U.S. patent application number 11/765776 was filed with the patent office on 2008-01-17 for potent parp inhibitors.
Invention is credited to Vincent L. Giranda, Philip J. Hajduk, Thomas D. Penning, Kathy Sarris, Daryl R. Sauer, Sheela A. Thomas.
Application Number | 20080015182 11/765776 |
Document ID | / |
Family ID | 38670990 |
Filed Date | 2008-01-17 |
United States Patent
Application |
20080015182 |
Kind Code |
A1 |
Penning; Thomas D. ; et
al. |
January 17, 2008 |
Potent PARP Inhibitors
Abstract
The present invention relates to 1H-benzimidazole-4-carboxamides
of formula (I), ##STR1## their preparation, and their use as
inhibitors of the enzyme poly(ADP-ribose)polymerase for the
preparation of drugs.
Inventors: |
Penning; Thomas D.;
(Elmhurst, IL) ; Thomas; Sheela A.; (Libertyville,
IL) ; Hajduk; Philip J.; (Mundelein, IL) ;
Sauer; Daryl R.; (Trevor, WI) ; Sarris; Kathy;
(Deerfield, IL) ; Giranda; Vincent L.; (Gurnee,
IL) |
Correspondence
Address: |
ROBERT DEBERARDINE;ABBOTT LABORATORIES
100 ABBOTT PARK ROAD
DEPT. 377/AP6A
ABBOTT PARK
IL
60064-6008
US
|
Family ID: |
38670990 |
Appl. No.: |
11/765776 |
Filed: |
June 20, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60805235 |
Jun 20, 2006 |
|
|
|
Current U.S.
Class: |
514/217.06 ;
514/233.2; 514/252.17; 514/267; 540/600; 544/115; 544/250 |
Current CPC
Class: |
A61P 9/10 20180101; A61P
25/00 20180101; A61P 9/00 20180101; A61P 15/00 20180101; A61P 9/04
20180101; A61P 19/00 20180101; A61P 3/10 20180101; A61P 1/04
20180101; A61P 25/16 20180101; A61P 35/00 20180101; A61P 31/00
20180101; A61P 31/14 20180101; A61P 37/08 20180101; A61P 29/00
20180101; A61P 13/12 20180101; A61P 19/06 20180101; A61P 17/00
20180101; A61P 37/06 20180101; A61P 31/04 20180101; A61P 19/02
20180101; A61P 27/02 20180101; C07D 487/04 20130101; A61P 1/16
20180101; A61P 15/14 20180101; A61P 35/02 20180101 |
Class at
Publication: |
514/217.06 ;
514/233.2; 514/252.17; 514/267; 540/600; 544/115; 544/250 |
International
Class: |
A61K 31/517 20060101
A61K031/517; A61K 31/496 20060101 A61K031/496; A61K 31/5377
20060101 A61K031/5377; A61K 31/55 20060101 A61K031/55; A61P 29/00
20060101 A61P029/00; A61P 31/00 20060101 A61P031/00; A61P 35/00
20060101 A61P035/00; C07D 233/02 20060101 C07D233/02; C07D 239/72
20060101 C07D239/72; C07D 295/00 20060101 C07D295/00 |
Claims
1. A compound of Formula (I) ##STR10## or a pharmaceutically
acceptable salt thereof, wherein R.sub.1, R.sub.2, R.sub.3 and
R.sub.4 are independently selected from the group consisting of
hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, cyano,
haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro,
NR.sub.AR.sub.B, and (NR.sub.AR.sub.B)carbonyl; X is aryl,
arylalkyl, alkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl,
heterocycle, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl,
cycloalkyl, cycloalkylalkyl, NR.sub.CR.sub.D,
(NR.sub.CR.sub.D)carbonyl, (NR.sub.CR.sub.D)alkyl,
(NR.sub.CR.sub.D)carbonylalkyl, or -alkyl-CO.sub.2G.sub.1; wherein
if X is aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heteroarylcarbonyl, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, cycloalkyl, or cycloalkylalkyl then X may be
unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, Z,
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, nitro, --CN, halogen, haloalkyl, alkoxy, alkylcarbonyl,
alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy,
arylalkoxycarbonyl, arylalkylcarbonyl, carboxy, carboxyalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylcarbonyl,
heteroaryl, heteroarylalkyl, heteroarylcarbonyl,
heteroarylcarbonylalkyl, heterocycle, heterocyclealkyl,
heterocyclealkylcarbonyl, heterocyclecarbonyl,
heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR.sub.CR.sub.D,
(NR.sub.CR.sub.D)alkyl, (NR.sub.CR.sub.D)carbonyl,
(NR.sub.CR.sub.D)carbonylalkyl, and oxo; wherein the aryl and the
heteroaryl moieties of Z are independently unsubstituted or
substituted with 1, 2, 3, 4, or 5 substituents selected from the
group consisting of alkyl, formyl, halogen, and haloalkyl, and the
heterocycle and cycloalkyl moieties of Z are independently
unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents
selected from the group consisting of alkyl, oxo, formyl, halogen,
and haloalkyl; G.sub.1 is hydrogen, alkyl, alkenyl, haloalkyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl,
cycloalkylalkyl, heterocycle, or heterocyclealkyl; wherein the
aryl, the aryl moiety of arylalkyl, the heteroaryl, the heteroaryl
moiety of heteroarylakyl, the cycloalkyl, the cycloalkyl moiety of
cycloalkylalkyl, the heterocycle, and the heterocycle moiety of
heterocyclealkyl are independently unsubstituted or substituted
with 1, 2, 3, 4, or 5 substituents independently selected from the
group consisting of alkyl, alkenyl, alkynyl, nitro, --CN, halogen,
haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl,
hydroxy, hydroxyalkyl, NR.sub.AR.sub.B, (NR.sub.AR.sub.B)alkyl,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkyl, and oxo;
R.sub.C and R.sub.D are independently selected from the group
consisting of hydrogen, alkyl, alkylcarbonyl,
alkylcarbonyloxyalkylcarbonyl, arylcarbonyl, aryl, arylalkyl,
arylalkylcarbonyl, carboxyalkyl, carboxyalkylcarbonyl, cycloalkyl,
cycloalkylalkyl, haloalkyl, haloalkylcarbonyl, heteroaryl,
heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, heterocyclealkylcarbonyl,
(NR.sub.AR.sub.B)alkyl, and (NR.sub.AR.sub.B)alkylcarbonyl; wherein
if R.sub.C or R.sub.D are aryl, arylalkyl, arylalkylcarbonyl,
arylcarbonyl, cycloalkyl, cycloalkylalkyl, heteroalyl,
heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, or heterocyclealkylcarbonyl, then R.sub.C or
R.sub.D may be unsubstituted or substituted with 1, 2, 3, 4, or 5
substituents independently selected from the group consisting of
alkyl, alkenyl, alkynyl, nitro, --CN, halogen, haloalkyl, oxo,
alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy,
arylalkylcarbonyl, and arylalkoxycarbonyl; R.sub.A and R.sub.B are
independently selected from the group consisting of hydrogen,
alkyl, haloalkyl, and alkylcarbonyl; and n is 1.
2. A compound of Formula (I) ##STR11## or a pharmaceutically
acceptable salt thereof, wherein R.sub.1, R.sub.2, R.sub.3 and
R.sub.4 are hydrogen; X is aryl, arylalkyl, alkyl, heteroaryl,
heteroarylcarbonyl, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, hydroxyalkyl, cycloalkyl,
(NR.sub.CR.sub.D)carbonyl, or (NR.sub.CR.sub.D)alkyl; wherein if X
is aryl, arylalkyl, heteroaryl, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, or cycloalkyl, then X may be unsubstituted or
substituted with 1 or 2 substituents, Z, independently selected
from the group consisting of alkyl, nitro, --CN, halogen, alkoxy,
alkoxycarbonyl, aryl, arylalkyl, arylalkoxycarbonyl, carboxy,
cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycle,
heterocyclealkyl, heterocyclealkylcarbonyl, NR.sub.CR.sub.D,
(NR.sub.CR.sub.D)alkyl, (NR.sub.CR.sub.D)carbonyl, and oxo; wherein
the aryl and the heteroaryl moieties of Z are independently
unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents
selected from the group consisting of alkyl, formyl, halogen, and
haloalkyl, and the heterocycle and cycloalkyl moieties of Z are
independently unsubstituted or substituted with 1, 2, 3, 4, or 5
substituents selected from the group consisting of alkyl, oxo,
formyl, halogen, and haloalkyl; R.sub.C and R.sub.D are
independently selected from the group consisting of hydrogen,
alkyl, alkylcarbonyl, alkylcarbonyloxyalkylcarbonyl, aryl,
arylalkyl, arylalkylcarbonyl, arylcarbonyl, carboxyalkyl,
carboxyalkylcarbonyl, cycloalkyl, haloalkyl, haloalkylcarbonyl,
heteroaryl, heteroarylcarbonyl, heterocyclealkyl,
heterocyclecarbonyl, heterocyclealkylcarbonyl,
(NR.sub.AR.sub.B)alkyl, and (NR.sub.AR.sub.B)alkylcarbonyl; wherein
if R.sub.C or R.sub.D are arylalkylcarbonyl, arylcarbonyl,
heteroarylcarbonyl, heterocyclealkyl, heterocyclecarbonyl, or
heterocyclealkylcarbonyl, then R.sub.C or R.sub.D may be
unsubstituted or substituted with one substituent selected from the
group consisting of alkoxy, alkylcarbonyl and arylalkoxycarbonyl;
R.sub.A and R.sub.B are independently selected from the group
consisting of hydrogen, alkyl, and alkylcarbonyl; and n is 1.
3. A compound of Formula (II) ##STR12## or a pharmaceutically
acceptable salt thereof, wherein R.sub.1, R.sub.2, R.sub.3 and
R.sub.4 are independently selected from the group consisting of
hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, cyano,
haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro,
NR.sub.AR.sub.B, and (NR.sub.AR.sub.B)carbonyl; X is aryl,
arylalkyl, alkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl,
heterocycle, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl,
cycloalkyl, cycloalkylalkyl, NR.sub.CR.sub.D,
(NR.sub.CR.sub.D)carbonyl, (NR.sub.CR.sub.D)alkyl,
(NR.sub.CR.sub.D)carbonylalkyl, or -alkyl-CO.sub.2G.sub.1; wherein
if X is aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heteroarylcarbonyl, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, cycloalkyl, or cycloalkylalkyl then X may be
unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, Z,
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, nitro, --CN, halogen, haloalkyl, alkoxy, alkylcarbonyl,
alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy,
arylalkoxycarbonyl, arylalkylcarbonyl, carboxy, carboxyalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylcarbonyl,
heteroaryl, heteroarylalkyl, heteroarylcarbonyl,
heteroarylcarbonylalkyl, heterocycle, heterocyclealkyl,
heterocyclealkylcarbonyl, heterocyclecarbonyl,
heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR.sub.CR.sub.D,
(NR.sub.CR.sub.D)alkyl, (NR.sub.CR.sub.D)carbonyl,
(NR.sub.CR.sub.D)carbonylalkyl, and oxo; wherein the aryl and the
heteroaryl moieties of Z are independently unsubstituted or
substituted with 1, 2, 3, 4, or 5 substituents selected from the
group consisting of alkyl, formyl, halogen, and haloalkyl, and the
heterocycle and cycloalkyl moieties of Z are independently
unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents
selected from the group consisting of alkyl, oxo, formyl, halogen,
and haloalkyl; G.sub.1 is hydrogen, alkyl, alkenyl, haloalkyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl,
cycloalkylalkyl, heterocycle, or heterocyclealkyl; wherein the
aryl, the aryl moiety of arylalkyl, the heteroaryl, the heteroaryl
moiety of heteroarylakyl, the cycloalkyl, the cycloalkyl moiety of
cycloalkylalkyl, the heterocycle, and the heterocycle moiety of
heterocyclealkyl are independently unsubstituted or substituted
with 1, 2, 3, 4, or 5 substituents independently selected from the
group consisting of alkyl, alkenyl, alkynyl, nitro, --CN, halogen,
haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl,
hydroxy, hydroxyalkyl, NR.sub.AR.sub.B, (NR.sub.AR.sub.B)alkyl,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkyl, and oxo;
R.sub.C and R.sub.D are independently selected from the group
consisting of hydrogen, alkyl, alkylcarbonyl,
alkylcarbonyloxyalkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl,
arylcarbonyl, carboxyalkyl, carboxyalkylcarbonyl, cycloalkyl,
cycloalkylalkyl, haloalkyl, haloalkylcarbonyl, heteroaryl,
heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, heterocyclealkylcarbonyl,
(NR.sub.AR.sub.B)alkyl, and (NR.sub.AR.sub.B)alkylcarbonyl; wherein
if R.sub.C or R.sub.D are aryl, arylalkyl, arylalkylcarbonyl,
arylcarbonyl, cycloalkyl, cycloalkylalkyl, heteroaryl,
heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, or heterocyclealkylcarbonyl, then R.sub.C or
R.sub.D may be unsubstituted or substituted with 1, 2, 3, 4, or 5
substituents independently selected from the group consisting of
alkyl, alkenyl, alkynyl, nitro, --CN, halogen, haloalkyl, oxo,
alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy,
arylalkylcarbonyl, and arylalkoxycarbonyl; and R.sub.A and R.sub.B
are independently selected from the group consisting of hydrogen,
alkyl, haloalkyl, and alkylcarbonyl.
4. A compound of Formula (III) ##STR13## or a pharmaceutically
acceptable salt thereof, wherein R.sub.1, R.sub.2, R.sub.3 and
R.sub.4 are independently selected from the group consisting of
hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, cyano,
haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro,
NR.sub.AR.sub.B, and (NR.sub.AR.sub.B)carbonyl; X is aryl,
arylalkyl, alkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl,
heterocycle, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl,
cycloalkyl, cycloalkylalkyl, NR.sub.CR.sub.D,
(NR.sub.CR.sub.D)carbonyl, (NR.sub.CR.sub.D)alkyl,
(NR.sub.CR.sub.D)carbonylalkyl, or -alkyl-CO.sub.2G.sub.1; wherein
if X is aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heteroarylcarbonyl, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, cycloalkyl, or cycloalkylalkyl then X may be
unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, Z,
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, nitro, --CN, halogen, haloalkyl, alkoxy, alkylcarbonyl,
alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy,
arylalkoxycarbonyl, arylalkylcarbonyl, carboxy, carboxyalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylcarbonyl,
heteroaryl, heteroarylalkyl, heteroarylcarbonyl,
heteroarylcarbonylalkyl, heterocycle, heterocyclealkyl,
heterocyclealkylcarbonyl, heterocyclecarbonyl,
heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR.sub.CR.sub.D,
(NR.sub.CR.sub.D)alkyl, (NR.sub.CR.sub.D)carbonyl,
(NR.sub.CR.sub.D)carbonylalkyl, and oxo; wherein the aryl and the
heteroaryl moieties of Z are independently unsubstituted or
substituted with 1, 2, 3, 4, or 5 substituents selected from the
group consisting of alkyl, formyl, halogen, and haloalkyl, and the
heterocycle and cycloalkyl moieties of Z are independently
unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents
selected from the group consisting of alkyl, oxo, formyl, halogen,
and haloalkyl; G.sub.1 is hydrogen, alkyl, alkenyl, haloalkyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl,
cycloalkylalkyl, heterocycle, or heterocyclealkyl; wherein the
aryl, the aryl moiety of arylalkyl, the heteroaryl, the heteroaryl
moiety of heteroarylakyl, the cycloalkyl, the cycloalkyl moiety of
cycloalkylalkyl, the heterocycle, and the heterocycle moiety of
heterocyclealkyl are independently unsubstituted or substituted
with 1, 2, 3, 4, or 5 substituents independently selected from the
group consisting of alkyl, alkenyl, alkynyl, nitro, --CN, halogen,
haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl,
hydroxy, hydroxyalkyl, NR.sub.AR.sub.B, (NR.sub.AR.sub.B)alkyl,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkyl, and oxo;
R.sub.C and R.sub.D are independently selected from the group
consisting of hydrogen, alkyl, alkylcarbonyl,
alkylcarbonyloxyalkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl,
carboxyalkyl, carboxyalkylcarbonyl, cycloalkyl, cycloalkylalkyl,
haloalkyl, haloalkylcarbonyl, heteroaryl, heteroarylalkyl,
heteroarylcarbonyl, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, heterocyclealkylcarbonyl,
(NR.sub.AR.sub.B)alkyl, and (NR.sub.AR.sub.B)alkylcarbonyl; wherein
if R.sub.C or R.sub.D are aryl, arylalkyl, arylalkylcarbonyl,
cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl,
heteroarylcarbonyl, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, or heterocyclealkylcarbonyl, then R.sub.C or
R.sub.D may be unsubstituted or substituted with 1, 2, 3, 4, or 5
substituents independently selected from the group consisting of
alkyl, alkenyl, alkynyl, nitro, --CN, halogen, haloalkyl, oxo,
alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy,
arylalkylcarbonyl, and arylalkoxycarbonyl; and R.sub.A and R.sub.B
are independently selected from the group consisting of hydrogen,
alkyl, haloalkyl, and alkylcarbonyl.
5. A compound according to claim 3 wherein X is aryl or arylalkyl
wherein the aryl or arylalkyl may be unsubstituted or substituted
with 1, 2, 3, 4, or 5 substituents, Z, independently selected from
the group consisting of alkyl, alkenyl, alkynyl, nitro, --CN,
halogen, haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl,
alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl,
arylalkoxy, arylalkoxycarbonyl, arylalkylcarbonyl, carboxy,
carboxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy,
cycloalkylcarbonyl, heteroaryl, heteroarylalkyl,
heteroarylcarbonyl, heteroarylcarbonylalkyl, heterocycle,
heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl,
heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR.sub.CR.sub.D,
(NR.sub.CR.sub.D)alkyl, (NR.sub.CR.sub.D)carbonyl, and
(NR.sub.CR.sub.D)carbonylalkyl; wherein the aryl and the heteroaryl
moieties of Z are independently unsubstituted or substituted with
1, 2, 3, 4, or 5 substituents selected from the group consisting of
alkyl, formyl, halogen, and haloalkyl, and the heterocycle and
cycloalkyl moieties of Z are independently unsubstituted or
substituted with 1, 2, 3, 4, or 5 substituents selected from the
group consisting of alkyl, oxo, formyl, halogen, and haloalkyl.
6. A compound according to claim 3 wherein X is heteroaryl which
may be unsubstituted or substituted with 1, 2, 3, 4, or 5
substituents, Z, independently selected from the group consisting
of alkyl, alkenyl, alkynyl, nitro, --CN, halogen, haloalkyl,
alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy,
arylalkoxycarbonyl, arylalkylcarbonyl, carboxy, carboxyalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylcarbonyl,
heteroaryl, heteroarylalkyl, heteroarylcarbonyl,
heteroarylcarbonylalkyl, heterocycle, heterocyclealkyl,
heterocyclealkylcarbonyl, heterocyclecarbonyl,
heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR.sub.CR.sub.D,
(NR.sub.CR.sub.D)alkyl, (R.sub.CR.sub.D)carbonyl, and
(NR.sub.CR.sub.D)carbonylalkyl; wherein the aryl and the heteroaryl
moieties of Z are independently unsubstituted or substituted with
1, 2, 3, 4, or 5 substituents selected from the group consisting of
alkyl, formyl, halogen, and haloalkyl, and the heterocycle and
cycloalkyl moieties of Z are independently unsubstituted or
substituted with 1, 2, 3, 4, or 5 substituents selected from the
group consisting of alkyl, oxo, formyl, halogen, and haloalkyl.
7. A compound according to claim 3 wherein X is heterocycle or
heterocyclealkyl wherein the heterocycle or heterocyclealkyl may be
unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, Z,
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, nitro, --CN, halogen, haloalkyl, alkoxy, alkylcarbonyl,
alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy,
arylalkoxycarbonyl, arylalkylcarbonyl, carboxy, carboxyalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylcarbonyl,
heteroaryl, heteroarylalkyl, heteroarylcarbonyl,
heteroarylcarbonylalkyl, heterocycle, heterocyclealkyl,
heterocyclealkylcarbonyl, heterocyclecarbonyl,
heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR.sub.CR.sub.D,
(NR.sub.CR.sub.D)alkyl, (NR.sub.CR.sub.D)carbonyl,
(NR.sub.CR.sub.D)carbonylalkyl, and oxo; wherein the aryl and the
heteroaryl moieties of Z are independently unsubstituted or
substituted with 1, 2, 3, 4, or 5 substituents selected from the
group consisting of alkyl, formyl, halogen, and haloalkyl, and the
heterocycle and cycloalkyl moieties of Z are independently
unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents
selected from the group consisting of alkyl, oxo, formyl, halogen,
and haloalkyl.
8. A compound according to claim 4 wherein X is heteroarylcarbonyl,
heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl,
(NR.sub.CR.sub.D)carbonyl, (NR.sub.CR.sub.D)alkyl, or aryl wherein
if X is heteroarylcarbonyl, heterocyclealkyl, heterocyclecarbonyl,
or aryl, then X may be unsubstituted or substituted with 1, 2, 3,
4, or 5 substituents, Z, independently selected from the group
consisting of alkyl, alkenyl, alkynyl, nitro, --CN, halogen,
haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy,
arylalkoxycarbonyl, arylalkylcarbonyl, carboxy, carboxyalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylcarbonyl,
heteroaryl, heteroarylalkyl, heteroarylcarbonyl,
heteroarylcarbonylalkyl, heterocycle, heterocyclealkyl,
heterocyclealkylcarbonyl, heterocyclecarbonyl,
heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR.sub.CR.sub.D,
(NR.sub.CR.sub.D)alkyl, (NR.sub.CR.sub.D)carbonyl,
(NR.sub.CR.sub.D)carbonylalkyl, and oxo; wherein the aryl and the
heteroaryl moieties of Z are independently unsubstituted or
substituted with 1, 2, 3, 4, or 5 substituents selected from the
group consisting of alkyl, formyl, halogen, and haloalkyl, and the
heterocycle and cycloalkyl moieties of Z are independently
unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents
selected from the group consisting of alkyl, oxo, formyl, halogen,
and haloalkyl.
9. A compound according to claim 1 wherein R.sub.1, R.sub.2,
R.sub.3 and R.sub.4 are hydrogen.
