CA2518398A1 - 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

Heterocyclic Kinase Tnhibitors: Methods of Use and Synthesis CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to U.S. Provisional Application Serial No.
60/4.53,457, filed on March 10, 2003, U.S. Provisional Application Serial No. 60/460,910, filed on April 7, 2003, U.S. Provisional Application Serial l~To. 60/463,025, filed on April 15, 2003, and U.S.
Provisional Application Serial lVo. 60/502,710, filed September 12, 2003, each of which is incorporated by reference herein in its entirety.
EACI~~ROI11~~TLD
Kinases are a class of enzymes that function in the cafalysis of phosphoryl transfer.
Protein kinases participate in the signaling events, which control the activation, growth and differentiation of cells in response to extracellular mediators and to changes in the environment.
In general, kinases fall into several groups; those that preferentially phosphorylate serine and/or threonine residues are generally referred to as serine/threonine kinases and those that preferentially phosphorylate tyrosine residues are generally referred to as tyrosine kinases [S.K.
Hanks and T. Hunter, FASEB J., 1995, 9, 576-596]. The tyrosine kinases include membrane-~ 5 spanning growth factor receptors such as EGFR (S. Iwashita and M.
Kobayashi, Cellular Signaling, 1992, 4, 123-132), and cytosolic non-receptor kinases such as Lck, ZAP-70 and Syk kinases (C. Chan et. Al., Ann. Rev. Immun., 1994, 12, 555-592).
Inappropriately high protein kinase activity has been implicated in many diseases resulting from abnormal cellular function. This might arise either directly or indirectly, for 2o example by failure of the proper control. mechanisms for the kinase, related for example to mutation, over-expression or inappropriate activation of the enzyme; or by the over- or underproduction of cytokines or growth factors also participating in the transduction of signals upstream or downstream of the kinase. In all of these instances, selective inhibition of the kinase could have a beneficial effect.
25 T cells plays a key role in transplant rejection, autoimmune diseases and the initiation of inflammatory responses and are thus a primary target for pharmaceutical intervention in these indications. The activation of T cells is a complex process that results in cell growth and differentiation. The engagement of the T cell receptor on mature peripheral T
cells initiates multiple intracellular signals that lead to cellular proliferation and the acquisition of comple~~

functions. The biochemical mechanisms that couple receptor binding to these intracellular events have been investigated (J.E.M., Van Leeuwen, and L.E. Samelson, Current Opin. Immun.
1999, 1 l, 242-248). The Syk family of tyrosine kinases, comprising Syk and ZAP-70, play a role in the initiation and the amplification of receptor signal transduction (I2.F-I. Chu et.al., hnmunol. Rev. 1998, 165, 167-180). ZAP-70 is expressed solely in T cells and I\Tl~ cells. Syk is found in B cells, mast cells, neutrophils, macrophages, and platelets and is involved in B cell receptor and Fc receptor signal transduction. Thus, kinase inhibitors of ZAP-70 and Syk have potential therapeutic benefits for treating diseases resulting from activation and differentiation of T cells, NK cells, B cells, mast cells, neutrophils, macrophages, and platelets.
S~T1VIM~11~~' The invention relates to novel compounds and compositions including those compounds, as well as methods of using and malting the compounds. The compounds are heterocyclic compounds that are useful in therapeutic applications, including modulation of disease or disease symptoms in a subject (e.g., mammal, human, dog, cat, horse). The compounds (including 1s stereoisomers thereof are created either singly or in a combinatorial fashion to give structurally, and stereochemically diverse libraries of compounds. The compounds are useful as ZAP-70 and Syk inhibitors through their binding to these receptors.
In one aspect, the invention features a compound of the formula (I) Q
(R2)n x N ~. R
formula (I) wherein;
A forms a benzene, pyridine, pyrimidine, thiophene, pyrrole, imidazole, pyrrazole, thiazole, or oxazole ring;
~ 1S O, S, ~R3, 1~(R3)~(R3), C(O)9 ~~5)~(~)9 ~(~)~5~ or alkyl, RX is H, cycloalkyl, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylallcyl, slkynyl, arylslkenyl, heteroarylalkenyl, arylalkynyl, heteroarylslkynyl, R5O-alkyl, (RS)3Si, aryl, wherein R~ is optionally substituted with 1-4 R4;

each Rz is independently H, NRsz, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halo, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each of which is optionally substituted ~~ith 1-4~ R~; wherein Rz is not hfle when ~-Rx is I~Ie and Q is NHaryl substituted with hater~cycyl; and wherein Rz is not acetyl when X-Rx is arylalkenyl;
n is 0-3;
each R3 is independently H, alkyl, RsO-alkyl, or arylalkyl;
each R4 is independently halo, OH, CF3, C(O)Rs, NR3z, N(R3)C(O)Rs, CN, OCF3, SOzRs9 or SiRs3; or alkyloxy, aryloxy, alkyl, heterocyclyl, RsO-alkyl, cycloalkyl, aryl, alkylthio, 1o haloalkyloxy, heteroaryl, or arylalkyl, each of which is optionally substituted with 1-4 R6;
each Rs is independently H, or alkyl;
each R6 is independently halo, OH, CF3, alkyl, alkyloxy, N(Rs)-alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl;
each R' is independently halo, CN, ORS, CF3, N(Rs)C(O)Rs, C(O)Rs, OCF3, SCF3, NRsz, 15 C(O)NRsz, OH, R50-alkyl, alkyl, alkylsulfonyl, heterocyclyl, or heteroaryl, each of which is optionally substituted with 1-4 R8;
each R$ is independently ORS or alkyl;
Q is H, halo, C(O)Rs, C(O)R9, C(S)Rs, C(S)R9, C(O)NRsz, C(O)NRsR~, S(O)Rs, S(O)R9, S(O)NRsz, S(O)NRSR~, SOzRs, SOZR9, SOzNRsz, SOzNRsR9, NRsz, NRsR9, R9S-alkyl, alkyl, or 2o heterocyclyl, wherein each alkyl or heterocyclyl is optionally substituted with 1-4 Rlo;
each R9 is independently aryl, heterocyclyl, heteroaryl, arylallcyl, or heteroarylalkyl, each of which is optionally substituted with 1-4 Rlo;
each Rl° is independently alkyl, CF3, C(NH)NRSRI l, C(NH)R11, CN, RszN-alkyl, NRsRII-alkyl, RsO-alkyl, Rl l, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is 25 optionally substituted with alkyl or ORs; and each Rl1 is independently arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl.
In some instances, A forms a benzene ring.
In another aspect, the invention features a compound of formula (II) O Het R~
x \ H ~.R
R~, formula (II) wherein;
X 1s ~, S, NR3, N(R3)N(R3), C(~), N(Rs)C(~), C(O)NRs, or alkyl;
Rx is H, cycloalkyl, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, RsO-alkyl, (Rs)3Si, acyl, wherein Rx is optionally substituted with 1-4 R4;
each R2 is independently H, NRs2, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, 1 o heterocyclyl, aryl, halo, acetyl, arylallcyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each of which is optionally substituted with 1-4 R';
each Rz' is independently H, halo, NH2, alkyl, OH, C(O)Me, aryl, heteroaryl;
each R3 is independently H, alkyl, R50-alkyl, or arylalkyl;
~ 5 each R4 is independently halo, OH, CF3, C(O)Rs, NR3z, N(R3)C(O)Rs, CN, OCF3, SOZRs, or SiRs3; or alkyloxy, aryloxy, alkyl, heterocyclyl, RsO-alkyl, cycloalkyl, aryl, alkylthio, haloalkyloxy, heteroaryl, or arylalkyl, each of which is optionally substituted with 1-4 R6;
each Rs is independently H, or alkyl;
each R~ is independently halo, OH, CF3, alkyl, alkyloxy, N(Rs)-alkyl, heteroaryl, 2o heteroarylalkyl, or heterocyclyl;
each R7 is independently halo, CN, ORs, CF3, N(Rs)C(O)Rs, C(O)Rs, OCF3, SCF3, NRsa, C(O)NRsz, OH, RsO-alkyl, all~yl, alkylsulfonyl, heterocyclyl, or heteroaryl, each of which is optionally substituted with 1-4 R8;
each R8 is independently ORs or alkyl;
25 Het is heterocyclyl optionally substituted with 1-4 Rl°;
each Rl° is independently allcyl, CF3, C(NH)NRSRII, C(NH)Rll, CN, RsZN-allcyl, NRsRl1-alkyl, RsO-alkyl, R11, heteroaryl, heterocyclyl, or heterocyclylallcyl, each of which is optionally substituted with alkyl or ORs; and each Rl1 is independently arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl.
In some instances, Het is attached through a ring-nitrogen atom.
In some instances, R2~ is H.
In some instances, Het is attached through a ring-nitrogen atom; ~ is I~TR3, or alkyl; and RX is cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, car hater~cyclyl wherein R~ is optionally substituted pith 1-4 R4; and R2~ is H.
In some instances, Het is ~1o R1o X10 X10 X10 N."", ~N""" ~ ~ N."". N~~~
'2 R1o R1o ~N~ ~N~ N N or S ~/ S ~ S~ ~/ ~ ~N.~".
In other instances, Het is N CAN ~ ~ ~ N
N
N ~N~
~N~ ~ ~ O N-O 1'i'f O
O O
\N-> O
HO H~N ~N ~N 'N
N N N~ ~N~ N
O
O O
O O
~N ~ . ~ HN
HN HN HN
~,N~ ~N-~ N-~ ~,N~
N v O O O O
O
In another aspect, the invention features a compound of formula (III), ,R~~
HN

w N X, Rx R2~
formula (III) wherein, ~ 1S O, S, NR3, N(R3)N(R3)9 ~(~)9 N(RS)~(~)9 ~(~)~59 or alkyl;
Rx is H, cycloalkyl, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, RSO-alkyl, (RS)3Si, aryl, wherein RX is optionally substituted with 1-4 R4;
each RZ is independently H, NRSZ, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halo, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each of which is optionally substituted with 1-4 R'; wherein Rz is not Me when X-Rx is Me and R12 is aryl substituted with heterocyclyl;
each RZ~ is independently H, halo, NHZ, alkyl, OH, C(O)Me, aryl, heteroaryl;
each R3 is independently H, alkyl, R50-alkyl, or arylalkyl;
each R4 is independently halo, OH, CF3, C(O)R5, NR32, N(R3)C(O)R5, CN, OCF3, SOZRS, 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 RS is independently H, or alkyl;
2o each R6 is independently halo, OH, CF3, alkyl, alkyloxy, N(RS)-alkyl, heteroaryl, heteroarylallcyl, or heterocyclyl;
each R' is independently halo, CN, ORS, CF3, N(R5)C(O)R5, C(O)R5, OCF3, SCF3, NRsz, C(O)NRsa, OH, R50-alkyl, allcyl, alkylsulfonyl, heterocyclyl, or heteroaryl, each of which is optionally substituted with 1-4 R8;
each R8 is independently ORS or allcyl;
each Rl2 is independently aryl or heteroaryl, optionally substituted with 1-4 R13;
each R13 is independently heterocyclyl optionally substituted with alkyl or ORS.
In some instances R2~ is H.

