U.S. patent application number 11/710164 was filed with the patent office on 2007-07-12 for pyrrolo[2,3-d]pyrimidine compounds.
This patent application is currently assigned to Pfizer Inc. Invention is credited to Todd A. Blumenkopf, Mark E. Flanagan, Michael J. Munchhof.
Application Number | 20070161666 11/710164 |
Document ID | / |
Family ID | 22798508 |
Filed Date | 2007-07-12 |
United States Patent
Application |
20070161666 |
Kind Code |
A1 |
Blumenkopf; Todd A. ; et
al. |
July 12, 2007 |
Pyrrolo[2,3-d]pyrimidine compounds
Abstract
A compound of the formula ##STR1## wherein R.sup.1, R.sup.2 and
R.sup.3 are as defined above, useful as inhibitors of protein
kinases, such as the enzyme Janus Kinase 3.
Inventors: |
Blumenkopf; Todd A.; (Old
Lyme, CT) ; Flanagan; Mark E.; (Gales Ferry, CT)
; Munchhof; Michael J.; (Salem, CT) |
Correspondence
Address: |
PFIZER INC.
PATENT DEPARTMENT, MS8260-1611
EASTERN POINT ROAD
GROTON
CT
06340
US
|
Assignee: |
Pfizer Inc
|
Family ID: |
22798508 |
Appl. No.: |
11/710164 |
Filed: |
February 22, 2007 |
Related U.S. Patent Documents
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Application
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Patent Number |
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11112307 |
Apr 21, 2005 |
7192963 |
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11710164 |
Feb 22, 2007 |
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10463724 |
Jun 16, 2003 |
6962993 |
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11112307 |
Apr 21, 2005 |
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09891028 |
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6696567 |
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10463724 |
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60214287 |
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Current U.S.
Class: |
514/265.1 ;
544/280 |
Current CPC
Class: |
A61P 19/00 20180101;
A61P 3/10 20180101; A61P 11/06 20180101; A61P 3/00 20180101; A61P
21/00 20180101; A61P 5/00 20180101; C07D 487/04 20130101; A61P
37/00 20180101; A61P 37/02 20180101; A61P 9/02 20180101; A61P 17/06
20180101; A61P 35/02 20180101; A61P 43/00 20180101; A61P 1/04
20180101; A61P 37/06 20180101; A61K 31/505 20130101; A61P 7/06
20180101; A61P 17/00 20180101; A61P 25/28 20180101; A61P 35/00
20180101; A61P 19/02 20180101; A61P 29/00 20180101; A61P 25/00
20180101 |
Class at
Publication: |
514/265.1 ;
544/280 |
International
Class: |
A61K 31/519 20060101
A61K031/519; C07D 487/02 20060101 C07D487/02 |
Claims
1-27. (canceled)
28. A method for treating a disorder or condition selected from the
group consisting of rheumatoid arthritis and psoriasis comprising
administering to a mammal an effective amount of a compound of the
formula ##STR11## or a pharmaceutically acceptable salt thereof;
wherein R.sup.1 is a group of the formula ##STR12## wherein y is 0,
1 or 2; R.sup.4 is selected from the group consisting of hydrogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylsulfonyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl wherein the
alkyl, alkenyl and alkynyl groups are optionally substituted by
deuterium, hydroxy, amino, trifluoromethyl,
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.6)acyloxy,
(C.sub.1-C.sub.6)alkylamino, ((C.sub.1-C.sub.6)alkyl).sub.2amino,
cyano, nitro, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl or
(C.sub.1-C.sub.6)acylamino; or R.sup.4 is
(C.sub.3-C.sub.10)cycloalkyl wherein the cycloalkyl group is
optionally substituted by deuterium, hydroxy, amino,
trifluoromethyl, (C.sub.1-C.sub.6)acyloxy,
(C.sub.1-C.sub.6)acylamino, (C.sub.1-C.sub.6)alkylamino,
((C.sub.1-C.sub.6)alkyl).sub.2amino, cyano,
cyano(C.sub.1-C.sub.6)alkyl, trifluoromethyl(C.sub.1-C.sub.6)alkyl,
nitro, nitro(C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.6)acylamino;
R.sup.5 is (C.sub.2-C.sub.9)heterocycloalkyl wherein the
heterocycloalkyl groups must be substituted by one to five groups
consisting of carboxy, cyano, amino, deuterium, hydroxy,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo,
(C.sub.1-C.sub.6)acyl, (C.sub.1-C.sub.6)alkylamino,
amino(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy-CO--NH,
(C.sub.1-C.sub.6)alkylamino-CO--, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkylamino,
amino(C.sub.1-C.sub.6)alkyl, hydroxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)acyloxy(C.sub.1-C.sub.6)alkyl, nitro,
cyano(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl,
nitro(C.sub.1-C.sub.6)alkyl, trifluoromethyl,
trifluoromethyl(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)acylamino,
(C.sub.1-C.sub.6)acylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)acylamino,
amino(C.sub.1-C.sub.6)acyl,
amino(C.sub.1-C.sub.6)acyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)acyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)acyl,
R.sup.15R.sup.16N--CO--O--,
R.sup.15R.sup.16N--CO--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-S(O).sub.m, R.sup.15R.sup.16NS(O).sub.m,
R.sup.15R.sup.16NS(O).sub.m (C.sub.1-C.sub.6)alkyl,
R.sup.15S(O).sub.m R.sup.16N,
R.sup.15S(O).sub.mR.sup.16N(C.sub.1-C.sub.6)alkyl, and a group of
the formula II ##STR13## wherein: m is 0, 1 or 2; R.sup.15 and
R.sup.16 are each independently selected from hydrogen or
(C.sub.1-C.sub.6)alkyl; 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).sub.n
wherein n is 0, 1 or 2; oxygen, carbonyl or --C(.dbd.N-cyano)-; Y
is S(O).sub.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.sub.1-C.sub.6)alkyl; or Z is S(O).sub.n wherein n is 0, 1 or 2;
R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.11 are each
independently selected from the group consisting of hydrogen or
(C.sub.1-C.sub.6)alkyl optionally substituted by deuterium,
hydroxy, amino, trifluoromethyl, (C.sub.1-C.sub.6)acyloxy,
(C.sub.1-C.sub.6)acylamino, (C.sub.1-C.sub.6)alkylamino,
((C.sub.1-C.sub.6)alkyl).sub.2amino, cyano,
cyano(C.sub.1-C.sub.6)alkyl, trifluoromethyl(C.sub.1-C.sub.6)alkyl,
nitro, nitro(C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.6)acylamino;
R.sup.12 is (C.sub.6-C.sub.10)aryl, (C.sub.2-C.sub.9)heteroaryl,
tetrazolyl, or (C.sub.2-C.sub.9)heterocycloalkyl, wherein the aryl,
heteroaryl, tetrazolyl, and heterocycloalkyl groups are optionally
substituted by one to four groups consisting of hydrogen,
deuterium, amino, halo, oxo, hydroxy, nitro, carboxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
trifluoromethyl, trifluoromethoxy, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.1-C.sub.6)alkyl-CO--NH--, (C.sub.1-C.sub.6)alkoxy-CO--NH--,
(C.sub.1-C.sub.6)alkyl-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy-CO--NH--(C.sub.1-C.sub.6)alkoxy, carboxy,
carboxy(C.sub.1-C.sub.6)alkyl, carboxy(C.sub.1-C.sub.6)alkoxy,
benzyloxycarbonyl(C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkoxy,
(C.sub.6-C.sub.10)aryl, amino, amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonylamino,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkoxycarbonylamino,
(C.sub.1-C.sub.6)alkylamino, ((C.sub.1-C.sub.6)alkyl).sub.2amino,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)alkyl, hydroxy,
(C.sub.1-C.sub.6)alkoxy, carboxy, carboxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy-CO--NH--, (C.sub.1-C.sub.6)alkyl-CO--NH--,
cyano, (C.sub.5-C.sub.9)heterocycloalkyl, amino-CO--NH--,
(C.sub.1-C.sub.6)alkylamino-CO--NH--,
((C.sub.1-C.sub.6)alkyl).sub.2amino-CO--NH--,
(C.sub.6-C.sub.10)arylamino-CO--NH--,
(C.sub.5-C.sub.9)heteroarylamino-CO--NH--,
(C.sub.1-C.sub.6)alkylamino-CO--NH--(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylamino-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.5-C.sub.9)heteroarylamino-CO--NH--(C.sub.1-C.sub.6)alkyl,
cyano(C.sub.1-C.sub.6)alkyl,
carboxy(C.sub.1-C.sub.6)alkyl(C.sub.1-C.sub.6)alkoxy,
carboxy(C.sub.1-C.sub.6)alkyl, sulfonylamino, aminosulfonyl,
sulfonylamino(C.sub.1-C.sub.6)alkyl,
sulfonylaminocarboxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfonyl,
(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylsulfonyl,
(C.sub.6-C.sub.10)arylsulfonylamino,
(C.sub.6-C.sub.10)arylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.10)cycloalkyl, (C.sub.3-C.sub.10)cycloalkoxy,
(C.sub.1-C.sub.6)alkylamino, ((C.sub.1-C.sub.6)alkyl).sub.2amino,
(C.sub.6-C.sub.10)arylamino, (C.sub.1-C.sub.6)alkylthio,
(C.sub.6-C.sub.10)arylthio, (C.sub.1-C.sub.6)alkylsulfinyl,
(C.sub.6-C.sub.10)arylsulfinyl, (C.sub.1-C.sub.6)alkylsulfonyl,
(C.sub.6-C.sub.10)arylsulfonyl, (C.sub.1-C.sub.6)acyl,
(C.sub.1-C.sub.6)alkoxy-CO--NH--, (C.sub.1-C.sub.6)alkylamino-CO--,
(C.sub.5-C.sub.9)heteroaryl, (C.sub.2-C.sub.9)heterocycloalkyl or
(C.sub.6-C.sub.10)aryl wherein the heteroaryl, tetrazolyl,
heterocycloalkyl and aryl groups which are optionally substituted
on R.sup.12 may be further substituted by one to three groups
consisting of halo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-CO--NH--, (C.sub.1-C.sub.6)alkoxy-CO--NH--,
(C.sub.1-C.sub.6)alkyl-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy-CO--NH--(C.sub.1-C.sub.6)alkoxy, carboxy,
carboxy(C.sub.1-C.sub.6)alkyl, carboxy(C.sub.1-C.sub.6)alkoxy,
benzyloxycarbonyl(C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkoxy,
(C.sub.6-C.sub.10)aryl, amino, amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonylamino,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkoxycarbonylamino,
(C.sub.1-C.sub.6)alkylamino, ((C.sub.1-C.sub.6)alkyl).sub.2amino,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)alkyl, hydroxy,
(C.sub.1-C.sub.6)alkoxy, carboxy, carboxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy-CO--NH--, (C.sub.1-C.sub.6)alkyl-CO--NH--,
cyano, (C.sub.5-C.sub.9)heterocycloalkyl, amino-CO--NH--,
(C.sub.1-C.sub.6)alkylamino-CO--NH--,
((C.sub.1-C.sub.6)alkyl).sub.2-amino-CO--NH--,
(C.sub.6-C.sub.10)arylamino-CO--NH--,
(C.sub.5-C.sub.9)heteroarylamino-CO--NH--,
(C.sub.1-C.sub.6)alkylamino-CO--NH--(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylamino-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.5-C.sub.9)heteroarylamino-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfonyl,
(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylsulfonyl,
(C.sub.6-C.sub.10)arylsulfonylamino,
(C.sub.6-C.sub.10)arylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.5-C.sub.9)heteroaryl and (C.sub.2-C.sub.9)heterocycloalkyl;
R.sup.2 and R.sup.3 are each independently selected from the group
consisting of hydrogen, deuterium, amino, halo, hydroxy, nitro,
carboxy, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
trifluoromethyl, trifluoromethoxy, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.10)cycloalkyl wherein the
alkyl, alkoxy or cycloalkyl groups are optionally substituted by
one to three groups selected from halo, hydroxy, carboxy, amino
(C.sub.1-C.sub.6)alkylthio, (C.sub.1-C.sub.6)alkylamino,
((C.sub.1-C.sub.6)alkyl).sub.2amino, (C.sub.5-C.sub.9)heteroaryl,
(C.sub.2-C.sub.9)heterocycloalkyl, (C.sub.3-C.sub.9)cycloalkyl or
(C.sub.6-C.sub.10)aryl; or R.sup.2 and R.sup.3 are each
independently (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.3-C.sub.10)cycloalkoxy, (C.sub.1-C.sub.6)alkylamino,
((C.sub.1-C.sub.6)alkyl).sub.2amino, (C.sub.6-C.sub.10)arylamino,
(C.sub.1-C.sub.6)alkylthio, (C.sub.6-C.sub.10)arylthio,
(C.sub.1-C.sub.6)alkylsulfinyl, (C.sub.6-C.sub.10)arylsulfinyl,
(C.sub.1-C.sub.6)alkylsulfonyl, (C.sub.6-C.sub.10)arylsulfonyl,
(C.sub.1-C.sub.6)acyl, (C.sub.1-C.sub.6)alkoxy-CO--NH--,
(C.sub.1-C.sub.6)alkylamino-CO--, (C.sub.5-C.sub.9)heteroaryl,
(C.sub.2-C.sub.9)heterocycloalkyl or (C.sub.6-C.sub.10)aryl wherein
the heteroaryl, heterocycloalkyl and aryl groups are optionally
substituted by one to three halo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-CO--NH--, (C.sub.1-C.sub.6)alkoxy-CO--NH--,
(C.sub.1-C.sub.6)alkyl-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy-CO--NH--(C.sub.1-C.sub.6)alkoxy, carboxy,
carboxy(C.sub.1-C.sub.6)alkyl, carboxy(C.sub.1-C.sub.6)alkoxy,
benzyloxycarbonyl(C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkoxy,
(C.sub.6-C.sub.10)aryl, amino, amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonylamino,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkoxycarbonylamino,
(C.sub.1-C.sub.6)alkylamino, ((C.sub.1-C.sub.6)alkyl).sub.2amino,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)alkyl, hydroxy,
(C.sub.1-C.sub.6)alkoxy, carboxy, carboxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy-CO--NH--, (C.sub.1-C.sub.6)alkyl-CO--NH--,
cyano, (C.sub.5-C.sub.9)heterocycloalkyl, amino-CO--NH--,
(C.sub.1-C.sub.6)alkylamino-CO--NH--,
((C.sub.1-C.sub.6)alkyl).sub.2amino-CO--NH--,
(C.sub.6-C.sub.10)arylamino-CO--NH--,
(C.sub.5-C.sub.9)heteroarylamino-CO--NH--,
(C.sub.1-C.sub.6)alkylamino-CO--NH--(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylamino-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.5-C.sub.9)heteroarylamino-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfonyl,
(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylsulfonyl,
(C.sub.6-C.sub.10)arylsulfonylamino,
(C.sub.6-C.sub.10)arylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.5-C.sub.9)heteroaryl or (C.sub.2-C.sub.9)heterocycloalkyl;
with the proviso that R.sup.5 must be substituted by the group of
formula II; alone or in combination with one or more additional
agents which modulate a mammalian immune system or with
anti-inflammatory agents.
29. The method according to claim 28, wherein R.sup.5 is
(C.sub.2-C.sub.9)heterocycloalkyl optionally substituted by one to
three groups selected from deuterium, hydroxy,
(C.sub.1-C.sub.6)alkyl, halo, (C.sub.1-C.sub.6)alkoxy and a group
of formula II.
30. The method according to claim 28, wherein a is 0; b is 1; X is
carbonyl; c is 0; d is 0; e is 0; f is 0; and g is 0.
31. The method according to claim 28, wherein a is 0; b is 1; X is
carbonyl; c is 0; d is 1; e is 0; f is 0, and g is 0.
32. The method according to claim 28, wherein a is 0; b is 1; X is
carbonyl; c is 1; d is 0; e is 0; f is 0; and g is 0.
33. The method according to claim 28, wherein a is 0; b is 1; X is
--C(.dbd.N-cyano)-; c is 1; d is 0; e is 0; f is 0; and g is 0.
34. The method according to claim 28, wherein a is 0; b is 0; c is
0; d is 0; e is 0; f is 0; g is 1; and Z is --C(O)--O--.
35. The method according to claim 28, wherein a is 0; b is 1; X is
S(O).sub.n; n is 2; c is 0; d is 0; e is 0; f is 0; and g is 0.
36. The method according to claim 28, wherein a is 0; b is 1; X is
S(O).sub.n; n is 2; c is 0; d is 2; e is 0; f is 1; g is 1; and Z
is carbonyl.
37. The method according to claim 28, wherein a is 0; b is 1; X is
S(O).sub.n; n is 2; c is 0; d is 2; e is 0; f is 1; and g is 0.
38. The method according to claim 28, wherein a is 0; b is 1; X is
carbonyl; c is 1; d is 0; e is 1; Y is S(O).sub.n; n is 2; f is 0;
and g is 0.
39. The method according to claim 28, wherein a is 0; b is 1; X is
S(O).sub.n; n is 2; c is 1; d is 0; e is 0; f is 0; and g is 0.
