Title of Invention

PYRIMIDINE COMPOUNDS

Abstract

The present invention relates to A compound of formula (I) wherein each of R<sup>2</sup> and R<sup>4</sup>, independently, is R<sup>1</sup> halogen, nitro, cyano, isothionitro, SR<sup>e</sup> or CR<sup>e</sup> or R<sup>2</sup> and R<sup>4</sup>, taken together, is carbonyl; R<sup>3</sup> is R<sup>e</sup>, alkenyl, alkynyl, OR<sup>c</sup>, OC(0)R<sup>c</sup> S02R<sup>c</sup> S(0)R<sup>c</sup>, S(02)NR<sup>c</sup>R<sup>c</sup>', SR<sup>c</sup> NR<sup>c</sup>R<sup>d</sup>, NRCCORDC(0)0R<sup>d</sup> NROC(0)NR<sup>c</sup>R<sup>d</sup>, NR<sup>c</sup>SO2R<sup>c</sup>, COR<sup>c</sup>, C(O)0R<sup>c</sup>, or C(0)NR<sup>c</sup>R<sup>d</sup>; R<sup>5</sup> is H or alkyl; n is O, 1, 2. 3, 4, 5, or 6; X is O, S, S{0), S(02), or NR<sup>c</sup>; Y is a covalent bond, CH<sup>3</sup>, C{0), C=N-R<sup>c</sup>, C=N-OR<sup>c</sup>, C=N-SR<sup>c</sup>, O2 S3 S(0), S(02),orNR<sup>c</sup>; Z is N or CH; one of U and V is N, and the other is CR<sup>c</sup>; and W is O, S. S(0), S(02), NR<sup>c</sup>, or NC(0)R<sup>c</sup>; in which each of R<sup>a</sup> and R<sup>b</sup> independently, is H, alkyl, aryl, heteroaryl; and each of R<sup>c</sup> and R<sup>d</sup> independently, is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl.

Full Text

BACKGROUND Interleukin-12 CIL-12) is a heterodimeric cytokine (p70) composed of two subunits +35 and p40), and plays key roles in immune responses by bridgiag innate resistance and antigen-specific adaptive immunity. Trinchieri (1993) Immunol Today 14: 335. For example, it promotes type 1 Thelper cell (Thl) responses and, hence, cell-mediated immunity. Chan et al. il99\)JExp Med 173: 869; Seder et al. (1993) Proc Natl Acad Sci USA 90:10188; Manetti et al. (1993) J Exp Med 177:1199; and Hsieh et al. (1993) Science 260: 547. Overproduction of IL-12 causes excessive Thl responses, and may result in inflammatory disorders, such as insulin-dependent diabetes mellitus, multiple sclerosis, rheumatoid arthritis, psoriasiSj Crohn's disease, or sepsis. See, for example, Gately et al. (1998) Annu Rev Immunol. 16:495; and Abbas etal {1996) Nature 3+3: 787. Thus, inhibiting IL-12 overproduction is an approach to treat the just-mentioned diseases. Trembleau et al. {1995) Immmunoi. Today 16: 383; and Adorini et al. (1997) Chem. Immunol. 68:175. For example, overproduction of 11+12 and the resultant excessive Thl type responses can be suppressed by modulating 11+12 production. A compound that down-regulates IL-12 production can be used for treating inflanunatory diseases. Ma et al. (1998) Eur Cytokine Netw 9: 54. and RH, taken together, is carbonyl; R3 is R+ alkenyl, alkynyl, 0R+ OC(0)R'. SO2R', S(0)RS SCOa)NR*=R', SR', NRTl', NR'+COR', NR=C(0)OR*', NR'=C(0)NR'R+ NR'SOjR', COR', C(0)OR', or C(0)NR'+'; R5 is H or aOcyl; n is 0,1, 2, 3,4,5, or 6; X is O, S, S(0), S(02), or NR'; Y is a covalent bond, CH2, C(0), C=N-R+ C=N-OR+ C=N-SR', O, S, S(0), S(02), or NR"; Z is N or CH; one of U and V is N, and the other is CR"; and W is 0, S, S(0), SCOi), +fR+ or NC(0)R+ in which each of R' and R*", independently, is H, allcyl, aryl, heteroaryl; and each of R'+ and R+, independently, is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcaibonyl. Note that the left atom shown in any substituted group described above is closest to the pyrimidine ring. Also note that when n is 2 or greater, the just-described pyrinndine compound may have two or more different C(R+R+) moieties, or when there are more than one R*+-containing substituted groups in a pyrimidine compound, the R° moieties can be the same or different. The same rules apply to other similar situations. Further note that R*+ can be a monovaJait or bivalent substitutait. Referring to formula (I), a subset of the pyrimidine compounds of this invention is featured by that R+ is NC(R*R'+. In these compounds, U can be N, V can be CH, Z can be N, and W can be O. In addition, X can be O or NR"'; R" can be H, methyl, ethyl, or acetyl; Y can be a covalent bond, O, S, or CH2, and n can be 0,1, 2, 3, or 4. hi some embodiments, R3 is aryl, heteroaryl (e.g., pyridinyl), OR", SR", C(0)OR+ NR'R**. or C(0)NR'=R'. hi other embodiments, R3 is in which each of A and A', indqpendently, is O, S, or NH; each of R' and R*+ indepeaiently, is H, alkyl, aryl, or heteroaryl; and m is 1 or 2. In this subset of pyrimidine compounds, R° or R"*, preferably, is in which B is NR', G, or S; B' is N or CR'; R" is H, halogen, CN, alkyl, cyclyl, aikyloxy, alkylcarbonyi, alkyloxycarbonjl, aryloxycarbonyl, heteroaryloxycarbonyl. hydroxyaJkyi, alkylamino, or alkylaminocarbonyl; R"* is H, halogen, NO2, CN, alkyl, aryl. heteroaryl, OR+ OC(0)R=, SO2R'. S(0)R+ S(02)NR'=R', SR% NR1l+ NR'COR*', NR'qO)OR+ NR'C(0)NRTI+ NR'SOaR+ COR', C(0)OR+ or C(0)NRTl+; R' is H, allcs+, or alkylcarbonyl; p is 0,1, or 2; andqisO, 1,2,3, or 4. R+ or R+, preferably, is wherein R+ is H+methyi, ethyJ, propyi, cyclopropyi, metboxyi+ethoxy, halogen, or methoxycarbonyl; R" is F, CI, CN, methyl, methoxy, ethoxy, 0C(O)CH3, OC(0)CjHs, C(0)OH, C(0)OC2H5, C(0)NH2, NHC(0)CH3. or S(02)NH2; R* is H, methyl, ethyl, or acetyl; and q is 0,1, or 2. Another subset of the pyrimidine compounds of this invention is featured by that R+ is aryl or heteroaryl. In these compounds, U can be N, V can be CH, Z can be N, and W can be O. IQ addition, X can be O or NR'; R" can be H, methyl, ethyl, or acetyl; Y can be a covalent bond, 0, S, or CHj, and n can be 0,1, 2, 3, or 4. In some embodiments, R3 is aryl, heteroaryl (eg., pyridinyl, such as pyridin-2-yl or pyridin-3-yl), OR+ SR", C(0)OR+ NR'R+ or C(0)NR'+'. In other embodiments. R3 is in which each of A and A', independently, is O, S, orNH; each of R' and R+ independently, is H, alkyl, aryl or heteroaryl; and m is 1 or 2. Bi this second subset of pyrimidine compoimds, Ri, preferably, is in which D is O, S, or NR""; R" is benzo, halogen, CN, hydroxyl, alkyl, aryl, heteroaryl, alkoxyl, aryloxyl, or heteroaryloxyl; Rm is H, alkyl, or alkylcarbonyl; and r is 0,1, or 2. Preferably, R1 is and R+ is methyl, ethyl, propyl, or benzo; and r can be 1 or 2. A third subset of the pyrimidine compounds of formula (I) is featured by that Ri is NCCR+R*); each of R2 and R, is H; R3 is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, alkyloxycarbonyl, alkylaminocarbonyl, or alkylcarbonyl; R5 is H or alkyl; n is 0,1, 2, 3,4, 5, or 6; X is NR"; Y is covalmt bond, CH2, C(0), C=N-R', C=N-OR", C=N-SR+ O, S, S(0), SCOj), or NR"; Z is N or CH; one of U and V is N, and the other is CR"; and W is O, S, S(0), S(02), MR", or NC(0)R'; in which each of R" and R+ independently, is H, alkyl, aryl, heteroaryl; and R"+ is H, alkyl, aiyl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl. In this third subset of pyrimidine compounds, preferably, one ofR-andR+'is H or alkyl; and the other is aryl or heteroaryl optionally substituted with R+ and R*'q; R+ being halogoi, CN, alkyl, alkyloxy, alkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, hydroxyalkyl, alkylamino, or alkylaminocarbonyl; Rh being halogen, CN, hydroxyl, alkyl, aryl, hetCToaryl, alkoxyl, aryloxyl, or heteroaryloxyl; and q being 0,1, 2, 3, or 4. Preferably, one of R'andR** is H or alkyl; and the other is in which R+ is H, alkyl, alkoxyl, methoxycafbonyl, or halogen; R** is halogen, CN, hydroxyl, alkyl, aryl, heteroaryl, alkoxyl, aryloxyl, or heteroaryloxyl; and q is 0,1,2, 3, or 4. hi some embodiments, X is NH; Y is O; n is 2, or R3 is heteroaryl (e.g., pyridinyl or 1-oxy-pyridinyl) or heterocyclyl {e.g., l/f-pyridin-2-one). hi other embodiments, U is N; V is CH; and R3 is heteroaryl or heterocyclyl. Preferably, X is NH; Y is O; n is 2; and one of R" and R** is H; and the other is in which Rg can be CN, hydroxyalkyl, alkylamino, alkylaminocarbonyl alkyloxycarbonyl (e.g., C{O)0CH3), or halogen (F, CI, Br, or I) when R3 is heteroaryl (e.g., pyridinyl), or R+ can be halogen (e.g., I), alkyl (e.g., methyl), or alkyloxycarbonyl (e.g., methoxycaibonyl) when R3 is heterocyclyl (e.g., IK-pyridin-2-one). Alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl, and heterocyclyl moitioned above include both substituted and imsubstituted moieties. The term "substituted" refers to one or more substituents (which may be the same or different), each replacing a hydrogen atom. Examples of substituents include, but are not limited to, halogen (F, CI, Br, or I), hydroxyl, amino, alkylamino, arylamino, diallcylamino, diarylamino, cyano, nitro, merc+to, caibonyl, carbamido, carbamyl, caiboxyl, thioureido, thiocyanato, sulfoamido, alkyl, alkenyl, alkyloxy, aryl, heteroaryl, cyclyl, heterocyclyl, wherein alkyl, alkenyl, alkyloxy, aryl, heteroaryl cyclyl, and heterocyclyl are optionally substituted with alkyl, aryl, heteroaryl, halogen, hydroxyl, amino, mercapto, cyano, ornitro. As used herein, the term "alkyl" refers to a straight-chained or branched alkyl group containing 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, tert-hvtyl, and n-pentyl. Similarly, the term "alkenyl" or "alkynyl" refers to a straight-chained or branched alkenyl or alkynyl group containing 1 to 6 carbon atoms. The term "aryl" refers to a hydrocarbon ring system (mono-cycUc or bi-cyclic) having at least one aromatic ring. Examples of aryl moieties include, but are not limited to, phenyl, n+hthyl, and pyrenyl. The term "heteroaryl" refers to a hydrocarbon ring system (mono-cyclic or bi-cyclic) having at least one aromatic ring which contains at least one heteroatom such as 0, N, or S as part of the ring system and the reminder being carboiL Examples of heteroaryl moieties include, but are not limited to, furyl, pyrrolyl, thieoyl, oxazolyl, imidazoiyl, thiazolyl, pyridmyl, pyrimidinyl, quinazolinyl, and mdolyl. The terms "cyclyl" and "heterocyclyl" refer to a partially or fully saturated mono-cyclic or bi-cyclic ring system having &om 4 to 14 ring atoms. A heterocyclyl ring contains one or more heteroatoms (e.g., O, N, or S) as part of the ring system and the remainder being carbon. Exemplary cyclyl and heterocyclyl rings are cycylohexane, piperidine, piperazine, morpholine, thiomorpholine, 1,4-oxazepane, and i//-pyridin-2-one. The term "sulfanyl" refers to a thio group. Set forth below are exemplary componnds of this invention: N- {2-[3-(3,4-dimethoxy-phenyl)-propyl]-6-morpholin-4-yl-pyriinidin-4-yl} -N'-(lH-indol-3-S'lmethylene)-hydrazine (Compound 1) N-(2-n-butoxy-6-morpholin-4-yl-pyrimidin-4-yl)-N'-(lH-indol-3-yhnethylene)-hydrazine (Compound 