In some instances Rl2 is H I I H I H
N N N CN\ N' N
OH N CN
\ \ \ \ \ ~N
I/ I/ I/ I/ I/ I/
H I H H H
N N N N CN~ N
C~ C~ CY N C
N N N N
N I wN I wN I wN I N I ~N
/ a / /
s H I I H I H
N N N CNJ N N
OH N CN
I \ \ I \ I \ I \ I wN
I/ / / / /
H I H H H
N N N N CN~ N
C~ C~ C~' N C
N N N N
N I wN I wN I wN I N or I wN
/
In another aspect, the invention features a compound of formula (IV) Q

~R2)n / I \
~N~~. Rx for111u1a (~) v~herein, ~ is ~, S, NR3,1V(R3)I~T(R3), C(~), N(RS)C(O), C(~)NRS, or alkyl;

Rx is H, cycloalkyl, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, R50-alkyl, (Rs)3Si, acyl, wherein Rx is optionally substituted with 1-4 R4;
each RZ is independently H, NRs2, alkyl, cycloalkyl, alkenyl9 alkynyl, heteroaryl, heterocyclyl, aryl, halo, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, auyloxy, or heteroaryloxy, each of which is optionally substitvited with 1-4~ R'; wherein R2 is not l~Ie when X-Rx is lVle and Q is NHAryI
substituted with heterocycyl; and wherein RZ is not acetyl when X-R~' is arylalkenyl;
each R3 is independently H, alkyl, RsO-alkyl, or arylalkyl;
each R4 is independently halo, OH, CF3, C(O)Rs, NR3Z, N(R3)C(O)Rs, CN, OCF3, SOzRs, or SiRs3; or allcyloxy, aryloxy, alkyl, heterocyclyl, R50-alkyl, cycloalkyl, aryl, alkylthio, haloalkyloxy, heteroaryl, or arylalkyl, each of which is optionally substituted with 1-4 R6;
each Rs is independently H, or alkyl;
each R~ is independently halo, OH, CF3, alkyl, alkyloxy, N(Rs)-alkyl, heteroaryl, 15 heteroarylalkyl, or heterocyclyl;
each R' is independently halo, CN, ORS, CF3, N(Rs)C(O)Rs, C(O)Rs, OCF3, SCF3, NRsz, C(O)NRs2, OH, R50-alkyl, alkyl, alkylsulfonyl, heterocyclyl, or heteroaryl, each of which is optionally substituted with 1-4 R8;
each R$ is independently ORs or alkyl;
2o Q is H, halo, C(O)Rs, C(O)R9, C(S)Rs, C(S)R9, C(O)NRs2, C(O)NRSR9, S(O)Rs, S(O)R9, S(O)NRsz, S(O)NRSR9, SOZRs, SOZR9, SOZNRs2, S02NRSR9, NRs2, NRsR9, R9S-alkyl, alkyl, or heterocyclyl, wherein each alkyl or heterocyclyl is optionally substituted with 1-4 Rlo;
each R~ is independently aryl, heterocyclyl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted with 1-4 Rlo;
25 each Rl° is independently alkyl, CF3, C(NH)NRSRII, C(NH)R11, CN, RsZN-alkyl, NRsRI l-all~yl, R50-alkyl, Rll, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is optionally substituted with alkyl or ORs;
each Rl1 is independently arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl; and R14 is halo, NH2, alkyl, OH, C(O)Ie~Ie, aryl, heteroaryl, or C(O)NHRs.
3o In yet another aspect, the invention features a compound of formula (V) Q
(Rz)n A ~ \
.N- 'RY
f~rmula (V) wherein;
A forms a benzene, pyridine, pyrimidine, thiophene, pyrrole, imidazole, pyrrazole, thiazolc, or oxa~ole ring;
RY is H, halo, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkynyl, arylallcenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl, wherein R~ is optionally substituted with 1-4 R4;
each Ra is independently H, NR52, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halo, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each of which is optionally substituted with 1-4 R'; wherein RZ is not Me when RY is halo, indole substituted with halo, phenyl, or phenyl substituted with halo; wherein RZ is not isopropyl when RY is phenyl substituted with halo; wherein RZ is not alkynyl substituted with heterocyclyl when RY is indole substituted with halo; wherein RZ is not phenyl when RY is H, wherein RZ is not halo when RY is indole substituted with halo or phenyl substituted with halo; and wherein RZ
is not acetyl when RY is phenyl or substituted phenyl;
n is 0-3;
2o each R3 is independently H, alkyl, R50-alkyl, or arylalkyl;
each R4 is independently halo, OH, CF3, C(O)R5, NR32, N(R3)C(O)R5, CN, OCF3, SOaRS, or S1R53; or alkyloxy, aryloxy, alkyl, heterocyclyl, R5O-alkyl, cycloalkyl, aryl, alkylthio, haloalkyloxy, heteroaryl, or arylalkyl, each of which is optionally substituted with 1-4 R~;
each RS is independently H, or allcyl;
each R6 is independently halo, OH, CF3, alkyl, alkyloxy, N(RS)-alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl;
each R7 is independently halo, CN, ORS, CF3, N(RS)C(O)R5, C(O)R5, OCF3, SCF3, NRsaa C(O)NR52, OH, RSO-alkyl, alkyl, alkylsulfonyl, heterocyclyl, or heteroaryl, each of which is optionally substituted with 1-4. R8;

each R$ is independently ORs or alkyl;
Q is H, halo, C(O)Rs, C(O)RD, C(S)Rs, C(S)R9, C(O)NRsz, C(O)NRsR9, S(O)Rs, S(O)R9, S(O)NRs2, S(O)NRsR9, SO2Rs, S~?R~, SOZNRs2, SOZNRsR9, IVRs2, NRsR9, R9S-alkyl, alkyl, Or heterocyclyl, wherein each alkyl or heterocyclyl is optionally substituted with 1-4~ Rl°;
each R9 is independently aryl, heterocyclyl, heteroaryl, arylallcyl, or heteroarylalkyl, each of which is optionally substituted with 1-4~ Rl°;
each Rl° is independently alkyl, CF3, C(NH)NRsRlI, C(NH)R11, CIV, RsZIV-alkyl, NRsRiI-alkyl, RsO-alkyl, R11, heteroanyl, heterocyclyl, or heterocyclylalkyl, each of which is optionally substituted with alkyl or ORs; and each Rl1 is independently arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl.
In some instances A forms a benzene ring.
W one aspect, the invention features a compound of formula (VI), wherein O Het R~
s N RY
R~
formula (Vl) wherein, RY is H, halo, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkynyl, arylalkenyl, heteroarylallcenyl, arylallcynyl, or heteroarylalkynyl, wherein RY is optionally substituted with 1-4 R4;
each RZ is independently H, NRs2, alkyl, cycloalkyl, allcenyl, allcynyl, heteroaryl, heterocyclyl, aryl, halo, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, 2o arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each of which is optionally substituted with 1-4 R7; wherein Ra is not Me when RY is halo, indole substituted with halo, phenyl, or phenyl substituted with halo; wherein RZ is not isopropyl when RY is phenyl substituted with halo;
each RZ~ is independently H, halo, NH2, alkyl, OH, C(O)Me, aryl, heteroaryl;
each R3 is independently H, alkyl, RsO-alkyl, or arylalkyl;

each R4 is independently halo, OH, CF3, C(O)Rs, NR3z, N(R3)C(O)Rs, CN, OCF3, SOaRs, or SiRs3; 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 RS is independently H, or alkyl;
each R6 is independently halo, OH, CF3, alkyl, alkyloxy, N(Rs)-alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl;
each R' is independently halo, CN, ORS, CF3, N(Rs)C(O)Rs, C(O)Rs, OCF3, SCF3, NRsz, C(O)NRsz, OH, RsO-alkyl, alkyl, alkylsulfonyl, heterocyclyl, or heteroaryl, each of which is optionally substituted with 1-4 R8;
each R$ is independently ORS or alkyl;
Het is heterocyclyl optionally substituted with 1-4 Rlo;
each Rt° is independently alkyl, CF3, C(NH)NRSRII, C(NH)R11, CN, Rs2N-alkyl, NRsRl1-alkyl, R50-allcyl, R11, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is optionally substituted with alkyl or ORS; and 15 each Rl l is independently arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl.
In some instances, Het is attached through a ring-nitrogen atom; Rz is not H;
and R2~ is H.
In some instances, Het is R1o R1D R1o R1° R1o R1o N~~~
N~~
N,~" ~ ~~ N~",.
R1D ~ ~ R1D R10 or ~N~"" ~Nv". N N~""
S ~/ S ~ S~ ~/ ~N"""
In some instances Het is W CAN
N N
N v ~N~
~N~ ~ ~ O N
O 'ft's O
O O
N
H~ H~~ ~N ~N ~N
N v N N~ ~N~ N
O
O O ~ O
HQ Q
H HN HN
~,N~ ~,N-~ N-~ ~N~
N v O O O O
O
In another aspect, the invention features a compound of formula (VII) ~R~~
HN

