PYRIMIDINE CARBOXAMIDES AND RELATED COMPOUNDS AND METHODS FOR TREATING INFLAMMATORY CONDITIONS

Abstract: Compounds having utility as anti-inflammatory agents in general and, more specifically, for the prevention and/or treatment of immuno-inflammatory and autoimmune diseases are disclosed. The compounds are pyrimidine- or pyrazine-containing compounds and, in one embodiment, are carboxyamides of the same. Methods are also disclosed for preventing and/or treating inflammatory conditions by administering to an animal in need thereof and effective amount of a compound of this invention, preferably in the form of a pharmaceutical composition.

Description: Description PYRIMIDINE CARBOXAMIDES AND RELATED COMPOUNDS AND METHODS FOR TREATING INFLAMMATORY CONDITIONS Technical Field The present invention relates generally to compounds that block intracellular signal transduction and activation of transcription factors, and to methods for preventing or treating immunoinflammatory and autoimmune diseases. Background ofthe Invention Signals necessary for cell growth, differentiation, response to bioregulatory molecules, infectious agents and physiological stress involve changes in the rates of gene expression. The ability to respond appropriately to such signaling events challenge the survival of the cell and ultimately the organism. Perturbations in the normal regulation of these specific genetic responses can result in pathogenic events which lead to acute and chronic disease. In certain autoimmune diseases or chronic inflammatory states, continuous activation of T-cells eventually leads to a self-perpetuating destruction of normal tissues or organs. This is caused by the induction of adhesion molecules, chemotaxis of leukocytes, activation of leukocytes and the production of mediators of inflammation. All of these events are regulated at the level of transcription for the production of new proteins, including cytokines. The production of cytokines, as well as a number of other cellular regulators, is controlled by a family of proteins known as transcription factors (TFs). These transcription factors, when activated, bind to specific regions on the DNA and act as molecular switches or messengers to induce or upregulate gene expression. The activation of these TFs is caused by a variety of external signals including physiological stress, infectious agents and other bioregulatory molecules. Once the plasma membrane receptors are activated, a cascade of protein kinases and second messengers are induced which, in turn, result in the production of RNA transcripts. The end result is the production of proinflammatory proteins via translation and processing ofthe RNA transcripts. This activation system can, at times, be very robust. For example, a specific set of external signals could result in a single transcription factor to induce many proteins responsible for a given disease. Therefore, regulating this process by disrupting the production of activated TF(s) has the potential to attenuate the production of the associated pathological proteins, thereby halting or reversing the course ofthe disease. Two transcription factors, NFKB and AP-1, have been shown to regulate the production of many proinflammatory cytokines and related proteins that are elevated in immunoinflammatory diseases. These TFs regulate interieukin- 1 (LL-1), interleukin-2 (IL-2), tumor necrosis factor-α (TNFα), interleukin-6 (BL-6) and interleukin-8 (LL-8) levels in a variety of cell types. For example, NFKB and other related complexes are involved in the rapid induction of genes whose products function in protective and proliferative responses upon exposure of cells to external stimuli. Similarly, AP-1 has a significant role in the regulation of interleukin-2 (LL-2) and tumor necrosis factor-α (TNF-α) transcription during T-cell activation. In addition, TNF-α and IL-1 are strong activators of collagenase, gelatinase and stromelysin gene expression, which require a single AP-1 binding site in the promoter region of these genes. Therefore, an inhibitor of NFKB and/or AP-1 activation would coordinately repress the activities of a series of proteinases. In addition, cell adhesion molecules are also controlled by these TFs. All of these proteins have been shown to play a role in diseases, including osteoarthritis, transplant rejection, ischemia, reperfusion injury, trauma, certain cancers and viral disorders, and autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, glomerulonephritis, lupus and juvenile diabetes. In summary, the role of these TFs is to act as a transducer for certain stimuli that lead to immune, inflammatory, and acute phase responses. Since many diseases are caused by the inappropriate production of proteins, conventional therapeutic approaches have focused on inhibiting function or activity of individual effector proteins. These treatments have not always proved to be effective and, at times, are associated with many undesirable side effects. Therefore, there is a need for new therapies for the prevention and/or treatment of immunoinflammatory and autoimmune diseases. More specifically, there is a need for compounds that prevent, preferably by inhibiting transcription at an early stage, the production of proteins associated with immunoinflammatory and autoimmune diseases. Furthermore, these compounds should inhibit the kinase(s) that regulate the activation of TFs such as NFKB and AP-1. The present invention fulfills these needs and provides further related advantages. Summary ofthe Invention In brief, this invention is directed to compounds that block the activation of transcription factors (TFs), particularly NFKB and AP-1, and are believed to function through inhibition of a family of specific kinases. This results in a decrease in a number of proinflammatory proteins, including LL-1, LL-2, LL-8 and/or TNFα, which are responsible for tissue and organ damage associated with diseases such as rheumatoid arthritis, osteoarthritis, related autoimmune disorders and tissue rejection. Accordingly, compounds of the present invention are useful in, for example, the prevention of organ and tissue rejection associated with transplantation. Furthermore, the compounds of this invention also have utility in the prevention and/or treatment of immunoinflammatory and autoimmune diseases, as well as having general activity as anti-inflammatory agents. In one embodiment of this invention, compounds are disclosed having the following general structure (I): (I) wherein A is C-Rβ when B is N, and A is N when B is C-Ri, and wherein Ri, R 2 , Rt, R 5 and Rβ are as defined in the following detailed description. In another embodiment, a pharmaceutical composition is disclosed containing one or more compounds of this invention in combination with a pharmaceutically or prophylactically acceptable carrier or diluent. In a further embodiment, methods are disclosed for preventing and/or treating inflammatory conditions by administering to a warm-blooded animal in need thereof an effective amount of a compound of this invention. Such inflammatory conditions include both immunoinflammatory conditions and autoimmune diseases. In the practice ofthe disclosed methods, the compounds are preferably administered to the warm-blooded animal in the form of a pharmaceutical composition. These and other aspects of this invention will become evident upon reference to the attached figures and the following detailed description. Brief Description ofthe Drawings Figure 1 illustrates a reaction scheme for the synthesis of representative pyrimidine-containing compounds of this invention. Figure 2 illustrates a reaction scheme for the synthesis of representative pyrazine-containing compounds of this invention. Figure 3 illustrates the ability of a representative compound of this invention to inhibit the activation of NFKB and AP-1. Figure 4 illustrates the ability of a representative compound of this invention to inhibit LL-2 and LL-8. Figure 5 illustrates the ability of a representative compound of this invention to cause a dose-dependent suppression of alloantigen-induced PLN proliferation. Detailed Description ofthe Invention As mentioned above, the compounds of this invention block activation of transcription factors (TFs), and thus have utility as anti-inflammatory agents in general, and in the prevention and/or treatment of a variety of conditions, including (but not limited to) immunoinflammatory and autoimmune diseases. The compounds are believed to function by inhibiting, at an early stage, transcription of deleterious proteins associated with such conditions or diseases. It is believed that this is achieved by inhibiting the kinase(s) that regulate the activation of TFs, such as NFKB and/or AP-1. By disrupting the production of these activated TFs, synthesis of pathological proteins, including proinflammatory cytokines, associated with a series of immunoinflammatory and autoimmune diseases are effectively blocked at a transcriptional level. Accordingly, the compounds of this invention have activity in both the prevention and treatment of immunoinflammatory diseases such as rheumatoid arthritis, osteoarthritis and transplant rejection (tissue and organ), as well as autoimmune diseases such as multiple sclerosis. The compounds of this invention are generally represented by the following general structure (I): (I) wherein A is C-Rβ when B is N, and A is N when B is C-Ri, and wherein Ri, R 2 , R,, R 5 and Rβ are as defined below. Thus, when A is C-Rβ and B is N, structure (I) is a pyrimidine-containing compound having structure (II), and when A is N and B is C-Ri, structure (I) is a pyrazine-containing compound having structure (III): (π) (III) In structures (I), (II) and (UI) above, R 5 is selected from the following chemical moieties (i) through (iv): (0 (ϋ) (iii) (iv) wherein R 7 is selected from hydrogen, -CH 3 and -CH 2 CβHs; and Rg is selected from hydrogen and an unsubstituted or substituted Ci-galkyl, Cβ-naryl, C .