40. The method according to claim 28, wherein a is 1; b is 1; X is
carbonyl; c is 1; d is 0; e is 0; f is 0; and g is 0.
41. The method according to claim 28, wherein a is 0; b is 1; X is
S(O).sub.n; c is 0; d is 1; e is 1; Y is S(O).sub.n; n is 2; f is
0; and g is 0.
42. The method according to claim 28, wherein a is 0; b is 1; X is
S(O).sub.n; c is 0; d is 1; e is 1; Y is S(O).sub.n; n is 2; f is
1; and g is 0.
43. The method according to claim 28, wherein a is 0; b is 1; X is
oxygen; c is 0; d is 1; e is 1; Y is S(O).sub.n; n is 2; f is 1;
and g is 0.
44. The method according to claim 28, wherein a is 0; b is 1; X is
oxygen; c is 0; d is 1; e is 1; Y is S(O).sub.n; n is 2; f is 0;
and g is 0.
45. The method according to claim 28, wherein a is 0; b is 1; X is
carbonyl; c is 1; d is 1; e is 1; Y is S(O).sub.n; f is 0; and g is
0.
46. The method according to claim 28, wherein a is 0; b is 1; X is
carbonyl; c is 1; d is 1; e is 1; Y is S(O).sub.n; n is 2; f is 1;
and g is 0.
47. The method according to claim 28, wherein R.sup.12 is
(C.sub.6-C.sub.10)aryl or (C.sub.2-C.sub.9)heteroaryl or tetrazolyl
wherein the aryl or heteroaryl or tetrazolyl group is optionally
substituted by one to four groups consisting of hydrogen, halo,
hydroxy, carboxy, trifluoromethyl, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkyl-CO--NH--, amino,
amino(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylamino,
((C.sub.1-C.sub.6)alkyl).sub.2amino, cyano, amino-CO--NH--,
(C.sub.1-C.sub.6)alkylamino-CO--NH--,
((C.sub.1-C.sub.6)alkyl).sub.2amino-CO--NH--,
(C.sub.5-C.sub.9)heteroarylamino-CO--NH--,
(C.sub.1-C.sub.6)alkylsulfonyl,
(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.6-C.sub.10)arylsulfonylamino,
(C.sub.1-C.sub.6)alkylsulfonylamino, and
(C.sub.1-C.sub.6)alkoxy-CO--NH--.
48. The method according to claim 28, wherein said one or more
additional agents is selected from the group consisting of
cyclosporin A, rapamycin, tacrolimus, leflunomide, deoxyspergualin,
mycophenolate, azathioprine, daclizumab, muromonab-CD3,
antithymocyte globulin, aspirin, acetaminophen, ibuprofen,
naproxen, piroxicam, prednisolone and dexamethasone.
49. A method for treating a disorder or condition selected from the
group consisting of rheumatoid arthritis and psoriasis comprising
administering to a mammal an effective amount of a compound
selected from the group consisting of
4-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin--
1-ylmethyl}-benzenesulfonamide;
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1--
carboxylic acid (4-sulfamoyl-phenyl)-amide;
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1--
carboxylic acid (4-nitro-phenyl)-amide;
1-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin--
1-yl}-2-tetrazol-1-yl-ethanone;
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1--
carboxylic acid (4-methylsulfamoyl-phenyl)-amide;
(3-Hydroxy-pyrrolidin-1-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimid-
in-4-yl)-amino]-piperidin-1-yl}-methanone;
[2-({4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidi-
ne-1-carbonyl}-amino)-thiazol-4-yl]-acetic acid;
5-(2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperid-
in-1-yl}-2-oxo-ethyl)-thiazolidine-2,4-dione;
{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1--
yl}-thiazolidin-3-yl-methanone;
Methyl-[4-methyl-1-(5-nitro-thiazol-2-yl)-piperidin-3-yl]-(7H-pyrrolo[2,3-
-d]pyrimidin-4-yl)-amine;
[2-({4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidi-
ne-1-carbonyl}-amino)-thiazol-4-yl]-acetic acid ethyl ester;
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1--
carboxylic acid (4-methanesulfonyl-phenyl)-amide;
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1--
carboxylic acid thiazol-2-ylamide;
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1--
carboxylic acid (4-cyano-phenyl)-amide;
{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1--
yl}-pyrrolidin-1-yl-methanone; Furan-2-carboxylic acid
(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]piperidine-
-1-sulfonyl}-ethyl)-amide;
{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1--
yl}(tetrahydro-furan-3-yl)-methanone;
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1--
carboxylic acid isoxazol-3-ylamide;
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1--
carboxylic acid (6-cyano-pyridin-3-yl)-amide;
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1--
carboxylic acid (4-methyl-thiazol-2-yl)-amide;
2-Cyclopropyl-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-ami-
no]-piperidin-1-yl}-ethanone;
Cyclopentyl-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]--
piperidin-1-yl}-Methanone;
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1--
carboxylic acid (3-methyl-isoxazol-4-yl)-amide;
[4-({4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidi-
ne-1-carbonyl}-amino)-phenyl]-acetic acid;
[1-(5-Amino-thiazol-2-yl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-
-d]pyrimidin-4-yl)-amine;
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1--
carboxylic acid (3-methyl-isothiazol-5-yl)-amide;
3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-
-1-carbonyl}-cyclopentanone; and
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1--
carboxylic acid benzyl-methyl-amide; or a pharmaceutically
acceptable salt thereof;
50. The method according to claim 49 further comprising
administering one or more additional agents which modulate a
mammalian immune system or with antiinflamatory agents.
51. The method according to claim 50, wherein said one or more
additional agents is selected from the group consisting of
cyclosporin A, rapamycin, tacrolimus, leflunomide, deoxyspergualin,
mycophenolate, azathioprine, daclizumab, muromonab-CD3,
antithymocyte globulin, aspirin, acetaminophen, ibuprofen,
naproxen, piroxicam, prednisolone and dexamethasone.
52. A pharmaceutically acceptable salt of a compound selected from
the group consisting of
4-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin--
1-ylmethyl}-benzenesulfonamide;
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1--
carboxylic acid (4-sulfamoyl-phenyl)-amide;
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1--
carboxylic acid (4-nitro-phenyl)-amide;
1-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin--
1-yl}-2-tetrazol-1-yl-ethanone;
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1--
carboxylic acid (4-methylsulfamoyl-phenyl)-amide;
(3-Hydroxy-pyrrolidin-1-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimid-
in-4-yl)-amino]-piperidin-1-yl}-methanone;
[2-({4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidi-
ne-1-carbonyl}-amino)-thiazol-4-yl]-acetic acid;
5-(2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperid-
in-1-yl-2-oxo-ethyl)-thiazolidine-2,4-dione;
{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1--
yl}-thiazolidin-3-yl-methanone;
Methyl-[4-methyl-1-(5-nitro-thiazol-2-yl)-piperidin-3-yl]-(7H-pyrrolo[2,3-
-d]pyrimidin-4-yl)-amine;
[2-({4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidi-
ne-1-carbonyl}-amino)-thiazol-4-yl]-acetic acid ethyl ester;
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1--
carboxylic acid (4-methanesulfonyl-phenyl)-amide;
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1--
carboxylic acid thiazol-2-ylamide;
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1--
carboxylic acid (4-cyano-phenyl)-amide;
{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1--
yl}-pyrrolidin-1-yl-methanone; Furan-2-carboxylic acid
(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-
e-1-sulfonyl}-ethyl)-amide;
{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1--
yl}(tetrahydro-furan-3-yl)-methanone;
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1--
carboxylic acid isoxazol-3-ylamide;
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1--
carboxylic acid (6-cyano-pyridin-3-yl)-amide;
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1--
carboxylic acid (4-methyl-thiazol-2-yl)-amide;
2-Cyclopropyl-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-ami-
no]-piperidin-1-yl}-ethanone;
Cyclopentyl-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]--
piperidin-1-yl}-Methanone;
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1--
carboxylic acid (3-methyl-isoxazol-4-yl)-amide;
[4-({4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidi-
ne-1-carbonyl}-amino)-phenyl]-acetic acid;
[1-(5-Amino-thiazol-2-yl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-
-d]pyrimidin-4-yl)-amine;
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1--
carboxylic acid (3-methyl-isothiazol-5-yl)-amide;
3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-
-1-carbonyl{-cyclopentanone; and
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1--
carboxylic acid benzyl-methyl-amide.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This non-provisional application is based upon and claims
priority from U.S. provisional patent application No. 60/214,287,
filed Jun. 26, 2000.
BACKGROUND OF THE INVENTION
[0002] 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.
[0003] 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.
[0004] 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
[0005] The present invention relates to a compound of the formula
##STR2## or the pharmaceutically acceptable salt thereof;
wherein
[0006] R.sup.1 is a group of the formula ##STR3## wherein y is 0, 1
or 2;
[0007] R.sup.4 is selected from the group consisting of hydrogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylsulfonyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl wherein the
alkyl, alkenyl and alkynyl groups are optionally substituted by
deuterium, hydroxy, amino, trifluoromethyl,
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.6)acyloxy,
(C.sub.1-C.sub.6)alkylamino, ((C.sub.1-C.sub.6)alkyl).sub.2amino,
cyano, nitro, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl or
(C.sub.1-C.sub.6)acylamino; or R.sup.4 is
(C.sub.3-C.sub.10)cycloalkyl wherein the cycloalkyl group is
optionally substituted by deuterium, hydroxy, amino,
trifluoromethyl, (C.sub.1-C.sub.6)acyloxy,
(C.sub.1-C.sub.6)acylamino, (C.sub.1-C.sub.6)alkylamino,
((C.sub.1-C.sub.6)alkyl).sub.2amino, cyano,
cyano(C.sub.1-C.sub.6)alkyl, trifluoromethyl(C.sub.1-C.sub.6)alkyl,
nitro, nitro(C.sub.1-C.sub.6)alkyl or
(C.sub.1-C.sub.6)acylamino;
[0008] R.sup.5 is (C.sub.2-C.sub.9)heterocycloalkyl wherein the
heterocycloalkyl groups must be substituted by one to five groups
consisting of carboxy, cyano, amino, deuterium, hydroxy,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halo,
(C.sub.1-C.sub.6)acyl, (C.sub.1-C.sub.6)alkylamino,
amino(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy-CO--NH,
(C.sub.1-C.sub.6)alkylamino-CO--, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkylamino,
amino(C.sub.1-C.sub.6)alkyl, hydroxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)acyloxy(C.sub.1-C.sub.6)alkyl, nitro,
cyano(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl,
nitro(C.sub.1-C.sub.6)alkyl, trifluoromethyl,
trifluoromethyl(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)acylamino,
(C.sub.1-C.sub.6)acylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)acylamino,
amino(C.sub.1-C.sub.6)acyl,
amino(C.sub.1-C.sub.6)acyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)acyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)acyl,
R.sup.15R.sup.16N--CO--O--,
R.sup.15R.sup.16N--CO--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-S(O).sub.m, R.sup.15R.sup.16NS(O).sub.m,
R.sup.15R.sup.16NS(O).sub.m(C.sub.1-C.sub.6)alkyl,
R.sup.15S(O).sub.mR.sup.16N,
R.sup.15S(O).sub.mR.sup.16N(C.sub.1-C.sub.6)alkyl wherein m is 0, 1
or 2 and R.sup.15 and R.sup.16 are each independently selected from
hydrogen or (C.sub.1-C.sub.6)alkyl; and a group of the formula
##STR4## wherein a is 0, 1, 2, 3 or 4; [0009] b, c, e, f and g are
each independently 0 or 1; [0010] d is 0, 1, 2, or 3; [0011] X is
S(O).sub.n wherein n is 0, 1 or 2; oxygen, carbonyl or
--C(.dbd.N-cyano)-; [0012] Y is S(O).sub.n wherein n is 0, 1 or 2;
or carbonyl; and [0013] Z is carbonyl, C(O)O--, C(O)NR-- wherein R
is hydrogen or (C.sub.1-C.sub.6)alkyl; or Z is S(O).sub.n wherein n
is 0, 1 or 2;
[0014] R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.11
are each independently selected from the group consisting of
hydrogen or (C.sub.1-C.sub.6)alkyl optionally substituted by
deuterium, hydroxy, amino, trifluoromethyl,
(C.sub.1-C.sub.6)acyloxy, (C.sub.1-C.sub.6)acylamino,
(C.sub.1-C.sub.6)alkylamino, ((C.sub.1-C.sub.6)alkyl).sub.2amino,
cyano, cyano(C.sub.1-C.sub.6)alkyl,
trifluoromethyl(C.sub.1-C.sub.6)alkyl, nitro,
nitro(C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.6)acylamino;
[0015] R.sup.12 is (C.sub.8-C.sub.10)aryl,
(C.sub.2-C.sub.9)heteroaryl, (C.sub.3-C.sub.10)cycloalkyl or
(C.sub.2-C.sub.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.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl, trifluoromethyl, trifluoromethoxy,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.3-C.sub.10)cycloalkyl, (C.sub.1-C.sub.8)alkyl-CO--NH--,
(C.sub.1-C.sub.6)alkoxy-CO--NH--,
(C.sub.1-C.sub.6)alkyl-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy-CO--NH--(C.sub.1-C.sub.6)alkoxy, carboxy,
carboxy(C.sub.1-C.sub.6)alkyl, carboxy(C.sub.1-C.sub.6)alkoxy,
benzyloxycarbonyl(C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkoxy,
(C.sub.8-C.sub.10)aryl, amino, amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonylamino,
(C.sub.8-C.sub.10)aryl(C.sub.1-C.sub.6)alkoxycarbonylamino,
(C.sub.1-C.sub.6)alkylamino, ((C.sub.1-C.sub.6)alkyl).sub.2amino,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)alkyl, hydroxy,
(C.sub.1-C.sub.6)alkoxy, carboxy, carboxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy-CO--NH--, (C.sub.1-C.sub.6)alkyl-CO--NH--,
cyano, (C.sub.5-C.sub.9)heterocycloalkyl, amino-CO--NH--,
(C.sub.1-C.sub.6)alkylamino-CO--NH--,
((C.sub.1-C.sub.6)alkyl).sub.2amino-CO--NH--,
(C.sub.8-C.sub.10)arylamino-CO--NH--,
(C.sub.5-C.sub.9)heteroarylamino-CO--NH--,
(C.sub.1-C.sub.6)alkylamino-CO--NH--(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylamino-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.5-C.sub.9)heteroarylamino-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylcyano,
(C.sub.1-C.sub.6)alkylcarboxy(C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkylcarboxy, sulfonylamino, aminosulfonyl,
sulfonylamino(C.sub.1-C.sub.6)alkyl,
sulfonylaminocarboxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfonyl,
(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylsulfonyl,
(C.sub.6-C.sub.10)arylsulfonylamino,
(C.sub.6-C.sub.10)arylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.10)cycloalkyl, (C.sub.3-C.sub.10)cycloalkoxy,
(C.sub.1-C.sub.6)alkylamino, ((C.sub.1-C.sub.6)alkyl).sub.2amino,
(C.sub.8-C.sub.10)arylamino, (C.sub.1-C.sub.6)alkylthio,
(C.sub.8-C.sub.10)arylthio, (C.sub.1-C.sub.6)alkylsulfinyl,
(C.sub.6-C.sub.10)arylsulfinyl, (C.sub.1-C.sub.6)alkylsulfonyl,
(C.sub.6-C.sub.10)arylsulfonyl, (C.sub.1-C.sub.6)acyl,
(C.sub.1-C.sub.6)alkoxy-CO--NH--, (C.sub.1-C.sub.6)alkylamino-CO--,
(C.sub.5-C.sub.9)heteroaryl, (C.sub.2-C.sub.9)heterocycloalkyl or
(C.sub.6-C.sub.10)aryl wherein the heteroaryl, heterocycloalkyl and
aryl groups which are optionally substituted on R.sup.12 may be
further substituted by one-to three groups consisting of halo,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyl-CO--NH--,
(C.sub.1-C.sub.6)alkoxy-CO--NH--,
(C.sub.1-C.sub.6)alkyl-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy-CO--NH--(C.sub.1-C.sub.6)alkoxy, carboxy,
carboxy(C.sub.1-C.sub.6)alkyl, carboxy(C.sub.1-C.sub.6)alkoxy,
benzyloxycarbonyl(C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkoxy,
(C.sub.8-C.sub.10)aryl, amino, amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonylamino,
(C.sub.8-C.sub.10)aryl(C.sub.1-C.sub.6)alkoxycarbonylamino,
(C.sub.1-C.sub.6)alkylamino, ((C.sub.1-C.sub.6)alkyl).sub.2amino,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)alkyl, hydroxy,
(C.sub.1-C.sub.6)alkoxy, carboxy, carboxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy-CO--NH--, (C.sub.1-C.sub.6)alkyl-CO--NH--,
cyano, (C.sub.5-C.sub.9)heterocycloalkyl, amino-CO--NH--,
(C.sub.1-C.sub.6)alkylamino-CO--NH--,
((C.sub.1-C.sub.6)alkyl).sub.2amino-CO--NH--,
(C.sub.8-C.sub.10)arylamino-CO--NH--,
(C.sub.5-C.sub.9)heteroarylamino-CO--NH--,
(C.sub.1-C.sub.6)alkylamino-CO--NH--(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.8-C.sub.10)arylamino-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.5-C.sub.9)heteroarylamino-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfonyl,
(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.8-C.sub.10)arylsulfonyl,
(C.sub.6-C.sub.10)arylsulfonylamino,
(C.sub.8-C.sub.10)arylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.5-C.sub.9)heteroaryl and
(C.sub.2-C.sub.9)heterocycloalkyl;
[0016] R.sup.2 and R.sup.3 are each independently selected from the
group consisting of hydrogen, deuterium, amino, halo, hydroxy,
nitro, carboxy, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
trifluoromethyl, trifluoromethoxy, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.10)cycloalkyl wherein the
alkyl, alkoxy or cycloalkyl groups are optionally substituted by
one to three groups selected from halo, hydroxy, carboxy, amino
(C.sub.1-C.sub.6)alkylthio, (C.sub.1-C.sub.6)alkylamino,
((C.sub.1-C.sub.6)alkyl).sub.2amino, (C.sub.5-C.sub.9)heteroaryl,
(C.sub.2-C.sub.9)heterocycloalkyl, (C.sub.3-C.sub.9)cycloalkyl or
(C.sub.8-C.sub.10)aryl; or R.sup.2 and R.sup.3 are each
independently (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.3-C.sub.10)cycloalkoxy. (C.sub.1-C.sub.6)alkylamino,
((C.sub.1-C.sub.6)alkyl).sub.2amino, (C.sub.8-C.sub.10)arylamino,
(C.sub.1-C.sub.6)alkylthio, (C.sub.8-C.sub.10)arylthio,
(C.sub.1-C.sub.6)alkylsulfinyl, (C.sub.8-C.sub.10)arylsulfinyl,
(C.sub.1-C.sub.6)alkylsulfonyl, (C.sub.8-C.sub.10)arylsulfonyl,
(C.sub.1-C.sub.6)acyl, (C.sub.1-C.sub.6)alkoxy-CO--NH--,
(C.sub.1-C.sub.6)alkyamino-CO--, (C.sub.5-C.sub.9)heteroaryl,
(C.sub.2-C.sub.9)heterocycloalkyl or (C.sub.8-C.sub.10)aryl wherein
the heteroaryl, heterocycloalkyl and aryl groups are optionally
substituted by one to three halo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-CO--NH--, (C.sub.1-C.sub.6)alkoxy-CO--NH--,
(C.sub.1-C.sub.6)alkyl-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy-CO--NH--(C.sub.1-C.sub.6)alkoxy, carboxy,
carboxy(C.sub.1-C.sub.6)alkyl, carboxy(C.sub.1-C.sub.6)alkoxy,
benzyloxycarbonyl(C.sub.1-C.sub.6)alkoxy.
