U.S. patent application number 11/602176 was filed with the patent office on 2007-04-12 for fused-aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto.
This patent application is currently assigned to Arena Pharmaceuticlas, Inc.. Invention is credited to Imelda Calderon, Jin Sun Karoline Choi, Beatriz Fioravanti, Robert M. Jones, Albert S. Ren, Carleton R. Sage, Graeme Semple, Young-Jun Shin, Yifeng Xiong.
Application Number | 20070082874 11/602176 |
Document ID | / |
Family ID | 34083412 |
Filed Date | 2007-04-12 |
United States Patent
Application |
20070082874 |
Kind Code |
A1 |
Jones; Robert M. ; et
al. |
April 12, 2007 |
Fused-aryl and heteroaryl derivatives as modulators of metabolism
and the prophylaxis and treatment of disorders related thereto
Abstract
The present invention relates to certain fused aryl and
heteroaryl derivatives of Formula (I) that are modulators of
metabolism. ##STR1## Accordingly, compounds of the present
invention are useful in the prophylaxis or treatment of metabolic
disorders and complications thereof, such as, diabetes and
obesity.
Inventors: |
Jones; Robert M.; (San
Diego, CA) ; Semple; Graeme; (San Diego, CA) ;
Xiong; Yifeng; (San Diego, CA) ; Shin; Young-Jun;
(San Diego, CA) ; Ren; Albert S.; (San Diego,
CA) ; Calderon; Imelda; (San Diego, CA) ;
Fioravanti; Beatriz; (Tucson, AZ) ; Choi; Jin Sun
Karoline; (San Diego, CA) ; Sage; Carleton R.;
(Cardiff-by-the-Sea, CA) |
Correspondence
Address: |
COZEN O'CONNOR, P.C.
1900 MARKET STREET
PHILADELPHIA
PA
19103-3508
US
|
Assignee: |
Arena Pharmaceuticlas, Inc.
San Diego
CA
|
Family ID: |
34083412 |
Appl. No.: |
11/602176 |
Filed: |
November 20, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11355785 |
Feb 16, 2006 |
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11602176 |
Nov 20, 2006 |
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10890549 |
Jul 13, 2004 |
7132426 |
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11355785 |
Feb 16, 2006 |
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60487443 |
Jul 14, 2003 |
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60510644 |
Oct 10, 2003 |
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Current U.S.
Class: |
514/81 ;
514/262.1; 544/244; 544/262 |
Current CPC
Class: |
C07D 215/233 20130101;
A61P 3/08 20180101; A61P 5/50 20180101; A61P 3/10 20180101; C07D
471/04 20130101; A61P 3/00 20180101; A61P 3/04 20180101; C07D
487/04 20130101; A61P 43/00 20180101; C07D 473/00 20130101; A61P
3/06 20180101 |
Class at
Publication: |
514/081 ;
514/262.1; 544/244; 544/262 |
International
Class: |
A61K 31/519 20060101
A61K031/519; A61K 31/675 20060101 A61K031/675; C07F 9/6512 20060101
C07F009/6512; C07D 487/04 20060101 C07D487/04 |
Claims
1. A compound of Formula (I): ##STR739## or a pharmaceutically
acceptable salt, hydrate or solvate thereof; wherein: A and B are
each independently C.sub.1-3 alkylene optionally substituted with 1
to 4 substituents selected from the group consisting of C.sub.1-3
alkyl, C.sub.1-4 alkoxy, carboxy, cyano, C.sub.1-3 haloalkyl and
halogen; D is O, S, S(O), S(O).sub.2, CR.sub.1R.sub.2 or
N--R.sub.2, wherein R.sub.1 is selected from the group consisting
of H, C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogen and hydroxyl; E is
N, C or CR.sub.3, wherein R.sub.3 is H or C.sub.1-8 alkyl; - - - is
a single bond when E is N or CR.sub.3, or a double bond when E is
C; K is a C.sub.3-6 cycloalkylene or C.sub.1-3 alkylene wherein
each are optionally substituted with 1 to 4 substituents selected
from the group consisting of C.sub.1-3 alkyl, C.sub.1-4 alkoxy,
carboxy, cyano, C.sub.1-3 haloalkyl and halogen; or K is a bond; Q
is NR.sub.4, O, S, S(O) or S(O).sub.2, wherein R.sub.4 is H or
C.sub.1-8 alkyl and the C.sub.1-8 alkyl is optionally substituted
with C.sub.2-8 dialkylamine; T is N or CR.sub.5; M is N or
CR.sub.6; J is N or CR.sub.7; U is C or N; V is N, CR.sub.8 or V is
a bond; W is N or C; X is O, S, N, CR.sub.9 or NR.sub.11; Y is O,
S, N, CR.sub.10 or NR.sub.12; Z is C or N; R.sub.5, R.sub.6,
R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are each independently
selected from the group consisting of H, C.sub.1-5 acyloxy,
C.sub.2-6 alkenyl, C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4
alkylcarboxamide, C.sub.2-6 alkynyl, C.sub.1-4 alkylsulfonamide,
C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4
alkylthio, C.sub.1-4 alkylureyl, amino, C.sub.1-4 alkylamino,
C.sub.2-8 dialkylamino, carboxamide, cyano, C.sub.3-6 cycloalkyl,
C.sub.2-6 dialkylcarboxamide, C.sub.2-6 dialkylsulfonamide,
halogen, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkylsulfinyl, C.sub.1-4 haloalkylsulfonyl, C.sub.1-4
haloalkylthio, hydroxyl, hydroxylamino and nitro; wherein said
C.sub.2-6 alkenyl, C.sub.1-8 alkyl, C.sub.2-6 alkynyl and C.sub.3-6
cycloalkyl are optionally substituted with 1, 2, 3 or 4
substituents selected from the group consisting of C.sub.1-5 acyl,
C.sub.1-5 acyloxy, C.sub.1-4 alkoxy, C.sub.1-4 alkylamino,
C.sub.1-4 alkylcarboxamide, C.sub.1-4 alkylthiocarboxamide,
C.sub.1-4 alkylsulfonamide, C.sub.1-4 alkylsulfinyl, C.sub.1-4
alkylsulfonyl, C.sub.1-4 alkylthio, C.sub.1-4 alkylthioureyl,
C.sub.1-4 alkylureyl, amino, carbo-C.sub.1-6-alkoxy, carboxamide,
carboxy, cyano, C.sub.2-8 dialkylamino, C.sub.2-6
dialkylcarboxamide, C.sub.1-4 dialkylthiocarboxamide, C.sub.2-6
dialkylsulfonamide, C.sub.1-4 alkylthioureyl, C.sub.1-4 haloalkoxy,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylsulfinyl, C.sub.1-4
haloalkylsulfonyl, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylthio,
halogen, hydroxyl, hydroxylamino and nitro; R.sub.11 and R.sub.12
are each independently selected from C.sub.2-6 alkenyl, C.sub.1-8
alkyl, C.sub.2-6 alkynyl or C.sub.3-6 cycloalkyl each optionally
substituted with 1, 2, 3 or 4 substituents selected from the group
consisting of C.sub.1-5 acyl, C.sub.1-5 acyloxy, C.sub.1-4 alkoxy,
C.sub.1-4 alkylamino, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylthiocarboxamide, C.sub.1-4 alkylsulfonamide, C.sub.1-4
alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
C.sub.1-4 alkylthioureyl, C.sub.1-4 alkylureyl, amino,
carbo-C.sub.1-6-alkoxy, carboxamide, carboxy, cyano, C.sub.2-8
dialkylamino, C.sub.2-6 dialkylcarboxamide, C.sub.1-4
dialkylthiocarboxamide, C.sub.2-6 dialkylsulfonamide, C.sub.1-4
alkylthioureyl, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkylsulfinyl, C.sub.1-4 haloalkylsulfonyl, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkylthio, halogen, hydroxyl,
hydroxylamino and nitro; Ar.sub.1 is aryl or heteroaryl each
optionally substituted with R.sub.13, R.sub.14, R.sub.15, R.sub.16,
and R.sub.17; wherein R.sub.13 is selected from the group
consisting of C.sub.1-5 acyl, C.sub.1-6 acylsulfonamide, C.sub.1-5
acyloxy, C.sub.2-6 alkenyl, C.sub.1-4 alkoxy, C.sub.1-8 alkyl,
C.sub.1-4 alkylamino, C.sub.1-6 alkylcarboxamide, C.sub.1-4
alkylthiocarboxamide, C.sub.2-6 alkynyl, C.sub.1-4
alkylsulfonamide, C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl,
C.sub.1-4 alkylthio, C.sub.1-4 alkylthioureyl, C.sub.1-4
alkylureyl, amino, arylsulfonyl, carbamimidoyl,
carbo-C.sub.1-6-alkoxy, carboxamide, carboxy, cyano, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkyloxy, C.sub.2-6 dialkylamino,
C.sub.2-6 dialkylcarboxamide, C.sub.2-6 dialkylthiocarboxamide,
guanidinyl, halogen, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkylsulfinyl, C.sub.1-4 haloalkylsulfonyl, C.sub.1-4
haloalkylthio, heterocyclic, heterocyclic-oxy,
heterocyclicsulfonyl, heterocyclic-carbonyl, heteroaryl,
heteroarylcarbonyl, hydroxyl, nitro, C.sub.4-7 oxo-cycloalkyl,
phenoxy, phenyl, sulfonamide, sulfonic acid, and thiol, and wherein
said C.sub.1-5 acyl, C.sub.1-6 acylsulfonamide, C.sub.1-4 alkoxy,
C.sub.1-8 alkyl, C.sub.1-4 alkylamino, C.sub.1-6 alkylsulfonamide,
C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio, arylsulfonyl,
carbamimidoyl, C.sub.2-6 dialkylamino, heterocyclic,
heterocyclic-carbonyl, heteroaryl, phenoxy and phenyl are
optionally substituted with 1 to 5 substituents selected
independently from the group consisting of C.sub.1-5 acyl,
C.sub.1-5 acyloxy, C.sub.2-6 alkenyl, C.sub.1-4 alkoxy, C.sub.1-7
alkyl, C.sub.1-4 alkylamino, C.sub.1-4 alkylcarboxamide, C.sub.2-6
alkynyl, C.sub.1-4 alkylsulfonamide, C.sub.1-4 alkylsulfinyl,
C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio, C.sub.1-4 alkylureyl,
carbo-C.sub.1-6-alkoxy, carboxamide, carboxy, cyano, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkyloxy, C.sub.2-6 dialkylamino,
C.sub.2-6 dialkylcarboxamide, halogen, C.sub.1-4 haloalkoxy,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylsulfinyl, C.sub.1-4
haloalkylsulfonyl, C.sub.1-4 haloalkylthio, heteroaryl,
heterocyclic, hydroxyl, nitro, phenyl, and phosphonooxy, and
wherein said C.sub.1-7 alkyl and C.sub.1-4 alkylcarboxamide are
each optionally substituted with 1 to 5 substituents selected from
the group consisting of C.sub.1-4 alkoxy and hydroxy; or R.sub.13
is a group of Formula (A): ##STR740## wherein: "p" and "r" are
independently 0, 1, 2 or 3; and R.sub.18 is H, C.sub.1-5 acyl,
C.sub.2-6 alkenyl, C.sub.1-8 alkyl, C.sub.1-4 alkylcarboxamide,
C.sub.2-6 alkynyl, C.sub.1-4 alkylsulfonamide,
carbo-C.sub.1-6-alkoxy, carboxamide, carboxy, cyano, C.sub.3-7
cycloalkyl, C.sub.2-6 dialkylcarboxamide, halogen, heteroaryl or
phenyl, and wherein said heteroaryl or phenyl optionally
substituted with 1 to 5 substituents selected independently from
the group consisting of C.sub.1-4 alkoxy, amino, C.sub.1-4
alkylamino, C.sub.2-6 alkynyl, C.sub.2-8 dialkylamino, halogen,
C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl and hydroxyl; R.sub.14,
R.sub.15, R.sub.16, and R.sub.17 are each independently selected
form the group consisting of H, C.sub.1-5 acyl, C.sub.1-5 acyloxy,
C.sub.2-6 alkenyl, C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4
alkylcarboxamide, C.sub.2-6 alkynyl, C.sub.1-4 alkylsulfonamide,
C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4
alkylthio, C.sub.1-4 alkylureyl, carbo-C.sub.1-6-alkoxy,
carboxamide, carboxy, cyano, C.sub.3-7 cycloalkyl, C.sub.2-6
dialkylcarboxamide, halogen, C.sub.1-4 haloalkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkylsulfinyl, C.sub.1-4
haloalkylsulfonyl, C.sub.1-4 haloalkylthio, hydroxyl and nitro; or
two adjacent R.sub.14, R.sub.15, R.sub.16 and R.sub.17 together
with the atoms to which they are attached form a 5, 6 or 7 member
cycloalkyl, cycloalkenyl or heterocyclic group fused with Ar.sub.1
wherein the 5, 6 or 7 member group is optionally substituted with
halogen; and R.sub.2 is selected from the group consisting of
C.sub.1-8 alkyl, C.sub.2-6 alkynyl, amino, aryl, carboxamide,
carboxy, cyano, C.sub.3-6-cycloalkyl, C.sub.1-4 haloalkoxy,
C.sub.1-4 haloalkyl, halogen, heteroaryl and hydroxyl; and wherein
said C.sub.1-8 alkyl, aryl and heteroaryl are each optionally
substituted with 1 to 5 substituents selected from the group
consisting of C.sub.1-5 acyl, C.sub.1-5 acyloxy, C.sub.1-4 alkoxy,
C.sub.1-8 alkyl, C.sub.1-4 alkylamino, C.sub.1-4 alkylcarboxamide,
C.sub.1-4 alkylthiocarboxamide, C.sub.1-4 alkylsulfonamide,
C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4
alkylthio, C.sub.1-4 alkylthioureyl, C.sub.1-4 alkylureyl, amino,
carbo-C.sub.1-6-alkoxy, carboxamide, carboxy, cyano,
C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-heteroalkylene, C.sub.2-8
dialkylamino, C.sub.2-6 dialkylcarboxamide, C.sub.2-6
dialkylthiocarboxamide, C.sub.2-6 dialkylsulfonamide, C.sub.1-4
alkylthioureyl, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkylsulfinyl, C.sub.1-4 haloalkylsulfonyl, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkylthio, halogen, heterocyclic,
hydroxyl, hydroxylamino and nitro; or R.sub.2 is
--Ar.sub.2--Ar.sub.3 wherein Ar.sub.2 and Ar.sub.3 are each
independently aryl or heteroaryl each optionally substituted with 1
to 5 substituents selected from the group consisting of H,
C.sub.1-5 acyl, C.sub.1-5 acyloxy, C.sub.1-4 alkoxy, C.sub.1-8
alkyl, C.sub.1-4 alkylcarboxamide, C.sub.1-4 alkylthiocarboxamide,
C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4
alkylthio, amino, C.sub.1-4 alkylamino, carbo-C.sub.1-6-alkoxy,
carboxamide, carboxy, cyano, C.sub.3-6-cycloalkyl, C.sub.2-8
dialkylamino, C.sub.2-6 dialkylcarboxamide, C.sub.1-4 haloalkoxy,
C.sub.1-4 haloalkyl, halogen, hydroxyl and nitro; or R.sub.2 is a
group of Formula (B): ##STR741## wherein: R.sub.19 is H, C.sub.1-8
alkyl, C.sub.3-7 cycloalkyl, aryl, heteroaryl or OR.sub.21; and
R.sub.20 is F, Cl, Br, CN or NR.sub.22R.sub.23; where R.sub.21 is
H, C.sub.1-8 alkyl or C.sub.3-7 cycloalkyl, and R.sub.22 and
R.sub.23 are independently H, C.sub.1-8 alkyl, C.sub.3-7
cycloalkyl, aryl or heteroaryl; or R.sub.2 is a group of Formula
(C): ##STR742## wherein: G is: i) --C(O)--, --C(O)NR.sub.25--,
--NR.sub.25C(O)--, --NR.sub.25--, --NR.sub.25C(O)O--,
--OC(O)NR.sub.25--, --CR.sub.25R.sub.26NR.sub.27C(O)--,
--CR.sub.25R.sub.26C(O)NR.sub.27--, --C(O)O--, --OC(O)--, --C(S)--,
--C(S)NR.sub.25--, --C(S)O--, --OC(S)--, --CR.sub.25R.sub.26--,
--O--, --S--, --S(O)--, --S(O).sub.2-- or a bond when D is
CR.sub.2R.sub.3; or ii) --CR.sub.25R.sub.26C(O)--, --C(O)--,
--CR.sub.25R.sub.26C(O)NR.sub.27--, --C(O)NR.sub.25--, --C(O)O--,
--C(S)--, --C(S)NR.sub.25--, --C(S)O--, --CR.sub.25R.sub.26--,
--S(O).sub.2--, or a bond when D is NR.sub.2; wherein R.sub.25,
R.sub.26 and R.sub.27 are each independently H or C.sub.1-8 alkyl;
and R.sub.24 is H, C.sub.1-8 alkyl, C.sub.3-7 cycloalkyl, phenyl,
heteroaryl, or heterocyclic each optionally substituted with 1 to 5
substituents selected from the group consisting of C.sub.1-5 acyl,
C.sub.1-5 acyloxy, C.sub.2-6 alkenyl, C.sub.1-4 alkoxy, C.sub.1-7
alkyl, C.sub.1-4 alkylamino, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylthiocarboxamide, C.sub.1-4 alkylsulfonamide, C.sub.1-4
alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
C.sub.1-4 alkylthioureyl, C.sub.1-4 alkylureyl, amino,
carbo-C.sub.1-6-alkoxy, carboxamide, carboxy, cyano, C.sub.3-7
cycloalkyl, C.sub.2-8 dialkylamino, C.sub.2-6 dialkylcarboxamide,
C.sub.2-6 dialkylthiocarboxamide, C.sub.2-6 dialkylsulfonamide,
C.sub.1-4 alkylthioureyl, C.sub.1-4 haloalkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkylsulfinyl, C.sub.1-4
haloalkylsulfonyl, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylthio,
halogen, heteroaryl, heterocyclic, hydroxyl, hydroxylamino, nitro,
phenyl, phenoxy, and sulfonic acid, wherein said C.sub.1-4 alkoxy,
C.sub.1-7 alkyl, C.sub.1-4 alkylamino, heteroaryl, phenyl and
phenoxy are each optionally substituted with 1 to 5 substituents
selected from the group consisting of C.sub.1-5 acyl, C.sub.1-5
acyloxy, C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4 alkylamino,
C.sub.1-4 alkylcarboxamide, C.sub.1-4 alkylthiocarboxamide,
C.sub.1-4 alkylsulfonamide, C.sub.1-4 alkylsulfinyl, C.sub.1-4
alkylsulfonyl, C.sub.1-4 alkylthio, C.sub.1-4 alkylthioureyl,
C.sub.1-4 alkylureyl, amino, carbo-C.sub.1-6-alkoxy, carboxamide,
carboxy, cyano, C.sub.3-7 cycloalkyl, C.sub.2-8 dialkylamino,
C.sub.2-6 dialkylcarboxamide, C.sub.2-6 dialkylthiocarboxamide,
C.sub.2-6 dialkylsulfonamide, C.sub.1-4 alkylthioureyl, C.sub.1-4
haloalkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylsulfinyl,
C.sub.1-4 haloalkylsulfonyl, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkylthio, halogen, heterocyclic, hydroxyl, hydroxylamino,
nitro, and phenyl; provided that Z and U are not both N.
2. The compound according to claim 1 wherein: M, J, X, and W are
all N; T is CR.sub.5; Y is CR.sub.10; V is a bond; and Z and U are
both C.
3. The compound according to claim 1 wherein: M, J, X, and W are
all N; T is CR.sub.5, wherein R.sub.5 is --H, --CH.sub.3, or
--N(CH.sub.3).sub.2; Y is CR.sub.10, wherein R.sub.10 is --H or
--CH.sub.3; V is a bond; and Z and U are both C.
4. The compound according to claim 1 wherein: M, J, X, and W are
all N; T is C--H; Y is C--H; V is a bond; and Z and U are both
C.
5. The compound according to claim 1 wherein is a single bond.
6. The compound according to claim 1 wherein Q is O.
7. The compound according to claim 1 wherein Q is S, S(O) or
S(O).sub.2.
8. The compound according to claim 1 wherein Q is NR.sub.4.
9. The compound according to claim 1 wherein R.sub.4 is C.sub.1-8
alkyl optionally substituted with C.sub.2-8 dialkylamino.
10. The compound according to claim 1 wherein R.sub.4 is selected
from the group consisting of methyl, ethyl, isopropyl, and
2-dimethylamino-ethyl.
11. The compound according to claim 1 wherein R.sub.4 is H.
12. The compound according to claim 1 wherein K is selected from
the group consisting of --CH.sub.2--, --CH.sub.2CH.sub.2--, and
--CH(CH.sub.3)CH.sub.2--.
13. The compound according to claim 1 wherein K is a bond.
14. The compound according to claim 1 wherein both A and B are
--CH.sub.2--.
15. The compound according to claim 1 wherein A is
--CH.sub.2CH.sub.2-- and B is --CH.sub.2--.
16. The compound according to claim 1 wherein both A and B are
--CH.sub.2CH.sub.2--.
17. The compound according to claim 1 wherein A is --CH.sub.2-- and
B is --CH.sub.2CH.sub.2CH.sub.2--.
18. The compound according to claim 1 wherein E is CH and D is
N--R.sub.2.
19. The compound according to claim 1 wherein E is CH and D is
CHR.sub.2.
20. The compound according to claim 1 wherein R.sub.2 is a group of
Formula (C): ##STR743## wherein G is: --NHC(O)--, --NH--,
--NHC(O)O--, --CH.sub.2NHC(O)--, or a bond; and R.sub.24 is H,
C.sub.1-8 alkyl, or heteroaryl, each optionally substituted with 1
to 2 substituents selected from the group consisting of C.sub.1-4
alkoxy, and C.sub.1-7 alkyl.
21. The compound according to claim 1 wherein R.sub.2 is of Formula
(C): ##STR744## wherein: G is --CR.sub.25R.sub.26C(O)--, --C(O)--,
--C(O)NR.sub.25--, --C(O)O--, --C(S)NR.sub.25--,
--CR.sub.25R.sub.26--, or a bond, wherein R.sub.25, and R.sub.26
are each independently H or C.sub.1-8 alkyl; and R.sub.24 is H,
C.sub.1-8 alkyl, C.sub.3-7 cycloalkyl, phenyl, heteroaryl, or
heterocyclic each optionally substituted with 1 to 5 substituents
selected from the group consisting of C.sub.1-4 alkoxy, C.sub.1-7
alkyl, C.sub.1-4 alkylamino, amino, carbo-C.sub.1-6-alkoxy,
carboxy, C.sub.3-7 cycloalkyl, C.sub.2-8 dialkylamino, C.sub.1-4
haloalkoxy, C.sub.1-4 haloalkyl, halogen, heteroaryl, heterocyclic,
hydroxyl, and nitro, wherein said C.sub.1-4 alkoxy, C.sub.1-7
alkyl, C.sub.1-4 alkylamino, heteroaryl, and phenyl are each
optionally substituted with 1 to 5 substituents selected from the
group consisting of C.sub.1-4 alkoxy, carbo-C.sub.1-6-alkoxy,
carboxamide, carboxy, C.sub.3-7 cycloalkyl, halogen, heterocyclic,
and phenyl.
22. The compound according to claim 1 wherein R.sub.2 is
--C(O)OR.sub.24 and R.sub.24 is C.sub.1-8 alkyl, C.sub.3-7
cycloalkyl, phenyl, heteroaryl, or heterocyclic each optionally
substituted with 1 to 5 substituents selected from the group
consisting of C.sub.1-4 alkoxy, C.sub.1-7 alkyl, C.sub.1-4
alkylsulfonyl, amino, carbo-C.sub.1-6-alkoxy, carboxy, cyano,
C.sub.3-7 cycloalkyl, C.sub.2-8 dialkylamino, C.sub.1-4 haloalkoxy,
C.sub.1-4 haloalkyl, halogen, heteroaryl, heterocyclic, hydroxyl,
phenyl, phenoxy, and sulfonic acid, wherein said C.sub.1-7 alkyl,
phenyl and phenoxy are each optionally substituted with 1 to 5
substituents selected from the group consisting of amino, C.sub.1-4
haloalkoxy, and heterocyclic.
23. The compound according to claim 1 wherein R.sub.2 is
--C(O)OR.sub.24 and R.sub.24 is C.sub.1-8 alkyl, or C.sub.3-7
cycloalkyl each optionally substituted with 1 to 5 substituents
selected from the group consisting of C.sub.1-4 alkoxy, C.sub.1-7
alkyl, C.sub.1-4 alkylsulfonyl, carboxy, cyano, C.sub.3-7
cycloalkyl, C.sub.2-8 dialkylamino, C.sub.1-4 haloalkoxy, C.sub.1-4
haloalkyl, halogen, heteroaryl, heterocyclic, hydroxyl, phenyl,
phenoxy, and sulfonic acid.
24. The compound according to claim 1 wherein R.sub.2 is
--C(O)OR.sub.24 and R.sub.24 is C.sub.1-8 alkyl, or C.sub.3-7
cycloalkyl wherein said C.sub.3-7 cycloalkyl is optionally
substituted with 1 to 5 substituents selected from the group
consisting of C.sub.1-4 alkoxy, C.sub.1-7 alkyl, carboxy, C.sub.2-8
dialkylamino, and halogen.
25. The compound according to claim 1 wherein R.sub.2 is
--C(O)OR.sub.24 and R.sub.24 is C.sub.1-8 alkyl, or C.sub.3-7
cycloalkyl
26. The compound according to claim 1 wherein R.sub.2 is
--C(O)R.sub.24 and R.sub.24 is C.sub.1-8 alkyl, C.sub.3-7
cycloalkyl, phenyl, heteroaryl, or heterocyclic each optionally
substituted with 1 to 5 substituents selected from the group
consisting of C.sub.2-6 alkenyl, C.sub.1-4 alkoxy, C.sub.1-7 alkyl,
C.sub.1-4 alkylsulfonyl, amino, carbo-C.sub.1-6-alkoxy, carboxy,
cyano, C.sub.3-7 cycloalkyl, C.sub.2-8 dialkylamino, C.sub.1-4
haloalkoxy, C.sub.1-4 haloalkyl, halogen, heteroaryl, heterocyclic,
hydroxyl, phenyl, phenoxy, and sulfonic acid, wherein said
C.sub.1-7 alkyl, phenyl and phenoxy are each optionally substituted
with 1 to 5 substituents selected from the group consisting of
amino, C.sub.1-4 haloalkoxy, and heterocyclic.
27. The compound according to claim 1 wherein R.sub.2 is
--C(O)R.sub.24 and R.sub.24 is C.sub.1-8 alkyl, heteroaryl, or
heterocyclic each optionally substituted with 1 to 5 substituents
selected from the group consisting of H, C.sub.1-4 alkoxy,
C.sub.1-8 alkyl, amino, carboxy, halogen, heteroaryl, hydroxyl,
phenoxy, and sulfonic acid, wherein said alkyl and phenoxy are
optionally substituted with 1 to 5 substituents selected from the
group consisting of amino, C.sub.1-4 haloalkoxy, and
heterocyclic.
28. The compound according to claim 1 wherein Ar.sub.1 is aryl or
heteroaryl optionally substituted with R.sub.13, R.sub.14,
R.sub.15, R.sub.16, and R.sub.17; wherein R.sub.13 is selected from
the group consisting of C.sub.1-6 acylsulfonamide, C.sub.1-4
alkoxy, C.sub.1-8 alkyl, C.sub.1-4 alkylamino, C.sub.1-6
alkylcarboxamide, C.sub.1-4 alkylsulfonamide, C.sub.1-4
alkylsulfonyl, C.sub.1-4 alkylthio, amino, carbamimidoyl,
carboxamide, carboxy, cyano, C.sub.2-6 dialkylamino, halogen,
heterocyclic, heterocyclic-oxy, heterocyclic-carbonyl, heteroaryl,
heteroarylcarbonyl, and sulfonamide, and wherein said C.sub.1-6
acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4
alkylamino, C.sub.1-4 alkylsulfonamide, alkylsulfonyl, C.sub.1-4
alkylthio, carbamimidoyl, C.sub.2-6 dialkylamino, heterocyclic,
heterocyclic-carbonyl, and heteroaryl are each optionally
substituted with 1 to 5 substituents selected independently from
the group consisting of C.sub.1-6 acylsulfonamide, C.sub.1-4
alkoxy, C.sub.1-7 alkyl, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylsulfonyl, carboxy, C.sub.3-7 cycloalkyloxy, C.sub.2-6
dialkylamino, C.sub.2-6 dialkylcarboxamide, heteroaryl,
heterocyclic, hydroxyl, phenyl, and phosphonooxy, and wherein said
C.sub.1-7 alkyl and C.sub.1-4 alkylcarboxamide are each optionally
substituted with 1 to 5 substituents selected from the group
consisting of C.sub.1-4 alkoxy and hydroxy; and R.sub.14, R.sub.15,
R.sub.16, and R.sub.17 are each independently selected form the
group consisting of C.sub.1-6 acylsulfonamide, C.sub.1-4 alkoxy,
C.sub.1-8 alkyl, C.sub.1-4 alkylamino, C.sub.1-4 alkylcarboxamide,
C.sub.1-4 alkylsulfonamide, C.sub.1-4 alkylsulfonyl, C.sub.1-4
alkylthio, amino, carbamimidoyl, carboxamide, cyano, C.sub.2-6
dialkylamino, and halogen.
29. The compound according to claim 28 wherein Ar.sub.1 is
aryl.
30. The compound according to claim 28 wherein Ar.sub.1 is
heteroaryl.
31. The compound according to claim 1 wherein Ar.sub.1 is phenyl
optionally substituted with R.sub.13, R.sub.14, R.sub.15, R.sub.16,
and R.sub.17; wherein R.sub.13 is selected from the group
consisting of C.sub.1-6 acylsulfonamide, C.sub.1-4 alkoxy,
C.sub.1-8 alkyl, C.sub.1-4 alkylamino, C.sub.1-6 alkylcarboxamide,
C.sub.1-4 alkylsulfonamide, C.sub.1-4 alkylsulfonyl, C.sub.1-4
alkylthio, amino, carbamimidoyl, carboxamide, carboxy, cyano,
C.sub.2-6 dialkylamino, C.sub.1-4 haloalkyl, halogen, heterocyclic,
heterocyclic-oxy, heterocyclic-carbonyl, heteroaryl,
heteroarylcarbonyl, and sulfonamide, and wherein said C.sub.1-6
acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4
alkylamino, C.sub.1-4 alkylsulfonamide, C.sub.1-4 alkylsulfonyl,
C.sub.1-4 alkylthio, carbamimidoyl, C.sub.2-6 dialkylamino,
heterocyclic, heterocyclic-carbonyl, and heteroaryl are each
optionally substituted with 1 to 5 substituents selected
independently from the group consisting of C.sub.1-6
acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-7 alkyl, C.sub.1-4
alkylcarboxamide, C.sub.1-4 alkylsulfonyl, carboxy, C.sub.3-7
cycloalkyloxy, C.sub.2-6 dialkylamino, C.sub.2-6
dialkylcarboxamide, heteroaryl, heterocyclic, hydroxyl, phenyl, and
phosphonooxy, and wherein said C.sub.1-7 alkyl and C.sub.1-4
alkylcarboxamide are each optionally substituted with 1 to 5
substituents selected from the group consisting of C.sub.1-4 alkoxy
and hydroxy; and R.sub.14, R.sub.15, R.sub.16, and R.sub.17 are
each independently selected form the group consisting of C.sub.1-6
acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4
alkylamino, C.sub.1-4 alkylcarboxamide, C.sub.1-4 alkylsulfonamide,
C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio, amino, carbamimidoyl,
carboxamide, cyano, C.sub.2-6 dialkylamino, C.sub.1-4 haloalkyl,
and halogen.
32. The compound according to claim 1 wherein Ar.sub.1 is phenyl
optionally substituted with R.sub.13, R.sub.14, R.sub.15, R.sub.16,
and R.sub.17; wherein R.sub.13 is selected from the group
consisting of C.sub.1-6 acylsulfonamide, C.sub.1-4 alkoxy,
C.sub.1-8 alkyl, C.sub.1-4 alkylamino, C.sub.1-6 alkylcarboxamide,
C.sub.1-4 alkylsulfonamide, C.sub.1-4 alkylsulfonyl, C.sub.1-4
alkylthio, carbamimidoyl, carboxamide, carboxy, cyano, C.sub.2-6
dialkylamino, halogen, heterocyclic, heterocyclic-oxy,
heterocyclic-carbonyl, heteroaryl, heteroarylcarbonyl, and
sulfonamide, and wherein said C.sub.1-4 alkoxy, C.sub.1-8 alkyl,
C.sub.1-4 alkylamino, C.sub.1-6 alkylcarboxamide, C.sub.1-4
alkylsulfonamide, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
carbamimidoyl, C.sub.2-6 dialkylamino, heterocyclic,
heterocyclic-carbonyl, and heteroaryl are each optionally
substituted with 1 to 5 substituents selected independently from
the group consisting of C.sub.1-6 acylsulfonamide, C.sub.1-4
alkoxy, C.sub.1-7 alkyl, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylsulfonyl, carboxy, C.sub.2-6 dialkylamino, C.sub.2-6
dialkylcarboxamide, heteroaryl, heterocyclic, hydroxyl, phenyl, and
phosphonooxy, and wherein said C.sub.1-7 alkyl and C.sub.1-4
alkylcarboxamide are each optionally substituted with 1 to 5
substituents selected from the group consisting of C.sub.1-4 alkoxy
and hydroxy; and R.sub.14, R.sub.15, R.sub.16, and R.sub.17 are
each independently selected form the group consisting of C.sub.1-6
acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4
alkylamino, C.sub.1-4 alkylcarboxamide, C.sub.1-4 alkylsulfonamide,
C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio, amino, carbamimidoyl,
carboxamide, cyano, C.sub.2-6 dialkylamino, and halogen.
33. The compound according to claim 1 wherein Ar.sub.1 is phenyl
optionally substituted with R.sub.13, R.sub.14, R.sub.15, R.sub.16,
and R.sub.17; wherein R.sub.13 is selected from the group
consisting of C.sub.1-6 acylsulfonamide, C.sub.1-4 alkoxy,
C.sub.1-8 alkyl, C.sub.1-4 alkylamino, C.sub.1-6 alkylcarboxamide,
C.sub.1-4 alkylsulfonamide, C.sub.1-4 alkylsulfonyl, C.sub.1-4
alkylthio, carbamimidoyl, carboxamide, carboxy, cyano, C.sub.2-6
dialkylamino, halogen, heterocyclic, heterocyclic-oxy,
heterocyclic-carbonyl, heteroaryl, heteroarylcarbonyl, and
sulfonamide, and wherein said C.sub.1-4 alkoxy, C.sub.1-8 alkyl,
C.sub.1-4 alkylamino, C.sub.1-6 alkylcarboxamide, C.sub.1-4
alkylsulfonamide, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
carbamimidoyl, C.sub.2-6 dialkylamino, heterocyclic,
heterocyclic-carbonyl, and heteroaryl are each optionally
substituted with 1 to 5 substituents selected independently from
the group consisting of C.sub.1-6 acylsulfonamide, C.sub.1-4
alkoxy, C.sub.1-7 alkyl, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylsulfonyl, carboxy, C.sub.2-6 dialkylamino, C.sub.2-6
dialkylcarboxamide, heteroaryl, heterocyclic, hydroxyl, phenyl, and
phosphonooxy, and wherein said C.sub.1-7 alkyl and C.sub.1-4
alkylcarboxamide are each optionally substituted with 1 to 5
substituents selected from the group consisting of C.sub.1-4 alkoxy
and hydroxy; and R.sub.14, R.sub.15, R.sub.16, and R.sub.17 are
each independently selected form the group consisting of C.sub.1-8
alkyl, and halogen.
34. The compound according to claim 1 wherein Ar.sub.1 is pyridyl
optionally substituted with R.sub.13, R.sub.14, R.sub.15, and
R.sub.16; wherein R.sub.13 is selected from the group consisting of
C.sub.1-6 acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-8 alkyl,
C.sub.1-4 alkylamino, C.sub.1-6 alkylcarboxamide, C.sub.1-4
alkylsulfonamide, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
amino, carbamimidoyl, carboxamide, carboxy, cyano, C.sub.2-6
dialkylamino, halogen, heterocyclic, heterocyclic-oxy,
heterocyclic-carbonyl, heteroaryl, and sulfonamide, and wherein
said C.sub.1-6 acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-8 alkyl,
C.sub.1-4 alkylamino, C.sub.1-4 alkylsulfonamide, alkylsulfonyl,
C.sub.1-4 alkylthio, carbamimidoyl, C.sub.2-6 dialkylamino,
heterocyclic, heterocyclic-carbonyl, and heteroaryl are each
optionally substituted with 1 to 5 substituents selected
independently from the group consisting of C.sub.1-6
acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-7 alkyl, C.sub.1-4
alkylcarboxamide, C.sub.1-4 alkylsulfonyl, carboxy, C.sub.3-7
cycloalkyloxy, C.sub.2-6 dialkylamino, C.sub.2-6
dialkylcarboxamide, heteroaryl, heterocyclic, hydroxyl, phenyl, and
phosphonooxy, and wherein said C.sub.1-7 alkyl and C.sub.1-4
alkylcarboxamide are each optionally substituted with 1 to 5
substituents selected from the group consisting of C.sub.1-4 alkoxy
and hydroxy; and R.sub.14, R.sub.15, and R.sub.16 are each
independently selected form the group consisting of C.sub.1-6
acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4
alkylamino, C.sub.1-4 alkylcarboxamide, C.sub.1-4 alkylsulfonamide,
C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio, amino, carbamimidoyl,
carboxamide, cyano, C.sub.2-6 dialkylamino, and halogen.
35. The compound according to claim 1 wherein Ar.sub.1 is pyridyl
optionally substituted with R.sub.13, R.sub.14, R.sub.15, and
R.sub.16; wherein R.sub.13 is selected from the group consisting of
C.sub.1-6 acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-8 alkyl,
C.sub.1-4 alkylamino, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
amino, C.sub.2-6 dialkylamino, halogen, heterocyclic, and
sulfonamide, and wherein said C.sub.1-4 alkoxy, C.sub.1-8 alkyl,
C.sub.1-4 alkylamino, alkylsulfonyl, C.sub.1-4 alkylthio, C.sub.2-6
dialkylamino, and heterocyclic are each optionally substituted with
1 to 5 substituents selected independently from the group
consisting of C.sub.1-6 acylsulfonamide, C.sub.1-4 alkoxy,
C.sub.1-4 alkylsulfonyl, C.sub.3-7 cycloalkyloxy, heteroaryl,
hydroxyl, phenyl, and phosphonooxy; and R.sub.14, R.sub.15, and
R.sub.16 are each independently selected form the group consisting
of C.sub.1-6 acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-8 alkyl,
C.sub.1-4 alkylamino, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylsulfonamide, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
amino, carbamimidoyl, carboxamide, cyano, C.sub.2-6 dialkylamino,
and halogen.
36. The compound according to claim 1 wherein Ar.sub.1 is pyridyl
optionally substituted with R.sub.13, R.sub.14, R.sub.15, and
R.sub.16; wherein R.sub.13 is selected from the group consisting of
C.sub.1-6 acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-8 alkyl,
C.sub.1-4 alkylamino, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
amino, C.sub.2-6 dialkylamino, halogen, heterocyclic, and
sulfonamide, and wherein said C.sub.1-4 alkoxy, C.sub.1-8 alkyl,
C.sub.1-4 alkylamino, alkylsulfonyl, C.sub.1-4 alkylthio, C.sub.2-6
dialkylamino, and heterocyclic are each optionally substituted with
1 to 5 substituents selected independently from the group
consisting of C.sub.1-6 acylsulfonamide, C.sub.1-4 alkoxy,
C.sub.1-4 alkylsulfonyl, C.sub.3-7 cycloalkyloxy, heteroaryl,
hydroxyl, phenyl, and phosphonooxy; and R.sub.14, R.sub.15, and
R.sub.16 are each independently selected form the group consisting
of C.sub.1-8 alkyl, and halogen.
37. The compound according to claim 1 is of Formula (H7):
##STR745## wherein: A is --CH.sub.2--, or --CH.sub.2CH.sub.2--; B
is --CH.sub.2--, --CH.sub.2CH.sub.2--, or
--CH.sub.2CH.sub.2CH.sub.2--; E is CH; is a single bond; D is
N--R.sub.2; K is --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH(CH.sub.3)CH.sub.2--, or a bond; Q is O, S, S(O), S(O).sub.2,
NH; R.sub.5 is H, CH.sub.3 or N(CH.sub.3).sub.2; R.sub.10 is H or
CH.sub.3; R.sub.2 is --CR.sub.25R.sub.26C(O)R.sub.24,
--C(O)R.sub.24, --C(O)NR.sub.25R.sub.24, --R.sub.24,
--C(O)OR.sub.24, --C(S)NR.sub.25R.sub.24, or
--CR.sub.25R.sub.26R.sub.24, wherein R.sub.24 is C.sub.1-8 alkyl,
C.sub.3-7 cycloalkyl, phenyl, heteroaryl, or heterocyclic each
optionally substituted with 1 to 5 substituents selected from the
group consisting of C.sub.2-6 alkenyl, C.sub.1-4 alkoxy, C.sub.1-7
alkyl, C.sub.1-4 alkylsulfonyl, amino, carbo-C.sub.1-6-alkoxy,
carboxy, cyano, C.sub.3-7 cycloalkyl, C.sub.2-8 dialkylamino,
C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl, halogen, heteroaryl,
heterocyclic, hydroxyl, phenyl, phenoxy, and sulfonic acid, wherein
said C.sub.1-7 alkyl, phenyl and phenoxy are each optionally
substituted with 1 to 5 substituents selected from the group
consisting of amino, C.sub.1-4 haloalkoxy, and heterocyclic; and
R.sub.25 and R.sub.26 are each independently H or C.sub.1-8 alkyl;
and Ar.sub.1 is aryl or heteroaryl optionally substituted with
R.sub.13, R.sub.14, R.sub.15, R.sub.16, and R.sub.17; wherein
R.sub.13 is selected from the group consisting of C.sub.1-6
acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4
alkylamino, C.sub.1-6 alkylcarboxamide, C.sub.1-4 alkylsulfonamide,
C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio, amino, carbamimidoyl,
carboxamide, carboxy, cyano, C.sub.2-6 dialkylamino, halogen,
heterocyclic, heterocyclic-oxy, heterocyclic-carbonyl, heteroaryl,
and sulfonamide, and wherein said C.sub.1-6 acylsulfonamide,
C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4 alkylamino, C.sub.1-4
alkylsulfonamide, alkylsulfonyl, C.sub.1-4 alkylthio,
carbamimidoyl, C.sub.2-6 dialkylamino, heterocyclic,
heterocyclic-carbonyl, and heteroaryl are each optionally
substituted with 1 to 5 substituents selected independently from
the group consisting of C.sub.1-6 acylsulfonamide, C.sub.1-4
alkoxy, C.sub.1-7 alkyl, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylsulfonyl, carboxy, C.sub.3-7 cycloalkyloxy, C.sub.2-6
dialkylamino, C.sub.2-6 dialkylcarboxamide, heteroaryl,
heterocyclic, hydroxyl, phenyl, and phosphonooxy; and wherein said
C.sub.1-7 alkyl and C.sub.1-4 alkylcarboxamide are each optionally
substituted with 1 to 5 substituents selected from the group
consisting of C.sub.1-4 alkoxy and hydroxy; and R.sub.14, R.sub.15,
R.sub.16, and R.sub.17 are each independently selected form the
group consisting of C.sub.1-6 acylsulfonamide, C.sub.1-4 alkoxy,
C.sub.1-8 alkyl, C.sub.1-4 alkylamino, C.sub.1-4 alkylcarboxamide,
C.sub.1-4 alkylsulfonamide, C.sub.1-4 alkylsulfonyl, C.sub.1-4
alkylthio, amino, carbamimidoyl, carboxamide, cyano, C.sub.2-6
dialkylamino, and halogen.
38. The compound according to claim 1 is of Formula (H7) wherein: A
and B are both --CH.sub.2CH.sub.2--; E is CH; is a single bond; D
is N--R.sub.2; K is a bond; Q is O, or NH; R.sub.5 and R.sub.10 are
both H; R.sub.2 is --C(O)OR.sub.24 wherein R.sub.24 is C.sub.1-8
alkyl, or C.sub.3-7 cycloalkyl each optionally substituted with 1
to 5 substituents selected from the group consisting of C.sub.1-4
alkoxy, C.sub.1-7 alkyl, C.sub.1-4 alkylsulfonyl, amino,
carbo-C.sub.1-6-alkoxy, carboxy, cyano, C.sub.3-7 cycloalkyl,
C.sub.2-8 dialkylamino, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl,
halogen, heteroaryl, heterocyclic, hydroxyl, phenyl, and phenoxy;
and Ar.sub.1 is aryl or heteroaryl optionally substituted with
R.sub.13, R.sub.14, R.sub.15, R.sub.16, and R.sub.17; wherein
R.sub.13 is selected from the group consisting of C.sub.1-6
acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4
alkylamino, C.sub.1-6 alkylcarboxamide, C.sub.1-4 alkylsulfonamide,
C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio, amino, carbamimidoyl,
carboxamide, carboxy, cyano, C.sub.2-6 dialkylamino, halogen,
heterocyclic, heterocyclic-oxy, heterocyclic-carbonyl, heteroaryl,
and sulfonamide, and wherein said C.sub.1-6 acylsulfonamide,
C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4 alkylamino, C.sub.1-4
alkylsulfonamide, alkylsulfonyl, C.sub.1-4 alkylthio,
carbamimidoyl, C.sub.2-6 dialkylamino, heterocyclic,
heterocyclic-carbonyl, and heteroaryl are each optionally
substituted with 1 to 5 substituents selected independently from
the group consisting of C.sub.1-6 acylsulfonamide, C.sub.1-4
alkoxy, C.sub.1-7 alkyl, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylsulfonyl, carboxy, C.sub.3-7 cycloalkyloxy, C.sub.2-6
dialkylamino, C.sub.2-6 dialkylcarboxamide, heteroaryl,
heterocyclic, hydroxyl, phenyl, and phosphonooxy, and wherein said
C.sub.1-7 alkyl and C.sub.1-4 alkylcarboxamide are each optionally
substituted with 1 to 5 substituents selected from the group
consisting of C.sub.1-4 alkoxy and hydroxy; and R.sub.14, R.sub.15,
R.sub.16, and R.sub.17 are each independently selected form the
group consisting of C.sub.1-4 alkoxy, C.sub.1-8 alkyl, and
halogen.
39. The compound according to claim 1 wherein: A and B are both
--CH.sub.2CH.sub.2--; E is CH; is a single bond; D is N--R.sub.2 K
is a bond; Q is O, or NH; R.sub.5 and R.sub.10 are both H; R.sub.2
is --C(O)OR.sub.24 wherein R.sub.24 is C.sub.1-8 alkyl or C.sub.3-7
cycloalkyl; Ar.sub.1 is phenyl, 3-pyridyl, or 2-pyridyl each
optionally substituted with R.sub.13, R.sub.14, R.sub.15, R.sub.16,
and R.sub.17, wherein R.sub.11 is selected from the group
consisting of C.sub.1-6 acylsulfonamide, C.sub.1-4 alkoxy,
C.sub.1-8 alkyl, C.sub.1-4 alkylamino, C.sub.1-6 alkylcarboxamide,
C.sub.1-4 alkylsulfonamide, C.sub.1-4 alkylsulfonyl, C.sub.1-4
alkylthio, carbamimidoyl, carboxamide, carboxy, cyano, C.sub.2-6
dialkylamino, halogen, heterocyclic, heterocyclic-oxy,
heterocyclic-carbonyl, heteroaryl, heteroarylcarbonyl, and
sulfonamide, and wherein said C.sub.1-4 alkoxy, C.sub.1-8 alkyl,
C.sub.1-4 alkylamino, C.sub.1-6 alkylcarboxamide, C.sub.1-4
alkylsulfonamide, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
carbamimidoyl, C.sub.2-6 dialkylamino, heterocyclic,
heterocyclic-carbonyl, and heteroaryl are each optionally
substituted with 1 to 5 substituents selected independently from
the group consisting of C.sub.1-6 acylsulfonamide, C.sub.1-4
alkoxy, C.sub.1-7 alkyl, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylsulfonyl, carboxy, C.sub.2-6 dialkylamino, C.sub.2-6
dialkylcarboxamide, heteroaryl, heterocyclic, hydroxyl, phenyl, and
phosphonooxy, and wherein said C.sub.1-7 alkyl and C.sub.1-4
alkylcarboxamide are each optionally substituted with 1 to 5
substituents selected from the group consisting of C.sub.1-4 alkoxy
and hydroxy; and R.sub.14, R.sub.15, R.sub.16, and R.sub.17 are
each independently CH.sub.3, or F.
40. The compound according to claim 39 wherein R.sub.2 is selected
from the group consisting of methoxycarbonyl, ethoxycarbonyl,
iso-propoxycarbonyl, n-propoxycarbonyl, n-butoxycarbonyl,
tert-butoxycarbonyl, iso-butoxycarbonyl, and
n-pentyloxycarbonyl.
41. The compound according to claim 40 wherein R.sub.13 is selected
from the group consisting of sulfamoyl, acetylsulfamoyl,
propionylsulfamoyl, butyrylsulfamoyl, pentanoylsulfamoyl,
methanesulfonyl, ethanesulfonyl, propane-1-sulfonyl, hydroxymethyl,
2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxy-butyl,
phosphonooxymethyl, 2-phosphonooxy-ethyl, 3-phosphonooxy-propyl,
and 4-phosphonooxy-butyl.
42. The compound according to claim 1 wherein said compound is
selected from the group consisting of:
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid tert-butyl ester;
4-[1-(4-Methanesulfonyl-phenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
oxy]-piperidine-1-carboxylic acid tert-butyl ester;
4-[1-(4-Methanesulfonyl-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin--
4-yloxy]-piperidine-1-carboxylic acid tert-butyl ester;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid isobutyl ester;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid isopropyl ester;
1-(4-Methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyri-
midine;
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
oxy]-piperidin-1-yl}-pyridin-3-yl-methanone.
(3-Fluoro-phenyl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyri-
midin-4-yloxy]-piperidin-1-yl}-methanone;
(1-tert-Butyl-5-methyl-1H-pyrazol-4-yl)-{4-[1-(4-methanesulfonyl-phenyl)--
1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)--
1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-pi-
peridine-1-carboxylic acid tert-butyl ester;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-pi-
peridine-1-carboxylic acid isopropyl ester;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-pi-
peridine-1-carboxylic acid isobutyl ester;
Furan-2-yl-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-
-yloxy]-piperidin-1-yl}-methanone;
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(1-methyl-1H-pyrrol-2-yl)-methanone;
2-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-p-
iperidin-1-yl}-1-pyridin-3-yl-ethanone;
2-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-p-
iperidin-1-yl}-1-pyridin-2-yl-ethanone;
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(5-methyl-pyridin-3-yl)-methanone;
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(2-methyl-pyridin-3-yl)-methanone;
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(6-methyl-pyridin-3-yl)-methanone;
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(5-methyl-isoxazol-3-yl)-methanone;
2-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-p-
iperidin-1-yl}-1-thiophen-2-yl-ethanone;
4-(1-Benzyl-azetidin-3-yloxy)-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,-
4-d]pyrimidine;
3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-pi-
peridine-1-carboxylic acid tert-butyl ester;
1-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-p-
iperidin-1-yl}-3,3-dimethyl-butan-2-one;
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-pyrazin-2-yl-methanone;
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(5-methyl-pyrazin-2-yl)-methanone;
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-pyrimidin-5-yl-methanone;
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-pyridazin-4-yl-methanone;
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-thiophen-2-yl-methanone;
(3,4-Dimethyl-isoxazol-5-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo-
[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
3-tert-Butoxy-1-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimi-
din-4-yloxy]-piperidin-1-yl}-propan-1-one;
(3-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]--
piperidin-1-yl}-3-oxo-propyl)-methyl-carbamic acid tert-butyl
ester;
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(6-trifluoromethyl-pyridin-3-y l)-methanone;
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-c-
yclohexyl}-carbamic acid tert-butyl ester;
N-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-cyclohe-
xane-1,4-diamine;
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(4-methyl-[1,2,3]thiadiazol-5-yl)-methanone;
(3,5-Dimethyl-isoxazol-4-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo-
[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
(2,5-Dimethyl-2H-pyrazol-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazo-
lo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(3-methyl-isoxazol-5-yl)-methanone;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carbothioic acid pyridin-4-ylamide;
N-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-
-cyclohexyl}-nicotinamide;
3-tert-Butoxy-N-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimi-
din-4-ylamino]-cyclohexyl}-propionamide;
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-c-
yclohexyl}-carbamic acid tert-butyl ester;
(3,5-Dimethyl-isoxazol-4-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo-
[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
4-[1-(3,5-Bis-trifluoromethyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy-
]-piperidine-1-carboxylic acid tert-butyl ester;
3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-azet-
idine-1-carboxylic acid isopropyl ester;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid butyl ester;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid propyl ester;
4-[1-(3-Fluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1--
carboxylic acid tert-butyl ester;
4-[1-(2,4-Difluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-
e-1-carboxylic acid tert-butyl ester;
{4-[1-(2,4-Difluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-cycloh-
exyl}-carbamic acid tert-butyl ester;
{4-[1-(3-Fluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-cyclohexyl-
}-carbamic acid tert-butyl ester;
N-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-cyclohe-
xane-1,4-diamine;
{3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-p-
iperidin-1-yl}-(6-methyl-pyridin-3-yl)-methanone;
{3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-p-
iperidin-1-yl}-(2-methyl-pyridin-3-yl)-methanone;
{3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-p-
iperidin-1-yl}-(5-methyl-pyridin-3-yl)-methanone;
{3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-p-
iperidin-1-yl}-pyridin-3-yl-methanone;
{3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-p-
iperidin-1-yl}-(1-methyl-1H-pyrrol-3-yl)-methanone;
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-cyc-
lohexyl}-carbamic acid tert-butyl ester;
N-[1-(2,4-Difluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-cyclohexane--
1,4-diamine;
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(4-trifluoromethyl-pyridin-3-yl)-methanone;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid cyclohexyl ester;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid tetrahydro-pyran-4-yl ester;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid cyclopentyl ester;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid tetrahydro-furan-3-yl ester;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid tetrahydro-furan-3-yl ester;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid tetrahydro-thiopyran-4-yl ester;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid cyclobutyl ester;
(6-tert-Butyl-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[-
3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
(4-{[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]--
methyl}-cyclohexyl)-carbamic acid tert-butyl ester;
N-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-
-cyclohexylmethyl}-nicotinamide;
N-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-
-cyclohexylmethyl}-6-methyl-nicotinamide;
4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
oxy]-piperidine-1-carboxylic acid tert-butyl ester;
4-({[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-methy-
l-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester;
4-{[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-m-
ethyl}-piperidine-1-carboxylic acid tert-butyl ester;
3-{[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-m-
ethyl}-piperidine-1-carboxylic acid tert-butyl ester;
4-({Ethyl-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-
-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester;
4-{1-[2-(2-Dimethylamino-ethoxy)-4-methanesulfonyl-phenyl]-1H-pyrazolo[3,-
4-d]pyrimidin-4-yloxy}-piperidine-1-carboxylic acid tert-butyl
ester;
3-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
amino]-piperidine-1-carboxylic acid tert-butyl ester;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid pyridin-3-ylmethyl esteracid tert-butyl
ester;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid 2-pyridin-3-yl-ethyl ester;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid 3-pyridin-3-yl-propyl ester;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid 2-dimethylamino-ethyl ester;
4-{[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-methyl-
-amino}-piperidine-1-carboxylic acid tert-butyl ester;
4-[1-(2,4-Difluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-
e-1-carboxylic acid tert-butyl ester;
4-({Ethyl-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimi-
din-4-yl]-amino}-methyl)-piperidine-1-carboxylic acid isopropyl
ester;
4-({Ethyl-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimi-
din-4-yl]-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl
ester;
4-[6-Dimethylamino-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimid-
in-4-yloxy]-piperidine-1-carboxylic acid tert-butyl ester;
1-(4-{[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-met-
hyl-amino}-piperidin-1-yl)-3,3-dimethyl-butan-2-one;
4-{[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-methyl-
-amino}-piperidine-1-carboxylic acid cyclobutyl ester; and
4-[({1-[4-(2-Methanesulfonyl-ethyl)-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-
-yl}-methyl-amino)-methyl]-piperidine-1-carboxylic acid tert-butyl
ester; or a pharmaceutically acceptable salt, hydrate or solvate
thereof.
43. The compound according to claim 1 wherein said compound is
selected from the group consisting of:
4-({[1-(2,5-Difluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-methyl-ami-
no}-methyl)-piperidine-1-carboxylic acid tert-butyl ester;
2-{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-
-yloxy]-piperidin-1-yl}-1-(4-trifluoromethoxy-phenyl)-ethanone;
2-{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-
-yloxy]-piperidin-1-yl}-1-(3-fluoro-phenyl)-ethanone;
2-{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-
-yloxy]-piperidin-1-yl}-1-pyridin-2-yl-ethanone;
(2,5-Dimethyl-furan-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,-
4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
4-({(2-Dimethylamino-ethyl)-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-
-d]pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylic acid
tert-butyl ester;
4-({(2-Dimethylamino-ethyl)-[1-(2-fluoro-4-methanesulfonyl-phenyl-
)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylic
acid tert-butyl ester;
4-[1-(2-Dimethylamino-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimid-
in-4-yloxy]-piperidine-1-carboxylic acid tert-butyl ester;
4-(2-{Ethyl-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-y-
l]-amino}-ethyl)-piperazine-1-carboxylic acid tert-butyl ester;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl]-
-piperidine-1-carboxylic acid tert-butyl ester;
4-{2-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-e-
thyl}-piperazine-1-carboxylic acid ethyl ester;
4-{2-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-p-
ropyl}-piperazine-1-carboxylic acid ethyl ester;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-sulfinyl]--
piperidine-1-carboxylic acid tert-butyl ester;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-sulfonyl]--
piperidine-1-carboxylic acid tert-butyl ester;
4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
sulfanyl]-piperidine-1-carboxylic acid tert-butyl ester;
4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
sulfanyl]-piperidine-1-carboxylic acid butyl ester;
4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
sulfanyl]-piperidine-1-carboxylic acid 2-methoxy-ethyl ester;
4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
sulfanyl]-piperidine-1-carboxylic acid 3,3-dimethyl-butyl ester;
4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
sulfanyl]-piperidine-1-carboxylic acid 4-methyl-pentyl ester;
4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
sulfanyl]-piperidine-1-carboxylic acid cyclopropylmethyl ester;
4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
sulfanyl]-piperidine-1-carboxylic acid cyclobutylmethyl ester;
4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
sulfanyl]-piperidine-1-carboxylic acid 2-cyclopropyl-ethyl ester;
(5-Bromo-furan-2-yl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazol-
o[3,4-d]pyrimidin-4-ylsulfanyl]-piperidin-1-yl}-methanone;
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(5-morpholin-4-ylmethyl-furan-2-yl)-methanone;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid pentyl ester;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid 1-ethyl-propyl ester;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid 2-ethyl-butyl ester;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid cyclopentylmethyl ester;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid 2-pyrrolidin-1-yl-ethyl ester;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid 2-morpholin-4-yl-ethyl ester;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid ethyl ester;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid 2,2-dimethyl-propyl ester;
(5-Butyl-pyridin-2-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d-
]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
Ethyl-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin--
4-yl]-(3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-ylmethyl)-amine;
Ethyl-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin--
4-yl]-(5
'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-ylmet-
hyl)-amine;
[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-(5
'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-amine;
4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
oxy]-piperidine-1-carboxylic acid isopropyl ester;
5'-Fluoro-4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-y-
loxy]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-5
'-methyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-6'-t-
rifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl;
[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]--
[-1-(3-isopropyl-[1,2,4]oxadiazol-5-ylmethyl)-pyrrolidin-3-yl]-amine;
[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]--
[1-(3-isopropyl-[1,2,4]oxadiazol-5-ylmethyl)-pyrrolidin-3-yl]-amine;
(4-Ethyl-pyridin-2-yl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyraz-
olo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol--
5-ylmethyl)-pyrrolidin-3-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;
1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol--
5-ylmethyl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;
(5'-Fluoro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl;-4-yl)-[1-(4-methanesu-
lfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;
(5-Bromo-pyridin-3-yl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyraz-
olo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
3-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
oxy]-pyrrolidine-1-carboxylic acid tert-butyl ester;
3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-py-
rrolidine-1-carboxylic acid tert-butyl ester;
3-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
amino]-pyrrolidine-1-carboxylic acid isopropyl ester;
(6-Chloro-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4--
d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
(5-Chloro-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4--
d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanone;
(2-Chloro-pyridin-4-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4--
d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
(4-Hydroxy-3-methoxy-phenyl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo-
[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
(4-Chloro-3-nitro-phenyl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,-
4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
1-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-p-
iperidin-1-yl}-3-methyl-butan-1-one;
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(6-pyrazol-1-yl-pyridin-3-yl)-methanone;
(2-Hydroxy-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-
-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
(5,6-Dichloro-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[-
3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
(5-Bromo-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d-
]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
5-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-p-
iperidine-1-carbonyl}-nicotinic acid;
(1H-Imidazol-4-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyr-
imidin-4-yloxy]-piperidin-1-yl}-methanone;
3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pyrr-
olidine-1-carboxylic acid tert-butyl ester;
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(6-pyrrolidin-1-yl-pyridin-3-yl)-methanone;
(6-Isobutylamino-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazo-
lo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
(6-Ethylamino-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[-
3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
(6-Cyclobutylamino-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyra-
zolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
(6-Isopropylamino-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyraz-
olo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
[6-(1-Ethyl-propylamino)-pyridin-3-yl]-{4-[1-(4-methanesulfonyl-phenyl)-1-
H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-[6-(1-propyl-butylamino)-pyridin-3-yl]-methanone;
5-Benzyloxy-2-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidi-
n-4-yloxy]-piperidine-1-carbonyl}-pyran-4-one;
Benzo[c]isoxazol-3-yl-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]-
pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
(4-Chloro-pyridin-2-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4--
d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
(4-Iodo-pyridin-2-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]-
pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
1-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-p-
iperidin-1-yl}-butan-2-one;
2-(5-Bromo-pyridin-3-yl)-1-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3-
,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;
(6-Fluoro-pyridin-2-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4--
d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
(5-Fluoro-pyridin-2-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4--
d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
(6-Chloro-pyridin-2-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4--
d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
(2-Chloro-5-fluoro-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyra-
zolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-[5-(2-methyl-pyrrolidin-1-ylmethyl)-pyridin-3-yl]-methanone;
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(6-methyl-pyridin-2-yl)-methanone;
5-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-p-
iperidine-1-carbonyl}-nicotinonitrile;
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(4-methoxy-pyridin-2-yl)-methanone;
(2-Fluoro-pyridin-4-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4--
d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
(2-Fluoro-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4--
d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
(6-Fluoro-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4--
d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(4-methoxy-thiophen-3-yl)-methanone;
2-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-p-
iperidine-1-carbonyl}-pyran-4-one;
(5-Ethyl-pyridin-2-yl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyraz-
olo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
(4-Ethoxy-phenyl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3-
,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(5-pyridin-2-yl-thiophen-2-yl)-methanone;
(5-Amino-pyridin-2-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d-
]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
(5-Amino-pyridin-2-yl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyraz-
olo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-y-
loxy]-piperidin-1-yl}-[5-(3-methyl-butylamino)-pyridin-2-yl]-methanone;
{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-y-
loxy]-piperidin-1-yl}-(4-trifluoromethoxy-phenyl)-methanone;
(5-Butyl-pyridin-2-yl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyraz-
olo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
(5-Ethylamino-pyridin-2-yl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H--
pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-y-
loxy]-piperidin-1-yl}-(5-isopropoxymethyl-pyridin-2-yl)-methanone;
(4-Difluoromethoxy-phenyl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-p-
yrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-y-
loxy]-piperidin-1-yl}-(5-isopropoxy-pyridin-2-yl)-methanone;
5-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-p-
iperidine-1-carbonyl}-pyridine-2-carboxylic acid methyl ester;
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-acetic acid ethyl ester;
{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-y-
loxy]-piperidin-1-yl}-(3-trifluoromethoxy-phenyl)-methanone;
1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol--
5-yl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;
1-(4-Chloro-phenyl)-2-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]-
pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;
2-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-p-
iperidin-1-yl}-1-(3-trifluoromethyl-phenyl)-ethanone;
4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
oxy]-5'-isopropoxy-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl;
1-(4-Methanesulfonyl-phenyl)-4-[1-(4-trifluoromethoxy-phenyl)-piperidin-4-
-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;
1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[1-(4-trifluoromethoxy-phenyl)-pi-
peridin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;
1-(4-Chloro-3-methyl-phenyl)-2-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazo-
lo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;
1-(3,4-Dichloro-phenyl)-2-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,-
4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;
5'-Bromo-4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
oxy]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl;
1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[1-(3-trifluoromethoxy-phenyl)-pi-
peridin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-5'-t-
rifluoromethyl-3,4,5,6-tetrahydro-2H-[12']bipyridinyl;
1-(2,4-Dimethoxy-phenyl)-2-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3-
,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;
1-(4-Difluoromethoxy-phenyl)-2-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazo-
lo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;
1-(4-Diethylamino-phenyl)-2-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[-
3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;
(2-{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin--
4-yloxy]-piperidin-1-yl}-5-methyl-pyrimidin-4-yl)-dimethyl-amine;
1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[1-(5-methyl-4-pyrrolidin-1-yl-py-
rimidin-2-yl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;
4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
sulfanyl]-piperidine-1-carboxylic acid isopropyl ester;
4-[1-(2-Methyl-4-propylamino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-
-piperidine-1-carboxylic acid isopropyl ester;
4-[1-(4-Isopropylamino-2-methyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylo-
xy]-piperidine-1-carboxylic acid isopropyl ester;
4-[1-(2-Methyl-4-morpholin-4-yl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylo-
xy]-piperidine-1-carboxylic acid isopropyl ester;
4-{1-[4-(2-Methoxy-ethylamino)-2-methyl-phenyl]-1H-pyrazolo[3,4-d]pyrimid-
in-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;
4-(1-{4-[(2-Methanesulfonyl-ethyl)-methyl-amino]-2-methyl-phenyl}-1H-pyra-
zolo[3,4-d]pyrimidin-4-yloxy)-piperidine-1-carboxylic acid
isopropyl ester;
4-[1-(4-Bromo-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperi-
dine-1-carboxylic acid isopropyl ester;
4-[1-(4-Propylamino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidi-
ne-1-carboxylic acid isopropyl ester;
4-[1-(4-Isopropylamino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piper-
idine-1-carboxylic acid isopropyl ester;
4-(1-{4-[4-(2-Methanesulfonyl-ethyl)-piperazin-1-yl]-2-methyl-phenyl}-1H--
pyrazolo[3,4-d]pyrimidin-4-yloxy)-piperidine-1-carboxylic acid
isopropyl ester;
4-(1-{2-Methyl-4-[(tetrahydro-furan-2-ylmethyl)-amino]-phenyl}-1H-
-pyrazolo[3,4-d]pyrimidin-4-yloxy)-piperidine-1-carboxylic acid
isopropyl ester;
4-[1-(4-Cyclopropylamino-2-methyl-phenyl)-1H-pyrazolo[3,4-d]pyrim-
idin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;
4-{1-[4-(2-Dimethylamino-ethylamino)-2-methyl-phenyl]-1H-pyrazolo[3,4-d]p-
yrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;
4-[1-(4-Morpholin-4-yl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piper-
idine-1-carboxylic acid isopropyl ester;
4-({[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4--
y]-isopropyl-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl
ester;
4-[1-(2-Fluoro-4-morpholin-4-yl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
oxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[1-(2-Fluoro-4-isopropylamino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylo-
xy]-piperidine-1-carboxylic acid isopropyl ester;
4-(1-{4-[(2-Methanesulfonyl-ethyl)-methyl-amino]-phenyl}-1H-pyrazolo[3,4--
d]pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester;
4-{1-[4-(2-Methoxy-ethylamino)-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-ylox-
y}-piperidine-1-carboxylic acid isopropyl ester;
4-(1-{4-[(Tetrahydro-furan-2-ylmethyl)-amino]-phenyl}-1H-pyrazolo[3,4-d]p-
yrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester;
4-(1-{4-[4-(2-Methanesulfonyl-ethyl)-piperazin-1-yl]-phenyl}-1H-pyrazolo[-
3,4-d]pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl
ester;
4-[1-(4-Amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-c-
arboxylic acid isopropyl ester;
4-({[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4--
yl]-isopropyl-amino}-methyl)-piperidine-1-carboxylic acid isopropyl
ester;
4-[1-(5-Ethyl-pyrimidin-2-yl)-piperidin-4-ylsulfanyl]-1-(2-fluoro-4-meth-
anesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine;
4-[1-(2-Fluoro-4-sulfamoyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-p-
iperidine-1-carboxylic acid isopropyl ester;
4-[1-(2-Fluoro-4-propionylsulfamoyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-
-yloxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[1-(4-Cyano-2-fluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piper-
idine-1-carboxylic acid isopropyl ester;
1-(2,5-Difluoro-4-methoxy-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl-
)-cyclohexyloxy]-1H-pyrazolo[3,4-d]pyrimidine;
4-[1-(2,5-Difluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin--
4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[1-(4-Fluoro-6-methoxy-pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylox-
y]-piperidine-1-carboxylic acid isopropyl ester;
4-[1-(6-Methoxy-2-methyl-pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylox-
y]-piperidine-1-carboxylic acid isopropyl ester;
4-[1-(2,5-Difluoro-4-sulfamoyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylox-
y]-piperidine-1-carboxylic acid isopropyl ester;
4-[1-(2-Fluoro-4-hydroxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridine-1-carboxylic acid isopropyl ester;
3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-p-
yrazolo[3,4-d]pyrimidin-1-yl}-N-propionyl-benzenesulfonamide;
3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-p-
yrazolo[3,4-d]pyrimidin-1-yl}-benzonitrile;
3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-p-
yrazolo[3,4-d]pyrimidin-1-yl}-benzenesulfonamide;
1-(2,5-Difluoro-4-methanesulfonyl-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadia-
zol-5-yl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;
1-(4-Fluoro-6-methoxy-pyridin-3-yl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5--
yl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;
4-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1-(6-methoxy--
2-methyl-pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine;
2,5-Difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ylox-
y]-pyrazolo[3,4-d]pyrimidin-1-yl}-benzenesulfonamide;
1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol--
5-yl)-cyclohexyloxy]-1H-pyrazolo[3,4-d]pyrimidine;
3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyraz-
olo[3,4-d]pyrimidin-1-yl}-N-propionyl-benzenesulfonamide;
3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyraz-
olo[3,4-d]pyrimidin-1-yl}-benzonitrile;
3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyraz-
olo[3,4-d]pyrimidin-1-yl}-benzenesulfonamide;
1-(2,5-Difluoro-4-methanesulfonyl-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadia-
zol-5-yl)-cyclohexyloxy]-1H-pyrazolo[3,4-d]pyrimidine;
1-(4-Fluoro-6-methoxy-pyridin-3-yl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5--
yl)-cyclohexyloxy]-1H-pyrazolo[3,4-d]pyrimidine;
4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1-(6-methoxy-2-me-
thyl-pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine;
2,5-Difluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-p-
yrazolo[3,4-d]pyrimidin-1-yl}-benzenesulfonamide;
4-[1-(2-Fluoro-4-methoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridine-1-carboxylic acid isopropyl ester;
4-[1-(4-Difluoromethoxy-2-fluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
oxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[1-(2-Fluoro-4-trifluoromethoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-y-
loxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[1-(2,5-Difluoro-4-methoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-
-piperidine-1-carboxylic acid isopropyl ester;
3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-p-
yrazolo[3,4-d]pyrimidin-1-yl}-phenol;
1-(2-Fluoro-4-methoxy-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-pi-
peridin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;
1-(4-Difluoromethoxy-2-fluoro-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol--
5-yl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;
1-(2-Fluoro-4-trifluoromethoxy-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-
-5-yl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;
1-(2,5-Difluoro-4-methoxy-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl-
)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;
3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyraz-
olo[3,4-d]pyrimidin-1-yl}-phenol;
1-(2-Fluoro-4-methoxy-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cy-
clohexyloxy]-1H-pyrazolo[3,4-d]pyrimidine;
1-(4-Difluoromethoxy-2-fluoro-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol--
5-yl)-cyclohexyloxy]-1H-pyrazolo[3,4-d]pyrimidine; and
1-(2-Fluoro-4-trifluoromethoxy-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-
-5-yl)-cyclohexyloxy]-1H-pyrazolo[3,4-d]pyrimidine; or a
pharmaceutically acceptable salt, hydrate or solvate thereof.
44. The compound according to claim 1 wherein said compound is
selected from the group consisting of:
4-[9-(6-Methanesulfonyl-pyridin-3-yl)-9H-purin-6-yloxy]-piperidine-1-carb-
oxylic acid isobutyl ester;
{4-[9-(6-Methanesulfonyl-pyridin-3-yl)-9H-purin-6-yloxy]-piperidin-1-yl}--
pyridin-3-yl-methanone;
4-[9-(4-Methanesulfonyl-phenyl)-9H-purin-6-yloxy]-piperidine-1-carboxylic
acid tert-butyl ester;
4-[9-(6-Methanesulfonyl-pyridin-3-y)-9H-purin-6-yloxy]-piperidine-1-carbo-
xylic acid tert-butyl ester and
4-[9-(2-Fluoro-4-methanesulfonyl-phenyl)-9H-purin-6-yloxy]-piperidine-1-c-
arboxylic acid tert-butyl ester; or a pharmaceutically acceptable
salt, hydrate or solvate thereof.
45. The compound according to claim 1 wherein said compound is
selected from the group consisting of:
4-[9-(2-Fluoro-4-propionylsulfamoyl-phenyl)-9H-purin-6-yloxy]-piperidine--
1-carboxylic acid isopropyl ester;
4-[9-(4-Cyano-2-fluoro-phenyl)-9H-purin-6-yloxy]-piperidine-1-carboxylic
acid isopropyl ester;
4-[9-(2-Fluoro-4-sulfamoyl-phenyl)-9H-purin-6-yloxy]-piperidine-1-carboxy-
lic acid isopropyl ester;
9-(2-Fluoro-4-methanesulfonyl-phenyl)-6-[1-(3-isopropyl-[1,2,4]oxadiazol--
5-yl)-piperidin-4-yloxy]-9H-purine;
3-Fluoro-4-{6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-p-
urin-9-yl}-N-propionyl-benzenesulfonamide;
3-Fluoro-4-{6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-p-
urin-9-yl}-benzonitrile;
3-Fluoro-4-{6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-p-
urin-9-yl}-benzenesulfonamide;
4-[9-(2,5-Difluoro-4-methanesulfonyl1-phenyl)-9H-purin-6-yloxy]-piperidin-
e-1-carboxylic acid isopropyl ester;
4-[9-(4-Fluoro-6-methoxy-pyridin-3-yl)-9H-purin-6-yloxy]-piperidine-1-car-
boxylic acid isopropyl ester;
4-[9-(6-Methoxy-2-methyl-pyridin-3-yl)-9H-purin-6-yloxy]-piperidine-1-car-
boxylic acid isopropyl ester;
4-[9-(2,5-Difluoro-4-sulfamoyl-phenyl)-9H-purin-6-yloxy]-piperidine-1-car-
boxylic acid isopropyl ester;
9-(2,5-Difluoro-4-methanesulfonyl-phenyl)-6-[1-(3-isopropyl-[1,2,4]oxadia-
zol-5-yl)-piperidin-4-yloxy]-9H-purine;
9-(4-Fluoro-6-methoxy-pyridin-3-yl)-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5--
yl)-piperidin-4-yloxy]-9H-purine;
6-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-9-(6-methoxy--
2-methyl-pyridin-3-yl)-9H-purine;
2,5-Difluoro-4-{6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ylox-
y]-purin-9-yl}-benzenesulfonamide;
9-(2-Fluoro-4-methanesulfonyl-phenyl)-6-[4-(3-isopropyl-[1,2,4]oxadiazol--
5-yl)-cyclohexyloxy]-9H-purine;
3-Fluoro-4-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-purin-
-9-yl}-N-propionyl-benzenesulfonamide;
3-Fluoro-4-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-purin-
-9-yl}-benzonitrile;
3-Fluoro-4-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-purin-
-9-yl}-benzenesulfonamide;
9-(2,5-Difluoro-4-methanesulfonyl-phenyl)-6-[4-(3-isopropyl-[1,2,4]oxadia-
zol-5-yl)-cyclohexyloxy]-9H-purine;
9-(4-Fluoro-6-methoxy-pyridin-3-yl)-6-[4-(3-isopropyl-[1,2,4]oxadiazol-5--
yl)-cyclohexyloxy]-9H-purine;
6-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-9-(6-methoxy-2-me-
thyl-pyridin-3-yl)-9H-purine; and
2,5-Difluoro-4-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-p-
urin-9-yl}-benzenesulfonamide; or a pharmaceutically acceptable
salt, hydrate or solvate thereof.
46. The compound according to claim 1 wherein said compound is
4-[3-(4-Methanesulfonyl-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ylox-
y]-piperidine-1-carboxylic acid tert-butyl ester; or a
pharmaceutically acceptable salt, hydrate or solvate thereof.
47. The compound according to claim 1 wherein said compound is
selected from the group consisting of:
3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol--
5-yl)-piperidin-4-yloxy]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;
3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-[-
1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;
3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-[-
1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-benzonitrile;
3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-[-
1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-benzenesulfonamide;
3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol--
5-yl)-cyclohexyloxy]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;
3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-[1,2,-
3]triazolo[4,5-d]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;
3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-[1,2,-
3]triazolo[4,5-d]pyrimidin-3-yl}-benzonitrile;
3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-[1,2,-
3]triazolo[4,5-d]pyrimidin-3-yl}-benzenesulfonamide;
3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[1,2,4]oxadia-
zol-5-yl)-cyclohexyloxy]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;
3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5--
yl)-cyclohexyloxy]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;
7-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-3-(6-methoxy-2-me-
thyl-pyridin-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine;
2,5-Difluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-[-
1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-benzenesulfonamide;
4-[3-(2-Fluoro-4-methanesulfonyl-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimid-
in-7-yloxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(2-Fluoro-4-propionylsulfamoyl-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyri-
midin-7-yloxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(4-Cyano-2-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy-
]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(2-Fluoro-4-sulfamoyl-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-y-
loxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyr-
imidin-7-yloxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(4-Fluoro-6-methoxy-pyridin-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-
-7-yloxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(6-Methoxy-2-methyl-pyridin-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-
-7-yloxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(2,5-Difluoro-4-sulfamoyl-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-
-7-yloxy]-piperidine-1-carboxylic acid isopropyl ester;
3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadia-
zol-5-yl)-piperidin-4-yloxy]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;
3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5--
yl)-piperidin-4-yloxy]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;
7-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-3-(6-methoxy--
2-methyl-pyridin-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine; and
2,5-Difluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ylox-
y]-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-benzenesulfonamide; or a
pharmaceutically acceptable salt, hydrate or solvate thereof.
48. The compound according to claim 1 wherein said compound is
4-[3-(4-Methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidin-7-yloxy]-piperi-
dine-1-carboxylic acid tert-butyl ester; or a pharmaceutically
acceptable salt, hydrate or solvate thereof.
49. The compound according to claim 1 wherein said compound is
selected from the group consisting of:
4-({Ethyl-[3-(4-methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidin-7-yl]-a-
mino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester;
4-[3-(4-Methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidin-7-ylsulfanyl]-p-
iperidine-1-carboxylic acid tert-butyl ester; and
4-[3-(4-Methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidin-7-yloxy]-piperi-
dine-1-carboxylic acid isopropyl ester; or a pharmaceutically
acceptable salt, hydrate or solvate thereof.
50. The compound according to claim 1 wherein said compound is
4-[8-(2-Fluoro-4-methanesulfonyl-phenyl)-[1,7]naphthyridin-4-yloxy]-piper-
idine-1-carboxylic acid isopropyl ester; or a pharmaceutically
acceptable salt, hydrate or solvate thereof.
51. The compound according to claim 1 wherein said compound is
selected from the group consisting of:
4-[8-(2-Fluoro-4-methanesulfonyl-phenyl)-quinolin-4-yloxy]-piperidine-1-c-
arboxylic acid isopropyl ester;
4-[8-(4-Methylsulfanyl-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylic
acid isopropyl ester;
4-[8-(4-Methanesulfonyl-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylic
acid isopropyl ester;
4-[8-(4-Isopropoxy-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylic
acid isopropyl ester;
4-[8-(4-Bromo-2-fluoro-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylic
acid isopropyl ester;
4-[8-(2-Fluoro-4-propionylsulfamoyl-phenyl)-quinolin-4-yloxy]-piperidine--
1-carboxylic acid isopropyl ester;
4-[8-(4-Cyano-2-fluoro-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylic
acid isopropyl ester;
4-[8-(2-Fluoro-4-sulfamoyl-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxy-
lic acid isopropyl ester;
4-[8-(2,5-Difluoro-4-methanesulfonyl-phenyl)-quinolin-4-yloxy]-piperidine-
-1-carboxylic acid isopropyl ester;
4-[8-(4-Fluoro-6-methoxy-pyridin-3-yl)-quinolin-4-yloxy]-piperidine-1-car-
boxylic acid isopropyl ester;
4-[8-(6-Methoxy-2-methyl-pyridin-3-yl)-quinolin-4-yloxy]-piperidine-1-car-
boxylic acid isopropyl ester;
4-[8-(2,5-Difluoro-4-sulfamoyl-phenyl)-quinolin-4-yloxy]-piperidine-1-car-
boxylic acid isopropyl ester;
2,5-Difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ylox-
y]-quinolin-8-yl}-benzenesulfonamide;
4-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-8-(6-methoxy--
2-methyl-pyridin-3-yl)-quinoline;
8-(4-Fluoro-6-methoxy-pyridin-3-yl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5--
yl)-piperidin-4-yloxy]-quinoline;
8-(2,5-Difluoro-4-methanesulfonyl-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadia-
zol-5-yl)-piperidin-4-yloxy]-quinoline;
3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-q-
uinolin-8-yl}-benzenesulfonamide;
3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-q-
uinolin-8-yl}-benzonitrile;
3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-q-
uinolin-8-yl}-N-propionyl-benzenesulfonamide;
8-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol--
5-yl)-piperidin-4-yloxy]-quinoline;
2,5-Difluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-q-
uinolin-8-yl}-benzenesulfonamide;
4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-8-(6-methoxy-2-me-
thyl-pyridin-3-yl)-quinoline;
8-(4-Fluoro-6-methoxy-pyridin-3-yl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5--
yl)-cyclohexyloxy]-quinoline;
8-(2,5-Difluoro-4-methanesulfonyl-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadia-
zol-5-yl)-cyclohexyloxy]-quinoline;
3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-quino-
lin-8-yl}-benzenesulfonamide;
3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-quino-
lin-8-yl}-benzonitrile;
3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-quino-
lin-8-yl}-N-propionyl-benzenesulfonamide; and
8-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol--
5-yl)-cyclohexyloxy]-quinoline; or a pharmaceutically acceptable
salt, hydrate or solvate thereof.
52. The compound according to claim 1 wherein said compound is
selected from the group consisting of:
4-[8-(2-Fluoro-4-methanesulfonyl-phenyl)-pyrido[3,4-d]pyrimidin-4-yloxy]--
piperidine-1-carboxylic acid isopropyl ester;
4-[8-(2-Fluoro-4-propionylsulfamoyl-phenyl)-pyrido
[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl
ester;
4-[8-(4-Cyano-2-fluoro-phenyl)-pyrido[3,4-d]pyrimidin-4-yloxy]-piperidine-
-1-carboxylic acid isopropyl ester;
4-[8-(2-Fluoro-4-sulfamoyl-phenyl)-pyrido[3,4-d]pyrimidin-4-yloxy]-piperi-
dine-1-carboxylic acid isopropyl ester;
4-[8-(2,5-Difluoro-4-methanesulfonyl-phenyl)-pyrido[3,4-d]pyrimidin-4-ylo-
xy]-piperidine-1-carboxylic acid isopropyl ester;
4-[8-(4-Fluoro-6-methoxy-pyridin-3-yl)-pyrido[3,4-d]pyrimidin-4-yloxy]-pi-
peridine-1-carboxylic acid isopropyl ester;
4-[8-(6-Methoxy-2-methyl-pyridin-3-yl)-pyrido
[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl
ester;
4-[8-(2,5-Difluoro-4-sulfamoyl-phenyl)-pyrido[3,4-d]pyrimidin-4-yloxy]-pi-
peridine-1-carboxylic acid isopropyl ester;
8-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol--
5-yl)-piperidin-4-yloxy]-pyrido[3,4-d]pyrimidine;
3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-p-
yrido[3,4-d]pyrimidin-8-yl}-N-propionyl-benzenesulfonamide;
3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-p-
yrido[3,4-d]pyrimidin-8-yl}-benzonitrile;
3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-p-
yrido[3,4-d]pyrimidin-8-yl}-benzenesulfonamide;
8-(2,5-Difluoro-4-methanesulfonyl-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadia-
zol-5-yl)-piperidin-4-yloxy]-pyrido[3,4-d]pyrimidine;
8-(4-Fluoro-6-methoxy-pyridin-3-yl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5--
yl)-piperidin-4-yloxy]-pyrido[3,4-d]pyrimidine;
4-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-8-(6-methoxy--
2-methyl-pyridin-3-yl)-pyrido[3,4-d]pyrimidine;
2,5-Difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ylox-
y]-pyrido[3,4-d]pyrimidin-8-yl}-benzenesulfonamide;
8-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol--
5-yl)-cyclohexyloxy]-pyrido[3,4-d]pyrimidine;
3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrid-
o[3,4-d]pyrimidin-8-yl}-N-propionyl-benzenesulfonamide;
3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrid-
o[3,4-d]pyrimidin-8-yl}-benzonitrile;
3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrid-
o[3,4-d]pyrimidin-8-yl}-benzenesulfonamide; 8-(2,
5-Difluoro-4-methanesulfonyl-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-
-yl)-cyclohexyloxy]-pyrido[3,4-d]pyrimidine;
8-(4-Fluoro-6-methoxy-pyridin-3-yl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5--
yl)-cyclohexyloxy]-pyrido[3,4-d]pyrimidine;
4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-8-(6-methoxy-2-me-
thyl-pyridin-3-yl)-pyrido[3,4-d]pyrimidine; and
2,5-Difluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-p-
yrido[3,4-d]pyrimidin-8-yl}-benzenesulfonamide; or a
pharmaceutically acceptable salt, hydrate or solvate thereof.
53. The compound according to claim 1 wherein said compound is
selected from the group consisting of:
3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol--
5-yl)-cyclohexyloxy]-pyrazolo[1,5-a]pyrimidine;
3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyraz-
olo[1,5-a]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;
3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyraz-
olo[1,5-a]pyrimidin-3-yl}-benzonitrile;
3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyraz-
olo[1,5-a]pyrimidin-3-yl}-benzenesulfonamide;
3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[1,2,4]oxadia-
zol-5-yl)-cyclohexyloxy]-pyrazolo[1,5-a]pyrimidine;
3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5--
yl)-cyclohexyloxy]-pyrazolo[1,5-a]pyrimidine;
7-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-3-(6-methoxy-2-me-
thyl-pyridin-3-yl)-pyrazolo[1,5-a]pyrimidine;
2,5-Difluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-p-
yrazolo[1,5-a]pyrimidin-3-yl}-benzenesulfonamide;
4-[3-(2-Fluoro-4-methanesulfonyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yloxy-
]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(2-Fluoro-4-propionylsulfamoyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl-
oxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(4-Cyano-2-fluoro-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidi-
ne-1-carboxylic acid isopropyl ester;
4-[3-(2-Fluoro-4-sulfamoyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yloxy]-pipe-
ridine-1-carboxylic acid isopropyl ester;
4-[3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-y-
loxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(4-Fluoro-6-methoxy-pyridin-3-yl)-pyrazolo[1,5-a]pyrimidin-7-yloxy]--
piperidine-1-carboxylic acid isopropyl ester;
4-[3-(6-Methoxy-2-methyl-pyridin-3-yl)-pyrazolo[1,5-a]pyrimidin-7-yloxy]--
piperidine-1-carboxylic acid isopropyl ester;
4-[3-(2,5-Difluoro-4-sulfamoyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yloxy]--
piperidine-1-carboxylic acid isopropyl ester;
3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol--
5-yl)-piperidin-4-yloxy]-pyrazolo[1,5-a]pyrimidine;
3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-p-
yrazolo[1,5-a]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;
3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-p-
yrazolo[1,5-a]pyrimidin-3-yl}-benzonitrile;
3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-p-
yrazolo[1,5-a]pyrimidin-3-yl}-benzenesulfonamide;
3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadia-
zol-5-yl)-piperidin-4-yloxy]-pyrazolo[1,5-a]pyrimidine;
3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5--
yl)-piperidin-4-yloxy]-pyrazolo[1,5-a]pyrimidine;
7-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-3-(6-methoxy--
2-methyl-pyridin-3-yl)-pyrazolo[1,5-a]pyrimidine;
2,5-Difluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ylox-
y]-pyrazolo[1,5-a]pyrimidin-3-yl}-benzenesulfonamide;
4-[3-(2-Fluoro-4-methanesulfonyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidi-
n-7-yloxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(2-Fluoro-4-propionylsulfamoyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrim-
idin-7-yloxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(4-Cyano-2-fluoro-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yloxy]-
-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(2-Fluoro-4-sulfamoyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl-
oxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyri-
midin-7-yloxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(4-Fluoro-6-methoxy-pyridin-3-yl)-2-methyl-pyrazolo[1,5-a]pyrimidin--
7-yloxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(6-Methoxy-2-methyl-pyridin-3-yl)-2-methyl-pyrazolo[1,5-a]pyrimidin--
7-yloxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(2,5-Difluoro-4-sulfamoyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidin--
7-yloxy]-piperidine-1-carboxylic acid isopropyl ester;
2,5-Difluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ylox-
y]-2-methyl-pyrazolo[1,5-a]pyrimidin-3-yl}-benzenesulfonamide;
7-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-3-(6-methoxy--
2-methyl-pyridin-3-yl)-2-methyl-pyrazolo[1,5-a]pyrimidine;
3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5--
yl)-piperidin-4-yloxy]-2-methyl-pyrazolo[1,5-a]pyrimidine;
3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadia-
zol-5-yl)-piperidin-4-yloxy]-2-methyl-pyrazolo[1,5-a]pyrimidine;
3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-
methyl-pyrazolo[1,5-a]pyrimidin-3-yl}-benzenesulfonamide;
3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-
methyl-pyrazolo[1,5-a]pyrimidin-3-yl}-benzonitrile;
3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-
methyl-pyrazolo[1,5-a]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;
3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol--
5-yl)-piperidin-4-yloxy]-2-methyl-pyrazolo[1,5-a]pyrimidine;
3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol--
5-yl)-cyclohexyloxy]-2-methyl-pyrazolo[1,5-a]pyrimidine;
3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-met-
hyl-pyrazolo[1,5-a]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;
3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-met-
hyl-pyrazolo[1,5-a]pyrimidin-3-yl}-benzonitrile;
3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-met-
hyl-pyrazolo[1,5-a]pyrimidin-3-yl}-benzenesulfonamide;
3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[1,2,4]oxadia-
zol-5-yl)-cyclohexyloxy]-2-methyl-pyrazolo[1,5-a]pyrimidine;
3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5--
yl)-cyclohexyloxy]-2-methyl-pyrazolo[1,5-a]pyrimidine;
7-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-3-(6-methoxy-2-me-
thyl-pyridin-3-yl)-2-methyl-pyrazolo[1,5-a]pyrimidine; and
2,5-Difluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-
-methyl-pyrazolo[1,5-a]pyrimidin-3-yl}-benzenesulfonamide; or a
pharmaceutically acceptable salt, hydrate or solvate thereof.
54. The compound according to claim 1 wherein said compound is
selected from the group consisting of:
4-[3-(2-Fluoro-4-methanesulfonyl-phenyl)-1-methyl-1H-pyrazolo[4,3-d]pyrim-
idin-7-yloxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(2-Fluoro-4-propionylsulfamoyl-phenyl)-1-methyl-1H-pyrazolo[4,3-d]py-
rimidin-7-yloxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(4-Cyano-2-fluoro-phenyl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-ylo-
xy]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(2-Fluoro-4-sulfamoyl-phenyl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-
-yloxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-1-methyl-1H-pyrazolo[4,3-d]p-
yrimidin-7-yloxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(4-Fluoro-6-methoxy-pyridin-3-yl)-1-methyl-]1H-pyrazolo[4,3-d]pyrimi-
din-7-yloxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(6-Methoxy-2-methyl-pyridin-3-yl)-1-methyl-1H-pyrazolo[4,3-d]pyrimid-
in-7-yloxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(2,5-Difluoro-4-sulfamoyl-phenyl)-1-methyl-1H-pyrazolo[4,3-d]pyrimid-
in-7-yloxy]-piperidine-1-carboxylic acid isopropyl ester;
3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol--
5-yl)-piperidin-4-yloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidine;
3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1-
methyl-1H-pyrazolo[4,3-d]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;
3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1-
methyl-1H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzonitrile;
3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1-
methyl-1H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzenesulfonamide;
3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadia-
zol-5-yl)-piperidin-4-yloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidine;
3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5--
yl)-piperidin-4-yloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidine;
7-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-3-(6-methoxy--
2-methyl-pyridin-3-yl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidine;
2,5-Difluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ylox-
y]-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzenesulfonamide;
3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol--
5-yl)-cyclohexyloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidine;
3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1-met-
hyl-1H-pyrazolo[4,3-d]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;
3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1-met-
hyl-1H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzonitrile;
3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1-met-
hyl-1H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzenesulfonamide;
3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[1,2,4]oxadia-
zol-5-yl)-cyclohexyloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidine;
3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5--
yl)-cyclohexyloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidine;
7-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-3-(6-methoxy-2-me-
thyl-pyridin-3-yl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidine; and
2,5-Difluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1-
-methyl-1H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzenesulfonamide; or a
pharmaceutically acceptable salt, hydrate or solvate thereof.
55. The compound according to claim 1 wherein said compound is
selected from the group consisting of:
4-[3-(2-Fluoro-4-methanesulfonyl-phenyl)-2-methyl-2H-pyrazolo[4,3-d]pyrim-
idin-7-yloxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(2-Fluoro-4-propionylsulfamoyl-phenyl)-2-methyl-2H-pyrazolo[4,3-d]py-
rimidin-7-yloxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(4-Cyano-2-fluoro-phenyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-ylo-
xy]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(2-Fluoro-4-sulfamoyl-phenyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-
-yloxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-2-methyl-2H-pyrazolo[4,3-d]p-
yrimidin-7-yloxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(4-Fluoro-6-methoxy-pyridin-3-yl)-2-methyl-2H-pyrazolo[4,3-d]pyrimid-
in-7-yloxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(6-Methoxy-2-methyl-pyridin-3-yl)-2-methyl-2H-pyrazolo[4,3-d]pyrimid-
in-7-yloxy]-piperidine-1-carboxylic acid isopropyl ester;
4-[3-(2,5-Difluoro-4-sulfamoyl-phenyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimid-
in-7-yloxy]-piperidine-1-carboxylic acid isopropyl ester;
3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol--
5-yl)-piperidin-4-yloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidine;
3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-
methyl-2H-pyrazolo[4,3-d]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;
3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-
methyl-2H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzonitrile;
3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-
methyl-2H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzenesulfonamide;
3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadia-
zol-5-yl)-piperidin-4-yloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidine;
3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5--
yl)-piperidin-4-yloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidine;
7-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-3-(6-methoxy--
2-methyl-pyridin-3-yl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidine;
2,5-Difluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ylox-
y]-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzenesulfonamide;
3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol--
5-yl)-cyclohexyloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidine;
3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-met-
hyl-2H-pyrazolo[4,3-d]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;
3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-met-
hyl-2H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzonitrile;
3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-met-
hyl-2H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzenesulfonamide;
3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[l,2,4]oxadia-
zol-5-yl)-cyclohexyloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidine;
3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5--
yl)-cyclohexyloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidine;
7-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-3-(6-methoxy-2-me-
thyl-pyridin-3-yl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidine; and
2,5-Difluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-
-methyl-2H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzenesulfonamide; or
pharmaceutically acceptable salt, hydrate or solvate thereof.
56. A pharmaceutical composition comprising at least one compound
according to claim 1 and a pharmaceutically acceptable carrier.