10. A compound selected from the group consisting of
3-phenyl-4H-pyrazolo[1,5-a]quinazolin-5-one;
3-(4-chloro-phenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-phenyl-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-tert-butyl-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-furan-2-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-thiophen-2-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-(4-methoxyphenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-(3-nitrophenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-(3-chlorophenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-biphenyl-2-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-biphenyl-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-(3-aminophenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-(2-chlorophenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-[3-(2-aminoethylamino)phenyl]-4H-pyrazolo[1,5-a]quinazolin-5-one;
N-{2-[3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)phenylamino]ethy-
l}-acetamide;
N-[3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)phenyl]acetamide;
benzyl 4-({acetyl
[3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)phenyl]amino}methyl)p-
iperidine-1-carboxylate;
2-[3-(2-dimethylaminoethylamino)phenyl]-4H-pyrazolo[1,5-a]quinazolin-5-on-
e; 2-piperidin-3-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-(1-methylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-(1-ethylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-(1-isobutylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-(1-cyclopropylmethylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-[1-(3-piperidin-1-ylpropionyl)piperidin-3-yl]-4H-pyrazolo[1,5-a]quinaz-
olin-5-one;
2-(1-propylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-(1-benzylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-(1-cyclopentylmethylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-(1-pyridin-4-ylmethylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-on-
e;
2-(1-isopropylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
methyl 4-(5-oxo-4,
5-dihydropyrazolo[1,5-a]quinazolin-2-yl)benzoate;
2-(3-fluoro-4-morpholin-4-ylphenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-cyclopropyl-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-(1-benzylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
N-[3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)phenyl]-3-piperidin-
-1-ylpropionamide;
2-piperidin-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-(4-pyrrolidin-1-ylmethylphenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-(1-methylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-(1-ethylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-(1-propylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-(1-cyclopropylmethylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-(1-isobutylpiperidin-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-(1-isopropylpiperidin-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-pyrrolidin-3-yl-4H-pyrazolo[1,5-a]quinazolin-5-one; benzyl
3-(5-oxo-4,
5-dihydropyrazolo[1,5-a]quinazolin-2-yl)pyrrolidine-1-carboxylate;
2-(1-methylpyrrolidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-(1-ethylpyrrolidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-(1-cyclopropylmethylpyrrolidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one-
; 2-piperidin-2-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-(1-methylpiperidin-2-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
(S)-2-acetylamino-4-methyl-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin--
3-ylmethyl)pentanamide;
(R)-2-methoxy-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)-2-
-phenylacetamide;
N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)isonicotinamide;
N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)-3-piperidin-1--
yl-propionamide;
N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)-3-pyrrolidin-1--
yl-propionamide;
2-morpholin-4-yl-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl-
)acetamide;
3-morpholin-4-yl-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl-
)-propionamide; 2-phenethyl-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-benzyl-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-piperidin-4-ylmethyl-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-(1-methylpiperidin-4-ylmethyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
2-(3-bromobenzyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;
3-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]benzonitrile;
2-[3-(aminomethyl)benzyl]pyrazolo[1,5-a]quinazolin-5(4H)-one;
2-(3-pyridin-3-ylbenzyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;
2-[3-(2-oxopyrrolidin-1-yl)benzyl]pyrazolo[1,5-a]quinazolin-5(4H)-one;
3'-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]-1,1'-bipheny-
l-2-carbaldehyde;
2-[3-(2-fluoropyridin-4-yl)benzyl]pyrazolo[1,5-a]quinazolin-5(4H)-one;
methyl
3-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]benzoat-
e;
3-[(4-methylpiperazin-1-yl)carbonyl]pyrazolo[1,5-a]quinazolin-5(4H)-on-
e; 3-(pyrrolidin-1-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;
N,N-dimethyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;
3-(piperidin-1-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;
N-cyclopropyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;
5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;
N-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;
N-ethyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;
N-benzyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;
5-oxo-N-(2-phenylethyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxami-
de; 3-(azepan-1-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;
3-(morpholin-4-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;
3-(piperazin-1-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;
N-cyclohexyl-5-oxo-4,
5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;
3-(1H-imidazol-1-ylcarbonyl)pyrazolo[1,5-a]quinazolin-S (4H)-one;
5-oxo-N-(piperidin-4-ylmethyl)-4,
5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;
3-{[3-(aminomethyl)piperidin-1-yl]carbonyl}pyrazolo[1,5-a]quinazolin-5(4H-
)-one;
5-oxo-N-phenyl-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide-
;
4-{[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)carbonyl]amino}but-
anoic acid;
3-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]benzoic
acid;
5-oxo-N-(2-piperidin-1-ylethyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-c-
arboxamide; 3-(hydroxymethyl)pyrazolo[1,5-a]quinazolin -5-(4H)-one;
3-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]benzamide;
3-(aminomethyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;
N-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]glycine;
4-chloro-N-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]butan-
amide;
4-oxo-4-{[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]-
amino}butanoic acid;
1-acetyl-N-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]piper-
idine-4-carboxamide;
2-oxo-2-{[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]amino}e-
thyl acetate;
3-(pyrrolidin-1-ylmethyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;
1-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]pyrrolidine-2,-
5-dione; and
N-((5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl)acetamide;
or a pharmaceutically acceptable salt thereof.
11. A method of treating inflammation in a mammal in recognized
need of such treatment comprising administering to the mammal a
therapeutically acceptable amount of a compound of Formula (I) of
claim 1 or a pharmaceutically acceptable salt thereof.
12. A method of treating sepsis in a mammal in recognized need of
such treatment comprising administering to the mammal a
therapeutically acceptable amount of a compound of Formula (I) of
claim 1 or a pharmaceutically acceptable salt thereof.
13. A method of treating septic shock in a mammal in recognized
need of such treatment comprising administering to the mammal a
therapeutically acceptable amount of a compound of Formula (I) of
claim 1 or a pharmaceutically acceptable salt thereof.
14. A method of treating cancer in a mammal in recognized need of
such treatment comprising administering to the mammal a
therapeutically acceptable amount of a compound of Formula (I) of
claim 1 or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition comprising a compound of Formula
(I) of claim 1 or a pharmaceutically acceptable salt thereof, in
combination with a therapeutically acceptable carrier.
Description
[0001] This application claims priority to the provisional
application Ser. No. 60/805,235 filed on Jun. 20, 2006.
TECHNICAL FIELD
[0002] The present invention relates to
1H-benzimidazole-4-carboxamides, their preparation, and their use
as inhibitors of the enzyme poly(ADP-ribose)polymerase for the
preparation of drugs.
BACKGROUND
[0003] Poly(ADP-ribose)polymerase (PARP) or
poly(ADP-ribose)synthase (PARS) has an essential role in
facilitating DNA repair, controlling RNA transcription, mediating
cell death, and regulating immune response. These actions make PARP
inhibitors targets for a broad spectrum of disorders. PARP
inhibitors have demonstrated efficacy in numerous models of
disease, particularly in models of ischemia reperfusion injury,
inflammatory disease, degenerative diseases, protection from
adverse effects of cytoxic compounds, and the potentiation of
cytotoxic cancer therapy. PARP has also been indicated in
retroviral infection and thus inhibitors may have use in
antiretroviral therapy. PARP inhibitors have been efficacious in
preventing ischemia reperfusion injury in models of myocardial
infarction, stroke, other neural trauma, organ transplantation, as
well as reperfusion of the eye, kidney, gut and skeletal muscle.
Inhibitors have been efficacious in inflammatory diseases such as
arthritis, gout, inflammatory bowel disease, CNS inflammation such
as MS and allergic encephalitis, sepsis, septic shock, hemmorhagic
shock, pulmonary fibrosis, and uveitis. PARP inhibitors have also
shown benefit in several models of degenerative disease including
diabetes (as well as complications) and Parkinsons disease. PARP
inhibitors can ameliorate the liver toxicity following
acetominophen overdose, cardiac and kidney toxicities from
doxorubicin and platinum based antineoplastic agents, as well as
skin damage secondary to sulfur mustards. In various cancer models,
PARP inhibitors have been shown to potentiate radiation and
chemotherapy by increasing cell death of cancer cells, limiting
tumor growth, decreasing metastasis, and prolonging the survival of
tumor-bearing animals.
SUMMARY OF THE INVENTION
[0004] In one embodiment, the present invention provides compounds
of Formula (I) ##STR2## or a pharmaceutically acceptable salt
thereof, wherein
[0005] R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are independently
selected from the group consisting of hydrogen, alkenyl, alkoxy,
alkoxycarbonyl, alkyl, alkynyl, cyano, haloalkoxy, haloalkyl,
halogen, hydroxy, hydroxyalkyl, nitro, NR.sub.AR.sub.B, and
(NR.sub.AR.sub.B)carbonyl;
[0006] X is aryl, arylalkyl, alkyl, heteroaryl, heteroarylalkyl,
heteroarylcarbonyl, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,
NR.sub.CR.sub.D, (NR.sub.CR.sub.D)carbonyl, (NR.sub.CR.sub.D)alkyl,
(NR.sub.CR.sub.D)carbonylalkyl, or -alkyl-CO.sub.2G.sub.1; wherein
if X is aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heteroarylcarbonyl, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, cycloalkyl, or cycloalkylalkyl then X may be
unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, Z,
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, nitro, --CN, halogen, haloalkyl, alkoxy, alkylcarbonyl,
alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy,
arylalkoxycarbonyl, arylalkylcarbonyl, carboxy, carboxyalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylcarbonyl,
heteroaryl, heteroarylalkyl, heteroarylcarbonyl,
heteroarylcarbonylalkyl, heterocycle, heterocyclealkyl,
heterocyclealkylcarbonyl, heterocyclecarbonyl,
heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR.sub.CR.sub.D,
(NR.sub.CR.sub.D)alkyl, (NR.sub.CR.sub.D)carbonyl,
(NR.sub.CR.sub.D)carbonylalkyl, and oxo; wherein the aryl and the
heteroaryl moieties of Z are independently unsubstituted or
substituted with 1, 2, 3, 4, or 5 substituents selected from the
group consisting of alkyl, formyl, halogen, and haloalkyl, and the
heterocycle and cycloalkyl moieties of Z are independently
unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents
selected from the group consisting of alkyl, oxo, formyl, halogen,
and haloalkyl;
[0007] G.sub.1 is hydrogen, alkyl, alkenyl, haloalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl,
cycloalkylalkyl, heterocycle, or heterocyclealkyl; wherein the
aryl, the aryl moiety of arylalkyl, the heteroaryl, the heteroaryl
moiety of heteroarylakyl, the cycloalkyl, the cycloalkyl moiety of
cycloalkylalkyl, the heterocycle, and the heterocycle moiety of
heterocyclealkyl are independently unsubstituted or substituted
with 1, 2, 3, 4, or 5 substituents independently selected from the
group consisting of alkyl, alkenyl, alkynyl, nitro, --CN, halogen,
haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl,
hydroxy, hydroxyalkyl, NR.sub.AR.sub.B, (NR.sub.AR.sub.B)alkyl,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkyl, and
oxo;
[0008] R.sub.C and R.sub.D are independently selected from the
group consisting of hydrogen, alkyl, alkylcarbonyl,
alkylcarbonyloxyalkylcarbonyl, arylcarbonyl, aryl, arylalkyl,
arylalkylcarbonyl, carboxyalkyl, carboxyalkylcarbonyl, cycloalkyl,
cycloalkylalkyl, haloalkyl, haloalkylcarbonyl, heteroaryl,
heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, heterocyclealkylcarbonyl,
(NR.sub.AR.sub.B)alkyl, and (NR.sub.AR.sub.B)alkylcarbonyl; wherein
if R.sub.C or R.sub.D are aryl, arylalkyl, arylalkylcarbonyl,
arylcarbonyl, cycloalkyl, cycloalkylalkyl, heteroaryl,
heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, or heterocyclealkylcarbonyl, then R.sub.C or
R.sub.D may be unsubstituted or substituted with 1, 2, 3, 4, or 5
substituents independently selected from the group consisting of
alkyl, alkenyl, alkynyl, nitro, --CN, halogen, haloalkyl, oxo,
alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy,
arylalkylcarbonyl, and arylalkoxycarbonyl;
[0009] R.sub.A and R.sub.B are independently selected from the
group consisting of hydrogen, alkyl, haloalkyl, and alkylcarbonyl;
and
[0010] n is 1.
DETAILED DESCRIPTION OF THE INVENTION
[0011] In another embodiment, the present invention provides
compounds of Formula (I) ##STR3## or a pharmaceutically acceptable
salt thereof, wherein
[0012] R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are hydrogen;
[0013] X is aryl, arylalkyl, alkyl, heteroaryl, heteroarylcarbonyl,
heterocycle, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl,
cycloalkyl, (NR.sub.CR.sub.D)carbonyl, or (NR.sub.CR.sub.D)alkyl;
wherein if X is aryl, arylalkyl, heteroaryl, heterocycle,
heterocyclealkyl, heterocyclecarbonyl, or cycloalkyl, then X may be
unsubstituted or substituted with 1 or 2 substituents, Z,
independently selected from the group consisting of alkyl, nitro,
--CN, halogen, alkoxy, alkoxycarbonyl, aryl, arylalkyl,
arylalkoxycarbonyl, carboxy, cycloalkylalkyl, heteroaryl,
heteroarylalkyl, heterocycle, heterocyclealkyl,
heterocyclealkylcarbonyl, NR.sub.CR.sub.D, (NR.sub.CR.sub.D)alkyl,
(NR.sub.CR.sub.D)carbonyl, and oxo; wherein the aryl and the
heteroaryl moieties of Z are independently unsubstituted or
substituted with 1, 2, 3, 4, or 5 substituents selected from the
group consisting of alkyl, formyl, halogen, and haloalkyl, and the
heterocycle and cycloalkyl moieties of Z are independently
unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents
selected from the group consisting of alkyl, oxo, formyl, halogen,
and haloalkyl;
[0014] R.sub.C and R.sub.D are independently selected from the
group consisting of hydrogen, alkyl, alkylcarbonyl,
alkylcarbonyloxyalkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl,
arylcarbonyl, carboxyalkyl, carboxyalkylcarbonyl, cycloalkyl,
haloalkyl, haloalkylcarbonyl, heteroaryl, heteroarylcarbonyl,
heterocyclealkyl, heterocyclecarbonyl, heterocyclealkylcarbonyl,
(NR.sub.AR.sub.B)alkyl, and (NR.sub.AR.sub.B)alkylcarbonyl; wherein
if R.sub.C or R.sub.D are arylalkylcarbonyl, arylcarbonyl,
heteroarylcarbonyl, heterocyclealkyl, heterocyclecarbonyl, or
heterocyclealkylcarbonyl, then R.sub.C or R.sub.D may be
unsubstituted or substituted with one substituent selected from the
group consisting of alkoxy, alkylcarbonyl and
arylalkoxycarbonyl;
[0015] R.sub.A and R.sub.B are independently selected from the
group consisting of hydrogen, alkyl, and alkylcarbonyl; and
[0016] n is 1.
[0017] In another embodiment the present invention provide
compounds of Formula (I) where X is selected from the group
consisting of aryl, heteroaryl, heterocycle, and cycloalkyl.
[0018] In another embodiment, the present invention provides
compounds of Formula (II) ##STR4## or a therapeutically acceptable
salt thereof, wherein
[0019] R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are independently
selected from the group consisting of hydrogen, alkenyl, alkoxy,
alkoxycarbonyl, alkyl, alkynyl, cyano, haloalkoxy, haloalkyl,
halogen, hydroxy, hydroxyalkyl, nitro, NR.sub.AR.sub.B, and
(NR.sub.AR.sub.B)carbonyl;
[0020] X is aryl, arylalkyl, alkyl, heteroaryl, heteroarylalkyl,
heteroarylcarbonyl, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,
NR.sub.CR.sub.D, (NR.sub.CR.sub.D)carbonyl, (NR.sub.CR.sub.D)alkyl,
(NR.sub.CR.sub.D)carbonylalkyl, or -alkyl-CO.sub.2G.sub.1; wherein
if X is aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heteroarylcarbonyl, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, cycloalkyl, or cycloalkylalkyl then X may be
unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, Z,
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, nitro, --CN, halogen, haloalkyl, alkoxy, alkylcarbonyl,
alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy,
arylalkoxycarbonyl, arylalkylcarbonyl, carboxy, carboxyalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylcarbonyl,
heteroaryl, heteroarylalkyl, heteroarylcarbonyl,
heteroarylcarbonylalkyl, heterocycle, heterocyclealkyl,
heterocyclealkylcarbonyl, heterocyclecarbonyl,
heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR.sub.CR.sub.D,
(NR.sub.CR.sub.D)alkyl, (NR.sub.CR.sub.D)carbonyl,
(NR.sub.CR.sub.D)carbonylalkyl, and oxo;
[0021] wherein the aryl and the heteroaryl moieties of Z are
independently unsubstituted or substituted with 1, 2, 3, 4, or 5
substituents selected from the group consisting of alkyl, formyl,
halogen, and haloalkyl, and the heterocycle and cycloalkyl moieties
of Z are independently unsubstituted or substituted with 1, 2, 3,
4, or 5 substituents selected from the group consisting of alkyl,
oxo, formyl, halogen, and haloalkyl;
[0022] G.sub.1 is hydrogen, alkyl, alkenyl, haloalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl,
cycloalkylalkyl, heterocycle, or heterocyclealkyl; wherein the
aryl, the aryl moiety of arylalkyl, the heteroaryl, the heteroaryl
moiety of heteroarylakyl, the cycloalkyl, the cycloalkyl moiety of
cycloalkylalkyl, the heterocycle, and the heterocycle moiety of
heterocyclealkyl are independently unsubstituted or substituted
with 1, 2, 3, 4, or 5 substituents independently selected from the
group consisting of alkyl, alkenyl, alkynyl, nitro, --CN, halogen,
haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl,
hydroxy, hydroxyalkyl, NR.sub.AR.sub.B, (NR.sub.AR.sub.B)alkyl,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkyl, and
oxo;
[0023] R.sub.C and R.sub.D are independently selected from the
group consisting of hydrogen, alkyl, alkylcarbonyl,
alkylcarbonyloxyalkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl,
arylcarbonyl, carboxyalkyl, carboxyalkylcarbonyl, cycloalkyl,
cycloalkylalkyl, haloalkyl, haloalkylcarbonyl, heteroaryl,
heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, heterocyclealkylcarbonyl,
(NR.sub.AR.sub.B)alkyl, and (NR.sub.AR.sub.B)alkylcarbonyl; wherein
if R.sub.C or R.sub.D are aryl, arylalkyl, arylalkylcarbonyl,
arylcarbonyl, cycloalkyl, cycloalkylalkyl, heteroaryl,
heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, or heterocyclealkylcarbonyl, then R.sub.C or
R.sub.D may be unsubstituted or substituted with 1, 2, 3, 4, or 5
substituents independently selected from the group consisting of
alkyl, alkenyl, alkynyl, nitro, --CN, halogen, haloalkyl, oxo,
alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy,
arylalkylcarbonyl, and arylalkoxycarbonyl; and
[0024] R.sub.A and R.sub.B are independently selected from the
group consisting of hydrogen, alkyl, haloalkyl, and
alkylcarbonyl.
[0025] In another embodiment, the present invention provides
compounds of Formula (III) ##STR5## or a pharmaceutically
acceptable salt thereof, wherein
[0026] R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are independently
selected from the group consisting of hydrogen, alkenyl, alkoxy,
alkoxycarbonyl, alkyl, alkynyl, cyano, haloalkoxy, haloalkyl,
halogen, hydroxy, hydroxyalkyl, nitro, NR.sub.AR.sub.B, and
(NR.sub.AR.sub.B)carbonyl;
[0027] X is aryl, arylalkyl, alkyl, heteroaryl, heteroarylalkyl,
heteroarylcarbonyl, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,
NR.sub.CR.sub.D, (NR.sub.CR.sub.D)carbonyl, (NR.sub.CR.sub.D)alkyl,
(NR.sub.CR.sub.D)carbonylalkyl, or -alkyl-CO.sub.2G.sub.1; wherein
if X is aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heteroarylcarbonyl, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, cycloalkyl, or cycloalkylalkyl then X may be
unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, Z,
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, nitro, --CN, halogen, haloalkyl, alkoxy, alkylcarbonyl,
alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy,
arylalkoxycarbonyl, arylalkylcarbonyl, carboxy, carboxyalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylcarbonyl,
heteroaryl, heteroarylalkyl, heteroarylcarbonyl,
heteroarylcarbonylalkyl, heterocycle, heterocyclealkyl,
heterocyclealkylcarbonyl, heterocyclecarbonyl,
heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR.sub.CR.sub.D,
(NR.sub.CR.sub.D)alkyl, (NR.sub.CR.sub.D)carbonyl,
(NR.sub.CR.sub.D)carbonylalkyl, and oxo; wherein the aryl and the
heteroaryl moieties of Z are independently unsubstituted or
substituted with 1, 2, 3, 4, or 5 substituents selected from the
group consisting of alkyl, formyl, halogen, and haloalkyl, and the
heterocycle and cycloalkyl moieties of Z are independently
unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents
selected from the group consisting of alkyl, oxo, formyl, halogen,
and haloalkyl;
[0028] G.sub.1 is hydrogen, alkyl, alkenyl, haloalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl,
cycloalkylalkyl, heterocycle, or heterocyclealkyl; wherein the
aryl, the aryl moiety of arylalkyl, the heteroaryl, the heteroaryl
moiety of heteroarylakyl, the cycloalkyl, the cycloalkyl moiety of
cycloalkylalkyl, the heterocycle, and the heterocycle moiety of
heterocyclealkyl are independently unsubstituted or substituted
with 1, 2, 3, 4, or 5 substituents independently selected from the
group consisting of alkyl, alkenyl, alkynyl, nitro, --CN, halogen,
haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl,
hydroxy, hydroxyalkyl, NR.sub.AR.sub.B, (NR.sub.AR.sub.B)alkyl,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkyl, and
oxo;
[0029] R.sub.C and R.sub.D are independently selected from the
group consisting of hydrogen, alkyl, alkylcarbonyl,
alkylcarbonyloxyalkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl,
carboxyalkyl, carboxyalkylcarbonyl, cycloalkyl, cycloalkylalkyl,
haloalkyl, haloalkylcarbonyl, heteroaryl, heteroarylalkyl,
heteroarylcarbonyl, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, heterocyclealkylcarbonyl,
(NR.sub.AR.sub.B)alkyl, and (NR.sub.AR.sub.B)alkylcarbonyl; wherein
if R.sub.C or R.sub.D are aryl, arylalkyl, arylalkylcarbonyl,
cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl,
heteroarylcarbonyl, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, or heterocyclealkylcarbonyl, then R.sub.C or
R.sub.D may be unsubstituted or substituted with 1, 2, 3, 4, or 5
substituents independently selected from the group consisting of
alkyl, alkenyl, alkynyl, nitro, --CN, halogen, haloalkyl, oxo,
alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy,
arylalkylcarbonyl, and arylalkoxycarbonyl; and
[0030] R.sub.A and R.sub.B are independently selected from the
group consisting of hydrogen, alkyl, haloalkyl, and
alkylcarbonyl.
[0031] In another embodiment, the present invention provides
compounds of Formula (II) wherein X is aryl or arylalkyl wherein
the aryl or arylalkyl may be unsubstituted or substituted with 1,
2, 3, 4, or 5 substituents, Z, independently selected from the
group consisting of alkyl, alkenyl, alkynyl, nitro, --CN, halogen,
haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy,
arylalkoxycarbonyl, arylalkylcarbonyl, carboxy, carboxyalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylcarbonyl,
heteroaryl, heteroarylalkyl, heteroarylcarbonyl,
heteroarylcarbonylalkyl, heterocycle, heterocyclealkyl,
heterocyclealkylcarbonyl, heterocyclecarbonyl,
heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR.sub.CR.sub.D,
(NR.sub.CR.sub.D)alkyl, (NR.sub.CR.sub.D)carbonyl, and
(NR.sub.CR.sub.D)carbonylalkyl; wherein the aryl and the heteroaryl
moieties of Z are independently unsubstituted or substituted with
1, 2, 3, 4, or 5 substituents selected from the group consisting of
alkyl, formyl, halogen, and haloalkyl, and the heterocycle and
cycloalkyl moieties of Z are independently unsubstituted or
substituted with 1, 2, 3, 4, or 5 substituents selected from the
group consisting of alkyl, oxo, formyl, halogen, and haloalkyl.
[0032] In another embodiment, the present invention provides
compounds of Formula (II) wherein X is heteroaryl which may be
unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, Z,
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, nitro, --CN, halogen, haloalkyl, alkoxy, alkylcarbonyl,
alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy,
arylalkoxycarbonyl, arylalkylcarbonyl, carboxy, carboxyalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylcarbonyl,
heteroaryl, heteroarylalkyl, heteroarylcarbonyl,
heteroarylcarbonylalkyl, heterocycle, heterocyclealkyl,
heterocyclealkylcarbonyl, heterocyclecarbonyl,
heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR.sub.CR.sub.D,
(NR.sub.CR.sub.D)alkyl, (NR.sub.CR.sub.D)carbonyl, and
(NR.sub.CR.sub.D)carbonylalkyl; wherein the aryl and the heteroaryl
moieties of Z are independently unsubstituted or substituted with
1, 2, 3, 4, or 5 substituents selected from the group consisting of
alkyl, formyl, halogen, and haloalkyl, and the heterocycle and
cycloalkyl moieties of Z are independently unsubstituted or
substituted with 1, 2, 3, 4, or 5 substituents selected from the
group consisting of alkyl, oxo, formyl, halogen, and haloalkyl.
