U.S. patent application number 14/011374 was filed with the patent office on 2014-07-31 for pyrazoloquinolones are potent parp inhibitors.
This patent application is currently assigned to AbbVie Inc.. The applicant listed for this patent is AbbVie Inc.. Invention is credited to Virajkumar B. Gandhi, Vincent L. Giranda, Jianchun Gong, Thomas D. Penning, Gui-Dong Zhu.
Application Number | 20140213610 14/011374 |
Document ID | / |
Family ID | 38229340 |
Filed Date | 2014-07-31 |
United States Patent
Application |
20140213610 |
Kind Code |
A1 |
Penning; Thomas D. ; et
al. |
July 31, 2014 |
PYRAZOLOQUINOLONES ARE POTENT PARP INHIBITORS
Abstract
Compounds of Formula (I) ##STR00001## inhibit the PARP enzyme
and are useful for treating a disease or a disorder associated with
PARP. Also disclosed are pharmaceutical compositions comprising
compounds of Formula (I), methods of treatment comprising compounds
of Formula (I), and methods of inhibiting the PARP enzyme
comprising compounds of Formula (I).
Inventors: |
Penning; Thomas D.;
(Elmhurst, IL) ; Zhu; Gui-Dong; (Gurnee, IL)
; Gandhi; Virajkumar B.; (Gurnee, IL) ; Gong;
Jianchun; (Deerfield, IL) ; Giranda; Vincent L.;
(Gurnee, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AbbVie Inc. |
North Chicago |
IL |
US |
|
|
Assignee: |
AbbVie Inc.
North Chicago
IL
|
Family ID: |
38229340 |
Appl. No.: |
14/011374 |
Filed: |
August 27, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11675570 |
Feb 15, 2007 |
8546368 |
|
|
14011374 |
|
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|
60773513 |
Feb 15, 2006 |
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Current U.S.
Class: |
514/293 ;
546/82 |
Current CPC
Class: |
A61P 13/12 20180101;
A61P 17/00 20180101; A61P 29/00 20180101; C07D 495/04 20130101;
A61P 31/12 20180101; A61P 9/00 20180101; A61P 19/02 20180101; A61P
37/06 20180101; A61P 27/02 20180101; A61P 35/00 20180101; C07D
491/04 20130101; A61K 31/497 20130101; A61P 25/16 20180101; A61P
37/08 20180101; A61P 7/00 20180101; A61P 1/16 20180101; C07D 471/04
20130101; A61K 31/535 20130101; A61P 3/08 20180101; A61P 19/00
20180101; A61P 3/10 20180101; A61P 19/06 20180101; A61P 11/00
20180101; A61P 35/02 20180101; A61P 31/04 20180101; A61P 1/04
20180101; A61P 25/00 20180101; A61P 9/10 20180101; A61K 31/47
20130101; A61P 43/00 20180101; A61K 31/53 20130101 |
Class at
Publication: |
514/293 ;
546/82 |
International
Class: |
C07D 471/04 20060101
C07D471/04 |
Claims
1.-19. (canceled)
20. A compound of Formula (I) ##STR00010## or a therapeutically
acceptable salt thereof, wherein R.sup.1 and R.sup.2 together with
the atoms to which they are attached form a 5, 6, 7, or 8 membered
heterocycle, the heterocycle may be unsubstituted or substituted
with 1, 2, or 3 substituents independently selected from the group
consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, C1-C6 alkyl, alkynyl, aryl,
arylalkoxycarbonyl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano,
haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, heterocyclecarbonylalkyl, heterocyclesulfonyl,
heteroaryl, heteroarylalkyl, hydroxy, hydroxyalkyl, nitro,
NR.sup.AR.sup.B, (NR.sup.AR.sup.B)alkyl, (NR.sup.AR.sup.B)carbonyl,
(NR.sup.AR.sup.B)carbonylalkyl, and (NR.sup.AR.sup.B)sulfonyl;
R.sup.3 is selected from the group consisting of alkenyl, alkoxy,
alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C1-C6 alkyl,
alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano,
haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, heterocyclecarbonylalkyl, heterocyclesulfonyl,
heteroaryl, heteroarylalkyl, hydrogen, hydroxy, hydroxyalkyl,
nitro, NR.sup.AR.sup.B, (NR.sup.AR.sup.B)alkyl,
(NR.sup.AR.sup.B)carbonyl, (NR.sup.AR.sup.B)carbonylalkyl, and
(NR.sup.AR.sup.B)sulfonyl; X is NR.sup.4; R.sup.4 is selected from
the group consisting of C1-C6 alkyl, alkoxycarbonylalkyl,
arylalkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl,
hydrogen, (NR.sup.AR.sup.B)alkyl, (NR.sup.AR.sup.B)carbonyl,
(NR.sup.AR.sup.B)carbonylalkyl, -alkyl-O--C(O)--(NR.sup.AR.sup.B),
formylalkyl, heteroarylalkyl, heterocyclealkyl, hydroxyalkyl,
alkoxyalkyl, and haloalkyl; and R.sup.A and R.sup.B are
independently selected from the group consisting of hydrogen, C1-C6
alkyl, aryl, arylalkyl, arylalkylcarbonyl, arylalkoxy,
arylalkoxycarbonyl, cycloalkyl, cycloalkylalkyl, and heterocycle;
if R.sup.3 is Cl-alkyl and R.sup.4 is Cl-alkyl and the ring formed
by R.sup.1 and R.sup.2 is heterocycle then the heterocycle may not
be substituted with methyl; wherein the aryl, cycloalkyl,
heterocycle and heterocyclealkyl represented by R.sup.3 and R.sup.4
either themselves or as part of another moiety, are independently
unsubstituted or substituted with 1, 2, or 3 substituents
independently selected from the group consisting of alkenyl,
alkoxy, alkoxyalkyl, alkoxycarbonyl, C1-C6-alkyl, alkylcarbonyl,
alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, aryl,
arylalkyl, arylalkoxy, arylalkoxycarbonyl, carboxy, cyano,
cycloalkyl, cycloalkylalkyl, formyl, haloalkoxy, haloalkyl,
halogen, hydroxy, hydroxyalkyl, mercapto, nitro, oxo,
--NR.sup.AR.sup.B, (NR.sup.AR.sup.B)alkyl,
(NR.sup.AR.sup.B)carbonyl, (NR.sup.AR.sup.B)carbonylalkyl,
(NR.sup.AR.sup.B)sulfonyl, alkylsulfonyl, heterocycle,
heterocyclealkyl, heteroaryl, and heteroarylalkyl, wherein the
substituent moieties are themselves further unsubstituted.
21. The compound of Formula (I) of claim 1 ##STR00011## or a
therapeutically acceptable salt thereof, wherein R.sup.1 and
R.sup.2 together with the atoms to which they are attached form a
5, 6, or 7 membered heterocycle, the heterocycle may be
unsubstituted or substituted with a substituent independently
selected from the group consisting of heterocycle and
NR.sup.AR.sup.B; R.sup.3 is selected from the group consisting of
C1-C6 alkyl, aryl, cycloalkyl, heterocycle, heteroaryl, hydrogen,
and (NR.sup.AR.sup.B)alkyl; X is NR.sup.4; R.sup.4 is selected from
the group consisting of C1-C6 alkyl,
-alkyl-O--C(O)--(NR.sup.AR.sup.B), alkoxycarbonylalkyl, arylalkyl,
carboxyalkyl, cyanoalkyl, hydrogen, haloalkyl, heteroarylalkyl,
heterocyclealkyl, hydroxyalkyl, formylalkyl, and
(NR.sup.AR.sup.B)alkyl; R.sup.A and R.sup.B are independently
selected from the group consisting of hydrogen, C1-C6 alkyl,
arylalkoxycarbonyl, cycloalkyl, cycloalkylalkyl, and heterocycle;
if R.sup.3 is Cl-alkyl and R.sup.4 is Cl-alkyl and the ring formed
by R.sup.1 and R.sup.2 is heterocycle then the heterocycle may not
be substituted with methyl; and wherein the aryl, cycloalkyl,
heterocycle and heterocyclealkyl represented by R.sup.3 and R.sup.4
either themselves or as part of another moiety, are independently
unsubstituted or substituted with 1, 2, or 3 substituents
independently selected from the group consisting of alkenyl,
alkoxy, alkoxyalkyl, alkoxycarbonyl, C1-C6-alkyl, alkylcarbonyl,
alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, aryl,
arylalkyl, arylalkoxy, arylalkoxycarbonyl, carboxy, cyano,
cycloalkyl, cycloalkylalkyl, formyl, haloalkoxy, haloalkyl,
halogen, hydroxy, hydroxyalkyl, mercapto, nitro, oxo,
--NR.sup.AR.sup.B, (NR.sup.AR.sup.B)alkyl,
(NR.sup.AR.sup.B)carbonyl, (NR.sup.AR.sup.B)carbonylalkyl,
(NR.sup.AR.sup.B)sulfonyl, alkylsulfonyl, heterocycle,
heterocyclealkyl, heteroaryl, and heteroarylalkyl, wherein the
substituent moieties are themselves further unsubstituted.
22. A compound according to claim 1, wherein R.sup.1 and R.sup.2
together with the atoms to which they are attached form a 5, 6, or
7 membered heterocycle, and the heterocycle is unsubstituted.
23. A compound according to claim 1, wherein R.sup.4 is C1-C6
alkyl; and R.sup.3 is selected from the group consisting of C1-C6
alkyl, aryl, cycloalkyl, heterocycle, and heteroaryl.
24. A compound according to claim 1 selected from the group
consisting of
1-cyclopropyl-3-methyl-4,6,8,9-tetrahydro-3H-7-oxa-2,3,4-triaza-cyclopent-
a[a]naphthalen-5-one;
1-cyclopropyl-3-methyl-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-c]-2,7-napht-
hyridin-5-one; and
7,9-dimethyl-1,2,3,4,6,7-hexahydro-5H-pyrazolo[3,4-h]-1,6-naphthyridin-5--
one; or a pharmaceutically acceptable salt thereof.
25. A pharmaceutical composition comprising a compound of Formula
(I) of claim 1 or a therapeutically acceptable salt thereof, in
combination with a therapeutically acceptable carrier.
Description
[0001] This application claims priority from U.S. Provisional
Patent Application Ser. No. 60/773,513, filed Feb. 15, 2006,
incorporated herein by reference.
TECHNICAL FIELD
[0002] The present invention relates to pyrazoloquinolones, 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)
##STR00002##
[0005] and therapeutically acceptable salts, prodrugs and salts of
prodrugs thereof, wherein
[0006] R.sup.1 and R.sup.2 together with the atoms to which they
are attached form a 5, 6, 7, or 8 membered cycloalkyl or
heterocycle, the cycloalkyl or heterocycle may be unsubstituted or
substituted with 1, 2, or 3 substituents independently selected
from the group consisting of alkenyl, alkoxy, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, C1-C6 alkyl, alkynyl, aryl,
arylalkoxycarbonyl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano,
haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, heterocyclecarbonylalkyl, heterocyclesulfonyl,
heteroaryl, heteroarylalkyl, hydroxy, hydroxyalkyl, nitro,
NR.sup.AR.sup.B, (NR.sup.AR.sup.B)alkyl, (NR.sup.AR.sup.B)carbonyl,
(NR.sup.AR.sup.B)carbonylalkyl, and (NR.sup.AR.sup.B)sulfonyl;
[0007] R.sup.3 is selected from the group consisting of alkenyl,
alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C1-C6
alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,
cyano, haloalkoxy, haloalkyl, halogen, heterocycle,
heterocyclealkyl, heterocyclecarbonyl, heterocyclecarbonylalkyl,
heterocyclesulfonyl, heteroaryl, heteroarylalkyl, hydrogen,
hydroxy, hydroxyalkyl, nitro, NR.sup.AR.sup.B,
(NR.sup.AR.sup.B)alkyl, (NR.sup.AR.sup.B)carbonyl,
(NR.sup.AR.sup.B)carbonylalkyl, and (NR.sup.AR.sup.B)sulfonyl;
[0008] X is NR.sup.4;
[0009] R.sup.4 is selected from the group consisting of C1-C6
alkyl, alkoxycarbonylalkyl, arylalkyl, carboxyalkyl, cyanoalkyl,
cycloalkyl, cycloalkylalkyl, hydrogen, (NR.sup.AR.sup.B)alkyl,
(NR.sup.AR.sup.B)carbonyl, (NR.sup.AR.sup.B)carbonylalkyl,
-alkyl-O--C(O)--(NR.sup.AR.sup.B), formylalkyl, heteroarylalkyl,
heterocyclealkyl, hydroxyalkyl, alkoxyalkyl, and haloalkyl; and
[0010] R.sup.A and R.sup.B are independently selected from the
group consisting of hydrogen, alkyl, aryl, arylalkyl,
arylalkylcarbonyl, arylalkoxy, arylalkoxycarbonyl, cycloalkyl,
cycloalkylalkyl, and heterocycle;
[0011] if R.sup.3 is Cl-alkyl and R.sup.4 is Cl-alkyl and the ring
formed by R.sup.1 and R.sup.2 is heterocycle then the heterocycle
may not be substituted with methyl or methylcarbonyl;
[0012] and if R.sup.3 is Cl-alkyl and R.sup.4 is Cl-alkyl and the
ring formed by R.sup.1 and R.sup.2 is a cycloalkyl then the
cycloalkyl must be substituted; and [0013] wherein the aryl,
cycloalkyl, heterocycle and heterocyclealkyl represented by R.sup.3
and R.sup.4 either themselves or as part of another moiety, are
independently unsubstituted or substituted with 1, 2, or 3
substituents independently selected from the group consisting of
alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, C1-C6-alkyl,
alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl,
alkynyl, aryl, arylalkyl, arylalkoxy, arylalkoxycarbonyl, carboxy,
cyano, cycloalkyl, cycloalkylalkyl, formyl, haloalkoxy, haloalkyl,
halogen, hydroxy, hydroxyalkyl, mercapto, nitro, oxo,
--NR.sup.AR.sup.B, (NR.sup.AR.sup.B)alkyl,
(NR.sup.AR.sup.B)carbonyl, (NR.sup.AR.sup.B)carbonylalkyl,
(NR.sup.AR.sup.B)sulfonyl, alkylsulfonyl, heterocycle,
heterocyclealkyl, heteroaryl, and heteroarylalkyl, wherein the
substituent moieties are themselves further unsubstituted.
DETAILED DESCRIPTION OF THE INVENTION
[0014] In another embodiment, the present invention provides
compounds of Formula (I)
##STR00003##
and therapeutically acceptable salts, prodrugs and salts of
prodrugs thereof, wherein
[0015] R.sup.1 and R.sup.2 together with the atoms to which they
are attached form a 5, 6, or 7 membered cycloalkyl or heterocycle,
the cycloalkyl or heterocycle may be unsubstituted or substituted
with a substituent independently selected from the group consisting
of heterocycle and NR.sup.AR.sup.B;
[0016] R.sup.3 is selected from the group consisting of C1-C6
alkyl, aryl, cycloalkyl, heterocycle, heteroaryl, hydrogen, and
(NR.sup.AR.sup.B)alkyl;
[0017] X is NR.sup.4;
[0018] R.sup.4 is selected from the group consisting of C1-C6
alkyl, -alkyl-O--C(O)--(NR.sup.AR.sup.B), alkoxycarbonylalkyl,
arylalkyl, carboxyalkyl, cyanoalkyl, hydrogen, haloalkyl,
heteroarylalkyl, heterocyclealkyl, hydroxyalkyl, formylalkyl, and
(NR.sup.AR.sup.B)alkyl;
[0019] R.sup.A and R.sup.B are independently selected from the
group consisting of hydrogen, C1-C6 alkyl, arylalkoxycarbonyl,
cycloalkyl, cycloalkylalkyl, and heterocycle;
[0020] if R.sup.3 is Cl-alkyl and R.sup.4 is Cl-alkyl and the ring
formed by R.sup.1 and R.sup.2 is heterocycle then the heterocycle
may not be substituted with methyl or methylcarbonyl;
[0021] and if R.sup.3 is Cl-alkyl and R.sup.4 is Cl-alkyl and the
ring formed by R.sup.1 and R.sup.2 is a cycloalkyl then the
cycloalkyl must be substituted; and
[0022] wherein the aryl, cycloalkyl, heterocycle and
heterocyclealkyl represented by R.sup.3 and R.sup.4 either
themselves or as part of another moiety, are independently
unsubstituted or substituted with 1, 2, or 3 substituents
independently selected from the group consisting of alkenyl,
alkoxy, alkoxyalkyl, alkoxycarbonyl, C1-C6-alkyl, alkylcarbonyl,
alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, aryl,
arylalkyl, arylalkoxy, arylalkoxycarbonyl, carboxy, cyano,
cycloalkyl, cycloalkylalkyl, formyl, haloalkoxy, haloalkyl,
halogen, hydroxy, hydroxyalkyl, mercapto, nitro, oxo,
--NR.sup.AR.sup.B, (NR.sup.AR.sup.B)alkyl,
(NR.sup.AR.sup.B)carbonyl, (NR.sup.AR.sup.B)carbonylalkyl,
(NR.sup.AR.sup.B)sulfonyl, alkylsulfonyl, heterocycle,
heterocyclealkyl, heteroaryl, and heteroarylalkyl, wherein the
substituent moieties are themselves further unsubstituted.
[0023] In another embodiment, the present invention provides
compounds of Formula (I)
##STR00004##
and therapeutically acceptable salts, prodrugs and salts of
prodrugs thereof, wherein
[0024] R.sup.1 and R.sup.2 together with the atoms to which they
are attached form a 5, 6, 7, or 8 membered cycloalkyl or
heterocycle, the cycloalkyl or heterocycle may be unsubstituted or
substituted with 1, 2, or 3 substituents independently selected
from the group consisting of alkenyl, alkoxy, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, C1-C6 alkyl, alkynyl, aryl,
arylalkoxycarbonyl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano,
haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, heterocyclecarbonylalkyl, heterocyclesulfonyl,
heteroaryl, heteroarylalkyl, hydroxy, hydroxyalkyl, nitro,
NR.sup.AR.sup.B, (NR.sup.AR.sup.B)alkyl, (NR.sup.AR.sup.B)carbonyl,
(NR.sup.AR.sup.B)carbonylalkyl, and (NR.sup.AR.sup.B)sulfonyl;
[0025] R.sup.3 is selected from the group consisting of alkenyl,
alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C2-C6
alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,
cyano, haloalkoxy, haloalkyl, halogen, heterocycle,
heterocyclealkyl, heterocyclecarbonyl, heterocyclecarbonylalkyl,
heterocyclesulfonyl, heteroaryl, heteroarylalkyl, hydrogen,
hydroxy, hydroxyalkyl, nitro, NR.sup.AR.sup.B,
(NR.sup.AR.sup.B)alkyl, (NR.sup.AR.sup.B)carbonyl,
(NR.sup.AR.sup.B)carbonylalkyl, and (NR.sup.AR.sup.B)sulfonyl;
[0026] X is NR.sup.4;
[0027] R.sup.4 is selected from the group consisting of C2-C6
alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, hydrogen,
(NR.sup.AR.sup.B)alkyl, hydroxyalkyl, alkoxyalkyl, and haloalkyl;
and R.sup.A and R.sup.B are independently selected from the group
consisting of hydrogen, alkyl, aryl, arylalkyl, arylalkylcarbonyl,
arylalkoxy, arylalkoxycarbonyl, cycloalkyl, cycloalkylalkyl, and
heterocycle; and
[0028] wherein the aryl, cycloalkyl, heterocycle and
heterocyclealkyl represented by R.sup.3 and R.sup.4 either
themselves or as part of another moiety, are independently
unsubstituted or substituted with 1, 2, or 3 substituents
independently selected from the group consisting of alkenyl,
alkoxy, alkoxyalkyl, alkoxycarbonyl, C1-C6-alkyl, alkylcarbonyl,
alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, aryl,
arylalkyl, arylalkoxy, arylalkoxycarbonyl, carboxy, cyano,
cycloalkyl, cycloalkylalkyl, formyl, haloalkoxy, haloalkyl,
halogen, hydroxy, hydroxyalkyl, mercapto, nitro, oxo,
--NR.sup.AR.sup.B, (NR.sup.AR.sup.B)alkyl,
(NR.sup.AR.sup.B)carbonyl, (NR.sup.AR.sup.B)carbonylalkyl,
(NR.sup.AR.sup.B)sulfonyl, alkylsulfonyl, heterocycle,
heterocyclealkyl, heteroaryl, and heteroarylalkyl, wherein the
substituent moieties are themselves further unsubstituted.
[0029] In another embodiment, the present invention provides
compounds of Formula (I) or a therapeutically acceptable salt
thereof wherein R.sup.1 and R.sup.2 together with the atoms to
which they are attached form a 5, 6, 7, or 8 membered
cycloalkyl.
[0030] In another embodiment, the present invention provides
compounds of Formula (I) or a therapeutically acceptable salt
thereof wherein R.sup.1 and R.sup.2 together with the atoms to
which they are attached form a 5, 6, 7, or 8 membered
heterocycle.
[0031] In another embodiment, the present invention provides
compounds of Formula (I) or a therapeutically acceptable salt
thereof wherein X is NR.sup.4.
[0032] In another embodiment, the present invention provides
compounds of Formula (I) or a therapeutically acceptable salt
thereof wherein R.sup.1 and R.sup.2 together with the atoms to
which they are attached form a 5, 6, 7, or 8 membered
cycloalkyl.
[0033] In another embodiment, the present invention provides
compounds of Formula (I) or a therapeutically acceptable salt
thereof wherein R.sup.1 and R.sup.2 together with the atoms to
which they are attached form a 5, 6, 7, or 8 membered
heterocycle.
[0034] In another embodiment, the present invention provides
compounds of Formula (I) or a therapeutically acceptable salt
thereof wherein R.sup.1 and R.sup.2 together with the atoms to
which they are attached form a 5, 6, 7, or 8 membered cycloalkyl;
and R.sup.3 is selected from the group consisting of C1-C6 alkyl,
aryl, cycloalkyl, heterocycle, heteroaryl, hydrogen, and
(NR.sup.AR.sup.B)alkyl.
[0035] In another embodiment, the present invention provides
compounds of Formula (I) or a therapeutically acceptable salt
thereof wherein R.sup.1 and R.sup.2 together with the atoms to
which they are attached form a 5, 6, 7, or 8 membered cycloalkyl;
and R.sup.3 is selected from the group consisting of aryl,
cycloalkyl, heterocycle, and heteroaryl.
[0036] In another embodiment, the present invention provides
compounds of Formula (I) or a therapeutically acceptable salt
thereof wherein R.sup.1 and R.sup.2 together with the atoms to
which they are attached form a 5, 6, 7, or 8 membered cycloalkyl; X
is NR.sup.4; R.sup.4 is C1-C6 alkyl; and R.sup.3 is selected from
the group consisting of aryl, cycloalkyl, heterocycle, and
heteroaryl.
[0037] In another embodiment, the present invention provides
compounds of Formula (I) or a therapeutically acceptable salt
thereof wherein R.sup.3 is selected from the group consisting of
aryl, cycloalkyl, heterocycle, and heteroaryl.
[0038] In another embodiment, the present invention provides
compounds of Formula (I) or a therapeutically acceptable salt
thereof wherein R.sup.4 is selected from the group consisting of
C1-C6 alkyl, -alkyl-O--C(O)--(NR.sup.AR.sup.B),
alkoxycarbonylalkyl, arylalkyl, carboxyalkyl, cyanoalkyl, hydrogen,
haloalkyl, heteroarylalkyl, heterocyclealkyl, hydroxyalkyl,
formylalkyl, and (NR.sup.AR.sup.B)alkyl.
[0039] In another embodiment, the present invention provides
compounds of Formula (I) or a therapeutically acceptable salt
thereof wherein R.sup.1 and R.sup.2 together with the atoms to
which they are attached form a 6 membered cycloalkyl.
[0040] In another embodiment, the present invention provides
compounds of Formula (I) or a therapeutically acceptable salt
thereof wherein R.sup.3 is a heterocycle.
[0041] In another embodiment, the present invention provides
compounds of Formula (I) or a therapeutically acceptable salt
thereof wherein R.sup.3 is pyrrolidinyl.
[0042] In another embodiment, the present invention provides
compounds of Formula (I) or a therapeutically acceptable salt
thereof wherein R.sup.1 and R.sup.2 together with the atoms to
which they are attached form a 6 membered cycloalkyl; and R.sup.3
is pyrrolidinyl.
[0043] In another embodiment, the present invention provides a
pharmaceutical composition comprising a compound of Formula (I), or
a therapeutically acceptable salt thereof, in combination with a
therapeutically acceptable carrier.
[0044] 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 therapeutically
acceptable salt thereof.
[0045] 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 therapeutically
acceptable salt thereof.
[0046] 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
therapeutically acceptable salt thereof.
[0047] 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 therapeutically acceptable
salt thereof.
[0048] 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 therapeutically acceptable salt thereof.
[0049] 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 therapeutically acceptable salt thereof.
[0050] 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 therapeutically
acceptable salt thereof.
[0051] 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
therapeutically acceptable salt thereof.
[0052] 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 therapeutically acceptable salt thereof.
[0053] 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
therapeutically acceptable salt thereof.
[0054] 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
therapeutically acceptable salt thereof.
[0055] 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
therapeutically acceptable salt thereof.
[0056] 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
therapeutically acceptable salt thereof.
[0057] 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 therapeutically acceptable salt
thereof.
[0058] 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
therapeutically acceptable salt thereof.
[0059] 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 therapeutically acceptable salt
thereof.
[0060] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically acceptable salt
thereof, to prepare a medicament for inhibiting the PARP enzyme in
a mammal in recognized need of such treatment.
[0061] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically acceptable salt
thereof, to prepare a medicament for inhibiting tumor growth in a
mammal in recognized need of such treatment.
[0062] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically acceptable salt
thereof, to prepare a medicament for treating cancer in a mammal in
recognized need of such treatment.
