MXPA05009722A - Heterocyclic kinase inhibitors: methods of use and synthesis. - Google Patents

Abstract

Inhibitors of kinases, compositions including the inhibitors, and methods of using the inhibitors and inhibitor compositions are described. The inhibitors and compositions including them are useful for treating disease or disease symptoms. The invention also provides for methods of making kinase inhibitor compounds, methods of inhibiting kinase activity, and methods for treating disease or disease symptom.

Description

HETEROCICLIC INHIBITORS OF KINASE: METHODS OF USE AND SYNTHESIS INTERREFERENCE WITH RELATED REQUESTS This application claims the priority of the provisional application of E.U.A. Serial No. 60 / 453,457, filed on March 10, 2003; the provisional application of E.U.A. Serial No. 60 / 460,910, filed on April 7, 2003; the provisional application of E.U.A. Serial No. 60 / 463,025, filed on April 15, 2003; and the provisional application of E.U.A. Serial No. 60 / 502,710, filed September 12, 2003; each of which is incorporated in its entirety as a reference herein.

BACKGROUND OF THE INVENTION Kinases are a class of enzymes that function in phosphoryl transfer catalysis. Protein kinases participate in signaling events, which control the activation, growth and differentiation of cells in response to extracellular mediators and changes in the environment. In general, kinases are divided into several groups; those which preferentially phosphorylate serine or threonine residues are generally referred to as serine / threonine kinases, and those which preferentially phosphorylate tyrosine residues are generally referred to as tyrosine kinases [S. K. Hanks and T. Hunter, FASEB J., 1995, 9, 576-596]. Tyrosine kinases include membrane-spanning growth factor receptors, such as EGFR (S. Iwashita and M. Kobayashi, Cellular Signaling, 1992, 4, 123-132), and non-receptor cytosolic kinases such as Lck, ZAP kinases. -70 and Syk (C. Chan et al., Ann. Rev. Immun., 1994, 12, 555-592). In many diseases that originate from an abnormal cellular function, an improperly high protein kinase activity has been implicated. This could arise directly or indirectly, for example due to a failure of the appropriate control mechanisms of the kinase, related for example with mutation, overexpression or inappropriate activation of the enzyme; or by the overproduction or underproduction of cytokines or growth factors that also participate in the transduction of preceding or subsequent signals to the kinase. In all these cases, the selective inhibition of the kinase could have a beneficial effect. T cells play a role in transplant rejection, in autoimmune diseases and in the initiation of inflammatory responses, and are therefore a major target of pharmaceutical intervention in these indications. T cell activation is a complex process that results in cell growth and differentiation. The coupling of the T cell receptor on the mature peripheral T cells initiates multiple intracellular signals that result in cell proliferation and acquisition of complex functions. The biochemical mechanisms that couple the binding of the receptor with these intracellular events have been investigated (J. E. M., Van Leeuwen and L. E. Samelson, Current Opin, Immun., 1999, 11, 242-248). The Syk family of tyrosine kinases, comprising Syk and ZAP-70, plays a role in the initiation and amplification of receptor signal transduction (D. H. Chu et al., Immunol Rev. 1998, 165, 167-180). ZAP-70 is expressed only in T cells and NK cells. Syk is found in B cells, mast cells, neutrophils, macrophages and platelets, and is involved in the signal transduction of the B cell receptor and the Fe receptor. In this way, the kappa inhibitors of ZAP-70 and Syk have potential therapeutic benefits to treat diseases resulting from the activation and differentiation of T cells, NK cells, B cells, mast cells, neutrophils, macrophages and platelets.