[0033] In another embodiment, the present invention provides
compounds of Formula (II) wherein X is heterocycle or
heterocyclealkyl wherein the heterocycle or heterocyclealkyl may be
unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, Z,
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, nitro, --CN, halogen, haloalkyl, alkoxy, alkylcarbonyl,
alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy,
arylalkoxycarbonyl, arylalkylcarbonyl, carboxy, carboxyalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylcarbonyl,
heteroaryl, heteroarylalkyl, heteroarylcarbonyl,
heteroarylcarbonylalkyl, heterocycle, heterocyclealkyl,
heterocyclealkylcarbonyl, heterocyclecarbonyl,
heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR.sub.CR.sub.D,
(NR.sub.CR.sub.D)alkyl, (NR.sub.CR.sub.D)carbonyl,
(NR.sub.CR.sub.D)carbonylalkyl, and oxo; wherein the aryl and the
heteroaryl moieties of Z are independently unsubstituted or
substituted with 1, 2, 3, 4, or 5 substituents selected from the
group consisting of alkyl, formyl, halogen, and haloalkyl, and the
heterocycle and cycloalkyl moieties of Z are independently
unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents
selected from the group consisting of alkyl, oxo, formyl, halogen,
and haloalkyl.
[0034] In another embodiment, the present invention provides
compounds of Formula (III) wherein X is heteroarylcarbonyl,
heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl,
(NR.sub.CR.sub.D)carbonyl, (NR.sub.CR.sub.D)alkyl, or aryl wherein
if X is heteroarylcarbonyl, heterocyclealkyl, heterocyclecarbonyl,
or aryl, then X may be unsubstituted or substituted with 1, 2, 3,
4, or 5 substituents, Z, independently selected from the group
consisting of alkyl, alkenyl, alkynyl, nitro, --CN, halogen,
haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy,
arylalkoxycarbonyl, arylalkylcarbonyl, carboxy, carboxyalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylcarbonyl,
heteroaryl, heteroarylalkyl, heteroarylcarbonyl,
heteroarylcarbonylalkyl, heterocycle, heterocyclealkyl,
heterocyclealkylcarbonyl, heterocyclecarbonyl,
heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR.sub.CR.sub.D,
(NR.sub.CR.sub.D)alkyl, (NR.sub.CR.sub.D)carbonyl,
(NR.sub.CR.sub.D)carbonylalkyl, and oxo; wherein the aryl and the
heteroaryl moieties of Z are independently unsubstituted or
substituted with 1, 2, 3, 4, or 5 substituents selected from the
group consisting of alkyl, formyl, halogen, and haloalkyl, and the
heterocycle and cycloalkyl moieties of Z are independently
unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents
selected from the group consisting of alkyl, oxo, formyl, halogen,
and haloalkyl.
[0035] In another embodiment, the present invention provides
compounds of Formula (I) wherein R.sub.1, R.sub.2, R.sub.3 and
R.sub.4 are hydrogen.
[0036] In another embodiment, the present invention provides
compounds of Formula (II) wherein R.sub.1, R.sub.2, R.sub.3 and
R.sub.4 are hydrogen.
[0037] In another embodiment, the present invention provides
compounds of Formula (III) wherein R.sub.1, R.sub.2, R.sub.3 and
R.sub.4 are hydrogen. In another embodiment, the present invention
provides compounds selected from the group consisting of
[0038] 3-phenyl-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0039] 3-(4-chloro-phenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0040] 2-phenyl-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0041] 2-tert-butyl-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0042] 2-furan-2-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0043] 2-thiophen-2-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0044] 2-(4-methoxyphenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0045] 2-(3-nitrophenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0046] 2-(3-chlorophenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0047] 2-biphenyl-2-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0048] 2-biphenyl-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0049] 2-(3-aminophenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0050] 2-(2-chlorophenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0051]
2-[3-(2-aminoethylamino)phenyl]-4H-pyrazolo[1,5-a]quinazolin-5-one-
;
[0052]
N-{2-[3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)phenylami-
no]ethyl}-acetamide;
[0053]
N-[3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)phenyl]aceta-
mide;
[0054] benzyl
4-({acetyl[3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)phenyl]amin-
o}methyl)piperidine-1-carboxylate;
[0055]
2-[3-(2-dimethylaminoethylamino)phenyl]-4H-pyrazolo[1,5-a]quinazol-
in-5-one;
[0056] 2-piperidin-3-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0057]
2-(1-methylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0058]
2-(1-ethylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0059]
2-(1-isobutylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0060]
2-(1-cyclopropylmethylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-
-5-one;
[0061]
2-[1-(3-piperidin-1-ylpropionyl)piperidin-3-yl]-4H-pyrazolo[1,5-a]-
quinazolin-5-one;
[0062]
2-(1-propylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0063]
2-(1-benzylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0064]
2-(1-cyclopentylmethylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-
-5-one;
[0065]
2-(1-pyridin-4-ylmethylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazoli-
n-5-one;
[0066]
2-(1-isopropylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0067] methyl
4-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)benzoate;
[0068]
2-(3-fluoro-4-morpholin-4-ylphenyl)-4H-pyrazolo[1,5-a]quinazolin-5-
-one;
[0069] 2-cyclopropyl-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0070]
2-(1-benzylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0071]
N-[3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)phenyl]-3-pi-
peridin-1-ylpropionamide;
[0072] 2-piperidin-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0073]
2-(4-pyrrolidin-1-ylmethylphenyl)-4H-pyrazolo[1,5-a]quinazolin-5-o-
ne;
[0074]
2-(1-methylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0075]
2-(1-ethylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0076]
2-(1-propylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0077]
2-(1-cyclopropylmethylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-
-5-one;
[0078]
2-(1-isobutylpiperidin-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0079]
2-(1-isopropylpiperidin-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0080] 2-pyrrolidin-3-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0081] benzyl
3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)pyrrolidine-1-carboxyl-
ate;
[0082]
2-(1-methylpyrrolidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0083]
2-(1-ethylpylrolidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0084]
2-(1-cyclopropylmethylpyrrolidin-3-yl)-4H-pyrazolo[1,5-a]quinazoli-
n-5-one;
[0085] 2-piperidin-2-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0086]
2-(1-methylpiperidin-2-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0087]
(S)-2-acetylamino-4-methyl-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quin-
azolin-3-ylmethyl)pentanamide;
[0088]
(R)-2-methoxy-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylme-
thyl)-2-phenylacetamide;
[0089]
N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)isonicoti-
namide;
[0090]
N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)-3-piperi-
din-1-yl-propionamide;
[0091]
N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)-3-pylrol-
idin-1-yl-propionamide;
[0092]
2-morpholin-4-yl-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-y-
lmethyl)acetamide;
[0093]
3-morpholin-4-yl-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-y-
lmethyl)-propionamide;
[0094] 2-phenethyl-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0095] 2-benzyl-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0096]
2-piperidin-4-ylmethyl-4H-pyrazolo[1,5-a]quinazolin-5-one;
[0097]
2-(1-methylpiperidin-4-ylmethyl)-4H-pyrazolo[1,5-a]quinazolin-5-on-
e;
[0098] 2-(3-bromobenzyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;
[0099]
3-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]benzoni-
trile;
[0100]
2-[3-(aminomethyl)benzyl]pyrazolo[1,5-a]quinazolin-5(4H)-one;
[0101]
2-(3-pyridin-3-ylbenzyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;
[0102]
2-[3-(2-oxopyrrolidin-1-yl)benzyl]pyrazolo[1,5-a]quinazolin-5(4H)--
one;
[0103]
3'-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]-1,1'--
biphenyl-2-carbaldehyde;
[0104]
2-[3-(2-fluoropyridin-4-yl)benzyl]pyrazolo[1,5-a]quinazolin-5(4H)--
one;
[0105] methyl
3-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]benzoate;
[0106]
3-[(4-methylpiperazin-1-yl)carbonyl]pyrazolo[1,5-a]quinazolin-5(4H-
)-one;
[0107]
3-(pyrrolidin-1-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;
[0108]
N,N-dimethyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxa-
mide;
[0109]
3-(piperidin-1-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;
[0110]
N-cyclopropyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carbox-
amide;
[0111]
5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;
[0112]
N-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide-
;
[0113]
N-ethyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;
[0114]
N-benzyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide-
;
[0115]
5-oxo-N-(2-phenylethyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-ca-
rboxamide;
[0116]
3-(azepan-1-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;
[0117]
3-(morpholin-4-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;
[0118]
3-(piperazin-1-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;
[0119]
N-cyclohexyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxa-
mide;
[0120]
3-(1H-imidazol-1-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;
[0121]
5-oxo-N-(piperidin-4-ylmethyl)-4,5-dihydropyrazolo[1,5-a]quinazoli-
ne-3-carboxamide;
[0122]
3-{[3-(aminomethyl)piperidin-1-yl]carbonyl}pyrazolo[1,5-a]quinazol-
in-5(4H)-one;
[0123]
5-oxo-N-phenyl-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide-
;
[0124]
4-{[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)carbonyl]amin-
o}butanoic acid;
[0125]
3-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]benzoic
acid;
[0126]
5-oxo-N-(2-piperidin-1-ylethyl)-4,5-dihydropyrazolo[1,5-a]quinazol-
ine-3-carboxamide;
[0127] 3-(Hydroxymethyl)pyrazolo[1,5-a]quinazolin -5-(4H)-one;
[0128]
3-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]benzami-
de;
[0129] 3-(aminomethyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;
[0130]
N-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]glycine-
;
[0131]
4-chloro-N-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methy-
l]butanamide;
[0132]
4-oxo-4-{[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]-
amino}butanoic acid;
[0133]
1-acetyl-N-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methy-
l]piperidine-4-carboxamide;
[0134]
2-oxo-2-{[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]-
amino}ethyl acetate;
[0135]
3-(pyrrolidin-1-ylmethyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;
[0136]
1-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]pyrroli-
dine-2,5-dione; and
[0137]
N-((5-Oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl)acetami-
de; In another embodiment, the present invention provides a
pharmaceutical composition comprising a compound of Formula (I), or
a pharmaceutically acceptable salt thereof, in combination with a
therapeutically acceptable carrier.
[0138] In another embodiment, the present invention provides a
method of inhibiting PARP in a mammal in recognized need of such
treatment comprising administering to the mammal a therapeutically
acceptable amount of a compound of Formula (I) or a
pharmaceutically acceptable salt thereof.
[0139] In another embodiment, the present invention provides a
method of treating cancer in a mammal in recognized need of such
treatment comprising administering to the mammal a therapeutically
acceptable amount of a compound of Formula (I) or a
pharmaceutically acceptable salt thereof.
[0140] In another embodiment, the present invention provides a
method for decreasing tumor volume in a mammal in recognized need
of such treatment comprising administering to the mammal a
therapeutically acceptable amount of a compound of Formula (I) or a
pharmaceutically acceptable salt thereof.
[0141] In another embodiment, the present invention provides a
method of treating leukemia, colon cancer, glioblastomas,
lymphomas, melanomas, carcinomas of the breast, or cervical
carcinomas in a mammal in recognized need of such treatment
comprising administering to the mammal a therapeutically acceptable
amount of a compound of Formula (I) or a pharmaceutically
acceptable salt thereof.
[0142] In another embodiment, the present invention provides a
method of potentiation of cytotoxic cancer therapy in a mammal in
recognized need of such treatment comprising administering to the
mammal a therapeutically acceptable amount of a compound of Formula
(I) or a pharmaceutically acceptable salt thereof.
[0143] In another embodiment, the present invention provides a
method of potentiation of radiation therapy in a mammal in
recognized need of such treatment comprising administering to the
mammal a therapeutically acceptable amount of a compound of Formula
(I) or a pharmaceutically acceptable salt thereof.
[0144] In another embodiment, the present invention provides a
method of treating ischemia reperfusion injury associated with, but
not limited to, myocardial infarction, stroke, other neural trauma,
and organ transplantation, in a mammal in recognized need of such
treatment comprising administering to the mammal a therapeutically
acceptable amount of a compound of Formula (I) or a
pharmaceutically acceptable salt thereof.
[0145] In another embodiment, the present invention provides a
method of reperfusion including, but not limited to, reperfusion of
the eye, kidney, gut and skeletal muscle, in a mammal in recognized
need of such treatment comprising administering to the mammal a
therapeutically acceptable amount of a compound of Formula (I) or a
pharmaceutically acceptable salt thereof.
[0146] In another embodiment, the present invention provides a
method of treating inflammatory diseases including, but not limited
to, arthritis, gout, inflammatory bowel disease, CNS inflammation,
multiple sclerosis, allergic encephalitis, sepsis, septic shock,
hemmorhagic shock, pulmonary fibrosis, and uveitis in a mammal in
recognized need of such treatment comprising administering to the
mammal a therapeutically acceptable amount of a compound of Formula
(I) or a pharmaceutically acceptable salt thereof.
[0147] In another embodiment, the present invention provides a
method of treating immunological diseases or disorders such as
rheumatoid arthritis and septic shock in a mammal in recognized
need of such treatment comprising administering to the mammal a
therapeutically acceptable amount of a compound of Formula (I) or a
pharmaceutically acceptable salt thereof.
[0148] In another embodiment, the present invention provides a
method of treating degenerative disease including, but not limited
to, diabetes and Parkinsons disease, in a mammal in recognized need
of such treatment comprising administering to the mammal a
therapeutically acceptable amount of a compound of Formula (I) or a
pharmaceutically acceptable salt thereof.
[0149] In another embodiment, the present invention provides a
method of treating hypoglycemia in a mammal in recognized need of
such treatment comprising administering to the mammal a
therapeutically acceptable amount of a compound of Formula (I) or a
pharmaceutically acceptable salt thereof.
[0150] In another embodiment, the present invention provides a
method of treating retroviral infection in a mammal in recognized
need of such treatment comprising administering to the mammal a
therapeutically acceptable amount of a compound of Formula (I) or a
pharmaceutically acceptable salt thereof.
[0151] In another embodiment, the present invention provides a
method of treating liver toxicity following acetominophen overdose
in a mammal in recognized need of such treatment comprising
administering to the mammal a therapeutically acceptable amount of
a compound of Formula (I) or a pharmaceutically acceptable salt
thereof.
[0152] In another embodiment, the present invention provides a
method of treating cardiac and kidney toxicities from doxorubicin
and platinum based antineoplastic agents in a mammal in recognized
need of such treatment comprising administering to the mammal a
therapeutically acceptable amount of a compound of Formula (I) or a
pharmaceutically acceptable salt thereof.
[0153] In another embodiment, the present invention provides a
method of treating skin damage secondary to sulfur mustards in a
mammal in recognized need of such treatment comprising
administering to the mammal a therapeutically acceptable amount of
a compound of Formula (I) or a pharmaceutically acceptable salt
thereof.
[0154] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a pharmaceutically acceptable salt
thereof, to prepare a medicament for inhibiting the PARP enzyme in
a mammal in recognized need of such treatment.
[0155] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a pharmaceutically acceptable salt
thereof, to prepare a medicament for inhibiting tumor growth in a
mammal in recognized need of such treatment.
[0156] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a pharmaceutically acceptable salt
thereof, to prepare a medicament for treating cancer in a mammal in
recognized need of such treatment.
[0157] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a pharmaceutically acceptable salt
thereof, to prepare a medicament for treating leukemia, colon
cancer, glioblastomas, lymphomas, melanomas, carcinomas of the
breast, or cervical carcinomas in a mammal in a mammal in
recognized need of such treatment.
[0158] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a pharmaceutically acceptable salt
thereof, to prepare a medicament for potentiation of cytotoxic
cancer therapy in a mammal in recognized need of such treatment
comprising administering to the mammal a therapeutically acceptable
amount of a compound of Formula (I) or a pharmaceutically
acceptable salt thereof.
[0159] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a pharmaceutically acceptable salt
thereof, to prepare a medicament for potentiation of radiation in a
mammal in recognized need of such treatment comprising
administering to the mammal a therapeutically acceptable amount of
a compound of Formula (I) or a pharmaceutically acceptable salt
thereof.
[0160] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a pharmaceutically acceptable salt
thereof, to prepare a medicament for treating ischemia reperfusion
injury associated with, but not limited to, myocardial infarction,
stroke, other neural trauma, and organ transplantation, in a mammal
in recognized need of such treatment comprising administering to
the mammal a therapeutically acceptable amount of a compound of
Formula (I) or a pharmaceutically acceptable salt thereof.
[0161] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a pharmaceutically acceptable salt
thereof, to prepare a medicament for treating reperfusion
including, but not limited to, reperfusion of the eye, kidney, gut
and skeletal muscle, in a mammal in recognized need of such
treatment comprising administering to the mammal a therapeutically
acceptable amount of a compound of Formula (I) or a
pharmaceutically acceptable salt thereof.
[0162] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a pharmaceutically acceptable salt
thereof, to prepare a medicament for treating inflammatory diseases
including, but not limited to, arthritis, gout, inflammatory bowel
disease, CNS inflammation, multiple sclerosis, allergic
encephalitis, sepsis, septic shock, hemmorhagic shock, pulmonary
fibrosis, and uveitis in a mammal in recognized need of such
treatment comprising administering to the mammal a therapeutically
acceptable amount of a compound of Formula (I) or a
pharmaceutically acceptable salt thereof.
[0163] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a pharmaceutically acceptable salt
thereof, to prepare a medicament for treating immunological
diseases or disorders such as rheumatoid arthritis and septic shock
in a mammal in recognized need of such treatment comprising
administering to the mammal a therapeutically acceptable amount of
a compound of Formula (I) or a pharmaceutically acceptable salt
thereof.
[0164] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a pharmaceutically acceptable salt
thereof, to prepare a medicament for treating degenerative disease
including, but not limited to, diabetes and Parkinsons disease, in
a mammal in recognized need of such treatment comprising
administering to the mammal a therapeutically acceptable amount of
a compound of Formula (I) or a pharmaceutically acceptable salt
thereof.
[0165] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a pharmaceutically acceptable salt
thereof, to prepare a medicament for treating hypoglycemia in a
mammal in recognized need of such treatment comprising
administering to the mammal a therapeutically acceptable amount of
a compound of Formula (I) or a pharmaceutically acceptable salt
thereof.
[0166] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a pharmaceutically acceptable salt
thereof, to prepare a medicament for treating retroviral infection
in a mammal in recognized need of such treatment comprising
administering to the mammal a therapeutically acceptable amount of
a compound of Formula (I) or a pharmaceutically acceptable salt
thereof.
[0167] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a pharmaceutically acceptable salt
thereof, to prepare a medicament for treating liver toxicity
following acetaminophen overdose in a mammal in recognized need of
such treatment comprising administering to the mammal a
therapeutically acceptable amount of a compound of Formula (I) or a
pharmaceutically acceptable salt thereof.
[0168] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a pharmaceutically acceptable salt
thereof, to prepare a medicament for treating cardiac and kidney
toxicities from doxorubicin and platinum based antineoplastic
agents in a mammal in recognized need of such treatment comprising
administering to the mammal a therapeutically acceptable amount of
a compound of Formula (I) or a pharmaceutically acceptable salt
thereof.
[0169] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a pharmaceutically acceptable salt
thereof, to prepare a medicament for treating skin damage secondary
to sulfur mustards in a mammal in recognized need of such treatment
comprising administering to the mammal a therapeutically acceptable
amount of a compound of Formula (I) or a pharmaceutically
acceptable salt thereof.
[0170] In another embodiment, the present invention provides
pharmaceutical compositions comprising a compound of Formula (I) or
a pharmaceutically acceptable salt thereof, in combination with a
therapeutically acceptable carrier.
Definitions
[0171] As used throughout this specification and the appended
claims, the following terms have the following meanings:
[0172] The term "alkenyl" as used herein, means a straight or
branched chain hydrocarbon containing from 2 to 10 carbons and
containing at least one carbon-carbon double bond formed by the
removal of two hydrogens. Representative examples of alkenyl
include, but are not limited to, ethenyl, 2-propenyl,
2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl,
2-methyl-1-heptenyl, and 3-decenyl.
[0173] The term "alkoxy" as used herein, means an alkyl group, as
defined herein, appended to the parent molecular moiety through an
oxygen atom. Representative examples of alkoxy include, but are not
limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,
tert-butoxy, pentyloxy, and hexyloxy.
[0174] The term "alkoxyalkyl" as used herein, means at least one
alkoxy group, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein. Representative
examples of alkoxyalkyl include, but are not limited to,
tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and
methoxymethyl.
[0175] The term "alkoxycarbonyl" as used herein, means an alkoxy
group, as defined herein, appended to the parent molecular moiety
through a carbonyl group, as defined herein. Representative
examples of alkoxycarbonyl include, but are not limited to,
methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.
[0176] The term "alkoxycarbonylalkyl" as used herein, means an
alkoxycarbonyl group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
[0177] The term "alkyl" as used herein, means a saturated, straight
or branched chain hydrocarbon containing from 1 to 10 carbon atoms.
Representative examples of alkyl include, but are not limited to,
methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,
tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,
2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl,
and n-decyl.
[0178] The term "alkylcarbonyl" as used herein, means an alkyl
group, as defined herein, appended to the parent molecular moiety
through a carbonyl group, as defined herein. Representative
examples of alkylcarbonyl include, but are not limited to, acetyl,
1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and
1-oxopentyl.
[0179] The term "alkylcarbonylalkyl" as used herein, means an
alkylcarbonyl group, as defined herein, appended to the parent
molecular moiety through a alkyl group, as defined herein.
[0180] The term "alkylcarbonyloxy" as used herein, means an
alkylcarbonyl group, as defined herein, appended to the parent
molecular moiety through an oxygen atom. Representative examples of
alkylcarbonyloxy include, but are not limited to, acetyloxy,
ethylcarbonyloxy, and tert-butylcarbonyloxy.
[0181] The term "alkylcarbonyloxyalkyl" as used herein, means an
alkylcarbonyloxy group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
[0182] The term "alkylcarbonyloxyalkylcarbonyl" as used herein,
means an alkylcarbonyloxyalkyl group, as defined herein, appended
to the parent molecular moiety through a carbonyl group.
[0183] The term "alkylenyl" as used herein, means a divalent group
derived from a saturated, straight or branched chain hydrocarbon of
from 1 to 6 carbon atoms. Representative examples include, but are
not limited to, --CH.sub.2--, --CH(CH.sub.3)--,
--C(CH.sub.3).sub.2--, --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, --CH.sub.2CH(CH.sub.3)CH.sub.2--.
[0184] The term "alkynyl" as used herein, means a straight or
branched chain hydrocarbon group containing from 2 to 10 carbon
atoms and containing at least one carbon-carbon triple bond.
Representative examples of alkynyl include, but are not limited, to
acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and
1-butynyl.
[0185] The term "aryl," as used herein, means a phenyl group or a
naphthyl group.
[0186] The term "arylalkyl" as used herein, means an aryl group, as
defined herein, appended to the parent molecular moiety through an
alkyl group, as defined herein. Representative examples of
arylalkyl include, but are not limited to, benzyl, 2-phenylethyl,
3-phenylpropyl, 1-methyl-3-phenylpropyl, and
2-naphth-2-ylethyl.
[0187] The term "arylalkoxy" as used herein, means an aryl group,
as defined herein, appended to the parent molecular moiety through
an alkoxy group, as defined herein.
[0188] The term "arylalkoxycarbonyl" as used herein, means an
arylalkoxy group, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
[0189] The term "arylalkylcarbonyl" as used herein, means an
arylalkyl group, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein. The
alkyl of arylalkylcarbonyl groups of the present invention may be
substituted with an alkoxy substituent.
[0190] The term "arylcarbonyl" as used herein, means an aryl group,
as defined herein, appended to the parent molecular moiety through
a carbonyl group, as defined herein The term "carbonyl" as used
herein, means a --C(O)-- group.
[0191] The term "carboxy" as used herein, means a --CO.sub.2H
group.
[0192] The term "cyano" as used herein, means a --CN group.
[0193] The term "carboxyalkyl" as used herein, means a carboxy
group, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein.
[0194] The term "carboxyalkylcarbonyl" as used herein, means a
carboxyalkyl group, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
[0195] The term "cycloalkyl" as used herein, means a saturated
cyclic hydrocarbon group containing from 3 to 8 carbons, examples
of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, and cyclooctyl.
[0196] The term "cycloalkylalkoxy" as used herein, means a
cycloalkyl group, as defined herein, appended to the parent
molecular moiety through an alkoxy group, as defined herein.
[0197] The term "cycloalkylalkyl" as used herein, means a
cycloalkyl group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of cycloalkylalkyl include, but are not
limited to, cyclopropylmethyl, 2-cyclobutylethyl,
cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptylbutyl.
