U.S. patent application number 14/589602 was filed with the patent office on 2015-12-10 for organic compounds.
The applicant listed for this patent is Peng LI, Lawrence P. WENNOGLE, Jun ZHAO, Hailin ZHENG. Invention is credited to Peng LI, Lawrence P. WENNOGLE, Jun ZHAO, Hailin ZHENG.
Application Number | 20150353556 14/589602 |
Document ID | / |
Family ID | 42233531 |
Filed Date | 2015-12-10 |
United States Patent
Application |
20150353556 |
Kind Code |
A1 |
LI; Peng ; et al. |
December 10, 2015 |
ORGANIC COMPOUNDS
Abstract
Optionally substituted (5- or 7-amino)-3,4-dihydro-(optionally
4-oxo, 4-thioxo or 4-imino)-1H-pyrrolo[3,4-d]pyrimidin-2(6H)-ones,
Compounds of Formula (I), processes for their production, their use
as pharmaceuticals and pharmaceutical compositions comprising
them.
Inventors: |
LI; Peng; (New Milford,
NJ) ; ZHAO; Jun; (Highland Park, NJ) ; ZHENG;
Hailin; (Teaneck, NJ) ; WENNOGLE; Lawrence P.;
(Hillsborough, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
LI; Peng
ZHAO; Jun
ZHENG; Hailin
WENNOGLE; Lawrence P. |
New Milford
Highland Park
Teaneck
Hillsborough |
NJ
NJ
NJ
NJ |
US
US
US
US |
|
|
Family ID: |
42233531 |
Appl. No.: |
14/589602 |
Filed: |
January 5, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13133147 |
Jun 6, 2011 |
8927556 |
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PCT/US2009/006437 |
Dec 7, 2009 |
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14589602 |
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61235888 |
Aug 21, 2009 |
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61120443 |
Dec 6, 2008 |
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Current U.S.
Class: |
514/171 ;
514/265.1; 544/280 |
Current CPC
Class: |
A61P 11/00 20180101;
A61P 25/28 20180101; A61P 43/00 20180101; A61K 31/5365 20130101;
A61P 37/06 20180101; A61P 11/06 20180101; A61P 25/22 20180101; A61K
31/00 20130101; A61P 25/18 20180101; A61P 15/12 20180101; A61P
15/10 20180101; A61P 25/00 20180101; A61P 9/10 20180101; A61P 15/06
20180101; A61P 15/00 20180101; A61P 25/24 20180101; C07D 487/04
20130101; A61K 8/49 20130101; A61P 9/12 20180101; A61Q 7/00
20130101; A61P 27/02 20180101; A61P 29/00 20180101; A61P 21/00
20180101; A61P 25/16 20180101; A61K 31/519 20130101; A61P 25/30
20180101; A61P 13/08 20180101; A61P 15/08 20180101; A61P 27/06
20180101; A61P 25/14 20180101; A61P 35/00 20180101; A61P 25/20
20180101; A61P 11/02 20180101; A61K 8/42 20130101; A61P 19/10
20180101; A61P 5/14 20180101; A61P 9/00 20180101; A61K 45/06
20130101; A61P 37/08 20180101 |
International
Class: |
C07D 487/04 20060101
C07D487/04; A61K 8/42 20060101 A61K008/42; A61K 8/49 20060101
A61K008/49; A61Q 7/00 20060101 A61Q007/00; A61K 31/519 20060101
A61K031/519; A61K 45/06 20060101 A61K045/06 |
Claims
1. A optionally substituted (5- or 7-amino)-3,4-dihydro-(optionally
4-oxo, 4-thioxo or 4-imino)-1H-pyrrolo[3,4-d]pyrimidin-2(6H)-one,
in free or salt form.
2. The compound according to claim 1, wherein said compound is a
Compound of formula II-A or II-B: ##STR00072## wherein (i) Q is
--C(.dbd.S)--, --C(.dbd.O)--, --C(.dbd.N(R.sub.7))- or
--C(R.sub.14)(R.sub.15)--; (ii) R.sub.1 is H or C.sub.1-6alkyl
(e.g., methyl or ethyl); (iii) R.sub.2 is H, C.sub.1-6alkyl (e.g.,
isopropyl, isobutyl, 2-methylbutyl, 2,2-dimethylpropyl) wherein
said alkyl group is optionally substituted with halo (e.g., fluoro)
or hydroxy (e.g., 1-hydroxypropan-2-yl, 3-hydroxy-2-methylpropyl),
for example, R.sub.2 may be a trifluoromethyl or
2,2,2-trifluoroethyl, N(R.sub.14)(R.sub.15)--C.sub.1-6alkyl (e.g.,
2-(dimethylamino)ethyl or 2-aminopropyl), arylC.sub.0-6alkyl (e.g.,
phenyl or benzyl), heteroarylC.sub.0-6alkyl (e.g.,
pyridinylmethyl), C.sub.1-6alkoxyarylC.sub.1-6alkyl (e.g.,
4-methoxybenzyl); -G-J wherein: G is a single bond or, alkylene
(e.g., methylene); J is cycloalkyl or heterocycloalkyl (e.g.,
oxetan-2-yl, pyrolyin-3-yl, pyrolyin-2-yl) optionally substituted
with one or more C.sub.1-6alkyl (e.g., (1-methylpyrolidin-2-yl)),
amino (e.g., --NH.sub.2), for example, -G-J may be
--C.sub.0-4alkyl-C.sub.3-8 cycloalkyl (e.g., cyclopentyl,
cyclohexyl or cyclopropylmethyl) optionally substituted with one or
more C.sub.1-6alkyl, amino (e.g., --NH.sub.2), for example,
2-aminocyclopentyl or 2-aminocyclohexyl, wherein said cycloalkyl
optionally contains one or more heteroatom selected from N and O
(e.g., pyrrolidinyl, for example, pyrrolidin-3-yl or
pyrrolidin-2-yl, 1-methyl-pyrrolindin-2-yl,
1-methyl-pyrrolindin-3-yl, 1-methyl-pyrrolindin-2-yl-methyl or
1-methyl-pyrrolindin-3-yl-methyl); (iv) R.sub.3 is 1) -D-E-F
wherein: D is a single bond, C.sub.1-6alkylene (e.g., methylene),
or arylalkylene (e.g., p-benzylene or --CH.sub.2C.sub.6H.sub.4--);
E is a single bond, C.sub.1-4alkylene (e.g., methylene)
C.sub.2-6alkynylene (e.g., ethynylene,
prop-2-yn-1-ylene),ethynylene, prop-2-yn-1-ylene),
--C.sub.0-4alkylarylene (e.g., phenylene or --C.sub.6H.sub.4--,
-benzylene- or --CH.sub.2C.sub.6H.sub.4--), wherein the arylene
group is optionally substituted with halo (e.g., Cl or F),
heteroarylene (e.g., pyridinylene or pyrimidinylene),
aminoC.sub.1-6alkylene (e.g., --CH.sub.2N(H)--), amino (e.g.,
--N(H)--); C.sub.3-8 cycloalkylene optionally containing one or
more heteroatom selected from N or O (e.g., piperidinylene), F is
H, halo (e.g., F, Br, Cl), C.sub.1-6alkyl (e.g., isopropyl or
isobutyl), haloC.sub.1-6alkyl (e.g., trifluoromethyl), aryl (e.g.,
phenyl), C.sub.3-8 cycloalkyl optionally containing at least one
atom selected from a group consisting of N or O (e.g., cyclopentyl,
cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydro-2H-pyran-4-yl, or
morpholinyl), said cycloalkyl is optionally substituted with
C.sub.1-6alkyl (e.g., methyl or isopropyl), for example,
1-methylpyrrolidin-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl,
piperidin-2-yl, 1-methylpiperidin-2-yl, 1-ethylpiperidin-2-yl,
heteroaryl optionally substituted with C.sub.1-6alkyl, (e.g.,
pyridyl, (for example, pyrid-2-yl), pyrimidinyl (for example,
pyrimidin-2-yl), thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl),
diazolyl (e.g., pyrazolyl (for example, pyrazol-1-yl) or imidazolyl
(for example, imidazol-1-yl, 4-methylimidazolyl,
1-methylimidazol-2-yl,), triazolyl (e.g., 1,2,4-triazol-1-yl),
tetrazolyl (e.g., tetrazol-5-yl), alkoxadiazolyl (e.g.,
5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g., pyrazol-1-yl), wherein
said heteroaryl is optionally substituted with halo (e.g., fluoro)
or haloC.sub.1-6alkyl, for example, 6-fluoropyrid-2-yl; amino
(e.g., --NH.sub.2), C.sub.1-6alkoxy, --O-haloC.sub.1-6alkyl (e.g.,
--O--CF.sub.3), C.sub.1-6alkylsulfonyl (for example, methylsulfonyl
or --S(O).sub.2CH.sub.3), --C(O)--R.sub.13,
--N(R.sub.14)(R.sub.15); or 2) a substituted heteroarylaklyl, e.g.,
substituted with haloalkyl; or 3) attached to the nitrogen on the
pyrrolo portion of Formula I and is a moiety of Formula A
##STR00073## wherein X, Y and Z are, independently, N or C, and
R.sub.8, R.sub.9, R.sub.11 and R.sub.12 are independently H or
halogen (e.g., Cl or F); and R.sub.10 is halogen, C.sub.1-6alkyl,
C.sub.1-6alkoxy (e.g., methoxy), C.sub.3-8 cycloalkyl,
heteroC.sub.3-8 cycloalkyl (e.g., pyrrolidinyl or piperidinyl)
haloC.sub.1-6alkyl (e.g., trifluoromethyl), aryl (e.g., phenyl),
heteroaryl (e.g., pyridyl, (for example, pyrid-2-yl) or e.g.,
thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl), diazolyl,
triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g.,
tetrazol-5-yl), alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol),
pyrazolyl (e.g., pyrazol-1-yl), C.sub.1-6alkyl sulfonyl (e.g.,
methyl sulfonyl), arylcarbonyl (e.g., benzoyl), heteroarylcarbonyl,
alkoxycarbonyl, (e.g., methoxycarbonyl), aminocarbonyl; wherein the
aryl, heteroaryl, cycloalkyl or heterocycloalkyl is optionally
substituted with one or more C.sub.1-6alkyl (e.g., methyl), halogen
(e.g., chloro or fluoro), haloC.sub.1-6alkyl (e.g.,
trifluoromethyl), hydroxy, carboxy, --SH, or an additional aryl or
heteroaryl (e.g., biphenyl or pyridylphenyl) preferably R.sub.10 is
phenyl or pyridyl, e.g., 2-pyridyl optionally substituted with the
substituents previously defined; provided that when X, Y or X is
nitrogen, R.sub.8, R.sub.9 or R.sub.10, respectively, is not
present; (v) R.sub.4 and R.sub.5 are independently H,
C.sub.1-6alkyl (e.g., methyl, isopropyl), C.sub.3-8 cycloalkyl
(e.g., cyclopentyl), C.sub.3-8 heterocycloalkyl (e.g.,
pyrrolidin-3-yl), aryl (e.g., phenyl) or heteroaryl (e.g.,
pyrid-4-yl, pyrid-2-yl or pyrazol-3-yl) wherein said aryl or
heteroaryl is optionally substituted with halo (e.g.,
4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C.sub.1-6alkyl,
C.sub.1-6alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl);
(vi) R.sub.6 is H, C.sub.1-6alkyl (e.g., methyl), hydroxy,
C.sub.1-6alkoxy, aryloxy, --N(R.sub.16)(R.sub.17), oxo (e.g.,
.dbd.O), or C.sub.3-8 cycloalkyl; (vii) R.sub.7 is H,
C.sub.1-6alkyl (e.g., methyl) or C.sub.3-8 cycloalkyl wherein said
cycloalkyl is optionally substituted with one or more oxo (e.g.,
2,5-dioxopyrrolidin-1-yl); (viii) R.sub.13 is
--N(R.sub.14)(R.sub.15), C.sub.1-6alkyl (e.g., methyl),
--OC.sub.1-6alkyl (e.g., --OCH.sub.3), haloC.sub.1-6alkyl
(trifluoromethyl), aryl (e.g., phenyl), or heteroaryl; and (ix)
R.sub.14 and R.sub.15 are independently H or C.sub.1-6alkyl; (x)
R.sub.16 and R.sub.17 are independently H, C.sub.1-6alkyl, aryl
(e.g., phenyl), heteroaryl, wherein said aryl or heteroaryl is
optionally substituted with halo (e.g., fluoro), C.sub.1-6alkoxy
(e.g., methoxy); in free or salt form.
3. The Compound according to claim 1, wherein said compound is a
Compound of formula I-A or I-B: ##STR00074## wherein (i) Q is
--C(.dbd.S)--, --C(.dbd.O)--, --C(.dbd.N(R.sub.6))- or
--C(R.sub.14)(R.sub.15)--; (ii) R.sub.1 is H or C.sub.1-6alkyl
(e.g., methyl or ethyl); (iii) R.sub.2 is H, C.sub.1-6alkyl (e.g.,
isopropyl, isobutyl, 2-methylbutyl, 2,2-dimethylpropyl) wherein
said alkyl group is optionally substituted with halo (e.g., fluoro)
or hydroxy (e.g., 1-hydroxypropan-2-yl, 3-hydroxy-2-methylpropyl),
--C.sub.0-4alkyl-C.sub.3-8 cycloalkyl (e.g., cyclopentyl,
cyclohexyl) optionally substituted with one or more amino (e.g.,
--NH.sub.2), for example, 2-aminocyclopentyl or 2-aminocyclohexyl),
wherein said cycloalkyl optionally contains one or more heteroatom
selected from N and O and is optionally substituted with
C.sub.1-6alkyl (e.g., 1-methyl-pyrrolindin-2-yl,
1-methyl-pyrrolindin-3-yl, 1-methyl-pyrrolindin-2-yl-methyl or
1-methyl-pyrrolindin-3-yl-methyl), C.sub.3-8 heterocycloalkyl
(e.g., pyrrolidinyl, for example, pyrrolidin-3-yl or
pyrrolidin-2-yl) optionally substituted with C.sub.1-6alkyl (e.g.,
methyl), for example, 1-methylpyrrolidin-3-yl or
1-methylpyrrolidin-2-yl, C.sub.3-8cycloalkyl-C.sub.1-6alkyl (e.g.,
cyclopropylmethyl), haloC.sub.1-6alkyl (e.g., trifluoromethyl,
2,2,2-trifluoroethyl), --N(R.sub.14)(R.sub.15)--C.sub.1-6alkyl
(e.g., 2-(dimethylamino)ethyl,2-aminopropyl), hydroxyC.sub.1-6alkyl
(e.g., (e.g., 3-hydroxy-2-methylpropyl, 1-hydroxyprop-2-yl),
arylC.sub.0-6alkyl (e.g., benzyl), heteroarylC.sub.1-6alkyl (e.g.,
pyridinylmethyl), C.sub.1-6alkoxyarylC.sub.1-6alkyl (e.g.,
4-methoxybenzyl); -G-J wherein: G is a single bond or, alkylene
(e.g., methylene); J is cycloalkyl or heterocycloalkyl (e.g.,
oxetan-2-yl, pyrolyin-3-yl, pyrolyin-2-yl) optionally substituted
with C.sub.1-6alkyl (e.g., (1-methylpyrolidin-2-yl)); (iv) R.sub.3
is 1) -D-E-F wherein: D is a single bond, C.sub.1-6alkylene (e.g.,
methylene), or arylalkylene (e.g., p-benzylene or
--CH.sub.2C.sub.6H.sub.4--); E is a single bond, C.sub.1-4alkylene
(e.g., methylene) C.sub.2-6alkynylene (e.g., ethynylene,
prop-2-yn-1-ylene),ethynylene, prop-2-yn-1-ylene),
--C.sub.0-4alkylarylene (e.g., phenylene or --C.sub.6H.sub.4--,
-benzylene- or --CH.sub.2C.sub.6H.sub.4--), wherein the arylene
group is optionally substituted with halo (e.g., Cl or F),
heteroarylene (e.g., pyridinylene or pyrimidinylene),
aminoC.sub.1-6alkylene (e.g., --CH.sub.2N(H)--), amino (e.g.,
--N(H)--); C.sub.3-8 cycloalkylene optionally containing one or
more heteroatom selected from N or O (e.g., piperidinylene), F is
H, halo (e.g., F, Br, Cl), C.sub.1-6alkyl (e.g., isopropyl or
isobutyl), haloC.sub.1-6alkyl (e.g., trifluoromethyl), aryl (e.g.,
phenyl), C.sub.3-8 cycloalkyl optionally containing at least one
atom selected from a group consisting of N or O (e.g., cyclopentyl,
cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydro-2H-pyran-4-yl, or
morpholinyl), said cycloalkyl is optionally substituted with
C.sub.1-6alkyl (e.g., methyl or isopropyl), for example,
1-methylpyrrolidin-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl,
piperidin-2-yl, 1-methylpiperidin-2-yl, 1-ethylpiperidin-2-yl,
heteroaryl optionally substituted with C.sub.1-6alkyl, (e.g.,
pyridyl, (for example, pyrid-2-yl), pyrimidinyl (for example,
pyrimidin-2-yl), thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl),
diazolyl (e.g., pyrazolyl (for example, pyrazol-1-yl) or imidazolyl
(for example, imidazol-1-yl, 4-methylimidazolyl,
1-methylimidazol-2-yl,), triazolyl (e.g., 1,2,4-triazol-1-yl),
tetrazolyl (e.g., tetrazol-5-yl), alkoxadiazolyl (e.g.,
5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g., pyrazol-1-yl), wherein
said heteroaryl is optionally substituted with halo (e.g., fluoro)
or haloC.sub.1-6alkyl, for example, 6-fluoropyrid-2-yl; amino
(e.g., --NH.sub.2), C.sub.1-6alkoxy, --O-haloC.sub.1-6alkyl (e.g.,
--O--CF.sub.3), C.sub.1-6alkylsulfonyl (for example, methylsulfonyl
or --S(O).sub.2CH.sub.3), --C(O)--R.sub.13,
--N(R.sub.14)(R.sub.15); or 2) a substituted heteroarylaklyl, e.g.,
substituted with haloalkyl; or 3) attached to the nitrogen on the
pyrrolo portion of Formula I and is a moiety of Formula A Formula A
wherein X, Y and Z are, independently, N or C, and R.sub.8,
R.sub.9, R.sub.11 and R.sub.12 are independently H or halogen
(e.g., Cl or F); and R.sub.10 is halogen, alkyl, cycloalkyl,
haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl), heteroaryl
(e.g., pyridyl, (for example, pyrid-2-yl) or e.g., thiadiazolyl
(for example, 1,2,3-thiadiazol-4-yl), diazolyl, triazolyl (e.g.,
1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl),
alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g.,
pyrazol-1-yl), alkyl sulfonyl (e.g., methyl sulfonyl), arylcarbonyl
(e.g., benzoyl), or heteroarylcarbonyl, alkoxycarbonyl, (e.g.,
methoxycarbonyl), aminocarbonyl; preferably phenyl or pyridyl,
e.g., 2-pyridyl; provided that when X, Y or X is nitrogen, R.sub.8,
R.sub.9 or R.sub.10, respectively, is not present; (v) R.sub.4 and
R.sub.5 are independently H, C.sub.1-6alkyl (e.g., methyl,
isopropyl), C.sub.3-8 cycloalkyl (e.g., cyclopentyl), C.sub.3-8
heterocycloalkyl (e.g., pyrrolidin-3-yl), aryl (e.g., phenyl) or
heteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or pyrazol-3-yl) wherein
said aryl or heteroaryl is optionally substituted with halo (e.g.,
4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C.sub.1-6alkyl,
C.sub.1-6alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl);
(vi) R.sub.6 is H, C.sub.1-6alkyl (e.g., methyl) or C.sub.3-8
cycloalkyl; (vii) R.sub.13 is --N(R.sub.14)(R.sub.15),
C.sub.1-6alkyl (e.g., methyl), --OC.sub.1-6alkyl (e.g.,
--OCH.sub.3), haloC.sub.1-6alkyl (trifluoromethyl), aryl (e.g.,
phenyl), or heteroaryl; and (viii) R.sub.14 and R.sub.15 are
independently H or C.sub.1-6alkyl, in free or salt form.
4. The Compound according to claim 1, wherein said compound is a
Compound of formula P-A or P-B: ##STR00075## wherein (i) X.dbd.O or
S (ii) R.sub.1 is H or C.sub.1-6alkyl (e.g., methyl or ethyl);
(iii) R.sub.2 is H, C.sub.1-6alkyl (e.g., isopropyl, isobutyl,
2-methylbutyl, 2,2-dimethyl propyl), --C.sub.0-66alkyl-C.sub.3-9
cycloalkyl (e.g., cyclopentyl, cyclohexyl or cyclopropylmethyl)
wherein said cycloalkyl is optionally substituted with one or more
groups selected from C.sub.1-4alkyl and amino (e.g., --NH.sub.2),
for example, 2-aminocyclopentyl or 2-aminocyclohexyl),
--C.sub.0-6alkyl-heteroC.sub.3-9 cycloalkyl (e.g., pyrrolidinyl,
for example, pyrrolidin-3-yl or pyrrolyin-2-yl; oxetan-2-yl;
tetrahydrofuran-2-yl or tetrahydrofuran-2-ylmethyl) wherein said
heterocycloalkyl is optionally substituted with one ore more
C.sub.1-6alkyl (e.g., methyl), for example, 1-methylpyrrolidin-2-yl
or 1-methylpyrrolidin-3-yl, haloC.sub.1-6alkyl (e.g.,
trifluoromethyl, 2,2,2-trifluoroethyl),
C.sub.0-6alkylaminoC.sub.0-6alkyl (e.g., 2-(dimethylamino)ethyl,
2-aminopropyl), hydroxyC.sub.1-6alkyl (e.g.,
3-hydroxy-2-methylpropyl or 2-hydroxy-1-methylethyl),
arylC.sub.0-6alkyl (e.g., phenyl or benzyl) wherein said aryl group
is optionally substituted with one or more C.sub.1-6alkoxy, for
example, 4-methoxybenzyl, heteroarylC.sub.1-6alkyl (e.g.,
pyridylmethyl), (iv) R.sub.3 is a) hydrogen, b) -D-E-F wherein D is
single bond, C.sub.1-6alkylene (e.g., methylene, ethynylene,
prop-2-yn-1-ylene), or arylC.sub.1-6alkylene (e.g., benzylene or
--CH.sub.2C.sub.6H.sub.4--); E is arylene (e.g., phenylene or
--C.sub.6H.sub.4--), wherein the arylene is optionally substituted
with one or more halo, arylC.sub.1-6alkylene (e.g., -benzylene- or
--CH.sub.2C.sub.6H.sub.4--), aminoC.sub.1-6alkylene (e.g.,
--CH.sub.2N(H)--), amino (e.g., --N(H)--), heteroarylene (e.g.,
pyrid-3-ylene) or heteroC.sub.3-9 cycloakylene (e.g.,
piperidin-4-ylene) wherein the heteroarylene and the
heterocycloalkylene are independently and optionally substituted
with one or more halo; and F is Hydrogen, C.sub.1-6alkyl (e.g.,
isobutyl, isopropyl), aryl (e.g., phenyl) wherein said aryl is
optionally substituted with one or more halo and/or
haloC.sub.1-6alkyl, heteroaryl (e.g., triazolyl, diazolyl,
oxadiazolyl, pyridyl, pyrimidinyl) wherein said heteroaryl is
optionally substituted with one or more groups selected from halo
(e.g., fluoro), C.sub.1-6alkyl and haloC.sub.1-6alkyl (e.g.,
trifluoromethyl), for example, pyrid-2-yl, 4,6-dimethyl-pyrid-2-yl,
5-fluoropyrimidin-2-yl, imidazol-1-yl, 4-methylimidazolyl,
1-methylimidazol-2-yl, pyrazol-1-yl, 1,2,4-triazol-1-yl,
5-methyl-1,2,4-oxadiazol-3-yl or pyrimidin-2-yl, heteroC.sub.3-9
cycloalkyl (e.g., piperidinyl, pyrrolidinyl) wherein said
heterocycloalkyl is optionally substituted with one or more
Cl.sub.-- 6alkyl (e.g., methyl), for example, pyrrolidin-1-yl,
pyrrolidin-2-yl, 1-methylpyrrolidin-2-yl, piperidin-2-yl,
1-methylpiperidin-2-yl, 1-ethylpiperidin-2-yl,
--N(R.sub.a)(R.sub.b) wherein R.sub.a and R.sub.b are independently
H or C.sub.1-6alkyl (e.g., --NH.sub.2, dimethylamino or
isopropylamino), aminocarbonyl (e.g., --C(O)NH.sub.2),
C.sub.1-6alkoxy, arylcarbonyl (e.g., benzoyl), heteroarylcarbonyl,
C.sub.1-6alkoxycarbonyl (e.g., methoxycarbonyl), C.sub.1-6alkyl
sulfonyl(e.g., --S(O).sub.2--CH.sub.3), halo (e.g., chloro or
fluoro), haloC.sub.1-6alkyl (e.g., --CF.sub.3), or
--O-haloC.sub.1-6alkyl (e.g., --O--CF.sub.3), c) R.sub.3 is
heteroarylC.sub.0-6alkyl, wherein the heteroaryl group is
optionally substituted with one or more C.sub.1-6 haloalkyl; or d)
R.sub.3 is a moiety of Formula A Formula A wherein X, Y and Z are,
independently, N or C, and R.sub.8, R.sub.9, R.sub.11 and R.sub.12
are independently H or halogen (e.g., Cl or F); and R.sub.10 is
hydrogen, halogen (e.g., fluoro or chloro), C.sub.1-6alkyl,
C.sub.3-9 cycloalkyl, C.sub.1-6 haloalkyl (e.g., trifluoromethyl),
aryl (e.g., phenyl) wherein said aryl is optionally substituted
with one or more halo and/or haloC.sub.1-6alkyl, heteroaryl wherein
said heteroaryl group is optionally substituted with one or more
groups selected from halo (e.g., fluoro), C.sub.1-6alkyl and
haloC.sub.1-6alkyl, e.g., pyridyl, (for example, pyrid-2-yl,
6-fluoro-pyrid-2-yl, 5-trifluoromethyl-pyrid-2-yl,
6-trifluoromethyl-pyrid-3-yl, 4,6-dimethylpyrid-2-yl), thiadiazolyl
(for example, 1,2,3-thiadiazol-4-yl), diazolyl (for example,
pyrazolyl, e.g., pyrazol-1-yl), triazolyl (for example,
1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl), oxadiazolyl
(e.g., 5-methyl-1,2,4-oxadiazol-3-yl), C.sub.1-6alkyl sulfonyl
(e.g., methyl sulfonyl), arylcarbonyl (e.g., benzoyl),
heteroarylcarbonyl, C.sub.1-6alkoxycarbonyl, (e.g.,
methoxycarbonyl), aminocarbonyl (i.e., --C(O)NH.sub.2),
--N(R.sub.a)(R.sub.b) wherein R.sub.a and R.sub.b are independently
H or C.sub.1-6alkyl (e.g., --NH.sub.2, dimethylamino or
isopropylamino), haloC.sub.1-6alkyl, --O-haloC.sub.1-6alkyl (e.g.,
--O--CF.sub.3), heteroC.sub.3-9 cycloalkyl-C.sub.0-6alkyl (e.g.,
piperidinyl, pyrrolidinyl, pyrrolidinylmethyl) wherein said
heterocycloalkyl is optionally substituted with one or more
C.sub.1-6alkyl (e.g., methyl), for example, pyrrolidin-1-yl,
pyrrolidin-2-yl, 1-methylpyrrolidin-2-yl, piperidin-2-yl,
1-methylpiperidin-2-yl, 1-ethylpiperidin-2-yl; provided that when
X, Y or Z is nitrogen, R.sub.8, R.sub.9 or R.sub.10, respectively,
is not present; (v) R.sub.4 and R.sub.5 are independently selected
from H, C.sub.1-6alkyl (e.g., methyl or isopropyl), C.sub.3-9
cycloalkyl (e.g., cyclopentyl), C.sub.3-9 heterocycloalkyl (e.g.,
pyrrolidin-3-yl), heteroaryl (e.g., pyrid-2-yl, pyrid-3-yl or
pyrid-4-yl, pyrazol-3-yl), aryl (e.g., phenyl) or
arylC.sub.1-6alkyl (e.g., benzyl), wherein the aryl group is
optionally substituted with one or more halo (e.g., F or Cl),
hydroxy and/or another aryl, (e.g., p-benzylaryl, e.g.,
biphenyl-4-ylmethyl); (vi) R.sub.6 is H or C.sub.1-6alkyl (e.g.,
ethyl); in free or salt form.