57. A method for treatment of a metabolic-related disorder in an
individual comprising administering to said individual in need of
such treatment a therapeutically effective amount of a compound
according to any claim 1.
58. The method according to claim 57 wherein said metabolic-related
disorder is selected from the group consisting of type I diabetes,
type II diabetes, inadequate glucose tolerance, insulin resistance,
hyperglycemia, hyperlipidemia, hypertriglyceridemia,
hypercholesterolemia, dyslipidemia and syndrome X.
59. The method according to claim 58 wherein said metabolic-related
disorder is type II diabetes.
60. The method according to claim 58 wherein said metabolic-related
disorder is hyperglycemia.
61. The method according to claim 58 wherein said metabolic-related
disorder is hyperlipidemia.
62. The method according to claim 58 wherein said metabolic-related
disorder is hypertriglyceridemia.
63. The method according to claim 58 wherein said metabolic-related
disorder is type I diabetes.
64. The method according to claim 58 wherein said metabolic-related
disorder is dyslipidemia.
65. The method according to claim 58 wherein said metabolic-related
disorder is syndrome X.
66. The method according to claim 57 wherein said individual is a
mammal.
67. The method according to claim 66 wherein said mammal is a
human.
68. A method of decreasing food intake of an individual comprising
administering to said individual in need thereof a therapeutically
effective amount of a compound of claim 1.
69. A method of inducing satiety in an individual comprising
administering to said individual in need thereof a therapeutically
effective amount of a compound according to claim 1.
70. A method of controlling or decreasing weight gain of an
individual comprising administering to said individual in need
thereof a therapeutically effective amount of a compound according
to claim 1.
71. The method according to claim 70 wherein said individual is a
mammal.
72. The method according to claim 71 wherein said mammal is a
human.
73. The method according to claim 72 wherein said human has a body
mass index of about 18.5 to about 45.
74. The method according to claim 72 wherein said human has a body
mass index of about 25 to about 45.
75. The method according to claim 72 wherein said human has a body
mass index of about 30 to about 45.
76. The method according to claim 72 wherein said human has a body
mass index of about 35 to about 45.
77. A method of modulating a RUP3 receptor in an individual
comprising contacting the receptor with a compound according to
claim 1.
78. The method of modulating the RUP3 receptor according to claim
77 wherein said compound is an agonist.
79. The method of modulating the RUP3 receptor according to claim
77 wherein said modulation of the RUP3 receptor is treatment of a
metabolic-related disorder.
80. The method of modulating the RUP3 receptor according to claim
79 wherein said metabolic-related disorder is selected from the
group consisting of type I diabetes, type II diabetes, inadequate
glucose tolerance, insulin resistance, hyperglycemia,
hyperlipidemia, hypertriglyceridemia, hypercholesterolemia,
dyslipidemia or syndrome X.
81. The method of modulating the RUP3 receptor according to claim
79 wherein said metabolic-related disorder is type II diabetes.
82. The method of modulating the RUP3 receptor according to claim
79 wherein said metabolic-related disorder is insulin
resistance.
83. The method of modulating the RUP3 receptor according to claim
79 wherein said metabolic-related disorder is hyperglycemia.
84. The method of modulating the RUP3 receptor according to claim
79 wherein said metabolic-related disorder is hyperlipidemia.
85. The method of modulating the RUP3 receptor according to claim
79 wherein said metabolic-related disorder is
hypertriglyceridemia.
86. The method of modulating the RUP3 receptor according to claim
79 wherein said metabolic-related disorder is type I diabetes.
87. The method of modulating the RUP3 receptor according to claim
79 wherein said metabolic-related disorder is dyslipidemia.
88. The method of modulating the RUP3 receptor according to claim
79 wherein said metabolic-related disorder is syndrome X.
89. The method of modulating the RUP3 receptor according to claim
77 wherein said individual is a mammal.
90. The method of modulating the RUP3 receptor according to claim
89 wherein said mammal is a human.
91. The method of modulating the RUP3 receptor according to claim
77 wherein said modulation of the RUP3 receptor reduces food intake
of said individual.
92. The method of modulating the RUP3 receptor according to claim
77 wherein said modulation of the RUP3 receptor induces satiety in
said individual.
93. The method of modulating the RUP3 receptor according to claim
77 wherein said modulation of the RUP3 receptor controls or reduces
weight gain of said individual.
94. The method of modulating the RUP3 receptor according to claim
93 wherein said individual is a mammal.
95. The method of modulating the RUP3 receptor according to claim
94 wherein said mammal is a human.
96. The method according to claim 95 wherein said human has a body
mass index of about 18.5 to about 45.
97. The method according to claim 95 wherein said human has a body
mass index of about 25 to about 45.
98. The method according to claim 95 wherein said human has a body
mass index of about 30 to about 45.
99. The method according to claim 95 wherein said human has a body
mass index of about 35 to about 45.
100. The method of producing a pharmaceutical composition
comprising admixing at least one compound of claim 1 and a
pharmaceutically acceptable carrier.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Ser. No.
11/355,785, filed Feb. 16, 2006, which is a divisional of U.S. Ser.
No. 10/890,549, now U.S. Pat. No. 7,132,426, filed Jul. 13,2004,
which in turn claims the benefit of U.S. Provisional Applications
Ser. Nos. 60/487,443, filed Jul. 14, 2003 and 60/510,644, filed
Oct. 10, 2003, each of which is hereby incorporated by reference in
its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to certain fused aryl and
heteroaryl derivatives that are modulators of glucose metabolism.
Accordingly, compounds of the present invention are useful in the
prophylaxis or treatment of metabolic disorders and complications
thereof, such as, diabetes and obesity.
BACKGROUND OF THE INVENTION
[0003] Diabetes mellitus is a serious disease afflicting over 100
million people worldwide. In the United States, there are more than
12 million diabetics, with 600,000 new cases diagnosed each
year.
[0004] Diabetes mellitus is a diagnostic term for a group of
disorders characterized by abnormal glucose homeostasis resulting
in elevated blood sugar. There are many types of diabetes, but the
two most common are Type I (also referred to as insulin-dependent
diabetes mellitus or IDDM) and Type II (also referred to as
non-insulin-dependent diabetes mellitus or NIDDM).
[0005] The etiology of the different types of diabetes is not the
same; however, everyone with diabetes has two things in common:
overproduction of glucose by the liver and little or no ability to
move glucose out of the blood into the cells where it becomes the
body's primary fuel.
[0006] People who do not have diabetes rely on insulin, a hormone
made in the pancreas, to move glucose from the blood into the cells
of the body. However, people who have diabetes either don't produce
insulin or can't efficiently use the insulin they produce;
therefore, they can't move glucose into their cells. Glucose
accumulates in the blood creating a condition called hyperglycemia,
and over time, can cause serious health problems.
[0007] Diabetes is a syndrome with interrelated metabolic,
vascular, and neuropathic components. The metabolic syndrome,
generally characterized by hyperglycemia, comprises alterations in
carbohydrate, fat and protein metabolism caused by absent or
markedly reduced insulin secretion and/or ineffective insulin
action. The vascular syndrome consists of abnormalities in the
blood vessels leading to cardiovascular, retinal and renal
complications. Abnormalities in the peripheral and autonomic
nervous systems are also part of the diabetic syndrome.
[0008] People with IDDM, which accounts for about 5% to 10% of
those who have diabetes, don't produce insulin and therefore must
inject insulin to keep their blood glucose levels normal. IDDM is
characterized by low or undetectable levels of endogenous insulin
production caused by destruction of the insulin-producing .beta.
cells of the pancreas, the characteristic that most readily
distinguishes IDDM from NIDDM. IDDM, once termed juvenile-onset
diabetes, strikes young and older adults alike.
[0009] Approximately 90 to 95% of people with diabetes have Type II
(or NIDDM). NIDDM subjects produce insulin, but the cells in their
bodies are insulin resistant: the cells don't respond properly to
the hormone, so glucose accumulates in their blood. NIDDM is
characterized by a relative disparity between endogenous insulin
production and insulin requirements, leading to elevated blood
glucose levels. In contrast to IDDM, there is always some
endogenous insulin production in NIDDM; many NIDDM patients have
normal or even elevated blood insulin levels, while other NIDDM
patients have inadequate insulin production (Rotwein, R. et al. N.
Engl. J. Med. 308, 65-71 (1983)). Most people diagnosed with NIDDM
are age 30 or older, and half of all new cases are age 55 and
older. Compared with whites and Asians, NIDDM is more common among
Native Americans, African-Americans, Latinos, and Hispanics. In
addition, the onset can be insidious or even clinically inapparent,
making diagnosis difficult.
[0010] The primary pathogenic lesion on NIDDM has remained elusive.
Many have suggested that primary insulin resistance of the
peripheral tissues is the initial event. Genetic epidemiological
studies have supported this view. Similarly, insulin secretion
abnormalities have been argued as the primary defect in NIDDM. It
is, likely that both phenomena are important contributors to the
disease process (Rimoin, D. L., et. al. Emery and Rimoin's
Principles and Practice of Medical Genetics 3.sup.rd Ed.
1:1401-1402 (1996)).
[0011] Many people with NIDDM have sedentary lifestyles and are
obese; they weigh approximately 20% more than the recommended
weight for their height and build. Furthermore, obesity is
characterized by hyperinsulinemia and insulin resistance, a feature
shared with NIDDM, hypertension and atherosclerosis.
[0012] Obesity and diabetes are among the most common human health
problems in industrialized societies. In industrialized countries a
third of the population is at least 20% overweight. In the United
States, the percentage of obese people has increased from 25% at
the end of the 1970s, to 33% at the beginning the 1990s. Obesity is
one of the most important risk factors for NIDDM. Definitions of
obesity differ, but in general, a subject weighing at least 20%
more than the recommended weight for his/her height and build is
considered obese. The risk of developing NIDDM is tripled in
subjects 30% overweight, and three-quarters with NIDDM are
overweight.
[0013] Obesity, which is the result of an imbalance between caloric
intake and energy expenditure, is highly correlated with insulin
resistance and diabetes in experimental animals and human. However,
the molecular mechanisms that are involved in obesity-diabetes
syndromes are not clear. During early development of obesity,
increase insulin secretion balances insulin resistance and protects
patients from hyperglycemia (Le Stunff, et al. Diabetes 43, 696-702
(1989)). However, after several decades, .beta. cell function
deteriorates and non-insulin-dependent diabetes develops in about
20% of the obese population (Pederson, P. Diab. Metab. Rev. 5,
505-509 (1989)) and (Brancati, F. L., et al., Arch. Intern. Med.
159, 957-963 (1999)). Given its high prevalence in modern
societies, obesity has thus become the leading risk factor for
NIDDM (Hill, J. O., et al., Science 280, 1371-1374 (1998)).
However, the factors which predispose a fraction of patients to
alteration of insulin secretion in response to fat accumulation
remain unknown.
[0014] Whether someone is classified as overweight or obese is
generally determined on the basis of their body mass index (BMI)
which is calculated by dividing body weight (kg) by height squared
(m.sup.2). Thus, the units of BMI are kg/m.sup.2 and it is possible
to calculate the BMI range associated with minimum mortality in
each decade of life. Overweight is defined as a BMI in the range
25-30 kg/M.sup.2, and obesity as a BMI greater than 30 kg/m.sup.2
(see TABLE below). There are problems with this definition in that
it does not take into account the proportion of body mass that is
muscle in relation to fat (adipose tissue). To account for this,
obesity can also be defined on the basis of body fat content:
greater than 25% and 30% in males and females, respectively.
TABLE-US-00001 CLASSIFICATION OF WEIGHT BY BODY MASS INDEX (BMI)
BMI CLASSIFICATION <18.5 Underweight 18.5-24.9 Normal 25.0-29.9
Overweight 30.0-34.9 Obesity (Class I) 35.0-39.9 Obesity (Class II)
>40 Extreme Obesity (Class III)
[0015] As the BMI increases there is an increased risk of death
from a variety of causes that is independent of other risk factors.
The most common diseases with obesity are cardiovascular disease
(particularly hypertension), diabetes (obesity aggravates the
development of diabetes), gall bladder disease (particularly
cancer) and diseases of reproduction. Research has shown that even
a modest reduction in body weight can correspond to a significant
reduction in the risk of developing coronary heart disease.
[0016] Compounds marketed as anti-obesity agents include Orlistat
(XENICAL.TM.) and Sibutramine. Orlistat (a lipase inhibitor)
inhibits fat absorption directly and tends to produce a high
incidence of unpleasant (though relatively harmless) side-effects
such as diarrhea. Sibutramine (a mixed 5-HT/noradrenaline reuptake
inhibitor) can increase blood pressure and heart rate in some
patients. The serotonin releaser/reuptake inhibitors fenfluramine
(Pondimin.TM.) and dexfenfluramine (Redux.TM.) have been reported
to decrease food intake and body weight over a prolonged period
(greater than 6 months). However, both products were withdrawn
after reports of preliminary evidence of heart valve abnormalities
associated with their use. Accordingly, there is a need for the
development of a safer anti-obesity agent.
[0017] Obesity considerably increases the risk of developing
cardiovascular diseases as well. Coronary insufficiency,
atheromatous disease, and cardiac insufficiency are at the
forefront of the cardiovascular complication induced by obesity. It
is estimated that if the entire population had an ideal weight, the
risk of coronary insufficiency would decrease by 25% and the risk
of cardiac insufficiency and of cerebral vascular accidents by 35%.
The incidence of coronary diseases is doubled in subjects less than
50 years of age who are 30% overweight. The diabetes patient faces
a 30% reduced lifespan. After age 45, people with diabetes are
about three times more likely than people without diabetes to have
significant heart disease and up to five times more likely to have
a stroke. These findings emphasize the inter-relations between
risks factors for NIDDM and coronary heart disease and the
potential value of an integrated approach to the prevention of
these conditions based on the prevention of these conditions based
on the prevention of obesity (Perry, I. J., et al., BMJ 310,
560-564 (1995)).
[0018] Diabetes has also been implicated in the development of
kidney disease, eye diseases and nervous-system problems. Kidney
disease, also called nephropathy, occurs when the kidney's "filter
mechanism" is damaged and protein leaks into urine in excessive
amounts and eventually the kidney fails. Diabetes is also a leading
cause of damage to the retina at the back of the eye and increases
risk of cataracts and glaucoma. Finally, diabetes is associated
with nerve damage, especially in the legs and feet, which
interferes with the ability to sense pain and contributes to
serious infections. Taken together, diabetes complications are one
of the nation's leading causes of death.
SUMMARY OF THE INVENTION
[0019] The present invention is drawn to compounds which bind to
and modulate the activity of a GPCR referred to herein as RUP3, and
uses thereof. The term RUP3 as used herein includes the human
sequences found in GeneBank accession numbers XM.sub.--066873 and
AY288416, and naturally-occurring allelic variants, mammalian
orthologs, and recombinant mutants thereof. A preferred human RUP3
for use in screening and testing of the compounds of the invention
is provided in the nucleotide sequence of Seq. ID. No:1 and the
corresponding amino acid sequence in Seq. ID. No:2.
[0020] One aspect of the present invention encompasses certain
fused aryl and heteroaryl derivatives as shown in Formula (I):
##STR2## or a pharmaceutically acceptable salt, hydrate or solvate
thereof;
[0021] wherein:
[0022] A and B are each independently C.sub.1-3 alkylene optionally
substituted with 1 to 4 substituents selected from the group
consisting of C.sub.1-3 alkyl, C.sub.1-4 alkoxy, carboxy, cyano,
C.sub.1-3 haloalkyl and halogen;
[0023] D is O, S, S(O), S(O).sub.2, CR.sub.1R.sub.2 or N--R.sub.2,
wherein R.sub.1 is selected from the group consisting of H,
C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogen and hydroxyl;
[0024] E is N, C or CR.sub.3, wherein R.sub.3 is H or C.sub.1-8
alkyl;
[0025] is a single bond when E is N or CR.sub.3, or a double bond
when E is C;
[0026] K is a C.sub.3-6 cycloalkylene or C.sub.1-3 alkylene wherein
each are optionally substituted with 1 to 4 substituents selected
from the group consisting of C.sub.1-3 alkyl, C.sub.1-4 alkoxy,
carboxy, cyano, C.sub.1-3 haloalkyl and halogen; or K is a
bond;
[0027] Q is NR.sub.4, O, S, S(O) or S(O).sub.2, wherein R.sub.4 is
H or C.sub.1-8 alkyl and the C.sub.1-8 alkyl is optionally
substituted with C.sub.2-8 dialkylamine;
[0028] T is N or CR.sub.5;
[0029] M is N or CR.sub.6;
[0030] J is N or CR.sub.7;
[0031] U is C or N;
[0032] V is N, CR.sub.8 or V is a bond;
[0033] W is N or C;
[0034] X is O, S, N, CR.sub.9 or NR.sub.11;
[0035] Y is O, S, N, CR.sub.10 or NR.sub.12;
[0036] Z is C or N;
[0037] R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are
each independently selected from the group consisting of H,
C.sub.1-5 acyloxy, C.sub.2-6 alkenyl, C.sub.1-4 alkoxy, C.sub.1-8
alkyl, C.sub.1-4 alkylcarboxamide, C.sub.2-6 alkynyl, C.sub.1-4
alkylsulfonamide, C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl,
C.sub.1-4 alkylthio, C.sub.1-4 alkylureyl, amino, C.sub.1-4
alkylamino, C.sub.2-8 dialkylamino, carboxamide, cyano, C.sub.3-6
cycloalkyl, C.sub.2-6 dialkylcarboxamide, C.sub.2-6
dialkylsulfonamide, halogen, C.sub.1-4 haloalkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkylsulfinyl, C.sub.1-4
haloalkylsulfonyl, C.sub.1-4 haloalkylthio, hydroxyl, hydroxylamino
and nitro; wherein said C.sub.2-6 alkenyl, C.sub.1-8 alkyl,
C.sub.2-6 alkynyl and C.sub.3-6 cycloalkyl are optionally
substituted with 1, 2, 3 or 4 substituents selected from the group
consisting of C.sub.1-5 acyl, C.sub.1-5 acyloxy, C.sub.1-4 alkoxy,
C.sub.1-4 alkylamino, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylthiocarboxamide, C.sub.1-4 alkylsulfonamide, C.sub.1-4
alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
C.sub.1-4 alkylthioureyl, C.sub.1-4 alkylureyl, amino,
carbo-C.sub.1-6-alkoxy, carboxamide, carboxy, cyano, C.sub.2-8
dialkylamino, C.sub.2-6 dialkylcarboxamide, C.sub.1-4
dialkylthiocarboxamide, C.sub.2-6 dialkylsulfonamide, C.sub.1-4
alkylthioureyl, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkylsulfinyl, C.sub.1-4 haloalkylsulfonyl, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkylthio, halogen, hydroxyl,
hydroxylamino and nitro;
[0038] R.sub.11 and R.sub.12 are each independently selected from
C.sub.2-6 alkenyl, C.sub.1-8 alkyl, C.sub.2-6 alkynyl or C.sub.3-6
cycloalkyl optionally each substituted with 1, 2, 3 or 4
substituents selected from the group consisting of C.sub.1-5 acyl,
C.sub.1-5 acyloxy, C.sub.1-4 alkoxy, C.sub.1-4 alkylamino,
C.sub.1-4 alkylcarboxamide, C.sub.1-4 alkylthiocarboxamide,
C.sub.1-4 alkylsulfonamide, C.sub.1-4 alkylsulfinyl, C.sub.1-4
alkylsulfonyl, C.sub.1-4 alkylthio, C.sub.1-4 alkylthioureyl,
C.sub.1-4 alkylureyl, amino, carbo-C.sub.1-6-alkoxy, carboxamide,
carboxy, cyano, C.sub.2-8 dialkylamino, C.sub.2-6
dialkylcarboxamide, C.sub.1-4 dialkylthiocarboxamide, C.sub.2-6
dialkylsulfonamide, C.sub.1-4 alkylthioureyl, C.sub.1-4 haloalkoxy,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylsulfinyl, C.sub.1-4
haloalkylsulfonyl, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylthio,
halogen, hydroxyl, hydroxylamino and nitro;
[0039] Ar.sub.1 is aryl or heteroaryl each optionally substituted
with R.sub.13, R.sub.14, R.sub.15, R.sub.16, and R.sub.17; wherein
R.sub.13 is selected from the group consisting of C.sub.1-5 acyl,
C.sub.1-6 acylsulfonamide, C.sub.1-5 acyloxy, C.sub.2-6 alkenyl,
C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4 alkylamino, C.sub.1-6
alkylcarboxamide, C.sub.1-4 alkylthiocarboxamide, C.sub.2-6
alkynyl, C.sub.1-4 alkylsulfonamide, C.sub.1-4 alkylsulfinyl,
C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio, C.sub.1-4
alkylthioureyl, C.sub.1-4 alkylureyl, amino, arylsulfonyl,
carbamimidoyl, carbo-C.sub.1-6-alkoxy, carboxamide, carboxy, cyano,
C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyloxy, C.sub.2-6
dialkylamino, C.sub.2-6 dialkylcarboxamide, C.sub.2-6
dialkylthiocarboxamide, guanidinyl, halogen, C.sub.1-4 haloalkoxy,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylsulfinyl, C.sub.1-4
haloalkylsulfonyl, C.sub.1-4 haloalkylthio, heterocyclic,
heterocyclic-oxy, heterocyclicsulfonyl, heterocyclic-carbonyl,
heteroaryl, heteroarylcarbonyl, hydroxyl, nitro, C.sub.4-7
oxo-cycloalkyl, phenoxy, phenyl, sulfonamide, sulfonic acid, and
thiol, and wherein said C.sub.1-5 acyl, C.sub.1-6 acylsulfonamide,
C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4 alkylamino, C.sub.1-6
alkylsulfonamide, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
arylsulfonyl, carbamimidoyl, C.sub.2-6 dialkylamino, heterocyclic,
heterocyclic-carbonyl, heteroaryl, phenoxy and phenyl are each
optionally substituted with 1 to 5 substituents selected
independently from the group consisting of C.sub.1-5 acyl,
C.sub.1-5 acyloxy, C.sub.2-6 alkenyl, C.sub.1-4 alkoxy, C.sub.1-7
alkyl, C.sub.1-4 alkylamino, C.sub.1-4 alkylcarboxamide, C.sub.2-6
alkynyl, C.sub.1-4 alkylsulfonamide, C.sub.1-4 alkylsulfinyl,
C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio, C.sub.1-4 alkylureyl,
carbo-C.sub.1-6-alkoxy, carboxamide, carboxy, cyano, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkyloxy, C.sub.2-6 dialkylamino,
C.sub.2-6 dialkylcarboxamide, halogen, C.sub.1-4 haloalkoxy,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylsulfinyl, C.sub.1-4
haloalkylsulfonyl, C.sub.1-4 haloalkylthio, heteroaryl,
heterocyclic, hydroxyl, nitro, phenyl, and phosphonooxy, and
wherein said C.sub.1-7 alkyl and C.sub.1-4 alkylcarboxamide are
each optionally substituted with 1 to 5 substituents selected from
the group consisting of C.sub.1-4 alkoxy and hydroxy; or
[0040] R.sub.13 is a group of Formula (A): ##STR3## wherein: [0041]
"p" and "r" are independently 0, 1, 2 or 3; and [0042] R.sub.18 is
H, C.sub.1-5 acyl, C.sub.2-6 alkenyl, C.sub.1-8 alkyl, C.sub.1-4
alkylcarboxamide, C.sub.2-6 alkynyl, C.sub.1-4 alkylsulfonamide,
carbo-C.sub.1-6-alkoxy, carboxamide, carboxy, cyano, C.sub.3-7
cycloalkyl, C.sub.2-6 dialkylcarboxamide, halogen, heteroaryl or
phenyl, and wherein said heteroaryl or phenyl optionally
substituted with 1 to 5 substituents selected independently from
the group consisting of C.sub.1-4 alkoxy, amino, C.sub.1-4
alkylamino, C.sub.2-6 alkynyl, C.sub.2-8 dialkylamino, halogen,
C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl and hydroxyl;
[0043] R.sub.14, R.sub.15, R.sub.16, and R.sub.17 are each
independently selected form the group consisting of H, C.sub.1-5
acyl, C.sub.1-5 acyloxy, C.sub.2-6 alkenyl, C.sub.1-4 alkoxy,
C.sub.1-8 alkyl, C.sub.1-4 alkylcarboxamide, C.sub.2-6 alkynyl,
C.sub.1-4 alkylsulfonamide, C.sub.1-4 alkylsulfinyl, C.sub.1-4
alkylsulfonyl, C.sub.1-4 alkylthio, C.sub.1-4 alkylureyl,
carbo-C.sub.1-6-alkoxy, carboxamide, carboxy, cyano, C.sub.3-7
cycloalkyl, C.sub.2-6 dialkylcarboxamide, halogen, C.sub.1-4
haloalkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylsulfinyl,
C.sub.1-4 haloalkylsulfonyl, C.sub.1-4 haloalkylthio, hydroxyl and
nitro; or
[0044] two adjacent R.sub.14, R.sub.15, R.sub.16 and R.sub.17
together with the atoms to which they are attached form a 5, 6 or 7
member cycloalkyl, cycloalkenyl or heterocyclic group fused with
Ar.sub.1 wherein the 5, 6 or 7 member group is optionally
substituted with halogen; and
[0045] R.sub.2 is selected from the group consisting of C.sub.1-8
alkyl, C.sub.2-6 alkynyl, amino, aryl, carboxamide, carboxy, cyano,
C.sub.3-6-cycloalkyl, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl,
halogen, heteroaryl and hydroxyl; and wherein said C.sub.1-8 alkyl,
aryl and heteroaryl are each optionally substituted with 1 to 5
substituents selected from the group consisting of C.sub.1-5 acyl,
C.sub.1-5 acyloxy, C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4
alkylanino, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylthiocarboxamide, C.sub.1-4 alkylsulfonamide, C.sub.1-4
alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
C.sub.1-4 alkylthioureyl, C.sub.1-4 alkylureyl, amino,
carbo-C.sub.1-6-alkoxy, carboxamide, carboxy, cyano,
C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-heteroalkylene, C.sub.2-8
dialkylamino, C.sub.2-6 dialkylcarboxamide, C.sub.2-6
dialkylthiocarboxamide, C.sub.2-6 dialkylsulfonamide, C.sub.1-4
alkylthioureyl, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkylsulfinyl, C.sub.1-4 haloalkylsulfonyl, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkylthio, halogen, heterocyclic,
hydroxyl, hydroxylamino and nitro; or
[0046] R.sub.2 is --Ar.sub.2--Ar.sub.3 wherein Ar.sub.2 and
Ar.sub.3 are each independently aryl or heteroaryl each optionally
substituted with 1 to 5 substituents selected from the group
consisting of H, C.sub.1-5 acyl, C.sub.1-5 acyloxy, C.sub.1-4
alkoxy, C.sub.1-8 alkyl, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylthiocarboxamide, C.sub.1-4 alkylsulfinyl, C.sub.1-4
alkylsulfonyl, C.sub.1-4 alkylthio, amino, C.sub.1-4 alkylamino,
carbo-C.sub.1-6-alkoxy, carboxamide, carboxy, cyano,
C.sub.3-6-cycloalkyl, C.sub.2-8 dialkylamino, C.sub.2-6
dialkylcarboxamide, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl,
halogen, hydroxyl and nitro; or
[0047] R.sub.2 is a group of Formula (B): ##STR4## wherein: [0048]
R.sub.19 is H, C.sub.1-8 alkyl, C.sub.3-7 cycloalkyl, aryl,
heteroaryl or OR.sub.21; and R.sub.20 is F, Cl, Br, CN or
NR.sub.22R.sub.23; where R.sub.21 is H, C.sub.1-8 alkyl or
C.sub.3-7 cycloalkyl, and R.sub.22 and R.sub.23 are independently
H, C.sub.1-8 alkyl, C.sub.3-7 cycloalkyl, aryl or heteroaryl;
or
[0049] R.sub.2 is a group of Formula (C): ##STR5## wherein: [0050]
G is: [0051] i) --C(O)--, --C(O)NR.sub.25--, --NR.sub.25C(O)--,
--NR.sub.25--, --NR.sub.25C(O)O--, --OC(O)NR.sub.25--,
--CR.sub.25R.sub.26NR.sub.27C(O)--,
--CR.sub.25R.sub.26C(O)NR.sub.27--, --C(O)O--, --OC(O)--, --C(S)--,
--C(S)NR.sub.25--, --C(S)O--, --OC(S)--, --CR.sub.25R.sub.26--,
--O--, --S--, --S(O)--, --S(O).sub.2-- or a bond when D is
CR.sub.2R.sub.3; or [0052] ii) --CR.sub.25R.sub.26C(O)--, --C(O)--,
--CR.sub.25R.sub.26C(O)NR.sub.27--, --C(O)NR.sub.25--, --C(O)O--,
--C(S)--, --C(S)NR.sub.25--, --C(S)O--, --CR.sub.25R.sub.26--,
--S(O).sub.2--, or a bond when D is NR.sub.2; [0053] wherein
R.sub.25, R.sub.26 and R.sub.27 are each independently H or
C.sub.1-8 alkyl; and R.sub.24 is H, C.sub.1-8 alkyl, C.sub.3-7
cycloalkyl, phenyl, heteroaryl, or heterocyclic each optionally
substituted with 1 to 5 substituents selected from the group
consisting of C.sub.1-5 acyl, C.sub.1-5 acyloxy, C.sub.2-6 alkenyl,
C.sub.1-4 alkoxy, C.sub.1-7 alkyl, C.sub.1-4 alkylamino, C.sub.1-4
alkylcarboxamide, C.sub.1-4 alkylthiocarboxamide, C.sub.1-4
alkylsulfonamide, C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl,
C.sub.1-4 alkylthio, C.sub.1-4 alkylthioureyl, C.sub.1-4
alkylureyl, amino, carbo-C.sub.1-6-alkoxy, carboxamide, carboxy,
cyano, C.sub.3-7 cycloalkyl, C.sub.2-8 dialkylamino, C.sub.2-6
dialkylcarboxamide, C.sub.2-6 dialkylthiocarboxamide, C.sub.2-6
dialkylsulfonamide, C.sub.1-4 alkylthioureyl, C.sub.1-4 haloalkoxy,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylsulfinyl, C.sub.1-4
haloalkylsulfonyl, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylthio,
halogen, heteroaryl, heterocyclic, hydroxyl, hydroxylamino, nitro,
phenyl, phenoxy, and sulfonic acid, wherein said C.sub.1-4 alkoxy,
C.sub.1-7 alkyl, C.sub.1-4 alkylamino, heteroaryl, phenyl and
phenoxy are each optionally substituted with 1 to 5 substituents
selected from the group consisting of C.sub.1-5 acyl, C.sub.1-5
acyloxy, C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4 alkylamino,
C.sub.1-4 alkylcarboxamide, C.sub.1-4 alkylthiocarboxamide,
C.sub.1-4 alkylsulfonamide, C.sub.1-4 alkylsulfinyl, C.sub.1-4
alkylsulfonyl, C.sub.1-4 alkylthio, C.sub.1-4 alkylthioureyl,
C.sub.1-4 alkylureyl, amino, carbo-C.sub.1-6-alkoxy, carboxamide,
carboxy, cyano, C.sub.3-7 cycloalkyl, C.sub.2-8 dialkylamino,
C.sub.2-6 dialkylcarboxamide, C.sub.2-6 dialkylthiocarboxamide,
C.sub.2-6 dialkylsulfonamide, C.sub.1-4 alkylthioureyl, C.sub.1-4
haloalkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylsulfinyl,
C.sub.1-4 haloalkylsulfonyl, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkylthio, halogen, heterocyclic, hydroxyl, hydroxylamino,
nitro, and phenyl; provided that Z and U are not both N.
[0054] One aspect of the present invention pertains to
pharmaceutical compositions comprising at least one compound of the
present invention and a pharmaceutically acceptable carrier.
[0055] One aspect of the present invention pertains to methods for
the treatment of a metabolic-related disorder in an individual
comprising administering to the individual in need of such
treatment a therapeutically effective amount of a compound of the
present invention or a pharmaceutical composition thereof.
[0056] One aspect of the present invention pertains to methods of
decreasing food intake of an individual comprising administering to
the individual in need thereof a therapeutically effective amount
of a compound of the present invention or pharmaceutical
composition thereof.
[0057] One aspect of the present invention pertains to methods of
inducing satiety in an individual comprising administering to the
individual in need thereof a therapeutically effective amount of a
compound of the present invention or pharmaceutical composition
thereof.
[0058] One aspect of the present invention pertains to methods of
controlling or decreasing weight gain of an individual comprising
administering to the individual in need thereof a therapeutically
effective amount of a compound of the present invention or
pharmaceutical composition thereof.
[0059] One aspect of the present invention pertains to methods of
modulating a RUP3 receptor in an individual comprising contacting
the receptor with a compound of the present invention. In some
embodiments, the compound is an agonist for the RUP3 receptor. In
some embodiments, the modulation of the RUP3 receptor is the
treatment of a metabolic-related disorder.
[0060] Some embodiments of the present invention include a method
of modulating a RUP3 receptor in an individual comprising
contacting the receptor with a compound of the present invention
wherein the modulation of the RUP3 receptor reduces food intake of
the individual.
[0061] Some embodiments of the present invention include a method
of modulating a RUP3 receptor in an individual comprising
contacting the receptor with a compound of the present invention
wherein the modulation of the RUP3 receptor induces satiety in the
individual.
[0062] Some embodiments of the present invention include a method
of modulating a RUP3 receptor in an individual comprising
contacting the receptor with a compound of the present invention
wherein the modulation of the RUP3 receptor controls or reduces
weight gain of the individual.
[0063] One aspect of the present invention pertains to use of a
compound of the present invention for production of a medicament
for use in the treatment of a metabolic-related disorder.
[0064] One aspect of the present invention pertains to use of a
compound of the present invention for production of a medicament
for use in decreasing food intake in an individual.
[0065] One aspect of the present invention pertains to use of a
compound of the present invention for production of a medicament
for use of inducing satiety in an individual.
[0066] One aspect of the present invention pertains to use of a
compound of the present invention for production of a medicament
for use in controlling or decreasing weight gain in an
individual.
[0067] One aspect of the present invention pertains to a compound
of the present invention for use in a method of treatment of the
human or animal body by therapy.
[0068] One aspect of the present invention pertains to a compound
of the present invention for use in a method of treatment of a
metabolic-related disorder of the human or animal body by
therapy.
[0069] One aspect of the present invention pertains to a compound
of the present invention for use in a method of decreasing food
intake of the human or animal body by therapy.
[0070] One aspect of the present invention pertains to a compound
of the present invention for use in a method of inducing satiety of
the human or animal body by therapy.
[0071] One aspect of the present invention pertains to a compound
of the present invention for use in a method of controlling or
decreasing weight gain of the human or animal body by therapy.
[0072] Some embodiments of the present invention pertain to methods
wherein the human has a body mass index of about 18.5 to about 45.
In some embodiments, the human has a body mass index of about 25 to
about 45. In some embodiments, the human has a body mass index of
about 30 to about 45. In some embodiments, the human has a body
mass index of about 35 to about 45.
[0073] In some embodiments the individual is a mammal. In some
embodiments the mammal is a human.
[0074] In some embodiments, the metabolic-related disorder is
hyperlipidemia, type 1 diabetes, type 2 diabetes mellitus,
idiopathic type 1 diabetes (Type 1b), latent autoimmune diabetes in
adults (LADA), early-onset type 2 diabetes (EOD), youth-onset
atypical diabetes (YOAD), maturity onset diabetes of the young
(MODY), malnutrition-related diabetes, gestational diabetes,
coronary heart disease, ischemic stroke, restenosis after
angioplasty, peripheral vascular disease, intermittent
claudication, myocardial infarction (e.g. necrosis and apoptosis),
dyslipidemia, post-prandial lipemia, conditions of impaired glucose
tolerance (IGT), conditions of impaired fasting plasma glucose,
metabolic acidosis, ketosis, arthritis, obesity, osteoporosis,
hypertension, congestive heart failure, left ventricular
hypertrophy, peripheral arterial disease, diabetic retinopathy,
macular degeneration, cataract, diabetic nephropathy,
glomerulosclerosis, chronic renal failure, diabetic neuropathy,
metabolic syndrome, syndrome X, premenstrual syndrome, coronary
heart disease, angina pectoris, thrombosis, atherosclerosis,
myocardial infarction, transient ischemic attacks, stroke, vascular
restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia,
hypertrygliceridemia, insulin resistance, impaired glucose
metabolism, conditions of impaired glucose tolerance, conditions of
impaired fasting plasma glucose, obesity, erectile dysfunction,
skin and connective tissue disorders, foot ulcerations and
ulcerative colitis, endothelial dysfunction and impaired vascular
compliance.
[0075] In some embodiments, the metabolic-related disorder is type
I diabetes, type II diabetes, inadequate glucose tolerance, insulin
resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia,
hypercholesterolemia, dyslipidemia or syndrome X. In some
embodiments, the metabolic-related disorder is type II diabetes. In
some embodiments, the metabolic-related disorder is hyperglycemia.
In some embodiments, the metabolic-related disorder is
hyperlipidemia. In some embodiments, the metabolic-related disorder
is hypertriglyceridemia. In some embodiments, the metabolic-related
disorder is type I diabetes. In some embodiments, the
metabolic-related disorder is dyslipidemia. In some embodiments,
the metabolic-related disorder is syndrome X.
[0076] One aspect of the present invention pertains to a method of
producing a pharmaceutical composition comprising admixing at least
one compound, as described herein, and a pharmaceutically
acceptable carrier.
[0077] This application is related to two U.S. Provisional Patent
Applications, Ser. Nos. 60/487,443 filed Jul. 14, 2003; and
60/510,644 filed Oct. 10, 2003, both which are incorporated by
reference in their entirety.
[0078] Applicant reserves the right to exclude any one or more of
the compounds from any of the embodiments of the invention.
Applicant additionally reserves the right to exclude any disease,
condition or disorder from any of the embodiments of the
invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0079] FIG. 1A shows RT-PCR analysis of RUP3 expression in human
tissues. A total of twenty-two (22) human tissues were
analyzed.
[0080] FIG. 1B shows the cDNA Dot-Blot analysis of RUP 3 expression
in human tissues.
[0081] FIG. 1C shows analysis of RUP3 by RT-PCR with isolated human
pancreatic islets of Langerhans.
[0082] FIG. 1D shows analysis of RUP3 expression with cDNAs of rat
origin by RT-PCR.
[0083] FIG. 2A shows a polyclonal anti-RUP3 antibody prepared in
Rabbits.
[0084] FIG. 2B shows the expression of RUP3 in insulin-producing
.beta. cells of pancreatic islets.
[0085] FIG. 3 shows in vitro functional activities of RUP3.
[0086] FIG. 4 shows a RUP3 RNA blot.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0087] The scientific literature that has evolved around receptors
has adopted a number of terms to refer to ligands having various
effects on receptors. For clarity and consistency, the following
definitions will be used throughout this patent document.
[0088] AGONISTS shall mean moieties that interact and activate the
receptor, such as the RUP3 receptor and initiates a physiological
or pharmacological response characteristic of that receptor. For
example, when moieties activate the intracellular response upon
binding to the receptor, or enhance GTP binding to membranes.
[0089] AMINO ACID ABBREVIATIONS used herein are set out in TABLE 1:
TABLE-US-00002 TABLE 1 ALANINE ALA A ARGININE ARG R ASPARAGINE ASN
N ASPARTIC ACID ASP D CYSTEINE CYS C GLUTAMIC ACID GLU E GLUTAMINE
GLN Q GLYCINE GLY G HISTIDINE HIS H ISOLEUCINE ILE I LEUCINE LEU L
LYSINE LYS K METHIONINE MET M PHENYLALANINE PHE F PROLINE PRO P
SERINE SER S THREONINE THR T TRYPTOPHAN TRP W TYROSINE TYR Y VALINE
VAL V ALANINE ALA A
[0090] The term ANTAGONISTS is intended to mean moieties that
competitively bind to the receptor at the same site as agonists
(for example, the endogenous ligand), but which do not activate the
intracellular response initiated by the active form of the
receptor, and can thereby inhibit the intracellular responses by
agonists or partial agonists. Antagonists do not diminish the
baseline intracellular response in the absence of an agonist or
partial agonist.
[0091] CHEMICAL GROUP, MOIETY OR RADICAL: [0092] The term
"C.sub.1-5 acyl" denotes a C.sub.1-5 alkyl radical attached to a
carbonyl wherein the definition of alkyl has the same definition as
described herein; some examples include but not limited to, acetyl,
propionyl, n-butanoyl, iso-butanoyl, sec-butanoyl, t-butanoyl
(i.e., pivaloyl), pentanoyl and the like. [0093] The term
"C.sub.1-5 acyloxy" denotes an acyl radical attached to an oxygen
atom wherein acyl has the same definition has described herein;
some examples include but not limited to acetyloxy, propionyloxy,
butanoyloxy, iso-butanoyloxy, sec-butanoyloxy, t-butanoyloxy and
the like.
[0094] The term "C.sub.1-6 acylsulfonamide" refers to a C.sub.1-6
acyl attached directly to the nitrogen of the sulfonamide, wherein
the definitions for C.sub.1-6 acyl and sulfonamide have the same
meaning as described herein, and a C.sub.1-6 acylsulfonamide can be
represented by the following formula: ##STR6## Some embodiments of
the present invention are when acylsulfonamide is a C.sub.1-5
acylsulfonamide, some embodiments are C.sub.1-4 acylsulfonamide,
some embodiments are C.sub.1-3 acylsulfonamide, and some
embodiments are C.sub.1-2 acylsulfonamide. Examples of an
acylsulfonamide include, but not limited to, acetylsulfamoyl
[--S(.dbd.O).sub.2NHC(.dbd.O)Me], propionylsulfamoyl
[--S(.dbd.O).sub.2NHC(.dbd.O)Et], isobutyrylsulfamoyl,
butyrylsulfamoyl, 2-methyl-butyrylsulfamoyl,
3-methyl-butyrylsulfamoyl, 2,2-dimethyl-propionylsulfamoyl,
pentanoylsulfamoyl, 2-methyl-pentanoylsulfamoyl,
3-methyl-pentanoylsulfamoyl, 4-methyl-pentanoylsulfamoyl, and the
like.
[0095] The term "C.sub.2-6 alkenyl" denotes a radical containing 2
to 6 carbons wherein at least one carbon-carbon double bond is
present, some embodiments are 2 to 4 carbons, some embodiments are
2 to 3 carbons, and some embodiments have 2 carbons. Both E and Z
isomers are embraced by the term "alkenyl." Furthermore, the term
"alkenyl" includes di- and tri-alkenyls. Accordingly, if more than
one double bond is present then the bonds may be all E or Z or a
mixtures of E and Z. Examples of an alkenyl include vinyl, allyl,
2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,
2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexanyl, 2,4-hexadienyl and the
like.
[0096] The term "C.sub.1-4 alkoxy" as used herein denotes a radical
alkyl, as defined herein, attached directly to an oxygen atom.
Examples include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy,
t-butoxy, iso-butoxy, sec-butoxy and the like.
[0097] The term "C.sub.1-8 alkyl" denotes a straight or branched
carbon radical containing 1 to 8 carbons, some embodiments are 1 to
6 carbons, some embodiments are 1 to 3 carbons, and some
embodiments are 1 or 2 carbons. Examples of an alkyl include, but
not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl,
sec-butyl, iso-butyl, t-butyl, pentyl, iso-pentyl, t-pentyl,
neo-pentyl, 1-methylbutyl [i.e.,
--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3], 2-methylbutyl [i.e.,
--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3], n-hexyl and the like.
[0098] The term "C.sub.1-4 alkylcarboxamido" or "C.sub.1-4
alkylcarboxamide" denotes a single C.sub.1-4 alkyl group attached
to the nitrogen of an amide group, wherein alkyl has the same
definition as found herein. The C.sub.1-5 alkylcarboxamido may be
represented by the following: ##STR7## Examples include, but not
limited to, N-methylcarboxamide, N-ethylcarboxamide;
N-n-propylcarboxamide, N-iso-propylcarboxamide,
N-n-butylcarboxamide, N-sec-butylcarboxamide,
N-iso-butylcarboxamide, N-t-butylcarboxamide and the like.
[0099] The term "C.sub.1-3 alkylene" refers to a C.sub.1-3 divalent
straight carbon group. In some embodiments C.sub.1-3 alkylene
refers to, for example, --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, and the like. In some embodiments,
C.sub.1-3 alkylene refers to --CH--, --CHCH.sub.2--,
--CHCH.sub.2CH.sub.2--, and the like wherein these examples relate
generally to "A".
[0100] The term "C.sub.1-4 alkylsulfinyl" denotes a C.sub.1-4 alkyl
radical attached to a sulfoxide radical of the formula: --S(O)--
wherein the alkyl radical has the same definition as described
herein. Examples include, but not limited to, methylsulfinyl,
ethylsulfinyl, n-propylsulfinyl, iso-propylsulfinyl,
n-butylsulfinyl, sec-butylsulfinyl, iso-butylsulfinyl, t-butyl, and
the like.
[0101] The term "C.sub.1-4 alkylsulfonamide" refers to the groups
##STR8## wherein C.sub.1-4 alkyl has the same definition as
described herein.
[0102] The term "C.sub.1-4 alkylsulfonyl" denotes a C.sub.1-4 alkyl
radical attached to a sulfone radical of the formula:
--S(O).sub.2-- wherein the alkyl radical has the same definiti+on
as described herein. Examples include, but not limited to,
methylsulfonyl, ethylsulfonyl, n-propylsulfonyl,
iso-propylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl,
iso-butylsulfonyl, t-butyl, and the like.
[0103] The term "C.sub.1-4 alkylthio" denotes a C.sub.1-4 alkyl
radical attached to a sulfide of the formula: --S-- wherein the
alkyl radical has the same definition as described herein. Examples
include, but not limited to, methylsulfanyl (i.e., CH.sub.3S--),
ethylsulfanyl, n-propylsulfanyl, iso-propylsulfanyl,
n-butylsulfanyl, sec-butylsulfanyl, iso-butylsulfanyl, t-butyl, and
the like.
[0104] The term "C.sub.1-4 alkylthiocarboxamide" denotes a
thioamide of the following formulae: ##STR9## wherein C.sub.1-4
alkyl has the same definition as described herein.
[0105] The term "C.sub.1-4 alkylthioureyl" denotes the group of the
formula: --NC(S)N-- wherein one are both of the nitrogens are
substituted with the same or different C.sub.1-4 alkyl groups and
alkyl has the same definition as described herein. Examples of an
alkylthioureyl include, but not limited to, CH.sub.3NHC(S)NH--,
NH.sub.2C(S)NCH.sub.3--, (CH.sub.3).sub.2N(S)NH--,
(CH.sub.3).sub.2N(S)NH--, (CH.sub.3).sub.2N(S)NCH.sub.3--,
CH.sub.3CH.sub.2NHC(S)NH--, CH.sub.3CH.sub.2NHC(S)NCH.sub.3--, and
the like.
[0106] The term "C.sub.1-4 alkylureyl" denotes the group of the
formula: --NC(O)N-- wherein one are both of the nitrogens are
substituted with the same or different C.sub.1-4 alkyl group
wherein alkyl has the same definition as described herein. Examples
of an alkylureyl include, but not limited to, CH.sub.3NHC(O)NH--,
NH.sub.2C(O)NCH.sub.3--, (CH.sub.3).sub.2N(O)NH--,
(CH.sub.3).sub.2N(O)NH--, (CH.sub.3).sub.2N(O)NCH.sub.3--,
CH.sub.3CH.sub.2NHC(O)NH--, CH.sub.3CH.sub.2NHC(O)NCH.sub.3--, and
the like.
[0107] The term "C.sub.2-6 alkynyl" denotes a radical containing 2
to 6 carbons and at least one carbon-carbon triple bond, some
embodiments are 2 to 4 carbons, some embodiments are 2 to 3
carbons, and some embodiments have 2 carbons. Examples of an
alkynyl include, but not limited to, ethynyl, 1-propynyl,
2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl,
2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl,
3-hexynyl, 4-hexynyl, 5-hexynyl and the like. The term "alkynyl"
includes di- and tri-ynes.
[0108] The term "amino" denotes the group --NH.sub.2.
[0109] The term "C.sub.1-4 alkylamino" denotes one alkyl radical
attached to an amino radical wherein the alkyl radical has the same
meaning as described herein. Some examples include, but not limited
to, methylamino, ethylamino, n-propylamino, iso-propylamino,
n-butylamino, sec-butylamino, iso-butylamino, t-butylamino, and the
like. Some embodiments are "C.sub.1-2 alkylamino."
[0110] The term "aryl" denotes an aromatic ring radical containing
6 to 10 ring carbons. Examples include phenyl and naphthyl.
[0111] The term "arylalkyl" defines a C.sub.1-C.sub.4 alkylene,
such as --CH.sub.2--, --CH.sub.2CH.sub.2-- and the like, which is
further substituted with an aryl group. Examples of an "arylalkyl"
include benzyl, phenethylene and the like.
[0112] The term "arylcarboxamido" denotes a single aryl group
attached to the nitrogen of an amide group, wherein aryl has the
same definition as found herein. The example is
N-phenylcarboxamide.
[0113] The term "arylureyl" denotes the group --NC(O)N-- where one
of the nitrogens are substituted with an aryl.
[0114] The term "benzyl" denotes the group
--CH.sub.2C.sub.6H.sub.5.
[0115] The term "carbo-C.sub.1-6-alkoxy" refers to a C.sub.1-6
alkyl ester of a carboxylic acid, wherein the alkyl group is as
defined herein. In some embodiments, the carbo-C.sub.1-6-alkoxy
group is bonded to a nitrogen atom and together form a carbamate
group (e.g., N--COO--C.sub.1-6-alkyl). In some embodiments, the
carbo-C.sub.1-6-alkoxy group is an ester (e.g.,
--COO--C.sub.1-6-alkyl). Examples include, but not limited to,
carbomethoxy, carboethoxy, carbopropoxy, carboisopropoxy,
carbobutoxy, carbo-sec-butoxy, carbo-iso-butoxy, carbo-t-butoxy,
carbo-n-pentoxy, carbo-iso-pentoxy, carbo-t-pentoxy,
carbo-neo-pentoxy, carbo-n-hexyloxy, and the like.
[0116] The term "carboxamide" refers to the group --CONH.sub.2.
[0117] The term "carboxy" or "carboxyl" denotes the group
--CO.sub.2H; also referred to as a carboxylic acid group.
[0118] The term "cyano" denotes the group --CN.
[0119] The term "C.sub.3-7 cycloalkenyl" denotes a non-aromatic
ring radical containing 3 to 6 ring carbons and at least one double
bond; some embodiments contain 3 to 5 carbons; some embodiments
contain 3 to 4 carbons. Examples include cyclopropenyl,
cyclobutenyl, cyclopentenyl, cyclopentenyl, cyclohexenyl, and the
like.
[0120] The term "C.sub.3-7 cycloalkyl" denotes a saturated ring
radical containing 3 to 6 carbons; some embodiments contain 3 to 5
carbons; some embodiments contain 3 to 4 carbons. Examples include
cyclopropyl, cyclobutyl, cyclopentyl, cyclopenyl, cyclohexyl,
cycloheptyl and the like.
[0121] The term "C.sub.4-8 diacylamino" denotes an amino group
bonded with two acyl groups defined herein wherein the acyl groups
may be the same or different, such as: ##STR10## Examples of
C.sub.4-8 diacylamino groups include, but limited to,
diacetylamino, dipropionylamino, acetylpropionylamino and the
like.
[0122] The term "C.sub.2-6 dialkylamino" denotes an amino
substituted with two of the same or different alkyl radicals
wherein alkyl radical has the same definition as described herein.
Some examples include, but not limited to, dimethylamino,
methylethylamino, diethylamino, methylpropylamino,
methylisopropylamino, ethylpropylamino, ethylisopropylamino,
dipropylamino, propylisopropylamino and the like. Some embodiments
are "C.sub.2-4 dialkylamino."
[0123] The term "C.sub.1-4 dialkylcarboxamido" or "C.sub.1-4
dialkylcarboxamide" denotes two alkyl radicals, that are the same
or different, attached to an amide group, wherein alkyl has the
same definition as described herein. A C.sub.1-4 dialkylcarboxamido
may be represented by the following groups: ##STR11## wherein
C.sub.1-4 has the same definition as described herein. Examples of
a dialkylcarboxamide include, but not limited to,
NN-dimethylcarboxamide, N-methyl-N-ethylcarboxamide,
N,N-diethylcarboxamide, N-methyl-N-isopropylcarboxamide, and the
like.
[0124] The term "C.sub.2-6 dialkylsulfonamide" refers to one of the
following groups shown below: ##STR12##
[0125] wherein C.sub.1-3 has the same definition as described
herein, for example but not limited to, methyl, ethyl, n-propyl,
isopropyl, and the like.
[0126] The term "C.sub.2-6 dialkylthiocarboxamido" or "C.sub.2-6
dialkylthiocarboxamide" denotes two alkyl radicals, that are the
same or different, attached to a thioamide group, wherein alkyl has
the same definition as described herein. A C.sub.1-4
dialkylthiocarboxamido may be represented by the following groups:
##STR13## Examples of a dialkylthiocarboxamide include, but not
limited to, N,N-dimethylthiocarboxamide,
N-methyl-N-ethylthiocarboxamide and the like.
[0127] The term "C.sub.2-6 dialkylsulfonylamino" refers to an amino
group bonded with two C.sub.1-3 alkylsulfonyl groups as defined
herein.
[0128] The term "ethynylene" refers to the carbon-carbon triple
bond group as represented below: ##STR14##
[0129] The term "formyl" refers to the group --CHO.
[0130] The term "C.sub.1-4 haloalkoxy" denotes a haloalkyl, as
defined herein, which is directly attached to an oxygen atom.
Examples include, but not limited to, difluoromethoxy,
trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy and the
like.
[0131] The term "C.sub.1-4 haloalkyl" denotes an C.sub.1-4 alkyl
group, defined herein, wherein the alkyl is substituted with one
halogen up to fully substituted and a fully substituted C.sub.1-4
haloalkyl can be represented by the formula C.sub.nL.sub.2n+1
wherein L is a halogen and "n" is 1, 2, 3 or 4; when more than one
halogen is present then they may be the same or different and
selected from the group consisting of F, Cl, Br and I, preferably
F. Examples of C.sub.1-4 haloalkyl groups include, but not limited
to, fluoromethyl, difluoromethyl, trifluoromethyl,
chlorodifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl and
the like.
[0132] The term "C.sub.1-4 haloalkylcarboxamide" denotes an
alkylcarboxamide group, defmed herein, wherein the alkyl is
substituted with one halogen up to fully substituted represented by
the formula C.sub.nL.sub.2n+1 wherein L is a halogen and "n" is 1,
2, 3 or 4. When more than one halogen is present they may be the
same or different and selected from the group consisting of F, Cl,
Br and I, preferably F.
[0133] The term "C.sub.1-4 haloalkylsulfinyl" denotes a haloalkyl
radical attached to a sulfoxide group of the formula: --S(O)--
wherein the haloalkyl radical has the same definition as described
herein. Examples include, but not limited to,
trifluoromethylsulfinyl, 2,2,2-trifluoroethylsulfinyl,
2,2-difluoroethylsulfinyl and the like.
[0134] The term "C.sub.1-4 haloalkylsulfonyl" denotes a haloalkyl
radical attached to a sulfone group of the formula: --S(O).sub.2--
wherein haloalkyl has the same definition as described herein.
Examples include, but not limited to, trifluoromethylsulfonyl,
2,2,2-trifluoroethylsulfonyl, 2,2-difluoroethylsulfonyl and the
like.
[0135] The term "C.sub.1-4 haloalkylthio" denotes a haloalkyl
radicaol directly attached to a sulfur wherein the haloalkyl has
the same meaning as described herein. Examples include, but not
limited to, trifluoromethylthio (i.e., CF.sub.3S--),
1,1-difluoroethylthio, 2,2,2-trifluoroethylthio and the like.
[0136] The term "halogen" or "halo" denotes to a fluoro, chloro,
bromo or iodo group.
[0137] The term "C.sub.1-2 heteroalkylene" refers to a C.sub.1-2
alkylene bonded to a heteroatom selected from O, S, S(O),
S(O).sub.2 and NH. Some represented examples include, but not
limited to, the groups of the following formulae: ##STR15## and the
like.
[0138] The term "heteroaryl" denotes an aromatic ring system that
may be a single ring, two fused rings or three fused rings wherein
at least one ring carbon is replaced with a heteroatom selected
from, but not limited to, the group consisting of O, S and N
wherein the N can be optionally substituted with H, C.sub.1-4 acyl
or C.sub.1-4 alkyl. Examples of heteroaryl groups include, but not
limited to, pyridyl, benzofuranyl, pyrazinyl, pyridazinyl,
pyrimidinyl, triazinyl, quinoline, benzoxazole, benzothiazole,
1H-benzimidazole, isoquinoline, quinazoline, quinoxaline and the
like. In some embodiments, the heteroaryl atom is O, S, NH,
examples include, but not limited to, pyrrole, indole, and the
like. Other examples include, but not limited to, those in TABLE
2A, TABLE 4, and the like.
[0139] The term "heterocyclic" denotes a non-aromatic carbon ring
(i.e., cycloalkyl or cycloalkenyl as defined herein) wherein one,
two or three ring carbons are replaced by a heteroatom selected
from, but not limited to, the group consisting of O, S, N, wherein
the N can be optionally substituted with H, C.sub.1-4 acyl or
C.sub.1-4 alkyl, and ring carbon atoms optionally substituted with
oxo or a thiooxo thus forming a carbonyl or thiocarbonyl group. The
heterocyclic group is a 3-, 4-, 5-, 6- or 7-membered containing
ring. Examples of a heterocyclic group include but not limited to
aziridin-1-yl, aziridin-2-yl, azetidin-1-yl, azetidin-2-yl,
azetidin-3-yl, piperidin-1-yl, piperidin-4-yl, morpholin-4-yl,
piperzin-1-yl, piperzin-4-yl, pyrrolidin-1-yl, pyrrolidin-3-yl,
[1,3]-dioxolan-2-yl and the like. Additional examples of
heterocyclic groups are shown in TABLES 2B, 2C, 2D, 2E, 2F and 2G,
infra.
[0140] The term "heterocyclic-carbonyl" denotes a heterocyclic
group, as defined herein, directly bonded to the carbon of a
carbonyl group (i.e., C.dbd.O). In some embodiments, a ring
nitrogen of the heterocyclic group is bonded to the carbonyl group
forming an amide. Examples include, but not limited to, ##STR16##
and the like.
[0141] In some embodiments, a ring carbon is bonded to the carbonyl
group forming a ketone group. Examples include, but not limited to,
##STR17## and the like.
[0142] The term "heterocyclic-oxy" refers to a heterocyclic group,
as defined herein, that is directly bonded to an oxygen atom.
Examples include the following: ##STR18## and the like.
[0143] The term "heterocycliccarboxamido" denotes a heterocyclic
group, as defined herein, with a ring nitrogen where the ring
nitrogen is bonded directly to the carbonyl forming an amide.
Examples include, but not limited to, ##STR19## and the like.
[0144] The term "heterocyclicsulfonyl" denotes a heterocyclic
group, as defined herein, with a ring nitrogen where the ring
nitrogen is bonded directly to an SO.sub.2 group forming an
sulfonamide. Examples include, but not limited to, ##STR20## and
the like.
[0145] The term "hydroxyl" refers to the group --OH.
[0146] The term "hydroxylamino" refers to the group --NHOH.
[0147] The term "nitro" refers to the group --NO.sub.2.
[0148] The term "C.sub.4-7 oxo-cycloalkyl" refers to a C.sub.4-7
cycloalkyl, as defmed herein, wherein one of the ring carbons is
replaced with a carbonyl. Examples of C.sub.4-7 oxo-cycloalkyl
include, but are not limited to, 2-oxo-cyclobutyl,
3-oxo-cyclobutyl, 3-oxo-cyclopentyl, 4-oxo-cyclohexyl, and the like
and represented by the following structures respectively:
##STR21##
[0149] The term "perfluoroalkyl" denotes the group of the formula
--C.sub.nF.sub.2n+1; stated differently, a perfluoroalkyl is an
alkyl as defmed herein wherein the alkyl is fully substituted with
fluorine atoms and is therefore considered a subset of haloalkyl.
Examples of perfluoroalkyls include CF.sub.3, CF.sub.2CF.sub.3,
CF.sub.2CF.sub.2CF.sub.3, CF(CF.sub.3).sub.2,
CF.sub.2CF.sub.2CF.sub.2CF.sub.3, CF.sub.2CF(CF.sub.3).sub.2,
CF(CF.sub.3)CF.sub.2CF.sub.3 and the like.
[0150] The term "phenoxy" refers to the group
C.sub.6H.sub.5O--.
[0151] The term "phenyl" refers to the group C.sub.6H.sub.5--.
[0152] The term "phosphonooxy" refers to a group with the following
chemical structure: ##STR22##
[0153] The term "sulfonamide" refers to the group
--SO.sub.2NH.sub.2.
[0154] The term "sulfonic acid" refers to the group
--SO.sub.3H.
[0155] The term "tetrazolyl" refers to the five membered heteroaryl
of the following formulae: ##STR23## In some embodiments, the
tetrazolyl group is further substituted at either the 1 or 5
position resepectively with a group selected from the group
consisting of C.sub.1-3 alkyl, C.sub.1-3 haloalkyl and C.sub.1-3
alkoxy.
[0156] The term "thiol" denotes the group --SH.
[0157] CODON shall mean a grouping of three nucleotides (or
equivalents to nucleotides) which generally comprise a nucleoside
(adenosine (A), guanosine (G), cytidine (C), uridine (U) and
thymidine (T)) coupled to a phosphate group and which, when
translated, encodes an amino acid.
[0158] COMPOSITION shall mean a material comprising at least two
compounds or two components; for example, and without limitation, a
Pharmaceutical Composition is a Composition comprising a compound
of the present invention and a pharmaceutically acceptable
carrier.
[0159] COMPOUND EFFICACY shall mean a measurement of the ability of
a compound to inhibit or stimulate receptor functionality, as
opposed to receptor binding affinity.
[0160] CONSTITUTIVELY ACTIVATED RECEPTOR shall mean a receptor
subject to constitutive receptor activation.
[0161] CONSTITUTIVE RECEPTOR ACTIVATION shall mean stabilization of
a receptor in the active state by means other than binding of the
receptor with its endogenous ligand or a chemical equivalent
thereof.
[0162] CONTACT or CONTACTING shall mean bringing the indicated
moieties together, whether in an in vitro system or an in vivo
system. Thus, "contacting" a RUP3 receptor with a compound of the,
invention includes the administration of a compound of the present
invention to an individual, preferably a human, having a RUP3
receptor, as well as, for example, introducing a compound of the
invention into a sample containing a cellular or more purified
preparation containing a RUP3 receptor.
[0163] ENDOGENOUS shall mean a material that a mammal naturally
produces. ENDOGENOUS in reference to, for example and not
limitation, the term "receptor" shall mean that which is naturally
produced by a mammal (for example, and not limitation, a human) or
a virus.
[0164] In contrast, the term NON-ENDOGENOUS in this context shall
mean that which is not naturally produced by a mammal (for example,
and not limitation, a human) or a virus. For example, and not
limitation, a receptor which is not constitutively active in its
endogenous form, but when manipulated becomes constitutively
active, is most preferably referred to herein as a "non-endogenous,
constitutively activated receptor." Both terms can be utilized to
describe both "in vivo" and "in vitro" systems. For example, and
not a limitation, in a screening approach, the endogenous or
non-endogenous receptor may be in reference to an in vitro
screening system. As a further example and not limitation, where
the genome of a mammal has been manipulated to include a
non-endogenous constitutively activated receptor, screening of a
candidate compound by means of an in vivo system is viable.
[0165] IN NEED OF PROPHYLAXIS OR TREATMENT as used herein refers to
a judgment made by a caregiver (e.g. physician, nurse, nurse
practitioner, etc. in the case of humans; veterinarian in the case
of animals, including non-human mammals) that an individual or
animal requires or will benefit from prophylaxis or treatment. This
judgment is made based on a variety of factors that are in the
realm of a caregiver's expertise, but that includes the knowledge
that the individual or animal is ill, or will be ill, as the result
of a disease, condition or disorder that is treatable by the
compounds of the invention. In general, "in need of prophylaxis"
refers to the judgment made by the caregiver that the individual
will become ill. In this context, the compounds of the invention
are used in a protective or preventive manner. However, "in need of
treatment" refers to the judgment of the caregiver that the
individual is already ill, therefore, the compounds of the present
invention are used to alleviate, inhibit or ameliorate the disease,
condition or disorder.
[0166] INDIVIDUAL as used herein refers to any animal, including
mammals, preferably mice, rats, other rodents, rabbits, dogs, cats,
swine, cattle, sheep, horses, or primates, and most preferably
humans.
[0167] INHIBIT or INHIBITING, in relationship to the term
"response" shall mean that a response is decreased or prevented in
the presence of a compound as opposed to in the absence of the
compound.
[0168] INVERSE AGONISTS shall mean moieties that bind the
endogenous form of the receptor or to the constitutively activated
form of the receptor, and which inhibit the baseline intracellular
response initiated by the active form of the receptor below the
normal base level of activity which is observed in the absence of
agonists or partial agonists, or decrease GTP binding to membranes.
Preferably, the baseline intracellular response is inhibited in the
presence of the inverse agonist by at least 30%, more preferably by
at least 50%, and most preferably by at least 75%, as compared with
the baseline response in the absence of the inverse agonist.
[0169] LIGAND shall mean an endogenous, naturally occurring
molecule specific for an endogenous, naturally occurring
receptor.
[0170] As used herein, the terms MODULATE or MODULATING shall mean
to refer to an increase or decrease in the amount, quality,
response or effect of a particular activity, function or
molecule.
[0171] PHARMACEUTICAL COMPOSITION shall mean a composition
comprising at least one active ingredient, whereby the composition
is amenable to investigation for a specified, efficacious outcome
in a mammal (for example, without limitation, a human). Those of
ordinary skill in the art will understand and appreciate the
techniques appropriate for determining whether an active ingredient
has a desired efficacious outcome based upon the needs of the
artisan.
[0172] THERAPEUTICALLY EFFECTIVE AMOUNT as used herein refers to
the amount of active compound or pharmaceutical agent that elicits
the biological or medicinal response in a tissue, system, animal,
individual or human that is being sought by a researcher,
veterinarian, medical doctor or other clinician, which includes one
or more of the following:
[0173] (1) Preventing the disease; for example, preventing a
disease, condition or disorder in an individual that may be
predisposed to the disease, condition or disorder but does not yet
experience or display the pathology or symptomatology of the
disease,
[0174] (2) Inhibiting the disease; for example, inhibiting a
disease, condition or disorder in an individual that is
experiencing or displaying the pathology or symptomatology of the
disease, condition or disorder (i.e., arresting further development
of the pathology and/or symptomatology), and
[0175] (3) Ameliorating the disease; for example, ameliorating a
disease, condition or disorder in an individual that is
experiencing or displaying the pathology or symptomatology of the
disease, condition or disorder (i.e., reversing the pathology
and/or symptomatology).
Compounds of the Present Invention:
[0176] One aspect of the present invention encompasses fused aryl
and heteroaryl derivatives as shown in Formula (I): ##STR24## or a
pharmaceutically acceptable salt, hydrate or solvate thereof;
wherein Ar.sub.1, M, T, J, Y, X, V, W, Z, U, Q, K, E, A, B, D, and
have the same definitions as described herein, supra and infra.
[0177] Some embodiments of the present invention encompass fused
aryl and heteroaryl derivatives as shown in Formula (I)
wherein:
[0178] A and B are independently C.sub.1-3 alkylene optionally
substituted with 1 to 4 substituents selected from the group
consisting of C.sub.1-3 alkyl, C.sub.1-4 alkoxy, carboxy, cyano,
C.sub.1-3 haloalkyl and halogen;
[0179] D is O, S, S(O), S(O).sub.2, CR.sub.1R.sub.2 or N--R.sub.2,
wherein R.sub.1 is selected from the group consisting of H,
C.sub.1-8 alkyl, C.sub.1-4 alkoxy, halogen and hydroxyl;
[0180] E is N, C or CR.sub.3, wherein R.sub.3 is H or C.sub.1-8
alkyl;
[0181] is a single bond when E is N or CR.sub.3, or a double bond
when E is C;
[0182] K is a C.sub.1-3 alkylene group optionally substituted with
1 to 4 substituents selected from the group consisting of C.sub.1-3
alkyl, C.sub.1-4 alkoxy, carboxy, cyano, C.sub.1-3 haloalkyl and
halogen; or K is a bond;
[0183] Q is NR.sub.4, O, S, S(O) or S(O).sub.2, wherein R.sub.4 is
H or C.sub.1-8 alkyl;
[0184] T is N or CR.sub.5;
[0185] M is N or CR.sub.6;
[0186] J is N or CR.sub.7;
[0187] U is C or N;
[0188] V is N, CR.sub.8 or V is a bond;
[0189] W is N or C;
[0190] X is O, S, N, CR.sub.9 or NR.sub.11;
[0191] Y is O, S, N, CR.sub.10 or NR.sub.12;
[0192] Z is C or N;
[0193] R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are
independently selected from the group consisting of H, C.sub.1-5
acyloxy, C.sub.2-6 alkenyl, C.sub.1-4 alkoxy, C.sub.1-8 alkyl,
C.sub.1-4 alkylcarboxamide, C.sub.2-6 alkynyl, C.sub.1-4
alkylsulfonamide, C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl,
C.sub.1-4 alkylthio, C.sub.1-4 alkylureyl, amino, C.sub.1-4
alkylamino, C.sub.2-8 dialkylamino, carboxamide, cyano, C.sub.3-6
cycloalkyl, C.sub.2-6 dialkylcarboxamide, C.sub.2-6
dialkylsulfonamide, halogen, C.sub.1-4 haloalkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkylsulfinyl, C.sub.1-4
haloalkylsulfonyl, C.sub.1-4 haloalkylthio, hydroxyl, hydroxylamino
and nitro; wherein said C.sub.2-6 alkenyl, C.sub.1-8 alkyl,
C.sub.2-6 alkynyl and C.sub.3-6 cycloalkyl are optionally
substituted with 1, 2, 3 or 4 substituents selected from the group
consisting of C.sub.1-5 acyl, C.sub.1-5 acyloxy, C.sub.1-4 alkoxy,
C.sub.1-4 alkylamino, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylthiocarboxamide, C.sub.1-4 alkylsulfonamide, C.sub.1-4
alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
C.sub.1-4 alkylthioureyl, C.sub.1-4 alkylureyl, amino,
carbo-C.sub.1-6-alkoxy, carboxamide, carboxy, cyano, C.sub.2-8
dialkylamino, C.sub.2-6 dialkylcarboxamide, C.sub.1-4
dialkylthiocarboxamide, C.sub.2-6 dialkylsulfonamide, C.sub.1-4
alkylthioureyl, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkylsulfinyl, C.sub.1-4 haloalkylsulfonyl, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkylthio, halogen, hydroxyl,
hydroxylamino and nitro;
[0194] R.sub.11 and R.sub.12 are independently selected from
C.sub.2-6 alkenyl, C.sub.1-8 alkyl, C.sub.2-6 alkynyl or C.sub.3-6
cycloalkyl each optionally substituted with 1, 2, 3 or 4
substituents selected from the group consisting of C.sub.1-5 acyl,
C.sub.1-5 acyloxy, C.sub.1-4 alkoxy, C.sub.1-4 alkylamino,
C.sub.1-4 alkylcarboxamide, C.sub.1-4 alkylthiocarboxamide,
C.sub.1-4 alkylsulfonamide, C.sub.1-4 alkylsulfinyl, C.sub.1-4
alkylsulfonyl, C.sub.1-4 alkylthio, C.sub.1-4 alkylthioureyl,
C.sub.1-4 alkylureyl, amino, carbo-C.sub.1-6-alkoxy, carboxamide,
carboxy, cyano, C.sub.2-8 dialkylamino, C.sub.2-6
dialkylcarboxamide, C.sub.1-4 dialkylthiocarboxamide, C.sub.2-6
dialkylsulfonamide, C.sub.1-4 alkylthioureyl, C.sub.1-4 haloalkoxy,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylsulfinyl, C.sub.1-4
haloalkylsulfonyl, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylthio,
halogen, hydroxyl, hydroxylamino and nitro;
[0195] Ar.sub.1 is aryl or heteroaryl optionally substituted with
R.sub.13, R.sub.14, R.sub.15, R.sub.16 and R.sub.17; wherein
R.sub.13 is selected from the group consisting of H, C.sub.1-5
acyl, C.sub.1-5 acyloxy, C.sub.2-6 alkenyl, C.sub.1-4 alkoxy,
C.sub.1-8 alkyl, C.sub.1-4 alkylcarboxamide, C.sub.2-6 alkynyl,
C.sub.1-4 alkylsulfonamide, C.sub.1-4 alkylsulfinyl, C.sub.1-4
alkylsulfonyl, C.sub.1-4 alkylthio, C.sub.1-4 alkylureyl, amino,
arylsulfonyl, carbo-C.sub.1-6-alkoxy, carboxamide, carboxy, cyano,
C.sub.3-7 cycloalkyl, C.sub.2-6 dialkylcarboxamide, halogen,
C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkylsulfinyl, C.sub.1-4 haloalkylsulfonyl, C.sub.1-4
haloalkylthio, heterocyclic, heterocyclicsulfonyl, heteroaryl,
hydroxyl, nitro, C.sub.4-7 oxo-cycloalkyl, phenoxy, phenyl,
sulfonamide and sulfonic acid, and wherein said C.sub.1-5 acyl,
C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4 alkylsulfonamide,
alkylsulfonyl, arylsulfonyl, heteroaryl, phenoxy or phenyl each
optionally substituted with 1 to 5 substituents selected
independently from the group consisting of C.sub.1-5 acyl,
C.sub.1-5 acyloxy, C.sub.2-6 alkenyl, C.sub.1-4 alkoxy, Cl-g alkyl,
C.sub.1-4 alkylcarboxamide, C.sub.2-6 alkynyl, C.sub.1-4
alkylsulfonamide, C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl,
C.sub.1-4 alkylthio, C.sub.1-4 alkylureyl, carbo-C.sub.1-6-alkoxy,
carboxamide, carboxy, cyano, C.sub.3-7 cycloalkyl, C.sub.2-6
dialkylcarboxamide, halogen, C.sub.1-4 haloalkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkylsulfinyl, C.sub.1-4
haloalkylsulfonyl, C.sub.1-4 haloalkylthio, heteroaryl,
heterocyclic, hydroxyl, nitro and phenyl; or
[0196] R.sub.13 is a group of Formula (A): ##STR25##
[0197] wherein: [0198] "p" and "r" are independently 0, 1, 2 or 3;
and [0199] R.sub.18 is H, C.sub.1-5 acyl, C.sub.24 alkenyl,
C.sub.1-8 alkyl, C.sub.1-4 alkylcarboxamide, C.sub.2-6 alkynyl,
C.sub.1-4 alkylsulfonamide, carbo-C.sub.1-6-alkoxy, carboxamide,
carboxy, cyano, C.sub.3-7 cycloalkyl, C.sub.2-6 dialkylcarboxamide,
halogen, heteroaryl or phenyl, and wherein the heteroaryl or phenyl
optionally substituted with 1 to 5 substituents selected
independently from the group consisting of
[0200] C.sub.1-4 alkoxy, amino, C.sub.1-4 alkylamino, C.sub.2-6
alkynyl, C.sub.2-8 dialkylamino, halogen, C.sub.1-4 haloalkoxy,
C.sub.1-4 haloalkyl and hydroxyl;
[0201] R.sub.14-R.sub.17 are independently selected form the group
consisting of H, C.sub.1-5 acyl, C.sub.1-5 acyloxy, C.sub.2-6
alkenyl, C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4
alkylcarboxamide, C.sub.2-6 alkynyl, C.sub.1-4 alkylsulfonamide,
C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4
alkylthio, C.sub.1-4 alkylureyl, carbo-C.sub.1-6-alkoxy,
carboxamide, carboxy, cyano, C.sub.3-7 cycloalkyl, C.sub.2-6
dialkylcarboxamide, halogen, C.sub.1-4 haloalkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkylsulfinyl, C.sub.1-4
haloalkylsulfonyl, C.sub.1-4 haloalkylthio, hydroxyl and nitro;
or
[0202] two adjacent R.sub.14, R.sub.15, R.sub.16 and R.sub.17
together with the atoms to which they are attached form a 5, 6 or 7
membered cycloalkyl, cycloalkenyl or heterocyclic group fused with
Ar.sub.1 wherein the 5, 6 or 7 membered group is optionally
substituted with halogen; and
[0203] R.sub.2 is selected from the group consisting of H,
C.sub.1-8 alkyl, C.sub.2-6 alkynyl, amino, aryl, carboxamide,
carboxy, cyano, C.sub.3-6-cycloalkyl, C.sub.1-4 haloalkoxy,
C.sub.1-4 haloalkyl, halogen, heteroaryl and hydroxyl; and wherein
said C.sub.1-8 alkyl, aryl and heteroaryl are each optionally
substituted with 1 to 5 substituents selected from the group
consisting of C.sub.1-5 acyl, C.sub.1-5 acyloxy, C.sub.1-4 alkoxy,
C.sub.1-8 alkyl, C.sub.1-4 alkylamino, C.sub.1-4 alkylcarboxamide,
C.sub.1-4 alkylthiocarboxamide, C.sub.1-4 alkylsulfonamide,
C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4
alkylthio, C.sub.1-4 alkylthioureyl, C.sub.1-4 alkylureyl, amino,
carbo-C.sub.1-6-alkoxy, carboxamide, carboxy, cyano,
C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-heteroalkylene, C.sub.2-8
dialkylamino, C.sub.2-6 dialkylcarboxamide, C.sub.2-6
dialkylthiocarboxamide, C.sub.2-6 dialkylsulfonamide, C.sub.1-4
alkylthioureyl, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkylsulfinyl, C.sub.1-4 haloalkylsulfonyl, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkylthio, halogen, heterocyclic,
hydroxyl, hydroxylamino and nitro; or
[0204] R.sub.2 is --Ar.sub.2--Ar.sub.3 wherein Ar.sub.2 and
Ar.sub.3 are independently aryl or heteroaryl each optionally
substituted with 1 to 5 substituents selected from the group
consisting of H, C.sub.1-5 acyl, C.sub.1-5 acyloxy, C.sub.1-4
alkoxy, C.sub.1-8 alkyl, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylthiocarboxamide, C.sub.1-4 alkylsulfinyl, C.sub.1-4
alkylsulfonyl, C.sub.1-4 alkylthio, amino, C.sub.1-4 alkylamino,
carbo-C.sub.1-6-alkoxy, carboxamide, carboxy, cyano,
C.sub.3-6-cycloalkyl, C.sub.2-8 dialkylamino, C.sub.2-6
dialkylcarboxamide, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl,
halogen, hydroxyl and nitro; or
[0205] R.sub.2 is a group of Formula (B): ##STR26## wherein: [0206]
R.sub.19 is H, C.sub.1-8 alkyl, C.sub.3-7 cycloalkyl, aryl,
heteroaryl or OR.sub.21; and R.sub.20 is F, Cl, Br, CN or
NR.sub.22R.sub.23; where R.sub.21 is H, C.sub.1-8 alkyl or
C.sub.3-7 cycloalkyl, and R.sub.22 and R.sub.23 are independently
H, C.sub.1-8 alkyl, C.sub.3-7 cycloalkyl, aryl or heteroaryl;
or
[0207] R.sub.2 is a group of Formula (C): ##STR27## wherein: [0208]
G is selected from the group consisting of: [0209] i) C(O),
C(O)NR.sub.25, C(O)O, OC(O), C(S), C(S)NR.sub.25, C(S)O, OC(S),
CR.sub.25R.sub.26, O, S, S(O) and S(O).sub.2 when D is
CR.sub.1R.sub.2, or [0210] ii) C(O), C(O)NR.sub.25, C(O)O, C(S),
C(S)NR.sub.25, C(S)O, CR.sub.25R.sub.26 and S(O).sub.2 when D is
NR.sub.2, [0211] wherein R.sub.25 and R.sub.26 are independently H
or C.sub.1-8 alkyl; and [0212] R.sub.24 is C.sub.1-8 alkyl,
C.sub.3-7 cycloalkyl, phenyl or heteroaryl optionally substituted
with 1 to 5 substituents selected from the group consisting of
C.sub.1-5 acyl, C.sub.1-5 acyloxy, C.sub.1-4 alkoxy, C.sub.1-7
alkyl, C.sub.1-4 alkylamino, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylthiocarboxamide, C.sub.1-4 alkylsulfonamide, C.sub.1-4
alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C-.sub.1-4 alkylthio,
C.sub.1-4 alkylthioureyl, C.sub.1-4 alkylureyl, amino,
carbo-C.sub.1-6-alkoxy, carboxamide, carboxy, cyano, C.sub.3-7
cycloalkyl, C.sub.2-8 dialkylamino, C.sub.2-6 dialkylcarboxamide,
C.sub.2-6dialkylthiocarboxamide, C.sub.2-6dialkylsulfonamide,
C.sub.1-4 alkylthioureyl, C.sub.1-4 haloalkoxy, C-.sub.1-4
haloalkyl, C.sub.1-4 haloalkylsulfinyl, C.sub.1-4haloalkylsulfonyl,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylthio, halogen, hydroxyl,
hydroxylamino and nitro; or
[0213] a pharmaceutically acceptable salt, hydrate or solvate
thereof; provided that Z and U are not both N.
[0214] It is appreciated that certain features of the invention,
which are, for clarity, described in the context of separate
embodiments, may also be provided in combination in a single
embodiment. Conversely, various features of the invention which
are, for brevity, described in the context of a single embodiment,
may also be provided separately or in any suitable
subcombination.
[0215] As used herein, "substituted" indicates that at least one
hydrogen atom of the chemical group is replaced by a non-hydrogen
substituent or group, the non-hydrogen substituent or group can be
monovalent or divalent. When the substituent or group is divalent,
then it is understood that this group is further substituted with
another substituent or group. When a chemical group herein is
"substituted" it may have up to the full valance of substitution;
for example, a methyl group can be substituted by 1, 2, or 3
substituents, a methylene group can be substituted by 1 or 2
substituents, a phenyl group can be substituted by 1, 2, 3, 4, or 5
substituents, a naphthyl group can be substituted by 1, 2, 3, 4, 5,
6, or 7 substituents and the like. Likewise, "substituted with one
or more substituents" refers to the substitution of a group with
one substituent up to the total number of substituents physically
allowed by the group. Further, when a group is substituted with
more than one group they can be identical or they can be
different.
[0216] It is understood and appreciated that compounds of the
present invention may have one or more chiral centers, and
therefore can exist as enantiomers and/or diastereomers. The
invention is understood to extend to and embrace all such
enantiomers, diastereomers and mixtures thereof, including but not
limited, to racemates. Accordingly, some embodiments of the present
invention pertain to compounds, such as those represented in
Formula (I) and other formulae used throughout this disclosure,
that are R enantiomers. Further, some embodiments of the present
invention pertain to compounds, such as those represented in
Formula (I) and other formulae used throughout this disclosure,
that are S enantiomers. In examples where more than one chiral
center is present, then, some embodiments of the present invention
include compounds that are RS or SR enantiomers. In further
embodiments, compounds of the present invention are RR or SS
enantiomers. It is understood that compounds of Formula (I) and
formulae used throughout this disclosure are intended to represent
all individual enantiomers and mixtures thereof, unless stated or
shown otherwise.
[0217] Compounds of the invention can also include tautomeric
forms, such as keto-enol tautomers, and the like. Tautomeric forms
can be in equilibrium or sterically locked into one form by
appropriate substitution. It is understood that the various
tautomeric forms are within the scope of the compounds of the
present invention.
[0218] Compounds of the invention can also include all isotopes of
atoms occurring in the intermediates and/or final compounds.
Isotopes include those atoms having the same atomic number but
different mass numbers. For example, isotopes of hydrogen include
deuterium and tritium.
[0219] In some embodiments, compounds of the invention are not
4-[1-(2,4-Dimethyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-piperid-
ine-1-carboxylic acid ethyl ester;
4-(1-m-Tolyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-piperidine-1-carboxyl-
ic acid ethyl ester;
4-[1-(4-Methoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-piperidine-
-1-carboxylic acid ethyl ester;
4-[1-(4-Chloro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-piperidine--
1-carboxylic acid ethyl ester; and
4-(1-Phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-piperidine-1-carboxyli-
c acid ethyl ester.
[0220] In some embodiments of the present invention, is a single
bond.
[0221] Some embodiments of the present invention pertain to
compounds wherein Q is NR.sub.4. In some embodiments, R.sub.4 is
C.sub.1-8 alkyl optionally substituted with C.sub.2-8 dialkylamino.
In some embodiments, R.sub.4 is selected from the group consisting
of methyl, ethyl, isopropyl, and 2-dimethylamino-ethyl. In some
embodiments, R.sub.4 is H (i.e., NH).
[0222] In some embodiments, compounds of the present invention can
be represented by Formula (Ia) as illustrated below: ##STR28##
wherein each variable in Formula (Ia) has the same meaning as
described herein, supra and infra.
[0223] In some embodiments, K is a bond.
[0224] In some embodiments, K is selected from the group consisting
of --CH.sub.2--, --CH.sub.2CH.sub.2--, and
--CH(CH.sub.3)CH.sub.2--.
[0225] In some embodiments, K is --CH.sub.2-- or
--CH.sub.2CH.sub.2--.
[0226] Some embodiments of the present invention pertain to
compounds wherein Q is O. Some embodiments of the present invention
can be represented by Formula (Ic) as illustrated below: ##STR29##
wherein each variable in Formula (Ic) has the same meaning as
described herein, supra and infra. In some embodiments, K is
--CH.sub.2-- or --CH.sub.2CH.sub.2--.
[0227] In some embodiments, compounds of the present invention are
represented by Formula (Ic) and K is a bond; these embodiments can
be represented by Formula (Id) as illustrated below: ##STR30##
wherein each variable in Formula (Id) has the same meaning as
described herein, supra and infra.
[0228] Some embodiments of the present invention pertain to
compounds wherein Q is S, S(O) or S(O).sub.2. In some embodiments,
Q is S. In some embodiments, Q is S(O). In some embodiments, Q is
S(O).sub.2. Some embodiments of the present invention can be
represented by Formulae (Ie), (If) and (Ig) respectively as shown
below: ##STR31## wherein each variable in Formulae (Ie), (If) and
(Ig) has the same meaning as described herein, supra and infra.
[0229] Some embodiments of the present invention pertain to
compounds wherein A and B are independently C.sub.1-2 alkylene
optionally substituted with 1 to 4 substituents selected from the
group consisting of C.sub.1-3 alkyl, C.sub.1-4 alkoxy, carboxy,
cyano, C.sub.1-3 haloalkyl and halogen.
[0230] Some embodiments of the present invention pertain to
compounds wherein both A and B are C.sub.1 alkylene groups
optionally substituted with 1 to 2 methyl groups.
[0231] In some embodiments, A and B are both --CH.sub.2--. Some
embodiments of the present invention and can be represented by
Formula (Ik) as shown below: ##STR32## wherein each variable in
Formula (Ik) has the same meaning as described herein, supra and
infra.
[0232] In some embodiments, both A and B are --CH.sub.2-- and E is
CH.
[0233] In some embodiments, both A and B are --CH.sub.2--, E is CH,
and D is N--R.sub.2.
[0234] Some embodiments of the present invention pertain to
compounds wherein A is a C.sub.1 alkylene group and B is a C.sub.2
alkylene group wherein A is optionally substituted with 1 to 2
methyl groups and B is optionally substituted with 1 to 4 methyl
groups. In some embodiments, A is --CH.sub.2-- or --CH-- and B is
--CH.sub.2CH.sub.2--. It is understood that when is a single bond
there are two methods to describe the same ABED ring system, for
examples, in some embodiments A is --CH.sub.2--, B is
--CH.sub.2CH.sub.2--, and for the same embodiments, A is
--CH.sub.2CH.sub.2-- and B is --CH.sub.2--. Therefore, it is
understood that either method is correct. Some embodiments of the
present invention can be represented by Formulae (Im) and (In)
respectively as shown below: ##STR33## wherein each variable in
Formulae (Im) and (In) has the same meaning as described herein,
supra and infra. In some embodiments, A is --CH.sub.2--, B is
--CH.sub.2CH.sub.2--, and K is a --CH.sub.2-- or
--CH.sub.2CH.sub.2--. In some embodiments, A is --CH.sub.2--, B is
--CH.sub.2CH.sub.2--, and K is a bond.
[0235] In some embodiments, A is --CH.sub.2CH.sub.2-- and B is
--CH.sub.2--, and E is CH.
[0236] In some embodiments, A is --CH.sub.2CH.sub.2-- and B is
--CH.sub.2--, E is CH and D is N--R.sub.2.
[0237] Some embodiments of the present invention pertain to
compounds wherein A is a C.sub.1 alkylene group and B is a C.sub.3
alkylene group wherein A is optionally substituted with 1 to 2
methyl groups and B is optionally substituted with 1 to 4 methyl
groups. In some embodiments, A is --CH.sub.2-- or --CH-- and B is
--CH.sub.2CH.sub.2CH.sub.2-- and can be represented by Formulae
(Ip) and (Iq) respectively as shown below: ##STR34## wherein each
variable in Formulae (Ip) and (Iq) has the same meaning as
described herein, supra and infra.
[0238] Some embodiments of the present invention pertain to
compounds wherein A is a C.sub.2 alkylene,group and B is a C.sub.1
alkylene group wherein A is optionally substituted with 1 to 4
methyl groups and B is optionally substituted with 1 to 2 methyl
groups. In some embodiments, A is --CHCH.sub.2-- and B is
--CH.sub.2--; these embodiments can be represented by Formula (It)
as shown below: ##STR35## wherein each variable in Formula (It) has
the same meaning as described herein, supra and infra.
[0239] Some embodiments of the present invention pertain to
compounds wherein A is CH.sub.2 and B is --CH.sub.2CH.sub.2--,
--CH.sub.2CH(CH.sub.3)--, --CH(CH.sub.3)CH.sub.2--,
--CH.sub.2CH(CF.sub.3)-- or --CH(CF.sub.3)CH.sub.2--. In some
embodiments, compounds of the invention are represented by Formulae
(Iv), (Iw) and (Ix) as shown below: ##STR36## wherein each variable
in Formulae (Iv), (Iw) and (Ix) has the same meaning as described
herein, supra and infra. In some embodiments, D is N--R.sub.2. In
some embodiments, E is CR.sub.3. In some embodiments, R.sub.3 is
H.
[0240] Some embodiments of the present invention pertain to
compounds wherein A is a C.sub.3 alkylene group and B is a C.sub.1
alkylene group wherein A is optionally substituted with 1 to 4
methyl groups and B is optionally substituted with 1 to 2 methyl
groups. In some embodiments, A is --CHCH.sub.2CH.sub.2-- and B is
--CH.sub.2--. Some embodiments, compounds of the present invention
can be represented by Formulae (IIa) as shown below: ##STR37##
wherein each variable in Formulae (IIa) has the same meaning as
described herein, supra and infra.
[0241] In some embodiments, A is --CH.sub.2-- and B is
--CH.sub.2CH.sub.2CH.sub.2--. Some embodiments, compounds of the
present invention can be represented by Formulae (IIb) as shown
below: ##STR38## wherein each variable in Formulae (IIb) has the
same meaning as described herein, supra and infra.
[0242] In some embodiments, A is --CH.sub.2--, B is
--CH.sub.2CH.sub.2CH.sub.2-- and E is CH.
[0243] In some embodiments, A is --CH.sub.2--, B is
--CH.sub.2CH.sub.2CH.sub.2--, E is CH, and D is N--R.sub.2.
[0244] Some embodiments of the present invention pertain to
compounds wherein A and B are both C.sub.2 alkylene groups
optionally substituted with 1 to 4 methyl groups. In some
embodiments, A is --CH.sub.2CH.sub.2-- or --CHCH.sub.2-- and B is
--CH.sub.2CH.sub.2--. In some embodiments, both A and B are
--CH.sub.2CH.sub.2--. Some embodiments of the present invention can
be represented by Formulae (IIc) and (IId) as shown below:
##STR39## wherein each variable in Formulae (IIc) and (IId) has the
same meaning as described herein, supra and infra. In some
embodiments, both A and B are --CH.sub.2CH.sub.2-- and E is CH. In
some embodiments, A and B are both --CH.sub.2CH.sub.2--, D is
N--R.sub.2, and E is CR.sub.3. In some embodiments, both A and B
are --CH.sub.2CH.sub.2--, E is CH, and D is N--R.sub.2. Some
embodiments of the present invention can be represented by Formula
(IIf) as shown below: ##STR40## wherein each variable in Formula
(IIf) has the same meaning as described herein, supra and infra. In
some embodiments, compounds have the Formula (IIf) and R.sub.3 is
H. In further embodiment, K is a bond. In still further
embodiments, K is --CH.sub.2-- or --CH.sub.2CH.sub.2--.
[0245] Some embodiments of the present invention pertain to
compounds of Formula (IIg) as shown below: ##STR41## wherein each
variable in Formula (IIg) has the same meaning as described herein,
supra and infra. In some embodiments, R.sub.3 is H and Q is O
(i.e., oxygen).
[0246] Some embodiments of the present invention pertain to
compounds wherein A is a C.sub.2 alkylene group and B is a C.sub.3
alkylene groups wherein A and B are optionally substituted with 1
to 4 methyl groups. In some embodiments, A is --CH.sub.2CH.sub.2--
or --CHCH.sub.2-- and B is --CH.sub.2CH.sub.2CH.sub.2-- and can be
represented by Formulae (IIh) and (IIi) as shown below: ##STR42##
wherein each variable in Formulae (IIh) and (IIi) has the same
meaning as described herein, supra and infra.
[0247] Some embodiments of the present invention pertain to
compounds wherein A is a C.sub.3 alkylene group and B is a C.sub.2
alkylene group wherein A and B are optionally substituted with 1 to
4 methyl groups. In some embodiments, A is --CHCH.sub.2CH.sub.2--
and B is --CH.sub.2CH.sub.2--; these embodiments can be represented
by Formula (IIk) as shown below: ##STR43## wherein each variable in
Formula (IIk) has the same meaning as described herein, supra and
infra.
[0248] Some embodiments of the present invention pertain to
compounds wherein A and B are both C.sub.3 alkylene groups
optionally substituted with 1 to 4 methyl groups. In some
embodiments, A is --CH.sub.2CH.sub.2CH.sub.2-- or
--CHCH.sub.2CH.sub.2-- and B is --CH.sub.2CH.sub.2CH.sub.2-- and
are represented by Formulae (IIm) and (IIn) respectively as shown
below: ##STR44## wherein each variable in Formulae (IIm) and (IIn)
has the same meaning as described herein, supra and infra.
[0249] Some embodiments of the present invention pertain to
compounds wherein is a single bond, these embodiments are
represented by Formula (IIo) as shown below: ##STR45## wherein each
variable in Formula (IIo) has the same meaning as described herein,
supra and infra.
[0250] Some embodiments of the present invention pertain to
compounds wherein E is N.
[0251] Some embodiments of the present invention pertain to
compounds wherein E is CR.sub.3.
[0252] Some embodiments of the present invention pertain to
compounds wherein R.sub.3 is H.
[0253] In some embodiments, E is CH and D is N--R.sub.2.
[0254] In some embodiments, E is CH and D is CHR.sub.2.
[0255] Some embodiments of the present invention pertain to
compounds wherein is a double bond. It is understood that when is a
double bond then E is CR.sub.3 (i.e., carbon atom) and E is not N
(i.e., a nitrogen atom).
[0256] Some embodiments of the present invention pertain to
compounds wherein K is a C.sub.1-3 alkylene group optionally
substituted with 1 to 4 substituents selected from the group
consisting of C.sub.1-3 alkyl, C.sub.1-4 alkoxy, carboxy, cyano,
C.sub.1-3 haloalkyl and halogen. In some embodiments, K is a
--CH.sub.2-- group. In some embodiments, K is a
--CH.sub.2CH.sub.2-- group.
[0257] Some embodiments of the present invention pertain to
compounds wherein K is a bond; these embodiments are represented by
Formula (IIq) as shown below: ##STR46## wherein each variable in
Formula (IIq) has the same meaning as described herein, supra and
infra. In some embodiments, Q is O (i.e., an oxygen atom).