BRIEF DESCRIPTION OF THE INVENTION The invention relates to novel compounds and compositions including said compounds, as well as to methods of use and preparation thereof. The compounds are heterocyclic compounds that are useful in therapeutic applications, including modulation of disease or symptoms of disease in a subject (e.g. mammal, human, dog, cat, horse). The compounds (which include the stereoisomers thereof) are created individually or combinatorially to give collections of structurally and stereochemically diverse compounds. The compounds are useful as inhibitors of ZAP-70 and Syk by their binding to these receptors. In one aspect, the invention features a compound of formula (I): formula (I) wherein: A forms a ring of benzene, pyridine, pyrimidine, thiophene, pyrrole, imidazole, pyrazole, thiazole, or oxazole; X is O, S, NR3, N (R3) N (R3), C (O), N (R5) C (0), C (0) NR5, or alkyl; R x is H, cycloalkyl, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, R 50 -alkyl, (R 5) 3 Si, acyl, wherein R x is optionally substituted with 1-4 R 4; each R2 is, independently, H, NR52, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halogen, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each one of which is optionally substituted with 1-4 R7, wherein R2 is not Me when X-Rx is Me and Q is NH-aryl substituted with heterocyclyl; and wherein R2 is not acetyl when X-Rx is arylalkenyl; n is 0-3; each R3 is, independently, H, alkyl, R50-alkyl, or arylalkyl; each R4 is, independently, halogen, OH, CF3, C (0) R5, NR32, N (R3) C (0) R5, CN, OCF3, S02R5 or SiR53; or alkyloxy, aryloxy, alkyl, heterocyclyl, R50-alkyl, cycloalkyl, aryl, alkylthio, haloalkyloxy, heteroaryl, or arylalkyl, each of which is optionally substituted with 1-4 R6; each R5 is, independently, H, or alkyl; each R6 is, independently, halogen, OH, CF3, alkyl, alkyloxy, N (R5) -alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl; each R7 is, independently, halogen, CN, OR5, CF3, N (R5) C (0) R5, C (0) R5, OCF3, SCF3, NR52, C (0) NR52, OH, R50-alkyl, alkyl, alkylsulfonyl, heterocyclyl, or heteroaryl, each of which is optionally substituted with 1-4 R8; each R8 is, independently, OR5 or alkyl; Q is H, halogen, C (0) R5, C (0) R9, C (S) R5, C (S) R9, C (0) NR52, C (0) NR5R9, S (0) R5, S ( 0) R9, S (0) NR52, S (0) NR5R9, S02R5, S02R9, S02NR52, S02NR5R9, NR52, NR5R9, R9S-alkyl, alkyl, or heterocyclyl, wherein each alkyl or heterocyclyl is optionally substituted with 1-4 R 0; each R9 is, independently, aryl, heterocyclyl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted with 1-4 R10; each R10 is, independently, alkyl, CF3, C (NH) NR5R11, C (NH) R11, CN, R52N-alkyl, NR5R1-alkyl, R50-alkyl, R11, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of the which is optionally substituted with alkyl or OR5; and each R 1 is, independently, arylalkyl, heteroarylaxy, cycloalkyl, or heterocyclyl. In some cases, A forms a benzene ring. In another aspect, the invention features a compound of formula formula (II) wherein: X is O, S, NR3, N (R3) N (R3), C (O), N (R5) C (0), C (0) NR5, or alkyl; R x is H, cycloalkyl, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, R 50 -alkyl, (R 5 Si, acyl, wherein R x is optionally substituted with 1-4 R 4 each R2 is, independently, H, NR52, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halogen, acetyl, arylalkyl, heteroarylaikyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each of which is optionally substituted with 1-4 R7, each R2 'is, independently, H, halogen, NH2, alkyl, OH, C (O) Me, aryl, heteroaryl, each R3 is, independently, H, alkyl , R50-alkyl, or arylalkyl, each R4 is, independently, halogen, OH, CF3, C (O) R5, NR32I N (R3) C (O) R5, CN, OCF3, SO2R5, or SiR53; or alkyloxy, aryloxy , alkyl, heterocyclyl, R5O-alkyl, cycloalkyl, aryl, alkylthio, haloalkyloxy, heteroaryl, or arylalkyl, each of which is optionally substituted with 1-4 R6; each R5 is, independently, H, or alkyl; each R6 is, independently, halogen, OH, CF3, alkyl, alkyloxy, N (R5) -alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl; each R7 is, independently, halogen, CN, OR5, CF3, N (R5) C (O) R5, C (O) R5, OCF3, SCF3, NR52, C (O) NR52, OH, R5O-alkyl, alkyl, alkylsulfonyl, heterocyclyl, or heteroaryl, each of which is optionally substituted with 1-4 R8; each R8 is, independently, OR5 or alkyl; Het is heterocyclyl optionally substituted with 1-4 R10; each R10 is, independently, alkyl, CF3, C (NH) NR5R11, C (NH) R11, CN, R52-N-alkyl, NR5R11-alkyl, R5O-alkyl, R11, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is optionally substituted with alkyl or OR5; and each R 1 is, independently, arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl. In some cases, Het is linked by means of a nitrogen atom of the ring. In some cases, R2 is H. In some cases, Het is attached via a ring nitrogen atom; X is NR3, or alkyl; and Rx is cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, or heterocyclyl, wherein R * is optionally substituted with 1-4 R4; and R2 is H. In some cases, Het is: In other cases, Het is: In another aspect, the invention features a compound of formula (III): formula (III) wherein, X is O, S, NR3, N (R3) N (R3), C (O), N (R5) C (0), C (0) NR5, or alkyl; R x is H, cycloalkyl, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, R 50 -alkyl, (R 5) 3S, acyl, wherein R x is optionally substituted with 1-4 R4; each R2 is, independently, H, NR52, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halogen, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each one of which is optionally substituted with 1-4 R7; wherein R2 is not Me when X-Rx is Me and R12 is aryl substituted with heterocyclyl; each R2 'is, independently, H, halogen, NI-, alkyl, OH, C (O) Me, aryl, heteroaryl; each R3 is, independently, H, alkyl, R50-alkyl, or arylalkyl; each R4 is, independently, halogen, OH, CF3, C (O) R5, NR32, N (R3) C (O) R5, CN, OCF3, SO2R5, or SR53; or alkyloxy, aryloxy, alkyl, heterocyclyl, R5O-alkyl, cycloalkio, aryl, alkylthio, haloalkyloxy, heteroaryl, or arylalkyl, each of which is optionally substituted with 1-4 R6; each R5 is, independently, H, or alkyl; each R6 is, independently, halogen, OH, CF3, alkyl, alkyloxy, N (R5) -alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl; each R7 is, independently, halogen, CN, OR5, CF3, N (R5) C (O) R5, C (O) R5, OCF3, SCF3, NR52, C (O) NR52, OH, R5O-alkyl, alkyl, alkylsulfonyl, heterocyclyl, or heteroaryl, each of which is optionally substituted with 1-4 R8; each R8 is, independently, OR5 or alkyl; each R 2 is, independently, aryl or heteroaryl, optionally substituted with 1-4 R 13; each R is, independently, heterocyclyl optionally substituted with alkyl or OR5. In some cases, R2 is H. In some cases, R12 is: In another aspect, the invention features a compound of formula (IV): formula (IV) wherein X is O, S, NR3, N (R3) N (R3), C (O), N (R5) C (0), C (0) NR5, or alkyl; R x is H, cycloalkyl, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, R 50 -alkyl, (R 5) 3 Si, acyl, wherein R x is optionally substituted with 1-4 R 4; each R2 is, independently, H, NR52, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halogen, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each one of which is optionally substituted with 1-4 R7; wherein R2 is not Me when X-Rx is Me and Q is NH-aryl substituted with heterocyclyl; and wherein R2 is not acetyl when X-Rx is arylalkenyl; each R3 is, independently, H, alkyl, R50-alkyl, or arylalkyl; each R4 is, independently, halogen, OH, CF3, C (0) R5, NR32, N (R3) C (0) R5, CN, OCF3, S02R5, or SiR53; or alkyloxy, aryloxy, alkyl, heterocyclyl, R50-alkyl, cycloalkyl, aryl, alkylthio, haloalkyloxy, heteroaryl, or arylalkyl, each of which is optionally substituted with 1-4 R6; each R5 is, independently, H, or alkyl; each R6 is, independently, halogen, OH, CF3, alkyl, alkyloxy, N (R5) -alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl; each R7 is, independently, halogen, CN, OR5, CF3, N (R5) C (O) R5, C (O) R5, OCF3, SCF3, NR52, C (O) NR52, OH, R5O-alkyl, alkyl, alkylsulfonyl, heterocyclyl, or heteroaryl, each of which is substituted optionally with 1-4 R8; each R8 is, independently, OR5 or alkyl; Q is H, halogen, C (O) R5, C (O) R9, C (S) R5, C (S) R9, C (O) NR52, C (O) NR5R9, S (O) R5, S (O) R9, S (O) NR52, S (O) NR5R9, SO2R5, SO2R9, SO2NR52, SO2NR5R9, NR52, NR5R9, R9S-alkyl, alkyl, or heterocyclyl , wherein each alkyl or heterocyclyl is optionally substituted with 1-4 R10; each R9 is, independently, aryl, heterocyclyl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted with 1-4 R10; each R10 is, independently, alkyl, CF3, C (NH) NR5R11, C (NH) R11, CN, R52N-alkyl, NR5R1-alkyl, R5O-alkyl, R1, heteroaryl, heterocyclyl, or heterocyclic alkyl, each which is optionally substituted with alkyl or OR5; each R 11 is, independently, arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl; and R14 is halogen, NH2, alkyl, OH, C (O) Me, aryl, heteroaryl, or C (0) NHR5. In another aspect, the invention features a compound of formula formula (V) wherein: A forms a ring of benzene, pyridine, pyrimidine, thiophene, pyrrole, imidazole, pyrazole, thiazole, or oxazole; Ry is H, halogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl, wherein Ry is optionally substituted with 1-4 R4; each R2 is, independently, H, NR52, alkyl, cycloalkyl, alkeniion, alkynyl, heteroaryl, heterocyclyl, aryl, halogen, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryl, each one of which is optionally substituted with 1-4 R7; wherein R2 is not Me when Ry is halogen, indole substituted with halogen, phenyl, or phenyl substituted with halogen; wherein R2 is not isopropyl when Ry is phenyl substituted with halogen; wherein R2 is not alkynyl substituted with heterocyclyl when Ry is indole substituted with halogen; wherein R2 is not phenyl when Ry is H; wherein R2 is not halogen when Ry is indole substituted with halogen or phenyl substituted with halogen; and wherein R2 is not acetyl when Ry is phenyl or substituted phenyl; n is 0-3; each R3 is, independently, H, alkyl, R50-aikyl, or arylalkyl; each R 4 is, independently, halogen, OH, CF 3) C (0) R 5, NR 32, N (R 3) C (0) R 5, CN, OCF 3 > S02R5, or S¡R53; or alkyloxy, aryloxy, alkyl, heterocyclyl, R50-alkyl, cycloalkyl, aryl, alkylthio, haloalkyloxy, heteroaryl, or arylalkyl, each of which is optionally substituted with 1-4 R6; each R5 is, independently, H, or alkyl; each R6 is, independently, halogen, OH, CF3, alkyl, alkyloxy, N (R5) -alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl; each R7 is, independently, halogen, CN, OR5, CF3, N (R5) C (0) R5, C (0) R5, OCF3, SCF3, NR52, C (0) NR52, OH, R50-alkyl, alkyl, alkylsulfonyl, heterocyclyl, or heteroaryl, each of which is optionally substituted with 1-4 R8; each R8 is, independently, OR5 or alkyl; Q is H, halogen, C (0) R5, C (0) R9, C (S) R5, C (S) R9, C (0) NR52, C (0) NR5R9, S (0) R5, S ( 0) R9, S (0) NR52, S (0) NR5R9, S02R5, S02R9, S02NR52, S02NR5R9, NR52, NR5R9, R9S-alkyl, alkyl, or heterocyclyl, wherein each alkyl or heterocyclyl is optionally substituted with 1-4 R10; each R9 is, independently, aryl, heterocyclyl, heteroaryl, arylalkyl or heteroarylalkyl, each of which is optionally substituted with 1-4 R, each R10 is, independently, alkyl, CF3, C (NH) NR5R11, C (NH) R11, CN, R52N-alkyl, NR5R1-alkyl, R50-alkyl, R11, heteroaryl, heteroclclyl, or heterocyclylalkyl, each of which is optionally substituted with alkyl or OR5; and each R is, independently, arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl. In some cases, A forms a benzene ring. In one aspect, the invention features a compound of formula (VI), formula (VI) wherein, Ry is H, halogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl, wherein Ry is optionally substituted with 1-4 R4; each R2 is, independently, H, NR52, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halogen, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each one of which is optionally substituted with 1-4 R7; wherein R2 is not Me when Ry is halogen, indole substituted with halogen, phenyl, or phenyl substituted with halogen; wherein R2 is not isopropyl when Ry is phenyl substituted with halogen; each R2 is, independently, H, halogen, NH2, alkyl, OH, C (0) Me, aryl, heteroaryl; each R3 is, independently, H, alkyl, R50-alkyl, or arylalkyl; each R4 is, independently, halogen, OH, CF3, C (O) R5, NR32, N (R3) C (0) R5, CN, OCF3, S02R5, or SiR53; or alkyloxy, aryloxy, alkyl, heterocyclyl, R50-alkyl, cycloalkyl, aryl, alkylthio, haloalkyloxy, heteroaryl, or arylalkyl, each of which is optionally substituted with 1-4 R6; each R5 is, independently, H, or alkyl; each R6 is, independently, halogen, OH, CF3, alkyl, alkyloxy, N (R5) -alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl; each R7 is, independently, halogen, CN, OR5, CF3, N (R5) C (O) R5, C (O) R5, OCF3, SCF3, NR52, C (O) NR52, OH, R5O-alkyl, alkyl, alkylsulfonyl, heterocyclyl, or heteroaryl, each of which is optionally substituted with 1-4 R8; each R8 is, independently, OR5 or alkyl; Het is heterocyclyl optionally substituted with 1-4 R 0; each R10 is, independently, alkyl, CF3, C (NH) NR5R11, C (NH) R11, CN, R52N-alkyl, NR5R1-alkyl, R5O-alkyl, R11, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is optionally substituted with alkyl or OR5; and each R 11 is, independently, arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl. In some cases, Het is linked by means of a ring nitrogen atom; R2 is not H; and R2 'is H. In some cases, Het is: In another aspect, the invention features a compound of formula (VII) formula (VII) wherein: Ry is H, halogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl, wherein Ry is optionally substituted with 1-4 R4; each R2 is, independently, H, NR52, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halogen, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each one of which is optionally substituted with 1-4 R7; wherein R2 is not phenyl when Ry is H; each R2 'is, independently, H, halogen, Nl-fe, alkyl, OH, C (0) Me, aryl, heteroaryl; each R3 is, independently, H, alkyl, R50-alkyl, or arylalkyl; each R4 is, independently, halogen, OH, CF3, C (0) R5, NR32, N (R3) C (0) R5, CN, OCF3, S02R5, or SiR53; or alkyloxy, aryloxy, alkyl, heterocyclyl, R50-alkyl, cycloalkyl, aryl, alkylthio, haioalkyloxy, heteroaryl, or arylalkyl, each of which is optionally substituted with 1-4 R6; each R5 is, independently, H, or alkyl; each R6 is, independently, halogen, OH, CF3, alkyl, alkyloxy, N (R5) -alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl; each R7 is, independently, halogen, CN, OR5, CF3, N (R5) C (0) R5, C (0) R5, OCF3, SCF3, NR52 > C (0) NR52, OH, R50-alkyl, alkyl, alkylsulfonyl, heterocyclyl, or heteroaryl, each of which is optionally substituted with 1-4 R8; each R8 is, independently, OR5 or alkyl; each R12 is, independently, aryl or heteroaryl, optionally substituted with 1-4 R13; each R13 is, independently, heterocyclyl optionally substituted with alkyl or OR5. In some cases, R2 is not H; and R2 is H. In some cases, R12 is: In one aspect, the invention features a compound of formula (Vill), formula (VIII) wherein, is H, halogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl, wherein Ry is optionally substituted with 1-4 R4; each R2 is, independently, H, NR52, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halogen, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each one of which is optionally substituted with 1-4 R7; wherein R2 is not Me when Ry is halogen, indole substituted with halogen, or phenyl optionally substituted with halogen; wherein R2 is not isopropyl when Ry is phenyl substituted with halogen; wherein R2 is not alkynyl substituted with heterocyclyl when Ry is indole substituted with halogen; wherein R2 is not phenyl when Ry is H; and wherein R2 is not acetyl when Ry is phenyl or substituted phenyl; each n is 0-3; each R3 is, independently, H, alkyl, R50-alkyl, or arylalkyl; each R4 is, independently, halogen, OH, CF3, C (0) R5, NR32, N (R3) C (0) R5, CN, OCF3, S02R5, or SiR53; or alkyloxy, aryloxy, alkyl, heterocyclyl, R50-alkyl, cycloalkyl, aryl, alkylthio, haloalkyloxy, heteroaryl, or arylalkyl, each of which is optionally substituted with 1-4 R6; each R5 is, independently, H, or alkyl; each R6 is, independently, halogen, OH, CF3, alkyl, alkyloxy, N (R5) -alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl; each R7 is, independently, halogen, CN, OR5, CF3I N (R5) C (0) R5, C (0) R5, OCF3, SCF3, NR52, C (0) NR52, OH, R50-alkyl, alkyl, alkylsulfonyl , heterocyclyl, or heteroanyl, each of which is optionally substituted with 1-4 R8; each R8 is, independently, OR5 or alkyl; Q is H, halogen, C (0) R5, C (0) R9, C (S) R5, C (S) R9, C (0) NR52, C (0) NR5R9, S (0) R5, S ( 0) R9, S (0) NR52, S (0) NR5R9, S02R5, S02R9, S02NR52, S02NR5R9, NR52, NR5R9, R9S-alkyl, alkyl, or heterocyclyl, wherein each alkyl or heterocyclyl is optionally substituted with 1-4 R10; each R 9 is, independently, aryl, heterocyclyl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted with 1-4 R 0; each R10 is, independently, alkyl, CF3, C (NH) NR5R11, C (NH) R11, CN, R52N-alkyl, NR5R11-alkyl, R50-alkyl, R11, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is optionally substituted with alkyl or OR5; each R 11 is, independently, arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl; and R14 is halogen, NH2, alkyl, OH, C (0) Me, aryl, heteroaryl, or C (0) NHR5. In some cases, n is 1 and R2 is not H. In another aspect, the invention presents the compound of formula (XIV), formula (XIV) wherein, X is O, S, NR3, N (R3) N (R3), C (O), N (R5) C (0), C (0) NR5, or alkyl; R is H, cycloalkyl, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, R 50 -alkylo, (R 5) 3 Si, acyl, wherein R x is optionally substituted with 1-4 R 4; each R2 is, independently, H, NR52, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halogen, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkyl, heteroarylalkyl, aryloxy, or heteroaryloxy, each of which is substituted optionally with 1-4 R7; n is 0-3; each R3 is, independently, H, alkyl, R50-alkyl, or arylalkyl; each R4 is, independently, halogen, OH, CF3, C (0) R5, NR32, N (R3) C (0) R5, CN, OCF3, S02R5, or SiR53; or alkyloxy, aryloxy, alkyl, heterocyclyl, R50-alkyl, cycloalkyl, aryl, alkylthio, haloalkyloxy, heteroaryl, or arylalkyl, each of which is optionally substituted with 1-4 R6; each R5 is, independently, H, or alkyl; each R6 is, independently, halogen, OH, CF3, alkyl, alkyloxy, N (R5) -alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl; each R7 is, independently, halogen, CN, OR5, CF3, N (R5) C (O) R5, C (O) R5, OCF3, SCF3, NR52, C (O) NR52, OH, R5O-alkyl, alkyl, alkylsulfonyl, heterocyclyl, or heteroaryl, each of which is optionally substituted with 1-4 R8; each R8 is, independently, OR5 or alkyl; Q is H, halogen, C (O) R5, C (O) R9, C (S) R5, C (S) R9, C (O) NR52, C (O) NR5R9, S (O) R5, S ( O) R9, S (O) NR52, S (O) NR5R9, SO2R5, SO2R9, SO2NR52, SO2NR5R9, NR52, NR5R9, R9S-alkyl, alkyl, or heterocyclyl, wherein each alkyl or heterocyclyl is optionally substituted with 1-4 R10; each R9 is, independently, aryl, heterocyclyl, heteroaryl, arylalkyl, or heteroarylalkium, each of which is optionally substituted with 1-4 R10; each R 10 is, independently, alkyl, CF 3, C (NH) NR 5 R 11, C (NH) R 1 CN, R 52 N -alkyl, NR 5 R 11 -alkyl, R 5 O -alkyl, R 11, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is optionally substituted with alkyl or OR5; and each R 11 is, independently, arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl. In another aspect, the invention features a method of preparing a compound of formula (II) formula (II) wherein X, Rx, R2, R and Het are as defined below. The method includes: treating the compound of formula (IX) with malonic acid, to give a ring expansion compound of formula (X); formula (IX) formula (X) coupling the compound of formula (X) with a Pd catalyst and compound of formula (XI) to give a compound of formula (Xll); formula (X) formula (XI) formula (XII) treating the compound of formula (XII) with POCI3 to give the chloride of formula (XIII), and coupling the carboxylic acid of formula (XII) with an amine of formula Het-H , to give the compound of formula (XIII); formula (XII) formula (XIII) and coupling the compound of formula (XIII) with one or more coupling agents to give a compound of formula (II), formula (XIII) formula (II) wherein, for formulas II and IX to XIII, X is O, S, NR3, N (R3) N (R3), C (0), N (R5) C (0) R5, C (0) NR5, or alkyl; R x is H, cycloalkyl, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, R 50 -alkyl, (R 5) s Si, acyl, wherein R x is optionally substituted with 1-4 R 4; each R2 is, independently, NR52, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halogen, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkyl, heteroarylalkinyl, aryloxy, or heteroaryloxy, each of which is optionally substituted with 1-4 R7; R2 'is H, halogen, NH2, alkyl, OH, C (O) e, aryl, heteroaryl; each R3 is, independently, H, alkyl, R5O-alkyl, or arylalkyl; each R4 is, independently, halogen, OH, CF3, C (O) R5, NR32, N (R3) C (O) R5, CN, OCF3l SO2R5, or SiR53; or alkyloxy, aryloxy, alkyl, heterocyclyl, R5O-alkyl, cycloalkyl, aryl, alkylthio, haloalkyloxy, heteroaryl, or arylalkyl, each of which is optionally substituted with 1-4 R6; each R5 is, independently, H, or alkyl; each R6 is, independently, halogen, OH, CF3, alkyl, alkyloxy, N (R5) -alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl; each R7 is, independently, halogen, CN, OR5, CF3, N (R5) C (O) R5, C (O) R5, OCF3, SCF3, NR52, C (O) NR52, OH, R5O-alkyl, alkyl, alkylsulfonyl, heterocyclyl, or heteroaryl, each of which is optionally substituted with 1-4 R8; each R8 is, independently, OR5 or alkyl; Het is heterocyclyl optionally substituted with 1-4 R 0; each R10 is, independently, alkyl, CF3, C (NH) NR5R11, C (NH) R11, CN, R52N-alkyl, NR5R1-alkyl, R5O-alkyl, R11, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is optionally substituted with alkyl or OR5; and each R 11 is, independently, arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl. In some cases, the H of Het-H is attached to a nitrogen. In some cases, the coupling agent is H2NRX. In some cases, the coupling agents are MgCl-Rx, and P.S. In some cases, the coupling agent is HSRX. In another aspect, the invention features a method of treating an immune disorder in a subject, comprising administering to the subject any of the compounds or compositions described herein. In some cases, the method includes administering an additional therapeutic agent. In some cases, the autoimmune disorder is lupus. In another aspect, the invention features a method of treating rejection of organ transplantation in a subject, which comprises administering to the subject any of the compounds or compositions described herein. In another aspect, the invention features a method of treating an inflammatory disorder in a subject, comprising administering to the subject any of the compounds or compositions described herein. In some cases, the method includes administering an additional therapeutic agent. The additional therapeutic agent can be an analgesic or a steroid. In some cases, the inflammatory disorder is arthritis. Arthritis may also be, for example, rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis or osteoarthritis. In some cases, the inflammatory disorder is inflammatory bowel disease or Crohn's disease. In another aspect, the invention features a composition that includes any of the compounds described herein. In some cases, the composition may include a pharmaceutically acceptable carrier. In some cases, the composition may include an additional therapeutic agent. In another aspect, the invention features a collection of the compounds of any of formulas (I) - (VIII). In yet another aspect, the invention features a method for inhibiting the production of IL-2 in a subject, which includes administering to the subject any of the compounds or compositions described herein. In a further aspect, the invention features a method for modulating ZAP-70 or Syk in a subject, which includes administering to the subject any of the compounds or compositions described herein. In other aspects, the compounds, compositions and methods described herein are any of the compounds of Table 1 herein. The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description that follows. Other features, objects and advantages of the invention will be apparent from the description and drawings, and from the claims.

