MXPA06008833A - Heteroarylaminopyrazole derivatives useful for the treatment of diabetes - Google Patents

Abstract

The present invention relates to heteroarylaminopyrazole compounds, pharmaceutical compositions, and methods for treating diabetes and related disorders.

Description

Derivatives of Heteroarylaminopyrazole Useful for the Treatment of Diabetes This application claims the benefits of the Provisional Application of the United States Act No. 60 / 548,331; filed on February 27, 2004, and l Interim Application of the United States Act No. 60 / 572,906 filed on May 20, 2004, the contents of which are hereby incorporated herein by reference in their entirety. FIELD OF THE INVENTION The present invention relates to heteroarylaminopyrazole compounds, pharmaceutical compositions and methods for the treatment of diabetes and related disorders BACKGROUND OF THE INVENTION Diabetes is characterized by alterations in glucose metabolism, manifested among other things by a high level of blood glucose in the diabetic patient. The underlying deficiencies lead to a classification of diabetes into two main groups. Type 1 diabetes, or insulin-dependent diabetes mellitus (IDD), occurs when patients lack beta-producing insulin cells in their pancreatic glands. Type 2 diabetes, or non-insulin-dependent diabetes mellitus (NIDDM), occurs in patients with impaired beta cell function and alterations in insulin action. The current treatment for type 1 patients is insulin injection, while the majority of type 2 patients are treated with agents that stimulate beta cell function or with agents that increase the sensitivity of tissues to insulin. Drugs currently used for the treatment of type 2 diabetes include alpha-glucosidase inhibitors, insulin sensitizers, insulin secretagogues and metformin. After a while, about half of the type 2 diabetic subjects lose the response to this type of agents. Insulin treatment is instituted after diet, exercise, and oral medication have failed to maintain an adequate blood glucose level. The disadvantages of insulin treatment are the need to inject the drug, the potential hypoglycemia and weight gain. Because of the problems with current treatments, new therapies are needed for the treatment of type 2 diabetes. In particular, new treatments are needed to preserve the normal secretion of insulin (glucose dependent). Such new drugs must have the following characteristics: dependence on glucose to promote insulin secretion (ie, compounds that stimulate insulin secretion only in the presence of elevated blood glucose levels), low rates of primary and secondary failure and preservation of the function of islet cells. INS-1 cells are a model for insulin secretion from islet beta cells. When maintained in the presence of betamercaptoethanol, these cells retain many of the characteristics of islet beta cells in situ. The cells secrete insulin in response to the physiologically relevant glucose concentration, with an EC50 of 6 mM glucose (Hohmeier, et al., Diabetes 49: 424, 2002). These cells also secrete insulin in response to multiple known secretagogues, including agents that raise the level of intracellular cyclic AMP, nutrients other than glucose and potassium chloride. This characteristic of INS-1 cells further demonstrates that the cells retain many of the signaling pathways that are involved in the secretory response of insulin, and as such are suitable for identification of compounds that affect these pathways. INS-1 cells are, therefore, useful tools for the determination of compounds that stimulate insulin secretion in the presence of glucose, and such compounds are useful in the treatment of diabetes and related disorders. DESCRIPTION OF THE INVENTION The invention provides heteroarylaminopyrazole derivatives of formula (I) (I where: is a substituted radical of aromatic heterocyclic ring selected from R is H or (C1-C6) alkyl; R1 is H, (C1-C6) alkyl optionally substituted by phenyl, said phenyl being optionally substituted with halo, or [tri (C1-C4) alkyl] silyl (C3-C6) alkenyl, (C3-C6) alkynyl, cycloalkyo ( C3-C6) optionally substituted with up to two substituents selected from the group consisting of (C1-C3) alkyl, CF3 and halo, haloalkyl (C1-C3), or phenyl, optionally substituted with up to two substituents selected from the group consisting of halo, alkyl (C1-C6), (C1-C6) alkoxy, (C1-C6) alkylthio, (C1-C3) haloalkyl, (C1-C3) haloalkoxy, and cyano; R 2 is H, halo, (C 1 -C 6) alkyl, pyridyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 6) alkoxy, (C 1 -C 6) alkylthio, halo and (C 1 -C 6) alkyl, substituted phenyl optionally with up to two substituents selected from the group consisting of (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkylthio, cyano and halo, pyrimidyl thienyl optionally substituted with up to two substituents selected from the group consisting of alkyl ( C1-C6), (C1-C6) alkoxy, (C1-C6) alkylthio, cyano and halo, benzothienyl, optionally substituted with up to two substituents selected from the group consisting of (C1-C6) alkyl, (C1-C6) alkoxy, (C 1 -C 6) alkylthio, cyano and halo, or furyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, (C 1 -C 6) alkylthio, cyano and halo; R3 is (C1-C6) alkyl, (C3-C6) cycloalkyl, (C2-C3) haloalkyl or phenyl optionally substituted with up to four substituents selected from the group consisting of (C1-C6) alkyl optionally substituted with a (C1-C4) alkoxy ), halo, haloalkyl (C1-C3), alkoxy (C1-C6), haloalkoxy (C1-C3), alkylthio (C1-C6) and cyano; R 4 is (C 1 -C 6) alkyl optionally substituted with (C 1 -C 4) alkoxy, (C 1 -C 6) alkoxy, (C 1 -C 6) alkylthio, (C 1 -C 3) haloalkyl, (C 1 -C 3) haloalkoxy, or halo; n = 0, 1, 2, or 3; X is CO2R7, CONR5R6, or SO2NH2; R5 is H, (C1-C6) alkyl, phenyl optionally substituted with halo or benzyl optionally substituted on the phenyl ring with halo; Rd is H or (C1-C6) alkyl; or R5 and R6, taken together with the N atom to which they are attached, can form a piperidine, morpholine, thiomorpholine or piperazine ring, said piperazine optionally substituted on the N with (C? -C3) alkyl; R7 is H, (C1-C6) alkyl, benzyl optionally substituted on the aryl ring with up to two substituents selected from the group consisting of halo, (C1-C6) alkyl, (C1-C3) alkoxy, halo (C1-C3) alkyl, haloalkoxy (C1-C3), and alkylthio (C1-C6); phenyl optionally substituted with up to two substituents selected from the group consisting of (C1-C6) alkyl, halo, (C1-C6) alkoxy, (C1-C3) haloalkyl, (C1-C3) haloalkoxy, and (C1-C6) alkylthio; and salts acceptable for pharmaceutical use thereof; with the proviso that the compound of formula (I) is not The terms identified above have the following meaning throughout the specification: The term "halo" means F, Br, Cl and I. The terms "(C 1 -C 3) alkyl" and "(C 1 -C 6) alkyl" mean a linear or branched saturated hydrocarbon radical of between about 1 and about 3 C atoms or between about 1 and about 6 C atoms respectively. Such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, butyl, tertbutyl, pentyl, hexyl, and the like. The term "(C3-C6) alkenyl" means a linear or branched unsaturated hydrocarbon radical containing a double bond and between about 3 and about 6 carbon atoms. The double bond can be located between two available carbon atoms in the chain. Such groups include, but are not limited to, alkyl, isopropenyl, 2-butenyl, 2-ethyl-2-butenyl, 1-hexenyl, and the like. The term "(C3-C6) alkynyl" means a linear or branched unsaturated hydrocarbon radical containing a triple bond and between about 3 and about 6 carbon atoms. The triple bond could be between two available carbon atoms in the chain. Such groups include, but are not limited to, propargyl, 2-butinyl, 1-methyl-2-butinyl, 3-hexynyl, and the like. The term "(C3-C3) cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The terms "(C 1 -C 4) alkoxy" and "(C 1 -C 6) alkoxy" mean a straight or branched saturated hydrocarbon radical of between about 1 and about 4 C atoms or between about 1 and about 6 C atoms, respectively, said radical being attached to an O atom. The O atom is the atom by which the alkoxy substituent is attached to the rest of the molecule. Such groups include, but are not limited to, methoxy, ethoxy, α-propoxy, isopropoxy, p-butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

The term "haloalkoxy (CI-C3)" means an alkoxy group (CI-C3) substituted at C with a halogen atom. Such groups include, but are not limited to, trifluoromethyl, difluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloroethoxy, 3-chloropropoxy, 1-fluoro-2,2-dichloroethoxy, and the like. The terms "haloalkyl (C1-C3)" and "haloalkyl (C2-C3)" mean an alkyl group (C3) and a (C2-C3) alkyl group, respectively, substituted at C with a halogen atom. Such groups include, but are not limited to, trifluoromethyl, difluoroethyl, 1-fluoro-2,2-dichloroethyl, 3-cyoropropyl, 4-bromohexyl, and the like. The term "[tri-(C 1 -C 4) alkylsilyl]" means a Si radical bearing three (C 1 -C 4) alkyl substituents, each substituent being independently selected. The Si atom is the atom through which the radical is bound to the rest of the molecule. Such groups include, but are not limited to, trimethylsilyl, tert-butyl-dimethylsilyl, and the like. The term "(C 1 -C 6) alkylthio" means a straight or branched saturated hydrocarbon radical of from about 1 to about 6 atoms, said radical being attached to an S atom. The S atom is the atom through which the substituent alkylthio binds to the rest of the molecule. Such groups include, but are not limited to, methylthio, ethylthio, p-propylthio, isopropylthio and the like.

The term "optionally substituted" means that the moiety thus modified may have from none to at least the maximum number of substituents indicated. Each substituent can replace any H atom in the rest so modified so that the replacement is chemically possible and chemically stable. When there are two or more substituents on any residue, each substituent is independently selected from any other substituent and may, therefore, be the same or different. In the formula (l), the point of attachment of the heterocyclic ring radicals is the union marked with a dotted line (-). The group X in each radical is fixed in ortho position with respect to the point of union of the radical. The optional groups R4 (up to n) on the radical can be located on any available C atom. Alternative Forms of the New Compounds. Also included in the compounds of the present invention are: (a) the stereoisomers thereof, (b) the pharmaceutically acceptable salts thereof, (c) the tautomers thereof, (d) the protected acids and the conjugated acids thereof, and (e) prodrugs thereof. The stereoisomers of these compounds may include, but are not limited to, enantiomers, diastereomers, racemic mixtures, and combinations thereof. Such stereoisomers can be prepared or separated using conventional techniques, either by reacting enatiomeric starting materials, or by separating isomers of compounds of the present invention. The isomers may include geometric isomers. Examples of geometric isomers include, but are not limited to, cis isomers or trans isomers from a double bond. Other isomers are contemplated among the compounds of the present invention. Shakers can be used either in pure form or in admixture with other isomers of the inhibitors described above. Pharmaceutically acceptable salts of the compounds of the present invention include salts commonly used in the form of alkali metal salts or as addition salts of free acids or free bases. The nature of the salt is not critical, as long as it is acceptable for pharmaceutical use. The acid addition salts acceptable for pharmaceutical use can be prepared from an inorganic acid or an organic acid. Examples of such acids are: hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acids. Suitable organic acids can be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic and sulphonic acids. Examples of types of organic and sulphonic acids include, but are not limited to, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic acid , anthranilic, mesylic, salicylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethane sulfonic, toluenesulfonic, sulphanilic, cyclohexylaminosulfonic, stearic, algenic,? / - hydroxybutyric, salicylic , galacturic and galacturonic, and combinations thereof. Tautomers of the compounds of the invention are encompassed by the present invention. Thus, for example, a carbonyl includes its hydroxy-tautomer. The protected acids include, but are not limited to, esters, hydroxyamino derivatives, amides, and sulfonamides.

The present invention includes prodrugs and salts of the prodrugs. The prodrug form is well known in the art to improve the properties of the parent compound, such properties include solubility, absorption, bioavailability and time of release (see, "Pharmaceutical Dosage Form and Drug Delivery Systems" (Sixth Edition), edited by Ansel et al., Published by Williams & Wilkins, pgs. 27-29, (1995), which is incorporated herein by way of reference). The commonly used prodrugs are designed to take advantage of the major biotransformation reactions of the drugs, and are also considered within the scope of the invention. The main biotransformation reactions of drugs include ia? / - dealkylation, O-dealkylation, aliphatic hydroxylation, aromatic hydroxylation,? / - oxidation, S-oxidation, deamination, hydrolysis reactions, glucuronidation, sulfation and acetylation (see Goodman and Gilman's The Pharmacological Basis of Therapeutics (Novena Edition), publisher Molinoff et al., Publ. by McGraw-Hill, p. 11-13, (1996), which is incorporated herein by way of reference). A comprehensive list of abbreviations used by organic chemists of ordinary practice in the art appears in the first volume of each volume of the Journal of Organic Chemistry; This list is typically represented in a table titled Standard List of Abbreviations. The abbreviations contained in said list, and all abbreviations used by organic chemists of ordinary practice in the art are incorporated herein by reference. For the purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th. Ed., 1986-87, inner face of lid. The abbreviations contained in said list, and all those used by chemists of ordinary practice in the art, are incorporated herein by reference. For the purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th. Ed., 1986-87. General Methods of Preparation In general, the compounds used in this invention can be prepared by standard techniques known in the art, by known processes analogous thereto, and / or by the processes described herein, using starting materials that can be purchased commercially. or produced according to conventional routine chemical methods. The following preparation methods are presented to assist the reader in the synthesis of the compounds of the present invention. Unless otherwise specified in the reaction schemes, the meanings of R1 -R7, X and they are the same as defined above. Reaction scheme A illustrates general methods of preparing compounds of Formula (la) [(I) where R = H]. An aminopyrazole of Formula (III) is reacted with a 2-chloro-, 2-bromo-, 2-iodo-, or 2-trifluoromethylsulfonate-heteroaryl carboxylic acid, carboxylic ester or carboxamide of Formula (IV), using Ullmann-type conditions (eg, copper (II) acetate in DMF, heated in a sealed tube for 16 h). Alternatively the coupling of Formula (III) to a. 2-chloro, 2-bromo, 2-iodo, or 2-trifluoromethylsulfonate-heteroaryl carboxylic acid, carboxamide or sulfonamide ester of Formula (IV) can also be carried out using Buchwald type conditions (cesium carbonate, BINAP and a palladium catalyst such as Pd2). (dba) 3 or Pd (OAc) 2, in anhydrous toluene, heating at 110 ° C for 16 h under an argon atmosphere). Reaction scheme A (such that X? C02H) LG = CI, Br, l, g OTf 0") a) Reaction scheme B illustrates the preparation of compounds of Formula (Id) [Formula (I) wherein X is COOH], and Formula (le) [Formula (I) wherein X is CONR5R6]. The ester compound of Formula (Ib) [Formula (I) wherein X is CO2R7] is prepared as in the reaction scheme A, the acid compound of Formula (Id) is hydrolyzed, usually in a weak aqueous base. The formula (Id) can then be converted to amides of Formula (Ie) by reaction with an amine R5R6NH, optionally in the presence of a mixture of coupling agents such as OBT, EDCI and triethylamine. Alternatively, a compound with a nitrile group of Formula (Ie) [Formula (I) wherein X is CN] can be hydrolyzed directly in aqueous base to give the amide of Formula (IF) [Formula (I) where X is CONR5R6 and R5 and R6 are H].

Reaction scheme B (le): 0), where X = CN RSR6NH hydrolysis when X = CN (lf) (l), X = CONR3Rs, (le): (I), X = CONRsRβ Reaction Scheme C illustrates the general method of preparing compounds of Formula (I) wherein R 2 is iodo, chloro or fluoro. The compound of Formula (Ig) [Formula (I) wherein R 2 is H] can be iodinated or chlorinated with a reagent such as N-iodosuccinimide (NIS) or N-chlorosuccinimide (NCS) to produce the compound of Formula (Ih) [ Formula (I) where R2 is I or Cl]. Similarly, treatment of the compound of Formula (Ig) with a fluorinating agent provides compounds of Formula (li) [Formula (I) wherein R2 is F].

Reaction scheme C N-halosuccinimide OD Reaction scheme D outlines the general method for preparing the compounds of Formula (I) in which X = SO2NH2. The N, N-dibenzylsulfonamide compound of Formula (Ij) is prepared using the Buchwaid coupling reaction type which is described in reaction scheme A and can be de-benzylated with sulfuric acid to give the compound of Formula (Ik).

Diagram of reaction D 1j): (I), X = S02N (Bp) 2 (Ik): (I), X = S02NH2 The compounds of Formula (Im) wherein R is (C1-C6) alkyl are prepared by / v-alkylation of the corresponding compounds of Formula (Ia) wherein R is H, using standard conditions such as those shown in reaction scheme E. Such conditions include an alkylating agent such as iodomethane, and a base such as sodium hydride and the reaction is carried out in an inert solvent such as DMF. In the case where X is a carboxylic ester, a standard hydrolysis (NaOH, H2O) is carried out to give the compounds of Formula (I) wherein R is alkyl and X is CO2H. Reaction scheme E Oa): (D, where R = H R = (C rCa) alkyl ('"# O where R is; C1-C6) alkyl when X = C? 2alkyl an additional step of hydrolysis gives (I), where R is (C1-C6) alkyl and X = CO2H Synthesis of intermediates Intermediates are commercially purchased or prepared by standard methods known in the art and / or by analogy with one of the procedures shown below. 5-Aminopyrazoles The 5-aminopyrazoles starting materials of Formula (III) are commercially available or can be prepared as shown in Reaction Schemes F, G or H. In Reaction Scheme F, the condensation of a substituted acetonitrile optionally with an appropriately substituted ester (VI), and base, gives the cyanoketone (VII). The esters of Formula (VI) wherein R is an optionally substituted phenyl, can be prepared, if necessary, from the corresponding brominated compound of Formula R1-Br, for example, by reaction with BuLi and CO2 to form an acid of Formula R1 -COOH, which can be esterified to (VI). The compound of Formula (VII) is then allowed to react with a substituted hydrazine of Formula (II) or a substituted hydrazone of Formula (V) to give the desired aminopyrazole (III). If cyanoketone (VII) is commercially available, the first step is omitted.

