Monocyclic-7H-pyrrolo[2,3-d]pyrimidine compounds,...

Details Monocyclic-7H-pyrrolo[2,3-d]pyrimidine compounds,... Monocyclic-7H-pyrrolo[2,3-d]pyrimidine compounds,...

1999-06-17

2003-10-21

Berch, Mark L (Department: 1609)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C540S481000, C540S600000, C544S061000, C544S117000

Reexamination Certificate

active

06635762

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to pyrrolo[2,3-d]pyrimidine compounds which are inhibitors of protein tyrosine kinases, such as the enzyme Janus Kinase 3 (hereinafter also referred to as JAK3) and as such are useful therapy as immunosuppressive agents for organ transplants, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, Leukemia and other indications where immunosuppression would be desirable.
This invention also relates to a method of using such compounds in the treatment of the above indications in mammals, especially humans, and the pharmaceutical compositions useful therefor.
JAK3 is a member of the Janus family of protein tyrosine kinases. Although the other members of this family are expressed by essentially all tissues, JAK3 expression is limited to hematopoetic cells. This is consistent with its essential role in signaling through the receptors for IL-2, IL-4, IL-7, IL-9 and IL-15 by non-covalent association of JAK3 with the gamma chain common to these multichain receptors. XSCID patient populations have been identified with severely reduced levels of JAK3 protein or with genetic defects to the common gamma chain, suggesting that immunosuppression should result from blocking signaling through the JAK3 pathway. Animal studies have suggested that JAK3 not only plays a critical role in B and T lymphocyte maturation, but that JAK3 is constitutively required to maintain T cell function. Modulation of immune activity through this novel mechanism can prove useful in the treatment of T cell proliferative disorders such as transplant rejection and autoimmune diseases.
SUMMARY OF THE INVENTION
The present invention relates to a compound of the formula
or the pharmaceutically acceptable salt thereof; wherein
R
1
is a group of the formula
or when n is at least 1, D and E, or D and X, are each CR
7
R
8
, the adjacent R
7
groups may be taken together, with the carbons to which they are attached, to form groups of the formulas
 wherein the dashed lines represent optional double bonds;
a is 0, 1 or 2;
m, A, B and X are as defined above; and
G, J, L and M are each independently oxygen, S(O)
d
wherein d is 0, 1 or 2, NR
6
or CR
7
R
8
wherein R
6
, R
7
and R
8
are as defined above;
or when n is 1, D and E are each CR
7
R
8
and m is 1, A and B are each CR
7
R
8
, the respective adjacent R
7
groups may be taken together, with the carbons to which they are attached, to form a group of the formula
wherein the dashed bond represent optional double bonds;
a, G, J. L and M are as define above;
r is 0 or 1;
c is 0, 1 or 2; and
R, W, Y and S are each independently oxygen, S(O)
d
wherein d is 0, 1 or 2, NR
6
or CR
7
R
8
wherein R
6
, R
7
and R
8
are as defined above;
R
2
and R
3
are each independently selected from the group consisting of hydrogen, deuterium, amino, halo, hydoxy, nitro, carboxy, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, trifluoromethyl,
wherein the dashed line represents optional double bonds;
m is 0, 1, 2 or 3;
n is 0, 1, 2 or 3;
X, B and D are each independently oxygen, S(O)
d
wherein d is 0, 1 or 2, NR
6
or CR
7
R
8
;
A and E are each CR
7
R
8
; and
R
6
is selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl, trifluoromethyl, trifluoromethyl(C
1
-C
6
)alkyl, (C
1
-C
6
)alkyl(difluoromethylene), (C
1
-C
3
)alkyl (difluoromethylene)(C
1
-C
3
)alkyl, (C
1
-C
6
)alkoxy(C
1
-C
6
)acyl, (C
1
-C
6
)alkylamino(C
1
-C
6
)acyl, ((C
1
-C
6
)alkyl)
2
amino(C
1
-C
6
)acyl, (C
6
-C
10
)aryl, (C
5
-C
9
)heteroaryl, (C
6
-C
10
)aryl(C
1
-C
6
)alkyl, (C
5
-C
9
)heteroaryl(C
1
-C
6
)acyl, (C
6
-C
10
)aryl(C
6
-C
10
)aryl, (C
6
-C
10
)aryl(C
6
-C
10
)aryl(C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkyl, hydroxy(C
2
-C
6
)alkyl, (C
1
-C
6
)acyloxy(C
2
-C
6
)alkyl, (C
1
-C
6
)alkoxy(C
