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. "These molecules are understood to mediate the inflammatory response associated with the immunological recognition of infectious agents.

These pro-inflammatory cytokines are suggested as an important mediators in many disease states or syndromes, inter alia, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease (IBS), septic shock, cardiopulmonary dysfunction, acute respiratory disease, cachexia, and therefore responsible for the progression and manifestation of human disease states.

There is therefore a long felt need for compounds and pharmaceutical compositions which comprise compounds, which can block, abate, control, mitigate, or prevent the release of cytokines from cells which produce them SUMMARY OF THE INVENTION The present invention meets the aforementioned needs in that it has been surprisingly found that certain [5,6] and [5,6, 6] fused ring pyrazolones and derivatives thereof are effective for inhibiting release of inflammatory cytokines, inter alia, interleukin-1 (IL-1) and tumor necrosis factor (TNF) from cells and thereby preventing, abating, or otherwise controlling enzymes which are proposed to be the active components responsible for the herein described disease states.

The first aspect of the present invention relates to compounds, including all enantiomeric and diasteriomeric forms and pharmaceutical acceptable salts thereof, said compounds having the formula: wherein R is : a) hydrogen; b)-O (CH2) kR3 ; or C)-NR4aR4b ; R3 is substituted or unsubstituted Ci-C4 alkyl, substituted or unsubstituted cyclic hydrocarbyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl ; the index k is from 0 to 5; R4a and R4b are each independently : a) hydrogen; or b)- [C(R5aR5b)]xR6; each R5a and R5b are independently hydrogen, -OR7, -N (R7)2, -CO2R7, -CON(R7)2 ; Ci-C4 linear, branched, or cyclic alkyl, and mixtures thereof ; R6 is hydrogen,-OR,-N (R7) 2, -CO2R7,- CON (R7) 2; substituted or unsubstituted Ci-C4 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl ; R7is hydrogen, a water-soluble cation, Cl-C4 alkyl, or substituted or unsubstituted aryl ; the index x is from 0 to 5; R1 is : a) substituted or unsubstituted aryl ; or b) substituted or unsubstituted heteroaryl ; R2a and R2b units are each independently selected from the group consisting of: a) hydrogen; b)-O (CH2) jR8 ; c) -(CH2)jNR9aR9b; d) -(CH2)jCO2R10 ; e) -(CH2)jOCO2R10 f) -(CH2)jCON(R10)2 ; g) two R2a or two R2b units from the same carbon atom can be taken together to form a carbonyl unit; h) one R2a and one R2b are taken together to form a double bond; i) one R2a and one R2b are taken together to form a substituted or unsubstituted ring comprising from 4 to 8 atoms, said ring selected from the group consisting of: i) carbocyclic ; ii) heterocyclic ; iii) aryl ; iv) heteroaryl ;, v) bicyclic ; and vi) heterobicyclic ; j) and mixtures thereof; R8, R9a, R9b, and R10 are each independently hydrogen, Ci-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 R10 units can be take together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; j is an index from 0 to 5; m is an index from 1 to 5, n is an index from 1 to 5; m + n = from 2 to 6.

Another aspect of the present invention relates to pharmaceutical compositions which can deliver the compounds of the present invention to a human or higher mammal, said compositions comprising: a) an effective amount of one or more of the compounds according to the present invention; and b) one or more pharmaceutically acceptable excipients.

A further aspect of the present invention relates to methods for controlling one or more inflammatory cytokine mediated or inflammatory cytokine modulated mammalian diseases or conditions, said method comprising the step of administering to a human or higher mammal and effective amount of a composition comprising one or more of the compounds according to the present invention.

These and other objects, features, and advantages will become apparent to those of ordinary skill in the art from a reading of the following detailed description and the appended claims. All percentages, ratios and proportions herein are by weight, unless otherwise specified.

All temperatures are in degrees Celsius (° C) unless otherwise specified. All documents cited are in relevant part, incorporated herein by reference; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds which are capable of mediating, controlling or otherwise inhibiting the extracellular release of certain cytokines, especially inflammatory cytokines, said cytokines playing a role in the stimulation, cause or manifestation of a wide variety of diseases, disease states, or syndromes.

For the purposes of the present invention the term"hydrocarbyl"is defined herein as any organic unit or moiety which is comprised of carbon atoms and hydrogen atoms. Included within the term hydrocarbyl are the heterocycles which are described herein below. Examples of various unsubstituted non-heterocyclic hydrocarbyl units include pentyl, 3-ethyloctanyl, 1, 3-dimethylphenyl, cyclohexyl, cis-3-hexyl, 7, 7-dimethylbicyclo [2.2. 1]-heptan-1-yl, and naphth-2-yl.

Included within the definition of"hydrocarbyl"are the aromatic (aryl) and non-aromatic carbocyclic rings, non-limiting examples of which include cyclopropyl, cyclobutanyl, cyclopentanyl, cyclohexane, cyclohexenyl, cycloheptanyl, bicyclo- [0. 1. 1]-butanyl, bicyclo- [0. 1. 2]-pentanyl, bicyclo- [0.1. 3]-hexanyl (thujanyl), bicyclo- [0. 2. 2]-hexanyl, bicyclo- [0. 1. 4]-heptanyl (caranyl), bicyclo- [2. 2.1]- heptanyl (norboranyl), bicyclo- [0. 2. 4]-octanyl (caryophyllenyl), spiropentanyl, diclyclopentanespiranyl, decalinyl, phenyl, benzyl, naphthyl, indenyl, 2H-indenyl, azulenyl, phenanthryl, anthryl, fluorenyl, acenaphthylenyl, 1,2, 3, 4-tetrahydronaphthalenyl, and the like.

The term"heterocycle"includes both aromatic (heteroaryl) and non-aromatic heterocyclic rings non-limiting examples of which include : pyrrolyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrazolyl, 2H- imidazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, isoxazolyl, oxazoyl, 1,2, 4-oxadiazolyl, 2H-pyranyl, 4H- pyranyl, 2H-pyran-2-one-yl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, s-triazinyl, 4H- 1, 2-oxazinyl, 2H-1, 3-oxazinyl, 1, 4-oxazinyl, morpholinyl, azepinyl, oxepinyl, 4H-1, 2-diazepinyl, indenyl 2H-indenyl, benzofuranyl, isobenzofuranyl, indolyl, 3H-indolyl, 1 H-indolyl, benzoxazolyl, 2H-1-benzopyranyl, quinolinyl, isoquinolinyl, quinazolinyl, 2H-1, 4-benzoxazinyl, pyrrolidinyl, pyrrolinyl, quinoxalinyl, furanyl, thiophenyl, benzimidazolyl, and the like each of which can be substituted or unsubstituted.

An example of a unit defined by the term"alkylenearyl"is a benzyl unit having the formula: whereas an example of a unit defined by the term"alkyleneheteroaryl"is a 2-picolyl unit having the formula: The term"substituted"is used throughout the specification. The term"substituted"is defined herein as"encompassing moieties or units which can replace a hydrogen atom, two hydrogen atoms, or three hydrogen atoms of a hydrocarbyl moiety. Also substituted can include replacement of hydrogen atoms on two adjacent carbons to form a new moiety or unit."For example, a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like. A two hydrogen atom replacement includes carbonyl, oximino, and the like.

A two hydrogen atom replacement from adjacent carbon atoms includes epoxy, and the like.

Three hydrogen replacement includes cyano, and the like. An epoxide unit is an example of a substituted unit which requires replacement of a hydrogen atom on adjacent carbons. The term substituted is used throughout the present specification to indicate that a hydrocarbyl moiety, inter alia, aromatic ring, alkyl chain, can have one or more of the hydrogen atoms replaced by a substituent. When a moiety is described as"substituted"any number of the hydrogen atoms may be replaced. For example, 4-hydroxyphenyl is a"substituted aromatic carbocyclic ring", (N, N- dimethyl-5-amino) octanyl is a"substituted C8 alkyl unit, 3-guanidinopropyl is a"substituted C3 alkyl unit, "and 2-carboxypyridinyl is a"substituted heteroaryl unit. "The following are non-limiting examples of units which can serve as a replacement for hydrogen atoms when a hydrocarbyl unit is described as"substituted." i) -[C(R12)2]p (CH=CH) qR12 ; wherein p is from 0 to 12; q is from 0 to 12; ii) -C (Z) R12; iii) -C(Z)2R12; iv) -C (Z) CH=CH2 ; v)-C (Z) N (R) 2 ; vi) -C(Z)NR12N(R12)2; vii) -CN; viii) -CNO; ix) -CF3, -CCl3, -CBr3 ; -N(R12)2; xi)-NR12CN ; xii)-NR C (Z) R ; xiii)-NR C (Z) N (R12)2 ; xiv) -NHN (R12)2 ; xv)-NHOR12 ; xvi) -NCS; xvii)-N02 ; xviii)-OR ; xix) -OCN; xx) -OCF3, -OCCl3, -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 Cl-C20 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, =NR12, and mixtures thereof. Suitable salt forming cations include, sodium, lithium, potassium, calcium, magnesium, ammonium, and the like.

The first aspect of the present invention as a whole, relates to novel compounds suitable for inhibiting release of inflammatory cytokines, said compounds having the formula: R is a substituent at the 2-position of the pyrimidin-4-yl portion of the general scaffold, said R unit is : a) an ether having the formula-0 [CH2] kR3 ; or b) a primary or secondary amino unit having the formula-NR4aR4b ; wherein R3 is substituted or unsubstituted Ci-C4 alkyl, substituted or unsubstituted cyclic hydrocarbyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl ; the index k is from 0 to 5.

The following are the various aspects of R units according to the present invention wherein R is an ether having the formula-O [CH2] kR3. However, the formulator is not limited to the herein exemplified iterations and examples.

A) R units encompassing ethers having the formula-OR3 (the index k equal to 0) and R3 is substituted or unsubstituted aryl. i) One 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 example of R: phenoxy, 2-fluorophenoxy, 3-fluorophenoxy, 4- fluorophenoxy, 2, 4-difluorophenoxy, 3-trifluoromethyl-phenoxy, 4- trifluoromethylphenoxy, 2, 4-trifluoromethyl phenoxy, and the like. 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) A further 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-methyoxy) 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 encompassing ethers having the formula-OR3 (the index k equal to 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 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 encompassing ethers having the formula-oCH2R3 (the index k 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. ii) A second iteration of this aspect of R wherein R is an ether having the formula -oCH2R3 and R3 is substituted or unsubstituted alkyleneheteroaryl. This iteration includes the following non-limiting examples: pyridin-3-ylethyl, (2-methyl-2-pyridin- 3-yl) ethyl, and the like.

D) R units encompassing ethers having the formula-OR3 (the index k equal to 1) and R3 is substituted or unsubstituted Ci-C4 alkyl. i) A first iteration of this aspect of R is an ether having the formula-OR3 and R3 is unsubstituted Ci-C4 linear, branched, or cyclic alkyl. This iteration includes the following non-limiting examples: methyl, ethyl, isopropyl, (S)-1-methypropyl, and the like. ii) A second iteration of this aspect of R is an ether having the formula-OR3 and R3 is a substituted C1-C4 linear, branched, or cyclic alkyl. This iteration includes the following non-limiting examples: 2-methoxyethyl, (S)-1-methy-3-methyoxypropyl, and the like.

The following are the various aspects of R units according to the present invention wherein R is an amine having the formula-NR4aR4b, R and R4b are each independently: a) hydrogen; or b) _ [C (R5aR5b)] xR6 ; each R5a and R5b are independently hydrogen,-oR7,-N (R7) 2,-CO2R7,-CoN (R7) 2; Cl-C4 linear, branched, or cyclic alkyl, and mixtures thereof; R6 is hydrogen, -OR7, -N (R7) 2,-Co2R7,- CON (R7) 2 ; substituted or unsubstituted Ci-C4 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl ; R7 is hydrogen, a water-soluble cation, Cl-C4 alkyl, or substituted or unsubstituted aryl ; the index x is from 0 to 5. However, the formulator is not limited to the herein exemplified iterations and examples.

A) R units encompassing chiral amino groups wherein R4a is hydrogen, R5a is hydrogen and R5b is methyl, said units having the formula: and the indicated stereochemistry. i) A first iteration of this aspect of R is an amine comprising an R6 which is substituted or unsubstituted phenyl. This iteration includes the following non- limiting examples: (S)-1-methyl-1-phenylmethylamino, (S)-1-methyl-1-(4- fluorophenyl) methylamino, (S)-1-methyl-1- (4-methylphenyl) methyl-amino, (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 comprising an R6 which is 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. iii) A third iteration of this aspect of R is an amine comprising an R6 which is Ci-C4 substituted or unsubstituted alkyl. This iteration includes the following non-limiting examples : (S)-1-methylpropylamino, (S)-1-methyl-2- (methoxy) ethylamino.

B) R units encompassing chiral amino groups wherein R4a is hydrogen, R5a and R5b are each Ci-C4 alkyl, said units having the formula: and the indicated stereochemistry when R5a, R5b and R6 are not the same. i) A first iteration of this aspect of R is an amine which does not have a chiral center, non-limiting examples of which includes 1, 1-dimethylethylamine, 1,1- dimethylbenzylamine and the like. ii) A second iteration of this aspect of R is an amine comprising an R6 which is substituted or unsubstituted Cl-C4 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 encompassing alkylenearyl amines wherein R4a is hydrogen, both R5a and R5b of R4b are hydrogen, R is substituted or unsubstituted aryl, said unit having the formula : wherein R11 is hydrogen or a"substituted unit"as defined herein above. i) A first iteration of this aspect comprises the following non-limiting examples of R units: benzylamino, (2-aminophenyl) methylamino ; (4-fluorophenyl) methylamino, (4-methoxyphenyl) methylamino ; (4-propanesulfonylphenyl) methylamino ; and the like. ii) A second iteration of this aspect comprises the following non-limiting examples of R units: (2-methylphenyl) methylamino ; (3-methylphenyl)-methylamino ; (4- methylphenyl) methylamino ; and the like.

