MX2008008273A - 4,5-dihydro- (1h)-pyrazole derivatives as cannabinoid cb1 receptor modulators - Google Patents

Abstract

This invention is directed to 4,5-dihydro -(1 H)-pyrazole (pyrazoline) derivatives as cannabinoid CB1 receptor modulators, to pharmaceutical compositions containing these compounds, to methods for the preparation of these compounds, methods for preparing novel intermediates useful for their synthesis, and methods for preparing compositions. The invention also relates to the uses of such compounds and compositions, particularly their use in administering them to patients to achieve a therapeutic effect in disorders in which CB1 receptors are involved, or that can be treated via manipulation of those receptors. The compounds have the general formula (I) wherein the symbols have the meanings given in the specification.

Description

DERIVATIVES OF 4,5-DIHYDRO- (1H) -PIRAZOL AS MODULATORS OF CANNABINOID RECEIVERS CBi TECHNICAL FIELD This invention is directed to derivatives of 4,5-dihydro- (1H) -pyrazol (pyrazoline) as modulators of CB-i cannabinoid receptors, to pharmaceutical compositions containing these compounds, to methods for the preparation of these compounds, to methods for preparing novel intermediates useful for their synthesis, and methods for preparing compositions. The invention also relates to the uses of such compounds and compositions, particularly their use in administration to patients to achieve a therapeutic effect in disorders in which CB-i receptors are involved, or which can be treated by manipulating those receptors. .

RELATED REQUESTS This application claims priority benefit under Article 87 EPC of EP 05 112482.4 filed on December 20, 2005, and also under Title 35 § 119 (e) of Provisional US Application No. 60/751, 667 filed on 20 December 2005, whose contents are incorporated herein by reference.

BACKGROUND OF THE INVENTION Cannabinoid receptors are part of the endo-cannabinoid system that is involved in various diseases, such as neurological, psychiatric, cardiovascular, gastrointestinal, reproductive, food and cancer disorders (De Petrocellis, 2004; Di Marzo, 2004; Lambert and Fowler, 2005; Vandevoorde and Lambert, 2005). Modulators of CBi receptors have several potential therapeutic applications such as drugs to treat psychosis, anxiety, depression, attention deficit, memory disorders, cognitive disorders, appetite disorders, obesity, addiction, appetite, drug dependence, neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, Huntington's disease, Tourette's syndrome, cerebral ischemia, cerebral stroke, craniocerebral trauma, infarction, damage to the spinal cord, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, disorders related to demyelination, as well as for the treatment of pain disorders, including neuropathic pain disorder, septic shock, glaucoma, diabetes, cancer, emesis, nausea, gastrointestinal disorders, gastric ulcers, day rrea, sexual disorders, impulse control disorders and cardiovascular disorders.

The CB2 receptors are predominantly in the immune system (spleen, tonsils, immune cells), but also in astrocytes, microglial cells and in the brainstem and have been linked to the perception of neuropathic pain as well as allergy / asthma and conditions (neuro) inflammatory (Van Sickle, 2005). Diaryylpyrazoline derivatives having antagonist or reverse agonist affinity in CBi cannabinoid receptors have been claimed in WO 01/70700, WO 03/026647, WO 03/026648-WO 2005/074920, and were described by Lange (2004, 2005). No derivatives of pyrazoline that act as agonists or partial agonists at the CB-i receptor have yet been reported, but certain pyrazoline derivatives have been claimed as pest controlling agents (JP 61 189270). There is abundant recent literature that contains general information about modulators of CB receptors (Lange and Kruse, 2004, 2005, Hertzog, 2004, Smith and Fathi, 2005, Thakur, 2005, Padgett, 2005, Muccioli, 2005, Raitio, 2005, Muccioli and Lambert, 2006). The objective of the present invention was to develop novel compounds with CB-i receptor agonist activity.

BRIEF DESCRIPTION OF THE INVENTION Surprisingly, it has been found that the modification of the original R 3 -aryl or 3-heteroaryl group in the pyrazolines of the prior art of the general formula (I) by means of a (substituted) alkyl molecular group in combination with a different substitution pattern in position 1 of the pyrazolone molecular group resulted in novel compounds with potent affinity for TBi-receptors. Even more, it was also found that some of the compounds of the invention act as partial agonists or total agonists in the CBi receptor, whereas it was found that other compounds of the invention act as antagonists or inverse agonists in the CB-i receptor. The majority of the compounds of the invention also showed affinity for the CB2 receptor. These compounds can act as CB2 receptor agonists, CB2 receptor antagonists or inverse agonists of the CB2 receptor. The present invention relates to compounds of the general formula (I): R, wherein - R represents an alkyl group of C2-? O, an alkenyl group of C4-? 0, a C4-10 alkynyl group. a heteroalkyl group of C2- [alpha] or, a cycloalkyl- group of Cs-β-alkyl-of C1-5 or a heterocycloalkyl- group of C5-8-alkyl- of C [beta] -5 wherein the heteroatom (s) ) are N, O or S, which are C2-? 0 alkenyl groups of C4-? or C-? al alkynyl, C2-? 0 heteroalkyl, Cs-? -Calkyl- alkyl- of C-? ? -5 or C5-8 heterocycloalkyl-alkyl- of d-5 may be substituted with 1-5 substituents selected from methyl, ethyl, hydroxy, amino or fluorine, or R represents an aryl-alkyl group of C? -3 or an aryl-heteroalkyl group of C1-3 in which the aryl groups may be substituted with 1-5 Y substituents, which may be the same or different, selected from the group of C -? - 3 alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl-de (C? -2) -amino, mono- or dialkyl- (C? -2) -amido, alkyl- (Ci ^ -sulfonyl) , dimethylsulfamido, C? -3-carbonyl alkoxy, carboxy, trifluoromethylsulfonyl, cyano, c arbamoyl, sulfamoyl, phenyl and acetyl, or R represents a cyclopropyl group, which cyclopropyl group can be substituted with 1-5 substituents selected from methyl, ethyl, fluorine or with an alkyl-C3 group. 5 linear or branched or with a benzyl or aryl group, in which the aryl or benzyl group can be substituted with 1-5 substituents Y, - R 1 represents hydrogen, hydroxy, C 1-3 alkoxy, acetyloxy or propionyloxy, - R 2 represents an aryl group which may be substituted with 1-5 Y substituents, wherein Y has the above-mentioned meaning, n is 0 or 1 R3 represents a linear C3.10 alkyl-, a branched C5.10 alkyl group , a cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl or cyclooctyl group, a bicycloalkyl- group of Cs-io, a tricycloalkyl- group of C6-? or a tetracycloalkyl- group of C8-n which groups can be substituted with 1-5 substituents selected from methyl, ethyl, hydroxy, amino, fluorine or R3 represents a C3-8 cycloalkyl group, which C3-8 cycloalkyl group is substituted with an aryl group, which aryl group can be substituted with 1-5 substituents Y, where Y has the previous meaning mentioned, or R3 represents a 2,2,2-trifluoroethyl or 2-fluoroethyl group or R3 represents a cyclohexyl group, which group is substituted with 1-5 substituents selected from methyl, ethyl, hydroxy, amino or fluorine, or R3 represents a heterocycloalkyl group of Cs-β, a bicycloheteroalkyl group of C 1 -io, a tricycloheteroalkyl group of C 7 - 0) which groups can be substituted with 1-5 substituents selected from methyl, ethyl, hydroxy, amino or fluorine, or R3 represents a C3-8 cycloalkyl-C-? -3 alkyl group, a Cs-io-C1-3 alkyl bicycloalkyl group) a C6-? 0-alkyl- alkyl tricycloalkyl group C? -3, which groups can be substituted with 1-5 substituents selected from methyl, ethyl, hydroxy, amino or fluorine, or R3 represents a C3-8 heterocycloalkyl-branched or linear C? -3 alkyl group , a bicycloheteroalkyl- group of Cs-io-C1-3alkyl, a tricycloheteroalkyl- group of C6-? or -alkyl- of C? -3, which groups they can be substituted with 1-5 substituents selected from methyl, ethyl, hydroxy, amino or fluorine, or R3 represents an aryl group, which group can be substituted with 1-5 substituents Y, wherein Y has the above-mentioned meaning, or R3 represents an aryl-C-alkyl-5 group or a C-5-diaryl-alkyl group, in which groups the phenyl or heteroaromatic rings can be substituted with 1-5 Y substituents, where Y has the meanings previously mentioned, or R3 represents a linear or branched C4-8 -alkenyl- or C-8-alkynyl group which C4-8 alkenyl- or C4-8 alkynyl-linear or branched groups can be substituted -3 fluorine atoms, or, when n = 1, R3 represents a straight or branched C2-? 0 heteroalkyl group, containing 1-2 heteroatoms selected from N, O or S, - R4 represents a hydrogen atom, an alkyl- C1-4 or R3 and R4 - together with the nitrogen atom to which they are attached - form a monocyclic, bicyclic or tricyclic heterocyclic group, having 5 to 11 ring atoms, saturated or unsaturated, non-aromatic or partially aromatic, which heterocyclic group can be substituted with 1-5 substituents selected from aryl, aryl-C-? -3 alkyl, diarylmethyl, or Y, wherein Y has the meanings mentioned above, - A represents a carbonyl group (C = 0) , thiocarbonyl (C = S) or sulfonyl (S02) with the proviso that when A represents a thiocarbonyl group (C = S), n has the value 1, and stereoisomers, prodrugs and N-oxides thereof, and compounds isotopically of the formula (I), as well as salts, hydrates, solvates, complexes and co njugados of said pharmacologically acceptable compounds of the formula (I), and their stereoisomers, prodrugs, N-oxides, or isotopically labeled analogues. The invention particularly relates to compounds of the general formula (I) wherein Ri represents a hydrogen atom, and the other symbols have the meanings given above. More particularly, the invention relates to a compound of the general formula (I) wherein R-i represents a hydrogen atom, A represents a carbonyl group, and the other symbols have the meanings given above. Still more particularly, the invention relates to compounds of the general formula (I) wherein Ri represents a hydrogen atom, A represents a carbonyl group, R 2 represents a phenyl, thienyl or pyridyl group, which phenyl, pyridyl or thienyl group it can be substituted with 1, 2 or 3 Y substituents, and the other symbols have the meanings given above. Also in particular, the invention relates to compounds of the general formula (I) wherein n = 1, Ri represents a hydrogen atom, A represents a carbonyl group, R 2 represents a phenyl, thienyl or pyridyl group, which phenyl group , pyridyl or thienyl can be substituted with 1, 2 or 3 Y substituents, and the other symbols have the meanings given above. Similarly, the invention particularly relates to compounds of the general formula (I) wherein n = 1, Ri and R4 represent hydrogen atoms, A represents a carbonyl group, R2 represents a phenyl, thienyl or pyridyl group, which The phenyl, pyridyl or thienyl group may be substituted with 1, 2 or 3 Y substituents, and the other symbols have the meanings given above. More particularly, the invention relates to compounds of the general formula (I) wherein n = 1, R represents a branched or linear C3-8 alkyl group, which branched or linear C3-8 alkyl group may be substituted with 1-3 fluorine atoms, R, and R4 represent hydrogen atoms, R2 represents a phenyl or pyridyl group, which phenyl or pyridyl group can be substituted with 1, 2 or 3 Y substituents, and the other symbols have the meanings given above. The compounds of the invention of the general formula (I), as well as the pharmacologically acceptable salts thereof, have CB-cannabinoid receptor modulating activity. They are useful in the treatment of disorders in which cannabinoid receptors are involved, or which can be treated by means of manipulation of those receptors. The invention is also directed to: a pharmaceutical composition for treating, for example, a disorder or condition that can be treated by the modulation of CB-i cannabinoid receptors, the composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; a method of treating a disorder or condition that can be treated by modulating CB cannabinoid receptors, the method comprising administering to a mammal in need of such treatment a compound of formula (I) or a pharmaceutically acceptable salt thereof; a pharmaceutical composition for treating, for example, a disorder or condition selected from the group consisting of psychosis, anxiety, depression, attention deficit, memory disorders, cognitive disorders, appetite disorders, obesity, addiction, appetite, drug dependence, neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremor, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischemia, cerebral stroke, craniocerebral trauma, infarction, damage to the spinal cord, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, demyelination related disorders, as well as for the treatment of pain disorders, including neuropathic pain disorders, septic shock, glaucoma, diabetes, cancer, emesis, nausea, gastrointestinal disorders, gastric ulcers, diarrhea ea, sexual disorders, impulse control disorders and cardiovascular disorders; a method of treating a disorder or condition selected from the group consisting of the disorders listed herein, the method comprising administering to a mammal in need of such treatment a compound of the formula (I) or a pharmaceutically acceptable salt thereof; a pharmaceutical composition for treatment of a disorder or condition selected from the group consisting of the disorders listed herein, the composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; a method of treating a disorder or condition that can be treated by CB-i cannabinoid receptor modulation, the method comprising administering to a patient in need of such treatment a compound of the formula (I) or a pharmaceutically acceptable salt thereof; a method of antagonizing a CB-i cannabinoid receptor, comprising administering to a subject in need thereof, an effective amount of a compound of the formula (I); The invention also provides the use of a compound or salt according to formula (I) for the manufacture of a medicament.

The invention further relates to combination therapies wherein a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of the invention, is administered concurrently or sequentially or as a preparation combined with another agent or therapeutic agents, for the treatment of one or more of the listed conditions. Such other therapeutic agent (s) may be administered prior to, concurrent with, or following the administration of the compounds of the invention. The invention also provides compounds, pharmaceutical compositions, equipment and methods for the treatment of a disorder or condition that can be treated by modulation of CB-i cannabinoid receptors, the method comprising administering to a patient in need of such treatment a compound of the formula (I) or a pharmaceutically acceptable salt thereof. The compounds of the invention possess cannabinoid receptor modulating activity CB- |. The (ant) agonist activity of the compounds of the invention is easily demonstrated, for example, by using one or more of the assays described herein or known in the art. The invention also provides methods for preparing the compounds of the invention and the intermediates used in those methods. The compounds of the present invention may contain one or more asymmetric centers and may accordingly exist as racemates and racemic mixtures, isolated enantiomers, diastereomeric mixtures and individual diastereomers. All the compounds of the present invention contain at least one chiral center (at the 4-position of the 4,5-dihydropyrazole ring). Additional asymmetric centers may be present depending on the nature of the various substituents in the molecule. Each such asymmetric center will independently produce two optical isomers and it is understood that all possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the scope of this invention. The present invention comprises all such isomeric forms of these compounds. The independent synthesis of these diastereomers or their chromatographic separations can be achieved, as is known in the art, by appropriate modification of the methodology described herein. Their absolute stereochemistry can be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, the racemic mixtures of the compounds can be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as coupling a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as crystallization. fractionated or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base, such as for example (-) - di-p-toluoyl-D-tartaric acid and / or (+) - di-p- acid. toluoyl-L-tartaric. The diastereomeric derivatives can then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods using chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound can be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art. The cis and trans isomers of the compound of the formula (I) or a pharmaceutically acceptable salt thereof are also within the scope of the invention, and this also applies to the tautomers of the compounds of the formula (I) or a pharmaceutically acceptable salt thereof. Some of the crystalline forms of the compounds may exist as polymorphs and as such are included in the present invention. In addition, some of the compounds can form solvates with water (ie hydrates) or with common organic solvents, and such solvates are also within the scope of this invention.

A compound of the formula (I) isotopically labeled or a pharmaceutically acceptable salt thereof, including compounds of the formula (I) isotopically labeled to be detectable by PET (for its acronym in English) or SPECT (for its acronym in English), they are also included within the scope of the invention, and the same applies to compounds of the formula (I) labeled with [13 C], [14 C], [3 H], [18 F], [125 l] or other isotopically enriched atoms, Suitable for binding to receptors or metabolism studies.

Definitions of chemical terms The term 'alkyl' refers to straight or branched hydrocarbon radicals. 'Alkyl- of (C? -3)', for example, means methyl, ethyl, n-propyl or isopropyl, and '(C 1-4) alkyl' means' methyl, ethyl, n-propyl, isopropyl, n- butyl, sec-butyl, isobutyl or tert-butyl '. The term 'alkenyl' denotes straight or branched hydrocarbon radicals having one or more carbon-carbon double bonds, such as vinyl, allyl, butenyl, etc. In the 'alkynyl' groups the straight or branched hydrocarbon radicals have one or more carbon-carbon triple bonds, such as ethynyl, propargyl, 1-butynyl, 2-butynyl, etc. The term 'acyl' means alkyl- (C ? -3) -carbonyl, arylcarbonyl or aryl-alkyl (C- | .3) -carbonyl. 'Hetero' as in 'heteroalkyl, heteroaromatic' etc. means N, O or S.? Eteroalkyl 'includes alkyl groups with heteroatoms at any position, thus including N-linked, O-linked or S-linked alkyl groups. The abbreviation 'aryl' means fused monocyclic or bicyclic aromatic or heteroaromatic groups, which heteroaromatic groups contain one or two heteroatoms selected from the group N, O, S. The aryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, phenyl, indazolyl, indolyl, indolizinyl, isoindolyl, benzo [b] furanyl, 1, 2,3,4-tetrahydronaphthyl, 1, 2, 3,4-tetrahydroisoquinolinyl, indanyl, indenyl, benzo [b] thiophenyl, 2,3-dihydro-1,4-benzodioxin = 5-yl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8- naphthyridinyl, naphthyl. The abbreviation 'halogen' means chlorine, fluorine, bromine or iodine. The abbreviation 'C3-8 cycloalkyl' means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. The abbreviation 'heterocycloalkyl- of Cs-β' refers to rings containing heteroatoms (N, O, S) including, but not limited to, piperidinyl, morpholinyl, azepanyl, pyrrolidinyl, thiomorpholinyl, piperazinyl, tetrahydrofuryl, tetrahydropyranyl. The abbreviation 'C5-10 bicycloalkyl group' refers to carbo-bicyclic ring systems which include but are not limited to bicyclo [2.2.1] heptanil, bicyclo [3.3.0] octanyl or the bicyclo group [3.1.1 ] heptanil. The abbreviation 'C6-tricycloalkyl group' or 'refers to carbo-tricyclic ring systems which include but are not limited to the 1-adamantyl, noradiminyl or 2-adamantyl groups. The abbreviation 'C8-n' tetracycloalkyl group refers to carbo-tetracyclic ring systems which include, but are not limited to, the cubyl, homocubyl or bishomocubyl groups.

The terms "oxy", "thio" and "carbo" as used herein as part of another group, respectively refer to an oxygen atom, a sulfur atom and a carbonyl group (C = O), which serve as a union between two groups, such as for example hydroxyl, oxyalkyl, thioalkyl, carboxyalkyl, etc. The term "amino" as used herein, alone or as part of another group refers to a nitrogen atom which may be terminal or a link between two other groups, wherein the group may be a primary, secondary or tertiary (two hydrogen atoms linked to the nitrogen atom, a hydrogen atom linked to the nitrogen atom, no hydrogen atom linked to the nitrogen atom, respectively).

The terms "sulfinyl" and "sulfonyl" as used herein as part of another group, respectively refer to an -SO- group or an -SO2- group. As used herein, unless otherwise indicated, the term "leaving group" shall mean a charged or uncharged atom or group that starts during a substitution or displacement reaction. Suitable examples include, but are not limited to, Br, Cl, I, mesylate, tosylate, and the like. The N-oxides of the aforementioned compounds are within the scope of the present invention. Tertiary amines may or may not give rise to N-oxide metabolites. The degree to which the N-oxidation takes place varies from trace amounts to near quantitative conversion. The N-oxides may be more active than their corresponding tertiary or less active amines. Although N-oxides are easily reduced to their corresponding tertiary amines by chemical means, in the human body this occurs in varying degrees. Some N-oxides undergo almost quantitative reductive conversion to the corresponding tertiary amines, in other cases the conversion is a mere trace reaction or even completely absent (Bickel, 1969).

Definitions of Other Terms With reference to substituents, the term "independently" means that when more than one such substituent is possible, such substituents may be the same or different from one another. To provide a more concise description, some of the quantitative expressions provided herein are not qualified with the term "approximately." It is understood that if the term "approximately" is used explicitly or not, each quantity given herein is intended to refer to the actual given value, and is also intended to refer to the approximation to such a given value, which would reasonably be inferred. based on normal knowledge in the art, including approximations due to the experimental and / or measurement conditions for such given value. Any compound that can be converted in vivo to provide the bioactive agent (ie, the compound of the formula (I)) is a prodrug within the scope and spirit of the application. Prodrugs are therapeutic agents that are inactive per se but that are transformed into one or more active metabolites. Accordingly, in the methods of treatment of the present invention, the term "administration" should comprise the treatment of the various disorders described with the specifically described compound or with a compound that may not be specifically described, but which becomes the compound specified in vivo after administration to the patient. Prodrugs are bioreversible derivatives of drug molecules used to overcome some barriers to the utility of the parent drug molecules. These barriers include, but are not limited to, solubility, permeability, stability, presystemic metabolism and limitations in achieving the objective (Bundgaard, 1985, King, 1994, Stella, 2004, Ettmayer, 2004, Járvinen, 2005). Prodrugs, ie, compounds that when administered to humans by any route, are metabolized to compounds having the formula (I), belong to the invention. In particular this refers to compounds with primary or secondary amino groups or hydroxy. Such compounds can react with organic acids to provide compounds having the formula (I) wherein a group is present which is easily removed after administration, for example, but not limited to, amidine, enamine, a Mannich base, a derivative hydroxyl-methylene, a 0- (acyloxymethylene carbamate) derivative, carbamate, ester, amide or enaminone. The term "composition" as used herein is intended to comprise a product comprising specified ingredients in predetermined amounts or proportions, as well as any product that results, directly or indirectly, from the combination of the ingredients specified in the specified quantities. This term in relation to pharmaceutical compositions is intended to comprise a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectly, from the combination, formation, complexes or aggregation of any two or more of the ingredients, or from the dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately associating the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active compound object is included in an amount sufficient to produce the desired effect according to the process or condition of the diseases. Correspondingly, the pharmaceutical compositions of the present invention comprise any composition prepared by mixing a compound of the present invention and a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" it is meant that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Dose. The affinity of the compounds of the invention for CB-i cannabinoid receptors was determined as described below. From the measured binding affinity for a given compound of the formula (I), a theoretical minimum effective dose can be estimated. At a compound concentration equal to twice the measured K value, almost 100% of the CB-i cannabinoid receptors are likely to be occupied by the compound. The conversion of that concentration to mg of compound per kg of patient provides a minimum theoretical effective dose, assuming ideal bioavailability. Pharmacokinetics, pharmacodynamics and other considerations may alter the dose actually administered at a higher or lower value. The dose of the compound to be administered will depend on the relevant indication, the age, weight and sex of the patient and can be determined by the doctor. The dosage will preferably be in the range from 0.01 mg / kg to 10 mg / kg. The typical daily dose of active ingredients varies on a wide scale and will depend on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient and can be determined by the physician. In general, oral and parenteral dosages will be on the scale of 0.1 to 1,000 mg per day of total active ingredients. The term "therapeutically effective amount" as used herein refers to an amount of therapeutic agent for treating or preventing a treatable condition by administration of an application composition. That amount is sufficient to exhibit a detectable therapeutic, preventive or improvement response in a tissue, animal or human system. The effect may include, for example, treatment or prevention of the conditions listed herein. The precise effective amount for a subject will depend on the size and health of the subject, the nature and degree of the condition being treated, the recommendations of the treating physician (researcher, veterinarian, medical doctor or other specialist), and the agents Therapeutics or combination of therapeutic agents selected for administration. Consequently, it is not useful to specify an exact amount of input. The term "pharmaceutically acceptable salt" refers to those salts that are, within the scope of deep medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and they are evaluated with a reasonable risk / benefit ratio. Pharmaceutically acceptable salts are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting compounds of the invention with non-toxic pharmaceutically acceptable bases or acids, including inorganic or organic bases and inorganic or organic acids. The term "treatment" as used herein, refers to any treatment of a condition or disease of a mammal, preferably a human, and includes: (1) preventing the disease or condition from occurring in a subject that may be predisposed to the disease but that has not yet been diagnosed suffering from it, (2) inhibit the disease or condition, that is, stop its development, (3) alleviate the disease or condition, that is, cause the condition to regress, or ( 4) alleviate the conditions caused by the disease, that is, stop the symptoms of the disease. The term "medical therapy" as used herein is intended to include prophylactic, diagnostic- and -therapeutic regimens carried out in vivo or ex vivo on humans or other mammals. The term "subject" as used herein, refers to an animal, preferably a mammal, more preferably a human, that has been the subject of a treatment, observation or experiment.