ι 2 aralkyl, C 3- ι 2 heterocycle and a C .i6heterocyclealkyl. The compounds of this invention further include pharmaceutically and prophylactically acceptable salts of compounds of structure (I). Compounds of structure (I) may contain proton donating groups (e.g., a carboxylic acid group) and/or proton accepting groups (e.g., a group with a nitrogen atom having a free lone pair of electrons, such as an amine group), and the salts of compounds of structure (I) may be formed and utilized in the practice ofthe invention. Thus, compounds ofthe invention may be in the form of a base addition salt (i.e., a salt of a proton donating group) or in the form of an acid addition salt (i.e., a salt of a proton accepting group), as well as the free acid or free base forms thereof. Acid addition salts of a free base amino compound of the invention may be prepared by methods well known in the art, and may be formed from organic and inorganic acids. Suitable organic acids include acetic, ascorbic, benzenesulfonic, benzoic, fumaric, maleic, methanesulfonic, and succinic acids. Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric and nitric acids. Base addition salts of a free acid carboxylic acid compound of the invention may also be prepared by methods well known in the art, and may be formed from organic and inorganic bases. Thus, the compounds of this invention also include those salts derived from inorganic bases such as the hydroxide or other salt of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like, and organic bases such as substituted ammonium salts. As used herein, the above terms have the following meaning: A "Ci-salkyl" is a straight chain or branched, cyclic or non-cyclic, saturated or unsaturated carbon chain containing from 1 to 8 carbon atoms. In one embodiment, the Ci-galkyl is a fully saturated, straight chain alkyl selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl. In another embodiment, the Ci-galkyl is a fully saturated cyclic alkyl selected from (but not limited to) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylenecyclopropyl and methylenecyclohexyl. In still a further embodiment, the Ci-galkyl is a fully saturated, branched alkyl selected from (but not limited to) isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl and isohexyl. In yet a further embodiment, the Ci-galkyl is an unsaturated straight chain alkyl selected from (but not limited to) ethylenyl, propylenyl, 1-butenyl, 1 -pentenyl and 1-hexenyl. A "Cβ-i ∑ aryl" is an aromatic moiety containing from 6 to 12 carbon atoms. In one embodiment, the Cβ-πaryl is selected from (but not limited to) phenyl, tetralinyl, and napthalenyl. In a preferred embodiment, the C 6 -ι 2 aryl is phenyl. A "C .i 2 aralkyl" is an arene containing from 7 to 12 carbon atoms, and has both aliphatic and aromatic units. In one embodiment, the C 7- ι 2 aralkyl is selected from (but not limited to) benzyl, ethylbenzyl, propylbenzyl and isobutylbenzyl. A "C 3- ι 2 heterocycle" is a compound that contains a ring made up of more than one kind of atom, and which contains 3 to 12 carbon atoms. In one embodiment, the C 3 -ι 2 heterocycle is selected from (but not limited to) pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyrrolidinyl, pyridinyl, pyrimidinyl and purinyl. In a further embodiment, the C 3 .ι 2 heterocycle includes the following structures: A is a compound that contains a C3-ι 2 heterocycle linked to a Ci-galkyl. In one embodiment, the C .ιβheterocyclealkyl is a methylene furan having the following structure: A "substituted" Cβ-i∑aryl, C 7 . 12 aralkyl, C3-i 2 heterocycle or Gnβheterocyclealkyl is a Ci-galkyl, C 7 .i 2 aralkyl, C 3 -i2heterocycle or C-nβheterocyclealkyl having one or more hydrogens replaced with a substituent selected from halogen (including -F, -Cl, -Br and -I), -OH, -R, -OR, -COOH, -COOR, -COR, -CONH2, -NH 2 , -NHR, -NRR, -SH, -SR, -SOOR, -SO 3 R and -SOR, where each occurrence of R is independently selected from an unsubstituted or substituted Cι.galkyl, Cβ-naryl, C 7 .ι 2 aralkyl, C 3 -i2heterocycle or as defined above. In one embodiment, the substituted Cι -8 alkyl is a Ci-ghaloalkyl including (but not limited to) -CF 3 and -C 2 F 5 . In structure (II) above, R2a is selected from halogen, an unsubstituted or substituted Ci-galkyl, Cβ-naryl, C 7 .ι 2 aralkyl, C 3 -i2heterocycle or Gnβheterocyclealkyl, -CN, -OR, -NHR, -NRR and -NRNCOR, wherein each occurrence of R is independently selected from an unsubstituted or substituted Ci-galkyl, Cβ-i∑aryl, C .ι 2 aralkyl, C 3 -i2heterocycle or Gnβheterocyclealkyl as defined above. In one embodiment, R2, is selected from -Cl, -F, -CN and -CF 3 . In structure (III) above, R2 b is halogen, such as -Cl or -F. In structure (II) above, R^ is selected from hydrogen, halogen, an unsubstituted or substituted Cι.galkyl, Cβ-ι 2 aryl, C 7 -i2aralkyl, Cs-πheterocycle or -CN, -OR, -NHR, -NRR and -NRNCOR, wherein each occurrence of R is independently selected from an unsubstituted or substituted Ci-galkyl, Cβ-i 2 aryl, C 7 .i 2 aralkyl, C 3 .i 2 heterocycle or O-iβheterocyclealkyl as defined above. In one embodiment, R a is selected from hydrogen, -CH 3 , -CF 3 , -C 2 F 5 , -C 2 H 5 , -C 6 H 5 and In structure (III) above, is selected from hydrogen, halogen, -CN, and an unsubstituted or substituted Cι.galkyl, Cβ-naryl, C 7 .ι 2 aralkyl, C 3 -i2heterocycle or In structures (I) and (II) above, Rβ is selected from hydrogen, halogen, and an unsubstituted or substituted Ci-galkyl, including (but not limited to) a Ci-ghaloalkyl (such as -CF 3 and -C 2 F 5 ). In one embodiment, Rβ is selected from hydrogen, -Cl, -F, -CH 3 and -CF 3 . In structures (I) and (III) above, Ri is selected from hydrogen, -CH 3 , -CF 3 and -C 2 H 5 . In one embodiment, the compounds of this invention have structure (II) above, wherein Ri is the chemical moiety (i). In this embodiment, the compounds disclosed herein have the following structure (IV): (IV) where R2,, R4a, Rβ, R7 and Rg are as defined above. In a preferred embodiment, representative compounds of structure (IV) contain za, R- , Rβ, 7 and Rg moieties as identified in Table 1 below. Table 1 Compounds of Structure (IV) -Cl -CF 3 -H -H -H -F -CH 3 -N(CH 3 ) 2 -CH 3 -Cl -CF 3 -H -NHPh wherein X, Y and Z are the same or different, and independently selected from hydrogen, - OH, -R, -OR, - COOH, -COOR, -COR, -CONH 2 , -NH 2 , -NHR, -NRR, -SH , -SR, -SOOR, ■ -SO 3 R and -SOR, where each occurrence of R is independently selected from an unsubstituted or substituted Cι. 8 alkyl, Cβ-ι 2 aryl, C .ι 2 aralkyl, C 3 .i 2 heterocycle or Gj-iβheterocyclealkyl. In a preferred embodiment ofthe compounds disclosed in Table 1 above, X, Y and Z are the same or different, and independently selected from -H, -Cl, -F, -CF3, -OH, -CH3 and -OCH 3 . In a further preferred embodiment, Rg is a 3,5- bis(trifluoromethyl)phenyl moiety or a 3-trifluoromethyl-5-halo-phenyl moiety. As mentioned above, in one embodiment of this invention the compounds have structure (II). Within one aspect of this embodiment, u is -CF 3 and R- & is -Cl. Such compounds include (but are not limited to): 2-chloro-4-trifluoromethyl-5-N-(3 l ,5'- bistrifluoromethylphenyl)pyrimidine carboxamide; 2-chloro-4-trifluoromethyl-5-N-(3',5 I - dichlorophenyl)pyrimidine carboxamide; 2-chloro-4-trifluoromethyl-5-N-(4'- trifluoromethylphenyl)pyrimidine carboxamide; 2-chloro-4-trifluoromethyl-5-N- (phenyl)pyrimidine carboxamide; 2-chloro-4-trifluoromethyl-5-N-(cyclohexyl)pyrimidine carboxamide; 2-chloro-4-trifluoromethyl-5-N-(3',4',5'-trichlorophenyl)pyrimidine carboxamide; 2-chloro-4-trifluoromethyl-5-N-(benzyl)pyrimidine carboxamide; 2-chloro- 4-trifluoromethyl-5-N-(4 , -(2 , , ,3 , -benzothiadiazole))pyrimidine carboxamide; 2-chloro- 4-trifluoromethyl-5-N-(3',5'-dichloro-6 , -hydroxyphenyl)pyrimidine carboxamide; 2- chloro-4-trifluoromethyl-5-N-(5'-(3 , -methylisoxazole))pyrimidine carboxamide; 2- chloro-4-trifluoromethyl-5-N-(3'-N-acyl-4'-fluoroaniline)pyrimidine carboxamide; 2- chloro-4-trifluoromethyl-5-N-(3-trifluoromethyl-5 l -ethoxycarbonylphenyl)pyrimidine carboxamide; 2-chloro-4-trifluoromethyl-5-N-(3'-trifluoromethyl-5- (carboxamide)phenyl) pyrimidine carboxamide; 2-chloro-4-trifluoromethyl-5-N-(3',5'- dichlorophenyl)-N-(methyl)pyrimidine carboxamide; and 2-chloro-4-trifluoromethyl-5- N-(3 ', 5'-dichlorophenyl)-N-(benzyl)pyrimidine carboxamide. Within another aspect of this embodiment, is -CF 3 and R 2 a is a moiety other than -Cl. Such compounds include (but are not limited to): 2-fluoro-4- trifluoromethyl-5-N-(3',5'-bistrifluoromethyl)pyrimidine carboxamide, 5-(3',5'- bis(trifluoromethyl)phenacyl)-2-methoxy-4-trifluoromethylpyrimidine; 4-trifluoromethyl- 5-N-(3',5'-dichlorophenyl)pyrimidine carboxamide; 2-dimethylamino-4-trifluoromethyl- 5-N-(3',5 l -dichlorophenyl)pyrimidine carboxamide; 2-triethylammonium chloride-4- trifluoromethyl-5-N-(3',5'-dichlorophenyl)pyrimidine carboxamide; 2-cyano-4- trifluoromethyl-5-N-[3\5^bistrifluoromethyl)phenyl]pyrimidine carboxamide; 2- hydrazino-4-trifluoromethyl-5-[N-(3',5 , -dichlorophenyl)pyrimidine-5-carboxamide; 2-[N- (l-Aminocitraconamide)]-4-trifluoromethyl-5-p > J-(3',5'-dichlorophenyl) pyrimidine-5- carboxamide; and 2-aminophenyl-4-trifluoromethyl-N-(3',5 , -dichlorophenyl)pyrimidine- 5-carboxamide. Within yet a further aspect of this embodiment, R-j, is -Cl and t, is a moiety other than -CF . Such compounds include (but are not limited to): 5-N-(3',5'- bis(trifluoromethyl)phenyl)-2,4-dichloro-6-methyl-pyrimidine carboxamide; 2-chloro-4- methyl-5-N-(3 l ,5 , -(bistrifluoromethyl)phenyl)pyrimidine carboxamide; 2,4-dichloro-5-N- (S'.S'-bis^rifluoromethy benzy pyrimidine-S-carboxamide; and 2-chloro-4-phenyl-5-N- (3\5'-(bistrifluoromethyl)phenyl)pyrimidine carboxamide. In another embodiment, the compounds of this invention have structure (III) above. Within one aspect of this embodiment, Ri is selected from hydrogen, -CH3 and -CF 3 . Such compounds include (but are not limited to) pyrazine-containing compounds which correspond to the pyrimidine-containing compounds disclosed above. In one embodiment of structure (III), b is -Cl, ib is -CF 3 and R 5 is a moiety of structure (i) above. A small number of compounds which fall within structure (I) above have been previously disclosed and/or are commercially available. However, such compounds have not been associated with the utilities of the present invention, or possess no recognized utility. Accordingly, compounds that fall within the scope of structure (I), and which have recognized utility, are specifically excluded from the novel compounds of structure (I). However, to the extent such compounds have not been disclosed for the utilities of the present invention, they are included in the various methods of this invention. To this end, the novel compounds of this invention do not include compounds of structure (IV) above where R 7 and Rg are both hydrogen, and where R-* * is selected from an unsubstituted, straight chain or branched, non-cyclic, saturated C 1 .3 alkyl (i.e., -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 and -CH(CH 3 ) 2 ), -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 and -OR, where R is as defined above. Similarly, the novel compounds of structure (IV) are subject to the following provisos: (a) when R-* is -Cl and Rβ is -H, R- a is not -CF 3 , -Cl, -CH 3 or -C(CH 3 ) 3 , (b) when R2a is -Cl and both R4, and Rβ are -H, Rg is not -CH(CN)CβH 5 or -(CH 2 ) 5 CH 3 , and (c) when R^ is -Cl and R 4a is -Cl, Rβ is not -Cl or The novel compounds of this invention also do not include compounds of structure (II) when R 5 is moiety (iii) and (a) R∑a is -CH 3 , -OCH 3 or -N(CH 3 ) 2 , or (b) Rg is -H or -CH 3 . Furthermore, the novel compounds of structure (III) when R 5 is moiety (i) are subject to the following proviso: when R2b is -Cl, H, and Ri are not both hydrogen. The compounds of this invention may be made by one skilled in organic synthesis by known techniques, as well as by the synthetic routes disclosed herein. For purpose of convenience, the compounds have been separated into pyrimidine-containing (structure (II)) and pyrazine-containing (structure (III)) compounds as set forth below. The pyrimidine-containing compounds of this invention may be prepared as illustrated by the reaction scheme of Figure 1. In general, commercially available β-keto esters 1 are heated at elevated temperatures (75-110°C) with a mixture of urea and triethylorthoformate (or a substituted orthoformate) to provide ureido derivatives 2. Treatment of these intermediates with sodium alkoxides, such as sodium ethoxide in an alcoholic solvent at 35-100°C, gives 2-hydroxypyrimidine esters 3 which, upon treatment with a chlorinating agent such as phosphorous oxychloride at elevated temperatures (75-120°C), yields 2-chloropyrimidine esters 4. The 2-hydroxypyrimidine esters 3 may also be treated with a mild base, such as lithium hydroxide, sodium hydroxide or potassium carbonate to provide the corresponding acid 3A, which may then be converted with a chlorinating agent, such as phosphorous oxychloride or thionyl chloride in an inert solvent or neat at 25-75°C, to the acid chloride 5. Compounds of structure 6 may be prepared using standard conditions known in the art by reacting the acid chloride 5 with an amine in the presence of a base, such as potassium carbonate or dimethylaminopyridine (DMAP), in a non-protic solvent, such as methylene chloride or EtOAc at 25-40°C, followed by standard workup. Alternatively, pyrimidine-containing compounds of this invention may also be made by the following combinatorial procedure. Commercially available and/or readily synthesized amines, anilines and related compounds may be reacted with the acid chloride 5 in EtOAc in the presence of basic Amberlyst 21 resin. The reactions are quenched with 50 μL of water and the final products are obtained in the organic layer and concentrated. This procedure may be done in a 96 well (1 mL deep well) plate and the final products isolated as dry powders. TLC analysis is performed on each compound and indicates the purity, and GC MS and HPLC analysis demonstrates that the desired products are synthesized (mass spectral analysis, molecular weight) and are greater than 80% pure. By this method, eighty distinct pyrimidine-containing compounds may be routinely synthesized at the same time in one 96 well plate. In addition, compound 4 may be reacted with various nucleophiles in an aprotic solvent and at ambient temperature to provide derivatives 7. These compounds can be hydrolyzed with base to yield compounds having structure 8. Compounds of structure 8 can be converted to the acid chloride as described above, and reacted with various amines to give compounds having structure 9 using known conditions, including the combinatorial approach described above. Alternatively, compounds of structure 7 can also be prepared by reacting the β-keto ester 1 in a sequential fashion with triethylorthoformate and acetic anhydride or N,N-dimethylformamide dimethyl acetal in DMF to give intermediate 10. Reacting intermediate 10 with a variety of amidines in alcoholic solvents provides intermediate 11 which, upon addition of base, provides compounds of structure 7. Pyrazine-containing compounds of structure (III) may be prepared as illustrated by the reaction scheme of Figure 2. The synthesis of these compounds may begin with readily available pyruvic acid derivatives 12. These compounds are condensed with commercially available 2-cyano-l,2-diamino-2-substituted ethenes 13 in an alcoholic solvent (such as MeOH) in the presence of an acid (such as HCl) at ambient temperatures (25-60°C) to provide the cyano pyrazines of structure 14. The pyrazines may then be converted to the corresponding carboxylic acids 15 using a strong base such as sodium hydroxide in water, or a strong acid such as HCl, at elevated temperatures (70-110°C). These carboxylic acids may then be converted to 5-chloro-2-carbonyl acid chloride derivatives 16 using a chlorinating agent such as POCI3 or SOCI2. Treatment of 16 with various amines or anilines at ambient temperatures in an inert solvent such as EtOAc or CH2CI2 provides compounds of structure 17. The carboxylic acids of structure 15 can also be converted to the hydroxy ester 18 by treatment with SOCl 2 and MeOH at a temperature of 25-60°C . Treatment of 18 with a chlorinating agent such as SOCl 2 or POCl 3 in the presence of DMF gives the chloro ester 19. Compound 19 can also be converted to the acid chloride 16 using a mild base such as potassium carbonate in an a protic solvent such as MeOH, followed by treatment with a chlorinating agent such as oxalyl chloride in an inert solvent such as methylene chloride at ambient temperatures. The pyrazine-containing compounds of this invention may also be synthesized by appropriate combinatorial techniques as described. In short, commercially available and/or readily synthesized amines, anilines and related compounds may be reacted with the acid chloride 16 in EtOAc in the presence of basic Amberlyst 21 resin. The reactions are quenched with 50 μL of water and the final products are obtained in the organic layer and concentrated. This procedure may be done in a 96 well (1 mL deep well) plate and the final products isolated as dry powders. TLC analysis is performed on each compound and indicates the purity, and GC and HPLC analysis demonstrates that the desired products are synthesized (mass spectral analysis, molecular weight) and are greater than 80% pure. By this method, eighty pyrazine-containing compounds may be routinely synthesized in one 96 well plate. Once synthesized, the compounds of this invention may be formulated for administration to a warm-blooded animal by a variety of techniques known to those skilled in the art. In one embodiment, the compound is in the form of a pharmaceutical composition for prophylactic or therapeutic use, and which contains at least one compound of this invention in combination with a pharmaceutically acceptable carrier or diluent. The compound is present in the composition in an amount which, upon administration to the animal, is effective in preventing or treating the condition of interest. Preferably, the composition includes a compound of this invention in an amount ranging from 0.01 mg to 250 mg per dosage, depending upon the route of administration, and more preferably from 1 mg to 60 mg. Appropriate concentrations, dosages and modes of administration may be readily determined by one skilled in the art. Suitable carriers or diluents are familiar to those skilled in the formulation field. For compositions formulated as liquid solutions, acceptable carrier or diluents include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostats and other common additives. The compositions of this invention may also be formulated as pills, capsules, granules or tablets which contain, in addition to the compound of this invention, diluents, dispersing and surface active agents, binders and lubricants. One skilled in the art may further