[0198] The term "cycloalkylcarbonyl" as used herein, means a
cycloalkyl group, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
[0199] The term "formyl" as used herein, means a --C(O)H group.
[0200] The term "halo" or "halogen" as used herein, means --Cl,
--Br, --I or --F.
[0201] The term "haloalkyl" as used herein, means at least one
halogen, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of haloalkyl include, but are not limited to, 3-chloropropyl,
chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and
2-chloro-3-fluoropentyl.
[0202] The term "haloalkoxy" as used herein, means at least one
halogen, as defined herein, appended to the parent molecular moiety
through an alkoxy group, as defined herein. Representative examples
of haloalkoxy include, but are not limited to, chloromethoxy,
2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.
[0203] The term "haloalkylcarbonyl" as used herein, means a
haloalkyl group, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
[0204] The term "heteroaryl," as used herein, means a monocyclic
heteroaryl ring or a bicyclic heteroaryl ring. The monocyclic
heteroaryl ring is a 5 or 6 membered ring. The 5 membered ring has
two double bonds and contains one, two, three or four heteroatoms
independently selected from the group consisting of N, O, and S.
The 6 membered ring has three double bonds and contains one, two,
three or four heteroatoms independently selected from the group
consisting of N, O, and S. The bicyclic heteroaryl ring consists of
the 5 or 6 membered heteroaryl ring fused to a phenyl group or the
5 or 6 membered heteroaryl ring is fused to another 5 or 6 membered
heteroaryl ring. Nitrogen heteroatoms contained within the
heteroaryl may be optionally oxidized to the N-oxide. The
heteroaryl is connected to the parent molecular moiety through any
carbon atom contained within the heteroaryl while maintaining
proper valence. Representative examples of heteroaryl include, but
are not limited to, benzothienyl, beizoxadiazolyl, cinnolinyl,
furopyridinyl, furyl, imidazolyl, indazolyl, indolyl, isoxazolyl,
isoquinolinyl, isothiazolyl, naplithyridinyl, oxadiazolyl,
oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,
pyrazolyl, pyrrolyl, pyridinium N-oxide, quinolinyl, tetrazolyl,
thiadiazolyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, and
triazinyl.
[0205] The term "heteroarylalkyl" as used herein, means a
heteroaryl, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein. Representative
examples of heteroarylalkyl include, but are not limited to,
pyridinymethyl.
[0206] The term "heteroarylcarbonyl" as used herein, means a
heteroaryl, as defined herein, appended to the parent molecular
moiety through a carbonyl group, as defined herein.
[0207] The term "heteroarylcarbonylalkyl" as used herein, means a
heteroarylcarbonyl, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
[0208] The term "heterocycle" or "heterocyclic" as used herein,
means a monocyclic or bicyclic heterocyclic ring. The monocyclic
heterocyclic ring consists of a 3, 4, 5, 6, 7, or 8 membered ring
containing at least one heteroatom independently selected from O,
N, and S. The 3 or 4 membered ring contains 1 heteroatom selected
from the group consisting of O, N and S. The 5 membered ring
contains zero or one double bond and one, two or three heteroatoms
selected from the group consisting of 0, N and S. The 6 or 7
membered ring contains zero, one or two double bonds and one, two
or three heteroatoms selected from the group consisting of O , N
and S. The bicyclic heterocyclic ring consists of a monocyclic
heterocyclic ring fused to a cycloalkyl group or the monocyclic
heterocyclic ring fused to a phenyl group or the monocyclic
heterocyclic ring fused to another monocyclic heterocyclic ring.
The heterocycle is connected to the parent molecular moiety through
any carbon or nitrogen atom contained within the heterocycle while
maintaining proper valence. Representative examples of heterocycle
include, but are not limited to, azetidinyl, azepanyl, aziridinyl,
diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl,
1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl,
isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl,
oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl,
piperazinyl, piperidinyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl,
pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl,
tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl,
thiazolidinyl, thiomolpholinyl, 1,1-dioxidothiomorpholinyl
(thiomorpholine sulfone), thiopyranyl, and trithianyl.
[0209] The term "heterocyclealkyl" as used herein, means a
heterocycle, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein.
[0210] The term "heterocyclealkylcarbonyl" as used herein, means a
heterocyclealkyl, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
[0211] The term "heterocyclecarbonyl" as used herein, means a
heterocycle, as defined herein, appended to the parent molecular
moiety through a carbonyl group, as defined herein.
[0212] The term "heterocyclecarbonylalkyl" as used herein, means a
heterocyclecarbonyl, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
[0213] The term "hydroxy" as used herein, means an --OH group.
[0214] The term "hydroxyalkyl" as used herein, means at least one
hydroxy group, as defined herein, is appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of hydroxyalkyl include, but are not
limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl,
2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.
[0215] The term "nitro" as used herein, means a --NO.sub.2
group.
[0216] The term "NR.sub.AR.sub.B" as used herein, means two groups,
R.sub.A and R.sub.B , which are appended to the parent molecular
moiety through a nitrogen atom.
[0217] The term "(NR.sub.AR.sub.B)alkyl" as used herein, means a
NR.sub.AR.sub.Bgroup, as defined herein, appended to the parent
molecular moiety through an alkyl group.
[0218] The term "(NR.sub.AR.sub.B)carbonyl" as used herein, means a
NR.sub.AR.sub.Bgroup, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
Representative examples of (NR.sub.AR.sub.B)carbonyl include, but
are not limited to, aminocarbonyl, (methylamino)carbonyl,
(dimethylamino)carbonyl, and (ethylmethylamino)carbonyl.
[0219] The term "(NR.sub.AR.sub.B)carbonylalkyl" as used herein,
means a (NR.sub.AR.sub.B)carbonyl group, as defined herein,
appended to the parent molecular moiety through an alkyl group, as
defined herein.
[0220] The term "(NR.sub.AR.sub.B)alkylcarbonyl" as used herein,
means a (NR.sub.AR.sub.B)alkyl group, as defined herein, appended
to the parent molecular moiety through a carbonyl group, as defined
herein.
[0221] The term "NR.sub.CR.sub.D" as used herein, means two groups,
R.sub.C and R.sub.D, which are appended to the parent molecular
moiety through a nitrogen atom.
[0222] The term "(NR.sub.CR.sub.D)alkyl" as used herein, means a
NR.sub.CR.sub.Dgroup, as defined herein, appended to the parent
molecular moiety through an alkyl group.
[0223] The term "(NR.sub.CR.sub.D)carbonyl" as used herein, means a
NR.sub.CR.sub.Dgroup, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
Representative examples of (NR.sub.CR.sub.D)carbonyl include, but
are not limited to, aminocarbonyl, (methylamino)carbonyl,
(dimethylamino)carbonyl, and (ethylmethylamino)carbonyl.
[0224] The term "(NR.sub.CR.sub.D)carbonylalkyl" as used herein,
means a (NR.sub.CR.sub.D)carbonyl group, as defined herein,
appended to the parent molecular moiety through an alkyl group, as
defined herein.
[0225] The term "oxo" as used herein, means a .dbd.O moiety.
[0226] Compounds of the present invention can exist as
stereoisomers, wherein asymmetric or chiral centers are present.
Stereoisomers are designated (R) or (S) depending on the
configuration of substituents around the chiral carbon atom. The
terms (R) and (S) used herein are configurations as defined in
IUPAC 1974 Recommendations for Section E, Fundamental
Stereochemistry, Pure Appl. Chem., (1976), 45: 13-30, hereby
incorporated by reference. The present invention contemplates
various stereoisomers and mixtures thereof and are specifically
included within the scope of this invention. Stereoisomers include
enantiomers, diastereomers, and mixtures of enantiomers or
diastereomers. Individual stereoisomers of compounds of the present
invention may be prepared synthetically from commercially available
starting materials which contain asymmetric or chiral centers or by
preparation of racemic mixtures followed by resolution well-known
to those of ordinary skill in the art. These methods of resolution
are exemplified by (1) attachment of a mixture of enantiomers to a
chiral auxiliary, separation of the resulting mixture of
diastereomers by recrystallization or chromatography and liberation
of the optically pure product from the auxiliary or (2) direct
separation of the mixture of optical enantiomers on chiral
chromatographic columns.
[0227] Compounds of the present invention were named by
ACD/ChemSketch version 5.06 (developed by Advanced Chemistry
Development, Inc., Toronto, ON, Canada) or were given names which
appeared to be consistent with ACD nomenclature.
Determination of Biological Activity
Inhibition of PARP
[0228] Nicotinamide[2,5',8-3H]adenine dinucleotide and strepavidin
SPA beads were purchased from Amersham Biosiences (UK) Recombinant
Human Poly(ADP-Ribose) Polymerase (PARP) purified from E.coli and
6-Biotin-17-NAD.sup.+, were purchase from Trevigen, Gaithersburg,
MD. NAD.sup.+, Histone, aminobenzamide, 3-amino benzamide and Calf
Thymus DNA (dcDNA) were purchased from Sigma, St. Louis, Mo. Stem
loop oligonucleotide containing MCAT sequence was obtained from
Qiagen. The oligos were dissoloved to 1 mM in annealing buffer
containing 10 mM Tris HCl pH 7.5, 1 mM EDTA, and 50 mM NaCl,
incubated for 5min at 95.degree. C., and followed by annealing at
45.degree. C. for 45 minutes. Histone H1 (95% electrophoretically
pure) was purchased from Roche, Indianapolis, Ind. Biotinylated
histone H1 was prepared by treating the protein with
Sulfo-NHS-LC-Biotin from Pierce Rockford, Ill. The biotinylation
reaction was conducted by slowly and intermittently adding 3
equivalents of 10 mM Sulfo-NHS-LC-Biotin to 100 .mu.M Histone H1 in
phosphate-buffered saline, pH 7.5, at 4.degree. C. with gentle
vortexing over 1 min followed by subsequent 4.degree. C. incubation
for 1 hr. Streptavidin coated (FlashPlate Plus) microplates were
purchased from Perkin Elmer, Boston, Mass.
[0229] PARP1 assay was conducted in PARP assay buffer containing 50
mM Tris pH 8.0, 1 mM DTT, 4 mM MgCl.sub.2. PARP reactions contained
1.5 .mu.M [.sup.3H]-NAD.sup.+ (1.6 uCi/mmol), 200 nM biotinylated
histone H1, 200 nM s1DNA, and 1 nM PARP enzyme. Auto reactions
utilizing SPA bead-based detection were carried out in 100 .mu.l
volumes in white 96 well plates. Reactions were initiated by adding
50 .mu.l of 2.times. NAD.sup.+ substrate mixture to 50 .mu.l of
2.times. enzyme mixture containing PARP and DNA. These reactions
were terminated by the addition of 150 .mu.l of 1.5 mM benzamide
(.about.1000-fold over its IC50). 170 .mu.l of the stopped reaction
mixtures were transferred to streptavidin Flash Plates, incubated
for 1 hr, and counted using a TopCount microplate scintillation
counter. The K.sub.i data was determined from inhibition curves at
various substrate concentrations and are shown in Table 1 for
compounds of the present invention TABLE-US-00001 TABLE 1
Inhibition of PARP (nM) 44 69 846 364 520 >9500 266 178 40 142
299 390 920 550 350 774 277 46 1700 256 831 211 >9500 35 6400
419 327 1000 214 1337 413 271 53 668 621 920 321 775 >9500
>9500 >9500 >9500 >9500 >9500 >9500 9390 >9500
>9500 >9500 >9500 7960 >9500 >9500 >9500 >9500
>9500 >9500 55 146 255 213 114 1230 92 86 1880 31 164
Cellular PARP Assay:
[0230] C41 cells were treated with a compound of the present
invention for 30 minutes in 96 well plate. PARP was then activated
by damaging DNA with 1 mM H.sub.2O.sub.2 for 10 minutes. The cells
were then washed with ice-cold PBS once and fixed with pre-chilled
methanol:acetone (7:3) at -20.degree. C. for 10 minutes. After
air-drying, the plates were rehydrated with PBS and blocked 5%
non-fat dry milk in PBS-tween (0.05%) (blocking solution) for 30
minutes at room temperature. The cells were incubated with anti-PAR
antibody 10H (1:50) in Blocking solution at 37.degree. C. for 60
minutes followed by washing with PBS-Tween20 5 times, and
incubation with goat anti-mouse fluorescein
5(6)-isothiocyanate-coupled antibody (1:50) and 1 .mu.g/ml
4',6-diamidino-2-phenylindole (DAPI) in blocking solution at
37.degree. C. for 60 minutes. After washing with PBS-Tween20 5
times, the analysis was performed using an finax Fluorescence
Microplate Reader (Molecular Devices, Sunnyvalle, Calif.), set at
the excitation wavelength of 490 nm and emission wavelength of 528
nm fluorescein 5(6)-isothiocyanate (FITC) or the excitation
wavelength of 355 nm and emission wavelength of 460 nm (DAPI). The
PARP activity (FITC signal) was normalized with cell numbers
(DAPI).
[0231] The cellular assay measures the formation of poly ADP-ribose
by PARP within cells and demonstrates that compounds of the present
invention penetrate cell membranes and inhibit PARP in intact
cells. The EC.sub.50s for representative compounds of the present
invention are provided in Table 2. TABLE-US-00002 TABLE 2 Cellular
Activity EC.sub.50 (nM) 16 9.6 1.1 >1000 24 >1000 106
[0232] As PARP inhibitors, the compounds of the present invention
have numerous therapeutic applications related to, ischemia
reperfusion injury, inflammatory diseases, degenerative diseases,
protection from adverse effects of cytotoxic compounds, and
potentiation of cytotoxic cancer therapy. In particular, compounds
of the present invention potentiate radiation and chemotherapy by
increasing cell death of cancer cells, limiting tumor growth,
decreasing metastasis, and prolonging the survival of tumor-bearing
mammals. Compounds of Formula (I) can treat leukemia, colon cancer,
glioblastomas, lymphomas, melanomas, carcinomas of the breast, and
cervical carcinomas.
[0233] Other therapeutic applications include, but are not limited
to, retroviral infection, arthritis, gout, inflammatory bowel
disease, CNS inflammation, multiple sclerosis, allergic
encephalitis, sepsis, septic shock, hemmorhagic shock, pulmonary
fibrosis, uveitis, diabetes, Parkinsons disease, myocardial
infarction, stroke, other neural trauma, organ transplantation,
reperfusion of the eye, reperfusion of the kidney, reperfusion of
the gut, reperfusion of skeletal muscle, liver toxicity following
acetominophen overdose, cardiac and kidney toxicities from
doxorubicin and platinum based antineoplastic agents, and skin
damage secondary to sulfur mustards. (G. Chen et al. Cancer Chemo.
Pharmacol. 22 (1988), 303; C. Thiemermann et al., Proc. Natl. Acad.
Sci. USA 94 (1997), 679-683 D. Weltin et al. Int. J.
Immunopharmacol. 17 (1995), 265-271; H. Kroger et al. Inflammation
20 (1996), 203-215; W. Elirlich et al. Rheumatol. Int. 15 (1995),
171-172; C. Szabo et al., Proc. Natl. Acad. Sci. USA 95 (1998),
3867-3872; S. Cuzzocrea et al. Eur. J. Pharmacol. 342 (1998),
67-76; V. Burkhart et al., Nature Medicine (1999), 5314-19).
[0234] When used in the above or other treatments, a
therapeutically effective amount of one of the compounds of the
present invention can be employed as a zwitterion or as a
pharmaceutically acceptable salt. By a "therapeutically effective
amount" of the compound of the invention is meant a sufficient
amount of the compound to treat or prevent a disease or disorder
ameliorated by a PARP inhibitor at a reasonable benefit/risk ratio
applicable to any medical treatment. It will be understood,
however, that the total daily usage of the compounds and
compositions of the present invention will be decided by the
attending physician within the scope of sound medical judgment. The
specific therapeutically effective dose level for any particular
patient will depend upon a variety of factors including the
disorder being treated and the severity of the disorder; activity
of the specific compound employed; the specific composition
employed, the age, body weight, general health, sex and diet of the
patient; the time of administration, route of administration, and
rate of excretion of the specific compound employed; the duration
of the treatment; drugs used in combination or coincidental with
the specific compound employed; and like factors well known in the
medical arts. For example, it is well within the skill of the art
to start doses of the compound at levels lower than those required
to achieve the desired therapeutic effect and to gradually increase
the dosage until the desired effect is achieved.
[0235] By "pharmaceutically acceptable salt" is meant those salts
which are, within the scope of sound medical judgment, suitable for
use in contact with the tissues of humans and lower animals without
undue toxicity, irritation, allergic response and the like and are
commensurate with a reasonable benefit/risk ratio. Pharmaceutically
acceptable salts are well-known in the art. The salts can be
prepared in situ during the final isolation and purification of the
compounds of the present invention or separately by reacting the
free base of a compound of the present invention with a suitable
acid. Representative acids include, but are not limited to
acetatic, citric, aspartic, benzoic, benzenesulfonic, butyric,
fumaric, hydrochloric, hydrobromic, hydroiodic, lactic, maleic,
methanesulfonic, pamoic, pectinic, pivalic, propionic, succinic,
tartaric, phosphic, glutamic, and p-toluenesulfonic. Also, the
basic nitrogen-containing groups can be quaternized with such
agents as lower alkyl halides such as methyl, ethyl, propyl, and
butyl chlorides, bromides and iodides; dialkyl sulfates like
dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides
such as decyl, lauryl, myristyl and stearyl chlorides, bromides and
iodides; arylalkyl halides like benzyl and phenethyl bromides and
others. Water or oil-soluble or dispersible products are thereby
obtained.
[0236] A compound of the present invention may be administered as a
pharmaceutical composition containing a compound of the present
invention in combination with one or more pharmaceutically
acceptable excipients. A pharmaceutically acceptable carrier or
excipient refers to a non-toxic solid, semi-solid or liquid filler,
diluent, encapsulating material or formulation auxiliary of any
type. The compositions can be administered parenterally,
intracisternally, intravaginally, intraperitoneally, topically (as
by powders, ointments, drops or transdermal patch), rectally, or
bucally. The term "parenteral" as used herein refers to modes of
administration which include intravenous, intramuscular,
intraperitoneal, intrasternal, subcutaneous and intraarticular
injection and infusion.
[0237] Pharmaceutical compositions for parenteral injection
comprise pharmaceutically-acceptable sterile aqueous or nonaqueous
solutions, dispersions, suspensions or emulsions, as well as
sterile powders for reconstitution into sterile injectable
solutions or dispersions just prior to use. Examples of suitable
aqueous and nonaqueous carriers, diluents, solvents or vehicles
include water, ethanol, polyols (such as glycerol, propylene
glycol, polyethylene glycol, and the like), carboxymethylcellulose
and suitable mixtures thereof, vegetable oils (such as olive oil),
and injectable organic esters such as ethyl oleate. Proper fluidity
may be maintained, for example, by the use of coating materials
such as lecithin, by the maintenance of the required particle size
in the case of dispersions, and by the use of surfactants.
[0238] These compositions can also contain adjuvants such as
preservative, wetting agents, emulsifying agents, and dispersing
agents. Prevention of the action of microorganisms may be ensured
by the inclusion of various antibacterial and antifungal agents,
for example, paraben, chlorobutanol, phenol sorbic acid, and the
like. It may also be desirable to include isotonic agents such as
sugars, sodium chloride, and the like. Prolonged absorption of the
injectable pharmaceutical form may be brought about by the
inclusion of agents which delay absorption, such as aluminum
monostearate and gelatin.
[0239] Compounds of the present invention may also be administered
in the form of liposomes. As is known in the art, liposomes are
generally derived from phospholipids or other lipid substances.
Liposomes are formed by mono- or multi-lamellar hydrated liquid
crystals that are dispersed in an aqueous medium. Any non-toxic,
physiologically-acceptable and metabolizable lipid capable of
forming liposomes can be used. The present compositions in liposome
form can contain, in addition to a compound of the present
invention, stabilizers, preservatives, excipients, and the like.
The preferred lipids are the phospholipids and the phosphatidyl
cholines (lecithins), both natural and synthetic. Methods to form
liposomes are known in the art. See, for example, Prescott, Ed.,
Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y.
(1976), p. 33 et seq.
[0240] Total daily dose of the compositions of the invention to be
administered to a human or other mammal host in single or divided
doses may be in amounts, for example, from 0.0001 to 300 mg/kg body
weight daily and more usually 1 to 300 mg/kg body weight. The dose,
from 0.0001 to 300 mg/kg body, may be given twice a day.
[0241] Abbreviations which have been used in the descriptions of
the examples that follow are: CDI for carbonyl diimidazole; DBU for
1,8-diazabicyclo[5.4.0]undec-7-ene; DME for 1,2-dimethoxyethane;
DMF for N,N-dimethylforamide; DMSO for dimethylsulfoxide; Et.sub.2O
for diethyl ether; EtOAc for ethyl acetate; EtOH for ethanol; HPLC
for high pressure liquid chromatography; LDA for lithium
diisopropylamide; MeOH for methanol; psi for pounds per square
inch; it for room temperature; TFA for trifluoroacetic acid; THF
for tetrahydrofuran, and TMS for trimethylsilane.
Synthetic Methods
[0242] The compounds and processes of the present invention will be
better understood in connection with the following synthetic
schemes which together illustrate the methods by which the
compounds of the invention may be prepared. The synthesis of
compounds of formula (I) wherein the groups R.sub.1, R.sub.2,
R.sub.3, R.sub.4, X, R.sub.A and R.sub.B are as set forth in the
summary of the invention unless otherwise noted, is exemplified in
Schemes 1-4.
[0243] Optimum reaction conditions and reaction times for each
individual step may vary depending on the particular reactants
employed and substituents present in the reactants used. Unless
otherwise specified, solvents, temperatures and other reaction
conditions may be readily selected by one of ordinary skill in the
art. Specific procedures are provided in the Synthetic Examples
section. Reactions may be worked up in the convention manner, e.g.
by eliminating the solvent from the residue and further purified
according to methodologies generally known in the art such as, but
are not limited to, crystallization, distillation, extraction,
trituration and chromatography. Unless otherwise described, the
starting materials and reagents are either commercially available
or may be prepared by one skilled in the art from commercially
available materials using methods described in the chemical
literature.
[0244] This invention is intended to encompass compounds having
formula (I) when prepared by synthetic processes or by metabolic
processes. Preparation of the compounds of the invention by
metabolic processes include those occurring in the human or animal
body (in vivo) or processes occurring in vitro.
[0245] Routine experimentation, including appropriate manipulation
of the reaction conditions, reagents used and sequence of the
synthetic route, protection of any chemical functionality that may
not be compatible with the reaction conditions, and deprotection at
suitable point in the reaction sequence of the method are included
in the scope of the invention. Suitable protecting groups and the
methods for protecting and deprotecting different substituents
using such suitable protecting groups are well know to those
skilled in the art; examples of which may be found in T. Greene and
P. Wuts, Protecting Groups in Chemical Synthesis (3.sup.rd ed.),
John Wiley & Sons, NY (1999), which is incorporated herein by
reference in its entirety. Synthesis of the compounds of formula
(I) may be accomplished by methods analogous to those described in
the following schemes and in specific examples.
[0246] Compounds of formula (I) wherein X is represented by R' and
R'' and one of R' and R'' is hydrogen, can be prepared using the
general procedure as illustrated in scheme 1. ##STR6##
[0247] Compound of formula (6) can be obtained by (a) deprotonation
of nitrile (3) with a base such as, but not limited to, n-butyl
lithium and the (b) contacting the anion obtained from step (a)
with an acid chloride (2) or an ester (1) wherein R.sup.101 is
C.sub.1-6 alkyl, to provide compound (4). Alternatively, the anion
obtained from step (a) can be treated with (1) wherein R.sup.101 is
hydrogen, in the presence of a coupling reagent such as, but not
limited to, N,N'-carbonyldiimidazole or
1,3-dicyclohexylcarbodiimide to provide compound (4). Treatment of
2-hydrazinobenzoic acid (5) and compound (4) in a acetic acid, in a
microwave reactor and at elevated temperature (for example,
150.degree. C.) generates 4H-pyrazolo[1,5-a]quinazolin-5-one (6)
wherein one of R' and R'' is hydrogen and the other is X (as
defined in formula (I)).