N~ RY
R2, formula (VII) wherein;
RY is H, halo, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl, wherein RY is optionally substituted with 1-4 R4;
each RZ is independently H, NR52, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halo, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each of which is optionally substituted with 1-4 R~; wherein Ra is not phenyl when R~ is H;
each RZ' is independently H, halo, NH2, alkyl, ~H, C(~)T~Ie, aryl, heteroaryl;
each R3 is independently H, alkyl, RS~-alkyl, or arylalkyl;

each R4 is independently halo, OH, CF3, C(O)R5, NR32, N(R3)C(O)R5, CN, OCF3, SOZRS, 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 Rg;
each RS is independently H9 or alkyl;
each R6 is independently halo, OH, CFA, alkyl, alkyloxy, N(R5)-alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl;
each R' is independently halo, CN, ORS, CF3, N(RS)C(O)R5, C(O)R5, OCF3, SCF3, C(O)NR52, OH, R5O-alkyl, alkyl, alkylsulfonyl, hetcrocyclyl, or heteroaryl, each of which is optionally substituted with 1-4 R8;
1o each R$ is independently ORS or alkyl;
each R12 is independently aryl or heteroaryl, optionally substituted with 1-4 R13;
each R~3 is independently heterocyclyl optionally substituted with alkyl or OR$.
In some instances R2 is not H; and R2' is H.
In some instances R12 1S
H I I H I H
N N N CN\ N~ N
OH N CN
w ~ ~ w ~N
a ~ ~ a ~ a ~ a ( a a H I H H H
N N N N CN~ N
c~ ~~ c~ N c N N N N
N I ~N I ~N I ~N I ~N I ~N
a a r a a H I I H I H
N N N CN\ N' N
OH N CN
~N
r ~/ ~/ ~
I H I H H H
N N N N CN~ N
C~ C~ C~ N C
N N N N
or wN wN wN wN wN wN
s ~i ~i ~i ~s ~i In one aspect, the invention features a compound of formula (VIII), Q
i N~ RY
formula (VIII) wherein, RY is H, halo, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkynyl, arylalkenyl, heteroarylallcenyl, arylalkynyl, or heteroarylallcynyl, wherein RY is optionally substituted with 1-4 R4;
each RZ is independently H, NRSZ, alkyl, cycloalkyl, allcenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halo, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each of which is optionally substituted with 1-4 R7; wherein RZ is not Me when RY is halo, indole substituted with halo, or phenyl optionally substituted with halo; wherein R~ is not isopropyl when R~ is phenyl 1 o substituted with halo; wherein RZ is not alkynyl substituted with heterocyclyl when RY is indole substituted with halo; 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, RS~-alkyl, or arylalkyl;

each Rø is independently halo, OH, CF3, C(O)RS, NR3z, N(R3)C(O)R5, CN, OCF3, SOZRS, or SiR53; or alkyloxy, aryloxy, alkyl, heterocyclyl, R50-alkyl, cycloalkyl, aryl, alkylthio, haloalkyloxy, heteroaryl, or arylalkyl, each of whlch is optionally substituted with 1-4 R~;
each RS is independently H, or alkyl;
each R6 is independently halo, OH, CF3, alkyl, alkyloxy, N(RS)-alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl;
each R' is independently halo, CN, ORS, CF3, N(RS)C(O)R5, C(O)R5, OCF3, SCF3, C(O)NRsz, OH, RSO-alkyl, alkyl, alkylsulfonyl, heterocyclyl, or heteroaryl, each of which is optionally substituted with 1-4~ R8;
t o each R$ is independently ORS or alkyl;
Q 1S H, halo, C(O)R', C(O)R9, C(S)RS, C(S)R9, C(O)NRSZ, C(O)NRSR°, S(O)R5, S(O)R9, S(O)NRsz, S(O)NRSR~, S02R5, SOzR9, SOzNRsz, SOzNR$R9, NRsz, NRSR°, R°S-alkyl, alkyl, or heterocyclyl, wherein each allcyl or heterocyclyl is optionally substituted with 1-4 Rlo;
each R9 is independently aryl, heterocyclyl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted with 1-4 RIO;
each Rl° is independently alkyl, CF3, C(NH)NRSRII, C(NH)R11, CN, RSZN-alkyl, NRSRI ~-alkyl, R50-alkyl, R' 1, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is optionally substituted with alkyl or ORS;
each Rl 1 is independently arylalkyl, heteroarylall~yl, cycloalkyl, or heterocyclyl; and Rl~ is halo, NHz, alkyl, OH, C(O)Me, aryl, heteroaryl, or C(O)NHRS.
In some instances, n is 1 and Rz is not H.
In another aspect, the invention features the compound of formula (XIV), Q
~R2)n I / ~ RX
N X
formula (XIV) wherein, 2o X is O, S, NR3, N(R3)N(R3), C(O), N(RS)C(O), C(O)NRS, or alkyl;
Rx is H, cycloalkyl, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroalylalkyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, R50-alkyl, (RS)3Si, aryl, wherein Rx is optionally substituted with 1-4 R4;

each Rz is independently H, NRSZ, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halo, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, aryloxy, or heteroaryloxy, each of which is optionally substituted with 1-4 R~;
n is 0-3;
each R3 is independently H, alkyl, RSO-alkyl, or arylalkyl;
each R4 is independently halo, OH, CF3, C(O)R5, NR3z, N(R3)C(O)RS, CN, OCF39 SOzRs, or SiRs3; or alkyloxy, aryloxy, alkyl, heterocyclyl, R50-alkyl, cycloalkyl, aryl, alkylthio, haloalkyloxy, heteroaryl, or arylalkyl, each ofwhich is optionally substituted with 1-4. R6;
each RS is independently H, or all~yl;
each R6 is independently halo, OH, CF3, alkyl, alkylo~cy, N(1Z5)-alkyl, heteroaryl, heteroarylalky~, or heterocyclyl;
each R' is independently halo, CN, ORS, CF3, N(RS)C(O)R5, C(O)R5, OCF3, SCF3, NRsz, C(O)NRsz, OH, R50-alkyl, alkyl, alkylsulfonyl, heterocyclyl, or heteroaryl, each of which is optionally substituted with 1-4 R8;
~5 each R8 is independently OR5 or alkyl;
Q is H, halo, C(O)R5, C(O)R9, C(S)R$, C(S)R9, C(O)NRSZ, C(O)NRSR9, S(O)R5, S(O)Rg, S(O)NRsz, S(O)NRSR9, SOzRS, SOZR9, SOzNRsz, SOzNRSR~, NRsz, NRSR9, RCS-alkyl, alkyl, or heterocyclyl, wherein each alkyl or heterocyclyl is optionally substituted with 1-4 Rlo;
each R9 is independently aryl, heterocyclyl, heteroaryl, axylalkyl, or heteroarylalkyl, each 20 of which is optionally substituted with 1-4 Rlo;
each Rl° is independently alkyl, CF3, C(NH)NRSRlI, C(NH)R11, CN, RSZN-alkyl, NRSRlI-alkyl, RSO-alkyl, R11, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is optionally substituted with alkyl or ORS; and each RI1 is independently arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl.
In yet another aspect, the invention features a method of making a compound of formula (II) O Het \ I ~.R'~
~N X
Ra.
formula (II) wherein X, I~~', I~z9 I~2~, and Het are as defined below. The the method includes;
treating the compound of formula (IX) with malonic acid, t~ provide a ring expansion compound of formula (X);

Hal I \ ~ H02C--~ Pacid Hal \ w N~ CO2H ~
N- \O
R2. H Ra. H
formula (IX) formula (X) coupling the compound of formula (X) with a Pd catalyst and a compound of formula (XI) to provide a compound of formula (XII);
COaH C02H
Hal \ \ Pd R2 * a I \ \
N~O R \B~OH~a ~ ~ N O
R2, H R2' H
formula (X) formula (XI) formula (XII) ~s treating the compound of formula (XII) with POC13 to provide the chloride of formula (XIII), and coupling the carboxylic acid of formula (XII) with an amine of formula Het-H to provide the compound of formula (XIII); and CO2H COHet R2 I \ \ POCI3 R2 I \ \
NCO CyNHa, / Ni~CI
Ra, H R2, fornula (XII) formula (XIIl) 2o coupling the compound of formula (XIII) with one or more coupling agents COHet COHet x i~ CI / f~ ~~R
R2' H R2' formula (VIII) formula (II) to provide a compound of formula (II), wherein for formulae II and I~ to VIII, X 1S ~, S, NR3, N(R3)N(R3), C(~), N(RS)C(O)R5, C(O)NRS, ~r alkyl;
Rx is H, cycloalkyl, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, R50-alkyl, (RS)3Si, aryl, wherein Rx is optionally substituted with 1-4. R4;
each R2 is independently NR52, alkyl, cycloalkyl, allcenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halo, arylall~yl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, 1 o heteroarylalkynyl, aryloxy, or heteroaryloxy, each of which is optionally substituted with 1-4 R7;
R2~ is H, halo, NHZ, alkyl, OH, C(O)Me, aryl, heteroaryl;
each R3 is independently Ii, alkyl, R50-allcyl, or arylalkyl;
each R4 is independently halo, OH, CF3, C(O)R5, NR32, N(R3)C(O)R5, CN, OCF3, SOZRS, or SiR53; or alkyloxy, aryloxy, alkyl, heterocyclyl, RSO-alkyl, cycloalkyl, aryl, alkylthio, ~5 haloalkyloxy, heteroaryl, or arylalkyl, each of which is optionally substituted with 1-4 R6;
each RS is independently H, or alkyl;
each R6 is independently halo, OH, CF3, alkyl, alkyloxy, N(RS)-alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl;
each R7 is independently halo, CN, ORS, CF3, N(RS)C(O)R5, C(O)R5, OCF3, SCF3, NR52, zo C(O)NRSZ, OH, R50-alkyl, alkyl, alkylsulfonyl, heterocyclyl, or heteroaryl, each of which is optionally substituted with 1-4 Rg;
each R$ is independently ORS or alkyl;
Het is heterocyclyl optionally substituted with 1-4 Rlo;
each Rl° is independently alkyl, CF3, C(NH)NRSRII, C(NH)Rl l, CN, R52N-allcyl, z5 NRSRlI-alkyl, R50-alkyl, R11, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is optionally substituted with alkyl or ORS; and each Rl I is independently arylalkyl, heteroarylalkyl, cycloalkyl, or h eterocyclyl.
In some instances, the H of Het-H is attached to a nitrogen.
In some instances, the coupling agent is HZNRx.

In some instances, the coupling agents are MgCl-Rx, and Pd.
In some instances the coupling agent is HSRx.
In another aspect, the invention features a method of treating an autoimmune disorder in a subject including administering to the subject any of the compounds or compositions described herein.
In some instances, the method includes administering an additional therapeutic agent.
In some instances the autoimmune disorder is lupus.
In another aspect, the invention features a method of treating organ transplant rejection in a subj ect comprising administering to the subj ect any of the any of the compounds or 1o 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 instances the method includes administering an additional therapeutic agent. The 15 additional therapeutic agent can be an analgesic, or a steroid.
In some instances, the inflarninatory disorder is arthritis. The arthritis can be, for example, rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis, or osteoarthritis.
In some instances, the inflammatory disorder is inflammatory bowel disease or Crohn's 2o disease.
In another aspect, the invention features a composition including any of the compounds described herein.
In some instances the composition can include a pharmaceutically acceptable tamer.
In some instance, the composition can include an additional therapeutic agent.
25 In another aspect, the invention features a library of the compounds of any of formulae (I)-(VIII).
In yet another aspect, the invention features a method of inhibiting IL-2 production in a subject including administering to the subject any of the compounds or compositions described herein.