Abbreviations ACN acetonitrile API-ES ionization at atmospheric pressure - electron spray BOC ter-butoxycarbonyl BSA bovine serum albumin CBi cannabinoid receptor subtype-1 CB2 cannabinoid receptor subtype-2 CHO Chinese hamster ovary (cells) CNS central nervous system CUR curtain gas DF voltage deflector DIPEA N, N-diphosopropyletilamine DMAP 4-dimethylaminopyridine DMEM Eagle medium Modified Dulbecco DMSO dimethylsulfoxide DSC differential scanning calorimetry EDCI cfoi + 1- (3 < iimetilamiropropil) -3 ^ 'lra? )? EP potential of FP entry potential of focus 9 gram (s) h hour (s) HOBt N-hydroxybenzotriazole HPLC high performance liquid chromatography IBMX 3-isobutyl-1-methylxanthine IS ion spray voltage MeOH methanol mg milligram (s) min min (s) ml milliliter (s) m.p. melting point c.q. melting scale MTBE methyl ter-butyl ether NEB gas nebulizer NMM N-methylmorpholine PBS phosphate buffered saline PET positron emission tomography Rf retention factor (thin layer chromatography) Rt retention time (LC / EM) TA room temperature SPECT single photon emission computed tomography TEM THF tetrahydrofuran temperature EXAMPLES EXAMPLE 1 Materials and Methods The 1H NMR spectrum was recorded in any of an instrument Varian 300 MHz, or a Varian UN400 instrument (400 MHz) using DMSO-d6 or CDCI3 as solvents with tetramethylsilane as internal standard. The 13C NMR spectrum was recorded on a Varian UN400 instrument using CDCI3 as solvent. Chemical shifts are given in ppm (scale d) downfield of tetramethylsilane. Coupling constants (J) are expressed in Hz. Instant chromatography was carried out using silica gel 60 (0.040-0.063 mm, Merck). Column chromatography was carried out using silica gel 60 (0.063-0.200 mm, Merck). Sepacore chromatographic separations were carried out using Supelco equipment, VersaFLASH ™ columns, VersaPak ™ silica cartridges, Büchi C-630 UV monitor, Büchi module C-605, Büchi C-660 fraction collector and Büchi C-pump manager 615 The melting points were recorded in a Büchi B-545 melting point apparatus or determined by DSC (differential scanning calorimetry) methods. The optical rotations ([a] o) were measured in an Optical Activity polarimeter. Specific rotations are given as degree / dm, the concentration values are reported as g / 100 ml of the specified solvent and were recorded at 23 ° C.

LC-EM instrumentation for method A and method B: Hardware: An Agilent 1100 LC / EM system was used which consisted of: G1322A G1311A solvent degasser quaternary pump G1313A G1316A autosampler for columns oven + G1315B DAD switch + standard flow cell G1946D (SL) -MSD Method To Column: Discovery C18 (150 x 4.6 mm) Supelco Mobile phase: Solution B 100% (16 min) Flow rate: 1.0 ml / min UV wavelength: 216 and 251 nm Sample: ~ 1 mg / ml in MeOH Volume injected: 3 μl Temperature: 22 ° C Detection of mass: API-ES positive Solution B: 9.65 g of Ammonium Acetate; 250 ml of H2O; 1350 ml of MeOH; 900 ml Acetonitrile Method B Column: Agilent Zorbax Extend-C18 (4.6 * 50 mm, 3.5 μm) Mobile phase: Gradient: 0 - 3 minutes: Solution A / Solution B = 20/80 (v / v)). > 3 minutes: Solution B, unless otherwise indicated. Flow rate: 1.0 ml / min. UV wavelength: 218 and 250 nm Sample: ~ 1 mg / ml in MeOH Volume injected: 1.0 μl Temperature: 22 ° C Mass detection: API-ES positive and negative Solution A: 9.65 g of ammonium acetate; 2250 ml of H20; 150 ml of MeOH; 100 ml of Acetonitrile Solution B: 9.65 g of Ammonium Acetate; 250 ml of H2O; 1350 ml of MeOH; 900 ml Acetonitrile Preparative LC / MS instrumentation and procedure for method C Sciex API 150 EX mass spectrometer with electron spray, 2 Shimadzu LC8A LC Pumps, Shimadzu SCL-10A VP System Controller, Shimadzu SPD-10A VP UV Meter, Gilson 215 Injector / Collector, Column: Phenomenex Luna C18 (2) 150 x 21.2 x 5 μ Eluent: A 100% Water + 0.1% Formic Acid at pH = 3: B 100% Acetonitrile + 0.1% Formic Acid Injection: 2.5 ml Divider: 1 to 50,000 with a refresh rate of 02 ml / min 25% H2O / 75% ACN met 0.25% HCOOH ) EM scan: from 100 - 900 amu stage 1 amu scan time 1 sec Method: Flow and gradient profiles Preparative LC / MS instrumentation and procedure for D method 3-minute analytical method The LC-MS system consists of 2 Perkin-Elmer 200-series micropumps. The pumps are connected to each other using a 50-μm T-mixer. The mixer is connected to the Gilson 215 autosampler. The LC method is: stage total flow time (ul / min) A (%) B (%) 0 0 2300 95 5 1 1.8 2300 0 100 2.5 2300 0 100 2.7 2300 95 5 3.0 2300 95 5 A = 100% Water with 0.2% HCOOH and 10 mmole NH4COOH pH = +/- 3 B = 100% ACN with 0.2% HCOOH The autosampler has an injection cycle of 2 ul. The autosampler is connected to a Waters Atlantis C18 30 * 4.6 mm column with 3 um particles. The column is heat-sealed in a kiln for Perkin-Elmer 200 series columns at 40 degrees Celsius. The column is connected to an Applied Biosystems ABI 785 UV meter with a flow cell of 2.7 ul. The wavelength is set at 254 nm. The UV meter is connected to a Sciex API 150EX mass spectrometer. The mass spectrometer has the following parameters: Scale scan: 150-900 Amu Polarity: positive Sweep mode: profile Resolution Q1: UNIT Step size: 0.10 amu Sweep time: 0.500 sec NEB (for its acronym in English): 10 CUR (for its acronym in English): 10 IS (for its acronym in English): 5200 TEM (for its acronym in English): 325 DF (for its acronym in English): 30 FP (for its acronym in English): 225 EP: 10 The light scattering detector is connected to the Sciex API 150. The light scattering detector is a Polymerlabs PLS2100 operating at 70 ° C and N2 pressure of 170 kPa. The complete system is controlled by a Dell precision 370 computer operating with Windows 2000.

EXAMPLE 2 General Aspects of Synthesis The pyrazoline derivatives can be obtained by published methods (Barluenga, 1999 (and references cited there), Wang, 2003). The synthesis of the compounds having the formula (I) is outlined in Scheme 1. The ketone derivatives of the general formula (II) can be prepared by various methods known to those skilled in the art. Examples are the application of the so-called Weinreb amide RC (= O) N (OCH3) CH3 which can be reacted with a Grignard reagent R2CH2MgCI or R2CH2MgBr or a RMgBr or RMgCI reaction with a Weinreb amide of the general formula R2CH2C (= 0) N (OCH3) CH3. Alternatively, a Grignard reagent R2CH2MgCI or R2CH2MgBr can be reacted with a cyanide analogue RiCN, followed by acid hydrolysis, for example using hydrochloric acid. A ketone derivative of the general formula (II) can be reacted wherein R and R2 have the meanings mentioned above with formaldehyde in the presence of an amine, such as piperidine and an acid, for example acetic acid, in an inert organic solvent such as methanol to provide a compound of the general formula (III), wherein R and R2 have the meanings mentioned above. This reaction can be classified as a so-called Mannich reaction, followed by removal of the amine applied. Alternatively, a ketone derivative of the general formula (II) can be reacted where R and R2 have the above-mentioned meanings, with N, N, N ', N'-tetramethyl-diaminomethane-in acetic anhydride to provide a compound of the general formula (III), wherein R and R2 have the meanings mentioned above (Ogata, 1987a, 1987b). The compound of the general formula (III) can be reacted with hydrazine or hydrazine hydrate in the presence of an inert organic solvent such as ethanol to provide a pyrazoline derivative of the general formula (IV), wherein R and R2 have the meanings previously mentioned and Ri represents a hydrogen atom. Alternatively, the compound of the general formula (III) can be oxidized with an oxidizing reagent such as hydrogen peroxide to provide an epoxyketone derivative of the general formula (V), wherein R and R2 have the meanings mentioned above. A compound of the general formula (V) can be reacted with hydrazine or hydrazine hydrate in the presence of an inert organic solvent such as ethanol to provide a pyrazoline derivative of the general formula (IV), wherein R and R have the above-mentioned meanings and Ri represents a hydroxy group.

A compound of the general formula (IV) can be reacted with a carboxylic acid R3-CO2H wherein R3 has the above-mentioned meaning in the presence of a so-called activating reagent or coupling reagent in an inert organic solvent such as dichloromethane to provide a pyrazoline derivative of the general formula (I), wherein n = 0, A represents a carbonyl group and all other symbols have the meanings given above. Additional information can be found on methods of activation and coupling of amines to carboxylic acids in the literature (Bodanszky and Bodanszky, 1994, Akaji, 1994, Albericio, 1997, Montalbetti and Falque, 2005). Alternatively, a compound of the general formula (IV) may be reacted wherein R, R1 and R2 have the above-mentioned meanings with an acid chloride R3-COCI wherein R3 has the above-mentioned meaning to provide a pyrazoline derivative of the general formula (I), where n = 0, A represents a carbonyl group and all other symbols have the meanings given above. A compound of the general formula (IV) can be reacted wherein R, R1 and R2 have the above-mentioned meanings with an isocyanate derivative R3-N = C = 0 (VII) wherein R3 has the above-mentioned meaning in the presence of an inert organic solvent such as diethyl ether to provide a pyrazoline-1-carboxamide derivative of the general formula (I), wherein n = 1 and R4 represents H, A represents a carbonyl group and all other symbols have the given meanings previously. The isocyanates R3-N = C = O can also be prepared in situ from the corresponding amine R3-NH and a so-called carbonyl donor such as phosgene, diphosgene (trichloromethyl chloroformate) or triphosgene (bis (trichloromethyl) carbonate). Alternatively, the sociotates R3-N = C = 0 can be prepared from the corresponding carboxylic acid R3-COOH by means of the acylazide R3-CON3 in a so-called Curtius rearrangement. An amine of the general formula R3R NH can be reacted where R3 and R have the above-mentioned meanings with a carbonylating agent such as phosgene and the like in the presence of an inert organic solvent such as toluene or benzene to provide a compound of the general formula (VI), wherein L represents a so-called leaving group such as chloride. A compound of the general formula (VI) can be reacted where L represents a so-called leaving group with a compound of the general formula (IV) wherein R, R1 and R have the meanings mentioned above to provide a pyrazoline derivative of the general formula (I), where n = 1 and all the other symbols have the meanings given above. Preferably, a base such as triethylamine or Hünigs base can be added in such reactions. Additionally, 4- (dimethylamino) pyridine (DMAP) can serve as a catalyst in such reactions. A compound of the general formula (IV) can be reacted wherein R, R1 and R2 have the above-mentioned meanings with an isothiocyanate derivative R3-N = C = S (Vlla) wherein R3 has the above-mentioned meaning in the presence of an inert organic solvent such as tetrahydrofuran to provide a pyrazoline-1-carbothioamide derivative of the general formula (I), wherein n = 1 and R4 represents H, A represents a thiocarbonyl group and all other symbols have the meanings given above .

SCHEME 1 (I) wherein n = 1 (I) wherein n = 1 Alternatively, a compound of the general formula (IV) may be reacted wherein R and R2 have the above-mentioned meanings and Ri represents a hydrogen atom with phosgene, diphosgene or triphosgene to provide a compound of the general formula (VIII) wherein R and R2 have the above-mentioned meanings and R ^ represents a hydrogen atom (Scheme 2). A compound of the general formula (VIII) can be reacted with a compound R3R4NH to provide a pyrazoline-1 -carboxamide derivative of the general formula (I), wherein n = 1, A represents a carbonyl group. A compound of the general formula can be reacted (IV) wherein R and R2 have the above-mentioned meanings and R represents a hydrogen atom with a sulfonyl chloride derivative of the general formula R3S02CI to provide a pyrazoline derivative of the general formula (I), wherein = 0, A represents a sulfonyl group and all other symbols have the meanings given above. Preferably, a base such as triethylamine or Hünigs base (DIPEA) can be added in such reactions.

SCHEME 2 1 (I) where n = 1 A compound of the general formula can be reacted (IV) wherein R and R2 have the above-mentioned meanings and R1 represents a hydrogen atom with a compound of the general formula R3R4NS02CI to provide a pyrazolidine derivative of the general formula (I), wherein n = 1, A represents a sulfonyl group and all other symbols have the meanings given above. Preferably, a base such as triethylamine or Hünigs base (DIPEA) can be added in such reactions.

A compound of the general formula R3R4NSO2CI can be obtained from a reaction of a sulphamic acid derivative R3R NS02OH with a chlorinating agent such as POCI3 in an inert organic solvent such as dichloromethane. A compound of the general formula R3R4NSO2OH can be obtained from a reaction of an amine R3R NH and chlorosulfonic acid in an inert organic solvent such as dichloromethane. Preferably, a base such as triethylamine or Hünigs base (DIPEA) may be added in such a reaction. The selection of the particular synthesis methods depends on factors known to those skilled in the art such as the compatibility of the functional groups with the reagents used, the possibility of using protecting groups, catalysts, activation and coupling reagents and the final structural characteristics present in the final compound that is being prepared. The compounds of the general formula (III), wherein R represents a phenyl group which is substituted with 1-3 substituents Y1 wherein Y1 represents halogen, CF3, OCF3 or OCH3, or R represents a pyridyl or thienyl group, and R2 represents a n-butyl, n-propyl, 1,1-dimethylpropyl, 1,1-dimethylbutyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl or 1,1-dimethyl-3,3,3- group trifluoropropyl, or R represents a phenyl group and R 2 represents a 1,1-dimethylpropyl group, 1,1-dimethylbutyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl or 1,1-dimethyl-3,3 , 3-trifluoropropyl are new. Such compounds are useful in the synthesis of compounds of the general formula (I).

The compounds of the general formula (IV) wherein R and Ri have the same meanings as those given in claim 1 and R2 represents a phenyl group which may be substituted with 1-5 Y2 substituents which may be the same or different, selected of the group C1_3alkoxy, hydroxy, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono-0 dialkyl- of mono- or dialkyl- (C-? - 2) -amido, alkyl- of (C1 -3) -sulfonyl, dimethylsulfamido, C? -3-carbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl, ortho-halogen, meta-halogen, ortho-C1-3-alkyl, meta-alkyl- C-? -3 and acetyl, or R2 represents a thienyl or pyridyl group, which groups can be substituted with one or two substituents Y, which group Y has the meaning according to claim 1, are new. Such compounds are useful in the synthesis of the compounds of the formula (I). The compounds of the general formula (VIII) wherein R and R2 have the same meanings as those given above and R1 represents hydrogen are new. Such compounds are useful in the synthesis of compounds of the general formula (I) wherein n = 1. The pharmacologically acceptable salts can be obtained using standard procedures well known in the art, for example by mixing a compound of the present invention with an acid suitable, for example an acid such as hydrochloric acid, or with an organic acid such as fumaric acid.

In accordance with these procedures, the compounds described below have been prepared. They are intended to further illustrate the invention in greater detail, and accordingly, are not supposed to restrict the scope of the invention in any way. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention described herein. Accordingly, it is intended that the specification and examples be considered by way of example only.

EXAMPLE 3 Synthesis and Spectral Data of Intermediaries Intermediary 11-1 Intermediary IL-1 To a magnetically stirred solution of hexanoic acid methoxy-methyl-amide (12.2 g, 77 mmol) at 0 ° C in tetrahydrofuran (THF) was slowly added benzylmagnesium chloride (20 weight percent solution in THF, 90 ml 116 mmol ) and the resulting mixture was allowed to react for two hours. The reaction mixture was poured into an excess of aqueous hydrochloric acid (4N solution) and extracted with tert-butyl methyl ether (MTBE). Concentration under vacuum, followed by purification by flash chromatography (heptane / ethyl acetate = 40/1 (v / v)) afforded 1-phenylheptan-2-one (Intermediate 11-1) (11.6 grams) as an oil; 1 H-NMR (300 MHz, CDCl 6) d 0.86 (t, J = 7, 3H), 1.20-1.27 (m, 4H), 1.52-1.60 (m, 2H), 2.40-2.46 (m, 2H), 3.68 ( s, 2H), 7.18-7.33 (m, 5H).

Intermediary II-2 Intermediary IL-2 4,4,4-trifluoro-N-methoxy-N-methylbutyramide (7.68 g) was obtained in 87% yield as an oil from the reaction of 4,4,4-trifluorobutyric acid (6J7 g) , 0.0477 moles) with N-methyl-N-methoxyamine.HCl in the presence of N-hydroxybenzotriazole (HOBt), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide.HCl (EDCI) and N-methylmorpholine (NMM) in dichloromethane as solvent (room temperature, 16 hours). H-NMR (400 MHz, CDCl 3) d 2.40-2.54 (m, 2H), 2.67-2.73 (m, 2H), 3.20 (s, 3H), 3.71 (s, 3H). 4,4,4-Trifluoro-N-methoxy-N-methylbutyramide (7.68 g) was converted to benzylmagnesium chloride at 0 ° C in tetrahydrofuran (THF) analogously to the procedure described for the synthesis of intermediate 11-1 to provide 6.37 grams (71%) of 5,5,5-trifluoro-1-phenylpentan-2-one (Intermediate II-2). Chromatographic purification with Sepacore (petroleum ether / diethyl ether = 47/1 (v / v)) was used to purify intermediate II-2. 1 H-NMR (400 MHz, CDCl 3) d 2.31-2.44 (m, 2H), 2.68-2.75 (m, 2H), 3.73 (s, 2H), 7.18-7.38 (m, 5H).

Intermediary II-3 Intermediary IL-3 Intermediate II-3 (6,6,6-trifluoro-1-phenyl-hexan-2-one) was prepared analogously to intermediate 11-1 from 5-methoxy-methyl-amide of acid 5, 5,5-trifluoropentanoic and benzylmagnesium chloride (20 weight percent solution in THF) at 0 ° C in tetrahydrofuran, as an oil; 1 H-NMR (400 MHz, CDCl 3) d 1.75-1.85 (m, 2H), 1.98-2.11 (m, 2H), 2.55 (t, J = 7, 2H), 3.69 (s, 2H), 7.18-7.22 (m, 2H), 7.26-7.37 (m, 3H). 5,5,5-trifluoropentanoic acid methoxy-methyl-amide: 1H-NMR (400 MHz, CDCI3) d 1.86-1.95 (m, 2H), 2.11-2.24 (m, 2H), 2.53 (br t, J = 7, 2H), 3.19 (s, 3H), 3.69 (s, 3H) . The methoxy-methyl-amide of 5,5,5-trifluoropentanoic acid was obtained from the reaction of 5,5,5-trifluoropentanoic acid and N-methyl-N-methoxy-amine.HCl in the presence of N-hydroxybenzotriazole, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide.HCl and N-methylmorpholine in dichloromethane.

Intermediary 11-4 Intermediary IL Intermediate 11-4 (6,6,6-trifluoro-1-phenyl-pentan-2-one) was prepared analogously to intermediate 11-1, from 4,4,4-trifluoro-N-methoxy- N-methyl-butyramide and benzylmagnesium chloride (20 weight percent solution in THF) at 0 ° C in tetrahydrofuran, as an oil; 1 H-NMR (400 MHz, CDCl 3) d 2.31-2.44 (m, 2H), 2.71 (t, J = 7, 2H), 3.73 (s, 2H), 7.18-7.22 (m, 2H), 7.26-7.38 (m, 5H). 4,4,4-trifluoro-N-methoxy-N-methyl-butyramide: 1 H-NMR (400 MHz, CDCl 3) d 2.41-2.53 (m, 2H), 2.70 (br t, J = 7, 2H), 3.20 (s, 3H), 3.71 (s, 3H). The 4,4,4-trifluoro-N-methoxy-N-methyl-butyramide was obtained from the reaction of 4,4,4-trifluorobutyric acid and N-methyl-N-methoxy-amine.HCl in the presence of N -hydroxybenzotriazole, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide.HCl and N-methylmorpholine in dichloromethane.

Intermediary II-5 Intermediary IL-5 Intermediate 11-5 (3,3-dimethyl-1-phenyl-hexan-2-one) was prepared analogously to intermediate 11-1 from 2,2-methoxy-methyl-amide dimethyl pentanoic acid and benzylmagnesium chloride (20 weight percent solution in THF) at 0 ° C in tetrahydrofuran, as an oil; 1 H-NMR (400 MHz, CDCl 3) d 0.89 (t, J = 7, 3H), 1.14-1.23 (m, 8H), 1.53-1.60 (m, 2H), 3.76 (s, 2H), 7.15- 7.33 (m, 5H). 2,2-dimethylpentanoic acid methoxy-methyl-amide: 1 H-NMR (400 MHz, CDCl 3) d 0.90 (t, J = 7, 3H), 1.20-1.29 (m, 8H), 1.55-1.60 (m, 2H), 3.17 (s, 3H), 3.67 (s, 3H). The 2,2-dimethylpentanoic acid methoxy-methyl-amide was obtained from the reaction of 2,2-dimethylpentanoic acid and N-methyl-N-methoxy-amine.HCl in the presence of N-hydroxybenzotriazole, 1- (3 -dimethylaminopropyl) -3-ethylcarbodiimide.HCl and N-methylmorpholine in dichloromethane.