6. The compound according to claim 1, selected from any of the
following: ##STR00076## ##STR00077## ##STR00078## ##STR00079##
##STR00080## ##STR00081## in free or salt form.
7. The compound according to claim 1, selected from any of the
following: ##STR00082## ##STR00083## ##STR00084## ##STR00085##
##STR00086## in free or salt form.
8. The compound according to claim 1, selected from any of the
following: ##STR00087## ##STR00088## ##STR00089## ##STR00090##
##STR00091## ##STR00092## in free or salt form.
9. A pharmaceutical composition comprising a compound according to
claim 1, in free or pharmaceutically acceptable salt form, in
admixture with a pharmaceutically acceptable diluent or
carrier.
10. A method of treating any of the following conditions:
Parkinson's disease, restless leg, tremors, dyskinesias,
Huntington's disease, Alzheimer's disease, and drug-induced
movement disorders; depression, attention deficit disorder,
attention deficit hyperactivity disorder, bipolar illness, anxiety,
sleep disorder, narcolepsy, cognitive impairment, dementia,
Tourette's syndrome, autism, fragile X syndrome, psychostimulant
withdrawal, and/or drug addiction; cerebrovascular disease, stroke,
congestive heart disease, hypertension, pulmonary hypertension,
and/or sexual dysfunction; asthma, chronic obstructive pulmonary
disease, and/or allergic rhinitis, as well as autoimmune and
inflammatory diseases; and/or female sexual dysfunction, exercise
amenorrhoea, anovulation, menopause, menopausal symptoms,
hypothyroidism, pre-menstrual syndrome, premature labor,
infertility, irregular menstrual cycles, abnormal uterine bleeding,
osteoporosis, multiple sclerosis, prostate enlargement, prostate
cancer, hypothyroidism, estrogen-induced endometrial hyperplasia or
carcinoma; and/or any disease or condition characterized by low
levels of cAMP and/or cGMP (or inhibition of cAMP and/or cGMP
signaling pathways) in cells expressing PDE1, and/or by reduced
dopamine D1 receptor signaling activity; and/or any disease or
condition that may be ameliorated by the enhancement of
progesterone signaling; comprising administering a therapeutically
effective amount of a compound according to claim 1, in free or
pharmaceutically acceptable salt form, or a pharmaceutical
composition, to a patient in need of such treatment.
11. (canceled)
12. (canceled)
13. (canceled)
14. The method of claim 13 further comprising administering a
compound or compounds selected from central nervous system
stimulants, modafinil, antidepressants, and gamma hydroxybutyrate,
to a patient in need thereof.
15. (canceled)
16. The method of claim 15, further comprising administering a
compound or compounds selected from a group consisting of
estradiol, estriol, estradiol esters, progesterone and progestins
to a patient in need thereof.
17. A method for the treatment of treatment for glaucoma or
elevated intraocular pressure comprising topical administration of
a therapeutically effective amount of a compound according to claim
1, in free or pharmaceutically acceptable salt form, in an
opthalmically compatible carrier to the eye of a patient in need
thereof.
18. A method for the treatment of psychosis, schizophrenia,
schizoaffective disorder, schizophreniform disorder, psychotic
disorder, delusional disorder, and mania, such as in acute manic
episodes and bipolar disorder, comprising administering a
therapeutically effective amount of a compound according to claim
1, in free or pharmaceutically acceptable salt form, to a patient
in need thereof.
19. A method for the treatment of traumatic brain injury comprising
administering to a patient in need thereof, a compound according to
claim 1, in free or pharmaceutically acceptable salt form.
20. A method for lengthening or enhancing growth of the eyelashes
by administering an effective amount of a prostaglandin analogue,
e.g., bimatoprost, concomitantly, simultaneously or sequentially
with an effective amount of a compound according to claim 1, in
free or salt form.
21. Use of the Compound according to claim 1, in free or
pharmaceutically acceptable salt form, or a pharmaceutical
composition for the manufacture of a medicament for the treatment
or prophylactic treatment of the following diseases: Parkinson's
disease, restless leg, tremors, dyskinesias, Huntington's disease,
Alzheimer's disease, and drug-induced movement disorders;
depression, attention deficit disorder, attention deficit
hyperactivity disorder, bipolar illness, anxiety, sleep disorder,
narcolepsy, cognitive impairment, dementia, Tourette's syndrome,
autism, fragile X syndrome, psychostimulant withdrawal, and/or drug
addiction; cerebrovascular disease, stroke, congestive heart
disease, hypertension, pulmonary hypertension, and/or sexual
dysfunction; asthma, chronic obstructive pulmonary disease, and/or
allergic rhinitis, as well as autoimmune and inflammatory diseases;
and/or female sexual dysfunction, exercise amenorrhoea,
anovulation, menopause, menopausal symptoms, hypothyroidism,
pre-menstrual syndrome, premature labor, infertility, irregular
menstrual cycles, abnormal uterine bleeding, osteoporosis, multiple
sclerosis, prostate enlargement, prostate cancer, hypothyroidism,
estrogen-induced endometrial hyperplasia or carcinoma; and/or any
disease or condition characterized by low levels of cAMP and/or
cGMP (or inhibition of cAMP and/or cGMP signaling pathways) in
cells expressing PDE1, and/or by reduced dopamine D1 receptor
signaling activity; and/or any disease or condition that may be
ameliorated by the enhancement of progesterone signaling.
22. (canceled)
23. A pharmaceutical comprising a Compound according to claim 1, in
free or pharmaceutically acceptable salt form, in combination or
association with a pharmaceutically acceptable diluent or carrier
for use in the treatment of any disease or condition selected from:
Parkinson's disease, restless leg, tremors, dyskinesias,
Huntington's disease, Alzheimer's disease, and drug-induced
movement disorders; depression, attention deficit disorder,
attention deficit hyperactivity disorder, bipolar illness, anxiety,
sleep disorder, narcolepsy, cognitive impairment, dementia,
Tourette's syndrome, autism, fragile X syndrome, psychostimulant
withdrawal, and/or drug addiction; cerebrovascular disease, stroke,
congestive heart disease, hypertension, pulmonary hypertension,
and/or sexual dysfunction; asthma, chronic obstructive pulmonary
disease, and/or allergic rhinitis, as well as autoimmune and
inflammatory diseases; and/or female sexual dysfunction, exercise
amenorrhoea, anovulation, menopause, menopausal symptoms,
hypothyroidism, pre-menstrual syndrome, premature labor,
infertility, irregular menstrual cycles, abnormal uterine bleeding,
osteoporosis, multiple sclerosis, prostate enlargement, prostate
cancer, hypothyroidism, estrogen-induced endometrial hyperplasia or
carcinoma; and/or any disease or condition characterized by low
levels of cAMP and/or cGMP (or inhibition of cAMP and/or cGMP
signaling pathways) in cells expressing PDE1, and/or by reduced
dopamine D1 receptor signaling activity; and/or any disease or
condition that may be ameliorated by the enhancement of
progesterone signaling; glaucoma or elevated intraocular pressure;
psychosis, schizophrenia, schizoaffective disorder,
schizophreniform disorder, psychotic disorder, delusional disorder,
and mania, such as in acute manic episodes and bipolar disorder;
and traumatic brain injury.
Description
[0001] This application claims priority from U.S. Provisional
Application No. 61/120,443, filed Dec. 6, 2008, and U.S.
Provisional Application No. 61/235,888, filed Aug. 21, 2009, the
contents of each of which are hereby incorporated by reference in
their entirety.
TECHNICAL FIELD
[0002] The present invention relates optionally substituted (5- or
7-amino)-3,4-dihydro-(optionally 4-oxo, 4-thioxo or
4-imino)-1H-pyrrolo[3,4-d]pyrimidin-2(6H)-ones, preferably a
compound of Formula I as described below, processes for their
production, their use as pharmaceuticals and pharmaceutical
compositions comprising them. Of particular interest are novel
compounds useful as inhibitors of phosphodiesterase 1 (PDE1), e.g.,
in the treatment of diseases involving disorders of the dopamine D1
receptor intracellular pathway, such as Parkinson's disease,
depression, narcolepsy, damage to cognitive function, e.g., in
schizophrenia, or disorders that may be ameliorated through
enhanced progesterone-signaling pathway, e.g., female sexual
dysfunction.
BACKGROUND OF THE INVENTION
[0003] Eleven families of phosphodiesterases (PDEs) have been
identified but only PDEs in Family I, the
Ca.sup.2+-calmodulin-dependent phosphodiesterases (CaM-PDEs), have
been shown to mediate both the calcium and cyclic nucleotide (e.g.
cAMP and cGMP) signaling pathways. The three known CaM-PDE genes,
PDE1A, PDE1B, and PDE1C, are all expressed in central nervous
system tissue. PDE1A is expressed throughout the brain with higher
levels of expression in the CA1 to CA3 layers of the hippocampus
and cerebellum and at a low level in the striatum. PDE1A is also
expressed in the lung and heart. PDE1B is predominately expressed
in the striatum, dentate gyrus, olfactory tract and cerebellum, and
its expression correlates with brain regions having high levels of
dopaminergic innervation. Although PDE1B is primarily expressed in
the central nervous system, it may be detected in the heart. PDE1C
is primarily expressed in olfactory epithelium, cerebellar granule
cells, and striatum. PDE1C is also expressed in the heart and
vascular smooth muscle.
[0004] Cyclic nucleotide phosphodiesterases decrease intracellular
cAMP and cGMP signaling by hydrolyzing these cyclic nucleotides to
their respective inactive 5'-monophosphates (5'AMP and 5'GMP).
CaM-PDEs play a critical role in mediating signal transduction in
brain cells, particularly within an area of the brain known as the
basal ganglia or striatum. For example, NMDA-type glutamate
receptor activation and/or dopamine D2 receptor activation result
in increased intracellular calcium concentrations, leading to
activation of effectors such as calmodulin-dependent kinase II
(CaMKII) and calcineurin and to activation of CaM-PDEs, resulting
in reduced cAMP and cGMP. Dopamine D1 receptor activation, on the
other hand, leads to activation of nucleotide cyclases, resulting
in increased cAMP and cGMP. These cyclic nucleotides in turn
activate protein kinase A (PKA; cAMP-dependent protein kinase)
and/or protein kinase G (PKG; cGMP-dependent protein kinase) that
phosphorylate downstream signal transduction pathway elements such
as DARPP-32 (dopamine and cAMP-regulated phosphoprotein) and cAMP
responsive element binding protein (CREB). Phosphorylated DARPP-32
in turn inhibits the activity of protein phosphates-1 (PP-1),
thereby increasing the state of phosphorylation of substrate
proteins such as progesterone receptor (PR), leading to induction
of physiologic responses. Studies in rodents have suggested that
inducing cAMP and cGMP synthesis through activation of dopamine D1
or progesterone receptor enhances progesterone signaling associated
with various physiological responses, including the lordosis
response associated with receptivity to mating in some rodents. See
Mani, et al., Science (2000) 287: 1053, the contents of which are
incorporated herein by reference.
[0005] CaM-PDEs can therefore affect dopamine-regulated and other
intracellular signaling pathways in the basal ganglia (striatum),
including but not limited to nitric oxide, noradrenergic,
neurotensin, CCK, VIP, serotonin, glutamate (e.g., NMDA receptor,
AMPA receptor), GABA, acetylcholine, adenosine (e.g., A2A
receptor), cannabinoid receptor, natriuretic peptide (e.g., ANP,
BNP, CNP), DARPP-32, and endorphin intracellular signaling
pathways.
[0006] Phosphodiesterase (PDE) activity, in particular,
phosphodiesterase 1 (PDE1) activity, functions in brain tissue as a
regulator of locomotor activity and learning and memory. PDE1 is a
therapeutic target for regulation of intracellular signaling
pathways, preferably in the nervous system, including but not
limited to a dopamine D1 receptor, dopamine D2 receptor, nitric
oxide, noradrenergic, neurotensin, CCK, VIP, serotonin, glutamate
(e.g., NMDA receptor, AMPA receptor), GABA, acetylcholine,
adenosine (e.g., A2A receptor), cannabinoid receptor, natriuretic
peptide (e.g., ANP, BNP, CNP), endorphin intracellular signaling
pathway and progesterone signaling pathway. For example, inhibition
of PDE1B should act to potentiate the effect of a dopamine D1
agonist by protecting cGMP and cAMP from degradation, and should
similarly inhibit dopamine D2 receptor signaling pathways, by
inhibiting PDE1 activity. Chronic elevation in intracellular
calcium levels is linked to cell death in numerous disorders,
particularly in neurodegerative diseases such as Alzheimer's,
Parkinson's and Huntington's Diseases and in disorders of the
circulatory system leading to stroke and myocardial infarction.
PDE1 inhibitors are therefore potentially useful in diseases
characterized by reduced dopamine D1 receptor signaling activity,
such as Parkinson's disease, restless leg syndrome, depression,
narcolepsy and cognitive impairment. PDE1 inhibitors are also
useful in diseases that may be alleviated by the enhancement of
progesterone-signaling such as female sexual dysfunction.
[0007] There is thus a need for compounds that selectively inhibit
PDE1 activity, especially PDE1A or PDE1B activity.
SUMMARY OF THE INVENTION
[0008] The invention provides optionally substituted (5- or
7-amino)-3,4-dihydro-(optionally 4-oxo, 4-thioxo or
4-imino)-1H-pyrrolo[3,4-d]pyrimidin-2(6H)-ones, preferably a
Compound of Formula II, e.g., II-A and II-B:
##STR00001##
wherein [0009] (i) Q is --C(.dbd.S)--, --C(.dbd.O)--,
--C(.dbd.N(R.sub.7))- or --C(R.sub.14)(R.sub.15)--; [0010] (ii)
R.sub.1 is H or C.sub.1-6alkyl (e.g., methyl or ethyl); [0011]
(iii) R.sub.2 is [0012] H, [0013] C.sub.1-6alkyl (e.g., isopropyl,
isobutyl, 2-methylbutyl, 2,2-dimethylpropyl) wherein said alkyl
group is optionally substituted with halo (e.g., fluoro) or hydroxy
(e.g., 1-hydroxypropan-2-yl, 3-hydroxy-2-methylpropyl), for
example, R.sub.2 may be a trifluoromethyl or 2,2,2-trifluoroethyl,
[0014] N(R.sub.14)(R.sub.15)--C.sub.1-6alkyl (e.g.,
2-(dimethylamino)ethyl or 2-aminopropyl), [0015] arylC.sub.0-6alkyl
(e.g., phenyl or benzyl), [0016] heteroarylC.sub.0-6alkyl (e.g.,
pyridinylmethyl), [0017] C.sub.1-6alkoxyarylC.sub.1-6alkyl (e.g.,
4-methoxybenzyl); [0018] -G-J wherein: [0019] G is a single bond
or, alkylene (e.g., methylene); [0020] J is cycloalkyl or
heterocycloalkyl (e.g., oxetan-2-yl, pyrolyin-3-yl, pyrolyin-2-yl)
optionally substituted with one or more C.sub.1-6alkyl (e.g.,
(1-methylpyrolidin-2-yl)), amino (e.g., --NH.sub.2), [0021] for
example, -G-J may be --C.sub.0-4alkyl-C.sub.3-8cycloalkyl (e.g.,
cyclopentyl, cyclohexyl or cyclopropylmethyl) optionally
substituted with one or more C.sub.1-6alkyl, amino (e.g.,
--NH.sub.2), for example, 2-aminocyclopentyl or 2-aminocyclohexyl,
wherein said cycloalkyl optionally contains one or more heteroatom
selected from N and O (e.g., pyrrolidinyl, for example,
pyrrolidin-3-yl or pyrrolidin-2-yl, 1-methyl-pyrrolindin-2-yl,
1-methyl-pyrrolindin-3-yl, 1-methyl-pyrrolindin-2-yl-methyl or
1-methyl-pyrrolindin-3-yl-methyl); [0022] (iv) R.sub.3 is [0023] 1)
-D-E-F wherein: [0024] D is a single bond, C.sub.1-6alkylene (e.g.,
methylene), or arylalkylene (e.g., p-benzylene or
--CH.sub.2C.sub.6H.sub.4--); [0025] E is [0026] a single bond,
[0027] C.sub.1-4alkylene (e.g., methylene) [0028]
C.sub.2-6alkynylene (e.g., ethynylene, prop-2-yn-1-ylene),
ethynylene, prop-2-yn-1-ylene), [0029] --C.sub.0-4alkylarylene
(e.g., phenylene or --C.sub.6H.sub.4--, -benzylene- or
--CH.sub.2C.sub.6H.sub.4--), wherein the arylene group is
optionally substituted with halo (e.g., Cl or F), [0030]
heteroarylene (e.g., pyridinylene or pyrimidinylene), [0031]
aminoC.sub.1-6alkylene (e.g., --CH.sub.2N(H)--), [0032] amino
(e.g., --N(H)--); [0033] C.sub.3-8cycloalkylene optionally
containing one or more heteroatom selected from N or O (e.g.,
piperidinylene), [0034] F is [0035] H, [0036] halo (e.g., F, Br,
Cl), [0037] C.sub.1-6alkyl (e.g., isopropyl or isobutyl), [0038]
haloC.sub.1-6alkyl (e.g., trifluoromethyl), [0039] aryl (e.g.,
phenyl), [0040] C.sub.3-8cycloalkyl optionally containing at least
one atom selected from a group consisting of N or O (e.g.,
cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl,
tetrahydro-2H-pyran-4-yl, or morpholinyl), said cycloalkyl is
optionally substituted with C.sub.1-6alkyl (e.g., methyl or
isopropyl), for example, 1-methylpyrrolidin-2-yl, pyrrolidin-1-yl,
pyrrolidin-2-yl, piperidin-2-yl, 1-methylpiperidin-2-yl,
1-ethylpiperidin-2-yl, [0041] heteroaryl optionally substituted
with C.sub.1-6alkyl, (e.g., pyridyl, (for example, pyrid-2-yl),
pyrimidinyl (for example, pyrimidin-2-yl), thiadiazolyl (for
example, 1,2,3-thiadiazol-4-yl), diazolyl (e.g., pyrazolyl (for
example, pyrazol-1-yl) or imidazolyl (for example, imidazol-1-yl,
4-methylimidazolyl, 1-methylimidazol-2-yl,), triazolyl (e.g.,
1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl),
alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g.,
pyrazol-1-yl), wherein said heteroaryl is optionally substituted
with halo (e.g., fluoro) or haloC.sub.1-6alkyl, for example,
6-fluoropyrid-2-yl; [0042] amino (e.g., --NH.sub.2), [0043]
C.sub.1-6alkoxy, [0044] --O-haloC.sub.1-6alkyl (e.g.,
--O--CF.sub.3), [0045] C.sub.1-6alkylsulfonyl (for example,
methylsulfonyl or --S(O).sub.2CH.sub.3), [0046] --C(O)--R.sub.13,
[0047] --N(R.sub.14)(R.sub.15); or [0048] 2) a substituted
heteroarylaklyl, e.g., substituted with haloalkyl; or [0049] 3)
attached to the nitrogen on the pyrrolo portion of Formula I and is
a moiety of Formula A
[0049] ##STR00002## [0050] wherein X, Y and Z are, independently, N
or C, and R.sub.8, R.sub.9, R.sub.11 and R.sub.12 are independently
H or halogen (e.g., Cl or F); and R.sub.10 is [0051] halogen,
[0052] C.sub.1-6alkyl, [0053] C.sub.1-6alkoxy (e.g., methoxy),
[0054] C.sub.3-8cycloalkyl, [0055] heteroC.sub.3-8cycloalkyl (e.g.,
pyrrolidinyl) [0056] haloC.sub.1-6alkyl (e.g., trifluoromethyl),
[0057] aryl (e.g., phenyl), [0058] heteroaryl (e.g., pyridyl, (for
example, pyrid-2-yl) or e.g., thiadiazolyl (for example,
1,2,3-thiadiazol-4-yl), diazolyl (e.g., imidazolyl or pyrazolyl),
triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g.,
tetrazol-5-yl), alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol),
pyrazolyl (e.g., pyrazol-1-yl), [0059] C.sub.1-6alkyl sulfonyl
(e.g., methyl sulfonyl), [0060] arylcarbonyl (e.g., benzoyl),
[0061] heteroarylcarbonyl, [0062] alkoxycarbonyl, (e.g.,
methoxycarbonyl), [0063] aminocarbonyl; [0064] wherein the aryl,
heteroaryl, cycloalkyl or heterocycloalkyl is optionally
substituted with one or more C.sub.1-6alkyl (e.g., methyl), halogen
(e.g., chloro or fluoro), haloC.sub.1-6alkyl (e.g.,
trifluoromethyl), hydroxy, carboxy, --SH, or an additional aryl or
heteroaryl (e.g., biphenyl or pyridylphenyl) [0065] preferably
R.sub.10 is phenyl or pyridyl, e.g., 2-pyridyl optionally
substituted with the substituents previously defined; [0066]
provided that when X, Y or X is nitrogen, R.sub.8, R.sub.9 or
R.sub.10, respectively, is not present; [0067] (v) R.sub.4 and
R.sub.5 are independently [0068] H, [0069] C.sub.1-6alkyl (e.g.,
methyl, isopropyl), [0070] C.sub.3-8cycloalkyl (e.g., cyclopentyl),
[0071] C.sub.3-8heterocycloalkyl (e.g., pyrrolidin-3-yl), [0072]
aryl (e.g., phenyl) or [0073] heteroaryl (e.g., pyrid-4-yl,
pyrid-2-yl or pyrazol-3-yl) [0074] wherein said aryl or heteroaryl
is optionally substituted with halo (e.g., 4-fluorophenyl), hydroxy
(e.g., 4-hydroxyphenyl), C.sub.1-6alkyl, C.sub.1-6alkoxy or another
aryl group (e.g., biphenyl-4-ylmethyl); [0075] (vi) R.sub.6 is H,
C.sub.1-6alkyl (e.g., methyl), hydroxy, C.sub.1-6alkoxy, aryloxy,
--N(R.sub.16)(R.sub.17), oxo (e.g., .dbd.O), or
C.sub.3-8cycloalkyl; [0076] (vii) R.sub.7 is H, C.sub.1-6alkyl
(e.g., methyl) or C.sub.3-8cycloalkyl wherein said cycloalkyl is
optionally substituted with one or more oxo (e.g.,
2,5-dioxopyrrolidin-1-yl); [0077] (viii) R.sub.13 is
--N(R.sub.14)(R.sub.15), C.sub.1-6alkyl (e.g., methyl),
--OC.sub.1-6alkyl (e.g., --OCH.sub.3), haloC.sub.1-6alkyl
(trifluoromethyl), aryl (e.g., phenyl), or heteroaryl; and [0078]
(ix) R.sub.14 and R.sub.15 are independently H or C.sub.1-6alkyl;
[0079] (x) R.sub.16 and R.sub.17 are independently H,
C.sub.1-6alkyl, aryl (e.g., phenyl), heteroaryl, wherein said aryl
or heteroaryl is optionally substituted with halo (e.g., fluoro),
C.sub.1-6alkoxy (e.g., methoxy); in free or salt form.
[0080] Compounds of Formula I, e.g. Formula I-A and I-B:
##STR00003##
wherein [0081] (i) Q is --C(.dbd.S)--, --C(.dbd.O)--,
--C(.dbd.N(R.sub.6))- or --C(R.sub.14)(R.sub.15)--; [0082] (ii)
R.sub.1 is H or C.sub.1-6alkyl (e.g., methyl or ethyl); [0083]
(iii) R.sub.2 is [0084] H, [0085] C.sub.1-6alkyl (e.g., isopropyl,
isobutyl, 2-methylbutyl, 2,2-dimethylpropyl) wherein said alkyl
group is optionally substituted with halo (e.g., fluoro) or hydroxy
(e.g., 1-hydroxypropan-2-yl, 3-hydroxy-2-methylpropyl), [0086]
--C.sub.0-4alkyl-C.sub.3-8cycloalkyl (e.g., cyclopentyl,
cyclohexyl) optionally substituted with one or more amino (e.g.,
--NH.sub.2), for example, 2-aminocyclopentyl or 2-aminocyclohexyl),
wherein said cycloalkyl optionally contains one or more heteroatom
selected from N and O and is optionally substituted with
C.sub.1-6alkyl (e.g., 1-methyl-pyrrolindin-2-yl,
1-methyl-pyrrolindin-3-yl, 1-methyl-pyrrolindin-2-yl-methyl or
1-methyl-pyrrolindin-3-yl-methyl), [0087] C.sub.3-8heterocycloalkyl
(e.g., pyrrolidinyl, for example, pyrrolidin-3-yl or
pyrrolidin-2-yl) optionally substituted with C.sub.1-6alkyl (e.g.,
methyl), for example, 1-methylpyrrolidin-3-yl or
1-methylpyrrolidin-2-yl, [0088] C.sub.3-8cycloalkyl-C.sub.1-6alkyl
(e.g., cyclopropylmethyl), [0089] haloC.sub.1-6alkyl (e.g.,
trifluoromethyl, 2,2,2-trifluoroethyl), [0090]
--N(R.sub.14)(R.sub.15)--C.sub.1-6alkyl (e.g.,
2-(dimethylamino)ethyl,2-aminopropyl), [0091] hydroxyC.sub.1-6alkyl
(e.g., (e.g., 3-hydroxy-2-methylpropyl, 1-hydroxyprop-2-yl), [0092]
arylC.sub.0-6alkyl (e.g., benzyl), [0093] heteroarylC.sub.1-6alkyl
(e.g., pyridinylmethyl), [0094] C.sub.1-6alkoxyarylC.sub.1-6alkyl
(e.g., 4-methoxybenzyl); [0095] -G-J wherein: [0096] G is a single
bond or, alkylene (e.g., methylene); [0097] J is cycloalkyl or
heterocycloalkyl (e.g., oxetan-2-yl, pyrolyin-3-yl, pyrolyin-2-yl)
optionally substituted with C.sub.1-6alkyl (e.g.,
(1-methylpyrolidin-2-yl)); [0098] (iv) R.sub.3 is [0099] 1) -D-E-F
wherein: [0100] D is a single bond, C.sub.1-6alkylene (e.g.,
methylene), or arylalkylene (e.g., p-benzylene or
--CH.sub.2C.sub.6H.sub.4--); [0101] E is [0102] a single bond,
[0103] C.sub.1-4alkylene (e.g., methylene) [0104]
C.sub.2-6alkynylene (e.g., ethynylene, prop-2-yn-1-ylene),
ethynylene, prop-2-yn-1-ylene), [0105] --C.sub.0-4alkylarylene
(e.g., phenylene or --C.sub.6H.sub.4--, -benzylene- or
--CH.sub.2C.sub.6H.sub.4--), wherein the arylene group is
optionally substituted with halo (e.g., Cl or F), [0106]
heteroarylene (e.g., pyridinylene or pyrimidinylene), [0107]
aminoC.sub.1-6alkylene (e.g., --CH.sub.2N(H)--), [0108] amino
(e.g., --N(H)--); [0109] C.sub.3-8cycloalkylene optionally
containing one or more heteroatom selected from N or O (e.g.,
piperidinylene), [0110] F is [0111] H, [0112] halo (e.g., F, Br,
Cl), [0113] C.sub.1-6alkyl (e.g., isopropyl or isobutyl), [0114]
haloC.sub.1-6alkyl (e.g., trifluoromethyl), [0115] aryl (e.g.,
phenyl), [0116] C.sub.3-8cycloalkyl optionally containing at least
one atom selected from a group consisting of N or O (e.g.,
cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl,
tetrahydro-2H-pyran-4-yl, or morpholinyl), said cycloalkyl is
optionally substituted with C.sub.1-6alkyl (e.g., methyl or
isopropyl), for example, 1-methylpyrrolidin-2-yl, pyrrolidin-1-yl,
pyrrolidin-2-yl, piperidin-2-yl, 1-methylpiperidin-2-yl,
1-ethylpiperidin-2-yl, [0117] heteroaryl optionally substituted
with C.sub.1-6alkyl, (e.g., pyridyl, (for example, pyrid-2-yl),
pyrimidinyl (for example, pyrimidin-2-yl), thiadiazolyl (for
example, 1,2,3-thiadiazol-4-yl), diazolyl (e.g., pyrazolyl (for
example, pyrazol-1-yl) or imidazolyl (for example, imidazol-1-yl,
4-methylimidazolyl, 1-methylimidazol-2-yl,), triazolyl (e.g.,
1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl),
alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g.,
pyrazol-1-yl), wherein said heteroaryl is optionally substituted
with halo (e.g., fluoro) or haloC.sub.1-6alkyl, for example,
6-fluoropyrid-2-yl; [0118] amino (e.g., --NH.sub.2), [0119]
C.sub.1-6alkoxy, [0120] --O-haloC.sub.1-6alkyl (e.g.,
--O--CF.sub.3), [0121] C.sub.1-6alkylsulfonyl (for example,
methylsulfonyl or --S(O).sub.2CH.sub.3), [0122] --C(O)--R.sub.13,
[0123] --N(R.sub.14)(R.sub.15); or [0124] 2) a substituted
heteroarylaklyl, e.g., substituted with haloalkyl; or [0125] 3)
attached to the nitrogen on the pyrrolo portion of Formula I and is
a moiety of Formula A
[0125] ##STR00004## [0126] wherein X, Y and Z are, independently, N
or C, and R.sub.8, R.sub.9, R.sub.11 and R.sub.12 are independently
H or halogen (e.g., Cl or F); and R.sub.10 is halogen, alkyl,
cycloalkyl, haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl),
heteroaryl (e.g., pyridyl, (for example, pyrid-2-yl) or e.g.,
thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl), diazolyl,
triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g.,
tetrazol-5-yl), alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol),
pyrazolyl (e.g., pyrazol-1-yl), alkyl sulfonyl (e.g., methyl
sulfonyl), arylcarbonyl (e.g., benzoyl), or heteroarylcarbonyl,
alkoxycarbonyl, (e.g., methoxycarbonyl), aminocarbonyl; preferably
phenyl or pyridyl, e.g., 2-pyridyl; provided that when X, Y or X is
nitrogen, R.sub.8, R.sub.9 or R.sub.10, respectively, is not
present; [0127] (v) R.sub.4 and R.sub.5 are independently [0128] H,
[0129] C.sub.1-6alkyl (e.g., methyl, isopropyl), [0130]
C.sub.3-8cycloalkyl (e.g., cyclopentyl), [0131]
C.sub.3-8heterocycloalkyl (e.g., pyrrolidin-3-yl), [0132] aryl
(e.g., phenyl) or heteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or
pyrazol-3-yl) wherein said aryl or heteroaryl is optionally
substituted with halo (e.g., 4-fluorophenyl), hydroxy (e.g.,
4-hydroxyphenyl), C.sub.1-6alkyl, C.sub.1-6alkoxy or another aryl
group (e.g., biphenyl-4-ylmethyl); [0133] (vi) R.sub.6 is H,
C.sub.1-6alkyl (e.g., methyl) or C.sub.3-8cycloalkyl; [0134] (vii)
R.sub.13 is --N(R.sub.14)(R.sub.15), C.sub.1-6alkyl (e.g., methyl),
--OC.sub.1-6alkyl (e.g., --OCH.sub.3), haloC.sub.1-6alkyl
(trifluoromethyl), aryl (e.g., phenyl), or heteroaryl; and [0135]
(viii) R.sub.14 and R.sub.15 are independently H or C.sub.1-6alkyl,
in free or salt form.
