes of the Adenosine 2A receptor

Human membranes for A2a receptors Recombinants were purchased from Receptor Biology, Inc. (USA).

Competitiveness tests were carried out by incubation of the membranes from hA2a receptors transfected into HEK293 cells, [3 H] ZM241385 as radioligand, buffer (50mM Tris-HCl (pH = 7.4), 10mM MgCl2, 1mM EDTA, 2 units / ml adenosine deaminase), and unlabeled ligand in a total volume of 0.2 ml for 90 min at 25 ° C NECA was used to determine non-specific binding. Leaked on Schleicher & Schuell GF / 52 filters (previously impregnated with 0.5% polyethyleneimine) in a Brandel cell collector. He unbound radioligand was removed with 3 x 3 ml of 50mM Tris-HCl (pH = 7.4) cooled with ice, 0.9% of NaCl

The results are shown in Table 1

TABLE 1

eleven

12

13

In Table 1 it can be seen that the compounds of formula (I) are potent inhibitors of the subtype of A2A adenosine receptor and are selective over the other subtypes of adenosine receptors.

The derivatives of pyrimidin-4-amine of the invention they are useful in the treatment or prevention of diseases that knows that they can improve by treatment with an antagonist of adenosine receptor and in particular with an antagonist of A 2A adenosine receptor. Such diseases are, for example ischemia, supraventricular arrhythmia, acute renal failure, asthma, damage of myocardial reperfusion, allergic reactions including but not limited to rhinitis, urticaria, scleroderma arthritis, others autoimmune diseases, inflammatory bowel diseases, diabetes mellitus, obesity, Parkinson's disease, disease Huntington, dystonia such as leg syndrome restless, dyskinesias such as those caused by use prolonged dopaminergic or neuroleptic medications or sleep disorders.

Consequently, derivatives of pyrimidin-4-amine of the invention, the pharmaceutically acceptable salts thereof, and the pharmaceutical compositions comprising said compound and / or the salts thereof, can be used in a treatment procedure of disorders of the human body that comprises administering to a subject in need of such treatment an effective amount of pyrimidin-4-amine derivative of the invention or a pharmaceutically acceptable salt thereof.

The present invention also provides pharmaceutical compositions comprising, as an ingredient active, at least one derivative of pyrimidin-4-amine of formula (I) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient, such as a vehicle or diluent. The active ingredient may comprise from 0.001% to 99% by weight, preferably 0.01% to 90% by weight of the composition, depending on the nature of the formulation and whether an additional dilution is made before application. Preferably, the compositions are prepared in a form appropriate for oral, topical, nasal, rectal administration, percutaneous or injectable.

Pharmaceutically acceptable excipients that are mixed with the active compound, or salts of said compound, to form the compositions of this invention are well known per se and the actual excipients used depend inter alia on the intended method of administration of the compositions.

The compositions of this invention are preferably adapted for injectable administration and per os . In this case, the compositions for oral administration may take the form of tablets, long-acting tablets, sublingual tablets, capsules, inhalation aerosols, inhalation solutions, dry inhalation powder or liquid preparations, such as mixtures, elixirs, syrups or suspensions, all of them containing the compound of the invention; Such preparations can be prepared by methods known in the art.

The diluents that can be used in the Preparation of the compositions include liquid diluents and solids that are compatible with the active ingredient, along with coloring or flavoring agents, if desired. The tablets or capsules may conveniently contain between 2 and 500 mg of the active ingredient or the equivalent amount of a salt of the same.

The liquid composition adapted for oral use It may be in the form of solutions or suspensions. The solutions may be aqueous solutions of a soluble salt or ortho derivative of the active compound together with, for example, sucrose to form a syrup The suspensions may comprise a insoluble active compound of the invention or a salt pharmaceutically acceptable thereof together with water, together with a suspending agent or a flavoring agent.

Compositions for parenteral injection are they can be prepared from soluble salts, which can be dried or not by freezing and that can be dissolved in an exempt aqueous medium of pyrogens or other fluid suitable for parenteral injection.

The effective doses are usually in the range of 2-2000 mg of active ingredient per day. The daily dosage can be administered in one or more treatments, preferably 1 to 4 treatments, per day.

The present invention is further illustrated. by the following examples. The examples only have illustrative purpose and are not intended to be limiting.

The synthesis of the compounds of the invention and of the intermediates used in it are illustrated by following Examples (1 to 118), including the preparation of intermediates 1 to 52, which do not limit the scope of the invention of no way.

General Reagents, starting products, and solvents were purchased from commercial sources. The term "concentration" refers to evaporation under vacuum using a Büchi rotary evaporator. When indicated, the reaction products were purified by flash chromatography on silica gel (40-63 µm) with the indicated solvent system. Spectroscopic data were measured on the Varian Gemeni 200, Varian Gemeni 300, Varian Enova 400 and Brucker DPX-250 Spectrometers. Melting points were measured on a Büchi 535 device. The HPLC-MS were performed on a Gilson instrument equipped with a Gilson 321 piston pump, a Gilson 864 vacuum degasifier, a Gilson 189 injection module, a 1/1000 Gilson splitter, a Gilson 307 pump, a Gilson 170 detector, and a Thermoquest Fennigan aQa detector. Semi-preparative purifications were performed using a Simmetri C18 reverse phase column (100 Å, 5 µm, 19 x 100 mm, Water), and water / ammonium formate (0.1%, pH = 3 ) and acetonitrile / ammonium formate (0.1%, pH = 3) as the mobile phase (from 30:70 to 70:30).

Intermediate one

Furan-2-carboxamidine (HCl)

To a solution of sodium methoxide (5.55 mmol) in methanol (50 mL) 2-furonitrile (5.0 g; 53.2 mmol). The mixture is stirred at room temperature for 3 hours. To the resulting solution is slowly added ammonium (3.14 g, 58.7 mmol) and the mixture is stirred at temperature ambient for 68 hours. The resulting suspension is filtered and the solvent evaporates. The solid obtained is washed with ethyl ether (3 x 25 mL) obtaining 7.5 g (96.2%) of furan-2-carboxamidine (HCl).

δ (200 MHz, DMSO): 6.88-6.86 (m, 1H); 7.89 (d, J = 3.8 Hz, 1H); 8.19 (s, 1 H); 9.22 (s, 3H).

Intermediate 2

2- (Furan-2-yl) pyrimidine-4,6-diol

To a solution of sodium ethoxide (0.191 mol) in Ethanol (90 mL) is added Intermediate 1 (5.6 g; 38.2 mmol). The The mixture is stirred at room temperature for 30 minutes and is add diethyl malonate (4.87 g, 30.4 mmol). The suspension is Hold at reflux for 32 hours. The solvent evaporates, and the residue is suspended in water (100 mL) and acidified to pH = 6 with 5N HCl The resulting solid is filtered and washed with water (50 mL), ethanol / ethyl ether (4: 1, 25 mL), and ethyl ether (2 x 25 mL). 2- (Furan-2-yl) pyrimidine-4,6-diol (4.2 g, 78%) is obtained as a yellow solid.

δ (300 MHz, DMSO): 5.00 (s, 1H); 6.60-6.70 (m, 1 H); 7.40 (d, J = 3.4 Hz, 1H); 7.80 (s, 1 H).

Intermediate 3

4,6-Dichloro-2- (furan-2-yl) pyrimidine

A suspension of intermediate 2 (3.0 g; 16.8 mmol) and N, N -diisopropylethylamine (3.85 g; 29.8 mmol) in phosphorus oxychloride (17 mL) is refluxed for 3 hours. The solvent is evaporated and dichloromethane (50 mL) and ice are added. The organic phase is decanted and washed with water (2 x 25 mL), saturated sodium bicarbonate solution (2 x 25 mL), and dried (Na2SO4). The solvent is evaporated to obtain 4,6-dichloro-2- (furan-2-yl) pyrimidine (3.15 g, 87%) as an amorphous solid.

δ (300 MHz, Cl 3 CD): 6.63-6.61 (m, 1H); 7.22 (s, 1 H); 7.46 (d, J = 3.4 Hz, 1H); 7.68 (s, 1 H).

Intermediate 4

6-Chloro-2- (furan-2-yl) pyrimidin-4-ylamine

A suspension of Intermediate 3 (2.0 g; 9.3 mmol) in methanol (14 mL) and 30% ammonium hydroxide (27 mL) is heated in a closed tube for 20 hours. The solvent evaporates partially. The resulting solid is filtered, washed with water (25 mL), ethyl ether (25 mL), and dries to obtain 6-Chloro-2- (furan-2-yl) pyrimidin-4-ylamine (1.48 g, 76%) as white solid.

δ (400 MHz, CDCl 3): 5.21 (bs, 2H); 6.31 (s, 1 H); 6.54 (m, 1 H); 7.28 (d, J1 = 3.7 Hz, 1H); 7.58 (s, 1 H).

Example 1 2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-ylamine

14

To a solution of Intermediate 4 (1.0 g; 5.1 mmol) in a DMF (20 mL) pyrazole (0.7 g; 10.2 mmol) and carbonate are added cesium (3.34 g; 10.2 mmol). The mixture is heated to 85 ° C. for 21 hours The solution is poured onto water (50 mL) and extracted with ethyl acetate (2 x 25 mL). The organic phase is washed with water (2 x 25 mL) and brine (25 mL), dry (Na2SO4), and the solvent evaporates. The resulting solid is purified by column chromatographic with silica gel, eluting with dichloromethane / methanol (3%), obtaining 2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-ylamine (0.64 g, 55%) as a white solid.

δ (250 MHz, CDCl 3): 5.12 (bs, 2H); 6.48-6.46 (m, 1 H); 6.57-6.55 (m, 1 H); 6.90 (s, 1 H); 7.31 (d, J = 3.6 Hz, 1H); 7.61 (s, 1 H); 7.75 (d, J = 1.2 Hz, 1H); 8.63 (d, J = 3.0 Hz, 1H).

Example 2 N - [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] acetamide

fifteen

To a solution of the compound described in example 1 (0.30 g; 1.32 mmol) in dichloromethane (7 mL) is added pyridine (0.21 g; 2.64 mmol) and acetyl chloride (0.21 g; 2.64 mmol). The mixture is stirred at room temperature for 5 hours and pyridine (52 mg; 0.66 mmol) and acetyl chloride (52 mg; 0.66 mmol) are added. The reaction is maintained for an additional 1.5 hours at room temperature. The solution is diluted with dichloromethane (20 mL), washed with 10% sodium hydroxide (2 x 10 mL), brine (10 mL), and dried (Na2SO4). The solvent evaporates. The residue is purified by chromatographic column with silica gel, eluting with ethyl acetate / n-hexane (1: 3), to give N - [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-illacetamide (0.33 g, 92%) as white solid.

δ (250 MHz, CDCl 3): 2.25 (s, 3H); 6.51-6.49 (m, 1 H); 6.61-6.58 (m, 1 HOUR); 7.36-7.34 (m, 1H); 7.62 (s, 1 H); 7.81 (s, 1 H); 8.21 (bs, 1H); 8.54 (s, 1 H); 8.65-8.63 (m, 1H).

Example 3 N - [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide

16

Obtained from the compound described in example 1 (0.34 g) using the procedure described in example 2. The residue is purified by chromatographic column with silica gel and ethyl acetate / n-hexane (1: 1) as eluent to give N - [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide (0.35 g, 83%) as a white solid.

δ (250 MHz, CDC 3): 1.28 (t, J = 7.3 Hz, 3H); 2.48 (q, J = 7.3 Hz, 2H); 6.50-6.48 (m, 1 H); 6.60-6.58 (m, 1 H); 7.34 (d, J = 3.6 Hz, 1H); 7.62 (s, 1 H); 7.79 (s, 1 H); 8.13 (bs, 1H); 8.58 (s, 1 H); 8.62 (d, J = 2.4 Hz, 1H).

Example 4 N - [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] isobutyramide

17

Obtained from the compound described in example 1 (0.10 g) using the procedure described in example 2. The residue is purified by chromatographic column with silica gel and dichloromethane / methanol (2%) as eluent to give N - [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] isobutyramide (90 mg, 72%) as a white solid.

δ (250 MHz, CDC 3): 1.28 (d, J = 7.0 Hz, 6H); 2.58 (h, J = 7.0 Hz, 1H); 6.49 (dd, J1 = 2.7; 1 Hz, J2 = 1.5 Hz, 1H); 6.60 (dd, J1 = 3.3 Hz, J2 = 1.5 Hz, 1H); 7.36 (dd, J1 = 3.6 Hz, J2 = 0.9 Hz, 1H); 7.65-7.63 (m, 1 H); 7.80-7.78 (m, 1 H); 8.08 (bs, 1H); 8.64-8.61 (m, 2H).

Example 5 N - [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] tert butyramide

18

Obtained from the compound described in example 1 (0.30 g) using the procedure described in example 2. The residue is purified by chromatographic column with silica gel and ethyl acetate / n-hexane (from 10:90 to 15:85 ) as eluent to give N - [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] tertbutyramide (25 mg, 6%) as a white solid.

δ (250 MHz, CDC 3): 1.35 (s, 9H); 6.49-6.47 (m, 1 H); 6.59 (dd, J1 = 3.4 Hz, J2 = 1.8 Hz, 1H); 7.36-7.35 (m, 1 H); 7.64-7.63 (m, 1 H); 7.78-7.77 (m, 1 H); 8.19 (bs, 1H); 8.62 (d, J = 2.7 Hz, 1H); 8.66 (s, 1 H).

Example 6 Cyclopropylcarboxylic acid [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] amide

19

Obtained from the compound described in the example 1 (0.20 g) using the procedure described in the example 2. The residue is purified by chromatographic column with silica gel and dichloromethane / methanol (2%) as eluent to give the acid cyclopropylcarboxylic [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] amide  (0.10 g, 39%) as white solid.

δ (250 MHz, CDCl 3): 0.98-0.91 (m, 2H); 1.20-1.13 (m, 2H); 1.59-1.51 (m, 1H); 6.49 (dd, J1 = 2.7 Hz, J2 = 1.5 Hz, 1H), 6.59 (dd, J1 = 3.6 Hz, J2 = 1.8 Hz, 1H); 7.35 (d, J = 3.6 Hz, 1H); 7.64-7.63 (m, 1 H); 7.77 (d, J = 1.5 Hz, 1H); 8.42 (bs, 1H); 8.56 (s, 1 H); 8.62 (d, J = 2.7 Hz, 1H).

Example 7 Cyclobutylcarboxylic acid [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] amide

twenty

Obtained from the compound described in the example 1 (0.15 g) using the procedure described in the example 2. The residue is purified by chromatographic column with silica gel and dichloromethane / methanol (0.5%) as eluent to give the acid cyclobutylcarboxylic [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] amide (0.14 g, 67%) as white solid.

δ (250 MHz, CDCl 3): 2.50-1.93 (m, 6H); 3.22 (q, J = 8.5 Hz, 1H); 6.49 (dd, J1 = 2.7 Hz, J2 = 1.8 Hz, 1H); 6.59 (dd, J1 = 3.3 Hz, J2 = 1.8 Hz, 1H); 7.35 (d, J = 3.3 Hz, 1H); 7.63 (m, 1 H); 7.79 (m, 1 H); 7.97 (bs, 1H); 8.62 (s, 1 H); 8.63 (s, 1 H).

Example 8 Cyclohexylcarboxylic acid [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] amide

twenty-one

Obtained from the compound described in the example 1 (0.15 g) using the procedure described in the example 2. The residue is purified by chromatographic column with silica gel and dichloromethane / methanol (0.5%) as eluent to give the acid cyclohexylcarboxylic [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] amide (0.20 g, 91%) as white solid.

δ (250 MHz, CDCl 3): 2.00-1.26 (m, 10H); 2.35-2.23 (m, 1H); 6.49 (dd, J1 = 2.7 Hz, J2 = 1.5 Hz, 1H); 6.59 (dd, J1 = 3.3 Hz, J2 = 1.8 Hz, 1H); 7.34 (dd, J1 = 3.3 Hz, J2 = 0.9 Hz, 1H); 7.63-7.62 (m, 1 H); 7.78 (m, 1 H); 8.14 (bs, 1H); 8.63-8.59 (m, 2H).

Example 9 3-Cyclopentyl- N - [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide

22

Obtained from the compound described in example 1 (0.20 g) using the procedure described in example 2. The residue is purified by chromatographic column with silica gel and ethyl acetate / n-hexane (from 10:90 to 20:80 ) as eluent to give 3-cyclopentyl- N - [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide (0.29 g, 94%) as white solid.

δ (250 MHz, CDCl 3): 1.18-1.07 (m, 2H); 1.86-1.51 (m, 9H); 2.43 (t, J = 7.4 Hz, 2H); 6.49 (dd, J1 = 2.7 Hz, J2 = 1.5 Hz, 1H); 6.59 (dd, J1 = 3.3 Hz, J2 = 1.5 Hz, 1H); 7.34 (dd, J1 = 3.3 Hz, J2 = 0.6 Hz, 1H); 7.63-7.62 (m, 1 H); 7.80-7.79 (m, 1 H); 8.16 (bs, 1H); 8.58 (s, 1 H); 8.63 (dd, J1 = 2.7 Hz, J2 = 0.6 Hz, 1H).

Example 10 N - [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -2- (4-methoxyphenyl) -acetamide

2. 3

Obtained from the compound described in example 1 (0.15 g) using the procedure described in example 2. The residue is purified by chromatographic column with silica gel and ethyl acetate / n-hexane (1: 4) as eluent to give N - [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -2- (4-methoxyphenyl) acetamide (63 mg, 27%) as a white solid.

δ (250 MHz, CDCl 3): 3.73 (s, 2H); 3.82 (s, 3 H); 6.50-6.48 (m, 1 H); 6.58-6.56 (m, 1 H); 6.91 (s, 1 H); 6.94 (s, 1 H); 7.32-7.23 (m, 3H); 7.61-7.60 (m, 1 H); 7.80-7.79 (m, 1 H); 8.06 (bs, 1H); 8.59 (s, 1 H); 8.62 (d, J = 2.7 Hz, 1H).

Example 11 2- (3,4-Dimethoxyphenyl) - N - [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] acetamide

24

Obtained from the compound described in example 1 (80 mg) using the procedure described in example 2. The residue is purified by chromatographic column with silica gel and dichloromethane / methanol (0.5%) as eluent to give 2- (3, 4-dimethoxyphenyl) - N - [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] acetamide (87 mg, 61%) as a white solid.

δ (250 MHz, CDCl 3): 3.73 (s, 2H); 3.90 (s, 6H); 6.51-6.48 (m, 1 H); 6.59-6.56 (m, 1 H); 6.84 (s, 1 H); 6.88 (s, 2H); 7.33 (d, J = 3.3 Hz, 1H); 7.61 (s, 1 H); 7.80 (s, 1 H); 8.10 (bs, 1H); 8.59 (s, 1 H); 8.63 (d, J = 2.7 Hz, 1H).

Example 12 N - [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl) -3-phenyl-propionamide

25

Obtained from the compound described in example 1 (0.20 g) using the procedure described in example 2. The residue is purified by chromatographic column with silica gel and ethyl acetate / n-hexane (1: 4) as eluent to give N - [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl) -3-phenyl propionamide (0.27 g, 85%) as a white solid.

δ (250 MHz, CDCl 3): 2.74 (t, J = 7.8 Hz, 2H); 3.08 (t, J = 7.8 Hz, 2H); 6.51-6.49 (m, 1 H); 6.60-6.57 (m, 1 H); 7.35-7.22 (m, 6H); 7.62 (s, 1 H); 7.81 (s, 1 H); 8.11 (bs, 1H); 8.58 (s, 1 H); 8.64 (m, 1 H).

Example 13 E -2-Phenylcyclopropylcarboxylic acid [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] amide

26

Obtained from the compound described in example 1 (0.15 g) using the procedure described in example 2. The residue is purified by chromatographic column with silica gel and dichloromethane / methanol (0.5%) as eluent to give E -2 acid -phenylcyclopropylcarboxylic [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] amide (0.23 g, 95%) as a white solid.

δ (250 MHz, CDCl 3): 1.49-1.40 (m, 1H); 1.86-1.75 (m, 2H); 2.71-2.63 (m, 1 H); 6.50-6.49 (m, 1 H); 6.57 (dd, J1 = 3.3 Hz, J2 = 1.8 Hz, 1H); 7.14-7.11 (m, 2H); 7.34-7.19 (m, 4H); 7.61 (m, 1 H); 7.79 (m, 1 H); 8.59-8.58 (m, 2H); 8.63 (d, J = 2.7 Hz, 1H).

Example 14 3,3,3-Trifluoro- N - [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide

27

To a solution of 3,3,3-trifluoropropionic acid (0.21; 1.65 mmol) in dichloromethane (4 mL) is added oxalyl chloride (0.21 g; 1.65 mmol) and a catalytic amount of DMF. The mixture is stirred at room temperature for 1 hour. This solution is cooled to 0 ° C and added at the same temperature to a solution of the compound of example 1 (125 mg; 0.44 mmol) and pyridine (123 mg; 1.65 mmol) in dichloromethane (4 mL): The mixture is stirred at temperature ambient for 22 hours and diluted with dichloromethane (8 mL). The organic phase is washed with water (2 x 8 mL) and brine (8 mL), dried (Na2SO4), and the solvent is evaporated. The residue is purified by chromatographic column with silica gel, eluting with ethyl acetate / n-hexane (1: 4), to give 3,3,3-trifluoro- N - [2- (furan-2-yl) -6 - (pyrazol-1-yl) pyrimidin-4-yl] propionamide (0.16 g, 87%) as a white solid.

δ (250 MHz, CDCl 3): 3.33 (q, J = 10.0 Hz, 2H); 6.52-6.50 (m, 1 H); 6.61-6.59 (m, 1 H); 7.36 (d, J = 3.6 Hz, 1H); 7.64-7.63 (m, 1 H); 7.82-7.81 (m, 1 H); 8.40 (bs, 1H); 8.54 (s, 1 H); 8.65-8.63 (m, 1H).

Example 15 3- (3,4-Dimethoxyphenyl) - N - [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide

28

Obtained from the compound described in example 1 (0.20 g) using the procedure described in example 14. The residue is purified by chromatographic column with silica gel and ethyl acetate / n-hexane (from 30:70 to 40:60 ) as eluent to give 3- (3,4-dimethoxyphenyl) - N - [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide (0.27 g, 72% ) as white solid.

δ (250 MHz, CDCl 3): 2.71 (t, J = 7.6 Hz, 2H); 3.02 (t, J = 7.6 Hz, 2H); 3.85 (s, 3 H); 3.86 (s, 3 H); 6.50 (dd, J1 = 2.7 Hz, J2 = 1.5 Hz, 1H); 6.59 (dd, J1 = 3.3 Hz, J2 = 1.8 Hz, 1H); 6.80-6.76 (m, 3H); 7.34 (dd, J1 = 3.3 Hz, J2 = 0.9 Hz, 1H); 7.62 (dd, J1 = 1.8 Hz , J2 = 0.9 Hz, 1H); 7.81 (dd, J1 = 1.1 Hz, J2 = 0.6 Hz, 1H); 8.07 (bs, 1H); 8.58 (s, 1 H); 8.64 (dd, J1 = 2.7 Hz, J2 = 0.6 Hz, 1H).

Example 16 N - [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -2-methyl-3-phenylpropionamide

29

Obtained from the compound described in example 1 (0.15 g) using the procedure described in example 14. The residue is purified by chromatographic column with silica gel and dichloromethane / methanol (1%) as eluent to give N - [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -2-methyl-3-phenylpropionamide (0.14 g, 51%) as a white solid.

δ (250 MHz, CDCl 3): 1.29 (d, J = 6.4 Hz, 3H); 2.79-2.62 (m, 2H); 3.16-3.08 (m, 1 H); 6.51-6.49 (m, 1 H); 6.59-6.57 (m, 1 H); 7.34-7.16 (m, 6H); 7.62 (m, 1 H); 7.80 (m, 1 H); 7.97 (bs, 1H); 8.63-8.61 (m, 2H).

Example 17 N - [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3-phenoxy-propionamide

30

Obtained from the compound described in example 1 (0.20 g) using the procedure described in example 14. The residue is purified by chromatographic column with silica gel and ethyl acetate / n-hexane (30:70) as eluent to give N - [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3-phenoxy-propionamide (0.23 g, 70%) as a white solid.

δ (250 MHz, CDCl 3): 2.91 (t, 2H); 4.37 (t, 2H); 6.50-6.49 (m, 1 H); 6.61-6.58 (m, 1 H); 7.01-6.94 (m, 3H); 7.35-7.27 (m, 3H); 7.64 (m, 1 H); 7.80 (m, 1 H); 8.58 (s, 1 H); 8.64 (d, J = 2.4 Hz, 1H).

Example 18 N - [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3- (pyridin-3-yl) -propionamide

31

Obtained from the compound described in example 1 (0.20 g) using the procedure described in example 14. The residue is purified by chromatographic column with silica gel and dichloromethane / methanol (2%) as eluent to give N - [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3- (pyridin-3-yl) propionamide (0.19 g, 60%) as a white solid.

δ (250 MHz, CDCl 3): 2.76 (t, J = 7.3 Hz, 2H); 3.09 (t, J = 7.3 Hz, 2H); 6.51-6.50 (m, 1 H); 6.60-6.58 (m, 1 H); 7.28-7.21 (m, 1 H); 7.34 (d, J = 3.6 Hz, 1H); 7.63-7.57 (m, 2H); 7.81 (s, 1 H); 8.13 (s, 1 H); 8.54-8.47 (m, 2H); 8.56 (s, 1 H); 8.64 (d, J = 2.4 Hz, 1H).

Example 19 N - [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3- (pyridin-3-yl) acetamide

32

Obtained from the compound described in example 1 (0.20 g) using the procedure described in example 14. The residue is purified by chromatographic column with silica gel and dichloromethane / methanol (2%) as eluent to give N - [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3- (pyridin-3-yl) acetamide (0.70 g, 23%) as white solid.

δ (250 MHz, DMSO): 3.89 (s, 2H); 6.65 (dd, J1 = 2.6 Hz, J2 = 1.3 Hz, 1H); 6.75 (dd, J1 = 3.5 Hz, J2 = 1.7 Hz, 1H); 7.37 (dd, J1 = 7.9 Hz, J2 = 4.8 Hz, 1H); 7.49 (dd, J1 = 3.5 Hz, J2 = 0.9 Hz, 1H); 7.77 (dt, J1 = 7.9 Hz, J2 = 1.7 Hz, 1H); 7.91 (m, 1 H); 7.97 (m, 1 H); 8.40 (s, 1 H); 8.48 (dd, J1 = 4.8 Hz, J2 = 1.7 Hz, 1H); 8.55 (d, J1 = 1.7 Hz, 1H); 8.77 (d, J1 = 2.6 Hz, 1H); 11.50 (s, 1 H).

