SA03240110B1 - 1,2-dihydropyrazol-1- and 1-2-dihydropyrazol -3- ones that control inflammatory cytokines - Google Patents

Abstract

Abstract: The present invention relates to compounds capable of extracellular release of inflammatory cytokines, said compounds, enantiomeric and diasteriomeric forms, or pharmacologically acceptable salts thereof, having the formula: (b) C1-C10 hydrocarbyl substituted or unsubstituted selected from The group consisting of: (i) cyclic alkyl, branched, or linear C1-C10; (2) C1-C10 aryl; (3) C1-C10 heterocyclic; (4) C1-C10 heteroaryl 55. where R is ether or amino, and R1 is a phenyl substituted, each R2 and R3 unit selected separately from the group consisting of: (a) hydrogen; And

Description

(v AD = Ye) hydropyrazole-"-ones All 1,2-dihydropyrazol-3-ones control inflammatory cytokines Full Description BACKGROUND The present invention relates to 2-dihydropyrazolo-3-compounds ones 1 which inhibit the extracellular release of inflammatory cytokines 1; said cytokines are responsible for one or more disease states in humans or in primates The present invention further relates to formulations including 1,2-dihydropyrazolo-3-ones © mentioned and the method (aid suppression; or otherwise control of enzymes known to be the active components responsible for the pathological stages described herein. Interleukin-1 (IL-1), tumor necrosis factor-a and e ( TNF- among the important biostimulants are collectively known as 'cytokines' These molecules are known to cause the inflammatory response associated with immune recognition of infectious agents.Ye suggests that these pro-inflammatory cytokines are important causative agents in many disease states or Symptoms of IS, among others, are rheumatoid arthritis, osteoarthritis (aie), inflammatory bowel disease (IBS), septic shock; cardiopulmonary dysfunction; acute respiratory illness; emaciation Therefore, it is responsible for the development and apparent symptoms of human disease states. Therefore, there is an urgent need for long-standing compounds and drug combinations, including “LS yo VO that can inhibit; dampen control over ease off; or inhibit the release of cytokines from the cells that produce them. GENERAL DESCRIPTION OF THE INVENTION The present invention satisfies the aforementioned needs in that it has been surprisingly shown that certain bicyclic pyrazolones and derivatives thereof are effective in inhibiting the release of inflammatory cytokines; Among others, dnterleukin-1 (IL-1) and tumor necrosis factor (TNF) cells are inhibited by Malls; dampen Or 0 in some other way controls the enzymes that are supposed to be the active components responsible for the pathological stages described here. Hala 1

v The first form of the present invention relates to compounds; including all enantiomeric and diasteriomeric forms and pharmaceutically acceptable salts thereof; Said compounds have the formula: 9 NT ¥ rR A \ rN, the R oo where +1 is: O[CHLR* (i) or “-NRSaR Sb(<2)4 is a “branched cyclic alkyl”; or linear C-C substituted or unsubstituted; aryl substituted or unsubstituted” heterocyclic circle substituted or unsubstituted; or heteroaryl substituted or not 0 substituted; The © function from zero to $0 is 1858 and JSR separately is: ) ) hydrogen; or (b) R7 (0 0 − 1065 and 855 separately is hydrogen '-CON(RS); -CO ,R8 -N(R8); -OR® ccyclicalkyl 0 branched; or linear “C-Cy and mixtures thereof; 187 is hydrogen; -OR® C=C alkyl --CON(RS) , «-CO,R8 -N(RS), substituted or unsubstituted; substituted or unsubstituted heterocyclic; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; 188 is hydrogen; cation Soluble in water; “Ci-Caalkyl or analyte is substituted or unsubstituted; the function Gem is 0 to 0 7 the RI is a phenyl substituted; each unit 182 and R3 is selected separately from the group formed of: (a) |hydrogen; and (b) hydrocarbyl and ©-,© substituted or unsubstituted chosen from the group consisting of: halah 1

ccyclic alkyl (1) ©-,© branched or linear; ¢Cg-Cyoaryl (Y) ¢C,-C)oheterocyclic (¥) C1-Cjoheteroaryl (¢). present drug formulations capable of delivering compounds of the present invention to a human or higher mammalian organism; Such compositions comprise: (a) an effective amount of one or more of the compounds of the present invention; and (b) one or more pharmacologic excipients. Another form of the present invention relates to methods for controlling one or more disease or inflammatory phases of the mammary glands that are induced or modified by a cytokine This method comprises the step of administration to a human or mammal of the highest effective amount of a formulation comprising one or more than the Wh compounds of the present invention. Another form of the present invention relates to forms of compounds of the present invention; which under normal physiological conditions; The vehicles will unlock as described here. yo These and other purposes, features, and features will become clear to the average person skilled in the art by reading the following detailed description and appended claims. all percentages; The proportions and amounts here are by weight; Unless specified otherwise. All temperatures are in degrees Celsius (*in Celsius) unless specified otherwise. incorporate here for reference all the documents cited in their relevant parts; The mention of any document is not an endorsement that it is prior art in relation to the present invention. © Detailed description of the invention The present invention relates to compounds which are capable of causing; Controlling or otherwise inhibiting the release of extracellular Ais cytokines—particularly inflammatory cytokines; these cytokines play a role in excitability; causing or manifesting a large number of disease stages or symptoms. Yo for purposes The present invention “hydrocarbyl’ laa al) herein is defined as any organic part or unit consisting of carbon atoms and hydrogen atoms. The term hydrocarbyl herein includes the heterocycles described herein below. Examples of hydrocarbyl units include lah 1

A Qo unsubstituted non-cyclic heterocyclic «1,3-dimethylphenyl (3-ethyloctanyl «pentyl Ae site -naphth-2-yl 5 <7,7-dimethylbicyclo[2.2.1]-heptan-1- yl “cis-3-hexyl” cyclohexyl is included in the definition of “hydrocarbyl” aromatic (aryl) and non-aromatic “carbocyclic” rings. Non-restrictive examples of these include “cyclopropyl” and “bicyclo-cyclopentanyl” «bicyclo-[0.1.1]-butanyl «cycloheptanyl »cyclohexenyl «cyclohexane 0 «bicyclo-[0.2.2]-hexanyl «bicyclo-[0.1.3]-hexanyl (thujanyl) <[0.1.2]-pentanyl ‎bicyclo- «bicyclo-[2.2.1]-heptanyl (norboranyl) » bicyclo-[0.1.4]-heptanyl (caranyl) «decalinyl «dicyclopentanespiranyl »spiropentanyl <[0.2.4]-octanyl (caryophyllenyl) <anthryl «phenanthryl <azulenyl «2H-indenyl «indenyl «naphthyl «benzyl «phenyl «1,2,3,4-tetrahydronaphthalenyl «acenaphthylenyl » fluorenyl 0 etc. The term heterocycle includes both rings aromatic (heteroaryl) and non- caromatic heterocyclic; triazolyl, isoxazolyl, oxazoyl, 1,2,4-oxadiazoly, 2H-pyranyl, 4H-pyranyl, 2H-pyran- 2-one-yl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, s-triazinyl, 4H- 0 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, 1H-indolyl, benzoxazolyl, 2H-1-benzopyranyl, quinolinyl, isoquinolinyl, quinazolinyl, 2H-1,4-benzoxazinyl, pyrrolidinyl, pyrrolinyl, quinoxalinyl, furanyl, thiophenyl, benzimidazolyl, Y. etc.; Each of them may or may not be replaced. An example of an 'alkylenearyl' unit would be a benzyl unit of the formula: = where an example of an 'alkylencheteroaryl' would be a 2-picolyl unit of the form vo: N= . 'ovo

A 0 The term 'substituted' is used throughout the specification. The term 'substituted' is defined here to include parts or units that can substitute for a hydrogen atom; two or three hydrogen atoms from a hydrocarbyl part also 'substituted' includes the substitution of two hydrogen on two adjacent carbon atoms to form a new unit or fragment. For example; a substituted unit that requires the replacement of one hydrogen atom includes halogen 71 ha; etc. The substitution of two hydrogen atoms includes coximino «carbonyl» etc. Substitution of two hydrogen atoms from two adjacent carbon atoms involves epoxy etc. The substitution of three hydrogen atoms includes cyano etc. An epoxide unit is an example of a substituent unit that requires the replacement of a hydrogen atom with neighboring carbon atoms. The term 'substituted' is used throughout the present specification to refer to a fraction <hydrocarbyl 0 among others; a caromatic ring calkyl chain that may have one or more hydrogen atoms substituted by a substituent. When a fraction is described as 'substituted' Any number of hydrogen atoms can be substituted. For example, 4-hydroxyphenyl would be an "inductive aromatic carbocyclic ring" (N,N-dimethyl-5-amino)octanyl would be an alkyl unit and the 3-guanidinopropyl substituent would be A C3 alkyl unit is a substituent and 2-carboxypyridinyl is a 'vo-substituted heteroaryl unit.' Below are unlimited examples of units that can substitute for hydrogen atoms when a hydrocarbyl unit is described as a 'substituted'. -[CR13 ),] (CH=CH) R! 3 (V) ¢ “[CRIPILCEDRE (Y) HCRB)ILCED,RE )( [CRI], C(Z)CH=CH, (¢) + .S[CREYLCENRDB), (0) ¢-[C(R13),],C(Z)NRIN(R! (VY) =[CR),L,CN )( ~[ CRI3),[,CNO )( -[C(R13),],CBr; [CR13),1,CCly «[CRI3],J,CFy (3) ve H[CRPINRE), (11) ¢-[C(R13),] NRBBCN (VV) h lan 1

For -[C(RI3)JNRIBC(Z)RI3 (VY) [CRI INRBCEZ)NR), (V7) [CRINHNRD), (1¢) -[C(R13),],NHORI3 (01) 0H [CRB)NCS (V1) HCRI)INO, (VY) [CRI3,L,ORE (14) [C(R13),]J,0CN (14) ¢-[C(R13),],0CBr3 «[C(R13),],0CCl; «-[C(R!3),], OCF}; (Y+) [CRB)LT [CRI Br +[CRI)LCL [CRLF (MN) 0 and mixtures thereof; {CRI),1,SCN (YY) -[CR13),],S0;M (TY) -[C(R13),],0S0;M (Y£) [CRI], SONRD), (Yo) M [CRB),LSORD (Y1) [CRB),1POH, (YY) [CR12),J,PO, (YA) for [C(R13), ],P(O)(OH), (V4) and mixtures thereof; v. where RIB is hydrogen; ccyclicalkyl branched ar linear mean aryl gaseous; C=C, alkylenearyl substituted or unsubstituted; and mixtures thereof; where M is hydrogen; or a cation-forming salt; Z is 0 = 5 - 1813 and mixtures thereof; m be from zero to OY be j from zero AY) A suitable cation-forming salt includes dithium sodium cammonium magnesium calcium potassium etc. 1,2-dihydropyrazol-3-ones 0 The present invention relates to compounds of 1,2-dihydropyrazol-3-ones that inhibit the release out of cells of inflammatory cytokines. The compounds of the present invention comprise three components. The first is YoVo

A 1,2-dihydropyrazol-3-one ring structure that may or may not be metabolized as described here below at the nitrogen atoms comprising position 1 and position ? of the ring system. The second element is the © position of the pyrimidine ring attached at the position; of the pyrimidine ring and substituted Ula) at position 1 of the pyrimidine ring whether m by an ether group or an amino group The third element is a phenyl group substituted at position ; of building the loop. The following is a description of the constituent compounds of the present invention. R is substituent at the ¥ position of the pyrimidin-4-yl part of the general structure; Said unit of R is: ether (i) of the form 184,[f0]©011-; or 0 (b) an amino unit of formula ¢-NR2R3 where RY is 1 and dna; branched or linear 0-0, substituted or unsubstituted; 1m Replaced or not replaced; heterocyclic and:©0-© substituted or unsubstituted; or heteroaryl and:©-:© substituted or not substituted; The Gen function is zero to #. The following are different configurations of the units of R according to the present invention where R is ether of formula 0 0[0©12][,84-]. however; Al-Sayegh does not abide by the repeated examples and meanings mentioned here. (a) The units of R include ethers of the form -OR* (function « equals zero) and R* hr aryl substituted or unsubstituted. (1) One of the frequent meanings of this form of R includes ethers of the form 014- and RY is a substituted or unsubstituted aryl. This frequent meaning includes the non-Y form. The determinant Jill of “3-fluorophenoxy” 2-fluorophenoxy “phenoxy R: 3-trifluoromethylphenoxy “2,4-difluorophenoxy” 4-fluorophenoxy “2,4-trifluoromethyl phenoxy” 4-trifluoromethylphenoxy etc. (¥) Other frequent meaning This form of R includes its ethers of the form -OR* and R* is a substituted or unsubstituted aryl This frequent meaning includes the indefinite examples “4-methylphenoxy” 3-methylphenoxy “2 -methylphenoxy :a— ll Yo -2,4 “4-cyanophenoxy” 3-cyanophenoxy “2-cyanophenoxy” dimethylphenoxy “4-ethylphenoxy etc. YoVvo

A q (7) An additional frequent meaning of this form of R includes ethers of the form 0144- and RY is a substituted or unsubstituted aryl. This frequent meaning includes the following indefinite 0 examples: «(4-methoxy)phenoxy «(3-methoxy)phenoxy «(2-methoxy)phenoxy «3-benzo[1,3]dioxol-5-yl ¢3-[(N-acetyl)amino]phenoxy etc. (=<) R units including ethers have the form -0184 (function n is zero) and RY is a substituted or unsubstituted aryl. (1) First recurring meaning This form of ethers Jody R has the formula -0184 and 184 is the unsubstituted heteroaryl This repeated meaning includes the following indefinite examples: “pyridin-4-yl” pyridin-3-yl “pyridin-2-yl” pyrimidin-4-yl «pyrimidin-2-yl 1 etc. (7) A second recurring meaning of this form of R includes ethers having the formula -OR% and RA being a substituted heteroaryl. This repeated meaning includes the following indefinite examples: “2-aminopyrimidin-4-yl etc. (c) R units containing ethers have the dye Wa)-OCH,R#8 is equal to 1) RY is either substituted or unsubstituted aryl. (0) A first repeated meaning of this form of ethers Jai R has the form 0011214-0011214 and 114 is a substituted or unsubstituted heteroaryl. This repeated meaning includes the following indefinite ALY: “2-aminopyrimidin-4- yl «pyrimidin-4-yl pyrimidin-2-yl «pyridin-4-yl »pyridin-3-yl «pyridin-2-yl «4-aminopyrimidin-6-yl etc. (Y) Y. A second recurring meaning of this form of R where R is an ether of the formula -OCH,R? and 184 is a substituted or unsubstituted alkyleneheteroaryl-aryl. This frequent meaning includes the following unspecified amethysts: pyridin-3-ylethyl «(2-methyl-2-pyridin-3-yl)ethyl etc. R Slay (9) including ethers has the formula OR? (function 8 equals 1) and RY 2 is a substituent or unsubstituted Cp alkyl Yo or is a -C3.Cyo carbocyclic unit ove

A Yo ins (1) first repeat of this form of R is “ether of the form -OR* and 14 is branched coyclicalkyl; or linear and unsubstituted ©,-0. This repeated meaning has The following unspecified examples: “(S)-1-methylpropyl 18001071 “ethyl imethyl etc. (7) A double repeating meaning of this form of R is ether of formula -034 and RY is cyclicalkyl ° branched; or linear M©0-,© substituted This repeated meaning includes the following indefinite examples: «(S)-1-methyl-3-methoxypropyl «2-methoxyethyl etc. (7) A third frequent meaning of this form of R is ether of formula -0144 and 184 is a carbocyclic unit and ©-:© substituted or unsubstituted This includes “cyclopropyl : sal) “cyclohexyl” 2,5-dimethylcyclopentyl “cyclopentyl etc. . Lad Ve the following are unspecified examples of different forms of R units according to the present invention where R includes an amino unit having the formula: Re J and O where 1852 and JSR are separately: (() hydrogen ; or A' (b) transversal.; 6c and 1860 are each separately “branched” cyclic alkyl hydrogen; or linear Cp-Cy substituted or unsubstituted. ¢-CON(RS), “- CO,R8 -N(R8), and mixtures of those; R7 is an alkyl «cums ju annalah; cp iia or linear CC substituted or unsubstituted; heterocyclic substituted or unsubstituted; aryl substituted or unsubstituted; or substituted or unsubstituted heteroaryl; RE -CON(RS), 08 -N(R8), «ORE + is hydrogen; a water-soluble cation talisman-,©; or aryl substituted or unsubstituted; the function is from zero to #. However, the formular is not limited to the examples and recurring meanings represented here. )) R units including racemic amino groups where 1552 is hydrogen; RO or ROD is hydrogen or alkyl B©-0; R7 is substituted or unsubstituted aryl or cheteroaryl Yo Said units have the formula: Yovo

11 H / yl R® .6c : (V) A first recurring meaning of this form includes units where both ROD SRO2 is hydrogen and R7 is aryl or aryl replaced Said units have the formula: H / N RD — ap asa ad ped BY aaa 5 “(2-amino-benzyl)amino “(4-fluorobenzyl)amino “benzylamino : ji” — <i «(4-methoxybenzyl)amino «(4-methylbenzyl)amino «(2-methylbenzyl)amino «(4-methanesulfonyl benzylamino) and -(4-propanesulfonyl)benzylamino (7) a second recurring meaning of this form Includes units where one unit of R68 and R66 Ve is hydrogen and the other is 06031 where R7 is aryl or “Jats aryl” Said unit has the formula: H m 12 i HC — Unspecified examples of this repeat include: “(a)-methylbenzylamino and -1-(4-fluorophenyl)-ethylamino 9) A third repeated meaning of this form includes units where is is both 1068 and 1855 is hydrogen and R7 is a heteroaryl or substituted heteroaryl Unspecified examples of this repeated meaning include: (pyridin-3-yl) «(pyridin-2-yl)methylamino «(pyridin-4) -yl)methylamino «methylamino and -(imidazol-2-yl)methylamino (b) R units comprising racemic amino groups where R92 is hydrogen; RO 9 or RED is hydrogen or alkyl B©-:©” and R7 is a branched cyclic alkyl; or in writing ©-,© replaced or not replaced; The units mentioned have the form m lah 1

VY H / 87 for RSS R : 1 ( first recurring meaning of this form includes units where both Rba and A R6b are hydrogen and 1,7 is hydrogen or a branched cyclic alkyl or linear C-Cq H / N°. Unspecified examples of this repeat include: “ethylamino “methylamino” “isobutylamino” propylamino and Y-cyclopropylmethylamino ) (meaning repeated A second of this form includes units where one unit of R62 and 1860 is hydrogen and the other is amethyl and RT is hydrogen or “branched cyclic alkyl or ha, 0-0). H / N m Vv. 0, 3 : Unspecified examples of this include isopropylamino :_ sill and -sec-butylamino (YF) A third recurring meaning of this form includes Cam units 10158 and REP are both hydrogens and R7 is a branched cyclic alkyl; or linear and 0©,0-0 is substituted. Non-specific examples of this repeated meaning include: 2-methoxy-2- 5 «2-methoxyethylamino -methylpropylamino Vo (?) A fourth repeated meaning of this form includes units where one unit is RO and REP It is hydrogen and the other is R705 S55 cmethyl is a branched or linear ceyclic alkyl Cc -Cs. Indefinite ib of this repeated meaning includes: “1-methyl-2-methoxyethylamino and -1,2-dimethyl-2-methoxyethylamino© (c) R units having racemic amino groups where 1858 is hydrogen; RE or REP is hydrogen or -CORS is 1.5 is hydrogen or 006171; R7 is hydrogen or a branched ceyclic alkyl; or linear M-0,©, substituted or unsubstituted; YoYo

