MX2008005110A - Pyrazoles useful in the treatment of inflammation - Google Patents

Abstract

There is provided compounds of formula (I), wherein R1, R2, X1, X2and n have meanings given in the description, and pharmaceutically-acceptable salts thereof, which compounds are useful in the treatment of diseases in which inhibition of the activity of a lipoxygenase (e.g. 15-lipoxygenase) is desired and/or required, and particularly in the treatment of inflammation.

Description

HELPFUL HELMETS IN THE TREATMENT OF INFLAMMATION FIELD OF THE INVENTION This invention relates to compounds for use as pharmaceutical agents; some of these compounds are novel and others are known. The invention also relates to the use of said compounds in the inhibition of the activity of lipoxygenases, such as 15-lipoxygenase, and therefore in the treatment of inflammatory diseases and inflammation in general. The invention also relates to novel compounds that are useful in such inhibition, to pharmaceutical compositions containing said compounds, and to synthetic routes for their production.

BACKGROUND OF THE INVENTION There are many diseases / disorders of an inflammatory nature. One of the main problems associated with existing treatments of inflammatory conditions is a lack of efficacy or the predominance of side effects (real or perceived). Asthma is a chronic inflammatory disease that affects 6-8% of the adult population of the industrialized world. In children, the incidence is even higher, being close to 10% in most countries. Asthma is the most common cause of hospitalization of children under fifteen years of age. Asthma treatment regimens are based on the severity of the condition. Mild cases are not treated or are treated only with inhaled ß-agonists. Patients with more severe asthma are usually treated with anti-inflammatory compounds on a regular basis. There is a remarkable suboptimal treatment of asthma, which is due in part to the perceived risks of existing maintenance therapy (mainly inhaled corticosteroids). These include the risks of growth retardation in children and loss of bone mineral density, which result in unnecessary morbidity and mortality. As an alternative to steroids, leukotriene receptor antagonists (LTRas) have been developed. These drugs can be administered orally but are considerably less effective than inhaled steroids, and usually do not satisfactorily control inflammation of the airways. This combination of factors has resulted in at least 50% of all asthma patients being treated inadequately. There is a similar pattern of suboptimal treatment in allergic disorders, where drugs are available to treat several common conditions but are underutilized in view of apparent side effects. Rhinitis, conjunctivitis and dermatitis may have an allergic component, but may also arise in the absence of underlying allergy. In fact, in many cases non-allergic conditions of this kind are more difficult to treat. Chronic obstructive pulmonary disease (COPD) is a common disease that affects 6% to 8% of the world population. The disease is potentially lethal and the morbidity and mortality of the condition are considerable. At present there is no known pharmacological treatment capable of changing the course of COPD. Other inflammatory disorders that may be mentioned include: (a) Pulmonary fibrosis (less common than COPD, but it is a serious disorder with a very poor prognosis, there is no curative treatment); (b) Inflammatory bowel disease (a group of disorders with a high morbidity rate, currently only a symptomatic treatment of the disorder is available); and (c) Rheumatoid arthritis and osteoarthritis (common disabling inflammatory joint disorders, currently there are no curative treatments and only moderately effective symptomatic treatments are available for the management of such conditions). Inflammation is also a common cause of pain. Inflammatory pain may appear for many reasons, such as infection, surgery, or other trauma. In addition, it is known that several types of malignancy have inflammatory components that are added to the symptomatology of patients. In this way, a new or alternative anti-inflammatory treatment would benefit all the aforementioned patient groups. In particular, there is a real and substantial clinical need, not covered, for an effective anti-inflammatory drug, capable of treating anti-inflammatory disorders such as asthma, without real or perceived side effects. Mammalian lipoxygenases are a family of structurally related enzymes that catalyze the oxygenation, among others, of arachidonic acid. Three types of human oxygenases are known to catalyze the insertion of molecular oxygen into arachidonic acid at carbon positions 5, 12 and 15. Thus, the enzymes are designated 5-, 12-, and 15-lipoxygenase, respectively. It is known that the metabolites of arachidonic acid that are formed after the action of lipoxygenases have a pronounced pathophysiological activity that includes proinflammatory effects. For example, the primary product of the action of 5-lipoxygenase on arachidonic acid is further converted by several enzymes to a variety of physiologically and pathophysiologically important metabolites. The most important of these, the leukotrienes, are potent bronchoconstrictors. Many efforts have been devoted to the development of drugs that inhibit the action of these metabolites, as well as the biological processes that form them. Drugs that have been developed for this purpose include 5-lipoxygenase inhibitors, FLAP inhibitors (5-lipoxygenase activating protein) and, as mentioned above, leukotriene receptor antagonists.

(LTRas). Another class of enzymes that metabolize arachidonic acid are cyclooxygenases. The metabolites of arachidonic acid that are produced by this process include prostaglandins, thromboxanes and prostacyclin, all of which possess physiological or pathophysiological activity.

In particular, prostaglandin PGE2 is a strong proinflammatory mediator, which also induces fever and pain. Consequently, several drugs have been developed to inhibit the formation of PGE2, including "NSAIDs" (non-spheroidal anti-inflammatory drugs) and "coxibs" (selective inhibitors of cyclo-oxygenase 2). These classes of compounds act predominantly by means of inhibition of one or more cyclooxygenases. Thus, in general, agents that are capable of blocking the formation of arachidonic acid metabolites are probably of benefit in the treatment of inflammation.

Prior Art Some pyrazole compounds that are structurally related to those described herein are commercially available. However, according to the applicant, these compounds have never been disclosed in any printed publication and therefore do not have the perceived usefulness attributed to them. JP 2-129171 describes various agrochemicals based on N-unsubstituted 5-trifluoromethylpyrazole. The use of these compounds as pharmaceutical agents is neither mentioned nor suggested. Pyrazole-based compounds have been disclosed in several publications. For example, international patent application WO 01/57024 discloses several pyrazoles which are useful for blocking voltage-dependent sodium channels; International applications WO 03/020217 and WO 01/58869, and U.S. Pat. UU No. 2004/0192667 describe various nitrogen containing heterocycles, including pyrazoles, which are useful as modulators of cannabinoid receptors; International patent application WO 99/20294 describes pyrazoles which are useful in the treatment of cystic fibrosis; International application WO 2005/007625 describes antituberculous compounds including pyrazoles; the US patent UU 2003/0091116 and international patent applications WO 01/19798, WO 99/32454 and WO 2004/055815 describe, among others, pyrazoles which may be useful as factor Xa inhibitors; and WO 01/21160 describes antiviral compounds that include pyrazoles. In none of these documents is there description of 3-amidopyrazoles 1 (N) -no substituted for use in the treatment of inflammation, nor as inhibitors of lipoxygenases. The international patent application WO 97/19062 describes several pyrazoles for the treatment of skin-related diseases and also mentions the use of said compounds in the treatment of various inflammatory diseases. However, this document does not mention or suggest 3-amido-pyrazoles that are substituted at the 4 or 5 position of the pyrazole ring with a halogen or trifluoromethyl group. International patent application WO 2004/096795 discloses several heterocycles including pyrazoles, as inhibitors of protein tyrosine kinases, and international patent application WO 01/55115 discloses several aromatic amides which may be useful as caspase activators and inducers of apoptosis . Accordingly, the compounds described in these documents may be useful, inter alia, in the treatment of cancer. There is no description or suggestion in any of these documents of the use of said compounds as inhibitors of lipoxygenases. The international patent application WO 2005/016877 discloses pyrazoles which may be useful in the inhibition of 11 β-hydroxysteroid dehydrogenase 1 (and therefore useful in the treatment of, among other things, diabetes). There is no specific description in this document of pyrazoles that are substituted in the 3-position with an aromatic amido group. Some pyrazolcarboxylic acid hydrazides, structurally unrelated to the compounds described herein, have been disclosed as anti-inflammatory agents in Tihanyi et al., Eur. J. Med. Chem. -Chim. Ther., 1984, 19, 433, and Goel et al., J. Chem. Inf. Comput. Sci. 1995, 35, 510. Vertuani et al., Journal of Pharmaceutical Sciences, Vol. 74, No. (1985), describe several pyrazoles that have anti-inflammatory and analgesic activity. There is no mention or suggestion of pyrazoles that are substituted in the pyrazole ring itself with a chloro, fluoro or trifluoromethyl group.

The international patent application WO 03/037274 describes several pyrazoles that may be useful in the treatment of inflammatory pain, whose mechanism works by blocking the sodium channels. This document relates mainly to pyrazoles that are 1 (? /) -substituted and also to pyrazoles which are substituted with an amido group in the 4-position. International patent application WO 03/068767 also refers, inter alia, to pyrazole-containing compounds that are useful in the treatment of inflammatory pain by opening the potassium ion channels.

However, this document refers specifically to pyrimidinylamido compounds. The international patent applications WO 2004/080999 and WO 2006/032852 describe various 3-amidopyrazoles for use in the treatment of inflammation. However, there is no description or suggestion in any of these documents of unsubstituted 3-amidopyrazoles? / - for use in such treatment. The international patent application WO 2006/032851 describes several 3-amidopyrazoles for use in the treatment of inflammation, in which the amido group is substituted with a heterocyclic bicyclic group. However, there is no description or suggestion of corresponding 3-amidopyrazoles in which the amido group is substituted with a monocyclic aromatic group.

DETAILED DESCRIPTION OF THE INVENTION According to the invention, a compound of formula I is provided, wherein, R1 and R2 independently represent H, Cl, F, CHF2 or CF3, with the proviso that at least one of R1 and R2 does not represent H; X1 represents halogen, -R3a, -OR3q or -S (0) 2N (R4j) R5j; X2 represents halogen, R3a, -CN, -C (0) R3, -C (0) OR3c, -C (0) N (R4a) R5a, -N (Rb) R5b, -N (R3d) C (0 ) R c, -N (R3e) C (0) N (R4d) R5d, -N (R3f) C (0) OR4e, -N3l -N02, -N (R3g) S (0) 2N (R4f) R5f, -OR3h, -OC (0) N (R4g) R5g, -OS (0) 2R3i, -S (0) mR3j, -S (0) 2N (R4h) R5h, -S (0) 2OH, -N (R3k ) S (0) 2R3m, -OC (0) R3n, -OC (0) OR3p, or -P (0) (OR4i) (OR5i); n represents 0, 1, 2, 3 or 4; m represents 0, 1 or 2; R3a represents, on each occasion in which it is used, C-? -6 alkyl optionally substituted with one or more substituents selected from F, Cl, -N (R4b) R5b, -N3, = 0 and -OR3h; R3b to R3h (in the case of R3h, each time it is used), R3k, R3n, R3q, R4a to R4j (in the case of R b, each time it is used), R5a, R5b (in each occasion on which it is used), R5d and R5f to R5j, independently represent hydrogen or C- | 6 alkyl optionally substituted with one or more substituents selected from F, Cl, -OCH3, -OCH2CH3, OCHF2 and -OCF3; or any of the pairs R4a and R5a, R4b and R5b, R4d and R5d, R4f and R5f, R4g and R5g, R4h and R5h, and R4j and R5 \ may be linked together to form a 3 to 6 member ring, said ring optionally contains an additional heteroatom (such as nitrogen or oxygen) in addition to the nitrogen atom to which these substituents are necessarily bound, and said ring is optionally substituted with = 0, or C 1-6 alkyl, said alkyl group is optionally substituted with one or more atoms of F; R 3, p R 3m and R 3P independently represent C 6 alkyl optionally substituted with one or more substituents selected from F, Cl, -OCH 3, -OCH 2 CH 3, OCHF 2 and -OCF 3) or a pharmaceutically acceptable salt thereof, to be used as a pharmaceutical agent. The compounds of formula I, or their pharmaceutically acceptable salts, may be in isolated form (ie, ex vivo). The pharmaceutically acceptable salts include acid addition salts and base addition salts. Said salts can be formed by conventional means, for example by reaction of a free acid free base form of a compound of formula I, with one or more equivalents of a suitable acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g., vacuum, freeze drying or filtration). The salts can also be prepared by exchanging a counterion of a compound of formula I in the form of a salt, with another counterion, for example using a suitable ion exchange resin. The compounds of formula I may contain double bonds and therefore may exist as geometric isomers E (entgegen) and Z (zusammen) on each individual double bond. All these isomers and their mixtures are included within the scope of the invention. The compounds of formula I may also exhibit tautomerism. All tautomeric forms and their mixtures are included within the scope of the invention. The compounds of formula I may also contain one or more asymmetric carbon atoms and therefore may exhibit optical isomerism or diastereoisomerism. The diastereoisomers can be separated using conventional techniques, for example chromatography or fractional crystallization. The various stereoisomers can be isolated by separation of a racemic mixture or other mixture of the compounds using conventional techniques, for example fractional crystallization or HPLC. Alternatively, the desired optical isomers can be made by reacting suitable optically active starting materials under conditions that do not cause racemization or epimerization (ie, a "chiral reserve" method), by reaction of the appropriate starting material with a "chiral auxiliary. "which can subsequently be removed at a suitable stage, by modification (i.e., a resolution that includes a dynamic resolution), for example with a homochiral acid, followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with a suitable chiral reagent or chiral catalyst, all under conditions known to the person skilled in the art. All stereoisomers and their mixtures are included within the scope of the invention. Unless otherwise specified, a Ci ^ alkyl defined herein (where q is the upper limit of the scale), can be ight chain or, when there is a sufficient number of carbon atoms (i.e. , a minimum of three), can be branched chain, or can be cyclic (thus forming, in the case of alkyl, a cycloalkyl group of C3q). In addition, when there are a sufficient number of carbon atoms (ie, a minimum of four), said groups can also be cyclic / acyclic parts. In addition, unless otherwise specified, said alkyl groups may also be saturated, or when there is a sufficient number of carbon atoms (i.e., a minimum of two), and unless otherwise specified, may be unsaturated (forming for example an alkenyl group of C2-q or an alkynyl group of C2-q).

