MXPA06005209A - Bicyclic pyrazolone cytokine inhibitors - Google Patents

Abstract

The present invention relates to 6,7-dihydro-5H-pyrazolo[1,2a]pyrazol-1-ones which inhibit the extracellular release of inflammatory cytokines, said cytokines responsible for one or more human or higher mammalian disease states. The present invention further relates to compositions comprising said 6,7-dihydro-5H-pyrazolo[1,2a]pyrazol-1-ones and methods for preventing, abating, or otherwise controlling enzymes which are understood to be the active components responsible for the herein described disease states.

Description

INHIBITORS OF BIKYCLIC PIRAZOLONE CYTOKINES FIELD OF THE INVENTION The present invention relates to 6,7-dihydro-5H-pyrazolo [1,2a] pyrazol-1-ones, which inhibit the extracellular release of the inflammatory cytokines responsible for more than one disease in humans or higher mammals. The present invention further relates to compositions comprising said 6,7-dihydro-5H-pyrazolo [1, 2a] pyrazole-1-ones and methods for preventing, knocking down, or otherwise controlling the enzymes that are meant to be the components assets responsible for the disease states described herein.

BACKGROUND OF THE INVENTION Interleukin-1 (IL-1) and tumor necrosis factor-a (TNF-a) are among the important biological substances known collectively as "cytokines". It is considered that these molecules mediate the inflammatory response associated with the immunological recognition of infectious agents. It has been suggested that these proinflammatory cytokines are important mediators in many disease states or syndromes, including rheumatoid arthritis, osteoarthritis, intestinal inflammation, septic shock, cardiopulmonary insufficiency, acute respiratory disease, cachexia, and are therefore responsible for the evolution and manifestation of disorders in the human being. Therefore, there has long been a need for compounds and pharmaceutical compositions comprising compounds that can block, decrease, control, mitigate, or prevent the release from the cytokines of the cells that produce them.

BRIEF DESCRIPTION OF THE INVENTION The present invention satisfies the aforementioned needs in that it has surprisingly been discovered that certain 3- (2-substituted-pyrimidin-4-yl) -6,7-dihydro-5H-pyrazolo [1, 2a] pyrazole-1-yones and derivatives of these are effective to inhibit the release of inflammatory cytokines, including interleukin-1 (IL-1) and tumor necrosis factor (TNF, for its acronym in English) of the cells and thus avoid, decrease or otherwise control the enzymes that are considered to be the active components responsible for the disease states described herein. The present invention encompasses three main aspects, each of which has its own specific categories, aspects, iterations and iterative examples. The main aspects of the present invention include: i) New compositions of matter, which are effective to inhibit the release of inflammatory cytokines, including interleukin-1 (IL-1) and tumor necrosis factor (TNF) of the cells; ii) pharmaceutical compositions or compositions (matrices) comprising said compositions of matter; and iii) methods for controlling, decreasing, preventing or alleviating the symptoms of diseases or disorders, which are controllable by administering said compositions of matter to a human or mammal, whether said composition of matter is administered alone or in a composition or within a pharmaceutical composition (matrix). The first principal aspect of the present invention relates to compounds, including all enantiomeric and diastereomeric forms and pharmaceutically acceptable salts thereof; said compounds have the formula: where R is: a) -O [CH2] kR3; or b) -NR aR4; R3 is substituted or unsubstituted, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl or alkylenearyl, substituted or unsubstituted heteroaryl or alkyleneheteroaryl alkyl; the index k is from 0 to 5; Each R4a and R4b are independently: a) Hydrogen; or b) - [C (R5aR5b)] mR6; each R5a and R5b is independently hydrogen, -OR7, -N (R7) 2 > -CO2R7, -CON (R7) 2; linear, branched or cyclic C 4 alkyl, and mixtures thereof; R6 is hydrogen, -OR7, -N (R7) 2, -CO2R7, -CON (R7) 2; C4-substituted or unsubstituted alkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R7 is hydrogen, a water-soluble cation, C, -C4-alkyl or substituted or unsubstituted aryl; the index m is from 0 to 5; R1 is: a) Substituted or unsubstituted aryl; or b) substituted or unsubstituted heteroaryl; L is a linking group selected from: i) - [C (R12) 2] -; ") - [C (R12) 2] nNR12 [C (R12) 2] n-; and iii) - [C (R12) 2] nO [C (R12) 2] n-; R 12 is hydrogen, C 4 alkyl, and mixtures thereof; or two R12 units can be taken together to form a carbonyl unit; the index n is a unit from 0 to 2; each R2 unit is independently chosen from: a) Hydrogen; b) - (CH2) jO (CH2) iR8; c) - (CH2) jNR9aR9b; d) - (CH2) jCO2R10; e) - (CH ^ OCO.R10 f) - (CH2) jCON (R10) 2; g) - (CH2) JOCON (R10) 2; h) two R2 units can be joined together to form a carbonyl unit; i) and mixtures thereof; each R8, R9a, R9b, and R10 are independently selected from hydrogen, C4 alkyl, and mixtures thereof; R9a and R9b can be taken together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; two units of R10 can be taken together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; j is an index from 0 to 5; Z is O, S, NR11 or ÑOR11; R11 is hydrogen or CrC4 alkyl. The second main aspect of the present invention relates to pharmaceutical compositions comprising: a) An effective amount of one or more new compositions of matter according to the present invention, which are effective to inhibit the release of inflammatory cytokines from cells; and b) one or more pharmaceutically acceptable excipients. The third main aspect of the present invention relates to the methods of use. As described hereinafter, the compounds of the present invention are effective to inhibit the release of inflammatory cytokines from cells in human or higher mammals, and therefore may serve to diminish, resolve or otherwise be used to treat one or more diseases or disease states related to the extracellular presence of inflammatory cytokines, for example osteoarthritis, rheumatoid arthritis, diabetes, and infection with the human immunodeficiency virus (HIV). The three major aspects of the present invention encompass the discovery that the compounds of the present invention, in addition to inhibiting the release of inflammatory cytokines from cells, have improved cellular potency and pharmacokinetic properties. This advantage is further exploited by providing a method for controlling diseases that are affected by the control or inhibition of the inhibitors of inflammatory cytokines; said method comprises the step of administering to a human or mammal superior an effective amount of a composition comprising one or more inhibitors of inflammatory cytokines according to the present invention.

These and other objects, features and advantages will be apparent to those with ordinary experience in the industry upon reading the following detailed description and the appended claims. All percentages, ratios and proportions herein are by weight unless otherwise specified. All temperatures are given in degrees Celsius (° C) unless otherwise indicated. The relevant parts of all the cited documents are incorporated herein by reference; The citation of any document should not be construed as an admission that it constitutes a prior industry with respect to the present invention.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 6,7-dihydro-5 / - / - pyrazolo [1, 2a] pyrazoi-1-ones. which are suitable for mediating, controlling or otherwise inhibiting the extracellular release of certain cytokines, especially inflammatory cytokines; said cytokines play a role in the stimulation, cause or manifestation of a wide variety of diseases, disease states, or syndromes. The following chemical hierarchy is used throughout the specification to particularly point out and vindicate clearly the units comprising the present invention. The term "hydrocarbyl" represents any organic molecule, organic functional group, including salts comprising inorganic atoms, including carboxylate salts, quaternary ammonium salts or for any portion, unit, fraction, and the like, of an organic molecule. Included within the term "hydrocarbyl" are the terms "acyclic" and "cyclic" units that divide the hydrocarbyl units into cyclical and non-cyclic families. The family of the acyclic units include the linear and branched alkyl, alkenyl and alkynyl units and their corresponding connection units, including alkylene, alkenylene (-CH = CH-), all of which may also be substituted by suitable substitutions by hydrogen defined later. Included within the "cyclic hydrocarbyl" family are carbocyclic, heterocyclic, aryl, and heteroaryl units, and their corresponding connection units, including arylene (eg, 1,4-phenylene), all of which may be substituted by substitutions. suitable for hydrogen as defined below. Included within the definition of carbocyclic are spirocyclic rings, bicyclic rings and bicyclic bridge rings, as well as fused rings, including tetralin. Spirocyclic rings, bicyclic rings and fused rings that comprise a heteroatom are divided into categories expressed on the basis of the following rules. For purposes of the present invention, the fused ring units, as well as the spirocyclic rings, bicyclic rings, and the like, which comprise a single heteroatom, will be considered to belong to the cyclic family of the heteroatom-containing ring. For example 1,2,3,4-tetrahydroquinoline corresponding to the formula: it is considered, for the purposes of the present invention, a heterocyclic unit. 6,7-dihydro-5H- [1] pyridine corresponding to the formula: it is considered, for the purposes of the present invention, a heteroaryl unit. When a fused ring unit contains heteroatoms in a both saturated and aryl ring, the aryl ring will predominate and determine the type of the Category to which the ring is assigned. For example 1, 2,3,4-tetrahydro- [1,8] naphthyridine corresponding to the formula: it is considered, for the purposes of the present invention, a heteroaryl unit. The compounds of the present invention comprise linking units. The linking units can be taken together with a substituted or unsubstituted cyclic hydrocarbyl unit to form a single common chemical portion. For example the one experienced in the industry refers to a methylene bond and a phenyl unit, when taken together, as a benzyl unit having the formula: and which is known herein as an "alkylenearyl" unit. Likewise, a heteroaryl unit taken together with a methylene is defined in the present invention by the term "alkyleneheteroaryl" (for example a 2-picolyl unit) corresponding to the formula: The term "substituted" is used throughout the specification. The term "substituted" is defined herein as "a hydrocarbyl portion, whether acyclic or cyclic, which has one or more hydrogen atoms replaced by a substituent or several substituents as defined below. Hydrogen atoms are capable of replacing one hydrogen atom, two hydrogen atoms, or three hydrogen atoms in one hydrocarbyl portion at a time, and these substituents can replace two hydrogen atoms in two adjacent carbons to form said substituent, new portion or unit. " For example, a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like. A substitution of two hydrogen atoms includes carbonyl, oximino and the like. The substitution of two hydrogen atoms from two adjacent carbon atoms includes the epoxy group, and the like. The replacement of three hydrogens includes cyano, and the like. In the present specification, the term "substituted" is used to indicate that a hydrocarbyl entity, among other aromatic rings, alkyl chains, etc., may have one or more hydrogen atoms substituted by a substituent. When an entity is described as "substituted", several hydrogen atoms may be substituted. For example, 4-hydroxyphenyl is a "substituted aromatic carbocyclic ring" (N, N-dimethy-5-amino) octanyl is a unit of "substituted C8 alkyl, 3-guanidinopropyl is a unit of" substituted C3 alkyl "and -carboxypyridinium is a "substituted heteroaryl unit." Although hydrogen atoms can be substituted by any unit, the following are non-limiting examples of units that can substitute a hydrogen atom on a hydrocarbyl unit whether cyclic or acyclic: i) - _C (R12) 2] p (CH = CH) qR12, where p has a value from 0 to 12, q from 0 to 12, ü) -C (Z) R12, iii) -C (Z) 2R12; ) -C (Z) CH = CH2; v) -C (Z) N (R12) 2; vi) -C (Z) NR12N (R12) 2; vii) -CN; viii) -CNO; ix) -CF3, -CCI3. -CBr3; Z) -N (R12) 2; xi) -NR12CN; xii) -NR12C (Z) R12; xiii) -NR12C (Z) N (R12) 2; xiv) -NHN (R12) 2; xv) -NHOR12; xvi) -NCS; xvii) -NO2; xviii) -OR12; xix) -OCN; xx) -OCF3, -OCCI3, -OCBr3; xxi) -F, -Cl, -Br, -I and mixtures thereof; xxii) -SCN; xxiii) -SO3M; xxiv) -OSO3M; xxv) -SO2N (R12) 2; xxvi) -SO2R12; xxvii) -P (O) H2; xxviii) -PO2; xxix) -P (O) (OH) 2; xxx) and mixtures thereof; wherein R12 is hydrogen, substituted or unsubstituted C ^ C ^ linear, branched or cyclic alkyl, C6-C20 aryl, C7-C20 alkylenearyl and mixtures thereof; M is hydrogen or a salt-forming cation; Z is = O, = S, = NR11 and mixtures thereof. Salt-forming cations include sodium, lithium, potassium, calcium, magnesium, ammonium, and the like. The compounds of the present invention have the formula: wherein R, R1, and R2 are defined later herein. R is a substituent in the second position of the pyrimidin-4-yl portion of the general structure; said unit R is: a) An ether corresponding to the formula -O [CH2] kR3; or b) a primary or secondary amine unit corresponding to the formula -NR4aR4b; wherein R3 is substituted or unsubstituted CrC4 alkyl, substituted or unsubstituted cyclic hydrocarbyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl or alkylenearyl, heteroaryl or substituted or unsubstituted alkylene-heteroaryl; the index k is from 0 to 5. The following are the various aspects of the R units according to the present invention, wherein R is an ether corresponding to the formula -O [CH2] kR3. However, the formulator is not limited by the iterations and examples illustrated here. A) R units that include ethers having the formula -OR 3 (the index k is equal to 0) and R 3 is a substituted or unsubstituted aryl. i) An iteration of this aspect of the unit R comprises ethers having the formula -OR3 and R3 is substituted or unsubstituted aryl. This iteration includes the following non-restrictive example of R: phenoxy, 2-fluorophenoxy, 3-fluorophenoxy, 4-fluorophenoxy, 2,4-difluorophenoxy, 3-trifluoromethyl-phenoxy, 4-trifluoromethylphenoxy, 2,4-trifluoromethyl phenoxy, and Similary. ii) Another iteration of this aspect of R comprises ethers having the formula -OR3 and R3 is substituted or unsubstituted aryl. This iteration includes the following non-limiting examples: 2-methylphenoxy, 3-methylphenoxy, 4-methylphenoxy, 2,4-dimethylphenoxy, 2-cyanophenoxy, 3-cyanophenoxy, 4-cyanophenoxy, 4-ethylphenoxy, and the like. iii) Another iteration of this aspect of R comprises ethers having the formula -OR3 and R3 is a substituted or unsubstituted aryl. This iteration includes the following non-limiting examples: (2-methyloxy) phenoxy, (3-methoxy) phenoxy, (4-methoxy) phenoxy, 3 - [(N-acetyl) amino] phenoxy, 3-benzo [1, 3 ] dioxol-5-yl and the like.

