Thiazolyl inhibitors of Tec family tyrosine kinases

Details Thiazolyl inhibitors of Tec family tyrosine kinases Thiazolyl inhibitors of Tec family tyrosine kinases

2001-12-20

2004-03-16

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C544S369000

Reexamination Certificate

active

06706717

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides for thiazolyl compounds useful as inhibitors of Tec family tyrosine kinases (especially inhibitors of Emt) and to pharmaceutical compositions containing such compounds. The present invention further provides for methods of using such compounds as immunosuppressive, anti-inflammatory, anti-allergic, and anti-cancer agents.
BACKGROUND OF THE INVENTION
The present invention relates to inhibitors of the Tec family tyrosine kinases, and particularly, inhibitors of Emt. The Tec family kinases include Emt [
e
xpressed
m
ainly in
T
cells; Gibson, S. et al., Blood 82, 1561-1572 (1993)], Txk [
T
-cell e
x
pressed
k
inase; Haire, R. N. et al., Hum. Mol. Genet. 3, 897-901 (1994)], Tec [
t
yrosine kinase
e
xpressed in hepatocellular
c
arcinoma cells; Mano et al., Oncogene 5, 1781-1786 (1990)], Btk [
B
ruton's
t
yrosine
k
inase; Vetrie, D. et al., Nature 361, 226-233, (1993)], and Bmx [
b
one
m
arrow kinase,
X
-linked; Tamagnon, L. et al., Oncogene 9, 3683-3688 (1994)].
Mammalian immunity relies on the activation of T cells upon antigen presentation. The molecular mechanisms of T cell activation are initiated by the sequential activation of three distinct classes of non-receptor protein tyrosine kinases (PTK) following the engagement of the T cell antigen receptor (TCR). These three classes of PTK are the Src family kinases (Lck and Lyn), the Syk family kinases (ZAP-70 and Syk), and the Tec family kinases (Emt, Txk, and Tec). Inhibition of one or more of these kinases will impede the initiation signals and block T cell activation following antigen presentation. Thus, small molecular weight inhibitors of these kinases can be applied to treat the diseases that are associated with unwanted T cell activation.
Emt, also known as Itk (
I
nterleukin-2-inducible
T
cell
k
inases) or Tsk (
T
-cell-
s
pecific tyrosine
k
inase), is expressed solely in T, natural killer, and mast cells. Emt is tyrosine-phosphorylated and activated in response to cross-linking of TCR, CD28, or CD2; and has been implicated in thymocyte development and the activation of T cells through TCR and CD28 engagement. Inside the cells, Emt is regulated by membrane recruitment followed by Lck phosphorylation and autophosphorylation. Emt is recruited to the membrane rafts for Lck phosphorylation through the interaction between the pleckstrin homology (PH) domain of Emt and the membrane lipid, phosphotidylinositol (3,4,5)-triphosphate [Bunnell et al., J. Biol. Chem. 275, 2219-2230 (2000)].
Gene knockout studies reveal that mice lacking Emt have decreased numbers of mature thymocytes, especially CD4+ T cells. The T cells isolated from such mice are compromised in their proliferative response to allogeneic MHC stimulation, and to anti-TCR/CD3 cross-linking [Liao X. C. and Littman, D. R., Immunity 3, 757-769 (1995)]. These T cells also exhibit defective PLC&ggr;1 tyrosine phosphorylation, inositol triphosphate production, Ca
2+
moblization, and cytokine production (such as IL-2 and IFN&ggr;) in response to TCR cross-linking [Schaeffer, E. M. et al., Science 284, 638-641 (1999)]. This genetic evidence indicates that Emt activity plays a requisite role in TCR signal transduction; and selective inhibition of Emt should have immunosuppressive, anti-inflammatory, and anti-proliferative effects. In addition, Emt-deficient mice are unable to establish functional Th2 cells (the IL-4 producing cells) and such mice are unable to clear parasitic infections depending upon a Th2 response [Fowell, D. J. et al., Immunity 11, 399-409 (1999)]. This observation also suggests that Emt may be an attractive target for modulating dysregulated allergic pathways mediated by Th2 cells.