AR heterocyclic substituted or unsubstituted; jats waryl or unsubstituted or heteroaryl substituted or unsubstituted; The aforementioned units have the formula: H / wg (1) A first Sie meaning for this body includes units derived from an alkyl unit containing camino acid methyl esters sf amino acids ° Including unspecified examples of this Repeated meaning: carboxylmethylamino (from (carboxymethyl)- “(glycine methylamino) (glycine methylester) and 1-(carboxy)ethylamino (from -(alanine) (7) repeated meaning A second of this form includes units derived from a substituted or unsubstituted aryl unit containing camino acid methyl esters s amino acids unspecified examples include: (a)-carboxybenzylamino (phenylalanine) and 1 -carboxy-2-(4- hydroxyphenyl)ethylamino from -(tyrosine) R Slang (3) containing amino chiral groups where 18548 is hydrogen; RO is hydrogen” ROP is Cp-Caalkyl and R7 is aryl or heteroaryl substituted or unsubstituted Vo; units listed have the formula: =A / N 87 &z with stereochemistry shown (1) A first recurring meaning of this form includes units where RO is cmethyl and R7 is aryl or aryl substituted. Indefinite examples of the repeated meaning include: (S)-(0)- (S)-1- «(S)-1-methyl-1-(4-fluorophenyl)methylamino «methylbenzylamino Y. (S) )-1-methyl-1-(2-methylphenyl) «methyl-1-(2-aminophenyl)methylamino ‎(S)-1- «(S)-1-methyl-1-(4-methylphenyl)methylamino ~ ~ «methylamino -methyl-1-(4-methoxyphenyl) -methylamino YoYo

V¢(7) A second recurring meaning of this form includes units where RO is Sethyl hydroxyethyl and R7 is a substituted aryl or aryl. Non-specific examples of this repeated meaning include: (S)-(avethylbenzylamino, (S)-1-(4-fluorophenyl)ethylamino, (S)-1-(2-aminophenyl)ethylamino, (S)-1 -ethyl-1-(2-methylphenyl)amino, (S)-1-(4- ° methylphenyl)ethylamino, (S)-1-(4-methoxyphenyl)-ethylamino, and -(S)- 1-(4-fluorophenyl)-2-hydroxyethylamino (e)_R units containing amino chiral groups where 1852 is hydrogen; RO is hydrogen.” ROP is 1terotate-:©; and R7 is is ccyclic alkyl branched; For this form includes units Cun is 1895 is methyl and R7 is cyclic alkyl branched; or linear m©-,0. All indefinite of this Vo includes the recurring meaning: (S) -1-methylpropylamino, (S)-1-methyl-1-methoxyethylamino, (S)-1-methyl- 2-(S)-methoxypropylamino, (S)-1,2-dimethyl-2-hydroxy propylamino, and -(8)-1,2-methyl-2-methoxypropylamino (V) a second recurring meaning of this form that includes units where ROD is 0-02 alkyl and R7 is Y. Branched or linear cyclic alkyl m©-,©. Non-specific examples of this repeated meaning include: (S)-1-ethylpropylamino, (S)-1-ethyl-1-methoxyethylamino, (S)-1-ethyl-2-(S)- methoxypropylamino, and -(S)-1-ethyl-2-methyl-2-methoxy propylamino ro (5) R units containing amino chiral groups where R52 is hydrogen; 1052 or RED is hydrogen or RS CO,RS is hydrogen or methyl and 187 is hydrogen \ovo

yo or branched coyclic alkyl; or linear C-Cy substituted or unsubstituted; heterocyclic substituted or unsubstituted; aryl substituted or unsubstituted heteroaryl substituted or unsubstituted; Said units have the formula: /o 4° with the indicated stereochemistry. (1) A first recurring meaning of this form includes AR units derived from an aryl unit containing camino acid methyl esters 5 amino acids The said units have the formula: H N 12 TRO “TN H where R8 is hydrogen or 08071. Undefined A Bd includes: R) (S)-(0))-carboxybenzylamino 01 unit derived from (L-phenylglycine (7) meaning A second repeat of this form includes units derived from a substituted or unsubstituted alkyl unit containing amino acid methyl esters s amino acids Non-specific examples of this repeated meaning include: 1-(S)-(carboxy)ethylamino (from (L-alanine is RT is a substituted phenyl. The units can be substituted by any “substituted” No group described here above. An initial configuration of the Rl units relates to a phenyl substituted chalogen on eg “d-chlorophenyl “4-fluorophenyl 2,4-difluorophenyl etc. A second body is attached to methyl substituted phenyl” eg 3-methylphenyl and 4-methylphenyl. A third body is attached to an inductive ring trifluoromethyl containing A Bd undefined: 3-trifluoromethylphenyl 0 Each unit 1582 and RI is selected separately from: 0) hydrogen; and (b) hydrocarbyl 0,©-,© substituted or unsubstituted selected from: YoYo

coyclic alkyl (V) branched or linear ¢C1-Cig ¢C-Cyo aryl (Y) ¢C1-Cyo heterocyclic (7) Cy-Cyp heteroaryl (¢)° includes definitions from Lad heteroaryl heterocyclic “aryl” cyclic alkyl related R2 and 183 units of the present invention; rings formed from functional groups and rings joined to the 1,2-dihydropyrazol-3-one ring structure by a bond. The bond typically consists of one or more alkylene units These units include: (J) l-tretin)-; Ve (b) 01.11 100) -; -(CH,),CONR!1), (—2) ¢-(CH,);,OCONR!), (2) (e) and mixtures thereof; where 189 is the circular ether unit; Within ¢fyranyl 5 pyranyl «La ye 18108 and 1100 or two 0 units of RI taken together to form a heterocyclic or heteroaryl unit containing of ? to 1 atoms; The flourishing of the function is from 0 to 5; be « is the function from zero to #. The first form of 82 and 183 relates to the 1,2-dihydropyrazol-3-one ring structures where 182 is RI, both hydrogens. One recurring meaning involves the generic compounds comprised by 4-(RY)-5-[2-R-pyrimidin-4-yl]-1,2-dihydro-pyrazol-3-one Y. The second body of 182 and 113 with 1,2-dihydropyrazole-3-one ring structures where R2 is a substituted or unsubstituted heterocyclic ring and 183 is a branched cyclic alkyl unit; or linear mo©-, substituted or unsubstituted. One recurring meaning includes the generic compounds contained in .1-(piperidin-4-yl)-2-methyl-4-(R")-5-[2-R-pyrimidin-4-y1}-1,2-dihydro -pyrazol-3-one The tertiary form of 182 and R3 relates to 1,2-dihydropyrazol-3-one ring structures where RZ is a branched coyclic alkyl unit Yo; or linear M0- , 0 is substituted or unsubstituted and 183 is a substituted or unsubstituted heterocyclic ring. [2-R-pyrimidin-4-yl}-1,2-dihydro-pyrazol-3-one \ovYo :

VY unspecified examples of second and third forms of units 182 and R3 include replaced or unsubstituted rings; Among others, constructions have the formula: 1p 0 tbr | 8 SX ~ > —R? AX N / Na oN yy b l 1 Neo or T . 1812 is -[C(R13),],C(O),R13 Indefinite examples of these include: “(CH,)CO,H

«-[C(CH;3),]COH «-[CH(CH,),]CO,CH; «[CH(CH,)]CO,H «-(CH,)CO,CH; 0

-[C(CH3),]CO,CH, or ALG water-soluble salts of acids.

The fourth form of RZ and R3 relates to the structures Sa 1,2-dihydropyrazol-3-one Ada R3 is 2 apart C-Cealkyl. One recurring meaning of this form relates to rings where Units 182 and 83 are the same; Within cla pe the generic compounds include 1,2-dimethyl-4-(R")-5-

1,2-diethyl-4-(R")-5-[2-R-[2-R-pyrimidin-4-y1]-1,2-dihydro-pyrazol-3-one 0 -pyrimidin-4- yl}-1,2-dihydro-pyrazol-3-one

However; Other forms of indeterminate examples include; among others; According to the general formulas aryl-2-(piperidin-4-yl)-4-(R)-5- [2-R-pyrimidin-4-yl]-1,2-dihydro- 1-91 1-( morpholin-4-yl)-2-(heteroaryl)-4-(R})- 5-[2-R-pyrimidin-4-yl]}- «pyrazol-3-one D 1-heteroaryl-2- substituted ~~ aryl-(4)-(R')-5-[2-R- 5 «1 ,2-dihydro- ~~ pyrazol-3-one -pyrimidin-4-yl}-1,2- dihydro-pyrazol-3-one The selection of the R2 83 units and their combinations is directly related to the classes described here below. For example, Jd compounds where both 182 and R3 are separately cethyl methyl or other lower alkyl are related to Phth4 isotopes.

Y. The isotopes (compounds) of the present invention are arranged into several classes to assist the jeweler in using an acceptable synthesis method for the preparation of isotopes not expressly represented herein. The arrangement of the phthalates does not increase or decrease the potency of the particular formulations described here.

‎YoYo

YA We conveniently obtain the isotopes (compounds) of the present invention in salt form; For example"; ctrifluoroacetate salt, especially after removing the protecting groups with trifluoroacetic acid in the last step of its preparation. With this, the jeweler may neutralize the isotopes or convert them into another salt form without changing the activity of the original compounds. The jeweler will also attend; If 0 this is appropriate or practical a prodrug that releases the active compound (isotope) upon absorption by the host. All these variants are incorporated into the present invention. The first A compounds to inhibit inflammatory cytokine release of the present invention are 4-R'-substituted-5-(2-R-substituted-pyrimidin-4-yl)-1,2-dihydropyrazol-3-ones. It has the general construction in the form: 0 MH R' \__N “H / = R Ve where and the first of class 1 has the formula: 0 n8 a “NH 8 / a 004 1 y RE are described below in table 1. Function 8 can be zero or 1. table 1 digit 0 ll 0 ll 2-fluorophenyl 4-fluorophenyl 3-fluorophenyl 4-fluorophenyl 4-fluorophenyl 4-fluorophenyl 2,6-difluorophenyl 4-fluorophenyl | o 2-cyanophenyl 4-fluorophenyl YovYoe

A 2440006 A Lanam AA ‎Snfuoromelhyipheny | TT] ata | AA / AH 1

Y 0 3-benzo[1,3]dioxol-5-yl 3-trifluoromethylphenyl fA) isotopes are unspecified examples of isotopes that include the first form of class 1. Isotopes of the first form of class 1 can be prepared 1 appropriately by the procedure shown here below. In the example “Jul!18 is 4-fluorophenyl with this the jeweler can; Substituting any suitable starting material for this cela! among others “methyl 4-chlorophenyl-acetate “methyl phenylacetate .methyl 3-(trifluoromethyl)phenylacetate 5 © Program 1: Class 1 Initial Body Preparation F. TT + OCH, 8 0 OCH; 0 no (0) oH ~~ — N y N SCH; SCH, x ) Reagents and conditions: (THF (LDA (i) -<6/L7*C; 1 h. F 0 0 OCH, TmH 0 | M (b) on 7 ° Na oN Nao oN TL T. XY Y yo. Reagents and conditions: (<) “CHCl, “CrO4 temperature A cad yall h. 8 8 0 0 OCH ; ww / NH | free (C) 0 | 7 Na oN and 0 L. ¢ ¥ Reagents and conditions: (C) HONNHC(O)NH, pyridine; 00*C; VY hour.

71 F F. 0 0 NH NH i / / NH 7 (d) ra NH he 9 I. 50.CH; © 3 Jal gall Reagent and conditions: (2) tH,O/THF/MeHO “@Oxone” room temperature, 1 hour. F F 0 0 pm | / 7 a | NH (9) 7 | NH YY SO.CHa 0 0 0-0 ° Reagents and Conditions: (e) phenol “THF” (NaH h and describe?; room temperature. Example 1 4-(4-fluorophenyl)-5-[2-(phenoxy)pyrimidin-4-yl]-1,2-dihydropyrazol-3-one (6) The following is a procedure for the preparation of 2s) 2- methylsulfanyl-pyrimidin-4-carbaldehyde from ((1964) 3407-3417 by Bredereck et al., Chem.

Ber., 97, pp. 11) Entered here as a translator. Return Ye. to the Pu! Three-Neck Flask! VY induces an inert atmosphere charged with N,N-dimethyl- (A+) formamide dimethyl acetyl g) YY) pyruvic aldehyde dimethyl acetal y g). The mixture is heated with re-condensation of the steam for 08 hours during which time the temperature decreases from 00°C to 8’00°C. The solution is cooled and methanol (4 liters) is added to dissolve the crude residue. The solution was then cooled to 17*C and 11.17 can 447 (molecule thiourea) was added. 1 After leaving the mixture to stir around “Aids Yo”, add 1,7 cas VEY (sodium methoxide molecule) on ¢ equal parts through aa aclu while maintaining the temperature of the solution within 5 degrees YA-YA *Celsius. The mixture was stirred for a period of ½ hours at ∼an temperature (Ad yall cooled down to ∼Ye; then methyl iodide (¥ kg) was added) during , 1 yo hour while maintaining the reaction temperature within 1 -117 7"C. Stirring continues for 18 hours at 1 °C

YY room temperature. The unreacted methyl iodide s methanol is removed by heating the solution at LACT at a pressure of £4 mm Hg to produce about 4.47 kg of a dark residue, which is divided between 1 liter of pele and 0 liters of ethyl acetste. The water part is extracted once. Again with cethyl acetate the organic layers are combined and concentrated by vacuum to provide 1488 g of oil purified through 1168 and OVY g of .4-dimethoxymethyl-2-methylsulfanyl-pyrimidine 0.

The dimethyl acetal produced above is hydrolyzed to a free aldehyde by heating up to Aye for ? hours in 1 mole HCl. The evolution of the reaction for neutralization using ethyl acetate to extract the product gives TEV g of crude product which is purified during 11168F to provide

1 «2-methylsulfanyl-pyrimidine-4-carbaldehyde 2-(4-fluorophenyl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-3-hydroxypropionic Preparation of 0 lithium diisopropylamide (?): to cold solution (-//-) of acid methyl ester mmol) in 47.8 (THF (4.? milliliters of a 7-mole solution in 1 g) methyl 4-fluorophenyl-acetate milliliters) A solution of THF (V+) is added dropwise (mL). The solution was stirred for 1 hour THF (Yo) in yo,v after which a solution of SA AVA at 1 mol in Ale YAY g; 10 (1) was added dropwise to the reaction mixture. 2-methylsulfanyl-pyrimidine-4-carbaldehyde (mL). Stirring was continued for 0 ½ min at -7/8*”C, then the reaction was quenched by decanting Yo)THF ethyl acetate reaction solution into saturated aqueous 01/1111. The aqueous phase was extracted with organic silica; dried (M,04850); nominate; Focused by suction. The crude residue is purified through (1:0) g (776) of the required product as an AY mixture to provide (hexanes [EtOAc /7F) 0

Distroemerates. .

111 NMR (300MHz, CDCl,) 6 8.52(dd,J=4.5, 1.5Hz,2H), 7.21-7.15(m,4H), 6.99(t,J=9.0Hz,2H), 5.38(d,J= 5.4Hz,1H), 3.83(d,J=5.4Hz,1H), 3.67(s,3H);

: R (M+H) veo preparation of 2-(4-fluorophenyl)-3-(methylsulfanyl-pyrimidin-4-yl)-3-0xo-propionic:(1) methyl ester to A suspension of 0:© in (Yo + (CH,Cly) pyridin was added. The mixture was stirred vigorously for one hour at room temperature. solution from

\oVo

YY

2-(4-fluorophenyl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-3-hydroxypropionic acid methyl prepared above on 0112010 (04 ml) is added dropwise to a chrome suspension. The crude oY was stirred; ester l) and filtered with ether (1 h; diluted by VT reaction mixture at room temperature for silica through filter 061146. The filter material was concentrated by vacuum and the resulting residue was purified through to provide 3.7 g (yield?; 7) of product required as a solid in color (0 hexanes [EtOAc 2772] yellow. 'H NMR (300MHz, CDCl,) § 8.79(d,J=4.8Hz,1H), 7.59 (d,]=4.8Hz,1H), 7.40 (dd,J=8.7, 5.4Hz,2H), 7.10(t,J=8.7Hz,2H), 5.97(s,1H), 3.79(s, 3H), 2.63(s,3H), (M+H) d ESI/MS: 4-(4-fluorophenvl)-5-(2-methvlsulfanylpyrimidin-4-yl)-1,2-dihydro-pyrazol- Prepare a 0 2-(4-fluorophenyl)-3-(2-h) solution of VY heated at 0*C for (4-(3-086 ¥.V) 4:) “¥ cmethylsulfanyl-pyrimidin -4-yl)-3-oxopropionic acid methyl ester pyridine 5 mmol) 8,8 can +107) carbazides HCL mmol); methanol raised in Alia aud retarded sole milliliters). The solution is then concentrated by vacuum to provide 10) and the resulting solid is removed by filtration. The filtrate is concentrated by vacuum to provide the desired compound ve as a white solid; which is used without further purification. 4-(4-fluorophenyl)-5-(2-methanesulfonylpyrimidin -4-yD-1,2-dihyvdro- pa a5 pyrazol-3-one (2): to a solution of 4-(4-fluorophenyl)-5-(2-methylsulfanylpyrimidin-p-1,2- 0137070-0778201-3-(4-71;4)¥ 01 mL body (0 in 001) methanol (THF) milliliters of mixture (Vi) added dropwise a solution of 0xone® (potassium peroxymonosulfate) (1,7 g; 51 mmol) in 001 (mL) water. The reaction was stirred for 1 hour at room temperature; diluted with NaHCO; aqueous and extracted three times with 601718061816. The organic layers are combined, dried, and concentrated by vacuum to provide the desired crude product that is used without further purification. 2-dihydropyrazol-3- one (2): To a solution of phenol (17+ pg Vir A mmol) in THF (©mL) add NaH (an +, YE) 8 ,51 mmol) and then a solution of 4-(4-fluorophenyl)-5-(2-hala 1

Yi methanesulfonylpyrimidin-4-yl)-1,2-dihydro-pyrazol-3-one crude; © Reported here above (77 gm 1.197 milligrams) in THF (Y) milliliters). The reaction mixture was stirred for an hour and a half at room temperature, diluted with NaHCO, and extracted twice with ethyl acetate. hind on MgSO, and concentrated by aspiration to provide the crude product © which was purified through silica (71 806 followed by EtOAc MeOH 700) to give the desired product as a yellow solid. The following are unspecified examples of compounds in Phase I for class 1 which can be prepared by the procedure described here above. -(2-hydroxyphenoxy)pyrimidin-4-y1]-4-(4-fluorophenyl)-1,2-dihydropyrazol-3- 01 one;5-[2-(4-hydroxyphenoxy)pyrimidin-4- yl]-4-(4-fluorophenyl)-1,2-dihydropyrazol-3- one, 5-[2-(2-N-acetylphenoxy)pyrimidin-4-yl]-4-(4-fluorophenyl )-1,2-dihydropyrazol-3- one;vo 5-[2-(3-N-acetylphenoxy)pyrimidin-4-yl]-4-(4-fluorophenyl)-1,2-dihydropyrazol- 3- one; 5-[2-(2-cyanophenoxy)pyrimidin-4-yl}-4-(4-fluorophenyl)-1,2-dihydropyrazol-3- one; 5-[ 2-(2-fluorophenoxy)pyrimidin-4-y1}-4-(4-fluorophenyl)-1,2-dihydropyrazol-3- Y.one; 5-[2-(4-fluorophenoxy)pyrimidin- 4-ylj-4-(4-fluorophenyl)-1,2-dihydropyrazol-3-one;5-(2-benzoxypyrimidin-4-yl)-4-(4-fluorophenyl)-1,2- dihydropyrazol-3-one;5-[2-(S)-(a-methylbenzoxy)pyrimidin-4-yl]-4-(4-fluorophenyl)-1,2-dihydropyrazol- 3-one ;YoYo yo 5-[2-(R)-(a-methylbenzoxy)pyrimidin-4-yl]-4-(4-fluorophenyl)-1,2- dihydropyrazol-3-one; Inflammatory according to the current invention have cytokin release inhibition compounds 1 The second body of the class General structure in the formula: 0

Ln

FN oN = m R54

RS a7 . The stereochemical form Y they are as described here below in table R74 “ROD (R52 (RI Cua) are hydrogen. With 187 ROD indicated above for isotopes from the table ? when not

YR isotopes with corresponding stereochemistry similarly fall into the second form range of 0 Table phenyl 4-fluorophenyl 4-fluorophenyl 4-fluorophenyl | 86 2-aminophenyl 4-fluorophenyl 2-methylphenyl 4-fluorophenyl 4-methylphenyl 4-fluorophenyl 4-methoxyphenyl 4-fluorophenyl 4-(propanesulfonyl)phenyl 4-fluorophenyl BE