[0063] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically 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.
[0064] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically 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 therapeutically acceptable
salt thereof.
[0065] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically 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 therapeutically acceptable salt
thereof.
[0066] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically 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 therapeutically acceptable salt thereof.
[0067] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically 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 therapeutically
acceptable salt thereof.
[0068] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically 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 therapeutically
acceptable salt thereof.
[0069] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically 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 therapeutically acceptable salt
thereof.
[0070] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically 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 therapeutically acceptable salt
thereof.
[0071] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically 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 therapeutically acceptable salt
thereof.
[0072] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically 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 therapeutically acceptable salt
thereof.
[0073] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically 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
therapeutically acceptable salt thereof.
[0074] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically 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 therapeutically acceptable salt
thereof.
[0075] In another embodiment, the present invention provides a use
of a compound of Formula (I), or a therapeutically 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 therapeutically acceptable
salt thereof.
DEFINITIONS
[0076] As used throughout this specification and the appended
claims, the following terms have the following meanings:
[0077] 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.
[0078] 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.
[0079] 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.
[0080] 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.
[0081] 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.
[0082] The term "alkyl" as used herein, means a 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.
[0083] The term "C1-C6 alkyl" as used herein, means a straight or
branched chain hydrocarbon containing from 1 to 6 carbon atoms.
[0084] The term "C.sub.1-alkyl" means methyl.
[0085] The term "C.sub.2-alkyl" means ethyl.
[0086] The term "C.sub.3-alkyl" means prop-1-yl and prop-2-yl
(isopropyl).
[0087] The term "C.sub.4-alkyl" means but-1-yl, but-2-yl,
2-methylprop-1-yl, and 2-methylprop-2-yl (tert-butyl).
[0088] The term "C.sub.5-alkyl" means 2,2-dimethylprop-1-yl
(neo-pentyl), 2-methylbut-1-yl, 2-methylbut-2-yl, 3-methylbut-1-yl,
3-methylbut-2-yl, pent-1-yl, pent-2-yl, and pent-3-yl.
[0089] The term "C.sub.6-alkyl" means 2,2-dimethylbut-1-yl,
2,3-dimethylbut-1-yl, 2,3-dimethylbut-2-yl, 3,3-dimethylbut-1-yl,
3,3-dimethylbut-2-yl, 2-ethylbut-1-yl, hex-1-yl, hex-2-yl,
hex-3-yl, 2-methylpent-1-yl, 2-methylpent-2-yl, 2-methylpent-3-yl,
3-methylpent-1-yl, 3-methylpent-2-yl, 3-methylpent-3-yl,
4-methylpent-1-yl, and 4-methylpent-2-yl.
[0090] 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.
[0091] 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.
[0092] The term "-alkyl-O--C(O)--(NR.sup.AR.sup.B)" as used herein,
means a (NR.sup.AR.sup.B)carbonyloxy group, as defined herein,
appended to the parent molecule through an alkyl group.
[0093] The term "alkylsulfonyl" as used herein, means an alkyl
group appended to the parent molecular moiety through a
sulfonyl.
[0094] The term "alkylthio" as used herein, means an alkyl group,
as defined herein, appended to the parent molecular moiety through
a sulfur atom. Representative examples of alkylthio include, but
are not limited, methylthio, ethylthio, tert-butylthio, and
hexylthio.
[0095] The term "alkylthioalkyl" as used herein, means an alkylthio
group, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of alkylthioalkyl include, but are not limited, methylthiomethyl
and 2-(ethylthio)ethyl.
[0096] 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.
[0097] The term "aryl," as used herein, means a phenyl group or a
naphthyl group.
[0098] The aryl groups are unsubstituted or substituted with one,
two, three, four, or five substituents independently selected from
the group consisting of alkenyl, alkoxy, alkoxyalkyl,
alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio,
alkylthioalkyl, alkynyl, carboxy, cyano, formyl, haloalkoxy,
haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro,
--NR.sup.AR.sup.B, (NR.sup.AR.sup.B)alkyl,
(NR.sup.AR.sup.B)carbonyl, and tetrazolyl.
[0099] 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.
[0100] 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. Representative examples of
arylalkoxy include, but are not limited to, 2-phenylethoxy,
3-naphth-2-ylpropoxy, and 5-phenylpentyloxy.
[0101] The term "arylalkoycarbonyl" as used herein, means an
arylalkoxy group, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
Representative examples of arylalkoxycarbonyl include, but are not
limited to, benzyloxycarbonyl and naphth-2-ylmethoxycarbonyl.
[0102] The term "carbonyl" as used herein, means a --C(O)--
group.
[0103] The term "carboxy" as used herein, means a --CO.sub.2H
group.
[0104] The term "carboxyalkyl" as used herein, means a carboxy
group, as defined herein, attached to the parent molecular moiety
through an alkyl group.
[0105] The term "cyano" as used herein, means a --CN group.
[0106] The term "cyanoalkyl" as used herein, means a cyano group
appended to the parent molecular moiety through an alkyl group.
[0107] 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.
[0108] The cycloalkyl groups are unsubstituted or substituted with
1, 2, 3, or 4 substituents selected from alkenyl, alkoxy,
alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,
alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy,
cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy,
hydroxyalkyl, mercapto, oxo, --NR.sup.AR.sup.B, and
(NR.sup.AR.sup.B)carbonyl.
[0109] 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.
[0110] The term "formyl" as used herein, means a --C(O)H group.
[0111] The term "formylalkyl" as used herein, means a formyl group,
as defined herein, attached to the parent molecular moiety through
an alkyl group.
[0112] The term "halo" or "halogen" as used herein, means --Cl,
--Br, --I or --F.
[0113] 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.
[0114] 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, chloromethyl,
2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and
2-chloro-3-fluoropentyl.
[0115] 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, benzoxadiazolyl, cinnolinyl,
furopyridinyl, furyl, imidazolyl, indazolyl, indolyl, isoxazolyl,
isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl,
pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl,
pyrrolyl, pyridinium N-oxide, quinolinyl, tetrazolyl, thiadiazolyl,
thiazolyl, thienopyridinyl, thienyl, triazolyl, and triazinyl.
[0116] The heteroaryl groups are unsubstituted or substituted with
1, 2, 3, or 4 substituents independently selected from alkenyl,
alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,
alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy,
cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy,
hydroxyalkyl, mercapto, nitro, --NR.sup.AR.sup.B, and
(NR.sup.AR.sup.B)carbonyl.
[0117] 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.
[0118] 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 O, 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, thiomorpholinyl,
1,1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl,
and trithianyl.
[0119] The heterocycles are unsubstituted or substituted with 1, 2,
or 3 substituents independently selected from alkenyl, alkoxy,
alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,
alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, aryl,
arylalkyl, arylalkoxy, arylalkoxycarbonyl, carboxy, cyano,
cycloalkyl, cycloalkylalkyl, formyl, haloalkoxy, haloalkyl,
halogen, hydroxy, hydroxyalkyl, mercapto, nitro, --NR.sup.AR.sup.B,
(NR.sup.AR.sup.B)alkyl, (NR.sup.AR.sup.B)carbonyl, sulfonyl,
alkylsulfonyl, tetrahydropyranyl, and heteroarylalkyl wherein the
heteroaryl is pyridinyl.
[0120] 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.
[0121] The term "heterocyclecarbonyl" as used herein, means a
heterocycle group, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
[0122] Representative examples of heterocyclecarbonyl include, but
are not limited to, 1,3-benzodioxol-4-ylcarbonyl,
pyridin-3-ylcarbonyl, pyrimidin-2-ylcarbonyl,
tetrahydrofuran-2-ylcarbonyl, tetrahydrofuran-3-ylcarbonyl,
tetrahydro-2H-pyran-2-ylcarbonyl, tetrahydro-2H-pyran-4-ylcarbonyl,
tetrahydrothien-2-ylcarbonyl and tetrahydrothien-3-ylcarbonyl.
The term "heterocyclecarbonylalkyl" as used herein, means a
heterocyclecarbonyl group, as defined herein, appended to the
parent molecular moiety through an alkyl group, as defined
herein.
[0123] The term "heterocyclesulfonyl" as used herein, means a
heterocycle group, as defined herein, appended to the parent
molecular moiety through a sulfonyl group, as defined herein.
[0124] The term "hydroxy" as used herein, means an --OH group.
[0125] 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.
[0126] The term "mercapto" as used herein, means a --SH group.
[0127] The term "nitro" as used herein, means a --NO.sub.2
group.
[0128] The term "nonaromatic" as used herein, means that a 4
membered nonaromatic ring contains zero double bonds, a 5 membered
nonaromatic ring contains zero or one double bond, a 6, 7, or 8
membered nonaromatic ring contains zero, one, or two double
bonds.
[0129] The term "NR.sup.AR.sup.B" as used herein, means two groups,
R.sup.A and R.sup.B, which are appended to the parent molecular
moiety through a nitrogen atom. R.sup.A and R.sup.B are each
independently hydrogen, alkyl, and alkylcarbonyl. Representative
examples of NR.sup.AR.sup.B include, but are not limited to, amino,
methylamino, acetylamino, and acetylmethylamino.
[0130] The term "(NR.sup.AR.sup.B)carbonyl" as used herein, means a
NR.sup.AR.sup.B group, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
Representative examples of (NR.sup.AR.sup.B)carbonyl include, but
are not limited to, aminocarbonyl, (methylamino)carbonyl,
(dimethylamino)carbonyl, and (ethylmethylamino)carbonyl.
[0131] The term "(NR.sup.AR.sup.B)carbonyloxy" as used herein,
means a (NR.sup.AR.sup.B)carbonyl group as defined herein appended
to the parent molecular moiety through an oxygen.
[0132] 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. NR.sub.C and R.sub.D are each
independently hydrogen, alkyl, and alkylcarbonyl. Representative
examples of NR.sub.CR.sub.D include, but are not limited to, amino,
methylamino, acetylamino, and acetylmethylamino.
[0133] The term "(NR.sub.CR.sub.D)carbonyl" as used herein, means a
NR.sub.CR.sub.D group, 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.
[0134] 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.
[0135] The term "(NR.sub.CR.sub.D)sulfonyl" as used herein, means a
NR.sub.CR.sub.D group, as defined herein, appended to the parent
molecular moiety through a sulfonyl group, as defined herein.
Representative examples of (NR.sub.CR.sub.D)sulfonyl include, but
are not limited to, aminosulfonyl, (methylamino)sulfonyl,
(dimethylamino)sulfonyl, and (ethylmethylamino)sulfonyl.
[0136] The term "NR.sup.AR.sup.B" as used herein, means two groups,
R.sup.A and R.sup.B, which are appended to the parent molecular
moiety through a nitrogen atom. R.sup.A and R.sup.B are each
independently hydrogen, alkyl, cycloalkyl, and alkylcarbonyl.
Representative examples of NR.sup.AR.sup.B include, but are not
limited to, amino, methylamino, acetylamino, and
acetylmethylamino.
[0137] The term "(NR.sup.AR.sup.B)carbonyl" as used herein, means a
NR.sup.AR.sup.B group, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
Representative examples of (NR.sup.AR.sup.B)carbonyl include, but
are not limited to, aminocarbonyl, (methylamino)carbonyl,
(dimethylamino)carbonyl, and (ethylmethylamino)carbonyl.
[0138] The term "oxo" as used herein, means a .dbd.O moiety.
[0139] The term "sulfinyl" as used herein, means a --SO--
group.
[0140] The term "sulfonyl" as used herein, means a --SO.sub.2--
group.
[0141] 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.
[0142] 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
[0143] 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 5 min 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.
[0144] 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 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 IC.sub.50). 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 PARP (K.sub.i, nM) 46 14.2 7.1 158 4.5 21.5
6.3 13 450 81 11 62 59 19.6 1.6 11.6 22.5 43 29 1.7 9 29 16.8 64
3.5 3.1 5.7 13.3 800 180 52 10 34 55 2.6 472 4.1 6.3 3 10 11 2.8
1.2 69 3.3 20.7 2.4 15.3 >8300 3.6 24.9 6 91 3.1 4.6 47 6.5 15.7
16.2 4.5 6.1 1.1 1.6 2.9 3.6 6.1 23 3.7 18.6 5 3.5 116 4.3 8.2 4.9
5.5 5.5 .7 56 395 2.7 800 9.6 16.4 5.3 9.5 8.5 31 226 20.2 10.3 866
5.8 11.4 3.5 4.5 17 45 35 12.2 5.3 2.4 5.4 3700 3.2 5.6 13 44 11.9
2.8 9.8 11.3 2.1 6.5 4.6 34 33 52 1.1 2.0 70 4.3 3.4 18 6.5 17 211
4 20 5.6 231 2.9 57 37 20 19 256 6 10 2 109 1.8 35 2 32 26 315 7 23
2.5 456 4 52 4 42 242 24 6 37 3.7 590 2.7 90 4 5 14 15 8 31 3 640 2
135 5 122 14 2.3 5 41 7.2 2.7 4.7 129 10 65 18 2.9 6 27 16 8 54 131
251 1 53 134 86 69 167 20 49 228 233 23 135 65 181 25 183 18 59 3
12 30 27 217 26 65 239 5 49 .4 3 5 40 245 17 88 9 3 39 14 25 12 60
72 61 27 155 307 163
Cellular PARD Assay:
[0145] 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 fmax 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).
[0146] 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) 2.3 1.5 45
1 18 2.6 7 0.3 11.9 35 0.9 46 1 14 115 <0.3 >1000 0.5 12.1
4.8 11 >1000 1.3 1.2 0.6 17.5 463 0.2 3.7 4.5 0.3 1.2 .6 2.3 7
.5 1.9 .6 1.2 .5 1.4 .8 .6 1 1.7 .3 .9 .5 1.6 .4 .3 .3 .7 17 2.1 .7
2.7 .5 1.9 >300 .7 1.8 3.2 .4 2.3 .5 3.6 .5 5.7 7.6 .5 .8 3.2 .7
40 1.1 1.5 .6 1 .5 .5 .3 5.6 .3 4.1 3.4 1.8 .5 4 .5 .6 .6 2.4 .7
3.5 1.7 .9 .6 3.3 1.5 >300 >300 .7 6.2 >300 10.6 8.7
>300 1.5 3.1 .5 2.4 1.8 14 >300 >1000 14 >300 63 7.9 .8
5.6 4.5 15 16 259 112 52 8.2 8.9 >300 57 >300 >300 191
>300 61
[0147] 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.
[0148] 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. Ehrlich 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).
[0149] 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.
[0150] 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.
[0151] 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.
[0152] 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.
[0153] 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.
[0154] 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.
[0155] 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.
[0156] 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.
[0157] Abbreviations which have been used in the descriptions of
the examples that follow are: DBU for
1,8-diazabicyclo[5.4.0]undec-7-ene; DMF for N,N-dimethylformamide;
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; TFA for trifluoroacetic
acid; THF for tetrahydrofuran, and TMS for trimethylsilane.
[0158] Compounds having formula I may be made by synthetic chemical
processes, examples of which are shown herein below. It is meant to
be understood that the order of the steps in the processes may be
varied, that reagents, solvents and reaction conditions may be
substituted for those specifically mentioned, and that vulnerable
moieties may be protected and deprotected, as necessary.
##STR00005##
[0159] Compounds of formula (4) wherein X and R.sup.3 are as
defined in formula (I) and ring A is cycloalkyl or heterocycle,
unsubstituted or substituted as defined in formula (I), can be
prepared from amines of formula (1) as shown in Scheme 1.
[0160] Amines of formula (1) can be reacted with unsubstituted or
substituted cyclic ketones of formula (2) in the presence of acid
such as, but not limited to, acetic acid, to provide alkenes of
formula (3). The reaction is generally conducted at a temperature
from about room temperature to about 70.degree. C.
[0161] Compounds of formula (3) when treated with isocyanates such
as, but not limited to, ethyl isocyanates, in pyridine or
4-methylpyridine, at reflux, provides compounds of formula (4).
##STR00006##
[0162] Aminopyrazoles (7) wherein R.sup.3 and R.sup.4 are as
defined in formula (I) can be prepared from the reaction of
hydrazines of formula (5) with an .alpha.-cyanoketone of formula
(6), in a solvent such as ethanol and the like, at the reflux
temperature of the solvent employed.
##STR00007##
[0163] Compounds of formula (8) wherein X and R.sup.3 are as
defined in formula (I), Y is NR.sup.AR.sup.B, alkoxy or haloalkoxy,
and ring A is cycloalkyl or heterocycle, unsubstituted or
substituted as defined in formula (I), and R.sup.A and R.sup.B are
as defined in formula (I), can be prepared by (a) allylic
halogenation, such as chlorination or bromination of ring A, and
(b) displacement of the halide with an appropriate nucleophile of
formula Y-H.
[0164] Allylic halogenation of compounds of formula (4) can be
accomplished by treatment of (4) with a halogenating agent such as,
but not limited to, bromosuccinimide or chlorosuccinimide, in the
presence of catalytic amount of radical initiator such as, but not
limited to, 2,2'-azobis(2-methylpropionitrile) or
m-chloroperbenzoic acid (MCPBA), at elevated (for example
40-70.degree. C.) or ambient temperature.
[0165] Displacement of the halide with a nucleophile can be
achieved in the presence of a base such as, but not limited to,
triethylamine or diisopropylethylamine, at a temperature from about
room temperature to about 100.degree. C.
##STR00008##
[0166] Compounds of formula (11) wherein X is as defined in formula
(I), Q is alkylenyl, ring A is cycloalkyl or heterocycle,
unsubstituted or substituted as defined in formula (I), ring B is
aryl, heteroaryl, heterocycle or cycloalkyl, each of which is
independently unsubstituted or substituted as described in formula
(I), and R.sup.101 and R.sup.102 are independently selected from
the group consisting of alkyl, cycloalkyl and heterocycle, can be
prepared from primary amines of formula (9) as shown in Scheme
4.
[0167] Primary amines of formula (9) can be monoalkylated by
compounds of formula R.sup.101--Z, wherein Z is halides, triflates
or mesylates, in the presence of a base such as, but not limited
to, triethylamine or diisopropylethylamine, at a temperature from
about room temperature to about 100.degree. C. The second
alkylation can be achieved with compounds of formula R.sup.102--Z
using similar reaction conditions to afford compounds of formula
(11). The alkylation can be conducted sequentially or in one
pot.
[0168] Alternatively, compounds of formula (10) can be obtained
from primary amines of formula (9) via reductive amination
conditions wherein (9) is treated with a ketones or aldehydes, in
the presence of an acid such as, but not limited to, acetic acid,
and a reducing agent such as, but not limited to, sodium
cyanoborohydride. Compounds of formula (11) wherein R.sup.A and
R.sup.B are independently alkyl, cycloalkyl or heterocycle, can be
prepared from (10) using similar reaction conditions.
Scheme 5
##STR00009##
[0170] Compounds of formula (14) wherein X is as defined in formula
(I), Q is alkylenyl, ring A is cycloalkyl or heterocycle,
unsubstituted or substituted as defined in formula (I), and
R.sup.101 and R.sup.102 are independently alkyl, cycloalkyl or
heterocycle, can be prepared from primary amines of formula (12) as
shown in Scheme 5, using reaction conditions as described in Scheme
4.
[0171] 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
1,3-dimethyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinolin-5-one
[0172] The title compound was prepared as described in Winters, G;
Sala, A; De Paoli, A.; Ferri, V. Synthesis 1984, 1052-1054.
Example 2
9-cyclobutylamino-1,3-dimethyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquin-
olin-5-one
Example 2A
9-bromo-1,3-dimethyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinolin-5-one
[0173] A solution of EXAMPLE 1 (966 mg, 4.45 mmol) in a mixture of
chloroform (30 mL) and N,N'-dimethylformamide (2 mL) was treated
with N-bromosuccinimide (791 mg, 4.45 mmol) and catalytic
2,2'-azobis(2-methylpropionitrile) (5 mg) at 65.degree. C. for 18
hours. The mixture was cooled, concentrated and the residue
partitioned between ethyl acetate and brine. The organic phase was
washed with water, concentrated and purified by flash
chromatography on silica gel eluting with 50% ethyl acetate in
hexanes to provide 1.14 g (87%) of the title compound. MS
(DCI/NH.sub.3) m/z 297 (M+H).sup.+.
Example 2B
9-cyclobutylamino-1,3-dimethyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquin-
olin-5-one
Step A
[0174] To a solution of EXAMPLE 2A (40 mg, 0.14 mmol) in 1:1
tetrahydrofuran/N,N'-dimethylformamide (4 mL) was added
cyclobutylamine (20 mg, 0.28 mmol) and diisopropylethylamine (49 L,
0.28 mmol) and the mixture heated at 50.degree. C. for 18 hours.
The mixture was cooled, concentrated, and the residue purified by
flash chromatography on silica gel using 70% ethyl acetate in
hexanes to give the title compound.
Step B
[0175] Purification of the free base from Step A by HPLC (Zorbax,
C-18, 250.times.2.54 column, Mobile phase A: 0.1% trifluoroacetic
acid in water; B: 0.1% trifluoroacetic acid in acetonitrile; [0176]
0-100% gradient) provided 12 mg (30%) of the title compound as a
trifluoroacetate salt. .sup.1H NMR (CD.sub.3OD) 1.85-1.97 (m, 3H),
1.98-2.12 (m, 2H), 2.18-2.39 (m, 4H), 2.40-2.53 (m, 2H), 2.56 (s,
3H), 2.76-2.90 (m, 1H), 3.84 (s, 3H), 4.04-4.19 (m, 1H), 4.79 (d,
J=3.0 Hz, 1H), 13.70 (br s, 1H).
Example 3
1,3-dimethyl-9-morpholin-4-yl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquino-
lin-5-one
[0177] The title compound was prepared according to the procedure
as described in Step A of EXAMPLE 2B, substituting morpholine for
cyclobutylamine (21% yield). .sup.1H NMR (CDCl.sub.3)
[0178] 1.60 (s, 1H), 1.65-1.79 (m, 2H), 1.84-1.96 (m, 1H),
2.04-2.16 (m, 1H), 2.50-2.57 (m, 2H), 2.57-2.64 (m, 6H), 3.54-3.62
(m, 2H), 3.62-3.71 (m, 2H), 3.99 (s, 3H), 4.08 (t, J=5.7 Hz, 1H),
13.70 (br s, 1H).
Example 4
1,3-dimethyl-9-piperidin-1-yl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquino-
lin-5-one
[0179] The title compound was prepared according to the procedure
as described in Step A of EXAMPLE 2B, substituting piperidine for
cyclobutylamine (72% yield). .sup.1H NMR (DMSO-d.sub.6)
[0180] 1.26-1.39 (m, 4H), 1.42-1.50 (m, 2H), 1.54-1.65 (m, 2H),
1.71-1.82 (m, 1H), 1.95-2.04 (m, 1H), 2.32-2.39 (m, 2H), 2.39-2.44
(m, 2H), 2.47 (s, 3H), 3.22-3.28 (m, 2H), 3.73 (s, 3H), 3.99-4.07
(m, 1H), 13.76 (br s, 1H).
Example 5
1,3-dimethyl-9-(4-methylpiperazin-1-yl)-3,4,6,7,8,9-hexahydropyrazolo[3,4--
c]isoquinolin-5-one
[0181] The title compound was prepared according to the procedure
as described in Step A of EXAMPLE 2B, substituting
1-methylpiperazine for cyclobutylamine (37% yield). .sup.1H NMR
(C.sub.5D.sub.5N) 1.52-1.66 (m, 2H), 1.74-1.83 (m, 1H), 1.96-2.05
(m, 1H), 2.27-2.36 (m, 2H), 2.74 (s, 3H), 2.74 (s, 3H), 2.76-2.79
(m, 1H), 3.01-3.12 (m, 3H), 3.13-3.24 (m, 2H), 3.29-3.36 (m, 1H),
3.60-3.68 (m, 1H), 3.98 (s, 3H), 4.22 (t, J=5.7 Hz, 1H), 14.18 (br
s, 1H).
Example 6
1-methyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinolin-5-one
[0182] A mixture of 8.5 g of pyridine and 10 mL of concentrated
hydrochloric acid was heated to 230.degree. C., added to EXAMPLE 1
(217 mg, 1.0 mmol) and the mixture heated at 230.degree. C. for 2
hours. After cooling, water was added and the suspension
neutralized with 10% sodium hydroxide. Dichloromethane (50 mL) was
added, the mixture was filtered and the solid collected, washed
with dichloromethane and water and dried. Purification by HPLC
(Zorbax, C-18, 250.times.2.54 column, Mobile phase A: 0.1%
trifluoroacetic acid in water; B: 0.1% trifluoroacetic acid in
acetonitrile; 0-100% gradient) provided 173 mg (73%) of the title
compound as the trifluoroacetate salt. .sup.1H NMR (DMSO-d.sub.6)
1.63-1.73 (m, 4H), 2.29-2.34 (m, 2H), 2.46 (s, 3H), 2.75-2.80 (m,
2H), 11.28 (br s, 1H).
Example 7
1-methyl-3-phenyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinolin-5-one
Example 7A
4-cyclohex-1-enyl-5-methyl-2-phenyl-2H-pyrazol-3-ylamine
[0183] A solution of 5-amino-3-methyl-1-phenylpyrazole (8.66 g, 50
mmol) in acetic acid (70 mL) was treated with cyclohexanone (10.6
mL, 100 mmol) at ambient temperature for 40 hours. The volatiles
were removed and the residue diluted with water and 10% sodium
hydroxide added until the pH=12. The mixture was stirred with 10 mL
of hexane for 30 minutes and the solid collected by filtration,
washed with water and hexane and dried to give 9.43 g (74%) of the
title compound. MS (DCI): m/z 254 (M+H).sup.+.