Example 20 E -3- (3,4-Dimethoxyphenyl) - N - [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] acrylamide

33

A solution of 3,4-dimethoxyphenylacrylic acid (0.55 g; 2.64 mmol) in thionyl chloride (4 mL) is stirred at 55 ° C for 1 hour. The solvent evaporates. The resulting oil is dissolved in dichloromethane (2 mL) and the solution is cooled to 0 ° C and added at the same temperature to a solution of the compound of example 1 (0.20 mg; 0.88 mmol) and pyridine (0.20 mg; 2.64 mmol) in dichloromethane (6 mL). The mixture is stirred at room temperature for 44 hours and diluted with dichloromethane (8 mL). The organic phase is washed with water (2 x 8 mL) and brine (8 mL), dried (Na2SO4), and the solvent is evaporated. The residue is purified by chromatographic column with silica gel, eluting with dichloromethane / ethanol (0.5%), to give E -3- (3,4-dimethoxyphenyl) - N - [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] acrylamide (0.70 g, 19%) as a white solid.

δ (250 MHz, CDCl 3): 3.93 (s, 3H); 3.94 (s, 3 H); 6.40 (d, J = 15.5 Hz, 1H); 6.52-6.50 (m, 1 H); 6.61-6.59 (m, 1 H); 6.90 (d, J = 8.2 Hz, 1H); 7.06 (d, J = 1.8 Hz, 1H); 7.16 (dd, J1 = 8.2 Hz, J2 = 1.8 Hz, 1H); 7.36 (dd, J1 = 3.3 Hz, J2 = 0.6 Hz, 1H); 7.64-7.63 (m, 1 H); 7.76 (d, J = 15.5 Hz, 1H); 7.82 (m, 1 H); 8.33 (bs, 1H); 8.66-8.65 (m, 1 H); 8.69 (s, 1 H).

Example 21 2- (Furan-2-yl) -6- (3,5-dimethylpyrazol-1-yl) pyrimidin-4-ylamine

3. 4

To a solution of intermediate 4 (2.0 g; 10.2 mmol) in dry DMSO (50 mL) 3,5-dimethylpyrazole is added (1.97 g; 20.5 mmol) and cesium carbonate (6.70 g; 20.6 mmol). The mixture is heated at 150 ° C for 9 hours. The solution is poured over water (150 mL) and extracted with ethyl acetate (3 x 100 mL). The organic phase is washed with water (3 x 100 mL), brine (100 mL), dry (Na2SO4), and the solvent evaporates. Solid resulting is purified by chromatographic column with silica gel, eluting with ethyl acetate / n-hexane (from 3: 7 up to 1: 1), obtaining 2- (furan-2-yl) -6- (3,5-dimethylpyrazol-1-yl) pyrimidin-4-ylamine (1.86 g, 71%) as white solid.

δ (250 MHz, CDCl 3): 2.29 (s, 3H); 2.78 (s, 3 H); 5.10 (bs, 2H); 6.00 (s, 1 H); 6.55-6.52 (m, 1 H); 6.84 (s, 1 H); 7.19 (d, J = 2.4 Hz, 1H); 7.58 (s, 1 H).

Example 22 N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] acetamide

35

Obtained from the compound described in example 21 (0.30 g) using the procedure described in example 2. The residue is purified by chromatographic column with silica gel and ethyl acetate / n-hexane (1: 1) as eluent to give N - [6- (3,5-dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] acetamide (0.25 g, 72%) as a white solid.

δ (250 MHz, CDCl 3): 2.23 (s, 3H); 2.29 (s, 3 H); 2.77 (s, 3 H); 6.02 (s, 1 H); 6.58-6.55 (m, 1 H); 7.24 (d, J = 3.3 Hz, 1H); 7.61-7.60 (m, 1 H); 8.17 (bs, 1H); 8.48 (s, 1 H).

Example 23 N - [6- (3,5-Dimethylpyrazol-1-i1) -2- (furan-2-yl) pyrimidin-4-yl] propionamide

36

Obtained from the compound described in example 21 (0.30 g) using the procedure described in example 2. The residue is purified by chromatographic column with silica gel and ethyl acetate / n-hexane (1: 4) as eluent to give N - [6- (3,5-dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] propionamide (0.26 g, 71%) as a white solid.

δ (250 MHz, CDCl 3): 1.27 (t, J = 7.6 Hz, 3H); 2.29 (s, 3 H); 2.46 (q, J = 7.6 Hz, 2H); 2.78 (s, 3 H); 6.03 (s, 1 H); 6.59-6.57 (m, 1 H); 7.25 (d, J = 2.7 Hz, 1H); 7.62-7.61 (m, 1 H); 8.12 (bs, 1H); 8.55 (s, 1 H).

Example 24 N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] isobutyramide

37

Obtained from the compound described in example 21 (0.15 g) using the procedure described in example 2. The residue is purified by chromatographic column with silica gel and dichloromethane / methanol (1%) as eluent to give N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] isobutyramide (0.11 g, 60%) as a white solid.

δ (250 MHz, CDCl 3): 1.28 (d, J = 7.0 Hz, 6H); 2.27 (s, 3 H); 2.56 (h, J = 7.0 Hz, 1H); 2.77 (s, 3 H); 6.02 (s, 1 H); 6.58-6.56 (m, 1 H); 7.26 (s, 1 H); 7.62-7.61 (m, 1 H); 8.03 (bs, 1H); 8.58 (s, 1 H).

Example 25 N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] tertbutyramide

38

Obtained from the compound described in example 21 (0.15 g) using the procedure described in example 2. The residue is purified by chromatographic column with silica gel and ethyl acetate / n-hexane (15:85) as eluent to give N - [6- (3,5-dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] tertbutyramide (95 mg, 48%) as a white solid.

δ (250 MHz, CDCl 3): 1.34 (s, 9H); 2.27 (s, 3 H); 2.77 (s, 3 H); 6.02 (s, 1 H); 6.57 (dd, J1 = 3.3 Hz, J2 = 1.8 Hz, 1H); 7.25 (d, J = 0.9 Hz, 1H); 7.62 (dd, J1 = 1.8 Hz, J2 = 0.9 Hz, 1H); 8.14 (bs, 1H); 8.62 (s, 1 H).

Example 26 Cyclopropylcarboxylic acid [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] amide

39

Obtained from the compound described in the example 21 (0.15 g) using the procedure described in the example 2. The residue is purified by chromatographic column with silica gel and dichloromethane / methanol (1%) as eluent to give acid cyclopropylcarboxylic [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] amide (70 mg, 37%) as white solid.

δ (250 MHz, CDCl 3): 0.97-0.89 (m, 2H); 1.21-1.13 (m, 2H); 1.59-1.49 (m, 1 H); 2.26 (s, 3H); 2.77 (s, 3 H); 6.01 (s, 1 H); 6.57 (dd, J1 = 3.3 Hz, J2 = 1.8 Hz, 1H); 7.24 (dd, J1 = 3.3 Hz, J2 = 0.9 Hz, 1H); 7.61 (dd, J1 = 1.8 Hz, J2 = 0.9 Hz, 1H); 8.39 (bs, 1H); 8.52 (s, 1 H).

Example 27 3-Cyclopentyl-N- [6- (3,5-dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] propionamide

40

Obtained from the compound described in the example 21 (0.15 g) using the procedure described in the example 2. The residue is purified by chromatographic column with silica gel and dichloromethane / n-hexane (from 90% to dichloromethane pure) as eluent to give 3-cyclopentyl-N- [6- (3,5-dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] propionamide (0.22 g, 99%) as white solid.

δ (250 MHz, CDCl 3): 1.16-1.07 (m, 2H); 1.83-1.51 (m, 9H); 2.28 (s, 3 H); 2.42 (t, J = 7.3 Hz, 2H); 2.77 (s, 3 H); 6.02 (s, 1 H); 6.57 (dd, J1 = 3.3 Hz, J2 = 1.8 Hz, 1H); 7.24 (d, J = 3.6 Hz, 1H); 7.61 (s, 1 H); 8.16 (bs, 1H); 8.54 (s, 1 H).

Example 28 N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] -2- (4-methoxyphenyl) acetamide

41

Obtained from the compound described in example 21 (0.15 g) using the procedure described in example 2. The residue is purified by chromatographic column with silica gel and dichloromethane / methanol (2%) as eluent to give N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] -2- (4-methoxyphenyl) acetamide (0.11 g, 46%) as white solid.

δ (250 MHz, CDCl 3): 2.28 (s, 3H); 2.76 (s, 3 H); 3.71 (s, 2H); 3.82 (s, 3 H); 6.01 (s, 1 H); 6.55 (dd, J1 = 3.3 Hz, J2 = 1.8 Hz, 1H); 6.89 (s, 1 H); 6.93 (s, 1 H); 7.26-7.20 (m, 3H); 7.59-7.58 (m, 1 H); 8.04 (s, 1 H); 8.54 (s, 1 H).

Example 29 2- (3,4-Dimethoxyphenyl) - N - [6- (3,5-dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] acetamide

42

Obtained from the compound described in example 21 (0.15 g) using the procedure described in example 2. The residue is purified by chromatographic column with silica gel and dichloromethane / methanol (2%) as eluent to give 2- (3, 4-dimethoxyphenyl) - N - [6- (3,5-dimethylpyrazol-l-yl) -2- (furan-2-yl) pyrimidin-4-yl] acetamide (0.12 g, 47%) as white solid.

δ (250 MHz, CDCl 3): 2.28 (s, 3H); 2.77 (s, 3 H); 3.71 (s, 2H); 3.89 (s, 3H); 3.90 (s, 3H); 6.02 (s, 1 H); 6.55 (dd, J1 = 3.3 Hz, J2 = 1.8 Hz, 1H); 6.82 (s, 1 H); 6.87 (s, 1 H); 6.88 (s, 1 H); 7.22 (dd, J1 = 3.3 Hz, J2 = 0.9 Hz, 1H); 7.59 (dd, J1 = 1.8 Hz, J2 = 0.9 Hz, 1H); 8.02 (bs, 1H); 8.54 (s, 1 H).

Example 30 N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] -3-phenyl propionamide

43

Obtained from the compound described in example 21 (0.15 g) using the procedure described in example 2. The residue is purified by chromatographic column with silica gel and dichloromethane / n-hexane (from 90% to pure dichloromethane) as eluent for give N - [6- (3,5-dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] -3-phenylpropionamide (0.23 g, 99%) as a white solid.

δ (250 MHz, CDCl 3): 2.29 (s, 3H); 2.72 (t, J = 7.6 Hz, 2H); 2.77 (s, 3 H); 3.07 (t, J = 7.6 Hz, 2H); 6.02 (s, 1 H); 6.57-6.55 (m, 1 H); 7.34-7.18 (m, 6H); 7.60 (m, 1 H); 8.15 (bs, 1H); 8.54 (s, 1 H).

Example 31 N - (6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] -3,3,3-trifluoropropionamide

44

Obtained from the compound described in example 21 (0.30 g) using the procedure described in example 14. The residue is purified by chromatographic column with silica gel and ethyl acetate / n-hexane (1: 4) as eluent to give N - [6- (3,5-dimethylpyrazol-l-yl) -2- (furan-2-yl) pyrimidin-4-yl] -3,3,3-trifluoropropionamide (0.21 g, 49%) as white solid .

δ (250 MHz, CDCl 3): 2.29 (s, 3H); 2.78 (s, 3 H); 3.30 (c, J = 10.0 Hz, 2H); 6.04-6.02 (m, 1 H); 6.59-6.57 (m, 1 H); 7.28-7.24 (m, 1H); 7.62-7.61 (m, 1 H); 8.30 (bs, 1H); 8.50 (s, 1 H).

Example 32 3- (3,4-Dimethoxyphenyl) - N - [6- (3,5-dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] propionamide

Four. Five

Obtained from the compound described in example 21 (0.15 g) using the procedure described in example 14. The residue is purified by chromatographic column with silica gel and dichloromethane / methanol (1%) as eluent to give 3- (3, 4-dimethoxyphenyl) - N - [6- (3,5-dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] propionamide (0.18 g, 67%) as white solid.

δ (250 MHz, CDCl 3): 2.70 (t, J = 7.6 Hz, 2H); 2.77 (s, 6H); 3.02 (t, J = 7.6 Hz, 2H); 3.85 (s, 3 H); 3.87 (s, 3 H); 6.03 (s, 1 H); 6.58-6.55 (m, 1 H); 6.82-6.75 (m, 3H); 7.23 (dd, J1 = 3.3 Hz, J2 = 0.9 Hz, 1H); 7.60 (dd, J1 = 1.8 Hz, J2 = 0.9 Hz, 1H); 8.09 (bs, 1H); 8.54 (s, 1 H).

Example 33 N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] -3-phenoxy propionamide

46

Obtained from the compound described in example 21 (0.15 g) using the procedure described in example 14. The residue is purified by chromatographic column with silica gel and dichloromethane / methanol (1%) as eluent to give N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] -3-phenoxypropionamide (0.21 g, 88%) as white solid.

δ (250 MHz, CDCl 3): 2.28 (s, 3H); 2.78 (s, 3 H); 2.89 (t, J = 6.1 Hz, 2H); 4.36 (t, J = 6.1 Hz, 2H); 6.02 (s, 1 H); 6.58-6.56 (m, 1 H); 7.00-6.93 (m, 3H); 7.33-7.24 (m, 3H); 7.62 (m, 1 H); 8.47 (bs, 1H); 8.54 (s, 1 H).

Example 34 N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) -pyrimidin-4-yl] -2- (pyridin-3-yl) acetamide

47

Obtained from the compound described in example 21 (0.15 g) using the procedure described in example 14. The residue is purified by chromatographic column with silica gel and dichloromethane / methanol (2.5%) as eluent to give N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) -pyrimidin-4-yl] -2- (pyridin-3-yl) acetamide (55 mg, 25%) as white solid.

δ (250 MHz, DMSO): 2.19 (s, 3H); 2.74 (s, 3 H); 3.87 (s, 2H); 6.20 (s, 1 H); 6.73 (dd, J1 = 3.4 Hz, J2 = 1.7 Hz, 1H); 7.30 (d, J = 3.4 Hz, 1H); 7.37 (dd, J1 = 7.7 Hz, J2 = 4.7 Hz, 11-1); 7.79-7.74 (m, 1 H); 7.96 (s, 1 H); 8.35 (s, 1 H); 8.50-8.46 (m, 1 H); 11.41 (s, 1 H).

Example 35 N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) -pyrimidin-4-yl] -2- (pyridin-3-yl) propionamide

48

Obtained from the compound described in example 21 (0.20 g) using the procedure described in example 14. The residue is purified by chromatographic column with silica gel and dichloromethane / methanol (2%) as eluent to give N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) -pyrimidin-4-yl] -2- (pyridin-3-yl) propionamide (97 mg, 31%) as white solid.

δ (250 MHz, DMSO): 2.23 (s, 3H); 2.74 (s, 3H); 2.97-2.81 (m, 4H); 6.22 (s, 1 H); 6.73-6.71 (m, 1 H); 7.34-7.27 (m, 2H); 7.71-7.66 (m, 1 H); 7.95 (m, 1 H); 8.37 (s, 1 H); 8.42-8.39 (m, 1 H); 8.49 (m, 1 H); 11.13 (s, 1 H).

Example 36 2- (Furan-2-yl) -6- (4-methylpyrazol-1-yl) pyrimidin-4-ylamine

49

Obtained from intermediate 4 (0.50 g) using the procedure described in example 21. The residue is Purify by chromatographic column with silica gel and acetate ethyl / n-hexane (1: 1) as eluent to give 2- (furan-2-yl) -6- (4-methylpyrazol-1-yl) pyrimidin-4-ylamine (0.29 g, 47%) as white solid.

δ (250 MHz, CDCl 3): 2.16 (s, 3H); 5.10 (bs, 2H); 6.57-6.55 (m, 1 H); 6.83 (s, 1 H); 7.29 (dd, J1 = 3.3 Hz, J2 = 0.6 Hz, 1H); 7.56 (s, 1 H); 7.61 (m, 1 H); 8.39 (s, 1 H).

Example 37 N - [2- (Furan-2-yl) -6- (4-methylpyrazol-1-yl) -pyrimidin-4-yl] propionamide

fifty

Obtained from the compound described in example 36 (0.19 g) using the procedure described in example 2. The residue is purified by chromatographic column with silica gel and dichloromethane as eluent to give N - [2- (furan-2-yl ) -6- (4-methylpyrazol-1-yl) -pyrimidin-4-yl] propionamide (0.20 g, 82%) as white solid.

δ (250 MHz, CDCl 3): 1.25 (t, J = 7.3 Hz, 2H); 2.16 (s, 3 H); 2.45 (q, J = 7.3 Hz, 2H); 6.59-6 57 (m, 1 H); 7.33 (d, J = 3.3 Hz, 1H); 7.62-7.60 (m, 2H); 8.12 (bs, 1H); 8.37 (s, 1 H); 8.51 (s, 1 H).

Example 38 2- (Furan-2-yl) -6- (3-methylpyrazol-1-yl) pyrimidin-4-ylamine

51

Obtained from intermediate 4 (0.50 g) using the procedure described in example 21. The residue is Purify by chromatographic column with silica gel and acetate ethyl / n-hexane (1: 1) as eluent to give 2- (furan-2-yl) -6- (3-methylpyrazol-1-yl) pyrimidin-4-ylamine (0.47 g, 76%) as white solid.

δ (250 MHz, CDCl 3): 2.37 (s, 3H); 5.10 (bs, 2H); 6.26 (d, J = 2.7Hz, 1H); 6.55 (dd, J1 = 3.3 Hz, J2 = 1.8 Hz, 1H); 6.82 (s, 1 H); 7.29 (dd, J1 = 3.3 Hz, J2 = 0.9 Hz, 1H); 7.60 (dd, J1 = 1.8 Hz, J2 = 0.9 Hz, 1H); 8.52-8.51 (m, 1H).

Example 39 N - [2- (Furan-2-yl) -6- (3-methylpyrazol-1-yl) -pyrimidin-4-yl] propionamide

52

Obtained from the compound described in example38 (0.20 g) using the procedure described in example 2. The residue is purified by chromatographic column with silica gel and dichloromethane / methanol (2%) as eluent to give N - [2- ( furan-2-yl) -6- (3-methylpyrazol-1-yl) -pyrimidin-4-yl] propionamide (0.17 g, 70%) as white solid.

δ (250 MHz, CDCl 3): 1.26 (t, J = 7.6 Hz, 3H); 2.36 (s, 3 H); 2.46 (q, J = 7.6 Hz, 2H); 6.28 (d, J = 2.4 Hz, 1H); 6.58 (dd, J1 = 3.6 Hz, J2 = 1.8 Hz, 1H); 7.33-7.31 (m, 1H); 7.61 (s, 1 H); 8.11 (bs, 1H); 8.51-8.49 (m, 2H).

Example 40 2- (Furan-2-il) -6- (3- trifluoromethylpyrazol-1-yl) pyrimidin-4-ylamine

53

Obtained from intermediate 4 (0.50 g) using the procedure described in example 21. The residue is Purify by chromatographic column with silica gel and dichloromethane / methanol (5%) as eluent to give 2- (furan-2-yl) -6- (3-trifluoromethylpyrazole- 1-yl) pyrimidin-4-ylamine (0.49 g, 65%) as white solid.

δ (250 MHz, CDCl 3): 5.22 (bs, 2H); 6.58 (dd, J1 = 3.3 Hz, J2 = 1.8 Hz, 1H); 6.72 (d, J = 2.7 Hz, 1H); 6.95 (s, 1 H); 7.32 (dd, J1 = 3.3 Hz, J2 = 0.9 Hz, 1H); 7.62 (dd, J1 = 1.8 Hz, J2 = 0.9 Hz, 1H); 8.70-8.69 (m, 1H).

Example 41 N - [2- (Furan-2-yl) -6- (3-trifluoromethylpyrazol-1-yl) pyrimidin-4-yl] propionamide

54

Obtained from the compound described in example 40 (0.15 g) using the procedure described in example 2. The residue is purified by chromatographic column with silica gel and dichloromethane / n-hexane (from 90% to pure dichloromethane) as eluent for give N - [2- (furan-2-yl) -6- (3-trifluoromethylpyrazol-1-yl) pyrimidin-4-yl] propionamide (0.18 g, 99%) as a white solid.

δ (250 MHz, CDCl 3): 1.27 (t, J1 = 7.6 Hz, 3H); 2.49 (q, J1 = 7.6 Hz, 2H); 6.60 (dd, J1 = 3.3 Hz, J2 = 1.8 Hz, 1H); 6.73 (d, J1 = 2.7 Hz, 1H); 7.35 (d, J1 = 3.3 Hz, 1H); 7.64 (s, 1 H); 8.18 (bs, 1H); 8.62 (s, 11-1); 8.96 (m, 1 H).

Example 42 2- (Furan-2-yl) -6- (5-methyl-3-trifluoromethylpyrazol-1-yl) pyrimidin-4-ylamine

55

Obtained from intermediate 4 (0.50 g) using the procedure described in example 21. The residue is Purify by chromatographic column with silica gel and acetate ethyl / n-hexane (from 10:90 to 30:70) as eluent to give 2- (furan-2-yl) -6- (5-methyl-3-trifluoromethylpyrazole- 1-yl) pyrimidin-4-ylamine  (0.13 g, 16%) as white solid.

δ (250 MHz, CDCl 3): 2.84 (s, 3H); 5.26 (bs, 2H); 6.45 (s, 1 H); 6.57-6.55 (m, 1 H); 6.91 (s, 1 H); 7.22 (dd, J1 = 3.3 Hz, J2 = 0.9 Hz, 1H); 7.61-7.60 (m, 1H).

Example 43 N - [2- (Furan-2-yl) -6- (5-methyl-3-trifluoromethylpyrazol-1-yl) pyrimidin-4-yl] propionamide

56

Obtained from the compound described in example 42 (0.25 g) using the procedure described in example 2. The residue is purified by chromatographic column with silica gel and ethyl acetate / n-hexane (1: 4) as eluent to give N - [2- (furan-2-yl) -6- (5-methyl-3-trifluoromethylpyrazol-1-yl) pyrimidin-4-yl] propionamide (0.23 g, 77%) as white solid.

δ (250 MHz, CDCl 3): 1.26 (t, J = 7.6 Hz, 3H); 2.48 (q, J = 7.6 Hz, 2H); 2.84 (s, 3 H); 6.47 (s, 1 H); 6.59 (dd, J1 = 3.3 Hz, J2 = 1.8 Hz, 1H); 7.28-7.26 (m, 1 H); 7.63 (dd, J1 = 1.8 Hz, J2 = 0.9 Hz, 1H); 8.16 (bs, 1H); 8.58 (s, 1 H).

Example 44 2- (Furan-2-yl) -6 - [[1,2,4] triazol-1-yl] pyrimidin-4-ylamine

57

Obtained from intermediate 4 (1.90 g) using the procedure described in example 21. The residue is Purify by chromatographic column with silica gel and dichloromethane / methanol (3%) as eluent to give 2- (furan-2-yl) -6 - [[1,2,4] triazol-1-yl] pyrimidin-4-ylamine (1.64 g, 74%) as white solid.

δ (250 MHz, CDCl 3): 6.51-6.49 (m, 1H); 6.70 (s, 1 H); 7.22 (d, J = 3.0 Hz, 1H); 8.01 (s, 1 H); 8.54 (s, 1 H); 9.19 (s, 1 H).

Example 45 N - [2- (Furan-2-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-yl] acetamide

58

Obtained from the compound described in example 44 (0.30 g) using the procedure described in example 2. The residue is purified by chromatographic column) with silica gel and ethyl acetate / n-hexane (1: 1) as eluent for give N - [2- (furan-2-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-yl] acetamide (79 mg, 22%) as a white solid.

δ (250 MHz, DMSO): 2.20 (s, 3H); 6.78-6.76 (m, 1 H); 7.54 (d, J = 3.8 Hz, 1H); 7.98 (bs, 1H); 8.36 (s, 1 H); 8.40 (s, 1 H); 9.60 (s, 1 H); 11.35 (s, 1 H).

Example 46 N - [2- (Furan-2-yl) -6 - ([1,2,4] triazol-l-yl) pyrimidin-4-yl] propionamide

59

Obtained from the compound described in example 44 (0.30 g) using the procedure described in example 2. The residue is purified by chromatographic column with silica gel and ethyl acetate / n-hexane (1: 1) as eluent to give N - [2- (furan-2-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-yl] propionamide (90 mg, 24%) as a white solid.

δ (250 MHz, DMSO): 1.09 (t, J = 7.5 Hz, 3H); 2.51 (q, J = 7.5 Hz, 3H); 6.79-6.77 (m, 1 H); 7.57-7.54 (m, 1 H); 7.99-7.98 (m, 1H); 8.41-8.39 (m, 2H); 9.61 (s, 1 H); 11.30 (s, 1 H).

Example 47 3,3,3-Trifluoro- N - [2- (furan-2-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-yl) -propionamide

60

Obtained from the compound described in example 44 (0.30 g) using the procedure described in example 14. The residue is purified by chromatographic column with silica gel and ethyl acetate / n-hexane (2: 3) as eluent to give 3,3,3-trifluoro- N - [2- (furan-2-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-yl) propionamide (0.18 g, 40% ) as white solid.

δ (250 MHz, DMSO): 3.76 (q, J = 10.9 Hz, 2H); 6.78-6.76 (m, 1 H); 7.57-7.55 (m, 1H); 7.99-7.98 (m, 1H); 8.31 (s, 1 H); 8.41 (s, 1 H); 9.61 (s, 1 H); 11.71 (s, 1 H).

Intermediate 5

4-Chloro-2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidine

To a solution of Intermediate 3 (0.34 g; 1.57 mmol) in DMF (8 mL) pyrazole (97 mg; 1.43 mmol) and carbonate are added cesium (0.51 g; 1.57 mmol). The mixture is heated at 65 ° C for 7 hours. The solvent evaporates. The resulting solid is washed with water (2 x 25 mL) and ethyl ether obtaining 4-chloro-2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidine (0.21 g, 54%) as white solid.

δ (300 MHz, CDCl 3): 6.58 (dd, J1 = 2.7 Hz, J2 = 1.6 Hz, 1H); 6.65 (dd, J1 = 3.4 Hz, J2 = 1.8 Hz, 1H); 7.45 (d, J = 3.4 Hz, 1H); 7.60 (s, 1 H); 7.86 (d, J = 1.6 Hz, 1H); 7.90 (s, 1 H); 8.67 (d, J = 2.7 Hz, 1H).