Sohenzol13Jdioxol31

Pyridin-2-yl 4-fluorophenyl

Pyridin-3-yl 4-fluorophenyl phenyl 4-fluorophenyl 4-fluorophenyl 4-fluorophenyl 2-aminophenyl 4-fluorophenyl 2-methylphenyl 4-fluorophenyl 4-methylphenyl 4-fluorophenyl 4-methoxyphenyl 4-fluorophenyl 4-(propanesulfonyl)phenyl 4- fluorophenyl 3-benzof1,3]dioxol-5-yl 4-fluorophenyl

YoVo

Yi

Yeve

L-CO,H 3-trifluoromethylphenyl using intermediates such as compound ©; as a convenient starting point; And others that fall within the description of this category can be appropriately prepared by the procedure shown here below. Ve A-E isotopes With this, the jeweler may replace “4-fluorophenyl in the following example” so that the 18 is “methyl phenylacetate” Implicit in cel al aptly which starting material is compatible with this -methyl 3-(trifluoromethyl)phenyl acetate 5 «methyl 4-chlorophenyl-acetate 0 1 program?: preparation of the second body of class 0 = 2 ) NH 0

YN

SO.CHs o 0 wu and free 1 NH

TO z N HN Ey v VY C 010 toluene “(S)-(o)-methylbenzylamine (1) and conditions: 4a 2S factors h. 1 example ve 2-(4-fluorophenyl)-3-[2-(S)-(1-phenylethylamino)pyrimidin-4-y1]-6,7-dihydro-5H-(Y)pyrazolo[1,2-alpyrazol-1 -one 2-(4-fluorophenyl)-3-[2-(S)-(1-phenylethylamino)pyrimidin-4-v11-6,7- sea a3 mL) YA) toluene dissolved in (V): ) dihydro-SH-pvrazolo[1,2-alpyrazol-1-one-d 2-(4-fluorophenyl)-3-[2-methylsulfonyl-pyrimidin-4-y1)-6,7-dihydro-5H-pyrazolo[ 1,2-alpyrazol-1-one, raw; ©; reported here above (AT) g; 7.7 milligrams of mah 1

YA Grammy) amines uncle i-leta --()-(-)-(5) ) 0 0 milliliters 41.6 milligrams). The resulting mixture is heated to Balt Ee for VY hours; Cool to room temperature and remove the solvent by vacuum. The resulting residue is purified through [EtOAc 0:1 (silica hexane) to provide the desired product which is the isotope 4© in Table ?. 8.18(d,J=5.1Hz,1H), 7.42-7.34(m,7H), 7.04 ° 6 (recommended TH NMR (300 MHz, (ddd, J=9.0, 6.9, 2.1Hz,2H) ), 6.39(d,J=5.1Hz, 1H), 5.68(bd s,1H), 5.10(m,1H), 3.97(dt,J=7.5, 7.5, 7.5Hz,2H), 2.45(bd s,2H), 1 .67(m,2H), 1.60(d,J=7.5Hz,3H); Calculated HRMS (M+H)* Jay 0 and [Jun Lar 51] The second class of inflammatory cytokine inhibitors according to the present invention is 4-R'-substituted-5-(2-R-substituted-pyrimidin-4-yl)-1,2-dihydropyrazol-3-ones 0 His The general construction is in the form: 3 5 8 sim A' { NN 5 jn = O(CH,)R4 where the first form of class ¥ includes 182 including a substituted or unsubstituted ring; R3 has the signifier unit 0-,© linear, branched or cyclic; and the function an is yellow as specified 1 in table here below. table 2-hydroxyphenyl piperidin-4-yl | 4-fluorophenyl Thydoyphent 2-N-acetylaminophenyl piperidin-4-yl | 4-fluorophenyl 3-N-acetylaminophenyl piperidin-4-yl | 4-fluorophenyl 2-cyanophenyl piperidin-4-yl | 4-fluorophenyl 4-fluorophenyl piperidin-4-yl |4-fluorophenyl ‎#-Tuoopheny] | (S)-a-methylbenzyl piperidin-4-yl | 4-fluorophenyl (R)-a-methylbenzyl piperidin-4-yl N-methylpiperidin-4-yi | 4-fluorophenyl \oVo

Yq bowl meth | Nomotylpenndyl | -fhonopheryl | 177 | A-flcorophenyT | 13 | &-fluorophenol | 171 Lol Alsad Ma bow mei morpholindyl | -flovophenyi | VY |174| Aloh Meq | Neaceuiperdindyl | Yesterday phenyl VEY | For God Hanem Nemst for Nick | bow | met] The following is an example of the preparation of compounds included in the first form of the isotopes of the class? according to the present invention. oY program Preparing the first body for the class? 0 8 0 y nl te A Reagents and conditions: (1) VA- “CHCl, “H,NNHCH, 45° to room temperature 0 hours.

7 0 0

F0

TL CH. + (=) rT

NH, 0

A depth F. 0 TL x KC Hy

N.

H r NBa q (HCl (NaCNBHj (Y)) Reagents and conditions: (b) (i) vapor re-condensation +0 h; lel Y room temperature “EtOH

TL

CH, p a + nu”

NBoc cot

Qe =)

SA

f.0

TL x °C Hj; ot 2 cl Pa, \ + oO, room temperature; Two hours - pyridine (—) Revealer and conditions: Jal gall 1 Ah

A 1 Nl 16 0 2 L 1 M A Ya F. Pes N=—-CHj 2 N | 1) Reagents and conditions: (3) DMF (NaH 0’C; 1 hour. 0 Sch (+) NT > SCH, nN Boc p 8 b N-—CH; E / 8 | 2 N Y N SO4,CH, 8 Boc a 5 Reveals and conditions: (e ) 0-55 (CHCl 0*Celsius; © minutes. YoVvo

0 1 and m mm OH / 2 a N . ©)

YN

SO0:CH3 8

Boc

VY

F.

Pes

N—CH; / pd N 0 AN

Boc

YY

1117 hr. VE; Room temperature; (NaH) Reagent and conditions: (f) Jal sal

F

0 round: 7 N 0 he N 0 \ depth 7 0 and a - b a / a ham N and N 0 N

H

3 § min. 50 room temperature; “CH,Cly” TFA (J) Reagents and conditions: 5 eg? 1 h/uh

A Ty 4-(4-fluorophenyl)-2-methyl-5-( 2-phenoxy-pyrimidin-4-yl)-1-piperidin-4-yl-1,2- dihydro-pyrazol-3 -one (£ )) preparation of (A) (4-fluorophenvl)-acetic acid N-methyl-hydrazide to a stirred solution at -/anhydrous of 1 ( methyl hydrazine mL 508.8 mmol) In 032012 001 (00 mL) a solution of commercially available 4-fluorophenyl-acetyl chloride (VY) g is added dropwise; 18.5 milligrams (mmol) in (Yeo) CHCl (mL). The reaction mixture was stirred for 2 hours at -8°C, after which it was slowly warmed to room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a pale yellow oil. Purification through (EtOAc) silica provided VN g (yield (£7) of product required: 7.28-7.23(m,2H), 6.99-6.92(m,2H), 3.87(s,2H), 6 01 (IH NMR (300 MHz, 3.190(s,2H), 3.11(s,3H); N'-methyl-hydrazino} -piperidine-1- -4 carboxylic acid tert-butyl ester (3). to a stirred solution of (4-fluorophenyl)-acetic acid m ¢A «(N-methyl -hydrazide (¥ total 11 mmol) in (Y + ethanol) milliliters) add the commercially available 4-oxo-piperidine-1 carboxylic acid tert-butyl ester (4 g; 11 mmol The reaction mixture is subjected to vapor re-condensation for Te min; then it is cooled to room temperature after the addition of 0.0 pa 4 (NaCNBHj 17.0 mmol). The pH of the reaction mixture is adjusted at about ?with HCl was concentrated and the reaction mixture was stirred for ?yl hours at room temperature.The mixture was neutralized with saturated sodium bicarbonate and extracted three times with CHCl) The combined organic layers were dried; Filter and concentrate by suction. Purification through (EtOAC) silica provides 7.7 g (yield 797) of product required. 8551048: T11,Y .(M+H) {N'-[2-(4-fluoro-phenyl)-acetyl]-N'-methyl-N-(2-methylsulfanyl- jean -4) pyrimidine-4-carbonyl)-hydrazino}-piperidine-1-carboxylic acid tert-butyl ester ve (4) to a stirred solution of {N'-[2-(4-fluoro-phenyl)-acetyl]-N '-methyl-hydrazino}- -4 “piperidine-1-carboxylic acid tert-butyl ester j)¥,¥ g; 0111 milligrams) YoYo

ve in 01 (pyridine milliliters) add 2-methylsulfanyl-pyrimidine-4-carbonyl chloride (.9 c. 15.7 mmol). The reaction mixture was stirred at room temperature s.d. 2 hours after which it was diluted with 11N 1101 and extracted three times with O©R11©; The combined organic layers (MgSO,) were dried, filtered, and concentrated by vacuum. Purification through [EtOAC (silica hexane) 0:1 provides 0.188 g (yield) of 7700 m of product required. 251/148: (M+H) YAY preparation of 4-[4-(4-(fluorophenyl)-2-methyl-3-(2-methylsulfanyl-pyrimidin-4-y1)-3-0X0- (11) 2,3-dihvdro-pyrazol-1-vl}-piperidine-1 carboxylic acid tert-butyl ester to a solution of {N'-[2-(4-fluoro-phenyl)-acetyl]-N. '-methyl-N-(2-methylsulfanyl- -4 «pyrimidine-4-carbonyl)-hydrazino } -piperidine-1-carboxylic acid tert-butyl ester Ov (1,004 gm 000 mmol) in DMF (Y) milliliters) at 0°C slowly add [VYY (NaH) mg of 7700 dispersed in mineral oil » 7.07 Ale mol). The reaction mixture [Sad] was stirred for 1 hour at 0*C and then quenched With 1011 N HCl, the aqueous layer was extracted three times with CH Cy and the combined organic layers were dried (MgSO,) filtered and concentrated by vacuum. The technology through (CHCl /MeOH /Y+) silica provides VEY + g (yield of (IVY a 1) desired product. (M+H) 5007 ESUMS: 4-[4-(4-fluorophenvyl)-2-methyl-5-(2-methanesulfonyl-pyrimidin) -4-y1)-3-:(01) oxo-2,3-dihvdro-pyrazol-1-yl]-piperidin-1 carboxylic acid tert-butyl ester to an undecylated of 4-[4-(4 -fluorophenyl)-2-methyl-5-(2-methylsulfanyl-pyrimidin-4-y1)-3- c0x0-2,3-dihydro-pyrazol-1-yl]-piperidine-1 carboxylic acid tert-butyl ester Wrap 11 aa (0.4 vo mmol) in CHCl (Yo) milliliters at 0*C add meta- aa €) chloroperbenzoic acid 17,?? mmol). After stirring for 0 minutes sodium bisulfite saturated Yo (ml tqr) was added and the reaction mixture was stirred for an additional glide period. The aqueous phase was extracted three times with “CHCl.” The combined organic phases were washed with saturated sodium bicarbonate; dried (m0/1850); Filter and concentrate by suction. The raw material is used without ve additional purification. Preparation of 4-[4-(4-fluorophenyl)-2-methyl-5-(2-phenoxy-pyrimidine-4-yl)-3-0x0-2,3-:(11) dihydro-pyvrazol-1 -yl]piperidine-1 carboxylic acid tert-butyl ester to ovo solution

a vo of phenol vs V1) total 176 mmol) in THF (© mL) by addition of NaH ye YE) dispersed in 260 g in mineral oil”; 1898 milligrams). after stirring for 0 minutes at room temperature; A solution of 4-[4-(4-fluorophenyl)-2-methyl-5-(2-methanesul fonyl -pyrimidin-4-yl)-3-0x0-2,3-dihydro-pyrazol- is added once 1-yl]- rN 08 ) \Y “piperidine-1 carboxylic acid tert-butyl ester 0 g; TS, + milligram) in THE ( milliliters). The reaction mixture was stirred at room temperature for 14 hours after which it was quenched by decanting in a saturated aqueous solution 0 The aqueous phase was extracted three times with CHCl The combined organic phases were washed with saturated sodium bicarbonate (MgSO,) od was dried and concentrated by vacuum. The crude residue without additional A is used in the next step. 0 Preparation of 4-(4-fluorophenvyl)-2-methyl-5-( 2-phenoxy-pyrimidin-4-yl)-1-piperidin-4-yl-:(15) 1,2-dihydro -pyrazol-3-one to a solution of 4-[4-(4-fluorophenyl)-2-methyl-5- (2-pheno xy-pyrimidine-4-yl)-3-0x0-2,3 -dihydro-pyrazol-1-yl]piperidine-1 15.7 cpa d) 1 “carboxylic acid tert-butyl ester mmol) in CHCl, .4 mL) added + TFA LY In CHCl, after stirring at room temperature for half an hour ve the reaction mixture was concentrated by vacuum. Purification by preparative HPLC analysis provided the desired product as salt 8.57(d,J=4.8Hz, 1H), trifluoroacetate. 7.46(dd,J=7.8, 7.8Hz,2H), 6 (means IH NMR (300MHz, 7.31(dd,J=7.5, 7.5Hz,2H), 7.26-7.19(m,3H), 7.06 (dd,J=8.7, 8.7Hz,2H), 6.90(d,J=4.8Hz,1H), 3.40(m, 1H), 3.52(s,3H), 3 33(m,2H), 2.65(m,2H), 2.27(m,2H), 1.73(m,2H).Y. Calculated for CysHp FNSOy (MAH) 437 R; Found 4371 45,1 Unlimited examples of other compounds containing The first form of the second class includes: 4-(4-fluorophenyl)-2-methyl-5- (2-phenoxy-pyrimidin-4-yl)-1 -(N-methyl)piperidin- 4-y]- 1,2-dihydro-pyrazol-3-one; Ye 4-(4-fluorophenyl)-2-methyl-5-(2-phenoxy-pyrimidin-4-y1)-1-b enzyl-1,2-dihydro-pyrazol-3-one; yoVo

that 4-(4-fluorophenyl)-2-methyl-5-[2-(2-fluorophenoxy)pyrimidin-4-yl]-1 -piperidin-4- yl-1,2-dihydro-pyrazol-3 -one; The inflammatory cytokine Jans of the present invention is the second form of the ¥ class of compounds having 4-R'-substituted-5-(2-R-substituted-pyrimidin-4-yl)-1,2- dihydro-pyrazol-3-ones of general construction in the formula: 0 ° 3C 4 R!

No 2 / Ns v=(

O(CH2),R' on a saturated or unsaturated ring R3 containing a dower alkyl unit R? where contains and is function 1 is zero; As specified in the table; Here below. 3-N-acetylaminophenyl piperidin-4-yl 4-fluorophenyl piperidin-4-yl piperidin-4-y1 piperidin-4-yl 4-fluoropheny] (S)-a-methylbenzyl piperidin-4-yl 4-fluorophenyl L | pend

Nery piperidine Europe 2-hydroxyphenyl | N-methylpiperidin-4-yl 4-fluorophenyl 4-hydroxyphenyl | N-methylpiperidin-4-yl 2-N-acetylaminopheny! | N-methylpiperidin-4-yl 4-fluorophenyl Al 2-cyanophenyl | N-methylpiperidin-4-yl 4-fluorophenyl 4-fluorophenyl | N-methylpiperidin-4-yl

N-methylpiperidin-4-yl | methyl | 4-fluorophenyl (S)-o-methylbenzyl | N-methylpiperidin-4-yl | methyl | 4-fluorophenyl (R)-a-methylbenzyl | N-methylpiperidin-4-yl 4-fluorophenyl

YoVvo

b The following is an example of the preparation of compounds included in the second form of the Class 1 isotopes according to the present invention. tf program preparing the second body for the class? LO N which [OR EM N 5 N SCH, L FE 0 R => | ety N Y N SCH, YA Reagents and conditions: (2) (DMF) “(NaH) 0*residue; 1 hour. ovo

Ya

F

0 free N (=) \ 7

CH; Mohs "N

SCH,

Ya

F

0 A N NBo¢ 2 “ett N 5033

Yq 0'C © minutes. ¢CHCl4 tm-CPBA (—2) Reagents and conditions:

f.0

N©) - —

CH, M N

SOCH, 73 8 0 I N NBoc 2 N erty

N Bah N he

Ya h. VE room temperature; dan ‘THF (NaH “phenol (5)) These are the reagents and conditions:

D E 0 CO 2 )® and SA 0 7 L Da F. Pes. NH ~ POLE Na, YY N he YY factors Reagent and conditions: (0) ¢CH,Cl,TFA ve temperature (48 yal min. Example; 4-(4-fluorophenyl)-2-piperidin-4-yl-5-(2-phenoxy- pyrimidin-4-yl)-1 -methyl-1,2-m (Y)) dihydro-pyrazol-3-one Preparation of (Ye) 2-methylsulfanyl-pyrimidine-4-carboxylic acid N-methyl-hydrazide To a stirred solution at temperature of -/la of (1 milliliter La + 1 milligram) in (Al*001(CHyCI), a solution of 2-methylsulfanyl-pyrimidine-4- A was added dropwise carbonyl chloride (g 0 milligram) in Can (CH,Cl, mLqr). 01 The reaction mixture was stirred for 2 hours at I and slowly warmed to room temperature. The reaction mixture was concentrated under reduced pressure to give oil Purple. The purification through JEtOAC (silica hexanes) 0:1 provides 1.58 g (yield 777) of the required compound. 8.69-8.64(m, 1H), 7.35-7.08(m, 1H), 3.40(s,3H), TH NMR (300MHz, CDCl) 3.36(s,2H), 2.59(s,3H); (M+H) Y44,) ESI/MS: 1 h Uh 1

£ 4-[N'-methyl-N'-(2-methvlsulfanyl-pyrimidine-4-carbonyl)-hvdrazino]- ja an lee solution (11) piperidine-1-carboxvlic acid tert-butyl ester «Yo 2 -methylsulfanyl-pyrimidine-4-carboxylic acid N-methyl-hydrazide from mL) add 7+ ethanol (mM) in 15.8 (i210) g; 76.4 mmol V (0.1) 4-0x0-piperidine-1-carboxylic acid tert-butyl ester 0 gram). The reaction mixture is subjected to vapor re-condensation for 1.5 hours; cooled to a temperature of milligrams). The reaction mixture was brought to 11117 g;

CHCl was saturated and extracted three times with sodium bicarbonate. The reaction mixture was neutralized with silica, filtered and concentrated by vacuum. Purification through MgSOy and desiccation of combined organic layers 0 (EtOAC) provides 11.7 g (yield) (XA) of desired product. 'H NMR (300MHz, CDCl) 6 8.70(q ,J=2.9Hz,1H), 7.36-7.27(m,1H), 4.16 ‎(9,9=6.9Hz,1H), 3.97-3.78(m,2H), 3.37(d,J=16Hz,3H ), 2.91-2.79(m,2H), 2.61 (s,3H), 1.93-1.89(m,2H), 1.70-1.65(m,2H), 1.48(d,J=8Hz,9H); -(M+H) YAY,Y :ESI/MS oe 4-{N-[2-(4-fluoro-phenyl)-acetyl]-N'-methyl-N'-(2-methylsulfanyl- T__Dir ‎pyrimidine-4-carbonyl)-hydrazino } -piperidine-1-carboxylic acid tert-butyl ester 4-[N'-methyl-N'-(2-methylsulfanyl-) to a stirred solution with a temperature of zero * Celsius from « pyrimidine-4-carbonyl)-hydrazino]-piperidine-1-carboxylic acid tert-butyl ester (mL) added Yo) pyridine mM) in ©),Y (aa YA) > 130 g; 07.4 milligrams). The reaction mixture (01) (4-fluorophenyl) acetyl chloride was slowly warmed to room temperature and then stirred for 2 hours. The reaction mixture was then concentrated by vacuum. The purification through Yi (EtOAc) 710 g of desired product: ' H NMR (300MHz, CDCl3) 5 8.80-8.70(m, 1H), 7.40-7.32(m, 1H), 7.29-7.18 (m,2H), 7.07-6.94(m,2H), 4.24-4.10( m,3H), 3.82-3.59(m,2H), 3.33(d,J=8.4Hz,3H), Yo 2.88-2.67(m.2H), 2.60(d,J=18.6Hz,3H), 1.96-1.92(m,2H), 1.70-1.65(m,2H), 1.48 (d,J=4.0,9H); evo