Example 7B
1-methyl-3-phenyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinolin-5-one
[0184] To a solution of EXAMPLE 7A (1.26 g, 5 mmol) in pyridine (10
mL) was added ethyl isocyanate (1.18 mL, 15 mmol). The solution was
heated at reflux for 7 hours, cooled, concentrated and the residue
triturated with methanol. The solid was collected by filtration,
washed with methanol and dried to give 493 mg (35%) of the title
compound. .sup.1H NMR (DMSO-d.sub.6) 1.72-1.83 (m, 4H), 2.49-2.55
(m, 2H), 2.57 (s, 3H), 3.05 (t, J=5.2 Hz, 2H), 7.24 (t, J=7.4 Hz,
1H), 7.43-7.53 (m, 2H), 8.19 (d, J=7.7 Hz, 2H), 11.27 (br s,
1H).
Example 8
3-(2-dimethylaminoethyl)-1-methyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoq-
uinolin-5-one
Example 8A
4-cyclohex-1-enyl-2-(2-dimethylaminoethyl)-5-methyl-2H-pyrazol-3-ylamine
[0185] A solution of
2-(2-dimethylaminoethyl)-5-methyl-2H-pyrazol-3-ylamine (0.998 g,
5.93 mmol) in acetic acid (10 mL) was treated with cyclohexanone
(1.23 mL, 11.86 mmol) at ambient temperature for two days. The
volatiles were removed and the residue partitioned between dilute
sodium hydroxide and ethyl acetate. The organic phase was washed
with water, concentrated and the residue purified by flash
chromatography on silica gel using 10% methanol in dichloromethane
to give a solid (1.10 g, 75%). MS (DCI): m/z 249 (M+H).sup.+.
Example 8B
3-(2-dimethylaminoethyl)-1-methyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoq-
uinolin-5-one
[0186] To a solution of EXAMPLE 8A (1.05 g, 4.22 mmol) in pyridine
(10 mL) was added ethyl isocyanate (1.0 mL, 12.68 mmol) and the
solution heated at reflux overnight. The mixture was cooled,
stirred with 15 mL ethyl acetate at ambient temperature for 5
minutes and the solid collected by filtration, washed with ethyl
acetate and dried to give 793 mg of the title compound. The mother
liquor was concentrated and the residue recrystallized from ethyl
acetate to give an additional 300 mg of the title compound (94%
overall yield). .sup.1H NMR (DMSO-d.sub.6) 1.64-1.75 (m, 4H), 2.16
(s, 6H), 2.34-2.39 (m, 5H), 2.59 (t, J=6.4 Hz, 2H), 2.83-2.87 (m,
2H), 4.18 (t, J=6.6 Hz, 2H).
Example 9
3-methyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinolin-5-one
[0187] The title compound was prepared according to the procedure
for EXAMPLE 8, substituting 1-methyl-1H-pyrazol-5-ylamine for
2-(2-dimethylaminoethyl)-5-methyl-2H-pyrazol-3-ylamine. .sup.1H NMR
(DMSO-d.sub.6): 1.67-1.77 (m, 4H), 2.38 (br d, J=1.8 Hz, 2H), 2.72
(br d, J=1.8 Hz, 2H), 3.82 (s, 3H), 7.68 (s, 1H), 11.90 (br s,
1H).
Example 10
1-methyl-6,7,8,9-tetrahydro-4H-isoxazolo[5,4-c]isoquinolin-5-one
Example 10A 4-Cyclohex-1-enyl-3-methyl-isoxazol-5-ylamine
[0188] The title compound was prepared according to the procedure
for EXAMPLE 7A, substituting 5-amino-3-methylisoxazole for
5-amino-3-methyl-1-phenylpyrazole (72% yield). MS (DCI/NH.sub.3)
m/z 179 (M+H).sup.+.
Example 10B
1-methyl-6,7,8,9-tetrahydro-4H-isoxazolo[5,4-c]isoquinolin-5-one
[0189] The title compound was prepared according to the procedure
as described in EXAMPLE 7B, substituting EXAMPLE 10A for EXAMPLE 7A
(67% yield). .sup.1H NMR (DMSO-d.sub.6) 1.69-1.79 (m, 4H), 2.46 (t,
J=4.6 Hz, 2H), 2.49 (s, 3H), 2.95 (t, J=4.8 Hz, 2H), 12.16 (br s,
1H).
Example 11
1-phenyl-6,7,8,9-tetrahydro-4H-isoxazolo[5,4-c]isoquinolin-5-one
Example 11A
4-cyclohex-1-enyl-3-phenylisoxazol-5-ylamine
[0190] The title compound was prepared according to the procedure
as described in EXAMPLE 7A, substituting 5-amino-3-phenylisoxazole
for 5-amino-3-methyl-1-phenylpyrazole (50% yield). MS
(DCI/NH.sub.3) m/z 241 (M+H).sup.+.
Example 11B
1-phenyl-6,7,8,9-tetrahydro-4H-isoxazolo[5,4-c]isoquinolin-5-one
[0191] The title compound was prepared according to the procedure
as described in EXAMPLE 7B, substituting EXAMPLE 11A for EXAMPLE 7A
(3% yield). .sup.1H NMR(C.sub.5D.sub.5N) 1.43-1.52 (m, 2H),
1.65-1.75 (m, 2H), 2.55 (t, J=6.3 Hz, 2H), 2.81 (t, J=6.4 Hz, 2H),
7.50-7.57 (m, 3H), 7.80-7.87 (m, 2H), 14.15 (br s, 1H).
Example 12
3-methyl-1-phenyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinolin-5-one
Example 12A
4-cyclohex-1-enyl-2-methyl-5-phenyl-2H-pyrazol-3-ylamine
[0192] The title compound was prepared according to the procedure
as described in EXAMPLE 7A, substituting
5-amino-1-methyl-3-phenylpyrazole for
5-amino-3-methyl-1-phenylpyrazole (36% yield). MS (DCI/NH.sub.3)
m/z 254 (M+H).sup.+.
Example 12B
3-methyl-1-phenyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinolin-5-one
[0193] The title compound was prepared according to the procedure
as described in EXAMPLE 7B, substituting EXAMPLE 12A for EXAMPLE 7A
(66% yield). .sup.1H NMR(C.sub.5D.sub.5N) 1.44-1.56 (m, 2H),
1.66-1.76 (m, 2H), 2.68 (t, J=5.7 Hz, 2H), 2.87 (t, J=5.8 Hz, 2H),
4.06 (s, 3H), 7.43-7.49 (m, 1H), 7.51-7.56 (m, 2H), 7.56-7.58 (m,
1H), 7.89 (t, J=1.7 Hz, 1H), 14.15 (br s, 1H).
Example 13
3-benzyl-1-methyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinolin-5-one
Example 13A
2-benzyl-4-cyclohex-1-enyl-5-methyl-2H-pyrazol-3-ylamine
[0194] The title compound was prepared according to the procedure
as described in EXAMPLE 7A, substituting
2-benzyl-5-methyl-2H-pyrazol-3-ylamine for
5-amino-3-methyl-1-phenylpyrazole (45% yield). MS (DCI/NH.sub.3)
m/z 268 (M+H).sup.+.
Example 13B
3-benzyl-1-methyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinolin-5-one
[0195] The title compound was prepared according to the procedure
as described in EXAMPLE 7B, substituting EXAMPLE 13A for EXAMPLE 7A
(55% yield). .sup.1H NMR(C.sub.5D.sub.5N) 1.64-1.78 (m, 4H), 2.57
(s, 3H), 2.80-2.91 (m, 4H), 5.67 (s, 2H), 7.21-7.24 (m, 1H),
7.26-7.32 (m, 2H), 7.44-7.49 (m, 2H), 14.15 (br s, 1H).
Example 14
3-phenyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinolin-5-one
Example 14A
4-cyclohex-1-enyl-2-phenyl-2H-pyrazol-3-ylamine
[0196] The title compound was prepared according to the procedure
for EXAMPLE 7A, substituting 5-amino-1-phenylpyrazole for
5-amino-3-methyl-1-phenylpyrazole (18% yield). MS (DCI/NH.sub.3)
m/z 240 (M+H).sup.+.
Example 14B
3-phenyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinolin-5-one
[0197] The title compound was prepared according to the procedure
as described in EXAMPLE 7B, substituting EXAMPLE 14A for EXAMPLE 7A
(23% yield). .sup.1H NMR(C.sub.5D.sub.5N) 1.66-1.80 (m, 4H), 2.79
(t, J=6.1 Hz, 2H), 2.85 (t, J=6.1 Hz, 2H), 7.25-7.30 (m, 1H),
7.41-7.50 (m, 2H), 8.19 (s, 1H), 8.54 (dd, J=8.6, 1.2 Hz, 2H),
14.15 (br s, 1H).
Example 15
3-methyl-1-thiophen-2-yl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinolin-5-
-one
Example 15A
4-cyclohex-1-enyl-2-methyl-5-thiophen-2-yl-2H-pyrazol-3-ylamine
[0198] The title compound was prepared according to the procedure
as described in EXAMPLE 7A, substituting
5-amino-1-methyl-3-(2-thienyl)pyrazole for
5-amino-3-methyl-1-phenylpyrazole (30% yield). MS (DCI/NH.sub.3)
m/z 260 (M+H).sup.+.
Example 15B
3-methyl-1-thiophen-2-yl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinolin-5-
-one
[0199] The title compound was prepared according to the procedure
as described in EXAMPLE 7B, substituting EXAMPLE 15A for EXAMPLE 7A
(73% yield). .sup.1H NMR(C.sub.5D.sub.5N) 1.54-1.60 (m, 2H),
1.69-1.77 (m, 2H), 2.87 (t, J=6.4 Hz, 4H), 4.02 (s, 3H), 7.24 (dd,
J=5.2, 3.7 Hz, 1H), 7.54 (dd, J=3.4, 0.9 Hz, 1H), 7.57 (d, J=0.9
Hz, 1H), 14.15 (br s, 1H).
Example 16
1-isopropyl-3-methyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinolin-5-one
Example 16A
4-cyclohex-1-enyl-5-isopropyl-2-methyl-2H-pyrazol-3-ylamine
[0200] The title compound was prepared according to the procedure
as described in EXAMPLE 7A, substituting
3-isopropyl-1-methyl-1H-pyrazol-5-amine for
5-amino-3-methyl-1-phenylpyrazole (13% yield). MS (DCI/NH.sub.3)
m/z 220 (M+H).sup.+.
Example 16B
1-isopropyl-3-methyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinolin-5-one
[0201] The title compound was prepared according to the procedure
as described in EXAMPLE 7B, substituting EXAMPLE 16A for EXAMPLE 7A
(44% yield). .sup.1H NMR(C.sub.5D.sub.5N) 1.51 (d, J=6.7 Hz, 6H),
1.68-1.81 (m, 4H), 2.87 (m, 2H), 2.93 (m, 2H), 3.32-3.47 (m, 1H),
3.95 (s, 3H), 13.45 (br, s 1H).
Example 17
1-cyclopropyl-3-methyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinolin-5-o-
ne
Example 17A
4-cyclohex-1-enyl-5-cyclopropyl-2-methyl-2H-pyrazol-3-ylamine
[0202] The title compound was prepared according to the procedure
as described in EXAMPLE 7A, substituting
3-cyclopropyl-1-methyl-1H-pyrazol-5-amine for
5-amino-3-methyl-1-phenylpyrazole (50% yield). MS (DCI/NH.sub.3)
m/z 218 (M+H).sup.+.
Example 17B
1-cyclopropyl-3-methyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinolin-5-o-
ne
[0203] The title compound was prepared according to the procedure
as described in EXAMPLE 7B, substituting EXAMPLE 17A for EXAMPLE 7A
(83% yield). .sup.1H NMR(C.sub.5D.sub.5N) 0.92-1.01 (m, 2H),
1.17-1.28 (m, 2H), 1.69-1.82 (m, 4H), 2.16-2.27 (m, 1H), 2.86 (t,
J=4.4 Hz, 2H), 3.06 (t, J=4.4 Hz, 2H), 3.91 (s, 3H), 13.46 (br s,
1H).
Example 19
1-cyclopropyl-3-methyl-4,6,8,9-tetrahydro-3H-7-oxa-2,3,4-triaza-cyclopenta-
[a]naphthalen-5-one
Example 19A
5-cyclopropyl-4-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-2H-pyrazol-3-ylamine
[0204] The title compound was prepared according to the procedure
as described in EXAMPLE 7A, substituting
3-cyclopropyl-1-methyl-1H-pyrazol-5-amine for
5-amino-3-methyl-1-phenylpyrazole and substituting
tetrahydro-4H-pyran-4-one for cyclohexanone (67% yield). MS
(DCI/NH.sub.3) m/z 220 (M+H).sup.+.
Example 19B
1-cyclopropyl-3-methyl-4,6,8,9-tetrahydro-3H-7-oxa-2,3,4-triaza-cyclopenta-
[a]naphthalen-5-one
[0205] The title compound was prepared according to the procedure
as described in EXAMPLE 7B, substituting EXAMPLE 19A for EXAMPLE 7A
(20% yield). .sup.1H NMR (DMSO-d.sub.6) 0.77-0.83 (m, 2H),
0.83-0.90 (m, 2H), 2.04-2.18 (m, 1H), 2.96-3.11 (m, 2H), 3.72 (s,
3H), 3.87 (t, J=5.6 Hz, 2H), 4.41 (s, 2H), 11.99 (br s, 1H)
Example 20
1-(3-chlorophenyl)-3-methyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinoli-
n-5-one
Example 20A
5-(3-chlorophenyl)-4-cyclohex-1-enyl-2-methyl-2H-pyrazol-3-ylamine
[0206] The title compound was prepared according to the procedure
as described in EXAMPLE 7A, substituting
5-(3-chlorophenyl)-2-methyl-2H-pyrazole-3-ylamine for
5-amino-3-methyl-1-phenylpyrazole (14% yield). MS (DCI/NH.sub.3)
m/z 288 (M+H).sup.+.
Example 20B
1-(3-chlorophenyl)-3-methyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinoli-
n-5-one
[0207] The title compound was prepared according to the procedure
as described in EXAMPLE 7B, substituting EXAMPLE 20A for EXAMPLE 7A
(3% yield). .sup.1H NMR (DMSO-d.sub.6) 0.52-1.62 (m, 2H), 1.64-1.74
(m, 2H), 2.37-2.48 (m, 4H), 3.88 (s, 3H), 7.47-7.51 (m, 3H),
7.53-7.58 (m, 1H), 12.04 (br s, 1H).
Example 21
3-methyl-1-thiophen-2-yl-4,6,7,8-tetrahydro-3H-2,3,4-triaza-as-indacen-5-o-
ne
Example 21A
4-cyclopent-1-enyl-2-methyl-5-thiophen-2-yl-2H-pyrazol-3-ylamine
[0208] The title compound was prepared according to the procedure
as described in EXAMPLE 7A, substituting
5-amino-1-methyl-3-(2-thienyl)pyrazole for
5-amino-3-methyl-1-phenylpyrazole and substituting cyclopentanone
for cyclohexanone (20% yield). MS (DCI/NH.sub.3) m/z 246
(M+H).sup.+.
Example 21B
3-methyl-1-thiophen-2-yl-4,6,7,8-tetrahydro-3H-2,3,4-triaza-as-indacen-5--
one
[0209] The title compound was prepared according to the procedure
as described in EXAMPLE 7B, substituting EXAMPLE 21A for EXAMPLE 7A
(70% yield). .sup.1H NMR (DMSO-d.sub.6) 2.07 (dt, J=15.0, 7.5 Hz,
2H), 2.71 (t, J=7.4 Hz, 2H), 3.16 (t, J=7.4 Hz, 2H), 3.89 (s, 3H),
7.15 (dd, J=4.6, 4.0 Hz, 1H), 7.45 (d, J=3.7 Hz, 1H), 7.56 (d,
J=5.2 Hz, 1H), 11.94 (br s, 1H).
Example 22
1-cyclopropyl-3-methyl-4,6,7,8-tetrahydro-3H-2,3,4-triaza-as-indacen-5-one
Example 22A
4-cyclopent-1-enyl-5-cyclopropyl-2-methyl-2H-pyrazol-3-ylamine
[0210] The title compound was prepared according to the procedure
as described in EXAMPLE 7A, substituting
3-cyclopropyl-1-methyl-1H-pyrazol-5-amine for
5-amino-3-methyl-1-phenylpyrazole and substituting cyclopentanone
for cyclohexanone (30% yield). MS (DCI/NH.sub.3) m/z 204
(M+H).sup.+.
Example 22B
1-cyclopropyl-3-methyl-4,6,7,8-tetrahydro-3H-2,3,4-triaza-as-indacen-5-one
[0211] The title compound was prepared according to the procedure
as described in EXAMPLE 7B, substituting EXAMPLE 22A for EXAMPLE 7A
(60% yield). .sup.1H NMR (DMSO-d.sub.6) 0.74-0.83 (m, 2H), 0.88
(dd, J=8.2, 2.4 Hz, 2H), 1.97-2.12 (m, 3H), 2.65 (t, J=6.9 Hz, 2H),
3.12 (t, J=7.3 Hz, 2H), 3.72 (s, 3H), 11.78 (br s, 1H).
Example 23
1-cyclopropyl-3-methyl-4,6,7,8,9,10-hexahydro-3H-2,3,4-triazacyclohepta[e]-
inden-5-one
Example 23A
4-Cyclohept-1-enyl-5-cyclopropyl-2-methyl-2H-pyrazol-3-ylamine
[0212] The title compound was prepared according to the procedure
as described in EXAMPLE 7A, substituting
3-cyclopropyl-1-methyl-1H-pyrazol-5-amine for
5-amino-3-methyl-1-phenylpyrazole and substituting cycloheptanone
for cyclohexanone (6% yield). MS (DCI/NH.sub.3) m/z 232
(M+H).sup.+.
Example 23B
1-cyclopropyl-3-methyl-4,6,7,8,9,10-hexahydro-3H-2,3,4-triazacyclohepta[e]-
inden-5-one
[0213] The title compound was prepared according to the procedure
as described in EXAMPLE 7B, substituting EXAMPLE 23A for EXAMPLE 7A
(30% yield). .sup.1H NMR (DMSO-d.sub.6) 0.76-0.80 (m, 2H),
0.82-0.89 (m, 2H), 1.41-1.48 (m, 2H), 1.59-1.66 (m, 2H), 1.83 (ddd,
J=11.2, 6.0, 5.7 Hz, 2H), 2.02-2.10 (m, 1H), 2.74-2.83 (m, 2H),
3.14-3.22 (m, 2H), 3.72 (s, 3H), 11.70 (br s, 1H).
Example 24
[0214] benzyl
3-(3-methyl-5-oxo-4,5,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinolin-1-yl)-p-
yrrolidine-1-carboxylate
Example 24A
N-carbobenzyloxypyrrolidine-3-carboxylic acid methyl ester
[0215] To a solution of N-carbobenzyloxypyrrolidine-3-carboxylic
acid (10.15 g, 40.72 mmol) and iodomethane (5.08 mL, 81.44 mmol) in
N,N'-dimethylformamide (80 mL) was added powdered potassium
hydrogen carbonate (8.15 g, 81.44 mmol) and the reaction mixture
stirred at ambient temperature for 5 hours. The mixture was
partitioned between ethyl acetate and brine and the organic phase
washed with water and concentrated. The residue was purified by
flash chromatography on silica gel using 5-50% ethyl acetate in
hexane to give the title compound (10.59 g, 99%). MS (DCI): m/z 264
(M+1).sup.+.
Example 24B benzyl 3-(2-cyanoacetyl)-pyrrolidine-1-carboxylate
[0216] To a solution of acetonitrile (708 .mu.L, 13.5 mmol) in
tetrahydrofuran (30 mL) was added n-butyl lithium (1.6 M solution
in hexane, 7.75 mL, 12.4 mmol) at -78.degree. C. The solution was
stirred at -78.degree. C. for 10 minutes and a solution of EXAMPLE
24A (3.0 g, 11.34 mmol) in 10 mL of tetrahydrofuran was added. The
mixture was stirred at -78.degree. C. for 1 hour and was warmed up
to -20.degree. C. over 3 hours. Water was added and the mixture
acidified to pH 3 with 2N hydrochloric acid. The mixture was
partitioned between ethyl acetate and brine and the organic phase
concentrated. The residue was purified by flash chromatography on
silica gel using 30-80% ethyl acetate in hexane to give the title
compound (1.91 g, 61%). MS (DCI): m/z 273 (M+1).sup.+.
Example 24C
benzyl
3-(5-amino-1-methyl-1H-pyrazol-3-yl)-pyrrolidine-1-carboxylate
[0217] A solution of EXAMPLE 24B (1.9 g, 7 mmol) and
methylhydrazine (367 .mu.L, 7 mmol) in ethanol (15 mL) was heated
at reflux for 4 hours. After cooling, the mixture was concentrated
and the residue purified by flash chromatography on silica gel
using 0-15% methanol in dichloromethane to give the title compound
(1.78 g, 85%). MS (DCI): m/z 301 (M+1).sup.+.
Example 24D
benzyl
3-(5-amino-4-cyclohex-1-enyl-1-methyl-1H-pyrazol-3-yl)pyrrolidine-1-
-carboxylate
[0218] A solution of EXAMPLE 24C (1.78 g, 5.92 mmol) and
cyclohexanone (1.23 mL, 11.85 mmol) in acetic acid (10 mL) was
stirred at ambient temperature overnight and at 55.degree. C. for 1
day. The acetic acid was removed and the residue partitioned
between sodium bicarbonate solution and ethyl acetate. The organic
phase was washed with water, concentrated and the residue purified
by flash chromatography on silica gel using 70-90% ethyl acetate in
hexane to provide the title compound as a light yellow solid (1.19
g, 53%). MS (DCI): m/z 381 (M+H).sup.+.
Example 24E
benzyl
3-(3-methyl-5-oxo-4,5,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinolin-1-
-yl)-pyrrolidine-1-carboxylate
[0219] To a stirring solution of EXAMPLE 24D (0.967 g, 2.54 mmol)
in pyridine (10 mL) was added ethyl isocyanate (0.6 mL, 7.62 mmol)
and the solution heated at reflux for 24 hours. After cooling, the
mixture was concentrated and the residue recrystallized from
methanol. The white solid was collected by filtration, washed with
methanol and dried to give the title compound (794 mg, 77%).
.sup.1H NMR (DMSO-d.sub.6): 1.66-1.77 (m, 4H), 2.01-2.17 (m, 1H),
2.18-2.27 (m, 1H), 2.37-2.43 (m, 2H), 2.86-2.92 (m, 2H), 3.33-3.46
(m, 1H), 3.49-3.64 (m, 2H), 3.68-3.76 (m, 1H), 3.76 (s, 3H),
3.77-3.85 (m, 1H), 5.08 (s, 2H), 7.29-7.35 (m, 1H), 7.34-7.39 (m,
5H).
Example 25
3-methyl-1-pyrrolidin-3-yl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinolin-
-5-one
[0220] A solution of EXAMPLE 24E (766 mg, 1.88 mmol) in a mixture
of dichloromethane (30 mL) and methanol (30 mL) was treated with
10% palladium on carbon (150 mg) under hydrogen at ambient
temperature for 6 hours. Solid material was filtered off and the
filtrate concentrated to provide the title compound (564 mg, 100%).
.sup.1H NMR (DMSO-d.sub.6): 1.67-1.79 (m, 4H), 2.01-2.11 (m, 1H),
2.22-2.32 (m, 1H), 2.38-2.43 (m, 2H), 2.85-2.91 (m, 2H), 3.16-3.26
(m, 2H), 3.30 (dd, J=11.0, 8.0 Hz, 1H), 3.46 (dd, J=11.2, 7.5 Hz,
1H), 3.78 (s, 3H), 3.81-3.88 (m, 1H).
Example 26
3-methyl-1-(1-methylpyrrolidin-3-yl)-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]i-
soquinolin-5-one
[0221] To a solution of EXAMPLE 25 (86 mg, 0.316 mmol) in methanol
(6 mL) was added formaldehyde (37 wt % in water, 118 .mu.L, 1.58
mmol) at ambient temperature and the solution stirred for 1 hour.
Sodium cyanoborohydride (99 mg, 1.58 mmol) was added and the
mixture stirred overnight and concentrated. The residue was
purified by HPLC (Zorbax, C-18, 250.times.2.54 column, Mobile phase
A: 0.1% trifluoroacetic acid in water; B: 0.1% trifluoroacetic acid
in acetonitrile; 0-100% gradient) to provide the title compound as
the trifluoroacetate salt (110 mg, 79%). .sup.1H NMR (CD.sub.3OD):
1.77-1.87 (m, 4H), 2.24-2.37 (m, 1H), 2.49 (t, J=6.0 Hz, 2H), 2.66
(dd, J=13.6, 6.0 Hz, 0.5H), 2.90-2.96 (m, 2.5H), 3.02 (s, 1H), 3.08
(s, 1H), 3.24-3.31 (m, 1H), 3.44 (dd, J=11.4, 7.8 Hz, 0.5H), 3.62
(dd, J=11.3, 7.6 Hz, 0.5H), 3.72-3.83 (m, 0.5H), 3.84 (s, 3H), 3.84
(m, 0.5H), 3.97-4.03 (m, 0.5H), 4.04-4.14 (m, 1H), 4.19-4.26 (m,
0.5H).
Example 27
1-(1-isopropylpyrrolidin-3-yl)-3-methyl-3,4,6,7,8,9-hexahydropyrazolo[3,4--
c]isoquinolin-5-one
[0222] The trifluoroacetate salt of the title compound was prepared
according to the procedure as described in EXAMPLE 26, substituting
acetone for formaldehyde (77% yield). .sup.1H NMR (CD.sub.3OD):
1.39-1.46 (m, 6H), 1.77-1.88 (m, 4H), 2.23-2.32 (m, 1H), 2.44-2.53
(m, 2.5H), 2.54-2.62 (m, 0.5H), 2.87-3.00 (m, 2H), 3.33-3.42 (m,
1H), 3.51-3.56 (m, 0.5H), 3.58-3.66 (m, 1H), 3.66-3.72 (m, 1H),
3.74-3.79 (m, 0.5H), 3.84 (s, 3H), 3.92 (dd, J=11.6, 7.3 Hz, 0.5H),
3.97 (dd, J=11.4, 5.0 Hz, 0.5H), 4.03-4.11 (m, 0.5H), 4.14-4.21 (m,
0.5H).