Reaction Scheme F O R2-CH2CN, base R '= lower alkyl (VI) In reaction scheme G, a nitrile of Formula (Vlll) is allowed to react with acetonitrile to form enaminonitrile (IX), which is then allowed to react with hydrazine (II) or hydrazone (V) to form (Illa) [( lll) where R2 = H].

Reaction Scheme G Reaction scheme H illustrates how the aminopyrazole of Formula (Illa) can be converted to other aminopyrazoles of Formula (III) by bromination and Suzuki coupling reaction to introduce a group R2 other than H. Reaction scheme H Pd Catalyst, base * Suitable esters of boronic acid include where R 'is a lower alkyl group, or two R' groups can form a ring such as R B (OR) 2 where R is a light alkyl group, or two ring forming groups and trimonic esters of boronic acid, such as Ó.BA) you Examples of aminopyrazole preparations are shown in the descriptions of Intermediates B-1, below. Hydrazines and Hydrazones The hydrazines and hydrazones starting materials of Formula (II) and Formula (V), respectively, are purchased commercially or, in the case of phenyl hydrazines (R3 = optionally substituted phenyl), can be prepared as shown. in Reaction Scheme I, in which a substituted aniline is converted to an intermediate diazonium salt which is subsequently reduced using tin chloride (ll) as a reducing agent. Reaction Scheme l R < w .i6_a substituent < Jls), [(ii), Ra = optionally substituted phenol optionally. The N-phenylhydrazones can be prepared as shown in the Scheme "Reaction J, from a phenyl halide or phenyl trifluoromethanesulfonate and a hydrazone such as benzophenone. hydrazone, in the presence of a Pd catalyst and a base Scheme of Reacdon J R ° Pt sub _ an optional substitution1 W = CI, Br, l, or OTf An example of preparation of an arylhydrazine is shown in the description of Intermediary A, below. Examples of preparation of arylhydrazones are shown in the description of Intermediary B, step I, and Intermediary C, step 2. Halopyridine- and Halopyrimidine-Carboxylic Acid and Sulfonamide Derivatives The halopyridin- and halopyrimidinecarboxylic acid derivatives used in the reactions of coupling with 5-aminopyrazoles are commercially available or direct means well known in the art are prepared directly. Other substituents of pyridine or pyrimidine can be introduced by standard means, such as that shown in Reaction Scheme K for the preparation of methyl 3-chloro-6-methoxypyridine-2-carboxylate. Reaction Scheme K An example of a similar preparation is shown in the description of Intermediary J below. The synthesis of an intermediate 2-halopyridine sulfonamide is illustrated in Reaction Scheme L. 2-Chloro-3-aminopyridine is converted to 2-chloropyridinesulfonyl chloride by reaction with sodium nitrite / acid and sulfuryl chloride. This compound is then allowed to react with dibenzylamine to give the intermediate 2-chloropyridin-3-sufonamide. This product can then be taken to a final product using the methods described in Reaction Schemes A and D. Reaction Scheme L H20 Specific Examples of the Invention The following specific examples are presented to illustrate the invention described herein, but limitations of the scope of the invention should not be considered in any way. Abbreviations and Acronyms When the following abbreviations are used throughout the memory, they have the following meaning: absolute abs Ac acetyl HAcO acetic acid uma atomic mass unit aq aqueous B1NAP 2.2, -Bis (diphenylphosphino) -1, 1 '-bibinyl Bn benzyl Boc f-butoxycarbonyl BTMAICI2 benzyltrimethylammonium dihydrochloride Bu butyl CI3CD deuterochloroform CDI carbonyl diimidazole Celite® registered trademark of Celite Corporation of diatomaceous earth CI-MS mass spectroscopy by concentrated chemical ionization / ad doublet DCM dichloromethane dd doubles double ddd doubles doublet doubles DMAP 4 - (? /,? / - dimethyl) amino pyridine DMF N, N-dimethyl formamide DMSO dimethylsulfoxide DMSO-c / 6 dimethylsulfoxide -dβ DOWEX® 66 Dowex hydroxide, anion weakly basic, macropore, mesh 25-50 dppf 1, 1'-bis (diphenylphosphino) ferrocene EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide chloride Ionization by impact of the ectrons The - MS Electronic Impact - Equiv Equiv Mass Spectrometry ES - MS Electrospray Mass Spectrometry Et Ethyl Et2O Diethyl Ether EÍ3 Triethylamine AcOEt Ethyl Acetate EtOH Ethanol Gram GC-MS Gas Chromatography - Mass Spectrometry h Hour (s) Hex hexanes 1H NMR Proton nuclear magnetic resonance HOAT 1-hydroxy-7-aza-benzotriazole HOBT 1-hydroxybenzotriazole HPLC High-performance liquid chromatography HPLC ES-MS High-resolution liquid chromatography - mass spectroscopy by electro-spraying KOíBu Potassium terbutoxide I liter LC- MS Liquid chromatography / mass spectroscopy LDA Diisopropylamide lithium m multiplet M molar ml milliliter m / z mass on charge Me methyl MeCN acetonitrile MeOH methanol mg milligram MHz megahertz min minute (s) mmol millimole mol mol pf melting point MS mass spectrometry N normal AcONa sodium acetate NBS? / - bromosuccinimide NCS / V-chlorosucc inimide NIS? / - iodosuccinimide NMM 4-methylmorpholine NMR nuclear magnetic resonance Pd2 (dba) 3 tris (dibenzylidene acetone) d palladium (0) Pd (OAc) 2 palladium acetate Pd (PPh3) tetrakis (triphenylphosphine) palladium (0) ) Pd / C Palladium on carbon (dppf) CI Pd [1, 1'-bis (diphenylphosphino) ferrocyanide] dichloropalladium (ll) Ph phenyl ppm parts per million Pr propyl psi pounds per square inch PTSA p-toluenesulfonic acid q quadruplet qt quintuplete Rf retention factor TLC ta room temperature TR retention time ( HPLC) s singlet TBAF tetrabutylammonium fluoride TBDMS f er- £ >; / F / 7d i meti I if I i I or TBDMSCI urea-dimethyl chloride / dimethylsilyl TBS fer-butyldimethylsilyl TFA Trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography TMS tetramethylsilane v / v volume by volume vol volume w / w weight by weight General Experimental Methods: Liquids and solutions sensitive to air and moisture were transferred via syringe or cannula and introduced into the reactors through a rubber septum. Commercial grade reagents and solvents were used without further purification. The term "reduced pressure concentration" refers to the use of a Buchi rotary evaporator at approximately 2000 Pa (15 mm Hg). All temperatures are reported without correction in degrees Celsius (° C). Thin layer chromatography (TLC) was used on EM Science glass plates precoated with silica gel 60 A F-254 250 μm. Column chromatography (flash chromatography) was performed in a Biotage system using pre-packaged silica gel cartridges of 32-63 microns, 60 A. Purification using reverse phase HPLC chromatography was performed using a Gilson 215 system, typically using a YMC Pro-C18 AS-342 column (150 x 20 mm ID). Typically, the mobile phase used was a mixture of H2O (A) and MeCN (B). The water could or could not be mixed with 0.1% TFA. A typical gradient would be: The electron impact mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with Hewlett Packard 5890 Gas Chromatograph, with a J & W DB-5 (0.25 μm, 30 m x 0.25 mm). The ion source was maintained at 250 ° C, and the spectra were swept in the range 50-800 μm at 2 seconds per scan. The high-resolution liquid chromatography-mass spectra (LC-MS) were obtained using the following alternatives: (A) A Hewlett-Packard 1100 HPLC equipped with a quaternary pump, with a variable wavelength detector equipment set at 254 nm , a YMC pro C-18 column (2 x 23 mm, 120A), and a mass spectrometer with trap for Finnigan LCQ ions with electrospray ionization. The spectra were swept in the 120-1200 uma range using a variable ionization time according to the number of ions in the source. The eluents were A: 2% acetonitrile in water with 0.02% TFA, and B: 2% water in acetonitrile with 0.018% TFA. The elution gradient from 10% to 95% B in 3.5 minutes at a flow rate of 1.0 ml / min was used with an initial retention of 0.5 minute and a final retention of 95% B of 0.5 minutes The total running time was 6.5 minutes or (B) Gilson HPLC equipped with two Gilson 306 pumps, a Gilson 215 Autosampler, a Wilson detector with diode array, a YMC Pro C-18 column (2 x 23mm, 120 A), and a single-quadrupole mass spectrometer Micromass LCZ with ionization by electrospray z-spray. The spectra were swept in the 120-800 uma range for 1.5 seconds. The ELSD data (Evaporation Light Scattering Detector) was also acquired as an analog channel. The eluents were A: 2% acetonitrile in water with 0.02% TFA, and B: 2% water in acetonitrile with 0.018% TFA. The elution gradient from 10% to 90% B after 3.5 minutes with a flow rate of 1.5 ml / min, was used with an initial retention of 0.5 minute and a final retention of 90% of B 0.5 minute. The total run time was 4.8 minutes. An extra interrupter valve was used in the column for interruption and regeneration. The one-dimensional routine NMR spectroscopy was performed on 300/400 MHz Varian Mercury-plus spectrometers. The samples were dissolved in deuterated solvents obtained from Cambridge Isotope Labs, and transferred to 5mm Wilmad ID NMR tubes. The spectra were acquired at 293 K. The chemical shifts were recorded on a ppm scale and referred to the appropriate solvent signals, such as 2.49 ppm for DMSO-c / s, 1.93 ppm for CD3CN, 3.30 ppm for CD3OD, 5.32 ppm for CI2CD2 and 7.26 ppm for CI3CD for 1H spectra, and 39.5 ppm for DMSO-ds, 1.3 ppm for CD3CN, 49.0 ppm for CD3OD, 53.8 ppm for CI2CD2 and 77.0 ppm for CI3CD for 13C spectra. Synthesis of intermediaries Hydrazines Intermediate A Preparation of hydrochloride (2,6-dimethylphenhydrazine) To a cooled (0 ° C) solution of 2,6-dimethylaniline (5.0 g, 41.3 mmol) in 50% aqueous CIH (45 ml), a cold (0 ° C) solution was slowly added under cooling. NO2Na (2.85 g, 41.3 mmol) in water (22.5 ml). The temperature was carefully monitored during the addition and not allowed to exceed 5 ° C. After the addition was complete, the light orange solution containing the intermediate diazonium salt was stirred at the same temperature for 20 min. A mixture of SnCl2 (11.0 g, 57.8 mmol) in concentrated CIH (30 mL) was added to the reaction by mixing for 5 minutes at 0 ° C. The reaction mixture was then heated to rt and stirred for 6 h. The precipitate was collected by filtration and washed with a small volume of cold water. Drying under vacuum gave the title compound as a white amorphous solid (7.00 g, 98%). The product was used in the next step without further purification. ES-MS m / z 137.0 (MH +); HPLC TR (min) 1, 09. 5-Aminopyrazoles Intermediary B Preparation of 3-tert-butyl-1- (2-methoxy-5-methylphenyl) -1 phyrazol-5-amine Step 1: Preparation of diphenylmethanone (2-methoxy-5-methylphenyl) hydrazone To a degassed stirred suspension of 3-iodo-4-methoxytoluene (19.84 g, 80 mmol, 1 equiv), benzophenone hydrazone (17.99 g, 88 mmol, 1.1 equiv), Xantphos (93 mg, 0 mg). , 16 mmol, 0.2 mol%), and Pd (OAc) 2 (36 mg, 0.16 mmol, 0.2 mol%) in anhydrous toluene (96 mL) was added NaOtBu (11.09 g, 112 mmol , 1, 4 equiv) in a portion at ta. The mixture was heated to 85 ° C and stirred for 12 h. The reaction mixture was cooled, diluted with 200 ml AcOEt and 100 ml of water, then the phases were separated. The insoluble residues of Pd were separated as well as the aqueous layer was removed. The organic phase was washed with 2 portions of 100 ml of water, then dried with Na 2 SO 4. The solution was concentrated under reduced pressure, yielding a yellowish orange solid. The solid was triturated in 50 ml of MeOH, collected by filtration, and washed with 50 ml of MeOH. Suction drying gave the title compound as a yellow solid (24.16 g, 95% yield). 1 H NMR (400 MHz, DMSO-d 6) D 2 25 (s, 3 H), 3.56 (s, 3 H), 6.53 (d, 1 H), 6.72 (d, 1 H), 7.30 (m, 6 H), 7.46 ( d, 2H), 7.56 (m, 1 H), 7.62 (m, 2H), 7.79 (s, 1H). ES-MS m / z 317.1 (MH +); HPLC TR (min) 4.26. Step 2: Preparation of 3-fer-butyl-1- (2-methoxy-5-methylphenyl) -1H-pyrazol-5-amine A suspension of the product obtained in step 1 (20.0 g, 63.2 mmol, 1 equiv), 4,4-dimethyl-3-oxopentanonothrile (23.75 g, 189.6 mmol, 3 eq), and p-toluenesulfonic acid monohydrate (18.03 g, 94.8 mmol, 1.5 equiv) in absolute EtOH (400 mL) was heated to reflux with stirring for 12 h. The color of the reaction began being yellow brown and then green. The RP-HPLC showed that the reaction was completed by 50-60%. The mixture was cooled to rt, then 100 ml of 1N CIH was added. The reaction was maintained with heating at reflux and stirring for 12 hours. The subsequent RP-HPLC indicated complete reaction. The mixture was cooled and the EtOH was evaporated under reduced pressure. The residue was diluted with 300 ml of AcOEt and 100 ml of 1N CIH and the layers were separated. The aqueous layer was extracted with AcOEt (4 x 75 ml). The combined organic and inorganic layers were analyzed by RP-HPLC; it was found that the organic layer contained substantial amounts of the product, PTSA and impurities, while the aqueous contained only traces of the product and some PTSA. Then the combined EtOAc was extracted with 2N CIH (4 x 50 ml). The combined acidified layers and the AcOEt layer were analyzed again; there was no remaining product in the organic layer, nor significant products in the acidified layers. All the combined acidified layers were washed once with 100 ml of Et2O, then alkalized to pH ~ 8 by the addition of solid NaHCO3. A pink solid was obtained, which was collected by filtration and washed with two 50 ml portions of water. The solid was triturated with 300 ml Et2O, collected by filtration and washed with 100 ml Et2O. Drying in vacuo gave the title compound as an off-white solid (13.3 g, 81% yield). 1 H NMR (400 MHz, DMSO-d6) D1, 18 (s, 9H), 2.25 (s, 3H), 3.74 (s, 3H), 4.69 (s, 2H), 5.25 (s) , 1 H), 7.01 (m, 2H), 7.13 (dd, 1 H). ES-MS m / z 260.2 (MH +); HPLC TR (min) 1, 47. Intermediary C Preparation of 3-fer-butyl-1- (2-methoxy-6-methylphenyl) -1H-pyrazol-5-amine Step 1: Preparation of 2-methoxy-6-methylphenyl trifluoromethanesulfonate To a mixture of 2-hydroxy-3-methoxytoluene (17.0 g, 0.123 mol) and triethylamine (19.72 ml, 0.141 mol) in dichloromethane (425 ml) was slowly added trifluoromethanesulfonic anhydride (45.13 g, 0.160 mol) under cooling to 0-5 ° C. The mixture was then heated to rt and stirred for 2 h. TLC (Eluent - AcOEt / Hexane 5%) indicated the disappearance of the starting material. The reaction mixture was concentrated by vacuum drying. Purification by silica gel chromatography using a gradient of hexanes-AcOEt / hexanes 10% as eluent gave 34.37 g (99.4%) of 2-methoxy-6-methylphenyl trifluoromethanesulfonate as a clear oil. 1 H NMR (400 MHz, CI2CD2) D 7.25 (t, 1 H), 6.90 (t, 2H), 3.90 (s, 3H), 2.37 (s, 3H); GC MS m / z 270 (M +); TR (min) 8.70. Step 2: Preparation of diphenylmethanone (2-methoxy-6-rhetillfeniDhydrazone A mixture of 2-methoxy-6-methylphenyl trifluoromethanesulfonate (3.0 g, 0.011 mol), benzophenone hydrazone (2.38 g, 0.012 mol), BINAP (0.691 g, 0.001 mol), and cesium carbonate (5.06 g) g, 0.016 mol) in toluene (50 ml) was degassed with nitrogen. Palladium (II) acetate (0.075 g, 0.33 mol) was added, and the mixture was heated at 100 ° C for 16 h. The completion of the reaction was monitored with TLC (Eluent - 5% AcOEt / Hexanes). The mixture was cooled to rt, concentrated in vacuo, and purified by silica gel chromatography using a gradient of hexanes-10% AcOEt / hexanes to reach 3.40 g (97%) of diphenylmethanone (2-methoxy-6-). methylphenyl) hydrazone. 1 H NMR (400 MHz, CI2CD2) d 7.65 (m, 2H), 7.55 (m, 3H), 7.40 (m, 2H), 7.30 (m, 3H), 6.85 ( m, 2H), 6.68 (m, 1 H), 3.70 (s, 3H), 2.67 (s, 3H); ES-MS m / z 317.1 (MH +); HPLC RT (min) 4.23. Step 3: Preparation of 3-fer-butyl-1- (2-methoxy-6-methylphenol-1H-pyrazole-5-amine A suspension of diphenylmethanone (2-methoxy-6-methylphenyl) hydrazone (12.1 g, 0.038 mol), 4,4-dimethyl-3-oxopentanenitrile (8.62 g, 0.069 mol), and p-toluenesulfonic acid monohydrate (43 , 65 g, 0.229 mol) in EtOH (217 ml) was heated to reflux for 16 h. The reaction was considered complete by TLC (Eluent - 5% EtOAc / Hexanes). The reaction mixture was cooled to rt and concentrated in vacuo. The residue was suspended in water (150 ml) and extracted with diethyl ether (6 x 100 ml). Extraction of the excess 4,4-dimethyl-3-oxopentanenitrile was monitored by TLC (Eluent - 15% AcOEt / Hexanes). The aqueous layer was made slightly alkaline with solid NaHCO3 at pH -9.0. The aqueous layer was extracted with dichloromethane (2 x 200, 1 x 150 ml). The organic layer was washed with water (150 ml), dried with sodium sulfate, filtered and concentrated by vacuum drying. The product was purified by silica gel chromatography using a gradient of 10-45% AcOEt / Hexanes as eluent, to give 3.28 g (33%) of 3-y-butyl-1- (2-methoxy-6-methylphenyl) ) -lH-p -razol-5-amine. 1 H NMR (400 MHz, CI2CD2) d 7.32 (t, 1 H), 6.92 (t, 2H), 5.50 (s, 1 H), 3.82 (s, 3H), 2, 02 (s, 3H), 1, 29 (s, 9H); ES-MS m / z 260 (MH +); HPLC TR (min) 1, 46. Intermediary D Preparation of 3- (2,2-dimethylpropyl) -1 - (2-methylphenyl) -1A / -pyrazol-5-ir] amine Step 1: Preparation of 5,5-dimethyl-3-oxohexanenitrile In a 500 ml dry balloon, acetonitrile (6.31, 153.6 mmol) dissolved in THF (50 ml) was treated with LiHMDS (156.3 ml, 1.0 M solution in THF) at -78 ° C. To this solution was added methyl 3,3-dimethylbutanoate in THF (50 ml) at -78 ° C. The solution was heated to rt, and NaHCO3 (100 mL, saturated solution) was added. It was separated in layers and the aqueous layer was extracted with ether (3 x 100 ml). The combined organic layer was dried with SO4Na2, filtered and concentrated under reduced pressure to give the desired product which was used in the next step without any purification. 1 H NMR (300 MHz, CI2CD2) d 3.47 (s, 2 H), 2.44 (s, 2 H), 1.03 (s, 9 H).