A1 5: AgA (M+H) preparation 4-[4-(4-fluorophenvl)-2-methyl-3-( 2-methylsulfanyl-pyrimidin-4-yl)-5-0x0 -_.(14) 2,5-dihydro-pvrazol-1-yl]-piperidine-1 carboxylic acid tert-butyl ester to a 0°C solution of 4-{N-[2-(4-fluoro) -phenyl)-acetyl]-N'-methyl-N'- 0m (2-methylsulfanyl-pyrimidine-4-carbonyl)-hydrazino }-piperidine-1-carboxylic acid YTV) OV tert-butyl ester g; 017 mmol) in DMF (04 mL) slowly added (TY) NaH (770 g dispersed in mineral oil; 00 mmol YY). The reaction mixture was stirred for half an hour at 0 C and then quenched with 1 N HCL HCI. The aqueous layer was extracted three times with F [1120]. The combined organic layers (MgSOy) 0 were filtered and concentrated by vacuum. Purification through (EtOAc 0 ) silica provides VY g (yield £60) of desired product: 'H NMR (300MHz, CDCl,) 6 8.50(d,J=4.9Hz, 1H), 7.35-7.29 (m,2H), 7.02 (tJ=6.8Hz,2H), 6.85(d,J=5.1Hz,1H), 4.42-4.32(m,3H), 3.28(s,3H), 2.88(t, 12.8Hz,2H), 2.58(s,3H), 2.79-2.39(m, 2H), 1.94(d,J=11.7Hz,2H), 1.50(s,9H); d:ESI/MS peh (.M+H) The same procedures used to convert compound 11 to the corresponding compound VE as described in Program ?; can be used to convert compound 18 to the corresponding compound 71 in Program 4. 4-(4-fluorophenvyl)-1-methyl-5-( 2-phenoxy-pyrimidin-4-yl)-2-piperidin-4-yl-1.2-:(Y)) dihydro-pyrazol-3- one trifluoro-acetic acid salt TH NMR (300MHz, CD,0D) § 8.64(dd,J=5.4, 2.1Hz,1H), 7.44-7.05(m,10H), 4.61- Y. 4.47(m ,1H), 3.55(m,2H), 3.39(bs,3H).65 Calculated for ¢£67,099Y CysHp FNSO, (MAH) LOCATED HELTON Compounds with class isotopes? of the present invention shall have the form: HLA 1

0 #3 m R! N R3 ~~ N at N—R* RP mw 4 Rr’ Cua Vehicles Included Class 1 Body ? It has the formula: 0 rR? m x 8 arr Rr? N 7 N - 3 m l] R®a 24 R' where R3 is The alkyl eh-renae of R60 and R7 are as described here below 0 in Table #. The isotopes described here have the stereochemical form indicated when the ROD is not hydrogen. 4-fluorophenyl piperidin-4-yl 2-aminophenyl piperidin-4-yl 2-methylphenyl piperidin-4-yl 4-methylphenyl piperidin-4-yl 4-methoxyphenyl piperidin-4-yl 4-(propanesulfonyl)phenyl piperidin-4-yl 3-benzo[1,3]dioxol-5-yl piperidin-4-yl Py zy pein \oVo ‏

A Lal Hah 1

using intermediates such as OY as a convenient starting point; Isotopes 189-778 and others interfering with the description of this class can suitably be prepared by the procedure described here below. In the following example; !18 is cd-fluorophenyl with this the jeweler may appropriately substitute any starting material compatible with this procedure; From Methy 4- «methyl phenylacetate .methyl 3-(trifluoromethyl)phenyl acetate 5 «chlorophenyl-acetate © Program ©: Preparation of the first body of the class? YoYo

£0 0, : beat F \ AQ 1

N

/ \ N > Boe —

SOLCH,

YY

HC, NHj

A (0) 0 . _ CH, 8

N

/ N N ~ Boe =

N—H

HCO

YY

2 hours

NH

f}

N

© =

J N NN Boc cm b tc

YY

1 Jh lag

£3 9 mi = N-—H 0 79am Reagents and conditions: (b) tCHLCl, (TFA, room temperature; 00 min. Jia © 4-(4-fluorophenyl) -2-methyl-5-[2-(1-phenylethylamino)-pyrimidin-4-yl}-1- (YY) piperidin-4-yl-1,2-dihydropvyrazol-3-one E04-{4 -(4-fluorophenyl)-2-methyl-3-0x0-5-[2-(1-phenylethylamino)- yaa a5 pyrimidin-4-vi]-2,3-dihydro-pvrazol-1-yl}-piperidine- 1-carboxvlic acid tert-butyl 4-[4-(4-fluorophenyl)-2-methyl-5-(2-methanesulfonyl- to denatured from (YY) ester pyrimidin-4-yl)-3-0x0-2 ,3-dihydro-pyrazol-1-yl]-piperidin-1 carboxylic acid tert- (allle ?1(toluene mmol) is added in VY can 1) OY butyl ester 0 mmol). After stirring at YE mL (V,00) (S)-(0)-methybenzyl amine was brought to room temperature and then concentrated by vacuum. The jelly is two hours; The add mixture is cooled 0 purified through (hexane [EtOAc 728 +) silica to provide the required product. Preparation of 4-(4-fluorophenyl)-2-methyl-5-[2-(1-phenylethylamino)-pyrimidin-4-vl}-1-m (YY) piperidin-4-yl-1,2 -dihvdropyrazol-3-one to a solution of 4-{4-(4-fluorophenyl)-2-methyl-5-(2-methanesulfonyl-pyrimidin-4-yl)-3-0x0-2,3-dihydro -pyrazol-1-yl}- 1) mmol) 11 g; 1) 77 » piperidine-1 carboxylic acid tert-butyl ester .CH)Cl, in TFA 770 ml) add 4 +) CH,Cly mmol) in 15.7 g; after stirring at room temperature for half an hour; The reaction mixture was concentrated by vacuum. The purification

YoYo

By preparative HPLC analysis, the desired product is available as a salt “—~[a]p -trifluoroacetate ? *sperm (MeOH A ¢c) 8.30(d,J=4.8Hz,1H), 7.42-6.96(m,9H), 6.50 E" TH NMR (300MHz, CD;0D) (d ,J=4.8Hz,1H), 5.14-5.08(m,1H), 4.10-4.02(m, 1H), 3.56(s,3H), 3 .50-3.42(m,1H), 3.38-3.22 (m,2H), 3.01-2.85(m,2H), 2.22-1.70(m,3H), 1.52(d,J=6.9Hz 3H).° Calculated for CprHygFNGO (MAH) £70 77.7 ?; found VTL Y EAT includes unlimited examples of other compounds with the first form of Class 2 ?: 4-(4-fluorophenyl)-2-methyl-5- {2-[ 1-(4-fluorophenyl) ethylamino ]-pyrimidin-4-yl}-1-piperidin-4-yl-1,2-dihydropyrazol-3-one;4-(4-fluorophenyl)-2-methyl-5-{2-[1 -(3-fluorophenyl)ethylamino]-pyrimidin-4- ve yl}-1-piperidin-4-yl-1,2-dihydropyrazol-3-one; 4-(4-fluorophenyl)-2-methyl -5- {2-[1-(2-fluorophenyl) ethylamino]-pyrimidin-4- y1}-1-piperidin-4-yl-1,2-dihydropyrazol-3-one; the second form of the class * One of the compounds that inhibit inflammatory cytokine release according to the present invention is 4-fluorophenyl-5-(2-R-substituted-pyrimidin-4-y1)-1,2-dihydropyrazol-3-ones having the general structure In the formula: :. Here below in Table 6. The isotopes described here have the chemical form ©stereotype indicated a) when the ROD is not hydrogen. And A A A A A A A A D Dron | Lipstick YoYo tA

Yovo

1 £9 eI] well] mel] pipendindy | 11 in| well moll pipenandyl [717] Pipendindyl Tex Ke Laven | 6 H60 | well | melyl|pipendind 1 | 715 methow yeyl | methyl methyl | pipendiny | 717] Feed well | methyl | Nmetiylpipendicdy | 7 + l mel] methyl | Nemetbylpipendind yl | 7YY methoxymelyI | methyl | methyl | Nemetbylpiperidind vl 7s methoxyelnd | methyl | saw it | Nemetbylpiperidindy1 | 73

CO] mel mel | Nmcthyipperdin 1] meh mophalndyl | TE methyl welll methyl | 00004 | 7 ely] mel] wey | mopholndl | 77 mel] well Matt 1 cyclohend | melyl| the morphol] 7 methoumetyl | met | mel | miorpholind yl | 775] _ methowyetyl | metyl| methyl | moholindyi | 777)

COM mei] The orhelndyl| rr |hydrogen mely[ meh] Nacelpipendindyl | 774 mel moll] melyl | Naceulpipendindyl | 75.eyeI| methyl] methyl | Nacebipendindsl | Fi vind] eli methyl | Neacelpipendindl | 77 curse aa | mel | TEE methouymethyl | blame | mabyl | The Accused Tomma | Tio-mothoxyetyl | mei methyl complementary dT | 7

COM mei] Otome Arat | Ti] as a convenient starting point; VY compound Jie can conveniently be prepared using intermediates of this class by the procedure shown here below. In Cay isotopes 74-719 and others interfering with 1 dah

a o 0 next example; RT is 4-100:0016071; With this, the jeweler may appropriately replace any starting material compatible with this procedure, including methyl 4- «methylphenylacetate .methyl 3-(trifluoromethyl)phenyl acetate 5 »chlorophenyl-acetate il mali Preparing the second body for the class? 1 9 + 7 No Moc l / = Amc YY )0 "“ OCH, o Q CH fae A N "po / = N—H { OCH3 AR Reagents and conditions: (1) stoluene 0 * latency; 2 hours. \ovo

) 0 0 CH, i 24 (=) but ~_\ TL ,\ / N= > 110 OCH, Y¢ 9 mi + \ :5 CL, ~ — N—H mow OCH, Yo Reagents and conditions: (b) +CH,Cl, TFA, room temperature; Yes, a minute. Example “ 4-(4-fluorophenvl)-5-[2-(2-methoxy-1-(S)-methyl-ethylamino)pyrimidin-4-y1]-2- (Y°) methyl-1- piperidin-4-yl-1,2-dihydropyrazol-3-one 0 4-{4-(4-fluorophenyl)-2-methyl-3-0x0-5-[2-(2-methoxy-1-(S) -methyl- jum a3 ethylamino)-pyrimidin-4-yl1]-2,3-dihydro-pyrazol-1-yl} -piperidine-1-carboxylic acid tert-butyl ester (;7): to solution from 4-[4-(4-fluorophenyl)-2-methyl-5-(2- methanesulfonyl-pyrimidin-4-yl)-3-0x0-2,3-dihydro-pyrazol-1-yl]- piperidin-1 VY carboxylic acid tert-butyl ester 0 (1 g VY mmol) in toluene (Yo) mL) added YE can X,Y) €) (S)-2-amino -3-methoxypropane milligram). After stirring at 809"C for 2 hours, the reaction mixture was cooled to room temperature and then concentrated by vacuum. Purification through (hexane [EtOAc 70+) silica provided the desired product. 4-(4-fluorophenyl)-5-[ 2-(2-methoxy-1-(S)-methyl-ethylamino)pyrimidin-4- yaaa)m(YO)y1]-2-methyl-1-piperidin-4-vl-1,2-dihydropyrazol- 3-one to a solution of -4{-4 ,(4-fluorophenyl)-2-methyl-3-0x0-5-[2-(2-methoxy-1-methyl-ethyl amino)- lah 1 ‏

oY pyrimidin-4-yl]-2,3-dihydro-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl cester 74 (1.0 g); VY mmol) in CHCl (44 mL) added + ¥/ TFA in .CH,Cl, after stirring at room temperature for half an hour; The reaction mixture was concentrated by vacuum. Purification by preparative HPLC analysis provides the desired product as the salt -trifluoroacetate and [E]- (MeOH «\,Y ¢) 45210 © NMR (300MHz, CD;0D) 6 8.32(d,J=4.8 Hz,1H), 7.33-7.28(m,2H), 7.10-7.04 111 ‎(m,2H), 6.64(d,J=4.8Hz,), 4.35-4.19(m,2H), 3.63(s, 3H) .68 calculated for 40 CpaHygFNOy (MH) 41,7?; Find 441,750 1 Includes unlimited examples of other compounds having the form All of class ?: 4-(4-fluorophenyl)-5-[2-(2-methoxy-1-(S)- methyl-ethylamino)-pyrimidin-4-yl]-2- methyl-1-(N-acetyl) piperidin-4-yl-1,2-dihydropyrazol-3-one; 4-(4-fluorophenyl) -5-[2-(1-(8)-methyl-propylamino)-pyrimidin-4-yl}-2-methyl-1- (N-acetyl) piperidin-4-yl-1,2-dihydropyrazol- 3-one;vo The third form of the class “of compounds that inhibit inflammatory cytokine release according to the present invention is 4-fluorophenyl-5-(2-R-substituted-pyrimidin-4-yl)-1,2- dihydropyrazol-3-ones have the general construction in the formula: 0 id : N'Y i” jo al 1 sim “A 5 x_ where R2 is the utalqite-:© ; 187 is aryl and RT (RSE and R7 are as described here below © in Table LV The isotopes described here have the stereochemical form indicated when ROP is not hydrogen. halah 1 oy 7 table

Prima] eon] pending [oY] wl] A | pipet met [Tor

Pinan | 00471 meme [TV]

Pin os 0 fy] mel To ei eal mono mei] ydrogen hei rin 7 mh ei TY] hin] apa mobo me [RE ent] a | 0:4 mem [71 rennin] Salpin T met [FV yovo of

Pda] Alef | opti | mel | 4]

CT except meth] 60031 | methyl | 117]

Pymdndol methyl | Matt Manam [methyl] 777] The methyl | 7]

Yovo

00 using compounds Jie intermediates (V4) as a point al appears appropriate; isotopes 578-749 and others interfering with the description of this class can conveniently be prepared by the procedure shown here below. In the following example, RI is 4-fluorophenyl With this, the jeweler may appropriately substitute any starting material compatible with this procedure” including “methylphenylacetate .methyl 3-(trifluoromethyl)phenyl acetate 5 “methyl 4-chlorophenyl-acetate 0 program mg 7 : Preparation of the third body of the class? v= N—H qn Yo Reagents and conditions: (1) toluene + ¢4555°9 hr. ovo

depth N 10 m for Neh, (=) ) N\ / = N-—H HC Yo 8 l 9 P an \ iy / = N—H Z 0, 1 AM : Reagents and Conditions: (b) ¢CHLCLy (TFA room temperature; Ye min. ex. 07 4-(4-fluorophenyl)-1-methyl -5-[2-(1-phenylethylamino)-pyrimidin-4-yl}-2- (YV) piperidin-4-vl-1,2-dihydropyrazol-3-one 0 4-{4-( 4-fluorophenyl)-2-methyl-5-0x0-3-[2-(1-phenylethylamino)- juwa 5 ‎pyrimidin-4-yl1]-2,5-dihydro-pyrazol-1-yl} -piperidine-1- carboxylic acid tert-butyl :(Y1) ester to unconverted from 4-[4-(4-fluorophenyl)-2-methyl-5-(2-methanesulfonyl- pyrimidin-4-y1)-3 ox0-2,3-dihydro-pyrazol-1-yl]-piperidine-1 carboxylic acid tert- VY cbutyl ester 0 )1 g; VY mmol) in toluene (+¥ mL) add (S)-(a)- YE «lik V,00) methylbenzyl amine mmol). After stirring at 90 * resting for two hours »; The reaction mixture was cooled to room temperature and concentrated by vacuum. Purification through silica (EtOAc /o+) in hexanes provides 0.0 g (ZA yield) of desired product: halah 1 ov "HNMR (300MHz, CDCly) 6 8.41(d,J). =4.9Hz,1H), 7.38-7.31(m,7H), 6.98 (tJ=8.7Hz,2H), 6.40(d,}=4.9Hz,1H), 4.40-4.31(m,1H), 4.1 9 -4.08(m,1H), 2.86-2.78(m,4H), 2.23(t,J=8Hz,2H), 1.91 (d.J=12.4Hz,3H), 1 :60(d,J=6.9Hz,3H ), 1.52(s,9H): (M+H)evY,¢ ESI/MS: 4-(4-fluorophenyl)-1 -methyl-5-[2-(1-phenvlethylamino )-pyrimidin-4-yl] -2- pa al oo 4-{4-(4-fluorophenyl)- (7?): to a solution of piperidin-4-yl-1 p-2-011170170107732201-3,. 2-methyl- 5-0x0-3-[2-(1 -phenylethylamino)-pyrimidin-4-y1] -2,5-dihydro-pyrazol-1-15,7 mM (as 7 «yl}-piperidine-1- carboxylic acid tert-butyl ester after stirring at 'CHCl' in TFA 770 mL) added 0 (CHyCl, in grams) in

HPLC room temperature for half an hour; The reaction mixture was concentrated by vacuum. Purification by 0 {MeOH 7 ¢) °£\[op preparative analysis provides £7 g (yield 45 7) of desired product: 'H NMR (300MHz, CD;0D) § 8.25(d,J=4.8 Hz,1H), 7.40-7.00(m,9H), 6.40 (d,J=4.8Hz 1H), 5.11 -5.05(m, 1H), 4.51-4.41 (m, 1H), 3.61-3.55(m,2H ), 3.33 (bd,J=1.5Hz,3H), 3.24-3.05(m,3H), 2.92-2.75(m,2H), 2.19-2.1 0(m,2H), 1.52 (d,J=6.9Hz 3H). Vo 977,741 177,7; Found 5 Co7Hp0FNgO (M+H)* for snd HRMS includes unlimited examples of other compounds containing a third form of class ?: 4-(4-fluorophenyl)-5- [2-(S)-(o -methylbenzylamino)pyrimidin-4-yl]-1-methyl-2- piperidin-4-yl-1 ,2-dihydropyrazol-3-one; 4-(4-fluorophenyl)-5-[2-(S)-(a-methylbenzylamino) pyrimidin-4-yl]-1 -methyl-2- Y. (N-acetyl) piperidin-4 -yl-1, 2-dihydropyrazole-3 -one; 4-(4-fluorophenyl)-5 -[2-(S)-(a-methylbenzylamino) pyrimidin-4-yl]-1-methyl-2- (N-methyl) piperidin-4-yl-1 ,2- dihydropyrazole-3-one; (4-{4-(4-fluorophenyl)-2-methyl-5-0x0-3 “[2-(S)-(o-methylbenzylamino)pyrimidin- 4-yl]-2,5-dihydropyrazol-1 -yl } piperidin-1-yl) acetic acid; Yo ovo oA 2-(4-{4-(4-fluorophenyl)-2-methyl-5-0x0-3-[2~(S)-(a-methylbenzylamino)pyrimidin-4-yl]-2,5- dihydropyrazol-1-y1} piperdin-1-yl) 2- methyl propionic acid; (4-{4-(4-fluorophenyl)-2-methyl-5-0x0-3-[2-(S)-(o-methylbenzylamino)pyrimidin- 4-yl]-2,5-dihydropyrazol-1-yl } piperdin-1-yl) acetic acid ethyl ester; ° 2-(4-{4-(4-fluorophenyl)-2-methyl-5-0x0-3-[2-(S)-(a-methylbenzylamino)pyrimidin-4-y1]-2,5-dihydropyrazol- 1-yl }piperdin-1-yl)-2- methyl propionic acid ethyl ester; Inflammatory according to the current invention cytokin The fourth body of the class? Compounds that inhibit the release of 4-fluorophenyl-5-(2-R-substituted-pyrimidin-4-yl)-1,2-dihydropyrazol-3-ones form 0 have the general structure in the formula:

Oo c 1 F \ l 2 / 11 a

RoR { 7 “R6b (R3 and 2l) Jaina is a parent-Ren substituted or not R7 “Cy-Caalkyl is p is The isotopes described here have the stereochemistry LA They are as described here below in the table RT and is hydrogen. RO is not indicated by Laie _ 1