Intermediate 6

2- (5-Bromfuran-2-yl) -4-chloro-6- (pyrazol-1-yl) pyrimidine

To a solution of Intermediate 5 (1.0 g; 4.0 mmol) in dry DMF (20 mL) is added N- bromosuccinimide (0.78 g; 4.4 mmol). The mixture is heated at 50 ° C for 2 hours. The mixture is poured onto water (75 ml) and extracted with ethyl acetate (2 x 25 mL). The organic phase is washed with water (2 x 25 mL), brine (25 mL), dried (Na2SO4), and the solvent is evaporated. The residue is purified by chromatographic column with silica gel and dichloromethane as eluent to give intermediate 6 (0.67 g, 51%) as a white solid.

δ (300 MHz, CDCl 3): 6.54-6.55 (m, 2H); 7.37-7.38 (m, 1 HOUR); 7.78 (s, 1 H); 7.81-7.82 (m, 1 H); 8.66-8.67 (m, 1H).

Example 48 2- (5-Bromfuran-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-ylamine

61

A suspension of Intermediate 6 (0.70 g; 2.13 mmol) in ethanol (22 mL) and 30% ammonium hydroxide (22 mL) is heat at 120 ° C in a closed tube for 2.30 hours. He solvent evaporates. The residue in ethyl acetate (50 mL) and the resulting solution is washed with water (2 x 25 mL), brine (25 mL), and it is dried (Na2SO4). The solvent evaporates. The residue is Purify by chromatographic column with silica gel and dichloromethane / ethyl acetate (1: 1) as eluent to give the desired compound (0.23 g, 36%) as white solid.

m.p .: 221.0-221.7 ° C.

δ (300 MHz, DMSO): 6.58 (dd, J1 = 2.6 Hz, J2 = 1.8 Hz, 1H); 6.78 (s, 1 H); 6.81 (d, J = 3.3 Hz, 1H); 7.34 (d, J = 3.3 Hz, 1H); 7.37 (bs, 2H); 7.85 (d, J = 1.8 Hz, 1H); 8.66 (d, J = 2.6 Hz, 1H).

Example 49 N - [2- (5-Bromofuran-2-yl) -6- (pyrazol-l-yl) pyrimidin-4-yl] propionamide

62

A solution of the compound described in the example 48 (0.10 g; 0.33 mmol) in propionic anhydride (1.5 mL) is heat at 140 ° C for 2 hours. The mixture is poured on ice and extracted with dichloromethane (30 mL). The organic phase is washed with saturated sodium bicarbonate solution (2 x 15 mL), water (15 mL), brine (15 mL), and dry (Na2SO4). The solvent is evaporates The residue is purified by chromatographic column with silica gel and dichloromethane / ethyl acetate (1: 1) as eluent to give compound 49 (0.10 g, 84%) as a white solid.

m.p .: 199.5-200.3ºC.

δ (300 MHz, DMSO): 1.08 (t, J = 7.6 Hz, 3H); 2.50 (q, J = 7.6 Hz, 2H); 6.67 (dd, J1 = 2.6 Hz, J2 = 1.7 Hz, 1H); 6.90 (d, J = 3.3 Hz, 1H); 7.53 (d, J = 3.3 Hz, 1H); 7.94 (d, J = 1.7 Hz, 1H); 8.48 (s, 1H) 8.81 (d, J = 2.6 Hz, 1H); 11.19 (bs, 1H).

Intermediate 7

4-Chloro-2- (5-chlorfuran-2-yl) -6- (pyrazol-1-yl) pyrimidine

To a solution of Intermediate 5 (1.0 g; 4.0 mmol) in dry DMF (20 mL) is added N- chlorosuccionimide (0.59 g; 4.4 mmol). The mixture is heated at 50 ° C for 2 hours. The mixture is poured onto water (75 ml) and extracted with ethyl acetate (2 x 25 mL). The organic phase is washed with water (2 x 25 mL), brine (25 mL), dried (Na2SO4), and the solvent is evaporated. 4-Chloro-2- (5-chlorfuran-2-yl) -6- (pyrazol-1-yl) pyrimidine (1.12g, 99%) is obtained as a white solid.

δ (300 MHz, CDCl 3): 6.41 (d, J = 3.6 Hz, 1H), 6.55 (dd, J1 = 2.7 Hz, J2 = 1.6 Hz, 1H); 7.41 (d, J = 3.6 Hz, 1H); 7.78 (s, 1 H); 7.82 (d, J = 1.6 Hz, 1H); 8.66 (d, J = 2.7 Hz, 1H).

Example 50 2- (5-Chlorofuran-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-ylamine

63

Obtained from intermediate 7 (1.17 g) using the procedure described in example 48. The residue is Purify by chromatographic column with silica gel and dichloromethane / ethyl acetate (1: 1) as eluent to give 2- (5-chlorfuran-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-ylamine (0.48 g, 44%) as white solid.

m.p .: 209.9-211.0 ° C.

δ (300 MHz, DMSO): 6.58 (dd, J1 = 2.6 Hz, J2 = 1.7 Hz, 1H); 6.72 (d, J = 3.6 Hz, 1H); 6.78 (s, 1 H); 7.37-7.36 (m, 3H); 7.85 (s, 1 H); 8.66 (d, J = 2.6 Hz, 1H).

Example 51

N - [2- (5-Chlorofuran-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide

64

Obtained from the compound described in example 50 (0.28 g) using the procedure described in example 49. The residue is purified by chromatographic column with silica gel and dichloromethane / ethyl acetate (3: 1) as eluent to give N - [2- (5-chlordeuran-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide (0.23 g, 72%) as a white solid.

m.p .: 189.3-190.1ºC.

δ (300 MHz, DMSO): 1.05 (t, J = 7.6 Hz, 3H); 2.46 (q, J = 7.6 Hz; 2H); 6.64 (dd, J1 = 2.8 Hz, J2 = 1.7 Hz, 11-1); 6.78 (d, J = 3.6 Hz, 1H); 7.54 (d, J = 3.6 Hz, 1H); 7.92 (d, J1 = 1.7 Hz, J2 = 0.6 Hz, 1H); 8.45 (s, 1 H); 8.78 (d, J1 = 2.8 Hz, J2 = 0.6 Hz, 1H); 11.16 (bs, 1H).

Intermediate 8

5-Methylfuran-2-carboxamidine (HCl)

The compound (3.71g, 87%) is obtained as a solid yellow starting from 5-methyl-2-furonitrile (2.85 g) using the procedure described for Intermediate 1.

δ (300 MHz, DMSO): 2.27 (s, 3H); 6.36 (d, J = 3.6 Hz, 1H); 7.64 (d, J = 3.6 Hz, 1H); 8.49 (bs, 4 H).

Intermediate 9

6-Amino-2- (5-methylfuran-2-yl) pyrimidin-4-ol

To a solution of Intermediate 8 (3.71 g, 23 mmol) and ethyl cyanoacetate (2.60 g, 23 mmol) in butanol (25 mL) is added potassium tert butoxide (5.45 g; 46 mmol). The mixture is stirred at 135 ° C for 18 hours. The solvent evaporates. The residue is purified by chromatographic column with silica gel and dichloromethane / methanol (from 2% to 10%) as eluent to give 6-amino-2- (5-methylfuran-2-yl) pyrimidin-4-ol (1.96 g, 44%) as white solid.

δ (300 MHz, DMSO): 2.19 (s, 3H) 4.82 (s, 1H) 6.16 (d, J = 3.3 Hz, 1H) 6.41 (s, 2H) 7.23 (d, J = 3.3 Hz, 1H).

Intermediate 10

6-Chloro-2- (5-methylfuran-2-yl) pyrimidin-4-ylamine

A suspension of Intermediate 9 (2.45 g, 10.2 mmol) and phosphorus pentachloride (2.12g, 10.2 mmol) in oxychloride Phosphorus (7 mL) is stirred at 90 ° C for 2 hours. The reaction is dilute with dichloromethane (50 mL) and ice is added slowly. The organic phase is decanted and washed with saturated solution of baking soda (2 x 25mL), water (2 x 25 mL), brine (25 mL), and it is dried (Na2SO4). The solvent evaporates. The residue is Purify by chromatographic column with silica gel and dichloromethane / ethanol (8%) as eluent to give 6-chloro-2- (5-methylfuran-2-yl) pyrimidin-4-ylamine (0.28 g, 13%) as white solid.

δ (300 MHz, DMSO): 2.35 (s, 3H); 6.27 (s, 1 H); 6.28 (d, J = 3.3 Hz, 1H); 7.05 (d, J = 3.3 Hz, 1H); 7.32 (bs, 2 H).

Example 52 2- (5-Methylfuran-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-ylamine

65

It is obtained from intermediate 9 (0.10 g) using the procedure described in example 21. The residue is Purify by chromatographic column with silica gel and dichloromethane / ethyl acetate (9: 1) as eluent to give 2- (5-methylfuran-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-ylamine (44 mg, 36%) as white solid.

δ (300 MHz, DMSO): 2.23 (s, 3H); 6.15-6.16 (m, 1H); 6.42-6.43 (m, 1 H); 6.58 (s, 1 H); 7.05 (d, J = 3.0 Hz, 1H); 7.11 (s, 2H); 7.69 (s, 1 H); 8.50 (d, J = 2.5 Hz, 1H).

Example 53 N - [2- (5-Methylfuran-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide

66

Obtained from the compound described in example 52 (40 mg) using the procedure described in example 49. The residue is purified by chromatographic column with silica gel and dichloromethane / ethyl acetate (4: 1) as eluent to give N - [2- (5-methylfuran-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide (11 mg, 19%) as a white solid.

δ (300 MHz, DMSO): 0.94 (t, J = 7.6 Hz, 3H); 2.26 (s, 3H); 2.36 (q, J = 7.6 Hz, 2H); 6.24 (dd, J1 = 3.3 Hz, J2 = 0.6 Hz, 1H); 6.51 (dd, J1 = 2.8 Hz, J2 = 1.7 Hz, 1H); 7.25 (d, J = 3.3 Hz, 1H); 7.80-7.78 (m, 1 H); 8.28 (s, 1 H); 8.63 (dd, J = 2.8 Hz, J2 = 0.6 Hz, 1H); 11.00 (bs, 1H).

Intermediate eleven

6-Amino-2- (furan-2-il) pyrimidin-4-ol

To a solution of sodium methoxide (44 mmol) in Methanol (10 mL) is added slowly intermediate 1 (1.60 g, 11 mmol). The mixture is stirred at room temperature for 30 minutes. and then ethyl cyanoacetate (1.00 g, 8.8 mmol) is added. The suspension is refluxed for 18 hours. The solvent is evaporates The residue is suspended in water (20 mL) and acidified to pH = 6 with 5N HCl. The resulting solid is filtered and washed with water (20 mL). Is obtained 6-Amino-2- (furan-2-il) pyrimidin-4-ol (0.79 g, 50%) as a yellow solid.

δ (200 MHz, DMSO): 5.01 (s, 1H); 6.57 (s, 2H); 6.69 (dd, J1 = 3.4 Hz, J2 = 1.7 Hz, 1H); 7.43 (d, J = 3.4 Hz, 1H); 7.91 (d, J = 1.7 Hz, 1H).

Intermediate 12

N- (6-Chloro-2-furan-2-yl-pyrimidin-4-yl) propionamide

A solution of Intermediate 11 (1.20 g, 6.78 mmol) and propionic anhydride (1.5 mL) in phosphorus oxychloride (12 mL) is stirred at 90 ° C for 18 hours. The solvent evaporates. HE The resulting oil is dissolved in dichloromethane (50 mL), washed with water (2 x 25 mL), and brine (25 mL). The organic phase dries (Na2SO4) and the solvent is evaporated. The resulting solid filter and wash with n-pentane (20 mL) to obtain intermediate 12 (1.40 g, 80%) as a brown solid.

δ (200 MHz, CDCl 3): 1.26 (t, J = 7.4 Hz, 3H); 2.49 (q, J = 7.2 Hz, 2H); 6.59 (dd, J1 = 3.4 Hz, J2 = 1.7 Hz, 1H); 7.39 (d, J = 3.4 Hz, 1H); 7.64 (s, 1 H); 8.10 (d, J = 1.71 Hz, 1H); 8.38 (bs, 1H).

Example 54 N - [2- (Furan-2-yl) -6- (pyridin-3-yl) pyrimidin-4-yl] propionamide

       \ vskip1.000000 \ baselineskip
    

67

       \ vskip1.000000 \ baselineskip
    

To a solution of intermediate 12 (1.20 g, 4.77 mmol) in 1,2-dimethoxyethane (120 mL) are added 3-pyridinylboronic acid (0.88 g, 7.15 mmol), potassium carbonate (1.31 g, 9.54 mmol), water ( 8 mL) and tetrakis (triphenylphosphine) palladium (0) (2.65 g, 2.38 mmol). The mixture is stirred at 80 ° C overnight. The reaction is filtered through Celite® and the organic phase is washed with saturated sodium bicarbonate solution (2 x 50 mL), water (2 x 50 mL), brine (50 mL), dried (Na2) SO4), and the solvent evaporates. The residue is purified by chromatographic column, eluting with ethyl acetate / n-hexane (from 1: 6 to pure ethyl acetate), followed by digestion in hot acetonitrile to give N - [2- (furan-2-yl) - 6- (pyridin-3-yl) pyrimidin-4-yl] propionamide (0.30 g, 21%) as a white solid.

m.p .: 251.8-253.2ºC.

δ (200 MHz, DMSO): 1.10 (t, J = 7.5 Hz, 3H); 2.50 (q, J = 7.5 Hz, 2H) 6.75 (dd, J1 = 3.0 Hz, J2 = 1.7 Hz, 1H); 7.43 (d, J = 3.5 Hz, 1H); 7.97 (s, 1 H); 8.06 (d, J = 5.6 Hz, 2H); 8.54 (s, 1 H); 8.81 (d, J = 5.6 Hz, 2H); 11.21 (bs, 1H).

Example 55 2- (Furan-2-yl) -6- (pyridin-3-yl) pyrimidin-4-yl] amide

       \ vskip1.000000 \ baselineskip
    

68

       \ vskip1.000000 \ baselineskip
    

To a solution of the compound of example 54 (0.20 g, 0.687 mmol) in ethanol (2 mL) 2N HCl (2 mL) is added. Mix Stir at 80 ° C for 1 hour. The solution is diluted with water (10 mL) and 2N NaOH is added until pH = 10. The mixture is extracted with dichloromethane (2 x 10 mL). The organic extracts are combined and wash with water (2 x 10 mL), dry (Na2SO4), and the solvent evaporates. The resulting solid is washed with ether ethyl, getting 2- (furan-2-yl) -6- (pyridin-3-yl) pyrimidin-4-ylamide (80 mg, 49%) as white solid.

m. p .: 232.7-233.1 ° C.

δ (200 MHz, CDCl 3) 5.13 (bs, 2H); 6.58 (dd, J1 = 3.5 Hz, J2 = 1.7 Hz, 1H); 6.75 (s, 1 H); 7.37 (d, J = 3.5 Hz, 1H); 7.64-7.63 (m, 1 H); 7.93 (d, J = 6.0 Hz, 2H); 8.77 (d, J = 6.0 Hz, 2H).

       \ newpage
    

Intermediate 13

Thiophen-2-Carboxamidine (HCl)

The compound (12.7 g, 85%) is obtained as a solid starting from thiophene-2-carbonitrile (10.0 g) using the procedure described for Intermediate 1.

δ (250 MHz, DMSO): 7.32 (m, 1H); 8.13 (m, 1 HOUR); 8.17 (m, 1 H); 8.94-8.33 (bs, 3H).

Intermediate 14

6-Amino-2- (thiophen-2-yl) pyrimidin-4-ol

The compound (6.13 g, 76%) is obtained as a solid brown from intermediate 13 (7.00 g) using the procedure described for Intermediate 11 (reaction time: 4 days).

δ (250 MHz, DMSO): 5.04 (bs, 1H); 6.52 (bs, 2H); 7.18 (bs, 1H); 7.78 (bs, 1H); 8.09 (bs, 1H).

Intermediate fifteen

6-Chloro-2- (thiophen-2-yl) pyrimidin-4-ylamine

To a suspension of Intermediate 14 (6.30 g; 32.6 mmol) in phosphorus oxychloride (20 mL) is refluxed for 24 hours The solvent evaporates and ice and water are added slowly. The resulting solid is filtered, washed with 2N NaOH, and dries up 6-Chloro-2- (thiophen-2-yl) pyrimidin-4-ylamine it is obtained (4.40 g, 64%) as a brown solid.

MS (M +): 211

Example 56 6- (Pirazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-ylamine

69

Obtained from intermediate 15 (3.00 g) using the procedure described in example 21. Crystallization of ethyl ether to give 6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-ylamine (1.00 g, 27%) as white solid.

δ (250 MHz, DMSO): 6.59-6.57 (m, 1H); 6.77 (s, 1 H); 7.20 -7.17 (m, 1H); 7.24 (bs, 2H); 7.72-7.70 (m, 1 H); 7.85-7.84 (m, 1 H); 7.97-7.95 (m, 1 H); 8.67 (d, J = 2.5 Hz, 1H).

Example 57 N - [6- (Pirazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] acetamide

70

Obtained from the compound described in example 56 (0.30 g) using the procedure described in example 2. The residue is purified by chromatographic column with silica gel and ethyl acetate / n-hexane (1: 4) as eluent to give N - [6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] acetamide (0.19 g, 55%) as a white solid.

δ (250 MHz, CDCl 3): 2.20 (s, 3H); 6.44-6.43 (m, 1 H); 7.08 (dd, J1 = 4.8 Hz, J2 = 3.6 Hz, 1H); 7.43 (dd, J1 = 4.8 Hz, J2 = 1.2 Hz, 1H); 7.74-7.73 (m, 1 H); 7.91 (dd, J1 = 3.6 Hz, J2 = 1.2 Hz, 1H); 8.39 (m, 1 H); 8.59-8.57 (m, 1H).

Example 58 N - [6- (Pirazol-1-i1) -2- (thiophen-2-yl) pyrimidin-4-yl] propionamide

71

Obtained from the compound described in example 56 (0.30 g) using the procedure described in example 2. The residue is purified by chromatographic column with silica gel and ethyl acetate / n-hexane (1: 4) as eluent to give N - [6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] propionamide (0.2 g, 54%) as a white solid.

δ (250 MHz, CDCl 3): 1.28 (t, J = 7.6 Hz, 3H); 2.51 (q, J = 7.6 Hz, 2H); 6.50-6.49 (m, 1 H); 7.15 (dd, J1 = 5.2 Hz, J2 = 3.9 Hz, 1H); 7.49 (dd, J1 = 5.2 Hz, J2 = 1.2 Hz, 1H); 7.80-7.79 (m, 1 H); 8.00-7.98 (m, 2H); 8.54 (s, 1 H); 8.66-8.65 (m, 1H).

Example 59 3-Cyclopentyl- N - [6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl) propionamide

72

Obtained from the compound described in example 56 (0.20 g) using the procedure described in example 2. The residue is purified by chromatographic column with silica gel and ethyl acetate / n-hexane (1: 9) as eluent to give 3-cyclopentyl- N - [6- (pyrazol-1-yl) -2- (thiophene-2-yl) pyrimidin-4-yl) propionamide (0.17 g, 57%) as a white solid.

δ (250 MHz, CDCl 3): 1.18-1.10 (m, 2H); 1.63-1.51 (m, H); 1.85-1.75 (m, 5H); 2.48 (t, J = 7.3 Hz, 2H); 6.50-6.49 (m, 1 H); 7.15 (dd, J1 = 4.9 Hz, J2 = 3.6 Hz, 1H); 7.50 (dd, J1 = 4.9 Hz, J2 = 1.2 Hz, 1H); 7.99 (dd, J1 = 3.9 Hz, J2 = 1.2 Hz, 2H); 8.00 (d, J = 1.2 Hz, 1H); 8.54 (s, 1 H); 8.65 (d, J = 2.7 Hz, 1H).

Example 60 3-Phenyl- N - [6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] propionamide

73

Obtained from the compound described in example 56 (0.20 g) using the procedure described in example 2. The residue is purified by chromatographic column with silica gel and ethyl acetate / n-hexane (1: 4) as eluent to give 3-phenyl- N - [6- (pyrazol-1-yl) -2- (thiophene-2-yl) pyrimidin-4-yl] propionamide (0.29 g, 94%) as a white solid.

δ (250 MHz, CDCl 3): 2.78 (t, J = 7.6 Hz, 2H); 3.09 (t, J = 7.6 Hz, 2H); 6.50 (dd, J1 = 2.7 Hz, J2 = 1.8 Hz, 1H); 7.15 (dd, J1 = 5.2 Hz, J2 = 3.6 Hz, 1H); 7.35-7.22 (m, 5H); 7.49 (dd, J1 = 5.2 Hz, J2 = 1.2 Hz, 1H); 7.81 (m, 1 H); 7.94 (bs, 1H); 7.97 (dd, J1 = 3.6 Hz, J2 = 1.2 Hz, 1H); 8.54 (s, 1 H); 8.65 (d, J = 2.6 Hz, 1H).

Example 61 3,3,3-Trifluoro- N - [6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] propionamide

74

Obtained from the compound described in example 56 (0.30 g) using the procedure described in example 14. The residue is purified by chromatographic column with silica gel and ethyl acetate / n-hexane (1: 4) as eluent to give 3,3,3-Trifluoro- N - [6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] propionamide (0.33 g, 76%) as white solid.

δ (250 MHz, CDCl 3): 3.37 (q, J = 10.3 Hz, 2H); 6.52-6.50 (m, 1 H); 7.15 (dd, J1 = 4.8 Hz, J2 = 3.6 Hz, 1H); 7.51 (dd, J1 = 4.8 Hz, J2 = 1.2 Hz, 1H); 7.81-7.80 (m, 1 H); 7.99 (dd, J1 = 3.6 - Hz, J2 = 1.2 Hz, 1H); 8.23 (bs, 1H); 8.48 (bs, 1H); 8.65-8.64 (m, 1H).

Example 62 3- (3,4-Dimethoxyphenyl) - N - [6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl) propionamide

75

Obtained from the compound described in example 56 (0.20 g) using the procedure described in example 14. The residue is purified by chromatographic column using ethyl acetate / n-hexane (1: 1) as eluent to give 3- ( 3,4-dimethoxyphenyl) - N - [6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl) propionamide (0.18 g, 51%) as white solid.

δ (250 MHz, CDC 3): 2.76 (t, J = 7.6 Hz, 2H); 3.04 (t, J = 7.6 Hz, 2H); 3.85 (s, 3 H); 3.87 (s, 3 H); 6.50 (dd, J1 = 2.7 Hz, J2 = 1.8 Hz, 1H); 6.80-6.77 (m, 3H); 7.15 (dd, J1 = 4.8 Hz, J2 = 3.6 Hz, 1H); 7.49 (dd, J1 = 4.8 Hz, J2 = 1.2 Hz, 1H); 7.81-7.80 (m, 1 H); 7.92 (bs, 1H); 7.97 (dd, J1 = 3.6 Hz, J2 = 1.2 Hz, 1H); 8.53 (s, 1 H); 8.65 (dd, J1 = 2.7 Hz, J2 = 0.6 Hz, 1H).

Example 63 3-Phenoxy- N - [6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] propionamide

76

Obtained from the compound described in example 56 (0.20 g) using the procedure described in example 14. The residue is purified by chromatographic column with silica gel and dichloromethane / methanol (2%) as eluent to give 3-phenoxy- N - [6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] propionamide (0.28 g, 85%) as a white solid.

δ (250 MHz, CDC 3): 2.95 (t, J = 6.0 Hz, 2H); 4.38 (t, J = 6.0 Hz, 2H); 6.50-6.49 (m, 1 H); 7.03-6.98 (m, 3H); 7.16 (dd, J1 = 4.8 Hz, J2 = 3.6 Hz, 1H); 7.37-7.29 (m, 2H); 7.50 (dd, J1 = 5.2 Hz, J2 = 1.2 Hz, 1H); 7.80-7.79 (m, 1 H); 8.00 (dd, J1 = 3.9 Hz, J2 = 1.2 Hz, 1H); 8.53 (s, 1 H); 8.63 (bs, 1H); 8.66 (dd, J1 = 2.7 Hz, J2 = 0.6 Hz, 1H).

Example 64 N - [6- (Pirazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] -2- (pyridin-3-yl) acetamide

77

Obtained from the compound described in example 56 (0.20 g) using the procedure described in example 14. The residue is purified by chromatographic column with silica gel and dichloromethane / methanol (2.5%) as eluent to give N - [6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] -2- (pyridin-3-yl) acetamide (0.17 g, 56%) as white solid.

δ (250 MHz, CDCl 3): 3.82 (s, 2H); 6.49 (dd, J1 = 2.7 Hz, J2 = 1.5 Hz, 1H); 7.16-7.13 (m, 1H); 7.37-7.32 (m, 1 H); 7.50 (dd, J1 = 4.9 Hz, J2 = 1.2 Hz, 1H); 7.77-7.73 (m, 1 H); 7.78 (dd, J1 = 1.5 Hz, J2 = 0.6 Hz, 1H); 7.98 (dd, J1 = 3.6 Hz, J2 = 1.2 Hz, 1H); 8.04 (bs, 1H); 8.51 (s, 1 H); 8.62-8.59 (m, 2H); 8.64 (dd, J1 = 2.7 Hz, J2 = 0.6 Hz, 1H).

Example 65 N - [6- (Pirazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] -3- (pyridin-3-yl) propionamide

78

Obtained from the compound described in example 56 (0.20 g) using the procedure described in example 14. The residue is purified by chromatographic column with silica gel and dichloromethane / methanol (2%) as eluent to give N - [6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] -3- (pyridin-3-yl) propionamide (0.13 g, 43%) as a white solid.

δ (250 MHz, CDCl 3): 2.81 (t, J = 7.3 Hz, 2H); 3.10 (t, J = 7.3 Hz, 2H); 6.51 (dd, J1 = 2.7 Hz, J2 = 1.5 Hz, 1H); 7.15 (dd, J1 = 5.2 Hz, J2 = 3.6 Hz, 1H); 7.25-7.21 (m, 1H); 7.50-7.48 (m, 1 H); 7.61 (dt, J1 = 7.9 Hz, J2 = 2.1 Hz, 1H); 7.82-7.81 (m, 1 H); 7.97 (dd, J1 = 3.6 Hz, J2 = 1.2 Hz, 1H); 8.15 (bs, 1H); 8.5 (dd, J1 = 4.8 Hz, J2 = 1.5 Hz, 1H); 8.54-8.52 (m, 2H); 8.65 (d, J = 2.7 Hz, 1H).

