Pyrrolo[2,3-d]pyrimidine compounds

Details Pyrrolo[2,3-d]pyrimidine compounds Pyrrolo[2,3-d]pyrimidine compounds

2001-06-25

2004-02-24

Berch, Mark L. (Department: 1624)

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

Organic compounds

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

Reexamination Certificate

active

06696567

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to pyrrolo[2,3-d]pyrimidine compounds which are inhibitors of protein 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, xeno transplantation, 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 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
wherein y is 0, 1 or 2;
R
4
is selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkylsulfonyl, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl wherein the alkyl, alkenyl and alkynyl groups are optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C
1
-C
4
)alkoxy, (C
1
-C
6
)acyloxy, (C
1
-C
6
)alkylamino, ((C
1
-C
6
)alkyl)
2
amino, cyano, nitro, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl or (C
1
-C
6
)acylamino; or R
4
is (C
3
-C
10
)cycloalkyl wherein the cycloalkyl group is optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C
1
-C
6
)acyloxy, (C
1
-C
6
)acylamino, (C
1
-C
6
)alkylamino, ((C
1
-C
6
)alkyl)
2
amino, cyano, cyano(C
1
-C
6
)alkyl, trifluoromethyl(C
1
-C
6
)alkyl, nitro, nitro(C
1
-C
6
)alkyl or (C
1
-C
6
)acylamino;
R
5
is (C
2
-C
9
)heterocycloalkyl wherein the heterocycloalkyl groups must be substituted by one to five groups consisting of carboxy, cyano, amino, deuterium, hydroxy, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, halo, (C
1
-C
6
)acyl, (C
1
-C
6
)alkylamino, amino(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy-CO—NH, (C
1
-C
6
)alkylamino-CO—, (C
2
-C
6
)alkenyl, (C
2
-C
6
) alkynyl, (C
1
-C
6
)alkylamino, amino(C
1
-C
6
)alkyl, hydroxy(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl, (C
1
-C
6
)acyloxy(C
1
-C
6
)alkyl, nitro, cyano(C
1
-C
6
)alkyl, halo(C
1
-C
6
)alkyl, nitro(C
1
-C
6
)alkyl, trifluoromethyl, trifluoromethyl(C
1
-C
6
)alkyl, (C
1
-C
6
)acylamino, (C
1
-C
6
)acylamino(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy(C
1
-C
6
)acylamino, amino(C
1
-C
6
)acyl, amino(C
1
-C
6
)acyl(C
1
-C
6
)alkyl, (C
1
-C
6
)alkylamino(C
1
-C
6
)acyl, ((C
1
-C
6
)alkyl)
2
amino(C
1
-C
6
)acyl, R
15
R
16
N—CO—O—, R
15
R
16
N-CO-(C
1
-C
6
)alkyl, (C
1
-C
6
)alkyl-S(O)
m
, R
15
R
16
NS(O)
m
, R
15
R
16
NS(O)
m
(C
1
-C
6
)alkyl, R
15
S(O)m R
16
N, R
15
S(O)mR
16
N(C
1
-C
6
)alkyl wherein m is 0, 1 or 2 and R
15
and R
15
are each independently selected from hydrogen or (C
1
-C
6
)alkyl; and a group of the formula
wherein a is 0, 1, 2, 3 or 4;
b, c, e, f and g are each independently 0 or 1;
d is 0, 1, 2, or 3;
X is S(O)
n
wherein n is 0, 1 or 2; oxygen, carbonyl or —C(═N-cyano)-;
Y is S(O)
n
wherein n is 0, 1 or 2; or carbonyl; and
Z is carbonyl, C(O)O—, C(O)NR— wherein R is hydrogen or (C
1
-C
6
)alkyl; or Z is S(O)
n
wherein n is 0, 1 or 2;
R
6
, R
7
, R
8
, R
9
, R
10
and R
11
are each independently selected from the group consisting of hydrogen or (C
1
-C
6
)alkyl optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C
1
-C
6
)acyloxy, (C
1
-C
6
)acylamino, (C
1
-C
6
)alkylamino, ((C
1
-C
6
)alkyl)
2
amino, cyano, cyano(C
1
-C
6
)alkyl, trifluoromethyl(C
1
-C
6
)alkyl, nitro, nitro(C
1
-C
6
)alkyl or (C
1
-C
6
)acylamino;
R
12
is (C
6
-C
10
)aryl, (C
2
-C
9
)heteroaryl, (C
3
-C
10
)cycloalkyl or (C
2
-C
9
)heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups are optionally substituted by one to four groups consisting of hydrogen, deuterium, amino, halo, oxo, hydroxy, nitro, carboxy, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, trifluoromethyl, trifluoromethoxy, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
3
-C
10
)cycloalkyl, (C
1
-C
6
)alkyl-CO—NH—, (C
1
-C
6
)alkoxy-CO—NH—, (C
1
-C
6
)alkyl-CO—NH—(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy-CO—NH—(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy-CO—NH—(C
1
-C
6
)alkoxy, carboxy, carboxy(C
1
-C
6
)alkyl, carboxy(C
1
-C
6
)alkoxy, benzyloxycarbonyl(C
1
-C
6
)alkoxy, (C
1
-C
6
)alkoxycarbonyl(C
1
-C
6
)alkoxy, (C
6
-C
10
)aryl, amino, amino(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxycarbonylamino, (C
6
-C
10
)aryl(C
1
-C
6
)alkoxycarbonylamino, (C
1
-C
6
)alkylamino, ((C
1
-C
6
)alkyl)
2
amino, (C
1
-C
6
)alkylamino(C
1
-C
6
)alkyl, ((C
1
-C
6
)alkyl)
2
amino(C
1
-C
6
)alkyl, hydroxy, (C
1
-C
6
)alkoxy, carboxy, carboxy(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxycarbonyl, (C
1
-C
6
)alkoxycarbonyl(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy-CO—NH—, (C
1
-C
6
)alkyl-CO—NH—, cyano, (C
5
-C
9
)heterocycloalkyl, amino-CO—NH—, (C
1
-C
6
)alkylamino-CO—NH—, ((C
1
-C
6
)alkyl)
2
amino-CO—NH—, (C
6
-C
10
)arylamino-CO—NH—, (C
5
-C
9
)heteroarylamino-CO—NH—, (C
1
-C
6
)alkylamino-CO—NH—(C
1
-C
6
)alkyl, ((C
1
-C
6
)alkyl)
2
amino-CO—NH—(C
1
-C
6
)alkyl, (C
6
-C
10
)arylamino-CO—NH—(C
1
-C
6
)alkyl, (C
5
-C
9
)heteroarylamino-CO—NH—(C
1
-C
6
)alkyl, (C
1
-C
6
)alkylcyano, (C
1
-C
6
)alkylcarboxy(C
1
-C
6
)alkoxy, (C
1
-C
6
)alkylcarboxy, sulfonylamino, aminosulfonyl, sulfonylamino(C
1
-C
6
)alkyl, sulfonylaminocarboxy(C
1
-C
6
)alkyl, (C
1
-C
6
)alkylsulfonyl, (C
1
-C
6
)alkylsulfonylamino, (C
1
-C
6
)alkylsulfonylamino(C
1
-C
6
)alkyl, (C
6
-C
10
)arylsulfonyl, (C
6
-C
10
)arylsulfonylamino, (C
6
-C
10
)arylsulfonylamino(C
1
-C
6
)alkyl, (C
1
-C
6
)alkylsulfonylamino, (C
1
-C
6
)alkylsulfonylamino(C
1
-C
6
)alkyl, (C
3
-C
10
)cycloalkyl, (C
3
-C
10
)cycloalkoxy, (C
1
-C
6
)alkylamino, ((C
1
-C
6
)alkyl)
2
amino, (C
6
-C
10
)arylamino, (C
1
-C
6
)alkylthio, (C
6
-C
10
)arylthio, (C
1
-C
6
)alkylsulfinyl, (C
6
-C
10
)arylsulfinyl, (C
1
-C
6
)alkylsulfonyl, (C
6
-C
10
)arylsulfonyl, (C
1
-C
6
)acyl, (C
1
-C
6
)alkoxy-CO—NH—, (C
1
-C
6
)alkyamino-CO—, (C
5
-C
9
)heteroaryl, (C
2
-C
9
)heterocycloalkyl or (C
6
-C
10
)aryl wherein the heteroaryl, heterocycloalkyl and aryl groups which are optionally substituted on R
12
may be further substituted by one to three groups consisting of halo, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkyl-CO—NH—, (C
1
-C
6
)alkoxy-CO—NH—, (C
1
-C
6
)alkyl-CO—NH—(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy-CO—NH—(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy-CO—NH—(C
1
-C
6
)alkoxy, carboxy, carboxy(C
1
-C
6
)alkyl, carboxy(C
1
-C
6
)alkoxy, benzyloxycarbonyl(C
1
-C
6
)alkoxy, (C
1
-C
6
)alkoxycarbonyl(C
1
-C
6
)alkoxy, (C
6
-C
10
)aryl, amino, amino(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxycarbonylamino, (C
6
-C
10
)aryl(C
1
-C
6
)alkoxycarbonylamino, (C
1
-C
6
)alkylamino, ((C
1
-C
6
)alkyl)
2
amino, (C
1
-C
6
)alkylamino(C
1
-C
6
)alkyl, ((C
1
-C
6
)alkyl)
2
amino(C
1
-C
6
)alkyl, hydroxy, (C
1
-C
6
)alkoxy, carboxy, carboxy(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxycarbonyl, (C
1
-C
6
)alkoxycarbonyl(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy-

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