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkoxy,
(C.sub.8-C.sub.10)aryl, amino, amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonylamino,
(C.sub.8-C.sub.10)aryl(C.sub.1-C.sub.6)alkoxycarbonylamino,
(C.sub.1-C.sub.6)alkylamino, ((C.sub.1-C.sub.6)alkyl).sub.2amino,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)alkyl, hydroxy,
(C.sub.1-C.sub.6)alkoxy, carboxy, carboxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy-CO--NH--, (C.sub.1-C.sub.6)alkyl-CO--NH--,
cyano, (C.sub.5-C.sub.9)heterocycloalkyl, amino-CO--NH--,
(C.sub.1-C.sub.6)alkylamino-CO--NH--,
((C.sub.1-C.sub.6)alkyl).sub.2amino-CO--NH--,
(C.sub.8-C.sub.10)arylamino-CO--NH--,
(C.sub.5-C.sub.9)heteroarylamino-CO--NH--,
(C.sub.1-C.sub.6)alkylamino-CO--NH--(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.8)alkyl).sub.2amino-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.8-C.sub.10)arylamino-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.5-C.sub.9)heteroarylamino-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfonyl,
(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.8-C.sub.10)arylsulfonyl,
(C.sub.8-C.sub.10)arylsulfonylamino,
(C.sub.8-C.sub.10)arylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.5-C.sub.9)heteroaryl or
(C.sub.2-C.sub.9)heterocycloalkyl;
[0017] with the proviso that R.sup.5 must be substituted by the
group of formula II.
[0018] The present invention also relates to the pharmaceutically
acceptable acid addition salts of compounds of the formula I. The
acids which are used to prepare the pharmaceutically acceptable
acid addition salts of the aforementioned base compounds of this
invention are those which form non-toxic add addition salts, I.e.,
salts containing pharmacologically acceptable anions, such as the
hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate,
bisulfate, phosphate, acid phosphate, acetate, lactate, citrate,
acid citrate, tartrate, bitartrate, succinate, maleate, fumarate,
gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)]salts.
[0019] The invention also relates to base addition salts of formula
I. The chemical bases that may be used as reagents to prepare
pharmaceutically acceptable base salts of those compounds of
formula I that are acidic in nature are those that form non-toxic
base salts with such compounds. Such non-toxic base salts include,
but are not limited to those derived from such pharmacologically
acceptable cations such as alkali metal cations (e.g., potassium
and sodium) and alkaline earth metal cations (e.g., calcium and
magnesium), ammonium or water-soluble amine addition salts such as
N-methylglucamine-(meglumine), and the lower alkanolammonium and
other base salts of pharmaceutically acceptable organic amines.
[0020] The term "Oxone.RTM." is a name of a monopersulfate compound
used in this invention, having the formula
2KHSO.sub.5.KHSO.sub.4.K.sub.2SO.sub.4, and sold by Aldrich
Chemical Company, P.O. Box 2060, Milwaukee, Wis. 53201, USA.
[0021] The term "alkyl", as used herein, unless otherwise
indicated, includes saturated monovalent hydrocarbon radicals
having straight or branched moieties or combinations thereof.
[0022] The term "alkoxy", as used herein, includes O-alkyl groups
wherein "alkyl" is defined above.
[0023] The term "halo", as used herein, unless otherwise indicated,
includes fluoro, chloro, bromo or iodo.
[0024] The compounds of this invention may contain double bonds.
When such bonds are present, the compounds of the invention exist
as cis and trans configurations and as mixtures thereof.
[0025] Unless otherwise indicated, the alkyl and alkenyl groups
referred to herein, as well as the alkyl moieties of other groups
referred to herein (e.g., alkoxy), may be linear or branched, and
they may also be cyclic (e.g., cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl or cycloheptyl) or be linear or branched
and contain cyclic moieties. Unless otherwise indicated, halogen
includes fluorine, chlorine, bromine, and iodine.
[0026] (C.sub.2-C.sub.9)Heterocycloalkyl when used herein refers to
pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl,
pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl,
chromenyl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl,
1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl,
piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl,
1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl,
1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,
tetrahydroazepinyl, piperazinyl, chromanyl, etc. One of ordinary
skill in the art will understand that the connection of said
(C.sub.2-C.sub.9)heterocycloalkyl rings is through a carbon or a
sp.sup.3 hybridized nitrogen heteroatom.
[0027] (C.sub.2-C.sub.9)Heteroaryl when used herein refers to
furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl,
isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl,
1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl,
1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4triazinyl,
1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl,
cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[1]pyrindinyl,
benzo[b]thiophenyl, 5, 6, 7, 8-tetrahydro-quinolin-3-yl,
benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl,
benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl,
isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl,
isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl,
benzoxazinyl; etc. One of ordinary skill in the art will understand
that the connection of said (C.sub.2-C.sub.9)heterocycloalkyl rings
is through a carbon atom or a sp.sup.3 hybridized nitrogen
heteroatom.
[0028] (C.sub.8-C.sub.10)aryl when used herein refers to phenyl or
naphthyl.
[0029] Compounds of formula (I) may be administered in a
pharmaceutically acceptable form either alone or in combination
with one or more additional agents which modulate a mammalian
immune system or with antiinflammatory agents. These agents may
include but are not limited to cyclosporin A (e.g. Sandimmune.RTM.
or Neoral.RTM., rapamycin, FK-506 (tacrolimus), leflunomide,
deoxyspergualin, mycopherolate (e.g. Cellcept.RTM.), azathioprine
(e.g. Imuran.RTM.), daclizumab (e.g. Zenapax.RTM.. OKT3 (e.g.
Orthoclone.RTM.), AtGam, aspirin, acetaminophen, ibuprofen,
naproxen, piroxicam, and antinflammatory steroids (e.g.
prednisolone or dexamethasone). These agents may be administered as
part of the same or separate dosage forms, via the same or
different routes of administration, and on the same or different
administration schedules according to standard pharmaceutical
practice.
[0030] The compounds of this invention include all conformatonal
isomers (e.g., cis and trans isomers. The compounds of the present
invention have asymmetric centers and therefore exist in different
enantiomeric and diastereomeric forms. This invention relates to
the use of all optical isomers and stereolsomers of the compounds
of the present invention, and mixtures thereof, and to all
pharmaceutical compositions and methods of treatment that may
employ or contain them. In this regard, the invention includes both
the E and Z configurations. The compounds of formula I may also
exist as tautomers. This invention relates to the use of all such
tautomers and mixtures thereof.
[0031] This invention also encompasses pharmaceutical compositions
containing prodrugs of compounds of the formula I. This invention
also encompasses methods of treating or preventing disorders that
can be treated or prevented by the inhibition of protein kinases,
such as the enzyme Janus Kinase 3 comprising administering prodrugs
of compounds of the formula I. Compounds of formula I having free
amino, amido, hydroxy or carboxylic groups can be converted into
prodrugs. Prodrugs include compounds wherein an amino acid residue,
or a polypeptide chain of two or more (e.g., two, three or four)
amino acid residues which are covalently joined through peptide
bonds to free amino, hydroxy or carboxylic acid groups of compounds
of formula I. The amino acid residues include the 20 naturally
occurring amino acids commonly designated by three letter symbols
and also include, 4-hydroxyproline, hydroxylsine, demosine,
isodemosine, 3-methylhistidine, norvlin, beta-alanine,
gamma-aminobutyric acid, citrulline, homocysteine, homoserine,
omithine and methioine sulfone. Prodrugs also include compounds
wherein carbonates, carbamates, amides and alkyl esters which are
covalently bonded to the above substituents of formula I through
the carbonyl carbon prodrug sidechain.
[0032] Preferred compounds of formula I include those wherein
R.sup.5 is (C.sub.2-C.sub.9)heterocycloalkyl optionally substituted
by one to three groups selected from deuterium, hydroxy,
(C.sub.1-C.sub.6)alkyl, halo, (C.sub.1-C.sub.6)alkoxy and a group
of formula II.
[0033] Other preferred compounds of formula I include those wherein
a is 0; b is 1; X is carbonyl; c is 0; d is 0; e is 0; f is 0; and
g is 0.
[0034] Other preferred compounds of formula I include those wherein
a is 0; b is 1; X is carbonyl; c is 0; d is 1; e is 0; f is 0, and
g is 0.
[0035] Other preferred compounds of formula I include those wherein
a is 0; b is 1; X is carbonyl; c is 1; d is 0; e is 0; f is 0; and
g is 0.
[0036] Other preferred compounds of formula I include those wherein
a is 0; b is 1; X is --C(.dbd.N=cyano)-; c is 1; d is 0; e is 0; f
is 0; and g is 0.
[0037] Other preferred compounds of formula I include those wherein
a is 0; b is 0; c is 0; d is 0; e is 0; f is 0; g is 1; and Z is
--C(O)--O--.
[0038] Other preferred compounds of formula I include those wherein
a is 0; b is 1; X is S(O).sub.n; n is 2; c is 0; d is 0; e is 0; f
is 0; and g is 0.
[0039] Other preferred compounds of formula I include those wherein
a is 0; b is 1; X is S(O).sub.n; n is 2; c is 0; d is 2; e is 0; f
is 1; g is 1; and Z is carbonyl.
[0040] Other preferred compounds of formula I include those wherein
a is 0; b is 1; X is S(O).sub.n; n is 2; c is 0; d is 2; e is 0; f
is 1; and g is 0.
[0041] Other preferred compounds of formula I include those wherein
a is 0; b is 1; X is carbonyl; c is 1; d is 0; e is 1; Y is
S(O).sub.n; n is 2; f is 0; and g is 0.
[0042] Other preferred compounds of formula I include those wherein
a is 0; b is 1; X is S(O).sub.n;n is 2; c is 1; d is 0; e is 0; f
is 0; and g is 0.
[0043] Other preferred compounds of formula I include those wherein
a is 1; b is 1; X is carbonyl; c is 1; d is 0; e is 0; f is 0; and
g is 0.
[0044] Other preferred compounds of formula I Include those wherein
a is 0; b is 1; X is S(O).sub.n; c is 0; d is 1; e is 1; Y is
S(O).sub.n; n is 2; f is 0; and g is 0.
[0045] Other preferred compounds of formula I include those wherein
a is 0; b is 1; X is S(O).sub.n; c is 0; d is 1; e is 1; Y is
S(O).sub.n; n is 2; f is 1; and g is 0.
[0046] Other preferred compounds of formula I include those wherein
a is 0; b is 1; X is oxygen; c is 0; d is 1; e is 1; Y is
S(O).sub.n; n is 2; f is 1; and g is 0.
[0047] Other preferred compounds of formula I include those wherein
a is 0; b is 1; X is oxygen; c is 0; d is 1; e is 1; Y is
S(O).sub.n; n is 2; f is 0; and g is 0.
[0048] Other preferred compounds of formula I include those wherein
a is 0; b is 1; X is carbonyl; c is 1; d is 1; e is 1; Y is S(O); f
is 0; and g is 0.
[0049] Other preferred compounds of formula I include those wherein
a is 0; b is 1; X is carbonyl; c is 1; d is 1; e is 1; Y is
S(O).sub.n; n is 2; f is 1; and g is 0.
[0050] Other preferred compounds of formula I include those wherein
R.sup.12 is (C.sub.8-C.sub.10)aryl or (C.sub.2-C.sub.9)heteroaryl
wherein the aryl or heteroaryl group is optionally substituted by
one to four groups consisting of hydrogen, halo, hydroxy, carboxy,
trifluormethyl, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkyl-CO--NH--, amino,
amino(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylamino,
((C.sub.1-C.sub.6)alkyl).sub.2amino, cyano, amino-CO--NH--,
(C.sub.1-C.sub.6)alkylamino-CO--NH--,
((C.sub.1-C.sub.6)alkyl).sub.2amino-CO--NH--,
(C.sub.5-C.sub.9)heteroarylamino-CO--NH--,
(C.sub.1-C.sub.6)alkylsulfonyl,
(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.8-C.sub.10)arylsufonylamino,
(C.sub.1-C.sub.6)alkylsulfonylamino, and
(C.sub.1-C.sub.6)alkoxy-CO--NH--.
[0051] Specific preferred compounds of formula I include those
wherein said compound is selected from the group consisting of:
[0052]
4-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-pip-
eridin-1-ylmethyl}-benzenesulfonamide;
[0053]
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperi-
dine-1-carboxylic acid (4-sulfamoyl-phenyl)-amide;
[0054]
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperi-
dine-1-carboxylic acid (4-nitro-phenyl)-amide;
[0055]
-(4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-pipe-
ridin-1-yl}-2-tetrazol-1-yl-ethanone;
[0056]
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperi-
dine-1-carboxylic acid (4-methylsulfamoyl-phenyl)-amide;
[0057]
(3-Hydroxy-pyrrolidin-1-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-amino]-piperidin-1-yl}-methanone;
[0058]
[2-({4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-p-
iperidine-1-carbonyl}-amino)-thiazol-4-yl]-acetic acid;
[0059]
Methyl-(4-methyl-5'-nitro-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-3-
-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amine;
[0060]
5-(2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]--
piperidin-1-yl}-2-oxo-ethyl)-thiazolidine-2,4-dione;
[0061]
{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piper-
idin-1-yl}-thiazolidin-3-yl-methanone;
[0062]
Methyl-[4-methyl-1-(5-nitro-thiazol-2-yl)-piperidin-3-yl]-(7H-pyrr-
olo[2,3-d]pyrimidin-4yl)-amine;
[0063]
[2-({4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-p-
iperidine-1-carbonyl}-amino)-thiazol-4yl]-acetic acid ethyl
ester;
[0064]
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperi-
dine-1-carboxylic acid (4-methanesulfonyl-phenyl)-amide;
[0065]
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperi-
dine-1-carboxylic acid thiazol-2-ylamide;
[0066]
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-piperid-
ine-1-carboxylic acid (4-cyano-phenyl)-amide;
[0067]
{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piper-
idin-1-yl}-pyrrolidin-1-yl-methanone;
[0068] Furan-2-carboxylic acid
(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino)]-piperidi-
ne-1-sulfonyl}-ethyl)-amide;
[0069]
{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piper-
idin-1-yl}(tetrahydro-furan-3-yl)-methanone;
[0070]
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperi-
dine-1-carboxylic acid isoxazol-3-ylamide;
[0071]
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperi-
dine-1-carboxylic acid (6-cyano-pyridin-3-yl)-amide;
[0072]
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4yl)-amino]-3,4,5,6-
-tetrahydro-2H-[1,2']bipyridinyl-5'-carbonitrile
[0073]
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperi-
dine-1-carboxylic acid (4-methyl-thiazol-2-yl)-amide;
[0074]
2-Cyclopropyl-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4--
yl)-amino]-piperidin-1-yl}-ethanone;
[0075]
Cyclopentyl-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)--
amino]-piperidin-1-yl}-Methanone;
[0076]
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperi-
dine-1-carboxylic acid (3-methyl-isoxazol-4-yl)-amide;
[0077]
[4-({4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-p-
iperidine-1-carbonyl}-amino)-phenyl]-acetic acid;
[0078]
[1-(5-Amino-thiazol-2-yl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrr-
olo[2,3-d]pyrimidin-4-yl)-amine;
[0079]
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperi-
dine-1-carboxylic acid (3-methyl-isothiazol-5-yl)-amide;
[0080]
3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-pip-
eridine-1-carbonyl}-cyclopentanone;
[0081]
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperi-
dine-1-carboxylic acid benzyl-methyl-amide; and
[0082]
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperi-
dine-1-carboxylic acid dimethylamide.