A table of piperidin-4-y1 directly | pipendndy eho]ppendmdy niles]ppendindy cyclopropyl piperidin-4-yl rin | pain a | operand] the [msm | pperdindy methoxyethyl piperidin-4-yl 1-hydroxy-1-methylethyl piperidin-4-yl

YoYoq meth]

I)

CC 00001 pen] rehome oe el pen] any nie] deni oe rehome eon con men] ment

EE]

EY

A 0001 mem The L 001 mem] Aa 6001 me]

YoVvo

Ta. ea] weil come mei mei methyl] Noches | methyl ct] methyl | Nenelhyipperaniot | methyl | EAT ini] 0001 methyl | Nonehyipporsanii | methyl a | 1h | methyl | Nomen] methyl] £42 I | methyl | Aja Ma'dim Marm | methyl | EAT Fla 60 AA 0041 | met ea mel] Lot 0 t 5 aa mel | LETTE © oral met] £51 ey] mel] momo | methyl ini] methyl] 00700041 | methyl | 657

CT An [methyl] moll Luo | £57 6s [methyl] morphol methyl | £55 ethoxy thousand | morpholinol | methyl 15

COM mei wholes [met [FX real me] 007547 | mel | 67] meni] methyl Nasovippendindyt | methyl 5]

TT iyi] moti] Nacmylperndindol | methyl 517] in] met] Nace bpenoin dl | mel 67 00601 methyl] Naceippondindo | metyi | 3+]

CC choxmet | methyl | N-aceyipendind | methyl [5 0000 ml | Naceipperdiniol | methyl | 57]

COM] methyl] Nueces | me [x is a convenient start; The ada (1 4) can conveniently be prepared using intermediates such as the isotope compound 79;-8© and others which are included in the description of this class by the procedure described here below. The goldsmith may substitute the dia with d-fluorophenyl RI is Jal in the example smethylphenylacetate appropriately Any starting material compatible with this procedure; including .methyl 3 -(trifluoromethyl)phenyl acetate “methyl 4-chlorophenyl-acetate 0 Preparation of the fourth body of the class? iA program 1 DL

m Bac “0 for F l + cH, /\

N

—(

SO,CH,

Yq “C00

OCH;

Boc ~~ y J p 1 barla eu, 7 N . C4

N—H

OCH,

YY

2 hours. (5320 toluene (1) Reagents and conditions: ovo

ly 9 i! (<=) SN \ \ / a .= 1160000 OCH; Ty ry Boc ,0 1 8 Men \ but / love m the OCH, YA Reagents and conditions: (b) tCHLCLy (TFA) room temperature; 0? min. Example A 4-(4-fluorophenyl)-5-[2-(2-methoxy-1-( S)-methylethylamino)-pyrimidin-4-yi]-1- (YA) methyl-2-piperidin-4-yl-1,2-dihydropyrazol-3-one 0 preparation 4-{4-(4 -fluorophenyl)-3-[2-(2-methoxy-1-(S)-methylethylamino)-pyrimidin- 4-vl]-2-methyl-5-0x0-2,5-dihydropyrazol-1-yl- 1-carboxvlic acid tert-butyl ester (YY) to an unconverted of 4-[4-(4-fluorophenyl)-2-methyl-3-(2-methanesulfonyl- pyrimidin-4-yl)-5 -0x0-2,5-dihydro-pyrazol-1-yl]-pipenidin-1 carboxylic acid tert- V4 cbutyl ester 00) 1 g; VY mmol) in Yo) toluene mL) add (S)-2-Y,)€)amino-3-methoxypropane g; YE millimol). After stirring at 00"*2 incubator for 2 hours, the reaction mixture was cooled to room temperature and then concentrated by vacuum. Purification through hexane [EtOAc 78 0( silica) provided the desired product. Preparation of 4-(4-fluorophenyl)-5 -[2-(2-methoxy-1-(S)-methylethylamino)-pyrimidin-4-d(YA)y1]-1-methvl-2-piperidin-4-vl-1,2-dihydropyrazol- 3-onc to a solution of -4{-4 ovo

a iy (4-fluorophenyl)-3-[2-(2- (S)-methoxy-1-methylethylamino) -pyrimidin-4-yl1]-2- cmethyl-5-0x0-2,5 -dihydropyrazol-1-yl-1-carboxylic acid tert-butyl ester (1.8 g); 11 mmol) in CH,CL, (+4 mL) add TFA 7710 in “CHCl” after stirring at room temperature for half an hour; The reaction mixture was concentrated by vacuum. Purification by preparative HPLC analysis Desired product availability as salt 111110103061216 NMR (300MHz, CD;0D) 5 8.30(d, 4.8Hz, 1H), 7.33-7.28(m,2H),7.10-7.04 111 ( m,2H), 6.47(d,J=4.8Hz,1H), 4.55-4.47(m, 1H), 4.24-4.18(m, 1H), 3.62-3.53(m,2H), 3.45-3.26( m,9H), 3.23-3.14(m, 2H), 2.93-2.78(m,2H), 2.20-2.13(m, 2H), 1.21(d,J=6.6Hz,3H). 85 Calculated VEY Cp3Hy9FNGO, (M+H)* Jay ?; Existing LEY, Yee includes unlimited examples of other compounds containing the second form of Class 4: 4-(4-fluorophenyl)-5 -[2-(S)-(1,2-dimethyl-2 -hydroxypropylamino)pyrimidin -4-yl] - 1-methyl-2-piperidin-4-yl-1 ,2-dihydropyrazol-3-one The compounds that include the class analogues; of the present invention are 4-R'-substituted-5-(2-D-R-substituted-pyrimidin-4-yl)-1 ,2-dihydropyrazol-3-ones having the general construction of the formula: N7 8 1 TNA 2c a b 8 Where is the first form of the art? have gel 0 sim AR \ l R2 Jn ol 04 ovo

AB" where both 182 and 83 are the same ,©-,© branched; RI RZ RH cyclic alkyl sf and 4 are as described here below in Table 4. Function 8 can be zero or 1. Table 3

methyl] 4-fluorophenyl 21 (01000430 Dr

hemi 0 uncle 4 fluorophenyl] what

4-fluorophenyl | oTA] HS 00 [L904 ED using intermediates such as compound © as a convenient starting point; The isotopes M 819-550 and others interfering with the description of this class can suitably be prepared by the procedure described here below. in d

the following example; The jeweler may appropriately substitute any starting material compatible with this procedure; Including “methyl 4-chlorophenyl-acetate” methylphenylacetate and 3-methyl (trifluoromethyl)phenyl acetate in addition; other alkylhydrazines; For example; ,2-diethylhydrazine dihydrochloride 1 can replace 1,2-dimethylhydrazine ee .dihydrochloride program 14 class initial body preparation; 0 8 0 yb OCH, 0 | 7 NY N SCH, v F. 0 1 WN—CH, N 24 en, N NY N SCHy r Revealing factors and conditions: 1) ( tethanol “CH3NHNHCH; re-condensation) © hours. F 0 )=( b one ir N 7 rt hg N SCHj v4 O Nas N 2 Net, N HC "SO,CH3 v. 0 m uh 1

a Reagents and conditions: (b) tH) O/THF/MeOH “Oxone®” room temperature; hours. F. 0 uh a CHj3 | Xa, Y N SO,CH, and 7 0 Condition Y N 0 3 Reagents and conditions: (—) 'THF (NaH "phenol) room temperature VE h. > Example + 4-(4-fluorophenyl)-1,2-dimethyl-5-( 2-phenoxypyrimidin-4-yl)-1 ,2-dihydropyrazol- 3-one (1) 4-(4 -fluorophenyl)-1,2-dimethyl-5-( 2-methylsulfanyl-pyrimidin-4-y1)-1,2-pa al dihydropyrazol-3-one (75): to a solution of ; )£1g .5 mmol) in ethanol. 1,2-dimethylhydrazine dihydrochloride (D.7 g ex 1 mmol) is added. After subjecting the mixture to steam re-condensation at /la*C for a period of days; The solution is cooled to room temperature. and divide between 100 (EtOAc) and a saturated aqueous solution of NaHCO (0 mL). the organic phase separates; Dried (MESO) filtered and concentrated by vacuum. The crude residue was purified by silica gel chromatography (e) (biotage system) hexanes [EtOAc] to yield 4 g (277) of (0) as a yellow solid: NMR (300MHz, CDCl,) 6 8.49(d,J=5.1Hz,2H), 7.31 -7.36(m,2H), 6.83-7.05 111 (m,2H), 6.83(d,J=5.1Hz, 1H), 3.55(s,3H ), 3.40(s,3H), 2.60(s,3H); (M+H)" 701 m/z MS-ESI YoYo

lv preparation 4-(4-fluorophenvl)-1,2-dimethyl-5-(2-methanesulfonyl-pyrimidin-4-yl1)-1,2- dihydropyrazol-3-one (+¥) to a solution of 2-(4-fluorophenyl)-3-(2-methylsulfanyl- V,£) F pyrimidin-4-yl)-3-0xo-propionic acid methyl ester g 1.5 mmol gram) in THF (Yo) mL) and MeOH (Yo) mL) add dropwise a solution of Oxone® 1.4 em (10 mmol) in water (1 lb ml). After stirring at room temperature for © hours; The reaction mixture was concentrated by vacuum. The resulting residue was diluted with CH,Cl (You (mL) and washed with a saturated aqueous NaHCO;(0.77 mL) solution. The German phase was extracted with 7 01”3 (CHCl) mL) and the combined organic phases (MgSOy) were dried, filtered, and concentrated by vacuum to yield 1.1 g (yield 7977) of desired product as a yellow solid, used unpurified 0 Additional: 115-2551 [MAH]T 111 m/z Preparation 4-(4-fluorophenyl)-1,2-dimethyl-5-(2-phenoxypyrimidin-4-y1)-1,2- :( ¥Y) dihydropyrazol-3-one To a solution of 0.79 (aa +,1Y) phenol mmol) in THF (© milliliters) sodium hydride (4 0.0 g 018) was added milligram). after stirring at room temperature for 10 minutes; A solution of 4-4-(4-fluorophenyl)-1,2-dimethyl-5-(2-methanesulfonyl-pyrimidin-4-yl)-1,2- lle 1*5 «71 (700, an) (dihydropyrazol) is added. -3-one mol) in THF (© milliliter) to the reaction mixture. The mixture was stirred at room temperature for; hours. The reaction was then quenched with 110 and diluted with EtOAc. The organic phase was washed with 1 N NaOH (twice)” dried (E50p048; filtered and concentrated by vacuum. The crude residue was purified by preparative HPLC ov. To provide the required product: NMR (300MHz, CDCly) 6 8.51(d,J=4.8Hz,1H), 7.48(t,J=8.1Hz,2H), 7.36-7.31 111(m,3H), 7.24(dd,J= 7.5,1.2Hz,2H), 7.04(t,J=9.0Hz,2H), 6.94(d,J=5.1Hz,1H), 3.53 (s,3H), 3.38(s,3H); Computed for EVA CoH gFN,O, (MAH) 77/,1?; in VY ATAY 1,2-diethyl-4-(4-fluorophenyl)-5-(2-phenoxypyrimidin-4-yl)- 1,2-dihydropyrazol-3- ve 'one' ovo

TA

111 NMR (300MHz, CDCl3) 6 8.50(d,J=4.9Hz,1H), 5 1-7.24(m,7H), 7.03 (t.J=8.8Hz,2H), 6.94(d,J=8.8Hz,1H ), 4.01 (q,J=7.1Hz,2H), 3.90(q,J=6.9Hz,2H), 1.32(t,J=7.1Hz,3H), 0.883(t,J=6.9Hz,3H); Wu Ramen [M+H*] calculated for m/z HRMS {{M+H]* 00 m/z MS-ESI 6.8/15 RQB present 0 inflammatory cytokine The second body of the class; of compounds that inhibit the release of 0 fah — /

N

for hd and 50 (R = Me) b . {R=EY) A

EF. 0 A and 2 N | %

YYN

RY q 4-fluorophenyl-5-(2-R-substituted-pyrimidin-4-yl)-forming; Jal according to the invention has the general structure in the formula: 1 2-dihydropyrazol-3-ones 0 0 fj a hmm 8 \ a R? 58 nH Accent oA q7

YoYo

where 82 and RI are the same as C-Cy cyclic alkyl sf (R? cyclic alkyl sf) and R60 RT they are as described here below in table 01. The isotopes described here have the chemical form The steric indicated when ROP is not hydrogen.

Ye l a l and eI] en] ay ovo] 00006 | om]

CC metoneny

COM ome].

vA for Syelohery methoxymethyl 4-fluorophenyl methoxyethyl 4-fluorophenyl 1-hydroxy-1-methylethyl 4-fluorophenyl uoropheny] using al intermediates such as compound “0” as a dot a appears appropriate; the isotopes 6; 70-5 and others interfering with the description of this class may suitably be prepared by the procedure set out here below. In the following example, the jeweler may suitably substitute any starting material compatible with this procedure; inclusive of “methyl 4-chlorophenyl-acetate “methyl phenylacetate and 3-methyl (trifluoromethyl)phenyl acetate © plus AY) alkyl hydrazines 5” for example; “1,2-diethylhydrazine dihydrochloride can To replace 1,2-dimethylhydrazine .dihydrochloride program: 01 preparation of the second body of the class; 9 6 F N “cH, + lm $0,CH; and 0 NT 00 \ The == KoCo,, NH: ~ L / OCH, - N—H 1100-6 OCH, vy "0 Reagents and Conditions: (1) ttoluene 010”C; (YY) 4-v11-)-1,2-dihvdropyrazol-3-one Preparation of 4-(4-fluorophenyl)-1 2-dimethyl-5-(2-methoxy-1-(S) Yovo

YY

A solution of ((:(YY)-methylethylamino)-pyrimidin-4-yl]-)-1,2-dihvdropyrazol-3-one 4-(4-fluorophenyl)-1,2-dimethyl-5-(2- methanesulfonyl-pyrimidin-4-yl)-1,2-©) toluene mM) in +,00 an «,¥+) add 71 (dihydropyrazol-3-one mmol). YE a 7.0 4( (S)-2-amino-3-methoxypropane mL) was incubated for 2 hours and then concentrated by vacuum. The residue (fe)sad (Ag) was purified from the reaction to re-condensate the vapor at 0 preparative to yield 17 mg (yield £67) of desired product as HPLC feedstock by analysis (MeOH 0.4©) = Y = yellow solid: W*[e] “HNMR (300MHz, CDCl,) 6 8.25(d,J=5.1Hz,1H), 7.41-7.35(m,2H),7.03-6.96 (m,2H), 6.41(d,J =4.8Hz,1H), 5.57(d,J=7.8Hz,1H), 4.29-4.24(m, 1H), 3.52(s,3H), 3.46(m,2H), 3.40(s,3H), 3.35 (s,3H), 1.29(d,J=6.6,3H); 01

IM+H]" 17 m/z MS-ESI

FVY NAY 4 Found 77,1477 [MHH]T CgHp3FNSO, calculated for m/z HRMS 1,2-dimethyl-4-(4-fluorophenyl)-5-[2-(S)-(a-methylbenzylamino) )pyrimidin-4-yl]-(MeOH RT¢)°Y~ = dg]¢1,2-dihvdropyrazol-3-one

HNMR (300MHz, CDCl,) 6 8.28(d,J = 4.9 Hz,1H), 7.35-730(m,2H), 7.05(,] = Vo 8.8Hz, 2H), 6.46(d,] = 4.8Hz, 1H), 4.02(m,1H), 3.61(s,3H), 3.57(s,3H), 1.24(s,3H), 1.23(s,3H), 1.21(d,J = 6.9Hz 3H); [M+H*] CyoHysFNSO calculated for m/z HRMS [11+11]; ¥A1 m/z MS-ESI

FATA present (FAY AVY 1,2-dimethyl-4-(4-fluorophenyl)-5- {2-(S)-[1-(4-fluorophenyl)ethylamino] 0 {(MeOH “+, A ke ° YA- = [a]**} 'pyrimidin-4-y1}-1 .2-dihydropyrazol-3-one 'H NMR (300MHz, CDCls) 8.23(d,J=4.8Hz,1H), 7.40 -7.29(m,4H), 7.08-6.96(m,4H), 5.81(br s,1H), 5.18-5.13(m,1H), 3.49(s,3H), 3.06(br s,3H), 1.59 (d,J=6.9Hz,3H); [M+H*] Cp3HpF)NsO J—a¥ Computed m/z HRMS ¢(M+H]" £YY m/z MS-ESI vo 77,1788 Found 77,77 evo

YY

1,2-dimethyl-4-(4-fluorophenyl)-5-[2-(S)-(methylpropylamino)pyrimidin-4-yl]-1,2- (MeOH «+,Y Ao ¢) °\ + = [a]* p ¢dihvdro-pyrazol-3-one 'H NMR (300MHz, CDCl,) 6 8.26(s,1H), 7.35(m,2H), 7.01(t,J=8.7,2H), 6.41 (d,J= 4.8Hz,1H), 4.03(m,1H), 3.53(s,3H), 3.36(s,3H), 1.25(d,J=6.3Hz,3H), 1.0 (t,J=7.5,3H); ° [M+H*] CyoH53FNO J—aY Calculated m/z HRMS [M+H]* Ye m/z MS-APCI

YOU VAAY MEROGRED (TOT, VAAY 1,2-dimethyl-4-(4-fluorophenvl)-5-[2-(S)-(1,2-dimethyl-2-hydroxypropylamino)- pyrimidin-4-vi]-1,2-dihydro -pyrazol-3-one; 'H NMR (300MHz, CDCl) 8.28(d,J=5.1Hz,1H), 7.36(dd,]=5.5,8.8Hz, 1 2H),6.97(t,J=8.8Hz) ,2H), 6.49(d,J=4.8Hz,1H), 3.95(br s,1H), 3.80(m,2H), 3.53 (s,3H), 3.33(s,3H), 3.04-2.89(m ,2H), 3.95-2.89(m,2H), 2.31-2.02(m,2H), 1.95-1.83 : (m,2H), 1.10(t,J=7.5Hz,3H); - [M+H* ] Cp3H3oFNgO5S calculated for the most beautiful m/z HRMS ¢(M+H*] £A% m/z MS-ESI present CAT (EAA YAS Yo 1,2-dimethyl-4-(4-fluorophenyl)-5) -[2-(S)-(1-methyl-2-methoxvethylamino)” (MeOH kCl°YY~ = [a]*'p¢pyrimidin-4-vl]-1,2-dihydropyrazol-3- one "HNMR (300MHz, CDCls) 8 8.25(d,J=5.1Hz,1H), 7.41-7.35(m,2H), 7.03-6.96 (m,2H), 6.41(d,J=4.8Hz,1H) , 5.57(d,J]=7.8Hz,1H), 4.29-4.24(m,1H), 3.52(s,3H), 3.46(m,2H), 3.40(s,3H), 3.35(s,3H) , 1.29(d,J=6.6,3H);Y.[M+H*] CygH,3FN5Oy Ja Calculated m/z HRMS ¢[M+H*] 7177 m/z MS-ESI

VY VAY 4 present 7, 1,2-dimethyl-4-(4-fluorophenyl)-5-[2-(isopropylamino)pyrimidin-4-y1}-1,2- ¢{(MeOH «+, ¢ ¢) as the same tdihydropyrazol-3-one "HNMR (300MHz, CDCl,) § 8.25(d,J=5.1Hz,1H), 7.41-7.35(m,2H), 7.03-6.96 Yo (m,2H), 6.41(d ,J=4.8Hz,1H), 5.57(d,J=7.8Hz,1H), 4.29-4.24(m,1H), 3.52(s,3H), 3.46(m,2H), 3.40(s,3H) , 3.35(s,3H), 1.29(d,J=6.6,3H);