Step 2: Preparation of 3- (2,2-dimethylpropyl) -1- (2-methylphenyl) -1H-pyrazol-5-yl] amine In a mixture of 5,5-dimethyl-3-oxohexanonitrile (1.5 g, 10.77 mmol) (step 1) and (2-methylphenyl) hydrazine hydrochloride (1.62, 10.24 mmol) was added aqueous CIH ( 1 N, 150 ml), and the reaction mixture was heated to reflux for 16 h. The resulting solution was cooled to rt, alkalized to pH 8 with aqueous NaOH solution (1 N). The precipitate was collected and the solid was dried under vacuum at 60 ° C to give 1.6 g (61%) of the desired product. 1 H NMR (300 MHz, CI2CD2) d 7.27-7.38 (m, 4 H), 5.42 (s, 1 H), 3.54 (br, s, 2 H), 2.40 ( s, 2 H), 2.12 (s, 3 H), 0.96 (s, 9 H); ES-MS m / z 244.2 (MH +); HPLC TR (min) 1.01. Intermediate E Preparation of 3-cyclopentyl-1- (2-methylphenyl) -1-t-pyrazol-S-amine Step 1: Preparation of 3-cyclopentyl-3-oxopropanonitrile To a suspension of HNa (2.75 g, 68.7 mmol) in THF (15 ml) at 70 ° C was added dropwise a solution of cyclopentanecarboxylate of methyl (8, 00 g, 62.4 mmol) and anhydrous acetonitrile (3.91 mL, 74.9 mmol) in THF (5 mL). The mixture was stirred for 16 h at 70-72 ° C, cooled to rt, and diluted with ethyl acetate in aqueous CIH. The organic layer was washed with water and dried with (MgSO4). Removal of the solvent produced 3-cyclopentyl-3-oxopropanonitrile, which was used without any other purification. Step 2: Preparation of 3-cyclopentyl-1- (2-methylphenyl) -1H-pyrazole-5-amine A solution of (2-methylphenyl) hydrazine hydrochloride (2.00 g, 14.6 mmol) and crude 3-cyclopentyl-3-oxopropanenitrile from the previous step (2.32 g, -14.6 mmol) in toluene (6 ml) was heated by reflux for 16 h. Removal of the solvent under reduced pressure produced a residue that was purified by silica gel chromatography using hexane / AcOEt (3: 1, v / v) as eluent. Concentrated under reduced pressure afforded 3-cyclopentyl-1- (2-methylphenyl!) - 1H-pyrazole-5-amino as a light orange solid (2.19 g, 62%). 1 H NMR (400 MHz, CI3CD) d 1, 58-1, 82 (m, 6H), 2.00-2.16 (m, 2H), 2.17-2.21 (s, 3H), 2, 93-3.11 (m, 1 H), 3.42-3.58 (s, 2H), 5.41-5.46 (s, 1 H), 7.20-7.28 (m, 2H) 7.29-7.37 (m, 2H); ES-MS m / z 241, 9 (MH +); HPLC RT (min) 1, 69.

Intermediate F Preparation of 3-fer-butyl-1- (2-methylphenyl-1-pyrazol-5-amine 4,4-D-methyl-3-oxopentanenitrile (36.7 g, 0.29 mol), hydrochloride 2 -methylphenyl (47.7 g, 0.29 mol), and glacial acetic acid (7.03 g, 6.7 ml, 0.12 mol) were dissolved in abs alcohol (585 ml) and heated to reflux for 18 h. After removing the solvent under reduced pressure, AcOEt and water (500 ml of each), sodium bicarbonate (42 g, 0.50 mol) was then carefully added. After the addition of hexane (500 ml), the organic phase was separated, washed with brine (500 ml), and dried with Na2SO4. The mixture was filtered through a silica gel pad (500 g) on a sintered glass funnel. The bed was eluted with hexanes / AcOEt (1: 1, v / v), and filtered and concentrated under reduced pressure. The resulting solid was triturated with hexanes / AcOEt (9: 1, v / v). It was filtered and degassed and dried under vacuum to obtain as a product a colorless solid (61.5 g, 93%). 1 H NMR (400 MHz, CI2CD2) d 1.29 (s, 9H), 2.12 (s, 3H), 3.56 (br, 2H), 5.48 (s, 1H), 7.28 (m, 2H), 7.31 (m, 2H). Intermediate G Preparation of 3- (4-fluorophenyl) -1 - (2-methylphenyl) -1H-pyrazol-5-amine Step 1: Preparation of 3-amino-3- (4-fluorophenyl) acrylonitrile, To a solution of 4-fluorobenzonitrile (5.00 g, 41.3 mmol) and acetonitrile (4.35 mL, 82.5 mmol) in toluene (100 mL) was added potassium fer-butoxide (13.9 g, 124 mmol). The mixture was stirred for 24 h, and then neutralized by the addition of aqueous sodium bicarbonate. The resulting suspension was extracted with dichloromethane (3 x 50 ml). The organic solution was washed with water, dried with (SO4Na2), and concentrated under reduced pressure. The residue was triturated with EtOH / Et2O to obtain 3-amino-3- (4-fluorophenyl) acrylonitrile (6.20 g, 93%) as a white solid. 1H NMR (300 MHz, acetone-d6) d 4.23 (s, 1 H), 6.20 (s, 2 H), 7.22 (ddd, 2 H), 7.71 (m, 2 H). Step 2: Preparation of 3- (4-fluorophenyl) -1- (2-methylphenyl) -1 / -pyrazol-5-amine To a solution of 3-amino-3- (4-fluorophenyl) acrylonitrile (600 mg, 3.70 mmol) in 1 N CIH (6 mL) was added (2-methylphenyl) hydrazine hydrochloride (558 mg, 3.51 mmol). The reaction was followed with reflux for 16 h, and cooled to rt. The resulting mixture was made alkaline to pH 12 by slow addition of 1 N aqueous sodium hydroxide solution. The precipitate was collected by filtration, and recrystallized from EtOH / Et2O to give the intermediate (800 mg, 81%) as a light orange solid. 1 H NMR (400 MHz, CI2CD2) d 2.20 (s, 3 H), 2.14 (br s, 2 H), 5.91 (s, 1 H), 7.06 (t, 2 H), 7.36. (d, 4H), 7.75 (m, 2H). This material was used without any type of purification. Intermediate H Preparation of 3-fer-butyl-1- (2-methoxy-6-methylphenyl) -4-methyl-1-tf-pyrazol-5-amine Step 1: Preparation of 4-bromo-3-fer-butyl-1- (2-methoxy-6-methylphenyl) -1H-pyrazole-5-amine To a solution of 3-fer-butyl-1- (2-methoxy-6-methylphenyl) -lH-pyrazol-5-amine (2.00 g, 7.71 mmol) (Intermediate C) in acetic acid (15 ml Bromine (1170 mg, 0.38 ml, 7.33 mmol) was added dropwise. This reaction mixture was stirred for 5 min at rt, and then diluted with water (100 ml), yielding a solid precipitate. The solid was collected by filtration, dissolved in AcOEt. The organic phase was washed with saturated NaHCO3 solution and brine and dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the product (2683 mg, 102%) containing minor impurities. ES-MS m / z 338.2 (MH +); HPLC TA (min) 3.06. Step 2: Preparation of 3-fer-butyl-1- (2-methoxy-6-methyphenyl) -4-methyl-1H-pyrazol-5-amine To a solution of 4-bromo-3-fer-butyl-1- (2-methoxy-6-methylphenyl) -1 / - / - pyrazol-5-amine (2.6 g, 7.68 mmol) in DMF ( 15 ml) was added methylboroxin (6.66 ml, 46.08 mmol), [1, 1'-bis (diphenylphosphino) -butane] palladium (II) dichloride (481, 97 mg, 0.80 mmol), and potassium carbonate (3.3 g, 23.04 mmol). The reaction mixture was stirred for 18 h at 155 ° C. The reaction was diluted with water (100 ml) and extracted with AcOEt (3 x 25 ml). The combined organic extract was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified with silica gel chromatography using 90% hexane / AcOEt, to obtain the product (1.7 g, 77%) as a pure solid. 1 H NMR (300 MHz, DMSO-d 6) d 1.24 (s, 9 H), 1.96 (s, 3 H), 1.99 (s, 3 H), 3.71 (s, 3 H), 4, 25 (s, 2H), 6.85 (d, 1 H), 6.94 (d, 1H), 7.23-7.29 (m, 1H). ES-MS m / z 274.2 (MH +); HPLC TR (min.) 1, 78. Intermediate I Preparation of 4- (4-fluorophenyl) -3-methyl-1- (2-methylphenyl) -1- -pyrazol-5-amine Step 1: Preparation of 4-bromo-3-methyl-1- (2-methylphenyl) -1H-pyrazole-5-amine To a solution of 3-methyl-1- (2-methylphenyl) -lH-pyrazol-5-amine (7.78 g, 41.7 mmol) in acetic acid (90 ml) was added a solution of bromine (6, 64 g, 41.6 mmol) in acetic acid (10 ml). The reaction mixture was stirred for 30 min. Water was added to the mixture, and alkalized using cold KOH solution (1 N). The white solid, 4-bromo-3-methyl-1- (2-methylphenyl) -lH-pyrazol-5-amine, was obtained and used in the next step without any further purification. Step 2: Preparation of 4- (4-fluorophenyl) -3-methyl-1- (2-methylphenyl) -1H-pyrazol-5-amine 4-Bromo-3-methyl-1- (2-methylphenyl) -l H-pyrazol-5-amine (2 g, 7.52 mmol), 4-fluorophenylboronic acid (2.10 g, 11.3 mmol) were dissolved, and Pd (PPh3) 4 (434 mg, 0.38 mmol) in DMF (20 ml), and Na2CO3 (saturated aqueous solution, 18 ml) was added. The mixture was degassed for 10 min and heated at 110 aC for 2 h. The reaction mixture was diluted, and the solid was filtered. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography using between 10 and 40% ethyl acetate in hexane to give 1.2 g (90% pure, 51%) of the desired compound. 1 H NMR (300 MHz, CI2CD2) d 7.25-7.34 (m, 6H), 7.08 (t, 2H), 3.62 (s, 2H), 2.20 (s, 3H), 2 , 14 (s, 3H). Intermediary J Preparation of methyl 3-chloro-6-methoxypyridine-2-carboxylate Step 1: Preparation of 3-chloro-6-methoxypyridine-2-carboxylic acid To a solution of 3,6-dichloropyridine-2-carboxylic acid (7.10 mmol, 1.36 g) in dioxane (15 ml) was added sodium methoxide (21.31 mmol, 1.15 g) in methanol dropwise . The mixture was stirred at 85 ° C for 14 h, cooled to rt, and diluted with ethyl acetate and aqueous HCl. The organic layer was washed with water and salt and dried (MgSO4). Removal of the solvent produced 3-chloro-6-methoxypyridine-2-carboxylic acid which was used in the next step without any purification Step 2: Preparation of methyl 3-chloro-6-methoxypyridine-2-carboxylate Thionyl chloride (5 ml) was added to 3-chloro-6-methoxypyridine-2-carboxylic acid (7.10 mmol, 1.30 g) under argon at rt, and the mixture was heated to reflux for 2 h. Then it was cooled to rt, the excess thionyl chloride was removed under reduced pressure to produce a yellow oil. Anhydrous methanol was then added slowly with stirring at 0 ° C, and the reaction solution was heated to rt and stirred for 4 h. The excess methanol was removed and the residue was neutralized with saturated NaHCO3 solution and extracted with AcOEt. The organic phase was dried with MgSO 4 and evaporated to obtain the product as a white solid which was used without any purification. 1 H NMR (400 MHz, DMSO-d 6) d 3.84 (s, 3 H), 3.86 (s, 3 H), 7.05 (d, 1 H), 7.92 (d, 1 H). Examples of the invention Example 1 Preparation of 2- (r3-fer-butyl-1- (2-methylphenyl) -1H-pyrazole-5-aminoamino-6-methyl-nicotinic acid A mixture of 2-chloro-6-methylnicotinic acid (122 mg, 0.71 mmol), potassium carbonate (108 mg, 0.78 mmol), 3-fer-butyl-1- (2-methylphenol) ) -1H-p¡razole-5-amine (Intermediate F, 163 mg, 0.71 mmol), and copper (II) acetate (2.6 mg, 0.014 mmol) in DMF (2 mL) was heated (150 ° C) in a sealed tube for 16 h. The mixture was cooled to rt, filtered on a silica gel pad using ethyl acetate as eluent, concentrated to dryness, and subjected to HPLC purification using an elution gradient of 30% to 90% acetonitrile in water. This produced 182.2 mg (70%) of the desired product. 1 H NMR (300 MHz, CD 3 OD) d 8.14 (d, 1 H), 7.14-7.51 (m, 4 H), 7.01 (s, 1 H), 6.80 (d, 1 H), 2.53 (s, 3 H), 2.10 (s, 3 H), 1, 40 (s, 9 H); ES-MS m / z 365.3 (MH +); HPLC TR (min) 3.23.