Example 66 E -3- (3,4-Dimethoxyphenyl) - N - [6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl) acrylamide

79

Obtained from the compound described in example 56 (0.30 g) using the procedure described in example 20. The residue is purified by chromatographic column with silica gel and dichloromethane / methanol (0.5%) as eluent to give E -3- ( 3,4-dimethoxyphenyl) - N - [6- (pyrazol-1-yl) -2- (thiophene-2-yl) pyrimidin-4-yl) acrylamide (0.20 g, 36%) as white solid.

δ (250 MHz, CDCl 3): 3.82 (s, 3H); 3.84 (s, 3 H); 6.68 (dd, J1 = 2.7 Hz, J2 = 1.7 Hz, 1H); 7.09-7.02 (m, 2H); 7.28-7.23 (m, 3H); 7.66 (d, J1 = 15.5 Hz, 1H); 7.84 (dd, J1 = 5.0 Hz, J2 = 1.3 Hz, 1H); 7.97 (d, J1 = 1.3 Hz, 1H); 8.12 (dd, J1 = 3.7 Hz, J2 = 1.0 Hz, 1H); 8.57 (s, 1 H); 8.82 (d, J1 = 2.7 Hz, 1H); 11.08 (s, 1 H).

Example 67 6- (3,5-Dimethylpyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-ylamine

80

Obtained from intermediate 15 (3.0 g) using the procedure described in example 21. The residue is Purify by chromatographic column with silica gel and acetate ethyl / n-hexane (3:10) as eluent to give 6- (3,5-Dimethylpyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-ylamine (1.75 g, 45%) as white solid.

δ (250 MHz, DMSO): 2.19 (s, 3H); 2.72 (s, 3H); 6.13 (s, 1 H); 6.73 (s, 1 H); 7.08 (bs, 2H); 7.19-7.15 (m, 1H); 7.70-7.67 (m, 1 HOUR); 7.82-7.79 (m, 1H).

Example 68 N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] acetamide

81

Obtained from the compound described in example 67 (0.30 g) using the procedure described in example 2. The residue is purified by chromatographic column with silica gel and ethyl acetate / n-hexane (3:10) as eluent to give N - [6- (3,5-dimethylpyrazol-1-yl) -2- (thiophene-2-yl) pyrimidin-4-yl] acetamide (80 mg, 23%) as a white solid.

δ (250 MHz, CDCl 3): 2.20 (s, 3H); 2.23 (s, 3H); 2.74 (s, 3 H); 5.96 (s, 1 H); 7.07 (dd, J1 = 4.8 Hz, J2 = 3.6 Hz, 1H); 7.40 (dd, J1 = 5.2 Hz, J2 = 1.2 Hz, 1H); 7.84 (dd, J1 = 3.6 Hz, J2 = 1.2 Hz, 1H); 7.94 (bs, 1H); 8.39 (s, 1 H).

Example 69 N - [6- (3,5-dimethylpyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] propionamide

82

Obtained from the compound described in example 67 (0.30 g) using the procedure described in example 2. The residue is purified by chromatographic column with silica gel and ethyl acetate / n-hexane (1: 4) as eluent to give N - [6- (3,5-dimethylpyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] propionamide (0.17 g, 47%) as a white solid.

δ (250 MHz, DMSO): 1.27 (t, J = 7.3 Hz, 3H); 2.28 (s, 3 H); 2.49 (q, J = 7.3 Hz, 2H); 2.80 (s, 3H); 6.02 (s, 1 H); 7.13 (dd, J1 = 4.9 Hz, J2 = 3.6 Hz, 1H); 7.46 (dd, J1 = 4.9 Hz, J2 = 1.2 Hz, 1H); 7.92-7.89 (m, 2H); 8.50 (s, 1 H).

Example 70 N - (6- (3,5-Dimethylpyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] -3,3,3-trifluoropropionamide

83

Obtained from the compound described in Example 67 (0.30g) by the procedure used in Example 14. Purification by silica gel column chromatography and ethyl acetate / n-hexane (15:85) as eluent yielded N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] -3,3,3-trifluoropropionamide (55 mg, 13%) as a white solid.

δ (250 MHz, CDCl 3): 2.32 (s, 3H); 2.84 (s, 3 H); 3.38 (q, J = 10.0 Hz, 2H); 6.06 (s, 1 H); 7.18-7.16 (m, 1H); 7.52-7.50 (m, 1 H); 7.96-7.94 (m, 1H); 8.12 (s, 1 H); 8.48 (bs, 1H).

Example 71 2- (Thiophen-2-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-ylamine

84

Obtained from Intermediate 15 (1.86 g) by the procedure described in Example 21. The crystallization from ethyl ether yielded 2- (thiophen-2-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-ylamine (1.81 g, 84%) as a white solid.

δ (250 MHz, MeOD): 6.67 (s, 1H); 7.06 (dd, J1 = 5.0 Hz, J2 = 3.6 Hz, 1H); 7.40 (dd, J1 = 5.0 Hz, J2 = 1.3 Hz, 1H); 7.88-7.86 (m, 1 H); 8.01 (s, 1 H); 9.19 (s, 1 H).

Example 72 N - [2- (Thiophen-2-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-yl] acetamide

85

Obtained from the compound described in Example 71 (0.30 g) by the procedure used in Example 2. Purification by silica gel column chromatography and ethyl acetate / n-hexane (from 1: 1 to 4: 1) as eluent yielded N - [2- (thiophen-2-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-yl] acetamide (0.21 g, 63%) as a white solid .

δ (250 MHz, DMSO): 2.15 (s, 3H); 7.20 (dd, J1 = 4.9 Hz, J2 = 3.8 Hz, 1H); 7.79 (dd, J1 = 4.9 Hz, J2 = 1.4 Hz, 1H); 8.11 (dd, J1 = 3.8 Hz, J2 = 1.4 Hz, 1H); 8.29 (s, 1 H); 8.34 (s, 1 H); 9.57 (s, 1 H); 11.00 (s, 1H).

Example 73 N - [2- (Thiophen-2-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-yl] propionamide

       \ vskip1.000000 \ baselineskip
    

86

       \ vskip1.000000 \ baselineskip
    

Obtained from the compound described in Example 71 (0.14 g) by the procedure used in Example 2. Crystallization from ethyl ether yielded N - [2- (thiophene-2-yl) -6 - ([1,2, 4] triazol-1-yl) pyrimidin-4-yl] propionamide (0.13 g, 75%) as a white solid.

δ (250 MHz, DMSO): 1.05 (t, J = 7.4 Hz, 3H); 2.49 (q, J = 7.4 Hz, 2H); 7.25-7.20 (m, 1H); 7.83-7.80 (m, 1 H); 8.14-8.12 (m, 1H); 8.34 (s, 1 H); 8.36 (s, 1 H); 9.58 (s, 1 H); 11.09 (s, 1 H).

Example 74 3,3,3-Trifluoro- N - [2- (thiophen-2-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-yl] propionamide

       \ vskip1.000000 \ baselineskip
    

87

       \ vskip1.000000 \ baselineskip
    

Obtained from the compound described in Example 71 (0.30 g) by the procedure used in Example 14. Purification by silica gel column chromatography and methylene chloride / methanol (10%) as eluent yielded 3.3.3 -trifluoro- N - [2- (thiophen-2-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-yl] propionamide (0.2 mg, 47%) as a white solid .

δ (250 MHz, DMSO): 3.57 (q, J = 11.0 Hz, 2H); 7.09-7.04 (m, 1H); 7.68-7.65 (m, 1 H); 8.00-7.97 (m, 1H); 8.10 (s, 1 H); 8.21 (s, 1 H); 9.45 (s, 1 H); 11.31 (s, 1 H).

Intermediate 16

3-Methylthiophene-2-carboxamidine (HCl)

3-Methylthiophene-2-carboxamidine (HCl), (3.25 g, 43%), was obtained as a white solid from 3-methylthiophene-2-carbonitrile (5.26 g) following the procedure described in the preparation of Intermediate 1.

δ (300 MHz, DMSO): 2.36 (s, 3H); 7.42 (bs, 4H); 8.24 (s, 1 H).

Intermediate 17

6-Amino-2- (3-methylthiophene-2-yl) pyrimidin-4-ol

Obtained from Intermediate 16 (3.20 g) by the procedure used in the preparation of Intermediate 11. Purification by silica gel column chromatography and methylene chloride / methanol (2%) as eluent followed by semi-preparative HPLC purification yielded 6-amino-2- (3-methylthiophene-2-yl) pyrimidin-4-ol (80 mg, 2%) as a white solid.

δ (300 MHz, DMSO): 2.36 (s, 3H); 5.07 (s, 1 H); 6.36 (bs, 2H); 6.82 (d, J = 4.9 Hz, 1H); 7.40 (d, J = 4.9 Hz, 1H).

       \ newpage
    

Intermediate 18

N - [6-Chloro-2- (3-methylthiophene-2-yl) pyrimidin-4-yl] propionamide

Obtained from Intermediate 17 (80 mg) by the procedure used in the preparation of Intermediate 12. Purification by silica gel column chromatography and methylene chloride as eluent yielded N - [6-Chloro-2- (3-methylthiophene -2-yl) pyrimidin-4-yl] propionamide (40 mg, 37%) as a white solid.

δ (300 MHz, DMSO): 0.93 (t, J = 7.4 Hz, 3H); 2.36-2.37 (m, 5H); 6.92 (d, J = 5.0 Hz, 1H); 7.54 (d, J = 5.0 Hz, 1H); 7.78 (s, 1 H).

Example 75 N - [2- (3-Methylthiophene-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide

88

Obtained from Intermediate 18 (40 mg) by the procedure used in Example 21. Purification by silica gel column chromatography and ethyl acetate / methylene chloride (1: 5) as eluent yielded N - [2- ( 3-methylthiophene-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide (5 mg, 11%) as a white solid.

δ (300 MHz, DMSO): 1.10 (t, J = 7.6 Hz, 3H); 2.54 (q, J = 7.6 Hz, 2H); 2.74 (s, 3 H); 6.68-6.67 (m, 1 H); 7.08 (d, J = 5.1 Hz, 1H); 7.95-7.94 (m, 1H); 8.42 (s, 1 H); 8.63 (d, J = 5.1 Hz, 1H); 10.89 (bs, 1H).

Intermediate 19

3-Amino-3- (furan-2-yl) acrylonitrile

To a solution of diisopropylamine (0.92 g, 9.13 mmol) in anhydrous THF (17 mL), cooled to -78 ° C, were added slowly 5.85 mL of a solution of n-butyllithium 1.56 M in hexane. The mixture was stirred at -78 ° C for 30 minutes and at then a solution of acetonitrile (0.33 was slowly added g, 8.06 mmol) in anhydrous THF (3.5 mL). After 30 minutes at same temperature, a solution of furan-2-carbonitrile (0.50 g, 5.37 mmol). The reaction mixture was maintained at -78 ° C for 20 minutes. and at room temperature overnight. Water (6 mL) was added and the solvent was evaporated under reduced pressure. The resulting solid is suspended in water (50 mL) and extracted with methylene chloride (3 x 25 mL) The combined organic phases were washed with brine (2 x 20 mL), dried over Na2SO4, and the solvent was evaporated under reduced pressure. The final product (0.70g, 97%) was obtained as a brown solid, which was used in the next stage without performing Other characterizations.

Intermediate twenty

4-Amino-6- (furan-2-yl) pyrimidine-2-thiol

To a solution of Intermediate 19 (1.38 g, 10.3 mmol) in ethanol (17 mL) sodium ethoxide (1.54 g, 22.63 was added mmol) and thiourea (1.56 g, 22.63 mmol). The mixture was maintained at reflux for 45 hours. The suspension obtained was cooled and They added 12 mL of water. The solution was acidified with 1 N HCl until pH = 5. The resulting solid was filtered, washed with water (2 x 20 mL), ethyl ether (10 mL) and dried. 4-amino-6- (furan-2-yl) pyrimidine-2-thiol (1.20 g, 60%) was obtained as a solid.

δ (250 MHz, DMSO): 6.27 (s, 1H); 6.71 (dd, J1 = 3.4 Hz, J2 = 1.7 Hz, 1H); 7.76-7.53 (m, 2H); 7.95 (dd, J1 = 1.7 Hz, J2 = 0.8 Hz, 1H); 12.14 (bs, 1H).

Intermediate twenty-one

6- (Furan-2-yl) -2-methylsulfanylpyrimidin-4-ylamine

To a solution of Intermediate 20 (1.87 g, 9.68 mmol) in 10% NaOH (15 mL) methyl iodide (1.51 g, 10.6 mmol). The mixture was stirred at room temperature for 2 hours. The solvent was partially evaporated under reduced pressure and 2N HCl was added until pH = 10. The resulting solid was filtered, washed with water (2 x 20 mL) and dried. 6- (Furan-2-yl) -2-methylsulfanylpyrimidin-4-ylamine  it was obtained (1.90 g, 95%) as a white solid.

δ (400 MHz, MeOD): 3.46 (s, 3H); 7.48 (s, 1 H); 7.52 (dd, J1 = 3.4 Hz, J2 = 1.7 Hz, 1H); 8.08 (dd, J1 = 3.4 Hz, J2 = 0.8 Hz, 1H); 8.59 (dd, J1 = 1.7 Hz, J2 = 0.8 Hz, 1H).

Intermediate 22

6- (Furan-2-il) -2- methanesulfonylpyrimidin-4-ylamine

To a suspension cooled to 0 ° C of Intermediate 21 (1.90 g, 9.20 mmol) in chloroform (70 mL) acid was added m-chloroperbenzoic acid (70%) (4.53 g, 18.39 mmol). The The mixture was stirred at 0 ° C for 45 minutes. The solvent evaporated partially under reduced pressure and the resulting solid was filtered, washed with ethyl ether and dried to obtain 1.36 g of the product final. The organic solution was washed with 2N NaOH (2 x 25 mL), dried (Na2SO4), and the solvent was evaporated under pressure reduced obtaining 0.47 g of the final product. (performance overall: 83%).

δ (400 MHz, MeOD): 4.27 (s, 3H); 7.6 (dd, J1 = 3.4 Hz, J2 = 1.7 Hz, 1H); 7.86 (s, 1 H); 8.27 (dd, J1 = 3.4 Hz, J2 = 0.8 Hz, 1H); 8.68 (dd, J1 = 1.7 Hz, J2 = 0.8 Hz, 1H).

Example 76 6- (Furan-2-yl) -2- (pyrazol-1-yl) pyrimidin-4-ylamine

89

To a solution of Intermediate 22 (1.16 g, 4.85 mmol) in anhydrous DMSO (20 mL) pyrazole (0.36 g, 5.33 mmol) was added and cesium carbonate (1.71 g; 5.33 mmol). The mixture was heated to 110 ° C for 2.5 hours and kept at room temperature overnight. The solution was poured onto water (60 mL) and extracted with ethyl acetate (3 x 40 mL). The organic phase was washed with water (2 x 50 mL), brine (50 mL), dried (Na2SO4), and the solvent was evaporated under reduced pressure. The oil obtained is purified by column chromatography on silica gel and chloride of methylene / methanol (5%) as eluent and the resulting solid is washed with ethyl ether. 6- (Furan-2-yl) -2- (pyrazol-1-yl) pyrimidin-4-ylamine (0.56 g, 51%) was obtained as a white solid.

δ (250 MHz, CDCl 3): 5.33 (bs, 2H); 6.47-6.46 (m, 1 H); 6.58-6.56 (m, 1 H); 6.68 (s, 1 H); 7.27 (s, 1 H); 7.56 (s, 1 H); 7.79 (s, 1 H); 8.63 (d, J = 2.4 Hz, 1H).

Example 77 N - [6- (Furan-2-yl) -2- (pyrazol-1-yl) pyrimidin-4-yl] acetamide

90

Obtained from the compound described in Example 76 (0.20 g) by the procedure used in Example 2. Purification by silica gel column chromatography and methylene chloride / methanol (2%) as eluent yielded N - [6- (furan-2-yl) -2- (pyrazol-1-yl) pyrimidin-4-yl] acetamide (0.19 g, 80%) as a white solid.

δ (250 MHz, CDCl 3): 2.21 (s, 3H); 6.46 (bs, 1H); 6.56-6.55 (m, 1 H); 7.31 (d, J = 3.6 Hz, 1H); 7.60 (s, 1 H); 7.77 (s, 1 H); 8.29 (s, 1 H); 8.55 (bs, 1H); 8.60 (d, J = 2.4 Hz, 1H).

Example 78 N - [6- (Furan-2-yl) -2- (pyrazol-1-yl) pyrimidin-4-yl] propionamide

91

Obtained from the compound described in Example 76 (0.28 g) by the procedure used in Example 2. Purification by silica gel column chromatography and methylene chloride / methanol (2%) as eluent yielded N - [6- (furan-2-yl) -2- (pyrazol-1-yl) pyrimidin-4-yl] propionamide (84 mg, 24%) as a light yellow solid.

δ (250 MHz, CDCl 3): 1.27 (t, J = 7.3 Hz, 3H); 2.47 (q, J = 7.3 Hz, 2H); 6.49-6.48 (m, 1 H); 6.58-6.57 (m, 1 H); 7.33 (d, J = 3.6 Hz, 1H); 7.61 (s, 1 H); 7.79 (s, 1 H); 8.34 (bs, 1H); 8.36 (d, J = 1.2 Hz, 1H); 8.64 (d, J = 2.4 Hz, 1H).

Example 79 3,3,3-Trifluoro- N - [6- (furan-2-yl) -2- (pyrazol-1-yl) pyrimidin-4-yl] propionamide

92

Obtained from the compound described in Example 76 (0.25 g) by the procedure used in Example 14. Purification by silica gel column chromatography and methylene chloride / methanol (4%) as eluent yielded 3.3.3 -trifluoro- N - [2- (furan-2-yl) -2- (pyrazol-1-yl) pyrimidin-4-yl] propionamide (0.19 mg, 49%) as a white solid.

δ (250 MHz, CDCl 3): 3.32 (q, J = 9.8 Hz, 2H); 6.51-6.49 (m, 1 H); 6.61-6.59 (m, 1 H); 7.37 (d, J = 3.6 Hz, 1H); 7.63 (s, 1 H); 7.80 (s, 1 H); 8.32 (s, 1 H); 8.63 (d, J = 2.4 Hz, 1H); 8.68 (bs, 1H).

Example 80 2- (3,5-Dimethylpyrazol-1-yl) -6- (furan-2-yl) pyrimidin-4-ylamine

93

Obtained from Intermediate 22 (3.00 g) by the procedure used in Example 76. The purification by silica gel column chromatography and chloroform / isopropanol (1: 1) as eluent, followed by a second column chromatography on silica gel and methylene chloride / methanol (5%) as eluent yielded 2- (3,5-dimethylpyrazol-1-yl) -6- (furan-2-yl) pyrimidin-4-ylamine  (0.15 g, 5%) as a white solid.

δ (250 MHz, CDCl 3): 2.33 (s, 3H); 2.72 (s, 3H); 5.18 (bs, 2H); 6.01 (s, 1 H); 6.54 (dd, J1 = 6.3 Hz, J2 = 1.8 Hz, 1H); 6.63 (s, 1 H); 7.15-7.13 (m, 1H); 7.55-7.54 (m, 1H).

Example 81 N - [2- (3,5-Dimethylpyrazol-1-yl) -6- (furan-2-yl) pyrimidin-4-yl] propionamide

94

Obtained from the compound described in Example 80 (95 mg) by the procedure used in Example 2. Purification by silica gel column chromatography and methylene chloride / methanol (10%) as eluent yielded N - [2- (3,5-Dimethylpyrazol-1-yl) -6- (furan-2-yl) pyrimidin-4-yl] propionamide (50 mg, 43%) as a white solid.

δ (250 MHz, CDCl 3): 1.25 (t, J = 7.6 Hz, 3H); 2.35 (s, 3 H); 2.45 (q, J = 7.6 Hz, 2H); 2.75 (s, 3 H); 6.05 (s, 1 H); 6.58-6.56 (m, 1 H); 7.24-7.23 (m, 1 H); 7.61 (s, 1 H); 8.27 (bs, 1H); 8.33 (s, 1 H).

Example 82 N - [2- (3,5-Dimethylpyrazol-1-yl) -6- (furan-2-yl) pyrimidin-4-yl] -2- (4-methoxyphenyl) acetamide

95

Obtained from the compound described in Example 80 (100 mg) by the procedure used in Example 2. Purification by silica gel column chromatography and methylene chloride / methanol (10%) as eluent yielded N - [2- (3,5-Dimethylpyrazol-1-yl) -6- (furan-2-yl) pyrimidin-4-yl] -2- (4-methoxyphenyl) acetamide (50 mg, 30%) as a white solid.

δ (250 MHz, CDCl 3): 2.32 (s, 3H); 2.71 (s, 3 H); 3.69 (s, 2H); 3.81 (s, 3H); 6.03 (s, 1 H); 6.57-6.55 (m, 1 H); 6.90 (d, J = 8.8 Hz, 2H); 7.24-7.20 (m, 3H); 7.60 (d, J = 1.5 Hz, 1H); 8.35 (s, 2H).

Example 83 6- (Furan-2-yl) -2 - ([1,2,4] triazol-1-yl) pyrimidin-4-ylamine

96

To a solution of Intermediate 22 (0.21 g, 0.88 mmol) in anhydrous DMF (3 mL) [1,2,4] triazole (60 mg, 0.88 mmol) and potassium carbonate (0.12 g; 0.88 mmol). The mixture was heated at 80 ° C for 2 hours. The solution was poured over water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The organic phase was washed with water (2 x 10 mL), brine (10 mL), dried (Na2SO4), and the solvent was evaporated under pressure reduced Purification by column chromatography of silica gel and methylene chloride as eluent yielded 6- (furan-2-yl) -2 - ([1,2,4] triazol-1-yl) pyrimidin-4-ylamine (70 mg, 35%) as a white solid.

δ (200 MHz, DMSO): 6.70 (s, 1H); 6.73-6.72 (m, 1 H); 7.30 (d, J = 3.4 Hz, 1H); 7.57 (bs, 2H); 7.93-7.92 (m, 1H); 8.22 (s, 1 H); 9.35 (s, 1 H).

Example 84 N - [6- (Furan-2-yl) -2 - ([1,2,4] triazol-1-yl) pyrimidin-4-yl] propionamide

97

Obtained from the compound described in Example 83 (45 mg) by the procedure used in Example 49. Purification by silica gel column chromatography and methylene chloride / methanol (1%) as eluent yielded N - [6- (furan-2-yl) -2 - ([1,2,4] triazol-1-yl) pyrimidin-4-yl] propionamide (16 mg, 28%) as a white solid.

δ (300 MHz, DMSO): 1.16 (t, J = 7.4 Hz, 3H); 2.53 (q, J = 7.4 Hz, 2H); 6.66 (dd, J1 = 3.4 Hz, J2 = 1.8 Hz, 1H); 7.43 (dd, J1 = 3.4, J2 = 0.8 Hz, 1H); 7.79 (dd, J1 = 1.8 Hz, J2 = 0.8 Hz, 1H); 8.12 (s, 1 H); 8.44 (s, 1 H); 9.34 (s, 1 H); 11.16 (bs, 1H).

Intermediate 2. 3

3-Amino-3- (pyridin-2-yl) acrylonitrile

To a solution of pyridine-2-carbonitrile (5.0 g, 48.0 mmol) in toluene (175 mL) was added potassium tertbutoxide (16.2 g, 0.144 mol) and acetonitrile (3.94 g, 96.0 mmol). The mixture is stirred at room temperature for 3 hours. To the mixture of reaction saturated sodium bicarbonate solution (200 was added mL) and the mixture was extracted with ethyl ether (2 x 200 mL). The phase The organic was dried (Na2SO4) and the solvent was evaporated under reduced pressure The final product (5.44 g, 78%) was obtained as a light brown solid that was used in the next stage without Perform other characterizations.

Intermediate 24

4-Amino-6- (pyridin-2-yl) pyrimidine-2-thiol

Obtained from Intermediate 23 (1.14 g) by the procedure used in the preparation of Intermediate 20. Crystallization from ethyl ether yielded 4-amino-6- (pyridin-2-yl) pyrimidine-2-thiol (1.28 g, 80%) as a white solid.

δ (250 MHz, DMSO): 6.70 (bs, 1H); 7.60 (m, 1 HOUR); 7.79 (bs, 1H); 8.15-7.98 (m, 2H); 8.74 (m, 1 HOUR); 11.21 (bs, 1H).

Intermediate 25

2-Methylsulfanyl-6- (pyridin-2-yl) pyrimidin-4-ylamine

Obtained from Intermediate 24 (4.0 g) by the procedure used in the preparation of Intermediate 21. Crystallization from ethyl ether yielded the product final (4.16 g, 97%) as an orange solid.

MS (M +): 218.

Intermediate 26

2-Methanesulfonyl-6- (pyridin-2-yl) pyrimidin-4-ylamine

Obtained from Intermediate 25 (4.16 g) by the procedure used in the preparation of Intermediate 22. Crystallization from ethyl ether yielded 2-methanesulfonyl-6- (pyridin-2-yl) pyrimidin-4-ylamine (3.89 g, 82%) as a white solid.

δ (250 MHz, DMSO): 3.38 (s, 3H); 7.59-7.53 (m, 2H); 7.86 (bs, 1H); 8.05-7.97 (m, 1 H); 8.34 (m, 1 H); 8.73 (m, 1 H).

Example 85 2- (Pirazol-1-yl) -6- (pyridin-2-yl) pyrimidin-4-ylamine

98

Obtained from Intermediate 26 (0.43 g) by the procedure used in Example 76. The purification by silica gel column chromatography and methylene chloride / methanol (2%) as eluent yielded 2- (pyrazol-1-yl) -6- (pyridin-2-yl) pyrimidin-4-ylamine (0.25 g, 47%) as a white solid.

δ (250 MHz, DMSO): 6.54 (t, J = 1.7 Hz, 1H); 7.38 (s, 1 H); 7.46 (bs, 2H); 7.56-7.50 (m, 1 H); 7.78-7.77 (m, 1 H); 7.99 (dt, J1 = 7.7 Hz, J2 = 1.7 Hz, 1H); 8.45 (d, J = 7.7 Hz, 1H); 8.71 (d, J = 2.7 Hz, 2H).

Example 86 N - [2- (Pirazol-1-yl) -6- (pyridin-2-yl) pyrimidin-4-yl] propionamide

99

Obtained from the compound described in Example 85 (0.19 g) by the procedure used in Example 2. Purification by silica gel column chromatography and methylene chloride / methanol (2%) as eluent yielded N - [2- (pyrazol-1-yl) -6- (pyridin-2-yl) pyrimidin-4-yl] propionamide (0.15 g, 65%) as a white solid.