B) R units that include ethers having the formula -OR3 (the index k equals 0) and R3 is substituted or unsubstituted heteroaryl. i) A first iteration of this aspect of R comprises ethers having the formula -OR3 and R3 is an unsubstituted heteroaryl. This iteration includes the following non-limiting examples: pyrimidin-2-yl, pyrimidin-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, and the like. ii) A second iteration of this aspect of R comprises ethers having the formula -OR3 and R3 is substituted heteroaryl. This iteration includes the following non-limiting examples: 2-aminopyrimidin-4-yl, and the like. C) R units that include ethers having the formula -OCH2R3 (the index k is equal to 1) and R3 is substituted or unsubstituted aryl. i) A first iteration of this aspect of R comprises ethers having the formula -OCH2R3 and R3 is substituted or unsubstituted heteroaryl. This iteration includes the following non-limiting examples: pyrimidin-2-yl, pyrimidin-4-yl, 2-aminopyrimidin-4-yl, 4-aminopyrimidin-6-yl, pyridin-2-yl, pyridin-3-yl , pyridin-4-yl, and the like. I) In a second iteration of this aspect of R, R is an ether having the formula -OCH2R3 and R3 is a substituted or unsubstituted alkylene-heteroaryl. This iteration includes the following non-limiting examples: pyridin-3-ylethyl, (2-methyl-2-pyridin-3-yl) ethyl, and the like. D) R units that include ethers having the formula -OR 3 (the index k is equal to 1) and R 3 is substituted or unsubstituted C 4 alkyl. i) A first iteration of this aspect of R is an ether having the formula -OR3 and R3 is linear, branched, or cyclic C4 unsubstituted alkyl. This iteration includes the following non-limiting examples: methyl, ethyl, isopropyl, (S) -l-methylpropyl, and the like. ii) A second iteration of this aspect of R is an ether having the formula -OR3 and R3 is a linear, branched or cyclic substituted C, -C4 alkyl. This iteration includes the following non-limiting examples: 2-methoxyethyl, (S) -1-methyl-3-methoxypropyl, and the like. The following are the various aspects of the R units according to the present invention, wherein R is an amine having the formula -NR4aR4b, R4a and R4b are each independently: a) Hydrogen; or b) - [C (R5aR5)] mR6; each unit R5a and R5b is independently hydrogen or straight, branched C4 alkyl, -OR7, -N (R7) 2, -CO2R7, -CON (R7) 2; cyclic alkyl and mixtures thereof; R6 is hydrogen, substituted or unsubstituted C4-C4 alkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; -OR7, -N (R7) 2, -CO2R7, -CON (R7) 2, R7 is hydrogen, a water-soluble cation, C4-alkyl or substituted or unsubstituted aryl; the index m is from 0 to 5. However, the formulator will not be limited by the iterations and examples illustrated here. A) R units that include chiral amino groups in which R4a is hydrogen, R5a is hydrogen and R5b is methyl; These units have the formula: H -N HA ": R ° H3C H and the indicated stereochemistry i) A first iteration of this aspect of R is an amine having a R6 group which is a substituted or unsubstituted phenyl This iteration includes the following examples non-limiting: (S) -1-methyl-1-phenylmethylamino, (S) -1-methyl-1- (4-fluorophenyl) methylamino, (S) -1-methyl-1- (4-methylphenyl) methylamino, ( S) -1-methyl-1 - (4-methoxyphenyl) methylamino, (S) -1-methyl-1 - (2-aminophenyl) methylamino, (S) -1-methyl-1 - (4-aminophenyl) methylamino, and the like ii) A second iteration of this aspect of R is an amine which contains a group R6 which is a substituted or unsubstituted heteroaryl This iteration includes the following non-limiting examples: (S) -1-methyl-1 - (pyridin-2-yl) methylamino, (S) -1-methyl-1- (pyridin-3-yl) methylamino, (S) -1-methyl-1 - (pyridin-4-yl) methylamino , (S) -1-methyl-1 - (furan-2-yl) methylamino, (S) -1-methyl-1- (3-benzo [1,3] dioxol-5-yl) methylamino, and the like 5 iii) A third iteration of this aspect of R is an amine having a group R6 which is a substituted or unsubstituted C, -C4 alkyl. This iteration includes the following non-limiting examples: (S) -l-methylpropylamino, (S) -1-methyl-2- (methoxy) ethylamino. B) R units that include chiral amino groups in which R 4a is hydrogen and R 5a and R 5 are C 1 -C 4 alkyl; These units have the formula: and the stereochemistry that is indicated when R5a, R5b and R6 are not the same. i) A first iteration of this aspect of R is an amine that has no chiral center, whose non-limiting examples include 1,1-dimethylethylamine, 1, 1- dimethylbenzylamine, and the like, ii) A second iteration of this aspect of R is an amine having a group R6 which is a substituted or unsubstituted CrC4 alkyl. This iteration includes the following non-limiting examples: (S) -1-methyl-2-hydroxy-2-methylpropylamine, (S) -1-methyl-2-hydroxy-2-methylbutylamine, and the like. C) R units including alkylenearylamines in which R 4a is hydrogen, R 5a and R 5b of R 4b are hydrogen and R 6 is substituted or unsubstituted aryl; said unit has the formula: wherein R12 is hydrogen or a "substituted unit" as defined above. i) A first iteration of this aspect includes the following non-limiting examples of R units: benzylamino, (2-aminophenyl) methylamino; (4- fluorophenyl) methylamino, (4-methoxyphenyl) methylamino; (4-propanesulfonylphenyl) methylamino;, and the like, i) A second iteration of this aspect includes the following non-limiting examples of R units: (2-methylphenyl) methylamino; (3-methylphenyl) -methylamino; (4-methylphenyl) methylamino;, and the like. D) R units that include amines in which R43 is hydrogen, R4b comprises R5a which is equal to hydrogen and R5b which is equal to -CO2R7 or -CON (R7) 2; the unit has the formula: i) A first iteration of this aspect of R is an amine having a group R6 which is a substituted or unsubstituted phenyl. This iteration includes the following non-limiting examples: wherein R11 is hydrogen or a "substitute" as defined above, ii) A second iteration of this aspect of R is an amine containing a group R6 which is a substituted or unsubstituted alkyl. This iteration includes the following non-limiting examples: The R1 units are selected from: a) Substituted or unsubstituted aryl; or b) substituted or unsubstituted heteroaryl. The first aspect of units R1 includes phenyl units substituted with halogen, which non-limiting examples include 4-fluorophenyl, 2,4-difluorophenyl, 4-chlorophenyl, and the like. Each unit R2 is independently selected from the group comprising: a) Hydrogen; b) - (CH2) iO (CH2) nR8; c) - (CH2) jNR9aR9b; d) - (CH ^ COaR10; e) - (CH2)] OCO2R10 f) - (CH ^ CONÍR10); g) - (CH2) JOCON (R10) 2; h) two R2 units can be joined together to form a carbonyl unit; i) and mixtures thereof; R8, R9a, R9b and R10 are independently hydrogen, C ^ -4 alkyl and mixtures thereof; R9a and R9b can join and form a carbocyclic or heterocyclic ring of 3 to 7 atoms; two R10 units can join and form a carbocyclic or heterocyclic ring having from 3 to 7 atoms; the index j has a value from 0 to 5, n is an index from 0 to 5. L is a link group selected from: 0 - [C (R12) 2] n-; ü) - [C (R12) 2] nNR12tC (R12) 2] n-; and iü) - [C (R12) 2] nO [C (R12) 2] -; R12 is hydrogen, CrC4 alkyl, and mixtures thereof; or two R12 units can be taken together to form a carbonyl unit; the index n is a unit from 0 to 2. The first aspect of the units L refers to compounds that include units L having the formula: - [C (R12) 2] nO [C (R12) 2] n- of whose first embodiment are the compounds having the formula: wherein each index n is equal to 0. The second aspect of the present invention that relates to units L comprises compounds having units L with the formula: - [C (R12) 2] p- the first embodiment of this aspect refers to compounds having the formula: The third aspect of the L units refers to compounds comprising units L having the formula: - [C (R12) 2] nNR12 [C (R12) 2] n- of which first embodiment are the compounds having the formula: where the linking unit is - [CH2] NH [C (O)] -. The fourth aspect of the L units refers to compounds that include L units that have the formula: - [C (R12) 2] - where two R12 units are taken together to form a carbonyl unit; said compounds have the formula: Z is O, S, NR11 or ÑOR11; R11 is hydrogen or C4 alkyl. The first aspect of the present invention in its relation to Z units comprises oxygen atoms that give rise to 2-R 1 -substituted-3- (2-R-substituted-pyrimidin-4-yl) -6,7-dihydro-5 - - pyrazole [1, 2a] pyrazol-1-ones; the second aspect comprises Z units containing sulfur atoms that give rise to 2-R 1 substituted -3- (2-R-substituted-pyrimidin-4-yl) -6,7-dihydro-5-pyrazole [1, 2a] pyrazole-1-thiones; and the third aspect of the present invention comprises Z units containing NR11 units that give rise to 2-R1substituted-3- (2-R-substituted-pyrimidin-4-yl) -6.7 -dihydro-5r7'-pyrrazol [1, 2a] pyrazol-1 -ideneamines and derivatives thereof. The analogs (compounds) of the present invention are arranged in several categories to assist the formulator in applying a rational synthetic strategy for the preparation of analogues which are expressly presented as examples herein. The provision in categories does not imply greater or lesser efficacy in any of the compositions of matter described in this document.

The compounds comprising Category I of the present invention are the 6,7-dihydro-5 / - / - pyrazolo [1, 2a] pyrazol-1-ones having the formula: The first aspect of which relates to the R units which are substituted alkylamines, non-limiting examples of which are described below in the present invention in Table I.

TABLE I The compounds comprising the first aspect of Category I of the present invention can be prepared by the procedure detailed below in Scheme I.

Scheme Reagents and conditions: (a) LDA, THF; -78 ° C at relative temperature, 1 h.

Reagents and conditions: (b) pyridine; reflux, 18 h. Reagents and conditions: (c) Oxone, H2O; relative temperature, 1 h.

Reagents and conditions: (d) toluene; reflux, 24 h.

EXAMPLE 1 (S) -3-r2- (2-methoxy-1-methyl-ethylamino) -pyrimidin-4-yn-2-o-tolyloxy-6,7-dihydro-5H-pyrazolof1.2-a1-pyrazol-1-one ( 4) The methoxy-methyl-amide starting material of 2-methylsulfanyl-pyrimidine-4-carboxylic acid can be prepared as follows. Preparation of 2-methylsulfanyl-pyrimidine-4-carboxylic acid methoxy-methyl-amide: to a slurry of 2-methylisulfanyl-pyrimidine-4-carboxylic acid (10.0 g, 59.2 mmol) in CH3CN (300 mL) is added in sequence : 1-hydroxybenzotriazole hydrate (9.59 g, 71.0 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (13.6 g, 71.0 mmol),? /, O-dimethylhydroxylamine hydrochloride (8.66 g, 88.8 mmol) , and triethylamine (Et3N) (24.9 mL, 178 mmol). The resulting slurry is stirred overnight at room temperature. After 16 hours, the reaction mixture is poured into a saturated aqueous solution of sodium bicarbonate (300 mL) and the layers are separated. The aqueous layer is extracted with ethyl acetate (3 x 250 mL). The organic layers are washed with saline, dried over sodium sulfate, filtered and concentrated in vacuo and the resulting residue is purified on silica (100% EtOAc) to yield 10.1 g (89% yield) of the desired product as a yellow oil 1 H NMR (300 MHz, CDCl 3) d 8.65 (d, J = 4.9 Hz, 1 H), 7.15 (br s, 1 H), 3.77 (br s, 3 H), 3.38 (br s, 3 H), 2.61 ( s, 3H); MS (ESI) m / z 214 (M + 1). Preparation of 3- (2-methylsulfanyl-pyrimidin-4-yl) -3-oxo-2-orio-tolyloxy-propionic acid methyl ester (1): to a cold solution (-78 ° C) of lithium diisopropylamide ( 31.5 mL of 1.8 M solution in THF, 56.6 mmol) in THF (180 mL) is added dropwise to a solution of ethyl- (2-methylphenoxy) acetate (10.0 g, 51.5 mmol) in THF (30 mL). After stirring for 1 h at -78 ° C, a solution of carboxylic acid of 2-methylsulfanyl-pyrimidine-4-methoxymethylamide (10.4 g, 48.9 mmol) in THF (30 mL) is added dropwise to the reaction mixture. After stirring for 20 min at -78 ° C, the reaction mixture is warmed to 0 ° C and stirred for a further 30 m. The reaction is quenched by pouring into saturated aqueous NH4CI. The aqueous phase is extracted with EtOAc (x2). The combined organic phases are dried (MgSO 4), filtered and concentrated in vacuo. The crude residue is purified by chromatography on silica gel (10% EtOAc / hexanes, followed by 30% EtOAc / hexanes) to yield 2.1 g (32%) of the desired product. 1 H NMR (300 MHz, CDCl 3) (observed 3: 1 mixture of zero tautomers: enol) tautomer keto: d 8.80 (d, J = 4.2 Hz, 1 H), 7.57 (d, J = 4.8 Hz, 1 H), 7.20-7.14 (m, 2H), 6.96 (t, J = 7.2 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1 H), 6.29 (s, 1 H), 4.30 (q, J = 7.2 Hz , 2H), 2.50 (s, 3H), 2.27 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H); ESI + MS: m / z (relative intensity) 347.1 (100, M + + H). Preparation of 3- (2-methylsulfanyl-pyrimidin-4-yl) -2-o-tolyloxy-6,7-dihydro-5H-pyrazolo [1,2-a] pyrazol-1-one (2): to a solution of pyrazolidine-bis-hydrochloride (1.7 g, 11.6 mmol) in pyridine (30 mL) was added 3- (2-methylsulfanyl-pyrimidin-4-yl) -3-oxo-2-orio-tolyloxy-propionic acid methyl ester, 1, (2.0 g. 5.78 mmol). The reaction mixture is heated at 110 ° C for 18 hours. The solvent is removed in vacuo and the resulting residue is purified by chromatography on silica gel (10% MeOH / EtOAc, followed by 20% MeOH / EtOAc) to yield 220 mg (10%) of the desired product as a yellow solid. H NMR (300 MHz, CDCl 3) d 8.56 (d, J = 5.4 Hz, 1 H), 7.57 (d, J = 5.4 Hz, 1 H), 7.23 (d, J = 7.5 Hz, 1 H), 7.10 ( dd, J = 7.5, 7.5 Hz, 1 H), 6.96 (dd, J = 7.5, 7.5 Hz, 1H), 6.82 (d, J = 7.5 Hz, 1H), 4.22 (t, J = 6.6 Hz, 2H) , 4.05 (t, J = 6.9 Hz, 2H), 2.72 (dddd, J = 6.9, 6.9, 6.9, 6.9 Hz, 2H), 2.62 (s, 3H), 2.48 (s, 3H); ESI + MS: m / z (relative intensity) 355.0 (100, M ++ H). Preparation of 3- (2-methanesulfonyl-pyrimidin-4-yl) -2-o-tolyloxy-6,7-dihydro-5H-pyrazolo [1,2-a] pyrazol-1-one (3): to a solution of 3 - (2-Methylsulfanyl-pyrimidin-4-yl) -2-o-tolyloxy-6,7-dihydro-5H-pyrazolo [1,2-a] pyrazol-1-one, 2, (0.20 g, 0.56 mmol) in THF: methanol (6 mL of a 1: 1 mixture) a solution of Oxone® (potassium peroxymonosulfate) (1.37 g, 2.24 mmol) in H2O (6 mL) is added dropwise. After stirring the reaction for 1 hour at room temperature, the solution is poured into saturated aqueous NaHCO3. The aqueous phase is extracted three times with EtOAc, the organic phases are combined, dried (MgSO4), filtered and concentrated in vacuo to yield the desired product, which is used without further purification. Preparation of (S) -3- [2- (2-methoxy-1-methyl-ethylamino) -pyrimidin-4-yl] -2-o-tolyloxy-6,7-dihydro-5H-pyrrazolo [1, 2- a] pyrazol-1-one (4): to a solution of 3- (2-methanesulfonyl-pyrimidin-4-yl) -2-o-tolyloxy-6,7-dihydro-5H-pyrazolo [1, 2-a] pyrazol-1-one, 3, (0.11 g, 0.28 mmol) in toluene (4 mL) is added (S) -1-methoxy-2-propylamine (0.10 g, 1.13 mmol). The reaction mixture is heated at 115 ° C for 24 hours. The solvent is removed in vacuo and the resulting residue is purified by preparative HPLC to yield 52 mg of the desired product as a yellow solid. 1 H NMR (300 MHz, CDCl 3) d 8.28 (d, J = 5.1 Hz, 1 H), 7.22 (d, J = 7.2 Hz, 1 H), 7.16 (d, J = 5.4 Hz, 1 H), 7.09 (t, J = 7.5 Hz, 1 H), 6.97 (t, J = 7.5 Hz, 1 H), 6.83 (d, J = 7.5 Hz, 1 H), 4.29-4.21 (m, 1H), 4.17 (t, J = 7.2 Hz, 2H), 4.01 (t, J = 7.2 Hz, 2H), 3.50 (dddd, J = 9.3, 9.3, 4.5, 4.5 Hz, 2H), 3.42 (s, 3H), 2.69 (dt, J = 7.2 Hz, 2H), 2.46 (s, 3H), 1.31 (d, J = 6.6 Hz, 3H); ESI + MS: m / z (relative intensity) 396.2 (90, M ++ H); calculated for C21H25N5O3: C, 63.78; H, 6.37; N, 17.71; determined as C, 63.63; H, 6.20; N, 17.05. The following are non-limiting examples of the compounds comprising the first aspect of Category I. (S) -3- [2- (2-hydroxy-1,2-dimethylpropylamino) -pyrimidin-4-yl] -2-o -thioyloxy-6,7-dihydro-5H-pyrazolo [1,2-a] pyrazol-1-one: 1 H NMR (300 MHz, d6-DMSO) d 8.32 (d, J = 5.1 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 7.08 (dd, J = 7.8, 7.8 Hz, 1 H), 6.94 (dd, J = 7.2, 7.2 Hz, 1H), 6.87-6.80 (m, 1H), 6.73 (d, J = 5.1 Hz, 1H), 4.40 (bd s, 1H), 4.15 (t, J = 6.3 Hz, 2H), 3.95 (bd s, 1H), 3.84 (t, J = 7.2 Hz, 2H), 3.40-3.35 ( m, 1H), 2.62-2.56 (m, 2H), 2.35 (s, 3H), 1.11 (s, 9H). HRMS calculated for C ^ H ^ N (M + H) + 410.2192; determined as 410.178. The second aspect of Category I refers to R units that are heterocycloamino or substituted or unsubstituted heteroarylamino, non-limiting examples of which are described later in Table II.

TABLE II The compounds comprising the second aspect of Category I of the present invention can be prepared by the process outlined above in Scheme I. Non-limiting examples of the compounds comprising the second aspect of Category I include: (S) -3 - [2- (Tetrahydro-pyran-4-ylammon) -pyrimidin-4-yl] -2-o-tolyloxy-6,7-dihydro-5H-pyrazolo [1,2-a] pyrazol-1-one: 1H NMR (300 MHz, CDCl 3) d 8.31 (d, J = 5.1 Hz, 1 H), 7.22 (d, J = 7.5 Hz, 1 H), 7.14 (d, J = 5.1 Hz, 1 H), 7.49 (t , J = 7.5 Hz, 2H), 7.30-7.22 (m, 4H), 7.09 (t, J = 6.6 Hz, 1 H), 6.99 (t, J = 7.2 Hz, 1 H), 6.81 (d, J = 5.1 Hz, 1 H), 3.95 (t, J = 7.2 Hz, 2H), 3.72 (t, J = 7.2 Hz, 2H), 2.57-2.47 (m, 4H). ESI + MS: m / z (relative intensity) 401.2 (100, M ++ H). Analysis calculated for C 22 H 25 N 5 O 3: C, 64.85; H, 6.18; N, 17.19, determined as: C, 64.27; H, 5.94; N, 16.73. The third aspect of Category I refers to R units which are substituted or unsubstituted arylamino or alkylenearylamino, non-limiting examples of which are described below in Table III.