D) R units encompassing amines wherein R4a is hydrogen, R4b comprises R5a equal to hydrogen and R5b equal to-Co2R7 or-CON (R7) ; said unit having the formula: i) A first iteration of this aspect of R is an amine comprising an R6 which is substituted or unsubstituted phenyl. This iteration includes the following non- limiting examples: wherein R"is hydrogen or a"substitute"as defined herein above. ii) A second iteration of this aspect of R is an amine comprising an R5 which is substituted or unsubstituted alkyl. This iteration includes the following non-limiting examples : R'units are selected from: a) substituted or unsubstituted aryl ; or b) substituted or unsubstituted heteroaryl.

The first aspect of R1 units encompasses halogen substituted phenyl units, non-limiting examples of which include 4-fluorophenyl, 2, 4-difluorophenyl, 4-chlorophenyl, and the like.

R2a and R2b units are each independently selected from the group consisting of: a) hydrogen; b)-O (CH2) jR8 ; c) -(CH2)jNR9aR9b; d)- (CH2) jC02R'° ; e)- (CH2) jOCO2R'° f)- (CH2) jCON (R'°) 2 ; g) two R2a or two R2b units from the same carbon atom can be taken together to form a carbonyl unit; h) one R2a and one R2b are taken together to form a double bond; i) one R2a and one R2b are taken together to form a substituted or unsubstituted ring comprising from 4 to 8 atoms, said ring selected from the group consisting of: i) carbocyclic ; ii) heterocyclic ; iii) aryl ; iv) heteroaryl ; v) bicyclic ; and vi) heterobicyclic ; j) and mixtures thereof; R8, R9a, R gb and R10 are each independently hydrogen, Ci-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 R10 units can be take together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; j is an index from 0 to 5.

[5, 61-Fused Rings Systems A first aspect of the present invention relates to ring scaffolds wherein the indices m and n are each equal to 2, thereby comprising a 2-(R1-substituted)-3-(2-R-substituted-pyrimidin-4-yl)- 5,6, 7, 8-tetrahydro-pyrazolo [1,2-a] pyridazin-1-one scaffolds having the formula: wherein the R2a and R2b units are each independently hydrogen,-(CH2) jCO2R1°,- (CH2) jCON (R10) 2, and mixtures thereof.

Iterations of this scaffold include the core scaffold having the formula: the 5,6, 7, 8-tetrahydro-pyrazolo [1, 2-a]-pyridazin-1-one 8-position esters and amides having the formula: as well as the 5,6, 7, 8-tetrahydro-pyrazolo [1, 2-a]-pyridazin-1-one 5-position esters and amides having the formula : A second aspect of the present invention as it relates to R2a and R2b units, comprises 2- (R1-substituted)-3-(2-R-substituted-pyrim idin-4-yl)-5, 6, 7, 8-tetrahydro-pyrazolo [1,2-a] pyridazin-1- one scaffolds having the formula: wherein each of the R2a and R2b units is independently selected form the group consisting of: a) hydrogen; b)-O (CH2) jR8; and c) -(CH2)jNR9aR9b.

Iterations of this aspect include 6-hydroxy-2-(R1-substituted)-3-(2-R-substituted-pyrimidin- 4-yl)-5, 6,7, 8-tetrahydro-pyrazolo [1, 2-a]-pyridazin-1-ones, 7-hydroxy-2-(R1-substituted)-3-(2-R- substituted-pyrimidin-4-yl)-5, 6,7, 8-tetrahydro-pyrazolo [1, 2-a]-pyridazin-1-ones, 6- (dimethylamino)- 2-(R1-substituted)-3-(2-R-substituted-pyrimidin-4-yl)-5,6, 7, 8-tetrahydro-pyrazolo [1, 2-a]-pyridazin-1- ones, 6-morpholino-2-(R1-substituted)-3-(2-R-substituted-pyrimidin -4-yl)-5,6, 7,8-tetrahydro- pyrazol [1,2-a]-pyridazin-1-ones A third aspect of the present invention as it relates to R2a and R2b units, comprises scaffolds wherein two adjacent R2a and R2b units are taken together to form a double bond, for example a 2-(R1-substituted)-3-(2-R-substituted-pyrim idin-4-yl)-5, 8-dihydro-pyrazolo [1,2-a]- pyridazin-1-one scaffolds having the formula: f5. 6, X1-Fused Rings Systems The present invention also relates to [5,6, X] -fused ring systems wherein X is a ring formed when one R2a and one R2b are taken together to form a substituted or unsubstituted ring comprising from 4 to 8 atoms. The rings formed are selected from the group consisting of: i) carbocyclic ; ii) heterocyclic ; iii) aryl ; iv) heteroaryl ; v) bicyclic ; and vi) heterobicyclic ; A first embodiment of this aspect relates to ring systems wherein one R2a and one R2b are taken together to form a 6-membered aryl ring, inter alia, the [5,6, 6]-fused rings system; 2-(R1- substituted)-3- (2-R-substituted-pyrimidin-4-yl)-5, 10-dihydro-pyrazolo [1, 2-b] phthalazin-1-one having the formula: Iterations of this aspect include analogs which are substituted on the C-ring, for example compounds having the formula: wherein R12 is a substituent as described herein above. A non-limiting example of the [5,6, 6] ring scaffolds of the present invention are the 2-(R1-substituted)-3-(2-R-substituted-pyrimidin-4-yl)- 5, 10-dihydro-pyrazolo [1, 2-b] phthalazin-1-one ring scaffolds, for example the compound having the formula : The first aspect of Category I analogs capable of inhibiting release of inflammatory cytokines according to the present invention relates to compounds comprising a 5,10-dihydro- pyrazol [1, 2-b] phthalazine-1-one scaffold having the formula : wherein R units are amines having the formula-NH [CHR] R6, and R1, R4a, R5, and R6 are described herein below in Table I. The stereochemistry of R5b is the configuration shown when R5b is not hydrogen.

TABLE I No. R1 R4a R5b R6 4-fluorophenyl phenyl 2 4-fluorophenyl H H 4-fluorophenyl 3 4-fluorophenyl H H 2-aminophenyl 4 4-fluorophenyl H H 2-methylphenyl 4-fluorophenyl 4-methylphenyl 4-fluorophenyl 4-methoxyphenyl 7 4-fluorophenyl H H 4-(propanesulfonyl)phenyl 8 4-fluorophenyl H H 3-benzo [1, 3] dioxol-5-yl 9 4-fluorophenyl H H pyridin-2-yl 10 4-fluorophenyl pyridin-3-yl 11 4-fluorophenyl H H 12 4-fluorophenyl H H methyl 4-fluorophenyl ethyl 14 4-fluorophenyl H H vinyl 15 4-fluorophenyl cyclopropyl 16 4-fluorophenyl H H cyclohexyl 17 4-fluorophenyl methoxymethyl 18 4-fluorophenyl H H methoxyethyl 19 4-fluorophenyl H H 1-hydroxy-1-methylethyl 20 4-fluorophenyl H H -CO2H 21 4-fluorophenyl H methyl phenyl 22 4-fluorophenyl H methyl 4-fluorophenyl 23 4-fluorophenyl H methyl 2-aminophenyl 24 4-fluorophenyl H methyl 2-methylphenyl 25 4-fluorophenyl methyl 4-methylphenyl 26 4-fluorophenyl methyl 4-methoxyphenyl 27 4-fluorophenyl H methyl 4- (propanesulfonyl) phenyl 28 4-fluorophenyl H methyl 3-benzo [1,3] dioxol-5-yl 29 4-fluorophenyl H methyl pyridin-2-yl 30 4-fluorophenyl H methyl pyridin-3-yl 31 4-fluorophenyl H methyl H 32 4-fluorophenyl H methyl methyl 33 4-fluorophenyl H methyl ethyl 34 4-fluorophenyl methyl vinyl 35 4-fluorophenyl methyl cyclopropyl 36 4-fluorophenyl methyl cyclohexyl 37 4-fluorophenyl H methyl methoxymethyl 38 4-fluorophenyl H methyl methoxyethyl - methyl 1-hydroxy-1-methylethyl 40 4-fluorophenyl H methyl-CO2H 41 3-trifluoromethylphenyl methyl phenyl 42 3-trifluoromethylphenyl H methyl 4-fluorophenyl 43 3-trifluoromethylphenyl H methyl 2-aminophenyl 44 3-trifluoromethylphenyl H methyl 2-methylphenyl 45 3-trifluoromethylphenyl H methyl 4-methylphenyl 46 3-trifluoromethylphenyl H methyl 4-methoxyphenyl 47 3-trifluoromethylphenyl H methyl 4- (propanesulfonyl) phenyl 48 3-trifluoromethylphenyl H methyl 3-benzo [1,3] dioxol-5-yl 49 3-trifluoromethylphenyl H methyl pyridin-2-yl 50 3-trifluoromethylphenyl H methyl pyridin-3-yl 51 3-trifluoromethylphenyl H methyl H 52 3-trifluoromethylphenyl H methyl methyl 53 3-trifluoromethylphenyl H methyl ethyl 54 3-trifluoromethylphenyl methyl vinyl 55 3-trifluoromethylphenyl H methyl cyclopropyl 56 3-trifluoromethylphenyl H methyl cyclohexyl 57 3-trifluoromethylphenyl H methyl methoxymethyl 58 3-trifluoromethylphenyl H methyl methoxyethyl 59 3-trifluoromethylphenyl H methyl 1-hydroxy-1-methylethyl 60 3-trifluoromethylphenyl H methyl -CO2H The following is a scheme for preparing compounds belonging to the first aspect of Category I according to the present invention. The first stage encompasses utilization of Type I intermediates, for example, intermediate 3 to introduce the selected R'unit into the assembling scaffold.

General Scheme for Intermediate Type I Reagents and conditions: (a) LDA, THF,-78 °C, 45 min.

Reagents and conditions: (b) CrO3, CH2CI2, rt, 16 hr.

EXAMPLE 1 2- (4-Fluorophenvl)-3- (2-methvlsulfanvl-pvrimidin-4-vl)-3-oxo- propionic acid methyl ester (3) The following is a procedure for the preparation of 2-methylsulfanyl-pyrimidine-4- carbaldehyde, 1, adapted from the procedure of H. Bredereck et al., Chem. Ber. , 97, pp 3407- 3417 (1964) included herein by reference.

To a 12 L 3-neck flask under inert atmosphere is charged N, N-dimethyl-formamide dimethyl acetyl (801 g) and pyruvic aldehyde dimethyl acetal (779 g). The mixture is heated to reflux for 18 hours during which time the temperature decreases 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 allowing the mixture to stir about 15 minutes, sodium methoxide (741 g, 13.7 mol) is added in 4 equal portions over 1 hour while maintaining the solution temperature in the range of 18-28 °C. The mixture is stirred for 5 hours at room temperature, cooled to 20 °C, then methyl iodide (2 kg) is added over 1.25 hours while maintaining the reaction temperature in the range of 17-29 °C. Stirring is continued for 18 hours at room temperature. The methanol and unreacted methyl iodide is removed by heating the solution at 35 °C @ 40 torr to produce about 4.46 kg of a dark residue which is partitioned between 14 L of water and 5 L of ethyl acetate. The water fraction is extracted a second time with ethyl acetate, the organic layers combined and concentrated in vacuo too afford 685 g of an oil which is purified over silica to 522 g of 4-dimethoxymethyl-2-methylsulfanyl- pyrimidine.

The dimethyl acetal obtained above is then hydrolyzed to the free aldehyde by heating to 60 °C for 3 hours in 1 M HCI. Workup for neutral using ethyl acetate to extract the product affords 347 g crude product which is purified over silica to afford 401 g of 2-methylsulfanyll-pyrimidine-4- carbaldehyde, 1.

Preparation of 2- (4-fluorophenyl)-3- (2-methylsulfanyl-pyrimidin-4-yl)-3- hydroxypropionic acid methyl ester (2): To a cold (-78 °C) solution of lithium diisopropylamide (21.4 mL of 2M solution in THF, 42.8 mmol) in THF (70 mL) is added dropwise a solution of methyl 4-fluorophenyl-acetate (6.0 g, 35.7 mmol) in THF (30 mL). The solution is stirred for 1 hour at-78 °C after which a solution of 2-methylsulfanyll-pyrimidine-4-carbaldehyde, 1, (6.0 g, 39.3 mmol) in THF (30 mL) is added dropwise to the reaction mixture. Stirring is continued for 45 minutes at-78 °C then the reaction is quenched by pouring the reaction solution into aqueous saturated NH4CI. The aqueous phase is extracted with ethyl acetate. The organic phases combined, dried (MgS04), filtered, and concentrated in vacuo. The crude residue is purified over silica (33% EtOAc/hexanes) to afford 8.7 g (76%) of the desired product as a mixture (1: 1) of diastereomers.

Preparation of 2- (4-fluorophenyl)-3- (2-methylsulfanyi-pyrimidin-4-yi)-3-oxo- propionic acid methyl ester (3): To a suspension of Cr03 in CH2CI2 (300 mL) is added pyridine.

The mixture is stirred vigorously for 1 hour at room temp. A solution of the crude 2- (4- fluorophenyl)-3- (2-methylsulfanyl-pyrimidin-4-yl)-3-hydroxypropionic acid methyl ester, 2, prepared above in CH2CI2 (50 mL) is added dropwise to the chromium suspension. The reaction mixture is stirred at room temperature for 16 hours, diluted with ether (1 L) and filtered through a pad of Celite. The filtrate is concentrated in vacuo and the resulting residue is purified over silica (25% EtOAc/hexanes) to afford 3.7 g (43% yield) of the desired product as a yellow solid.

The following example relates to the formation of 6, 7-dihydro-5H-pyrazolo [1,2-a] pyrazol-1- one ring systems utilizing pyrazolidine, however the formulator may substitute other cyclic hydrazine reagents to achieve other scaffolds according to the present invention, inter alia, the use of hexahydro-pyridazine to prepare 5,6, 7, 8-tetrahydro-pyrazolo [1,2-a] pyridazin-1-ones. In the example herein below, intermediate 3, prepared by the method described herein above is use to introduce as R'a 4-fluorophenyl unit, however, substitution for this unit can be accomplished during the preparation of the p-ketoester intermediate.