2
-C
6
)alkyl, piperazinyl(C
1
-C
6
)alkyl, (C
1
-C
6
)acylamino(C
1
-C
6
)alkyl, (C
6
-C
10
)aryl(C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl, (C
5
-C
9
)heteroaryl(C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl, (C
1
-C
6
)alkylthio(C
1
-C
6
)alkyl, (C
6
-C
10
)arylthio(C
1
-C
6
)alkyl, (C
1
-C
6
)alkylsulfinyl(C
1
-C
6
)alkyl, (C
6
-C
10
)arylsulfinyl(C
1
-C
6
)alkyl, (C
1
-C
6
)alkylsulfonyl(C
1
-C
6
)alkyl, (C
6
-C
10
)arylsulfonyl(C
1
-C
6
)alkyl, amino(C
1
-C
6
)alkyl, (C
1
-C
6
)alkylamino(C
1
-C
6
)alkyl, ((C
1
-C
6
)alkyl)
2
amino(C
1
-C
6
)alkyl, R
13
CO(C
1
-C
6
)alkyl wherein R
13
is R
20
O or R
20
R
21
N wherein R
20
and R
21
are each independently selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl, (C
6
-C
10
)aryl(C
1
-C
6
)alkyl or (C
5
-C
9
)heteroaryl(C
1
-C
6
)alkyl; or R
14
(C
2
-C
6
)alkyl wherein R
14
is (C
1
-C
6
)acylpiperazino, (C
6
-C
10
)arylpiperazino, (C
5
-C
9
)heteroarylpiperazino, (C
1
-C
6
)alkylpiperazino, (C
6
-C
10
)aryl(C
1
-C
6
)alkylpiperazino, (C
5
-C
9
)heteroaryl(C
1
-C
6
)alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C
1
-C
6
)alkylpiperidyl, (C
6
-C
10
)arylpiperidyl, (C
5
-C
9
)heteroarylpiperidyl, (C
6
-C
10
)aryl(C
1
-C
6
)alkylpiperidyl, (C
5
-C
9
)heteroaryl(C
1
-C
6
)alkylpiperidyl, (C
1
-C
6
)alkoxyacyl, (C
1
-C
6
)alkylaminoaryl, ((C
1
-C
6
)alkyl
2
aminoacyl or (C
1
-C
6
)acylpiperidyl;
R
7
and R
8
are each independently selected from the group consisting of hydrogen, deuterium, (C
1
-C
6
)alkyl, amino, hydroxy, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkylamino, ((C
1
-C
6
)alkyl)amino, (C
1
-C
6
)acylamino, (C
1
-C
6
)acyl(C
1
-C
6
)alkylamino, carboxy, (C
1
-C
6
)alkoxyacyl, (C
1
-C
6
)alkylaminoacyl, ((C
1
-C
6
)alkyl)
2
aminoacyl, aminoacyl, trifluoromethyl, trifluoromethyl(C
1
-C
6
)alkyl, (C
1
-C
6
)alkyl (difluoromethylene), (C
1
-C
3
)alkyl(difluoromethylene)(C
1
-C
3
)alkyl, (C
6
-C
10
)aryl, (C
5
-C
9
)heteroaryl, (C
6
-C
10
)aryl(C
1
-C
6
)alkyl, (C
5
-C
9
)heteroaryl(C
1
-C
6
)alkyl, (C
6
-C
10
)aryl(C
6
-C
10
)aryl, (C
6
-C
10
)aryl(C
6
-C
10
)aryl(C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkyl, hydroxy(C
1
-C
6
)alkyl, (C
1
-C
6
)acyloxy(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl, piperazinyl(C
1
-C
6
)alkyl, (C
1
-C
6
)acylamino(C
1
-C
6
)alkyl, piperidyl, (C
1
-C
6
)alkylpiperidyl, (C
6
-C
10
)aryl(C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl, (C
5
-C
9
)heteroaryl (C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl, (C
1
-C
6
)alkylthio(C
1
-C
6
)alkyl, (C
6
-C
10
)arylthio(C
1
-C
6
)alkyl, (C
1-C
6
)alkylsulfinyl(C
1-C
6
)alkyl, (C
6
-C
10
)arylsulfinyl(C
1
-C
6
)alkyl, (C
1
-C
6
)alkylsulfonyl(C
1
-C
6
)alkyl, (C
6
-C
10
)arylsulfonyl(C
1
-C
6
)alkyl, amino(C
1
-C
6
)alkyl, (C
1
-C
6
)alkylamino(C
1
-C
6
)alkyl, ((C
1
-C
6
)alkyl)
2
amino(C
1
-C
6
)alkyl, R
13
CO(C
1
-C
6
)alkyl or R
13
CO(C
3
-C
10
)cycloalkyl wherein R
13
is R
20
O or R
20
R
21
N wherein R
20
and R
21
are each independently selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl, (C
6
-C
10
)aryl(C
1
-C
6
)alkyl or (C
5
-C
9
)heteroaryl(C
1
-C
6
)alkyl; R
14
, R
14
(C
1
-C
6
)alkyl or R
14
(C
3
-C
10
)cycloalkyl wherein R
14
is (C
1
-C
6
)acylpiperazino, (C
6
-C
10
)arylpiperazino, (C
5
-C
9
)heteroarylpiperazino, (C
1
-C
6
)alkylpiperazino, (C
6
-C
10
)aryl(C
1
-C
6
)alkylpiperazino, (C
5
-C
9
)heteroaryl(C
1
-C
6
)alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C
1
-C
6
)alkylpiperidyl, (C
6
-C
10
)arylpiperidyl, (C
5
-C
9
)heteroarylpiperidyl, (C
6
-C
10
)aryl(C
1
-C
6
)alkylpiperidyl, (C
5
-C
9
)heteroaryl(C
1
-C
6
)alkylpiperidyl or (C
1
-C
6
)acylpiperidyl; or a group of the formula
wherein p is 0, 1, 2 or 3; and
Z is hydroxy, (C
1
-C
6
)alkoxy or NR
1
R
2
wherein R
1
and R
2
are each independently selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl, piperidyl, (C
1
-C
6
)alkylpiperidyl, (C
6
-C
10
)arylpiperidyl, (C
5
-C
9
)heteroarylpiperidyl, (C
6
-C
10
)aryl(C
1
-C
6
)alkylpiperidyl, (C
5
-C
9
)heteroaryl(C
1
-C
6
)alkylpiperidyl, (C
1
-C
6
)acylpiperidyl, (C
6
-C
10
)aryl, (C
5
-

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