Using the conditions described for Example 1, and by appropriate substitution of the starting materials, Examples 11-75 and 147-150 were prepared in a similar manner and are described in Table 1 below. Example 2 Preparation of 2- r3-cyclopentyl-1- (2-methylphenyl) -1H-pyrazol-5-ipamino nicotinic acid A mixture of 2-chloronicotinic acid (113 mg, 0.72 mmol), potassium carbonate (199 mg , 1.44 mmol), 3-cyclopentyl-1- (2-methylphenyl) -1-pyrazole-5-amine (174 mg, 0.72 mmol) (Intermediate E), and copper acetate (II) (6, 5 mg, 0.04 mmol) in DMF (3 ml) was heated (150 ° C) in a sealed tube for 16 h. The mixture was cooled to rt, filtered over a silica gel plug using ethyl acetate as eluent, concentrated to dryness, and subjected to HPLC purification with an elution gradient of 30% to 90% acetonitrile in water to obtain 59.7 mg (23%) of the desired product. 1 H NMR (300 MHz, CI2CD2) d 10.69 (s, 1 H), 8.36 (dd, 1 H), 8.16 (dd, 1 H), 7.52 (d, 2 H), 7.32-7.41 (m, 2 H), 6.93 (dd, 1 H), 6.82 (s, 1 H), 3.11-3.22 (m, 1 H), 2, 19-2.21 (m, 2 H), 1.94 (s, 3 H), 1, 65-1, 89 (m, 6 H); ES-MS m / z 363.2 (MH +), HPLC TR (min) 3.57. Example 3 Preparation of 3-fp- (5-fluoro-2-methylphenyl) -3-methyl-4-phenyl-1f / -pyrazol-5-pamino) isonicotinic acid A mixture of 3-iodoisonicotinic acid (180 mg, 0.72 mmol), potassium carbonate (199 mg, 1.44 mmol), 1- (5-fluoro-2-methylphenol) -3-methyl-4-phenyl-1 / - / -pyrazol-5-amine (202 mg, 0.72 mmol, synthesized in the same manner as intermediate F, using commercial 2-phenylacetoacetonitrile as a source of nitriles) and copper (II) acetate (6.5 mg, 0.04 mmol ) in DMF (1 ml) was heated (150 ° C) in a sealed tube for 16 h. The mixture was cooled to rt, filtered on a silica gel pad using ethyl acetate as eluent, concentrated to dryness, and subjected to HPLC purification with an elution gradient of 30% to 90% acetonitrile in water to obtain obtain 29.1 mg (10%) of the desired product. 1 H NMR (300 MHz, CN CD3) d 9.39 (br s, 1 H), 7.93 (s, 1 H), 7.86-7.90 (m, 2 H), 7.05-7 , 45 (m, 8 H), 2.38 (s, 3 H), 2.15 (s, 3 H); ESMS MS m / z 403.1 (MH +), HPLC TA (min) 2.40. Example 4 Preparation of the acid 3-. { f3-tert-butyl-1- (2-methylphenyl-1H-pyrazol-5-yn-amino} pyridine-2-carboxylic acid A mixture of 3-bromopyridine-2-carboxylic acid (71 mg, 0.35 mmol), potassium carbonate (53 mg, 0.39 mmol), 3-ee -butyl-1- (2-methylphenyl) -1H- pyrazole-5-amine (80 mg, 0.35 mmol) (Intermediate F), and copper (II) acetate (1.3 mg, 0.007 mmol) in DMF (1 ml) was heated (150 ° C) in a sealed tube for 16 h. The mixture was cooled to rt, filtered on a silica gel pad using ethyl acetate as eluent, concentrated to dryness, and subjected to HPLC purification with an elution gradient of 30% to 90% acetonitrile in water to obtain 2.8 mg (2.3%) of the desired product. H NMR (300 MHz, CD3OD) d 8.11 (dd, 2 H), 7.79 (dd, 1 H), 7.32-7.45 (m, 4 H), 6.45 (s, 1 H), 2.11 (s, 3 H), 1.40 (s, 9 H); ES-MS m / z 351, 0 (MH +), HPLC TA (min) 2.46. Example 5 Preparation of the acid 5-. { ri- (2,5-dimethylphenyl) -3- (4-fluorophenyl) -1-pyrazol-5-in-amino) -2- (thiomethyl) pyrimidine-4-carboxylic acid A mixture of 5-chloro-2- (thiomethyl) -pyrimidine-4-carboxylic acid (89 mg, 0.44 mmol), potassium carbonate (66 mg, 0.48 mmol), 1 ~ (2,5-dimethylphenyl) ) -3- (4-fluorophenyl) -1H-pyrazol-5-amine (123 mg, 0.44 mmol), synthesized in a manner similar to Intermediate G, and copper (II) acetate (1.6 mg, 0.009 mmol) in DMF (1 ml) was heated (150 ° C) in a sealed tube for 16 h. The mixture was cooled to rt, filtered over a silica gel plug using ethyl acetate as eluent, concentrated to dryness, and subjected to HPLC purification with an elution gradient of 30% to 90% acetonitrile in water to obtain obtain 24.2 mg (12.3%) of the desired product. 1 H NMR (300 MHz, CI2CD2) d 8.95 (s, 1 H), 8.90 (s, 1 H), 7.85 (dd, 2 H), 7.10-7.28 (m, 5 H), 7.62 (s, 1 H), 2.58 (s, 3 H), 2.38 (s, 3 H), 2.14 (s, 3 H); ES-MS m / z 406.3 (MH + -CO2), HPLC TA (min) 4.07. Example 6 Preparation of 2-r (3-methyl-1-phenyl-1-pyrazol-5-iDaminolnicotinamide Step 1: Preparation of 2-f (3-methyl-1-phenyl-1 H -pyrazol-5-yl acid amino-nicotinic To a solution of 3-methyl-1-phenyl-1 / - / - pyrazol-5-amine (600 mg, 3.46 mmol) and 2-chloronicotinic acid (546 mg, 3.46 mmol) in DMF (6 ml ), potassium carbonate (543 mg, 3.93 mmol) and copper (II) acetate (18 mg) were added. The mixture was stirred at 150 ° C for 18 h, and then cooled to rt, and diluted with ethyl acetate (2X) and water. The solution was adjusted to pH 2-3 using 1 N CIH aqueous solution. The mixture was extracted with AcOEt (3 x 5 mL), and then the combined organic extracts were washed with brine, dried (MgSO4), and concentrated at reduced pressure. The residue was purified by HPLC (20-90% acetonitrile in water) to obtain the product (126 mg, 18%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6) d 2.19 (s, 3 H), 6.62 (s, 1 H), 6.77 (m, 1 H), 7.34 (m, 1 H), 7 , 45 (m, 2H), 7.53 (m, 2H), 8.16 (d, 1 H), 8.22 (d, 1 H), 12.32 (s, 1H); ES-MS m / z 295.1 (MH +); HPLC TR (min) 2.17.

Step 2: Preparation of 2 - [(3-methyl-1-phenyl-1 - / - p¡razol-5-yl) amino-1-nicotinamide To a solution of 2 - [(3-methyl-1-phenyl-1 H -pyrazol-5-yl) amino] nicotinic acid (40 mg, 0.14 mmol), EDCI (52 mg, 0.27 mmol), HOAT (37 mg, 0.27 mmol), and triethylamine (0.06 ml, 0.41 mmol) in dichloromethane (4 ml) were added ammonia (7 N) in methanol (0.2 ml). The reaction mixture was stirred for 16 h at rt. The organic layer was washed with water, dried with MgSO 4, and then concentrated under reduced pressure. The product was purified on a preparative silica gel plate (1000 microns) with AcOEt / hexane (2: 1, v / v) to obtain the product as a white solid (22 mg, 55%). 1 H NMR (400 MHz, DMSO-d6) d 2.2 (s, 3 H), 6.63 (s, 1 H), 6.89 (m, 1 H), 7.38 (m, 1 H) , 7.50 (m, 4H), 7.71 (s, 1 H), 8.15 (d, 1 H), 8.24 (s, 1 H), 8.33 (d, 1 H), 11.56 (s, 1 H); ES-MS m / z 294.1 (MH +); HPLC TA (min) 2.02. Example 7 Preparation of 2-f r3- (4-fluorophenyl) -1 - (2-methylphen-D-1 H -pyrazol-5-yl] amino> nicotinamide A mixture of 2-chloronicotinamide (59 mg, 0.37 mmol), potassium carbonate (57 mg, 0.41 mmol), 3- (4-fluorophenyl) -1- (2-methylphenyl) -1 / - / - pyrazol-5-amine (100 mg, 0.37 mmol) (Intermediate G), and copper (II) acetate (1.4 mg, 0.007 mmol) in DMF (1 ml) was heated in a sealed tube (150 ° C) for 16 h. The mixture was cooled to rt, filtered through silica gel pad using ethyl acetate as eluent, concentrated to dryness and subjected to HPLC purification using elution gradient from 30% to 90% acetonitrile in water to obtain 20 mg (14%) of the desired product. 1 H NMR (300 MHz, CI2CD2) d 10.88 (s, 1 H), 8.48 (dd, 1 H), 7.89 (dd, 2 H), 7.74 (dd, 1 H), 7.35-7.50 (m, 4 H), 7.28 (s, 1 H), 7.12 (t, 2 H), 6.82 (dd, 1 H), 5.85 (br, s, 2 H), 2.16 (s, 3 H); ES-MS m / z 388.2 (MH +), HPLC TR (min) 3.61.

Using the conditions described for Example 7 above, and substituting The starting materials for the suitable ones, Examples 76-94 were prepared in a similar manner and are described in Table 1 below. Example 8 Preparation of the acid 2-fr3- (2,2-dimethylpropylM- (2-methylphenyl) -1H-pyrazole-5-iH amino.}. Nicotinic acid Step 1: Preparation of 2-. { [Ethyl 3- (2,2-dimethylpropi0-1- (2-methylpheni0-1 - pyrazole-5-ylaminolnicotinate To a 15 ml dry tube was added 3- (2,2-dimethylpropyl) -1- (2-methylphenyl) -1w-pyrazol-5-yl] amine (200 mg, 0.82 mmol) (Intermediate D), Ethyl 2-chloronicotinate (185 mg, 0.82 mmol), Pd2 (dba) 3 (37.6 mg, 0.041 mmol), BINAP (51.2 mg, 0.082 mmol), and Cs2CO3 (535.6 mg, 1.64 mmol). The content was then degassed by the addition of toluene (2 ml), and the mixture was then heated to 110 ° C for 20 h. The mixture was cooled to rt, filtered through a silica gel pad using ethyl acetate as eluent, concentrated by drying and subjected to HPLC purification using an elution gradient of 45% to 90% acetonitrile in water. to obtain 275 mg (85%) of the desired product. 1 H NMR (300 MHz, CD2Cl2) d 10.04 (s, 1 H), 8.44 (dd, 1 H), 8.21 (dd, 1 H), 7.34-7.48 (m, 4 H), 6.82 (dd, 1 H), 6.75 (s, 1 H), 4.19 (q, 2 H), 2.57 (s, 2 H), 2.12 (s, 3 H), 1, 28 (t, 3 H), 1.02 (s, 9 H); ES-MS m / z 393.3 (MH +); HPLC TA (min) 4.33. Step 2: Preparation of 2- (r3- (2,2-dimethylpropyl) -1- (2-methylphenyl) -1-pyrazol-5-riaminolnicotinic acid To a solution of 2-. { [3- (2,2-dimethylpropyl) -1- (2-methylphenyl) -lH-pyrazol-5-yl] amine} Ethyl nicotinate (266 mg, 0.68 mmol) (step 1) in a mixture of ethanol (1 ml) and THF (1 ml) was added lithium hydroxide monohydrate (284 mg, 6.8 mmol) in water (2%). ml), and the mixture was heated at 40 ° C for 1 h. The reaction mixture was cooled to rt, the pH of the solution was adjusted to 5 by adding 0.5N hydrochloric acid solution, and concentrated by drying. The crude product was redissolved in methanol and subjected to purification by HPLC using an elution gradient of 30% to 90% acetonitrile in water to obtain 240 mg (97%) of the desired product. 1 H NMR (300 MHz, CI2CD2) d 10.39 (s, 1 H), 8.43 (dd, 1 H), 8.14 (dd, 1 H), 7.25-7.42 (m, 4 H), 6.81-6.86 (m, 2 H), 2.57 (s, 2 H), 2.05 (s, 3 H), 1.00 (s, 9 H); ES-MS m / z 365.3 (MH +); HPLC RT (min) 3.67.

Using the conditions described in Example 8 above, and by substitution of the appropriate starting materials, Examples 85-116 and 129-146 were prepared in a similar manner and are described in Table 1 below. Using both Pd2 (dba) 3 and Pd (OAc) 2 in Step 1 for Example 116 give similar yields. EXAMPLE 9 Preparation of 2- f1- (2-chlorophenyl) -3- (4-fluorophenyl) -1-pyrazol-5-in-amino) nicotinic acid Step 1: Preparation of 2-. { [1- (2-chlorophenyl) -3- (4-fluorophenip-1 / - / - pyrazol-5-amine> ethyl-nicotinate) To a 15 ml dry tube was added 1- (2-chlorophenyl) -3- (4-fluorophenyl) -lH-pyrazol-5-amine (300 mg, 1.04 mmol), synthesized under the same conditions as the Intermediate G, ethyl 2-chloronicotinate (194 mg, 1.04 mmol), (dba) 3 Pd2 (48 mg, 0.05 mmol), BINAP (65 mg, 0.10 mmol), and Cs2CO3 (679 mg, 2.09 mmol). The content was then degassed by adding toluene (4 ml) and the mixture was heated at 110 ° C for 20 h. The mixture was cooled to rt, filtered through silica gel pad using ethyl acetate as eluent, concentrated by drying and subjected to HPLC purification using an elution gradient of 45% to 90% acetonitrile in water to obtain 410 mg (90%) of the desired product. 1 H NMR (300 MHz, CI2CD2) d 10.17 (s, 1 H), 8.46 (dd, 1 H), 8.22 (dd, 1 H), 7.89 (dd, 2 H), 7 , 48-7.64 (m, 4 H), 7.23 (s, 1 H), 7.12 (t, 2 H), 7.84 (dd, 1 H), 4.24 (q, 2) H), 1, 32 (t, 3 H); ES-MS m / z 437.2 (MH +); HPLC TA (min) 4.38. Step 2: Preparation of the acid 2-. { ri- (2-chloropheni-3- (4-fluorophen-1-H-pyrazole-5-pamino "fnicotinic To a solution of 2-. { [1- (2-chlorophenyl) -3- (4-fluorophenyl) -lH-pyrazol-5-yl] amino} Ethyl nicotinate (410 mg, 0.94 mmol) in a mixture of methanol (4 ml) and THF (4 ml) was added lithium hydroxide monohydrate (115 mg, 2.74 mmol) in water (8 ml), and the mixture was heated at 40 ° C for 1 h. The reaction mixture was cooled to rt, and the pH of the solution was adjusted to 5 by the addition of 0.5 N CIH solution (the mixture became turbid). The solid was filtered and washed with water. The solid was dried under vacuum at 60 ° C to give 380 mg of the desired product (99%). 1 H NMR (300 MHz, CI2CD2) d 10.18 (s, 1 H), 8.45 (dd, 1 H), 8.24 (dd, 1 H), 7.87 (dd, 2 H), 7 , 47-7.62 (m, 4 H), 7.23 (s, 1 H), 7.12 (t, 2 H), 6.85 (dd, 1 H); ES-MS m / z 351, 2 (MH +); HPLC TA (min) 2.58. Example 10 Preparation of 3-fr3-tert-butyl-1- (2,6-dimethylphenylMrt-pyrazol-5-yl) amino) pyridine-2-carboxylic acid Step 1: Preparation of 3-. { [(trifluoromethyl) sulfonipoxy} ethyl pyridine-2-carboxylate To 3-hydroxypyridine-2-carboxylic acid (25 g, 179.5 mmol) in a dry 1 I vessel were added 400 ml of ethanol and 100 ml of toluene followed by the addition of 10 ml of sulfuric acid. The mixture was heated to reflux (95 ° C) for 3 days. Then it was cooled to rt, the mixture was concentrated to 1/4 of its volume, and diluted with 600 ml of ethyl acetate and 200 ml of water. The aqueous layer was extracted with 200 ml of ethyl acetate, and the combined organic phases were washed with saturated NaHCO3 solution (3 x 200 ml), brine and dried with Na2SO4. The solid was filtered and the solvent was concentrated under reduced pressure to give, 9 g of ethyl 3-hydroxypyridine-2-carboxylate (73%), which was used in the next step without any purification. This ester (21.9 g, 131 mmol) was dissolved in pyridine and cooled to -40 ° C, followed by the addition of trifluoromethanesulfonic anhydride (48 g, 170 mmol). The reaction mixture was then heated at 0 ° C for 30 min, and then heated at rt for another 30 min. Water (100 ml) was added to facilitate the reaction. The mixture was extracted with ethyl acetate, and the combination of the organic layers was washed with saturated sodium bicarbonate solution (200 ml), water (200 ml), brine (200 ml), and dried with sodium sulfate. The solid was filtered and the solvent was removed under reduced pressure to give 39 g (99%) of the desired product, which was used in the next step without any purification. 1 H NMR (300 MHz, CI2CD2) d 8.73 (dd, 1 H), 7.72 (dd, 1 H), 7.62 (dd, 1 H), 4.46 (q, 2 H), 1 , 42 (t, 3 H). Step 2: Preparation of ethyl 3- (3-fer-butyl-1- (2,6-dimethylphenylo-1 H-pyrazol-5-yl) amino) pyridine-2-carboxylate To a dry 100 ml vessel was added 3-fer-butyl-1- (2,5-dimethylphenyl) -lH-pyrazol-5-amine (1.68 g, 6.9 mmol), synthesized in the same manner as Intermediary F using Intermediary A, 3-. { [(trifluoromethyl) sulfonyl] oxy} ethyl pyridine-2-carboxylate (1.88 g, 6.28 mmol) (from step 1), Pd2 (dba) 3 (0.28 g, 0.31 mmol), BINAP (0.39 g, 0, 63 mmol), and Cs2CO3 (4.1 g, 12.5 mmol). The content was degassed by adding toluene (10 ml) and the mixture was heated at 110 ° C for 4 h. The mixture was cooled to rt, filtered through Celite® with ethyl acetate as eluent, concentrated by drying and purified by silica gel chromatography with 10 to 30% ethyl acetate in hexane to obtain 1.4 g. (57%) of the desired product. 1 H NMR (300 MHz, CI2CD2) d 9.29 (s, 1 H), 8.19 (dd, 1 H), 7.82 (dd, 1 H), 7.41 (dd, 1 H), 7 , 31 (dd, 1 H), 7.19 (d, 2 H), 6.18 (s, 1 H), 4.28 (q, 2 H), 2.01 (s, 6 H), 1 , 39 (s, 9 H), 1, 32 (t, 3 H); ES-MS m / z 393.2 (H +); HPLC TR (min) 3.57. Similar yields for this step are obtained when Pd2 (dba) 3 is replaced by Pd (OAc) 2.