The following scheme illustrates the preparation of Intermediate Type II, for example, intermediate 5, which encompasses scaffold rings B and C.

General Scheme for Intermediate Type II 4 Reagents and conditions: (a) NaH, DMF, 90 °C, 3 hr.

Reagents and conditions: (b) SOCI2, MeOH, rt, 72 hr.

EXAMPLE 2 1, 2, 3, 4-Tetrahydrophthalazine (5) Preparation of 1, 4-dihydrophthalazine-2, 3-dicarboxylic acid di-fert-butyl ester (4): To a solution of di-tert-butylhydrazodiformate (3.0 g, 13.0 mmol) in DMF (20 mL) at room temp is added NaH (0.5 g, 13.0 mmol). After stirring 1 hour at room temp, 1, 2-bis-bromomethylbenzene (3.4 g, 13.0 mmol) is added to the reaction mixture. After stirring 1 hour at room temperature, another portion of NaH (0.5 g, 13.0 mmol) is added to the reaction mixture. The mixture is then heated to 90 °C for 3 hours, allowed to cool to room temperature and stirring is continued at room temp for 15 hours. The reaction can then be quenched by pouring the reaction solution into aqueous saturated NH4CI. The aqueous phase is extracted with ether, the organic phase dried (MgSO4), filtered and concentrated in vacuo. The crude residue is purified over silica (5% EtOAc/hexanes) to afford 1.0 g (23% yield) of the desired product as a clear oil.

Preparation of 1, 2,3, 4-tetrahydrophthalazine (5): 1, 4-dihydrophthalazine-2, 3- dicarboxylic acid di-tert-butyl ester, 4, (1.0 g, 3 mmol) is dissolved in MeOH (20 mL) and SOC) 2 (0.5 mL) added dropwise. After stirring at room temp for 72 hours, the solvent is removed in vacuo to afford 0.6 g of the desired product as white solid.

The following scheme illustrates the assembly of the 3-pyrimidin-4-yl-5, 10-dihydro- pyrazol [1, 2-b] phthalazine-1-one scaffold by the convergent step which condenses intermediates 3 and 5. The resulting intermediate is then transformed into the final compound having the selected R unit.

Reagents and conditions: (c) pyridine, reflux 16 hr.

Reagents and conditions: (d) OXONE°, THF/MeOH, rt 2 hr.

Reagents and conditions: (e) toluene, 140 °C 12 hr.

EXAMPLE 3 2-(4-Fluorophenyl)-3-[2-(S)-(1-phenylethylamino)pyrimidin-4- yl]-5,10-dihydropyrazolo[1, 2- blphthalazin-1-one (8) Preparation of 1-(4-fluorophenyl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-5, 10- dihydropyrazolo [1, 2-b] phthalazin-1-one (6): To a solution of 1,2, 3, 4-tetrahydro-phthalazine, 5, (0. 3 g, 1.4 mmol) in pyridine (5 mL) is added 2- (4-fluorophenyl)-3- (2-methylsulfanyl-pyrimidin-4-yl)- 3-oxo-propionic acid methyl ester, 3, (0.4 g, 1.4 mmol). The reaction mixture is then heated to reflux for 16 hours. The solvent is removed in vacuo and the resulting residue was purified by preparative HPLC to afford 0.2 g (45% yield) of the desired product as a tan solid.

Preparation of 2- (4-fluorophenyl)-3- (2-methanesulfonyl-pyrimidin-4-yl)-5, 10- dihydropyrazolo [1,2-b] phthalazin-1-one (7): To a solution of 1- (4-fluorophenyl)-3- (2- methylsulfanyl-pyrimidin-4-yl)-5, 10-dihydropyrazolo [1, 2-b] phthalazin-1-one, 6, (2.4 g, 6.8 mmol) in THF: MeOH (80 mL of 1: 1 mixture) is added dropwise a solution of OXONEe (16.8 g, 27.2 mmol) in H2O (80 mL). After stirring for 2 hours at room temperature the reaction mixture is diluted with aqueous saturated NaHC03 and extracted three times with ethyl acetate. The combined organic phases are dried (Na2SO4), filtered and concentrated in vacuo to afford 1.5 g (58% yield) of the desired product as a yellow solid.

Preparation of 2- (4-fluorophenyl)-3- [2- (S)- (1-phenylethylamino) pyrimidin-4-yl]-5, 10- dihydropyrazolo [1,2-b] phthalazin-1-one (8): 2- (4-fluorophenyl)-3- (2-methanesulfonyl-pyrimidin- 4-yl)-5, 10-dihydropyrazolo [1,2-b] phthalazin-1-one, 7, (0.9 g, 2.3 mmol) is dissolved in toluene (18 mL) together with (S)-(-)-a-methylbenzylamine (10.5 mL, 81.6 mmol). The resulting mixture is heated to 140 °C for 12 hours, cooled to room temperature and the solvent removed in vacuo.

The resulting residue is purified over silica (1: 1 EtOAc/hexanes) to afford 0.8 g (80% yield) of the desired product as a red sticky solid.

The first aspect of Category II analogs according to the present invention capable of inhibiting release of inflammatory cytokines relates to compounds comprising a 5,8-dihydro- pyrazol [1,2-a]-pyridazin-1-one scaffold wherein Rua and R2b are taken together to form a double bond, said scaffold having the formula: wherein R', R5b, and R6 are described in Table II. The stereochemistry of R5b is the configuration shown when R5b or R6is not hydrogen.

TABLE II No. R R R 61 4-fluorophenyl H phenyl 62 4-fluorophenyl H 4-fluorophenyl 63 4-fluorophenyl H 2-aminophenyl 64 4-fluorophenyl H 2-methylphenyl 65 4-fluorophenyl H 4-methylphenyl 66 4-fluorophenyl H 4-methoxyphenyl 67 4-fluorophenyl H 4- (propanesulfonyl) phenyl 68 4-fluorophenyl H 3-benzo [1,3] dioxol-5-yl 69 4-fluorophenyl H pyridin-2-yi 70 4-fluorophenyl H pyridin-3-yl 71 4-fluorophenyl 72 4-fluorophenyl H methyl 73 4-fluorophenyl H ethyl 74 4-fluorophenyl H vinyl 75 4-fluorophenyl H cyclopropyl 76 4-fluorophenyl cyclohexyl 77 4-fluorophenyl H methoxymethyl 78 4-fluorophenyl H methoxyethyl 79 4-fluorophenyl H 1-hydroxy-1-methylethyl 80 4-fluorophenyl H-C02H 81 4-fluorophenyl methyl phenyl 82 4-fluorophenyl methyl 4-fluorophenyl 83 4-fluorophenyl methyl 2-aminophenyl 84 4-fluorophenyl methyl 2-methylphenyl 85 4-fluorophenyl methyl 4-methylphenyl 86 4-fluorophenyl methyl 4-methoxyphenyl 87 4-fluorophenyl methyl 4-(propanesulfonyl)phenyl 88 4-fluorophenyl methyl 3-benzo [1,3] dioxol-5-yl 89 4-fluorophenyl methyl pyridin-2-yl 90 4-fluorophenyl methyl pyridin-3-yl 91 4-fluorophenyl methyl 92 4-fluorophenyl methyl methyl 93 4-fluorophenyl methyl ethyl 94 4-fluorophenyl methyl vinyl 95 4-fluorophenyl methyl cyclopropyl 96 4-fluorophenyl methyl cyclohexyl 97 4-fluorophenyl methyl methoxymethyl 98 4-fluorophenyl methyl methoxyethyl 99 4-fluorophenyl methyl 1-hydroxy-1-methylethyl 100 4-fluorophenyl methyl-CO2H The compounds which comprise the analogs of the first aspect of Category II can be prepared by the synthesis outline herein below in the following scheme.

Reagents and conditions: (a) NaH, DMF; 0 °C to 90 °C 4 hr.

Reagents and conditions: (b) SOCI2, MeOH ; 0 °C, 17 hr.

Reagents and conditions: (c) pyridine, 90 °C, 16 hr.

Reagents and conditions: (d) AXONE@, THF/MeOH/water; rt 2 hr.

Reagents and conditions: (e) (S)- (-)-a-methylbenzylamine, toluene; 140 °C for 12 hr.

EXAMPLE 4 2- (4-Fluorophenvl)-3-f2- (1-phenvlethvlamino) pvrimidin-4-v11-5, 8=dihvdro- ovrazolof1 2-alpvridazin-1-one (13) Preparation of 3, 6-dihydro-pyridazine-1, 2-dicarboxylic acid di-tert-butyl ester (9): To a solution of di-tert-butylhydrazodiformate (18.6 g, 80.0 mmol) in DMF (220 mL) cooled to 0 °C is added NaH (8.0 g of a 60% suspension in mineral oil, 200. 0 mmol) portionwise. After allowing the solution to warm and stir 45 minutes at room temp, cis-1, 4-dichloro-2-butene (8.4 mL, 80.0 mmol) is added dropwise to the reaction mixture. The mixture is then heated at 90 °C for 4 hours, cooled to room temperature and stirred an additional 15 hours. The reaction is quenched by pouring the contents of the reaction vessel into ice water. The resulting aqueous phase is extracted with ether, the combined organic phases washed with aqueous saturated NaHCO3, dried, filtered and concentrated in vacuo. The obtained crude product is taken up in hexane and the resulting solid recovered by filtration to afford 24 g of the desired product as white powder.

Preparation of 1,2, 3,4-tetrahydro-pyridazine (10): To a solution of 3,6-dihydro- pyridazine-1, 2-dicarboxylic acid di-fert-butyl ester, 9, (10.0 g, 35.2 mmol) in MeOH (140 mL) at 0 °C is added dropwise SOC12 (22.0 mL). After gradually warming to room temp and stirring for 17 hours, the solvent is removed in vacuo yielding a tan solid. The isolated solid is then dissolved in MeOH (10 mL) and diluted with ether (250 mL). The resulting white solid is collected by filtration to afford 4.3 g (79% yield) of the desired product as the di-HCI salt.

Preparation of 2-(4-fluorophenyl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-2,3,5 ,8- tetrahydro-pyrazolo [1, 2-a] pyridazin-1-one (11) To a solution of 1,2, 3,4-tetrahydro-pyridazine, 5, (5.4 g, 34.2 mmol) in pyridine (100 mL) is added 2- (4-fluorophenyl)-3- (2-methylsulfanyi-pyrimidin- 4-yl)-3-oxo-propionic acid methyl ester, 3, (7.3 g, 22.8 mmol). The reaction mixture is heated to 90 °C for 16 hours. The solvent is then removed in vacuo and the resulting residue purified over silica (100% EtOAc) to afford 3.5 g (43% yield) of the desired product as a yellow solid.

Preparation of 2- (4-fluorophenyl)-3- (2-methanesulfonyl-pyrimidin-4-yl)-2, 3,5, 8- tetrahydro-pyrazolo [1,2-a] pyridazin-1-one (12): To a solution of 2- (4-fluorophenyl)-3- (2- methylsulfanyl-pyrimidin-4-yl)-2, 3,5, 8-tetrahydro-pyrazolo [1,2-a] pyridazin-1-one, 11, (2.4 g, 6.8 mmol) in THF: MeOH (80 mL of 1: 1 mixture) is added dropwise a solution of OXONE (16.8 g, 27.2 mmol) in H2O (80 mL). After stirring 2 hours at room temp, the reaction mixture is diluted with aqueous saturated NaHC03 and extracted with EtOAc (3x). The combined organic phases are dried, filtered, and concentrated in vacuo to afford 1.5 g (58% yield) of the desired product as a yellow solid.

Preparation of 2- (4-fluorophenyl)-3- [2- (1- (S)-phenylethylamino) pyrimidin-4-yl]-5, 8- dihydropyrazolo [1,2-a] pyridazin-1-one (13) : 2- (4-Fluorophenyl)-3- (2-methanesulfonyl- pyrimidin-4-yl)-2, 3,5, 8-tetrahydro-pyrazolo [1,2-a] pyridazin-1-one, 12, (0.9 g, 2.3 mmol) is dissolved in toluene (18 mL) and (S)-(-)-a-methylbenzylamine (10.5 mL, 81.6 mmol) added. The resulting mixture is heated to 140 °C for 12 hours, cooled, and the solvent removed in vacuo. The resulting crude product is purified over silica (1: 1 EtOAc/hexanes) to afford 0.8 g (80% yield) of the desired product as a red sticky solid.