[0258] Some embodiments of the present invention pertain to
compounds wherein D is CR.sub.1R.sub.2 and can be represented by
Formula (IIt) as shown below: ##STR47## wherein each variable in
Formula (IIt) has the same meaning as described herein, supra and
infra. In some embodiments, R.sub.2 is selected from the group
consisting of H, amino, carboxamide, carboxy, cyano,
C.sub.3-6-cycloalkyl, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl,
halogen and hydroxyl. In some embodiments, R.sub.2 is selected from
the group consisting of OCH.sub.3, OCH.sub.2CH.sub.3,
OCH.sub.2CH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2,
OCH.sub.2(CH.sub.2).sub.2CH.sub.3, amino, carboxamide, carboxy,
cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, OCF.sub.3,
OCHF.sub.2, CF.sub.3, CHF.sub.2 and F. In some embodiments, R.sub.2
is C.sub.1-8 alkyl, aryl or heteroaryl optionally substituted with
1 to 5 substituents selected from the group consisting of C.sub.1-5
acyl, C.sub.1-5 acyloxy, C.sub.1-4 alkoxy, C.sub.1-8 alkyl,
C.sub.1-4 alkylamino, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylthiocarboxamide, C.sub.1-4 alkylsulfonamide, C.sub.1-4
alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
C.sub.1-4 alkylthioureyl, C.sub.1-4 alkylureyl, amino,
carbo-C.sub.1-6-alkoxy, carboxamide, carboxy, cyano,
C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-heteroalkylene, C.sub.2-8
dialkylamino, C.sub.2-6 dialkylcarboxamide, C.sub.2-6
dialkylthiocarboxamide, C.sub.2-6 dialkylsulfonamide, C.sub.1-4
alkylthioureyl, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkylsulfinyl, C.sub.1-4 haloalkylsulfonyl, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkylthio, halogen, heterocyclic,
hydroxyl, hydroxylamino and nitro. In some embodiments, R.sub.2 is
selected from the group consisting of CH.sub.3, CH.sub.2CH.sub.3,
CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH(CH.sub.3)(CH.sub.2CH.sub.3), CH.sub.2(CH.sub.2).sub.2CH.sub.3,
CH.sub.2(CH.sub.2).sub.3CH.sub.3. In some embodiments, R.sub.2 is
selected from the group consisting of CH.sub.2OCH.sub.3,
CH.sub.2CH.sub.2OCH.sub.3, CH.sub.2OCH.sub.2CH.sub.3,
CH.sub.2OCH.sub.2CH.sub.2CH.sub.3,
CH.sub.2CH.sub.2OCH.sub.2CH.sub.3,
CH.sub.2CH.sub.2OCH.sub.2CH.sub.2CH.sub.3,
CH.sub.2OCH(CH.sub.3).sub.2, CH.sub.2OCH.sub.2CH(CH.sub.3).sub.2,
CH.sub.2CO.sub.2H, CH.sub.2CH.sub.2CO.sub.2H, CH.sub.2OH,
CH.sub.2CH.sub.2OH and CH.sub.2CH.sub.2CH.sub.2OH. In some
embodiments, R.sub.2 is selected from the group consisting of
CH.sub.2SCH.sub.3, CH.sub.2SCH.sub.2CH.sub.3,
CH.sub.2SCH.sub.2CH.sub.2CH.sub.3, CH.sub.2SCH(CH.sub.3).sub.2,
CH.sub.2SCH.sub.2(CH.sub.2).sub.2CH.sub.3,
CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CH.sub.2SCH.sub.2CH.sub.3,
CH.sub.2CH.sub.2SCH.sub.2CH.sub.2CH.sub.3,
CH.sub.2CH.sub.2SCH(CH.sub.3).sub.2,
CH.sub.2CH.sub.2SCH.sub.2(CH.sub.2).sub.2CH.sub.3,
CH.sub.2S(O)CH.sub.3, CH.sub.2S(O)CH.sub.2CH.sub.3,
CH.sub.2S(O)CH.sub.2CH.sub.2CH.sub.3,
CH.sub.2S(O)CH(CH.sub.3).sub.2,
CH.sub.2S(O)CH.sub.2(CH.sub.2).sub.2CH.sub.3,
CH.sub.2CH.sub.2S(O)CH.sub.3, CH.sub.2CH.sub.2S(O)CH.sub.2CH.sub.3,
CH.sub.2CH.sub.2S(O)CH.sub.2CH.sub.2CH.sub.3,
CH.sub.2CH.sub.2S(O)CH(CH.sub.3).sub.2,
CH.sub.2CH.sub.2S(O)CH.sub.2(CH.sub.2).sub.2CH.sub.3,
CH.sub.2S(O).sub.2CH.sub.3, CH.sub.2S(O).sub.2CH.sub.2CH.sub.3,
CH.sub.2S(O).sub.2CH.sub.2CH.sub.2CH.sub.3,
CH.sub.2S(O).sub.2CH(CH.sub.3).sub.2,
CH.sub.2S(O).sub.2CH.sub.2(CH.sub.2).sub.2CH.sub.3,
CH.sub.2CH.sub.2S(O).sub.2CH.sub.3,
CH.sub.2CH.sub.2S(O).sub.2CH.sub.2CH.sub.3,
CH.sub.2CH.sub.2S(O).sub.2CH.sub.2CH.sub.2CH.sub.3,
CH.sub.2CH.sub.2S(O).sub.2CH(CH.sub.3).sub.2 and
CH.sub.2CH.sub.2S(O).sub.2CH.sub.2(CH.sub.2).sub.2CH.sub.3. In some
embodiments, R.sub.2 is selected from the group consisting of
CH.sub.2OCH.sub.2-cyclopropyl, CH.sub.2OCH.sub.2-cyclobutyl,
CH.sub.2OCH.sub.2-cyclopentyl, CH.sub.2OCH.sub.2-cyclohexyl,
CH.sub.2OCH.sub.2CH.sub.2-cyclopropyl,
CH.sub.2OCH.sub.2CH.sub.2-cyclobutyl,
CH.sub.2OCH.sub.2CH.sub.2-cyclopentyl,
CH.sub.2OCH.sub.2CH.sub.2-cyclohexyl,
CH.sub.2CH.sub.2OCH.sub.2-cyclopropyl,
C.sub.1-4.sub.2CH.sub.2OCH.sub.2-cyclobutyl,
CH.sub.2CH.sub.2OCH.sub.2-cyclopentyl,
CH.sub.2CH.sub.2OCH.sub.2-cyclohexyl,
CH.sub.2CH.sub.2OCH.sub.2CH.sub.2-cyclopropyl,
CH.sub.2CH.sub.2OCH.sub.2CH.sub.2-cyclobutyl,
CH.sub.2CH.sub.2OCH.sub.2CH.sub.2-cyclopentyl and
CH.sub.2CH.sub.2OCH.sub.2CH.sub.2-cyclohexyl. In some embodiments,
R.sub.2 is selected from the group consisting of
1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,
1,2,4-triazol-5-yl and 1,2,4-triazol-1-yl,
3-methyl-1,2,4-oxadiazol-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl,
3-ethyl-1,2,4-oxadiazol-5-yl, 3-ethyl-1,2,4-oxadiazol-5-yl,
5-methyl-1,3,4-oxadiazol-2-yl, 5-ethyl-1,3,4-oxadiazol-2-yl,
3-methyl-1,2,4-triazol-5-yl, 3-ethyl-1,2,4-triazol-5-yl,
3-methyl-1,2,4-triazol-1-yl, 3-ethyl-1,2,4-triazol-1-yl,
5-methyl-1,2,4-triazol-1-yl and 5-ethyl-1,2,4-triazol-1-yl.
[0259] In some embodiments R.sub.2 is a heteroaryl comprising
5-atoms in the aromatic ring and are represented by the following
formulae: TABLE-US-00003 TABLE 2A ##STR48## ##STR49## ##STR50##
##STR51## ##STR52##
wherein the 5-membered heteroaryl is bonded at any available
position of the ring, for example, a imidazolyl ring can be bonded
at one of the ring nitrogens (i.e., imidazol-1-yl group) or at one
of the ring carbons (i.e., imidazol-2-yl, imidazol-4-yl or
imiadazol-5-yl group). In some embodiments R.sub.2 is a 5-membered
heteroaryl, for example but not limited to those shown in TABLE 2A,
optionally substituted with 1 to 4 substituents selected from the
group consisting of C.sub.1-5 acyl, C.sub.1-5 acyloxy, C.sub.1-4
alkoxy, C.sub.1-8 alkyl, C.sub.1-4 alkylamino, C.sub.1-4
alkylcarboxamide, C.sub.1-4 alkylthiocarboxamide, C.sub.1-4
alkylsulfonamide, C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl,
C.sub.1-4 alkylthio, C.sub.1-4 alkylthioureyl, C.sub.1-4
alkylureyl, amino, carbo-C.sub.1-6-alkoxy, carboxamide, carboxy,
cyano, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-heteroalkylene, C.sub.2-8
dialkylamino, C.sub.2-6 dialkylcarboxamide, C.sub.2-6
dialkylthiocarboxamide, C.sub.2-6 dialkylsulfonamide, C.sub.1-4
alkylthioureyl, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkylsulfinyl, C.sub.1-4 haloalkylsulfonyl, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkylthio, halogen, heterocyclic,
hydroxyl, hydroxylamino and nitro.
[0260] In some embodiments R.sub.2 is a heteroaryl comprising
5-atoms in the aromatic ring and are represented by the following
formulae: ##STR53## wherein the 5-membered heteroaryl is bonded at
any available position of the ring as described above. In some
embodiments, R.sub.2 is a 5-membered heteroaryl optionally
substituted with 1 to 4 substituents selected from the group
consisting of C.sub.1-5 acyl, C.sub.1-5 acyloxy, C.sub.1-4 alkoxy,
C.sub.1-8 alkyl, C.sub.1-4 alkylamino, C.sub.1-4 alkylcarboxamide,
C.sub.1-4 alkylthiocarboxamide, C.sub.1-4 alkylsulfonamide,
C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4
alkylthio, C.sub.1-4 alkylthioureyl, C.sub.1-4 alkylureyl, amino,
carbo-C.sub.1--alkoxy, carboxamide, carboxy, cyano,
C.sub.3-6-cycloalkyl-C.sub.1-3-heteroalkylene, C.sub.2-8
dialkylamino, C.sub.2-6 dialkylcarboxamide, C.sub.2-6
dialkylthiocarboxamide, C.sub.2-6 dialkylsulfonamide, C.sub.1-4
alkylthioureyl, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkylsulfinyl, C.sub.1-4 haloalkylsulfonyl, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkylthio, halogen, heterocyclic,
hydroxyl, hydroxylamino and nitro.
[0261] In some embodiments R.sub.2 is a heterocyclic group
represented, for example, by the formulae in TABLE 2B.
TABLE-US-00004 TABLE 2B ##STR54## ##STR55## ##STR56## ##STR57##
##STR58##
[0262] It is understood that any one of the heterocyclic groups
shown in TABLES 2B to 2E may be bonded at any ring carbon or ring
nitrogen as allowed by the respective formula unless otherwise
specified. For example, a 2,5-dioxo-imidazolidinyl group may be
bonded at the ring carbon or at either of the two ring nitrogens to
give the following formulae respectively: ##STR59##
[0263] In some embodiments R.sub.2 is a heterocyclic represented,
for example, by the formulae in TABLE 2C. TABLE-US-00005 TABLE 2C
##STR60## ##STR61## ##STR62## ##STR63##
[0264] In some embodiments R.sub.2 is a heterocyclic represented,
for example, by the formulae in TABLE 2D. TABLE-US-00006 TABLE 2D
##STR64## ##STR65##
[0265] In some embodiments R.sub.2 is a heterocyclic represented,
for example, by the formulae in TABLE 2E. TABLE-US-00007 TABLE 2E
##STR66## ##STR67##
[0266] In some embodiments R.sub.2 is a heterocyclic represented,
for example, by the formulae in TABLE 2F wherein the C.sub.1-6
alkyl group on the respective ring nitrogen atoms may be the same
or different. TABLE-US-00008 TABLE 2F ##STR68##
[0267] In some embodiments R.sub.2 is a heterocyclic represented,
for example, by the formulae in TABLE 2G wherein the C.sub.1-6
alkyl group on the respective ring nitrogen atoms may be the same
or different. TABLE-US-00009 TABLE 2G ##STR69## ##STR70##
[0268] Some embodiments of the present invention pertain to
compounds of Formula (IIt) wherein R.sub.2 is --Ar.sub.2--Ar.sub.3
wherein Ar.sub.2 and Ar.sub.3 are independently aryl or heteroaryl
optionally substituted with 1 to 5 substituents selected from the
group consisting of H, C.sub.1-5 acyl, C.sub.1-5 acyloxy, C.sub.1-4
alkoxy, C.sub.1-8 alkyl, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylthiocarboxamide, C.sub.1-4 alkylsulfinyl, C.sub.1-4
alkylsulfonyl, C.sub.1-4 alkylthio, amino, carbo-C.sub.1-6-alkoxy,
carboxamide, carboxy, cyano, C.sub.3-6-cycloalkyl, C.sub.2-6
dialkylcarboxamide, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl,
halogen, hydroxyl and nitro.
[0269] In some embodiments Ar.sub.2 is a heteroaryl comprising
5-atoms in the aromatic ring and are represented by the following
formulae shown in TABLE 3. TABLE-US-00010 TABLE 3 ##STR71##
##STR72## ##STR73## ##STR74## ##STR75## ##STR76## ##STR77##
wherein the 5-membered heteroaryl is bonded at any position of the
ring, for example, a imidazolyl ring can be bonded at one of the
ring nitrogens (i.e., imidazol-1-yl group) or at one of the ring
carbons (i.e., imidazol-2-yl, imidazol-4-yl or imiadazol-5-yl
group) and Ar.sub.3 is bonded to any remaining available ring atom.
In some embodiments Ar.sub.2 is a heteroaryl and Ar.sub.3 is
phenyl. In some embodiments, Ar.sub.2 is a phenyl and Ar.sub.3 is
heteroaryl (such as a heteroaryl selected from TABLE 2A, supra). In
some embodiments the heteroaryl and phenyl are optionally
substituted with 1 to 5 substituents selected from the group
consisting of H, C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4
alkylcarboxamide, C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl,
C.sub.1-4 alkylthio, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl,
halogen, hydroxyl and nitro.
[0270] Some embodiments of the present invention pertain to
compounds of Formula (IIt) wherein R.sub.2 is Formula (B):
##STR78## wherein: [0271] R.sub.19 is C.sub.1-8 alkyl or C.sub.3-7
cycloalkyl; and R.sub.20 is F, Cl, Br or CN.
[0272] Some embodiments of the present invention pertain to
compounds of Formula (IIt) wherein R.sub.2 is Formula (C):
##STR79## wherein:
[0273] G is selected from the group consisting of C(O),
C(O)NR.sub.25, C(O)O, OC(O), C(S), C(S)NR.sub.25, C(S)O, OC(S),
CR.sub.25R.sub.26, O, S, S(O) and S(O).sub.2; wherein R.sub.25 and
R.sub.26 are independently H or C.sub.1-8 alkyl; and
[0274] R.sub.24 is C.sub.1-8 alkyl, C.sub.3-7 cycloalkyl, phenyl or
heteroaryl optionally substituted with 1 to 5 substituents selected
from the group consisting of C.sub.1-5 acyl, C.sub.1-5 acyloxy,
C.sub.1-4 alkoxy, C.sub.1-7 alkyl, C.sub.1-4 alkylamino, C.sub.1-4
alkylcarboxamide, C.sub.1-4 alkylthiocarboxamide, C.sub.1-4
alkylsulfonamide, C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl,
C.sub.1-4 alkylthio, C.sub.1-4 alkylthioureyl, C.sub.1-4
alkylureyl, amino, carbo-C.sub.1-6-alkoxy, carboxamide, carboxy,
cyano, C.sub.3-7 cycloalkyl, C.sub.2-8 dialkylamino, C.sub.2-6
dialkylcarboxamide, C.sub.2-6 dialkylthiocarboxamide, C.sub.2-6
dialkylsulfonamide, C.sub.1-4 alkylthioureyl, C.sub.1-4 haloalkoxy,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylsulfinyl, C.sub.1-4
haloalkylsulfonyl, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylthio,
halogen, hydroxyl, hydroxylamino and nitro.
[0275] Some embodiments of the present invention pertain to
compounds of Formula (IIt) wherein R.sub.2 is Formula (C) and G is
selected from the group consisting of C(O), C(O)NR.sub.25, C(O)O,
OC(O), C(S), C(S)NR.sub.25, C(S)O, OC(S) and CR.sub.25R.sub.26. In
some embodiments, R.sub.24 is C.sub.1-8 alkyl optionally
substituted with 1 to 5 substituents selected from the group
consisting of C.sub.1-5 acyl, C.sub.1-4 alkoxy, C.sub.1-7 alkyl,
C.sub.1-4 alkylcarboxamide, C.sub.1-4 alkylsulfonamide, C.sub.1-4
alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
carboxamide, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkylsulfinyl, C.sub.1-4 haloalkylsulfonyl, C.sub.1-4
haloalkyl, halogen and hydroxyl.
[0276] Some embodiments of the present invention pertain to
compounds of Formula (IIt) wherein R.sub.2 is Formula (C) and G is
selected from the group consisting of C(O), C(O)NR.sub.25, C(O)O,
OC(O), C(S), C(S)NR.sub.25, C(S)O, OC(S) and CR.sub.25R.sub.26. In
some embodiments, R.sub.24 is phenyl optionally substituted with 1
to 5 substituents selected from the group consisting of C.sub.1-5
acyl, C.sub.1-4 alkoxy, C.sub.1-7 alkyl, C.sub.1-4
alkylcarboxamide, C.sub.1-4 alkylsulfonamide, C.sub.1-4
alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
carboxamide, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkylsulfinyl, C.sub.1-4 haloalkylsulfonyl, C.sub.1-4
haloalkyl, halogen and hydroxyl.
[0277] Some embodiments of the present invention pertain to
compounds of Formula (IIt) wherein R.sub.2 is Formula (C) and G is
selected from the group consisting of C(O), C(O)NR.sub.25, C(O)O,
OC(O), C(S), C(S)NR.sub.25, C(S)O, OC(S) and CR.sub.25R.sub.26. In
some embodiments, R.sub.24 is heteroaryl optionally substituted
with 1 to 5 substituents selected from the group consisting of
C.sub.1-5 acyl, C.sub.1-4 alkoxy, C.sub.1-7 alkyl, C.sub.1-4
alkylcarboxamide, C.sub.1-4 alkylsulfonamide, C.sub.1-4
alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
carboxamide, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkylsulfinyl, C.sub.1-4 haloalkylsulfonyl, C.sub.1-4
haloalkyl, halogen and hydroxyl. In some embodiments, R.sub.24 is
selected from the group consisting of pyridinyl, pyridazinyl,
pyrimidinyl and pyrazinyl. In some embodiments, R.sub.24 is
pyridinyl.
[0278] Some embodiments of the present invention pertain to
compounds wherein R.sub.25 and R.sub.26 are independently H or
C.sub.1-2 alkyl.
[0279] Some embodiments of the present invention pertain to
compounds of Formula (IIt) wherein R.sub.2 is Formula (C) and G is
selected from the group consisting of O, S, S(O) and S(O).sub.2. In
some embodiments, R.sub.24 is C.sub.1-8 alkyl optionally
substituted with 1 to 5 substituents selected from the group
consisting of C.sub.1-5 acyl, C.sub.1-4 alkoxy, C.sub.1-7 alkyl,
C.sub.1-4 alkylcarboxamide, C.sub.1-4 alkylsulfonamide, C.sub.1-4
alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
carboxamide, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkylsulfinyl, C.sub.1-4 haloalkylsulfonyl, C.sub.1-4
haloalkyl, halogen and hydroxyl.
[0280] Some embodiments of the present invention pertain to
compounds of Formula (IIt) wherein R.sub.2 is Formula (C) and G is
selected from the group consisting of O, S, S(O) and S(O).sub.2. In
some embodiments, R.sub.24 is phenyl optionally substituted with 1
to 5 substituents selected from the group consisting of C.sub.1-5
acyl, C.sub.1-4 alkoxy, C.sub.1-7 alkyl, C.sub.1-4
alkylcarboxamide, C.sub.1-4 alkylsulfonamide, C.sub.1-4
alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
carboxamide, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkylsulfinyl, C.sub.1-4 haloalkylsulfonyl, C.sub.1-4
haloalkyl, halogen and hydroxyl.
[0281] Some embodiments of the present invention pertain to
compounds of Formula (IIt) wherein R.sub.2 is Formula (C) and G is
selected from the group consisting of O, S, S(O) and S(O).sub.2. In
some embodiments, R.sub.24 is heteroaryl optionally substituted
with 1 to 5 substituents selected from the group consisting of
C.sub.1-5 acyl, C.sub.1-4 alkoxy, C.sub.1-7 alkyl, C.sub.1-4
alkylcarboxamide, C.sub.1-4 alkylsulfonamide, C.sub.1-4
alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
carboxamide, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkylsulfinyl, C.sub.1-4 haloalkylsulfonyl, C.sub.1-4
haloalkyl, halogen and hydroxyl. In some embodiments, R.sub.24 is
selected from the group consisting of pyridinyl, pyridazinyl,
pyrimidinyl and pyrazinyl. In some embodiments, R.sub.24 is
pyridinyl.
[0282] Some embodiments of the present invention pertain to
compounds wherein R.sub.1 is H.
[0283] Some embodiments of the present invention pertain to
compounds wherein R.sub.2 is a group of Formula (C): ##STR80##
wherein G is:
[0284] --NHC(O)--, --NH--, --NHC(O)O--, --CH.sub.2NHC(O)--, or a
bond; and R.sub.24 is H, C.sub.1-8 alkyl, or heteroaryl, each
optionally substituted with 1 to 2 substituents selected from the
group consisting of C.sub.1-4 alkoxy, and C.sub.1-7 alkyl.
[0285] In some embodiments, R.sub.2 is selected from the group
consisting of the following: ##STR81##
[0286] Some embodiments of the present invention pertain to
compounds wherein R.sub.2 is of Formula (C): ##STR82## wherein:
[0287] G is --CR.sub.25R.sub.26C(O)--, --C(O)--, --C(O)NR.sub.25--,
--C(O)O--, --C(S)NR.sub.25--, --CR.sub.25R.sub.26--, or a bond,
wherein R.sub.25, and R.sub.26 are each independently H or
C.sub.1-8 alkyl; and R.sub.24 is H, C.sub.1-8 alkyl, C.sub.3-7
cycloalkyl, phenyl, heteroaryl, or heterocyclic each optionally
substituted with 1 to 5 substituents selected from the group
consisting of C.sub.1-4 alkoxy, C.sub.1-7 alkyl, C.sub.1-4
alkylamino, amino, carbo-C.sub.1-6-alkoxy, carboxy, C.sub.3-7
cycloalkyl, C.sub.2-8 dialkylamino, C.sub.1-4 haloalkoxy, C.sub.1-4
haloalkyl, halogen, heteroaryl, heterocyclic, hydroxyl, and nitro,
wherein said C.sub.1-4 alkoxy, C.sub.1-7 alkyl, C.sub.1-4
alkylamino, heteroaryl, and phenyl are each optionally substituted
with 1 to 5 substituents selected from the group consisting of
C.sub.1-4 alkoxy, carbo-C.sub.1-6-alkoxy, carboxamide, carboxy,
C.sub.3-7 cycloalkyl, halogen, heterocyclic, and phenyl.
[0288] In some embodiments, Formula (C) is
--CR.sub.25R.sub.26C(O)R.sub.24.
[0289] In some embodiments, Formula (C) is --C(O)R.sub.24.
[0290] In some embodiments, Formula (C) is
--C(O)NR.sub.25R.sub.24.
[0291] In some embodiments, Formula (C) is R.sub.24 (i.e., -G- is a
bond).
[0292] In some embodiments, Formula (C) is --C(O)OR.sub.24.
[0293] In some embodiments, Formula (C) is
--C(S)NR.sub.25R.sub.24.
[0294] In some embodiments, Formula (C) is
--CR.sub.25R.sub.26R.sub.24.
[0295] Some embodiments of the present invention pertain to
compounds wherein R.sub.2 is --C(O)OR.sub.24 and R.sub.24 is
C.sub.1-8 alkyl, C.sub.3-7 cycloalkyl, phenyl, heteroaryl, or
heterocyclic each optionally substituted with 1 to 5 substituents
selected from the group consisting of C.sub.1-4 alkoxy, C.sub.1-7
alkyl, C.sub.1-4 alkylsulfonyl, amino, carbo-C.sub.1-6-alkoxy,
carboxy, cyano, C.sub.3-7 cycloalkyl, C.sub.2-8 dialkylamino,
C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl, halogen, heteroaryl,
heterocyclic, hydroxyl, phenyl, phenoxy, and sulfonic acid, wherein
said C.sub.1-7 alkyl, phenyl and phenoxy are each optionally
substituted with 1 to 5 substituents selected from the group
consisting of amino, C.sub.1-4 haloalkoxy, and heterocyclic.
[0296] Some embodiments of the present invention pertain to
compounds wherein R.sub.2 is --C(O)OR.sub.24 and R.sub.24 is
C.sub.1-8 alkyl, or C.sub.3-7 cycloalkyl each optionally
substituted with 1 to 5 substituents selected from the group
consisting of C.sub.1-4 alkoxy, C.sub.1-7 alkyl, C.sub.1-4
alkylsulfonyl, carboxy, cyano, C.sub.3-7 cycloalkyl, C.sub.2-8
dialkylamino, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl, halogen,
heteroaryl, heterocyclic, hydroxyl, phenyl, phenoxy, and sulfonic
acid.
[0297] Some embodiments of the present invention pertain to
compounds wherein R.sub.2 is --C(O)OR.sub.24 and R.sub.24 is
C.sub.1-8 alkyl, or C.sub.3-7 cycloalkyl wherein said C.sub.3-7
cycloalkyl is optionally substituted with 1 to 5 substituents
selected from the group consisting of C.sub.1-4 alkoxy, C.sub.1-7
alkyl, carboxy, C.sub.2-8 dialkylamino, and halogen.
[0298] Some embodiments of the present invention pertain to
compounds wherein R.sub.2 is --C(O)OR.sub.24 and R.sub.24 is
C.sub.1-8 alkyl, or C.sub.3-7 cycloalkyl.
[0299] Some embodiments of the present invention pertain to
compounds wherein R.sub.2 is --C(O)R.sub.24 and R.sub.24 is
C.sub.1-8 alkyl, C.sub.3-7 cycloalkyl, phenyl, heteroaryl, or
heterocyclic each optionally substituted with 1 to 5 substituents
selected from the group consisting of C.sub.2-6 alkenyl, C.sub.1-4
alkoxy, C.sub.1-7 alkyl, C.sub.1-4 alkylsulfonyl, amino,
carbo-C.sub.1-6-alkoxy, carboxy, cyano, C.sub.3-7 cycloalkyl,
C.sub.2-8 dialkylamino, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl,
halogen, heteroaryl, heterocyclic, hydroxyl, phenyl, phenoxy, and
sulfonic acid, wherein said C.sub.1-7 alkyl, phenyl and phenoxy are
each optionally substituted with 1 to 5 substituents selected from
the group consisting of amino, C.sub.1-4 haloalkoxy, and
heterocyclic.
[0300] Some embodiments of the present invention pertain to
compounds wherein R.sub.2 is --C(O)R.sub.24 and R.sub.24 is
C.sub.1-8 alkyl, heteroaryl, or heterocyclic each optionally
substituted with 1 to 5 substituents selected from the group
consisting of H, C.sub.1-4 alkoxy, C.sub.1-7 alkyl, amino, carboxy,
halogen, heteroaryl, hydroxyl, phenoxy, and sulfonic acid, wherein
said C.sub.1-7 alkyl and phenoxy are optionally substituted with 1
to 5 substituents selected from the group consisting of amino,
C.sub.1-4 haloalkoxy, and heterocyclic.
[0301] Some embodiments of the present invention pertain to
compounds wherein R.sub.2 is --CH.sub.2R.sub.24, or --R.sub.24 and
R.sub.24 is C.sub.1-8 alkyl, C.sub.3-7 cycloalkyl, phenyl,
heteroaryl, or heterocyclic each optionally substituted with 1 to 5
substituents selected from the group consisting of C.sub.1-5 acyl,
C.sub.2-6 alkenyl, C.sub.1-4 alkoxy, C.sub.1-7 alkyl, C.sub.1-4
alkylsulfonyl, amino, carbo-C.sub.1-6-alkoxy, carboxy, cyano,
C.sub.3-7 cycloalkyl, C.sub.2-8 dialkylamino, C.sub.1-4 haloalkoxy,
C.sub.1-4 haloalkyl, halogen, heteroaryl, heterocyclic, hydroxyl,
phenyl, phenoxy, and sulfonic acid, wherein said C.sub.1-7 alkyl,
phenyl and phenoxy are each optionally substituted with 1 to 5
substituents selected from the group consisting of amino, C.sub.1-4
haloalkoxy, and heterocyclic.
[0302] Some embodiments of the present invention pertain to
compounds wherein R.sub.2 is --CH.sub.2R.sub.24, or --R.sub.24, and
R.sub.24 is C.sub.1-8 alkyl, C.sub.3-7 cycloalkyl, or heteroaryl
each optionally substituted with 1 to 5 substituents selected from
the group consisting of C.sub.1-5 acyl, C.sub.2-6 alkenyl,
C.sub.1-4 alkoxy, carbo-C.sub.1-6-alkoxy, carboxy, cyano, C.sub.3-7
cycloalkyl, and hydroxyl.
[0303] Some embodiments of the present invention pertain to
compounds wherein R.sub.2 is --S(O).sub.2R.sub.24 and R.sub.24 is
C.sub.1-8 alkyl, C.sub.3-7 cycloalkyl, phenyl, heteroaryl, or
heterocyclic each optionally substituted with 1 to 5 substituents
selected from the group consisting of C.sub.2-6 alkenyl, C.sub.1-4
alkoxy, C.sub.1-7 alkyl, C.sub.1-4 alkylsulfonyl, amino,
carbo-C.sub.1-6-alkoxy, carboxy, cyano, C.sub.3-7 cycloalkyl,
C.sub.2-8 dialkylamino, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl,
halogen, heteroaryl, heterocyclic, hydroxyl, phenyl, phenoxy, and
sulfonic acid, wherein said C.sub.1-7 alkyl, phenyl and phenoxy are
each optionally substituted with 1 to 5 substituents selected from
the group consisting of amino, C.sub.1-4 haloalkoxy, and
heterocyclic.
[0304] Some embodiments of the present invention pertain to
compounds wherein R.sub.2 is --S(O).sub.2R.sub.24 and R.sub.24 is
C.sub.1-8 alkyl, or heteroaryl and said heteroaryl is optionally
substituted with 1 to 5 C.sub.1-7 alkyl.
[0305] Some embodiments of the present invention pertain to
compounds wherein R.sub.2 is --CH.sub.2C(O)R.sub.24 and R.sub.24 is
C.sub.1-8 alkyl, C.sub.3-7 cycloalkyl, phenyl, heteroaryl, or
heterocyclic each optionally substituted with 1 to 5 substituents
selected from the group consisting of C.sub.2-6 alkenyl, C.sub.1-4
alkoxy, C.sub.1-7 alkyl, C.sub.1-4 alkylsulfonyl, amino,
carbo-C.sub.1-6-alkoxy, carboxy, cyano, C.sub.3-7 cycloalkyl,
C.sub.2-8 dialkylamino, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl,
halogen, heteroaryl, heterocyclic, hydroxyl, phenyl, phenoxy, and
sulfonic acid, wherein said C.sub.1-7 alkyl, phenyl and phenoxy are
each optionally substituted with 1 to 5 substituents selected from
the group consisting of amino, C.sub.1-4 haloalkoxy, and
heterocyclic.
[0306] Some embodiments of the present invention pertain to
compounds wherein R.sub.2 is --CH.sub.2C(O)R.sub.24 and R.sub.24 is
phenyl, heteroaryl, or heterocyclic each optionally substituted
with 1 to 5 substituents selected from the group consisting of
C.sub.1-4 alkoxy, C.sub.1-7 alkyl, C.sub.1-4 alkylsulfonyl, cyano,
C.sub.2-8 dialkylamino, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl,
halogen, heteroaryl, and phenyl.
[0307] Some embodiments of the present invention pertain to
compounds wherein R.sub.2 is --CH.sub.2C(O)NHR.sub.24 and R.sub.24
is C.sub.1-8 alkyl, C.sub.3-7 cycloalkyl, phenyl, heteroaryl, or
heterocyclic each optionally substituted with 1 to 5 substituents
selected from the group consisting of C.sub.2-6 alkenyl, C.sub.1-4
alkoxy, C.sub.1-7 alkyl, C.sub.1-4 alkylsulfonyl, amino,
carbo-C.sub.1-6alkoxy, carboxy, cyano, C.sub.3-7 cycloalkyl,
C.sub.2-8 dialkylamino, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl,
halogen, heteroaryl, heterocyclic, hydroxyl, phenyl, phenoxy, and
sulfonic acid, wherein said C.sub.1-7 alkyl, phenyl and phenoxy are
each optionally substituted with 1 to 5 substituents selected from
the group consisting of amino, C.sub.1-4 haloalkoxy, and
heterocyclic.
[0308] Some embodiments of the present invention pertain to
compounds wherein R.sub.2 is --CH.sub.2C(O)NHR.sub.24 and wherein
R.sub.24 is phenyl optionally substituted with 1 to 5 substituents
selected from the group consisting of C.sub.1-4 alkoxy, C.sub.1-8
alkyl, C.sub.1-4 haloalkyl, and halogen.
[0309] Some embodiments of the present invention pertain to
compounds wherein D is N--R.sub.2 and is represented by Formula
(IIv): ##STR83## wherein each variable in Formula (IIv) has the
same meaning as described herein, supra and infra. In some
embodiments, R.sub.2 is C.sub.1-8 alkyl, aryl or heteroaryl
optionally substituted with 1 to 5 substituents selected from the
group consisting of C.sub.1-5 acyl, C.sub.1-5 acyloxy, C.sub.1-4
alkoxy, C.sub.1-8 alkyl, C.sub.1-4 alkylamino, C.sub.1-4
alkylcarboxamide, C.sub.1-4 alkylthiocarboxamide, C.sub.1-4
alkylsulfonamide, C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl,
C.sub.1-4 alkylthio, C.sub.1-4 alkylthioureyl, C.sub.1-4
alkylureyl, amino, carbo-C.sub.1-6-alkoxy, carboxamide, carboxy,
cyano, C.sub.3-6-cycloalkyl,
C.sub.3-6-cycloalkyl-C.sub.1-3-heteroalkylene, C.sub.2-8
dialkylamino, C.sub.2-6 dialkylcarboxamide, C.sub.2-6
dialkylthiocarboxamide, C.sub.2-6 dialkylsulfonamide, C.sub.1-4
alkylthioureyl, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkylsulfinyl, C.sub.1-4 haloalkylsulfonyl, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkylthio, halogen, heterocyclic,
hydroxyl, hydroxylamino and nitro. In some embodiments, R.sub.2 is
pyridyl. In some embodiments, R.sub.2 is 2-pyridyl.
[0310] In some embodiments, R.sub.2 is selected from the group
consisting of CH.sub.2CH.sub.2C(CH.sub.3).sub.3,
CH.sub.2CH.sub.2CH(CH.sub.3).sub.2 and
CH.sub.2(CH.sub.2).sub.4CH.sub.3. In some embodiments, R.sub.2 is
selected from the group consisting of: CH.sub.3, CH.sub.2CH.sub.3,
CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH(CH.sub.3)(CH.sub.2CH.sub.3), CH.sub.2(CH.sub.2).sub.2CH.sub.3
and CH.sub.2(CH.sub.2).sub.3CH.sub.3. In some embodiments, R.sub.2
is selected from the group consisting of CH.sub.2OCH.sub.3,
CH.sub.2CH.sub.2OCH.sub.3, CH.sub.2OCH.sub.2CH.sub.3,
CH.sub.2OCH.sub.2CH.sub.2CH.sub.3,
CH.sub.2CH.sub.2OCH.sub.2CH.sub.3,
CH.sub.2CH.sub.2OCH.sub.2CH.sub.2CH.sub.3,
CH.sub.2OCH(CH.sub.3).sub.2, CH.sub.2OCH.sub.2CH(CH.sub.3).sub.2,
CH.sub.2CO.sub.2H, CH.sub.2CH.sub.2CO.sub.2H, CH.sub.2OH,
CH.sub.2CH.sub.2OH and CH.sub.2CH.sub.2CH.sub.2OH. In some
embodiments, R.sub.2 is selected from the group consisting of
CH.sub.2SCH.sub.3, CH.sub.2SCH.sub.2CH.sub.3,
CH.sub.2SCH.sub.2CH.sub.2CH.sub.3, CH.sub.2SCH(CH.sub.3).sub.2,
CH.sub.2SCH.sub.2(CH.sub.2).sub.2CH.sub.3,
CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2CH.sub.2SCH.sub.2CH.sub.3,
CH.sub.2CH.sub.2SCH.sub.2CH.sub.2CH.sub.3,
CH.sub.2CH.sub.2SCH(CH.sub.3).sub.2,
CH.sub.2CH.sub.2SCH.sub.2(CH.sub.2).sub.2CH.sub.3,
CH.sub.2S(O)CH.sub.3, CH.sub.2S(O)CH.sub.2CH.sub.3,
CH.sub.2S(O)CH.sub.2CH.sub.2CH.sub.3,
CH.sub.2S(O)CH(CH.sub.3).sub.2,
CH.sub.2S(O)CH.sub.2(CH.sub.2).sub.2CH.sub.3,
CH.sub.2CH.sub.2S(O)CH.sub.3, CH.sub.2CH.sub.2S(O)CH.sub.2CH.sub.3,
CH.sub.2CH.sub.2S(O)CH.sub.2CH.sub.2CH.sub.3,
CH.sub.2CH.sub.2S(O)CH(CH.sub.3).sub.2,
CH.sub.2CH.sub.2S(O)CH.sub.2(CH.sub.2).sub.2CH.sub.3,
CH.sub.2S(O).sub.2CH.sub.3, CH.sub.2S(O).sub.2CH.sub.2CH.sub.3,
CH.sub.2S(O).sub.2CH.sub.2CH.sub.2CH.sub.3,
CH.sub.2S(O).sub.2CH(CH.sub.3).sub.2,
CH.sub.2S(O).sub.2CH.sub.2(CH.sub.2).sub.2CH.sub.3,
CH.sub.2CH.sub.2S(O).sub.2CH.sub.3,
CH.sub.2CH.sub.2S(O).sub.2CH.sub.2CH.sub.3,
CH.sub.2CH.sub.2S(O).sub.2CH.sub.2CH.sub.2CH.sub.3,
CH.sub.2CH.sub.2S(O).sub.2CH(CH.sub.3).sub.2 and
CH.sub.2CH.sub.2S(O).sub.2CH.sub.2(CH.sub.2).sub.2CH.sub.3. In some
embodiments, R.sub.2 is CH.sub.2-cyclopropyl. In some embodiments,
R.sub.2 is selected from the group consisting of
CH.sub.2OCH.sub.2-cyclopropyl, CH.sub.2OCH.sub.2-cyclobutyl,
CH.sub.2OCH.sub.2-cyclopentyl, CH.sub.2OCH.sub.2-cyclohexyl,
CH.sub.2OCH.sub.2CH.sub.2-cyclopropyl,
CH.sub.2OCH.sub.2CH.sub.2-cyclobutyl,
CH.sub.2OCH.sub.2CH.sub.2-cyclopentyl,
CH.sub.2OCH.sub.2CH.sub.2-cyclohexyl,
CH.sub.2CH.sub.2OCH.sub.2-cyclopropyl,
CH.sub.2CH.sub.2OCH.sub.2-cyclobutyl,
CH.sub.2CH.sub.2OCH.sub.2-cyclopentyl,
CH.sub.2CH.sub.2OCH.sub.2-cyclohexyl,
CH.sub.2CH.sub.2OCH.sub.2CH.sub.2-cyclopropyl,
CH.sub.2CH.sub.2OCH.sub.2CH.sub.2-cyclobutyl,
CH.sub.2CH.sub.2OCH.sub.2CH.sub.2-cyclopentyl and
CH.sub.2CH.sub.2OCH.sub.2CH.sub.2-cyclohexyl. In some embodiments,
R.sub.2 is selected from the group consisting of
1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,
1,2,4-triazol-5-yl and 1,2,4-triazol-1-yl,
3-methyl-1,2,4-oxadiazol-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl,
3-ethyl-1,2,4-oxadiazol-5-yl, 3-ethyl-1,2,4-oxadiazol-5-yl,
5-methyl-1,3,4-oxadiazol-2-yl, 5-ethyl-1,3,4-oxadiazol-2-yl,
3-methyl-1,2,4-triazol-5-yl, 3-ethyl-1,2,4-triazol-5-yl,
3-methyl-1,2,4-triazol-1-yl, 3-ethyl-1,2,4-triazol-1-yl,
5-methyl-1,2,4-triazol-1-yl and 5-ethyl-1,2,4-triazol-1-yl.
[0311] In some embodiments, compounds are of Formula (IIv) and
R.sub.2 is a heteroaryl comprising 5-atoms in the ring selected
from the group shown in Table 2A. In some embodiments, R.sub.2 is a
5-membered heteroaryl optionally substituted with 1 to 4
substituents selected from the group consisting of C.sub.1-5 acyl,
C.sub.1-5 acyloxy, C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4
alkylamino, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylthiocarboxamide, C.sub.1-4 alkylsulfonamide, C.sub.1-4
alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
C.sub.1-4 alkylthioureyl, C.sub.1-4 alkylureyl, amino,
carbo-C.sub.1-6-alkoxy, carboxamide, carboxy, cyano,
C.sub.3-6-cycloalkyl-C.sub.1-3-heteroalkylene, C.sub.2-8
dialkylamino, C.sub.2-6 dialkylcarboxamide, C.sub.2-6
dialkylthiocarboxamide, C.sub.2-6 dialkylsulfonamide, C.sub.1-4
alkylthioureyl, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkylsulfinyl, C.sub.1-4 haloalkylsulfonyl, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkylthio, halogen, heterocyclic,
hydroxyl, hydroxylamino and nitro.
[0312] In some embodiments R.sub.2 is a heterocyclic group selected
from the groups shown in TABLE 2B to TABLE 2G.
[0313] Some embodiments of the present invention pertain to
compounds of Formula (IIv) wherein R.sub.2 is --Ar.sub.2--Ar.sub.3
wherein Ar.sub.2 and Ar.sub.3 are independently aryl or heteroaryl
optionally substituted with 1 to 5 substituents selected from the
group consisting of H, C.sub.1-5 acyl, C.sub.1-5 acyloxy, C.sub.1-4
alkoxy, C.sub.1-8 alkyl, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylthiocarboxamide, C.sub.1-4 alkylsulfinyl, C.sub.1-4
alkylsulfonyl, C.sub.1-4 alkylthio, amino, carbo-C.sub.1-6-alkoxy,
carboxamide, carboxy, cyano, C.sub.3-6-cycloalkyl, C.sub.2-6
dialkylcarboxamide, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl,
halogen, hydroxyl and nitro. In some embodiments Ar.sub.2 is a
heteroaryl comprising 5-atoms in the aromatic ring and selected
from the group shown in TABLE 3. In some embodiments Ar.sub.2 is a
heteroaryl and Ar.sub.3 is phenyl. In some embodiments, Ar.sub.2 is
a phenyl and Ar.sub.3 is heteroaryl (such as a heteroaryl selected
from TABLE 2A or TABLE 4, supra). In some embodiments, the
heteroaryl and the phenyl are optionally substituted with 1 to 5
substituents selected from the group consisting of C.sub.1-4
alkoxy, C.sub.1-8 alkyl, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio, cyano,
C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl, halogen, hydroxyl and
nitro.
[0314] Some embodiments of the present invention pertain to
compounds wherein D is N--R.sub.2. In some embodiments, R.sub.2 is
Formula (B): ##STR84## wherein R.sub.19 is C.sub.1-8 alkyl or
C.sub.3-7 cycloalkyl; and R.sub.20 is F, Cl, Br or CN.
[0315] Some embodiments of the present invention pertain to
compounds of Formula (IIv) wherein R.sub.2 is Formula (C):
##STR85##
[0316] wherein G is selected from the group consisting of C(O),
C(O)NR.sub.25, C(O)O, C(S), C(S)NR.sub.25, C(S)O, CR.sub.25R.sub.26
and S(O).sub.2, wherein R.sub.25 and R.sub.26 are independently H
or C.sub.1-8 alkyl; and
[0317] R.sub.24 is C.sub.1-8 alkyl, C.sub.3-7 cycloalkyl, phenyl or
heteroaryl optionally substituted with 1 to 5 substituents selected
from the group consisting of C.sub.1-5 acyl, C.sub.1-5 acyloxy,
C.sub.1-4 alkoxy, C.sub.1-7 alkyl, C.sub.1-4 alkylamino, C.sub.1-4
alkylcarboxamide, C.sub.1-4 alkylthiocarboxamide, C.sub.1-4
alkylsulfonamide, C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl,
C.sub.1-4 alkylthio, C.sub.1-4 alkylthioureyl, C.sub.1-4
alkylureyl, amino, carbo-C.sub.1-6-alkoxy, carboxamide, carboxy,
cyano, C.sub.3-7 cycloalkyl, C.sub.2-8 dialkylamino, C.sub.2-6
dialkylcarboxamide, C.sub.2-6 dialkylthiocarboxamide, C.sub.2-6
dialkylsulfonamide, C.sub.1-4 alkylthioureyl, C.sub.1-4 haloalkoxy,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylsulfinyl, C.sub.1-4
haloalkylsulfonyl, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylthio,
halogen, hydroxyl, hydroxylamino and nitro.
[0318] Some embodiments of the present invention pertain to
compounds of Formula (IIv) wherein R.sub.2 is Formula (C) and
R.sub.24 is C.sub.1-8 alkyl optionally substituted with 1 to 5
substituents selected from the group consisting of C.sub.1-5 acyl,
C.sub.1-4 alkoxy, C.sub.1-7 alkyl, C.sub.1-4 alkylcarboxamide,
C.sub.1-4 alkylsulfonamide, C.sub.1-4 alkylsulfinyl, C.sub.1-4
alkylsulfonyl, C.sub.1-4 alkylthio, carboxamide, C.sub.1-4
haloalkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylsulfinyl,
C.sub.1-4 haloalkylsulfonyl, C.sub.1-4 haloalkyl, halogen and
hydroxyl.
[0319] In some embodiments, the group -G-R.sub.24 is selected from
the group consisting of C(O)CH.sub.3, C(O)CH.sub.2CH.sub.3,
C(O)CH.sub.2CH.sub.2CH.sub.3, C(O)CH(CH.sub.3).sub.2,
C(O)CH.sub.2CH.sub.2CH.sub.2CH.sub.3, C(O)C(CH.sub.3).sub.3,
C(O)CH.sub.2C(CH.sub.3).sub.3, CH3, CH.sub.2CH.sub.3,
CH.sub.2CH.sub.2CH.sub.3, CH(CH3).sub.2,
CH(CH.sub.3)(CH.sub.2CH.sub.3), CH.sub.2(CH.sub.2).sub.2CH.sub.3,
C(CH.sub.3).sub.3, CH.sub.2(CH.sub.2).sub.3CH.sub.3,
C(O)NHCH.sub.3, C(O)NHCH.sub.2CH.sub.3,
C(O)NHCH.sub.2CH.sub.2CH.sub.3, C(O)NHCH(CH.sub.3).sub.2,
C(O)NHCH.sub.2(CH.sub.2).sub.2CH.sub.3, C(O)N(CH.sub.3).sub.2,
C(O)N(CH.sub.3)CH.sub.2CH.sub.3, C(O)NH(CH.sub.2CH.sub.3).sub.2,
CO.sub.2CH.sub.3, CO.sub.2CH.sub.2CH.sub.3,
CO.sub.2CH.sub.2CH.sub.2CH.sub.3, CO.sub.2CH(CH.sub.3).sub.2,
CO.sub.2CH.sub.2(CH.sub.2).sub.2CH.sub.3,
CO.sub.2C(CH.sub.3).sub.3, CO.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3,
CO.sub.2CH.sub.2CH(CH.sub.3).sub.2,
CO.sub.2CH.sub.2(CH.sub.2).sub.3CH.sub.3,
CO.sub.2CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3,
CO.sub.2CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3,
CO.sub.2CH.sub.2CH.sub.2CH(CH.sub.3).sub.2, and
CO.sub.2CH.sub.2C(CH.sub.3).sub.3.
[0320] Some embodiments of the present invention pertain to
compounds of Formula (IIIv) wherein R.sub.2 is Formula (C) and
R.sub.24 is phenyl optionally substituted with 1 to 5 substituents
selected from the group consisting of C.sub.1-5 acyl, C.sub.1-4
alkoxy, C.sub.1-7 alkyl, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylsulfonamide, C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl,
C.sub.1-4 alkylthio, carboxamide, C.sub.1-4 haloalkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkylsulfinyl, C.sub.1-4
haloalkylsulfonyl, C.sub.1-4 haloalkyl, halogen and hydroxyl.
[0321] Some embodiments of the present invention pertain to
compounds of Formula (IIv) wherein R.sub.2 is Formula (C) and
R.sub.24 is heteroaryl optionally substituted with 1 to 5
substituents selected from the group consisting of C.sub.1-5 acyl,
C.sub.1-4 alkoxy, C.sub.1-7 alkyl, C.sub.1-4 alkylcarboxamide,
C.sub.1-4 alkylsulfonamide, C.sub.1-4 alkylsulfinyl, C.sub.1-4
alkylsulfonyl, C.sub.1-4 alkylthio, carboxamide, C.sub.1-4
haloalkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylsulfinyl,
C.sub.1-4 haloalkylsulfonyl, C.sub.1-4 haloalkyl, halogen and
hydroxyl. In some embodiments, R.sub.24 is selected from the group
consisting of pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl. In
some embodiments, R.sub.24 is pyridinyl.
[0322] Some embodiments of the present invention pertain to
compounds wherein R.sub.25 and R.sub.26 are independently H or
C.sub.1-2 alkyl.
[0323] In some embodiments, A and B are both --CH.sub.2CH.sub.2--,
D is NR.sub.2, E is CH, is a single bond, and K is a single bond;
these embodiments can be represented by Formula (IIx) as shown
below: ##STR86## wherein each variable in Formula (IIx) has the
same meaning as described herein, supra and infra. In some
embodiments, compounds are of Formula (IIx) and Q is O (i.e., an
oxygen atom) or NH.
[0324] In some embodiments, compounds of the present invention are
of Formula (IIx) wherein R.sub.2 is Formula (C); these embodiments
can be represented by Formula (IIy) as shown below: ##STR87##
wherein each variable in Formula (IIy) has the same meaning as
described herein, supra and infra. In some embodiments, G is C(O),
C(O)NR.sub.25, C(O)O, C(S), C(S)NR.sub.25, C(S)O, CR.sub.25R.sub.26
or S(O).sub.2. In some embodiments, G is C(O) and can be
represented by Formula (IIz) as shown below: ##STR88## wherein each
variable in Formula (IIz) has the same meaning as described herein,
supra and infra. In some embodiments, G is C(O)O and can be
represented by Formula (IIIa) as shown below: ##STR89## wherein
each variable in Formula (IIIa) has the same meaning as described
herein, supra and infra.
[0325] In some embodiments, compounds are of either Formula (IIz)
or (IIa) and R.sub.24 is C.sub.1-8 alkyl, C.sub.3-7 cycloalkyl,
phenyl or heteroaryl optionally substituted with 1 to 5
substituents selected from the group consisting of C.sub.1-5 acyl,
C.sub.1-5 acyloxy, C.sub.1-4 alkoxy, C.sub.1-4 alkyl, C.sub.1-4
alkylamino, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylthiocarboxamide, C.sub.1-4 alkylsulfonamide, C.sub.1-4
alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
C.sub.1-4 alkylthioureyl, C.sub.1-4 alkylureyl, amino,
carbo-C.sub.1-6-alkoxy, carboxamide, carboxy, cyano,
C.sub.3-6-cycloalkyl, C.sub.2-8 dialkylamino, C.sub.2-6
dialkylcarboxamide, C.sub.2-6 dialkylthiocarboxamide, C.sub.2-6
dialkylsulfonamide, C.sub.1-4 alkylthioureyl, C.sub.1-4 haloalkoxy,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylsulfinyl, C.sub.1-4
haloalkylsulfonyl, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylthio,
halogen, hydroxyl, hydroxylamino and nitro.
[0326] In some embodiments, compounds are of either Formula (IIz)
or (IIIa) and R.sub.24 is C.sub.1-8 alkyl optionally substituted
with 1 to 5 substituents selected from the group consisting of
C.sub.1-5 acyl, C.sub.1-5 acyloxy, C.sub.1-4 alkoxy, C.sub.1-7
alkyl, C.sub.1-4 alkylamino, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylthiocarboxamide, C.sub.1-4 alkylsulfonamide, C.sub.1-4
alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
C.sub.1-4 alkylthioureyl, C.sub.1-4 alkylureyl, amino,
carbo-C.sub.1-6-alkoxy, carboxamide, carboxy, cyano,
C.sub.3-6-cycloalkyl, C.sub.2-8 dialkylamino, C.sub.2-6
dialkylcarboxamide, C.sub.2-6 dialkylthiocarboxamide, C.sub.2-6
dialkylsulfonamide, C.sub.1-4 alkylthioureyl, C.sub.1-4 haloalkoxy,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylsulfinyl, C.sub.1-4
haloalkylsulfonyl, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylthio,
halogen, hydroxyl, hydroxylamino and nitro.
[0327] In some embodiments, compounds are of either Formula (IIz)
or (IIIa) and R.sub.24 is phenyl optionally substituted with 1 to 5
substituents selected from the group consisting of C.sub.1-5 acyl,
C.sub.1-5 acyloxy, C.sub.1-4 alkoxy, C.sub.1-7 alkyl, C.sub.1-4
alkylamino, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylthiocarboxamide, C.sub.1-4 alkylsulfonamide, C.sub.1-4
alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
C.sub.1-4 alkylthioureyl, C.sub.1-4 alkylureyl, amino,
carbo-C.sub.1-6-alkoxy, carboxamide, carboxy, cyano,
C.sub.3-6-cycloalkyl, C.sub.2-8 dialkylamino, C.sub.2-6
dialkylcarboxamide, C.sub.2-6 dialkylthiocarboxamide, C.sub.2-6
dialkylsulfonamide, C.sub.1-4 alkylthioureyl, C.sub.1-4 haloalkoxy,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylsulfinyl, C.sub.1-4
haloalkylsulfonyl, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylthio,
halogen, hydroxyl, hydroxylamino and nitro. In some embodiments,
the phenyl is substituted with 1 to 4 substituents selected from
the group consisting of C.sub.1-5 acyl, C.sub.1-4 alkoxy, C.sub.1-7
alkyl, C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4
alkylthio, carboxamide, carboxy, C.sub.3-7 cycloalkyl, C.sub.2-8
dialkylamino, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkylsulfinyl, C.sub.1-4 haloalkylsulfonyl, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkylthio and halogen. In some
embodiments, the phenyl is substituted with 1 to 4 substituents
selected from the group consisting of C.sub.1-4 alkylsulfonyl,
C.sub.1-4 haloalkylsulfonyl and halogen.
[0328] In some embodiments, compounds are of either Formula (IIz)
or (IIIa) and R.sub.24 is heteroaryl optionally substituted with 1
to 5 substituents selected from the group consisting of C.sub.1-5
acyl, C.sub.1-5 acyloxy, C.sub.1-4 alkoxy, C.sub.1-7 alkyl,
C.sub.1-4 alkylamino, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylthiocarboxamide, C.sub.1-4 alkylsulfonamide, C.sub.1-4
alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
C.sub.1-4 alkylthioureyl, C.sub.1-4 alkylureyl, amino,
carbo-C.sub.1-6-alkoxy, carboxamide, carboxy, cyano,
C.sub.3-6-cycloalkyl, C.sub.2-8 dialkylamino, C.sub.2-6
dialkylcarboxamide, C.sub.2-6 dialkylthiocarboxamide, C.sub.2-6
dialkylsulfonamide, C.sub.1-4 alkylthioureyl, C.sub.1-4 haloalkoxy,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylsulfinyl, C.sub.1-4
haloalkylsulfonyl, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkylthio,
halogen, hydroxyl, hydroxylamino and nitro. In some embodiments,
the heteroaryl is substituted with 1 to 4 substituents selected
from the group consisting of C.sub.1-5 acyl, C.sub.1-4 alkoxy,
C.sub.1-7 alkyl, C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl,
C.sub.1-4 alkylthio, carboxamide, carboxy, C.sub.37 cycloalkyl,
C.sub.2-8 dialkylamino, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkylsulfinyl, C.sub.1-4 haloalkylsulfonyl, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkylthio and halogen. In some
embodiments, the heteroaryl is substituted with 1 to 4 substituents
selected from the group consisting of C.sub.1-4 alkylsulfonyl,
C.sub.1-4 haloalkylsulfonyl and halogen. In some embodiments, the
heteroaryl is a 5-memebered heteroaryl, for example, as shown in
TABLE 2A, supra. In some embodiments, the heteroaryl is a
6-membered heteroaryl, for example, as shown in TABLE 4, supra. In
some embodiments, the heteroaryl is selected from the group
consisting of pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl. In
some embodiments, the heteroaryl is pyridinyl.
[0329] In some embodiments, R.sub.24 is 1-methyl-1H-imidazole-4-yl,
or 2,4-dimethyl-thiazole-5-yl.
[0330] In some embodiments, compounds are of Formula (IIy), (IIx)
or (IIIa) and Q is NR.sub.4, O, S, S(O) or S(O).sub.2. In still
further embodiments, Q is NH or O.
[0331] Some embodiments of the present invention pertain to
compounds wherein Ar.sub.1 is aryl or heteroaryl optionally
substituted with R.sub.13, R.sub.14, R.sub.15, R.sub.16, and
R.sub.17;
[0332] wherein R.sub.13 is selected from the group consisting of
C.sub.1-6 acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-8 alkyl,
C.sub.1-4 alkylamino, C.sub.1-6 alkylcarboxamide, C.sub.1-4
alkylsulfonamide, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
amino, carbamimidoyl, carboxamide, carboxy, cyano, C.sub.2-6
dialkylamino, halogen, heterocyclic, heterocyclic-oxy,
heterocyclic-carbonyl, heteroaryl, heteroarylcarbonyl, and
sulfonamide, and wherein said C.sub.1-6 acylsulfonamide, C.sub.1-4
alkoxy, C.sub.1-8 alkyl, C.sub.1-4 alkylamino, C.sub.1-4
alkylsulfonamide, alkylsulfonyl, C.sub.1-4 alkylthio,
carbamimidoyl, C.sub.2-6 dialkylamino, heterocyclic,
heterocyclic-carbonyl, and heteroaryl are each optionally
substituted with 1 to 5 substituents selected independently from
the group consisting of C.sub.1-4 acylsulfonamide, C.sub.1-4
alkoxy, C.sub.1-7 alkyl, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylsulfonyl, carboxy, C.sub.3-7 cycloalkyloxy, C.sub.2-6
dialkylamino, C.sub.2-6 dialkylcarboxamide, heteroaryl,
heterocyclic, hydroxyl, phenyl, and phosphonooxy, and wherein said
C.sub.1-7 alkyl and C.sub.1-4 alkylcarboxamide are each optionally
substituted with 1 to 5 substituents selected from the group
consisting of C.sub.1-4 alkoxy and hydroxy; and
[0333] R.sub.14, R.sub.15, R.sub.16, and R.sub.17 are each
independently selected form the group consisting of C.sub.1-6
acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4
alkylamino, C.sub.1-4 alkylcarboxamide, C.sub.1-4 alkylsulfonamide,
C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio, amino, carbamimidoyl,
carboxamide, cyano, C.sub.2-6 dialkylamino, and halogen.
[0334] Some embodiments of the present invention pertain to
compounds wherein Ar.sub.1 is aryl.
[0335] Some embodiments of the present invention pertain to
compounds wherein Ar.sub.1 is heteroaryl.
[0336] Some embodiments of the present invention pertain to
compounds wherein Ar.sub.1 is phenyl optionally substituted with
R.sub.13, R.sub.14, R.sub.15, R.sub.16, and R.sub.17;
[0337] wherein R.sub.13 is selected from the group consisting of
C.sub.1-6 acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-8 alkyl,
C.sub.1-4 alkylamino, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylsulfonamide, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
amino, carbamimidoyl, carboxamide, carboxy, cyano, C.sub.2-6
dialkylamino, C.sub.1-4 haloalkyl, halogen, heterocyclic,
heterocyclic-oxy, heterocyclic-carbonyl, heteroaryl,
heteroarylcarbonyl, and sulfonamide, and wherein C.sub.1-6
acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4
alkylamino, C.sub.1-4 alkylsulfonamide, C.sub.1-4 alkylsulfonyl,
C.sub.1-4 alkylthio, carbamimidoyl, C.sub.2-6 dialkylamino,
heterocyclic, heterocyclic-carbonyl, and heteroaryl are each
optionally substituted with 1 to 5 substituents selected
independently from the group consisting of C.sub.1-6
acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-7 alkyl, C.sub.1-4
alkylcarboxamide, C.sub.1-4 alkylsulfonyl, carboxy, C.sub.3-7
cycloalkyloxy, C.sub.2-6 dialkylamino, C.sub.2-6
dialkylcarboxamide, heteroaryl, heterocyclic, hydroxyl, phenyl, and
phosphonooxy wherein said C.sub.1-7 alkyl and C.sub.1-4
alkylcarboxamide are each optionally substituted with 1 to 5
substituents selected from the group consisting of C.sub.1-4 alkoxy
and hydroxy; and
[0338] R.sub.14, R.sub.15, R.sub.16, and R.sub.17 are each
independently selected form the group consisting of C.sub.1-6
acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4
alkylamino, C.sub.1-4 alkylcarboxamide, C.sub.1-4 alkylsulfonamide,
C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio, amino, carbamimidoyl,
carboxamide, cyano, C.sub.2-6 dialkylamino, C.sub.1-4 haloalkyl,
and halogen.
[0339] Some embodiments of the present invention pertain to
compounds wherein Ar.sub.1 is phenyl optionally substituted with
R.sub.13, R.sub.14, R.sub.15, R.sub.16, and R.sub.17;
[0340] wherein R.sub.13 is selected from the group consisting of
C.sub.1-6 acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-8 alkyl,
C.sub.1-4 alkylamino, C.sub.1-6 alkylcarboxamide, C.sub.1-4
alkylsulfonamide, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
carbamimidoyl, carboxamide, carboxy, cyano, C.sub.2-6 dialkylamino,
halogen, heterocyclic, heterocyclic-oxy, heterocyclic-carbonyl,
heteroaryl, heteroarylcarbonyl, and sulfonamide, and wherein
C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4 alkylamino, C.sub.1-6
alkylcarboxamide, C.sub.1-4 alkylsulfonamide, C.sub.1-4
alkylsulfonyl, C.sub.1-4 alkylthio, carbamimidoyl, C.sub.2-6
dialkylamino, heterocyclic, heterocyclic-carbonyl, and heteroaryl
are each optionally substituted with 1 to 5 substituents selected
independently from the group consisting of C.sub.1-6
acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-7 alkyl, C.sub.1-4
alkylcarboxamide, C.sub.1-4 alkylsulfonyl, carboxy, C.sub.2-6
dialkylamino, C.sub.2-6 dialkylcarboxamide, heteroaryl,
heterocyclic, hydroxyl, phenyl, and phosphonooxy, and wherein said
C.sub.1-7 alkyl and C.sub.1-4 alkylcarboxamide are each optionally
substituted with 1 to 5 substituents selected from the group
consisting of C.sub.1-4 alkoxy and hydroxy; and
[0341] R.sub.14, R.sub.15, R.sub.16, and R.sub.17 are each
independently selected form the group consisting of C.sub.1-6
acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4
alkylamino, C.sub.1-4 alkylcarboxamide, C.sub.1-4 alkylsulfonamide,
C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio, amino, carbamimidoyl,
carboxamide, cyano, C.sub.2-6 dialkylamino, and halogen.
[0342] Some embodiments of the present invention pertain to
compounds wherein Ar.sub.1 is phenyl optionally substituted with
R.sub.13, R.sub.14, R.sub.15, R.sub.16, and R.sub.17;
[0343] wherein R.sub.13 is selected from the group consisting of
C.sub.1-4 acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-8 alkyl,
C.sub.1-4 alkylamino, C.sub.1-6 alkylcarboxamide, C.sub.1-4
alkylsulfonamide, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
carbamimidoyl, carboxamide, carboxy, cyano, C.sub.2-6 dialkylamino,
halogen, heterocyclic, heterocyclic-oxy, heterocyclic-carbonyl,
heteroaryl, heteroarylcarbonyl, and sulfonamide, and wherein said
C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4 alkylamino, C.sub.1-6
alkylcarboxamide, C.sub.1-4 alkylsulfonamide, C.sub.1-4
alkylsulfonyl, C.sub.1-4 alkylthio, carbamimidoyl, C.sub.2-6
dialkylamino, heterocyclic, heterocyclic-carbonyl, and heteroaryl
are each optionally substituted with 1 to 5 substituents selected
independently from the group consisting of C.sub.1-6
acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-7 alkyl, C.sub.1-4
alkylcarboxamide, C.sub.1-4 alkylsulfonyl, carboxy, C.sub.2-6
dialkylamino, C.sub.2-6 dialkylcarboxamide, heteroaryl,
heterocyclic, hydroxyl, phenyl, and phosphonooxy, and wherein said
C.sub.1-7 alkyl and C.sub.1-4 alkylcarboxamide are each optionally
substituted with 1 to 5 substituents selected from the group
consisting of C.sub.1-4 alkoxy and hydroxy; and
[0344] R.sub.14, R.sub.15, R.sub.16, and R.sub.17 are each
independently selected form the group consisting of C.sub.1-8
alkyl, and halogen.
[0345] Some embodiments of the present invention pertain to
compounds wherein Ar.sub.1 is phenyl. In some embodiments, the
phenyl is optionally substituted with R.sub.13. In some
embodiments, R.sub.13 is selected from the group consisting of H,
C.sub.1-5 acyl, C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4
alkylcarboxamide, C.sub.2-6 alkynyl, C.sub.1-4 alkylsulfonamide,
C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4
alkylthio, carboxamide, C.sub.3-7 cycloalkyl, halogen and
sulfonamide.
[0346] In some embodiments, R.sub.13 is selected from the group
consisting of C(O)CH.sub.3, C(O)CH.sub.2CH.sub.3,
C(O)CH.sub.2CH.sub.2CH.sub.3, C(O)CH(CH.sub.3).sub.2,
C(O)CH.sub.2CH.sub.2CH.sub.2CH.sub.3, OCH.sub.3, OCH.sub.2CH.sub.3,
OCH.sub.2CH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2,
OCH.sub.2CH.sub.2CH.sub.2CH.sub.3, CH.sub.3, CH.sub.2CH.sub.3,
CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2,
CH(CH.sub.3)(CH.sub.2CH.sub.3), CH.sub.2(CH.sub.2).sub.2CH.sub.3,
CH.sub.2(CH.sub.2).sub.3CH.sub.3, CH.sub.2(CH.sub.2).sub.4CH.sub.3,
CH.sub.2(CH.sub.2).sub.5CH.sub.3, C(O)NHCH.sub.3,
C(O)NHCH.sub.2CH.sub.3, C(O)NHCH.sub.2CH.sub.2CH.sub.3,
C(O)NHCH(CH.sub.3).sub.2, C(O)NHCH.sub.2(CH.sub.2).sub.2CH.sub.3,
CCH, S(O).sub.2NHCH.sub.3, S(O).sub.2NHCH.sub.2CH.sub.3,
S(O).sub.2NHCH.sub.2CH.sub.2CH.sub.3,
S(O).sub.2NHCH(CH.sub.3).sub.2,
S(O).sub.2NHCH.sub.2(CH.sub.2).sub.2CH.sub.3 and
S(O).sub.2NHCH(CH.sub.3)CH.sub.2CH.sub.3.
[0347] In some embodiments, R.sub.13 is selected from the group
consisting of S(O)CH.sub.3, S(O)CH.sub.2CH.sub.3,
S(O)CH.sub.2CH.sub.2CH.sub.3, S(O)CH(CH.sub.3).sub.2,
S(O)CH.sub.2(CH.sub.2).sub.2CH.sub.3,
S(O)CH(CH.sub.3)CH.sub.2CH.sub.3, S(O).sub.2CH.sub.3,
S(O).sub.2CH.sub.2CH.sub.3, S(O).sub.2CH.sub.2CH.sub.2CH.sub.3,
S(O).sub.2CH(CH.sub.3).sub.2,
S(O).sub.2CH.sub.2(CH.sub.2).sub.2CH.sub.3,
S(O).sub.2CH(CH.sub.3)CH.sub.2CH.sub.3, SCH.sub.3,
SCH.sub.2CH.sub.3, SCH.sub.2CH.sub.2CH.sub.3, SCH(CH.sub.3).sub.2
and SCH.sub.2(CH.sub.2).sub.2CH.sub.3.
[0348] In some embodiments, R.sub.13 is selected from the group
consisting of amino, arylsulfonyl, carboxy, cyano, C.sub.3-7
cycloalkyl, halogen, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl and
C.sub.1-4 haloalkylthio. In some embodiments, R.sub.13 is selected
from the group consisting of phenylsulfonyl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, Cl, F, Br, OCF.sub.3,
OCHF.sub.2, OCH.sub.2CF.sub.3, CF.sub.3, CHF.sub.2,
CH.sub.2CF.sub.3, SCF.sub.3, SCHF.sub.2 and SCH.sub.2CF.sub.3. In
some embodiments, R.sub.13 is selected from the group consisting of
heterocyclic, heteroaryl, C.sub.4-7 oxo-cycloalkyl, phenoxy and
phenyl. In some embodiments, R.sub.13 is selected from the group
consisting of morpholin-4-yl, thiomorpholin-4-yl,
1-oxo-1.lamda..sup.4-thiomorpholin-4-yl,
1,1-Dioxo-1.lamda..sup.6-thiomorpholin-4-yl, piperazin-1-yl,
4-methyl-piperazin-1-yl, 4-ethyl-piperazin-1-yl,
4-propyl-piperazin-1-yl, piperidin-1-yl, pyrrolidin-1-yl,
2,5-dioxo-imidazolidin-4-yl, 2,4-dioxo-thiazolidin-5-yl,
4-oxo-2-thioxo-thiazolidin-5-yl,
3-methyl-2,5-dioxo-imidazolidin-4-yl,
3-methyl-2,4-dioxo-thiazolidin-5-yl,
3-methyl-4-oxo-2-thioxo-thiazolidin-5-yl,
3-ethyl-2,5-dioxo-imidazolidin-4-yl,
3-ethyl-2,4-dioxo-thiazolidin-5-yl, and
3-ethyl-4-oxo-2-thioxo-thiazolidin-5-yl. In some embodiments,
R.sub.13 is selected from the group consisting of 1H-imidazol-4-yl,
[1,2,4]triazol-1-yl, [1,2,3]triazol-1-yl, [1,2,4]triazol-4-yl,
pyrrol-1-yl, pyrazol-1-yl, 1H-pyrazol-3-yl, imidazol-1-yl,
oxazol-5-yl, oxazol-2-yl, [1,3,4]oxadiazol-2-yl, [1,3
,4]thiadiazol-2-yl, [1,2,4]oxadiazol-3-yl, [1,2,4]thiadiazol-3-yl,
tetrazol-1-yl, pyrimidin-5-yl, pyrimidin-2-yl, pyrimidin-4-yl,
pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl,
1,3-dioxo-1,3-dihydro-isoindol-2-yl and [1,2,3]thiadiazol-4-yl. In
some embodiments, R.sub.13 is C.sub.1-8 alkyl or C.sub.1-4 alkoxy
optionally substituted with 1 to 5 substituents selected
independently from the group consisting of C.sub.1-4 alkoxy,
C.sub.1-4 alkylcarboxamide, C.sub.1-4 alkylsulfonamide, C.sub.1-4
alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
carbo-C.sub.1-6-alkoxy, carboxamide, carboxy, cyano, heterocyclic,
hydroxyl and phenyl. In some embodiments, R.sub.13 is C.sub.1-4
alkylsulfonyl optionally substituted with 1 to 5 substituents
selected independently from the group consisting of C.sub.1-4
alkoxy, carboxamide, heteroaryl, heterocyclic and phenyl. In some
embodiments, the C.sub.1-4 alkylsulfonyl is substituted with the
heteroaryl group. In some embodiments, the heteroaryl group is
selected from the group consisting of 1H-imidazol-4-yl,
[1,2,4]triazol-1-yl, [1,2,3]triazol-1-yl, [1,2,4]triazol-4-yl,
pyrrol-1-yl, pyrazol-1-yl, 1H-pyrazol-3-yl, imidazol-1-yl,
oxazol-5-yl, oxazol-2-yl, [1,3,4]oxadiazol-2-yl,
[1,3,4]thiadiazol-2-yl, [1,2,4]oxadiazol-3-yl,
[1,2,4]thiadiazol-3-yl, tetrazol-1-yl, pyrimidin-5-yl,
pyrimidin-2-yl, pyrimidin4-yl, pyridazin-3-yl, pyridazin-4-yl,
pyrazin-2-yl, 1,3-dioxo-1,3-dihydro-isoindol-2-yl and
[1,2,3]thiadiazol-4-yl. In some embodiments, R.sub.13 is
arylsulfonyl, heteroaryl, phenoxy or phenyl optionally substituted
with 1 to 5 substituents selected independently from the group
consisting of C.sub.1-5 acyl, C.sub.1-4 alkoxy, C.sub.1-8 alkyl,
C.sub.1-4 alkylsulfonamide, C.sub.1-4 alkylsulfinyl, C.sub.1-4
alkylsulfonyl, C.sub.1-4 alkylthio, carboxamide, carboxy, cyano,
halogen, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkylthio and hydroxyl. In some embodiments, R.sub.13 is
arylsulfonyl, heteroaryl, phenoxy or phenyl optionally substituted
with 1 to 5 substituents selected independently from the group
consisting of C.sub.1-4 alkoxy, C.sub.1-8 alkyl, cyano, halogen,
C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl and hydroxyl.
[0349] Some embodiments of the present invention pertain to
compounds wherein Ar.sub.1 is phenyl. In some embodiments, the
phenyl is optionally substituted with R.sub.13. In some
embodiments, R.sub.13 is a group of Formula (A): ##STR90##
wherein:
[0350] "p" and "r" are independently 0, 1, 2 or 3; and R.sub.18 is
H, C.sub.1-5 acyl, C.sub.2-6 alkenyl, C.sub.1-8 alkyl, C.sub.1-4
alkylcarboxamide, C.sub.2-6 alkynyl, C.sub.1-4 alkylsulfonamide,
carbo-C.sub.1-6-alkoxy, carboxamide, carboxy, cyano, C.sub.3-7
cycloalkyl, C.sub.2-6 dialkylcarboxamide, halogen, heteroaryl or
phenyl, and wherein the heteroaryl or phenyl may be optionally
substituted with 1 to 5 substituents selected independently from
the group consisting of C.sub.1-4 alkoxy, amino, C.sub.1-4
alkylamino, C.sub.2-6 alkynyl, C.sub.2-8 dialkylamino, halogen,
C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl and hydroxyl. In some
embodiments, p=0 and r=0. In some embodiments, R.sub.18 is
heteroaryl or phenyl each optionally substituted with 1 to 5
substituents selected independently from the group consisting of
C.sub.1-4 alkoxy, amino, C.sub.1-4 alkylamino, C.sub.2-6 alkynyl,
C.sub.2-8 dialkylamino, halogen, C.sub.1-4 haloalkoxy, C.sub.1-4
haloalkyl and hydroxyl. In some embodiments, the heteroaryl is
selected from the group consisting of 1H-imidazol-4-yl,
[1,2,4]triazol-1-yl, [1,2,3]triazol-1-yl, [1,2,4]triazol-4-yl,
pyrrol-1-yl, pyrazol-1-yl, 1H-pyrazol-3-yl, imidazol-1-yl,
oxazol-5-yl, oxazol-2-yl, [1,3,4]oxadiazol-2-yl,
[1,3,4]thiadiazol-2-yl, [1,2,4]oxadiazol-3-yl,
[1,2,4]thiadiazol-3-yl, tetrazol-1-yl, pyrimidin-5-yl,
pyrimidin-2-yl, pyrimidin-4-yl, pyridazin-3-yl, pyridazin-4-yl,
pyrazin-2-yl, 1,3-dioxo-1,3-dihydro-isoindol-2-yl and
[1,2,3]thiadiazol-4-yl. In some embodiments, p=0 and r=1. In some
embodiments, R.sub.18 is carbo-C.sub.1-6-alkoxy or carboxy. In some
embodiments, p=2 and r=1. In some embodiments, R.sub.18 is H,
C.sub.1-5 acyl or C.sub.1-8 alkyl.
[0351] Some embodiments of the present invention pertain to
compounds wherein Ar.sub.1 is phenyl. In some embodiments, the
phenyl is optionally substituted with R.sub.14, R.sub.15, R.sub.16
and R.sub.17. In some embodiments, R.sub.14, R.sub.15, R.sub.16 and
R.sub.17 are independently selected from the group consisting of H,
C.sub.1-5 acyl, C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4
alkylcarboxamide, C.sub.1-4 alkylureyl, carbo-C.sub.1-6-alkoxy,
carboxamide, carboxy, cyano, C.sub.3-7 cycloalkyl, halogen,
C.sub.1-4 haloalkoxy and C.sub.1-4 haloalkyl. In some embodiments,
one R.sub.14, R.sub.15, R.sub.16 and R.sub.17 is a halogen. In
further embodiments, the halogen is a fluorine atom.
[0352] Some embodiments of the present invention pertain to
compounds wherein Ar.sub.1 is phenyl and R.sub.13 is substituted at
the para position on the phenyl; these embodiments can be
represented by Formula (IIIc) as shown below: ##STR91## wherein
each variable in Formula (IIIc) has the same meaning as described
herein, supra and infra.
[0353] Some embodiments of the present invention pertain to
compounds wherein Ar.sub.1 is phenyl and two adjacent R.sub.14,
R.sub.15, R.sub.16 and R.sub.17 together with the atoms to which
they are attached form a 5, 6 or 7 membered cycloalkyl,
cycloalkenyl or heterocyclic group fused with the phenyl group
wherein the 5, 6 or 7 membered group is optionally substituted with
halogen. In some embodiments, the phenyl and two adjacent R.sub.14,
R.sub.15, R.sub.16 and R.sub.17 groups form a 5, 6 or 7 membered
fused cycloalkyl as represented in TABLE 5: TABLE-US-00011 TABLE 5
##STR92##
wherein "a" is 1, 2 or 3 to give a 5, 6 or 7 membered cycloalkyl
fused together with the phenyl group where two of the ring carbons
are shared between the cycloalkyl and phenyl group. In some
embodiments, 1, 2, or 3 ring carbons are replaced by a heteroatom
selected from, but not limited to, O, S, and N, wherein N is
substituted with H or C.sub.1-4 alkyl. In some embodiments, the two
adjacent groups form a 5 membered heterocyclic group with the
phenyl group. In some embodiments, the 5 membered heterocyclic
group with the phenyl group together is a
2,3-dihydro-benzofuran-5-yl or benzo[1,3]dioxol-5-yl group. In some
embodiments, the two adjacent groups form a 6 membered heterocyclic
group with the phenyl group. In some embodiments, the 6 membered
heterocyclic group with the phenyl group together is a
2,3-dihydro-benzo[1,4]dioxin-6-yl or
2,3-dihydro-benzo[1,4]dioxin-2-yl group. In some embodiments, the
two adjacent groups form a 7 membered heterocyclic group with the
phenyl group. In some embodiments, the 7 membered heterocyclic
group with the phenyl group together is a
3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl group.
[0354] Some embodiments of the present invention pertain to
compounds wherein Ar.sub.1 is pyridyl optionally substituted with
R.sub.13, R.sub.14, R.sub.15, and R.sub.16;
[0355] wherein R.sub.13 is selected from the group consisting of
C.sub.1-6 acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-8 alkyl,
C.sub.1-4 alkylamino, C.sub.1-6 alkylcarboxamide, C.sub.1-4
alkylsulfonamide, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
amino, carbamimidoyl, carboxamide, carboxy, cyano, C.sub.2-6
dialkylamino, halogen, heterocyclic, heterocyclic-oxy,
heterocyclic-carbonyl, heteroaryl, and sulfonamide, and wherein
C.sub.1-6 acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-8 alkyl,
C.sub.1-4 alkylamino, C.sub.1-4 alkylsulfonamide, alkylsulfonyl,
C.sub.1-4 alkylthio, carbamimidoyl, C.sub.2-6 dialkylamino,
heterocyclic, heterocyclic-carbonyl, and heteroaryl are each
optionally substituted with 1 to 5 substituents selected
independently from the group consisting of C.sub.1-6
acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-7 alkyl, C.sub.1-4
alkylcarboxamide, C.sub.1-4 alkylsulfonyl, carboxy, C.sub.3-7
cycloalkyloxy, C.sub.2-6 dialkylamino, C.sub.2-6
dialkylcarboxamide, heteroaryl, heterocyclic, hydroxyl, phenyl, and
phosphonooxy, and wherein said C.sub.1-7 alkyl and C.sub.1-4
alkylcarboxamide are each optionally substituted with 1 to 5
substituents selected from the group consisting of C.sub.1-4 alkoxy
and hydroxy; and
[0356] R.sub.14, R.sub.15, and R.sub.16 are each independently
selected form the group consisting of C.sub.1-6 acylsulfonamide,
C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4 alkylamino, C.sub.1-4
alkylcarboxamide, C.sub.1-4 alkylsulfonamide, C.sub.1-4
alkylsulfonyl, C.sub.1-4 alkylthio, amino, carbamimidoyl,
carboxamide, cyano, C.sub.2-6 dialkylamino, and halogen.
[0357] Some embodiments of the present invention pertain to
compounds wherein Ar.sub.1 is pyridyl optionally substituted with
R.sub.13, R.sub.14, R.sub.15, and R.sub.16;
[0358] wherein R.sub.13 is selected from the group consisting of
C.sub.1-6 acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-8 alkyl,
C.sub.1-4 alkylamino, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
amino, C.sub.2-6 dialkylamino, halogen, heterocyclic, and
sulfonamide, and wherein C.sub.1-4 alkoxy, C.sub.1l.sub.8 alkyl,
C.sub.1-4 alkylamino, alkylsulfonyl, C.sub.1-4 alkylthio, C.sub.2-6
dialkylamino, and heterocyclic are each optionally substituted with
1 to 5 substituents selected independently from the group
consisting of C.sub.1-4 acylsulfonamide, C.sub.1-4 alkoxy,
C.sub.1-4 alkylsulfonyl, C.sub.3-7 cycloalkyloxy, heteroaryl,
hydroxyl, phenyl, and phosphonooxy; and
[0359] R.sub.14, R.sub.15, and R.sub.16 are each independently
selected form the group consisting of C.sub.1-6 acylsulfonamide,
C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4 alkylamino, C.sub.1-4
alkylcarboxamide, C.sub.1-4 alkylsulfonamide, C.sub.1-4
alkylsulfonyl, C.sub.1-4 alkylthio, amino, carbamimidoyl,
carboxamide, cyano, C.sub.2-6 dialkylamino, and halogen.
[0360] Some embodiments of the present invention pertain to
compounds wherein Ar.sub.1 is pyridyl optionally substituted with
R.sub.13, R.sub.14, R.sub.15, and R.sub.16;
[0361] wherein R.sub.13 is selected from the group consisting of
C.sub.1-6 acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-8 alkyl,
C.sub.1-4 alkylamino, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
amino, C.sub.2-6 dialkylamino, halogen, heterocyclic, and
sulfonamide, and wherein C.sub.1-4 alkoxy, C.sub.1-8 alkyl,
C.sub.1-4 alkylamino, alkylsulfonyl, C.sub.1-4 alkylthio, C.sub.2-6
dialkylamino, and heterocyclic are each optionally substituted with
1 to 5 substituents selected independently from the group
consisting of C.sub.1-6 acylsulfonamide, C.sub.1-4 alkoxy,
C.sub.1-4 alkylsulfonyl, C.sub.3-7 cycloalkyloxy, heteroaryl,
hydroxyl, phenyl, and phosphonooxy; and
[0362] R.sub.14, R.sub.15, and R.sub.16 are each independently
selected form the group consisting of C.sub.1-8 alkyl, and
halogen.
[0363] Some embodiments of the present invention pertain to
compounds of Formula (IIId) as shown below: ##STR93## wherein each
variable in Formula (IIId) has the same meaning as described
herein, supra and infra.
[0364] Some embodiments of the present invention pertain to
compounds of Formulae (IIId-1) and (IIId-2) as shown below:
##STR94## wherein each variable in Formulae (IIId-1) and (IIId-2)
have the same meaning as described herein, supra and infra.
[0365] Some embodiments of the present invention pertain to
compounds wherein Ar.sub.1 is heteroaryl. In some embodiments, the
heteroaryl is optionally substituted with R.sub.13. In some
embodiments, R.sub.13 is selected from the group consisting of H,
C.sub.1-5 acyl, C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4
alkylcarboxamide, C.sub.2-6 alkynyl, C.sub.1-4 alkylsulfonamide,
C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4
alkylthio, carboxamide, C.sub.3-7 cycloalkyl, halogen and
sulfonamide. In some embodiments, R.sub.13 is selected from the
group consisting of C(O)CR.sub.3, C(O)CH.sub.2CH.sub.3,
C(O)CR.sub.2CH.sub.2CH.sub.3, C(O)CH(CH.sub.3).sub.2,
C(O)CH.sub.2CH.sub.2CH.sub.2CH.sub.3, OCH.sub.3, OCH.sub.2CH.sub.3,
OCH.sub.2CH.sub.2CH.sub.3, OCR(CH.sub.3).sub.2,
OCH.sub.2CH.sub.2CH.sub.2CH.sub.3, CH.sub.3, CH.sub.2CH.sub.3,
CH.sub.2CH.sub.2CH.sub.3, CR(CH.sub.3).sub.2,
CH(CH.sub.3)(CH.sub.2CH.sub.3), CH.sub.2(CH.sub.2).sub.2CH.sub.3,
CH.sub.2(CH.sub.2).sub.3CH.sub.3, CH.sub.2(CH.sub.2).sub.4CH.sub.3,
CH.sub.2(CH.sub.2).sub.5CH.sub.3, C(O)NHCH.sub.3,
C(O)NHCH.sub.2CH.sub.3, C(O)NHCH.sub.2CH.sub.2CH.sub.3,
C(O)NHCH(CH.sub.3).sub.2, C(O)NHCH.sub.2(CH.sub.2).sub.2CH.sub.3,
CCH, S(O).sub.2NHCH.sub.3, S(O).sub.2NHCH.sub.2CH.sub.3,
S(O).sub.2NHCH.sub.2CH.sub.2CH.sub.3,
S(O).sub.2NHCH(CH.sub.3).sub.2,
S(O).sub.2NHCH.sub.2(CH.sub.2).sub.2CH.sub.3 and
S(O).sub.2NHCH(CH.sub.3)CH.sub.2CH.sub.3.
[0366] In some embodiments, R.sub.13 is selected from the group
consisting of S(O)CH.sub.3, S(O)CH.sub.2CH.sub.3,
S(O)CH.sub.2CH.sub.2CH.sub.3, S(O)CH(CH.sub.3).sub.2,
S(O)CH.sub.2(CH.sub.2).sub.2CH.sub.3,
S(O)CH(CH.sub.3)CH.sub.2CH.sub.3, S(O).sub.2CH.sub.3,
S(O).sub.2CH.sub.2CH.sub.3, S(O).sub.2CH.sub.2CH.sub.2CH.sub.3,
S(O).sub.2CH(CH.sub.3).sub.2,
S(O).sub.2CH.sub.2(CH.sub.2).sub.2CH.sub.3,
S(O).sub.2CH(CH.sub.3)CH.sub.2CH.sub.3, SCH.sub.3,
SCH.sub.2CH.sub.3, SCH.sub.2CH.sub.2CH.sub.3, SCH(CH.sub.3).sub.2
and SCH.sub.2(CH.sub.2).sub.2CH.sub.3.
[0367] In some embodiments, R.sub.13 is selected from the group
consisting of amino, arylsulfonyl, carboxy, cyano, C.sub.3-7
cycloalkyl, halogen, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl and
C.sub.1-4 haloalkylthio. In some embodiments, R.sub.13 is selected
from the group consisting of phenylsulfonyl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, Cl, F, Br, OCF.sub.3,
OCHF.sub.2, OCH.sub.2CF.sub.3, CF.sub.3, CHF.sub.2,
CH.sub.2CF.sub.3, SCF.sub.3, SCHF.sub.2 and SCH.sub.2CF.sub.3. In
some embodiments, R.sub.13 is selected from the group consisting of
heterocyclic, heteroaryl, C.sub.4-7 oxo-cycloalkyl, phenoxy and
phenyl. In some embodiments, R.sub.13 is selected from the group
consisting of morpholin-4-yl, thiomorpholin-4-yl,
1-oxo-1.lamda..sup.4-thiomorpholin-4-yl,
1,1-Dioxo-1.lamda..sup.6-thiomorpholin-4-yl, piperazin-1-yl,
4-methyl-piperazin-1-yl, 4-ethyl-piperazin-1-yl,
4-propyl-piperazin-1-yl, piperidin-1-yl, pyrrolidin-1-yl,
2,5-dioxo-imidazolidin-4-yl, 2,4-dioxo-thiazolidin-5-yl,
4-oxo-2-thioxo-thiazolidin-5-yl,
3-methyl-2,5-dioxo-imidazolidin-4-yl,
3-methyl-2,4-dioxo-thiazolidin-5-yl,
3-methyl-4-oxo-2-thioxo-thiazolidin-5-yl,
3-ethyl-2,5-dioxo-imidazolidin-4-yl,
3-ethyl-2,4-dioxo-thiazolidin-5-yl, and
3-ethyl-4-oxo-2-thioxo-thiazolidin-5-yl. In some embodiments,
R.sub.13 is selected from the group consisting of 1H-imidazol-4-yl,
[1,2,4]triazol-1-yl, [1,2,3]triazol-1-yl, [1,2,4]triazol-4-yl,
pyrrol-1-yl, pyrazol-1-yl, 1H-pyrazol-3-yl, imidazol-1-yl,
oxazol-5-yl, oxazol-2-yl, [1,3,4]oxadiazol-2-yl,
[1,3,4]thiadiazol-2-yl, [1,2,4]oxadiazol-3-yl,
[1,2,4]thiadiazol-3-yl, tetrazol-1-yl, pyrimidin-5-yl,
pyrimidin-2-yl, pyrimidin-4-yl, pyridazin-3-yl, pyridazin-4-yl,
pyrazin-2-yl, 1,3-dioxo-1,3-dihydro-isoindol-2-yl and
[I,2,3]thiadiazol-4-yl. In some embodiments, R.sub.13 is C.sub.1-8
alkyl or C.sub.1-4 alkoxy, optionally substituted with 1 to 5
substituents selected independently from the group consisting of
C.sub.1-4 alkoxy, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylsulfonamide, C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl,
C.sub.1-4 alkylthio, carbo-C.sub.1-6-alkoxy, carboxamide, carboxy,
cyano, heterocyclic, hydroxyl and phenyl. In some embodiments,
R.sub.13 is C.sub.1-4 alkylsulfonyl optionally substituted with 1
to 5 substituents selected independently from the group consisting
of C.sub.1-4 alkoxy, carboxamide, heteroaryl, heterocyclic and
phenyl. In some embodiments, the C.sub.1-4 alkylsulfonyl is
substituted with the heteroaryl group. In some embodiments, the
heteroaryl is selected from the group consisting of
1H-imidazol-4-yl, [1,2,4]triazol-1-yl, [1,2,3]triazol-1-yl,
[1,2,4]triazol-4-yl, pyrrol-1-yl, pyrazol-1-yl, 1H-pyrazol-3-yl,
imidazol-1-yl, oxazol-5-yl, oxazol-2-yl, [1,3,4]oxadiazol-2-yl,
[1,3,4]thiadiazol-2-yl, [1,2,4]oxadiazol-3-yl,
[1,2,4]thiadiazol-3-yl, tetrazol-1-yl, pyrimidin-5-yl,
pyrimidin-2-yl, pyrimidin-4-yl, pyridazin-3-yl, pyridazin-4-yl,
pyrazin-2-yl, 1,3-dioxo-1,3-dihydro-isoindol-2-yl and
[1,2,3]thiadiazol-4-yl. In some embodiments, R.sub.13 is
arylsulfonyl, heteroaryl, phenoxy or phenyl optionally substituted
with 1 to 5 substituents selected independently from the group
consisting of C.sub.1-5 acyl, C.sub.1-4 alkoxy, C.sub.1-8 alkyl,
C.sub.1-4 alkylsulfonamide, C.sub.1-4 alkylsulfinyl, C.sub.1-4
alkylsulfonyl, C.sub.1-4 alkylthio, carboxamide, carboxy, cyano,
halogen, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkylthio and hydroxyl. In some embodiments, R.sub.13 is
arylsulfonyl, heteroaryl, phenoxy or phenyl optionally substituted
with 1 to 5 substituents selected independently from the group
consisting of C.sub.1-4 alkoxy, C.sub.1-8 alkyl, cyano, halogen,
C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl and hydroxyl.
[0368] Some embodiments of the present invention pertain to
compounds wherein Ar.sub.1 is heteroaryl. In some embodiments, the
heteroaryl is optionally substituted with R.sub.13. In some
embodiments, R.sub.13 is of Formula (A): ##STR95## wherein:
[0369] "p" and "r" are independently 0, 1, 2 or 3; and R.sub.18 is
H, C.sub.1-5 acyl, C.sub.2-6 alkenyl, C.sub.1-8 alkyl, C.sub.1-4
alkylcarboxamide, C.sub.2-6 alkynyl, C.sub.1-4 alkylsulfonamide,
carbo-C.sub.1-6-alkoxy, carboxamide, carboxy, cyano, C.sub.3-7
cycloalkyl, C.sub.2-6 dialkylcarboxamide, halogen, heteroaryl or
phenyl, and wherein the heteroaryl or phenyl may be optionally
substituted with 1 to 5 substituents selected independently from
the group consisting of C.sub.1-4 alkoxy, amino, C.sub.1-4
alkylamino, C.sub.2-6 alkynyl, C.sub.2-8 dialkylamino, halogen,
C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl and hydroxyl. In some
embodiments, p=0 and r=0. In some embodiments, R.sub.18 is
heteroaryl or phenyl optionally substituted with 1 to 5
substituents selected independently from the group consisting of
C.sub.1-4 alkoxy, amino, C.sub.1-4 alkylamino, C.sub.2-6 alkynyl,
C.sub.2-8 dialkylamino, halogen, C.sub.1-4 haloalkoxy, C.sub.1-4
haloalkyl and hydroxyl. In some embodiments, the heteroaryl is
selected from the group consisting of 1H-imidazol-4-yl,
[1,2,4]triazol-1-yl, [1,2,3]triazol-1-yl, [1,2,4]triazol-4-yl,
pyrrol-1-yl, pyrazol-1-yl, 1H-pyrazol-3-yl, imidazol-1-yl,
oxazol-5-yl, oxazol-2-yl,
[1,3,4]oxadiazol-2-[1,3,4]thiadiazol-2-yl, [1,2,4]oxadiazol-3-yl,
[1,2,4]thiadiazol-3-yl, tetrazol-1-yl, pyrimidin-5-yl,
pyrimidin-2-yl, pyrimidin-4-yl, pyridazin-3-yl, pyridazin-4-yl,
pyrazin-2-yl, 1,3-dioxo-1,3-dihydro-isoindol-2-yl and
[1,2,3]thiadiazol-4-yl. In some embodiments, p=0 and r=1. In some
embodiments, R.sub.18 is carbo-C.sub.1-6-alkoxy or carboxy. In some
embodiments, p=2 and r=1. In some embodiments, R.sub.18 is H,
C.sub.1-5 acyl or C.sub.1-8 alkyl.
[0370] Some embodiments of the present invention pertain to
compounds wherein Ar.sub.1 is heteroaryl. In some embodiments, the
heteroaryl is optionally substituted with R.sub.14, R.sub.15,
R.sub.16 and R.sub.17. In some embodiments, R.sub.14-R.sub.17 are
independently selected from the group consisting of H, C.sub.1-5
acyl, C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4
alkylcarboxamide, C.sub.1-4 alkylureyl, carbo-C.sub.1-6-alkoxy,
carboxamide, carboxy, cyano, C.sub.3-7 cycloalkyl, halogen,
C.sub.1-4 haloalkoxy and C.sub.1-4 haloalkyl. In some embodiments,
one R.sub.14, R.sub.15, R.sub.16 and R.sub.17 is halogen. In
further embodiments, the halogen is fluorine.
[0371] Some embodiments of the present invention pertain to
compounds wherein Ar.sub.1 is heteroaryl. In some embodiments, the
heteroaryl is optionally substituted with R.sub.14, R.sub.15,
R.sub.16 and R.sub.17 wherein two adjacent R.sub.14, R.sub.15,
R.sub.16 and R.sub.17 groups together with the atoms to which they
are attached form a 5, 6 or 7 membered cycloalkyl, cycloalkenyl or
heterocyclic group fused with the heteroaryl group wherein the 5, 6
or 7 membered group is optionally substituted with halogen. In some
embodiments, the two adjacent groups form a 5 membered heterocyclic
group fused with the heteroaryl group. In some embodiments, the two
adjacent groups form a 6 membered heterocyclic group fused with the
heteroaryl group. In some embodiments, the two adjacent groups form
a 7 membered heterocyclic group fused with the heteroaryl
group.