Step 3: Preparation of 3- (3-tert-butyl-1- (2,6-dimethylphenyl) -1 - / - pyrazol-5-ylmene) pyridine-2-carboxylic acid To a solution of 3-. { [3-Ier-butyl-1- (2,6-dimethylphenyl) -lH-pyrazol-5-yl] amino} Ethyl pyridine-2-carboxylate (2.10 g, 5.35 mmol) in a mixture of ethanol (5 ml) and THF (5 ml) was added lithium hydroxide monohydrate (1.12 mg, 26.8 mmol) in water (10 ml), and the mixture was heated at 40 ° C for 1 h. The reaction mixture was cooled to rt, the pH of the solution was adjusted to 5 by the addition of 0.5N hydrochloric acid, and the mixture was concentrated by drying. The crude mixture was dissolved in methanol and subjected to purification by HPLC using an elution gradient of 30% to 90% acetonitrile in water to obtain 1.65 g (85%) of the desired product. 1 H NMR (300 MHz, CI2CD2) d 10.22 (br, s, 1 H), 9.52 (s, 1 H), 8.03 (dd, 1 H), 7.86 (dd, 1 H) , 7.50 (dd, 1 H), 7.30 (dd, 1 H), 7.18 (d, 2 H), 2.02 (s, 6 H), 1.37 (s, 9 H); ES-MS m / z 321, 3 (MH +); HPLC TA (min.) 2.56. Example 11 Preparation of the acid 4-fr3-tert-butyl-1- (2,5-dimethylphenyl) -1H-pyrazole-5-ip amino} -2- (thiomethyl) pyrimidine-5-carboxylic acid Step 1: Preparation of 4- (f3-fe? -butiyl-l, 2,5-dimethylphenyl) -1 / -pyrazo-5-ipamino (thiomethyl) pyrimidine-5-carboxylate of eti / o To a 15 ml dry tube was added 3-fer-butyl-1- (2,5-dimethylphenyl) -1 i-p arazoin amine (106 mg, 0.44 mmol), synthesized in the same manner as intermediate F, 4 -chloro-2- (tiomef //) pir / m / d / n-5-carboxy / ato (101 mg, 0.44 mmol), Pd2 (dba) 3 (20 0.022 mmol), BINAP (27 mg, 0.044 mmol), and Cs2CO3 (199 mg, 0.61 mmol). The contents were degassed followed by the addition of toluene (2 ml), and the mixture was heated at 110 ° C for 20 h. The mixture was cooled to rt, filtered through silica gel filter using ethyl acetate as eluent, concentrated to dryness and subjected to purification by HPLC using an elution gradient of 45% to 90% aceionit in water to obtain 81 mg (42%) of the desired product. H NMR (300 M CI2CD2) d 10.23 (s, 1 H), 8.72 (s, 1 H), 7.24 (dd, 2 H), 7.16 (s, 1 H), 6, 78 (s, 1 4.20 (q, 2 H), 2.64 (s, 3 H), 2.38 (s, 3 H), 2.04 (s, 3 H), 1.34 (s) , 9 H), 1.28 (t, 3 ES-MS m / z 440.2 (MH +); HPLC TA (min) 4.66.

Step 2: Preparation of 4- (f3-te / - bufií-1-f2.5-d / mßt // phen / l) -1r -pírazol-5-yl-2- (methylthio) pyrimidine-5-carboxylic acid To a solution of ethyl 4- carboxylate. { [3-Ier-butyl-1- (2,5-dimethyphenyl) -1 pyrazol-5-yl] amino} -2- (methylthio) pyrimidine-5 (71 g, 0.16 mmol) in a mixture of ethane (0.5 ml) and THF (0.5 ml) was added lithium hydroxide monohydrate (68 mg, 1.6 mm in water (1 ml), and the mixture was heated at 40 ° C for 1 h.The reaction mixture was cooled to rt, the pH of the solution was adjusted to 5 by addition of 0.5N hydrochloric acid, the mixture The mixture was concentrated to dryness The crude mixture was dissolved in methanol and subjected to HPLC purification using an elution gradient of 30% to 90% acetonitrile in water to obtain 66 mg (99%) of the desired product.1H NMR (3 MHz, CI2CD2) d 10.50 (s, 1 H), 8.65 (s, 1 H), 7.17 (dd, 2 H), 7.12 (s, 1 H), 6.83 (s, H ), 2.68 (s, 3H), 2.27 (s, 3 H), 1.97 (s, 3 H), 1.35 (s, 9 H), ES-MS m / z 412.2 (MH + HPLC TR (min) 3.94 Example 12 Preparation of 3-ff3-fer-butyl-1- (2,6-dimethylphenyl) -4-fluoro-1A-pyrazolo-5-ipammo. 2-carboxyHco To a solution of acid 3-. { [3-fer-butyl-1- (2,6-dimethylphenyl) -lH-pyrazol-yl-amino} pyridine-2-carboxylic acid (Example 10, 50 mg, 0.14 mmol) in CH 3 CN (1 ml) s added. [(1- (chloromethyl) -4-fluoro-1,4-diazoniabicyclo [2.2.2] octane-bis- (tetrafiuoroborate)] (SELECTFLUOR ™) (48 mg, 0.14 mmol), and the mixture was stirred The mixture was concentrated and the residue was subjected to HPLC purification with an elution gradient of 10% to 90% acetonitrile in water to obtain 22 mg (42%) of the title compound. MHz, CD2Cl2) d 9.18 (s, 1 H), 8.04 (d, 1 H), 7.50 (dd, 1 H), 7.42 (m, 1 H), 7.28 (m , 1 H), 7.13 (m, 2 H), 2.12 (s, 6 H), 1.40 (s, 9 H) ES-MS m / z 383.1 (MH +); HPLC TA (min) 3.21 Example 13 Preparation of 3-fr3-fer-butyl-1- (2,6-dimethylphenyl) -4-iodo-1H-pyrazol-5-ylamino} pyridin-2-carboxylic acid To a solution of acid 3-. { [3-fer-butyl-1- (2,6-dimethylphenyl) -1w-pyrazol-5-yl] amino} pyridine-2-carboxylic acid (Example 10, 50 mg, 0.14 mmol) in a mixture of acetic acid / dichloromethane (1 ml of each) was added w-iodosuccinimide (31 mg, 0.14 mmol). The solution was stirred at rt for 12 h, and water (10 ml) was added. The reaction mixture was alkalized to pH 9 using KHO (1.0 M in ice-cooled solution). The aqueous layer was extracted with dichloromethane (50 ml), and the organic layer was washed sequentially with saturated sodium sulfite solution, brine and concentrated to dryness. The reaction mixture was subjected to purification by HPLC to obtain the desired product (51 mg, 75%). 1 H NMR (300 MHz, CI2CD2) d 9.70 (s, 1 H), 9.20 (s, 1 H), 8.04 (m, 1 H), 7.45 (m, 1 H), 7 , 20 (m, 2 H), 7.10 (m, 2 H), 2.12 (s, 6 H), 1.50 (s, 9 H). ES-MS m / z 490.9 (MH +); HPLC TA (min) 3.40.

Example 14 Preparation of 3- r3-fer-butyl-4-chloro-1-y2,6-dimethylphenyl) -1 / Y-pyrazol-5-yl] amino pyridin-2-carboxylic acid To a solution of acid 3-. { [3-Ier-butyl-1- (2,6-dimethylphenyl) -1w-pyrazol-5-yl] amino} pyridine-2-carboxylic acid (Example 10, 50 mg, 0.14 mmol) in a mixture of acetic acid / dichloromethane (1 ml of each) was added? / - chlorosuccinimide (18 mg, 0.14 mmol). The solution was stirred at rt for 12 h, water (10 mL) was added. The reaction mixture was made alkaline to pH 9 using KOH (1.0 M in ice-cooled solution). The aqueous layer was extracted with dichloromethane (50 ml), and the organic phase was washed sequentially with sodium sulfite, brine, and concentrated to dryness. The crude material was subjected to purification by HPLC to give the desired product (42 mg, 76%). 1 H NMR (300 MHz, CI2CD2) d 10.45 (s, 1 H), 9.30 (s, 1 H), 8.04 (d, 1 H), 7.50 (m, 1 H), 7 , 25 (m, 2 H), 7.15 (m, 2 H), 2.02 (s, 6 H), 1, 43 (s, 9 H). ES-MS m / z 399.0 (MH +); HPLC TA (min) 3.33. Example 15 Preparation of 2-ff3- (1,1-dimethylpropyl) -1 - (3-fluoro-2-methoxyphenyl) -1H-pyrazol-5-yl-amino} -? /,? / - dimetilnicotinamida To a solution of acid 2-. { [3- (1, 1-dimethylpropyl) -1- (3-fluoro-2-methoxyphenyl) -1f pyrazole-5-yl] amino} nicotinic, (Example 140, synthesized in a manner similar to the example (8, 50 mg, 0.13 mmol) in CH 3 CN (1 ml) was added one drop of dimethylformamide followed by oxalyl chloride (9 μl, 0.13 mmol). The mixture was stirred at rt for 1 h, followed by the addition of methylamine (16 / I of a 40% solution in water, 0.25 mmol) .The mixture was stirred at rt for 1 h and concentrated to dryness. dissolved methanol (1 ml), filtered through an octyl solid phase extraction tube and subjected to HPLC purification with an elution gradient of 10% to 90% acetonitrile in water to obtain 33 mg (70%) of the desired product: 1 H NMR (30 MHz, CI2CD2) d 8.30 (d, 1 H), 8.23 (s, 1 H), 7.50 (d, 1 H), 7.15-7.30 ( m, 3 H), 6.80 (t 1 H), 6.60 (s, 1 H), 3.77 (s, 3 H), 2.95 (br s, 6 H), 1, 70 ( q, 2 H), 1, 32 (s, 6 H), 0.85 (t, H) ES-MS m / z 426.2 (MH +); HPLC TR (min) 3.57. described for Example 15 above, and appropriately replacing the starting materials, is prepared Similarly, Examples 151-156 and are described in Table 1 below. Example 16 Preparation of 3-f (3-tert-butyl-1-methyl-1A / -p? Razol-5-? L) aminolpyridine-2-carboxamide Step 1: Preparation of 3-IT3-fe / -butyl-1-methyl-1-y-pyrazol-d-iDaminolpyridin -carbonitrile A mixture of 3-bromopyridine-2-carbonitrile (150 mg, 0.98 mmol), 3 -fe / - butyl mephi-1 # -pyrazol-5-amine (179 mg, 0.98 m), cesium carbonate (638.96 mmol), BINAP (98 mg, 0.16 mmol) and Pd2 (dba) 3 (90 mg, 0.10 mmol) was carried out in anhydrous toluene (2 ml) and heated at 80 ° C for 24 h under nitrogen atmosphere. The mixture was cooled to rt, diluted with ethyl acetate, it was filtered and reduced pressure concentrated. The residue was purified by silica gel chromatography using EtOAc / Hex (1: 9 to 1: 4, v / v) as eluent. The product thus obtained was a yellow oil (145 mg, 58%). ES-MS m / z 256.1 (MH +); HPLC RT (min) 2.37. Step 2: Preparation of 3-α (3-tert-butyl-1-methyl-1-pyrazol-5-yl) amino] pyridine-carboxamide To a solution of 3 - [(3-phe-butyI-1-meityl-1f-pyrazol-5-yl) amino-pyridine-carbonitrile (100 mg, 0.39 mmol) in MeOH (1 mL) was added an aqueous solution KOH (3 M, 1 me), and the mixture was stirred at 40 ° C for 48 h. The organic solvent was removed under reduced pressure, and the aqueous layer was acidified to pH 1 to 2 with 1N CIH aqueous solution. The mixture was extracted with ethyl acetate (3x). After removal of the solvent under reduced pressure, the crude residue was subjected to HPLC purification with an elution gradient of 20% to 90% acetonitrile in water to give the product as an oil (6.2 mg, 6%). . 1 NMR (400 MHz, CD3OD) d 1.35 (9H), 3.72 (s, 3H), 6.80 (s, 1H), 7.39-7.42 (m, 2H), 8.08 -8.11 (m, 1H). ES-MS 27 '4, 1 (MH +), HPLC TR (min) 1.47. Using the methods described below for Preparation Examples 1-16, and appropriate intermediates as starting materials, additional compounds of the invention were similarly prepared. These are listed in Table 1 below.