In still another aspect, the invention features a method of modulating ZAP-70 or Syk in a subject including administering to the subject any of the compounds or compositions described herein.
In other aspects, the compounds9 compositions, and methods delineated herein are those of any of the compounds of Table 1 herein.
The details of one or more embodiments of the invention are set forth in the accoanpa-vying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.
Y~ET~I1L~~ ~1~,~~C11~F'1~°1R~1~~T
The term "halo" refers to any radical of fluorine, chlorine, bromine or iodine. The term "alkyl" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1-Clo indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. The term "lower alkyl" refers to a Cl-Cg alkyl chain.
In the absence of any numerical designation, "alkyl" is a chain (straight or branched) having 1 to ~5 10 (inclusive) carbon atoms in it. The term "alkoxy" refers to an -O-alkyl radical. The term "alkylene" refers to a divalent alkyl (i.e., -R-). The term "alkylenedioxo"
refers to a divalent species of the structure -O-R-O-, in which R represents an alkylene. The term "aminoalkyl"
refers to an alkyl substituted with an amino. The term "mercapto" refers to an -SH radical. The term "thioalkoxy" refers to an -S-alkyl radical.
20 The term "alkenyl" refers to a hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, Cz-Clo indicates that the group may have from 2 to 10 (inclusive) carbon atoms in it. The term "lower alkenyl" refers to a Cz-C8 alkenyl chain.
In the absence of any numerical designation, "alkenyl" is a chain (straight or branched) having 2 25 to 10 (inclusive) carbon atoms in it.
The term "alkynyl" refers to a hydrocarbon chain that rnay be a straight chain or branched chain having one or more carbon-carbon triple bonds. The allcynyl moiety contains the indicated number of carbon atoms. For example, Cz-Clo indicates that the group may have from 2 to 10 (inclusive) carbon atoms in it. The term "lower alkynyl" refers to a Cz-Cg allcynyl chain.

In the absence of any numerical designation, "alkynyl" is a chain (straight or branched) having 2 to 10 (inclusive) carbon atoms in it.
The term "aryl" refers to a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system wherein 0, l, 2, 3, or 4~ atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl and the like. The term "arylalkyl" or the term "aralkyl"
refers to allcyl 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 teen "cycloalkyl" as employed herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, preferably 3 to 8 carbons, and more preferably 3 to 6 carbons, wherein the cycloalkyl group may be optionally substituted. Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
The term "heteroaryl" refers to an aromatic 5-8 rnembered monocyclic, 8-12 membered ~5 bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S
(e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, ~, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of heteroaryl groups include pyridyl, furyl or W ranyl, imidazolyl, 2o 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 "heteroarylallcenyl" refers to an alkenyl substituted with a heteroaryl. The term "heteroarylalkynyl" refers to an alkynyl substituted with a heteroaryl.
The term "heteroarylalkoxy" refers to an alkoxy substituted with heteroaryl.
25 The term "heterocyclyl" refers to a nonaromatic 5-8 membered monocyclic, 8-membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if 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 monocyelic, bicyclic, or tricyelic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be 3o substituted by a substituent. Examples of heterocyclyl groups include piperazinyl, pynolidinyl, dioxanyl, morpholinyl, 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 carbon an IV-o~~ide when attached to nitrogen, and a sulfoxide or sulfone when attached to sulfur.
The term "acyl" refers to an alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, or heteroarylcarbonyl substituent, any of which may be further substituted by substituents.
The term "sulfonyl" refers to a sulfur attached to two oxygen atoms through double bonds. An "alkylsulfonyl" refers to an alkyl substituted with a sulfonyl.
The term "substituents" refers to a group "substituted" on an alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl group at any atom of that group. Suitable substituents include, without limitation, halo, hydroxy, mercapto, oxo, nitro, haloalkyl, alkyl, aryl, aralkyl, alkoxy, thioalkoxy, aryloxy, amino, allcoxycarbonyl, amido, carboxy, alkanesulfonyl, alkylcarbonyl, and 15 cyano groups.
The term "Me" means methyl.
The term "Ac" means acetyl.
The term "dpp~' means 1,1 bis(diphenylphosphino) ferrocene.
The term "Mops" means 3-(N-Morpholino) propanesulfonic acid.
20 The term "BSA" means bovine serum albumin.
The term "LAT" means a palmitoylated p36/38 kDa plasma membrane-associated protein expressed in all T lymphocytes and it is the physiologic substrate of activated ZAP-70.
The term "TMB" means 3, 3', 5, 5' - Tetramethylbenzidine.
The term "kinase mediated disorder" means a disorder wherein a protein kinase is 25 involved in signaling, mediation, modulation, or regulation of the disease process or symptoms.
Kinase mediated disorders axe exemplified by the following classes of diseases and 'disorders:
cancer, autoimrnunological, metabolic, inflammatory, infection (bacterial, viral, yeast, fungal, etc.), diseases of the central nervous system, degenerative neural disease, allergy/asthma, dermatology, angiogenesis, neovasculari~ation, vasculogenesis, cardiovascular, and the like.

Table 1: Representative compounds of the invention**
i~u~~er MOLSTRUCTURE
O '"N~
N CI

o .'.N
I\
/O I \ N~OiC~S
'O
~~N~
~~O~N
O LN
I \
N N

O ,N~
I \ \
N N
O / O ,N~
/ i / i °~°N~
\N N \

1~

2~

3~

3~

4~

o i o ,,,N~
o i ~ i ~~o~i N N

5~

~7 C
O '~N~
\ I \ \
N N~C~

o , a Nn N
N '0 CHI

N
O N
O \ ~ ~ \ a / N NsCli~
~~I
:v 80 ~~) 0 / O N\ /
\O \ I \ \ OH
/ N~N ~ \

O / O N
C i O \ W W
Ni\N ~ \
82 ~~, ~0 \ ~ ~ \ \
N ~ \

C i ~n o \ I \ \ r~0 / N N

p o N ~5p /i 0 \ \ \
C
/ N N ~~\
/ p N \ N\
~N
O \ ~ \ \ /
N N ~ \
86 p / 0 N \
~N
i \ \ / N
N ~ \
87 ( / o N \ N
I I ~N
0 \ I \ \ /
/ N N I \ F
F F
8$ ~~ o N
/I i\ .N
o \ i\ \ / N
/ N N I \ F
F F

9~
i i O
N
OH

r O ..,N~
N

9i N ~
O \ \"",\N/
\\
101 ~ I ~ ci o / I w w 10~
N
O \ \""..~
~O I / ~ \ \
/ N N I \ F
F F

1~~

N
O ,,,N~
CI
N G

N
O~N
CI \N"CI

N
~n ,I
N N ~ I F
l F
F

N
a N
I\
I ri~a I
i o ~N~
I
I -N
\ \
I~ I~

12t ~F

14~

N

N ~ I \
-.
N- \ I GH3 N

N I \ N \ I
N- \ I I -~ O
~3 ~co \ / N v -N / \ \ / -N

N
O
N
_ I \
N- \ I I -N I \

N
O
N
N- \ I I \ ~ I \

N
O CI
N
_ ~ ~~ -N
N- ~ ~ ~ -N
~5%

o N
N- ~ \ N F

F
N N ~ ~ \ / -N

N
_ _ O CFh N- ~ ~ ~ \ N

O N
F
\ / ~ ~ N ~ ~ F

N N
F
N- \ ~ ~ \ N N
F

N

N
N
_ / F
N- ~ ~ N F F

cl ~ ~ _ CI N N ~ ~ ~ ~ -N

N
O
N
_ ~ ~ N ~ ~ CI
N- ~ ~ ~ -N

N
O
N
_ ~ ~~--N
N- \ / ~ -N

N
0 H~
N
N= ~ / ~ -N

N
\\ \ ~ /O
\N N

N
N\\ \ ~ O
I / / / I / I CI
\ \N

N
O
N
N- ~ ~ ~ \ ~ CH3 177 ,N
I\
/
Nc o I \ I \ I
N ~ N
O

N
N- ~ ~ ~ \ ~ ~ \ ONE

N

N I ~ F
N- \ / ~ -N

cl ~ ~ - -N
F Pl ~ \ \ / -N

N

N
N- \ I ~ -N
N

N
~>-N CHI
N- ~ / I -N

N

N I
I ~~N
N- \ I ~ -N F

N ~
O-I--F
N- I \ I ~ ~F

N
\\ \ ~ 0 I / / / \ F
\ '~ I N I //
N
\\ \ ~ /0 I / / / CI \ CI
\ N I N I /

N

I \
I \ / I \ /
F / N \N /

O F
N
_ ~ ~~N -F
NC ~ ~ I .N F F

N
0 \ oN
I/
\ / I \
Cl / N \N /

N
/0 / iN
\I
\ / \
FSCvO I / N w I /

F ~ I -F P ~ \ ~ \ =N
L/

N
O \ //
/ \ ~ /
N'~N \N /
LhC /

N- \ I I \ N~ I
I-L,C

N
N- ~ ~ ~ \ N ~ ~ 0 FhC CND

H~C-CH O
Na N ~ ~ ~ ~ -N

o~~
2~a p \ /N
/ ~ \ . ~ /
~N /
H,t / I
\
208 y 'i N
\yI~ ~O
NJ \ \
IN I / /

N
O
N -N- \ / ~ \ N~N
N
O G
N
_ ~ ~~--N
N- ~ ~ ~ 'N

O \ //N
/ \
~IN \N I /
OH
/

y / O
N
N ~ ~ ~ ~ -N

N
O
N -_ ~ ~ N a N- t ~ / N
N
O
N
_ ~ ~~N U
N- ~ ~ ~ -N

N
/ /N
G / \ ~ I
G I / N \N I /
221 Ii ~ r N
t I
N~/ ' Bn tTd ~ /
ay B ~ I _ N -P! I \ ~ I -N

F ~ I
~N I ~ I ~ -N

N' ~ I , N
CH N I ~ ~ I =N

N N

~3 - ~ I I ~ N I ~ F

N
O H~
N I
_ ~ ~~-N
N- ~ I ~ -N F

N
_ I ~ N ~ I
N- \ I I F

22~

N
O F
N
N- ~ ~ ~ -N G

N
O
N- \ I I \ N
-F
F

_ / \ N \ / \ ~
N- \ / / -N
23~

N

F F
F
F
\ / /

p F
N I ~ F
F
P- ~ I I -N

N
O C
s' N
N- \ / / N ~ S

N
O / iN
/ ~ ~ I
N wN ~ /

O
N
CHI
N- ~ I I \ N ~GH~

2~.~

N
O
N- \ I I ~ N~ \N
I

F \ I
N
d N I ~ ~ I -N

\ / \ /
N r \ r \ -N

N

N I
N
N- ~ ~ / -N
255 ' i N r..J
n o N~
U

N

N
~~S
N-257 ,, w r\
, ~-~rJ

C.