Yovo

The highest m/z HRMS ¢[M+H"*] YVY m/z MS-ESI calculated [M+H*] C;oH3FN5O, Jay, just YY NAY EL 1,2-dimethyl- 4-(4-fluorophenvl)-5-[2-(pyridin-4-ylamino)pyrimidin-4-vi]-1,2- dihydropyrazol-3-one; IH NMR (300MHz, CD50D) 6 8.47 (d,J=6.0Hz,2H), 8.32(d,J=4.9Hz,1H), 7.41 > (d,J=5.3Hz,1H), 7.27(m,2H), 7.03(t,J =8.8Hz,2H), 6.51(d,J=4.9Hz,1H), 3.57(s,3H), 3.34(s,3H); m/z HRMS ¢({M+H*] 711 m/z MS-ESI calculated for [M+H*]Cy HygFNO 7 present in SAV YTUA 1,2-dimethyl-4-(4-fluorophenyl)-5-[2-(pyridin-3-ylamino) pyrimidin-4-y1]-1.2-0 dihydropyrazol-3-one;IH NMR (300MHz, CDCl,) 6 8.62(d,J=5.9Hz,1H), 8.32(d,J=4.9Hz, 1H), 7.71 (m,1H), 7.38(m,2H), 7.26(m,1H), 6.99(t,J=8.8Hz,2H), 6.52(m,1H), 6.46 (d ,J=4.9Hz,1H), 4.79(d,J=5.1Hz,2H), 3.52(s,3H), 3.30(s,3H);d 115-8551 1 m/z ?m/ z HRMS ¢[M+H*] calculated for [M+H*] CpHyoFNO (FAY, 1 TAY in FAY VIAL 1,2-dimethyl-4-(4-fluorophenyl)-5-{ 2-(pyridin-2-ylamino)pyrimidin-4-yl}-1,2- dihydropyrazol-3-one; TH NMR (300MHz, CDCl,) 6 8.62(d,J=4.0Hz,1H) , 8.32(d,J=5.1Hz,1H), 7.71 (dt,J=1.5,7.7Hz,1H), 7.61-7.60(m,1H), 7.41-7.32(m,2H), 7.29-7.23 (m,1H), 7.00 Y. (1,J=8.8Hz,2H), 6.55(br s,1H), 6.47(d,J=4.9Hz, 111), 4.80(d,J=5.1Hz ,2H), 3.53 (s,3H), 3.31(br s,3H); m/z HRMS ¢[M+H*] 741 m/z MS-ESI calculated for [M+H* ] Cy H,0FNgO ara present in FAV VIVY M 1,2-diethyl-4-(4-fluorophenyl)-5-[2-(S)-(o-methylbenzylamino)pyrimidin-4-yl]- OVEt = [0] ¢1,2-dihvdro-pyrazol-3-one One Decken «(MeOH 'ovo

S Yo "HNMR (300MHz, CDCl3) § 8.23(d,J=5.1Hz,1H), 7.42-7.29(m,2H), 7.69 (t.J=8.8Hz,2H), 6.43(d, J=5.1Hz,1H), 5.33(m, 1H), 4.15(m, 1H), 4.05-3.75(br s,2H), 3.75-3.34(br s5,2H), 1.61(s,3H) , 1.33-1.28(m,6H); [M+H"*] 1 m/z MS-ESI ; m/z HRMS calculated for [M+H*] CpsHy7FNO lye found 77,7187 1,2-diethyl-4-(4-fluorophenyl)-5-[2-(S)-(1-methyl-) 2-methoxvethylamino) ¢pyrimidin-4-yl]-1,2-dihydropyrazol-3-one d His] = Jf Ke + \,+« “(MeOH” HNMR (300MHz, CDC) § 8.26) d,J=5.1Hz,1H), 7.40(dd,J=5.5,8.8Hz,2H), 7.00 (t,J=8.8Hz,2H), 6.45(d,J=5.1Hz,1H), 5.68(br s,1H), 4.29(m, 1H), 4.01(q,J=7.1Hz, 2H), 3.87(q,J=6.9Hz,2H), 3.47(m,1H), 3.41( s,3H), 1.37-1.29(m,6H), 0.929(t, 01 J=6.9Hz,3H); m/z HRMS ¢{M+H]* 5001 m/z MS-ESI Calculated [M+H*] C;;H,,FNO, J—aY 4 found CE YATY 1,2-dimethyl-4-(4-fluorophenyl)-5-[2-[( N-propanesulfonylpiperidin- 4-yl)amino]-m pyrimidin-4-yl]-1,2-dihydro-pyrazol-3-one; ), 7.36(m,2H), 6.98(t,J=9Hz,2H), 6.38(d,J=5.1Hz,1H), 5.26(d,J=7.2Hz,1H), 4.16(m, 1H), 3.51(s,3H), 3.35(s,3H), 1.27 (d,J=6.3,6H), [M+H]* 147 m/z MS-APCI ; m/ z HRMS calculated for [M+H*]C gH,;FN5O (FEY AVY. 0 +. found in FEY AVIA) includes unlimited examples of other compounds containing the Class 4 second form: 1,2- diethyl-4-(4-fluorophenyl)-5-[2-(S)-(o-methylbenzylamino)pyrimidin-4-y1] - 1,2-dihydropyrazol-3-one; 1,2-dimethyl -4-(4-fluorophenyl)-5-[2-(thiazol e-2-ylamino) pyrimidin-4-yl]-1,2- dihydro-pyrazol-3-one; Yo 1,2-diethyl-4-(4-fluorophenyl)-5-[2-(benzimidazol-2 -ylamino) pyrimidin-4-yl]-1,2- dihydro-pyrazol-3-one; h bah 1

Other compounds of the present invention are not directly included in the classes defined herein above; which may be prepared by means of the procedures and modifications announced above; Include the following:

5-(2-phenoxypyrimidin-4-yl1)-4-(4-fluorophenyl)-1,2-dihydropyrazol-3-one; 2-benzothiazol-2-yl-4-(4-fluorophenyl)-5-[2-(1-phenylethylamino)-pyrimidin-4-y1]- 1,2-dihydropyrazol-3-one; 5 4-(4-fluorophenyl)-1-(2-methoxyethyl)-5-[2-(2-methoxy-1- methylethylamino)pyrimidin-4-yl]-2-methyl-1,2-dihydropyrazol-3- one; 4-(4-fluorophenyl)-1-(2-methoxycthyl)-5-[2-(1-phenylethylamino)-pyrimidin-4-yl]- 2-methyl-1,2-dihydropyrazol-3-one; 4-(4-fluorophenyl)-1-(2-methoxyethyl)-5-(2-phenoxypyrimidin-4-yl)-2-methyl-1,2- Ve dihydropyrazol-3-one; 4-(4-fluorophenyl)- 1-methyl-5-[2-methoxypyrimidin-4-yl]-2-piperidin-4-yl-1,2- dihydropyrazol-3-one;

4-(4-fluorophenyl)-1-(piperidin-4-yl)-5-[2-(2-methoxy-1- methylethylamino)pyrimidin-4-yl]-2-phenyl-1,2-dihydropyrazol-3 -one; Yo 4-(4-fluorophenyl)-1-(piperidin-4-y1)-5-[2-(2-methoxy-1- methylethylamino)pyrimidin-4-yl]-2-(4-chloro)phenyl-1 ,2-dihydropyrazol-3-one; 4-(4-fluorophenyl)-2-(2-methoxyethyl)-5-[2-(2-methoxy-1- methylethylamino)pyrimidin-4-yl]-1-methyl-1,2-dihydropyrazol-3-one ; 4-(4-fluorophenyl)-2-(2-methoxyethyl)-5-(2-phenoxypyrimidin-4-yl)-1-methyl-1,2- Y.dihydropyrazol-3-one; 4-(4-fluorophenyl)-2-(2-methoxyethyl)-5-[2-(2-hydroxy-1,2-dimethylpropylamino)- pyrimidin-4-yl]}-1-methyl-1,2-dihydropyrazol -3-one; 2-(4-chlorophenyl)-4-(4-fluorophenyl)-5-[2-(1-phenylethylamino)-pyrimidin-4-yl]- 1,2-dihydropyrazol-3-one; Yo 4-(4-fluorophenyl)-1-methoxymethyl-5-(2-phenoxypyrimidin-4-y1)-1,2- dihydropyrazol-3-one;

evo

1-(piperidin-4-yl)-2-methyl-4-(4-fluorophenyl)-5-[ 2-(tetrahydropyran-4-yl)pyrimidin-4-yl1]-1,2- dihydro-pyrazol-3-one. The compounds mentioned and described herein have been shown to in many cases exhibit activities (mei1 in the cell-based assay described here below or those indicated herein) at a level of less than 1 oo micromole (HM) The compounds of the present invention are able to effectively inhibit the production of inflammatory cytokine by cells and thus allow to reduce the severity of; recovery Control; suppression; disability; or preventing one or more of the pathological phases or symptoms related to the extracellular release of one or more cytokines Inflammatory disease cases include those related to the following non-restricted examples: (1) 1 (1M1) 1-Salt01©16: understood as Molecule responsible for a large number of disease stages, among others: rheumatoid arthritis; osteoarthritis (hada) as well as other disease states related to the degeneration of connective tissue. (?) icycloxygenase-2 (COX-2) release inhibitors cytokine from Led a idl: inhibitors of inducible 0076-2 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)). vo 7) 'Tumor necrosis factor-o' (TNF-a) suggests that this pro-inflammatory cytokine is an important mediator of many disease states or symptoms; among others rheumatoid aia; osteitis aie inflammatory bowel disease (IBS) septic shock; cardiopulmonary dysfunction; Respiratory disease and emaciation. A Each condition or disease disorder that the jeweler wishes to treat may require different levels or quantities of the compounds described herein to obtain a therapeutic level. This quantity can be determined by the jeweler by any of the known testing procedures known to the manufacturer. The present invention relates further to forms of the present compounds; which under normal physiological conditions in humans or avian mammals release the compounds described here. A repeat of this vo-hisha includes pharmacologically acceptable salts of the isotopes described herein. The jeweler; For the purposes of compatibility with the method of delivery; cexcipients etc.; One salt form can be selected from the present isotopes uh 1

YA SS from AT because the compounds themselves are the active species that attenuate the pathological processes described here. Related to this body are various source forms of the 'prodrug' of the isotopes of the present invention. It may be desired to formulate compounds of the present invention as chemical species which by themselves are not active against the cytokine activity described herein but are instead ally Adal isotopic forms When it reaches the body of a human or higher mammal it undergoes a chemical reaction catalyzed by the normal function of the body; among others enzymes in the stomach; blood serum; said chemical reaction releases the original. The term 'lie! Active drug substance. Formulations The present invention Lad relates to compositions or preparations that include compounds that inhibit inflammatory cytokine release according to the present invention. As dale the compositions of the present invention include: (a) an effective amount of 1,2-dihydropyrazol-3-ones of the present invention which are effective for inhibiting the release of inflammatory cytokines; and (b) one or more pharmacologic excipients. For the purposes of the present invention the terms 'excipient' and 'carrier' are used interchangeably throughout the description of the present invention and the terms mentioned herein are defined as 'ingredients used in the practice of preparing a safe and effective pharmacological composition'. The jeweler will understand that the excipients are primarily used to serve in the delivery of a safe medicinal substance; stable; ©” and functional; They serve not only as part of the overall carrier medium for conduction but also as means to achieve effective absorption by active ingredient users. The excipient may serve a simple and direct role as an inert filler except that the excipient as used herein may form part of a pH-stabilizing system or packaging to ensure that the ingredients are safely delivered to the equipment. The jeweler can also take advantage of the fact that the compounds of the present invention have improved cellular potency; ve improved pharmacokinetic properties; Plus improved oral bioavailability. Ham Bah 1

VA The present invention also relates to compositions or preparations comprising a primary source or “primary drug” form of compounds that inhibit inflammatory cytokine release according to the present invention. As dele such primary source incorporating compositions of the present invention include: 00 effective amounts of one or more derivatives of the bicyclic pyrazolones of the present invention which release the corresponding isotope into the body and which are effective in inhibiting inflammatory and 01185 release; and (ix) one or more pharmacologically acceptable excipients. METHOD OF USE The present invention also relates to a method for controlling the level of one or SI of the proinflammatory cytokines “0 among others” Interleukin-1 (IL). -1) Tumor lysis factor-a (TNF-a) Interleukin-8 (IL-8) «Interleukin-6 (IL-6) and thus (Sa) control the causing or suppression of cases of pathologically affected by extracellular levels of inflammatory cytokines.The present method includes the step of administering to a human or mammal the highest effective amount of a combination comprising one or more inflammatory cytokine inhibitors of the present invention.ve Because the inflammatory cytokine inhibitors of the invention The current can arrive in such a way that more than one locus of control can be achieved; it can simultaneously control more than one disease state.Examples of non-restrictive diseases include the control or suppression of an inflammatory cytokine clade; thus controlling excess cytokine activity; These include osteoarthritis, rheumatoid arthritis, diabetes mellitus, human immunodeficiency virus (HIV) oY infection. Procedures The compounds of the present invention can be evaluated for their efficacy; For example; The Gul inhibition constants 56 values for Ca and L1 can be obtained by any method chosen by the jeweler. Non-restrictive examples of suitable tests include: ( ) - UV Visible Subject Enzyme Test as described by: (L.

Al Reiter, Int.

J.

Peptide Protein Res., 43, 87-96 (1994). Yo (Y) Enzyme Test for a Fluorescent Substance as Described by: (Thomberry et al., Nature, 356, 768-774 (1992)).

As (©) PBMC cell test as described in US Patent 57047711 1s

Xoo) March 01 and others”; Published by Batchelor All of the above references are merged here by reference. In addition to that; Inhibition of tumor lysis factor (TNF-a) can be measured using human mononuclear cells (THP-1) stimulated with lipopolysaccharide (LPS) as described in: (1) (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)). (Y) US Patent 67597741 31 Cirillo et al. Released? Oct Yoo incorporated with reference and mentioned here below in the relevant section. (Say 1 Monitoring activation of cytokine production by measuring TNF-a inhibition in lipopolysaccharide-excited 1117 cells. All cells and reagents were diluted In 1640 RPMI with phenol red and “L-glutamine” with extra L-glutamine (total: lon streptomycin s penicillin (© units/ml) from JS and fetal bovine serum (ZY FBS) (GIBCO) all final concentrate). The test is performed under sterile conditions; only the test compound preparation is non-sterile. Initial storage solutions are prepared in DMSO followed by dilution in RPMI 0 is 2 times greater than the required final test concentration. Lda 1110-1 flocculate (7* 01 cells/mL; final concentration?” American Type Culture Company (Md “Rockville”) was added to polypropylene round-bottom culture dishes of 97 Sample (3790 ¢Costar sterile) containing 10 µL test compound (concentrated twice) or DMSO carrier medium (comparative examples; blank). DMSO concentration should not be more than 70.7 as final concentration. Pre-incubate cell mixture for up to 1 min at 7"C; 728,00 Pre-seasoned with lipopolysaccharide (LPS) final concentration 1 µg/mL; 1-2630 Sigma serotype 1.601 0111.34; Stored in 1 mL fons stock in Coie's water carrier medium blocked with endotoxin at -18*C). axa final incubation is You μl. Incubation lasts (; hours) as described above. The test ends with centrifugation of the plates within minutes at room temperature; 0001 rpm (077 ?sg); The supernatants were then transferred to clean dishes with A in HLA 1

AY

available ELISA and stored at -<10+* pending until analysis for human 0-1117 by the Camarillo group; California). The calculated value of 10 is the concentration of commercially available Biosource #KHC301 5 (Biosource #KHC301) 1117-0 in a maximum yield of 750 test compounds causing a reduction of % While particular applications of the present invention have been depicted and described, it is clear to those skilled in In art there is the possibility of making various other changes and modifications without deviating from the spirit and scope of the invention.Therefore 0 All these modifications and changes that fall within the scope of this invention are covered in the attached claims.

Claims (1)