formulate the compounds of this invention in any appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington 's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1990 (incorporated herein by reference). In another embodiment, the present invention provides methods for preventing or treating a variety of conditions. Such methods include administering a compound of this invention to a warm-blooded animal in need thereof in an amount sufficient to prevent or treat the condition. Such methods include systemic administration of a compound of this invention, preferably in the form of a composition as disclosed above. As used herein, systemic administration includes oral and parental methods of administration. For oral administration, suitable pharmaceutical compositions include powders, granules, pills, tablets and capsules, as well as liquids, syrups, suspensions and emulsions. These compositions may also include flavorants, preservatives, suspending, thickening and emulsifying agents, and other pharmaceutically acceptable additives. For parental administration, the compounds of the present invention may be prepared in aqueous injectable solutions which may contain, in addition to the compound of this invention, buffers, antioxidants, bacteriostats and other additives commonly employed in such solutions. As mentioned above, compounds ofthe present invention can be used to prevent or treat a wide variety of disorders, diseases and/or illnesses. In particular, the compounds may be administered to a warm-blooded animal for prevention or treatment of rheumatoid arthritis, osteoarthritis, tissue and/or organ transplant rejection, sepsis, ARDS, asthma, trauma, oxidative stress, cell death, irradiation damage, ischemia, reperfusion, cancer, viral infection, and autoimmune diseases such as psoriasis, inflammatory bowel disease, glomerulonephritis, lupus, uveitis and chronic hepatitis. Compounds of this invention may be screened by known and accepted techniques for their ability to function as prophylactically and/or therapeutically active agents. For example, the compounds may be evaluated in in vitro and/or in vivo assays indicative of the compound's antinflammatory and immunosuppressive properties. To this end, such compounds may first be evaluated in a number of cell-based assays which determine the ability of a compound to prevent activation of NFKB and AP-l(5ee Example 56). Next, the compound's ability to attenuate cytokine levels (such as LL-2 and LL-8), which are known to be elevated in certain disease states, may be determined (see Example 57). The compounds may then be evaluated in an appropriate animal model, including rodent models of inflammation and immunosuppression (see Example 58). It should be recognized that, for example, in the case of immunosuppressive drugs and other agents which have utility for the treatment of rheumatoid arthritis (RA), numerous studies have been performed directed to the activity of such drugs. To this end, cyclosporin A has been used in clinical trials since the late 1970's as a second-line drug and is recommended to be used only in patients with active RA. Thus, Experiment 58 was performed utilizing cyclosporin A as a positive control. A recent review of such immunosuppressive drugs, including relevant assays for the same, is presented by R P. Carlson in Exp. Opin. Invest. Drugs 4(9):853-859, 1995 (incoφorated herein by reference in its entirety, including cited references). The following examples are presented for purpose of illustration, not limitation. EXAMPLES To summarize the examples that follow, Examples 1-54 disclose the synthesis of representative compounds of this invention, as well as intermediates thereof; Example 55 discloses the synthesis of representative compounds by combinational chemistry techniques; Examples 56-57 disclose the ability of representative compounds of this invention to inhibit NFKB, AP-1 and cytokines; and Example 58 discloses the activity of a representative compound of this invention in both graft versus host disease and contact sensitivity models. Example 1 2-CHLORO-4-TRIFLUOROMETHYL-5-N- [3^5'-BIS(TRIFLUOROMETOYL)PHENYL]PYRI IDINE CARBOXAMIDE To a mixture of 3,5-bistrifluoromethylaniline (0.20 g, 0.92 mmol), Amberlyst A-21 ion exchange resin (0.02 g) in EtOAc (5 mL) was added a solution of 2- chloro-4-trifluoromethylpyrimidine-5-carbonyl chloride (0.27 g, 1.13 mmol) in EtOAc (5 mL). The mixture was stirred for 0.5 h, then quenched with water (0.20 mL). The organic layer was separated, dried over MgSO 4 , filtered and the solvent removed under reduced pressure. The resulting oil was recrystallized from EtOH H 2 O to provide the title compound (0.21 g, 53% yield) as a white solid; m.p. 162-163°C. Example 2 2-CHLORO-4-TRIFLUOROMETHYL-5-N- (4'-TRIFLUOROMETHYLPHENYL)PYRIMIDINE CARBOXAMIDE The title compound was prepared as described in Example 1, but employing 4-trifluoromethylaniline (0.1 g, 0.41 mmol) in place of 3,5- bistrifluoromethylaniline and the acid chloride (0.10 g, 0.41 mmol), resulting in a 24% yield; m.p. 172-173°C. Example 3 2-CHLORO-4-TRIF UOROMETHYL- 5-N-(PHENYL)PYRIMIDINE CARBOXAMIDE The title compound was prepared as described in Example 1, but employing aniline (0.04 g, 0.39 mmol) and the acid chloride (0.22 g, 0.90 mmol), resulting in a 62% yield; m.p. 108-181°C. Example 4 2-CHLORO-4-TR LUOROMETHYL- 5-N-(CYCLOHEXYL)PYRIMIDI E CARBOXAMIDE The title compound was prepared as described in Example 1, but employing cyclohexylamine (0.02 g, 0.18 mmol) and the acid chloride (0.05 g, 0.22 mmol), resulting in a 33% yield; m.p. 150-151°C. Example 5 2-CHLORO-4-TRIFLUOROMETHYL- 5-N-(BENZYL)PYRIMIDINE CARBOXAMIDE The title compound was prepared as described above in Example 1, but employing benzylamine (0.09 g, 0.92 mmol) and the acid chloride (0.25 g, 1.0 mmol), resulting in a 78% yield; m.p. 152-153°C. Example 6 2-CHLORO-4-TRIFLUOROMETHYL-5-N-(3',4',5'- TRICHLOROPHENYL)PYRIMIDINE CARBOXAMIDE The title compound was prepared as described in Example 1, but employing 3,4,5-trichloroaniline (0.15 g, 0.61 mmol) and the acid chloride (0.15 g, 0.61 mmol), resulting in a 55% yield; m.p. 200-201°C. Example 7 2-CHLORO-4-TRIFLUOROMETHYL-5-N-(4-(2',l',3' -BENZOTHIADIAZOLE))PYRIMIDINE CARBOXAMIDE The title compound was prepared as described above in Example 1, but employing 4-amino-2,l,3-benzothiadiazole (0.01 g, 0.07 mmol) and the acid chloride (0.025 g, 0.10 mmol), resulting in a 60% yield; m.p. 179- 180°C. Example 8 2-CHLORO-4-TRIFLUOROMETHYL-5-N-(3',5'-DICHLORO- 6'-HYDROXYPHENYL)PYRIMIDINE CARBOXAMIDE The title compound was prepared as described in Example 1, but employing 3,5-dichloro-6-hydroxyaniline (0.02 g, 0.11 mmol) and the acid chloride (0.04 g, 0.16 mmol), and purified by chromatography (Siθ 2 , 1 : 1 hexanes/EtOAc) to provide the compound in a 10% yield; m.p. 211-213°C. Example 9 2-CHLORO-4-TRIFLUOROMETHYL-5-N-[5'-(3'-METHYL- ISOXAZOLE)]PYRIMIDI E CARBOXAMIDE The title compound was prepared as described in Example 1, but employing 5-amino-3-methylisoxazole (0.02 g, 0.17 mmol) and the acid chloride (0.03 g, 0.10 mmol), resulting in a 75% yield; m.p. 170-171°C. Example 10 2-CHLORO-4-TRIFLUOROMETHYL-5-N-(3'-N-ACYL- 4'-FLUORO-A ILINE)PYRIMIDINE CARBOXAMIDE A solution of 2-fluoro-5-nitroaniline (1.97 g, 12.60 mmol) and a 1:1 mixture of Ac 2 θ/pyridine (20 mL) was stirred for 18 h. The resulting precipitate was filtered and washed with MeOH to provide N-acyl-2-fluoro-5-nitroaniline. The N-acyl-2-fluoro-5-nitroaniline (0.99 g, 5.00 mmol) was dissolved in EtOH (25 mL), and then 10% Pd/C (0.12 g) was added and the solution stirred under H 2 for 5 h. The suspension was filtered through celite and the filtrate evaporated to dryness. The resulting oil was chromatographed (SiO 2 , 1:3 hexanes/EtOAc) to provide 3-N-acyl-4-fluoro-aniline as a yellow oil. The aniline derivative was then coupled to 2- chloro-4-trifluoromethylpyrimidine-5-carbonyl chloride as described in Example 1 to provide the title compound in a 47% yield; m.p. 126-127°C. Example 11 2-CHLORO-4-TRIFLUOROMETHYL-5-N-(3 , -TRIFLUOROMETHYL- 5'-CARBOXAMIDEPHENYL) PYRIMIDINE CARBOXAMIDE To a solution of 3-nitro-5-trifluoromethylbenzoic acid (1.00 g, 4.25 mmol) in CH 2 CI- 2 (50 mL) was added oxalyl chloride (1.45 g, 13.8 mmol) followed by DMF (3 drops). An immediate evolution of gas occurred and the reaction was stirred for 18 h. The solvent was removed under reduced pressure, the resulting oil was dissolved in THF (80 mL) and cooled to 0°C. To the cold solution, NH4OH (22 mL) in THF (15 mL) was added dropwise and the mixture was stirred 18 h at room temperature. The mixture was concentrated to remove the THF and the resulting precipitate was filtered and dried. The solid was dissolved in EtOH (25 mL) and 10% Pd/C (0.12 g) was added, and the suspension was stirred 15 h under a blanket of H 2 . The reaction was filtered through celite, and the filtrate evaporated to dryness to provide 3-carboxamide-5-trifluoromethylaniline as a yellow oil. This compound was then coupled to 2-chloro-4-trifluoromethylpyrimidine-5-carbonyl chloride as described in Example 1 to provide the title compound in a 55% yield; m.p. 218-219°C. Example 12 2-CHLORO-4-TRIFLUOROMETHYL-5-N-(3'-TRIFLUOROMETHYL- 5'-ETHOXYCARBONYLPHENYL) PYRIMIDINE CARBOXAMIDE To a solution of 3-nitro-5-trifluoromethylbenzoic acid (0.36 g, 1.53 mmol) in CH 2 C1 2 (20 mL) was added oxalyl chloride (0.58 g, 4.60 mmol) followed by DMF (3 drops). An immediate evolution of gas occurred and the reaction was stirred for 18 h. The solvent was removed under reduced pressure, the resulting oil was dissolved in THF (80 mL) and cooled to 0°C. To the cooled solution was added EtOH (5 