2) N-(2-(4-hydroxybutyl)-6-moipholin-4-yl-pyrimidin-4-yl)-N'-(lH-indol-3-ylmethylene)-hydrazine (Compoimd 3) N-[2-(2-[l,3]dioxan-2-yl-etbyl)-6-morpholin-4-yl-pyrimidin-4-yl]-N'-(lH-indol-3-ylmethylene)-hydrazine (Compound 4) N-(lH-indol-3-ylmethylene)-N'-[2-(3-methoxy-propyl)-6-morpholin-4-yl-pyrimidin-4-yl]-hydrazine (Compound 5) 3- {4-[N' -(lH-indol-3-ylmethylene)-hydrazino]-6-moipholin-4-yl-pyrimidin-2-ylsulfanyl}-propan-l-ol (Compound 6) 3-{2-[N'-(lH-indol-3-ylmethylene)-hydrazino]-6-morpholin-4-yl-pyrimidin-4-ylsulfanyl}-propan-l"Ol (Compound 7) N-[2-(2,2-dimethyl-[l,3]dioxolan-4-ylmethoxy)-6-morpholin-4-yl-pyrimidin-4-yl]-N'-(lH-indol-3-ylmethylene)-hydra2ine (Compoimd 8) N-{2-[2-(3,4-dimethoxy-phenyl)-ethoxy]-6-morpholin-4-yI-pyiimidin-4-yl}-N'-(lH-indol-3-ylmethylene)-hydra2ine (Compound 9) N-(lH-indol-3-ylmethylene)-N'-[6-moTpholin-4-yl-2-(2-pyridin-2-yl-ethoxy)-pyrimidin-4-yl]-hydrazine (Compound 10) N-(lH-indol-3-yhnethylene)-N'-[6-morpholin-4-yl-2-(3-pyridin-2-yl-propyl)-pyrimidin-4-yl]-hydra2ine (Compound 11) N-(3-methyl-benzylidene)-N'-[6-morpholin-4-yl-2-(2-pyridin-2-yl-ethoxy)' pyrimidin-4-yl]-hydrazine (Compound 12) N-{3-ethyl-beiizylidene)-N'-[6-morphoIin-4-yl-2-(2-pyridin-2-yl-ethoxy)-pyriiiiidin-4-yl]-hydrazme (Compound 13) N-(3-methyl-benzylidene)-N'-[6-morpholm-4-yl-2-{3-pyridm-2-yl-pTopyl)-pyrimidin-4-yl3-hydrazme(Conq)ound 14) N-[6-mDrphoIm-4-yl-2-{2-pyridm-2-yl-ethoxy)-pyrimidm-4-yl]-N'-(l-m-tolyl-ettiylidene)-hydra2me (Compound 15) N-[l-(lH-mdol-3-yl)-ethylidene]-N'-[6-morpholin-4-yI-2-(2-pyridm-2-yl-ethQxy)-pyrimidin-4-yI]-hydrazine (Compound 16) - 3-methyl-benzaldehydeC)-[6-morpholm-4-yl-2- lH-indole-3-carbaldehydeO-[6-morpholm-4-yl-2-(2-pyridin-2-y!-ethoxy)-pyrimidin-4-yl]-oxime (Compound 18) N-(lH-iiidDl-3-ylmethylene)-N'-{6-moipholm-4-yl-2-[2-(pyridm-3-yloxy)-ethoxy]-pyriinidm-4-yl}-hydrazme (Compound 19) N-(3-meihyl-benzylidene)-N'-{6-morpholm-4-yl-2-[2-(pyridin-3-yloxy)-ethoxy]-pyrmiidia-4-yl}-hydrazme (Compound 20) butyl-{4-[N'-(lH-mdol-3-ylmethylene)-hydrazino]-6-mDrpholin-4-yl-pyrimidin-2-yl}-amine (Compound 21) N-(3-methyl-benzyIidene)-N'-[6-morphoIm-4-yi-2-(pyridin-3-yIoxy)-pyrimidin-4-yl]-hydrazine (Compound 22) N-(3-methylbenzlidene)-N'-(5-methyl-6-morpholin-4-yl-2-phenylpyrimidm-4- yl)hydrazine (Compoimd 23) N-(3-methyI-braizylidene)-N'-(2-phenyl-6-thiomorpholin-4-)d-pyrimidm-4- yl)-hydrazine (Compound 24) (2,3-dimethyl-l H-indole-5-yl)- {6-morpholin-4-yl-2-[2-(pyridm-3-yloxy)-ethoxy3-pyriniidin-4-yl}-amine (Compound 25) (2,3-dimethyI-lH-indole-5-yl)-{4-mDrpholin-4-yl-6-[2-(pyridin-3-yloxy)-ethoxy]-pyrimidin-2-y1)-amine (Compoimd 26) 3 - {4-[N'-(3-me1iiy!-benzyUdene)-hydrazino]-6-morpholin-4-yl-pyrimidin-2-yl}-propionic acid ethyl ester (Compound 27) N-(3-methyl-benzylide3ie>N'- {6-morpliolin-4-yl-2-[2-(l -oxy-pyridin-2-yl)-ethoxy]-pyrimidin-4-yl}-hydrazine (Compound 28) l-(2-{4-|+'-{3-methyl-benzylidene)-hydrazino]-6-morpholin-4-yl-pyriinidiii-2-yloxy}-ethyl)-lH-pyridm-2-one (Compound 29) N-(3-iodo-b6n2ylidene)-N'-[6-morpholin-4-yI-2-(2-pyridin-2-yl-ethoxy)-pyriniidin-4-yl]-hydrazine (Compound 30) N-(3~fluoro-benzylidene)-N'-t6-morphoIin-4-yI-2-(2-pyridin-2-yl-ethoxy)-pyrimidin-4-yl]-hydrazine (Compound 31) N-(3-chloro-ben2ylidene)-N'-[6-morpholm-4-yl-2-(2-pyridm-2-yl-ethoxy)-pyrimidin-4-yl]-hydfazme (Compoimd 32) N-(3-bromo-benzylidaie)-N'-[6-morphoiin-4-yl-2-(2-pyridm-2-yl-ethoxy)-pyrimidin-4-yl]-"hydrazine (Compound 33) 3-{[6-morphDlm-4-yl-2-(2-pyridm-2-yl-ethoxy)-pyrimidm-4-yl]-hydrazonomethyl}-benzoic acid methyl ester (Compound 34) l-(2-{4-|K'-(3-iodo-benzylidene)-hydrazmo]-6-morphoIin-4-yl-pyrimidin-2-yloxy}-ethyl)-lH-pyridiD-2-one (Compound 35) 3- {[6-morpholm-4-yl-2-(2-pyridin-2-yl-ethoxy)-pyriniidm-4--yl]- hydrazonomefliyl}-benzoic acid N-methyl amide (Compound 36) (3-{[6-moipboliQ-4-yl-2-(2-pyridin-2-yl-ethoxy)-pyrimidin-4-yl]-hydrazonomethyl}-phenyl)-methanol (Compound 37) N,N-Diethyl-4-{4-[N"-(3-methyl-benzylidene)-hydrazino]-6-morpholin-4-yl-pyrimidm-2-yl}-butyramide (Compound 38) 4- {4-[N' -(3-Methyl-benzyIidene>-hydrazino]-6-morpholin-4-yl-pyrimidin-2- yI}-l-(4-methyl-pip6razin-l-yl>-butan-l-one (Compound 39) 4-{4-[JV+'-(3-Methyl-benzylidene)-hydrazino]-6-moipholin-4-yl-pyrimidin-2- yl}-JV-pyridm-4-yhnethyl-butyramide (Compound 40) 4_{4_[Ar'-(3-Methyl-benzylidene)-hydrazmo]-6-morpholin-4-yl-pyrimidin-2-yl}-JV-pyridin-4-yl-butyraniide (Compound 41)- Their structures are depicted below: Compound 1: In another aspect, this invention features a phamaceutical composition that contains a phannaceutically acceptable carrier and an effective amount of at least one of the pyrimidine compounds of this invention. In further another aspect, the present invention features a method for treating an IL-12 overproduction-related disorder (e.g., rheumatoid arthritis, sepsis, Crohn's disease, multiple sclerosis, psoriasis, or insulin-dependent diabetes mellitus). The method includes administering to a subject (e.g., a hutnan or an animal) in need thereof an effective amount of one or more pyrimidine compounds of this invention. The method can also include the step of identifying that the subject is in need of treatment of diseases or disorders described above. The identification can be in the judgment of a subject or a health professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test ox a diagnostic method). The pyrimidine compounds of this invention include the confounds themselves, as well as their salts and their prodrugs, if +plicable. Such salts, for example, can be fonned between a positively charged substituent (e.g., amino) on a compound and an anion. Suitable anions include, but are not limited to, chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, triiluoroacetate, and acetate. Likewise, a negatively charged substituent (e.g., carboxylate) on a compound can form a salt with a cation. Suitable cations include, but are not limited to, sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as teteramethylammonium ion. Examples of prodrugs include esters and other phamiaceutically acceptable derivatives, which, upon administration to a subject, are enable of providing the pyrimidine compounds described above (see Goodman and Gilman's, The Pharmacological basis of Therapeutics, 8* ed., McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs"). In addition, some of the pyrimidine compounds of this invention have one or mote double bonds, or one or more asymmetric craiters. Such compounds can occur as racemates, racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures, and cis- or trans- or E- or Z- double isomeric forms. Further, the aforementioned pyrimidine compounds also include their JV-oxides. The term "JV-oxides" refers to one or more nitrogen atoms, when present in a pyrimidine compound, are in iV-oxide form, i.e., N-» O. Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable pyrimidine compounds. The term "stable", as used herein, refers to compoimds which possess stability sufficient to allow manufactmre and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., treating IL-12 overproduction-related disorders such as rheumatoid arthritis, sepsis, Crohn's disease, multiple sclerosis, psoriasis, or insulin-dependent diabetes meUitus). Also within the scope of this invention are a composition containing one or more of the pyrimidine compounds described above for use in treating an IL-12 ovaproduction-related disorder, and the use of such a composition for the manufacture of a medicament for the just-described use. Other features, objects, and advantages of the invention will be apparent from the description and from the claims, DETAILED DESCRIPTION The compounds described above can be prepared fay methods well known in the art, as well as by the synthetic routes disclosed herein. For example, a pyrimidine compound can be prepared by using 2, 4,6-trichloro-pyrimidine as a starting material. The three chloro groups can be displaced by various substitutes. More specifically, first chloro group (e.g., at position 6) can react with, e.g., morpholine, to form a morpholinyl pyrimidine. 2-Aryl and 2-alkylpyimidinde dichloro compounds can also be prepared by reacting an amidine with a malonic ester followed by treatment with phosphorous oxychloride. Second chloro group can be replaced by reacting with a nucleophile, such as an alcohol in the presence of base, e.g., sodium hydride. In othar examples, a compound of formula (I), wherein Y is CH2 (e.g., Compound 1), can be prepared by reacting the pyrimidine chloride with a.Grignard reagent, an organotin reagent, an organocopper reagent, an organoboric acid, or an organozinc reagent in the presence of an organopalladium compound as a catalyst Isomeric forms may be produced. The desired isomeric product can be separated firom others by, e.g., high performance liquid chromatogr+hy. Third chloro group undergoes a displacement reaction with, e.g., hydrazine, and the primary amine of the coupled hydrazine moiety iurther reacts with an aldehyde, e.g., indole-3-carboxaldehyde to form a hydrazone linkage. Thus, a pyrimidine compound of this invention is obtained. If preferred, other types of linkages can be prepared by similar reactions. Sensitive moieties on a pyrimidinyl intermediate and a nucleophile can be protected prior to couplii+. The chemicals used in the above-described synthetic routes may include, for example, solvents, reagents, catalysts, and protecting group and deprotecting group reagents. The methods described above may also additionally include steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis of the pyrimidine compoimds. In addition, various synthetic steps may be performed in an alternate sequence or order to give the desired compoimds. Synthetic chemistry transformations and protecting group methodologies protection and deprotection) useful in synthesizing applicable pyrimidine compounds aie known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (19S9); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3"+ Ed., John Wiley aM Sons (1999); L. Fieser andM. Fieser, Fieser and Fieser's Reagents for Orgmiic Synthesis, John Wiley and Sons (1994); and L Paquette, ed.. Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof. A pyrimidme compound thus obtained can be further purified by flash column chromatography, high performance liquid chromatograhy, or crystallization- Also within the scope of this invention is a pharmaceutical composition that contains an effective amount of one or more of the pyrimidine compounds of this invention and a pharmaceutically acceptable carrier. Further, the present invention covers a method of administering an effective amount of such a compound to a subject in need of treatment of IL-12 overproduction related diseases (e.g,, rheumatoid Euthritis, sepsis, Crohn's disease, multiple SCLEROSIS, psoriasis, or insulin-dependent diabetra mellins). "An effective amount' refers to the amount of the compound whichls required to confer a therapeutic effect on the treated subject. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described in Freireich et al, (1966) Cancer Chemother Rep 50: 219. Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardley, N.Y., 1970, 537. An effective amount of the pyrimddine compound of this invention can range from about 0.001 mg/Kg to about 1000 mg/Kg. Effective doses will also vary, as recognized by those skilled in the art, depending on die diseases treated, route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatments such as use of other agents. To practice the method of the present invention, a pyrimidine compound, as a component of a pharmaceutical composition, can be administered orally, parenterally, by inhalation spray, topically, rectaliy, nasally, buccally, vaginally or via an implanted reservoir. The term '•parenteral" as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrastemal, intrathecal, intralesional and intracranial injection or infusion techniques. A sterile injectable composition, for example, a sterile injectable aqueous or oleaginous suspension, can be formulated according to techniques known in the art using suitable dispereing or wettmg agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are mannitol, water. Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or diglycerides). Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural phannaceutically-acceptable oils, such as olive oil or castor oil, eqjecially in their polyoxyethylated versions. These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents. Other commonly used surfactants such as Tweens or Spans or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable sohd, liquid, or other dosage forms can also be used for the purposes of formulation. A composition for oral administration can be any orally acceptable dosage form including, but not lunlted to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions, hi the case of tablets for oral use, carriers which are commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, mefiil diluents include lactose and dried com starch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added. A nasal aerosol or inhalation composition can be prepared according to techniques well-known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. A pyrimidine compound of this invention can also be administered in the form of suppositories for rectal administratioa The carrier in the phamiaceutical composition must be "acceptable" in the sense of being compatible with the active ingredient of the formulation (and preferably, capable of stabilizing it) and not deleterious to the subject to be treated. For example, solubilizing agents such as cyclodextrins, which form specific, more soluble complexes with the compounds of this invention, or one or more solubilizing agents, can be utilized as phannaceutical excipients for delivery of the pyrimidine compounds. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfete, and D&C Yellow # 10. The biological activities of a pyrimidine compound can be evaluated by a number of cell-based assays. One of such assays can be conducted using cells ftom human peripheral blood mononuclear cells (PBMC) or human monocytic cell line (THP-1). TTie cells are stimulated with a combination of human interferon-y (IFNy) and lipopolysaccharide or a combination of IFNy and Staphylococcus aureus Cowan I in the presence of a test compound. The level of inhibition of IL-12 production can be measured by detennining the amount of p70 by using a sandwich ELISA assay with anti-human lL-12 antibodies. IC50 of the test compound can then be determined. Specifically, PBMC or THP-1 cells are incubated witti the test compound. Cell viabiUty was assessed using the bioreduction of MTS [3-(4,5-dimethy]thiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazoIiuml (Promega, Madison, WI). A pyrimidine compoimd can also be evaluated by animal studies. For example, one of such studies involves the ability of a test compound to treat adjuvant arthritis (i.e., a IL-12 overproduction related disorder) in rats. Without fiurther elaboration, it is believed that the above description has adequately cabled the present invention. The following specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. All of the publications cited herein are hereby incorporated by reference in their entirety. Example 1. Preparation of Compound 1: N-i2-f3-f3.4~dimettioxv-phen\+Vpropvl1-6-morpholin-4-yl-pvrimidin-4-vl}-N' -f lH-indol-3 -vlmethvleneVhvdrazine To a solution of 3-(3,4-dimeUioxyphenyI)-propyI iodide (1.224 g, 4.0 nunol) in 20 mL dry THF, highly active zinc (suspension in THF, Rieke metal from Aldiich, 5.2 mL 0.05g/mL, 4.0 mmol) was added to obtain a mixture. The mixture was stirred at room temperature overnight. 2,4-dichloro-6-morpholinopyrimidine (0-932 g. 4.0 mmol) and /r«/w-ben2yl-(chloro)-bis-(triphenylphosphine)palladium(iri (0.03 g, 0.04 mmol) were added to the mixture, and stirred at 60°C for 2 days. After routine workup, 4~chloro-2-[3- 'H NMR (300 MHz, CDCU), 5 (ppm): 6.70-6.80 (m, 3H); 6,32 (s, IH); 3.87 (s, 3H); 3.85 (s, 3H); 3.73-3.78 (m, 4H)-, 3.60-3.64 (m. 4H); 2.76 (d, J= 7.8 Hz, 2H); 2.63 (d, /= 7.5 Hz, 2H); and 2.01-2.12 (m, 2H). MS (ESI): m/z 380,2 (M+H). Further, 4-chloro-2-[3-(3,4-dimethoxyphettyl)propyl]-6-morpholinDpyrimidine (0.34 g, 0.90 mmol) was reacted wifli hydrazine (0.29 g, 9imnoI) to obtain 2-[3-(3,4-dimethoxyphenyl)propyl]-4-faydrazino~6-morpbolinopyrimidine as a white solid (0.30 g, 0.80 mmol, 89%). 'H NMR (300 MHz, CDCU), 6 (ppm): 6.73-6.80 (m, 3H); 5.88 (s, IH); 5.74 (s, IH); 3.87 (s. 3H); 3.85 (s, 3H); 3.76-3.79 (m, 4H); 3.69 (d. J= 0.6 Hz, 2H); 3.56-3.60 (m, 4H); 2.64 (d, J= 7.5 Hz, 4H); and 2.00-2.15 (m, 2H). MS (ESI): m/z 374.2 (M-H). A 5 mL methanol solution containing 2-[3-(3,4-dimethoxy[Aeayl)-propyl]-4-hydrazino-6-morpholinopyrimidine (0.177 g, 0.50 mmol), indole-3-carboxaldehyde (0.073 g, 0.50 mmol), and AcOH (20 mg, cat.) was stirred at 70'C for 4 hours. Solvent was removed and the crude residue was purified using flash chromatography to give Compound 1 as a light brown solid (0.21 g, 0.42 mmol, 84 %). 'H NMR (300 MHz, CDCb), 5 (ppm): 8.57 (br s, IH); 8.45 (br s, IH); 8.29-S.32 (m, IH); 8.00 (s, IH); 7.39-7.43 (m, 2H); 7.23-7.34 (m, 2H); 6.74-6.80 (m, 3H); 6.30 (s, IH); 3.86 (s, 3H); 3.85 (s. 3H); 3.78-3.84 (m, 4H); 3.67-3.70 (m. 4H); 2.63-2.71 (m, 4H), and 2.03-2.13 (m, 2H). MS (ESI): m/z 501.2 (M+H). Example 2. Preparation of Compound 2: N-(2-p-butoxv-6-moiphoUn-4-vl-pvrimidin-4-ylVN'-(l H-indol-3 -yhnethvleneVhvdrazinft To a solution of 2,4, 6-trichloro pyiimidine (25 g, 136 mmol) in ai2Cl2 (500 mL) at -78°C, morpholine (11.89 mL, 136 mmol) was slowly added, followed by DIPEA (25 ttiL, 143 mmol). The obtained reaction mixture was stjired at -78°C for 5 h, and thm wanned up to room temperature. The reaction mixture was washed with water. The obtained organic phase was dried over Na2S04. The solvent was removed under reduced pressure. The crued residue, 2,4-Dichloro-6-(iQorpholin-4-yl)pyriimdine, was xecrystallized from EtOAc to give white crystals (24.7 g, 77%) 15g. 'H NMR (300 MHz, CDCI3), 5 (ppm): 6.40 (s. IH); and 4.0 - 3.5 (m, 8H). MS (ESI): m/z 234-0 (M+H). To a solution of n-butanol (0.633 g, 8.54 mmol) in anhydrous DMF (50 mL) at 0°C under the N2,"NaH (0.307 g, 12.8 mmol) was added qiiickly. The obtained suspension was stirred for 0.5 h at 0°C. 2,4-Dichloro-6-(morpholin-4-yl)pyrimidine (2 g, 8.54 mmol) was added to the su+ension. After the suspension was wanned to room temperature and stirred for 12 h, the reaction mixture was quenched with ice/brine and ertracted with 200 mL EtOAc. The extract was washed with brine, and dried over Na2S04. The solvent was removed under reduced pressure. The crude residue was purified using flash chromatogr+hy (silica; EtOAc/Hesane : 1/6) to yield 1.4 g of 2-n-butoxy-4-chloro-6-(morpholin-4-y])pyrimidine (white solid, 60%). 'H NMR (300 MHz, CDCI3), 6 (ppm): 6.20 (s, IH); 4.26 (t, /= 6.6 Hz, 2H); 3.78 - 3.70 (m, 4H); 3.66-3.56 (m, 4H); 1.80- 1.68 (m, 2H); 1.54- 1.40 (m, 2H); and 0.96 (t,J= 6.9. 3H). MS (ESI): m/z 272.1 (M+H). To a solution of 2-n-butoxy-4-chloro-6-(morphoIin-4-yl)pyriniidine (1,38 g, 5.1 mmol) in dioxane (50ml), anhydrous hydrazine (1.6 mL, 50 mmol) was added. The obtained reaction mixture was heated to 95*C, and stirred for 12 h imder Nj-Afler cooling to room temperature, the reaction mixture was quenched with ice-brine and extracted with EtOAc (200 mL). The organic extract was washed with brine, water, and dried over NazS04. The solvent was removed under reduced pressure. Ihe crude residue was recrystalljzed from methanol to obtain 2-n-butoxy-4-hydrazino-6-(morphoIin-4-y])pyrimidine as white crystals (1.10 g, 81%). 'H NMR (300 MHz, CDCU). S (ppm): 5.89 (br s, IH), 5.49 (s, IH), 4.26 (t, J = 6.6.2H),3.84-3.78(m,6H), 3.62-3.47 (m.4H), 1.82-1.67 (m.2H), 1.55-1.42 (m, 2H), and 0.96 (t, J= 6.9, 3H); MS (ESI): m/z 268.2 (M+H). To a solution of 2-n-butoxy-4-hydrazmo-6-(morpholin-4-yl)pyriiiiidme (200 mg. 0.748 mmol) in MeOH (20 mL), indole~3-carboxaldehyde (108.6 mg, 0.748 minol) and acetic acid (a drop) were added sequentiaily. The obtained reaction mixture was stirred at room temperature for 12 h. White precipitate was formed, collected, and washed with 2 roL methanol to give 200g of Compoimd 2 (68%). 'HNMR (300 MHz, CDCI3), 5 (ppm): 8.36 (br s, IH), 8.30 (dd, J= 6.6,1.8, IH), 8.05 (s, IH), S.OO (s, IH), 7.44 - 7.40 (m, 2H)+ 7.33 - 7.24 (m, 2H), 6.13 (s, IH), 4.26 (t, 2H, J=6.6), 3.84-3.78 (m.4H), 3.70-+3.64 (m, 4H), 1.80- 1.70 (m, 2H), 1.54 - 1.42 (m, 2H), and 0.96 (t, J= 6.9, 3H); MS (ESI): m/z 395.2 (M+H). Example 3. Preparation of Compound 3: N-f2-('4-hvdroxvbutvl)-6-morpholin-4-vl-pvrimidin-4-vlVN'-("lH-indol-3-vlmethvleneVhvdrazine A mixture of 4-ethoxy-4-oxo-butylzinc bromide (50 mL 0.5M in THF, 25 mmol), 2,4-dicliloro-6-morphoUnopyrimidine (4.68 g, 20.0 mmol) and ft-ans-benzyl(chloro)bis(triphenylphosphine)palladium(II) (0.15 g, 0.2 mmol) in THF (total volume 80 mL) was stirred at 60'C for 2 days. After routine woilaip, flash chromatography purification was performed to obtain 4-chloro-2-(4-ethoxy-4-oxo-butyl)-6-moipholinopyrimidine as a white solid (2.073 g, 6.60 mmol, 33.0%). To a solution of 4-chloro-2-(4-ethoxy-4-oxo-butyl)-6-morpholinopyrimidine (1.108 g, 3.54 mmol) in 50 mL THF at -78°C, a diisobutylaluminum hydride (DIBAL) solution (4.72 mLl.5 M in Toluene, 7.08 mmol) was slowly added. After addition, the obtained reaction mixture was warmed up slowly to 0°C and kept at 0°C for 10 min. After routine workup, flash chromatography was performed to obtain 4-chloro-2-(4-hydroxybutyI)-6-morpho]mopyrimidine (0.76 g, 2.80 mmol. 79%) as light yellow solid. 