DETAILED DESCRIPTION OF THE INVENTION The term "halo" or "halogen" refers to any radical of fluorine, chlorine, bromine or iodine. The term "alkyl" refers to a hydrocarbon chain which may be a straight or branched chain, containing the indicated number of carbon atoms. For example, C1-C10 indicates that the group may have from 1 to 10 carbon atoms (inclusive). The term "lower alkyl" refers to an alkyl chain of C-i-Ce- In the absence of any numeric designation, "alkyl" is a chain (straight or branched) having from 1 to 10 carbon atoms (inclusive). The term "alkoxy" refers to a radical -O-alkyio. The term "alkylene" refers to a divalent alkyl (i.e., -R-). The term "alkylene dioxo" refers to a divalent species of the structure -O-R-O-, wherein R represents an alkylene. The term "aminoalkyl" refers to an alkyl substituted with an amino. The term "mercapto" refers to a -SH radical. The term "thioalkoxy" refers to a -S-alkyl radical. The term "alkenyl" refers to a hydrocarbon chain which may be a straight or branched chain having one or more carbon-carbon double bonds. The alkenyl portion contains the indicated number of carbon atoms. For example, C2-C10 indicates that the group can have from 2 to 10 carbon atoms (inclusive). The term "lower alkenyl" refers to a C2-C8 alkenyl chain. In the absence of any numerical designation, "alkenyl" is a chain (straight or branched) having from 2 to 10 carbon atoms (inclusive). The term "alkynyl" refers to a hydrocarbon chain which may be a straight or branched chain having one or more triple carbon-carbon bonds. The alkynyl portion contains the indicated number of carbon atoms. For example, C2-C10 indicates that the group can have from 2 to 10 carbon atoms (inclusive). The term "lower alkynyl" refers to a C2-C8 alkynyl chain. In the absence of any numerical designation, "alkynyl" is a chain (straight or branched) having from 2 to 10 carbon atoms (inclusive). The term "aryl" refers to a 6-carbon or bicyclic monocyclic aromatic ring system of 10 carbons, wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted with a substituent. Examples of aryl groups include phenyl, naphthyl and the like. The term "arylalkyl" or the term "aralkyl" refers to alkyl substituted with an aryl. The term "arylalkenyl" refers to an alkenyl substituted with an aryl. The term "arylalkynyl" refers to an alkynyl substituted with an aryl. The term "arylalkoxy" refers to an alkoxy substituted with aryl. The term "cycloalkyl", as used herein, includes saturated and partially unsaturated cyclic hydrocarbon groups having from 3 to 12 carbons, preferably from 3 to 8 carbons, and most preferably from 3 to 6 carbons, wherein the cycloalkyl group it may be optionally substituted. Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and cyclooctyl. The term "heteroaryl" refers to a 5- to 8-membered monocyclic aromatic ring system, bicyclic of 8-12 members, or tricyclic of 11-14 members, having 1-3 heteroatoms if it is monocyclic, 1-6 heteroatoms if is bicyclic, or 1-9 heteroatoms if it is tricyclic, said heteroatoms are selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S, if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted with a substituent. Examples of heteroaryl groups include pyridyl, furyl or furanyl, imidazolyl, benzimidazolyl, pyrimidinyl, thiophenyl or thienyl, quinolinyl, indolyl, thiazolyl and the like. The term "heteroarylalkyl" or the term "heteroaralkyl" refers to an alkyl substituted with a heteroaryl. The term "heteroarylalkenyl" refers to an alkenyl substituted with a heteroaryl. The term "heteroarylalkyl" refers to an alkynyl substituted with a heteroaryl. The term "heteroarylalkoxy" refers to an alkoxy substituted with heteroaryl. The term "heterocyclyl" refers to a non-aromatic monocyclic ring system of 5-8 members, bicyclic of 8-12 members, or tricyclic of 1-14 members, having 1-3 heteroatoms if it is monocyclic, 1-6 heteroatoms if it is bicyclic, or 1-9 heteroatoms if it is tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S, if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted with a substituent. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morphoiinium, tetrahydrofuranyl, and the like. The term "heterocyclylalkyl" refers to an alkyl substituted with a heterocyclyl. The term "oxo" refers to an oxygen atom, which forms a carbonyl when attached to a carbon, an N-oxide when attached to a nitrogen, and a sulfoxide or sulfone when attached to a sulfur. The term "acyl" refers to an alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, or heteroarylcarbonyl substituent, any of which may be further substituted with substituents. The term "sulfonyl" refers to a sulfur bonded to two oxygen atoms by double bonds. An "alkylsulfonyl" refers to an alkyl substituted with a sulfonyl. The term "substituent" refers to a group "substituted" in an alkyl group, cycloalkyl, aryl, heterocyclyl, or heteroaryl, in any atom of that group. Suitable substituents include, without limitation, halogen, hydroxy, mercapto, oxo, nitro, haloalkyl, alkyl, aryl, aralkyl, alkoxy, thioalkoxy, aryloxy, amino, alkoxycarbonyl, amido, carboxy, alkanesulfonyl, alkylcarbonyl and cyano groups. The term "Me" means methyl. The term "Ac" means acetyl. The term "dppf means 1,1-bis (diphenylphosphino) ferrocene The term" Mops "means 3- (N-morpholino) propanesulfonic acid The term" BSA "means bovine serum albumin The term" LAT "means a palmitoylated protein associated with the plasma membrane, of p36 / 38 kDa, expressed on all T lymphocytes, and is the physiological substrate of activated ZAP-70. The term "TMB" means S.S'.S.S'-tetramethylbenzidine. "kinase mediated disorder" means a disorder wherein a protein kinase is involved in the signaling, mediation, modulation or regulation of the process or symptoms of the disease.Kinease-mediated disorders are exemplified by the following classes of diseases and disorders: cancer, autoimmune, metabolic, inflammatory diseases, infection (bacterial, viral, yeast, fungus, etc.), diseases of the central nervous system, degenerative neural disease, allergy / asthma, diseases dermal, angiogenesis, neovascularization, vasculogenesis, cardiovascular disease, and the like.