mL) in THF (15 mL) and the mixture was stirred for 18 h at room temperature. The mixture was concentrated to remove the THF and the resulting precipitate was filtered and dried. The solid was dissolved in EtOH (25 mL) and 10% Pd/C (0.12 g) was added and the suspension was stirred for 15 h under a blanket of H 2 . The reaction was filtered through celite and the filtrate evaporated to dryness to provide 3-ethoxycarbonyl-5- trifluoromethylaniline as a yellow oil. This compound was then coupled to 2-chloro-4- trifluoromethyl pyrimidine-5-carbonyl chloride as described above to provide the title compound in a 12% yield; m.p. 67-71°C. Example 13 2-CHLORO-4-TRIFLUOROMETHYL-5-N-(3\5 , -DICHLOROPHENYL)- 5-N-(METHY )PYRIMIDINE CARBOXAMIDE To a solution of 2-chloro-4-trifluoromethyl-5-N-(3,5-dichlorophenyl)- pyrimidine carboxamide (0.086 g, 0.23 mmol) in DMF (20 mL) was added NaH (0.02 g, 0.53 mmol). The mixture was stirred for 0.3 h at room temperature and then Mel (0.100 mL, 1.61 mmol) was added and stirring continued for 2 h. The solution was acidified with 2N HCl and then extracted with EtOAc (3X). The combined organic layers were dried over MgSO 4 , filtered and the solvent removed under reduced pressure. The resulting oil was chromatographed (SiO 2 , 7:1 hexanes/EtOAc) to provide the title compound (6% yield) as a white solid; m.p. 124-125°C. Example 14 2-CHLORO-4-TRFLUOROMETHYL-5-N-(3',5'-DICHLOROPHENYL)- 5-N-(BENZYL)PYRIMIDINE CARBOXAMIDE A mixture of benzaldehyde (1.04 g, 9.40 mmol), 3,5-dichloroaniline (1.71 g, 10.60 mmol), and HOAc (0.20 mL) in MeOH (35 mL) was cooled to 0°C. Then a solution of NaBH 3 CN (28.0 mL, 28.0 mmol, 1.0 M solution in THF) was added dropwise via a syringe pump over 0.25 h. The solution was allowed to stir an additional 0.3 h at 0°C, and then room temperature for 18 h. The excess NaBH 3 CN was quenched with HCl and the solvent was removed under reduced pressure. The resulting oil was dissolved in EtOAc H 2 O, basified with NaOH, and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO , filtered and the solvent removed under reduced pressure. The resulting oil was purified by chromatography (SiO 2 , 15:1 hexanes EtOAc) to provide N-benzyl-3,5-dichloroaniline as a white solid. This compound was coupled to 2-chloro-4-trifluoromethylpyrimidine-5- carbonyl chloride as described and purified by chromatography (SiO ∑ , 9:1 hexanes/EtOAc) to provide the title compound (15% yield) as a white foam; m.p. 102- 104°C. Example 15 5-N-[3', 5'-BlS(TRIFLUOROMETHYL)PHENYL]- 2,4-DICHLORO-6-METHYLPYRIMIDINE CARBOXAMIDE 5-Carbethoxy-6-methyluracil was prepared as reported in the literature (Lamon, J. Het. Chem., 261, 1969); m.p. 180-182°C. The ethyl ester was then hydrolyzed as described for 2-hydroxy-4-methylpyrimidine-5-carboxylic acid to provide 2,4-dihydroxy-6-methylpyrimidine-5-carboxylic acid in a 95% yield; m.p. >230°C. The 2,4-dihydroxy-6-methyl pyrimidine-5-carboxylic acid was heated at reflux with POCI 3 . The reaction mixture was concentrated and 2,4-dichloro-6- methylpyrimidine-5-carbonyl chloride was obtained by distillation (b.p. 70-80°C, 1.5 mm/Hg). The 2,4-dichloro-6-methylpyrimidine-5-carbonyl chloride (0.15 g, 0.67 mmol) was immediately reacted with 3,5-bis(trifluoromethyl)aniline (0.15 g, 0.67 mmol) in a similar manner to that described in Example 1 to provide the title compound (0.06 g, 24% - based upon starting 2,4-dihydroxy-6-methylpyrimidine-5-carboxylic acid); m.p. 174-176°C. Example 16 2,4-DlCHLOROPYRIMIDINE-5-CARBONYL CHLORIDE The title compound was prepared as described in the literature (Smith and Christensen, J. Org. Chem. 20:829, 1955) starting from 2,4-dihydroxypyrimidine-5- carboxylic acid. The compound was obtained by distillation; b.p. 90-100°C (1.5 mm/Hg) in a yield of 46%; 'HΝMR (CDCI3) δ 9.29. Example 17 ETHYL UREIDOMETHYLEΝE ACETOACETATE A mixture of ethyl acetoacetate (200 g, 1.54 mol), urea (105 g, 1.54 mole) and triethyl orthoformate (228 g, 1.54 mol) was heated at 140°C under Ν 2 for 22 h. The reaction mixture was cooled and filtered to provide the title compound in a 51% yield (156 g); m.p. 173-174°C. Example 18 ETHYL UREIDOMETHYLENE BENZOYLACETATE The title compound was prepared as described in Example 17, but employing ethyl benzoylacetate (30 g, 156 mmol), resulting in a yield of 21% (12 g); m.p. 124-126°C. Example 19 ETHYL 2-HYDROXY-4-METHYLPYRIMIDINE-5-CARBOXYLATE A solution of ethyl ureidomethylene acetoacetate (50 g, 250 mmol) NaOEt (22.1 g, 325 mmol) in EtOH (500 mL) was stirred at room temperature under N 2 for 3 days. The resulting solid was filtered and dried to yield the title compound as a sodium salt in a yield of 88% (45 g); m.p. >220°C (dec). Example 20 ETHYL 2-HYDROXY-4-PHENYLPYRMIDINE-5-CARBOXYLATE The title compound was prepared as described in Example 19, but employing ethyl ureidomethylene benzoyl acetate (12 g, 45 mmol), resulting in a yield of 15% (6 g); m.p. >260°C, (dec). Example 21 ETHYL 2-CHLORO-4-METHY PYPJMIDINE-5-CARBOXYLATE A solution of ethyl 2-hydroxy-4-methylpyrimidine-5-carboxylate (5 g, 27.5 mmol) and POCl 3 (84 g, 550 mmol) was heated at reflux under N 2 for 1 h. The reaction was cooled and concentrated. The residue was partitioned between CHCI 3 and H 2 O and the organic layer was dried (Na 2 SO ), filtered, and concentrated to yield the title compound in a yield of 27% (1.5 g); 'HNMR (CDCI3) δ 9.04 (s, IH), 4.42 (q, 2H), 2.85 (s, 3H), 1.43 (t, 3H). Example 22 ETHYL 2-CHLORO-4-PHENYLPYRIMIDINE-5-CARBOXYLATE The title compound was prepared as described in Example 21, but employing 2-hydroxy-4-phenylpyrimidine-5-carboxylate (6 g, 25 mmol) to give the title compound (5.5 g, 18%); m.p. 45-47°C. Example 23 2-CLORO-4-METHYLPYRIMIDINE-5-CARBOXYLIC ACID A solution of ethyl 2-chloro-4-methylpyrimidine-5-carboxylate (1.0 g, 5 mmol), NaOH (0.24 g, 6 mmol) in H 2 O (30 mL) was stirred at room temperature for 3 h. The solution was acidified with 6N HCl and the resulting solid was filtered and dried to give the title compound (0.67 g 78%), ! HNMR (DMSO-dβ) δ 9.01 (s, IH), 2.75 (s, 3H). Example 24 2-CHLORO-4-PHENYLPYRJMTOINE-5-CARBOXYLIC ACID The title compound was prepared as described in Example 23, but employing 2-chloro-4-phenylpyrimidine-5-carboxylate (4.5 g, 17 mmol), resulting in a yield of 87% (3.9 g); m.p. 105-110°C. Example 25 2-CHLORO-4-METHYLPYRIMIDINE-5-CARBONYL CHLORIDE A solution of 2-chloro-4-methylpyrimidine-5-carboxylic acid (0.81 g, 4.70 mmol), oxalyl chloride (0.89 g, 7.05 mmol), DMF (2 drops) in CH 2 C1 2 (23 mL) was stirred at room temperature under N2 for 4 h. The solution was concentrated and distilled to give the title compound (0.55 g,61%); b.p. 90-100°C, 1.3 mm/Hg; 1HNMR (CDCI3) δ d 9.02 (s, IH), 2.74 (s, 3H). Example 26 2-CHLORO-4-PHENYLPYRIMIDINE-5-CARBONYL CHLORIDE The compound was prepared as described above in Example 25, but employing 2-chloro-4-phenylpyrimidine-5-carboxylic acid (3.8 g, 14 mmol), resulting in a yield of53 %; m.p. 42°C. Example 27 2-CHLOROPYRIMIDINE-5-CARBONYLCHLORIDE The compound was prepared as described in the literature (see, Arukwe, J. Undheim, K. Acta Chemica Scand. B40:764, 1986). Example 28 ETHYL ETHOXYMETHYLENE-4,4,4-TRIFLUOROACETOACETATE A solution of 4,4,4-trifluoroacetoacetate (46 g, 0.25 mol) triethyl orthoformate (74 g, 0.50 mol) and Ac 2 O (77 g, 0.75 mol) was heated at 120-140°C for 7 h. The mixture was concentrated and distilled to give the title compound in a 98% yield (58.6 g); b.p. 80-90°C, 1.5 mm/Hg. Example 29 2,4-BlS(TRIFLUOROMETHYL)PYRIMIDINE-5-CARBONYL CHLORIDE A solution of ethyl ethoxymethylene-4,4,4-trifluoroacetoacetate (15 g, 62.5 mmol) and trifluoroacetamidine (12.6 g, 112.5 mmol) in EtOH (50 mL) was heated at reflux for 24 h under N 2 . The reaction mixture was cooled and concentrated. Chromatography (SiO 2 , 20% EtOAc/hexane) afforded ethyl-2,4-bis (trifluoromethyl)pyrimidine-5-carboxylate as an oil (7.0 g, 39 %), 'HNMR (CDC1 3 ) δ 9.37 (s, IH), 3.70 (q, 2H), 1.27 (t, 3H). A solution of ethyl-2,4-bis(trifluoromethyl)pyrimidine-5-carboxylate (5.0 g, 17 mmol) and NaOH (0.72 g, 18 mmol) in EtOH (20 mL) and H 2 O (50 mL) was stirred at room temperature for 1 h. The solution was acidified (HCl) and the resulting solid was filtered and dried to give 2,4-bis (trifluoromethyl)-pyrimidine-5-carboxylic acid (1.5 g, 25%), m.p. 59°C, 'HNMR (DMSO-d 6 ) δ 9.62 (s, IH). The desired acid chloride was obtained from 2,4-bis(trifluoromethyl)- pyrimidine-5-carboxylic acid in a manner similar to that described in Example 25 in a yield of 44%; b.p. 105°C (1.5 mm/Hg); 1HNMR (CDC1 3 ) δ 9.12 (s, IH). Example 30 2-CHLORO-4-TRIFLUOROMETHYLPYRIMIDINE-5-CARBOXYLIC ACID A solution of 2-chloro-4-trifluoromethylpyrimidine-5-carbonyl chloride (2.1 g, 8.6 mmol) in H 2 O (10 mL) was stirred at 0°C under N 2 for 0.5 h. The resulting solid was filtered and dried to give the title compound (1.91 g, 98% yield); m.p. 232- 234°C (dec). Example 31 2-CYANO-4-TRIFLUOROMETHYLPYRIMIDINE-5-CARBONYLCHLORIDE To a solution of 2-chloro-4-trifluoromethylpyrimidine-5-carboxylic acid (2.80 g, 12.4 mmol) in THF (50 mL) at 0°C. was added Me 3 N (bubbled for 5 minutes). The reaction was kept at 0°C for 0.25 h and the resulting solid was filtered to provide 2- trimethylammonium chloride-4-trifluoromethylpyrimidine-5-carboxylic acid (3.40 g, 97% yield); m.p. 120-121°C (dec). A solution of 2-trimethylammonium chloride-4- trifluoromethylpyrimidine-5-carboxylic acid (3.62 g, 12.7 mmol) and KCN (0.99 g, 15.2 mmol) in DMF (36.5 mL) and H 2 O (18.3 mL) was stirred at room temperature under N 2 for 0.25 h. The reaction mixture was concentrated and dissolved in EtOAc (400 mL). The EtOAc layer was washed with H 2 O (4 X 100 mL), brine (100 mL) and dried (Na 2 SO ). The EtOAc layer was filtered and concentrated to yield 2-cyano-4- trifluoromethylpyrimidine-5-carboxylic acid (2.03 g, 74% yield); m.p. 148-149°C (dec). A solution of 2-cyano-4-trifluoromethylpyrirnidine-5-carboxylic acid (2.0 g, 9.2 mmol), oxalyl chloride (1.4 g, 11 mmol) and DMF (4 drops) in CH 2 C1 2 (46 mL) was stirred at room temperature under N 2 for 0.75 h. The reaction was concentrated and distilled (b.p. 100°C, 1.5 mm/Hg) to give the title compound (1.8 g, 82% yield); 1 HNMR (CDC1 3 ) δ 9.49 (s, IH). Example 32 2-PHENYLPYRIMIDINE-5-CARBONYL CHLORIDE A solution of ethyl 3-N,N-dimethylamino-2-formylacrylate (4.0 g, 23 mmol) (Arnold, Coll. Czech. Chem. Commun. 