'H NMR {300 MHz, CDCIs), 5 (ppm): 6.33 (s, IH), 3.76-3.79 (m. 4H); 3.61-3.68 (m, 6H); 2.76 {l,J= 7.8 Hz, 2H); 1.81-1.91 (m, 2H); and 1.60-1.74 (m, 3H). MS (ESI): m/z 370.2 (M+H). Following the typical procedure, 4-chloro-2-(4-hydroxybutyl)-6-morpholinopynmidine (0.542 g, 2.00 mmol, 1.00 equiv.) was reacted with hydrazine and indoIe-3-cait)oxaldehyde to give Compound 3 as an off-white solid (0.75 g, 1.90 mmol, 95%). 'HNMR(30a MHz, DMSO-dg), 5 (ppm): 11.47 (s, IH); 10.64 (s, IH); 8.25 (s, IH); 8.1S (d, /= 6.6 Hz, IH); 7.71 (s. IH); 7.43 (d. /= 8.4 Hz, IH); 7.17-7.20 (m, 2H); 6.16 (s, IH), 4.37 (t, J= 4.8 Hz, IH); 3.72 (br s, 4H); 3.55 (br s, 4H); 3.41-3.45 (m, 2H); 2.49-2.54 (m,2H), 1.66-1.76 (m 2H); and 1.42-1.53 (m 2H). MS (ESI): m/z 395.1 (M+H). Example 4. Preparation of Compound 4: N-f2-(2-["l,31dioxan-2-yl-ethvl>6-morphoiin-4-yl-pvrimidin-4-yI]-N'-flH-indol-3-yhnethvleneVhvdrazine Compound 4 was prepared in a similar manner as described in Example 1. +H NMR (300 MHz, DMSad«), 6 (ppm): 11.46 (s, IH); 10.64 (s, IH); 8.25 (s, IH); 8.18 (d. J=6.6Hz. IH); 7.71 (s, IH); 7.43 (d, 7=6.0 Hz, 7.5Hz, IH); 7.16-7.19 (m. 2H); 6.15 (s, IH), 4.58 {i,J= 5.1 Hz, IH); 4.00 (dd, J= 11.4 Hz, 4.5 Hz. 2H); 3.64-3.72 (m, 6H); 3.54 (br s. 4H); 2.50-2.59 (m, 2H); 1.80-1.94 (m. 3H), and I.33(d,y=9.6Hz, IH). MS (ESI): m/z 437.2 (M+H). Example 5. Preparation of Compound 5: N-(lH-indol-3-vImethvleDeVN'-r2-l'3-m6tfaoxv-propvl)-6-morpholin-4-vl-pvriniidin-4-yl1-hvdrazine Following flie procedure for the synthesis of N-(2-(4-Hydroxybutyl)-6-morpholin-4-yl-pyrimidin-4-yl)-N'-(lH-indol-3-yImethylene)-hydrazine (Compound 3), 4-chloro-2-(3-hydroxypiopyl)-6-morpholinopyrimidine (0.81 g, 3.15 mmol) was synthesized, methylated with sodiiim hydride (0.48 g, 6.30 mmol) for 10 min, and Mel (0.895 g, 6.30 mmol) for 5 h in 30 mL THF at 0»C to give 4-chloro-2-(3-m6thoxypropyI)-6-moipholinopyrLmidine as colorless viscous oil (0.792 g, 3.03 mmol, 96%y 'H NMR (300 MHz, CDCI3X 5 (ppm): 6.32 (s, IH), 375-3.79 (m, 4H); 3.61-3.64 (m, 4H); 3.44 (t, J= 6.6 Hz, 2H); 3.34 (s, 3H); 2.78 (t. J= 7.8 Hz, 2H); and 2.00-2.09 (m, 2H). MS (ESI): m/z 262.1 (M+H). Following the typical procedure, 4-chloro-2-(3-methoxypropyl)-6-morpholinopyrimidine (0.783 g, 3.00 mmol) was treated with hydrazine and indoIe-3-carboxaldehyde sequentially to yield 0.89 g of Compound 5 (2.26 mmol, 75%). +HNMR (300 MHz, DMSO-de), 5 (ppm): 1J.46 (s, IH); 10.64 (s. IH); 8.26 (s, IH); 8.17-8.20 (m, IH); 7.72 (d, J"= 2.4 Hz, IH); 7.43 (dd, 7= 6.0 Hz, 2.4 Hz, IH); 7.15-7.21 (lii, 2H); 6.16 (s, IH), 3.70-3.73 (m, 4H); 3.52-3.56 (m, 4H); 3.37 (t, J = 6.9 Hz, 2H); 3.23 (s, 3H); 2.50-2.57 (m, 2H), and 1.88-1.97 (m, 2H). MS (ESI): m/z 395.2 (M+H). Example 6. Preparation of Compound 6: 3-(4-[N'-flH-iadol-3-vlmethvleiieV hvdrazino1-6-morpholin-4-vl-pvrimidin-2-vlsulfanvll-propaD-l-oI Compound 6 was prepared in a similar manner as described in Example 2. 'HNMR(300MHz,DMSO-d6), S(ppm): 11.48 (s, IH); 10.68 (s, IH); 8.26 (s, IH); S.15-8.18 (m, IH); 7.73 (d,y=2.1 Hz, IH); 7.42-7.44 (m, IH); 7.16-7.20 (m, 2H); 6.04 (s, IH), 4.53 (t, J= 5.1 Hz, IH); 3.65-3.71 (m. 4H); 3.48-3.56 (m, 6H); 3.06 (t, /= 7.2 Hz, 2H), and 1.76-1.85 (m, 2H). MS (ESI): m/z 413.1 (M+H). Example 7. Preparation of Compouad 7: 3-l2-rN'-flH-indol-3-vlmethvlene>-hvdrazino]-6-morphQlin-4-vl-pwimidin-4-vIsulfanvl}-propan-l-ol Compoimd 7 was prq)ared in a similar manner as described in Example 2. 'H NMR. (300 MHz,DMSad6), 5 (ppm): 11.34 (s, IH); 10.48 (s, IH); 8.45 (d. y= 7.8 Hz, IH); 8.25 (s, IH); 7.64 (d. /= 2.7 Hz, IH); 7.40 (d, 7= 8.1 Hz, IH); 7.05-7.19 (m, 2H); 6.08 (s, IH), 4.60 (t, J= 5.1 Hz, IH); 3.50-3.68 (m. lOH); 3.20-3.30 (m, 2H); and 1.78-1.86 (m, 2H). MS (ESI): m/z 413.1 (M+H). Example 8, Preparation of Compound 8: N-f2-(2+-digieflivl-fl.3jdioxolaii-4- vlmethoxvV6-moTphoUn-4-vl-pvrimidin--4'Vl]-N'-flH-iridoI-3-vlmethvlepeV hydrazine Compound 8 was prepared in a similar manner as described in Exanple 2. 'H NMR (300MHZ, CDCI3), 5 (ppm): 8.38 (br s, IH); 8.30 (dd, J= 11,1.8, IH), 8.02 (br s. IH); 8.00 (s, IH); 7.44 - 7.41 (m, 2H); 7.32 - 7.26 (m, 2H); 6.14 (s, IH); 4.51-4.42 (m, 2H);, 4.22 - 4.12 (m, 2H); 3.96 - 3.91 (m, IH); 3.84 - 3.79 (m, 4H); 3.70-3.64 (m, 4H); 1.47 (s, 3H); and 1.38(s+3H). MS (ESI): m/z 453.2 (M+H). Example 9. PreparatJon of Compound 9: N-(2-r2-(3,4-dimeflioxy-phcnvl)-ethoxv]-6-morpholin-4-vl-pvrimidin-4-vIl-N'-(lH-indol-3-Ylmethylene)-hx4razine Compound 9 was prepared in a similar manner as described in Example 2. +H NMR (300 MHz, CDCU), 5 (ppm): 8.43 (bs, IH); 8.30 (d, 7= 7.5HE IH); 8.2 (bs, IH); 8.02 (d. J= 2.7Hz, IH); 7.46-7.40 (m, 2H); 7.30-7.26 (m, 2H); 6.82 (d, J' = 1 Hz, 3H);4.45 (d.7=3.6Hz, IH); 4.45 (t, J=5.2Hz, 2H);3.87 (d, J=3.9Hz,3H); . 3.86 (d, J= 3.9H2, 3H); 3.81 (s, 4H); 3.67(s, 4H); and 3.04 (t, J=5.0Hz, 2H). MS (ESI): m/z 503.2 (M+H). Example 10. Preparation of Compound 10: N-("lH"indol-3-vImethvlene)-N'-r6-morpholin-4-vi-2-f2-pvridin-2-vl-etfaoxy)-pvrimidin-4-vl"|-hvdraziiie Compovmd 10 was prepared in a similar manner as described in Example 2. +H NMR (300 MHz. CDCla ), 5 (ppm): 9.3 (bs, IH); 8.66 (s, IH); 8.55-8.53 (m, IH); 8.28-8.26 (m, IH); 8.04 (s, IH); 7.62-7.57 (m. IH); 7.41-7.10 (m, 6H); 6.08 (s. IH); 4.64 (t. J= 6.6Hz, 2H); 3.76 (s, 4H); 3.62 (s, 4H); and 3.26 (t, J= 6.6Hz, 2H). MS (ESI): m/z 444.2 (M+H). Example 11. Preparation of Compotmd 11: N-(lH-indoI-3-YlmethvleneVN'-r6-morpholiii-4-vl-2-f3-pvridin-2-vI-propvlV-pyrimidin-4-Yl]-hvdrazine Compound 11 was prepared in a similar manner as d+cribed in Example 1. 'H NMR (300 MHz, DMSO-dg), 5 (ppm): 11.47 (s, IH); 10.65 (s, IH); 8.50(d, i= 4.5 Hz, IH); 8.26 (s, IH); 8.20-8.18 (m, IH); 7.72-7.68 (m, 2H); 7.45-7.42 (m, IH); 7.29-7.18 (m, 4H); 6.17(s, IH); 3.73 (s, 4H); 3.5 (s, 4H); 2.79 (t, /= 7.5 Hz, 2H); 2-58-2.51 (m, 2H); and 2.18-2.06 (m, 2H). MS (ESI): m/z 442.2 (M+H). Example 12. Preparation of Compoimd 12: N-f3-methvl-benzvlidene)-N'-f6-morpholm-4-vl-2-f2-pvridm-2-vl-ethoxY)-pvrimidiD-4-yl]-hvdraz3ne Compoiind 12 was prepared in a similar manner as described in Exan+le 2. 'H NMR (300 MHz, CDCI3), 6 (ppm): 8.55-8.48 (m, 2H); 7.71 (s, IH); 7.65-7.55 (m, IH); 7.49-7.42 (m, 2H); 7.30-7.15 (m, 4H); 6.08 (s, IH); 4.64 (t, /= 6.6 Hz, 2H); 3.81-3.75 (m, 4H); 3.64-3.61 (m, 4H); 3.25 (t, /= 7.0 Hz, 2H); and 2.38 (s, 3H). MS (ESI): m/z 419.2 (M+H). Sample 13. Preparation of Compoimd 13: N-f3-ethvl-benzvlidene)-N'-r6-morpholin-4-vl-2-(2-pyridin-2-vl-ethoxv)-pvrimidin-4-vl1-hvdrazine Compound 13 was prepared in a similar manner as described in Example 2. 'H NMR (300 MHz, CDCI3), 5 (ppm): 8.58-8.50 (m, IH); 8.43 (s, IH); 7.95 (s, IH); 7.64-7.58 (m, 2H); 7.30-7.25 (m, IH); 7.18-7.05 (m, 3H); 6.07(s, IH); 4.65 (t, /= 6.9 Hz, 2H); 3.80-3.76 (m. 4H); 3.64-3.6I(m, 4H); 3.26(t, /= 6.9 Hz, 2H); 2.40 (q,y= 7.6Hz. 2H); and 1.45 (t, J= 1.6 Hz, 3H). MS (ESI): m/z 433.3 (M+H). Example 14. Preparation of Compomid 14: N-(3-meth\d-beD2vlideDe)-N'-r6-morpholin-4-vl-2-(3-pYridin-2-vl-propvlVpvrimidin-4-vl1-hvdrazine Compound 14 was prepared in a similar manner as described in Example 1. +H NMR (300 MHz, CDCls), 5 (ppm): 9.6 (bs, IH); 8.53 (d, J= 4.5 Hz, IH); 7.76 (s, IH); 7.56 (t, 7= 6 Hz, IH); 7.49-7.47 (m, 2H); 7.28 (m, IH); 7.18-7.06 (m, 3H); 6.26 (s, IH); 3.81-3.79 (m, 4H); 3.69-3-67 (m, 4H); 2.89 (t, J= 7.8Hz, 2H); 2.71 (t, /= 7.5 Hz, 2H); 2.39 (s, 3H); and 2.22 (t, J= 7.5Hz, 2H). MS (ESi): m/z 417.2 (M+H). Example 15. PreparatJon of Compound 15: N-[6-mo]:pholm-4-vl-2-(2-pviidiii-2-vl-ethoxv)-pyrniitdm-4-vl]-N'-f 1 -w-tolyl-ethylidaieVhvdrazine Compound 15 was prepared in a similar manner as described in Example 2. +H NMR (300 MHz, CDClj), 5 (ppm): 8.56 (bs, IH), 7.66-7.46 (m, 4H), 7.32-7.26 (m, 2H), 7.16-7.14 (m. 2H), 6.44(s, IH). 4.69 (t, J=6.9H2,2H), 3.80-3.77 (m, 4H), 3.63-3.60 (m, 4H), 3.31 (t, J=6.9Hz, 2H), 2.39 (s, 3H). MS (ESI): m/z 433.2 (M+H). Example 16. Preparation of Compound 16: N-["l-flH-indol-3-vlVetfavlideDe'|-N'-r6-morpholin-4-vl-2-f2-pvridin-2-vl-ethoxyVpyrimidiii-4-vl]-hvdrazine Compound 16 was prepared in a similar manner as described in Example 2. +H NMR (300 MHz, CDCI3), 5 (ppm): 9.35 (bs, IH); 8.54 (dd, J= 0.9,4.2 Hz, IH); 8.33 (d, 7= 7.5 Hz, IH); 7.93 (s, IH); 7.5S (t, J = 7.2 Hz. IH); 7.36-7.33 (m, 2H); 7.27-7.120 (m, 4H); 6.49 (s, IH); 4.6 8(t, J- 7.2 Hz, 2H); 3.76-3.73 (m, 4H); 3.60-3-57 (m, 4H); 3.50 (s, 3H); and 3.33-3.28 (t, / = 7.0 Hz, 2H). MS (ESI): m/z 458.2 (M+H). Example 17. Preparation of Compound 17: 3-Methvl-benzaldehvde 0-[6-morpholin-4-vl-2-f2-pvridin-2-vl-etboxv)"P>Timidin-4-vl1-oxime Compoimd 17 was prepared in a similar manner as described in Exaniple 2. 'H NMR (300 MHz, CDCI3), 5 (ppm): 8.56-8.53 (m, IH); 8.45 (s, IH); 7.62-7.50 (m, 3H); 7.38-7.26 (m, 3H); 7.18-7.10 (m, IH); 6.17 (s, IH); 4.68 (t, J= 6.9 Hz, 2H); 3.80-3.76 (m, 4H); 3.67-3.64 (m, 4H); 3.29 (t, 7= 6.9Hz, 2H); and 2.41 (s, 3H). MS (ESI): m/z 420.1 (M+H). Example 18. Preparation of Compound 18: lH-indoIe-3-carfaald6hvdeO-[6-morphoIin-4-vl-2-f2-pvridin-2-vl-ettioxvVpyrimidio-4-yl]-oxime Compound 18 was prepared in a similar manner as described in Example 2. 'HNMR (300 MHz, DMSO-d&), 6 (ppm); 11.82 (bs, IH); 8.81 (s, IH); 8.50 (d, J= 4.5 Hz, IH); 8.04 (d, J=6.9Hz, IH); 7.93(s, IH); 7.72 (t. J = 6.9 Hz, IH); 7.49 (d, 7= 6.9 Hz, IH); 7.33 (d, J= 7.8Hz, IH); 7.30-7.18 (m, 3H); 6.22 (s, IH); 4.57 (t, / = 6.3Hz, 2H); 3.67 (s, 4H); 3.56 (s, 4H); and 3.15 (t, J=6.3 Hz, 2H). MS (ESI): m/z 445.2 (M+H). Example 19. Preparation of Compound 19: N-flH-indol-S-vlmethvleneVN'-16-niorpholin-4-vl-2-r2-fpvridm-3-vloxv)-ethoxv]-pYrmiidin-4-vl>-hvdrazuie Compound 19 was prepared in a similar manner as described in Example 2. 