PICTURE The compounds comprising the third aspect of Category I of the present invention can be prepared by the process outlined above in Scheme I. Non-limiting examples of the compounds comprising the third aspect of Category I include: (S) -3 - [2- (1-phenylethylamino) -pyrimidin-4-yl] -2-o-tolyloxy-6,7-dihydro-5H-pyrazolo [1,2-a] pyrazol-1-one: 1 H NMR (300 MHz, CDCl 3 ) d 8.31 (d, J = 5.1 Hz, 1 H), 7.40-7.22 (m, 5H), 7.20 (d, J = 7.5 Hz, 1 H), 7.12 (d, J = 5.1 Hz, 1 H), 7.07 (t, J = 6.9 Hz, 1 H), 6.95 (t, J = 7.5 Hz, 1 H), 6.80 (d, J = 7.8 Hz, 1 H), 5.50 (bd s, 1 H), 5.12- 5.09 (m, 1 H), 3.97-3.89 (m, 2H), 3.75-3.60 (m, 1 H), 2.44 (s, 3H), 2.60-2.40 (m, 2H), 1.45 (d, J = 6.6 Hz, 2H). HRMS calculated for C 25 H 26 N 5 O 2 (M + H) + 428.2087; determined as 428.2088. 3- [2- (2,6-Dichlorophenylamino) -pyrimidin-4-yl] -2-o-tolyloxy-6,7-dihydro-5H-pyrazolo [1,2-a] pyrazol-1-one: 1H NMR ( 300 MHz, CDCI3) d 8.43 (d, J = 5.1 Hz, 1H), 7.46 (d, J = 7.8 Hz, 2H), 7.36 (d, J = 5.7 Hz, 1H), 7.27-7.21 (m, 2H) , 7.12-7.06 (m, 2H), 6.94 (t, J = 7.5 Hz, 2H), 6.81 (d, J = 8.1 Hz, 1 H), 3.98 (t, J = 6.9 Hz, 2H), 3.84 (t , J = 6.9 Hz, 2H), 2.51 (dddd, J = 6.9, 6.9, 6.9, 6.9 Hz, 2H), 2.46 (s, 1 H). ESI + MS: m / z (relative intensity) 468.0 (100, M ++ H). The fourth aspect of Category I refers to R units that are unsubstituted or substituted aryloxy or alkylearyloxy, non-limiting examples of which are described later in Table IV.

TABLE IV The compounds comprising the fourth aspect of Category I of the present invention can be prepared by the process outlined above in Scheme I. Non-limiting examples of the compounds comprising the fourth aspect of Category I include: 3- (2- phenoxy-pyrimidin-4-yl) -2-o-tolyloxy-6,7-dihydro-5H-pyrazolo [1,2-a] pyrazol-1-one: 1 H NMR (300 MHz, CDCl 3) d 8.63 (d, J = 5.1 Hz, 1H), 7.62 (d, J = 5.4 Hz, 1 H), 7.49 (t, J = 7.5 Hz, 2H), 7.30-7.22 (m, 4H), 7.09 (t, J = 7.5 Hz, 1 H), 6.96 (t, J = 7.2 Hz, 1 H), 6.82 (d, J = 5.1 Hz, 1 H), 5.15 (bd s, NH), 4.13 (t, J = 6.9 Hz, 1 H) , 4.07-4.00 (m, 4H), 3.55 (t, J = 11.7 Hz, 2H), 2.69 (dddd, J = 6.9 Hz, 2H), 2.46 (s, 3H), 2.05 (d, J = 11.7 Hz, 1H), 1.66-1.55 (m, 4H). ESI + MS: m / z (relative intensity) 408.2 (100, M + + H). calculated for C23H20N4O3: C, 68.99; H, 5.03; N, 13.99, determined as: C, 69.02; H, 5.01; N, 13.81. The compounds comprising Category II of the present invention are the 6,7-dihydro-5 - / - pyrazolo [1, 2a] pyrazol-1-ones having the formula: whose first aspect refers to R units that are substituted or unsubstituted arylamino or alkylarylamino, non-limiting examples of which are described below in Table V.

TABLE V The compounds comprising the first aspect of Category II of the present invention can be prepared by the process detailed below in Scheme II.

Scheme II Reagents and conditions: (a) K2CO3, 1-crown-6, THF; relative temperature, 20 h. Reagents and conditions: (b) pyrazolidine, pyridine; heat, 2 days. Reagents and conditions: (c) Oxone, H2O; relative temperature, 1.5 h.

Reagents and conditions: (d) NMP; 90 ° C at relative temperature, 1.5 h.

EXAMPLE 2 (S) -2- (2-chlorobenzyl) -3- [2- (1-phenylethylamino) -pyrimidin-4-yl] -6,7-dihydro-5H-pyrazolo [1,2-a] pyrazole-1-one (9) Preparation of 2- (2-chlorobenzyl) -3- (2-methylsulfanyl-pyrimidin-4-yl) -3-oxo-propionic acid tert-butyl ester (6): to a solution of 3- (2-methylsulfanyl-pyrimidin-4-yl) -3-oxo-propionic acid, tert-butyl ester, 5, (1.6 g, 6.0 mmol) in THF (15 mL) is added 18-crown-6 (6.3 g, 23.9 mmol) and potassium carbonate (3.3 g, 23.9 mmol). Subsequently, 2-chlorobenzyl bromide (1.2 mL, 9.0 mmol) is added and the mixture is stirred for 20 hours at room temperature. The mixture is diluted with water and ethyl acetate, and the aqueous layer is washed over saline, dried over MgSO filtered, and the filtrate concentrated in vacuo. The crude residue is purified by chromatography on silica gel (20% EtOAc / hexanes) to yield 1.9 g (81%) of the desired product: 1 H NMR (300 MHz, CDCl 3) (keto form) d 8.76 (d, J = 5.1 Hz, 1 H), 7.52 (dd, J = 7.2, 1.8 Hz, 1H), 7.38 (m, 1H), 7.26-7.18 (m, 3H), 4.96 (t, J = 7.2 Hz, 1H), 3.52 ( dd, J = 7.2, 1.8 Hz, 2H), 2.60 (s, 3H), 1.49 (s, 9H); ESI + MS: m / z 393 M ++ H. Preparation of 2- (2-chlorobenzyl) -3- (2-methylsulfanyl-pyrimidin-4-yl) -6,7-dihydro-5H-pyrazolo [1,2-a] pyrazol-1-one (7): to a solution of 2- (2-Chlorobenzyl) -3- (2-methylsulfanyl-pyrimidin-4-yl) -3-oxo-propionic acid tert-butyl ester, 6 (2.0 g, 5.7 mmol)) in pyridine (40 mL) add pyrazolidine dihydrochloride (1.2 g, 8.1 mmol). After stirring the reaction for 10 min at room temperature, the mixture is stirred at 90 ° C for 2.5 hours and then at 60 ° C for 17 hours. The solution is concentrated in vacuo and the resulting crude product is purified on silica (EtOAc followed by 20% MeOH / EtOAc) to yield 460 mg (22%) of the desired product: 1 H NMR (300 MHz, CDCl 3) d 8.58 (d, J = 5.1 Hz, 1 H), 7.42-7.2 (m, 4H), 6.96 (d, J = 5.1 Hz, 1 H), 4.42-4.3 (m, 4H), 4.10 (s, 2H), 2.95-2.75 (m, 2H), 2.58 (s, 3H); ESI + MS: m / z (relative intensity) 373, (100, M ++ H). Preparation of 2- (2-chlorobenzyl) -3- (2-methanesulfonyl-pyrimidin-4-yl) -6,7-dihydro-5H-pyrazolo [1,2-a] pyrazol-1-one (8): to a cold solution (0 ° C) of 2- (2-chlorobenzyl) -3- (2-methylsulfanyl-pyrimidin-4-yl) -6,7-dihydro-5H-pyrazole [ 1, 2-a] pyrazol-1-one, 7, (460 mg, 1.23 mmol)) in THF / MeOH (20 mL of 1: 1 mixture) a solution of Oxone® (potassium peroxymonosulfate) is added dropwise. ) (3.0 g, 4.9 mmol) in H2O (15 mL). After stirring the reaction for 1.5 hours at room temperature, the solution is poured into saturated aqueous NaHCO3. The aqueous phase is extracted three times with EtOAc and the combined organic layers are washed with saline, dried (MgSO4), filtered and concentrated in vacuo to yield 316 mg of the desired product, which is used without further purification. Preparation of (S) -2- (2-chlorobenzyl) -3- [2- (1-phenylethylamino) -pyrimidin-4-yl] -6,7-dihydro-5H-pyrazolo [1,2-a] pyrazole-1- ona (9): to a solution of 2- (2-chlorobenzyl) -3- (2-methanesulfonyl-pyrimidin-4-yl) -6,7-dihydro-5H-pyrazolo [1,2-a] pyrazole-1 -one, 8, (0.10 g, 0.26 mmol) in NMP (2 mL) is added alpha-methylbenzylamine (0.10 mL, 0.78 mmol). After stirring for 1.5 hours at 90 ° C, the reaction mixture is diluted with methanol (to 5 mL) and purified by reverse liquid phase chromatography (CH3CN / water / 1% TFA) to achieve 27 mg (23% ) of the desired product: 1 H NMR (300 MHz, CDCl 3) d 8.27 (d, J = 5.1 Hz, 1 H), 7.38-7.12 (m, 9 H), 6.52 (d, J = 5.1 Hz, 1 H), 5.06 (q, br, 1 H), 4.07-3.95 (m, 4H), 4.02 (s, 2H), 2.58-2.45 (m, 2H), 1.58 (d, J = 7.0 Hz, 3H); ESI "MS: m / z (relative intensity) 446.0 (100, M + -H) The following are non-limiting examples of the compounds comprising the first aspect of Category II. (S ^^ - methylbenzyl -Sp-l- phenylethylamino-pyrimidine ^ -ip-ß ^ -dihydro-5H-pyrazolo [1,2-a] pyrazol-1-one: 1 H NMR (300 MHz, CDCl 3) d 8.00 (d, J = 5.1 Hz, 1 H), 7.28-6.90 (m, 8H), 6.78 (d, J = 7.2 Hz, 1 H), 6.45 (d, J = 5.1 Hz, 1 H), 4.94 (q, br, 1H), 4.07-3.95 (m, 4H), 4.02 (s, 2H), 2.58-2.45 (m, 2H), 2.26 (s, 3H), 1.56 (d, J = 7.2 Hz, 3H), ESI + MS: m / z (relative intensity) 426.0 ( 100, M ++ H).

(S) -2- (4-fluorobenzyl) -3- [2- (1-phenylethylamino) -pyrimidin-4-yl] -6,7-dihydro-5H-pyrazolo [1,2-a] pyrazole-1- ona: 1 H NMR (300 MHz, CDCl 3) d 8.16 (d J = 5.1 Hz, 1 H), 7.40-7.20 (m, 5 H), 7.18-7.02 (m, 2 H), 6.84 (dd, J = 7.2, 1.8 Hz, 2H), 6.68 (s, J = 5.1 Hz, 1H), 4.96 (q, br, 1 H), 4.18-4.04 (m, 4H), 2.58-2.45 (m, 2H), 1.58 (d, J = 7.2 Hz, 3H); ESI "MS: m / z (relative intensity) 430.0 (100, M ++ H) 2- (2-chlorobenzyl) -3- [2- (2,6-difluorophenylamino) -pyrimidin-4-yl] -6 , 7-dihydro-5H-pyrazolo [1,2-a] pyrazol-1-one: 1 H NMR (300 MHz, CDCl 3) d 8.42 (d, J = 5.1 Hz, 1 H), 7.39-7.14 (m, 7H ), 6.72 (d, J = 5.1 Hz, 1 H), 4.16 (t, J = 6.9 Hz, 2H), 4.07 (t, J = 6.9 Hz, 2H), 4.03 (s, 2H), 2.67 (dddd, J = 6.9, 6.9, 6.9, 6.9 Hz, 2H); ESI "MS: m / z (relative intensity) 453.8 (100, M + -H). 2- (2-Chlorobenzyl) -3- [2- (2-methoxy-1-methyl-ethylamino) -pyrimidin-4-yl] -6,7-dihydro-5H-pyrazolo [1,2-a] pyrazole-1- ona: 1 H NMR (300 MHz, CDCl 3) d < XF020 > 8.14 (d, J = 5.1 Hz, 1 H), 7.38 (d, J = 5.4 Hz, 1H), 7.18-7.10 (m, 3H), 6.61 (d, J = 5.4 Hz, 1 H), 4.40-4.23 (m, 5H), 4.07 (s, 2H), 3.45 (d, J = 5.4 Hz, 2H), 3.38 (s, 3H), 2.82 (dddd, J = 6.9, 6.9, 6.9, 6.9 Hz, 2H); ESI "MS: m / z (relative intensity) 413.9 (100, M ++ H) The second aspect of Category II refers to R units that are substituted or unsubstituted alkylamines, non-limiting examples of which more are described go ahead in Table VI.

TABLE VI The compounds comprising the second aspect of Category II of the present invention can be prepared by the process detailed below in Scheme II. Non-limiting examples of the compounds comprising the second aspect of Category II include: (S) -2- (2-chlorobenzyl) -3- [2- (2-hydroxy-1,2-dimethylpropylamino) -pyrimidin-4-yl] -6.7-dihydro-5H-pyrazolo [1,2-a] pyrazol-1-one: 1 H NMR (300 MHz, CDCl 3) d 8.23 (d, J = 5.1 Hz, 1 H), 7.39-7.34 (m, 1H ), 7.26-7.13 (m, 3H), 8.58 (d, J = 5.1 Hz, 1H), 4.15-4.10 (m, 7H), 2.8-2.75 (m, 2H), 1.26 (d, J = 9.1 Hz, 6H), 1.20 (d, J = 6.8 Hz, 3H); ESI 'MS: m / z (relative intensity) 428.0 (100, M + -H). (S) -3- [2- (2-Hydroxy-1,2-dimethylpropylamino) -pyrimidin-4-yl] -2- (2-methyl-benzyl) -6,7-dihydro-5H-pyrazolo [1,2- a] pyrazol-1-one: 1H NMR (300 MHz, CDCI3) d 7.98 (d, J = 5.1 Hz, 1 H), 7.29-6.98 (m, 3H), 6.85 (d, J = 5.1 Hz, 1 H), 6.52 (d, J = 5.1 Hz , 1 H), 4.30-4.10 (m, 4H), 3.99 (q, J = 7.2.Hz, 1 H), 2.88-2.72 (m, 2H), 2.26 (s, 3H), 1.26-1.15 (m, 9H); ESI "MS: m / z (rel intensity) 408.0 (100, M + -H). (S) -2- (4-fluorobenzyl) -3- [2- (2-hydroxy-1,2-dimethylpropylamino) -pyrimidine -4-yl] -6,7-dihydro-5H-pyrazolo [1,2-a] pyrazol-1-one: 1 H NMR (300 MHz, CDCl 3) d 8.15 (d, J = 5.1 Hz, 1H), 7.12 -7.05 (m, 2H), 6.88 (dd, J = 7.2, 1.8 Hz, 2H), 6.72 (d, J = 5.1 Hz, 1 H), 4.28-4.06 (m, 4H), 3.88 (s, 2H) , 2.82-2.70 (m, 2H), 1.26-1.15 (m, 9H), ESI + MS: m / z (relative intensity) 412.1 (100, M ++ H) The third aspect of Category II refers to units R which are substituted or unsubstituted heterocycloamino or heteroarylamino ", non-limiting examples of which are described below in Table VII.

TABLE VII The following is an example of the preparation of a compound comprising the third aspect of Category II. Preparation of 2- (2-chlorobenzyl) -3- [2- (tetrahydro-pyran-4-ylamino) -pyrimidin-4-yl] -6,7-dihydro-5H-pyrazolo [1,2-a] pyrazole- 1-one: to a solution of 2- (2-chlorobenzyl) -3- (2-methanesulfonyl-pyrimidin-4-yl) -6,7-dihydro-5H-pyrazolo [1,2-a] pyrazole- 1-one, 8, (0.10, 0.26 mmol) in NMP (2 mL) is added amino tetrahydropyran (0.09 mL, 0.78 mmol). After stirring for 1.5 hours at 90 ° C, the reaction mixture is diluted with methanol (to 5 mL) and purified by reverse liquid phase chromatography (CH3CN / water / 1% TFA) to achieve 44 mg (40% ) of the desired product. 1 H NMR (300 MHz, CDCl 3) d 8.30 (d, J = 5.1 Hz, 1 H), 7.39-7.12 (m, 4 H), 6.57 (d, J = 5.1 Hz, 1 H), 4.10-3.94 (m, 9H), 3.60-3.48 (m, 2H), 2.80-2.68 (m, 2H), 2.95-1.95 (m, 2H), 1.65-1.50 (m, 2H); ESI "MS: m / z (relative intensity) 426.0 (100, M + -H) The fourth aspect of Category II refers to R units that are unsubstituted or substituted aryloxy or alkylenylaryloxy, non-limiting examples of which are described later in Table VIII.

TABLE VIII The following is a non-limiting example of the preparation of a compound comprising the fourth aspect of Category II; said preparation uses intermediate 8 of Scheme II described above.