TABLE 1 Representative compounds of the invention TABLE 1 (CONTINUED) Number Molecular structure TABLE 1 (CONTINUED) TABLE 1 (CONTINUED) TABLE 1 (CONTINUED) TABLE 1 (CONTINUED) TABLE 1 (CONTINUED) Molecular structure TABLE 1 (CONTINUED) Number Molecular structure TABLE 1 (CONTINUED) Molecular structure number TABLE 1 (CONTINUED) Molecular structure TABLE 1 (Continued) TABLE 1 (Continued) TABLE 1 (Continued) TABLE 1 (CONTINUED) Molecular structure number 66 TABLE 1 (CONTINUED) Number Molecular structure TABLE 1 (CONTINUED) Molecular structure number TABLE 1 (CONTINUED) S5 TABLE 1 (CONTINUED) Molecular structure number TABLE 1 (CONTINUED) Number Molecular structure TABLE 1 (CONTINUED) Number Molecular structure TABLE 1 (Continued) TABLE 1 (Continued) Molecular structure number TABLE 1 (Continued) Molecular structure number TABLE 1 (Continued) Number Molecular structure TABLE 1 (Continued) Number Molecular structure TABLE 1 (Continued) Molecular structure number 129 TABLE 1 (Continued) Number Molecular structure TABLE 1 ÍContinuacion) Number Molecular structure TABLE 1 (Continued) Molecular structure number TABLE 1 ÍContinuación) Molecular structure number QUADR0 1 (Continued) Molecular structure number 160 TABLE 1 (Continued) TABLE 1 (Continued) TABLE 1 (Continued) TABLE 1 (Continued) fifteen TABLE 1 (Continued) TABLE 1 (Continued) TABLE 1 (Continued) Molecular structure number TABLE 1 (Continued) TABLE 1 (Continued) Molecular structure number 202 TABLE 1 (Continued) Number Molecular structure TABLE 1 fContinuación) Molecular structure number TABLE 1 (Continued) TABLE 1 (Continued) Molecular structure 225 TABLE 1 (Continued) TABLE 1 (Continued) Molecular structure number TABLE 1 (Continued) TABLE 1 (Continued) TABLE 1 (Continued) QUADR0 1 (Continued) Molecular structure number TABLE 1 (Continued) Number Molecular structure TABLE 1 (Continued) Molecular structure TABLE 1 (Continued) TABLE 1 (Continued) QUADR0 1 (Continued) Number Molecular structure TABLE 1 (Continued) TABLE 1 (Continued) Number Molecular structure TABLE 1 (Continued) Molecular structure TABLE 1 fContinuation) TABLE 1 fContinuation) QUADR0 1 (Continued) Molecular structure TABLE 1 (Continued) Molecular structure number TABLE 1 (Continued) Number Molecular structure TABLE 1 (Continued) TABLE 1 (Continued) TABLE 1 (Continued) 20 TABLE 1 (Continued) Molecular structure number TABLE 1 (Continued) TABLE 1 (Continued) Number Molecular structure TABLE 1 (Continued) TABLE 1 (Continued) TABLE 1 (Continued) TABLE 1 (Continuation ^ TABLE 1 (Continued) TABLE 1 (Continued) TABLE 1 fContinuación) TABLE 1 (Continued) 305 TABLE 1 (Continued) Molecular structure number TABLE 1 (Continued) TABLE 1 (Continued) TABLE 1 (Continued) Four. Five TABLE 1 (Continued) TABLE 1 (Continued) TABLE 1 (Continued) 20 TABLE 1 (Continued) Molecular structure TABLE 1 Continuation) Number Molecular structure 436 TABLE 1 (Continued) Molecular structure number 44S TABLE 1 (Continued) 450 ** In the above structures, hydrogen atoms attached to secondary nitrogen atoms are not represented. The compounds, compositions and methods described herein are useful for inhibiting ZAP-70 and Syk. Accordingly, the compounds, compositions and methods described are useful for treating diseases or symptoms of diseases mediated by ZAP-70 and Syk in a mammal, in particular in a human. Diseases mediated by ZAP-70 and Syk are exemplified by the following: lupus, rejection of organ transplantation and inflammatory disorders. Examples of inflammatory disorders include arthritis (e.g. rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis or osteoarthritis), inflammatory bowel disease and Crohn's disease. The compounds, compositions and methods of the present invention are useful for treating, for example, lupus, rejection of organ transplantation (for example kidney, liver, heart, lung, pancreas (islet cells), bone marrow, cornea, intestine). thin, allografts or skin xenografts) and inflammatory disorders. Examples of inflammatory disorders include, without limitation, arthritis (e.g., rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis or osteoarthritis), asthma, allergy, eczema, inflammatory bowel disease, and Crohn's disease. . Other aspects of this invention relate to compositions having a compound of any of the formulas described herein and a pharmaceutically acceptable carrier; or a compound of any of the formulas described herein, an additional therapeutic agent (e.g., anti-inflammatory drugs, nonsteroidal anti-inflammatory drugs (NSAIDs), spheroids, and the like), and a pharmaceutically acceptable carrier; or a compound of any of the formulas described herein, an additional therapeutic agent and a pharmaceutically acceptable carrier, wherein the additional therapeutic agent is a kinase binding agent (eg, a polypeptide, an antibody or an organic molecule). Yet another aspect of this invention relates to a method of treating a subject (e.g., a mammal) having a disorder or symptom of a kinase-mediated disorder (including, without limitation, pain and inflammation). The method includes administering to the subject (which includes a subject identified in need of such treatment) an effective amount of a compound described herein, or a composition described herein, to produce such an effect. The identification of a subject in need of such treatment can be based on the criteria of a subject or a health care professional, and can be subjective (for example, an opinion) or objective (for example, measurable with a test or diagnostic method). The invention further relates to a product (ie, a compound of any of the formulas herein) made by the methods described above. The combinations of substituents and variables contemplated by this invention are only those that result in stable compounds. The term "stable", as used herein, refers to compounds that have sufficient stability to allow manufacture and whose integrity is maintained for a period sufficient to be useful for the purposes specified herein (e.g., their therapeutic administration or prophylactic to a subject).

Synthesis of heterocyclic kinase inhibitors The compounds of formula (II) (wherein the variables of all formulas (e.g. formula (II)) are as defined herein, are prepared by treating the compound of formula (IX) with malonic acid, to give a ring expansion compound, which is then coupled with a compound containing R2, to give the compound of formula (XII). formula (IX) formula (XII) The compound of formula (XII) is treated with a chlorinating agent, such as POCI3, and the carboxylic acid is coupled with a heterocyclic compound (for example heteroaryl or heterocyclyl) ("Het"), to give a compound of formula (XIII). formula (XII) formula (XIII) The resulting compound is then coupled with one or more coupling agents to give a compound of formula (Li).

Formula (XIII) Formula (II) Although the previous example is shown with a quinoline nucleus, other heterocyclic nuclei may also be used. For example, the above synthesis can be carried out by replacing the starting material of formula (IX) above with the following exemplary heterocycles: These compounds are illustrative only and do not limit the scope of the synthetic schemes. The term "coupling agent" means a chemical agent that is used in a reaction that forms a bond between a chemical portion and another chemical portion of the coupling agent. Some examples of coupling agents include transition metals, such as Pd, Cu and Mg and transition metal catalysts, as well as boron-containing compounds, such as boranes. Coupling agents can also include nucleophiles, such as amines, alkoxides, sulfides or the corresponding protonated forms. As the person skilled in the art can appreciate, for the persons with average knowledge in the matter, additional methods of synthesis of the compounds of the formulas of the present will be evident. In addition, the various synthetic steps can be performed in an alternative sequence or order to give the desired compounds. The synthetic chemical transformations and the protective group methodology (protection and deprotection), useful for synthesizing the compounds described herein, are known, and include for example those described by R. Larock, "Comprehensive Organic Transformations", VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 2nd ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, "Fieser and Fieser's Reagents for Organic 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. The compounds of this invention may contain one or more asymmetric centers and therefore occur as racemates and racemic mixtures, individual enantiomers, individual diastereomers and diastereomeric mixtures. All isomeric forms of these compounds are expressly included in the present invention. The compounds of this invention can also be represented in multiple tautomeric forms, in such cases, the invention expressly includes all tautomeric forms of the compounds described herein (for example, the alkylation of a ring system can produce alkylation at multiple sites, and the invention expressly includes all these reaction products). All of these isomeric forms of the compounds are expressly included in the present invention. All crystalline forms of the compounds described herein are expressly included in the present invention. As used herein, the compounds of this invention, which include the compounds of the formulas described above, include pharmaceutically acceptable derivatives or prodrugs thereof. A "pharmaceutically acceptable derivative or prodrug" means any salt, ester, salt of an ester or other pharmaceutically acceptable derivative of a compound of this invention that, after its administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention. Particularly favorable derivatives and prodrugs are those which increase the bioavailability of the compounds of this invention when administered to a mammal (for example by allowing an orally administered compound to be more readily absorbed into the blood), or which increase the supply of the original compound towards a biological compartment (for example the brain or the lymphatic system) with respect to the original species. Preferred prodrugs include derivatives wherein a group is added to the structure of the formulas described herein that increases aqueous solubility or active transport through the intestinal membrane. The compounds of this invention can be modified by adding appropriate functionalities to increase the selective biological properties. Such modifications are known in the art and include those that increase biological penetration in a given biological compartment (eg, blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter the metabolism and alter the rate of excretion. The pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, benzoate, benzenesulfonate, butyrate, citrate, digluconate, dodecylsulfate, formate, fumarate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, iodide, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, tosylate and undecanoate. Salts derived from appropriate bases include the alkali metal (eg sodium), alkaline earth metal (eg magnesium), ammonium and N- (alkyl) 4+ salts. This invention also contemplates the quaternization of any group containing basic nitrogen of the compounds described herein. By means of said quaternization, soluble or dispersible products can be obtained in water or oil. The compounds of the formulas described herein can be administered, for example, by intravenous, intraarterial, subdermal, intraperitoneal, intramuscular or subcutaneous injection.; or orally, orally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from approximately 0.001 to 100 mg / kg of body weight, preferably between 10 mg and 1000 mg / dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods of the present contemplate the administration of an effective amount of compound or composition to obtain the desired or declared effect. Normally, the pharmaceutical compositions of this invention will be administered approximately 1 to 6 times a day or, alternatively, as a continuous infusion. Said administration can be used as a chronic or acute therapy. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending on the host treated and the particular mode of administration. A typical preparation will contain about 5% to 95% active compound (w / w). Alternatively, said preparations contain about 20% to 80% active compound. Lower or higher doses than indicated may be required. The specific dosage and treatment regimens for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health status, sex and diet of the patient, the time of administration, the rate of excretion, the combination of drugs, the severity and course of the disease, condition or symptoms, the patient's disposition to the disease, condition or symptoms, and the criterion of the attending physician. After improvement of a patient's condition a maintenance dose of the compound, composition or combination may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, can be reduced depending on the symptoms, up to an amount in which the condition of improvement is retained. However, patients may require intermittent long-term treatment after any recurrence of the symptoms of the disease. The pharmaceutical compositions of this invention comprise a compound of the formulas described herein or a pharmaceutically acceptable salt thereof; an additional agent that includes for example a steroid or an analgesic; and any pharmaceutically acceptable carrier, adjuvant or excipient. The alternative compositions of this invention comprise a compound of the formulas described herein or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, adjuvant or excipient. The compositions described herein include the compounds of the formulas indicated herein and also additional therapeutic agents if present, in amounts effective to obtain a modulation of the disease or symptoms of disease, including kinase-mediated disorders or symptoms thereof. . The compositions are made by methods which include the steps of combining one or more compounds described herein with one or more carriers and, optionally, one or more additional therapeutic agents as described herein. The term "pharmaceutically acceptable carrier or adjuvant" refers to a vehicle or adjuvant that can be administered to a patient together with a compound of this invention, and that does not destroy the pharmacological activity thereof and is harmless when administered in sufficient doses. to supply a therapeutic amount of the compound. The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oily suspension. This suspension can be formulated according to known techniques using dispersing or wetting agents (such as for example Tween 80) and suitable 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 used are mannitol, water, Ringer's solution and sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspension media. For this purpose any soft fixed oil, including synthetic mono- or diglycerides, may be employed. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, just like natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyethoxylated versions. These oily solutions or suspensions may also contain a long chain alcohol diluent or dispersant, or carboxymethylcellulose or similar dispersing agent, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, such as emulsions or suspensions. For formulation purposes other commonly used surfactants, such as Tweens and Spans or other similar emulsifying agents, or bioavailability enhancers, which are commonly used in the manufacture of solid, liquid or other pharmaceutically acceptable dosage forms may also be used. dose. The pharmaceutical compositions of this invention can be administered orally in any orally acceptable dosage form including, without limitation, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, vehicles that are commonly used include lactose and corn starch. Lubricating agents such as magnesium stearate are also commonly added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oil phase and combined with emulsifying or suspending agents. If desired, certain sweetening or flavoring or coloring agents may be added. The pharmaceutical compositions of this invention can be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature, and therefore fuses in the rectum to release the active components. Such materials include, without limitation, cocoa butter, beeswax and polyethylene glycols. Pharmaceutically acceptable carriers, adjuvants and excipients that can be used in the pharmaceutical compositions of this invention, include, without limitation, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS), such as succinate a-tocopherol polyethylene glycol 1000, surfactants used in pharmaceutical dosage forms, such as Tweens or other similar polymeric delivery matrices, whey protein such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial mixtures of glyceride of saturated vegetable fatty oils, water, salts or electrolytes such as protamine sulfate, disodium acid phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol , sodium carboxymethylcellulose, polyacryl ats, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and wool grease. Cyclodextrins such as a-, β-, or cyclodextrin can also be advantageously used to increase the supply of compounds of the formulas described herein. In some cases, the pH of the formulation can be adjusted with pharmaceutically acceptable acids, bases or buffers to improve the stability of the formulated compounds or their delivery form. The term parenteral, as used herein, includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection, or infusion techniques. Topical administration of the pharmaceutical compositions of this invention is useful when the desired treatment includes areas or organs easily accessible by topical administration. For topical application to the skin, the pharmaceutical composition must be formulated in a suitable ointment containing the active components suspended or dissolved in a vehicle. Carriers for topical administration of the compounds of this invention include, without limitation, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene and polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated as a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents. Suitable carriers include, without limitation, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention can also be applied topically in the lower intestinal tract with a rectal suppository formulation or in a suitable enema formulation. Also included in this invention are transdermal topical patches. The pharmaceutical compositions of this invention can be administered by nasal spray or inhalation. Such compositions are prepared according to the known techniques of pharmaceutical formulations, and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to improve blockability, fluorocarbons or other known solubilizing or dispersing agents. When the compositions of this invention comprise a combination of a compound of the formulas described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent must be present in amounts of between about 1 to 100%, preferably between 5 and 95% of the dose normally administered in a monotherapy regimen. The additional agents can be administered separately from the compounds of this invention as part of a multiple dose regimen. Alternatively, the agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.