The second aspect of Category II analogs according to the present invention capable of inhibiting release of inflammatory cytokines relates to compounds comprising a 5,6, 7,8-tetrahydro- pyrazol [1, 2-a]-pyridazin-1-one scaffold having the formula: wherein R, R', R2a, and R2b are described herein Table III TABLE III No. R1 R2a R 101 4-fluorophenyl H-OH 1- (S)-phenylethylamino 102 4-fluorophenyl H-OH 1- (S)- (4-fluorophenyl) ethylamino 103 4-fluorophenyl H-OH 1- (S)- (2-aminophenyl) ethylamino 104 4-fluorophenyl H-OH 1- (S)- (2-methylphenyl) ethylamino 105 4-fluorophenyl H-OH 1- (S)- (4-methylphenyl) ethylamino 106 4-fluorophenyl H-OH 1- (S)- (4-methoxyphenyl) ethylamino 107 4-fluorophenyl H-OH 1- (S)- (4-propanesulfonylphenyl) ethylamino 108 4-fluorophenyl H -OH 1-(S)-(3-benzo [1,3] dioxol-5-yl) ethylamin 109 4-fluorophenyl H-OH 1- (S)- (pyridin-2-yl) ethylamino 110 4-fluorophenyl H -OH 1-(S)-(pyridin-3-yl)ethylamino 111 4-fluorophenyl H-OH methylamino 112 4-fluorophenyl H -OH ethylamino 113 4-fluorophenyl H -OH propylamino 114 4-fluorophenyl H-OH cyclopropylamino 115 4-fluorophenyl-OH cyclopropylmethylamino 116 4-fluorophenyl H -OH tert-butylamino 117 4-fluorophenyl H -OH 1-(S)-(cyclopropyl)ethylamino 118 4-fluorophenyl H -OH 1-(S)-cyclopropylmethyl)ethylamino 119 4-fluorophenyl H -OH 1-(R)-(α)-(carboxy)benzylamino 120 4-fluorophenyl H -OH 1-(S)-(α)-(methyl)benzylamino 121 4-fluorophenyl -OH -OH 1-(S0-phenylethylamino 122 4-fluorophenyl-OH-OH 1- (S)- (4-fluorophenyl) ethylamino 123 4-fluorophenyl-OH-OH 1- (S)- (2-aminophenyl) ethylamino 124 4-fluorophenyl -OH -OH 1-(S)-(2-methylphenyl0ethylamino 125 4-fluorophenyl-OH-OH 1- (S)- (4-methylphenyl) ethylamino 126 4-fluorophenyl-OH-OH 1- (S)- (4-methoxyphenyl) ethylamino 127 4-fluorophenyl-OH-OH 1- (S)- (4-propanesulfonylphenyl) ethylamino 128 4-fluorophenyl-OH-OH 1- (S)- (3-benzo [1,3] dioxol-5-yl) ethylamin 129 4-fluorophenyl-OH-OH 1- (S)- (pyridin-2-yl) ethylamino 130 4-fluorophenyl -OH -OH 1-(S)-(pyridin-3-yl)ethylamino 131 4-fluorophenyl-OH-OH methylamino 132 4-fluorophenyl-OH-OH ethylamino 133 4-fluorophenyl-OH-OH propylamino 134 4-fluorophenyl-OH-OH cyclopropylamino 135 4-fluorophenyl-OH-OH cyclopropylmethylamino 136 4-fluorophenyl-OH-OH tert-butylamino 137 4-fluorophenyl -OH -OH 1-(S)-(cyclopropyl)ethylamino 138 4-fluorophenyl -OH -OH 1-(S)-(cyclopropylmethyl)ethylamino 139 4-fluorophenyl-OH-OH 1- (R)- (a)- (carboxy) benzylamino 140 4-fluorophenyl-OH-OH 1- (S)- (a)- (methyl) benzylamino 141 4-fluorophenyl-OCH3-OCH3 1- (S)-phenylethylamino 142 4-fluorophenyl -OCH3 -OCH3 1-(S)-(4-fluorophenyl)ethylamino 143 4-fluorophenyl-OCH3-OCH3 1- (S)- (2-aminophenyl) ethylamino 144 4-fluorophenyl -OCH3 -OCH3 1-(S)-(2-methylphenyl)ethylamino 145 4-fluorophenyl -OCH3 -OCH3 1-(S)-(4-methylphenyl)ethylamino 146 4-fluorophenyl-OCH3-OCH3 1- (S)- (4-methoxyphenyl) ethylamino 147 4-fluorophenyl-OCH3-OCH3 1- (S)- (4-propanesulfonylphenyl) ethylamino 148 4-fluorophenyl-OCH3-OCH3 1- (S)- (3-benzo [1,3] dioxol-5-yl) ethylamin 149 4-fluorophenyl -OCH3 -OCH3 1-(S)-(pyridin-2-yl)ethylamino 150 4-fluorophenyl-OCH3-OCH3 1-(S)-(pyridin-3-yl) ethylamino 151 4-fluorophenyl-OCH3-OCH3 methylamino 152 4-fluorophenyl-OCH3-OCH3 ethylamino 153 4-fluorophenyl-OCH3-OCH3 propylamino 154 4-fluorophenyl-OCH3-OCH3 cyclopropylamino 155 4-fluorophenyl-OCH3-OCH3 cyclopropylmethylamino 156 4-fluorophenyl-OCH3-OCH3 tert-butylamino 157 4-fluorophenyl -OCH3 -OCH3 1-(S)-(cyclopropyl)ethylamino 158 4-fluorophenyl-OCH3-OCH3 1- (S)- (cyclopropylmethyl) ethylamino 159 4-fluorophenyl -OCH3 -OCH3 1-(R)-(α)-(carboxy)benzylamino 160 4-fluorophenyl -OCH3 -OCH3 1-(S)-(α)-(methyl)benzylamino For the second aspect of Category II, intermediates such as compound 13, can be utilized to prepare the analogs listed in Table IV, for example, compound 14.

Reagents and conditions: (a) OS04, K3Fe (CN) 6 ; t-BuOH: H20, rt 12 hr.

EXAMPLE 5 <BR> <BR> <BR> <BR> <BR> 2- (4-Fluorophenvl)-6, 7-dihvdroxv-3-f2- (1-phenvlethvlamino) pvrimidin-4-vl1-<BR> <BR> <BR> <BR> <BR> <BR> <BR> 5, 6, 7"8=tetrahvdropvrazolo1, 2-alpvridazin-1-one (14) Preparation of 2- (4-Fluorophenyl)-6, 7-dihydroxy-3- [2- (1-phenylethylamino)- pyrimidin-4-yl]-5, 6, 7,, 8-tetrahydropyrazolo [1, 2-a] pyridazin-1-one (14): To a solution of 2- (4- fluorophenyl)-3-[2-(1-phenylethylamino)pyrimidin-4-yl]-5,8-d ihydro-pyrazolo[1, 2-a] pyridazin-1-one, 13, (0.8 g, 1.88 mmol) in t-BuOH : H20 (24 mL of 1: 1 mixture) is added K3Fe (CN) 6 (1.9 g, 5.64 mmol), K2CO3 (0.8 g, 5.6 mmol) and NaHC03 (0.5 g, 5.6 mmol), followed by osmium tetroxide (0.1 g, 0.3 mmol). The resulting mixture is stirred at room temperature for 12 hours. The reaction is quenched by the addition of aqueous saturated KHS04 solution (10 mL). The aqueous phase is extracted with EtOAc (3x) and the combined organic phases are dried, filtered and concentrated in vacuo. The resulting crude product is purified over silica (100% EtOAc) to afford 0.4 g (48% yield) of the desired product.

In addition, a compound such as 14 can itself be utilized as an intermediate to other analogs, for example, compound 15.

Reagents and conditions: (b) NaH, CH31, toluene, rt 62 hr.

EXAMPLE 6 2- (4-Fluorophenvl)-6, 7-dimethoxv-3-2- (1- (S)-phenvlethvlamino) pvrimidin-4-vll-5, 6, 7, 8- tetrahvdropvrazolof1, 2-alpvridazin-1-one (15) Preparation of 2- (4-fluorophenyl)-6, 7-dimethoxy-3- [2- (1- (S)-phenylethylamino)- pyrimidin-4-yl]-5, 6,7, 8-tetrahydropyrazolo [1,2-a] pyridazin-1-one (15): To a solution of 2- (4- fluorophenyl)-6, 7-dihydroxy-3- [2- (1-phenylethylamino) pyrimidin-4-yl]-5, 6, 7"8-tetrahydropyrazolo- [1,2-a] pyridazin-1-one, 14, (0.42 g, 0.91 mmol) in THF (2 mL) is added NaH (0.09 g, 2.30 mmol).

After stirring at room temp for 1 hour, methyl iodide (0.14 g, 2.30 mmol) is added dropwise to the reaction mixture. After stirring for 62 hours at room temp, the mixture is concentrated in vacuo, dissolved in EtOAc and washed with aqueous saturated NaHC03. The organic phase is dried, filtered, concentrated in vacuo and the resulting residue purified over silica (100% EtOAc) to afford 0.07 g (16% yield) of the desired product as a yellow solid.

The first aspect of Category III analogs according to the present invention capable of inhibiting release of inflammatory cytokines relates to compounds comprising a 5,6, 7,8-tetrahydro- pyrazol [1, 2-a]-pyridazin-1-one scaffold having the formula: wherein R comprises an ether. R, R1 and R10 are described herein below in Table II and the analogs have the indicated stereochemistry.

TABLE IV No. - 61 H 4-fluorophenyl phenoxy 62 H 4-fluorophenyl 2-fluorophenoxy 63 H 4-fluorophenyl 3-fluorophenoxy 64 H 4-fluorophenyl 4-fluorophenoxy 65 H 4-fluorophenyl 2, 6-difluorophenoxy 66 H 4-fluorophenyl 2-cyanophenoxy 67 H 4-fluorophenyl 3-cyanophenoxy 68 H 4-fluorophenyl 2-trifluoromethylphenoxy 69 H 4-fluorophenyl 4-trifluoromethylphenoxy 70 H 4-fluorophenyl 2-methylphenoxy 71 H 4-fluorophenyl 4-methylphenoxy 72 H 4-fluorophenyl 2, 4-dimethylphenoxy 73 H 4-fluorophenyl 3-N-acetylaminophenoxy 74 H 4-fluorophenyl 2-methoxyphenoxy 75 H 4-fluorophenyl 4-methoxyphenoxy 76 H 4-fluorophenyl 3-benzo [1,3] dioxol-5-yl 77 methyl 4-fluorophenyl phenoxy 78 methyl 4-fluorophenyl 2-fluorophenoxy 79 methyl 4-fluorophenyl 3-fluorophenoxy 80 methyl 4-fluorophenyl 4-fluorophenoxy 81 methyl 4-fluorophenyl 2, 6-difluorophenoxy 82 methyl 4-fluorophenyl 2-cyanophenoxy 83 methyl 4-fluorophenyl 3-cyanophenoxy 84 methyl 4-fluorophenyl 2-trifluoromethylphenoxy 85 methyl 4-fluorophenyl 4-trifluoromethylphenoxy 86 methyl 4-fluorophenyl 2-methylphenoxy 87 methyl 4-fluorophenyl 4-methylphenoxy 88 methyl 4-fluorophenyl 2, 4-dimethylphenoxy 89 methyl 4-fluorophenyl 3-N-acetylaminophenoxy 90 methyl 4-fluorophenyl 2-methoxyphenoxy 91 methyl 4-fluorophenyl 4-methoxyphenoxy 92 methyl 4-fluorophenyl 3-benzo [1,3] dioxol-5-yl 93 H 4-chlorophenyl phenoxy 94 H 4-chlorophenyl 2-fluorophenoxy 95 H 4-chlorophenyl 3-fluorophenoxy 96 H 4-chlorophenyl 4-fluorophenoxy 97 4-chlorophenyl 2, 6-difluorophenoxy 98 H 4-chlorophenyl 2-cyanophenoxy 99 H 4-chlorophenyl 3-cyanophenoxy 100 H 4-chlorophenyl 2-trifluoromethylphenoxy 101 H 4-chlorophenyl 4-trifluoromethylphenoxy 102 H 4-chlorophenyl 2-methylphenoxy 103 H 4-chlorophenyl 4-methylphenoxy 104 4-chlorophenyl 2, 4-dimethylphenoxy 105 H 4-chlorophenyl 3-N-acetylaminophenoxy 106 H 4-chlorophenyl 2-methoxyphenoxy 107 4-chlorophenyl 4-methoxyphenoxy 108 H 4-chlorophenyl 3-benzo [1,3] dioxol-5-yl 109 methyl 4-chlorophenyl phenoxy 110 methyl 4-chlorophenyl 2-fluorophenoxy 111 methyl 4-chlorophenyl 3-fluorophenoxy 112 methyl 4-chlorophenyl 4-fluorophenoxy 113 methyl 4-chlorophenyl 2, 6-difluorophenoxy 114 methyl 4-chlorophenyl 2-cyanophenoxy 115 methyl 4-chlorophenyl 3-cyanophenoxy 116 methyl 4-chlorophenyl 2-0trifluoromethylphenoxy 117 methyl 4-chlorophenyl 4-trifluoromethylphenoxy 118 methyl 4-chlorophenyl 2-methylphenoxy 119 methyl 4-chlorophenyl 4-methylphenoxy 120 methyl 4-chlorophenyl 2, 4-dimethylphenoxy 121 methyl 4-chlorophenyl 3-N-acetylaminophenoxy 122 methyl 4-chlorophenyl 2-methoxyphenoxy 123 methyl 4-chlorophenyl 4-methoxyphenoxy 124 methyl 4-chlorophenyl 3-benzo [1,3] dioxol-5-yl The compounds which comprise the analogs of the first aspect of Category III can be prepared by the synthesis outline herein below in the following scheme.

Reagents and conditions: (a) C2O2CL2, CH2CI2 ; rt 18 hr.

Reagents and conditions: (b) CH2CI2, rt 3 hr.

Reagents and conditions: (c) TEA, CH2Cl2, ; rt 18 hr.

Reagents and conditions: (d) NaOH, MeOH, rt 20 min.

Reagents and conditions: (e) TMS-CHN2, CH2CI2/MeOH ; 20 min rt.

Reagents and conditions: (f) OXONE#, THF/MeOH, rt 4 hr Reagents and conditions: (g) phenol, NaH, THF; rt 1 hr.

EXAMPLE 7 2-(4-Fluorophenyl)-3-oxo-1-(3-phenoxyphenyl)-5,6,7,8-tetradh dro-3H-pyrazolo[1,2- alpvridazine-5-carboxvlic acid methyl ester (22) Preparation of 2-methylsulfanyl-pyrimidine-4-carbonyl chloride (16): To a solution of 2-methylsulfanyl-pyrimidine-4-carboxylic acid (20 g, 117.7 mmol) in CH2CI2 (100 mL) is added oxalyl chloride (17.2 g, 197 mmol) and DMF (20 drops). The reaction solution is stirred at room temperature for 18 hours after which the solvent is removed in vacuo to afford 21.2 g, (95% yield) of the desired product as a dark green solid.