[0083] The present invention also relates to a pharmaceutical
composition for (a) treating or preventing a disorder or condition
selected from organ transplant rejection, xeno transplation, 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
autoimmune diseases or (b) the inhibition of protein kinases or
Janus Kinase 3 (JAK3) in a mammal, including a human, comprising an
amount of a compound of formula I or a pharmaceutically acceptable
salt thereof, effective in such disorders or conditions and a
pharmaceutically acceptable carrier.
[0084] The present invention also relates to a method for the
inhibition of protein typrosine kinases or Janus Kinase 3 (JAK3) in
a mammal, including a human, comprising administering to said
mammal an effective amount of a compound of formula I or a
pharmaceutically acceptable salt thereof.
[0085] The present invention also relates to a method for treating
or preventing a disorder or condition selected from organ
transplant rejection, xeno transplation, 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 autoimmune diseases in a mammal,
including a human, comprising administering to said mammal an
amount of a compound of formula I or a pharmaceutically acceptable
salt thereof, effective in treating such a condition.
DETAILED DESCRIPTION OF THE INVENTION
[0086] The following reaction Schemes illustrate the preparation of
the compounds of the present invention. Unless otherwise indicated
R.sup.2, R.sup.3, R.sup.4 and R.sup.5 in the reaction Schemes and
the discussion that follow are defined as above. ##STR5## ##STR6##
##STR7## ##STR8## ##STR9## ##STR10##
[0087] In reaction 1 of Preparation A, the
4-chloropyrrolo[2,3-d]pyrimidine compound of formula XXI, wherein R
is hydrogen or a protecting group such as benzenesulfonyl or
benzyl, is converted to the 4-chloro-5-halopyrrolo[2,3-d]pyrimidine
compound of formula XX, wherein Y is chloro, bromo or iodo, by
reacting XXI with N-chlorosuccinimide, N-bromosuccinimide or
N-iodosuccinimide. The reaction mixture is heated to reflux, in
chloroform, for a time period between about 1 hour to about 3
hours, preferably about 1 hour. Alternatively, in reaction 1 of
Preparation A, the 4-chloropyrrolo[2,3-d]pyrimidine of formula XXI,
wherein R is hydrogen, is converted to the corresponding
4-chloro-5-aminopyrrolo[2,3-d]pyrimidine of formula XX, wherein Y
is nitro, by reacting XXI with nitric acid in sulfuric acid at a
temperature between about -10.degree. C. to about 10.degree. C.,
preferably about 0.degree. C., for a time period between about 5
minutes to about 15 minutes, preferably about 10 minutes. The
compound of formula XXI, wherein Y is nitro, is converted to the
corresponding 4-chloro-5-aminopyrrolo[2,3-d]pyrimidine of the
formula XX, wherein Y is amino, by reacting XXI under a variety of
conditions known to one skilled in the art such as palladium
hydrogenolysis or tin(IV)chloride and hydrochloric acid.
[0088] In reaction 2 of Preparation A, the
4-chloro-5-halopyrrolo[2,3-d]pyrimidine compound of formula XX,
wherein R is hydrogen, is converted to the corresponding compound
of formula XIX, wherein R.sup.2 is (C.sub.1-C.sub.6)alkyl or
benzyl, by treating XX with N-butyllithium, at a temperature of
about -78.degree. C., and reacting the dianion intermediate so
formed with an alkylhalide or benzylhalide at a temperature between
about -78.degree. C. to room temperature, preferably room
temperature. Alternatively, the dianion so formed is reacted with
molecular oxygen to form the corresponding
4-chloro-5-hydroxypyrrolo[2,3-d]pyrimidine compound of formula XIX,
wherein R.sup.2 is hydroxy. The compound of formula XX, wherein Y
is bromine or iodine and R is benzenesulfonate, is converted to the
compound of formula XIX, wherein R.sup.2 is (C.sub.6-C.sub.12)aryl
or vinyl, by treating XX with N-butyllithium, at a temperature of
about -78.degree. C., followed by the addibon of zinc chloride, at
a temperature of about -78.degree. C. The corresponding organo zinc
intermediate so formed is then reacted with aryliodide or vinyl
iodide in the presence of a catalytic quantity of palladium. The
reaction mixture is stirred at a temperature between about
50.degree. C. to about 80.degree. C., preferably about 70.degree.
C., for a time period between about 1 hour to about 3 hours,
preferably about 1 hour.
[0089] In reaction 3 of Preparation A, the compound of formula XIX
is converted to the corresponding compound of formula XVI by
treating XIX with N-butyllithium, lithium diisopropylamine or
sodium hydride, at a temperature of about -78.degree. C., in the
presence of a polar aprotic solvent, such as tetrahydrofuran. The
anionic intermediate so formed is further reacted with (a)
alkylhalide or benzylhalide, at a temperature between about
-78.degree. C. to room temperature, preferably -78.degree. C., when
R.sup.3 is alkyl or benzyl; (b) an aldehyde or ketone, at a
temperature between about -78.degree. C. to room temperature,
preferably -78.degree. C., when R.sup.3 is alkoxy; and (c) zinc
chloride, at a temperature between about -78.degree. C. to room
temperature, preferably -78.degree. C., and the corresponding
organozinc intermediate so formed is then reacted with aryliodide
or vinyl iodide in the presence of a catalytic quantity of
palladium. The resulting reaction mixture is stirred at a
temperature between about 50.degree. C. to about 80.degree. C.,
preferably about 70.degree. C., for a time period between about 1
hour to about 3 hours, preferably about 1 hour. Alternatively, the
anion so formed is reacted with molecular oxygen to form the
corresponding 4-chloro-6-hydroxypyrrolo[2,3-d]pyrimidine compound
of formula XVI, wherein R.sup.3 is hydroxy.
[0090] In reaction 1 of Preparation B, the
4-chloropyrrolo[2,3-d]pyrimidine compound of formula XXI is
converted to the corresponding compound of formula XXII, according
to a procedure analogous to that described above in reaction 3 of
Preparation A.
[0091] In reaction 2 of Preparation B, the compound of formula XXII
is converted to the corresponding compound of formula XVI,
according to procedures analogous to that described above in
reactions 1 and 2 of Preparation A.
[0092] In reaction 1 of Preparation C, the 4-methylpyridine
compound of formula XXXI is converted to the corresponding compound
of formula XXX by first alkylating XXXI with benzylchloride in the
presence of a polar aprotic solvent, such as acetone. The reaction
mixture is stirred at a temperature between about 40.degree. C. to
about 80.degree. C. for a time period between about 4 hours to
about 24 hours. The pyridinium intermediate so formed is then
reduced with a reducing agent, such as sodium borohydride, in the
presence of a polar protic solvent, such as methanol, ethanol,
water or mixtures thereof. The reaction is stirred at a temperature
between about 0.degree. C. to a about room temperature, for a time
period between about 18 hours to 24 hours.
[0093] In reaction 2 of Preparation C, the compound of formula XXX
is converted to the corresponding compound of formula XXIX by
treating XXX with borotrifluoride etherate in the presence of a
reducing agent and an aprotic solvent, such as tetrahydrofuran. The
reaction mixture is stirred at a temperature between about
0.degree. C. to room temperature, for a time period between about 1
hour to about 3 hours. The intermediate complex so formed is then
basified with aqueous sodium hydroxide and then treated with an
oxidizing agent, such as hydrogen peroxide or Oxone.RTM., at a
temperature between about 0.degree. C. to room temperature, for a
time period between about 12 hours to about 24 hours.
[0094] In reaction 3 of Preparation C, the compound of formula XXIX
is treated with an oxidizing agent, such as chromium oxide or
dimethylsulfoxide, oxalylchloride or SO.sub.3-pyridine complex, for
a time period between about 1 hour to 3 hours, at ambient
temperature. The ketone intermediate so formed, is then treated
with an amine (R.sup.4--NH.sub.2) in the presence of an acid, such
as acetic acid, at about room temperature, for a time period
between about 2 to about 24 hours, in an organic solvent such as
methanol, ethanol or tetrahydrofuran. The corresponding imine
intermediate so formed is then treated with a reducing agent, such
as sodium borohydride or sodium cyanoborohydride or sodium
triacetoxyborohydride, at ambient temperature, for a time period
about 2 to about 24 hours.
[0095] In reaction 1 of Scheme 1, the
4-chloropyrrolo[2,3-d]pyrimidine compound of formula XVII is
converted to the corresponding compound of formula XVI, wherein R
is benzenesulfonyl or benzyl, by treating XVII with benzenesulfonyl
chloride, benzylchloride or benzylbromide in the presence of a
base, such as sodium hydride or potassium carbonate, and a polar
aprotic solvent, such as dimethylformamide or tetrahydrofuran. The
reaction mixture is stirred at a temperature between about
0.degree. C. to about 70.degree. C., preferably about 30.degree.
C., for a time period between about 1 hour to about 3 hours,
preferably about 2 hours.
[0096] In reaction 2 of Scheme 1, the
4-chloropyrrolo[2,3-d]pyrimidine compound of formula XVI is
converted to the corresponding 4-aminopyrrolo[2,3-d]pyrimidine
compound of formula XV by coupling XVI with an amine of the formula
HNR.sup.4R.sup.5. The reaction is carried out in an alcohol
solvent, such as tert-butanol, methanol or ethanol, or other high
boiling organic solvents, such as dimethylformamide, triethylamine,
1,4-dioxane or 1,2-dichloroethane, at a temperature between about
60.degree. C. to about 120.degree. C., preferably about 80.degree.
C. Typical reaction times are between about 2 hours to about 48
hours, preferably about 16 hours. When R.sup.5 is a nitrogen
containing heterocycloalkyl group, each nitrogen must be protected
by a protecting group, such a benzyl. Removal of the R.sup.5
protecting group is carried out under conditions appropriate for
that particular protecting group in use which will not affect the R
protecting group on the pyrrolo[2,3-d]pyrimidine ring. Removal of
the R.sup.5 protecting group, when benzyl, is carried out in an
alcohol solvent, such as ethanol, in the present of hydrogen and a
catalyst, such as palladium hydroxide on carbon. The R.sup.5
nitrogen containing hetrocycloalkyl group so formed may be further
reacted with a variety of different electrophiles of formula II.
For urea formation, electrophiles of formula II such as
isocyanates, carbamates and carbamoyl chlorides are reacted with
the R.sup.5 nitrogen of the heteroalkyl group in a solvent, such as
acetonitrile or dimethylformamide, in the presence of a base, such
as sodium or potassium carbonate, at a temperature between about
20.degree. C. to about 100.degree. C. for a time period between
about 24 hours to about 72 hours. For amide and sulfonamide
formation, electrophiles of formula II, such as acylchlorides and
sulonyl chlorides, are reacted with the R.sup.5 nitrogen of the
heteroalkyl group in a solvent such as methylene chloride in the
presence of a base such as pyridine at ambient temperatures for a
time period between about 12 hours to about 24 hours. Amide
formation may also be carried out by reacting a carboxylic acid
with the heteroalkyl group in the presence of a carbodiimide such
as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in a solvent such
as methylene chloride at ambient temperatures for 12-24 hours. For
alkyl formation, electophiles of formula II, such as
.alpha.,.beta.-unsaturated amides, acids, nitrites, esters, and
.alpha.-halo amides, are reacted with the R.sup.5 nitrogen of the
heteroalkyl group in a solvent such as methanol at ambient
temperatures for a time period between about 12 hours to about 18
hours. Alkyl formation may also be carried out by reacting
aldehydes with the heteroalkyl group in the presence of a reducing
agent, such as sodium cyanoborohydride, in a solvent, such as
methanol, at ambient temperature for a time period between about 12
hours to about 18 hours.
[0097] In reaction 3 of Scheme 1, removal of the protecting group
from the compound of formula XV, wherein R is benzenesulfonyl, to
give the corresponding compound of formula I, is carried out by
treating XV with an alkali base, such as sodium hydroxide or
potassium hydroxide, in an alcohol solvent, such as methanol or
ethanol, or mixed solvents, such as alcohol/tetrahydrofuran or
alcohol/water. The reaction is carried out at room temperature for
a time period between about 15 minutes to about 1 hour, preferably
30 minutes. Removal of the protecting group from the compound of
formula XV, wherein R is benzyl, is conducted by treating XV with
sodium in ammonia at a temperature of about -78.degree. C. for a
time period between about 15 minutes to about 1 hour.
[0098] In reaction 1 of Scheme 2, the
4-chloropyrrolo[2,3-d]pyrimidine compound of formula XX is
converted to the corresponding 4-aminopyrrolo[2,3-d]pyrimidine
compound of formula XXIV, according to a procedure analogous to
that described above in reaction 2 of Scheme 1.
[0099] In reaction 2 of Scheme 2, the
4-amino-5-halopyrrolo[2,3-d]pyrimidine compound of formula XXIV,
wherein R is benzenesulfonate and Z is bromine or iodine, is
converted to the corresponding compound of formula XXIII by
reacting XXIV with (a) arylboronic acid, when R.sup.2 is aryl, in
an aprotic solvent, such tetrahydrofuran or dioxane, in the
presence of a catalytic quantity of palladium (0) at a temperature
between about 50.degree. C. to about 100.degree. C., preferably
about 70.degree. C., for a time period between about 2 hours to
about 48 hours, preferably about 12 hours; (b) alkynes, when
R.sup.2 is alkynyl, in the presence of a catalytic quantity of
copper (I) iodide and palladium (0), and a polar solvent, such as
dimethylformamide, at room temperature, for a time period between
about 1 hour to about 5 hours, preferably about 3 hours; and (c)
alkenes or styrenes, when R.sup.2 is vinyl or styrenyl, in the
presence of a catalytic quantity of palladium in dimethylformamide,
dioxane or tetrahydrofuran, at a temperature between about
80.degree. C. to about 100.degree. C., preferably about 100.degree.
C., for a time period between about 2 hours to about 48 hours,
preferably about 48 hours.
[0100] In reaction 3 of Scheme 2, the compound of formula XXIII is
converted to the corresponding compound of formula XV, according to
a procedure analogous to that described above in reaction 3 of
Preparation A.
[0101] In reaction 1 of Scheme 3, the compound of formula XVII is
converted to the corresponding compound of formula I, according to
a procedure analogous to that described above in reaction 2 of
Scheme 1.
[0102] The compounds of the present invention that are basic in
nature are capable of forming a wide variety of different salts
with various inorganic and organic acids. Although such salts must
be pharmaceutically acceptable for administration to animals, it is
often desirable in practice to initially isolate the compound of
the present invention from the reaction mixture as a
pharmaceutically unacceptable salt and then simply convert the
latter back to the free base compound by treatment with an alkaline
reagent and subsequently convert the latter free base to a
pharmaceutically acceptable add addition salt. The acid addition
salts of the base compounds of this invention are readily prepared
by treating the base compound with a substantially equivalent
amount of the chosen mineral or organic acid in an aqueous solvent
medium or in a suitable organic solvent, such as methanol or
ethanol. Upon careful evaporation of the solvent, the desired solid
salt is readily obtained. The desired acid salt can also be
precipitated from a solution of the free base in an organic solvent
by adding to the solution an appropriate mineral or organic
add.
[0103] Those compounds of the present invention that are acidic in
nature, are capable of forming base salts with various
pharmacologically acceptable cations. Examples of such salts
include the alkali metal or alkaline-earth metal salts and
particularly, the sodium and potassium salts. These salts are all
prepared by conventional techniques. The chemical bases which are
used as reagents to prepare the pharmaceutically acceptable base
salts of this invention are those which form non-toxic base salts
with the acidic compounds of the present invention. Such non-toxic
base salts include those derived from such pharmacologically
acceptable cations as sodium, potassium calcium and magnesium, etc.
These salts can easily be prepared by treating the corresponding
acidic compounds with an aqueous solution containing the desired
pharmacologically acceptable cations, and then evaporating the
resulting solution to dryness, preferably under reduced pressure.