TABLE 1 Example No. LC-MS TR Structure name IUPAC [M + H] + [min] Acid 2-. { [3-tert-butyl-1 - (2-methylphenyl) -1 H-pyrrazol-5-yl] amino} -6- 3,23 365,3 Methylnicotinic Acid 2-. { [3-cyclopentyl-1- (2-methylphenyl) -1H-pyrazole-5, 3,57, 363, 2-yl] amino]} nicotinic Acid 3-. { [1 - (5-fluoro-2-methylphenyl) -3-methyl-4-phenyl-1 H -pyrazol-5- 2,40 403,1-yl] amino} Sonicotinic Acid 3-. { [3-tert-butyl-1- (2-methylphenyl) -1H-pyrazol-5-yl] amino} pyridin-2- 2,46 351 carboxylic Acid 5-. { [1 - (2,5-dimethylphenyl) -3- (4- 450.1, [M + H] + fluorophenyl) -1 H -pyrazol-5-yl] amino} -2- 4.07 (-C02) = (methylthio) pyrimidine-4-carboxylic acid 406.3 00 CD CD ^ - Acid 2-. { [3-tert-butyl-1- (2-methoxy-5-33-methylphenyl) -1H-pyrazol-5-yl] -amino} -5- 3.70 399.2 fluoronicotinic Acid 2-. { [3-tert-butyl-1- (5-fluoro-2-methylphenyl) -1 H -pyrazol-5-yl] amino} -5- 3.89 387.2 fluoronicotinic Acid 2-. { [3-tert-butyl-1 - (2-methylphenyl) -3H-pyrazol-5-yl] amino} -5- 3.69 369.2 fluoronicotinic Acid 2-. { [3- (4-fluorophenyl) -1- (2-54 methylphenyl) -1 H -pyrazol-5-yl] amino} -6- 3,53 403,2 methylnicotinic Acid 2-. { [1 - (2,5-dimethylphenyl) -3-phenyl-1H-pyrazol-5-yl] amino} -6- 3.60 399.3 methylnicotinic Acid 2-. { [1 - (2,5-dimethylphenyl) -3- (4-56 fluorophenyl) -1 H -pyrazol-5-yl] amino} -6- 3.81 417.1 methylnicotinic CM oo -Nt 00 Acid 3-. { [3-tert-butyl-1- (2,5-69 dimethylphenyl) -1 H -pyrazole-5-3.04 321, 3-yl] amino} pyridip-2-carboxylic Acid 3-. { [3-tert-butyl-1- (2-methoxyphenyl) -1 H -pyrazole-5 - 2,46-367 il] amino} pyridine-2-carboxylic Acid 5-. { [3-tert-butyl-1- (2-methoxyphenyl) -1 H -pyrazol-5-yl] amino} - 3,42 413,9 2- (Methylthio) pyrimidine-4-carboxylic acid CD 00 2-. { [3-tert-Butyl-1- (5-fluoro-2-methylphenyl) -1 H -pyrazole-5,48-368,2 il] amino} nicotinamide 2-. { [3-tert-butyl-1 - (5-fluoro-2-methylphenyl) -1 H-pyrazol-5-yl] amylo} -6- 3.64 382.2 Methylnicotinamide or CGJ C35 2-. { [1 - (2,5-dimethylphenyl) -3- (4-88 fluorofepil) -1 H -pyrazol-5-yl] amino} - 3,92 416.2 6-methylnicotinamide 2-. { [3- (4-fluorophenyl) -1- (2-9-methylphenyl) -1H-pyrazol-5-yl] amino} - 3.77 402.2 6-methylnicotinamide 2-. { [1- (5-fluoro-2-methylphenyl) -3- (4-90 fluorophenyl) -1H-pyrazol-5-yl] amino} - 3,22 434.2 4,6-dimethylnicotinamide4,6-dimethyl-2-. { [1- (2-methylphenyl) -3-91-phenyl-1H-pyrazol-5- 2,96- 398.2-yl] amino} nicotinamide 2-. { [1 - (2,5-dimethylphenyl) -3-phenyl-1 H-92 pyrazol-5-yl] amino} -4.6- 3.13 412.2 dimethylnicotinamide 2-. { [3- (4-fluorophenyl) -1- (2-methylphenyl) -1H-pyrazol-5-yl] amino} - 3,14 416,1 4,6-dimethylnicotinamide CM or o "sf Acid 2-. { [3-tert-butyl-1- (2,6- 100 dimethylphenyl) -1 H-pyrrazol-5- 3,64 365,2 il] amino} nicotinic Acid 2-. { [3-tert-butyl-1 - (2-methoxy-6-methylphenyl) -1 H-pyrazol-5-3.39 381, 3-yl] amino} nicotine Acid 2-. { [3-tert-butyl-1 - (2-methoxy-5-10-methylphenyl) -1H-pyrazole-5,49-381, 2-yl] amino} nicotinic O O 2-. { [3-tert-butyl-1 - (5-methoxy-2-methylphenyl) -1 H-pyrazole-5,23-40,9,2-yl] amino} Ethyl nicotinate 2-. { [3-tert-butyl-1- (2,4-difluorophenyl) -119 1 H-pyrazol-5-yl] amino} -6- 4,01 415.2 ethyl methylnicotinate 2-. { [3- (1,1-dimethylpropyl) -1- (2-methylphenyl) -1 H-pyrazol-5-yl] amino]} - 4,37 393,3 methyl ßnicotinate LO O CD O 1 ^ -O 136 Acid 2-. { [3-tert-butyl-1- (3-fluoro-2, 342, 383.1 methylphenyl) -1H-pyrazol-5-yl] amino} - 6-methylnicotinic Acid 2-. { [3- (1,1-dimethylpropyl) -1- 137 (3-fluoro-2-methylphenyl) -1H-pyrazole-3,37-397,15-yl] amino} -6-methynicotinic Acid 2-. { [3-tert-butyl-1- (2-ethylphenyl) -138 1H-pyrazol-5-yl] amino} nicotinic 3.29 365.2 Acid 2-. { [3- (1, 1-dimethylpropyl) -1- 142 (2-fluoro-5-methoxyphenyl) -1 H- 3,79 399.2 pyrazol-5-yl] amino} nicotinic 143 3-. { [1- (2-chlorophenyl) -3-methyl-4-phenyl-2.85 405 1 H-pyrazol-5-yl] amino} pyridine-2-carboxylic Acid 3-. { [3-tert-butyl-1- (2,6- 144 dimethylphenyl) -1 H -pyrazol-5- 3,639-yl] amino]} -6-methoxypyridine-2-carboxylic acid 6-methoxy-3- acid. { [3-methyl-1- (2-methylphenyl) -4-phenyl-1 H -pyrazol-5, 3,36,415-yl] amino]} pyridine-2-carboxylic acid Acid 3-. { [3-tert-butyl-1 - (3-fluoro-2-methylphenyl) -1 H -pyrazole-5,62-369] amino]} pyridine-2-carboxylic Acid 2-. { [3-tert-butyl-1 - (2-methoxy-6-methylphenyl) -1H-pyrazol-5-yl] amino} - 147 6- (trifluoromethyl) -nicot [nico 3.58 449.2 #FIRST NAME? Acid 2-. { [3-benzyl-1 - (2,5- 157 dimethylphenyl) -1 H -pyrazol-5-yl] amino} nicotinic 2- ( { 1 - (2,5-dimethylphenyl) -3- 158 [(trimethylsilyl) methyl] -1 H -pyrazol-5-yl] -amino) nicotinic acid #FIRST NAME? Acid 2-. { [1 - (2,5-dimethylphenyl) -3- 159 prop-1-yn-1-yl-1 H-pyrazol-5-yl] amino} -6-methylnicotinic 2- (. {1- (2-methoxy-6,1-methylphenyl) -3 - [(1 E) -prop-1-en-1-yl] -1H-pyrazol-5-yl}. amino) nicotinic 2- ( { 1 - (2,5-Dimethylphenyl) -3- [1-161- (trifluoromethyl) cyclopropyl] -1H-pyrazoloi-5-yl} amino) nicotinic acid 2-. { [3-tert-Butyl-4-iodo-1- (2-methoxy-162-6-methylphenyl) -1H-pyrazol-5-yl] amino} -6-methylnicotinic 2-. { [3-tert-butyl-4-fluoro-1- (2-methoxy-163-6-methylphenyl) -1H-pyrazol-5-yl] amino} -6-methylnicotinic 2-. { [3-tert-butyl-1- (2,5-dimethylphenyl) -173 1 H-pyrazol-5-yl] amino} -N, N-dimethylnotinamide N-benzyl-2-. { [3-tert-butyl-1- (2-methoxy-6-methylphenyl) -1 H -pyrazol-5-yl] amino} nicotinamide N- [3-tert-Butyl-1- (2,5-dimethylphenyl) -175 1 H -pyrazol-5-yl] -3- (morpholin-4-ylcarbonyl) pyridin-2-amine As used herein, several terms are defined below.

When presenting elements of the present invention or the preferred embodiment (s) thereof, the articles "a", "an", "the" and "said" are intended to imply that there is one or more of the elements. The terms "comprising", "including" and "having" are intended to be encompassing and mean that there may be additional elements other than those listed. The term "subject" as used herein includes mammals (e.g., humans and animals). The term "treatment" includes any process, action, application, therapy or the like, where a subject, including a human being, is provided with medical help in order to improve the condition of the subject, directly or indirectly, or the delay of the advance of a condition or disorder in the subject. The term "combination therapy" or "co-therapy" means the administration of two or more therapeutic agents to treat the condition and / or the diabetic disorder. Such administration encompasses the co-administration of two or more agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of the active components or in multiple, separate capsules, for each inhibitory agent. In addition, such administration encompasses the use of each type of therapeutic agent in a sequential manner. The phrase "therapeutically effective" means the amount of each agent administered that achieves the goal of improvement in a severe diabetic condition or disorder, while avoiding or minimizing the adverse side effects associated with the therapeutic treatment given.

The term "acceptable for pharmaceutical use" means that the item in question is suitable for use in a pharmaceutical product. The compounds of the present invention can be used in the treatment of diabetes, including both types, type 1 and type 2 (non-insulin dependent diabetes mellitus). Such treatment can also delay the onset of diabetes and the complications of diabetes. The compounds can be used to prevent the development of type 2 diabetes in subjects with impaired glucose tolerance. Other diseases and conditions that can be treated or prevented by using the compounds of the invention include: Juvenile Diabetes with Onset in Maturity (MODY ) (Herman, et al., Diabetes 43:40, 1994); Adult Autoimmune Latent Diabetes (LADA) (Zimmet, et al., Diabetes Med. 11: 299, 1994); glucose intolerance (IGT) (Expert Committee for the Classification of Diabetes Mellitus, Diabetes Care 22 (Suplem.1): S5, 1999); fasting glucose intolerance (IFG) (Charles, et al., Diabetes 40: 796, 1991); gestational diabetes (Metzger, Diabetes, 40: 197, 1991); and metabolic syndrome X. The compounds of the present invention may also be effective in disorders such as obesity, and in the treatment of atherosclerosis, hyperlipidemia, hypercholesterolemia, low HDL levels, hypertension, cardiovascular disease (including atherosclerosis, coronary heart disease). , coronary artery disease and hypertension), cerebrovascular disease and peripheral vascular disease. The compounds of the present invention can also be used in the treatment of physiological disorders related to, for example, cell differentiation to produce lipid accumulator cells, regulation of insulin sensitivity and blood glucose levels, which are involved in, for example, the abnormal function of pancreatic beta cells, insulin secreting tumors and / or autoimmune hypoglycaemia due to self-antibodies against insulin, auto-antibodies to the insulin receptor, or auto-antibodies that are stimulators of pancreatic beta cells , differentiation of macrophages that leads to the formation of atherosclerotic plaques, inflammatory response, carcinogenesis, hyperplasia, expression of adipocyte genes, differentiation of adipocytes, reduction in the mass of pancreatic beta cells, insulin secretion, sensitivity of the tissues to the insulin, liposarcomatous cell growth, sick polycystic ovarian disease, chronic anovulation, hyperandrogenism, progesterone production, steroidogenesis, redox potential and oxidative stress in cells, production of nitric oxide synthase (NOS), increased levels of gamma glutamyl transpeptidase, catalase, plasma triglycerides, HDL and LDL-cholesterol, and similar. The compounds of the present invention can also be used in methods of the invention to treat the secondary causes of diabetes (Expert Committee on Classification of Diabetes Mellitus, Diabetes Care 22 (Suppl 1): S5, 1999). Such secondary causes include excess glucocorticoids, excessive hormonal elevation, pheochromocytoma, and drug-induced diabetes. Drugs that can induce diabetes include, but are not limited to, pyriminil, nicotinic acid, glucocorticoids, phenytoin, thyroid hormone, ß-adrenergic agents, α-interferon, and drugs used in HIV infection. The compounds of the present invention may be used alone or in combination with additional therapies and / or compounds known to those skilled in the art of treating diabetes and related disorders. Alternatively, the methods and compounds described herein may be used, partially or completely, in combination therapy.

The compounds of the invention can be administered in combination with other therapies known in the treatment of diabetes, including PPAR agonists, drugs of the sulfonylurea type., secretagogues other than sulfonylureas, inhibitors of a-glucosidase, insulin sensitizers, insulin secretagogues, hepatic glucose reducers, insulin and anti-obesity drugs. Such therapies can be administered prior to, at the same time as or following the administration of the invention compounds. Insulin includes both short-acting and long-acting forms and insulin formulations. PPAR agonists can include agonists of any of the PPAR subunits or of the combination thereof. For example, PPAR agonists may include PPAR-a, PPAR-?, PPAR-d agonists or some combination of two or three of the PPAR subunits. PPAR agonists include, for example, rosiglitazone, troglitazone and pioglitazone. Sulfonylurea-like drugs include, for example, glyburide, glimepiride, chlorpropamide, tolbutamide and glipizide. Alpha-glucosidase inhibitors that may be useful in the treatment of diabetes when administered with a compound of the invention include acarbose, miglitol and voglibose. Insulin sensitizers that can be used in the treatment of diabetes include PPAR-? Agonists. such as glitazones (troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, and the like); biguanides such as metformin and phenformin; inhibitors of the protein thyroxine phosphatase-1B (PTP-1 B); inhibitors of dipeptidyl peptidase IV (DPP-IV); and thiazolidinediones and non-thiazolidinediones. Reducing hepatic glucose release that may be useful in the treatment of diabetes when administered with a compound of the invention include metformin, such as Glucophage and Glucophage XR. Insulin secretagogues that may be useful in the treatment of diabetes when administered with a compound of the invention include sulfonylurea and drugs other than the sulfonylurea: GLP-1, GIP, secretin, nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide, glipizide. GLP-1 derivatives include GLP-1 derivatives with longer half-lives than native GLP-1, such as, for example, GLP-1 derivatized with fatty acids and exendin. In one embodiment of the invention, the compounds of the invention are used in combination with insulin secretagogues to increase the sensitivity of pancreatic beta cells to the insulin secretagogue. The compounds of the invention can also be used in methods in combination with anti-obesity drugs. Anti-obesity drugs include β-3 agonists; CB-1 antagonists; neuropeptide Y5 inhibitors; appetite suppressants, such as, for example, sibutramine (Meridia) and iipase inhibitors, such as, for example, orlistat (Xenical). The compounds of the invention can also be used in methods of the invention in combination with drugs commonly used for the treatment of lipid disorders in diabetic patients. Such drugs include, but are not limited to, inhibitors of HMG-CoA reductase, nicotinic acid, lipid-lowering drugs (stanol esters, sterol glycosides such as tiqueside, and azetidinones such as ezetimibe), ACAT inhibitors (such as avasimibe), bile acid sequestrants, bile acid reuptake inhibitors, inhibitors of microsomal transport of triglycerides, and fibric acid derivatives.

HMG-CoA inhibitors include, for example, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, cerivastatin, and ZD-4522. Derivatives of fibric acid include, for example, clofibrate, fenofibrate, bezafibrate, ciprofibrate, beclofibrate, etofibrate and gemfibrozil. Sequestrants include, for example, cholestyramine, colestipol, and dialkylaminoalkyl derivatives of a crosslinked dextran. The compounds of the invention can also be used in combination with anti-hypertensive drugs, such as, for example, beta-blockers and ACE inhibitors. Examples of additional antihypertensive agents for use in combination with the compounds of the present invention include calcium channel blockers (Type L and Type T, eg, diltiazem, verapamil, nifedipine, amlodipine and mibefradil), diuretics (eg, chlorothiazide, hydrochlorothiazide, flumetiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid, trichinaphene, chlorthalidone, furosemide, muslimimine, bumetanide, triamtrenene, amiloride, spironolactone), renin inhibitors, ACE inhibitors (eg captoprii, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists (eg losarían, irbesartan, valsaran), ET receptor antagonisms (eg sitaxsentan, atrsenfan), neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual inhibitors of NEP-ACE) (om apatrilate and gemopatrilate), and nitrates. Such co-therapies may be administered in some combination of two or more drugs (eg, a compound of the invention in combination with an insulin sensitizer and an anti-obesity drug). Such co-therapies can be administered in the form of pharmaceutical compositions, as described above. Based on well-known assays used to determine the efficacy for the treatment of previously identified conditions in mammals, and by comparison of these results with the result of known medicaments that are used to treat these conditions, the effective dose of the compounds of this The procedure can be determined with the treatment of each desired indication. The amount of the active component (eg compounds) to be administered in the treatment of one of these conditions can vary widely according to considerations such as the particular compound and the dosage unit employed, the mode of administration, the treatment period , the age and sex of the patient treated, and the nature and extent of the condition treated. The total amount of the active ingredient to be administered may be generally between about 0.0001 mg / kg and about 200 mg / kg, and preferably from about 0.01 mg / kg to about 200 mg / kg of body weight per day. A dosage unit may contain about 0.05 mg to about 1500 mg of active ingredient, and may be administered one or more times per day. The daily dose for administration by injection, including intravenous, muscle, subcutaneous and parenteral injection and the use of infusion techniques can be from about 0.01 to about 200 mg / kg. The daily rectal dose regimen may be from 0.01 to 200 mg / kg of total body weight. The transdermal concentration may be that required to maintain a daily dose of 0.01 to 200 mg / kg. Of course, the initial specificity and the continuous dose regimen for each patient will vary according to the nature and severity of the condition as determined by the intervening physician, the activity of the specific compound employed, the age of the patient, the patient's diet , the time of administration, the route of administration, the level of excretion of the drug, the combination of drugs and the like. The desired mode of treatment and the number of doses of a compound of the present invention can be determined by skill in the art using conventional treatment tests. The compounds of this invention can be used to achieve the desired pharmacological effect by administration to a patient in need thereof in an appropriate pharmaceutical composition. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for a particular disease or condition. Therefore, the present invention includes pharmaceutical compositions that are composed of acceptable vehicles for pharmaceutical use and a therapeutically effective amount of a compound. An acceptable vehicle for pharmaceutical use is any vehicle that is relatively non-toxic and harmless to the patient at those concentrations consistent with an effective activity of the active ingredient, so that no side effects attributable to the vehicle may be detrimental to the beneficial effects of the active ingredient. A therapeutically effective amount of a compound is that amount which produces a result or exerts an influence on a particular condition treated. The compounds described herein can be administered with an acceptable carrier for pharmaceutical use using any effective conventional unit dosage form, including, for example, controlled and immediate release preparations, orally, parenterally, topically and similarly. For oral administration, the compounds can be formulated in solid or liquid preparations, such as for example, capsules, pills, tablets, tablets in the form of stamps, lozenges, candies, powders, solutions, suspensions or emulsions, and can be prepared according to methods known in the art for the preparation of pharmaceutical compositions. The solid unit dosage form can be a capsule of either hard or soft gelatin, containing, for example, surfactants, lubricants and inert fillers such as lactose, sucrose, calcium phosphate and corn starch. In another embodiment, the compounds of this invention can be compressed with the conventional bases for tablets such as lactose, sucrose and corn starch and combinations with gums such as acacia, corn starch or gelatin, disintegrating agents that improve dispersion and dissolution of the tablet. after administration, such as potato starch, alginic acid, corn starch and guar gum, lubricants that help improve the flow of the tablet granulate and prevent the adhesion of the tablet material to the surfaces of the matrix and punches , such as talc, stearic acid or magnesium stearate, zinc or calcium, pigments, coloring agents and flavorings intended to improve the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in liquid dosage forms include diluents such as water and alcohols, for example ethanol, benzyl alcohol, and polyethylene alcohols, with or without the addition of surfactants, suspending agents or emulsifiers. Various other agents may appear as a cover or otherwise modifying the physical form of the dosage unit. For example, tablets, pills or capsules can be covered with shellac, sugar or both. The dispersible powders and granules are suitable for the preparation of aqueous suspensions. They provide the active ingredient in admixture with the dispersing or wetting agent, a suspending agent and one or more preservatives. The available dispersants or the wetting and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, the sweeteners, flavors, colorants and agents described above, may also be present. The pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions. The oil phase can be an oil such as paraffin or a mixture of vegetable oils. Suitable emulsifying agents can be: (1) natural gums such as acacia gum and tragacanth gum, (2) natural phosphatides such as soybean and lecithin, (3) esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylenated sorbitan monooleate. The emulsions may also contain sweeteners and flavors. Oily suspensions may be formulated by suspending the active ingredient in vegetable oils such as, for example, arachis oil, olive oil, sesame oil, coconut oil or in mineral oils such as liquid paraffin. Oily suspensions may contain a thickening agent such as, for example, beeswax, solid paraffin or cetyl alcohol. The suspensions may contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavorings and one or more sweetening agents such as sucrose or saccharin. Syrups and elixirs can be formulated with sweetening agents such as, for example, glycerin, propylene glycol, sucrose or sorbitol. Such preparations may also contain a demulcent, preservative, flavoring and coloring agent. The compounds of this invention may also be administered parenterally, either intramuscularly, subcutaneously, intravenously or intraperitoneally, as injectable doses of the compound in a physiologically acceptable diluent with a pharmaceutical carrier, which may be a sterile liquid or mixture of such fluids. such as water, saline, aqueous dextrose and related sugar solutions; an alcohol, glycols, glycerol ketals, ethers, an oil; a fatty acid, an ester of fatty acid or glyceride, or an acetylated fatty acid glyceride with or without the addition of acceptable surfactants, suspending agents or emulsifiers for pharmaceutical use, and other pharmaceutical adjuvants. The parenteral compositions of this invention may typically contain about 0.5% to 25% per kilo of active ingredient weight in the solution. Preservatives and buffers can also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-inonic surfactant having a hydrophilic-lipophilic balance (HLB) of between about 12 and about 17. The proportion of surfactant in such formulation may be between about 5% and about 15% by weight. The surfactant may be a single component having the aforementioned HLB or it may be a mixture of two or more components with the desired HLB. The pharmaceutical compositions may be in the form of sterile aqueous suspensions. Such suspensions can be formulated according to known methods using suitable dispersing or wetting agents and suspending agents, dispersing or wetting agents and agents that can be natural phosphatides, a condensation product of an alkylene oxide with a fatty acid, a product of condensation of ethylene oxide with a long aliphatic alcohol chain, a condensation product of ethylene oxide with an ester derived from a fatty acid and hexitol, or a condensation product of ethylene oxide with an ester derived from a fatty acid and hexitol anhydride.