N\\ \ ~ o / / v W
N t~
~CI
25~
N--N, I
N

o a N
_ ~ ~~--N
N- ~ ~ ~ N

o _ i s N-n N\ N

~' I o N
N~~

F
F
O
N

N
~N

I ~ ~ i N /
F

269 ~ F
F
N F
N
N- ~ / ~ -N

N N
O
N
N-S
2v~

s / v N~
~ ~ 0 H
U

N

/
'N
\ ~ \

O~N
I
I / CH I /

r.~
O N
I ~
I r~N I \
F \ I
F~F

O N
I\l I N~N I \
\ CFh 2so S

30~

30i 31 °I

r \ O N
/ / \ OH
N
/

31~

32~
N
O / O ~~,N~
~O \ ~ \ \ / ~ O
F
\ F

O / N
~O \ ~ ~ \ \
/
OH

C
/o / o N
\o \ ~ ~ i / N N
D~~

/Q / O N
\o \ ~ ~ i N
O~~

33r 34~

N
~~' Ia B N N I \ F
F F

.r Gf.l ' 'ra"N w W I/ r r 38~

39~

O O ~..N
~O \ ~ ~ \ \
N ~ \
CFI

4.0~

/O / 0 ...N~
~ I / / / ci w ~N I w I

4.09 41~

q.2~

4~2~

N
/ N
CO \ / \ ~iN
I J
\ I N N [°\~I

O / O ~ N~CFi O / \ /
C \ I \ I N N \ I N

4.33 N
°H3 /° a ° ~ N
\o \ I a \ /
N
43~
N
° / ° N
\ \ \ / N

O / O ~N~
° \ \ / J
\ ~ I /\N \ ~ N

/ ~ N~\/~NWa \ \ / N

~N't~
o \ \ /
a ~ ~ / N ~ N

a/ ~ ~ \
N
~O \ ~ \ \ / NJ ~ /N
/ N~ \

N~N
O O N \ I
~D \ \ \ / N

N

I
~O \ \ \ / N

/o / 0 \ I \ \ / N
~N~

\ \ / N
\
448 ~~'N~
~N /
0 / \ I N iC~ i \ ~ \ I / \ I N
0 / \ /
N N

~N
I N ~N
\ ~ NJ
I Ni N

450 ,,oH
N
/
~N N
~O \ ~ / \
\ I N N \ ~ OH
*~' In the structures above, the hydrogen atoms bonded to secondary nitrogen atoms are not depicted.
The compounds, compositions and methods described herein are useful in inhibiting ZAP-70 and Syk. Accordingly, the compounds, compositions and methods described are useful in treating ZAP-70 and Syk mediated diseases or disease symptoms in a mammal, in particular a human. ZAP-70 and Syk mediated diseases are exemplified by the following:
lupus, organ transplant rejection, and inflammatory disorders. Examples of inflammatory disorders include arthritis (e.g., rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis, traumatic arthritis, 1o rubella artlu-itis, psoriatic arthritis, or osteoarthritis), inflammatory bowel disease, and Crohn's disease.
The compounds, compositions and methods of the present invention are useful in treating, for example, lupus, organ transplant rejection (e.g., kidney, liver, heart, lunch, pancreas (islet cells), bone marrow, cornea, small bowel, skin allogra$s or xenografts), and inflammatory ~5 disorders. Examples of inflammatory disorders include, but are not limited to, 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 a composition having a compound of any of the 2a formulae described herein and a pharmaceutically acceptable Garner; or a c~mpound of any of the formulae described herein, an additional therapeutic agent (e.g., anti-inflammatory; non-steroidal anti-inflammatory drugs (NSAID); steroid, and the like), and a pharmaceutically acceptable carrier; or a compound of any of the formulae described herein, an additional therapeutic agent, and a pharmaceutically acceptable carrier, wherein the additional therapeutic 25 agent is an kinase binding agent (e.g., a polypeptide, an antibody or organic molecule).

Yet another aspect of this invention relates to a method of treating a subject (e.g., mammal) having a kinase mediated disorder or disorder symptom (including, but not limited to pain and inflammation). The method includes administering to the subject (including a subject identified as in need of such treatment) an effective amount of a compound described herein, or a composition described herein to produce such effect. Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method).
The invention further relates to a product (i.e., a compound of any of the formulae herein) made by the methods described above.
1 o Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term "stable", as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).
Synthesis of Heterocyclic Kinase Inhibitors Compounds of the formula (II) (where variables for all formulae (e.g., formula (II)) are as defined herein) are prepared by treating the compound of formula (IX) with malonic acid to provide a ring expansion compound, which is then coupled with a compound containing RZ to 2o provide the compound of formula (XII).
O CO~H
Hal R2 ~O
N
R2, H N O
R2' H
formula (IX) formula (XII) The compound of formula (XII) is treated with a chlorinating agent, such as P~C13, and the carboxylic acid is coupled with a heterocyclic (e.g., heteroaryl or heterocyclyl) compound ("Het") to provide a compound of formula (XIII).
CO2H COHet ~2 ~2 a ~ \~ w ~ y N ~ f~ CI
~2~ H