Intermediary II-6 or Intermediary IL-6 Intermediate II-6 (3,3-dimethyl-1-phenyl-pentan-2-one) was prepared analogously to intermediate 11-1 from 2,2, N-trimethyl-N-methoxy-butyramide and chloride of benzylmagnesium (20 weight percent solution in THF) at 0 ° C in tetrahydrofuran, as an oil; 1 H-NMR (400 MHz, CDCl 3) d 0.81 (t, J = 7, 3H), 1.15 (s, 6H), 1.64 (q, J = 7.5, 2H), 3.76 (s, 2H), 7.15-7.33 (m, 5H). 2,2, N-trimethyl-N-methoxy-butyramide: 1 H-NMR (400 MHz, CDCl 3) d 0.85 (t, J = 7, 3 H), 1.21 (s, 6 H), 1.61-1.69 (m, 2H), 3.18 (s, 3H), 3.67 (s, 3H). The 2,2, N-trimethyl-N-methoxy-butyramide was obtained from the reaction of 2,2-dimethylbutyric acid and N-methyl-N-methoxy-amine.HCl in the presence of N-hydroxybenzotriazole, 1- ( 3-dimethylaminopropyl) -3-ethylcarbodiimide.HCl and N-methylmorpholine in dichloromethane.

Intermediary 11-7 Intermediary IL-7 Intermediate II-7 (3,3-dimethyl-5,5,5-trifluoro-1-phenyl-pentan-2-one) was prepared analogously to intermediate 11-1 from 4,4,4 -trifluoro-2,2, N-trimethyl-N-methoxy-butyramide and benzylmagnesium chloride (20 weight percent solution in THF) at 0 ° C in tetrahydrofuran, as an oil; H-NMR (400 MHz, CDCl 3) d 1.34 (s, 6H), 2.47 (d, J ~ 12, 1 H), 2.52 (d, J-12, 1 H), 3.84 (s, 2H), 7.15 ( br d, J ~ 8, 2H), 7.23-7.36 (m, 3H). 4,4,4-trifluoro-2,2, N-trimethyl-N-methoxy-butyramide: 1 H-NMR (400 MHz, CDCl 3) d 1.35 (s, 6H), 2.55 (d, J ~ 12, 1 H) , 2.60 (d, J ~ 12, 1 H), 3.19 (s, 3H), 3J0 (s, 3H). 4,4) 4-trifluoro-2,2, N-trimethyl-N-methoxy-butyramide was obtained from the reaction of 4,4,4-trifluoro-2,2-dimethylbutyric acid and N-methyl-N -methoxy-amine.HCl in the presence of N-hydroxybenzotriazole, 1- (3-dimethylaminopropyl) -3-ethylcarbodumide.HCl and N-methylmorpholine in dichloromethane.

Intermediary II-8 Intermediary IL-8 3-Fluorobenzyl bromide (25 g, 0.132 mol) in 3-fluorobenzyl magnesium bromide in anhydrous diethyl ether (85 ml) was converted using magnesium (3.17 g) in the presence of catalytic amounts of iodine and 1,2-dibromoethane. The 3-fluorobenzyl magnesium bromide formed in situ was reacted with pentanenitrile (11 ml) in toluene (100 ml) at 110 ° C for 2 hours. After hydrolysis of the mixture formed with concentrated hydrochloric acid (12 N) at 80 ° C for 4 hours and subsequent extraction with toluene, 1- (3-fluorophenyl) -hexan-2-one was obtained in a yield of 86% as a oil. 1 H-NMR (400 MHz, CDCl 3) d 0.87 (t, J = 7, 3H), 1.22-1.33 (m, 2H), 1.50-1.59 (m, 2H), 2.46 (t, J = 7, 2H) , 3.68 (s, 2H), 6.90-7.00 (m, 3H), 7.26-7.32 (m, 2H).

Intermediary 11-9 Intermediary IL-9 2-Fluorobenzyl bromide was converted into 2-fluorobenzyl magnesium bromide in anhydrous diethyl ether using magnesium in the presence of catalytic amounts of iodine and 1,2-dibromoethane analogously to the procedure described for the synthesis of Intermediate II-8. The 2-fluorobenzyl magnesium bromide formed in situ was reacted with pentanenitrile in toluene at 110 ° C for 2 hours. After hydrolysis of the mixture formed with concentrated hydrochloric acid (12 N) at 80 ° C for 20 hours, 1- (2-fluorophenyl) -hexan-2-one was obtained in a 70% yield as an oil. 1 H-NMR (400 MHz, CDCl 3) d 0.88 (t, J = 7, 3H), 1.24-1.35 (m, 2H), 1.53-1.62 (m, 2H), 2.48 (t, J = 7, 2H), 3.72 (br s, 2H), 6.98-7.28 (m, 4H).

Intermediary 11-10 Intermediary IL-10 To a magnetically stirred solution of N-methoxy-N-methyl-2- (pyridin-3-yl) acetamide (12 g, 67 mmol) at -15 ° C in tetrahydrofuran (THF) was slowly added n-chloride. butylmagnesium (2 M solution in THF, 75 ml, 150 mmol) and the resulting mixture was reacted for 1 hour at -15 ° C and successively stirred at room temperature overnight. The reaction mixture was poured in excess of aqueous NH CI and extracted twice with ethyl acetate. Concentration under vacuum, followed by chromatographic purification on Sepacore (ethyl acetate) afforded 1- (pyridin-3-yl) hexan-2-one (Intermediate 11-10) (5.95 grams, 50% yield) as an oil; 1 H-NMR ~ (400 ^ MHz, CDCl 6) d 0.89 (t, J = 7, 3H), 1.24-1.35 (m, 2H), 1.52-1.62 (m, 2H), 2.50 (t, J = 7, 2H ), 3.70 (s, 2H), 7.25-7.29 (m, 1 H), 7.52-7.57 (m, 1 H), 8.45 (br d, J = 2, 1 H), 8.52 (dd, J ~ 6 y 2, 1 H).

Intermediary 111-1 Intermediary 111-1 To a magnetically stirred solution of 1-phenylheptan-2-one (Intermediate 11-1) (11.6 grams, 61 mmol) in methanol (100 mL) were added piperidine (1 mL) and acetic acid (1 mL), followed by a formaldehyde solution (20 ml of a 35% solution in water, 226 mmol) and the resulting mixture was stirred at 55 ° C for 60 hours. The reaction mixture was cooled to room temperature, concentrated and taken in a mixture of MTBE and water. The organic layer was collected, dried over Na 2 SO, filtered and concentrated to give 2-phenyl-oct-1-en-3-one (Intermediate 111-1) (11.4 grams) as an oil. Intermediary 111-1: 1 H-NMR (400 MHz, CDCl 3) d 0.80 (t, J = 7, 3 H), 1.18-1.30 (m, 4 H), 1.54-1.63 (m, 2 H), 2.65 (t, J = 7, 2H), 5.80 (s, 1 H), 6.02 (s, 1H), 7.20-7.32 (m, 5H).

Intermediary III-2 Intermediary IM-2 ,5,5-Trifluoro-1-phenylpentan-2-one (Intermediate II-2) was reacted in methanol with piperidine and acetic acid, followed by a solution of formaldehyde (35% solution in water) and the resulting mixture was stirred at 55 ° C for 60 hours in a manner analogous to the procedure described for the synthesis of intermediate IM-1 to give 6,6,6-trifluoro-4-methoxymethyl-2-phenyl-hex-1-en-3-one ( intermediary III-2) with a yield of 16%. Chromatographic purification with Sepacore (petroleum ether / diethyl ether = 19/1 (v / v)) was used to purify intermediate III-2. 1 H-NMR (400 MHz, CDCl 3) d 2.28-2.42 (m, 1 H), 2.70-2.85 (m, 1 H), 3.29 (s, 3 H), 3.47-3.60 (m, 2 H), 3.68-3.76 (m , 1 H), 6.01 (s, 1 H), 6.13 (s, 1H), 7.28-7.40 (m, 5H).

Intermediary III-3 Intrusario III-3 Intermediate III-3 (2-phenyl-hept-1-en-3-one) was prepared analogously to intermediate 111-1, from 1-phenylhexan-2-one, piperidine, acetic acid and formaldehyde solution (35% solution in water) at 55 ° C for 60 hours. Intermediary III-3: 1 H-NMR (400 MHz, CDCl 3) d 0.91 (t, J = 7, 3H), 1.30-1.40 (m, 2H), 1.59-1.69 (m, 2H), 2.73 (t, J = 7, 2H), 5.87 (s, 1 H), 6.09 (s, 1 H), 7.28-7.40 (m, 5H).

Intermediary III-4 Intermediary III4 Intermediate III-4 (7,7,7-trifluoro-2-phenyl-hept-1-en-3-one) was prepared analogously to intermediate 111-1, from 6,6,6- trifluoro-1-phenylhexan-2-one, piperidine, acetic acid and formaldehyde solution (35% solution in water) at 55 ° C for 60 hours. Intermediary III-4: 1 H-NMR (400 MHz, CDCI3) d 1.89-1.98 (m, 2H), 2.09-2.22 (m, 2H), 2.84 (t, J = 7, 2H), 5.91 (s, 1 H), 6.13 (s, 1 H), 7.26-7.40 (m, 5H).

Intermediary Intermediary III-5 Intermediary III-5 (6,6,6-trifluoro-2-phenyl-hex-1-en-3-one) was prepared analogously to intermediate 111-1 with some modifications (temperature and amount of formaldehyde used), from 5,5,5-trifluoro-1-phenylpentan-2-one, piperidine, acetic acid and formaldehyde solution (1.1 molar equivalent of CH20, 35% solution in water) at 40 ° C for 40 hours with a yield of 57%. Purification was carried out by chromatographic purification with Sepacore (petroleum ether / diethyl ether = 39/1 (v / v)). Rf = 0.4 (petroleum ether / diethyl ether = 9/1 (v / v)). Intermediary III-5: 1 H-NMR (400 MHz, CDCI 3) d 2.43-2.56 (m, 2 H), 3.03 (t, J = 7, 2 H), 5.97 (s, 1 H), 6.19 (s, 1 H) , 7.26-7.40 (m, 5H).

Intermediary III-6 Intermediary IH-6 Intermediate 111-6 (4,4-dimethyl-2-phenyl-hept-1-en-3-one) was prepared analogously to intermediate 111-1, from 3,3-dimethyl- 1-Phenylhexan-2-one, piperidine, acetic acid and formaldehyde solution (35% solution in water) at 55 ° C for 60 hours. Intermediary III-6: 1 H-NMR (400 MHz, CDCI3) d 0.83 (t, J = 7, 3H), 1.02 (s, 6H), 1.10-1.19 (m, 2H), 1.40-1.50 (m, 2H ), 5.13 (s, 1 H), 5.45 (s, 1 H), 7.09-7.38 (m, 5H).

Intermediary III-7 Intermediary III-7 Intermediate III-7 (4,4-dimethyl-2-phenyl-hex-1-en-3-one) was prepared in a manner analogous to intermediate 111-1, from 3,3-dimethyl- 1-phenylpentan-2-one, piperidine, acetic acid and formaldehyde solution (35% solution in water) at 55 ° C for 60 hours. Intermediary III-7: 1 H-NMR (400 MHz, CDCI3) d 0.81 (t, J = 7, 3H), 1.09 (s, 6H), 1.59 (q, J = 7, 2H), 5.20 (s, 1 H), 5.52 (s, 1 H), 7.29-7.37 (m, 5H).

Intermediary 11 l-S Intermediary III-8 Intermediate 111-8 (4,4-dimethyl-6,6,6-trifluoro-2-phenyl-hex-1-en-3-one) was prepared analogously to intermediate 111-1, a Starting from 3,3-dimethyl-5,5,5-trifluoro-1-phenylpentan-2-one, piperidine, acetic acid and formaldehyde solution (35% solution in water) at 55 ° C for 60 hours. Intermediary III-8: 1 H-NMR (400 MHz, CDCl 3) d 1.22 (s, 6H), 2.49 (d, J ~ 12, 1 H), 2.56 (d, J ~ 12, 1 H), 5.29 (s, 1 H), 5.57 (s, 1 H), 7.29-7.39 (m, 5H).

Intermediary III-9 Intermediary III-9 Intermediary III-9 (2- (3-fluorophenyl) -hept-1-en-3-one) was prepared in a manner analogous to intermediate 111-1, from 1- (3-fluorophenyl) - hexan-2-one, piperidine, acetic acid and formaldehyde solution (35% solution in water) at 55 ° C for 60 hours. Intermediary III-9: 1 H-NMR (400 MHz, CDCl 3) d 0.93 (t, J = 7, 3 H), 1.30-1.41 (m, 2 H), 1.60-1.69 (m, 2 H), 2 J 5 (t, J = 7, 2H), 5.93 (s, 1 H), 6.15 (s, 1 H), 7.00-7.09 (m, 3H) 7.28-7.35 (m, 1 H).

Intermediary 111-10 Intermediary 111-10 The intermediate 111-10 (2- (2-fluorophenyl) -hept-1-en-3-one) was prepared in a manner analogous to intermediate 111-1, from 1- (2-fluorophenyl) - hexan-2-one, piperidine, acetic acid and formaldehyde solution (35% solution in water) at 55 ° C for 60 hours. Intermediary 111-10: 1 H-NMR (400 MHz, CDCl 3) d 0.91 (t, J = 7, 3 H), 1.30-1.40 (m, 2 H), 1.59-1.69 (m, 2 H), 2.70 (t, J = 7, 2H), 5.88 (s, 1 H), 6.26 (s, 1 H), 6.98-7.37 (m, 4H).

Intermediary 111-11 Intermediate 111-11 To a magnetically stirred ice-cooled solution of 1- (pyridin-3-yl) hexan-2-one (6 g, 34 mmol) and N, N, N ', N'-tetramethyldiaminemethane (7) ml, 51 mmol) at 0 ° C was slowly added acetic anhydride (AC2O) (4.8 ml, 51 mmol). The resulting mixture was reacted for 30 minutes at 45 ° C and successively cooled to room temperature. The reaction mixture was poured into excess ice and brine was added. Extraction with ethyl acetate (2x) and dichloromethane followed by drying (Na2SO4) of the combined organic layers, filtration and concentration under vacuum afforded the crude product. Subsequent chromatographic purification with Sepacore (ethyl acetate) afforded 2- (pyridin-3-yl) hept-1-en-3-one (Intermediate 111-11) (3.86 grams, 60% yield); 1 H-NMR (400 MHz, CDCl 6) d 0.93 (t, J = 7, 3H), 1.32-1.43 (m, 2H), 1.62-1.71 (m, 2H), 2.81 (t, J = 7, 2H), 6.06 (s, 1 H), 6.28 (s, 1 H), 7.25-7.31 (m, 1 H), 7.63-7.68 (m, 1 H), 8.53-8.58 (m, 2H).

Intermediary 111-12 Intermediary 111-12 The intermediate 111-12 (2- (4-chlorophenyl) -hept-1-en-3-one) was prepared in analogous manner to intermediate 111-1, from 1- (4-chlorophenyl) -hexan-2- Ona, piperidine, acetic acid and formaldehyde solution (35% solution in water) at 55 ° C for 60 hours. Intermediary 111-12: 1 H-NMR (400 MHz, CDCl 3) d 0.92 (t, J = 7, 3H), 1.30-1.41 (m, 2H), 1.59-1.68 (m, 2H), 2J4 (t, J = 7, 2H), 5.92 (s, 1 H), 6.13 (s, 1 H), 7.24 (br d, J = 8, 2H), 7.32 (br d, J = 8, 2H).

Intermediary 111-13 Intermediary 111-13 The intermediate 111-13 (2- (thien-3-yl) -hept-1-en-3-one) was prepared analogously to intermediate 111-1, from 1- (thien-3-l) hexan-2-one, piperidine, acetic acid and formaldehyde solution (35% solution in water) at 55 ° C for 60 hours. Intermediary 111-13: 1 H-NMR (400 MHz, CDCl 3) d 0.93 (t, J = 7, 3H), 1.31-1.42 (m, 2H), 1.61-1.69 (m, 2H), 2.77 (t, J ~ 8, 2H), 6.03 (s, 1 H), 6.04 (s, 1 H), 7.18 (dd, J = 6 and 2, 1 H), 7.28 (dd, J ~ 6 and 3, 1 H), 7.51 -7.53 (m, 1 H).

Intermediary IV-2 Intermediary IV-2 Intermediary IV-2 (3- (n-butyl) -4- (3-fluorophenyl-4,5-dihydropyrazole) was prepared analogously to 3- (n-pentyl) -4-phenyl-4,5-dihydropyrazole (Intermediate IV-1, see preparation of compound 1), from 2- (3-fluorophenyl) -hept-1-en-3-one and hydrazine hydrate Some characteristic NMR signals of the pyrazoline ring proton: (400 MHz, CDCl 3) d 3.37 (t, J ~ 10, 1 H, H 5), 3.81 (t, J ~ 10, 1 H, H 5), 3.99 (t, J ~ 9, 1 H, H 4).

Intermediary IV-3 Intermediary IV-3 The intermediate IV-3 (3- (n-butyl) -4- (2-fluorophenyl-4,5-dihydropyrazole) was prepared analogously to 3- (n-pentyl) -4-phenyl-4 , 5-dihydropyrazole (Intermediate IV-1), from 2- (2-fluorophenyl) -hept-1-en-3-one and hydrazine hydrate Some characteristic NMR signals of the pyrazoline ring proton: (400 MHz, CDCl3) d 3.37 (t, J ~ 9, 1 H, H5), 3J8 (t, J ~ 10, 1 H, H5), 4.35 (t, J ~ 10, 1 H, H4).

Intermediary VII-1 ° ^. * C * N r Intermediary VII-1 A solution of (endo-1 R, 2S, 4R) -1, 7,7-trimethylbicyclo [2.2.1] was slowly added to a magnetically stirred diphosgene solution (4.26 ml, 0.0353 mol) in dichloromethane (90 ml). ] hept-2-ylamine (CAS 32511-34-5) and N, N-dimethylaniline (15.2 ml, 0.12 mole)) in dichloromethane (90 ml) at 0 ° C. The resulting mixture was allowed to reach room temperature and stirred for 30 minutes. The mixture was concentrated and the residue was taken up in dichloromethane, washed (3x with 1 N HCl and 1x with brine), dried (MgSO), filtered and concentrated under vacuum to give endo-2-isocyanate - [(1R, 2S, 4R) -1,7,7-trimethylbicyclo [2.2.1] heptane (10.43 g, yield 97%, H-NMR (400 MHz, CDCl 3) d 0.85 (s, 3H), 0.86 (s, 3H), 0.89 ( s, 3H), 1.11 (dd, J = 13.2 and 4.2, 1 H), 1.21-1.28 (m, 1 H), 1.30-1.38 (m, 1 H), 1.67 (t, J = 4, 1 H), 1.71-1.83 (m, 2H), 2.26-2.34 (m, 1 H), 3.75 (ddd, J = 10.5, 4.1 and 2.3, 1 H) Optical rotation ([a] D) = + 40.2 ( c = 1.07, dichloromethane).

Intermediary VII-2 C, lfl Intermediary VII-2 3-Isocyanate - [(1R, 2R, 3R, 5S) -2,7J-trimethylbicyclo [3.1.1] heptane (intermediate VII-2) was prepared from the reaction of (-) - 3-amino- [ (1 R, 2R, 3R, 5S) -2J, 7-trimethylbicyclo [3.1.1] heptane (CAS 69460-11-3) and triphosgene in the presence of DIPEA in dichloromethane at 0 ° C. 1 H-NMR (400 MHz, CDCl 3) d 0.95 (s, 3 H), 1.00 (d, J = 9, 1 H), 1.13 (d, J = 7, 3 H), 1.23 (s, 3 H), 1.80- 1.90 (m, 2H), 1.93-2.00 (m, 1 H), 2.04-2.13 (m, 1 H), 2.38-2.44 (m, 1 H), 2.49-2.58 (m, 1 H), 3.80-3.88 (m, 1 H).

Intermediary VII-3 Intermediary VI I -3 Intermediary VII-3 was prepared from diphosgene, cumylamine and N, N-dimethylaniline in dichloromethane analogously to the procedure described for intermediate VII-1. 1 H-NMR (400 MHz, CDCl 3) d 1.71 (s, 6H), 7.22-7.29 (m, 1 H), 7.32-7.38 (m, 2H), 7.42-7.46 (m, 2H).

Intermediary VII-4 VIM broker Intermediate VII-4 was prepared from diphosgene, 1- (4-fluorophenyl) -1- (methyl) ethylamine and N.N-dimethylaniline in dichloromethane analogously to the procedure described for intermediate VII-1. 1 H-NMR (400 MHz, CDCl 3) d 1.70 (s, 6H), 6.99-7.05 (m, 2H), 7.37-7.43 (m, 2H). 3- (n-Butyl) -4- (2-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1-carbonyl chloride Intermediate VIII-1 To a magnetically stirred solution of 3- (n-butyl) -4- (2-fluorophenyl) -4,5-dihydro- (1 H) -pyrazole (Intermediate (IV-3) crude (2.0 grams, 8.93 mmol maximum) in dichloromethane (25 ml) were added successively DIPEA (1.50 g, 2.0 ml, 11.61 mmol) and triphosgene (0.79 g), 2.68 mmoles, dissolved in 10 ml of dichloromethane) at 0 ° C and the resulting solution was allowed to reach room temperature and subsequently reacted at room temperature for 1 hour. Chromatographic purification on a column (eluent: dichloromethane) afforded 3- (n-butyl) -4- (2-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1-carbonyl chloride (Intermediate VIII- 1) pure (1.26 g, yield -50%). 1 H-NMR (400 MHz, CDCl 3) d 0.86 (t, J = 7, 3 H), 1.22-1.36 (m, 2 H), 1.42-1.60 (m, 2 H), 2.08-2.18 (m, 1 H), 2.27 -2.40 (m, 1 H), 3.96 (dd, J = 12 and 7, 1 H), 4.34 (t, J = 12, 1 H), 4.54-4.64 (m, 1 H), 7.08-7.22 (m , 3H), 7.30-7.38 (m, 1 H). 3- (n-Pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-carbonyl chloride Intermediary VIII-2 To a magnetically stirred solution of 3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazole (116 ml of a 0.25 M solution in dichloromethane) was added DIPEA (116 ml of a solution 0.30 M in dichloromethane) and triphosgene (0.3 equivalent moles as a solution in dichloromethane) at 0 ° C and the resulting solution was allowed to reach room temperature and subsequently reacted at room temperature for 1 hour to provide a stock solution of 3- (n-pentyl) chloride Crude -4-phenyl-4,5-dihydro- (1H) -pyrazol-1-carbonyl (Intermediate VIII-2). This stock solution was used in reactions in parallel with various amines, to prepare compounds 103-123.

EXAMPLE 4 Synthesis of Specific Compounds Compound 1 Nr (1 R.2S.5R) -rel-6,6-dimethylbicyclo [3.1.1lheptan-2-methyn-3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -p Razol-1 -carboxamide Part A: To a magnetically stirred solution of 2-phenyl-oct-1-en-3-one (Intermediate 111-1) (5 grams, 24.7 mmol) in ethanol (30 ml) was added hydrazine hydrate (2.46 ml, 50.7 mmoles) and the resulting solution was heated at reflux temperature for 4 hours. The resulting solution was allowed to reach room temperature, concentrated and taken in a mixture of MTBE and water. The organic layer was collected, dried over Na 2 SO) filtered and concentrated to give crude 3- (n-pentyl) -4-phenyl-4,5-dihydropyrazole (Intermediate IV-1) (4.8 grams) as an impure oil which was used immediately in the subsequent stage. (Intermediary IV-1) some NMR signals characteristic of protons of the pyrazoline ring: (400 MHz, CDCI3) d 3.36 (t, J ~ 10, 1 H), 3.81 (t, J - 10, 1 H), 4.00 (t , J ~ 10, 1 H).