The term "halogen", when used herein, includes fluorine, chlorine, bromine and iodine. In the compounds of formula I, the person skilled in the art will appreciate that - (X2) n represents one to four optional substituents (since n can represent 0). When n represents 2, 3, or 4, that is, when there are 2, 3 or 4 separate substituents X2, these substituents are in no way interdependent, that is, when n represents 2, the two substituents X2 may represent the same or different groups . For the avoidance of doubt, when a phrase such as "R3b to R3h" is used herein, the skilled person will understand that it means R3b, R3c, R3d, R3e, R3f, R3g and R3h, inclusive. For the avoidance of doubt, in cases where the identity of two or more substituents in a compound of formula I may be the same, the actual identities of the respective substituents are in no way interdependent. For example, when X1 and X2 are both R3a, where R3a is an alkyl group of C6-6, the respective alkyl groups may be the same or different. Similarly, when the groups are substituted with more than one substituent as defined herein, the identities of the individual substituents are not considered interdependent. For example, when X1 represents C- [alpha] -6 alkyl substituted with -OR3h, and X2 represents -OR3h, then the identity of the two -OR3h groups is not considered interdependent. Compounds of the invention that may be mentioned include those in which: X1 represents -OR3q, or preferably halogen or -R3a; or R1 and R2 independently represent H, Cl, F or CF3. Additional compounds of the invention that may be mentioned include those in which: R4b and R5b are not linked together as defined above; when n represents 1, 2, 3 or 4, and at least one of the substituents X2 is located in the ortho position (with respect to the point of attachment of the phenyl ring with the group -N (H) C (0) - of the compound of formula I), then X2 represents halogen, -R3a, -CN, -C (0) R3b, -C (0) OR3c, -C (0) N (R4a) R5a, -N3, -N02, - OR3h, -OC (0) N (R4g) R5g, -OS (0) 2R3i, -S (0) mR3i, -S (0) 2N (R4h) R5h, -S (0) 2OH, -OC (0) R3n, -OC (0) OR3p, or -P (0) (OR4i) (OR5i); when X1 represents an ortho substituent or (when n is 1, 2, 3 or 4) there is a substituent X2 located in an ortho position (with respect to the point of attachment of the phenyl ring with the group -N (H) C (0 ) - of the compound of formula I), then X1 represents, S (0) 2N (R4i) R5j, or preferably halogen, or X2 represents halogen, -CN, -C (0) R3b, -C (0) OR3c, - C (0) N (R4a) R5a, -N (R4b) R5b, -N (R3d) C (0) R c, -N (R3e) C (0) N (R4d) R5d, -N (R3f) C (0) OR4e, -N3, -N02) -N (R3g) S (0) 2N (R4f) R5f, -OC (0) N (R4g) R5g, -OS (0) 2R3i, -S (0) 2N (R4h) R5h, -S (0) 2OH, -N (R3k) S (0) 2R3m, -OC (0) R3n, -OC (0) OR3p or -P (0) (OR4i) (OR5i). Preferred compounds of formula I include those wherein R1 and R2 independently represent H, F or Cl.

Highly preferred compounds of formula I include those in which: n is 2 or 3 (for example 2), or preferably 0 or 1 (for example 1); when any of the pairs R4a and R5a, R4b and R5b, R4d and R5d, R4f and R5f, R49 and R5g, R4h and R5h, and R4j and R5i, are joined together, they form a ring of 5 to 6 members, said ring optionally contains an additional heteroatom (such as nitrogen or oxygen), and is optionally substituted with methyl, CHF2 or CF3 (thus forming for example a pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl ring (for example, 4-methylpiperazinyl)); R3a represents C6-6 alkyl optionally substituted with one or more substituents selected from F and -OR3h. Additional preferred compounds of formula I include those in which: R 1 represents CF 3 or, preferably, H, Cl or F; R2 represents CHF2 or, preferably, H, Cl or CF3; when R1 represents Cl, then R2 represents CHF2, CF3 or, preferably, H or Cl; when R1 represents H, then R2 represents Cl or CF3; when R1 represents F, then R2 represents H; when R1 represents CF3, then R2 represents H or CF3; when R2 represents H, then R1 represents CF3 or, preferably, Cl or F; when R2 represents Cl, then R represents H or Cl; when R2 represents CF3, then R1 represents Cl, CF3 or, preferably, H; when R2 represents CHF2, then R represents Cl; X1 represents -S (0) 2N (R j) R 5j, preferably -OR 3q, preferably F, Cl or R 3a (such as C 1-3 alkyl (for example C 1-2) (for example methyl), substituted optionally with one or more fluorine atoms (thus forming, for example, a group -CHF2 or CF3)); X2 represents F, Cl, Br, -R3a, -CN, -C (0) R3b, -C (0) OR3c, -C (0) N (R4a) R5a, -N (R4b) R5b, -N (R3d ) C (0) R4c, -N (R3e) C (0) N (R4d) R5d, -N (R3,) C (0) OR4e, -N3, -N02, -N (R3g) S (0) 2N (R4f) R5f, -OR3h, -OC (0) N (R4g) R5g, -OS (O) 2R3i, -S (0) mR3j or -S (0) 2N (R4h) R5h; R 3a represents C 1 - alkyl - (for example ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopropylmethyl or, especially, methyl) optionally substituted with one or more F atoms (thus forming, for example, a -CHF 2 group) or CF3); R3b, R3c, R3h, R4a to R4h, R4i, R5a, R5b, R5d, R5f to R5h and R5j independently represent hydrogen or C-γ alkyl (for example methyl), or the relevant pairs (ie, R i and R5i , preferably, R4a and R5a, R4b and R5b, R4d and R5d, R4f and R5f, R4g and R4g and R4h and R5h) may be linked together as defined above; R3d to R3g independently represent C1-2 alkyl (eg, methyl) or, more particularly, hydrogen; R3 'and R3j independently represent C-1.4 alkyl (for example from C-2) (for example methyl) optionally substituted with one or more F atoms (thus forming, for example, a CF3 group); R3q represents a C -? 4 alkyl group (for example from C -? 2) (for example methyl), said alkyl group is unsubstituted or is preferably substituted with one or more fluorine atoms (thus forming, for example , a group -CHF2 or -CF3). Highly preferred compounds of formula I include those in which: X1 represents -OCF3, -OCHF2, -S (0) 2N (H) CH3, -S (0) 2N (CH3) 2, or preferably, F, Cl , CH3 or CF3; X2 represents -CN, -C (0) N (R4a) R5a, -N (R4b) R5b, -N (H) C (0) R4c, -S (0) 2CH3, -S (0) 2CF3, -S (0) 2N (R4h) R5h, or preferably F, Cl, -R3a or -OR3h; R 3a represents isopropyl (said group is preferably unsubstituted) or methyl (said group is optionally substituted as defined above); R3h represents hydrogen or C- alkyl (eg, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopropylmethyl or, preferably, methyl) optionally substituted with one or more fluorine atoms (thus forming, for example, -CHF2 or CF3); R4a, R4b, R4c, R4h, R5a, R5 and R5h independently represent hydrogen, methyl or ethyl, or the relevant pairs (ie, R4a and R5a, R by R5b and R4h and R5h ^ are joined together to form a ring of pyrrolidinyl, piperidinyl, morpholinyl or 4-methylpiperazinyl; R4j and R5j may be linked together as described above (for example to form a pyrrolidinyl, piperidinyl, morpholinyl or 4-methylpiperazinyl ring), or they may independently represent ethyl or, preferably, hydrogen or methyl. Additional preferred compounds of formula I include those in which X1 is selected from -OCF3, -OCHF2, -S (0) 2N (H) CH3, -S (0) 2N (CH3) 2, preferably F, Cl and CF3 , and (X2) n is not present (i.e., n represents 0) or, preferably, represents a single substituent selected from isopropyl or, more particularly, F, Cl, CF3, methyl and methoxy. More preferred compounds of formula I include those in which: X1 is in the 2-position or, preferably 3 or, particularly in the 4-position, with respect to the point of attachment of the phenyl ring with the remainder of the compound of formula I , or preferably represents -OCF3, -OCHF2, -S (0) 2N (H) CH3, -S (0) 2N (CH3) 2 or, preferably, F or Cl; X2 is absent or, particularly, represents isopropyl or preferably F or Cl, or is in the 4-position, preferably in the 2-position. Particularly preferred compounds of the formula I include the compounds of the examples described below. The compounds of formula I can be prepared according to techniques that are well known to those skilled in the art, for example as described below.

According to a further aspect of the invention, there is provided a method of preparing a compound of formula I, said process comprising: (i) For the compounds of formula I wherein R2 represents CHF2, Cl, F or CF3, the reaction of a corresponding compound of formula I wherein R2 represents hydrogen, with an appropriate base (or mixture of bases), such as potassium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, sodium hydride, potassium tert-butoxide, or an organolithium base such as n-BuLi, s-BuLi, i-BuLi, lithium diisopropylamide or lithium 2,2,6,6-tetramethylpiperidine (said organolithium base optionally is in the presence of an additive (eg, a coordination agent of lithium such as an ether) (for example dimethoxyethane), or an amine (for example tetramethylethylenediamine (TMEDA), (-) sparteine or 1,3-dimethyl-3 A5,6-tetrahydro-2 (1H) -pyrimidinone (DMPU) , etc.), followed by inactivation with a suitable electrophile such as: (a) for the compounds of formula I wherein R2 represents CHF2 or CF, a compound formula II, RcLia " where Rc represents CHF2 or CF3, Lla represents a group suitable leaving, such as a halogen group (for example iodine or bromine) or sulfonate (such as -OS02CF3, OS02CH3 and -OS02-aryl (for example -O-tosyl)). When the compound of formula II is a trifluoromethylating agent, it may be a dibenzothiophenyl tetrafluoroborate (for example 5- (trifluoromethyl) -dibenzothiophene tetrafluoroborate); (b) for compounds of formula I wherein R2 represents Cl or F, an electrophile that provides a source of these atoms. For example, for chlorine atoms the reactants include? / - chlorosuccinimide, chlorine, iodine monochloride and hexachloroethane, and for fluorine atoms the reactants include xenon difluoride, SELECTFLUOR® ([1- (chloromethyl) bis- (tetrafluoroborate)] -4-fluoro-1, 4-diazoniobicyclo [2.2.2] octane]), CF3OF, perchloro fluoride, F2 and acetyl hypofluoride. The person skilled in the art will appreciate that the corresponding compounds of formula I wherein R 2 represents hydrogen (on which the above reaction is carried out), may require protection at the nitrogen atom of the pyrazole ring system, preferably with a protecting group which also be a metalation targeting group (such as a benzenesulfonyl group or an SEM group (ie, a -CH2OC2H4Si (CH3) 3) The reaction can be carried out in the presence of a suitable solvent, such as a polar aprotic solvent ( for example, tetrahydrofuran or diethyl ether) at temperatures lower than room temperature (for example, from 0 ° C to -78 ° C), under an inert atmosphere, followed (as appropriate) by deprotection by removing the low protective? / - group. standard conditions (for example, when a benzenesulfonyl group is used, by hydrolysis, or when an SEM group is used, by reaction in the presence of HCl in EtOH). Formula I wherein R2 represents CF3, the reaction of a compound corresponding to a compound of formula I, but in which R2 represents bromine, or preferably iodine, with CuCF3 (or a source of CuCF3), for example in the presence of HMPA and DMF. The person skilled in the art will appreciate that the CuCF3 reagent may not be isolated as such, and may be prepared according to the procedures described by Burton D.G .; Wiemers D. M .; J. Am. Chem. Soc, 1985, 107, 5014-5015; and Mawson S.D .; HT Weavers; Tetrahedron Letters, 1993, Vol. 34, No. 19, 3139-3140 (for example by reaction of zinc and for example CF2Br2 in DMF, thus forming ZnCF3 (or a source thereof), followed by treatment with CuBr in HMPA) . (iii) The reaction of a compound of formula III, or a protected or O-protected derivative thereof (for example ester), wherein R1 and R2 are as defined above, with a compound of formula IV, wherein X1, X2 and n are as defined above, under coupling conditions, for example near room temperature or above it (for example up to 40-180 ° C)Optionally in the presence of a suitable base (for example sodium hydride, sodium bicarbonate, potassium carbonate, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] - 7-undequeno, sodium hydroxide / - ethyldiisopropylamine, / - (methylpolystyrene) -4- (methylamino) pyridine, butyllithium (e.g. n-, s- or t-butyllithium) or mixtures thereof), a suitable solvent (e.g. tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, dimethylsulfoxide, water or triethylamine) and a suitable coupling agent (eg 1, 1 '-carbonyldiimidazole,? /, / - dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (or hydrochloride thereof), carbonate /, / '-? disuccinimidyl benzotriazol-1 -iloxitris (dimethylamino) phosphonium , 2- (1 H-benzotriazol-1-yl) -1, 1, 3,3-tetr hexafluorophosphate ametiluronio, benzotriazol-1 -iloxitrispirrolidinofosfonio hexafluorophosphate tris-pyrrolidino-bromo, tetrafluo born rbo rock 2- (1 / - benzotriazole-1-yl) -1, 1, 3,3-tetramethyluronium hexafluorophosphate, 1-dicyclohexylcarbodiimide -3-propiloximetilpoliestireno hexafluorophosphate, 0- (7-azabenzotriazole-1-yl) - /, /, / ', /?' -? tetramethyluronium tetrafluoroborate or 0-benzotriazol-1-¡l -? /, ? /,? / ',? /' - tetramethyluronium). Alternatively, the compounds of formula III can be activated first by treatment with a suitable reagent (for example oxalyl chloride, thionyl chloride, etc.), optionally in the presence of a suitable solvent (for example dichloromethane, THF, toluene or benzene), and a suitable catalyst (e.g., DMF), resulting in the formation of the respective acyl chloride. Then, this activated intermediate can be reacted with a compound of formula IV under normal conditions, such as those described above. The person skilled in the art will appreciate that when the compounds of formula IV are of a liquid nature, they can serve as a solvent and as a reagent in this reaction. Alternative methods for carrying out this step include the reaction of an O-protected derivative of a compound of formula III (for example, an ethyl ester) with a compound of formula IV, the latter compound can be treated first with a suitable reagent (by trimethylaluminum example), for example in an inert atmosphere and in the presence of a suitable solvent (for example dichloromethane). (iv) The reaction of a compound of formula V,, wherein R1 and R2 are as defined above, with a suitable base, such as described in step (i) of the above process, followed by reaction with a compound of formula VI, wherein X1, X2 and n are as defined above, followed by inactivation with a suitable proton source (e.g., water or saturated aqueous solution of NH4CI). This reaction can be carried out under conditions similar to those described above with respect to step (i) of the process. Therefore, one skilled in the art will appreciate that it may be necessary to protect the pyrazole nitrogen. (v) For the compounds of formula I wherein R2 represents hydrogen and R1 is as defined above, the removal of the group J from a compound of formula VII, wherein J represents -Si (Rl) 3 or -Sn (Rz) 3 (wherein each R1 independently represents an alkyl group of C1.6 (for example methyl or isopropyl) or an aryl group (for example phenyl), and each Rz independently represents C1-6 alkyl (for example methyl or butyl)), and R1, X1, X2 and n are as defined above. When J represents -Si (Rl) 3, the reaction can be carried out in the presence of a reagent suitable for the removal of the silyl group, such as a source of halide anions (for example tetrabutylammonium fluoride, tetramethylammonium fluoride, hydrogen fluoride or potassium fluoride), for example in the presence of a suitable solvent (for example tetrahydrofuran), at room temperature. When J represents Sn (Rz) 3, the reaction can be a standard hydrolysis, for example the reaction with water or an aqueous acid (for example hydrochloric acid) in. presence of a suitable solvent (for example dioxane, tetrahydrofuran, MeOH or EtOH (or mixtures thereof)). (vi) The reaction of a compound of formula VIII, wherein R1 and R2 are as defined above, with a compound of formula IV as defined above, for example under coupling conditions as described above for step (iii) of the above process. Preferred conditions include reaction in the presence of a base, solvent but without coupling reagent. In this case, the compound of formula IV can also be used in excess. (vii) For compounds of formula I wherein one of R1 or R2 represents CHF2, CF3, Cl or F, and the other represents H, the reaction of a compound corresponding to a compound of formula I but in which one of R1 or R2 represents bromine or iodine and the other represents H (as appropriate), with a suitable organolithium base (for example γ-BuLi, s-BuLi or n-BuLi), optionally in the presence of an additive (such as described above for step (i) of the process), followed by inactivation with a compound of formula II as defined above, or a source of chlorine or fluorine atoms, as described for process (i) above.