Preparation of 1-(methylsulfanyl-pyrimidine-4-carbonyl) hexahydro-pyridazine-3- carboxylic acid methyl ester (17): To a solution of hexahydro-pyridazine-3-carboxylic acid methyl ester (1.5 g, 8.3 mmol) in CH2CI2 (80 mL) is added 2-methylsulfanyl-pyrimidine-4-carbonyl chloride, 16, (1.. 41 g, 7.5 mmol) and triethylamine (1.2 mL, 8.3 mmol). The mixture is stirred at room temperature for 3 hours. The reaction solution is then diluted with1 N HCI (100 mL) and the organic phase is decanted. The aqueous phase is extracted with additional solvent and the organic layers are combined, dried, and concentrated in vacuo. The crude product is purified over silica (ethyl acetate/hexane 1: 1) to afford 0.9 g (36% yield) of the desired product as a yellow solid.

Preparation of 2- (4-fluorobenzoyl)-I- (2-methylsulfanyi-pyrimidine-4-carbonyl)- hexahydro-pyridazine-3-carboxylic acid methyl ester (18): To a solution of 1- (methylsulfanyl- pyrimidine-4-carbonyl) hexahydro-pyridazine-3-carboxylic acid methyl ester, 17, (0.9 g, 3 mmol) in CH2CI2 (80 mL) is added 4-fluorophenylacetyl chloride (0.63 mL, 4.6 mmol) and triethylamine (0.55 mL, 3.6 mmol). The reaction solution is stirred at room temperature for 18 hours then dilute with 1 N HCI (50 mL) and the organic layer decanted. The organic phase is extracted with additional solvent, the organic layers are combined, dried, and concentrated in vacuo to afford the crude product. The crude material is purified over silica (ethyl acetate/hexane 1: 1) to afford 1. 15 g (89% yield) of the desired product as a yellow solid.

Preparation of 2- (4-fluorophenyl)-I- (3-methylsulfanyi-pyrimidin-4-yl)-3-oxo-5, 6, 7, 8- tetrahydro-3H-pyrazolo [1, 2-a] pyridazine-5-carboxylic acid (19): To a solution of 2- (4- <BR> <BR> <BR> fluorobenzoyl)-1-(2-methylsulfanyl-pyrimidine-4-carbonyl)-he xahydro-pyridazine-3-carboxylic acid methyl ester, 18, (1.13 g, 2.62 mmol) in methanol (40 mL) is added NaOH (1.26 g, 31.4 mmol).

The reaction is stirred at room temperature for 20 minutes then diluted wit 1 N HCI (50 mL). The solution is extracted with ethyl acetate (3 x 250 mL), the organic layers are combined, dried, and concentrated in vacuo to afford 0.83 g (79% yield). of an oil which is used without further purification.

Preparation of 2- (4-fluorophenyl)-I- (3-methylsulfanyi-pyrimidin-4-yi)-3-oxo-5, 6,7, 8- tetrahydro-3H-pyrazolo [1,2-a] pyridazine-5-carboxylic acid methyl ester (20): To a solution of 2- (4fluorophenyl)-1- (3-methylsulfanylphenyl)-3-oxo-5, 6,7, 8-tetrahydro-3H-pyrazolo [1,2- a] pyridazine-5-carboxylic acid, 19, (0.83 g, 2.1 mmol) in methylene chloride (50 mL) is added trimethylsilyl-diazomethane (1.5 mL of a 2 M solution is hexane, 3 mmol). The reaction is stirred for 20 minutes at room temperature then concentrated in vacuo to afford the crude product as an oil which is purified over silica (hexane/ethyl acetate 1: 4) to afford 0.51 g (59% yield) of the desired product as a yellow foam.

Preparation of 2- (4fluorophenyl)-I- (3-methanesulfonyi-pyrimidin-4-yl)-3-oxo-5, 6,7, 8- tetrahydro-3H-pyrazolo [1,2-a] pyridazine-5-carboxylic acid methyl ester (21): To a stirred solution of Preparation of 2- (4fluorophenyl)-1- (3-methylsulfanylphenyl)-3-oxo-5, 6,7, 8-tetrahydro- 3H-pyrazolo [1,2-a] pyridazine-5-carboxylic acid methyl ester, 20, (0.51, 1.23 mmol) in methanol (30 mL) is cooled to 0 °C. Oxone (2.27 g, 3.7 mmol) is dissolved in water (30 mL) and added dropwise to the reaction solution over 1 hour. The solution is allowed to warm to room temperature and stir a total of 3 additional hours. NaHC03 (sat. ) is added until the pH is about 7.

The reaction solution is then extracted several times with ethyl acetate, the organic phases combined, dried, and concentrated in vacuo to afford 0.5 g (91 % yield) of the desired product as a yellow foam.

Preparation of 2- (4-fluorophenyl)-1- (2-phenoxy-pyrimidin-4-yl)-3-oxo-5, 6,7, 8- tetrahydro-3H-pyrazolo [1,2-a] pyridazine-5-carboxylic acid methyl ester (22): To a solution of 2- (4fluorophenyl)-1- (3-methanesulfonyl-pyrimidin-4-yl)-3-oxo-5, 6,7, 8-tetrahydro-3H-pyrazolo [1,2- a] pyridazine-5-carboxylic acid methyl ester, 21, (0.033 g, 0.074 mmol) in THF (3 mL) is added phenol and NaH (0.009 g, 0.22 mmol). The reaction mixture is stirred at room temperature for 1 hour. The reaction is quenched by the addition of 1 N HCI (20 mL) and the solution is extracted with ethyl acetate (3 x 25 mL). The organic phases are combined, washed with brine, dried, and concentrated in vacuo to afford the crude product which is purified over silica (hexanes/ethyl acetate 1: 3) to afford 0.012 g (35% yield) of the desired product as a white solid. 1H NMR (300 MHz, CDCI3) 8 8.64 (d, J = 4.6 Hz 1 H), 7.59-7. 63 (m, 2 H), 7.40-7. 45 (m, 3 H), 7.28-7. 30 (m, 1 H), 7. 18 (d, J = 8.4 Hz, 2 H), 7.03-7. 08 (m, 2 H), 4.50-4. 56 (m, 1 H), 3.99-4. 04 (m, 1 H), 3.86 (s, 1 H), 3.01-3. 10 (m, 1 H), 2.33-2. 41 (m, 1 H), 1.86 (br s, 2 H), 1.64 (br s, 3 H) ; ESI/MS : 461 (M+H).

Other compounds according to this aspect of Category I I I can be formed by the following procedure.

Reagents and conditions: (a) LiOH, MeOH/water, ret, 3 hr.

EXAMPLE 8 Preparation of 2- (4-fluorophenyl)-1- (2-phenoxy-pyrimidin-4-yl)-3-oxo-5, 6,7, 8- tetrahydro-3H-pyrazolo [1,2-a] pyridazine-5-carboxylic acid (23): To a solution of 2- (4- fluorophenyl)-1- (2-phenoxy-pyrimidin-4-yl)-3-oxo-5, 6,7, 8-tetrahydro-3H-pyrazolo [1,2-a] pyridazine- 5-carboxylic acid methyl ester, 22, (0.02 g, 0.0143 mmol) in methanol (1 mL) and water (1 mL) is added LiOH (0.016 g, 0.65 mmol). The reaction solution is stirred at room temperature for 3 hours then quenched by the addition of 1 N HCI (20 mL). The reaction solution is extracted with ethyl acetate (3 x 50 mL), the organic layers are combined, washed with brine, dried, and concentrated in vacuo to afford 0.012 g (63% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCI3) 8 8.45 (dd, J = 4.6, 2.1 Hz, 1 H), 7.14-7. 44 (m, 7 H), 6.84-6.. 95 (m, 3 H), 4.93 (dd, J = 11.7, 9.3 Hz, 1 H), 4.23 (brd, J= 12.9 Hz, 1 H), 3.04-3. 11 (m, 1 H), 2.46-2. 52 (m, 2 H), 1.71-1. 93 (m, 2 H), APCI/MS : 447 (M + H).

2- (4-Fluorophenyl)-1- [2- (4-fluorophenoxy) pyrimidin-4-yl]-3-oxo-5, 6,7, 8-tetrahydro-3H- pyrazol [1,2-a] pyridazine-5-carboxylic acid : H NMR (300 MHz, CDCI3) 8 8.50 (d, J = 5.1 Hz, 1 H), 7.36 (dd, J = 8. 7,5. 4 Hz, 2 H), 7.20-7. 31 (m, 4 H), 7.02 (t, J = 8. 7 Hz, 2 H), 6.97 (d, J = 5. 1 Hz, 1 H), 5.23-5. 25 (m, 1 H), 4.24 (d, J = 11.4 Hz, 1 H), 3.74 (s, 3H), 2.94-2. 99 (m, 1 H), 2.54-2. 59 (m, 1 H), 1.82-2. 00 (m, 3 H); ESI/MS : 479 (M+H).

The second aspect of Category III analogs according to the present invention capable of inhibiting release of inflammatory cytokines relates to compounds comprising a 5, 6,7, 8-tetrahydro- pyrazol [1, 2-a]-pyridazin-1-one scaffold having the formula: wherein R units are amines having the formula -NH[CHR5b]R6, and RI, R5b, R6, and R10 are described herein below in Table I. The stereochemistry of R5b is the configuration shown when R5b is not hydrogen.

TABLE V No. R R R6 Rlu 125 orophenyl H H 126 4-fluorophenyl H methyl 127 4-fluorophenyl H ethyl 128 4-fluorophenyl H vinyl 129 4-fluorophenyl cyclopropyl 130 4-fluorophenyl cyclohexyl 131 4-fluorophenyl methoxymethyl 132 4-fluorophenyl methoxyethyl H 133 4-fluorophenyl H 1-hydroxy-1-methylethyl H 134 4-fluorophenyl H -CO2H 135 4-fluorophenyl phenyl 136 4-fluorophenyl 4-fluorophenyl H 137 4-fluorophenyl H 2-aminophenyl 138 4-fluorophenyl + 2-methylphenyl 139 4-fluorophenyl 4-methylphenyl 140 4-fluorophenyl 4-methoxyphenyl 141 4-fluorophenyl H 4-(propanesulfonyl)phenyl H 142 4-fluorophenyl H 3-benzo [1,3] dioxol-5-yl H 143 4-fluorophenyl H pyridin-2-yl H 144 4-fluorophenyl H pyridin-3-yl 145 4-fluorophenyl methyl H H 146 4-fluorophenyl methyl methyl 147 4-fluorophenyl methyl ethyl 148 4-fluorophenyl methyl vinyl 149 4-fluorophenyl methyl cyclopropyl 150 4-fluorophenyl methyl cyclohexyl 151 4-fluorophenyl methyl methoxymethyl 152 4-fluorophenyl methyl methoxyethyl 153 4-fluorophenyl methyl 1-hydroxy-1-methylethyl H 154 4-fluorophenyl methyl-CO2H H 155 4-fluorophenyl methyl phenyl 156 4-fluorophenyl methyl 4-fluorophenyl 157 4-fluorophenyl methyl 2-aminophenyl 158 4-fluorophenyl methyl 2-methylphenyl 159 4-fluorophenyl methyl 4-methylphenyl 160 4-fluorophenyl methyl 4-methoxyphenyl 161 4-fluorophenyl 4-(propanesulfonyl)phenyl H 162 4-fluorophenyl methyl 3-benzo [1,3] dioxol-5-yl H 163 4-fluorophenyl methyl pyridin-2-yl 164 4-fluorophenyl methyl pyridin-3-yl 165 4-fluorophenyl H H methyl 166 4-fluorophenyl H methyl methyl 167 4-fluorophenyl ethyl methyl 168 4-fluorophenyl vinyl methyl 169 4-fluorophenyi cyclopropyl methyl 170 4-fluorophenyl H cyclohexyl methyl 171 4-fluorophenyl methoxymethyl methyl 172 4-fluorophenyl methoxyethyl methyl 173 4-fluorophenyl H 1-hydroxy-1-methylethyl methyl 174 4-fluorophenyl-CO2H methyl 175 4-fluorophenyl H phenyl methyl 176 4-fluorophenyl 4-fluorophenyl methyl 177 4-fluorophenyl H 2-aminophenyl methyl 178 4-fluorophenyl H 2-methylphenyl methyl 179 4-fluorophenyl 4-methylphenyl methyl 180 4-fluorophenyl 4-methoxyphenyl methyl 181 4-fluorophenyl H 4-(propanesulfonyl)phenyl methyl 182 4-fluorophenyl H 3-benzo [1,3] dioxol-5-yl methyl 183 4-fluorophenyl H pyridin-2-yl methyl 184 4-fluorophenyl H pyridin-3-yl methyl 185 4-fluorophenyl methyl methyl 186 4-fluorophenyl methyl methyl methyl 187 4-fluorophenyl methyl ethyl methyl 188 4-fluorophenyl methyl vinyl methyl 189 4-fluorophenyl methyl cyclopropyl methyl 190 4-fluorophenyl methyl cyclohexyl methyl 191 4-fluorophenyl methyl methoxymethyl methyl 192 4-fluorophenyl methyl methoxyethyl methyl 193 4-fluorophenyl methyl 1-hydroxy-1-methylethyl methyl 194 4-fluorophenyl methyl-CO2H methyl 195 4-fluorophenyl methyl phenyl methyl 196 4-fluorophenyl methyl 4-fluorophenyl methyl 197 4-fluorophenyl methyl 2-aminophenyl methyl 198 4-fluorophenyl methyl 2-methylphenyl methyl 199 4-fluorophenyl methyl 4-methylphenyl methyl 200 4-fluorophenyl methyl 4-methoxyphenyl methyl 201 4-fluorophenyl methyl 4-(propanesulfonyl) phenyl methyl 202 4-fluorophenyl methyl 3-benzo [1,3] dioxol-5-yl methyl 203 4-fluorophenyl methyl pyridin-2-yl methyl 204 4-fluorophenyl methyl pyridin-3-yl methyl The compounds which comprise the analogs of the second aspect of Category III can be prepared by the synthesis outline herein below in the following scheme.

Reagents and conditions: (a) (S)- (-)-a-methylbenzylamine, toluene; 100 °C 4 hr.

Reagents and conditions: (b) LiOH, MeOH/water; rt 3 hr.