Example 28
3-methyl-1-(1-propylpyrrolidin-3-yl)-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]i-
soquinolin-5-one
[0223] The trifluoroacetate salt of the title compound was prepared
according to the procedure as described in EXAMPLE 26, substituting
propionaldehyde for formaldehyde (67% yield). .sup.1H NMR
(CD.sub.3OD): 1.06 (t, J=7.5 Hz, 3H), 1.75-1.89 (m, 6H), 2.21-2.35
(m, 1H), 2.43-2.54 (m, 2.5H), 2.58-2.66 (m, 0.5H), 2.89-2.99 (m,
2H), 3.19-3.26 (m, 1H), 3.29-3.35 (m, 1H), 3.48 (dd, J=11.5, 8.1
Hz, 0.5H), 3.64 (dd, J=11.0, 7.4 Hz, 0.5H), 3.71-3.82 (m, 1H), 3.84
(s, 3H), 3.98 (dd, J=11.4, 7.67 Hz, 0.5H), 4.04-4.11 (m, 1H),
4.17-4.23 (m, 0.5H).
Example 29
1-(1-cyclopropylmethylpyrrolidin-3-yl)-3-methyl-3,4,6,7,8,9-hexahydropyraz-
olo[3,4-c]isoquinolin-5-one
[0224] The trifluoroacetate salt of the title compound was prepared
according to the procedure as described in EXAMPLE 26, substituting
cyclopropanecarboxyaldehyde for formaldehyde (66% yield). .sup.1H
NMR (CD.sub.3OD): 0.45-0.50 (m, 2H), 0.74-0.79 (m, 2H), 1.14-1.23
(m, 1H), 1.77-1.88 (m, 4H), 2.23-2.35 (m, 1H), 2.47-2.54 (m, 2.5H),
2.59-2.67 (m, 0.5H), 2.88-3.00 (m, 2H), 3.18 (dd, J=7.2, 2.0 Hz,
1H), 3.26 (dd, J=7.3, 1.2 Hz, 1H), 3.29-3.40 (m, 1H), 3.56 (dd,
J=11.6, 8.2 Hz, 0.5H), 3.69 (dd, J=11.6, 7.6 Hz, 0.5H), 3.76-3.84
(m, 1H), 3.84 (s, 1.5H), 3.85 (s, 1.5H), 3.97-4.04 (m, 0.5H),
4.08-4.16 (m, 1H), 4.18-4.24 (m, 0.5H).
Example 30
1-(1-cyclobutylpyrrolidin-3-yl)-3-methyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-
-c]isoquinolin-5-one
[0225] The trifluoroacetate salt of the title compound was prepared
according to the procedure as described in EXAMPLE 26, substituting
cyclobutanone for formaldehyde (69% yield). .sup.1H NMR
(CD.sub.3OD): 1.77-1.88 (m, 4H), 1.89-2.00 (m, 2H), 2.21-2.33 (m,
3H), 2.34-2.43 (m, 2H), 2.49 (t, J=5.8 Hz, 2.5H), 2.54-2.63 (m,
0.5H), 2.87-3.00 (m, 2H), 3.19-3.27 (m, 1H), 3.42 (dd, J=11.6, 8.2
Hz, 0.5H), 3.53 (dd, J=11.6, 7.6 Hz, 0.5H), 3.62-3.74 (m, 1H), 3.84
(s, 3H), 3.88-3.93 (m, 1H), 3.95-4.01 (m, 0.5H), 4.02-4.06 (m,
0.5H), 4.07-4.13 (m, 0.5H), 4.16-4.22 (m, 0.5H).
Example 31
(S)-3-methyl-1-pyrrolidin-2-yl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquin-
olin-5-one
[0226] The trifluoroacetate salt of the title compound was prepared
according to the procedure as described in EXAMPLES 24B-E and
EXAMPLE 25, substituting N-carbobenzyloxy-L-proline methyl ester
for EXAMPLE 24A. .sup.1H NMR (CD.sub.3OD): 1.78-1.91 (m, 4H),
2.13-2.20 (m, 1H), 2.22-2.31 (m, 2H), 2.47-2.57 (m, 3H), 2.87-2.99
(m, 2H), 3.39-3.48 (m, 1H), 3.51-3.61 (m, 1H), 3.88 (s, 3H),
4.98-5.41 (m, 1H).
Example 32
(S)-3-M
ethyl-1-(1-methylpyrrolidin-2-yl)-3,4,6,7,8,9-hexahydropyrazolo[3,-
4-e]isoquinolin-5-one
[0227] A solution of EXAMPLE 31 (100 mg, 0.37 mmol), triethylamine
(52 L, 0.37 mmol) and formaldehyde (37% in water, 31 L, 1.11 mmol)
in 1:1 methanol/N,N'-dimethylformamide (6 mL) was stirred at
ambient temperature for 2 hours. Sodium cyanoborohydride (70 mg,
1.11 mmol) and zinc chloride (50 mg, 0.37 mmol) were added and the
mixture stirred at 50.degree. C. for 18 hours. The mixture was
concentrated and the residue purified by HPLC (Zorbax C-8, 0.1%
trifluoroacetic acid/acetonitrile/water) to provide the
trifluoroacetate salt of the title compound. Treatment of a
methanol solution of the trifluoroacetate salt with a solution of
hydrochloric acid in ether gave the title compound as the
hydrochloride salt (13 mg, 12%). .sup.1H NMR (CD.sub.3OD):
[0228] 1.79-1.91 (m, 4H), 2.10-2.24 (m, 2H), 2.26-2.36 (m, 1H),
2.49-2.55 (m, 2H), 2.69-2.78 (m, 1H), 2.80-2.88 (m, 1H), 2.93-3.01
(m, 1H), 2.96 (s, 3H), 3.32-3.39 (m, 1H), 3.81-3.87 (m, 1H), 3.91
(s, 3H), 4.97 (t, J=8.4 Hz, 1H).
Example 33
(S)-3-methyl-1-(1-propyl-pyrrolidin-2-yl)-3,4,6,7,8,9-hexahydropyrazolo[3,-
4-c]isoquinolin-5-one
[0229] The title compound as the hydrochloride salt was prepared
according to the procedure for EXAMPLE 32, substituting
propionaldehyde for formaldehyde (10% yield). .sup.1H NMR
(CD.sub.3OD): 0.97 (t, J=7.3 Hz, 3H), 1.64-1.77 (m, 2H), 1.80-1.90
(m, 4H), 2.06-2.14 (m, 1H), 2.15-2.23 (m, 1H), 2.23-2.32 (m, 1H),
2.48-2.56 (m, 2H), 2.66-2.74 (m, 1H), 2.79-2.87 (m, 1H), 2.91-3.00
(m, 1H), 3.07-3.16 (m, 1H), 3.22-3.29 (m, 2H), 3.85-3.90 (m, 1H),
3.91 (s, 3H), 5.01 (t, J=8.4 Hz, 1H).
Example 34
(S)-1-(1-isopropylpyrrolidin-2-yl)-3-methyl-3,4,6,7,8,9-hexahydropyrazolo[-
3,4-c]isoquinolin-5-one
[0230] The hydrochloride salt of the title compound was prepared
according to the procedure as described in EXAMPLE 32, substituting
acetone for formaldehyde (42% yield). .sup.1H NMR (CD.sub.3OD):
1.33 (dd, J=6.7, 3.0 Hz, 6H), 1.79-1.92 (m, 4H), 2.03-2.12 (m, 1H),
2.15-2.28 (m, 2H), 2.52 (t, J=6.1 Hz, 2H), 2.63-2.72 (m, 1H),
2.81-2.91 (m, 1H), 2.92-3.01 (m, 1H), 3.35-3.43 (m, 1H), 3.69-3.77
(m, 2H), 3.92 (s, 3H), 5.10 (t, J=7.8 Hz, 1H).
Example 35 (A-936655.3)
(S)-1-(1-cyclopropylmethylpyrrolidin-2-yl)-3-methyl-3,4,6,7,8,9-hexahydrop-
yrazolo[3,4-c]isoquinolin-5-one
[0231] The hydrochloride salt of the title compound was prepared
according to the procedure as described in EXAMPLE 32, substituting
cyclopropane carboxaldehyde for formaldehyde (36% yield). .sup.1H
NMR (CD.sub.3OD): 0.35-0.42 (m, 2H), 0.65-0.71 (m, 2H), 1.06-1.13
(m, 1H), 1.78-1.92 (m, 4H), 2.05-2.13 (m, 1H), 2.18-2.25 (m, 1H),
2.27-2.33 (m, 1H), 2.48-2.55 (m, 2H), 2.67-2.76 (m, 1H), 2.79-2.88
(m, 1H), 2.91-3.00 (m, 1H), 3.08-3.19 (m, 2H), 3.36-3.42 (m, 1H),
3.91 (s, 3H), 3.96-4.01 (m, 1H), 5.02 (t, J=8.5 Hz, 1H).
Example 36
(S)-1-(1-cyclobutylpyrrolidin-2-yl)-3-methyl-3,4,6,7,8,9-hexahydropyrazolo-
[3,4-c]isoquinolin-5-one
[0232] The hydrochloride salt of the title compound was prepared
according to the procedure as described in EXAMPLE 32, substituting
cyclobutanone for formaldehyde (27% yield). .sup.1H NMR
(CD.sub.3OD): 1.71-1.83 (m, 4H), 1.85-1.93 (m, 3H), 1.94-2.02 (m,
1H), 2.17-2.26 (m, 3H), 2.26-2.31 (m, 1H), 2.32-2.39 (m, 1H),
2.49-2.56 (m, 2H), 2.62-2.71 (m, 1H), 2.83-2.91 (m, 1H), 2.91-3.00
(m, 1H), 3.23-3.29 (m, 1H), 3.73-3.80 (m, 1H), 3.93 (s, 3H),
3.94-4.00 (m, 1H), 4.93 (t, J=7.6 Hz, 1H).
Example 37
(S)-1-(1-isobutylpyrrolidin-2-yl)-3-methyl-3,4,6,7,8,9-hexahydropyrazolo[3-
,4-c]isoquinolin-5-one
[0233] The hydrochloride salt of the title compound was prepared
according to the procedure as described in EXAMPLE 32, substituting
isobutyraldehyde for formaldehyde (29% yield). .sup.1H NMR
(CD.sub.3OD): 1.09 (d, J=6.7 Hz, 6H), 1.80-1.90 (m, 4H), 2.07-2.12
(m, 1H), 2.14-2.19 (m, 1H), 2.23-2.30 (m, 1H), 2.51 (s, 2H),
2.66-2.74 (m, 1H), 2.79-2.88 (m, 1H), 2.91-3.00 (m, 1H), 3.07 (t,
J=6.0 Hz, 2H), 3.11-3.16 (m, 1H), 3.32-3.36 (m, 1H), 3.91 (s, 3H),
3.93-3.97 (m, 1H), 5.00-5.06 (m, 1H).
Example 38
3-methyl-1-methylaminomethyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinol-
in-5-one
Example 38A
methyl-(3-methyl-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-c]isoquinolin-
-1-ylmethyl)carbamic acid benzyl ester
[0234] The title compound was prepared according to the procedure
as described in EXAMPLE 24B-E, substituting
methyl(benzyloxycarbonylmethylamino)acetate for EXAMPLE 24A. MS
(DCI/NH.sub.3) m/z 381 (M+H).sup.+.
Example 38B
3-methyl-1-methylaminomethyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinol-
in-5-one
[0235] A solution of EXAMPLE 38A (160 mg) in trifluoroacetic acid
(10 mL) was heated at 60.degree. C. for 18 hours. The mixture was
cooled, diluted with acetonitrile and concentrated. The residue was
purified by HPLC (Zorbax C-8, 0.1% trifluoroacetic
acid/acetonitrile/water) and the trifluoroacetate salt dissolved in
methanol and treated with a solution of hydrochloric acid in ether
to provide the title compound as the hydrochloride salt (82 mg,
79%). .sup.1H NMR (DMSO-d.sub.6): 1.67-1.79 (m, 4H), 2.38-2.45 (m,
2H), 2.66 (t, J=4.3 Hz, 3H), 2.84-2.95 (m, 2H), 3.86 (s, 3H),
4.40-4.44 (m, 2H), 9.06 (br s, 1H), 12.17 (br s, 1H).
Example 39
[0236]
benzyl[4-(3-methyl-5-oxo-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoqui-
nolin-1-yl)benzyl]carbamate
[0237] The title compound was prepared according to the procedure
for Example 24B-E, substituting methyl
4-(benzyloxycarbonylaminomethyl)benzoate for Example 24A. .sup.1H
NMR (DMSO-d.sub.6) 1.48-1.59 (m, 2H), 1.62-1.74 (m, 2H), 2.36-2.49
(m, 4H), 3.87 (s, 3H), 4.28 (d, J=6.1 Hz, 2H), 5.07 (s, 2H),
7.28-7.34 (m, 3H), 7.35-7.41 (m, 3H), 7.46 (d, J=8.3 Hz, 2H), 7.86
(t, J=6.0 Hz, 1H).
Example 40
1-(4-aminomethylphenyl)-3-methyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoqu-
inolin-5-one
[0238] A solution of Example 39 (90 mg, 0.2 mmol) in
trifluoroacetic acid (10 mL) was stirred at 50.degree. C. for 4
hours. After cooling, the mixture was concentrated and the residue
purified by HPLC (Zorbax, C-18, 250.times.2.54 column, Mobile phase
A 0.1% trifluoroacetic acid in water, B 0.1% trifluoroacetic acid
in acetonitrile, 0-100% gradient) to provide 70 mg of the title
compound as the trifluoroacetate salt. .sup.1H NMR (CD.sub.3OD)
1.53-1.63 (m, 2H), 1.71-1.80 (m, 2H), 2.42-2.54 (m, 4H), 3.92 (s,
3H), 4.21 (s, 2H), 7.52-7.65 (m, 4H).
Example 41
1-(4-dimethylaminomethylphenyl)-3-methyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-
-c]isoquinolin-5-one
[0239] The trifluoroacetate salt of the title compound was prepared
according to the procedure as described in Example 26, substituting
Example 40 for Example 25. .sup.1H NMR (CD.sub.3OD) 1.58-1.65 (m,
2H), 1.73-1.81 (m, 2H), 2.49 (q, J=6.4 Hz, 4H), 2.91 (s, 6H), 3.93
(s, 3H), 4.40 (s, 2H), 7.58-7.68 (m, 4H).
Example 42
1-[4-(isopropylamino-methyl)-phenyl]-3-methyl-3,4,6,7,8,9-hexahydropyrazol-
o[3,4-c]isoquinolin-5-one
[0240] The trifluoroacetate salt of the title compound was prepared
according to the procedure as described in Example 26, substituting
Example 40 for Example 25, and substituting acetone for
formaldehyde. .sup.1H NMR (CD.sub.3OD) 1.43 (d, J=6.8 Hz, 6H),
1.52-1.65 (m, 2H), 1.72-1.82 (m, 2H), 2.41-2.54 (m, 4H), 3.44-3.55
(m, 1H), 3.93 (s, 3H), 4.29 (s, 2H), 7.56-7.67 (m, 4H).
Example 43
1-(4-cyclohexylaminomethylphenyl)-3-methyl-3,4,6,7,8,9-hexahydropyrazolo[3-
,4-c]isoquinolin-
[0241] The trifluoroacetate salt of the title compound was prepared
according to the procedure as described in Example 26, substituting
Example 40 for Example 25 and substituting cyclohexanone for
formaldehyde. .sup.1H NMR (CD.sub.3OD) 1.20-1.32 (m, 2H), 1.32-1.50
(m, 3H), 1.54-1.64 (m, 2H), 1.70-1.82 (m, 3H), 1.92 (dd, J=9.0, 2.9
Hz, 2H), 2.16-2.27 (m, 2H), 2.39-2.55 (m, 4H), 3.10-3.25 (m, 1H),
3.92 (s, 3H), 4.30 (s, 2H), 7.56-7.66 (m, 4H).
Example 44
1-(4-cyclopentylaminomethylphenyl)-3-methyl-3,4,6,7,8,9-hexahydropyrazolo[-
3,4-c]isoquinolin-5-one
[0242] The trifluoroacetate salt of the title compound was prepared
according to the procedure for Example 26, substituting Example 40
for Example 25 and substituting cyclopentanone for formaldehyde.
.sup.1H NMR (CD.sub.3OD) 1.50-1.63 (m, 2H), 1.64-1.80 (m, 6H),
1.81-1.94 (m, 2H), 2.12-2.32 (m, 2H), 2.33-2.61 (m, 4H), 3.52-3.77
(m, 1H), 3.92 (s, 3H), 4.28 (s, 2H), 7.43-7.71 (m, 4H).
Example 45
1,3-dimethyl-4,6,7,8-tetrahydro-3H-2,3,4-triaza-as-indacen-5-one
[0243] The title compound was prepared as described in Winters, G;
Sala, A; De Paoli, A.; Ferri, V. Synthesis 1984, 1052-1054.
Example 46
1-(4-cycloheptylaminomethylphenyl)-3-methyl-3,4,6,7,8,9-hexahydropyrazolo[-
3,4-c]isoquinolin-5-one
[0244] The trifluoroacetate salt of the title compound was prepared
according to the procedure as described in EXAMPLE 26, substituting
EXAMPLE 40 for EXAMPLE 25 and substituting cycloheptanone for
formaldehyde. .sup.1H NMR (CD.sub.3OD) 1.52-1.59 (m, 4H), 1.61-1.68
(m, 4H), 1.71-1.78 (m, 4H), 1.78-1.90 (m, 2H), 2.10-2.28 (m, 2H),
2.37-2.59 (m, 4H), 3.26-3.43 (m, 1H), 3.92 (s, 3H), 4.30 (s, 2H),
7.45-7.69 (m, 4H).
Example 47
[0245] The trifluoroacetate salt of the title compound was prepared
according to the procedure as described in Example 26, substituting
EXAMPLE 40 for EXAMPLE 25 and substituting 2-methylpropionaldehyde
for formaldehyde. .sup.1H NMR (CD.sub.3OD) 1.05 (d, J=6.7 Hz, 6H),
1.50-1.67 (m, 2H), 1.67-1.85 (m, 2H), 1.95-2.16 (m, 1H), 2.35-2.60
(m, 4H), 2.94 (d, J=7.0 Hz, 2H), 3.93 (s, 3H), 4.29 (s, 2H),
7.44-7.76 (m, 4H).
Example 48
1-4-(cyclobutylaminomethyl)phenyl)-3-methyl-3,4,6,7,8,9-hexahydropyrazolo[-
3,4-c]isoquinolin-5-one
[0246] The trifluoroacetate salt of the title compound was prepared
according to the procedure as described in Example 26, substituting
EXAMPLE 40 for EXAMPLE 25 and substituting cyclobutanone for
formaldehyde. .sup.1H NMR (CD.sub.3OD) 1.42-1.66 (m, 2H), 1.69-1.83
(m, 2H), 1.86-2.02 (m, 2H), 2.17-2.30 (m, 2H), 2.28-2.42 (m, 2H),
2.41-2.58 (m, 4H), 3.81-3.90 (m, 1H), 3.92 (s, 3H), 4.17 (s, 2H),
7.34-7.77 (m, 4H).
Example 49
1-{4-[(cyclopropylmethylamino)methyl]phenyl}-3-methyl-3,4,6,7,8,9-hexahydr-
opyrazolo[3,4-c]isoquinolin-5-one
[0247] The trifluoroacetate salt of the title compound was prepared
according to the procedure as described in Example 26, substituting
EXAMPLE 40 for EXAMPLE 25 and substituting cyclopropyl aldehyde for
formaldehyde. .sup.1H NMR (CD.sub.3OD) 0.26-0.53 (m, 2H), 0.59-0.81
(m, 2H), 1.02-1.24 (m, 1H), 1.49-1.65 (m, 2H), 1.68-1.85 (m, 2H),
2.34-2.59 (m, 4H), 3.00 (d, J=7.3 Hz, 2H), 3.93 (s, 3H), 4.30 (s,
2H), 7.50-7.71 (m, 4H).
Example 50
1-{4-[(biscyclopropylmethylamino)methyl]phenyl}-3-methyl-3,4,6,7,8,9-hexah-
ydropyrazolo[3,4-e]isoquinolin-5-one
[0248] The trifluoroacetate salt of the title compound was isolated
as a side product from the synthesis of EXAMPLE 49. .sup.1H NMR
(CD.sub.3OD) 0.20-0.49 (m, 4H), 0.80 (d, J=7.9 Hz, 4H), 1.01-1.26
(m, 2H), 1.52-1.69 (m, 2H), 1.70-1.90 (m, 2H), 2.37-2.61 (m, 4H),
2.88-3.19 (m, 2H), 3.19-3.36 (m, 2H), 3.93 (s, 3H), 4.58 (s, 2H),
7.48-7.81 (m, 4H).
Example 51
3-methyl-1-(4-propylaminomethylphenyl)-3,4,6,7,8,9-hexahydropyrazolo[3,4-c-
]isoquinolin-5-one
[0249] The trifluoroacetate salt of the title compound was prepared
according to the procedure as described in Example 26, substituting
EXAMPLE 40 for EXAMPLE 25 and substituting propionaldehyde for
formaldehyde. .sup.1H NMR (CD.sub.3OD) 1.04 (t, J=7.5 Hz, 3H),
1.48-1.65 (m, 2H), 1.66-1.86 (m, 4H), 2.37-2.60 (m, 4H), 2.92-3.16
(m, 2H), 3.92 (s, 3H), 4.28 (s, 2H), 7.39-7.81 (m, 4H).
Example 52
1-dimethylaminomethyl-3-methyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquin-
olin-5-one
[0250] Using the procedure as described in EXAMPLE 26, substituting
EXAMPLE 38 for EXAMPLE 25 provided the trifluoroacetate salt of the
title compound. Treatment of the methanol solution of the
trifluoroacetate salt with a solution of hydrochloric acid in ether
gave the title compound as the hydrochloride salt (30% yield).
.sup.1H NMR (CD.sub.3OD) 1.78-1.92 (m, 4H), 2.51 (t, J=6.1 Hz, 2H),
2.92 (t, J=6.0 Hz, 2H), 3.02 (s, 6H), 3.92 (s, 3H), 4.63 (s,
2H).
Example 53
1-[(isopropylmethylamino)methyl]-3-methyl-3,4,6,7,8,9-hexahydropyrazolo[3,-
4-e]isoquinolin-5-one
[0251] The trifluoroacetate salt of the title compound was prepared
according to the procedure as described in Example 26, substituting
EXAMPLE 38 for EXAMPLE 25 and substituting acetone for
formaldehyde. Treatment of the methanol solution of the
trifluoroacetate salt with a solution of hydrochloric acid in ether
gave the title compound as the hydrochloride salt (39% yield).
.sup.1H NMR (CD.sub.3OD) 1.45 (dd, J=6.7, 1.8 Hz, 6H), 1.78-1.93
(m, 4H), 2.51 (t, J=6.1 Hz, 2H), 2.91 (s, 3H), 2.93-2.98 (m, 2H),
3.80-3.88 (m, 1H), 3.92 (s, 3H), 4.43 (d, J=14.7 Hz, 1H), 4.74 (d,
J=14.7 Hz, 1H).
Example 54
(S)-3-methyl-1-piperidin-2-yl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquino-
lin-5-one
[0252] The trifluoroacetate salt of the title compound was prepared
according to the procedures as described in EXAMPLES 24 and 25,
substituting (R)-(+)-1-(carboxybenzyl)-2-piperidine carboxylic acid
for 1-N-carboxybenzylpyrrolidine-3-carboxylic acid, followed by
purification by HPLC (Zorbax, C-18, 250.times.2.54 column, Mobile
phase A: 0.1% trifluoroacetic acid in water; B: 0.1%
trifluoroacetic acid in acetonitrile; 0-100% gradient). .sup.1H NMR
(CD.sub.3OD) 1.76-1.83 (m, 4H), 1.85 (d, J=6.1 Hz, 2H), 1.87-1.90
(m, 1H), 1.93-2.03 (m, 2H), 2.28 (d, J=13.4 Hz, 1H), 2.44-2.57 (m,
2H), 2.78-2.88 (m, 1H), 2.94-3.05 (m, 1H), 3.16-3.27 (m, 1H), 3.47
(d, J=12.5 Hz, 1H), 3.89 (s, 3H), 4.65 (d, J=8.8 Hz, 1H).
Example 55
3-methyl-1-{4-[(2-methyltetrahydro
furan-3-ylamino)methyl]phenyl}-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoqui-
nolin-5-one
[0253] The trifluoroacetate salt of the title compound was prepared
according to the procedure as described in EXAMPLE 26, substituting
EXAMPLE 40 for EXAMPLE 25 and substituting
2-methyltetrahydrofuran-3-one for formaldehyde. .sup.1H NMR(C
D.sub.3 OD) 1.32 (d, J=6.4 Hz, 3H), 1.52-1.63 (m, 2H), 1.69-1.84
(m, 2H), 2.10-2.24 (m, 1H), 2.40-2.57 (m, 4H), 3.55-3.68 (m, 1H),
3.93 (s, 3H), 3.94-4.01 (m, 2H), 4.00-4.14 (m, 1H), 4.18-4.27 (m,
1H), 4.34 (s, 2H), 7.47-7.75 (m, 4H).
Example 56
1-(3-aminomethylphenyl)-3-methyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoqu-
inolin-5-one
Example 56A
methyl 3-[(4-methoxybenzylamino)methyl]benzoate
[0254] To a solution of 4-methoxybenzylamine (5.6 g, 41.2 mmol) in
methanol (100 mL) was added methyl 3-formylbenzoate (5.2 g, 31.7
mmol) at ambient temperature. The solution was stirred for 30
minutes and sodium cyanoborohydride (3.0 g) was added. The mixture
was stirred at ambient temperature overnight and concentrated to
about 20 mL. Water (100 mL) was added and the mixture acidified
with 2N hydrochloric acid to a pH of 3. The mixture was partitioned
between ethyl acetate and brine and the organic phase separated and
concentrated. The residue was purified by flash chromatography on
silica gel using 10% methanol in ethyl acetate to give 6.0 g (67%)
of the title compound. MS (DCI): m/z 286 (M+H).sup.+.