δ (250 MHz, CDCl 3): 1.28 (t, J = 7.6 Hz, 2H); 2.49 (q, J = 7.6 Hz, 2H); 6.53-6.51 (m, 1 H); 7.45-7.39 (m, 1 H); 7.90-7.83 (m, 2H); 8.30 (bs, 1H); 8.47 (dd, J1 = 7.9 Hz, J2 = 0.9 Hz, 1H); 8.77-8.72 (m, 2H); 9.08 (s, 1 H).

Example 87 2- (3,5-Dimethylpyrazol-1-yl) -6- (pyridin-2-yl) pyrimidin-4-ylamine

100

Obtained from Intermediate 26 (3.90 g) by the procedure used in Example 76. The purification by silica gel column chromatography and methylene chloride / acetonitrile (from 4: 1 to 1: 4) as eluent, followed by a second silica gel column chromatography using methylene chloride / acetonitrile / methanol (1: 4: 0.25) as eluent yielded 2- (3,5-dimethylpyrazol-1-yl) -6- (pyridin-2-yl) pyrimidin-4-ylamine (0.42 g, 10%) as a white solid.

δ (250 MHz, CDCl 3): 2.35 (s, 3H); 2.79 (s, 3 H); 5.26 (bs, 2H); 6.05 (s, 1 H); 7.41-7.36 (m, 2H); 7.85 (dt, J1 = 7.6 Hz, J2 = 1.8 Hz, 1H); 8.38-8.34 (m, 1 H); 8.70-8.67 (m, 1H).

Example 88 N - [2- (3,5-Dimethylpyrazol-1-yl) -6- (pyridin-2-yl) pyrimidin-4-yl] propionamide

101

Obtained from the compound described in Example 87 (0.17 g) by the procedure used in Example 2. Purification by silica gel column chromatography and methylene chloride / methanol (from 100% methylene chloride to methylene chloride / 95: 5 methanol as eluent yielded N - [2- (3,5-dimethylpyrazol-1-yl) -6- (pyridin-2-yl) pyrimidin-4-yl] propionamide (0.10 g, 64%) as a white solid

δ (250 MHz, CDCl 3): 1.26 (t, J = 7.6 Hz, 3H); 2.36 (s, 3 H); 2.46 (q, J = 7.6 Hz, 2H); 2.81 (s, 3H); 6.08 (s, 1 H); 7.40 (ddd, J1 = 7.6 Hz, J2 = 1.8 Hz, 1H); 7.85 (dt, J1 = 7.6 Hz, J2 = 1.8 Hz, 1H); 8.36-8.31 (m, 2H); 8.76-8.73 (m, 1 H); 9.05 (s, 1 H).

Example 89 N - [2- (3,5-Dimethylpyrazol-1-yl) -6- (pyridin-2-yl) pyrimidin-4-yl] -2- (4-methoxyphenyl) acetamide

102

Obtained from the compound described in Example 87 (0.17 g) by the procedure used in Example 2. Purification by silica gel column chromatography and methylene chloride / methanol (1% to 5%) as eluent, followed of a second silica gel column chromatography using methylene chloride / methanol (from 100% methylene chloride to 90:10 methylene chloride / methanol) as eluent yielded N - [2- (3,5-dimethylpyrazol-1-yl ) - 6- (pyridin-2-yl) pyrimidin-4-yl] -2- (4-methoxyphenyl) acetamide (94 mg, 31%) as a white solid.

δ (250 MHz, CDCl 3): 2.34 (s, 3H); 2.78 (s, 3 H); 3.71 (s, 2H); 3.81 (s, 3H); 6.07 (s, 1 H); 6.89-6.87 (m, 1 H); 6.93-6.91 (m, 1H); 7.26-7.21 (m, 2H); 7.40 (ddd, J1 = 7.6 Hz, J2 = 4.8 Hz, 1H); 7.84 (dt, J1 = 7.6 Hz, J2 = 1.8 Hz, 1H); 8.25 (bs, 1H); 8.33 (dt, J1 = 7.6 Hz, J2 = 1.2 Hz, 1H); 8.74 (dt, J1 = 4.8 Hz, J2 = 1.8 Hz, 1H); 9.06 (s, 1 H).

Intermediate 27

3-Amino-3- (pyridin-3-yl) acrylonitrile

Obtained from pyridine-3-carbonitrile (5.00 g) by the procedure used in the preparation of Intermediate 23 (reaction time: 3 days). Crystallization in ethyl ether yielded 3-amino-3- (pyridin-3-yl) acrylonitrile  (2.81 g, 40%) as a white solid.

δ (250 MHz, DMSO): 4.58 (s, 1H); 6.96 (s, 2H); 7.46 (dd, J1 = 7.9 Hz, J2 = 4.6 Hz, 1H); 7.98-7.93 (ni, 1H); 8.64 (dd, J1 = 4.7 Hz, J2 = 1.6 Hz, 1H); 8.77 (dd, J1 = 2.5 Hz, J2 = 0.8 Hz, 1H).

Intermediate 28

4-Amino-6- (pyridin-3-yl) pyrimidine-2-thiol

Obtained from Intermediate 27 (2.81 g) by the procedure used in the preparation of Intermediate 20. Crystallization from ethyl ether yielded 4-amino-6- (pyridin-3-yl) pyrimidine-2-thiol (3.28 g, 83%) as a white solid.

δ (200 MHz, DMSO): 7.53 (dd, J1 = 8.1 Hz, J2 = 4.7 Hz, 2H); 7.67 (s, 2H); 8.12-8.07 (m, 1 H); 8.71 (d, J = 4.7 Hz, 1H); 8.85 (s, 1 H); 12.40 (bs, 1H).

Intermediate 29

2-Methylsulfanyl-6- (pyridin-3-yl) pyrimidin-4-ylamine

Obtained from Intermediate 28 (3.00 g) by the procedure used in the preparation of Intermediate 21. Crystallization from ethyl ether yielded the product final (2.96 g, 92%) as a solid that was used in the following stage without performing other characterizations.

Intermediate 30

2-Methanesulfonyl-6- (pyridin-3-yl) pyrimidin-4-ylamine

Obtained from Intermediate 29 (2.00 g) by the procedure used in the preparation of Intermediate 22. Crystallization from ethyl ether yielded 2-methanesulfonyl-6- (pyridin-3-yl) pyrimidin-4-ylamine (1.90 g, 83%) as a white solid.

MS (M +): 250

Example 90

2- (Pirazol-1-yl) -6- (pyridin-3-yl) pyrimidin-4-ylamine

103

Obtained from Intermediate 30 (1.00 g) by the procedure used in Example 76. The purification by silica gel column chromatography and methylene chloride / methanol (2% to 3%) as eluent yielded 2- (pyrazol-1-yl) -6- (pyridin-3-yl) pyrimidin-4-ylamine (0.24 g, 25%) as a white solid.

δ (250 MHz, DMSO): 6.55-6.53 (m, 1H); 6.91 (s, 1 H); 7.45 (bs, 2H); 7.56 (dd, J1 = 7.9 Hz, J2 = 4.9 Hz, 1H); 7.78 (s, 11-1); 8.46-8.41 (m, 1 H); 8.72-8.69 (m, 2H); 9.26-9.24 (m, 1H).

Example 91 N - [2- (Pirazol-1-yl) -6- (pyridin-3-yl) pyrimidin-4-yl] propionamide

104

Obtained from the compound described in Example 90 (0.14 g) by the procedure used in Example 2. Purification by silica gel column chromatography and methylene chloride / methanol (2%) as eluent, followed by a second chromatography on silica gel column and methylene chloride / methanol (5%) as eluent yielded N - [2- (pyrazol-1-yl) -6- (pyridin-3-yl) pyrimidin-4-yl] propionamide (54 mg , 31%) as a white solid.

δ (250 MHz, DMSO): 1.10 (t, J = 7.4 Hz, 3H); 2.53 (q, J = 7.4 Hz, 2H); 6.63 (m, J1 = 2.6 Hz, J2 = 1.4 Hz, 1H); 7.65-7.60 (m, 1 H); 7.88-7.87 (m, 1 H); 8.51 (t, J = 1.4 Hz, 1H); 8.55 (s, 1 H); 8.78 (dd, J1 = 4.6 Hz, J2 = 1.4 Hz, 1H); 8.84 (dd, J1 = 2.6 Hz, J2 = 0.5 Hz, 1H); 9.35 (d, J = 1.9 Hz, 1H); 11.36 (s, 1 H).

Example 92 2- (3,5-Dimethylpyrazol-1-yl) -6- (pyridin-3-yl) pyrimidin-4-ylamine

105

Obtained from Intermediate 30 (1.77 g) by the procedure used in Example 76. The purification by silica gel column chromatography and methylene chloride / methanol (4%) as eluent yielded 2- (3,5-dimethylpyrazol-1-yl) -6- (pyridin-3-yl) pyrimidin-4-ylamine (0.35 g, 8%) as a white solid.

δ (250 MHz, CDCl 3): 2.18 (s, 3H); 2.63 (s, 3H); 6.09 (s, 1 H); 6.86 (s, 1 H); 7.37 (bs, 2H); 7.56 (dd, J1 = 8.0 Hz, J2 = 4.7 Hz, 1H); 8.34 (dt, J1 = 8.0 Hz, J2 = 1.6 Hz, 1H); 8.69 (dd, J1 = 4.7 Hz, J2 = 1.6 Hz, 1 H); 9.17 (d, J = 2.2 Hz, 1H).

Example 93 N - [2- (3,5-Dimethylpyrazol-1-yl) -6- (pyridin-3-yl) pyrimidin-4-yl] propionamide

106

Obtained from the compound described in Example 92 (0.15 g) by the procedure used in Example 2. Purification by silica gel column chromatography and methylene chloride / methanol (from 100% methylene chloride to methylene chloride / Methanol 98: 2) as eluent yielded N - [2- (3,5-dimethylpyrazol-1-yl) -6- (pyridin-3-yl) pyrimidin-4-yl] propionamide (74 mg, 41%) as a white solid

δ (250 MHz, CDCl 3): 1.27 (t, J = 7.6 Hz, 3H); 2.48 (q, J = 7.6 Hz, 2H); 2.80 (s, 3H); 6.09 (s, 1 H); 7.46 (dd, J1 = 8.2 Hz, J2 = 5.2 Hz, 1H); 8.40-8.35 (m, 2H); 8.54 (s, 1 H); 8.60 (d, J = 2.4 Hz, 1H); 8.77-8.74 (m, 1 H); 9.39-9.38 (m, 1H).

Example 94 N - (2- (3,5-Dimethylpyrazol-1-yl) -6- (pyridin-3-yl) pyrimidin-4-yl] -2- (4-methoxyphenyl) acetamide

107

Obtained from the compound described in Example 92 (0.15 g) by the procedure used in Example 2. Purification by silica gel column chromatography and methylene chloride / methanol (from 100% methylene chloride to methylene chloride / 95: 5 methanol as eluent yielded N - [2- (3,5-dimethylpyrazol-1-yl) -6- (pyridin-3-yl) pyrimidin-4-yl] -2- (4-methoxyphenyl) acetamide ( 0.20 g, 86%) as a white solid.

δ (250 MHz, CDCl 3): 2.34 (s, 3H); 2.77 (s, 3 H); 3.72 (s, 2H); 3.81 (s, 3H); 6.07 (s, 1 H); 6.91 (d, J = 8.8 Hz, 2H); 7.23 (d, J = 8.8 Hz, 2H); 7.47-7.42 (m, 1 H); 8.40-8.33 (m, 2H); 8.56 (s, 1 H); 8.76-8.73 (m, 1 H); 9.38-9.36 (m, 1H).

       \ newpage
    

Intermediate 31

3-Amino-3- (pyridin-4-yl) acrylonitrile

Obtained from pyridine-4-carbonitrile (5.00 g) by the procedure used in the preparation of Intermediate 23 (reaction time: 12 hours). Crystallization in ethyl ether yielded 3-amino-3- (pyridin-4-yl) acrylonitrile, which was used in the next stage without performing other characterizations.

Intermediate 32

4-Amino-6- (pyridin-4-yl) pyrimidine-2-thiol

Obtained from Intermediate 31 through the procedure used in the preparation of Intermediate 20. The crystallization from ethyl ether yielded 4-amino-6- (pyridin-4-yl) pyrimidine-2-thiol (7.43 g, overall yield: 76%) as a solid that was used in the next stage without performing other characterizations.

Intermediate 33

2-Methylsulfanyl-6- (pyridin-4-yl) pyrimidin-4-ylamine

Obtained from Intermediate 32 (7.00 g) by the procedure used in the preparation of Intermediate 21. Crystallization from ethyl ether yielded the product final (6.12 g, 82%) as a solid that was used in the following stage without performing other characterizations.

Intermediate 3. 4

2-Methanesulfonyl-6- (pyridin-4-yl) pyrimidin-4-ylamine

Obtained from Intermediate 33 (2.00 g) by the procedure used in the preparation of Intermediate 22. Crystallization from ethyl ether yielded 2-methanesulfonyl-6- (pyridin-4-yl) pyrimidin-4-ylamine (2.29 g, 99%) as a solid that was used in the next stage without performing other characterizations.

Example 95 2- (Pirazol-1-yl) -6- (pyridin-4-yl) pyrimidin-4-ylamine

108

Obtained from Intermediate 34 (2.00 g) by the procedure used in Example 76. The purification by silica gel column chromatography and methylene chloride / methanol (3%) as eluent yielded 2- (pyrazol-1-yl) -6- (pyridin-4-yl) pyrimidin-4-ylamine (0.32 g, 17%) as a white solid.

δ (250 MHz, DMSO): 6.56-6.54 (m, 1 H); 6.95 (s, 1 H); 7.53 (bs, 2H); 7.79-7.78 (m, 1 H); 8.02-8.00 (m, 2H); 8.70-8.68 (m, 1 H); 8.76-8.74 (m, 2H).

Example 96 N - [2- (Pirazol-1-yl) -6- (pyridin-4-yl) pyrimidin-4-yl] propionamide

109

       \ vskip1.000000 \ baselineskip
    

Obtained from the compound described in Example 95 (0.15 g) by the procedure used in Example 2. Purification by silica gel column chromatography and methylene chloride / methanol (2%) as eluent yielded N - [2- (pyrazol-1-yl) -6- (pyridin-4-yl) pyrimidin-4-yl] propionamide (64 mg, 22%) as a white solid.

δ (250 MHz, DMSO): 1.10 (t, J = 7.7 Hz, 3H); 2.53 (q, J = 7.7 Hz, 2H); 6.65-6.63 (m, 1 H); 7.89-7.88 (m, 1 H); 8.12-8.10 (m, 2H); 8.59 (s, 1 H); 8.83-8.80 (m, 3H); 11.4 (bs, 1H).

Intermediate 35

3- (Furan-2-il) -3-oxopropionic ethyl acid ester

To a solution of 60% sodium hydride (95.4 mmol) in diethyl carbonate (90 mL) was added slowly 2-acetylfuran (5.50 g, 45.4 mmol). The solution resulting was stirred at room temperature for 1 hour and at 90 ° C for 2 hours The reaction mixture was poured onto water / ice and acetic acid (5 mL) was added. The mixture was extracted with acetate ethyl (2 x 75 mL). The organic phase was washed with water (2 x 50 mL), brine (50 mL), dried (Na2SO4), and the solvent was evaporated under reduced pressure. Purification by flash chromatography on silica gel column and acetate ethyl / n-hexane (4: 1) as eluent yielded the final product (5.90 g, 71%) as a reddish oil.

δ (200 MHz, CDCl 3): 1.26 (t, J = 7.2 Hz, 3H); 3.86 (s, 2H); 4.21 (q, J = 7.2 Hz, 2H); 6.58 (dd, J1 = 3.4 Hz, J2 = 1.7 Hz, 1H); 7.28 (d, J = 3.4 Hz, 1H); 7.62 (d, J = 1.7 Hz, 1H).

Intermediate 36

6- (Furan-2-yl) -2- (pyridin-2-yl) pyrimidin-4-ol

To a solution of potassium tertbutoxide (0.87 g, 7.79 mmol) in butanol (3 mL) Intermediate 35 (1.00 g, 5.49 mmol) and pyridine-2-carboxamidine (HCl) (1.08 g, 6.86 mmol). The mixture was heated at 135 ° C for 5 hours. The resulting solid was filtered and washed with n-pentane Purification by chromatography flash column silica gel and methylene chloride / methanol (1% at 3%) as eluent yielded 6- (furan-2-yl) -2- (pyridin-2-yl) pyrimidin-4-ol  (0.33 g, 25%) as a white solid.

δ (200 MHz, CDCl 3): 6.58 (s, 1H); 6.75 (dd, J1 = 3.4 Hz, J2 = 1.7 Hz, 1H); 7.39 (d, J = 3.4 Hz, 1H); 7.66-7.72 (m, 1 H); 7.97 (s, 1 H); 8.06-8.14 (m, 1H); 8.49 (d, J = 7.7 Hz, 1H); 8.77 (d, J = 4.7 Hz, 1H).

Intermediate 37

4-Chloro-6- (furan-2-yl) -2- (pyridin-2-yl) pyrimidine

Obtained from Intermediate 36 (0.33 g) by the procedure used in the preparation of Intermediate 10. 4-Chloro-6- (furan-2-yl) -2- (pyridin-2-yl) pyrimidine (0.36 g, 78%) was obtained as a brown solid.

MS (M +): 257.

Example 97 6- (Furan-2-yl) -2- (pyridin-2-yl) pyrimidin-4-ylamine

110

Obtained from Intermediate 37 (0.28 g) by the procedure used in Example 48. The purification by silica gel column chromatography and methylene chloride / methanol (5%) as eluent yielded 6- (furan-2-yl) -2- (pyridin-2-yl) pyrimidin-4-ylamine (0.16 mg, 62%) as a white solid.

δ (300 MHz, CDCl 3): 5.55 (bs, 2H); 6.51 (dd, J1 = 3.4 Hz, J2 = 1.7 Hz, 1H); 6.78 (s, 1 H); 7.26 (d, J = 3.4 Hz, 1H); 7.34 (dd, J1 = 8.1 Hz, J2 = 5.3 Hz, 1H); 7.52-7.51 (m, 1 H); 7.80 (dt, J1 = 7.6 Hz, J2 = 1.7 Hz, 1H); 8.50 (d, J = 8.1 Hz, 1H); 8.77-8.74 (m, 1H).

Example 98 N - [6- (Furan-2-yl) -2- (pyridin-2-yl) pyrimidin-4-yl] propionamide

111

Obtained from the compound described in Example 97 (0.10 g) by the procedure used in Example 49. Crystallization from n-pentane yielded N - [6- (furan-2-yl) -2- (pyridin-2- il) pyrimidin-4-yl] propionamide (63 mg, 51%) as a white solid.

δ (300 MHz, CDCl 3): 1.24 (t, J = 7.5 Hz, 3H); 2.45 (q, J = 7.5 Hz, 2H); 6.56 (dd, J1 = 3.4, J2 = 1.8 Hz, 1H); 7.36 (d, J = 3.4 Hz, 1H); 7.43-7.39 (m, 1 H); 7.60-7.59 (m, 1 H); 7.88 (dt, J1 = 7.6 Hz, J2 = 1.8 Hz, 1H); 8.48 (s, 2 H); 8.60 (d, J = 8.1 Hz, 1H); 8.82-8.81 (m, 1H).

Intermediate 38

3-Methylpyridine-2-carboxamidine (HCl)

Obtained from 3-methylpyridine-2-carbonitrile (5.15 g) by the procedure used in the preparation of Intermediate 1. Crystallization from ethyl ether yielded the product final (3.13 g, 42%) as a white solid.

δ (300 MHz, DMSO): 2.41 (s, 3H); 7.56-7.67 (m, 5H); 8.40 (s, 1 H); 8.56 (d, J = 3.8 Hz, 1H).

Intermediate 39

6-Amino-2- (3-methylpyridin-2-yl) pyrimidin-4-ol

Obtained from Intermediate 38 (2.91 g) by the procedure used in the preparation of Intermediate 11. Purification by column chromatography of silica gel and methylene chloride / methanol (2% to 5%) as eluent surrendered 6-amino-2- (3-methylpyridin-2-yl) pyrimidin-4-ol (0.58 g, 17%) as a white solid.

δ (300 MHz, DMSO): 2.52 (s, 3H); 5.05 (s, 1 H); 6.57 (s, 2H); 7.47 (dd, J1 = 7.6 Hz ,: J2 = 4.7 Hz, 1H); 7.80 (d, J = 7.6 Hz, 1H); 8.50 (d, J = 4.7 Hz, 1H); 11.26 (bs, 1H).

Intermediate 40

N - [6-Chloro-2- (3-methylpyridin-2-yl) pyrimidin-4-yl] propionamide

Obtained from Intermediate 39 (0.60 g) by the procedure used in the preparation of Intermediate 12. Purification by silica gel column chromatography and methylene chloride / methanol (5%) as eluent yielded N - [6-Chlorine -2- (3-methylpyridin-2-yl) pyrimidin-4-yl] propionamide (0.14 g, 17%) as a white solid.

δ (300 MHz, DMSO): 1.10 (t, J = 7.4 Hz, 3H); 2.40-2.50 (m, 5H); 7.60 (dd, J1 = 7.6 Hz, J2 = 4.7 Hz, 1H); 8.00 (d, J = 7.6 Hz, 1H); 8.20 (s, 1 H); 8.60 (d, J = 4.7 Hz, 1H); 11.40 (bs, 1H).

Examples 99 and 100

2- (3-Methylpyridin-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-ylamine and N - [2- (3-methylpyridin-2-yl) -6- (pyrazol-1-yl ) pyrimidin-4-yl] propionamide

112

Obtained from Intermediate 40 (0.14 g) by the procedure used in Example 21 (reaction temperature: 110 ° C). Purification by silica gel column chromatography and methylene chloride / methanol (2%) as eluent yielded 2- (3-methylpyridin-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-ylamine (12 mg, 8%) and N - [2- (3-methylpyridin-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide (5 mg, 4%) as white solids.

Example 99

δ (300 MHz, DMSO): 2.33 (s, 3H); 6.54 (dd, J1 = 2.7 Hz, J2 = 1.7 Hz, 1H); 6.91 (s, 1 H); 7.31 (bs, 2H); 7.37 (dd, J1 = 7.8 Hz, J2 = 4.7 Hz, 1H); 7.74-7.71 (m, 1 H); 7.85 (dd, J1 = 1.7 Hz, J2 = 0.6 Hz, 1H); 8.38 (bs, 1H) 8.44 (dd, J1 = 4.7 Hz, J2 = 1.1 Hz, 1H); 8.50 (dd, J1 = 2.75 Hz, J2 = 0.6 Hz, 1H).

Example 100

δ (300 MHz, DMSO): 1.08 (t, J = 7.6 Hz, 3H); 2.40 (s, 1 H); 2.46 (q, J = 7.6 Hz, 2H); 6.63 (dd, J1 = 2.8 Hz, J2 = 1.7 Hz, 1H); 7.81-7.78 (m, 1 H); 7.96-7.94 (m, 1H); 8.51-8.49 (m, 1 H); 8.62 (s, 1 H); 8.64 (dd, J1 = 2.8 Hz, J2 = 0.6 Hz, 1H); 11.24 (bs, 1H).

Intermediate 41

Pyridine-3-Carboxamidine (HCl)

Obtained from pyridine-3-carbonitrile (10.0 g) by the procedure used in the preparation of Intermediate 1. Crystallization from ethyl ether yielded the product final (11.64 g, 99%) as a white solid.

δ (200 MHz, DMSO): 7.66-7.70 (m, 1H); 8.23 (d, J = 6.4 Hz, 1H); 8.80-8.90 (m, 5H); 9.00 (s, 1H).

Intermediate 42

2- (Pyridin-3-yl) pyrimidine-4,6-diol

Obtained from Intermediate 41 (11.64 g) by the procedure used in the preparation of Intermediate 2. Crystallization from ethyl ether yielded the product final (13.68 g, 75%) as a white solid.

MS (M +): 189.

Intermediate 43

4,6-Dichloro-2- (pyridin-3-yl) pyrimidine

Obtained from Intermediate 42 (12.80 g) by the procedure used in the preparation of Intermediate 3 (reaction time: 40 hours). Crystallization in ethyl ether yielded 4,6-dichloro-2- (pyridin-3-yl) pyrimidine  (6.50 g, 42%) as a solid that was used in the next stage without performing other characterizations.

Intermediate 44

6-Chloro-2- (pyridin-3-yl) pyrimidin-4-ylamine

Obtained from Intermediate 43 (2.00 g) by the procedure used in the preparation of Intermediate 48 (reaction time: 21 hours). Crystallization in ethyl ether yielded 6-chloro-2- (pyridin-3-yl) pyrimidin-4-ylamine (2.14 g, 78%) as a solid that was used in the next stage without performing other characterizations.

Example 101 6- (Pirazol-1-yl) -2- (pyridin-3-yl) pyrimidin-4-ylamine

113

Obtained from Intermediate 44 (1.80 g) by the procedure used in Example 21. The crystallization from ethyl ether yielded 6- (pyrazol-1-yl) -2- (pyridin-3-yl) pyrimidin-4-ylamine (1.40 g, 67%) as a white solid.

δ (250 MHz, DMSO): 6.61-6.59 (m, 1 H); 6.89 (s, 1 H); 7.35 (bs, 2H); 7.57-7.51 (m, 1 H); 7.87-7.86 (m, 1 HOUR); 8.71-8.66 (m, 2H); 8.86-8.83 (m, 1 H); 9.55-9.53 (m, 1H).

Example 102 N - (6- (Pirazol-1-yl) -2- (pyridin-3-yl) pyrimidin-4-yl] acetamide

114

Obtained from the compound described in Example 101 (0.30 g) by the procedure used in Example 2. Purification by silica gel column chromatography and methylene chloride / methanol (4%) as eluent yielded N - [6- (pyrazol-1-yl) -2- (pyridin-3-yl) pyrimidin-4-yl] acetamide (80 mg, 23%) as a white solid.

δ (250 MHz, CDCl 3): 2.33 (s, 3H); 6.53-6.51 (m, 1 H); 7.46-7.40 (m, 1 HOUR); 7.83-7.82 (m, 1 H); 8.56 (bs, 1H); 8.70-8.64 (m, 3H); 8.75-8.72 (m, 1 HOUR); 9.65-9.64 (m, 1H).

Example 103 N - [6- (Pirazol-1-yl) -2- (pyridin-3-yl) pyrimidin-4-yl] propionamide

115

Obtained from the compound described in Example 101 (0.30 g) by the procedure used in Example 2. Purification by silica gel column chromatography and methylene chloride / methanol (4%) as eluent yielded N - [6- (pyrazol-1-yl) -2- (pyridin-3-yl) pyrimidin-4-yl] propionamide (0.16 g, 41%) as a white solid.