Alternatively, they may also be prepared by mixing lower alkanolic
solutions of the acidic compounds and the desired alkali metal
alkoxide together, and then evaporating the resulting solution to
dryness in the same manner as before. In either case,
stoichiometric quantities of reagents are preferably employed in
order to ensure completeness of reaction and maximum yields of the
desired final product.
[0104] The compositions of the present invention may be formulated
in a conventional manner using one or more pharmaceutically
acceptable carriers. Thus, the active compounds of the invention
may be formulated for oral, buccal, intranasal, parenteral (e.g.,
intravenous, intramuscular or subcutaneous) or rectal
administration or in a form suitable for administration by
inhalation or insufflation. The active compounds of the invention
may also be formulated for sustained delivery.
[0105] For oral administration, the pharmaceutical compositions may
take the form of, for example, tablets or capsules prepared by
conventional means with pharmaceutically acceptable excipients such
as binding agents (e.g., pregelatinized maize starch,
polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers
(e.g., lactose, microcrystalline cellulose or calcium phosphate);
lubricants (e.g., magnesium stearate, talc or silica);
disintegrants (e.g., potato starch or sodium starch glycolate); or
wetting agents (e.g., sodium lauryl sulphate). The tablets may be
coated by methods well known in the art. Liquid preparations for
oral administration may take the form of, for example, solutions,
syrups or suspensions, or they may be presented as a dry product
for constitution with water or other suitable vehicle before use.
Such liquid preparations may be prepared by conventional means with
pharmaceutically acceptable additives such as suspending agents
(e.g., sorbitol syrup, methyl cellulose or hydrogenated edible
fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous
vehicles (e.g., almond oil, oily esters or ethyl alcohol); and
preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic
acid).
[0106] For buccal administration, the composition may take the form
of tablets or lozenges formulated in conventional manner.
[0107] The active compounds of the invention may be formulated for
parenteral administration by injection, including using
conventional catheterization techniques or infusion. Formulations
for injection may be presented in unit dosage form, e.g., in
ampules or in multi-dose containers, with an added preservative.
The compositions may take such forms as suspensions, solutions or
emulsions in oily or aqueous vehicles, and may contain formulating
agents such as suspending, stabilizing and/or dispersing agents.
Alternatively, the active ingredient may be in powder form for
reconstitution with a suitable vehicle, e.g., sterile pyrogen-free
water, before use.
[0108] The active compounds of the invention may also be formulated
in rectal compositions such as suppositories or retention enemas,
e.g., containing conventional suppository bases such as cocoa
butter or other glycerides.
[0109] For intranasal administration or administration by
inhalation, the active compounds of the invention are conveniently
delivered in the form of a solution or suspension from a pump spray
container that is squeezed or pumped by the patent or as an aerosol
spray presentation from a pressurized container or a nebulizer,
with the use of a suitable propellant, e.g.,
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
the case of a pressurized aerosol, the dosage unit may be
determined by providing a valve to deliver a metered amount. The
pressurized container or nebulizer may contain a solution or
suspension of the active compound. Capsules and cartridges (made,
for example, from gelatin) for use in an inhaler or insufflator may
be formulated containing a powder mix of a compound of the
invention and a suitable powder base such as lactose or starch.
[0110] A proposed dose of the active compounds of the invention for
oral, parenteral or buccal administration to the average adult
human for the treatment of the conditions referred to above (e.g.,
rheumatoid arthritis) is 0.1 to 1000 mg of the active ingredient
per unit dose which could be administered, for example, 1 to 4
times per day.
[0111] Aerosol formulations for treatment of the conditions
referred to above (e.g., asthma) in the average adult human are
preferably arranged so that each metered dose or "puff" of aerosol
contains 20 .mu.g to 1000 .mu.g of the compound of the invention.
The overall daily dose with an aerosol will be within the range 0.1
mg to 1000 mg. Administration may be several times daily, for
example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses
each time.
[0112] A compound of formula (I) administered in a pharmaceutically
acceptable form either alone or in combination with one or more
additional agents which modulate a mammlian immune system or with
antiinflammatory agents, agents which may include but are not
limited to cyclosporin A (e.g. Sandimmune.RTM. or Neoral.RTM.,
rapamycin, FK-506 (tacrolimus), leflunomide, deoxyspergualin,
mycophenolate (e.g. Cellcept.RTM., azathioprine (e.g. Imuran.RTM.),
daclizumab (e.g. Zenapax.RTM.), OKT3 (e.g. Orthocolone.RTM.),
AtGam, aspirin, acctaminophen, ibuprofen, naproxen, piroxicam, and
antiinflmmatory steroids (e.g. prednisolone or dexamethasone); and
such agents may be administered as part of the same or separate
dosage forms, via the same or different routes of administration,
and on the same or different administration schedules according to
standard pharmaceutical practice.
[0113] FK506 (Tacrolimus) is given orally at 0.10-0.15 mg/kg body
weight, every 12 hours, within first 48 hours postoperative. Does
is monitored by serum Tacrolimus trough levels.
[0114] Cyclosporin A (Sandimmune oral or intravenous formulation,
or Neoral.RTM., oral solution or capsules) is given orally at 5
mg/kg body weight, every 12 hours within 48 hours postoperative.
Dose is monitored by blood Cyclosporin A trough levels.
[0115] The active agents can be formulated for sustained delivery
according to methods well known to those, of ordinary skill in the
art. Examples of such formulations can be found in U.S. Pat. Nos.
3,538,214, 4,060,598, 4,173,626, 3,119,742, and 3,492,397.
[0116] The ability of the compounds of formula I or their
pharmaceutically acceptable salts to inhibit Janus Kinase 3 and,
consequently, demonstrate their effectiveness for treating
disorders or conditions characterized by Janus Kinase 3 is shown by
the following in vitro assay tests.
Biological Assay
JAK3 (JH1:GST) Enzymatic Assay
[0117] The JAK3 kinase assay utilizes a protein expressed in
baculovirus-infected SF9 cells (a fusion protein of GST and the
catalytic domain of human JAK3) purified by affinity chromatography
on glutathione-Sepaharose. The substrate for the reaction is
poly-Glutamic acid-Tyrosine (PGT (4:1), Sigma catalog # P0275),
coated onto Nunc Maxi Sorp plates at 100 .mu.g/ml overnight at
37.degree. C. The morning after coating, the plates are washed
three times and JAK3 is added to the wells containing 100 .mu.l of
kinase buffer (50 mM HEPES, pH 7.3, 125 mM NaCl, 24 mM MgCl2)+0.2
uM ATP+1 mM Na orthovanadate.) The reaction proceeds for 30 minutes
at room temperature and the plates is washed three more times. The
level of phosphorylated tyrosine in a given well is quantitated by
standard ELISA assay utilizing an anti-phosphotyrosine antibody
(ICN PY20, cat. #69-151-1).
Inhibition of Human IL-2 Dependent T-Cell Blast Proliferation
[0118] This screen measures the inhibitory effect of compounds on
IL-2 dependent T-Cell blast proliferation in vitro. Since signaling
through the IL-2 receptor requires JAK-3, cell active inhibitors of
JAK-3 should inhibit IL-2 dependent T-Cell blast proliferation.
[0119] The cells for this assay are isolated from fresh human
blood. After separation of the mononuclear cells using Accuspin
System-Histopaque-1077 (Sigma # A7054), primary human T-Cells are
isolated by negative selection using Lympho-Kwik T (One Lambda,
Inc., Cat # LK-50T). T-Cells are cultured at 1-2.times.10.sup.6/ml
in Media (RPMI+10% heat-inactivated fetal calf serum (Hyclone Cat #
A-1111-L)+1% Penicillin/Streptomycin (Gibco)) and induce to
proliferate by the addition of 10 ug/ml PHA (Murex Diagnostics, Cat
# HA 16). After 3 days at 37.degree. C. in 5% CO.sub.2, cells are
washed 3 times in Media, resuspended to a density of
1-2.times.10.sup.8 cells/ml in Media plus 100 Units/ml of human
recombinant IL-2 (R&D Systems, Cat # 202-IL). After 1 week the
cells are IL-2 dependent and can be maintained for up to 3 weeks by
feeding twice weekly with equal volumes of Media+100 Units/ml of
IL-2.
[0120] To assay for a test compounds ability to inhibit IL-2
dependent T-Cell proliferation, IL-2 dependent cells are washed 3
times, resuspended in media and then plated (50,000 cells/well/0.1
ml) in a Flat-bottom 96-well microtiter plate (Falcon # 353075).
From a 10 mM stock of test compound in DMSO, serial 2-fold
dilutions of compound are added in triplicate wells starting at 10
uM. After one hour, 10 Units/ml of IL-2 is added to each test well.
Plates are then incubated at 37.degree. C., 5% CO.sub.2 for 72
hours. Plates are then pulsed with .sup.3H-thymidine (0.5 uCi/well)
(NEN Cat # NET-027A), and incubated an additional 18 hours. Culture
plates are then harvested with a 96-well plate harvester and the
amount of .sup.3H-thymidine incorporated into proliferating cells
is determined by counting on a Packard Top Count scintillation
counter. Data is analyzed by plotting the % inhibition of
proliferation verses the concentration of test compound. An
IC.sub.50 value (uM) is determined from this plot.
[0121] The following Examples illustrate the preparation of the
compounds of the present invention but it is not limited to the
details thereof. Commercial reagents were utilized without further
purification. THF refers to tetrahydrofuran. DMF refers to
N,N-dimethylformamide. Low Resolution Mass Spectra (LRMS) were
recorded on either a Hewlett Packard 5989.RTM., utilizing chemical
ionization (ammonium), or a Fisons (or Micro Mass) Atmospheric
Pressure Chemical Ionization (APCI) platform which uses a 50/50
mixture of acetonitrile/water with 0.1% formic acid as the ionizing
agent. Room or ambient temperature refers to 20-25.degree. C.
EXAMPLE 1
Furan-2-yl-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-pi-
peridin-1-yl}-methanone
Method A
1-Benzyl-4-methyl-pyridinium chloride
[0122] To a stirred solution of 4-methylpyridine (26 mL/0.268 mol)
in 70 mL of acetone was added 31 mL (0.268 mol) of benzylchloride.
The resulting mixture was stirred at 50.degree. C. for 18 hours.
After cooling to room temperature, the reaction was filtered,
washed with acetone and dried under reduced pressure affording 38 g
of the title compound. The filtrate was concentrated under reduced
pressure producing an additional 5.6 grams of the title compound
(74% combined yield). LRMS: 184.
Method B
1-Benzyl-4-methyl-1,2,3,6-tetrahydro-pyridine
[0123] To a stirred solution of the product from Method A (38
grams/0.171 mol) dissolved in 140 mL of 10:1 ethanol/water at
0.degree. C. was added 16 grams (0.427 mol) of sodium borohydride
portion-wise over 25 minutes. The resulting mixture stirred for 18
hours at room temperature, at which time, the reaction was quenched
upon addition of 100 mL of water. The reaction mixture was
filtered, the filter cake washed with water and ethylacetate, and
the combined filtrates concentrated under reduced pressure to
remove the organics. The residue was diluted with water (100 mL)
and extracted 3 times with 150 mL with ethylacetate. The combined
ethylacetate extracts were dried over Na.sub.2SO.sub.4 and
concentrated to dryness in vacuo affording 32 grams (100%) of the
title compound as a yellow oil. LRMS: 188 (M+1).
Method C
1-Benzyl-4-methyl-piperidin-3-ol
[0124] To a solution of the product from Method B (72.45
grams/0.387 mol) dissolved in 240 mL of THF was added 21.4 grams of
NaBH.sub.4 and the mixture cooled to 0.degree. C. A solution of
borontrifluoride etherate (109.4 mL dissolved in 200 mL of THF) was
then added dropwise over 1.5 hours. Once added, the reaction
mixture was brought to room temperature and stirred for 2 hours.
The reaction was again cooled to 0.degree. C. and 29.3 mL of water
were added dropwise over 15 minutes followed by dropwise addition
of 2N sodium hydroxide (97.5 mL) over 20 minutes. The resulting
mixture stirred at 0.degree. C. for 40 minutes and was then brought
to room temperature. Hydrogen peroxide (30%) (97.5 mL) was added
dropwise at a rate so as not to exceed 50.degree. C. in the
reaction mixture (approximately 30 minutes). When the addition was
complete, the reaction mixture stirred for 10 minutes, then was
cooled to 0.degree. C. Concentrated hydrochloric acid (97.5 mL) was
added over 5 minutes, the reaction mixture was reduced to one third
its volume in vacuo, and the pH adjusted to 9-10 with 6N sodium
hydroxide (aq). The resulting mixture was extracted three times
with ether, the combined ether layers dried over MgSO.sub.4 and
evaporated to dryness in vacuo affording 65.32 grams (79%) of the
title compound as yellow oil. LRMS: 206.1 (M+1).
[0125] Alternative Method: To a solution of the product from Method
B (18.7 grams/0.1 mol) in THF (150 mL) was added NaBH.sub.4 (6.5
grams/0.170 mol) at room temperature under N.sub.2. The slurry was
cooled to 0.degree. C., and BF.sub.3--OEt.sub.2 (15 mL, 16.8
grams/0.118 mol) in THF (25 mL) was slowly added through an
addition funnel. The addition was kept slow enough to keep the
temperature of the reaction mixture below 0.degree. C. After the
addition; the reaction mixture was stirred at 0.degree. C. for 1
hour and room temperature for 1.5 hours. The reaction was re-cooled
to 0.degree. C. and water (50 mL) was added slowly to destroy the
excess borane. The reaction was stirred at room temperature for 2
hours, followed by the addition of Oxone.RTM. (110 grams/0.343 mol)
in water (500 mL) at 0.degree. C. The reaction mixture was allowed
to warm to room temperature and stirred overnight. The reaction was
quenched upon addition of solid NaHSO.sub.3 until all excess
oxidant was destroyed (Kl/starch test paper). The pH of the
reaction mixture was 1-2. The reaction mixture was then extracted 3
times with 50 mL ethyl acetate, the aqueous layer adjusted to pH 12
with 6 N sodium hydroxide and extracted with ethyl acetate (4 times
with 100 mL). The organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, and concentrated in vacuo affording 19.0 grams
(92%) of the title compound as an oil. LRMS: 206.1 (M+1).
Method D
1-Benzyl-4-methyl-piperidin-3-ol-toluene-4-sulfonic acid salt
[0126] To a stirred solution of the product from Method C (65.32
grams/0.318 mol) dissolved in 175 mL of acetone and cooled to
0.degree. C. was added a solution of para-toluenesulfonic acid
monohydrate in 350 mL of acetone (dropwise) over 2 hours and the
resulting mixture stirred at 0.degree. C. for 1.5 hours. The
precipitate was filtered and the filter cake washed with 90 mL of
diisopropyl ether. The solid product was then dried in vacuo
affording 58.55 grams (100%) of the title compound as a white
solid. LRMS: 378.5 (M+1).
Method E
1-Benzyl-4-methyl-piperidin-3-one
[0127] To a solution of the product from Method D (9.8 grams/0.026
mol) and 31.7 mL of diisopropylethylamine dissolved in 250 mL of
dichloromethane and cooled to 0.degree. C. was added (dropwise)
12.4 grams of SO.sub.3 pyridine complex dissolved in 153 mL of
dimethylsulfoxide over a 40 minute period. Once added, the reaction
stirred for 1.5 hours, at room temperature and was then quenched
upon addition of 200 mL of saturated NaHCO.sub.3 (aq). The
dichloromethane was removed in vacuo and the remaining aqueous
residue extracted four times with diisopropyl ether (150 mL). The
combined ether layers were washed four times with water (100 mL),
dried over Na.sub.2SO.sub.4 and concentrated to dryness in vacuo
affording 3.81 grams (72.97%) of the title compound as yellow oil.
LRMS: 204 (M+1).
Method F
(1-Benzyl-4-methyl-piperidin-3-yl)-methyl-amine
[0128] To a stirred solution of the product from Method E (3.81
grams/0.019 mol) and 38 mL of 2.0 M methylamine in THF was added
2.2 mL of acetic add and the resulting mixture stirred at room
temperature for 1.5 hours. Triacetoxysodiumborohydride
(NaB(OAc).sub.3H) (7.94 grams/0.038 mol) was added as a solid and
the new mixture stirred at room temperature for 18 hours. The
reaction was quenched with 2 N hydrochloric acid and the pH
adjusted to 1. The reaction mixture was washed two times with
ether, the aqueous layer then adjusted to pH of 12 with 6 N sodium
hydroxide (aq) and extracted three times with dichloromethane The
combined dichloromethane layers were dried over Na.sub.2SO.sub.4,
filtered and evaporated to dryness in vacuo affording 3.51 grams
(87.75%) of the title compound as dark yellow oil. LRMS: 219.1
(M+1).