Example 56B
methyl
3-{[benzyloxycarbonyl-(4-methoxybenzyl)amino]methyl}benzoate
[0255] To a mixture of EXAMPLE 56A (6 g, 21 mmol), potassium
carbonate (5 g, 36 mmol), dioxane (150 mL) and water (50 mL) was
added benzyl chlorofomate (3.4 mL, 23 mmol) at ambient temperature
and the mixture stirred overnight. Catalytic piperazine was added
and the mixture stirred for another 30 minutes and concentrated.
The residue was partitioned between dilute hydrochloric acid and
ethyl acetate and the organic phase was washed with water and
concentrated. The residue was purified by flash chromatography on
silica gel using 20% ethyl acetate in hexane to give 8.2 g (93%) of
the title compound. MS (DCI): m/z 420 (M+H).sup.+.
Example 56C
benzyl[3-(2-cyanoacetyl)benzyl]-(4-methoxybenzyl)carbamate
[0256] A solution of acetonitrile (1.46, 28 mmol) in
tetrahydrofuran (180 mL) was treated with n-butyl lithium (1.6 M
solution in hexane, 14 mL, 22.2 mmol) at -78.degree. C. for 10
minutes. A solution of EXAMPLE 56B (7.8 g, 18.6 mmol) in 40 mL of
tetrahydrofuran was added and the mixture stirred at -78.degree. C.
for 1 hour and at ambient temperature for 1 hour. After quenching
with water, the mixture was acidified with 2N hydrochloric acid to
a pH of 3. The mixture was partitioned between ethyl acetate and
brine and the organic phase washed with water and concentrated. The
residue was purified by flash chromatography on silica gel using
30% ethyl acetate in hexane to give 7.7 g (96%) of the title
compound. MS (DCI): m/z 429 (M+H).sup.+.
Example 56D
benzyl[3-(5-amino-1-methyl-1H-pyrazol-3-yl)benzyl]-(4-methoxybenzyl)carbam-
ate
[0257] To a suspension of EXAMPLE 56C (7.7 g, 18 mmol) in ethanol
(60 mL) was added methylhydrazine (1.4 mL, 27 mmol) at ambient
temperature and the solution heated to reflux for 4 hours. After
cooling, the mixture was concentrated and the residue purified by
flash chromatography on silica gel using ethyl acetate to give 4.5
g (56%) of the title compound. MS (DCI): m/z 456 (M+H).sup.+.
Example 56E
benzyl[3-(5-amino-4-cyclohex-1-enyl-1-methyl-1H-pyrazol-3-yl)benzyl]-(4-me-
thoxybenzyl)carbamate
[0258] A solution of EXAMPLE 56D (4.5 g, 10 mmol) in acetic acid
(100 mL) was treated with cyclohexanone (2 mL, 20 mmol) at ambient
temperature for 4 days. The mixture was concentrated and the
residue partitioned between dilute sodium hydroxide and ethyl
acetate. The organic layer was washed with water and concentrated
and the residue purified by flash chromatography on silica gel
using ethyl acetate to give 3.8 g (71%) of the title compound. MS
(DCI): m/z 537 (M+H).sup.+.
Example 56F
benzyl
(4-methoxybenzyl)-[3-(3-methyl-5-oxo-4,5,6,7,8,9-hexahydropyrazolo[-
3,4-c]isoquinolin-1-yl)benzyl]carbamate
[0259] To a solution of EXAMPLE 56E (3.8 g, 7.1 mmol) in pyridine
(100 mL) was added ethyl isocyanate (1.6 mL, 21 mmol) and the
solution stirred at ambient temperature for 24 hours. The mixture
was heated at reflux overnight, cooled, concentrated and the
residue purified by flash chromatography on silica gel using ethyl
acetate to give 3.4 g (85%) of the title compound. MS (DCI): m/z
563 (M+H).sup.+.
Example 56G
1-(3-aminomethylphenyl)-3-methyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoqu-
inolin-5-one
[0260] A solution of EXAMPLE 56F (3.4 g) in trifluoroacetic acid
(20 mL) was stirred at 55.degree. C. for 6 hours. The mixture was
concentrated and the residue purified by HPLC (Zorbax, C-18,
250.times.2.54 column, Mobile phase A: 0.1% trifluoroacetic acid in
water; B: 0.1% trifluoroacetic acid in acetonitrile; 0-100%
gradient) to give the title compound (1.3 g, 50%) as the
trifluoroacetate salt. .sup.1H NMR (CD.sub.3OD) 2.28-2.40 (m, 2H),
2.44-2.57 (m, 2H), 3.08-3.37 (m, 4H), 4.69 (s, 3H), 4.93 (s, 2H),
8.26-8.37 (m, 3H), 8.43 (s, 1H).
Example 57
1-{3-[(dimethylamino)methyl]phenyl}-3-methyl-3,4,6,7,8,9-hexahydro-5H-pyra-
zolo[3,4-c]isoquinolin-5-one
Example 57A
benzyl[3-(3-methyl-5-oxo-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinolin-1-
-yl)benzyl]carbamate
[0261] The title compound was prepared according to the procedure
for Example 24B-E, substituting methyl
3-(benzyloxycarbonylaminomethyl)benzoate for Example 24A.
Example 57B
1-(3-aminomethylphenyl)-3-methyl-3,4,6,7,8,9-hexahydropyrazolo[3,4-c]isoqu-
inolin-5-one
[0262] The trifluoroacetate salt of the title compound was prepared
as described in Example 40, substituting Example 57A for Example
39.
Example 57C
1-{3-[(dimethylamino)methyl]phenyl}-3-methyl-3,4,6,7,8,9-hexahydro-5H-pyra-
zolo[3,4-c]isoquinolin-5-one
[0263] The trifluoroacetate salt of the title compound was prepared
according to the procedure for Example 26, substituting Example 57B
for Example 25. MS (DCI): m/z 337 (M+H).sup.+; .sup.1H NMR (400
MHz, CD.sub.3OD): .delta. 1.58-1.64 (m, 2H), 1.74-1.79 (m, 2H),
2.46-2.53 (m, 4H), 2.90 (s, 6H), 3.93 (s, 3H), 4.40 (s, 2H),
7.60-7.62 (m, 2H), 7.65-7.69 (m, 2H); Anal. Calcd for
C.sub.20H.sub.24N.sub.4O.1.5 TFA: C, 54.44; H, 5.06; N, 11.04.
Found: C, 54.14; H, 4.75; N, 11.01.
Example 58
3-methyl-1-[(2S)-1-propylpiperidin-2-yl]-3,4,6,7,8,9-hexahydro-5H-pyrazolo-
[3,4-c]isoquinolin-5-one
[0264] The hydrochloride salt of the title compound was prepared
according to procedure as describe in Example 26, substituting
Example 54 for Example 25, and substituting propionaldehyde for
formaldehyde. The trifluoroacete salt was treated with 1.0 M
solusion of HCl in ether to yield the HCl salt. MS (DCI/NH.sub.3)
m/z 329 (M+H).sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD): .delta.
0.86 (t, J=7.36 Hz, 3H), 1.60-1.71 (m, 1H), 1.73-1.79 (m, 2H),
1.79-1.84 (m, J=8.59 Hz, 2H), 1.84-1.90 (m, 2H), 1.90-1.97 (m, 2H),
1.98-2.08 (m, 2H), 2.23-2.33 (m, 1H), 2.49-2.58 (m, 2H), 2.76-2.88
(m, 1H), 2.93-3.07 (m, 3H), 3.18-3.28 (m, 1H), 3.76 (d, J=11.97 Hz,
1H), 3.92 (s, 3H), 4.66 (dd, J=11.66, 2.76 Hz, 1H). Anal. Calcd for
C.sub.19H.sub.28N.sub.4O.1.9
[0265] HCl: C, 57.38; H, 7.58; N, 14.09. Found: C, 57.08; H, 7.97;
N, 13.79.
Example 59
1-azetidin-3-yl-3-methyl-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-c]isoquinol-
in-5-one
[0266] The trifluoroacetate salt of the title compound was prepared
according to the procedures for Examples 24A-24E and Example 25,
substituting N-carbobenzyloxyazetidine-3-carboxylic acid for
N-carbobenzyloxypyrrolidine-3-carboxylic acid. MS (DCI): m/z 259
(M+H).sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 1.66-1.75
(m, 4H), 2.37-2.41 (m, 2H), 2.70 (br s, 2H), 3.84 (s, 3
[0267] H), 4.22-4.31 (m, 4H), 4.42 (q, J=8.08 Hz, 1H), 8.94 (br s,
1H), 11.92 (br s, 1H); Anal. Calcd for
C.sub.14H.sub.18N.sub.4O.1.32 TFA: C, 48.88; H, 4.76; N, 13.70.
Found: C, 48.86; H, 4.53; N, 13.80.
Example 60
1-(1-cyclobutylazetidin-3-yl)-3-methyl-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3-
,4-c]isoquinolin-5-one
[0268] The trifluoroacetate salt of the title compound was prepared
according to the procedure for Example 26, substituting Example 59
for Example 25, and cyclobutanone for formaldehyde. MS (DCI): m/z
313 (M+H).sup.+; .sup.1H NMR (500 MHz, Pyridine-d.sub.5): .delta.
1.51-1.77 (m, 6H), 2.07-2.14 (m, 2H), 2.30-2.37 (m, 2H), 2.70 (t,
J=5.95 Hz, 2H), 2.81 (t, J=5.80 Hz, 2H), 3.91-3.96 (m, 1H), 4.01
(s, 3H), 4.37 (t, J=7.93 Hz, 2H), 4.61-4.66 (m, 1H), 4.71 (t,
J=8.85 Hz, 2H); Anal. Calcd for C.sub.18H.sub.24N.sub.4O.1.6 TFA:
C, 51.46; H, 5.21; N, 11.32. Found: C, 51.46; H, 5.32; N,
11.28.
Example 61
1-[4-(aminomethyl)benzyl]-3-methyl-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-c-
]isoquinolin-5-one
[0269] The trifluoroacetate salt of the title compound was prepared
according to the procedure for Examples 24B-24E and Example 25,
substituting methyl
4-((benzyloxycarbonylamino)methyl)phenyl)acetate for Example 24A.
MS (DCI): m/z 323 (M+H).sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 1.61-1.72 (m, 4H), 2.42 (t, J=5.37 Hz, 2H), 2.65 (t, J=5.98
Hz, 2H), 3.86 (s, 3H), 4.07 (s, 2H), 4.24 (s, 2H), 7.23 (d, J=8.59
Hz, 2H), 7.36 (d, J=8.29 Hz, 2H).
Example 62
3-methyl-1-[(2R)-1-(2-phenylethyl)pyrrolidin-2-yl]-3,4,6,7,8,9-hexahydro-5-
H-pyrazolo[3,4-c]isoquinolin-5-one
[0270] The hydrochloride salt of the title compound was prepared
according to procedure for Example 26 substituting
phenylacetaldehyde for formaldehyde, and substituting Example 102
for Example 25. The trifluoroacetate salt was treated with 1.0 M
solution of HCl in ether to yield the HCl salt. MS (DCI/NH.sub.3)
m/z 377 (M+H).sup.+; .sup.1H NMR (500 MHz, CD.sub.3OD): .delta.
1.75-1.89 (m, 4H), 2.03-2.12 (m, 1H), 2.14-2.22 (m, 1H), 2.24-2.33
(m, 1H), 2.46-2.55 (m, 2H), 2.66-2.74 (m, 1H), 2.77-2.87 (m, 2H),
2.93-3.03 (m, 1H), 3.04-3.12 (m, 1H), 3.34-3.42 (m, 1H), 3.46-3.54
(m, 1H), 3.59-3.68 (m, 1H), 3.91 (s, 3H), 3.92-3.97 (m, 1H), 5.04
(t, J=8.09 Hz, 1H), 7.17-7.20 (m, 2H), 7.21-7.23 (m, 1H), 7.25-7.29
(m, 2H).
Example 63
3-methyl-1-piperidin-3-yl-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-c]isoquino-
lin-5-one
[0271] The title compound was prepared according to procedures for
Examples 24A-24E and Example 25 substituting 1-benzyl
piperidine-1,3-dicarboxylate for 1-benzyl
pyrrolidine-1,3-dicarboxylate. The product as TFA salt was treated
with 1.0 M solution of HCl in ether to yield the HCl salt. MS
(DCI/NH.sub.3) m/z 287 (M+H).sup.+; .sup.1H NMR (500 MHz,
CD.sub.3OD): .delta. 1.65-1.78 (m, 5H), 1.80-1.88 (m, 2H),
1.98-2.07 (m, 1H), 2.36-2.46 (m, 2H), 2.81-2.97 (m, 3H), 2.99-3.11
(m, 1H), 3.27 (d, J=12.21 Hz, 1H), 3.37 (d, J=11.90 Hz, 1H),
3.52-3.59 (m, 1H), 3.79 (s, 3H). Anal. Calcd for
C.sub.16H.sub.22N.sub.4O.2.4HCl: C, 51.40; H, 6.58; N, 14.99.
Found: C, 51.69; H, 6.46; N, 14.64.
Example 64
3-methyl-1-piperidin-4-yl-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-e]isoquino-
lin-5-one
[0272] The title compound was prepared as trifluoroacetate salt
according to procedure for Examples 24A-24E and Example 25
substituting 1-benzyl piperidine-1,4-dicarboxylate for 1-benzyl
pyrrolidine-1,3-dicarboxylate. MS (DCI/NH.sub.3) m/z 287
(M+H).sup.+; .sup.1H NMR (500 MHz, CD.sub.3OD): .delta. 1.67-1.79
(m, 4H), 1.85-1.95 (m, 2H), 1.97-2.05 (m, 2H), 2.35-2.46 (m, 2H),
2.85-2.94 (m, 2H), 3.06 (q, J=11.60 Hz, 2H), 3.27-3.34 (m, 3H),
3.77 (s, 3H); Anal. Calcd for C.sub.16H.sub.22N.sub.4O.1.0 TFA: C,
54.00; H, 5.79; N, 13.99. Found: C, 53.98; H, 5.61; N, 13.87.
Example 65
1-cyclopropyl-3,7-dimethyl-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-c]isoquin-
olin-5-one
[0273] The title compound was prepared according to procedure for
Examples 7A-7B substituting 4-methylcyclohexanone for
cyclohexanone. Yield: 47%. MS (DCI/NH.sub.3) m/z 258 (M+H).sup.+;
.sup.1H NMR (500 MHz, DMSO-d.sub.6): .delta. 0.72-0.76 (m, 1H),
0.82-0.87 (m, 3H), 1.04 (d, J=6.41 Hz, 3H), 1.26-1.38 (m, 1H),
1.67-1.78 (m, 1H), 1.82-1.91 (m, 2H), 2.07-2.17 (m, 1H), 2.62 (dd,
J=16.48, 3.97 Hz, 1H), 2.88-3.01 (m, 1H), 3.16 (d, J=20.14 Hz, 1H),
3.70 (s, 3H), 11.86 (br s, 1H). Anal. Calcd for
C.sub.15H.sub.19N.sub.3O: C, 70.01; H, 7.44; N, 16.33. Found: C,
70.00; H, 7.56; N, 16.36.
Example 66
1-cyclopropyl-3-methyl-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-c]-2,7-naphth-
yridin-5-one
Example 66A
benzyl
1-cyclopropyl-3-methyl-5-oxo-4,5,8,9-tetrahydro-3H-pyrazolo[3,4-c][-
2,7]naphthyridine-7(6H)-carboxylate
[0274] The title compound was prepared according to procedure for
Examples 7A-7B substituting benzyl-4-oxo-1-piperidine carboxylate
for cyclohexanone. MS (DCI/NH.sub.3) m/z 379 (M+H).sup.+.
Example 66B
1-cyclopropyl-3-methyl-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-c]-2,7-naphth-
yridin-5-one
[0275] A solution of Example 66A (180 mg, 0.48 mmol) in
trifluoroacetic acid (5 mL) was heated at 50.degree. C. for 16 h.
After cooling, acetonitrile was added and the mixture concentrated
on a rotary evaporator. The residue was separated by HPLC (Zorbax
C-18, 0.1% TFA/CH.sub.3CN/H.sub.2O) to provide the title product as
trifluoroacetate salt. This product was treated with 1.0 M solution
of HCl in ether to yield the HCl salt. Yield: 92 mg (60%). MS
(DCI/NH.sub.3) m/z 245 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6): .delta. 0.77-0.85 (m, 2H), 0.86-0.92 (m, 2H),
2.04-2.17 (m, 1H), 3.24-3.32 (m, 2H), 3.33-3.41 (m, 2H), 3.74 (s,
3H), 3.84-3.96 (m, 2H), 5.27 (br s, 1H), 9.64 (br s, 1H). Anal.
Calcd for C.sub.13H.sub.16N.sub.4O.2.1HCl: C, 48.91; H, 5.69; N,
17.46. Found: C, 48.91; H, 5.88; N, 17.11.
Example 67
3-ethyl-1-(1-methylpyrrolidin-2-yl)-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4--
c]isoquinolin-5-one
[0276] The title compound was prepared as TFA salt according to
procedure for Example 69A-69F, substituting (.+-.)-1-benzyl
2-methylpyrrolidine-1,2-dicarboxylate for (R)-1-benzyl 2-methyl
pyrrolidine-1,2-dicarboxylate and ethylhydrazine for
(2,2,2-Trifluoro-ethyl)-hydrazine HCl salt. MS (DCI): m/z 301
(M+H).sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 1.42 (t,
J=7.36 Hz, 2H), 1.75-1.91 (m, 4H), 2.02-2.26 (m, 2H,) 2.23-2.37 (m,
1H), 2.52 (t, J=5.68 Hz, 2H), 2.59-2.77 (m, 1H), 2.77-2.89 (m, 1H),
2.88-3.03 (m, 1H), 2.96 (s, 3H), 3.26-3.41 (m, 1H), 3.75-3.93 (m,
1H), 4.30 (q, J=7.36 Hz, 2H), 4.96 (t, J=8.29 Hz, 1H).
Example 68
1-{4-[(dimethylamino)methyl]benzyl}-3-methyl-3,4,6,7,8,9-hexahydro-5H-pyra-
zolo[3,4-c]isoquinolin-5-one
[0277] The trifluoroacetate salt of the title compound was prepared
according to procedure for Example 26 substituting Example 61 for
Example 25. MS (DCI/NH.sub.3) m/z 351 (M+H).sup.+; .sup.1H NMR (500
MHz, DMSO-d.sub.6): .delta. 1.61 (m, 4H), 2.34-2.37 (m, 2H),
2.61-2.65 (m, 2H), 2.70 (s, 3H), 2.71 (s, 3H), 3.80 (s, 3H), 4.19
(s, 2H), 4.22 (d, J=5.19 Hz, 2H), 7.25 (d, J=8.24 Hz, 2H), 7.39 (d,
J=7.93 Hz, 2H), 9.61 (s, 1H). Anal. Calcd for
C.sub.21H.sub.26N.sub.4O.2 TFA: C, 51.90; H, 4.88; N, 9.68. Found:
C, 51.91; H, 4.20; N, 9.42.
Example 69
1-[(2R)-1-methylpyrrolidin-2-yl]-3-(2,2,2-trifluoroethyl)-3,4,6,7,8,9-hexa-
hydro-5H-pyrazolo[3,4-c]isoquinolin-5-one
Example 69A
(R)-benzyl 2-(2-cyanoacetyl)pyrrolidine-1-carboxylate
[0278] The title compound was prepared according to procedure for
Example 24B, substituting (R)-1-benzyl
2-methylpyrrolidine-1,2-dicarboxylate for EXAMPLE 24A. MS (DCI):
m/z 273 (M+1).sup.+.
Example 69B
(R)-2-[5-Amino-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-pyrrolidine-1-ca-
rboxylic acid benzyl ester
[0279] To a solution of Example 69A (3.0 g, 11 mmol) in ethanol (10
mL) was added (2,2,2-Trifluoro-ethyl)-hydrazine HCl salt (2.3 g, 11
mmol) and triethylamine (1.84 mL, 13.2 mmol) at rt. The solution
was heated under reflux for 4 h. After cooling, the reaction
mixture was concentrated and the residue was separated by flash
chromatography to give Example 69B. Yield: 3.5 g (88%). MS (DCI):
m/z 369 (M+H).sup.+.
Example 69C
(R)-2-[5-Amino-4-cyclohex-1-enyl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl-
]-pyrrolidine-1-carboxylic acid benzyl ester
[0280] The title compound was prepared according to the procedure
for Example 24D, substituting Example 69B for Example 24C. Yield:
50%. MS (DCI): m/z 449 (M+H).sup.+.
Example 69D
benzyl
(2R)-2-[5-oxo-3-(2,2,2-trifluoroethyl)-4,5,6,7,8,9-hexahydro-3H-pyr-
azolo[3,4-c]isoquinolin-1-yl]pyrrolidine-1-carboxylate
[0281] The title compound was prepared according to the procedure
for 24E, substituting Example 69D for Example 24D. Yield: 33%. MS
(DCI): m/z 475 (M+H).sup.+.
Example 69E
1-[(2R)-pyrrolidin-2-yl]-3-(2,2,2-trifluoroethyl)-3,4,6,7,8,9-hexahydro-5H-
-pyrazolo[3,4-c]isoquinolin-5-one
[0282] A solution of Example 69D (0.55 g, 1.16 mmol) in TFA (10 ml)
was heated at 50.degree. C. for 6 h. Volatile were removed and the
residual was purified by HPLC(C-18, 0-100% gradient CH.sub.3CN with
0.1% TFA in water with 0.1% TFA) to provide Example 69E. MS (DCI):
m/z 341 (M+H).sup.+.
Example 69F
1-[(2R)-1-methylpyrrolidin-2-yl]-3-(2,2,2-trifluoro
ethyl)-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-e]isoquinolin-5-one
[0283] The title compound was prepared as TFA salt according to the
procedure for Example 26, substituting Example 69E for 25. MS
(DCI): m/z 355 (M+H).sup.+; .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 1.74-1.98 (m, 5H), 2.04-2.26 (m, 2H), 2.26-2.39 (m, 1H),
2.53-2.67 (m, 2H), 2.71-2.81 (m, 1H), 2.82-2.95 (m, 1H), 2.98 (s,
2H), 3.00-3.09 (m, 1H), 3.30-3.43 (m, 1H), 3.67-3.94 (m, 1H),
4.95-5.21 (m, 3H).
Example 70
3-methyl-1-(1-methylpiperidin-3-yl)-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4--
c]isoquinolin-5-one
[0284] The title compound was prepared according to procedure for
Example 26 substituting Example 63 for Example 25. The product was
treated with 1.0 M solution of HCl in ether to yield the HCl salt.
Yield: 31%. MS (DCI/NH.sub.3) m/z 301 (M+H).sup.+; .sup.1H NMR (500
MHz, pyridine-d.sub.5): .delta. 1.65-1.75 (m, 4H), 1.77-1.84 (m,
1H), 1.85-1.93 (m, 1H), 2.24-2.32 (m, 1H), 2.58-2.68 (m, 1H),
2.78-2.83 (m, 3H), 2.84 (s, 3H), 3.08-3.15 (m, 1H), 3.29-3.42 (m,
2H), 3.47-3.57 (m, 1H), 3.82-3.91 (m, 1H), 3.97 (s, 3H), 4.38-4.47
(m, 1H), 5.40 (br s, 1H). Anal. Calcd for
C.sub.17H.sub.24N.sub.4O.2.1HCl: C, 54.17; H, 6.98; N, 14.86.
Found: C, 54.37; H, 6.95; N, 14.56.
Example 71
2-{1-[(2R)-1-methylpyrrolidin-2-yl]-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyrazol-
o[3,4-c]isoquinolin-3-yl}ethyl ethylcarbamate
[0285] The title compound was prepared according to the procedure
for Example 69A-69F, substituting 2-hydrazino-ethanol for
(2,2,2-Trifluoro-ethyl)-hydrazine HCl salt. MS (DCI): m/z 388
(M+H).sup.+; .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 0.94 (t,
J=7.17 Hz, 3H), 1.62-1.96 (m, 4H), 2.06-2.24 (m, 2H), 2.25-2.35 (m,
1H), 2.51 (s, 3H), 2.69-2.75 (m, 1H), 2.77-2.86 (m, 1H), 2.89-3.09
(m, 4H), 3.32-3.43 (m, 2H), 3.62-3.92 (m, 1H), 4.31-4.43 (m, 1H),
4.42-4.63 (m, 3H), 4.96 (t, J=8.39 Hz, 1H).
Example 72
3-{5-oxo-1-[(2R)-pyrrolidin-2-yl]-4,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-c]-
isoquinolin-3-yl}propanamide
Example 72A
benzyl
(2R)-2-[3-(2-cyanoethyl)-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyrazolo[3,-
4-c]isoquinolin-1-yl]pyrrolidine-1-carboxylate
[0286] The title compound was prepared according to the procedure
for Example 69D, substituting 3-hydrazino-propionitrile for
(2,2,2-Trifluoro-ethyl)-hydrazine HCl salt. MS (DCI): m/z 446
(M+H).sup.+;
Example 72B
3-{5-oxo-1-[(2R)-pyrrolidin-2-yl]-4,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-c]-
isoquinolin-3-yl}propanamide
[0287] The title compound was prepared as TFA salt according to the
procedure for Example 69E, substituting Example 72A for Example
69D. MS (DCI): m/z 330 (M+H).sup.+. .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 1.72-1.94 (m, 4H), 2.07-2.32 (m, 3H), 2.42-2.58
(m, 3H), 2.79 (t, J=6.41 Hz, 2H), 2.83-3.00 (m, 2H), 3.37-3.50 (m,
1H), 3.48-3.65 (m, 1H), 4.42-4.55 (m, 2H), 5.11-5.22 (m, 1H).