[0372] Some embodiments of the present invention pertain to
compounds wherein R.sub.3 and R.sub.4 are independently H or
CH.sub.3.
[0373] Some embodiments of the present invention pertain to
compounds wherein M and J are both N (i.e., nitrogen atom) and T is
CR.sub.5. In some embodiments, Z and U are both C (i.e., a carbon
atom); these embodiments can be represented by Formula (IIIe) as
shown below: ##STR96## wherein each variable in Formula (IIIe) has
the same meaning as described herein, supra and infra.
[0374] Some embodiments of the present invention pertain to
compounds wherein V is a bond; these embodiments are represented by
Formula (IIIg) as shown below: ##STR97## wherein each variable in
Formula (IIIg) has the same meaning as described herein, supra and
infra.
[0375] Some embodiments of the present invention pertain to
compounds wherein W is N.
[0376] Some embodiments of the present invention pertain to
compounds wherein X is CR.sub.9 and Y is CR.sub.10. In some
embodiments, V is a bond and represented by Formula (IIIi):
##STR98## wherein each variable in Formula (IIIi) has the same
meaning as described herein, supra and infra. In some embodiments W
is N (i.e., a nitrogen atom).
[0377] Some embodiments of the present invention pertain to
compounds wherein X is N and Y is CR.sub.10. In some embodiments, V
is a bond and represented by Formula (IIIk): ##STR99## wherein each
variable in Formula (IIIk) has the same meaning as described
herein, supra and infra. In some embodiments W is N (i.e., a
nitrogen atom).
[0378] Some embodiments of the present invention pertain to
compounds wherein X is CR.sub.9 and Y is N. In some embodiments, V
is a bond and represented by Formula (IIIm): ##STR100## wherein
each variable in Formula (IIIm) has the same meaning as described
herein, supra and infra. In some embodiments W is N (i.e., a
nitrogen atom).
[0379] Some embodiments of the present invention pertain to
compounds wherein X and Y are both N. In some embodiments, V is a
bond and represented by Formula (IIIo): ##STR101## wherein each
variable in Formula (IIIo) has the same meaning as described
herein, supra and infra. In some embodiments W is N (i.e., a
nitrogen atom).
[0380] Some embodiments of the present invention pertain to
compounds having the Formula (H7): ##STR102## wherein:
[0381] A is --CH.sub.2--, or --CH.sub.2CH.sub.2--;
[0382] B is --CH.sub.2--, --CH.sub.2CH.sub.2--, or
--CH.sub.2CH.sub.2CH.sub.2--;
[0383] E is CH;
[0384] is a single bond;
[0385] D is N--R.sub.2;
[0386] K is --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH(CH.sub.3)CH.sub.2--, or a bond;
[0387] Q is O, S, S(O), S(O).sub.2, NH;
[0388] R.sub.5 is H, CH.sub.3 or N(CH.sub.3).sub.2;
[0389] R.sub.10 is H or CH.sub.3;
[0390] R.sub.2 is --CR.sub.25R.sub.26C(O)R.sub.24, --C(O)R.sub.24,
--C(O)NR.sub.25R.sub.24, --R.sub.24, --C(O)OR.sub.24,
--C(S)NR.sub.25R.sub.24, or --CR.sub.25R.sub.26R.sub.24, wherein
R.sub.24 is C.sub.1-8 alkyl, C.sub.3-7 cycloalkyl, phenyl,
heteroaryl, or heterocyclic each optionally substituted with 1 to 5
substituents selected from the group consisting of C.sub.2-6
alkenyl, C.sub.1-4 alkoxy, C.sub.1-7 alkyl, C.sub.1-4
alkylsulfonyl, amino, carbo-C.sub.1-6-alkoxy, carboxy, cyano,
C.sub.3-7 cycloalkyl, C.sub.2-8 dialkylamino, C.sub.1-4 haloalkoxy,
C.sub.1-4 haloalkyl, halogen, heteroaryl, heterocyclic, hydroxyl,
phenyl, phenoxy, and sulfonic acid, wherein said C.sub.1-7 alkyl,
phenyl and phenoxy are each optionally substituted with 1 to 5
substituents selected from the group consisting of amino, C.sub.1-4
haloalkoxy, and heterocyclic; and R.sub.25 and R.sub.26 are each
independently H or C.sub.1-8 alkyl; and
[0391] Ar.sub.1 is aryl or heteroaryl optionally substituted with
R.sub.13, R.sub.14, R.sub.15, R.sub.16, and R.sub.17; wherein
R.sub.13 is selected from the group consisting of C.sub.1-6
acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4
alkylamino, C.sub.1-6 alkylcarboxamide, C.sub.1-4 alkylsulfonamide,
C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio, amino, carbamimidoyl,
carboxamide, carboxy, cyano, C.sub.2-6 dialkylamino, halogen,
heterocyclic, heterocyclic-oxy, heterocyclic-carbonyl, heteroaryl,
and sulfonamide, and wherein C.sub.1-6 acylsulfonamide, C.sub.1-4
alkoxy, C.sub.1-8 alkyl, C.sub.1-4 alkylamino, C.sub.1-4
alkylsulfonamide, alkylsulfonyl, C.sub.1-4 alkylthio,
carbamimidoyl, C.sub.2-6 dialkylamino, heterocyclic,
heterocyclic-carbonyl, and heteroaryl are each optionally
substituted with 1 to 5 substituents selected independently from
the group consisting of C.sub.1-6 acylsulfonamide, C.sub.1-4
alkoxy, C.sub.1-7 alkyl, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylsulfonyl, carboxy, C.sub.3-7 cycloalkyloxy, C.sub.2-6
dialkylamino, C.sub.2-6 dialkylcarboxamide, heteroaryl,
heterocyclic, hydroxyl, phenyl, and phosphonooxy wherein said
C.sub.1-7 alkyl and C.sub.1-4 alkylcarboxamide are each optionally
substituted with 1 to 5 substituents selected from the group
consisting of C.sub.1-4 alkoxy and hydroxy; and
[0392] R.sub.14, R.sub.15, R.sub.16, and R.sub.17 are each
independently selected form the group consisting of C.sub.1-6
acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4
alkylamino, C.sub.1-4 alkylcarboxamide, C.sub.1-4 alkylsulfonamide,
C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio, amino, carbamimidoyl,
carboxamide, cyano, C.sub.2-6 dialkylamino, and halogen.
[0393] Some embodiments of the present invention pertain to
compounds having the Formula (H7):
[0394] A and B are both --CH.sub.2CH.sub.2--;
[0395] E is CH;
[0396] is a single bond;
[0397] D is N--R.sub.2;
[0398] K is a bond;
[0399] Q is O, or NH;
[0400] R.sub.5 and R.sub.10 are both H;
[0401] R.sub.2 is --C(O)OR.sub.24 wherein R.sub.24 is C.sub.1-8
alkyl, or C.sub.3-7 cycloalkyl each optionally substituted with 1
to 5 substituents selected from the group consisting of C.sub.1-4
alkoxy, C.sub.1-7 alkyl, C.sub.1-4 alkylsulfonyl, amino,
carbo-C.sub.1-6-alkoxy, carboxy, cyano, C.sub.3-7 cycloalkyl,
C.sub.2-8 dialkylamino, C.sub.1-4 haloalkoxy, C.sub.1-4 haloalkyl,
halogen, heteroaryl, heterocyclic, hydroxyl, phenyl, and phenoxy;
and
[0402] Ar.sub.1 is aryl or heteroaryl optionally substituted with
R.sub.13, R.sub.14, R.sub.15, R.sub.16, and R.sub.17; wherein
R.sub.13 is selected from the group consisting of C.sub.1-6
acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4
alkylamino, C.sub.1-6 alkylcarboxamide, C.sub.1-4 alkylsulfonamide,
C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio, amino, carbamimidoyl,
carboxamide, carboxy, cyano, C.sub.2-6 dialkylamino, halogen,
heterocyclic, heterocyclic-oxy, heterocyclic-carbonyl, heteroaryl,
and sulfonamide, and wherein C.sub.1-4 acylsulfonamide, C.sub.1-4
alkoxy, C.sub.1-8 alkyl, C.sub.1-4 alkylamino, C.sub.1-4
alkylsulfonamide, alkylsulfonyl, C.sub.1-4 alkylthio,
carbamimidoyl, C.sub.2-6 dialkylamino, heterocyclic,
heterocyclic-carbonyl, and heteroaryl are each optionally
substituted with 1 to 5 substituents selected independently from
the group consisting of C.sub.1-6 acylsulfonamide, C.sub.1-4
alkoxy, C.sub.1-7 alkyl, C.sub.1-4 alkylcarboxamide, C.sub.1-4
alkylsulfonyl, carboxy, C.sub.3-7 cycloalkyloxy, C.sub.2-6
dialkylamino, C.sub.2-6 dialkylcarboxamide, heteroaryl,
heterocyclic, hydroxyl, phenyl, and phosphonooxy wherein said
C.sub.1-7 alkyl and C.sub.1-4 alkylcarboxamide are each optionally
substituted with 1 to 5 substituents selected from the group
consisting of C.sub.1-4 alkoxy and hydroxy; and
[0403] R.sub.14, R.sub.15, R.sub.16, and R.sub.17 are each
independently selected form the group consisting of C.sub.1-4
alkoxy, C.sub.1-8 alkyl, and halogen.
[0404] Some embodiments of the present invention pertain to
compounds having the Formula (H7):
[0405] A and B are both --CH.sub.2CH.sub.2--;
[0406] E is CH;
[0407] is a single bond;
[0408] D is N--R.sub.2
[0409] K is a bond;
[0410] Q is O, or NH;
[0411] R.sub.5 and R.sub.10 are both H;
[0412] R.sub.2 is --C(O)OR.sub.24 wherein R.sub.24 is C.sub.1-8
alkyl or C.sub.3-7 cycloalkyl;
[0413] Ar.sub.1 is phenyl, 3-pyridyl, or 2-pyridyl each optionally
substituted with R.sub.13, R.sub.14, R.sub.15, R.sub.16, and
R.sub.17,
[0414] wherein R.sub.13 is selected from the group consisting of
C.sub.1-6 acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-8 alkyl,
C.sub.1-4 alkylamino, C.sub.1-6 alkylcarboxamide, C.sub.1-4
alkylsulfonamide, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylthio,
carbamimidoyl, carboxamide, carboxy, cyano, C.sub.2-6 dialkylamino,
halogen, heterocyclic, heterocyclic-oxy, heterocyclic-carbonyl,
heteroaryl, heteroarylcarbonyl, and sulfonamide, and wherein
C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.1-4 alkylamino, C.sub.1-6
alkylcarboxamide, C.sub.1-4 alkylsulfonamide, C.sub.1-4
alkylsulfonyl, C.sub.1-4 alkylthio, carbamimidoyl, C.sub.2-6
dialkylamino, heterocyclic, heterocyclic-carbonyl, and heteroaryl
are each optionally substituted with 1 to 5 substituents selected
independently from the group consisting of C.sub.1-6
acylsulfonamide, C.sub.1-4 alkoxy, C.sub.1-7 alkyl, C.sub.1-4
alkylcarboxamide, C.sub.1-4 alkylsulfonyl, carboxy, C.sub.2-6
dialkylamino, C.sub.2-6 dialkylcarboxamide, heteroaryl,
heterocyclic, hydroxyl, phenyl, and phosphonooxy wherein said
C.sub.1-7 alkyl and C.sub.1-4 alkylcarboxamide are each optionally
substituted with 1 to 5 substituents selected from the group
consisting of C.sub.1-4 alkoxy and hydroxy; and
[0415] R.sub.14, R.sub.15, R.sub.16, and R.sub.17 are each
independently CH.sub.3, or F.
[0416] In some embodiments, R.sub.2 is selected from the group
consisting of methoxycarbonyl, ethoxycarbonyl, iso-propoxycarbonyl,
n-propoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl,
iso-butoxycarbonyl, and n-pentyloxycarbonyl.
[0417] In some embodiments, R.sub.11 is selected from the group
consisting of
[0418] sulfamoyl [i.e., --S(O).sub.2NH.sub.2],
[0419] acetylsulfamoyl [i.e., --S(O).sub.2NHC(O)CH.sub.3],
[0420] propionylsulfamoyl [i.e.,
--S(O).sub.2NHC(O)CH.sub.2CH.sub.3],
[0421] butyrylsulfamoyl [i.e.,
--S(O).sub.2NHC(O)CH.sub.2CH.sub.2CH.sub.3],
[0422] pentanoylsulfamoyl [i.e.,
--S(O).sub.2NHC(O)CH.sub.2CH.sub.2CH.sub.2CH.sub.3],
[0423] methanesulfonyl [i.e., --S(O).sub.2CH.sub.3],
[0424] ethanesulfonyl [i.e., --S(O).sub.2CH.sub.2CH.sub.3],
[0425] propane-1-sulfonyl [i.e.,
--S(O).sub.2CH.sub.2CH.sub.2CH.sub.3],
[0426] hydroxymethyl (i.e., --CH.sub.2OH),
[0427] 2-hydroxyethyl (i.e., --CH.sub.2CH.sub.2OH),
[0428] 3-hydroxypropyl (i.e., --CH.sub.2CH.sub.2CH.sub.2OH),
[0429] 4-hydroxy-butyl (i.e.,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH),
[0430] phosphonooxymethyl [i.e., --CH.sub.2OP(O)(OH).sub.2],
[0431] 2-phosphonooxy-ethyl [i.e.,
--CH.sub.2CH.sub.2OP(O)(OH).sub.2],
[0432] 3-phosphonooxy-propyl [i.e.,
--CH.sub.2CH.sub.2CH.sub.2OP(O)(OH).sub.2], and
[0433] 4-phosphonooxy-butyl [i.e.,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2OP(O)(OH).sub.2].
[0434] Inventors have discovered that a variety of fused aromatic
rings can be utilized in the present invention. The fused ring
system is generically represented by the ring designated by
variables G, F, J, U, W, V, X, Y and Z in Formula (I) as well as
other formulae disclosed herein. In some embodiments, the fused
ring is a 6-6 fused ring wherein two ring atoms (i.e., U and Z) are
mutually shared by both rings. In some embodiments, the fused ring
system is a 6-5 fused ring wherein two ring atoms (i.e., U and Z)
are mutally shared by both rings. Representative fused rings of the
present invention include, but not limited to, those disclosed in
TABLE 6 shown below: TABLE-US-00012 TABLE 6 ##STR103## No. Fused
Ring system M T J Y X V W Z U H1 ##STR104## N CR.sub.5 N CR.sub.10
CR.sub.9 CR.sub.8 C C C H2 ##STR105## N CR.sub.5 N CR.sub.10
CR.sub.9 N C C C H3 ##STR106## N CR.sub.5 N N CR.sub.9 N C C C H4
##STR107## N CR.sub.5 N N CR.sub.9 CR.sub.8 C C C H5 ##STR108## N
CR.sub.5 N CR.sub.10 N CR.sub.8 C C C H6 ##STR109## N CR.sub.5 N
CR.sub.10 CR.sub.9 A Bond N C C H7 ##STR110## N CR.sub.5 N
CR.sub.10 N A Bond N C C H8 ##STR111## N CR.sub.5 N N CR.sub.9 A
Bond N C C H9 ##STR112## N CR.sub.5 N N N A Bond N C C H10
##STR113## N CR.sub.5 N NR.sub.12 CR.sub.9 A Bond C C C H11
##STR114## N CR.sub.5 N NR.sub.12 N A Bond C C C H12 ##STR115## N
CR.sub.5 N O N A Bond C C C H13 ##STR116## N CR.sub.5 N S N A Bond
C C C H14 ##STR117## N CR.sub.5 N O CR.sub.9 A Bond C C C H15
##STR118## N CR.sub.5 N S CR.sub.9 A Bond C C C H16 ##STR119##
CR.sub.6 CR.sub.5 N CR.sub.10 CR.sub.9 CR.sub.8 C C C H17
##STR120## CR.sub.6 CR.sub.5 N CR.sub.10 CR.sub.9 N C C C H18
##STR121## CR.sub.6 CR.sub.5 N N CR.sub.9 N C C C H19 ##STR122##
CR.sub.6 CR.sub.5 N N CR.sub.9 CR.sub.8 C C C H20 ##STR123##
CR.sub.6 CR.sub.5 N CR.sub.10 N CR.sub.8 C C C H21 ##STR124##
CR.sub.6 CR.sub.5 N CR.sub.10 CR.sub.9 A Bond N C C H22 ##STR125##
CR.sub.6 CR.sub.5 N CR.sub.10 N A Bond N C C H23 ##STR126##
CR.sub.6 CR.sub.5 N N CR.sub.9 A Bond N C C H24 ##STR127## CR.sub.6
CR.sub.5 N N N A Bond N C C H25 ##STR128## CR.sub.6 CR.sub.5 N
NR.sub.12 CR.sub.9 A Bond C C C H26 ##STR129## CR.sub.6 CR.sub.5 N
NR.sub.12 N A Bond C C C H27 ##STR130## CR.sub.6 CR.sub.5 N O N A
Bond C C C H28 ##STR131## CR.sub.6 CR.sub.5 N S N A Bond C C C H29
##STR132## CR.sub.6 CR.sub.5 N O CR.sub.9 A Bond C C C H30
##STR133## CR.sub.6 CR.sub.5 N S CR.sub.9 A Bond C C C H31
##STR134## CR.sub.6 N CR.sub.7 CR.sub.10 CR.sub.9 CR.sub.8 C C C
H32 ##STR135## CR.sub.6 N CR.sub.7 CR.sub.10 CR.sub.9 N C C C H33
##STR136## CR.sub.6 N CR.sub.7 N CR.sub.9 N C C C H34 ##STR137##
CR.sub.6 N CR.sub.7 N CR.sub.9 CR.sub.8 C C C H35 ##STR138##
CR.sub.6 N CR.sub.7 CR.sub.10 N CR.sub.8 C C C H36 ##STR139##
CR.sub.6 N CR.sub.7 CR.sub.10 CR.sub.9 A Bond N C C H37 ##STR140##
CR.sub.6 N CR.sub.7 CR.sub.10 N A Bond N C C H38 ##STR141##
CR.sub.6 N CR.sub.7 N CR.sub.9 A Bond N C C H39 ##STR142## CR.sub.6
N CR.sub.7 N N A Bond N C C H40 ##STR143## CR.sub.6 N CR.sub.7
NR.sub.12 CR.sub.9 A Bond C C C H41 ##STR144## CR.sub.6 N CR.sub.7
NR.sub.12 N A Bond C C C H42 ##STR145## CR.sub.6 N CR.sub.7 O N A
Bond C C C H43 ##STR146## CR.sub.6 N CR.sub.7 S N A Bond C C C H44
##STR147## CR.sub.6 N CR.sub.7 O CR.sub.9 A Bond C C C H45
##STR148## CR.sub.6 N CR.sub.7 S CR.sub.9 A Bond C C C H46
##STR149## N CR.sub.5 N CR.sub.10 S A Bond C C C H47 ##STR150## N
CR.sub.5 N CR.sub.10 O A Bond C C C H48 ##STR151## N CR.sub.5 N
CR.sub.10 NR.sub.11 A Bond C C C H49 ##STR152## N CR.sub.5 N N S A
Bond C C C H50 ##STR153## N CR.sub.5 N N O A Bond C C C H51
##STR154## N CR.sub.5 N N NR.sub.11 A Bond C C C H52 ##STR155## N
CR.sub.5 N CR.sub.10 CR.sub.9 A Bond C N C H53 ##STR156## N
CR.sub.5 N N CR.sub.9 A Bond C N C H54 ##STR157## N CR.sub.5 N
CR.sub.10 N A Bond C N C H55 ##STR158## CR.sub.6 CR.sub.5 N
CR.sub.10 S A Bond C C C H56 ##STR159## CR.sub.6 CR.sub.5 N
CR.sub.10 O A Bond C C C H57 ##STR160## CR.sub.6 CR.sub.5 N
CR.sub.10 NR.sub.11 A Bond C C C H58 ##STR161## CR.sub.6 CR.sub.5 N
N S A Bond C C C H59 ##STR162## CR.sub.6 CR.sub.5 N N O A Bond C C
C H60 ##STR163## CR.sub.6 CR.sub.5 N N NR.sub.9 A Bond C C C H61
##STR164## CR.sub.6 CR.sub.5 N CR.sub.10 CR.sub.9 A Bond C N C H62
##STR165## CR.sub.6 CR.sub.5 N N CR.sub.9 A Bond C N C H63
##STR166## CR.sub.6 CR.sub.5 N CR.sub.10 N A Bond C N C H64
##STR167## CR.sub.6 N CR.sub.7 CR.sub.10 S A Bond C C C H65
##STR168## CR.sub.6 N CR.sub.7 CR.sub.10 O A Bond C C C H66
##STR169## CR.sub.6 N CR.sub.7 CR.sub.10 NR.sub.11 A Bond C C C H67
##STR170## CR.sub.6 N CR.sub.7 N S A Bond C C C H68 ##STR171##
CR.sub.6 N CR.sub.7 N O A Bond C C C H69 ##STR172## CR.sub.6 N
CR.sub.7 N NR.sub.11 A Bond C C C H70 ##STR173## CR.sub.6 N
CR.sub.7 CR.sub.10 CR.sub.9 A Bond C N C H71 ##STR174## CR.sub.6 N
CR.sub.7 N CR.sub.9 A Bond C N C H72 ##STR175## CR.sub.6 N CR.sub.7
CR.sub.10 N A Bond C N C H73 ##STR176## N CR.sub.5 N CR.sub.10
CR.sub.9 A Bond C C N H74 ##STR177## N CR.sub.5 N N CR.sub.9 A Bond
C C N H75 ##STR178## N CR.sub.5 N CR.sub.10 N A Bond C C N H76
##STR179## N CR.sub.5 N N N A Bond C C N H77 ##STR180## CR.sub.6
CR.sub.5 N CR.sub.10 CR.sub.9 A Bond C C N H78 ##STR181## CR.sub.6
CR.sub.5 N N CR.sub.9 A Bond C C N H79 ##STR182## CR.sub.6 CR.sub.5
N CR.sub.10 N A Bond C C N H80 ##STR183## CR.sub.6 CR.sub.5 N N N A
Bond C C N H81 ##STR184## CR.sub.6 N CR.sub.7 CR.sub.10 CR.sub.9 A
Bond C C N H82 ##STR185## CR.sub.6 N CR.sub.7 N CR.sub.9 A Bond C C
N H83 ##STR186## CR.sub.6 N CR.sub.7 CR.sub.10 N A Bond C C N H84
##STR187## CR.sub.6 N CR.sub.7 N N A Bond C C N H85 ##STR188## N
CR.sub.5 CR.sub.7 CR.sub.10 CR.sub.9 CR.sub.8 C C C H86 ##STR189##
N CR.sub.5 CR.sub.7 N CR.sub.9 CR.sub.6 C C C H87 ##STR190## N
CR.sub.5 CR.sub.7 CR.sub.10 N CR.sub.8 C C C H88 ##STR191## N
CR.sub.5 CR.sub.7 CR.sub.10 CR.sub.9 N C C C H89 ##STR192## N
CR.sub.5 CR.sub.7 N N CR.sub.8 C C C H90 ##STR193## N CR.sub.5
CR.sub.7 N CR.sub.9 N C C C H91 ##STR194## N CR.sub.5 CR.sub.7
CR.sub.10 CR.sub.9 A Bond N C C H92 ##STR195## N CR.sub.5 CR.sub.7
CR.sub.10 N A Bond N C C H93 ##STR196## N CR.sub.5 CR.sub.7 N
CR.sub.9 A Bond N C C H94 ##STR197## N CR.sub.5 CR.sub.7 N N A Bond
N C C H95 ##STR198## N CR.sub.5 CR.sub.7 NR.sub.12 CR.sub.9 A Bond
C C C H96 ##STR199## N CR.sub.5 CR.sub.7 NR.sub.12 N A Bond C C C
H97 ##STR200## N CR.sub.5 CR.sub.7 O CR.sub.9 A Bond C C C H98
##STR201## N CR.sub.5 CR.sub.7 O N A Bond C C C H99 ##STR202## N
CR.sub.5 CR.sub.7 S CR.sub.9 A Bond C C C H100 ##STR203## N
CR.sub.5 CR.sub.7 S N A Bond C C C H101 ##STR204## N CR.sub.5
CR.sub.7 CR.sub.10 O A Bond C C C H102 ##STR205## N CR.sub.5
CR.sub.7 CR.sub.10 S A Bond C C C H103 ##STR206## N CR.sub.5
CR.sub.7 CR.sub.10 NR.sub.11 A Bond C C C H104 ##STR207## N
CR.sub.5 CR.sub.7 N O A Bond C C C H105 ##STR208## N CR.sub.5
CR.sub.7 N S A Bond C C C H106 ##STR209## N CR.sub.5 CR.sub.7 N
NR.sub.11 A Bond C C C H107 ##STR210## N CR.sub.5 CR.sub.7
CR.sub.10 CR.sub.9 A Bond C N C H108 ##STR211## N CR.sub.5 CR.sub.7
N CR.sub.9 A Bond C N C H109 ##STR212## N CR.sub.5 CR.sub.7
CR.sub.10 N A Bond C N C H110 ##STR213## N CR.sub.5 CR.sub.7
CR.sub.10 CR.sub.9 A Bond C C N H111 ##STR214## N CR.sub.5 CR.sub.7
CR.sub.10 N A Bond C C N H112 ##STR215## N CR.sub.5 CR.sub.7 N
CR.sub.9 A Bond C C N H113 ##STR216## N CR.sub.5 CR.sub.7 N N A
Bond C C N H114 ##STR217## CR.sub.6 CR.sub.5 N N N A Bond C N C
H115 ##STR218## CR.sub.6 N CR.sub.7 N N A Bond C N C H116
##STR219## N CR.sub.5 CR.sub.7 N N A Bond C N C
[0435] Some embodiments of the present invention pertain to
compounds wherein M, J, X, and W are all N; T is CR.sub.5; Y is
CR.sub.10; V is a bond; and Z and U are both C.
[0436] Some embodiments of the present invention pertain to
compounds wherein M, J, X, and W are all N; T is CR.sub.5, wherein
R.sub.5 is --H, --CH.sub.3, or --N(CH.sub.3).sub.2; Y is CR.sub.10,
wherein R.sub.10 is --H or --CH.sub.3; V is a bond; and Z and U are
both C.
[0437] Some embodiments of the present invention pertain to
compounds wherein M, J, X, and W are all N; T is C--H; Y is C--H; V
is a bond; and Z and U are both C.
[0438] In some embodiments of the present invention a compound is
not one or more of the compounds illustrated in Table 7, infra.
TABLE-US-00013 TABLE 7 Structure Chemical Name ##STR220##
4-[1-(2,4-Dimethyl-phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-
ylamino]-piperidine-1-carboxylic acid ethyl ester ##STR221##
4-(1-m-Tolyl-1H-pyrazolo[3,4- d]pyrimidin-4-ylamino)-piperidine-
1-carboxylic acid ethyl ester ##STR222##
4-[1-(4-Methoxy-phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-
ylamino]-piperidine-1-carboxylic acid ethyl ester ##STR223##
4-[1-(4-Chloro-phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-
ylamino]-piperidine-1-carboxylic acid ethyl ester ##STR224##
4-(1-Phenyl-1H-pyrazolo[3,4- d]pyrimidin-4-ylamino)-piperidine-
1-carboxylic acid ethyl ester
[0439] Some embodiments of the present invention pertain to
compounds wherein R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9 and
R.sub.10 are independently selected from the group consisting of H,
C.sub.1-4 alkoxy, C.sub.1-8 alkyl, C.sub.2-6 alkynyl, amino,
C.sub.3-7 cycloalkyl and C.sub.1-4 haloalkyl.
[0440] In some embodiments, R.sub.5, R.sub.6, R.sub.7, R.sub.8,
R.sub.9 and R.sub.10 are independently H or C.sub.1-8 alkyl.
[0441] In some embodiments, R.sub.5, R.sub.6, R.sub.7, R.sub.8,
R.sub.9 and R.sub.10 are independently H or CH.sub.3.
[0442] In some embodiments, R.sub.5 is H.
[0443] Some embodiments of the present invention pertain to
compounds wherein R.sub.11 and R.sub.12 are independently selected
from the group consisting of H, C.sub.1-8 alkyl, C.sub.2-6 alkynyl,
C.sub.3-7 cycloalkyl and C.sub.1-4 haloalkyl. In some embodiments,
R.sub.11 and R.sub.12 are independently H or C.sub.1-8 alkyl.
[0444] In some embodiments, R.sub.11 and R.sub.12 are independently
H or C.sub.1-8 alkyl.
[0445] In some embodiments, R.sub.11 and R.sub.12 are independently
H or CH.sub.3.
[0446] Some embodiments of the present invention include compounds
illustrated in TABLES A, B, C, D, E, F, G, I, J, and K shown below.
TABLE-US-00014 TABLE A Cmpd# Structure Chemical Name A1 ##STR225##
4-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-piperidine-1-carboxylic acid tert-butyl ester A2 ##STR226##
4-[1-(4-Methanesulfonyl-phenyl)- 3-methyl-1H-pyrazolo[3,4-
d]pyrimidin-4-yloxy]-piperidine-1- carboxylic acid tert-butyl ester
A3 ##STR227## 4-[1-(4-Methanesulfonyl-phenyl)-
3,6-dimethyl-1H-pyrazolo[3,4- d]pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid tert-butyl ester A4 ##STR228##
4-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-piperidine-1-carboxylic acid isobutyl ester A5 ##STR229##
4-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-piperidine-1-carboxylic acid isopropyl ester A6 ##STR230##
1-(4-Methanesulfonyl-phenyl)-4- (piperidin-4-yloxy)-1H-
pyrazolo[3,4-d]pyrimidine A7 ##STR231##
{4-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-piperidin-l-yl}-pyridin-3-yl- methanone A8 ##STR232##
(3-Fluoro-phenyl)-{4-[1-(4- methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidin-1-yl}-methanone A9
##STR233## (1-tert-Butyl-5-methyl-1H-pyrazol-
4-yl)-{4-[1-(4-methanesulfonyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-yloxy]-piperidin-1- yl)-methanone A10 ##STR234##
(5-tert-Butyl-2-methyl-2H-pyrazol- 3-yl)-{4-[1-(4-methanesulfonyl-
phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yloxy]-piperidin-1-
yl}-methanone A11 ##STR235## 4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- ylamino]-piperidine-1-carboxylic
acid tert-butyl ester A12 ##STR236##
4-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
ylamino]-piperidine-1-carboxylic acid isopropyl ester A13
##STR237## 4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- ylamino]-piperidine-1-carboxylic
acid isobutyl ester A14 ##STR238## Furan-2-yl-{4-[1-(4-
methanesulfonyl-phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yloxy]-
piperidin-1-yl}-methanone A15 ##STR239##
{4-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-piperidin-l-yl}-(1-methyl- 1H-pyrrol-2-yl)-methanone A16
##STR240## 2-{4-[1-(4-Methanesulfonyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-yloxy]-piperidin-1- yl}-1-pyridin-3-yl-ethanone A17
##STR241## 2-{4-[1-(4-Methanesulfonyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-yloxy]-piperidin-1- yl}-1-pyridin-2-yl-ethanone A18
##STR242## {4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidin-1-yl{-(5-methyl-
pyridin-3-yl)-methanone A19 ##STR243##
{4-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-piperidin-1-yl{-(2-methyl- pyridin-3-yl)-methanone A20
##STR244## {4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidin-1-yl}-(6-methyl-
pyridin-3-yl)-methanone A21 ##STR245##
{4-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-piperidin-1-yl}-(5-methyl- isoxazol-3-yl)-methanone A22
##STR246## 2-{4-[1-(4-Methanesulfonyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-yloxy]-piperidin-1- yl}-1-thiophen-2-yl-ethanone A23
##STR247## 4-(1-Benzyl-azetidin-3-yloxy)-1-
(4-methanesulfonyl-phenyl)-1H- pyrazolo[3,4-d]pyrimidine A24
##STR248## 3-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- ylamino]-piperidine-1-carboxylic
acid tert-butyl ester A25 ##STR249## 1-{4-[1-(4-Methanesulfonyl-
phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yloxy]-piperidin-1-
yl}-3,3-dimethyl-butan-2-one A26 ##STR250##
{4-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-piperidin-1-yl}-pyrazin-2- yl-methanone A27 ##STR251##
{4-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-piperidin-1-yl}-(5-methyl- pyrazin-2-yl)-methanone A28
##STR252## {4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidin-1-yl}-pyrimidin-5-
yl-methanone A29 ##STR253## {4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidin-1-yl}-pyridazin-4-
yl-methanone A30 ##STR254## {4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidin-1-yl}-thiophen-2-
yl-methanone A31 ##STR255## (3,4-Dimethyl-isoxazol-5-yl)-{4-[1-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidin-1-yl}-methanone A32
##STR256## 3-tert-Butoxy-1-{4-[1-(4- methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidin-1-yl }-propan-1-one
A33 ##STR257## (3-{4-[1-(4-Methanesulfonyl-
phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yloxy]-piperidin-1-
yl}-3-oxo-propyl)-methyl-carbamic acid tert-butyl ester A34
##STR258## {4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidin-1-yl}-(6-
trifluoromethyl-pyridin-3-yl)- methanone A35 ##STR259##
{4-[1-(4-Methanesulfonyl-phenyl)- ylamino]-cyclohexyl}-carbamic
acid tert-butyl ester A36 ##STR260##
N-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-yl]-
cyclohexane-1,4-diamine A37 ##STR261##
{4-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-piperidin-1-yl}-(4-methyl- [1,2,3]thiadiazol-5-yl)-methanone
A38 ##STR262## (3,5-Dimethyl-isoxazol-4-yl)-{4-
[1-(4-methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidin-1-yl}-methanone A39
##STR263## (2,5-Dimethyl-2H-pyrazo-3-yl)-{4-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidin-1-yl}-methanone A40
##STR264## 1-{4-[1-(4-Methanesulfonyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-ylozy]-piperidin-1- yl}-2-(3-methyl-isoxazol-5-yl)-
ethanone A41 ##STR265## 4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidine-1-carbothioic acid
pyridin-4-ylamide A42 ##STR266## N-{4-[1-(4-Methanesulfonyl-
phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-ylamino]-
cyclohexyl}-nicotinamide A43 ##STR267## 3-tert-Butoxy-N-{4-[1-(4-
methanesulfonyl-phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-
ylamino]-cyclohexyl}- propionamide A44 ##STR268##
{4-[1-(3,5-Bis-trifluoromethyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-ylamino]- cyclohexyl}-carbamic acid tert- butyl ester
A45 ##STR269## (3,5-Dimethyl-isoxazol-4-yl)-{4-[1-
(4-methanesulfonyl-phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yloxy]-
piperidin-1-yl}-methanone A46 ##STR270##
4-[1-(3,5-Bis-trifluoromethyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-yloxy]-piperidine-1- carboxylic acid tert-butyl ester
A47 ##STR271## 3-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-azetidine-1-carboxylic acid
isopropyl ester A48 ##STR272## 4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidine-1-carboxylic acid
butyl ester A49 ##STR273## 4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidine-1-carboxylic acid
propyl ester A50 ##STR274## 4-[1-(3-Fluoro-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidine-1-carboxylic acid
tert- butyl ester A51 ##STR275## 4-[1-(2,4-Difluoro-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidine-1-carboxylic acid
tert- butyl ester A52 ##STR276## {4-[1-(2,4-Difluoro-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4- ylamino]-cyclohexyl}-carbamic acid
tert-butyl ester A53 ##STR277## {4-[1-(3-Fluoro-phenyl)-1H-
ylamino]-cyclohexyl}-carbamic acid tert-butyl ester A54 ##STR278##
N-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-yl]-
cyclohexane-1,4-diamine A55 ##STR279##
{3-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
ylamino]-piperidin-1-yl}-(6- methyl-pyridin-3-yl)-methanone A56
##STR280## {3-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- ylamino]-piperidin-1-yl}-(2-
methyl-pyridin-3-yl)-methanone A57 ##STR281##
{3-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
ylamino]-piperidin-1-yl}-(5- methyl-pyridin-3-yl)-methanone A58
##STR282## {3-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- ylamino]-piperidin-1-yl}-pyridin-3-
yl-methanone A59 ##STR283## {3-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- ylamino]-piperidin-1-yl}-(1-
methyl-1H-pyrrol-3-yl)-methanone A60 ##STR284##
{4-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-cyclohexyl}-carbamic acid tert-butyl ester A61 ##STR285##
N-[1-(2,4-Difluoro-phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl]-
cyclohexane-1,4-diamine A62 ##STR286##
N{4-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
trifluoromethyl-pyridin-3-yl)- methanone A63 ##STR287##
4-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-piperidine-1-carboxylic acid cyclohexyl ester A64 ##STR288##
4-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-piperidine-1-carboxylic acid tetrahydro-pyran-4-yl ester A65
##STR289## 4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidine-1-carboxylic acid
cyclopentyl ester A66 ##STR290## 4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidine-1-carboxylic acid
tetrabydro-furan-3-yl ester
A67 ##STR291## 4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidine-1-carboxylic acid
tetrahydro-furan-3-yl ester A68 ##STR292##
4-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-piperidine-1-carboxylic acid tetrahydro-thiopyran-4-yl ester
A69 ##STR293## 4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidine-1-carboxylic acid
cyclobutyl ester A70 ##STR294##
(6-tert-Butyl-pyridin-3-yl)-{4-[1-(4- methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidin-1-yl}-methanone A71
##STR295## (4-{[1-(4-Methanesulfonyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-ylamino]-methyl}- cyclohexyl)-carbamic acid
tert-butyl ester A72 ##STR296## N-{4-[1-(4-Methanesulfonyl-
phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-ylamino]-
cyclohexylmethyl}-nicotinamide A73 ##STR297##
N-{4-[1-(4-Methanesulfonyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-ylamino]- cyclohexylmethyl}-6-methyl- nicotinamide
A74 ##STR298## 4-[1-(2-Fluoro-4-methanesulfonyl-
phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid tert-butyl ester A75 ##STR299##
4-({[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4-yl]- methyl-amino
}-methyl)-piperidine- 1-carboxylic acid tert-butyl ester A76
##STR300## 4-{[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- ylamino]-methyl}-piperidine-1-
carboxylic acid tert-butyl ester A77 ##STR301##
3-{[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
ylamino]-methyl}-piperidine-1- carboxylic acid tert-butyl ester A78
##STR302## 4-({Ethyl-[1-(4-methanesulfonyl-
phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl]-amino}-methyl)-
piperidine-1-carboxylic acid tert- butyl ester A79 ##STR303##
4-{1-[2-(2-Dimethylamino-ethoxy)- 4-methanesulfonyl-phenyl]-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy}- piperidine-1-carboxylic acid
tert- butyl ester A80 ##STR304## 3-[1-(2-Fluoro-4-methanesulfonyl-
phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-ylamino]-piperidine-
1-carboxylic acid tert-butyl ester A81 ##STR305##
4-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-piperidine-1-carboxylic acid pyridin-3-ylmethyl esteracid
tert- butyl ester A82 ##STR306## 4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidine-1-carboxylic acid
2-pyridin-3-yl-ethyl ester A83 ##STR307##
4-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-piperidine-1-carboxylic acid 3-pyridin-3-yl-propyl ester A84
##STR308## 4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidine-1-carboxylic acid
2-dimethylamino-ethyl ester A85 ##STR309##
4-{[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4-yl]- methyl-amino}-piperidine-1-
carboxylic acid tert-butyl ester A86 ##STR310##
4-[1-(2,5-Difluoro-phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid tert- butyl ester A87 ##STR311##
4-({Ethyl-[1-(2-fluoro-4- methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yl]- amino}-methyl)-piperidine-1-
carboxylic acid isopropyl ester A88 ##STR312##
4-({Ethyl-[1-(2-fluoro-4- methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yl]- amino}-methyl)-piperidine-1-
carboxylic acid tert-butyl ester A89 ##STR313##
4-[6-Dimethylamino-1-(4- methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidine-1-carboxylic acid
tert- butyl ester A90 ##STR314## 1-(4-{[1-(4-Methanesulfonyl-
phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl]-methyl-amino}-
piperidin-1-yl)-3,3-dimethyl-butan- 2-one A91 ##STR315##
4-{[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4-yl]- methyl-amino}-piperidine-1-
carboxylic acid cyclobutyl ester A92 ##STR316##
4-[({1-[4-(2-Methanesulfonyl- ethyl)-phenyl]-1H-pyrazolo[3,4-
d]pyrimidin-4-yl}-methyl-amino)- methyl]-piperidine-1-carboxylic
acid tert-butyl ester A93 ##STR317##
4-({[1-(2,5-Difluoro-phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl]-
methyl-amino}-methyl)-piperidine- 1-carboxylic acid tert-butyl
ester A94 ##STR318## 2-{4-[1-(2-Fluoro-4-
methanesulfonyl-phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yloxy]-
piperidin-1-yl}-1-(4- trifluoromethoxy-phenyl)-ethanone A95
##STR319## 2-{4-[1-(2-Fluoro-4- methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidin-1-yl}-1-(3-fluoro-
phenyl)-ethanone A96 ##STR320## 2-{4-[1-(2-Fluoro-4-
methanesulfonyl-phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yloxy]-
piperidin-1-yl}-1-pyridin-2-yl- ethanone A97 ##STR321##
(2,5-Dimethyl-furan-3-yl)-{4-[1- (4-methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidin-1-yl}-methanone A98
##STR322## 4-({(2-Dimethylamino-ethyl)-[1-
(4-methanesulfonyl-phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl]-
amino}-methyl)-piperidine-1- carboxylic acid tert-butyl ester A99
##STR323## 4-({(2-Dimethylamino-ethyl)-[1-
(2-fluoro-4-methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4-yl]- amino}-methyl)-piperidine-1-
carboxylic acid tert-butyl ester A100 ##STR324##
4-[1-(2-Dimethylamino-4- methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidine-1-carboxylic acid
tert butyl ester A101 ##STR325## 4-(2-{Ethyl-[1-(4-methanesulfonyl-
phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl]-amino}-ethyl)-
piperazine-1-carboxylic acid tert- butyl ester A102 ##STR326##
4-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
ylsulfanyl]-piperidine-1-carboxylic acid tert-butyl ester A103
##STR327## 4-{2-[1-(4-Methanesulfonyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-yloxy]-ethyl }- piperazine-1-carboxylic acid ethyl
ester A104 ##STR328## 4-{2-[1-(4-Methanesulfonyl-
phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yloxy]-propyl}-
piperazine-1-carboxylic acid ethyl ester A105 ##STR329##
4-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidine-4-
sulfinyl]-piperidine-1-carboxylic acid tert-butyl ester A106
##STR330## 4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidine-4- sulfonyl]-piperidine-1-carboxylic
acid tert-butyl ester A107 ##STR331##
4-[1-(2-Fluoro-4-methanesulfonyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-ylsulfanyl]- piperidine-1-carboxylic acid tert- butyl
ester A108 ##STR332## 4-[1-(2-Fluoro-4-methanesulfonyl-
phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-ylsulfanyl]-
piperidine-1-carboxylic acid butyl ester A109 ##STR333##
4-[1-(2-Fluoro-4-methanesulfonyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-ylsulfanyl]- piepridine-1-carboxylic acid 2-
methoxy-ethyl ester A110 ##STR334##
4-[1-(2-Fluoro-4-methanesulfonyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-ylsulfanyl]- piperidine-1-carboxylic acid 3,3-
dimethyl-butyl ester A111 ##STR335##
4-[1-(2-Fluoro-4-methanesulfonyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-ylsulfanyl]- piperidine-1-carboxylic acid 4-
methyl-pentyl ester A112 ##STR336##
4-[1-(2-Fluoro-4-methanesulfonyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-ylsulfanyl]- piperidine-1-carboxylic acid
cyclopropylmethyl ester A113 ##STR337##
4-[1-(2-Fluoro-4-methanesulfonyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-ylsulfanyl]- piperidine-1-carboxylic acid
cyclobutylmethyl ester A114 ##STR338##
4-[1-(2-Fluoro-4-methanesulfonyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-ylsulfanyl]- piperidine-1-carboxylic acid 2-
cyclopropyl-ethyl ester A115 ##STR339##
(5-Bromo-furan-2-yl)-{4-[1-(2- fluoro-4-methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- ylsulfanyl]-piperidin-1-yl}-
methanone A116 ##STR340## {4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidin-1-yl}-(5-
morpholin-4-ylmethyl-furan-2-yl)- methanone A117 ##STR341##
4-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-piperidine-1-carboxylic acid pentyl ester A118 ##STR342##
4-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-piperidine-1-carboxylic acid 1-ethyl-propyl ester A119
##STR343## 4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidine-1-carboxylic acid
2-ethyl-butyl ester A120 ##STR344##
4-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-piperidine-1-carboxylic acid cyclopentylmethyl ester A121
##STR345## 4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidine-1-carboxylic acid
2-pyrrolidin-1-yl-ethyl ester A122 ##STR346##
4-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-piperidine-1-carboxylic acid 2-morpholin-4-yl-ethyl ester
A123 ##STR347## 4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidine-1-carboxylic acid
ethyl ester A124 ##STR348## 4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidine-1-carboxylic acid
2,2-dimethyl-propyl ester A125 ##STR349##
(5-Butyl-pyridin-2-yl)-{4-[1-(4- methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidin-1-yl}-methanone A126
##STR350## Ethyl-[1-(2-fluoro-4- methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yl]- (3,4,5,6-tetrahydro-2H-
[1,2']bipyridinyl-4-ylmethyl)-amine A127 ##STR351##
Ethyl-[1-(2-fluoro-4- methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yl]-(5'-
trifluoromethy[3,4,5,6-tetrahydro-
2H-[1,2']bipyridinyl-4-ylmethyl)- amine A128 ##STR352##
[1-(4-Methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yl]-(5'-
trifluoromethyl-3,4,5,6-tetrahydro-
2H-[1,2']bipyridinyl-4-yl)-amine A129 ##STR353##
4-[1-(2-Fluoro-4-methanesulfonyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester
A130 ##STR354## 5'-Fluoro-4-[1-(4-methanesulfonyl-
phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yloxy]-3,4,5,6-
tetrahydro-2H-[1,2']bipyridinyl
A131 ##STR355## 4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-5'-methyl-3,4,5,6-tetrahydro-
2H-[1,2']bipyridinyl A132 ##STR356##
4-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-6'-trifluoromethyl-3,4,5,6- tetrahydro-2H-[1,2']bipyridinyl
A133 ##STR357## [1-(2-Fluoro-4-methanesulfonyl-
phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl]-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-ylmethyl)- pyrrolidin-3-yl]-amine A134
##STR358## [1-(2-Fluoro-4-methanesulfonyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-yl]-[1-(3-isopropyl- [1,2,4]oxadiazol-5-ylmethyl)-
pyrrolidin-3-yl]-amine A135 ##STR359##
(4-Ethyl-pyridin-2-yl)-{4-[1-(2- fluoro-4-methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidin-1-yl}-methanone
A136 ##STR360## 1-(2-Fluoro-4-methanesulfonyl-
phenyl)-4-[1-(3-isopropyl- [1,2,4]oxadiazol-5-ylmethyl)-
pyrrolidin-3-yloxy]-1H- pyrazolo[3,4-d]pyrimidine A137 ##STR361##
1-(2-Fluoro-4-methanesulfonyl- phenyl)-4-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-ylmethyl)- piperidin-4-yloxy]-1H-
pyrazolo[3,4-d]pyrimidine A138 ##STR362##
(5'-Fluoro-3,4,5,6-tetrahydro-2H- [1,2']bipyridinyl-4-yl)-[1-(4-
pyrazolo[3,4-d]pyrimidin-4-yl]- amine A139 ##STR363##
(5-Bromo-pyridin-3-yl)-{4-[1-(2- fluoro-4-methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidin-1-yl}-methanone
A140 ##STR364## 3-[1-(2-Fluoro-4-methanesulfonyl-
phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yloxy]-pyrrolidine-
1-carboxylic acid tert-butyl ester A141 ##STR365##
3-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester A142
##STR366## 3-[1-(2-Fluoro-4-methanesulfonyl-
phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-ylamino]-
pyrrolidine-1-carboxylic acid isopropyl ester A143 ##STR367##
(6-Chloro-pyridin-3-yl)-{4-[1-(4- methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidin-1-yl}-methanone A144
##STR368## (5-Chloro-pyridin-3-yl)-{4-[1-(4-
methanesulfonyl-phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yloxy]-
piperidin-1-yl}-methanone A145 ##STR369##
{4-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-piperidin-1-yl}-(1-methyl-3-
trifluoromethyl-1H-pyrazol-4-yl)- methanone A146 ##STR370##
(2-Chloro-pyridin-4-yl)-{4-[1-(4- methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidin-1-yl}-methanone A147
##STR371## (4-Hydroxy-3-methoxy-pheny)-{4-
[1-(4-methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidin-1-yl}-methanone A148
##STR372## (4-Chloro-3-nitro-phenyl)-{4-[1-(4-
methanesulfonyl-phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yloxy]-
piperidin-1-yl}-methanone A149 ##STR373##
1-{4-[1-(4-Methanesulfonyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-yloxy]-piperidin-1- yl}-3-methyl-butan-1-one A150
##STR374## {4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidin-1-yl}-(6-pyrazol-
1-yl-pyridin-3-yl)-methanone A151 ##STR375##
(2-Hydroxy-pyridin-3-yl)-{4-[1-(4- methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidin-1-yl}-methanone A152
##STR376## (5,6-Dichloro-pyridin-3-yl)-{4-[1-
(4-methanesulfonyl-phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yloxy]-
piperidin-1-yl}-methanone A153 ##STR377##
(5-Bromo-pyridin-3-yl)-{4-[1-(4- methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidin-1-yl}-methanone A154
##STR378## 5-{4-[1-(4-Methanesulfonyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-yloxy]-piperidine-1- carbonyl}-nicotinic acid A155
##STR379## (1H-Imidazol-4-yl)-{4-[1-(4- methanesulfonyl-phenyl)-1H-
piperidin-1-yl}-methanone A156 ##STR380##
3-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester A157
##STR381## {4-pyrazolo[3,4-d]pyrimidin-4-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidin-1-yl}-(6-
pyrrolidin-1-yl-pyridin-3-yl)- methanone A158 ##STR382##
(6-Isobutylamino-pyridin-3-yl)-{4-
[1-(4-methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidin-1-yl}-methanone A159
##STR383## (6-Ethylamino-pyridin-3-yl)-{4-[1-
(4-methanesulfonyl-phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yloxy]-
piperidin-1-yl}-methanone A160 ##STR384##
(6-Cyclobutylamino-pyridin-3-yl)- {4-[1-(4-methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidin-1-yl}-methanone
A161 ##STR385## (6-Isopropylamino-pyridin-3-yl)-
{40-[1-(4-methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-piperidin-1-yl}-methanone A162 ##STR386##
[6-(1-Ethyl-propylamino)-pyridin- 3-yl]-{4-[1-(4-methanesulfonyl-
phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yloxy]-piperidin-1-
yl}-methanone A163 ##STR387## {4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidin-1-yl}-[6-(1-propyl-
butylamino)-pyridin-3-yl]- methanone A164 ##STR388##
5-Benzyloxy-2-{4-[1-(4- methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]-
piperidine-1-carbonyl}-pyran-4-one A165 ##STR389##
Benzo[c]isoxazol-3-yl-{4-[1-(4- methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidin-1-yl}-methanone A166
##STR390## (4-Chloro-pyridin-2-yl)-{4-[1-(4-
methanesulfonyl-phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yloxy]-
piperidin-1-yl}-methanone A167 ##STR391##
(4-Iodo-pyridin-2-yl)-{4-[1-(4- methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidin-1-yl}-methanone A168
##STR392## 1-{4-[1-(4-Methanesulfonyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-yloxy]-piperidin-1- yl}-butan-2-one A169 ##STR393##
2-(5-Bromo-pyridin-3-yl)-1-{4-[1- (4-methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidin-1-yl}-ethanone A170
##STR394## (6-Fluoro-pyridin-2-yl)-{4-[1-(4-
methanesulfonyl-phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yloxy]-
piperidin-1-yl}-methanone A171 ##STR395##
(5-Fluoro-pyridin-2-yl)-{4 [1-(4- methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidin-1-yl}-methanone A172
##STR396## (6-Chloro-pyridin-2-yl)-{4-[1-(4-
methanesulfonyl-phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yloxy]-
piperidin-1-yl}-methanone A173 ##STR397##
(2-Chloro-5-fluoro-pyridin-3-yl)- {4-[1-(4-methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidin-1-yl}-methanone
A174 ##STR398## {4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidin-1-yl}-[5-(2-
methyl-pyrrolidin-1-ylmethyl)- pyridin-3-yl]-methanone A175
##STR399## {4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidin-1-yl}-(6-methyl-
pyridin-2-yl)-methanone A176 ##STR400## 5-{4-[1-(4-Methanesulfonyl-
phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yloxy]-piperidine-1-
carbonyl}-nicotinonitrile A177 ##STR401##
{4-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-piperidin-1-yl}-(4-methoxy- pyridin-2-yl)-methanone A178
##STR402## (2-Fluoro-pyridin-4-yl)-{4-[1-(4-
methanesulfonyl-phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yloxy]-
piperidin-1-yl}-methanone A179 ##STR403##
(2-Fluoro-pyridin-3-yl)-{4-[1-(4- methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidin-1-yl}-methanone A180
##STR404## (6-Fluoro-pyridin-3-yl)-{4-[1-(4-
methanesulfonyl-phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yloxy]-
piperidin-1-yl}-methanone A181 ##STR405##
{4-[1-(4-Methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-piperidin-1-yl}-(4-methoxy- thiophen-3-yl)-methanone A182
##STR406## 2-{4-[1-(4-Methanesulfonyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-yloxy]-piperidine-1- carbonyl}-pyran-4-one A183
##STR407## (5-Ethyl-pyridin-2-yl)-{4-[1-(2-
fluoro-4-methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-piperidin-1-yl}-methanone A184 ##STR408##
(4-Ethoxy-phenyl)-{4-[1-(2-fluoro- 4-methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidin-1-yl}-methanone A185
##STR409## {4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidin-1-yl}-(5-pyridin-2-
yl-thiophen-2-yl)-methanone A186 ##STR410##
(5-Amino-pyridin-2-yl)-{4-[1-(4- methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidin-1-yl}-methanone A187
##STR411## (5-Amino-pyridin-2-yl)-{4-[1-(2-
fluoro-4-methanesulfonyl-phenyl)- 1H-pyrazol[3,4-d]pyrimidin-4-
yloxy]-piperidin-1-yl}-methanone A188 ##STR412##
{4-[1-(2-Fluoro-4-methanesulfonyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-yloxy]-piperidin-1- yl}-[5-(3-methyl-butylamino)-
pyridin-2-yl]-methanone A189 ##STR413##
{4-[1-(2-Fluoro-4-methanesulfonyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-yloxy]-piperidin-1- yl}-(4-trifluoromethoxy-phenyl)-
methanone A190 ##STR414## (5-Butyl-pyridin-2-yl)-{4-[1-(2-
fluoro-4-methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-piperidin-1-yl}-methanone A191 ##STR415##
(5-Ethylamino-pyridin-2-yl)-{4-[1- (2-fluoro-4-methanesulfonyl-
phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yloxy]-piperidin-1-
yl}-methanone A192 ##STR416## {4-[1-(2-Fluoro-4-methanesulfonyl-
phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yloxy]-piperidin-1-
yl}-(5-isopropoxymethyl-pyridin-2- yl)-methanone A193 ##STR417##
(4-Difluoromethoxy-phenyl)-{4-[1- (2-fluoro-4-methanesulfonyl-
phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yloxy]-piperidin-1-
yl}-methanone A194 ##STR418## {4-[1-(2-Fluoro-4-
methanesulfonyl-phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yloxy]-
piperidin-1-yl}-(5-isopropoxy- pyridin-2-yl)-methanone A195
##STR419## {4-[1-(4-Methanesulfonyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-yloxy]-piperidine-1- carbonyl}-pyridine-2-carboxylic
acid
methyl ester A196 ##STR420## {4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidin-1-yl}-acetic acid
ethyl ester A197 ##STR421## {4-[1-(2-Fluoro-4-
methanesulfonyl-phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yloxy]-
piperidin-1-yl}-(3- trifluoromethoxy-phenyl)- methanone A198
##STR422## 1-(2-Fluoro-4-methanesulfonyl-
phenyl)-4-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-1H-pyrazolo[3,4- d]pyrimidine A199 ##STR423##
1-(4-Chloro-phenyl)-2-{4-[1-(4- methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidin-1-yl}-ethanone A200
##STR424## 2-{4-[1-(4-Methanesulfonyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-yloxy]-piperidin-1- yl}-1-(3-trifluoromethyl-phenyl)-
ethanone A201 ##STR425## 4-[1-(2-Fluoro-4-methanesulfonyl-
phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yloxy]-5'-
isopropoxy-3,4,5,6-tetrahydro-2H- [1,2']bipyridinyl A202 ##STR426##
1-(4-Methanesulfonyl-phenyl)-4-[1- piperidin-4-yloxy]-1H-
(4-trifluoromethoxy-phenyl)- pyrazolo[3,4-d]pyrimidine A203
##STR427## 1-(2-Fluoro-4-methanesulfonyl-
phenyl)-4-[1-(4-trifluoromethoxy- phenyl)-piperidin-4-yloxy]-1H-
pyrazolo[3,4-d]pyrimidine A204 ##STR428##
1-(4-Chloro-3-methyl-phenyl)-2- {4-[1-(4-methanesulfonyl-phenyl)-
1H-piperidin-1-yl}-ethanone A205 ##STR429##
1-(3,4-Dichloro-phenyl)-2-{4-[1- (4-methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidin-1-yl}-ethanone A206
##STR430## 5'-Bromo-4-[1-(4-methanesulfonyl-
phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yloxy]-3,4,5,6-
tetrahydro-2H-[1,2']bipyridinyl A207 ##STR431##
1-(2-Fluoro-4-methanesulfonyl- phenyl)-piperidin-4-yloxy]-1H-
phenyl)-4-[1-(3-trifluoromethoxy- pyrazolo[3,4-d]pyrimidine A208
##STR432## 4-[1-(4-Methanesulfonyl-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-5'-trifluoromethyl-3,4,5,6-
tetrahydro-2H-[1,2']bipyridinyl A209 ##STR433##
1-(2,4-Dimethoxy-phenyl)-2-{4-[1- (4-methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidin-1-yl}-ethanone A210
##STR434## 1-(4-Difluoromethoxy-phenyl)-2-
{4-[1-(4-methanesulfonyl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-piperidin-1-yl}-ethanone A211 ##STR435##
1-(4-Diethylamino-phenyl)-2-{4-[1- (4-methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidin-1-yl}-ethanone A212
##STR436## (2-{4-[1-(2-Fluoro-4- methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidin-1-yl}-5-methyl-
pyrimidin-4-yl)-dimethyl-amine A213 ##STR437##
1-(2-Fluoro-4-methanesulfonyl- phenyl)-4-[1-(5-methyl-4-
pyrrolidin-1-yl-pyrimidin-2-yl)- piperidin-4-yloxy]-1H-
pyrazolo[3,4-d]pyrimidine A214 ##STR438##
4-[1-(2-Fluoro-4-methanesulfonyl- phenyl)-1H-pyrazolo[3,4-
d]-pyrimidin-4-ylsulfanyl-]- piperidine-1-carboxylic acid isopropyl
ester A215 ##STR439## 4-[1-(2-Methyl-4-propylamino-
phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester A216 ##STR440##
4-[1-(4-Isopropylamino-2-methyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester
A217 ##STR441## 4-[1-(2-Methyl-4-morpholin-4-yl-
phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester A218 ##STR442##
4-{1-[4-(2-Methoxy-ethylamino)-2- methyl-phenyl]-1H-pyrazolo[3,4-
d]pyrimidifl-4-ylOXy}-piperidine-1- carboxylic acid isopropyl ester
A219 ##STR443## 4-(1-{4-[(2-Methanesulfonyl-
ethyl)-methyl-amino]-2-methyl- phenyl}-1H-pyrazolo[3,4-
d]pyrimidin-4-yloxy)-piperidine-1- carboxylic acid isopropyl ester
A220 ##STR444## 4-[1-(4-Bromo-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidine-1-carboxylic acid
isopropyl ester A221 ##STR445## 4-[1-(4-Propylamino-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidine-1-carboxylic acid
isopropyl ester A222 ##STR446## 4-[1-(4-Isopropylamino-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidine-1-carboxylic acid
isopropyl ester A223 ##STR447## 4-(1-{4-[4-(2-Methanesulfonyl-
ethyl)-piperazin-1-yl]-2-methyl- phenyl}-1H-pyrazolo[3,4-
d]pyrimidin-4-yloxy)-piperidine-1- carboxylic acid isopropyl ester
A224 ##STR448## 4-(1-{2-Methyl-4-[(tetrahydro-
furan-2-ylmethyl)-amino]-phenyl}- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy)-piperidine-1-carboxylic acid isopropyl ester A225 ##STR449##
4-[1-(4-Cyclopropylamino-2- methyl-phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester
A226 ##STR450## 4-{1-[4-(2-Dimethylamino-
ethylamino)-2-methyl-phenyl]-1H- pyrazolo[3,4-d]pyrimidin-4-yloxy}-
piperidine-1-carboxylic acid isopropyl ester A227 ##STR451##
4-[1-(4-Morpholin-4-yl-phenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-
yloxy]-piperidine-1-carboxylic acid isopropyl ester A228 ##STR452##
4-({[1-(2-Fluoro-4- methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yl]- isopropyl-amino}-methyl)-
piperidine-1-carboxylic acid tert- butyl ester A229 ##STR453##
4-[1-(2-Fluoro-4-morpholin-4-yl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester
A230 ##STR454## 4-[1-(2-Fluoro-4-isopropylamino-
phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester A231 ##STR455##
4-(1-{4-[(2-Methanesulfonyl- ethyl)-methyl-amino]-phenyl}-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy)- piperidine-1-carboxylic acid
isopropyl ester A232 ##STR456## 4-{1-[4-(2-Methoxy-ethylamino)-
phenyl]-1H-pyrazolo[3,4- d]-pyrimidin-4-yloxy}-piperidine-1-
carboxylic acid isopropyl ester A233 ##STR457##
4-(1-{4-[(Tetrahydro-furan-2- ylmethyl)-amino]-phenyl}-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy)- piperidine-1-carboxylic acid
isopropyl ester A234 ##STR458## 4-(1-{4-[4-(2-Methanesulfonyl-
ethyl)-piperazin-1-yl]-phenyl}-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy)- piperidine-1-carboxylic acid
isopropyl ester A235 ##STR459## 4-[1-(4-Amino-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidine-1-carboxylic acid
isopropyl ester A236 ##STR460## 4-({[1-(2-Fluoro-4-
methanesulfonyl-phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl]-
isopropyl-amino}-methyl)- piperidine-1-carboxylic acid isopropyl
ester A237 ##STR461## 4-[1-(5-Ethyl-pyrimidin-2-yl)-
piperidin-4-ylsulfanyl]-1-(2-fluoro- 4-methanesulfonyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidine A238 ##STR462##
1-(2-Fluoro-4-methanesulfonyl- phenyl)-4-(piperidin-4-yloxy)-1H-
pyrazolo[3,4-d]pyrimidine A239 ##STR463##
4-[1-(2-Fluoro-4-sulfamoyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester
A240 ##STR464## 4-[1-(2-Fluoro-4- propionylsulfamoyl-phenyl)-1H-
pyrazolo[3,4-d]pyrimidin-4-yloxy]- piperidine-1-carboxylic acid
isopropyl ester A241 ##STR465## 4-[1-(4-Cyano-2-fluoro-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidine-1-carboxylic acid
isopropyl ester A242 ##STR466## 1-(2,5-Difluoro-4-methoxy-phenyl)-
4-[4-(3-isopropyl-[1,2,4]oxadiazol- 5-yl)-cyclohexyloxy]-1H-
pyrazolo[3,4-d]pyrimidine A243 ##STR467## 4-[1-(2,5-Difluoro-4-
methanesulfonyl-phenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester A244 ##STR468##
4-[1-(4-Fluoro-6-methoxy-pyridin-
3-yl)-1H-pyrazolo[3,4-d]pyrimidin- 4-yloxy]-piperidine-1-carboxylic
acid isopropyl ester A245 ##STR469##
4-[1-(6-Methoxy-2-methyl-pyridin-
3-yl)-1H-pyrazolo[3,4-d]pyrimidin- 4-yloxy]-piperidine-1-carboxylic
acid isopropyl ester A246 ##STR470##
4-[1-(2,5-Difluoro-4-sulfamoyl- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester
A247 ##STR471## 4-[1-(2-Fluoro-4-hydroxy-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidine-1-carboxylic acid
isopropyl ester A248 ##STR472## 3-Fluoro-4-{4-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-pyrazolo[3,4-d]pyrimidin-1- yl}-N-propionyl-
benzenesulfonamide A249 ##STR473## 3-Fluoro-4-{4-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-pyrazolo[3,4-d]pyrimidin-1- yl}-benzonitrile A250 ##STR474##
3-Fluoro-4-{4-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-pyrazolo[3,4-d]pyrimidin-1- yl}-benzenesulfonamide A251
##STR475## 1-(2,5-Difluoro-4-methanesulfonyl-
phenyl)-4-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-1H-pyrazolo[3,4- d]pyrimidine A252 ##STR476##
1-(4-Fluoro-6-methoxy-pyridin-3- yl)-4-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4- yloxy]-1H-pyrazolo[3,4-
d]pyrimidine A253 ##STR477## 4-[1-(3-Isopropyl-[1,2,4]oxadiazol-
5-yl)-piperidin-4-yloxy]-1-(6- methoxy-2-methyl-pyridin-3-yl)-
1H-pyrazolo[3,4-d]pyrimidine A254 ##STR478##
2,5-Difluoro-4-{4-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4- 1H-pyrazolo[3,4-d]pyrimidin-1-
yl}-benzenesulfonamide A255 ##STR479##
1-(2-Fluoro-4-methanesulfonyl- phenyl)-4-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)- cyclohexyloxy]-1H-pyrazolo[3,4-
d]pyrimidine A256 ##STR480## 3-Fluoro-4-{4-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)- cyclohexyloxy]-pyrazolo[3,4-
d]pyrimidin-1-yl}-N-propionyl- benzenesulfonamide A257 ##STR481##
3-Fluoro-4-{4-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-pyrazolo[3,4- d]pyrimidin-1-yl}-benzonitrile A258
##STR482## 3-Fluoro-4-{4-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-pyrazolo[3,4- d]pyrimidin-1-yl}- benzenesulfonamide
A259 ##STR483## 1-(2,5-Difluoro-4-methanesulfonyl-
phenyl)-4-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-1H-pyrazolo[3,4- d]pyrimidine A260 ##STR484##
1-(4-Fluoro-6-methoxy-pyridin-3- yl)-4-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)- cyclohexyloxy]-1H-pyrazolo[3,4-
d]pyrimidine
A261 ##STR485## 4-[4-(3-Isopropyl-[1,2,4]oxadiazol-
5-yl)-cyclohexyloxy]-1-(6- methoxy-2-methyl-pyridin-3-yl)-
1H-pyrazolo[3,4-d]pyrimidine A262 ##STR486##
2,5-Difluoro-4-{4-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-pyrazolo[3,4- d]pyrimidin-1-yl}- benzenesulfonamide
A263 ##STR487## 4-[1-(2-Fluoro-4-methoxy-phenyl)-
1H-pyrazolo[3,4-d]pyrimidin-4- yloxy]-piperidine-1-carboxylic acid
isopropyl ester A264 ##STR488## 4-[1-(4-Difluoromethoxy-2-fluoro-
phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester A265 ##STR489##
4-[1-(2-Fluoro-4-trifluoromethoxy- phenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester
A266 ##STR490## 4-[1-(2,5-Difluoro-4-methoxy-
phenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester A267 ##STR491##
3-Fluoro-4-{4-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-pyrazolo[3,4-d]pyrimidin-1- yl}-phenol A268 ##STR492##
1-(2-Fluoro-4-methoxy-phenyl)-4-
[1-(3-isopropyl-[1,2,4]oxadiazol-5- yl)-piperidin-4-yloxy]-1H-
pyrazolo[3,4-d]pyrimidine A269 ##STR493##
1-(4-Difluoromethoxy-2-fluoro- phenyl)-4-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4- yloxy]-1H-pyrazolo[3,4-
d]pyrimidine A270 ##STR494## 1-(2-Fluoro-4-trifluoromethoxy-
phenyl)-4-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-1H-pyrazolo[3,4- d]pyrimidine A271 ##STR495##
1-(2,5-Difluoro-4-methoxy-phenyl)-
4-[1-(3-isopropyl-[1,2,4]oxadiazol- 5-yl)-piperidin-4-yloxy]-1H-
pyrazolo[3,4-d]pyrimidine A272 ##STR496##
3-Fluoro-4-{4-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-pyrazolo[3,4- d]pyrimidin-1-yl}-phenol A273
##STR497## 1-(2-Fluoro-4-methoxy-phenyl)-4-
[4-(3-isopropyl-[1,2,4]oxadiazol-5- yl)-cyclohexyloxy]-1H-
pyrazolo[3,4-d]pyrimidine A274 ##STR498##
1-(4-Difluoromethoxy-2-fluoro- phenyl)-4-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)- cyclohexyloxy]-1H-pyrazolo[3,4-
d]pyrimidine A275 ##STR499## 1-(2-Fluoro-4-trifluoromethoxy-
phenyl)-4-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-1H-pyrazolo[3,4- d]pyrimidine
[0447] TABLE-US-00015 TABLE B Cmpd # Structure Chemical Name B1
##STR500## 4-[9-(6-Methanesulfonyl-pyridin-3-
yl)-9H-purin-6-yloxy]-piperidine-1- carboxylic acid isobutyl ester
B2 ##STR501## 9-(6-Methanesulfonyl-pyridin-3-yl)-
6-(piperidin-4-yloxy)-9H-purine B3 ##STR502##
{4-[9-(6-Methanesulfonyl-pyridin-
3-yl)-9H-purin-6-yloxy]-piperidin- 1-yl}-pyridin-3-yl-methanone B4
##STR503## 4-[9-(4-Methanesulfonyl-phenyl)-
9H-purin-6-yloxy]-piperidine-1- carboxylic acid tert-butyl ester B5
##STR504## 4-[9-(6-Methanesulfonyl-pyridin-3-
yl)-9H-purin-6-yloxy]-piperidine-1- carboxylic acid tert-butyl
ester B6 ##STR505## 4-[9-(2-Fluoro-4-methanesulfonyl-
phenyl)-9H-purin-6-yloxy]- piperidine-1-carboxylic acid tert- butyl
ester B7 ##STR506## 4-[9-(2-Fluoro-4-
propionylsulfamoyl-phenyl)-9H- purin-6-yloxyl]-piperidine-1-
carboxylic acid isopropyl ester B8 ##STR507##
4-[9-(4-Cyano-2-fluoro-phenyl)- 9H-purin-6-yloxy]-piperidine-1-
carboxylic acid isopropyl ester B9 ##STR508##
4-[9-(2-Fluoro-4-sulfamoyl- phenyl)-9H-purin-6-yloxy]-
piperidine-1-carboxylic acid isopropyl ester B10 ##STR509##
9-(2-Fluoro-4-methanesulfonyl- phenyl)-6-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4- yloxy]-9H-purine B11 ##STR510##
3-Fluoro-4-{6-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-purin-9-yl}-N-propionyl- benzenesulfonamide B12 ##STR511##
3-Fluoro-4-{6-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-purin-9-yl}-benzonitrile B13 ##STR512##
3-Fluoro-4-{6-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-purin-9-yl}- benzenesulfonamide B14 ##STR513##
4-[9-(2,5-Difluoro-4- methanesulfonyl-phenyl)-9H-purin-
6-yloxy]-piperidine-1-carboxylic acid isopropyl ester B15
##STR514## 4-[9-(4-Fluoro-6-methoxy-pyridin-
3-yl)-9H-purin-6-yloxy]-piperidine- 1-carboxylic acid isopropyl
ester B16 ##STR515## 4-[9-(6-Methoxy-2-methyl-pyridin-
3-yl)-9H-purin-6-yloxy]-piperidine- 1-carboxylic acid isopropyl
ester B17 ##STR516## 4-[9-(2,5-Difluoro-4-sulfamoyl-
phenyl)-9H-purin-6-yloxy]- piperidine-1-carboxylic acid isopropyl
ester B18 ##STR517## 9-(2,5-Difluoro-4-methanesulfonyl-
phenyl)-6-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-9H-purine B19 ##STR518## 9-(4-Fluoro-6-methoxy-pyridin-3-
yl)-6-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-9H-purine B20 ##STR519## 6-[1-(3-Isopropyl-[1,2,4]oxadiazol-
5-yl)-piperidin-4-yloxy]-9-(6- methoxy-2-methyl-pyridin-3-yl)-
9H-purine B21 ##STR520## 2,5-Difluoro-4-{6-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4- yloxy]-purin-9-yl}-
benzenesulfonamide B22 ##STR521## 9-(2-Fluoro-4-methanesulfonyl-
phenyl)-6-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-9H-purine B23 ##STR522##
3-Fluoro-4-{6-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-purin-9-yl}-N- propionyl-benzenesulfonamide B24
##STR523## 3-Fluoro-4-{6-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-purin-9-yl}- benzonitrile B25 ##STR524##
3-Fluoro-4-{6-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-purin-9-yl}- benzenesulfonamide B26 ##STR525##
9-(2,5-Difluoro-4-methanesulfonyl- phenyl)-6-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)- cyclohexyloxy]-9H-purine B27 ##STR526##
9-(4-Fluoro-6-methoxy-pyridin-3- yl)-6-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)- cyclohexyloxy]-9H-purine B28 ##STR527##
6-[4-(3-Isopropyl-[1,2,4]oxadiazol- 5-yl)-cyclohexyloxy]-9-(6-
methoxy-2-methyl-pyridin-3-yl)- 9H-purine B29 ##STR528##
2,5-Difluoro-4-{6-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-purin-9-yl}- benzenesulfonamide
[0448] TABLE-US-00016 TABLE C Cmpd # Structure Chemical Name C1
##STR529## 4-[3-(4-Methanesulfonyl-phenyl)-
3H-[1,2,3]triazolo[4,5-d]pyrimidin-
7-yloxy]-piperidine-1-carboxylic acid tert-butyl ester C2
##STR530## 3-(2-Fluoro-4-methanesulfonyl-
phenyl)-7-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-3H-[1,2,3]triazolo[4,5- d]pyrimidine C3 ##STR531##
3-Fluoro-4-{7-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-[1,2,3]triazolo[4,5- d]pyrimidin-3-yl}-N-propionyl-
benzenesulfonamide C4 ##STR532## 3-Fluoro-4-{7-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4- yloxy]-[1,2,3]triazolo[4,5-
d]pyrimidin-3-yl}-benzonitrile C5 ##STR533##
3-Fluoro-4-{7-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-[1,2,3]triazolo[4,5- d]pyrimidin-3-yl}- benzenesulfonamide
C6 ##STR534## 3-(2-Fluoro-4-methanesulfonyl-
phenyl)-7-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-3H- [1,2,3]triazolo[4,5-d]pyrimidine C7 ##STR535##
3-Fluoro-4-{7-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-[1,2,3]triazolo[4,5- d]pyrimidin-3-yl}-N-propionyl-
benzenesulfonamide C8 ##STR536## 3-Fluoro-4-{7-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)- cyclohexyloxy]-[1,2,3]triazolo[4,5-
d]pyrimidin-3-yl}-benzonitrile C9 ##STR537##
3-Fluoro-4-{7-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-[1,2,3]triazolo[4,5- d]pyrimidin-3-yl}-
benzenesulfonamide C10 ##STR538##
3-(2,5-Difluoro-4-methanesulfonyl- phenyl)-7-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)- cyclohexyloxy]-3H-
[1,2,3]triazolo[4,5-d]pyrimidine C11 ##STR539##
3-(4-Fluoro-6-methoxy-pyridin-3- yl)-7-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)- cyclohexyloxy]-3H-
[1,2,3]triazolo[4,5-d]pyrimidine C12 ##STR540##
7-[4-(3-Isopropyl-[1,2,4]oxadiazol- 5-yl)-cyclohexyloxy]-3-(6-
methoxy-2-methyl-pyridin-3-yl)- [1,2,3]triazolo[4,5-d]pyrimidine
C13 ##STR541## 2,5-Difluoro-4-{7-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)- cyclohexyloxy]-[1,2,3]triazolo[4,5-
d]pyrimidin-3-yl}- benzenesulfonamide C14 ##STR542##
4-[3-(2-Fluoro-4-methanesulfonyl- phenyl)-3H-[1,2,3]triazolo[4,5-
d]pyrimidin-7-yloxy]-piperidine-1- carboxylic acid isopropyl ester
C15 ##STR543## 4-[3-(2-Fluoro-4- propionylsulfamoyl-phenyl)-3H-
[1,2,3]triazolo[4,5-d]pyrimidin-7- yloxy]-piperidine-1-carboxylic
acid isopropyl ester C16 ##STR544## 4-[3-(4-Cyano-2-fluoro-phenyl)-
3H-[1,2,3]triazolo[4,5-d]pyrimidin-
7-yloxy]-piperidine-1-carboxylic acid isopropyl ester C17
##STR545## 4-[3-(2-Fluoro-4-sulfamoyl-
phenyl)-3H-[1,2,3]triazolo[4,5- d]pyrimidin-7-yloxy]-piperidine-1-
carboxylic acid isopropyl ester C18 ##STR546##
4-[3-(2,5-Difluoro-4- methanesulfonyl-phenyl)-3H-
[1,2,3]triazolo[4,5-d]pyrimidin-7- yloxy]-piperidine-1-carboxylic
acid isopropyl ester C19 ##STR547##
4-[3-(4-Fluoro-6-methoxy-pyridin- 3-yl)-3H-[1,2,3]triazolo[4,5-
d]pyrimidin-7-yloxy]-piperidine-1- carboxylic acid isopropyl ester
C20 ##STR548## 4-[3-(6-Methoxy-2-methyl-pyridin-
3-yl)-3H-[1,2,3]triazolo[4,5- d]pyrimidin-7-yloxy]-piperidine-1-
carboxylic acid isopropyl ester C21 ##STR549##
4-[3-(2,5-Difluoro-4-sulfamoyl- phenyl)-3H-[1,2,3]triazolo[4,5-
d]pyrimidin-7-yloxy]-piperidine-1- carboxylic acid isopropyl ester
C22 ##STR550## 3-(2,5-Difluoro-4-methanesulfonyl-
phenyl)-7-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-3H-[1,2,3]triazolo[4,5- d]pyrimidine C23 ##STR551##
3-(4-Fluoro-6-methoxy-pyridin-3- yl)-7-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4- yloxy]-3H-[1,2,3]triazolo[4,5-
d]pyrimidine C24 ##STR552## 7-[1-(3-Isopropyl-[1,2,4]oxadiazol-
5-yl)-piperidin-4-yloxy]-3-(6- methoxy-2-methyl-pyridin-3-yl)-
3H-[1,2,3]triazolo[4,5-d]pyrimidine C25 ##STR553##
2,5-Difluoro-4-{7-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4- yloxy]-[1,2,3]triazolo[4,5-
d]pyrimidin-3-yl}- benzenesulfonamide
[0449] TABLE-US-00017 TABLE D Cmpd # Structure Chemical Name D1
##STR554## 4-[3-(4-Methanesulfonyl-phenyl)-
isoxazolo[4,5-d]pyrimidin-7-yloxy]- piperidine-1-carboxylic acid
tert- butyl ester D2 ##STR555## 4-({Ethyl-[3-(4-methanesulfonyl-
phenyl)-isoxazolo[4,5-d]pyrimidin-
7-yl]-amino}-methyl)-piperidine-1- carboxylic acid tert-butyl ester
D3 ##STR556## 4-[3-(4-Methanesulfonyl-phenyl)-
isoxazolo[4,5-d]pyrimidin-7- ylsulfanyl]-piperidine-1-carboxylic
acid tert-butyl ester D4 ##STR557##
4-[3-(4-Methanesulfonyl-phenyl)-
isoxazolo[4,5-d]pyrimidin-7-yloxy]- piperidine-1-carboxylic acid
isopropyl ester
[0450] TABLE-US-00018 TABLE E Cmpd # Structure Chemical Name E1
##STR558## 4-[8-(2-Fluoro-4-methanesulfonyl-
phenyl)-[1,7]naphthyridin-4-yloxy]- piperidine-1-carboxylic acid
isopropyl ester
[0451] TABLE-US-00019 TABLE F Cmpd # Structure Chemical Name F1
##STR559## 4-[8-(2-Fluoro-4-methanesulfonyl-
phenyl)-quinolin-4-yloxy]- piperidine-1-carboxylic acid isopropyl
ester F2 ##STR560## 4-[8-(4-Methylsulfanyl-phenyl)-
quinolin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester F3
##STR561## 4-[8-(4-Methanesulfonyl-phenyl)-
quinolin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester F4
##STR562## 4-[8-(4-Isopropoxy-phenyl)-
quinolin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester F5
##STR563## 4-[8-(4-Bromo-2-fluoro-phenyl)-
quinolin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester F6
##STR564## 4-[8-(2-Fluoro-4- propionylsulfamoyl-phenyl)-
quinolin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester F7
##STR565## 4-[8-(4-Cyano-2-fluoro-phenyl)-
quinolin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester F8
##STR566## 4-[8-(2-Fluoro-4-sulfamoyl- phenyl)-quinolin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester F9 ##STR567##
4-[8-(2,5-Difluoro-4- methanesulfonyl-phenyl)-quinolin-
4-yloxy]-piperidine-1-carboxylic acid isopropyl ester F10
##STR568## 4-[8-(4-Fluoro-6-methoxy-pyridin-
3-yl)-quinolin-4-yloxy]-piperidine- 1-carboxylic acid isopropyl
ester F11 ##STR569## 4-[8-(6-Methoxy-2-methyl-pyridin-
3-yl)-quinolin-4-yloxy]-piperidine- 1-carboxylic acid isopropyl
ester F12 ##STR570## 4-[8-(2,5-Difluoro-4-sulfamoyl-
phenyl)-quinolin-4-yloxy]- piperidine-1-carboxylic acid isopropyl
ester F13 ##STR571## 2,5-Difluoro-4-{4-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4- yloxy]-quinolin-8-yl}-
benzenesulfonamide F14 ##STR572##
4-[1-(3-Isopropyl-[1,2,4]oxadiazol- 5-yl)-piperidin-4-yloxy]-8-(6-
methoxy-2-methyl-pyridin-3-yl)- quinoline F15 ##STR573##
8-(4-Fluoro-6-methoxy-pyridin-3- yl)-4-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4- yloxy]-quinoline F16 ##STR574##
8-(2,5-Difluoro-4-methanesulfonyl- phenyl)-4-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4- yloxy]-quinoline F17 ##STR575##
3-Fluoro-4-{4-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-quinolin-8-yl}- benzenesulfonamide F18 ##STR576##
3-Fluoro-4-{4-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-quinolin-8-yl}-benzonitrile F19 ##STR577##
3-Fluoro-4-{4-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-quinolin-8-yl}-N-propionyl- benzenesulfonamide F20
##STR578## 8-(2-Fluoro-4-methanesulfonyl-
phenyl)-4-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-quinoline F21 ##STR579## 2,5-Difluoro-4-{4-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)- cyclohexyloxy]-quinolin-8-yl}-
benzenesulfonamide F22 ##STR580##
4-[4-(3-Isopropyl-[1,2,4]oxadiazol- 5-yl)-cyclohexyloxy]-8-(6-
methoxy-2-methyl-pyridin-3-yl)- quinoline F23 ##STR581##
8-(4-Fluoro-6-methoxy-pyridin-3- yl)-4-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)- cyclohexyloxy]-quinoline F24 ##STR582##
8-(2,5-Difluoro-4-methanesulfonyl- phenyl)-4-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)- cyclohexyloxy]-quinoline F25 ##STR583##
3-Fluoro-4-{4-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-quinolin-8-yl}- benzenesulfonamide F26 ##STR584##
3-Fluoro-4-{4-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-quinolin-8-yl}- benzonitrile F27 ##STR585##
3-Fluoro-4-{4-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-quinolin-8-yl}-N- propionyl-benzenesulfonamide F28
##STR586## 8-(2-Fluoro-4-methanesulfonyl-
phenyl)-4-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-quinoline
[0452] TABLE-US-00020 TABLE G Cmpd # Structure Chemical Name G1
##STR587## 4-[8-(2-Fluoro-4-methanesulfonyl-
phenyl)-pyrido[3,4-d]pyrimidin-4- yloxy]-piperidine-1-carboxylic
acid isopropyl ester G2 ##STR588## 4-[8-(2-Fluoro-4-
propionylsulfamoyl-phenyl)- pyrido[3,4-d]pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester G3 ##STR589##
4-[8-(4-Cyano-2-fluoro-phenyl)- pyrido[3,4-d]pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester G4 ##STR590##
4-[8-(2-Fluoro-4-sulfamoyl- phenyl)-pyrido[3,4-d]pyrimidin-4-
yloxy]-piperidine-1-carboxylic acid isopropyl ester G5 ##STR591##
4-[8-(2,5-Difluoro-4- methanesulfonyl-phenyl)-
pyrido[3,4-d]pyrimidin-4-yloxy]- piperidine-1-carboxylic acid
isopropyl ester G6 ##STR592## 4-[8-(4-Fluoro-6-methoxy-pyridin-
3-yl)-pyrido[3,4-d]pyrimidin-4- yloxy]-piperidine-1-carboxylic acid
isopropyl ester G7 ##STR593## 4-[8-(6-Methoxy-2-methyl-pyridin-
3-yl)-pyrido[3,4-d]pyrimidin-4- yloxy]-piperidine-1-carboxylic acid
isopropyl ester G8 ##STR594## 4-[8-(2,5-Difluoro-4-sulfamoyl-
phenyl)-pyrido[3,4-d]pyrimidin-4- yloxy]-piperidine-1-carboxylic
acid isopropyl ester G9 ##STR595## 8-(2-Fluoro-4-methanesulfonyl-
phenyl)-4-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-pyrido[3,4-d]pyrimidine G10 ##STR596##
3-Fluoro-4-{4-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-pyrido[3,4-d]pyrimidin-8- yl}-N-propionyl-
benzenesulfonamide G11 ##STR597## 3-Fluoro-4-{4-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-pyrido[3,4-d]pyrimidin-8- yl}-benzonitrile G12 ##STR598##
3-Fluoro-4-{4-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-pyrido[3,4-d]pyrimidin-8- yl}-benzenesulfonamide G13
##STR599## 8-(2,5-Difluoro-4-methanesulfonyl-
phenyl)-4-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-pyrido[3,4-d]pyrimidine G14 ##STR600##
8-(4-Fluoro-6-methoxy-pyridin-3- yl)-4-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4- yloxy]-pyrido[3,4-d]pyrimidine
G15 ##STR601## 4-[1-(3-Isopropyl-[1,2,4]oxadiazol-
5-yl)-piperidin-4-yloxy]-8-(6- methoxy-2-methyl-pyridin-3-yl)-
pyrido[3,4-d]pyrimidine G16 ##STR602##
2,5-Difluoro-4-{4-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-pyrido[3,4-d]pyrimidin-8- yl}-benzenesulfonamide G17
##STR603## 8-(2-Fluoro-4-methanesulfonyl-
phenyl)-4-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-pyrido[3,4- d]pyrimidine G18 ##STR604##
3-Fluoro-4-{4-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-pyrido[3,4- d]pyrimidin-8-yl}-N-propionyl-
benzenesulfonamide G19 ##STR605## 3-Fluoro-4-{4-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)- cyclohexyloxy]-pyrido[3,4-
d]pyrimidin-8-yl}-benzonitrile G20 ##STR606##
3-Fluoro-4-{4-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-pyrido[3,4- d]pyrimidin-8-yl}- benzenesulfonamide
G21 ##STR607## 8-(2,5-Difluoro-4-methanesulfonyl-
phenyl)-4-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-pyrido[3,4- d]pyrimidine G22 ##STR608##
8-(4-Fluoro-6-methoxy-pyridin-3- yl)-4-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)- cyclohexyloxy]-pyrido[3,4- d]pyrimidine G23
##STR609## 4-[4-(3-Isopropyl-[1,2,4]oxadiazol-
5-yl)-cyclohexyloxy]-8-(6- methoxy-2-methyl-pyridin-3-yl)-
pyrido[3,4-d]pyrimidine G24 ##STR610##
2,5-Difluoro-4-{4-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-pyrido[3,4- d]pyrimidin-8-yl}-
benzenesulfonamide
[0453] TABLE-US-00021 TABLE I Cmpd # Structure Chemical Name I1
##STR611## 4-[3-(2-Fluoro-4-methanesulfonyl-
phenyl)-1-methyl-1H-pyrazolo[4,3-
d]pyrimidin-7-yloxy]-piperidine-1- carboxylic acid isopropyl ester
I2 ##STR612## 4-[3-(2-Fluoro-4- propionylsulfamoyl-phenyl)-1-
methyl-1H-pyrazolo[4,3- d]pyrimidin-7-yloxy]-piperidine-1-
carboxylic acid isopropyl ester I3 ##STR613##
4-[3-(4-Cyano-2-fluoro-phenyl)-1- methyl-1H-pyrazolo[4,3-
d]pyrimidin-7-yloxy]-piperidine-1- carboxylic acid isopropyl ester
I4 ##STR614## 4-[3-(2-Fluoro-4-sulfamoyl-
phenyl)-1-methyl-1H-pyrazolo[4,3-
d]pyrimidin-7-yloxy]-piperidine-1- carboxylic acid isopropyl ester
I5 ##STR615## 4-[3-(2,5-Difluoro-4-
methanesulfonyl-phenyl)-1-methyl- 1H-pyrazolo[4,3-d]pyrimidin-7-
yloxy]-piperidine-1-carboxylic acid isopropyl ester I6 ##STR616##
4-[3-(4-Fluoro-6-methoxy-pyridin- 3-yl)-1-methyl-1H-pyrazolo[4,3-
d]pyrimidin-7-yloxy]-piperidine-1- carboxylic acid isopropyl ester
I7 ##STR617## 4-[3-(6-Methoxy-2-methyl-pyridin-
3-yl)-1-methyl-1H-pyrazolo[4,3- d]pyrimidin-7-yloxy]-piperidine-1-
carboxylic acid isopropyl ester I8 ##STR618##
4-[3-(2,5-Difluoro-4-sulfamoyl- phenyl)-1-methyl-1H-pyrazolo[4,3-
d]pyrimidin-7-yloxy]-piperidine-1- carboxylic acid isopropyl ester
I9 ##STR619## 3-(2-Fluoro-4-methanesulfonyl-
phenyl)-7-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-1-methyl-1H-pyrazolo[4,3- d]pyrimidine I10 ##STR620##
3-Fluoro-4-{7-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-1-methyl-1H-pyrazolo[4,3- d]pyrimidin-3-yl}-N-propionyl-
benzenesulfonamide I11 ##STR621## 3-Fluoro-4-{7-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-1-methyl-1H-pyrazolo[4,3- d]pyrimidin-3-yl}-benzonitrile I12
##STR622## 3-Fluoro-4-{7-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-1-methyl-1H-pyrazolo[4,3- d]pyrimidin-3-yl}-
benzenesulfonamide I13 ##STR623##
3-(2,5-Difluoro-4-methanesulfonyl- phenyl)-7-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-1-methyl-1H-pyrazolo[4,3- d]pyrimidine I14 ##STR624##
3-(4-Fluoro-6-methoxy-pyridin-3- yl)-7-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-1-methyl-1H-pyrazolo[4,3- d]pyrimidine I15 ##STR625##
7-[1-(3-Isopropyl-[1,2,4]oxadiazol- 5-yl)-piperidin-4-yloxy]-3-(6-
methoxy-2-methyl-pyridin-3-yl)-1- methyl-1H-pyrazolo[4,3-
d]pyrimidine I16 ##STR626## 2,5-Difluoro-4-{7-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-1-methyl-1H-pyrazolo[4,3- d]pyrimidin-3-yl}-
benzenesulfonamide I17 ##STR627## 3-(2-Fluoro-4-methanesulfonyl-
phenyl)-7-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-1-methyl-1H- pyrazolo[4,3-d]pyrimidine I18
##STR628## 3-Fluoro-4-{7-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-1-methyl-1H- pyrazolo[4,3-d]pyrimidin-3-yl}-N-
propionyl-benzenesulfonamide I19 ##STR629##
3-Fluoro-4-{7-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-1-methyl-1H- pyrazolo[4,3-d]pyrimidin-3-yl}-
benzonitrile I20 ##STR630## 3-Fluoro-4-{7-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)- cyclohexyloxy]-1-methyl-1H-
pyrazolo[4,3-d]pyrimidin-3-yl}- benzenesulfonamide I21 ##STR631##
3-(2,5-Difluoro-4-methanesulfonyl- phenyl)-7-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)- cyclohexyloxy]-1-methyl-1H-
pyrazolo[4,3-d]pyrimidine I22 ##STR632##
3-(4-Fluoro-6-methoxy-pyridin-3- yl)-7-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)- cyclohexyloxy]-1-methyl-1H-
pyrazolo[4,3-d]pyrimidine I23 ##STR633##
7-[4-(3-Isopropyl-[1,2,4]oxadiazol- 5-yl)-cyclohexyloxy]-3-(6-
methoxy-2-methyl-pyridin-3-yl)-1- methyl-1H-pyrazolo[4,3-
d]pyrimidine I24 ##STR634## 2,5-Difluoro-4-{7-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)- cyclohexyloxy]-1-methyl-1H-
pyrazolo[4,3-d]pyrimidin-3-yl}- benzenesulfonamide
[0454] TABLE-US-00022 TABLE J Cmpd # Structure Chemical Name J1
##STR635## 4-[3-(2-Fluoro-4-methanesulfonyl-
phenyl)-2-methyl-2H-pyrazolo[4,3-
d]pyrimidin-7-yloxy]-piperidine-1- carboxylic acid isopropyl ester
J2 ##STR636## 4-[3-(2-Fluoro-4- propionylsulfamoyl-phenyl)-2-
methyl-2H-pyrazolo[4,3- d]pyrimidin-7-yloxy]-piperidine-1-
carboxylic acid isopropyl ester J3 ##STR637##
4-[3-(4-Cyano-2-fluoro-phenyl)-2- methyl-2H-pyrazolo[4,3-
d]pyrimidin-7-yloxy]-piperidine-1- carboxylic acid isopropyl ester
J4 ##STR638## 4-[3-(2-Fluoro-4-sulfamoyl-
phenyl)-2-methyl-2H-pyrazolo[4,3-
d]pyrimidin-7-yloxy]-piperidine-1- carboxylic acid isopropyl ester
J5 ##STR639## 4-[3-(2,5-Difluoro-4-
methanesulfonyl-phenyl)-2-methyl- 2H-pyrazolo[4,3-d]pyrimidin-7-
yloxy]-piperidine-1-carboxylic acid isopropyl ester J6 ##STR640##
4-[3-(4-Fluoro-6-methoxy-pyridin- 3-yl)-2-methyl-2H-pyrazolo[4,3-
d]pyrimidin-7-yloxy]-piperidine-1- carboxylic acid isopropyl ester
J7 ##STR641## 4-[3-(6-Methoxy-2-methyl-pyridin-
3-yl)-2-methyl-2H-pyrazolo[4,3- d]pyrimidin-7-yloxy]-piperidine-1-
carboxylic acid isopropyl ester J8 ##STR642##
4-[3-(2,5-Difluoro-4-sulfamoyl- phenyl)-2-methyl-2H-pyrazolo[4,3-
d]pyrimidin-7-yloxy]-piperidine-1- carboxylic acid ester J9
##STR643## 3-(2-Fluoro-4-methanesulfonyl-
phenyl)-7-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-2-methyl-2H-pyrazolo[4,3- d]pyrimidine J10 ##STR644##
3-Fluoro-4-{7-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-2-methyl-2H-pyrazolo[4,3- d]pyrimidin-3-yl}-N-propionyl-
benzenesulfonamide J11 ##STR645## 3-Fluoro-4-{7-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-2-methyl-2H-pyrazolo[4,3- d]pyrimidin-3-yl}-benzonitrile J12
##STR646## 3-Fluoro-4-{7-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-2-methyl-2H-pyrazolo[4,3- d]pyrimidin-3-yl}-
benzenesulfonamide J13 ##STR647##
3-(2,5-Difluoro-4-methanesulfonyl- phenyl)-7-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-2-methyl-2H-pyrazolo[4,3- d]pyrimidine J14 ##STR648##
3-(4-Fluoro-6-methoxy-pyridin-3- yl)-7-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-2-methyl-2H-pyrazolo[4,3- d]pyrimidine J15 ##STR649##
7-[1-(3-Isopropyl-[1,2,4]oxadiazol- 5-yl)-piperidin-4-yloxy]-3-(6-
methoxy-2-methyl-pyridin-3-yl)-2- methyl-2H-pyrazolo[4,3-
d]pyrimidine J16 ##STR650## 2,5-Difluoro-4-{7-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-2-methyl-2H-pyrazolo[4,3- d]pyrimidin-3-yl}-
benzenesulfonamide J17 ##STR651## 3-(2-Fluoro-4-methanesulfonyl-
phenyl)-7-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-2-methyl-2H- pyrazolo[4,3-d]pyrimidine J18
##STR652## 3-Fluoro-4-{7-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-2-methyl-2H- pyrazolo[4,3-d]pyrimidin-3-yl}-N-
propionyl-benzenesulfonamide J19 ##STR653##
3-Fluoro-4-{7-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-2-methyl-2H- pyrazolo[4,3-d]pyrimidin-3-yl}-
benzonitrile J20 ##STR654## 3-Fluoro-4-{7-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)- cyclohexyloxy]-2-methyl-2H-
pyrazolo[4,3-d]pyrimidin-3-yl}- benzenesulfonamide J21 ##STR655##
3-(2,5-Difluoro-4-methanesulfonyl- phenyl)-7-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)- cyclohexyloxy]-2-methyl-2H-
pyrazolo[4,3-d]pyrimidine J22 ##STR656##
3-(4-Fluoro-6-methoxy-pyridin-3- yl)-7-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)- cyclohexyloxy]-2-methyl-2H-
pyrazolo[4,3-d]pyrimidine J23 ##STR657##
7-[4-(3-Isopropyl-[1,2,4]oxadiazol- 5-yl)-cyclohexyloxy]-3-(6-
methoxy-2-methyl-pyridin-3-yl)-2- methyl-2H-pyrazolo[4,3-
d]pyrimidine J24 ##STR658## 2,5-Difluoro-4-{7-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)- cyclohexyloxy]-2-methyl-2H-
pyrazolo[4,3-d]pyrimidin-3-yl}- benzenesulfonamide
[0455] TABLE-US-00023 TABLE K Cmpd # Structure Chemical Name K1
##STR659## 3-(2-Fluoro-4-methanesulfonyl-
phenyl)-7-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-pyrazolo[1,5- a]pyrimidine K2 ##STR660##
3-Fluoro-4-{7-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-pyrazolo[1,5- a]pyrimidin-3-yl}-N-propionyl-
benzenesulfonamide K3 ##STR661## 3-Fluoro-4-{7-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)- cyclohexyloxy]-pyrazolo[1,5-
a]pyrimidin-3-yl}-benzonitrile K4 ##STR662##
3-Fluoro-4-{7-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-pyrazolo[1,5- a]pyrimidin-3-yl}- benzenesulfonamide
K5 ##STR663## 3-(2,5-Difluoro-4-methanesulfonyl-
phenyl)-7-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-pyrazolo[1,5- a]pyrimidine K6 ##STR664##
3-(4-Fluoro-6-methoxy-pyridin-3- yl)-7-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)- cyclohexyloxy]-pyrazolo[1,5- a]pyrimidine
K7 ##STR665## 7-[4-(3-Isopropyl-[1,2,4]oxadiazol-
5-yl)-cyclohexyloxy]-3-(6- methoxy-2-methyl-pyridin-3-yl)-
pyrazolo[1,5-a]pyrimidine K8 ##STR666##
2,5-Difluoro-4-{7-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-pyrazolo[1,5- a]pyrimidin-3-yl}- benzenesulfonamide
K9 ##STR667## 4-[3-(2-Fluoro-4-methanesulfonyl-
phenyl)-pyrazolo[1,5-a]pyrimidin- 7-yloxy]-piperidine-1-carboxylic
acid isopropyl ester K10 ##STR668## 4-[3-(2-Fluoro-4-
propionylsulfamoyl-phenyl)- pyrazolo[1,5-a]pyrimidin-7-yloxy]-
piperidine-1-carboxylic acid isopropyl ester K11 ##STR669##
4-[3-(4-Cyano-2-fluoro-phenyl)- pyrazolo[1,5-a]pyrimidin-7-yloxy]-
piperidine-1-carboxylic acid isopropyl ester K12 ##STR670##
4-[3-(2-Fluoro-4-sulfamoyl- phenyl)-pyrazolo[1,5-a]pyrimidin-
7-yloxy]-piperidine-1-carboxylic acid isopropyl ester K13
##STR671## 4-[3-(2,5-Difluoro-4- methanesulfonyl-phenyl)-
pyrazolo[1,5-a]pyrimidin-7-yloxy]- piperidine-1-carboxylic acid
isopropyl ester K14 ##STR672## 4-[3-(4-Fluoro-6-methoxy-pyridin-
3-yl)-pyrazolo[1,5-a]pyrimidin-7- yloxy]-piperidine-1-carboxylic
acid isopropyl ester K15 ##STR673##
4-[3-(6-Methoxy-2-methyl-pyridin- 3-yl)-pyrazolo[1,5-a]pyrimidin-7-
yloxy]-piperidine-1-carboxylic acid isopropyl ester K16 ##STR674##
4-[3-(2,5-Difluoro-4-sulfamoyl- phenyl)-pyrazolo[1,5-a]pyrimidin-
7-yloxy]-piperidine-1-carboxylic acid isopropyl ester K17
##STR675## 3-(2-Fluoro-4-methanesulfonyl-
phenyl)-7-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-pyrazolo[1,5-a]pyrimidine K18 ##STR676##
3-Fluoro-4-{7-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-pyrazolo[1,5-a]pyrimidin-3- yl}-N-propionyl-
benzenesulfonamide K19 ##STR677## 3-Fluoro-4-{7-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-pyrazolo[1,5-a]pyrimidin-3- yl}-benzonitrile K20 ##STR678##
3-Fluoro-4-{7-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-pyrazolo[1,5-a]pyrimidin-3- yl}-benzenesulfonamide K21
##STR679## 3-(2,5-Difluoro-4-methanesulfonyl-
phenyl)-7-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-pyrazolo[1,5-a]pyrimidine K22 ##STR680##
3-(4-Fluoro-6-methoxy-pyridin-3- yl)-7-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-pyrazolo[1,5-a]pyrimidine K23 ##STR681##
7-[1-(3-Isopropyl-[1,2,4]oxadiazol- 5-yl)-piperidin-4-yloxy]-3-(6-
methoxy-2-methyl-pyridin-3-yl)- pyrazolo[1,5-a]pyrimidine K24
##STR682## 2,5-Difluoro-4-{7-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-pyrazolo[1,5-a]pyrimidin-3- yl}-benzenesulfonamide K25
##STR683## 4-[3-(2-Fluoro-4-methanesulfonyl-
phenyl)-2-methyl-pyrazolo[1,5- a]pyrimidin-7-yloxy]-piperidine-1-
carboxylic acid isopropyl ester K26 ##STR684## 4-[3-(2-Fluoro-4-
propionylsulfamoyl-phenyl)-2- methyl-pyrazolo[1,5-a]pyrimidin-7-
yloxy]-piperidine-1-carboxylic acid isopropyl ester K27 ##STR685##
4-[3-(4-Cyano-2-fluoro-phenyl)-2-
methyl-pyrazolo[1,5-a]pyrimidin-7- yloxy]-piperidine-1-carboxylic
acid isopropyl ester K28 ##STR686## 4-[3-(2-Fluoro-4-sulfamoyl-
phenyl)-2-methyl-pyrazolo[1,5- a]pyrimidin-7-yloxy]-piperidine-1-
carboxylic acid isopropyl ester K29 ##STR687##
4-[3-(2,5-Difluoro-4- methanesulfonyl-phenyl)-2-methyl-
pyrazolo[1,5-a]pyrimidin-7-yloxy]- piperidine-1-carboxylic acid
isopropyl ester K30 ##STR688## 4-[3-(4-Fluoro-6-methoxy-pyridin-
3-yl)-2-methyl-pyrazolo[1,5- a]pyrimidin-7-yloxy]-piperidine-1-
carboxylic acid isopropyl ester K31 ##STR689##
4-[3-(6-Methoxy-2-methyl-pyridin- 3-yl)-2-methyl-pyrazolo[1,5-
a]pyrimidin-7-yloxyj-piperidine-1- carboxylic acid isopropyl ester
K32 ##STR690## 4-[3-(2,5-Difluoro-4-sulfamoyl-
phenyl)-2-methyl-pyrazolo[1,5- a]pyrimidin-7-yloxy]-piperidine-1-
carboxylic acid isopropyl ester K33 ##STR691##
2,5-Difluoro-4-{7-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4- yloxy]-2-methyl-pyrazolo[1,5-
a]pyrimidin-3-yl}- benzenesulfonamide K34 ##STR692##
7-[1-(3-Isopropyl-[1,2,4]oxadiazol- 5-yl)-piperidin-4-yloxy]-3-(6-
methoxy-2-methyl-pyridin-3-yl)-2- methyl-pyrazolo[1,5-a]pyrimidine
K35 ##STR693## 3-(4-Fluoro-6-methoxy-pyridin-3-
yl)-7-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-2-methyl-pyrazolo[1,5- a]pyrimidine K36 ##STR694##
3-(2,5-Difluoro-4-methanesulfonyl- phenyl)-7-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4- yloxy]-2-methyl-pyrazolo[1,5-
a]pyrimidine K37 ##STR695## 3-Fluoro-4-{7-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4- yloxy]-2-methyl-pyrazolo[1,5-
a]pyrimidin-3-yl}- benzenesulfonamide K38 ##STR696##
3-Fluoro-4-{7-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-
yloxy]-2-methyl-pyrazolo[1,5- a]pyrimidin-3-yl}-benzonitrile K39
##STR697## 3-Fluoro-4-{7-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4- yloxy]-2-methyl-pyrazolo[1,5-
a]pyrimidin-3-yl}-N-propionyl- benzenesulfonamide K40 ##STR698##
3-(2-Fluoro-4-methanesulfonyl- phenyl)-7-[1-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-4- yloxy]-2-methyl-pyrazolo[1,5-
a]pyrimidine K41 ##STR699## 3-(2-Fluoro-4-methanesulfonyl-
phenyl)-7-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-2-methyl- pyrazolo[1,5-a]pyrimidine K42 ##STR700##
3-Fluoro-4-{7-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-2-methyl- pyrazolo[1,5-a]pyrimidin-3-yl}-N-
propionyl-benzenesulfonamide K43 ##STR701##
3-Fluoro-4-{7-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-
cyclohexyloxy]-2-methyl- pyrazolo[1,5-a]pyrimidin-3-yl}-
benzonitrile K44 ##STR702## 3-Fluoro-4-{7-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)- cyclohexyloxy]-2-methyl-
pyrazolo[1,5-a]pyrimidin-3-yl}- benzenesulfonamide K45 ##STR703##
3-(2,5-Difluoro-4-methanesulfonyl- phenyl)-7-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)- cyclohexyloxy]-2-methyl-
pyrazolo[1,5-a]pyrimidine K46 ##STR704##
3-(4-Fluoro-6-methoxy-pyridin-3- yl)-7-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)- cyclohexyloxy]-2-methyl-
pyrazolo[1,5-a]pyrimidine K47 ##STR705##
7-[4-(3-Isopropyl-[1,2,4]oxadiazol- 5-yl)-cyclohexyloxy]-3-(6-
methoxy-2-methyl-pyridin-3-yl)-2- methyl-pyrazolo[1,5-a]pyrimidine
K48 ##STR706## 2,5-Difluoro-4-{7-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)- cyclohexyloxy]-2-methyl-
pyrazolo[1,5-a]pyrimidin-3-yl}- benzenesulfonamide
[0456] Additionally, compounds of the present invention, such as
Formula (I) and related Formulae, encompass all pharmaceutically
acceptable salts, solvates, and particularly hydrates, thereof.