Preparation of 2- (2-chlorobenzyl) -3- (2-phenoxy-pyrimidin-4-yl) -β-dihydro-SH-pyrazoloyl-α-pirazyl-1-one: to a solution of phenol (0.18 g, 1.00 mmol ) in THF (4 mL) is added sodium hydride (0.10 g of a 60% dispersion in mineral oil, 1.60 mmol). After stirring for 5 minutes at room temperature, a solution of 2- (2-chlorobenzyl) -3- (2-methanesulfonyl-pyrimidin-4-yl) -6,7-dihydro-5H-pyrazolo [1,2-a] ] pyrazol-1 -one, 8, (0.21 g, 0.50 mmol) in THF (5 mL) is added to the reaction mixture. After stirring 1.5 hours at room temperature, the mixture is diluted with saturated aqueous NaHCO3. The aqueous phase is extracted three times with CHCl3 and the combined organic phases are washed with saturated aqueous NaHCO3, dried (MgSO4), filtered and concentrated in vacuo. The crude residue is purified on silica (5% MeOH / CHCl 3) to yield 100 mg of the desired product as a yellow solid: 1 H NMR (300 MHz, CDCl 3) d 8.63 (d, J = 5.4 Hz, 1 H), 7.47 ( t, J = 7.8 Hz, 2H), 7.40 (d, J = 5.4 Hz, 1 H), 7.29-7.10 (m, 7H), 4.16 (t, J = 6.9 Hz, 2H), 4.07 (s, 2H) , 3.91 (t, J = 6.9 Hz, 2H), 2.61 (dddd, J = 6.9, 6.9, 6.9, 6.9 Hz, 2H); ESI + MS: m / z (relative intensity) 418.9 (100, M + + H). The compounds comprising Category III of the present invention are 6,7-dihydro-5 - / - pyrazolo [1, 2a] pyrazol-1-ones having the formula: whose first aspect refers to R units that were described above, the R1 units that are substituted and unsubstituted aryl, and the L units are - [C (R12) 2] nNR12 [C (R12) 2] n- non-limiting examples of which are described later in Table IX.

TABLE IX The compounds comprising the first aspect of Category III of the present invention can be prepared by the process detailed below in Scheme III. Scheme III Reagents and conditions: (a) NaOH, H2O, CH2Cl2; relative temperature, 3 h. 11 Reagents and conditions: (b) H2, Pd / C, MeOH; relative temperature, 16 h. 12 Reagents and conditions: (c) EDCI, HOBt, DMF; relative temperature, 22 h.

Reagents and conditions: (d) DBU, DMF; relative temperature, 2 h.

Reagents and conditions: (e) NaOH, THF / H2O; relative temperature, 1.5 h. 14 15 Reagents and conditions: (f) EDCI, HOBt, DMF; relative temperature, 6 days. 16 Reagents and conditions: (g) Oxone, THF / MeOH; relative temperature, 1.5 h.

Reagents and conditions: (h) NaH, phenol, THF; relative temperature, 1.5 h.

EXAMPLE 3 2-Chloro-benzylamide of 1-oxo-3- (2-phenoxy-pyrimidin-4-id-6,7-dihydro-1H, 5H-pyrazolori, 2-alpyrazole-2-carboxylic acid (17) Preparation of benzyl ester of 2- (2'-ethoxycarbonylacetyl) -pyrazolidin-1-carboxylic acid (10): To a solution of sodium hydroxide (93.0 mL of a solution of 1 N, 93.0 mmol) is added CH2Cl2 (280 mL) followed by benzyl ester of the pyrazolidin-1-carboxylic acid (15.0 g, 61.8 mmol) and then ethyl-3-chloro-3-oxopropionate (11.1 mL, 86.5 mmol) After stirring the biphasic mixture for 3 hours at room temperature, the mixture is quenched by pouring in saturated aqueous NH4CI The organic phase is dried (MgSO4), filtered and concentrated in vacuo The crude residue is purified on silica (10% EtOAc / hexanes) to yield 15.5 g (78% yield) of the desired product. 1 H NMR (300 MHz, CDCl 3) d 7.38 (s, 5 H), 5.23 (dd, J = 11.8, 8.4 Hz, 2 H), 4.19-4.07 (m, 4 H), 3.65 (d, J = 15.9 Hz, 1 H ), 3.31 (d, J = 15.9 Hz, 1 H), 3.20-3.15 (m, 2H), 2.20 -2.04 (m, 2H), 1.26 (t, J = 7.2 Hz, 3H); ESI + MS: m / z (relative intensity) 321.0 (100, M + + H). Preparation of 3-oxo-3-pyrazolidin-1-yl-propionic acid ethyl ester (11): a solution of benzyl ester of the acid a solution of 2- (2-ethoxycarbonylacetyl) -pyrazolidin-1-carboxylic acid, 10, (15.5 g, 48.0 mmol) in MeOH (300 mL) is washed with nitrogen gas. Palladium (1.5 g) is added, 10% by weight on activated carbon) to the reaction mixture. A hydrogen balloon is fixed to the flask and the solution is stirred at room temperature for 16 hours. The mixture is filtered through celite and washed thoroughly with MeOH. The filtrate is concentrated in vacuo to yield 8.8 g of the crude product which is used without further purification. Preparation of 3- [2- (2-methylsu-phenylamino-pyrimidine-4-carbonyl) -pyrazolidin-1-yl] -3-oxo-propionic acid ethyl ester (12): to a solution of 3-oxo-ethyl ester 3-pyrazolidin-1-yl-propionic, 11, (8.8 g, 47.7 mmol) in DMF (165 mL) was added 2-methylsulfanyl-pyrimidine-4-carboxylic acid (8.5 g, 50.1 mmol), followed by 1-hydroxybenzotriazole (12.9 g, 95.5 mmol) and then 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (11.0 g, 57.3 mmol). The reaction mixture is stirred at room temperature for 22 hours, then poured into saturated aqueous NaHCO3. The aqueous phase is extracted three times with EtOAc and the combined organic phases are dried (MgSO4), filtered and concentrated in vacuo to yield 10.5 g of the desired compound which is used without further purification.

Preparation of 3- (2-Methylsuifanyl-pyrimidin-4-yl) -1-oxo-6,7-dihydro-1,5W-pyrazolo [1,2-a] pyrazole-2-carboxylic acid ethyl ester (13) : to a solution of 3- [2- (2-methylsulfanyl-pyrimidin-4-carbonyl) -pyrazolidin-1-yl] -3-oxo-propionic acid ethyl ester, 12, (9.6 g, 28.4 mmol) in DMF (280 mL) was added 1,8-diazabicyclo [5.4.0] -undec-7-ene (12.7 mL, 85.2 mmol). The reaction solution is stirred for 2 hours at room temperature and then diluted with H2O. The aqueous phase is extracted three times with CHCl3. The combined organic phases are washed with saturated aqueous NH4CI (x3), dried (MgSO4), filtered and concentrated in vacuo. The residue is purified on silica (5% MeOH / CHCl3) to yield 3.1 g of the desired product. ? NMR (300 MHz, CDCl 3) d 8.67 (d, J = 5.1 Hz, 1 H), 7.61 (d, J = . 1 Hz, 1 H), 4.33 (q, J = 7.2 Hz, 2 H), 4.31 (t, J = 7.2 Hz, 2 H), 4.09 (t, J = 7. 2 Hz, 2H), 2.74 (dddd, 7.2, 7.2, 7.2, 7.2 Hz, 2H), 2.61 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H); ESI + MS: m / z (relative intensity) 321.1 (100, M ++ H). Preparation of 3- (2-methylsulfanyl-pyrimidin-4-yl) -1-oxo-6,7-dihydro-1H, 5H-pyrazolo [1,2-a] pyrazole-2-carboxylic acid (14): a 3- (2-Methylsulfanyl-pyrimidin-4-yl) -1-oxo-6,7-dihydro-1 H, 5H-pyrazolo [1,2-a] pyrazole-2-carboxylic acid ethyl ester solution, 13 , (2.7 g, 8.4 mmol) in THF (85 mL) is added aqueous NaOH (42 mL of 1N solution, 42.0 mmol). The solution is stirred for 18 hours at room temperature and then diluted with saturated aqueous NaHCO3 and the aqueous phase is extracted twice with CHCl3. The aqueous phase is then acidified to pH 1 with 1 N of HCl and extracted twice with CHCl3. The combined organic layers are dried (MgSO4), filtered and concentrated in vacuo to yield 2.3 g of the desired product, which is used without further purification. Preparation of 3- (2-methylsulfanyl-pyrimidin-1-yl-1-oxo-T-dihydro-IH.SW-pyrazoloyl-α-pyrazole-2-carboxylic acid 2-chlorobenzylamide (15): to a solution of 3-chlorobenzylamide. (2-methylsulfanyl-pyrimidin-4-yl) -1-oxo-6,7-dihydro-1A7, 5 / - / - pyrazolo [1,2- a] pyrazole-2-carboxylic acid, 14, (0.23 g, 0.78 mmol) and 2-chlorobenzylamine (0.10 mL, 0.78 mmol) in DMF (3 mL) is added 1-hydroxybenzotriazole (0.21 g, 1.57 mmol) and then 1- (3-dimethylamino-propyl) -3- hydrochloride. Ethylcarbodiimide (0.18 g, 0.94 mmol) The reaction solution is stirred at room temperature for 6 days and then poured into saturated aqueous NaHCO3 The aqueous phase is extracted three times with EtOAc and the combined organic phases are washed with saturated aqueous NH4CI, and H2O, dried (MgSO4), filtered and concentrated in vacuo to yield the desired product, which is used without further purification: 1 H NMR (300 MHz, CDCl 3) d 9.49 (bd s, NH ), 8.69 (d, J = 5.1 Hz, 1 H), 8.16 (d, J = 5.1 Hz, 1 H), 7.44-7.37 (m, 2H), 7.25-7.19 (m, 2H), 4.70 (d, J = 5.4 Hz, 2H), 4.41 (t, J = 7.2 Hz, 2H), 4.14 (t, J = 7.2 Hz, 2H), 2.78 (dd, J = 7.5, 7.5, 7.5, 7.5 Hz, 2H), 2.06 (s, 3H); ESI + MS: m / z (relative intensity) 415.9 (100, M + + H). Preparation of 3- (2-methanesulfonyl-pyrimidin-4-yl) -1-oxo-6,7-dihydro-1 H, 5H-pyrrazolo [1,2-a] pyrazole-2-chlorobenzylamide carboxylic acid (16): to a solution of 3- (2-methylsufanyl-pyrimidin-4-yl) -1-oxo-6,7-dihydro-1 -, 5H-pyrrazolo [1,2-a] 2-chlorobenzylamide. ] pyrazole-2-carboxylic acid, 15, (0.20 g, 0.48 mmol) in THF / MeOH (8 mL of a 1: 1 mixture) was added dropwise to a solution of Oxone® (potassium peroxymonosulfate) (in H2O ( 8 mL) After stirring the reaction for 1.5 hours at room temperature, the solution was poured into saturated aqueous NaHCO3 The aqueous phase was extracted with CHCl3 (x3) The combined organic phases were dried (MgSO4), filtered and filtered. Concentrate in vacuo to produce the desired product, which is used without further purification Preparation of 2-chlorobenzylamide of 1-oxo-3- (2-phenoxy-pyrimidin-4-yl) -6,7-dihydro- 1W, 5W-pyrazolo [1,2-a] pyrazole-2-carboxylic acid (17): to a solution of phenol (0.09 g, 1.00 mmol) in THF (2 mL) Sodium hydride (0.05 g of a 60% dispersion in mineral oil is added0.80 mmol). After stirring for 5 minutes at room temperature to a solution of 2-chlorobenzylamide of 3- (2-methanesulfonyl-pyrimidin-4-yl) -1-oxo-6,7-dihydro-1H, 5H- pyrazolo [1,2-a] p-aceol-2-carboxylic acid, 16, (0.18 g, 0.40 mmol) in THF (3 mL) is added to the reaction mixture. After stirring for 1.5 hours at room temperature, the mixture is diluted with saturated aqueous NaHCO3. The aqueous phase is extracted with CHCl3 (x3). The combined organic phases are washed with saturated aqueous NaHCO3, dried (MgSO4), filtered and concentrated in vacuo. The crude residue is purified on silica (5% MeOH / CHCl3) to yield 110 mg of the desired product as a white solid: 1 H NMR (300 MHz, CDCl 3) d 9.59 (bd s, NH), 8.75 (d, J = 5.1 Hz, 1H), 8.49 (d, J = 7.2 Hz, 1 H), 7.49-7.20 (m, 9H), 4.72 (d, J = 5.4 Hz, 2H), 4.04 (t, J = 7.2 Hz, 2H) , 3.98 (t, J = 7.2 Hz, 2H), 2.57 (dddd, J = 6.9, 6.9, 6.9, 6.9 Hz, 2H); ESI + MS: m / z (relative intensity) 462.1 (100, M ++ H); HRMS m / z calculated for C24H20CIN5O3 (M + H +) 462.1333, determined as 462.1320. The following are non-limiting examples of compounds according to the first aspect of Category III. 1-Oxo-3- (2-phenoxy-pyrimidin-4-yl) -6,7-dihydro-1H, 5H-pyrazoo [1,2- a] pyrazole-2-carboxylic acid (2-chlorophenyl) -amide: 1 H NMR (300 MHz, CDCl 3) d 11.53 (s, NH), 8.79 (d, J = 5.1 Hz, 1 H), 8.50 (dd, J = 8.1, 1.5 Hz, 1 H), 8.41 (d, J = 5.1 Hz , 1H), 7.48 (t, J = 8.1 Hz, 2H), 7.41 (dd, J = 8.1, 1.5 Hz, 1H), 7.34-7.21 (m, 5H), 7.03 (ddd, J = 7.5, 7.5, 1.8 Hz, 1H), 6.94-6.85 (m, 1 H), 4.09 (t, J = 7.2 Hz, 2H), 4.01 (t, J = 7.2 Hz, 2H), 2.62 (dddd, J = 7.2, 7.2, 7.2 , 7.2 Hz, 2H); ESI + MS: m / z (relative intensity) 447.9./ (100, M ++ H); HRMS m / z calculated for C 24 H 20 CIN 5 O 3 (M + H +) 462.1333, determined as 462.1320. The compounds comprising Category IV of the present invention are 6,7-dihydro-5H-pyrazolo [1,2a] pyrazole-1-ones having the formula: whose first aspect refers to the R units that were described above, the R1 units that are substituted or unsubstituted aryl, and the L units are- [C (R12) 2] - where two R12 units are taken together to form a carbonyl unit, non-limiting examples of which are described later in Table X.

TABLE X The compounds comprising the first aspect of Category IV of the present invention can be prepared by the process detailed below in Scheme IV.

Scheme IV 18 Reagents and conditions: (a) n-butyllithium, DIPA, THF; -78 ° C, 30 min. 18 19 Reagents and conditions: (b) Dess-Martin periodinane, H2O; relative temperature, 1 h. 19 20 Reagents and conditions: (c) pyrazolidine, TEA; reflux, 4 h. 21 Reagents and conditions: (d) 12, CCL4 / pyridine; 0 ° C, 30 min. 21 22 Reagents and conditions: (e) isopropylmagnesium chloride, 2-chlorobenzaldehyde, THF; -40 ° C to 0 ° C, 1 h. 22 23 Reagents and conditions: (f) MnO2, CH2CI2; relative temperature, 18 h. 23 24 Reagents and conditions: (d) Oxone THF / MeOH; relative temperature, 1.5 h. 24 25 Reagents and conditions: (h) phenol, NaH, THF; relative temperature, 1.5 h.

EXAMPLE 4 2- (2-chlorobenzoyl) -3- (2-phenoxy-pyrimidin-4-yl) -6,7-dihydro-5H-pyrrazoloyl, 2- alpyrazol-1-one (25) The following is a procedure for the preparation of 2-methylsulfanyl-pyrimidin-4-carbaldehyde adapted from the procedure of H. Bredereck et al., Chem. Ber., 97: 3407-3417 (1964), included in the present description as a reference.

To a 3-neck flask of 12 I under an inert atmosphere are added N, N-dimethylformamide dimethylacetal (801 g) and pyruvaldehyde dimethylacetal (779 g). The mixture is heated to reflux for 18 hours; during this time the temperature drops from about 109 ° C to about 80 ° C. The solution is cooled and methanol (4 L) is added to dissolve the crude residue. The solution is then cooled to 20 ° C and thiourea (892 g, 11.7 mol) is added.