EXAMPLES EXAMPLE 1 Synthesis of 2-aminoquinolines 1 2 5-iodoisatin-1 (10 g, 36.3 mmol) and malonic acid (7.5 g, 72 mmol) in 200 mL of glacial acetic acid were refluxed overnight. The precipitate was collected by filtration and washed with AcOH and acetone. The solid was then refluxed with EtOH for 1 h. Filtration and washing with EtOH and Et20 yielded 6-iodo-2-oxo-1,2-dihydro-quino-4-carboxylic acid, 2, yielding 8.8 g (76%). 1 H-NMR (400 MHz, DMSO-de): d 14.0 (br s, 1 H), 12.13 (s, 1 H), 8.56 (d, 1 H, J = 8.1 Hz), 7.83 (dd, 1 H, J = 8.7.1.8 Hz), 7.17 (d, 1H, J = 8.4 Hz), 6.93 (s, 1 H).

A mixture of 6-iodo-2-oxo-1,2-dihydro-quinoline-4-carboxylic acid 2 (3.15 g, 10 mmol), 3,4- (methylenedioxyl) phenylboronic acid (2.49 g, 15 mmol) , K3P04 (8.49 g, 40 mmol), and Pd (OAc) 2 (112 mg, 0.5 mmol) in 60 mL of degassed H20, was heated under argon at 60 ° C for 2 h. After cooling to room temperature, the solid was collected by filtration, washed with H20 and acetone. After treated with 20 mL of 1M HCl, the resulting greenish yellow solid was refiltered and washed with H2O. Drying under vacuum over P205 gave 2.53 g (82%) of product 3 as a yellow-green solid. 1 H-NMR (400 MHz, DMSO-d 6): d 14.0 (br s, 1 H), 12.11 (s, 1 H), 8.34 (s, 1 H), 7.79 (d, 1 H, J = 7.6 Hz), 7.40 (d, H, J = 8.6 Hz), 7.18 (s, 1 H), 7.08 (d, 1 H, J = 7.1 Hz), 7.01 (d, 1 H, J = 8.2 Hz), 6.91 (s, 1 H), 6.06 (s, 2H). 6-Benzo [1,3] dioxol-5-yl-2-oxo-1,2-dihydro-quinoline-4-carboxylic acid 3 (1.0 g, 3.2 mol) in 10 mL of oxyphosphorus chloride was refluxed during reflux. 4h, and then cooled to room temperature. The solution was concentrated to dryness to yield a brownish yellow solid. The solid was then dissolved in 20 mL of methylene dichloride. Diisopropylethylamine (1.50 g, 1.5 mmol) and 2- (S) -pyrrolidinylmethyl-pyrrolidine (0.59 g, 3.84 mmol) were added slowly at 0 ° C to the solution. The mixture was allowed to stir at room temperature for 12 h. After the solvent was removed by rotary evaporation, the residue was dissolved in ethyl acetate, washed with saturated aqueous solution of NaHCO 3 and brine. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (EtsN-AcOEt 5:95), to give (6-benzo [1,3] di0xol-5-yl-2-doro-quinolin-4-yl) - ( 2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl) -metadone, 4 (1.20 g, 81%). MS m / z 464.2 (M ++ 1); 1 H-NMR (400 MHz, CDCl 3): d 8.05 (m, 1 H), 7.93 (m, 1 H), 7.85 (br s, 1 H), 7.41 (s, 1 H), 7.13 (m, 1 H ), 7.11 (s, 1H), 6.92 (m, 1 H), 6.03 (s, 1 H), 4.58 (m, 1 H), 3.92 (m, 0.5H), 3.75 (m, 0.5H), 3.38 -3.13 (m, 2H), 2.94 (m, 3H), 2.35-2.15 (m, 2H), 2.04 (m, 3H), 2.01-1.85 (m, 4H), 1.83 (m, 1 H).

The 2-chloroquinoline 4 (80 mg, 0.17 mg) was heated for 12 h at 120 ° C in benzylamine (0.3 mL). An LC-MS analysis indicated that the reaction was complete. The reaction mixture was then dissolved in 3 mL of DMSO / CH3CN (3: 1), and purified by preparative LC to give product 5. MS m / z 535.3 (M ++ 1).

EXAMPLE 2 Synthesis of 2-alkylquinolines The solution of 4-chlorobenzyl magnesium chloride (0.43 mL, 0.25 M solution in Et20) was added to a mixture of 2-chloroquinoline 4 (25 mg, 0.054 mg) and PdCI2 (dppf) (2.2 mg, 0.0027 mmol) in 0.5 mL of dioxane, under argon. The reaction mixture was stirred at 100 ° C for 12 h. After cooling to room temperature, aqueous NH 4 Cl solution was added. The mixture was extracted with EtOAc and washed with brine. The organic layer was dried over Na2SO4, and concentrated. The residue was purified by preparative LC to give product 6. MS m / z 554.3 (M ++ 1).

EXAMPLE 3 Synthesis of 6-substituted quinolines Procedure A To a 25 ml round bottom flask loaded with bis (pinacoate) diborus (279 mg, 1.1 mmol), KOAc (294, 3.0 mmol) and PdCI2 (dppf) (24.5 mg, 0.03 mmol), was added a solution of 6-iodoquinoline 7 (607 mg, 1.0 mmol) in DMSO (6 mL). The mixture was completely degassed by alternately connecting the flask to vacuum and to argon. This resulting mixture was then heated to 80 ° C overnight, diluted with EtOAc (40 mL) and filtered through CELITE. The resulting product, 8, after concentrating, was used in the following steps without further purification. The molecular weight is 608.3 and the LC-MS showed 609.2 (M ++ 1).

Under argon, 6-boronate 8 (15 mg, 0.025 mmol) in dioxane (2.0 mL) was added to the flask which was charged with Pd (dppf) CI2 (2 mg), CS2CO3 (17 mg, 0.055 mmol), and 3 , 4-ethylenedioxyiobenzene (15 mg, 0.057 mmol). The mixture was completely degassed by alternately connecting the flask to vacuum and to argon. The resulting solution was heated to 70 ° C and stirred overnight. It was diluted with EtOAc after cooling to room temperature. The solid was removed by filtration through CELITE and washed with some EtOAc. It was concentrated to remove the solvent and the resulting residue was purified by LC to give the product 9. The exact mass is 616 and the LC-MS showed 617 (++ 1).

Procedure B A reaction vessel was loaded with 6-iodoquinoline 7 (25.0 mg, 0.041 1 mmol, 1.00 eq), Pd (dppf) CI2 (1.5 mg, 0.0021, 0.050 eq), K3PO4 (35.0 mg, 0.164 mmol, 4.00 eq) and 3,5-dichlorophenylboronic acid (15.7 mg, 0.0811 mmol, 2.00 eq). After flooding the vessel with argon, dioxane (2.0 mL) was introduced under argon and the resulting suspension was stirred overnight at 80 ° C. The crude reaction mixture was allowed to cool to room temperature, filtered through CELITE with the aid of EtOAc and concentrated. The crude residue was purified by LC to give product 10. LC-S m / z 627.2 (M ++ 1). An identical procedure was used for the synthesis of 6-aryl-quinolines from the corresponding 6-bromo-quinoline.

Procedure C To a round bottom flask loaded with 6-iodoquinoline 7 (61 mg, 0.1 mmol), phenylacetylene (1 molar equivalent), Pd (PPh 3) 2 Cl 2 (4.0 mg), and Cul (1.0 mg), was added Et 3 N ( 2 mL). The mixture was completely degassed by connecting the flask alternately to vacuum and argon, and then it was heated to 45-50 ° C and stirred overnight. The mixture was diluted with EtOAc (20 mL) after cooling to room temperature and filtered through CELITE. After concentrating, the crude product 11 was used in the next step without further purification. A small portion was purified by LC. The exact mass is 582 and the LC-MS showed 583 (M ++ 1).

Under H2 (1 atm), the crude acetylene compound 1 (15 mg) was reduced with H2 in the presence of 5% Pd / C (5 mg) in methanol, at room temperature, overnight. The mixture was filtered through CELITE to remove the catalyst and concentrated under reduced pressure to give the crude product. Compound 12 was further purified by LC. The exact mass is 586 and the LC-MS showed 587 (M ++ 1).

Under H2 (1 atm), the crude acetylene compound 11 (15 mg) was reduced in the presence of 5% palladium in barium sulfate (5 mg) in methanol, at room temperature, overnight. The mixture was filtered through CELITE to remove the catalyst and concentrated under reduced pressure to give the crude product. The preparative LC gave the pure product 13 for analysis. The exact mass is 584 and the LC-MS showed 585 (M ++ 1).

EXAMPLE 4 Synthesis of 2-thioquinolines Under argon, to the solution of 2-chloroquinoline 4 (15 mg, 0.032 mmol) and 4-chlorobenzyl mercaptan (8.6 mg, 0.048 mmol) in dry DMF (1.0 mL), was added Cs2C03 (16 mg, 0.048 mmol). The resulting mixture was heated to 80 ° C and stirred at this temperature for two hours. After cooling to room temperature, EtOAc (20 mL) was added to dilute the mixture and the organic phase was washed with water and brine and dried over Na2SO4. After concentration, the residue was purified by LC to give product 14. The exact mass is 586 and the LC-MS showed 587 (M ++ 1).