General Methods for the Preparation of Compounds of the
Invention.
[0457] The novel compounds of the present invention can be readily
prepared according to a variety of synthetic manipulations, all of
which would be familiar to one skilled in the art. Certain methods
for the preparation of compounds of the present invention include,
but are not limited to, those described in Schemes, infra.
##STR707##
[0458] An appropriate nucleophilic species can be used to displace
chloride, bromide or triflate from the bicyclic heterocycle. This
conversion may be carried out under a range of conditions such as
thermal heating and microwave heating and may or may not be
catalyzed by addition of further reagents such as acid, base or
transition metal salts etc (Scheme 1).
[0459] Bicyclic heterocycle halides may most conveniently be
prepared by either direct halogenation of the parent heterocycle,
for example with bromine or by radical bromination with N-bromo
succinimide, or by conversion of the hydroxy compound (which may
exist in the amide form when M=N and or J=N) to the chloride by
treatment with a chlorinating agent such as but not limited to
POCl.sub.3, PCl.sub.5 or some combination thereof (Scheme 2).
##STR708##
[0460] Many bicyclic heterocycles can be prepared using methods
described or adapted from the literature. For example, the
pyrazolopyrimidine of structure H7 in Table 6 may be prepared as
follows (scheme 3) ##STR709##
[0461] Subsequent treatment with POCl.sub.3 and nucleophilic
displacement with amino or alkoxide nucleophiles as outlined above
can afford compounds of the invention in one of the embodiments.
##STR710##
[0462] Similar approaches may be taken with other 6,5 fused systems
(Scheme 4), wherein an amino carboxamide derivative may be
condensed with other small carbon fragments. Compounds of the type
shown by examples H11 (Bull Chem Soc. Jap. (1979) 52, 208; H12, H13
(Leibigs Ann. Chim (1979), 10, 1534), H15 (Indian J.Chem, Sec B.
(1994), 33B, 436), H49, H50 and H51 (Bioorg Med Chem Lett, (2002),
12, 2133) may each be made by this general procedure by starting
from the protected pyrazole, isoxazole, thiazole and thiophene
respectively and cyclising by heating with either a small
carboxylic acid, aldehyde or with a mixture of triethyl
orthoformate and acetic anhydride (Scheme 4).
[0463] It is probable that other 6,5 fused heterocycles containing
a pyrimidine ring (such as H6, H8, H9, H10 (see WO9749706, H12,
H14, H46, H47 and H48) may also be prepared by analogous synthetic
routes from the appropriate amido amine species. However, in some
instances it may be more facile to fuise the 5-membered ring onto
the already formed 6-membered ring rather than vice-versa. For
example, compounds of example H8 and H9 may be formed from a common
intermediate species (Scheme 5). ##STR711##
[0464] In some such cases it may be more useful to displace the
chloride group with the appropriate nucleophilic component before
completing the ring cyclization reaction. ##STR712##
[0465] Similar strategies can be applied to the synthesis of
pyridinyl 2,3-fused heterocycles. For example, heterocycles such as
H22 may be prepared from the amino-5-membered heterocycle by
condensation with an appropriate malonic ester 28 derivative
(Heterocyclic communications, (2000), 6, 463) Scheme 6 or as in
Scheme 6b from aldhehydic substituted N-Aryl pyrazoles to form
regioisomeric pyrazolo[4,3-c]pyridines. Heterocycles such as H21,
H27 and H28 may be prepared by using similar strategies.
Heterocycles such as H25 and H26 may be prepared as described in
WO9635689 and WO1087892 respectively (Scheme 6). ##STR713##
[0466] As with the fused pyrimidinyl series, it may sometimes be
more prudent to allow the 5-membered ring to be formed second to
produce the fused heterocycle.
[0467] For example heterocycles H23 (WO 01053263) and H24 (WO
9808847) (Scheme 7) may be prepared from a common intermediate:
##STR714##
[0468] In addition, alternative condensation methods may be used,
such as those described in J.Med Chem, (2003), 46, 4702 for the
preparation of pyridylfurans: the same method would be adaptable
for the synthesis of H30 which is also described in WO 9847903, if
the thiol was used as the starting point in place of the alcohol.
##STR715##
[0469] In addition, the same ketone intermediates may be used to
prepare the analogous oximes which may be cyclised to the
pyridylisoxazole (H27) and pyridylisothiazole (H28) respectively,
by treatment with an appropriate acid catalyst, such as
polyphosphoroic acid or by use of a acid catalyst and heating under
Dean-Stark conditions (Scheme 9). ##STR716##
[0470] In some examples of 6,5-fused systems, in particular where
the 5-membered ring is fused onto a 3-pyridyl ring it may be
necessary to activate the ring system to be more reactive towards
nucleophiles for the formation of an appropriate intermediate by,
for example oxidation of the pyridyl nitrogen to the N-oxide, e.g.
Acta. Pol. Pharm. (1984), 41, 601 enabling the formation of
heterocycles H38 and H39 (Scheme 10). ##STR717##
[0471] Alternatively, the position of this nitrogen may be used to
advantage by enhancing nucleophilic reaction at the 4-position
relative to the nitrogen in some examples, e.g. H41 may be prepared
by nucleophilic reaction followed by cyclization, J.Mol. Structure,
(1987), 158, 99, or H42 may be prepared by condensation with
hydroxylamine followed by cyclization, a process enhanced by the
presence of the nitrogen in the pyridyl ring portion (Scheme 11).
##STR718##
[0472] It is with a combination of several of the methods described
above, that a range of 6,5-fused bicyclic templates may be
prepared. In each case the templates serve to orientate the
appropriate groups Ar.sub.1 and the Q-K-(EBDA) portion around a
central locus in the correct orientation for maximum biological
activity. In the same way, the appropriate groups may also be
arrayed around a 6,6-fused bicyclic core. Indeed, 6,6-fused
pyrimidines may be prepared according to a similar strategy
employed for the preparation of 6,5-fused pyrimidines, that is that
the pyrimidine ring may be formed second, from the condensation of
an aryl amino carboxamide derivative.
[0473] In this manner, heterocycles H1 (see: Tetrahedron (2000),
56, 5499; J.Am.Chem.Soc. (2002), 124, 1594), H2 (WO 0202549), H3
(WO 980820), H4 and H5 (Montash fur Chemie, (1978) 109, 527) may be
prepared from the appropriately substituted phenyl or heterocyclic
rings. ##STR719##
[0474] In an alternative embodiment, the pyrimidine ring may be the
bicyclic ring component to which the aryl group Ar.sub.1 is
attached, in which case the ring system may be prepared from the
appropriate aminopyridyl aryl ketone intermediate (where either M
or T=N), a procedure in which the pyrimidine ring is formed by an
intramolecular cyclisation process by nucleophilic displacement of
a suitable leaving group, R, by an amino moiety formed by, for
example, reduction of the oxime of the precursor ketone.
Chlorination of the resultant urea-like intermediate and subsequent
reduction provides the required ring system (J. Heterocyclic Chem,
(1989) 26, 105) (Scheme 13). ##STR720##
[0475] 6,6-fused species wherein one of the 6-membered rings is a
2-pyridyl ring, which again may be formed by fusing an appropriate
building block onto an existing amino substituted phenyl or
heterocyclic ring, e.g. ##STR721##
[0476] In this way heterocyclic templates of the type H16 (Yakugaku
Zasshi (1987) 107, 123); H17 (WO 02040480); H18, H19 and H20 (WO
9835967) may be prepared. In a variant of the above method, the
critical Ar.sub.1 group may be optionally introduced at a later
stage in the synthesis, via transition metal catalyzed biaryl
coupling protocols well known to those in the art (Scheme 15).
Other transition metal mediated N arylations of bicyclic
heterocycles have been reported, such as those described in
Tetrahedron Lett., 44, 2003, 3359-3362, wherein arylation is
achieved with under mild conditions using aryl boronic acids in the
presence of copper(II)acetate, molecular sieves and a base, which
is preferably phenanthroline. In addition to this report other
efficient exocyclic N--H arylations of heterocyclic functions have
been developed. The most commonly used strategy is based on
palladium, nickel or copper catalysis with aryl halides or aryl
sulfonates. ##STR722##
[0477] 3-Aryl pyrazolo[4,3-d]pyrimidines, type H51, have been
described in the literature (Bioorganic Medicinal Chemistry Lett.
12, 2002, 2133-2136). Treatment of N-alkyl pyrazole (74) with
benzyl thioacetimidate hydrobromide in refluxing pyridine affords
the intermediate pyrazolopyrimidinone (75) in moderate yield
(Scheme 16). ##STR723##
[0478] Again, target analogues retaining this bicyclic core are
obtained via the standard halogenation, nucleophilic displacement
sequence described in Scheme 1 and Scheme 20. In some embodiments
one of the heteroatoms maybe incorporated into the 6:5 ring
junction, such examples include heterocyclic cores H51-54, H61-63,
H70-84 and H110-113 in Table 6. ##STR724##
[0479] 3-Arylpyrazolo[1,5-a]pyrimidines of type H53 are well known
in the art and may be obtained from arylacetonitriles as depicted
in Scheme 17. Conversion to the intermediate ketonitriles (78, 79,
80) may be effected via a variety of synthetic methodologies as
depicted. Cyclization to amino pyrazoles of all intermediates can
be achieved thermally with hydrazine HCl in alcoholic solvents such
as ethanol or isopropyl alcohol. Construction of the second 6
membered ring maybe undertaken using a variety of beta-keto esters
in refluxing dioaxane or THF to afford pyrazolo[1,5-a]pyrimidinones
of type 82 which are elaborated further via a standard halogenation
nucleophilic displacement sequence. In an alternative embodiment
the 3-Arylpyrazolo[1,5-a]pyrimidine (Scheme 18) core can be
synthesized by the synthetic scheme outlined in Scheme 18, wherein
Ar.sub.1 is introduced via a key transition metal catalyst mediated
Negishi or Suzuki type coupling. It is also noteworthy at this
juncture to mention that 7-chloro-3-bromopyrazolo[1,5-a]pyrimidine
(87) may also be prepared from the 7-chloro fused bicycle via
direct bromination with N-bromosuccinimide (see for ref J. Med.
Chem, 1976, vol. 19, No. 4, 512). ##STR725##
[0480] Other preferred core scaffolds of the present invention that
contain heteroatoms at the ring junction positions include the
pyrazolo[1,5-a]triazines and the pyrrolo[1,2-a]pyrimidines depicted
in Scheme 18b below. Again, similar organic chemistry strategies
can be harnessed to fuise a 6 membered ring on to the pyrazole or
pyrrole core. Reaction of the 4-aryl-3-amino pyrazole with
ethylacetimidate to produce an intermediate amidine is the key step
in the construction of the pyrazolo[1,5-a]triazine 91, reaction of
this intermediate with deiethyl carbonate in the presence of sodium
ethoxide produces the 6:5 triazinone with can then be subjected to
the standard chlorination, nucleophilic displacement steps to
produce Rup-3 selective insuilin secretogogues of the present
invention (for reference see J. Med. Chem. 2000, 43, 3, 449).
Alternatively, pyrrolo[1,2-a]pyrimidines can be constructed from
trisubstituted pyrroles by reaction with ethyl acetoacetate in
refluxung dioxane (for reference see WO/9835967) (Scheme 18b).
##STR726##
[0481] Pyrrolo[2,3-d]pyrimidine derivatives of the current
invention may be obtained via methodologies depicted in Scheme 19a
(J. Med. Chem, 1997, 40, 1749-1754). The Knoevenagel derived
malonitrile derivative can be readily brominated with 1-1.3
equivalents of NBS in the presence of catalytic benzoyl peroxide.
Subsequent reaction with Ar.sub.1NH.sub.2 affords aminopyrrole
intermediate (97). Acylation followed by hydrolysis of the nitrile
and phosphoric acid mediated cyclization is a proven strategy for
synthesis of the pyrimidine ring. ##STR727##
[0482] Alternative synthetic routes may be adopted such as the Heck
mediated cyclization of 5-alkynyl-4-anilinopyrimidines as depicted
in Scheme 19b. ##STR728##
[0483] To facilitate rapid entry into many of the compounds of the
invention microwave synthesis can be optionally utilized (Scheme
20). The Smith synthesizer from Personal Chemistry is a
commercially available focused field heating instrument that
provides safer and more uniform conditions for performing the base
catalyzed substitution reactions depicted in Schemes. Bases
employed for such conversions (whereby Q=NR.sub.4) include tertiary
amines such as triethylamine, Hunig's base (i.e.
diisopropyl-ethylamine), N-methylmorpholine and the like.
Alternatively, one skilled in the art can employ alkali metal
hydrides, alkali metal carbonates (such as, Li.sub.2CO.sub.3,
Na.sub.2CO.sub.3, K.sub.2CO.sub.3 and the like), an alkali metal
hydrogencarbonate (such as, LiHCO.sub.3, NaHCO.sub.3, KHCO.sub.3
and the like). Wherein Q=N, inert lower alkyl alcoholic solvent can
be emplyed (such as, MeOH, EtOH, i-PrOH, n-BuOH and the like) or
wherein Q=O, an ethereal solvent such as tetrahydrofuran,
1,4-dioxane, and the like can be used. Reaction times to access
typical examples such as, 104 and 105, can range from about 300 s
to about 3000 s and when conventional thermal methods are employed
(wherein Q=O) about 20 mins to about 48 h. ##STR729##
[0484] As illustrated in Scheme 21, a similar transition metal
catalysed couplings were utilized to obtain molecules of general
formula 107-111 (Scheme 21) wherein the "Ar.sub.1" substituent
(Hal=Br, I) of intermediate 106 is modified to give analogs with
alkyl amino substituents (i.e., NR.sub.aR.sub.b, wherein R.sub.a
and R.sub.b are each independently H, C.sub.1-6 alkyl or a
substituted C.sub.1-6 alkyl, or R.sub.a and R.sub.b together with
the nitrogen form a heterocyclic ring, as described herein).
Alternatively, the linker atom can be oxygen by utilizing the CuI
catalysed method for aromatic C--O formation described by Buchwald
(see for reference S. L. Buchwald; Organic Lett., 2002, 4, 6,
973-976) by utilizing, for example, 10 mol % CuI, 20 mol %
1,10-phenanthroline, 2 equivalents of Cs.sub.2CO.sub.3, at
110.degree. C. for 18 h (Scheme 21d), with an "Ar.sub.1" iodo
substitution in the substrate. Additional important organometallic
transformations from halo intermediates 106 to active analogues of
the current invention include the well know palladium catalyzed
couplings of appropriately substituted aryl boronic acids via the
"Suzuki coupling reaction" to introduce aryl or heteroaryl groups
[Ar.sub.4] (Scheme 21e).
[0485] The Suzuki coupling represents a widely used method for the
synthesis of biaryl compounds and is already applied on industrial
scale. Unfortunately, for a long time this reaction was limited to
the use of aryl bromides, aryl iodides or electron-deficient aryl
chlorides as starting materials. Thus, a general approach to the
desired biaryl compounds using the cheap and easy available aryl
chlorides was not available. In the last two years, however,
several new protocols for the Suzuki coupling with aryl chlorides
were developed. These methods allow an efficient synthesis of
biaryls, independently of the substitution pattern and electronic
properties of the starting materials. These concepts which were
developed by the research groups of Fu, Buchwald, Guram, Beller as
well as Trudell and Nolan are highlighted in "Modem methods of the
Suzuki cross coupling: the long expected general synthetic routes
using aryl chlorides. Groger, Harald, Journal fuer Praktische
Chemie (Weinheim, Germany) (2000), 342(4), 334-339. Alternatively
additional functionality maybe introduced using other metal
catalyzed transformations such as cyanation using zinc(II)cyanide
under microwave irradiation conditions to obtain compounds of
general formula 108 or the well documented Pd catalyzed
"Sonogashira reaction" (Scheme 21c) for introduction of terminal
alkynes. Most recently the Sonogashira Coupling has been described
to produce almost quantitative yields of desired product using
appropriate reaction conditions in the complete absence of
palladium catalysts (for ref see "First Examples of
Transition-Metal Free Sonogashira-Type Couplings" Leadbeater,
Nicholas E.; Marco, Maria; Tominack, Bonnie J, Organic Letters
(2003), 5(21), 3919-3922, and also transition-metal-free
Sonogashira-type coupling reactions in water, Appukkuttan, Prasad;
Dehaen, Wim; Van der Eycken, Erik, European Journal of Organic
Chemistry (2003), (24), 4713-4716 ##STR730## ##STR731##
[0486] One particular embodiment is when the Hal group on
"Ar.sub.1" is located at the para position of a phenyl ring. In
another particular embodiment of the invention, the Hal group is
chloro at the 2 position of a trisubstituted pyridyl moiety
(intermediate 113). Organotransition metal catalysed methods for
substitution of this halogen are depicted in Scheme 22.
[0487] A particular substitution for compounds of the present
invention is wherein D=NCOOR.sub.c wherein R.sub.c is C.sub.1-6
alkyl, or C.sub.3-7 cycloalkyl and each can be further substituted.
Urethanes of this type can be prepared directly from intermediates
depicted in Schemes 20 and 21 when D=NH. In certain reactions, use
of a suitable nitrogen protecting group (such as, .sup.tBoc, Cbz,
Moz, Alloc, Fmoc and the like) may be necessary during further
chemical modification of the core. Deprotection maybe achieved
using standard reagents familiar to one skilled in the art (these
might include TFA, mineral acid, Palladium/hydrogen gas and the
like in an alcoholic or ethereal solvent system chosen from
methanol, ethanol, tert-butanol, THF, 1,4-dioxane, and the like).
On occasion wherein the target molecule contains 2 protecting
groups, an orthogonal protection strategy may be adopted. The
deprotected secondary amine (D=NH) can subsequently be modified
accordingly. ##STR732##
[0488] Schemes 23 and 24 and 25 illustrate such chemistries wherein
generation of a carbamate, urea or amide can be executed using an
appropriate reaction in the presence of a base, for example, a
tertiary amine base such as TEA, DIEA and the like, in an inert
solvent system.
[0489] As illustrated in Scheme 23, urethane 116 can be obtained by
a urethane reaction using R.sub.cOCO-halide (wherein R.sub.a is as
described supra, and halide is chloro, bromo, or iodo, particularly
useful is chloro) in an inert solvent with or without a base.
Suitable bases include an alkali metal carbonate (such as, sodium
carbonate, potassium carbonate, and the like), an alkali metal
hydrogencarbonate (such as, sodium hydrogencarbonate, potassium
hydrogencarbonate, and the like), an alkali hydroxide (such as,
sodium hydroxide, potassium hydroxide, and the like), a tertiary
amine (such as, N-N-diisopropylethylamine, triethylamine,
N-methylmorpholine, and the like), or an aromatic amine (such as,
pyridine, imidazole, poly-(4-vinylpyridine), and the like). The
inert solvent includes lower halocarbon solvents (such as,
dichloromethane, dichloroethane, chloroform, and the like),
ethereal solvents (such as, tetrahydrofuran, dioxane, and the
like), aromatic solvents (such as, benzene, toluene, and the like),
or polar solvents (such as, N,N-dimethylformamide, dimethyl
sulfoxide, and the like). Reaction temperature ranges from about
-20.degree. C. to 120.degree. C., preferably about 0.degree. C. to
100.degree. C. ##STR733##
[0490] As shown in Scheme 24, the amine intermediate obtained from
acidic deprotection of 117 can be functionalized to amides
represented by species 118. Carbamate 117 is first reacted with 4N
HCl in dioxane or alternatively TFA in dichloromethane and further
reacted with a carboxylic acid (R.sub.dCO.sub.2H, wherein as used
in Scheme 24, R.sub.d is Ar.sub.2, or a
C.sub.1-6-alkylene-Ar.sub.2; Ar.sub.2/3 can be substituted or
unsubstituted and has the same meaning as described herein) with a
dehydrating condensing agent in an inert solvent with or without a
base to provide the amide 118 of the present invention. The
dehydrating condensing agent includes dicyclohexylcarbodiimide
(DCC), 1,3-diisopropylcarbodiimide (DIC),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
(EDC.HCl), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate
(PyBroP), benzotriazoloyloxytris(dimethylamino)-phosphonium
hexafluorophosphate (BOP), O-(7-azabenzo
triazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
(HATU), or 1-cyclohexyl-3-methylpolystyrene-carbodiimide. The base
includes a tertiary amine (such as, N,N-diisopropylethylamine,
triethylamine, and the like). The inert solvent includes lower
halocarbon solvents (such as, dichloromethane, dichloroethane,
chloroform, and the like), ethereal solvents (such as,
tetrahydrofuran, dioxane, and the like), nitrile solvents (such as,
acetonitrile, and the like), amide solvents (N,N-dimethylformamide,
N,N-dimethylacetamide, and the like) and mixtures thereof.
Optionally, 1-hydroxybenzotriazole (HOBT),
HOBT-6-carboxaamidomethyl polystyrene, or
1-hydroxy-7-azabenzotriazole (HOAT) can be used as a reactant
agent. Reaction temperature ranges from about -20.degree. C. to
50.degree. C., preferably about 0.degree. C. to 40.degree. C.
##STR734##
[0491] Alternatively, amides 118 of the present invention can be
obtained by an amidation reaction using an acid halide (such as,
R.sub.dCOCl) and a base in an inert solvent. The base includes an
alkali metal carbonate (such as, sodium carbonate, potassium
carbonate, and the like), an alkali metal hydrogencarbonate (such
as, sodium hydrogencarbonate, potassium hydrogencarbonate, and the
like), an alkali hydroxide (such as, sodium hydroxide or potassium
hydroxide, and like), a tertiary amine (such as,
N,N-diisopropylethylamine, triethylamine, N-methylmorpholine, and
the like), or an aromatic amine (such as, pyridine, imidazole,
poly-(4-vinylpyridine), and the like). The inert solvent includes
lower halocarbon solvents (such as, dichloromethane,
dichloroethane, chloroform, and the like), ethereal solvents (such
as, tetrahydrofuran, dioxane, and the like), amide solvents (such
as, N,N-dimethylacetamide, N,N-dimethylformamide, and the like),
aromatic solvents (benzene, toluene, pyridine, and the like) and
mixtures thereof. Reaction temperature ranges from about
-20.degree. C. to 50.degree. C., preferably about 0.degree. C. to
40.degree. C.
[0492] Also illustrated in Scheme 24, amide 118 can be reacted with
a reducing agent in an inert solvent to provide the amine 119 of
the present invention. The reducing agent includes alkali metal
aluminum hydrides (such as, lithium aluminum hydride, and the
like), alkali metal borohydrides (such as, lithium borohydride, and
the like), alkali metal trialkoxyaluminum hydrides (such as,
lithium tri-tert-butoxyaluminum hydride, and the like),
dialkylaluminum hydrides (such as, di-isobutylaluminum hydride, and
the like), borane, dialkylboranes (such as, di-isoamyl borane, and
the like), alkali metal trialkylboron hydrides (such as, lithium
triethylboron hydride, and the like). The inert solvent includes
ethereal solvents (such as, tetrahydrofuran, dioxane, and the
like), aromatic solvents (such as, toluene, and the like) and
mixtures thereof. Reaction temperature ranges from about
-78.degree. C. to 200.degree. C., preferably about 50.degree. C. to
120.degree. C.
[0493] Alternatively, the amine 119 of the present invention can be
obtained by a reductive amination reaction using the acid
deprotected secondary amine intermediate with an aldehyde
(R.sub.dCHO) and a reducing agent in an inert solvent with or
without an acid. The reducing agent includes sodium
triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride,
borane-pyridine complex, and the like. The inert solvent includes
lower alkyl alcohol solvents (such as, methanol, ethanol, and the
like), lower halocarbon solvents (such as, dichloromethane,
dichloroethane, chloroform, and the like), ethereal solvents (such
as, tetrahydrofuran, dioxane, and the like), aromatic solvents
(such as, benzene, toluene, and the like) and mixtures thereof. The
acid includes an inorganic acid (such as, hydrochloric acid,
sulfuric acid, and the like) or an organic acid (such as, acetic
acid, and the like). Reaction temperature ranges from about
-20.degree. C. to 120.degree. C., preferably about 0.degree. C. to
100.degree. C. In addition, this reaction can optionally be carried
out under microwave conditions.
[0494] In an alternative manner, the intermediate amine product of
acid deprotection of 117 can be alkylated directly with an
alkylating agent, such as R.sub.d-halide (wherein R.sub.d is
substituted or unsubstituted C.sub.1-6 alkyl, or substituted or
unsubstituted C.sub.1-6 alkyl-Ar, and halide is chloro, bromo and
iodo), in the presence of a base and in an inert solvent to provide
amine 119. The base includes an alkali metal carbonate (such as,
sodium carbonate, potassium carbonate, and the like), an alkali
metal hydride (such as, sodium hydride, potassium hydride, and the
like), alkali metal alkoxide (such as, potassium tert-butoxide,
sodium tert-butoxide, and the like); alkyl lithiums (such as,
tert-butyl lithium, n-butyl lithium and the like). The inert
solvents include, ethereal solvents (such as, tetrahydrofuran,
dioxane), aromatic solvents (such as, benzene, toluene, and the
like), amide solvents (such as, N,N-dimethylformamide, and the
like) and mixtures thereof. Reaction temperature ranges from about
-20.degree. C. to 120.degree. C., preferably about 0.degree. C. to
100.degree. C.
[0495] Also shown in Scheme 24 is the preparation of additional
compounds of the invention via alkylating the nitrogen of ureas
represented by 118 with an alkyl-halide (wherein halide is chloro,
bromo and iodo) in the presence of a base in an inert solvent to
provide di-substituted urea. The base includes an alkali metal
hydride (such as, sodium hydride, potassium hydride, and the like),
alkali metal alkoxide (such as, potassium tert-butoxide, sodium
tert-butoxide, and the like); alkyl lithiums (such as, tert-butyl
lithium, n-butyl lithium and the like). The inert solvents include,
ethereal solvents (such as, tetrahydrofuran, dioxane), aromatic
solvents (such as, benzene, toluene, and the like), amide solvents
(such as, N,N-dimethylformamide, and the like) and mixtures
thereof. Reaction temperature ranges from about -20.degree. C. to
120.degree. C., preferably about 0.degree. C. to 100.degree. C.
[0496] In addition, as illustrated in Scheme 25, urea 121 can be
obtained from deprotecting common intermediate 120 and allowing the
amine (i.e., D=NH) to react with a variety isocyanates (R.sub.aNCO,
wherein R.sub.a has the same meaning as described herein) in an
inert solvent with or without a base. Suitable bases include an
alkali metal carbonate (such as, sodium carbonate, potassium
carbonate, and the like), an alkali metal hydrogencarbonate (such
as, sodium hydrogencarbonate, potassium hydrogencarbonate, and the
like), an alkali hydroxide (such as, sodium hydroxide, potassium
hydroxide, and the like), a tertiary amine (such as,
N,N-diisopropylethylamine, triethylamine, N-methylmorpholine, and
the like), or an aromatic amine (such as, pyridine, imidazole, and
the like). The inert solvent includes lower halocarbon solvents
(such as, dichloromethane, dichloroethane, chloroform, and the
like), ethereal solvents (such as, tetrahydrofuran, dioxane, and
the like), aromatic solvents (such as, benzene, toluene, and the
like), or polar solvents (such as, N,N-dimethylformamide, dimethyl
sulfoxide, and the like). Reaction temperature ranges from about
-20.degree. C. to 120.degree. C., preferably about 0.degree. C. to
100.degree. C. ##STR735##
[0497] Further, as illustrated in Scheme 25b, thiourea 122 can be
obtained from deprotecting common intermediate 120 and allowing the
amine (i.e., D=NH) to react with a variety thioisocyanates
(R.sub.aNCS, wherein R.sub.a has the same meaning as described
herein) in an inert solvent with or without a base. Suitable bases
include an alkali metal carbonate (such as, sodium carbonate,
potassium carbonate, and the like), an alkali metal
hydrogencarbonate (such as, sodium hydrogencarbonate, potassium
hydrogencarbonate, and the like), an alkali hydroxide (such as,
sodium hydroxide, potassium hydroxide, and the like), a tertiary
amine (such as, N,N-diisopropylethylamine, triethylamine,
N-methylmorpholine, and the like), or an aromatic amine (such as,
pyridine, imidazole, and the like). The inert solvent includes
lower halocarbon solvents (such as, dichloromethane,
dichloroethane, chloroform, and the like), ethereal solvents (such
as, tetrahydrofuran, dioxane, and the like), aromatic solvents
(such as, benzene, toluene, and the like), or polar solvents (such
as, N,N-dimethylformamide, dimethyl sulfoxide, and the like).
Reaction temperature ranges from about -20.degree. C. to
120.degree. C., preferably about 0.degree. C. to 100.degree. C.
##STR736##
[0498] Scheme 26 illustrates the synthesis of para-alkyl sulfones
(124) of the present invention, wherein R.sub.10-R.sub.13 have the
same meaning as described herein where W=a heterocycle selected
from Table 6 [H1-H116]. The common methods for preparing these
sulfones include the oxidation of sulfides or the sulfonylation of
arenes using aryl sulfonyl halides or aryl sulfonic acids in th
presence of a strong acid catalyst (see for general reference: the
Organic Chemistry of Sulfur; Oae S., Ed.; Plenum Press: New York,
1977). Optimal conversion to the arene 124 was achieved thermally
wherein Hal is preferably iodo using 5 mol % (CuOTf).sub.2.PhH and
10 mol % N,N'-dimethylethylenediamine in DMSO by the method of Wang
et al (see for reference Wang Z.; Baskin J. M., Org. Lett., 2002,
4, 25, 4423-4425). In some embodiments, R.sub.10 and R.sub.13 are
each independently H, halogen, or C.sub.1-6 alkyl; R.sub.11 and
R.sub.12 are both H; Hal=Br, I.
[0499] Synthesis of the 3,5-oxadiazolo variant is depicted in
Scheme 27. Zinc(II)chloride catalyzed coupling of amidoxime 126
with 4-hydroxypiperidine, CNBr derived 128 yielded building block
129 after acidic workup, which was subsequently utilized in
reaction sequences depicted as illustrated in Schemes 1 & 20.
##STR737##
[0500] In a preferred embodiment of the present invention a
sulfonamide group may be introduced into the meta or para Ar
position. This can be accomplished via several amenable synthetic
multi step manipulations including the reaction of ammonia with
sulfonyl chlorides (Scheme 28A) or alternatively sulfonamides can
be obtained by reacting sulfinic acid salts with an electrophilic
nitrogen source such as hydroxylamine-O-sulfonic acid or
bis-(2,2,2-trichloroethyl)-azodicarboxylate. Preferably
3-methoxy-3-oxapropane-1-sulfinate can serve as a sulfinate donor
moiety through a simple alkylation and be subsequently removed via
a beta-elimination reaction. Reaction of the resulting sulfinate
with an electrophilic nitrogen source provides the primary
sulfonamide analogue of the current invention. Such intermediates
may be optionally further modified to amides such as those
represented by general formulae 132. Acylsulfonamides of this type
can be obtained by an amidation reaction using an acid halide or
anhydride (such as, R.sub.gCOCl or (R.sub.gCO).sub.2O) and a base
in an inert solvent (Scheme 28C). The base includes an alkali metal
carbonate (such as, sodium carbonate, potassium carbonate, and the
like), an alkali metal hydrogencarbonate (such as, sodium
hydrogencarbonate, potassium hydrogencarbonate, and the like), an
alkali hydroxide (such as, sodium hydroxide or potassium hydroxide,
and like), a tertiary amine (such as, N,N-diisopropylethylamine,
triethylamine, N-methylmorpholine, and the like), or an aromatic
amine (such as, pyridine, imidazole, poly-(4-vinylpyridine), and
the like). The inert solvent includes lower halocarbon solvents
(such as, dichloromethane, dichloroethane, chloroform, and the
like), ethereal solvents (such as, tetrahydrofuran, dioxane, and
the like), amide solvents (such as, N,N-dimethylacetamide,
N,N-dimethylformamide, and the like), aromatic solvents (benzene,
toluene, pyridine, and the like) and mixtures thereof. Reaction
temperature ranges from about -20.degree. C. to 50.degree. C.,
preferably about 0.degree. C. to 40.degree. C. ##STR738##
[0501] Protecting groups may be required for various functionality
or functionalities during the synthesis of some of the compounds of
the invention. Accordingly, representative protecting groups that
are suitable for a wide variety of synthetic transformations are
disclosed in Greene and Wuts, Protective Groups in Organic
Synthesis, 3rd edition, John Wiley & Sons, New York, 1999, the
disclosure of which is incorporated herein by reference in its
entirety.
[0502] The present invention also encompasses diastereomers as well
as optical isomers, e.g. mixtures of enantiomers including racemic
mixtures, as well as individual enantiomers and diastereomers,
which arise as a consequence of structural asymmetry in certain
compounds of Formula (I). Separation of the individual isomers or
selective synthesis of the individual isomers is accomplished by
application of various methods which are well known to
practitioners in the art.
[0503] The compounds described herein can be asymmetric (e.g.,
having one or more stereocenters). All stereoisomers, such as
enantiomers and diastereomers, are intended unless otherwise
indicated. Compounds of the present invention that contain
asymmetrically substituted carbon atoms can be isolated in
optically active or racemic forms. Methods on how to prepare
optically active forms from optically active starting materials are
known in the art, such as by resolution of racemic mixtures or by
stereoselective synthesis. Many geometric isomers of olefins,
C.dbd.N double bonds, disubstituted cycloalkyl groups (i.e.,
1,4-cyclohexyl), and the like can also be present in the compounds
described herein, and all such stable isomers are contemplated in
the present invention. Cis and trans geometric isomers of the
compounds of the present invention are described and may be
isolated as a mixture of isomers or as separated isomeric
forms.
Indications and Methods of Prophylaxis and/or Treatment
[0504] In addition to the foregoing beneficial uses for compounds
of the present invention disclosed herein, compounds of the
invention are useful in the treatment of additional diseases.
Without limitation, these include the following.
[0505] The most significant pathologies in Type II diabetes are
impaired insulin signaling at its target tissues ("insulin
resistance") and failure of the insulin-producing cells of the
pancreas to secrete an appropriate degree of insulin in response to
a hyperglycemic signal. Current therapies to treat the latter
include inhibitors of the .beta.-cell ATP-sensitive potassium
channel to trigger the release of endogenous insulin stores, or
administration of exogenous insulin. Neither of these achieves
accurate normalization of blood glucose levels and both carry the
risk of inducing hypoglycemia. For these reasons, there has been
intense interest in the development of pharmaceuticals that
function in a glucose-dependent action, i.e. potentiators of
glucose signaling. Physiological signaling systems which function
in this manner are well-characterized and include the gut peptides
GLP1, GIP and PACAP. These hormones act via their cognate G-protein
coupled receptor to stimulate the production of cAMP in pancreatic
.beta.-cells. The increased cAMP does not appear to result in
stimulation of insulin release during the fasting or preprandial
state. However, a series of biochemical targets of cAMP signaling,
including the ATP-sensitive potassium channel, voltage-sensitive
potassium channels and the exocytotic machinery, are modified in
such a way that the insulin secretory response to a postprandial
glucose stimulus is markedly enhanced. Accordingly, agonists of
novel, similarly functioning, .beta.-cell GPCRs, including RUP3,
would also stimulate the release of endogenous insulin and
consequently promote normoglycemia in Type II diabetes.
[0506] It is also established that increased cAMP, for example as a
result of GLP1 stimulation, promotes .beta.-cell proliferation,
inhibits .beta.-cell death and thus improves islet mass. This
positive effect on .beta.-cell mass is expected to be beneficial in
both Type II diabetes, where insufficient insulin is produced, and
Type I diabetes, where .beta.-cells are destroyed by an
inappropriate autoimmune response.
[0507] Some .beta.-cell GPCRs, including RUP3, are also present in
the hypothalamus where they modulate hunger, satiety, decrease food
intake, controlling or decreasing weight and energy expenditure.
Hence, given their function within the hypothalamic circuitry,
agonists or inverse agonists of these receptors mitigate hunger,
promote satiety and therefore modulate weight.
[0508] It is also well-established that metabolic diseases exert a
negative influence on other physiological systems. Thus, there is
often the codevelopment of multiple disease states (e.g. type I
diabetes, type II diabetes, inadequate glucose tolerance, insulin
resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia,
hypercholesterolemia, dyslipidemia, obesity or cardiovascular
disease in "Syndrome X") or secondary diseases which clearly occur
secondary to diabetes (e.g. kidney disease, peripheral neuropathy).
Thus, it is expected that effective treatment of the diabetic
condition will in turn be of benefit to such interconnected disease
states.
[0509] In some embodiments of the present invention the
metabolic-related disorder is hyperlipidemia, type 1 diabetes, type
2 diabetes mellitus, idiopathic type 1 diabetes (Type 1b), latent
autoimmune diabetes in adults (LADA), early-onset type 2 diabetes
(EOD), youth-onset atypical diabetes (YOAD), maturity onset
diabetes of the young (MODY), malnutrition-related diabetes,
gestational diabetes, coronary heart disease, ischemic stroke,
restenosis after angioplasty, peripheral vascular disease,
intermittent claudication, myocardial infarction (e.g. necrosis and
apoptosis), dyslipidemia, post-prandial lipemia, conditions of
impaired glucose tolerance (IGT), conditions of impaired fasting
plasma glucose, metabolic acidosis, ketosis, arthritis, obesity,
osteoporosis, hypertension, congestive heart failure, left
ventricular hypertrophy, peripheral arterial disease, diabetic
retinopathy, macular degeneration, cataract, diabetic nephropathy,
glomerulosclerosis, chronic renal failure, diabetic neuropathy,
metabolic syndrome, syndrome X, premenstrual syndrome, coronary
heart disease, angina pectoris, thrombosis, atherosclerosis,
myocardial infarction, transient ischemic attacks, stroke, vascular
restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia,
hypertrygliceridemia, insulin resistance, impaired glucose
metabolism, conditions of impaired glucose tolerance, conditions of
impaired fasting plasma glucose, obesity, erectile dysfunction,
skin and connective tissue disorders, foot ulcerations and
ulcerative colitis, endothelial dysfunction and impaired vascular
compliance.
[0510] One aspect of the present invention pertains to methods for
treatment of a metabolic-related disorder in an individual
comprising administering to the individual in need of such
treatment a therapeutically effective amount of a compound as
described herein or a pharmaceutical composition thereof. In some
embodiments the metabolic-related disorder is type I diabetes, type
II diabetes, inadequate glucose tolerance, insulin resistance,
hyperglycemia, hyperlipidemia, hypertriglyceridemia,
hypercholesterolemia, dyslipidemia or syndrome X. In some
embodiments the metabolic-related disorder is type II diabetes. In
some embodiments the metabolic-related disorder is hyperglycemia.
In some embodiments the metabolic-related disorder is
hyperlipidemia. In some embodiments the metabolic-related disorder
is hypertriglyceridemia. In some embodiments the metabolic-related
disorder is type I diabetes. In some embodiments the
metabolic-related disorder is dyslipidemia. In some embodiments the
metabolic-related disorder is syndrome X. In some embodiments the
individual is a mammal. In some embodiments the mammal is a
human.
[0511] One aspect of the present invention pertains to methods of
decreasing food intake of an individual comprising administering to
the individual in need thereof a therapeutically effective amount
of a compound of the present invention or pharmaceutical
composition thereof. In some embodiments the individual is a
mammal. In some embodiments the mammal is a human.
[0512] One aspect of the present invention pertains to methods of
inducing satiety in an individual comprising administering to the
individual in need of such treatment a therapeutically effective
amount of a compound of the present invention or pharmaceutical
composition thereof. In some embodiments the individual is a
mammal. In some embodiments the mammal is a human.
[0513] One aspect of the present invention pertains to methods of
controlling or decreasing weight gain of an individual comprising
administering to the individual in need of such treatment a
therapeutically effective amount of a compound of the present
invention or pharmaceutical composition thereof. In some
embodiments the individual is a mammal. In some embodiments the
mammal is a human.
[0514] Some embodiments of the present invention pertain to methods
wherein the human has a body mass index of about 18.5 to about 45.
In some embodiments, the human has a body mass index of about 25 to
about 45. In some embodiments, the human has a body mass index of
about 30 to about 45. In some embodiments, the human has a body
mass index of about 35 to about 45.
[0515] One aspect of the present invention pertains to methods of
modulating a RUP3 receptor in an individual comprising contacting
the receptor with a compound of the present invention or a
pharmaceutical composition thereof. In some embodiments, the
compound is an agonist. In some embodiments, the compound is an
inverse agonist. In some embodiments, the compound is an
antagonist. In some embodiments, the modulation of the RUP3
receptor is treatment of a metabolic-related disorder and
complications thereof. In some embodiments, the metabolic-related
disorder is type I diabetes, type II diabetes, inadequate glucose
tolerance, insulin resistance, hyperglycemia, hyperlipidemia,
hypertriglyceridemia, hypercholesterolemia, dyslipidemia or
syndrome X. In some embodiments, the metabolic-related disorder is
type II diabetes. In some embodiments, the metabolic-related
disorder is hyperglycemia. In some embodiments, the
metabolic-related disorder is hyperlipidemia. In some embodiments,
the metabolic-related disorder is hypertriglyceridemia. In some
embodiments, the metabolic-related disorder is type I diabetes. In
some embodiments, the metabolic-related disorder is dyslipidemia.
In some embodiments, the metabolic-related disorder is syndrome X.
In some embodiments, the individual is a mammal. In some
embodiments, the mammal is a human.
[0516] Some embodiments of the present invention include a method
of modulating a RUP3 receptor in an individual comprising
contacting the receptor with a compound of the present invention
wherein the modulation of the RUP3 receptor reduces food intake of
the individual. In some embodiments the individual is a mammal. In
some embodiments the mammal is a human. In some embodiments the
human has a body mass index of about 18.5 to about 45. In some
embodiments the human has a body mass index of about 25 to about
45. In some embodiments the human has a body mass index of about 30
to about 45. In some embodiments the human has a body mass index of
about 35 to about 45.
[0517] Some embodiments of the present invention include a method
of modulating a RUP3 receptor in an individual comprising
contacting the receptor with a compound of the present invention
wherein the modulation of the RUP3 receptor induces satiety in the
individual. In some embodiments the individual is a mammal. In some
embodiments the mammal is a human. In some embodiments the human
has a body mass index of about 18.5 to about 45. In some
embodiments the human has a body mass index of about 25 to about
45. In some embodiments the human has a body mass index of about 30
to about 45. In some embodiments the human has a body mass index of
about 35 to about 45.
[0518] Some embodiments of the present invention include a method
of modulating a RUP3 receptor in an individual comprising
contacting the receptor with a compound of the present invention
wherein the modulation of the RUP3 receptor controls or reduces
weight gain of the individual. In some embodiments the individual
is a mammal. In some embodiments the mammal is a human. In some
embodiments the human has a body mass index of about 18.5 to about
45. In some embodiments the human has a body mass index of about 25
to about 45. In some embodiments the human has a body mass index of
about 30 to about 45. In some embodiments the human has a body mass
index of about 35 to about 45.
[0519] One aspect of the present invention pertains to use of a
compound as described herein, for production of a medicament for
use in treatment of a metabolic-related disorder. In some
embodiments, the metabolic-related disorder is type II diabetes,
inadequate glucose tolerance, insulin resistance, hyperglycemia,
hyperlipidemia, hypertriglyceridemia, hypercholesterolemia,
dyslipidemia or syndrome X.
[0520] One aspect of the present invention pertains to use of a
compound as described herein, for production of a medicament for
use in decreasing food intake of an individual. In some
embodiments, the individual is a mammal. In some embodiments, the
mammal is a human. In some embodiments, the human has a body mass
index of about 18.5 to about 45. In some embodiments, the human has
a body mass index of about 25 to about 45. In some embodiments, the
human has a body mass index of about 30 to about 45. In some
embodiments, the human has a body mass index of about 35 to about
45.
[0521] One aspect of the present invention pertains to use of a
compound as described herein, for production of a medicament for
use of inducing satiety in an individual. In some embodiments, the
individual is a mammal. In some embodiments, the mammal is a human.
In some embodiments, the human has a body mass index of about 18.5
to about 45. In some embodiments, the human has a body mass index
of about 25 to about 45. In some embodiments, the human has a body
mass index of about 30 to about 45. In some embodiments, the human
has a body mass index of about 35 to about 45.
[0522] One aspect of the present invention pertains to use of a
compound as described herein, for production of a medicament for
use in controlling or decreasing weight gain in an individual. In
some embodiments, the individual is a mammal. In some embodiments,
the mammal is a human. In some embodiments, the human has a body
mass index of about 18.5 to about 45. In some embodiments, the
human has a body mass index of about 25 to about 45. In some
embodiments, the human has a body mass index of about 30 to about
45. In some embodiments, the human has a body mass index of about
35 to about 45.
[0523] One aspect of the present invention pertains to a compound,
as described herein, for use in a method of treatment of the human
or animal body by therapy.
[0524] One aspect of the present invention pertains to a compound,
as described herein, for use in a method of treatment of a
metabolic-related disorder of the human or animal body by
therapy.
[0525] One aspect of the present invention pertains to a compound,
as described herein, for use in a method of decreasing food intake
of the human or animal body by therapy.
[0526] One aspect of the present invention pertains to a compound,
as described herein, for use in a method of inducing satiety of the
human or animal body by therapy.
[0527] One aspect of the present invention pertains to a compound,
as described herein, for use in a method of controlling or
decreasing weight gain of the human or animal body by therapy.
Pharmaceutical Compositions
[0528] A further aspect of the present invention pertains to
pharmaceutical compositions comprising one or more compound of the
present invention and one or more pharmaceutically acceptable
carriers. Some embodiments of the present invention pertain to
pharmaceutical compositions comprising a compound of the present
invention and a pharmaceutically acceptable carrier.
[0529] Some embodiments of the present invention include a method
of producing a pharmaceutical composition comprising admixing at
least one compound according to any of the compound embodiments
disclosed herein and a pharmaceutically acceptable carrier.
[0530] Formulations may be prepared by any suitable method,
typically by uniformly mixing the active compound(s) with liquids
or finely divided solid carriers, or both, in the required
proportions, and then, if necessary, forming the resulting mixture
into a desired shape.
[0531] Conventional excipients, such as binding agents, fillers,
acceptable wetting agents, tabletting lubricants, and disintegrants
may be used in tablets and capsules for oral administration. Liquid
preparations for oral administration may be in the form of
solutions, emulsions, aqueous or oily suspensions, and syrups.
Alternatively, the oral preparations may be in the form of dry
powder that can be reconstituted with water or another suitable
liquid vehicle before use. Additional additives such as suspending
or emulsifying agents, non-aqueous vehicles (including edible
oils), preservatives, and flavorings and colorants may be added to
the liquid preparations. Parenteral dosage forms may be prepared by
dissolving the compound of the invention in a suitable liquid
vehicle and filter sterilizing the solution before filling and
sealing an appropriate vial or ampoule. These are just a few
examples of the many appropriate methods well known in the art for
preparing dosage forms.
[0532] A compound of the present invention can be formulated into
pharmaceutical compositions using techniques well known to those in
the art. Suitable pharmaceutically-acceptable carriers, outside
those mentioned herein, are known in the art; for example, see
Remington, The Science and Practice of Pharmacy, 20th Edition,
2000, Lippincott Williams & Wilkins, (Editors: Gennaro, A. R.,
et al.).
[0533] While it is possible that, for use in the prophylaxis or
treatment, a compound of the invention may, in an alternative use,
be administered as a raw or pure chemical, it is preferable however
to present the compound or active ingredient as a pharmaceutical
formulation or composition further comprising a pharmaceutically
acceptable carrier.
[0534] The invention thus further provides pharmaceutical
formulations comprising a compound of the invention or a
pharmaceutically acceptable salt or derivative thereof together
with one or more pharmaceutically acceptable carriers thereof
and/or prophylactic ingredients. The carrier(s) must be
"acceptable" in the sense of being compatible with the other
ingredients of the formulation and not overly deleterious to the
recipient thereof.
[0535] Pharmaceutical formulations include those suitable for oral,
rectal, nasal, topical (including buccal and sub-lingual), vaginal
or parenteral (including intramuscular, sub-cutaneous and
intravenous) administration or in a form suitable for
administration by inhalation, insufflation or by a transdermal
patch. Transdermal patches dispense a drug at a controlled rate by
presenting the drug for absorption in an efficient manner with a
minimum of degradation of the drug. Typically, transdermal patches
comprise an impermeable backing layer, a single pressure sensitive
adhesive and a removable protective layer with a release liner. One
of ordinary skill in the art will understand and appreciate the
techniques appropriate for manufacturing a desired efficacious
transdermal patch based upon the needs of the artisan.
[0536] The compounds of the invention, together with a conventional
adjuvant, carrier, or diluent, may thus be placed into the form of
pharmaceutical formulations and unit dosages thereof, and in such
form may be employed as solids, such as tablets or filled capsules,
or liquids such as solutions, suspensions, emulsions, elixirs, gels
or capsules filled with the same, all for oral use, in the form of
suppositories for rectal administration; or in the form of sterile
injectable solutions for parenteral (including subcutaneous) use.
Such pharmaceutical compositions and unit dosage forms thereof may
comprise conventional ingredients in conventional proportions, with
or without additional active compounds or principles, and such unit
dosage forms may contain any suitable effective amount of the
active ingredient commensurate with the intended daily dosage range
to be employed.
[0537] For oral administration, the pharmaceutical composition may
be in the form of, for example, a tablet, capsule, suspension or
liquid. The pharmaceutical composition is preferably made in the
form of a dosage unit containing a particular amount of the active
ingredient. Examples of such dosage units are capsules, tablets,
powders, granules or a suspension, with conventional additives such
as lactose, mannitol, corn starch or potato starch; with binders
such as crystalline cellulose, cellulose derivatives, acacia, corn
starch or gelatins; with disintegrators such as corn starch, potato
starch or sodium carboxymethyl-cellulose; and with lubricants such
as talc or magnesium stearate. The active ingredient may also be
administered by injection as a composition wherein, for example,
saline, dextrose or water may be used as a suitable
pharmaceutically acceptable carrier.
[0538] Compounds of the present invention or a solvate or
physiologically functional derivative thereof can be used as active
ingredients in pharmaceutical compositions, specifically as RUP3
receptor modulators. By the term "active ingredient" is defined in
the context of a "pharmaceutical composition" and shall mean a
component of a pharmaceutical composition that provides the primary
pharmacological effect, as opposed to an "inactive ingredient"
which would generally be recognized as providing no pharmaceutical
benefit.
[0539] The dose when using the compounds of the present invention
can vary within wide limits, and as is customary and is known to
the physician, it is to be tailored to the individual conditions in
each individual case. It depends, for example, on the nature and
severity of the illness to be treated, on the condition of the
patient, on the compound employed or on whether an acute or chronic
disease state is treated or prophylaxis is conducted or on whether
further active compounds are administered in addition to the
compounds of the present invention. Representative doses of the
present invention include, but not limited to, about 0.001 mg to
about 5000 mg, about 0.001 to about 2500 mg, about 0.001 to about
1000 mg, 0.001 to about 500 mg, 0.001 mg to about 250 mg, about
0.001 mg to 100 mg, about 0.001 mg to about 50 mg, and about 0.001
mg to about 25 mg. Multiple doses may be administered during the
day, especially when relatively large amounts are deemed to be
needed, for example 2, 3 or 4, doses. Depending on the individual
and as deemed appropriate from the patient's physician or
care-giver it may be necessary to deviate upward or downward from
the doses described herein.
[0540] The amount of active ingredient, or an active salt or
derivative thereof, required for use in treatment will vary not
only with the particular salt selected but also with the route of
administration, the nature of the condition being treated and the
age and condition of the patient and will ultimately be at the
discretion of the attendant physician or clinician. In general, one
skilled in the art understands how to extrapolate in vivo data
obtained in a model system, typically an animal model, to another,
such as a human. Typically, animal models include, but are not
limited to, the rodents diabetes models as described in Example 5,
infra (as well as other animal models known in the art, such as
those reported by Reed and Scribner in Diabetes, Obesity and
Metabolism, 1, 1999, 75-86). In some circumstances, these
extrapolations may merely be based on the weight of the animal in
the respective model in comparison to another, such as a mammal,
preferably a human, however, more often, these extrapolations are
not simply based on weights, but rather incorporate a variety of
factors. Representative factors include, but not limited to, the
type, age, weight, sex, diet and medical condition of the patient,
the severity of the disease, the route of administration,
pharmacological considerations such as the activity, efficacy,
pharmacokinetic and toxicology profiles of the particular compound
employed, whether a drug delivery system is utilized, on whether an
acute or chronic disease state is being treated or prophylaxis is
conducted or on whether further active compounds are administered
in addition to the compounds of the Formula (I) and as part of a
drug combination. The dosage regimen for treating a disease
condition with the compounds and/or compositions of this invention
is selected in accordance with a variety factors as cited above.
Thus, the actual dosage regimen employed may vary widely and
therefore may deviate from a preferred dosage regimen and one
skilled in the art will recognize that dosage and dosage regimen
outside these typical ranges can be tested and, where appropriate,
may be used in the methods of this invention.
[0541] The desired dose may conveniently be presented in a single
dose or as divided doses administered at appropriate intervals, for
example, as two, three, four or more sub-doses per day. The
sub-dose itself may be further divided, e.g., into a number of
discrete loosely spaced administrations. The daily dose can be
divided, especially when relatively large amounts are administered
as deemed appropriate, into several, for example 2, 3 or 4, part
administrations. If appropriate, depending on individual behavior,
it may be necessary to deviate upward or downward from the daily
dose indicated.
[0542] The compounds of the present invention can be administrated
in a wide variety of oral and parenteral dosage forms. It will be
obvious to those skilled in the art that the following dosage forms
may comprise, as the active component, either a compound of the
invention or a pharmaceutically acceptable salt of a compound of
the invention.
[0543] For preparing pharmaceutical compositions from the compounds
of the present invention, the selection of a suitable
pharmaceutically acceptable carrier can be either solid, liquid or
a mixture of both. Solid form preparations include powders,
tablets, pills, capsules, cachets, suppositories, and dispersible
granules. A solid carrier can be one or more substances which may
also act as diluents, flavouring agents, solubilizers, lubricants,
suspending agents, binders, preservatives, tablet disintegrating
agents, or an encapsulating material.
[0544] In powders, the carrier is a finely divided solid which is
in a mixture with the finely divided active component.
[0545] In tablets, the active component is mixed with the carrier
having the necessary binding capacity in suitable proportions and
compacted to the desire shape and size.
[0546] The powders and tablets may contain varying percentage
amounts of the active compound. A representative amount in a powder
or tablet may contain from 0.5 to about 90 percent of the active
compound; however, an artisan would know when amounts outside of
this range are necessary. Suitable carriers for powders and tablets
are magnesium carbonate, magnesium stearate, talc, sugar, lactose,
pectin, dextrin, starch, gelatin, tragacanth, methylcellulose,
sodium carboxymethylcellulose, a low melting wax, cocoa butter, and
the like. The term "preparation" is intended to include the
formulation of the active compound with encapsulating material as
carrier providing a capsule in which the active component, with or
without carriers, is surrounded by a carrier, which is thus in
association with it. Similarly, cachets and lozenges are included.
Tablets, powders, capsules, pills, cachets, and lozenges can be
used as solid forms suitable for oral administration.
[0547] For preparing suppositories, a low melting wax, such as an
admixture of fatty acid glycerides or cocoa butter, is first melted
and the active component is dispersed homogeneously therein, as by
stirring. The molten homogenous mixture is then poured into
convenient sized molds, allowed to cool, and thereby to
solidify.
[0548] Formulations suitable for vaginal administration may be
presented as pessaries, tampons, creams, gels, pastes, foams or
sprays containing in addition to the active ingredient such
carriers as are known in the art to be appropriate.
[0549] Liquid form preparations include solutions, suspensions, and
emulsions, for example, water or water-propylene glycol solutions.
For example, parenteral injection liquid preparations can be
formulated as solutions in aqueous polyethylene glycol solution.
Injectable preparations, for example, sterile injectable aqueous or
oleaginous suspensions may be formulated according to the known art
using suitable dispersing or wetting agents and suspending agents.
The sterile injectable preparation may also be a sterile injectable
solution or suspension in a nontoxic parenterally acceptable
diluent or solvent, for example, as a solution in 1,3-butanediol.
Among the acceptable vehicles and solvents that may be employed are
water, Ringer's solution, and isotonic sodium chloride solution. In
addition, sterile, fixed oils are conventionally employed as a
solvent or suspending medium. For this purpose any bland fixed oil
may be employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid find use in the
preparation of injectables.
[0550] The compounds according to the present invention may thus be
formulated for parenteral administration (e.g. by injection, for
example bolus injection or continuous infusion) and may be
presented in unit dose form in ampoules, pre-filled syringes, small
volume infusion or in multi-dose containers with an added
preservative. The pharmaceutical compositions may take such forms
as suspensions, solutions, or emulsions in oily or aqueous
vehicles, and may contain formulatory agents such as suspending,
stabilizing and/or dispersing agents. Alternatively, the active
ingredient may be in powder form, obtained by aseptic isolation of
sterile solid or by lyophilization from solution, for constitution
with a suitable vehicle, e.g. sterile, pyrogen-free water, before
use.
[0551] Aqueous formulations suitable for oral use can be prepared
by dissolving or suspending the active component in water and
adding suitable colorants, flavours, stabilizing and thickening
agents, as desired.
[0552] Aqueous suspensions suitable for oral use can be made by
dispersing the finely divided active component in water with
viscous material, such as natural or synthetic gums, resins,
methylcellulose, sodium carboxymethylcellulose, or other well known
suspending agents.
[0553] Also included are solid form preparations which are intended
to be converted, shortly before use, to liquid form preparations
for oral administration. Such liquid forms include solutions,
suspensions, and emulsions. These preparations may contain, in
addition to the active component, colorants, flavors, stabilizers,
buffers, artificial and natural sweeteners, dispersants,
thickeners, solubilizing agents, and the like.
[0554] For topical administration to the epidermis the compounds
according to the invention may be formulated as ointments, creams
or lotions, or as a transdermal patch.
[0555] Ointments and creams may, for example, be formulated with an
aqueous or oily base with the addition of suitable thickening
and/or gelling agents. Lotions may be formulated with an aqueous or
oily base and will in general also contain one or more emulsifying
agents, stabilizing agents, dispersing agents, suspending agents,
thickening agents, or coloring agents.
[0556] Formulations suitable for topical administration in the
mouth include lozenges comprising active agent in a flavored base,
usually sucrose and acacia or tragacanth; pastilles comprising the
active ingredient in an inert base such as gelatin and glycerin or
sucrose and acacia; and mouthwashes comprising the active
ingredient in a suitable liquid carrier.
[0557] Solutions or suspensions are applied directly to the nasal
cavity by conventional means, for example with a dropper, pipette
or spray. The formulations may be provided in single or multi-dose
form. In the latter case of a dropper or pipette, this may be
achieved by the patient administering an appropriate, predetermined
volume of the solution or suspension. In the case of a spray, this
may be achieved for example by means of a metering atomizing spray
pump.
[0558] Administration to the respiratory tract may also be achieved
by means of an aerosol formulation in which the active ingredient
is provided in a pressurized pack with a suitable propellant. If
the compounds of the Formula (I) or pharmaceutical compositions
comprising them are administered as aerosols, for example as nasal
aerosols or by inhalation, this can be carried out, for example,
using a spray, a nebulizer, a pump nebulizer, an inhalation
apparatus, a metered inhaler or a dry powder inhaler.
Pharmaceutical forms for administration of the compounds of the
Formula (I) as an aerosol can be prepared by processes well-known
to the person skilled in the art. For their preparation, for
example, solutions or dispersions of the compounds of the Formula
(I) in water, water/alcohol mixtures or suitable saline solutions
can be employed using customary additives, for example benzyl
alcohol or other suitable preservatives, absorption enhancers for
increasing the bioavailability, solubilizers, dispersants and
others, and, if appropriate, customary propellants, for example
include carbon dioxide, CFC's, such as, dichlorodifluoromethane,
trichlorofluoromethane, or dichlorotetrafluoroethane; and the like.
The aerosol may conveniently also contain a surfactant such as
lecithin. The dose of drug may be controlled by provision of a
metered valve.
[0559] In formulations intended for administration to the
respiratory tract, including intranasal formulations, the compound
will generally have a small particle size for example of the order
of 10 microns or less. Such a particle size may be obtained by
means known in the art, for example by micronization. When desired,
formulations adapted to give sustained release of the active
ingredient may be employed.
[0560] Alternatively the active ingredients may be provided in the
form of a dry powder, for example, a powder mix of the compound in
a suitable powder base such as lactose, starch, starch derivatives
such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone
(PVP). Conveniently the powder carrier will form a gel in the nasal
cavity. The powder composition may be presented in unit dose form
for example in capsules or cartridges of, e.g., gelatin, or blister
packs from which the powder may be administered by means of an
inhaler.
[0561] The pharmaceutical preparations are preferably in unit
dosage forms. In such form, the preparation is subdivided into unit
doses containing appropriate quantities of the active component.
The unit dosage form can be a packaged preparation, the package
containing discrete quantities of preparation, such as packeted
tablets, capsules, and powders in vials or ampoules. Also, the unit
dosage form can be a capsule, tablet, cachet, or lozenge itself, or
it can be the appropriate number of any of these in packaged
form.
[0562] Tablets or capsules for oral administration and liquids for
intravenous administration are preferred compositions.
[0563] The compounds according to the invention may optionally
exist as pharmaceutically acceptable salts including
pharmaceutically acceptable acid addition salts prepared from
pharmaceutically acceptable non-toxic acids including inorganic and
organic acids. Representative acids include, but are not limited
to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,
ethenesulfonic, dichloroacetic, formic, fumaric, gluconic,
glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic,
maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic,
pamoic, pantothenic, phosphoric, succinic, sulfiric, tartaric,
oxalic, p-toluenesulfonic and the like, such as those
pharmaceutically acceptable salts listed in Journal of
Pharmaceutical Science, 66, 2 (1977); incorporated herein by
reference in its entirety.
[0564] The acid addition salts may be obtained as the direct
products of compound synthesis. In the alternative, the free base
may be dissolved in a suitable solvent containing the appropriate
acid, and the salt isolated by evaporating the solvent or otherwise
separating the salt and solvent. The compounds of this invention
may form solvates with standard low molecular weight solvents using
methods known to the skilled artisan.
[0565] Compounds of the present invention can be converted to
"pro-drugs." The term "pro-drugs" refers to compounds that have
been modified with specific chemical groups known in the art and
when administered into an individual these groups undergo
biotransformation to give the parent compound. Pro-drugs can thus
be viewed as compounds of the invention containing one or more
specialized non-toxic protective groups used in a transient manner
to alter or to eliminate a property of the compound. In one general
aspect, the "pro-drug" approach is utilized to facilitate oral
absorption. A thorough discussion is provided in T. Higuchi and V.
Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the
A.C.S. Symposium Series; and in Bioreversible Carriers in Drug
Design, ed. Edward B. Roche, American Pharmaceutical Association
and Pergamon Press, 1987, both of which are hereby incorporated by
reference in their entirety.
[0566] Some embodiments of the present invention include a method
of producing a pharmaceutical composition for "combination-therapy"
comprising admixing at least one compound according to any of the
compound embodiments disclosed herein, together with at least one
known pharmaceutical agent as described herein and a
pharmaceutically acceptable carrier.
[0567] In some embodiments the pharmaceutical agents is selected
from the group consisting of: apolipoprotein-B secretion/microsomal
triglyceride transfer protein (apo-B/MTP) inhibitors, MCR-4
agonists, cholescystokinin-A (CCK-A) agonists, serotonin and
norepinephrine reuptake inhibitors (for example, sibutramine),
sympathomimetic agents, .beta..sub.3 adrenergic receptor agonists,
dopamine agonists (for example, bromocriptine),
melanocyte-stimulating hormone receptor analogs, cannabinoid 1
receptor antagonists [for example, SR141716:
N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H--
pyrazole-3-carboxamide], melanin concentrating hormone antagonists,
leptons (the OB protein), leptin analogues, leptin receptor
agonists, galanin antagonists, lipase inhibitors (such as
tetrahydrolipstatin, i.e., Orlistat), anorectic agents (such as a
bombesin agonist), Neuropeptide-Y antagonists, thyromimetic agents,
dehydroepiandrosterone or an analogue thereof, glucocorticoid
receptor agonists or antagonists, orexin receptor antagonists,
urocortin binding protein antagonists, glucagon-like peptide-1
receptor agonists, ciliary neutrotrophic factors (such as
Axokine.TM.), human agouti-related proteins (AGRP), ghrelin
receptor antagonists, histamine 3 receptor antagonists or reverse
agonists, neuromedin U receptor agonists, noradrenergic anorectic
agents (for example, phentermine, mazindol and the like), appetite
suppressants (for example, bupropion) and the like. In further
embodiments, the pharmaceutical agent is selected from the group
consisting of orlistat, sibutramine, bromocriptine, ephedrine,
leptin, and pseudoephedrine.
[0568] In some embodiments the pharmaceutical agents is selected
from the group consisting of: sulfonylureas, meglitinides,
biguanides, .alpha.-glucosidase inhibitors, peroxisome
proliferators-activated receptor-.gamma. (i.e., PPAR-.gamma.)
agonists, insulin, insulin analogues, HMG-CoA reductase inhibitors,
cholesterol-lowering drugs (for example, fibrates that include:
fenofibrate, bezafibrate, gemfibrozil, clofibrate and the like;
bile acid sequestrants which include: cholestyramine, colestipol
and the like; and niacin), antiplatelet agents (for example,
aspirin and adenosine diphosphate receptor antagonists that
include: clopidogrel, ticlopidine and the like),
angiotensin-converting enzyme inhibitors, angiotensin II receptor
antagonists and adiponectin.
[0569] It is noted that when the RUP3 receptor modulators are
utilized as active ingredients in a pharmaceutical composition,
these are not intended for use only in humans, but in other
non-human mammals as well. Indeed, recent advances in the area of
animal health-care mandate that consideration be given for the use
of active agents, such as RUP3 receptor modulators, for the
treatment of obesity in domestic animals (e.g., cats and dogs), and
RUP3 receptor modulators in other domestic animals where no disease
or disorder is evident (e.g., food-oriented animals such as cows,
chickens, fish, etc.). Those of ordinary skill in the art are
readily credited with understanding the utility of such compounds
in such settings.
Combination Therapy--Prophylaxis and Treatment
[0570] In the context of the present invention, a compound as
desribed herein or pharmaceutical composition thereof can be
utilized for modulating the activity of RUP3 receptor mediated
diseases, conditions and/or disorders as described herein. Examples
of modulating the activity of RUP3 receptor mediated diseases
include the prophylaxis or treatment of metabolic related disorders
such as, but not limited to, type I diabetes, type II diabetes,
inadequate glucose tolerance, insulin resistance, hyperglycemia,
hyperlipidemia, hypertriglyceridemia, hypercholesterolemia,
dyslipidemia and syndrome X. Other examples of modulating the
activity of RUP3 receptor mediated diseases include the prophylaxis
or treatment of obesity and/or overweight by decreasing food
intake, inducing satiation (i.e., the feeling of fullness),
controlling weight gain, decreasing body weight and/or affecting
metabolism such that the recipient loses weight and/or maintains
weight.
[0571] While the compounds of the invention can be administered as
the sole active pharmaceutical agent (i.e., mono-therapy), they can
also be used in combination with other pharmaceutical agents (i.e.,
combination-therapy) for the treatment of the
diseases/conditions/disorders described herein. Therefore, another
aspect of the present invention includes methods of prophylaxis
and/or treatment of a metabolic related disorder or a weight
related disorder, such as obesity, comprising administering to an
individual in need of prophylaxis and/or treatment a
therapeutically effective amount of a compound of the present
invention, for example Formula (I), in combination with one or more
additional pharmaceutical agent as described herein.
[0572] Suitable pharmaceutical agents that can be used in
combination with the compounds of the present invention include
anti-obesity agents such as apolipoprotein-B secretion/microsomal
triglyceride transfer protein (apo-B/MTP) inhibitors, MCR-4
agonists, cholescystokinin-A (CCK-A) agonists, serotonin and
norepinephrine reuptake inhibitors (for example, sibutramine),
sympathomimetic agents, .beta.3 adrenergic receptor agonists,
dopamine agonists (for example, bromocriptine),
melanocyte-stimulating hormone receptor analogs, cannabinoid 1
receptor antagonists [for example, SR141716:
N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H--
pyrazole-3-carboxamide], melanin concentrating hormone antagonists,
leptons (the OB protein), leptin analogues, leptin receptor
agonists, galanin antagonists, lipase inhibitors (such as
tetrahydrolipstatin, i.e., Orlistat), anorectic agents (such as a
bombesin agonist), Neuropeptide-Y antagonists, thyromimetic agents,
dehydroepiandrosterone or an analogue thereof, glucocorticoid
receptor agonists or antagonists, orexin receptor antagonists,
urocortin binding protein antagonists, glucagon-like peptide-1
receptor agonists, ciliary neutrotrophic factors (such as
Axokine.TM. available from Regeneron Pharmaceuticals, Inc.,
Tarrytown, N.Y. and Procter & Gamble Company, Cincinnati,
Ohio), human agouti-related proteins (AGRP), ghrelin receptor
antagonists, histamine 3 receptor antagonists or reverse agonists,
neuromedin U receptor agonists, noradrenergic anorectic agents (for
example, phentermine, mazindol and the like) and appetite
suppressants (for example, bupropion).
[0573] Other anti-obesity agents, including the agents set forth
infra, are well known, or will be readily apparent in light of the
instant disclosure, to one of ordinary skill in the art.
[0574] In some embodiments, the anti-obesity agents are selected
from the group consisting of orlistat, sibutramine, bromocriptine,
ephedrine, leptin, and pseudoephedrine. In a further embodiment,
compounds of the present invention and combination therapies are
administered in conjunction with exercise and/or a sensible
diet.
[0575] It will be understood that the scope of combination-therapy
of the compounds of the present invention with other anti-obesity
agents, anorectic agents, appetite suppressant and related agents
is not limited to those listed above, but includes in principle any
combination with any pharmaceutical agent or pharmaceutical
composition useful for the treatment of overweight and obese
individuals.
[0576] Other suitable pharmaceutical agents, in addition to
anti-obesity agents, that can be used in combination with the
compounds of the present invention include agents useful in the
treatment of metabolic related disorders and/or concomitant
diseases thereof. For example, but not limited to, congestive heart
failure, type I diabetes, type II diabetes, inadequate glucose
tolerance, insulin resistance, hyperglycemia, hyperlipidemia,
hypertriglyceridemia, hypercholesterolemia, dyslipidemia, syndrome
X, retinopathy, nephropathy and neuropathy. Prophylaxis or
treatment of one or more of the diseases cited herein include the
use of one or more pharmaceutical agents known in the art belonging
to the classes of drugs referred to, but not limited to, the
following: sulfonylureas, meglitinides, biguanides,
.alpha.-glucosidase inhibitors, peroxisome proliferators-activated
receptor-.gamma. (i.e., PPAR-.gamma.) agonists, insulin, insulin
analogues, HMG-CoA reductase inhibitors, cholesterol-lowering drugs
(for example, fibrates that include: fenofibrate, bezafibrate,
gemfibrozil, clofibrate and the like; bile acid sequestrants which
include: cholestyramine, colestipol and the like; and niacin),
antiplatelet agents (for example, aspirin and adenosine diphosphate
receptor antagonists that include: clopidogrel, ticlopidine and the
like), angiotensin-converting enzyme inhibitors, angiotensin II
receptor antagonists, adiponectin and the like. In accordance to
one aspect of the present invention, a compound of the present can
be used in combination with a pharmaceutical agent or agents
belonging to one or more of the classes of drugs cited herein.
[0577] It will be understood that the scope of combination-therapy
of the compounds of the present invention with other pharmaceutical
agents is not limited to those listed herein, supra or infra, but
includes in principle any combination with any pharmaceutical agent
or pharmaceutical composition useful for the prophylaxis or
treatment of diseases, conditions or disorders that are linked to
metabolic related disorders.
[0578] Some embodiments of the present invention include methods of
prophylaxis or treatment of a disease, disorder, condition or
complication thereof as described herein, comprising administering
to an individual in need of such prophylaxis or treatment a
therapeutically effective amount or dose of a compound of the
present invention in combination with at least one pharmaceutical
agent selected from the group consisting of: sulfonylureas,
meglitinides, biguanides, .alpha.-glucosidase inhibitors,
peroxisome proliferators-activated receptor-.gamma. (i.e.,
PPAR-.gamma.) agonists, insulin, insulin analogues, HMG-CoA
reductase inhibitors, cholesterol-lowering drugs (for example,
fibrates that include: fenofibrate, bezafibrate, gemfibrozil,
clofibrate and the like; bile acid sequestrants which include:
cholestyramine, colestipol and the like; and niacin), antiplatelet
agents (for example, aspirin and adenosine diphosphate receptor
antagonists that include: clopidogrel, ticlopidine and the like),
angiotensin-converting enzyme inhibitors, angiotensin II receptor
antagonists and adiponectin. In some embodiments, methods of the
present invention include compounds of the present invention and
the pharmaceutical agents are administered separately. In further
embodiments, compounds of the present invention and the
pharmaceutical agents are administered together.
[0579] Suitable pharmaceutical agents that can be used in
conjunction with compounds of the present invention include
sulfonylureas. The sulfonylureas (SU) are drugs which promote
secretion of insulin from pancreatic .beta. cells by transmitting
signals of insulin secretion via SU receptors in the cell
membranes. Examples of the sulfonylureas include glyburide,
glipizide, glimepiride and other sulfonylureas known in the
art.
[0580] Suitable pharmaceutical agents that can be used in
conjunction with compounds of the present invention include the
meglitinides. The meglitinides are benzoic acid derivatives
represent a novel class of insulin secretagogues. These agents
target postprandial hyperglycemia and show comparable efficacy to
sulfonylureas in reducing HbA1c. Examples of meglitinides include
repaglinide, nateglinide and other meglitinides known in the
art.
[0581] Suitable pharmaceutical agents that can be used in
conjunction with compounds of the present invention include the
biguanides. The biguanides represent a class of drugs that
stimulate anaerobic glycolysis, increase the sensitivity to insulin
in the peripheral tissues, inhibit glucose absorption from the
intestine, suppress of hepatic gluconeogenesis, and inhibit fatty
acid oxidation. Examples of biguanides include phenformin,
metformin, buformin, and biguanides known in the art.
[0582] Suitable pharmaceutical agents that can be used in
conjunction with compounds of the present invention include the
.alpha.-glucosidase inhibitors. The .alpha.-glucosidase inhibitors
competitively inhibit digestive enzymes such as .alpha.-amylase,
maltase, .alpha.-dextrinase, sucrase, etc. in the pancreas and or
small intestine. The reversible inhibition by .alpha.-glucosidase
inhibitors retard, diminish or otherwise reduce blood glucose
levels by delaying the digestion of starch and sugars. Examples of
.alpha.-glucosidase inhibitors include acarbose,
N-(1,3-dihydroxy-2-propyl)valiolamine (generic name; voglibose),
miglitol, and .alpha.-glucosidase inhibitors known in the art.
[0583] Suitable pharmaceutical agents that can be used in
conjunction with compounds of the present invention include the
peroxisome proliferators-activated receptor-.gamma. (i.e.,
PPAR-.gamma.) agonists. The peroxisome proliferators-activated
receptor-.gamma. agonists represent a class of compounds that
activates the nuclear receptor PPAR-.gamma. and therefore regulate
the transcription of insulin-responsive genes involved in the
control of glucose production, transport and utilization. Agents in
the class also facilitate the regulation of fatty acid metabolism.
Examples of PPAR-.gamma. agonists include rosiglitazone,
pioglitazone, tesaglitazar, netoglitazone, GW-409544, GW-501516 and
PPAR-.gamma. agonists known in the art.
[0584] Suitable pharmaceutical agents that can be used in
conjunction with compounds of the present invention include the
HMG-CoA reductase inhibitors. The HMG-CoA reductase inhibitors are
agents also referred to as Statin compounds that belong to a class
of drugs that lower blood cholesterol levels by inhibiting
hydroxymethylglutalyl CoA (HMG-CoA) reductase. HMG-CoA reductase is
the rate-limiting enzyme in cholesterol biosynthesis. The statins
lower serum LDL concentrations by upregulating the activity of LDL
receptors and are responsible for clearing LDL from the blood. Some
representative examples the statin compounds include rosuvastatin,
pravastatin and its sodium salt, simvastatin, lovastatin,
atorvastatin, fluvastatin, cerivastatin, rosuvastatin,
pitavastatin, BMS's "superstatin", and HMG-CoA reductase inhibitors
known in the art.
[0585] Suitable pharmaceutical agents that can be used in
conjunction with compounds of the present invention include the
Fibrates. Fibrate compounds belong to a class of drugs that lower
blood cholesterol levels by inhibiting synthesis and secretion of
triglycerides in the liver and activating a lipoprotein lipase.
Fibrates have been known to activate peroxisome
proliferators-activated receptors and induce lipoprotein lipase
expression. Examples of fibrate compounds include bezafibrate,
beclobrate, binifibrate, ciplofibrate, clinofibrate, clofibrate,
clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate,
pirifibrate, ronifibrate, simfibrate, theofibrate, and fibrates
known in the art.
[0586] Suitable pharmaceutical agents that can be used in
conjunction with compounds of the present invention include the
angiotensin converting enzyme (ACE) inhibitors. The angiotensin
converting enzyme inhibitors belong to the class of drugs that
partially lower blood glucose levels as well as lowering blood
pressure by inhibiting angiotensin converting enzymes. Examples of
the angiotensin converting enzyme inhibitors include captopril,
enalapril, alacepril, delapril; ramipril, lisinopril, imidapril,
benazepril, ceronapril, cilazapril, enalaprilat, fosinopril,
moveltopril, perindopril, quinapril, spirapril, temocapril,
trandolapril, and angiotensin converting enzyme inhibitors known in
the art.
[0587] Suitable pharmaceutical agents that can be used in
conjunction with compounds of the present invention include the
angiotensin II receptor antagonists. Angiotensin II receptor
antagonists target the angiotensin II receptor subtype 1 (i.e.,
AT1) and demonstrate a beneficial effect on hypertension. Examples
of angiotensin II receptor antagonists include losartan (and the
potassium salt form), and angiotensin II receptor antagonists known
in the art.
[0588] Other treatments for one or more of the diseases cited
herein include the use of pharmaceutical agents known in the art
belonging to the classes of drugs referred to, but not limited to,
the following: amylin agonists (for example, pramlintide), insulin
secretagogues (for example, GLP-1 agonists; exendin-4;
insulinotropin (NN2211); dipeptyl peptidase inhibitors (for
example, NVP-DPP-728), acyl CoA cholesterol acetyltransferase
inhibitors (for example, Ezetimibe, eflucimibe, and like
compounds), cholesterol absorption inhibitors (for example,
ezetimibe, pamaqueside and like compounds), cholesterol ester
transfer protein inhibitors (for example, CP-529414, JTT-705,
CETi-1, and like compounds), microsomal triglyceride transfer
protein inhibitors (for example, implitapide, and like compounds),
cholesterol modulators (for example, NO-1886, and like compounds),
bile acid modulators (for example, GT103-279 and like compounds)
and squalene synthase inhibitors.
[0589] Squalene synthesis inhibitors belong to a class of drugs
that lower blood cholesterol levels by inhibiting synthesis of
squalene. Examples of the squalene synthesis inhibitors include
(S)-.alpha.-[Bis[2,2-dimethyl-1-oxopropoxy)methoxy]
phosphinyl]-3-phenoxybenzenebutanesulfonic acid, mono potassium
salt (BMS-188494) and squalene synthesis inhibitors known in the
art.
[0590] In accordance with the present invention, the combination
can be used by mixing the respective active components either all
together or independently with a physiologically acceptable
carrier, excipient, binder, diluent, etc., as described herein
above, and administering the mixture or mixtures either orally or
non-orally as a pharmaceutical composition. When a compound or a
mixture of compounds of Formula (I) are administered as a
combination therapy with another active compound the therapeutic
agents can be formulated as a separate pharmaceutical compositions
given at the same time or at different times, or the therapeutic
agents can be given as a single composition.
Other Utilities
[0591] Another object of the present invention relates to
radio-labeled compounds of Formula (I) that would be useful not
only in radio-imaging but also in assays, both in vitro and in
vivo, for localizing and quantitating the RUP3 receptor in tissue
samples, including human, and for identifying RUP3 receptor ligands
by inhibition binding of a radio-labeled compound. It is a further
object of this invention to develop novel RUP3 receptor assays of
which comprise such radio-labeled compounds.
[0592] The present invention embraces isotopically-labeled
compounds of Formula (I) and any subgenera herein, such as but not
limited to, Formula (Ia) through Formula (IIIo). An "isotopically"
or "radio-labeled" compounds are those which are identical to
compounds disclosed herein, but for the fact that one or more atoms
are replaced or substituted by an atom having an atomic mass or
mass number different from the atomic mass or mass number typically
found in nature (i.e., naturally occurring). Suitable radionuclides
that may be incorporated in compounds of the present invention
include but are not limited to .sup.2H (also written as D for
deuterium), .sup.3H (also written as T for tritium), .sup.11C,
.sup.13C, .sup.14C, .sup.13N, .sup.15N, .sup.15O, .sup.17O,
.sup.18O, .sup.18F, .sup.35S, .sup.36Cl, .sup.82Br, .sup.75Br,
.sup.76Br, .sup.77Br, .sup.123I, .sup.124I, .sup.125I and
.sup.131I. The radionuclide that is incorporated in the instant
radio-labeled compounds will depend on the specific application of
that radio-labeled compound. For example, for in vitro RUP3
receptor labeling and competition assays, compounds that
incorporate .sup.3H, .sup.14C, .sup.82Br, .sup.125I, .sup.131I,
.sup.35S or will generally be most useful. For radio-imaging
applications .sup.11C, .sup.18F, .sup.125I, .sup.123I, .sup.124I,
.sup.131I, .sup.75Br, .sup.76Br or .sup.77Br will generally be most
useful.
[0593] It is understood that a "radio-labeled" or "labeled
compound" is a compound of the present invention that has
incorporated at least one radionuclide; in some embodiments the
radionuclide is selected from the group consisting of .sup.3H,
.sup.14C, .sup.125I, .sup.35S and .sup.82Br.
[0594] Certain isotopically-labeled compounds of the present
invention are useful in compound and/or substrate tissue
distribution assays. In some embodiments the radionuclide .sup.3H
and/or .sup.14C isotopes are useful in these studies. Further,
substitution with heavier isotopes such as deuterium (i.e.,
.sup.2H) may afford certain therapeutic advantages resulting from
greater metabolic stability (e.g., increased in vivo half-life or
reduced dosage requirements) and hence may be preferred in some
circumstances. Isotopically labeled compounds of the present
invention can generally be prepared by following procedures
analogous to those disclosed in the Schemes supra and Examples
infra, by substituting an isotopically labeled reagent for a
non-isotopically labeled reagent. Other synthetic methods that are
useful are discussed infra. Moreover, it should be understood that
all of the atoms represented in the compounds of the invention can
be either the most commonly occurring isotope of such atoms or the
more scarce radio-isotope or nonradio-active isotope.
[0595] Synthetic methods for incorporating radio-isotopes into
organic compounds are applicable to compounds of the invention and
are well known in the art. These synthetic methods, for example,
incorporating activity levels of tritium into target molecules, are
as follows:
[0596] A. Catalytic Reduction with Tritium Gas--This procedure
normally yields high specific activity products and requires
halogenated or unsaturated precursors.
[0597] B. Reduction with Sodium Borohydride [.sup.3H]--This
procedure is rather inexpensive and requires precursors containing
reducible functional groups such as aldehydes, ketones, lactones,
esters, and the like.
[0598] C. Reduction with Lithium Aluminum Hydride [.sup.3H ]--This
procedure offers products at almost theoretical specific
activities. It also requires precursors containing reducible
functional groups such as aldehydes, ketones, lactones, esters, and
the like.
[0599] D. Tritium Gas Exposure Labeling--This procedure involves
exposing precursors containing exchangeable protons to tritium gas
in the presence of a suitable catalyst.
[0600] E. N-Methylation using Methyl Iodide [.sup.3H]--This
procedure is usually employed to prepare O-methyl or N-methyl
(.sup.3H) products by treating appropriate precursors with high
specific activity methyl iodide (.sup.3H). This method in general
allows for higher specific activity, such as for example, about
70-90 Ci/mmol.
[0601] Synthetic methods for incorporating activity levels of
.sup.125I into target molecules include:
[0602] A. Sandmeyer and like reactions--This procedure transforms
an aryl or heteroaryl amine into a diazonium salt, such as a
tetrafluoroborate salt, and subsequently to .sup.125I labeled
compound using Na.sup.125I. A represented procedure was reported by
Zhu, D.-G. and co-workers in J. Org. Chem. 2002, 67, 943-948.
[0603] B. Ortho .sup.125Iodination of phenols--This procedure
allows for the incorporation of .sup.125I at the ortho position of
a phenol as reported by Collier, T. L. and co-workers in J. Labeled
Compd Radiopharm. 1999, 42, S264-S266.