[0136] In a further embodiment, the compound of formula I is a
compound wherein Q is C(.dbd.O) or C(.dbd.S) and R.sub.6 is H or
C.sub.1-6alkyl, in free or salt form. In still another embodiment,
the compound of formula II is a compound wherein Q is C(.dbd.O) or
C(.dbd.S) and R.sub.6 is H, C.sub.1-6alkyl (e.g., methyl), hydroxy,
C.sub.1-6alkoxy, aryloxy, --N(R.sub.16)(R.sub.17), oxo (e.g.,
.dbd.O), or C.sub.3-8cycloalkyl, in free or salt form.
[0137] The invention further provides compounds of Formula I (I-A
and I-B) as follows: [0138] 1.1 Formula I, wherein Q is
--C(.dbd.S)--; [0139] 1.2 Formula I, wherein Q is
--C(.dbd.N(R.sub.6))--; [0140] 1.3 Formula I, wherein Q is
--C(R.sub.14)(R.sub.15)--; [0141] 1.4 Formula I, or any of 1.1-1.3,
wherein R.sub.3 is -D-E-F; [0142] 1.5 Formula 1.4, D is a single
bond, C.sub.1-6alkylene (e.g., methylene), or arylalkylene (e.g.,
benzylene or --CH.sub.2C.sub.6H.sub.4--); [0143] 1.6 Formula 1.4,
wherein D is a single bond; [0144] 1.7 Formula 1.4, wherein D is
C.sub.1-6alkylene (e.g., methylene); [0145] 1.8 Formula 1.4,
wherein D is methylene; [0146] 1.9 Formula 1.4, wherein D is
arylalkylene (e.g., benzylene or --CH.sub.2C.sub.6H.sub.4--);
[0147] 1.10 Formula 1.4, wherein D is benzylene or
--CH.sub.2C.sub.6H.sub.4--; [0148] 1.11 Any of formulae 1.4-1.10,
wherein E is a single bond, C.sub.1-6alkylene (e.g., methylene),
C.sub.2-6alkynylene (e.g., ethynylene, prop-2-yn-1-ylene),
--C.sub.0-4 alkylarylene (e.g., phenylene or --C.sub.6H.sub.4--,
-benzylene- or --CH.sub.2C.sub.6H.sub.4--), wherein the arylene
group is optionally substituted with halo (e.g., Cl or F),
heteroarylene (e.g., pyridinylene or pyrimidinylene),
aminoC.sub.1-6 alkylene (e.g., --CH.sub.2N(H)--), amino (e.g.,
--N(H)--); C.sub.3-8cycloalkylene optionally containing one or more
heteroatom selected from N or O (e.g., piperidinylene); [0149] 1.12
Any of formulae 1.4-1.10, wherein E is a single bond; [0150] 1.13
Any of formulae 1.4-1.10, wherein E is C.sub.1-6alkylene (e.g.,
methylene); [0151] 1.14 Any of formulae 1.4-1.10, wherein E is
C.sub.2-6alkynylene (e.g., ethynylene, prop-2-yn-1-ylene); [0152]
1.15 Any of formulae 1.4-1.10, wherein E is methylene; [0153] 1.16
Any of formulae 1.4-1.10, wherein E is ethynylene; [0154] 1.17 Any
of formulae 1.4-1.10, wherein E is prop-2-yn-1-ylene; [0155] 1.18
Any of formulae 1.4-1.10, wherein E is --C.sub.0-4alkylarylene
(e.g., phenylene or --C.sub.6H.sub.4--, -benzylene- or
--CH.sub.2C.sub.6H.sub.4--), wherein the arylene group is
optionally substituted with halo (e.g., Cl or F); [0156] 1.19 Any
of formulae 1.4-1.10, wherein E is phenylene or --C.sub.6H.sub.4--;
[0157] 1.20 Any of formulae 1.4-1.10, wherein E is heteroarylene
(e.g., pyridylene or pyrimidylene); [0158] 1.21 Any of formulae
1.4-1.10, wherein E is pyridylene; [0159] 1.22 Any of formulae
1.4-1.10, wherein E is pyrimidylene; [0160] 1.23 Any of formulae
1.4-1.10, wherein E is aminoC.sub.1-6alkylene (e.g.,
--CH.sub.2N(H)--); [0161] 1.24 Any of formulae 1.4-1.10, wherein E
is amino (e.g., --N(H)--); [0162] 1.25 Any of formulae 1.4-1.10,
wherein E is C.sub.3-8cycloalkylene optionally containing one or
more heteroatom selected from N or O (e.g., piperidinylene); [0163]
1.26 Any of formulae 1.4-1.25, wherein F is H, halo (e.g., F, Br,
Cl), C.sub.1-6alkyl (e.g., isopropyl or isobutyl),
haloC.sub.1-6alkyl (e.g., trifluoromethyl), aryl (e.g., phenyl),
C.sub.3-8cycloalkyl optionally containing at least one atom
selected from a group consisting of N or O (e.g., cyclopentyl,
cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydro-2H-pyran-4-yl, or
morpholinyl), said cycloalkyl is optionally substituted with
C.sub.1-6alkyl (e.g., methyl or isopropyl), for example,
1-methylpyrrolidin-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl,
piperidin-2-yl, 1-methylpiperidin-2-yl, 1-ethylpiperidin-2-yl;
heteroaryl optionally substituted with C.sub.1-6alkyl (e.g.,
pyridyl, (for example, pyrid-2-yl), pyrimidinyl (for example,
pyrimidin-2-yl), thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl),
diazolyl (e.g., pyrazolyl (for example, pyrazol-1-yl) or imidazolyl
(for example, imidazol-1-yl, 4-methylimidazolyl,
1-methylimidazol-2-yl,), triazolyl (e.g., 1,2,4-triazol-1-yl),
tetrazolyl (e.g., tetrazol-5-yl), alkoxadiazolyl (e.g.,
5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g., pyrazol-1-yl), wherein
said heteroaryl is optionally substituted with halo (e.g., fluoro)
or haloC.sub.1-6alkyl, for example, 6-fluoropyrid-2-yl; amino
(e.g., --NH.sub.2), C.sub.1-6alkoxy, --O-haloC.sub.1-6alkyl (e.g.,
--O--CF.sub.3), C.sub.1-6alkylsulfonyl (for example, methylsulfonyl
or --S(O).sub.2CH.sub.3), C(O)--R.sub.13 or
--N(R.sub.14)(R.sub.15); [0164] 1.27 Any of formulae 1.4-1.26,
wherein F is H; [0165] 1.28 Any of formulae 1.4-1.26, wherein F is
halo (e.g., F, Br, Cl); [0166] 1.29 Any of formulae 1.4-1.26,
wherein F is fluoro or chloro; [0167] 1.30 Any of formulae
1.4-1.26, wherein F is C.sub.1-6alkyl (e.g., isopropyl or
isobutyl); [0168] 1.31 Any of formulae 1.4-1.26, wherein F is
isopropyl; [0169] 1.32 Any of formulae 1.4-1.26, wherein F is
isobutyl; [0170] 1.33 Any of formulae 1.4-1.26, wherein F is
haloC.sub.1-6alkyl (e.g., trifluoromethyl); [0171] 1.34 Any of
formulae 1.4-1.26, wherein F is trifluoromethyl; [0172] 1.35 Any of
formulae 1.4-1.26, wherein F is aryl (e.g., phenyl); [0173] 1.36
Any of formulae 1.4-1.26, wherein F is phenyl; [0174] 1.37 Any of
formulae 1.4-1.26, wherein F is C.sub.3-8cycloalkyl optionally
containing at least one atom selected from a group consisting of N
or O (e.g., cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl
tetrahydro-2H-pyran-4-yl, morpholinyl); and optionally substituted
with C.sub.1-6alkyl (e.g., methyl or isopropyl), for example,
1-methylpyrrolidin-2-yl,), for example, 1-methylpyrrolidin-2-yl,
pyrrolidin-1-yl, pyrrolidin-2-yl, 1-methylpyrrolidin-2-yl,
piperidin-2-yl, 1-methylpiperidin-2-yl, 1-ethylpiperidin-2-yl;
[0175] 1.38 Any of formulae 1.4-1.26, wherein F is cyclopentyl or
cyclohexyl; [0176] 1.39 Any of formulae 1.4-1.26, wherein F is
1-methylpyrrolidin-2-yl; [0177] 1.40 Any of formulae 1.4-1.26,
wherein F is heteroaryl optionally substituted with C.sub.1-6alkyl
(e.g., pyridyl, (for example, pyrid-2-yl), pyrimidinyl (for
example, pyrimidin-2-yl), thiadiazolyl (for example,
1,2,3-thiadiazol-4-yl), diazolyl (e.g., pyrazolyl (for example,
pyrazol-1-yl) or imidazolyl (for example, imidazol-1-yl,
4-methylimidazolyl, 1-methylimidazol-2-yl,), triazolyl (e.g.,
1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl),
alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g.,
pyrazol-1-yl), wherein said heteroaryl is optionally substituted
with halo (e.g., fluoro) or haloC.sub.1-6alkyl; [0178] 1.41 Any of
formulae 1.4-1.26, wherein F is pyrid-2-yl optionally substituted
with halo (e.g., fluoro); [0179] 1.42 Any of formulae 1.4-1.26,
wherein F is 6-fluoro-pyrid-2-yl; [0180] 1.43 Any of formulae
1.4-1.26, wherein F is pyrimidinyl (for example, pyrimidin-2-yl);
[0181] 1.44 Any of formulae 1.4-1.26, wherein F is pyrazolyl (e.g.,
pyrazol-1-yl); [0182] 1.45 Any of formulae 1.4-1.26, wherein F is
triazolyl (e.g., 1,2,4-triazol-1-yl); [0183] 1.46 Any of formulae
1.4-1.26, wherein F is diazolyl (e.g., pyrazolyl (for example,
pyrazol-1-yl) or imidazolyl (for example, imidazol-1-yl,
4-methylimidazolyl, 1-methylimidazol-2-yl,); [0184] 1.47 Any of
formulae 1.4-1.26, wherein F is C.sub.1-6alkyl-oxadiazolyl (e.g.,
5-methyl-1,2,4-oxadiazolyl); [0185] 1.48 Any of formulae 1.4-1.26,
wherein F is amino (e.g., --NH.sub.2); [0186] 1.49 Any of formulae
1.4-1.26, wherein F is C.sub.1-6alkoxy; [0187] 1.50 Any of formulae
1.4-1.26, wherein F is --O-haloC.sub.1-6alkyl (e.g.,
--O--CF.sub.3); [0188] 1.51 Any of formulae 1.1-1.26, wherein F is
--C(O)--R.sub.13; [0189] 1.52 Any of formulae 1.1-1.26, wherein F
is --N(R.sub.14)(R.sub.15); [0190] 1.53 Any of formulae 1.1-1.26,
wherein F is C.sub.1-6alkylsulfonyl; [0191] 1.54 Any of formulae
1.1-1.26, wherein F is methylsulfonyl or --S(O).sub.2CH.sub.3;
[0192] 1.55 Formula I or any of 1.1-1.25, wherein R.sub.3 is a
substituted heteroarylaklyl, e.g., substituted with haloalkyl;
[0193] 1.56 Formula I or any of 1.1-1.25, wherein R.sub.3 is
attached to the nitrogen on the pyrrolo portion of Formula I and is
a moiety of Formula A
[0193] ##STR00005## [0194] wherein X, Y and Z are, independently, N
or C, and R.sub.8, R.sub.9, R.sub.11 and R.sub.12 are independently
H or halogen (e.g., Cl or F); and R.sub.10 is halogen, alkyl,
cycloalkyl, haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl),
heteroaryl (e.g., pyridyl, (for example, pyrid-2-yl) or e.g.,
thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl), diazolyl,
triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g.,
tetrazol-5-yl), alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol),
pyrazolyl (e.g., pyrazol-1-yl), alkyl sulfonyl (e.g., methyl
sulfonyl), arylcarbonyl (e.g., benzoyl), or heteroarylcarbonyl,
alkoxycarbonyl, (e.g., methoxycarbonyl), aminocarbonyl; preferably
phenyl or pyridyl, e.g., 2-pyridyl; provided that when X, Y or X is
nitrogen, R.sub.8, R.sub.9 or R.sub.10, respectively, is not
present; [0195] 1.57 Formula 1.56, wherein R.sub.3 is a moiety of
Formula A, R.sub.8, R.sub.9, R.sub.11 and R.sub.12 are each H and
R.sub.10 is phenyl; [0196] 1.58 Formula 1.56, wherein R.sub.3 is a
moiety of Formula A, R.sub.8, R.sub.9, R.sub.11 and R.sub.12 are
each H and R.sub.10 is pyridyl or thiadiazolyl; [0197] 1.59 Formula
1.56, wherein R.sub.3 is a moiety of Formula A, R.sub.8, R.sub.9,
R.sub.11 and R.sub.12 are each H and R.sub.10 is pyrid-2-yl
optionally substituted with halo (e.g., fluoro); [0198] 1.60
Formula 1.56, wherein R.sub.3 is a moiety of Formula A and X, Y and
Z are all C; [0199] 1.61 Formula 1.56, wherein R.sub.10 is
pyrimidinyl; [0200] 1.62 Formula 1.56, wherein R.sub.10 is
5-fluoropyrmidinyl; [0201] 1.63 Formula 1.56, wherein R.sub.10 is
pyrazol-1-yl; [0202] 1.64 Formula 1.56, wherein R.sub.10 is
1,2,4-triazol-1-yl; [0203] 1.65 Formula 1.56, wherein R.sub.10 is
aminocarbonyl; [0204] 1.66 Formula 1.56, wherein R.sub.10 is
methylsulfonyl; [0205] 1.67 Formula 1.56, wherein R.sub.10 is
5-methyl-1,2,4-oxadiazol-3-yl; [0206] 1.68 Formula 1.56, wherein
R.sub.10 is 5-fluoropyrimidin-2-yl; [0207] 1.69 Formula 1.56,
wherein R.sub.10 is trifluoromethyl; [0208] 1.70 Formula 1.56,
wherein R.sub.3 is a moiety of Formula A, X and Z are C, and Y is
N; [0209] 1.71 Formula I or any of 1.1-1.70, wherein R.sub.2 is H;
C.sub.1-6alkyl (e.g., isopropyl, isobutyl, neopentyl,
2-methylbutyl, 2,2-dimethylpropyl) wherein said alkyl group is
optionally substituted with halo (e.g., fluoro) or hydroxy (e.g.,
1-hydroxypropan-2-yl, 3-hydroxy-2-methylpropyl);
--C.sub.0-4alkyl-C.sub.3-8cycloalkyl (e.g., cyclopentyl,
cyclohexyl) wherein said cycloalkyl optionally contains one or more
heteroatom selected from N and O and said alkylcycloalkyl is
optionally substituted with one or more amine (e.g., --NH.sub.2),
for example, 2-aminocyclopentyl or 2-aminocyclohexyl),
C.sub.1-6alkyl (e.g., 1-methyl-pyrrolindin-2-yl,
1-methyl-pyrrolindin-3-yl, 1-methyl-pyrrolindin-2-yl-methyl or
1-methyl-pyrrolindin-3-yl-methyl); C.sub.3-8heterocycloalkyl (e.g.,
pyrrolidinyl, for example, pyrrolidin-3-yl) optionally substituted
with C.sub.1-6alkyl (e.g., methyl), for example,
1-methylpyrrolidin-3-yl; C.sub.3-8cycloalkyl-C.sub.1-6alkyl (e.g.,
cyclopropylmethyl); haloC.sub.1-6alkyl (e.g., trifluoromethyl,
2,2,2-trifluoroethyl); --N(R.sub.14)(R.sub.15)--C.sub.1-6alkyl
(e.g., 2-(dimethylamino)ethyl,2-aminopropyl); hydroxyC.sub.1-6alkyl
(e.g., (e.g., 3-hydroxy-2-methylpropyl, 1-hydroxyprop-2-yl);
arylC.sub.0-6alkyl (e.g., benzyl); heteroarylC.sub.1-6alkyl (e.g.,
pyridinylmethyl); C.sub.1-6alkoxyarylC.sub.1-6alkyl (e.g.,
4-methoxybenzyl); -G-J wherein: G is a single bond or, alkylene
(e.g., methylene) and J is cycloalkyl or heterocycloalkyl (e.g.,
oxetan-2-yl, pyrolyin-3-yl, pyrolyin-2-yl) optionally substituted
with C.sub.1-6alkyl (e.g., (1-methylpyrolidin-2-yl)); [0210] 1.72
Formula 1.69, wherein R.sub.2 is H; [0211] 1.73 Formula 1.69,
wherein R.sub.2 is C.sub.1-6alkyl (e.g., isopropyl, isobutyl,
neopentyl, 2-methylbutyl, 2,2-dimethylpropyl) wherein said alkyl
group is optionally substituted with halo (e.g., trifluoroethyl) or
hydroxy (e.g., 1-hydroxypropan-2-yl, 3-hydroxy-2-methylpropyl);
[0212] 1.74 Formula 1.69, wherein R.sub.2 is isobutyl; [0213] 1.75
Formula 1.69, wherein R.sub.2 is 3-hydroxy-2-methylpropyl; [0214]
1.76 Formula 1.69, wherein R.sub.2 is 1-hydroxypropan-2-yl; [0215]
1.77 Formula 1.69, wherein R.sub.2 is
--C.sub.0-4alkyl-C.sub.3-8cycloalkyl (e.g., cyclopentyl,
cyclohexyl) wherein said cycloalkyl optionally contains one or more
heteroatom selected from N and O and is optionally substituted with
one or more amino (e.g., --NH.sub.2), for example,
2-aminocyclopentyl or 2-aminocyclohexyl), C.sub.1-6alkyl (e.g.,
1-methyl-pyrrolindin-2-yl, 1-methyl-pyrrolindin-3-yl,
1-methyl-pyrrolindin-2-yl-methyl or
1-methyl-pyrrolindin-3-yl-methyl); [0216] 1.78 Formula 1.69,
wherein R.sub.2 is 1-methyl-pyrrolindin-2-yl,
1-methyl-pyrrolindin-3-yl, 1-methyl-pyrrolindin-2-yl-methyl or
1-methyl-pyrrolindin-3-yl-methyl; [0217] 1.79 Formula 1.69, wherein
R.sub.2 is C.sub.3-8heterocycloalkyl (e.g., pyrrolidinyl, for
example, pyrrolidin-3-yl) optionally substituted with
C.sub.1-6alkyl (e.g., methyl), for example, 1-methylpyrrolidin-3-yl
or 1-methylpyrrolidin-2-yl; [0218] 1.80 Formula 1.69, wherein
R.sub.2 is 1-methylpyrrolidin-3-yl; [0219] 1.81 Formula 1.69,
wherein R.sub.2 is C.sub.3-8cycloalkyl-C.sub.1-6alkyl (e.g.,
cyclopropylmethyl); [0220] 1.82 Formula 1.69, wherein R.sub.2 is
--N(R.sub.14)(R.sub.15)--C.sub.1-6alkyl (e.g.,
2-(dimethylamino)ethyl, 2-aminopropyl); [0221] 1.83 Formula 1.69,
wherein R.sub.2 is heteroarylC.sub.1-6alkyl (e.g.,
pyridinylmethyl), [0222] 1.84 Formula 1.69, wherein R.sub.2 is
C.sub.1-6alkoxyarylC.sub.1alkyl (e.g., 4-methoxybenzyl; [0223] 1.85
Formula 1.69, wherein R.sub.2 is arylC.sub.0-6alkyl (e.g., benzyl);
[0224] 1.86 Formula 1.69, wherein R.sub.2 is cyclopentyl or
cyclohexyl; [0225] 1.87 Formula I or any of 1.1-1.70, wherein
R.sub.2 is -G-J; G is a single bond or, alkylene (e.g., methylene);
and J is cycloalkyl or heterocycloalkyl (e.g., oxetan-2-yl,
pyrolyin-3-yl, pyrolyin-2-yl) optionally substituted with C.sub.1-6
alkyl (e.g., (1-methylpyrolidin-2-yl)); [0226] 1.88 Formula 1.87,
wherein G is alkylene (e.g., methylene); [0227] 1.89 Formula 1.87,
wherein G is methylene; [0228] 1.90 Formula 1.87, wherein J is
cycloalkyl or heterocycloalkyl (e.g., oxetan-2-yl, pyrolyin-3-yl,
pyrolyin-2-yl) optionally substituted with alkyl (e.g.,
1-methylpyrolidin-2-yl); [0229] 1.91 Formula 1.87, wherein J is
oxetan-2-yl, pyrolyin-3-yl, pyrolyin-2-yl; [0230] 1.92 Formula
1.87, wherein J is (1-methylpyrolidin-2-yl); [0231] 1.93 Any of the
preceding formulae wherein R.sub.4 and R.sub.5 are independently H,
C.sub.1-6alkyl (e.g., methyl, isopropyl), C.sub.3-8cycloalkyl
(e.g., cyclopentyl), C.sub.3-8heterocycloalkyl (e.g.,
pyrrolidin-3-yl), or aryl (e.g., phenyl) or heteroaryl (e.g.,
pyrid-4-yl, pyrid-2-yl or pyrazol-3-yl) wherein said aryl or
heteroaryl is optionally substituted with halo (e.g.,
4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C.sub.1-6alkoxy
or another aryl group (e.g., biphenyl-4-ylmethyl); [0232] 1.94
Formula 1.93, wherein either R.sub.4 or R.sub.5 is H; [0233] 1.95
Formula 1.93, wherein either R.sub.4 or R.sub.5 is C.sub.1-6alkyl
(e.g., methyl, isopropyl); [0234] 1.96 Formula 1.93, wherein either
R.sub.4 or R.sub.5 is isopropyl; [0235] 1.97 Formula 1.93, wherein
either R.sub.4 or R.sub.5 is C.sub.3-8cycloalkyl (e.g.,
cyclopentyl); [0236] 1.98 Formula 1.93, wherein either R.sub.4 or
R.sub.5 is C.sub.3-8heterocycloalkyl (e.g., pyrrolidin-3-yl);
[0237] 1.99 Formula 1.93, wherein either R.sub.4 or R.sub.5 is aryl
(e.g., phenyl) optionally substituted with halo (e.g.,
4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C.sub.1-6alkyl,
C.sub.1-6alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl);
[0238] 1.100 Formula 1.93, wherein either R.sub.4 or R.sub.5 is
4-hydroxyphenyl; [0239] 1.101 Formula 1.93, wherein either R.sub.4
or R.sub.5 is 4-fluorophenyl; [0240] 1.102 Formula 1.93, wherein
either R.sub.4 or R.sub.5 is heteroaryl (e.g., pyrid-4-yl,
pyrid-2-yl or pyrazol-3-yl) optionally substituted with halo (e.g.,
4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C.sub.1-6alkyl,
C.sub.1-6alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl);
[0241] 1.103 Formula 1.93, wherein either R.sub.4 or R.sub.5 is
phenyl; [0242] 1.104 Any of the foregoing formulae, wherein R.sub.6
is H, C.sub.1-6alkyl (e.g., methyl) or C.sub.3-8cycloalkyl; [0243]
1.105 Formula 1.104, wherein R.sub.6 is H; [0244] 1.106 Formula
1.104, wherein R.sub.6 is C.sub.1-6alkyl (e.g., methyl); [0245]
1.107 Formula 1.104, wherein R.sub.6 is methyl; [0246] 1.108 Any of
the foregoing formulae, wherein R.sup.13 is
--N(R.sub.14)(R.sub.15), C.sub.1-6alkyl (e.g., methyl),
--OC.sub.1-6alkyl (e.g., --OCH.sub.3), haloC.sub.1-6alkyl, aryl
(for example phenyl), or heteroaryl; [0247] 1.109 Formula 1.108,
wherein R.sup.13 is --N(R.sub.14)(R.sub.15) (e.g., --NH.sub.2)
[0248] 1.110 Formula 1.108, wherein R.sup.13 is C.sub.1-6alkyl
(e.g., methyl); [0249] 1.111 Formula 1.108, wherein R.sup.13 is
--OC.sub.1-6alkyl (e.g., --OCH.sub.3), [0250] 1.112 Formula 1.108,
wherein R.sup.13 is --OCH.sub.3; [0251] 1.113 Formula 1.108,
wherein R.sup.13 is haloC.sub.1-6alkyl (e.g., trifluoromethyl);
[0252] 1.114 Formula 1.108, wherein R.sup.13 is trifluoromethyl;
[0253] 1:115 Formula 1.108, wherein R.sup.13 is aryl (e.g.,
phenyl); [0254] 1.116 Formula 1.108, wherein R.sup.13 is heteroaryl
(e.g., pyridiyl); [0255] 1.117 Any of the preceding formulae,
wherein R.sub.14 and R.sub.15 are independently H or C.sub.1-6alkyl
(e.g., methyl); [0256] 1.118 Formula I or any of 1.1-1.117, wherein
either R.sub.14 or R.sub.15 is independently H; [0257] 1.119
Formula 1 or any of 1.1-1.117, wherein either R.sub.14 or R.sub.15
is C.sub.1-6alkyl (e.g., methyl); [0258] 1.120 Formula I or any of
1.1-1.117, wherein either R.sub.14 or R.sub.15 is methyl; [0259]
1.121 any of the preceding formulae wherein compound of formula I
is
[0259] ##STR00006## [0260] 1.122 any of the preceding formulae
wherein compound of formula I is
[0260] ##STR00007## [0261] 1.123 any of the preceding formulae
wherein R.sub.3 of formula I is 4-methoxybenzyl; [0262] 1.124 any
of the preceding formulae wherein R.sub.3 of formula I is
4-(6-fluoropyrid-2-yl)benzyl; [0263] 1.125 any of the preceding
formulae wherein --N(R.sub.4)(R.sub.5) of formula I is phenylamino,
hydroxyphenylamino or fluorophenylamino; [0264] 1.126 any of the
preceding formulae wherein compound of formula I is selected from a
group consisting of:
[0264] ##STR00008## ##STR00009## ##STR00010## ##STR00011##
##STR00012## [0265] 1.127 any of the preceding formulae wherein the
compounds inhibit phosphodiesterase-mediated (e.g., PDE1-mediated,
especially PDE1B-mediated) hydrolysis of cGMP, e.g., with an
IC.sub.50 of less than 25 .mu.M, preferably less than 1 .mu.M,
preferably less than 500 nM, preferably less than 200 nM in an
immobilized-metal affinity particle reagent PDE assay, for example,
as described in Example 23, [0266] in free or salt form.