δ (250 MHz, CDCl 3): 1.30 (t, J = 7.6, 3H); 2.56 (q, J = 7.6 Hz, 2H); 6.53-6.51 (m, 1 H); 7.46-7.40 (m, 1 H); 7.82-7.81 (m, 1 H); 8.36 (bs, 1H); 8.75-8.64 (m, 4H); 9.64-9.63 (m, 1H).

Example 104 6- (3,5-Dimethylpyrazol-1-yl) -2- (pyridin-3-yl) pyrimidin-4-ylamine

116

Obtained from Intermediate 44 (1.50 g) by the procedure used in Example 21. The purification by silica gel column chromatography and methylene chloride / methanol (5%) as eluent yielded 6- (3,5-Dimethylpyrazol-1-yl) -2- (pyridin-3-yl) pyrimidin-4-ylamine (1.25 g, 63%) as a white solid.

δ (250 MHz, DMSO): 2.20 (s, 3H); 2.76 (s, 3H); 6.15 (s, 1 H); 6.86 (s, 1 H); 7.18 (bs, 2H); 7.56-7.51 (m, 1 H); 8.53-8.52 (m, 1 HOUR); 8.69-8.66 (m, 1 H); 9.42-9.41 (m, 1H).

Example 105 N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (pyridin-3-yl) pyrimidin-4-yl] acetamide

117

Obtained from the compound described in Example 104 (0.30 g) by the procedure used in Example 2. Purification by silica gel column chromatography and methylene chloride / methanol (4%) as eluent, followed by a second chromatography on silica gel column using ethyl acetate / n-hexane / methanol (85: 13: 2) as eluent yielded N - [6- (3,5-dimethylpyrazol-1-yl) -2- (pyridin-3-yl ) pyrimidin-4-yl] acetamide (92 mg, 26%) as a white solid.

δ (250 MHz, CDCl 3): 2.30 (s, 3H); 2.31 (s, 3H); 2.81 (s, 3H); 6.04 (s, 1 H); 7.41 (dd, J1 = 7.9 Hz, J2 = 4.8 Hz, 1H); 8.46 (bs, 1H); 8.60-8.55 (m, 2H); 8.71 (dd, J1 = 4.8 Hz, J2 = 1.5 Hz, 1H); 9.58-9.56 (m, 1H).

Example 106 N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (pyridin-3-yl) pyrimidin-4-yl] propionamide

118

Obtained from the compound described in Example 104 (0.30 g) by the procedure used in Example 2. Purification by silica gel column chromatography and methylene chloride / methanol (4% to 10%) as eluent yielded N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (pyridin-3-yl) pyrimidin-4-yl] propionamide (0.13 g, 34%) as a white solid.

δ (250 MHz, CDCl 3): 1.29 (t, J = 7.6 Hz, 3H); 2.30 (s, 3H); 2.53 (q, J = 7.6 Hz, 2H); 2.83 (s, 3H); 6.05 (s, 1 H); 7.42 (ddd, J1 = 8.1 Hz, J2 = 4.8 Hz, 1H); 8.08 (bs, 1H); 8.60 (dt, J1 = 8.1 Hz, J2 = 2.0 Hz, 1H); 8.65 (s, 1 H); 8.72 (dd, J1 = 4.8 Hz, J2 = 1.5 Hz, 1H); 9.59-9.57 (m, 1H).

Example 107 N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (pyridin-3-yl) pyrimidin-4-yl] -3,3,3-trifluoropropionamide

119

Obtained from the compound described in Example 104 (0.30 g) by the procedure used in Example 14. Purification by silica gel column chromatography and methylene chloride / methanol (4% to 10%) as eluent yielded N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (pyridin-3-yl) pyrimidin-4-yl] -3,3,3-trifluoropropionamide (0.11 g, 28%) as a white solid .

δ (250 MHz, DMSO): 2.24 (s, 3H); 2.81 (s, 3H); 3.77 (q, J = 10.9 Hz, 2H); 6.25 (s, 1H) 7.61 (dd, J1 = 7.9 Hz, J2 = 4.7 Hz, 1H); 8.47 (s, 1 H); 8.60 (dd, J1 = 7.9 Hz, J2 = 1.4 Hz, 1H) 8.75 (dd, J1 = 4.7 Hz, J2 = 1.4 Hz, 1H); 9.46 (s, 1 H); 11.41 (s, 1 H).

Example 108 2- (Pyridin-3-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-ylamine

120

Obtained from Intermediate 44 (1.50 g) by the procedure used in Example 21. The purification by silica gel column chromatography and methylene chloride / methanol (4%) as eluent yielded 2- (pyridin-3-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-ylamine (0.26 g, 15%) as a white solid.

δ (250 MHz, DMSO): 6.83 (s, 1H); 7.57-7.52 (m, 3H); 8.34 (s, 1 H); 8.74-8.69 (m, 2H); 9.58-9.57 (m, 1 HOUR); 9.67 (s, 1 H).

Example 109 3,3,3-Trifluoro-N- [2- (pyridin-3-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-yl] propionamide

121

Obtained from the compound described in the Example 108 (0.15 g) by the procedure used in the Example 14. Purification by column chromatography of silica gel and methylene chloride / methanol (4% to 10%) as eluent yielded 3,3,3-trifluoro-N- [2- (pyridin-3-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-yl] propionamide (73 mg, 33%) as a white solid.

δ (250 MHz, DMSO): 3.83 (q, J = 10.9 Hz, 2H); 7.95-7.90 (m, 1H); 8.45 (s, 1 H); 8.46 (s, 1 H); 8.97-8.93 (m, 1H); 9.10 (d, J = 8.2 Hz, 1H); 9.74 (bs, 1H); 9.95 (s, 1 H); 11.81 (s, 1 H).

Intermediate Four. Five

6- (Furan-2-yl) -2- (pyridin-3-yl) pyrimidin-4-ol

Obtained from Intermediate 35 (1.00 g) and of Intermediate 41 (1.08 g) by the procedure used in the preparation of Intermediate 36. Crystallization in n-pentane yielded the final product (0.27 g, 20%) Like a brown solid.

δ (200 MHz, DMSO): 6.26 (s, 1H); 6.64 (d, J = 1.7 Hz, 1H); 7.12 (d, J = 3.4 Hz, 1H); 7.44-7.50 (m, 1 H); 7.81 (s, 1 H); 8.54 (s, 1 H); 8.62 (d, J = 4.7 Hz, 1H); 9.41 (s, 1 H).

Intermediate 46

4-Chloro-6- (furan-2-yl) -2- (pyridin-3-yl) pyrimidine

Obtained from Intermediate 45 (0.69 g) by the procedure used in the preparation of Intermediate 10. Purification by column chromatography of silica gel and methylene chloride / methanol (methylene chloride 100% to methylene chloride / methanol 85:15) yielded the final product (0.32 g, 43%) as a brown solid, which was used in the following stage without performing other characterizations.

Example 110 6- (Furan-2-yl) -2- (pyridin-3-yl) pyrimidin-4-ylamine

122

Obtained from Intermediate 46 (0.32 g) by the procedure used in Example 48. The purification by silica gel column chromatography and methylene chloride as eluent yielded 6- (furan-2-yl) -2- (pyridin-3-yl) pyrimidin-4-ylamine (80 mg, 27%) as a white solid.

δ (300 MHz, DMSO): 6.69 (dd, J1 = 3.6 Hz, J2 = 1.9 Hz, 1H); 6.70 (s, 1 H); 7.15 (bs, 2H); 7.28 (dd, J1 = 3.3 Hz, J2 = 0.8 Hz, 1H); 7.51 (dd, J1 = 8.0 Hz, J2 = 4.7 Hz, 1H); 7.89 (dd, J1 = 1.9 Hz, J2 = 0.8 Hz, 1H); 8.61 (dt, J1 = 8.0 Hz, J2 = 1.9 Hz, 1H); 8.66 (bs, 1H); 9.47 (bs, 1H).

Example 111 N - [6- (Furan-2-yl) -2- (pyridin-3-yl) pyrimidin-4-yl] propionamide

123

Obtained from the compound described in Example 110 (55 mg) by the procedure used in Example 49. Crystallization from n-pentane yielded N - [6- (furan-2-yl) -2- (pyridin-3- il) pyrimidin-4-yl] propionamide (28 mg, 41%) as a white solid.

δ (300 MHz, DMSO): 1.11 (t, J = 7.6 Hz, 3H); 2.53 (q, J = 7.6 Hz, 2H); 6.79-6.77 (m, 1 H); 7.51 (d, J = 3.6 Hz, 1H); 7.59 (dd, J1 = 8.5 Hz, J2 = 4.4 Hz, 1H); 8.03-8.02 (m, 1H); 8.37 (s, 1 H); 8.75-8.68 (m, 2H); 9.57 (d, J = 1.8 Hz, 1H); 11.01 (s, 1 H).

Intermediate 47

6-Amino-2- (pyridin-4-yl) -pyrimidin-4-ol

Obtained from pyridine-4-carboxamidine (hydrochloride) (2.13 g), by the procedure used in the Preparation of Intermediate 6. Crystallization from ethyl ether yielded the final product (1.22 g, 48%) as a white solid.

δ (300 MHz, DMSO): 5.27 (s, 1H); 6.70 (s, 2 H); 8.00 (d, J = 6.1 Hz, 2H); 8.71 (d, J = 6.1 Hz, 2H); 11.74 (bs, 1H).

Intermediate 48

N - [6-Chloro-2- (pyridin-4-yl) pyrimidin-4-yl] propionamide

Obtained from Intermediate 47 (1.22 g) by the procedure used in the preparation of Intermediate 12. Purification by silica gel column chromatography and ethyl acetate / n-hexane (from 2: 1 to 4: 1) as eluent yielded 0.90 g impure N - [6-Chloro-2- (pyridin-4-yl) pyrimidin-4-yl] propionamide. Purification (0.49 g) by silica gel column chromatography and chloroform / methanol (3%) as eluent yielded the final product (0.35 g, 38%) as a white solid.

δ (200 MHz, ClCD 3): 1.29 (t, J = 7.5 Hz, 3H); 2.57 (q, J = 7.5 Hz, 2H); 8.20 (d, J = 6.1 Hz, 2H); 8.26 (s, 1 H); 8.40 (bs, 1H); 8.80 (d, J = 6.1 Hz, 2H).

       \ newpage
    

Examples 112 and 113

N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (pyridin-4-yl) pyrimidin-4-yl] propionamide and 6- (3,5-dimethylpyrazol-1-yl) -2- (pyridin-4-yl) pyrimidin-4-ylamine

124

Obtained from Intermediate 48 (0.17 g) by the procedure used in Example 21 (reaction temperature: 85 ° C, reaction time: 20 hours). Purification by semi-preparative HPLC yielded N - [6- (3,5-dimethylpyrazol-1-yl) -2- (pyridin-4-yl) pyrimidin-4-yl] propionamide (19 mg, 9%) and 6 - (3,5-Dimethylpyrazol-1-yl) -2- (pyridin-4-yl) pyrimidin-4-ylamine (5 mg, 3%) as white solids.

Example 112

δ (300 MHz, CDCl 3): 1.30 (t, J = 7.4 Hz, 3H); 2.30 (s, 3H); 2.53 (q, J = 7.4 Hz, 2H); 2.85 (s, 3 H); 6.05 (s, 1 H); 8.12 (bs, 1H); 8.17 (d, J = 6.1 Hz, 2H); 8.70 (s, 1 H); 8.77 (d, J = 6.1 Hz, 2H).

Example 113

δ (300 MHz, CDCl 3): 2.33 (s, 3H); 2.84 (s, 3 H); 5.02 (bs, 2H); 6.06 (s, 1 H); 7.00 (s, 1 H); 8.21-8.19 (m, 2H); 8.76 (bs, 2H).

Intermediate 49

6- (Furan-2-yl) -2- (pyridin-4-yl) pyrimidin-4-ol

Obtained from Intermediate 35 (1.00 g) by the procedure used in the preparation of Intermediate 36. Crystallization in n-pentane yielded the final product (0.38 g, 29%) as a brown solid.

δ (200 MHz, DMSO): 6.74 (dd, J1 = 3.4 Hz, J2 = 1.7 Hz, 1H); 7.37 (d, J = 3.4 Hz, 1H); 7.96 (d, J = 1.7 Hz, 1H); 8.16 (d, J = 6.4 Hz, 2H); 8.79 (d, J = 6.4 Hz, 2H).

Intermediate fifty

4-Chloro-6- (furan-2-i1) -2- (pyridin-4-yl) pyrimidine

Obtained from Intermediate 49 (0.63 g) by the procedure used in the preparation of Intermediate 15 (reaction time: 2 hours). 4-Chloro-6- (furan-2-yl) -2- (pyridin-4-yl) pyrimidine (0.51 g, 76%) was obtained as a brown solid.

δ (200 MHz, CDCl 3): 6.66-6.68 (m, 1H); 7.49 (d, J = 3.4 Hz, 1H); 7.65 (d, J = 1.7 Hz, 1H); 7.68 (s, 1 H); 8.44 (d, J = 4.9 Hz, 2H); 8.83 (d, J = 4.9 Hz, 2H).

Example 114 6- (Furan-2-i1) -2- (pyridin-4-i1) pyrimidin-4-ylamine

       \ vskip1.000000 \ baselineskip
    

125

       \ vskip1.000000 \ baselineskip
    

Obtained from Intermediate 50 (0.51 g) by the procedure used in Example 48. The purification by silica gel column chromatography and methylene chloride / methanol (from 100% methylene chloride to chloride methylene / methanol 98: 2) as eluent yielded 6- (furan-2-yl) -2- (pyridin-4-yl) pyrimidin-4-ylamine (0.24 g, 51%) as a white solid.

δ (300 MHz, CDCl 3): 4.99 (bs, 2H); 6.57-6.55 (m, 1 H); 6.75 (s, 1 H); 7.28 (d, J = 3.6 Hz, 1H); 7.55-7.54 (m, 1H); 8.25 (d, J = 6.1 Hz, 2H); 8.72 (d, J = 6.1 Hz, 2H).

Example 115 N - [6- (Furan-2-yl) -2- (pyridin-4-yl) pyrimidin-4-yl] propionamide

126

Obtained from the compound described in Example 114 (0.14 g) by the procedure used in Example 49. Crystallization from ethyl ether yielded N - [6- (furan-2-yl) -2- (pyridin-4-yl ) pyrimidin-4-yl] propionamide (0.13 g, 75%) as a white solid.

δ (300 MHz, DMSO): 1.10 (t, J = 7.6 Hz, 3H); 2.53 (q, J = 7.6 Hz, 2H); 6.78 (dd, J1 = 3.4 Hz, J2 = 1.8 Hz, 1H); 7.51 (d, J = 3.4 Hz, 1H); 8.03 (d, J = 2.4 Hz, 1H); 8.29 (d, J = 6.1 Hz, 2H); 8.41 (s, 1 H); 8.80 (d, J = 6.1 Hz, 2H); 11.07 (s, 1 H).

Intermediate 51

6- (Furan-2-yl) -2- (thiazol-2-yl) pyrimidin-4-ol

Obtained from Intermediate 35 (1.00 g) and thiazol-2-carboxamidine (HCl) through the procedure used in the preparation of the Intermediate 36. Purification by silica gel column chromatography and chloroform / methanol (5%) as eluent yielded the final product (0.40 g, 29%) as a white solid.

δ (300 MHz, CDCl 3): 6.60 (s, 1H); 6.74-6.72 (m, 1 H); 7.27-7.24 (m, 1 HOUR); 7.97 (s, 1 H); 8.15-8.12 (m, 2H).

Intermediate 52

4-Chloro-6- (furan-2-yl) -2- (thiazol-2-yl) pyrimidine

Obtained from Intermediate 51 (0.39 g) by the procedure used in the preparation of Intermediate 10. Purification by column chromatography of silica gel and methylene chloride as eluent yielded 4-chloro-6- (furan-2-yl) -2- (thiazol-2-yl) pyrimidine (0.20 g, 48%) as a light yellow solid.

δ (300 MHz, CDCl 3): 6.64-6.62 (m, 1 H); 7.53-7.51 (m, 1 H); 7.59-7.57 (m, 1 H); 7.64 (s, 1 H); 7.67 (s, 1 H); 8.09 (s, 1 H).

Example 116 6- (Furan-2-yl) -2- (thiazol-2-yl) pyrimidin-4-ylamine

       \ vskip1.000000 \ baselineskip
    

127

       \ vskip1.000000 \ baselineskip
    

Obtained from Intermediate 52 (0.20 g) by the procedure used in Example 48. The purification by silica gel column chromatography and methylene chloride / ethyl ether (7: 3) as eluent yielded 6- (furan-2-yl) -2- (thiazol-2-yl) pyrimidin-4-ylamine (95 mg, 51%) as a white solid.

δ (300 MHz, CDCl 3): 5.22 (bs, 2H); 6.56 (dd, J1 = 3.4 Hz, J2 = 1.8 Hz, 1H); 6.76 (s, 1 H); 7.32 (dd, J1 = 3.6 Hz, J2 = 0.8 Hz, 1H); 7.48 (d, J = 3.0 Hz, 1H); 7.55 (dd, J1 = 1.8 Hz, J2 = 0.8 Hz, 1H); 7.99 (d, J = 3.0 Hz, 1H).

Example 117 N - [6- (Furan-2-yl) -2- (thiazol-2-yl) pyrimidin-4-yl] propionamide

128

Obtained from the compound described in Example 116 (95 mg) by the procedure used in Example 49. Purification by silica gel column chromatography and ethyl acetate / n-hexane (1: 1 to 100 ethyl acetate %) as eluent yielded N - [6- (furan-2-yl) -2- (thiazol-2-yl) pyrimidin-4-yl] propionamide (68 mg, 58%) as a white solid.

δ (300 MHz, CDCl 3): 1.27 (t, J = 7.4 Hz, 3H); 2.48 (q, J = 7.4 Hz, 2H); 6.59 (dd, J1 = 3.6 Hz, J2 = 1.7 Hz, 1H); 7.40 (dd, J1 = 3.6 Hz, J2 = 0.8 Hz, 1H); 7.53 (d, J = 3.3 Hz, 1H); 7.63 (dd, J1 = 1.7 Hz, J2 = 0.8 Hz, 1H); 8.02 (d, J = 3.3 Hz, 1H); 8.24 (bs, 1H); 8.47 (s, 1 H).

Example 118 2- (4-Fluorophenyl) - N - [6- (furan-2-yl) -2- (thiazol-2-yl) pyrimidin-4-yl] acetamide

129

A solution of the compound described in Example 116 (98 mg, 0.4 5) and 4-fluorophenylacetyl chloride (164 µL, 1.20 mmol) in pyridine (6 mL) was heated at 120 ° C overnight. The solvent was evaporated under reduced pressure. Methylene chloride (20 mL) was added and the solution was washed with water (2 x 10 mL), brine (10mL), and dried (Na2SO4). The solvent was evaporated under reduced pressure. Purification by silica gel column chromatography, eluting with ethyl acetate / n-hexane (from 100% n-hexane to 1: 1 ethyl acetate / n-hexane), yielded 2- (4-fluorophenyl) - N - [6- (furan-2-yl) -2- (thiazol-2-yl) pyrimidin-4-yl] acetamide (62 mg, 59%) as a white solid.

δ (300 MHz, CDCl 3): 3.74 (s, 2H); 6.58 (dd, J1 = 3.4 Hz, J2 = 1.8 Hz, 1H); 7.07 (t, J = 8.6 Hz, 2H); 7.32-7.27 (m, 2H); 7.38 (dd, J1 = 3.4 Hz, J2 = 0.8 Hz, 1H); 7.52 (d, J = 3.0 Hz, 1H); 7.61 (d, J = 2.8 Hz, 1H); 8.00 (d, J = 3.0 Hz, 1H); 8.22 (bs, 1H); 8.46 (s, 1 H).

Example 119 N - (Cyclopropylmethyl) -2- (2-furyl) -6- (pyrazol-1-yl) pyrimidin-4-amine

130

A solution of Intermediate 5 (0.50 g, 2.03 mmol) and cyclopropylmethylamine (0.43 g, 6.08 mmol) in pentanol (12.5 mL) was heated at 100 ° C overnight. The solvent was evaporated under reduced pressure. Purification by silica gel column chromatography, eluting with chloroform, yielded N - (cyclopropylmethyl) -2- (2-furyl) -6- (1 H -pyrazol-1-yl) pyrimidin-4-amine (0.55 g, 70 %) as a solid .

m.p .: 100.9-101.7 ° C.

δ (300 MHz, CDCl 3): 0.27-0.32 (m, 2H); 0.57-0.63 (m, 2H); 1.06-1.18 (m, 1 H); 3.24 (bs, 2H); 5.48 (bs, 1H); 6.47 (dd, J1 = 2.6 Hz, J2 = 1.6 Hz, 1H); 6.56 (dd, J1 = 3.3 Hz, J2 = 1.6 Hz, 1H); 6.78 (s, 1 H); 7.29 (dd, J1 = 3.3 Hz, J2 = 0.8 Hz, 1H); 7.61 (dd, J1 = 1.9 Hz, J2 = 0.8 Hz, 1H); 7.76 (d, J = 0.8 Hz, 1H); 8.66 (dd, J1 = 2.6 Hz, J2 = 0.8 Hz, 1H).

Example 120 ( 2R ) -2 - {[2- (2-Furil) -6- (pyrazol-1-yl) pyrimidin-4-yl] amino} propan-1-ol

131

Obtained from Intermediate 5 (100 mg) and ( R ) -2-aminopropanol (189 µL, 2.43 mmol) by the procedure used in Example 119. Purification by silica gel column chromatography and methylene chloride / methanol (from 100% methylene chloride to 95: 5 methylene chloride / methanol) as eluent yielded ( 2R ) -2 - {[2- (2-furyl) -6- (pyrazol-1-yl) pyrimidin-4-yl ] amino} propan-1-ol (88 mg, 76%) as a white solid.

m.p .: 163.0-163.8 ° C.

δ (300 MHz, CDCl 3): 1.32 (d, J = 6.7 Hz, 3H); 3.65-3.83 (m, 3H); 4.11 (bs, 1H); 5.27 (bs, 1H); 6.47 (dd, J1 = 2.5 Hz, J2 = 1.7 Hz, 1H); 6.55 (dd, J1 = 3.3 Hz, J2 = 1.7 Hz, 1H); 6.84 (s, 1 H); 7.29 (dd, J1 = 3.3 Hz, J2 = 0.8 Hz, 1H); 7.61 (dd, J1 = 1.6 Hz, J2 = 0.8 Hz, 1H); 7.75 (dd, J1 = 1.6 Hz, J2 = 0.7 Hz, 1H); 8.64 (dd, J1 = 2.5 Hz, J2 = 0.7 Hz, 1H).

Example 121 3 - {[2- (2-Furil) -6- (pyrazol-1-yl) pyrimidin-4-yl] amino} propan-1-ol

132

Obtained from Intermediate 5 (100 mg) and 3-amino-1-propanol (93 µL, 1.22 mmol) by the procedure used in the Example 119. Purification by column chromatography of silica gel and methylene chloride / methanol (methylene chloride 100% to methylene chloride / methanol 95: 5) as eluent yielded 3 - {[2- (2-furyl) -6- (pyrazol-1-yl) pyrimidin-4-yl] amino} propan-1-ol (104 mg, 90%) as a white solid.

δ (300 MHz, CDCl 3): 1.80-1.86 (m, 2H); 3.70 (bs, 4H); 5.31 (bs, 1H); 6.47 (dd, J1 = 2.6 Hz, J2 = 1.6 Hz, 1H); 6.55 (dd, J1 = 3.5 Hz, J2 = 1.6 Hz, 1H); 6.82 (s, 1 H); 7.29 (dd, J1 = 3.5 Hz, J2 = 0.8 Hz, 1H); 7.61 (dd, J1 = 1.6 Hz, J2 = 0.8 Hz, 1H); 7.75 (dd, J1 = 1.6 Hz, J2 = 0.8 Hz, 1H) 8.64 (dd, J1 = 2.6 Hz, J2 = 0.8 Hz, 1H).

Example 122 N - [2- (2-Furil) -6- (pyrazol-1-yl) pyrimidin-4-yl] ethane-1,2-diamine

133

The precursor intermediate tert -butyl 2 - {[2- (2-furyl) -6- (pyrazol-1-yl) pyrimidin-4-yl] amino} ethylcarbamate was obtained from Intermediate 5 (145 mg) and N- BOC-ethylenediamine (279 µL, 1.76 mmol) by the procedure used in Example 119. Purification by silica gel column chromatography and methylene / methanol chloride (from 100% methylene chloride to methylene chloride / methanol 95: 5) as eluent yielded 351 mg, 80%.

To a solution of the tert -butyl 2 - {[2- (2-furyl) -6- (pyrazol-1-yl) pyrimidin-4-yl] amino} ethyl} precursor intermediate intermediate
mato (0.28 g, 0.76 mmol) in chloroform (1.7 mL) trifluoroacetic acid (0.58 mL, 7.56 mmol) was added. The mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure. To the residue was added water (25 mL), potassium carbonate to basic pH, and extracted with methylene chloride (2 x 20 mL). The organic phase was dried (Na2SO4) and the solvent was evaporated under reduced pressure. Crystallization of the residue obtained in ethyl ether / diisopropyl ether (1: 1) yielded N - [2- (2-furyl) -6- (pyrazol-1-yl) pyrimidin-4-yl] ethane-1,2-diamine (77 mg, 38%) as a white solid.

m.p .: 104.1-105.1 ° C.

δ (300 MHz, CDCl 3): 2.99-3.03 (t, J = 5.9 Hz, 2H); 3.46-3.50 (m, 2H); 5.69 (bs, 1H); 6.47 (dd, J1 = 2.6 Hz, J2 = 1.6 Hz, 1H); 6.55 (dd, J1 = 3.4 Hz, J2 = 1.8 Hz, 1H); 6.83 (s, 1 H); 7.29 (d, J = 3.3 Hz, 1H) 7.60-7.61 (m, 1H); 7.75-7.76 (m, 1 H); 8.65 (d, J = 2.6 Hz, 1H).

Example 123 2- (2-Furil) - N - [2- (4-methoxyphenyl) ethyl] -6- (pyrazol-1-yl) pyrimidin-4-amine

       \ vskip1.000000 \ baselineskip
    

134

       \ vskip1.000000 \ baselineskip
    

Obtained from Intermediate 5 (100 mg) and (4-methoxyphenyl) ethylamine (177 µL, 1.22 mmol) by the procedure used in Example 119. Purification by silica gel column chromatography and n-hexane / acetate ethyl (from 10: 1 to 2: 1) as eluent yielded 2- (2-furyl) - N - [2- (4-methoxyphenyl) ethyl] -6- (pyrazol-1-yl) pyrimidin-4-amine ( 111 mg, 76%) as an oil.