The sterile injectable preparation can also be a sterile injectable solution or suspension in an acceptable non-toxic parenteral diluent or solvent. The diluents or solvents that may be employed are, for example, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as solvents or suspension media. For this purpose, fixed or some volatile oils can be used, including mono or synthetic diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables. A composition of the invention can also be used in the form of suppositories for rectal administration. This composition can be prepared by mixing the drug (compound) with a suitable non-irritating excipient, which is solid at ordinary temperature but liquid at the rectal temperature and which melts in the rectum to release the drug. Such materials are, for example, cocoa butter and polyethylene glycol. Another formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such patches can be used to provide a continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, U.S. Patent No. 5,023,252, incorporated herein by reference). Such patches can be constructed for the continuous, pulsatile or demand release of pharmaceutical agents. It may be desirable or necessary to introduce the pharmaceutical composition by u? mechanical release device. The construction and use of mechanical release devices for the delivery of pharmaceutical agents is well known in the art. For example, direct techniques for administering a drug directly to the brain usually locate a part of a catheter within the patient's ventricular system to pass through the hemato-encephalic barrier. One such implantable delivery system, used for the transport of agents to specific regions of the body, is described in U.S. Patent No. 5,011,472, incorporated herein by reference. The compositions of the invention may also contain other conventional composition ingredients acceptable for pharmaceutical use, generally referred to as carriers or diluents, as needed or desired. Any of the compositions of this invention can be preserved by the addition of an antioxidant such as ascorbic acid or other acceptable preservatives. Conventional procedures can be used to prepare such compositions in appropriate dosage forms. The compounds described herein can be administered as a single pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination does not cause unacceptable adverse effects. For example, the compounds of this invention can be combined with known anti-obesity compounds, or with antidiabetics or other similar indication agents, as well as mixtures and combinations thereof. The compounds described herein may also be used, in the form of a free base or in compositions, in research and diagnosis, or as an analytical reference standard. Therefore, the present invention includes compositions that are constituted by an inert carrier and an effective amount of a compound identified by the methods described herein, or a salt or ester thereof. An inert vehicle is a material that does not interact with the compound to be transported to which it serves as support, means of coexistence, capacity, traceable material or similar to the compound to be transported. An effective amount of a compound is that amount that produces a result or exerts an influence on the particular procedure that is being executed. The formulations used for subcutaneous, intravenous, intramuscular and similar use; Suitable pharmaceutical vehicles, and formulation and administration techniques can be prepared by any of the methods well known in the art, (see, Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 20th edition, 2000). It should be apparent to one of ordinary skill in the art that changes and modifications to this invention can be made without departing from the spirit or scope of the invention as described herein. Biological evaluation To the effect that this invention can be better understood, the following examples are presented. These examples are for the sole purpose of illustration, and will not be considered as limiting the invention in any way. All the publications mentioned here are incorporated as a reference in their entirety. Demonstration of the activity of the compounds of the present invention can be achieved through in vitro, ex vivo and in vivo assays that are well known in the art. For example, to demonstrate the effectiveness of treatment agents for diabetes and related disorders such as Syndrome X, glucose intolerance and hyperinsulinemia, the following tests can be used. In vitro assay Insulin secretion from INS-1 cells.

INS-1 cells were isolated from rat insulinoma induced by X-rays (Asfari, et al., Endocrinology 130: 167, 1992). INS-1 cells were seeded at 30,000 cells per well in 96-well Biocoat Collagenl Cellware 96-well plates and incubated for 4 to 5 days. The cells were treated for two days with complete medium (RPMI 1640, 10% Fetal Bovine Serum, 100 μg / ml Penicillin / Streptomycin, 0.5 mM sodium pyruvate, 10 mM HEPES and 50 μM beta-mercaptoethanol) adjusted to 3 mM glucose. After two days of treatment, the cells were washed with Krebs-Ringer-Bicarbonate-HEPES (KRBH) containing 3 mM glucose. The cells were then incubated for 30 days in the same buffer. The cells were incubated for an additional 2 h in the presence of the desired concentration of glucose and compounds. The supernatants were collected.

To determine the amount of insulin secreted, the supernatants were mixed with anti-insulin antibodies and an amount of a 125-insulin tracer in phosphate saline containing 0.5% bovine serum albumin. Protein A beads coated with SPA (scintillation proximity assay) were added. Plates were incubated for 5-20 h and counted with a scintillation counter to measure insulin levels. The activity for compounds at a given concentration was expressed as stimulation of insulin secretion relative to the controls. Insulin secretion from scat scattered rat cells. Insulin secretion from dispersed rat islets mediated by a number of compounds of the present invention was measured as follows. Islets of Langerhans, obtained from male Sprague-Dawley rats (200-250 g) were digested using collagen. Scattered islet cells were treated with trypsin, seeded in 96-well V-bottom plates, and pelleted. The cells were grown until the next day in medium with or without compounds of this invention. The media was aspirated and the cells were preincubated with Krebs-Ringer-HEPES buffer containing 3 mM glucose for 30 minutes at 37 ° C. The pre-incubation buffer was removed and the cells were incubated at 37 ° C with Krebs-Ringer-HEPES buffer containing glucose concentrations (eg 8 mM) with or without compounds for an appropriate time. In some studies, an appropriate concentration of GLP-1 or forskolin was also included. A portion of the supernatant was extracted and the insulin content was measured by SPA. The results were expressed as "so many times more than control" (FOC). In this assay, an increase in the insulin secretion of scattered islet cells was defined as an increase of at least 1, 4 times. In vivo test Effect of the compounds on intraperitoneal glucose tolerance in rats. The in vivo activities of the compounds of this invention were examined when a dose is administered orally. Rats with an overnight fast received an oral dose of control vehicle or compound. Three hours later, the blood glucose level was measured, and the rats were given 2 g / kg of intraperitoneal glucose. Blood glucose was measured after 15, 30 and 60 minutes. Representative compounds of this invention significantly reduced blood glucose levels relative to the vehicle following the IPGTT (intraperitoneal glucose tolerance test) technique. Method to measure an effect on cardiovascular parameters Cardiovascular parameters (heart rate and blood pressure) are also evaluated. SHR rats are given orally once a day vehicle or test compound for 2 weeks. Blood pressure and heart rate are determined using a method described by Grinsell, et al., (Am. J. Hypertens., 13: 370-375, 2000). In monkeys, blood pressure and heart rate are monitored as described by Shen, et al., (J. Pharmacol. Exp. Therap 278: 1435-1443, 1996). Method for measuring triglyceride levels of hApoAl mice (obtained from Jackson Laboratories, Bar Harbor, ME) are bled (by the eyes or the caudal vein) and are grouped according to the average levels of triglycerides in blood. They receive oral doses (by packaging in vehicles acceptable for pharmaceutical use) with the test compound once a day for 8 days. Blood samples are obtained from the animals again from the eyes or the caudal vein and the level of serum triglycerides is determined. In each case the triglyceride levels are measured using a Technicon Axon autoanalyzer (Bayer Corporation, Tarrytown, NY). Method for measuring cholesterol and HDL levels To determine HDL-cholesterol levels in plasma, blood samples are taken from hApoAl mice and are grouped according to equivalent plasma HDL-cholesterol levels. Mice are dosed orally once a day with vehicle and test compound for 7 days, and then blood samples are taken again on day 8. The plasma HDL-cholesterol level is analyzed using the Clinical Synchronous System (CX4) (Beckman Coulter, Fullerton, CA). Method to measure the levels of total cholesterol, HDL-cholesterol, triglycerides and glucose. In another in vivo assay, blood samples are taken from obese monkeys, oral doses are administered once a day with vehicle or test compound for 4 hours. weeks, and then blood is drawn again. The serum is analyzed for total cholesterol, HDL-cholesterol, triglycerides and glucose using the Synchron Clinicoal (CX4) system (Beckman Coulter, Fullerton, CA). The analysis of lipoprotein subclasses is performed by NMR spectroscopy as described by Oliver, et al., (Proc Nati, Acad Sci USA 98: 5306-5311, 2001). All publications and patents mentioned in the above specification are incorporated herein by reference. Various modifications and variations of the described compositions and methods of the invention will be apparent to those skilled in the art, without departing from the scope or spirit of the invention. While the invention has been described in connection with specific preferred embodiments, it should be understood that the claimed invention should not be unduly limited to such specific embodiments. In fact, several modifications of the above modes of carrying out the invention that are obvious to those skilled in the field of molecular biology or related fields are intended to fall within the scope of the following claims. Those skilled in the art will recognize, or may inquire, to use no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents should be encompassed by the following claims.

Claims (37)