'HNMR:"(300 MHZ, CDCI3), 5 (ppm); 9.20 (br s, IH); 8.30 (br s, IH); 8.29 (t, J= 3.3 Hz, IH); 8.18-8.12 (m, 2H); 7.44 -7.41 (m, 2H); 7.26-7.18 (m, 5H); 6.08 (s, IH); 4.66 (t. /= 4.8 Hz, 2H); 4.29 (t, J= 5.0 Hz, 2H); 3.80-3.76 (m, 4H); and 3.67-3.62 (m, 4H). MS (ESI): m/z 460.2 (M+H). Example 20. Preparation of Compound 20: N-(3-methvl-benzylidene)-N'-{6-morpholin-4-vl-2-[2-(pvridiD-3-vloxv)-ethoxv")-pvrimidin-4-vU-hvdrazine Compound 20 was prepared in a similar manner as described in Example 2. 'H NMR (300 MHz, CDCI3), 5 (ppm): 8.55 (s, IH); 8.34 (br s, IH); 8.30-8.23 (m, IH); 7.78 (s, IH); 7.50-7.47 (m, 2H); 7.32-7.24 (m, IH); 7.20-7.17 (m, 3H); 6.14 (s, IH); 4.66 (t, 7= 5.0 Hz, 2H); 4.35 (t, /= 4.8 Hz, 2H); 3.83-3.80 (m. 4H); 3.68-3.65 (m, 4H); and 2.40(s, 3H). MS (ESI): m/z 435.2 (M+H). Example 21. Preparation of Compound 21: Bntvl-l4-rN'-f lH-indol-3-vlmethvleneV hvdrazino]-6-morpIiolin-4-vl-pvriimdin-2-vll-amine Compound 21 was prepared in a similar manner as described in Example 2. 'H NMR (300 MHz, CDCI3), 6 ppm: 8.41 (bs, IH), 8.33-8.30 (m, IH), 8.19 ( bs, IH), 7.95 (s, IH), 7.41-7.37 (m, 2H). 7.29-7.25 (m, 2H). 5.96 (s,lH). 4.65 (t,>4 Hz, IH), 3.83-3.80 (m, 4H). 3.65-3.62 (m, 4H), 3.36 (dd. 7=6.3,13.5 Hz, 2H), 1.60-1.55 (m, 2H), 1.35-1.33 (m. 4H). 0.92-0.87 (m, 3H). MS (ESI): m/z 408.2 (M+H). Example 22. Preparation of Compotmd 22: N-f3-Methvl-benzylidaie")-N'-f6-morpholic-4-vl--2-fpyridin-3-vIoxvVpvrimidm--4-vl1--hvdrazme To a solution of 3-hydroxypyridine (950 mg, 10 mmol) in anhydrous THF (50 mL) at 0°C under the nitrogen protection was added NaH (60% in oil) (480 mg, 12 mmol). The suspension was stirred for 0.5 h at 0°C, and 2,4,6-trichloropyrimidine (1.84 g, 10 rtmiol) was added. After the mixture warmed to room temperature and stirred for 2 h, the reaction was quenched by ice brine and extracted with EtOAc (300 mL). The organic phase was washed with brine, dried (Na2S04), filtered, evaporated in vacuo. The cure product was purified by fla+ chromatography on a column of siUca gel (EtOAc-Hexane, 1:7). The product (l.SOg, 7.4mmol) in CH2CI2 (150 mL) at 0°C was added slowly morpholine (2.5g, 28 mmol). The reaction mixture was stirred at 0°C for 1 h and anothsr 1 h at room temperature. The mixture was washed with water. The organic phase was dried (Na2S04), filtered and evaporated in vacuo and presented three isomers. The isomers was separated by flash chromatogr+hy on a column of silica gel (EtOAc-Hexane, 1:7 and 1: 3) to obtain 4-[6-chloro-2-+yridin-3-yloxy)-pyrimidin-4-yl]-morpholine (320mg, 14.7%). +H NMR(300 MHz, CDCI3). 5 (ppm): 8.51(d, IH, +=2.7 Hz), 8.44(dd, IH, J=1.5,M33 Hz), 7.53-7.49 (m, IH), 7.34-7.3 (m, IH), 6.25 (s, IH), 3.71-3.67(m, 4H),3.51-3.48(m,4H). MS (ESI): m/z 293.1. To a solution of 4-[6-chloro-2-(pyridin-3-yloxy)-pyrimidin-4-yl]-morpholine (295mg, 1 mmol) in THF (10 mL) was added anhydrous hydrazine (0,320 ml, 10 mmol) under the nitrogen protection. The mixture was heated at 70°C for 15 min. After cooling to room tempCTature, the reaction mixture was quenched by ice brine and extracted with EtOAc (100 mL). The organic phase was washed with brine (10 mL) and water (10ml x 2), dried (Na2S04), filtered, evaporated, and purified by flash chromatography on a colimm of silica gel (CH2CI2 and CH2Cl2-MeOH, 95:5) and to give [6-morpholin-4-yl-2-(pyridin-3-yloxy)-pyrimidin-4-yl]-hydrazine (180 mg) in 62% yield. M/2 (M+1) 289.2 To a solution of [6-morpholin-4-yl-2Mpyridin-3-y!oxy)~pyrimidin-4-yl]-hydrazine (180 mg) (145 mg, 0.5 mmol) and m-tolylaldehyde (72 mg, 0.6 mmol) in MeOH (10 mL) was added acetic acid (1 drop). The reaction mixture was stirred at room temperature for 12 h and white solid was precipitated. The resulting precipitate was collected by filtration and washed with little amount of metanol and to give 125 mg of Compound 22 in 64 % yield. 'HNMR(300MHZ, CDCI3), 5 (ppm): 8.71(s, IH), 8.S7(d, lH,>=2.4Hz), 8.44(dd, IH, +1.5, 3.2 Hz), 7.78(s,lH), 7.56-7.52(m,lH), 7.46-7.43(m, 2H), 7.34-7.26(m. 2H), 7.17(d, 1H,+8.1 Hz), 6.17 (s, IH), 3.76-3.73(m, 4H), 3.57-3.54(m, 4H), 2.38(8, 3H). MS (ESI): m/z 391.2. Example 23. Preparation of Compound 23: N-f3-Meaivlben2lidene)-N'-fS-methvl-6-morpholin-4-vl-2-phenvlpvrimidin-4-vl)hvdrazine BenzamidJne hydrochloride (7.06 g, 0.045 mol) and dimethyl metiylmalonate (6.0 g, 0.041 mol) were dissolved in methanol (100 mL). Sodium methoxide (21.5 inL, 0.099 mol, 25 wt % solution in methanol) was added and the solution was stirred at room temperature for 18 h. The volume of solvent was redcued to approximately 50 mL under reduced pressure, then poured onto ice water. This solution was neutralized with HOAc which produced a white precipitate. This precipitate was collected and dried to produce a white soHd (6.1 g, 74 %). 'H NMR (DMSO-dfi) 8 (ppm)1.68 (s, 3H), 7.70-7.87 (m, 3H), 8.21 (d. J=8.4 Hz). MS (ESI): m/z 203.1 (M+H)+ 5-Methyl-2-phenyl-pyrimidine-4,6-dioI (3.3 $, 0.016 mol) and POCI3 were heated to 60C for 3 hrs. The solution was allowed to cool to room temperature then poured onto ice. The resultant white precipitate was filtered and dried to produce the desired compound as a white solid (810 mg, 21 %). 'H NMR (DMSO-dfi) 8 (ppm) 2.40 (s, 3H), 7.51-7.56 (m, 3H). 8.23 (d, 8.4 Hz). MS (ESQ: m/z 239.1 (M+H)* 4,6-DicMoro-5-methyl-2-phenylp>Timidine (2.5 g, 0.010 moi) and morpholine (2.93 g, 0.031 mol) were dissolved in THF (50 mL) and heated to reflux for 3 hrs. The solution was allowed to cool then EtOAc (100 mL) and water (100 mL) wa-e added. The EtOAc layer was washed with water (3x100 mL), dried over MgS04, filtered and solvent was removed undCT reduced pressure. The resultant sohd was used without further purification (2.66 g, 92 %). MS (ESI): m/z 298.1 (M+Hf 4-(6-Chloro-5-methyl-2-phenylpyrimidin-4-yl)morpholine (439 mg, 1.51 mmoi) was dissolved in THF (50 mL). Hydrazine (0.25 mL, 7.96 mmol) was added and the solution was heated to refliix for 18 hrs. The reactioirwas allowed to cool the solvent was removed imder reduced pressure. EtOAc (100 mL) and water (100 mL) wCTe added. The EtOAc layer was washed with water (3x 100 mL), dried over MgS04, filtered and solvent was removed under reduced pressure to produce a white solid (374 mg). This solid was redissolved in THF (50 mL) and m-tolualdebyde (157 mg, 1.31 mmol) was added. The solution was heated to reflux for 4 hrs then allowed to cool. Solvent was removed under reduced pressure then EtOAc (100 mL) and water (100 mL) were added. The EtOAc layer was washed vfith water (3x100 mL), dried over MgS04, filtered and solvent was removed under reduced pressure. The crude product was purified by silcagel column chromatography, eluting with 25 % EtOAc/hexane to produce the pure desired product as a yellow solid (313 mg, 53 %). +H NMR (DMSO-dfi) 5 (ppm) 2.26 (s, 3H), 2.36 (s, 3H), 3.35 (m, 4H), 3.75-3.78 (m, 4H), 7.20 (d, J=6.9 Hz), 7.33 (t, J=6.9 Hz), 7.47-7.52 (m, 5H), 8.19 (s, IH), 8.35-8.3S (m, 2H). 10.60 (s, IH). MS (ESI): m/z 388.3 (M+H)* Example 24. Preparation of Compoxmd 24: N-f3-methvl-benzvhdene1->P-f2-phenvl-6-ihiomorphoUn-4-vl-pvrimidin-4-vlVhvdrazine Compoimd 24 was prepared in a similar maimer as d+cribed in Example 23. +H-NMR (DMSO-dfi) 5 2.36 (s, 3H), 2.76 (s, 4H), 4.07 (s, 4H). 6.36 (s, IH), 7.19 (d, J=8.1 Hz). 7.32 (t,>«.l Hz), 7.47-7.57 (m, 5H), 8.09 (s, IH), 8.30-8.31 (m, IH), 11.02 (s,lH). MS (ESI): m/z 389.1. Example 25. Preparation of Conrooimd 25: f2.3-Dmiethvl-lH-mdole-5-vl)-f6-morpholin-4-vl~2-r2-fpvridm-3-vloxvVethoxvl -pvrirDidm-4-vll -amine To a solution of 2-(pyridin-3-yIoxy)-ethanoI (3.48 g, 25 mmol) in 40 mL of anhydrous THF at room temperature under the N2,2,4, 6-trichloro pyrimidine {4.56 g, 25 mmol) was added followed by portionwise addition of NaH (60% suspension in oil, 1.1 g, 27.5 mmol). After 30 min of stirring readtion was quenched with water, water layer extracted with EtOAc, combined organic solutions washed with brine and dried over MgS04. Purification using flash chromatography (silica; dichlorometbane/acetone/methanol: 3/1/0.1) afforded mixture of 4.6-dichloro-2- and 2,6-dichloro-4- [2-(pyridin-3-yloxy)-ethoxy]-pyrimidines (3.72 g, 52%), (NMR ratio 1:1.2) as an oil. To a solution of the above mixture (3.72 g, 13 mmol) in 20 mL of 1,4-dioxane was added DIPEA (2.49 mL, 14.3 mmol), followed by 2,3-dimethyl-5-amino-indole (2.08 g, 13 mmol) and a mixture was refluxed for 1 hour. Solvent was removed \mder reduced pressure and reaction mixture was separated using colmmi chromatography (siUca; dichloromethane/acetona'methanol: 3/1/0.1) to afford {6-chloro-2-[2-(pyridin-3-y]oxy)-ethoxy]-pyrimidin-4-yl}-amine(2.07 g,39%). An mixture of {4-chloro-6-[2-+yridin-3-yloxy)-eflioxy]-pyrimidin-4-yl}-amine and {2-cIiloro-6-[2-(pyridin-3-yloxy)-ethoxy]-pyrimidin-4-yl}-amine (2.5 g, 47%) was also obtained and used in another reaction. A solution of {6-chloro-2-[2-(pyridin-3-yloxy)-ethoxy]-pyrimidin-4-yl}-ainine (2.07 g, 5.05 mmol) and morpholine (1.32 mL, 15.15 mmol) in 1,4-dioxane was heated at 110 "C for 24 hours. Solvent was removed under reduced pressure and reaction mixture was purified using flash chromatography (siUca; dichloromethane/acetone/methanol: 3/1/0.1) to afford Compoimd 25 (2 g, 86%) as a colorless solid. 'H NMR (300 MHz, CDCI3), 5 (ppm): 8.34 (br s, IH), 8.23 (dd, IH, J= 3.6, 2.1), 7.96 (brs, IH), 7.34-7.21 (m. 4H), 6.98(dd, IH, J= 8.4,1.8 Hz), 6.60 (brs, IH), 5.36 (s, IH), 4.65 (t, 2H. +5.1 Hz), 4.34 (t, 2H, >=5.1 Hz), 3.66 (m, 4H), 3.42 (m, 4H), 2.37(s, 3H), and 2.20 (s, 3H). MS (ESI): m/z 461.5 (M+H). Example 26. Preparation of Compound 26: (2.3-Dimethvl-lH-iDdole-5-vlVf4-morpholui-4-vl-6-[2-fpYridm-3-vloxv)-ethoxv1"pvrimidin-2-vU-amine Reaction of a mixture of {4-chloro-6-[2-(pyridiin-3-yloxy)-ethoxy]-pyrimidin-4-yl}-amine and {2-chloro-6-[2-(pyridin-3-yloxy)-ethoxy]-pyriinidin-4-yl}-amine (2.5g, 47%) and(2.5g, 6.1 mmol) with morpholine was carried out as described in Example 24. Purification by flash chromatography and recrystallization from ethor-pentane gave 0.3 g of Compound 26. +H NMR (300 MHz, CDCI3), 6 (ppm): 8.36 (br s, IH). 8.24 (m, IH), 7.85 (m, IH), 7.70 (brs, IH), 7.26-7.14 (m, 4H), 6.78 (brs, IH), 5.42 (s, IH), 4.68 (t, 2H, J=5.1), 4.31 (t, 2H, J=5.1), 3.70 (m, 4H), 3.54 (m, 4H), 2.35(s, 3H), and 2.18 (s, 3H). MS (ESI): m/z 461.5 (M+H). Example 27. Preparation of Compound 27: 3-f4-rN'-f3-Methvl-benzvlideneV hvdrazino]-6-morpholin-4-vl-pvrimidin-2-vll-propionic acid ethvl ester Compound 27 was prepared in a similar manner as described in Example 1. 