[0604] C. Aryl and heteroaryl bromide exchange with .sup.125I--This
method is generally a two step process. The first step is the
conversion of the aryl or heteroaryl bromide to the corresponding
tri-alkyltin intermediate using for example, a Pd catalyzed
reaction [i.e. Pd(Ph.sub.3P)4] or through an aryl or heteroaryl
lithium, in the presence of a tri-alkyltinhalide or hexaalkylditin
[e.g., (CH.sub.3).sub.3SnSn(CH.sub.3).sub.3]. A represented
procedure was reported by Bas, M.-D. and co-workers in J. Labeled
Compd Radiopharm. 2001, 44, S280-S282.
[0605] A radio-labeled RUP3 receptor compound of the present
invention can be used in a screening assay to identify/evaluate
compounds. In general terms, a newly synthesized or identified
compound (i.e., test compound) can be evaluated for its ability to
reduce binding of the "radio-labeled compound of the present
invention" to the RUP3 receptor. Accordingly, the ability of a test
compound to compete with the "radio-labeled compound of the present
invention" for the binding to the RUP3 receptor directly correlates
to its binding affinity.
[0606] The labeled compounds of the present invention bind to the
RUP3 receptor. In one embodiment the labeled compound has an
IC.sub.50 less than about 500 .mu.M, in another embodiment the
labeled compound has an IC.sub.50 less than about 100 .mu.M, in yet
another embodiment the labeled compound has an IC.sub.50 less than
about 10 .mu.M, in yet another embodiment the labeled compound has
an IC.sub.50 less than about 1 .mu.M, and in still yet another
embodiment the labeled inhibitor has an IC.sub.50 less than about
0.1 .mu.M.
[0607] Other uses of the disclosed receptors and methods will
become apparent to those in the art based upon, inter alia, a
review of this disclosure.
[0608] As will be recognized, the steps of the methods of the
present invention need not be performed any particular number of
times or in any particular sequence. Additional objects,
advantages, and novel features of this invention will become
apparent to those skilled in the art upon examination of the
following examples thereof, which are intended to be illustrative
and not intended to be limiting.
EXAMPLES
[0609] The examples are provided to further define the invention
without, however, limiting the invention to the specifics of these
examples.
Example 1
96-well Cyclic AMP Membrane Assay for RUP3
Materials:
[0610] 1) Adenlyl cyclase Activation Flashplate Assay kit from
Perkin Elmer--96 wells (SMP004B) and .sup.125I tracer (NEX130)
which comes with the kit. Keep in refrigerator, in a box, and do
not expose the Flashplates to light. [0611] 2)
Phosphocreatine--Sigma P-7936 [0612] 3) Creatine
Phosphokinase--Sigma C-3755 [0613] 4) GTP--Sigma G-8877 [0614] 5)
ATP--Sigma A-2383 [0615] 6) IBMX--Sigma I-7018 [0616] 7) Hepes--1M
solution in distilled water--Gibco #15630080 [0617] 8) MgCl2--Sigma
M-1028--1M Solution [0618] 9) NaCl--Sigma--S6546--5M Solution
[0619] 10) Bradford Protein Assay Kit--Biorad # 5000001 [0620] 11)
Proclin 300--Sigma #4-8126
[0621] Binding Buffer--filter through 45-micron Nalgene filter and
keep in refrigerator. All buffers and membranes should be kept cold
(in ice bucket) while performing assay. [0622] 20 mM Hepes, pH7.4
[0623] 1 mM MgCl2 [0624] 100 mM NaCl
[0625] 2.times. Regeneration Buffer (make in binding buffer):
[0626] 20 mM Phosphocreatine (1.02 gm/200 mL binding buffer) [0627]
20 units Creatine phosphokinase (4 mg/200 mL) [0628] 20 .mu.M GTP
(make up 10.46 mg/mL in binding buffer and add 200 .mu.L/200 mL)
[0629] 0.2 mM ATP (22.04 mg/200 mL) [0630] 100 mM IBMX (44.4 mg
IBMX dissolved in 1 mL 100% DMSO first and then add the entire
amount to [0631] 200 mL of buffer).
[0632] Regeneration buffer can be aliquotted into 40-45 mL portions
(in 50 mL sterile tubes) and kept frozen for up to 2 months. Simply
put the tube in a beaker with room temperature water to thaw out
the regeneration buffer on the day of the assay.
A. Assay Procedure
[0633] 1) Pipet 50 .mu.L regeneration buffer in all 96 wells using
Matrix 1250 8-channel pipettor. [0634] 2) Pipet 5 .mu.L DMSO in
columns 1 and columns 11 and 12. [0635] 3) Pipet 50 .mu.L cAMP
standards in columns 11 and 12 in this format: 50 pmole/well for
row A, 25 pmole/well for row B, 12.5 pmol/well for row C, 5
picomol/well for row D, 2.5 pmole/well for row E, 1.25 pmole/well
for row F, 0.5 pmole/well for row G, and 0 pmole/well (buffer only)
for row H. [0636] 4) Pipet 5 .mu.L compounds from each well of a
compound dilution plate, for IC50s, using the following dilution
scheme: [0637] Well H: 400 .mu.M compound (final concentration of
compound in reaction mix=5/100.times.400 .mu.M=20 .mu.M [0638] Well
G: 1:10 dilution of Well H (i.e. 5 .mu.L compound from well H+45
.mu.L 100% DMSO) (final concentration=2 .mu.M) [0639] Well F: 1:10
dilution of well G (final concentration=0.2 .mu.M) [0640] Well E:
1:10 dilution of well F (final concentration=0.02 .mu.M) [0641]
Well D: 1:10 dilution of well E (final concentration=0.002 .mu.M)
[0642] Well C: 1:10 dilution of well D (final concentration=0.0002
.mu.M) [0643] Well B: 1:10 dilution of well C (final
concentration=0.00002 .mu.M) [0644] Well A: 1:10 dilution of well B
(final concentration=0.000002 .mu.M) [0645] IC.sub.50s or
EC.sub.50s are done in triplicate. One Flashplate can therefore be
set up to handle 3 compounds. (i.e., columns 2, 3, and 4 are for
compound #1, columns 5, 6, and 7 are for compound #2, and columns
8, 9, and 10 are for compound #3.) [0646] 5) Add 50 .mu.L of RUP3
membranes to all wells in Columns 2 to 10. (Prior to the start of
the assay, the frozen membrane pellets for both RUP3 and CMV (cells
transfected with an expression plasmid containing no RUP3
sequences), are suspended in binding buffer, usually 1 mL binding
buffer for 1 plate of membranes. The membranes are kept in ice all
the time, and a polytron (Brinkmann polytron, model # PT-3100) is
used (setting 6-7, for 15-20 seconds) to obtain a homogeneous
membrane suspension.) Protein concentration is determined by
Bradford protein assay kit using instructions given in the kit,
using the standard supplied with the kit as a reference. The
protein concentration of the membranes is adjusted with binding
buffer, so that 50 .mu.L membranes=15 ug protein (i.e. 0.3 mg/mL
protein). [0647] 6) In column 1, Wells A, B, C, and D, add 50 .mu.L
RUP3 membranes. To wells E, F, G, and H, add 50 .mu.L CMV
membranes, (CMV membranes being of the same protein concentration
as the RUP3 membranes). [0648] 7) Incubate 1 hour at room
temperature with agitation on a rotating platform shaker. Cover
with foil while shaking. [0649] 8) After 1 hour, add (to all 96
wells), 100 .mu.L of the .sup.125I tracer in detection buffer
supplied with the Flashplate kit plus proclin, made up in the
following manner: [0650] Pipet per 10 mL per Flashplate: 100 mL of
detection buffer+1 mL .sup.125I+0.2 mL of Proclin (the proclin
helps to stop the production of cAMP). Make a smaller quantity of
detection buffer mix if you have fewer plates. [0651] 9) Shake the
plates on a rotating platform shaker for 2 hours, covering the
plates with lead sheeting. [0652] 10) Seal the plates with the
plastic film sealers provided with the Flashplate kit. [0653] 11)
Count the plates using a TRILUX 1450 Microbeta Counter. See the
door of the counter to determine which counting protocol to use.
[0654] 12) Data is analyzed on the Arena Database according to the
RUP3 non-fusion, IC.sub.50 EC.sub.50 for 96-well cAMP membrane
assay, and the compound numbers and the concentrations of compounds
must be entered by the user. B. Membrane Cyclase Criteria
[0655] 1) Signal to Noise: [0656] An acceptable signal-to-noise
ratio for RUP3 can vary from 4 to 6. The raw cpms are approximately
1800 to 2500 for RUP3 and 3500-4500 for CMV. The cpm (or ultimately
pmoles of cAMP/well) cannot be outside the standard curve, and
should not approach well A of the standard curve (50 pmole/well)
and well H (no cAMP). Generally, the pmoles of cAMP produced by
RUP3 receptor are around 11 to 13 pmole/well (for 15 ug/well
protein), and for CMV are between 2 to 3 pmole/well (for 15 ug
protein/well).
[0657] 2) Standard Curve: [0658] The slope should be linear and the
error bars for duplicates should be very small. The receptor and
CMV controls cannot be off scale of the standard curve, as
described above. If the receptor controls are off the high end of
the standard curve,i.e. 50 pmole/well or higher, one must repeat
the experiment using less protein. However, such a case has not
been observed with transiently transfected RUP3 membranes (10 ug
DNA/15 cm plate, using 60 .mu.L Lipofectamine, and preparing
membranes after 24 hour of transfection.)
[0659] 3) The IC.sub.50 or EC.sub.50 curve should be at 100% (+ or
- 20%) of control RUP3 membranes at the top, and should go down to
0 (or up to 20%) at the bottom. The standard error of the
triplicate determinations should be + or - 10%.
C. Stimulation of cAMP in HIT-T15 Cells
[0660] HIT-T15 (ATCC CRL#1777) is an immortalized hamster
insulin-producing cell line. These cells express RUP3 and therefore
can be used to assess the ability of RUP3 ligands to stimulate or
inhibit cAMP accumulation via its endogenously expressed receptor.
In this assay, cells are grown to 80% confluence and then
distributed into a 96-well Flashplate (50,000 cells/ well) for
detection of cAMP via a "cAMP Flashplate Assay" (NEN, Cat #
SMP004). Briefly, cells are placed into anti-cAMP antibody-coated
wells that contain either vehicle, the test ligand(s) at a
concentration of interest, or 1 .mu.M forskolin. The latter is a
direct activator of adenylyl cyclase and serves as a positive
control for stimulation of cAMP in HIT-T15 cells. All conditions
are tested in triplicate. After a 1 hour incubation to allow for
stimulation of cAMP, a Detection Mix containing .sup.125I-cAMP is
added to each well and the plate is allowed to incubate for another
1 hour. The wells are then aspirated to remove unbound
.sup.125I-cAMP. Bound .sup.125I-cAMP is detected using a Wallac
Microbeta Counter. The amount of cAMP in each sample is determined
by comparison to a standard curve, obtained by placing known
concentrations of cAMP in some wells on the plate.
D. Stimulation of Insulin Secretion in HIT-T15 Cells
[0661] It is known that stimulation of cAMP in HIT-T15 cells causes
an increase in insulin secretion when the glucose concentration in
the culture media is changed from 3 mM to 15 mM. Thus, RUP3 ligands
can also be tested for their ability to stimulate glucose-dependent
insulin secretion (GSIS) in HIT-T15 cells. In this assay, 30,000
cells/well in a 12-well plate are incubated in culture media
containing 3 mM glucose and no serum for 2 hours. The media is then
changed; wells receive media containing either 3 mM or 15 mM
glucose, and in both cases the media contains either vehicle (DMSO)
or RUP3 ligand at a concentration of interest. Some wells receive
media containing 1 .mu.M forskolin as a positive control. All
conditions are tested in triplicate. Cells are incubated for 30
minutes, and the amount of insulin secreted into the media is
determined by ELISA, using a kit from either Peninsula Laboratories
(Cat # ELIS-7536) or Crystal Chem Inc. (Cat # 90060).
E. Stimulation of Insulin Secretion in Isolated Rat Islets
[0662] As with HIT-T15 cells, it is known that stimulation of cAMP
in isolated rat islets causes an increase in insulin secretion when
the glucose concentration in the culture media is changed from 60
mg/dl to 300 mg/dl. RUP3 is an endogenously expressed GPCR in the
insulin-producing cells of rat islets. Thus, RUP3 ligands can also
be tested for their ability to stimulate GSIS in rat islet
cultures. This assay is performed as follows: [0663] A. Select
75-150 islet equivalents (IEQ) for each assay condition using a
dissecting microscope. Incubate overnight in low-glucose culture
medium. (Optional.) [0664] B. Divide the islets evenly into
triplicate samples of 25-40 islet equivalents per sample. Transfer
to 40 .mu.m mesh sterile cell strainers in wells of a 6-well plate
with 5 mL of low (60 mg/dl) glucose Krebs-Ringers Buffer (KRB)
assay medium. [0665] C. Incubate 30 minutes (1 hour if overnight
step skipped) at 37.degree. C. and 5% CO.sub.2. Save the
supernatants if a positive control for the RIA is desired. [0666]
D. Move strainers with islets to new wells with 5 mL/well low
glucose KRB. This is the second pre-incubation and serves to remove
residual or carryover insulin from the culture medium. Incubate 30
minutes. [0667] E. Move strainers to next wells (Low 1) with 4 or 5
mL low glucose KRB. Incubate @ 37.degree. C. for 30 minutes.
Collect supernatants into low-binding polypropylene tubes
pre-labelled for identification and keep cold. [0668] F. Move
strainers to high glucose wells (300 mg/dl, which is equivalent to
16.7 mM). Incubate and collect supernatants as before. Rinse islets
in their strainers in low-glucose to remove residual insulin. If
the rinse if to be collected for analysis, use one rinse well for
each condition (i.e. set of triplicates.) [0669] G. Move strainers
to final wells with low-glucose assay medium (Low 2). Incubate and
collect supernatants as before. [0670] H. Keeping cold, centrifuge
supernatants at 1800 rpm for 5 minutes @ 4-8.degree. C. to remove
small islets/islet pieces that escape the 40 mm mesh. Remove all
but lower 0.5-1 mL and distribute in duplicate to pre-labelled
low-binding tubes. Freeze and store at <-20.degree. C. until
insulin concentrations can be determined. [0671] I. Insulin
determinations are done as above, or by Linco Labs as a custom
service, using their rat insulin RIA (Cat. # RI-13K).
Example 2
[0671] A. RT-PCR Analysis of RUP3 Expression in Human Tissues (FIG.
1A).
[0672] RT-PCR was applied to determine the tissue distribution of
RUP3. Oligonucleotides used for PCR had the following sequences:
TABLE-US-00024 ZC47: 5'-CATTGCCGGGCTGTGGTTAGTGTC-3',; (forward
primer) (SEQ ID NO:3) ZC48: 5'-GGCATAGATGAGTGGGTTGAGCAG-3',;
(reverse primer) (SEQ ID NO:4)
[0673] and the human multiple tissue cDNA panels (MTC, Clontech)
were used as templates (1 ng cDNA per PCR amplification).
Twenty-two (22) human tissues were analyzed. PCR was performed
using Platinum PCR SuperMix (Life Technologies, Inc.; manufacture
instructions were followed) in a 50 .mu.l reaction by the following
sequences: step 1, 95.degree. C. for 4 min; step 2, 95.degree. C.
for 1 min; step 3, 60.degree. C. for 30 sec; step 4, 72.degree. C.
for 1 min; and step 5, 72.degree. C. for 7 min. Steps 2 through 4
were repeated 35 times.
[0674] The resulting PCR reactions (15 .mu.l) were loaded on a 1.5%
agarose gel to analyze the RT-PCR products, and a specific 466
base-pair DNA fragment representing RUP3 was specifically amplified
from cDNA of pancreas origin. Low expression was also evident in
subregions of brain.
B. cDNA Dot-Blot Analysis of RUP3 Expression in Human Tissues (FIG.
1B).
[0675] Results from RT-PCR analysis were further confirmed in cDNA
dot-blot analysis. In this assay, a dot-blot membrane containing
cDNA from 50 human tissues (Clontech) was hybridized with a
.sup.32p-radiolabelled DNA probe having sequences derived from
human RUP3. Hybridyzation signals were seen in pancreas and fetal
liver, suggesting these tissues express RUP3. No significant
expression was detected in other tissues analyzed.
C. Analysis of RUP3 by RT-PCR with Isolated Human Pancreatic Islets
of Langerhans (FIG. 1C).
[0676] Further analysis of RUP3 by RT-PCR with isolated human
pancreatic islets of Langerhans showed robust expression of RUP3 in
islet cells but not in control samples.
D. Analysis of RUP3 Expression with cDNAs of Rat Origin by RT-PCR
(FIG. 1D).
[0677] RUP3 expression was further analyzed with cDNAs of rat
origin by RT-PCR technique. Tissue cDNAs used for this assay were
obtained from Clontech except those for hypothalamus and islets,
which were prepared in house. Concentrations of each cDNA sample
were normalized via a control RT-PCR analysis of the house-keeping
gene GAPDH before assaying for RUP3 expression. Oligonucleotides
used for PCR had the following sequences: TABLE-US-00025 rat RUP3
("rRUP3") forward: 5'-CATGGGCCCTGCACCTTCTTTG-3'; (SEQ ID NO:5)
rRUP3 reverse: 5'-GCTCCGGATGGCTGATGATAGTGA-3'. (SEQ ID NO:6)
PCR was performed using Platinum PCR SuperMix (Life Technologies,
Inc.; manufacture instructions were followed) in a 50 .mu.ul
reaction by the following sequences: step 1, 95.degree. C. for 4
min; step 2, 95.degree. C. for 1 min; step 3, 60.degree. C. for 30
sec; step 4, 72.degree. C. for 1 min; and step 5, 72.degree. C. for
7 min. Steps 2 through 4 were repeated 35 times.
[0678] The resulting PCR reactions (15 .mu.l) were loaded on a 1.5%
agarose gel to analyze the RT-PCR products, and a specific 547
base-pair DNA fragment representing rat RUP3 was specifically
amplified from cDNA of pancreas origin, revealing a similar
expression profile with human. Of particular note, robust
expression was seen in isolated islets and hypothalamus.
Example 3
RUP3 Protein Expression is Restricted to .beta. Cell Lineage of
Pancreatic Islets (FIG. 2).
[0679] A. A Polyclonal Anti-RUP3 Antibody was Prepared in Rabbits
(FIG. 2A).
[0680] Rabbits were immunized with an antigenic peptide with
sequence derived from rat RUP3 ("rRUP3"). The peptide sequence was
RGPERTRESAYHIVTISHPELDG and shared 100% identity with mouse RUP3 in
the corresponding region. A cysteine residue was incorporated at
the N-terminal end of this antigenic peptide to facilitate KLH
crosslinking before injecting into rabbits. The resulting antisera
("anti-rRUP3") and the corresponding preimmune sera ("pre-rRUP3")
were tested for immune reactivity to mouse RUP3 in immunobloting
assays (lanes 1 though 4). In this assay, the GST-RUP3 fusion
protein was readily recognized by the anti-rRUP3 antisera (lane 4),
but not by the preimmune sera (lane 2). The immunoreactive signal
could be efficiently eliminated when the immunobloting assay was
performed in the presence of excess antigenic peptide (lane 6).
[0681] B. RUP3 Expression in Insulin-Producing .beta. Cells of
Pancreatic Islets (FIG. 2B).
[0682] Rat pancreas was perfused with 4% paraformaldehyde (PFA) in
PBS and embedded in OCT embedding medium. Ten micron sections were
prepared, fixed on glass slides, and immunostained with either
pre-rRUP3 (FIG. 2B, panel a) or with anti-rRUP3 antisera (FIG. 2B,
panels c and e) followed by secondary staining with donkey
anti-rabbit IgG conjugated to the fluorochrome Cy-3. Each section
was also co-immunostained with a monoclonal anti-insulin antibody
(Santa Cruz, FIG. 2B, panels b and d) in primary staining followed
by a secondary staining with donkey anti-mouse IgG conjugated with
FITC, or with a goat anti-glucagon antibody (Santa Cruz, FIG. 2B,
panel f) and donkey anti-goat IgG coupled to FITC.
Immunofluorescent signals were examined under a fluorescent
microscope. RUP3 was found expressed in insulin producing cells
(panels c and d), but not in glucagons producing cells (panels e
and f). These data demonstrated that RUP3 is expressed in .beta.
cells but not in .beta. cells of the rat pancreatic islets.
Analogous results were obtained when mouse pancreatic sections were
investigated for RUP3 expression.
Example 4
Functional Activities of RUP3 In Vitro (FIG. 3).
[0683] It was established that RUP3 stimulates the production of
cAMP by cotransfection of 293 cells with: (1) a CRE-Luciferase
reporter, wherein the ability to stimulate the production of
firefly luciferase depends on increased cAMP in cells, and (2) an
expression plasmid encoding the human form of RUP3 (FIG. 3A). Note
that cells co-transfected with an expression plasmid containing no
RUP3 sequences ("CMV" in FIG. 3A) produce very little luciferase
activity, whereas cells transfected with an expression plasmid
encoding RUP3 ("RUP3" in FIG. 3A) have at least a 10-fold increase
in luciferase activity. This indicates that RUP3 stimulates the
production of cAMP when introduced into 293 cells. This property of
RUP3 is conserved across species, because hamster RUP3 stimulates
luciferase activity when introduced into 293 cells in a manner
analogous to that described for human RUP3 (FIG. 3B).
[0684] It is established that, when cAMP is increased in
insulin-producing cells of the pancreas, these cells exhibit an
enhanced ability to secrete insulin when glucose concentrations
rise. To test whether RUP3 might impart enhanced glucose-dependent
insulin release, retrovirus containing human RUP3 was used to
generate Tu6 cells that express high levels of RUP3. Tu6 cells
produce insulin, but do not express appreciable levels of RUP3 and
do not normally exhibit an increase in insulin release when
increased glucose is present in the culture media. As shown in FIG.
3C, Tu6 cells transduced with a control virus that contains no
receptor are still able to produce insulin, but do not show an
increase in insulin secretion when the concentration of glucose in
the culture media is shifted from 1 mM to 16 mM. By contrast, Tu6
cells transduced with RUP3-containing retrovirus display
significant glucose-dependent insulin secretion (FIG. 3C).
Example 5
In vivo Effects of RUP3 Agonists on Glucose Homeostasis in
Rats.
[0685] A. Oral Glucose Tolerance Test (oGTT)
[0686] Male Sprague Dawley rats weighing approximately 200 g-250 g
were fasted for 15 hours and randomly grouped (n=6) to receive a
RUP3 agonist (Compounds A194, A214 or D4) at 3, 10 or 30 mg/kg.
Compounds were delivered orally via a gavage needle (p.o., volume 3
mL/kg). At time 0, levels of blood glucose were assessed using a
glucometer (Elite XL, Bayer), and rats were administered either
vehicle (20% hydroxypropyl-beta-cyclodextrin) or test compound.
Thirty minutes after administration of test compound, levels of
blood glucose were again assessed, and rats were administered
dextrose orally at a dose of 2 g/kg. Blood glucose measurements
were then taken 30 min, 60 min, and 120 min after this time. Table
8 shows the mean percentage inhibition of glucose excursion for
each test compound, averaged across the six animals in the
treatment group. These results demonstrated that the RUP3 agonists,
Compounds A194, A214 and D4 lowered blood glucose after challenge
with glucose. TABLE-US-00026 TABLE 8 Mean % Inhibition of Glucose
Excursion % inhibition of glucose Compound excursion (dose, mg/kg)
A194 15%, (30) A214 33%, (10) D4 12%, (30)
Example 6
Generation of Tu6/RUP3 Stable Lines
[0687] To produce Tu6 cells that express RUP3 at high levels, a
retrovirus bearing an expression cassette for RUP3 was generated.
Briefly, RUP3 coding sequence was cloned into the retroviral vector
pLNCX2 (Clontech, Cat # 6102-1). The amphotropic packaging cell
line PT-67 (Clontech, K1060-D) was then transfected with either the
parental vector pLNCX2 or pLNCX2/RUP3 using Lipofectamine and
stable lines were established using guidelines provided by the
PT-67 vendor. Retrovirus-containing supernatant was obtained by
collecting media from the resultant stables according to the
manufacturer's directions. Tu6 cells, in a 10 cm dish, were then
infected with retrovirus by incubating in a solution of 1 mL viral
supernatant/9 mL culture media containing 40 ug/mL polybrene for 24
hours. The medium was then changed to culture media containing 300
ug/mL G418. G418-resistant clones were ultimately created by virtue
of the neomycin-resistance gene cassette present in the pLNCX2
vector, thus indicating the successful integration of retrovirus
into the Tu6 genome. The expression of RUP3 in the Tu6/RUP3
G418-resistant colonies was confirmed by Northern blot.
Example 7
Insulin Secretion, Tu6 Stables
[0688] To measure insulin secretion from rodent insulin-producing
cell lines, cells were first cultured overnight in serum-free,
glucose-deficient media. The following morning, the cells were then
placed in the same media supplemented with either 1 mM or 16 mM
glucose. After an incubation of 4 hours, the media was collected
and analyzed for insulin content using a Rat Insulin
Enzyme-Immunoassay (EIA) System (Amersham Pharmacia Biotech, Cat. #
RPN 2567). Typically, the assay was performed using multiple
dilutions of sample media in order to ensure that the sample
measurements fell within the boundaries of the standard curve
(generated using known amounts of insulin), as recommended by the
manufacturer.
Example 8
Receptor Binding Assay
[0689] In addition to the methods described herein, another means
for evaluating a test compound is by determining binding affinities
to the RUP3 receptor. This type of assay generally requires a
radiolabelled ligand to the RUP3 receptor. Absent the use of known
ligands for the RUP3 receptor and radiolabels thereof, compounds of
Formula (I) can be labelled with a radioisotope and used in an
assay for evaluating the affinity of a test compound to the RUP3
receptor.
[0690] A radiolabelled RUP3 compound of the present invention can
be used in a screening assay to identify/evaluate compounds. In
general terms, a newly synthesized or identified compound (i.e.,
test compound) can be evaluated for its ability to reduce binding
of the "radiolabelled compound of the present invention" to the
RUP3 receptor. Accordingly, the ability to compete with the
"radio-labelled compound of the present invention" or Radiolabelled
RUP3 Ligand for the binding to the RUP3 receptor directly
correlates to its binding affinity of the test compound to the RUP3
receptor.
Assay Protocol for Determining Receptor Binding for RUP3:
[0691] A. RUP3 Receptor Preparation
[0692] 293 cells (human kidney, ATCC), transiently transfected with
10 ug human RUP3 receptor and 60 .mu.L Lipofectamine (per 15-cm
dish), were grown in the dish for 24 hours (75% confluency) with a
media change and removed with 10 mL/dish of Hepes-EDTA buffer (20
mM Hepes+10 mM EDTA, pH 7.4). The cells were then centrifuged in a
Beckman Coulter centrifuge for 20 minutes, 17,000 rpm (JA-25.50
rotor). Subsequently, the pellet was resuspended in 20 mM Hepes+1
mM EDTA, pH 7.4 and homogenized with a 50-mL Dounce homogenizer and
again centrifuged. After removing the supernatant, the pellets were
stored at -80.degree. C, until used in binding assay. When used in
the assay, membranes were thawed on ice for 20 minutes and then 10
mL of incubation buffer (20 mM Hepes, 1 mM MgCl.sub.2, 100 mM NaCl,
pH 7.4) added. The membranes were then vortexed to resuspend the
crude membrane pellet and homogenized with a Brinkmann PT-3100
Polytron homogenizer for 15 seconds at setting 6. The concentration
of membrane protein was determined using the BRL Bradford protein
assay.
[0693] B. Binding Assay
[0694] For total binding, a total volume of 50 .mu.L of
appropriately diluted membranes (diluted in assay buffer containing
50 mM Tris HCl (pH 7.4), 10 mM MgCl.sub.2, and 1 mM EDTA; 5-50 ug
protein) is added to 96-well polyproylene microtiter plates
followed by addition of 100 .mu.L of assay buffer and 50 .mu.L of
Radiolabelled RUP3 Ligand. For nonspecific binding, 50 .mu.L of
assay buffer is added instead of 100 .mu.L and an additional 50
.mu.L of 10 uM cold RUP3 is added before 50 .mu.L of Radiolabelled
RUP3 Ligand is added. Plates are then incubated at room temperature
for 60-120 minutes. The binding reaction is terminated by filtering
assay plates through a Microplate Devices GF/C Unifilter filtration
plate with a Brandell 96-well plate harvestor followed by washing
with cold 50 mM Tris HCI, pH 7.4 containing 0.9% NaCl. Then, the
bottom of the filtration plate are sealed, 50 .mu.L of Optiphase
Supermix is added to each well, the top of the plates are sealed,
and plates are counted in a Trilux MicroBeta scintillation counter.
For compound competition studies, instead of adding 100 .mu.L of
assay buffer, 100 .mu.L of appropriately diluted test compound is
added to appropriate wells followed by addition of 50 .mu.L of
Radiolabelled RUP3 Ligand.
[0695] C. Calculations
[0696] The test compounds are initially assayed at 1 and 0.1 .mu.M
and then at a range of concentrations chosen such that the middle
dose would cause about 50% inhibition of a Radio-RUP3 Ligand
binding (i.e., IC.sub.50). Specific binding in the absence of test
compound (B.sub.O) is the difference of total binding (B.sub.T)
minus non-specific binding (NSB) and similarly specific binding (in
the presence of test compound) (B) is the difference of
displacement binding (B.sub.D) minus non-specific binding (NSB).
IC.sub.50 is determined from an inhibition response curve,
logit-log plot of % B/B.sub.O vs concentration of test
compound.
[0697] K.sub.i is calculated by the Cheng and Prustoff
transformation: K.sub.i=IC.sub.50/(1+[L]/K.sub.D)
[0698] where [L] is the concentration of a Radio-RUP3 Ligand used
in the assay and K.sub.D is the dissociation constant of a
Radio-RUP3 Ligand determined independently under the same binding
conditions.
CHEMISTRY EXAMPLES SYNTHESES OF COMPOUNDS OF THE PRESENT
INVENTION
[0699] The compounds of the invention and their synthesis are
further illustrated by the following examples. The following
examples are provided to further define the invention without,
however, limiting the invention to the particulars of these
examples. The compounds described herein, supra and infra, are
named according to the CS Chem Draw Ultra Version 7.0.1, AutoNom
version 2.2. In certain instances common names are used and it is
understood that these common names would be recognized by those
skilled in the art. Chemistry: Proton nuclear magnetic resonance
(.sup.1H NMR) spectra were recorded on a Varian Mercury Vx-400
equipped with a 4 nucleus auto switchable probe and z-gradient or a
Bruker Avance-400 equipped with a QNP (Quad Nucleus Probe) or a BBI
(Broad Band Inverse) and z-gradient. Chemical shifts are given in
parts per million (ppm) with the residual solvent signal used as
reference. NMR abbreviations are used as follows: s=singlet,
d=doublet, t=triplet, q=quartet, m=multiplet, br=broad. Microwave
irradiations were carried out using the Emyrs Synthesizer (Personal
Chemistry). Thin-layer chromatography (TLC) was performed on silica
gel 60 F.sub.254 (Merck), preparatory thin-layer chromatography
(prep TLC) was preformed on PK6F silica gel 60 A 1 mm plates
(Whatman), and column chromatography was carried out on a silica
gel column using Kieselgel 60, 0.063-0.200 mm (Merck). Evaporation
was done in vacuo on a Buchi rotary evaporator. Celite 545.RTM. was
used during palladium filtrations.
[0700] LCMS specs: 1) PC: HPLC-pumps: LC-10AD VP, Shimadzu Inc.;
HPLC system controller: SCL-10A VP, Shimadzu Inc; UV-Detector:
SPD-10A VP, Shimadzu Inc; Autosampler: CTC HTS, PAL, Leap
Scientific; Mass spectrometer: API 150EX with Turbo Ion Spray
source, AB/MDS Sciex; Software: Analyst 1.2. 2) Mac: HPLC-pumps:
LC-8A VP, Shimadzu Inc; HPLC system controller: SCL-10A VP,
Shimadzu Inc.
[0701] UV-Detector: SPD-10A VP, Shimadzu Inc; Autosampler: 215
Liquid Handler, Gilson Inc; Mass spectrometer: API 150EX with Turbo
Ion Spray source, AB/MDS Sciex Software: Masschrom 1.5.2.
Example 9
Example 9.1
Preparation of
4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid tert-butyl ester (Compound A1)
[0702] Step 1: Preparation of
5-amino-1-(4-methanesulfonyl-phenyl)-1H-pyrazole-4-carbonitrile.
[0703] A round-bottomed flask (100 mL), equipped with a reflux
condenser and N.sub.2 inlet septum, was charged with
4-(methylsulfonyl)phenylhydrazine hydrochloride (2 g, 9 mmol), and
sodium methoxide (0.49 g, 9 mmol). Methanol (20 mL) was added under
a stream of nitrogen at room temperature. The reaction mixture was
stirred for 15-20 minutes until the purple color disappeared and a
white precipitate was formed. This was followed by the addition of
ethoxymethylenemalononitrile (1.1 g, 9 mmol) and stirring at room
temperature for an additional 10 mins, subsequently the reaction
mixture was brought to reflux for 150 mins. The cooled reaction
mixture was filtered and concentrated under reduced pressure to
afford the crude product. The solid residue was dissolved in
EtOAc/H.sub.2O. The EtOAc layer was collected, washed with
saturated aqueous NaCl, dried over NaSO.sub.4 and concentrated to
give second portion of the crude product. The crude product was
purified by flash chromatography (10% CH.sub.3OH/CH.sub.2Cl.sub.2)
and recrystallized from methanol to give a yellow crystalline
product (625 mg, 26%). .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta.
3.27 (s, 3H), 6.98 (s, 2H), 7.81 (d, 2H), 7.88 (s, 1H), 8.06 (s,
2H). LCMS: calculated for C.sub.11H.sub.11N.sub.4O.sub.2S 262.05,
observed 262.9 (MH.sup.+).
[0704] Step 2: Preparation of 1-(4-methanesulfonyl-phenyl)-1
H-pyrazolo[3,4-d]pyrimidin-4-ol.
[0705] A mixture of
5-amino-1-(4-methanesulfonyl-phenyl)-1H-pyrazole-4-carbonitrile
(540 mg), formic acid (10 mL) and 1 mL H.sub.2O was refluxed
overnight at 102.degree. C. After cooling to room temperature, a
white precipitate was observed. The mixture was diluted with
H.sub.2O (10 mL), filtered through a funnel and washed thoroughly
with H.sub.2O, CH.sub.3OH, and diethyl ether. The white solid was
collected and dried under vacuum to give a crude product (300 mg,
50% yield). .sup.1 HNMR (DMSO-d.sub.6, 400 MHz) .delta. 3.26 (s,
3H), 8.12 (d, 2H), 8.29 (s, 1H), 8.42 (d, 2H), 8.44 (d, 1H), 12.61
(s, 1H). LCMS: calculated C.sub.12H.sub.10N.sub.4O.sub.3S 290.05,
observed 291.2 (MH.sup.+).
[0706] Step 3: Preparation of
4-Chloro-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine
[0707] Into a 50 mL round-bottomed equipped with a reflux condenser
and N.sub.2 inlet septum was place a stir bar,
1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (93
mg, 0.32 mmol), dimethylaniline (0.3 mL) and POCl.sub.3 (10 mL).
The reaction mixture was stirred at room temperature under N.sub.2
for 5 minutes and brought to reflux for 6 hrs. After cooling down
to room temperature, the reaction mixture was poured into ice and
extracted with CH.sub.2Cl.sub.2 quickly. The crude product was then
purified by flash chromatography (EtOAc:Hex=1:1), 24 mg of product
was obtained (27% yield). .sup.1H NMR (DMSO-d.sub.6, 400 MHz)
.delta. 3.29 (s, 3H), 8.19 (d, 2H), 8.53 (d, 2H), 8.89 (s, 1H),
9.08 (s, 1H). LCMS calculated C.sub.12H.sub.9ClN.sub.4O.sub.2S
308.01, observed 309.1 (MH.sup.+).
[0708] Step 4: Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid tert-butyl ester (Compound A1).
[0709] Into a 16 mL reaction vial was placed sodium hydride (7.8
mg, 60% in oil, 0.195 mmol) and 0.5 mL of THF.
4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester (10 mg,
0.0487 mmol) was added to the suspension and the mixture was
stirred 20 min under N.sub.2 at room temperature, followed by the
slow addition of
4-chloro-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine
(10 mg, 0.0325 mmol). After stirring overnight under N.sub.2 at
room temperature, all of the starting chloropyrazolopyrimidine had
been converted as indicated by LCMS. The reaction mixture was then
concentrated under vacuum and purified by flash column
chromatography using 50% EtOAc/Hex as eluent. .sup.1 HNMR
(CDCl.sub.3, 400 MHz) .delta. 1.49 (s, 9H), 1.85 (m, 2H), 2.09 (m,
2H), 3.10 (s, 3H), 3.32 (m, 2H), 3.86 (m, 2H), 5.60 (m, 1H), 8.09
(d, 2H), 8.26 (s, 1H), 8.61 (d, 2H), 8.66 (s, 1H). LCMS: calculated
for C.sub.22H.sub.27N.sub.5O.sub.5S 473.17, observed 474.4
(MH.sup.+).
Example 9.2
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
oxy]-piperidine-1-carboxylic acid tert-butyl ester (Compound
A2)
[0710] Step 1: Preparation of
5-Amino-1-(4-methanesulfonyl-phenyl)-3-methyl-1H-pyrazole-4-carbonitrile
[0711] Following the above general procedure in Example 9.1, the
title compound,
5-amino-1-(4-methanesulfonyl-phenyl)-3-methyl-1H-pyrazole-4-car-
bonitrile, was synthesized using 1-ethoxyethylidenemalononitrile
and 4-(methylsulfonyl)phenylhydrazine hydrochloric acid as a yellow
solid. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.18(s, 3H),
3.26(s, 3H), 6.94 (s, 2H), 7.9(d, 2H), 8.03(s, 2H). LCMS:
calculated C.sub.12H.sub.12N.sub.4O.sub.2S 276.07, observed 277.1
(MH.sup.+).
[0712] Step 2: Preparation of
1-(4-Methanesulfonyl-phenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ol.
[0713] Following the general procedure described in Example 9.1,
the title compound,
1-(4-methanesulfonyl-phenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ol,
was prepared and isolated. .sup.1H NMR (DMSO-d.sub.6/CDCl.sub.3,
400 MHz) .delta. 2.54 (s, 3H), 3.13 (s, 3H), 8.02 (d, 2H), 8.05 (s,
1), 8.42 (d, 2H), 12.41(s, 1H). LCMS: calculated
C.sub.13H.sub.12N.sub.4O.sub.3S 304.06, observed 305.1
(MH.sup.+).
[0714] Step 3: Preparation of
4-Chloro-1-(4-methanesulfonyl-phenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrim
idine.
[0715] Following general procedure in Example 9. 1, the title
compound was isolated and purified by flash column chromatography.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 2.84 (s, 3H), 3.011 (s,
3H), 8.11 (d, 2H), 8.60 (d, 2H), 8.87 (s, 1H). LCMS: calclated for
C.sub.14H.sub.13ClN.sub.4O.sub.2S 336.04, observed 337.2
(MH.sup.+).
[0716] Step 4: Preparation of
4-[1-(4-Methanesulfonyl-phenyl)3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylo-
xy]-piperidine-1-carboxylic acid tert-butyl ester (Compound
A2).
[0717] Compound A2 was prepared by general procedure in Example
9.1. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.49 (s, 9H), 1.89
(m, 2H), 2.07 (m, 2H), 2.70 (s, 3H), 3.09 (s, 3H), 3.49 (m, 2H),
3.88 (m, 2H), 5.62 (m, 1H), 8.08 (d, 2H), 8.58 (s, 2H), 8.61 (s,
1H). LCMS calculated for C.sub.23H.sub.29N.sub.5O.sub.5S 487.19,
observed 488.4 (MH.sup.+).
Example 9.3
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin--
4-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (Compound
A3)
[0718] Step 1: Preparation of
N-[4-Cyano-2-(4-methanesulfonyl-phenyl)-5-methyl-2H-pyrazol-3-yl]-acetami-
de.
[0719] To a 50 mL round-bottomed equipped with a reflux condenser
and N.sub.2 inlet septum was placed a stir bar,
5-amino-1-(4-methanesulfonyl-phenyl)-3-methyl-1H-pyrazole-4-carbonitrile
(85 mg, 0.31 mmol), and acetyl chloride (5 mL). The reaction
mixture was stirred under N.sub.2 for 24 hrs at 60.degree. C. The
acetyl chloride was removed under reduced pressure and solid
residue washed with CH.sub.2Cl.sub.2 and EtOAc and collected by
filtration. The crude product was then purified by flash
chromatography (EtOAc:Hex=1:1) and recrystalized from methanol. 55
mg of product was obtained (56% yield). .sup.1H NMR (DMSO-d.sub.6,
400 MHz) .delta. 2.07 (s, 3H), 2.36 (s, 3H), 3.29 (s, 3H), 7.81 (d,
2H), 8.09 (d, 2H), 10.7 (s, 1H). LCMS: calculted
C.sub.14H.sub.14N.sub.4O.sub.3S 318.08, observed 319.1
(MH.sup.+).
[0720] Step 2: Preparation of
1-(4-Methanesulfonyl-phenyl)-3,6-dimethyl-1,5-dihydro-pyrazolo[3,4-d]pyri-
midin4-one
[0721] In to a 50 mL round-bottomed equipped with a stir bar and a
reflux condenser was added,
N-[4-cyano-2-(4-methanesulfonyl-phenyl)-5-methyl-2H-pyrazol-3-yl]-acetami-
de (30 mg, 0.079 mmol), H.sub.2O (0.6 mL), and ethanol (1 mL)
followed by 20% aquous KOH (0.33 mL). The reaction mixture turned
purple and the solid dissolved after addition of KOH. Hydrogen
peroxide (0.25 mL) was then added to the above solution. After
stirring 15 min at room temperature, the reaction mixture was
heated at 75.degree. C. overnight. After cooled to room temperature
acetic acid was added slowly until the pH attained a range between
6-6.5. The mixture was then diluted with H.sub.2O and methanol. The
resulting precipitate was collected by filtration and washed with
H.sub.2O, methanol, diethyl ether and dried under vacuum. The crude
product was used directly in the next step without further
purification. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 1.71 (s,
2H), 2.39 (s, 3H), 2.51 (s, 1H), 3.25 (s, 3H), 8.05 (d, 2H), 8.46
(d, 2H). LCMS: calculated C.sub.14H.sub.14N.sub.4O.sub.3S 318.08,
observed 319.1 (MH.sup.+).
[0722] Step 3: Preparation of
4-Chloro-1-(4-methanesulfonyl-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-d]pyri-
midine.
[0723] Following the general procedure in Example 9.1, the title
compound was isolated and purified by flash column chromatography.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 2.79 (s, 3H), 2.86 (s,
3H), 3.09 (s, 3H), 8.10 (d, 2H), 8.61 (d, 2H). LCMS: calculated for
C.sub.14H.sub.13ClN.sub.4O.sub.2S 336.04, observed 337.2
(MH.sup.+).
[0724] Step 4: Preparation of
4-[1-(4-methanesulfonyl-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin--
4-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (Compound
A3).
[0725] Compound A3 was prepared using general procedure in Example
9.1. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.49 (s, 9H), 1.89
(m, 2H), 2.07 (m, 2H), 2.66 (s, 3H), 2.70 (s, 3H), 3.08 (s, 3H),
3.49 (m, 2H), 3.68 (m, 2H), 5.65 (m, 1H), 8.05 (d, 2H), 8.59 (d,
2H). LCMS: calculated for C.sub.24H.sub.31N.sub.5O.sub.5S 501.2,
observed 502.4 (MH.sup.+).
Example 9.4
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid isobutyl ester (Compound A4)
General Procedure for Carbamate Formation
[0726] A mixture of Compound A6 (150 mg, 0.367 mmol),
isobutylchloroformate (0.057 mL, 0.44 mmol) and triethyl amine (0.1
mL) in DMF (8 mL) was stirred at rt for 1 hour. Water was added to
the mixture and precipitate was collected. Compound A4 was obtained
as a solid (88%). .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.95
(d, 6H), 1.86-1.98 (m, 3H), 2.11-2.13 (m, 2H), 3.10 (s, 3H),
3.37-3.43 (m, 2H), 3.89-3.95 (m, 4H), 5.64-5.68 (m, 1H), 8.09-8.12
(m, 2H), 8.26 (s, 1H), 8.60-8.63 (m, 2H), 8.67 (s, 1H). Exact mass
calculated for C.sub.22H.sub.27N.sub.5O.sub.5S 473.2, found 474.3
(MH.sup.+).
Example 9.5
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid isopropyl ester (Compound A5)
[0727] Compound A5 was obtained via general procedure described in
Example 9.4 as a solid (95%). .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 1.26 (d, 6H), 1.82-1.86 (m, 2H), 2.01-2.10 (m, 2H), 3.10
(s, 3H), 3.34-3.45 (m, 2H), 3.90-3.93 (m, 2H), 4.94 (sept, 1H),
5.44-5.48 (m, 1H), 8.09-8.12 (m, 2H), 8.26 (s, 1H), 8.60-8.62 (m,
2H), 8.67 (s, 1H). Exact mass calculated for
C.sub.21H.sub.25N.sub.5O.sub.5S 459.2, found 460.3 (MH.sup.+).
Example 9.6
Preparation of
1-(4-Methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyri-
midine (Compound A6)
General Deprotection Method
[0728] Into a 200 mL round-bottomed flask was placed a stir bar,
Compound A1 (1.2 g), anhydrous acetonitrile (50 mL), and
dichloromethane (15 mL). 4M HCl in 1,4-dioxane (15 mL) was added
under nitrogen and the mixture was stirred at 40.degree. C. for 10
minutes. The solution turned cloudy. The precipitate was isolated
and purified by HPLC to give Compound A6. .sup.1H NMR
(DMSO-d.sub.6, 400 MHz) .delta. 2.04 (m, 2H), 2.25 (m, 2H), 3.21
(m, 2H), 3.28 (s, 3H), 3.32 (m, 2H), 5.60 (m, 1H), 8.16 (d, 2H),
8.61 (d, 2H), 8.70 (s, 1H), 8.79 (s, 1H). LCMS: calculated for
C.sub.17H.sub.19N.sub.5O.sub.3S 373.12, observed 374.1
(MH.sup.+).
Example 9.7
Preparation of
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-pyridin-3-yl-methanone (Compound A7)
General Amide Formation Method
[0729] Into a 500 mL round-bottomed flask was placed Compound A6
(146 mg, 0.36 mmol) and triethylamine (300 .mu.l). DMF (15 mL) was
added to completely dissolve the solid material. Nicotinoyl
chloride hydrochloride (96 mg, 0.54 mmol) was added to the solution
and the mixture was stirred overnight under N.sub.2 at room
temperature. After all of the starting amine was completely
converted as indicated by LCMS, the reaction was stopped by
quenching with water. The reaction mixture was then concentrated
under vacuum and purified by preparative HPLC to give Compound A7.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 2.06 (m, 2H), 2.22 (m,
2H), 3.09 (s, 3H), 3.55 (m, 1H), 3.79 (m, 2H), 4.15 (m, 1H), 5.76
(m, 1H), 7.86 (m, 1H), 8.11 (d, 2H), 8.28 (s, 1H), 8.33 (d, 1H),
8.61 (d, 2H), 8.68 (s, 1H), 8.84 (m, 1H), 8.92 (m, 1H). LCMS
calculated for C.sub.23H.sub.22N.sub.6O.sub.4S 478.14, observed
479.1 (MH.sup.+).
Example 9.8
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid butyl ester (Compound A48)
[0730]
1-(4-Methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-
-d]pyrimidine hydrochloride (0.17 mmol, 60 mg), n-butyl
chloroformate (0.19 mmol, 24 .mu.L) and triethylamine (0.51 mmol,
71 .mu.L) were dissolved in DMF (2 mL) and stirred for 60 minutes
at room temperature. The reaction mixture was quenched with water
followed by an extraction with ethylacetate. Removal of organic
solvents in vacuo provided Compound A48 as a white solid (40 mg,
50%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 8.67 (s,
1H); 8.62 (d, 2H); 8.26 (s, 1H); 8.11 (d, 2H); 5.62 (h, 1H); 4.12
(t, 2H); 3.92 (m, 2H); 3.39 (m, 2H); 3.10 (s, 3H); 2.11 (m, 2H);
1.65 (m, 2H), 1.56 (p, 2H); 1.42 (s, 2H); 0.97 (t, 3H). Exact mass
calculated for C.sub.22H.sub.27N.sub.5O.sub.5S 473.55, found 474.4
(MH.sup.+).
Example 9.9
Preparation of
4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
sulfanyl]-piperidine-1-carboxylic acid cyclopropylmethyl ester
(Compound A 112)
[0731] Di-imidazol-1-yl-methanone (0.25 mmol, 41 mg), and
cyclopropylmethanol (0.25 mmol, 20 .mu.L) were dissolved in DMSO (2
mL) and stirred for 30 minutes at room temperature. Then,
1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-ylsulfanyl)-1H-pyraz-
olo[3,4-d]pyrimidine hydrochloride (0.18 mmol, 80 mg) and
triethylamine (0.54 mmol, 75 .mu.L) were added. The mixture was
heated in a microwave for 5 minutes at 120.degree. C. The progress
of the reaction was monitored by thin layer chromatography and
LCMS. Purification by HPLC provided Compound A112 as a white solid
(26 mg, 29%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 8.72
(s, 1H); 8.41 (s, 1H); 7.87 (m, 3H); 4.40 (h, 1H); 4.01 (m, 2H);
3.87 (d, 2H); 3.19 (m, 2H); 3.06 (s, 3H); 2.17 (m, 2H); 1.73 (m,
2H); 1.07 (m, 1H); 0.51 (m, 2H); 0.25 (m, 2H). Exact mass
calculated for C.sub.22H.sub.24FN.sub.5O.sub.4S.sub.2 505.59, found
506.20 (MH.sup.+).
Example 9.10
Preparation of
4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
sulfanyl]-piperidine-1-carboxylic acid cyclobutylmethyl ester
(Compound A113)
[0732] Di-imidazol-1-yl-methanone (0.25 mmol, 41 mg), and
cyclobutyl methanol (0.25 mmol, 24 .mu.L) were dissolved in DMSO (2
mL) and stirred for 30 minutes at room temperature. Then,
1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-ylsulfanyl)-1H-pyraz-
olo[3,4-d]pyrimidine hydrochloride (0.18 mmol, 80 mg) and
triethylamine (0.54 mmol, 75 .mu.L) were added. The mixture was
heated in a microwave for 5 minutes at 120.degree. C. The progress
of the reaction was monitored by thin layer chromatography and
LCMS. Purification by HPLC provided Compound A113 as a white solid
(29 mg, 31%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 8.71
(s, 1H); 8.22 (s, 1H); 7.87 (m, 3H); 4.37 (h, 1H); 4.00 (m, 4H);
3.16 (m, 2H); 3.05 (s, 3H); 2.56 (m, 1H); 2.12 (m, 2H); 2.01 (m,
2H); 1.85 (m, 2H); 1.73 (m, 4H). Exact mass calculated for
C.sub.23H.sub.26FN.sub.5O.sub.4S.sub.2 519.61, found 520.3
(MH.sup.+).
Example 9.11
Preparation of
4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
sulfanyl]-piperidine-1-carboxylic acid 2-cyclopropyl-ethyl ester
(Compound A114)
[0733] Di-imidazol-1-yl-methanone (0.25 mmol, 41 mg), and
2-cyclopropyl-ethanol (0.25 mmol, 32 .mu.L) were dissolved in DMSO
(2 mL) and stirred for 30 minutes at room temperature. Then,
1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-ylsulfanyl)-1H-pyraz-
olo[3,4-d]pyrimidine hydrochloride (0.18 mmol, 80 mg) and
triethylamine (0.54 mmol, 75 .mu.L) were added. The mixture was
heated in a microwave for 5 minutes at 120.degree. C. The progress
of the reaction was monitored by thin layer chromatography and
LCMS. Purification by HPLC provided Compound A114 as a white solid
(35 mg, 36%)..sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 8.71
(s, 1H); 8.21 (s, 1H); 7.86 (m, 3H); 4.37 (m, 1H); 4.10 (t, 2H);
3.96 (s broad, 2H); 3.19 (m, 2H); 3.04 (s, 3H); 2.12 (m, 2H); 1.72
(m, 2H); 1.48 (m, 2H); 1.39 (m, 2H); 1.00 (m, 2H); 0.65 (m, 1H).
Exact mass calculated for C.sub.23H.sub.26FN.sub.5O.sub.4S.sub.2
519.61, found 520.3 (MH.sup.+).
Example 9.12
Preparation of
(5-Bromo-furan-2-yl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1-pyrazolo-
[3,4-d]pyrimidin-4-ylsulfanyl]-piperidin-1-yl}-methanone (Compound
A115)
[0734] Oxalyl chloride (0.51 mmol, 45 .mu.L) and DMF (catalytic
amount) were added to 5-bromo-furan-2-carboxylic acid (0.18 mmol,
36 mg) in dichloromethane (3 mL). The reaction mixture was stirred
for 40 minutes at room temperature. The organic solvents were
removed in vaccuo. The concentrate was re-dissolved in
dichloromethane and
1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-ylsulfanyl)-1H-pyraz-
olo[3,4-d]pyrimidine hydrochloride (0.16 mmol, 70 mg) and
triethylamine (0.47 mmol, 66 .mu.L) were added and stirred for 1.5
hours at room temperature. The progress of the reaction was
monitored by thin layer chromatography and LCMS. Purification by
HPLC provided Compound A115 as a white solid (45 mg, 41%). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 8.74 (s, 1H); 8.25 (s,
1H); 7.87 (m, 3H); 7.00 (d, 1H) ; 6.49 (s, 1H); 4.50 (h, 1H); 4.34
(m, 2H); 3.42 (s broad, 2H); 2.70 (s, 3H); 2.28 (m, 2H); 1.85 (m,
2H). Exact mass calculated for
C.sub.22H.sub.19BrFN.sub.5O.sub.4S.sub.2 580.45, found 582.3
(MH.sup.+).
Example 9.13
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1carboxylic acid pentyl ester (Compound A117)
[0735] Di-imidazol-1-yl-methanone (0.51 mmol, 83 mg), and
n-pentanol (0.51 mmol, 56 .mu.L) were dissolved in DMSO (1 mL) and
stirred for 30 minutes at room temperature. Then,
1-(4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyri-
midine (0.17 mmol, 70 mg) and triethylamine (0.51 mmol, 72 .mu.L)
were added and heated in a microwave at 120.degree. C. for 6
minutes. The progress of the reaction was monitored by LCMS. The
reaction mixture was quenched with water and the product was
extracted with ethylacetate. Removal of organic solvents in vacuo
and purification by HPLC provided Compound A117 as a white solid
(33 mg, 32%). Exact mass calculated for
C.sub.23H.sub.29N.sub.5O.sub.5S 487.57, found 488.20
(MH.sup.+).
Example 9.14
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid 1-ethyl-propyl ester (Compound A118)
[0736] Di-imidazol-1-yl-methanone (0.51 mmol, 83 mg), and
pentan-3-ol (0.51 mmol, 56 .mu.L) were dissolved in DMSO (1 mL) and
stirred for 30 minutes at room temperature. Then,
1-(4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyri-
midine (0.17 mmol, 70 mg) and triethylamine (0.51 mmol, 72 .mu.L)
were added and heated in a microwave at 120.degree. C. for 6
minutes. The progress of the reaction was monitored by LCMS. The
reaction mixture was quenched with water and the product was
extracted with ethylacetate. Removal of organic solvents in vacuo
and purification by HPLC provided Compound A118 as a white solid
(14 mg, 14%). Exact mass calculated for
C.sub.23H.sub.29N.sub.5O.sub.5S 487.57, found 488.20
(MH.sup.+).
Example 9.15
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid 2-ethyl-butyl ester (Compound A119)
[0737] Di-imidazol-1-yl-methanone (0.51 mmol, 83 mg), and
2-ethyl-butan-1-ol (0.51 mmol, 52 mg) were dissolved in DMSO (1 mL)
and stirred for 30 minutes at room temperature. Then,
1-(4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyri-
midine (0.17 mmol, 70 mg) and triethylamine (0.51 mmol, 72 .mu.L)
were added and heated in a microwave at 120.degree. C. for 6
minutes. The progress of the reaction was monitored by LCMS. The
reaction mixture was quenched with water and the product was
extracted with ethylacetate. Removal of organic solvents in vacuo
and purification by HPLC provided Compound A119 as a white solid
(38 mg, 36%). Exact mass calculated for
C.sub.24H.sub.31N.sub.5O.sub.5S 501.60, found 502.3 (MH.sup.+).
Example 9.16
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid cyclopentylmethyl ester (Compound
A120)
[0738] Di-imidazol-1-yl-methanone (0.51 mmol, 83 mg), and
cyclopentyl-methanol (0.51 mmol, 51 mg) were dissolved in DMSO (1
mL) and stirred for 30 minutes at room temperature. Then,
1-(4-methanesulfonyl-phenyl)-4-(piperidin4-yloxy)-1H-pyrazolo[3,4-d]pyrim-
idine (0.17 mmol, 70 mg) and triethylamine (0.51 mmol, 72 .mu.L)
were added and heated in a microwave at 120.degree. C. for 6
minutes. The progress of the reaction was monitored by LCMS. The
reaction mixture was quenched with water and the product was
extracted with ethylacetate. Removal of organic solvents in vacuo
and purification by HPLC provided Compound A120 as a white solid
(30 mg, 29%). Exact mass calculated for
C.sub.24H.sub.29N.sub.5O.sub.5S 499.58, found 500.4 (MH.sup.+).
Example 9.17
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid 2,2-dimethyl-propyl ester (Compound
A124)
[0739]
1-(4-Methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-
-d]pyrimidine hydrochloride (0.17 mmol, 70 mg), neopentyl
chloroformate (0.25 mmol, 37 .mu.L) and triethylamine (0.51 mmol,
72 .mu.L) were dissolved in DMF (2 mL) and stirred for 60 minutes
at room temperature. Progress of the reaction was monitored by TLC
and LCMS. The reaction mixture was quenched with water. The product
was extracted with ethyl acetate. Removal of organic solvents in
vacuo and purification by HPLC provided Compound A124 as a white
solid (28 mg, 27%). Exact mass calculated for
C.sub.23H.sub.29N.sub.5O.sub.5S 487.57, found 488.20
(MH.sup.+).
Example 9.18
Preparation of
(5-Butyl-pyridin-2-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d-
]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound A125)
[0740] 5-Butyl-pyridine-2-carboxylic acid (92 mg, 0.51 mmol) and
isopropyl chloroformate (70 .mu.L, 0.51 mmol) were dissolved in DMF
and stirred at room temperature for 40 min.
1-(4-Methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyri-
midine hydrochloride (70 mg, 0.17 mmol) and triethylamine (72
.mu.L, 0.51 mmol) were added next and continued to stir for 24
hours. Progress of the reaction was monitored by TLC and LCMS.
Removal of organic solvents in vacuo and purification by HPLC
afforded Compound A125 as a white solid (13 mg, 13%). Exact mass
calculated for C.sub.27H.sub.30N.sub.6O.sub.4S 534.63, found 535.20
(MH.sup.+).
Example 9.19
Preparation of
(4-Difluoromethoxy-phenyl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-p-
yrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone
(Compound A193)
[0741] 4-Difluoromethoxy-benzoic acid (527 mg, 2.8 mmol) and HATU
(1.06 g, 2.8 mmol) were stirred together in DMF at room temperature
for 30 min.
1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3-
,4-d]pyrimidine hydrochloride (800 mg, 1.87 mmol) and triethylamine
(785 .mu.L, 5.61 mmol) were added next. The resulting mixture was
allowed to stir for 24 hours. Progress of the reaction was
monitored by TLC and LCMS. Removal of organic solvents in vacuo and
purification by HPLC afforded Compound A193 as a beige solid (127
mg, 32%). Exact mass calculated for
C.sub.25H.sub.22F.sub.2N.sub.5O.sub.5S 561.53, found 562.2
(MH.sup.+).
Example 9.20
Preparation of
1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol--
5-yl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine (Compound
A198)
[0742] Step 1: Preparation of N-hydroxy-isobutyramidine.
[0743] A solution of isobutyronitrile (276 g, 4.0 mol) in EtOH (2.0
L) was combined with hydroxylamine (50% aqueous solution, 1.1 L, 16
mol), and refluxed for 5 h. The solvent was then removed in vacuo,
and the residual water was azeotropically removed with toluene. The
residue was then taken up in CH.sub.2Cl.sub.2, dried over
MgSO.sub.4, and the solvent was removed to afford a white solid
(402 g, 98% yield). .sup.1H NMR (CDCl.sub.3) .delta. 7.94 (br s, 1
H), 4.55 (br s,2 H), 2.47 (m, 1 H), 1.20 (d, 6 H, J=7.1 Hz).
[0744] Step 2: Preparation of 1-cyano-4-hydroxypiperidine.
[0745] A 5-liter, 3-neck flask was equipped with mechanical
stirring, a reflux condenser, and a powder addition funnel. Sodium
bicarbonate (840 g, 10 mmol) was added via the powder funnel while
stirring, then water (ca. 300-400 mL) was gradually added while
vigorously stirring to form a thick, uniform slurry. The flask was
then placed in an ice bath, and a solution of 4-hydroxypiperidine
(506 g, 5.00 mol) in CH.sub.2Cl.sub.2 (1.0 L) was added, and the
contents were vigorously mixed while cooling. A solution of
cyanogen bromide (640 g, 6.0 mol) in CH.sub.2Cl.sub.2 (600 mL) was
added in a dropwise fashion over 2 h, and stirring was continued
for an additional 30 min. The ice bath was removed, and the
mechanical stirrer was replaced by a magnetic stirrer, and the
reaction mixture was stirred for 16 h. The flask was once again
placed under mechanical stirring, and sodium carbonate (100 g) was
added in order to ensure complete neutralization. MgSO.sub.4 (500
g) was added, and vigorous stirring was continued for 15 min. The
resulting suspension was filtered, rinsing with CH.sub.2Cl.sub.2
(2.0 L). A light amber, viscous oil was obtained upon solvent
removal to give 1-cyano-4-hydroxypiperidine (574 g, 91% yield.
.sup.1H NMR (CDCl.sub.3) .delta. 3.80 (m, 1 H), 3.39 (m, 2 H), 3.05
(m, 2 H), 1.87 (m, 2 H), 1.70 (br s, 1 H), 1.62 (m, 2 H); MS m/z
212.1 (M.sup.+).
[0746] Step 3: Preparation of
1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ol.
[0747] In a variation of the method described by Yarovenko et al,
(Bull. Acad. Sci. USSR, Div. Chem. Sci. 1991, 40, 1924) ZnCl.sub.2,
(1 N in ether, 120 mL, 120 mmol) was added in a dropwise fashion
over 15 min to a magnetically stirred solution of
N-hydroxy-isobutyramidine (12.2 g, 120 mmol) and
4-hydroxy-piperidine-1-carbonitrile (12.6 g, 100 mmol) in ethyl
acetate (500 mL). Precipitate formed immediately upon addition, and
at a point the stirring bar became immobilized in the matrix,
requiring the reaction to be manually shaken for the remainder of
addition. After standing for 15 min, the supernatant was decanted
and filtered, and the residue was rinsed twice with ether,
furnishing a hard white precipitate which was collected by
filtration. This material was taken up in conc. HCl (50 mL),
diluted to 4 N with EtOH (100 mL), and refluxed for 1 h. Upon
cooling, a white precipitate was removed by filtration, then the
filtrate was reduced to 50 mL and diluted with 100 mL water. Solid
Na.sub.2CO.sub.3 was added until the mixture was basic,
CH.sub.2Cl.sub.2 was added, and the resulting mixture was filtered,
rinsing with CH.sub.2Cl.sub.2. The organic extract was separated,
dried over MgSO.sub.4, and the solvent was removed to afford a
viscous, amber oil as
1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ol (15.0 g, 71%
yield): .sup.1H NMR (CDCl.sub.3) .delta. 3.95 (m,3 H), 3.37 (m, 2
H), 2.88 (m, 1 H), 2.34 (br s, 1 H), 1.93 (m, 2 H), 1.63 (m, 2 H),
1.28 (d, 6 H, J=7.1 Hz); MS m/z 212.3 (M.sup.+).
[0748] Step 4: Preparation of
1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol--
5-yl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine (Compound
A198).
[0749] 1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ol (338
mg, 1.6 mmol) and sodium hydride (87 mg, 3.66 mmol) were stirred
together in dry THF (2 mL) at room temperature for 30 minutes.
4-Chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidi-
ne was then added and the reaction continued to stir at room
temperature for 45 minutes. Its progress was monitored by thin
layer chromatography and LCMS. The reaction was treated with water
and the desired compound was extracted with ethyl acetate. Organic
layer was evaporated in vacuo. Purification by HPLC provided the
desired Compound A198 as a white solid (600 mg, 98%). Exact mass
calculated for C.sub.22H.sub.24FN.sub.7O.sub.4S 501.53. found 502.2
(MH.sup.+).
Example 9.21
Preparation of
2-{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-
-yloxy]-piperidin-1-yl}-1-(4-trifluoromethoxy-phenyl)-ethanone
(Compound A94)
General Alkylation Method
[0750] In a 10 mL round-bottomed flask fitted with a N.sub.2 inlet
was placed a stir bar,
1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3-
,4-d]pyrimidine (43 mg, 0.1 mmol), K.sub.2CO.sub.3 (138 mg, 1 mmol)
and DMF(1 mL). 2-Bromo-1-(4-trifluoromethoxy-phenyl)-ethanone (30
mg, 0.1 mmol) was added in one portion. The reaction mixture was
stirred at room temperature for 30 minutes. The resulting
suspension was filtered and concentrated under vacuum. The crude
was purified by preparative HPLC to give Compound A94. .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 2.43 (m, 2H), 2.59 (m, 2H), 3.14 (s,
3H), 3.68 (m, 2H), 3.78 (m, 2H), 4.78 (s, 2H), 5.81 (m, 1H), 7.35
(d, 2H), 7.96 (m, 3H), 8.01 (m, 2H), 8.42 (s, 1H), 8.65 (s, 1H).
Exact mass calculated for C.sub.26H.sub.23F.sub.4N.sub.5O.sub.5S
593.14. found 594.3 (MH.sup.+).
Example 9.22
Preparation of
2-{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-
-yloxy]-piperidin-1-yl}-1-(3-fluoro-phenyl)-ethanone (Compound
A95)
[0751] Compound A95 was prepared in a similar manner as described
in Example 9.21; purified by preparative HPLC. .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 2.43 (m,2H), 2.59 (m,2H), 3.14
(s,3H), 3.73 (m, 4H), 4.78 (s, 2H), 5.81 (m, 1H), 7.37 (m, 1H),
7.51 (m, 1H), 7.63 (m, 1H), 7.71 (m, 1H), 7.96 (m, 3H), 8.01 (m,
2H), 8.41 (s, 1H), 8.65 (s, 1H). Exact mass calculated for
C.sub.25H.sub.23F.sub.2N.sub.5O.sub.4S 527.14. found 528.3
(MH.sup.+).
Example 9.23
Preparation of
2-{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-
-yloxy]-piperidin-1-yl}-1-pyridin-2-yl-ethanone (Compound A96)
[0752] Compound A96 was prepared in a similar manner as described
in Example 9.21; purified by preparative HPLC. .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 2.46 (m, 2H), 2.53 (m, 2H), 3.14 (s,
3H), 3.60 (m, 2H), 3.80 (m, 2H), 4.99 (s, 2H), 5.86 (m, 1H), 7.61
(m, 1H), 7.91 (m, 1H), 7.96 (m, 3H), 8.11 (m, 1H), 8.40 (s, 1H),
8.65 (s, 1H), 8.68 (m, 1H). Exact mass calculated for
C.sub.24H.sub.23FN.sub.6O.sub.4S 510.15. found 511.3
(MH.sup.+).
Example 9.24
Preparation of
4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
oxy]-piperidine-1-carboxylic acid tert-butyl ester (Compound A74);
and
4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
oxy]-piperidine-1-carboxylic acid isopropyl ester (Compound
A129)
[0753] Step 1: Preparation of
5-Amino-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazole-4-carbonitrile.
[0754] (2-Fluoro-4-methanesulfonyl-phenyl)-hydrazine (1 g, 4.89
mmol) and sodium methoxide (30 mg, 0.489 mmol) were dissolved in
methanol under N.sub.2 at room temperature. The mixture was stirred
for 10 min and 2-ethoxymethylene-malononitrile (0.6 g, 4.91 mmol)
was added. The reaction mixture was stirred for 30 min and then
brought to reflux for 2 hours. The solvent was removed under
reduced pressure; the residue was suspended in water and extracted
with ethyl acetate. The organic layer was washed with water, brine
and was dried over sodium sulfate. The solvent was concentrated,
affording
5-amino-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazole-4-carbonitrile
as a yellow solid (1.2 g, 87.5%). .sup.1H NMR (400 MHz
DMSO-d.sub.6) .delta. (ppm): 7.96 (d, 1H); 7.93 (m, 1H); 7.80 (s,
1H); 7.74 (m, 1H); 6.89 (s, 2H); 3.24(s, 3H). Exact mass calculated
for C.sub.1H.sub.9FN.sub.4O.sub.2S 280.04. found 281.30 (MH.sup.+,
100%).
[0755] Step 2: Preparation of
1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol.
[0756]
5-Amino-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazole-4-carbon-
itrile (1.2 g, 4.28 mmol) was suspended in formic acid (20 mL, 530
mmol) and water (2 mL) and the mixture brought to reflux for 18 h.
The reaction mixture was cooled down and 15 mL of water were added,
causing the precipitation of
1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol
(0.774 g, 58.6%) as a white solid. The solid was retrieved by
filtration and thoroughly washed with water, methanol and ether.
The powder was kept under high vacuum overnight. .sup.1H NMR (400
MHz DMSO-d.sub.6) .delta. (ppm): 12.4 (s, 1H); 8.29 (s, 1H); 8.00
(d, 1H); 7.97 (m, 1H); 7.82 (m, 2H); 3.21(s, 3H). Exact mass
calculated for C.sub.12H.sub.9FN.sub.4O.sub.3S 308.04. found 309.30
(MH.sup.+, 100%).
[0757] Step 3: Preparation of
4-Chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidi-
ne.
[0758]
1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin--
4-ol (0.774 g, 2.51 mmol) was suspended in POCl.sub.3 (23 mL, 251
mmol) and dimethylaniline (0.69 mL) and the mixture brought to
reflux for 18 h. The solvent was concentrated under reduced
pressure and the residue loaded to a column of silica gel. The
product was eluted using 5% ethyl acetate/dichloromethane. Removal
of solvent afforded
4-chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidi-
ne as a white solid (0.781 g, 95%). .sup.1H NMR (400 MHz
DMSO-d.sub.6) .delta. (ppm): 9.14 (s, 1H); 9.07 (s, 1H); 8.34 (d,
1H); 8.24 (m, 1H); 8.20 (m, 1H); 3.55(s, 3H). Exact mass calculated
for C.sub.12H.sub.8ClFN.sub.4O.sub.2S 326. found 327.2 (MH.sup.+,
100%).
[0759] Step 4: Preparation of
4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
oxy]-piperidine-1-carboxylic acid tert-butyl ester (Compound
A74).
[0760] In a 500 mL round-bottomed flask equipped with a N.sub.2
inlet septum was placed a stir bar, NaH (60% in mineral oil, 1.8 g,
45.6 mmol) and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl
ester (1.53 g, 7.6 mmol). THF (anhydrous, 80 mL) was added to the
mixture. The resulting suspension was stirred about 30 min at room
temperature.
4-Chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidi-
ne (2.5 g, 7.6 mmol) was then added in one portion. The mixture was
stirred overnight under N.sub.2 at room temperature and the
resulting slurry turned slightly yellowish. The slurry was added
CH.sub.2Cl.sub.2 and filtered. The filtrate was concentrated under
vacuum to give the crude product. Column chromatography
purification using 50% EtOAc/Hexane gave Compound A74 as an
off-white solid. Exact mass calculated for
C.sub.22H.sub.26FN.sub.5O.sub.5S: 491.16. found 492.1
(MH.sup.+).
[0761] Step 5: Preparation of
1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3-
,4-d]pyrimidine (Compound A238).
[0762] In a 500 mL round-bottomed flask was placed a stir bar,
Compound A74 (4.00 g), acetonitrile (80 mL), and dichloromethane
(24 mL). 4M HCl in 1,4-dioxane (24 mL) was added under nitrogen and
the mixture was stirred at room temperature for 20 minutes. The
solution turned cloudy. The precipitate was isolated and dried
under vacuum to give
1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3-
,4-d]pyrimidine. Exact mass calculated for
C.sub.17H.sub.18FN.sub.5O.sub.3S: 391.11. found 392.1
(MH.sup.+).
[0763] Step 6: Preparation of
4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
oxy]-piperidine-1-carboxylic acid isopropyl ester (Compound
A129).
[0764] In a 50 mL round-bottom flask was placed
1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3-
,4-d]pyrimidine (80 mg, 0.2 mmol) and triethylarnine(200 .mu.l).
DMF (3 mL) was added to completely dissolve the solid material. The
reaction flask was immersed in an ice-bath. Isopropyl chloroformate
(1.0M in toluene, 0.22 mL) was added to the solution and the
mixture was stirred 2 h under N.sub.2 at 0.degree. C. After all of
the starting amine was completely converted as indicated by LCMS,
the reaction was stopped by quenching with water. The reaction
mixture was then concentrated under vacuum and purified by
preparative HPLC to give
4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
oxy]-piperidine-1-carboxylic acid isopropyl ester (Compound A129).
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.27 (d, 6H), 1.9 (m,
2H), 2.12 (m, 2H), 3.13 (s, 3H), 3.40 (m, 2H), 3.91 (m, 2H), 4.97
(m, 1H), 5.63 (m, 1H), 7.95 (m,3H), 8.34 (s,1H), 8.63 (s, 1H).
Exact mass calculated for C.sub.21H.sub.24FN.sub.5O.sub.5S: 477.15.
found 478.2 (MH.sup.+).
Example 9.25
Preparation of
(4-Ethyl-pyridin-2-yl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyraz-
olo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound
A135)
General Procedure for the Preparation of Amides.
[0765] In a 50 mL reaction vial fitted with a N.sub.2 inlet was
placed a stir bar, 4-ethyl-pyridine-2-carboxylic acid,
O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (180 mg) and DMF (15 mL). The mixture was
stirred 20 min at room temperature under N.sub.2.
1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3-
,4-d]pyrimidine (310 mg) and triethylamine (403 .mu.l) was added.
After stirred 3-8 hours at room temperature under N.sub.2, the
reaction mixture was filtered through a syringe filter. The
filtrate was concentrated to give crude Compound A135. The crude
product was further purified by preparative HPLC. .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 1.35 (s, 3H), 2.04 (m, 1H), 2.13 (m,
2H), 2.25 (m, 1H), 2.88 (m, 2H), 3.13 (s, 3H), 3.45 (m, 1H), 3.71
(m, 3H), 3.87 (m, 1H), 4.12 (m, 1H), 5.76 (m, 1H), 7.60 (d, 1H),
7.64 (s, 1H), 7.95 (m, 1H), 8.35 (s, 1H), 8.63 (s, 1H), 8.73 (d,
1H). Exact mass calculated for C.sub.25H.sub.25FN.sub.6O.sub.4S
524.16, found 525.2 (MH.sup.+).
Example 9.26
Preparation of
(5-Bromo-pyridin-3-yl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyraz-
olo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound
A139)
[0766] Compound A139 was prepared in a similar manner as described
in Example 9.25, and purified by preparative HPLC. Exact mass
calculated for C.sub.23H.sub.20BrFN.sub.6O.sub.4S 574.04, found
575.2 (MH.sup.+).
Example 9.27
Preparation of
(5-Ethyl-pyridin-2-yl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyraz-
olo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound
A183)
[0767] Compound A183 was prepared in a similar manner as described
in Example 9.25, and purified by preparative HPLC. .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 1.37 (t, 3H), 2.02 (m, 1H), 2.15 (m,
2H), 2.26 (m, 1H), 2.87 (m, 2H), 3.14 (s, 3H), 3.45 (m, 1H), 3.71
(m, 1H), 3.87 (m, 1H), 4.13 (m, 1H), 5.76 (m, 1H), 7.75 (d, 1H),
7.94 (m, 3H), 8.06 (m, 1H), 8.36 (s, 1H), 8.65 (s, 1H), 8.72 (s,
1H). Exact mass calculated for C.sub.25H.sub.25FN.sub.6O.sub.4S
524.16, found 525.2 (MH.sup.+).
Example 9.28
Preparation of
(4-Ethoxy-phenyl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3-
,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound
A184)
[0768] In a 50 mL round-bottomed flask fitted with N2 inlet was
placed
1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3-
,4-d]pyrimidine (50 mg, 0.117 mmol) and triethylamine (65 .mu.l)
and THF (0.8 mL). The reaction flask was immersed in an ice-bath.
4-Ethoxy-benzoyl chloride (24 mg, 0.129 mmol) was added to the
solution and the mixture was stirred 2 h under N.sub.2 at 0.degree.
C. After all of the starting amine was completely converted as
indicated by LCMS, the reaction was stopped by quenching with
water. The reaction mixture was then concentrated under vacuum and
purified by column chromatography using EtOAc as eluent to give
Compound A184. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.43 (t,
3H), 1.96 (m, 2H), 2.17 (m, 2H), 3.13 (s, 3H), 3.55 (m, 2H), 4.06
(m, 2H), 4.12 (m, 2H), 5.71 (m, 1H), 6.92 (d, 2H), 7.43 (d, 2H),
7.92 (m, 3H), 8.33 (s, 1H), 8.62 (s, 1H). Exact mass calculated for
C.sub.26H.sub.26FN.sub.5O.sub.5S 539.16, found 540.2
(MH.sup.+).
Example 9.29
Preparation of
(5-Butyl-pyridin-2-yl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyraz-
olo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound
A190)
[0769] Compound A190 was prepared in a similar manner as described
in Example 9.25, and purified by preparative HPLC. .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 0.96 (t, 3H), 1.41 (m, 2H), 1.67 (m,
2H), 2.00 (m, 1H), 2.14 (m, 2H), 2.26 (m, 1H), 2.76 (t, 2H), 3.13
(s, 3H), 3.46 (m, 1H), 3.74 (m, 3H), 3.83 (m, 1H), 4.16 (m, 1H),
5.75 (m, 1H), 7.68 (d, 1H), 7.89 (m, 1H), 7.95 (m, 3H), 8.34 (s,
1H), 8.62 (s, 1H), 8.63 (s, 1H). Exact mass calculated for
C.sub.27H.sub.29FN.sub.6O.sub.4S 552.20, found 553.4
(MH.sup.+).
Example 9.30
Preparation of
{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-y-
loxy]-piperidin-1-yl}-(5-isopropoxymethyl-pyridin-2-yl)-methanone
(Compound A192)
[0770] Step 1: Preparation of
5-Isopropoxymethyl-pyridine-2-carbonitrile.
[0771] In a microwave reaction tube was placed
2-chloro-5-isopropoxymethyl-pyridine (0.12 g, 0.66 mmol),
Zn(CN).sub.2 (0.077 g, 0.66 mmol),
tetrakis(triphenylphosphino)dipalladium (76 mg, 0.066 mmol), DMF (2
mL). The reaction mixture was heated at 180.degree. C. for 5
minutes. The resulted mixture was worked up by
CH.sub.2Cl.sub.2/H.sub.2O. The CH.sub.2Cl.sub.2 layer was dried and
concentrated to give the crude product. The crude was purified by
column chromatography by using 30% EtOAc/Hexane. .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 1.26 (d, 6H), 3.73 (m, 1H), 4.59 (s,
2H), 7.68 (d, 1H), 7.85 (m, 1H), 8.67 (s, 1H). Exact mass
calculated for C.sub.10H.sub.12N.sub.2O 176.09, found 177.2
(MH.sup.+).
[0772] Step 2: Preparation of
5-lsopropoxymethyl-pyridine-2-carboxylic acid.
[0773] In a 25 mL round-bottom flask was place ethanol (4 mL)
solution of 5-isopropoxymethyl-pyridine-2-carbonitrile (1 g, 5.7
mmol). A solution of KOH (1.6 g, 28.36 mmol) in ethanol (6 mL) was
added. The mixture was refluxed overnight and cooled down to room
temperature. The resulted gel like mixture was added H.sub.2O and
acidified with 6 mL of 10% HCl. The aqueous solution was extracted
with EtOAc. The organic extracts were dried and concentrated to
give the crude 5-isopropoxymethyl-pyridine-2-carboxylic acid. The
crude product was further purified by column chromatography using
20% MeOH/CH.sub.2Cl.sub.2. .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 1.26 (d, 6H), 3.74 (m, 1H), 4.63 (s, 2H), 7.94 (d, 1H),
8.21 (m, 1H), 8.60 (s, 1H). Exact mass calculated for
C.sub.10H.sub.13NO.sub.3 195.09, found 196.2 (MH.sup.+).
[0774] Step 3: Preparation of
{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-y-
loxy]-piperidin-1-yl}-(5-isopropoxymethyl-pyridin-2-yl)-methanone
(Compound A192).
[0775] Compound A192 was prepared in a similar manner as described
in Example 9.25, and purified by preparative HPLC. .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 1.25 (d, 6H), 1.96 (m, 1H), 2.07 (m,
1H), 2.15 (m, 1H), 2.25 (m, 1H), 3.13 (s, 3H), 3.55 (m, 1H), 3.73
(m, 3H), 3.90 (m, 1H), 4.22 (m, 1H), 4.58 (s, 2H), 5.73 (m, 1H),
7.68 (d, 1H), 7.86 (m, 1H), 7.95 (m, 3H), 8.33 (s, 1H), 8.60 (d,
1H), 8.63 (s, 1H). Exact mass calculated for
C.sub.28H.sub.30FN.sub.5O.sub.5S 567.20, found 568.4
(MH.sup.+).
Example 9.31
Preparation of
{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-y-
loxy]-piperidin-1-yl}-(5-isopropoxy-pyridin-2-yl)-methanone
(Compound A194)
[0776] Step 1: Preparation of 5-Isopropoxy-pyridine-2-carboxylic
acid 5-Isopropoxy-pyridine-2-carboxylic acid was prepared in a
similar manner as described in Example 9.30 and purified by column
chromatography. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.41 (d,
6H), 4.70 (m, 1H), 7.33 (m, 1H), 8.16 (d, 1H), 8.24 (d, 1H). Exact
mass calculated for C.sub.9H.sub.11NO.sub.3 181.07, found 182.2
(MH.sup.+).
[0777] Step 2: Preparation of
{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-y-
loxy]-piperidin-1-yl}-(5-isopropoxy-pyridin-2-yl)-methanone
(Compound A194).
[0778] Compound A194 was prepared in a similar manner as described
in Example 9.25, and purified by preparative HPLC. .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 1.42 (d, 6H), 2.06 (m, 1H), 2.09 (m,
1H), 2.18 (m, 1H), 2.25 (m, 1H), 3.13 (s, 3H), 3.56 (m, 1H), 3.83
(m, 2H), 4.16 (m, 1H), 4.70 (m, 2H), 5.75 (m, 1H), 7.45 (d, 1H),
7.71 (d, 1H), 7.95 (m, 3H), 8.34 (s, 1H), 8.38 (d, 1H), 8.64 (s,
1H). Exact mass calculated for C.sub.26H.sub.27FN.sub.6O.sub.5S
554.17, found 555.4 (MH.sup.+).
Example 9.32
Preparation of
4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
oxy]-5'-isopropoxy-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl
(Compound A201)
[0779] In a 50 mL round-bottomed flask equipped with a N.sub.2
inlet septum was placed a stir bar, NaH (60% in mineral oil, 364
mg, 0.91 mmol) and
5'-isopropoxy-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-ol (215 mg,
0.91 mmol). THF (anhydrous, 3 mL) was added to the mixture. The
resulting suspension was stirred about 30 min at room temperature.
4-Chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidi-
ne (297 mg, 0.91 mmol) was then added in one portion. The mixture
was stirred overnight under N.sub.2 at room temperature and the
resulting slurry turned slightly yellowish. The slurry was added
CH.sub.2Cl.sub.2 and filtered. The filtrate was concentrated under
vacuum to give the crude product. Purification by preparative HPLC
gave the desired product as an off-white solid. .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 1.36 (d, 6H), 2.17 (m, 2H), 2.30 (m,
2H), 3.13 (s, 3H), 3.74 (m, 2H), 3.97 (m, 2H), 4.50 (m, 1H), 5.76
(m, 1H), 7.04 (d, 1H), 7.60 (m, 1H), 7.87 (m, 1H), 7.94 (m, 3H),
8.34 (s, 1H), 8.64 (s, 1H). Exact mass calculated for
C.sub.26H.sub.28FN.sub.5O.sub.4S 525.18, found 526.2 (MH.sup.+)
Example 9.33
Preparation of
1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[1-(4-trifluoromethoxy-phenyl)-pi-
peridin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine (Compound A203)
[0780] Compound A203 was prepared in a similar manner as described
in Example 9.32 and purified by preparative HPLC. .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 2.46(m, 2H), 2.50(m, 2H), 3.14(s,
3H), 3.60(m, 2H), 3.78(m, 2H), 5.79(m, 1H), 7.36(d, 2H), 7.57(d,
2H), 7.95(m, 3H), 8.40(s, 1H), 8.66(s, 1H), 11.15(m, 2H). Exact
mass calculated for C.sub.24H.sub.21F.sub.4N.sub.5O.sub.4S 551.13,
found 552.2 (MH.sup.+).
Example 9.34
Preparation of
1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[1-(3-trifluoromethoxy-phenyl)-pi-
peridin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine (Compound A207)
[0781] Compound A207 was prepared in a similar manner as described
in Example 9.32 and purified by preparative HPLC. .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 2.29(m, 2H), 2.49(m, 2H), 3.14(s,
3H), 3.48(m, 2H), 3.73(m, 2H), 5.74(m, 1H), 7.06(d, 1H), 7.14(s,
1H), 7.27(m, 1H), 7.45(t, 1H), 7.95(m, 3H), 8.38(s, 1H), 8.66(s,
1H), 8.82(m, 2H). Exact mass calculated for
C.sub.24H.sub.2F.sub.4N.sub.5O.sub.4S 551.13, found 552.2
(MH.sup.+).
Example 9.35
Preparation of
5'-Fluoro-4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-y-
loxy]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl (Compound A130)
[0782] General Procedure for palladium catalyzed amination of aryl
bromides with the nitrogen of piperidine.
[0783] To a 5 mL conical microwave vial was added sequentially
Pd.sub.2(dba).sub.3 (2.5 mol %),
1,3-bis(2,6-di-i-propylphenyl)-4,5-dihydroimidazolium
tetrafluoroborate (5 mol%), dioxane (anhydrous, 1 mL added per 0.3
mmol of piperdine substrate), piperidine substrate (1.0 equiv.),
aryl bromide (0.9-1.3 equiv.), and KOt-Bu (1.0 M soln in THF, 3.5
equiv.). The vial was sealed under N.sub.2 and heated by microwave
irradiation at 120.degree. C. to 130.degree. C. for 10-40 min (as
monitored by LC/MS). The reaction mixture was cooled to rt and
diluted with EtOAc (25 mL) and H.sub.2O (25 mL). The layers were
mixed and separated and the aqueous phase was back-extracted with
EtOAc (25 mL). The combined organics were dried over MgSO.sub.4,
filtered and concentrated. The products were purified by
reverse-phase HPLC: Phenomenex.RTM. Luna C18 column (10.mu.,
250.times.21.2 mm), 5% (v/v) CH.sub.3CN (containing 1% v/v TFA) in
H.sub.2O (containing 1% v/v TFA) gradient to 95% H.sub.2O, 20
mL/min, .lamda.=280 nm.
[0784] HPLC/MS for
5'-Fluoro-4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-y-
loxy]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl (Compound A130):
Waters.RTM. YMC.TM. ODS-A C18 column (5.mu., 50.times.4.6 mm), 5%
v/v CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing 1%
v/v TFA) gradient to 99% v/v CH.sub.3CN in H.sub.2O, 3.5 mL/min,
t.sub.r=1.79 min, ESI.sup.+=387.3 (M+H).
Example 9.36
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-5'-m-
ethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl (Compound A131)
[0785] Compound A131 was prepared in a similar manner as described
in Example 9.35 and purified by preparative HPLC. HPLC/MS:
Alltech.RTM. Prevail C18 column (5.mu., 50.times.4.6 mm), 5% v/v
CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing 1% v/v
TFA) gradient to 99% v/v CH.sub.3CN in H.sub.2O, 3.5 mL/min,
t.sub.r=1.82 min, ESI.sup.+=465.2 (M+H).
Example 9.37
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-6'-t-
rifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl (Compound
A132)
[0786] Compound A132 was prepared in a similar manner as described
in Example 9.35 and purified by preparative HPLC. HPLC/MS:
Alltech.RTM. Prevail C18 column (5.mu., 50.times.4.6 mm), 5% v/v
CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing 1% v/v
TFA) gradient to 99% v/v CH.sub.3CN in H.sub.2O, 3.5 mL/min,
t.sub.r=3.00 min, ESI.sup.+=519.3 (M+H).
Example 9.38
Preparation of
(5'-Fluoro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-[1-(4-methanesul-
fonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine (Compound
A138)
[0787] Compound A138 was prepared in a similar manner as described
in Example 9.35 and purified by preparative HPLC. HPLC/MS:
Discovery C18 column (5.mu., 50.times.2.1 mm), 5% v/v CH.sub.3CN
(containing 1% v/v TFA) in H.sub.2O (containing 1% v/v TFA)
gradient to 99% v/v CH.sub.3CN in H.sub.2O, 0.75 mL/min,
t.sub.r=1.62 min, ESI.sup.+=468.3 (M+H).
Example 9.39
Preparation of
(6-Chloro-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4--
d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound A143)
[0788] General procedure for coupling
1-(4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyri-
midine hydrochloride with carboxylic acids.
[0789] To a solution of
1-(4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyri-
midine hydrochloride (35 mg, 0.086 mmol) in DMF (1.5 mL) and
Et.sub.3N (45 .mu.L, 0.33 mmol) was added the desired carboxylic
acid, for Compound A143 the desired acid was 6-chloro-nicotinic
acid (0.11 mmol, 1.3 equiv), followed by HATU (49 mg, 0.129 mmol).
The reactions were stirred at rt overnight diluted with CH.sub.3CN
and filtered. The compounds were purified directly by reverse-phase
HPLC: Phenomenex.RTM. Luna C18 column (10.mu., 250.times.21.2 mm),
5% (v/v) CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing
1% v/v TFA) gradient to 95% H.sub.2O, 20 mL/min, .lamda.=280
nm.
[0790] HPLC/MS for
(6-chloro-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4--
d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound A143);
Waters.RTM. YMC.TM. ODS-A C18 column (5.mu., 50.times.4.6 mm), 5%
v/v CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing 1%
v/v TFA) gradient to 99% v/v CH.sub.3CN in H.sub.2O, 3.5 mL/min,
t.sub.r=2.56 min, ESI.sup.+=513.0 (M+H).
Example 9.40
Preparation of
(5-Chloro-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4--
d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound A144)
[0791] Compound A144 was prepared in a similar manner as described
in Example 9.39 and purified by preparative HPLC. HPLC/MS:
Waters.RTM. YMC.TM. ODS-A C18 column (5.mu., 50.times.4.6 mm), 5%
v/v CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing 1%
v/v TFA) gradient to 99% v/v CH.sub.3CN in H.sub.2O, 3.5 mL/min,
t.sub.r=2.61 min, ESI.sup.+=513.0 (M+H).
Example 9.41
Preparation of
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanone
(Compound A145)
[0792] Compound A145 was prepared in a similar manner as described
in Example 9.39 and purified by preparative HPLC. HPLC/MS:
Waters.RTM. YMC.TM. ODS-A C18 column (5.mu., 50.times.4.6 mm), 5%
v/v CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing 1%
v/v TFA) gradient to 99% v/v CH.sub.3CN in H.sub.2O, 3.5 mL/min,
t.sub.r=2.58 min, ESI.sup.+=550.1 (M+H).
Example 9.42
Preparation of
(2-Chloro-pyridin-4-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4--
d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound A146)
[0793] Compound A146 was prepared in a similar manner as described
in Example 9.39 and purified by preparative HPLC. HPLC/MS:
Waters.RTM. YMC.TM. ODS-A C18 column (5.mu., 50.times.4.6 mm), 5%
v/v CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing 1%
v/v TFA) gradient to 99% v/v CH.sub.3CN in H.sub.2O, 3.5 mL/min,
t.sub.r=2.58 min, ESI.sup.+=513.1 (M+H).
Example 9.43
Preparation of
(4-Hydroxy-3-methoxy-phenyl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo-
[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound
A147)
[0794] Compound A147 was prepared in a similar manner as described
in Example 9.39 and purified by preparative HPLC. HPLC/MS:
Waters.RTM. YMC.TM. ODS-A C18 column (5.mu., 50.times.4.6 mm), 5%
v/v CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing 1%
v/v TFA) gradient to 99% v/v CH.sub.3CN in H.sub.2O, 3.5 mL/min,
t.sub.r=2.35 min, ESI.sup.+=524.3 (M+H).
Example 9.44
Preparation of
(4-Chloro-3-nitro-phenyl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,-
4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound
A148)
[0795] Compound A148 was prepared in a similar manner as described
in Example 9.39 and purified by preparative HPLC. HPLC/MS:
Waters.RTM. YMC.TM. ODS-A C18 column (5.mu., 50.times.4.6 mm), 5%
v/v CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing 1%
v/v TFA) gradient to 99% v/v CH.sub.3CN in H.sub.2O, 3.5 mL/min,
t.sub.r=2.83 min, ESI.sup.+=557.3 (M+H).
Example 9.45
Preparation of
1-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-p-
iperidin-1-yl}-3-methyl-butan-1-one (Compound A149)
[0796] Compound A149 was prepared in a similar manner as described
in Example 9.39 and purified by preparative HPLC. HPLC/MS:
Waters.RTM. YMC.TM. ODS-A C18 column (5.mu., 50.times.4.6 mm), 5%
v/v CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing 1%
v/v TFA) gradient to 99% v/v CH.sub.3CN in H.sub.2O, 3.5 mL/min,
t=2.75 min, ESI.sup.+=458.0 (M+H).
Example 9.46
Preparation of
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(6-pyrazol-1-yl-pyridin-3-yl)-methanone (Compound
A150)
[0797] Compound A150 was prepared in a similar manner as described
in Example 9.39 and purified by preparative HPLC. HPLC/MS:
Waters.RTM. YMC.TM. ODS-A C18 column (5.mu., 50.times.4.6 mm), 5%
v/v CH.sub.3CN (containing 1% v/v TFA) in H20 (containing 1% v/v
TFA) gradient to 99% v/v CH.sub.3CN in H.sub.2O, 3.5 mL/min,
t.sub.r=2.70 min, ESI.sup.+=545.4 (M+H).
Example 9.47
Preparation of
(2-Hydroxy-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-
-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound A151)
[0798] Compound A151 was prepared in a similar manner as described
in Example 9.39 and purified by preparative HPLC. HPLC/MS:
Waters.RTM. YMC.TM. ODS-A C18 column (5.mu., 50.times.4.6 mm), 5%
v/v CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing 1%
v/v TFA) gradient to 99% v/v CH.sub.3CN in H.sub.2O, 3.5 mL/min,
t.sub.r=1.95 min, ESI.sup.+=495.3 (M+H).
Example 9.48
Preparation of
(5,6-Dichloro-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[-
3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound
A152)
[0799] Compound A152 was prepared in a similar manner as described
in Example 9.39 and purified by preparative HPLC. HPLC/MS:
Waters.RTM. YMC.TM. ODS-A C18 column (5.mu., 50.times.4.6 mm), 5%
v/v CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing 1%
v/v TFA) gradient to 99% v/v CH.sub.3CN in H.sub.2O, 3.5 mL/min,
t.sub.r=2.81 min, ESI.sup.+=546.9 (M+H).
Example 9.49
Preparation of
(5-Bromo-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d-
]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Com pound A153)
[0800] Compound A153 was prepared in a similar manner as described
in Example 9.39 and purified by preparative HPLC. HPLC/MS:
Waters.RTM. YMC.TM. ODS-A C18 column (5.mu., 50.times.4.6 mm), 5%
v/v CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing 1%
v/v TFA) gradient to 99% v/v CH.sub.3CN in H.sub.2O, 3.5 mL/min,
t.sub.r=2.66 min, ESI.sup.+=559.2 (M+H).
Example 9.50
Preparation of
5-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-p-
iperidine-1-carbonyl}-nicotinic acid (Compound A154)
[0801] Compound A154 was prepared in a similar manner as described
in Example 9.39 and purified by preparative HPLC. HPLC/MS:
Waters.RTM. YMC.TM. ODS-A C18 column (5.mu., 50.times.4.6 mm), 5%
v/v CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing 1%
v/v TFA) gradient to 99% v/v CH.sub.3CN in H.sub.2O, 3.5 mL/min,
t.sub.r=2.04 min, ESI.sup.+=523.3 (M+H).