Method G
(1-Benzyl-4-methyl-piperidin-3-yl)-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-
-amine
[0129] A mixture of 4-chloropyrrolo[2,3-d]pyrimidine (2.4 grams,
15.9 mmol), prepared by the method of Davoll, J. Am. Chem. Soc.,
(1960), 82, 131, the product from Method F (1.7 grams, 7.95 mmol)
and 10 mL of triethylamine were heated in a sealed tube at
100.degree. C. for 4 days. After cooling to room temperature and
concentration under reduced pressure, the residue was purified by
flash chromatography (silica; 3% methanol in dichloromethane)
affording 1.0 grams (38%) of the title compound as a colorless oil.
LRMS: 336.1 (M+1).
Method H
Methyl-(4-methyl-piperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine
[0130] To the product from Method G (0.7 grams, 2.19 mmol)
dissolved in 15 mL of ethanol was added 0.5 grams of 20% palladium
hydroxide on carbon (50% water) (Aldrich) and the resulting mixture
agitated (Parr-Shaker) under an atmosphere of hydrogen (50 psi) at
room temperature for 2 days. The Celite filtered reaction mixture
was concentrated to dryness in vacuo and the residue purified by
flash chromatography (silica; 5% methanol in dichoromethane)
affording 0.48 grams (90%) of the title compound. LRMS: 246.1
(M+1).
Method I
[1-(4-Methoxy-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo-
[2,3-d]pyrimidin-4-yl)-amine
[0131] To a stirred solution of 1 mL of pyridine and 9 ml of
dichloromethane was added 40 mg (0.163 mmol) of the product from
Method H and 20 L of 4-methoxy-benzenesulfonyl chloride and the
resulting mixture stirred at room temperature for 18 hours. The
reaction was then quenched upon addition of saturated NaHCO.sub.3
(aq), the organic layer was removed and the aqueous layer extracted
with dichloromethane. The dichloromethane layer was dried over
Na.sub.2SO.sub.4 and concentrated to dryness in vacuo. The residue
was purified by PTLC (silica; 10:1 dichloromethane/methanol)
affording 22 mg (32%) of the title compound as a light yellow
solid. LRMS: 416.5 (M+1).
[0132] The title compounds for examples 2-297 were prepared by a
method analogous to that described in Example 1.
EXAMPLE 2
[1-(4-Methoxy-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo-
[2,3-d]pyrimidin-4-yl)-amine
[0133] LRMS: 416.
EXAMPLE 3
(1-Benzenesulfonyl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrim-
idin-4-yl)-amine
[0134] LRMS: 386.
EXAMPLE 4
2-(2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidi-
ne-1-sulfonyl}-ethyl)-isoindole-1,3-dione
[0135] LRMS: 483.
EXAMPLE 5
Cyclohexanecarboxylic acid
(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-
e-1-sulfonyl}-ethyl)-amide
[0136] RMS: 463.
EXAMPLE 6
2-Chloro-N-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-p-
iperidine-1-sulfonyl)-ethyl)-benzamide
[0137] LRMS: 492.
EXAMPLE 7
4-Chloro-N-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-
-piperidine-1-sulfonyl}-ethyl)-benzamide
[0138] LRMS: 492.
EXAMPLE 8
Furan-2-carboxylic acid
(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-
e-1-sulfonyl}-ethyl)-amide
LRMS: 447.
EXAMPLE 9
3-Methoxy-N-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino-
]-piperidine-1-sulfonyl}-ethyl)-benzamide
[0139] LRMS: 487.
EXAMPLE 10
Isoxazole-5-carboxylic acid
(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-
e-1-sulfonyl}-ethyl)-amide
[0140] LRMS: 448.
EXAMPLE 11
2,4-Difluoro-N-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-am-
ino]-piperidine-1-sulfonyl}-ethyl)-benzamide
[0141] LRMS: 493.
EXAMPLE 12
3-Chloro-N-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-
-piperidine-1-sulfonyl}-ethyl)-benzamide
[0142] LRMS: 492.
EXAMPLE 13
3-Fluoro-N-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-
-piperidine-1-sulfonyl}-ethyl)-benzamid
[0143] LRMS: 475.
EXAMPLE 14
2-Fluoro-N-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-
-piperidine-1-sulfonyl}-ethyl)-benzamide
[0144] LRMS: 475.
EXAMPLE 15
4-Fluoro-N-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-
-piperidine-1-sulfonyl}-ethyl)-benzamide
[0145] LRMS: 475.
EXAMPLE 16
N-(2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidi-
ne-1-sulfonyl}-ethyl)-benzamide
[0146] LRMS: 457.
EXAMPLE 17
Cyclopropanecarboxylic acid
(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-
e-1-sulfonyl}-ethyl)-amide
[0147] LRMS: 421.
EXAMPLE 18
Cyclopentanecarboxylic acid
(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-
e-1-sulfonyl}-ethyl)-amide
[0148] LRMS: 449.
EXAMPLE 19
Cyclopentyl-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-p-
iperidin-1-yl}-methanone
[0149] LRMS: 342.
EXAMPLE 20
Tetrahydro-furan-2-carboxylic acid
(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-
e-1-sulfonyl}-ethyl)-amide
[0150] LRMS: 451.
EXAMPLE 21
Tetrahydro-furan-3-carboxylic acid
(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-
e-1-sulfonyl}-ethyl)-amide
[0151] LRMS: 451.
EXAMPLE 22
{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-y-
l}-(tetrahydro-furan-2-yl)-methanone
[0152] LRMS: 344.
EXAMPLE 23
{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-y-
l}-(tetrahydro-furan-3-yl)-methanone
[0153] LRMS: 344.
EXAMPLE 24
Cyclohexanecarboxylic acid
(3-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-
-1-yl}-3-oxo-propyl)-amide
[0154] LRMS: 427.
EXAMPLE 25
2-Cyclopropyl-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amin-
o]-piperidin-1-yl}-ethanone
[0155] LRMS: 328.
EXAMPLE 26
2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine--
1-carbonyl}-pyrrolidine-1-carboxylic acid tert-butyl ester
[0156] LRMS: 443.
EXAMPLE 27
{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-y-
l}-pyrrolidin-2-yl-methanone
[0157] LRMS: 343.
EXAMPLE 28
1-(2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidi-
ne-1-carbonyl}-pyrrolidin-1-yl)-ethanone hydrochloride
[0158] LRMS: 385.
EXAMPLE 29
Furan-3-yl-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-pi-
peridin-1-yl}-methanone
[0159] LRMS: 340.
EXAMPLE 30
{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1yl-
}-pyridin-2-yl-methanone
[0160] LRMS: 351.
EXAMPLE 31
{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-y-
l}-phenyl-methanone
[0161] LRMS: 350.
EXAMPLE 32
1-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-
-yl}-2-phenyl-ethanone
[0162] LRMS: 364.
EXAMPLE 33
2-Cyclopropyl-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amin-
o]-piperidin-1-yl}-ethanone hydrochloride
[0163] LRMS: 364.
EXAMPLE 34
2-{4-Methyl-3[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-
-carbonyl}-pyrrolidine-1-carboxylic acid tert-butyl ester
[0164] LRMS: 443.
EXAMPLE 35
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl-amino]-piperidine-1-ca-
rboxylic acid benzylamide
[0165] LRMS: 379.
EXAMPLE 36
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid phenylamide
[0166] LRMS: 365.
EXAMPLE 37
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid tetrahydro-furan-3-yl ester
[0167] LRMS: 360.
EXAMPLE 38
1-(4-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidi-
ne-1-carbonyl}-piperidin-1-yl)-ethanone
[0168] LRMS: 399.
EXAMPLE 39
2-Cyclopentyl-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amin-
o]-piperidin-1-yl}-ethanone
[0169] LRMS: 356.
EXAMPLE 40
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid cyclohexylamide
[0170] LRMS: 371.
EXAMPLE 41
Azetidin-3-yl-{4-methyl-3-[methyl-(7pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-p-
iperidin-1-yl}-methanone trifluoroacetate
[0171] LRMS: 443.
EXAMPLE 42
{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-y-
l}-pyrrolidin-1-yl-methanone
[0172] LRMS: 343.
EXAMPLE 43
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid methyl-phenyl-amide
[0173] LRMS: 379.
EXAMPLE 44
{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-y-
l}-morpholin-4-yl-methanone
[0174] LRMS: 359.
EXAMPLE 45
Methyl-(4-methyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-3-yl)-(7H-pyrrolo-
[2,3-d]pyrimidin-4-yl)-amine
[0175] LRMS: 323.
EXAMPLE 46
Methyl-(4-methyl-1-thiazol-2-yl-piperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidi-
n-4-yl)-amine
[0176] LRMS: 329.
EXAMPLE 47
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid pyridin-3-ylamide
[0177] LRMS: 366.
EXAMPLE 48
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (4-fluoro-phenyl)-amide
[0178] LRMS: 383.
EXAMPLE 49
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (4-nitro-phenyl)-amide
[0179] LRMS: 410.
EXAMPLE 50
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (4-methoxy-phenyl)-amide
[0180] LRMS: 395.
EXAMPLE 51
4-({4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-
-1-carbonyl}-amino)-benzoic acid ethyl ester
[0181] LRMS: 437.
EXAMPLE 52
{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-y-
l}-piperidin-1-yl-methanone
[0182] LRMS: 357.
EXAMPLE 53
Methyl-(4-methyl-5'-nitro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-3-yl)-(7-
H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine
[0183] LRMS: 368.
EXAMPLE 54
4-Methyl-3-[methyl-(7H
-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid
(3-fluoro-phenyl)-amide
[0184] LRMS: 383.
EXAMPLE 55
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-piperidine-1-ca-
rboxylic acid (2,4-difluoro-phenyl)-amide
[0185] LRMS: 401.
EXAMPLE 56
Methyl-[4-methyl-1-(pyrrolidine-1-sulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,-
3-d]pyrimidin-4-yl)-amine
[0186] LRMS: 379.
EXAMPLE 57
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (3-methoxy-phenyl)-amide
[0187] LRMS: 395.
EXAMPLE 58
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (3-nitro-phenyl)-amide.
[0188] LRMS: 410.
EXAMPLE 59
1-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine--
1-carbonyl}-pyrrolidine-2-carboxylic acid methyl ester
[0189] LRMS: 401.
EXAMPLE 60
Methyl-[4-methyl-1-(5-nitro-thiazol-2-yl)-piperidin-3-yl]-(7H-pyrrolo[2,3--
d]pyrimidin-4-yl)-amine
[0190] LRMS: 374.
EXAMPLE 61
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-3,4,5,6,-tetra-
hydro-2H-[1,2']bipyridinyl-5'-carboxylic acid methyl ester
[0191] LRMS: 381.
EXAMPLE 62
{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-3,4,5,6-tetra-
hydro-2H-[1,2']bipyridinyl-5'-yl)-methanol
[0192] LRMS: 353.
EXAMPLE 63
Methyl-[4-methyl-1-(piperidine-1-sulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-
-d]pyrimidin-4-yl)-amino
[0193] LRMS: 393.
EXAMPLE 64
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (3-cyano-phenyl)-amide
[0194] LRMS: 390.
EXAMPLE 65
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (3,4-difluoro-phenyl)-amide
[0195] LRMS: 401.
EXAMPLE 66
Methyl-[4-methyl-1-(morpholine-4-sulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-
-d]pyrimidin-4-yl)-amine
[0196] LRMS: 395.
EXAMPLE 67
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (4-chloro-phenyl)-amide
[0197] LRMS: 399.
EXAMPLE 68
Methyl-[4-methyl-1-(6-methyl-pyridazin-3-yl)-piperidin-3yl]-(7H-pyrrolo[2,-
3-d]pyrimidin-4-yl)-amine
[0198] LRMS: 338.
EXAMPLE 69
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (4-cyano-phenyl)-amide
[0199] LRMS: 390.
EXAMPLE 70
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid biphenyl-4ylamide
[0200] LRMS: 441.
EXAMPLE 71
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (4-trifluoromethyl-phenyl)-amide
[0201] LRMS: 433.
EXAMPLE 72
Methyl-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-pip-
eridine-1-sulfonyl}-ethyl)-carbamic acid benzyl ester
[0202] LRMS: 501.
EXAMPLE 73
Cyclopropyl-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-p-
iperidin-1-yl}-methanone
[0203] LRMS: 314.
EXAMPLE 74
Cyclobutyl-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-pi-
peridin-1-yl}-methanone
[0204] LRMS: 328.
EXAMPLE 75
Tetrahydro-furan-3-carboxylic acid
methyl-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-pi-
peridine-1-sulfonyl}-ethyl)-amide
[0205] LRMS: 465.
EXAMPLE 76
Cyclohexanecarboxylic acid
methyl-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-pi-
peridine-1-sulfonyl}-ethyl)-amide
[0206] LRMS: 477.
EXAMPLE 77
(5,7-Dichloro-1H-indol-2-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimid-
in-4-yl)-amino]-piperidin-1-yl}-methanone
[0207] LRMS: 458.
EXAMPLE 78
4-({4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-
-1-carbonyl}-amino)-benzoic acid
[0208] LRMS: 409.
EXAMPLE 79
(1-Benzooxazol-2-yl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyri-
midin-4-yl)-amine
[0209] LRMS: 363.
EXAMPLE 80
(1H-Indol-2-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amin-
o]-piperidin-1-yl}-methanone
[0210] LRMS: 389.
EXAMPLE 81
(5-Fluoro-1H-indol-2-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-
-yl)-amino]-piperidin-1-yl}-methanone
[0211] LRMS: 407.
EXAMPLE 82
(5-Methoxy-3-methyl-benzofuran-2-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d-
]pyrimidin-4-yl)-amino]-piperidin-1-yl}-methanone
[0212] LRMS: 434.
EXAMPLE 83
(5-Chloro-benzofuran-2-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-
-4-yl)-amino]-piperidin-1-yl}-methanone
[0213] LRMS: 424.
EXAMPLE 84
{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-y-
l}-(5-nitro-benzofuran-2-yl)-methanone
[0214] LRMS: 435.
EXAMPLE 85
(5-Chloro-2,3-dihydro-benzofuran-2-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-
-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-methanone
[0215] LRMS: 426.
EXAMPLE 86
(4-Hydroxy-piperidin-1-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-
-4-yl)-amino]-piperidin-1-yl}-methanone
[0216] LRMS: 373.
EXAMPLE 87
1-(2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidi-
ne-1-carbonyl}-benzofuran-5-yl)-ethanone
[0217] LRMS: 432.
EXAMPLE 88
1-(3-Methyl-2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4yl)-amino]--
piperidine-1-carbonyl}-1H-Indol-5-yl)-ethanone
[0218] LRMS: 445.
EXAMPLE 89
[1-(5-Chloro-benzothiazol-2-yl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrol-
o[2,3-d]pyrimidin-4-yl)-amine
[0219] LRMS: 413.
EXAMPLE 90
(3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-
-1-carbonyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-carbamic acid tert-butyl
ester
[0220] LRMS: 470.
EXAMPLE 91
3-(4-Chloro-phenoxy)-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-y-
l)-amino]-piperidin-1yl}-propan-1-one
[0221] LRMS: 428.
EXAMPLE 92
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid pyridin-2-ylamide
[0222] LRMS: 366.
EXAMPLE 93
1-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine--
1-carbonyl}-piperidine-4-carboxylic acid amide hydrochloride
[0223] LRMS: 436.
EXAMPLE 94
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (5-chloro-pyridin-2-yl)-amide
[0224] LRMS: 400.
EXAMPLE 95
3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine--
1-carbonyl}-cyclopentanone
[0225] LRMS: 356.
EXAMPLE 96
(3-Hydroxy-cyclopentyl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4--
yl)-amino]-piperidin-1-yl}-methanone
[0226] LRMS: 358.
EXAMPLE 97
4-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine--
1-carbonyl}-cyclohexanone
[0227] LRMS: 370.
EXAMPLE 98
3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine--
1-carbonyl}-cyclohexanone
[0228] LRMS: 370.
EXAMPLE 99
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (5-nitro-pyridin-2-yl)-amide
[0229] LRMS: 413.
EXAMPLE 100
[4-({4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-
e-1-carbonyl}-amino)-phenyl]-acetic acid
[0230] LRMS: 423.
EXAMPLE 101
(4-Amino-piperidin-1-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-
-yl)-amino]-piperidin-1-yl}-methanone hydrochloride
[0231] LRMS: 408.
EXAMPLE 102
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (6-methyl-pyridin-2-yl)-amide
[0232] LRMS: 380.
EXAMPLE 103
1-Methyl-4-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-pi-
peridine-1-carbonyl}-pyrrolidin-2-one
[0233] LRMS: 371.
EXAMPLE 104
1-Benzyl-3-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-pi-
peridine-1-carbonyl}-pyrrolidin-2-one
[0234] LRMS: 447.
EXAMPLE 105
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (5-trifluoromethyl-pyridin-2-yl)-amide
[0235] LRMS: 434.
EXAMPLE 106
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-cyclohexanecar-
boxylic acid (4-cyano-phenyl)-amide
[0236] LRMS: 389.
EXAMPLE 107
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (4-carbamoyl-phenyl)-amide
[0237] LRMS: 408.
EXAMPLE 108
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (4-sulfamoyl-phenyl)-amide
[0238] LRMS: 444.