[0267] In a particular embodiment, the Compound of the Invention is
a Compound of Formula I wherein Q is C(.dbd.O) or C(.dbd.S) and
R.sub.6 is H or C.sub.1-6alkyl, in free or salt form.
[0268] In a particular embodiment, the Compound of the Invention is
a Compound of Formula I wherein [0269] (i) Q is --C(.dbd.S)--,
--C(.dbd.O)--; [0270] (ii) R.sub.1 is H or alkyl (e.g., methyl);
[0271] (iii) R.sub.2 is H, alkyl (e.g., isobutyl, 2-methylbutyl,
2,2-dimethyl propyl), cycloalkyl (e.g., cyclopentyl, cyclohexyl),
haloalkyl (e.g., trifluoromethyl, 2,2,2-trifluoroethyl),
alkylaminoalkyl (e.g., 2-(dimethylamino)ethyl), hydroxyalkyl (e.g.,
3-hydroxy-2-methyl propyl), arylalkyl (e.g., benzyl),
heteroarylalkyl (e.g., pyridylmethyl), or alkoxyarylalkyl (e.g.,
4-methoxybenzyl); [0272] (iv) R.sub.3 is a substituted
heteroarylaklyl, e.g., substituted with haloalkyl or [0273] R.sub.3
is attached to the nitrogen on the pyrrolo portion of Formula I and
is a moiety of Formula A
##STR00013##
[0273] wherein X, Y and Z are, independently, N or C, and R.sub.8,
R.sub.9, R.sub.11 and R.sub.12 are independently H or halogen
(e.g., Cl or F); and R.sub.10 is halogen, alkyl, cycloalkyl,
haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl), heteroaryl
(e.g., pyridyl, (for example, pyrid-2-yl) or e.g., thiadiazolyl
(for example, 1,2,3-thiadiazol-4-yl), diazolyl, triazolyl (e.g.,
1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl),
alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g.,
pyrazol-1-yl), alkyl sulfonyl (e.g., methyl sulfonyl), arylcarbonyl
(e.g., benzoyl), or heteroarylcarbonyl, alkoxycarbonyl, (e.g.,
methoxycarbonyl), aminocarbonyl; preferably phenyl or pyridyl,
e.g., 2-pyridyl; provided that when X, Y or X is nitrogen, R.sub.8,
R.sub.9 or R.sub.10, respectively, is not present; [0274] (v)
R.sub.4 is aryl (e.g., phenyl); [0275] (vi) R.sub.5 is H, alkyl,
cycloalkyl (e.g., cyclopentyl), heteroaryl, aryl, p-benzylaryl
(e.g., biphenyl-4-ylmethyl); [0276] (vii) R.sub.6 is H,
C.sub.1-6alkyl (e.g., methyl) or C.sub.3-8cycloalkyl; [0277] (viii)
R.sub.13 is --N(R.sub.14)(R.sub.15), C.sub.1-6alkyl (e.g., methyl),
--OC.sub.1-6alkyl (e.g., --OCH.sub.3), haloC.sub.1-6alkyl
(trifluoromethyl), aryl (e.g., phenyl), or heteroaryl; and [0278]
(ix) R.sub.14 and R.sub.15 are independently H or C.sub.1-6alkyl,
in free or salt form (hereinafter, Compound of Formula I(i)).
[0279] In still another embodiment, the Compound of the Invention
is a Compound of Formula I wherein [0280] (i) Q is --C(.dbd.S)--,
--C(.dbd.O)--; [0281] (ii) R.sub.1 is H or alkyl (e.g., methyl);
[0282] (iii) R.sub.2 is H, alkyl (e.g., isopropyl, isobutyl,
2-methylbutyl, 2,2-dimethyl propyl), cycloalkyl (e.g., cyclopentyl,
cyclohexyl), haloalkyl (e.g., trifluoromethyl,
2,2,2-trifluoroethyl), alkylaminoalkyl (e.g.,
2-(dimethylamino)ethyl), hydroxyalkyl (e.g., 3-hydroxy-2-methyl
propyl), arylalkyl (e.g., benzyl), heteroarylalkyl (e.g.,
pyridylmethyl), or alkoxyarylalkyl (e.g., 4-methoxybenzyl); [0283]
(iv) R.sub.3 is D-E-F wherein [0284] 1. D is single bond, alkylene
(e.g., methylene), or arylalkylene (e.g., benzylene or
--CH.sub.2C.sub.6H.sub.4--); [0285] 2. E is a alkylene (e.g.,
methylene, ethynylene, prop-2-yn-1-ylene), arylene (e.g., phenylene
or --C.sub.6H.sub.4--), alkylarylene (e.g., -benzylene- or
--CH.sub.2C.sub.6H.sub.4--), aminoalkylene (e.g., --CH.sub.2N(H)--)
or amino (e.g., --N(H)--); and [0286] 3. F is alkyl (e.g.,
isobutyl), aryl (e.g., phenyl), heteroaryl (e.g., pyrid-2-yl,
1,2,4-triazolyl), heteroC.sub.3-8cycloalkyl (e.g., pyrolidin-1-yl),
amino (e.g., --NH.sub.2), C.sub.1-6alkoxy, or --O-haloalkyl (e.g.,
--O--CF.sub.3); [0287] (v) R.sub.4 is aryl (e.g., phenyl),
heteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or pyrazol-3-yl) or
heterocycloalkyl (e.g., pyrrolidin-3-yl); and [0288] (vi) R.sub.5
is H, alkyl, cycloalkyl (e.g., cyclopentyl), heteroaryl, aryl,
p-benzylaryl (e.g., biphenyl-4-ylmethyl); [0289] (vii) R.sub.6 is
H, C.sub.1-6alkyl (e.g., methyl) or C.sub.3-8cycloalkyl; [0290]
(viii) R.sub.13 is --N(R.sub.14)(R.sub.15), C.sub.1-6alkyl (e.g.,
methyl), --OC.sub.1-6alkyl (e.g., --OCH.sub.3), haloC.sub.1-6alkyl
(trifluoromethyl), aryl (e.g., phenyl), or heteroaryl; and [0291]
(x) R.sub.14 and R.sub.15 are independently H or alkyl, wherein
"alk", "alkyl", "haloalkyl" or "alkoxy" refers to C.sub.1-6alkyl
and "cycloalkyl" refers to C.sub.3-8 cycloalkyl unless specifically
specified; in free or salt form (hereinafter, Compound of Formula
I(ii)).
[0292] In still another embodiment, the invention provides a
compound of Formula II-A or II-B as follows: [0293] 2.1 Formula
II-A or II-B, wherein Q is --C(.dbd.S)--, --C(.dbd.O)--,
--C(.dbd.N(R.sub.7))- or --C(R.sub.14)(R.sub.15); [0294] 2.2
Formula II-A or II-B, wherein Q is --C(.dbd.S)--; [0295] 2.3
Formula II-A or II-B, wherein Q is --C(.dbd.O); [0296] 2.4 Formula
II-A or II-B, wherein Q is --C(.dbd.N(R.sub.7))- or
--C(R.sub.14)(R.sub.15)--; [0297] 2.5 Formula II-A or II-B, or any
of 2.1-2.4, wherein R.sub.1 is H or C.sub.1-6alkyl (e.g., methyl or
ethyl); [0298] 2.6 Formula II-A or II-B, or any of 2.1-2.4, wherein
R.sub.1 is C.sub.1-6alkyl (e.g., methyl or ethyl); [0299] 2.7
Formula II-A or II-B, or any of 2.1-2.6, wherein R.sub.2 is [0300]
H, [0301] C.sub.1-6alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl,
2,2-dimethylpropyl) wherein said alkyl group is optionally
substituted with halo (e.g., fluoro) or hydroxy (e.g.,
1-hydroxypropan-2-yl, 3-hydroxy-2-methylpropyl), for example,
R.sub.2 may be a trifluoromethyl or 2,2,2-trifluoroethyl, [0302]
N(R.sub.14)(R.sub.15)--C.sub.1-6alkyl (e.g., 2-(dimethylamino)ethyl
or 2-aminopropyl), [0303] arylC.sub.0-6alkyl (e.g., phenyl or
benzyl), [0304] heteroarylC.sub.0-6alkyl (e.g., pyridinylmethyl),
[0305] C.sub.1-6alkoxyarylC.sub.1-6alkyl (e.g., 4-methoxybenzyl);
[0306] -G-J wherein: [0307] G is a single bond or, alkylene (e.g.,
methylene); [0308] J is cycloalkyl or heterocycloalkyl (e.g.,
oxetan-2-yl, pyrolyin-3-yl, pyrolyin-2-yl) optionally substituted
with one or more C.sub.1-6alkyl (e.g., (1-methylpyrolidin-2-yl)),
amino (e.g., --NH.sub.2), [0309] for example, -G-J may be
--C.sub.0-4alkyl-C.sub.3-8cycloalkyl (e.g., cyclopentyl, cyclohexyl
or cyclopropylmethyl) optionally substituted with one or more
C.sub.1-6alkyl, amino (e.g., --NH.sub.2), for example,
2-aminocyclopentyl or 2-aminocyclohexyl, wherein said cycloalkyl
optionally contains one or more heteroatom selected from N and O
(e.g., pyrrolidinyl, for example, pyrrolidin-3-yl or
pyrrolidin-2-yl, 1-methyl-pyrrolindin-2-yl,
1-methyl-pyrrolindin-3-yl, 1-methyl-pyrrolindin-2-yl-methyl or
1-methyl-pyrrolindin-3-yl-methyl); [0310] 2.8 Formula II-A or II-B,
or any of 2.1-2.7, wherein R.sub.2 is C.sub.1-6alkyl (e.g.,
isopropyl, isobutyl, 2-methylbutyl, 2,2-dimethylpropyl) wherein
said alkyl group is optionally substituted with halo (e.g., fluoro)
or hydroxy (e.g., 1-hydroxypropan-2-yl, 3-hydroxy-2-methylpropyl),
for example, R.sub.2 may be a trifluoromethyl or
2,2,2-trifluoroethyl; [0311] 2.9 Formula II-A or II-B, or any of
2.1-2.7, wherein R.sub.2 is C.sub.1-6alkyl (isopropyl, isobutyl,
2-methylbutyl, 2,2-dimethylpropyl; [0312] 2.10 Formula II-A or
II-B, or any of 2.1-2.9, wherein R.sub.3 is [0313] 1) -D-E-F
wherein: [0314] D is a single bond, C.sub.1-6alkylene (e.g.,
methylene), or arylalkylene (e.g., p-benzylene or
--CH.sub.2C.sub.6H.sub.4--); [0315] E is [0316] a single bond,
[0317] C.sub.1-4alkylene (e.g., methylene) [0318]
C.sub.2-6alkynylene (e.g., ethynylene, prop-2-yn-1-ylene),
ethynylene, prop-2-yn-1-ylene), [0319] --C.sub.0-4alkylarylene
(e.g., phenylene or --C.sub.6H.sub.4--, -benzylene- or
--CH.sub.2C.sub.6H.sub.4--), wherein the arylene group is
optionally substituted with halo (e.g., Cl or F), [0320]
heteroarylene (e.g., pyridinylene or pyrimidinylene), [0321]
aminoC.sub.1-6alkylene (e.g., --CH.sub.2N(H)--), [0322] amino
(e.g., --N(H)--); [0323] C.sub.3-8cycloalkylene optionally
containing one or more heteroatom selected from N or O (e.g.,
piperidinylene), [0324] F is [0325] H, [0326] halo (e.g., F, Br,
Cl), [0327] C.sub.1-6alkyl (e.g., isopropyl or isobutyl), [0328]
haloC.sub.1-6alkyl (e.g., trifluoromethyl), [0329] aryl (e.g.,
phenyl), [0330] C.sub.3-8cycloalkyl optionally containing at least
one atom selected from a group consisting of N or O (e.g.,
cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl,
tetrahydro-2H-pyran-4-yl, or morpholinyl), said cycloalkyl is
optionally substituted with C.sub.1-6alkyl (e.g., methyl or
isopropyl), for example, 1-methylpyrrolidin-2-yl, pyrrolidin-1-yl,
pyrrolidin-2-yl, piperidin-2-yl, 1-methylpiperidin-2-yl,
1-ethylpiperidin-2-yl, [0331] heteroaryl optionally substituted
with C.sub.1-6alkyl, (e.g., pyridyl, (for example, pyrid-2-yl),
pyrimidinyl (for example, pyrimidin-2-yl), thiadiazolyl (for
example, 1,2,3-thiadiazol-4-yl), diazolyl (e.g., pyrazolyl (for
example, pyrazol-1-yl) or imidazolyl (for example, imidazol-1-yl,
4-methylimidazolyl, 1-methylimidazol-2-yl,), triazolyl (e.g.,
1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl),
alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g.,
pyrazol-1-yl), wherein said heteroaryl is optionally substituted
with halo (e.g., fluoro) or haloC.sub.1-6alkyl, for example,
6-fluoropyrid-2-yl; [0332] amino (e.g., --NH.sub.2), [0333]
C.sub.1-6alkoxy) [0334] --O-haloC.sub.1-6alkyl (e.g.,
--O--CF.sub.3), [0335] C.sub.1-6alkylsulfonyl (for example,
methylsulfonyl or --S(O).sub.2CH.sub.3), [0336] --C(O)--R.sub.13,
[0337] --N(R.sub.14)(R.sub.15); or [0338] 2) a substituted
heteroarylaklyl, e.g., substituted with haloalkyl; or [0339] 3)
attached to the nitrogen on the pyrrolo portion of Formula I and is
a moiety of Formula A
[0339] ##STR00014## [0340] wherein X, Y and Z are, independently, N
or C, and R.sub.8, R.sub.9, R.sub.11 and R.sub.12 are independently
H or halogen (e.g., Cl or F); and R.sub.10 is [0341] halogen,
[0342] C.sub.1-6alkyl, [0343] C.sub.1-6alkoxy (e.g., methoxy),
[0344] C.sub.3-8cycloalkyl, [0345] heteroC.sub.3-8cycloalkyl (e.g.,
pyrrolidinyl or piperidinyl), [0346] haloC.sub.1-6alkyl (e.g.,
trifluoromethyl), [0347] aryl (e.g., phenyl), [0348] heteroaryl
(e.g., pyridyl, (for example, pyrid-2-yl) or e.g., thiadiazolyl
(for example, 1,2,3-thiadiazol-4-yl), diazolyl, triazolyl (e.g.,
1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl),
alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g.,
pyrazol-1-yl), [0349] C.sub.1-6alkyl sulfonyl (e.g., methyl
sulfonyl), [0350] arylcarbonyl (e.g., benzoyl), [0351]
heteroarylcarbonyl, [0352] alkoxycarbonyl, (e.g., methoxycarbonyl),
[0353] aminocarbonyl; [0354] wherein the aryl, heteroaryl,
cycloalkyl or heterocycloalkyl is optionally substituted with one
or more C.sub.1-6alkyl (e.g., methyl), halogen (e.g., chloro or
fluoro), haloC.sub.1-6alkyl (e.g., trifluoromethyl), hydroxy,
carboxy, --SH, or an additional aryl or heteroaryl (e.g., biphenyl
or pyridylphenyl) [0355] preferably R.sub.10 is phenyl or pyridyl,
e.g., 2-pyridyl optionally substituted with the substituents
previously defined; [0356] provided that when X, Y or X is
nitrogen, R.sub.8, R.sub.9 or R.sub.10, respectively, is not
present; [0357] 2.11 Formula II-A or II-B, or any of 2.1-2.9,
wherein R.sub.3 is attached to the nitrogen on the pyrrolo portion
of Formula I and is a moiety of Formula A
[0357] ##STR00015## [0358] wherein X, Y and Z are, independently, N
or C, and R.sub.8, R.sub.9, R.sub.11 and R.sub.12 are independently
H or halogen (e.g., Cl or F); and R.sub.10 is [0359] halogen,
[0360] C.sub.1-6alkyl, [0361] C.sub.1-6alkoxy (e.g., methoxy),
[0362] C.sub.3-8cycloalkyl, [0363] heteroC.sub.3-8cycloalkyl (e.g.,
pyrrolidinyl or piperidinyl), [0364] haloC.sub.1-6alkyl (e.g.,
trifluoromethyl), [0365] aryl (e.g., phenyl), [0366] heteroaryl
(e.g., pyridyl, (for example, pyrid-2-yl) or e.g., thiadiazolyl
(for example, 1,2,3-thiadiazol-4-yl), diazolyl, triazolyl (e.g.,
1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl),
alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g.,
pyrazol-1-yl), [0367] C.sub.1-6alkyl sulfonyl (e.g., methyl
sulfonyl), [0368] arylcarbonyl (e.g., benzoyl), [0369]
heteroarylcarbonyl, [0370] alkoxycarbonyl, (e.g., methoxycarbonyl),
[0371] aminocarbonyl; [0372] wherein the aryl, heteroaryl,
cycloalkyl or heterocycloalkyl is optionally substituted with one
or more C.sub.1-6alkyl (e.g., methyl), halogen (e.g., chloro or
fluoro), haloC.sub.1-6alkyl (e.g., trifluoromethyl), hydroxy,
carboxy, --SH, or an additional aryl or heteroaryl (e.g., biphenyl
or pyridylphenyl) [0373] preferably R.sub.10 is phenyl or pyridyl,
e.g., 2-pyridyl optionally substituted with the substituents
previously defined; [0374] provided that when X, Y or X is
nitrogen, R.sub.8, R.sub.9 or R.sub.10, respectively, is not
present; [0375] 2.12 Formula II-A or II-B, or any of 2.1-2.9,
wherein R.sub.3 is attached to the nitrogen on the pyrrolo portion
of Formula I and is a moiety of Formula A
[0375] ##STR00016## [0376] wherein X, Y and Z are, independently, N
or C, and R.sub.8, R.sub.9, R.sub.11 and R.sub.12 are independently
H or halogen (e.g., Cl or F); and R.sub.10 is [0377]
C.sub.1-6alkoxy (e.g., methoxy), [0378] C.sub.3-8cycloalkyl, [0379]
heteroC.sub.3-8cycloalkyl (e.g., pyrrolidinyl or piperidinyl)
[0380] haloC.sub.1-6alkyl (e.g., trifluoromethyl), [0381] aryl
(e.g., phenyl), [0382] heteroaryl (e.g., pyridyl, (for example,
pyrid-2-yl) or e.g., thiadiazolyl (for example,
1,2,3-thiadiazol-4-yl), diazolyl, triazolyl (e.g.,
1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl),
alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g.,
pyrazol-1-yl), [0383] wherein the aryl, heteroaryl, cycloalkyl or
heterocycloalkyl is optionally substituted with one or more
C.sub.1-6alkyl (e.g., methyl), halogen (e.g., chloro or fluoro),
haloC.sub.1-6alkyl (e.g., trifluoromethyl), hydroxy, carboxy, --SH,
or an additional aryl or heteroaryl (e.g., biphenyl or
pyridylphenyl) [0384] preferably R.sub.10 is phenyl, pyridyl,
piperidinyl or pyrrolidinyl optionally substituted with the
substituents previously defined, e.g. optionally substituted with
halo or alkyl; [0385] provided that when X, Y or X is nitrogen,
R.sub.8, R.sub.9 or R.sub.10, respectively, is not present; [0386]
2.13 Formula II-A or II-B, or any of 2.1-2.12, wherein R.sub.4 and
R.sub.5 are independently [0387] H, [0388] C.sub.1-6alkyl (e.g.,
methyl, isopropyl), [0389] C.sub.3-8 cycloalkyl (e.g.,
cyclopentyl), [0390] C.sub.3-8heterocycloalkyl (e.g.,
pyrrolidin-3-yl), [0391] aryl (e.g., phenyl) or [0392] heteroaryl
(e.g., pyrid-4-yl, pyrid-2-yl or pyrazol-3-yl) [0393] wherein said
aryl or heteroaryl is optionally substituted with halo (e.g.,
4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C.sub.1-6alkyl,
C.sub.1-6alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl);
[0394] 2.14 Formula II-A or II-B, or any of 2.1-2.13, wherein
R.sub.4 is H and R.sub.5 is aryl (e.g., phenyl) optionally
substituted with halo (e.g., 4-fluorophenyl), hydroxy (e.g.,
4-hydroxyphenyl), C.sub.1-6alkyl, C.sub.1-6alkoxy or another aryl
group (e.g., biphenyl-4-ylmethyl); [0395] 2.15 Formula II-A or
II-B, or any of 2.1-2.14, wherein R.sub.6 is H, C.sub.1-6alkyl
(e.g., methyl), hydroxy, C.sub.1-6alkoxy, aryloxy,
--N(R.sub.16)(R.sub.17), oxo (e.g., .dbd.O), or
C.sub.3-8cycloalkyl; [0396] 2.16 Formula II-A or II-B, or any of
2.1-2.14, wherein R.sub.6 is --N(R.sub.16)(R.sub.17); [0397] 2.17
Formula II-A or II-B, or any of 2.1-2.16, wherein R.sub.7 is H,
(e.g., methyl) or C.sub.3-8cycloalkyl wherein said cycloalkyl is
optionally substituted with one or more oxo (e.g.,
2,5-dioxopyrrolidin-1-yl); [0398] 2.18 Formula II-A or II-B, or any
of 2.1-2.16, wherein R.sub.7 is H or C.sub.1-6alkyl (e.g., methyl);
[0399] 2.19 Formula II-A or II-B, or any of 2.1-2.18, wherein
R.sub.14 and R.sub.15 are independently H or C.sub.1-6alkyl; [0400]
2.20 Formula II-A or II-B, or any of 2.1-2.19, wherein R.sub.16 and
R.sub.17 are independently H, C.sub.1-6alkyl, aryl (e.g., phenyl),
heteroaryl, wherein said aryl or heteroaryl is optionally
substituted with halo (e.g., fluoro), C.sub.1-6alkoxy (e.g.,
methoxy); [0401] 2.21 Formula II-A or II-B, or any of 2.1-2.19,
wherein R.sub.16 is H and R.sub.17 is aryl (phenyl) wherein said
aryl or heteroaryl is optionally substituted with halo (e.g.,
fluoro), C.sub.1-6alkoxy (e.g., methoxy), [0402] 2.22 any of the
preceding formulae wherein the compound is selected from any of the
following:
[0402] ##STR00017## ##STR00018## ##STR00019## ##STR00020##
##STR00021## [0403] 2.23 any of the preceding formulae wherein the
compound is selected from any of the following:
[0403] ##STR00022## ##STR00023## ##STR00024## ##STR00025##
##STR00026## [0404] 2.24 any of the preceding formulae wherein the
compounds inhibit phosphodiesterase-mediated (e.g., PDE1-mediated,
especially PDE1A-mediated or PDE1B-mediated) hydrolysis of cGMP,
e.g., with an IC.sub.50 of less than 10 .mu.M, preferably less than
25 .mu.M, preferably less than 1 .mu.M, more preferably less than
500 nM, preferably less than 200 nM in an immobilized-metal
affinity particle reagent PDE assay, for example, as described in
Example 23, in free or salt form.
[0405] In another embodiment, the invention provides an (optionally
1-, 3-, 5-, 6- and/or
7-substituted)-pyrrolo[3,4-d]pyrimidine-(2,4-dione or
4-thioxo-2-one), in free or salt form.