Part B: To a magnetically stirred solution of (-) - cis-mertanilamine (2.4 ml, 14.2 mmol) (CAS 38235-68-6)) in dichloromethane (40 ml) was added triethylamine (2 ml, 14.2 mmol). The resulting solution was slowly added to a solution of triphosgene (1.4 grams, 4.7 mmol) in dichloromethane (60 ml) and the resulting mixture was stirred at room temperature for 16 hours. The mixture was then poured into water and extracted with dichloromethane, dried over Na 2 SO 4, filtered and concentrated to give cis-myrtanyl isocyanate (2.12 grams) as an oil.

Part C: 3- (n-pentyl) -4-phenyl-4,5-dihydropyrazole (2.2 grams, . 3 mmoles) in benzene (25 ml) and treated with cis-myrtanyl isocyanate (2.12 g, 11.8 mmol) and 5 drops of triethylamine and the resulting solution was stirred at room temperature for 16 hours. The solution was concentrated, followed by purification by flash chromatography (heptane / ethyl acetate = 6: 1 (v / v)) to give N - [(1 R, 2S, 5R) -rel-6,6-dimethylbicyclo [3.1 .1] heptan-2-methyl] -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide] as an oil. 1 H-NMR (400 MHz, CDCl 3) d 0.85-0.95 (m, 4H), 1.06 (s, 3H), 1.19-1.31 (m, 7H), 1.38-1.60 (m, 3H), 1.82-2.41 (m , 9H), 3.22-3.40 (m, 2H), 3.83-3.90 (m, 1 H), 4.12 (dd, J = 12 and 7, 1 H), 4.18-4.26 (m, 1 H), 5.92-5.96 (m, 1 H), 7.15 (br d, J ~ 8, 2H), 7.25-7.37 (m, 3H). LC / MS (Method A). Retention time: 7.07 minutes: Molecular mass found (API-ES, positive sweep) = 396.

Analogously compounds 2-84 were prepared: Compound 2 N- (1-adamantyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-carboxamide LC / MS (Method A). Retention time: 8.04 minutes: Molecular mass found (API-ES, positive sweep) = 394. Rf (dichloromethane / methanol = 99/1 (v / v)) = 0.3.

Compound 3 Isomer-exo N- (Exo-bicycloi2.2.1lhept-2-yl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide LC / MS ( Method A). Retention time: 9.26 minutes: Molecular mass found (API-ES, positive sweep) = 354. Rf (dichloromethane / methanol = 99/1 (v / v)) = 0.2.

Compound 4 N-Phenyl-3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide LC / MS (Method A). Retention time: 4.35 minutes: Molecular mass found (API-ES, positive sweep) = 336. Rf (dichloromethane / methanol) = 99/1 (v / v)) = 0.4.

Compound 5 Nr (1 R, 2S.5R) -rel-6,6-dimethylbicyclof3.1.11heptan-2-metin-3- (benzyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide ( from the isocyanate derived from (-) - cis-myrtanylamine (CAS 38235-68-6)) LC / MS (Method A). Retention time: 4.96 minutes: Molecular mass found (API-ES, positive sweep) = 416. Rf (dichloromethane / methanol = 99/1 (v / v)) = 0.25.

Compound 6 N- (1-adamantyl) -3- (benzyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide 1 H-NMR (400 MHz, CDCl 3) d 1.65-1.75 (m, 6H), 2.06-2.13 (m, 9H), 3.20 (d, J ~ 14, 1 H), 3.65 (d, J ~ 14, 1 H), 3.84 (dd, J ~ 11 and 6.1 H), 3.95- 4.00 (m, 1 H), 4.14 (t, J ~ 11, 1 H), 5.85 (br s, 1 H), 7.05-7.11 (m, 4H), 7.22-7.36 (m, 6H). LC / MS (Method A). Retention time: 5.34 minutes: Molecular mass found (API-ES, positive sweep) = 414. Melting point: 61 ° C Compound 7 Nr (1 R, 2S, 5R) -rel-6,6-dimethylbichlorochloro.1.1 heptan-2-methyl-3- (n-butyl) -4-phenyl-4,5-dihydro- (1 H) - pyrazole-1-carboxamide (from the isocyanate derived from (-) - cis-myrtanylamine (CAS 38235-68-6)) LC / MS (Method B). Retention time: 5.03 minutes: Molecular mass found (API-ES, positive sweep) = 382. Rf (dichloromethane / methanol = 99/1 (v / v)) = 0.2. 1 H-NMR (400 MHz, CDCl 3) d 0.80-0.90 (m, 3H), 0.92 (d, J ~ 10, 1 H), 1.06 (s, 3 H), 1.21 (s, 3 H), 1.22-1.60 (m , 5H), 1.82-2.41 (m, 8H), 3.23-3.40 (m, 2H), 3.87 (ddd, J ~ 11, 7 and 2, 1 H), 4.12 (br dd, J ~ 11 and 7, 1 H), 4.18-4.26 (m, 1 H), 5.95 (br t, J ~ 7, 1 H), 7.15 (br d, J ~ 8, 2 H), 7.25-7.37 (m, 3 H).

Compound 8 N-1 (1 R.2S.5R) -rel-6,6-dimethylbicyclof3.1.nheptan-2-methyl-3-r3- (1-piperidinyl) propyn-4-phenyl-4,5-dihydro- (1 H ) -pyrazol-1 -carboxamide (from the isocyanate derived from (-) - cis-myrtanylamine (CAS 38235-68-6)) 1 H-NMR (400 MHz, CDCl 3) d 0.92 (d, J = 10, 1 H ), 1.07 (s, 3H), 1.21 (s, 3H), 1.38-2.43 (m, 24H), 3.21-3.38 (m, 2H), 3.84-3.90 (m, 1H), 4.13 (dd, J = 11 and 6, 1 H), 4.19-4.26 (m, 1 H), 5.97 (br t, J - 7, 1 H), 7.15 (br d, J ~ 8, 2 H), 7.25-7.40 (m, 3 H) .

Compound 9 Nr (1 R.2S.5R) -rel-6.6-dimethylbicyclof3.1.1lheptan-2-methylene-3- (n-propyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol- 1 -carboxamide (from the isocyanate derived from (-) - cis-mrtlanamine (CAS 38235-68-6)) 1 H-NMR (400 MHz, CDCl 3) d 0.85-0.95 (m, 4H), 1.16 (s, 3H), 1. 21 (s, 3H), 1.41-1.61 (m, 2H), 1.83-2.17 (m, 8H), 2.25-2.41 (m, 2H), 3.22-3.39 (m, 2H), 3.83-3.90 (m, 1 H), 4.12 (dd, J = 12 and 7, 1 H), 4.18-4.26 (, 1 H), 5.93-5.99 (m, 1 H), 7.15 (br d, J ~ 8, 2H), 7.26- 7.36 (m, 3H).

N- (benzyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-carboxamide LC / MS (Method B). Retention time: 5J6 minutes: Molecular mass found (API-ES, positive sweep) = 350. Moving phase gradient: 0 - 5 minutes: Solution A / Solution B = 30/70 (v / v)). > 5 minutes: Solution B. Rf (dichloromethane / methanol = 99/1 (v / v)) = 0.2.

Compound 11 N- (1-adamantyl) methyl-3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide LC / MS (Method B). Retention time: 6.28 minutes: Molecular mass found (API-ES, positive sweep) = 408. Mobile phase gradient: 0 - 3 minutes: Solution A / Solution B = 20/80 (v / v)). > 3 minutes: Solution B. Rf (dichloromethane / methanol = 99/1 (v / v)) = 0.2.

Compound 12 N- (cyclohexylmethyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-carboxamide LC / MS (Method B). Retention time: 7.01 minutes: Molecular mass found (API-ES, positive scan) = 356. Mobile phase gradient: 0 - 5 minutes: Solution A / Solution B = 30/70 (v / v)). > 5 minutes: Solution B. Rf (dichloromethane / methanol = 99/1 (v / v)) = 0.2.

Compound 13 N-rendo- (1 R, 2S.4R) -1 J.7-trimethylbicyclo2.2.1lhept-2-n-3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol -1-carboxamide (from isocyanate (intermediate VII-1) derived from 1 R - (+) - bornilamin (CAS 32511-34-5)) 1 H-NMR (400 MHz, CDCl 3) d 0.80-0.94 (m, 10H), 0.97 (s, 3H), 1.20-1.69 (m, 10H), 1.74-1.83 (m, 1 H), 2.00-2.22 (m, 2H), 2.33-2.45 (m, 1 H), 3.83- 3.89 (m, 1 H), 4.09-4.27 (m, 3H), 6.02 (br d, J ~ 10, 1 H), 7.16 (br d, J ~ 8, 2H), 7.27-7.37 (m, 3H) . LC / MS (Method B). Retention time: 7.43 minutes: Molecular mass found (API-ES, positive sweep) = 396. Moving phase gradient: 0 - 3 minutes: Solution A / Solution B = 20/80 (v / v)). > 3 minutes: Solution B. Rf (dichloromethane / methanol = 99/1 (v / v)) = 0.3.

N-rendo- (1S) -1, 3,3-tr.methyl-2-chlorhe2.2.11hept-2-n-3- (n-pentin-4-phenyl-4,5-dihydro- ( 1 H) -pyrazol-1 -carboxamide (from the isocyanate derived from endo- (1S) -1, 3,3-trimethylbicyclo2.2.nheptan-2-amine (CAS 301822-76-4) LC / MS (Method B) Retention time: 5.83 minutes: Molecular mass found (API-ES, positive sweep) = 396. Moving phase gradient: 0-5 minutes: Solution A / Solution B = 15/85 (v / v)). > 5 minutes: Solution B. Rf (dichloromethane / methanol = 99/1 (v / v)) = 0.3.

Compound 15 Nf (1 R, 2S, 5R) -rel-6,6-dimethylbicyclof3.1.nheptan-2-metin-3- (n-propyl) -4- (2-pyridyl) -4.5-dihydro- (1 H) -pyrazol-1 -carboxamide (from the isocyanate derived from (-) - cis-myrtanylamine (CAS 38235-68-6)) H-NMR (400 MHz, CDCl 3) d 0.85-0.94 (m, 4H), 1.15 ( s, 3H), 1.20-2.40 (m, 18H), 3.20-3.39 (m, 2H), 3.99-4.07 (m, 1 H), 4.22-4.30 (m, 1 H), 4.37 (dd, J = 12 and 7, 1 H), 5.93-5.99 (m, 1 H), 7.14-7.23 (m, 2H), 7.65-7.71 (m, 1 H), 8.57-8.60 (m, 2H).

Compound 16 N- (1-phenyl-ethyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro-f 1 H) -pyrazol-1-carboxamide LC / MS (Method B). Retention time: 4.50 minutes: Molecular mass found (API-ES, positive sweep) = 364. Rf (dichloromethane / methanol = 99/1 (v / v)) = 0.25.

Compound 17 N- (2-adamantyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-carboxamide LC / MS (Method B). Retention time: 5.55 minutes: Molecular mass found (API-ES, positive sweep) = 394. Melting point: 71 ° C. Rf (dichloromethane / methanol = 99/1 (v / v)) = 0.2.

Compound 18 N- (1-naphthyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazole-1-carboxamide 1 H-NMR (400 MHz, CDCl 3) d 0.90 (t, J = 7, 3H), 1.25-1.37 (m, 4H), 1.55-1.65 (m, 2H), 2.12-2.32 (m, 2H), 4.02 (dd, J = 10 and 6, 1 H), 4.26 ( dd, J = 12 and 6, 1 H), 4.39 (t, J ~ 12, 1 H), 7.20-7.57 (m, 8H), 7.62 (d, J = 8, 1 H), 7.62 (d, J = 8, 1 H), 7.87 (d, J = 8, 1 H), 7.96 (d, J = 8, 1 H), 8.14 (d, J = 8, 1 H), 8.60 (br s, 1 H) ). Rf (dichloromethane / methanol = 99/1 (v / v)) = 0.3.

Compound 19 N- (1-methyl-1-pheny1-ethyl) -3- (n-pentii) -4-phenyl-4,5-dihydro- (1 H) -pyrazol- -carboxamide 1H-NMR (300 MHz, CDCI3) d 0.86 (t, J = 7, 3H), 1.20-1.60 (m, 6H), 1.75 (s, 3H), 1.78 (s, 3H), 2.00-2.20 (m, 2H), 3.79-3.85 ( m, 1 H), 4.05-4.22 (m, 2H), 6.37 (br s, 1 H), 7.13-7.37 (m, 8H), 7.46-7.51 (m, 2H). Rf (dichloromethane / methanol = 99/1 (v / v)) = 0.2.

Compound 20 N- (2,2-diphenylpropyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-carboxamide LC / MS (Method B). Retention time: 4.99 minutes: Molecular mass found (API-ES, positive sweep) = 454. Rf (dichloromethane / methanol = 99/1 (v / v)) = 0.3.

Compound 21 N - ((3-trifluoromethyl) benzyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyzole-1 -carboxamide LC / MS (Method B). Retention time: 4.43 minutes: Molecular mass found (API-ES, positive sweep) = 418.

Rf (dichloromethane / methanol = 99/1 (v / v)) = 0.2.

Compound 22 N- (2,2-d.methylpropyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -p-aceol-1-carboxamide LC / MS (Method B). Retention time: 4.36 minutes: Molecular mass found (API-ES, positive sweep) = 330. Rf (dichloromethane / methanol = 99/1 (v / v)) = 0.3.

Compound 23 N- (naphthalen-1-yl-methyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide LC / MS (Method B). Retention time: 6.41 minutes: Molecular mass found (API-ES, positive sweep) = 400. Rf (dichloromethane / methanol = 99/1 (v / v)) = 0.3.

Compound 24 N - [(3-dimethylamino) -2,2-d.methylpropyl-3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1- 1 H-NMR carboxamide (400 MHz, CDCl 3) d 0.80-0.90 (m, 3H), 0.96 (br s, 6H), 1.20-1.28 (m, 4H), 1.46-1.57 (m, 2H), 2.00-2.16 ( m, 2H), 2.24 (s, 2H), 2.32 (s, 6H), 3.15-3.27 (m, 2H), 3.87 (dd, J ~ 11 and 7, 1 H), 4.10 (dd, J ~ 11 and 7, 1H), 4.23 (br t, J ~ 11, 1 H), 7.14-7.18 (m, 2H), 7.26-7.38 (m, 4H).

Compound 25 N-rendo- (1R.2S.4R) -1, 7J-trimethylb-cyclor2.2.1lhept-2-ill-3- (n-butyl) -4-phenyl-4,5-dihydro- (1 H) - pyrazole-1-carboxamide (from the isocyanate derived from 1 R - (+) - bornylamine (CAS 32511-34-5)) 1 H-NMR (400 MHz, CDCl 3) d 0.80-0.94 (m, 10H), 0.97 ( s, 3H), 1.20-1.70 (m, 8H), 1.72-1.84 (m, 1 H), 2.01-2.10 (m, 1 H), 2.14-2.24 (m, 1 H), 2.34-2.44 (m, 1 H), 3.82-3.89 (m, 1 H), 4.09-4.27 (m, 3H), 6.01 (br d, J ~ 9, 1 H), 7.16 (br d, J ~ 8, 2H), 7.26- 7.37 (m, 3H).

Compound 26 N- (2- (4-fluorophenyl) -1,1-dimethyl-ethyl) -3- (n-butyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide 1H-NMR ( 400 MHz, CDCl 3) d 0.84 (t, J = 7, 3 H), 1.20-1.52 (m, 10 H), 1.97-2.17 (m, 2 H), 3.02 (d, J = 13, 1 H), 3.09 (d , J = 13, 1 H), 3.88 (dd, J = 10 and 6, 1 H), 4.08-4.15 (m, 1 H), 4.18-4.24 (m, 1 H), 5.76 (br s, 1 H ), 6.93-7.01 (m, 2H), 7.12-7.18 (m, 4H), 7.26-7.38 (m, 3H).

Compound 27 N-rendo- (1 R.2S.4R) -1.7J-trimethylbicyclo [2.2.11hept-2-n-3- (4,4,4-trifluoro-n-butyl) -4-phenyl-4,5 -dihydro- (1 H) -pyrazol-1 -carboxamide (from the isocyanate derived from 1 R - (+) - borni! amine (CAS 32511-34-5)) 1 H-NMR (400 MHz, CDCl 3) d 0.84 -0.94 (m, 7H), 0.97 (s, 3H), 1.20-1.29 (m, 1 H), 1.36-1.47 (m, 1 H), 1.53-1.63 (m, 1 H), 1.67 (br t, J ~ 4, 1 H), 171-1.89 (m, 3H), 2.00-2.23 (m, 4H), 2.35-2.51 (m, 1 H), 3.86-3.93 (m, 1 H), 4.08-4.30 ( m, 3H), 6.00 (br d, J ~ 9, 1 H), 7.15 (br d, J ~ 8, 2H), 7.26-7.39 (m, 3H).

Compound 28 N- (2- (4-fluorophenyl) -1,1-dimethyl-ethyl) -3- (4,4,4-trifluoro-n-butyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol -1-carboxamide 1 H-NMR (400 MHz, CDCl 3) d 1.38 (s, 3 H), 1.39 (s, 3 H), 1.67-1.84 (m, 2H), 1.92-2.16 (m, 4H), 3.02 (d, J = 13, 1 H), 3.08 (d, J = 13, 1 H), 3.91 (dd, J = 11 and 7, 1 H), 4.06-4.13 (m, 1 H), 4.24 (t, J = 11, 1 H), 5.72 (br s, 1 H), 6.94-7.00 (m, 2H), 7.12-7.18 (m, 4H ), 7.28-7.40 (m, 3H).

Compound 29 N- (2- (4-fluorophenyl) -1,1-dimethyl-etl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-carboxamide 1H-NMR ( 400 MHz, CDCI3) d 0.84 (t, J = 7, 3H), 1.14-1.30 (m, 4H), 1.32-1.54 (m, 8H), 1.96-2.14 (m, 2H), 3.03 (d, J = 13, 1H), 3.09 (d, J = 13, 1H), 3.88 (dd, J = 11 and 6, 1H), 4.08-4.14 (m, 1H), 4.21 (t, J = 11, 1H), 5.76 (br s, 1H), 6.93-7.00 (m, 2H), 7.13-7.18 (m, 4H), 7.28-7.38 (m, 3H).

Compound 30 N-rendo- (1R, 2S.4R) -1JJ-trimethylbicyclo [2.2.1lhept-2-n-3- (1,1-dimethyl-n-butyl) -4-phenyl-4,5-dihydro - (1 H) -pyrazol-1 -carboxamide (from the isocyanate derived from 1R - (+) - phenylamine (CAS 32511-34-5)) 1 H-NMR (400 MHz, CDCl 3) d 0.73-0.93 (m, 13H ), 0.97 (s, 3H), 1.05 (s, 3H), 1.10-1 JO (m, 8H), 1J3-1.85 (m, 1H), 2.36-2.45 (m, 1H), 3.88-3.95 (m, 1H), 4.02-4.21 (m, 3H), 6.12 (br d, J ~ 9, 1H), 7.13-7.19 (m, 2H), 7.21-7.32 (m, 3H).

Compound 31 N-fendo- R.2S.4R) -1.7.7-trimethylbicyclo2.2.nhept-2-in-3- (3.3.3-trifluoropropyl) -4-phenyl-4,5-dihydro- (1 H ) -p-acetyl-1-carboxamide (from the isocyanate derived from 1 R - (+) - pyrimidine (CAS 32511-34-5)) 1 H-NMR (400 MHz, CDCl 3) d 0.81-0.94 (m , 7H), 0.97 (s, 3H), 1. 21-1.30 (m, 1 H), 1.36-1.48 (m, 1 H), 1.52-1.70 (m, 2H), 1.74-1.85 (m, 1 H), 2.30-2.48 (m, 5H), 3.88- 3.95 (m, 1H), 4.10-4.33 (m, 3H), 5.96 (br d, J ~ 9, 1H), 7.17 (br d, J = 8, 2H), 7.28-7.40 (m, 3H).

Compound 32 N-rendo- (1 R.2S.4R) -1.7J-trimethyl-1,2-chloro-2,1-lhept-2-ill-3- (1,1-dimethylpropyl) -4-phenyl-4,5-dihydro- (1 H ) -pyrazol-1 -carboxamide (from the isocyanate derived from 1 R - (+) - pyrimamine (CAS 32511-34-5)) 1 H-NMR (400 MHz, CDCl 3) d 0.77 (t, J = 7 , 3H), 0.81-0.95 (m, 0H), 0.97 (s, 3H), 1.04 (s, 3H), 1.10-1 JO (m, 6H), 1.74-1.85 (m, 1 H), 2.34-. 46 (m, 1 H), 3.88-3.94 (m, 1 H), 4.02-4.20 (m, 3H), 6.13 (br d, J ~ 9, 1 H), 7.13-.18 (m, 2H), 7.21-7.33 (m, 3H).

Compound 33 N- (2- (4-fluorophenyl) -1,1-dimethyl-ethyl) -3- (1,1-dimethylpropyl) -4-phenyl-, 5-dihydro- (1 H) -pyrazol-1 -carboxamide 1H-NMR (400 MHz, CDCI3) d 0.72 (t, J = 7, 3H), 0.83 (s, 3H), .99 (s, 3H), 1.22-1.31 (m, 2H), 1.40 (s, 6H), 2.97 -3.09 (m, 2H), 3.88-3.94 (m, H), 4.01-4.14 (m, 2H), 5.84 (br s, 1 H), 6.93-7.01 (m, 2H), 7.11-7.19 (m, 4H), .22-7.33 (m, 3H).

Compound 34 N-rendo- (1 R.2S.4R) -1 JJ-trimethylbicyclo2.2.nhept-2-n-3- (1,1-dimethyl-3,3,3-trifluoropropyl) -4-ferrile 475-dihydro- (1 H) -pyrazol-1 -carboxamide (from isocyanate derived from 1 R - (+) - pyrimamine (CAS 32511-34-5)) 1 H-NMR (400 MHz, CDCl 3) d 0.81 -0.95 (m, 7H), 0.97 (s, 3H), 1. 09-1.60 (m, 9H, including 2 singlet of Me at 1.12 and 1.13 ppm), 1.66-1.71 (m, 1 H), 1.75-1.85 (m, 1 H), 2.24-2.47 (m, 3H), 3.91 -3.98 (m, 1 H), 4.08-4.24 (m, 3H), 6.01-6.08 (m, 1 H), 7.13-7.19 (m, 2H), 7.24-7.36 (m, 3H).

Compound 35 N-rendo- (1 R) -1, 3,3-trimethyl-phenylchloride.2.2.nhept-2-in-3- (n-butyl) -4-phenyl-4,5-dihydro- (1 H) - pyrazole-1-carboxamide (from the isocyanate derived from endo- (1 R) -1,3,3-trimethylbicyclo [2.2.nheptan-2-amino] 1 H-NMR (400 MHz, CDCl 3) d 0.78-0.89 (m, 6H), 1.05-1.78 (m, 17H), 2.01-2.22 (m, 2H), 3.56 (dd, J = 10 and 2, 1 H), 3.83-3.91 (m, 1 H), 4.09-4.27 (m , 2H), 6.07 (br d, J ~ 10, 1 H), 7.14-7.18 (m, 2H), 7.26-7.37 (m, 3H).