AY the chemo elements and the enantiomeric diastereomeric forms or all enantiomeric forms ccompound BKRM-1 that are pharmacologically acceptable thereof; The said compound has the formula: salts or diasteriomeric salts Y Q = 1 TNA, / \ot R 1 Hr: ROS ; where Ar-O[CHyLR* () ° “-NRJ5aR5b (b)” 1 is substituted or unbranched aryl; or linear M,0-,© substituted or unsubstituted; or substituted heterocyclic; contrast circle - “+0 substituted; Function 8 is from 0 to 4 and 58 and 55c separately is: 0 0 hydrogen; or (1 00 [CRERO)] RT (b) vv are respectively: ROD 868 and hy hydrogen; (1) k ¢-OR8 (V) vo ¢N(RS), ( ¥) 5 :-CO,R® (49( wv :-CON(R®), (°) VA substituted or unsubstituted; Cp-Cy branched; or linear coyclic alkyl (1) 1) and mixtures of that; (V) Y. i R7 1 hydrogen; (1) ow 1 huh AY substituted or unsubstituted; C1-Cy branched; or linear coyclic alkyl (Y) Yr substituted or unsubstituted; heterocyclic (7) Yt substituted or unsubstituted; aryl 5) Yo or unsubstituted; Jase heteroaryl (5) 7 «OR? (1) for “N(R, ()0) YA and ¢-COR® (A) Ys ~CON(R®), (4) r.aryl-substituted or “Cy-Cualkyl” Soluble in the cation is hydrogen; RB ry cation or unsubstituted; YY 0 zero to Gem for function not to be substituted; phenyl sa ni vi apart from the group formed by : R3 each unit selects 182 ve hydrogens; and ( ) 7 substituted or unsubstituted selected from the group consisting of: CC hydrocarbyl (b) branched or linear and 0-r); ccyclic alkyl (1) vA ¢Cg-Cyoaryl (V) 4 ¢Cy-Cyoheterocyclic (¥) £9. C1-Cygheteroaryl (£) £9 has the formula: 1 according to the claim compound “-0 A' \ 1 R?{J = 00” Y Substituted or unsubstituted: RY where r ¢C;-Cy alkyl (1) ¢ is 1 til lah ¢C4-C, carbocyclic (¥) > ¢C,-C, heterocyclic (¥) 1 aryl (%) tumor; Or ¢C,-C, heteroaryl (°) A 1 and the gen function is zero to #. .4-fluorophenyl is an R! According to the element of protection? Where is compound 7-compound 1 1 ?-compound according to the claim? where RY is the unsubstituted or substituted aryl 1. Function 8 is zero or Y 1 ©#-Wh compound of the protector; where RY is selected from the group consisting of phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2- Y cyanophenyl, 3-cyanophenyl, 2-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3 2- methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 3-N-acetyl-aminophenyl, 3 2-methoxyphenyl, 4-methoxyphenyl, ° .3-benzo[1,3]dioxol-5-yl 5 + compound honorably- 1 1 According to the claim? where both 12 and 17 are Y 51 : 07000 and 0-:© substituted or unsubstituted from: cyclic alkyl()) 1 branched; or 0-0 m steps; aryl(Y) 3 meg-n; ¢C;-Cyp heterocyclic(Y)° .C-Cypheteroaryl (¢ ) 4 00 no-compound according to claim >7 where R? is selected from the group consisting of tert-butyl isobutyl “sec-butyl” butyl “isopropyl” propyl “ethyl “anethyl Y v and cyclopropyl-methyl Wiha compound oS e=A 01 for claim 7 where 183 is selected from the group consisting of N-methylmorpholin- s morpholin-4-yl «N-methylpiperidin-4 -yl “piperidin-4-yl Y v 4-21 substituted or unsubstituted. compound BKRM-1 1 according to the claim > where RA is selected from the set formed by YoYo Blood phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2- Y cyanophenyl, 3-cyanophenyl, 2-trifluoromethylphenyl, 4-trifluoromethylphenyl, ¥ 2-methylphenyl, 4- methylphenyl, 2,4-dimethylphenyl, 3-N-acetyl-aminophenyl, ¢ 2-methoxyphenyl, 4-methoxyphenyl ° .3-benzo[1,3]dioxo0l-5-yl5 -01 The compound of claim 1 is selected from the group consisting of: 4-(4-fluoropenyl)-2-methyl-5 -(2-phenoxy-pyrimidin-4-yl)-1-piperidin-4-yl-1,2- Y dihydro-pyrazol-3-one; : ¥ 4-(4-fluoropenyl)-2-methyl-5-(2-phenoxy-pyrimidin-4-yl)-1-piperidin-4-yl-1,2- 3 dihydro-pyrazol-3 -one; ° 4-(4-fluorophenyl)-2-methyl-5-[2-(2-fluorophenoxy)pyrimidin-4-yl]-1-piperidin-4- 1 yl-1,2-dihydro-pyrazol -3-one; 7 4-(4-fluorophenyl)-2-methyl-5-[2-(3-fluorophenoxy)pyrimidin-4-yl1]-1-piperidin-4- A yl-1,2-dihydro-pyrazol -3-one; q 4-(4-fluorophenyl)-2-methyl-5-[2-(4-fluorophenoxy)-pyrimidin-4-yl]-1-piperidin-4- ye yl-1,2-dihydro- pyrazol-3-one; 1 | 4-(4-fluorophenyl)-2-ethyl-5-(2-phenoxy-pyrimidin-4-yl)-1-piperidin-4-yl-1,2- YY dihydro-pyrazol- 3-one;VY 4-(4-fluorophenyl)-2-ethyl-5-[2-(2-fluorophenoxy)-pyrimidin-4-yl]-1-piperidin-4- ¥ yl-1, 2-dihydro-pyrazol-3-one;vo 4-(4-fluorophenyl)-2-ethyl-5-[2-(3-fluorophenoxy)-pyrimidin-4-yl]-1-piperidin-4- 1 yl-1,2-dihydro-pyrazol-3-one;VY 4-(4-fluorophenyl)-2-ethyl-5-[2-(4-fluorophenoxy)-pyrimidin-4-yl]-1 -piperidin-4- YA yl-1,2-dihydro-pyrazol-3-one;V4 4-(4-fluorophenyl)-2-methyl-5-(2-phenoxy-pyrimidin-4-yl) -1-morpholin-4-yl-1,2- Y.dihydro-pyrazol-3-one;71 YoYo 4-(4-fluorophenyl)-2-methyl-5-[2-(2-fluorophenoxy)-pyrimidin-4-yl]-1-morpholin- YY 4-yl-1,2-dihydro-pyrazol -3-one; YY 4-(4-fluorophenyl)-2-methyl-5-[2-(3-fluorophenoxy)-pyrimidin-4-yl]-1-morpholin- Yi 4-yl-1,2-dihydro- pyrazol-3-one; Yo 4-(4-fluorophenyl)-2-methyl-5-[2-(4-fluorophenoxy)-pyrimidin-4-yl]-1-morpholin- YY 4-yl-1,2-dihydro- pyrazol-3-one; YY 4-(4-fluorophenyl)-2-ethyl-5-(2-phenoxy-pyrimidin-4-yl)-1-morpholin-4-yl-1,2- YA dihydro-pyrazol-3- one; Ye 4-(4-fluorophenyl)-2-ethyl-5-[2-(2-fluorophenoxy)-pyrimidin-4-yl}-1-morpholin-4- vr.yl-1,2-dihydro -pyrazol-3-one; 71 4-(4-fluorophenyl)-2-ethyl-5-[2-(3-fluorophenoxy)-pyrimidin-4-yl}- 1 -morpholin-4- YY yl-1,2-dihydro- pyrazol-3-one; YY 4-(4-fluorophenyl)-2-ethyl-5-[2-(4-fluorophenoxy)-pyrimidin-4-yl]-1-morpholin-4- Ys yl-1,2-dihydro- pyrazol-3-onc; vo 4-(4-fluorophenyl)-2-methyl-5-(2-phenoxy-pyrimidin-4-yl)-1-N-methylpiperidin-4- x b yl-1,2-dihydro-pyrazol 4-(4-fluorophenyl)-2-methyl-5-[2-(2-fluorophenoxy)-pyrimidin-4-yl}-1-N- vA methylpiperidin-4-yl 1,2-dihydro-pyrazol-3-one; vq 4-(4-fluorophenyl)-2-methyl-5-[2-(3-fluorophenoxy)pyrimidin-4-y1]-1-N- £ methylpiperidin-4-yl-1,2-dihydro -pyrazol-3-one; £3 4-(4-fluorophenyl)-2-methyl-5-[2-(4-fluorophenoxy)pyrimidin-4-yl]-1-N- 2 methylpiperidin-4-yl-1,2- dihydro-pyrazol-3-one; gy 4-(4-fluorophenyl)-2-ethyl-5-(2-phenoxy-pyrimidin-4-yl)-1-N-methylpiperidin-4- £4 yl-1,2-dihydro-pyrazol -3-one; to 4-(4-fluorophenyl)-2-ethyl-5-[2-(2-fluorophenoxy)pyrimidin-4-yl]}-1-N- £1 methylpiperidin-4-yl-1,2 -dihydro-pyrazol-3-one; 1 YoYo AY 4-(4-fluorophenyl)-2-ethyl-5-[2-(3-fluorophenoxy)pyrimidin-4-yl]-1-N- 5 methylpiperidin-4-yl-1,2-dihydro-pyrazol-3 -one; and £4 4-(4-fluorophenyl)-2-ethyl-5-[2-(4-fluorophenoxy)pyrimidin-4-yl]-1-N- o. methylpiperidin-4-yl-1,2-dihydro-pyrazol-3-one; 51 According to the © claim, where 12 are selected from the group consisting of β-11 N-methylmorpholin-4- and “morpholin-4-yl “N-methylpiperidin-4-yl” pipeidin-4-yl Y yl r is substituted or unsubstituted. -11-1 compound according to claim 7, where 183 is selected from the group consisting of cyclo- “tert-butyl” isobutyl “sec-butyl” butyl “isopropyl” propyl “ethyl” methyl Y .propylmethyl ¥ IY) is a compound according to the +7 claim, where RY is selected from the group consisting of <2-fluorophenyl “phenyl Y” given to them 2-3 s “2,6-difluorophenyl “4-fluorophenyl 2-trifluoromethylphenyl «3-cyanophenyl »2-cyanophenyl 3 -4 4-dimethylphenyl <4-methylphenyl <2-methylphenyl «trifluoromethylphenyl 3 2« «4-methoxyphenyl »2-methoxyphenyl «3-N-acetyl -aminophenyl ° and -3,benzo[1,3]dioxol-5-yl 1 selects 12 from group consisting of N- «pipeidin-4-yl morpholin-4-yl »methylpiperidin-4-yl 7 and N-methylmorpholin-4-yl substituted or not dad A selects 183 from the group consisting of butyl “sopropyl” propyl cethyl (methyl “tert-butyl” isobutyl ¢sec-butyl q and ccyclo -propylmethyl and the function n is zero or A Ye 1 64- The compound according to claim 1 is selected from the group consisting of: 4-(4-fluorophenyl)-1-methyl-5 -(2-phenoxy-pyrimidin-4-yl)-2-piperidin-4-yl-1,2- Y dihydro-pyrazol-3-one;3 4-(4-fluorophenyl)-1-methyl-5-[ 2-(2-fluorophenoxy)pyrimidin-4-yl]-2-piperidin-4- ¢ yl-1,2-dihydro-pyrazol-3-one; ° 4-(4-fluorophenyl)-1-methyl-5-[2-(3-fluorophenoxy)pyrimidin-4-yl}-2-piperidin-4- 1yl-1,2-dihydro-pyrazol-3-one ; v d lah 1 AA 4-(4-fluorophenyl)-1-methyl-5-[2-(4-fluorophenoxy)pyrimidin-4-yl]-2-piperidin-4- A yl-1,2-dihydro-pyrazol-3-one ; 9 4-(4-fluorophenyl)-1-ethyl-5-(2-phenoxy-pyrimidin-4-yl)-2-piperidin-4-yl-1,2- 01 dihydro-pyrazol-3-one; 1 4-(4-fluorophenyl)-1-ethyl-5-[2-(2-fluorophenoxy)pyrimidin-4-yl]-2-piperidin-4-yl- VY 1,2-dthydro-pyrazol-3-one ; yy 4-(4-fluorophenyl)-1-ethyl-5-[2-(3-fluorophenoxy)pyrimidin-4-y1]-2-piperidin-4-yl- ¥ 1,2-dihydro-pyrazol-3-one ; Vo 4-(4-fluorophenyl)-1-ethyl-5-[2-(4-fluorophenoxy)pyrimidin-4-yl]-2-piperidin-4-yl- 5 1,2-dihydro-pyrazol-3-one ; VY 4-(4-fluorophenyl)-1-methyl-5- (2-phenoxy-pyrimidin-4-yl)-2-morpholin-4-yl-1,2- VA dihydro-pyrazol-3-one; V4 4-(4-fluorophenyl)- 1-methyl-5-[2-(2-fluorophenoxy)pyrimidin-4-y1] -2-morpholin- Y. 4-yl-1,2-dihydro-pyrazol-3- one; 71 4-(4-fluorophenyl)-1-methyl-5-[2-(3-fluorophenoxy)pyrimidin-4-y1] -2-morpholin- YY 4-yl-1,2-dihydro-pyrazol-3-one ; YY 4-(4-fluorophenyl)-1-methyl-5-[2-(4-fluorophenoxy)pyrimidin-4-y1] -2-morpholin- Ye 4-yl-1,2-dihydro-pyrazol-3-one ; Yo 4-(4-fluorophenyl)-1 -ethyl-5-(2-phenoxy-pyrimidin-4-yl)-2-morpholin-4-yl-1,2- 74 dihydro-pyrazol-3-one; L-4-(4-fluorophenyl)-1-ethyl-5-[2-(2-fluorophenoxy)pyrimidin-4- y1]-2-morpholin-4- YA yl-1,2-dihydro-pyrazol- 3-one; 1 4-(4-fluorophenyl)-1-ethyl-5-[2-(3 -fluorophenoxy)pyrimidin-4-yl]-2-morpholin-4- Y.yl-1,2-dihydro-pyrazol-3- one; 3 4-(4-fluorophenyl)-1-ethyl-5-[2-(4-fluorophenoxy)pyrimidin-4 -yl]-2-morpholin-4- YY yl-1,2-dihydro-pyrazol-3-one ; vv YovYo 4-(4-fluorophenyl)-1-methyl-5 -(2-phenoxy-pyrimidin-4-yl)-2-N-methylpip eridin-4- Yi yl-1,2-dihydro-pyrazol- 3-one; vo 4-(4-fluorophenyl)-1-methyl-5 -[2-(2-fluorophenoxy)pyrimidin-4-y1}-2-N- 4 methylpiperidin-4-yl-1 ,2-dihydro -pyrazol-3-one; vv 4-(4-fluorophenyl)-1-methyl-5- [2-3 -fluorophenoxy)pyrimidin-4-yl]-2-N- YA methylpiperidin-4-yl-1,2-dihydro - pyrazol-3-one; ra 4-(4-fluorophenyl)-1 -methyl-5-[2-(4-fluorophenoxy)pyrimidin-4-yl] -2-N- 3 methylpiperidin-4-yl-1,2-dihydro -pyrazol-3-one; 3 4-(4-fluorophenyl)-1-ethyl-5- (2-phenoxy-pyrimidin-4-y1)-2 -N-methylpiperidin-4- 3yl-1,2-dihydro-pyrazol- 3-one; 31 4-(4-fluorophenyl)-1-ethyl-5- [2-(2-fluorophenoxy)pyrimidin-4-yl]-2-N- 33 methylpiperidin-4-yl-1,2-dihydro -pyrazol-3-one; go 4-(4-fluorophenyl)-1-ethyl-5-[2-(3 -fluorophenoxy)pyrimidin-4-y1}-2-N- £1 methylpiperidin-4-yl-1,2- dihydro-pyrazol-3-one; and 7 4-(4-fluorophenyl)-1-ethyl-5- [2-(4-fluorophenoxy)pyrimidin-4-yl]-2-N- 8 methylpiperidin-4-yl-1,2- dihydro-pyrazol-3-one; 5 -1© 1 compound according to claim >7 where both 8 and 1283 are methyl or Y both are cethyl selected RY from the group consisting of 2-flucrophenyl «phenyl -3 “2-cyanophenyl “2,6-difluorophenyl “4-fluorophenyl ~~ “fluorophenyl 1 -3 “4-trifluoromethylphenyl 2-trifluoromethylphenyl “cyanophenyl ¢ -2” 3-N-acetyl-aminopheny ¢2 ,4-dimethylphenyl «4-methylphenyl «mcthylphenyl ° 3-benzo[1,3] dioxol-5-yl1 5 «4-methoxyphenyl «2-methoxyphenyl 1 and the function n v is zero or . 1E011 the compound of claim 11 is selected from the group consisting of: 1,2-dimethyl-4-(4-fluorophenyl)-5 -(2-phenoxypyrimidin-4-yl)-1, 2-dihydropyrazole- Y 3-one; 3 mah 1 1,2-diethyl-4-(4-fluorophenyl)-5-(2-phenoxypyrimidin-4-yl)- 1,2-dihydropyrazol-3- ¢ one; ° 1,2-dimethyl-4-(4-fluorophenyl)-5 -[2-(2-fluorophenoxy)pyrimidin-4-y1] -1,2- 1 dihydropyrazol-3-one; v 1,2-diethyl-4-(4-fluorophenyl)-5- [2-(2-fluorophenoxy)pyrimidin-4-yl] -1,2- A dihydropyrazol-3-one; 4 1,2-dimethyl-4- (4-fluorophenyl)-5-[2-(3 -fluorophenoxy)pyrimidin-4-yl]-1,2-1 dihydropyrazol-3-one; 11 1,2-diethyl-4-(4-fluorophenyl)-5-[2-(3 -fluorophenoxy)pyrimidin-4-yl]-1,2- VY dihydropyrazol-3-one; Vy 1 ,2-dimethyl-4-(4-fluorophenyl)-5-[2-(4-fluorophenoxy)pyrimidin-4-y1] -1,2- Ve dihydropyrazol-3-one; and vo 1,2-diethyl-4-(4-fluorophenyl)-5- (2-(4-fluorophenoxy)pyrimidin-4-yl] -1,2- 5 dihydropyrazol-3-one; 7 has the formula: 1 of claimant Wh (compound) compound -17 01 0 P wo F NA / - N—H ~~ R?Y substituted or unsubstituted selected from: CC hydrocarbyl where each 182 and 1883 separately is + 'C1-Cip branched cyclic alkyl )1 ) ¢ tCy-Cyp aryl (?)° and ¢C¢-Cyo heterocyclic (1) 1 -C1-Cyg heteroaryl (¢ ) 7 \ oevo + be 87 is hydrogen; Cr-Caaliyl or 028©- RE is hydrogen; methyl or a salt 9 cation formation; 1 selects 187 from the group consisting of: (1) 1 hydrogen; “cyclic alkyl (7) VY branched or linear C-Cy substituted or unsubstituted; Co-Cioaryl (7) Ww substituted or not substituted; Cp-Cyoheterocyclic (4) Vi substituted or unsubstituted; C-Cyoheteroaryl (©) vo substituted or unsubstituted; =A is a compound of claim 11 where R® is hydrogen. -11-1 is a compound of claim VA where 187 is aryl 00-m© substituted or unsubstituted Y. =e 1 Compound according to claim 11 where 182 are selected from the group consisting of tert-butyl “isobutyl” sec-butyl “butyl isopropyl propyl “ethyl” methyl Y 1 and .cyclopropyl-methyl -71 01 compound according to claim 11, where 18 are selected from the group consisting of N-methylmorpholin-4- 5 «morpholin-4-yl «N-methylpiperidin-4-yl «pipeidin-4-yl Y v is a substituted or non-substituted. —YY 0 is a compound according to claim VA wherein RP is selected from the group consisting of tert-butyl “isobutyl” sec-butyl “butyl” isopropyl “propyl ethyl “methyl ¥ 01 and .cyclopropyl -methyl is selected 3p from the group consisting of (pipeidin-4-yl (N-methylmorpholin-4-yl 5 émorpholin-4-yl «N-methylpiperidin-4-yl ¢] inferred or ° unsubstituted. The RT It is a substituted or unsubstituted Co-Croaryl. -methylpiperidin-4-yl «pipeidin-4-yl Y yl substituted or unsubstituted. e / ah 1 ay where 187 is selected from the group consisting of 0 of the protective element Wh compound -740001 “tert-butyl “isobutyl” sec-butyl “butyl” isopropyl “propyl ethyl “methyl Y . cyclopropyl-methyl s v, where 182 are selected from the group of 18 according to the protection element compound 7© 1 N-methylmorpholin-4- and morpholin-4-yl (N-methylpiperidin-4-yl " pipeidin-4-yl Y “propyl ethyl” methyl substituted or unsubstituted; 183 is selected from the group consisting of 1 yl and is cyclopropyl-methyl s “tert-butyl isobutyl” sec-butyl “butyl” isopropyl ¢ Substituted or unsubstituted. Ce-Crg aryl is ° or methyl is R35 R? where both 1 of the protectant Wha compound are 1-71 ethyl 1-both Y Selected from the group consisting of: 117 according to the protection element compound -?17 1 4-(4-fluorophenyl)-2-methyl-5- {2-[(phenyl)methylamino] -pyrimidin-4 -yl}-1- Y piperidin-4-yl-1,2-dihydropyrazol-3-one;v 4-(4-fluorophenyl)-2-methyl-5-{2-[(2-fluorophenyl)methylamino]- pyrimidin-4-yl} - ¢ 1-piperidin-4-yl-1,2-dihydropyrazol-3-one; ° 4-(4-fluorophenyl)-2-methyl-5-{2-[(3-fluorophenyl)methylamino] -pyrimidin-4-yl}- 1 1-piperidin-4-yl-1,2-dihydropyrazol-3 -one; v 4-(4-fluorophenyl)-2-methyl-5- {2-[(4-fluorophenyl)methylamino] -pyrimidin-4-yl}- A 1-piperidin-4-yl-1,2-dihydropyrazol-3 -one; 9 4-(4-fluorophenyl)-2-methyl-5- {2-[(2-aminophenyl)methylamino]-pyrimidin-4-yl}- Ye 1-piperidin-4-yl-1,2-dihydropyrazol-3 -one; 11 4-(4-fluorophenyl)-2-methyl-5-{2-{(3-aminophenyl)methylamino]-pyrimidin-4-yl} - VY 1-piperidin-4-yl-1,2-dihydropyrazol-3 -one; VY 4-(4-fluorophenyl)-2-methyl-5-{2-[(4-aminophenyl)methylamino]-pyrimidin-4-yl}- Ve 1-piperidin-4-yl-1,2-dihydropyrazol-3 -one; Yo 4-(4-fluorophenyl)-2-methyl-5- {2-[(phenyl)methylamino]-pyrimidin-4-yl}-1- a morpholin-4-yl1-1,2-dihydropyrazol- 3-one; For YoYo 4-(4-fluorophenyl)-2-methyl-5- {2-[(2-fluorophenyl)methylamino}-pyrimidin-4-yl1} - VA 1-morpholin-4-yl-1,2-dihydropyrazol-3- one; 4 4-(4-fluorophenyl)-2-methyl-5-{2-[(3-fluorophenyl)methylamino]-pyrimidin-4-yl } - Y. 1-morpholin-4-yl-1,2-dihydropyrazol- 3-one; 711 4-(4-fluorophenyl)-2-methyl-5-{2-[ (4-fluorophenyl)methylamino]-pyrimidin-4-yl} - YY I-morpholin-4-yl-1,2-dihydropyrazol-3 -one; YY 4-(4-fluorophenyl)-2-methyl-5-{2-[(2-aminophenyl)methylamino]-pyrimidin-4-y1} - ve 1-morpholin-4-yl-1,2-dihydropyrazol-3 -one; Yo 4-(4-fluorophenyl)-2-methyl-5- {2-[(3-aminophenyl)methylamino]-pyrimidin-4-y1} - v1 1-morpholin-4-y1-1,2-dihydropyrazol-3 -one; 7 4-(4-fluorophenyl)-2-methyl-5- )2-] (4-aminophenyl)methylamino]-pyrimidin-4-y1 }- YA 1-morpholin-4-yl-1,2-dihydropyrazol-3 -one; Ya 4-(4-fluorophenyl)-2-methyl-5- {2-[(phenyl)methylamino]-pyrimidin-4-y1}-1- (N-Yr. acetyl)-piperidin-4-yl-1, 2-dihydropyrazole-3-one; 71 4-(4-fluorophenyl)-2-methyl-5- {2-[(2-fluorophenyl)methylamino]-pyrimidin-4-y1 } - vy 1-(N-acetyl)-piperidin-4-yl-1 ,2-dihydropyrazol-3-one; vy 4-(4-fluorophenyl)-2-methyl-5- {2-[(3-fluorophenyl)methylamino]-pyrimidin-4-y1} - + 1-(N-acetyl)-piperidin-4-yl-1 ,2-dihydropyrazol-3-one; vo 4-(4-fluorophenyl)-2-methyl-5- {2-[(4-fluorophenyl)methylamino]-pyrimidin-4-y1} - 4 1-(N-acetyl)-piperidin-4-yl-1 ,2-dihydropyrazol-3-one; vy 4-(4-fluorophenyl)-2-methyl-5- {2-[(2-aminophenyl)methylamino]-pyrimidin-4-yl }- YA 1-(N-acetyl)-piperidin-4-yl-1 ,2-dihydropyrazol-3-one; vq 4-(4-fluorophenyl)-2-methyl-5- {2-[(3-aminophenyl)methylamino] -pyrimidin-4-y1}- 2 1-(N-acetyl)-piperidin-4-yl-1 ,2-dihydropyrazol-3-one; £3 4-(4-fluorophenyl)-2-methyl-5- {2-[(4-aminophenyl)methylamino] -pyrimidin-4-yl}- 7 1-(N-acetyl)-piperidin-4-yl- 1,2-dihydropyrazol-3-one; 313 has the formula: 1 according to the claim compound NT ¥ J - — w b / = N—H 4 i.e. Y 8 Sm » 1587 and 13 separately are hydrocarbyl «©-,© substituted or unsubstituted select From: “cyclic alkyl (1) ° branched ar ¢C,-Cyq linear 1C;-Cyg aryl (Y) 1 heterocyclic (7) 1 R .C;-C heteroaryl (9) A 4 is R® bitter toilette- R troph R® is hydrogen; cmethyl or salt forming “0” cation; select 187 from the group consisting of: (1) ( 1 hydrogen; aryl (7) VY substituted or unsubstituted; VY (?) substituted or unsubstituted heteroaryl; Ve (;) heterocyclic substituted or unsubstituted; and “cyclic alkyl 0 Vo branched; or linear C-Cp substituted or unsubstituted. 