26:3051, 1961), benzamidine hydrochloride (4.0 g, 26 mmol) and sodium (0.65 g, 28 mmol) in EtOH (40 mL) was heated at reflux for 1 h. The solution was filtered and concentrated and the residue partitioned between EtOAc and dilute HCl (10%). The organic layer was dried (Na 2 SO ), and concentrated to give ethyl 2-phenylpyrimidine-5-carboxylate (4.0 g, 75% yield); m.p. >220°C (dec). The corresponding 2-phenylpyrimidine-5-carboxylic acid was prepared in a yield of 80% (0.35 g) starting from ethyl 2-phenylpyrimidine-5-carboxylate in a similar manner to that described in Example 23; m.p. > 220°C (dec). The title compound was prepared in a quantitative yield from 2- phenylpyrimidine-5-carboxylic acid in a similar manner to that described in Example 25; m.p. 135°C. Example 33 ETHYL 2-TRFLUOROMETHYL-4-HYDROXYPYRIMIDINE-5-CARBOXYLATE A solution of diethyl ethoxymethylene alonate (35.0 g, 162 mmol), trifluoroacetamidine (18 g, 162 mmol) and NaOEt (11.0 g, 162 mmol) in EtOH (200 mL) was heated at reflux for 6 h. The reaction mixture was concentrated and H 2 O (48 mL) was added. The resulting solid was filtered, washed with Et2θ (300 mL) and H 2 O (200 mL), and dried to give the title compound (21 g, 50% yield); m.p. >220°C (dec); 1HNMR (DMSO-dβ) δ 8.38, 4.16 (q, 2H), 1.25 (q, 3H) . Example 34 2-TR1IT.UOROMETHYL-4-CHLOROPYRIMIDINE-5-CARBONYL CHLORIDE A solution of ethyl 2-trifluoromethyl-4-hydroxypyrimidine-5-carboxylate (5.00 g, 19.4 mmol) and NaOH (0.93 g, 23.3 mmol) in H 2 O (20 mL) was stirred at 60°C for 15 h. The reaction was acidified (cone HCl) and concentrated until a solid began to form. The solid was filtered and dried to give 2-trifluoromethyl-4-hydroxypyrimidine-5- carboxylic acid (2.1 g, 53% yield); 1HNMR (DMSO-dβ) δ 8.83 (s, IH). A solution of 2-trifluoromethyl-4-hydroxypyrimidine-5-carboxylic acid (2.0 g, 10.4 mmol), POCl 3 (32 g, 212 mmol) and SOCl 2 (25 g, 212 mmol) was heated at reflux for 4 days. The reaction was concentrated and distilled (b.p. 90-95°C, 1.5 mm/Hg) to provide the title compound (2.1 g, 81% yield), 'HNMR (CDC1 3 ) δ 9.45 (s, IH). Example 35 2-CHLORO-4-PENTAFLUOROETHYLPYRIMIDINE-5-CARBONYL CHLORIDE A solution of ethyl 2-hydroxy-4-pentafluoroethylpyrimidine-5- carboxylate (4.0 g, 13 mmol) and NaOH (1.60 g, 39 mmol) in EtOH (20 mL) and H 2 O (45 mL) was heated at reflux for 1 h. The solution was cooled and acidified (cone HCl). The resulting solid was filtered and dried to provide 2-hydroxy-4- pentafluoroethylpyrimidine-5-carboxylic acid (3.3 g, 98% yield); 1H NMR (DMSO-dβ) δ 9.90 (bs, IH), 8.43 (s, IH). A solution of 2-hydroxy-4-pentafluoroethylpyrimidine-5-carboxylic acid (3.33 g, 12.9 mmol) in SOCl 2 (27.7 g, 233 mmol) was heated at reflux for 0.5 h. Then POCI3 (35.6 g, 233 mmol) was added to the reaction mixture and heating continued for 36 h. The reaction mixture was concentrated and distilled (b.p. 80-85°C, 1 mm/Hg) to give the title compound (1.2 g, 35% yield). 1H NMR (DMSO-d 6 ) δ 9.18 (s, IH). Example 36 4-TRIFLUOROMETHYL-5-N- (3',5'-DICHLOROPHENYL)PYRIMIDINE CARBOXAMIDE A solution of 2-chloro-4-trifluoromethyl-5-N-(3,5- dichlorophenyl)pyrimidine carboxamide (0.10 g, 0.27 mmol), Mg 2 O (0.024 g, 0.59 mmol) and 5% Pd/C (0.01 g) in EtOH (1.8 mL) and water (0.9 mL) was stirred at room temperature under a blanket of H2 for 2.5 h. The reaction mixture was concentrated and chromatographed (Siθ2, 9% EtOAc/hexane) to yield the title compound (0.05 g, 53% yield); m.p. 189-190°C. Example 37 2-DIMETHYLAMINO-4-TRIFLUOROMETHYL- 5-N-(3',5'-DICHLOROPHENYL) PYRIMIDINE CARBOXAMIDE A solution of 2-chloro-4-trifluoromethyl-5-N-(3,5- dichloropheny pyrimidine carboxamide (0.13 g, 0.36 mmol) and dimethyl amine (0.10 g, 2.20 mmol) in MeOH was stirred at room temperature for 3 h. The reaction mixture was concentrated and chromatographed (SiO 2 , 5% EtOAc/hexane) to afford the title compound (0.022 g, 16% yield); m.p. 163-164°C. Example 38 2-TRIETHYLAMMONIUM CHLORIDE-4-TRIFLUOROMETHYL- 5-N-(3',5'-DICHLOROPHENYL) PYRIMIDINE CARBOXAMIDE A solution of 2-chloro-4-trifluoromethyl-5-N-(3',5'- dichlorophenyl)pyrimidine carboxamide (0.10 g, 0.27 mmol) and triethylamine (0.027 g, 0.27 mmol) in dry THF was stirred for 24 h. The solid was filtered, washed with Et 2 θ, and dried to afford the title compound (0.031 g, 24% yield); m.p. 158-159°C. Example 39 2-CHLORO-4-METHYL-5-N-[3',5'-BIS(TRIFLUORO- METHYL)PHENYL]PYRIMIDINE CARBOXAMIDE A solution of 2-chloro-4-methylpyrimidine-5-carbonyl chloride (0.10 g, 0.53 mmol), 3,5-bis(trifluoromethyl)aniline (0.12 g, 0.53 mmol) and Amberlyst A-21 resin (0.10g) in EtOAc (5.3 mL) was stirred at room temperature for 1 h. The solution was filtered, concentrated and chromatographed (SiO 2 , 10% EtOAc/hexane) to afford the title compound (0.17 g, 84% yield); m.p. 156-157°C. Example 40 2,4-DlCHLORO-5-N-[3 ', 5'-BIS(TRIFLUORO- METHYL)BENZYL]PYRIMIDINE-5-CARBOXAMIDE The title compound was prepared as described in Example 1, but employing 2,4-dichloropyrimidine-5-carbonylchloride (0.10 g, 0.40 mmol) and 3,5- bistrifluoromethylbenzylamine (0.10 g, 0.45 mmol) to give the compound in a 61% yield (0.12 g); m.p. 144-145°C. Example 41 2,4-DlCHLORO-5-N-[3',5'-BIS(TRIFLUORO- ME1ΗYL)PHENYL]PYRIMIDINE-5-CARBOXAMIDE The title compound was prepared as described in Example 1, but employing 2,4-dichloropyrimidine-5-carbonyl chloride to give the compound in a 97% yield (0.28 g); m.p. 104-105°C. Example 42 2-C YANO-4-TRFLUOROMETHYL-5-N-[3 ', 5'-BIS(TRIFLUORO- METHYL)PHENYL]PYRIMIDINE CARBOXAMIDE The title compound was prepared as described in Example 1, but employing 2-cyano-4-trifluoromethylpyrimidine-5-carbonyl chloride (0.11 g, 0.46 mmol) to give the compound in a 96% yield (0.19 g); m.p. 146-147°C. Example 43 2-CHLORO-4-PHENYL-5-N-[3',5'-BIS(TRIFLUORO- METHYL)PHENYL]PYRIMIDINE CARBOXAMIDE A solution of 2-chloro-4-phenylpyrimidine-5-carbonyl chloride (0.10 g, 0.40 mmol), 3,5-bis(trifluoromethyl) aniline (0.08 g, 0.40 mmol) and Et 3 N (0.04 g, 0.40 mmol) in EtOAc was stirred at room temperature for 2 h. The solution was concentrated and chromatographed (SiO 2 , 5% EtOH/CHCl 3 ) to afford the title compound (0.08 g, 45% yield); m.p. 154°C. Example 44 2-HYDRAZINO-4-TRIFLUOROMETHYL-5-N- (3',5'-DICHLOROPHENYL)PYRIMIDINE-5-CARBOXAMIDE A solution of 2-chloro-4-trifiuoromethyl-5-N-(3 , ,5'- dichlorophenyl)pyrimidine carboxamide (0.10 g, 0.27 mmol) and hydrazine (0.009 g, 0.54 mmol) in THF was stirred under N 2 at room temperature for 14 h. The solution was filtered, concentrated and chromatographed (SiO 2 , 20% EtOAc/hexane) to afford the title compound (0.08 g, 79% yield), 'HNMR (acetone-d 6 ) δ 10.08 (bs, IH), 9.64 (bs, IH), 8.89 (s, IH), 7.80 (s, 2H), 7.24 (s, IH), 2.79 (bs, 2H). Example 45 2-[N-( 1 -AMINOCITRACONAMIDE)]-4-TRIFLUOROMETHYL- 5-πsf-(3 , ,5'-DICHLOROPHENYL)]-PYRIMIDINE-5-CARBOXAMIDE A solution of 2-hydrazino-4-trifluoromethyl-5-[N-(3 l ,5'- dichlorophenyl)pyrimidine carboxamide (0.08 g, 0.21 mmol) and citraconic anhydride (0.024 g, 0.21 mmol) in CHC1 3 (2.1 mL) was heated at reflux under N 2 for 24 h. The solution was concentrated and chromatographed (Siθ2, 33% EtOAc/hexane) to afford the title compound (0.06 g, 62% yield); m.p. 182-183°C. Example 46 2-PHENYLAMINO-4-TRIFLUOROMETHYL- 5-N-(3',5'-DICHLOROPHENYL)-PYRIMIDINE-5-CARBOXAMIDE A solution of 2-chloro-4-trifluoromethyl-5-N-(3',5'- dichlorophenyl)pyrimidine carboxamide (0.10 g, 0.27 mmol) and aniline (0.06 g, 0.59 mmol) in dry THF (2.7 mL) was stirred at room temperature under N for 18 h. The reaction mixture was filtered, concentrated and chromatographed (SiO 2 , 50% CHCl 3 /hexane) to afford the title compound (0.10 g, 91% yield); m.p. 228-229°C. Example 47 METHYL 5-CHLORO-6-METHYL-2-PYRAZINE CARBOXYLATE. To a solution of methyl 4,5-dihydro-6-methyl-5-oxo-2-pyrazine carboxylate (M. Mano, T. Seo, K. Imai, Chem. Pharm. Bull 10:3057-3063, 1980) in DMF (20 mL) was added POCl 3 (20 mL). The reaction was refluxed for 0.5 h and then poured into ice. The aqueous layer was extracted with CHC1 3 dried (MgSO 4 ) and concentrated. The residue was chromatographed (SiO 2 , CHC1 3 ) to provide the title compound (2.34 g, 52% yield); m.p. 49-50°C. Example 48 5-CHLORO-6-METHYL-2-PYRAZINECARBOXYLIC ACID A mixture of methyl 5-chloro-6-methyl-2-pyrazine carboxylate (0.16 g, 0.86 mmol), K 2 CO 3 (0.31 g, 2.18 mmol) and H 2 O was stirred for 2 h at room temperature. The reaction was filtered and acidified (20% HCl), and the resulting solid collected to provide the title compound (0.057 g, 39% yield); m.p. 116-117°C. Example 49 2-CHLORO-5-N-(BISTRIFLUOROMETHYL ANILINE) PYRAZINE CARBOXAMIDE The title compound was prepared in a yield of 51% (0.08 g) using the same procedure as outlined in Example 1, except substituting 2-chloro-5-pyrazine carbonyl chloride (0.1 g, 0.57 mmol.) in place of the pyrimidine carbonyl chloride; m.p. 101-102°C. Example 50 2-TRIMETHYLAMMONIUM CHLORIDE-4-TRIFLUOROMETHYL- 5-PYRIMIDINE CARBOXYLIC ACID A solution of 2-chloro-4-trifluoromethylpyrimidine-5-carboxylic acid (6.0 g, 27 mmol) and excess