[0248] Compounds having general formula (I) wherein X is
NR.sub.CR.sub.Dalkyl, R.sub.C is hydrogen or alkyl, and R.sub.D is
alkyl, alkylcarbonyl, heteroarylcarbonyl, heterocyclealkylcarbonyl
or NR.sub.AR.sub.Balkylcarbonyl, can be prepared as shown in Scheme
2. ##STR7##
[0249] A 3-cyano-4H-pyrazolo[1,5-a]quinazolin-5-one (7), prepared
using the conditions as described in Scheme 1, or purchased, can be
reduced to the 3-aminomethyl analog (8) using an appropriate
reducing agent such as ammonia in methanol and Raney nickel, under
about 60 psi of hydrogen gas. Coupling of (8) with a carboxylic
acid of formula R.sub.102COOH wherein R.sub.102 is alkyl,
heteroaryl, heterocyclealkyl or NR.sub.AR.sub.Balkyl, in the
presence of a coupling reagent such as, but not limited to,
1,3-dicyclohexylcarbodiimide, a coupling auxiliary such as, but not
limited to, 1-hydroxybenzotriazole hydrate, and a base such as, but
not limited to diisopropylethyl amine, provides compound of formula
(9). The reaction is generally performed in a solvent such as, but
not limited to, N,N-dimethylacetamide, at ambient temperature or
with heating (for example, at about 100-150.degree. C.) and
optionally in a microwave reactor. Compound (8) can also be coupled
with an acid chloride R.sub.102COC1 in the presence of a base such
as pyridine and in a solvent such as DMF, or alternatively, (8) can
be coupled with an anhydride (R.sub.102CO).sub.2O in the presence
of a base such as diisopropylethylamine and in a solvent such as
methanol. Compound (8) can also be alkylated with an halide of
formula R.sub.103X wherein R.sub.103 is alkyl, aralkyl,
heteroarylalkyl, heterocyclealkyl or NR.sub.AR.sub.Balkyl, in the
presence of a base such as sodium ethoxide or can be reacted with
an aldehyde R.sub.104CHO or ketone R.sub.104R.sub.105C(O) wherein
R.sub.104 and R.sub.105 are alkyl, aryl, aralkyl, heteroaryl,
heteroarylalkyl, heterocyclealkyl or NR.sub.AR.sub.Balkyl, under
reductive amination conditions, such as sodium cyanoborohydride in
methanol, to give the N-alkyl analog (10).
[0250] Compounds having general formula (I) wherein X is aryl,
heteroaryl, heteroarylalkyl, or aralkyl, can be prepared as shown
in Scheme 3. ##STR8##
[0251] A bromo 2- or 3-aryl, heteroaryl, heteroarylalkyl, or
aralkyl-4H-pyrazolo[1,5-a]quinazolin-5-one of formula (11), where A
is aryl, heteroaryl, heteroarylalkyl, is prepared using the
conditions as described in Scheme 1. This compound can be
carbonylated under palladium catalysis in the presence of methanol
or other alcohols to give the methyl ester (12). Saponification
using, for example, sodium hydroxide in ethanol, gave the acid
(13). Acid (13) can be converted to amide (14) using an amine
NHR.sub.CR.sub.D under standard peptide coupling conditions such as
1,3-dicyclohexylcarbodiimide or 1,1'-carbonyldiimidazole. Bromide
(11) can also be coupled with an aryl or heteroaryl boronic acid or
an aryl or heteroaryl trialkylstannane under palladium catalysis
conditions to provide compounds of formula (15), where Ar is aryl
or heteroaryl. In addition, bromide (11) can be converted to
nitrile (16) using zinc cyanide under palladium catalysis
conditions. Nitrile (16) can be reduced to amine (17) using, for
example, Raney nickel and hydrogen. Amines of formula (17) can be
further functionalized to amides (18) wherein R.sub.102 is alkyl,
arylalkyl, heterocycle, heterocyclealkyl, or NR.sub.AR.sub.Balkyl,
and substituted amines (19) as described for the preparation of (9)
and (10) in Scheme 2.
[0252] Compounds having general formula (I) wherein X is
NR.sub.CR.sub.Dcarbonyl, R.sub.C and R.sub.D are hydrogen, alkyl,
aryl, heteroaryl, heterocycle, heterocyclealkyl or
(NR.sub.AR.sub.B)alkyl, can be prepared as shown in Scheme 4.
##STR9##
[0253] A 2- or 3-carboalkoxy-4H-pyrazolo[1,5-a]quinazolin-5-one
(20), is prepared using the conditions as described in Scheme 1.
This compound can be saponified to the corresponding carboxylic
acid (21) under standard acidic (ie, hydrochloric acid) or basic
(ie, sodium hydroxide) conditions. Reduction using a reducing agent
such as lithium aluminum hydride in tetrahydrofuran provided the
alcohol (22). This can be converted to ether (23) wherein R.sub.102
is alkyl, heteroaryl, heterocyclealkyl or (NR.sub.AR.sub.B)alkyl,
under standard Williamson ether synthesis conditions with an alkyl
halide or under standard Mitsunobu conditions. Alternately, acid
(21) can be converted to amide (24) using an amine NHR.sub.CR.sub.D
under standard peptide coupling conditions such as
1,3-dicyclohexylcarbodiimide or 1,1'-carbonyldiimidazole.
[0254] The following Examples are intended as an illustration of
and not a limitation upon the scope of the invention as defined in
the appended claims. The compounds of this invention can be
prepared by a variety of synthetic routes.
EXAMPLE 1
3-phenyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[0255] A mixture of 2-hydrazinobenzoic acid (0.15 g, 0.8 mmol) and
3-oxo-2-phenyl-propionitrile (0.116 g, 0.8 mmol) in acetic acid
(0.2 mL) was heated in a microwave (Personal Chemistry
SmithSynthesizer) at 150.degree. C. for 10 minutes. The
precipitated product was filtered, washed with methanol and diethyl
ether and dried. .sup.1H NMR (DMSO-d.sub.6) .delta. 12.10 (s, 1H),
8.10-8.19 (m, 3H) 7.88-7.96 (m, 1H), 7.59 (d, J=7.3 Hz, 2H), 7.52
(t, J=7.8 Hz, 1H), 7.42 (t, J=7.6 Hz, 2Hz), 7.28 (t, J=7.3 Hz,
1H).
EXAMPLE 2
3-(4-chloro-phenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0256] The title compound was prepared as described in EXAMPLE 1,
substituting 2-(4-chlorophenyl)-3-oxo-propionitrile for
3-oxo-2-phenylpropionitrile. .sup.1H NMR (DMSO-d.sub.6) .delta.
12.14 (s, 1H), 8.12-8.19 (m, 2H) 7.89-7.94 (m, 1H), 7.62 (d, J=7.7
Hz, 2H), 7.53 (t, J=7.5 Hz, 1H), 7.44-7.48 (m, 2H).
EXAMPLE 3
2-phenyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[0257] The title compound was prepared as described in EXAMPLE 1,
substituting 3-oxo-3-phenylpropionitrile for
3-oxo-2-phenylpropionitrile. .sup.1H NMR (DMSO-d.sub.6) .delta.
12.30 (s, 1H), 8.15-8.18 (m, 2H) 7.97 (d, J=7.1 Hz, 2H), 7.91 (t,
J=7.8 Hz, 1H), 7.45-7.53 (m, 3H), 7.40 (t, J=7.2 Hz, 1H), 6.38 (s,
1H).
EXAMPLE 4
2-tert-butyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[0258] The title compound was prepared as described in EXAMPLE 1,
substituting 4,4-dimethyl-3-oxo-pentanenitrile for
3-oxo-2-phenylpropionitrile. .sup.1H NMR (DMSO-d.sub.6) .delta.
12.09 (s, 1H), 8.11 (dd, J=8.0, 1.2 Hz, 1H) 8.02 (d, J=7.7 Hz, 2H),
7.82-7.87 (m, 1H), 7.41-7.46 (m, 1H), 5.80 (s, 1H), 1.32 (s,
9H).
EXAMPLE 5
2-furan-2-yl-4H-pyrazolo[1,5-a]quinazolin-5-one
[0259] The title compound was prepared as described in EXAMPLE 1,
substituting 3-furan-2-yl-3-oxopropionitrile for
3-oxo-2-phenylpropionitrile. .sup.1H NMR (DMSO-d.sub.6) .delta.
12.28 (s, 1H), 8.08-8.17 (m, 2H), 7.90 (td, J=7.8, 1.5 Hz, 1H),
7.80 (d, J=1.8 Hz, 1H), 7.50 (t, J=7.7 Hz, 1H), 6.99 (d, J=3.4 Hz,
1H), 6.64 (dd, J=3.4, 1.8 Hz, 1H), 6.19 (s, 1H).
EXAMPLE 6
2-thiophen-2-yl-4H-pyrazolo[1,5-a]quinazolin-5-one
[0260] The title compound was prepared as described in EXAMPLE 1,
substituting 3-oxo-3-thiophen-2-yl-propionitrile for
3-oxo-2-phenylpropionitrile. .sup.1H NMR (DMSO-d.sub.6) .delta.
12.30 (s, 1H), 8.15 (d, J=8.0 Hz, 1H) 8.08 (d, J=7.7 Hz, 1H), 7.90
(td, J=7.8, 1.5 Hz, 1H), 7.58-7.65 (m, 2H), 7.47-7.53 (m, 1H), 7.15
(dd, J=5.1, 3.5 Hz, 1H), 6.30 (s, 1H).
EXAMPLE 7
2-(4-methoxyphenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0261] The title compound was prepared as described in EXAMPLE 1,
substituting 3-(4-methoxyphenyl)-3-oxo-propionitrile for
3-oxo-2-phenylpropionitrile. .sup.1H NMR (DMSO-d.sub.6) .delta.
12.25 (s, 1H), 8.12-8.17 (m, 2H), 7.87-7.92 (m, 3H), 7.46-7.51 (m,
1H), 7.03 (d, J=8.9 Hz, 2H), 6.30 (s, 1H), 3.82 (s, 3H).
EXAMPLE 8
2-(3-nitrophenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0262] The title compound was prepared as described in EXAMPLE 1,
substituting 3-(3-nitrophenyl)-3-oxo-propionitrile for
3-oxo-2-phenylpropionitrile. .sup.1H NMR (DMSO-d.sub.6) .delta.
12.40 (s, 1H), 8.74-8.76 (m, 1H), 8.42 (dd, J=6.4, 1.5 Hz, 1H),
8.16-8.26 (m, 3H), 7.90-7.95 (m, 1H), 7.78 (t, J=8.0 Hz, 1H),
7.52-7.56 (m, 1H), 6.59 (s, 1H).
EXAMPLE 9
2-(3-chlorophenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0263] The title compound was prepared as described in EXAMPLE 1,
substituting 3-(3-chlorophenyl)-3-oxo-propionitrile for
3-oxo-2-phenylpropionitrile. .sup.1H NMR (DMSO-d.sub.6) .delta.
12.37 (s, 1H), 8.19 (d, J=7.9 Hz, 1H), 8.16 (dd, J=7.9, 1.2 Hz,
1H), 8.04 (t, J=1.8 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H), 7.87-7.94 (m,
1H), 7.45-7.54 (m, 3H), 6.49 (s, 1H).
EXAMPLE 10
2-biphenyl-2-yl-4H-pyrazolo[1,5-a]quinazolin-5-one
[0264] The title compound was prepared as described in EXAMPLE 1,
substituting 3-biphenyl-2-yl-3-oxo-propionitrile for
3-oxo-2-phenylpropionitrile. .sup.1H NMR (DMSO-d.sub.6) .delta.
11.94 (s, 1H), 8.11 (dd, J=7.9, 1.2 Hz, 1H), 8.05 (d, J=8.2 Hz,
1H), 7.85-7.92 (m, 2H), 7.46-7.53 (m, 3H), 7.33-7.41 (m, 4H), 7.28
(dd, J=7.8, 1.7 Hz, 2H), 5.19 (s, 1H).
EXAMPLE 11
2-biphenyl-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one
[0265] The title compound was prepared as described in EXAMPLE 1,
substituting 3-biphenyl-4-yl-3-oxo-propionitrile for
3-oxo-2-phenylpropionitrile. .sup.1H NMR (DMSO-d.sub.6) .delta.
12.29 (s, 1H), 8.14-8.20 (m, 2H), 7.92 (td, J=7.3, 2.1 Hz, 2H),
7.57-7.63 (m, 1H), 7.53 (t, J=7.0 Hz, 1H), 7.44-7.50 (m, 2H), 6.39
(s, 1H).
EXAMPLE 12
2-(3-am inophenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0266] A mixture of EXAMPLE 8 (1.07 g, 3.5 mmol) and 10% palladium
on carbon (0.2 g) in methanol (25 mL) was stirred overnight under 1
atmosphere of hydrogen and filtered. The filtrate was concentrated
and the residue crystallized from methanol to provide the title
compound (0.58 g, 60%). .sup.1H NMR (DMSO-d.sub.6) .delta. 12.23
(s, 1H), 8.10-8.18 (m, 2H), 7.86-7.95 (m, 1H), 7.49 (t, J=7.0 Hz,
1H), 7.19 (s, 1H), 7.05-7.12 (m, 2H), 6.56-6.63 (m, 1H), 6.20 (s,
1H), 5.19 (s, 2H).
EXAMPLE 13
2-(2-chlorophenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0267] The title compound was prepared as described in EXAMPLE 1,
substituting 3-(2-chlorophenyl)-3-oxo-propionitrile for
3-oxo-2-phenylpropionitrile. .sup.1H NMR (DMSO-d.sub.6) .delta.
12.34 (s, 1H), 8.15-8.21 (m, 2H), 8.07 (d, J=8.2 Hz, 2H), 7.90-7.95
(m, 1H), 7.73-7.81 (m, 4H), 7.51 (q, J=7.7 Hz, 3H), 7.40 (t, J=7.3
Hz, 1H), 6.44 (s, 1H).
EXAMPLE 14
2-[3-(2-aminoethylamino)phenyl]-4H-pyrazolo[1,5-a]quinazolin-5-one
[0268] A solution of EXAMPLE 12 (0.06 g, 0.2 mmol) and tert-butyl
(2-oxoethyl)carbamate (0.035 g, 0.2 mmol) in ethanol (1 mL) and
acetonitrile (1 mL) was treated with sodium cyanoborohydride (0.014
g, 0.2 mmol) and acetic acid (0.2 mL). The mixture was heated in a
microwave at 170.degree. C. for 40 minutes and concentrated. The
residue was purified by flash chromatography on silica gel with 10%
methanol/dichloromethane/0.1% ammonium hydroxide to provide the
title compound. .sup.1H NMR (DMSO-d.sub.6) .delta. 12.30 (s, 1H),
10.06 (s, 1H), 8.11-8.19 (m, 2H), 7.89-7.96 (m, 1H), 7.58-7.67 (m,
2H), 7.52 (t, J=7.6 Hz, 1H), 7.39 (t, J=7.9 Hz, 1H), 6.27 (s, 1H),
3.30-3.36 (m, 4H), 2.08 (s, 3H).
EXAMPLE 15
N-{2-[3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)phenylamino]ethyl-
}-acetamide
[0269] The title compound was obtained as a byproduct in the
purification of EXAMPLE 14. .sup.1H NMR (DMSO-d.sub.6) .delta.
12.25 (s, 1H), 8.12-8.18 (m, 2H), 7.91 (td, J=7.8, 1.5 Hz, 2H),
7.47-7.53 (m, 1H), 7.13-7.20 (m, 2H), 6.60-6.68 (m, 1H), 6.27 (s,
1H), 3.22-3.26 (m, 2H), 3.14-3.19 (m, 2H), 1.76 (s, 3H).
EXAMPLE 16
N-[3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)phenyl]acetamide
[0270] A solution of EXAMPLE 12 (0.04 g, 0.1 mmol) and acetic
anhydride (0.02 mL, 1.5 mmol) in acetonitrile was treated with
triethylamine (0.1 mL, 0.8 mmol). The mixture was stirred overnight
at ambient temperature and filtered to provide the title compound.
.sup.1H NMR (DMSO-d.sub.6) .delta. 12.27 (s, 1H), 10.04 (s, 1H),
8.11-8.20 (m, 3H), 7.87-7.95 (m, 1H), 7.58-7.66 (m, 2H), 7.48-7.56
(m, 1H), 7.38 (t, J=7.8 Hz, 1H), 6.27 (s, 1H), 2.06-2.12 (m,
3H).
EXAMPLE 17
benzyl 4-({acetyl
[3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)phenyl]amino}methyl)p-
iperidine-1-carboxylate
[0271] The title compound was prepared as described in EXAMPLE 14,
substituting benzyl 4-formylpiperidine-1-carboxylate for tert-butyl
(2-oxoethyl)carbamate. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.15-8.20
(m, 2H), 7.88-7.98 (m, 3H), 7.49-7.57 (m, 2H), 7.30-7.38 (m, 6H),
6.49 (s, 1H), 5.05 (s, 2H), 3.94 (s, 2H), 3.64 (d, J=6.8 Hz, 2H),
3.37-3.42 (m, 1H), 3.35 (s, 3H), 1.77-1.84 (m, 2H), 1.68 (d, J=12.0
Hz, 3H), 1.09 (t, J=6.9 Hz, 2H).
EXAMPLE 18
2-[3-(2-dimethylaminoethylamino)phenyl]-4H-pyrazolo[1,5-a]quinazolin-5-one
[0272] A solution of EXAMPLE 12 (0.04 g, 0.1 mmol) and
(2-bromoethyl) dimethylamine (0.02 g, 0.1 mmol) in acetonitrile (1
mL) was treated with potassium carbonate (0.04 g, 0.3 mmol). The
mixture was stirred overnight at 50.degree. C. and filtered. The
filtrate was concentrated and purified by flash chromatography on
silica gel with 10% methanol/dichloromethane to provide the title
compound. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.12-8.18 (m, 2H),
7.86-7.95 (m, 1H), 7.49 (t, J=7.6 Hz, 1H), 7.12-7.20 (m, 3H), 6.64
(s, 1H), 6.27 (s, 1H), 3.23-3.26 (m, 3H), 2.57-2.65 (m, 1H), 2.31
(s, 6H), 1.24 (s, 1H), 0.85 (s, 1H).
EXAMPLE 19
2-piperidin-3-yl-4H-pyrazolo[1,5-a]quinazolin-5-one
[0273] The title compound was prepared as described in EXAMPLE 1,
substituting tert butyl 3-(2-cyanoacetyl)piperidine-1-carboxylate
for 3-oxo-2-phenylpropionitrile. .sup.1H NMR (DMSO-d.sub.6) .delta.
12.23 (s, 1H), 8.85 (s, 2H), 8.13 (d, J=8.0 Hz, 1H), 8.04 (d, J=7.7
Hz, 1H), 7.88 (td, J=7.8, 1.53 Hz, 1H), 7.46-7.51 (m, 1H), 5.91 (s,
1H), 3.44-3.52 (m, 1H), 3.27-3.33 (m, 2H), 3.09-3.21 (m, 2H), 2.92
(s, 1H), 2.04-2.11 (m, 1H), 1.84-1.91 (m, 1H), 1.71-1.82 (m,
1H).
EXAMPLE 20
[0274]
2-(1-methylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0275] A solution of EXAMPLE 19 (0.04 g, 0.1 mmol) and formaldehyde
(36% in water, 0.018 mL, 2 mmol) in methanol (1 mL) was treated
with sodium cyanoborohydride (0.009 g, 0.1 mmol) and acetic acid
(0.1 mL). The mixture was stirred overnight at ambient temperature
and concentrated. The residue was purified by HPLC on a C18 column
with 0-100% acetonitrile/water/0.1% trifluoroacetic acid to provide
the title compound as the trifluoroacetate salt. .sup.1H NMR
(CD.sub.3OD) .delta. 8.23 (d, J=7.1 Hz, 1H), 8.15 (d, J=8.0 Hz,
1H), 7.84-7.89 (m, 1H), 7.46-7.52 (m, 1H), 5.95 (s, 1H), 3.63-3.74
(m, 1H), 3.35-3.48 (m, 3H), 3.05-3.17 (m, 1H), 2.94 (s, 3H),
2.15-2.24 (m, 1H), 2.01-2.08 (m, 1H), 1.84-1.95 (m, 2H).
EXAMPLE 21
2-(1-ethylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0276] The title compound was prepared as the trifluoroacetate salt
as described in EXAMPLE 20, substituting acetaldehyde for
formaldehyde. .sup.1H NMR (CD.sub.3OD) .delta. 8.23 (dd, J=8.0, 1.5
Hz, 1H), 8.14 (d, J=8.0 Hz, 1H), 7.87 (td, J=7.8, 1.2 Hz, 1H),
7.47-7.51 (m, 1H), 5.96 (s, 1H), 3.65 (s, 1H), 3.49 (d, J=7.1 Hz,
1H), 3.19 (dd, J=7.2, 2.3 Hz, 3H), 3.01 (s, 1H), 2.19 (s, 1H), 2.03
(s, 1H), 1.85-1.97 (m, 2H), 1.40 (t, J=7.4 Hz, 3H).
EXAMPLE 22
2-(1-isobutylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0277] The title compound was prepared as the trifluoroacetate salt
as described in EXAMPLE 20, substituting 2-methylpropionaldehyde
for formaldehyde. .sup.1H NMR (DMSO-d.sub.6) .delta. 12.26 (s, 1H),
8.12-8.19 (m, 1H), 8.02 (d, J=7.6 Hz, 1H), 7.86-7.92 (m, 1H), 7.49
(t, J=7.6 Hz, 1H), 5.90 (s, 1H), 3.66 (s, 1H), 3.37-3.47 (m, 9H),
3.17 (d, J=4.9 Hz, 1H), 2.82 (s, 3H), 2.07 (s, 1H), 1.91 (s, 1H),
1.79 (s, 1H), 1.60 (s, 1H).
EXAMPLE 23
2-(1-cyclopropylmethylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0278] The title compound was prepared as the trifluoroacetate salt
as described in EXAMPLE 20, substituting cyclopropanecarbaldehyde
for formaldehyde. .sup.1H NMR (CD.sub.3OD) .delta. 8.23 (dd, J=8.0,
1.5 Hz, 1H), 8.14 (d, J=8.3 Hz, 1H), 7.86 (td, J=7.8, 1.5 Hz, 1H),
7.46-7.51 (m, 1H), 5.95 (s, 1H), 3.74 (s, 1H), 3.32-3.42 (m, 3H),
3.07 (d, J=7.4 Hz, 3H), 2.20 (d, J=7.4 Hz, 1H), 2.05 (s, 1H),
1.85-1.97 (m, 2H), 1.14-1.24 (m, 1H), 0.74-0.84 (m, 2H), 0.41-0.50
(m, 2H).
EXAMPLE 24
2-[1-(3-piperidin-1-ylpropionyl)piperidin-3-yl]-4H-pyrazolo[1,5-a]quinazol-
in-5-one
[0279] A solution of EXAMPLE 19 (0.1 g, 0.4 mmol),
3-piperidin-1-ylpropionic acid (0.06 g, 0.4 mmol),
1-hydroxybenzotriazole (0.098 g, 0.7 mmol),
benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate
(0.377 g, 0.7 mmol) and diisopropylethylamine (0.4 mL, 2.2 mmol) in
N,N'-dimethylformamide (4 mL) was heated in a microwave at
150.degree. C. for 10 minutes. The mixture was concentrated and
purified by HPLC on a C18 column with 0-100%
acetonitrile/water/0.1% trifluoroacetic acid to provide the title
compound as the trifluoroacetate salt. .sup.1H NMR (CD.sub.3OD)
.delta. 8.20-8.26 (m, 1H), 8.11 (dd, J=8.3, 4.6 Hz, 1H), 7.83-7.89
(m, 1H), 7.44-7.50 (m, 1H), 5.92 (d, J=11.0 Hz, 1H), 4.65-4.79 (m,
1H), 4.08-4.14 (m, 1H), 4.01-4.05 (m, 1H), 3.48-3.59 (m, 5H),
3.35-3.42 (m, 2H), 2.92-3.04 (m, 5H), 2.16-2.23 (m, 1H), 1.84-1.95
(m, 4H), 1.73-1.82 (m, 2H), 1.49-1.60 (m, 1H).