Example 9.51
Preparation of
(1H-Imidazol-4-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazol[3,4-d]pyri-
midin-4-yloxy]-piperidin-1-yl}-methanone (Compound A155)
[0802] Compound A155 was prepared in a similar manner as described
in Example 9.39 and purified by preparative HPLC. HPLC/MS:
Waters.RTM. YMC.TM. ODS-A C18 column (5.mu., 50.times.4.6 mm), 5%
v/v CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing 1%
v/v TFA) gradient to 99% v/v CH.sub.3CN in H.sub.2O, 3.5 mL/min,
t.sub.r=1.73 min, ESI.sup.+=468.3 (M+H).
Example 9.52
Preparation of
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(6-pyrrolidin-1-yl-pyridin-3-yl)-methanone (Compound
A157)
[0803] Compound A157 was prepared in a similar manner as described
in Example 9.39 and purified by preparative HPLC. HPLC/MS:
Waters.RTM. YMC.TM. ODS-A C18 column (5.mu., 50.times.4.6 mm), 5%
v/v CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing 1%
v/v TFA) gradient to 99% v/v CH.sub.3CN in H.sub.2O, 3.5 mL/min,
t.sub.r=2.08 min, ESI.sup.+=548.3 (M+H).
Example 9.53
Preparation of
(6-Isobutylamino-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazo-
lo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound
A158)
[0804] Compound A158 was prepared in a similar manner as described
in Example 9.39 and purified by preparative HPLC. HPLC/MS:
Waters.RTM. YMC.TM. ODS-A C18 column (5.mu., 50.times.4.6 mm), 5%
v/v CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing 1%
v/v TFA) gradient to 99% v/v CH.sub.3CN in H.sub.2O, 3.5 mL/min,
t.sub.r=2.58 min, ESI.sup.+=550.1 (M+H).
Example 9.54
Preparation of
(6-Ethylamino-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[-
3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound
A159)
[0805] Compound A159 was prepared in a similar manner as described
in Example 9.39 and purified by preparative HPLC. HPLC/MS:
Waters.RTM. YMC.TM. ODS-A C18 column (5.mu., 50.times.4.6 mm), 5%
v/v CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing 1%
v/v TFA) gradient to 99% v/v CH.sub.3CN in H.sub.2O, 3.5 mL/min,
t.sub.r=1.96 min, ESI.sup.+=522.3 (M+H).
Example 9.55
Preparation of
(6-Cyclobutylamino-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyra-
zolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound
A160)
[0806] Compound A160 was prepared in a similar manner as described
in Example 9.39 and purified by preparative HPLC. HPLC/MS:
Waters.RTM. YMC.TM. ODS-A C18 column (5 .mu.l, 50.times.4.6 mm), 5%
v/v CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing 1%
v/v TFA) gradient to 99% v/v CH.sub.3CN in H.sub.2O, 3.5 mL/min,
t.sub.r=2.15 min, ESI.sup.+=548.4 (M+H).
Example 9.56
Preparation of
(6-Isopropylamino-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyraz-
olo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound
A161)
[0807] Compound A161 was prepared in a similar manner as described
in Example 9.39 and purified by preparative HPLC. HPLC/MS:
Waters.RTM. YMC.TM. ODS-A C18 column (5.mu., 50.times.4.6 mm), 5%
v/v CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing 1%
v/v TFA) gradient to 99% v/v CH.sub.3CN in H.sub.2O, 3.5 mL/min,
t.sub.r=2.05 min, ESI.sup.+=536.2 (M+H).
Example 9.57
Preparation of
[6-(1-Ethyl-propylamino)-pyridin-3-yl]-{4-[1-(4-methanesulfonyl-phenyl)-1-
H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone
(Compound A162)
[0808] Compound A162 was prepared in a similar manner as described
in Example 9.39 and purified by preparative HPLC. HPLC/MS:
Waters.RTM. YMC.TM. ODS-A C18 column (5.mu., 50.times.4.6 mm), 5%
v/v CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing 1%
v/v TFA) gradient to 99% v/v CH.sub.3CN in H.sub.2O, 3.5 mL/min,
t.sub.r=2.13 min, ESI.sup.+=550.2 (M+H).
Example 9.58
Preparation of
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-[6-(1-propyl-butylamino)-pyridin-3-yl]-methanone
(Compound A163)
[0809] Compound A163 was prepared in a similar manner as described
in Example 9.39 and purified by preparative HPLC. HPLC/MS:
Waters.RTM. YMC.TM. ODS-A C18 column (5.mu., 50.times.4.6 mm), 5%
v/v CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing 1%
v/v TFA) gradient to 99% v/v CH.sub.3CN in H.sub.2O, 3.5 mL/min,
t.sub.r=2.40 min, ESI.sup.+=578.5 (M+H).
Example 9.59
Preparation of
5-Benzyloxy-2-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidi-
n-4-yloxy]-piperidine-1-carbonyl}-pyran-4-one (Compound A164)
[0810] Compound A164 was prepared in a similar manner as described
in Example 9.39 and purified by preparative HPLC. HPLC/MS:
Waters.RTM. YMC.TM. ODS-A C18 column (5.mu., 50.times.4.6 mm), 5%
v/v CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing 1%
v/v TFA) gradient to 99% v/v CH.sub.3CN in H.sub.2O, 3.5 mL/min,
t.sub.r=2.64 min, ESI.sup.+=602.3 (M+H).
Example 9.60
Preparation of
Benzo[c]isoxazol-3-yl-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]-
pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound A165)
[0811] Compound A165 was prepared in a similar manner as described
in Example 9.39 and purified by preparative HPLC. HPLC/MS:
Waters.RTM. YMC.TM. ODS-A C18 column (5.mu., 50.times.4.6 mm), 5%
v/v CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing 1%
v/v TFA) gradient to 99% v/v CH.sub.3CN in H.sub.2O, 3.5 mL/min,
t.sub.r=2.85 min, ESI.sup.+=519.4 (M+H).
Example 9.61
Preparation of
(4-Chloro-pyridin-2-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4--
d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound A166)
[0812] Compound A166 was prepared in a similar manner as described
in Example 9.39 and purified by preparative HPLC. HPLC/MS:
Alltech.RTM. Prevail C18 column (5.mu., 50.times.4.6 mm), 5% v/v
CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing 1% v/v
TFA) gradient to 99% v/v CH.sub.3CN in H.sub.2O, 3.5 mL/min,
t.sub.r=2.62 min, ESI.sup.+=513.2 (M+H).
Example 9.62
Preparation of
1-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-p-
iperidin-1-yl}-butan-2-one (Compound A168)
[0813] To a solution of
1-(4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyri-
midine hydrochloride (30.0 mg, 0.073 m mmol) and Et.sub.3N (35
.mu.L) in dioxane (1.5 mL) was added bromomethyl ethyl ketone (22
.mu.L, 0.219 mmol). The mixture was heated by microwave irradiation
at 100.degree. C. for 10 min. The mixture was diluted with
CH.sub.3CN (3 mL) and purified by reverse-phase HPLC:
Phenomenex.RTM. Luna C18 column (10.mu., 250.times.21.2 mm), 5%
(v/v) CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing 1%
v/v TFA) gradient to 95% H.sub.2O, 20 mL/min, .lamda.=214 nm to
give Compound A168 (7.8 mg, 0.014 mmol, 19% yield) isolated as a
white solid. HPLC/MS: Alltech.RTM. Prevail C18 column (5.mu.,
50.times.4.6 mm), 5% v/v CH.sub.3CN (containing 1% v/v TFA) in
H.sub.2O (containing 1% v/v TFA) gradient to 99% v/v CH.sub.3CN in
H.sub.2O, 3.5 mL/min, t.sub.r=1.69 min, ESI.sup.+=444.3 (M+H).
Example 9.63
Preparation of
2-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-p-
iperidine-1-carbonyl}-pyran-4-one (Compound A182)
[0814] Compound A182 was prepared in a similar manner as described
in Example 9.39 and purified by preparative HPLC. HPLC/MS:
Alltech.RTM. Prevail C18 column (5.mu., 50.times.4.6 mm), 5% v/v
CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing 1% v/v
TFA) gradient to 99% v/v CH.sub.3CN in H.sub.2O, 3.5 mL/min,
t.sub.r=2.14 min, ESI.sup.+=496.2 (M+H).
Example 9.64
Preparation of
5'-Bromo-4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
oxy]-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl (Compound A206); and
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-5'-t-
rifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl (Compound
A208)
[0815] Step 1: Preparation of General Procedure for Aromatic
Substitution of 2-chloropyridines with 4-hydroxypiperidine.
[0816] A solution of piperidin-4-ol (100 mg, 0.99 mmol), desired
2-chlorpyridine (0.99 mmol, 1.0 equiv.), and DIPEA (345 .mu.L, 1.98
mmol) in isopropanol (1.5 mL) was heated by microwave irradiation
at 160.degree. C. for 2.5 h. The reaction was purified directly by
silica gel chromatography to give the desired
3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-ol (using
5-bromo-2-chloropyridine,
5'-bromo-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-ol was isolated
in 27% yield, 69.1 mg, 0.27 mmol; using
5-trifluoromethyl-2-chloropyridine,
5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-ol was
isolated in 62% yield, 150.1 mg, 0.61 mmol).
[0817] HPLC/MS for
5'-bromo-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-ol: Alltech.RTM.
Prevail C18 column (5.mu., 50.times.4.6 mm), 5% v/v CH.sub.3CN
(containing 1% v/v TFA) in H.sub.2O (containing 1% v/v TFA)
gradient to 99% v/v CH.sub.3CN in H.sub.2O, 3.5 mL/min,
t.sub.r=1.17 min, ESI.sup.+=258.9 (M+H).
[0818] HPLC/MS for
5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-ol:
Alltech.RTM. Prevail C18 column (5.mu., 50.times.4.6 mm), 5% v/v
CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing 1% v/v
TFA) gradient to 99% v/v CH.sub.3CN in H.sub.2O, 3.5 mL/min,
t.sub.r=1.47 min, ESI.sup.+=247.1 (M+H).
[0819] Step 2: Preparation of General addition procedure of a
hydroxyl piperidine to
4-Chloro-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine.
[0820] To a solution of desired
5'-bromo-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-ol (69 mg, 0.27
mmol, 1.0 equiv.) in THF (1.5 mL) under N.sub.2 at rt was added NaH
(60% wt/wt dispersion in mineral oil, 25 mg, 0.62 mmol, 2.3
equiv.). After stirring for 5 min
4-chloro-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimid-
ine (64.1 mg, 0.21 mmol) was added and the reaction was stirred at
rt for 2 h. The mixture was diluted with H.sub.2O (0.5 mL) and
CH.sub.3CN (3.0 mL) and purified directly by by reverse-phase HPLC:
Phenomenex.TM. Luna C18 column (10.mu., 250.times.21.2 mm), 5%
(v/v).CH.sub.3CN (containing 1% v/v TFA) in H.sub.2O (containing 1%
v/v TFA) gradient to 95% H.sub.2O, 20 mL/min, .lamda.=214 nm to
give Compound A206 (2.5 mg, 0.0056 mmol, 3% yield) as a white
solid.
[0821] Compound A206: Preparation of HPLC/MS: Alltech.RTM. Prevail
C18 column (5.mu., 50.times.4.6 mm), 5% v/v CH.sub.3CN (containing
1% v/v TFA) in H.sub.2O (containing 1% v/v TFA) gradient to 99% v/v
CH.sub.3CN in H.sub.2O, 3.5 mL/min, t.sub.r=2.78 min,
ESI.sup.+=531.2 (M+H).
[0822] Compound A208: Preparation of HPLC/MS: Discovery.TM. C18
column (5.mu., 50.times.2.1 mm), 5% v/v CH.sub.3CN (containing 1%
v/v TFA) in H.sub.2O (containing 1% v/v TFA) gradient to 99% v/v
CH.sub.3CN in H.sub.2O, 0.75 mL/min, t.sub.r=2.86 min,
ESI.sup.+=519.3 (M+H).
Example 9.65
Preparation of
1-[2-Fluoro-4-(methanesulfonyl)phenyl]-4-[[1-(3-isopropyl-1,2,4-oxadiazol-
-5-yl)-3-pyrrolidinyl]oxy]-1H-pyrazolo-[3,4-d]pyrimidine
hydrochloride (Compound A136)
[0823] Step 1: Preparation of
(RS)-3-Hydroxy-1-[(3-isopropyl-1,2,4-oxadiazol-5-yl)methyl]pyrrolidine.
[0824] A mixture of 5-chloromethyl-3-isopropyl-[1,2,4]oxadiazole
(1.6 g, 10 mmol) and (RS)-3-hydroxypyrrolidine (960 mg, 11 mmol)
were combined neat, diluted with MeCN (10 mL), and K.sub.2CO.sub.3
(2.75 g, 20 mmol) was added. The mixture was heated at 65.degree.
C. for 1 h, and was filtered upon cooling: The solvent was removed
and the residue was taken up in CH.sub.2Cl.sub.2 and rinsed with
water. The organic extract was dried over MgSO.sub.4, the solvent
was removed, and the residue was taken up in ether and filtered in
order to remove a small amount of quaternary ammonium byproduct.
Solvent removal from the filtrate gave
(RS)-3-hydroxy-1-[(3-isopropyl-1,2,4-oxadiazol-5-yl)methyl]pyrrolidine
as an amber oil (1.72 g, 82% yield): .sup.1H NMR (DMSO-d.sub.6)
.delta. 4.76 (d, 1 H, J=4.5 Hz), 4.19 (m, 1 H), 3.90 (s, 2 H), 3.05
(m, 1 H), 2.79 (m, 1 H), 2.69 (m, 1 H), 2.53 (m, 1 H), 2.43 (m, 1
H), 1.98 (m, 1 H), 1.54 (m, 1 H), 1.25 (d, 6 H, J=6.8 Hz); MS m/z
212.1 (M.sup.+).
[0825] Step 2: Preparation of
1-[2-Fluoro-4-(methanesulfonyl)phenyl]-4-[[1-(3-isopropyl-1,2,4-oxadiazol-
-5-yl)-3-pyrrolidinyl]oxy]-1H-pyrazolo-[3,4-d]pyrimidine
hydrochloride (Compound A136).
[0826] A solution of
1-(3-isopropyl-[1,2,4]oxadiazol-5-ylmethyl)-pyrrolidin-3-ol (422
mg, 2.0 mmol) in anhydrous THF (5 mL) was added to a stirred
suspension of NaH (60% mineral oil dispersion, 480 mg, 12 mmol) in
anhydrous THF under N.sub.2. After stirring for 10 min,
4-chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidi-
ne (654 mg, 2.0 mmol) was added, and the reaction mixture was
stirred for 18 h. The reaction was then quenched with water and
extracted with ether. The organic extract was rinsed with brine,
dried over MgSO.sub.4, and the solvent was removed. The residue was
triturated in hot ether (3.times.10 mL), and the ether rinses
decanted, combined, and reduced in volume. Crystallization from
ether/CH.sub.2Cl.sub.2 4:1 gave 425 mg of a white solid. The
filtrate was combined with the residue from the ether rinses and
subjected to flash chromatography (0.5% 7N NH.sub.3/MeOH in
CH.sub.2Cl.sub.2) to furnish an additional 100 mg of product, for a
total yield of 525 mg (53% yield). The product was taken up in
CH.sub.2Cl.sub.2 and treated with 1 N HCl/ether (3.0 mL), then the
solvent was removed to furnish Compound A136 as a white powder (570
mg): .sup.1H NMR (CDCl.sub.3) .delta. 8.62(s, 1 H), 8.34 (s, 1 H),
7.95 (m, 3 H), 5.81 (m, 1 H), 4.02 (m, 2 H), 3.24 (m, 1 H), 3.15
(s, 3 H), 3.10 (m, 3 H), 2.79 (m,1 H), 2.54 (m, 1 H), 2.20 (m, 1
H), 1.35 (d, 6 H, J=6.8 Hz); MS m/z 502.0 (M.sup.+).
Example 9.66
Preparation of
1-[4-(Methanesulfonyl)phenyl]-4-[[1-[(4-trifluoromethoxy)phenyl]-4-piperi-
dinyl]oxy]-1H-pyrazolo-[3,4-d]pyrimidine (Compound A202)
[0827] Step 1: Preparation of
4-Hydroxy-1-(4-trifluoromethoxy-)-phenylpiperidine.
[0828] A mixture of 4-(trifluoromethoxy)bromobenzene (2.41 g, 10.0
mmol), 4-hydroxypiperidine (1.21 g, 12.0 mmol),
tris(dibenzylideneacetone)dipalladium(0) (137 mg, 0.15 mmol), and
2-(di-t-butylphosphino)biphenyl (107 mg, 0.36 mmol) under N.sub.2
was combined with lithium bis(trimethylsilyl)amide (1.0 M in THF,
22 mL, 22 mmol). The reaction mixture was heated at 65.degree. C.
for 2 h, and then was cooled to ambient temperature and quenched
with 1 N HCl (35 mL) to pH 7. The resulting mixture was extracted
with EtOAc (20 mL), and the organic extract was rinsed with brine,
dried over MgSO.sub.4, and the solvent was removed. The residue was
subjected to flash chromatography (2% 7N methanolic ammonia in
CH.sub.2Cl.sub.2), and a waxy, amber solid was obtained upon
solvent removal (1.4 g, 54% yield): .sup.1H NMR (CDCl.sub.3)
.delta. 7.02 (d, 2 H, J=8.7 Hz), 6.83 (d, 2 H, J=8.4 Hz), 3.79 (m,
1 H), 3.45 (m, 2 H), 2.86 (m, 2 H), 1.94 (m, 2 H), 1.62 (m, 2 H),
1.49 (s, 1 H); MS m/z 261.9 (M.sup.+).
[0829] Step 2: Preparation of
1-[4-(Methanesulfonyl)phenyl]-4-[[1-[(4-trifluoromethoxy)
phenyl]-4-piperidinyl]oxy]-1H-pyrazolo-[3,4-d]pyrimidine (Compound
A202).
[0830] Compound A202 was synthesized from
4-hydroxy-1-(4-trifluoromethoxy-)-phenylpiperidine and
4-chloro-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine
by a similar method as described in Example 9.65, however after
stirring overnight at room temperature, heating at 65.degree. C.
for 1 h was required to drive the reaction to completion. The
reaction was worked up in the same manner, but isolation of the
free base was accomplished by crystallization from EtOAc. Upon
preparation of the HCl salt a white solid was obtained (570 mg, 50%
yield): .sup.1H NMR (DMSO-d.sub.6) .delta. 8.82(s, 1 H), 8.70 (s, 1
H), 8.56 (d, 2 H, J=9.4 Hz), 8.16 (d, 2 H, J=9.4 Hz), 7.55 (m, 2
H), 7.41 (d, 2 H, J=8.2 Hz), 5.71 (m, 1 H), 3.71 (m, 2 H), 3.46 (m,
2 H), 3.29 (s, 3 H), 2.36 (m, 2 H), 2.19 (m, 2 H); MS m/z 534.2
(M.sup.+).
Example 9.67
Preparation of (Compound A238)
[0831] Compound A203 was prepared in a similar manner as described
in Example 9.6 as a solid. Exact mass calculated for
C.sub.17H.sub.18FN.sub.5O.sub.3S 391.1, found 392.2 (MH.sup.+).
Example 9.68
Preparation of
4-[-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]-pyrimidin-4-yl-
sulfanyl]-piperidine-1-carboxylic acid tert-butyl ester (Compound
107)
[0832] To a solution of 4-mercapto-piperidine-1-carboxylic acid
tert-butyl ester (3.09 g, 14.22 mmol) in DMF (50 mL) was added
K.sub.2CO.sub.3. After 45 minutes stirring at room temperature,
4-chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidi-
ne (4.65 g, 14.22 mmol) was added. After 1 hour stirring reaction
was extracted with ethyl acetate and washed with water. Some
product crashed out in the organic layer. This was collected by
filtration. Remaining organic layer was dried over anhydrous
MgSO.sub.4, filtered and concentrated to provide Compound A107 as a
white solid. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.48 (9H,
s), 1.77 (2H, m), 2.18 (2H, m), 3.20-3.13 (5H, m), 3.99 (2H, m),
4.42 (1H, m), 7.95 (3H, m), 8.30 (1H, s), 8.78 (1H, s). Exact mass
calculated for C.sub.22H.sub.26FN.sub.5O.sub.4S.sub.2 507.1, found
508.3 (MH.sup.+).
Example 9.69
Preparation of
4-[-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]-pyrimidin-
[0833] 4-ylsulfanyl]-piperidine-1-carboxylic acid isopropyl ester
(Compound A214)
4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
sulfanyl]-piperidine-1-carboxylic acid tert-butyl ester (3.54 g,
6.97 mmol) was treated with 4M HCl in 1,4-dioxanes (40 mL). After 2
hours stirring at room temperature,
1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-ylsulfanyl)-1H-pyraz-
olo[3,4-d]pyrimidine hydrochloride was collected by filtration. To
a mixture of
1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-ylsulfanyl)-1H-pyraz-
olo[3,4-d]pyrimidine hydrochloride (3.0 g, 6.76 mmol) in DMF (27
mL) was added triethyl amine (2.05 g, 20.28 mmol). After 30 minutes
stirring, isopropyl chloroformate (7.44 mmol) as a 1.0 M solution
in toluene was added to the reaction and reaction was stirred for
two hours. HCl salts had crashed out and were removed by
filtration. Filtrate was extracted with ethyl acetate (100 mL) and
washed with water (4.times.100 mL). Organic was dried over
anhydrous MgSO.sub.4, filtered and concentrated in vacuo to yield
Compound A214 as a white solid. .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 1.27 (d, J=6.3 Hz, 6H), 1.77 (2H, m), 2.18 (2H, m), 3.13
(3H, s), 3.21 (2H, m), 4.04 (2H, m), 4.48-4.40 (1H, m), 4.99-4.90
(1H, m), 7.98-7.92 (3H, m), 8.30 (1H, s), 8.79 (1H, s). Exact mass
calculated for C.sub.21H.sub.24FN.sub.5O.sub.4S.sub.2 493.1, found
494.3 (MH.sup.+).
Example 9.70
Preparation of General Procedure of Coupling Acids with Amine
[0834] A solution of the carboxylic acid (0.139 mmol) and HATU (53
mg, 0.139 mmol) in DMF (6 mL) was stirred at room temperature for
one hour. To the solution was added triethyl amine (34 mg, 0.332
mmol) and the amine, such as,
1-(4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyri-
midine (40 mg, 0.107 mmol). After overnight stirring at room
temperature, the reaction were extracted with DCM (5 mL), washed
with 1M aq citric acid (5 mL), followed by water (3.times.5 mL).
Organics were dried over anhydrous Na.sub.2SO.sub.4. Organics were
concentrated in vacuo and purified by HPLC to provide the desired
compound as a TFA salt.
[0835] The following representative compounds of the present
invention were prepared in a manner similar to that described above
in this general procedure: [0836]
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(5-methyl-pyridin-3-yl)-methanone (Compound A18);
[0837]
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(6-trifluoromethyl-pyridin-3-yl)-methanone (Compound
A34); [0838]
2-(5-Bromo-pyridin-3-yl)-1-{4-[1-(4-methanesulfonyl-phenyl)-1H-py-
razolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone (Compound
A169); [0839]
(6-Fluoro-pyridin-2-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyraz-
olo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound
A170); [0840]
(6-Chloro-pyridin-2-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyraz-
olo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound A
172); [0841]
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
oxy]-piperidin-1-yl}-[5-(2-methyl-pyrrolidin-1-ylmethyl)-pyridin-3-yl]-met-
hanone (Compound A174); [0842]
5-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-p-
iperidine-1-carbonyl}-nicotinonitrile (Compound A176); and [0843]
5-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-p-
iperidine-1-carbonyl}-pyridine-2-carboxylic acid methyl ester
(Compound A195).
[0844] The table below shows the corresponding MS data for
Compounds A18, A34, A169, A170, A172, A174, A176, and A195.
TABLE-US-00027 MS Data Found Compound Exact Mass No. Formula Mass
(MH.sup.+) A18 C.sub.24H.sub.24N.sub.6O.sub.4S 492.16 493.4 A34
C.sub.24H.sub.21F.sub.3N.sub.6O.sub.4S 546.13 547.3 A169
C.sub.24H.sub.23BrN.sub.6O.sub.4S 570.07 573.2 A170
C.sub.23H.sub.21FN.sub.6O.sub.4S 496.13 497.1 A172
C.sub.23H.sub.21ClN.sub.6O.sub.4S 512.1 513.2 A174
C.sub.29H.sub.33N.sub.7O.sub.4S 575.23 576.3 A176
C.sub.24H.sub.21N.sub.7O.sub.4S 503.14 504.2 A195
C.sub.25H.sub.24N.sub.6O.sub.6S 536.15 537.2
Example 9.71
Preparation of General Alkylation Procedure
[0845] To a mixture of
1-(4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyri-
midine (50 mg, 0.122 mmol) in DMF (1.5 mL) was added triethyl amine
(38 mg, 0.379 mmol) and the desired alkyl bromide (0.159 mmol).
After stirring overnight at room temperature, the reaction was
diluted in CH.sub.3CN, CH.sub.3OH, and H.sub.2O and purified by
HPLC to provide the desired Compound as a TFA salt.
[0846] The following representative compounds of the present
invention were prepared in a manner similar to that described above
in this general procedure: [0847]
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-acetic acid ethyl ester (Compound A196); [0848]
1-(4-Chloro-phenyl)-2-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]-
pyrimidin 4-yloxy]-piperidin-1-yl}-ethanone (Compound A199); [0849]
2-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-p-
iperidin-1-yl}-1-(3-trifluoromethyl-phenyl)-ethanone (Compound
A200); [0850]
1-(4-Chloro-3-methyl-phenyl)-2-{4-[1-(4-methanesulfonyl-phenyl)-1-
H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone
(Compound A204); [0851]
1-(3,4-Dichloro-phenyl)-2-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,-
4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone (Compound A205);
[0852]
1-(2,4-Dimethoxy-phenyl)-2-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3-
,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone (Compound A209);
[0853]
1-(4-Difluoromethoxy-phenyl)-2-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazo-
lo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone (Compound
A210); and [0854]
1-(4-Diethylamino-phenyl)-2-{4-[1-(4-methanesulfonyl-phenyl)-1H-p-
yrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone (Compound
A211).
[0855] The table below shows the corresponding MS data for
Compounds A196, A199, A200, A204, A205, A209, A210, and A211.
TABLE-US-00028 MS Data Compound Exact Found Mass No. Formula Mass
(MH.sup.+) A196 C.sub.21H.sub.25N.sub.5O.sub.5S 459.16 460.3 A199
C.sub.25H.sub.24ClN.sub.5O.sub.4S 525.12 526.4 A200
C.sub.26H.sub.24F.sub.3N.sub.5O.sub.4S 559.15 560.3 A204
C.sub.26H.sub.26ClN.sub.5O.sub.4S 539.14 540.1 A205
C.sub.25H.sub.23Cl.sub.2N.sub.5O.sub.4S 559.08 560.2 A209
C.sub.27H.sub.29N.sub.5O.sub.6S 551.18 552.3 A210
C.sub.26H.sub.25F.sub.2N.sub.5O.sub.5S 557.15 558.3 A211
C.sub.29H.sub.34N.sub.6O.sub.4S 562.24 563.2
Example 9.72
Preparation of
(5-Amino-pyridin-2-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d-
]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound A186)
[0856] To a solution of 3-aminopicloinic acid (245 mg, 1.77 mmol)
in 30 mL DMF, HATU (673 mg, 1.77 mmol) and triethylamine (1 mL,
7.72 mmol) were added. After 5 minutes,
1-(4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyri-
midine (HCl salt, 660 mg, 1.61 mmol) was added and mixture was
stirred for 45 minutes. Mixture was extracted with IM NaOH solution
and methylene chloride; organic phases were dried over MgSO.sub.4,
filtered, and concentrated. Residue was purified by HPLC to give
Compound A186 as a white solid (TFA salt, 389 mg, 36%). Exact mass
calculated for C.sub.23H.sub.23N.sub.7.sub.O.sub.4S 493.15, found
494.4 (MH.sup.+).
Example 9.73
Preparation of
(5-Amino-pyridin-2-yl){4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazo-
lo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound
A187)
[0857] To a solution of 3-aminopicloinic acid (290 mg, 2.10 mmol)
in 40 mL DMF, HATU (801 mg, 2.11 mmol) and triethylamine (1.17 mL,
8.44 mmol) were added. After 5 minutes,
1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3-
,4-d]pyrimidine (HCl salt, 660 mg, 1.91 mmol) was added and mixture
was stirred for 45 minutes. Mixture was purified by HPLC to give
Compound A187 as a white solid (TFA salt, 1.03 g, 79%). Exact mass
calculated for C.sub.23H.sub.22FN.sub.7O.sub.4S 511.14, found 512.2
(MH.sup.+).
Example 9.74
Preparation of
(5-Ethylamino-pyridin-2-yl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H--
pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone
(Compound A191)
[0858] A mixture of
(5-amino-pyridin-2-yl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyraz-
olo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound
A187-TFA salt, 500 mg, 0.799 mmol), bromoethane (60.mu., 0.80
mmol), and potassium carbonate (331 mg, 2.39 mmol) in 7 mL
acetonitrile were stirred at room temperature. After 1 hour,
mixture was continued to be stirred under reflux. After 45 min,
there was still no product formation observed. Mixture was cooled
to r.t., sodium hydride dispersion (70 mg, 1.75 mmol) was added,
and stirred at room temperature. After 90 minutes, more sodium
hydride dispersion (70 mg, 1.75 mmol) was added and mixture was
stirred under reflux for 90 minutes. Mixture was purified by HPLC
to give Compound A191 as an oil (TFA salt, 10 mg, 2%). Exact mass
calculated for C.sub.25H.sub.26FN.sub.7O.sub.4S 539.18. found 540.3
(MH.sup.+).
Example 9.75
Preparation of
{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-y-
loxy]-piperidin-1-yl}-[5-(3-methyl-butylamino)pyridin-2-yl]-methanone
(Compound A188)
[0859] Compound A188 was prepared in a similar manner as described
in Example 9.74 as an oil (TFA salt, 6.6 mg, 1%). Exact mass
calculated for C.sub.28H.sub.32FN.sub.7O.sub.4S 581.22. found 582.6
(MH.sup.+).
Example 9.76
Preparation of
4-[1-(4-Bromo-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-ca-
rboxylic acid isopropyl ester (Compound A220)
[0860] A mixture of 4-hydroxy-piperidine-1-carboxylic acid
isopropyl ester (727 mg, 3.88 mmol), and sodium hydride (465 mg,
19.4 mmol) in THF (12 mL) was stirred for 30 min at 60.degree. C.
1-(4-Bromo-phenyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidine was added
to the mixture at room temperature and stirred for 1.0 hr at RT.
The reaction was quenched with water and the product extracted in
ethyl acetate. The organic layer was concentrated in vacuo to
provide Compound A220 as a white solid (1.3 g, 81%). .sup.1H
NMR(CDCl.sub.3, 400 MHz) .delta. 1.19 (d, 6H), 1.73-1.85 (m,2H),
1.98-2.08 (m,2H), 3.26-3.34 (m,2H), 3.78-3.87 (m, 2H), 4.88 (h,
1H), 5.54 (h, 1H), 7.57 (d, 2H), 8.07 (d, 2H), 8.13 (s, 1H), 8.55
(s, 1H). Exact mass calculated for C.sub.20H.sub.22BrN.sub.5O.sub.3
460.3. found 462.3 (MH.sup.+).
Example 9.77
Preparation of
4-[1-(4-Propylamino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidi-
ne-1-carboxylic acid isopropyl ester (Compound A221)
[0861] General Amination Method
[0862] A mixture of
4-[1-(4-bromo-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-c-
arboxylic acid isopropyl ester (Compound A220, 100 mg, 0.22 mmol),
n-propylamine (130 mg, 2.2 mmol), L-proline (46 mg, 0.40 mmol),
copper iodide (42 mg, 0.22 mmol) and potassium carbonate (71 mg,
0.51 mmol) in DMSO (2.5 mL) was heated under microwave irradiation
for 50 min at 100.degree. C. The crude mixture was concentrated in
vacuo and purified by HPLC to provide Compound A221 as a white
solid (6 mg, 6%). .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.95
(t, 3H), 1.20 (d, 6H), 1.54-1.56 (m, 2H), 1.80-1.89 (m, 2H),
1.97-2.07 (m, 2H), 3.07 (t, 2H), 3.25-3.34 (m, 2H), 3.76-3.87 (m,
2H), 4.88 (h, 1H), 5.51 (h, 1H), 6.67 (d, 2H), 7.71 (d, 2H), 8.08
(s, 1H), 8.50 (s, 1H). Exact mass calculated for
C.sub.23H.sub.30N.sub.6O.sub.3 438.52, found 439.4 (MH.sup.+).
Example 9.78
Preparation of
4-[1-(4-Isopropylamino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piper-
idine-1-carboxylic acid isopropyl ester (Compound A222)
[0863] Compound A222 was prepared in a similar manner as described
in Example 9.77. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.20 (d,
6H), 1.28 (d, 6H), 1.74-1.85 (m, 2H), 1.99-2.09 (m, 2H), 3.26-3.36
(m, 2H), 3.52-3.60 (m, 2H), 3.79-3.89 (m, 2H), 4.88 (h, 1H), 5.51
(h, 1H), 7.46 (d, 2H), 7.99 (s, 1H), 8.21 (d, 2H), 8.49 (s, 1H).
Exact mass calculated for C.sub.23H.sub.30N.sub.6O.sub.3 438.52.
found 439.4 (MH.sup.+).
Example 9.79
Preparation of
4-[1-(4-Morpholin-4-yl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piper-
idine-1-carboxylic acid isopropyl ester (Compound A227)
[0864] Compound A227 was prepared in a similar manner as described
in Example 9.77. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.19 (d,
6H), 1.73-1.84 (m, 2H), 1.97-2.06 (m, 2H), 3.12-3.19 (m, 4H),
3.25-3.35 (m, 2H), 3.76-3.87 (m, 6H), 4.87 (h, 1H), 5.52 (h, 1H),
6.99 (d, 2H), 7.90 (d, 2H), 8.10 (s, 1H), 8.51 (s, 1H). Exact mass
calculated for C.sub.23H.sub.30N.sub.6O.sub.4 466.53. found 467.3
(MH.sup.+).
Example 9.80
Preparation of
4-[1-(2-Fluoro-4-isopropylamino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylo-
xy]-piperidine-1-carboxylic acid isopropyl ester (Compound
A230)
[0865] A mixture of
4-[1-(2-fluoro-4-iodo-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperi-
dine-1-carboxylic acid isopropyl ester (263 mg, 0.50 mmol),
isopropylamine (450.mu., 5.0 mmol), L-proline (86 mg, 0.75 mmol),
copper iodide (95 mg, 0.50 mmol) and potassium carbonate (207 mg,
1.50 mmol) in DMSO (4.0 mL) was heated under microwave irradiation
for 50 min at 100.degree. C. The crude mixture was concentrated in
vacuo and purified by HPLC to provide Compound A230 as a white
solid (80 mg, 35%). .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.20
(d, 6H), 1.26 (d, 6H), 1.75-1.88 (m, 2H), 1.98-2.09 (m, 2H),
3.28-3.37 (m, 2H), 3.55-3.63 (m, 1H), 3.78-3.87 (m, 2H), 4.88 (h,
1H), 5.55 (h, 1H), 6.90-7.08 (m, 2H), 7.44-7.50 (m, 1H), 8.17 (s,
1H), 8.53 (s, 1H). Exact mass calculated for
C.sub.23H.sub.29FN.sub.6O.sub.3 456.51. found 457.3 (MH.sup.+).
Example 9.81
Preparation of
4-[1-(2-Fluoro-4-morpholin-4-yl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylo-
xy]-piperidine-1-carboxylic acid isopropyl ester (Compound
A229).
[0866] Compound A229 was prepared in a similar manner as described
in Example 9.80. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.20 (d,
6H), 1.74-1.86 (m, 2H), 1.97-2.07 (m, 2H), 3.13-3.19 (m, 4H),
3.25-3.36 (m, 2H), 3.76-3.87 (m, 6H), 4.87 (h, 1H), 5.52 (h, 1H),
6.66-6.76 (m, 2H), 7.33-7.43 (m, 1H), 8.15 (s, 1H), 8.50 (s, 1H).
Exact mass calculated for C.sub.24H.sub.29FN.sub.6O.sub.4 484.52.
found 485.4 (MH.sup.+).
Example 9.82
Preparation of
4-(1-{4-[4-(2-Methanesulfonyl-ethyl)-piperazin-1-yl]-2-methyl-phenyl}-1H--
pyrazolo[3,4-d]pyrimidin-4-yloxy)-piperidine-1-carboxylic acid
isopropyl ester (Compound A223)
[0867] General Amination Procedure.
[0868] A solution of
4-[1-(4-iodo-2-methyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperi-
dine-1-carboxylic acid isopropyl ester (78 mg, 0.15 mmol),
1-(2-methanesulfonyl-ethyl)-piperazine (0.75 mmol, 5.0 eq), CuI
(0.15 mmol, leq), L-proline (0.27 mmol, 1.8 eq), and potassium
carbonate (0.15 mmole, 1 eq) in DMSO (2 mL) was heated at
120.degree. C. for 1 hour under microwave conditions. The crude was
purified through prep-LCMS 5-95% to provide Compound A223 as a
brown sticky oil (5 mg, 6%). Exact mass calculated for
C.sub.28H.sub.39N.sub.7O.sub.5S 585.3. found LCMS (ESI) m/z 586.6
(M+H.sup.+, 90%).
Example 9.83
Preparation of
4-(1-{2-Methyl-4-[(tetrahydro-furan-2-ylmethyl)-amino]-phenyl}-1H-pyrazol-
o[3,4-d]pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl
ester (Compound A224)
[0869] Compound A224 was prepared in a similar manner as described
in Example 9.82 as a peach powder (36.8 mg, 50%). Exact mass
calculated for C.sub.26H.sub.34N.sub.5O.sub.4 494.3. found LCMS
(ESI) m/z 495.6 (M+H.sup.+, 71%).
Example 9.84
Preparation of
4-[1-(4-Cyclopropylamino-2-methyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-y-
loxy]-piperidine-1-carboxylic acid isopropyl ester (Compound
A225)
[0870] Compound A225 was prepared in a similar manner as described
in Example 9.82 as an off-white powder. Exact mass calculated for
C.sub.24H.sub.30N.sub.6O.sub.3 450.2. found LCMS (ESI) m/z 451.4
(M+H.sup.+, 97%).
Example 9.85
Preparation of
4-{1-[4-(2-Dimethylamino-ethylamino)2-methyl-phenyl]-1H-pyrazolo[3,4-d]py-
rimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester
(Compound A226)
[0871] Compound A226 was prepared in a similar manner as described
in Example 9.82 as a white powder (8.4 mg, 12%). Exact mass
calculated for C.sub.25H.sub.35N.sub.7O.sub.3 481.3. found LCMS
(ESI) m/z 482.4 (M+H.sup.+, 100%).
Example 9.86
Preparation of
4-(1-{4-[(2-Methanesulfonyl-ethyl)-methyl-amino]-phenyl}-1H-pyrazolo[3,4--
d]pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester
(Compound A231)
[0872] Compound A231 was prepared in a similar manner as described
in Example 9.82 as an off-white powder. Exact mass calculated for
C.sub.24H.sub.32N.sub.6O.sub.5S 516.2. found LCMS (ESI) m/z 517.6
(M+H.sup.+, 78%).
Example 9.87
Preparation of
4-{1-[4-(2-Methoxy-ethylamino)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy-
}-piperidine-1-carboxylic acid isopropyl ester (Compound A232)
[0873] Compound A232 was prepared in a similar manner as described
in Example 9.82 as an off-white powder. Exact mass calculated for
C.sub.23H.sub.30N.sub.6O.sub.4 454.2. found LCMS (ESI) m/z 455.5
(M+H.sup.+, 89%)
Example 9.88
Preparation of
4-(1-{4-[(Tetrahydro-furan-2-ylmethyl)-amino]-phenyl}-1H-pyrazolo[3,4-d]p-
yrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester
(Compound A233).
[0874] Compound A233 was prepared in a similar manner as described
in Example 9.82 as a yellow powder (5.3 mg, 7%). Exact mass
calculated for C.sub.25H.sub.32N.sub.6O.sub.4 480.2. found LCMS
(ESI) m/z 481.6 (M+H.sup.+, 92%).
Example 9.89
Preparation of
4-(1-{4-[4-(2-Methanesulfonyl-ethyl)-piperazin-1-yl]-phenyl}-1H-pyrazolo[-
3,4-d]pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl
ester (Compound A234)
[0875] Compound A234 was prepared in a similar manner as described
in Example 9.82 as a brown powder. Exact mass calculated for
C.sub.27H.sub.37N.sub.7O.sub.5S 571.3. found LCMS (ESI) m/z 572.6
(M+H.sup.+, 74%).
Example 9.90
Preparation of
4-[1-(4-Amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-c-
arboxylic acid isopropyl ester (Compound A235)
[0876] Compound A235 was prepared in a similar manner as described
in Example 9.82 as an off-white powder (7.3 mg, 12%). Exact mass
calculated for C.sub.20H.sub.24N.sub.6O.sub.3 396. found LCMS (ESI)
m/z 397.1 (M+H.sup.+, 70%).
Example 9.91
Preparation of
4-[1-(5-Ethyl-pyrimidin-2-yl)-piperidin-4-ylsulfanyl]-1-(2-fluoro-4-metha-
nesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound A237)
[0877] A mixture of
1-(2-fluoro-4-methanesulfonyl-phenyl)-4-piperidin-4-ylsulfanyl)-1H-pyrazo-
lo[3,4-d]pyrimidine hydrochloride (250 mg, 0.56 mmol),
2-chloro-5-ethyl-pyrimidine (680 .mu.L, 5.6 mmol), and
triethylamine (315 .mu.L, 2.24 mmol) in isopropanol (4 mL) was
heated under microwave irradiation for 15 min at 150.degree. C. The
crude mixture was concentrated in vacuo and purified by HPLC to
provide Compound A237 as a white solid (100 mg, 35%). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 1.18 (t, 3H), 1.82-1.94 (m, 2H),
2.28-2.37 (m, 2H), 2.53 (q, 2H), 3.06 (s, 3H), 3.55-3.64 (m, 2H),
4.41-4.55 (m, 3H), 7.82 (m, 3H), 8.24 (s, 1H), 8.37 (s, 2H), 8.74
(s, 1H). Exact mass calculated for
C.sub.23H.sub.24FN.sub.7O.sub.2S.sub.2 513.61. found 514.4
(MH.sup.+).
Example 9.92
Preparation of
3-tert-Butoxy-1-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimi-
din-4-yloxy]-piperidin-1-yl}-propan-1-one (Compound A32)
[0878] Compound A32 was prepared in a similar manner as described
in Example 9.25 as a solid (95%). .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 1.26 (d, 6H), 1.82-1.86 (m, 2H), 2.01-2.10 (m, 2H), 3.10
(s, 3H), 3.34-3.45 (m, 2H), 3.90-3.93 (m, 2H), 4.94 (sept, 1H),
5.44-5.48 (m, 1H), 8.09-8.12 (m, 2H), 8.26 (s, 1H), 8.60-8.62 (m,
2H), 8.67 (s, 1 H). Exact mass calculated for
C.sub.21H.sub.25N.sub.5O.sub.5S 459.2. found 460.3 (MH.sup.+).
Example 9.93
Preparation of
(3-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]--
piperidin-1-yl}-3-oxo-propyl)-methyl-carbamic acid tert-butyl ester
(Compound A33)
[0879] Compound A33 was prepared in a similar manner as described
in Example 9.25 as a solid (37%). Exact mass calculated for
C.sub.26H.sub.34N.sub.6O.sub.6S 558.2. found 559.3 (MH.sup.+).
Example 9.94
Preparation of
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-c-
yclohexyl}-carbamic acid tert-butyl ester (Compound A35)
[0880] A mixture of
4-chloro-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine
(308 mg, 1 mmol), (4-amino-cyclohexyl)-carbamic acid tert-butyl
ester (257 mg, 1.2 mmol) and potassium carbonate (166 mg, 1.2 mmol)
in THF (10 mL) was stirred at rt overnight. The mixture was
purified by column chromatography to provide Compound A35 as a
solid (76%). .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.46 (s,
9H), 1.74-2.04 (m, 8H), 3.09 (s, 3H), 3.73 (s, 1H), 4.62 (s, 1H),
8.07-8.09 (m, 3H), 8.49 (s, 1H), 8.57-8.59 (m, 2H). Exact mass
calculated for C.sub.23H.sub.30N.sub.6O.sub.4S 486.2. found 487.2
(MH.sup.+).
Example 9.95
Preparation of
N-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-cyclohe-
xane-1,4-diamine (Compound A36)
[0881] Compound A36 was prepared in a similar manner as described
in Example 9.6 as a solid (98%). Exact mass calculated for
C.sub.18H.sub.22N.sub.6O.sub.2S 386.2. found 387.1 (MH.sup.+).
Example 9.96
Preparation of
N-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-
-cyclohexyl}-nicotinamide (Compound A42)
[0882] Compound A42 was prepared in a similar manner as described
in Example 9.25 as a solid (65%). Exact mass calculated for
C.sub.24H.sub.25N.sub.7O.sub.3S 491.2. found 492.3 (MH.sup.+).
Example 9.97
Preparation of
3-tert-Butoxy-N-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimi-
din-4-ylamino]-cyclohexyl}-propionamide (Compound A43)
[0883] Compound A43 was prepared in a similar manner as described
in Example 9.25 as a solid (24%). .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 1.23 (s, 9H), 1.89-1.90 (m, 4H), 2.02-2.03 (m, 4H), 2.51
(t, 2H), 3.12 (s, 3H), 3.64 (t, 2H), 4.09 (s, 2H), 7.35-7.37 (m,
1H), 8.13 (d, 2H), 8.26 (s, 1H), 8.32 (s, 1H), 8.45 (d, 2H),
11.5-11.6 (m, 1 H). Exact mass calculated for
C.sub.25H.sub.34N.sub.6O.sub.5S 514.2. found 515.6 (MH.sup.+).
Example 9.98
Preparation of
(4-{[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]--
methyl}-cyclohexyl)carbamic acid tert-butyl ester (Compound
A71)
[0884] Compound A71 was prepared in a similar manner as described
in Example 9.94 as a solid (100%). .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta. 1.35-1.85 (m, 19H), 3.09 (s, 3H), 3.61 (s, 2H),
3.73-3.76 (m, 1H), 4.64 (s, 1H), 8.07-8.11 (m, 3H), 8.50 (s, 1H),
8.57-8.60 (m, 2H). Exact mass calculated for
C.sub.24H.sub.32N.sub.6O.sub.4S 500.2. found 501.3 (MH.sup.+).
Example 9.99
Preparation of
N-(4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-
-cyclohexylmethyl}-nicotinamide (Compound A72)
[0885] Compound A72 was prepared in a similar manner as described
in Example 9.25 as a solid (91%). Exact mass calculated for
C.sub.25H.sub.27N.sub.7O.sub.3S 505.2. found 506.3 (MH.sup.+).
Example 9.100
Preparation of
N-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-
-cyclohexylmethyl}-6-methyl-nicotinamide (Compound A73)
[0886] Compound A73 was prepared in a similar manner as described
in Example 9.25 as a solid (94%). Exact mass calculated for
C.sub.26H.sub.29N.sub.7O.sub.3S 519.2. found 520.5 (MH.sup.+).
Example 9.101
Preparation of
4-(2-{Ethyl-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-y-
l]-amino}-ethyl)-piperazine-1-carboxylic acid tert-butyl ester
(Compound A101)
[0887] Compound A101 was prepared in a similar as described in
Example 9.94 as a solid (9%). Exact mass calculated for
C.sub.25H.sub.35N.sub.7O.sub.4S 529.3. found 530.3 (MH.sup.+).
Example 9.102
Preparation of
4-({[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4--
yl]-isopropyl-amino}-methyl)-piperidine-1-carboxylic acid
tert-butyl ester (Compound A228).
[0888] Compound A228 was prepared in a similar manner as described
in Example 9.94 as a solid (120 mg, 71%). Exact mass calculated for
C.sub.26H.sub.35FN.sub.6O.sub.4S 546.2. found 547.7 (MH.sup.+).
Example 9.103
Preparation of
4-({[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4--
yl]-isopropyl-amino}-methyl)-piperidine-1-carboxylic acid isopropyl
ester (Compound A236)
[0889] Compound A236 was prepared in a similar manner as described
in Example 9.4 as a sticky oil (509 mg, 80%). Exact mass calculated
for C.sub.25H.sub.33FN.sub.6O.sub.4S 532.2. found 533.3
(MH.sup.+).
Example 9.104
Preparation of
4-[1l2-Fluoro4-sulfamoyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridine-1-carboxylic acid isopropyl ester (Compound A239)
[0890] Step 1: Preparation of
3-fluoro-4-hydrazino-benzenesulfonamide.
[0891] In a 500 mL round-bottomed flask fitted with a condenser and
N.sub.2 inlet septum was placed a stir bar,
3,4-difluoro-benzenesulfonamide (10 g, 52 mmol), anhydrous
hydrazine (10.56 mL, 336 mmol), and acetonitrile (180 mL). The
mixture was refluxed for 6 h under N.sub.2. The solvent was then
removed under vacuum and the residue was treated with H.sub.20. The
separated solid was filtered and washed with H.sub.2O to give the
desired product. Exact mass calculated for
C.sub.6H.sub.8FN.sub.3O.sub.2S 205.03. found 206.1 (MH.sup.+).
[0892] Step 2:
4-[1-(2-Fluoro-4-sulfamoyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-p-
iperidine-1-carboxylic acid isopropyl ester (Compound A239).
[0893] Compound A239 was made in a similar manner as described in
Example 9.24; purified by HPLC. .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 1.26 (d, 6H), 1.87 (m, 2H), 2.10 (m, 2H), 3.37 (m, 2H),
3.91 (m, 2H), 4.91 (m, 1H), 5.01 (s, 2H), 5.62 (m, 1H), 7.91 (m,
3H), 8.31 (s, 1H), 8.61 (s, 1H). Exact mass calculated for
C.sub.20H.sub.23FN.sub.6O.sub.5S 478.14. found 479.3
(MH.sup.+).
Example 9.105
Preparation of (1-tert-Butyl-5-methyl-1H-pyrazol-4-yl)-{4-[l
-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidi-
n-1-yl}-methanone (Compound A9)
[0894] Compound A9 were prepared the same way as described in
Example 9.104. .sup.1H NMR (CDCl3, 400 MHz) .delta. 1.62 (s, 9H),
2.01 (m, 2H), 2.22 (m, 2H), 2.47 (s, 3H), 3.09 (s, 3H), 3.65 (m,
1H), 3.96 (m, 1H), 4.23 (m, 1H), 4.55 (m, 1H), 5.72 (m, 1H), 6.50
(s, 1H), 8.10 (d, 2H), 8.28 (s, 1H), 8.62 (d, 2H), 8.68 (s, 1H).
Exact mass calculated for C.sub.26H.sub.31N.sub.7O.sub.4S 537.22.
found 538.4 (MH.sup.+).
Example 9.106
Preparation of
(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)--
1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone
(Compound A10)
[0895] Compound A10 were prepared the same way as described in
Example 9.104. .sup.1H NMR (CDCl3, 400 MHz) .delta. 1.30 (s, 9H),
1.97 (m, 2H), 2.20 (m, 2H), 3.11 (s, 3H), 3.63 (m, 2H), 3.86 (s,
1H), 3.94 (s, 3H), 4.13 (m, 1H), 5.72 (m, 1H), 6.18 (s, 1H), 8.10
(d, 2H), 8.28 (s, 1H), 8.62 (d, 2H), 8.68 (s, 1H). Exact mass
calculated for C.sub.26H.sub.31N.sub.7O.sub.4S 537.22. found 538.4
(MH.sup.+).
Example 9.107
Preparation of
(3-Fluoro-phenyl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyri-
midin-4-yloxy]-piperidin-1-yl}-methanone (Compound A8)
[0896] In a 16 mL reaction vial was placed sodium hydride (48 mg,
60% in oil, 1.2 mmol) and 5 mL of THF.
(3-Fluoro-phenyl)-(4-hydroxy-piperidin-1-yl)-methanone (66 mg, 0.3
mmol) was added to the suspension and the mixture was stirred 60
min under N.sub.2 at room temperature, followed by the addition of
4-chloro-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine
(60 mg, 0.2 mmol). After stir another 2 hrs under N.sub.2 at room
temperature, all of the starting chloropyrozolepyrimidines was
completely converted as indicated by LCMS. The reaction mixture was
then filtered through a syringe filter and purified HPLC to give
Compound A8. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.95 (m,
2H), 2.21 (m, 2H), 3.11 (s, 3H), 3.45 (m, 1H), 3.68 (m, 1H), 3.75
(m, 1H), 4.20 (s, 1H), 5.72 (m, 1H), 7.12 (m, 1H), 7.16 (m, 1H),
7.22 (m,1H), 7.41 (m, 1H), 8.11 (d, 2H), 8.27 (s, 1H), 8.62 (d,
2H), 8.67 (s, 1H). Exact mass calculated for
C.sub.24H.sub.22FN.sub.5O.sub.4S 495.14. found 496.3
(MH.sup.+).
Example 9.108
Preparation of
1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol--
5-ylmethyl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine
(Compound A137)
[0897] Compound A137 were prepared the same way as described in
Example 9.107. .sup.1H NMR (CDCl3, 400 MHz) .delta. 1.35 (d, 6H),
2.06 (m, 2H), 2.19 (m, 2H), 2.60 (m, 2H), 2.92 (m, 2H), 3.13 (m,
2H), 3.90 (s, 2H), 5.47 (m, 1H), 7.94 (m, 3H), 8.32 (s, 1H), 8.61
(s, 1H). Exact mass calculated fo C.sub.23H.sub.26FN.sub.7O.sub.4S
515.18. found 516.4 (MH.sup.+).
Example 9.109
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-pi-
peridine-1-carboxylic acid tert-butyl ester (Compound A11)
[0898] Compound A11 was prepared in a similar manner as described
in Example 9.94 as a white solid. .sup.1H NMR (DMSO-d.sub.6, 400
MHz) .delta. 1.42 (s, 9H), 1.48 (m, 2H), 1.97 (m, 2H), 2.92 (m,
2H), 3.26 (s, 3H), 3.99 (m, 2H), 4.33 (m, 1H), 8.10 (d, 2H), 8.45
(s, 2H), 8.50 (s, 1H), 8.56 (d, 2H). Exact mass calculated for
C.sub.22H.sub.28N.sub.6O.sub.4S 472.19. found 473.4 (MH.sup.+).
Example 9.110
Preparation of
3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-pi-
peridine-1-carboxylic acid tert-butyl ester (Compound A24)
[0899] Compound A24 were prepared in a similar manner as described
in Example 9.94. .sup.1H NMR (CDCL3, 400 MHz) .delta. 1.40 (m, 2H),
1.47 (s,9H), 1.66 (m, 1H), 1.79 (m, 1H), 3.09 (s,3H), 3.49 (m, 3H),
3.79 (m, 1H), 4.31 (m, 1H), 5.83 (m, 1H), 8.08 (d, 2H), 8.19 (s,
1H), 8.51 (s, 1H), 8.59 (d, 2H). Exact mass calculated for
C.sub.22H.sub.28N.sub.6O.sub.4S 472.19. found 473.4 (MH.sup.+).
Example 9.111
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-pi-
peridine-1-carboxylic acid isopropyl ester (Compound A12)
[0900] Step 1: Preparation of
[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-piperidin-
-4-yl-amine.
[0901] In a 100 mL round-bottomed flask was placed a stir bar,
compound A11 (1 g), acetonitrile (40 mL), and dichloromethane (12
mL). After the compound was dissolved, 4M HCl in 1,4-dioxane (12
mL) was added under nitrogen and the mixture was stirred at room
temperature for 20 minutes. The solution was concentrated to about
60% of the original volume. The precipitate was isolated to give
[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-piperidin-
-4-yl-amine. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 1.98 (m,
2H), 2.11 (m, 2H), 3.02 (m, 2H), 3.26 (s, 3H), 3.36 (m, 2H), 4.44
(m, 1H), 8.11 (d, 2H), 8.47 (s, 1H), 8.56 (d, 2H), 8.79 (s, 1H).
Exact mass calculated for C.sub.17H.sub.20N.sub.6O.sub.2S 372.14.
found 373.2 (MH.sup.+).
[0902] Step 2: Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-pi-
peridine-1-carboxylic acid isopropyl ester (Compound A12).
[0903] Compound A12 was prepared in a similar manner as described
in Example 9.4. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.27 (d,
6H), 1.89 (m, 2H), 2.14 (m, 2H), 2.92 (m, 2H), 3.12 (s, 3H), 4.01
(m, 2H), 4.26 (m, 2H), 4.95 (m, 1H), 8.14 (d, 2H), 8.23 (s, 1H),
8.33 (s, 1H), 8.46 (d, 2H), 11.88 (s, 1H). Exact mass calculated
for C.sub.21H.sub.26N.sub.6O.sub.4S 458.17. found 459.4
(MH.sup.+).
Example 9.112
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-pi-
peridine-1-carboxylic acid isobutyl ester (Compound A13)
[0904] Compound A13 was prepared in a similar manner as described
in Example 9.4. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.96 (d,
6H), 1.57 (m, 2H), 1.97 (m, 2H), 2.22 (m, 2H), 3.01 (m, 2H), 3.12
(s, 3H), 3.90 (d, 2H), 4.25 (m, 2H), 4.38 (m, 1H), 8.09 (d, 2H),
8.15 (s, 1H), 8.49 (s, 1H), 8.57 (d, 2H), 11.88 (s, 1H). Exact mass
calculated for C.sub.22H.sub.28N.sub.6O.sub.4S 472.19. found 473.4
(MH.sup.+).
Example 9.113
Preparation of
{3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-p-
iperidin-1-yl}-(6-methyl-pyridin-3-yl)-methanone (Compound A55)
[0905] Step 1: Preparation of
[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-piperidin-
-3-yl-amine.
[0906] In a 20 mL round-bottomed flask was placed a stir bar,
compound A24 (215 mg) and acetonitrile (8 mL). After the compound
was dissolved, 4M HCl in 1,4-dioxane (2 mL) was added under
nitrogen and the mixture was stirred at room temperature for 20
minutes. The solution was concentrated to about 60% of the original
volume. The precipitate was isolated to give
[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-piperidin-
-3-yl-amine. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 1.98 (m,
2H), 2.11 (m, 2H), 3.02 (m, 2H), 3.26 (s, 3H), 3.36 (m, 2H), 4.44
(m, 1H), 8.11 (d, 2H), 8.47 (s, 1H), 8.56 (d, 2H), 8.79 (s, 1H).
Exact mass calculated for C.sub.17H.sub.20N.sub.6O.sub.2S 372.14.
found 373.2 (MH.sup.+).
[0907] Step 2: Preparation of
{3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-p-
iperidin-1-yl}-(6-methyl-pyridin-3-yl)-methanone (Compound
A55).
[0908] Compound A55 was prepared in a similar manner as described
in Example 9.25. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 1.67
(m, 1H), 1.77 (m, 1H), 1.97 (m, 1H), 2.11 (m, 1H), 2.55 (s,3H),
3.20 (m, 1H), 3.26 (s, 3H), 3.50 (m, 1H), 3.80 (m, 1H), 4.05 (m,
1H), 4.19 (m, 1H), 4.34 (m, 1H), 4.61 (m, 1H), 7.53 (m, 1H), 8.05
(m, 1H), 8.11 (d, 2H), 8.32 (m, 1H), 8.41 (m, 1H), 8.55 (m, 2H),
8.64 (m, 1H). Exact mass calculated for
C.sub.24H.sub.25N.sub.7O.sub.3S 491.17. found 492.3 (MH.sup.+).
Example 9.114
Preparation of
(3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-p-
iperidin-1-yl}-(2-methyl-pyridin-3-yl)-methanone (Compound A56)
[0909] Compound A56 was prepared in a similar manner as described
in Example 9.25. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 1.70
(m, 1H), 1.77 (m, 1H), 1.97 (m, 1H), 2.11 (m, 1H), 2.33 (m, 1H),
2.55 (m, 1H), 3.10 (m,2H), 3.26 (s, 3H), 3.50 (m, 1H), 4.05 (m,
1H), 4.10 (m, 1H), 4.34 (m, 1H), 4.56 (m, 1H), 7.53 (m, 1H), 8.11
(d, 2H), 8.13 (m, 1H), 8.40 (m, 1H), 8.51 (m, 1H), 8.55 (m, 2H),
8.57 (m,2H). Exact mass calculated for
C.sub.24H.sub.25N.sub.7O.sub.3S 491.17. found 492.3 (MH.sup.+).
Example 9.115
Preparation of
{3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-p-
iperidin-1-yl}-(5-methyl-pyridin-3-yl)-methanone (Compound A57)
[0910] Compound A57 was prepared in a similar manner as described
in Example 9.25. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 1.67
(m, 1H), 1.80 (m, 1H), 1.97 (m, 1H), 2.09 (m, 1H), 2.33 (m, 1H),
2.40 (m, 1H), 2.69 (m,2H), 3.26 (s, 3H), 3.40 (m, 1H), 3.70 (m,
1H), 4.17 (m,2H), 4.10 (m, 1H), 4.34 (m, 1H), 4.56 (m, 1H), 7.64
(m, 1H), 8.11 (d, 2H), 8.20 (m, 1H), 8.35 (m, 1H), 8.45 (m, 1H),
8.55 (m, 2H), 8.57 (m,2H). Exact mass calculated for
C.sub.24H.sub.25N.sub.7O.sub.3S 491.17. found 492.3 (MH.sup.+).
Example 9.116
Preparation of
{3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-p-
iperidin-1-yl}-pyridin-3-yl-methanone (Compound A58)
[0911] Compound A58 was prepared in a similar manner as described
in Example 9.25. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 1.67
(m, 1H), 1.80 (m, 1H), 1.97 (m, 1H), 2.09 (m, 1H), 2.33 (m, 1H),
2.40 (m, 1H), 2.69 (m,2H), 3.26 (s, 3H), 3.40 (m, 1H), 3.70 (m,
1H), 4.17 (m,2H), 4.10 (m, 1H), 4.34 (m, 1H), 4.56 (m, 1H), 7.64
(m, 1H), 8.11 (d, 2H), 8.20 (m, 1H), 8.35 (m, 1H), 8.45 (m, 1H),
8.55 (m, 2H), 8.57 (m,2H). Exact mass calculated for
C.sub.23H.sub.23N.sub.7O.sub.3S 477.16. found 478.3 (MH.sup.+).
Example 9.117
Preparation of
(3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-p-
iperidin-1-yl}-(1-methyl-1H-pyrrol-3-yl)-methanone (Compound
A59)
[0912] Compound A59 was prepared in a similar manner as described
in Example 9.25. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 1.60
(m, 1H), 1.69 (m, 1H), 1.87 (m, 1H), 2.11 (m, 1H), 2.69 (m,2H),
3.11 (m, 2H), 3.26 (s, 3H), 3.62 (s, 3H), 4.10 (m, 1H), 4.20 (m,
1H), 4.39 (m, 1H), 6.01 (m, 1H), 6.49 (m, 1H), 6.83 (s, 1H), 8.11
(d, 2H), 8.46 (s, 1H), 8.48 (s, 1H), 8.35 (m,1H), 8.56 (d, 2H),
8.57 (s, 1H). Exact mass calculated for
C.sub.23H.sub.25N.sub.7O.sub.3S 479.17. found 480.3 (MH.sup.+).
Example 9.118
Preparation of
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(4-trifluoromethyl-pyridin-3-yl)-methanone (Compound
A62)
[0913] Compound A62 was prepared in a similar manner as described
in Example 9.25. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 1.86
(m, 1H), 1.90 (m, 1H), 2.08 (m, 1H), 2.20 (m, 1H), 3.28 (s, 3H),
3.60 (m, 1H), 3.69 (m, 1H), 4.04 (m, 1H), 4.13 (m, 1H), 5.71 (m,
1H), 7.89 (d, 1H), 8.15 (d, 2H), 8.18 (m, 1H), 8.56 (d, 2H), 8.71
(s, 1H), 8.80 (s, 1H), 8.85 (m, 1H), 8.93 (m, 1H). Exact mass
calculated for C.sub.24H.sub.21F.sub.3N.sub.6O.sub.4S 546.13. found
547.2 (MH.sup.+).
Example 9.119
Preparation of
(6-tert-Butyl-pyridin-3-yl){4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3-
,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound
A70)
[0914] Step 1: Preparation of 6-tert-butyl-nicotinonitrile.
[0915] In an oven dried 500 mL round-bottomed flask equipped with
N.sub.2 inlet was placed 3-cyanopyridine (2 g) dissolved completely
in 100 mL of anhydrous Et.sub.2O. To the above solution under
N.sub.2 was added drop-wise 1.7 M t-BuLi in pentane using a
syringe. The addition was completed in about 30 min. The resulting
mixture was stirred for 20 hrs under N.sub.2 at room temperature.
The mixture was then cooled in an ice-bath for 20 min. Ice cooled
water (300 mL) was added dropwise. The dark greenish suspension
cleared out and became light yellowish solution. The solution was
extracted with EtOAc/H2O. The organic extracts was concentrated,
and purified by column chromatography on silica gel using
15%EtOAc/Hex. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.38 (s,
9H), 7.46 (d, 1H), 7.88 (m, 1H), 8.82 (s, 1H). Exact mass
calculated for C.sub.10H.sub.12N.sub.2 160.10. found 161.2
(MH.sup.+).
[0916] Step 2: Preparation of 6-tert-butyl-nicotinic acid.
[0917] In a 5 mL reaction vial was placed
6-tert-butyl-nicotinonitrile (160 mg) and 1.5 mL of conc. HCl. The
mixture was heated overnight at 80.degree. C. The resulting mixture
was concentrated under vacuum. The residue was purified by HPLC.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.49 (s, 9H), 7.81 (d,
1H), 8.76 (m, 1H), 9.48 (s, 1H). Exact mass calculated for
C.sub.10H.sub.13NO.sub.2 179.09. found 180.2 (MH.sup.+).
[0918] Step 3: Preparation of
(6-tert-Butyl-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[-
3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound
A70).
[0919] In a 20 mL reaction vial was placed a stir bar,
4-t-butylnictinic acid (30 mg),
O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (60 mg) and DMF (1 mL). The mixture was stirred
10 min at room temperature under N.sub.2.
1-(4-Methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyri-
midine (17.2 mg) and triethylamine (100 .mu.l) was added. After
stirred 3 hours at room temperature under N.sub.2, the reaction
mixture was filtered through a syringe filter. The filtrate was
concentrated and purified by HPLC. .sup.1H NMR (DMSO-d.sub.6, 400
MHz) .delta. 1.34 (s,9H), 1.88 (m, 2H), 2.14 (m,2H), 3.28 (s, 3H),
3.62 (m, 3H), 4.06 (m, 1H), 5.72 (m, 1H), 7.53 (d, 1H), 7.84 (m,
1H), 8.15 (d, 2H), 8.18 (m, 1H), 8.55 (d, 2H), 8.60 (m, 1H), 8.66
(s, 1H), 8.81 (s, 1H). Exact mass calculated for
C.sub.27H.sub.30N.sub.6O.sub.4S 534.20. found 535.4 (MH.sup.+).
Example 9.120
Preparation of
4-{[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-m-
ethyl}-piperidine-1-carboxylic acid tert-butyl ester (Compound
A76)
[0920] Compound A76 were prepared the same way as described in
Example 9.94. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.41 (s,
9H), 1.77 (m, 2H), 1.86 (m, 1H), 2.69 (m, 2H), 3.07 (s, 3H), 3.54
(m, 3H), 4.12 (m, 2H), 6.44 (m, 1H), 8.03 (d, 2H), 8.16 (s, 1H),
8.45 (s, 1H), 8.55 (d, 2H). Exact mass calculated for
C.sub.23H.sub.30N.sub.6O.sub.4S 486.20. found 487.4 (MH.sup.+).
Example 9.121
Preparation of
4-({[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-methy-
l-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester
(Compound A75)
[0921] Step 1: Preparation of
4-methylcarbamoyl-piperidine-1-carboxylic acid tert-butyl ester
[0922] To a stirred solution of 1-t-butoxycarbonyl-iso-nipecotic
acid (10 g) and Et.sub.3N (5.92 mL) in THF (32 mL) was added
drop-wise iso-butylchloroformate (5.66 mL) at 0.degree. C. The
resulting mixture was stirred at 0.degree. C. for 30 min before
diluted with THF (120 mL) and added 2M methylamine (80 mL). The
reaction mixture was stirred overnight at room temperature. Excess
THF was removed under vacuum. The residue was taken into H.sub.2O
and extracted into EtOAc. The organic extracts were washed with 1N
NaOH, followed by brine. After dried over Na.sub.2SO.sub.4, it was
concentrated to give the crude product.
[0923] Step 2: Preparation of
4-Methylaminomethyl-piperidine-1-carboxylic acid tert-butyl ester
In a 32 mL reaction vial was placed a stir bar and
4-methylcarbamoyl-piperidine-1-carboxylic acid tert-butyl ester
(0.97 g) dissolved in 12.8 mL anhydrous THF. The solution was
cooled to 0.degree. C. with an ice-bath. A 65% toluene solution of
Red-A1 (3.66 mL) was added dropwise at 0.degree. C. After the
addition was completed, the mixture was stirred under N.sub.2 at
room temperature until all the starting materials were just
consumed. The reaction mixture was worked up with H.sub.2O at
0.degree. C., extracted with EtOAc (.times.3). The EtOAc extract
was washed with saturated NaCl solution. After drying over
Na.sub.2SO.sub.4, the organic layer was concentrated to give 550 mg
of crude product.
[0924] Step 3: Preparation of
4-({[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-methy-
l-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester
(Compound A75).
[0925] Compound A75 was prepared the in a similar manner as
described in 9.94 by using
4-chloro-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine
and methylaminomethyl-piperidine-1-carboxylic acid tert-butyl ester
and purified by preparative thin layer chromatography. .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 1.27 (m, 2H), 1.44 (s, 9H), 1.63 (m,
2H), 2.03 (m, 1H), 2.69 (m, 2H), 3.09 (s, 3H), 3.49 (s, 3H), 4.12
(m, 2H), 8.08 (d, 2H), 8.18 (s, 1H), 8.49 (s, 1H), 8.57 (d, 2H).
Exact mass calculated for C.sub.24H.sub.32N.sub.6O.sub.4S 500.22.
found 501.4 (MH.sup.+).
Example 9.122
Preparation of
3-{[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-m-
ethyl}-piperidine-1-carboxylic acid tert-butyl ester (Compound
A77)
[0926] Compound A77 was prepared in a similar manner as described
in Example 9.94 and purified by preparative thin layer
chromatography using 50% EtOAc/Hex. .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta. 1.44 (s, 9H), 1.83 (m, 2H), 1.91 (m, 2H), 2.73 (m,
2H), 3.10 (s, 3H), 3.59 (s, 3H), 4.13 (m, 2H), 8.08 (d, 2H), 8.15
(s, 1H), 8.49 (s, 1H), 8.57 (d, 2H). Exact mass calculated for
C.sub.23H.sub.30N.sub.6O.sub.4S 486.20. found 487.4 (MH.sup.+).
Example 9.123
Preparation of
4-({[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4--
yl]-isopropyl-amino}-methyl)-piperidine-1-carboxylic acid isopropyl
ester (Compound A236)
[0927] Compound A236 was prepared in a similar manner as described
in Example 9.121 as a sticky oil (509 mg, 80%). Exact
mass-calculated for C.sub.25H.sub.33FN.sub.6O.sub.4S 532.2. found
533.3 (MH.sup.+).
Example 9.124
Preparation of
4-({Ethyl-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-
-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester
(Compound A78)
[0928] Step 1: Preparation of
4-(acetylamino-methyl)-piperidine-1-carboxylic acid tert-butyl
ester.
[0929] In a 32 mL reaction vial was placed a stir bar, Et.sub.3N
(0.5 mL) and 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl
ester (1.3 g) dissolved in 10 mL anhydrous THF. Acetic acid
chloride (0.48 g) was added dropwise through a syringe at 0.degree.
C. The mixture was stirred 2 hrs at room temperature. After worked
up with H.sub.2O at 0.degree. C., it was extracted with EtOAc. The
organic extracts were washed with 2M NaOH solution, NaHSO.sub.4 and
saturated NaCl solution. After dried over Na.sub.2SO.sub.4, it was
concentrated to give crude
4-(acetylamino-methyl)-piperidine-1-carboxylic acid tert-butyl
ester. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.14 (m, 2H), 1.45
(s, 9H), 1.65 (m,2H), 1.68 (m, 1H), 1.99 (s, 3H), 2.66 (m, 2H),
3.14 (m, 2H), 4.12 (m, 2H), 5.51 (m, 1H). Exact mass calculated for
C.sub.13H.sub.24N.sub.2O.sub.3 256.18. found 257.4 (MH.sup.+).
[0930] Step 2: Preparation of
4-Methylaminomethyl-piperidine-1-carboxylic acid tert-butyl
ester.
[0931] 4-Methylaminomethyl-piperidine-1-carboxylic acid tert-butyl
ester was prepared in a similar manner as described in Example
9.121. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.11 (m, 3H), 1.26
(m, 2H), 1.45 (s, 9H), 1.64 (m, 1H), 1.71 (m, 2H), 2.50 (m, 2H),
2.65 (m, 4H), 4.12 (m, 2H). Exact mass calculated for
C.sub.13H.sub.26N.sub.2O.sub.2 242.20. found 243.4 (MH.sup.+).
[0932] Step 3: Preparation of
4-({Ethyl-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-
-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester
(Compound A78).
[0933] Compound A78 was prepared in a similar manner as described
in Example 9.121. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.26
(m, 3H), 1.36 (m, 2H), 1.40 (s, 9H), 1.63 (m, 2H), 2.03 (m, 1H),
2.69 (m, 2H), 3.09 (s, 3H), 3.68 (m, 2H), 3.82 (m, 2H), 4.12 (m,
2H), 8.08 (d, 2H), 8.09 (s, 1H), 8.46 (s, 1H), 8.57 (d, 2H). Exact
mass calculated for C.sub.25H.sub.34N.sub.6O.sub.4S 514.24. found
515.4 (MH.sup.+).
Example 9.125
Preparation of
4-({Ethyl-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimi-
din-4-yl]-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl
ester (Compound A88)
[0934] Compound A88 was prepared in a similar manner as described
in Example 9.121. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.26
(m, 3H), 1.36 (m, 2H), 1.40 (s, 9H), 1.63 (m, 2H), 2.03 (m, 1H),
2.69 (m, 2H), 3.09 (s, 3H), 3.68 (m, 2H), 3.82 (m, 2H), 4.12 (m,
2H), 7.90 (m, 1H), 7.93 (m, 1H), 7.96 (m, 1H), 8.12 (s, 1H), 8.41
(s, 1H). Exact mass calculated for C.sub.25H.sub.33FN.sub.6O.sub.4S
532.23. found 533.4 (MH.sup.+).
Example 9.126
Preparation of
4-{1-[2-(2-Dimethylamino-ethoxy)-4-methanesulfonyl-phenyl]-1H-pyrazolo[3,-
4-d]pyrimidin-4-yloxy}-piperidine-1-carboxylic acid tert-butyl
ester (Compound A79)
[0935] Step 1: Preparation of
1-[2-(2-dimethylamino-ethoxy)-4-methanesulfonyl-phenyl]-1H-pyrazolo[3,4-d-
]pyrimidin-4-ol.
[0936] In a reaction vial was placed a stir bar and NaH (60% in
oil, 90 mg). Dimethylaminoethanol (200 mg) was dissolved in dioxane
(1.5 mL) and added to the reaction vial under N.sub.2. The mixture
was stirred at room temperature for 1 hour before
1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol
(50 mg) was added. The reaction mixture was heated at 70.degree. C.
for 60 hours. The resulting solution was concentrated under vacuum
and
1-[2-(2-dimethylamino-ethoxy)-4-methanesulfonyl-phenyl]-1H-pyrazolo[3,4-d-
]pyrimidin-4-ol was purified by preparative HPLC. .sup.1H NMR
(DMSO-d.sub.6, 400 MHz) .delta. 2.68 (s, 6H), 3.36 (s, 3H), 3.40
(m,2H), 4.54 (m, 2H), 7.74 (m, 1H), 7.78 (m, 1H), 7.85 (m, 1H),
8.10 (s, 1H), 8.37 (s, 1H), 9.75 (s, 1H), 12.5 (s, 1H). Exact mass
calculated for C.sub.16H.sub.19N.sub.5O.sub.4S 377.12. found 377.9
(MH.sup.+).
[0937] Step 2: Preparation of
{2-[2-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-5-methanesulfonyl-phenoxy]-
-ethyl}-dimethyl-amine.
[0938] In a reaction vial was placed a stir bar,
1-[2-(2-dimethylamino-ethoxy)-4-methanesulfonyl-phenyl]-1H-pyrazolo[3,4-d-
]pyrimidin-4-ol (50 mg), POCl.sub.3 (0.5 mL) and
N,N-dimethylaniline (15 .mu.l). The reaction mixture was stirred at
100.degree. C. for 1 hour. Upon cooling the reaction mixture to the
room temperature, a white precipitate formed. The mixture was left
sealed over the weekend at room temperature. After concentrated
under the vacuum, the residue was washed with Et.sub.2O and
filtered to give
{2-[2-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-5-methanesulfonyl-phenoxy]-
-ethyl}-dimethyl-amineas a white solid. Exact mass calculated for
C.sub.16H.sub.18ClN.sub.5O.sub.3S 395.08. found 396 (MH.sup.+).
[0939] Step 3: Preparation of
4-{1-[2-(2-Dimethylamino-ethoxy)-4-methanesulfonyl-phenyl]-1H-pyrazolo[3,-
4-d]pyrimidin-4-yloxy}-piperidine-1-carboxylic acid tert-butyl
ester (Compound A79).
[0940] In a reaction vial was place a stir bar, NaH (60% in oil,
110 mg), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester
(70 mg) and THF (3 mL). The mixture was stirred at room temperature
for 15 min under N.sub.2.
{2-[2-(4-Chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-5-methanesulfonyl-
-phenoxy]-ethyl}-dimethyl-amine was then added. The mixture was
stirred at 80.degree. C. for 30 min. After cooled down to room
temperature, the reaction was quenched with H.sub.2O and product
was extracted with CH.sub.2Cl.sub.2. The organic extracts were
concentrated under vacuum. The residue was purified by silica
column chromatography using 20% MeOH/CH.sub.2Cl.sub.2 as eluent to
give
4-{1-[2-(2-dimethylamino-ethoxy)-4-methanesulfonyl-phenyl]-1H-pyrazolo[3,-
4-d]pyrimidin-4-yloxy}-piperidine-1-carboxylic acid tert-butyl
ester. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.49 (s, 9H), 1.88
(m,2H), 2.10 (m, 2H), 2.20 (s, 6H), 2.67 (t, 2H), 3.10 (s, 3H),
3.32 (m, 2H), 3.87 (m, 2H), 4.28 (t, 2H), 5.59 (m, 1H), 7.70 (m,
3H), 8.25 (s, 1H), 8.54 (s, 1H). Exact mass calculated for
C.sub.26H.sub.36N.sub.6O.sub.6S 560.24. found 561.4 (MH.sup.+).
Example 9.127
Preparation of
4-({(2-Dimethylamino-ethyl)-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-
-d]pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylic acid
tert-butyl ester (Compound A98)
[0941] Step 1: Preparation of
4-(2-dimethylamino-ethylcarbamoyl)piperidine-1-carboxylic acid
tert-butyl ester.
[0942] 4-(2-Dimethylamino-ethylcarbamoyl)-piperidine-1-carboxylic
acid tert-butyl ester was prepared from
1-t-butoxycarbonyl-iso-nipecotic acid (5 g), iso-butylchloroformate
(2.83 mL) and N,N-dimethyl-1,2-ethylenediamine (2.63 mL). Exact
mass calculated for C.sub.15H.sub.29N.sub.3O.sub.3 299.22. found
300.4 (MH.sup.+).
[0943] Step 2: Preparation of
4-[(2-dimethylamino-ethylamino)-methyl]-piperidine-1-carboxylic
acid tert-butyl ester.
[0944]
4-[(2-Dimethylamino-ethylamino)-methyl]-piperidine-1-carboxylic
acid tert-butyl ester was made in a similar manner as described in
Example 9.121. Exact mass calculated for
C.sub.15H.sub.31N.sub.3O.sub.2 285.24. found 286.4 (MH.sup.+).
[0945] Step 3: Preparation of
4-({(2-Dimethylamino-ethyl)-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-
-d]pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylic acid
tert-butyl ester (Compound A98).
[0946] Compound A98 was prepared in a similar manner as described
in Example 9.121. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.28
(m, 2H), 1.46 (s,9H), 1.72 (m, 2H), 2.04 (m, 4H), 2.66 (m, 2H),
3.01 (s, 6H), 3.10 (s, 3H), 3.44 (m, 2H), 3.68 (m, 2H), 4.22 (m,
2H), 8.05 (s, 1H), 8.08 (d, 2H), 8.47 (s, 1H), 8.53 (d, 2H), 12.0
(s, 1H). Exact mass calculated for C.sub.27H.sub.39N.sub.7O.sub.4S
557.28. found 558.4 (MH.sup.+).
Example 9.128
Preparation of
4-({(2-Dimethylamino-ethyl)-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyr-
azolo[3,4-d]pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylic
acid tert-butyl ester (Compound A99)
[0947] Compound A99 was prepared in a similar manner as described
in Example 9.127. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.28
(m, 2H), 1.47 (s,9H), 1.72 (m, 2H), 2.04 (m,2H), 2.66 (m,2H), 3.01
(s, 6H), 3.13 (s, 3H), 3.46 (m, 2H), 3.69 (m, 2H), 4.22 (m, 4H),
8.05 (s, 1H), 7.88 (m, 1H), 7.91 (m, 1H), 7.94 (m, 1H), 8.11 (s,
1H), 8.44 (s, 1H), 12.0 (s, 1H). Exact mass calculated for
C.sub.27H.sub.38FN.sub.7O.sub.4S 575.27. found 576.4
(MH.sup.+).
Example 9.129
Preparation of
{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)1H-pyrazolo[3,4-d]pyrimidin-4-yl-
oxy]-piperidin-1-yl}-(4-trifluoromethoxy-phenyl)-methanone
(Compound A189)
[0948] In a 50 mL round-bottomed flask was placed
1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3-
,4-d]pyrimidine (300 mg, 0.7 mmol) and triethylamine (584 .mu.l).
DMF (6 mL) was added to completely dissolve the solid material. The
reaction flask was immersed in an ice-bath. Trifluoromethoxybenzoyl
chloride (180 mg, 0.8 mmol) was added to the solution and the
mixture was stirred 2 h under N.sub.2 at 0.degree. C. After all of
the starting amine was completely converted as indicated by LCMS,
the reaction was stopped by quenching with water. The reaction
mixture was then concentrated under vacuum and purified by
preparative HPLC. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.98
(m, 1H), 2.12 (m, 2H), 2.27 (m, 1H), 3.13 (s, 3H), 3.51 (m, 1H),
3.79 (m, 2H), 4.21 (m, 1H), 5.76 (m, 1H), 7.31 (d,2H), 7.52 (d,
2H), 7.95 (m,3H), 8.36 (s, 1H), 8.65 (s, 1H). Exact mass calculated
for C.sub.25H.sub.21F.sub.4N.sub.5O.sub.5S 579.12. found 580.2
(MH.sup.+).
Example 9.130
Preparation of
{4-[1-(3,5-Bis-trifluoromethyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylam-
ino]-cyclohexyl}-carbamic acid tert-butyl ester (Compound A44)
[0949]
1-(3,5-Bis-trifluoromethyl-phenyl)-4-chloro-1H-pyrazolo[3,4-d]pyri-
midine (147 mg, 0.4 mmol), (4-amino-cyclohexyl)-carbamic acid
tert-butyl ester (0.44 mmole, 1.1 eq) and diisopropylethyl amine
(0.44 mmol, 1.1 eq) were dissolved in THF (3 mL) and then stirred
at room temperature over night. THF was removed in vacuo and the
solid residue was re-dissolved in 30/70 mixture of water and ACN
gave yellow solid. The solid was washed with water and dried in
vacuo provided compound A44 as creamy green solid (179 mg, 82%).
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.43 (s, 9H), 1.75 (m,
2H), 1.98-1.97 (m, 2H), 2.04 (m, 2H), 2.95 (sb, 2H), 4.12 (q, 1H),
4.62 (m, 1H), 7.80 (s, 1H), 8.09 (s, 1H), 8.50 (s, 1H), 8.94 (s,
2H). Exact mass calculated for
C.sub.24H.sub.26F.sub.6N.sub.6O.sub.2 544.2. Found 545.5
(MH.sup.+).
Example 9.131
Preparation of
4-[1-(3,5-Bis-trifluoromethyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy-
]-piperidine-1-carboxylic acid tert-butyl ester (Compound A46)
[0950]
1-(3,5-Bis-trifluoromethyl-phenyl)-4-chloro-1H-pyrazolo[3,4-d]pyri-
midine (73 mg, 0.2 mmole), 4-hydroxy-piperidine-1-carboxylic acid
tert-butyl ester (0.3 mmole, 1.5 eq) and NaH (1.2 mmol, 6 eq) were
dissolved in THF (3 mL) and then stirred at room temperature
overnight. THF solvent was removed in vacuo and the oily solid
residue was re-dissolved in water and extracted with ethyl acetate
provided compound A46 as greenish yellow oil (111 mg, 90%). .sup.1H
NMR (CDCl.sub.3, 400 MHz) .delta. 1.48 (s, 9H), 1.88-1.84 (m, 2H),
2.09 (m, 2H), 3.35-3.29 (m, 2H), 3.87-3.80 (m, 2H), 5.62-5.59 (m,
1H), 7.81 (s, 1H), 8.26 (s, 1H), 8.69 (s, 1H), 8.96 (s, 2H). Exact
mass calculated for C.sub.23H.sub.23F.sub.6N.sub.5O.sub.3 531.17.
found 532.2 (MH.sup.+).
Example 9.132
Preparation of
(3,5-Dimethyl-isoxazol-4-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo-
[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound
A45)
[0951] Compound A45 was prepared in a similar manner as described
in Example 9.1 as creamy yellow solid (75 mg, 100%). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 1.50 (s, 9H), 1.87-1.85 (m, 2H),
2.11-2.09 (m, 2H), 2.88 (s, 3H), 3.28-3.23 (m, 2H), 3.36-3.31 (m,
4H), 3.88 (m, 2H), 5.62-5.59 (m, 1H), 7.41 (d, 2H), 8.18 (d, 2H),
8.21 (s, 1H), 8.62 (s, 1H). Exact mass calculated for
C.sub.24H.sub.31N.sub.5O.sub.5S 501.2. found 502.3 (MH.sup.+).
Example 9.133
Preparation of
4-[1-(3-Fluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1--
carboxylic acid tert-butyl ester (Compound A50)
[0952] Compound A50 was prepared in a similar manner as described
in Example 9.1 as a yellow solid (86 mg, 100%). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 1.49 (s, 9H), 1.89-1.84 (m, 2H), 2.09
(m, 2H), 3.36-3.29 (m, 2H), 3.85 (m, 2H), 5.59 (m, 1H), 7.07-7.03
(m, 1H), 7.52-7.46 (m, 1H), 8.08 (t, 2H), 8.21 (s, 1H), 8.64 (s,
1H). Exact mass calculated for C.sub.21H.sub.24FN.sub.5O.sub.3
413.19. found 414.4(MH.sup.+).
Example 9.134
Preparation of
{4-[1-(3-Fluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-cyclohexyl-
}-carbamic acid tert-butyl ester (Compound A53)
[0953] Compound A53 was made in a similar manner as described in
Example 9.130 as a white solid (108 mg, 100%). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 1.47 (s, 9H), 1.93-1.85 (m, 4H),
2.00-1.97 (m, 4H), 3.79 (sb, 1H), 4.02 (sb, NH), 4.85 (sb, 1H),
7.14 (t, 1H), 7.52 (tt, 1H), 7.90 (d, 1H), 7.95 (d, 1H), 8.19 (s,
1H), 8.26 (s, 1H), 11.5 (s, NH). Exact mass calculated for
C.sub.22H.sub.27FN.sub.6O.sub.2 426.22. found 427.4(MH.sup.+).
Example 9.135
Preparation of
{4-[1-(2,4-Difluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-cycloh-
exyl}-carbamic acid tert-butyl ester (Compound A52)
[0954] Compound A52 was prepared in a similar manner as described
in Example 9.130 as white solid (63 mg, 71%). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 1.47 (s, 9H), 1.93-1.87 (m, 4H),
2.01-1.98 (m, 4H), 3.79 (sb, 1H), 4.03 (sb, 1H), 4.88 (sb, 1H),
7.10 (t, 2H), 7.59-7.53 (m, 1H), 8.20 (s, 1H), 8.23 (s, 1H), 11.5
(s, 1H). Exact mass calculated for
C.sub.22H.sub.26F.sub.2N.sub.6O.sub.2 444.2. found
445.5(MH.sup.+).
Example 9.136
Preparation of
4-[1-(2,4-Difluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-
e-1-carboxylic acid tert-butyl ester (Compound A51)
[0955] Compound A51 was prepared in a similar manner as described
in Example 9.131 as a white solid (89 mg, 99%). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 1.49 (s, 9H), 1.88-1.84 (m, 2H), 2.09
(m, 2H), 3.36-3.30 (m, 2H), 3.86 (m, 2H), 5.60-5.58 (m, 1H),
7.10-7.05 (m, 2H), 7.61 (m, 1H), 8.26 (s, 1H), 8.58 (s, 1H). Exact
mass calculated for C.sub.21H.sub.23F.sub.2N.sub.5O.sub.3 431.2.
found 432.2(MH.sup.+).
Example 9.137
Preparation of
N-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-cyclohe-
xane-1,4-diamine (Compound A54)
[0956]
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yla-
mino]-cyclohexyl}-carbamic acid tert-butyl ester (30 mg, 0.06 mmol)
was dissolved in 4M HCl in dioxane (2 mL) and then stirred
overnight at 40.degree. C. The resulting solution was evaporated to
provide compound A54 as a white solid (24 mg, 100%). Exact mass
calculated for C.sub.18H.sub.22N.sub.6O.sub.2S 386.2. found
387.2(MH.sup.+).
Example 9.138
Preparation of
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-cyc-
lohexyl}-carbamic acid tert-butyl ester (Compound A60)
[0957] Compound A60 was prepared in a similar manner as described
in Example 9.131 as a white solid (45 mg, 46%). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 1.21-1.12 (m, 2H), 1.44 (s, 9H),
1.72-1.67 (m, 2H), 2.14 (db, 2H), 2.25 (db, 2H), 3.10 (s, 3H),
3.46-3.42 (m, 1H), 4.47 (sb, 1H), 5.38-5.33 (m, 1H), 8.10 (d, 2H),
8.25 (s, 1H), 8.60 (d, 2H), 8.65 (s, 1H). Exact mass calculated for
C.sub.23H.sub.29N.sub.5O.sub.5S 487.2. found 488.4(MH.sup.+).
Example 9.139
Preparation of
N-[1-(2,4-Difluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-cyclohexane--
1,4-diamine (Compound A61)
[0958] Following the general deprotection method in Example 9.6,
compound A61 was obtained as yellow solid (11 mg, 100%). Exact mass
calculated for C.sub.17H.sub.18F.sub.2N.sub.6 344.2. found
345.2(MH.sup.+).
Example 9.140
Preparation of
4-[1-(2,5-Difluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-
e-1-carboxylic acid tert-butyl ester (Compound A86)
[0959] Compound A86 was prepared in a similar manner as described
in Example 9.131 as a white solid (29 mg, 45%). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 1.49 (s, 9H), 1.89-1.84 (m, 2H),
2.12-2.07 (m, 2H), 3.36-3.29 (m, 2H), 3.89-3.58 (m, 2H), 5.60-5.58
(m, 1H), 7.19-7.17 (m, 1H), 7.31-7.28 (m, 1H), 7.43-7.39 (m, 1H),
8.27 (s, 1H), 8.60 (s, 1H). Exact mass calculated for
C.sub.21H.sub.23F.sub.2N.sub.5O.sub.3 431.18. found
432.3(MH.sup.+).
Example 9.141
Preparation of
4-[({1-[4-(2-Methanesulfonyl-ethyl)-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-
-yl}-methyl-amino)-methyl]-piperidine-1-carboxylic acid tert-butyl
ester (Compound A92)
[0960] Compound A92 was prepared in a similar manner as described
in Example 9.94 as a yellow solid (33 mg, 42%). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 1.33-1.28 (m, 2H), 1.47 (s, 9H), 1.73
(m, 1H), 2.07 (m, 1H), 2.81 (m, 2H), 2.90 (s, 3H), 3.27-3.23 (m,
2H), 3.36-3.33 (m, 2H), 3.50 (sb, 3H), 3.79 (m, 2H), 4.15 (m, 2H),
7.41 (d, 2H), 8.13-1.11 (m, 3H), 8.50 (sb, 1H). Exact mass
calculated for C.sub.26H.sub.36N.sub.6O.sub.4 S 528.2. found
529.3(MH.sup.+).
Example 9.142
Preparation of
4-({[1-(2,5-Difluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-methyl-ami-
no}-methyl)-piperidine-1-carboxylic acid tert-butyl ester (Compound
A93)
[0961] Compound A93 was prepared in a similar manner as described
in Example 9.94 as a yellow solid (7 mg, 10%). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 1.30 (m, 2H), 1.46 (s, 9H), 1.72 (m,
2H), 2.11-2.07 (m, 1H), 2.71 (m, 2H), 3.58 (s, 3H), 3.81 (m, 2H),
4.15 (m, 2H), 7.24-7.20 (m, 1H), 7.36-7.27 (m, 2H), 8.28 (s, 1H),
8.51 (s, 1H). Exact mass calculated for
C.sub.23H.sub.28F.sub.2N.sub.6O.sub.2 458.2. found
459.4(MH.sup.+).
Example 9.143
Preparation of
4-[1-(2-Methyl-4-propylamino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-
-piperidine-1-carboxylic acid isopropyl ester (Compound A215)
[0962]
4-[1-(4-Iodo-2-methyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-
-piperidine-1-carboxylic acid isopropyl ester (78 mg, 0.15 mmol),
propyl amine (0.75 mmole, 5 eq), proline (0.27 mole, 1.8 eq),
copper iodide (0.15 mmole, 1 eq), and potassium carbonate (0.15
mmole, 1 eq) were dissolved in DMSO (2 mL) and then stirred at
100.degree. C. for 30 mins in microwave. The crude was purified
through Prep-TLC (Hexane:Ethyl Acetate=1:1, Rf=0.7) to provid
compound A215 as white solid (36 mg, 53%). .sup.1H NMR 400 MHz
CDCl.sub.3 .delta. (ppm): 8.51 (s, 1H); 8.20(s, 1H);
7.40-7.36(m,1H); 7.30-7.21 (m,2H); 5.63-5.58 (m, 1H); 4.95 (sep,
1H); 3.89 (m, 2H); 3.41-3.35 (m, 2H); 3.23-3.19 (m,2H); 2.16-2.03
(m,4H); 1.89-1.86 (m,2H); 1.27 (d,6H); 1.04 (t,2H). Exact mass
calculated for C.sub.24H.sub.32N.sub.6O.sub.3 452.2. found LCMS
(ESI) m/z 453.4(M+H.sup.+, 100%).
Example 9.144
Preparation of
4-[1-(4-Isopropylamino-2-methyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylo-
xy]-piperidine-1-carboxylic acid isopropyl ester (Compound
A216)
[0963] Compound A216 was prepared in a similar manner as described
in Example 9.143 as yellow oil (25 mg, 38%). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 1.28 (d, 6H), 1.42 (d, 6H), 1.93-1.88
(m, 2H), 2.14-2.11 (m, 2H), 2.21 (s, 3H), 3.44-3.37 (m, 2H), 3.69
(sep, 1H), 3.93-3.89 (m, 2H), 4.96 (sep, 1H), 5.63 (m, 1H), 7.50
(s, 2H), 7.54 (s, 1H), 8.24 (s, 1H), 8.57 (s, 1H). Exact mass
calculated for C.sub.24H.sub.32N.sub.6O.sub.3 452.2. found 453.4
(MH.sup.+).