EXAMPLE 5 Test DELFIA Before starting the kinase reactions, the compounds were preincubated with ZAP-70. The preincubation reactions contained Mops 62.5 mM, pH 7.0, 12.5 mM MgCl2, 12.5% glycerol, 3.1 nM ZAP-70, 62.5 nM biotinylated poly (glu, Tyr), 0.1 mg / ml BSA, 6.25% DMSO and 0-100 mM of compound, in a total volume of 40 ml. After a 10 minute incubation at room temperature, 10 ml of 5 mM ATP was added to start the reaction. The reactions were incubated at room temperature for 30 minutes and were terminated by adding 5 ml of 500 mM EDTA. The amount of phosphate transferred to poly (glu, biotinylated tyr) was measured using the enhanced lanthanide fluorescence immunoassay by dissociation (DELFIA) from Perkin Elmer, according to the manufacturer's protocol. Briefly, biotinylated poly (gly, tyr) was captured in streptavidin-coated plates, washed twice and then incubated with europium-labeled anti-phosphotyrosine antibody. The free antibody was removed with six washes. The europium was dissociated from the antibody and the europium fluorescence was measured using an excitation wavelength of 340 nm and an emission wavelength of 615 nM.

TABLE 2 In vitro activity of representative compounds Number Activity 1 B 2 B 3 A 4 C 5 B A TO A A 10 A 1 1 B 12 C 13 C 14 TO 15 C 16 C 17 C 18 C 19 C 20 A 21 A 22 C 23 C 24 C 25 C 26 A 27 C 28 A 29 B 30 C 31 C 32 A 33 B 34 B 35 C 36 C 37 C 38 B 39 B 40 C 41 C 42 B 43 C 44 C 45 C 46 C 47 B 48 B 49 B 50 C 51 C 52 C 53 C 54 C 55 C 56 C 57 C 58 B 59 B 60 C 61 B 62 B 63 B 64 B 65 C 66 B 67 A 68 C 69 A 70 C 71 A 72 B 73 B 74 B 75 B 76 C 77 C 78 B 79 B 80 A 81 B 82 B 83 B 84 A 85 B 86 B 87 A 88 A 89 B .90 B 91 C 92 C 93 A 94 B 95 B 96 B 97 B 98 C 99 C 100 A 101 B 102 B 103 B 104 B 105 C 106 C 107 C 108 B 109 B 110 A 11 1 A 112 A 113 A 114 A 115 A 116 B 117 C 1 18 B 119 A 120 B 121 B 122 B 123 B 124 B 125 C 126 C 127 C 128 A 129 B 130 B 131 B 132 B 133 B 134 B 135 B 136 B 137 B 138 A 139 B 140 C 141 B 143 B 144 B 145 B 146 B 147 B 148 B 149 B 150 A 151 A 152 A 153 A 154 A 155 A 156 A 157 A 158 A 159 A 160 A 161 A 162 A 163 A 164 A 165 A 166 A 167 A 168 A 169 A 170 A 171 A 172 A 173 A 174 A 175 A 176 A 177 A 178 A 179 A 180 A 181 A 182 A 183 A 184 A 185 A 186 A 187 A 188 A 89 A 190 A 191 A 192 A 193 A 194 A 195 A 196 A 197 A 198 A 199 TO 200 A 201 A 202 A 203 A 204 A 205 A 206 A 207 A 208 A 209 A 210 A 211 A 212 A 213 A 214 A 215 A 216 A 217 A 218 A 219 A 220 A 221 A 222 A 223 A 224 A 225 A 226 A 227 A 228 A 229 A 230 A 231 A 232 A 233 A 234 A 235 A 236 A 237 A 238 A 239 A 240 A 241 A 242 A 243 A 244 A 245 A 246 A 247 A 248 A 249 A 250 A 251 A 252 A 253 A 254 A 255 A 256 A 257 A 258 A 259 A 260 A 261 A 262 A 263 A 264 A 265 A 266 A 267 A 268 A 269 A 270 A 271 A 272 A 273 A 274 A 275 A 276 A 277 A 278 A 279 A 280 C 281 C 282 B 283 C 284 C 285 B 286 C 287 B 288 B 289 B 290 B 291 A 292 C 293 B 294 C 295 B 296 B 297 A 298 B 299 C 300 C 301 1,785 μ? 302 C 303 C 304 B 305 C 306 C 307 B 308 B 309 B 310 C 311 B 312 B 313 B 314 B 315 C 316 B 317 C 318 B 319 C 320 B 321 B 322 323 A 324 C 325 C 326 C 327 A 328 B 329 A 330 C 331 C 332 A 333 A 334 A 335 A 336 A 337 A 338 A 339 A 340 A 341 A 342 A 343 A 344 C 345 A 346 A 347 A 348 C 349 C 350 A 351 C 352 C 353 A 354 A 355 A 356 A 357 B 358 C 359 C 360 B 361 B 362 A 363 B 364 B 365 B 366 B 367 A 368 A 369 A 370 A 371 A 372 B 373 B 374 B 375 B 376 B 377 A 378 A 379 A 380 A 381 A 382 A 383 A 384 C 385 B 386 B 387 B 388 B 389 C 390 A 391 A 392 C 393 C 394 A 395 C 396 C 397 C 398 C 399 A 400 C 401 C 402 C 403 C 404 C 405 C 406 C 407 C 408 A 409 A 410 C 411 C 412 A 413 B 414 A 415 A 416 A 417 A 418 A 419 A 420 A 421 A 422 A 423 A 424 A 425 A 426 A 427 A 428 C 429 C 430 C 431 B 432 C 433 C 434 C 435 C 436 C 437 C 438 C 439 C 440 C 441 C 442 C 443 C 444 C 445 C 446 C 447 C 448 C 449 C * "?" Means that the compound has a Cl50> 10 μ? In vitro, "B" means that the compound has an Cl50 between 1 and 10 μ? in vitro, and "C" means that the compound has a Cl50 < 1 μ? in vitro EXAMPLE 6 Testing of cell-based ZAP-70 mediated LAT phosphorylation The activity of the tyrosine kinase ZAP-70 present in the activated Jurkat T cells was measured by determining the phosphorylation state of LAT. LAT is a palmitoylated p36 / 38 kDa protein associated with the plasma membrane, expressed in all T lymphocytes, and is the physiological substrate of activated ZAP-70. When Jurkat cells are stimulated with an anti-CD3 monoclonal antibody, which is intertwined with the surface-CD3 antigen receptor complex, ZAP-70 is activated and phosphorylates two tyrosine residues in LAT, Tyr-191 and Tyr-226 . Therefore, the determination of the phosphorylation of Tyr-191 and Tyr-226 of LAT in Jurkat T cells stimulated with anti-CD3, is a specific measure of the intracellular activity of ZAP-70.

Accordingly, compounds that inhibit the phosphorylation of Tyr-191 and Tyr-226 of LAT indicate a successful antagonism of the tyrosine kinase activity ZAP-70 or the preceding activation of the ZAP-70 pathway. Jurkat cells (ATCC) grown at 15-20 X 10 6 cells / mL are preincubated for 15 minutes at 37 ° C with inhibitory compounds or vehicle (DMSO), and then stimulated for 5 minutes by adding a final concentration of 1 mg / mL monoclonal antibody anti-CD3 (UCHT-1 or OKT-3; E-Bioscience). The cells are then lysed with a detergent-based buffer and the extracts are used for immunoprecipitation of all phosphotyrosine-containing proteins, using a commercially available phosphotyrosine-specific monoclonal antibody (4G10, Upstate Biotechnology Inc.) and agarose beads conjugated to Protein A. After washing the immune complexes to remove bound proteins unspecifically, the immunoprecipitated phosphotyrosine proteins are released from the boiling and denaturing agarose beads, and separated by SDS-PAGE and transferred to nitrocellulose membranes. Phosphorylated LAT is then detected in Tyr-191 and Tyr-226 by standard Western blotting technology, using commercially available phospho-specific antibodies that react specifically with phospho-Tyr-191 or phospho-Tyr-226 in LAT (Upstate Biotechnology Inc. ), an enzyme conjugated secondary antibody (goat rabbit anti-IgG antiserum conjugated to horseradish peroxidase), and a Storm Imaging system (Amersham-Pharmacia).

Inhibition was observed with the representative compounds described herein.

EXAMPLE 7 Cell-based IL-2 inhibition test The production of IL-2 was measured in Jurkat cells after co-stimulation with anti-CD3 and anti-CD28 antibodies. Cells were seeded at 1 x 105 / well (200 μl / culture well) in 96-well plates precoated with anti-CD3 antibody (BD Biocoat T cell activation plates, human anti-CD3 plate = Cat. No. 354725 from BD BioSciences). Anti-CD28 antibody (eBioScience, Cat # 16-0289-85, functional grade, co-stimulator, clone 28.2) was added to the plate at the final concentration of 20 ng / well. The cells were incubated 48 h, after which a 50 μ aliquot was removed. of cellular supernatant for the titration of IL-2. The titration of IL-2 was done using the Endogen enzyme-linked immunosorbent (ELISA) test kit (Endogen of Pierce, Cat # EH2-IL2-5) as described by the manufacturer. In summary, this test consists of using a 96-well microtiter plate that has been pre-coated with anti-IL-2 antibodies to capture human IL-2. To detect the captured IL-2, a second biotinylated anti-IL-2 antibody is added to all the cavities. This results in a sandwich of any IL-2 (capture of Ab IL-2 C detection IL-2 C-Ab biotin).

After removing unbound antibodies with a series of washes, a horseradish peroxidase conjugate (HRP) with a high affinity for biotin is added. The unbound HRP-streptavidin is removed and then the enzyme-linked bound antibodies can be measured by means of a chromogenic reaction by adding TMB substrate. The resulting chromogenic reaction is stopped using H2SO4 (stop solution) and the optical density of each well is then read at the appropriate wavelength. The degree of substrate conversion is determined colorimetrically by measuring the absorbance, which is proportional to the amount of IL-2. The representative compounds described herein showed inhibition of IL-2. All references cited herein, printed, electronic, on computer readable storage media, or otherwise, are expressly incorporated in their entirety as a reference, including without limitation summaries, articles, journals, publications, texts, treaties, web sites, Internet, databases, patents and patent publications. Various embodiments of the invention have been described. However, it will be understood that various modifications can be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