EXAMPLE 9 2-(4-fluorophenyl)-3-oxo-1-[2-(1-(S)-(phenylethylamino)pyrim idin-4-yl]-5,6,7,8-tetrahydro- 3H-pvrazolor1, 2-alpvridazine-5-carboxvlic acid methyl ester (24) Preparation of 2- (4-fluorophenyl)-3-oxo-1- [2- (1- (S)-phenylethylamino) pyrimidin-4- yl]-5, 6,7, 8-tetrahydro-3H-pyrazolo [1,2-a] pyridazine-5-carboxylic acid methyl ester (24): To a solution of 2- (4fluorophenyl)-1- (3-methanesulfonyl-pyrimidin-4-yl)-3-oxo-5, 6, 7,8-tetrahydro-3H- pyrazol [1,2-a] pyridazine-5-carboxylic acid methyl ester, 21, (0.10 g, 0.22 mmol) in toluene (1.4 mL) is added (S)- (-)-a-methylbenzylamine (1.4 mL, 1.12 mmol). The reaction solution is heated to 100 °C for 4 hours after which the reaction is cooled and diluted with 1 N HCI. The resulting solution is extracted with ethyl acetate (3 x 25 mL), the organic layers are combined, dried, and concentrated in vacuo to afford 0.071 g (66% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCI3) 8 8.22 (ddd, J = 11.4, 5.1, 2.1 Hz, I H), 7.22-7. 37 (m, 7 H), 6.97 (dt, J = 8.7, 2.1 Hz, 2 H), 6.41 (ddd, J = 15.6, 5.1, 2.1 Hz, 1 H), 5.72-5. 83 (m, 1 H), 5.2 (br s, 2 H), 5.52- 5.62 (m, 1 H), 3.77 (s, 3 H), 3.47 (d, J = 2.7 Hz, 1 H), 2.47-2. 51 (m, 2 H), 2.00 (br s, 1 H) ; 1.41 (d, J = 6.6 Hz, 3 H); APCI/MS : 487 (M+H).

EXAMPLE 10 2-(4-Fluorophenyl)-3-oxo-1-[2-(1-(S)-(phenylethylamino)pyrim idin-4-yl]-5,6,7,8-tetrahydro- 3H-pyrazolofl, 2-alpVridazine-5-carboxvlic acid (25) Preparation of 2- (4-fluorophenyl)-3-oxo-1- [2- (1- (S)-phenylethylamino) pyrimidin-4- yl]-5, 6,7, 8-tetrahydro-3H-pyrazolo [1, 2-a] pyridazine-5-carboxylic acid (25): To a solution of Preparation of 2- (4-fluorophenyl)-3-oxo-1- [2- (S)- (1-phenylethylamino) pyrimidin-4-yl]-5, 6,7, 8- tetrahydro-3H-pyrazolo [1,2-a] pyridazine-5-carboxylic acid methyl ester, 24, (0.066 g, 0.14 mmol) in methanol (2 mL) and water (2 mL) is added LiOH (0.033 g, 1.36 mmol). The mixture is stirred at room temperature for 3 hours then diluted with 1 N HCI (25 mL) after which the solution is extracted with ethyl acetate (3 x 50 mL). The combined organic layers are washed with brine, dried, and concentrated in vacuo to afford 0.043 g (65% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCI3) 8 8.13-8. 19 (m, 1 H), 7.22-7. 34 (m, 7 H), 6.97 (t, J = 8.7 Hz, 2 H), 6.34 (dd, J = 15. 3,5. 1 Hz, 1 H), 5.11-5. 24 (m, 2 H), 3.56 (br s, 1 H), 2.96 (br s, 1 H), 2.52-2. 64 (m, 2 H), 1.79-1. 96 (m, 2 H), 1.57 (d, J = 6.9 Hz, 3 H): ESI/MS : 474 (M+H).

2-(4-Fluorophenyl)-3-oxo-1-[2-(1-(S)-methyl-methoxyethylamin o) pyrimidin-4-yl]-5, 6,7, 8- tetrahydro-3H-pyrazolo [1,2-a] pyridazine-5-carboxylic acid methyl ester :'H NMR (300 MHz, CDCI3) 8 8. 25 (d, J = 5. 1 Hz, 1 H), 7.43 (dd, J = 9. 0,. 7 Hz, 2 H), 6.99 (t, J = 9. 0 Hz, 2 H), 6.44 (d, J = 5. 1 Hz, 1 H), 5.50-5. 54 (m, 1 H), 5.. 26 (d, J = 3.6 Hz, 1 H), 4.15-4. 25 (m, 2 H), 3.76 (s, 3 H), 3.37-3. 47 (m, 4 H), 2. 95-3. 06 (m, 1 H), 2.51-2. 62 (m, 1 H), 1.92-2. 02 (m, 3 H), 1.23-1. 30 (m, 3 H); ESI/MS : 456 (M+H).

The third aspect of Category III analogs according to the present invention capable of inhibiting release of inflammatory cytokines relates to compounds comprising a 5,6, 7,8-tetrahydro- pyrazol [1, 2-a]-pyridazin-1-one scaffold having the formula: wherein R is an ether moiety of the formula :-OR3. Table vol describes the various values of R, R', and R'° TABLE Vi No. R R R 205 4 4-fluorophenyl phenoxy 206 H 4-fluorophenyl 2-fluorophenoxy 207 H 4-fluorophenyl 3-fluorophenoxy 208 H 4-fluorophenyl 4-fluorophenoxy 209 4-fluorophenyl 2, 6-difluorophenoxy 210 4-fluorophenyl 2-cyanophenoxy 211 H 4-fluorophenyl 3-cyanophenoxy 212 H 4-fluorophenyl 2-trifluoromethylphenoxy 213 H 4-fluorophenyl 4-trifluoromethylphenoxy 214 H 4-fluorophenyl 2-methylphenoxy 215 H 4-fluorophenyl 4-methylphenoxy 216 4-fluorophenyl 2, 4-dimethylphenoxy 217 H 4-fluorophenyl 3-N-acetylaminophenoxy 218 H 4-fluorophenyl 2-methoxyphenoxy 219 H 4-fluorophenyl 4-methoxyphenoxy 220 H 4-fluorophenyl 3-benzo [1,3] dioxol-5-yl 221 methyl 4-fluorophenyl phenoxy 222 methyl 4-fluorophenyl 2-fluorophenoxy 223 methyl 4-fluorophenyl 3-fluorophenoxy 224 methyl 4-fluorophenyl 4-fluorophenoxy 225 methyl 4-fluorophenyl 2, 6-difluorophenoxy 226 methyl 4-fluorophenyl 2-cyanophenoxy 227 methyl 4-fluorophenyl 3-cyanophenoxy 228 methyl 4-fluorophenyl 2-trifluoromethylphenoxy 229 methyl 4-fluorophenyl 4-trifluoromethylphenoxy 230 methyl 4-fluorophenyl 2-methylphenoxy 231 methyl 4-fluorophenyl 4-methylphenoxy 232 methyl 4-fluorophenyl 2, 4-dimethylphenoxy 233 methyl 4-fluorophenyl 3-N-acetylaminophenoxy 234 methyl 4-fluorophenyl 2-methoxyphenoxy 235 methyl 4-fluorophenyl 4-methoxyphenoxy 236 methyl 4-fluorophenyl 3-benzo [1,3] dioxol-5-yl The compounds which comprise the third aspect of Category III analogs can be prepared by the procedure outlined in the following scheme.

Reagents and conditions: (a) (Boc) 2O, TEA, CH2CI2 ; rt, 12 hr.

Reagents and conditions: (b) CH2CI2, TEA, rt, 10 hr.

Reagents and conditions: (c) TFA, CH2CI2/water ; 0 °C 2 hr-rt 1 hr.

Reagents and conditions: (d) TEA, CH2Cl2 ; rt 12 hr.

Reagents and conditions: (e) NaOH, MeOH ; rt 15 hr.

Reagents and conditions: (f) CH2N2, ET20/EtOAc ; rt 5 min.

Reagents and conditions: (g) Oxon, THF/MeOH/water; rt 5 hr.

Reagents and conditions: (h) phenol, NaOH, THF: rt 8 hr. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> EXAMPLE 11<BR> <BR> <BR> <BR> <BR> 2- (4-Fluorophenyl)-1-oxo-3- (2-phenoxvaVrimidin-4-vl)-5, 6, 7, 8-tetrahvdro-1 H-pVrazol 2- alpvridazine-5 (S)-carboxviic acid methvl ester (33) Preparation of tetrahydro-pyridazine-1, 3-dicarboxylic acid 1-tert-butyl ester 3- (S)- methylester (26): To piperazic acid methyl ester (3.44 g, 19 mmol) in methylene chloride (150 mL) is added (Boc) 20 (4.2 g, 19 mmol) and triethylamine (2.65 mL, 19 mmol). The reaction mixture is stirred 12 hours concentrated in vacuo to provide a yellow oil which is purified over silica (ethyl acetate/hexane 1: 1) to afford 4.5 g (98% yield) of the desired product as a light yellow oil.

Preparation of 2- (2-methylsulfanylpyrimidine-4-carbonyl)-tetrahydropyridazine -1, 3- dicarboxylic acid 1-tert-butyl 3- (S)-methylester (27): To a solution of tetrahydro-pyridazine-1,3- dicarboxylic acid 1-tert-butyl ester 3- (S)-methylester, 26, (3.91 g, 15.9 mmol) in methylene chloride (200 mL) is added 2-methanesulfanylpyrimidine-4-carbonyl chloride, 16, (3.32 g, 17.6 mmol) and triethylamine (3.5 mL, 25.3 mmol) such that the pH is approximately neutral. The resulting mixture is stirred for 10 hours at room temperature and the mixture washed with water (100 mL), brine (100 mL), dried and concentrated in vacuo to afford an oil which is purified over silica (ethyl acetate/hexane 1: 1) to afford 5.22 g (83% yield) of the desired product as a yellow oil.

Preparation of 2- (2-methylsulfanylpyrimidine-4-carbonyl)-tetrahydropyridazine -1, 3- dicarboxylic acid 3- (S)-methylester (28): To a solution of 2- (2-methylsulfanylpyrimidine-4- carbonyl)-tetrahydropyridazine-1, 3-dicarboxylic acid 1-tert-butyl 3- (S)-methylester, 27, (7 g, 17.6 mmol) in methylene chloride (50 mL) is added trifluoroacetic acid (50 mL) at) °C. The reaction is stirred for 2 hours in the cold, 1 hour at room temperature, then concentrated in vacuo to a residue which can be taken up in toluene and re-concentrated to afford 7.2 g (100% yield) of the desired yield as the trifluoroacetate salt as a yellow oil which is used without further purification.

Preparation of 1- [2- (4-fluorophenyl)-2-oxo-ethyl]-2- (2-methylsulfanylpyrimmidin-4- carbonyl)-hexahydropyridazine-3- (S)-carboxylic acid (29): To a solution of 2- (2- <BR> <BR> <BR> methylsulfanyl-pyrimidine-4-carbonyl)-tetrahydropyridazine-1 , 3-dicarboxylic acid 3- (S)-methylester, 28, (7.2 g, 17.6 mmol) in methylene chloride (150 mL) is added 4-fluorophenylacetyl chloride (3 g, 17.6 mmol) and triethylamine (3.65 mL, 26.4 mmol). The resulting mixture is stirred for 12 hours then concentrated in vacuo to afford a brown oil. The crude residue is purified by prep HPLC to afford 5.33 g (70% yield) of the desired product as a yellow oil.

Preparation of 2- (4-fluorophenyl)-3- (2-methylsulfanylpyrimidin-4-yl)-1-oxo-5, 6,7, 8- tetrahydro-1H-pyrazolo [1,2-a] pyridazine-5- (S)-carboxylic acid (30): To a solution of 1- [2- (4- <BR> <BR> <BR> <BR> fluorophenyl)-2-oxo-ethyl]-2- (2-methylsulfanylpyrimmidin-4-carbonyl)-hexahydropyridazine- 3- (S)- carboxylic acid, 29, (1 g) in methanol (170 mL) is added NaOH (0.23 g, 5.8 mmol). The resulting mixture is stirred for 15 hours and the mixture is concentrated in vacuo to provide a residue which is dissolved in water (150 mL). The solution is acidified to pH 1 with 3 N HCI and extracted with ethyl acetate (300 mL). The organic layer is concentrated in vacuo and the resulting crude material is purified by prep HPLC to afford 7.0 g (76% yield) of the desired product as a cream- colored solid.

Preparation of 2- (4-fluorophenyl)-3- (2-methylsulfanylpyrimidin-4-yl)-1-oxo-5, 6,7, 8- tetrahydro-1H-pyrazolo [1,2-a] pyridazine-5- (S)-carboxylic acid methyl ester (31): To a solution of 2- (4-fluorophenyl)-3- (2-methylsulfanylpyrimidin-4-yl)-1-oxo-5, 6, 7, 8-tetrahydro-1H- pyrazol [1,2-a] pyridazine-5-carboxylic acid, 30, in diethyl ether/ethyl acetate (2.5 : 1, 7o mL) is added freshly generated diazomethane in diethyl ether (5 mL). The reaction is stirred for 5 minutes then quenched by the addition of HOAc (0.5 mL). The resulting solution is washed with NaHCO3, brine, dried, and concentrated in vacuo to afford 1 g (98% yield) of the desired product as a light yellow solid.

Preparation of 2- (4-fluorophenyl)-3- (2-methanesulfonylpyrimidin-4-yl)-1-oxo-5, 6,7, 8- tetrahydro-1H-pyrazolo [1,2-a] pyridazine-5- (S)-carboxylic acid methyl ester (32): To a solution of 2- (4-fluorophenyl)-3- (2-methylsulfanylpyrimidin-4-yl)-1-oxo-5, 6,7, 8-tetrahydro-1 H- pyrazol [1,2-a] pyridazine-5-carboxylic acid methyl ester, 31, (0.48 g, 1.16 mmol) 1: 1 THF/methanol (50 mL) is added Oxonee (2.14 g, 3.5 mmol) in water (50 mL). The reaction mixture is stirred for 5 hours at room temperature, reduced in volume in vacuo to about 25 mL and ethyl acetate (200 mL) is added. The organic phase is treated with NaHCO3, brine, dried, and concentrated in vacuo to afford 0.5 g of the desired product as a yellow solid.