Example 73
3-methyl-1-(1-methylpiperidin-4-yl)-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4--
c]isoquinolin-5-one
[0288] The title compound was prepared according to procedure for
Example 26 substituting Example 64 for Example 25. The product was
treated with 1.0 M solution of HCl in ether to yield the HCl salt.
Yield: 59%. MS (DCI/NH.sub.3) m/z 301 (M+H).sup.+; .sup.1H NMR (500
MHz, CD.sub.3OD): .delta. 1.77-1.88 (m, 5H), 2.07-2.18 (m, 2H),
2.19-2.25 (m, 2H), 2.50 (t, J=5.95 Hz, 2H), 2.92 (s, 3H), 2.96-3.02
(m, 2H), 3.15-3.24 (m, 2H), 3.57-3.65 (m, 2H), 3.83 (s, 3H). Anal.
Calcd for C.sub.17H.sub.24N.sub.4O.2.1HCl: C, 54.18; H, 6.98; N,
14.86. Found: C, 54.11; H, 7.09; N, 14.70.
Example 74
3-{1-[(2R)-1-methylpyrrolidin-2-yl]-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyrazol-
o[3,4-c]isoquinolin-3-yl}propanenitrile
Example 74A
3-{5-oxo-1-[(2R)-pyrrolidin-2-yl]-4,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-c]-
isoquinolin-3-yl}propanenitrile
[0289] The title compound was prepared according to the procedure
for Example 69E, substituting Example 72A for Example 69D. MS
(DCI): m/z 326 (M+H).sup.+.
Example 74B
3-{1-[(2R)-1-methylpyrrolidin-2-yl]-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyrazol-
o[3,4-c]isoquinolin-3-yl}propanenitrile
[0290] The title compound was prepared according to the procedure
for Example 26, substituting Example 74A for Example 25. MS (DCI):
m/z 326 (M+H).sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 1.86
(d, J=5.52 Hz, 3H), 2.04-2.42 (m, 4H), 2.56 (s, 3H), 2.74 (s, 1H),
2.89 (s, 1H), 2.99 (s, 3H), 3.07 (t, J=6.29 Hz, 2H), 3.31-3.47 (m,
1H), 3.60-3.97 (m, 1H), 4.32-4.74 (m, 2H), 5.01 (t, J=7.98 Hz,
1H).
Example 75
3-[2-(dimethylamino)benzyl]-1-[(2R)-pyrrolidin-2-yl]-3,4,6,7,8,9-hexahydro-
-5H-pyrazolo[3,4-c]isoquinolin-5-one
[0291] The title compound was prepared according to the procedures
for Examples 69B-69E, substituting
(2-hydrazino-phenyl)-dimethyl-amine for
(2,2,2-Trifluoro-ethyl)-hydrazine HCl salt. MS (DCI): m/z 392
(M+H).sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 1.54-2.00
(m, 4H), 2.07-2.32 (m, 3H), 2.44-2.67 (m, 3H), 2.95 (t, J=5.98 Hz,
2H), 3.01 (s, 6H), 3.35-3.47 (m, 1H), 3.46-3.62 (m, 1H), 5.18 (t,
J=7.36 Hz, 1H), 5.59 (s, 2H), 7.04-7.21 (m, 2H), 7.34-7.44 (m, 1H),
7.47-7.50 (m, 1H).
Example 76
1-[(2R)-1-cyclobutylpyrrolidin-2-yl]-3-(3-hydroxybenzyl)-3,4,6,7,8,9-hexah-
ydro-5H-pyrazolo[3,4-c]isoquinolin-5-one
Example 76A
3-(3-hydroxybenzyl)-1-[(2R)-pyrrolidin-2-yl]-3,4,6,7,8,9-hexahydro-5H-pyra-
zolo[3,4-c]isoquinolin-5-one
[0292] The title compound was prepared according to the procedure
for Example 69E, substituting 3-hydroxybenzylhydrazine for
(2,2,2-Trifluoro-ethyl)-hydrazine HCl salt. MS (DCI): m/z 365
(M+H).sup.+;
Example 76B
1-[(2R)-1-cyclobutylpyrrolidin-2-yl]-3-(3-hydroxybenzyl)-3,4,6,7,8,9-hexah-
ydro-5H-pyrazolo[3,4-c]isoquinolin-5-one
[0293] The title compound was prepared as TFA salt according to the
procedure for Example 26, substituting Example 76A for Example 25,
and cyclobutanone for formaldehyde. MS (DCI): m/z 419 (M+H).sup.+;
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 1.55-1.77 (m, 3H),
1.76-2.01 (m, 5H), 2.08-2.38 (m, 5H), 2.54 (t, J=5.68 Hz, 2H),
2.58-2.75 (m, 1H), 2.77-3.03 (m, 2H), 3.12-3.28 (m, 1H), 3.63-3.77
(m, 1H), 3.80-4.01 (m, 1H), 4.93 (t, J=7.67 Hz, 1H), 5.29-5.43 (m,
1H), 5.44-5.61 (m, 1H), 6.56 (s, 1H), 6.59-6.78 (m, 2H), 7.11 (t,
J=7.82 Hz, 1H).
Example 77
3-[3-(dimethylamino)propyl]-1-pyrrolidin-2-yl-3,4,6,7,8,9-hexahydro-5H-pyr-
azolo[3,4-c]isoquinolin-5-one
Example 77A
benzyl
(2R)-2-[5-oxo-3-(3-oxopropyl)-4,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-
-c]isoquinolin-1-yl]pyrrolidine-1-carboxylate
[0294] A solution of Example 72A (2.0 g, 4.5 mmol) in acetic acid
(10 ml) was treated with Raney nickel (200 mg) at rt. The reaction
mixture was stirred under hydrogen for 6 h. Solid material was
filtered off and the filtrate was concentrated. The residue was
separated by flash chromatography to give Example 77A. Yield: 0.5 g
(25%). MS (DCI): m/z 449 (M+H).sup.+.
Example 77B
benzyl
(2R)-2-{3-[3-(dimethylamino)propyl]-5-oxo-4,5,6,7,8,9-hexahydro-3H--
pyrazolo[3,4-c]isoquinolin-1-yl}pyrrolidine-1-carboxylate
[0295] The title compound was prepared according to the procedure
for Example 26, substituting Example 77A for formaldehyde, and
dimethyl amine for Example 25. MS (DCI): m/z 4 480 (M+H).sup.+.
Example 77C
3-[3-(dimethylamino)propyl]-1-pyrrolidin-2-yl-3,4,6,7,8,9-hexahydro-5H-pyr-
azolo[3,4-c]isoquinolin-5-one
[0296] The title compound was prepared as TFA salt according to the
procedure for Example 69E, substituting Example 77B for Example
69D. MS (DCI): m/z 344 (M+H).sup.+; .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 1.73-1.94 (m, 5H), 2.07-2.36 (m, 6H), 2.44-2.67
(m, 3H), 2.87 (s, 6H), 2.91-3.07 (m, 1H), 3.06-3.24 (m, 2H),
3.39-3.51 (m, 1H), 3.52-3.62 (m, 1H), 5.21 (t, J=7.17 Hz, 2H).
Example 78
1-cyclobutyl-3-[3-(ethylamino)propyl]-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,-
4-c]isoquinolin-5-one
Example 78A
3-(1-cyclobutyl-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-c]isoquinolin--
3-yl)propanenitrile
[0297] The title compound was prepared according to the procedure
for Example 85B-85D, substituting 3-hydrazino-propionitrile for
Example 85A. MS (DCI): m/z 299 (M+H).sup.+;
Example 78B
3-(1-cyclobutyl-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-c]isoquinolin--
3-yl)propanal
[0298] The title compound was prepared according to the procedure
for Example 77A, substituting Example 78A for Example 72A. MS
(DCI): m/z 4 300 (M+H).sup.+.
Example 78C
1-cyclobutyl-3-[3-(ethylamino)propyl]-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,-
4-c]isoquinolin-5-one
[0299] The title compound was prepared as TFA salt according to the
procedure for Example 26, substituting Example 78B for formaldehyde
and ethylamine for Example 25. MS (DCI): m/z 329 (M+H).sup.+;
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 1.15 (t, J=7.32 Hz,
3H), 1.56-1.80 (m, 3H), 1.77-1.90 (m, 1H), 1.92-2.08 (m, 4H),
2.22-2.32 (m, 4H), 2.33-2.41 (m, 2H), 2.79 (s, 2H), 2.83-3.07 (m,
4H), 3.54-3.91 (m, 2H), 4.25 (t, J=6.71 Hz, 1H), 8.41 (s, 2H).
Example 79
1-cyclobutyl-3-(3-pyrrolidin-1-ylpropyl)-3,4,6,7,8,9-hexahydro-5H-pyrazolo-
[3,4-c]isoquinolin-5-one
[0300] The title compound was prepared as TFA salt according to the
procedure for Example 26, substituting Example 78B for formaldehyde
and pyrrolidine for Example 25. MS (DCI): m/z 355 (M+H).sup.+;
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 1.60-1.77 (m, 4H),
1.77-1.89 (m, 2H), 1.92-2.03 (m, 3H), 2.05-2.16 (m, 2H), 2.16-2.40
(m, 6H), 2.79 (s, 2H), 2.86-3.03 (m, 2H), 3.04-3.21 (m, 2H), 3.55
(dd, J=10.37, 5.19 Hz, 3H), 3.67-3.95 (m, 2H), 4.23 (t, J=6.71 Hz,
1H), 9.64 (s, 1H).
Example 80
1-cyclobutyl-3-[3-(dimethylamino)propyl]-3,4,6,7,8,9-hexahydro-5H-pyrazolo-
[3,4-c]isoquinolin-5-one
[0301] The title compound was prepared as TFA salt according to the
procedure for Example 26, substituting Example 78B for formaldehyde
and dimethyl amine for Example 25. MS (DCI): m/z 329 (M+H).sup.+;
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 1.52-1.78 (m, 3H),
1.78-1.88 (m, 1H), 1.91-2.06 (m, 1H), 2.05-2.18 (m, 2H), 2.21-2.35
(m, 4H), 2.37 (s, 2H), 2.72 (d, J=4.88 Hz, 6H), 2.79 (s, 2H),
2.90-3.12 (m, 2H), 3.71-3.91 (m, 2H), 4.24 (t, J=6.87 Hz, 2H),
10.63 (s, 1H).
Example 81
3-(1-cyclobutyl-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-c]isoquinolin--
3-yl)propanoic acid
[0302] A suspension of Example 78A (100 mg, 0.34 mmol) in 6N HCl
(20 ml) was heated at 100.degree. C. for 20 h. After cooling to
room temperature the formed solid was collected by filtration,
washed with water and MeOH to give Example 81 (100 mg, 90%). MS
(DCI): m/z 318 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.60-1.77 (m, 5H), 1.76-1.91 (m, 1H), 1.90-2.08 (m, 1H),
2.16-2.31 (m, 4H), 2.30-2.43 (m, 2H), 2.65-2.86 (m, 5H), 3.77 (t,
J=8.31 Hz, 1H), 4.36 (t, J=6.95 Hz, 2H), 12.00 (s, 2H).
Example 82
3-isopropyl-1-(1-methylpyrrolidin-2-yl)-3,4,6,7,8,9-hexahydro-5H-pyrazolo[-
3,4-e]isoquinolin-5-one
[0303] The title compound was prepared as TFA salt according to
procedure for Example 69A-69F, substituting (.+-.)-1-benzyl
2-methylpyrrolidine-1,2-dicarboxylate for (R)-1-benzyl 2-methyl
pyrrolidine-1,2-dicarboxylate and isopropylhydrazine for
(2,2,2-Trifluoro-ethyl)-hydrazine HCl salt. MS (DCI): m/z 315
(M+H).sup.+; .sup.1H NMR (500 MHz, CD.sub.3OD): .delta. 1.51 (dd,
J=6.71, 3.66 Hz, 6H), 1.71-1.95 (m, 3H), 2.05-2.25 (m, 2H),
2.24-2.37 (m, 1H), 2.41-2.56 (m, 2H), 2.69-2.78 (m, 1H), 2.77-2.89
(m, 1H), 2.90-3.03 (m, 1H), 2.96 (s, 3H), 3.29-3.44 (m, 2H),
3.77-3.96 (m, 1H), 4.73-4.91 (m, 2H).
Example 83
4-[(1-cyclobutyl-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-c]isoquinolin-
-3-yl)methyl]benzonitrile
[0304] The title compound was prepared according to procedure for
Example 85A-85D substituting 4-cyanobenzaldehyde for
pyridine-3-aldehyde. MS (DCI/NH.sub.3) m/z 359 (M+H).sup.+; .sup.1H
NMR (500 MHz, CDCl.sub.3): .delta. 1.56-1.59 (m, 1H), 1.76-1.84 (m,
2H), 1.91-1.98 (m, 1H), 2.03-2.10 (m, 1H), 2.32-2.39 (m, 2H),
2.41-2.50 (m, 5H), 2.86 (t, J=5.34 Hz, 2H), 3.77-3.82 (m, 1H), 5.61
(s, 2H), 7.51 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.8 Hz, 2H), 14.20 (br
s, 1H).
Example 84
1-cyclobutyl-3-{4-[(isopropylamino)methyl]benzyl}-3,4,6,7,8,9-hexahydro-5H-
-pyrazolo[3,4-c]isoquinolin-5-one
Example 84A
4-[(1-cyclobutyl-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-c]isoquinolin-
-3-yl)methyl]benzaldehyde
[0305] The title compound was prepared according to procedure for
Example 77A, substituting Example 83 for Example 72A. MS (DCI): m/z
362 (M+H).sup.+.
Example 84B
1-cyclobutyl-3-{4-[(isopropylamino)methyl]benzyl}-3,4,6,7,8,9-hexahydro-5H-
-pyrazolo[3,4-c]isoquinolin-5-one
[0306] The title compound was prepared as TFA salt according to
procedure for Example 26, substituting Example 84A for formaldehyde
and isopropyl amine for Example 25. MS (DCI): m/z 405 (M+H).sup.+;
.sup.1H NMR (500 MHz, DMSO-d.sub.6): .delta. 1.35 (d, J=6.71 Hz,
6H), 1.55-1.82 (m, 3H), 1.90 (s, 1H), 1.95-2.15 (m, 1H), 2.17-2.51
(m, 6H), 2.50-2.67 (m, 2H), 2.68-2.88 (m, 1H), 3.27 (d, J=5.80 Hz,
1H), 3.71-3.85 (m, 1H), 4.04 (s, 2H), 5.46 (s, 2H), 7.23 (d, J=8.24
Hz, 2H), 7.43 (d, J=8.24 Hz, 2H), 9.54 (s, 2H).
Example 85
1-cyclobutyl-3-(pyridin-3-ylmethyl)-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4--
c]isoquinolin-5-one
Example 85A Pyridin-3-ylmethyl-hydrazine
[0307] To a solution of pyridine-3-aldehyde (5 g, 46.7 mmol) in
methanol (100 mL) was added hydrazine (1.05 mL, 46.7 mmol). The
reaction mixture was stirred at rt for 1 h. After purging with
nitrogen, 10% Pd/C (200 mg) was added. The reaction mixture was
purged with hydrogen and stirred under hydrogen at rt overnight.
Solid material was removed, and the filtrate was concentrated to
give a crude Example 85A. This material was used without further
purification.
[0308] Yield: 5.2 g (91%). MS (DCI): m/z 124 (M+H).sup.+.
Example 85B
5-Cyclobutyl-2-pyridin-3-ylmethyl-2H-pyrazol-3-ylamine
[0309] To a solution of 3-cyclobutyl-3-oxo-propionitrile (3.3 g, 32
mmol) in ethanol (100 mL) was added Example 85A (3.9 g, 32 mmol) at
rt. The solution was heated under reflux for 4 h. After cooling,
the reaction mixture was concentrated and the residue was separated
by flash chromatography (silica gel, 0-15% gradient MeOH in
CH.sub.2Cl.sub.2) to give Example 85B (6.8 g). Yield: 93%. MS
(DCI): m/z 229 (M+H).sup.+.
Example 85C
5-Cyclobutyl-4-cyclohex-1-enyl-2-pyridin-3-ylmethyl-2H-pyrazol-3-ylamine
[0310] To a solution of Example 85B (4 g, 17.5 mmol) in acetic acid
(150 mL) was added cyclohexanone (3 mL). The solution was stirred
at 50.degree. C. for 24 h. After cooling, the reaction mixture was
concentrated. The residual oil was partitioned between sodium
bicarbonate solution and ethyl acetate. The organic phase was
washed with water and concentrated. The residue was purified by
flash column chromatography to give Example 85C. Yield: 3.2 g
(59%). MS (DCI): m/z 309 (M+H).sup.+.
Example 85D
1-cyclobutyl-3-(pyridin-3-ylmethyl)-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4--
c]isoquinolin-5-one
[0311] To a solution of Example 85C (4 g, 18 mmol) in anhydrous
pyridine (50 mL) was added ethyl isocyanate (3 mL) under nitrogen.
The solution was heated at 50.degree. C. for 6 h and under reflux
overnight. The volatile were removed and the residual solid was
purified by flash chromatography to give Example 85D. Yield: 4.2 g
(70%). MS (DCI): m/z 335 (M+H).sup.+, .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 1.58 (s, 1H), 1.72-1.86 (m, 5H), 1.87-2.17 (m,
2H), 2.27-2.61 (m, 6H), 2.84 (s, 2H), 3.62-3.90 (m, 1H), 7.20 (dd,
J=7.80, 4.75 Hz, 1H), 7.78 (d, J=7.80 Hz, 1H), 8.48 (d, J=3.05 Hz,
1H), 8.77 (s, 1H).
Example 86
1-cyclobutyl-3-(piperidin-3-ylmethyl)-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,-
4-c]isoquinolin-5-one
[0312] Example 85D was hydrogenated in the presence of 10%
palladium on carbon overnight to provide Example 86 (1.8 g). Yield:
56%. MS (DCI): m/z 341 (M+H).sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 0.92-1.28 (m, 1H), 1.49-1.62 (m, 1H),
1.62-1.76 (m, 7H), 1.74-1.91 (m, 1H), 1.91-2.08 (m, 1H), 2.12-2.44
(m, 6H), 2.57-2.89 (m, 4H), 3.01 (d, J=11.60 Hz, 1H), 3.10-3.29 (m,
1H), 3.71-3.84 (m, 1H), 3.98-4.22 (m, 2H).
Example 87
1-cyclobutyl-3-{3-[(dimethylamino)methyl]benzyl}-3,4,6,7,8,9-hexahydro-5H--
pyrazolo[3,4-c]isoquinolin-5-one
Example 87A
3-[(1-cyclobutyl-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-c]isoquinolin-
-3-yl)methyl]benzonitrile
[0313] The title compound was prepared according to procedure for
Example 85B-85D, substituting 3-hydrazinomethyl-benzonitrile for
Example 85A. MS (DCI): m/z 359 (M+H).sup.+.
Example 87B
3-[(1-cyclobutyl-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-c]isoquinolin-
-3-yl)methyl]benzaldehyde
[0314] The title compound was prepared according to procedure for
Example 77A, substituting Example 87A for Example 72A. MS (DCI):
m/z 362 (M+H).sup.+.
Example 87C
1-cyclobutyl-3-{3-[(dimethylamino)methyl]benzyl}-3,4,6,7,8,9-hexahydro-5H--
pyrazolo[3,4-c]isoquinolin-5-one
[0315] The title compound was prepared as TFA salt according to
procedure for Example 26, substituting Example 87B for formaldehyde
and dimethylamine for Example 25. MS (DCI): m/z 391 (M+H).sup.+;
.sup.1H NMR (500 MHz, CD.sub.3OD): .delta. 1.72-1.85 (m, 5H),
1.84-2.00 (m, 1H), 1.96-2.18 (m, 1H), 2.28-2.41 (m, 4H), 2.48 (t,
J=5.34 Hz, 2H), 2.81 (s, 6H), 2.91 (t, J=5.19 Hz, 2
[0316] H), 3.88 (t, J=8.54 Hz, 1H), 4.27 (s, 2H), 5.49 (s, 2H),
7.11-7.31 (m, 1H), 7.38-7.43 (m, 1H), 7.46 (t, J=7.48 Hz, 1H).
Example 88
1-cyclobutyl-3-[3-(hydroxymethyl)benzyl]-3,4,6,7,8,9-hexahydro-5H-pyrazolo-
[3,4-c]isoquinolin-5-one
[0317] A solution of Example 87B (50 mg, 0.14 mmol) in methylene
chloride (10 ml) was treat with sodium borohydride (20 mg, 0.58
mmol) at rt for 1 h. Volatiles were removed and the residual solid
was purified by HPLC(C-18, 0-100% gradient CH.sub.3CN with 0.1% TFA
in water with 0.1% TFA) to give Example 88 as TFA salt. Yield: 36
mg (72%). MS (DCI): m/z 364 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6): .delta. 1.71 (d, J=4.27 Hz, 5H), 1.74-1.88 (m, 1H),
1.87-2.08 (m, 1H), 2.16-2.33 (m, 4H), 2.39 (s, 1H), 2.43-2.56 (m,
2H), 2.82 (s, 2H), 3.64-3.90 (m, 1H), 3.99 (s, 2H), 5.40-5.45 (m,
2H), 7.11 (d, J=7.02 Hz, 1H), 7.25 (s, 1H), 7.29-7.53 (m, 2H), 8.17
(s, 2H).
Example 89
1-cyclobutyl-3-[(1-methylpiperidin-3-yl)methyl]-3,4,6,7,8,9-hexahydro-5H-p-
yrazolo[3,4-c]isoquinolin-5-one
[0318] The title compound was prepared as TFA salt according to the
procedure for Example 26, substituting Example 86 for 25. MS (DCI):
m/z 355 (M+H).sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
1.15-1.41 (m, 1H), 1.59-1.84 (m, 6H), 1.85-1.96 (m, 1H), 1.96-2.20
(m, 2H), 2.24-2.59 (m, 7H), 2.80-2.85 (m, 3H), 2.86-2.98 (m, 4H),
3.31-3.41 (m, 1H), 3.48 (d, J=12.58 Hz, 1H), 3.77-3.95 (m, 1H),
4.08-4.29 (m, 2H).
Example 90
ethyl
(1-cyclobutyl-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-c]isoquino-
lin-3-yl)acetate
[0319] The title compound was prepared according to procedure for
Example 85B-85D, substituting hydrazino-acetic acid ethyl ester for
Example 85A. MS (DCI): m/z 330 (M+H).sup.+; .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 1.27 (t, J=7.06 Hz, 3H), 1.70-1.85 (m, 4H),
1.85-1.97 (m, 1H), 1.96-2.20 (m, 1H), 2.27-2.45 (m, 4H), 2.48 (t,
J=4.91 Hz, 2H), 2.90 (t, J=4.91 Hz, 2H), 3.69-3.94 (m, 1H), 4.22
(q, J=7.06 Hz, 2H), 5.02 (s, 2H).
Example 91
1-cyclobutyl-3-(2-hydroxyethyl)-3,4,6,7,8,9-hexahydro-5H-pyrrolo[2,3-c]iso-
quinolin-5-one
[0320] A solution of Example 90 (100 mg, 0.3 mmol) in methalene
chloride (10 ml) was treat with sodium borohydride (20 mg, 0.58
mmol) at rt for 1 h. Volatiles were removed, and the residual solid
was washed with methanol and dried to give Example 91 (40 mg, 47%).
MS (DCI): m/z 288 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6):
.delta. 1.65-1.76 (m, 4H), 1.76-1.88 (m, 1H), 1.90-2.05 (m, 1H),
2.17-2.30 (m, 3H), 2.32-2.43 (m, 2H), 2.78 (s, 2H), 3.70 (d, J=4.58
Hz, 2H), 3.73-3.88 (m, 1H), 4.15-4.26 (m, 2H), 4.62-4.85 (m, 1H),
11.67 (s, 2H).
Example 92
(1-cyclobutyl-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-c]isoquinolin-3--
yl)acetic acid
[0321] A solution of Example 90 (100 mg, 0.3 mmol) in a mixture of
THF (5 ml) and methanol (5 ml) was treated with a 1N solution of
lithium hydroxide (2 mL) at rt for 10 h. The mixture was
neutralized with 1N HCl to a pH of 7. The formed solid was
collected by filtration, washed with methanol and dried to give
Example 92 (30 mg, 32%). MS (DCI): m/z 302 (M+H).sup.+; .sup.1H NMR
(500 MHz, DMSO-d.sub.6): .delta. 1.65-1.76 (m, 5H), 1.75-1.88 (m,
1H), 1.87-2.06 (m, 1H), 2.18-2.34 (m, 4H), 2.33-2.45 (m, 1H), 2.80
(s, 2H), 3.70-3.87 (m, 1H), 4.93 (s, 2H).
Example 93
1-cyclobutyl-3-[2-(1H-tetrazol-5-yl)ethyl]-3,4,6,7,8,9-hexahydro-5H-pyrazo-
lo[3,4-c]isoquinolin-5-one
[0322] To a suspension of Example 78A (150 mg, 0.5 mmol) and
trimethylsily azide (582 mg, 5.0 mmol) in toluene (20 ml) was added
dibutyltin oxide (28 mg, 0.34 mmol). The reaction mixture was
heated at 100.degree. C. for 3 days. Volatiles were removed, and
the residual solid was washed with methanol and dried to give
Example 93 (100 mg, 60%). MS (DCI): m/z 340 (M+H).sup.+; .sup.1H
NMR (500 MHz, CD.sub.3OD): .delta. 1.70-1.85 (m, 4H), 1.82-1.95 (m,
1H), 1.94-2.13 (m, 1H), 2.24-2.38 (m, 4H), 2.48 (t, J=5.03 Hz, 2H),
2.72-2.90 (m, 2H), 3.48 (q, J=6.92 Hz, 2H), 3.69-3.89 (m, 1H), 4.63
(t, J=6.87 Hz, 2H).