Compound 36 N- (1-methyl-1-phenyl-ethyl) -3- (n-butyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-carboxamide 1 H-NMR (400 MHz, CDCl 3) d 0.86 (t, J = 7, 3H), 1.21-1.33 (m, 2H), 1.38-1.54 (m, 2H), 1.75 (s, 3H), 1.77 (s, 3H), 2.04-2.22 (m, 2H) ), 3.82 (dd, J = 9.7 and 5.6, 1 H), 4.07-4.20 (m, 2H), 6.38 (br s, 1 H), 7.13-7.36 (m, 8H), 7.48 (br d J ~ 8 , 2H).

Compound 37 N- (2-adamantyl) -3- (n-butyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-carboxamide 1 H-NMR (400 MHz, CDCl 3) d 0.86 ( t, J = 7, 3H), 1.23-1.34 (m, 2H), 1.41-1.53 (m, 2H), 1.62-2.10 (m, 15H), 2.13-2.22 (m, 1H), 3.86 (dd, J = 10.5 and 6.5, 1H), 3.98-4.03 (m 1H), 4.13-4.26 (m, 2H), 6.38 (br d, J ~ 8, 1 H), 7.16 (br d, J ~ 8, 2H), 7.24-7.36 (m, 3H).

Compound 38 N -hexo- (1R, 2R, 4R) -1, 7J-trimethylb1ciclof2.2.nhept-2-ill-3- (n-butyl) -4-phenyl-4,5-dihydro- (1H) -pyrazol-1 -carboxamide (from isocyanate derived from exo-1R-bornylamine.) 1 H-NMR (400 MHz, CDCl 3) d 0.79-0.92 (m, 10H), 0.98 (s, 3H), 1.12-1.77 (m , 9H), 1.86-1.93 (m, 1H), 1.99-2.19 (m, 2H), 3.80-3.90 (m, 2H), 4.07-4.25 (m, 2H), 6.06 (br d, J ~ 9, 1 H), 7.15 (br d, J ~ 8, 2H), 7.26-7.37 (m, 3H).

Compound 39 N- (2-phenyl-1,1-dimethyl-etl) -3- (n-butyl) -4- (3-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide 1H- NMR (400 MHz, CDCl 3) d 0.85 (t, J = 7, 3H), 1.20-1.32 (m, 2H), 1.37-1.51 (m, 8H), 1.98-2.18 (m, 2H), 3.03 (d, J = 18, 1 H), 3.11 (d, J = 18, 1 H), 3.88 (dd, J = 11 and 7, 1 H), 4.07-4.24 (m, 2H), 5.82 (br s, 1 H ), 6.84-7.04 (m, 3H), 7.17-7.36 (m, 6H).

Compound 40 N- (2-phenyl-1,1-dimethyl-ethyl) -3- (n-butyl) -4- (2-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide 1H-NMR ( 400 MHz, CDCl 3) d 0.85 (t, J = 7, 3H), 1.20-1.32 (m, 2H), 1.34-1.53 (m, 8H), 2.00-2.19 (m, 2H), 3.03 (d, J = 18, 1 H), 3.11 (d, J = 18, 1H), 3.89 (dd, J = 11 and 7, 1 H), 4.20 (t, J = 11, 1 H), 4.47 (dd, J = 11 and 7, 1 H), 5.81 (br s, 1H), 7.05-7.31 (m, 9H).

N-Phenyl-3- (4-chlorobenzyl) -4- (4-chlorophenyl) -4,5-dihydro- (1H) -pyrazol-1 -carboxamide Melting point: 156 ° C.

Compound 42 N- (4-methoxyphenyl) -3- (4-chlorobenzyl) -4- (4-chlorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide Melting point: 116- 119 ° C.

Compound 43 N-fend- (1 R, 2S.4R) -1 J.7-trimethoxychloride.2.2lhept-2-n-3- (n-butyl) -4- (2-methoxyphenyl) -4.5- dihydro- (1 H) -pyrazol-1-carboxamide (from the isocyanate derived from 1 R - (+) - bornylamine (CAS 32511-34-5 ^)) 1 H-NMR (400 MHz, CDCl 3) d 0.84 -0.95 (m, 10H), 0.97 (s, 3H), 1.20-1.68 (m, 8H), 1.73-1.83 (m, 1 H), 2.01-2.11 (m, 1H), 2.16-2.26 (m, 1 H), 2.34-2.44 (m, 1 H), 3.78-3.85 (m, 4H), 4.08-4.23 (m, 2H), 4.50-4.58 (m, 1H), 5.98-6.03 (m, 1 H), 6.86-6.96 (m, 2H), 7.06 (dd, J = 8 and 2, 1 H), 7.22-7.28 (m, 1H).

Compound 44 N- (1-methy1-1-phenyl-ethyl) -3- (n-butyl) -4- (2-methoxyphenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide 1H-NMR (400 MHz, CDCl 3) d 0.85 (t, J = 7, 3H), 1.24-1.56 (m, 4H), 1.75 (s, 3H), 1.76 (s, 3H), 2.01-2.11 ( m, 1H), 2.16-2.25 (m, 1 H), 3.75-3.82 (m, 4H), 4.07 (t, J = 11, 1 H), 4.53 (dd, J = 11 and 7, 1 H), 6.36 (br s, 1 H), 6.87 (d, J = 8, 1H), 6.90-6.95 (m, 1 H), 7.06 (dd, J = 8 and 2, 1 H), 7.19-7.28 (m, 2H), 7.33 (t, J = 8, 2H), 7.48 (br d, J = 8, 2H).

Compound 45 N-fend- (1 R, 2S, 4R) -1 JJ-trimetibicyclo [2.2.1lhept-2-n-3- (n-butyl) -4- (2-fluorophenyl) -4,5-dihydro - (1 H) -pyrazol-1 -carboxamide (from the isocyanate derived from 1 R - (+) - phenylamine (CAS 32511-34-5)) 1 H-NMR (400 MHz, CDCl 3) d 0.85-0.95 (m , 10H), 0.97 (s, 3H), 1.21-1.83 (m, 9H), 2.05-2.14 (m, 1 H), 2.19-2.28 (m, 1 H), 2.35-2.45 (m, 1 H), 3.82-3.90 (m, 1 H), 4.13-4.24 (m, 2H), 4.49 (dd, J = 11 and 7, 1 H), 6.01 (br d, J ~ 9, 1 H), 7.03-7.18 ( m, 3H), 7.23-7.30 (m, 1 H).

Compound 46 N-rendo- (1 R.2S.4R) -1 JJ-trimethylbichlorchlor2.2.1lhept-2-in-3- (n-butyl) -4- (pyrid-3-yl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide (from isocyanate derived from 1 R - (+) - bornylamine (CAS 32511-34-5)) 1 H-NMR (400 MHz, CDCl 3) d 0.85-0.94 (m, 10H), 0.97 (s, 3H), 1.21-1.70 (m, 8H), 1.74-1.84 (m, 1H), 2.02-2.12 (m, 1 H), 2.16-2.27 (m, 1 H), 2.33- 2.46 (m, 1 H), 3.82-3.89 (m, 1H), 4.12-4.28 (m, 3H), 6.02 (br d, J ~ 9, 1H), 7.28-7.33 (m, 1 H), 7.47- 7.52 (m, 1 H), 8.47 (br d, J ~ 2, 1 H), 8.56 (dd, J = 5 and 2, 1 H).

Compound 47 Nr (1R, 2R, 3R, 5S) -2JJ-trimethylbicyclo3.1.1lhept-3-ill-3- (n-butyl) -4- (3-fluorophenyl) -4,5-dihydro- (1H ) -pyrazol-1 -carboxamide (from the isocyanate derived from (1 R.2R.3R, 5S) - (-) - isopinocampheyl-amine (CAS 69460-11-3)) 1 H-NMR (400 MHz, CDCl 3) d 0.87 (t, J = 7, 3H), 0.96 (d, J = 9, 1 H), 1.02-2.00 (m, 14H), 2.02-2.10 (m, 1 H), 2.13-2.23 (m, 1 H) , 2.36-2.46 (m, 2H), 2.58-2.70 (m, 2H), 3.83-3.90 (m, 1 H), 3.98-4.27 (m, 4H), 5.82 (br d, J ~ 9, 1 H) , 6.85-6.90 (m, 1 H), 6.94-7.01 (m, 2H), 7.27-7.34 (m, 1 H).

Compound 48 N-Fendo- (1 R) -1.3.3-trimethylbicycloi2.2.1lhept-2-ill-3- (n-butyl) -4- (2-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol -1-carboxamide (from the isocyanate derivative of endo- (1 R) -1, 3,3-trimeti! Bicic! Or2.2.pheptan-2-amine 1 H-NMR (400 MHz, CDCl 3) d 0.75-0.83 (m , 6H), 1.02, 1.03, 1.04, 1.05 (4 x singlet of diastereomeric CH3 groups, 6H), 1.08-1 JO (m, 11 H), 1. 95-2.18 (m, 2H), 3.48 (br d, J-10, 1 H), 3.76-3.84 (m, 1 H), 4.08-4.17 (m, 1 H), 4. 37-4.47 (m, 1 H), 5.99 (br d, J ~ 10, 1 H), 6.95-7.09 (m, 3H), 7.15-7.22 (m, 1 HOUR).

Compound 49 N- [2- (trifluoromethyl) benzin-3- (n-butyl) -4- (3-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide 1 H-NMR (400 MHz, CDCl 3 ) d 0.85 (t, J = 7, 3H), 1.21 -1.32 (m, 2H), 1.39-1.53 (m, 2H), 2.01-2.20 (m, 2H), 3.89 (dd, J = 11 and 6.4, 1 H), 4.09-4.15 (m, 1 H), 4.23 (t, J = 11, 1 H), 4.70 (d, J = 7, 2H), 6.36 (br t, J = 7, 1 H), 6.84- 6.89 (m, 1 H), 6.92-7.02 (m, 2H), 7.28-7.40 (m, 2H), 7.52-7.57 (m, 1 H), 7.63-7.70 (m, 2H).

Compound 50 N -hexo- (1 R.2R.4R) -1 JJ-tr'met¡lb¡c¡chlor2.2.nhept-2-il1-3- (n-butyl) -4- (2-fluorophenyl) - 4,5-dihydro- (1 H) -pyrazol-1 -carboxamide (from isocyanate derived from exo-1 R-born!! Amin 1 H-NMR (400 MHz, CDCl 3) d 0.81-0.92 (m, 10H), 0.97 (s, 3H), 1.11-1.77 (m, 9H), 1.89 (dd, J = 13 and 9, 1 H), 2.03-2.22 (m, 2H), 3.80-3.90 (m, 2H) , 4.13-4.23 (m, 1 H), 4.43-4.51 (m, 1 H), 6.06 (br d, J ~ 9, 1 H), 7.03-7.15 (m, 3H), 7.22-7.30 (m, 1 H).

Compound 51 N- (1-methyl-1-phenyl-ethyl) -3- (n-butyl) -4- (3-fluorophenyl) -4,5-dihydro- (1 H) -pyzole-1 -carboxamide 1H-NMR ( 400 MHz, CDCl 3) d 0.87 (t, J = 7, 3 H), 1.24-1.56 (m, 4 H), 1.75 (s, 3 H), 1.77 (s, 3 H), 2.02-2.11 (m, 1 H), 2.15-2.24 (m, 1 H), 3.81 (dd, j = 9.3 and 4.8 Hz, 1 H), 4.07-4.19 (m, 2H), 6.36 (br s, 1 H), 6.86-6.90 (m, 1 H), 6.93-7.01 (m, 2H), 7.20-7.37 (m, 4H), 7.45-7.50 (m, 2H).

N- (1-methyl-1-phenyl-ethyl) -3- (n-butyl) -4- (4-chlorophenyl) -4,5-dihydro- (1 H) -pyzole-1 -carboxamide 1H-NMR ( 400 MHz, CDCI3) d 0.87 (t, J = 7, 3H), 1.23-1.55 (m, 4H), 1.74 (s, 3H), 1.78 (s, 3H), 1.99-2.09 (m, 1 H), 2.12-2.22 (m, 1 H), 3.78 (dd, J = 10 and 5.5 Hz, 1 H ), 4.05-4.19 (m, 2H), 6.36 (br s, 1 H), 7.10 (br d, J = 8, 2H), 7.20-7.37 (m, 5H), 7.48 (br d, J = 8, 2H).

Compound 53 N-f2- (trifluoromethyl) benzyl-3- (n-butyl) -4- (4-chlorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide 1H-NMR (400 MHz, CDCl 3) d 0.85 (t, J = 7, 3H), 1.20-1.53 (m, 4H), 1.98-2.18 (m, 2H), 3.86 (dd, J = 11 and 6.5, 1 H), 4.08- 4.15 (m, 1 H), 4.23 (t, J = 11, 1H), 4.69 (brd, J = 6.3, 2H), 6.36 (brt, J = 6.3, 1H), 7.09 (brd, J = 8, 2H ), 7.31 (br d, J = 8, 2H), 7.35-7.41 (m, 1H), 7.51-7.58 (m, 1H), 7.63-7.70 (m, 2H).

Compound 54 N- [endo- (1R.2S.4R) -1JJ-tr'metlbicyclo2.2.1lhept-2-yl-3- (cyclopropylmethyl) -4-phenyl-4,5-dihydro- (1H) -pyrazole -1-carboxamide (from isocyanate derived from 1 R - (+) - bornylamine (CAS 32511-34-5)) 1 H-NMR (400 MHz, CDCl 3) d -0.04-0.08 (m, 2H), 0.39- 0.53 (m, 2H), 0.75-0.94 (m, 8H), 0.97 (s, 3H), 1.21-1.29 (m, 1H), 1.35-1.46 (m, 1H), 1.57-1.69 (m, 2H), 1.74-1.84 (m, 1H), 1.90-1.98 (m, 1H), 2.15-2.24 (m, 1H), 2.33-2.44 (m, 1H), 3.83-3.89 (m, 1H), 4.12-4.33 (m , 3H), 6.02-6.09 (m, 1H), 7.16 (br d, J = 8, 2H), 7.25-7.37 (m, 3H).

Compound 55 N-rendo- (1 R.2S.4R) -1 JJ-trimethylbichlocl2.2.1lhept-2-ill-3- (n-butyl) -4- (4-fluorophenyl) -4,5-dihydro - (1 H) -pyrazol-1 -carboxamide (from isocyanate derived from 1 R - (+) - bornylamine (CAS 32511-34-5)) 1 H-NMR (400 MHz, CDCl 3) d 0.85-0.95 (m , 10H), 0.97 (s, 3H), 1.20-1.69 (m, 9H), 1.73-1.85 (m, 1 H), 2.01-2.10 (m, 1 H), 2.14-2.24 (m, 1 H), 2.34-2.45 (m, 1 H), 3.79-3.86 (m, 1 H), 4.08-4.25 (m, 2H), 6.01 (br d, J ~ 9, 1 H), 7.00-7.06 (m, 2H) , 7.11-7.16 (m, 2H).

Compound 56 N- (1-methyl-1-phenyl-ethyl) -3- (n-butyl) -4- (4-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide 1H-NMR ( 400 MHz, CDCl 3) d 0.85 (t, J = 7, 3H), 1.22-1.54 (m, 4H), 1.75 (s, 3H), 1.77 (s, 3H), 2.00-2.09 (m, 1H), 2.13 -2.22 (m, 1 H), 3.78 (dd, J = 9 and 5.5, 1 H), 4.07-4.18 (m, 2H), 6.36 (br s, 1 H), 7.00-7.06 (m, 2H), 7.10-7.16 (m, 2H), 7.20-7.25 (m, 1 H), 7.32-7.37 (m, 2H), 7.46-7.50 (m, 2H).

Compound 57 N- (adamant-2-yl) -3- (n-butyl) -4- (4-fluorophenyl) -4,5-dihydro- (1 H) -pyzole-1 -carboxamide 1 H-NMR (400 MHz, CDCl 3) d 0.85 (t, J = 7, 3H), 1.22-1.54 (m, 4H), 1.62-2.09 (m, 15H), 2.13-2.22 (m, 1 H), 3.82 (dd, J = 10 and 6, 1 H), 3.97-4.03 (m, 1 H), 4.08-4.23 (m, 2H), 6.37 (br d, J = 9, 1 H), 7.00-7.06 (m, 2H), 7.10-7.16 (m, 2H).

Compound 58 N- (1-methyl-1- (4-fluorophenyl) -ethyl) -3- (n-butyl) -4- (4-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide 1H- NMR (400 MHz, CDCl 3) d 0.87 (t, J = 7, 3H), 1.21-1.56 (m, 4H), 1 J2 (s, 3H), 1.75 (s, 3H), 2.00-2.22 (m, 2H), 3.74-3J8 (m, 1 H), 4.07-4.17 (m, 2H), 6.34 (br s , 1 H), 6.98-7.06 (m, 4H), 7.09-7.15 (m, 2H), 7.40-7.46 (m, 2H). LC / MS (Method D). Retention time: 2.09 min; Molecular mass found = 400.

Compound 59 N- (1-methyl-1 - (4-fluorophenyl) -ethyl) -3- (n-butyl) -4-phenyl-4,5-dihydro- (1 H) -pyzole-1 -carboxamide 1H- NMR (400 MHz, CDCl 3) d 0.87 (t, J = 7, 3H), 1.22-1.35 (m, 2H), 1.38-1.57 (m, 2H), 1.72 (s, 3H), 1.75 (s, 3H) , 2.01-2.22 (m, 2H), 3.78-3.82 (m, 1 H), 4.09-4.19 (m, 2H), 6.35 (br s, 1 H), 6.98-7.04 (m, 2H), 7.13-7.17 (m, 2H), 7.25-7.37 (m, 3H), 7.41-7.47 (m, 2H). LC / MS (Method D). Retention time: 2.05 min; Molecular mass found = 382.

Compound 60 N- (1-methyl-1-phenyl-ethyl) -3- (n-pentyl) -4- (2-fluorophenyl) -4,5-dithyro- (1 H) -pyrazol-1 -carboxamide LC / MS (Method D). Retention time: 2.13 min; Molecular mass found = 396.

Compound 61 N-rendo- (1 R.2S.4R) -1 JJ-trimethylbicycloclof2.2.nhept-2-ill-3- (n-pentyl) -4- (2-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1-carboxamide (from the isocyanate derived from 1 R - (+) - bornylamine (CAS 32511-34-5)) LC / MS (Method D). Retention time: 2.33 min; Molecular mass found = 414.

Compound 62 N- (1-methyl-1- (4-fluorophenyl) -ethyl) -3- (n-pentyl) -4- (2-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide LC / MS (Method D). Retention time: 2.12 min; Molecular mass found = 414.

Compound 63 N- (1-methyl-1- (4-fluorophenyl) -ethyl) -3- (n-pentyl) -4- (3-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide LC / MS (Method D). Retention time: 2.12 min; Molecular mass found = 414 Compound 64 N- (adamant-2-yl) -3- (n-pentyl) -4- (2-fluorophenyl) -4,5-dihydro- (1 H) -pyzole-1 -carboxamide LC / MS (Method D) ). Retention time: 2.36 min; Molecular mass found = 412.

Compound 65 N- (adamant-2-yl) -3- (n-pentyl) -4- (3-fluorophenyl) -4,5-dihydro- (1 H) -pyzole-1 -carboxamide LC / MS (Method D). Retention time: 2.36 min; Molecular mass found = 412.

Compound 66 N- (1-methyl-1-phenyl-ethyl) -3- (n-butyl) -4- (benzorbltiophen-3-yl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide LC / MS (Method D). Retention time: min; Molecular mass found = 419.

Compound 67 N-fendo- (1 R, 2S, 4R) -1 JJ-trimethylbichlichlor.2.2.1lhept-2-yl-3- (n-butyl) -4- (benzo [b1thiophen-3-yl) -4.5- dihydro- (1 H) -pyrazol-1 -carboxamide (from the isocyanate derived from 1 R - (+) - pyrilamine (CAS 32511-34-5)) LC / MS (Method D). Retention time: 2.34 min; Molecular mass found = 438.

Compound 68 N- (1-methyl-1-phenyl-ethyl) -3- (n-butyl) -4- (thiophen-3-in-4,5-dihydro- (1 H) -pyzole-1 -carboxamide 1H-NMR (400 MHz, CDCl 3) d 0.85 (t, J = 7, 3H), 1.21-1.57 (m, 4H), 1.74 (s, 3H), 1.77 (s, 3H), 2.05-2.25 (m, 2H), 3J9 ( dd, J ~ 11 and 7, 1 H), 4. 08-4.13 (m, 1 H), 4.28 (dd, J ~ 11 and 7, 1 H) 6.36 (br s, 1 H), 6.91 (dd, J = 6 and 2, 1 H), 7.06-7.08 (m, 1 H), 7.19-7.24 (m, 1 H), 7.30-7.37 (m, 3H), 7.45-7.49 (m, 2H). LC / MS (Method D). Retention time: 2.00 min; Molecular mass found = 370.

Compound 69 N- (1-methyl-1-phenyl-ethyl) -3- (but-3-ynyl) -4- (2-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide LC / MS (Method D). Retention time: 1.80 min; Molecular mass found = 378.

Compound 70 N-fendo- (1 R.2S.4R) -1 JJ-trimethylbicyclo [2.2.nhept-2-ill-3- (but-3-ynyl) -4- (2-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1-carboxamide (from the isocyanate derived from 1 R - (+) - bornylamine (CAS 32511-34-5)) LC / MS (Method D). Retention time: 1.99 min; Molecular mass found = 396.

Compound 71 N-rendo- (1 R.2S, 4R) -1 JJ-trimeticlbof2.2.1lhept-2-n-3- (1-phenylcyclopropyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide (from isocyanate derived from 1 R - (+) - bornylamine (CAS 32511-34-5)) LC / MS (Method D). Retention time: 2.27 min; Molecular mass found = 442.

Compound 72 N- (1-methyl-1-phenyl-ethyl) -3- (1-phenylcyclopropyl) -4-phenyl-4,5-dihydro- (1H) -pyrazol-1 -carboxamide LC / MS (Method D) . Retention time: 2.10 min; Molecular mass found = 424.

Compound 73 N-fendo-d R.2S.4RV1 J J-trimethylbichlichlor.2.2.1lhept-2-yl-3- (2,2,3,3-tetramethylcyclopropyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide (from the isocyanate derived from 1 R - (+) - pyrimamine (CAS 32511-34-5)) LC / MS (Method D). Retention time: 2.46 min; Molecular mass found = 422.

Compound 74 N- (1-methyl-1-phenyl-ethyl) -3- (2,2,3,3-tetramethylcyclopropyl) -4-phenyl-4,5-dihydro- (1H) -pyrazol-1 -carboxamide LC / MS (Method D) . Retention time: 2.21 min; Molecular mass found = 404.

Compound 75 Nr (1 R, 2R, 3R, 5S) -2JJ-trimethylbicyclo [3.1.1lhept-3-in-3- (n-butl) -4- (4-chlorophenyl) -4.5- dihydro- (H) -pyrazol-1 -carboxamide (from the isocyanate derived from (1R, 2R, 3R, 5S) - (-) - isopinocampheylamine (CAS 69460-11-3)) LC / MS (Method D) . Retention time: 2.37 min; Molecular mass found = 416.

Compound 76 N- (1-Methyl-1-phenyl-ethyl) -3- (n-pentyl) -4- (3-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide LC / MS (Method D). Retention time: 2.15 min; Molecular mass found = 396.

Compound 77 N-fendo- (1 R.2S.4R) -1 JJ-trimethyl-1,2-chloro.2.1-hept-2-yl-3- (n-pentyl) -4- (3-fluorophenyl) -4,5-dihydro - (1 H) -pyrazol-1 -carboxamide (from isocyanate derived from 1 R - (+) - bornylamine (CAS 32511-34-5)) LC / MS (Method D). Retention time: 2.32 min; Molecular mass found = 414.