[0406] In still another embodiment, the Compounds of the Invention
is a Compound of Formula P-A or P-B:
##STR00027##
wherein [0407] (i) X .dbd.O or S [0408] (ii) R.sub.1 is H or
C.sub.1-6alkyl (e.g., methyl or ethyl); [0409] (iii) R.sub.2 is
[0410] H, [0411] C.sub.1-6alkyl (e.g., isopropyl, isobutyl,
2-methylbutyl, 2,2-dimethyl propyl), [0412]
--C.sub.0-6alkyl-C.sub.3-9cycloalkyl (e.g., cyclopentyl, cyclohexyl
or cyclopropylmethyl) wherein said cycloalkyl is optionally
substituted with one or more groups selected from C.sub.1-4alkyl
and amino (e.g., --NH.sub.2), for example, 2-aminocyclopentyl or
2-aminocyclohexyl), [0413]
--C.sub.0-6alkyl-heteroC.sub.3-9cycloalkyl (e.g., pyrrolidinyl, for
example, pyrrolidin-3-yl or pyrrolyin-2-yl; oxetan-2-yl;
tetrahydrofuran-2-yl or tetrahydrofuran-2-ylmethyl) wherein said
heterocycloalkyl is optionally substituted with one ore more
C.sub.1-6alkyl (e.g., methyl), for example, 1-methylpyrrolidin-2-yl
or 1-methylpyrrolidin-3-yl, [0414] haloC.sub.1-6alkyl (e.g.,
trifluoromethyl, 2,2,2-trifluoroethyl), [0415]
C.sub.0-6alkylaminoC.sub.0-6alkyl (e.g., 2-(dimethylamino)ethyl,
2-aminopropyl), [0416] hydroxyC.sub.1-6alkyl (e.g.,
3-hydroxy-2-methylpropyl or 2-hydroxy-1-methylethyl), [0417]
arylC.sub.0-6alkyl (e.g., phenyl or benzyl) wherein said aryl group
is optionally substituted with one or more C.sub.1-6alkoxy, for
example, 4-methoxybenzyl, [0418] heteroarylC.sub.1-6alkyl (e.g.,
pyridylmethyl), [0419] (iv) R.sub.3 is [0420] a) hydrogen, [0421]
b) -D-E-F wherein [0422] D is single bond, C.sub.1-6alkylene (e.g.,
methylene, ethynylene, prop-2-yn-1-ylene), or arylC.sub.1-6alkylene
(e.g., benzylene or --CH.sub.2C.sub.6H.sub.4--); [0423] E is [0424]
arylene (e.g., phenylene or --C.sub.6H.sub.4--), wherein the
arylene is optionally substituted with one or more halo, [0425]
arylC.sub.1-6alkylene (e.g., -benzylene- or
--CH.sub.2C.sub.6H.sub.4--), [0426] aminoC.sub.1-6alkylene (e.g.,
--CH.sub.2N(H), [0427] amino (e.g., --N(H)--), [0428] heteroarylene
(e.g., pyrid-3-ylene) or heteroC.sub.3-9cycloakylene (e.g.,
piperidin-4-ylene) wherein the heteroarylene and the
heterocycloalkylene are independently and optionally substituted
with one or more halo; and [0429] F is [0430] Hydrogen, [0431]
C.sub.1-6alkyl (e.g., isobutyl, isopropyl), [0432] aryl (e.g.,
phenyl) wherein said aryl is optionally [0433] substituted with one
or more halo and/or haloC.sub.1-6alkyl, [0434] heteroaryl (e.g.,
triazolyl, diazolyl, oxadiazolyl, pyridyl, pyrimidinyl) wherein
said heteroaryl is optionally substituted with one or more groups
selected from halo (e.g., fluoro), C.sub.1-6alkyl and
haloC.sub.1-6alkyl (e.g., trifluoromethyl), for example,
pyrid-2-yl, 4,6-dimethyl-pyrid-2-yl, 5-fluoropyrimidin-2-yl,
imidazol-1-yl, 4-methylimidazolyl, 1-methylimidazol-2-yl,
pyrazol-1-yl, 1,2,4-triazol-1-yl, 5-methyl-1,2,4-oxadiazol-3-yl or
pyrimidin-2-yl, [0435] heteroC.sub.3-9cycloalkyl (e.g.,
piperidinyl, pyrrolidinyl) wherein said heterocycloalkyl is
optionally substituted with one or more C.sub.1-6alkyl (e.g.,
methyl), for example, pyrrolidin-1-yl, pyrrolidin-2-yl,
1-methylpyrrolidin-2-yl, piperidin-2-yl, 1-methylpiperidin-2-yl,
1-ethylpiperidin-2-yl, [0436] --N(R.sub.a)(R.sub.b) wherein R.sub.a
and R.sub.b are independently H or C.sub.1-6alkyl (e.g.,
dimethylamino or isopropylamino), aminocarbonyl (e.g.,
--C(O)NH.sub.2), [0437] C.sub.1-6alkoxy, [0438] arylcarbonyl (e.g.,
benzoyl), [0439] heteroarylcarbonyl, [0440] C.sub.1-6alkoxycarbonyl
(e.g., methoxycarbonyl), [0441] C.sub.1-6alkyl sulfonyl (e.g.,
--S(O).sub.2--CH.sub.3), [0442] halo (e.g., chloro or fluoro),
[0443] haloC.sub.1-6alkyl (e.g., --CF.sub.3), or [0444]
--O-haloC.sub.1-6alkyl (e.g., --O--CF.sub.3), [0445] c) R.sub.3 is
heteroarylC.sub.0-6alkyl, wherein the heteroaryl group is
optionally substituted with one or more C.sub.1-6haloalkyl; or
[0446] d) R.sub.3 is a moiety of Formula A
[0446] ##STR00028## [0447] wherein X, Y and Z are, independently, N
or C, and R.sub.8, R.sub.9, R.sub.11 and R.sub.12 are independently
H or halogen (e.g., Cl or F); and [0448] R.sub.10 is [0449]
hydrogen, [0450] halogen (e.g., fluoro or chloro), [0451]
C.sub.1-6alkyl, [0452] C.sub.3-9cycloalkyl, [0453]
C.sub.1-6haloalkyl (e.g., trifluoromethyl), [0454] aryl (e.g.,
phenyl) wherein said aryl is optionally substituted with one or
more halo and/or haloC.sub.1-6alkyl, [0455] heteroaryl wherein said
heteroaryl group is optionally substituted with one or more groups
selected from halo (e.g., fluoro), C.sub.1-6alkyl and
haloC.sub.1-6alkyl, e.g., pyridyl, (for example, pyrid-2-yl,
6-fluoro-pyrid-2-yl, 5-trifluoromethyl-pyrid-2-yl,
6-trifluoromethyl-pyrid-3-yl, 4,6-dimethylpyrid-2-yl), thiadiazolyl
(for example, 1,2,3-thiadiazol-4-yl), diazolyl (for example,
pyrazolyl, e.g., pyrazol-1-yl), triazolyl (for example,
1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl), oxadiazolyl
(e.g., 5-methyl-1,2,4-oxadiazol-3-yl), [0456] C.sub.1-6alkyl
sulfonyl (e.g., methyl sulfonyl), [0457] arylcarbonyl (e.g.,
benzoyl), [0458] heteroarylcarbonyl, [0459]
C.sub.1-6alkoxycarbonyl, (e.g., methoxycarbonyl), [0460]
aminocarbonyl (i.e., --C(O)NH.sub.2), [0461] --N(R.sub.a)(R.sub.b)
wherein R.sub.a and R.sub.b are independently H or C.sub.1-6alkyl
(e.g., dimethylamino or isopropylamino), [0462] haloC.sub.1-6alkyl,
[0463] --O-haloC.sub.1-6alkyl (e.g., --O--CF.sub.3), [0464]
heteroC.sub.3-9cycloalkyl-C.sub.0-6alkyl (e.g., piperidinyl,
pyrrolidinyl, pyrrolidinylmethyl) wherein said heterocycloalkyl is
optionally substituted with one or more C.sub.1-6alkyl (e.g.,
methyl), for example, pyrrolidin-1-yl, pyrrolidin-2-yl,
1-methylpyrrolidin-2-yl, piperidin-2-yl, 1-methylpiperidin-2-yl,
1-ethylpiperidin-2-yl; [0465] provided that when X, Y or Z is
nitrogen, R.sub.8, R.sub.9 or R.sub.10, respectively, is not
present; [0466] (v) R.sub.4 and R.sub.5 are independently selected
from [0467] H, [0468] C.sub.1-6alkyl (e.g., methyl or isopropyl),
[0469] C.sub.3-9cycloalkyl (e.g., cyclopentyl), [0470]
C.sub.3-9heterocycloalkyl (e.g., pyrrolidin-3-yl), [0471]
heteroaryl (e.g., pyrid-2-yl, pyrid-3-yl or pyrid-4-yl,
pyrazol-3-yl), aryl (e.g., phenyl) or arylC.sub.1-6alkyl (e.g.,
benzyl), wherein the aryl group is optionally substituted with one
or more halo (e.g., F or Cl), hydroxy and/or another aryl, (e.g.,
p-benzylaryl, e.g., biphenyl-4-ylmethyl); [0472] (vi) R.sub.6 is H
or C.sub.1-6alkyl (e.g., ethyl); in free or salt form.
[0473] The invention further provides compounds of Formula P-A or
P-B as follows: [0474] 3.1. Formula P-A or P-B wherein, R.sub.1 is
H or C.sub.1-6alkyl (e.g., methyl or ethyl); [0475] 3.2. Formula
P-A or P-B wherein, R.sub.1 is H; [0476] 3.3. Formula P-A or P-B
wherein, R.sub.1 is C.sub.1-6alkyl (e.g., methyl or ethyl); [0477]
3.4. Formula P-A or P-B wherein, R.sub.1 is methyl; [0478] 3.5.
Formula P-A or P-B or any of 1.1-3.4 wherein, R.sub.2 is [0479] H,
[0480] C.sub.1-6alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl,
2,2-dimethyl propyl), [0481] --C.sub.0-6alkyl-C.sub.3-9cycloalkyl
(e.g., cyclopentyl, cyclohexyl or cyclopropylmethyl) wherein said
cycloalkyl is optionally substituted with one or more groups
selected from C.sub.1-4alkyl and amino (e.g., --NH.sub.2), for
example, 2-aminocyclopentyl or 2-aminocyclohexyl), [0482]
--C.sub.0-6alkyl-heteroC.sub.3-9cycloalkyl (e.g., pyrrolidinyl, for
example, pyrrolidin-3-yl or pyrrolyin-2-yl; oxetan-2-yl;
tetrahydrofuran-2-yl or tetrahydrofuran-2-ylmethyl) wherein said
heterocycloalkyl is optionally substituted with one ore more
C.sub.1-6alkyl (e.g., methyl), for example, 1-methylpyrrolidin-2-yl
or 1-methylpyrrolidin-3-yl, [0483] haloC.sub.1-6alkyl (e.g.,
trifluoromethyl, 2,2,2-trifluoroethyl), [0484]
C.sub.0-6alkylaminoC.sub.0-6alkyl (e.g., 2-(dimethylamino)ethyl,
2-aminopropyl), [0485] hydroxyC.sub.1-6alkyl (e.g.,
3-hydroxy-2-methylpropyl or 2-hydroxy-1-methylethyl), [0486]
arylC.sub.0-6alkyl (e.g., phenyl or benzyl) wherein said aryl group
is optionally substituted with one or more C.sub.1-6alkoxy, for
example, 4-methoxybenzyl, [0487] heteroarylC.sub.1-6alkyl (e.g.,
pyridylmethyl); [0488] 3.6. Formula P-A or P-B or any of 1.1-3.5,
wherein R.sub.2 is H; [0489] 3.7. Formula P-A or P-B or any of
1.1-3.5, wherein R.sub.2 is C.sub.1-6alkyl; [0490] 3.8. Formula 3.7
wherein, R.sub.2 is isopropyl, isobutyl, 2,2-dimethylpropyl, or
2-methylbutyl; [0491] 3.9. Formula 3.7 wherein, R.sub.2 is
isobutyl; [0492] 3.10. Formula 3.7 wherein, R.sub.2 is
2,2-dimethylpropyl; [0493] 3.11. Formula P-A or P-B or any of
1.1-3.5, wherein R.sub.2 is hydroxyC.sub.1-6 alkyl; [0494] 3.12.
Formula 3.11, wherein R.sub.2 is 2-hydroxy-1-methylethyl; [0495]
3.13. Formula P-A or P-B or 1.1-3.5 wherein R.sub.2 is
--C.sub.0-6alkyl-C.sub.3-9cycloalkyl (e.g., cyclopentyl, cyclohexyl
or cyclopropylmethyl) wherein said cycloalkyl is optionally
substituted with one or more groups selected from C.sub.1-4alkyl
and amino (e.g., --NH.sub.2), for example, 2-aminocyclopentyl or
2-aminocyclohexyl); [0496] 3.14. Formula 3.13 wherein R.sub.2 is
C.sub.3-9cycloalkyl-C.sub.1-6alkyl; [0497] 3.15. Formula 3.13
wherein R.sub.2 is cyclopentyl, cyclohexyl or cyclopropylmethyl;
[0498] 3.16. Formula 3.13 wherein R.sub.2 is cyclopropylmethyl;
[0499] 3.17. Formula 3.13 wherein R.sub.2 is 2-aminocyclopentyl;
[0500] 3.18. Formula 3.13 wherein R.sub.2 is 2-aminocyclohexyl;
[0501] 3.19. Formula P-A or P-B or any of 1.1-3.5, wherein R.sub.2
is haloC.sub.1-6alkyl (e.g., trifluoromethyl,
2,2,2-trifluoroethyl); [0502] 3.20. Formula 3.19, wherein R.sub.2
is 2,2,2-trifluoroethyl; [0503] 3.21. Formula P-A or P-B or any of
1.1-3.5, wherein R.sub.2 is
--C.sub.0-6alkyl-heteroC.sub.3-9cycloalkyl (e.g., pyrrolidinyl, for
example, pyrrolidin-3-yl or pyrrolyin-2-yl; oxetan-2-yl;
tetrahydrofuran-2-yl or tetrahydrofuran-2-ylmethyl) wherein said
heterocycloalkyl is optionally substituted with one ore more
C.sub.1-6alkyl (e.g., methyl), for example, 1-methylpyrrolidin-2-yl
or 1-methylpyrrolidin-3-yl; [0504] 3.22. Formula 3.21, wherein
R.sub.2 is pyrrolidinyl (e.g., pyrrolidin-3-yl); [0505] 3.23.
Formula 3.21, wherein R.sub.2 is 1-methylpyrrolidin-3-yl; [0506]
3.24. Formula P-A or P-B or any of 1.1-3.5, wherein R.sub.2 is
C.sub.0-6alkylaminoC.sub.0-6alkyl (e.g., 2-(dimethylamino)ethyl,
2-aminopropyl); [0507] 3.25. Formula 3.24, wherein R.sub.2 is
2-(dimethylamino)ethyl; [0508] 3.26. Formula 3.24, wherein R.sub.2
is 2-aminopropyl; [0509] 3.27. Formula P-A or P-B or any of
1.1-3.5, wherein R.sub.2 is arylC.sub.0-6alkyl (e.g., phenyl or
benzyl) wherein said aryl group is optionally substituted with one
or more C.sub.1-6alkoxy, for example, 4-methoxybenzyl; [0510] 3.28.
Formula 3.27, wherein R.sub.2 is benzyl;
[0511] 3.29. Formula P-A or P-B or any of 1.1-3.5, wherein R.sub.2
is heteroarylC.sub.1-6alkyl (e.g., pyridylmethyl); [0512] 3.30.
Formula 3.29, wherein R.sub.2 is pyridylmethyl; [0513] 3.31. Any of
the preceding formulae wherein R.sub.3 is [0514] a) hydrogen,
[0515] b) -D-E-F wherein [0516] D is single bond, C.sub.1-6alkylene
(e.g., methylene, ethynylene, prop-2-yn-1-ylene), or
arylC.sub.1-6alkylene (e.g., benzylene or
--CH.sub.2C.sub.6H.sub.4--); [0517] E is [0518] arylene (e.g.,
phenylene or --C.sub.6H.sub.4--), wherein the arylene is optionally
substituted with one or more halo, [0519] arylC.sub.1-6alkylene
(e.g., -benzylene- or --CH.sub.2C.sub.6H.sub.4--), [0520]
aminoC.sub.1-6alkylene (e.g., --CH.sub.2N(H)--), [0521] amino
(e.g., --N(H)--), [0522] heteroarylene (e.g., pyrid-3-ylene) or
heteroC.sub.3-9cycloakylene (e.g., piperidin-4-ylene) wherein the
heteroarylene and the heterocycloalkylene are independently and
optionally substituted with one or more halo; and [0523] F is
[0524] hydrogen, [0525] C.sub.1-6alkyl (e.g., isobutyl, isopropyl),
[0526] aryl (e.g., phenyl) wherein said aryl is optionally
substituted with one or more halo and/or haloC.sub.1-6alkyl, [0527]
heteroaryl (e.g., triazolyl, diazolyl, oxadiazolyl, pyridyl,
pyrimidinyl) wherein said heteroaryl is optionally substituted with
one or more groups selected from halo (e.g., fluoro),
C.sub.1-6alkyl and haloC.sub.1-6alkyl (e.g., trifluoromethyl), for
example, pyrid-2-yl, 4,6-dimethyl-pyrid-2-yl,
5-fluoropyrimidin-2-yl, imidazol-1-yl, 4-methylimidazolyl,
1-methylimidazol-2-yl, pyrazol-1-yl, 1,2,4-triazol-1-yl,
5-methyl-1,2,4-oxadiazol-3-yl or pyrimidin-2-yl, [0528]
heteroC.sub.3-9cycloalkyl (e.g., piperidinyl, pyrrolidinyl) wherein
said heterocycloalkyl is optionally substituted with one or more
C.sub.1-6alkyl (e.g., methyl), for example, pyrrolidin-1-yl,
pyrrolidin-2-yl, 1-methylpyrrolidin-2-yl, piperidin-2-yl,
1-methylpiperidin-2-yl, 1-ethylpiperidin-2-yl, [0529]
--N(R.sub.a)(R.sub.b) wherein R.sub.a and R.sub.b are independently
H or C.sub.1-6alkyl (e.g., --NH.sub.2, dimethylamino or
isopropylamino), aminocarbonyl (e.g., --C(O)NH.sub.2), [0530]
C.sub.1-6alkoxy, [0531] arylcarbonyl (e.g., benzoyl), [0532]
heteroarylcarbonyl, [0533] C.sub.1-6alkoxycarbonyl (e.g.,
methoxycarbonyl), [0534] C.sub.1-6alkyl sulfonyl(e.g.,
--S(O).sub.2--CH.sub.3), [0535] halo (e.g., chloro or fluoro),
[0536] haloC.sub.1-6alkyl (e.g., --CF.sub.3), or [0537]
--O-haloC.sub.1-6alkyl (e.g., --O--CF.sub.3), [0538] c) R.sub.3 is
heteroarylC.sub.0-6alkyl wherein the heteroaryl group is optionally
substituted with one or more C.sub.1-6haloalkyl; or [0539] d)
R.sub.3 is a moiety of Formula A
[0539] ##STR00029## [0540] wherein X, Y and Z are, independently, N
or C, and R.sub.8, R.sub.9, R.sub.11 and R.sub.12 are independently
H or halogen (e.g., Cl or F); and [0541] R.sub.10 is [0542]
hydrogen, [0543] halogen (e.g., fluoro or chloro), [0544]
C.sub.1-6alkyl, [0545] C.sub.3-9cycloalkyl, [0546]
C.sub.1-6haloalkyl (e.g., trifluoromethyl), [0547] aryl (e.g.,
phenyl) wherein said aryl is optionally substituted with one or
more halo and/or haloC.sub.1-6alkyl, [0548] heteroaryl wherein said
heteroaryl group is optionally substituted with one or more groups
selected from halo (e.g., fluoro), C.sub.1-6alkyl and
haloC.sub.1-6alkyl, e.g., pyridyl, (for example, pyrid-2-yl,
6-fluoro-pyrid-2-yl, 5-trifluoromethyl-pyrid-2-yl,
6-trifluoromethyl-pyrid-3-yl, 4,6-dimethylpyrid-2-yl), thiadiazolyl
(for example, 1,2,3-thiadiazol-4-yl), diazolyl (for example,
pyrazolyl, e.g., pyrazol-1-yl), triazolyl (for example,
1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl), oxadiazolyl
(e.g., 5-methyl-1,2,4-oxadiazol-3-yl), [0549] C.sub.1-6alkyl
sulfonyl (e.g., methyl sulfonyl), [0550] arylcarbonyl (e.g.,
benzoyl), [0551] heteroarylcarbonyl, [0552]
C.sub.1-6alkoxycarbonyl, (e.g., methoxycarbonyl), aminocarbonyl
(i.e., --C(O)NH.sub.2), [0553] --N(R.sub.a)(R.sub.b) wherein
R.sub.a and R.sub.b are independently H or C.sub.1-6alkyl (e.g.,
--NH.sub.2, dimethylamino or isopropylamino), [0554]
haloC.sub.1-6alkyl, [0555] --O-haloC.sub.1-6alkyl (e.g.,
--O--CF.sub.3), [0556] heteroC.sub.3-9cycloalkyl-C.sub.0-6alkyl
(e.g., piperidinyl, pyrrolidinyl, pyrrolidinylmethyl) wherein said
heterocycloalkyl is optionally substituted with one or more
C.sub.1-6alkyl (e.g., methyl), for example, pyrrolidin-1-yl,
pyrrolidin-2-yl, 1-methylpyrrolidin-2-yl, piperidin-2-yl,
1-methylpiperidin-2-yl, 1-ethylpiperidin-2-yl; [0557] provided that
when X, Y or Z is nitrogen, R.sub.8, R.sub.9 or R.sub.10,
respectively, is not present; [0558] 3.32. Formula 3.31, wherein
R.sub.3 is -D-E-F and D, E and F are previously defined in Formula
P-A or P-B; [0559] 3.33. Formula 3.31 or 3.32, wherein D is single
bond, C.sub.1-6alkylene (e.g., methylene, ethynylene,
prop-2-yn-1-ylene), or arylC.sub.1-6alkylene (e.g., benzylene or
--CH.sub.2C.sub.6H.sub.4--); [0560] 3.34. Formula 3.31 or 3.32,
wherein D is C.sub.1-6alkylene (e.g., methylene, ethynylene,
prop-2-yn-1-ylene); [0561] 3.35. Formula 3.31 or 3.32, wherein D is
a single bond; [0562] 3.36. Formula 3.31 or 3.32, wherein D is
arylC.sub.1-6alkylene; [0563] 3.37. Formula 3.31 or 3.32, wherein D
is benzylene; [0564] 3.38. Any of formulae P-A or P-B or 3.31-3.37,
wherein E is [0565] arylene (e.g., phenylene or
--C.sub.6H.sub.4--), wherein the arylene is optionally substituted
with one or more halo, [0566] arylC.sub.1-6alkylene (e.g.,
-benzylene- or --CH.sub.2C.sub.6H.sub.4--), [0567]
aminoC.sub.1-6alkylene (e.g., --CH.sub.2N(H)--), [0568] amino
(e.g., --N(H)--), [0569] heteroarylene (e.g., pyrid-3-ylene) or
heteroC.sub.3-9cycloakylene (e.g., piperidin-4-ylene) wherein the
heteroarylene and the heterocycloalkylene are independently and
optionally substituted with one or more halo; [0570] 3.39. any of
formulae P-A or P-B or 3.31-3.38, wherein E is
aminoC.sub.1-6alkylene (e.g., --CH.sub.2N(H)--); [0571] 3.40. any
of formulae P-A or P-B or 3.31-3.38, wherein E is arylene (e.g.,
phenylene or --C.sub.6H.sub.4--) wherein the arylene is optionally
substituted with one or more halo; [0572] 3.41. any of formulae P-A
or P-B or 3.31-3.38, wherein E is heteroC.sub.3-9cycloakylene
(e.g., piperidin-4-ylene) wherein the heterocycloalkylene is
optionally substituted with one or more halo; [0573] 3.42. any of
formulae P-A or P-B or 3.31-3.38, wherein E is heteroarylene (e.g.,
pyrid-3-ylene) wherein the heteroarylene is optionally substituted
with one or more halo; [0574] 3.43. any of formulae P-A or P-B or
3.31-3.38, wherein E is arylC.sub.1-6alkylene (e.g., benzylene or
--C.sub.6H.sub.4--) wherein the arylalkylene is optionally
substituted with one or more halo; [0575] 3.44. Any of formulae P-A
or P-B or 3.31-3.43, wherein F is [0576] Hydrogen, [0577]
C.sub.1-6alkyl (e.g., isobutyl, isopropyl), [0578] aryl (e.g.,
phenyl) wherein said aryl is optionally substituted with one or
more halo and/or haloC.sub.1-6alkyl, [0579] heteroaryl (e.g.,
triazolyl, diazolyl, oxadiazolyl, pyridyl, pyrimidinyl) wherein
said heteroaryl is optionally substituted with one or more groups
selected from halo (e.g., fluoro), C.sub.1-6alkyl and
haloC.sub.1-6alkyl (e.g., trifluoromethyl), for example,
pyrid-2-yl, 4,6-dimethyl-pyrid-2-yl, 5-fluoropyrimidin-2-yl,
imidazol-1-yl, 4-methylimidazolyl, 1-methylimidazol-2-yl,
pyrazol-1-yl, 1,2,4-triazol-1-yl, 5-methyl-1,2,4-oxadiazol-3-yl or
pyrimidin-2-yl, [0580] heteroC.sub.3-9cycloalkyl (e.g.,
piperidinyl, pyrrolidinyl) wherein said heterocycloalkyl is
optionally substituted with one or more C.sub.1-6alkyl (e.g.,
methyl), for example, pyrrolidin-1-yl, pyrrolidin-2-yl,
1-methylpyrrolidin-2-yl, piperidin-2-yl, 1-methylpiperidin-2-yl,
1-ethylpiperidin-2-yl, [0581] --N(R.sub.a)(R.sub.b) wherein R.sub.a
and R.sub.b are independently H or C.sub.1-6alkyl (e.g.,
--NH.sub.2, dimethylamino or isopropylamino), aminocarbonyl (e.g.,
--C(O)NH.sub.2), [0582] C.sub.1-6alkoxy, [0583] arylcarbonyl (e.g.,
benzoyl), [0584] heteroarylcarbonyl, [0585] C.sub.1-6alkoxycarbonyl
(e.g., methoxycarbonyl), [0586] C.sub.1-6alkyl sulfonyl (e.g.,
--S(O).sub.2--CH.sub.3), [0587] halo (e.g., chloro or fluoro),
[0588] haloC.sub.1-6alkyl (e.g., --CF.sub.3), or [0589]
--O-haloC.sub.1-6alkyl (e.g., --O--CF.sub.3), [0590] 3.45. Formula
3.44, wherein F is aryl (e.g., phenyl) wherein said aryl is
optionally substituted with one or more halo and/or
haloC.sub.1-6alkyl;
[0591] 3.46. Formula 3.44, wherein F is phenyl optionally
substituted with one or more halo and/or haloC.sub.1-6alkyl; [0592]
3.47. Formula 3.44, wherein F is C.sub.1-6alkoxy (e.g., methoxy);
[0593] 3.48. Formula 3.47, wherein F is methoxy; [0594] 3.49.
Formula 3.44, wherein F is --O-haloC.sub.1-6alkyl (e.g.,
--OCF.sub.3); [0595] 3.50. Formula 3.44 or 3.49, wherein F is
--OCF.sub.3; [0596] 3.51. Formula 3.44, wherein F is halo (e.g.,
chloro or fluoro); [0597] 3.52. Formula 3.44, wherein F is
--N(R.sub.a)(R.sub.b) wherein R.sub.a and R.sub.b are independently
H or C.sub.1-6alkyl (e.g., dimethylamino or isopropylamino); [0598]
3.53. Formula 3.44, wherein F is heteroC.sub.3-9cycloalkyl (e.g.,
piperidinyl, pyrrolidinyl) wherein said heterocycloalkyl is
optionally substituted with one or more C.sub.1-6alkyl (e.g.,
methyl), for example, pyrrolidin-1-yl, pyrrolidin-2-yl,
1-methylpyrrolidin-2-yl, piperidin-2-yl, 1-methylpiperidin-2-yl,
1-ethylpiperidin-2-yl; [0599] 3.54. Formula 3.44 or 3.53 wherein F
is pyrrolidin-1-yl; [0600] 3.55. Formula 3.44 or 3.53 wherein F is
pyrrolidin-2-yl; [0601] 3.56. Formula 3.44 or 3.53 wherein F is
1-methylpyrrolidin-2-yl; [0602] 3.57. Formula 3.44 or 3.53 wherein
F is piperidin-2-yl; [0603] 3.58. Formula 3.44 or 3.53 wherein F is
1-methylpiperidin-2-yl; [0604] 3.59. Formula 3.44 or 3.53 wherein F
is 1-ethylpiperidin-2-yl; [0605] 3.60. Formula 3.44, wherein F is
C.sub.1-6alkyl (e.g., isobutyl, isopropyl); [0606] 3.61. Formula
3.44 or 3.60, wherein F is isobutyl; [0607] 3.62. Formula 3.44 or
3.60, wherein F is isopropyl; [0608] 3.63. Formula 3.44, wherein F
is heteroaryl (e.g., triazolyl, diazolyl, oxadiazolyl, pyridyl,
pyrimidinyl) wherein said heteroaryl is optionally substituted with
one or more groups selected from halo (e.g., fluoro),
C.sub.1-6alkyl and haloC.sub.1-6alkyl (e.g., trifluoromethyl), for
example, pyrid-2-yl, 4,6-dimethyl-pyrid-2-yl,
5-fluoropyrimidin-2-yl, imidazol-1-yl, 4-methylimidazolyl,
1-methylimidazol-2-yl, pyrazol-1-yl, 1,2,4-triazol-1-yl,
5-methyl-1,2,4-oxadiazol-3-yl or pyrimidin-2-yl; [0609] 3.64.
Formula 3.44 or 3.63, wherein F is pyridyl (e.g., pyrid-2-yl);
[0610] 3.65. Formula 3.44 or 3.63, wherein F is pyridyl (e.g.,
pyrid-2-yl) optionally substituted with one or more groups selected
from halo (e.g., fluoro), C.sub.1-6alkyl and haloC.sub.1-6alkyl
(e.g., trifluoromethyl); [0611] 3.66. Formula 3.44 or 3.63, wherein
F is 6-fluoro-pyrid-2-yl; [0612] 3.67. Formula 3.44 or 3.63,
wherein F is imidazolyl optionally substituted with C.sub.1-6alkyl;
[0613] 3.68. Formula 3.44 or 3.63, wherein F is imidazol-1-yl;
[0614] 3.69. Formula 3.44 or 3.63, wherein F is
4-methylimidazol-1-yl; [0615] 3.70. Formula 3.44 or 3.63, wherein F
is 1-methylimidazol-2-yl; [0616] 3.71. Formula 3.44 or 3.63,
wherein F is 1,2,4-triazol-1-yl; [0617] 3.72. Formula 3.44, wherein
F is aminocarbonyl (e.g., --C(O)NH.sub.2); [0618] 3.73. Formula
3.44, wherein F is arylcarbonyl (e.g., benzoyl); [0619] 3.74.