After the mixture is kept under stirring for about 15 minutes, sodium methoxide (741 g, 13. 7 moles) in 4 equal portions for more than 1 hour, while the temperature of the solution is maintained in the range of 18-28 CC. The mixture is stirred for 5 hours at room temperature, cooled to 20 ° C, then methyl iodide (2 k) is added for 1.25 hours while maintaining the reaction temperature in the range of 17-29 ° C. Stirring is maintained for 18 hours at room temperature. Methanol and unreacted methyl iodide are removed by heating the solution at 35 ° C to 5 KPa (40 torr) and obtaining approximately 4.46 k of a dark colored residue that is distributed between 14 L of water and 5 L of water. ethyl acetate. The aqueous fraction is extracted a second time with ethyl acetate; the organic layers are combined. and concentrating in vacuo to obtain 685 g of an oil which is purified with silica and 522 g of 4-dimethoxymethyl-2-methylsulfanyl-pyrimidine are produced. The dimethyl acetal thus obtained is hydrolysed to obtain the free aldehyde by heating it at 60 ° C for 3 hours in 1 M HCl. The continuation of the process for neutralization using ethyl acetate to extract the product, produces 347 g of the crude product which is purified on silica to produce 401 g of 2-methylsulfanyl-pyrimidine-4-carbaldehyde. Preparation of tert-butyl ester of 3-hydroxy-3- (2-methylsulfanyl-pyrimidin-4-yl) -propionic acid (18): to a cold (0 ° C) solution of diisopropylamine (5.7 mL, 40.5 mmol) in THF (130 mL) is added dropwise n-butyl lithium (16.2 mL of a 2.5 M solution in hexanes, 40.5 mmol). The mixture is stirred for 45 minutes at 0 ° C, then the solution is cooled to -78 ° C. Tert-butyl acetate (5.5 mL, 40.5 mmol) is added dropwise to the reaction mixture. After stirring for 40 minutes at -78 ° C, a solution of 2-methylsulfanyl-pyrimidine-4-carbaldehyde (5.0 mg, 32.4 mmol) is added dropwise. After 30 minutes at -78 ° C, the solution is poured into saturated aqueous NH4CI. The aqueous phase is extracted with EtOAc. The organic phase is dried (MgSO 4), filtered and concentrated in vacuo. The crude residue is purified on silica (5% EtOAc / hexanes, followed by 20% EtOAc / hexanes) to yield 7.2 g (82% yield) of the desired product. 1 H NMR (300 MHz, CDCl 3) d 8.52 (d, J = 5.1 Hz, 1 H), 7.22 (d, J = 5.1 Hz, 1 H), 5.00 (dd, J = 8.4, 3.6 Hz, 1 H), 2.93 (dd, J = 16.5, 3.6 Hz, 1 H), 2.70 (dd, J = 16.5, 7.8 Hz, 1 H), 2.58 (s, 3H), 1.46 (s, 9H); ESI + MS: m / z (relative intensity) 271.1 (85, M ++ H). Preparation of 3- (2-methylsulfanyl-pyrimidin-4-yl) -3-oxo-propionic acid tert-butyl ester (19): to a solution of tert-butyl ester of 3-hydroxy-3- (2) acid -methylsulfanyl-pyrimidin-4-yl) -propionic, 18, (5.6 g, 20.9 mmol) in CH 2 Cl 2 is added Dess-Martin periodinone (10.7 g, 25.1 mmol) followed by H 2 O (0.5 mL, 25.1 mmol) . After stirring for 1 hour at room temperature, the solution is poured into saturated aqueous Na2S204. The aqueous phase is extracted with CH2Cl2, then with EtOAc. The combined organic phases are dried (MgSO 4), filtered and concentrated in vacuo. The crude residue is purified on silica (10% EtOAc / hexanes) to yield 5.6 g (95% yield) of the desired product. 1 H NMR (300 MHz, CDCl 3) of enolic tautomer (observed 3: 1 mixture of tautomeric keto enol): d 12.34 (s, OH), 8.67 (d, J = 5.1 Hz, 1 H), 7.48 (d, J = 5.1 Hz, 1 H), 6.35 (s, 1 H), 2.62 (s, 3 H), 1.57 (s, 9 H); ESI + MS: m / z (relative intensity) 269.1 (30, M ++ H). Preparation of 3- (2-methylsulfanyl-pyrimidin-4-yl) -6,7-dihydro-5H-pyrazolo [1,2-a] pyrazol-1-one (20): to a solution of tert-butyl ester of the 3- (2-methylsulfanyl-pyrimidin-4-yl) -3-oxo-propionic acid, 19, (6.8 g, 25.4 mmol), pyrazolidin dihydrochloride (5.5 g, 38.1 mmol) and molecular sieves of 4 -angstrom (8.5 g) in toluene is added triethylamine (10.6 mL, 76.1 mmol). The reaction mixture is stirred for 4 hours at reflux. The solution is filtered through celite and washed with ether. The resulting yellow solid is purified on silica (10% MeOH / coroform) to yield 5 g of the desired product as a yellow solid: 1 H NMR (300 MHz, CDCl 3) d 8.72 (d, J = 5.1 Hz, 1H), 7.62 ( d, J = 5.1 Hz, 1 H), 6.08 (s, 1 H), 4.26 (t, J = 7.5 Hz, 2H), 3.80 (t, J = 7.8 Hz, 2H), 2.62 (dddd, J = 7.5 , 7.5, 7.5, 7.5 Hz, 2H), 2.60 (s, 3H); ESI + MS: m / z (relative intensity) 249.1 (70, M ++ H).

Preparation of 2-iodo-3- (2-methylsufanyl-pyrimidin-4-yl) -6,7-dihydro-5H-pyrazolo [1,2-a] pyrazol-1-one (21): to a cold solution ( 0 ° C) of 3- (2-methylsulfanyl-pyrimidin-4-yl) -6,7-dihydro-5H-pyrazolo [1,2-a] pyrazol-1-one, 20, (4.7 g, 19.1 mmol) , in carbon tetrachloride / pyridine (140 mL of a 1: 1 mixture) a solution of iodine in carbon tetrachloride / pyridine (80 mL of a 1: 1 mixture) is added dropwise. After stirring at 0 ° C for 30 minutes, the ice bath is removed and the mixture is stirred at room temperature. After stirring at room temperature for 1 hour, the reaction mixture is poured into saturated aqueous Na2S203. The aqueous phase is extracted with EtOAc (x3). The combined organic phases are dried (MgSO 4), filtered and concentrated in vacuo. The resulting yellow solid is purified by chromatography on silica gel (5% MeOH / chloroform) to yield 4.2 g of the desired product. 1 H NMR (300 MHz, CDCl 3) d 8.72 (d, J = 5.1 Hz, 1 H), 7.97 (d, J = 5.1 Hz, 1 H), 4.31 (t, J = 6.9 Hz, 2 H), 4.10 (t, J = 6.9 Hz, 2H), 2.74 (dddd, J = 6.9, 6.9, 6.9, 6.9 Hz, 2H), 2.62 (s, 3H); ESI + MS: m / z (relative intensity) 375.0 (100, M + + H). Preparation of 2 - [(2-chlorophenyl) -hydroxy-methyl] -3- (2-methylsulfanyl-pyrimidin-4-yl) -6,7-dihydro-5H-pyrazolo [1,2-a] pyrazole- 1-one (22): to a cold suspension (-40 ° C) of 2-iodo-3- (2-methylsulfanyl-pyrimidin-4-yl) -6,7-dihydro-5H-pyrazolo [1, 2- a] pyrazolo-1-one, 21, (0.40 g, 1.07 mmol) in THF (3 mL) is added dropwise isopropylmagnesium chloride (0.59 mL of a 2 M solution in THF, 1.18 mmol). After stirring for 30 minutes at -40 ° C, a solution of 2-chlorobenzaldehyde (0.16 mL, 1.40 mmol) is added dropwise. The reaction mixture is allowed to warm to 0 ° C for more than 1 hour.

The mixture is quenched by pouring into saturated aqueous NH4CI. The aqueous phase is extracted three times with EtOAc and the combined organic phases are dried (MgSO4), filtered and concentrated in vacuo. The crude residue is purified on silica (10% MeOH / chloroform) to yield 240 mg (58% yield) of the desired product. 1 H NMR (300 MHz, CDCl 3) d 8.56 (d, J = 5.1 Hz, 1 H), 7.78 (dd, J = 7.2, 1.8 Hz, 1 H), 7.34-7.18 (m, 2H), 7.01 (d, J = . 1 Hz, 1 H), 6.21 (s, 1 H), 4.20-4.01 (m, 5H), 2.80-2.70 (m, 2H), 2.58 (s, 3H); ESI + MS: m / z (relative intensity) 371.1 (100, M + + H). Preparation of 2- (2-chlorobenzoyl) -3- (2-methylsulfanyl-pyrimidin-4-yl) -6,7-dihydro-5H-pyrazolo [1,2-a] pyrazol-1-one (23): a a solution of 2 - [(2-chlorophenyl) -hydroxy-methyl] -3- (2-methylsulfanyl-pyrimidin-4-yl) -6,7-dihydro-5H-pyrazolo [1,2-a] pyrazole -1-one, 22, (0.22 g, 0.56 mmol) in CH2Cl2 (3 mL) is added manganese (IV) oxide (0.30 g, 3.40 mmol). After stirring for 18 hours at room temperature, the mixture is filtered through celite and washed with CH2Cl2. The filtrate is concentrated in vacuo. The crude residue is purified on silica (5% MeOH / chloroform) to yield 165 mg (69% yield) of the desired product. 1 H NMR (300 MHz, CDCl 3) d 8.69 (d, J = 5.1 Hz, 1 H), 7.78 (dd, J = 7.2, 1.8 Hz, 1 H), 7.81 (d, J = 5.1 Hz, 1 H), 7.46-7.33 (m, 4H), 4.44 (t, J = 7. 2 Hz, 2H), 4.03 (t, J = 7.2 Hz, 2H), 2.76 (dddd, J = 7.2, 7.2, 7.2, 7.2 Hz, 2H), 2.63 (s, 3H); ESI + MS: m / z (relative intensity) 387.1 (100, M + + H).

Preparation of 2- (2-chlorobenzoyl) -3- (2-methanesulfonyl-pyrimidin-4-yl) -6,7-dihydro-5H-pyrazolo [1,2-a] pyrazol-1-one (24): to a solution 2- (2-Chlorobenzoyl) -3- (2-methylsulfanyl-pyrimidin-4-yl) -6,7-dihydro-5H-pyrazolo [1,2-a] pyrazol-1-one, 23, (0.15 g , 0.39 mmol)) in THF / MeOH (3 mL of a 1: 1 mixture) is added dropwise a solution of Oxone® (potassium peroxymonosulfate) (0.72 g, 1.16 mmol) in H2O (3 mL). After stirring the reaction for 1.5 h at room temperature, the solution is poured into saturated aqueous NaHCO3. The aqueous phase is extracted three times with CHCl3 and the combined organic phases are dried (MgSO4), filtered and concentrated in vacuo. The crude product is used without further purification. Preparation of 2- (2-chlorobenzoyl) -3- (2-phenoxy-pyrimidin-4-yl) -6, 7-dihydro-5H-pyrazolo [1,2-a] pyrazol-1-one (25): To a solution of phenol (0.04 g, 0.43 mmol) in THF (1 mL) is added sodium hydride (0.02 g) from a dispersion to 60% in mineral oil, 0.32 mmol). After stirring for 5 minutes at room temperature, a solution of 2- (2-chlorobenzoyl) -3- (2-methanesulfonyl-pyrimidin-4-yl) -6,7-dihydro-5H-pyrazolo [1,2-a] ] pyrazol-1-one, 24, (0.09 g, 0.21 mmol) in THF (2 mL) is added to the reaction mixture. After stirring 1.5 h at room temperature, the mixture is diluted with saturated aqueous NaHCO3. The aqueous phase is extracted three times with CHCl3 and the combined organic phases are washed with saturated aqueous NaHCO3, dried (MgSO4), filtered and concentrated in vacuo. The crude residue is purified on silica (10% MeOH / CHCl3) to yield 30 mg of the desired product. 1 H NMR (300 MHz, CDCl 3) d 8.77 (d, J = 5.1 Hz, 1 H), 8.04 (d, J = 5.1 Hz, 1 H), 7.49 (t, J = 7.8 Hz, 1 H), 7.41-7.20 (m , 9H), 4.00 (t, J = 7.2 Hz, 2H), 3.95 (t, J = 7.2 Hz, 2H), 2.54 (dddd, J = 7.5, 7.5, 7.5, 7.5 Hz, 2H); ESI "MS: m / z (relative intensity) 431.1 (100, M + -H) The following is a non-exhaustive example of the compounds comprising the second aspect of Category III 2- (2-chlorobenzyl) -3- [2- (2-methoxy-1-methyl-ethylamino) -pyrimidin-4-yl] -6,7-dihydro-5H-pyrazolo [1,2-a] pyrazol-1-one: 1 H NMR (300 MHz, CDCl 3) d 8.14 (d, J = 5.1 Hz, 1 H), 7.38 (d, J = 5.4 Hz, 1 H), 7.18-7.10 (m, 3H), 6.61 (d, J = 5.4 Hz, 1 H), 4.40 -4.23 (m, 5H), 4.07 (s, 2H), 3.45 (d, J = 5.4 Hz, 2H), 3.38 (s, 3H), 2.82 (dddd, J = 6.9, 6.9, 6.9, 6.9 Hz, 2H ); ESI 'MS: m / z (relative intensity) 413.9 (100, M ++ H) It has been observed that in many cases the compounds detailed and described above exhibit activities (IC50 in the cellular evaluation described below or those are cited herein) at a level below 1 micromol (μM) Each of the disorders or conditions that the formulator wishes to treat may require different levels or amounts of the compounds described herein. to obtain a therapeutic level. The formulator can determine this amount by any of the test procedures known to the one experienced in the industry. Diseases affected by the activity of cytokines The following diseases are affected by the presence of undesirable levels of extracellular cytokines.

A) The analogs of the present invention are directed to the interruption of the extracellular release of interleukin-1 (IL-1), which has been implicated as the molecule responsible for a large number of disease states, including rheumatoid arthritis 1'2.3, osteoarthritis 4'5'6,7'8'9 as well as other disease states that are related to connective tissue degradation (periodontal disease, muscle degeneration) .10 B) Analogs of the present invention are also directed to the interruption of the extracellular release of the Cyclooxygenase-2 (COX-2), which has been shown to be increased due to cytokines.11 Disease states and conditions that are allegedly affected by COX-2 include fever, malaise, myalgia, and headache.12 C) The analogs of the present invention are also directed to the interruption of the extracellular release of tumor necrosis factor-a (TNF-a). This proinflammatory cytokine is suggested as an important mediator in many disease states or syndromes, including rheumatoid arthritis, osteoarthritis, acute and chronic inflammatory diseases, which are induced by entodoxin, or irritable bowel disease (IBD). in English), Crohn's disease and ulcerative colitis, septic shock, cardiopulmonary dysfunction, watery respiratory disease, and cachexia. D) The analogs of the present invention, which are effective antagonists, are capable of modulating, controlling or otherwise decreasing the release of unwanted cytokines or excessive cytokines or can be used to treat other disease states related to activity. of cytokines. Non-limiting examples of diseases or disease states linked to the activity of cytokines include congestive heart failure; hypertension; 13 chronic obstructive pulmonary disease (COPD) and septic shock syndrome; 14 tuberculosis, adult respiratory distress syndrome, asthma; 15 atherosclerosis; 16 muscle degeneration and periodontal disease; 17 cachexia, Reiter's syndrome , gout, acute synovitis, eating disorders, including anorexia and bulimia nervosa; 18 fever, malaise, myalgia, and headaches.19 In addition, other disease states have been linked to the activity of cytokines. Non-limiting examples of diseases, disease states, syndromes (both chronic and acute), which are related to unwanted or excessive release of inflammatory cytokines include diabetes20 and HIV / AIDS.21 The following are non-limiting examples of the connection between excessive expression, and unwanted extracellular release of cytokines and diseases or disease states. Congestive heart failure Tumor necrosis factor alpha (TNF-a), as well as other proinflammatory cytokines, including interleukin-1β (IL-1β) and IL-6, have been found in patients with advanced heart failure due to cardiomyopathies Ischemic or idiopathic. 2223'24'25 For example Aukrust et al.26 has determined that patients with congestive heart failure have high plasma levels of inflammatory cytokines, including TNF-a, IL-1β. It has been determined by Behr et al.27 that congestive heart failure due to volume overload in rats is associated with alterations in the expression and binding to cytokine receptors, monocyte chemotactic protein-1 (MCP-1). Therefore, it is well established that the inhibition of cytokines, for example by 6,7-dihydro-5H-pyrazolo [1, 2a] pyrazol-1-ones according to the present invention, which inhibit the extracellular release of cytokines Inflammatory, are effective as a method to control, mediate or otherwise modulate congestive heart failure or other cardiac diseases associated with the unwanted release of extracellular cytokines.

Crohn's disease Compounds that affect the activity of tumor necrosis factor alpha (TNF-a), for example the selective analogues of the present invention, have been determined to mediate Crohn's disease. For example, Stack et al.28 exposed patients to a double blind test to a human antibody developed by genetic engineering aTNF-a, CDP571. A single infusion of 5 mg / kg of this antibody modulator of TNF-a activity reduced the activity of Crohn's disease in 2 weeks. Data such as these suggest that neutralization of TNF-α, for example by an antibody or other factor such as a compound that inhibits cytokine activity, is an effective strategy in the management of Crohn's disease. The compounds of the present invention capable of inhibiting TNF-α are suitable for use in a method for treating Crohn's disease. Each of the disease states or conditions that the formulator wishes to treat may require different levels or amounts of the compounds described herein to obtain a therapeutic level. The formulator can determine this amount by any of the test procedures known to the one experienced in the industry. The following refers to the connection between the activity of the cytokine and disease or disease states and are included herein as a reference. 1. Dinarello, C.A. et al., Rev Infect Disease, 6:51, (1984). 2. Maini, R.E., The Lancet, 354: 1932, (1999). 3. Weinblatt, M.E., New England Journal of Medicine (New England Journal of Medicine), 340, 253, (1999). 4. Pelletier and Pelletier, J Rheum, 16:19, (1989). 5. Pelletier et al., Am J Path, 142: 95, (1993). 6. Farahat et al., Ann Rheum Dis, 52: 870, (1993). 7. Tiku et al., Cell Immunol, 140: 1, (1992). 8. Webb et al., O and C, 5: 427, (1997). 9. Westacott et al., O and C, 8: 213, (2000). 10. Howells, Oral Diseases, 1: 266, (1995). 11. M. K. O'Banion et al., Proc. Nati Acad. Sci. USA, 89, 4888 (1998). 12. Beisael, American Journal of Clinical Nutrition, 62: 813, (1995). 13. Singh, et al., Journal of Hypertension (Journal of Hypertension), 9: 867 (1996); 14. Dinarello, C. A., Nutrition (Nutrition) 11: 492 (1995); 15. Renzetti, et al. Inflammation Res. 46: S143; 16. Elhage, et al., Circulation 97: 242 (1998); 17. Howells, Oral Dis. 1: 266 (1995); 18. Holden, et al., Medical Hypothesis 47: 423 (1996); 19. Beisel, American Journal of Clinical Nutrition, 62: 813 (1995).