Compound 78 N- (1-methyl-1-phenyl-ethyl) -3- (n-pentyl) -4- (4-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide LC / MS ( Method D). Retention time: 2.07 min; Molecular mass found = 396.

Compound 79 N-rendo- (1 R.2S.4R) -1 JJ-trimethobicichlor.2.2.1lhept-2-ill-3- (n-pentyl) -4- (4-fluorophenyl) -4,5-dihydro- ( 1 H) -prazole-1-carboxamide (from the isocyanate derived from 1 R - (+) - bornylamine (CAS 32511-34-5)) LC / MS (Method D). Retention time: 2.31 min; Molecular mass found = 414.

Compound 80 Nr (1S.2S, 3S.5R) -2JJ-trimethylbicyclof3.1.nhept-3-in-3- (n-butyl) -4- (3-fluorophenyl) -4,5-dihydro- (1 H) - pyrazole-1-carboxamide (from the isocyanate derived from (1S, 2S, 3S, 5R) - (+) - isopinocampheylamine LC / MS (Method D) Retention time: 2.23 min; Molar mass found = 400.

Compound 81 N- (1-methyl-1- (4-fluorophenyl) -ethyl) -3- (n-butyl) -4- (3-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide LC / MS (Method D). Retention time: 2.08 min; Molecular mass found = 400.

Compound 82 N- (1-methyl-1- (4-fluorophenyl) -ethyl) -3- (n-butyl) -4- (2-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide LC / MS (Method D). Retention time: 2.05 min; Molecular mass found = 400.

Compound 83 Nr (1S.2S, 3S, 5R) -2JJ-trimethylbicyclof3.1.11hept-3-ill-3- (n-butyl) -4- (2-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol -1-carboxamide (from isocyanate derived from (1S, 2S, 3S, 5R) - (+) - isopynecampheylamine LC / MS (Method D) Retention time: 2.23 min; Molar mass found = 400.

Compound 84 N-rendo- (1 R.2S.4R) -1.7.7-trimethylbicyclo2.2.1lhept-2-n-3- (n-butyl) -4- (thien-3-yl) -4,5-dih Dro- (1 H) -pyrazol-1 -carboxamide (from the isocyanate derived from 1 R - (+) - pyrimidine (CAS 32511-34-5)) LC / MS (Method D). Retention time: 2.21 min; Molecular mass found = 387.

Compound 85 N- [endo- (1 R.2S.4R) -1 JJ-trimethylbicyclof2.2.nhept-2-ill-3- (3,3,3-trifluoro-1-methoxymethyl-propyl) -4-phenyl-4 , 5-dihydro- (1 H) -pyrazol-1 -carboxamide, mixture of diastereomer A and diastereomer B Part A It was converted to 6,6,6-trifluoro-4-methoxymethyl-2-phenyl-hex-1-en-3 -one (Intermediary III-2) with hydrazine hydrate in 3- (3,3,3-trifluoro-1-methoxymethyl-propyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazole (Intermediate IV -2) analogously to the procedure described for the synthesis of intermediate IV-1.

Part B 3- (3,3,3-Trifluoro-1-methoxymethyl-propyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazole was converted to N - [(1 R, 2S, 5R) -rel-6,6-dimethylbicyclo [3.1.1] heptan-2-methyl] -3- (3,3,3-trifluoro-1-methoxymethyl-propyl) -4-phenyl-4,5-dihydro- (1 H) -p.sup.-1-carboxamide analogously to the procedure described for the synthesis of compound 13 (by reaction with the isocyanate derived from 1 R - (+) - pyrilamine (CAS 32511-34-5)). This reaction afforded a mixture of diastereoisomers. A mixture containing diastereomer A and diastereomer B was obtained by chromatographic purification with Sepacore (petroleum ether / diethyl ether = 1/1 (v / v)). Rf (diastereomer A) = 0.15, Rf (diastereomer B) = 0.20. 1 H NMR (400 MHz, CDCl 3); Mixture containing diastereomer A and diastereomer B: d 0.82-0.94 (m, 7H), 0.97 (s, 3H), 1.08-1.61 (m, 3H), 1.68 (br t, J = 4.5, 1 H), 1.74 -1.84 (m, 1 H), 2.23-2.49 (m, 3H), 2.78-2.85 (m, 1 H), 3.13 and 3.15 (2xs, (OCH3 signals, 3H), 3.17-3.35 (m, 2H), 3.93-3.98 (m, 1 H), 4.13-4.28 (m, 3H), 5.93 (br d, J ~ 9, 1 H), 7.19 (br d, J ~ 8, 2H), 7.28-7.38 (m, 3H).

Compound 86 N-fendo- (1 R.2S.4R) -1 JJ-trimethylbicyclof2.2.1lhept-2-yl-3- (n-butyl) -4-hydroxy-4-phenyl-4,5-dihydro- (1 H) -prazole-1-carboxamide Part A 1-Phenylhexan-2-one was reacted in methanol with piperidine and acetic acid, followed by a solution of formaldehyde (35% solution in water) and the resulting mixture was stirred at 55 ° C for 60 hours in a manner analogous to described procedure for the synthesis of intermediate 111-1 to provide 2-phenyl-hept-1-en-3-one (intermediate III-3) in 70% yield. 1 H-NMR (400 MHz, CDCl 3) d 0.91 (t, J = 7, 3 H), 1.29-1.40 (m, 2 H), 1.59-1.69 (m, 2 H), 2 J 2 (t, J = 7, 2 H), 5.87 (s, 1 H), 6.09 (s, 1 H), 7.28-7.40 (m, 5H).

Part BA a mixture of 2-phenyl-hept-1-en-3-one (3J6 g, 0.02 mole), 12 ml of H202 (37% aqueous solution) in 20 ml of methanol was slowly added a mixture of 2 ml of water and 1 ml of concentrated aqueous NaOH (Cf.

EP0114487). The resulting mixture is cooled to room temperature and stirred for 16 hours. The mixture is poured into water and extracted twice with diethyl ether. The diethyl ether layers were combined and filtered on Hyflo and successively washed with water, aqueous acetic acid solution and brine. The resulting solution is dried over Na2SO4, filtered and concentrated to give 2J9 grams of impure product. Flash chromatography (petroleum ether / ethyl ether = 49/1 (v / v) of the crude product afforded 1.31 g of 1- (2-phenyloxyranyl) -pentan-1-one (Intermediate V-1) as an oil in yield 32% .1H-NMR (400 MHz, CDCl3) d 0.88 (t, J = 7, 3H), 1.23-1.35 (m, 2H), 1.47-1.63 (m, 2H), 2.40-2.61 (m, 2H) ), 3.02 (d, J = 6, 1 H), 3.24 (d, j = 6, 1 H), 7.32-7.40 (m, 3H), 7.45-7.50 (M, 2H).

Part C 1- (2-phenyloxyranyl) -pentan-1-one was converted with hydrazine hydrate to 3- (n-butyl) -4-hydroxy-4-phenyl-4,5-dihydro- (1 H) -pyrazole (Intermediary IV-3) in a manner analogous to the procedure described for the synthesis of intermediate IV-1.

Part E 3- (n-Butyl) -4-hydroxy-4-phenyl-4,5-dihydro- (1 H) -pyrazole was converted into N - [(1 R, 2S, 5R) -rel-6,6-dimethylbicyclo [3.1.1] heptan-2-methyl] -3- (n-butyl) -4-hydroxy-4-phenyl-4, 5-dihydro- (1 H) -pyrazol-1 -carboxamide analogously to the process for the synthesis of compound 13 (by reaction with the isocyanate derived from 1 R - (+) - pyrilamine (CAS 32511-34-5)) . 1 H-NMR (400 MHz, CDCl 3) d 0.81-0.94 (m, 10H), 0.96 (s, 3H), 1.21-1.32 (m, 3H), 1.35-1.70 (m, 5H), 1.74-1.86 (m, 1H), 2.01-2.11 (m, 1 H), 2.15-2.28 (m, 1 H), 2.32-2.45 (m, 1 H), 3.10 and 3.65 (2x br s, OH, 1 H), 4.01-4.20 (m, 3H), 6.06-6.14 (m, 1 H), 7.27-7.43 (m, 5H).

Compound 87 1- (1-naphthoyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol 3- (n-pentyl) -4-phenyl-4,5-dihydropyrazole (0J5 grams) , 3.47 mmoles) was dissolved in toluene (10 ml) and treated with 1-naphthoyl chloride (0.522 ml, 3.47 mmoles) and the resulting solution was stirred at room temperature for 16 hours. The solution was concentrated, followed by purification by flash chromatography (heptane / ethyl acetate = 6: 1 (v / v)) to give 1- (1-naphthoyl) -3- (n-pentyl) -4-phenyl-4 , 5-dihydro- (1 H) -pyrazol (690 mg) as an oil.

LC / MS (Method B). Retention time: 5.87 minutes: Molecular mass found (API-ES, positive sweep) = 371. Moving phase gradient: 0 - 5 minutes: Solution A Solution B = 30/70 (v / v)). > 5 minutes: Solution B. Rf (dichloromethane / methanol = 99/1 (v / v)) = 0.35. 1 H-NMR (400 MHz, CDCl 3) d 0.80-0.90 (m, 3H), 1.02-1.40 (m, 6H), 1.92-2.11 (m, 2H), 4.21-4.30 (m, 2H), 4.57-4.65 (m, 1 H), 7.20 (d, J = 8, 2H), 7.29-7.55 (m, 6H) , 7.66 (d, J = 8, 1 H), 7.84-7.94 (m, 2H), 8.03 (br d, J = 8, 1 H).

Analogously compounds 88-94 were prepared: Compound 88 f3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-ill- [1- (4-chlorophenyl) cyclopentylmethanone LC / MS (Method C). Retention time: 4.05 min; Molecular mass found = 423.

Compound 89 [3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-ylHnaft-2-D-methanone LC / MS (Method C). Retention time: 3.52 min; Molecular mass found = 371.

Compound 90 r 3 - (n-pentyl) -4-phenyl-4,5-dihydro- (1H) -pyrazol-1-yl- (diphenylmethyl) methanone LC / MS (Method C). Retention time: 3.81 min; Molecular mass found = 411.

Compound 91 r3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-yn- (3-c! orobenzothien-2-i! 1 methanone LC / MS (Method C). of retention: 3.77 min; Molecular mass found = 411.

Compound 92 r3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-yl- (benzofuran-2-yl methanone LC / MS (Method C) Retention time: 3.48 min Molecular mass found = 361.

Compound 93 r3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-ill-r2.4.4- (trimethyl) pentill methanone LC / MS (Method C). Retention time: 3.98 min; Molecular mass found = 357.

Compound 94 r3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -p -razol-1-ill-r3- (trifluoromethyl) feniri methanone 1H-NMR (400 MHz, CDCl3) d 0.85 ( t, J = 7, 3H), 1.19-1.30 (m, 4H), 1.44-1.60 (m, 2H), 2.05-2.23 (m, 2H), 4.10-4.25 (m, 2H), 4.51 (t, J = 11, 1 H), 7.15-7.20 (m, 2H), 7.29-7.41 (m, 3H), 7.54-7.59 (m, 1 H), 7J3 (d, J = 8, 1 H), 8.18 (d) , J = 8, 1 H), 8.33 (br s, 1 H).

Compound 95 (cis-3A5-Trimethylpiperazin-1-yl) [3- (n-pentyl) -4-phenyl-4,5-dihydro- (1H) -pyrazol-1-yl-1-methanone Part AA a magnetically stirred solution of N- (tert-butoxycarbonyl) -cis-3,5-dylmethylpiperazine (19 J grams, 90 mmol) in 1,4-dioxane (400 ml) was added successively a mixture of NaOH (230 ml of a 2N solution, 460 mmol) and phosphorous acid (230 ml of a solution 2 in 230 ml water, 460 mmol) followed by formaldehyde (110 ml, 37% solution in water, 1.46 moles) and the resulting mixture was Reacted for 3.5 hours at 63 ° C. The reaction mixture was allowed to reach room temperature and extracted twice with dichloromethane. The organic layers were harvested and washed with water and brine respectively and subsequently dried over Na 2 SO 4, filtered and concentrated to give crude N-tert-butoxycarbonyl-cis-3,4,5-trimethylpiperazine (12 grams).

Part BA a magnetically stirred solution of crude N-tert-butoxycarbonyl-cis-3,4,5-trimethylpiperazine (12 grams, ~ 53 mmol) in dichloromethane (180 ml) was added excess trifluoroacetic acid (40 ml) and the mixture The resulting mixture was stirred at room temperature overnight. Aqueous NaOH was added and the reaction mixture was extracted twice with dichloromethane (2 x 100 ml). The organic layers were collected, dried over Na 2 SO 4, filtered and concentrated to give cis-3,4,5-trimethylpiperazine (3.44 grams, yield ~ 30%). 1 H-NMR (400 MHz, CDCl 3) d 1.05 (d, J = 6, 6H), 1.65 (br s, 1 H), 2.03-2.13 (m, 2H), 2.27 (s, 3H), 2.53 (d , J ~ 10, 1 H), 2.57 (d, J ~ 10, 1 H), 2.82-2.88 (m, 2H).

Part CA a magnetically stirred solution of cis-3,4,5-trimethylpiperazine (1.5 grams, 12J mmoles) in toluene (25 ml) was added phosgene (8 ml of a 20% solution in toluene, 15 mmole) and triethylamine ( 1.7 ml) and a catalytic amount of dimethylaminopyridine (DMAP). The resulting solution was stirred for 10 minutes at room temperature and 3- (n-pentyl) -4-phenyl-4,5-dihydropyrazole (2.5 grams, 12 mmol) was added and the resulting mixture was stirred at room temperature for 16 hours . The mixture was then concentrated under vacuum, followed by purification by flash chromatography (dichloromethane / 7M NH3 in methanol = 97.5 / 2.5 (v / v)) to yield (cis-3,4,5-trimethylpiperazin-1-yl) [3 - (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-yl] methanone (compound 26) (1.9 grams) as an oil. 1 H-NMR (300 MHz, CDCl 3) d 0.81-0.87 (m, 3H), 1.11 (d, J = 6, 6H), 1.21-1.26 (m, 4H), 1.44-1.50 (m, 2H), 2.00- 2.30 (m, 7H), 2.71-2.82 (m, 2H), 3.82 (dd, J ~ 11 and 7, 1 H), 3.97 (dd, J ~ 11 and 7, 1 H), 4.13-4.23 (m, 3H), 7.14-7.18 (m, 2H), 7.25-7.36 (m, 3H).

Compounds 96 and 97 1: relative configuration 1 2: relative configuration 2 Diastereomer A Diastereomer B N-endo-r (1 R.2S, 4R) -1 JJ-trimethylbichlichlor.2.2.1lhept-2-in-3- (n-pentyl) -4-phenyl-4,5-dihydro- (1H) -pyrazol- 1 -carboxamide (compound 27, diastereomer A) and N-endo-r (1R, 2S, 4R) -1 JJ-trimethylbicyclor2.2.1lhept-2-n-3- (n-pentyl) -4-phenyl- 4,5-dihydro- (1H) -pyrazol-1-carboxamide (compound 28, diastereomer B) Separation by preparative HPLC of compound 13 gave compounds 96 and 97 respectively. Separation procedure by preparative HPLC: a prepHPLC LC80 column was packed (internal diameter: 8 cm) with 800 grams of Chiralpak AD, 20 μ. Acetone / methanol (95/5 (v / v)) was used as the mobile phase. UV detection 220 nm.

Flow rate: 2 ml / minute. Compound 96: Optical rotation ([a] D) = +124 (c = 1.3, MeOH). 1 H-NMR (400 MHz, CDCl 3) d 0.80-0.92 (m, 10H), 0.97 (s, 3H), 1.20-1.69 (m, 10H), 1.74-1.83 (m, 1 H), 2.00-2.22 (m , 2H), 2.33-2.45 (m, 1 H), 3.83-3.89 (m, 1 H), 4.09-4.27 (m, 3H), 6.02 (br d, J ~ 10, 1 H), 7.16 (br d , J ~ 8, 2H), 7.27-7.37 (m, 3H). 13 C-NMR (100 MHz, CDCl 3) d 13.74, 13.93, 18.74, 20.00, 22.32, 25.76, 28.05, 28.27, 28.45, 31.35, 38.20, 44.97, 47.99, 49.29, 53.30, 53.58, 54.42, 127.54, 127.64, 129.05, 139.67, 155.87, 158.88. Compound 97: Optical rotation ([a] D) = - 85 (c = 1.55, MeOH). 1 H-NMR (400 MHz, CDCl 3) d 0.80-0.94 (m, 10H), 0.97 (s, 3H), 1.20-1.69 (m, 10H), 1.74-1.83 (m, 1 H), 2.00-2.22 (m , 2H), 2.33-2.45 (m, 1 H), 3.83-3.89 (m, 1 H), 4.09-4.27 (m, 3H), 6.02 (br d, J ~ 10, 1 H), 7.16 (br d , J ~ 8, 2H), 7.27-7.37 (m, 3H). 13 C-NMR (100 MHz, CDCl 3) d 13.73, 13.93, 18.73, 20.00, 22.31, 25.75, 28.03, 28.26, 28.46, 31.36, 38.12, 44.99, 48.00, 49.37, 53.34, 53.62, 54.41, 127.56, 127.68, 129.06, 139.71, 155.78, 158.83.

Compounds 98 and 99 Diastereomer A Diastereomer B N-endo-f (1 R.2S.4R) -1 JJ-trimethoxychloride.2.2lhept-2-ill-3- (n-butyl) -4- (3-fluorophenyl) - 4,5-dihydro- (1 H) -pyrazol-1 -carboxamide (compound 98, diastereomer A) and N-endo - [(1 R, 2S, 4R) -1 JJ-trimethylbicyclor2.2.1lhept-2-n -3- (n-butyl) -4- (3-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide (compound 99, diastereomer B) Column chromatographic separation (gradient: petroleum ether to petroleum ether / ethyl acetate = 4/1 (v / v)) of N-endo - [(1 R, 2S, 4R) -1 , 7,7-trimethylbicyclo [2.2.1] hept-2-yl] -3- (n-butyl) -4- (3-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide provided compounds 98 and 99, respectively.

Compound 98: Optical rotation ([] D) = -116 (c = 1.16, MeOH). 1 H-NMR (400 MHz, CDCI3) d 0.84-0.95 (m, 10H), 0.97 (s, 3H), 1.21-1.69 (m, 8H), 1.73-1.84 (m, 1H), 2.02-2.11 (m, 1 H), 2.16 -2.26 (m, 1 H), 2.35-2.45 (m, 1 H), 3.86 (dd, J = 11 and 7, 1 H), 4.09-4.23 (m, 3H), 6.01 (br d, J ~ 9, 1 H), 6.88 (br d, J ~ 8, 1 H), 6. 94-7.02 (m, 2H), 7.27-7.34 (m, 1 H). Compound 99: Optical rotation ([a] D) = + 127 (c = 1.0, MeOH). 1 H-NMR (400 MHz, CDCl 3) d 0.84-0.95 (m, 10H), 0.97 (s, 3H), 1.21-1.69 (m, 8H), 1 J3-1.84 (m, 1 H), 2.02-2.11 ( m, 1 H), 2.16-2.26 (m, 1 H), 2.35-2.45 (m, 1H), 3.86 (dd, J = 11 and 7, 1 H), 4.09-4.23 (m, 3H), 6.01 (br d, J ~ 9, 1 H), 6.88 (br d, J ~ 8, 1 H), 6.94-7.02 (m, 2H), 7.27-7.34 (m, 1 H).

Compounds 100 and 101 1: relative configuration 1 and 2: relative configuration 2 Diastereomer A Diastereomer B N-endo-f (1 R.2S.4R) -1 JJ-trimethylbicyclof2.2.1lhept-2-ill-3- (n-butyl) -4- (4-chlorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide (compound 100, diastereomer A) and N-endo - [(1 R, 2S, 4R) -1 JJ-trimethylbicyclo [2.2.11hept-2-ill-3- (n-butyl) -4- (4-chlorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide (compound 101, diastereomer B) The column chromatographic separation (gradient: petroleum ether to petroleum ether / ethyl acetate) ethyl = 4/1 (v / v)) of N-endo - [(1 R, 2S, 4R) -1 J, 7-trimethylbicyclo [2.2.1] hept-2-yl] -3- (n-butyl) ) -4- (4-chlorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide gave compounds 100 and 101, respectively. Compound 100: Optical rotation ([a] D) = -120 (c = 1.0, MeOH). 1 H-NMR (400 MHz, CDCl 3) d 0.82-0.94 (m, 10H), 0.97 (s, 3H), 1.20-1.69 (m, 8H), 1.73-1.84 (m, 1 H), 2.00-2.09 (m , 1 H), 2.13-2.23 (m, 1 H), 2.34-2.44 (m, 1 H), 3.83 (dd, J = 107 and 6.3, 1 H), 4.07-4.23 (m, 3H), 6.01 ( br d, J ~ 9, 1 H), 7.11 (br d, J = 8.4, 2H), 7.32 (br d, J = 8.4, 2H). Compound 101: Optical rotation ([a] D) = + 169 (c = 1.1, MeOH). 1 H-NMR (400 MHz, CDCl 3) d 0.82-0.92 (m, 10H), 0.97 (s, 3H), 1.20-1.69 (m, 8H), 1.73-1.84 (m, 1 H), 2.00-2.09 (m , 1 H), 2.13-2.23 (m, 1 H), 2.34-2.44 (m, 1 H), 3.83 (dd, J = 10.7 and 6.3, 1 H), 4.07-4.23 (m, 3H), 6.01 ( br d, J ~ 9, 1 H), 7.11 (br d, J = 8.4, 2H), 7.32 (br d, J = 8.4, 2H).

Compound 102 N- (1, 2,2,6,6-pentamethylpiperidin-4-yl) -3- (n-butyl) -4- (2-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide To a magnetically stirred solution of 3- (n-butyl) -4- (2-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carbonyl chloride (Intermediate VIII-1) (1.26 g, 4.5 mmol) in dichloromethane (25 ml) was slowly added 1, 2,2,6,6-pentamethylpiperidine (1.97 g, 11.6 mmol dissolved in 10 ml of dichloromethane) and the resulting mixture was stirred for 16 hours at room temperature. The mixture was poured into water. The organic layer was separated and collected, dried over Na 2 SO, filtered and concentrated under vacuum and subsequently purified by column chromatography (eluent: dichloromethane / methanol / aqueous ammonia 25% = 87.5 / 12 / 0.5 (v / v)) to give N - (1, 2,2,6,6-pentamethylpiperidin-4-yl) -3- (n-butyl) -4- (2-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 - pure carboxamide (1.35 g, 73% yield) LC / MS method C: Retention time: 1.27 minutes: Molar mass found = 417.

Compound 103 N- (4-methoxyphenyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1H) -pyrazol-1-carboxamide Compound 103 was prepared analogously to the procedure described for 34 U a Starting from 3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carbonyl chloride (Intermediate VIII-2) in dichloromethane in the presence of 1.2 molar equivalents of DIPEA and 1.0 molar equivalents of para-methoxyaniline. The mixture was reacted for 18 hours at 30 ° C to provide N- (4-methoxyphenyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide . LC / MS method C: Retention time: 3.28 minutes: Molecular mass found = 366.