trimethyl amine in THF (60 mL) was stirred for 5 min. The solid was filtered and dried to yield 97% (7.1 g) of the title compound; 1H ΝMR (DMSO-d6) δ 9.19 (s, IH), 2.72 (s, 9H). Example 51 2-FLUORO-4-TRFLUOROMETHYL- 5-PYRIMIDIΝE CARBOXYLIC ACID A mixture of 2-trimethylammonium chloride-4-trifluoromethyl-5- pyrimidine carboxylic acid (4.3 g, 15 mmol), KF (1.8 g, 30 mmol), DMF (40 mL) and H2O (20 mL) was stirred for 0.5h. The mixture was concentrated, acidified and extracted with Et 2 θ. The Et 2 O layer was concentrated to yield 47% (1.6 g) of the title compound; 1H NMR (DMSO-d6) δ 9.41 (s, IH). Example 52 2-FLUORO-4-TRIFLUOROMETHYL- 5-PYRIMIDINE CARBONYL CHLORIDE The title compound was prepared as described in Example 25, but employing a solution of 2-fluoro-4-trifluoromethylpyrimidine-5-carboxylic acid (1.5 g, 7.1 mmol) and oxalyl chloride (1.0 g, 8 mmol), DMF (2 drops) in CH 2 C1 2 (30 mL) resulted in a 75% yield (1.2 g); 1H NMR (CDC1 3 ) δ 9.42 (s, IH). Example 53 2-FLUORC)-4-TRIF UOROMETHYL-5-N-[3 , ,5 , -BLS(TRIFLUOROMETHYL)PHENYL] PYRIMIDINE CARBOXAMIDE The title compound was prepared as described in Example 1, but employing a solution of 2-fluoro-4-trifluoromethylpyrimidine-5-carbonyl chloride (0.05 g, 0.22 mmol) and 3,5-bis(trifluoromethyl)aniline (45 mg, 0.2 mmol) in EtOAc (2 mL) resulted in a 22% yield (0.02 g); m.p. 133-135°C. Example 54 2-CHLORO-4-TRIFLUOROMETHYL- 5-PYRIMIDINE CARBONYL CHLORIDE The title compound was prepared as described in Example 25, but employing a solution of 2-chloro-4-trifluoromethylpyrimidine-5-carboxylic acid (1.5 g, 7.1 mmol) and oxalyl chloride (1.0 g, 8 mmol) in CH 2 C1 2 (30 mL) resulted in a 70% yield (l.lg); 1H NMR (CDC1 3 ) δ 9.31 (s, IH). Example 55 SYNTHESIS OF REPRESENTATIVE COMPOUNDS BY COMBINATORIAL CHEMISTRY TECHNIQUES This example illustrates the synthesis of a representative class of compounds of this invention by combinatorial chemistry. It should be understood that, while a specific class of compounds are illustrated in this example, the following procedure may be employed to synthesize other compounds of this invention. Into wells 2-11 of a 96 well 1 mL plate (rows 1 and 12 left open as controls) was added 5 mg of Amberlyst 21 resin, 0.2 mL of EtOAc and 22.4 μmol of 80 different amine derivatives. Then to each well was added 25.0 μmol of the appropriate 5-carbonyl chloride (for example 2-chloro-4-trifluoromethylpyrimidine-5-carbonyl chloride). The 96 well plate was sonicated for 0.3 h and 50 μL of H 2 O was added to each well. The plate was sonicated for an additional 0.25 h, and the EtOAc layer from each well was removed and concentrated to provide 80 individual compounds. Thin- layer chromatography, HPLC and GC/MS analysis indicated that the desired compounds had been produced at >90% purity. This approach can be used to generate large numbers of derivatives for each substituted pyrimidine prepared, and can be used to routinely prepare >160 derivatives for each ofthe different 5-carbonyl pyrimidines. Example 56 INHIBITION OF THE ACΉVAΉON OF NFKB AND AP- 1 A. NFKB ASSAY Stable human Jurkat T-cells containing an NFKB binding site (from the MHC promoter) fused to a minimal SV-40 promoter driving luciferase expression were used in this experiment. Cells were split to 3 x 10 5 cells/mL every 2-3 days (cell concentration should not exceed 1 x IO 6 cells/mL to keep the cells proliferating in log phase). These cells were counted, resuspended in fresh medium containing 10% Serum- Plus at a density of 1 x IO 6 cells/mL and plated in 96 well round bottom plates (200 μL per well) 18 hours prior to starting the experiment. Compounds of this invention, dissolved in dimethyl sulfoxide (3.3, 0.33 and 0.03 μg/mL), were then added to the 96 well plates containing the cells and the plates are incubated for 0.5 h at 37°C. Then 50 ng/mL of phorbol 12-myristate-13- acetate (PMA) and 1 μg/mL of phytohemagglutinin (PHA) was added to each well and the cells were incubated for an additional 5 h at 37°C. The plates were centrifuged at 2200 RPM for 3 minutes at room temperature and then the medium was removed. To each well was added 60 μL of cell lysis buffer and the plates were left at room temperature for 0.25 h. Then 40 μL of each cell extract was transferred to a black 96 well plate and 50 μL of luciferase substrate buffer was added. Luminescence was immediately measured using a Packard TopCount. B. AP-1 ASSAY For AP-1, the assay was run as described above for NFKB except stable Jurkat T-cells were used that contained a collagenase promoter driving luciferase expression. In addition, the concentration of PMA used was 5 ng mL. C. RESULTS The results of the above assays for a representative compound of this invention, 2-chloro-4-trifluoromethyl-5-N-(3',5'-bistrifluoromethylphenyl)pyrimidine carboxamide, as percent inhibition versus control are presented in Figure 3. This figure also indicates activity of β-actin which was employed in these assays as a control cell line indicating effects on transcription. The lack of β-actin activity evidences selectivity of the test compounds for the transcription factors AP-1 and NFKB. Expressed as IC 5 o's, the results of these assays on additional test compounds are summarized in Table 2 below. Table 2 Test Compound NFκB/AP-1 (Example #). IC™ ( uM 1 0.03 2 0.75 6 0.8 8 6.0 10 1.0 11 5.0 12 0.4 13 5.0 15 0.8 39 0.075 41 0.6 42 >10 43 0.5 45 2.0 Based on the results of this experiment, representative compounds of this invention were found to be effective at inhibiting the activation of transcription factors (i.e., NFKB and AP-1) involved in gene transcription, and therefore have utility as, for example, immunosuppressive agents. Example 57 INHIBITION OF CYTOKINES To determine the effects of compounds on PMA/PHA-induced cytokine production, supernatants from either the NFKB (for IL-8) and AP-1 (for LL-2) reporter gene assays of Example 56 were collected and saved. Cytokine levels in the supernatants (25-50 μL aliquots) were determined by ELISA. The results of this experiment for a representative compound of this invention, 2-chloro-4-trifluoromethyl- 5-N-(3',5'-bistrifluoromethylphenyl)pyrirnidine carboxamide, is presented in Figure 4 (expressed as percent inhibition versus control). Example 58 IN Vivo ACTIVITY OF REPRESENTATIVE COMPOUND The murine popliteal lymph node (PLN) assay is a graft vs. host model that predicts activity of compounds in blocking human transplant rejection. The delayed- type hypersensitivity response to oxazolone is a standard contact sensitivity model. Both of these models are used routinely to evaluate compounds that are used clinically. For example, cyclosporin and cyclophosphamide are active in these models and are used clinically (Morris et al., Transplantation Proceedings 22(Suppl. 1): 110-112, 1990). A. POPLITEAL LYMPH NODE MODEL Spleens were removed from donor BALB/c mice and splenocytes were isolated then irradiated (3,000 rads) to prevent donor cell proliferation. After washing and adjusting cell density, 2.5x10 6 cells were injected subcutaneously into the left hind footpad of C3H mice. On day 4, the mice were sacrificed and left popliteal lymph nodes (PLNs) were weighed . The compound of Example 1, 2-chloro-4-trifluoromethyl-5-N-(3',5'- bistrifluoromethylphenyl)pyrimidine carboxamide, was administered once daily by intraperitoneal injection beginning one day before footpad injection (day 0) through day 4. The compound was suspended, immediately prior to use, at a concentration of 5 mg/mL in 0.25% methyl cellulose (Sigma) using a glass-teflon homogenizer. For doses of 10, 20 and 30 mg/kg, appropriate dilutions of the stock solution were made so that 0.1 mL/10 g body weight was administered by intraperitoneal injection. The results of this experiment, presented in Figure 5, demonstrate that a representative compound of this invention caused a dose-dependent suppression of alloantigen-induced PLN proliferation. The lowest dose of this compound, 10 mg/kg, caused a 52% inhibition of proliferation whereas cyclosporin A, at 12 mg/kg, caused a 35% inhibition. B. DELAYED TYPE HYPERSENSITIVITY STUDY On day 0, oxazolone (100 μL of a 3% solution) was applied to the shaved abdomen of mice. On day 7, a challenge application of oxazolone was applied (10 μL) around the right ear. The compound of Example 1, 2-chloro-4-trifluoromethyl- 5-N-(3,5-bistrifluoromethylphenyl)pyrimidine carboxamide, was administered from days -2 to 7 by intraperitoneal injection. It was prepared immediately prior to use by suspending it in 0.25% methyl cellulose (Sigma) using a glass-teflon homogenizer. For each dose, 0.1 mL/10 g body weight of the suspension was administered. The compound was prepared at the highest concentration for that study and appropriate dilutions of the stock solution were made so that 0.1 mL/10 g body weight was administered. Twenty four hours later, the difference in right vs. left ear thickness was measured. The results of this experiment are presented in Table 3 below. Table 3 Effect on the DTH Resoonse to Oxazolone Compound Dose Right-Left Ear P Value (mg/kg) (mean ± SEM) (vs. vehicle) Vehicle only — 0.30 ± 0.02 — Test Cpd. 10 (i.p.) 0.27 ± 0.01 0.163 Test Cpd. 30 (i.p.) 0.13 ± 0.02 <0.001* Cyclophosphamide 50 (i.p.) 0.08 ± 0.01 <0.001 "One animal died during study The test compound (30 mg/kg i.p.) and cyclophosphamide (50 mg/kg i.p.) significantly attenuated the delayed-type response to oxazolone by 56% and 73%, respectively. It will be appreciated that, although specific embodiments of this invention have been described herein for purpose of illustration, various modifications may be made without departing from the spirit and scope ofthe invention.