Example 94
1-cyclobutyl-3-{[1-(methylsulfonyl)piperidin-3-yl]methyl}-3,4,6,7,8,9-hexa-
hydro-5H-pyrazolo[3,4-c]isoquinolin-5-one
[0323] To a solution of Example 86 (170 mg, 0.5 mmol) in pyridine
(5 mL) was added methanesulfonyl chloride (68 mg, 0.6 mmol). The
reaction mixture was stirred at rt for 1 h and concentrated. The
residual solid was washed with MeOH, and dried to give Example 94.
Yield: 102 mg (49%). MS (DCI): m/z 419 (M+H).sup.+; .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 0.86-1.24 (m, 1H), 1.26-1.57 (m,
1H), 1.64 (s, 1H), 1.67-1.82 (m, 5H), 1.81-1.93 (m, 1H), 1.92-2.07
(m, 2H), 2.15 (s, 1H), 2.22-2.37 (m, 5H), 2.35-2.48 (m, 2H),
2.67-2.80 (m, 1H), 2.80 (s, 3H), 2.81-2.87 (m, 3H), 3.46 (d, J=3.36
Hz, 2H), 3.81 (d, J=8.24 Hz, 1H).
Example 95
1-cyclobutyl-3-[3-(1H-tetrazol-5-yl)benzyl]-3,4,6,7,8,9-hexahydro-5H-pyraz-
olo[3,4-c]isoquinolin-5-one
Example 95A
3-((1-cyclobutyl-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-c]isoquinolin-
-3-yl)methyl)benzonitrile
[0324] The title compound was prepared according to procedure for
Example 85A-85D substituting 3-cyanobenzaldehyde for
pyridine-3-aldehyde. MS (DCI/NH.sub.3) m/z 359 (M+H).sup.+.
Example 95B
1-cyclobutyl-3-[3-(1H-tetrazol-5-yl)benzyl]-3,4,6,7,8,9-hexahydro-5H-pyraz-
olo[3,4-c]isoquinolin-5-one
[0325] To a suspension of Example 95A (150 mg) and trimethylsily
azide (582 mg) in toluene (20 ml) was added dibutyltin oxide (28
mg). The mixture was heated at 100.degree. C. for 3 days. Solid
material was collected by filtration, washed with methanol and
dried to give Example 95. Yield:
[0326] 100 mg. MS (DCI/NH.sub.3) m/z 402 (M+H).sup.+; .sup.1H NMR
(500 MHz, CD.sub.3OD): .delta. 1.81 (s, 2H), 1.92 (m, 1H),
2.02-2.11 (m, 1H), 2.35-2.44 (m, 4H), 2.51 (m, 2H), 2.91 (br s,
2H), 3.84-3.90 (m, 1H), 5.37 (br s, 1H), 5.51 (s, 2H), 5.51 (s,
2H), 7.30 (m, 2H), 7.97 (m, 2H),
Example 96
7,9-dimethyl-1,2,3,4,6,7-hexahydro-5H-pyrazolo[3,4-h]-1,6-naphthyridin-5-o-
ne
Example 96A
5-chloro-N-(4-cyano-1,3-dimethyl-1H-pyrazol-5-yl)pentanamide
[0327] To a solution of
5-amino-1,3-dimethyl-1H-pyrazole-4-carbonitrile (1.59 g, 11.67
mmol) in anhydrous pyridine (15 mL) was slowly added
5-chlorovaleryl chloride (1.80 mL, 14.0 mmol) at 0.degree. C. After
addition, the reaction mixture was allowed to warm up to rt and
stirr at rt overnight. The reaction mixture was concentrated on a
rotavapor and the residue was partitioned between ethyl acetate and
brine. The organic phase was washed with brine and concentrated.
The residue was separated by flash chromatography (silica gel,
50-80% gradient EtOAc in hexane) to provide Example 96A. Yield:
2.42 g (81%). MS (DCI): m/z 255 (M+H).sup.+.
Example 96B
7,9-dimethyl-1,2,3,4,6,7-hexahydro-5H-pyrazolo[3,4-h]-1,6-naphthyridin-5-o-
ne
[0328] To a stirring solution of 2,2,6,6-tetramethylpiperidine
(1.66 mL, 9.8 mmol) in anhydrous THF (20 mL) was added
n-butyllithium (2.5 M solution in hexane, 3.92 mL, 9.8 mmol) at
-20.degree. C. The solution was stirred at -20.degree. C. for 30
min, and a solution of Example 96A (1.0 g, 3.92 mmol) in 10 ml, of
anhydrous THF was added dropwise. The resulting dark red mixture
was stirred at the same temperature for 30 min. The reaction was
quenched with water, and the mixture was concentrated. The residue
was partitioned between ethyl acetate and brine. The formed solid
material in the bi-phase mixture was collected by filtration,
washed with EtOAc and water. The obtained crude product was
recrystallized from methanol to give Example 96. Yield: 343 mg
(40%). MS (DCI): m/z 219 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta. 1.71-1.79 (m, 2H), 2.33-2.37 (m, 5H),
3.20-3.25 (m, 2H), 3.65 (s, 3H), 6.04 (br s, 1H), 11.06 (br s,
1H).
Example 97
1-{[cyclohexyl(methyl)amino]methyl}-3-methyl-3,4,6,7,8,9-hexahydro-5H-pyra-
zolo[3,4-c]isoquinolin-5-one
[0329] The title compound was prepared according to procedure for
Example 53 substituting cyclohexanone for acetone. Yield: 34%. MS
(DCI/NH.sub.3) m/z 329 (M+H).sup.+; .sup.1H NMR (500 MHz,
CD.sub.3OD): .delta. 1.23-1.32 (m, 1H), 1.38-1.48 (m, 2H),
1.58-1.69 (m, 2H), 1.71-1.77 (m, 1H), 1.79-1.84 (m, 2H), 1.85-1.90
(m, 2H), 1.94-2.01 (m, 2H), 2.13-2.22 (m, 2H), 2.50 (t, J=5.95 Hz,
2H), 2.92 (s, 3H), 2.95-3.03 (m, 2H), 3.43-3.52 (m, 1H), 3.92 (s,
3H), 4.42 (d, J=14.65 Hz, 1H), 4.80 (d, J=14.65 Hz, 1H); Anal.
Calcd for C.sub.19H.sub.28N.sub.4O.1.6HCl: C, 59.00; H, 7.71; N,
14.48. Found: C, 59.07; H, 7.36; N, 14.20.
Example 98
3-methyl-1-[1-(2-phenylethyl)piperidin-4-yl]-3,4,6,7,8,9-hexahydro-5H-pyra-
zolo[3,4-c]isoquinolin-5-one
[0330] The title compound was prepared according to procedure for
Example 73 substituting phenylacetaldehyde for formaldehyde. Yield:
34%. MS (DCI/NH.sub.3) m/z 391 (M+H).sup.+; .sup.1H NMR (500 MHz,
CD.sub.3OD): .delta. 1.78-1.89 (m, 5H), 2.11-2.20 (m, 2H),
2.22-2.29 (m, 2H), 2.46-2.54 (m, 2H), 2.98 (q, J=5.59 Hz, 2H),
3.08-3.14 (m, 2H), 3.18-3.26 (m, 2H), 3.36-3.42 (m, 2H), 3.77 (d,
J=12.51 Hz, 2H), 3.83 (s, 3H), 7.27-7.30 (m, 1H), 7.31-7.33 (m,
1H), 7.33-7.36 (m, 2H), 7.36-7.38 (m, 1H); Anal. Calcd for
C.sub.24H.sub.30N.sub.4O.2.1HCl: C, 61.71; H, 6.93; N, 11.99.
[0331] Found: C, 61.89; H, 6.75; N, 11.81.
Example 99
3-methyl-1-[(2S)-1-methylpiperidin-2-yl]-3,4,6,7,8,9-hexahydro-5H-pyrazolo-
[3,4-c]isoquinolin-5-one
[0332] The title compound was prepared according to procedure for
Example 26 substituting Example 54 for Example 25. The TFA salt was
treated with 1.0 M soln of HCl in ether to yield the HCl salt.
Yield: 54 mg, 58%. MS (DCI/NH.sub.3) m/z 301 (M+H).sup.+; .sup.1H
NMR (400 MHz, CD.sub.3OD): .delta. 1.72-1.85 (m, 3H), 1.86-1.95 (m,
3H), 1.96-2.08 (m, 3H), 2.22-2.32 (m, 2H), 2.49-2.57 (m, 2H),
2.73-2.76 (m, 3H), 2.78-2.87 (m, 1H), 2.98-3.09 (m, 1H), 3.55-3.66
(m, 1H), 3.92 (s, 3H), 4.60 (d, J=11.66 Hz, 1H).
Example 100
3-methyl-1-{[methyl(propyl)amino]methyl}-3,4,6,7,8,9-hexahydro-5H-pyrazolo-
[3,4-c]isoquinolin-5-one
[0333] The title compound was prepared according to procedure for
Example 53 substituting propionaldehyde for acetone. Yield: 50%. MS
(DCI/NH.sub.3) m/z 259 (M+H).sup.+; .sup.1H NMR (500 MHz,
CD.sub.3OD): .delta. 1.04 (t, J=7.48 Hz, 3H), 1.78-1.92 (m, 6H),
2.50 (t, J=6.10 Hz, 2H), 2.88-2.96 (m, 2H), 2.98 (s, 3H), 3.15-3.26
(m, 1H), 3.33-3.43 (m, 1H), 3.92 (s, 3H), 4.54 (d, J=14.95 Hz, 1H),
4.73 (d, J=14.65 Hz, 1H).
Example 101
1-{[(cyclopropylmethyl)(methyl)amino]methyl}-3-methyl-3,4,6,7,8,9-hexahydr-
o-5H-pyrazolo[3,4-c]isoquinolin-5-one
[0334] The title compound was prepared according to procedure for
Example 53 substituting cyclopropanecarboxaldehyde for acetone.
Yield: 49%. MS (DCI/NH.sub.3) m/z 301 (M+H).sup.+; .sup.1H NMR (500
MHz, CD.sub.3OD): .delta. 0.47-0.52 (m, 2H), 0.78-0.84 (m, 2H),
1.21-1.29 (m, 1H), 1.80-1.90 (m, 4H), 2.51 (t, J=5.95 Hz, 2H), 2.95
(t, J=5.80 Hz, 2H), 3.04 (s, 3H), 3.17 (dd, J=13.27, 7.48 Hz, 1H),
3.32-3.37 (m, 1H), 3.92 (s, 3H), 4.53 (d, J=14.65 Hz, 1H), 4.84 (d,
J=14.65 Hz, 1H).
Example 102
3-methyl-1-[(2R)-pyrrolidin-2-yl]-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-c]-
isoquinolin-5-one
[0335] The title compound was prepared according to procedure for
Examples 24B-24E and Example 25 substituting (R)-1-benzyl
2-methylpyrrolidine-1,2-dicarboxylate for Example 24A. MS
(DCI/NH.sub.3) m/z 273 (M+H).sup.+; .sup.1H NMR (500 MHz,
CD.sub.3OD): .delta. 1.79-1.91 (m, 4H), 2.16-2.30 (m, 3H),
2.46-2.59 (m, 3H), 2.88-3.01 (m, 2H), 3.39-3.49 (m, 1H), 3.53-3.60
(m, 1H), 3.89 (s, 3H), 5.18 (t, J=6.90 Hz, 1H).
Example 103
3-methyl-1-[(2R)-1-methylpyrrolidin-2-yl]-3,4,6,7,8,9-hexahydro-5H-pyrazol-
o[3,4-c]isoquinolin-5-one
[0336] The title compound was prepared according to procedure for
Example 26 substituting Example 102 for Example 25. The TFA salt
was treated with 1.0 M solution of HCl in ether to yield the HCl
salt. Yield: 33 mg (56%). MS (DCI/NH.sub.3) m/z 287 (M+H).sup.+;
.sup.1H NMR (500 MHz, CD.sub.3OD): .delta. 1.79-1.91 (m, 4H),
2.10-2.24 (m, 2H), 2.26-2.34 (m, 1H), 2.49-2.55 (m, 2H), 2.70-2.76
(m, 1H), 2.80-2.88 (m, 1H), 2.93-2.96 (m, 1H), 2.96 (s, 3H),
3.33-3.39 (m, 1H), 3.81-3.87 (m, 1H), 3.91 (s, 3H), 4.98 (t, J=8.39
Hz, 1H).
Example 104
1-[(2R)-1-(cyclopropylmethyl)pyrrolidin-2-yl]-3-methyl-3,4,6,7,8,9-hexahyd-
ro-5H-pyrazolo[3,4-c]isoquinolin-5-one
[0337] The title compound was prepared according to procedure for
Example 26, substituting Example 102 for Example 25, and
cyclopropanecarboxaldehyde for formaldehyde. The TFA salt was
treated with 1.0 M solution of HCl in ether to yield the HCl salt.
Yield: 41 mg (56%). MS (DCI/NH.sub.3) m/z 327 (M+H).sup.+; .sup.1H
NMR (500 MHz, CD.sub.3OD): .delta. 0.33-0.44 (m, 2H), 0.63-0.71 (m,
2H), 1.05-1.16 (m, 1H), 1.77-1.91 (m, 4H), 2.04-2.13 (m, 1H),
2.19-2.26 (m, 1H), 2.26-2.35 (m, 1H), 2.47-2.56 (m, 2H), 2.67-2.76
(m, 1H), 2.78-2.88 (m, 1H), 2.90-3.01 (m, 1H), 3.09-3.19 (m, 2H),
3.35-3.43 (m, 1H), 3.91 (s, 3H), 3.96-4.03 (m, 1H), 5.04 (t, J=8.54
Hz, 1H).
Example 105
3-methyl-1-(1-propylpiperidin-3-yl)-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4--
c]isoquinolin-5-one
[0338] The title compound was prepared according to procedure for
Example 26 substituting Example 63 for Example 25, and substituting
propionaldehyde for formaldehyde. The TFA salt was treated with 1.0
M solution of HCl in ether to yield the HCl salt. Yield: 16 mg
(12%). MS (DCI/NH.sub.3) m/z 329 (M+H).sup.+; .sup.1H NMR (500 MHz,
C.sub.5D.sub.5N): .delta. 0.78 (t, J=7.32 Hz, 3H), 1.67-1.72 (m,
2H), 1.73-1.77 (m, 2H), 1.79-1.84 (m, 1H), 1.87-1.93 (m, 1H),
1.94-2.03 (m, 2H), 2.32 (d, J=13.43 Hz, 1H), 2.65-2.78 (m, 2H),
2.84 (t, J=5.80 Hz, 2H), 2.94-3.04 (m, 2H), 3.10-3.18 (m, 1H),
3.27-3.42 (m, 2H), 3.59 (d, J=7.63 Hz, 1H), 3.92 (d, J=10.98 Hz,
1H), 3.99 (s, 3H), 4.43-4.60 (m, 1H), 5.22 (br s, 1H)
Example 106
1-(3-{[(cyclopropylmethyl)amino]methyl}phenyl)-3-methyl-3,4,6,7,8,9-hexahy-
dro-5H-pyrazolo[3,4-c]isoquinolin-5-one
[0339] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 363 (M+H).sup.+.
Example 107
1-(3-{[bis(cyclopropylmethyl)amino]methyl}phenyl)-3-methyl-3,4,6,7,8,9-hex-
ahydro-5H-pyrazolo[3,4-c]isoquinolin-5-one
[0340] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 417 (M+H).sup.+.
Example 108
1-{3-[(cyclobutylamino)methyl]phenyl}-3-methyl-3,4,6,7,8,9-hexahydro-5H-py-
razolo[3,4-c]isoquinolin-5-one
[0341] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 363 (M+H).sup.+.
Example 109
1-{3-[(dicyclobutylamino)methyl]phenyl}-3-methyl-3,4,6,7,8,9-hexahydro-5H--
pyrazolo[3,4-c]isoquinolin-5-one
[0342] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 417 (M+H).sup.+.
Example 110
1-{3-[(cyclopentylamino)methyl]phenyl}-3-methyl-3,4,6,7,8,9-hexahydro-5H-p-
yrazolo[3,4-c]isoquinolin-5-one
[0343] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 377 (M+H).sup.+.
Example 111
3-methyl-1-{3-[(propylamino)methyl]phenyl}-3,4,6,7,8,9-hexahydro-5H-pyrazo-
lo[3,4-c]isoquinolin-5-one
[0344] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 351 (M+H).sup.+.
Example 112
1-{3-[(cycloheptylamino)methyl]phenyl}-3-methyl-3,4,6,7,8,9-hexahydro-5H-p-
yrazolo[3,4-c]isoquinolin-5-one
[0345] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 405 (M+H).sup.+.
Example 113
1-{3-[(cyclohexylamino)methyl]phenyl}-3-methyl-3,4,6,7,8,9-hexahydro-5H-py-
razolo[3,4-c]isoquinolin-5-one
[0346] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 391 (M+H).sup.+.
Example 114
1-{3-[(isopropylamino)methyl]phenyl}-3-methyl-3,4,6,7,8,9-hexahydro-5H-pyr-
azolo[3,4-c]isoquinolin-5-one
[0347] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 351 (M+H).sup.+.
Example 115
1-{3-[(isobutylamino)methyl]phenyl}-3-methyl-3,4,6,7,8,9-hexahydro-5H-pyra-
zolo[3,4-c]isoquinolin-5-one
[0348] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 365 (M+H).sup.+.
Example 116
[0349] benzyl
3-(3-methyl-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-c]isoquinolin-1-y-
l)azetidine-1-carboxylate
[0350] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 393 (M+H).sup.+.
Example 117
3-methyl-1-(1-methylazetidin-3-yl)-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-c-
]isoquinolin-5-one
[0351] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 273 (M+H).sup.+.
Example 118
3-methyl-1-(1-propylazetidin-3-yl)-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-c-
]isoquinolin-5-one
[0352] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 301 (M+H).sup.+.
Example 119
1-(1-isopropylazetidin-3-yl)-3-methyl-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,-
4-c]isoquinolin-5-one
[0353] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 301 (M+H).sup.+.
Example 120
1-(1-cyclopentylazetidin-3-yl)-3-methyl-3,4,6,7,8,9-hexahydro-5H-pyrazolo[-
3,4-c]isoquinolin-5-one
[0354] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 327 (M+H).sup.+.
Example 121
1-(1-cyclohexylazetidin-3-yl)-3-methyl-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3-
,4-e]isoquinolin-5-one
[0355] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 341 (M+H).sup.+.
Example 122
1-(1-cycloheptylazetidin-3-yl)-3-methyl-3,4,6,7,8,9-hexahydro-5H-pyrazolo[-
3,4-c]isoquinolin-5-one
[0356] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 355 (M+H).sup.+.
Example 123
1-[1-(cyclopropylmethyl)azetidin-3-yl]-3-methyl-3,4,6,7,8,9-hexahydro-5H-p-
yrazolo[3,4-c]isoquinolin-5-one
[0357] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 313 (M+H).sup.+.
Example 124
1-(1-isobutylazetidin-3-yl)-3-methyl-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-
-c]isoquinolin-5-one
[0358] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 315 (M+H).sup.+.
Example 125
benzyl
2-(3-ethyl-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-c]isoquinoli-
n-1-yl)pyrrolidine-1-carboxylate
[0359] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 421 (M+H).sup.+.
Example 126
3-ethyl-1-pyrrolidin-2-yl-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-c]isoquino-
lin-5-one
[0360] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 287 (M+H).sup.+.
Example 127
benzyl
4-[(3-methyl-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-c]isoquino-
lin-1-yl)methyl]benzylcarbamate
[0361] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 457 (M+H).sup.+.
Example 128
benzyl
2-[5-oxo-3-(2,2,2-trifluoroethyl)-4,5,6,7,8,9-hexahydro-3H-pyrazolo-
[3,4-c]isoquinolin-1-yl]pyrrolidine-1-carboxylate
[0362] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 475 (M+H).sup.+.
Example 129
1-(1-cyclobutylpyrrolidin-2-yl)-3-ethyl-3,4,6,7,8,9-hexahydro-5H-pyrazolo[-
3,4-c]isoquinolin-5-one
[0363] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 341 (M+H).sup.+.
Example 130
1-[1-(cyclopropylmethyl)pyrrolidin-2-yl]-3-ethyl-3,4,6,7,8,9-hexahydro-5H--
pyrazolo[3,4-c]isoquinolin-5-one
[0364] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 341 (M+H).sup.+.
Example 131
1-(1-cyclopentylpyrrolidin-2-yl)-3-ethyl-3,4,6,7,8,9-hexahydro-5H-pyrazolo-
[3,4-c]isoquinolin-5-one
[0365] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 355 (M+H).sup.+.
Example 132
1-(1-cyclohexylpyrrolidin-2-yl)-3-ethyl-3,4,6,7,8,9-hexahydro-5H-pyrazolo[-
3,4-c]isoquinolin-5-one
[0366] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 369 (M+H).sup.+.
Example 133
1-(1-cycloheptylpyrrolidin-2-yl)-3-ethyl-3,4,6,7,8,9-hexahydro-5H-pyrazolo-
[3,4-c]isoquinolin-5-one
[0367] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 383 (M+H).sup.+.
Example 134
3-ethyl-1-(1-isopropylpyrrolidin-2-yl)-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3-
,4-c]isoquinolin-5-one
[0368] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 329 (M+H).sup.+.
Example 135
3-ethyl-1-[1-(1-ethylpropyl)pyrrolidin-2-yl]-3,4,6,7,8,9-hexahydro-5H-pyra-
zolo[3,4-c]isoquinolin-5-one
[0369] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 357 (M+H).sup.+.
Example 136
1-{4-[(cyclobutylamino)methyl]benzyl}-3-methyl-3,4,6,7,8,9-hexahydro-5H-py-
razolo[3,4-c]isoquinolin-5-one
[0370] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 376 (M+H).sup.+.
Example 137
1-{4-[(dicyclobutylamino)methyl]benzyl}-3-methyl-3,4,6,7,8,9-hexahydro-5H--
pyrazolo[3,4-c]isoquinolin-5-one
[0371] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 431 (M+H).sup.+.
Example 138
1-{4-[(cyclopentylamino)methyl]benzyl}-3-methyl-3,4,6,7,8,9-hexahydro-5H-p-
yrazolo[3,4-c]isoquinolin-5-one
[0372] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 391 (M+H).sup.+.
Example 139
1-{4-[(cyclohexylamino)methyl]benzyl}-3-methyl-3,4,6,7,8,9-hexahydro-5H-py-
razolo[3,4-c]isoquinolin-5-one
[0373] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 405 (M+H).sup.+.
Example 140
1-[(2R)-pyrrolidin-2-yl]-3-(2,2,2-trifluoroethyl)-3,4,6,7,8,9-hexahydro-5H-
-pyrazolo[3,4-c]isoquinolin-5-one
[0374] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 341 (M+H).sup.+.
Example 141
1-[(2R)-1-isopropylpyrrolidin-2-yl]-3-(2,2,2-trifluoroethyl)-3,4,6,7,8,9-h-
exahydro-5H-pyrazolo[3,4-c]isoquinolin-5-one
[0375] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 383 (M+H).sup.+.
Example 142
1-[(2R)-1-cyclobutylpyrrolidin-2-yl]-3-(2,2,2-trifluoroethyl)-3,4,6,7,8,9--
hexahydro-5H-pyrazolo[3,4-c]isoquinolin-5-one
[0376] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 395 (M+H).sup.+.
Example 143
1-[(2R)-1-(cyclopropylmethyl)pyrrolidin-2-yl]-3-(2,2,2-trifluoroethyl)-3,4-
,6,7,8,9-hexahydro-5H-pyrazolo[3,4-c]isoquinolin-5-one
[0377] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 395 (M+H).sup.+.
Example 144
1-[(2R)-1-cyclopentylpyrrolidin-2-yl]-3-(2,2,2-trifluoroethyl)-3,4,6,7,8,9-
-hexahydro-5H-pyrazolo[3,4-c]isoquinolin-5-one
[0378] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 409 (M+H).sup.+.
Example 145
1-[(2R)-1-cyclohexylpyrrolidin-2-yl]-3-(2,2,2-trifluoro
ethyl)-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-e]isoquinolin-5-one
[0379] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 423 (M+H).sup.+.
Example 146
1-[(2R)-1-cycloheptylpyrrolidin-2-yl]-3-(2,2,2-trifluoroethyl)-3,4,6,7,8,9-
-hexahydro-5H-pyrazolo[3,4-c]isoquinolin-5-one
[0380] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 437 (M+H).sup.+.
Example 147
2-{5-oxo-1-[(2R)-pyrrolidin-2-yl]-4,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-c]-
isoquinolin-3-yl}ethyl ethylcarbamate
[0381] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 374 (M+H).sup.+.
Example 148
2-{1-[(2R)-1-isopropylpyrrolidin-2-yl]-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyra-
zolo[3,4-c]isoquinolin-3-yl}ethyl ethylcarbamate
[0382] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 415 (M+H).sup.+.
Example 149
2-{5-oxo-1-[(2R)-1-propylpyrrolidin-2-yl]-4,5,6,7,8,9-hexahydro-3H-pyrazol-
o[3,4-c]isoquinolin-3-yl}ethyl ethylcarbamate
[0383] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 415 (M+H).sup.+.
Example 150
2-{1-[(2R)-1-cyclobutylpyrrolidin-2-yl]-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyr-
azolo[3,4-c]isoquinolin-3-yl}ethyl ethylcarbamate
[0384] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 428 (M+H).sup.+.
Example 151
2-{1-[(2R)-1-(cyclopropylmethyl)pyrrolidin-2-yl]-5-oxo-4,5,6,7,8,9-hexahyd-
ro-3H-pyrazolo[3,4-c]isoquinolin-3-yl}ethyl ethylcarbamate
[0385] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 428 (M+H).sup.+.