Claims (45)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound of formula (I): formula (I) wherein: A forms a ring of benzene, pyridine, pyrimidine, thiophene, pyrrole, imidazole, pyrazole, thiazole, or oxazole; X is O, S, NR3, N (R3) N (R3), C (O), N (R5) C (0), C (0) NR5, or alkyl; R x is H, cycloalkyl, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, R 50 -alkyl, (R 5) 3 Si, acyl, wherein R is optionally substituted with 1-4 R 4; each R2 is, independently, H, NR52, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halogen, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each one of which is optionally substituted with 1-4 R7, wherein R2 is not Me when X-Rx is Me and Q is NH-aryl substituted with heterocyclyl; and wherein R2 is not acetyl when X-Rx is arylalkenyl; n is 0-3; each R3 is, independently, H, alkyl, Realkyl, or arylalkyl; each R4 is, independently, halogen, OH, CF3, C (0) R5, NR32, N (R3) C (0) R5, CN, OCF3, S02R5 or SR53; or alkyloxy, aryloxy, alkyl, heterocyclyl, R50-alkyl, cycloalkyl, aryl, alkylthio, haloalkyloxy, heteroaryl, or arylalkium, each of which is optionally substituted with 1-4 R6; each R5 is, independently, H, or alkyl; each R6 is, independently, halogen, OH, CF3, alkyl, alkyloxy, N (R5) -alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl; each R7 is, independently, halogen, CN, OR5, CF3 > N (R5) C (0) R5, C (0) R5, OCF3, SCF3, NR52, C (0) NR52, OH, R50-alkyl, alkyl, alkylsulfonyl, heterocyclyl, or heteroaryl, each of which is substituted optionally with 1-4 R8; each R8 is, independently, OR5 or alkyl; Q is H, halogen, C (0) R5, C (0) R9, C (S) R5, C (S) R9, C (0) NR52, C (0) NR5R9, S (0) R5, S ( 0) R9, S (0) NR52, S (0) NR5R9, S02R5, S02R9, S02NR52, S02NR5R9, NR52, NR5R9, R9S-alkyl, alkyl, or heterocyclyl, wherein each alkyl or heterocyclyl is optionally substituted with 1-4 R 0; each R9 is, independently, aryl, heterocyclyl, heteroaryl, arylalkio, or heteroarylalkyl, each of which is optionally substituted with 1-4 R10; each R10 is, independently, alkyl, CF3, C (NH) NR5R11, C (NH) R11, CN, R52N-alkyl, NR5R1-alkyl, Realkyl, R1, heteroaryl, heterocyclyl, or heterocyclylalkyl, each which is optionally substituted with alkyl or OR5; and each R 11 is, independently, arylalkio, heteroarylalkyl, cycloalkyl, or heterocyclyl. 2. The compound according to claim 1, further characterized in that A forms a benzene ring. 3. The compound according to claim 1, further characterized in that it is of the formula (II): formula (II) wherein: X is O, S, NR3, N (R3) N (R3), C (O), N (R5) C (0), C (0) NR5, or alkyl; R x is H, cycloalkyo, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, arylalkenium, heteroarylanyl, arylalkynyl, heteroarylalkynyl, R 50 -alkyl, (R 5) 3 Si, acyl, wherein R x is optionally substituted with 1-4 R 4; each R2 is, independently, H, NR52, alkyl, cycloalkio, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halogen, acetyl, arylalkyl, heteroarylalkyl, arylalkeniio, heteroarylalkonyl, arylalkyl, heteroarylalkyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each one of which is optionally substituted with 1-4 R7; each R2 'is, independently, H, halogen, NH2, alkyl, OH, C (0) Me, aryl, heteroaryl; each R3 is, independently, H, alkyl, Realkyl, or arylalkyl; each R4 is, independently, halogen, OH, CF3, C (O) R5, NR32, N (R3) C (O) R5, CN, OCF3, SO2R5, or SiR53; or alkyloxy, aryloxy, alkyl, heterocyclyl, R50-alkyl, cycloalkio, aryl, alkylthio, haloalkyloxy, heteroaryl, or arylalkyl, each of which is optionally substituted with 1-4 R6; each R5 is, independently, H or alkyl; each R6 is, independently, halogen, OH, CF3, alkyl, alkyloxy, N (R5) -alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl; each R7 is, independently, halogen, CN, OR5, CF3, N (R5) C (0) R5, C (0) R5, OCF3, SCF3, NR52, C (0) NR52, OH, R5O-alkyl, alkyl, alkylsulfonyl, heterocyclyl, or heteroaryl, each of which is optionally substituted with 1-4 R8; each R8 is, independently, OR5 or alkyl; Het is heterocyclyl optionally substituted with 1-4 R10; each R10 is, independently, alkyl, CF3, C (NH) NR5R11, C (NH) R11, CN, R52-N-alkyl, NR5R1-alkyl, R5O-alkyl, R11, heteroaryl, heterocyclyl, or heterocyclylalkyl, each which is optionally substituted with alkyl or OR5; and each R1 is, independently, arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl. 4. The compound of formula (II) according to claim 3, further characterized in that Het is attached by means of a ring nitrogen atom. 5. The compound of formula (II) according to claim 3, further characterized in that R2 'is H. 6. The compound of formula (II) according to claim 3, further characterized in that Het is bound by of a ring nitrogen atom; X is NR3 or alkyl; and R x is cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or heterocyclic, wherein R x is optionally substituted with 1-4 R 4; and R2 is H. 7. The compound of formula (II) according to claim 3, further characterized in that Het is: 8. - The compound of formula (II) according to claim 3, further characterized in that Het is: 9. The compound according to claim characterized further in that it is of the formula (III): formula (lil) wherein: X is O, S, NR3, N (R) N (R3), C (O), N (R5) C (0), C (0) NR5, or alkyl; R x is H, cycloalkyl, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, R 50 -alkyl, (R 5) 3 Si, acyl, wherein R x is optionally substituted with 1-4 R 4; each R2 is, independently, H, NR52, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halogen, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each one of which is optionally substituted with 1-4 R7; wherein R2 is not Me when X-Rx is Me and R12 is aryl substituted with heterocyclyl; each R2 'is, independently, H, halogen, NH2, alkyl, OH, C (O) Me, aryl, heteroaryl; each R3 is, independently, H, alkyl, R5O-alkyl or arylalkyl; each R4 is, independently, halogen, OH, CF3, C (O) R5, NR32, N (R3) C (O) R5, CN, OCF3, S02R5, or SiR53; or alkyloxy, aryloxy, alkyl, heterocyclyl, R5O-alkyl, cycloalkyl, aryl, alkylthio, haloalkyloxy, heteroaryl or arylalkyl, each of which is optionally substituted with 1-4 R6; each R5 is, independently, H or alkyl; each R6 is, independently, halogen, OH, CF3, alkyl, alkyloxy, N (R5) -alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl; each R7 is, independently, halogen, CN, OR5, CF3, N (R5) C (0) R5, C (O) R5, OCF3, SCF3 (NR52, C (O) NR52, OH, R5O-alkyl, alkyl, alkylsulfonyl, heterocyclyl, or heteroaryl, each of which is optionally substituted with 1-4 R8, each R8 is independently OR5 or alkyl, each R12 is independently aryl or heteroaryl, optionally substituted with 1-4 R3; and each R13 is independently heterocyclyl optionally substituted with alkyl or OR5 10. The compound of formula (III) according to claim 9, further characterized in that R2 is H. 11. The compound of formula (III) of according to claim 9, further characterized in that R12 is: 12. - A compound of formula (IV): formula (IV) wherein: X is O, S, NR3, N (R3) N (R3), C (O), N (R5) C (0), C (0) NR5, or alkyl; R x is H, cycloalkyl, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, R 50 -alkyl, (R 5) 3 Si, acyl, wherein R x is optionally substituted with 1-4 R 4; each R2 is, independently, H, NR52, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halogen, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each one of which is optionally substituted with 1-4 R7; wherein R2 is not Me when X-Rx is Me and Q is NH-aryl substituted with heterocyclyl; and wherein R2 is not acetyl when X-Rx is arylalkenyl; each R3 is, independently, H, alkyl, RsO-alkyl or arylalkyl; each R4 is, independently, halogen, OH, CF3, C (0) R5, NR32, N (R3) C (0) R5, CN, OCF3, S02R5, or SiR53; or alkyloxy, aryloxy, alkyl, heterocyclyl, R50-alkyl, cycloalkyl, aryl, alkylthio, haloacyloxy, heteroaryl, or arylalkyl, each of which is optionally substituted with 1-4 R6; each R5 is, independently, H or alkyl; each Rs is, independently, halogen, OH, CF3, alkyl, alkyloxy, N (R5) -alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl; each R7 is, independently, halogen, CN, OR5, CF3, N (R5) C (0) R5, C (0) R5, OCF3, SCF3, NR52, C (0) NR52, OH, R50-alkyl, alkyl, alkylsulfonyl, heterocyclyl, or heteroaryl, each of which is optionally substituted with 1-4 R8; each R8 is, independently, OR5 or alkyl; Q is H, halogen, C (0) R5, C (0) R9, C (S) R5, C (S) R9, C (0) NR52, C (0) NR5R9, S (0) R5, S ( 0) R9, S (0) NR52, S (0) NR5R9, S02R5, S02R9, S02NR52, S02NR5R9, NR52, NR5R9, R9S-alkyl, alkyl, or heterocyclyl, wherein each alkyl or heterocyclyl is optionally substituted with 1-4 R10; each R 9 is, independently, aryl, heterocyclyl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted with 1-4 R 0; each R10 is, independently, alkyl, CF3, C (NH) NR5R11, C (NH) R11, CN, R52N-alkyl, NR5R11-alkyl, Realkyl, R1, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is optionally substituted with alkyl or OR5; each R 11 is, independently, arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl; and R14 is halogen, NH2, alkyl, OH, C (0) Me, aryl, heteroaryl, or C (0) NHR5. 13. A compound of formula (V): formula (V) wherein: A forms a ring of benzene, pyridine, pyrimidine, thiophene, pyrrole, imidazole, pyrazole, thiazole, or oxazole; Ry is H, halogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl, wherein Ry is optionally substituted with 1-4 R4; each R2 is, independently, H, NR52, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halogen, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each one of which is optionally substituted with 1-4 R7; wherein R2 is not Me when Ry is halogen, indole substituted with halogen, phenyl, or phenyl substituted with halogen; wherein R2 is not isopropyl when Ry is phenyl substituted with halogen; wherein R2 is not alkynyl substituted with heterocyclyl when Ry is indole substituted with halogen; wherein R2 is not phenyl when Ry is H; wherein R2 is not halogen when Ry is indole substituted with halogen or phenyl substituted with halogen; and wherein R2 is not acetyl when Ry is phenyl or substituted phenyl; n is 0-3; each R3 is, independently, H, alkyl, R50-alkyl, or arylalkyl; each R4 is, independently, halogen, OH, CF3, C (O) R5, NR32, N (R3) C (O) R5, CN, OCF3, SO2R5, or SiR53; or alkyloxy, aryloxy, alkyl, heterocyclyl, R5O-alkyl, cycloalkyl, aryio, alkylthio, haloalkyloxy, heteroaryl, or arylalkyl, each of which is optionally substituted with 1-4 R6; each R5 is, independently, H or alkyl; each R6 is, independently, halogen, OH, CF3, alkyl, alkyloxy, N (R5) -alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl; each R7 is, independently, halogen, CN, OR5, CF3, N (R5) C (O) R5, C (O) R5, OCF3, SCF3, NR52, C (O) NR52, OH, R5O-alkyl, alkyl, alkylsulfony, heterocyclyl, or heteroaryl, each of which is optionally substituted with 1-4 R8; each R8 is, independently, OR5 or alkyl; Q is H, halogen, C (O) R5, C (O) R9, C (S) R5, C (S) R9, C (O) NR52, C (O) NR5R9, S (O) R5, S ( O) R9, S (O) NR52, S (O) NR5R9, SO2R5, SO2R9, SO2NR52, SO2NR5R9, NR52, NR5R9, R9S-alkyl, alkyl, or heterocyclyl, wherein each alkyl or heterocyclyl is optionally substituted with 1 -4 R10; each R 9 is, independently, aryl, heterocyclyl, heteroaryl, arylalkyl or heteroarylalkyl, each of which is optionally substituted with 1-4 R 0; each R10 is, independently, alkyl, CF3, C (NH) NR5R11, C (NH) R11, CN, R52N-alkyl, NR5R1-alkyl, R5O-alkyl, R1, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of the which is optionally substituted with alkyl or OR5; and each R 11 is, independently, arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl. 14. - The compound of formula (V) according to claim 13, further characterized in that A forms a benzene ring. 15. The compound according to claim 13, further characterized in that it is of the formula (VI): formula (VI) wherein: Ry is H, halogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl, wherein Ry is optionally substituted with 1-4 R4; each R2 is, independently, H, NR52, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halogen, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each one of which is optionally substituted with 1-4 R7; wherein R2 is not Me when Ry is halogen, indole substituted with halogen, phenyl, or phenyl substituted with halogen; wherein R2 is not isopropyl when Ry is phenyl substituted with halogen; each R2 is, independently, H, halogen, NH2, alkyl, OH, C (O) Me, aryl, heteroaryl; each R3 is, independently, H, alkyl, R5O-alkyl, or arylalkyl; each R4 