Analogously compounds 104-123 were prepared: Compound 104 N- (4-methoxyphenyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-carboxamide LC / MS method C: Retention time: 3J4 min; Molecular mass found = 378.

Compound 105 N- (phenethyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1H) -pyrazol-1-carboxamide LC / MS method C: Retention time: 3.34 min; Molecular mass found = 364.

Compound 106 Trans-cyclopropyl configuration N- (2-phenyl-trans-cyclopropyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyzole-1 -carboxamide LC / MS method C: Retention time: 3.40 min; Molecular mass found = 376.

Compound 107 N- (1-naphthalen-1-yl-ethyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide LC / EM method C: Time of Retention: 3.61 min; Molecular mass found = 414.

Compound 108 N-r2- (Trifluoromethyl) pheny1) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyzole-1 -carboxamide LC / MS method C: Time of Retention: 3.81 min; Molecular mass found = 404.

Compound 109 N -cycloheptyl-3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-carboxamide LC / MS method C: Retention time: 3 J4 min; Molecular mass found = 356.

Compound 110 N-cyclooctyl-3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide LC / MS method C: Retention time: 3.81 min; Molecular mass found = 370.

Compound 111 N- (1, 2,3,4-tetrahydronaphthalen-1-yl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1H) -pyrazol-1 -carboxamide LC / EM method C : Retention time: 3.61 min; Molecular mass found = 390.

Compound 112 N-f2.2- (diphenyl) etyl-3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-carboxamide LC / MS method C: Retention time: 3.59 min; Molecular mass found = 440.

Compound 113 (3-pentyl-4-phenyl-4,5-d-hydropyrazol-1-yl) - [4- (2-pyrimidinyl) piperazin-1-ylmetanone LC / MS method C: Retention time: 3.13 min; Molecular mass found = 407.

Compound 114 N-r2- (4-fluorophenyl) ethill-3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -p¡razole-1 -carboxamide LC / EM method C: Retention time : 3.21 min; Molecular mass found = 382.

Compound 115 (3-Pentyl-4-phenyl-4,5-dihydropyrazol-1-yl) -iazepan-1-illmetanone LC / MS method C: Retention time: 3.59 min; Molecular mass found = 342.

Compound 116 N- (quinolin-3-yl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-carboxamide LC / MS method C: Retention time: 3.08 min; Molecular mass found = 387.

Compound 117 N-p- (ethyl) propin-3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-carboxamide LC / MS method C: Retention time: 3.30 min; Molecular mass found = 330.

Compound 118 N- (2,2,2-trifluoroethyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-carboxamide LC / MS method C: Retention time: 2.87 min; Molecular mass found = 342.

Compound 119 N- (pyridin-3-ylmethyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-carboxamide LC / MS method C: Retention time: 2.41 min; Molecular mass found = 351.

Compound 120 N- (2-indanyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-carboxamide LC / MS method C: Retention time: 3.27 min; Molecular mass found = 376.

Compound 121 (3-Pentyl-4-phenyl-4,5-dihydropyrazol-1-yl) - (1, 2,3,4-tetrahydroisoquinolin-2-yl) methanone LC / MS method C: Retention time: 3.48 min; Molecular mass found = 376.

Compound 122 N- (methyl), N- (naphthalen-1-ylmethyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide LC / EM method C: Retention time: 3.62 min; Molecular mass found = 414.

Compound 123 N- (3,3-diphenylpropyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1H) -pyrazol-1-carboxamide LC / MS method C: Retention time: 3.59 min; Molecular mass found = 454.

Compound 124 N- (naphth-1 -yl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazolocarbothiamide N- (naphth-1-yl) -3 - (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazolecarboxyiamide was obtained from 3- (n-pentyl) -4-phenyl-4,5-dihydropyrazole and an equimolar amount of 1-naphthyl isothiocyanate in tetrahydrofuran at 30 ° C for 5 hours. LC / MS (Method C). Retention time: 3.65 min; Molecular mass found = 402.

Compound 125 Np- (ethyl) propin-3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazolcarboxyiamide N- (1- (ethyl) propyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazolocarbothiamide was obtained from 3- (n-pentyl) -4-phenyl-4,5-dihydropyrazole and an equimolar amount of 1- (ethyl) isothiocyanate ) propyl in tetrahydrofuran at 30 ° C for 5 hours. LC / MS (Method C). Retention time: 3.69 min; Molecular mass found = 346.

Compound 126 N- [pyridin-3-ylmetin-3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazolocarbothymid N- (pyridin-3-ylmethyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazolecarboxyiamide was obtained from 3- (n-pentyl) -4-phenyl-4,5-dihydropyrazole and an equimolar amount of isothiocyanate of pyridin-3-ylmethyl in tetrahydrofuran at 30 ° C for 5 hours. LC / MS (Method C). Retention time: 3.83 min; Molecular mass found = 367.Compound 127 N-phexo-bicyclo2.2.1lhept-2-ill-3- (n-pentyl) -4-phenyl-4,5-dhydro- (1 H) -pyrazolocarbothymide The N- [exo-bicyclo [2.2 .1] hept-2-yl] -3- (n-pentyl) -4-phenyl-4,5-dihydro- (IH) -pyrazolocarbotamide was obtained from 3- (n-pentyl) -4-phenyl- 4,5-dihydropyrazole and an equimolar amount of racemic exo-bicyclo [2.2.1] hept-2-yl sothiocyanate in tetrahydrofuran at 30 ° C for 5 hours. LC / MS (Method C). Retention time: 3.89 min; Molecular mass found = 370.

Compound 128 1- (naphthalen-1-ylsulfonyl) -3- (n-butyl) -4- (2-fluorophenyl) -4,5-dihydro- (IH) -pyrazole 3- (n-butyl) -4- ( 2-fluorophenyl) -4,5-dihydropyrazole (Intermediate IV-3) crude (1.50 grams, 5J1 mmoles maximum) in dichloromethane (20 ml) and DIPEA (0.81 g, 1.09 ml, 6.28 mmoles) and 1-naphthalenesulfonyl chloride (1.42 g, 6.28 mmoles dissolved in 10 ml of dichloromethane) and the resulting magnetically stirred solution was reacted at room temperature for 16 hours. The resulting mixture was poured into water. The organic layer was separated and collected, dried over Na 2 SO 4, filtered and concentrated, followed by purification by flash chromatography (dichloromethane) to give 1- (naphthalene-1-ylsulfonyl) -3- (n-butyl) -4- (2 Fluorophenyl) -4,5-dihydro- (1 H) -pyrazol (2.07 g, 88% yield). Rf = 0.4 (dichloromethane). LC / MS (Method D). Retention time: 2.04 min; Molecular mass found = 411.

The following were prepared analogously: Compound 129 1- (Naphthalen-2-ylsulfonyl) -3- (n-butyl) -4- (2-fluorophenyl) -4,5-dihydro- (IH) -pyrazole LC / MS (Method D). Retention time: 2.00 min; Molecular mass found = 411.

Compound 130 Nr (1 R, 2S, 5R) -rel-6,6-dimethylbicyclo3.1.nheptan-2-methyl-3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol -1-sulfonamide Part A A magnetically stirred solution of (-) - cis-myrtanylamine (2.0 g, 13 mmol) (CAS 38235-68-6)) in dichloromethane (25 ml) was added triethylamine (4 ml) and chlorosulfonic acid (0.865 ml, 13 mmol, dissolved in dichloromethane (5 ml)) at 0 °. C. The resulting solution was allowed to reach room temperature and reacted for 16 hours.

The reaction mixture was poured into excess 1 M hydrochloric acid. [(1 R, 2S, 5R) -rel-6,6-dimethylbicyclo [3.1.1] heptan-2-methyl] sulfamic acid precipitated crude (3.41 grams) ) was collected by filtration.

Part BA a magnetically stirred solution of [(1 R, 2S, 5R) -rel-6,6-dimethylbicyclo [3.1.1] heptan-2-methyl] sulfamic acid (3.41 g) in dichloromethane (25 ml) was added slowly POCI3 (2.78 ml of POCI3 dissolved in dichloromethane (25 ml)). The resulting mixture was heated at reflux temperature for 16 hours. Subsequent concentration under vacuum afforded crude [(1 R, 2S, 5R) -rel-6,6-dimethylbicyclo [3.1.1] heptan-2-methyljsulfamic acid chloride (5.31 g). 1 H-NMR (300 MHz, CDCl 3) d 0.95 (d, J = 10, 1 H), 1.04 (s, 3 H), 1.23 (s, 3 H), 1.43-1.60 (m, 1 H), 1.82-2.09 ( m, 5H), 2.25-2.46 (m, 2H), 3.25-3.40 (m, 2H), 5.66 (br s, 1 H).

Part C 3- (n-pentyl) -4-phenyl-4,5-dihydropyrazole (3.4 grams, 15J mmoles) was dissolved in toluene (25 ml) and treated with [(1R, 2S, 5R) -rel. Crude 6,6-dimethylbicyclo [3.1.1] heptan-2-methyl] sulfamic (5.31 g, maximum 15.7 mmol) and triethylamine (2.2 ml, 15.7 mmol) and the resulting solution was magnetically stirred at room temperature for 96 hours. The solution was concentrated to provide a crude oil (7.7 grams). Column chromatographic purification (heptane / ethyl acetate = 1: 1 (v / v), followed by another column chromatographic separation using as eluent heptane / ethyl acetate = 6: 1 (v / v) gave N- [ (1 R, 2S, 5R) -rel-6,6-dimethylbicyclo [3.1.1] heptan-2-methyl] -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pirazol-1-sulfonamide (675 mg) as an oil, Rf = 0.3 (heptane / ethyl acetate = 6: 1 (v / v)). 1 H-NMR (400 MHz, CDCl 3) d 0.83 (t, J = 7, 3H), 0.93 (d, J = 10, 1 H), 1.01 (s, 3H), 1.20-1.29 (m, 7H), 1.41-1.60 (m, 3H), 1.85-2.43 (m, 9H) , 3.22-3.28 (m, 2H), 3.64-3.71 (m, 1 H), 4.02-4.09 (m, 1 H), 4.12-4.19 (m, 1 H), 4.66 (br t, J = 7, 1 H), 7.19-7.23 (m, 2H), 7.28-7.38 (m, 3H).

EXAMPLE 5 Formulations used in animal studies For oral administration (p.o.): at the desired amount (0.5-5 mg) of solid compound 1 in a glass tube, some glass beads were added and the solid was vortexed for 2 minutes. After addition of 1 ml of a 1% solution of methylcellulose in water and 2% (v / v) of Poloxamer 188 (Lutrol F68), the compound was suspended by whirlpool for 10 minutes. The pH was adjusted to 7 with a few drops of aqueous NaOH (0.1 N). The remaining particles in the suspension were further suspended using an ultrasonic bath.

For intraperitoneal administration (i.p.): at the desired amount (0.5-15 mg) of solid compound 1 in a glass tube, some glass beads were added and the solid was ground in a vortex for 2 minutes. After addition of 1 ml of a solution of methyl cellulose 1% and mannitol 5% in water, the compound was suspended in a vortex for 10 minutes. Finally, the pH was adjusted to 7.

EXAMPLE 6 Pharmacological Methods In vitro affinity for cannabinoid CBi receptors The affinity of the compounds of the invention for CB cannabinoid receptors! can be determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabinoid receptor CBi is stably transfected in conjunction with [3 H] CP-55,940 as radioligand. After incubation of a fresh cell membrane preparation with the ligand [3H], with or without addition of the compounds of the invention, separation of bound and free ligand is carried out by filtration on glass fiber filters. The radioactivity in the filter is measured by liquid scintillation counting.

In vitro affinity for CB cannabinoid receptors? The affinity of the compounds of the invention for CB2 cannabinoid receptors can be determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabinoid receptor CB2 is stably transfected in conjunction with [3H] CP-55.940 as a radioligand. After incubation of a fresh cell membrane preparation with the ligand [3H], with or without addition of the compounds of the invention, separation of bound and free ligand is carried out by filtration on glass fiber filters. The radioactivity in the filter is measured by liquid scintillation counting.

(Ant) akonismo in vitro for cannabinoid receptors CBi Antagonism / agonism in vitro with the CBi receptor can be evaluated with the human CBi receptor cloned in Chinese hamster ovary (CHO) cells. CHO cells are grown in a culture medium of Dulbecco's Modified Eagle's Medium (DMEM), supplemented with 10% heat inactivated fetal calf serum. The medium is aspirated and replaced with DMEM, without fetal calf serum, but containing [3H] -arachidonic acid and incubated overnight in a cell culture oven (C02 5% / air 95%; 37 ° C; saturated with water). During this period, [3H] -arachidonic acid is incorporated into the membrane phospholipids. On the test day, the medium is aspirated and the cells are washed three times using 0.5 ml of DMEM, containing 0.2% bovine serum albumin (BSA). Agonist stimulation for CBi leads to activation of PLA2 followed by release of [3H] -arachidonic acid in the medium. This release induced by CBi agonists is antagonized in a concentration dependent manner by antagonists of CB-i receptors, such as, for example, rimonabant.

(Ant) in vitro akonism for CB cannabinoid receptors? Functional activity in CB2 cannabinoid receptors was evaluated using a cAMP accumulation assay stimulated by forskolin. The ability of the compounds to stimulate and inhibit the activity of adenylate cyclase was evaluated in Chinese hamster ovary K-cells (CHO) expressing the human CB2 receptor (Euroscreen, Brussels). CHO cells were grown in a CHO-S-SFM-II culture medium, supplemented with 10% heat-inactivated fetal calf serum, 2 mM glutamine, 400 μg / ml Hygromycin B and 500 μg / ml G418 a 37 ° C in air 93% / CO2 5%. For incubation with the test compounds, confluent cultures grown in 24-well plates were used. Each condition or substance was tested routinely in quadruplicate. The cells were loaded with 1 mCi of [3 H] -adenine in 0.5 ml of medium per well. After 2 hours, the cultures were washed with 0.5 ml of PBS containing 1 mM IBMX and incubated for 20 minutes with 0.5 ml of PBS containing 1 mM IBMX and 3 x 10'7 M forskolin with or without the test compound. Antagonistic effects of the test compounds were determined as inhibition of [3 H] cAMP formation decreased by 0.1 μM of JWH-133. After aspiration the reaction was stopped with 1 ml of trichloroacetic acid (5% w / v). The [3 H] -ATP and [3 H] -cAMP formed in the cell extract were tested as follows: a volume of 0.8 ml of the extract was passed over Dowex columns (50WX-4200- 400 mesh) and aluminum oxide columns, eluted with water and 0.1 M midazole (pH = 7.5). The eluates were mixed with 7 ml of Ultima-Flo [AP] and the radioactivity β was counted with a liquid scintillation counter. The conversion of [3 H] -ATP into [3 H] -cAMP was expressed as the ratio in percentage radioactivity in the cAMP fraction compared to the radioactivity in both cAMP and ATP fractions, and the basal activity was subtracted to correct for activity spontaneous The reference compounds for assessing adenylate cyclase activity mediated by CB2 cannabinoid receptors were the complete CB2 cannabinoid receptor agonists JWH-133 (Huffman, 1999b) and WIN 55,212-2 (Huffman, 1999a), and the inverse agonist or antagonist SR-144528 (Rinaldi-Carmona, 1998). The compounds were studied in a concentration scale of 10'10 M to 10"6 M. The pECso and the pA2 were calculated according to the Cheng-Prusoff equation (Cheng and Prusoff, 1973). independent in triplicate.

EXAMPLE 7 Results of Pharmacological Tests The affinity data for CB- | / CB2 cannabinoid receptors, expressed as pKi values (average results from at least three independent experiments, carried out according to the protocols given above) as well as the functional data of receptor agonists CBi of representative compounds of this invention are shown in the following table.

TABLE 1 Affinities for CBi and CB2 receptors and functional agonist activity for CBi of representative compounds of this invention These dice illustrate the affinities of representative compounds for the CBi and CB2 receptors as well as the agonist properties for CBi achieved by the structural modifications that form the basis of the present invention.

TABLE 2 Functional agonist / antagonist activity for CB2 of representative compounds of this invention These data illustrate the functional agonist or antagonist activity for cannabinoid-CB2 of representative compounds of the present invention.

EXAMPLE 8 Pharmaceutical Preparations For clinical use, the compounds of the formula (I) are formulated in pharmaceutical compositions which are important and novel embodiments of the invention because of the presence of the compounds, more particularly the specific compounds described herein. The types of pharmaceutical compositions that can be used include, but are not limited to, tablets, chewable tablets, capsules (including microcapsules), solutions, parenteral solutions, ointments (creams and gels), suppositories, suspensions, and other types described in present or apparent to a person skilled in the art from the specification and general knowledge in the art. The compositions are used for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, buccal, rectal, parenteral, or other administration modes. The pharmaceutical formulation contains at least one compound of the formula (I) in admixture with a pharmaceutically acceptable adjuvant, diluent and / or carrier. The total amount of active ingredients suitably is in the range of from about 0.1% (w / w) to about 95% (w / w) of the formulation, suitably from 0.5% to 50% (w / w) and preferably from 1 % to 25% (p / p). The compounds of the invention can be brought into forms suitable for administration by means of usual processes using auxiliary substances such as liquid or solid ingredients, powders, such as pharmaceutically usual liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavorings , dyes and / or buffer substances. Frequently, the auxiliary substances used that may be mentioned are magnesium carbonate, titanium dioxide, lactose, sucrose, sorbitol, mannitol and other sugars or sugar alcohols, talc, lactoprotein, gelatin, starch, amylopectin, cellulose and its derivatives, oils animals and vegetables such as fish liver oil, sunflower, peanut or sesame, polyethylene glycol, and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol, as well as with disintegrating and lubricating agents such as stearate magnesium, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture can then be processed into pellets or compressed into tablets. The active ingredients can be pre-mixed separately with other non-active ingredients, before being mixed to form a formulation. The active ingredients can also be mixed together, before being mixed with the non-active ingredients to form a formulation. Soft gelatin capsules can be prepared with capsules containing a mixture of the active ingredients of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules. Hard gelatin capsules may contain granules of the active ingredients. Hard gelatine capsules can also contain the active ingredients in combination with solid powder ingredients such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin. Unit doses for rectal administration can be prepared (i) in the form of suppositories containing the active substance mixed with a neutral fat base; (ii) in the form of a rectal gelatin capsule containing the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for rectal gelatin capsules; (iii) in the form of a ready-to-use microenema; or (iv) in the form of a dry microenema formulation to be reconstituted in a suitable solvent immediately prior to administration. The liquid preparations can be prepared in the form of syrups, elixirs, drops or concentrated suspensions, eg, solutions or suspensions containing the active ingredients and the remaining consisting, for example of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain coloring agents, flavoring agents, preservatives, saccharin, and carboxymethylcellulose or other thickening agents. The liquid preparations can also be prepared in the form of a dry powder to be reconstituted with a suitable solvent before use. Solutions for parenteral administration can be prepared as a solution of a formulation of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients, preservatives and / or buffering ingredients. Solutions for parenteral administration can also be prepared as a dry preparation to be reconstituted with a suitable solvent before use. Also provided in accordance with the present invention are formulations and 'parts kits' comprising one or more containers filled with one or more of the ingredients of a pharmaceutical composition of the invention, for use in medical therapy. Associated with such containers may be various written materials such as instructions for use, or a notification in the form prescribed by the government agency that regulates the manufacture, use or sale of pharmaceutical products, which notification reflects approval by the manufacturing agency , use or sale for human or veterinary administration. The use of the formulations of the present invention in the manufacture of medicaments for use in the treatment of a condition in which modulation of CB-i cannabinoid receptors, and methods of medical treatment or comprising the administration of a therapeutically effective total amount of at least one compound of the formula (I), as such or, in the case of prodrugs, after administration, to a patient suffering from, or susceptible to suffering from, a condition in the which modulation of CB cannabinoid receptors is required or desired. The invention has been described with reference to several specific and preferred modalities and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

REFERENCES Albericio, F., et al., Tetrahedron Lett., 38, 4853-4856, 1997. Akaji, K. et al., Tetrahedron Lett., 35, 3315-3318, 1994. Barluenga et al. Chem. Eur. J., 5, (3) 883-896, 1999 Bickel, MH, "The pharmacology and Biochemistry of N-oxides", Pharmaco-loqical Reviews, 21 (4), 325-355, 1969. Bodanszky, M. and A. Bodanszky: 7? 7e Practice of Peptide Synthesis, Springer-Verlag, New York, ISBN: 0-387-57505-7, 1994. Bundgaard, H. (editor), "Design of Prodrugs", Elsevier, 1985. Cheng, Y. and Prusoff, WH, Biochem. Pharmacol., 22, 3099-3108, 1973. De Petrocellis, L. et al. Br. J. Pharmacol., 141, 765-774, 2004. Di Marzo, V. et al., Nature Rev. Drug Discov., 3, 771-784, 2004. Ettmayer, P. et al., "Lessons learned. from marketed and research prodrugs ", J.Med.Chem., 47, 2393-2404, 2004. Hertzog, DL Expert Opin. Ther. Patents, 14, 1435-1452, 2004 Huffman et al., Curr. Med. Chem., 6, 705-720, 1999 Huffman et al., Bioorg. Med. Chem., 7, 2905-2914, 1999 Járvinen, T., "Design and Pharmaceutical applications of prodrugs", p. 733-796 in: S.C. Gad "Drug Discovery Handbook", John Wiley &Sons, New Jersey, USA, 2005. King, FD, (editor), page 215 in: "Medicinal Chemistry: Principles and Practice", 1994. Lambert, DM and Fowler, CJJ Med. Chem., 48, 5059-5087, 2005. Lange, JHM et al., J. Med. Chem., 47, 627-643, 2004. Lange, JHM et al., Bioorg. Med. Chem. Lett, 15, 4794-4798, 2005. Lange, JHM and Kruse, CG, C. Curr Opin, Drug Discovery Dev, 7, 498-506, 2004 Lange, JHM and Kruse, CG Drug Discov. Today, 10, 693-702, 2005; Montalbetti, CAGN &V. Falque, Tetrahedron, 61, 10827-52. 2005. Muccioli, G.G. et al., Curr. Med. Chem., 12, 1361-1394, 2005 Muccioli, G.G. and Lambert, D.M .., Expert Opin. Ther. Patents, 16, 1405-1423, 2006 Ogata, J. co /., J. Med. Chem. 1987, 30, 1054-1068, 1987a Ogata, J., et al., J. Med. Chem. 1987, 30 , 1497-1502, 1987b Padgett, LW Life Se, 77, 1767-1798, 2005. Raitio, K.H., et al., Curr. Med. Chem., 12, 1217-1237, 2005.