SUMMARY OF THE INVENTION
The present invention provides thiazolyl compounds of the following formula I and salts thereof for use as Emt tyrosine kinase inhibitors:
where
Q
1
is thiazolyl;
Q
2
is aryl or heteroaryl optionally independently substituted with one or more (preferably one to three) substituents R
1a
;
Z is
(1) —O—,
(2) —S—,
(3) —NR
4
—,
(4) —CR
4
R
5
—,
(5) —CR
4
R
5
—O—CR
4a
R
5a
,
(6) —CR
4
R
5
—NR
4b
—CR
4a
R
5a
—,
(7) —CR
4
R
5
—S—CR
4a
R
5a
—,
(8) —CR
4
R
5
—O—,
(9) —O—CR
4
R
5
—,
(10) —CR
4
R
5
—NR
4b
—,
(11) —NR
4b
—CR
4
R
5
—,
(12) —CR
4
R
5
—S—,
(13) —S—CR
4
R
5
—,
(14) —S(O)
q
— where q is 1 or 2,
(15) —CR
4
R
5
—S(O)
q
—, or
(16) —S(O)
q
—CR
4
R
5
—;
R
1
and R
1a
are independently
(1) hydrogen or R
6
,
(2) —OH or —OR
6
,
(3) —SH or —SR
6
,
(4) —C(O)
q
H, —C(O)
q
R
6
, or —O—C(O)
q
R
6
,
(5) —SO
3
H or —S(O)
q
R
6
,
(6) halo,
(7) cyano,
(8) nitro,
(9) —Z
4
—NR
7
R
8
,
(10) —Z
4
—N(R
9
)—Z
5
—NR
10
R
11
,
(11) —Z
4
—N(R
12
)—Z
5
—R
6
, or
(12) —P(O)(OR
6
)
2
;
R
2
and R
3
are each independently H, —Z
4
—R
6a
, or —Z
4
—NR
7a
R
8a
R
4
, R
4a
, R
4b
, R
5
and R
5a
are each independently hydrogen, alkyl, aryl, aralkyl, cycloalkyl, or heteroarylalkyl;
R
6
, R
6a
, R
6b
and R
6c
, are independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl, each of which is unsubstituted or substituted with Z
1
, Z
2
and one or more (preferably, one or two) groups Z
3
,
R
7
, R
7a
, R
8
, R
8a
, R
9
, R
10
, R
11
and R
12
(1) are each independently hydrogen, or —Z
4
R
6b
; or
(2) R
7
and R
8
, or R
7a
and R
8a
may together be alkylene, alkenylene, or heteroalkylene, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which they are attached, which ring is unsubstituted or substituted with Z
1
, Z
2
and one or more groups Z
3
, or
(3) any two of R
9
, R
10
and R
11
may together be alkylene, alkenylene or heteroalkylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more Z
1
, Z
2
and Z
3
;
Z
1
, Z
2
and Z
3
are each independently
(1) hydrogen or Z
6
,
(2) —OH or —OZ
6
,
(3) —SH or —SZ
6
,
(4) —C(O)
q
H, —C(O)
q
Z
6
, or —O—C(O)
q
Z
6
,
(5) —SO
3
H, S(O)
q
Z
6
, or S(O)
q
N(Z
9
)Z
6
,
(6) halo,
(7) cyano,
(8) nitro,
(9) —Z
4
—NZ
7
Z
8
,
(10) —Z
4
—N(Z
9
)—Z
5
—NZ
7
Z
8
,
(11) —Z
4
—N(Z
10
)—Z
5
—Z
6
,
(12) —Z
4
—N(Z
10
)—Z
5
—H, (13) oxo,
(14) any two of Z
1
, Z
2
, and Z
3
on a given substituent may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; or
(15) any two of Z
1
, Z
2
, and Z
3
on a given substituent may together be —O—(CH
2
)
q
—O—;
Z
4
and Z
5
are each independently
(1) a single bond,
(2) —Z
11
—S(O)
q
—Z
12
—,
(3) —Z
11
—C(O)—Z
12
—,
(4) —Z
11
—C(S)—Z
12
—,
(5) —Z
11
—O—Z
12
—,
(6) —Z
11
—S—Z
12
—,
(7) —Z
11
—O—C(O)—Z
12
—,
(8) —Z
11
—C(O)—O—Z
12
—; or
(9) alkyl
Z
6
and Z
6a
are independently
(i) alkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl;
(ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or
(iii) a group (i) or (ii) which is independently substituted by one or more (preferably 1 to 3) of the groups (2) to (15) of the definition of Z
1
;
Z
7
, Z
8
, Z
9
and Z
10
(1) are each independently hydrogen or —Z
4
—Z
6a
;
(2) Z
7
and Z
8
may together be alkylene, alkenylene, or heteroalkylene completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more Z
1
, Z
2
and Z
3
, or
(3) Z
7
or Z
8
, together with Z
9
, may be alkylene, alkenylene, or heteroalkylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more Z
1
, Z
2
and Z
3
;
Z
11
, and Z
12
are each independently
(1) a single bond,
(2) alkylene,
(3

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