Preparation of 2- (4-fluorophenyl)-3- (2-phenoxypyrimidin-4-yl)-1-oxo-5, 6,7, 8- tetrahydro-1H-pyrazolo [1,2-a] pyridazine-5- (S)-carboxylic acid methyl ester (33): NaOH (0.112 g, 2.8 mmol) is added to a solution of phenol (0.316 g, 3.36 mmol) in THF (100 mL). 2- (4- Fluorophenyl)-3-(2-methanesulfonylpyrimidin-4-yl)-1-oxo-5, 6,7, 8-tetrahydro-1 H-pyrazolo [1, 2- a] pyridazine-5-carboxylic acid methyl ester, 32, (0.5 g) is dissolved in THF (50 mL) and added dropwise to the solution over 5 minutes. The resulting mixture is stirred at room temperature for 8 hours after which water (20 mL) is added. The solution is extracted with ethyl acetate (100 mL the organic layer washed with brine (50 mL) and concentrated in vacuo to afford 0.278 g (54% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, Ceci3) 8 1.75 (m, 2 H), 1.97 (m 1 H), 2.42 (d, J = 12.8 Hz, 1 H), 3.27 (m, 1 H), 3.27 (m, 1 H), 3.6 (s, 3 H), 4.5 (br d, J = 12.8 Hz, 1 H), 5.25 (m, 1 H), 6.87 (d, J = 5.7 Hz, 1 H), 7.05 (m, 2H), 7.23 (m, 2 H), 7.35 (m, 3 H), 7.52 (m, 2 H), 8.42 (d, J = 5.7 Hz, 1 H): exact mass calc. for C25H21FN4O4 460.46, MS-ESI (M+1) 461.

The fourth aspect of Category III analogs according to the present invention capable of inhibiting release of inflammatory cytokines relates to compounds comprising a 5,6, 7,8-tetrahydro- pyrazol [1, 2-a]-pyridazin-1-one scaffold having the formula: wherein R units are amines having the formula-NH [CHR5b] R6, and R', R5b, R6, and R10 are described herein below in Table VII. The stereochemistry of R5b is the configuration shown when R5b is not hydrogen TABLE Vil No. R1 R5 237 4-fluorophenyl H H H 238 4-fluorophenyl H methyl H 239 4-fluorophenyl ethyl H 240 4-fluorophenyl H vinyl 241 4-fluorophenyl H cyclopropyl 242 4-fluorophenyl cyclohexyl H 243 4-fluorophenyl H methoxymethyl H 244 4-fluorophenyl methoxyethyl H 245 4-fluorophenyl H 1-hydroxy-1-methylethyl H 246 4-fluorophenyl H-CO2H 247 4-fluorophenyl phenyl H 248 4-fluorophenyl H 4-fluorophenyl H 249 4-fluorophenyl H 2-aminophenyl H 250 4-fluorophenyl H 2-methylphenyl H 251 4-fluorophenyl 4-methylphenyl H 252 4-fluorophenyl 4-methoxyphenyl H 253 4-fluorophenyl H 4-(propanesulfonyl) phenyl 254 4-fluorophenyl H 3-benzo [1,3] dioxol-5-yl 255 4-fluorophenyl H pyridin-2-yl 256 4-fluorophenyl H pyridin-2-yl 257 4-fluorophenyl methyl H H 258 4-fluorophenyl methyl methyl 259 4-fluorophenyl methyl ethyl 260 4-fluorophenyl methyl vinyl 261 4-fluorophenyl methyl cyclopropyl 262 4-fluorophenyl methyl cyclohexyl 263 4-fluorophenyl methyl methoxymethyl 264 4-fluorophenyl methyl methoxyethyl 265 4-fluorophenyl methyl 1-hydroxy-1-methylethyl H 266 4-fluorophenyl methyl-CO2H H 267 4-fluorophenyl methyl phenyl 268 4-fluorophenyl methyl 4-fluorophenyl 269 4-fluorophenyl methyl 2-aminophenyl 270 4-fluorophenyl methyl 2-methylphenyl 271 4-fluorophenyl methyl 4-methylphenyl 272 4-fluorophenyl methyl 4-methoxyphenyl 273 4-fluorophenyl methyl 4-(propanesulfonyl) phenyl 274 4-fluorophenyl methyl 3-benzo [1,3] dioxol-5-yl 275 4-fluorophenyl methyl pyridin-2-yl 276 4-fluorophenyl methyl pyridin-3-yl 277 4-fluorophenyl H H methyl 278 4-fluorophenyl H methyl methyl 279 4-fluorophenyl H ethyl methyl 280 4-fluorophenyl vinyl methyl 281 4-fluorophenyl cyclopropyl methyl 282 4-fluorophenyl H cyclohexyl methyl 283 4-fluorophenyl H methoxymethyl methyl 284 4-fluorophenyl H methoxyethyl methyl 285 4-fluorophenyl H 1-hydroxy-1-methylethyl methyl 286 4-fluorophenyl-CO2H methyl 287 4-fluorophenyl H phenyl methyl 288 4-fluorophenyl H 4-fluorophenyl methyl 289 4-fluorophenyl H 2-aminophenyl methyl 290 4-fluorophenyl H 2-methylphenyl methyl 291 4-fluorophenyl 4-methylphenyl methyl 292 4-fluorophenyl H 4-methoxyphenyl methyl 293 4-fluorophenyl H 4- (propanesulfonyl) phenyl methyl 294 4-fluorophenyl H 3-benzo [1,3] dioxol-5-yl methyl 295 4-fluorophenyl H pyridin-2-yl methyl 296 4-fluorophenyl H pyridin-3-yl methyl 297 4-fluorophenyl methyl H methyl 298 4-fluorophenyl methyl methyl methyl 299 4-fluorophenyl methyl ethyl methyl 300 4-fluorophenyl methyl vinyl methyl 301 4-fluorophenyl methyl cyclopropyl methyl 302 4-fluorophenyl methyl cyclohexyl methyi 303 4-fluorophenyl methyl methoxymethyl methyl 304 4-fluorophenyl methyl methoxyethyl methyl 305 4-fluorophenyl methyl 1-hydroxy-1-methylethyl methyl 306 4-fluorophenyl methyl-CO2H methyl 307 4-fluorophenyl methyl phenyl methyl 308 4-fluorophenyl methyl 4-fluorophenyl methyl 309 4-fluorophenyl methyl 2-aminophenyl methyl 310 4-fluorophenyl methyl 2-methylphenyl methyl 311 4-fluorophenyl methyl 4-methylphenyl methyl 312 4-fluorophenyl methyl 4-methoxyphenyl methyl 313 4-fluorophenyl methyl 4-(propanesulfonyl)phenyl methyl 314 4-fluorophenyl methyl 3-benzo [1,3] dioxol-5-yl methyl 315 4-fluorophenyl methyl pyridin-2-yll methyl 316 4-fluorophenyl methyl pyridin-3-yl methyl The compounds which comprise the analogs of the fourth aspect of Category))) can be prepared by the synthesis outline herein below in the following scheme starting with intermediate 32.

The fifth aspect of Category III analogs according to the present invention capable of inhibiting release of inflammatory cytokines relates to compounds comprising a 5,6, 7,8-tetrahydro- pyrazol [1, 2-a]-pyridazin-1-one scaffold having the formula : wherein R, R', R9a, and R9b are defined herein below in Table VIII.

TABLE VIII No. R1 R 317 4-fluorophenyl phenoxy H H 318 4-fluorophenyl 2-fluorophenoxy H H 319 4-fluorophenyl 3-fluorophenoxy H H 320 4-fluorophenyl 4-fluorophenoxy H H 321 4-fluorophenyl 2, 6-difluorophenoxy H H 322 4-fluorophenyl 2-cyanophenoxy H H 323 4-fluorophenyl 3-cyanophenoxy H H 324 4-fluorophenyl 2-trifluoromethylphenoxy H H 325 4-fluorophenyl 4-trifluoromethylphenoxy H H 326 4-fluorophenyl 2-methylphenoxy H H 327 4-fluorophenyl 4-methylphenoxy H H 328 4-fluorophenyl 2, 4-dimethylphenoxy H H 329 4-fluorophenyl 3-N-acetylaminophenoxy H H 330 4-fluorophenyl 2-methoxyphenoxy H H 331 4-fluorophenyl 4-methoxyphenoxy H H 332 4-fluorophenyl 3-benzo [1,3] dioxol-5-yl H 333 4-fluorophenyl phenoxy methyl methyl 334 4-fluorophenyl 2-fluorophenoxy methyl methyl 335 4-fluorophenyl 3-fluorophenoxy methyl methyl 336 4-fluorophenyl 4-fluorophenoxy methyl methyl 337 4-fluorophenyl 2, 6-difluorophenoxy methyl methyl 338 4-fluorophenyl 2-cyanophenoxy methyl methyl 339 4-fluorophenyl 3-cyanophenoxy methyl methyl 340 4-fluorophenyl 2-trifluoromethylphenoxy methyl methyl 341 4-fluorophenyl 4-trifluoromethylphenoxy methyl methyl 342 4-fluorophenyl 2-methylphenoxy methyl methyl 343 4-fluorophenyl 4-methylphenoxy methyl methyl 344 4-fluorophenyl 2, 4-dimethylphenoxy methyl methyl 345 4-fluorophenyl 3-N-acetylaminophenoxy methyl methyl 346 4-fluorophenyl 2-methoxyphenoxy methyl methyl 347 4-fluorophenyl 4-methoxyphenoxy methyl methyl 348 4-fluorophenyl 3-benzo [1,3] dioxol-5-yl methyl methyl 349 4-fluorophenyl 1-(S)-phenylethylamino H 350 4-fluorophenyl 1- (S)- (4-fluorophenyl) ethylamino H H 351 4-fluorophenyl 1-(S)-(2-aminophenyl)ethylamino H H 352 4-fluorophenyl 1-(S)-(2-aminophenyl)ethylamino H H 353 4-fluorophenyl 1- (S)- (4-methylphenyl) ethylamino H H 354 4-fluorophenyl 1- (S)- (4-methoxyphenyl) ethylamino H H 355 4-fluorophenyl 1-(S)-(4-propanesulfonylphenyl)ethylamino H H 356 4-fluorophenyl 1- (S)- (3-benzo [1,3] dioxol-5-yl) ethylamino H H 357 4-fluorophenyl 1- (S)- (pyridin-2-yl) ethylamino H H 358 4-fluorophenyl 1-(S)-(pyridin-3-yl) ethylamino H H 359 4-fluorophenyl methylamino H 360 4-fluorophenyl ethylamino H H 361 4-fluorophenyl propylamino H H 362 4-fluorophenyl cyclopropylamino H 363 4-fluorophenyl cyclopropylmethylamino H 364 4-fluorophenyl tert-butylamino H H 365 4-fluorophenyl 1- (S)- (cyclopropyl) ethylamino H H 366 4-fluorophenyl 1-(S)-(cyclopropylmethyl) ethylamino 367 4-fluorophenyl 1- (R)- (a)- (carboxy) benzylamino H H 368 4-fluorophenyl 1- (S)- (a)- (methyl) benzylamino H H 369 4-fluorophenyl 1-(S)-phenylethylamino methyl methyl 370 4-fluorophenyl 1- (S)- (4-fluorophenyl) ethylamino methyl methyl 371 4-fluorophenyl 1- (S)- (2-aminophenyl) ethylamino methyl methyl 372 4-fluorophenyl 1-(S)-(2-methylphenyl)ethylamino methyl methyl 373 4-fluorophenyl 1- (S)- (4-methylphenyl) ethylamino methyl methyl 374 4-fluorophenyl 1- (S)- (4-methoxyphenyl) ethylamino methyl methyl 375 4-fluorophenyl 1- (S)- (4-propanesulfonylphenyl) ethylamino methyl methyl 376 4-fluorophenyl 1- (S)- (3-benzo [1,3] dioxol-5-yl) ethylamino methyl methyl 377 4-fluorophenyl 1-(S)-(pyridin-2-yl)ethylamino methyl methyl 378 4-fluorophenyl 1- (S)- (pyridin-3-yl) ethylamino methyl methyl 379 4-fluorophenyl methylamino methyl methyl 380 4-fluorophenyl ethylamino methyl methyl 381 4-fluorophenyl propylamino methyl methyl 382 4-fluorophenyl cyclopropylamino methyl methyl 383 4-fluorophenyl cyclopropylmethylamino methyl methyl 384 4-fluorophenyl terf-butylamino methyl methyl 385 4-fluorophenyl 1-(S)-(cyclopropyl)ethylamino methyl methyl 386 4-fluorophenyl 1- (S)- (cyclopropylmethyl) ethylamino methyl methyl 387 4-fluorophenyl 1- (R)- (a)- (carboxy) benzylamino methyl methyl 388 4-fluorophenyl 1-(S)-(α)-(methyl)benzylamino methyl methyl Another iteration of this aspect relates to compounds wherein R9a and R9b are taken together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms. Table IX describes compounds encompassed by this iteration of the fifth aspect of Category III.