This reaction can be carried out in the presence of a suitable solvent as described above for step (i) of the process, at a low temperature (for example -78 ° C to -120 ° C), under an inert atmosphere, (viii ) The reaction of a compound of the formula VINA, or a derivative? / - protected therefrom (for example in the pyrazole ring), wherein R1 and R2 are as defined above, with a compound of formula VIIIB, VIIIB wherein L1 represents a suitable leaving group, such as halogen (eg chlorine, bromine and iodine), -OS02CF3, -B (OH) 2, -Sn (Rz) 3 (wherein Rz is as defined above), - Pb (OC (0) CH3) 3, -Bi (W) 2, -Bi (W) 2 (OC (0) CH3) 2, -Bi (W) 2 (OC (0) CF3) 2 or -l ( W) (BF4), and W represents an aryl or heteroaryl group, both optionally substituted with one or more groups selected from X2 as defined above (e.g., W represents the phenyl ring of the compound of formula I as defined above ) and X1, X2 and n are as defined above, for example in the presence of a catalyst preferably containing Pd or Cu, and a base such as potassium or sodium hydroxide, potassium carbonate, potassium tert-butoxide and? /? / lithium diisopropylamide. Catalysts that may be mentioned include Pd2 (dba) 3 (tris (dibenzylideneacetone) dipalladium (0)); the bases that may be mentioned include cesium carbonate; ligands that may be mentioned include 2,2'-bis (diphenylphosphino) -1, 1'-binaphthyl; and solvents that can be used include toluene. Said reactions can be used at elevated temperature (for example at about 90 ° C) under an inert atmosphere (for example, argon). The compounds of formula III (or their derivatives) wherein R 2 represents H or CF 3, can be prepared by reaction of a compound of formula IX, or an equivalent enol ether (e.g., a methyl enol ether or an enol ether of silyl (e.g., trimethylsilyl)), or an O-protected derivative (e.g., in the carboxylic acid) thereof, wherein Rd represents H or CF3 and R1 is as defined above, with hydrazine (or a hydrate or derivative thereof (eg, benzylhydrazine)), for example in the presence of an alcoholic solvent (eg, EtOH) at elevated temperature (eg, a Reflux). Compounds of formula III wherein one of R1 or R2 represents Cl or F, and the other represents CHF2, H or CF3, or both R1 and R2 represent Cl or F, can be prepared by the reaction of a corresponding compound of formula III wherein both R1 and R2 represent H, or one of R1 or R2 represents H and the other represents, CHF2 or CF3, with an electrophile that provides a source of chlorine or fluorine atoms as described above in the preparation of the compounds of formula I (step (i) (b) of the above process), under the known reaction conditions, for example in the presence of a suitable solvent (for example, water). In this way pyrazoles substituted with 4-halogen, 5-halogen or 4,5-dihalogen relevant can be prepared. Compounds of formula III wherein one of R1 or R2 represents fluorine and the other represents H, can be prepared from 4-nitropyrazole-3-carboxylic acid or 5-nitropyrazole-3-carboxylic acid (as appropriate), using a suitable reagent for the conversion of the nitro group to a fluorine group (such as sodium fluoride, potassium fluoride, tetramethylammonium fluoride or tetrabutylammonium fluoride), under conditions known to those skilled in the art. The compounds of formula III wherein one of R1 or R2 represents Cl or F and the other represents H, can be prepared by reaction of a compound corresponding to a compound of formula III but in which one of R1 or R2 represents amino and the other represents H (as appropriate, ie 4- or 5-aminopyrazole-3-carboxylic acid), followed by conversion of the amino group to a diazonium salt (using reagents and known conditions, for example NaN02 and HCl at 5%). ° C), and then the addition of a suitable nucleophile for conversion to a Cl or F. Suitable nucleophiles include chlorides or fluorides of potassium, sodium or copper. Alternatively, for the introduction of the fluorine group, the suitable diazonium salt can be treated with a compound that provides a source of fluoroborate salts (for example tetrafluoroborate), for example by introducing a cold aqueous solution of NaBF4, HBF or NH4BF4, thus forming suitable diazonium fluoroborate (for example, diazonium tetrafluoroborate), which can then be heated. The compounds of formula III wherein R 1 represents CHF 2, F, Cl or CF 3 can be prepared from the corresponding compounds of formula III wherein R 1 represents H, for example according to a procedure described by R. Storer et al., Nucleosides & Nucleotides 18, 203 (1999). Suitable reagents that can be used for the introduction of the CHF2, F, Cl or CF3 group are as described above for the preparation of the compounds of formula I (step (i) of the above process). Alternatively, the compounds of formula III can be prepared by oxidation of a compound of formula X, wherein R1 and R2 are as defined above, under known oxidation conditions, for example mild or strong oxidation conditions (for example using an aqueous solution of potassium permanganate and heating under reflux), as appropriate. The compounds of formula III wherein R 2 is as defined above (e.g., H, Cl or F) can be prepared by reaction of a compound of formula XI, or a protected or O-protected derivative thereof (eg, ester), wherein J and R1 are as defined above. For compounds of formula III wherein R2 represents Cl or F, the reaction may be with a suitable halogenation reagent (i.e., of chlorination or fluorination), such as cesium fluoroxysulfate, or one described above for step (i) (b) of the process, optionally in the presence of a suitable solvent (e.g., hexane, diethyl ether, tetrahydrofuran, or , 4-dioxane, or mixtures thereof), under known conditions. For the compounds of formula III wherein R2 represents H, the reaction may be with reagents and under conditions as described above for the preparation of the compounds of formula I (step (v) of the process). The compounds of formula III wherein R1 and R2 are as defined above can be prepared by oxidation of a compound of formula XIA, wherein R1 and R2 are as defined above, under oxidation conditions known to those skilled in the art, such as those described above with respect to the preparation of the above compounds of formula III (ie, from a compound of formula X). The compounds of formula III (or protected derivatives thereof) wherein R 2 represents H, and R 1 is as defined above (and preferably represents Cl or F), can be prepared by reaction of a compound of formula XIB, or a protected derivative thereof (for example an ester, such as a C 1-6 ester (for example ethyl)), wherein R 1 is as defined above (and preferably represents Cl or F), with diazomethane or a derivative protected therefrom (for example, trimethylsilyldiazomethane), for example under known conditions (for example in the presence of a suitable solvent (for example, diethyl ether) or at low temperatures (for example, from 0 ° C to room temperature)). The compounds of formula III or X can be prepared by reaction of a corresponding compound of formula V with a suitable base, such as that described with respect to the preparation of the compounds of formula I, step (i) of the process (and in particular organolithiums), followed by reaction with a suitable electrophile. For example, in the case of the compounds of formula III, for the introduction of a carboxylic acid group (or a protected derivative thereof), the electrophile may be a source of C02 (eg, CO2 gaseous), said addition going followed by the addition of a suitable proton source (e.g., HCl), or a compound of formula XV as defined below (e.g., methyl or ethyl chloroformate) or, in the case of compounds of formula X, a compound of formula XVI as defined below (e.g. methyl iodide), or the like. Compounds of formula VI wherein X 1 represents -S 2 N (R 4i) R 5i and X 2, n, R 4j and R 5j are as defined above, can be prepared by reaction of a compound of formula XIC, wherein X2 and n are as defined above, with a compound of formula XID, H2N (R4j) R5j XID wherein R4 'and R5i are as defined above, eg under known conditions (eg in the presence of a suitable base (cf. for example triethylamine), and a suitable solvent (for example dichloromethane)), followed by hydrogenation of the isolated nitro intermediate, for example under known conditions (for example, in the presence of a suitable catalyst (for example Pd on carbon (10%)) , and a suitable solvent (for example MeOH)). The compounds of formula V can be prepared from a compound of formula XIE, or a derivative? / - protected therefrom, wherein J and R are as defined above, using the known reagents and methods, for example as described above for the preparation of the compounds of formula I (route (v) of the process ), or for the preparation of the compounds of formula III (the process including the reaction with a compound of formula XI). The compounds of formula VII can be prepared by reacting a compound of formula IV as defined above, with: (I) a compound of formula XII, wherein R and J are as defined above; or (II) a compound of formula XI as defined above (or a / V-protected or O-protected derivative thereof (eg, ester)), for example under coupling conditions similar to those described above for the Preparation of the compounds of formula I (step (iii) or (vi) of the above process). The compounds of formulas VIII and X can be prepared from the compounds of formula III, and the compounds of formula XI, respectively, under dimerization conditions, for example in the presence of thionyl chloride or oxalyl chloride (optionally in the presence of a suitable solvent and catalyst, such as that defined above for step (iii) of the process). Another dimerization reagent includes carbodiimides such as 1, 3-dicyclohexylcarbodumide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI, or hydrochloride thereof), optionally in the presence of a suitable base (for example 4-dimethylaminopyridine). Compounds of formula X wherein R 2 represents CHF 2, Cl, F or CF 3 can be prepared from a corresponding compound of formula X (or a protected derivative thereof) wherein R 2 represents H, for example under the conditions and reagents described previously in the preparation of the compounds of formula I (step (i) of the above process). Alternatively, compounds of formula X can be prepared by means of A / -alkylation of a compound of formula XMA, wherein T represents optionally substituted C-? 6 alkyl (eg, methyl), and R and R 2 are as defined above, under known dealkylation conditions, for example by reaction with a suitable reagent (e.g. pyridine), at high temperature (for example 150 ° C to 22 ° C). Said reaction can be carried out in the presence of a suitable solvent, but preferably there is no additional solvent. Alternatively, compounds of formula X can be prepared from a compound of formula XIIB, or a derivative? / - protected therefrom, wherein J and R1 are as defined above, using the known reagents and methods, for example those described above for the preparation of the compounds of formula I (route (v) process), or for the preparation of the compounds of formula III (the process including the reaction with a compound of formula XI). Compounds of formula XI (or a protected or protected O-derivative thereof (eg, ester)) wherein R1 is as defined above and preferably represents H or CF3, can be prepared by reaction of a compound of formula XIII, XIII wherein Re represents R1 as defined above, preferably H or CF3, and J is as defined above, with a compound of formula XIV, N2-C (H) -C (0) OH XIV or an O-protected derivative of the same (for example ester), for example at elevated temperature (for example between 80 ° C and 120 ° C), for between 1 and 3 days, optionally in the presence of an inert gas and preferably without the presence of solvent. Compounds of formula XI (or a protected / O-protected or O-protected derivative thereof (e.g. ester)) wherein R1 and J are as defined above, can be prepared by oxidation of a compound of formula XIIB as defined above, under known oxidation conditions, for example as those described above for the preparation of the compounds of formula III (the process including the reaction with a compound of formula X). Alternatively, the compounds of formula XII and XIIB (or when a protected or protected O-derivative thereof (e.g., ester)) is applicable wherein R1 and J are as defined above, may be prepared by reaction of a compound of formula XIE, as defined above, with a suitable base (or mixture of bases) such as those listed in process (i) above, followed by inactivation with a suitable electrophile, such as: (a) For the compounds of formula XI, a source of CO2 (for example, CO 2 gas, said addition is followed by the addition of a suitable proton source (for example HCl)), or a compound of formula XV, RfC (0) OL1c XV wherein R f represents C 1-6 alkyl and Ll c represents a suitable leaving group such as halogen (e.g., iodine, bromine, or chlorine); or (b) For compounds of formula XIIB, a compound of formula XVI, CH3L1d XVI or the like (ie, another suitable methylation reagent), wherein L1d represents a suitable leaving group such as halogen (e.g., iodine or bromine) or a sulfonate group (such as -OS02CF3, OS02CH3 and -OS02-aryl (for example -O-tosyl)). Compounds of formula XIA can be prepared by reaction of 1-aminopyridinium iodide with a compound of formula XVII, (R1) (CI) C = C (CI) (R2) XVII wherein R1 and R2 are as defined above, and the geometry of the double bond can be cis or trans, for example under known conditions (for example in the presence of a suitable base (for example potassium carbonate) and a suitable solvent (for example THF)). The person skilled in the art will appreciate that the geometry around the double bond can make the reaction regioselective. The compounds of formula XIE can be prepared by reaction of a compound of formula XVIII, J - 1 XVIII wherein R1 and J are as defined above, with diazomethane, under known conditions, for example according to the procedures described by T. Hanamoto and others, Chem. Commun., 2041 (2005), for example in the presence of a suitable solvent (for example hexane, diethyl ether, tetrahydrofuran or 1,4-dioxane, or mixtures thereof), and optionally in the presence of an inert gas. . The compounds of the formulas II, IV, V, VI, VIIIA, VIIIB, IX, XIB, XIC, XID, XIIA, XIII, XIV, XV, XVI, XVII and XVIII are commercially available, or are known in the literature, or they can be obtained by means of procedures analogous to the processes described herein, or by means of conventional synthetic procedures according to the normal techniques, from available starting materials, using the appropriate reagents and reaction conditions. In this regard, the person skilled in the art can consult, among others, "Comprehensive Organic Synthesis" by BM Trost and I. Fleming, Pergamon Press, 1991. Substituents X1 and X2 (if present) as defined above, can be modifying one or more times, before or during the processes described above for the preparation of the compounds of formula I, by methods that are well known in the art. Examples of such methods include substitutions, reductions, oxidations, alkylations, acylations, hydrolysis, esterifications and etherifications. The precursor groups can be changed to a different group, or to the groups defined in formula I, at any time during the reaction sequence. When R1 or R2 represent a Cl or F group, said groups may be interconverted (or converted from another halogen group) one or more times, after or during the above described procedures for the preparation of the compounds of formula I. Suitable reagents include NiCI2 (for conversion to a chlorine group). The person skilled in the art can also consult "Comprehensive Organic Functional Group Transformations" by AR Katritzky, O. Meth-Cohn and CW Rees, Pergamon Press, 1995. Other transformations that may be mentioned include the conversion of a halogen group (preferably iodine or bromine) to a cyano or 1-alkynyl group (for example by reaction with a compound that is a source of cyano anions (for example sodium, potassium, copper (I) or zinc cyanide), or with 1 -alkino, depending on appropriate). This latter reaction can be carried out in the presence of a suitable coupling catalyst (for example a catalyst based on palladium or copper) and a suitable base (for example a tri (C1-6 alkyl)) amine, such as triethylamine, tributylamine or ethyldiisopropylamine). In addition, amino groups and hydroxy groups can be introduced according to the normal conditions using the known reagents. The compounds of the invention can be isolated from their reaction mixtures using conventional techniques. Those skilled in the art will appreciate that in the methods described above and those shown below, it may be necessary to protect the functional groups of the intermediates with protecting groups. For example, it may be necessary to protect the pyrazole nitrogen. Suitable nitrogen protecting groups include those that form: (i) carbamate groups (i.e., alkoxy- or aryloxy-carbonyl groups); (ii) amide groups (eg, acetyl groups); (iii) A / -alkyl groups (e.g., benzyl or SEM groups); (iv)? / - sulfonyl groups (e.g.,? / - arylsulfonyl groups); (v) groups? / - phosphinyl and? / - phosphoryl (for example, diarylphosphinyl and diarylphosphoryl groups); or (vi) a? / silyl group (for example, a? / -trimethylsilyl group).