is, independently, halogen, OH, CF3, C (O) R5, NR32, N (R3) C (O) R5, CN, OCF3) SO2R5, or SiR53; or alkyloxy, aryloxy, alkyl, heterocyclyl, R50-alkyl, cycloalkyl, aryl, alkylthio, haloalkyloxy, heteroaryl, or arylalkyl, each of which is optionally substituted with 1-4 R6; each R5 is, independently, H or alkyl; each R6 is, independently, halogen, OH, CF3, alkyl, alkyloxy, N (R5) -alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl; each R7 is, independently, halogen, CN, OR5, CF3, N (R5) C (O) R5, C (O) R5, OCF3, SCF3, NR52, C (O) NR52, OH, R5O-alkyl, alkyl, alkylsulfonyl, heterocyclyl, or heteroaryl, each of which is optionally substituted with 1-4 R8; each R8 is, independently, OR5 or alkyl; Het is heterocyclyl optionally substituted with 1-4 R10; each R 0 is, independently, alkyl, CF 3, C (NH) NR 5 R C (NH) R 11, CN, R 52 N-alkyl, NR 5 R 11 -alkyl, R 5 O-alkyl, R 11, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which which is optionally substituted with alkyl or OR5; and each R 11 is, independently, arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl. 16. The compound of formula (VI) according to claim 15, further characterized in that Het is attached by means of a nitrogen atom of the ring; R2 is not H; and R2 'is H. 17. The compound of formula (VI) according to claim 15, further characterized in that Het is: 18. - The compound of formula (VI) according to claim 15, further characterized in that Het is: 19. The compound according to claim further characterized in that it is of the formula (VII): formula (VII) wherein: Ry is H, halogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkyne , wherein Ry is optionally substituted with 1-4 R4; each R2 is, independently, H, NR52, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halogen, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each one of which is optionally substituted with 1-4 R7; wherein R2 is not phenyl when Ry is H; each R2 is, independently, H, halogen, H2, alkyl, OH, C (0) Me, aryl, heteroaryl; each R3 is, independently, H, alkyl, R50-alkyl, or arylalkyl; each R4 is, independently, halogen, OH, CF3, C (O) R5, NR32, N (R3) C (0) R5, CN, OCF3, S02R5, or SiR53; or alkyloxy, aryloxy, alkyl, heterocyclyl, R50-alkyl, cycloalkyl, aryl, alkylthio, haloalkyloxy, heteroaryl, or arylalkyl, each of which is optionally substituted with 1-4 R6; each R5 is, independently, H or alkyl; each R6 is, independently, halogen, OH, CF3, alkyl, alkyloxy, N (R5) -alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl; each R7 is, independently, halogen, CN, OR5, CF3, N (R5) C (O) R5, C (O) R5, OCF3 > SCF3, NR52, C (0) NR52, OH, R50 -alkyl, alkyl, alkylsulfonyl, heterocyclyl, or heteroaryl, each of which is optionally substituted with 1-4 R8; each R8 is, independently, OR5 or alkyl; each R12 is, independently, aryl or heteroaryl, optionally substituted with 1-4 R13; and each R 3 is, independently, heterocyclyl optionally substituted with alkyl or OR 5. 20. The compound of formula (VII) according to claim 19, further characterized in that R2 is not H; and R2 is H. 21. The compound of formula (VII) according to claim 19, further characterized in that R 2 is: 22. - A compound of formula (VIII): formula (VIII) wherein: Ry is H, halogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl, wherein Ry is optionally substituted with 1-4 R4; each R2 is, independently, H, NR52, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halogen, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each one of which is optionally substituted with 1-4 R7; wherein R2 is not Me when Ry is halogen, indole substituted with halogen, or phenyl optionally substituted with halogen; wherein R2 is not isopropyl when Ry is phenyl substituted with halogen; wherein R2 is not alkynyl substituted with heterocyclyl when Ry is indole substituted with halogen; wherein R2 is not phenyl when Ry is H; and wherein R2 is not acetyl when Ry is phenyl or substituted phenyl; each n is 0-3; each R3 is, independently, H, alkyl, Realkyl, or arylalkyl; each R4 is, independently, halogen, OH, CF3, C (0) R5, NR32, N (R3) C (0) R5, CN, OCF3, S02R5, or SiR53; or alkyloxy, aryloxy, alkyl, heterocyclyl, R50-alkyl, cycloalkyl, aryl, alkylthio, haloalkyloxy, heteroaryl, or arylalkyl, each of which is optionally substituted with 1-4 R6; each R5 is, independently, H or alkyl; each R6 is, independently, halogen, OH, CF3, alkyl, alkyloxy, N (R5) -alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl; each R7 is, independently, halogen, CN, OR5, CF3, N (R5) C (0) R5, C (0) R5, OCF3, SCF3, NR52, C (0) NR52, OH, R50-alkyl, alkyl, alkylsulfonyl, heterocyclyl, or heteroaryl, each of which is optionally substituted with 1-4 R8; each R8 is, independently, OR5 or alkyl; Q is H, halogen, C (0) R5, C (0) R9, C (S) R5, C (S) R9, C (0) NR52, C (0) NR5R9, S (0) R5, S ( 0) R9, S (0) NR52, S (0) NR5R9, S02R5, S02R9, S02NR52, S02NR5R9, NR52, NR5R9, R9S-alkyl, alkyl, or heterocyclyl, wherein each alkyl or heterocyclyl is optionally substituted with 1-4 R10; each R 9 is, independently, aryl, heterocyclyl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted with 1-4 R 0; each R10 is, independently, alkyl, CF3, C (NH) NR5R11, C (NH) R11, CN, R52N-alkyl, NR5R11-alkyI, R50-alkyl, R11, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is optionally substituted with alkyl or OR5; each R1 is, independently, arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl; and R14 is halogen, NH2, alkyl, OH, C (0) Me, aryl, heteroaryl, or C (0) NHR5. 23. - The compound of formula (VIII) according to claim 22, further characterized in that n is 1 and R2 is not H. 24. A compound of formula (XIV): formula (XIV) where: X is O, S, NR3, N (R3) N (R3), C (O), N (R5) C (0) C (0) NR5, or alkyl; R x is H, cycloalkyl, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, R 50 -alkyl, (R 5) 3 Si, acyl, wherein R is optionally substituted with 1-4 R 4; each R2 is, independently, H, NR52, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halogen, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkyl, heteroarylalkyl, aryloxy, or heteroaryloxy, each of which is substituted optionally with 1-4 R7; n is 0-3; each R3 is, independently, H, alkyl, R50-alkyl, or arylalkyl; each R4 is, independently, halogen, OH, CF3, C (0) R5, NR32, N (R3) C (0) R5, CN, OCF3, S02R5, or SiR53; or alkyloxy, aryloxy, alkyl, heterocyclyl, R50-alkyl, cycloalkyl, aryl, alkylthio, haloalkyloxy, heteroaryl, or arylalkyl, each of which is optionally substituted with 1-4 Rs; each R5 is, independently, H or alkyl; each R6 is, independently, halogen, OH, CF3, alkyl, alkyloxy, N (R5) -alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl; each R7 is, independently, halogen, CN, OR5, CF3, N (R5) C (O) R5, C (0) R5, OCF3, SCF3, NR52, C (O) NR52, OH, R5O-alkyl, alkyl, alkylsulfonyl, heterocyclyl, or heteroaryl, each of which is optionally substituted with 1-4 R8; each R8 is, independently, OR5 or alkyl; Q is H, halogen, C (O) R5, C (O) R9, C (S) R5, C (S) R9, C (0) NR52, C (0) NR5R9, S (0) R5, S ( 0) R9, S (0) NR52, S (O) NR5R9, S02R5, SO2R9, SO2NR52, S02NR5R9, NR52, NR5R9, R9S-alkyl, alkyl, or heterocyclyl, wherein each alkyl or heterocyclyl is optionally substituted with 1-4 R10; each R 9 is, independently, aryl, heterocyclyl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted with 1-4 R 0; each R10 is, independently, alkyl, CF3, C (NH) NR5R11, C (NH) R11, CN, R52N-alkyl, NR5R1i-alkyl, Realkyl, R \ heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is substituted optionally with alkyl or OR5; and each R 11 is, independently, arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl. 25. A method for preparing a compound of formula (II): formula (II) wherein X, Rx, R2, R2 'and Het are as defined below; the comprising: treating the compound of formula (IX) with malonic acid, to give a ring expansion compound of formula (X): formula (IX) formula (X) coupling the compound of formula (X) with a Pd catalyst and a compound of formula (XI) to give a compound of formula (XII): formula (X) formula (XI) formula (XII) treating the compound of formula (XII) with POCI3 to give the chloride of formula (XIII), and coupling the carboxylic acid of formula (XII) with an amine of formula Het-H , to give the compound of formula (XIII): formula (XII) formula (XIII) and coupling the compound of formula (XIII) with one or more coupling agents to give a compound of formula (II): formula (XIII) formula (II) wherein, for formulas II and IX to XIII, X is O, S, NR3, N (R3) N (R3), C (O), N (R5) C (O) R5, C (O) NR5, or alkyl; R x is H, cycloalicylic, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, R 50 -alkyl, (R 5) 3 Si, acl, wherein R x is optionally substituted with 1-4 R 4; each R2 is, independently, NR52, alkyl, cycloaikyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halogen, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkyl, heteroarylalkyl, aryloxy, or heteroaryloxy, each of which is optionally substituted with 1-4 R7; R2 'is H, halogen, NH2, alkyl, OH, C (O) Me, aryl, heteroaryl; each R3 is, independently, H, alkyl, R5O-alkyl, or arylalkyl; each R4 is, independently, halogen, OH, CF3, C (O) R5, NR32, N (R3) C (O) R5, CN, OCF3, SO2R5, or SR53; or alkyloxy, aryloxy, alkyl, heterocyclyl, R5O-alkyl, cycloaikyl, aryl, alkylthio, haloalkyloxy, heteroaryl, or arylalkyl, each of which is optionally substituted with 1-4 R6; each R5 is, independently, H or alkyl; each R6 is, independently, halogen, OH, CF3, alkyl, alkyloxy, N (R5) -alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl; each R7 is, independently, halogen, CN, OR5, CF3, N (R5) C (0) R5, C (0) R5, OCF3, SCF3, NR52, C (0) NR52, OH, R50-alkyl, alkyl, alkylsulfonyl, heterocyclyl, or heteroaryl, each of which is optionally substituted with 1-4 R8; each R8 is, independently, OR5 or alkyl; Het is heterocyclyl optionally substituted with 1-4 R10; each R10 is, independently, alkyl, CF3, C (NH) NR5R11, C (NH) R11, CN, R52N-alkyl, NR5R11-alkyl, R50-alkyl, R1, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is optionally substituted with alkyl or OR5; and each R1 is, independently, arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl. 26. The method according to claim 25, further characterized in that the H of Het-H is attached to a nitrogen. 27. - The method according to claim 25, further characterized in that the coupling agent is H2NRX. 28. - The method according to claim 25, further characterized in that the coupling agent is MgCI-Rx and Pd. 29. - The method according to claim 25, further characterized in that the coupling agent is HSRX. 30. - The use of the compounds claimed in claims 1-24, for preparing a medicament for the treatment of an autoimmune disorder in a subject. 31. The use claimed in claim 30, wherein an additional therapeutic agent is also administrable. 32. - The use claimed in claim 30, wherein the autoimmune disorder is lupus. 33. The use of the compounds claimed in claims 1-24, to prepare a medicament for the treatment of rejection of organ transplantation in a subject. 34. The use claimed in claim 33, wherein an additional therapeutic agent is also administrable. 35.- The use of the compounds claimed in claims 1-24, for preparing a medicament for the treatment of an inflammatory disorder in a subject. 36. The use claimed in claim 35, wherein an additional therapeutic agent is also administrable. 37. The use claimed in claim 36, wherein the additional therapeutic agent is an analgesic or a steroid. 38. - The use claimed in claim 35, wherein the inflammatory disorder is arthritis. 39. The use claimed in claim 38, wherein the arthritis is rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis or osteoarthritis. 40. The use claimed in claim 35, wherein the inflammatory disorder is inflammatory bowel disease or Crohn's disease. 41. A composition comprising any of the compounds claimed in claims 1-24. 42. - The composition according to claim 41, further characterized in that it comprises a pharmaceutically acceptable carrier. 43. - The composition according to claim 41, further characterized in that it comprises an additional therapeutic agent. 44. - A collection of the compounds of any of formulas (I) - (VIII). 45. The use of a compound as claimed in any of claims 1-24, for preparing a medicament for inhibiting the production of IL-2 in a subject. 46 - The use of a compound as claimed in any of claims 1-24, for preparing a medicament for modulating ZAP-70 in a subject.