δ (300 MHz, CDCl 3): 2.92 (t, J = 7.0 Hz, 2H); 3.65 (bs, 2H); 3.80 (s, 3H); 5.28 (bs, 1H); 6.47 (dd, J1 = 2.5 Hz, J2 = 1.7 Hz, 1H); 6.55 (dd, J1 = 3.3 Hz, J2 = 1.7 Hz, 1H); 6.80 (s, 1 H); 6.85-6.88 (m, 2H); 7.15-7.18 (m, 2H); 7.29 (dd, J = 3.3 Hz, J2 = 0.7 Hz, 1H); 7.59-7.60 (m, 1 H); 7.76 (d, J = 1.1 Hz, 1H); 8.65 (dd, J1 = 2.6 Hz, J2 = 0.7 Hz, 1H).

Example 124 N - [2- (3,4-Dimethoxyphenyl) ethyl] -2- (2-furyl) -6- (pyrazol-1-yl) pyrimidin-4-amine

       \ vskip1.000000 \ baselineskip
    

135

       \ vskip1.000000 \ baselineskip
    

Obtained from Intermediate 5 (100 mg) and (3,4-dimethoxyphenyl) ethylamine (177 µL, 1.22 mmol) by the procedure used in Example 119. Purification by silica gel column chromatography and methylene chloride / Methanol (from 100% methylene chloride to 99: 1 methylene chloride / methanol) as eluent yielded N - [2- (3,4-dimethoxyphenyl) ethyl] -2- (2-furyl) -6- (pyrazole-1 -il) pyrimidin-4-amine (77 mg, 49%) as an oil.

δ (300 MHz, CDCl 3): 2.92 (t, J = 7.0 Hz, 2H); 3.67 (bs, 2H); 3.87 (s, 3 H); 3.88 (s, 3 H); 5.30 (bs, 1H); 6.47 (dd, J1 = 2.5 Hz, J2 = 1.7 Hz, 1H); 6.55 (dd, J1 = 3.3 Hz, J2 = 1.7 Hz, 1H); 6.75-6.76 (m, 1 H); 6.80-6.82 (m, 3H); 7.29 (dd, J1 = 3.3 Hz, J2 = 0.9 Hz, 1H); 7.60 (dd, J1 = 1.7 Hz, J2 = 0.9 Hz, 1H); 7.75-7.77 (m, 1 H); 8.65 (dd, J = 2.6 Hz, J2 = 0.7 Hz, 1H).

Example 125 2- (2-Furil) -6- (pyrazol-1-yl) - N - [2- (pyridin-2-yl) ethyl] pyrimidin-4-amine

       \ vskip1.000000 \ baselineskip
    

136

       \ vskip1.000000 \ baselineskip
    

Obtained from Intermediate 5 (100 mg) and 2- (2-aminoethyl) pyridine (145 µL, 1.22 mmol) by the procedure used in Example 119. Purification by silica gel column chromatography and methylene chloride / Methanol (from 100% methylene chloride to 8: 2 methylene chloride / methanol) as eluent yielded 2- (2-furyl) -6- (pyrazol-1-yl) - N - [2- (pyridin-2-yl ) ethyl] pyrimidin-4-amine (86 mg, 64%) as a white solid.

m. p .: 110.2-110.9 ° C.

δ (300 MHz, CDCl 3): 3.14 (t, J = 6.5 Hz, 2H); 3.88 (bs, 2H); 5.95 (bs, 1H); 6.47 (dd, J1 = 2.5 Hz, J2 = 1.7 Hz, 1H); 6.55 (dd, J1 = 3.3 Hz, J2 = 1.7 Hz, 1H); 6.84 (s, 1 H); 7.14-7.20 (m, 2H); 7.29 (dd, J1 = 3.3 Hz, J2 = 0.8 Hz, 1H); 7.59-7.65 (m, 2H); 7.75-7.76 (m, 1 H); 8.56-8.59 (m, 1 H); 8.65 (dd, J1 = 2.5 Hz, J2 = 0.8 Hz, 1H).

Example 126 2- (2-Furil) -6- (pyrazol-1-yl) - N - [2- (pyridin-3-yl) ethyl] pyrimidin-4-amine

       \ vskip1.000000 \ baselineskip
    

137

       \ vskip1.000000 \ baselineskip
    

Obtained from Intermediate 5 (100 mg) and 3- (2-aminoethyl) pyridine (149 mg, 1.22 mmol) by the procedure used in Example 119. Purification by silica gel column chromatography and chloroform / methanol (from 100% chloroform to 100: 1 chloroform / methanol as eluent yielded 2- (2-furyl) -6- (pyrazol-1-yl) - N - [2- (pyridin-3-yl) ethyl] pyrimidin-4- amine (94 mg, 70%) as a white solid.

m. p .: 164.0-164.9 ° C.

δ (300 MHz, CDCl 3): 3.00 (t, J = 6.9 Hz, 2H); 3.71-3.75 (m, 2H); 5.30 (s, 1 H); 6.48 (s, 1 H); 6.55-6.56 (m, 1 H); 6.82 (s, 1 H); 7.24-7.30 (m, 3H); 7.57-7.60 (m, 2H); 7.76 (s, 1 H); 8.50-8.53 (m, 2H); 8.65-8.66 (m, 1H).

Example 127 2- (2-Furil) - N - (3-phenylpropyl) -6- (pyrazol-1-yl) pyrimidin-4-amine

       \ vskip1.000000 \ baselineskip
    

138

       \ vskip1.000000 \ baselineskip
    

Obtained from Intermediate 5 (100 mg) and 3-phenylpropylamine (173 µL, 1.22 mmol) by the procedure used in Example 119. Purification by silica gel column chromatography and n-hexane / ethyl acetate (from 10: 1 to 2: 1) as eluent yielded 2- (2-furyl) - N - (3-phenylpropyl) -6- (pyrazol-1-yl) pyrimidin-4-amine (124 mg, 89%) as a white solid

δ (300 MHz, CDCl 3): 2.01 (q, J = 7.5 Hz, 2H); 2.76 (t, J = 7.5 Hz, 2H); 3.41 (bs, 2H); 5.34 (bs, 1H); 6.47 (cid, J1 = 2.5 Hz, J2 = 1.7 Hz, 1H); 6.56 (dd, J1 = 3.3 Hz, J2 = 1.7 Hz, 1H); 6.77 (s, 1 H); 7.19-7.31 (m, 6H); 7.61 (s, 1 H); 7.76 (s, 1 H); 8.65-8.66 (m, 1H).

Example 128 2- (2-Furil) - N - [3- (imidazol-1-yl) propyl] -6- (pyrazol-1-yl) pyrimidin-4-amine

139

Obtained from Intermediate 5 (100 mg) and 3- (imidazol-1-yl) propylamine (145 µL, 1.22 mmol) by the procedure used in Example 119. Purification by silica gel column chromatography and chloride chloride methylene / methanol (from 100% methylene chloride at 97: 3) as eluent yielded 2- (2-furyl) - N - [3- (imidazol-1-yl) propyl] -6- (pyrazole-1-yl) pyrimidin-4-amine (122 mg, 90%) as a white solid.

δ (300 MHz, CDCl 3): 2.18 (q, J = 6.7 Hz, 2H); 3.43-3.50 (m, 2H); 4.11 (t, J = 6.7 Hz, 2H); 5.26 (bs, 1H); 6.49 (dd, J1 = 2.6 Hz, J2 = 1.7 Hz, 1H); 6.58 (dd, J1 = 3.3 Hz, J2 = 1.7 Hz, 1H); 6.79 (s, 1 H); 6.97-6-98 (m, 1H); 7.10-7.11 (m, 1H); 7.30 (dd, J1 = 3.3 Hz, J2 = 0.8 Hz, 1H); 7.54 (bs, 1H); 7.63 (dd, J1 = 1.7 Hz, J2 = 0.8 Hz, 1H) 7.76-7.77 (dd, J1 = 1.7 Hz, J2 = 0.8 Hz, 1H); 8.66 (dd, J1 = 2.6 Hz, J2 = 0.8 Hz, 1H).

Intermediate 53

2- (Thiophen-2-yl) pyrimidine-4,6-diol

Obtained from Intermediate 13 (1.35 g) by the procedure used in the preparation of Intermediate 2. Crystallization from diisopropyl ether yielded 2- (thiophen-2-yl) pyrimidine-4,6-diol (0.44 g, 34%) as a light yellow solid.

δ (300 MHz, DMSO): 5.15 (s, 1H); 7.07-7.19 (m, 1H); 7.72-7.78 (m, 1 HOUR); 8.00-8.02 (m, 1H).

Intermediate 54

4,6-Dichloro-2- (thiophene-2-yl) pyrimidine

Obtained from Intermediate 53 (0.44 g) by the procedure used in the preparation of Intermediate 3. Crystallization from diisopropyl ether yielded 4,6-dichloro-2- (thiophen-2-yl) pyrimidine (0.41 g, 78%) as a brown solid.

δ (300 MHz, CDCl 3): 7.12-7.20 (m, 2H); 7.54-7.60 (m, 1 HOUR); 8.05-8.08 (m, 1H).

Intermediate 55

4-Chloro-6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidine

Obtained from Intermediate 54 (0.69 g) by the procedure used in the preparation of Intermediate 5. Purification by column chromatography of silica gel and n-hexane / ethyl acetate (from 100% n-hexane to n-hexane / acetate ethyl 3: 1) as eluent yielded 4-chloro-6- (pyrazol-1-yl) -2- (thiophene-2-yl) pyrimidine (0.49 g, 68%) as a white solid.

δ (300 MHz, CDCl 3): 6.56 (s, 1H); 7.16-7.20 (m, 1H); 7.54-7.58 (m, 1 HOUR); 7.75 (s, 1 H); 7.84 (s, 1 H); 8.08-8.11 (m, 1H); 8.68 (s 1H).

Example 129 N - (Cyclopropylmethyl) -6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-amine

140

Obtained from Intermediate 55 (100 mg) and cyclopropylmethylamine (99 µL, 1.14 mmol) by the procedure used in Example 119. Purification by silica gel column chromatography and n-hexane / ethyl acetate (95: 5 to 90:10) as eluent yielded N - (cyclopropylmethyl) -6- (pyrazol-1-yl) -2- (thiophene-2-yl) pyrimidin-4-amine (98 mg, 87%) as a white solid .

m. p .: 134.6-135.3 ° C.

δ (300 MHz, CDCl 3): 0.31 (m, 2H); 0.60 (m, 2H); 1.08-1.18 (m, 1 H); 3.27 (bs, 2H); 5.32 (bs, 1H); 6.47 (dd, J1 = 2.5 Hz, J2 = 1.7 Hz, 1H); 6.76 (s, 1 H); 7.13 (dd, J1 = 4.9 Hz, J2 = 3.6 Hz, 1H); 7.44 (dd, J1 = 4.9 Hz, J2 = 1.2 Hz, 1H); 7.75 (bs, 1H); 7.97 (d, J1 = 3.6 Hz, J2 = 1.2 Hz, 1H); 8.67 (d, J = 2.2 Hz, 1H).

Example 130 ( 2R ) -2 - {[6- (Pirazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] amino} propan-1-ol

141

Obtained from Intermediate 55 (100 mg) and (R) -2-aminopropanol (177 µL, 2.28 mmol) by the procedure used in Example 119. Purification by silica gel column chromatography and n-hexane / acetate ethyl (from 100% n-hexane to 3: 2 n-hexane / ethyl acetate) as eluent yielded ( 2R ) -2 - {[6- (pyrazol-1-yl) -2- (thiophene-2-yl ) pyrimidin-4-yl] amino} propan-1-ol (87 mg, 76%) as a white solid.

m.p .: 135.7-136.9 ° C.

δ (300 MHz, CDCl 3): 1.33 (d, J = 6.9 Hz, 3H); 3.66-3.72 (m, 1 H); 3.81-3.87 (m, 1 H); 4.23 (bs, 1H); 5.15 (bs, 1H); 6.48-6.49 (m, 1 H); 6.82 (s, 1 H); 7.14 (dd, J1 = 5.1 Hz, J2 = 3.7 Hz, 1H); 7.46 (dd, J1 = 5.1 Hz, J2 = 1.2 Hz, 1H); 7.76 (m, 1 H); 7.97 (dd, J1 = 3.7 Hz, J2 = 1.2 Hz, 1H); 8.66 (dd, J1 = 2.7 Hz, J2 = 1.9 Hz, 1H).

Example 131 3 - {[6- (Pirazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] amino} propan-1-ol

142

Obtained from Intermediate 55 (100 mg) and 3-amino-1-propanol (87 µL, 1.14 mmol) by the procedure used in the Example 119. Purification by column chromatography of silica gel and n-hexane / ethyl acetate (from 100% n-hexane to n-hexane / acetate ethyl 3: 2) as eluent yielded 3 - {[6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] amino} propan-1-ol (94 mg, 82%) as a white solid.

m.p .: 129.9-130.8 ° C.

δ (300 MHz, CDCl 3): 1.87 (q, J = 6.0 Hz, 2H); 3.73 (bs, 5H); 5.30 (s, 1 H); 6.47 (dd, J1 = 2.6 Hz, J2 = 1.7 Hz, 1H); 6.79 (s, 1 H); 7.13 (dd, J1 = 4.9 Hz, J2 = 3.6 Hz, 1H); 7.45 (dd, J1 = 4.9 Hz, J2 = 1.2 Hz, 1H); 7.75 (dd, J1 = 1.7 Hz, J2 = 0.8 Hz, 1H); 7.96 (dd, J1 = 3.6 Hz, J2 = 1.2 Hz, 1H); 8.65 (dd, J1 = 2.6 Hz, J2 = 0.8 Hz, 1H).

Example 132 N - (2-Aminoethyl) -N- [6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] amine

144

Obtained from Intermediate 55 (100 mg) and N-BOC-ethylenediamine (180 µL, 1.14 mmol) by the synthesis procedure used in Example 122. Purification of the final product by silica gel column chromatography and silica chloride. methylene / methanol / NH4OH (95: 2.5: 2.5) as eluent yielded N - (2-aminoethyl) -N- [6- (pyrazol-1-yl) -2- (thiophene-2-yl) pyrimidin -4-yl] amine (86 mg, 47%) as a solid.

m.p .: 146.6-147.1 ° C.

δ (300 MHz, CDCl 3): 01 (t, J = 5.8 Hz, 2H); 3.50 (bs, 2H); 5.59 (bs, 1H); 6.46-6.48 (m, 1 H); 6.80 (s, 1 H); 7.11-7.15 (m, 1H); 7.45 (dt, J1 = 4.9 Hz, J2 = 1.1 Hz, 1H); 7.75-7.76 (m, 1 H); 7.97 (dd, J1 = 3.7 Hz, J2 = 1.1 Hz, 1H); 8.66 (d, J = 2.7 Hz, 1H).

Example 133 N- [2- (4-Methoxyphenyl) ethyl] -6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-amine

       \ vskip1.000000 \ baselineskip
    

145

       \ vskip1.000000 \ baselineskip
    

Obtained from Intermediate 55 (100 mg) and (4-methoxyphenyl) ethylamine (166 µL, 1.14 mmol) by the procedure used in Example 119. Purification by silica gel column chromatography and n-hexane / acetate ethyl (from 100% n-hexane to 4: 1 n-hexane / ethyl acetate) as eluent yielded N - [2- (4-methoxyphenyl) ethyl] -6- (pyrazol-1-yl) -2- (thiophene -2-yl) pyrimidin-4-amine (121 mg, 84%) as a white solid.

m.p .: 99.6-100.4ºC.

δ (300 MHz, CDCl 3): 2.92 (t, J = 7.0 Hz, 2H); 3.67 (bs, 2H); 3.81 (m, 3 H); 5.12 (bs, 1H); 6.47 (dd, J1 = 2.6 Hz, J2 = 1.7 Hz, 1H); 6.87 (dt, J1 = 4.4 Hz, J2 = 2.6 Hz, 2H); 7.11-7.26 (m, 3H); 7.45 (dd, J1 = 4.9 Hz, J2 = 1.4 Hz, 1H); 7.75 (d, J = 0.8 Hz, 1H); 7.98 (dd, J1 = 3.6 Hz, J2 = 1.1 Hz, 1H); 8.66 (dd, J1 = 2.6 Hz, J2 = 0.8 Hz, 1H).

Example 134 N - [2- (3,4-Dimethoxyphenyl) ethyl] -6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-amine

       \ vskip1.000000 \ baselineskip
    

146

       \ vskip1.000000 \ baselineskip
    

Obtained from Intermediate 55 (100 mg) and (3,4-dimethoxyphenyl) ethylamine (192 µL, 1.14 mmol) by the procedure used in Example 119. Purification by silica gel column chromatography and n-hexane / Ethyl acetate (from 85:15 to 70:30) as eluent yielded N - [2- (3,4-dimethoxyphenyl) ethyl] -6- (pyrazol-1-yl) -2- (thiophene-2-yl) pyrimidin-4-amine (117 mg, 76%) as a solid.

m.p .: 116.2-117.3 ° C.

δ (300 MHz, CDCl 3): 2.93 (t, J = 7.0 Hz, 2H); 3.70 (bs, 2H); 3.88 (s, 3 H); 3.89 (m, 3 H); 5.16 (bs, 1H); 6.47 (dd, J1 = 2.6 Hz, J2 = 1.7 Hz, 1H); 6.77-6.85 (m, 4H); 7.13 (dd, J1 = 4.9 Hz, J2 = 3.6 Hz, 11-1); 7.45 (dd, J1 = 4.9 Hz, J2 = 1.4 Hz, 1H); 7.75 (d, J = 0.8 Hz, 1H); 7.98 (dd, J1 = 3.6 Hz, J2 = 1.1 Hz, 11-1); 8.66 (dd, J1 = 2.6 Hz, J2 = 0.8 Hz, 1H).

Example 135 6- (Pirazol-1-yl) - N - [2- (pyridin-2-yl) ethyl] -2- (thiophene-2-yl) pyrimidin-4-amine

147

Obtained from Intermediate 55 (100 mg) and 2- (2-aminoethyl) pyridine (137 µL, 1.22 mmol) by the procedure used in Example 119. Purification by silica gel column chromatography and n-hexane / ethyl acetate (from n-hexane 100% to n-hexane / ethyl acetate 2: 3) as eluent yielded 6- (pyrazol-1-yl) - N - [2- (pyridin-2-yl) ethyl] - 2- (thiophen-2-yl) pyrimidin-4-amine (58 mg, 44%) as a white solid.

m.p .: 132.9-133.6 ° C.

δ (300 MHz, CDCl 3): 3.16 (t, J = 6.5 Hz, 2H); 3.90 (bs, 2H); 5.88 (t, J = 5.2 Hz, 1H); 6.46 (dd, J1 = 2.6 Hz, J2 = 1.6 Hz, 1H); 6.79 (s, 1 H); 7.11-7.21 (m, 3H); 7.44 (dd, J1 = 5.1 Hz, J2 = 1.2 Hz, 1H); 7.63 (dt, J1 = 7.7 Hz, J2 = 1.9 Hz, 1H); 7.74-7.75 (m, 1 H); 7.98 (dd, J1 = 3.6 Hz, J2 = 0.7 Hz, 1H) 8.58 (m, 1H) 8.65 (dd, J1 = 2.6 Hz, J2 = 0.7 Hz, 1H).

Example 136 6- (Pirazol-1-yl) - N - [2- (pyridin-3-yl) ethyl] -2- (thiophen-2-yl) pyrimidin-4-amine

148

Obtained from Intermediate 55 (100 mg) and 3- (2-aminoethyl) pyridine (139 mg, 1.14 mmol) by the procedure used in Example 119. Purification by silica gel column chromatography and n-hexane / acetate ethyl (from 1: 1 to 100% ethyl acetate) as eluent yielded 6- (pyrazol-1-yl) - N - [2- (pyridin-3-yl) ethyl] -2- (thiophene-2-yl ) pyrimidin-4-amine (106 mg, 80%) as a white solid.

m.p .: 159.0-160.5 ° C.

δ (300 MHz, CDCl 3): 3.02 (t, J = 7.14 Hz, 2 H) 3.75 (m, 2 H) 5.16 (s, 1H) 6.48 (m, J = 2.75, 1.65 Hz, 1H) 6.78 (s, 1H) 7.14 (dd, J = 5.08, 3.71 Hz, 1H) 7.25 (dd, J = 4.53, 0.69 Hz, 1H) 7.28 (dd, J = 4.81, 0.69 Hz, 1H) 7.47 (dd, J = 4.94, 1.37 Hz, 1H) 7.59 (m, J = 7.69, 1.65, 0.55 Hz, 1 H) 7.75 (dd, J = 1.51, 0.69 Hz, 1H) 7.99 (dd, J = 3.71, 1.24 Hz, 1H) 8.51 (dd, J = 4.67, 1.65 Hz, 1H) 8.55 (d, J = 1.65 Hz, 1H) 8.67 (dd, J = 2.75, 0.82 Hz, 1H).

Example 137 N - (3-Phenylpropyl) -6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-amine

149

Obtained from Intermediate 55 (100 mg) and 3-phenylpropylamine (162 µL, 1.14 mmol) by the procedure used in Example 119. Purification by silica gel column chromatography and n-hexane / ethyl acetate (from 95: 5 to 90:10) as eluent yielded N - (3-phenylpropyl) -6- (pyrazol-1-yl) -2- (thiophene-2-yl) pyrimidin-4-amine (98 mg, 72%) Like a white solid

m.p .: 83.6-84.5 ° C.

δ (300 MHz, CDCl 3): 2.02 (q, J = 7.4 Hz, 2H); 2.76 (t, J = 7.4 Hz, 2H); 3.44 (bs, 2H); 5.17 (bs, 1H); 6.47 (dd, J1 = 2.7 Hz, J2 = 1.7 Hz, 1H); 6.74 (s, 1 H); 7.22-7.31 (m, 6H); 7.45 (dd, J1 = 5.1 Hz, J2 = 1.2 Hz, 1H); 7.75 (dd, J1 = 1.7 Hz, J2 = 0.6 Hz, 1H); 7.95 (dd, J1 = 3.7 Hz, J2 = 1.2 Hz, 1H); 8.66 (dd, J1 = 2.7 Hz, J2 = 0.6 Hz, 1H).

Example 138 N - [3- (Imidazol-1-yl) propyl] -6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-amine

150

Obtained from Intermediate 5 (100 mg) and 3- (imidazol-1-yl) propylamine (136 µL, 1.14 mmol) by the procedure used in Example 119. Purification by column chromatography on silica gel and chloride methylene / methanol (97: 3) as eluent yielded N - [3- (imidazol-1-yl) propyl] -6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-amine (130 mg, 98%) as a white solid.

δ (300 MHz, CDCl 3): 2.20 (q, J = 7.0 Hz, 2H); 3.46-3.54 (m, 2H); 4.11 (t, J = 7.0 Hz, 2H); 5.14 (bs, 1H); 6.48 (dd, J1 = 2.7 Hz, J2 = 1.7 Hz, 1H); 6.77 (s, 1 H); 6.97 (t, J = 1.2 Hz, 1H); 7.10 (t, J = 1.2 Hz, 1H); 7.14 (dd, J1 = 5.1 Hz, J2 = 3.7 Hz, 1H); 7.47 (dd, J1 = 5.1 Hz, J2 = 1.2 Hz, 1H); 7.54 (s, 1 H); 7.75 (dd, J1 = 1.5 Hz, J2 = 0.7 Hz, 1H) 7.97 (dd, J1 = 3.7 Hz, J2 = 1.2 Hz, 1H); 8.66 (dd, J1 = 2.7 Hz, J2 = 0.7 Hz, 1H).

Example 139 Ethyl 6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-ylcarbamate

151

A solution of the compound described in the Example 56 (0.37 g, 1.52 mmol), diethyl pyrocarbonate (246 µL, 1.67 mmol) and dimethylaminopyridine (50 mg, 0.41 mmol) in tetrahydrofuran (4 mL) was heated at 45 ° C overnight. The reaction was poured over water (40 mL) and the mixture was extracted with ethyl acetate (2 x 25 mL) The organic phase was washed with water (2 x 25 mL), brine (25 mL), dried (Na2SO4), and the solvent was evaporated under pressure reduced Purification by column chromatography of silica gel, using n-hexane / ethyl acetate (9: 1) as eluent yielded ethyl 6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-ylcarbamate (34 mg, 7%) as a white solid.

δ (300 MHz, CDCl 3): 1.35 (t, J = 7.0 Hz, 3H); 4.31 (d, J = 7.0 Hz, 2H); 6.50 (dd, J1 = 2.6 Hz, J2 = 1.2 Hz, 1H); 7.15 (dd, J1 = 5.1 Hz, J2 = 3.7 Hz, 1H); 7.49 (dd, J1 = 5.1 Hz, J2 = 1.6 Hz, 1H); 7.52 (bs, 1H); 7.80 (dd, J1 = 1.6 Hz, J2 = 0.7 Hz, 1H); 7.99 (dd, J1 = 3.7 Hz, J2 = 1.2 Hz, 11-1); 8.33 (s, 1 H); 8.66 (dd, J1 = 2.6 Hz, J2 = 0.7 Hz, 1H).

Example 140 1- [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3- (2-phenyl-cyclopropyl) urea

152

To a solution cooled to -78 ° C of the compound described in Example 1 (0.22 g, 0.97 mmol) in anhydrous THF (14 mL) 0.78 mL of n-butyllithium was slowly added (2.5 M solution in hexane). The mixture was stirred at -78 ° C for 1 hour and then a solution of slowly added phenylcyclopropylisocyanate (0.22 mg, 1.40 mmol) in anhydrous THF (2 mL) The mixture was kept at room temperature for 2 hours. Water (15 mL) was added and the organic phase was diluted with acetate ethyl (20 mL). The organic phase was washed with brine (2 x 20 mL), dried (Na2SO4), and the solvent was evaporated under pressure reduced Purification by column chromatography of silica gel, using methylene chloride / methanol (99: 1) as eluent, followed by HPLC purification semi-preparatory yielded 1- [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3- (2-phenyl-cyclopropyl) urea  (150 mg, 40%) as a white solid.

δ (400 MHz, DMSO): 1.18-1.32 (m, 1H); 2.05-2.12 (m, 1H): 2.81-2.88 (m, 1H): 6.64 (s, 1H); 6.76 (dd, J1 = 3.3 Hz, J2 = 1.8 Hz, 1H); 7.14-7.22 (m, 3H); 7.26-7.31 (m, 2H); 7.44 (d, J = 3.1 Hz, 11-1); 7.89 (s, 1 H); 7.91 (s, 1 H); 7.98 (s, 1 H); 8.10 (bs, 1H); 8.75 (d, J = 2.3 Hz, 1H); 9.96 (bs, 1H).