EXAMPLE 109
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (5-methyl-thiazol-2-yl)-amide
[0239] LRMS: 386.
EXAMPLE 110
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (5,6-dichloro-benzothiazol-2-yl)-amide
[0240] LRMS: 491.
EXAMPLE 111
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (4-methyl-thiazol-2-yl)-amide
[0241] LRMS: 386.
EXAMPLE 112
Azetidin-1-yl-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-
-piperidin-1-yl}-methanone hydrochloride
[0242] LRMS: 365.
EXAMPLE 113
[2-({4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-
e-1-carbonyl}-amino)-thiazol-4-yl]-acetic acid ethyl ester
[0243] LRMS: 458.
EXAMPLE 114
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (4,5-dimethyl-thiazol-2-yl)-amide
[0244] LRMS: 400.
EXAMPLE 115
[2-({4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-
e-1-carbonyl}-amino)-thiazol-4-yl]-acetic acid
[0245] LRMS: 430.
EXAMPLE 116
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid benzothiazol-2-ylamide
[0246] LRMS: 422.
EXAMPLE 117
4Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-ca-
rboxylic acid thiazol-2-ylamide
[0247] LRMS: 372.
EXAMPLE 118
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid
[6-(2-dimethylamino-ethylamino)-pyridin-3-yl]-amide
[0248] LRMS: 452.
EXAMPLE 119
N-(4-Chloro-phenyl)-2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl-
)-amino]-piperidin-1-yl}-acetamide
[0249] LRMS: 413.
EXAMPLE 120
N,N-Dimethyl-2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino-
]-piperidin-1-yl}-acetamide
[0250] LRMS: 331.
EXAMPLE 121
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid
[6-(2-pyrrolidin-1-yl-ethylamino)-pyridin-3-yl]amide
[0251] LRMS: 478.
EXAMPLE 122
{2-[5-({4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperi-
dine-1-carbonyl}-amino)-pyridin-2-yloxy]-ethyl}-carbamic acid
tert-butyl ester
[0252] LRMS: 525.
EXAMPLE 123
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid [6-(2-amino-ethoxy)-pyridin-3-yl]-amide
[0253] LRMS: 425.
EXAMPLE 124
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (4-methylsulfamoyl-phenyl)-amide
[0254] LRMS: 458.
EXAMPLE 125
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (4-methanesulfonyl-phenyl)-amide
[0255] LRMS: 443.
EXAMPLE 126
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (5-methyl-[1,3,4]thiadiazol-2yl)-amide
[0256] LRMS: 387.
EXAMPLE 127
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (4-methylsulfamoyl-phenyl)-amide hydrochloride
[0257] LRMS: 495.
EXAMPLE 128
Methyl-[4-methyl-1-(1-phenyl-ethyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyri-
midin-4-yl)-amine
[0258] LRMS: 350.
EXAMPLE 129
(3-Hydroxy-pyrrolidin-1-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidi-
n-4-yl)-amino]-piperidin-1-yl}-methanone
[0259] LRMS: 359.
EXAMPLE 130
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid tert-butyl ester
[0260] LRMS: 346.
EXAMPLE 131
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid [4-(2-dimethylamino-ethyl)-thiazol-2-yl]-amide
[0261] LRMS: 443.
EXAMPLE 132
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid 4-methanesulfonyl-benzylamide
[0262] LRMS: 457.
EXAMPLE 133
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (4-acetylsulfamoyl-phenyl)-amide.
[0263] LRMS: 486.
EXAMPLE 134
1-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-
-yl)}-2-phenyl-ethane-1,2-dione
[0264] LRMS: 378.
EXAMPLE 135
Methyl-[4-methyl-1-(6-methylamino-pyrimidin-4-yl)-piperidin-3-yl]-(7H-pyrr-
olo[2,3-d]pyrimidin-4-yl)-amine
[0265] LRMS: 353.
EXAMPLE 136
Methyl-[4-methyl-1-(6-pyrrolidin-1-yl-pyrimidin-4-yl)-piperidin-3-yl]-(7H--
pyrrolo[2,3-d]pyrimidin-4-yl)-amine
[0266] LRMS: 393.
EXAMPLE 137
[1-(6-Benzylamino-pyrimidin-4-yl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrr-
olo[2,3-d]pyrimidin-4-yl)-amine
[0267] LRMS: 429.
EXAMPLE 138
N,N-Dimethyl-N'-(6-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-a-
mino]-piperidin-1-yl}-pyrimidin-4-yl)-ethane-1,2-diamine
[0268] LRMS: 410.
EXAMPLE 139
[1-(6-Chloro-pyrimidin-4-yl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2-
,3-d]pyrimidin-4-yl)-amine
[0269] LRMS: 358.
EXAMPLE 140
[1-(2-Fluoro-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyr-
imidin-4-yl)-amine
[0270] LRMS: 354
EXAMPLE 141
[1-(2-Chloro-pyrimidin-4-yl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2-
,3-d]pyrimidin-4-yl)-amine
[0271] LRMS: 359.
EXAMPLE 142
[1-(4-Chloro-pyrimidin-2-yl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2-
,3-d]pyrimidin-4-yl)-amine
[0272] LRMS: 359.
EXAMPLE 143
Methyl-[4-methyl-1-(2-methylamino-pyrimidin-4-yl)-piperidin-3-yl]-(7H-pyrr-
olo[2,3-d]pyrimidin-4-yl)-amine
[0273] LRMS: 353.
EXAMPLE 144
Methyl-[4-methyl-1-(4-pyrrolidin-1-yl-pyrimidin-2-yl)-piperidin-3-yl]-(7H--
pyrrolo[2,3-d]pyrimidin-4-yl)-amine
[0274] LRMS: 353.
EXAMPLE 145
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (3-methyl-isoxazol-5-yl)-amide
[0275] LRMS: 370.
EXAMPLE 146
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (3-methyl-isoxazol-4-yl)-amide
[0276] LRMS: 370.
EXAMPLE 147
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (5-methyl-isoxazol-3-yl)-amide
[0277] LRMS: 370.
EXAMPLE 148
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide
[0278] LRMS: 412.
EXAMPLE 149
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid isoxazol-3-ylamide
[0279] LRMS: 356.
EXAMPLE 150
N-Methyl-3-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-pi-
peridin-1-yl}-propionamide
[0280] LRMS: 331.
EXAMPLE 151
1-{4-Methyl-3[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1--
yl}-propan-2-one
[0281] LRMS: 302.
EXAMPLE 152
{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-y-
l}-oxo-acetic acid methyl ester
[0282] LRMS: 332.
EXAMPLE 153
(1-Cyclohexylmethyl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyri-
midin-4-yl)-amine
[0283] LRMS: 342.
EXAMPLE 154
[1-(5-Amino-thiazol-2-yl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3--
d]pyrimidin-4-yl)-amine
[0284] LRMS: 344.
EXAMPLE 155
Methyl-(4-methyl-piperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4yl)-amine
[0285] LRMS: 246.
EXAMPLE 156
3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-
-yl}-3-oxo-propionic acid methyl ester
[0286] LRMS: 346.
EXAMPLE 157
(1-Benzenesulfonylmethyl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d-
]pyrimidin-4-yl)-amine
[0287] LRMS: 400.
EXAMPLE 158
(3-Hydroxy-pyrrolidin-1-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidi-
n-4-yl)-amino]-piperidin-1yl}-methanone
[0288] LRMS: 359.
EXAMPLE 159
1-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-
-yl}-propane-1,2-dione
[0289] LRMS: 316.
EXAMPLE 160
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (6-sulfamoyl-pyridin-3-yl)-amide
[0290] LRMS: 445.
EXAMPLE 161
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (6-acetylamino-pyridin-3-yl)-amide
[0291] LRMS: 423.
EXAMPLE 162
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid
[4-(2-dimethylamino-ethylsulfamoyl)-phenyl]-amide
[0292] LRMS: 515.
EXAMPLE 163
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4yl)-amino]-piperidine-1-ca-
rboxylic acid (6-cyano-pyridin-3-yl)-amide
[0293] LRMS: 391.
EXAMPLE 164
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-3,4,5,6,-tetra-
hydro-2H-[1,2']bipyridinyl-5'-sulfonic acid pyridin-2-ylamide
[0294] LRMS: 479.
EXAMPLE 165
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid [6-(pyrrolidine-1-carbonyl)-pyridin-3-yl]-amide
[0295] LRMS: 463.
EXAMPLE 166
2-Imidazol-1-yl-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-am-
ino]-piperidin-1-yl}-ethanone
[0296] LRMS: 354.
EXAMPLE 167
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-3,4,5,6-tetrah-
ydro-2H-[1,2']bipyridinyl-5'-carboxylic acid methylamide
[0297] LRMS: 380.
EXAMPLE 168
{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-3,4,5,6-tetra-
hydro-2H-[1,2']bipyridinyl-5'-yl}-morpholin-4-yl-methanone
[0298] LRMS: 436.
EXAMPLE 169
5-({4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-
-1-carbonyl}-amino)-pyridine-2-carboxylic acid propylamide
[0299] LRMS: 451.
EXAMPLE 170
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-3,4,5,6-tetrah-
ydro-2H-[1,2']bipyridinyl-5'-carboxylic acid amide
[0300] LRMS: 366.
EXAMPLE 171
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-3,4,5,6-tetrah-
ydro-2H-[1,2']bipyridinyl-5'-carbonitrile
[0301] LRMS: 348.
EXAMPLE 172
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid [4-(pyrrolidine-1-sulfonyl)-phenyl]-amide
[0302] LRMS: 498.
EXAMPLE 173
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid [4-(morpholine-4-sulfonyl)-phenyl]-amide
[0303] LRMS: 5.14.
EXAMPLE 174
(3-Hydroxy-pyrrolidin-1-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidi-
n-4-yl)-amino]-piperidin-1-yl}-methanone
[0304] LRMS: 359.
EXAMPLE 175
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid [6-(morpholine-4-carbonyl)-pyridin-3-yl]-amide
[0305] LRMS: 479.
EXAMPLE 176
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid [6-(morpholine-4-carbonyl)-pyridin-3-yl]-amide
[0306] LRMS: 479.
EXAMPLE 177
2-Imidazol-1-yl-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-am-
ino]-piperidin-1-yl}-ethanone
[0307] LRMS: 354.
EXAMPLE 178
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid isoxazol-3-ylamide
[0308] LRMS: 356.
EXAMPLE 179
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (2,5-dimethyl-2H-pyrazol-3-yl)-amide
[0309] LRMS: 383.
EXAMPLE 180
4-Methyl-3-[methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-ca-
rboxylic acid (5-cyclopropyl-2-methyl-2H-pyrazol-3-yl)-amide
[0310] LRMS: 409.
EXAMPLE 181
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (3-methyl-isothiazol-5-yl)-amide
[0311] LRMS: 386.
EXAMPLE 182
4-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-
-ylmethyl}-benzoic acid
[0312] LRMS: 380.
EXAMPLE 183
Methyl-[4-methyl-5'-(pyrrolidine-1-sulfonyl)-3,4,5,6-tetrahydro-2H-[1,2']b-
ipyridinyl-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine
[0313] LRMS: 456.
EXAMPLE 184
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-3,4,5,6-tetrah-
ydro-2H-[1,2']bipyridinyl-5'-sulfonic acid methylamide
[0314] LRMS: 416.
EXAMPLE 185
4-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-
ylmethyl}-benzenesulfonamide
[0315] LRMS: 415.
EXAMPLE 186
N-tert-Butyl-4-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino-
]-piperidin-1-ylmethyl}-benzenesulfonamide
[0316] LRMS: 472
EXAMPLE 187
1-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-
-yl}-2-pyrazol-1-yl-ethanone
[0317] LRMS: 354.
EXAMPLE 188
Methyl-[4-methyl-1-(5-nitro-benzooxazol-2-yl)-piperidin-3-yl]-(7H-pyrrolo[-
2,3-d]pyrimidin-4-yl)-amine
[0318] LRMS: 408.
EXAMPLE 189
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-3,4,5,6-tetrah-
ydro-2H-[1,2']bipyridinyl-5'-sulfonic acid
(2-hydroxy-ethyl)-amide
[0319] LRMS: 446.
EXAMPLE 190
N-tert-Butyl-4-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4yl)-amino]-
-piperidin-1-ylmethyl}-benzenesulfonamide
[0320] LRMS: 471.
EXAMPLE 191
N-Methyl-2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-pi-
peridin-1-yl}-2-oxo-acetamide
[0321] LRMS: 331.
EXAMPLE 192
[1-(5-Ethanesulfonyl-benzooxazol-2-yl)-4-methyl-piperidin-3-yl]-methyl-(7H-
-pyrrolo[2,3-d]pyrimidin-4-yl)-amine
[0322] LRMS: 455.
EXAMPLE 193
Methyl-[4-methyl-1-(5-methyl-benzooxazol-2-yl)-piperidin-3-yl]-(7H-pyrrolo-
[2,3-d]pyrimidin-4-yl)-amine
[0323] LRMS: 377.
EXAMPLE 194
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (6-chloro-pyridin-3-yl)-amide
[0324] LRMS: 400.
EXAMPLE 195
Methyl-(4-methyl-1-quinolln-2-yl-piperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimid-
in-4-yl)-amine
[0325] LRMS: 373.
EXAMPLE 196
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-3,4,5,6-tetrah-
ydro-2H-[1,2']bipyridinyl-5'-sulfonic acid amide
[0326] LRMS: 402.
EXAMPLE 197
1-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-
-yl}-2-pyrrolidin-1-yl-ethane-1,2-dione
[0327] LRMS: 371.
EXAMPLE 198
Methyl-[4-methyl-1-(4-methyl-benzooxazol-2-yl)-piperidin-3-yl]-(7H-pyrrolo-
[2,3-d]pyrimidin-4-yl)-amine
[0328] LRMS: 377.
EXAMPLE 199
1-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-
-yl}-2-morpholin-4-yl-ethane-1,2-dione
[0329] LRMS: 387.
EXAMPLE 200
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (6methanesulfonyl-pyridin-3-yl)-amide
[0330] LRMS: 444.
EXAMPLE 201
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (6-methanesulfonyl-pyridin-3-yl)-amide
[0331] LRMS: 444.
EXAMPLE 202
Methyl-[4-methyl-1-(6-nitro-benzooxazol-2-yl)-piperidin-3-yl]-(7H-pyrrolo[-
2,3-d]pyrimidin-4-yl)-amine
[0332] LRMS: 408.
EXAMPLE 203
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (6-methanesulfonyl-pyridin-3-yl)-amide
[0333] LRMS: 444.
EXAMPLE 204
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (6-methanesulfonyl-pyridin-3-yl)-amide
[0334] LRMS: 444.
EXAMPLE 205
Methyl-[4-methyl-1-(6-nitro-benzooxazol-2-yl)-piperidin-3-yl]-(7H-pyrrolo[-
2,3-d]pyrimidin-4-yl)-amine
[0335] LRMS: 408.
EXAMPLE 206
Methyl-[4-methyl-1-(toluene-3-sulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)-amine
[0336] LRMS: 400.
EXAMPLE 207
Methyl-[4-methyl-1-(4-trifluoromethyl-benzenesulfonyl)-piperidin-3-yl]-(7H-
-pyrrolo[2,3-d]pyrimidin-4-yl)-amine
[0337] LRMS: 454.
EXAMPLE 208
(1-Benzothiazol-2-yl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyr-
imidin-4-yl)-amine
[0338] LRMS: 379.
EXAMPLE 209
[1-(5,7-Dimethyl-benzooxazol-2-yl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyr-
rolo[2,3-d]pyrimidin-4-yl)-amine
[0339] LRMS: 391.
EXAMPLE 210
2-{4-Methyl-3-[methyl-(7H
-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-benzooxazole-6-carb-
oxylic acid methyl ester
[0340] LRMS: 421.
EXAMPLE 211
Methyl-[4-methyl-1-(6-methyl-benzooxazol-2-yl)-piperidin-3-yl]-(7H-pyrrolo-
[2,3-d]pyrimidin-4-yl)-amine
[0341] LRMS: 377.
EXAMPLE 212
[1-(6-Methoxy-benzooxazol-2-yl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrol-
o[2,3-d]pyrimidin-4-yl)-amine
[0342] LRMS: 393.
EXAMPLE 213
Methyl-[4-methyl-1-(5-trifluoromethyl-benzothiazol-2-yl)-piperidin-3-yl]-(-
7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine
[0343] LRMS: 447.
EXAMPLE 214
[1-(5,7-Dichloro-benzooxazol-2-yl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyr-
rolo[2,3-d]pyrimidin-4-yl)-amine
[0344] LRMS: 432.
EXAMPLE 215
[1-(6-Chloro-pyridine-3-sulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrr-
olo[2,3-d]pyrimidin-4-yl)-amine
[0345] LRMS: 422.
EXAMPLE 216
[1-(4-Chloro-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[-
2,3-d]pyrimidin-4-yl)-amine
[0346] LRMS: 421.
EXAMPLE 217
[1(4-Fluoro-benzenesulfonyl)-4-methyl-piperidin-3yl]-methyl-(7H-pyrrolo[2,-
3-d]pyrimidin-4-yl)-amine
[0347] LRMS: 404.