Formula 3.44, wherein F is heteroarylcarbonyl; [0620] 3.75. Formula
3.44, wherein F is C.sub.1-6alkoxycarbonyl (e.g., methoxycarbonyl);
[0621] 3.76. Formula 3.44, wherein F is haloC.sub.1-6alkyl (e.g.,
--CF.sub.3); [0622] 3.77. Formula 3.44, wherein F is halo (e.g.,
chloro or fluoro); [0623] 3.78. Formula 3.44, wherein F is
C.sub.1-6alkyl sulfonyl (e.g., --S(O).sub.2--CH.sub.3);
[0624] 3.79. Any of formulae 3.1-3.31, wherein R.sub.3 is H; [0625]
3.80. Any of formulae 3.1-3.31, wherein R.sub.3 is a
heteroarylC.sub.0-6 alkyl optionally substituted with
C.sub.1-6haloalkyl; [0626] 3.81. Any of formulae 3.1-3.31, wherein
R.sub.3 is a moiety of Formula A as hereinbefore described in
Formula P-A or P-B:
[0626] ##STR00030## [0627] wherein X, Y and Z are, independently, N
or C, and R.sub.8, R.sub.9, R.sub.11 and R.sub.12 are independently
H or halogen (e.g., Cl or F); and [0628] R.sub.10 is [0629]
hydrogen, [0630] halogen (e.g., fluoro or chloro), [0631]
C.sub.1-6alkyl, [0632] C.sub.3-9cycloalkyl, [0633]
C.sub.1-6haloalkyl (e.g., trifluoromethyl), [0634] aryl (e.g.,
phenyl) wherein said aryl is optionally substituted with one or
more halo and/or haloC.sub.1-6alkyl, [0635] heteroaryl wherein said
heteroaryl group is optionally substituted with one or more groups
selected from halo (e.g., fluoro), C.sub.1-6alkyl and
haloC.sub.1-6alkyl, e.g., pyridyl, (for example, pyrid-2-yl,
6-fluoro-pyrid-2-yl, 5-trifluoromethyl-pyrid-2-yl,
6-trifluoromethyl-pyrid-3-yl, 4,6-dimethylpyrid-2-yl), thiadiazolyl
(for example, 1,2,3-thiadiazol-4-yl), diazolyl (for example,
pyrazolyl, e.g., pyrazol-1-yl), triazolyl (for example,
1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl), oxadiazolyl
(e.g., 5-methyl-1,2,4-oxadiazol-3-yl), [0636] C.sub.1-6alkyl
sulfonyl (e.g., methyl sulfonyl), [0637] arylcarbonyl (e.g.,
benzoyl), [0638] heteroarylcarbonyl, [0639]
C.sub.1-6alkoxycarbonyl, (e.g., methoxycarbonyl), aminocarbonyl
(i.e., --C(O)NH.sub.2), [0640] --N(R.sub.a)(R.sub.b) wherein
R.sub.a and R.sub.b are independently H or C.sub.1-6alkyl (e.g.,
--NH.sub.2, dimethylamino or isopropylamino), haloC.sub.1-6alkyl,
[0641] --O-haloC.sub.1-6alkyl (e.g., --O--CF.sub.3), [0642]
heteroC.sub.3-9cycloalkyl-C.sub.0-6alkyl (e.g., piperidinyl,
pyrrolidinyl, pyrrolidinylmethyl) wherein said heterocycloalkyl is
optionally substituted with C.sub.1-6alkyl (e.g., methyl), for
example, pyrrolidin-1-yl, pyrrolidin-2-yl, 1-methylpyrrolidin-2-yl,
piperidin-2-yl, 1-methylpiperidin-2-yl, 1-ethylpiperidin-2-yl;
[0643] provided that when X, Y or Z is nitrogen, R.sub.8, R.sub.9
or R.sub.10, respectively, is not present; [0644] 3.82. Formula
3.81, wherein the moiety of Formula A is benzyl (i.e., X, Y and Z
are carbon) and R.sub.10 is selected from [0645] hydrogen, [0646]
halogen (e.g., fluoro or chloro), [0647] C.sub.1-6alkyl, [0648]
C.sub.3-9cycloalkyl, [0649] C.sub.1-6haloalkyl (e.g.,
trifluoromethyl), [0650] aryl (e.g., phenyl) wherein said aryl is
optionally substituted with one or more halo and/or
haloC.sub.1-6alkyl, [0651] heteroaryl wherein said heteroaryl group
is optionally substituted with one or more groups selected from
halo (e.g., fluoro), C.sub.1-6alkyl and haloC.sub.1-6alkyl, e.g.,
pyridyl, (for example, pyrid-2-yl, 6-fluoro-pyrid-2-yl,
5-trifluoromethyl-pyrid-2-yl, 6-trifluoromethyl-pyrid-3-yl,
4,6-dimethylpyrid-2-yl), thiadiazolyl (for example,
1,2,3-thiadiazol-4-yl), diazolyl (for example, pyrazolyl, e.g.,
pyrazol-1-yl), triazolyl (for example, 1,2,4-triazol-1-yl),
tetrazolyl (e.g., tetrazol-5-yl), oxadiazolyl(e.g.,
5-methyl-1,2,4-oxadiazol-3-yl), [0652] C.sub.1-6alkyl sulfonyl
(e.g., methyl sulfonyl), [0653] arylcarbonyl (e.g., benzoyl),
[0654] heteroarylcarbonyl, [0655] C.sub.1-6alkoxycarbonyl, (e.g.,
methoxycarbonyl), [0656] aminocarbonyl (i.e., --C(O)NH.sub.2),
[0657] --N(R.sub.a)(R.sub.b) wherein R.sub.a and R.sub.b are
independently H or C.sub.1-6alkyl (e.g., --NH.sub.2, dimethylamino
or isopropylamino), [0658] haloC.sub.1-6alkyl, [0659]
--O-haloC.sub.1-6alkyl (e.g., --O--CF.sub.3), [0660]
heteroC.sub.3-9cycloalkyl-C.sub.0-6alkyl (e.g., piperidinyl,
pyrrolidinyl, pyrrolidinylmethyl) wherein said heterocycloalkyl is
optionally substituted with one or more C.sub.1-6alkyl (e.g.,
methyl), for example, pyrrolidin-1-yl, pyrrolidin-2-yl,
1-methylpyrrolidin-2-yl, piperidin-2-yl, 1-methylpiperidin-2-yl,
1-ethylpiperidin-2-yl; [0661] provided that when X, Y or Z is
nitrogen, R.sub.8, R.sub.9 or R.sub.10, respectively, is not
present; [0662] 3.83. Formula 3.81 or 3.82, wherein R.sub.10 is
aryl (e.g., phenyl) wherein said aryl is optionally substituted
with one or more halo and/or haloC.sub.1-6alkyl; [0663] 3.84.
Formula 3.81 or 3.82, wherein R.sub.10 is heteroaryl wherein said
heteroaryl group is optionally substituted with one or more groups
selected from halo (e.g., fluoro), C.sub.1-6alkyl and
haloC.sub.1-6alkyl, e.g., pyridyl, (for example, pyrid-2-yl,
6-fluoro-pyrid-2-yl, 5-trifluoromethyl-pyrid-2-yl,
6-trifluoromethyl-pyrid-3-yl, 4,6-dimethylpyrid-2-yl), thiadiazolyl
(for example, 1,2,3-thiadiazol-4-yl), diazolyl (for example,
pyrazolyl, e.g., pyrazol-1-yl), triazolyl (for example,
1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl), oxadiazolyl
(e.g., 5-methyl-1,2,4-oxadiazol-3-yl); [0664] 3.85. Formula 3.81 or
3.82, wherein R.sub.10 is pyrid-2-yl or pyrid-3-yl optionally
substituted with one or more groups selected from halo (e.g.,
fluoro), C.sub.1-6alkyl and haloC.sub.1-6alkyl; [0665] 3.86.
Formula 3.81 or 3.82, wherein R.sub.10 is 6-fluoro-pyrid-2-yl;
[0666] 3.87. Formula 3.81 or 3.82, wherein R.sub.10 is
4,6-dimethylpyrid-2-yl; [0667] 3.88. Formula 3.81 or 3.82, wherein
R.sub.10 is halogen (e.g., fluoro); [0668] 3.89. Formula 3.81 or
3.82, wherein R.sub.10 is hydrogen; [0669] 3.90. Formula 3.81 or
3.82, wherein R.sub.10 is C.sub.1-6alkyl; [0670] 3.91. Formula 3.81
or 3.82, wherein R.sub.10 is C.sub.3-9cycloalkyl; [0671] 3.92.
Formula 3.81 or 3.82, wherein R.sub.10 is C.sub.1-6haloalkyl (e.g.,
trifluoromethyl), [0672] 3.93. Formula 3.81 or 3.82, wherein
R.sub.10 is C.sub.1-6alkyl sulfonyl (e.g., methyl sulfonyl; [0673]
3.94. Formula 3.81 or 3.82, wherein R.sub.10 is
heteroC.sub.3-9cycloalkyl-C.sub.0-6alkyl (e.g., piperidinyl,
pyrrolidinyl, pyrrolidinylmethyl) wherein said heterocycloalkyl is
optionally substituted with one or more C.sub.1-6alkyl (e.g.,
methyl), for example, pyrrolidin-1-yl, pyrrolidin-2-yl,
1-methylpyrrolidin-2-yl, piperidin-2-yl, 1-methylpiperidin-2-yl,
1-ethylpiperidin-2-yl; [0674] 3.95. Formula 3.81 or 3.82, wherein
R.sub.10 is, pyrrolidin-1-yl or pyrrolidin-2-yl; [0675] 3.96.
Formula 3.81 or 3.82, wherein R.sub.10 is 1-methylpyrrolidin-2-yl;
[0676] 3.97. Formula 3.81 or 3.82, wherein R.sub.10 is
piperidin-2-yl; [0677] 3.98. Formula 3.81 or 3.82, wherein R.sub.10
is 1-methylpiperidin-2-yl; [0678] 3.99. Formula 3.81 or 3.82,
wherein R.sub.10 is 1-ethylpiperidin-2-yl; [0679] 3.100. Formula
3.81 or 3.82, wherein R.sub.10 is C.sub.1-6alkyl sulfonyl (e.g.,
methyl sulfonyl); [0680] 3.101. Formula 3.81 or 3.82, wherein
R.sub.10 is arylcarbonyl (e.g., benzoyl); [0681] 3.102. Formula
3.81 or 3.82, wherein R.sub.10 is heteroarylcarbonyl; [0682] 3.103.
Formula 3.81 or 3.82, wherein R.sub.10 is C.sub.1-6alkoxycarbonyl,
(e.g., methoxycarbonyl); [0683] 3.104. Formula 3.81 or 3.82,
wherein R.sub.10 is aminocarbonyl (i.e., --C(O)NH.sub.2); [0684]
3.105. Formula 3.81 or 3.82, wherein R.sub.10 is
haloC.sub.1-6alkyl; [0685] 3.106. Formula 3.81 or 3.82, wherein
R.sub.10 is --O-haloC.sub.1-6alkyl (e.g., --O--CF.sub.3); [0686]
3.107. Formula 3.81 or 3.82, wherein R.sub.10 is
--N(R.sub.a)(R.sub.b) wherein R.sub.a and R.sub.b are independently
H or C.sub.1-6alkyl (e.g., --NH.sub.2, dimethylamino or
isopropylamino); [0687] 3.108. any of formulae 3.81-3.107, wherein
R.sub.8, R.sub.9, R.sub.11 and R.sub.12 are independently H or
halogen (e.g., Cl or F); [0688] 3.109. formulae 3.81-3.107, wherein
R.sub.8, R.sub.9, R.sub.11 and R.sub.12 are H; [0689] 3.110.
formulae 3.81-3.107, wherein R.sub.8, R.sub.9, R.sub.11 and
R.sub.12 are independently halogen (e.g., Cl or F); [0690] 3.111.
any of formulae 3.81-3.110, wherein X, Y and Z are all C; [0691]
3.112. any of formulae 3.81, 3.83-3.110, wherein either X, Y and/or
Z are/is N; [0692] 3.113. Any of the preceding formulae, wherein
R.sub.6 is H or C.sub.1-6alkyl (e.g., ethyl); [0693] 3.114. Formula
3.113, wherein R.sub.6 is H; [0694] 3.115. Formula 3.113, wherein
R.sub.6 is C.sub.1-6alkyl; [0695] 3.116. Formula 3.113, wherein
ethyl; [0696] 3.117. any of Formulae 1.1-3.116 wherein R.sub.4 and
R.sub.5 are independently selected from [0697] H, [0698]
C.sub.1-6alkyl (e.g., methyl or isopropyl), [0699]
C.sub.3-9cycloalkyl (e.g., cyclopentyl), [0700]
C.sub.3-9heterocycloalkyl (e.g., pyrrolidin-3-yl), [0701]
heteroaryl (e.g., pyrid-2-yl, pyrid-3-yl or pyrid-4-yl,
pyrazol-3-yl), [0702] aryl (e.g., phenyl) or arylC.sub.1-6alkyl
(e.g., benzyl), wherein the aryl group is optionally substituted
with one or more halo (e.g., F or Cl), hydroxy and/or another aryl,
(e.g., p-benzylaryl, e.g., biphenyl-4-ylmethyl); [0703] 3.118.
Formula 3.117 wherein R.sub.4 or R.sub.5 is H; [0704] 3.119.
Formula 3.118 wherein R.sub.4 or R.sub.5 is C.sub.1-6alkyl (e.g.,
methyl or isopropyl); [0705] 3.120. Formula 3.119 wherein R.sub.4
or R.sub.5 is C.sub.3-9cycloalkyl (e.g., cyclopentyl); [0706]
3.121. Formula 3.120 wherein R.sub.4 or R.sub.5 is
C.sub.3-9heterocycloalkyl (e.g., pyrrolidin-3-yl); [0707] 3.122.
Formula 3.121 wherein R.sub.4 or R.sub.5 is heteroaryl (e.g.,
pyrid-2-yl, pyrid-3-yl or pyrid-4-yl, pyrazol-3-yl); [0708] 3.123.
Formula 3.122 wherein R.sub.4 or R.sub.5 is aryl (e.g., phenyl) or
arylC.sub.1-6alkyl (e.g., benzyl), wherein the aryl group is
optionally substituted with one or more halo (e.g., fluoro),
hydroxy and/or another aryl, (e.g., p-benzylaryl, e.g.,
biphenyl-4-ylmethyl); [0709] 3.124. Formula 3.117 wherein R.sub.4
is H, and R.sub.5 is phenyl optionally substituted with halo,
hydroxy and/or another aryl; [0710] 3.125. any of the preceding
formulae wherein X.dbd.O or Sh; [0711] 3.126. Formula 3.125,
wherein X.dbd.O; [0712] 3.127. Formula 3.125, wherein X.dbd.S;
[0713] 3.128. any of Formulae 3.1-3.127, wherein the compound is
Compound of Formula P-A; [0714] 3.129. any of Formulae 3.1-3.127,
wherein the compound is Compound of Formula P-B; [0715] 3.130. any
of the preceding formulae wherein the compound is selected from any
of the following: [0716] 3.131. any of the preceding formulae
wherein the compound is selected from any of the following:
[0716] ##STR00031## ##STR00032## ##STR00033## ##STR00034##
##STR00035## [0717] 3.132. a compound of any one of the preceding
formulae wherein said compound inhibits phosphodiesterase-mediated
(e.g., PDE1-mediated, especially PDE1 B-mediated) hydrolysis of
cGMP, e.g., with an IC.sub.50 of less than 25 .mu.M, preferably
less than 10 .mu.M, preferably less than 25 .mu.M, preferably less
than 1 .mu.M, more preferably less than 500 nM, preferably less
than 200 nM in an immobilized-metal affinity particle reagent PDE
assay, for example, as described in Example 23.
[0718] In a further embodiment, the Compounds of the Invention are
the compounds of Formula P-A or P-B as hereinbefore described,
wherein: [0719] (i) X.dbd.O; [0720] (ii) R.sub.1 is C.sub.1-6alkyl
(e.g. methyl or ethyl); [0721] (iii) R.sub.2 is C.sub.1-6alkyl
(e.g. isopropyl, isobutyl, 2-methylbutyl, 2,2-dimethyl propyl);
[0722] (iv) R.sub.3 is a moiety of Formula A as described above in
Formula P-A and P-B, wherein X, Y, Z, R.sub.3, R.sub.9, R.sub.11
and R.sub.12 are previously defined and R.sub.10 is C.sub.1-6alkoxy
(e.g., methoxy), [0723] aryl (e.g., phenyl) or heteroaryl (e.g.
pyridyl, for example, pyrid-2-yl) or wherein said aryl and
heteroaryl are independently and optionally substituted with one or
more halo (e.g., fluoro); [0724]
heteroC.sub.3-9cycloalkyl-C.sub.0-6alkyl (e.g., piperidinyl,
pyrrolidinyl, pyrrolidinylmethyl) wherein said heterocycloalkyl is
optionally substituted with one or more C.sub.1-6alkyl (e.g.,
methyl), for example, pyrrolidin-1-yl, pyrrolidin-2-yl,
1-methylpyrrolidin-2-yl, piperidin-2-yl, 1-methylpiperidin-2-yl,
1-ethylpiperidin-2-yl; [0725] (v) R.sub.4 is aryl (e.g., phenyl)
optionally substituted with one or more halo (e.g., F or Cl),
hydroxy and/or another aryl; [0726] (vi) R.sub.5 is H; [0727] (vii)
R.sub.6 is H, in free or salt form.
[0728] In still a further embodiment, the Compounds of the
Invention are the compounds of Formula P-A or P-B, wherein: [0729]
(i) X=0; [0730] (ii) R.sub.1 is methyl; [0731] (iii) R.sub.2 is
C.sub.1-6alkyl (e.g. isopropyl, isobutyl, 2-methylbutyl,
2,2-dimethyl propyl); [0732] (iv) R.sub.3 is a moiety of Formula A
as described above in Formula P-A and P-B, wherein X, Y, Z are C,
R.sub.8, R.sub.9, R.sub.11 and R.sub.12 are previously defined and
R.sub.10 is [0733] aryl (e.g., phenyl) or heteroaryl (e.g. pyridyl,
for example, pyrid-2-yl) or wherein said aryl and heteroaryl are
independently and optionally substituted with one or more halo
(e.g., fluoro); or [0734] heteroC.sub.3-9cycloalkyl-C.sub.0-6alkyl
(e.g., piperidinyl, pyrrolidinyl, pyrrolidinylmethyl) wherein said
heterocycloalkyl is optionally substituted with one or more
C.sub.1-6alkyl (e.g., methyl), for example, pyrrolidin-1-yl,
pyrrolidin-2-yl, 1-methylpyrrolidin-2-yl, piperidin-2-yl,
1-methylpiperidin-2-yl, 1-ethylpiperidin-2-yl; [0735] (v) R.sub.4
is phenyl optionally substituted with one or more halo (e.g., F or
Cl), hydroxy and/or another aryl; [0736] (vi) R.sub.5 is H; [0737]
(vii) R.sub.6 is H, in free or salt form.
[0738] If not otherwise specified or clear from context, the
following terms herein have the following meanings: [0739] (a)
"Alkyl" as used herein is a saturated or unsaturated hydrocarbon
moiety, preferably saturated, preferably having one to six carbon
atoms, which may be linear or branched, and may be optionally
mono-, di- or tri-substituted, e.g., with halogen (e.g., chloro or
fluoro), hydroxy, or carboxy. [0740] (b) "Cycloalkyl" as used
herein is a saturated or unsaturated nonaromatic hydrocarbon
moiety, preferably saturated, preferably comprising three to eight
carbon atoms, at least some of which form a nonaromatic mono- or
bicyclic, or bridged cyclic structure, and which may be optionally
substituted, e.g., with halogen (e.g., chloro or fluoro), hydroxy,
or carboxy. Wherein the cycloalkyl optionally contains one or more
atoms selected from N and O and/or S, said cycloalkyl may also be a
heterocycloalkyl. [0741] (c) "Heterocycloalkyl" is, unless
otherwise indicated, saturated or unsaturated nonaromatic
hydrocarbon moiety, preferably saturated, preferably comprising
three to nine carbon atoms, at least some of which form a
nonaromatic mono- or bicyclic, or bridged cyclic structure, wherein
at least one carbon atom is replaced with N, O or S, which
heterocycloalkyl may be optionally substituted, e.g., with halogen
(e.g., chloro or fluoro), hydroxy, or carboxy. [0742] (d) "Aryl" as
used herein is a mono or bicyclic aromatic hydrocarbon, preferably
phenyl, optionally substituted, e.g., with alkyl (e.g., methyl),
halogen (e.g., chloro or fluoro), haloalkyl (e.g.,
trifluoromethyl), hydroxy, carboxy, or an additional aryl or
heteroaryl (e.g., biphenyl or pyridylphenyl). [0743] (e)
"Heteroaryl" as used herein is an aromatic moiety wherein one or
more of the atoms making up the aromatic ring is sulfur or nitrogen
rather than carbon, e.g., pyridyl or thiadiazolyl, which may be
optionally substituted, e.g., with alkyl, halogen, haloalkyl,
hydroxy or carboxy. [0744] (f) Wherein E is phenylene, the
numbering is as follows:
[0744] ##STR00036## [0745] (g) It is intended that wherein the
substituents end in "ene", for example, alkylene, phenylene or
arylalkylene, said substitutents are intended to bridge or be
connected to two other substituents. Therefore, methylene is
intended to be --CH.sub.2-- and phenylene intended to be
--C.sub.6H.sub.4-- and arylalkylene is intended to be
--C.sub.6H.sub.4--CH.sub.2-- or --CH.sub.2--C.sub.6H.sub.4--.
[0746] (h) For ease of reference, the atoms on the
pyrolo-pyrimidine core of the Compounds of the Invention are
numbered in accordance with the numbering depicted below, unless
otherwise noted.
##STR00037##
[0747] Compounds of the Invention may exist in free or salt form,
e.g., as acid addition salts. In this specification unless
otherwise indicated, language such as "Compounds of the Invention"
is to be understood as embracing the compounds e.g., Compound of
Formula I, or any of 1.11.127, a Compound of Formula I(i) or I(ii),
a Compound of Formula II, e.g., any of 2.1-2.24, Formula P-A or
P-B, or any of 3.1-3.132, in any form, for example, in free or acid
addition salt form, or where the compounds contain acidic
substituents, in base addition salt form. The Compounds of the
Invention are intended for use as pharmaceuticals, therefore
pharmaceutically acceptable salts are preferred. Salts which are
unsuitable for pharmaceutical uses may be useful, for example, for
the isolation or purification of free Compounds of the Invention or
their pharmaceutically acceptable salts, are therefore also
included.
[0748] Compounds of the Invention may in some cases also exist in
prodrug form. A prodrug form is compound which converts in the body
to a Compound of the Invention. For example, when the Compounds of
the Invention contain hydroxy or carboxy substituents, these
substituents may form physiologically hydrolysable and acceptable
esters. As used herein, "physiologically hydrolysable and
acceptable ester" means esters of Compounds of the Invention which
are hydrolysable under physiological conditions to yield acids (in
the case of Compounds of the Invention which have hydroxy
substituents) or alcohols (in the case of Compounds of the
Invention which have carboxy substituents) which are themselves
physiologically tolerable at doses to be administered.
[0749] Therefore, wherein the Compound of the Invention contains a
hydroxy group, for example, Compound-OH, the acyl ester prodrug of
such compound, i.e., Compound-O--C(O)--C.sub.1-4alkyl, can
hydrolyze in the body to form physiologically hydrolysable alcohol
(Compound-OH) on the one hand and acid on the other (e.g.,
HOC(O)--C.sub.1-4alkyl). Alternatively, wherein the Compound of the
Invention contains a carboxylic acid, for example, Compound-C(O)OH,
the acid ester prodrug of such compound,
Compound-C(O)O--C.sub.1-4alkyl can hydrolyze to form
Compound-C(O)OH and HO--C.sub.1-4alkyl. As will be appreciated, the
term thus embraces conventional pharmaceutical prodrug forms.
[0750] The invention also provides methods of making the Compounds
of the Invention and methods of using the Compounds of the
Invention for treatment of diseases and disorders as set forth
below (especially treatment of diseases characterized by reduced
dopamine D1 receptor signaling activity, such as Parkinson's
disease, Tourette's Syndrome, Autism, fragile X syndrome, ADHD,
restless leg syndrome, depression, cognitive impairment of
schizophrenia, narcolepsy and diseases that may be alleviated by
the enhancement of progesterone-signaling such as female sexual
dysfunction), or a disease or disorder such as psychosis or
glaucoma). This list is not intended to be exhaustive and may
include other diseases and disorders as set forth below.
[0751] In another embodiment, the invention further provides a
pharmaceutical composition comprising a Compound of the Invention,
e.g., a Compound of Formula I, or any of 1.11.127, or a Compound of
Formula I(i) or in free or pharmaceutically acceptable salt form,
in admixture with a pharmaceutically acceptable carrier. In another
embodiment, the invention further provides a pharmaceutical
composition comprising a Compound of the Invention, e.g., a
Compound of Formula II, or any of 2.1-2.24, Formula P-A or P-B, or
any of 3.1-3.132, in free or pharmaceutically acceptable salt form,
in admixture with a pharmaceutically acceptable carrier.
DETAILED DESCRIPTION OF THE INVENTION
Methods of Making Compounds of the Invention
[0752] The Compounds of the Invention and their pharmaceutically
acceptable salts may be made using the methods as described and
exemplified herein and by methods similar thereto and by methods
known in the chemical art. Such methods include, but not limited
to, those described below. If not commercially available, starting
materials for these processes may be made by procedures, which are
selected from the chemical art using techniques which are similar
or analogous to the synthesis of known compounds. In particular,
the intermediates and starting materials for the Compounds of the
Invention may be prepared by methods and processes as described in
PCT/US2007/070551. All references cited herein are hereby
incorporated by reference in their entirety.
[0753] The Compounds of the Invention include their enantiomers,
diastereoisomers, tautomers and racemates, as well as their
polymorphs, hydrates, solvates and complexes. Some individual
compounds within the scope of this invention may contain double
bonds. Representations of double bonds in this invention are meant
to include both the E and the Z isomer of the double bond. In
addition, some compounds within the scope of this invention may
contain one or more asymmetric centers. This invention includes the
use of any of the optically pure stereoisomers as well as any
combination of stereoisomers.
[0754] It is also intended that the Compounds of the Invention
encompass their stable and unstable isotopes. Stable isotopes are
nonradioactive isotopes which contain one additional neutron
compared to the abundant nuclides of the same species (i.e.,
element). It is expected that the activity of compounds comprising
such isotopes would be retained, and such compound would also have
utility for measuring pharmacokinetics of the non-isotopic analogs.
For example, the hydrogen atom at a certain position on the
Compounds of the Invention may be replaced with deuterium (a stable
isotope which is non-raradioactive). Examples of known stable
isotopes include, but not limited to, deuterium, .sup.13C,
.sup.15N, .sup.18O. Alternatively, unstable isotopes, which are
radioactive isotopes which contain additional neutrons compared to
the abundant nuclides of the same species (i.e., element), e.g.,
.sup.123I, .sup.131I, .sup.125I, .sup.11C, .sup.18F, may replace
the corresponding abundant species of I, C and F. Another example
of useful isotope of the compound of the invention is the .sup.11C
isotope. These radio isotopes are useful for radio-imaging and/or
pharmacokinetic studies of the compounds of the invention.
[0755] Melting points are uncorrected and (dec) indicates
decomposition. Temperature are given in degrees Celsius (.degree.
C.); unless otherwise stated, operations are carried out at room or
ambient temperature, that is, at a temperature in the range of
18-25.degree. C. Chromatography means flash chromatography on
silica gel; thin layer chromatography (TLC) is carried out on
silica gel plates. NMR data is in the delta values of major
diagnostic protons, given in parts per million (ppm) relative to
tetramethylsilane (TMS) as an internal standard. Conventional
abbreviations for signal shape are used. Coupling constants (J) are
given in Hz. For mass spectra (MS), the lowest mass major ion is
reported for molecules where isotope splitting results in multiple
mass spectral peaks Solvent mixture compositions are given as
volume percentages or volume ratios. In cases where the NMR spectra
are complex, only diagnostic signals are reported.
TERMS AND ABBREVIATIONS
[0756] BuLi=n-butyllithium
[0757] Bu.sup.tOH=tert-butyl alcohol,
[0758] CAN=ammonium cerium (IV) nitrate,
[0759] DIPEA=diisopropylethylamine,
[0760] DMF=N,N-dimethylforamide,
[0761] DMSO=dimethyl sulfoxide,
[0762] Et.sub.2O=diethyl ether,
[0763] EtOAc=ethyl acetate,
[0764] equiv.=equivalent(s),
[0765] h=hour(s),
[0766] HPLC=high performance liquid chromatography,
[0767] LDA=lithium diisopropylamide
[0768] MeOH=methanol,
[0769] NBS=N-bromosuccinimide
[0770] NCS=N-chlorosuccinimide
[0771] NaHCO.sub.3=sodium bicarbonate,
[0772] NH.sub.4OH=ammonium hydroxide,
[0773]
Pd.sub.2(dba).sub.3=tris[dibenzylideneacetone]dipalladium(0)
[0774] PMB=p-methoxybenzyl,
[0775] POCl.sub.3=phosphorous oxychloride,
[0776] SOCl.sub.2=thionyl chloride,
[0777] TFA=trifluoroacetic acid,
[0778] THF=tetrahedrofuran.