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Claims (18)

NOVELTY OF THE INVENTION CLAIMS

1. - Compounds of the general formula (I) wherein - R represents an alkyl- group of C2-? 0, an alkenyl- group of C4-? or, an alkynyl- group of C4-? or, a heteroalkyl- group of C2. 10, a C-8 cycloalkyl-C-5-alkyl group or a Cs-β-alkyl-d-5-heterocycloalkyl group wherein the heteroatom (s) is (are) N, O or S, which C2-? 0 alkyl group, C4-? 0 alkenyl group, C4-? Alkynyl group or heteroalkyl group of C2-? Or C5-8 cycloalkyl- group C5-C5-alkyl or C5-8 heterocycloalkyl-C5-5-alkyl group can be substituted with 1-5 substituents selected from methyl, ethyl, hydroxy, amino or fluorine, or R represents an aryl group C? -3 alkyl or an aryl-heteroalkyl group of C? -3 in which the aryl groups can be substituted with 1-5 Y substituents, which may be the same or different, selected from the alkyl group of C? -3 or C? -3 alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C? -2) -amino, mono- or dialkyl (C) ? 2) -amido, (C? -3) -sulfonyl-alkyl, dimethylsulfamido, C? -3-carbonyl alkoxy, carboxyl, trifluo romethylsulfonyl, cyano, carbamoyl, sulphamoyl, phenyl and acetyl, or R represents a cyclopropyl group, which cyclopropyl group can be substituted with 1-5 substituents selected from methyl, ethyl, fluorine or with a linear C3-5 alkyl group or branched or with a benzyl or aryl group, in which the aryl or benzyl group may be substituted with 1-5 substituents Y, - R 1 represents hydrogen, hydroxy, C 1 -3 alkoxy, acetyloxy or propionyloxy, - R 2 represents a aryl group which may be substituted with 1-5 Y substituents, wherein Y has the abovementioned meanings, - n is 0 or 1 -R3 represents a linear C3-10 alkyl group. a branched alkyl group of C5-10. a cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl or cyclooctyl group, a C 5-10 bicycloalkyl group, a C 1 -io tricycloalkyl group OR a C 8 -ne tetracycloalkyl group which groups may be substituted with 1-5 selected substituents of methyl, ethyl, hydroxy, amino, fluorine or R3 represents a C3.8 cycloalkyl group which C3-8 cycloalkyl group is substituted with an aryl group, which aryl group can be substituted with 1-5 Y substituents wherein Y has the meanings mentioned above, or R3 represents a 2,2,2-trifluoroethyl or 2-fluoroethyl group or R3 represents a cyclohexyl group which group is substituted with 1-5 substituents selected from methyl, ethyl, hydroxy, amino or fluorine , or R3 represents a C5-8 heterocycloalkyl group, a bicycloheteroalkyl group of C 1 -io, a tricycloheteroalkyl group of C 1o, which groups can be substituted with 1-5 substituents selected from methyl, ethyl, idroxy, amino or fluorine, or R3 represents a C3-8-cycloalkyl-C1-3 alkyl group, a C5-? 0-alkyl- C-3-alkylcycloalkyl group, a C6-tricycloalkyl- group ? -alkyl- of C? -3, which groups can be substituted with 1-5 substituents selected from methyl, ethyl, hydroxy, amino or fluorine, or R3 represents a C3-8 heterocycloalkyl-C1-alkyl group -3 branched or linear, a bicycloheteroalkyl- C5-10-alkyl group-C1.3, a tricycloheteroalkyl- C6-? Or -alkyl- group of C? -3 > which groups can be substituted with 1-5 substituents selected from methyl, ethyl, hydroxy, amino or fluorine, or R3 represents an aryl group, which group can be substituted with 1-5 Y substituents, wherein Y has the meanings above mentioned, or R3 represents an aryl-alkyl- group of d-5 or a diaryl-C1-6 alkyl group, in which groups the phenyl or heteroaromatic rings may be substituted with 1-5 Y substituents, wherein Y has the above-mentioned meanings, or R3 represents an alkenyl- group of C -8 or a linear or branched C4-8 alkynyl- group, which linear or branched C4-8 alkenyl- or C4-8 alkenyl- C4-8 alkynyl groups can be substituted with 1-3 fluorine atoms, or, when n = 1, R3 represents a heteroalkyl- group of branched C2-? 0 or linear, which contains 1-2 heteroatoms selected from N, O or S, -R4 represents a hydrogen atom, a C? -4 alkyl group or R3 and R4 - together with the nitrogen atom to which they are attached - form a monocyclic, bicyclic or tricyclic heterocyclic, saturated or unsaturated, non-aromatic or partially aromatic tricyclic group, having 5 to 11 ring atoms, which heterocyclic group can be substituted with 1-5 substituents selected from aryl, aryl-C-alkyl? -3, diarylmethyl, or Y, wherein Y has the meanings mentioned above, -A represents a carbonyl group (C = 0), thiocarbonyl (C = S) or sulfonyl (SO2) with the proviso that when A represents a group thiocarbonyl (C = S), n has the value 1, and stereoisomers, prodrugs and N-oxides of themselves, and compounds of the formula (I) isotopically labeled, as well as the pharmacologically acceptable salts, hydrates, solvates, complexes and conjugates of said compounds of the formula (I) and their stereoisomers, prodrugs, N-oxides, or isotopically analogues marked.

2. The compounds according to claim 1 of the general formula (I), further characterized in that Ri represents a hydrogen atom, and the other symbols have the meanings given in claim 1.

3.- The compounds in accordance with claim 2 of the general formula (I) further characterized in that A represents a carbonyl group, and the other symbols have the meanings given in claim 2.

4. The compounds according to claim 3 of the general formula (I) further characterized in that R 2 represents a phenyl, thienyl or pyridyl group, which phenyl, pyridyl or thienyl group may be substituted with 1, 2 or 3 Y substituents, and the other symbols have the meanings given in claim 3.

5. - The compounds according to claim 4 of the general formula (I) further characterized in that n is 1, and the other symbols have the same meanings given in claim 4.

6. The compounds according to claim 5 of the general formula (I) further characterized in that R4 represents a hydrogen atom, and the other symbols have the same meanings given in claim 5.

7. The compounds according to claim 6 of the general formula (I) characterized further because R represents a branched or linear C3-8 alkyl group, which branched or linear C3_8 alkyl group can be substituted with 1-3 fluorine atoms, and the other symbols have the same meanings given in claim 6.

8 The compounds according to claim 1 further characterized because they are: N - [(1 R, 2S, 5R) -rel-6,6-dimethylbicyclo [3.1.1] heptan-2-methyl] -3- (n -pentil) -4-feni-4, 5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (1-adamantyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -p-aceol-1-carboxamide; N- (Exo-bicyclo [2.2.1] hept-2-yl) -3- (n-pentyl) -4-phenyl-4,5-d, h -dro- (1 H) -pyrazol-1-carboxamide; N-phenyl-3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N - [(1 R, 2S, 5R) -rel-6,6-dimethylbicyclo [3.1.1] heptan-2-methyl] -3- (benzyl) -4-phenyl-4,5-dihydro- (1 H ) -pyrazol-1 -carboxamide; N- (1-adamantyl) -3- (benzyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N - [(1 R, 2S, 5R) -rel-6,6-dimethylbicyclo [3.1.1] heptan-2-methyl] -3- (n-butyl) -4-phenyl-4,5-dihydro- ( 1 H) -pyrazol-1-carboxamide; N-tíl R ^ S.dR ^ rel -?.? - dimetilbiciclotSl.ljheptan ^ -metilj-S-IS-pi-piperidinyl) propyl] -4-phenyl-4,5-dihydro- (1 H) - pyrazole-1-carboxamide; N- [(1 R, 2S, 5R) -rel-6,6-dimethylbicyclo [3.1.1] heptan-2-methyl] -3- (n-propyl) -4-phenyl-4,5-dihydro- ( 1 H) -pyrazol-1 -carboxamide; N- (benzyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (1-adamantyl) methyl-3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (cyclohexylmethyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- [endo- (1 R, 2S, 4R) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] -3- (n-pentyl) -4-phenyl-4,5-dihydro - (1 H) -pyrazol-1 -carboxamide; N- [endb ~ - (1S) '- 1, 3,3-trimethylbicyclo [2.2.1] hept-2-yl] -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N - [(1 R, 2S, 5R) -rel-6,6-dimethylbicyclo [3.1.1] heptan-2-methyl] -3- (n-propyl) -4- (2-pyridyl) -4.5 -dihydro- (1 H) -pyrazol-1 -carboxamide; N- (1-phenyl-ethyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1H) -pyrazol-1 -carboxamide; N- (2-adamantyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (1-naphthyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (1-methyl-1-phenyl-ethyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (2,2-diphenylpropyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N - ((3-trifluoromethyl) benzyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (2,2-dimethylpropyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (naphthalen-1-yl-methyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N - [(3-dimethylamino) -2,2-dimethylpropyl] -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- [endo- (1 R, 2S, 4R) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] -3- (n-butyl) -4-phenyl-4,5 -dihydro- (1 H) -pyrazol-1 -carboxamide; N- (2- (4-fluorophenyl) -1,1-dimethyl-ethyl) -3- (n-butyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- [endo- (1 R, 2S, 4R) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] -3- (4,4,4-trifluoro-n-butyl) -4 phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (2- (4-fluorophenyl) -1,1-dimethyl-ethyl) -3- (4,4,4-trifluoro-n-butyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (2- (4-fluorophenyl) -1,1-d-methyl-ethyl) -3- (n-pentyl) -4-phenyl-4,5-d -hydro- (1 H) -p Razol-1-carboxamide; N- [endo- (1 R, 2S, 4R) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] -3- (1,1-dimethyl-n-butyl) -4 phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- [endo- (1 R, 2S, 4R) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] -3- (3,3,3-trifluoropropyl) -4-phenol -4,5-dihydro- (1 H) -pyrazol-1-carboxamide; N- [endo- (1 R, 2S, 4R) -1, 7J-trimethylbicyclo [2.2.1] hept-2-yl] -3- (1, 1-dimethylpropyl) -4-phenyl-4,5-dih Dro- (1 H) -pyrazol-1 -carboxamide; N- (2- (4-fluorophenyl) -1,1-dimethyl-ethyl) -3- (1,1-dimethylpropyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- [endo- (1 R, 2S, 4R) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] -3- (1,1-dimethyl-3,3,3- trifluoropropyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- [endo- (1 R) -1,3,3-trimethylbicyclo [2.2.1] hept-2-yl] -3- (n-butyl) -4-phenyl-4,5-dihydro- (1 H) ) -pyrazol-1-carboxamide; N- (1-methyl-1-phenyl-ethyl) -3- (n-butyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (2-adamantyl) -3- (n-butyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-carboxamide; N- [exo- (1R, 2R, 4R) -1 JJ-trimethylbicyclo [2.2.1] hept-2-yl] -3- (n-butyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (2-phenyl-1,1-dimethyl-ethyl) -3- (n-butyl) -4- (3-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (2-phenyl-1,1-dimethyl-ethyl) -3- (n-butyl) -4- (2-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N-Phenyl-3- (4-chlorobenzyl) -4- (4-chlorophenyl) -4,5-dihydro- (1 H) -pyrazol-1-carboxamide; N- (4-methoxy-phenyl) -3- (4-chlorobenzyl) -4- (4-chlorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- [endo- (1 R, 2S, 4R) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] -3- (n-butyl) -4- (2-methoxyphenyl) -4.5 -dihydro- (1 H) -pyrazol-1 -carboxamide; N- (1-methyl-1-phenyl-ethyl) -3- (n-butyl) -4- (2-methoxyphenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- [endo- (1 R, 2S, 4R) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] -3- (n-butyl) -4- (2-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- [endo- (1 R, 2S, 4R) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] -3- (n-butyl) -4- (pyrid-3-yl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- [(1 R, 2R, 3R, 5S) -2,7,7-trimethyl-cyclo [3.1.1] hept-3-yl] -3- (n-butyl) -4- (3-fluorophenyl) -4 , 5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- [endo- (1 R) -1,3,3-trimethylbicyclo [2.2.1] hept-2-yl] -3- (n-butyl) -4- (2-fluorophenyl) -4,5-dih Dro- (1 H) -pyrazol-1 -carboxamide; N- [2- (trifluoromethyl) benzyl] -3- (n-butyl) -4- (3-fluorophenyl) -4,5-dihydro- (1H) -pyrazol-1 -carboxamide; N- [exo- (1R, 2R, 4R) -1 JJ-trimethyl-lbicyclo [2.2.1] hept-2-yl] -3- (n-butyl) -4- (2-fluorophenyl) -4, 5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (1-methyl-1-phenyl-ethyl) -3- (n-butyl) -4- (3-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (1-methyl-1-phenyl-ethyl) -3- (n-butyl) -4- (4-chlorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- [2- (trifluoromethyl) benzyl] -3- (n-butyl) -4- (4-chlorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- [endo- (1 R, 2S, 4R) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] -3- (cyclopropylmethyl) -4-phenyl-4,5-dihydro - (1 H) -pyrazol-1 -carboxamide; N- [endo- (1 R, 2S, 4R) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] -3- (n-butyl) -4- (4-fluorophenyl) -4 , 5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (1-methyl-1-phenyl-ethyl) -3- (n-butyl) -4- (4-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (adamant-2-yl) -3- (n-butyl) -4- (4-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (1-methyl-1- (4-fluorophenyl) -ethyl) -3- (n-butyl) -4- (4-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1-carboxamide; N- (1-methyl-1- (4-fluorophenyl) -ethyl) -3- (n-butyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-carboxamide; N- (1-methyl-1-phenyl-ethyl) -3- (n-pentyl) -4- (2-fluorophenyl) -4,5-d ihydro- (1 H) -pyrazol-1 -carboxamide; N- [endo- (1 R, 2S, 4R) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] -3- (n-pentyl) -4- (2-fluorophenyl) -4 , 5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (1-methyl-1- (4-fluorophenyl) -ethyl) -3- (n-pentyl) -4- (2-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (1-methyl-1- (4-fluorophenyl) -ethyl) -3- (n-pentyl) -4- (3-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (adamant-2-yl) -3- (n-pentyl) -4- (2-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1-carboxamide; N- (adamant-2-yl) -3- (n-pentyl) -4- (3-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (1-methyl-1-phenyl-ethyl) -3- (n-butyl) -4- (benzo [b] thiophen-3-yl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- [endo- (1 R, 2S, 4R) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] -3- (n-butyl) -4- (benzo [b] thiophene) 3-yl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (1-methyl-1-phenyl-ethyl) -3- (n-butyl) -4- (thiophen-3-yl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (1-methyl-1-phenyl-ethyl) -3- (but-3-ynyl) -4- (2-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- [endo- (1 R, 2S, 4R) -1, 7J-trimethylbicyclo [2.2.1] hept-2-yl] -3- (but-3-ynyl) -4- (2-fluorophenyl) -4 , 5-hydroxy- (1H) -pyrazol-1 -carboxamide; N- [endo- (1 R, 2S, 4R) -1 J, 7-trimethylbicyclo [2.2.1] hept-2-yl] -3- (1-phenylcyclopropyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-carboxamide; N- (1-methyl-1-phenyl-ethyl) -3- (1-phenyl-cyclopropyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-carboxamide; N- [endo- (1 R, 2S, 4R) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] -3- (2,2,3,3-tetramethylcyclopropyl) -4-phenyl -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (1-methyl-1-phenyl-ethyl) -3- (2,2,3,3-tetramethylcyclopropyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N - [(1 R, 2R, 3R, 5S) -2JJ-trimethylbicyclo [3.1.1] hept-3-yl] -3- (n-butyl) -4- (4-chlorophenyl) -4,5-dihydro - (1 H) -pyrazol-1 -carboxamide; N- (1-methyl-1-phenyl-ethyl) -3- (n-pentyl) -4- (3-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- [endo- (1 R, 2S, 4R) -1 JJ-trimethylbicyclo [2.2.1] hept-2-yl] -3- (n-pentyl) -4- (3-fluorophenyl) -4.5- dihydro- (1 H) -pyrazol-1 -carboxamide; N- (1-methyl-1-phenyl-ethyl) -3- (n-pentyl) -4- (4-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- [endo- (1R, 2S, 4R) -1 JJ-trimethylbicyclo [2.2.1] hept-2-yl] -3- (n-pentyl) -4- (4-fluorophenyl) -4,5-dihydro - (1 H) -pyrazol-1-carboxamide; N - [(1S, 2S, 3S, 5R) -2JJ-trimethylbicyclo [37lt] hept-3-yl] -3 ^ (n-butyl) -4- (3-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (1-methyl-1- (4-fluorophenyl) -ethyl) -3- (n-butyl) -4- (3-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (1-methyl-1- (4-fluorophenyl) -ethyl) -3- (n-butyl) -4- (2-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- [(1S, 2S, 3S, 5R) -2JJ-trimethylbicyclo [3.1.1] hept-3-yl] -3- (n-butyl) -4- (2-fluorophenyl) -4.5- dihydro- (1 H) -pyrazol-1 -carboxamide; N- [endo- (1 R, 2S, 4R) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] -3- (n-butyl) -4- (thien-3-yl) -4,5-dihydro- (1 H) -pyrazol-1-carboxamide; N- [endo- (1 R, 2S, 4R) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] -3- (3,3,3-trifluoro-1-methoxymethyl-propyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- [endo- (1 R, 2S, 4R) -1 J, 7-trimethylbicyclo [2.2.1] hept-2-yl] -3- (n-butyl) -4-hydroxy-4-phenyl-4 , 5-dihydro- (1 H) -pyrazol-1 -carboxamide; 1- (1-naphthyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol; [3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-yl] - [1- (4-chlorophenyl) cyclopentyljmetanone; [3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-yl] - (naphth-2-yl) methanone; [3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-yl] - (diphenylmethyl) methanone; [3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -yl] - (3-chlorobenzothien-2-yl] -methanone; [3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-yl] - (benzofuran-2-yl] methanone; [3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-yl] - [2,4,4- (trimethyl) pentyl] methanone; [3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) - pyrazol-1-yl] - [3- (trifluoromethyl) phenyl] methanone; (cis-3,4,5-trimethylpiperazin-1-yl) [3- (n-pentyl) -4-phenyl-4,5-dihydro - (1 H) -pyrazol-1-yl] methanone; N-endo - [(1 R, 2S, 4R) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] -3- ( n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide (diastereomer A); N-endo - [(1 R, 2S, 4R) -1, 7,7- trimethylbicyclo [2.2.1] hept-2-yl] -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -p-acetyl-1 -carboxamide (diastereomer B); endo - [(1 R, 2S, 4R) -1 JJ-trimethylbicyclo [2.2.1] hept-2-yl] -3- (n-butyl) -4- (3-fluorophenyl) -4,5- dihydro- (1 H) -pyrazol-1 -carboxamide (diastereomer A); N-endo - [(1 R, 2S, 4R) -1,7,7-trimethylbicyclo [2.2.1] hept-2-yl] - 3- (n-butyl) -4- (3-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -ca rboxamide (diastereomer B); N-endo - [(1 R, 2S, 4R) -1, 7J-trimethylbicyclo [2.2.1] hept-2-yl] -3- (n-butyl) -4- (4-chlorophenyl) -4.5 -dihydro- (1 H) -pyrazol-1 -carboxamide (diastereomer A); N-endo - [(1 R, 2S, 4R) -1 JJ-trimethylbicyclo [2.2.1] hept-2-yl] -3- (n-butyl) -4- (4-chlorophenyl) -4.5- dihydro- (1 H) -pyrazol-1-carboxamide (diastereomer B); N- (1, 2,2,6, 6-pentamethylpiperidin-4-yl) -3- (n-butyl) -4- (2-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (4-methoxyphenyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (4-methoxyphenyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (phenethyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (2-phenyl-trans-cyclopropyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (1-naphthalen-1-yl-ethyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- [2- (trifluoromethyl) phenyl] -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-carboxamide; N-cycloheptyl-3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N-cyclooctyl-3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1-carboxamide; N- (1, 2,3, 4-tetrahydronaphthalen-1 -yl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- [2,2- (diphenyl) ethyl] -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; (3-pentyl-4-phenyl-4,5-dihydropyrazol-1 -yl) - [4- (2-pyrimidinyl) piperazin-1-yl] methanone; N- [2- (4-fluorophenyl) ethyl] -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; (3-pentyl-4-phenyl-4,5-dihydropyrazol-1-yl) - [azepan-1-yl] methanone; N- (quinolin-3-yl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- [1- (ethyl) propyl] -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (2,2,2-Trifluoroethyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (pyridin-3-methylmethyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1H) -pyrazol-1 -carboxamide; N- (2-Indanyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; (3-pentyl-4-phenyl-4,5-dihydropyrazol-1-yl) - (1, 2,3,4-tetrahydroisoquinolin-2-yl) methanone; N- (methyl), N- (naphthalen-1-ylmethyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (3,3-diphenypropyl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazol-1 -carboxamide; N- (naphth-1-yl) -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazolocarboxyiamide; N- [1- (ethyl) propyl] -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazolcarboxyiamide; N- [pyridin-3-ylmethyl] -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazolcarboxyiamide; N- [Exo-bicyclo [2.2.1] hept-2-yl] -3- (n-pentyl) -4-phenyl-4,5-dihydro- (1 H) -pyrazolocarboxyiamide; 1- (naphthalen-1-ylsulfonyl) -3- (n-butyl) -4- (2-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol; 1- (naphthalen-2-ylsulfonyl) -3- (n-butyl) -4- (2-fluorophenyl) -4,5-dihydro- (1 H) -pyrazol; N - [(1 R, 2S, 5R) -rel-6,6-dimethylbicyclo [3.1.1] heptan-2-methyl] -3- (n-pentyl) -4-phenyl-4,5-dihydro- ( 1 H) -pyrazol-1-sulfonamide. 9.- Compounds of the general formula (IV). wherein R and Ri have the same meanings given in claim 1 and R2 represents a phenyl group which may be substituted with 1-5 substituents Y2 which may be the same or different, selected from the alkoxy group; of C? -3, hydroxy, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl- (C? -2) -amino, mono- or dialkyl- (C? -2) -amido, alkyl- of (C? -3) -sulfonyl, dimethylsulfamido, C? -3-carbonyl alkoxy, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl, ortho-halogen, meta-halogen, ortho-C-? 3 -alkyl, meta-alkyl- of C? -3 and acetyl, or R2 represents a thienyl or pyridyl group, which groups can be substituted with one or two substituents Y, which group Y has the meaning given in claim 1, such compounds being useful in the synthesis of compounds of the general formula (I). 10. Compounds of the general formula (VIII) (VI ") wherein R and R2 have the same meanings given in claim 1 and Ri represents hydrogen, such compounds being useful in the synthesis of-the-compounds-of the formula general (I) wherein n = 1. 11. A compound of any of claims 1-8, or a pharmacologically acceptable salt, hydrate, solvate or complex thereof, for use as a medicament. , characterized in that it contains a compound of one of claims 1-8, or a pharmacologically acceptable salt, hydrate, solvate or complex thereof 13.- A pharmaceutical composition comprising, in addition to a pharmaceutically acceptable carrier and / or at least a pharmaceutically acceptable auxiliary substance, a pharmacologically active amount of at least one compound of one of claims 1-8, or a pharmacologically acceptable salt, hydrate, solvate or complex thereof, as an active ingredient 14. The pharmaceutical composition according to claim 13, further characterized in that it is for the prevention or treatment of multiple sclerosis, traumatic brain injury, pain, appetite disorders, epilepsy, Alzheimer's disease, Tourette's syndrome, ischemia. cerebral or gastrointestinal disorders. 15. The pharmaceutical composition according to claim 13, further characterized in that it additionally comprises: at least one additional therapeutic agent. 16. A method of preparing pharmaceutical compositions of claim 13, characterized in that a compound of one of claims 1-8 is taken to a suitable form for administration. 17. A pharmaceutical composition prepared by mixing a compound of claim 1 and a pharmaceutically acceptable carrier and / or at least one pharmaceutically acceptable auxiliary substance. 18. Use of a compound of claims 1-8 for the preparation of a pharmaceutical composition for the treatment of multiple sclerosis, traumatic brain injury, pain, appetite disorders, epilepsy, Alzheimer's disease, Tourette's syndrome, cerebral ischemia and gastrointestinal disorders.