EXAMPLE 218
4-{4-Methyl-3-[methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-
-sulfonyl}-benzonitrile
[0348] LRMS: 411.
EXAMPLE 219
4-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine--
1-sulfonyl}-benzenesulfonyl fluoride
[0349] LRMS: 468.
EXAMPLE 220
2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine--
1-sulfonyl}-benzonitrile
[0350] LRMS: 411.
EXAMPLE 221
1-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-
-yl}-1yl}-2-tetrazol-1-yl-ethanone
[0351] LRMS: 356.
EXAMPLE 222
Methyl-[4-methyl-1-(2,2,2-trifluoro-ethanesulfonyl)-piperidin-3-yl]-(7H-py-
rrolo]2,3-d]pyrimidin-4-yl)-amine
[0352] LRMS: 392.
EXAMPLE 223
[1-(2,6-Difluoro-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrr-
olo[2,3-d]pyrimidin-4-yl)-amine
[0353] LRMS: 422.
EXAMPLE 224
[1-(4-tert-Butyl-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrr-
olo[2,3-d]pyrimidin-4yl)-amine
[0354] LRMS: 442.
EXAMPLE 225
[1-(2,4-Difluoro-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrr-
olo[2,3-d]pyrimidin-4-yl)-amine
[0355] LRMS: 422.
EXAMPLE 226
Methyl-[4-methyl-1-(2-trifluoromethyl-benzenesulfonyl)-piperidin-3-yl]-(7H-
-pyrrolo[2,3-d]pyrimidin-4-yl)-amine
[0356] LRMS: 454.
EXAMPLE 227
[1-(3,5-Bis-trifluoromethyl-benzenesulfonyl)-4-methyl-piperidin-3-yl]-meth-
yl-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-amine
[0357] LRMS: 522.
EXAMPLE 228
[1-(3,5-Dichloro-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrr-
olo[2,3-d]pyrimidin-4-yl)-amine
[0358] LRMS: 455.
EXAMPLE 229
4-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine--
1-sulfonyl}-benzoic acid
[0359] LRMS: 431.
EXAMPLE 230
[1-(6-Chloro-pyridine-3-sulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrr-
olo[2,3-d]pyrimidin-4-yl)-amine
[0360] LRMS: 422.
EXAMPLE 231
[1-(4-Chloro-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[-
2,3-d]pyrimidin-4-yl)-amine
[0361] LRMS: 421.
EXAMPLE 232
[1-(4-Fluoro-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[-
2,3-d]pyrimidin-4-yl)-amine
[0362] LRMS: 404.
EXAMPLE 233
4-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine--
1-sulfonyl}-benzonitrile
[0363] LRMS: 411.
EXAMPLE 234
4-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine--
1-sulfonyl}-benzenesulfonyl fluoride
[0364] LRMS: 468.
EXAMPLE 235
2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine--
1-sulfonyl}-benzonitrile
[0365] LRMS: 411.
EXAMPLE 236
1-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-
-yl}-2-tetrazol-1-yl-ethanone
[0366] LRMS: 356.
EXAMPLE 237
Methyl-[4-methyl-1-(2,2,2-trifluoro-ethanesulfonyl)-piperidin-3-yl]-(7H-py-
rrolo[2,3-d]pyrimidin-4-yl)-amine
[0367] LRMS: 392.
EXAMPLE 238
[1-(2,6-Difluoro-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrr-
olo[2,3-d]pyrimidin-4-yl)-amine
[0368] LRMS: 422.
EXAMPLE 239
[1-(4-tert-Butyl-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrr-
olo[2,3-d]pyrimidin-4-yl)-amine
[0369] LRMS: 442.
EXAMPLE 240
[1-(2,4-Difluoro-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrr-
olo[2,3-d]pyrimidin-4-yl)-amine
[0370] LRMS: 422.
EXAMPLE 241
Methyl-[4-methyl-1-(2-trifluoromethyl-benzenesulfonyl)-piperidin-3-yl]-(7H-
-pyrrolo[2,3d]pyrimidin-4-yl)-amine
[0371] LRMS: 454.
EXAMPLE 242
[1-(3,5-Bis-trifluoromethyl-benzenesulfonyl)-4-methyl-piperidin-3-yl]-meth-
yl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine
[0372] LRMS: 522.
EXAMPLE 243
[1-(3,5-Dichloro-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-7H-pyrro-
lo[2,3-d]pyrimidin-4-yl)-amine
[0373] LRMS: 455.
EXAMPLE 244
4-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine--
1-sulfonyl}-benzoic acid
[0374] LRMS: 431.
EXAMPLE 245
(3-Fluoro-phenyl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-am-
ino]-piperidin-1-yl}-methanone
[0375] LRMS: 368.
EXAMPLE 246
Isothiazol-4-yl-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amin-
o]-piperidin-1-yl}-methanone
[0376] LRMS: 357.
EXAMPLE 247
{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-y-
l}-thiophen-3-yl-methanone
[0377] LRMS: 356.
EXAMPLE 248
{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-y-
l}-(5-methyl-1H-pyrazol-3-yl)-methanone
[0378] LRMS: 354.
EXAMPLE 249
(5-Methyl-isoxazol-3-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-
-yl)-amino]-piperidin-1-yl}-methanone.
[0379] LRMS: 355.
EXAMPLE 250
{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-y-
l}-(5-methyl-thiophen-2-yl)-methanone
[0380] LRMS: 371.
EXAMPLE 251
(4-Fluoro-phenyl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-am-
ino]-piperidin-1-yl}-methanone
[0381] LRMS: 368.
EXAMPLE 252
Methyl-[4-methyl-1-(3-nitro-benzenesulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2-
,3-d]pyrimidin-4-yl)-amine
[0382] LRMS: 431.
EXAMPLE 253
[1-(3-Fluoro-benzenesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[-
2,3-d]pyrimidin-4-yl)-amine
[0383] LRMS: 404.
EXAMPLE 254
(2-Fluoro-phenyl)-(4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-am-
ino]-piperidin-1-yl}-methanone
[0384] LRMS: 368.
EXAMPLE 255
(1,5-Dimethyl-1H-pyrazol-3-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrim-
idin-4-yl)-amino]-piperidin-1-yl}-methanone
[0385] LRMS: 368.
EXAMPLE 256
{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-y-
l}-(2-methyl-thiazol-4-yl)-methanone
[0386] LRMS: 371.
EXAMPLE 257
{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-y-
l}-thiazol-4-yl-methanone
[0387] LRMS: 357.
EXAMPLE 258
(4-Methyl-isothiazol-5-yl)-{4-methyl-3-[methyl-(7H
-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-methanone
[0388] LRMS: 371.
EXAMPLE 259
2,2-Dimethyl-5-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-am-
ino]piperidin-1-yl}-2-oxo-ethyl)-[1,3]dioxolan-4-one
[0389] LRMS: 403.
EXAMPLE 260
2-Cyclopropyl-N-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-a-
mino]-piperidine-1-sulfonyl}-ethyl)-acetamide
[0390] LRMS: 436.
EXAMPLE 261
N-(2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidi-
ne-1-sulfonyl}-ethyl)-methanesulfonamide
[0391] LRMS: 432.
EXAMPLE 262
(3-Hydroxy-pyrrolidin-1-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidi-
n-4-yl)-amino]-piperidin-1-yl}-methanone
[0392] LRMS: 359.
EXAMPLE 263
4-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-
-ylmethyl}-benzonitrile
[0393] LRMS: 362.
EXAMPLE 264
3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine--
1-sulfonyl}-benzenesulfonyl fluoride
[0394] LRMS: 469.
EXAMPLE 265
2,2-Dimethyl-5-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-am-
ino]-piperidin-1-yl}-2-oxo-ethyl)-[1,3]dioxolan-4-one
[0395] LRMS: 402.
EXAMPLE 266
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid benzyl ester
[0396] LRMS: 381.
EXAMPLE 267
4-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-
-ylmethyl}-benzenesulfonamide
[0397] LRMS: 416.
EXAMPLE 268
[1-(1H-Imidazol-2-ylmethyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,-
3-d]pyrimidin-4-yl)-amine
[0398] LRMS: 326.
EXAMPLE 269
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid 2-chloro-benzyl ester
[0399] LRMS: 415.
EXAMPLE 270
Methyl-[4-methyl-1-(1-methyl-1H-imidazol-2-ylmethyl)-piperidin-3-yl]-(7H-p-
yrrolo[2,3-d]pyrimidin-4-yl)-amine
[0400] LRMS: 340.
EXAMPLE 271
1-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-
yl}-2-phenoxy-ethanone
[0401] LRMS: 380.
EXAMPLE 272
2-(4-Fluoro-phenoxy)-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-y-
l)-amino]-piperidin-1-yl}-ethanone
[0402] LRMS: 381.
EXAMPLE 273
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid 2,2,2-trichloro-ethyl ester
[0403] LRMS: 420.
EXAMPLE 274
2-(2-Chloro-phenoxy)-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-y-
l)-amino]-piperidin-1-yl}-ethanone
[0404] LRMS: 415.
EXAMPLE 275
2-(3-Chloro-phenoxy)-1-{4-methyl-3-[methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl-
)-amino]-piperidin-1-yl}-ethanone
[0405] LRMS: 415.
EXAMPLE 276
2-Methanesulfonyl-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)--
amino]-piperidin-1-yl}-ethanone
[0406] LRMS: 367.
EXAMPLE 277
2-(1,1-Dioxo-tetrahydro-1$I %
6&-thiophen-3-yl)-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-
-amino]-piperidin-1-yl}-ethanone
[0407] LRMS: 407.
EXAMPLE 278
Methyl-[4-methyl-1-(1-phenyl-ethyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyri-
midin-4-yl)-amine
[0408] LRMS: 351.
EXAMPLE 279
1-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-
}-2-(toluene-4-sulfonyl)-ethanone
[0409] LRMS: 443.
EXAMPLE 280
2-Hydroxy-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-p-
iperidin-1-yl}-ethanone
[0410] LRMS: 304.
EXAMPLE 281
1-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-
-yl}-3-nitro-propan-1-one
[0411] LRMS: 347.
EXAMPLE 282
5-(2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino[-piperidi-
n-1-yl}-2-oxo-ethyl)-thiazolidine-2,4-dione
[0412] LRMS: 404.
EXAMPLE 283
3-Hydroxy-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3d]pyrimidin-4-yl)-amino]-pi-
peridin-1yl}-propan-1-one
[0413] LRMS: 318.
EXAMPLE 284
N-(4-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidi-
n-1-yl}-4-oxo-butyl)-methanesulfonamide
[0414] LRMS: 410.
EXAMPLE 285
4-Methyl-3-[methyl-(7H
-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid
2,2-dimethyl-propyl ester
[0415] LRMS: 360.
EXAMPLE 286
1-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-
-yl}-2-(thiazolidine-3-sulfonyl)-ethanone
[0416] LRMS: 440.
EXAMPLE 287
(3,4-Dihydroxy-pyrrolidin-1-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyri-
midin-4-yl)-amino]-piperidin-1-yl}-methanone
[0417] LRMS: 376.
EXAMPLE 288
4-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine--
1-carbonyl}-thiazolidin-2-one
[0418] LRMS: 376
EXAMPLE 289
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid prop-2-ynyl ester
[0419] LRMS: 328.
EXAMPLE 290
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (2-cyano-ethyl)-amide
[0420] LRMS: 342.
EXAMPLE 291
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (2-cyano-ethyl)-amide
[0421] LRMS: 342.
EXAMPLE 292
1-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-cyclohexyl--
ethanone oxime
[0422] LRMS: 302.
EXAMPLE 293
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid cyanomethyl-methyl-amide
[0423] LRMS: 342.
EXAMPLE 294
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-yl)-amino]-piperidine-1-car-
boxylic acid isopropyl ester
[0424] LRMS: 332.
EXAMPLE 295
4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-c-
arboxylic acid (2-cyano-ethyl)-methyl-amide
[0425] LRMS: 356.
EXAMPLE 296
4-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-
-ylmethyl}-pyridin-1-ol
[0426] LRMS: 355.
EXAMPLE 297
{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-y-
l}-acetonitrile
[0427] LRMS: 285.
EXAMPLE 298
[1-(2-Fluoro-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyr-
imidin-4-yl)-amine
Method J
[0428] To a solution of the product from Method H (50 mg, mmols?)
dissolved in 5 mL of methanol was added 154 ul (mmols?) of
2-fluoro-benzaldehyde. The resulting mixture stirred at room
temperature for 4 hours, at which time, x mg (y mmol) of sodium
cyanoborohydride were added and the new mixture stirred at room
temperature for 18 hours. The reaction was quenched upon addition
of 2 drops of 1N NaOH (aq) and the mixture concentrated under
reduced pressure to remove the methanol. The residue was dissolved
in chloroform and washed with water. The aqueous layer was back
washed three times with chloroform, the combined chloroform
extracts dried over MgSO.sub.4 and concentrated to dryness in
vacuo. The crude product was then purified by flash chromatography
(silica; 2.5% methanol in chloroform) affording 36 mg (47.5%) of
the title compound as a white solid. LRMS: 372.4 (M+1).
[0429] The title compounds for examples 299-324 were prepared by
the method analogous to that described in Example 298.
EXAMPLE 299
(1-Benzyl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl-
)-amine
[0430] LRMS: 336.
EXAMPLE 300
(1-Furan-2-ylmethyl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyri-
midin-4-yl)-amine
[0431] LRMS: 326.
EXAMPLE 301
[1-(4-Methoxy-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]py-
rimidin-4-yl)-amine
[0432] LRMS: 366.
EXAMPLE 302
[1-(4-Fluoro-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyr-
imidin-4-yl)-amine
[0433] LRMS: 354.
EXAMPLE 303
Methyl-(4-methyl-1-pyridin-3-ylmethyl-piperidin-3-yl)-(7H-pyrrolo[2,3-d]py-
rimidin-4-yl)-amine
[0434] LRMS: 337.
EXAMPLE 304
Methyl-(4-methyl-1-thiazol-2-ylmethyl-piperidin-3-yl)-(7H-pyrrolo[2,3-d]py-
rimidin-4-yl)-amine
[0435] LRMS: 343.
EXAMPLE 305
Methyl-(4-methyl-1-pyridin-2-ylmethyl-piperidin-3-yl)-(7H-pyrrolo[2,3-d]py-
rimidin-4-yl)-amine
[0436] LRMS: 337.
EXAMPLE 306
Methyl-[4-methyl-1-(1phenyl-ethyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrim-
idin-4-yl)-amine
[0437] LRMS: 350.
EXAMPLE 307
(1-Benzyl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl-
)-amine
[0438] LRMS: 336.
EXAMPLE 308
(1-Benzyl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl-
)-amine
[0439] LRMS: 336.
EXAMPLE 309
3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-
-ylmethyl}-benzonitrile
[0440] LRMS: 361.
EXAMPLE 310
[1-(3-Fluoro-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyr-
imidin-4-yl)-amine
[0441] LRMS: 354.
EXAMPLE 311
[1-(3-Methoxy-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]py-
rimidin-4yl)-amine
[0442] LRMS: 366.
EXAMPLE 312
3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-
-ylmethyl}-benzoic acid
[0443] LRMS: 380.
EXAMPLE 313
[1-(2-Fluoro-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyr-
imidin-4-yl)-amine
[0444] LRMS: 354.
EXAMPLE 314
[1-(2,6-Difluoro-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d-
]pyrimidin-4-yl)-amine
[0445] LRMS: 372.
EXAMPLE 315
Methyl-(4-methyl-1-phenethyl-piperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-
-yl)-amine
[0446] LRMS: 350.
EXAMPLE 316
[1-(2,3-Difluoro-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d-
]pyrimidin-4-yl)-amine
[0447] LRMS: 372.
EXAMPLE 317
[1-(3,4-Difluoro-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d-
]pyrimidin-4-yl)-amine
[0448] LRMS: 372.
EXAMPLE 318
[1-(4-Methanesulfonyl-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[-
2,3-d]pyrimidin-4-yl)-amine
[0449] LRMS: 414.
EXAMPLE 319
Methyl-{4-methyl-1-[4-(piperidine-1-sulfonyl)-benzyl]-piperidin-3-yl}-(7H--
pyrrolo[2,3-d]pyrimidin-4-yl)-amine
[0450] LRMS: 483.
EXAMPLE 320
[1-(3,5-Difluoro-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d-
]pyrimidin-4-yl)-amine
[0451] LRMS: 372.
EXAMPLE 321
[1-(3-Chloro-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyr-
imidin-4-yl)-amine
[0452] LRMS: 371.
EXAMPLE 322
[1-(3,5-Difluoro-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d-
]pyrimidin-4-yl)-amine
[0453] LRMS: 372.
EXAMPLE 323
[1-(3-Chloro-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyr-
imidin-4-yl)-amine
[0454] LRMS: 371.
EXAMPLE 324
[1-(3,5-Dichloro-benzyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d-
]pyrimidin-4-yl)-amine
[0455] LRMS: 405.
* * * * *