formula (XII) formula (XIII) The resulting compound is then coupled with one or more coupling agents to provide a compound of formula (II).
COHet COHet R2 / ~ \ fV!_X_R'' I'z /
I X
~~~~ \ N~~,R
~z~ ~2, formula (XIII) formula (II) While the example above is shown with a quinoline core, other heterocyclic cores cam also be used. For example, the synthesis above can be performed by substituting the exemplary heterocycles below for the starting material of formula (IX) above:
O O O O
o N ~ o '~ o ~ ' o N N N N N NH
H H H S
These compounds are merely illustrative and are not intended to limit the scope of synthetic schemes.
The term "coupling agent" means a chemical agent that is used in a reaction that forms a bond between one chemical moiety and another moiety from the coupling agent.
Some examples of coupling agents include transition metals such as Pd, Cu, and Mg and and transition ~5 metal catalysts, as well as boron containing compounds such as boranes.
Coupling agents can also include nucleophiles such as amines, alkoxides, sulfides or corresponding protonated forms.
As can be appreciated by the skilled artisan, further methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art.
Additionally, the various synthetic steps may be performed in an alternate sequence or order to 2o give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Laxock, GonrpYelaerasive ~r,~anie Ti~arasformatiaras, VCH Publishers (19$9); T.VJ
Greens and P.CiM.
Wuts, Pf-otective CBroups ira ~rganic S'ytathesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser 25 and M. Fieser, Fiesea~ ezrzel ~%iese~,'s Reez~erats for ~r~cc~.ic Synthesis, John ~7Viley and Sons (1994);
loo and L. Paquette, ed., Encyclopedia of Reagents for OYgafiic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof.
The compounds of this invention may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of these compounds are expressly included in the present invention. The compounds of this invention may also be represented in multiple tautomeric forms, in such instances, the invention expressly includes all tautomeric forms of the compounds described herein (e.g., alkylation of a ring system may result in alkylation at multiple sites, the invention expressly includes all such reaction products).
All such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.
As used herein, the compounds of this invention, including the compounds of formulae described herein, are defined to include pharmaceutically acceptable derivatives or prodrugs thereof. A "pharmaceutically acceptable derivative or prodrug" means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention. Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a marmnal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species. Preferred prodrugs include derivatives where a group which enhances aqueous solubility or active transport through the gut membrane is appended to the structure of formulae described herein.
The compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological compartment (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
Pharmaceutically acceptable salts of the compounds of this invention include those 3o derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, benzoate, ber~enesulfonatea butyrate, citrate, digluconate, dodecylsulfate, formate, fumarate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, malonate, methanesulfonate, 2 naphthalenesulfonate, nicotinate, nitrate, palmoate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tautrate, tosylate and undecanoate. Salts deri~red from appropriate bases include alkali anetal (e.g., sodium), alkaline earth metal (e.g.9 magnesium), armnonium and 1~T-(alkyl)4+ salts. This invention also envisions the quaterni~ation of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaterni~ation.
The compounds of the forniulae described herein can, for example, be administered by 1o injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.001 to about 100 mg/kg of body weight, preferably dosages between 10 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods herein contemplate 15 administration of an effective amount of compound or compound composition to achieve the desired or stated effect. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion.
Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary 2o depending upon the host treated and the particular mode of administration.
A typical preparation will contain from about 5% to about 95% active compound (w/w). Alternatively, such preparations contain from about 20% to about 80% active compound.
Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the 25 activity of the specific compound employed, the age, body weight, general health status sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient's disposition to the disease, condition or symptoms, and the judgment of the treating physician.
Upon improvement of a patient's condition, a maintenance dose of a compound, 3o composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
Pharmaceutical compositions of this invention comprise a compound of the formulae described herein or a pharmaceutically acceptable salt thereof9 an additional agent izmluding for example, a steroid or an analgesic9 and any pharmaceutically acceptable carrier, adjuvant or vehicle. Alternate compositions of this invention comprise a compound of the formulae described herein or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, adjuvant or vehicle. The compositions delineated herein include the compounds of the formulae delineated herein, as well as additional therapeutic agents if present, in amounts effective for achieving a modulation of disease or disease symptoms, including kinase mediated disorders or symptoms thereof. The compositions are made by methods including the steps of combining one or more compounds delineated herein with one or more carriers and, optionally, one or more additional therapeutic agents delineated herein.
The term "pharmaceutically acceptable earner or adjuvant" refers to a carrier or adjuvant ~ 5 that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver 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 oleaginous suspension. This suspension may be 2o formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injeetable 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 may be employed are maxmitol, water, Ringer's solution and isotonic sodium chloride 25 solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or curboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of forniulation.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring andlor coloring agents may be added.
The pharmaceutical compositions of this invention may also be administered in the form ' ~5 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 -ternperature bLlt liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
2o Pharmaceutically acceptable Garners, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self emulsifying drug delivery systems (SEDDS) such as d-a tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as 25 human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium tuisilicate, polyvinyl pyrrolidone, eellulose-based substances, polyethylene glycol, sodium carboxynethylcellulose, polyacrylates, 3o waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

Cyclodextrins such as c~ -, ~i-, and 'y cyclodextrin, may also be advantageously used to enhance delivery of compounds of the formulae described herein.
In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases car buffers to enhance the stability of the formulated compound ~r its delivery form.
The term parentcral 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 1o when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene ~5 polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a Garner with suitable emulsifying agents. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecarlol, benzyl alcohol and water. The pharmaceutical compositions 20 of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches are also included in this invention.
The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of 25 pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
When the compositions of this invention comprise a combination of a compound of the formulae described herein and one or more additional therapeutic or prophylactic agents, both 3o the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to q5°9° of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
lE~~arILgliales:
Example 1: Synthesis of 2-Aminoquinolines O COZH

HO20 ~ ~ .
Co2H AcOH
H 110°C / N O
H
1p 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 ~5 EtOH and EtzO gave 6-Iodo-2-oxo-1,2-dihydro-quinoline-4-carboxylic acid 2 as the product, yielding 8.8 g (76%). 1H-NMR (400 MHz, DMSO-d6): 8 14.0 (br s, 1H), 12.13 (s, 1H), 8.56 (d, 1H, J= 8.1 Hz); 7.83 (dd, 1H, J= 8.7, 1.8 Hz), 7.17 (d, 1H, J= 8.4 Hz), 6.93 (s, 1H).
COpH O ~ COaH
I
O ~ 5 mol%~2 + KsPOa HO ~
N O B(OH)z z H 60°C

A mixture of 6-I~do-2-oxo-1,2-dihydro-quinoline-4-carboxylic acid 2 (3.15 g, 10 mrnol), 3,4-(methylenedioxyl)phenylboronic acid (2.49 g, 15 mmol), I~3PO4 (8.49 g, 40 mmol), and Pd(OAc)Z (112 mg, 0.5 mmol) in 60 mL of degassed HBO was heated under argone at 60°C for 2 25 h. After cooling to room temperature, the solid was collected by filtration, washed with H20 and acetone. It was then treated with 20 mL of 1M HCI, the resulting greenish yellow solid was filtered again and washed with HZO. Drying in vacuo over P205 yielded 2.53 g (82%) of product 3 as a greenish yellow solid. 1H-NMR (400 MHz, DMSO-d~): ~ 14.0 (br s, 1H), 12.11 (s, 1H), 8.34 (s, 1H), 7.79 (d, 1H, .J~= 7.6 Hz), 7.40 (d, 1H, .I = 8.6 Hz), 7.18 (s, 1H), 7.08 (d, 1H, .7= 7.1 Hz), 7.01 (d, 1H, ~J= 8.2 Hz), 6.91 (s, 1H), 6.06 (s, 2H).
N
° ~ CO2H O O oN~
1) POCK, 110°C, ~ h O
2) RZNH, DIEA, DCM, rt H~O ~
N- 'CI
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 oxyphosphourus chloride was refluxed for 4h and 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, 11.5 mmol) and 2-(S)-pyrroldinylinethyl pyrrolidine (0.59 g, 3.84 mmol) were slowly added into the solution at 0°C. The mixture was allowed to stir at room temperature for 12 h.
After removing the solvent by rotaxy evaporation, the residue was dissolved in ethyl acetate, washed with saturated aqueous 15 NaHCO3 and brine. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (Et3N-AcOEt 5:95) to give (6-B enzo [ 1,3 ] dioxol-5-yl-2-chloro-quinolin-4-yl)-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone 4 (1.20 g, 81%). MS m/z 464.2 (M++1); 1H-NMR (400 MHz, CDCl3): b 8.05 (m, 1H), 7.93 (m, 1H), 7.85 (br s, 1H), 7.41 (s, 1H), 7.13 (m, 1H), 7.11 (s, 1H), 6.92 (m, 1H), 6.03(s, 20 1H), 4.58 (m, 1H), 3.92 (m, 0.5H), 3.75 (m, O.SH), 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, 1H).
io7 C
Benzyl amine 120°C

2-Chloroquinoline ~~ (~0 mg, 0.17 mg) in benzylamine (0.3 mL) was heated for 12 h at 120°C. 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 yield product 5. MS m/z 535.3 (M++1).
Example 2: Synthesis of 2-AIk,~Quinolines R-MgCI
5 mol°/PdCIZ(dpp~
dioxane 60°C
The solution of 4-chlorobenzyl magnesium chloride (0.43 mL, 0.25 M solution in Et20) was added into a mixture of 2-chloroquinoline 4 (25 mg, 0.054mg) and PdCl2(dpp~ (2.2 mg, 0.0027 mmol) in 0.5 mL of dioxane under argone. The reaction mixture was stirred at 100°C for 12 h. After cooling to room temperature, aqueous NHq.CI was added. The mixture was extracted with EtOAc, and washed with brine. The organic layer was dried over Na2SO4., and 10~

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 Ouinolines Pr~cedaare A:
O ,N~
I
/ N N \
H
s To a 25 ml round bottom flask charged with bis(pinacolato)diboron (279 mg, 1.1 mmol), KOAc (294, 3.0 mmol) and PdCl2(dppfj (24.5 mg, 0.03 mmol) was added a solution of 6-1 o iodoquinoline 7 (607 mg, 1.0 mmol) in DMSO (6 mL). The mixture was thoroughly degassed by alternately connected the flask to vacuum and Argon. This resulting mixture was then heated at 80 °C overnight, diluted by EtOAc (40 mL) and filtered through CELITE.
The resulting product 8 was used in next steps without further purification after concentration.
Molecular weight is 608.3 and LC-MS showed 609.2 (M++ 1).
\ \
CF3 ~ H ~ / CF3 Under Argon, the 6-boronate 8 (15 mg, 0.025 nunol) in dioxane (2.0 mL) was added to the flask which was charged with Pd(dppf)Clz (2 mg), CsZCO3 (17 mg, 0.055 mmol), and 3,4-2o ethylenedioxyiodobenzene (15 mg, 0.057 n~nol). The mixture was thoroughly degassed by alternately c~nnected the flask to vacuum and Argon. The resulting solution was heated to 70 °C

and stirred overnight. It was diluted by EtOAc after cooled to room temperature. The solid was removed by filter through CELITE and washed by some EtOAc. Concentration to remove the solvent and the resulting residue purified by LC to give product 9. Exact Mass is 616 and LC-Ms showed 617 (h/I+ + 1 ).
procedure E:
O N
O~ \ \ \
I / N~H \