[0779] The synthetic methods in this invention are illustrated
below. The significances for the R groups are as set forth above
for formula I unless otherwise indicated.
[0780] In an aspect of the invention, compounds (I)-A and (I)-B may
be formed by reacting a compound of 1-A and 1-B respectively with
for example a R.sub.3--X in a solvent such as DMF and a base such
as K.sub.2CO.sub.3 or cesium carbonate at room temperature or with
heating:
##STR00038##
wherein all the substitutents are as defined previously; X is a
leaving group such as a halogen, mesylate, or tosylate.
[0781] Alternatively, compounds (I)-A and (I)-B may be synthesized
by reacting a compound of 1-C and 1-D respectively with for example
a R.sub.4R.sub.5NH in a solvent such as DMF or in neat condition
with heating. 1-C or 1-D can react with R.sub.4NH.sub.2 at first to
give 1-E or 1-F, and then 1-E or 1-F may react with R.sub.5--X to
give (I)-A or (I)-B.
##STR00039## ##STR00040##
wherein all the substituents are as defined previously; X is a
leaving group such as a halogen group.
[0782] Compound 1-C, e.g., wherein Q is C(.dbd.O) and X is a chloro
group, may be prepared by, e.g., reacting compound 1-G with a
chlorinating reagent such as hexachloroethane in the presence of a
strong base or lithium reagent such as LiHMDS. Compound 1-D, e.g.,
wherein Q is C(.dbd.O) and X is a chloro group, may be prepared by,
e.g., reacting compound 1-H with a chlorinating reagent such NCS in
a solvent such as CCl.sub.4. Sometimes, R.sub.3 can be a protective
group such as a para-methoxybenzyl (PMB) group. Under this
circumstance, compound 1-C or 1-D with the PMB substituent as
R.sub.3 can be deprotected using a reagent such as TFA/TFMSA, and
then reacts with a different R.sub.3-L under basic conditions for
rapidly synthesizing 1-C or 1-D analogs.
##STR00041##
[0783] Compounds (I)-G and (I)-H may be formed by reacting a
compound of (I)-I and (I)-J respectively with for example a
R.sub.3-L in a solvent such as DMF and a base such as
K.sub.2CO.sub.3 at room temperature or with heating:
##STR00042##
wherein all the substituents are as defined previously; L is a
leaving group such as a halogen group.
[0784] (1,3-optionally
substituted)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione cores,
e.g., Intermediate 2, may be prepared by reacting (1,3-optionally
substituted)-pyrimidine-2,4-dione, e.g., Intermediate 1, e.g., with
sodium hydride and para-toluenesulfonylmethyl isocyanide.
##STR00043##
[0785] Alternatively, (1,3-optionally
substituted)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione cores,
e.g., Intermediate 2 wherein Q is C(.dbd.O), may be prepared by
reacting (1,3-optionally substituted)-pyrimidine-2,4-dione, e.g.,
Intermediate 1, e.g., with a strong base such as sodium hydride and
a reagent such as TsCHR.sub.6NC in a solvent such as THF.
Alternatively, intermediate 1 may react with
para-toluenesulfonylmethyl isocyanide to construct the pyrrole
ring, and the substituent R.sub.6 may introduced at later
steps.
##STR00044##
[0786] Intermediate 3-A and 3-B may be formed by reacting compound
2-A and 2-B with for example a R.sub.3--X in a solvent such as DMF
and a base such as K.sub.2CO.sub.3 or cesium carbonate at room
temperature or with heating.
##STR00045##
[0787] Compound 4-A and 4-B, wherein X is halo, e.g., Cl, Br or I,
may be prepared by halogenating compound 3-A and 3-B. For example,
compound 4-A may be formed by reacting Compound 3-A with, e.g.,
N-chlorosuccinimide (NCS), hexachloroethane, N-bromosuccinimide
(NBS), N-iodosuccinimide (NIS) or I.sub.2 in a solvent such as THF
and a base such as LiHMDS, LDA or BuLi at room or low temperature.
Compound 4-B may be prepared by, e.g., reacting compound 3-B with a
chlorinating reagent such NCS in a solvent such as CCl.sub.4.
##STR00046##
[0788] Compound (I)-A and (I)-B wherein Q is C(.dbd.O) may then be
prepared by reacting a compound of 4-A and 4-B respectively with,
for example an HN(R.sub.4)(R.sub.5) at elevated temperature. The
reaction may be accelerated by adding a catalytic amount of acid
such as trichloroacetic acid (TCA).
##STR00047##
[0789] Alternatively, Compound 5-A or 5-B may be formed by the
amination of 4-A or 4-B with R.sub.4NH.sub.2 or R.sub.5NH.sub.2 to
give IIIc or IVd under basic conditions upon heating, and then IIIc
or IVd may react with R.sub.5-L or R.sub.4-L under basic conditions
to give compound 5-A or 5-B.
##STR00048##
wherein all the substituents are as defined previously; L is a
leaving group such as a halogen group. Compound 5-A or 5-B may also
be synthesized from protected intermediate 6-A or 6-B. After
deprotection, the obtained intermediate 7-A or 7-B can react with
R.sub.2-L in a solvent such as DMF and a base such as
K.sub.2CO.sub.3 at room temperature or with heating to give
compound 5-A or 5-B.
##STR00049##
wherein all the substituents are as defined previously; L is a
leaving group such as a halogen group; P.sub.2 is a protective
group, such as para-methoxy benzyl (PMB) group.
[0790] The 4-thioxo Compounds of the invention, e.g., Compounds of
Formula (I) wherein Q is C(.dbd.S) may then be prepared by reacting
compound 5-A or 5-B with P.sub.4S.sub.10 in a microwave vial in the
presence of a base, e.g., pyridine, and heating the mixture to an
elevated temperature, e.g., in a microwave, e.g., to about
150.degree. C. The invention thus provides methods of making a
4-thioxo Compound of the Invention, Compound of Formula (I) wherein
Q of is C(.dbd.S) as hereinbefore described, for example,
comprising reacting an optionally substituted
3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-2(6H)-one of Formula I with
P.sub.4S.sub.10 in the presence of a base, e.g., pyridine, and
heating the reaction mixture to an elevated temperature, e.g., to
>50.degree. C., e.g., >100.degree. C., e.g., >150.degree.
C., for example, in a microwave to about 150.degree. C.
[0791] The 4-imino Compounds of the Invention, e.g., Compounds of
Formula (I) wherein Q is C(.dbd.N(R.sub.6)) or Formula II wherein Q
is C(.dbd.N(R.sub.7)) may in turn be converted from the 4-thioxo
derivative (i.e., Compounds of Formula (I) wherein with Q is
X(.dbd.S) by reacting the 4-thioxo derivative with
NH.sub.2(R.sub.6) or Formula II wherein Q is C(.dbd.N(R.sub.7)) in
the presence of HgCl.sub.2, e.g., in a solvent such as THF, and
heating the reaction mixture to an elevated temperature, e.g., in a
microwave, e.g., to about 110.degree. C. The invention also
provides methods of making 4-imino Compounds of the Invention,
e.g., Compounds of Formula I, wherein Q of Formula I is
C(.dbd.N(R.sub.6)) or Formula II wherein Q is C(.dbd.N(R.sub.7)) as
hereinbefore described, for example, comprising reacting a the
Compound of Formula I wherein Q is C(.dbd.S), with
NH.sub.2(R.sub.6) or Formula II wherein Q is C(.dbd.N(R.sub.7)) in
the presence of HgCl.sub.2, e.g., in a solvent such as THF, and
heating the reaction mixture in a microwave, e.g., to
>50.degree. C., e.g., >75.degree. C., e.g., >100.degree.
C., for example, in a microwave to about 110.degree. C.
[0792] The Compounds of the Invention, e.g., Compounds of Formula
(I) wherein Q is CH.sub.2 may also be prepared by reacting compound
5-A or 5-B with a reducing agent, e.g., diisobutylaluminum hydride
(DIBAL-H), lithium aluminum hydride, sodium borohydride,
preferably, DIBAL-H. The invention therefore provides methods of
making the Compounds of the Invention, e.g., Compounds of Formula
I, wherein Q is CH.sub.2 comprising reacting compound 5-A or 5-B
with a reducing agent, e.g., diisobutylaluminum hydride (DIBAL-H),
lithium aluminum hydride, sodium borohydride, preferably,
DIBAL-H.
Methods of Using Compounds of the Invention
[0793] The Compounds of the Invention are useful in the treatment
of diseases characterized by disruption of or damage to cAMP and
cGMP mediated pathways, e.g., as a result of increased expression
of PDE1 or decreased expression of cAMP and cGMP due to inhibition
or reduced levels of inducers of cyclic nucleotide synthesis, such
as dopamine and nitric oxide (NO). By preventing the degradation of
cAMP and cGMP by PDE1B, thereby increasing intracellular levels of
cAMP and cGMP, the Compounds of the Invention potentiate the
activity of cyclic nucleotide synthesis inducers.
[0794] The invention provides methods of treatment of any one or
more of the following conditions: [0795] (i) Neurodegenerative
diseases, including Parkinson's disease, restless leg, tremors,
dyskinesias, Huntington's disease, Alzheimer's disease, and
drug-induced movement disorders; [0796] (ii) Mental disorders,
including depression, attention deficit disorder, attention deficit
hyperactivity disorder, bipolar illness, anxiety, sleep disorders,
e.g., narcolepsy, cognitive impairment, dementia, Tourette's
syndrome, autism, fragile X syndrome, psychostimulant withdrawal,
and drug addiction; [0797] (iii) Circulatory and cardiovascular
disorders, including cerebrovascular disease, stroke, congestive
heart disease, hypertension, pulmonary hypertension, and sexual
dysfunction; [0798] (iv) Respiratory and inflammatory disorders,
including asthma, chronic obstructive pulmonary disease, and
allergic rhinitis, as well as autoimmune and inflammatory diseases;
[0799] (v) Any disease or condition characterized by low levels of
cAMP and/or cGMP (or inhibition of cAMP and/or cGMP signaling
pathways) in cells expressing PDE1; and/or [0800] (vi) Any disease
or condition characterized by reduced dopamine D1 receptor
signaling activity, comprising administering an effective amount of
a Compound of the Invention, e.g., a compound according to any of
Formula I or 1-1.127, or a composition comprising a Compound of the
Invention, e.g., a compound according to any of Formula I or
1-1.127, to a human or animal patient in need thereof. In another
aspect, the invention provides a method of treatment of the
conditions disclosed above comprising administering a
therapeutically effective amount of a Compound of Formula II, or
any of 2.1-2.24, Formula P-A or P-B, or any of 3.1-3.132, as
hereinbefore described, in free or pharmaceutically acceptable salt
form, to a human or animal patient in need thereof.
[0801] In an especially preferred embodiment, the invention
provides methods of treatment or prophylaxis for narcolepsy. In
this embodiment, PDE1 Inhibitors may be used as a sole therapeutic
agent, but may also be used in combination or for co-administration
with other active agents. Thus, the invention further comprises a
method of treating narcolepsy comprising administering
simultaneously, sequentially, or contemporaneously administering
therapeutically effective amounts of [0802] (i) a PDE 1 Inhibitor
of the Invention, e.g., a compound according to any of Formula I or
1.1-1.127, or I(i) or I(ii); and [0803] (ii) a compound to promote
wakefulness or regulate sleep, e.g., selected from (a) central
nervous system stimulants-amphetamines and amphetamine like
compounds, e.g., methylphenidate, dextroamphetamine,
methamphetamine, and pemoline; (b) modafinil, (c) antidepressants,
e.g., tricyclics (including imipramine, desipramine, clomipramine,
and protriptyline) and selective serotonin reuptake inhibitors
(including fluoxetine and sertraline); and/or (d) gamma
hydroxybutyrate (GHB), in free or pharmaceutically acceptable salt
form, to a human or animal patient in need thereof. In another
embodiment, the invention provides methods of treatment or
prophylaxis for narcolepsy as herein before described, wherein the
PDE1 inhibitor is in a form of a pharmaceutical composition. In
still another embodiment, the methods of treatment or prophylaxis
for narcolepsy as hereinbefore described, comprises administering a
therapeutically effective amount of a Compound of Formula II, or
any of 2.1-2.24, Formula P-A or P-B, or any of 3.1-3.132 as
hereinbefore described, in free or pharmaceutically acceptable salt
form, as a sole therapeutic agent or use in combination for
co-administered with another active agent.
[0804] In another embodiment, the invention further provides
methods of treatment or prophylaxis of a condition which may be
alleviated by the enhancement of the progesterone signaling
comprising administering an effective amount of a Compound of the
Invention, e.g., a compound according to any of Formula 1-1.127 or
Formula I, I(i) or I(ii) in free or pharmaceutically acceptable
salt form, to a human or animal patient in need thereof. The
invention also provides methods of treatment as disclosed here,
comprising administering a therapeutically effective amount of a
Compound of Formula H, or any of 2.1-2.24, Formula P-A or P-B, or
any of 3.1-3.132 as hereinbefore described, in free or
pharmaceutically acceptable salt form. Disease or condition that
may be ameliorated by enhancement of progesterone signaling
include, but are not limited to, female sexual dysfunction,
secondary amenorrhea (e.g., exercise amenorrhoea, anovulation,
menopause, menopausal symptoms, hypothyroidism), pre-menstrual
syndrome, premature labor, infertility, for example infertility due
to repeated miscarriage, irregular menstrual cycles, abnormal
uterine bleeding, osteoporosis, autoimmmune disease, multiple
sclerosis, prostate enlargement, prostate cancer, and
hypothyroidism. For example, by enhancing progesterone signaling,
the PDE 1 inhibitors may be used to encourage egg implantation
through effects on the lining of uterus, and to help maintain
pregnancy in women who are prone to miscarriage due to immune
response to pregnancy or low progesterone function. The novel PDE 1
inhibitors, e.g., as described herein, may also be useful to
enhance the effectiveness of hormone replacement therapy, e.g.,
administered in combination with estrogen/estradiol/estriol and/or
progesterone/progestins in postmenopausal women, and
estrogen-induced endometrial hyperplasia and carcinoma. The methods
of the invention are also useful for animal breeding, for example
to induce sexual receptivity and/or estrus in a nonhuman female
mammal to be bred.
[0805] In this embodiment, PDE 1 Inhibitors may be used in the
foregoing methods of treatment or prophylaxis as a sole therapeutic
agent, but may also be used in combination or for co-administration
with other active agents, for example in conjunction with hormone
replacement therapy. Thus, the invention further comprises a method
of treating disorders that may be ameliorated by enhancement of
progesterone signaling comprising administering simultaneously,
sequentially, or contemporaneously administering therapeutically
effective amounts of [0806] (i) a PDE 1 Inhibitor, e.g., a compound
according to any of Formula 1.1-1.127 or Formula I, and [0807] (ii)
a hormone, e.g., selected from estrogen and estrogen analogues
(e.g., estradiol, estriol, estradiol esters) and progesterone and
progesterone analogues (e.g., progestins) in free or
pharmaceutically acceptable salt form, to a human or animal patient
in need thereof. In another embodiment, the invention provides the
method described above wherein the PDE 1 inhibitor is a Compound of
Formula II, or any of 2.1-2.24, Formula P-A or P-B, or any of
3.1-3.132 as hereinbefore described, in free or pharmaceutically
acceptable salt form.
[0808] The invention also provides a method for enhancing or
potentiating dopamine D1 intracellular signaling activity in a cell
or tissue comprising contacting said cell or tissue with an amount
of a Compound of the Invention sufficient to inhibit PDE activity.
The invention further provides a method for enhancing or
potentiating dopamine D1 intracellular signaling activity in a cell
or tissue comprising contacting said cell or tissue with an amount
of a Compound of Formula II, or any of 2.1-2.24, Formula P-A or
P-B, or any of 3.1-3.132 as hereinbefore described, in free or salt
form, sufficient to inhibit PDE1 activity, e.g., PDE1A or PDE1B
activity.
[0809] The invention also provides a method for enhancing or
potentiating progesterone signaling activity in a cell or tissue
comprising contacting said cell or tissue with an amount of a
Compound of the Invention sufficient to inhibit PDE1B activity.
[0810] The invention also provides a method for treating a
PDE1-related, especially PDE1B-related disorder, a dopamine D1
receptor intracellular signaling pathway disorder, or disorders
that may be alleviated by the enhancement of the progesterone
signaling pathway in a patient in need thereof comprising
administering to the patient an effective amount of a Compound of
the Invention that inhibits PDE1B, wherein PDE1B activity modulates
phosphorylation of DARPP-32 and/or the GluR1 AMPA receptor.
Similarly, the invention provides a method for treating a
PDE1-related, especially PDE1B-related disorder, a dopamine D1
receptor intracellular signaling pathway disorder, or disorders
that may be alleviated by the enhancement of the progesterone
signaling pathway in a patient in need thereof comprising
administering to the patient an effective amount of a Compound of
Formula II or any of 2.1-2.24, Formula P-A or P-B, or any of
3.1-3.132 as hereinbefore described, in free or pharmaceutically
acceptable salt form.
[0811] In another aspect, the invention also provides a method for
the treatment for glaucoma or elevated intraocular pressure
comprising topical administration of a therapeutically effective
amount of a phospodiesterase type I (PDE1) Inhibitor of the
Invention, in free or pharmaceutically acceptable salt form, in an
opthalmically compatible carrier to the eye of a patient in need
thereof. However, treatment may alternatively include a systemic
therapy. Systemic therapy includes treatment that can directly
reach the bloodstream, or oral methods of administration, for
example.
[0812] The invention further provides a pharmaceutical composition
for topical ophthalmic use comprising a PDE1 inhibitor; for example
an ophthalmic solution, suspension, cream or ointment comprising a
PDE1 Inhibitor of the Invention, in free or ophthamalogically
acceptable salt form, in combination or association with an
ophthamologically acceptable diluent or carrier.
[0813] Optionally, the PDE1 inhibitor may be administered
sequentially or simultaneously with a second drug useful for
treatment of glaucoma or elevated intraocular pressure. Where two
active agents are administered, the therapeutically effective
amount of each agent may be below the amount needed for activity as
monotherapy. Accordingly, a subthreshold amount (i.e., an amount
below the level necessary for efficacy as monotherapy) may be
considered therapeutically effective and also may also be referred
alternatively as an effective amount. Indeed, an advantage of
administering different agents with different mechanisms of action
and different side effect profiles may be to reduce the dosage and
side effects of either or both agents, as well as to enhance or
potentiate their activity as monotherapy.
[0814] The invention thus provides the method of treatment of a
condition selected from glaucoma and elevated intraocular pressure
comprising administering to a patient in need thereof an effective
amount, e.g., a subthreshold amount, of an agent known to lower
intraocular pressure concomitantly, simultaneously or sequentially
with an effective amount, e.g., a subthreshold amount, of a PDE1
Inhibitor of the Invention, in free or pharmaceutically acceptable
salt form, such that amount of the agent known to lower intraocular
pressure and the amount of the PDE1 inhibitor in combination are
effective to treat the condition.
[0815] In one embodiment, one or both of the agents are
administered topically to the eye. Thus the invention provides a
method of reducing the side effects of treatment of glaucoma or
elevated intraocular pressure by administering a reduced dose of an
agent known to lower intraocular pressure concomitantly,
simultaneously or sequentially with an effective amount of a PDE1
inhibitor. However, methods other than topical administration, such
as systemic therapeutic administration, may also be utilized.
[0816] The optional additional agent or agents for use in
combination with a PDE1 inhibitor may, for example, be selected
from the existing drugs comprise typically of instillation of a
prostaglandin, pilocarpine, epinephrine, or topical beta-blocker
treatment, e.g. with timolol, as well as systemically administered
inhibitors of carbonic anhydrase, e.g. acetazolamide.
Cholinesterase inhibitors such as physostigmine and echothiopate
may also be employed and have an effect similar to that of
pilocarpine. Drugs currently used to treat glaucoma thus include,
e.g., [0817] 1. Prostaglandin analogs such as latanoprost
(Xalatan), bimatoprost (Lumigan) and travoprost (Travatan), which
increase uveoscleral outflow of aqueous humor. Bimatoprost also
increases trabecular outflow. [0818] 2. Topical beta-adrenergic
receptor antagonists such as timolol, levobunolol (Betagan), and
betaxolol, which decrease aqueous humor production by the ciliary
body. [0819] 3. Alpha.sub.2-adrenergic agonists such as brimonidine
(Alphagan), which work by a dual mechanism, decreasing aqueous
production and increasing uveo-scleral outflow. [0820] 4.
Less-selective sympathomimetics like epinephrine and dipivefrin
(Propine) increase outflow of aqueous humor through trabecular
meshwork and possibly through uveoscleral outflow pathway, probably
by a beta.sub.2-agonist action. [0821] 5. Miotic agents
(parasympathomimetics) like pilocarpine work by contraction of the
ciliary muscle, tightening the trabecular meshwork and allowing
increased outflow of the aqueous humour. [0822] 6. Carbonic
anhydrase inhibitors like dorzolamide (Trusopt), brinzolamide
(Azopt), acetazolamide (Diamox) lower secretion of aqueous humor by
inhibiting carbonic anhydrase in the ciliary body. [0823] 7.
Physostigmine is also used to treat glaucoma and delayed gastric
emptying.
[0824] For example, the invention provides pharmaceutical
compositions comprising a PDE1 Inhibitor of the Invention and an
agent selected from (i) the prostanoids, unoprostone, latanoprost,
travoprost, or bimatoprost; (ii) an alpha adrenergic agonist such
as brimonidine, apraclonidine, or dipivefrin and (iii) a muscarinic
agonist, such as pilocarpine. For example, the invention provides
ophthalmic formulations comprising a PDE-1 Inhibitor of the
Invention together with bimatoprost, abrimonidine, brimonidine,
timolol, or combinations thereof, in free or ophthamalogically
acceptable salt form, in combination or association with an
ophthamologically acceptable diluent or carrier. In addition to
selecting a combination, however, a person of ordinary skill in the
art can select an appropriate selective receptor subtype agonist or
antagonist. For example, for alpha adrenergic agonist, one can
select an agonist selective for an alpha 1 adrenergic receptor, or
an agonist selective for an alpha.sub.2 adrenergic receptor such as
brimonidine, for example. For a beta-adrenergic receptor
antagonist, one can select an antagonist selective for either
.beta..sub.1, or .beta..sub.2, or .beta..sub.3, depending on the
appropriate therapeutic application. One can also select a
muscarinic agonist selective for a particular receptor subtype such
as M.sub.1-M.sub.5.
[0825] The PDE 1 inhibitor may be administered in the form of an
ophthalmic composition, which includes an ophthalmic solution,
cream or ointment. The ophthalmic composition may additionally
include an intraocular-pressure lowering agent.
[0826] In yet another example, the PDE-1 Inhibitors disclosed may
be combined with a subthreshold amount of an intraocular
pressure-lowering agent which may be a bimatoprost ophthalmic
solution, a brimonidine tartrate ophthalmic solution, or
brimonidine tartrate/timolol maleate ophthalmic solution.
[0827] In addition to the above-mentioned methods, it has also been
surprisingly discovered that PDE1 inhibitors are useful to treat
psychosis, for example, any conditions characterized by psychotic
symptoms such as hallucinations, paranoid or bizarre delusions, or
disorganized speech and thinking, e.g., schizophrenia,
schizoaffective disorder, schizophreniform disorder, psychotic
disorder, delusional disorder, and mania, such as in acute manic
episodes and bipolar disorder. Without intending to be bound by any
theory, it is believed that typical and atypical antipsychotic
drugs such as clozapine primarily have their antagonistic activity
at the dopamine D2 receptor. PDE1 inhibitors, however, primarily
act to enhance signaling at the dopamine D1 receptor. By enhancing
D1 receptor signaling, PDE1 inhibitors can increase NMDA receptor
function in various brain regions, for example in nucleus accumbens
neurons and in the prefrontal cortex. This enhancement of function
may be seen for example in NMDA receptors containing the NR2B
subunit, and may occur e.g., via activation of the Src and protein
kinase A family of kinases.
[0828] Therefore, the invention provides a new method for the
treatment of psychosis, e.g., schizophrenia, schizoaffective
disorder, schizophreniform disorder, psychotic disorder, delusional
disorder, and mania, such as in acute manic episodes and bipolar
disorder, comprising administering a therapeutically effective
amount of a phosphodiesterase-1 (PDE1) Inhibitor of the Invention,
in free or pharmaceutically acceptable salt form, to a patient in
need thereof.
[0829] PDE 1 Inhibitors may be used in the foregoing methods of
treatment prophylaxis as a sole therapeutic agent, but may also be
used in combination or for co-administration with other active
agents. Thus, the invention further comprises a method of treating
psychosis, e.g., schizophrenia, schizoaffective disorder,
schizophreniform disorder, psychotic disorder, delusional disorder,
or mania, comprising administering simultaneously, sequentially, or
contemporaneously administering therapeutically effective amounts
of: [0830] (i) a PDE 1 Inhibitor of the invention, in free or
pharmaceutically acceptable salt form; and [0831] (ii) an
antipsychotic, e.g., [0832] Typical antipsychotics, e.g., [0833]
Butyrophenones, e.g. Haloperidol (Haldol, Serenace), Droperidol
(Droleptan); [0834] Phenothiazines, e.g., Chlorpromazine
(Thorazine, Largactil), Fluphenazine (Prolixin), Perphenazine
(Trilafon), Prochlorperazine (Compazine), Thioridazine (Mellaril,
Melleril), Trifluoperazine (Stelazine), Mesoridazine, Periciazine,
Promazine, Triflupromazine (Vesprin), Levomepromazine (Nozinan),
Promethazine (Phenergan), Pimozide (Orap); [0835] Thioxanthenes,
e.g., Chlorprothixene, Flupenthixol (Depixol, Fluanxol),
Thiothixene (Navane), Zuclopenthixol (Clopixol, Acuphase); [0836]
Atypical antipsychotics, e.g., [0837] Clozapine (Clozaril),
Olanzapine (Zyprexa), Risperidone (Risperdal), Quetiapine
(Seroquel), Ziprasidone (Geodon), Amisulpride (Solian),
Paliperidone (Invega), Aripiprazole (Abilify), Bifeprunox;
norclozapine,
[0838] in free or pharmaceutically acceptable salt form, to a
patient in need thereof.
[0839] In a particular embodiment, the Compounds of the Invention
are particularly useful for the treatment or prophylaxis of
schizophrenia.
[0840] Compounds of the Invention, in free or pharmaceutically
acceptable salt form, are particularly useful for the treatment of
Parkinson's disease, schizophrenia, narcolepsy, glaucoma and female
sexual dysfunction.
[0841] In still another aspect, the invention provides a method of
lengthening or enhancing growth of the eyelashes by administering
an effective amount of a prostaglandin analogue, e.g., bimatoprost,
concomitantly, simultaneously or sequentially with an effective
amount of a PDE1 inhibitor of the Invention, in free or
pharmaceutically acceptable salt form, to the eye of a patient in
need thereof.
[0842] In yet another aspect, the invention provides a method for
the treatment or prophylaxis of traumatic brain injury comprising
administering a therapeutically effective amount of a PDE1
inhibitor of the invention, in free or pharmaceutically acceptable
salt form, to a patient in need thereof. Traumatic brain injury
(TBI) encompasses primary injury as well as secondary injury,
including both focal and diffuse brain injuries. Secondary injuries
are multiple, parallel, interacting and interdependent cascades of
biological reactions arising from discrete subcellular processes
(e.g., toxicity due to reactive oxygen species, overstimulation of
glutamate receptors, excessive influx of calcium and inflammatory
upregulation) which are caused or exacerbated by the inflammatory
response and progress after the initial (primary) injury. Abnormal
calcium homeostasis is believed to be a critical component of the
progression of secondary injury in both grey and white matter. For
a review of TBI, see Park et al., CMAJ (2008) 178(9):1163-1170, the
contents of which are incorporated herein in their entirety.
Studies have shown that the cAMP-PKA signaling cascade is
down-regulated after TBI and treatment of PDE IV inhibitors such as
rolipram to raise or restore cAMP level improves histopathological
outcome and decreases inflammation after TBI. As Compounds of the
present invention is a PDE1 inhibitor useful for modulating cAMP
and/or calcium levels, it is believed that these compounds are also
useful for the treatment of TBI, e.g., by restoring cAMP level
and/or calcium homeostasis after traumatic brain injury.