1 1 ?- compound according to the YA claim where “157 is hydrogen.” of claim 79 where 187 is aryl 00-m© substituted or unsubstituted Y. 1 1 ?- compound according to claim 74 where 182 is selected from the group consisting of tert-butyl « isobutyl “sec-butyl butyl < isopropyl “propyl “ethyl” methyl Y 1 and cyclopropyl-methyl YoYo qe according to claim 4 where 183 is selected from the group formed by γ = YY 1 N- 4-methylmorpholin- and “morpholin-4-yl “N-methylpiperidin-4-yl” pipeidin-4-yl Y substituted or unsubstituted.yl from the group formed by R? where YA is selected According to the protectant compound —FY 1 tert-butyl «isobutyl «sec-butyl «butyl »isopropyl «propyl «ethyl »methyl Y cpipeidin-4-yl 783 is selected from the group consisting of cyclopropyl-methyl 5 1 Substituted or N-methylmorpholin-4-yl 5 smorpholin-4-yl «N-methylpiperidin-4-yl ¢ Substituted or unsubstituted. 6-00 aryl Unsubstituted. And 17 is > where 18 is selected from the group consisting of YT according to the protective element compound ; 4- «4-(ethanesuhfonyl)phenyl «4-(methanesulfonyl)phenyl «methoxy-phenyl ¥ pyridine-3- «pyridine-2-yl «3-benzo{1,3]dioxol-5-yl «(propanesulfonyl)phenyl ¢ -pyridin-4-yl 5 «yl ° cethyl smethyl is R7 where the protective TF is yea ial according to compound ©? cyclopropyl Y -1-hydroxyethyl and «1-hydroxy-1-methyl-ethyl < 1-methoxy-1-methyl-ethyl and according to claim 9 where 182 are selected from the group formed by compound = F N-methylmorpholin-4- and <morpholin-4-yl «(N-methylpiperidin-4-yl 4-1-alpha and Y-substituted or unsubstituted agglutinin.yl of the group formed by RP According to claim 9? Consisting of YA according to the protective compound —FA N-methylmorpholin-4- and “morpholin-4-yl (N-methylpiperidin-4-yl “pipeidin-4-yl Y” propyl cethyl methyl replaced or not replaced; 183 is selected from the group consisting of yl 1 s—a Ry cyclopropyl-methyl and <tert-butyl “isobutyl” sec-butyl “butyl” isopropyl ¢ substituted or unsubstituted. Cg-Cyg aryl > ovo a1 from The group formed by RT where TA is selected according to the protective element compound -? phenyl «4-(methanesulfonyl)phenyl «methoxy-phenyl 1 and pyridine-3- «pyridine-2-yl 3-1 ,3]dioxol-5-yl «(propanesulfonyl)phenyl ¢ .pyridin-4-yl 5 «yl ° cethyl methyl sa, where A is YA according to the protective compound compound -56 0 1 «1-methoxyethyl «methoxymethyl chydroxymethyl «cyclohexyl »cyclopropyl Y .1-hydroxyethyl and <1-hydroxy-1 -methyl-ethyl «1-methoxy-1-methyl-ethyl ¥ or methyl and 1883 is R? According to the claim £0 where each of the compound is —£Y 01 ethyl both of them Y 187 is selected from the group consisting of Cua 00 according to the claim compound compound -17 01 4- « 4-methylphenyl 2-methylphenyl <2-aminophenyl «4-fluorophenyl «phenyl Y 4- 4-(ethanesuhfonyl)phenyl «4-(methanesulfonyl)phenyl «methoxy-phenyl 1 pyridine-3- «pyridine-2-yl 3-01 ,3]dioxol-5-yl «(propanesulfonyl)phenyl ¢ .pyridin-4-yl 5 «yl ° ethyl methyl hr R7 where it is 41 according to the protection element compound -47 0 «1- methoxyethyl «methoxymethyl hydroxymethyl »cyclohexyl «cyclopropyl Y .1-hydroxyethyl and «1-hydroxy-1-methyl-ethyl a -methoxy-1-methyl-ethyl v is selected from the group consisting of: YA according to the element Protective compound:40 1 4-(4-fluorophenyl)-5-[2-(S)-(a-methylbenzyl amino)pyrimidin-4-yl]-1-methyl-2- Y piperidin-4 -yl-1,2-dihydropyrazol-3-one; ¥ 4-(4-fluorophenyl)-5 -[2-(S)-(a-methylbenzylamino)pyrimidin-4-yl] -2-methyl-1- ¢ piperidin-4-yl-1,2-dihydropyrazol-3 -one; ° (4-{4-(4-fluorophenyl)-2-methyl-5-0xo0-3-[2-(S)-(c-methylbenzylamino)pyrimidin-1 4-y1]-2,5-dihdydropyrazol-1 -yl}piperidin-1-yl) acetic acid, 7 1 halah qv 2-(4-{4-(4-fluorophenyl)-2-methyl-5-0x0-3-[2-(S)-( a-methylbenzylamino) A pyrimidin-4-y1]-2,5-dihydropyrazol-1-yl}piperidin-1-yl)-2-methyl propionic q acid; 1 (4-{4-(4-fluorophenyl)-2-methyl-5-0x0-3-[2-(S)-(a-methylbenzylamino)pyrimidin-1 4-yl]-2,5-dihydropyrazol-1 -yl} piperidin-1-yl) acetic acid ethyl ester; VY 2-(4-{4-(4-fluorophenyl)-2-methyl-5-oxo0-3-[2-(S)-(a-1 methylbenzylamino)pyrimidin-4-y1]-2,5-dihydropyrazol -1-yl} piperidin-1-yl)-2- ¥ methyl propionic acid ethyl ester; Ve 4-(4-fluorophenyl)-5-[2-(S)-(a-methylbenzylamino)pyrimidin-4-yl}-1,2-dimethyl- 1 1,2-dihydropyrazol-3-one; VY 4-(4-fluorophenyl)-5-[2-(2-hydroxy-1-(S)-methyl-2-methylpropylamino)-VA pyrimidin-4-yl]-1,2-dimethyl-1,2- dihydropyrazole-3-one; 14 4-(4-fluorophenyl)-5-[2-(2-methoxy-1-(S)-methylethylamino)-pyrimidin-4-yl}-1,2- Y. dimethyl-1,2-dihydropyrazol-3 -one; 711 4-(4-fluorophenyl)-5-[2-(S)-(a-methylbenzylamino)pyrimidin-4-yl]-1-methyl-2-(2-YY methoxyethyl)-1,2-dihydropyrazol-3 -one; YY 4-(4-fluorophenyl)-5-{2-(S)-(a-methylbenzylamino)pyrimidin-4-yl]-2-methyl-1-(2- Ye methoxyethyl)-1,2-dihydropyrazol-3 -one; Yo 4-(4-fluorophenyl)-5-[2-(2-hydroxy-1-(S)-methyl-2-methylpropylamino)-™ pyrimidin-4-yl}-1-methyl-2-(2-methoxyethyl) )-1,2-dihydropyrazol-3-one; Yv 4-(4-fluorophenyl)-5-[2-(2-hydroxy-1-(S)-methyl-2-methylpropylamino)- YA pyrimidin-4-y1]-1,2-dimethyl-1,2- dihdydropyrazole-3-one; Yq 4-(4-fluorophenyl)-5-[2-(2-methoxy-1-(S)-methylethylamino)-pyrimidin-4-yl]-2- rv. methyl-1-piperidin-4-yl-1,2-dihydropyrazol-3-one; 4 4-(4-fluorophenyl)-5-[2-[2-methoxy-1-(S)-methylbenzylamino)pyrimidin-4-yl}-1-5 rv .methyl-2-piperidin-4-yl-1 ,2-dihydropyrazol-3-one YY 1 are lah aA and the enantiomeric diastereomeric forms or all enantiomeric forms ccompound©4;- Compound 01 are pharmacologically acceptable than that; The said compound has the formula: salts or diasteriomeric salts Y 09 v F \ A / ~ R v ; . where R is “NH[C(R®R™)R’ each of the R® 3 R® separately is cethyl methyl o and mixtures thereof; + RT is hydrogen; alkyl mint; branched or C)-Cyp linear substituted or unsubstituted; aryl v is substituted or not substituted; heteroaryl y is substituted or unsubstituted; A Each unit of 1.82 and R3 is a branched cyclic alkyl sas; or linear 0,©-,© substituted or not 8 substituted; heterocyclic «©-, substituted or unsubstituted; and mixtures of it. 1 1;- the compound of claim £0 Cua 1# has the formula: / 3 oh 5 or -~ 8 of pe Y v where RT is alkyl substituted or unsubstituted and ©-,©; or substituted or unsubstituted phenyl. 00 7;- compound of claim 7; Cua selects 10 from the group consisting of (S)-(a)-methylbenzylamino, (S)-1-methyl-1-(4-fluorophenyl) methylamino, 7 (S)-1-methyl-1-(2). -aminophenyl)methylamino, (S)-1-methyl-1-(2- ¥ methylphenyl)methylamino, (S)-1-methyl-1-(4-methylphenyl) ¢ methylamino, (S)-1-methyl-1 -(4-methoxyphenyl)-methylamino, (S)- ° (a)ethylbenaylamino, (S)-1-(4-fluorophenyl)ethylamino, (S)-1-(2- 1 aminophenyl)ethylamino, (S)- 1-ethyl-1-(2-methylphenyl)amino, (S)-1-(4- 7 methylphenyl)ethylamino, (S)-1-(4-methoxyphenyl)-ethylamino, A eve aq (S)-1-(4-fluorophenyl)-2-hydroxyethylamino 9 1 8 ?- is a compound according to the claim $Y where RE is selected from the group consisting of N-methylmorpholin-4- 5 “morpholin-4-yl (N-methylpiperidin-4-yl “pipeidin-4-yl Y yl Y substituted or unsubstituted; 183 is selected from the group consisting of “propyl” ethyl “methyl ctert-butyl) «iso-butyl «sec-butyl «butyl »isopropyl ¢ and .cyclopropyl-methyl 1 4;- compound according to claim £Y where Ly 182 of the group formed by <isopropyl “propyl “ethyl “methyl Y” ant “tert-butyl isobutyl “sec-butyl cyclopropyl-methyl 5 1 and wR' selects the group consisting of cpipeidin-4-yl <morpholin-4-yl « N-methylpiperidin-4-yl ¢ and N-methylmorpholin-4-yl substituted or 0 > unsubstituted .01 0.©- compound according to claim 49 where 1 is selected from the group consisting of (S)-1-methylpropylamino, (S)-1-methyl-1-methoxyethylamino, (S)-1-methyl-2-(S)- Y methoxypropylamino, (S)-1,2-methyl-2- methoxypropylamino, (S)-1- ¥ ethylpropylamino, (S)-1-ethyl-1-methoxyethylamino, (S)-1-ethyl-2-(S)- 3 methoxypropylamino, ° .(S)-1-ethyl- 2-methyl-2-methoxypropylaminos -#1 #1 is a compound according to claim 0 © where 12 are selected from the group consisting of “morpholin-4-yl” N-methylpiperidin-4-yl “pipcidin-4 -yl Y and N-methylmorpholin-4- Y 1 substituted or unsubstituted; rR? is selected from the group consisting of propyl «ethyl methyl ctert-butyl <iso-butyl »sec-butyl «butyl »isopropyl ¢ and .cyclopropylmethyl OY) compound according to the claim 50 where RP is selected from the group formed by “tert-butyl “isobutyl” sec-butyl butyl “isopropyl” propyl <ethyl methyl Y 1 and ¢cyclopropyl-methyl and rR? is selected from the group formed by pipeidin-4-yl “morpholin-4-yl < N-methylpiperidin-4-yl and N-methylmorpholin-4-yl substituted or unsubstituted. ‎—oF 01 Composition includes: ‎YoYo You or enantiomer forms (1,2-dihydropyrazol-3-ones) as an active substance of one or more (00 Y) and diastereomeric or salts thereof; the said compound has the formula: r Q N 2 A TNA /b ~ R ¢ where +1 is: 0 2s1m0]0-; Ar ()) 1 “-NR35aR5b (b) 7 substituted or branched aryl; or linear n,©-© substituted or unsubstituted; ceyclic alkyl is RY is + substituent or heteroaryl substituted or unsubstituted; or heterocyclic unsubstituted; heterocyclic 0 0 unsubstituted; the function is 8 from 0 to 0 are 853 and 859 separately: 1 hydrogen; OR (0 VY [C(RERE)], RT(b)vr) are each separately: ROP and is 66 f 4 H? (1) vo ¢-ORS8 (Y) V1 and (©) 1 -CO,R8 (%) VA ¢-CON(R?), (°) V4 substituted or unsubstituted C-Cy branched or linear cyclic alkyl (1) Ye and mixtures thereof; (V) 71 is: R7 is vy hydrogen; (1) vy substituted or unsubstituted; C-Cy branched; or linear ceyclic alkyl (7) Ye substituted or unsubstituted; heterocyclic (7) Yo ove 011 substituted or unsubstituted; aryl (5) 75 substituted or unsubstituted; heteroaryl (©) Yv “OR? (1) YA “NR, )( Ya and +=COsR” (A) r. “—CON(R®), (3) 1 aryl “C;-Cyalkyl celal soluble in cation is hydrogen; RY cation is TY substituted or unsubstituted; TY 0 is function 0 from zero to Yt substituted ?; Selected from the group consisting of: CC hydrocarbyl (wo) YA “C1-Cro branched or linear” cyclic alkyl (1) va ¢Ce-Cioaryl (V) £¢C,-Cjoheterocyclic (¥) 1 and ¢ C1-Cyoheteroaryl (4) 1" is pharmacologically acceptable. or a mammal with the highest effective amount of a drug combination comprising: Y or enantiomer forms ¢1,2-dihydropyrazol-3-ones (a) an effective amount of one or more r and diastereomeric or salts thereof; The aforementioned compound has the formula: Q, i Ā i.” TNA / b ~ R ° is: ROS Gs a yovo AI or =O[CH,LR¢ () v NRSTRS> b) A substituent or aryl substituent or unsubstituted; C-Cpp branched; or linear cyclic alkyl is RY be 4-substituted or heteroaryl-substituted or unsubstituted; or unsubstituted heterocyclic; inverting circle 0 0 zero to en unsubstituted; Function 1 stands alone: JSR is 0838 and 0 hydrogens; (=) Vs are each separately: ROD is 1068 and VO H; (1) 5 “ORS (Y) b ¢N(R®), (7) VA -CO,RS8 (¢) V4 :-CON(R®), (°)2 substituted or unsubstituted; branched Cp-Cy; or linear ceyclic alkyl (7) Y\ and mixtures of (V) YY ia RTOS vr hydrogen; (1) Yi substituted or unsubstituted; Cp-Cy branched; or linear cyclic alkyl (Y) Yo substituted or unsubstituted; (7) heterocyclic ( 1 substituted or unsubstituted; aryl (?) 7 substituted or unsubstituted; heteroaryl (©) YA “~OR® (1) Ya NERY, (V) v. and +COR® ( A) 0 «~CON(R®), (3) ry YoYo 1 aryl is soluble in water, zelen-0, the cation is hydrogen; RE cation is TY substituent or unsubstituted; re 0 zero to em is Yo substituent; phenyl is RY substituent i is from the group consisting of: R3 and RZ selects each unit of vy hydrogen; f ( ) 0 y©-,© substituent or unsubstituted chosen from the group consisting of: hydrocarbyl (b) re ¢C1-Crp branched or linear cyclic alkyl (1) 2 moiety; (¥ ) 1 ¢C;-C)oheterocyclic b (?) deafness with deafness-? and (9) 3 pharmacologically acceptable expipients (b) one or more excipients 3 excitatory cytokines method 06000 to control the level of one or more of the 00 01 —00 tumor lysis factor-0 e dnterleukin -1 (IL-1) for inflammation is selected from the group consisting of Y Interleukin-8 (IL-8) «Interleukin-6 (IL-6) «(TNF-o) Tumor Necrosis Factor-a. and cytokines Inducing or suppressing disease states affected by ele levels so that extracellular inflammatory 4 can be controlled; the current method includes the step of administering to a human or mammal a higher effective amount o of a drug combination comprising: 1 or enantiomer forms ¢1,2-dihydropyrazol-3-ones (a) A significant amount of one or more dihydropyrazoles or salts thereof; said compound has the formula: A 0 N 7 8 1 ALA / Ba ~ R 4 where 1 is: 0 thqryt[m?r (i) '1 aa (2) vv \oVYo 0 substituted or aryl substituted or unsubstituted; CC branched; or linear cyclic alkyl be 184 is 0" substituted or heteroaryl substituted or unsubstituted; or heterocyclic heterocyclic (Jats unsubstituted © 04; the function is from zero to 0 on Acuity: JSR is 558 and wn H; OR ( ) 0 ¢-[C(R6R)] RT (<=) 8 aa are all over ROD is 1868 and 4 H;) 1 ( Ye -ORS (Y) 71 refql-; (V) YY ¢-CO,R8 (¢) Yr :-CON(RS), (2) ve substituted or unsubstituted; C-Cy branched; or linear coyclic alkyl (7) Yo and mixtures thereof; (V) v1 for 18 is: vy hydrogen; (1) YA substituted or unsubstituted; C)-Cy branched; or linear ccyclic alkyl (Y) 74 substituted or unsubstituted heterocyclic (¥) 7 substituted or unsubstituted aryl (?) 1 substituted or unsubstituted heteroaryl (©) YY «OR® (1) rr N(R), (VY) 2 and COR? (A) vo «CON, (1) 1 aryl or « water soluble C-Caalkyl cation is hydrogen; R8 cation is ry is substituted or unsubstituted; A fo the function 00 is from zero to ra yovo Yio is a phenyl substituent of A is 2 unit 2 and 183 is picked apart from the group consisting of: JS 0(a) - hydrogen; and 1 and,©-© substituted or unsubstituted selected from the group consisting of: hydrocarbyl (=) gy; branched C-Cip ha or “cyclic alkyl (V) 2 cor0-f); (Y) fo ¢ Cy-Cioheterocyclic (¥) £1 and ¢ C-Cyoheteroaryl (¢ ) 7 M (b) One or more of the pharmacologicly acceptable Ex 001010045 Substances. YoYo