. McDaniel et al., Proc Soc, Exp, Biol Med, 211: 24, (1996). 21. Kreuzer et al., Clinical Experiments Immunology, 45: 559, (1997). 22. Levine B, Kalman J, Mayer L, et al. Elevated circulating levéis of tumor necrosis factor in severe chronic heart failure (Elevated circulating levels of tumor necrosis factor in severe chronic heart failure). New England Journal of Medicine (New England Journal of Medicine), 323, 236-241 (1990). 23. Dutka DP, Elbom JS, Delamere F. et al., Tumor necrosis factor alpha in severe congestive cardiac failure (The tumor necrosis factor alpha in severe congestive heart failure). British Heart Journal (British Heart Journal), 70 141-143 (1993). 4: Torre-Amione g, Kapadia S, Lee J. et al. Tumor necrosis factor-a and tumor necrosis factor receptors in the failing human heart (The tumor necrosis factor alpha and tumor necrosis factor receptors in human heart failure). Circulation, 93, 704-711 (1996). 5 Packer M. Is tumor necrosis factor an important neurohormonal mechanism in chronic heart failure? (Is tumor necrosis factor an important neurohormonal mechanism in chronic heart failure?) Circulation, 92, 1379-1382 (1995). 26. Pal Aukrust et al. Cytokine Network in Congestive Heart Failure Secondary to Ischemic or Idiopathic Dilated Cardiomyopathy (The cytokine network in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy), American Journal of Cardiology, 83, 376-382 ( 1999). 27. Behr TM et al., Monocyte Chemoattractant Protein-1 is Upregulated in Rats with Volume-Overload Congestive Heart Failure (Monocyte chemoattractant protein 1 is up-regulated in rats with congestive heart failure due to volume overload), Circulation ( Circulation), 102, 1315-1322 (2000). 28. Stack, W A; Mann, S D; Roy, A J; et al., The Lancet; Feb 22, 1977; 349, 9051. The present invention also relates to forms of the present compounds, which under the normal physiological conditions of humans or higher mammals, release the compounds described herein. An iteration of this aspect includes the pharmaceutically acceptable salts of the analogs described herein. For purposes of compatibility with the mode of delivery, excipients, and the like, the formulator may choose a salt form of the present analogs, since the compounds themselves are the active species that alleviates the disease processes described herein.

Prodrug Forms The various precursor or "prodrug" forms of the analogs of the present invention are related to this aspect. It may be desirable to formulate the compounds of the present invention as a chemical species which by itself is not an antagonist of the melamine concentrating hormone as described herein, but instead are forms of the present analogues which when supplied to a lower human or animal will experience a chemical reaction catalyzed by the normal function of the body, among other enzymes present in the stomach, blood serum; said chemical reaction releases the original analogue. The term "prodrug" refers to these species that are converted in vivo to the active pharmaceutical compound. The prodrugs of the present invention may have any form suitable for the formulator, for example the esters are common forms of prodrugs. In the present case, however, the prodrug can necessarily exist in a form where a covalent bond is divided by the action of an enzyme present at the "target site." For example, a CC covalent bond can be selectively divided by one or more enzymes at said target site, and therefore, a prodrug can be used in a form other than an easily hydrolysable precursor, including esters, amides, and the like For the purposes of the present invention, the term " "pharmaceutically acceptable prodrug" is defined herein as an "antagonist of the modified melanin-modifying hormone in order to be transformed in vivo in the therapeutically active form, either by means of a single or multiple biological transformations when in contact with the tissues of humans or mammals to which the prodrug has been administered, and without toxicity, irritation or excessive allergic response, and achieve the desired result. "A A detailed description of the prodrug derivatives can be found in the following references that are included in the present document: a) Design of Produrgs, edited by H. Bundgaard, (Elsevier, 1985); b) Methods in Enzymology, 42: 309-396, edited by K. Widder et al. (Academic Press, 1985); c) A Textbook of Drug Design and Development (edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5, "Design and Application of Prodrugs"). By H. Bundgaard, 113-191 (1991); d) Advance Drug Delivery Reviews, H. Bundgaard, 8, 1-38 (1992); e) Chem Pharm Bul !, N. Kakeya et al., 32, 692 (1984). FORMULATIONS The present invention also relates to compositions or formulations conforming the compounds inhibiting the release of inflammatory cytokines according to the present invention. In general, the compositions of the present invention are constituted by: a) An effective amount of one or more 6,7-dihydro-5H-pyrazolo [1, 2a] pyrazole-1-ones and derivatives thereof according to the present invention, which are effective in inhibiting the release of inflammatory cytokines; and b) one or more pharmaceutically acceptable excipients. For the purposes of the present invention, the term "excipient" and "carrier" are used interchangeably throughout the description of the present invention and are defined herein as "ingredients that are used in practice in formulating a safe pharmaceutical composition and effective". The formulator will understand that the excipients are used primarily to deliver a safe, stable and functional pharmaceutical product and that they not only function as a portion of the total carrier, but also as a means to achieve effective absorption in the container of the active ingredient. An excipient can perform a function as simple and direct as that of being an inert filler or that of an excipient in the sense that is used herein as part of a pH stabilizing system or a coating that ensures the safe supply of the ingredients in the stomach. The formulator can also take advantage of the fact that the compounds of the present invention are better in terms of cellular potency, pharmacokinetic properties and also have a better oral bioavailability.

The present invention also relates to compositions or formulations containing a precursor or "prodrug" form of the inflammatory cytokine release inhibiting compounds according to the present invention. For purposes of the present invention, as it relates to the subject of chemical entities that are converted in viyo to 6,7-dihydro-5-pyrido [1,2-a] -pyrazolo-1-ones, the terms "prodrug," "derivative," , "and" precursor "are considered to be interchangeable and represent the same concept. In general, compositions of the present invention which contain precursors are made up of: a) An effective amount of one or more derivatives or prodrug of 6,7-dihydro-5H-pyrazolo [1, 2a] pyrazol-1-ones according to present invention that acluates to release in vivo the corresponding analogue that is effective to inhibit the release of inflammatory cilocines; and b) one or more pharmaceutically acceptable excipients. The present invention also relates to compositions or formulations comprising the compounds inhibiting the release of inflammatory cyclocins according to the present invention, which are effective in providing analgesia. In general, the compositions of the present invention are made by: a) An effective amount of one or more 6,7-dihydro-5 / - / - pyrazolo [1, 2a] pyrazole-1-ones are derivatives or prodrugs thereof according to the present invention, which are effective to inhibit the release of inflammatory cytokines; b) an effective caníidad. of one or more compounds that have analgesic properties; and c) one or more pharmaceutically acceptable excipients. The following are non-limiting examples of compounds that have analgesic or compound properties that are effective in providing pain relief and that can be combined appropriately with the compounds of the present invention: Acefaminophen, aspirin, difunisal, dipyrone, ibuprofen, naproxen, fenoprofen, fenbufen , keíoprofeno, flurbiprofeno, indomeiacina, keforolaco, diclofenaco, flocíafenina, piroxicamo, celecoxib, and rofecoxib. The following are non-limiting examples of added ingredients, which may be combined with the compounds of the present invention: caffeine, compactable ampheiamines, comparative anihylisiamines, comparative anidepressants. In addition, narcotic opioid analgesics can be combined to form pharmaceutical compositions to form pharmaceutical compositions, for example oxycodone (Percadan, Percacei, Oxyconine, Tylox), peidin / meperidine (Demerol), meadone (Physepione, Dolophine), levorphanol (Dromoran, Levodromoran) , hydromorphone (Dilaudid), and buprenorphine (Temgesic).

The term "effective quality" is defined in the present as a canine that achieves the desired pharmaceutic result but that is also within the field of safe medical practices. For example, it has been known for a long time that the use of some pharmaceutically active compounds, including opiates, can lead to physical or psychological dependence. The caníidad that coníiene the compositions of the present invention can be of varying quantities depending on the active ingredient, on the level of activity of the active ingredient, and the habits and practices as has been established by means of tests or those that have been accepted for the time. in medical practice. The formulator will understand that the excipients are used primarily to deliver a safe, stable and functional pharmaceutical product and that they not only function as a portion of the carrier, but also as a means to achieve effective absorption in the container of the active ingredient. An excipient may perform a simple and directed function such as that of being an inert filler or that of an excipient in the sense that is used herein as part of a pH stabilizing system or a coating that ensures the safe supply of the ingredients. in the stomach. The formulator can also take advantage of the fact that the compounds of the present invention are better in terms of cell poise, pharmacokinetic properties and also have a better oral bioavailability.

METHOD OF USE The present invention also refers to a method to control the level of one or more inflammation-inducing cytokines, including inleleucine-1 (IL-1), the factor of tumor necrosis-a (TNF-a), nyelleucine-6 (IL-6) and inerleucine-8 (IL-8), and thereby conirrolar, mediate, or reduce the disorders affected by ex-cellular epidermal inflammatory levels. The present method includes the step comprising administering to a human or a higher mammal an effective amount of a composition that contains one or more inflammatory cyclin inhibitors according to the present invention. Because the inflammatory cytokine inhibitors of the present invention can be delivered in a way that they reach more than one control site, more than one disorder can be modulated at the same time. Non-limiting examples of diseases affected by the control or inhibition exerted by the inhibitors of inflammatory cytokines by modulating the excessive activity thereof, include osteoarthritis, rheumatoid arthritis, diabetes and infection by the human immunodeficiency virus (HIV). Furthermore, it has now been surprisingly determined that the analogs (compounds) of the present invention are capable of providing analgesia in humans and higher mammals. Thus, the present invention relates to a method for providing analgesia and / or pain relief to humans or higher mammals, which comprises the step of administering to said human or mammal superior an effective amount of a 6,7-dihydro -5H- pyrazolo [1, 2a] pyrazol-1-one described above. The present invention further comprises a method for providing analgesia and / or pain relief to humans or higher mammals, which comprises the step of administering to said human or mammal superior a pharmaceutical composition comprising: a) An effective amount of one or more 6,7-dihydro-5H-pyrazolo [1, 2a] pyrazol-1-ones and derivatives thereof according to the present invention, which are effective to inhibit the release of inflammatory cilocines; b) an effective canicity of one or more compounds that have analgesic properties; and c) one or more pharmaceutically acceptable excipients. The third aspect of the methods of the present invention relates to reducing psoriasis in humans and higher mammals; said method comprises the step of administering to a human or mammal superior an effective amount of a 6,7-dihydro-5-pyrazolo [1, 2a] pyrazol-1-one according to the present invention. It has been well established that the control of cytokine activity is directly related to the formation of psoriasis and the inhibition of this activity can be used as a therapy to control this condition. For example see: Lamoíalos J., et al., "Novel Biological Immunoiherapies for Psoriasis" (New Biological Immunotherapies for psoriasis). Expert Opinion Investigative Drugs; (2003); 12, 1111-1121. The present invention comprises a method to control the excellular release of cyclooxygenase-2 (COX-2) cytokines in humans and higher mammals; said method comprises the step of administering to said human or higher mammals one or more 6,7-dihydro-5H-pyrazolo [1, 2a] pyrazole-1-ones and derivatives thereof according to the present invention. The present invention comprises a method to control the ex-cellular liberation of the factor of alpha tumor necrosis (TNF-a), in humans and higher mammals; said method comprises the step of administering to said humans or higher mammals one or more 6,7-dihydro-5 / V-pyrazolo [1,2-a] pyrazole-1-ones and derivatives thereof according to the present invention. The present invention comprises a method for controlling a disease or disease condition in humans or higher mammals; said illness or disease disease is chosen from congestive heart failure; hypertension; chronic obstructive pulmonary disease (COPD) and septic shock syndrome; Iuberculosis, respiratory failure in adults, and asthma; aerosol; muscle degeneration and periodontal disease; cachexia, Reiíer syndrome, goía, acute synovitis, anorexia, bulimia nervosa; fever, malaise, myalgia and headaches; said method comprises the step of administering to said human or higher mammals one or more 6,7-dihydro-5 - / - pyrazolo [1,2a] pyrazole-1 -ones and derivatives thereof according to the present invention.

The present invention comprises a method for the prevention of plasma levels of inflammatory cilocins in humans or higher mammals wherein said cytokines are selected from TNF-α, IL-1β, and IL-6, thereby conirring or thereby causing heart failure. congestive in humans or higher mammals; said method comprises the step of administering to said humans or higher mammals one or more 6,7-dihydro-5H-pyrazoium [1,2-pyrazole-1-ones and derivatives thereof according to the present invention. The present invention comprises a method for eradicating Crohn's disease or alleviating its symptoms in humans by controlling the excellular release of cytokines; said method comprises the step of administering to said humans one or more 6,7-dihydro-5H-pyrazolo [1, 2a] pyrazole-1-ones and derivatives thereof according to the present invention. The present invention also comprises a method for treating psoriasis in humans, which comprises the step of administering to said human a pharmaceutical composition comprising: a) An effective amount of one or more 6,7-dihydro-5H-pyrazolo [1] , 2a) pyrazole-1-ones and derivatives thereof according to the present invention, which are effective to inhibit and / or control the release of inflammatory cytokines and thereby control psoriasis; and b) one or more pharmaceutically acceptable excipients. for purposes of the present invention, the term "effective efficacy" refers to the nature of one or more 6,7-dihydro-5-pyrazolo [1,2a] pyrazole-1-ones given to a patient who The need for frailty is defined in the present as "a canine of a pharmaceutically active compound that produces the alleviation of symptoms or the suppression of the cytokine activity as measured directly, for example by means of a test or laboratory procedure, or indirectly, for example, because of the patient's ability not to experience unwanted symptoms of disease or disease status. " These symptoms necessarily depend on one or more factors, including the level of activity of the cyanocin, the age of the patient, the degree of progression of the disease, diseases or diseases of the disease, the expected result (the cure completes in a chronic disease or temporal relief as in an acute condition of the disease). It is recognized that the compositions of the present invention can be supplied in various dosages, and therefore, the effective amount can be determined on a patient-by-patient basis, if necessary. PROCEDURES The efficacy of the compounds of the present invention can be evaluated, for example, by measuring the kinokin inhibition constants, K, and the IC 50 values can be obtained by any time selected by the formulator. Non-restrictive examples of suitable forms of evaluation include: i) UV-visible substrates enzyme assay (enzyme analysis of UV-visible radiation) as described by L. Al Reiier, Int. J. Peptide Protein Res., 43: 87- 96 (1994). ii) Fluorescent subsyria enzyme assay (Enzyme analysis of fluorescent substrates) as described by Thornberry et al. in Nature (Naíuraleza), 356: 768-774 (1992). iii) Analysis of peripheral blood mononuclear cells as described in U.S. Pat. no. 6,204,261 B1 de Baíchelor et al. granted on March 20, 2001. Each of the above publications is considered incorporated in this description as a reference. In addition, the inhibition of the factor of tumor necrosis, TNF-α, can be measured by using human monocytic cells (THP-1) stimulated by lipopolysaccharides (LPS) in the manner described in the following publication: i) KM Mohier et al. , "Protection Againsí a Leíhal Dose of Endotoxin by an Inhibitor of Tumor Necrosis Facíor Processing" (Protection against a lethal dose of endotoxin by an inhibitor of the process of factorial necrosis of juice), Nature (Naíuraleza), 370: 218-220 (1994) ). I) U.S. Pat. no. 6,297,381 B1 of Cirillo et al. granted on October 2, 2001, which is considered incorporated in this description as a reference and from which a relevant part is reproduced.