Example 141 1- [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3-propylurea

       \ vskip1.000000 \ baselineskip
    

153

       \ vskip1.000000 \ baselineskip
    

Obtained from the compound described in the Example 1 (0.22 g) and propylisocyanate (0.12 g, 1.40 mmol) by the procedure used in Example 140. Purification by silica gel column chromatography and chloride methylene / methanol (99: 1) as eluent yielded 1- [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-441-3-propylurea (68 mg, 20%) as a white solid.

δ (300 MHz, DMSO): 0.94 (t, J = 7.4 Hz, 3H); 1.53 (h, J = 7.4 Hz, 2 H); 3.18 (q, J = 7.4 Hz, 2H); 6.65 (dd, J1 = 2.7 Hz, J2 = 1.7 Hz, 1H); 6.75 (dd, J1 = 3.4 Hz, J2 = 1.7 Hz, 1H); 7.44 (dd, J1 = 3.4 Hz, J2 = 0.8 Hz, 1H); 7.86 (bs, 1H); 7.92 (dd, J1 = 1.7 Hz, J2 = 0.7 Hz, 1H); 7.96 (dd, J1 = 1.7 Hz, J2 = 0.8 Hz, 1H); 8.75 (dd, J1 = 2.7 Hz, J2 = 0.7 Hz, 1H); 9.97 (bs, 1H).

Example 142 1- [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3-isopropylurea

       \ vskip1.000000 \ baselineskip
    

154

       \ vskip1.000000 \ baselineskip
    

Obtained from the compound described in the Example 1 (0.22 g) and isopropylisocyanate (0.12 g, 1.40 mmol) by the procedure used in Example 140. The purification by silica gel column chromatography and methylene chloride / methanol (99: 1) as eluent yielded 1- [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3-isopropylurea (147 mg, 48%) as a white solid.

δ (400 MHz, DMSO): 1.19 (d, J = 6.7 Hz, 6H); 3.84 (h, J = 6.7 Hz, 1H); 6.64 (s, 1 H); 6.75 (s, 1 H); 7.42 (d, J = 3.1 Hz, 1H); 7.80 (s, 1 H); 7.92 (s, 1 H); 7.97 (s, 1 H); 8.75 (d, J = 2.3 Hz, 1H); 9.87 (s, 1 H).

Example 143 1-Cyclopentyl-3- [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] urea

155

Obtained from the compound described in the Example 1 (0.22 g) and cyclopentyl isocyanate (0.16 g, 1.40 mmol) by the procedure used in Example 140. The purification by silica gel column chromatography and methylene chloride / methanol (99: 1) as eluent yielded 1-cyclopentyl-3- [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] urea (125 mg, 38%) as a white solid.

δ (300 MHz, DMSO): 1.42-1.54 (m, 2H); 1.55-1.66 (m, 2H); 1.67-1.75 (m, 2H); 1.84-1.96 (m, 2H); 3.99-4.09 (m, 1H); 6.65 (dd, J1 = 2.7 Hz, J2 = 1.6 Hz, 1H); 6.76 (dd, J1 = 3.4 Hz, J2 = 1.6 Hz, 1H); 7.43 (d, J = 2.7 Hz, 1H); 7.76 (s, 1 H); 7.92 (d, J = 1.1 Hz, 1H); 7.97 (s, 1 H); 8.10 (bs, 1H); 8.75 (d, J = 2.7 Hz, 1H); 9.89 (s, 1 H).

Example 144 1- [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3- (4-methoxyphenyl) urea

156

Obtained from the compound described in the Example 1 (0.22 g) and 4-methoxyphenyl isocyanate (0.21 g, 1.40 mmol) by the procedure used in the Example 140. Purification by silica column chromatography gel and methylene chloride / methanol (98: 2) as eluent yielded 1- [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3- (4-methoxyphenyl) urea (82 mg, 22%) as a white solid.

δ (400 MHz, DMSO): 3.75 (s, 3H); 6.66 (dd, J1 = 2.7 Hz, J2 = 1.8 Hz, 1H); 6.78 (dd, J1 = 3.3 Hz, J2 = 1.8 Hz, 1H); 6.93-7.0 (m, 2H); 7.46-7.52 (m, 3H); 7.89 (s, 1 H); 7.94 (s, 1 H); 8.03 (s, 1 H); 8.78 (d, J = 2.7 Hz, 1H); 10.13 (s, 1 H); 10.17 (bs, 1H).

Example 145 1- [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3-phenethylurea

157

Obtained from the compound described in the Example 1 (0.22 g) and phenethyl isocyanate (0.21 g, 1.40 mmol) by the procedure used in Example 140. Purification by silica gel column chromatography and chloride methylene / methanol (99: 1) as eluent yielded 1- [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3-phenethylurea (35 mg, 10%) as a white solid.

δ (400 MHz, DMSO): 2.83 (t, J = 7.0 Hz, 2H); 3.47 (q, J = 7.0 Hz, 2H); 6.64 (dd, J1 = 2.7 Hz, J2 = 1.6 Hz, 1H); 6.72 (dd, J1 = 3.3 Hz, J2 = 1.8 Hz, 1H); 7.18-7.24 (m, 1H); 7.26-7.34 (m, 5H); 7.64 (bs, 1H); 7.90-7.92 (m, 2H); 7.93-7.95 (m, 1 H); 8.73 (d, J = 2.7 Hz, 1H); 9.98 (bs, 1H).

Example 146 1-Benzyl-3- [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] urea

158

Obtained from the compound described in the Example 1 (0.22 g) and benzyl isocyanate (0.19 g, 1.40 mmol) by the procedure used in Example 140. Purification by silica gel column chromatography and chloride methylene / methanol (99: 1 to 85: 5) as eluent, followed by a semi-preparative HPLC purification rendered 1-Benzyl-3- [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] urea (10 mg, 3%) as a white solid.

MS (M +): 360.

Claims (19)

1. A compound of formula (I) 159 in the that R 1 and R 2 represent, independently, a monocyclic or polycyclic heteroaryl group optionally substituted by one or more selected substituents from the group consisting of halogen atoms, lower alkyl, linear or branched, optionally substituted, cycloalkyl, hydroxy, lower alkoxy, linear or branched, substituted optionally, -SH, lower alkyl, linear or branched, optionally substituted, cyano, -NR'R '', -CO_ {R}, in which R 'and R' 'each independently represent an atom of hydrogen or a lower alkyl group, linear or branched, optionally substituted or R 'and R' 'together with the nitrogen atom to which they are attached form a cyclic group;

R 3 represents a group selected from -COR 4, -CON (R 4) R 5, -COOR 4 and -R 4 in the that R 4 represents a group selected from:

?

hydrogen atoms,

?

a lower alkyl group, linear or branched, which is optionally substituted by one or more halogen atoms or by one or more cycloalkyl groups, hydroxy, lower alkoxy, lower alkylthio, amino, mono- or dialkylamino, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl and nitrile;

?

a group of formula:

160 in the that: m, o and p are, independently, 0 or 1; n and q are independently selected from integers from 0 to 6; R a and R b are independently an atom of hydrogen or a lower alkyl group; G is a group selected from groups cycloalkyl, aryl or heteroaryl which are substituted optionally by one or more halogen atoms or by one or more lower alkyl, cycloalkyl, lower haloalkyl groups, hydroxy, lower alkoxy, lower alkylthio, amino, mono- or dialkylamino, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkoxycarbonyl and nitrile; and R 5 represents a hydrogen atom or a lower alkyl, cycloalkyl or benzyl group; or R 4 and R 5 together with the nitrogen atom to which they are attached form a saturated or unsaturated ring that is optionally substituted by one or more lower alkyl groups, cycloalkyl or benzyl; or pharmaceutically acceptable salts of themselves; with the proviso that the compound is not 2,6-dipyridin-4-ylpyrimidin-4-amine. 2. A compound according to claim 1 in the that R 1 represents a monocyclic heteroaryl group selected from the group consisting of furyl, thienyl groups, thiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, triazolyl, pyrimidinyl and pyridyl; said groups are optionally substituted by one or more substituents) selected from the group consisting of halogen atoms and lower alkyl, linear or branched, substituted optionally 3. A compound according to claim 2 in the that R 1 represents a monocyclic heteroaryl group selected from the group consisting of furyl, thienyl groups, pyrazolyl, triazolyl, thiazolyl and pyridyl; these groups are optionally substituted by one or more selected substituents of the group consisting of halogen and lower alkyl atoms, linear or branched, optionally substituted. 4. A compound according to any of the previous claims wherein R2 represents a group monocyclic heteroaryl selected from the group consisting of pyrazolyl, furyl, thiazolyl, oxazolyl, pyridyl groups, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, imidazolyl and triazolyl; said groups are optionally substituted by one or more substituents selected from the group consisting of atoms of halogen and lower alkyl, linear or branched, substituted optionally 5. A compound according to claim 4 in the that R2 represents a monocyclic heteroaryl group selected from the group consisting of pyrazolyl groups, furyl, thiazolyl, pyridyl, thienyl and triazolyl; these groups are optionally substituted by one or more selected substituents of the group consisting of halogen and lower alkyl atoms, linear or branched, optionally substituted. 6. A compound according to any of the previous claims wherein R 4 represents a group selected from:

?

hydrogen atoms,

?

a lower alkyl group, linear or branched, which is optionally substituted by one or more halogen atoms;

?

a group of formula:

161 at that: o and p are independently 0 or 1; n and q are independently selected from integers from 0 to 6; R a and R b are independently an atom of hydrogen or a lower alkyl group; G is a group selected from groups cycloalkyl, arite or heteroaryl which are substituted optionally by one or more halogen atoms or by one or more lower alkoxy groups; and R 5 represents a hydrogen atom. 7. A compound according to any of the previous claims wherein R 4 represents a group selected from:

?

hydrogen atoms,

?

a lower alkyl group, linear or branched, which is optionally substituted by one or more halogen atoms;

?

a group selected from cycloalkylalkyl, phenylalkyl, heteroarylalkyl groups, phenoxyalkyl and heteroaryloxyalkyl; these groups are optionally substituted by one or more halogen atoms or by one or more lower alkoxy groups;

and R 5 represents a hydrogen atom. 8. A compound according to any of the previous claims wherein R1 is a group 2-furyl and R2 is a pyrazolyl group that is optionally substituted by one or more lower alkyl groups. 9. A compound according to claim 1, which is one of: 2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-ylamine N- [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] acetamide N - [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide N - [2- (Furan-2-i1) -6- (pyrazol-1-yl) pyrimidin-4-yl] isobutyramide N - [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] tert-butyramide [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] amide of cyclopropanecarboxylic acid [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] amide of cyclobutanecarboxylic acid [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] amide of cyclohexanecarboxylic acid 3-Cyclopentyl- N - [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide N - [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -2- (4-methoxyphenyl) -acetamide 2- (3,4-Dimethoxyphenyl) - N - [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] acetamide N - [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl) -3-phenyl-propionamide E -2-Phenylcyclopropanecarboxylic acid [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] amide 3,3,3-Trifluoro- N - [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide 3- (3,4-Dimethoxyphenyl) - N - [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide N - [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -2-methyl-3-phenylpropionamide N - [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3-phenoxy-propionamide N - [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3- (pyridin-3-yl) -propionamide N - [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3- (pyridin-3-yl) acetamide E -3- (3,4-Dimethoxyphenyl) - N - [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] acrylamide 2- (Furan-2-yl) -6- (3,5-dimethylpyrazol-1-yl) pyrimidin-4-ylamine N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] acetamide N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] propionamide N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] isobutyramide N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] tert -butyramide [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] amide of cyclopropanecarboxylic acid 3-Cyclopentyl- N - [6- (3,5-dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] propionamide N - [6- (3, 5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] -2- (4-methoxyphenyl) acetamide 2- (3,4-Dimethoxyphene) - N - [6- (3, 5-dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] acetamide N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] -3-phenyl propionamide N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] -3,3,3-trifluoropropionamide 3- (3,4-Dimethoxyphenyl) - N - [6- (3, 5-dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] propionamide N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) pyrimidin-4-yl] -3-phenoxy propionamide N - [6- (3, 5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) -pyrimidin-4-yl] -2- (pyridin-3-yl) acetamide N - [6- (3,5-Dimethylpyrazol-1-yl) -2- (furan-2-yl) -pyrimidin-4-yl] -2- (pyridin-3-yl) propionamide 2- (Furan-2-yl) -6- (4-methylpyrazol-1-yl) pyrimidin-4-ylamine N - [2- (Furan-2-yl) -6- (4-methylpyrazol-1-yl) -pyrimidin-4-yl] propionamide 2- (Furan-2-yl) -6- (3-methylpyrazol-1-yl) pyrimidin-4-ylamine N- [2- (Furan-2-yl) -6- (3-methylpyrazol-1-yl) -pyrimidin-4-yl] propionamide 2- (Furan-2-il) -6- (3- trifluoromethylpyrazol-1-yl) pyrimidin-4-ylamine N- [2- (Furan-2-yl) -6- (3-trifluoromethylpyrazol-1-yl) pyrimidin-4-yl] propionamide 2- (Furan-2-yl) -6- (5-methyl-3-trifluoromethylpyrazol-1-yl) pyrimidin-4-ylamine N- [2- (Furan-2-yl) -6- (5-methyl-3-trifluoromethylpyrazol-1-yl) pyrimidin-4-yl] propionamide 2- (Furan-2-yl) -6 - [[1,2,4] triazol-1-yl] pyrimidin-4-ylamine N- [2- (Furan-2-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-yl] acetamide N- [2- (Furan-2-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-yl] propionamide 3,3,3-Trifluoro-N- [2- (furan-2-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-yl) -propionamide 2- (5-Bromofuran-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-ylamine N- [2- (5-Bromofuran-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide 2- (5-Chlorofuran-2-i l) -6- (pyrazol-1-yl) pyrimidin-4-ylamine N- [2- (5-Chlorofuran-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide 2- (5-Methylfuran-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-ylamine N- [2- (5-Methylfuran-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide N- [2- (Furan-2-yl) -6- (pyridin-3-yl) pyrimidin-4-yl] propionamide 2- (Furan-2-yl) -6- (pyridin-3-yl) pyrimidin-4-yl] amide 6- (Pirazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-ylamine N- [6- (Pirazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] acetamide N- [6- (Pirazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] propionamide 3-Cyclopentyl-N- [6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl) propionamide 3-Phenyl-N- [6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] propionamide 3,3,3-Trifluoro-N- [6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] propionamide 3- (3,4-Dimethoxyphenyl) -N- [6- (pyrazol-1-yl) -2- (thiophene-2-yl) pyrimidin-4-yl) propionamide 3-Phenoxy-N- [6- (pyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] propionamide N- [6- (Pirazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] -2- (pyridin-3-yl) acetamide N- [6- (Pirazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] -3- (pyridin-3-yl) propionamide E-3- (3,4-Dimethoxyphenyl) -N- [6- (pyrazol-1-yl) -2- (thiophene-2-yl) pyrimidin-4-yl) acrylamide 6- (3,5-Dimethylpyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-ylamine N- [6- (3,5-Dimethylpyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] acetamide N- [6- (3,5-dimethylpyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] propionamide N- [6- (3,5-Dimethylpyrazol-1-yl) -2- (thiophen-2-yl) pyrimidin-4-yl] -3,3,3-trifluoropropionamide 2- (Thiophen-2-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-ylamine N- [2- (Thiophen-2-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-yl] acetamide N- [2- (Thiophen-2-yl) -6 - ([1, 2,4] triazol-1-yl) pyrimidin-4-yl] propionamide 3, 3, 3-Trifluoro-N- [2- (thiophen-2-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-yl] propionamide N- [2- (3-Methylthiophene-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide 6- (Furan-2-yl) -2- (pyrazol-1-yl) pyrimidin-4-ylamine N- [6- (Furan-2-yl) -2- (pyrazol-1-yl) pyrimidin-4-yl] acetamide N- [6- (Furan-2-yl) -2- (pyrazol-1-yl) pyrimidin-4-yl] propionamide 3,3,3-Trifluoro-N- [6- (furan-2-yl) -2- (pyrazol-1-yl) pyrimidin-4-yl] propionamide 2- (3,5-Dimethylpyrazol-1-yl) -6- (furan-2-yl) pyrimidin-4-ylamine N- [2- (3,5-Dimethylpyrazol-1-yl) -6- (furan-2-yl) pyrimidin-4-yl] propionamide N- [2- (3,5-Dimethylpyrazol-1-yl) -6- (furan-2-yl) pyrimidin-4-yl] -2- (4-methoxyphenyl) acetamide 6- (Furan-2-yl) -2 - ([1,2,4] triazol-1-yl) pyrimidin-4-ylamine N- [6- (Furan-2-yl) -2 - ([1,2,4] triazol-1-yl) pyrimidin-4-yl] propionamide 2- (Pirazol-1-yl) -6- (pyridin-2-yl) pyrimidin-4-ylamine N- [2- (Pirazol-1-yl) -6- (pyridin-2-yl) pyrimidin-4-yl] propionamide 2- (3,5-Dimethylpyrazol-1-yl) -6- (pyridin-2-yl) pyrimidin-4-ylamine N- [2- (3,5-Dimethylpyrazol-1-yl) -6- (pyridin-2-yl) pyrimidin-4-yl] propionamide N- [2- (3,5-Dimethylpyrazol-1-yl) -6- (pyridin-2-yl) pyrimidin-4-yl] -2- (4-methoxyphenyl) acetamide 2- (Pirazol-1-yl) -6- (pyridin-3-yl) pyrimidin-4-ylamine N- [2- (Pirazol-1-yl) -6- (pyridin-3-yl) pyrimidin-4-yl] propionamide 2- (3,5-Dimethylpyrazol-1-yl) -6- (pyridin-3-yl) pyrimidin-4-ylamine N- [2- (3,5-Dimethylpyrazol-1-yl) -6- (pyridin-3-yl) pyrimidin-4-yl] propionamide N- [2- (3,5-Dimethylpyrazol-1-yl) -6- (pyridin-3-yl) pyrimidin-4-yl] -2- (4-methoxyphenyl) acetamide 2- (Pirazol-1-yl) -6- (pyridin-4-yl) pyrimidin-4-ylamine N- [2- (Pirazol-1-yl) -6- (pyridin-4-yl) pyrimidin-4-yl] propionamide 6- (Furan-2-yl) -2- (pyridin-2-yl) pyrimidin-4-ylamine N- [6- (Furan-2-yl) -2- (pyridin-2-yl) pyrimidin-4-yl] propionamide 2- (3-Methylpyridin-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-ylamine N- [2- (3-methylpyridin-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] propionamide 6- (Pirazol-1-yl) -2- (pyridin-3-yl) pyrimidin-4-ylamine N- [6- (Pirazol-1-yl) -2- (pyridin-3-yl) pyrimidin-4-yl] acetamide N- [6- (Pirazol-1-yl) -2- (pyridin-3-yl) pyrimidin-4-yl] propionamide 6- (3,5-Dimethylpyrazol-1-yl) -2- (pyridin-3-yl) pyrimidin-4-ylamine N- [6- (3,5-Dimethylpyrazol-1-yl) -2- (pyridin-3-yl) pyrimidin-4-yl] acetamide N- [6- (3,5-Dimethylpyrazol-1-yl) -2- (pyridin-3-yl) pyrimidin-4-yl] propionamide N- [6- (3,5-Dimethylpyrazol-1-yl) -2- (pyridin-3-yl) pyrimidin-4-yl] -3,3,3-trifluoropropionamide 2- (Pyridin-3-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-ylamine 3,3,3-Trifluoro-N- [2- (pyridin-3-yl) -6 - ([1,2,4] triazol-1-yl) pyrimidin-4-yl] propionamide 6- (Furan-2-yl) -2- (pyridin-3-yl) pyrimidin-4-ylamine N- [6- (Furan-2-yl) -2- (pyridin-3-yl) pyrimidin-4-yl] propionamide N- [6- (3,5-Dimethylpyrazol-1-yl) -2- (pyridin-4-yl) pyrimidin-4-yl] propionamide 6- (3,5-Dimethylpyrazol-1-yl) -2- (pyridin-4-yl) pyrimidin-4-ylamine 6- (Furan-2-yl) -2- (pyridin-4-yl) pyrimidin-4-ylamine N- [6- (Furan-2-yl) -2- (pyridin-4-yl) pyrimidin-4-yl] propionamide 6- (Furan-2-yl) -2- (thiazol-2-yl) pyrimidin-4-ylamine N- [6- (Furan-2-yl) -2- (thiazol-2-yl) pyrimidin-4-yl] propionamide 2- (4-Fluorophenyl) -N- [6- (furan-2-yl) -2- (thiazol-2-yl) pyrimidin-4-yl] acetamide N- (Cyclopropylmethyl) -2- (2-furyl) -6- (pyrazol-1-yl) pyrimidin-4-amine (2 R) -2 - {[2- (2-Furil) -6- (pyrazol-1-yl) pyrimidin-4-yl] amino} propan-1-o1 3 - {[2- (2-Furil) -6- (pyrazol-1-yl) pyrimidin-4-yl] amino} propan-1-ol N- [2- (2-Furil) -6- (pyrazol-1-yl) pyrimidin-4-yl] ethane-1,2-diamine 2- (2-Furil) -N- [2- (4-methoxyphenyl) ethyl] -6- (pyrazol-1-yl) pyrimidin-4-amine N- [2- (3,4-Dimethoxyphenyl) ethyl] -2- (2-furyl) -6- (pyrazol-1-yl) pyrimidin-4-amine 2- (2-Furil) -6- (pyrazol-1-yl) -N- [2- (pyridin-2-yl) ethyl] pyrimidin-4-amine 2- (2-Furil) -6- (pyrazol-1-yl) -N- [2- (pyridin-3-yl) ethyl] pyrimidin-4-amine 2- (2-Furil) -N- (3-phenylpropyl) -6- (pyrazol-1-yl) pyrimidin-4-amine 2- (2-Furil) -N- [3- (imidazol-1-yl) propyl] -6- (pyrazol-1-yl) pyrimidin-4-amine N- (Cyclopropylmethyl) -6- (pyrazol-1-yl) -2- (tien-2-yl) pyrimidin-4-amine (2R) -2 - {[6- (Pirazol-1-yl) -2- (tien-2-yl) pyrimidin-4-yl] amino} propan-1-ol 3 - {[6- (Pirazol-1-yl) -2- (tien-2-yl) pyrimidin-4-yl] amino} propan-1-ol N- (2-Aminoethyl) -N- [6- (pyrazol-1-yl) -2- (tien-2-yl) pyrimidin-4-yl] amine N- [2- (4-Methoxyphenyl) ethyl] -6- (pyrazol-1-yl) -2- (tien-2-yl) pyrimidin-4-amine N- [2- (3,4-Dimethoxyphenyl) ethyl] -6- (pyrazol-1-yl) -2- (tien-2-yl) pyrimidin-4-amine 6- (Pirazol-1-yl) -N- [2- (pyridin-2-yl) ethyl] -2- (tien-2-yl) pyrimidin-4-amine 6- (Pirazol-1-yl) -N- [2- (pyridin-3-yl) ethyl] -2- (tien-2-yl) pyrimidin-4-amine N- (3-Phenylpropyl) -6- (pyrazol-1-yl) -2- (tien-2-yl) pyrimidin-4-amine N- [3- (Imidazol-1-yl) propyl] -6- (pyrazol-1-yl) -2- (tien-2-yl) pyrimidin-4-amine Ethyl 6- (pyrazol-1-yl) -2- (tien-2-yl) pyrimidin-4-ylcarbamate 1- [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3- (2-phenyl-cyclopropyl) urea 1- [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3-propylurea 1- [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3-isopropylurea 1-Cyclopentyl-3- [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] urea 1- [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3- (4-methoxy-phenyl) urea 1- [2- (Furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] -3-phenethylurea 1-Benzyl-3- [2- (furan-2-yl) -6- (pyrazol-1-yl) pyrimidin-4-yl] urea 10. A compound according to any one of the claims 1 to 9 for use in the treatment of a disease or pathological condition susceptible to improvement by antagonism of an adenosine receptor. 11. A compound according to claim 10 for use in the treatment of a disease or pathological condition in the disease or pathological condition is ischemia, arrhythmia supraventricular, acute renal failure, asthma, reperfusion damage myocardial, allergic reactions including but not limited to rhinitis, urticaria, scleroderma arthritis, other diseases autoimmune, inflammatory bowel diseases, diabetes mellitus, obesity, Parkinson's disease, Huntington, dystonia such as leg syndrome restless, dyskinesias such as those caused by use prolonged dopaminergic or neuroleptic medications or sleep disorders. 12. A compound according to any one of the claims 1 to 9 for use in the treatment of a disease or pathological condition susceptible to improvement by Adenosine A2A receptor antagonism. 13. A compound according to claim 12 for use in the treatment of a disease or pathological condition in the disease or pathological condition is ischemia, arrhythmia supraventricular disease, Parkinson's disease, Huntington, dystonia such as leg syndrome restless, dyskinesias such as those caused by use prolonged dopaminergic or neuroleptic medications or sleep disorders. 14. A pharmaceutical composition comprising a compound as defined in any one of the claims 1 to 9 mixed with a diluent or carrier pharmaceutically acceptable. 15. Use of a compound as defined in any one of claims 1 to 9 in the preparation of a medicine to treat a disease or pathological condition susceptible of improvement by antagonism of a receptor adenosine 16. Use of a compound according to claim 15 in which the disease or pathological condition is ischemia, supraventricular arrhythmia, acute renal failure, asthma, damage of Myocardial reperfusion, allergic reactions including but not limited to rhinitis, urticaria, scleroderma arthritis, others autoimmune diseases, inflammatory bowel diseases, diabetes mellitus, obesity, Parkinson's disease, disease Huntington, dystonia such as leg syndrome restless, dyskinesias such as those caused by use prolonged dopaminergic or neuroleptic medications or sleep disorders. 17. Use of a compound as defined in any one of claims 1 to 9 in the preparation of a medicine to treat a disease or pathological condition susceptible of improvement by antagonism of the A 2A receptor of the adenosine 18. Use according to claim 17, wherein the disease or pathological condition is ischemia, arrhythmia supraventricular disease, Parkinson's disease, Huntington, dystonia such as leg syndrome restless, dyskinesias such as those caused by use prolonged dopaminergic or neuroleptic medications or sleep disorders. 19. A combination product comprising a compound according to any one of claims 1 to 9 and other compound selected from (a) L-DOPA, (b) dopamine antagonists, (c) dopamine inhibitors decarboxylase, (d) inhibitors of catechol-O-methyltransferase and (e) monoamine oxidase inhibitors for simultaneous use, separate or sequential.