In addition, those skilled in the art will appreciate that when there are two protected functional groups (for example, when the carboxylic acid group of the compound of formula III is an ester and the pyrazole nitrogen is protected with a benzenesulfonyl group), then the two groups they can be deprotected in one step (for example, a hydrolysis step known to those skilled in the art). Additional protecting groups for the pyrazole nitrogen include a methyl group, said methyl group can be removed under normal conditions, for example using a pyridine hydrochloride salt at elevated temperature, for example using microwave radiation in a sealed container at 200 ° C. . The protection and deprotection with the functional groups can occur before or after a reaction of the aforementioned schemes. The protecting groups can be removed according to techniques that are well known to those skilled in the art, and as described below. For example, the protected compounds / intermediates described herein can be chemically converted to deprotected compounds using the normal deprotection techniques. The type of chemistry involved will dictate the need and type of protective groups, and also the sequence to perform the synthesis. The use of protecting groups is fully described in "Protective Groups in Organic Chemistry", edited by JW F McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis", third edition, T.

W. Greene & P.G.M. Wutz, Wiley-lnterscience (1999). The compounds of formula I and their salts are useful because they possess pharmacological activity. Therefore, said compounds or salts are indicated as pharmaceutical agents. Some compounds of formula I are novel per se. The phenyl group bearing X1 and X2 in the compounds of the formula I that is defined above, can also be presented as follows: wherein the scribbled line cutting the bond represents the point of attachment of the phenyl group with the rest of the compound of formula I, one of X3, X4, X5, X6 and X7 represents X1 as defined above, and the others represent H or X2 as defined above. According to a further aspect of the invention, there is provided a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, with the proviso that: (A) when R 1 represents Cl, R 2 represents H, and: (1) X3, X4, X6 and X7 represent all H, then X5 does not represent Br, I or -C (0) CH3; (2) X3, X5, X6 and X7 represent all H, then X4 does not represent -C (0) CH3; (3) X3, X6 and X7 represent all H, then X4 does not represent Cl when X5 represents methyl or methoxy; (4) X3, X5 and X7 represent all H, then X4 and X6 do not represent both -C (0) OCH3 nor -C (0) 0-isopropyl; (5) X4, X6 and X7 represent all H, then X5 does not represent F when X3 represents methyl; (6) X3, X6 and X7 represent all H, then X5 does not represent F when X4 represents -N02; (7) X4, X5 and X6 represent H, then X7 does not represent isopropyl when X3 represents methyl; (8) X3, X5 and X7 represent H, then X4 and X6 do not represent both methoxy; (9) X4, X5, X6 and X7 represent all H, then X3 does not represent methoxy. (B) when R1 represents H, R2 represents CF3, X4, X6 and X7 represent all H, then X3 does not represent chlorine or CF3 when X5 represents -N02. According to a further aspect of the invention, there is provided a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, with the additional conditions that when R2 represents CF3 and: (I) R1 represents H or Cl , X7 represents H and: (a) X4, X5 and X6 represent all H, then X3 does not represent CF3; (b) X4 and X6 represent both H, then X3 does not represent bromine when X5 represents -N02; (c) X4 and X5 represent both H, then X3 does not represent chlorine when X6 represents CF3; (d) X4 represents H, then X3 does not represent chlorine when X5 represents -N02 and X6 represents chlorine; (II) R1 represents H or Cl, then X3, X4, X5, X6 and X7 do not represent all F; (III) R1 represents Cl and X4, X6 and X7 represent all H, then X3 does not represent chlorine or CF3 when X5 represents -N02; (IV) R1 represents H, X3 represents Cl, then: (i) X4, X5, X6 and X7 do not represent all H; (ii) X4 does not represent Cl when X5 and X6 represent H or Cl and X7 represents H; (iii) X5 does not represent Cl or Br when X4, X6 and X7 represent all H; (V) X7 does not represent Cl when X5 represents H, Cl or -N02 and X4 and X6 represent both H; (v) X5 does not represent Cl when X6 represents Cl and X4 and X7 represent both H; (V) R1 represents H and X3 represents Br, then X5 does not represent -OCF3 when X4, X6 and X7 represent all H; (VI) R represents H and X3 represents F or I, then X5 does not represent -N02 when X4, X6 and X7 represent all H; (VII) R1 represents H and X3 represents -N02, then X5 does not represent Cl or CF3 when X4, X6 and X7 represent all H; (VIII) R1 represents H, X3 represents CF3, then X5 does not represent -N02 when X4 and X6 represent both H and X7 represents Cl; (IX) R1 represents H, X3 represents CF3, then X5 does not represent Cl, when X4, X6 and X7 represent all H. Although the compounds of formula I and their salts may have pharmacological activity as such, some may or may be prepared pharmaceutically acceptable derivatives (for example "protected") of the compounds of the invention, which do not possess said activity but which can be administered parenterally or orally and to be subsequently metabolized in the body to form the compounds of the invention. Therefore, said compounds (which may have some pharmacological activity, provided that said activity is appreciably less than that of the "active" compounds in which they are metabolized), can be described as "prodrugs" of the compounds of formula I. All prodrugs of the compounds of formula I are included within the scope of the invention. The "prodrug of a compound of formula I" includes compounds that form a compound of formula I in an experimentally detectable amount, within a predetermined time after oral or parenteral administration (eg, about one hour). The compounds of formula I and their salts are useful in particular because they can inhibit the activity of lipoxygenases (particularly 15-lipoxygenase), that is, they prevent the action of 15-lipoxygenase or a complex of which the 15-enzyme is part. lipoxygenase, or they can cause a modulating effect of 15-lipoxygenase, for example as shown by the test described below. In this manner, the compounds of the invention can be useful in the treatment of those conditions in which the inhibition of a lipoxygenase, particularly 15-lipoxygenase, is required. In this way, the compounds of formula I are expected to be useful in the treatment of inflammation. It will be understood by those skilled in the art that the term "inflammation" includes any condition characterized by a localized or general protective response that may be caused by physical trauma, infection, chronic diseases such as those mentioned above, or chemical or physiological reactions. to external stimuli (for example as part of an allergic response). Any of these responses, which can serve to destroy, dilute or sequester both the noxious agent and the injured tissue, can be manifested, for example, by heat, swelling, pain, redness, dilation of blood vessels or increased blood flow, leukocyte invasion of the affected area, loss of function or other known symptoms that are associated with inflammatory conditions. It will be understood that the term "inflammation" includes any disease, disorder or inflammatory condition per se, any condition that has an associated inflammatory component., or any condition characterized by symptoms of inflammation that includes, among others, acute, chronic, ulcerative, specific, allergic and necrotic inflammation, and other known forms of inflammation. Thus, the term also includes, for the purposes of the invention, inflammatory pain or fever. Accordingly, the compounds of formula I and their salts may be useful in the treatment of asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, allergic disorders, rhinitis, inflammatory bowel disease, ulcers, inflammatory pain, fever, atherosclerosis, coronary artery disease, vasculitis, pancreatitis, arthritis, osteoarthritis, rheumatoid arthritis, conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis, stroke, diabetes, autoimmune diseases, Alzheimer's disease, multiple sclerosis, sarcoidosis, Hodgkin's disease and other malignancies, and any other disease with an inflammatory component. The compounds of formula I and their salts may also have effects that are not linked with inflammatory mechanisms, such as in the reduction of bone loss in a subject. Conditions that may be mentioned in this regard include osteoporosis, osteoarthritis, Paget's disease or periodontal diseases. Thus, the compounds of formula I and their pharmaceutically acceptable salts can be useful for increasing bone mineral density, as well as for reducing the incidence or healing of fractures in subjects. The compounds of formula I and their salts are indicated for the therapeutic and prophylactic treatment of the aforementioned conditions. According to a further aspect of the present invention, there is provided a method of treating a disease that is associated or that can be modulated by the inhibition of a lipoxygenase (such as 15-lipoxygenase), or a method of treating a disease in which inhibits the activity of a lipoxygenase, and particularly 15-lipoxygenase (for example inflammation), is desired or required, said method comprising administering a therapeutically effective amount of a compound of formula I, as defined above, or a pharmaceutically acceptable salt thereof, to a patient suffering from said condition, or is susceptible to said condition. "Patient" includes mammalian patients (including humans). The term "effective amount" refers to an amount of a compound that confers a therapeutic effect on the treated patient. The effect can be objective (that is, measurable by means of some test or marker) or subjective (that is, the subject gives an indication or feels an effect). The compounds of formula I and their salts are normally administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, by any other parenteral route or by inhalation, in a pharmaceutically acceptable dosage form. The compounds of formula I and their salts can be administered alone but are preferably administered by means of known pharmaceutical formulations, including tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, etc. Said formulations can be prepared according to standard or accepted pharmaceutical practice. According to a further aspect of the invention, a pharmaceutical formulation is provided which includes a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. In addition, the invention provides a process for the preparation of a pharmaceutical formulation as defined above, said method comprising contacting a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable adjuvant, diluent or carrier. The compounds of formula I and their salts can also be combined with other therapeutic agents that are useful in the treatment of inflammation as defined herein (eg, NSAIDs, coxibs, corticosteroids, analgesics, 5-lipoxygenase inhibitors, FLAP inhibitors. (5-lipoxygenase activating protein), and leukotriene receptor antagonists (LTRas), or therapeutic agents that are useful in the treatment of inflammation). According to a further aspect of the invention, there is provided a combination product comprising: (A) A compound of formula I as defined above, or a pharmaceutically acceptable salt thereof; and (B) Another therapeutic agent that is useful in the treatment of inflammation, wherein each of the components (A) and (B) is formulated in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. Said combination products serve for the administration of the compound of the invention in conjunction with the other therapeutic agent, and can therefore be presented as separate formulations, wherein at least one of the formulations comprises the compound of formula I or a salt thereof, and at least one comprises the other therapeutic agent; or they can be presented (ie, formulated) as a combined preparation (i.e., presented as a single formulation that includes the compound of the invention and the other therapeutic agent). Thus, there is also provided: (1) a pharmaceutical formulation that includes a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, another therapeutic agent that is useful in the treatment of inflammation, and an adjuvant , diluent or pharmaceutically acceptable vehicle; and (2) a kit of parts comprising the components: (a) a pharmaceutical formulation that includes a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; and (b) a pharmaceutical formulation that includes another therapeutic agent that is useful in the treatment of inflammation, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, said components (a) and (b) are each provided in a suitable form for its administration as a whole. In addition, the invention provides a method for preparing a combination product as defined above, said method comprising associating a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, with the other therapeutic agent that is useful in the treatment of inflammation, and at least one adjuvant, diluent or pharmaceutically acceptable carrier, by "associating" it is understood that the two components are made suitable for administration one in conjunction with the other. Thus, for the method of preparing a team of parts as defined above, "associating" the two components includes that the two components of the team of parts: (i) can be provided as separate formulations (ie, independently a of another), which subsequently are brought together to be used in conjunction with one another in combination therapy, or (ii) can be packaged and presented together as separate components of a "combination package" to be used in conjunction with the another in combination therapy. The compounds of formula I and their pharmaceutically acceptable salts can be administered at varying doses. Oral, pulmonary and topical doses may vary from about 0.01 mg / kg of body weight per day (mg / kg / day) to about 100 mg / kg / day, preferably about 0.01 mg / kg / day to about 10 mg / kg / day, preferably about 0.01 mg / kg / day to about 5.0 mg / kg / day. For example, for oral administration, the compositions typically contain between about 0.01 mg and about 500 mg, preferably between 1 mg and about 100 mg of the active ingredient. Preferred intravenous doses will vary from about 0.001 mg / kg / hour to about 10 mg / kg / hour during an infusion at constant speed. Advantageously, the compounds can be administered in a single daily dose, or the total daily dose can be administered in divided doses of two, three or four times a day. In any case, the physician or the skilled professional will be able to determine the actual dose that is most suitable for an individual patient, which will probably vary with the route of administration, the type and severity of the condition treated, as well as with the species, age, weight, sex, renal function, liver function and response of the particular patient treated. The doses mentioned above are examples of the average case; of course, there may be individual cases that merit higher or lower dose scales, and these are within the scope of this invention. The compounds of formula I may have the advantage that they are effective or selective inhibitors of lipoxygenases, and particularly 15-lipoxygenase. The compounds of formula I may also have the advantage that they may be more effective, less toxic, longer-acting, more potent, produce fewer side effects, be more easily absorbed, or have an improved pharmacokinetic profile (eg, greater oral bioavailability). or lesser elimination) than the compounds known from the prior art; or they may have other useful pharmacological, physical or chemical properties over the known compounds of the prior art, for use under the indicated conditions or in others.