lU cFa A reaction vessel was charged with 6-iodoquinoline 7 (25.0 mg, 0.0411 mmol, 1.00 equiv), Pd(dppf)C12 (1.5 mg, 0.0021, 0.050 equiv), K3P04 (35.0 mg, 0.164 mmol, 4.00 equiv) and 3,5-dichlorophenylboronic acid (15.7 mg, 0.0811 mmol, 2.00 equiv). After flushing the vessel with argon, dioxane (2.0 mL) was introduced under argon and the resulting supension was stirred overnight at 80 °C. The crude reaction mixture was allowed to cool to rt, filtered through CELITE with the aid of EtOAc and concentrated. The crude residue was purified by LC to give product 10. LC-MS 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:
O N

\ \
N
H I \ li I \
CF3 11 ~ CF3 11~

To a round bottom flask charged with the 6-iodoquinoline 7 (61 mg, 0.1 mmol), phenylacetylene (1 molar equiv.), Pd(PPh3)ZCl2 (4~.0 mg), and CuI (1.0 mg) was added Et3MT (2 mL). The mixture was thor~ughly degassed by alternately connected the flask to vacuum and Argon and then heated to 4~5-50 °C and stirred overnight. The mixture was dihited with Et~A.c (20 ml) after cooling to room temperature and filtered through CELITE. After concentration, the crude product 11 was used in the next step without further purification. A
small portion was purified by LC. Exact Mass is 582 and LC-MS showed 583 (M++ I).
--Under HZ (1 atm), the crude acetylene compound 11 (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 LC-MS
showed 587 (M++ 1).
2o Under H2 (1 atm), the crude acetylene compound 11 (15 mg) was reduced in the presence of 5% palladium on 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. Preparative LC gave the pure product 13 for testing. The Exact Mass is 584 and LC-MS showed 585 (M+ + 1).
Example 4: Synthesis of 2-Thioduinolines /o O N
~\
N a ci n 14 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 CsZC03 (16 mg, 0.048 mmol).
o The resulting mixture was heated up to 80 °C and stirred at this temperature for two hours. After cooled to room temperature, EtOAc (20 ml) was added to dilute the mixture and the organic phase was washed by water and brine and dried over NaZS04. After concentration, the residue was purified by LC to yield product 14. The Exact Mass is 586 and LC-MS showed 587 (M+ +1).
15 Example 5: DELFIAAssay Before initiation of kinase reactions, compounds were pre-incubated with ZAP-70. Pre-incubation reactions contained 62.5 mM Mops pH 7.0, 12.5 mM MgCl2, 12.5%
glycerol, 3.1 nM
ZAP-70, 62.5 nM biotinylated poly(glu,Tyr), 0.1 mglml BSA, 6.25% DMSO and 0-100 mM
compound in a total volume of 40 ml. After a 10 minute room temperature incubation, 10 ml of 20 5 mM ATP was added to start the reaction. Reactions were incubated at room temperature for 30 minutes then terminated by addition of 5 ml 500 mM EDTA. The amount of phosphate transferred to biotinylated poly(glu,tyr) was measured using the Dissociation Enhanced Lanthanide Fluorescence Immuno-assay (DELFIA) from Perkin Eliner according to manufacturers protocol. Briefly, biotinylated poly (gly,tyr) was captured on streptavidin coated 25 plates, washed twice, then incubated with Europium labeled-anti-phosphotyrosine antibody.
Fr ee antibody was remo~red with sia~ gashes, Europium was dissociated from the antibody, and ii2 Europium fluorescence was measured at using an excitation wavelength of 340 nM
and au emission wavelength of 615 nM.
'1L'able B: hi vi~s'~ ~ctavity of representative ~~~xp~unds'~
Y~~arrrP~er Actieriiy B

A

13 ~ C

C

A

C

C

~o C

B
c 4.5 C

67 .4 7~ C

104. B

1~7 C

112' A

114. A

14.1 B

14.2 B

14.4. B

1 a~9 B
15~ A

15~. A

184. A

21~ A

254. A

2~a0A

Z84~A

301 1.785,uM

3~3 C
3~4 B

39.0 A
3~.1 A

374. B

4.00 C
4.01 C
4.02 C
4.03 C

4.07C

4.~8A

4.09A

4.13B

414.A

4.15A

4.39C

~54~0C

44.3 C

44.4. C

4,~.~ C

4~Q.~ C

44r C

44.3 C

44.~ C

'' "A"
means the compound has an ICso of >10 ~,M ifi vitro, "B" means the compound has an ICSo between 1 and ,uM
isa vitro, and "C"
means the compound has an ICso of <
1 ,uM
iya vity-o.

Example 6: Cell-based Assay of ZAP-70-mediated LAT Phosphorylation 5 ZAP-70 tyrosine kinase activity present in activated Jurkat T cells was measured by assessing the phosphorylation status of LAT. LAT is a pahnitoylated p36/38 kDa plasma membrane-associated protein expressed in all T lymphocytes and it is the physiologic substrate of activated ZAP-70. When Jurkat cells are stimulated with an anti-CD3 monoclonal antibody, which crosslinks the surface antigen receptor-CD3 complex, ZAP-70 becomes activated and ~o phosphorylates two tyrosine residues on LAT, Tyr-191 ~z Tyr-226. Therefore, assessment of LAT
Tyr-191 and Tyr-226 phosphorylation in anti-CD3 stimulated Jurkat T cells is a specific measure of intracellular ZAP-70 activity Accordingly, compounds that inhibit Tyr-191 and Tyr-226 phosphorylation of LAT indicate successful antagonism of ZAP-70 tyrosine kinase activity or upstream activation of the ZAP-70 pathway.
Jurlcat cells (ATCC) cultured at 15-20 X 106 cells/mL are pre-incubated for 15 mins at 370 °C with inhibitor compounds, or carrier (DMSO), and then are stimulated for 5 min. by the addition of 1 mg/mL final concentration of anti-CD3 monoclonal antibody (UCHT-1 or OKT 3;
E-Bioscience). The cells are then lysed by a detergent-based buffer and extracts are used for immunoprecipitation of all phosphotyrosine-containing proteins using a commercially available 2o phosphotyrosine specific monoclonal antibody (4(x10; Upstate Biotechn~logy Inc.) and protein-A-conjugated agarose beads. After washing the irmnune complexes to remove non-specifically bound proteins, the inununoprecipitated phosphotyrosine proteins are liberated from the agarose beads by boiling and denaturing and are resolved by SDS-PAGE and transferred to nitrocellulose membranes. LAT phosphorylated on Tyr-191 and Tyr-226 is then detected by standard western blotting technology using commercially available phospho-specific antibodies that react specifically with either phospho-Tyr-191 or phospho-Tyr-226 on LAT (Upstate Biotechnology Inc.), an enzyme-conjugated secondary antibody (horseradish peroxidase-conjugated goat anti-rabbit IgG antiserum), and ~. Storm Imaging system (Amersham-Phamiacia).
Inhibition was observed with representative compounds described herein.
Example 7: IL-2 Inhibition Cell-based Assay IL-2 production was measured in Jurkat cells following co-stimulation with Anti-CD3 and Anti-CD28 antibodies. Cells were seeded at 1 x 10$ /well (200 pl/well of culture) in 96 1o well plates precoated with anti-CD3 antibody (BD Biocoat T cell activation plates, Anti-human CD3 plate = Cat. No. 354725 from BD BioSciences). Anti-CD28 antibody (eBioScience, Cat#
16-0289-85; Functional Grade, co-stimulatory, clone 28.2) is added to the plate at the final concentration of 20 nglwell. Cells are incubated for 48 hrs after which a 50 ~.l aliquot of cell supernatant is removed for IL-2 titration. IL-2 titration was performed using the Endogen enzyme-linked immunosorbent assay (ELISA) Kit (Endogen of Pierce, Cat# EH2-IL2-5) as described by the manufacturer. In brief, this assay consists of using a 96 well microtiter plate that has been pr ecoated with anti-IL-2 antibodies for the capture of human IL-2. In order to detect the captured IL-2, a biotinylated second anti-IL-2 antibody is added to all wells. This results in a sandwiching of any IL-2 (capture IL-2 Ab C IL-2 C detection IL-2-biotin Ab).
2o Following the removal of unbound antibodies, by a series of washings, a horseradish peroxidase (HRP) conjugate with a high affinity for biotin is added. Unbound Strepavidin-HRP is removed and the bound enzyme labeled antibodies can then be measured via a chromogenic reaction with the addition of TMB substrate. The resulting chromogenic reaction is stopped using HzSOa (Stop Solution) and the optical density of each well is then read at the appropriate wavelength. The level of substrate conversion is colormeterically determined by measuring the absorbance that is proportional to the amount of IL-2.
Representative compounds described herein demonstrated IL-2 inhibition.
All references cited herein, whether in print, electronic, computer readable storage media or other form, are e~~pressly incorporated by referenoe in their entirety, including but not limited 3o to, abstracts, articles, journals, publications, texts, treatises, Internet web sites, databases, patents, and patent publications.

A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

Claims (46)

1. A compound of the formula (I) wherein;
A forms a benzene, pyridine, pyrimidine, thiophene, pyrrole, imidazole, pyrrazole, thiazole, or oxazole ring;
X is O, S, NR3, N(R3)N(R3), C(O), N(R5)C(O), C(O)NR5, or alkyl;
R x is H, cycloalkyl, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, R5O-alkyl, (R5)3Si, acyl, wherein R x is optionally substituted with 1-4 R4;
each R2 is independently H, NR5 2, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halo, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each of which is optionally substituted with 1-4 R7; wherein R2 is not Me when X-R x is Me and Q is NHaryl substituted with heterocycyl; and wherein R2 is not acetyl when X-R x is arylalkenyl;
n is 0-3;
each R3 is independently H, alkyl, R5O-alkyl, or arylalkyl;
each R4 is independently halo, OH, CF3, C(O)R5, NR3 2, N(R3)C(O)R5, CN, OCF3, SO2R5, or SiR5 3; 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 halo, OH, CF3, alkyl, alkyloxy, N(R5)-alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl;

each R7 is independently halo, CN, OR5, CF3, N(R5)C(O)R5, C(O)R5, OCF3, SCF3, NR5 2, C(O)NR5 2, 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, halo, C(O)R5, C(O)R9, C(S)R5, C(S)R9, C(O)NR5 2, C(O)NR5R9, S(O)R5, S(O)R9, S(O)NR5 2, S(O)NR5R9, SO2R5, SO2R9, SO2NR5 2, SO2NR5R9, NR5 2, 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, R5 2N-alkyl, NR5R11-alkyl, R5O-alkyl, R11, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is optionally substituted with alkyl or OR5; and each R11 is independently arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl.

2. The compound of claim 1, formula (I), wherein A forms a benzene ring.

3. The compound of claim 1, formula (II) wherein;
X is O, S, NR3, N(R3)N(R3), C(O), N(R5)C(O), C(O)NR5, or alkyl;
R X is H, cycloalkyl, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, R5O-alkyl, (R5)3Si, aryl, wherein R X is optionally substituted with 1-4 R4;
each R2 is independently H, NR5 2, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halo, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each of which is optionally substituted with 1-4 R7;
each R2' is independently H, halo, NH2, alkyl, OH, C(O)Me, aryl, heteroaryl;
each R3 is independently H, alkyl, R5O-alkyl, or arylalkyl;
each R4 is independently halo, OH, CF3, C(O)R5, NR3 2, N(R3)C(O)R5, CN, OCF3, SO2R5, or SiR5 3; 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 halo, OH, CF3, alkyl, alkyloxy, N(R5)-alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl;
each R7 is independently halo, CN, OR5, CF3, N(R5)C(O)R5, C(O)R5, OCF3, SCF3, NR5 2, C(O)NR5 2, 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, R5 2N-alkyl, NR5R11-alkyl, R5O-alkyl, R11, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is optionally substituted with alkyl or OR5; and each R11 is independently arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl.

4. The compound of claim 3, formula (II), wherein Het is attached through a ring-nitrogen atom.

5. The compound of claim 3, formula (II), wherein R2' is H.

6. The compound of claim 3, formula (II), wherein;
Het is attached through a ring-nitrogen atom;
X is NR3, or alkyl; and R X is cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, or heterocyclyl wherein R X
is optionally substituted with 1-4 R4; and R2' is H.

7. The compound of claim 3, formula (II), wherein Het is

8. The compound of claim 3, formula (II), wherein Het is

9. The compound of claim 1, formula (III), wherein, X is O, S, NR3, N(R3)N(R3), C(O), N(R5)C(O), C(O)NR5, or alkyl;
R x is H, cycloalkyl, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, R5O-alkyl, (R5)3Si, acyl, wherein R x is optionally substituted with 1-4 R4;
each R2 is independently H, NR5 2, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halo, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each of which is optionally substituted with 1-4 R7; wherein R2 is not Me when X-R x is Me and R12 is aryl substituted with heterocyclyl;
each R2' is independently H, halo, NH2, alkyl, OH, C(O)Me, aryl, heteroaryl;
each R3 is independently H, alkyl, R5O-alkyl, or arylalkyl;
each R4 is independently halo, OH, CF3, C(O)R5, NR3 2, N(R3)C(O)R5, CN, OCF3, SO2R5, or SiR5 3; 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 halo, OH, CF3, alkyl, alkyloxy, N(R5)-alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl;
each R7 is independently halo, CN, OR5, CF3, N(R5)C(O)R5, C(O)R5, OCF3, SCF3, NR5 2, C(O)NR5 2, 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 R13; and each R13 is independently heterocyclyl optionally substituted with alkyl or OR5.

10. The compound of claim 9 formula (III) wherein R2' is H.

11. The compound of claim 9 formula (III), wherein 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(O), C(O)NR5, or alkyl;