'H NMR (300 MHz, CDCI3), 6 (ppm): 8.22 (s, IH); 7.69(s, IH); 8.07 (s, IH); 7.47 (m, 2H); 7.28 (t, J= 7.5 Hz, IH); 7.17 (d, J= 7.5 Hz, IH); 6.23(s, IH); 4.13 (q, J = 7.2 Hz, 2H); 3.78-3.81 (m, 4H); 3.62-3.65 (m, 4H); 2.9S (t, /= 7.2 Hz, 2H); 2.77 (t, y= 7.2 Hz. 2H); 2.39 (s, 3H); and 1.24 (t, 7= 7.2 Hz, 3H). MS (ESI): m/z 398.2 (M+H). Example 28. Preparation of Compound 28: N-f3-Methvl-bepzvlidene)-N'-{6-morpholin-4-vl-2-r2-('l-oxv-pvridin-2-vlVettioxvl-pvriroiHin-4-v1) -hydrazine To a solution of 4-[6-chIoro-2-(2-pyridin-2-yl-eflioxy)-pyrimidin-4-yl3-moipholine (1.61 fe 5.0 mmol) in CH2CI2 (40 ml) was added methanol (10 ml) followed by the addition of MCPBA (70%, 1.43 g, 5.8 mmol) in one portion. The reaction mixture was stirred overnight at room temperature, affording a clear solution. The solution was cast into saturated aqueous NaHCOs (35 mL) then the organic phase was separated, washed with 10% aqueous Na2S203 (40 mL) and brine (40 mL), and dried (Na2S04), filtered and evaporated in vacuo to give a pure product, 4-{6-chloro-2-[2~(lK)xy-pyridin-2-yl)-ethoxy]-pyrinudin-4-yi)-morpholineas awhite solid, (1.46 g, 86.7%). 'H-NMR (CDCI3) (ppm), /(Hz): 8.25-8.23 (m, IH); 7.41-7.7.38 (m, IH); 7.20-7.16 (m, 2H); 6.14 (s, IH); 4.71 (t, >+.0,2H); 3.77-3.73 (m, 4H); 3.63-3.53(m, 4H); and 3.40 (t, 7=6.0, 2H). Anhydrous hydrazine (0.640 ml, 20 mmol) was added to a solution of 4-{6-ch!oro-2-[2-(l-oxy-pyridin-2-yl)-ethoxy]-pyTimidin-4-yl}>-morpholine (1.35 g, 4.0 mmol) in dioxane (15 ml) under the nitrogen protection. The obtained mixture was heated at 95-100°C for 2 h. After it was cooled down, the solvent was evaporated in vacuo until the white sohd began to precipitate (to a half the original volume), and then H2O (15 ml) was added. The resulting precipitate was collected by filtration and washed with water (until the pH was neutral). {6-Morpholin-4-yl-2-[2-(l -oxy-pyridin-2-yl)-ethoxy]-pyriniidin-4-yl}-hydrazine (1.02 g) has been obtained in 76.7% yield. +H-NMR(DMSO-ds>(ppm),/(Hz): 8.25 (bs, IH); 7.66(s, IH); 7.44-7.41 (m, IH); 7.33-7.25 (m, 2H); 5.59 (s, IH); 4.46 (t, /=6.0,2H); 3.64-3.61 (m, 4H); 3.41-3.38 (m, 4); and 3.17 (t, .+=6., 2H). To a solution {6-morpholin-4-yl-2-[2-(l-oxy-pyridin-2-yI)-ethoxy]-pyrimidin-4-yl}-hydrazine (820 mg. 2.46 mmol) and m-tolualdehyde (97%, 320 mg, 2.58 mmol) in methanol (7 mL) acetic acid (2 drops) was added. The reaction mixture was heated under reflux for 15 min. Upon cooling to room temperature, a precipitating has been formed, and the soUd was collected by filtration, washed with Uttle amount of methanol and Et20, and dried to afford 950 mg (89%) of N-(3-Methyl-benzyIidene)-N'-{6-moipholin-4-yl-2-[2-(l-oxy-pyridm-2-yl)-ethoxy]-pyrimidin-4-yl}-hydrazine as a white soUd (m.p. 187-188"C). 'H NMR (300 MHz, CDCI3), 5 (ppm): 10.86 (s, IH); 8.28-8.26 (m, IH); 7.98 (s, IH); 7.50-7.43 (m, 3H); 7.33-7.26 (m, 3H); 7.17 (d, +7.8 Hz, IH); 6.05 (s, IH); 4.53 (t, y=6.3 Hz, 2H); 3.68-3.64 (m, 4H); 3.54-3.50 (m, 4H); 3.21 (t. J=6.3,2H); and 2.33 (S.3H). ESMS calcd forCjsHzeNsOj: 434.21; Found: 457.2 (M+Na)"". As shown in the scheme above, l-(hydroxy-ethyI)-lH-pyridm-2-one (1.5 g, 10.7 ramol) was coupled with 4-(2,6-dichloropyrimidin-4-yl)-moipholine in the presence of sodium hydride in DMF. Ailer addition of water, precipitate was filtered out, washed with water, and dried to afford almost a desired regioisomer (1.7 g, 47%). The obtained regioisomer was refiuxed with 3.5 equivalents of hydrazine in dioxane. Water was added to the reaction mixture, and precipitate was fonned. The precipitate was collected by filtration, washed 3 times with water, and dried to give a hydrazrae derivative (1,7 g, 85%), Condensation with /w-tolyl aldehyde afforded title compound (2.1 g, 95%). 'H NMR (DMSO-dfi): 5 10.90 (s. IH), 7.98 (s, IH). 7.62 (dd, J= 6.8,2.1Hz, IH). 7.49 (d, J= 7.5 Hz, IH), 7.48 (s, IH), 7.41 (td, /= 7.8, 2.1 Hz, IH), 7.29 (t, J= 7.5 Hz, IH), 7.17 (d, J= 7.8 Hz, IH), 6.39 (d, J= 9.3 Hz, IH), 6.20 (t, J= 6.2 Hz, IH), 6.05 (s, IH), 4.43 (t, J= 5.1 Hz, 2H),4.22 (t, J= 5.2 Hz, 2H), 3.66 (m, 4H), 3.52 (m.4H),2.34(s,3H). ESMS calcd for CijHa+sOs:- 434.21; Found: 457.2 QA+lSf. Example 30. Prqiaration of Compound 30:7tf+f3-iodo-beDzvlideneV//'-r6-morpholiii-4-yl-2-('2-pvridin-2-vl-ethoxvVpvrimidin-4-vl1-hvdrazme Compound 30 was prqiared in a similar manner as described in Example 29. 'H NMR (DMSO-de): 6 10.97(s, IH), 8.51 (d. J= 4.5 Hz, IH), 8.00 (s, IH), 7.95 (s, IH), l.n-l.lG (m, 3H), 7.34 (d, 7 = 7.8 Hz, IH), 7.26-7.18 (m, 2H), 6.08 ESMS calcd for C22H23IN6O2: 530.09; Found: 531.1 (M+l)"". Example 31. Preparation of Compound 31: JV-f 3-flttoro-benzvlideneV-jy'-r6-morpfaolin-4-vl-2-f2-pvridin-2"Vl-ethoxv>-pvrimidin-4-YlVhvdraziDc Compound 31 was prepared in a similar manner as described in Example 29. 'HNMR (DMSOde): 5 10.98 (s, IH). 8.51 (d, J= 3.9 Hz. IH), 8.01 (s, IH), 7.72 (td, y = 7.6,1.8 Hz, IH), 7.57 (brd, J= 9.9 Hz, IH), 7.51-7.40 (m, 2H), 7.33 (d, J = 7.2 Hz, IH), 7.24 (dd, 7= 7.6, 5.2 Hz, IH). 7.20 (brt, J= 7.8 Hz, IH); 6.11 (s, IH), 4.54 (t, J= 6.8 Hz, 2H), 3.65 (m, 4H), 3.54 {m, 4H), 3.14 (t, /= 6.7 Hz, 2H). ESMS calcd for C22H23FN6O2: 422.19; Found: 445.2 (M4-23)*. Example 32. Preparation of Compound 32: jV-(3-chlon>-benzviidene)-A"-r6-morpholin-4-vl-2-f2-pvridin-2-vl-ethoxv)-pvriniidin-4-yl]-hvdrazine Compound 32 was prepared in a similar manner as described in Example 29. 'HNMR (DMSO-de): 5 U.OO (s, IH), 8.51 (d,/=4.5 Hz, IH), 8.00 (s, IH), 7.74-7.70 (m. 2H), 7.65 (d, J= 6.6 Hz. IH), 7.45-7.41 (m, 2H). 7.33 (d, J= 7.8 Hz, IH), 7.24 (dd, J= 7.8.4.8 Hz, IH), 6.09 (s, IH), 4.54 (t, J= 6.6 Hz, 2H), 3.66 (m, 4H), 3.54 (m, 4H), 3.14 (t, J= 6.6 Hz, 2H). ESMS calcd for C22H23CIN6O2:438.16; Found: 461.2 QA+2Zf. Example 33. Preparation of Compound 33: JV-f3-bromo-ben2vlidene)-jy'-f6-morpholin-4-yl-2-(2-pvridin-2-vl-ethoxv)-pvrimidin-4-vl1-hvdrazine Compound 33 was prepared in a similar manner as described in Example 29. 'H NMR (DMSOde): 5 10.99 (s, IH), 8.51 (d, J= 4.2 Hz, IH), 7.98 (s, IH), 7.86 (s, IH), 7.72 {X,J= 8.5 Hz. IH), 7.71 (d, 7= 8.1 Hz, IH), 7.54 (d, /= 7.5 Hz, IH), 7.38-7.32 (m, 2H), 7.24 (dd, /= 7.2,4.8 Hz, IH), 6.09 (s, IH), 4.54 (t, J= 6.6 Hz, 2H), 3.66 (m, 4H), 3.53 (m, 4H), 3.14 (t, J= 6.6 Hz, 2H). ESMS calcd for CaaHzsBrNeOj: 482.11; Found: 505.10 (M+23)'*'. ;fcample 34. Preparation of Compound 34: 3-|[6-Morpholin-4-vl-2-f2-pvridin-2-vl-etboxv')-pvrimidin-4-vl]-hydrazonomethvU-benzoic acid methyl ester Compound 34 was prepared in a similar maraier as described in Example 29. +HNMi(DMS0-d6): 6 11.00 (s, IH), 8.51 {d,7=5.4Hz, IH), 8.12 (s, IH), 8.10 (s, IH), 8.06 (d, J= 8.1 Hz. IH), 7.93 (d. 7= 6.6 Hz, IH), 7.73 (t, J= 1.6 Hz, IH), 7.57 (t, 7= 8.0 Hz, IH), 7.34 (d,7= 7.8 Hz, IH), 7.24 (dd, 7= 6.0,4.5 Hz. IH), 6.07 (s, IH), 4.55 (t, 7= 6.4 Hz, 2H), 3.88 (s, 3H), 3.68 (m, 4H), 3.53 (m, 4H), 3.15 (t, 7= 6.6 Hz, 2H). ESMS calcd for C34H26N6O4: 462.20; Found: 463.3(M+I)'". Example 35. Preparation of Compound 35: l-f2-l4-fN'-f3-Iodo-benzvlideneV hvdraziDo]-6-morpholin-4-yl-pyrimidin-2-vlQxvl-ethvlViJj-pvridin-2-one Compound 35 was prepared in a similar maimer as described in Example 29. 'HNMR (DMSO-de): 6 11.02 (s, IH), 8.00 (s, IH), 7.93 (s, IH), 7.75-7.69 (m, 2H), 7.61 (dd, 7= 7.0,1.8Hz, IH). 7.41 (td,7= 7.9,2.1 Hz, IH), 7.20 (t,7= 8.0Hz, IH), 6.38 (d, 7= 8.4 Hz, IH), 6.19 (t, 7= 6.7 Hz, IH), 6.06 (s, IH), 4.43 (t, 7= 5.3 Hz, 2H), 4.22 (t, 7= 5.3 Hz. 2H). 3.66 (m, 4H), 3.53 (m, 4H), 3.14 (t, 7= 6.6 Hz, 2H). ESMS calcd for C22H23IN6O3: 546.09; Found; 569.2 (M+23)*. Example 36. Preparation of Compound 36: 3-ff6-Morpholin-4"Vl-2-f2-Pvridin-2-vl-ethoxvVpvrimidin-4-vl1-hvdrazonometlivl}-benzoic acidN-methvl amide Compound 36 was prepared in a similar maimer as described in Example 29. 'HNMR(DMSO-de): 6 11.00 (s, IH), 8.6 (s, IH), 8.41 (d,7= 5.4Hz, IH), 8.12 (s, IH), 8.11 (s, IH), 8.0 (d,7= 8.1 Hz, IH). 7.83 (d,7= 6.8Hz, IH), 7.73 (t,7= 7.2 Hz, IH), 7.57 {t,J= 8.0 Hz, IH), 7.34 (d, J= 7.8 Hz, IH), 7.34 (dd, J= 6.0,4.5 Hz, IH), 6.07 (s, IH), 4.55 (t, J= 6A Hz, 2H), 3.5-3.0 (m, 7H). ESMS calcd for C24H27N703:461.2; Found: 485.1(M+Na)*. Example 37. Preparation of Compound 37: C3-U6-Morpholin-4-vl-2-(2-pyridm-2-++-ethoxy)-pvrimidin-4-vl"l-hvdrazonomethvll-phenvn-inethanol Compound 37 was prepared in a similar maimer as described in Example 29. 'HNMR (DMSO-dfi): 5 10.86 (s, IH), S-Sl+d, J = 3.9 Hz, IH). 8.03 (s, IH), 7.73 (td, /= 7.8 and 1.8 Hz, IH), 7.39 (m. 2H), 7.39-7.32 (m, 3H), 7.24 (dd, J= 6.3 and 4.8 Hz, IH), 6.06 (s, IH), 5.25 (t, J= 5.7 Hz, IH), 4.54 (t, 7 = 6.8 Hz, 2H); 4.53 (d, J= 6.5 Hz, 2H), 3.66 (m, 4H), 3.53 (m, 4H), 3.14 (t, /= 6.9 Hz, 2H). ESMS clcd for CaaHaeNeOa: 434.49; Found: 435.2 (U+lf. Compounds 38-41 were prepared by the following method. 4-Carbamimidoyl-butiric acid ethyl ester hydrochloride was prepared following a procedure starting from 4-cyanobutyrate (6.49 g, 43.9 mmol) and coupled with diethyl malonate ia the presraice of sodium ethylate to afford desired dihydroxypyrimidine (1.27g, 15%). Treatment of the dihydroxypyrimidine with phosphoras oxychloride gave dichloro-daivative (0.88 g, 60%), which was convertec into morpholine derivative (0.89 g, 85%) after reacting witti DIPEA and morpholine tQ THF. The dichloro-derivative was refluxed in dioxane with 4 equivalents of hydrazine to afford a hydrazine derivative (0.52 g, 59%») that was condensed with m-tolyl aldehyde to obtain hydrazone (0.61 g, 88%). The hydrazone was hydrolyzed with KOH in methanol to yield an acid: 4-{4-[JV'-(3-Methyl-benzylidene)-hydrazino.+ 6-morphDlin-4-yl-pyrimidin-2-yl}-butyric acid (0.47 g, 82%). To a solution of the acid, EDC, DMAP, and an appropriate amine in DMF were added. The obtained reaction mixture was stirred overnight at room temperature, and was distributed betweai dichloromethane and water layers. The dichloromethane layer was washed two times with water, brine, and dried. The obtained amide (70-80% yield) was isolated by column chromatography. Example 38. Preparation of Compound 38: 7+.A'-DietfavI-4-f4-rA+"-f3-methvl-beDzvlidene")-hvdrazino]-6"morpholm-4-vl-pvrimidin-2-vI)-btttvramide +H NMR {CDCI3): 5 8.38 (brs, IH), 7.71 (s, IH), 7.47 (m, 2H), 7.31-7.26 (m, 2H), 7.17 (d,J= 7.5 Hz, IH), 6.24 (s, IH), 3.78 (m, 4H), 3.66 (m, 4H), 3.37 (q, /= 7.2 Hz, 2H), 3.30 (q, J= 7.2 Hz, 2H), 2.67 (t, /= 7.4 Hz, 2H), 2.39 (m, 4H), 2.13 (qv, /= 7.4 Hz, 2H), 1.13 (t,/= 7.4 Hz, 3H), 1.11 (t./= 7.4 Hz, 3H). ESMS calcd for C24H34N6O2: 438.27; Fomid: 439.30 (M+lf. Example 39. Preparation of Compound 39: 4-f4-[jy'-f3-Methvl-benzvlidene")- hvdrazmo1-6-moipholm-4-vl-pvrimidin-2-vl)-l-(4-methvr-piperazin-l-vlVbutan-l- one +H NMR (CDCI3): 6 8.36 (brs, IH), 7.71 (s, IH), 7.46 (m, 2H), 7.31-7.26 (m, 2H), 7.17 (d, J= 7.8 Hz, IH), 6.25 (s, IH), 3.80 (m, 4H), 3.65 (m, 6H), 3.46 (t, /= 4.9 Hz, 2H), 2.67 (t, /= 7.4 Hz, 2H), 2.42-2.34 (m, 8H), 2.30 (s, 3H), 2.11 (qv, J'= 7.5 Hz,2H). ESMS calcd for CzsHjsNTOa: 465.29; Found: 466.30 (M+lf. Example 40. Preparation of Compound 40: 4-f 4-fJV'-(3-Methvl-benzvlideDe)-hvdrazino1-6-morpholin-4-vl-pvriniidin-2-vl)-JV-pvridin-4-vlmethvl--butvrainide +H NMR (CDCI3): 5 8.59 (brs, IH), 7.92 (s, IH), 7.60 (m, 2H), 7.37 (m, 2H), 7.22-7.11 (m, 4H), 7.00 (m, IH), 6.15 (s, IH), 4.36 (d, J= 5.7 Hz, 2H), 3.68 (m, 4H), 3.53 (m, 4H), 2.62 (t, y= 7.4 Hz, 2H), 2.31 (s, 3H), 2.25 (t, /= 6.9 Hz, 2H), 2.05 (qv, /=6.SHz. 2H). ESMS calcd for C26H31N7O2: 473.25; Found: 474.30 (M+l)"". Example 41. Preparation of Compound 41: 4-l4-rJV+'-(3-Methvl-beDzvlideneV hydrazmol-6"morpholin-4-yl-pvri3nidin--2-vlt-+-pvridin-4-vl-butyramide 'H NMR (CDCI3): 5 9.43 (s, IH), 8.68 (brs, IH). 