Biological Testing The test used exploits the ability of lipoxygenases to oxidize polyunsaturated fatty acids containing a 1,4-cis-pentadiene configuration to their corresponding hydroperoxy or hydroxyl derivatives. In this particular test, lipoxygenase was a purified 15-lipoxygenase and the fatty acid was arachidonic acid. The test is carried out at room temperature (20-22 ° C) and the following is added to each well of a 96-well microtiter plate: a) 35 μL of phosphate buffer saline (PBS) (pH 7.4); b) inhibitor (ie, compound) or vehicle (0.5 μl DMSO); c) 10 μL of a 10x concentrated solution of 15-lipoxygenase in PBS; the plates are incubated 5 minutes at room temperature; d) 5 μL 0.125 mM arachidonic acid in PBS; then the plate is incubated for 10 minutes at room temperature; e) the enzymatic reaction is terminated with the addition of 100 μL of MeOH; and f) the amount of 15-hydroperoxy-eicosatetraenoic acid, or 15-hydroxy-eicosatetraenoic acid is measured by reverse phase HPLC. The invention is illustrated by means of the following examples, in which the following abbreviations are used: ac. aqueous BuLi n-butyl lithium DMAP 4-dimethylaminopyridine DMF dimethylformamide DIPEA diisopropylethylamine EtOAc ethyl acetate EtOH ethanol MeOH methanol MS mass spectrum NMR nuclear magnetic resonance t. to. ambient temperature sat saturated TBTU 0-benzotriazol-1-yl -? /,? /,? / ',? /' -tetramethyluronium tetrafluoroborate THF tetrahydrofuran The starting materials and chemical reagents specified in the syntheses described below are commercially available, example, from Sigma-Aldrich Fine Chemicals. Unless indicated otherwise, one or more tautomeric forms of the compounds of the examples described below can be prepared in situ or isolated. It is considered that all tautomeric forms of the compounds of the examples described below are disclosed.

Synthesis of intermediaries: 1-Benzenesulfonyl-3-methylpyrazole (I) A mixture of 3-methylpyrazole (5 g, 60.9 mmol), benzenesulfonyl chloride (8.55 mL, 67 mmol) and triethylamine (9.3 mL, 67 mmol) in acetonitrile, was heated to reflux for 2 h, it was allowed to cool and concentrated. EtOAc (300 mL) was added and the solution was filtered and concentrated to give a solid residue that crystallized from EtOAc, to give the title compound as a whitish powder (yield: 7.92 g, 58%). H-NMR (DMSO-de): d 8.35 (d, 1 H), 7.97-7.94 (m, 2H), 7.78 (tt, 1 H), 7.66 (t, 2H), 6.43 (d, 1 H), 2.17 (s, 3H).

-Chloro-1 - (2-chlorobenzenesulfonyl) -3-methylprazole (II) To a solution of 1-benzenesulfonyl-3-methylpyrazole (940 mg, 4.5 mmol, see intermediate (I) above) in THF (50%). mL), at -78 ° C, BuLi (1.6M, 5.9 mL, 9.45 mmol) was added under argon. The mixture was stirred for approximately 30 min before adding hexachloroethane (3.7 g, . 8 mmol). After stirring at -78 ° C for 18 h, NH4Cl was added (ac, sat., 50 mL) and the mixture was allowed to arrive at t. to. Water (50 mL) was added, the layers were separated and the aqueous phase was extracted with EtOAc (2 x 100 mL).

The combined organic phase was dried (Na2SO4) and concentrated. Purification by chromatography (EtOAc 1: 4 / heptane), followed by recrystallization from EtOAc / heptane, gave the title compound as white crystals (yield: 1.1 g, 84%). 1 H-NMR (DMSO-d 6): d 8.17 (dd, 1 H), 7.87-7.67 (m, 4H), 2.15 (s, 3H).

-Chloro-3-methylpyrazole (III) To a solution of 5-chloro-1- (2-chlorobenzenesulfonyl) -3-methylpyrazole (6.9 g, 27 mmol, see intermediate (II) above) in EtOH (50 mL) , sodium ethoxide (2.5M, 16.1 mL, 40.3 mmol) was added. The solution was stirred for 30 min at t. to. and water (100 mL) was added; the mixture was neutralized with HCl (aqueous, 2M) and extracted with EtOAc (3 x 100 mL). The concentration of the combined organic phase produced precipitation before the complete removal of the solvent. The precipitate was separated by filtration and the filtrate was concentrated, to give the title compound as a brown oil which crystallized on standing (yield: 1.0 g, 33%), which was used without further purification. 1 H-NMR (DMSO-de): d 12.66 (br s, 1 H), 6.03 (d, 1 H), 2.20 (s, 3 H).

-Chloro-3-methylpyrazole (III) (alternative synthesis) A mixture of 5-chloro-1,3-dimethylpyrazole (7.00 g, 54 mmol) and pyridine hydrochloride (37.0 g, 320 mmol) was heated to 200 ° C. for 18 h. Hydrochloric acid (aq, 2M, 200 mL) was added after cooling to ~60 ° C, and the mixture was extracted with EtOAc (3x100 mL). The combined organic extract was washed with NaCl (aq, sat., 150 mL), dried (Na2SO4) and concentrated in vacuo to give the product as white crystals (yield 4.03 g, 64%). MS (M + + H) m / z 117. 1 H NMR (DMSO-d 6, 400 MHz) d 12.66 (s, 1 H), 6.02 (s, 1 H), 2.20 (s, 3H).

-Chloropyrazole-3-carboxylic acid (IV) A solution of KMn0 (3.5 g, 22 mmol) in water (120 mL) was added in portions over a period of 5 h at 70 ° C to a solution of 5-chloro-3 -methylpyrazole (1.0 g, 8.8 mmol, see intermediate (III) above) in water (50 mL) and tert-butanol (1 mL). The mixture was stirred at 70 ° C overnight and filtered through Celite®. The colorless filtrate was concentrated and acidified with HCl (aq, 2M). Filtration gave the title compound as a white powder that was used without further purification (yield: 913 mg, 80%). 1 H NMR (DMSO-d 6): d 6.80 (s, 1 H), 4.40 (br s, 1 H). 1-Benzenesulfonylpyrazole (V) A solution of pyrazole (5 g, 73 mmol), benzenesulfonyl chloride (8.5 mL, 67 mmol) and triethylamine (6.8 mL, 67 mmol) in acetonitrile (250 mL) was stirred for 30 min at reflux . The mixture was cooled and filtered. The filtrate was concentrated to a yellow residue which was purified by chromatography (EtOAc 1: 4 / heptane). Recrystallization from EtOAc / heptane gave the title compound as colorless plates (yield: 11.99 g, 86%). 1 H-NMR (DMSO-d 6): d 8.48 (d, 1 H), 7.97 (d, 2 H), 7.90 (d, 1 H), 7.79 (t, 1 H), 7.67 (t, 2 H), 7.61- 7.60 (m, 1 H).

-Chloropyrazole (VI) To a solution of 1-benzenesulfonylpyrazole (750 mg, 3.6 mmol; see intermediate (V) above) in THF (50 mL), at -78 ° C, BuLi (1.6M, 3.4 mL, 5.4 mmol) was added under argon. The mixture was stirred for 45 min before adding hexachloroethane (1.70 g, 7.2 mmol) in one portion. After stirring at -78 ° C for 10 min, the mixture was allowed to warm to 10-15 ° C for 75 min. The mixture was poured into H20 / NH CI (1: 1, ac, sat., 50 mL). The layers were separated and the aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic phase was dried (Na2SO4) and concentrated. The semisolid residue was dissolved in MeOH (30 mL), followed by the addition of sodium methoxide (30% in MeOH, 1.6 mL, 7.2 mmol). It stirred at t. to. for 45 min, NaHCO3 (aq, sat., 1 mL) was added and extracted; Concentration of the extract and purification of the residue by chromatography (EtOAc 1: 1 / heptane) gave the title compound as a white solid (yield: 78 mg, 21%). 1-Benzenesulfonyl-3-chloropyrazole (VID) A solution of 5-chloropyrazole (35 mg, 0.34 mmol, see intermediate (VI) above), benzenesulfonyl chloride (0.044, mL, 0.34 mmol) and triethylamine (0.047 mL, 0.34 mmol ) in acetonitrile (250 mL), was stirred for 4 h at 60 ° C. The mixture was cooled and concentrated, purification by chromatography (EtOAc 1: 4 / heptane) gave the title compound as colorless needles (yield: 42 mg , 51%). 1 H-NMR (DMSO-de): d 8.61 (d, 1 H), 8.01 (d, 2H), 7.84 (t, 1 H), 7.71 (t, 2H), 7.79 (d, 1 H). 4,5-Dichloropyrazole-3-carboxylic acid (VIII) A stirred solution of 5-chloropyrazole-3-carboxylic acid (3.00 g, 20.5 mmol, see intermediate (IV) above) in water (2.0 L), was bubbled slowly with chlorine gas for 3 ha t. to. The solution was stirred for 18 h in an open flask and then concentrated in vacuo. The resulting suspension was extracted with EtOAc (3x100 mL); The combined organic phase was washed with NaCl (aq, sat., 100 mL), dried (Na 2 SO) and concentrated in vacuo to give the product as a white powder (yield 3.20 g, 86%). MS (M'-H) m / z 179. 1 H NMR (DMSO-de, 400 MHz) d 14.44 (s, 1 H), 14.09 (s, 1 H). 4,5-Bis (trifluoromethyl) pyrazole-3-carboxylic acid (IX) (a) 2,3-Bys (trifluoromethyl) pyrazolo [1,5-alpyridine A mixture of 1-aminopyridinium iodide (3.00 g, 13.51 mmol), K2C03 (3.73 g, 27.02 mmol) and 2,3-dichloro-1,1,1,4,4-hexafluoro-but-2-ene (mixture of cis- and trans- isomers, 9.18 g, 39.41 mmol), was stirred in THF (100 mL) at t. to. for 24 h. The mixture was partitioned between EtOAc (100 mL), water (100 mL) and hydrochloric acid (2M, 5 mL).; The phases were separated and the organic phase was washed with NaCl (50 mL), dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in MeOH (25 mL) and filtered through Celite®. The filtrate was concentrated to give the title compound as slightly yellow needles (yield: 2.95 g, 86%). 1 H NMR (CDCl 3> 400 MHz) d 8.45 (ddd, 1 H), 7.75 (dd, 1 H), 7.39 (ddd, 1 H), 7.02 (ddd, 1 H). (b) 4,5-Bis (trifluoromethyl) pyrazole-3-carboxylic acid To a mixture of 2,3-bis (trifluoromethyl) pyrazolo [1,5-a] pyridine (2.49 g, 9.80 mmol), BuOH (30 mL) and water (120 mL), KMn0 (7.74 g, 49.0 mmol) was added in portions. After stirring at t. to. for 24 h, the mixture was filtered through Celite®. The filtrate was washed with CH2Cl2 (2x50 mL), and then the pH was adjusted to 1 with concentrated hydrochloric acid (ac). The mixture was concentrated in vacuo to give a solid which was extracted with acetone (3x20 mL). The combined extract was concentrated and the residue was crystallized from hydrochloric acid (aa, 0.1 M, 2.5 mL). The solid was collected, washed with water (2x0.5 mL) and dried under vacuum, to give the title compound as a white solid (yield: 1.63 g, 67%). 13 C NMR (CD 3 OD, 100 MHz) d 159.2 (s), 141.3 (q), 137.7 (s), 122.4 (q), 121.6 (q), 112.4 (q). 4-Trifluoromethyl-pyrazole-3-carboxylic acid ethyl ester (X) To a stirred solution of ethyl 4,4,4-trifluoro-2-butynate (0.50 g, 3.0 mmol) in diethyl ether (10 mL) was added slowly under argon, at 0 ° C, a solution of trimethylsilyldiazomethane in diethyl ether (2.0 M, 1.8 mL, 3.6 mmol). The mixture was stirred at 0 ° C for 5 min; The ice bath was removed and the solution was stirred at room temperature for 2 h. The mixture was concentrated and the residue was purified by flash column chromatography (EtOAc / heptane) to give the product as a white powder (yield: 465 mg, 75%). 1 H NMR (DMSO-d 6, 400 MHz) d 14.1 (br. S, 1 H), 8.49 (s, 1 H), 4.30 (q, 2 H), 1.28 (t, 3 H). 4-Chloro-5-trifluoromethyl-pyrazole-3-carboxylic acid (XI) To a mixture of 5-trifluoromethyl-4-chloro-3-methylpyrazole (5.0 g, 27.1 mmol), f-BuOH (50 mL) and water (250 mL) ), KMn0 (10.7 g, 67.7 mmol) was added in portions. The mixture was stirred at 75 ° C for 3 days. After cooling to t. a., the precipitate was separated by filtration and the filtrate was concentrated in vacuo. Concentrated hydrochloric acid (aq, 10 mL) was added and the mixture was extracted with EtOAc (5x30 mL). The combined extract was washed with NaCl (aq, sat., 50 mL), dried (Na2SO4) and concentrated in vacuo to give the product as a white solid (yield 4.90 g, 84%). MS (M - H) m / z = 213. 2-Amino -? / - methylbenzenesulfonamide (XII) (a)? / - Methyl-2-nitrobenzenesulfonamide To a mixture of methylamine hydrochloride (810 mg, 12 mmol) and triethylamine (3.34 mL, 24 mmol) in CH2Cl2 (100 mL ), at 0 ° C, 2-nitrobenzenesulfonyl chloride (2.22 g, 10 mmol) was added in portions. The mixture was allowed to warm to t. a., was stirred 1 h and then MeOH (20 mL) was added. The mixture was stirred for an additional 1.5 h at t. to. and then CH2CI2 (50 mL) was added. The mixture was washed with hydrochloric acid (aq, 1 M, 100 mL) and NaCl (aq, sat., 50 mL), dried (Na2SO4) and concentrated in vacuo to give yellow needles. Recrystallization of CH2Cl2 / MeOH gave the subtitle compound as slightly yellow needles (yield 1.41 g, 65%). 1 H NMR (DMSO-d 6, 400 MHz) d 8.00-7.95 (m, 2H), 7.95-7.86 (m, 3H), 2.54 (d, 3H). (b) 2-Amino -? / - methylbenzenesulfonamide? / -methyl-2-nitrobenzenesulfonamide (1.40 g, 6.47 mmol) in MeOH (30 mL) was hydrogenated over Pd in carbon (10%, 300 mg), at room temperature and environmental pressure during 2.5 h. The mixture was filtered through Celite® and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (EtOAc / heptane) to give the title compound (1.10 g, 91%) as a colorless oil. 1 H NMR (DMSO-de, 400 MHz) d 7.46 (dd, 1 H), 7.33 (q, 1 H), 7.26 (ddd, 1 H), 6.81 (dd, 1 H), 6.62 (ddd, 1 H) , 5.90 (s, 2H), 2.36 (d, 3H). 2-Amino-N, N'-dimethylbenzenesulfonamide (XIII) (a)? /,? / - Dimethyl-2-nitrobenzenesulfonamide Prepared by means of a procedure analogous to that described above for? / -methyl-2-nitrobenzenesulfonamide, using dimethylamine hydrochloride (978 mg, 12 mmol) in place of methylamine hydrochloride. Yield: 1.15 g (51%) of white needles. 1 H NMR (DMSO-de, 400 MHz): d 8.00-7.83 (m, 4H), 2.82 (s, 6H). (b) 2-Amino -? /,? / - dimethylbenzenesulfonamide Prepared by a procedure analogous to that described above for 2-amino-? / - methylbenzenesulfonamide, from N, N-dimethyl-2-nitrobenzenesulfonamide (1.15 g, 5.0 mmol) in place of? / - methyl-2-nitrobenzenesulfonamide. Yield: 889 mg (89%) of an almost colorless solid. 1 H NMR (DMSO-de, 400 MHz): d 7.39 (dd, 1 H), 7.31 (ddd, 1 H), 6.87 (dd, 1 H), 6.65 (ddd, 1 H), 6.05 (s, 2H) 2.64 (s, 6H). 5-difluoromethyl-4-chloropyrazole-3-carboxylic acid (XIV) (a) 5-D-Fluoromethylpyrazole-3-carboxylic acid To a mixture of 5-difluoromethyl-3-methylpyrazole (500 mg, 3.78 mmol), f-BuOH (10 mL) and water (100 mL), KMn04 (2.74 g, 9.45 mmol) was added in portions. The mixture was stirred at 75 ° C for 18 h. After cooling to t. a., the precipitate (Mn02) was removed by filtration and the filtrate was concentrated. HCl was added (ac, conc; 2.0 mL) and the mixture was extracted with EtOAc (5x20 mL). The combined extract was washed with NaCl (aq, sat., 25 mL), dried (Na2SO) and concentrated. The material was purified using a reversed phase column (RP-18) and CH3CN / water (1: 2) as eluent (yield: 250 mg, 41%). MS (M-H) m / z = 161. 1 H NMR (DMSO-de, 400 MHz) d 14.27 (s, 1 H), 13.60 (br. S, 1 H), 7.03 (t, 1 H), 6.97 (s, 1 H). (b) 5-Difluoromethyl-4-chloropyrazol-3-carboxylic acid A stirred solution of 5-difluoro-methylpyrazole-3-carboxylic acid (100 mg, 0.62 mmol) in water (100 mL) was bubbled with chlorine gas slowly to a . to. for 3 h. The solution was stirred for 18 h in an open flask and concentrated. The suspension was extracted with EtOAc (3x20 mL), the combined organic phase was washed with NaCl (aq, sat., 25 mL), dried (Na2SO) and concentrated in vacuo, to give the product as a white powder (yield 106 mg, 87%). MS (MH) m / z = 195, 197.