EXAMPLE 25
2-(1-propylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0280] The title compound was prepared as described in EXAMPLE 20,
substituting propionaldehyde for formaldehyde. The crude product
was purified by flash chromatography on silica gel with 0-10%
methanol/dichloromethane/0.1% ammonium hydroxide. .sup.1H NMR
(CD.sub.3OD) .delta. 8.23 (d, J=8.0, Hz, 1H), 8.13 (d, J=8.0 Hz,
1H), 7.87 (t, J=7.4 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H), 5.96 (s, 1H),
3.47-3.57 (m, 1H), 3.34-3.43 (m, 1H), 3.14 (t, J=8.1 Hz, 4H),
2.14-2.26 (m, 1H), 1.83-1.94 (m, 4H), 1.14-1.24 (m, 1H), 1.07 (t,
J=7.2 Hz, 4H).
EXAMPLE 26
2-(1-benzylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0281] The title compound was prepared as described in EXAMPLE 20,
substituting benzaldehyde for formaldehyde. HPLC purification was
followed by flash chromatography on silica gel with 0-10%
methanol/dichloromethane/0.1% ammonium hydroxide. .sup.1H NMR
(CD.sub.3OD) .delta. 8.21 (dd, J=8.0, 1.5 Hz, 1H), 8.06 (d, J=8.3
Hz, 1H), 7.82-7.88 (m, 1H), 7.35-7.46 (m, 6H), 5.87 (s, 1H),
3.84-3.93 (m, 2H), 3.09-3.18 (m, 2H), 2.67 (s, 1H), 2.48-2.57 (m,
1H), 2.07-2.14 (m, 1H), 1.79-1.91 (m, 2H), 1.68 (s, 1H).
EXAMPLE 27
2-(1-cyclopentylmethylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0282] The title compound was prepared as described in EXAMPLE 20,
substituting cyclopentanecarboxaldehyde for formaldehyde. HPLC
purification was followed by flash chromatography on silica gel
with 0-10% methanol/dichloromethane/0.1% ammonium hydroxide.
.sup.1H NMR (CD.sub.3OD) .delta. 8.21 (d, J=8.0, Hz, 1H), 8.11 (d,
J=7.7 Hz, 1H), 7.82-7.87 (m, 1H), 7.45 (t, J=8.1 Hz, 1H), 5.88 (s,
1H), 3.19-3.25 (m, 1H), 3.01-3.11 (m, 2H), 2.47 (d, J=7.1 Hz, 2H),
2.32 (s, 1H), 2.17 (dt, J=15.1, 7.6 Hz, 2H), 2.07 (dd, J=13.0, 3.8
Hz, 1H), 1.78-1.87 (m, 4H), 1.61-1.70 (m, 2H), 1.52-1.61 (m, 3H),
1.19-1.29 (m, 2H).
EXAMPLE 28
2-(1-pyridin-4-ylmethylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0283] The title compound was prepared as described in EXAMPLE 20,
substituting pyridine-4-carboxaldehyde for formaldehyde. HPLC
purification was followed by flash chromatography on silica gel
with 0-10% methanol/dichloromethane/0.1% ammonium hydroxide.
.sup.1H NMR (CD.sub.3OD) .delta. 8.45-8.50 (m, 2H), 8.20 (dd,
J=8.0, 1.5 Hz, 1H), 8.08 (d, J=7.3 Hz, 1H), 7.78-7.86 (m, 1H),
7.42-7.48(m, 3H), 5.86 (s, 1H), 3.64 (s, 1H), 3.49 (q, J=7.06 Hz,
1H), 3.01-3.10 (m, 2H), 2.87 (s, 1H), 2.24-2.31 (m, 1H), 2.17 (td,
J=11.1, 3.5 Hz, 1H), 2.05 (s, 1H), 1.74-1.86 (m, 2H), 1.58 (d,
J=12.6 Hz, 1H).
EXAMPLE 29
2-(1-isopropylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0284] A solution of EXAMPLE 19 (0.07 g, 0.3 mmol) and
2-iodopropane (0.09 mL, 0.9 mmol) in dioxane (2 mL) and was treated
with sodium hydride (0.01 g, 0.4 mmol). The mixture was stirred
overnight at 65.degree. C., cooled to ambient temperature, treated
with water and concentrated. The residue was purified by flash
chromatography on silica gel with 10% methanol/dichloromethane to
provide the title compound. .sup.1H NMR (CD.sub.3OD) .delta. 8.21
(dd, J=8.0, 1.5 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.81-7.87 (m, 1H),
7.42-7.47 (m, 1H), 5.88 (s, 1H), 3.21 (dt, J=11.3, 1.9, 1H),
2.99-3.10 (m, 2H), 2.92 (dt, J=13.2, 6.6 Hz, 1H), 2.51 (t, J=11.0
Hz, 1H), 2.38 (td, J=11.5, 2.8 Hz, 1H), 2.09 (ddd, J=9.0, 3.8, 3.7
Hz, 1H), 1.83-1.92 (m, 1H), 1.70-1.82 (m, 1H), 1.59 (qd, J=12.3,
4.0 Hz, 1H), 1.14-1.19 (m, 6H).
EXAMPLE 30
methyl
4-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)benzoate
[0285] The title compound was prepared as described in EXAMPLE 1,
substituting methyl 4-(2-cyanoacetyl) benzoate for
3-oxo-2-phenylpropionitrile. .sup.1H NMR (DMSO-d.sub.6) .delta.
12.37 (s, 1H), 8.11-8.21 (m, 4H) 8.04-8.08 (m, 2H), 7.89-7.98 (m,
1H), 7.53 (t, J=7.6 Hz, 1H), 6.50 (s, 1H), 3.89 (s, 3H).
EXAMPLE 31
2-(3-fluoro-4-morpholin-4-ylphenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0286] The title compound was prepared as described in EXAMPLE 1,
substituting
3-(3-fluoro-4-morpholin-4-ylphenyl)-3-oxo-propionitrile for
3-oxo-2-phenylpropionitrile. .sup.1H NMR (DMSO-d.sub.6) .delta.
12.30 (s, 1H), 8.15 (d, J=8.1 Hz, 2H), 7.86-7.95 (m, 1H), 7.69-7.78
(m, 2H), 7.49 (t, J=7.8 Hz, 1H), 7.11 (t, J=8.6 Hz, 1H), 6.37 (s,
1H), 3.77 (s, 4H), 3.09 (d, J=4.1 Hz, 4H).
EXAMPLE 32
2-cyclopropyl-4H-pyrazolo[1,5-a]quinazolin-5-one
EXAMPLE 32A
3-cyclopropyl-3-oxopropionitrile
[0287] A solution of acetonitrile (0.25 mL, 4.8 mmol) in
tetrahydrofuran (3 mL) was cooled to -78.degree. C. and treated
with 1.6 M n-butyl lithium in hexanes (3 mL, 4.8 mmol). The mixture
was stirred at -78.degree. C. for 2 hours and a solution of
cyclopropanecarbonyl chloride (0.22 mL, 2.4 mmol) in
tetrahydrofuran (1 mL) was added. The mixture was stirred for 1
hour and 20% hydrochloric acid was added until the pH=3. The
mixture was diluted with ethyl acetate, washed with water and
brine, filtered through silica gel and concentrated to provide the
title compound.
EXAMPLE 32B
2-cyclopropyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[0288] The title compound was prepared as described in EXAMPLE 1,
substituting EXAMPLE 32A for 3-oxo-2-phenylpropionitrile. .sup.1H
NMR (DMSO-d.sub.6) .delta. 12.07 (s, 1H), 8.10 (dd, J=8.0, 1.5 Hz,
1H), 7.98 (d, J=7.7 Hz, 1H), 7.84 (td, J=7.8, 1.5 Hz, 1H),
7.39-7.47 (m, 1H), 5.62 (s, 1H), 1.95-2.03 (m, 1H), 0.96 (ddd,
J=8.3, 6.4, 4.0 Hz, 2H), 0.78 (ddd, J=7.0, 4.5, 4.1 Hz, 2H).
EXAMPLE 33
2-(1-benzylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
EXAMPLE 33A
3-(1-benzylpiperidin-4-yl)-3-oxo-propionitrile
[0289] The title compound was prepared as described in EXAMPLE 32A,
substituting methyl 1-benzylpiperidin-4-carboxylate for
cyclopropanecarbonyl chloride.
EXAMPLE 33B
2-(1-benzylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0290] The title compound was prepared as described in EXAMPLE 1,
substituting EXAMPLE 33A for 3-oxo-2-phenylpropionitrile. .sup.1H
NMR (CD.sub.3OD) .delta. 8.22 (d, J=7.8 Hz, 1H), 8.06 (s, 1H),
7.81-7.89 (m, 1H), 7.45-7.56 (m, 6H), 5.89 (s, 1H), 4.36 (s, 2H),
3.51-3.65 (m, 2H), 3.13-3.29 (m, 2H), 2.25-2.29 (m, 2H), 1.96-2.11
(m, 1H).
EXAMPLE 34
N-[3-(5-oxo-4,
5-dihydropyrazolo[1,5-a]quinazolin-2-yl)phenyl]-3-piperidin-1-ylpropionam-
ide
[0291] A solution of EXAMPLE 12 (0.1 g, 0.4 mmol),
3-piperidinopropionic acid (60 mg, 0.4 mmol),
1-hydroxybenzotriazole (0.098 g, 0.7 mmol),
benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate
(0.377 g, 0.7 mmol) and diisopropylethylamine (0.4 mL, 2.2 mmol) in
N,N'-dimethylformamide (4 mL) was heated in a microwave at
100.degree. C. for 15 minutes. The mixture was concentrated and
purified by flash chromatography on silica gel with 10%
methanol/dichloromethane to provide the title compound. .sup.1H NMR
(CD.sub.3OD) .delta. 8.23-8.27 (m, 3H), 7.89 (td, J=7.8, 1.5 Hz,
1H), 7.68 (d, J=8.3 Hz, 1H), 7.59 (dd, J=7.1, 2.2 Hz, 1H),
7.48-7.56 (m, 1H), 7.42 (t, J=8.0 Hz, 1H), 6.33 (s, 1H), 3.62 (s,
2H), 3.51 (t, J=6.6 Hz, 2H), 3.04 (s, 2H), 2.96 (t, J=6.8 Hz, 2H),
1.98 (d, J=3.4 Hz, 2H), 1.82 (s, 3H), 1.58 (s, 1H).
EXAMPLE 35
2-piperidin-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one
[0292] A mixture of EXAMPLE 33 (0.15 g, 0.4 mmol) and 10% palladium
on carbon (0.02 g) in methanol (5 mL) was stirred overnight under 1
atmosphere hydrogen and filtered. The filtrate was concentrated and
the residue purified by flash chromatography on silica gel with 10%
methanol/dichloromethane to provide the title compound. .sup.1H NMR
(CD.sub.3OD) .delta. 8.22 (dd, J=7.9, 1.2 Hz, 1H), 8.11 (d, J=8.2
Hz, 1H), 7.83-7.88 (m, 1H), 7.47 (t, J=7.6 Hz, 1H), 5.91 (s, 1H),
3.50 (dt, J=13.0, 3.7 Hz, 2H), 3.12-3.19 (m, 2H), 2.29 (dd, J=15.0,
3.4 Hz, 2H), 1.99-2.08 (m, 2H).
EXAMPLE 36
2-(4-pyrrolidin-1-ylmethylphenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0293] The title compound was prepared as described in EXAMPLE 1,
substituting 3-oxo-3-(4-pyrrolidin-1-ylmethylphenyl)propionitrile
for 3-oxo-2-phenylpropionitrile. .sup.1H NMR (CD.sub.3OD) .delta.
8.22-8.29 (m, 2H), 8.07 (d, J=8.2 Hz, 2H), 7.89-7.93 (m, 1H), 7.62
(d, J=8.2 Hz, 2H), 7.52 (t, J=7.2 Hz, 1H), 6.40 (s, 1H), 4.43 (s,
2H), 3.50-3.57 (m, 2H), 3.19-3.27 (m, 2H), 2.18-2.25 (m, 2H),
1.98-2.07 (m, 2H).
EXAMPLE 37
2-(1-methylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0294] The title compound was prepared as described in EXAMPLE 20,
substituting EXAMPLE 35 for EXAMPLE 19. The crude product was
purified by flash chromatography on silica gel with 0-10%
methanol/dichloromethane/0.1% ammonium hydroxide. .sup.1H NMR
(DMSO-d.sub.6) .delta. 12.12 (s, 1H), 8.12 (d, J=7.1 Hz, 1H), 8.01
(d, J=8.0 Hz, 1H), 7.83-7.87 (m, 1H), 7.43-7.47 (m, 1H), 5.79 (s,
1H), 2.98-3.07 (m, 2H), 2.67-2.77 (m, 1H), 2.38 (s, 5H), 1.95-2.02
(m, 2H), 1.72-1.83 (m, 2H).
EXAMPLE 38
2-(1-ethylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0295] The title compound was prepared as described in EXAMPLE 21,
substituting EXAMPLE 35 for EXAMPLE 19. The crude product was
purified by flash chromatography on silica gel with 0-10%
methanol/dichloromethane/0.1% ammonium hydroxide. .sup.1H NMR
(DMSO-d.sub.6) .delta. 12.18 (s, 1H), 8.13 (d, J=7.1 Hz, 1H), 8.01
(d, J=8.6 Hz, 1H), 7.87 (td, J=7.8, 1.5 Hz, 1H), 7.44-7.49 (m, 1H),
5.81 (s, 1H), 3.51 (s, 2H), 3.17 (d, J=5.2 Hz, 1H), 3.08 (s, 2H),
2.99 (s, 2H), 2.16 (s, 2H), 2.02 (s, 2H) 1.27 (s, 3H).
EXAMPLE 39
2-(1-propylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0296] The title compound was prepared as described in EXAMPLE 25,
substituting EXAMPLE 35 for EXAMPLE 19. .sup.1H NMR (DMSO-d.sub.6)
.delta. 8.12 (dd, J=7.8, 1.4 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H),
7.84-7.88 (m, 1H), 7.44-7.48 (m, 1H), 5.81 (s, 1H), 3.15 (s, 1H),
2.85-2.90 (m, 4H), 2.04-2.13 (m, 2H), 1.88-1.99 (m, 3H), 1.65 (s,
2H), 0.91 (t, J=7.5 Hz, 4H).
EXAMPLE 40
2-(1-cyclopropylmethylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0297] The title compound was prepared as described in EXAMPLE 23,
substituting EXAMPLE 35 for EXAMPLE 19. The crude product was
purified by flash chromatography on silica gel with 0-10%
methanol/dichloromethane/0.1% ammonium hydroxide. .sup.1H NMR
(DMSO-d.sub.6) .delta. 12.18 (s, 1H), 8.11-8.14 (m, 1H), 8.01 (d,
J=8.0 Hz, 1H), 7.84-7.88 (m, 1H), 7.46 (d, J=7.5 Hz, 1H), 5.81 (s,
1H), 3.15-3.25 (m, 4H), 2.76-2.86 (m, 1H), 2.56-2.67 (m, 1H),
1.99-2.10 (m, 2H), 1.83-1.93 (m, 3H), 0.98 (s, 1H) 0.54 (s, 2H),
0.24 (s, 2H).
EXAMPLE 41
2-(1-isobutylpiperidin-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one
[0298] The title compound was prepared as described in EXAMPLE 22,
substituting EXAMPLE 35 for EXAMPLE 19. The crude product was
purified by flash chromatography on silica gel with 0-10%
methanol/dichloromethane/0.1% ammonium hydroxide. .sup.1H NMR
(DMSO-d.sub.6) .delta. 12.15 (s, 1H), 8.13 (d, J=6.8 Hz, 1H), 8.00
(d, J=8.3 Hz, 1H), 7.84-7.89 (m, 1H), 7.46 (t, J=7.1 Hz, 1H), 5.81
(s, 1H), 3.56 (s, 1H), 3.17 (d, J=5.2 Hz, 1H), 2.90-3.01 (m, 4H),
2.12 (s, 3H), 2.07 (s, 2H), 1.86-1.94 (m, 1H), 0.97 (s, 6H).
EXAMPLE 42
2-(1-isopropylpiperidin-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one
[0299] The title compound was prepared as described in EXAMPLE 28,
substituting EXAMPLE 35 for EXAMPLE 19. .sup.1H NMR (CD.sub.3OD)
.delta. 8.22 (d, J=8.0 Hz, 1H), 8.11 (d, J=8.3 Hz, 1H), 7.82-7.88
(m, 1H), 7.47 (t, J=7.7 Hz, 1H), 5.91 (s, 1H), 3.48-3.58 (m, 4H),
3.22 (s, 2H), 2.34 (s, 2H), 2.14 (s, 2H), 1.39 (d, J=6.8 Hz,
7H).
EXAMPLE 43
2-pyrrolidin-3-yl-4H-pyrazolo[1,5-a]quinazolin-5-one
EXAMPLE 43A
benzyl 3-(2-cyanoacetyl)pyrrolidine-1-carboxylate
[0300] A mixture of benzyl 3-carbomethoxypyrrolidine-1-carboxylate
(1 g, 4 mmol) and thionyl chloride (5 mL) was heated at reflux for
10 minutes and stirred overnight at ambient temperature. The
mixture was concentrated, dried and substituted for
cyclopropanecarbonyl chloride in EXAMPLE 32A to provide the title
compound.
EXAMPLE 43B
2-pyrrolidin-3-yl-4H-pyrazolo[1,5-a]quinazolin-5-one
[0301] The title compound was prepared as described in EXAMPLE 1,
substituting EXAMPLE 43A for 3-oxo-2-phenylpropionitrile. .sup.1H
NMR (CD.sub.3OD) .delta. 8.21-8.24 (m, 1H), 8.15 (d, J=8.3 Hz, 1H),
7.86 (td, J=7.8, 1.5 Hz, 1H), 7.46-7.51 (m, 1H), 5.97 (s, 1H),
3.73-3.79 (m, 1H), 3.66 (d, J=6.8 Hz, 2H), 3.50 (s, 1H), 3.42-3.47
(m, 1H), 2.46-2.52 (m, 1H), 2.27-2.33 (m, 1H).
EXAMPLE 44
benzyl
3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)pyrrolidine-1-ca-
rboxylate
[0302] The filtrate from EXAMPLE 43B was concentrated and purified
by flash chromatography on silica gel with 10%
methanol/dichloromethane to provide the title compound. .sup.1H NMR
(DMSO-d.sub.6) .delta. 8.11 (s, 1H), 7.99 (s, 1H), 7.84 (s, 1H),
7.44 (s, 1H), 7.33 (s, 5H), 5.85 (s, 1H), 5.08 (s, 2H), 3.75 (s,
1H), 3.49 (s, 1H), 2.27 (s, 1H), 2.09 (s, 1H).
EXAMPLE 45
2-(1-methylpyrrolidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0303] The title compound was prepared as described in EXAMPLE 20,
substituting EXAMPLE 43B for EXAMPLE 19. The crude product was
purified by flash chromatography on silica gel with 0-10%
methanol/dichloromethane/0.1% ammonium hydroxide. .sup.1H NMR
(CD.sub.3OD) .delta. 8.22 (dd, J=7.8, 1.7 Hz, 1H), 8.14 (d, J=8.3
Hz, 1H), 7.86 (td, J=7.8, 1.5 Hz, 1H), 7.45-7.51 (m, 1H), 5.97 (s,
1H), 3.81-3.89 (m, 1H), 3.66-3.74 (m, 2H), 3.44-3.56 (m, 2H), 3.00
(s, 3H), 2.54-2.64 (m, 1H), 2.36 (ddd, J=14.9, 13.4, 6.8 Hz,
1H).
EXAMPLE 46
2-(1-ethylpyrrolidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0304] The title compound was prepared as described in EXAMPLE 21,
substituting EXAMPLE 43B for EXAMPLE 19. The crude product was
purified by flash chromatography on silica gel with 0-10%
methanol/dichloromethane/0.1% ammonium hydroxide. .sup.1H NMR
(CD.sub.3OD) .delta. 8.18-8.24 (m, 1H), 8.10 (d, J=8.2 Hz, 1H),
7.81-7.88 (m, 1H), 7.46 (t, J=7.6 Hz, 1H), 5.92 (s, 1H), 3.57-3.65
(m, 1H), 3.28 (s, 1H), 3.00-3.08 (m, 1H), 2.87-2.97 (m, 2H),
2.75-2.84 (m, 2H), 2.36-2.44 (m, 1H), 2.16 (td, J=13.8, 7.2 Hz,
1H), 1.18-1.25 (m, 3H).
EXAMPLE 47
2-(1-cyclopropylmethylpyrrolidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0305] The title compound was prepared as described in EXAMPLE 23,
substituting EXAMPLE 43B for EXAMPLE 19. The crude product was
purified by flash chromatography on silica gel with 0-10%
methanol/dichloromethane/0.1% ammonium hydroxide. .sup.1H NMR
(CD.sub.3OD) .delta. 8.21 (dd, J=8.0, 1.5 Hz, 1H), 8.10 (d, J=8.3
Hz, 1H), 7.82-7.87 (m, 1H), 7.45 (t, J=7.7 Hz, 1H), 5.92 (s, 1H),
3.54-3.62 (m, 1H), 3.28 (d, J=8.3 Hz, 2H), 3.01 (ddd, J=9.74 7.8,
6.1 Hz, 1H), 2.78-2.85 (m, 3H), 2.33-2.40 (m, 1H), 2.08-2.17 (m,
1H), 0.92-1.02 (m, 1H), 0.53-0.60 (m, 2H), 0.17-0.24 (m, 2H).
EXAMPLE 48
2-piperidin-2-yl-4H-pyrazolo[1,5-a]quinazolin-S -one
EXAMPLE 48A
benzyl 2-(2-cyanoacetyl)piperidine-1-carboxylate
[0306] The title compound was prepared as described in EXAMPLE 43A,
substituting benzyl-2-carbomethoxypiperidin-1-carboxylate for
benzyl 3-carbomethoxypyrrolidine-1-carboxylate.
EXAMPLE 48B
2-piperidin-2-yl-4H-pyrazolo[1,5-a]quinazolin-5-one
[0307] The title compound was prepared as described in EXAMPLE 1,
substituting EXAMPLE 48A for 3-oxo-2-phenylpropionitrile. .sup.1H
NMR (CD.sub.3OD) .delta. 8.18-8.27 (m, 2H), 7.87-7.92 (m, 1H),
7.50-7.56 (m, 1H), 6.07 (s, 1H), 4.46 (dd, J=1.8, 3.2 Hz, 1H), 3.49
(s, 2H), 3.19 (td, J=12.6, 3.1 Hz, 1H), 2.29-2.37 (m, 1H),
1.94-2.04 (m, 3H), 1.75-1.85 (m, 2H).
EXAMPLE 49
2-(1-methylpiperidin-2-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one
[0308] The title compound was prepared as described in EXAMPLE 20,
substituting EXAMPLE 48B for EXAMPLE 19. The crude product was
purified by flash chromatography on silica gel with 0-10%
methanol/dichloromethane/0.1% ammonium hydroxide. .sup.1H NMR
(CD.sub.3OD) .delta. 8.24 (dd J=7.9, 1.2 Hz, 1H), 8.15 (d, J=8.2
Hz, 1H), 7.85-7.90 (m, 1H), 7.50 (t, J=7.6 Hz, 1H), 6.05 (s, 1H),
3.55-3.63 (m, 1H), 3.49 (q, J=7.0 Hz, 1H), 3.24-3.30(m, 1H), 2.60
(td, J=12.0, 3.5 Hz, 1H), 2.4 (s, 3H), 1.90-1.94 (m, 2H), 1.82-1.89
(m, 2H), 1.52-1.62 (m, 1H), 1.18 (t, J=7.0 Hz, 1H).
EXAMPLE 50
(S)-2-acetylamino-4-methyl-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-
-ylmethyl)pentanamide
EXAMPLE 50A
3-aminomethyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[0309] A suspension of 1.5 g of
3-cyano-4H-pyrazolo[1,5-a]quinazolin-5-one in 150 mL of 20% ammonia
in methanol was shaken with 15 g of aqueous Raney nickel at ambient
temperature under 60 psi of hydrogen for 70 minutes. The suspension
was diluted with 150 mL of methanol and warmed to dissolve the
precipitated product. Filtration through a nylon membrane and
concentration of the filtrate yielded the title compound. MS(ESI)
m/z 198 (M+H-NH3).sup.+.