Inhibition of cytokine production can be observed by measuring TNF-α inhibition in THP cells stimulated by lipopollsaccharides. All cells and reagents are diluted in RPMI 1640 culíivo medium with phenol red and L-glutamine enriched with additional L-glu- amine (total: 4 mM), penicillin and srepi- mycin (50 units / mL each) and fetal bovine serum (FBS) 3%) (GIBCO, all the concentrations are final). The analysis is performed under sterile conditions, with the exception of the preparation of the test compound. The initial stock solutions are made in dimethylsulfoxide and then diluted in the medium of RPMI 1640 at a concentration 2 times higher than the desired final test concentration. Confluent THP.1 cells (2 x 10 6 cells / mL, final conc, American Type Culíure Company, Rockville, Md.) Are added to 96-well round bottom polypropylene culfivo plates (Costar 3790, sterile) containing 125 μl of the test compound (double concentration) or DMSO vehicle (controls, targets). The concentration of dimethyl disulfoxide should not exceed 0.2% final. The cell mixture is preincubated for 30 minutes at 37 ° C, 5% CO2 before stimulating with lipopolysaccharide (LPS, 1 μg / mL final, Sigma L-2630, from E. coli 0111.B4 serotype, stored as 1 mg / mL of maimeria premium in a diluted H2O vehicle screened by endo-toxin at -80 ° C). Whites (not sipulated) receive the H2O vehicle; The final incubation volume is 250 μl. The incubation (4 hours) is carried out in the manner already described above. The analysis is completed by centrifugation of the plates 5 minimates at ambient temperature, 167.5-1600 rpm (4033 g); the supernatants are transferred to clean 96-well plates and stored at -80 ° C until analyzed for TNF-a with a commercially available ELISA kit (Biosource No. KHC3015, Camarillo, Ca.). The IC50 value calculated is the concentration of the test compound that causes a 50% decrease in the maximum production of TNF-a. It has been determined that the compounds of the present invention are surprisingly effective in providing analgesia, or otherwise in alleviating pain in humans or higher mammals. A convenient means for assessing pain and for measuring the effective amount of compound (s) necessary to achieve analgesia and thereby providing a means to determine the amount of compound (s) comprising a pharmaceutical composition of the present invention and the canine of compound (s) necessary for use in the methods described in the present, is the model of thermal hyperalgesia in rales, as described further below. The model of thermal hyperalgesia in rales, that is to say "Hargreaves Meíhod "[Hargreaves, K., et al., Pain, (1988), 32: 77-88], is used to determine the level at which the sysiemic administration of test compounds attenuates the hyperalgesia response subsequent to an intraplanar injection. of carrageenan: Analgesia test period: Male Sprague-Dawley rats weighing 100-150 g are used, housed two per shoebox cage in veníilated hygienic enclosures for animals, with condylar temperature and humidity and regular light cycles. The animals were acclimatized for one week before they were used, and all animals were used in accordance with the guidelines of the United States Department of Agriculture for compassionate care on the first day of the study. Each animal was acclimated to the test equipment and the initial values of the leg reir (PWL) were recorded to a radiant heat source. The animals were dosed orally with the vehicle or the test compound. Thirty minutes later, each animal received an intrariliar injection of 0.01 mL of carrageenan (1.2% solution, weight / volume) in the left rear part. Four hours after injection of carrageenan, the animals were taken back to the test equipment to determine the PWL of the inflamed leg. The animals were then sacrificed with an overdose of carbon dioxide. Statistical analysis of damages: the change is calculated from before to after the PWL for each animal. The spatial comparison between the planning groups in these two points of exíremo is made through an ANCOVA model with terms of time, as well as measurements before the treatment as a covariant of the initial values. The relevant part of all documents cited in the section "Detailed description of the invention" are incorporated herein by reference and should not be construed that the citation of said documents is the admission that they constitute the earlier industry with respect to this invention. While particular embodiments of the present invention have been illustrated and described, it will be apparent to those skilled in the art that various changes and modifications can be made without deviating from the spirit and scope of the invention. It has been intended, therefore, to cover in the appended claims all changes and modifications within the scope of the invention.

Claims (36)

NOVELTY OF THE INVENTION CLAIMS

1. A compound that includes all the enantiomeric and diastereomeric forms and pharmaceutically acceptable salts thereof; the compound corresponds to the formula: wherein R is: a) -O [CH2] kR3; or b) -NR4aR4b; R 3 is unsubstituted or substituted C 4 alkyl, unsubstituted or substituted carbocyclic, unsubstituted or unsubstituted heterocyclic, substituted or unsubstituted aryl or alkylenearyl, heteroaryl or substituted or unsubstituted heteroaryl heteroaryl; the index k is from 0 to 5; each R4a and R4 is independently: a) hydrogen; or b) - [C (R5aR5b)] mR6; each R5a and R5 is independently hydrogen, -OR7, -N (R7) 2, -CO2R7, -CON (R7) 2; linear, branched or cyclic CrC4 alkyl and mixtures thereof; R6 is hydrogen, -OR7, -N (R7) 2, -CO2R7, -CON (R7) 2; unsubstituted or substituted C1-C4 alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R7 is hydrogen, a water-soluble cation, C4-alkyl or substituted or unsubstituted aryl; the index m is from 0 to 5; R1 is: a) aryl subsumed or unsubstituted; or b) substituted or unsubstituted heteroaryl; L is a linking group selected from: i) - [C (R12) 2] n-; I) - [C (R12) 2] nNR12 [C (R12) 2] n-; and iii) - [C (R12) 2] nO [C (R12) 2] p-; R 12 is hydrogen, C 4 alkyl, and mixtures thereof; or two R12 units can be taken to form a carbonyl unit; the index n is a unit from 0 to 2; each R2 unit is independently chosen from: a) hydrogen; b) - (CH2) p (C2) μa; c) - (CH2) jNR9aR9b; d) - (CH2) jCO2R10; e) - (CH2) JOCO2R10 f) - (CH2) jCON (R0) 2; g) - (CH2) JOCON (R10) 2; h) two R2 units can be joined together to form a carbonyl unit; i) and mixtures thereof; each R8, R9a, R9b, and R10 are independently selected from hydrogen, C1-C4 alkyl, and mixtures thereof; R9a and R9b can be taken together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; two units of R10 can be taken together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; j is an index from 0 to 5; Z is O, S, NR11 or ÑOR11; R11 is hydrogen or CrC4 alkyl.

2. The compound according to claim 1, further characterized in that R is chosen from 2-methyl-2-hydroxy-1- (S) -methylpropylamine, 1- (S) -methylbenzylamine, 2-methoxy-1- (S) ) -methylethyl amine, 2-meityl-2-cyano-1- (S) -methylpropylamine, 2-meityl-2-hydroxy-1- (f?) - methylpropylamine, 1- (R) -methylbenzylamine, 2-meioxy-1 - (. £?) - methylamidolamine, 2-methyl-2-cyano-1- (R) -methylpropylamine, pyran-4-ylamino, piperidin-4-ylamino, pyridin-2-ylamino, pyridin-3-ylamino, pyridine -4-ylamino, pyrimidin-2-ylamino, pyrimidin-4-ylamino, and pyrimidin-5-llamino.

3. The compound according to claim 1 or 2, further characterized in that R1 is chosen from 2-meitylphenyl, 3-meitylphenyl, 4-mephenylphenyl, 2,6-dimethyiphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2, 6-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, and 2,6-difluorophenyl.

4. The compound according to claim 1, further characterized because the formula:

5. The compound according to claim 4, further characterized in that R is a unit having the formula -OR3 and R3 is aryl substituted or unsubstituted.

6. The compound according to claim 4 or 5, further characterized in that R3 is chosen to be defenoxi, 2-fluorophenoxy, 3-fluorophenoxy, 4-fluorophenoxy, 2,4-difluorophenoxy, 3-trifluoromethyl-phenoxy, 4-trifluoromethyiphenoxy, 2.4 -trifluoromethyl phenoxy, 2-meitylphenoxy, 3-meityl-phenoxy, 4-meitylphenoxy, 2,4-dimethylfenoxy, 2-cyano-phenoxy, 3-cyano-phenoxy, 4-cyano-phenoxy, 4-efilphenoxy, (2-meioxy) phenoxy, meioxy) phenoxy, (4-meioxy) phenoxy, 3 - [(N-acetyl) amino] phenoxy, and 3-benzo [1, 3] dioxoI-5-yl.

7. The compound according to any of claims 4-6, further characterized because R is a unit that has the formula -OR3 and R3 is chosen from pyrimidin-2-yl, pyrimidin-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-aminopyrimidin-4-yl.

8. The compound according to any of claims 4-7, further characterized in that R is a unit having the formula -OR3 and R3 is linear, branched, or cyclic C4 alkyl, susfifuuted or not susi fi ed.

9. The compound according to any of claims 4-8, further characterized in that R3 is chosen from 2-meioxy-yl, or (S) -1-mephyl-3-meioxypropyl.

10. The compound according to any of claims 4-9, further characterized because R is a unit that has the formula: wherein R6 is a solid or non-solid phenol.

11. The compound according to any of claims 4-10, further characterized because R is chosen from (S) -1-meityl-1-phenylmethylamino, (S) -1-methyl-1- (4-fluorophenyl) -methylamino , (S) -1-methyl-1- (4-methylphenyl) methylamino, (S) -1-methyl-1- (4-methoxyphenyl) -methylamino, (S) -1-methyl-1- (2-aminophenyl) methylamino, and (S) -1-methyl-1 - (4-aminophenyl) methylamino.

12. The compound according to any of claims 4-11, further characterized in that R is chosen from (S) -1-mephyl-1 - (pyridin-2-yl) -methylamino, (S) -1-methyl-1 - ( pyridin-3-yl) -methylamino, (S) -1-meityl-1- (pyridin-4-yl) meitylamino, (S) -1-meityl-1- (furan-2-yl) meitylamino, and (S) -1- mephyl-1 - (3-benzo [1,3] dioxol-5-yl) meitylamino.

13. The compound according to any of claims 4-12, further characterized in that R is chosen from (S) -1-methylpropylamino or (S) -1-methyl-2- (methoxy) and yamino.

14. The compound according to claim 4, further characterized because R has the formula: and the stereochemistry that is indicated when R5a, R5 and R6 are not the same.

15. The compound according to claim 14, further characterized in that R is chosen from 1,1-dimethylelylylamine, 1,1-dimethylbenzylamine, (S) -1-methyl-2-hydroxy-2-methypropropylamine, (S) - 1-meityl-2-hydroxy-2-melilbuyilamine, benzylamino, (2-aminophenyl) -methylamino; (4-fluorophenyl) -methylamino, (4-meioxyphenyl) -methylamino; (4-propanesulfonylphenyl) -methylamino, (2-meitylphenyl) -melylamine; (3-methylphenyl) -methylamino; and (4-mephylphenyl) metylamino.

16. The compound according to claim 1, further characterized by the formula:

17. The compound according to claim 16, further characterized in that R is a unit that has the formula -OR3 and R3 is aryl susliluido or not susíiuuido.

18. The compound according to claim 16 or 17, further characterized in that R3 is chosen from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3-uro-trifluoromethyl, 4-trifluoromethyiphenyl, 2, 4-trifluoromethylphenyl, 2-methylphenyl, 3-methyl-phenyl, 4-methyl-phenyl, 2,4-dimethylphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 4-eylphenyl, (2-meioxyl) phenyl, meioxy) phenyl, (4-meioxy) phenyl, 3 - [(N-acetyl) amino] phenyl, and 3-benzo [1,3] dioxol-5-yl.

19. The compound according to any of claims 16-18, further characterized in that R is a unit having the formula -OR3 and R3 is chosen from pyrimidin-2-yl, pyrimidin-4-yl, pyridin-2-yl , pyridin-3-yl, pyridin-4-yio, 2-aminopyrimidin-4-yl.

20. The compound according to any of claims 16-19, further characterized in that R is a unit having the formula -OR3 and R3 is linear, branched, or cyclic C 4 alkyl, susi or unsubstituted.

21. The compound according to any of claims 16-20, further characterized in that R3 is chosen from 2-mefoxieyl, or (S) -1-meityl-3-meioxypropyl.

22. The compound according to any of claims 16-21, further characterized because R is a unit that has the formula: wherein R6 is phenyl unsubstituted or unsuspended.

23. The compound according to any of claims 16-22, further characterized in that R is chosen from (S) -1-meityl-1-phenylmethylamino, (S) -1-methyl-1- (4-fluorophenyl) mef Lamino, (S) -1-methyl-1 - (4-methylphenyl) meyilamino, (S) -1-methyl-1- (4-methoxyphenyl) -methylamino, (S) -1-methyl-1 - ( 2-aminophenyl) meylamino, and (S) -1-methyl-1- (4-aminophenyl) meitylamino.

24. The compound according to any of claims 16-23, further characterized in that R is chosen from (S) -1-mephyl-1 - (pyridin-2-yl) mephilam, (S) -1-methyl -1 - (pyridin-3-yl) meitylamino, (S) -1-meityl-1- (pyridin-4-yl) meitylamino, (S) -1-methyl-1 - (furan-2-yl) meitylamino, and (S) -1-meityl-1 - (3-benzo [1,3] dloxol-5-yl) -methylamino.

25. The compound according to any of claims 16-24, further characterized in that R is chosen from (S) -1-methylpropylamino or (S) -1-methyl-2- (methoxy) -philamino.

26. The compound according to any of claims 16-26, further characterized in that R has the formula: and the stereochemistry that is indicated when R5a, R5 and R6 are not the same.

27. The compound according to any of claims 16-27, further characterized in that R is selected from 1,1-dimethylethylamine, 1,1-dimethylenylbenzylamine, (S) -1-methyl-2-hydroxy-2-methypropropylamine, (S) -1-meityl-2-hydroxy-2-melilbuyylamine, benzylamino, (2-aminophenyl) meitylamino; (4-fluorophenyl) mef-lamino, (4-mefoxyphenyl) meyilamno; (4-propanesulfonylphenyl) -methylamino, (2-meitylphenyl) -methylamino; (3-meitylphenyl) -methylamino; and (4-meitylphenyl) meitylamino.

28. The compound according to claim 1, further characterized by the formula: wherein L is chosen from -CH2NHC (O) -, -NHC (O) -, and -C (O) -.

29. A compound selected from: S) -3- [2- (2-Meioxy-1-meitylyl-ylamino) -pyrimidin-4-yl] -2-o-yloxy-6,7-dihydro-5H-pyrazolo [ 1,2-a] pyrazol-1-one; S) -3- [2- (2-hydroxy-1,2-dimethylpropylamino) -pyrimidin-4-yl] -2-o-yloxyloxy-6,7-dihydro-5H-pyrazolo [1,2-a] pyrazole -1-one; (S) -3- [2- (Ieirahydro-pyran-4-ylamino) -pyridin-4-yl] -2-o-yloxyloxy-6,7-dihydro-5H-pyrazolo [1,2- a] pyrazole-1 -one; (S) -3- [2- (1-phenylethylamino) -pyrimidin-4-yl] -2-o-yl-yloxy-6,7-dihydro-5H-pyrazolo [1,2-a] pyrazoI-1- ona; 3- [2- (2,6-Dichlorophenylamino) -pyrimidin-4-yl] -2-o-yloxy-6,7-dihydro-5H-pyrazolo [1,2-a] pyrazole-1 -one; 3- (2-phenoxy-pyrimidin-4-yl) -2-o-tolyloxy-6,7-dihydro-5H-pyrazolo [1,2-a] pyrazol-1-one; (S) -2- (2-chlorobenzyl) -3- [2- (1-phenylethylamino) -pyrimidin-4-yl] -6,7-dihydro-5H-pyrazolo [1,2-a] p razol-1-one; (S) -2- (2-me yylbenzyl) -3- [2- (1-phenylethylamino) -pyrimidin-4-yl] -6,7-dihydro-5H-pyrazolo [1,2-a] pyrazole-1- ona; (S) -2- (4-Fluorobenzyl) -3- [2- (1-phenylethylamino) -pyrimidin-4-yl] -6,7-dihydro-5H-pyrazolo [1,2-a] pyrazole-1 - ona; 2- (2-Chlorobenzyl) -3- [2- (2,6-difluorophenylamino) -pyrimidin-4-yl] -6,7-dihydro-5H-pyrazolo [1,2-a] pyrazol-1-one; (S) -2- (2-chlorobenzyl) -3- [2- (2-hydroxy-1,2-dimethylampylamino) -pyrimidin-4-yl] -6,7-dihydro-5H-pyrazolo [1,2- a] pyrazole-1 -one; (S) -3- [2- (2-Hydroxy-1,2-dimethylapropylamino) -pyrimidin-4-yl] -2- (2-me yylbenzyl) -6,7-dihydro-5H-pyrazolo [1, 2-a] pyrazol-1-one; (S) -2- (4-fluorobenzyl) -3- [2- (2-hydroxy-1,2-dimethylpropylamino) -pyrimidin-4-yl] -6,7-dihydro-5H-pyrazolo [1,2- a] pyrazol-1-one; 2- (2-Chlorobenzyl) -3- [2- (teirahydro-pyrn-4-ylammon) -pyrimidin-4-yl] -6,7-dihydro-5H-pyrazolo [1,2-a] pyrazole-1 -one; 2- (2-Chlorobenzyl) -3- (2-phenoxy-pyrimidin-4-yl) -6,7-dihydro-5H-pyrazolo [1,2-a] pyrazol-1-one; 2-Ciobenzylamide of 1-Oxo-3- (2-phenoxy-pyrimidin-4-yl) -6,7-dihydro-1 - /, 5H-pyrazolo [1,2-a] pyrazole-2-carboxylic acid; 1- (2-phenoxy-pyrimidin-4-yl) -6,7-dihydro-1 H, 5H-pyrazolo [1,2-a] pyrazole-2-acid (2-chlorophenyl) -amide. carboxylic; 2- (2-Chlorobenzyl) -3- [2- (2-meioxy-1-mephyl-ephilamno) -pyrimidin-4-yl] -6,7-dihydro-5H-pyrazolo [1,2-a] pyrazole-1 -one; 2- (2-chlorobenzoyl) -3- (2-phenoxy-pyrimidin-4-yl) -6,7-dihydro-5H-pyrazolo [1,2-a] pyrazol-1-one; and 2- (2-chlorobenzyl) -3- [2- (2-meioxy-1-mephyl-ephilamino) -pyrimidin-4-yl] -6,7-dihydro-5H-pyrazolo [1,2- a] pyrazole -1-ona.