EXAMPLES EXAMPLE 1 4-Chloro- / v- (2-chloro-4-fluorophenyl) pyrazole-3-carboxamide (a) 4-Chloro-3-methylpyrazole hydrochloride A stirred solution of 3-methylpyrazole (50 mmol, 4.10 g) in carbon tetrachloride (50 mL) was saturated with chlorine gas at -78 ° C. The temperature was allowed to rise to t. to. and the mixture was stirred overnight. The suspension was diluted with pentane (50 mL) and stirred 30 min more. The white crystalline solid was separated by filtration, washed with pentane (2x50 mL) and dried, to give the sub-title compound (yield 7.50 g (98%)). MS (M ++ H) m / z = 117. 1 H NMR (DMSO-de, 400 MHz) d 13.38 (s, 2 H), 7.68 (s, 1 H), 2.16 (s, 3H). 13 C NMR (DMSO-de, 100 MHz) d 139.1, 132.2, 106.8, 9.3. (b) 4-Chloropyrazole-3-carboxylic acid A well-stirred mixture of 4-chloro-3-methyl pyrazole hydrochloride (20 mmol, 3.06 g, see step (a)) and potassium permanganate (50 mmol, 11.4 g) in water (500 mL), was stirred for 3 days at t. to. and then for 5 h at 70 ° C. The mixture was filtered and concentrated. Hydrochloric acid (aq, 1 M, 50 mL) was added and the mixture was extracted with EtOAc (5x50 mL). The combined extract was washed with NaCl (aq, sat.), Dried (Na2SO4) and concentrated to give 640 mg (22%) of the subtitle compound as a white solid. 1 H NMR (DMSO-de, 400 MHz) d 13.47 (br s, 2H), 7.92 (br s, 1 H). (c) 3,8-Dichlorodipyrazolo [1, 5-a: 1 ', 5'-d1pyrazin-4,9-dione A mixture of 4-chloropyrazol-3-carboxylic acid (2.0 mmol, 300 mg, see step ( b) above) in thionyl chloride (25 mL) was heated to reflux for 3 days. The excess thionyl chloride was removed in vacuo and the crude product was used in the next step without purification. d) 4-Chloro-? / - (2-chloro-4-fluorophenyl) pyrazole-3-carboxamide A mixture of 3,8-dichlorodipyrazolo [1, 5-a: 1 ', 5'-d] pyrazine- 4,9-dione (0.20 mmol, 51 mg) and 2-chloro-4-fluoroaniline (1.0 mmol, 146 mg) was heated at 120 ° C for 1 h, cooled to room temperature and diluted with pentane (5 mL ). The precipitate was separated by filtration and washed with pentane (30 mL). By crystallization of EtOH: water (4: 1, 20 mL) 84 mg (77%) of the title compound was obtained as a white solid. 1 H NMR (DMSO-d 6, 400 MHz) d 13.8 (br s, 1 H), 9.65 (s, 1 H), 8.20 (s, 1 H), 7.96 (dd, 1 H), 7.57 (dd, 1 H) ), 7.28 (ddd, 1 H).

EXAMPLE 2 5-Chloro -? / - (2-chloro-4-fluorophenyl) pyrazole-3-carboxamide (a) 5-Chloro-3-methylpyrazole A mixture of 5-chloro-1,3-dimethylpyrazole (2.6 mmol) and pyridine hydrochloride (13.1 mmol) in a sealed 5 mL vessel was heated using microwave radiation for 2 h 200 ° C. After cooling to t. a., EtOAc (15 mL) was added and the mixture was washed with HCl (aa, 2M, 10 mL), NaCl (aq, sat.), dried (MgSO), and concentrated to yield the sub-title compound. as a white solid (yield: 210 mg (67%)). MS (M + + H) m / z = 117. 1 H-NMR (DMSO-d 6, 400 MHz), d 12.66 (br s, 1 H), 6.03 (m, 1 H), 2.19 (s, 3 H). (b) 5-Chloropyrazole-3-carboxylic acid A mixture of 5-chloro-3-methylpyrazole (3.6 mmol, see step (a) above), water (6 mL) and tert-butanol (1.2 mL), heated at 75 ° C, after which KMn0 (1.42 g, 9 mmol) was added. The mixture was stirred at 75 ° C overnight and filtered hot. The solid was washed with boiling water. The combined cold filtrate was extracted with EtOAc and the combined extract was washed with NaCl (aq, sat.), Dried (MgSO), and concentrated. The crude solid was recrystallized from EtOAc / hexane / pentane to give the subtitle compound as white crystals (yield: 350 mg (67%)). 1 H-NMR (DMSO-de, 400 MHz), d 13.65 (br s, 1 H), 6.80 (s, 1 H). (c) 5-Chloro -? / - (2-chloro-4-fluorophenyl) pyrazole-3-carboxamide A mixture of 5-chloropyrazole-3-carboxylic acid (1 mmol.; see step (b) above) and SOCI2 (1 mL), was heated to reflux for 18 h, cooled and concentrated. A portion of the resulting white solid (70 mg) was mixed with DMAP (0.27 mmol) and 2-chloro-4-fluoroaniline (0.27 mmol) in CH 2 Cl 2 (10 mL) and stirred at 60 ° C for 20 h. After cooling to t. a., the solid was filtered off and washed with CH2Cl2. The solid was dissolved in EtOAc (15 mL) and washed with HCl (aq, 1 M) and NaCl (aq, sat.). The organic phase was dried (MgSO) and concentrated. A crystallization (EtOH / water) gave the title compound as a white powder (yield: 28.9 mg (39%)). MS (M + + H) m / z = 274. 1 H NMR (DMSO-de, 400 MHz), d 10.21 (br s, 1 H), 7.58 (dd, 2 H), 7.27-7.32 (m, 1 H) , 7.09 (br s, 1 H).

EXAMPLE 3 5-Chloro -? - (2,4-dichlorophenyl) pyrazole-3-carboxamide To a solution of 1-benzenesulfonyl-3-chloropyrazole (30 mg, 0.12 mmol, see intermediate (VII) above) in THF (2 mL), at -78 ° C, was added BuLi (1.6M, 0.116 mL, 0.19 mmol) under argon. The mixture was allowed to stir 30 min before adding 2,4-dichlorophenylisocyanate (46 mg, 0.25 mmol). The mixture was stirred at -78 ° C for a further 18 h, after which NH CI (aq, sat, 2 mL) and EtOAc (20 mL) were added. The layers were separated and the aqueous phase was extracted with EtOAc (10 mL). The combined organic phase was dried (Na2SO) and concentrated. Purification by chromatography (EtOAc / heptane 1: 4) gave a white solid residue which was dissolved in MeOH (10 mL). Sodium methoxide (30% in MeOH, 0.024 mL, 0.1 mmol) was added and the mixture was stirred at t. to. for 3 days, after which NH4CI (aq, sat, 20 mL) was added. The mixture was diluted with water (30 mL) and the EtOH was removed in vacuo. The aqueous residue was extracted with EtOAc (3 x 50 mL) and the combined extract was dried (Na 2 SO) and concentrated. Chromatography (EtOAc / heptane 1: 4) gave the title compound as a white solid (yield: 7 mg (35%)). H-NMR (DMSO-de): d 13.4 (br s, 1 H), 10.2 (s, 1 H), 7.76 (s, 1 H), 7. 57 (s, 1 H), 7.48 (dd, 1 H), 7.10 (s, 1 H).

EXAMPLE 4 3-Chloro- / V- (2,3-dichlorophenyl) pyrazole-5-carboxamide (a) (2,3-Dichloro-phenyl) amide of 2-benzenesulfonyl-5-chloroprazole-3-carboxylic acid 1-Benzenesulfonyl-3-chloropyrazole (0.41 mmol, see intermediate (VII)) was dissolved in dry THF (10 mL) under argon at -78 ° C. BuLi (0.38 mL, 1.6M in hexane, 0.62 mmol) was added and the mixture was stirred for 45 min, after which 2,3-dichlorophenylisocyanate (116 mg, 0.62 mmol) was added. The mixture was stirred for 18 h at -78 ° C. NH 4 Cl (aq, sat., 10 mL) was added and the mixture was extracted with EtOAc (3 x 30 mL). The combined extract was dried (Na2SO) and concentrated. Purification by chromatography gave the subtitle compound (115 mg, 65%) as a white powder. 1 H-NMR (DMSO-de): 10.97 (s, 1 H), 8.08 (d, 2 H), 7.85 (t, 1 H), 7.75-7.70 (m, 3 H), 7.60 (d, 1 H), 7.46 (t, 1 H), 7.13 (s, 1 H). (b) 5-chloropyrazole-carboxylic acid (2,3-dichlorophenyl) amide. 2-Benzenesulfonyl-5-chloropyrazole-3-carboxylic acid (2,3-dichlorophenyl) -amide (88 mg, 0.20 mmol) was dissolved in EtOH (5 mL), after which sodium hydroxide (aq, 4M, 0.3 mmol, 77 μL) was added. The mixture was heated at 70 ° C for 2 h and concentrated. NaCl (aq, sat, 10 mL) was added and the mixture was extracted with EtOAc (3 x 10 mL). The combined organic extract was dried (Na2SO), filtered through Celite® and concentrated. Purification by chromatography gave the title compound (18 mg, 30%) as a white powder. 1 H-NMR (DMSO-de): 14.12 (s, 1 H), 10.29 (s, 1 H), 7.59 (d, 2H), 7. 42 (t, 1 H), 7.07 (s, 1 H).