8.43 (d, J= 4.8 Hz, 2H), 7.75 (s, IH), 7.51 (d,/= 5.4 Hz, 2H), 7.44 (m, 2H), 7.27 (t. /= 7.2 Hz, 1H),7.16 (d, J= 6.9 Hz, IH), 6.23 (s, IH), 3.77 (m, 4H), 3.64 (m, 4H), 2.72 (t, /= 6.9Hz, 2H), 2.46 (t, J= 6.9 Hz, 2H), 2:37 (s, 3H),, 2.15 (qv,y= 6.9 Hz, 2H). ESMS cicd for C25H29NTO2: 459.24; Found: 460.30 (M+lf. Example 42. In vitro assays Reagents. Staphylococcus aureus Cowan I (SAC) was obtained from Calbiochem (La Jolla, CA), and lipopolyaccharide (LPS, Serratia marscencens) was obtained from Sigma (St. Louis, MO). Human and mouse recombin+it IFNy were purchased from Boehringer Mannheim (Mannheim, Germany) and Pharmingen (San Diego, CA), respectively. Human In Vitro Assay. Human PBMC were isolated by cemtrifugation using Ficoli-Paque (Pharmacia Biotech, Uppsala, Sweden) and prepared in RPMI medium siqiplemented with 10% fetal calf serum (FCS), 100 U/mL penicillin, and 100 jig/mL streptomycin. PBMC were plated in wells of a 96-well plate at a concentration of 5 x 10+ cells/well, and primed by adding IFNy (30 U/mL) for 22 h and stimulated by adding LPS (1 ng/mL), or by adding IFNy (100 U/mL) and then stimulated by adding SAC (0.01%). A test pyrimidine compound was dissolved in DMSO, and added to wells of the 96-well plate. The final DMSO concentration was adjusted to 0.25% in all cultures, including the compound-free control. Human THP-1 cells were plated in wells, primed by adding IFNy (100 U/mL) for 22 h and stimulated by adding SAC (0.025%) in the presence of different concentrations of the pyrimidine compound. Cell-free supematants were taken 18 h later for measurement of cytokines. Cell viability was assessed using the bioreduction of MTS. Cell survival was estimated by deteimining the ratio of the absorbance in compoimd-freated gro+gis VCTSUS compound-free control. The supernatant was assayed for the amount of IL-12p40, IL-12p70, or IL-10 by xising a sandwich ELISA with anti-human antibodies, i.e., a Human IL-12 p40 ELISA kit fivsm R&D Systems (Berkeley. CA), and a Human 7Lr 12 p70 or IL-10 ELISA kit from Endogen (Cambridge, MA). Assays WCTO based on the manufacturer's instructions. Murine In Vitro Assay. Balb/c mice (Taconic, Gennantown, NY) were immunized with Mycobacterium tuberculosis H37Ra (Difco, Defroit, MI). The splenocytes were harvested 5 days and preared in RPMI medium stipplemented with 10% FCS and antibiotics in a flat bottom 96-well plate with 1 x 106 cells/well. The splenocytes were then stimulated with a combination of IFNy (60 ng/mL) and SAC (0.025%) [or LPS (20 fig/mL)] in the presence of a test compound. Ceil-free supematants were taken 24 h later for the measurement of cytokines. The preparation of compound and the assessment of cell viability were carried out as described above. Mouse IL-12 p70, IL-IO, IL-lp, and TNFa were measured using ELISA kits from Endogen, according to the manufacturer's instructions. The biological activities of pyrimidine compounds were tested on human PBMC or THP+l cells. Unexpectedly, some of the test compounds have ICso values as low as Example 43. /n vivo assays Treatment of adjuvant arthritis in rats: Adjuvant arthritis (AA) was induced in female Lewis rats by the intracutaneous injection (base of the tail) of 0.1 mL of a 10 mg/mL bacterial suspension made from ground, heat-killed Mycobacterium tuberculosis H37Ra suspended in incomplete Freund's adjuvant. Rats were given a test compound orally once a day for 12 days, starting the day following the induction. The developmait of polyarthritis was monitored daily by macroscopic inspection and assi+mient of an arthritis index to each animal, during the critical period (days 10 to 25 post-immunization). The intensity of polyarthritis was scored according to the following scheme: (a) Grade each paw from 0 to 3 based on erythema, swelling, and deformity of &e joints: 0 for no erythema or swelling; 0.5 if swelling is detectable in at least one joint; 1 for mild swelling and erythema; 2 for swelling and erythema of both tarsus and carpus; and 3 for ankylosis and bony deformity. Maximum score for all 4 paws was thus 12. (+) Grade for o&erpartsofthe body: for each ear, 0.5 for redn+s and another 0.5 if knots are present; 1 for connective tissue swelling (saddle nose); and I for the presence of knots or kinks in the tail. The highest possible arthritic index was 16. Oral administration of pyrimidine compounds of this invention (e.g.. Compound 12) reproducibly reduced the arthritic score and delayed the development of polyarthritis in a dose-dependent manner. The arthritis score used in this model was a reflection ofthe inflammatory state ofthe structures monitored and theresults - therefore show the ability of the test compound to provide relief for this aspect of the pathology. Treatment of Crohn's disease in dinitrobenzene sulfonic acid-induced inflammatory bowel syndrome model rats: Wistar derived male or female rats weighing 200 ± 20 g and fasted for 24 hours were used. Distal colitis was induced by intra-colonic instillation of 2,4-dinitrobenzene sulfonic acid (DNBS, 25 mg in 0.5 mL ethanol 30%) after which air (2 mL) was gently injected through the cannula to ensure that Ihe solution remained in the colon. A test compound and/or vehicle was administered orally 24 and 2 hours before DNBS instillation and then daily for 5 days. One control group" was similarly treated with vehicle alone while the other is treated with vehicle plus DKBS. The animals were sacrificed 24 hours after the final dose of test compound admirustration and each colon was removed and weigihed. Colon-to~ body weight ratio was then calculated for each animal according to the formula: Colon (g)/BW X 100. The "Net" increase in ratio of Vehicle-control + DNBS group relative to Vehicle-control group was used as a base for comparison with test substance treated groups and expressed as *'% Deduction." Pyrimidine compounds of this invention (e.g.. Compound 12) reproducibly had about 30% deductioa A 30% or more reduction in colon-to-body weight ratio, relative to the vehicle treated control group, was considered significant. Rats treated with test substance orally showed a marked reduction in the inflammatory response. These experiments were repeated three times and the effects were reproducible. Treatment of Crohn's disease in CD4* CD45Rb''+ T cell-reconstituted SCW colitis model mice: Spleen cells were prepared from normal female BALB/c mice. For cell purification, the following anti-mouse antibodies were used to label non-CD4'+ T ceUs: B220 (RA3-6B2), CDUb (Ml/70), and CD8a (53-+.72). All antibodies were obtained from BioSource (Camarillo, CA). M450 anti-rat IgG-coated magnetic beads (Dynal, Oslo, Norway) were used to bind the antibodies and negative selection was accomplished using an MPC-1 magnetic concentrator. Ilie enriched CD4* cells were then labeled for cell sorting with FITC-conjugated CD45RB (16A, Phaimingen, San DiegOi CA) and PE-conjugated CD4 (CT-CD4, Caltag, BurUngame, CA). CD4'+ CD45RB'+* cells were operationally defined as the upper 40% of CD45Rb-staining CD4+ cells and sorted iinder sterile conditions by flow cytomedy. Harvested cells were resuspended at 4+ 1 O+AnL in PBS and injected 100 +L intraperitoneally iato female C.B-17 SCID mice. Pyrimidine compounds of this invention (e.g.. Compound 12) and/or vehicle was orally administCTed once a day, 5 days per week, starting the day following the transfer. The transplanted SCID mice were weighed wedcly and their clinical condition was monitored. Colon tissue samples were fixed in 10% buffered formalin and embedded in paraffin. Sections (4 μm) collected from ascending, .transverse, and descending colon were cut and stained with hematoxylin and eosin. The severity of colitis was detenrdned based on histological examination of the distal colon sections, whereby the extent of colonic inflanamation was graded on a scale of 0-3 in each of four -criteria: crypt elongation, cell infiltration, dqiletion of goblet cells, and the number of crypt abscesses. LP lymphocytes were isolated from freshly obtmied colonic specimens. After removal of payer's patches, the colon was washed in Ca/Mg-fiee HESS, cut into 0.5 cm pieces and incubated twice in HESS containing EDTA (0.75 mM), DTT (1 mM), and antibiotics (amphotericin 2.5 p-g/mL, gentamicin 50 +g/mL flx)m Sigma) at SyC for 15 min. Next, the tissue was digested fiu+er in RPMI containing 0.5 mg/mL coUagenase D, 0.01 mg/mL DNase 1 (Boehringer Manheim), and aatibiotics at 37°C. LP cells were then layered on a 40-100% Percoll gradient (Phaimacia, Uppsala, Sweden), and lymphocyte-enriched populations were isolated from the cells at the 40-100% interface. To measure cytokine production, 48-well plates were coated with 10 jig/mL murine anti-CD3e antibody (145-2C11) in carbonate buffer (PH 9.6) overnight at 4*'C. 5xlO+LPceUs were then cultured in 0.5ml of complete medium in precoated wells in the presence of 1 fig/mL soluble anti-CD28 antibody (37.51). Purified antibodies were obtained from Pharmingai. Culture supematants were removed after 48 h and assayed for cytokine production. Murine IFNy was measured using an ELISA kit from +dogen (Cambridge, MA), according to the manufactuira's instnictions. Histological analysis showed that oral administration of pyrimidine compounds of tths invention (e.g., Compound 12) reduced colonic inflammation as compared to vehicle control. The supprrasive effect was dose-dependrait with a substantial reduction at a dose of 10 mg/kg. The calculated colon-to-body weight ratio was consistent with the histological score, showing atternation by treatment with the test compound. Furthennore, analysis of cytokines from LP cells in response to anti-CD3 