30. A composition comprising: one or more bicyclic pyrazolones including all the enanimeric and diaseromeric forms and pharmaceutically acceptable salts thereof, said compound having the formula: wherein R is: a) -O [CH2] kR3; or b) -NR4aR4b; R 3 is C 1 -C 4 alkyl substituted or unsubstituted, carbocyclic unsubstituted or unsubstituted, heterocyclic unsubstituted or unsubstituted, unsubstituted or unsubstituted aryl or alkylenearyl, heteroaryl or unsubstituted or unsubstituted alkylene or heteroaryl heteroaryl; the index k is from 0 to 5; each R4a and R4b is independently: a) hydrogen; or b) - [C (R5aR5b)] mR6; each R5a and R5b is independently hydrogen, -OR7, -N (R7) 2, -CO2R7, -CON (R7) 2; linear, branched or cyclic C ^ - ^ alkyl, and mixtures thereof; R6 is hydrogen, -OR7, -N (R7) 2, -CO2R7, -CON (R7) 2; unsubstituted or unsubstituted alkyl C 1, solid or non-solid heteroaryl, unsubstituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R7 is hydrogen, a water-soluble cation, C4-alkyl or substituted or unsubstituted aryl; the index m is from 0 to 5; R1 is: a) unsubstituted or unsubstituted aryl; or b) unsubstituted or unsubstituted heteroaryl; L is a linking group selected from: i) - [C (R12) 2] n-; ii) - [C (R12) 2] nNR12 [C (R12) 2] n-; and iii) - [C (R12) 2] nO [C (R12) 2] -; R 12 is hydrogen, C 1 -C 4 alkyl, and mixtures thereof; or two R12 units can be added to form a carbonyl unit; the index n is a unit from 0 to 2; each R2 unit is independently chosen from: a) hydrogen; b) - (CH2) jO (CH2) jR8; c) - (CH2) jNR9aR9b; d) - (CH2), C02R10. e) - (CH ^ OCO.R10 f) - (CH ^ CO ^ R10); g) - (CH ^ OCONÍR10 ^; h) two R2 units can be joined together to form a carbonyl unit; I) and mixtures thereof; each R8, R9a, R9b, and R10 are independently selected from hydrogen, C ^ Qj alkyl, and mixtures thereof; R9a and R9 can be conjugated to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; two units of R10 may be taken to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; j is an index from 0 to 5; Z is O, S, NR11 or ÑOR11; R11 is hydrogen or CrC4 alkyl.

31. A pharmaceutical composition comprising: a) an effective amount of one or more bicyclic pyrazolones including all enaniomeric and diastereomeric forms and pharmaceutically acceptable salts thereof; the compound has the formula: where R is: a) -O [CH2] kR3; or b) -NR4aR4b; R 3 is unsubstituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted carbocyclic, unsubstituted or unsubstituted heterocyclic, substituted or unsubstituted or unsubstituted aryl, or alkylenearyl, heteroaryl or substituted or unsubstituted alkylene or heteroaryl; the index k is from 0 to 5; each R4a and R4b is independently: a) hydrogen; or b) - [C (R5aR5b)] mR6; each R5a and R5b is independently hydrogen, -OR7, -N (R7) 2, -CO2R7, -CON (R7) 2; C, -C 4 linear, branched or cyclic alkyl and mixtures thereof; R6 is hydrogen, -OR7, -N (R7) 2, -CO2R7, -CON (R7) 2; alkyl substituted or unsubstituted C, -C 4, substituted or unsubstituted heteroaryl, unsubstituted or unsuspended aryl, or unsupported or unsubstituted heteroaryl; R 7 is hydrogen, a water-soluble cation, C, -C 4 -alkyl or unsubstituted or non-suscepted aryl; the index m is from 0 to 5; R1 is: a) unsubstituted or unsubstituted aryl; or b) suspended or non-solidified heleroaryl; L is a linking group selected from: i) - [C (R12) 2] n-; ii) - [C (R12) 2] pNR12 [C (R12) 2] -; and iii) - [C (R12) 2] pO [C (R12) 2] -; R 12 is hydrogen, C 1 O alkyl, and mixtures thereof; or two R12 units can be taken together to form a carbonyl unit; the index n is a unit from 0 to 2; each R2 unit is independently chosen from: a) hydrogen; b) - (CH ^ -OÍCH ^ -R8; c) - (CH ^ NR ^ R90; d) - (CH2) jCO2R10; e) - (CH2) jOCO2R10 f) - (CH ^ CONÍR10); g) - (C 2) pCON (R 10) 2; h) two R2 units can be joined together to form a carbonyl unit; i) and mixtures thereof; each R8, R9a, R9, and R10 are independently selected from hydrogen, CrC4 alkyl, and mixtures thereof; R9a and R9b can be taken together to form a carbocyclic or heyerocyclic ring comprising from 3 to 7 atoms; two units of R10 may be conjugated to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; j is an index from 0 to 5; Z is O, S, NR11 or ÑOR11; R11 is hydrogen or C1-C4 alkyl; and b) one or more pharmaceutically acceptable excipients.

32. The use of a pharmaceutical composition comprising one or more of the compounds, including all the enantiomeric and diastereomeric forms and the pharmaceutically acceptable salts thereof, which has the formula: wherein R is: a) -O [CH2] kR3; or b) -NR4aR b; R3 is unsubstituted or unsubstituted, unsubstituted or unsubstituted C1-C4alkyl, unsubstituted or unsubstituted carbocyclic, unsubstituted or unsubstituted heteroaryl, unsubstituted or unsubfused alkylaryl, heteroaryl or alkylene-substituted or unsubstituted alkylene-alkyl aryl; the index k is from 0 to 5; each R43 and R4b is independently: a) hydrogen; or b) - [C (R5aR5b)] mR6; each R5a and R5b is independently hydrogen, -OR7, -N (R7) 2, -CO2R7, -CON (R7) 2; linear, branched or cyclic C1-C4 alkyl and mixtures thereof; R6 is hydrogen, -OR7, -N (R7) 2, -CO2R7, -CON (R7) 2; Alkyl, unsubstituted or unsubstituted CrC4, unsubstituted or unsubstituted heteroaryl, unsubstituted or unsubstituted aryl or unsubstituted or unsubstituted heteroaryl; R 7 is hydrogen, a water-soluble cation, C 1 -C 4 -alkyl, or unsubstituted or non-substituted aryl; the index m is from 0 to 5; R1 is: a) unsubstituted or non-susi fi ed aryl; or b) suspended or non-solidified airborne; L is a linking group selected from: i) - [C (R12) 2] n-; ii) - [C (R12) 2] nNR12 [C (R12) 2] n-; and iii) - [C (R12) 2] nO [C (R12) 2] n-; R 12 is hydrogen, alkyl and mixtures thereof; or two R12 units can be taken together to form a carbonyl unit; the index n is a unit from 0 to 2; each R2 unit is independently chosen from: a) hydrogen; b) - (CH ^ OICH ^ R8; c) - (CH ^ NR ^ R90; d) - (CH2) jCO2R10; e) - (CH ^ OCO ^ 10 f) - (CH ^ CONÍR10); g) - (CH2) JOCON (R10) 2; h) two R2 units can be joined together to form a carbonyl unit; i) and mixtures thereof; each R8, R9a, R9b, and R10 are independently selected from hydrogen, alkyl 0, -0-4, and mixtures thereof; R9a and R9b may be conjugated to form a carbocyclic or heyerocyclic ring comprising from 3 to 7 atoms; two units of R 10 can be conjugated to form a carbocyclic or heyerocyclic ring comprising from 3 to 7 atoms; j is an index from 0 to 5; Z is O, S, NR11 or ÑOR11; R11 is hydrogen or C4 alkyl, to prepare a medicament for controlling the excellular release of cycloxygenase-2 (COX-2) cytokines in humans and higher mammals.

33. The use of a pharmaceutical composition comprising one or more of the compounds, including all the enaniomeric and diastereomeric forms and the pharmaceutically acceptable salts thereof, which has the formula: wherein R is: a) -O [CH2] kR3; or b) -NR4aR4b; R3 is unsubstituted or unsubstituted or unsubstituted, unsubstituted or unsubstituted carbocyclic Cr C4 alkyl, unsubstituted or unsubstituted heterocyclic, unsubstituted or unsubstituted or unsubstituted aryl or alkylenearyl, heteroaryl or unsubstituted or unsubstituted alkylene or heteroaryl heteroaryl; the index k is from 0 to 5; each R4a and R4b is independently: a) hydrogen; or b) - [C (R5aR5b)] mR6; each R5a and R5b is independently hydrogen, -OR7, -N (R7) 2, -CO2R7, -CON (R7) 2; C, -C 4 linear, branched or cyclic alkyl and mixtures thereof; R6 is hydrogen, -OR7, -N (R7) 2, -CO2R7, -CON (R7) 2; unsubstituted or unsubstituted C 4 alkyl, unsubstituted or unsubstituted heterocycle, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R7 is hydrogen, a water-soluble cation, C-C4 alkyl or substituted or non-substituted aryl; the index m is from 0 to 5; R1 is: a) aryl susíifuido or not susíifuido; or b) solid or non-solidified airborne; L is a linking group selected from: i) - [C (R12) 2] -; I) - [C (R12) 2] nNR12 [C (R12) 2] -; and iii) - [C (R12) 2] pO [C (R12) 2] n-; R12 is hydrogen, CrC4 alkyl, and mixtures thereof; or two R12 units can be taken to form a carbonyl unit; the index n is a unit from 0 to 2; each R2 unit is independently chosen from: a) hydrogen; b) - (CH2) jO (CH2) jR8; c) - (CH2) jNR9aR9b; d) - (CH2) jCO2R10; e) - (CHOCO ^ 10 f) - (CH2) jCON (R10) 2; g) - (CH2) pCON (R10) 2; h) two R2 units can be joined together to form a carbonyl unit; i) and mixtures thereof; each R8, R9a, R9b, and R10 are independently selected from hydrogen, C, -C4 alkyl, and mixtures thereof; R9a and R9b can be taken together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; two units of R 10 can be conjugated to form a carbocyclic or heyerocyclic ring comprising from 3 to 7 atoms; j is an index from 0 to 5; Z is O, S, NR11 or ÑOR11; R11 is hydrogen or CrC4 alkyl to prepare a medicament for conferring the ex-cellular release of tumor necrosis factor alpha (TNF-α) in humans and higher mammals.

34. The use of a pharmaceutical composition comprising one or more of the compounds, including all the enanimeric and diastereomeric forms and the pharmaceutically acceptable salts thereof, which has the formula: wherein R is: a) -O [CH2] kR3; or b) -NR4aR4; R 3 is unsubstituted or unsubstituted C 4 alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted or unsubstituted aryl or alkylearyl, substituted or unsubstituted or substituted heteroaryl or alkylene-heteroaryl; the index k is from 0 to 5; each R4a and R4b is independently: a) hydrogen; or b) - [C (R5aR5b)] mR6; each R5a and R5b is independently hydrogen, -OR7, -N (R7) 2, -CO2R7, -CON (R7) 2; linear, branched or cyclic C 4 alkyl, and mixtures thereof; R6 is hydrogen, -OR7, -N (R7) 2, -C02R7, -CON (R7) 2; alkyl substituted or unsubstituted C C4. heterocyclic or unsubstituted heterocycle, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R7 is hydrogen, a water-soluble cation, C ^ O alkyl, or unsubstituted or non-substituted aryl; the index m is from 0 to 5; R1 is: a) Substituted or unsubstituted aryl; or b) substituted or unsubstituted heteroaryl; L is a linking group selected from: i) - [C (R12) 2] n-; ii) - [C (R12) 2] nNR12 [C (R12) 2] -; and iii) - [C (R12) 2] pO [C (R12) 2] -; R 12 is hydrogen, C, -C 4 alkyl, and mixtures thereof; or two R12 units can be added to form a carbonyl unit; the index n is a unit from 0 to 2; each R2 unit is independently chosen from: a) hydrogen; b) - (CH2) jO (CH2) jR8; c) - (CH2) lNR9aR9b. d) - (CH2), C02R10; e) - (CH ^ OCO.R10 f) - (CH ^ CONÍR10);,; g) - (CH ^ JOCONÍR10);,; h) two R2 units can be joined together to form a carbonyl unit; i) and mixtures thereof; each R8, R9a, R9b, and R10 are independently selected from hydrogen, C4 alkyl, and mixtures thereof; R9a and R9b can be taken together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; two units of R10 can be taken together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; j is an index from 0 to 5; Z is O, S, NR11 or ÑOR11; R11 is hydrogen or CrC4 alkyl, to prepare a medicament for controlling a disease or disease state in humans or higher mammals; the disease or disease state is chosen from congestive heart failure; hypertension; chronic obstructive pulmonary disease (COPD) and septic shock syndrome; Iuberculosis, respiratory failure in adults, and asthma; atherosclerosis; muscle degeneration and periodontal disease; cachexia, Reiíer syndrome, gout, acute synovitis, anorexia, bulimia nervosa; fever, malaise, myalgia and headaches.

35. The use of a pharmaceutical composition comprising one or more of the compounds, including all the enantiomeric and diastereomeric forms and pharmaceutically acceptable salts thereof, which has the formula: wherein R is: a) -O [CH2] kR3; or b) -NR4aR4b; R 3 is unsubstituted or unsubstituted CrC 4 alkyl, unsubstituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, unsubstituted or substituted or unsubstituted aryl or alkylene aryl, substituted or unsubstituted heteroaryl or heteroaryl heteroaryl; the index k is from 0 to 5; each R4a and R4b is independently: a) hydrogen; or b) - [C (R5aR5b)] mR8; each R5a and R5b is independently hydrogen, -OR7, -N (R7) 2, -CO2R7, -CON (R7) 2; C, -C 4 linear, branched or cyclic alkyl and mixtures thereof; R6 is hydrogen, -OR7, -N (R7) 2, -CO2R7, -CON (R7) 2; unsubstituted or unsubstituted alkyl substituted, unsubstituted or unsubstituted heteroaryl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R7 is hydrogen, a water-soluble cation, C-, C4-alkyl, or aryl, susi fi ed or unsubstituted; the index m is from 0 to 5; R1 is: a) substituted or unsubstituted aryl; or b) solid or non-solidified airborne; L is a linking group selected from: i) - [C (R12) 2] n-; ii) - [C (R12) 2] pNR12 [C (R12) 2] p-; and iii) - [C (R12) 2] nO [C (R12) 2] -; R 12 is hydrogen, C 1 -C 4 alkyl, and mixtures thereof; or two R12 units can be taken together to form a carbonyl unit; the index n is a unit from 0 to 2; each R2 unit is independently chosen from: a) hydrogen; b) - (CH ^ -OÍCH ^ -R8; c) - (CH2) jNR9aR9b; d) - (CHICAR10; e) - (CH2) pCO2R10 f) - (CH ^ CO ^ R10); g) - (CH2) JOCON (R10) 2; h) two R2 units can be joined together to form a carbonyl unit; i) and mixtures thereof; each R8, R9a, R9b, and R10 are independently selected from hydrogen, C ^ alkyl, and mixtures thereof; R9a and R9b can be taken together to form a carbocyclic or heyerocyclic ring comprising from 3 to 7 atoms; two units of R10 can be pooled together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; j is an index from 0 to 5; Z is O, S, NR11 or ÑOR11; R11 is hydrogen or C4 alkyl, to prepare a medicament for the prevention of plasma levels of inflammatory cilocines in humans or higher mammals, further characterized in that the cyanococci are selected from TNF-α, IL-1β, and IL-6, coniroling or thereby irritating congestive heart failure in humans or higher mammals.

36. The use of a pharmaceutical composition containing one or more of the compounds, including all enanimeric and diastereomeric forms and pharmaceutically acceptable salts thereof, having the formula: wherein R is: a) -O [CH2] kR3; or b) -NR ^ R *; R3 is unsubstituted or unsubstituted substituted, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, unsubstituted or unsubstituted, unsubstituted or unsubstituted aryl or alkylenearyl, heteroaryl or unsubstituted or unsubstituted alkylene or heteroaryl heteroaryl; the index k is from 0 to 5; each R4a and R4 is independently: a) hydrogen; or b) - [C (R5aR5b)] mR6; each R5a and R5b is independently hydrogen, -OR7, -N (R7) 2, -CO2R7, -CON (R7) 2; C, -C 4 linear, branched or cyclic alkyl and mixtures thereof; R6 is hydrogen, -OR7, -N (R7) 2, -CO2R7, -CON (R7) 2; unsubstituted or unsubstituted alkyl CrC4, unsubstituted or unsubstituted heterocarbon, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 7 is hydrogen, a water-soluble cation, C, -C 4 -alkyl, or susi-substituted or non-substituted aryl; the index m is from 0 to 5; R1 is: a) unsubstituted or unsubstituted aryl; or b) heteroaryl unsubstituted or unsubstituted; L is a linking group selected from: i) - [C (R12) 2] n-; ii) - [C (R12) 2] nNR12 [C (R12) 2] n-; and iii) - [C (R12) 2] nO [C (R12) 2] -; R 12 is hydrogen, C 4 alkyl, and mixtures thereof; or two R12 units can be taken together to form a carbonyl unit; the index n is a unit from 0 to 2; each R2 unit is independently chosen from: a) hydrogen; b) - (CH jOÍCH ^ jR8; c) - (CH2) jNR9aR9b; d) - (CH2) jCO2R10; e) - (CH2) OCO2R10 f) - (CH2) JCON (R10) 2; g) - (CH2) JOCON (R10) 2; h) two R2 units can be joined together to form a carbonyl unit; i) and mixtures thereof; each R8, R9a, R9b, and R10 are independently selected from hydrogen, C, -C4 alkyl, and mixtures thereof; R9a and R9b can be taken together to form a carbocyclic or heyerocyclic ring comprising from 3 to 7 atoms; two units of R10 can be taken together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; j is an index from 0 to 5; Z is O, S, NR11 or ÑOR11; R11 is hydrogen or C4 alkyl, to prepare a medicament for treating Crohn's disease or alleviating its symptoms in humans by controlling the extracellular release of cytokines.