TABLE IX No. R1 R R9a-R9b ring 389 4-fluorophenyl phenoxy morpholin-4-yl 390 4-fluorophenyl 2-fluorophenoxy morpholin-4-yl 391 4-fluorophenyl 3-fluorophenoxy morpholin-4-yl 392 4-fluorophenyl 4-fluorophenoxy morpholin-4-yl 393 4-fluorophenyl 3-cyanophenoxy morpholin-4-yl 394 4-fluorophenyl 4-methylphenoxy morpholin-4-yl 395 4-fluorophenyl 3-N-acetylaminophenoxy morpholin-4-yl 396 4-fluorophenyl 4-methoxyphenoxy morpholin-4-yl 397 4-fluorophenyl phenoxy 398 4-fluorophenyl 2-fluorophenoxy piperadin-1-yl 399 4-fluorophenyl 3-fluorophenoxy piperadin-1-yl 400 4-fluorophenyl 4-fluorophenoxy piperadin-1-yl 401 4-fluorophenyl 3-cyanophenoxy piperadin-1-yl 402 4-fluorophenyl 4-methylphenoxy piperadin-1-yl 403 4-fluorophenyl 3-N-acetylaminophenoxy piperadin-1-yl 404 4-fluorophenyl 4-methoxyphenoxy piperadin-1-yl 405 4-fluorophenyl phenoxy piperazin-1-yl 406 4-fluorophenyl 2-fluorophenoxy piperazin-1-yl 407 4-fluorophenyl 3-fluorophenoxy piperazin-1-yl 408 4-fluorophenyl 4-fluorophenoxy piperazin-1-yl 409 4-fluorophenyl 3-cyanophenoxy piperazin-1-yi 410 4-fluorophenyl 4-methylphenoxy piperazin-1-yl 411 4-fluorophenyl 3-N-acetylaminophenoxy piperazin-1-yl 412 4-fluorophenyl 4-methoxyphenoxy piperazin-1-yl 413 4-fluorophenyl phenoxy cyclohexyl 414 4-fluorophenyl 2-fluorophenoxy cyclohexyl 415 4-fluorophenyl 3-fluorophenoxy cyclohexyl 416 4-fluorophenyl 4-fluorophenoxy cyclohexyl 417 4-fluorophenyl 3-cyanophenoxy cyclohexyl 418 4-fluorophenyl 4-methylphenoxy cyclohexyl 419 4-fluorophenyl 3-N-acetylaminophenoxy cyclohexyl 420 4-fluorophenyl 4-methoxyphenoxy cyclohexyl 421 4-fluorophenyl 1-(S)-phenylethylamino morpholin-4-yi 422 4-fluorophenyl 1- (S)- (4-fluorophenyl) ethylamino morpholin-4-yi 423 4-fluorophenyl 1- (S)- (pyridin-2-yl) ethylamino morpholin-4-yl 424 4-fluorophenyl 1-(S)-(pyridin-3-yl)ethylamino morpholin-4-yl 425 4-fluorophenyl ethylamino morpholin-4-yl 426 4-fluorophenyl propylamino rriorpholin-4-yl 427 4-fluorophenyl cyclopropylamino morpholin-4-yl 428 4-fluorophenyl cyclopropylmethylamino morpholin-4-yl 429 4-fluorophenyl tert-butylamino morpholin-4-yl 430 4-fluorophenyl 1- (S)- (a)- (methyl) benzylamino morpholin-4-yl 431 4-fluorophenyl 1-(S)-phenylethylamino piperadin-1-yl 432 4-fluorophenyl 1-(S)-(4-fluorophenyl)ethylamino piperadin-1-yl 433 4-fluorophenyl 1-(S)-(pyridin-2-yl)ethylamino piperadin-1-yl 434 4-fluorophenyl 1-(S)-(pyridin-3-yl)ethylamino piperadin-1-yl 435 4-fluorophenyl ethylamino piperadin-1-yl 436 4-fluorophenyl propylamino piperadin-1-yl 437 4-fluorophenyl cyclopropylamino piperadin-1-yl 438 4-fluorophenyl cyclopropylmethylamino piperadin-1-yl 439 4-fluorophenyl tert-butylamino piperadin-1-yl 4402441 4-fluorophenyl 1- (S)- (a)- (methyl) benzylamino piperadin-1-yl 442 4-fluorophenyl 1- (S)-phenylethylamino piperazin-1-yl 443 4-fluorophenyl 1- (S)- (4-fluorophenyl) ethylamino piperazin-1-yl 444 4-fluorophenyl 1-(S)-(pyridin-2-yl)ethylamino piperazin-1-yl 445 4-fluorophenyl 1- (S)- (pyridin-3-yl) ethylamino piperazin-1-yl 446 4-fluorophenyl ethylamin piperazin-1-yl 447 4-fluorophenyl propylamino piperazin-1-yl 448 4-fluorophenyl cyclopropylamino piperazin-1-yl 449 4-fluorophenyl cyclopropylmethylamino piperazin-1-yl 450 4-fluorophenyl tert-butylamino piperazin-1-yl 451 4-fluorophenyl 1- (S)- (a)- (methyl) benzylamino piperazin-1-yl 452 4-fluorophenyl 1-(S)-phenylethylamino cyclohexyl 453 4-fluorophenyl 1- (S)- (4-fluorophenyl) ethylamino cyclohexyl 454 4-fluorophenyl 1- (S)- (pyridin-2-yl) ethylamino cyclohexyl 455 4-fluorophenyl 1- (S)- (pyridin-3-yl) ethylamino cyclohexyl 456 4-fluorophenyl ethylamin cyclohexyl 457 4-fluorophenyl propylamino cyclohexyl 458 4-fluorophenyl cyclopropylamino cyclohexyl 459 4-fluorophenyl cyclopropylmethylamino cyclohexyl 460 4-fluorophenyl tert-butylamino cyclohexyl 461 4-fluorophenyl 1- (S)- (a)- (methyl) benzylamino cyclohexyl Other compounds according to the present invention include : 2- (4-Fluorophenyl)-5- (piperazine-1-carbonyl)-3- (2-phenoxypyrimidin-4-yl)-5, 6,7, 8- tetrahydro-3H-pyrazolo [1,2-a] pyridazin-1-one : 2- (4-Fluorophenyl)-8- (piperazine-1-carbonyl)-3- (2-phenoxypyrimidin-4-yl)-5, 6,7, 8- tetrahydropyrazolo [1,2-a] pyridazin-1-one 2- (4-Fluorophenyl)-8- (morpholine-4-carbonyl)-3- (2-phenoxypyrimidin-4-yl)-5, 6,7, 8- tetrahydropyrazolo [1,2-a] pyridazin-1-one ; 2- (4-Fluorophenyl)-5- (morpholine-4-carbonyl)-3- [2- (4-fluorophenoxy) pyrimidin-4-yl]- 5,6, 7, 8- tetrahydropyrazolo [1,2-a] pyridazin-1-one ; 2- (4-Fluorophenyl)-8- (morpholine-4-carbonyl)-3- [2- (4-fluorophenoxy) pyrimidin-4-yl]- 5,6, 7, 8- tetrahydropyrazolo [1,2-a] pyridazin-1-one ; 2- (4-Fluorophenyl)-5- (morpholine-4-carbonyl)-3- {2- [1- (S)- (a)- (methyl) benzylamino]- pyrimidin-4-yl}-5, 6,7, 8- tetrahydropyrazolo [1, 2-a] pyridazin-1-one ; 2- (4-Fluorophenyl)-8- (morpholine-4-carbonyl)-3- {2- [1- (S)- (a)- (methyl) benzylamino]- pyrimidin-4-yl}-5, 6,7, 8- tetrahydropyrazolo [1,2-a] pyridazin-1-one ; 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 analogs which are not expressly example herein. The arrangement into categories does not imply increased or decreased efficacy for any of the compositions of matter described herein.

Compounds listed and described herein above have been found in many instances to exhibit activities (ICso in the cell based assay described herein below or ones which are referenced herein) at a level below 1 micromolar (M).

The compounds of the present invention are capable of effectively blocking the production of inflammatory cytokine production from cells, which thereby allows for the mitigation, alleviation, control, abatement, retardation, or prevention of one or more disease states or syndromes which are related to the extracellular release of one or more cytokines. Inflammatory disease states include those which are related to the following non-limiting examples: i) Interleukin-1 (IL-1) : implicated as the molecule responsible for a large number of disease states, inter alia, rheumatoid arthritis, osteoarthritis, as well as other disease states which relate to connective tissue degradation. ii) Cycloxygenase-2 (COX-2): inhibitors of cytokine release are proposed as inhibitors of inducible COX-2 expression, which has been shown to be increased by cytokines. M. K. O'Banion et al., Proc. Natl. Acad. Sci. U. S. A., 89,4888 (1998). iii) Tumor Necrosis Factor-a (TNF-a): This pro-inflammatory cytokine is suggested as an important mediator in many disease states or syndromes, inter alia, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease (IBS), septic shock, cardiopulmonary dysfunction, acute respiratory disease, and cachexia.

Each of the disease states or conditions which the formulator desires to treat may require differing levels or amounts of the compounds described herein to obtain a therapeutic level. The formulator can determine this amount by any of the known testing procedures known to the artisan.

The present invention further relates to forms of the present compounds, which under normal human or higher mammalian physiological conditions, release the compounds described herein. One iteration of this aspect includes the pharmaceutically acceptable salts of the analogs described herein. The formulator, for the purposes of compatibility with delivery mode, excipients, and the like, can select one salt form of the present analogs over another since the compounds themselves are the active species which mitigate the disease processes described herein.

Related to this aspect are the various precursor of"pro-drug"forms of the analogs of the present invention. It may be desirable to formulate the compounds of the present invention as a chemical species which itself is not active against the cytokine activity described herein, but instead are forms of the present analogs which when delivered to the body of a human or higher mammal will undergo a chemical reaction catalyzed by the normal function of the body, infer alia, enzymes present in the stomach, blood serum, said chemical reaction releasing the parent analog. The term"pro-drug"relates to these species which are converted in vivo to the active pharmaceutical.

FORMULATIONS The present invention also relates to compositions or formulations which comprise the inflammatory cytokine release-inhibiting compounds according to the present invention. In general, the compositions of the present invention comprise: a) an effective amount of one or more bicyclic pyrazolones and derivatives thereof according to the present invention which are effective for inhibiting release of inflammatory cytokines; and b) one or more pharmaceutical 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 said terms are defined herein as, "ingredients which are used in the practice of formulating a safe and effective pharmaceutical composition. " The formulator will understand that excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient. An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating to insure delivery of the ingredients safely to the stomach. The formulator can also take advantage of the fact the compounds of the present invention have improved cellular potency, pharmacokinetic properties, as well as improved oral bioavailability.

The present invention also relates to compositions or formulations which comprise a precursor or"pro-drug"form of the inflammatory cytokine release-inhibiting compounds according to the present invention. In general, these precursor-comprising compositions of the present invention comprise: a) an effective amount of one or more derivatives of bicyclic pyrazolones according to the present invention which act to release in vivo the corresponding analog which is effective for inhibiting release of inflammatory cytokines; and b) one or more pharmaceutical acceptable excipients.

METHOD OF USE The present invention also relates to a method for controlling the level of one or more inflammation inducing cytokines, inter alia, interleukin-1 (IL-1), Tumor Necrosis Factor-a (TNF-a), interleukin-6 (IL-6), and interleukin-8 (IL-8) and thereby controlling, mediating, or abating disease states affected by the levels of extracellular inflammatory cytokines. The present method comprises the step of administering to a human or higher mammal an effective amount of a composition comprising one or more of the inflammatory cytokine inhibitors according to the present invention.

Because the inflammatory cytokine inhibitors of the present invention can be delivered in a manner wherein more than one site of control can be achieved, more than one disease state can be modulated at the same time. Non-limiting examples of diseases which are affected by control or inhibition of inflammatory cytokine inhibitors, thereby modulating excessive cytokine activity, include osteoarthritis, rheumatoid arthritis, diabetes, human Immunodeficiency virus (HIV) infection.

PROCEDURES The compounds of the present invention can be evaluated for efficacy, for example, measurements of cytokine inhibition constants, K ;, and IC50 values can be obtained by any method chosen by the formulator.

Non-limiting examples of suitable assays include : i) UV-visible substrate enzyme assay as described by L. Al Reiter, Int. J. Peptide Protein Res. , 43,87-96 (1994). ii) Fluorescent substrate enzyme assay as described by Thornberry et al., Nature, 356,768-774 (1992). iii) PBMC Cell assay as described in U. S. 6,204, 261 B1 Bachelor et al., issued March 20,2001.

Each of the above citations is included herein by reference.

In addition, Tumor Necrosis Factor, TNF-a, inhibition can be measured by utilizing lipopolysaccharide (LPS) stimulated human monocytic cells (THP-1) as described in: i) K. M. Mohler et al.,"Protection Against a Lethal Dose of Endotoxin by an Inhibitor of Tumour Necrosis Factor Processing", Nature, 370, pp 218-220 (1994). ii) U. S. 6,297, 381 B1 Cirillo et al., issued October 2,2001, incorporated by reference and reproduced herein below in relevant portion thereof.

The inhibition of cytokine production can be observed by measuring inhibition of TNF-a in lipopolysaccharide stimulated THP cells. All cells and reagents are diluted in RPMI 1640 with phenol red and L-glutamine, supplemented with additional L-glutamine (total : 4 mM), penicillin and streptomycin (50 units/mL each) and fetal bovine serum (FBS 3%) (GIBCO, all conc. Final).

Assay is performed under sterile conditions, only test compound preparation is non-sterile. Initial stock solutions are made in DMSO followed by dilution into RPMI 1640 2-fold higher than the desired final assay concentration. Confluent THP. 1 cells (2 x 106 cells/mL, final conc. ; American Type Culture Company, Rockville, Md. ) are added to 96 well polypropylene round bottomed culture plates (Costar 3790; sterile) containing 125 L test compound (2-fold concentrated) or DMSO vehicle (controls, blanks). DMSO concentration should not exceed 0.2% final. Cell mixture is allowed to preincubate for 30 minutes at 37 °C, 5% CO2 prior to stimulation with lipopolysaccharide (LPS, 1 g/mL final ; Sigma L-2630, from E. coli serotype 0111. B4; stored as 1 mg/mL stock in endotoxin screened diluted H2O vehicle at-80 °C). Blanks (unstimulated) receive H20 vehicle; final incubation volume is 250 1L. Incubation (4 hours) proceeds as described above. Assay is to be terminated by centrifuging plates 5 minutes at room temperature, 1600 rpm (4033 g) ; supernatants are then transferred to clean 96 well plates and stored at-80 °C until analyzed for human TNF-a by a commercially available ELISA kit (Biosource &num KHC3015, Camarillo, Ca. ). The calculated IC50 value is the concentration of the test compound that caused a 50% decrease in the maximal TNF-a production.

While particular embodiments of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.