HETEROCYCLIC KINASE INHIBITORS: METHODS OF USE AND SYNTHESIS

INHIBITEURS DE KINASE HETEROCYCLIQUES : PROCEDES D'UTILISATION ET DE SYNTHESE

English 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.

French Abstract

L'invention concerne des inhibiteurs de kinase, des compositions contenant ces inhibiteurs, et des procédés d'utilisation de ces inhibiteurs et des compositions d'inhibiteurs. Ces inhibiteurs et les compositions les contenant sont utiles dans le traitement de maladies ou de symptômes de maladies. Cette invention porte aussi sur des procédés de fabrication de composés inhibiteurs de kinase, des procédés d'inhibition de l'activité de la kinase, et des procédés de traitement de maladies ou de symptômes de maladies.

Claims

WHAT IS CLAIMED IS:
1. A compound of the formula (I)
<IMG>
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;
128

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)
<IMG>
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,
129

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
130

R2' is H.
7. The compound of claim 3, formula (II), wherein
Het is
<IMG>
8. The compound of claim 3, formula (II), wherein
Het is
<IMG>
9. The compound of claim 1, formula (III),
131

<IMG>
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.
132

10. The compound of claim 9 formula (III) wherein R2' is H.
11. The compound of claim 9 formula (III), wherein
R12 is
<IMG>
12. A compound of formula (IV)
<IMG>
133

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
134

R14 is halo, NH2, alkyl, OH, C(O)Me, aryl, heteroaryl, or C(O)NHR5.
13. A compound of the formula (V)
<IMG>
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;
135

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
<IMG>
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
136

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
137

<IMG>
18. The compound of claim 15, formula (VI), wherein
Het is
<IMG>
19. The compound of claim 13, formula (VII)
<IMG>
wherein;
138

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
139

<IMG>
22. A compound of the formula (VIII),
<IMG>
wherein,
140

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;
141

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),
<IMG>
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;
142

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)
<IMG>
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);
<IMG>
coupling the compound of formula (X) with a Pd catalyst and a compound of
formula
(XI) to provide a compound of formula (XII);
143

<IMG>
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
<IMG>
coupling the compound of formula (XIII) with one or more coupling agents
<IMG>
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;
144

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.
145

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.
146

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.
147

Description

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
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~~

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
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;
2

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
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)

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
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
4

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
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
X10
~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),

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
,R~~
HN
R2
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.

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
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
R14
~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;

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
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)

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
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;

CA 02518398 2005-09-07
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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;

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
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
11

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WO 2004/080463 PCT/US2004/007286
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
R2
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;
12

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WO 2004/080463 PCT/US2004/007286
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,
NRSZ9
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
13

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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;
14

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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,
NRSZ9
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;

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WO 2004/080463 PCT/US2004/007286
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)
16

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WO 2004/080463 PCT/US2004/007286
O Het
R2
\ 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);
O C02H
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
17

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WO 2004/080463 PCT/US2004/007286
COHet COHet
R2 R2
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.
18

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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.
19

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WO 2004/080463 PCT/US2004/007286
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.

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
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-
12
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,
21

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
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.
22

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Table 1: Representative compounds of the invention**
i~u~~er MOLSTRUCTURE
O '"N~
N CI
23

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
o .'.N
I\
/O I \ N~OiC~S
'O
~~N~
~~O~N
O LN
I \
N N
11
24

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
12
13
14
O ,N~
I \ \
N N
O / O ,N~
/ i / i °~°N~
\N N \
16
17

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
13
1~
21
22
23
26

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
24
2~
26
27
28
29
27

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
3~
32
33
34
28

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
36
3~
38
39
41
29

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
42
43
44
46
47

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
48
4~
51
o i o ,,,N~
o i ~ i
~~o~i
N N
52
53
31

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
54
56
57
59
32

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
5~
62
63
64
33

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
66
~7
68
69
C
O '~N~
\ I \ \
N N~C~
71
34

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
72
73
o , a Nn
N
N '0
CHI
74
76
77

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
78
N
O N
O \ ~ ~ \ a
/ N NsCli~
~~I
:v
80 ~~)
0 / O N\ /
\O \ I \ \ OH
/ N~N ~ \
81
O / O N
C i
O \ W W
Ni\N ~ \
82 ~~,
O / 0 N
~0 \ ~ ~ \ \
N ~ \
83
0 / O N
C i ~n
o \ I \ \ r~0
/ N N
36

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
84
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
89
37

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
9D
9~
i
i O
N
OH
92
r
O ..,N~
N
93
94
38

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
96
9i
98
99
100
N ~
O \ \"",\N/
\\
101 ~ I ~ ci
o / I w w
39

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
102
10~
N
O \ \""..~
~O I / ~ \ \
/ N N I \ F
F F
104
105
106
107