Example 9.145
Preparation of
4-[1-(2-Methyl-4-morpholin-4-yl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylo-
xy]-piperidine-1-carboxylic acid isopropyl ester (Compound
A217)
[0964] Compound A217 was prepared in a similar manner as described
in Example 9.143 as yellow oil (47 mg, 65%). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 1.28 (d, 6H), 1.94-1.89 (m, 2H),
2.15-2.09 (m, 2H), 2.19 (s, 3H), 3.45-3.39 (m, 2H), 3.53-3.50 (m,
4H), 3.94-3.88 (m, 2H), 4.12-4.10 (m, 4H), 4.96 (sep, 1H), 5.64 (m,
1H), 7.35 (d, 1H), 7.42 (s, 1H), 7.47 (d, 1H), 8.29 (s, 1H), 8.59
(s, 1H). Exact mass calculated for C.sub.25H.sub.32N.sub.6O.sub.4
480.3. found 481.4 (MH.sup.+).
Example 9.146
Preparation of
4-{1-[4-(2-Methoxy-ethylamino)-2-methyl-phenyl]-1H-pyrazolo[3,4-d]pyrimid-
in-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester (Compound
A218)
[0965] Compound A218 was prepared in a similar manner as described
in Example 9.143 as yellow oil (25 mg, 36%). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 1.27 (d, 6H), 1.90-1.86 (m, 2H),
2.12-2.03 (m, 2H), 2.12 (s, 3H), 3.40 (s, 3H), 3.45-3.35 (m, 4H),
3.71-3.66 (m, 2H), 3.90 (m, 2H), 4.95 (sep, 1H), 5.62-5.59 (m, 1H),
7.10 (sb, 2H), 7.33 (d, 1H), 8.20 (s, 1H). Exact mass calculated
for C.sub.24H.sub.32N.sub.6O.sub.4 468.3. found
469.4(MH.sup.+).
Example 9.147
Preparation of
4-(1-{4-[(2-Methanesulfonyl-ethyl)-methyl-amino]-2-methyl-phenyl}-1H-pyra-
zolo[3,4-d]pyrimidin-4-yloxy)-piperidine-1-carboxylic acid
isopropyl ester (Compound A219)
[0966] Compound A219 was prepared in a similar manner as described
in Example 9.143 as white gummy solid (6 mg, 7.5%). Exact mass
calculated for C.sub.25H.sub.34N.sub.6O.sub.5S 530.2. found
531.5(MH.sup.+).
Example 9.148
Preparation of
(2-{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin--
4-yloxy]-piperidin-1-yl}-5-methyl-pyrimidin-4-yl)dimethyl-amine
(Compound A212).
[0967]
1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-piperidin-4-yloxy)-1H-pyra-
zolo[3,4-d]pyrimidine HCl salt (0.3 g, 0.97 mmol) and
(2-chloro-6-methyl-pyrimidin-4-yl)-dimethyl-amine (285 mg, 0.97
mmol) were dissolved in DMF (10 mL). The solution was treated with
K.sub.2CO.sub.3 (398 mg, 2.91 mmol) at an ambient temperature.
After stirring at 65.degree. C. for five hours, the reaction was
poured into H.sub.2O (20 mL). The organic compound was extracted
with ethyl acetate (30 mL) and washed with brine. The ethyl acetate
layer was dried over MgSO.sub.4 and concentrated under vacuum. The
residue was purified over SiO.sub.2 to afford Compound A212 (312
mg, 65.2%). .sup.1H NMR (400 Mz, DMSO-d.sub.6) .delta. 8.69 (s,
1H), 8.64 (s, 1H), 8.17 (dd, J=8.4, 1.8, 1H), 8.08 (d, J=4.2, 1H),
8.01 (dd, J=8.4, 1.8, 1H), 7.72 (s, 1H), 5.65 (m, 1H),
4.23.about.4.20 (m, 2H), 3.50.about.3.46 (m, 2H), 3.39 (s, 3H),
3.00 (s, 6H), 2.13 (s, 3H), 2.10.about.2.09 (m, 2H),
1.77.about.1.72 (m, 2H). LCMS 527.5[M+1].
Example 9.149
Preparation of
1-(2-Fluoro-4-methanesulfonyl-phenyl)4-[1-(4-methyl-6-pyrrolidin-1-yl-pyr-
imidin-2-yl)-piperidin-4-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidine.
(Compound A2 13)
[0968]
1-(2-Fluoro-4-methanesulfonyl-phenyl)4-(piperidin-4-yloxy)-1H-pyra-
zolo[3,4-d]pyrimidine HCl salt (0.3 g, 0.97 mmol) and
(2-chloro-6-methyl-pyrimidin-4-yl)-dimethyl-amine (285 mg, 0.97
mmol) were dissolved in DMF (10 mL). The solution was treated with
K.sub.2CO.sub.3 (398 mg, 2.91 mmol) at an ambient temperature.
After stirring at 65.degree. C. for five hours, the reaction was
poured into H.sub.2O (20 mL). The organic compound was extracted
with ethyl acetate (30 mL) and washed with brine. The ethyl acetate
layer was dried over MgSO.sub.4 and concentrated under vacuum. The
residue was purified over SiO.sub.2 to afford Compound A213 (312
mg, 65.2%) as a white crystal. .sup.1H NMR (400 Mz, DMSO-d.sub.6)
.delta. 8.68 (s, 1H), 8.64 (s, 1H), 8.17 (dd, J=8.4, 1.8, 1H), 8.08
(d, J=4.2, 1H), 8.01 (dd, J=8.4, 1.8, 1H), 7.62 (s, 1H), 5.68 (m,
1H), 4.23.about.4.19 (m, 2H), 3.62.about.3.58 (m, 4H),
3.50.about.3.46 (m, 2H), 3.39 (s, 3H), 3.00 (s, 6H), 2.13 (s, 3H),
2.10.about.2.09 (m, 2H), 1.86.about.1.83 (m, 4H), 1.77.about.1.72
(m, 2H). LCMS 563.4[M+1].
Example 9.150
Preparation of
Furan-2-yl-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-
-yloxy]-piperidin-1-yl}-methanone (Compound A14)
[0969] Compound A14 was prepared in a similar manner as described
in Example 9.104 as an off-white solid (25 mg, 59%). .sup.1H NMR
400 MHz CDCl.sub.3 .delta. (ppm):2.25 (m, 2H); 2.48 (m, 2H); 3.35
(s, 3H); 3.95 (m, 2H); 4.42 (m, 2H); 5.97 (m, 1H); 6.75 (m, 1H);
7.28 (d, 1H); 7.75 (d, 1H); 8.35 (d, 2H); 8.52 (s, 1H); 8.86 (d,
2H); 8.93 (s, 1H). Exact mass calculated for
C.sub.22H.sub.21N.sub.5O.sub.5S 467.13. found 468.4 (MH.sup.+,
100%).
Example 9.151
Preparation of
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(1-methyl-1H-pyrrol-2-yl)methanone (Compound A15)
[0970] Compound A15 was prepared in a similar manner as described
in Example 9.25 as a grayish solid (22 mg, 54%). .sup.1H NMR 400
MHz CDCl.sub.3 .delta. (ppm): 8.68 (s, 1H); 8.63 (d, 2H); 8.28 (s,
1H); 8.11 (d, 2H); 6.73 (t, 1H); 6.38 (m, 1H); 6.10 (m, 1H); 5.71
(m, 1H); 4.20 (m, 2H); 3.81 (s, 3H); 3.65 (m, 2H); 3.10 (s, 3H);
2.19 (m, 2H); 1.96 (m, 2H). Exact mass calculated for
C.sub.23H.sub.24N.sub.6O.sub.4S 480.16. found 481.3 (MH.sup.+,
100%).
Example 9.152
Preparation of
2-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-p-
iperidin-1-yl}-1-pyridin-3-yl-ethanone (Compound A16)
[0971] Compound A16 was prepared in a similar manner as described
in Example 9.21 as a yellow solid (27 mg, 45%). .sup.1H NMR 400 MHz
CDCl.sub.3 .delta. (ppm): 9.12 (d, 1H); 8.73 (d, 1H); 8.72 (s, 1H);
8.56 (s, 1H); 8.50 (d, 2H); 8.28 (m, 1H); 8.08 (d, 2H); 7.50 (m,
1H); 5.38 (m, 1H); 3.87 (s, 2H); 3.21 (s, 3H); 2.81 (m, 2H); 2.46
(m, 2H); 2.04 (m, 2H); 1.76 (m, 2H). Exact mass calculated for
C.sub.24H.sub.24N.sub.6O.sub.4S 492.16. found 493.3 (MH.sup.+,
100%).
Example 9.153
Preparation of
2-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-p-
iperidin-1-yl}-1-thiophen-2-yl-ethanone (Compound A22)
[0972] Compound A22 was prepared in a similar manner as described
in Example 9.21 as an off-white solid (24 mg, 32%). .sup.1H NMR 400
MHz CDCl.sub.3 .delta. (ppm): 8.75 (s, 1H); 8.60 (d, 1H); 8.49 (d,
2H); 8.16 (m, 1H); 8.09 (d, 2H); 8.02 (m, 1H); 7.32 (m, 1H); 5.55
(m, 1H); 5.05 (m, 2H); 3.46 (m, 4H); 3.20 (s, 3H); 2.25 (m, 4H).
Exact mass calculated for C.sub.23H.sub.23N.sub.5O.sub.4S.sub.2
497.12. found 498.3 (MH.sup.+, 100%).
Example 9.154
Preparation of
1-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-p-
iperidin-1-yl}-3,3-dimethyl-butan-2-one (Compound A25)
[0973] Compound A25 was prepared in a similar manner as described
in Example 9.21 as an off-white solid (29 mg, 55%). .sup.1H NMR 400
MHz CDCl.sub.3 .delta. (ppm): 8.69 (s, 1H); 8.49 (d, 1H); 8.40 (d,
2H); 8.01 (m, 2H); 5.48 (m, 1H); 4.49 (m, 2H); 3.40 (m, 1H); 3.12
(s, 3H); 2.98 (m, 3H); 2.12 (m, 4H); 1.03 (s, 9H). Exact mass
calculated for C.sub.23H.sub.29N.sub.5O.sub.4S 471.19. found 472.4
(MH.sup.+, 100%).
Example 9.155
Preparation of
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(5-methyl-pyridin-3-yl)-methanone (Compound A18)
[0974] Compound A18 was prepared in a similar manner as described
in Example 9.25 as a solid (39 mg, 66%). .sup.1H NMR 400 MHz
CDCl.sub.3 .delta. (ppm): 8.82 (s, 1H); 8.67 (s, 1H); 8.58 (m, 2H);
8.51 (m, 1H); 8.46 (m, 1H); 8.17 (m, 2H); 7.71 (m, 1H); 5.71 (m,
1H); 4.06 (m, 1H); 3.62 (m, 2H); 3.29 (s, 3H); 2.36 (s, 3H); 2.17
(m, 2H); 1.89 (m, 2H). Exact mass calculated for
C.sub.24H.sub.24N.sub.6O.sub.4S 492.16. found 493.3 (MH.sup.+,
100%).
Example 9.156
Preparation of
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(2-methyl-pyridin-3-yl)-methanone (Compound A19)
[0975] Compound A19 was obtained in a similar manner as described
in Example 9.25 as an off-white solid (35 mg, 48%). .sup.1H NMR 400
MHz CDCl.sub.3 .delta. (ppm): 8.74 (s, 1H); 8.58 (s, 1H); 8.55 (m,
1H); 8.49 (m, 2H); 8.08 (m, 2H); 7.87 (m, 1H); 7.44 (m, 1H); 5.63
(m, 1H); 3.59 (m, 2H); 3.38 (m, 1H); 3.24 (m, 1H); 3.21 (s, 3H);
2.45 (s, 3H); 2.16 (m, 1H); 1.98 (m, 1H); 1.84 (m, 1H); 1.72 (m,
1H). Exact mass calculated for C.sub.24H.sub.24N.sub.6O.sub.4S
492.16. found 493.3 (MH.sup.+, 100%).
Example 9.157
Preparation of {4-[1-(4-Methanesulfonyl-phenyl)
H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(6-methyl-pyridin-3-y-
l)methanone (Compound A20)
[0976] Compound A20 was obtained in a similar manner as described
in Example 9.25 as an off-white solid (40 mg, 55%). .sup.1H NMR 400
MHz CDCl.sub.3 .delta. (ppm): 8.59 (s, 1 H); 8.43 (s, 1H); 8.42 (m,
1H); 8.34 (m, 2H); 7.94 (m, 2H); 7.75 (m, 1H); 7.29 (m, 1H); 5.49
(m, 1H); 3.31 (m, 4H); 3.06 (s, 3H); 2.35 (s, 3H); 1.93 (m, 2H);
1.65 (m, 2H). Exact mass calculated for
C.sub.24H.sub.24N.sub.6O.sub.4S 492.16. found 493.3 (MH.sup.+,
100%).
Example 9.158
Preparation of
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(5-methyl-isoxazol-3-yl)methanone (Compound A21)
[0977] Compound A21 was obtained in a similar manner as described
in Example 9.25 as a brownish solid (18 mg, 24%). .sup.1H NMR 400
MHz CDCl.sub.3 .delta. (ppm): 8.46 (s, 1H); 8.40 (d, 2H); 8.06 (s,
1 H); 7.89 (d, 2H); 6.11 (s, 1H); 5.52 (m, 1H); 3.98 (m, 2H); 3.55
(m, 2H); 2.89 (s, 3H); 2.28 (s, 3H); 1.97 (m, 2H); 1.82 (m, 2H).
Exact mass calculated for C.sub.22H.sub.22N.sub.6O.sub.5S 482.14.
found 483.2 (MH.sup.+, 100%).
Example 9.159
Preparation of
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(6-methyl-pyridin-3-yl)methanone (Compound A80)
[0978] Compound A80 was obtained in a similar manner as described
in Example 9.94 as a yellowish solid (75 mg, 58%). Exact mass
calculated for C.sub.22H.sub.27FN.sub.6O.sub.4S 490.18. found 491.3
(MH.sup.+, 100%).
Example 9.160
Preparation of
4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
oxy]-piperidine-1-carboxylic acid tert-butyl ester (Compound
A74)
[0979] Compound A74 was obtained in a similar manner as described
in Example 9.1 as a white solid (30 mg, 23%). .sup.1H NMR 400MHz
CDCl.sub.3 .delta. (ppm): 8.56 (s, 1H); 8.26 (s, 1H); 7.88 (m, 3H);
5.54 (m, 1H); 3.81 (m, 2H); 3.27 (m, 2H); 3.06 (s, 3H); 2.03 (m,
2H); 1.80 (m, 2H); 1.43 (s, 9H). Exact mass calculated for
C.sub.22H.sub.26FN.sub.5O.sub.5S 491.16. found 492.4 (MH.sup.+,
100%).
Example 9.161
Preparation of
4-[6-Dimethylamino-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimid-
in-4-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (Compound
A89)
[0980] Step 1: Preparation of
1-chloro-N'-[4-cyano-2-(4-methanesulfonyl-phenyl)-2H-pyrazol-3-yl]-N,N-di-
methyl-formamidine.
[0981] A solution of
5-amino-1-(4-methanesulfonyl-phenyl)-1H-pyrazole-4-carbonitrile
(1.2 g, 4.57 mmol) and phosgeniminium chloride (0.900 g, 7.08 mmol)
in dry 1,2-dichloroethane was refluxed for 4 h. The solvent was
removed under reduced pressure and the residue was purified by
flash chromatography (30 to 50% ethyl acetate/hexanes) to yield
1-chloro-N'-[4-cyano-2-(4-methanesulfonyl-phenyl)-2H-pyrazol-3-yl]-N,N-di-
methyl-formamidine (1.3 g, 80%) as a yellowish solid. Exact mass
calculated for C.sub.14H.sub.14ClN.sub.5O.sub.2S 351.06. found
352.20 (MH.sup.+, 100%).
[0982] Step 2: Preparation of
[4-Chloro-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]--
dimethyl-amine.
[0983] A stream of dry hydrogen chloride was passed through a
solution of
1-chloro-N'-[4-cyano-2-(4-methanesulfonyl-phenyl)-2H-pyrazol-3-yl]-N,N-di-
methyl-formamidine (0.600 g, 1.70 mmol) in 1,2-dichloroethane (20
mL) for 1 h. The solution was stirred at rt for 3 days. The solvent
was removed under reduced pressure and the crude washed several
times with dichloromethane.
[4-Chloro-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]--
dimethyl-amine recrystalized in dichloromethane and it was
retrieved by filtration as an off-white solid (0.4 g, 67%). Exact
mass calculated for C.sub.14H.sub.14ClN.sub.5O.sub.2S 351.06. found
352.20 (MH.sup.+, 100%).
[0984] Step 3: Preparation of
4-[6-Dimethylamino-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimid-
in-4-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (Compound
A89).
[0985] Compound A89 was made in a similar manner as described in
Example 9.1 as a white solid (100 mg, 90%). .sup.1H NMR (400 MHz
DMSO-d.sub.6) .delta. (ppm): 8.37 (d, 2H); 8.02 (s, 1H); 7.88 (d,
2H); 5.26 (m, 1H); 3.49 (m, 2H); 3.12 (m, 5H); 3.05 (s, 6H); 1.79
(m, 2H); 1.50 (m, 2H); 1.22 (s, 9H). Exact mass calculated for
C.sub.24H.sub.32N.sub.6O.sub.5S 516.22. found 517.3 (MH.sup.+,
100%).
Example 9.162
Preparation of
4-{Ethyl-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimid-
in-4-yl]-amino}-methyl)piperidine-1-carboxylic acid isopropyl ester
(Compound A87)
[0986] Compounds A87 was made in a similar manner as described in
Example 9.24 by using Compound A88. It was obtained as a white
solid (32 mg, 50%). .sup.1H NMR 400 MHz CDCl.sub.3 .delta. (ppm):
8.41 (s, 1H); 8.13 (s, 1H); 7.86 (m, 2H); 7.79 (m, 1H); 4.85 (m,
1H); 4.41 (s, 2H); 3.66 (m, 4H); 3.05 (s, 3H); 2.67 (m, 2H); 2.08
(d, 1H); 1.65 (s, 2H); 1.39 (m, 4H); 1.18 (d, 6H). Exact mass
calculated for C.sub.24H.sub.31FN.sub.6O.sub.4S 518.21. found 519.5
(MH.sup.+, 100%).
Example 9.163
Preparation of
4-[1-(2-Dimethylamino-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimid-
in-4-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (Compound
A100)
[0987] Step 1: Preparation of
1-(2-dimethylamino-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin--
4-ol.
[0988]
1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin--
4-ol (0.520 g, 1.68 mmol) was dissolved in DMSO (3 mL) and
dimethylamine (2M solution in THF) (4 mL, 150 mmol) was added. The
mixture was heated at 120.degree. C. for 15 h. The solvent was
removed under reduced pressure and the crude was purified by HPLC,
yielding
1-(2-dimethylamino-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin--
4-ol as an off-white solid (0.500 g, 89%). Exact mass calculated
for C.sub.14H.sub.15N.sub.5O.sub.3S 333.09. found 334.4 (MH.sup.+,
100%).
[0989] Step 2: Preparation of
4-[1-(2-Dimethylamino-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimid-
in-4-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (Compound
A100).
[0990]
1-(2-Dimethylamino-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyr-
imidin-4-ol (66 mg, 0.200 mmol), 4-hydroxy-piperidine-1-carboxylic
acid tert-butyl ester (61 mg, 0.300 mmol) and triphenylphosphine
(52 mg, 0.200 mmol) were dissolved in toluene (5 mL) and the
mixture stirred at 0.degree. C. for 15 min. Diisopropyl
azodicarboxylate (28 .mu.L, 0.200 mmol) was then added and the
reaction kept going at rt for 16 h. The solvent was removed under
reduced pressure and the crude was purified by HPLC. Compound A100
was obtained as a yellowish solid. Exact mass calculated for
C.sub.24H.sub.32N.sub.6O.sub.5S 516.22. found 517.3 (MH.sup.+,
100%). .sup.1R NMR (400 MHz CDCl.sub.3) .delta. (ppm): 8.50 (s,
1H); 8.22 (s, 1H); 7.42(m, 3H); 5.52 (m, 1H); 3.81 (m, 2H); 3.26
(m, 2H); 3.03 (s, 3H); 2.47 (s, 6H); 2.03 (m, 2H); 1.80 (m, 2H);
1.42 (s, 9H).
Example 9.164
Preparation of
4-{2-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-e-
thyl}-piperazine-1-carboxylic acid ethyl ester (Compound A103)
[0991] Compound A103 was made in a similar manner as described in
Example 9.131 as a white solid (46 mg, 49%). .sup.1H NMR (400 MHz
DMSO-d.sub.6). .delta. (ppm): 8.78 (s, 1H); 8.66 (s, 1H);8.50(m,
2H); 8.10 (m, 2H); 4.90 (s, 2H); 4.00 (m, 4H); 3.49 (m, 5H); 3.12
(s, 3H); 3.02(m, 3H); 14 (t, 3H). Exact mass calculated for
C.sub.21H.sub.26N.sub.6O.sub.5S 474.17. found 475.3 (MH.sup.+,
100%).
Example 9.165
Preparation of
4-{2-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-p-
ropyl}-piperazine-1-carboxylic acid ethyl ester (Compound A104)
[0992] Compound A104 was obtained in a similar manner as described
in Example 9.131 as a white solid (47 mg, 48%). .sup.1H NMR (400
MHz DMSO-d.sub.6) .delta. (ppm): 8.66 (s, 1H); 8.45 (s, 1H);
8.37(m, 2H); 7.98 (m, 2H); 5.73 (m, 1H); 3.87 (m, 4H); 3.37 (m,
5H); 3.06 (s, 3H); 3.02(m, 3H); 1.30(d, 3H); 1.14 (t, 3H). Exact
mass calculated for C.sub.22H.sub.28N.sub.6O.sub.5S 488.18. found
489.30 (MH.sup.+, 100%).
Example 9.166
Preparation of
(5-Fluoro-pyridin-2-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4--
d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound A171)
[0993] Compound A171 was prepared in a similar manner as described
in Example 9.25 as an orange solid (15.5 mg; 50.7%). Exact mass
calculated for C.sub.23H.sub.21FN.sub.6O.sub.4S 496.13. found
497.10 (MH.sup.+, 100%).
Example 9.167
Preparation of
(2-Chloro-5-fluoro-pyridin-3-yl{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazo-
lo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound
A173)
[0994] Compound A173 was obtained in a similar manner as described
in Example 9.25 as a brownish solid (14.9 mg, 46.2%). Exact mass
calculated for C.sub.23H.sub.20ClFN.sub.6O.sub.4S 530.09. found
531.10 (MH.sup.+, 100%).
Example 9.168
Preparation of
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(4-methoxy-pyridin-2-yl)-methanone (Compound A177)
[0995] Compound A177 was obtained in a similar manner as described
in Example 9.25 as an off-white solid (11.7 mg, 37.6%). Exact mass
calculated for C.sub.24H.sub.24N.sub.6O.sub.5S 508.15. found 509.1
(MH.sup.+, 100%).
Example 9.169
Preparation of
(2-Fluoro-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4--
d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound A179)
[0996] Compound A179 was obtained in a similar manner as described
in Example 9.25 as an orange solid (11.7 mg, 37.6%). Exact mass
calculated for C.sub.23H21FN.sub.6O.sub.4S 496.13. found 497.10
(MH.sup.+, 100%).
Example 9.170
Preparation of
(6-Fluoro-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4--
d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound A180)
[0997] Compound A180 was obtained in a similar manner as described
in Example 9.25 as a brownish solid (15.5 mg, 50%). Exact mass
calculated for C.sub.23H.sub.21FN.sub.6O.sub.4S 496.13. found
497.10 (MH.sup.+, 100%).
Example 9.171
Preparation of
(4-Iodo-pyridin-2-yl)-{4-[1-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]p-
yrimidin-4-yloxy]-piperidin-1-yl}-methanone (Compound A167)
[0998] Compound A167 was obtained in a similar manner as described
in Example 9.25 as a brownish solid (15.5 mg, 50%). Exact mass
calculated for C.sub.23H.sub.21IN.sub.6O.sub.4S 604.04. found 605.1
(MH.sup.+, 100%).
Example 9.172
Preparation of
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(4-methoxy-thiophen-3-yl)-methanone (Compound
A181)
[0999] Compound A181 was obtained in a similar manner as described
in Example 9.25 as a white solid (7.2 mg, 23%). Exact mass
calculated for C.sub.23H.sub.23N.sub.5O.sub.5S.sub.2 513.11. found
514.2 (MH.sup.+, 100%).
Example 9.173
Preparation of
4-(1-Benzyl-azetidin-3-yloxy)1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-
-d]pyrimidine (Compound A23)
[1000] 1-Benzyl-azetidin-3-ol hydrochloride salt (0.59 mmol, 117
mg) and sodium hydride were dissolved in dimethyl acetamide (2 mL)
and stirred at room temperature for 30 minutes.
4-Chloro-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine
(0.49 mmol, 150 mg) was added slowly and the mixture was stirred at
70.degree. C. for 20 minutes. The reaction mixture was quenched
with water followed by an extraction with ethyl acetate. Removal of
organic solvents in vacuo and purification by flash chromatography
provided compound A23 as a white solid (88 mg, 41%). .sup.1HNMR
(400 MHz, DMSO-d.sub.6) .delta. (ppm): 8.90 (s, 1H); 8.53 (s, 1H);
8.30 (d, 2H); 8.16 (d, 2H); 7.43 (m, 5H); 6.19 (m, 1H); 4.59 (m,
2H); 4.42 (d, 1H); 4.00 (d, 1H); 3.65 (d, 1H); 3.35 (m, 1); 3.30
(s, 3H).
Example 9.174
Preparation of
3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-azet-
idine-1-carboxylic acid isopropyl ester (Compound A47)
[1001] Step 1: Preparation of
4-(azetidin-3-yloxy)-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrim-
idine.
[1002]
4-(1-Benzyl-azetidin-3-yloxy)-1-(4-methanesulfonyl-phenyl)-1H-pyra-
zolo[3,4-d]pyrimidine (0.01 mmol, 46 mg) was dissolved in a mixture
of ethyl acetate (5 mL) and methanol (5 mL). Palladium catalyst (30
mg, 65% by wt) was added to the reaction. The mixture was exposed
to hydrogen gas for 60 minutes at room temperature and atmospheric
pressure. The mixture was passed through celite to remove palladium
catalyst. Removal of organic solvents in vacuo and purification by
flash chromatography provided
4-(azetidin-3-yloxy)-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,-
4-d]pyrimidine as a white solid (11 mg, 5%). .sup.1H NMR (400 MHz,
MeOH-d.sub.4) .delta. (ppm): 8.45 (m, 2H); 8.37 (d, 2H); 8.05 (d,
2H); 4.54 (m, 1H); 4.35 (dd, 2H); 3.69 (m, 2H); 3.09 (s, 3H). LCMS
(ESI), m/z 346.2 (M+H+, 100%).
[1003] Step 2: Preparation of
3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-azet-
idine-1-carboxylic acid isopropyl ester (Compound A47).
[1004] Compound A47 was made in a similar manner as described in
Example 9.24 as a white solid (26 mg, 55%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. (ppm): 8.66 (s, 1H); 8.62 (d, 2H); 8.31 (s,
1H); 8.11 (d, 2H); 5.65 (m, 1H); 4.93 (h, 1H); 4.48 (m, 2H); 4.18
(m, 2H); 3.11 (s, 3H); 1.25 (d, 6H). LCMS (ESI), m/z 432.3 (M+H+,
100%)
Example 9.175
Preparation of
{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-y-
loxy]-piperidin-1-yl}-(3-trifluoromethoxy-phenyl)-methanone
(Compound A197)
[1005] Compound A197 was made in a similar manner as described in
Example 9.28 as a white solid (221 mg, 46%). Exact mass calculated
for C.sub.25H.sub.22F.sub.3N.sub.5O.sub.2S 579.56. found 580.4
(MH.sup.+).
Example 9.176
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid propyl ester (Compound A49)
[1006] Compound A49 was made in a similar manner as described in
Example 9.24 as a white solid (36 mg, 46%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. (ppm): 8.69 (s, 1H); 8.62 (d, 2H); 8.26 (s,
1H); 8.10 (d, 2H); 5.61 (h, 1H); 4.22 (t, 2H); 4.08 (m, 2H); 3.40
(m, 2H); 3.10 (s, 3H); 2.11 (m, 2H); 1.87 (m, 2H), 1.64 (s, 2H);
0.97 (t, 3). LCMS (ESI), m/z 460.3 (MH+, 100%)
Example 9.177
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid cyclohexyl ester (Compound A63)
[1007] Carbonyldiimidizole (0.28 mmol, 46 mg), and cyclohexanol
(0.28 mmol, 34 .mu.L) were dissolved in DMF (2 mL) and stirred for
30 minutes at room temperature. Then,
1-(4-Methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyri-
midine hydrochloride salt (0.16 mmol, 60 mg) and triethylamine
(0.84 mmol, 118 .mu.L) were added and continued to stir at
60.degree. C. for 24 hours. The reaction mixture was quenched with
water followed by an extraction with ethylacetate. Removal of
organic solvents in vacuo and purification by HPLC provided
compound A63 as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. (ppm): 8.67 (s, 1H); 8.61 (d, 2H); 8.26 (s, 1H); 8.11 (d,
2H); 5.62 (h, 1H); 4.71 (h, 1H); 3.91 (m, 2H); 3.38 (m, 2H); 3.10
(s, 3H); 2.10 (m, 2H); 1.87 (m, 4H), 1.65 (m, 6H); 1.28 (m, 2H).
LCMS (ESI), m/z 500.4 (MH+, 100%)
Example 9.178
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid tetrahydro-pyran-4-yl ester (Compound
A64)
[1008] Compound A64 was made in a similar manner as described in
Example 9.177 as a white solid (7 mg, 9%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. (ppm): 8.67 (s, 1H); 8.62 (d, 2H); 8.26 (s,
1H); 8.11 (d, 2H); 5.13 (h, 1H); 4.89 (h, 1H); 3.92 (m, 4H); 3.58
(m, 2H); 3.40 (m, 2H); 3.11 (s, 3H); 2.12 (m, 2H), 1.90 (m, 4H);
1.71 (m, 2H). LCMS (ESI), m/z 502.3 (MH+, 100%)
Example 9.179
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid cyclopentyl ester (Compound A65)
[1009] Compound A65 was made in a similar manner as described in
Example 9.177 as a white solid (13 mg, 18%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. (ppm): 8.67 (s, 1H); 8.62 (d, 2H); 8.26 (s, 1
H); 8.11 (d, 2H); 5.61 (h, 1H); 5.14 (m, 1 H); 3.89 (m, 2H); 3.36
(m, 2H); 3.10 (s, 3H); 2.10 (m, 2H); 1.88 (m, 4H), 1.74 (m, 4H);
1.61 (m, 2H). LCMS (ESI), m/z 486.3 (MH+, 100%)
Example 9.180
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid tetrahydro-furan-3-yl ester (Compound
A67)
[1010] Compound A67 was made in a similar manner as described in
Example 9.177 as a white solid (12 mg, 16%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. (ppm): 8.67 (s, 1H); 8.61 (d, 2H); 8.26 (s,
1H); 8.10 (d, 2H); 5.63 (h, 1H); 5.30 (m, 1H); 3.91 (m, 6H); 3.41
(m, 2H); 3.11 (s, 3H); 2.18 (m, 4H); 1.95 (m, 2H). LCMS (ESI), m/z
488.3 (MH+, 100%)
Example 9.181
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid tetrahydro-furan-3-yl ester (Compound
A66)
[1011] Compound A65 was made in a similar manner as described in
Example 9.177 as a white solid (11 mg, 15%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. (ppm): 8.67 (s, 1H); 8.61 (d, 2H); 8.26 (s,
1H); 8.11 (d, 2H); 5.63 (h, 1H); 5.29 (m, 1H); 3.90 (m, 6H); 3.41
(m, 2H); 3.11 (s, 3H); 2.18 (m, 4H); 1.97 (m, 2H). LCMS (ESI), m/z
488.2 (MH+, 100%)
Example 9.182
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid tetrahydro-thiopyran-4-yl ester (Compound
A68)
[1012] Compound A68 was made in a similar manner as described in
Example 9.177 as a white solid (4 mg, 5%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. (ppm): 8.67 (s, 1H); 8.61 (d, 2H); 8.26 (s,
1H); 8.11 (d, 2H); 5.63 (h, 1 H); 4.80 (h, 1 H); 4.22 (m, 2H); 3.41
(m, 2H); 3.11 (s, 3H); 2.79 (m, 2H); 2.64 (m, 2H); 2.15 (m, 4H);
1.91 (m, 4H). LCMS (ESI), m/z 518.2 (MH+, 100%)
Example 9.183
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid cyclobutyl ester (Compound A69)
[1013] Compound A65 was made in a similar manner as described in
Example 9.177 as a white solid (13 mg, 19%). .sup.1H-NMR(400 MHz,
CDCl.sub.3) .delta. (ppm): 8.67 (s, 1H); 8.6 (d, 2H); 8.26 (s, 1H);
8.10 (d, 2H); 5.632 (h, 1H); 4.97 (p, 1H); 3.89 (m, 2H); 3.40 (m,
2H); 3.10 (s, 3H); 2.36 (m, 2H); 2.10 (m, 4H); 1.88 (m, 4H). LCMS
(ESI), m/z 472.4 (MH+, 100%)
Example 9.184
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid pyridin-3-ylmethyl esteracid tert-butyl
ester (Compound A81)
[1014] Compound A81 was made in a similar manner as described in
Example 9.177 as a white solid (31 mg, 28%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. (ppm): 8.93 (s, 1H); 8.81 (d, 1H); 8.67 (s,
1H); 8.61 (d, 2H); 8.30 (d, 1H); 8.26 (s, 1H); 8.11 (d, 2H); 7.84
(m, 1H); 5.65 (h, 1H); 5.33 (s, 2H); 3.91 (m, 2H); 3.50 (m, 2H);
3.11 (s, 3H); 2.15 (m, 2H); 1.91 (m, 2H). LCMS (ESI), m/z 509.0
(MH+, 100%)
Example 9.185
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid 2-pyridin-3-yl-ethyl ester (Compound
A82)
[1015] Compound A82 was made in a similar manner as described in
Example 9.177 as a white solid (35 mg, 30%). .sup.1H NMR (400 MHz,
MeOH-d.sub.4) .delta. (ppm): 7.54 (s broad, 1H); 7.44 (m, 1H); 7.36
(m, 3H); 7.24 (d, 1H); 7.09 (s, 1H); 6.85 (d, 2H); 6.71 (m, 1H);
4.37(h, 1H); 3.4 (t, 2H); 2.52 (m, 2H); 2.10 (m, 2H); 1.97 (t,
2H);1.94 (s, 3); 0.81 (m, 2H); 0.56 (m, 2H). LCMS (ESI), m/z 523.2
(MH+, 100%)
Example 9.186
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid 3-pyridin-3-yl-propyl ester (Compound
A83)
[1016] Compound A83 was made-in a similar manner as described in
Example 9.177 as a white solid (28 mg, 24%). .sup.1H NMR (400 MHz,
MeOH-d.sub.4) .delta. (ppm): 7.64 (s broad, 1H); 7.38 (m, 4H); 7.16
(d, 1H); 7.10 (s, 1H); 6.84 (d, 2H); 6.66 (m, 1H); 4.38(h, 1H);
2.89 (t, 2H); 2.57 (m, 2H); 2.12 (m, 2H); 1.89 (s, 3H); 1.68 (t,
2H); 0.81 (m, 4H); 0.59 (m, 2H). LCMS (ESI), m/z 537.2 (MH+,
100%)
Example 9.187
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid 2-dimethylamino-ethyl (Compound A84)
[1017] Compound A84 was made in a similar manner as described in
Example 9.177 as a white solid (16 mg, 15%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. (ppm): 7.37 (m, 3H); 7.11 (s, 1H); 6.83 (d,
2H); 4.39 (h, 1H); 2.95 (t, 2H); 2.61 (m, 2H); 2.03(m, 2H); 1.89
(s, 3H); 1.37 (t, 2H); 1.03 (s, 6H); 0.86 (m, 2H); 0.60 (m, 2H).
LCMS (ESI), m/z 489.2 (MH+, 100%)
Example 9.188
Preparation of
4-{[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-methyl-
-amino}-piperidine-1-carboxylic acid tert-butyl ester (Compound
A85)
[1018] Compound A85 was made in a similar manner as described in
Example 9.130 as a yellow solid (750 mg, 95%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. (ppm): 8.59 (d, 2H); 8.51 (s broad, 1H);
8.12 (s, 1H); 8.08 (d, 2H); 4.18 (m, 2H); 3.59 (s broad, 2H); 3.10
(s, 3H); 2.73 (m, 2H); 1.91 (m, 1H); 1.79 (m, 2); 1.70 (s broad,
3H); 1.43 (s, 9H). LCMS (ESI), m/z 487.1 (MH+, 100%)
Example 9.189
Preparation of
1-(4-{[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-met-
hyl-amino}-piperidin-1-yl)-3,3-dimethyl-butan-2-one (Compound
A90)
[1019] Compound A90 was made in a similar manner as described in
Example 9.21 as a white solid (14 mg, 12%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. (ppm): 8.58 (d, 2H); 8.09 (t, 3H); 3.59 (s
broad, 2H); 3.39 (s, 2H); 3.09 (s, 3H); 2.95 (m, 2H); 2.05 (m, 2H);
1.79 (m, 3H); 1.66 (m, 4H); 1.16 (s, 9H). LCMS (ESI), m/z 485.3
(MH+, 100%).
Example 9.190
Preparation of
4-{[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-methyl-
-amino}-piperidine-1-carboxylic acid cyclobutyl ester (Compound
A91)
[1020] Compound A91 was made in a similar manner as described in
Example 9.177 as a white solid (62 mg, 35%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. (ppm): 8.60 (d, 2H); 8.57 (s broad, 1H); 8.13
(s, 1H); 8.07 (d, 2H); 4.93 (p,1H); 4.22 (m, 2H); 3.58 (s broad,
2H); 3.10 (s, 3H); 2.75 (s broad, 2H); 2.34 (m, 2H); 2.06 (m, 2H),
1.93 (m, 1H); 1.75 (m, 7H). LCMS (ESI), m/z 485.2 (MH+, 100%).
Example 9.191
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl]-
-piperidine-1-carboxylic acid tert-butyl ester (Compound A102)
[1021]
4-Chloro-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine
(1.23 mmol, 250 mg), 4-mercapto-piperidine-1-carboxylic acid
tert-butyl ester (1.23 mmol, 268 mg) and potassium carbonate (1.4
mmol, 203 mg) were dissolved in DMF (10 mL) and stirred for 60
minutes at room temperature. Its progress was followed by thin
layer chromatography and LCMS. The reaction mixture was quenched
with water followed by an extraction with ethylacetate. Removal of
organic solvents in vacuo and purification by column chromatography
provided compound A102 as a white solid (264 mg, 66%). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. (ppm): 8.83 (s, 1H); 8.61 (d, 2H);
8.24 (s, 1H); 8.11 (d, 2H); 4.42 (h, 1H); 4.00 (m, 2H); 3.20 (m,
2H); 3.15 (s, 3H); 2.19 (m, 2H); 1.77 (m, 2H); 1.46 (s, 9H). LCMS
(ESI), m/z 490.3 (MH+, 100%)
Example 9.192
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-sulfinyl]--
piperidine-1-carboxylic acid tert-butyl ester (Compound A105)
[1022] Compound A102 (0.51 mmol, 250 mg) was dissolved in
1,2-dichloroethane (15 mL). To this was added MCPBA (0.51 mmol, 88
mg). The mixture was allowed to stir overnight at room temperature.
Its progress was monitored by thin layer chromatography and LCMS.
The reaction mixture was washed with a solution of ammonium
chloride in water (pH10) and a solution of sodium bicarbonate in
water. The product was extracted with dichloromethane. Removal of
organic solvents in vacuo and purification by HPLC provided
compound A105 as a white solid (29 mg, 12%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. (ppm): 9.12 (s, 1H); 9.03 (s, 1H); 8.66 (d,
2H); 8.15 (d, 2H); 4.22 (m, 1H); 4.20 (m, 2H); 3.43 (m, 1H); 3.13
(s, 3H); 2.74 (m, 2H); 2.26 (m, 1H); 2.00 (m, 2H), 1.57 (s, 9H).
LCMS (ESI), m/z 506.2 (MH+, 100%)
Example 9.193
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-sulfonyl]--
piperidine-1-carboxylic acid tert-butyl ester (Compound A106)
[1023] Compound A102 (0.31 mmol, 150 mg) was dissolved in
1,2-dichloroethane (15 mL). To this was added MCPBA in excess (1.5
mmol, 268 mg). The mixture was refluxed for 1.0 hour. Its progress
was monitored by thin layer chromatography and LCMS. The reaction
mixture was washed with a solution of ammonium chloride in water
(pH10) and a solution of sodium bicarbonate in water. The product
was extracted in dichloromethane. Removal of organic solvents in
vacuo and purification by HPLC provided compound A106 as a white
solid (46 mg, 25%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
(ppm): 9.31 (s, 1H); 8.86 (s, 1H); 8.65 (d, 2H); 8.17 (d, 2H); 4.25
(m, 3H); 3.90 (m, 1H); 3.13 (s, 3H); 2.80 (m, 1H); 2.03 (m, 2H);
1.86 (m, 2H); 1.70 (s, 9H). LCMS (ESI), m/z 522.3 (MH+, 100%)
Example 9.194
Preparation of
4-[1-(2-Fluoro4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yls-
ulfanyl]-piperidine-1-carboxylic acid butyl ester (Compound
A108)
[1024] Step 1: Preparation of
1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-ylsulfanyl)-1H-pyraz-
olo[3,4-d]pyrimidine.
[1025] Compound A107 (1.22 mmol, 620 mg) was dissolved in
dichloromethane (15 mL). To this was added a solution of 4M HCl in
dioxane (8 mL) at room temperature. The reaction was stirred for 30
minutes at 40.degree. C. The progress of the reaction was monitored
by LCMS. Evaporation of organic solvents in vacuo provided
1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-ylsulfanyl)-1H-pyraz-
olo[3,4-d]pyrimidine as a white solid. (530 mg, 98%). LCMS (ESI),
m/z 408.2 (MH+, 100%).
[1026] Step 2: Preparation of
4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
sulfanyl]-piperidine-1-carboxylic acid butyl ester (Compound
A108).
[1027] Compound A108 was made in a similar manner as described in
Example 9.177 as a white solid (43 mg, 54%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. (ppm): 8.72 (s, 1H); 8.23 (s, 1H); 7.87 (m,
3H); 4.36 (h, 1H); 4.01 (m, 4H); 3.16 (m, 2H); 3.05 (s, 3H); 2.12
(m, 2H); 1.70 (m, 2H); 1.58 (m, 2H); 1.35 (s, 2H); 0.88 (t, 3H).
LCMS (ESI), m/z 508.4 (MH+, 100%)
Example 9.195
Preparation of
4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
sulfanyl]-piperidine-1-carboxylic acid 2-methoxy-ethyl ester
(Compound A109)
[1028] Compound A109 was made in a similar manner as described in
Example 9.177 as a white solid (4 mg, 5%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. (ppm): 8.71 (s, 1H); 8.24 (s, 1H); 7.87 (m,
3H); 4.37 (m, 1H); 4.20 (m, 2H); 3.99 (m, 2H); 3.56 (m, 2H); 3.33
(s, 3H); 3.17 (m, 2H); 3.06 (s, 3H); 2.12 (m, 2H); 1.72 (m, 2H).
LCMS (ESI), m/z 510.3 (MH+, 100%)
Example 9.196
Preparation of
4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
sulfanyl]-piperidine-1-carboxylic acid 3,3-dimethyl-butyl ester
(Compound A110)
[1029] Compound A110 was made in a similar manner as described in
Example 9.177 as a white solid (22 mg, 24%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. (ppm): 8.71 (s, 1H); 8.23 (s, 1H); 7.87 (m,
3H); 4.36 (h, 1H); 4.10 (t, 2H); 3.96 (s broad, 2H); 3.15 (m, 2H);
3.04 (s, 3H); 2.12 (m, 2H); 1.71 (m, 2H); 1.51 (t, 2H); 0.85 (s,
9H). LCMS (ESI), m/z 536.2 (MH+, 100%).
Example 9.197
Preparation of
4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
sulfanyl]-piperidine-1-carboxylic acid 4-methyl-pentyl ester
(Compound A111)
[1030] Compound A111 was made in a similar manner as described in
Example 9.177 as a white solid. LCMS (ESI), m/z 536.2 (MH+,
100%).
Example 9.198
Preparation of
{4-[1-(4-Methanesulfonyl-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridin-1-yl}-(5-morpholin-4-ylmethyl-furan-2-yl)-methanone (Compound
A116)
[1031] 5-Morpholin-4-ylmethyl-furan-2-carboxylic acid (0.12 mmol,
25 mg), and isopropylchloroformate (0.12 mmol, 17 .mu.L) and
triethylamine (0.12 mmol, 17 .mu.L) were dissolved in DMSO (2 mL)
and stirred for 30 minutes at room temperature. Then,
1-(4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyri-
midine (0.12 mmol, 50 mg) and excess triethylamine were added. The
mixture was heated in a microwave for 5 minutes at 120.degree. C.
The progress of the reaction was monitored by thin layer
chromatography and LCMS. Purification by HPLC provided compound
A116 as a white solid. LCMS (ESI), m/z 567.3 (MH+, 100%).
Example 9.199
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid 2-pyrrolidin-1-yl-ethyl ester (Compound
A121)
[1032] Compound A121 was made in a similar manner as described in
Example 9.177 as a white solid (29 mg, 27%). LCMS (ESI), m/z 515.3
(MH+, 100%)
Example 9.200
Preparation of
4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pipe-
ridine-1-carboxylic acid 2-morpholin-4-yl-ethyl ester (Compound
A122)
[1033] Compound A122 was made in a similar manner as described in
Example 9.177 as a white solid (20 mg, 20%). LCMS (ESI), m/z 531.3
(MH+, 100%)
Example 9.201
Preparation of
4-[1-4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piper-
idine-1-carboxylic acid ethyl ester (Compound A123)
[1034]
1-(4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-
-d]pyrimidine hydrochloride salt (0.17 mmol, 70 mg),
ethylchloroformate (0.25 mmol, 25 .mu.L) and triethylamine (0.51
mmol, 72 .mu.L) were dissolved in DMF (2 mL) and stirred for 60
minutes at room temperature. Progress of the reaction was monitored
by TLC and LCMS. The reaction mixture was quenched with water. The
product was extracted with ethyl acetate. Removal of organic
solvents in vacuo and purification by HPLC provided compound A123
as a white solid (14 mg, 15%). Exact mass calculated for
C.sub.20H.sub.23N.sub.5O.sub.5S 445.49. found 446.10
(MH.sup.+).
Example 9.202
Preparation of
Ethyl-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin--
4-yl]-(3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-ylmethyl)amine
(Compound A126)
[1035] A mixture of
ethyl-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin--
4-yl]-piperidin-4-ylmethyl-amine hydrochloride salt (30 mg, 0.064
mmol), 2-bromopyridine (0.62 .mu.L, 0.64 mmol), and triethylamine
(26 .mu.L, 0.19 mmol) in DMF (1.0 mL) was heated under microwave
irradiation for 30 minutes at 165.degree. C. The crude mixture was
purified by HPLC to provide compound A126 as a white solid (5 mg,
15%). Exact mass calculated for C.sub.25H.sub.28FN.sub.7O.sub.2S
509.2. found 510.5 (MH.sup.+).
Example 9.203
Preparation of
Ethyl-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin--
4-yl]-(5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-ylmeth-
yl)-amine (Compound A127)
[1036] A mixture of
ethyl-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin--
4-yl]-piperidin-4-ylmethyl-amine hydrochloride salt (30 mg, 0.064
mmol), 2-bromo-5-trifluoromethylpyridine (188 mg, 0.83 mmol), and
triethylamine (27 .mu.L, 0.19 mmol) in DMF (1.0 mL) was heated
under microwave irradiation for 20 minutes at 165.degree. C. The
crude mixture was purified by HPLC to provide compound A127 as a
white solid (19 mg, 51%). Exact mass calculated for
C.sub.26H.sub.27F.sub.4N.sub.7O.sub.2S 557.19. found 578.3
(MH.sup.+).
Example 9.204
Preparation of
[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-(5'-trifl-
uoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-amine
(Compound A128)
[1037] A mixture of
[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-piperidin-
-4-yl-amine (100 mg, 0.24 mmol), 2-bromo-4-trifluoromethylpyridine
(166 mg, 0.73 mmol), and potassium carbonate (102 mg, 0.73 mmol) in
DMF (1.0 mL) was heated under microwave irradiation for 20 minutes
at 165.degree. C. The crude mixture was purified by HPLC to provide
compound A128 as a white solid (41 mg, 32%). Exact mass calculated
for C.sub.23H.sub.22F.sub.3N.sub.7O.sub.2S 517.15. found 518.2
(MH.sup.+).
Example 9.205
Preparation of
[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]--
[1-(3-isopropyl-[1,2,4]oxadiazol-5-ylmethyl)-pyrrolidin-3-yl]-amine
(Compound A133)
[1038] A mixture of
1-(3-isopropyl-[1,2,4]oxadiazol-5-ylmethyl)-pyrrolidin-3-yl)-amine
(354 mg, 1.68 mmol),
4-chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidi-
ne (500 mg, 1.53 mmol), and potassium carbonate (3.18 g, 23 mmol)
in THF (20 mL) was refluxed for 2 hours. Water was added to the
reaction mixture and the product was extracted with ethylacetate.
The ethylacetate layer was dried over MgSO.sub.4. The organic layer
was concentrated in vacuo to afford compound A133 as a white solid
(700 mg, 91%). Exact mass calculated for
C.sub.22H.sub.25FN.sub.8O.sub.3S 500.18. found 501.1
(MH.sup.+).
Example 9.206
Preparation of
[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]--
[1-(3-isopropyl-[1,2,4]oxadiazol-5-ylmethyl)-pyrrolidin-3-yl]-amine
(Compound A134)
[1039] Compound A134 was made in a similar manner as described in
Example 9.205 as a white solid (712 mg, 93%). Exact mass calculated
for C.sub.22H.sub.25FN.sub.8O.sub.3S 500.18. found 501.1
(MH.sup.+).
Example 9.207
Preparation of
3-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
oxy]-pyrrolidine-1-carboxylic acid tert-butyl ester (Compound
A140)
[1040] A mixture of 3-hydroxy-pyrrolidine-1-carboxylic acid
tert-butyl ester (431 mg, 2.3 mmol) and sodium hydride (92 mg, 3.82
mmol) in THF (10 mL) was stirred for 30 minutes at room
temperature. Then
4-chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidi-
ne (500 mg, 1.53 mmol) was added and stirred overnight at room
temperature. The reaction mixture was quenched with water and the
product extracted with ethyl acetate. The ethylacetate layer was
dried over MgSO.sub.4, concentrated in vacuo, and purified by flash
chromatography to afford compound A140 as a white solid (495 mg,
45%). Exact mass calculated for C.sub.21H.sub.24FN.sub.5O.sub.5S
477.15. found 478.2 (MH.sup.+).
Example 9.208
Preparation of
3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-py-
rrolidine-1-carboxylic acid tert-butyl ester (Compound A141)
[1041] Compound A141 was made in a similar manner as described in
Example 9.205 as a white solid (723 mg, 49%). Exact mass calculated
for C.sub.21H.sub.26N.sub.6O.sub.4S 458.17. found 459.2
(MH.sup.+).
Example 9.209
Preparation of
3-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl-
amino]-pyrrolidine-1-carboxylic acid isopropyl ester (Compound
A142)
[1042] A mixture of
[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]--
pyrrolidin-3-yl-amine (20 mg, 0.048 mmol), isopropylchloroformate
(7.2 .mu.L, 0.52 mmol), and triethylamine (20 .mu.L, 144 mmol) in
DMF (500 .mu.L) was stirred for 2 hours at room temperature. The
reaction was purified by HPLC to afford compound A142 as a white
solid (9 mg, 41%). Exact mass calculated for
C.sub.20H.sub.23FN.sub.6O.sub.4S 462.15 found 463.3 (MH.sup.+).
Example 9.210
Preparation of
3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pyrr-
olidine-1-carboxylic acid tert-butyl ester (Compound A156)
[1043] Compound A156 was made in a similar manner as described in
Example 9.207 as a white solid (758 mg, 68%). Exact mass calculated
for C.sub.21H.sub.25N.sub.5O.sub.5S 459.16. found 460.2
(MH.sup.+).
Example 9.211
Preparation of
{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pip-
eridin-1-yl}-(5-pyridin-2-yl-thiophen-2-yl)methanone (Compound
A185)
[1044] Compound A185 was made in a similar manner as described in
Example 9.25 as a white solid (5 mg, 9%). Exact mass calculated for
C.sub.27H.sub.24N.sub.6O.sub.4S.sub.2 560.13. found 561.4
(MH.sup.+).
EXAMPLE 10
Example 10.1
Preparation of
4-[9-(6-Methanesulfonyl-pyridin-3-yl)-9H-purin-6-yloxy]-piperidine-1-carb-
oxylic acid isobutyl ester (Compound B1)
General Method for Addition of a Chloroformate
[1045] Compound B2, see Example 10.2, (75 mg, 0.17 mmol) and TEA
(0.34 mmol, 2 equiv.) were dissolved in anhydrous DMF (3 mL) and
isobutyl chloroformate was added into the solution then stirred at
room temp for 30 minutes. The crude product was purified through
HPLC provided Compound B1 as a white solid (46 mg, 57%). .sup.1H
NMR 400 MHz CDCl.sub.3 .delta. (ppm): 9.23 (s, 1H), 8.62 (s, 1H),
8.55 (d, 1H), 8.34 (d, 1H), 8.32 (s, 1H), 5.65 (m, 1H), 3.98-3.95
(m, 2H), 3.90 (d, 2H), 3.43-3.37 (m, 2H), 3.31 (s, 3H), 2.13 (m,
2H), 2.00-1.93 (m, 3H), 0.955 (d, 6H). Exact mass calculated for
C.sub.21H.sub.26N.sub.6O.sub.5S 474.17, LCMS (ESI) m/z 475.4
(M+H.sup.+, 100%)
Example 10.2
Preparation of
9-(6-Methanesulfonyl-pyridin-3-yl)-6-(piperidin-4-yloxy)-9H-purine
(Compound B2)
[1046] Prepared using a similar procedure as described in Example
9.6 to give Compound B2 as a tan solid (171 mg, 95%). .sup.1H NMR
400 MHz CDCl.sub.3 .delta. (ppm): 9.41(s, 1H); 9.07(s, 1H); 8.79
(d, 1H); 8.70 (s, 1H); 8.34 (d, 1H); 5.64 (m, 1H); 3.36 (s, 3H);
3.32 (m, 2H); 3.23 (m, 2H); 2.26 (m, 2H); 2.08 (m, 2H). Exact mass
calculated for C.sub.16H.sub.18N.sub.6O.sub.3S 374.12, observed
LCMS (ESI) m/z 375.2 (M+H.sup.+, 100%).
Example 10.3
Preparation of
{4-[9-(6-Methanesulfonyl-pyridin-3-yl)-9H-purin-6-yloxy]-piperidin-1-yl}--
pyridin-3-yl-methanone (Compound B3)
[1047] Using a similar procedure as described in Example 9.7,
Compound B3 was prepared and isolated as a cream solid (47 mg,
58%). .sup.1H NMR 400 MHz CDCl.sub.3 .delta. (ppm): 9.23 (s, 1H);
8.70 (m, 2H); 8.62 (s, 1H); 8.55 (d, 1H); 8.54 (d, 1H); 7.80 (m,
1H); 5.76 (m, 1H); 4.18 (bs, 1H); 3.79 (m, 2H); 3.47 (m, 1H); 3.31
(s, 3H); 2.25 (m, 1H); 2.12 (m, 1H); 2.00 (1H). LCMS: calculated
for C.sub.22H.sub.21N.sub.7O.sub.4S 479.14, observed 480.3
(M+H.sup.+, 100%)
Example 10.4
Preparation of
4-[9-(4-Methanesulfonyl-phenyl)-9H-purin-6-yloxy]-piperidine-1-carboxylic
acid tert-butyl ester (Compound B4)
General Procedure of Purine Formation
[1048] Step 1: Preparation of
4-[5-amino-6-(4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidin-
e-1-carboxylic acid tert-butyl ester.
[1049]
4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-pi-
peridine-1-carboxylic acid tert-butyl ester (647 mg, 1.3 mmol) was
dissolved in ethyl acetate under nitrogen and then 10% Pd/C was
added. The mixture was stirred at room temperature for 4 hours to
afford
4-[5-amino-6-(4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidin-
e-1-carboxylic acid tert-butyl ester as a tan solid (535 mg, 89%).
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.77-1.67 (m,4H), 1.48
(s,9H), 3.04 (s,3H), 3.31-3.24 (m, 2H), 3.82 (m, 2H), 5.32 (m,1H),
6.96 (s, NH), 7.53 (t, NH), 7.70 (t, 1H), 7.71 (d, 2H), 8.16 (s,
1H). Exact mass calculated for C.sub.21H.sub.29N.sub.5O.sub.5S
463.19. found 464.3 (MH.sup.+).
[1050] Step 2: Preparation of
4-[9-(4-Methanesulfonyl-phenyl)-9H-purin-6-yloxy]-piperidine-1-carboxylic
acid tert-butyl ester (Compound B4).
[1051]
4-[5-Amino-6-(4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-pi-
peridine-1-carboxylic acid tert-butyl ester (300 mg, 0.6 mmol) was
dissolved in mixture of triethyl orthoformate (4 mL) and acetic
anhydride (4 mL), and then the mixture was refluxed at 140.degree.
C. for 15 hours. The crude product was quenched with saturated
sodium bicarbonate and extracted with ethyl acetate, then dried in
vacuo. Solid was precipitated out in acetonitrile/water and
provided Compound B4 as a peach solid (205 mg, 67%). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 1.48 (s, 9H), 1.95-1.91 (m, 2H),
2.14-2.11 (m,2H), 3.12 (s,3H), 3.34-3.27 (m, 2H), 3.94-3.91 (m,
2H), 5.61 (m, 1H), 8.06 (d, 2H), 8.19 (d, 2H), 8.29 (s, 1H), 8.61
(s, 1H). Exact mass calculated for C.sub.22H.sub.27N.sub.5O.sub.5S
473.17. found 474.3 (MH+).
Example 10.5
Preparation of
4-[9-(6-Methanesulfonyl-pyridin-3-yl)-9H-purin-6-yloxy]-piperidine-1-carb-
oxylic acid tert-butyl ester (Compound B5)
[1052] Compound B5 was prepared in a similar manner as described in
Example 10.4 except using
4-[5-amino-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-pip-
eridine-1-carboxylic acid tert-butyl ester and was obtained as a
peach solid (502 mg, 81%). .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 1.49 (s, 9H), 1.95-1.91 (m, 2H), 2.14-2.11 (m,2H), 3.31
(s,3H), 3.35-3.25 (m, 2H), 3.94-3.90 (m, 2H), 5.61 (m, 1H), 8.32
(s, 1H), 8.33 (d, 1H), 8.55 (d, 1H), 8.61 (s, 1H), 9.22 (s, 1H).
Exact mass calculated for C.sub.21H.sub.26N.sub.6O.sub.5S 474.17.
found 475.3(MH.sup.+).
Example 10.6
Preparation of
4-[9-(2-Fluoro-4-methanesulfonyl-phenyl)-9H-purin-6-yloxy]-piperidine-1-c-
arboxylic acid tert-butyl ester (Compound B6)
[1053] Using a similar procedure as described in Example 10.4
afforded Compound B6 as a yellow solid (75 mg, 25%). .sup.1H NMR
400 MHz CDCl.sub.3 .delta. (ppm): 8.59 (s, 1H); 8.26 (s, 1H); 8.19
(d, 2H); 8.15 (t, 1H); 7.98 (d, 1H); 5.62 (m, 1H); 3.93-3.81 (m,
2H); 3.35-3.27 (m, 2H); 3.14 (s,3H); 2.10 (m,2H); 1.97-1.92 (m,
2H); 1.49 (s, 9H). LCMS: calculated for
C.sub.22H.sub.26FN.sub.5O.sub.5S 491.16, observed 492.3(M+H.sup.+,
100%).
EXAMPLE 11
Example 11.1
Preparation of
4-[3-(4-Methanesulfonyl-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ylox-
y]-piperidine-1-carboxylic acid tert-butyl ester (Compound C1)
[1054] Step 1: Preparation of
7-chloro-3-(4-methanesulfonyl-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-
.
[1055] To a solution of
(6-chloro-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine
in dichloromethane (8 mL) and 50% aqueous acetic acid (6 mL) was
added sodium nitrite (64.6 mg, 0.937 mmol) in water (1 mL) dropwise
at room temperature. After the addition was complete, the reaction
was stirred for additional 15 minutes at room temperature. The
organic layer was then separated, washed with water, and dried over
anhydrous magnesium sulfate. Filtration followed by removal of
volatiles under high vacuum afforded the desired product as a
yellow solid (205 mg, 77.8%).
[1056] Step 2: Preparation of
4-[3-(4-Methanesulfonyl-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ylox-
y]-piperidine-1-carboxylic acid tert-butyl ester (Compound C1).
[1057] Compound C1 was obtained as a yellow solid. (101.1 mg, 66%)
via a similar procedure as described in Example 9.1 using
7-chloro-3-(4-methanesulfonyl-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine
and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester.
.sup.1H NMR (400 MHz DMSO-d.sub.6) .delta. (ppm): 8.92 (s, 1H);
8.52 (d, 2H); 8.24 (d, 2H); 5.68 (m, 1H); 3.78 (m, 2H); 3.31 (s,
3H); 3.26 (m, 2H); 2.12 (m, 2H); 1.76 (m, 2H); 1.42 (s, 9H). LCMS
(ESI) calculated for C.sub.21H.sub.26N.sub.6O.sub.5S: observed m/z
475.3 (MH.sup.+, 100%).
EXAMPLE 12
Example 12.1
Preparation of
4-[3-(4-Methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidin-7-yloxy]-piperi-
dine-1-carboxylic acid tert-butyl ester (Compound D1)
[1058] Step 1: Preparation of 4-Methanesulfonyl-benzoic acid phenyl
ester.
[1059] To a solution of the 4-methanesulfonyl-benzoic acid (20 g,
99.9 mmol) in CH.sub.2Cl.sub.2 (150 mL), was oxalyl chloride (13.1
mL, 149.9 mmol) added. The reaction mixture was cooled to 0.degree.
C. and treated with DMF (2 mL). The reaction was warmed to room
temperature and maintained for 10 h. The reaction was concentrated
under vacuum and dissolved with CH.sub.2Cl.sub.2 (200 mL). The
reaction was treated with phenol (10.5 mL, 120 mmol) followed by
Et.sub.3N (16.7 mL, 120 mmol) at 0.degree. C. The reaction was
warmed to room temperature and stirred for 7 hr. The reaction was
extracted with CH.sub.2Cl.sub.2 (500 mL), dried and concentrated
under vacuum. The desired compound, 4-methanesulfonyl-benzoic acid
phenyl ester, was obtained by recrystallization from methanol (200
mL) as a white crystal in 78% yield (21.5 g). .sup.1H NMR (400 Mz,
DMSO-d.sub.6) .delta. 8.41 (d, J=7.1, 2H), 8.39 (d, J=7.1, 2H),
7.55.about.7.51 (m, 2H), 7.37.about.7.35 (m, 3H), 3.35 (s, 3H).
LCMS 277.0 [M+H].
[1060] Step 2: Preparation of
1-(4-Methanesulfonyl-phenyl)-2-nitro-ethanone.
[1061] To a suspension of potassium tert-butoxide (24.3 g, 217.1
mmol) in DMSO (150 mL), was added CH.sub.3NO.sub.2 (11.7 mL, 217.1
mmol) added at 0.degree. C. After stirring for 1 h,
4-methanesulfonyl-benzoic acid phenyl ester (20.0 g, 72.4 mmol) was
added in one portion at 0.degree. C. The reaction was warmed to
room temperature and stirred for 5 hr. The reaction was poured into
ice-water (200 mL) and followed by adding urea (2.17 g, 36.2 mmol).
The reaction was acidified with 5.0 M HCl to pH=.about.5 at
0.degree. C. The reaction was added to water (1 L) and stirred for
1 h. The pale yellow solid was filtered and dried under vacuum to
afford the desired compound (13.2 g, 75.2%). .sup.1H NMR (400 Mz,
DMSO-d.sub.6) .delta. 8.19 (m, 4H), 6.63 (s, 2H), 3.35 (s, 3H).
LCMS 244.5 [M+H].
[1062] Step 3: Preparation of
1-(4-Methanesulfonyl-phenyl)-2-nitro-ethanone oxime.
[1063] To a solution of
1-(4-methanesulfonyl-phenyl)-2-nitro-ethanone (12.5 g, 51.4 mmol)
in ethanol (100 mL), was added NH.sub.2OH.HCl (3.57 g, 51.4 mmol)
and acetic acid (33 mL) at room temperature. The reaction was
refluxed for 3 h and cooled to room temperature. The reaction was
concentrated under vacuum and extracted with ethyl acetate (200
mL). The reaction was concentrated to afford the crude compound
which was recrystallized from petroleum ether/hexane (1/3) as white
crystals (10.3 g, 83.4%). .sup.1H NMR (400 Mz, DMSO-d.sub.6)
.delta. 12.81 (s, 1H), 8.03 (m, 4H), 5.93 (s, 2H), 3.28 (s, 3H).
LCMS 259.2[M+H].
[1064] Step 4: Preparation of
3-(4-Methanesulfonyl-phenyl)-4-nitro-isoxazole-5-carboxylic acid
ethyl ester.
[1065] To a solution of
1-(4-methanesulfonyl-phenyl)-2-nitro-ethanone oxime (10.0 g, 38.7
mmol) in ether (100 mL) and THF (50 mL) was added ethyl chloro
ethyloxalate (4.29 mL, 38.7 mmol) at ambient temperature. The
reaction was stirred for 16 h and concentrated under vacuum. The
residue was washed with ether (100 mL). The solid was filtered and
washed with ether. The compound was dissolved in THF (50 mL) and
ether (100 mL) and treated with a solution of Et.sub.3N (.about.1.5
mL) in THF (10 mL). The completion of the reaction was determined
by TLC. The reaction was poured into H.sub.2O (200 mL). The organic
layer was dried over MgSO.sub.4 and concentrated to afford the
crude desired compound as a solid. The compound was recrystallized
in Ethyl acetate/Hexane (50 mL/150 mL) to afford the desired
compound (6.2 g, 47%) as a yellowish crystal. .sup.1H NMR (400 Mz,
DMSO) .delta. 8.40 (d, J=7.1, 2H), 8.21 (d, J=7.1, 2H), 3.35 (s,
3H), 2.63 (q, 2H), 1.05 (t, 3H).
[1066] Step 5: Preparation of
4-Amino-3-(4-methanesulfonyl-phenyl)-isoxazole-5-carboxylic acid
ethyl ester.
[1067] 3-(4-Methanesulfonyl-phenyl)-4-nitro-isoxazole-5-carboxylic
acid ethyl ester (6.2 g) was suspended in sat. NH.sub.4Cl (100 mL)
and treated with Zn (10.0 g) at room temperature. The reaction was
stirred for 3 h and ethyl acetate (100 mL) was added. After
stirring for 1 h, zinc was filtered off. The ethyl acetate was
taken and washed with H.sub.2O, dried over MgSO.sub.4 and
concentrated under vacuum to afford the crude product (4.3 g, 77%).
The product was crystallized in ethyl acetate/hexane (1/3) to
afford the desired compound. LCMS 311.1 [M+H].
[1068] Step 6: Preparation of
4-Amino-3-(4-methanesulfonyl-phenyl)-isoxazole-5-carboxylic acid
amide.
[1069] To a solution of
4-amino-3-(4-methanesulfonyl-phenyl)-isoxazole-5-carboxylic acid
ethyl ester (4.0 g, 12.9 mmol) in methanol (50 mL) and THF (50 mL),
was added a NH.sub.4OH solution (100 mL) at room temperature. The
reaction was stirred for 24 h. The precipitates were filtered and
washed with H.sub.2O. (100 mL). The compound was dried in vacuo to
afford the crude product which was used for the next step without
further purification. LCMS 282.1 [M+H].
[1070] Step 7: Preparation of
3-(4-methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidin-7-ol.
[1071] To a suspension of
4-amino-3-(4-methanesulfonyl-phenyl)-isoxazole-5-carboxylic acid
amide (2.5 g, 8.9 mmol) in CH(OEt).sub.3 (30 mL), was added acetic
anhydride (10 mL) at ambient temperature. The reaction was heated
to reflux for 5 h and cooled to room temperature. The reaction was
concentrated under vacuum and poured into H.sub.2O (50 mL). The
organic material was extracted with ethyl acetate(50 mL), dried
over MgSO.sub.4 and concentrated under vacuum. The crude product
was used for the next step without further purification. LCMS 292.0
[M+H].
[1072] Step 8: Preparation of
7-chloro-3-(4-methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidine.
[1073] 3-(4-Methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidin-7-ol
(0.5 g, 1.7 mmol) was suspended in POCl.sub.3 (10 mL) and refluxed
for 12 h. The reaction was poured into ice carefully and
precipitates filtered. The solid was dissolved in ethyl acetate (15
mL) and purified under SiO.sub.2 with 30% ethyl acetate in hexane
to afford the desired compound (0.42 g, 80.1%).
[1074] Step 9: Preparation of
4-[3-(4-Methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidin-7-yloxy]-piperi-
dine-1-carboxylic acid tert-butyl ester (Compound D1).
[1075] 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.1
g, 0.49 mmol) was dissolved in anhydrous THF (5 mL) and treated
with NaH, 60% oil dispersion (20 mg, 0.49 mmol) at ambient
temperature. After stirring for 10 min,
7-chloro-3-(4-methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidine
(0.15 g, 0.49 mmol) was added. The reaction was stirred for 3 h and
concentrated under vacuum. The residue was purified by column
chromatography using ethyl acetate and hexane (1/1) to afford
4-[3-(4-methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidin-7-yloxy]-piperi-
dine-1-carboxylic acid tert-butyl ester (0.14 g, 61%). .sup.1H NMR
(400 Mz, DMSO-d.sub.6) .delta. 8.51 (s, 1H), 8.42 (d, J=7.1, 2H),
8.34 (d, J=7.1, 2H), 4.11.about.3.83 (m, 4H), 3.52 (m, 1H), 3.26
(s, 3H), 1.41.about.1.22 (m, 4H). LCMS 475.3[M+H].
Example 12.2
Preparation of
4-({ethyl-[3-(4-methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidin-7-yl]-a-
mino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester
(Compound D2)
[1076] 4-Ethylaminomethyl-piperidine-1-carboxylic acid tert-butyl
ester (0.12 g, 0.49 mmol) was dissolved in anhydrous THF (5 mL) and
treated with NaH, 60% oil dispersion (20 mg, 0.49 mmol) at ambient
temperature. After stirring for 10 min,
7-chloro-3-(4-methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidine
(0.15 g, 0.49 mmol) was added. The reaction was stirred for 3 h and
concentrated under vacuum. The residue was subjected to SiO.sub.2
with ethyl acetate and hexane (1/1) to afford Compound D2 (0.82 g,
61%). .sup.1H NMR (400 Mz, DMSO-d.sub.6) .delta. 8.49 (s, 1H), 8.41
(d, J=7.1, 2H), 8.34 (d, J=7.1, 2H), 4.10.about.3.74 (m, 7H), 3.52
(m, 1H), 3.25 (t, 3H), 1.41.about.1.22 (m, 4H). LCMS
516.3[M+H].
Example 12.3
Preparation of
4-[3-(4-Methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidin-7-ylsulfanyl]-p-
iperidine-1-carboxylic acid tert-butyl ester (Compound D3)
[1077]
7-Chloro-3-(4-methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidine
(0.19 mmol, 60 mg), 4-mercapto-piperidine-1-carboxylic acid
tert-butyl ester (0.25 mmol, 54 mg) and potassium carbonate (0.28
mmol, 35 mg) were dissolved in DMF (10 mL) and stirred for 90
minutes at room temperature. Its progress was monitored by thin
layer chromatography and LCMS. The reaction was treated with water
and the desired compound was extracted with ethyl acetate. The
organic layer was evaporated in vacuo. Purification by HPLC
provided compound D3 as a white solid (40 mg, 35%). .sup.1H NMR
(400 Mz, CDCl.sub.3) .delta. 9.03 (s, 1H); 8.71 (d, 2H); 8.15 (d,
2H); 4.44 (h, 1H); 4.02 (m, 2H); 3.22 (m, 2H); 3.13 (s, 3H); 2.19
(m, 2H); 1.82 (m, 2H); 1.47 (s, 9H). LCMS (ESI), m/z 491.1 (MH+,
100%)
Example 12.4
Preparation of
4-[3-(4-methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidin-7-yloxy]-piperi-
dine-1-carboxylic acid isopropyl ester (Compound D4)
[1078]
4-[3-(4-Methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidin-7-yloxy]-
-piperidine-1-carboxylic acid tert-butyl ester (1.2 g, 2.53 mmol)
was dissolved in CH.sub.2Cl.sub.2 (5 mL) and cooled to 0.degree. C.
The reaction was treated with 4.0 M HCl in dioxane (2.0 mL) at the
same temperature. The reaction was warmed to room temperature and
stirred for five hours. The reaction was concentrated under vacuum
and crystallized in methanol (10 mL). The precipitate was filtrated
and dried to afford the HCl salt of the amine. The salt was stirred
in CH.sub.2Cl.sub.2 (20 mL) and treated with Et.sub.3N and chloro
isopropylchloroformate at 0.degree. C. After stirring for five
hours, the reaction was poured into H.sub.2O (20 mL). The organic
compound was extracted with CH.sub.2Cl.sub.2 (30 mL) and washed
with brine. The ethyl acetate layer was dried over MgSO.sub.4 and
concentrated under vacuum. The residue was purified over SiO.sub.2
to afford Compound D4 (970 mg, 83.4%). .sup.1H NMR (400 Mz,
DMSO-d.sub.6) .delta. 8.50 (s, 1H), 8.41 (d, J=7.0, 2H), 8.35 (d,
J=7.0, 2H), 4.11.about.3.83 (m, 4H), 3.52 (m, 1H), 3.47 (m, 1H),
3.25 (d, 6H), 1.41.about.1.22 (m, 4H). LCMS 461.6 [M+H].
Example 13.1
Preparation of
4-[8-(4-Bromo-2-fluoro-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylic
acid isopropyl ester (Compound F5)
[1079] Step 1: Preparation of
2-[(2-iodo-phenylamino)-methylene]-malonic acid diethyl ester.
[1080] 2-Iodoaniline (50 g, 228.3 mmol) and
2-ethoxymethylene-malonic acid diethyl ester (50 mL, 251.1 mmol)
were mixed and the solution was stirred at 110.degree. C. for 3 h.
The crude was dissolved in dichloromethane and it was purified by
silica plug. The product was eluted with ethyl acetate/hexanes
(10-50%) and the solvent removed under reduced pressure to afford
2-[(2-iodo-phenylamino)-methylene]-malonic acid diethyl ester as an
off-white powder (81.4 g, 91.6%). .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 1.49 (t, 3H), 1.54 (t, 3H), 4.40 (q, 2H), 4.52 (q, 2H),
7.01-7.05 (m, 1H), 7.36-7.39 (m, 1H), 7.52-7.56 (m, 1H), 8.59 (d,
1H). Exact mass calculated for C.sub.14H.sub.16INO.sub.4 389.01.
found 390.1 (MH.sup.+).
[1081] Step 2: Preparation of
8-iodo-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl
ester.
[1082] In a 2-neck round bottomed flask (250 mL), phenylether (60
mL) was put to reflux on a heating mantel. When it started boiling,
p-toluenesulfonic acid (0.140 g) was added.
2-[(2-iodo-phenylamino)-methylene]-malonic acid diethyl ester was
dissolved in phenylether (20 mL) and the mixture was poured into
the boiling solvent. The mixture was refluxed for 3 h. The crude
was transferred to a bequer and cooled to room temperature. Hexanes
(600 mL) were added and a precipitate was observed. The mixture was
stirred for 5 min, followed by filtration of the solid and thorough
wash with hexanes to afford
8-iodo-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester as
a grayish solid (2 g, 46%). .sup.1H NMR (DMSO-d.sub.6, 400 MHz)
.delta. 1.43 (t, 3H), 4.39 (q, 2H), 7.36 (t, 1H), 8.32 (d, 1H),
8.37 (d, 1H), 8.63 (s, 1H), 11.4 (s, 1H). Exact mass calculated for
C.sub.12H.sub.10INO.sub.3 342.97. found 343.9 (MH.sup.+).
[1083] Step 3: Preparation of
8-iodo-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid.
[1084] 8-Iodo-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl
ester (2 g, 5.83 mmol) was suspended in 10% NaOH in water (20 mL).
The mixture was stirred under reflux for 1 h. The crude was cooled
to room temperature and acidified with concentrated HCl. The solid
was filtered off and thoroughly washed with water to afford
8-iodo-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid as a pinkish
solid (1.5 g, 81.6%). .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta.
7.04 (t, 1H), 8.12-8.16 (m, 2H), 8.71 (s, 1H). Exact mass
calculated for C.sub.10H.sub.6INO.sub.3 314.94. found 316
(MH.sup.+).
[1085] Step 4: Preparation of 8-iodo-1H-quinolin-4-one.
[1086] 8-Iodo4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (15.69
g, 49.8 mmol) was suspended in phenylether (40 mL) and the mixture
heated to boiling. After 30 min, reaction was completed by LCMS.
The crude was transferred to a bequer and cooled to room
temperature. Hexanes (500 mL) were added and the mixture was
stirred for 10 min. The solid was retrieved by filtration,
thoroughly washed with hexanes and purified by HPLC to afford
8-iodo-1H-quinolin-4-one as a brownish solid (4.4 g, 23%). .sup.1H
NMR (DMSO-d.sub.6, 400 MHz) .delta. 6.14 (d, 1H), 7.09 (t, 1H),
7.88 (d, 1H), 8.08 (dd, 1H), 8.16 (dd, 1H). Exact mass calculated
for C.sub.9H.sub.6INO 270.95. found 271.8 (MH.sup.+).
[1087] Step 5: Preparation of 4-chloro-8-iodo-quinoline.
[1088] 8-Iodo-1H-quinolin-4-one (3.36 g, 8.72 mmol) was suspended
in POCl.sub.3 (8 mL, 87.2 mmol) and catalytic anhydrous DMF (6.72
.mu.L) was added. The mixture was refluxed for 1 h. The hot crude
was poured over ice and the mixture stirred until ice was
completely melted. Solid was filtered off, thoroughly washed with
water and kept in the vacuum oven overnight to afford
4-chloro-8-iodo-quinoline as a grayish solid (2.47 g, 98%). .sup.1H
NMR (DMSO-d.sub.6, 400 MHz) .delta. 7.45 (t, 1H), 7.81 (d, 1H),
8.19 (dd, 1H), 8.45 (dd, 1H), 8.87 (d, 1H). Exact mass calculated
for C.sub.9H.sub.5ClIN 288.92. found 289.9 (MH.sup.+).
[1089] Step 6: Preparation of
8-(4-bromo-2-fluoro-phenyl)-4-chloro-quinoline.
[1090] To a solution of 4-chloro-8-iodo-quinoline (14 5 mg, 0.5
mmol) and tetrakis(triphenylphosphine)palladium (57 mg, 0.05 mmol)
in THF (1 mL) was added 0.5M THF solution of
2-fluoro-4-bromozinciodide (1 mL) under N.sub.2. The reaction
mixture was heated overnight at 65.degree. C. The resulting mixture
was diluted with CH.sub.2Cl.sub.2 and filtered through a syringe
filter. The filtrate was concentrated and the residue was purified
by column chromatography using 15% EtOAc/Hexane to give
8-(4-bromo-2-fluoro-phenyl)-4-chloro-quinoline. .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 7.41 (m, 3H), 7.52 (d, 1H), 7.74 (m,
2H), 8.34 (m, 1H), 8.78 (d, 1H). Exact mass calculated for
C.sub.15H.sub.8BrClFN 334.95. found 336.2 (MH.sup.+).
[1091] Step 7: Preparation of
4-[8-(4-bromo-2-fluoro-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylic
acid isopropyl ester (Compound F5).
[1092] In a 10 mL reaction vial equipped with a N.sub.2 inlet
septum was placed a stir bar, NaH (60% in mineral oil, 40 mg, 1
mmol) and 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester
(37 mg, 0.2 mmol). THF (anhydrous, 1.2 mL) was added to the
mixture. The resulting suspension was stirred about 30 min at room
temperature. 8-(4-Bromo-2-fluoro-phenyl)-4-chloro-quinoline (1 g,
0.5 mmol) was then added in one portion. The mixture was stirred
overnight under N.sub.2 at 65.degree. C. and the resulting slurry
turned slightly yellowish. The slurry was added CH.sub.2Cl.sub.2
and filtered. The filtrate was concentrated under vacuum to give
the crude product. Purification by column chromatography gave the
desired Compound F5 as an off-white solid. .sup.1H NMR (CDCl.sub.3,
400 MHz) .delta. 1.27 (d, 6H), 1.97 (m, 2H), 2.05 (m, 2H), 3.59 (m,
2H), 3.75 (m, 2H), 4.84 (m, 1H), 4.94 (m, 1H), 6.76 (d, 1H), 7.39
(m, 3H), 7.56 (t, 1H), 7.67 (d, 1H), 8.31 (d, 1H), 8.74 (d, 1H).
Exact mass calculated for C.sub.24H.sub.24BrFN.sub.2O.sub.3 486.10.
found 487.2 (MH.sup.+).
Example 13.2
Preparation of
4-[8-(4-Methylsulfanyl-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylic
acid isopropyl ester (Compound F2)
[1093] Step 1: Preparation of
4-(8-chloro-quinolin-4-yloxy)-piperidine-1-carboxylic acid
isopropyl ester.
[1094] In a 50 mL round-bottomed flask equipped with a N.sub.2
inlet septum was placed a stir bar, NaH (60% in mineral oil, 1.1 g,
30 mmol) and 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester
(0.93 g, 5 mmol). THF (anhydrous, 20 mL) was added to the mixture.
The resulting suspension was stirred about 30 min at room
temperature. 4,8-Dichloro-quinoline (1 g, 0.5 mmol) was then added
in one portion. The mixture was stirred overnight under N.sub.2 at
80.degree. C. and the resulting slurry turned slightly yellowish.
The slurry was added CH.sub.2Cl.sub.2 and filtered. The filtrate
was concentrated under vacuum to give the crude product.
Purification by column chromatography gave
4-(8-chloro-quinolin-4-yloxy)-piperidine-1-carboxylic acid
isopropyl ester as an off-white solid. .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta. 1.26 (d, 6H), 1.97 (m, 2H), 2.05 (m, 2H), 3.58 (m,
2H), 3.73 (m, 2H), 4.82 (m, 1H), 4.94 (m, 1H), 6.81 (d, 1H), 7.42
(t, 1H), 7.84 (d, 1H), 8.16 (d, 1H), 8.87 (d, 1H). Exact mass
calculated for C.sub.18H.sub.21ClN.sub.2O.sub.3 348.12. found 349.2
(MH.sup.+)
[1095] Step 2: Preparation of
4-[8-(4-methylsulfanyl-phenyl)quinolin-4-yloxy]-piperidine-1-carboxylic
acid isopropyl ester.
[1096] In a 25 mL round-bottomed flask equipped with a reflux
condenser and N2 inlet septum was placed a stir bar,
4-(8-chloro-quinolin-4-yloxy)-piperidine-1-carboxylic acid
isopropyl ester (198 mg, 0.57 mmol), 4-methylthiophenylboronic acid
(287 mg, 1.7 mmol), tetrakis(triphenylphosphine)palladium (98 mg,
0.085 mmol), 2M sodium carbonate (0.6 mL) and toluene (4 mL). The
mixture was refluxed 36 h under N2. The resulting mixture was
diluted with ethyl acetate and extracted with H.sub.2O. The organic
extract was dried and concentrated to give the crude product. The
crude product was purified by column chromatography to using 50%
EtOAc/Hexane and preparative HPLC to give the desired product.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.27 (d, 6H), 2.04 (m,
2H), 2.17 (m, 2H), 2.55 (s, 3H), 3.59 (m, 2H), 3.83 (m, 2H), 4.97
(m, 1H), 5.09 (m, 1H), 7.14 (s, 1H), 7.41 (m, 4H), 7.81 (t, 1H),
7.90 (d, 1H), 8.38 (d, 1H), 9.11 (s, 1H). Exact mass calculated for
C.sub.25H.sub.28N.sub.2O.sub.3S 436.18. found 437.2 (MH.sup.+).
Example 13.3
Preparation of
4-[8-(4-Methanesulfonyl-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylic
acid isopropyl ester (Compound F3)
[1097] In a 25 mL round-bottomed flask immersed in an ice-bath was
placed a stir bar and Compound F2 (16 mg, 0.037 mmol) in
CH.sub.2Cl.sub.2 (5 mL). A solution of mCPBA (19 mg, 0.081 mmol)
dissolved in CH.sub.2Cl.sub.2 (1 mL) was added at 0.degree. C. The
mixture was stirred at 0.degree. C. for 30 min. A solution of
sodium bisulfite was added. The organic phase was separated, dried
and concentrated to give the crude product. The crude was purified
by HPLC. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.29 (d, 6H),
2.04 (m, 2H), 2.20 (m, 2H), 3.16 (s, 3H), 3.59 (m, 2H), 3.85 (m,
2H), 4.97 (m, 1H), 5.14 (m, 1H), 7.23 (s, 1H), 7.66 (d, 2H), 7.92
(m, 2H), 8.12 (d, 2H), 8.48 (d, 1H), 9.08 (d, 1H). Exact mass
calculated for C.sub.25H.sub.28N.sub.2O.sub.5S 468.17. found 469.2
(MH.sup.+).
Example 13.4
Preparation of
4-[8-(4-Isopropoxy-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylic
acid isopropyl ester (Compound F4)
[1098] In a 25 mL round-bottomed flask equipped with a reflux
condenser and N2 inlet septum was placed a stir bar,
4-(8-chloro-quinolin-4-yloxy)-piperidine-1-carboxylic acid
isopropyl ester (200 mg, 0.57 mmol), 4-isopropoxyphenylboronic acid
(304 mg, 1.7 mmol), 2M sodium carbonate (0.6 mL) and toluene (4
mL). The mixture was degassed for a few minutes.
Tetrakis(triphenylphosphine) palladium (98 mg, 0.085 mmol) was
added to the above mixture. The reaction mixture was refluxed
overnight under N2. The resulting mixture was diluted with ethyl
acetate and extracted with H.sub.2O. The organic extract was dried
and concentrated to give the crude product. The crude product was
purified by column chromatography to using 50% EtOAc/Hexane and
preparative HPLC to give the desired product. .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 1.28 (d, 6H), 1.39 (d, 6H), 2.03 (m,
2H), 2.17 (m, 2H), 3.59 (m, 2H), 3.85 (m, 2H), 4.63 (m, 1H), 4.97
(m, 1H), 5.12 (m, 1H), 7.04 (s, 1H), 7.22 (d, 1H), 7.37 (d, 2H),
7.81 (t, 1H), 7.90 (d, 1H), 8.36 (d, 1H), 9.06 (d, 1H). Exact mass
calculated for C.sub.27H.sub.32N.sub.2O4 448.24. found 449.4
(MH.sup.+).
EXAMPLE 14
Protocol for RUP3 Dose Responses in Melanophores
[1099] Melanophores are maintained in culture as reported by
Potenza, M. N. and Lerner, M. R., in Pigment Cell Research, Vol. 5,
372-378, 1992 and transfected with the RUP3 expression vector
(pCMV) using electroporation. Following electroporation, the
transfected cells are plated into 96 well plates for the assay. The
cells are then allowed to grow for 48 hours in order to both
recover from the electroporation procedure and attain maximal
receptor expression levels.
[1100] On the assay day, the growth medium on the cells is replaced
with serum-free buffer containing 10 nM melatonin. The melatonin
acts via an endogenous Gi-coupled GPCR in the melanophores to lower
intracellular cAMP levels. In response to lowered cAMP levels, the
melanophores translocate their pigment to the center of the cell.
The net effect of this is a significant decrease in the absorbance
reading of the cell monolayer in the well, measured at 600-650
nM.
[1101] After a 1-hour incubation in melatonin, the cells become
completely pigment-aggregated. At this point a baseline absorbance
reading is collected. Serial dilutions of test compounds are then
added to the plate and compounds that stimulate RUP3 produce
increases in intracellular cAMP levels. In response to these
increased cAMP levels, the melanophores translocate their pigment
back into the cell periphery. After one hour, stimulated cells are
fully pigment-dispersed. The cell monolayer in the dispersed state
absorbs much more light in the 600-650 nm range. The measured
increase in absorbance compared to the baseline reading allows one
to quantitate the degree of receptor stimulation and plot a
dose-response curve.
[1102] The compounds in the above examples were screened using the
melanophore assay. Representative compounds and their corresponding
EC.sub.50 values are shown in Table 10 below: TABLE-US-00029 TABLE
10 RUP3 (EC.sub.50) Compound (nM) A5 12.7 B5 59.1 C1 13.0
[1103] Other compounds in the Examples showed EC.sub.50 activities
in the melanophore assay of less than about 10 .mu.M. Each of the
embodiments of the present invention may in the alternative be
limited to relate to those compounds that demonstrate about 100
fold or greater binding to RUP3 compared to the
corticotrophin-releasing factor-1 (CRF-1) receptor; a recent review
of CRF-1 compounds can be found in Expert Opin. Ther. Patents 2002,
12(11), 1619-1630, incorporated herein by reference in its
entirety.
EXAMPLE 15
Food Intake Study
[1104] Male ZDF (Zucker diabetic fatty) rats weighing 350 g-400 g
were dosed independently with two structurally divergent chemotypes
exhibiting agonism to the RUP3 receptor. Rats were dosed daily via
oral gavage with either vehicle (100% PEG 400), First Compound (30
mg/kg, 100 mg/kg), or Second Compound (10 mg/kg, 30 mg/kg) at a
volume of 3 ml/kg. Body weight and food intake were monitored and
recorded daily. Table 11 shown below illustrates the body weight
(g) and cumulative food intake (g) taken after both seven days and
14 days of dosing. TABLE-US-00030 TABLE 11 Cumulative Food Intake
(g) Body Weight (g) Substance Dose (mg/Kg) Week 1 Week 2 Week 1
Week 2 First Vehicle 321 672 390 395 Compound 30 mg/Kg 271 557 383
383 100 mg/Kg 211 457 361 376 Second Vehicle 261 563 393 393
Compound 10 mg/Kg 217 459 388 390 30 mg/Kg 159 307 377 373
[1105] Those skilled in the art will recognize that various
modifications, additions, substitutions, and variations to the
illustrative examples set forth herein can be made without
departing from the spirit of the invention and are, therefore,
considered within the scope of the invention. All documents
referenced above, including, but not limited to, printed
publications, and provisional and regular patent applications, are
incorporated herein by reference in their entirety.
Sequence CWU 1
1
7 1 1191 DNA Homo sapiens 1 atgtacccat acgacgtccc agactacgct
ggaagcttgg aatcatcttt ctcatttgga 60 gtgatccttg ctgtcctggc
ctccctcatc attgctacta acacactagt ggctgtggct 120 gtgctgctgt
tgatccacaa gaatgatggt gtcagtctct gcttcacctt gaatctggct 180
gtggctgaca ccttgattgg tgtggccatc tctggcctac tcacagacca gctctccagc
240 ccttctcggc ccacacagaa gaccctgtgc agcctgcgga tggcatttgt
cacttcctcc 300 gcagctgcct ctgtcctcac ggtcatgctg atcacctttg
acaggtacct tgccatcaag 360 cagcccttcc gctacttgaa gatcatgagt
gggttcgtgg ccggggcctg cattgccggg 420 ctgtggttag tgtcttacct
cattggcttc ctcccactcg gaatccccat gttccagcag 480 actgcctaca
aagggcagtg cagcttcttt gctgtatttc accctcactt cgtgctgacc 540
ctctcctgcg ttggcttctt cccagccatg ctcctctttg tcttcttcta ctgcgacatg
600 ctcaagattg cctccatgca cagccagcag attcgaaaga tggaacatgc
aggagccatg 660 gctggaggtt atcgatcccc acggactccc agcgacttca
aagctctccg tactgtgtct 720 gttctcattg ggagctttgc tctatcctgg
acccccttcc ttatcactgg cattgtgcag 780 gtggcctgcc aggagtgtca
cctctaccta gtgctggaac ggtacctgtg gctgctcggc 840 gtgggcaact
ccctgctcaa cccactcatc tatgcctatt ggcagaagga ggtgcgactg 900
cagctctacc acatggccct aggagtgaag aaggtgctca cctcattcct cctctttctc
960 tcggccagga attgtggccc agagaggccc agggaaagtt cctgtcacat
cgtcactatc 1020 tccagctcag agtttgatgg cgaattcgga tccaagggca
attctgcaga tatccagcac 1080 agtggcggcc gctcgagtct agagggcccg
cggttcgaag gtaagcctat ccctaaccct 1140 ctcctcggtc tcgattctac
gcgtaccggt catcatcacc atcaccattg a 1191 2 396 PRT Homo sapiens 2
Met Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Gly Ser Leu Glu Ser Ser 1 5
10 15 Phe Ser Phe Gly Val Ile Leu Ala Val Leu Ala Ser Leu Ile Ile
Ala 20 25 30 Thr Asn Thr Leu Val Ala Val Ala Val Leu Leu Leu Ile
His Lys Asn 35 40 45 Asp Gly Val Ser Leu Cys Phe Thr Leu Asn Leu
Ala Val Ala Asp Thr 50 55 60 Leu Ile Gly Val Ala Ile Ser Gly Leu
Leu Thr Asp Gln Leu Ser Ser 65 70 75 80 Pro Ser Arg Pro Thr Gln Lys
Thr Leu Cys Ser Leu Arg Met Ala Phe 85 90 95 Val Thr Ser Ser Ala
Ala Ala Ser Val Leu Thr Val Met Leu Ile Thr 100 105 110 Phe Asp Arg
Tyr Leu Ala Ile Lys Gln Pro Phe Arg Tyr Leu Lys Ile 115 120 125 Met
Ser Gly Phe Val Ala Gly Ala Cys Ile Ala Gly Leu Trp Leu Val 130 135
140 Ser Tyr Leu Ile Gly Phe Leu Pro Leu Gly Ile Pro Met Phe Gln Gln
145 150 155 160 Thr Ala Tyr Lys Gly Gln Cys Ser Phe Phe Ala Val Phe
His Pro His 165 170 175 Phe Val Leu Thr Leu Ser Cys Val Gly Phe Phe
Pro Ala Met Leu Leu 180 185 190 Phe Val Phe Phe Tyr Cys Asp Met Leu
Lys Ile Ala Ser Met His Ser 195 200 205 Gln Gln Ile Arg Lys Met Glu
His Ala Gly Ala Met Ala Gly Gly Tyr 210 215 220 Arg Ser Pro Arg Thr
Pro Ser Asp Phe Lys Ala Leu Arg Thr Val Ser 225 230 235 240 Val Leu
Ile Gly Ser Phe Ala Leu Ser Trp Thr Pro Phe Leu Ile Thr 245 250 255
Gly Ile Val Gln Val Ala Cys Gln Glu Cys His Leu Tyr Leu Val Leu 260
265 270 Glu Arg Tyr Leu Trp Leu Leu Gly Val Gly Asn Ser Leu Leu Asn
Pro 275 280 285 Leu Ile Tyr Ala Tyr Trp Gln Lys Glu Val Arg Leu Gln
Leu Tyr His 290 295 300 Met Ala Leu Gly Val Lys Lys Val Leu Thr Ser
Phe Leu Leu Phe Leu 305 310 315 320 Ser Ala Arg Asn Cys Gly Pro Glu
Arg Pro Arg Glu Ser Ser Cys His 325 330 335 Ile Val Thr Ile Ser Ser
Ser Glu Phe Asp Gly Glu Phe Gly Ser Lys 340 345 350 Gly Asn Ser Ala
Asp Ile Gln His Ser Gly Gly Arg Ser Ser Leu Glu 355 360 365 Gly Pro
Arg Phe Glu Gly Lys Pro Ile Pro Asn Pro Leu Leu Gly Leu 370 375 380
Asp Ser Thr Arg Thr Gly His His His His His His 385 390 395 3 24
DNA Artificial Homo sapiens Primer 3 cattgccggg ctgtggttag tgtc 24
4 24 DNA Artificial Homo sapiens Primer 4 ggcatagatg agtgggttga
gcag 24 5 22 DNA Artificial Rat Primer 5 catgggccct gcaccttctt tg
22 6 24 DNA Artificial Rat Primer 6 gctccggatg gctgatgata gtga 24 7
23 PRT Artificial Chemically synthesized peptide 7 Arg Gly Pro Glu
Arg Thr Arg Glu Ser Ala Tyr His Ile Val Thr Ile 1 5 10 15 Ser His
Pro Glu Leu Asp Gly 20
* * * * *