antibody and anti-CD28 antibody demonstrated that LP cells from vehicle control produced an augmented level of IFNy and treatment with test substance greatly diminished the production. These results clearly demonstrated the potential of the test substance in treatment of inflammatory bowel disease represented hy Crohn's disease. OTHER EMOBDIMENTS All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features. From the above description, one skilled m the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adq)t it to various usages and conditions. For example, compoimds structurally analogous a pyrimidine compound described in the specification also can be made, screened for their inhibiting LL-12 activities, and used to practice this invention. Thus, other embodiments are also within the claims. WE CLAIM: 1. A compound of formula (I) wherein each of R2 and R4, independently, is Rc, halogen, nitro, cyano, isothionitro, SRc or ORc; or R2 and R4, taken together, is carbonyl; R3 is Rc, alkeny], alkyny], ORc OC(0)Rc, SO2Rc, S(0)Rc, S(02)NRcRd', SRc, NRcRd NRcCORd NRC(0)ORd, NRC(0)NRcR'd, NRcS02Rd CORc, C(0)ORc, or C(0)NRcRd; R5 is H or alkyl; n is O, 1,2, 3,4, 5, or 6; X is O,S,S(0), S(02),orNRc; Y is a covalent bond, CH2, C(0), C=N-Rc C=N-0RC C=N-SRC, O, S, S(0), S{02), or NRc; Z is N or CH; one of U and V is N, and the other is CRc; and W is O, S, S(0), S{02), NRc or NC{0)Rc; in which each of Ra and RB, independently, is H, alkyl, aryl, heteroaryl; and each of Rc and Rd, independently, is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl. 2. The compound as claimed in claim 1. wherein U is N and V is CH. 3. The compound as claimed in claim 1, wherein Z is N and W is O. 4. The compound as claimed in claim I, wherein X is O or NRc. 5. The compound as claimed in claim 1, wherein Y is a covalent bond, O, S, or CH2, and n is 0, 1,2, 3, or 4. 6. The compound as claimed in claim 5, wherein R3 is aryl or heteroaryl. 7. The compound as claimed in claim 5, wherein R3 is ORcSRc C(0)ORcNRcRd or C(0)NRcRd. in which each of A and A , independently, is O, S, or NH; each of Rc and Rf, independently is H, alkyl, aryl, or heteroaryl; and m is 1 or 2. Rg is H, halogen, CN, alkyl. cyclyl, alkyloxy, alkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, hydroxyalkyl, aikylamino, or alkylaminocarbony; R*' is H, halogen, NO2, CN, alkyl, aryl, heteroaryl, ORc, OC(0)Rc, SO2Rc, S(0)Rcc S(02)NRcRd SRc, NRcR'd, NRccOR'd, NRCC(o)ORd, NRcC(0)NRcR'd, NRCSOZRD, C0R\ C(0)0R', or C(0)NRcRd; R' is H, alkyl, or alkylcarbonyl; p isO, l,or 2; and q is 0, 1,2, 3,or 4. in which Rg, RH, RI, and q are as defined in claim 10; and the other of Ra and Rb is H or alkyl. 11. The compound as claimed in claim 10, wherein Rg is H, methyl, ethyl, propyl, cyclopropyl, methoxy, ethoxy, methoxycarbonyl or halogen; Rh is F, CI, CN, methyl, methoxy, ethoxy, 0C(0)CH3, OC(0)C2H5. C(0)OH, C(0)OC2H5, C(0)NH2, NHC(0)CH3, or S(02)NH2; R' is H, methyl, ethyl, or acetyl, and q is 0, ], or 2. 12. The compound as claimed in claim 11, wherein U is N, V is CH, Z is N, and W is O. 13. The compound as claimed in claim 12, wherein X is Nrc; and Rc is H, methyl, ethyl, or acetyl. 14. The compound as claimed in claim 13, wherein Y is a covalent bond, O, S, or CH2; and n is 0, 1,2, 3, or 4. 15. The compound as claimed in claim 14, wherein Rcc is Rc 0Rc SRc C(0)ORc, or C(0)NRcRd 16. The compound as claimed in claim 15, wherein R3 is aryl, heteroaiyl, hydroxyl, alkyloxy, or heteroaryloxy. 17. The compound as claimed in claim 1, wherein Rt is in which DisO,S,orNRm; RJ is benzo, halogen, CN, hydroxyl, alkyl, aryl, heteroaryl, alkoxyl, aryloxyl, or heteroaryioxyl; Rm is H, alkyl, or alkyJcarbonyJ; and r is 0, 1, or 2. 18. The compound as claimed in claim 17, wherein X is NRc; and Rc is H, methyl, ethyl, or acetyl. 19. The compound as claimed in claim 18, wherein U is N, V is CH, Z is N, and W isO. 20. The compound as claimed in claim 19, wherem Y is a covalent bond, O, S, or CH2;andnisO,l,2, 3,or4. 21. The compound as claimed in claim 20, wherein R3 is aryl or heteroaryl. 22. The compound as claimed in claim 20, wherein R3 is ORc, SRc C(0)ORc, NRCVD, or C(0)NRcRd 23. The compound as claimed in claim 20, wherein R3 is in which each of A and A, independently, is O, S, or NH; each of Re and Rf independently is H, alkyl, aryl, or heteroaryl; and m is 1 or 2. 24. The compound as claimed in claim 20, wherein R1 is in which Rmis H, alkyl, or alkylcarbonyl; RJ is methyl, ethyl, propyl, or benzo; and r is 1 or 2. 25. The compound as claimed in claim 1, wherein 26. The compound as claimed in claim 25, wherein X is NH. 27. The compound as claimed in claim 25, wherein one of Ra and RB is H or alkyl; and the other is aryl or heteroaryl optionally substituted with Rg and RH; RG being halogen, CN, alkyl, alkyloxy, alkyicarbonyl, alkyloxycarbonyl, aryloxycarbonyl, heieroaryloxycarbonyl, hydroxyalkyl, alkylamino, or alkylaminocarbonyl; R' being halogen, CN, hydroxy!, alkyl, aryl, heteroaryl, alkoxyl, aryloxyl, or heteroaryloxyl; and q being 0, 1, 2, 3, or 4. 28. The compound as claimed in claim 27, wherein one of Ra and Rb is H or alkyl; and the other is in which Rg is H, alkyl, alkoxyl, methoxycarbonyl, or halogen; Rhis halogen, CN, hydroxyl, alkyl, aryl, heteroaryl, alkoxyl, aryloxyl, or heteroaryloxyl; and q is O, 1,2, 3, or 4. 29. The compound as claimed in claim 25, wherein U is N, V is CH, Z is N, and W isO. 30. The compound as claimed in claim 29, wherein R3 is heteroaryl or heterocyclyl. 31. The compound as claimed in claim 30, wherein R3 is pyridinyl. 32. The compound as claimed in claim 30, wherein R3 is 1-oxy-pyridinyl 33. The compound as claimed in claim 30, wherein R3 is lH-pyridin-2-one. 34. The compound as claimed in claim 30, wherein n is 2, and Y is O 35. The compound as claimed in claim 34, wherein X is NH. 36. The compound as claimed in claim 35, wherein one of Ra and Rb is H or alkyl; and the other is in which Rg is H, alkyl, aikoxyl, methoxycarbonyl, or halogen; Rh is halogen, CN, hydroxyl, alkyl, aryl, heteroaryl, aikoxyl, aryloxyl, or heteroaryloxyl; and q is 0, 1, 2, 3, or 4. 37. The compound as claimed in claim 36, wherein one of Ra and Rb is H; and the other is in which Rg is as defined in claim 36. 38. The compound as claimed in claim 1, wherein the compound is: N-{2-[3-(3,4-dimethoxy-phenyl)-propyI]-6-morpholin-4-yl-pyrimidin-4-yl}-N'- (lH-indol-3-ylmethylene)-hydrazine, N-(2-n-butoxy-6-morpholin-4-yl-pyrimidin-4-yl)-N'-(lH-indol-3-yhnethylene)-hydrazine, N-(2-(4-hydroxybutyl)-6-morpholin-4-yl-pyrimidin-4-yl)-N'-(lH-indo|-3-yhnethylene)-hydrazine, N-[2-(2-[l,3Jdioxan-2-yI-ethyI)-6-morphotin-4-yI-pyrimidin-4-yI]-N'-(IH-indol-3-ylmethylene)-hydrazine N-(lH-indol-3-ylmethylene)-N'-[2-{3-methoxy-propyI)-6-morpholm-4-yl-pyriniidin-4-yl]-hydrazine. 3-{4-[N'-(lH-indol-3-ylraethylene)-hydrazinol-6-niorpholin-4-yl-pyriinidin-2-yIsulfanyI}-propan-l-ol, 3-{2-[N'-(lH-indol-3-ylmethylene)-hydrazino]-6-morpholin-4-yl-pyrimidin-4-ylsulfany 1} -propan-1 -ol, N-[2-(2,2-dimethyl-[l,3]dioxolan-4-ylmethoxy)-6-morpholin-4-yl-pyrimidin-4-yl]-N'-(lH-indol-3-yimethylene)-hydrazine, N-{2-[2-(3,4-dimethoxy-phenyl)-ethoxy]-6-morpholin-4-yl-pyrimidin-4-yl}-N'-(lH-indol-3-ylmethylene)-hydrazine, N-(lH-indol-3-ylmethylene)-N'-[6-morpholin-4-yl-2-(2-pyridin-2-yI-ethoxy)-pyrimidin-4-yiJ-hydrazine, N-(lH-indol-3-ylmethylene)-N'-[6-morpholin-4-yl-2-(3-pyridin-2-yl-propyl)-pyrimidin-4-y I]-hydrazine, N-(3-methyl-benzylidene)-N'-[6-morpholin-4-yl-2-(2-pyridin-2-yl-ethoxy)-pyrimidin-4-yI]-hydrazine, N-(3-ethyl-benzyiidene)-N'-[6-morpholin-4-yl-2-(2-pyridin-2-yl-ethoxy)-pyrimidin-4-yl]-hydrazine, N-(3-methyl-benzyHdene)-N'-[6-morphoUn-4-yl-2-(3-pyridin-2-yl-propyl)-pyrimidin-4-yl]-hydrazine, N-[6-morpholin-4-yl-2-{2-pyridin-2-yl-ethoxy)-pyrimidin-4-yl]-N'-(l-m-tolyl-ethylidene)-hydrazine, N-[l-(lH-indol-3-yI)-elhylidene]-N'-[6-morpholin-4-yl-2-{2-pyridin-2-y|-ethoxy)-pyriinidin-4-y I]-hydrazine, 3-methyi-benzaIdehydeO-[6-morphoIin-4-yI-2-(2-pyridin-2-yl-ethoxy)-pyrimidin-4-yl]-oxime, lH-indole-3-carbaldehyde 0-[6-morpholin-4-yl-2-{2-pyridin-2-yl-ethoxy)-pyrimidin-4-yl]-oxime, N-(IH-indoi-3-yImethyIene)-N'-{6-morpholin-4-yi-2-[2-(pyridin-3-yioxy)-ethoxy]-pyrimidin-4-yl} -hydrazine, N-(3-methyI-benzylidene)-N'-{6-morpholin-4-yl-2-[2-(pyridin-3-yloxy)-ethoxy]-pyriniidin-4-y 1} -hydrazine, butyl-{4-[N'-(lH-indol-3-ylmethylene)-hydrazino]-6-morpholin-4-yl-pyrimidin-2-yI}-amine, N-(3-methyl-benzylidene)-N'-[6-inorpholin-4-yl-2-(pyridin-3-yloxy)-pyrimidin-4-yl]-hydrazine, N-(3-methyl-benzylidene)-N'-(5-methyl-6-morpholin-4-yl-2-phenylpyrimidin-4-yl)hydrazine, N-(3-methy]-benzylidene)-N'-(2-phenyl-6-thiomorpholin-4-yl-pyriniidin-4-yl)hydrazine, {2,3-dimethyI-lH-indole-5-yl)-{6-morpholin-4-yl-2-[2-pyridin-3-yloxy)-ethoxy]-pyrimidin-4-yI} -amine, (2,3-dimethyI-lH-indole-5-yl)-{4-morpholin-4-yl-6-[2-pyridm-3-yloxy)-ethoxy]-pyrimidin-2-yl} -amine, 3-{4-[N'-(3-methyl-benzylidene)-hydrazino]-6-morpholin-4-yl-pyrimidin-2-yl}-propionic acid ethyl ester, N-(3-methyl-benzylidene)-N'-{6-morpholin-4-yl-2-[2-(l-oxy-pyridin-2-yl)-ethoxy]pyrimidin-4-yl}-hydrazine, l-(2-{4-[N'-(3-methyl-benzyiidene)-hydrazino]-6-morpholin-4-yl-pyrimidin-2-yloxy}-ethyl)-l//-pyridin-2-one, N-(3-iodo-benzylidene)-N'-[6-morphoUn-4-yl-2-(2-pyridin-2-yl-ethoxy)-pyrimidin-4-yl]-hydrazine, N-(3-fluoro-benzylidene)-N'-[6-morpho!in-4-yl-2-(2-pyridin-2-yl-ethoxy)-pyrimidin-4-yl]-hydrazine, N-(3-chloro-benzyIidene)-N'-[6-morphoh'n-4-yI-2-(2-pyridin-2-yI-ethoxy)-pyrimidin-4-yl]-hydrazine, N-(3-bromo-benzyUdene)-N'-[6-morpholin-4-yl-2- (2-pyridin-2-yl-ethoxy)-pyrimidin-4-yI]-hydrazine, 3-{[6-morpholin-4-yl-2-(2-pyridin-2-yl-ethoxy)-pyrimidin-4-yl]-hydrazonomethyl}-benzoic acid methyl ester, l-(2-{4-[N'-(3-iodo-benzylidene)-hydrazino]-6-moTpholin-4-yl-pyriniidin-2-yloxy}-ethyl)-lH-pyridin-2-one, 3-{[6-morpholin-4-yl-2-{2-pyridin-2-yl-ethoxy)-pyrimidin-4-yl]-hydrazonomethyl}-benzoic acid N-melhyl amide, (3-{[6-morpho!in-4-yl-2-(2-pyridin-2-yl-ethoxy)-pyrimidin-4-yi]-hydrazonomethyl}-phenyl)-methanol, N,N-Diethyl-4-{4-[N"-(3-methyl-benzylidene)-hydrazino]-6-morpholin-4-yl-pyrimidin-2-yl} -butyramide, 4-{4-[N'-(3-Methyl-benzyIidene)-hydrazino]-6-morphoIin-4-yl-pyrimidin-2-yl} -1 -(4-methyl-piperazin-1 -yl)-butan-1 -one, 4-{4-[N'-{3-Methy 1-benzy lidene)-hydrazino]-6-morpholin-4-yl-pyrimidin-2-yl} -N-pyridin-4-ylmethyl-butyramide, or 4-{4-[N-(3-Methyl-benzylidene)-hydrazino]-6-morpholin-4-yl-pyrimidin-2-yl}-N-pyridin-4-yl-butyramide.

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