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
108
1~~
110
111
112
N
O ,,,N~
CI
N G
113
N
O~N
CI \N"CI
41

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
114
N
~n
,I
N N ~ I F
l F
F
115
N
a N
I\
I ri~a
I
i
116
o ~N~
I
I -N
\ \
I~ I~
117
118
119
42

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
120
121
122
123
124
125
43

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
126
12t
128
0
~F
129
130
131
44

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
132
133
134
135
136
137

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
138
139
140
141
142
143
46

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
144
14~
146
147
148
149
47

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
150
N
0
N ~ I \
-.
N- \ I GH3
151
N
0
N I \ N \ I
N- \ I I -~ O
~3
152
0
~co \ / N v -
N / \ \ / -N
153
N
O
N
_ I \
N- \ I I -N I \
154
N
O
N
N- \ I I \ ~ I \
155
48

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
156
N
O CI
N
_ ~ ~~ -N
N- ~ ~ ~ -N
~5%
158
o N
N- ~ \ N F
159
0
F
N N ~ ~ \ / -N
160
0
N
_ _
O CFh
N- ~ ~ ~ \ N
161
49

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
162
O N
F
\ / ~ ~ N ~ ~ F
0
N N
F
N- \ ~ ~ \ N N
F
164
N
0
N
N
_ / F
N- ~ ~ N F F
165
166
0
cl ~ ~ _
CI N N ~ ~ ~ ~ -N
167

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
168
N
O
N
_ ~ ~ N ~ ~ CI
N- ~ ~ ~ -N
170
N
O
N
_ ~ ~~--N
N- \ / ~ -N
171
172
N
0 H~
N
N= ~ / ~ -N
173
N
\\ \ ~ /O
\N N
51

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
174
N
N\\ \ ~ O
I / / / I / I CI
\ \N
175
N
O
N
N- ~ ~ ~ \ ~ CH3
176
177 ,N
I\
/
Nc o I \ I \ I
N ~ N
O
178
N
N- ~ ~ ~ \ ~ ~ \ ONE
179
N
0 G
N I ~ F
N- \ / ~ -N
52

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
180
0
cl ~ ~ - -
N
F Pl ~ \ \ / -N
182
183
184
185
53

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
186
N
0
N
N- \ I ~ -N
N
0
N
~>-N CHI
N- ~ / I -N
188
N
0 F
N I
I ~~N
N- \ I ~ -N F
189
190
0
N ~
O-I--F
N- I \ I ~ ~F
191
54

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
192
N
\\ \ ~ 0
I / / / \ F
\ '~ I N I //
N
\\ \ ~ /0
I / / / CI \ CI
\ N I N I /
194
N
0
I \
I \ / I \ /
F / N \N /
195
O F
N
_ ~ ~~N -
F
NC ~ ~ I .N F F
196
N
0 \ oN
I/
\ / I \
Cl / N \N /
197
N
/0 / iN
\I
\ / \
FSCvO I / N w I /

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
198
0
F ~ I -
F P ~ \ ~ \ =N
L/
200
N
O \ //
/ \ ~ /
N'~N \N /
LhC /
201
0
N- \ I I \ N~ I
I-L,C
2U2
0
N
N- ~ ~ ~ \ N ~ ~ 0
FhC CND
203
H~C-
CH O
Na
N ~ ~ ~ ~ -N
56

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
204
o~~
2~a
206
207
p \ /N
/ ~ \ . ~ /
~N /
H,t / I
\
208 y
'i
N
\yI~ ~O
NJ \ \
IN I / /
209
57

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
210
N
O
N -
N- \ / ~ \ N~N
N
O G
N
_ ~ ~~--N
N- ~ ~ ~ 'N
212
O \ //N
/ \
~IN \N I /
OH
/
213
214
215
y
/ O
N
N ~ ~ ~ ~ -N
58

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
216
N
O
N -
_ ~ ~ N a
N- t ~ / N
N
O
N
_ ~ ~~N U
N- ~ ~ ~ -N
218
219
220
N
/ /N
G / \ ~ I
G I / N \N I /
221 Ii
~ r
N
t I
N~/ ' Bn
tTd ~ /
ay
59

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
222
CH3 O
B ~ I _
N -
P! I \ ~ I -N
223
CH3 O
F ~ I
~N I ~ I ~ -N
224
0
N' ~ I ,
N
CH N I ~ ~ I =N
225
N N
0
~3
- ~ I I ~ N I ~ F
226
N
O H~
N I
_ ~ ~~-N
N- ~ I ~ -N F
227
0
N
_ I ~ N ~ I
N- \ I I F

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
228
22~
230
N
O F
N
N- ~ ~ ~ -N G
231
232
233
N
O
N- \ I I \ N
-F
F
61