EXAMPLE 5 5-Chloro -? / - (2,4-difluorophenyl) pyrazole-3-carboxamide (a) 2-Benzenesulfonyl-5-chloropyrazole-3-carboxylic acid (2,4-difluoro-phenyl) -amide The subtitle compound was prepared according to the procedure described in example 4 (a) starting from 1-Benzenesulfonyl-3-chloropyrazole (0.41 mmol, see intermediary (VII)), BuLi (0.38 mL, 1.6M in hexane, 0.62 mmol) and 2,4-difluorophenylisocyanate (96 mg, 0.62 mmol). Yield: 91 mg (55%). 1 H-NMR (DMSO-de): 10.93 (s, 1 H), 8.07 (d, 2 H), 7.89-7.82 (m, 2 H), 7.75-7.70 (m, 2 H), 7.42 (d t, 1 H), 7.21-7.13 (m, 2H). (b) 5-chloropyrazole-3-carboxylic acid (2,4-difluoro-phenyl) amide The title compound was prepared according to the procedure described in example 4 (b) from (2,4-difluorophenyl) ) amide of 2-benzenesulfonyl-5-chloropyrazole-3-carboxylic acid (98 mg, 0.25 mmol). Yield: 36 mg (56%). 1 H-NMR (DMSO-de): 8.61 (s, 1 H), 7.90 (s, 1 H), 7.53 (d, 1 H), 7.39 (d, 1 H), 7.25 (s, 1 H), 6.80 (s, 1 H).

EXAMPLE 6? / - (2-Chloro-4-fluorophenyl) -4-fluoropyrazole-3-carboxamide (a) 4-Fluoropyrazole-3-carboxylic acid ethyl ester The subtitle compound was prepared from pyrazole-3-carboxylic acid ethyl ester according to a literature procedure (R. Storer et al., Nucleosides &; Nucleotides 18, 203 (1999)). A mixture of the subtitle compound and unreacted starting material (~2: 1) was obtained and used without further purification. (b) 4-Fluoropyrazole-3-carboxylic acid To a solution of a mixture (~2: 1) of 4-fluoropyrazole-3-carboxylic acid ethyl ester and pyrazole-3-carboxylic acid ethyl ester (1.2 g, 8 mmol, see step (a) above) in dioxane (9 mL), sodium hydroxide (aq, 2M, 18 mmol, 9 mL) was added to t. to. and stirred for 16 h. A second portion of aqueous sodium hydroxide (2M, 18 mmol, 9 mL) was added and the mixture was stirred for another 4 h. The mixture was acidified with HCl (aq, 2M, 20 mL), concentrated, stirred with MeOH (30 mL) and filtered. The filtrate was concentrated and the residue was crystallized from HCl (aq, 0.01 M) to give a mixture of the subtitle compound and pyrazole-3-carboxylic acid (~ 3: 1), as a white solid (yield: 267 mg (- 2 mmol, -25%)). This mixture was used without further purification. 1 H-NMR (DMSO-d 6): d 13.7-13.1 (br s, 1.3 H), 7.9-7.7 (m, 1 H), 7.73 (d, 0.3 H), 6.70 (d, 0.3 H). (c)? / - (2-Chloro-4-fluorophenyl) -4-fluoropyrazole-3-carboxamide A (-3: 1) mixture of 4-fluoropyrazole-3-carboxylic acid and pyrazole-3-carboxylic acid (85 mg , 0.69 mmol), TBTU (242 mg, 0.75 mmol), 2-chloro-4-fluoro-phenylamine (130 mg, 0.89 mmol), and DPEA (239 μL, 1.37 mmol) in DMF (2.5 mL), was stirred at t. to. for 3 days and at 85 ° C for 16 h. It was added TBTU (36 mg, 0.10 mmol) and the mixture was stirred for 1 hour at 85 ° C. The mixture was cooled and water (10 mL) and NaCl (aq, sat, 10 mL) were added. The mixture was extracted with EtOAc (5 x 20 mL). The combined extract was dried (Na2SO), concentrated and purified by chromatography to give the title compound as a mixture (-10: 1) with pyrazole-3-carboxylic acid (2-chloro-4-fluorophenyl) amide. 1 H-NMR (DMSO-de): d 13.47 (s, 1 H), 9.56 (s, 1 H), 8.00 (d, 1 H), 7.99-7.86 (m, 1 H), 7.55 (dd, 1 H ), 7.27 (ddd, 1 H).

EXAMPLE 7 5-Chloro -? / - (4-fluorophenyl) pyrazole-3-carboxamide To a solution of 1-benzenesulfonyl-3-chloropyrazole (100 mg, 0.41 mmol, see intermediate (VII)) in THF (10 mL), BuLi (1.6M, 0.38 mL, 0.62 mmol) was added under argon, -78 ° C. The mixture was stirred for 10 min before adding 4-fluoro-phenylisocyanate (0.071 mL, 0.62 mmol). Stirring was continued at -78 ° C for 18 h, after which NH 4 Cl (aa, sat, 6 mL), water and finally EtOAc was added. The phases were separated and the aqueous phase was extracted with EtOAc. The combined extract was concentrated to give a brown oil, which crystallized upon standing. The solid was dissolved in EtOH (10 mL) and sodium hydroxide (aq, 4M, 0.62 mmol, 0.15 mL) was added. The mixture was stirred at t. to. for 20 min before adding NH CI (ac, sat, 6 mL). The mixture was diluted with water (15 mL) and the EtOH was removed in vacuo. The aqueous phase was extracted with EtOAc (3 x 50 mL) and the combined organic phase was dried (Na2SO4) and concentrated. Purification by chromatography (EtOAc / heptane, 1: 4) gave the title compound as a white solid (yield: 49 mg (50%)). 1 H-NMR (DMSO-de): d 13.99 (br s, 1 H), 10.26 (s, 1 H), 7.73-7.69 (m, 2H), 7.20 (t, 2H), 7.07 (br s, 1 H).

EXAMPLE 8 5-Chloro- / V- (4-chlorophenyl) pyrazole-3-carboxamide (a) (2-Benzenesulfonyl-5-chloropyrazole-3-carboxylic acid (4-chlorophenyl) -amide) The subtitle compound was prepared according to the procedure described in example 4 (a), from 1- Benzenesulfonyl-3-chloropyrazole (100 mg, 0.41 mmol, see broker) (Vil)), BuLi (0.38 mL, 1.6M in hexane, 0.62 mmol) and 4-chlorophenylisocyanate (105 mg, 0.62 mmol). 1 H-NMR (DMSO-de): 12.7 (s, 1 H), 8.01-7.94 (m, 4H), 7.83 (t, 1 H), 7.70 (t, 2H), 7.56 (d, 2H), 6.98 ( s, 1 H). (b) 5-Chloropyrazol-3-carboxylic acid (4-chlorophenyl) amide The title compound was prepared according to the procedure described in example 4 (b), from (4-chlorophenyl) amide 2-Benzenesulfonyl-5-chloropyrazole-3-carboxylic acid (123 mg, 0.30 mmol). Yield: 12 mg (15%). 1 H-NMR (DMSO-de): d 13.68 (s, 1 H), 11.67 (s, 1 H), 7.77 (d, 2H), 7. 50 (d, 2H), 7.00 (s, 1 H).

EXAMPLE 9? / - (2-Chloro-4-fluorophenyl) -5- (trifluoromethyl) pyrazole-3-carboxamide (a) 1, 1, 1-Trifluoro-4-methoxypent-3-en-2-one A mixture of 2-methoxypropene (7.7 g, 132 mmol) and pyridine (9.7 mL, 120 mmol) was added dropwise to anhydride of trifluoroacetic acid (25.2 g, 120 mmol), while cooling to -30 ° C. Diethyl ether (50 mL) was added and the mixture was left 18 h at t. to. By filtration and concentration a yellow oil was obtained which was taken in CH2Cl2. The mixture was washed with HCl (ac, 0.1 M; 50 mL), and water (50 mL); dried (Na2SO4) and concentrated, yielding 23 g of an orange oil which was used in the next step without further purification. 1 H NMR (CDCl 3) d 5.68 (s, 1 H), 3.80 (s, 3 H), 2.41 (s, 3 H). (b) 3-Methyl-5-trifluoromethyl-pyrazole To a solution of 1,1-trifluoro-4-methoxypent-3-en-2-one (10 g, 59 mmol, see step (a) above) in EtOH (30 mL), hydrazine hydrate (4.0 g, 79 mmol) was added dropwise. The mixture was heated, refluxed for 2 h, cooled and concentrated. The residue was taken up in diisopropyl ether and dried (Na 2 SO 4). One concentration gave the subtitle compound, which was used in the next step without further purification. Yield: 7.0 g (79%). 1 H-NMR (CDCl 3) d 6.15 (s, 1 H), 2.29 (s, 3H). (c) 5-Trifluoromethyl-pyrazole-3-carboxylic acid A mixture of 3-methyl-5-trifluoromethyl-pyrazole (3.0 g, 20 mmol; see step (b) above) and KMn0 (3.0 g) in water (80 mL), heated at 80 ° C for 18 h. The mixture was filtered through Celite®. The filtrate was acidified with HCl (aqueous, 2M) and extracted with diethyl ether (3 x 50 mL). The combined extract was dried (Na2SO) and concentrated. The resulting compound (yellow crystals) was used without further purification. Yield: 1.6 g (44%) .. (d) A / - (2-Chloro-4-fluorophenyl) -5- (trifluoromethyl) pyrazole-3-carboxamide To a solution of 5-trifluoromethylpyrazole-3-carboxylic acid (200 mg, 1.1 mmol, see step (c) above), 2-chloro-4-fluoroaniline (189 mg, 1.3 mmol) and DIPEA (285 mg, 2.2 mmol) in DMF (10 mL), TBTU (417 mg) was added. mg, 1.3 mmol). The mixture was left at t. to. for 18 h, followed by the addition of water (50 mL) and extraction with EtOAc (3 x 30 mL). The combined extract was washed with water (50 mL), dried (Na2SO4) and concentrated. Purification by chromatography (EtOAc / Hept 1: 10 to 1: 1) gave the title compound as a colorless solid. Yield: 12 mg (4%). 1 H-NMR (DMSO-de) d 14.69 (s, 1 H), 10.33 (s, 1 H), 7.60 (dd, 2H), 7.50 (br s, 1 H), 7.31 (dt, 2H).

EXAMPLES 10-29 General procedures Method A A mixture of the relevant substituted pyrazole-3-carboxylic acid (intermediate VIII, 1.2 mmol) and SOCI2 (10 mL) was stirred at 80 ° C for 18 h. After cooling to t. a., the mixture was concentrated and the residue dried. A mixture of the relevant arylamine (3.6 mmol) and CH2Cl2 (10 mL) was added to the residue. The mixture was stirred at 60 ° C for 18 h. After cooling to t. to. The mixture was concentrated and the residue was acidified with HCl (aq, 1M, 10 mL). The mixture was extracted with EtOAc (4x10 mL); The combined organic phase was then washed with NaCl (aq, sat, 20 mL), dried (Na2SO) and concentrated in vacuo. The residue was recrystallized from EtOH / water (1: 1) and EtOAc / hexane (2: 1).

Method B A mixture of the relevant substituted pyrazole-3-carboxylic acid (intermediate XI or XIV, 1.2 mmol) and SOCI2 (10 mL) was stirred at 80 ° C for 18 h. After cooling to t. a., the mixture was concentrated and the residue was dried in vacuo. A mixture of the relevant arylamine (2.4 mmol), DMAP (1.6 mmol) and CH2Cl2 (10 mL) was added to the residue. The mixture was stirred at 60 ° C for 18 h. After cooling to t. a., the mixture was concentrated and the residue was acidified with HCl (aq, 1 M, 10 mL). The mixture was extracted with EtOAc (4x10 mL), the combined organic phase was washed with NaCl (aq, sat, 20 mL), dried (Na2SO4) and concentrated. The residue was recrystallized from EtOH / water (1: 1) and EtOAc / hexane (2: 1).

Method C A mixture of TBTU (642 mg, 2.0 mmol), the relevant substituted pyrazole-3-carboxylic acid (intermediate IV, 1.0 mmol), the relevant arylamine (1.0 mmol), DIPEA (348 μL, 2.0 mmol) and DMAP ( 12 mg, 0.1 mmol) in dry DMF (5 mL), was stirred at 80 ° C for 3 days. After cooling to t. a., the mixture was concentrated and the residue was acidified with HCl (aq, 1 M, 10 mL). The mixture was extracted with EtOAc (4x10 mL), the combined organic phase was then washed with NaCl (aq, sat, 20 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (EtOAc / heptane).

Method D To a solution of the relevant arylamine (0.50 mmol) in CH2Cl2 (2 mL) was added trimethylaluminum (0.63 mL, 2.0M in hexane, 1.25 mmol) under argon, at 0 ° C. A solution of the relevant substituted pyrazole-3-carboxylic acid ester (intermediate X, 0.25 mmol) in CH2Cl2 (2 mL) was added, and the mixture was allowed to warm to t. to. The mixture was stirred at t. to. for 24 h and it was emptied into HCl (aq, 0.01 M, 10 mL). The pH was adjusted to -3 by dropwise addition of HCl (aq, 2M). The mixture was extracted with EtOAc (3x25 mL), the combined organic phase was washed with NaCl (aq, sat, 30 mL), dried (Na2SO) and concentrated. The residue was purified by chromatography (EtOAc / heptane) and recrystallized from ethyl acetate / heptane.

Method E To a solution of the relevant arylamine (1 mmol) in DMF (2 mL) was added sodium hydride (60% in mineral oil, 60 mg, 1.5 mrnol), at t. to. The mixture was stirred for 5 min, then a solution of the relevant substituted pyrazole-3-carboxylic acid ester (intermediate X, 0.5 mmol) in DMF (2 mL) was added, and the mixture was stirred at t. to. for 15 h. The mixture was poured into NaHCO3 (aq, sat, 15 mL) and extracted with EtOAc (3x20 mL). The combined extract was washed with NaCl (aq, sat, 20 mL), dried (Na2SO) and concentrated. The crude product was purified by chromatography (EtOAc / heptane).