R x is H, cycloalkyl, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, R5O-alkyl, (R5)3Si, acyl, wherein R x is optionally substituted with 1-4 R4;
each R2 is independently H, NR5 2, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halo, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each of which is optionally substituted with 1-4 R7; wherein R2 is not Me when X-R x is Me and Q is NHAryl substituted with heterocycyl; and wherein R2 is not acetyl when X-R x is arylalkenyl;
each R3 is independently H, alkyl, R5O-alkyl, or arylalkyl;
each R4 is independently halo, OH, CF3, C(O)R5, NR3 2, N(R3)C(O)R5, CN, OCF3, SO2R5, or SiR5 3; 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 halo, OH, CF3, alkyl, alkyloxy, N(R5)-alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl;
each R7 is independently halo, CN, OR5, CF3, N(R5)C(O)R5, C(O)R5, OCF3, SCF3, NR5 2, C(O)NR5 2, 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, halo, C(O)R5, C(O)R9, C(S)R5, C(S)R9, C(O)NR5 2, C(O)NR5R9, S(O)R5, S(O)R9, S(O)NR5 2, S(O)NR5R9, SO2R5, SO2R9, SO2NR5 2, SO2NR5R9, NR5 2, 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, R5 2N-alkyl, NR5R11-alkyl, R5O-alkyl, R11, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is optionally substituted with alkyl or OR5;
each R11 is independently arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl; and R14 is halo, NH2, alkyl, OH, C(O)Me, aryl, heteroaryl, or C(O)NHR5.

13. A compound of the formula (V) wherein;
A forms a benzene, pyridine, pyrimidine, thiophene, pyrrole, imidazole, pyrrazole, thiazole, or oxazole ring;
R Y is H, halo, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl, wherein R Y is optionally substituted with 1-4 R4;
each R2 is independently H, NR5 2, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halo, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each of which is optionally substituted with 1-4 R7; wherein R2 is not Me when R Y is halo, indole substituted with halo, phenyl, or phenyl substituted with halo; wherein R2 is not isopropyl when R Y is phenyl substituted with halo; wherein R2 is not alkynyl substituted with heterocyclyl when R Y is indole substituted with halo; wherein R2 is not phenyl when R Y is H, wherein R2 is not halo when R Y is indole substituted with halo or phenyl substituted with halo; and wherein R2 is not acetyl when R Y is phenyl or substituted phenyl;
n is 0-3;
each R3 is independently H, alkyl, R5O-alkyl, or arylalkyl;
each R4 is independently halo, OH, CF3, C(O)R5, NR3 2, N(R3)C(O)R5, CN, OCF3, SO2R5, or SiR5 3; 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 halo, OH, CF3, alkyl, alkyloxy, N(R5)-alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl;

each R7 is independently halo, CN, OR5, CF3, N(R5)C(O)R5, C(O)R5, OCF3, SCF3, NR5 2, C(O)NR5 2, 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, halo, C(O)R5, C(O)R9, C(S)R5, C(S)R9, C(O)NR5 2, C(O)NR5R9, S(O)R5, S(O)R9, S(O)NR5 2, S(O)NR5R9, SO2R5, SO2R9, SO2NR5 2, SO2NR5R9, NR5 2, 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, R5 2N-alkyl, NR5R11-alkyl, R5O-alkyl, R11, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is optionally substituted with alkyl or OR5; and each R11 is independently arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl.

14. The compound of claim 13, formula (V), wherein A forms a benzene ring.

15. The compound of claim 13, formula (VI), wherein wherein, R Y is H, halo, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl, wherein R Y is optionally substituted with 1-4 R4;
each R2 is independently H, NR5 2, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halo, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each of which is optionally substituted with 1-4 R7; wherein R2 is not Me when R Y is halo, indole substituted with halo, phenyl, or phenyl substituted with halo; wherein R2 is not isopropyl when R Y is phenyl substituted with halo;
each R2' is independently H, halo, NH2, alkyl, OH, C(O)Me, aryl, heteroaryl;
each R3 is independently H, alkyl, R5O-alkyl, or arylalkyl;
each R4 is independently halo, OH, CF3, C(O)R5, NR3 2, N(R3)C(O)R5, CN, OCF3, SO2R5, or SiR5 3; 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 halo, OH, CF3, alkyl, alkyloxy, N(R5)-alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl;
each R7 is independently halo, CN, OR5, CF3, N(R5)C(O)R5, C(O)R5, OCF3, SCF3, NR5 2, C(O)NR5 2, 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, R5 2N-alkyl, NR5R11-alkyl, R5O-alkyl, R11, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is optionally substituted with alkyl or OR5; and each R11 is independently arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl.

16. The compound of claim 15, formula (VI), wherein Het is attached through a ring-nitrogen atom;
R2 is not H; and R2' is H.

17. The compound of claim 15, formula (VI), wherein Het is

18. The compound of claim 15, formula (VI), wherein Het is

19. The compound of claim 13, formula (VII) wherein;

R Y is H, halo, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl, wherein R Y is optionally substituted with 1-4 R4;
each R2 is independently H, NR5 2, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halo, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each of which is optionally substituted with 1-4 R7; wherein R2 is not phenyl when R Y is H;
each R2' is independently H, halo, NH2, alkyl, OH, C(O)Me, aryl, heteroaryl;
each R3 is independently H, alkyl, R5O-alkyl, or arylalkyl;
each R4 is independently halo, OH, CF3, C(O)R5, NR32, N(R3)C(O)R5, CN, OCF3, SO2R5, or SiR5 3; 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 halo, OH, CF3, alkyl, alkyloxy, N(R5)-alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl;
each R7 is independently halo, CN, OR5, CF3, N(R5)C(O)R5, C(O)R5, OCF3, SCF3, NR5 2, C(O)NR5 2, 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 R13; and each R13 is independently heterocyclyl optionally substituted with alkyl or OR5.

20. The compound of claim 19 formula (VII), wherein R2 is not H; and R2' is H.

21. The compound of claim 19 formula (VII), wherein R12 is

22. A compound of the formula (VIII), wherein, R Y is H, halo, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl, wherein R Y is optionally substituted with 1-4 R4;
each R2 is independently H, NR5 2, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halo, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each of which is optionally substituted with 1-4 R7; wherein R2 is not bile when R Y is halo, indole substituted with halo, or phenyl optionally substituted with halo; wherein R2 is not isopropyl when R Y is phenyl substituted with halo; wherein R2 is not alkynyl substituted with heterocyclyl when R Y is indole substituted with halo; wherein R2 is not phenyl when R Y is H; and wherein R2 is not acetyl when R Y is phenyl or substituted phenyl;
each n is 0-3;
each R3 is independently H, alkyl, R5O-alkyl, or arylalkyl;
each R4 is independently halo, OH, CF3, C(O)R5, NR32, N(R3)C(O)R5, CN, OCF3, SO2R5, or SiR5 3; 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 halo, OH, CF3, alkyl, alkyloxy, N(R5)-alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl;
each R7 is independently halo, CN, OR5, CF3, N(R5)C(O)R5, C(O)R5, OCF3, SCF3, NR5 2, C(O)NR5 2, 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, halo, C(O)R5, C(O)R9, C(S)R5, C(S)R9, C(O)NR5 2, C(O)NR5R9, S(O)R5, S(O)R9, S(O)NR5 2, S(O)NR5R9, SO2R5, SO2R9, SO2NR5 2, SO2NR5R9, NR5 2, 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, R5 2N-alkyl, NR5R11-alkyl, R5O-alkyl, R11, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is optionally substituted with alkyl or OR5;

each R11 is independently arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl; and R14 is halo, NH2, alkyl, OH, C(O)Me, aryl, heteroaryl, or C(O)NHR5.

23. The compound of claim 22, formula (VIII), wherein n is 1 and R2 is not H.

24. The compound of formula (XIV), wherein, X is O, S, NR3, N(R3)N(R3), C(O), N(R5)C(O), C(O)NR5, or alkyl;
R X is H, cycloalkyl, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, R5O-alkyl, (R5)3Si, acyl, wherein R X is optionally substituted with 1-4 R4;
each R2 is independently H, NR5 2, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halo, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, aryloxy, or heteroaryloxy, each of which is optionally substituted with 1-4 R7;
n is 0-3;
each R3 is independently H, alkyl, R5O-alkyl, or arylalkyl;
each R4 is independently halo, OH, CF3, C(O)R5, NR3 2, N(R3)C(O)R5, CN, OCF3, SO2R5, or SiR5 3; 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 halo, OH, CF3, alkyl, alkyloxy, N(R5)-alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl;
each R7 is independently halo, CN, OR5, CF3, N(R5)C(O)R5, C(O)R5, OCF3, SCF3, NR5 2, C(O)NR5 2, 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, halo, C(O)R5, C(O)R9, C(S)R5, C(S)R9, C(O)NR5 2, C(O)NR5R9, S(O)R5, S(O)R9, S(O)NR5 2, S(O)NR5R9, SO2R5, SO2R9, SO2NR5 2, SO2NR5R9, NR5 2, 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, R5 2N-alkyl, NR5R11-alkyl, R5O-alkyl, R11, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is optionally substituted with alkyl or OR5; and each R11 is independently arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl.

25. A method of making a compound of formula (II) wherein X, R X, R2, R2', and Het are as defined below, the method comprising;
treating the compound of formula (IX) with malonic acid, to provide a ring expansion compound of formula (X);
coupling the compound of formula (X) with a Pd catalyst and a compound of formula (XI) to provide a compound of formula (XII);

treating the compound of formula (XII) with POCl3 to provide the chloride of formula (XIII), and coupling the carboxylic acid of formula (XII) with an amine of formula Het-H to provide the compound of formula (XIII); and coupling the compound of formula (XIII) with one or more coupling agents to provide a compound of formula (II), wherein for formulae 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, cycloalkyl, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, R5O-alkyl, (R5)3Si, acyl, wherein R x is optionally substituted with 1-4 R4;
each R2 is independently NR5 2, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halo, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, aryloxy, or heteroaryloxy, each of which is optionally substituted with 1-4 R7;
R2' is H, halo, NH2, alkyl, OH, C(O)Me, aryl, heteroaryl;
each R3 is independently H, alkyl, R5O-alkyl, or arylalkyl;

each R4 is independently halo, OH, CF3, C(O)R5, NR32, N(R3)C(O)R5, CN, OCF3, SO2R5, or SiR5 3; 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 halo, OH, CF3, alkyl, alkyloxy, N(R5)-alkyl, heteroaryl, heteroarylalkyl, or heterocyclyl;
each R7 is independently halo, CN, OR5, CF3, N(R5)C(O)R5, C(O)R5, OCF3, SCF3, NR5 2, C(O)NR5 2, 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, R5 2N-alkyl, NR5R11-alkyl, R5O-alkyl, R11, heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is optionally substituted with alkyl or OR5; and each R11 is independently arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl.

26. The method of claim 25, wherein the H of Het-H is attached to a nitrogen.

27. The method of claim 25, wherein the coupling agent is H2NR x.

28. The method of claim 25, wherein the coupling agents are MgCl-R x, and Pd.

29. The method of claim 25, wherein the coupling agent is HSR x.

30. A method of treating an autoimmune disorder in a subject comprising administering to the subject any of the compounds of claims 1-24.

31. The method of claim 30, further comprising administering an additional therapeutic agent.

32. The method of claim 30, wherein the autoimmune disorder is lupus.

33. A method of treating organ transplant rejection in a subject comprising administering to the subject any of the compounds of claims 1-24.

34. The method of claim 339 further comprising administering an additional therapeutic agent.

35. A method of treating an inflammatory disorder in a subject comprising administering to the subject any of the compounds of claims 1-24.

36. The method of claim 35, further comprising administering an additional therapeutic agent.

37. The method of claim 36, wherein the additional therapeutic agent is an analgesic, or a steroid.

38. The method of claim 35, wherein the inflammatory disorder is arthritis.

39. The method of claim 38, wherein the arthritis is rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis, or osteoarthritis.

40. The method of claim 35, wherein the inflammatory disorder is inflammatory bowel disease or Crohn's disease.

41. A composition comprising any of the compounds of claims 1-24.

42. The composition of claim 41, further comprising a pharmaceutically acceptable carrier.

43. The composition of claim 41, further comprising an additional therapeutic agent.

44. A library of the compounds of any of formulas (I)-(VIII).

45. A method of inhibiting IL-2 production in a subject comprising administering to the subject a compound of any of claims 1-24-.

46. A method of modulating ZAP-70 in a subject comprising administering to the subject a compound of any of claims 1-24.