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
234
0
_ / \ N \ / \ ~
N- \ / / -N
23~
236
237
N
0
F F
F
F
\ / /
233
239
62

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
240
p F
N I ~ F
F
P- ~ I I -N
242
N
O C
s'
N
N- \ / / N ~ S
243
N
O / iN
/ ~ ~ I
N wN ~ /
244
O
N
CHI
N- ~ I I \ N ~GH~
245
63

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
246
2~.~
248
249
N
O
N- \ I I ~ N~ \N
I
250
0
F \ I
N
d N I ~ ~ I -N
251
64

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
252
0
\ / \ /
N r \ r \ -N
253
254
N
0
N I
N
N- ~ ~ / -N
255 ' i
N r..J
n
o
N~
U
256
N
0
N
~~S
N-
257 ,,
w
r\
, ~-~rJ
0
C.

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
258
N\\ \ ~ o
/ / v
W
N t~
~CI
25~
N-
-N, I
N
260
261
o a
N
_ ~ ~~--N
N- ~ ~ ~ N
262
o _ i
s
N-
263
n
N\ N
6
~' I o N
N~~
66

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
264
255
266
F
F
O
N
267
N
~N
0
I ~ ~ i
N /
F
268
269 ~ F
F
N F
N
N- ~ / ~ -N
67

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
270
N N
O
N
N-
S
2v~
272
273
s
/ v N~
~ ~ 0 H
U
274
N
0 N
/
'N
\ ~ \
275
O~N
I
I / CH I /
68

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
276
277
278
r.~
O N
I ~
I r~N I \
F \ I
F~F
279
O N
I\l
I N~N I \
\ CFh
2so
281
69

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
282
283
284
285
286
287

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
288
289
290
291
292
293
71

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
294
295
296
297
298
0
S
299
72

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
300
30~
302
303
304
305
73

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
306
30i
308
309
310
31 °I
74

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
312
313
314
315
r
\ O N
/ / \ OH
N
/
316
317

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
318
31~
320
321
322
323
76

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
324
32~
N
O / O ~~,N~
~O \ ~ \ \ / ~ O
F
\ F
326
327
O / N
~O \ ~ ~ \ \
/
OH
328
C
/o / o N
\o \ ~ ~ i
/ N N
D~~
329
/Q / O N
\o \ ~ ~ i
N
O~~
77

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
330
339
332
333
334
335
78

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
336
33r
338
339
340
341
79

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
342
343
344
345
346
347

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
348
34~
350
351
352
353
81

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
354
N
~~'
Ia
B N N I \ F
F F
355
356
357
358
359
82

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
360
369
362
363
364
365
83

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
366
367
368
369
370
371
84

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
372
373
374
375
376
377

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
378
378
380
381
382
383
.r
Gf.l
' 'ra"N w
W I/ r
r
0
86

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
384
38~
386
387
388
389
87

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
390
399
392
393
394
395
88

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
396
39~
398
O O ~..N
~O \ ~ ~ \ \
N ~ \
CFI
399
400
401
89

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
402
4.0~
404
405
406
/O / 0 ...N~
~ I / / / ci
w ~N I w I
407

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
408
4.09
410
411
412
413
91

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
414
41~
416
417
418
419
92

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
420
q.2~
422
423
424
425
93

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
426
4~2~
428
N
/ N
CO \ / \ ~iN
I J
\ I N N [°\~I
429
O / O ~ N~CFi
O / \ /
C \ I \ I N N \ I N
430
431
94

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
432
4.33
434
435
436
437

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
438
N
°H3
/° a ° ~ N
\o \ I a \ /
N
43~
N
° / ° N
\ \ \ / N
440
O / O ~N~
° \ \ / J
\ ~ I /\N \ ~ N
441
/ ~ N~\/~NWa
\ \ / N
442
~N't~
o \ \ /
a ~ ~ / N ~ N
443
a/ ~ ~ \
N
~O \ ~ \ \ / NJ ~ /N
/ N~ \
96

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
444
N~N
O O N \ I
~D \ \ \ / N
445
N
0 0 N
I
~O \ \ \ / N
446
/o / 0
\ I \ \ / N
~N~
447
0 / 0 N
\ \ / N
\
448 ~~'N~
~N /
0 / \ I N iC~ i
\ ~ \ I / \ I N
0 / \ /
N N
449 N/
~N
I N ~N
\ ~ NJ
I Ni N
97

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
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).
98

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
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
99

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
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

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
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,
101

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
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
102

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
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
103

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
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.
104

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
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
105

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
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
I 1
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
3
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
106

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
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

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
C
Benzyl amine
120°C
4 5
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
4
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~

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
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
CF3
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
109

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
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
1
\ \
N
H I \ li I \
CF3 11 ~ CF3
11~

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
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
I11

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
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