Claims: Claims 1. A compound having the structure: including pharmaceutically acceptable salts thereof, wherein R 5 is selected from the following chemical moieties: R 7 is selected from hydrogen, -CH 3 , and -CTfeCβHs; Rg is selected from hydrogen and an unsubstituted or substituted Cι.galkyl, C -i2 aralkyl, C 3 -i2heterocycle and a C -2 o heterocyclealkyl; R-ja is selected from halogen, an unsubstituted or substituted Ci-galkyl, Cβ-naryl, C 7- ι 2 aralkyl, C 3 -i 2 heterocycle or C^oheterocyclealkyl, -CN, -OR, -NRR and -NRNCOR; R a is selected from hydrogen, halogen, an unsubstituted or substituted Cι.galkyl, -CN, -OR, -NRR and -NRNCOR; and Rβ is selected from hydrogen, halogen and an unsubstituted or substituted Ci-galkyl; and wherein each occurrence of R is independently selected from an unsubstituted or substituted Ci-galkyl, Cβ-naryl, C-z-πaralkyl, C 3 -i 2 heterocycle or with the provisos that: (a) when R 5 is -CONR 7 Rg, (i) R 7 and Rg are not both hydrogen, (ii) Rz, is not selected from -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -OR, and an unsubstituted, straight chain or branched, non-cyclic, saturated Cι -3 alkyl, -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 and -OR, (iii) when R_ is -Cl and Rβ is -H, t a is not selected from -CF 3 , -Cl, -CH 3 and -C(CH 3 ) 3 , (iv) when R2a is -Cl and both R^ and Rβ are -H, Rg is not -CH(CN)C 6 H 5 , and (v) when R-^ is -Cl and R* a is -Cl, Rβ is not selected from -Cl and -CH 2 C1; and (b) when R 5 is -N(R 7 )C(=O)Rβ, (i) R2, is not selected from -CH , -OCH 3 and -N(CH 3 ) 2 , and (ii) Rg is not selected from -H and -CH 3 . 2. The compound of claim 1 having the structure: 3. The compound of claim 2 wherein R^ is selected from -CF3, -Cl, -F, -CH 3 and -H. 4. The compound of claim 2 wherein R_ is selected from -Cl, -OCH 3 , -H, -N(CH 3 ) 2 , -CF 3 , -CN, -NHNH 2 and -NHC 6 H S . 5. The compound of claim 2 wherein Rβ is selected from -H, -CF 3 , -CH 3 and -Cl. 6. The compound of claim 2 wherein R 7 is selected from -H and -CH 3 . 7. The compound of claim 2 wherein Rg is wherein X, Y and Z are the same or different, and independently selected from hydrogen, -OH, -R, -OR, -COOH, -COOR, -COR, -CONH 2 , -NH 2 , -NHR, -NRR, -SH, -SR, -SOOR, -SO 3 R and -SOR. 8. The compound of claim 2 wherein R^ is -CF 3 and R 2 -, is -Cl. 9. The compound of claim 2 wherein R^ is -CF 3 . 10. The compound of claim 9 wherein the compound is selected from 2- fluoro-4-trifluoromethyl-5-N-(3 , ,5 , -bistrifluoromethyl)pyrin-idine carboxamide, 5-(3',5'- bis(trifluoromethyl)phenacyl)-2-methoxy-4-trifluoromethylpyrimidine; 4-trifluoromethyl-5-N- (3^5'-dicMorophenyl)pyrimidine carboxamide; 2-dimethylamino-4-trifluoromethyl-5-N-(3 , ,5'- dichlorophenyl)pyrimidine carboxamide; 2-triethylammonium chloride-4-trifluoromethyl-5-N- (S'jS'-dichloropheny^pyrimidine carboxamide; 2-cyano-4-trifluoromethyl-5-N-[3',5'- (bistrifluoromethyl)phenyl]pyrimidine carboxamide; 2-hydrazino-4-trifluoromethyl-5-[N-(3 , ,5'- dichlorophenyl)pyrimidine-5-carboxamide; 2-[N-(l-aminocitraconamide)]-4-trifluoromethyl-5- [N-(3',5'-dichlorophenyl) pyrimidine-5-carboxamide; and 2-aminophenyl-4-trifluoromethyl-N- (3\5'-dichlorophenyl)pyrimidine-5-carboxamide. 11. The compound of claim 2 wherein R-^ is -Cl. 12. The compound of claim 11 wherein the compound selected from 5-N- [3 , ,5 , -bis(trifluoromethyl)phenyl]-2,4-dichloro-6-methyl-pyrimidine carboxamide; 2-chloro-4- methyl-5-N-[3',5'-(bistrifluoromethyl)phenyl]pyrimidine carboxamide; 2,4-dichloro-5-N-[3',5'- bis(trifluoromethyl)benzyl]pyrimidine-5-carboxamide; and 2-chloro-4-phenyl-5-N-[3',5'- (bistrifluoromethyl)phenyl]pyrimidine carboxamide. 13. The compound of claim 2 wherein Rg is a 3, 5 -disubstituted phenyl moiety, wherein both substituents are electron withdrawing groups. 14. The compound of claim 13 wherein both substituents are -CF 3 . 15. The compound of claim 13 wherein at least one of the substituents is -CF 3- 16. The compound of claim 2 wherein t a is selected from -H, -CH 3 , -CF 3 , -CF 2 CF 3 , -C 6 H 5 and -CH 2 C 6 H 5 . 17. The compound of claim 2 wherein R^ is selected from -Cl, -F, -CN and -CF 3 . 18. The compound of claim 2 wherein R-* is selected from -Cl and -F. 19. The compound of claim 2 wherein Rβ is -H. 20. A compound having the structure: including pharmaceutically acceptable salts thereof, wherein Rs is selected from the following chemical moieties: R is selected from hydrogen, -CH 3 , and -CH 2 CβH 5 ; Rg is selected from hydrogen and an unsubstituted or substituted Cι.galkyl, Cβ-i∑aryl, C7.12 aralkyl, C 3 .ι 2 heterocycle and a Ct-20 heterocyclealkyl; R 2b is halogen; R» b is selected from hydrogen, halogen, -CN, and an unsubstituted or substituted Ci-galkyl, Cβ-naryl, C 7- i2aralkyl, C 3 -i2heterocycle or C^oheterocyclealkyl; and Ri is selected from hydrogen, -CH 3 , -CF 3 and -CH 2 CH 3 ; and wherein each occurrence of R is independently selected from an unsubstituted or substituted Ci-galkyl, Cβ-naryl, C 7 -ι 2 aralkyl, C 3 .ι 2 heterocycle or with the proviso that when R5 is -CONR 7 Rg and R 2 b is -Cl, R_« > and Ri are not both hydrogen. 21. The compound of claim 20 wherein H, is an unsubstituted Ci-galkyl. 22. The compound of claim 20 wherein R 2 b is selected from -Cl and -F. 23. The compound of claim 20 wherein Ri is selected from -H and -CH 3 . 24. The compound of claim 20 wherein R 7 is selected from -H and -CH 3 . 25. The compound of claim 20 wherein Rg is wherein X, Y and Z are the same or different, and independently selected from hydrogen, -OH, -R, -OR, -COOH, -COOR, -COR, -CONH 2 , -NH 2 , -NHR, -NRR, -SH, -SR, -SOOR, -SO 3 R and -SOR. 26. The compound of claim 20 wherein R»b is -CF 3 and R 2 b is -Cl. 27. The compound of claim 20 wherein M , is -CF 3 . 28. The compound of claim 20 wherein R 2 b is -Cl. 29. The compound of claim 20 wherein Rg is a 3,5-disubstituted phenyl moiety, wherein both substituents are electron withdrawing groups. 30. The compound of claim 29 wherein both substituents are -CF3. 31. The compound of claim 29 wherein at least one of the substituents is -CF 3 . 32. The compound of claim 20 wherein R 4 b is selected from -H, -CH 3 , -CF 3 , -CF2CF3, -CβH 5 and -CH 2 CβH 5 . 33. The compound of claim 20 wherein Ri is -H. 34. A composition comprising a compound of claims 1-33 and a pharmaceutically acceptable carrier or diluent. 35. A composition comprising a compound of claims 1-33 and a pharmaceutically or prophylactically acceptable carrier or diluent. 36. Use of a compound of claims 1-33 as an active therapeutic substance. 37. Use of a compound of claims 1-33 for the manufacture of a medicament for treating an inflammatory condition. 38. The use of claim 37 wherein the inflammatory condition is an immunoinflammatory condition. 39. The use of claim 38 wherein the immunoinflammatory condition is selected from rheumatoid arthritis, osteoarthritis, transplant rejection, sepsis, ARDS and asthma. 40. The use of claim 38 wherein the immunoinflammatory condition is rheumatoid arthritis. 41. The use of claim 37 wherein the inflammatory condition is an autoimmune disease. 42. The use of claim 41 wherein the autoimmune disease is selected from multiple sclerosis, psoriasis, inflammatory bowel disease, glomerulonephritis, lupus, uveitis and chronic hepatitis. 43. The use of claim 37 wherein the inflammatory condition is selected from trauma, oxidative stress, cell death, irradiation damage, ischemia, reperfusion, cancer and viral infection. 44. The use of claim 37 wherein the inflammatory condition is transplant rejection.

Inventors: GAYO LEAH M, GOLDMAN MARK E, PALANKI MOORTHY S S, RANSONE-FONG LYNN J, SULLIVAN ROBERT W, SUTO MARK J, GAYO, LEAH, M., GOLDMAN, MARK, E., PALANKI, MOORTHY, S., S., RANSONE-FONG, LYNN, J., SULLIVAN, ROBERT, W., SUTO, MARK, J.
Applicants: GAYO LEAH M, GOLDMAN MARK E, PALANKI MOORTHY S S, RANSONE FONG LYNN J, SIGNAL PHARM INC, SULLIVAN ROBERT W, SUTO MARK J, GAYO, LEAH, M., GOLDMAN, MARK, E., PALANKI, MOORTHY, S., S., RANSONE-FONG, LYNN, J., SIGNAL PHARMACEUTICALS, INC., SULLIVAN, ROBERT, W., SUTO, MARK, J.
Application year: 1996
Main classification: C07D239
IPC codes: A61K31, A61P29, C07D239, C07D241, C07D403