Method F A mixture of the relevant substituted pyrazole-3-carboxylic acid (intermediate IV or IX, 1.0 mmol) and SOCI2 (10 mL) was stirred at 80 ° C for 18 h. After cooling to t. a., the mixture was concentrated and the residue was dried in vacuo. A mixture of the relevant arylamine (1.0 mmol), DMAP (12 mg, 0.10 mmol), DMF (0.5 mL) and pyridine (1 mL) was added. The mixture was stirred at 80 ° C for 21 h and concentrated in vacuo. The residue was purified by chromatography (EtOAc / heptane).

TABLE 1 EXAMPLES (Ei.) 10 a 29 TABLE 2 Physical properties of the compounds of examples 10-29 EXAMPLE 30 The title compounds of the examples were tested with the biological test described above and were found to exhibit an Cl50 of 10 μM or less. For example, the following representative compounds of the examples exhibited the following CI5o values: Example 1: 85 nM; Example 5: 265 nM; Example 6: 114 nM; Example 7: 182 nM; Example 8: 78 nM; Example 19: 69 nM;

Claims (31)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula I, wherein R1 and R2 independently represent H, Cl, F, CHF2 or CF3, with the proviso that at least one of R1 and R2 does not represent H; X1 represents halogen, -R3a, -OR3q or -S (0) 2N (R4j) R5j; X2 represents halogen, R3a, -CN, -C (0) R3b, -C (0) OR3c, -C (0) N (R4a) R5a, -N (R4b) R5b, -N (R3d) C (0) R c, -N (R3e) C (0) N (R4d) R5d, -N (R3f) C (0) OR4e, -N3, -N02, -N (R39) S (0) 2N (R4f) R5f, -OR3h, -OC (0) N (R4g) R5g, -OS (0) 2R3i, -S (0) mR3j, -S (0) 2N (R4h) R5h, -S (0) 2OH, -N (R3k ) S (0) 2R3m, -OC (0) R3p, OC (0) OR3p, or -P (0) (OR4i) (OR5i); n represents 0, 1, 2, 3 or 4; m represents 0, 1 or 2; R3a represents C? -6 alkyl optionally substituted with one or more substituents selected from F, Cl, -N (R4b) R5b, -N3, = 0 and -OR3h; R3b to R3h, R3k, R3n, R3q, R4a to R4i, R5a, R5b, R5d and R5f to R5i, independently represent hydrogen or C6.6 alkyl optionally substituted with one or more substituents selected from F, Cl, -OCH3, -OCH2CH3, OCHF2 and -OCF3; or any of the pairs R4a and R5a, R4b and R5b, R4d and R5d, R4f and R5f, R4g and R59, R4h and R5h, and R4j and R5j, may be linked together to form a 3 to 6 member ring, said ring optionally contains an additional heteroatom in addition to the nitrogen atom to which these substituents are necessarily bound, and said ring is optionally substituted with = 0, or C 1-6 alkyl, said alkyl group is optionally substituted with one or more F atoms; R3 ', R3j, R3m and R3p independently represent C- | 6 alkyl optionally substituted with one or more substituents selected from F, Cl, -OCH3, -OCH2CH3, OCHF2 and -OCF3, or a pharmaceutically acceptable salt thereof, to be used as a pharmaceutical agent.

2. The compound according to claim 1, further characterized in that X1 represents halogen or -R3a.

3. The compound according to claim 1 or claim 2, further characterized in that R1 and R2 independently represent H, F or Cl.

4. The compound according to any of the preceding claims, further characterized in that n is O or

5. The compound according to claim 4, further characterized in that n is 1.

6. The compound according to any of the preceding claims, further characterized in that when any of the pairs R4a and R5a, R4b and R5b, R4d and R5d, R4f and R5f, R4g and R59, R4h and R5h, and R4j and R5j, are linked together, form a ring of 5 to 6 members, said ring optionally contains an additional heteroatom and is optionally substituted with methyl , -CHF2 or CF3

7. The compound according to any of the preceding claims, further characterized in that X1 represents -OR3q, F, Cl or R3a.

8. The compound according to claim 7, further characterized in that X1 represents F, Cl or alkyl of d.3 optionally substituted with one or more fluorine atoms.

9. The compound according to claim 8, further characterized in that X1 represents F, Cl, CH3 or CF3.

10. The compound according to any of the preceding claims, further characterized in that X2 represents F, Cl, Br, -R3a, -CN, -C (0) R3b, -C (0) OR3c, -C (0) N (R4a) R5a, -N (R4b) R5b, -N (R3d) C (0) R4c, -N (R3e) C (0) N (R4d) R5d, -N (R3f) C (0) OR4e, -N3, -N02, -N (R39) S (0) 2N (R4f) R5f, -OR3h, -OC (0) N (R4g) R59, -OS (0) 2R3i, -S (0) mR3i or - S (0) 2N (R4h) R5h.

11. The compound according to claim 10, further characterized in that X2 represents -CN, -C (0) N (R4a) R5a, -N (R4b) R5b, -N (H) C (0) R4c, - S (0) 2CH3, -S (0) 2CF3, -S (0) 2N (R4h) R5h, F, Cl, -R3a or -OR3h.

12. The compound according to any of the preceding claims, further characterized in that R3a represents C- | 6 alkyl optionally substituted with one or more substituents selected from F and -OR3h.

13. - The compound according to claim 12, further characterized in that R3a represents C - alquilo alkyl optionally substituted with one or more atoms of F.

14. The compound according to any of the preceding claims, further characterized in that R3b, R3c, R3h, R4a to R4h, Rj, R5a, R5b, R5d, R5f to R5h and R5i independently represent hydrogen or C-? 4 alkyl, or the relevant pairs are linked between yes.

15. The compound according to any of claims 1 to 10, or 12 to 14, further characterized in that R3d to R3g independently represent C-? -2 alkyl or hydrogen.

16. The compound according to any of claims 1 to 10, or 12 to 15, further characterized in that R3 'and R3j independently represent C? -4 alkyl optionally substituted with one or more atoms of F.

17. - The compound according to any of the preceding claims, further characterized in that R3h represents hydrogen or C- [alpha] alkyl optionally substituted with one or more fluorine atoms.

18. The compound according to any of the preceding claims, further characterized in that R4a, R4b, R4c, R4h, R5a, R5b and R5h independently represent hydrogen, methyl or ethyl, or the relevant pairs are linked together to form a pyrrolidinyl, piperidinyl, morpholinyl or 4-methylpiperazinyl ring.

19. - A pharmaceutical formulation that includes a compound as claimed in any of claims 1 to 18, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

20. The use of a compound as claimed in any of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease in which it is desired or required inhibit the activity of a lipoxygenase.

21. The use claimed in claim 20, wherein the lipoxygenase is 15-lipoxygenase.

22. The use claimed in claim 20 or claim 21, wherein the disease is inflammation or has an inflammatory component.

23. The use claimed in claim 22, wherein the inflammatory disease is asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, allergic disorders, rhinitis, inflammatory bowel disease, ulcers, inflammatory pain, fever, atherosclerosis, disease of the coronary artery, vasculitis, pancreatitis, arthritis, osteoarthritis, rheumatoid arthritis, conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis, stroke, diabetes, autoimmune diseases, Alzheimer's disease, multiple sclerosis, sarcoidosis , Hodgkin's disease or other malignancies.

24. - A compound of the formula la, wherein one of X3, X4, X5, X6 and X7 represents X1 and the others represent H or X2, and X1, X2, R1 and R2 are as defined in any of claims 1 to 18, or a pharmaceutically acceptable salt of the same, with the proviso that: (A) when R1 represents Cl, R2 represents H, and (1) X3, X4, X6 and X7 represent all H, then X5 does not represent Br, I or -C (0) CH3; (2) X3, X5, X6 and X7 represent all H, then X4 does not represent -C (0) CH3; (3) X3, X6 and X7 represent all H, then X4 does not represent Cl when X5 represents methyl or methoxy; (4) X3, X5 and X7 represent all H, then X4 and X6 do not represent both -C (0) OCH3 nor -C (0) 0-isopropyl; (5) X4, X6 and X7 represent all H, then X5 does not represent F when X3 represents methyl; (6) X3, X6 and X7 represent all H, then X5 does not represent F when X4 represents -N02; (7) X4, X5 and X6 represent H, then X7 does not represent isopropyl when X3 represents methyl; (8) X3, X5 and X7 represent H, then X4 and X6 do not represent both methoxy; (9) X4, X5, X6 and X7 represent all H, then X3 does not represent methoxy; or (B) when R1 represents H, R2 represents CF3, X4, X6 and X7 represent all H, then X3 does not represent chlorine or CF3 when X5 represents -N02.

25. - The compound or salt according to claim 24, further characterized in that it has the additional conditions that when R2 represents CF3 and: (I) R1 represents H or Cl, X7 represents H and (a) X4, X5 and X6 represent all H, then X3 does not represent CF3; (b) X4 and X6 represent both H, then X3 does not represent bromine when X5 represents -N02; (c) X4 and X5 represent both H, then X3 does not represent chlorine when X6 represents CF3; (d) X4 represents H, then X3 does not represent chlorine when X5 represents -N02 and X6 represents chlorine; (II) R1 represents H or Cl, then X3, X4, X5, X6 and X7 do not represent all F; (III) R1 represents Cl and X4, X6 and X7 represent all H, then X3 does not represent chlorine or CF3 when X5 represents -N02; (IV) R1 represents H, X3 represents Cl, then: (i) X4, X5, X6 and X7 do not represent all H; (ii) X4 does not represent Cl when X5 and X6 represent H or Cl and X7 represents H; (iii) X5 does not represent Cl or Br when X4, X6 and X7 represent all H; (iv) X7 does not represent Cl when X5 represents H, Cl or -N02 and X4 and X6 represent both H; (v) X5 does not represent Cl when X6 represents Cl and X4 and X7 represent both H; (V) R represents H and X3 represents Br, then X5 does not represent -OCF3 when X4, X6 and X7 represent all H; (VI) R1 represents H and X3 represents F or I, then X5 does not represent -N02 when X4, X6 and X7 represent all H; (VII) R1 represents H and X3 represents -N02, then X5 does not represent Cl or CF3 when X4, X6 and X7 represent all H; (VIII) R1 represents H, X3 represents CF3, then X5 does not represent -N02 when X4 and X6 represent both H and X7 represents Cl; or (IX) R1 represents H, X3 represents CF3, then X5 does not represent Cl when X4, X6 and X7 represent all H. 26.- A combination product comprising (A) a compound of formula I as claimed in any of claims 1 to 18, or a pharmaceutically acceptable salt thereof; and (B) another therapeutic agent that is useful in the treatment of inflammation, wherein each of the components (A) and (B) is formulated in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. 27. The combination product according to claim 26, further characterized in that it comprises a pharmaceutical formulation that includes a compound of formula I as claimed in any of claims 1 to 18, or a pharmaceutically acceptable salt thereof, another therapeutic agent that is useful in the treatment of inflammation, and a pharmaceutically acceptable adjuvant, diluent or carrier. 28. The combination product according to claim 26, further characterized in that it comprises a set of parts comprising the following components: (a) a pharmaceutical formulation that includes a compound of formula I as claimed in any of the claims 1 to 18, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; and (b) a pharmaceutical formulation that includes another therapeutic agent that is useful in the treatment of inflammation, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; said components (a) and (b) are provided in a form that is suitable for administration one in conjunction with the other. 29. A process for the preparation of a compound of the formula as claimed in claim 24 or 25, comprising: (i) for the compounds of formula I wherein R2 represents CHF2, Cl, F or CF3, the reaction of a corresponding compound of formula I wherein R2 represents hydrogen, with an appropriate base, followed by inactivation with a suitable electrophile; (ii) for compounds of formula I wherein R2 represents CF3, the reaction of a compound corresponding to a compound of formula I but in which R2 represents bromine or iodine, with CUCF3 (or a source of CuCF3); (iii) the reaction of a compound of formula or a protected or O-protected derivative thereof, wherein R1 and R > 2 are as defined in claim 1, with a compound of formula IV, where X? , X v2 and n are as defined in claim 1; (iv) the reaction of a compound of formula V, wherein R1 and R2 are as defined in claim 1, with a suitable base, followed by reaction with a compound of formula VI, wherein X1, X2 and n are as defined in claim 1, followed by inactivation with a suitable proton source; (v) for the compounds of formula I wherein R2 represents hydrogen and R1 is as defined in claim 1, the removal of the group J from a compound of formula VII, where, each «R Dt independently represents a C1-6 alkyl group or an aryl group, and each Rz independently represents C6-6 alkyl), and R1, X1, X2 and n are as defined in claim 1, with a reagent suitable for removal of the silyl group (when J represents -Si (R ') 3), or by hydrolysis (when J represents -Sn (Rz) 3); (vi) the reaction of a compound of formula VIII, wherein R1 and R2 are as defined in claim 1, with a compound of formula IV as defined above; (vii) for the compounds of formula I wherein one of R or R2 represents CHF2, CF3, Cl or F, and the other represents H, the reaction of a compound corresponding to a compound of formula I but in which one of R1 or R2 represents bromine or iodine and the other represents H (as appropriate), with a suitable organolithium base, optionally in the presence of an additive, followed by inactivation with a suitable electrophile; or (viii) the reaction of a compound of formula VIIIA, or a derivative? / - protected therefrom, wherein R and R2 are as defined in claim 1, with a compound of formula VIIIB, VIIIB wherein L1 represents a suitable leaving group and X1, X2 and n are as defined in claim 1. 30.- A method of preparing a pharmaceutical formulation as claimed in claim 19, which comprises associating a compound of formula I as claimed in any of claims 1 to 18, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable adjuvant, diluent or carrier. 31. A method of preparing a combination product as claimed in any of claims 26 to 28, which comprises associating a compound of formula I as claimed in any of claims 1 to 18, or a pharmaceutically acceptable salt thereof, with the other therapeutic agent that is useful in the treatment of immation, and at least one pharmaceutically acceptable adjuvant, diluent or carrier.