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
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
1 B
2 B
3 A
4 C
B
8 A
7 A
8 A
9 A
A
11 B
12 C
13 ~ C
14 A
C
16 C
17 C
18 C
19 C
A
21 A
22 C
23 C
24 C
C
26 A
27 C
28 A
29 B
C
31 C
32 A
33 B
113

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
34 B
35 C
36 C
37 C
38 B
39 B
~o C
41 C
B
c
44 C
4.5 C
46 C
47 B
48 B
49 B
50 C
51 C
52 C
53 C
54 C
55 C
56 C
57 C
58 B
59 B
60 C
61 B
62 B
63 B
64 B
65 C
66 B
67 .4
58 C
59
7~ C
114

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
71 A
72 B
73 B
74 B
75 B
78 C
77 C
78 B
79 B
80 A
81 B
82 B
83 B
84 A
85 B
86 B
87 A
88 A
89 B
90 B
91 C
92 C
93 A
94 B
95 B
96 B
97 B
98 C
99 C
100 A
101 B
102 B
103 B
104. B
105 C
105 C
1~7 C
115

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
108 B
109 B
110 A
111 A
112' A
113 A
114. A
115 A
118 B
917 C
118 B
119 A
120 B
121 B
122 B
123 B
124 B
125 C
126 C
127 C
128 A
129 B
130 B
131 B
132 B
133 B
134 B
135 B
136 B
137 B
138 A
139 B
140 C
14.1 B
14.2 B
143 B
14.4. B
116

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
145 B
146 B
147 B
148 B
1 a~9 B
15~ A
151 A
15Z A
153 A
15~. A
155 A
156 A
157 A
158 A
159 A
160 A
161 A
162 A
163 A
164 A
165 A
166 A
167 A
168 A
169 A
170 A
171 A
172 A
173 A
174 A
175 A
176 A
177 A
178 A
979 A
180 A
181 A
117

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
182 A
183 A
184. A
185 A
185 A
187 A
188 A
189 A
990 A
191 A
192 A
193 A
194 A
195 A
196 A
197 A
198 A
199 A
200 A
201 A
202 A
203 A
204 A
205 A
206 A
207 A
208 A
209 A
210 A
211 A
212 A
213 A
214 A
215 A
21~ A
217 A
218 A
118

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
219 A
220 A
221 A
222 A
223 A
224 A
225 A
226 A
227 A
228 A
229 A
230 A
231 A
232 A
233 A
234 A
235 A
236 A
237 A
238 A
239 A
240 A
241 A
242 A
243 A
244 A
245 A
246 A
247 A
248 A
249 A
250 A
251 A
252 A
253 A
254. A
255 A
119

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
256 A
257 A
258 A
259 A
2~a0A
281 A
262 A
263 A
Z84~A
265 A
265 A
287 A
268 A
269 A
270 A
271 A
272 A
273 A
274 A
275 A
276 A
277 A
278 A
279 A
280 C
281 C
282 B
283 C
284 C
285 B
286 C
287 B
288 B
289 B
290 B
291 A
292 C
120

CA 02518398 2005-09-07
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293 B
294 C
295 B
295 B
297 A
298 B
299 C
300 C
301 1.785,uM
302 C
3~3 C
3~4 B
305 C
306 C
307 B
308 B
309 B
310 C
311 B
312 B
313 B
314 B
315 C
316 B
317 C
318 B
319 C
320 B
321 B
322 -
323 A
324 C
325 C
326 C
327 A
328 B
329 A
121

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330 C
331 C
332 A
333 A
334 A
335 A
335 A
337 A
338 A
339 A
39.0 A
3~.1 A
342 A
343 A
344 C
345 A
346 A
347 A
348 C
349 C
350 A
351 C
352 C
353 A
354 A
355 A
356 A
357 B
358 C
359 C
360 B
361 B
352 A
353 B
38Q B
355 B
388 B
122

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WO 2004/080463 PCT/US2004/007286
367 A
368 A
369 A
370 A
371 A
372 B
373 B
374. B
375 B
3T6 B
377 A
378 A
379 A
380 A
381 A
382 A
383 A
384 C
385 B
386 B
387 B
388 B
389 C
390 A
391 A
392 C
393 C
394 A
395 C
396 C
397 C
398 C
399 A
4.00 C
4.01 C
4.02 C
4.03 C
123

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
404 C
405 C
406 C
4.07C
4.~8A
4.09A
490 C
411 C
412 A
4.13B
414.A
4.15A
416 A
417 A
418 A
419 A
420 A
421 A
422 A
423 A
424 A
425 A
426 A
427 A
428 C
429 C
430 C
431 B
432 C
433 C
434 C
435 C
436 C
437 C
Q38 C
4.39C
~54~0C
124

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
441 C
442 C
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
125

CA 02518398 2005-09-07
WO 2004/080463 PCT/US2004/007286
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.
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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.
127