1. Claims Having thus specially described and determined the nature of the present invention and the way it has to be put into practice, it is claimed to claim as property and exclusive right. 1. A heteroarylaminopyrazole derivative of Formula (I) ( where is a substituted aromatic heterocyclic ring radical selected from R is H, or (C1-C6) alkyl; R1 is H, alkyl (Cl-Cß) optionally substituted with phenyl, said phenyl being optionally substituted with halo, or [(C1-C) trialkyl] silyl, (C3-C6) alkenyl, (C3-C6) alkynyl, cycloalkyl ( C3-C6) optionally substituted with up to two substituents selected from the group consisting of (C1-C3) alkyl, CF3 and halo, halo (C1-C3) alkyl, or phenyl optionally substituted with up to two substituents selected from the group consisting of halo, alkyl ( C1-C6), (C1-C6) alkoxy, (C1-C6) alkylthio, (C1-C3) haloalkyl, (C1-C3) haloalkoxy and cyano; R2 is H, halo, (C1-C6) alkyl, pyridyl optionally substituted with up to two substituents selected from the group consisting of (C1-C6) alkoxy, alkylthio (Cl-Cß), halo and alkyl (Cl-Cß), substituted phenyl optionally with up to two substituents selected from the group consisting of (C1-C6) alkyl, (C1-C6) alkoxy, alkylthio (d-Cß), cyano and halo, pyrimidyl, thienyl optionally substituted with up to two substituents selected from the group consisting of alkyl (Cl-Cß), (C 1 -C 6) alkoxy, alkylthio (Cl-Cß), cyano and halo, benzothienyl, optionally substituted with up to two substituents selected from the group consisting of alkyl (Cl-Cß), alkoxy (C1-Ce) , (C 1 -C 6) alkylthio, cyano and halo, or furyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, (C 1 -C 6) alkylthio, cyano and halo; R3 is (C1-C6) alkyl (C3-C6) cycloalkyl, (C2-C3) haloalkyl or phenyl optionally substituted with more than four substituents selected from the group consisting of alkyl (Cl-Ce) optionally substituted with a (C1-C) alkoxy ), halo, haloalkyl (C1-C3) alkoxy (C1-C6), haloalkoxy (C1-C3), alkylthio (C1-C6) and cyano; R 4 is (C 1 -C 6) alkyl optionally substituted by a (C 1 -C) alkoxy, (C 1 -C 6) alkoxy, (C 1 -C 6) alkylthio, (C 1 -C 3) haloalkyl, (C 1 -C 3) haloalkoxy, or halo; n = 0, 1, 2, or 3; X is CO2R7, CONR5R6, or SO2NH2; R5 is H, (C1-C6) alkyl, phenyl optionally substituted with halo or benzyl optionally substituted on the phenyl ring with halo; R6 is H or (C1-C6) alkyl; or R5 and R6, taken together with the N atom to which they are attached, can form a piperidine, morpholine, thiomorpholine or piperazine ring, said piperazine optionally substituted at N with (C1-C3) alkyl; R7 is H, (C1-C6) alkyl, benzyl optionally substituted with up to two substituents selected from the group consisting of halo, (C1-C6) alkyl, alkoxy (CI-C3), haloalkyl (CI-C3), haloalkoxy (CI-) C3) and alkylthio (C1-C6); phenyl optionally substituted with up to two substituents selected from (C1-C6) alkyl, halo, (C1-C6) alkoxy, haloalkyl (CI-C3), haloalkoxy (C1-C3) and alkylthio (C1-C6); and salts acceptable for pharmaceutical use thereof; with the proviso that the compound of Formula (I) is not
2. 2. The compound of claim 1, wherein is a substituted aromatic heterocyclic ring radical selected from R is H, or (C1-C6) alkyl; R1 is H, alkyl (CI -CT) optionally substituted with phenyl, said phenyl being optionally substituted with halo or [(C1-C) trialkyl] silyl, (C3-C6) alkenyl, (C3-C6) alkynyl, cycloalkyl (C3) -C6) optionally substituted with up to two substituents selected from the group consisting of alkyl (CI-C3), CF3 and halo, haloalkyl (C1-C3) or phenyl optionally substituted with up to two substituents selected from the group consisting of halo, alkyl (C1- C6), (C1-C6) alkoxy, (C1-C6) alkylthio, haloalkyl (CI-C3), haloalkoxy (C1-C3) and cyano; R2 is H, halo, (C1-C6) alkyl, pyridyl optionally substituted with up to two substituents selected from the group consisting of alkoxy (Cl-Cß), alkylthio (Cl-Cß), halo and alkyl (Cl-Cß), phenyl optionally substituted with up to two substituents selected from the group consisting of (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkylthio, cyano and halo, pyrimidyl, thienyl optionally substituted with up to two groups selected from the group consisting of alkyl (Cl-Cß), alkoxy (CI-CT), alkylthio (C 1 -C 6), cyano and halo, benzothienyl, optionally substituted with up to two groups selected from the group consisting of alkyl (Cl-Cß), alkoxy (Cl-Cß) , alkylthio (Cl-Cß), cyano and halo, or furyl optionally substituted with up to two groups selected from the group consisting of (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, (C 1 -C 4) alkylthio and halo; R3 is (C1-C6) alkyl, (C3-Ce) cycloalkyl, (C2-C3) haloalkyl or phenyl optionally substituted with up to four groups selected from the group consisting of (C1-C6) alkyl optionally substituted by an alkoxy (C-? -C4), halo, haloalkyl (C1-C3), alkoxy (Cl-Cß), haloalkoxy (CI-C3), alkylthio (C1-C6) and cyano; R 4 is alkyl (Cl-Cß) optionally substituted by a (C 1 -C) alkoxy, (C 1 -C 6) alkoxy, (C 1 -C 6) alkylthio, haloalkyl (CI-C 3), halo (C 1 -C 3) alkoxy or halo; n = 0, 1, 2, or 3; X is CO2R7, CONR5R6, or SO2NH2; R 5 is H, alkyl (Cl-Cß), phenyl optionally substituted with halo or benzyl optionally substituted on the phenyl ring with halo; R6 is H or (C1-C6) alkyl; or R5 and R6, taken together with the N atom to which they are attached, can form a piperidine, morpholine, thiomorpholine or piperazine ring, said piperazine optionally substituted with (C1-C3) alkyl; R7 is H, (C1-C6) alkyl, benzyl optionally substituted on the aryl ring with up to two substituents selected from the group consisting of halo, (C1-C6) alkyl, alkoxy (CI-C3), haloalkyl (CI-C3), haloalkoxy (C1-C3) and alkylthio (C1-C6); phenyl optionally substituted with up to two substituents selected from the group consisting of (C1-C6) alkyl, halo, (C1-C6) alkoxy, (C1-C3) haloalkyl, haloalkoxy (CI-C3) and (C1-C6) alkylthio; and salts acceptable for pharmaceutical use thereof.
3. 3. The compound of claim 1, wherein it is a substituted heterocyclic aromatic ring radical selected from R is H, or (C1-C6) alkyl; R1 is H, (C1-C6) alkyl optionally substituted with phenyl, said phenyl being optionally substituted with halo, or [(C1-C) trialkyl] -silyloyl, cycloalkyl (C3-Ce) optionally substituted with up to two substituents selected from the group constituted by alkyl (CI-C3), CF3 and halo, haioalkyl (C1-C3) or phenyl optionally substituted with up to two substituents selected from the group consisting of halo, (C1-C6) alkyl, (C1-C6) alkoxy, alkylthio (C1) -C6), haloalkyl (C1-C3), haloalkoxy (CI-C3) and cyano; R2 is H, halo, (C1-C6) alkyl, pyridyl optionally substituted with up to two substituents selected from the group consisting of (C1-C6) alkoxy, (C1-C6) alkylthio, halo, and (C1-C6) alkyl, phenyl optionally substituted with up to two substituents selected from the group consisting of (C 1 -C 6) alkyl, alkoxy (Cl-Cβ), alkylthio (CI -CT), cyano and halo, pyrimidyl; R3 is (C1-C6) alkyl, (C3-C6) cycloalkyl, (C2-C3) haloalkyl or phenyl optionally substituted with up to four substituents selected from the group consisting of (C1-C6) alkyl optionally substituted with a (C1-C4) alkoxy ), halo, haloalkyl (CI-C3), (C1-C6) alkoxy, haloalkoxy (CI-C3), alkylthio (C1-C6) and cyano; R4 is (C1-C6) alkyl optionally substituted by a (C1-C4) alkoxy, (C1-C6) alkoxy, (C1-C6) alkylthio, haloalkyl (CI-C3), haloalkoxy (CI-C3) or halo; n = 0, 1, or 2; X is CO2R7 or CONR5R 6; R5 is H or (C1-C6) alkyl; R6 is H or (C1-C6) alkyl; or R5 and R6, taken together with the N atom to which they are attached, can form a piperidine, morpholine, thiomorpholine or piperazine ring, said piperazine optionally substituted at N with (C1-C3) alkyl; R7 is H, (C1-C6) alkyl; and salts acceptable for pharmaceutical use thereof.
4. 4. The compound of claim 1, wherein is a substituted heterocyclic aromatic ring radical selected from R is H, or (C1-C6) alkyl; R1 is H, (C1-Ce) alkyl optionally substituted with phenyl, said phenyl optionally substituted with halo, or [(C1-C4) trialkyl] silyl, cycloalkyl (C3-Ce) optionally substituted with up to two substituents selected from the group constituted by alkyl (CI-C3), CF3 and halo, haloalkyl (CI-C3) or phenyl optionally substituted with up to two substituents selected from the group consisting of halo, alkyl (Cl-Cß), alkoxy (C1-C6), alkylthio ( C1-C6), haloalkyl (C1-C3), haloalkoxy (CI-C3) and cyano; R2 is H, halo, (C1-C6) alkyl, phenyl optionally substituted with up to two substituents selected from the group consisting of (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkylthio, cyano and halo; R3 is (C1-C6) alkyl, (C3-C6) cycloalkyl, hal (C2-C3) alkyl or phenyl optionally substituted with up to four substituents selected from the group consisting of (C1-CT) alkyl optionally substituted with an alkoxy (C1 -C), halo, haloalkyl (CI-C3), alkoxy (C1-C6), haloalkoxy (CI-C3), alkylthio (C1-C6) and cyano; R 4 is (C 1 -C 6) alkyl optionally substituted with a (C 1 -C 4) alkoxy, alkoxy (Cl-Cß), alkylthio (C 1 -C 6), haloalkyl (C 1 -C 3), haloalkoxy (C 1 -C 3) or. halo; n = 0, 1, or 2; X is CO2R7 or CONR5R6; R5 is H or (C1-C6) alkyl; R6 is H or (C1-C6) alkyl; R7 is H, (C1-C6) alkyl, and pharmaceutically acceptable salts thereof.
5. 5. The compound of claim 1, wherein is a substituted aromatic heterocyclic ring radical selected from R is H, or (C1-C6) alkyl; R1 is H, alkyl (Cl-Cß) optionally substituted with phenyl, said phenyl being optionally substituted with halo or [(C1-C4) trialkyl] silyl, (C3-C6) cycloalkyl optionally substituted with up to two substituents selected from the group consisting of alkyl (CI-C3), CF3 and halo, haloalkyl (CI-C3) or phenyl optionally substituted with up to two substituents selected from the group consisting of halo, (C1-C6) alkyl, (C1-C6) alkoxy, alkylthio (Cl-) Cß), haloalkyl (C 1 -C 3), haloalkoxy (C 1 -C 3) and cyano; R2 is H, halo, (C1-C6) alkyl, phenyl optionally substituted with up to two substituents selected from the group consisting of (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkylthio, cyano and halo; R3 is (C1-C6) alkyl, (C3-Ce) cycloalkyl, (C2-C3) haloalkyl or phenyl optionally substituted with up to four substituents selected from the group consisting of alkyl (Cl-Ce) optionally substituted with a (C1-C4) alkoxy ), halo, haloalkyl (C 1 -C 3), alkoxy (C 1 -C 6), haloalkoxy (C 1 -C 3), alkylthio (C 1 -C 6) and cyano; R4 is (C1-C3) alkyl optionally substituted by a (C1-C4) alkoxy, (C1-Ce) alkoxy, (C1-C6) alkylthio, (C1-C3) haloalkyl, (C1-C3) haloalkoxy or halo; n = 0, 1, or 2; X is CO2R7 or CONR5R6; R5 is H or (C1-C6) alkyl; R6 is H or (C1-C6) alkyl; R7 is H, (C1-C6) alkyl, and pharmaceutically acceptable salts thereof.
6. 6. A compound according to claim 1 selected from the group consisting of: 2- Acid. { [3-Ier-butyl-1 - (2-methylphenyl) -1H-pyrazol-5-yl] amino} -6-methylnicotinic; Acid 2-. { [3-cyclopentyl-1- (2-methylphenyl) -1H-pyrazol-5-yl] amino} nicotinic; Acid 3-. { [3-tert-butyl-1- (2-methylphenyl) -1 / - / - pyrazol-5-yl] amino} pyridine-2-carboxylic acid; Acid 2-. { [3- (2,2-dimethylpropyl) -1- (2-methylphenyl) -1H-pyrazol-5-yl] amino} nicotinic; Acid 2-. { [1- (2-chlorophenyl) -3- (4-fluorophenyl) -1 H -pyrazol-5-yl] amino} nicotinic; Acid 3-. { [3-fer-butyl-1 - (2,6-dimethylphenyl) -1 H -pyrazol-5-yl] amino} pyridine-2-carboxylic acid; Acid 2-. { [3-fer-butyl-1 - (5-fluoro-2-methylphenyl) -1 H -pyrazol-5-yl] amino} nicotinic; Acid 2-. { [3-tert-butyl-1- (2,5-dimethylphenyl) -1H-pyrazol-5-yl] amino} nicotinic; Acid 2-. { [3-Ier-butyl-1 - (5-fluoro-2-methylphenyl) -1 / - -p-aceol-5-yl-amino} -6-methylnicotinic; Acid 2-. { [3-Ier-butyl-1 - (2-methoxy-6-methylphenyl) -1H-pyrazol-5-yl] amino} -6-methylnicotinic; Acid 2-. { [3-Ier-butyl-1- (2,5-d-methylphenyl) -1-pyrazol-5-yl] amino]} -6-methylnicotinic; Acid 2-. { [3-Fer-butyl-1- (2-methoxy-6-methylphenyl) -1 / - / - pyrazol-5-yl] amino} -5-fluoronicotinic; Acid 2-. { [3-fer-butyl-1 - (2,6-dimethyphenyl) -1 / -pyrazol-5-yl] amino} -5-fluoronicotinic; Acid2-. { [3-fer-butyl-1- (5-fluoro-2-methylphenyl) -1 / t'-pyrazol-5-yl] amino} -5-fluorine; Acid 2-. { [3-Ier-butyl-1 - (2,5-dimethylphenyl) -1 H -pyrazol-5-yl] amino} -5-fluoronicotinic; Acid 2-. { [3-fer-butyl-1 - (2,5-dimethylphenyl) -1 H -pyrazol-5-yl] amino} -5-fluoronicotinic; Acid 2-. { [3-cyclohexyl-1- (2-methylphenyl) -1 H -pyrazol-5-yl] amino} nicotinic; Acid 2-. { [1 - (5-fluoro-2-methylphenyl) -3- (4-fluorophenyl) -1 / - / - pyrazol-5-yl] amino} nicotinic; Acid 2-. { [1- (2-methylphenyl) -3-phenyl-1 H -pyrazol-5-yl] amino} nicotinic; Acid 2-. { [3- (4-fluorophenyl) -1 - (2-methylphenyl) -1 / - / - pyrazol-5-yl] amino} nicotinic; Acid 2-. { [1 - (2,5-dimethylphenyl) -3- (4-fluorophenyl) -1 H -pyrazol-5-yl] amino} nicotinic; Acid 2-. { [1 - (2,5-dimethylphenyl) -3-phenyl-1-pyrazol-5-yl] amino} nicotinic; Acid 2-. { [3- (4-fluorophenyl) -1 - (2-methoxy-5-methylphenyl) -1 H -pyrazol-5-yl] amino} tubic; Acid 2-. { [3- (4-fluorophenyl) -1 - (5-methoxy-2-methylphenyl) -1 H -pyrazI-5-yl] amino} nicotinic; Acid 2-. { [1- (2,5-dimethylphenyl) -3-phenyl-1H-pyrazol-5-yl] amino} -6-methynicotinic; Acid 2-. { [1- (2,5-dimethylphenyl) -3- (4-fluorophenyl) -1H-pyrazol-5-yl] amino} -6-methylnicotinic; Acid 2-. { [3- (4-fluorophenyl) -1 - (2-methoxy-6-methylphenyl) -1 / - / - pyrazol-5-yl] amino} -6- methylnicotinic; Acid 2-. { [3- (1, 1-dimethylpropyl) -1- (3-methoxy-2-methylphenyl) -1H-pyrazol-5-yl] amino} nicotinic; Acid 2-. { [3- (1, 1 -dimethylpropyl) -1 - (5-fluoro-2-methylphenyl) -1 H -pyrazol-5-yl] amino} nicotinic; Acid 2-. { [3-tert-butyl-1- (2-chlorophenyl) -1H-pyrazol-5-yl] amino} tubic; Acid 2-. { [3-fer-butyl-1 - (2,6-dimethylphenyl) -1 - / - pyrazol-5-yl] amino} nicotinic; Acid 2-. { [3-fer-butyl-1 - (2-methoxy-6-methylphenyl) -1-pyrazol-5-yl] amino} nicotinic; and Acid 3-. { [3-tert-butyl-1- (2-methoxy-6-methylphenyl) -1H-pyrazol-5-yl] amino} -5- (trifluoromethyl) pyridine-2-carboxylic acid.
7. 7. A pharmaceutical composition comprising an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in combination with a vehicle acceptable for pharmaceutical use.
8. 8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier and one or more pharmaceutical agents.
9. The pharmaceutical composition of claim 14, wherein said pharmaceutical agent is selected from the group consisting of PPAR ligands, insulin secretagogues, sulfonylurea drugs, α-glucosidase inhibitors, insulin sensitizers, compounds that reduce the release of hepatic glucose, insulin and insulin derivatives, biguanides, protein tyrosine phosphatase-B, dipeptidyl peptidase IV, inhibitors of 11beta-HSD, anti-obesity drugs, inhibitors of HMG-CoA reductase, nicotinic acid, reducing drugs lipids, ACAT inhibitors, bile acid sequestrants, bile acid release inhibitors, microsomal triglyceride transport inhibitors, fibric acid derivatives, β-blockers, ACE inhibitors, calcium channel inhibitors, renin inhibitors , T-1 receptor antagonists, ET receptor antagonists, neutral endopeptidase inhibitors, inhibitors vasopepsidase, and nitrates.
10. A method of treating diabetes comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutical composition of claim 7.
11. 11. The method of the claim 10, wherein said diabetes is selected from the group consisting of type 1 diabetes, type 2 diabetes, juvenile diabetes with onset at maturity, latent autoimmune diabetes of the adult, and gestational diabetes.
12. A method of treating Syndrome X comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutical composition of claim 7.
13. 13. A method of treating related disorders with diabetes comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutical composition of claim 7.
14. The method of claim 13, wherein said disorder related to diabetes is selected from the group consisting of hyperglycemia, hyperinsulinemia, glucose intolerance, fasting glucose intolerance, dyslipidemia, hypertriglyceridemia and insulin resistance.
15. 15. A method of treatment for preventing secondary causes of diabetes comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutical composition of claim 7.
16. 16. The method of the claim 15, where said secondary cause is selected from the group consisting of excess glucocorticoids, excessive hormonal elevation, pheochromocytoma and drug-induced diabetes.
17. 17. A method of treating diabetes comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 in combination with one or more pharmaceutical agents.
18. 18. The method of claim 17, wherein said pharmaceutical agent is selected from the group consisting of PPAR agonists, drugs of the sulfonylurea type, secretagogues other than sulfonylureas, a-glucosidase inhibitors, insulin sensitizers, insulin secretagogues, reducing compounds of the release of hepatic glucose, insulin, and anti-obesity agents.
19. The method of claim 18, wherein said diabetes is selected from the group consisting of type 1 diabetes, type 2 diabetes, juvenile diabetes with onset at maturity, adult latent autoimmune diabetes, and gestational diabetes.
20. 20. A method of treating Syndrome X comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 in combination with one or more pharmaceutical agents.
21. The method of claim 20, wherein said pharmaceutical agent is selected from a group consisting of PPAR agonists, sulfonylurea drugs, secretagogues other than sulfonylureas, a-glucosidase inhibitors, insulin sensitizers, insulin secretagogues, reducing compounds of the release of hepatic glucose, insulin and anti-obesity agents.
22. 22. A method of treating disorders related to diabetes comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 in combination with one or more pharmaceutical agents.
23. The method of claim 22, wherein said diabetes-related disorder diabetes is selected from the group consisting of hyperglycemia, hyperinsulinemia, glucose intolerance, fasting glucose intolerance, dyslipidemia, hypertriglyceridemia, and insulin resistance.
24. The method of claim 23, wherein said pharmaceutical agent is selected from the group consisting of PPAR agonists, sulfonylurea drugs, secretagogues other than sulfonylureas, a-glucosidase inhibitors, insulin sensitizers, insulin secretagogues, decreasing compounds hepatic glucose, insulin, and anti-obesity agents.
25. 25. A method of treating or preventing secondary causes of diabetes comprising a step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 in combination with one or more pharmaceutical agents.
26. The method of claim 25, wherein said pharmaceutical agent is selected from the group consisting of PPAR agonists, sulfonylurea drugs, secretagogues other than sulfonylureas, a-glucosidase inhibitors, insulin sensitizers, insulin secretagogues, release of hepatic glucose, insulin, and anti-obesity agents
27. 27. A method of treating diabetes, Syndrome X, disorders related to diabetes or secondary causes of diabetes, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 in combination with one or more agents selected from the group consisting of inhibitors of HMG-CoA reductase, nicotinic acid, lipid-lowering drugs, ACAT inhibitors, bile acid sequestrants, bile acid reuptake inhibitors, microsomal lipid transport inhibitors, fibric acid derivatives, β-blockers, ACE inhibitors, calcium channel blockers, diuretics, renin inhibitors, AT-1 receptor antagonists, ET receptor antagonists, neutral endopeptidase inhibitors, vasopepsidase inhibitors and nitrates.
28. The method of claim 27, wherein said diabetes-related disorder is selected from the group consisting of hyperglycemia, hyperinsulinemia, glucose intolerance, fasting glucose intolerance, dyslipidemia, hypertriglyceridemia, and insulin resistance.
29. 29. The method of any of claims 17 to 28, wherein the compound of claim 1 and one or more pharmaceutical agents are administered as a single dose pharmaceutical formulation.
30. 30. A method of treating cardiovascular disease comprising a step of administering to a subject in need thereof a therapeutically effective amount of a polypeptide of claim 1 or a pharmaceutical composition of claim 7.
31. 31. The method of claim 30, wherein said cardiovascular disease is selected from atherosclerosis, coronary heart disease, coronary artery disease and hypertension.
32. 32. The method of treating obesity comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutical composition of claim 7.
33. 33. A method of stimulating secretion of insulin in a subject in need thereof by administering to said subject a compound of claim 1 or a pharmaceutical composition of claim 7.
34. 34. Compounds according to claim 1 for the treatment and / or prophylaxis of diabetes and disorders related to diabetes.
35. 35. Medicament containing at least one compound according to claim 1 in combination with at least one pharmaceutically safe carrier or excipient suitable for pharmaceutical use.
36. 36. Use of the compounds according to claim 1 for the preparation of a medicament for the treatment and / or prophylaxis of diabetes and disorders related to diabetes.
37. 37. Medicaments according to claim 35 for the treatment and / or prophylaxis of diabetes.