Example 152
2-{1-[(2R)-1-cyclopentylpyrrolidin-2-yl]-5-oxo-4,5,6,7,8,9-hexahydro-3H-py-
razolo[3,4-c]isoquinolin-3-yl}ethyl ethylcarbamate
[0386] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 442 (M+H).sup.+.
Example 153
2-{1-[(2R)-1-cyclohexylpyrrolidin-2-yl]-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyr-
azolo[3,4-c]isoquinolin-3-yl}ethyl ethylcarbamate
[0387] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 456 (M+H).sup.+.
Example 154
2-{1-[(2R)-1-cycloheptylpyrrolidin-2-yl]-5-oxo-4,5,6,7,8,9-hexahydro-3H-py-
razolo[3,4-c]isoquinolin-3-yl}ethyl ethylcarbamate
[0388] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 470 (M+H).sup.+.
Example 155
3-{5-oxo-1-[(2R)-pyrrolidin-2-yl]-4,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-c]-
isoquinolin-3-yl}propanenitrile
[0389] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 312 (M+H).sup.+.
Example 156
3-{1-[(2R)-1-isopropylpyrrolidin-2-yl]-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyra-
zolo[3,4-c]isoquinolin-3-yl}propanenitrile
[0390] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 354 (M+H).sup.+.
Example 157
3-{1-[(2R)-1-cyclobutylpyrrolidin-2-yl]-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyr-
azolo[3,4-c]isoquinolin-3-yl}propanenitrile
[0391] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 366 (M+H).sup.+.
Example 158
3-{1-[(2R)-1-(cyclopropylmethyl)pyrrolidin-2-yl]-5-oxo-4,5,6,7,8,9-hexahyd-
ro-3H-pyrazolo[3,4-c]isoquinolin-3-yl}propanenitrile
[0392] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 366 (M+H).sup.+.
Example 159
3-{1-[(2R)-1-cyclopentylpyrrolidin-2-yl]-5-oxo-4,5,6,7,8,9-hexahydro-3H-py-
razolo[3,4-c]isoquinolin-3-yl}propanenitrile
[0393] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 380 (M+H).sup.+.
Example 160
3-{1-[(2R)-1-cyclohexylpyrrolidin-2-yl]-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyr-
azolo[3,4-c]isoquinolin-3-yl}propanenitrile
[0394] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 394 (M+H).sup.+.
Example 161
3-{1-[(2R)-1-cycloheptylpyrrolidin-2-yl]-5-oxo-4,5,6,7,8,9-hexahydro-3H-py-
razolo[3,4-c]isoquinolin-3-yl}propanenitrile
[0395] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 408 (M+H).sup.+.
Example 162
3-(3-hydroxybenzyl)-1-pyrrolidin-2-yl-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,-
4-c]isoquinolin-5-one
[0396] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 365 (M+H).sup.+.
Example 163
3-(3-hydroxypropyl)-1-[(2R)-pyrrolidin-2-yl]-3,4,6,7,8,9-hexahydro-5H-pyra-
zolo[3,4-c]isoquinolin-5-one
[0397] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 451 (M+H).sup.+.
Example 164
3-[3-(cyclopentylamino)propyl]-1-[(2R)-pyrrolidin-2-yl]-3,4,6,7,8,9-hexahy-
dro-5H-pyrazolo[3,4-e]isoquinolin-5-one
[0398] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 384 (M+H).sup.+.
Example 165
3-(3-hydroxybenzyl)-1-[(2R)-1-methylpyrrolidin-2-yl]-3,4,6,7,8,9-hexahydro-
-5H-pyrazolo[3,4-c]isoquinolin-5-one
[0399] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 379 (M+H).sup.+.
Example 166
3-(3-hydroxybenzyl)-1-[(2R)-1-isopropylpyrrolidin-2-yl]-3,4,6,7,8,9-hexahy-
dro-5H-pyrazolo[3,4-c]isoquinolin-5-one
[0400] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 407 (M+H).sup.+.
Example 167
1-[(2R)-1-(cyclopropylmethyl)pyrrolidin-2-yl]-3-(3-hydroxybenzyl)-3,4,6,7,-
8,9-hexahydro-5H-pyrazolo[3,4-c]isoquinolin-5-one
[0401] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 419 (M+H).sup.+.
Example 168
1-[(2R)-1-cyclopentylpyrrolidin-2-yl]-3-(3-hydroxybenzyl)-3,4,6,7,8,9-hexa-
hydro-5H-pyrazolo[3,4-c]isoquinolin-5-one
[0402] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 433 (M+H).sup.+.
Example 169
1-[(2R)-1-cyclohexylpyrrolidin-2-yl]-3-(3-hydroxybenzyl)-3,4,6,7,8,9-hexah-
ydro-5H-pyrazolo[3,4-c]isoquinolin-5-one
[0403] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 447 (M+H).sup.+.
Example 170
1-[(2R)-1-cycloheptylpyrrolidin-2-yl]-3-(3-hydroxybenzyl)-3,4,6,7,8,9-hexa-
hydro-5H-pyrazolo[3,4-e]isoquinolin-5-one
[0404] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 461 (M+H).sup.+.
Example 171
3-[3-(dimethylamino)propyl]-1-pyrrolidin-2-yl-3,4,6,7,8,9-hexahydro-5H-pyr-
azolo[3,4-c]isoquinolin-5-one
[0405] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 344 (M+H).sup.+.
Example 172
3-[3-(methylamino)propyl]-1-pyrrolidin-2-yl-3,4,6,7,8,9-hexahydro-5H-pyraz-
olo[3,4-c]isoquinolin-5-one
[0406] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 330 (M+H).sup.+.
Example 173
3-[3-(ethylamino)propyl]-1-pyrrolidin-2-yl-3,4,6,7,8,9-hexahydro-5H-pyrazo-
lo[3,4-c]isoquinolin-5-one
[0407] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 344 (M+H).sup.+.
Example 174
3-[3-(isopropylamino)propyl]-1-pyrrolidin-2-yl-3,4,6,7,8,9-hexahydro-5H-py-
razolo[3,4-c]isoquinolin-5-one
[0408] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 358 (M+H).sup.+.
Example 175
3-[3-(cyclopropylamino)propyl]-1-pyrrolidin-2-yl-3,4,6,7,8,9-hexahydro-5H--
pyrazolo[3,4-c]isoquinolin-5-one
[0409] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 356 (M+H).sup.+.
Example 176
3-[3-(cyclobutylamino)propyl]-1-pyrrolidin-2-yl-3,4,6,7,8,9-hexahydro-5H-p-
yrazolo[3,4-c]isoquinolin-5-one
[0410] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 370 (M+H).sup.+.
Example 177
3-[3-(cyclohexylamino)propyl]-1-pyrrolidin-2-yl-3,4,6,7,8,9-hexahydro-5H-p-
yrazolo[3,4-c]isoquinolin-5-one
[0411] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 398 (M+H).sup.+.
Example 178
1-pyrrolidin-2-yl-3-(3-pyrrolidin-1-ylpropyl)-3,4,6,7,8,9-hexahydro-5H-pyr-
azolo[3,4-c]isoquinolin-5-one
[0412] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 370 (M+H).sup.+.
Example 179
3-(3-piperidin-1-ylpropyl)-1-pyrrolidin-2-yl-3,4,6,7,8,9-hexahydro-5H-pyra-
zolo[3,4-c]isoquinolin-5-one
[0413] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 384 (M+H).sup.+.
Example 180
3-(3-morpholin-4-ylpropyl)-1-pyrrolidin-2-yl-3,4,6,7,8,9-hexahydro-5H-pyra-
zolo[3,4-c]isoquinolin-5-one
[0414] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 386 (M+H).sup.+.
Example 181
1-cyclobutyl-3-[3-(methylamino)propyl]-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3-
,4-c]isoquinolin-5-one
[0415] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 315 (M+H).sup.+.
Example 182
1-cyclobutyl-3-[3-(isopropylamino)propyl]-3,4,6,7,8,9-hexahydro-5H-pyrazol-
o[3,4-c]isoquinolin-5-one
[0416] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 343 (M+H).sup.+.
Example 183
1-cyclobutyl-3-[3-(cyclopropylamino)propyl]-3,4,6,7,8,9-hexahydro-5H-pyraz-
olo[3,4-c]isoquinolin-5-one
[0417] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 341 (M+H).sup.+.
Example 184
1-cyclobutyl-3-[3-(cyclobutylamino)propyl]-3,4,6,7,8,9-hexahydro-5H-pyrazo-
lo[3,4-c]isoquinolin-5-one
[0418] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 355 (M+H).sup.+.
Example 185
1-cyclobutyl-3-[3-(cyclopentylamino)propyl]-3,4,6,7,8,9-hexahydro-5H-pyraz-
olo[3,4-c]isoquinolin-5-one
[0419] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 369 (M+H).sup.+.
Example 186
1-cyclobutyl-3-[3-(cyclohexylamino)propyl]-3,4,6,7,8,9-hexahydro-5H-pyrazo-
lo[3,4-c]isoquinolin-5-one
[0420] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 382 (M+H).sup.+.
Example 187
1-cyclobutyl-3-(3-piperidin-1-ylpropyl)-3,4,6,7,8,9-hexahydro-5H-pyrazolo[-
3,4-c]isoquinolin-5-one
[0421] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 369 (M+H).sup.+.
Example 188
[0422] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 371 (M+H).sup.+.
Example 189
3-(1-cyclobutyl-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-c]isoquinolin--
3-yl)propanenitrile
[0423] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 297 (M+H).sup.+.
Example 190
3-(1-cyclobutyl-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-c]isoquinolin--
3-yl)propanal
[0424] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 300 (M+H).sup.+.
Example 191
1-cyclobutyl-3-(3-hydroxypropyl)-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-c]i-
soquinolin-5-one
[0425] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 302 (M+H).sup.+.
Example 192
1-cyclobutyl-3-[4-(dimethylamino)benzyl]-3,4,6,7,8,9-hexahydro-5H-pyrazolo-
[3,4-c]isoquinolin-5-one
[0426] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 377 (M+H).sup.+.
Example 193
3-isopropyl-1-(1-isopropylpyrrolidin-2-yl)-3,4,6,7,8,9-hexahydro-5H-pyrazo-
lo[3,4-c]isoquinolin-5-one
[0427] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 343 (M+H).sup.+.
Example 194
1-[1-(cyclopropylmethyl)pyrrolidin-2-yl]-3-isopropyl-3,4,6,7,8,9-hexahydro-
-5H-pyrazolo[3,4-c]isoquinolin-5-one
[0428] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 355 (M+H).sup.+.
Example 195
1-(1-cyclobutylpyrrolidin-2-yl)-3-isopropyl-3,4,6,7,8,9-hexahydro-5H-pyraz-
olo[3,4-c]isoquinolin-5-one
[0429] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 355 (M+H).sup.+.
Example 196
1-(1-cyclopentylpyrrolidin-2-yl)-3-isopropyl-3,4,6,7,8,9-hexahydro-5H-pyra-
zolo[3,4-c]isoquinolin-5-one
[0430] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 369 (M+H).sup.+.
Example 197
1-(1-cyclohexylpyrrolidin-2-yl)-3-isopropyl-3,4,6,7,8,9-hexahydro-5H-pyraz-
olo[3,4-c]isoquinolin-5-one
[0431] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 383 (M+H).sup.+.
Example 198
3-[(1-cyclobutyl-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-c]isoquinolin-
-3-yl)methyl]benzonitrile
[0432] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 359 (M+H).sup.+.
Example 199
1-cyclobutyl-3-{4-[(methylamino)methyl]benzyl}-3,4,6,7,8,9-hexahydro-5H-py-
razolo[3,4-c]isoquinolin-5-one
[0433] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 377 (M+H).sup.+.
Example 200
1-cyclobutyl-3-{4-[(ethylamino)methyl]benzyl}-3,4,6,7,8,9-hexahydro-5H-pyr-
azolo[3,4-c]isoquinolin-5-one
[0434] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 391 (M+H).sup.+.
Example 201
1-cyclobutyl-3-{4-[(dimethylamino)methyl]benzyl}-3,4,6,7,8,9-hexahydro-5H--
pyrazolo[3,4-c]isoquinolin-5-one
[0435] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 391 (M+H).sup.+.
Example 202
1-cyclobutyl-3-{4-[(cyclopropylamino)methyl]benzyl}-3,4,6,7,8,9-hexahydro--
5H-pyrazolo[3,4-c]isoquinolin-5-one
[0436] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 403 (M+H).sup.+.
Example 203
1-cyclobutyl-3-{4-[(cyclobutylamino)methyl]benzyl}-3,4,6,7,8,9-hexahydro-5-
H-pyrazolo[3,4-c]isoquinolin-5-one
[0437] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 417 (M+H).sup.+.
Example 204
1-cyclobutyl-3-{4-[(cyclohexylamino)methyl]benzyl}-3,4,6,7,8,9-hexahydro-5-
H-pyrazolo[3,4-c]isoquinolin-5-one
[0438] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 445 (M+H).sup.+.
Example 205
1-cyclobutyl-3-[4-(hydroxymethyl)benzyl]-3,4,6,7,8,9-hexahydro-5H-pyrazolo-
[3,4-c]isoquinolin-5-one
[0439] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 364 (M+H).sup.+.
Example 206
1-cyclobutyl-3-{4-[(cyclopentylamino)methyl]benzyl}-3,4,6,7,8,9-hexahydro--
5H-pyrazolo[3,4-c]isoquinolin-5-one
[0440] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 431 (M+H).sup.+.
Example 207
1-cyclobutyl-3-{3-[(methylamino)methyl]benzyl}-3,4,6,7,8,9-hexahydro-5H-py-
razolo[3,4-c]isoquinolin-5-one
[0441] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 377 (M+H).sup.+.
Example 208
1-cyclobutyl-3-{3-[(ethylamino)methyl]benzyl}-3,4,6,7,8,9-hexahydro-5H-pyr-
azolo[3,4-c]isoquinolin-5-one
[0442] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 391 (M+H).sup.+.
Example 209
1-cyclobutyl-3-{3-[(cyclopropylamino)methyl]benzyl}-3,4,6,7,8,9-hexahydro--
5H-pyrazolo[3,4-c]isoquinolin-5-one
[0443] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 403 (M+H).sup.+.
Example 210
1-cyclobutyl-3-{3-[(cyclobutylamino)methyl]benzyl}-3,4,6,7,8,9-hexahydro-5-
H-pyrazolo[3,4-c]isoquinolin-5-one
[0444] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 417 (M+H).sup.+.
Example 211
1-cyclobutyl-3-{[1-(cyclopropylmethyl)piperidin-3-yl]methyl}-3,4,6,7,8,9-h-
exahydro-5H-pyrazolo[3,4-c]isoquinolin-5-one
[0445] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 395 (M+H).sup.+.
Example 212
1-cyclobutyl-3-[(1-isopropylpiperidin-3-yl)methyl]-3,4,6,7,8,9-hexahydro-5-
H-pyrazolo[3,4-c]isoquinolin-5-one
[0446] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 383 (M+H).sup.+.
Example 213
1-cyclobutyl-3-[(1-isobutylpiperidin-3-yl)methyl]-3,4,6,7,8,9-hexahydro-5H-
-pyrazolo[3,4-c]isoquinolin-5-one
[0447] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 397 (M+H).sup.+.
Example 214
1-cyclobutyl-3-[(1-cyclobutylpiperidin-3-yl)methyl]-3,4,6,7,8,9-hexahydro--
5H-pyrazolo[3,4-c]isoquinolin-5-one
[0448] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 395 (M+H).sup.+.
Example 215
1-cyclobutyl-3-[(1-cyclopentylpiperidin-3-yl)methyl]-3,4,6,7,8,9-hexahydro-
-5H-pyrazolo[3,4-c]isoquinolin-5-one
[0449] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 409 (M+H).sup.+.
Example 216
1-cyclobutyl-3-[(1-cyclohexylpiperidin-3-yl)methyl]-3,4,6,7,8,9-hexahydro--
5H-pyrazolo[3,4-c]isoquinolin-5-one
[0450] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 423 (M+H).sup.+.
Example 217
1-cyclobutyl-3-[(1-cycloheptylpiperidin-3-yl)methyl]-3,4,6,7,8,9-hexahydro-
-5H-pyrazolo[3,4-c]isoquinolin-5-one
[0451] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 437 (M+H).sup.+.
Example 218
1-cyclobutyl-3-[(1-tetrahydro-2H-pyran-4-ylpiperidin-3-yl)methyl]-3,4,6,7,-
8,9-hexahydro-5H-pyrazolo[3,4-c]isoquinolin-5-one
[0452] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 425 (M+H).sup.+.
Example 219
1-cyclobutyl-3-{[1-(pyridin-2-ylmethyl)piperidin-3-yl]methyl}-3,4,6,7,8,9--
hexahydro-5H-pyrazolo[3,4-c]isoquinolin-5-one
[0453] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 432 (M+H).sup.+.
Example 220
1-cyclobutyl-3-{[1-(pyridin-3-ylmethyl)piperidin-3-yl]methyl}-3,4,6,7,8,9--
hexahydro-5H-pyrazolo[3,4-c]isoquinolin-5-one
[0454] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 432 (M+H).sup.+.
Example 221
1-cyclobutyl-3-{[1-(pyridin-4-ylmethyl)piperidin-3-yl]methyl}-3,4,6,7,8,9--
hexahydro-5H-pyrazolo[3,4-c]isoquinolin-5-one
[0455] The title compound was prepared as TFA salt according to the
procedure for related examples. MS (DCI): m/z 432 (M+H).sup.+.
Example 222
3-isopropyl-1-pyrrolidin-2-yl-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-c]isoq-
uinolin-5-one
[0456] MS (DCI): m/z 301 (M+H).sup.+.
Example 223
benzyl
methyl[(3-methyl-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-c]isoq-
uinolin-1-yl)methyl]carbamate
[0457] The title compound was prepared according to procedure for
related example. MS (DCI): m/z 381 (M+H).sup.+.
Example 224
3-methyl-1-[(25)-piperidin-2-yl]-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-c]i-
soquinolin-5-one
[0458] The title compound was prepared as TFA salt according to
procedure for related example. MS (DCI): m/z 287 (M+H).sup.+.
Example 225
1-{[cyclobutyl(methyl)amino]methyl}-3-methyl-3,4,6,7,8,9-hexahydro-5H-pyra-
zolo[3,4-c]isoquinolin-5-one
[0459] The title compound was prepared as HCl salt according to
procedure for related example. MS (DCI): m/z 301 (M+H).sup.+.
Example 226
1-{[cyclopentyl(methyl)amino]methyl}-3-methyl-3,4,6,7,8,9-hexahydro-5H-pyr-
azolo[3,4-c]isoquinolin-5-one
[0460] The title compound was prepared as HCl salt according to
procedure for related example. MS (DCI): m/z 315 (M+H).sup.+.
Example 227
1-[(2S)-1-(cyclopropylmethyl)piperidin-2-yl]-3-methyl-3,4,6,7,8,9-hexahydr-
o-5H-pyrazolo[3,4-c]isoquinolin-5-one
[0461] The title compound was prepared as HCl salt according to
procedure for related example. MS (DCI): m/z 341 (M+H).sup.+.
Example 228
1-[(2S)-1-cyclobutylpiperidin-2-yl]-3-methyl-3,4,6,7,8,9-hexahydro-5H-pyra-
zolo[3,4-c]isoquinolin-5-one
[0462] The title compound was prepared as HCl salt according to
procedure for related example. MS (DCI): m/z 341 (M+H).sup.+.
Example 229
1-[(2S)-1-isobutylpiperidin-2-yl]-3-methyl-3,4,6,7,8,9-hexahydro-5H-pyrazo-
lo[3,4-c]isoquinolin-5-one
[0463] The title compound was prepared as HCl salt according to
procedure for related example. MS (DCI): m/z 343 (M+H).sup.+.
Example 230
1-[(2S)-1-cyclopentylpiperidin-2-yl]-3-methyl-3,4,6,7,8,9-hexahydro-5H-pyr-
azolo[3,4-c]isoquinolin-5-one
[0464] The title compound was prepared as HCl salt according to
procedure for related example. MS (DCI): m/z 355 (M+H).sup.+.
Example 231
[0465] benzyl
(2R)-2-(3-methyl-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-c]isoquinoli-
n-1-yl)pyrrolidine-1-carboxylate
[0466] The title compound was prepared according to procedure for
related example. MS (DCI): m/z 407 (M+H).sup.+.
Example 232
3-methyl-1-[(2R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-2-yl]-3,4,6,7,8,9-he-
xahydro-5H-pyrazolo[3,4-c]isoquinolin-5-one
[0467] The title compound was prepared as HCl salt according to
procedure for related example. MS (DCI): m/z 357 (M+H).sup.+.
Example 233
[0468] benzyl
3-(3-methyl-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-c]isoquinolin-1-y-
l)piperidine-1-carboxylate
[0469] The title compound was prepared according to procedure for
related example. MS (DCI): m/z 421 (M+H).sup.+.
Example 234
[0470] benzyl
1-cyclopropyl-3-methyl-5-oxo-3,4,5,6,8,9-hexahydro-7H-pyrazolo[3,4-c]-2,7-
-naphthyridine-7-carboxylate
[0471] The title compound was prepared according to procedure for
related example. MS (DCI): m/z 379 (M+H).sup.+.
Example 235
[0472] benzyl
4-(3-methyl-5-oxo-4,5,6,7,8,9-hexahydro-3H-pyrazolo[3,4-c]isoquinolin-1-y-
l)piperidine-1-carboxylate
[0473] The title compound was prepared according to procedure for
related example. MS (DCI): m/z 421 (M+H).sup.+.
Example 236
1-(1-isopropylpiperidin-3-yl)-3-methyl-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3-
,4-e]isoquinolin-5-one
[0474] The title compound was prepared as HCl salt according to
procedure for related example. MS (DCI): m/z 329 (M+H).sup.+.
Example 237
1-[1-(cyclopropylmethyl)piperidin-3-yl]-3-methyl-3,4,6,7,8,9-hexahydro-5H--
pyrazolo[3,4-c]isoquinolin-5-one
[0475] The title compound was prepared as HCl salt according to
procedure for related example. MS (DCI): m/z 341 (M+H).sup.+.
Example 238
1-(1-cyclobutylpiperidin-3-yl)-3-methyl-3,4,6,7,8,9-hexahydro-5H-pyrazolo[-
3,4-e]isoquinolin-5-one
[0476] The title compound was prepared as HCl salt according to
procedure for related example. MS (DCI): m/z 341 (M+H).sup.+.
Example 239
1-(1-cyclopentylpiperidin-3-yl)-3-methyl-3,4,6,7,8,9-hexahydro-5H-pyrazolo-
[3,4-e]isoquinolin-5-one
[0477] The title compound was prepared as HCl salt according to
procedure for related example. MS (DCI): m/z 355 (M+H).sup.+.
Example 240
3-methyl-1-[1-(2-phenylethyl)piperidin-3-yl]-3,4,6,7,8,9-hexahydro-5H-pyra-
zolo[3,4-c]isoquinolin-5-one
[0478] The title compound was prepared as HCl salt according to
procedure for related example. MS (DCI): m/z 391 (M+H).sup.+.
Example 241
3-methyl-1-(1-tetrahydro-2H-pyran-4-ylpiperidin-3-yl)-3,4,6,7,8,9-hexahydr-
o-5H-pyrazolo[3,4-c]isoquinolin-5-one
[0479] The title compound was prepared as HCl salt according to
procedure for related example. MS (DCI): m/z 371 (M+H).sup.+.
Example 242
1-[1-(cyclopentylmethyl)piperidin-3-yl]-3-methyl-3,4,6,7,8,9-hexahydro-5H--
pyrazolo[3,4-c]isoquinolin-5-one
[0480] The title compound was prepared as HCl salt according to
procedure for related example. MS (DCI): m/z 369 (M+H).sup.+.
Example 243
3-methyl-1-(1-propylpiperidin-4-yl)-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4--
c]isoquinolin-5-one
[0481] The title compound was prepared as HCl salt according to
procedure for related example. MS (DCI): m/z 329 (M+H).sup.+.
Example 244
1-(1-isopropylpiperidin-4-yl)-3-methyl-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3-
,4-c]isoquinolin-5-one
[0482] The title compound was prepared as HCl salt according to
procedure for related example. MS (DCI): m/z 329 (M+H).sup.+.
Example 245
1-[1-(cyclopropylmethyl)piperidin-4-yl]-3-methyl-3,4,6,7,8,9-hexahydro-5H--
pyrazolo[3,4-c]isoquinolin-5-one
[0483] The title compound was prepared as HCl salt according to
procedure for related example. MS (DCI): m/z 341 (M+H).sup.+.
Example 246
1-(1-cyclobutylpiperidin-4-yl)-3-methyl-3,4,6,7,8,9-hexahydro-5H-pyrazolo[-
3,4-c]isoquinolin-5-one
[0484] The title compound was prepared as HCl salt according to
procedure for related example. MS (DCI): m/z 341 (M+H).sup.+.
Example 247
1-cyclopropyl-3,6-dimethyl-4,6,7,8-tetrahydrocyclopenta[d]pyrazolo[3,4-b]p-
yridin-5(3H)-one compound with
1-cyclopropyl-3,7-dimethyl-4,6,7,8-tetrahydrocyclopenta[d]pyrazolo[3,4-b]-
pyridin-5(3H)-one (1:1)
[0485] The title compound was prepared according to procedure for
related example. MS (DCI): m/z 244 (M+H).sup.+.
Example 248
1-[(2S)-1-isopropylpiperidin-2-yl]-3-methyl-3,4,6,7,8,9-hexahydro-5H-pyraz-
olo[3,4-c]isoquinolin-5-one
Example 249
1-(1-cyclobutylpyrrolidin-3-yl)-3,4-dimethyl-3,4,6,7,8,9-hexahydro-5H-pyra-
zolo[3,4-c]isoquinolin-5-one
[0486] MS (DCI): m/z 341 (M+H).sup.+.
* * * * *