EXAMPLE 50B
(S)-2-acetylamino-4-methyl-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-
-ylmethyl)pentanamide
[0310] To a microwave vial containing 125 mg of
polystyrene-1,3-dicyclohexylcarbodiimide resin (Argonaut
Technologies, 1.2 mmol/g) was added N-acetyl-L-leucine (10.4 mg,
0.06 mmol) in N,N'-dimethylacetamide (0.3 mL). A solution of
1-hydroxybenzotriazole (6.8 mg, 0.05 mmol) in
N,N'-dimethylacetamide (0.7 mL) was added, followed by the addition
of diisopropylethylamine (27.7 .mu.L, 0.15 mmol) in
N,N'-dimethylacetamide (0.7 mL), and EXAMPLE 50A (11.2 mg, 0.05
mmol) in N,N'-dimethylacetamide (1 mL). The mixture was heated in a
microwave at 130.degree. C. for 10 minutes, MP-carbonate
(macroporous polystyrene anion-exchange resin, Argonaut
Technologies) was added and the mixture shaken overnight. The
mixture was filtered, concentrated and the residue dissolved in 1:1
dimethylsulfoxide/methanol and purified by HPLC on a C18 column
with 0-100% acetonitrile/water/0.1% trifluoroacetic acid to give
the title compound. .sup.1H NMR (DMSO-d.sub.6) .delta. 0.80 (d,
3H), 0.87 (d, 3H), 1.43 (t, 2H), 1.49-1.60 (m, 1H), 1.83-1.88 (m,
3H), 4.17-4.21 (m, 2H), 4.24 (t, 1H), 7.51 (t, 1H), 7.65-7.73 (m,
1H), 7.91 (t, 1H), 8.07 (d, 1H).
EXAMPLE 51
(R)-2-methoxy-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)-2--
phenylacetamide
[0311] The title compound was prepared as described in EXAMPLE 50
using (R)-(-)-.alpha.-methoxyplienylacetic acid in place of
N-acetyl-L-leucine. .sup.1H NMR (DMSO-d.sub.6) .delta. 3.24-3.32
(m, 3H), 4.21-4.25 (m, 2H), 4.61-4.70 (m, 1H), 7.27-7.39 (m, 5H),
7.51 (t, 1H), 7.62-7.67 (m, 1H), 7.90 (t, 1H), 8.06 (d, 1H), 8.16
(d, 1H).
EXAMPLE 52
N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)isonicotinamide
[0312] The title compound was prepared as the trifluoroacetate salt
as described in EXAMPLE 50 using pyridine-4-carboxylic acid in
place of N-acetyl-L-leucine. .sup.1H NMR (DMSO-d.sub.6) .delta.
4.46-4.48 (m, 2H), 7.55 (t, 1H), 7.73-7.76 (m, 1H), 7.76-7.79 (m,
2H), 7.82-7.84 (m, 1H), 7.93 (t, 1H), 8.10 (d, 1H), 8.19 (d, 1H),
8.68-8.71 (m, 1H), 8.71-8.75 (m, 2H).
EXAMPLE 53
N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)-3-piperidin-1-yl-
-propionamide
[0313] The title compound was prepared as the trifluoroacetate salt
as described in EXAMPLE 50 using 3-piperidinopropionic acid in
place of N-acetyl-L-leucine. .sup.1H NMR (DMSO-d.sub.6) .delta.
0.99-1.97 (m, 6H), 2.60-2.63 (m, 1H), 2.67 (t, 1H), 2.80-3.03 (m,
2H), 3.30 (t, 2H), 3.34-3.53 (m, 2H), 4.20-4.33 (m, 2H), 7.51-7.66
(m, 1H), 7.79-7.84 (m, 1H), 7.89-8.03 (m, 1H), 8.12 (d, 1H), 8.22
(d, 1H).
EXAMPLE 54
N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)-3-pyrrolidin-1-y-
l-propionamide
[0314] The title compound was prepared as the trifluoroacetate salt
as described in EXAMPLE 50 using 3-pyrrolidinopropionic acid in
place of N-acetyl-L-leucine. .sup.1H NMR (DMSO-d.sub.6) .delta.
1.77-1.95 (m, 2H), 1.99-2.11 (m, 2H), 2.58-2.60 (m, 1H), 2.63 (t,
1H), 2.95-3.06 (m, 2H), 3.36 (t, 2H), 3.46-3.59 (m, 2H), 4.24-4.31
(m, 2H), 7.47-7.63 (m, 1H), 7.77-7.82 (m, 1H), 7.90-7.98 (m, 1H),
8.05-8.15 (m, 1H), 8.15-8.23 (m, 1H).
EXAMPLE 55
2-morpholin-4-yl-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)-
acetamide
[0315] The title compound was prepared as the trifluoroacetate salt
as described in EXAMPLE 50 using morpholin-4-yl-acetic acid in
place of N-acetyl-L-leucine. .sup.1H NMR (DMSO-d.sub.6) .delta.
2.97-3.34 (m, 4H), 3.65-3.95 (m, 6H), 4.26-4.38 (m, 2H), 7.53 (t,
1H), 7.75-7.83 (m, 1H), 7.92 (t, 1H), 8.08 (d, 1H), 8.20 (d,
1H).
EXAMPLE 56
3-morpholin-4-yl-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)-
-propionamide
[0316] The title compound was prepared as the trifluoroacetate salt
as described in EXAMPLE 50 using 3-morpholinopropionic acid in
place of N-acetyl-L-leucine. .sup.1H NMR (DMSO-d.sub.6) .delta.
2.58-2.60 (m, 1H), 2.64 (t, 2H), 2.78-3.96 (m, 9H), 4.23-4.31 (m,
2H), 7.54 (t, 1H), 7.74-7.82 (m, 1H), 7.93 (t, 1H), 8.08 (d, 1H),
8.18 (d, 1H).
EXAMPLE 57
2-phenethyl-4H-pyrazolo[1,5-a]quinazolin-5-one
EXAMPLE 57A
3-oxo 5-phenyl-pentanenitrile
[0317] A solution of cyanoacetic acid (1.0 g, 11.8 mmol) in
tetrahydrofuran (20 mL) was cooled to -78.degree. C. and treated
with 1.6 M n-butyl lithium in hexanes (14.7 mL, 23.5 mmol). The
mixture was warmed to -20.degree. C. over 2 hours, cooled to
-78.degree. C. and treated with 3-phenylpropionyl chloride
(prepared by refluxing a solution of 3-phenylpropionic acid (1.0 g,
6.7 mmol) in thionyl chloride (4 mL) for 3 hours, evaporating and
drying). The mixture was stirred at -78.degree. C. for 1 hour and
20% hydrochloric acid added until the pH=3. The mixture was diluted
with diethyl ether, washed with saturated sodium bicarbonate, and
the organic layer separated and concentrated. The crude product was
purified by flash chromatography on silica gel using 0-50% ethyl
acetate/hexanes to provide the title compound. MS (ESI) m/e 191
(M+H+NH.sub.3).
EXAMPLE 57B
2-phenethyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[0318] A mixture of 2-hydrazinobenzoic acid (0.17 g, 0.9 mmol) and
EXAMPLE 57A (0.155 g, 0.9 mmol) in acetic acid (3 mL) was heated in
a microwave at 150.degree. C. for 10 minutes. The precipitated
product was washed with methanol and diethyl ether and dried.
.sup.1H NMR (DMSO-d.sub.6) .delta. 12.10 (s, 1H), 8.09-8.14 (m,
1H), 8.02 (d, J=7.9 Hz, 1H), 7.82-7.88 (m, 1H), 7.44 (t, J=7.6 Hz,
1H), 7.26-7.32 (m, 4H), 7.16-7.22 (m, 1H), 5.78 (s, 1H), 2.92-3.01
(m, 4H).
EXAMPLE 58
2-benzyl-4H-pyrazolo[1,5-a]quinazolin-5-one
EXAMPLE 58A
3-oxo-4-phenyl-butyronitrile
[0319] The title compound was prepared as described in EXAMPLE 57A,
substituting phenylacetyl chloride for 3-phenylpropionyl chloride.
MS (ESI) m/e 177 (M+H+NH.sub.3).sup.+.
EXAMPLE 58B
2-benzyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[0320] The title compound was prepared as described in EXAMPLE 57B,
substituting EXAMPLE 58A for EXAMPLE 57A. The crude product was
purified by flash chromatography on silica gel with 50% ethyl
acetate/hexanes. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.11 (dd,
J=7.9, 1.2 Hz, 1H), 8.04 (d, J=8.2 Hz, 1H), 7.82-7.89 (m, 1H),
7.42-7.49 (m, 1H), 7.29-7.33 (m, 4H), 7.22 (td, J=5.6, 2.8 Hz, 1H),
5.67 (s, 1H), 3.99 (s, 2H).
EXAMPLE 59
2-piperidin-4-ylmethyl-4H-pyrazolo[1,5-a]quinazolin-5-one
EXAMPLE 59A
tert-butyl 4-(3-cyano-2-oxopropyl)piperidine-1-carboxylate
[0321] A solution of tert-butyl
4-carboxymethylpiperidine-1-carboxylate (1 g, 4.1 mmol) in
tetrahydrofuran (5 mL) was treated with 1,1'-carbonyldiimidazole
(0.67 g, 4.1 mmol). The mixture was heated at 55.degree. C. for 2
hours, cooled and submitted to the conditions described in EXAMPLE
57A, substituting the solution obtained above for 3-phenylpropionyl
chloride. MS (ESI) m/e 284 (M+H+NH.sub.3).sup.+.
EXAMPLE 59B
2-piperidin-4-ylmethyl-4H-pyrazolo[1,5-a]quinazolin-5-one
[0322] The title compound was prepared as described in EXAMPLE 57B,
substituting EXAMPLE 59A for EXAMPLE 57A. The crude product was
purified by flash chromatography on silica gel with 10%
methanol/dichloromethane/0.1% ammonium hydroxide. .sup.1H NMR
(DMSO-d.sub.6) .delta. 8.11 (dd, J=7.9, 1.2 Hz, 1H), 8.00 (d, J=7.9
Hz, 1H), 7.78-7.85 (m, 1H), 7.43 (t, J=7.5 Hz, 1H), 5.72 (s, 1H),
3.35-3.39 (m, 1H), 3.17 (s, 1H), 2.91 (d, J=11.9 Hz, 2H), 2.40-2.49
(m, 3H), 1.65-1.74 (m, 1H), 1.60 (d, J=11.9 Hz, 2H), 1.05-1.14 (m,
2H).
EXAMPLE 60
2-(1-methylpiperidin-4-ylmethyl)-4H-pyrazolo[1,5-a]quinazolin-5-one
A solution of
[0323] EXAMPLE 59 (0.034 g, 0.1 mmol) and 36% formaldehyde in water
(0.05 mL, 0.6 mmol) in methanol (2 mL) was treated with sodium
cyanoborohydride (0.006 g, 0.1 mmol) and acetic acid (0.2 mL). The
mixture was stirred at ambient temperature for 2 hours and
concentrated. The crude product was purified by flash
chromatography on silica gel with 10% methanol/dichloromethane to
provide the title compound. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.11
(d, J=7.7 Hz, 1H), 8.01 (d, J=8.3 Hz, 1H), 7.81-7.86 (m, 1H), 7.44
(t, J=7.7 Hz, 1H), 5.74 (s, 1H), 2.72 (d, J=l 1.4 Hz, 2H), 2.54 (d,
J=6.8 Hz, 2H) 2.13 (s, 3H), 1.82 (s, 2H), 1.54-1.66 (m, 3H),
1.18-1.29 (m, 2H).
EXAMPLE 61
2-(3-Bromobenzyl) pyrazolo[1,5-a]quinazolin-5(4H)-one
EXAMPLE 61A
4-(3-Bromophenyl)-3-oxobutanenitrile
[0324] The title compound was prepared as described in EXAMPLE 32A,
substituting 2-(3-bromophenyl)acetyl) chloride-for
cyclopropanecarbonyl chloride.
EXAMPLE 61B
2-(3-Bromobenzyl) pyrazolo[1,5-a]quinazolin-5(4H)-one
[0325] The title compound was prepared as described in EXAMPLE 1,
substituting Example 61A for 3-oxo-2-phenylpropionitrile and using
3 mL of acetic acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 4.01 (s, 2H) 5.73 (s, 1H) 7.26-7.35 (m, 2H) 7.41-7.48 (m, 2H),
7.52-7.55 (m, 1H) 7.86 (dd, J=8.29, 7.06 Hz, 1H) 8.03 (d, J=7.67
Hz, 1H) 8.12 (dd, J=7.98, 1.53 Hz, 1H) 12.09 (s, 1H).
EXAMPLE 62
3-[(5-Oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]benzonitrile
[0326] A mixture of Example 61B (0.075 g, 0.212 mmol), dicyanozinc
(0.03 g, 0.254 mmol) and tetrakis(triphenylphosphine)palladium(0)
(0.024 g, 0.021 mmol) in DMF (2 mL) was heated in a microwave
(Personal Chemistry SmithSynthesizer) at 150.degree. C. for 10
minutes. The mixture was evaporated and purified by chromatography
on silica gel with 10% MeOH/CH.sub.2Cl.sub.2 to provide the desired
product. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 4.08 (s,
2H) 5.76 (s, 1H) 7.46 (t, J=7.63 Hz, 1H) 7.53 (t, J=7.63 Hz, 1H)
7.69 (dd, J=12.36, 7.78 Hz, 2H) 7.79-7.88 (m, 2H) 8.02 (d, J=7.93
Hz, 1H) 8.12 (d, J=7.93 Hz, 1H) 12.12 (s, 1H).
EXAMPLE 63
2-[3-(Aminomethyl)benzyl]pyrazolo[1,5-a]quinazolin-5(4H)-one
[0327] A mixture of Example 62 (0.32 g, 1.066 mmol) and 3 g
raney-nickel in methanol ammonia (30 mL) was stirred under a
hydrogen atmosphere at 60 psi for 3.5 hr. The mixture was filtered
then evaporated and purified by chromatography on silica gel with
10% MeOH/CH.sub.2Cl.sub.2 to provide the desired product. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 3.17 (s, 1H) 3.71 (s, 2H)
3.97 (s, 2H) 5.66 (s, 1H) 7.14-7.20 (m, 2H) 7.22-7.29 (m, 2H)
7.42-7.47 (m, 1H) 7.82-7.87 (m, 1H) 8.03 (d, J=8.29 Hz, 1H) 8.11
(dd, J=7.98, 1.53 Hz, 1H).
EXAMPLE 64
2-(3-Pyridin-3-ylbenzyl)pyrazolo[1,5-a]quinazolin-5(4H)-one
[0328] A mixture of Example 61B (0.05 g, 0.141 mmol),
pyridine-3-ylboronic acid (0.018 g, 0.148 mmol) cesium fluoride
(0.064 g, 0.423 mmol) and tetrakis(triphenylphosphine)palladium(0)
(0.1 g, 0.014 mmol) in DME (2 mL) was heated in a microwave
(Personal Chemistry SmithSynthesizer) at 150.degree. C. for 10
minutes. The mixture was filtered evaporated. The residue was
purified by HPLC on a C18 column with 0-100%
CH.sub.3CN/H.sub.2O/0.1% TFA to provide the desired product.
.sup.1H NMR (400 MIz, DMSO-d.sub.6) .delta. ppm 4.10 (s, 2H) 5.75
(s, 1H) 7.41-7.51 (m, 3H) 7.63-7.73 (m, 2H) 7.76 (s, 1H), 7.83-7.88
(m, 1H) 8.04 (d, J=7.67 Hz, 1H) 8.12 (dd, J=8.13, 1.38Hz, 1H) 8.35
(dt, J=7.98, 1.84 Hz, 1H) 8.68 (dd, J=5.06, 1.38 Hz, 1H) 9.01 (d,
J=2.15 Hz, 1H) 12.08 (s, 1H).
EXAMPLE 65
2-[3-(2-Oxopyrrolidin-1-yl)benzyl]pyrazolo[1,5-a]quinazolin-5(4H)-one
[0329] A mixture of Example 61B (0.1 g, 0.282 mmol),
pyrrolidin-2-one (0.048 g, 0.565 mmol) cesium carbonate (0.130 g,
0.395 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.026 g,
0.028 mmol) and
(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.025 g,
0.043 mmol) in DME (2 mL) was heated in a microwave (Personal
Chemistry SmithSynthesizer) at 200.degree. C. for 60 minutes. The
mixture was filtered evaporated. The residue was purified by
chromatography on silica gel with 20% to 80% ethyl acetate in
hexane to provide the desired product. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 2.01-2.08 (m, 2H) 2.47 (t, J=8.09 Hz, 2H)
3.81 (t, J=7.02 Hz, 2H) 3.99 (s, 2H) 5.67 (s, 1H), 7.08 (d, J=7.63
Hz, 1H) 7.30 (t, J=7.78 Hz, 1H) 7.43-7.50 (m, 2H) 7.66 (s, 1H)
7.80-7.88 (m, 1H) 8.04 (d, J=8.24 Hz, 1H) 8.12 (d, J=7.93 Hz,
1H).
EXAMPLE 66
3'-[(5-Oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]-1,1'-biphenyl-
-2-carbaldehyde
[0330] The title compound was prepared as described in EXAMPLE 64,
substituting 2-(formylphenyl)boronic acid-for pyridine-3-ylboronic
acid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 4.09 (s, 2H)
5.75 (s, 1H) 7.32 (d, J=7.02 Hz, 1H) 7.40-7.49 (m, 4H), 7.52 (d,
J=7.63 Hz, 1H) 7.56-7.61 (m, 1H) 7.75 (d, J=1.22 Hz, 1H) 7.85 (s,
1H) 7.88-7.95 (m, 1H) 8.04 (d, J=8.24 Hz, 1H) 8.11 (dd, J=7.93,
1.53 Hz, 1H) 9.90 (s, 1H).
EXAMPLE 67 (A-998677.0)
2-[3-(2-Fluoropyridin-4-yl)benzyl]pyrazolo[1,5-a]quinazolin-5(4H)-one
[0331] A mixture of Example 61B (0.1 g, 0.282 mmol),
2-fluoro-4-(tributylstannyl)pyridine (0.11 g, 0.285 mmol)
triethylamine (0.11 g, 1.1 mmol),
tris(dibenzylideneacetone)dipalladium(0) (0.039 g, 0.01 mmol) and
tri-o-tolylphosphine (0.007 g, 0.023 mmol) in DMF (2 mL) was heated
at 100.degree. C. for 6 hr. The mixture was diluted with EtOAc and
washed with sat NaHCO.sub.3, H.sub.2O and brine, then evaporated.
The residue was purified by chromatography on silica gel with 20%
to 80% ethylacetate in hexane to provide the desired product.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 4.10 (s, 2H) 5.75
(s, 1H) 7.44-7.53 (m, 4H) 7.68-7.74 (m, 2H) 7.83-7.88 (m, 2H) 8.04
(d, J=8.24 Hz, 1H) 8.11 (d, J=6.71 Hz, 1H) 8.30 (d, J=5.49 Hz,
1H).
EXAMPLE 68
Methyl
3-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]benzoate
[0332] A mixture of Example 61B (0.25 g, 0.706 mmol) triethylamine
(0.2 ml, 1.542 mmol) and
dichlorobis(diphenylphosphino)dipalladium(II)dichloromethane (0.03
g, 0.041 mmol) in methanol (10 mL) under carbon monoxide at 50psi
was heated at 100.degree. C. for 3 hr. The mixture was filtered
then evaporated and purified by chromatography on silica gel with
10% MeOH/CH.sub.2Cl.sub.2 to provide the desired product. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 3.81-3.86 (m, 3H) 4.09 (s,
2H) 5.71 (s, 1H) 7.44-7.50 (m, 2H) 7.62 (d, J=7.63 Hz, 1H)
7.81-7.88 (m, 2H) 7.91 (s, 1H) 8.03 (d, J=7.63 Hz, 1H) 8.12 (dd,
J=7.93, 1.22 Hz, 1H).
EXAMPLE 69
3-[(4-Methylpiperazin-1-yl)carbonyl]pyrazolo[1,5-a]quinazolin-5(4H)-one
EXAMPLE 69A
5-Oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxylic acid
[0333] A mixture of 2-hydrazinylbenzoic acid hydrochloride (1.05 g,
5.57 mmol), (E)-ethyl 2-cyano-3-ethoxyacrylate (0.9 g, 5.32 mmol)
and sodium acetate (0.457 g, 5.57 mmol) in DMF (7 mL) was heated to
140.degree. C. for 2 h then cooled. Water (5 mL) was added and the
mixture was stirred at rt for 1 h then filtered. The solid was
washed with H.sub.2O, EtOH and Et.sub.2O then dried. The solid was
dissolved in EtOH (10 mL), treated with a 1M solution of sodium
hydroxide (23 mL, 23 mmol) and the mixture was heated at 80.degree.
C. for 18 hr. The mixture was filtered hot then cooled and
acidified with acetic acid and 10% HCl. The precipitated product
was filtered, washed with H.sub.2O and Et.sub.2O, dried well and
used without any further purification.
EXAMPLE 69B
3-[(4-Methylpiperazin-1-yl)carbonyl]pyrazolo[1,5-a]quinazolin-5(4H)-one
[0334] A mixture Example 69A (0.1 g, 0.44 mmol), 1-methyl
piperazine (0.045 g, 0.45 mmol) and CDI (0.075 g, 0.53 mmol) in DMF
(1 mL) and pyridine (1 mL) was stirred overnight at ambient
temperature. The mixture was evaporated and purified by
chromatography on silica gel with 10% MeOH/CH.sub.2Cl.sub.2 to
provide the desired product. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 2.38 (s, 3H) 2.58 (s, 4H) 3.65-3.70 (m, 4H) 7.15 (s,
1H) 7.56 (t, J=7.48 Hz, 1H) 7.88-7.96 (m, 1H) 8.07 (s, 1H) 8.12 (d,
J=8.24 Hz, 1H) 8.18 (d, J=7.02 Hz, 1H).
EXAMPLE 70
3-(Pyrrolidine-1-carbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one
[0335] The title compound was prepared as described in Example 69B,
substituting pyrrolidine for 1-methyl piperazine in Example 69 B.
The mixture was evaporated and purified by chromatography on silica
gel with 10% MeOH/CH.sub.2Cl.sub.2 to provide the desired product.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 1.85 (s, 2H) 1.99
(s, 2H) 3.50 (s, 2H) 3.75 (s, 2H) 7.59 (s, 1H) 7.96 (s, 1H) 8.14
(d, J=8.24 Hz, 1H) 8.20 (d, J=7.93 Hz, 1H), 8.25 (s, 1H).
EXAMPLE 71
N,N-Dimethyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide
[0336] The title compound was prepared as described in Example 69B,
substituting dimethylamine for 1-methyl piperazine in Example 69B.
The mixture was evaporated and purified by chromatography on silica
gel with 10% MeOH/CH.sub.2Cl.sub.2 to provide the desired product.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 3.32 (s, 6H) 7.57
(t, J=7.48 Hz, 1H) 7.92-7.97 (m, 1H) 8.12-8.20 (m, 3H) 11.32 (s,
1H).
EXAMPLE 72
3-(Piperidine-1-carbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one
[0337] The title compound was prepared as described in Example 69B,
substituting piperidine for 1-methyl piperazine in Example 69B. The
mixture was evaporated and purified by chromatography on silica gel
with 10% MeOH/CH.sub.2Cl.sub.2 to provide the desired product.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 1.51-1.57 (m, 4H)
1.60-1.67 (m, 2H) 3.56-3.61 (m, 4H) 7.56 (t, J=7.63 Hz, 1H)
7.90-7.95 (m, 1H) 8.04 (s, 1H) 8.12 (d, J=7.93 Hz, 1H), 8.15-8.20
(m, 1H) 11.58 (s, 1H).
EXAMPLE 73
N-Cyclopropyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide
[0338] The title compound was prepared as described in Example 69B,
substituting cyclopropylamine for 1-methyl piperazine in Example 69
B. The mixture was evaporated and purified by chromatography on
silica gel with 10% MeOH/CH.sub.2Cl.sub.2 to provide the desired
product. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.56 (ddd,
J=6.67, 4.45, 4.22 Hz, 2H) 0.72 (td, J=6.98, 5.06 Hz, 2H) 2.82
(ddd, J=7.44, 3.61, 3.38 Hz, 1H) 7.53-7.59 (m, 1H) 7.89-7.97 (m,
1H) 8.10 (d, J=7.98 Hz, 1H) 8.19 (dd, J=7.98, 1.23 Hz, 1H) 8.26 (s,
1H), 8.34 (d, J=3.38 Hz, 1H) 10.69 (s, 1H).
EXAMPLE 74
5-Oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide
[0339] The title compound was prepared as described in Example 69B,
substituting ammonia for 1-methyl piperazine in Example 69B. The
mixture was evaporated and purified by chromatography on silica gel
with 10% MeOH/CH.sub.2Cl.sub.2 to provide the desired product.
.sup.1H H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.32 (s, 1H)
7.54-7.63 (m, 1H) 7.84 (s, 1H) 7.90-7.97 (m, 1H) 8.11 (d, J=8.29
Hz, 1H) 8.19 (dd, J=7.98, 1.23 Hz, 1H) 8.29 (s, 1H) 10.62 (s,
1H)
EXAMPLE 75
N-Methyl-5-Oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide
[0340] The title compound was prepared as described in Example 69B,
substituting methanamine for 1-methyl piperazine in Example 69B.
The mixture was evaporated and purified by chromatography on silica
gel with 10% MeOH/CH.sub.2Cl.sub.2 to provide the desired product.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 2.78 (d, J=4.58 Hz,
3H) 7.57 (t, J=7.63 Hz, 1H) 7.91-7.96 (m, 1H) 8.10 (d, J=8.24 Hz,
1H) 8.18 (d, J=7.63 Hz, 1H) 8.26 (s, 1H), 8.31 (d, J=4.58 Hz, 1H)
10.70 (s, 1H).
EXAMPLE 76
N-Ethyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide
[0341] The title compound was prepared as described in Example 69B,
substituting ethanamine for 1-methyl piperazine in Example 69B. The
residue was purified by HPLC on a C18 column with 0-100%
CH.sub.3CN/H.sub.2O/0.1% TFA to provide the desired product as the
trifluoroacetate salt. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
ppm 1.14 (t, J=7.17 Hz, 3H) 3.23-3.30 (m, 2H) 7.54-7.60 (m, 1H)
7.91-7.97 (m, 1H) 8.09-8.14 (m, 2H) 8.19 (dd, J=7.48, 2.59 Hz, 1H)
8.29-8.36 (m, 1H).
EXAMPLE 77
N-Benzyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide
[0342] The title compound was prepared as described in Example 69B,
substituting phenylmethanamine for 1-methyl piperazine in Example
69B. The residue was purified by HPLC on a C18 column with 0-100%
CH.sub.3CN/H.sub.2O/0.1% TFA to provide the desired product as the
trifluoroacetate salt. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
ppm 4.49 (d, J=5.80 Hz, 2H) 7.23-7.31 (m, 1H) 7.35 (d, J=4.27 Hz,
4H) 7.57 (t, J=7.17 Hz, 1H) 7.91-7.97 (m, 1H), 8.11 (d, J=7.63 Hz,
1H) 8.19 (dd, J=7.93, 1.22 Hz, 1H) 8.36 (s, 1H) 8.90 (t, J=5.95 Hz,
1H) 10.74 (s, 1H).
EXAMPLE 78
5-Oxo-N-(2-phenylethyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamid-
e
[0343] The title compound was prepared as described in Example 69B,
substituting phenethylamine for 1-methyl piperazine in Example 69B.
The residue was purified by HPLC on a C18 column with 0-100%
CH.sub.3CN/H.sub.2O/0.1% TFA to provide the desired product as the
trifluoroacetate salt. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
ppm 2.82-2.89 (m, 2H) 3.45-3.51 (m, 2H) 7.21 (t, J=7.17 Hz, 1H)
7.25-7.33 (m, 4H) 7.57 (t, J=7.63 Hz, 1H) 7.91-7.97 (m, 1H) 8.10
(d, J=7.93 Hz, 1H) 8.18 (dd, J=7.93, 1.22 Hz, 1H) 8.30 (s, 1H) 8.48
(t, J=5.49 Hz, 1H).
EXAMPLE 79
3-(Azepane-1-carbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one
[0344] The title compound was prepared as described in Example 69B,
substituting azepane for 1-methyl piperazine in Example 69 B. The
mixture was evaporated and purified by chromatography on silica gel
with 10% MeOH/CH.sub.2Cl.sub.2 to provide the desired product.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 1.51-1.57 (m, 4H)
1.75 (s, 4H) 3.57 (s, 2H) 3.70 (s, 2H) 7.57 (t, J=7.63 Hz, 1H)
7.92-7.97 (m, 1H) 8.09-8.15 (m, 2H) 8.18-8.20 (m, 1H) 11.29 (s,
1H).
EXAMPLE 80
3-(Morpholine-4-carbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one
[0345] The title compound was prepared as described in Example 69B,
substituting morpholine for 1-methyl piperazine in Example 69B. The
mixture was evaporated and purified by chromatography on silica gel
with 10% MeOH/CH.sub.2Cl.sub.2 to provide the desired product.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 3.34 (s, 8H)
7.54-7.58 (m, 1H) 7.91-7.95 (m, 1H) 8.08-8.13 (m, 2H) 8.16-8.19 (m,
1H).
EXAMPLE 81
3-(Piperazin-1-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one
[0346] The title compound was prepared as described in Example 69B,
substituting tert-butyl piperazine-1-carboxylate for 1-methyl
piperazine in Example 69 B. The reaction mix was evaporated then
treated with 1 mL CH.sub.2Cl.sub.2 and 1 mL of TFA and stirred for
1 hr then evaporated. The mixture was evaporated and purified by
chromatography on silica gel with 10% MeOH/CH.sub.2Cl.sub.2/0.1%
NH.sub.4OH to provide the desired product. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 2.84-2.90 (m, 4H) 3.60-3.66 (m, 4H) 7.54
(t, J=7.48 Hz, 1H) 7.89-7.94 (m, 1H) 8.05 (s, 1H) 8.11 (d, J=8.24
Hz, 1H) 8.17 (d, J=7.93 Hz, 1H)
EXAMPLE 82
N-Cyclohexyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide
[0347] The title compound was prepared as described in Example 69B,
substituting cyclohexylamine for 1-methyl piperazine in Example 69
B. The mixture was evaporated and purified by chromatography on
silica gel with 10% MeOH/CH.sub.2Cl.sub.2 to provide the desired
product. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 1.11-1.19
(m, 1H) 1.25-1.34 (m, 4H) 1.62 (d, J=12.82 Hz, 1H) 1.71-1.78 (m,
2H) 1.85 (d, J=8.85 Hz, 2H) 3.77 (dd, J=7.48, 3.81 Hz, 1H) 7.56 (t,
J=7.63 Hz, 1H) 7.91-7.96 (m, 1H) 8.11 (t, J=8.24 Hz, 2H) 8.18 (d,
J=7.93 Hz, 1H).
EXAMPLE 83
3-(1H-Imidazol-1-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one
[0348] The title compound was prepared as described in Example 69B,
substituting pyridin-4-amine for 1-methyl piperazine in Example 69
B. The mixture was evaporated and purified by chromatography on
silica gel with 10% MeOH/CH.sub.2Cl.sub.2 to provide the desired
product. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 7.18 (s,
1H) 7.63 (t, J=7.63 Hz, 1H) 7.85 (s, 1H) 7.96-8.02 (m, 1H) 8.20
(dd, J=19.68, 7.48 Hz, 2H) 8.45-8.50 (m, 2H).
EXAMPLE 84
5-Oxo-N-(piperidin-4-ylmethyl-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carb-
oxamide
[0349] The title compound was prepared as described in Example 69,
substituting tert-butyl 4-(aminomethyl)piperidine-1-carboxylate for
1-methyl piperazine in Example 69 B. The reaction mix was
evaporated then treated with 1 mL CH.sub.2Cl.sub.2 and 1 mL of TFA
and stirred for 1 hr then evaporated. The residue was purified by
HPLC on a C18 column with 0-100% CH.sub.3CN/H.sub.2O/0.1% TFA to
provide the desired product as the trifluoroacetate salt. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 1.34 (d, J=12.21 Hz, 2H)
1.82 (s, 3H) 2.87 (s, 2H) 3.16-3.21 (m, 3H) 7.58 (t, J=7.63 Hz, 1H)
7.93-7.97 (m, 1H) 8.11 (d, J=7.63 Hz, 1H) 8.19 (dd, J=7.93, 1.22
Hz, 1H) 8.45 (t, J=5.80 Hz, 2H).
EXAMPLE 85
3-(3-(Aminomethyl)piperidine-1-carbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-on-
e
[0350] The title compound was prepared as described in Example 69B,
substituting tert-butyl piperidin-3-ylmethylcarbamate for 1-methyl
piperazine in Example 69 B. The reaction mix was evaporated then
treated with 1 mL CH.sub.2Cl.sub.2 and 1 mL of TFA and stirred for
1 hr then evaporated. The residue was purified by HPLC on a C18
column with 0-100% CH.sub.3CN/H.sub.2O/0.1% TFA to provide the
desired product as the trifluoroacetate salt. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.26-1.36 (m, 1H) 1.39-1.50 (m, 1H)
1.66-1.75 (m, 1H) 1.80-1.91 (m, 2H) 2.78 (qd, J=12.79, 7.06 Hz, 2H)
2.93 (s, 1H) 3.38-3.41 (m, 1H) 4.14 (s, 2H) 7.53-7.62 (m, 1H)
7.91-7.97 (m, 1H) 8.06 (s, 1H) 8.10-8.21 (m, 2H).
EXAMPLE 86
5-Oxo-N-phenyl-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide
[0351] The title compound was prepared as described in Example 69B,
substituting aniline for 1-methyl piperazine in Example 69 B. The
mixture was evaporated and purified by chromatography on silica gel
with 10% MeOR/CH.sub.2Cl.sub.2 to provide the desired product.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.11 (t, J=7.36 Hz,
1H) 7.37 (t, J=7.98 Hz, 2H) 7.59 (t, J=7.67 Hz, 1H) 7.73 (d, J=7.67
Hz, 2H) 7.93-7.99 (m, 1H) 8.13-8.23 (m, 2H) 8.53 (s, 1H) 10.05 (s,
1H) 10.93 (s, 1H).
EXAMPLE 87
4-{[(5-Oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)carbonyl]amino}butano-
ic acid
[0352] The title compound was prepared as described in Example 69B,
substituting 4-aminobutanoic acid for 1-methyl piperazine in
Example 69 B. The mixture was evaporated and purified by
chromatography on silica gel with 10% MeOH/CH.sub.2Cl.sub.2 to
provide the desired product. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.76 (dq, J=7.36, 7.16 Hz, 2H) 2.30 (t, J=7.36 Hz, 2H)
3.25-3.30 (m, 2H) 7.56 (t, J=7.67 Hz, 1H) 7.89-7.96 (m, 1H) 8.10
(d, J=7.67 Hz, 1H) 8.18 (dd, J=7.98, 1.23 Hz, 1H) 8.29 (s, 1H)
8.34-8.38 (m, 1H).
EXAMPLE 88
3-(5-Oxo-4,5-dihydro pyrazolo[1,5-a]quinazolin-2-yl)methyl)benzoic
acid
[0353] Example 68 (0.15 g, 0.45 mmol) was dissolved in EtOH (10
mL), treated with a 1M solution of sodium hydroxide (3 mL, 3 mmol)
and the mixture was heated at 80.degree. C. for 18 hr. The mixture
was filtered then acidified with acetic acid and 10% HCl. The
precipitated product was filtered, washed with H.sub.2O and
Et.sub.2O then dried well. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 4.04-4.11 (m, 2H) 5.71 (s, 1H) 7.45 (td, J=7.63, 4.58
Hz, 2H) 7.59 (d, J=8.24 Hz, 1H) 7.80 (d, J=7.63 Hz, 1H) 7.84-7.90
(m, 2H) 8.04 (d, J=8.24 Hz, 1H) 8.12 (d, J=7.02 Hz, 1H) 12.11 (s,
1H) 12.93 (s, 1H).
EXAMPLE 89
5-Oxo-N-(2-(piperidin-1-yl)ethyl)-4,
5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide
[0354] The title compound was prepared as described in Example 69B,
substituting 2-(piperidin-1-yl)ethanamine for 1-methyl piperazine
in Example 69B. The mixture was evaporated and purified by
chromatography on silica gel with 10% MeOH/CH.sub.2Cl.sub.2 to
provide the desired product. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 1.39-1.41 (m, 1H) 1.64-1.73 (m, 3H) 1.84 (d, J=14.34
Hz, 2H) 2.92-3.00 (m, 2H) 3.24 (q, J=5.80 Hz, 2H) 3.56 (d, J=11.60
Hz, 2H) 3.63 (q, J=6.10 Hz, 2H) 7.59 (t, J=7.63 Hz, 1H) 7.93-7.99
(m, 1H) 8.12 (d, J=7.93 Hz, 1H) 8.20 (dd, J=7.93, 1.22 Hz, 1H) 8.29
(s, 1H) 8.68 (t, J=5.65 Hz, 1H) 10.81 (s, 1H).
EXAMPLE 90
3-(Hydroxymethyl)pyrazolo[1,5-a]quinazolin -5-(4H)-one
EXAMPLE 90A
Methyl
-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxylate
[0355] A mixture of 2-hydrazinylbenzoic acid hydrochloride (1.05 g,
5.57 mmol), (E)-ethyl 2-cyano-3-ethoxyacrylate (0.9 g, 5.32 mmol)
and sodium acetate (0.457 g, 5.57 mmol) in DMF (7 mL) was heated to
140.degree. C. for 2 h then cooled. Water (5 mL) was added and the
mixture was stirred at ambient temperature for 1 h then filtered.
The solid was washed with H.sub.2O, EtOH and Et.sub.2O then
dried.
EXAMPLE 90B
3-(Hydroxymethyl)pyrazolo[1,5-a]quinazolin -5-(4H)-one
[0356] A mixture Example 90A (0.1 g, 0.39 mmol) and lithium
aluminum hydride (0.044 g, 1.16 mmol) in THF (5 mL) was refluxed
for 3 h then cooled and quenched with water and 15% NaOH. The
mixture was filtered, evaporated and purified by chromatography on
silica gel with 10% MeOH/CH.sub.2Cl.sub.2 to provide the desired
product. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 4.47 (s,
2H) 7.46-7.52 (m, 1H) 7.78 (s, 1H) 7.83-7.91 (m, 1H) 8.07 (d,
J=7.93 Hz, 1H) 8.14 (dd, J=7.93, 1.22 Hz, 1H) 12.15 (s, 1H).
EXAMPLE 91
3-(5-Oxo-4,5-dihydro
pyrazolo[1,5-a]quinazolin-2-yl)methyl)benzamide
[0357] A mixture Example 88 (0.15 g, 0.47 mmol), 2M solution of
NH.sub.3 in MeOH (0.5 mL, 0.1 mmol) and CDI (0.076 g, 0.54 mmol) in
DMF (1 mL) and pyridine (1 mL) was stirred overnight at ambient
temperature then evaporated. The residue was purified by HPLC on a
C18 column with 0-100% CH.sub.3CN/H.sub.2O/0.1% TFA to provide the
desired product as the trifluoroacetate salt. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 4.04 (s, 2H) 5.69 (s, 1H) 7.33 (s, 1H)
7.39 (t, J=7.63 Hz, 1H) 7.44-7.49 (m, 2H) 7.73 (d, J=7.63 Hz, 1H)
7.81-7.89 (m, 2H) 7.95 (s, 1H) 8.04 (d, J=7.93 Hz, 1H) 8.11 (dd,
J=7.93, 1.22 Hz, 1H) 12.11 (s, 1H).
EXAMPLE 92
3-(Aminomethyl)pyrazolo[1,5-a]quinazolin -5-(4H)-one
EXAMPLE 92A
Methyl
-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxylate
[0358] A mixture of 2-hydrazinylbenzoic acid hydrochloride (10 g,
53 mmol), 2-(ethoxymethylene)malononitrile (6.5 g, 53.2 mmol) and
sodium ethoxide (4.85 g, 257 mmol) in EtOH (100 mL) was refluxed
overnight then cooled to ambient temperature. Water was added and
the mixture was stirred at ambient temperature for 1 h then
filtered. The solid was washed with H.sub.2O, EtOH and Et.sub.2O
then dried.
EXAMPLE 92B
3-(Aminomethyl)pyrazolo[1,5-a]quinazolin -5-(4H)-one
[0359] The title compound was prepared as described in Example 63.
The residue was purified by HPLC on a C18 column with 0-100%
CH.sub.3CN/H.sub.2O/0.1% TFA to provide the desired product as the
trifluoroacetate salt. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
ppm 4.08 (s, 2H) 7.54 (t, J=7.63 Hz, 1H) 7.89 (s, 1H) 7.90-7.94 (m,
1H) 8.00 (s, 1H) 8.11 (d, J=7.93 Hz, 1H) 8.18 (dd, J=7.93, 1.22 Hz,
1H).
EXAMPLE 93
N-[(5-Oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]glycine
[0360] A mixture of Example 92B (0.1 g, 0.47 mmol), 2-oxoacetic
acid (0.035 g, 0.47 mmol) and sodium cyanoborohydride (0.029 g,
0.45 mmol) in MeOH (2 mL) was refluxed overnight then evaporated.
The residue was purified by HPLC on a C 18 column with 0-100%
CH.sub.3CN/H.sub.2O/0.1% TFA to provide the desired product as the
trifluoroacetate salt. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 2.54 (s, 2H) 4.08 (q, J=5.42 Hz, 2H) 7.52-7.57 (m, 1H)
7.89-8.00 (m, 4H) 8.11 (d, J=7.67 Hz, 1H) 8.18 (d, J=7.06 Hz, 1H)
12.34 (s, 1H).
EXAMPLE 94
4-Chloro-N-((5-Oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl)butana-
mide
[0361] A mixture of Example 92B (0.1 g, 0.47 mmol),
4-chlorobutanoyl chloride (0.066 g, 0.47 mmol) in DMF (1 mL) and
pyridine (1 mL) was stirred overnight at room temperature then
evaporated. The residue was purified by HPLC on a C18 column with
0-100% CH.sub.3CN/H.sub.2O/0.1% TFA to provide the desired product
as the trifluoroacetate salt. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.92-2.00 (m, J=6.98, 6.98, 6.98, 6.98 Hz, 2H) 2.27 (t,
J=7.36 Hz, 2H) 3.63 (q, J=6.55 Hz, 2H) 4.21 (d, J=5.52 Hz, 2H)
7.47-7.53 (m, 1H) 7.86-7.92 (m, 1H) 8.07 (d, J=7.98 Hz, 1H) 8.15
(dd, J=7.98, 1.23 Hz, 1H) 11.96 (s, 1H).
EXAMPLE 95
4-Oxo-4-((5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methylamino)buta-
noic acid
[0362] A mixture of Example 92B (0.1 g, 0.47 mmol) and
dihydrofuran-2,5-dione (0.047 g, 0.47 mmol) in CH.sub.3CN (2 mL)
was heated to 80.degree. C. overnight then evaporated. The residue
was purified by HPLC on a C18 column with 0-100%
CH.sub.3CN/H.sub.2O/0.1% TFA to provide the desired product as the
trifluoroacetate salt. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
ppm 2.35 (t, J=7.02 Hz, 2H) 2.46 (t, J=6.71 Hz, 2H) 4.20 (d, J=5.49
Hz, 2H) 7.49 (t, J=7.63 Hz, 1H) 7.69-7.73 (m, 1H) 7.85-7.91 (m, 1H)
8.06 (d, J=7.63 Hz, 1H) 8.10-8.17 (m, 1H) 8.27 (t, J=5.49 Hz, 1H)
12.01 (s, 1H).
EXAMPLE 96
1-Acetyl-N-((5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl)piperi-
dine-4-carboxamide
[0363] A mixture of Example 92B (0.1 g, 0.47 mmol) and
1-acetylpiperidine-4-carbonyl chloride (0.089 g, 0.47 mmol) in DMF
(1 mL) and pyridine (1 mL) was stirred overnight. The precipitated
solids were filtered and washed with H.sub.2O and Et.sub.2O then
dried well. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
1.32-1.41 (m, 1H) 1.46-1.55 (m, 1H) 1.69 (t, J=14.19 Hz, 2H) 1.98
(s, 3H) 2.35-2.41 (m, 1H) 2.52-2.60 (m, 1H) 3.00 (dd, J=12.21,
10.68 Hz, 1H) 3.80 (d, J=13.73 Hz, 1H) 4.20 (d, J=5.80 Hz, 2H) 4.33
(d, J=13.43 Hz, 1H) 7.47-7.52 (m, 1H) 7.70 (s, 1H) 7.86-7.92 (m,
1H) 8.06 (d, J=8.24 Hz, 1H) 8.15 (dd, J=7.93, 1.22 Hz, 1H) 8.24 (t,
J=5.49 Hz, 1H) 11.97 (s, 1H).
EXAMPLE 97
2-oxo-2-{[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]amino}et-
hyl acetate
[0364] The title compound was prepared as described in Example 96,
substituting 2-chloro-2-oxoethyl acetate for
1-acetylpiperidine-4-carbonyl chloride. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 2.09 (s, 3H) 4.25 (d, J=5.83 Hz, 2H) 4.47
(s, 2H) 7.47-7.52 (m, 1H) 7.70 (s, 1H) 7.85-7.91 (m, 1H) 8.07 (d,
J=8.29 Hz, 1H) 8.15 (d, J=7.98 Hz, 1H) 8.36 (t, J=5.52 Hz, 1H)
EXAMPLE 98
3-(Pyrrolidin-1-ylmethyl)pyrazolo[1,5-a]quinazolin -5-(4H)-one
[0365] A mixture of Example 92B (0.1 g, 0.47 mmol),
1-bromo-4-chlorobutane (0.08 g, 0.47 mmol) and sodium ethoxide
(0.032 g, 0.47 mmol) in EtOH (2 mL) was stirred overnight then
evaporated. The residue was purified by HPLC on a C18 column with
0-100% CH.sub.3CN/H.sub.2O/0.1% TFA to provide the desired product
as the trifluoroacetate salt. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 1.84 (ddd, J=6.87, 3.66, 3.51 Hz, 3H) 3.08-3.10 (m, 5H)
4.09 (s, 2H) 7.54 (t, J=7.63 Hz, 1H) 7.90-7.99 (m, 2H) 8.11 (d,
J=8.54 Hz, 1H) 8.18 (d, J=7.93 Hz, 1H)
EXAMPLE 99
1-((5-Oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl)pyrrolidine-2,5-
-dione
[0366] A mixture Example 95 (0.05 g, 0.44mmol) and CDI (0.039 g,
0.24 mmol) in DMF (2 mL) was stirred overnight at ambient
temperature. The mixture was evaporated and purified by
chromatography on silica gel with 10% MeOH/CH.sub.2Cl.sub.2 to
provide the desired product. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 2.66 (s, 4H) 4.59 (s, 2H) 7.47-7.54 (m, 1H) 7.62 (s,
1H) 7.88 (s, 1H) 8.05 (d, J=8.24 Hz, 1H) 8.16 (d, J=7.02 Hz,
1H)
EXAMPLE 100
N-((5-Oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl)acetamide
[0367] A mixture of Example 92B (0.1 g, 0.47 mmol), acetic
anhydride (0.048 g, 0.47 mmol) and diisopropyl ethylamine (0.2 ml,
1.15 mmol) in MeOH (2 ml) was heated to 40.degree. C. overnight.
The mixture was evaporated and purified by chromatography on silica
gel with 10% MeOH/CH.sub.2Cl.sub.2 to provide the desired product.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 1.85 (s, 3H) 4.19
(d, J=5.49 Hz, 2H) 7.49 (t, J=7.48 Hz, 1H) 7.73 (s, 1H) 7.88 (t,
J=7.48 Hz, 1H) 8.06 (d, J=8.24 Hz, 1H) 8.15 (d, J=7.63 Hz, 1H) 8.26
(s, 1H)
* * * * *