[0843] The present invention also provides [0844] (i) a Compound of
the Invention for use as a pharmaceutical, for example for use in
any method or in the treatment of any disease or condition as
hereinbefore set forth, [0845] (ii) the use of a Compound of the
Invention in the manufacture of a medicament for treating any
disease or condition as hereinbefore set forth, [0846] (iii) a
pharmaceutical composition comprising a Compound of the Invention
in combination or association with a pharmaceutically acceptable
diluent or carrier, and [0847] (iv) a pharmaceutical composition
comprising a Compound of the Invention in combination or
association with a pharmaceutically acceptable diluent or carrier
for use in the treatment of any disease or condition as
hereinbefore set forth.
[0848] Therefore, the invention provides use of a Compound of the
Invention for the manufacture of a medicament for the treatment or
prophylactic treatment of the following diseases: Parkinson's
disease, restless leg, tremors, dyskinesias, Huntington's disease,
Alzheimer's disease, and drug-induced movement disorders;
depression, attention deficit disorder, attention deficit
hyperactivity disorder, bipolar illness, anxiety, sleep disorder,
narcolepsy, cognitive impairment, dementia, Tourette's syndrome,
autism, fragile X syndrome, psychostimulant withdrawal, and/or drug
addiction; cerebrovascular disease, stroke, congestive heart
disease, hypertension, pulmonary hypertension, and/or sexual
dysfunction; asthma, chronic obstructive pulmonary disease, and/or
allergic rhinitis, as well as autoimmune and inflammatory diseases;
and/or female sexual dysfunction, exercise amenorrhoea,
anovulation, menopause, menopausal symptoms, hypothyroidism,
pre-menstrual syndrome, premature labor, infertility, irregular
menstrual cycles, abnormal uterine bleeding, osteoporosis, multiple
sclerosis, prostate enlargement, prostate cancer, hypothyroidism,
estrogen-induced endometrial hyperplasia or carcinoma; and/or any
disease or condition characterized by low levels of cAMP and/or
cGMP (or inhibition of cAMP and/or cGMP signaling pathways) in
cells expressing PDE1, and/or by reduced dopamine D1 receptor
signaling activity; and/or any disease or condition that may be
ameliorated by the enhancement of progesterone signaling.
[0849] The invention also provides use of a Compound of the
Invention, in free or pharmaceutically acceptable salt form, for
the manufacture of a medicament for the treatment or prophylactic
treatment of: [0850] a) glaucoma or elevated intraocular pressure,
[0851] b) psychosis, for example, any conditions characterized by
psychotic symptoms such as hallucinations, paranoid or bizarre
delusions, or disorganized speech and thinking, e.g.,
schizophrenia, schizoaffective disorder, schizophreniform disorder,
psychotic disorder, delusional disorder, and mania, such as in
acute manic episodes and bipolar disorder, [0852] c) traumatic
brain injury.
[0853] The phrase "Compounds of the Invention" or "PDE 1 inhibitors
of the Invention" encompasses any and all of the compounds
disclosed herewith, e.g., a Compound of Formula I or any of
1.1-1.127, Formula II-A, II-B, or any of 2.1-2.24, and Formula P-A
or P-B, or any of 3.1-3.132, in free or salt form.
[0854] The words "treatment" and "treating" are to be understood
accordingly as embracing prophylaxis and treatment or amelioration
of symptoms of disease as well as treatment of the cause of the
disease.
[0855] For methods of treatment, the word "effective amount" is
intended to encompass a therapeutically effective amount to treat a
specific disease or disorder.
[0856] The term "pulmonary hypertension" is intended to encompass
pulmonary arterial hypertension.
[0857] The term "patient" include human or non-human (i.e., animal)
patient. In particular embodiment, the invention encompasses both
human and nonhuman. In another embodiment, the invention
encompasses nonhuman. In other embodiment, the term encompasses
human.
[0858] The term "comprising" as used in this disclosure is intended
to be open-ended and does not exclude additional, unrecited
elements or method steps.
[0859] Compounds of the Invention are in particular useful for the
treatment of Parkinson's disease, narcolepsy and female sexual
dysfunction.
[0860] Compounds of the Invention may be used as a sole therapeutic
agent, but may also be used in combination or for co-administration
with other active agents. For example, as Compounds of the
Invention potentiate the activity of D1 agonists, such as dopamine,
they may be simultaneously, sequentially, or contemporaneously
administered with conventional dopaminergic medications, such as
levodopa and levodopa adjuncts (carbidopa, COMT inhibitors, MAO-B
inhibitors), dopamine agonists, and anticholinergics, e.g., in the
treatment of a patient having Parkinson's disease. In addition, the
novel PDE 1 inhibitors of the Invention, e.g., the Compounds of the
Invention as described herein, may also be administered in
combination with estrogen/estradiol/estriol and/or
progesterone/progestins to enhance the effectiveness of hormone
replacement therapy or treatment of estrogen-induced endometrial
hyperplasia or carcinoma.
[0861] Dosages employed in practicing the present invention will of
course vary depending, e.g. on the particular disease or condition
to be treated, the particular Compound of the Invention used, the
mode of administration, and the therapy desired. Compounds of the
Invention may be administered by any suitable route, including
orally, parenterally, transdermally, or by inhalation, but are
preferably administered orally. In general, satisfactory results,
e.g. for the treatment of diseases as hereinbefore set forth are
indicated to be obtained on oral administration at dosages of the
order from about 0.01 to 2.0 mg/kg. In larger mammals, for example
humans, an indicated daily dosage for oral administration will
accordingly be in the range of from about 0.75 to 150 mg,
conveniently administered once, or in divided doses 2 to 4 times,
daily or in sustained release form. Unit dosage forms for oral
administration thus for example may comprise from about 0.2 to 75
or 150 mg, e.g. from about 0.2 or 2.0 to 50, 75 or 100 mg of a
Compound of the Invention, together with a pharmaceutically
acceptable diluent or carrier therefor.
[0862] Pharmaceutical compositions comprising Compounds of the
Invention may be prepared using conventional diluents or excipients
and techniques known in the galenic art. Thus oral dosage forms may
include tablets, capsules, solutions, suspensions and the like.
EXAMPLES
[0863] The synthetic methods for various Compounds of the Present
Invention are illustrated below. Other compounds of the Invention
and their salts may be made using the methods as similarly
described below and/or by methods similar to those generally
described in the detailed description and by methods known in the
chemical art. The Compounds of the Invention can also be made by
using general or specific synthetic methods disclosed in U.S.
Provisional Application No. 61/235,888, filed Aug. 21, 2009, the
contents of which are hereby incorporated by reference in their
entirety
Example 1
6-(4-(6-fluoropyridin-2-yl)benzyl)-1-isobutyl-3-methyl-7-(phenylamino)-1H--
pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
##STR00050##
[0864] 1) 1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione
[0865] A suspension of 3-Methyluracil (3.0 mg, 23.8 mmol), isobutyl
iodide (7 mL, 60 mmol) and cesium carbonate (11.6 g, 35.7 mmol) in
DMF (30 mL) is stirred at room temperature over a weekend. Solvent
is removed under vacuum. The residue is treated with water, and
then extracted with dichloromethane four times. The combined
organic phase is washed with brine, dried over anhydrous sodium
sulfate, and then filtered through a short silica gel column. The
filtrate is concentrated to dryness to give product as off white
solids, which is used for the next reaction without further
purification. MS (ESI) m/z 183.1 [M+H].sup.+.
2)
1-isobutyl-3-methyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
[0866] Sodium hydride (95%, 1.74 g, 69 mmol) is suspended in 20 mL
of anhydrous THF, and then a mixture of
1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione (approx. 23 mmol)
and p-toluenesulfonylmethyl isocyanide (97%, 7.0 g, 35 mmol) in 20
mL of anhydrous THF is added dropwise over 80 minutes at 0.degree.
C. The mixture is stirred at room temperature for an hour after the
completion of the addition, and then carefully quenched with water.
The mixture is diluted with 50 mL of saturated NaHCO.sub.3, and
then extracted with CH.sub.2Cl.sub.2 five times. The combined
organic phase is washed with brine, and then dried with anhydrous
Na.sub.2SO.sub.4. After filtration, the filtrate is evaporated to
dryness under reduced pressure to give product as light brown
solids, which is used for the next reaction without further
purification. MS (ESI) m/z 222.2 [M+H].sup.+.
3)
6-(4-(6-fluoropyridin-2-yl)benzyl)-1-isobutyl-3-methyl-1H-pyrrolo[3,4-d-
]pyrimidine-2,4(3H,6H)-dione
[0867] A suspension of
1-isobutyl-3-methyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
(540 mg, 2.46 mmol), 2-(4-(chloromethyl)phenyl)-6-fluoropyridine
(0.60 g, 2.7 mmol) and cesium carbonate (1.6 g, 4.9 mmol) in
anhydrous DMF is stirred at room temperature for 10 minutes. The
mixture is diluted with 200 mL of water, and then extracted with
CH.sub.2Cl.sub.2 three times. The combined organic phase is washed
with brine, and then dried with anhydrous Na.sub.2SO.sub.4. After
filtration, the filtrate is concentrated under vacuum. The residue
is purified by silica gel chromatography to give product as pale
yellow solids (705 mg, yield: 71%). MS (ESI) m/z 407.2
[M+H].sup.+.
4)
7-chloro-6-(4-(6-fluoropyridin-2-yl)benzyl)-1-isobutyl-3-methyl-1H-pyrr-
olo[3,4-d]pyrimidine-2,4(3H,6H)-dione
[0868]
6-(4-(6-fluoropyridin-2-yl)benzyl)-1-isobutyl-3-methyl-1H-pyrrolo[3-
,4-d]pyrimidine-2,4(3H,6H)-dione (81 mg, 0.2 mmol) is dissolved in
a mixture of CCl.sub.4 and DMF (3/1, v/v), and then
N-chlorosuccinimide (27 mg, 0.2 mmol) is added. The reaction
mixture is heated in a Biotage microwave at 100.degree. C. for 30
minutes. Solvents are removed under vacuum, and the residue is
purified by a semi-preparative HPLC to give pure product as off
white solids (50 mg, yield 70%). MS (ESI) m/z 441.2
[M+H].sup.+.
5)
7-chloro-6-(4-(6-fluoropyridin-2-yl)benzyl)-1-isobutyl-3-methyl-1H-pyrr-
olo[3,4-d]pyrimidine-2,4(3H,6H)-dione
[0869]
7-chloro-6-(4-(6-fluoropyridin-2-yl)benzyl)-1-isobutyl-3-methyl-1H--
pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (22 mg, 0.05 mmol) is
dissolved in anhydrous CH.sub.2Cl.sub.2, and then trichloroacetic
acid (8.2 mg, 0.05 mmol) was added, followed by aniline (14 uL,
0.15 mmol). The reaction mixture is heated in a Biotage microwave
instrument at 100.degree. C. for 2 hours. The mixture is purified
by a semi-preparative HPLC to give 6 mg of product as pale yellow
solids. MS (ESI) m/z 498.3 [M+H].sup.+.
Example 2
6-(4-(6-fluoropyridin-2-yl)benzyl)-3-methyl-1-neopentyl-7-(phenylamino)-1H-
-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
##STR00051##
[0871] The synthetic procedure of this compound is analogous to
EXAMPLE 1 wherein neopentyl iodide is used in step 1 instead of
isobutyl iodide. MS (ESI) m/z 416.2 [M+H].sup.+.
Example 3
1-Isobutyl-6-(4-methoxybenzyl)-3-methyl-7-(phenylamino)-1H-pyrrolo[3,4-d]p-
yrimidine-2,4(3H,6H)-dione
##STR00052##
[0873] The synthetic procedure of this compound is analogous to
EXAMPLE 1 wherein 1-(chloromethyl)-4-methoxybenzene is used in step
3 instead of 2-(4-(chloromethyl)phenyl)-6-fluoropyridine. MS (ESI)
m/z 433.2 [M+H].sup.+.
Example 4
7-(2,5-dioxopyrrolidin-1-yl)-1-isobutyl-3-methyl-6-(4-(pyridin-2-yl)benzyl-
)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
##STR00053##
[0874] 1)
1-isobutyl-3-methyl-6-(4-(pyridin-2-yl)benzyl)-1H-pyrrolo[3,4-d]-
pyrimidine-2,4(3H,6H)-dione
[0875] A suspension of
1-isobutyl-3-methyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
(100 mg, 0.45 mmol), 2-(4-(bromomethyl)phenyl)pyridine (160 mg,
0.65 mmol) and potassium carbonate (120 mg, 0.87 mmol) in anhydrous
DMF is stirred at room temperature overnight. After routine workup,
the obtained crude product is purified by a semi-preparative HPLC
to give pure product as white solids. MS (ESI) m/z 389.2
[M+H].sup.+.
2)
7-(2,5-dioxopyrrolidin-1-yl)-1-isobutyl-3-methyl-6-(4-(pyridin-2-yl)ben-
zyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
[0876]
1-isobutyl-3-methyl-6-(4-(pyridin-2-yl)benzyl)-1H-pyrrolo[3,4-d]pyr-
imidine-2,4(3H,6H)-dione (186 mg, 0.48 mmol) is dissolved in a
mixture of CCl.sub.4 and DMF (3/1, v/v), and then
N-chlorosuccinimide (67 mg, 0.51 mmol) is added. The reaction
mixture is heated in a Biotage microwave at 100.degree. C. for 30
min. Solvents are removed under vacuum, and the residue is purified
by a semi-preparative HPLC to give pure product as white solids (40
mg, yield 20%). MS (ESI) m/z 486.2 [M+H].sup.+.
Example 5
1-Isobutyl-6-(4-methoxybenzyl)-3-methyl-5-(phenylamino)-1H-pyrrolo[3,4-d]p-
yrimidine-2,4(3H,6H)-dione
##STR00054##
[0877] 1)
5-chloro-1-isobutyl-6-(4-methoxybenzyl)-3-methyl-1H-pyrrolo[3,4--
d]pyrimidine-2,4(3H,6H)-dione
[0878]
1-isobutyl-6-(4-methoxybenzyl)-3-methyl-1H-pyrrolo[3,4-d]pyrimidine-
-2,4(3H,6H)-dione (106 mg, 0.3 mmol) and hexachloro ethane (368 mg,
1.55 mmol) are dissolved in anhydrous THF, and then 1.0M LiHMDS in
THF (0.6 mL, 0.6 mmol) is added dropwise. The reaction mixture is
stirred at room temperature for an hour, and then quenched with
saturated ammonium chloride aqueous solution. The mixture is
purified by silica-gel column chromatography to give 60 mg of pure
product (yield: 51%). MS (ESI) m/z 376.1 [M+H].sup.+.
2)
1-Isobutyl-6-(4-methoxybenzyl)-3-methyl-5-(phenylamino)-1H-pyrrolo[3,4--
d]pyrimidine-2,4(3H,6H)-dione
[0879]
5-chloro-1-isobutyl-6-(4-methoxybenzyl)-3-methyl-1H-pyrrolo[3,4-d]p-
yrimidine-2,4(3H,6H)-dione (14 mg, 0.025 mmol) is placed in a
Biotage microwave tube, and then aniline (0.5 mL, 5.4 mmol) is
added. The mixture was heated at 180.degree. C. for 4 h. The
mixture is purified by a semi-preparative HPLC to give 13 mg of
pure product (yield: 81%). MS (ESI) m/z 433.2 [M+H].sup.+.
Example 6
6-((4-Pyridin-2yl)-benzyl)-1-isobutyl-3-methyl-5-(phenylamino)-1H-pyrrolo[-
3,4-d]pyrimidine-2,4(3H,6H)-dione
##STR00055##
[0880] 1)
5-chloro-1-isobutyl-3-methyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,-
6H)-dione
[0881] To a solution of
5-chloro-1-isobutyl-6-(4-methoxybenzyl)-3-methyl-1H-pyrrolo[3,4-d]pyrimid-
ine-2,4(3H,6H)-dione (14 mg, 0.032 mmol) in CH.sub.2Cl.sub.2 (0.5
mL) is added TFA (100 .mu.L) and TFMSA (50 .mu.L). The mixture is
stirred at r.t. for 2 h, and then carefully basified with saturated
NaHCO.sub.3 aqueous solution, followed by extractions with
CH.sub.2Cl.sub.2. The combined organic phase is dried over sodium
sulfate, filtered, and concentrated to dryness under reduced
pressure to give crude product, which is used in the next step
without further purification. MS (ESI) m/z 256.1 [M+H].sup.+.
2)
5-chloro-1-isobutyl-3-methyl-6-(4-(pyridin-2-yl)benzyl)-1H-pyrrolo[3,4--
d]pyrimidine-2,4(3H,611)-dione
[0882] A suspension of crude
5-chloro-1-isobutyl-3-methyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
(0.032 mmol), 2-(4-(chloromethyl)phenyl)pyridine (9.7 mg, 0.048
mmol) and cesium carbonate (15.6 mg, 0.048 mmol) in anhydrous DMF
is stirred at room temperature for 3 h, and then diluted with
saturated NaHCO.sub.3 aqueous solution, followed by extractions
with CH.sub.2Cl.sub.2. The combined organic phase is dried over
sodium sulfate, filtered, and concentrated to dryness under reduced
pressure to give crude product, which is used in the next step
without further purification. MS (ESI) m/z 423.1 [M+H].sup.+.
3)
6-((4-Pyridin-2yl)-benzyl)-1-isobutyl-3-methyl-5-(phenylamino)-1H-pyrro-
lo[3,4-d]pyrimidine-2,4(3H,611)-dione
[0883] Crude
5-chloro-1-isobutyl-3-methyl-6-(4-(pyridin-2-yl)benzyl)-1H-pyrrolo[3,4-d]-
pyrimidine-2,4(3H,6H)-dione (0.032 mmol) is placed in a Biotage
microwave tube, and then aniline (0.2 mL) is added. The mixture is
heated at 150.degree. C. for an hour, and then purified by a
semi-preparative HPLC to give 7 mg of pure product (overall yield:
46%). MS (ESI) m/z 480.2 [M+H].sup.+.
Example 7
1-isobutyl-3-methyl-7-(phenylamino)-6-(4-(pyridin-2-yl)benzyl)-1H-pyrrolo[-
3,4-d]pyrimidine-2,4(3H,6H)-dione
##STR00056##
[0885] The synthetic procedure of this compound is analogous to
EXAMPLE 1 wherein 2-(4-(chloromethyl)phenyl)pyridine is used in
step 3 instead of 2-(4-(chloromethyl)phenyl)-6-fluoropyridine. MS
(ESI) m/z 480.2 [M+H].sup.+.
Example 8
7-(3-fluorophenylamino)-1-isobutyl-3-methyl-6-(4-(pyridin-2-yl)benzyl)-1H--
pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
##STR00057##
[0887] The synthetic procedure of this compound is analogous to
EXAMPLE 1 wherein 2-(4-(chloromethyl)phenyl)pyridine is used in
step 3 instead of 2-(4-(chloromethyl)phenyl)-6-fluoropyridine, and
3-fluorobenzenamine is used in step 5 instead of aniline. MS (ESI)
m/z 498.2 [M+H].sup.+.
Example 9
1-isobutyl-3-methyl-7-(methyl(phenyl)amino)-6-(4-(pyridin-2-yl)benzyl)-1H--
pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
##STR00058##
[0889] The synthetic procedure of this compound is analogous to
EXAMPLE 1 wherein 2-(4-(chloromethyl)phenyl)pyridine is used in
step 3 instead of 2-(4-(chloromethyl)phenyl)-6-fluoropyridine, and
N-methyl benzenamine is used in step 5 instead of aniline. MS (ESI)
m/z 494.3 [M+H].sup.+.
Example 10
6-(4-(1H-1,2,4-triazol-1-yl)benzyl)-1-isobutyl-3-methyl-5-(phenylamino)-1H-
-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
##STR00059##
[0891] The synthetic procedure of this compound is analogous to
EXAMPLE 6 wherein 1-(4-(bromomethyl)phenyl)-1H-1,2,4-triazole is
used in step 2 instead of 2-(4-(chloromethyl)phenyl)pyridine. MS
(ESI) m/z 470.2 [M+H].sup.+.
Example 11
1-isobutyl-6-(4-methoxybenzyl)-3,7-dimethyl-5-(phenylamino)-1H-pyrrolo[3,4-
-d]pyrimidine-2,4(3H,6H)-dione
##STR00060##
[0892] 1)
1-isobutyl-3,7-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-d-
ione
[0893] Sodium hydride (95%, 116 mg, 4.6 mmol) is suspended in 10 mL
of anhydrous THF, and then a mixture of
1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione (300 mg, 1.65 mmol)
and 1-(p-toluenesulfonyl)-ethyl isocyanide (413 mg, 1.98 mmol) in 5
mL of anhydrous THF is added dropwise over 1 h at 0.degree. C. The
mixture is stirred at room temperature for 3 h at room temperature
after the completion of the addition, and then carefully quenched
with water. The mixture is diluted with saturated NaHCO.sub.3, and
then extracted with CH.sub.2Cl.sub.2 five times. The combined
organic phase is washed with brine, and then dried with anhydrous
Na.sub.2SO.sub.4. After filtration, the filtrate is evaporated to
dryness under reduced pressure, and the residue is purified by
basic alumina column chromatography to give 247 mg of product
(yield: 64%). MS (ESI) m/z 236.1 [M+H].sup.+.
2)
1-isobutyl-6-(4-methoxybenzyl)-3,7-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-
-2,4(3H,6H)-dione
[0894] A suspension of
1-isobutyl-3,7-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
(78 mg, 0.33 mmol), 1-(chloromethyl)-4-methoxybenzene (88 .mu.L,
0.63 mmol) and cesium carbonate (344 mg, 1.06 mmol) in anhydrous
DMF is stirred at room temperature overnight. The mixture is
diluted with 30 mL of water, and then extracted with
CH.sub.2Cl.sub.2 three times. The combined organic phase is washed
with brine, and then dried with anhydrous Na.sub.2SO.sub.4. After
filtration, the filtrate is concentrated under vacuum. The residue
is purified by basic alumina column chromatography to give 110 mg
of product (yield: 93%). MS (ESI) m/z 356.2 [M+H].sup.+.
3)
5-chloro-1-isobutyl-6-(4-methoxybenzyl)-3,7-dimethyl-1H-pyrrolo[3,4-d]p-
yrimidine-2,4(3H,6H)-dione
[0895]
1-isobutyl-6-(4-methoxybenzyl)-3,7-dimethyl-1H-pyrrolo[3,4-d]pyrimi-
dine-2,4(3H,6H)-dione (103 mg, 0.29 mmol) and hexachloroethane (400
mg, 1.7 mmol) are dissolved in anhydrous THF, and then 1.0M LiHMDS
in THF (1.4 mL, 1.4 mmol) is added dropwise. The reaction mixture
is stirred at room temperature for an hour, and then quenched with
saturated ammonium chloride aqueous solution. The mixture is
purified by silica-gel column chromatography to give pure product
as off-white solids (yield: 64%). MS (ESI) m/z 390.2
[M+H].sup.+.
4)
1-isobutyl-6-(4-methoxybenzyl)-3,7-dimethyl-5-(phenylamino)-1H-pyrrolo[-
3,4-d]pyrimidine-2,4(3H,6H)-dione
[0896]
5-chloro-1-isobutyl-6-(4-methoxybenzyl)-3,7-dimethyl-1H-pyrrolo[3,4-
-d]pyrimidine-2,4(3H,6H)-dione (12 mg, 0.03 mmol) is placed in a
Biotage microwave tube, and then aniline (0.22 mL) is added. The
mixture was heated at 150.degree. C. for 3 h., and then purified by
a semi-preparative HPLC to give 4 mg of pure product. MS (ESI) m/z
447.3 [M+H].sup.+.
Example 12
1-isobutyl-3-methyl-6-(4-(1-methylpyrrolidin-2-yl)benzyl)-5-(phenylamino)--
1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
##STR00061##
[0898] The synthetic procedure of this compound is analogous to
EXAMPLE 6 wherein tert-butyl
2-(4-(bromomethyl)phenyl)pyrrolidine-1-carboxylate is used in step
2 instead of 2-(4-(chloromethyl)phenyl)pyridine. The obtained
tert-butyl
2-(4-((5-chloro-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrrolo[3-
,4-d]pyrimidin-6-yl)methyl)phenyl)pyrrolidine-1-carboxylate is
deprotected with TFA in CH.sub.2Cl.sub.2 at room temperature to
give
5-chloro-1-isobutyl-3-methyl-6-(4-(pyrrolidin-2-yl)benzyl)-1H-pyrrolo[3,4-
-d]pyrimidine-2,4(3H,6H)-dione, which is N-methylated with 37%
formaldehyde aqueous solution and sodium borohydride in methanol at
room temperature to give
5-chloro-1-isobutyl-3-methyl-6-(4-(1-methylpyrrolidin-2-yl)benzyl)-1H-pyr-
rolo[3,4-d]pyrimidine-2,4(3H,6H)-dione in a good overall yield. The
obtained intermediate reacts with aniline using the procedure
described in step 3 of EXAMPLE 6 to give pure product after HPLC
purification. MS (ESI) m/z 486.3 [M+H].sup.+.
Example 13
1-isobutyl-3-methyl-5-(phenylamino)-6-(4-(pyridin-4-yl)benzyl)-1H-pyrrolo[-
3,4-d]pyrimidine-2,4(3H,6H)-dione
##STR00062##
[0900] The synthetic procedure of this compound is analogous to
EXAMPLE 6 wherein 4-(4-(chloromethyl)phenyl)pyridine is used in
step 2 instead of 2-(4-(chloromethyl)phenyl)pyridine. MS (ESI) m/z
480.3 [M+H].sup.+.
Example 14
6-(4-(1H-imidazol-1-yl)benzyl)-1-isobutyl-3-methyl-5-(phenylamino)-1H-pyrr-
olo[3,4-d]pyrimidine-2,4(3H,6H)-dione
##STR00063##
[0902] The synthetic procedure of this compound is analogous to
EXAMPLE 6 wherein 1-(4-(chloromethyl)phenyl)-1H-imidazole is used
in step 2 instead of 2-(4-(chloromethyl)phenyl)pyridine. MS (ESI)
m/z 469.3 [M+H].sup.+.
Example 15
7-(4-hydroxyphenylamino)-1-isobutyl-3-methyl-6-(4-(pyridin-2-yl)benzyl)-1H-
-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
##STR00064##
[0904] The synthetic procedure of this compound is analogous to
EXAMPLE 1 wherein 2-(4-(chloromethyl)phenyl)pyridine is used in
step 3 instead of 2-(4-(chloromethyl)phenyl)-6-fluoropyridine, and
4-aminophenol is used in step 5 instead of aniline. MS (ESI) m/z
496.2 [M+H].sup.+.
Example 16
1-isobutyl-3-methyl-5-(methyl(phenyl)amino)-6-(4-(pyridin-2-yl)benzyl)-1H--
pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
##STR00065##
[0906] The synthetic procedure of this compound is analogous to
EXAMPLE 6 wherein N-methyl benzenamine is used in step 3 instead of
aniline. MS (ESI) m/z 494.3 [M+H].sup.+.
Example 17
1-isobutyl-3-methyl-5-(phenylamino)-6-(4-(trifluoromethyl)benzyl)-1H-pyrro-
lo[3,4-d]pyrimidine-2,4(3H,6H)-dione
##STR00066##
[0908] The synthetic procedure of this compound is analogous to
EXAMPLE 6 wherein 1-(bromomethyl)-4-(trifluoromethyl)benzene is
used in step 2 instead of 2-(4-(chloromethyl)phenyl)pyridine. MS
(ESI) m/z 471.2 [M+H].sup.+.
Example 18
5-(4-fluorophenylamino)-1-isobutyl-3-methyl-6-(4-(pyridin-2-yl)benzyl)-1H--
pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
##STR00067##
[0910] The synthetic procedure of this compound is analogous to
EXAMPLE 6 wherein 4-fluorobenzenamine is used in step 3 instead of
aniline. MS (ESI) m/z 498.3 [M+H].sup.+.
Example 19
1-isobutyl-3-methyl-7-(phenylamino)-6-(4-(trifluoromethyl)benzyl)-1H-pyrro-
lo[3,4-d]pyrimidine-2,4(3H,6H)-dione
##STR00068##
[0912] The synthetic procedure of this compound is analogous to
EXAMPLE 1 wherein 1-(bromomethyl)-4-(trifluoromethyl)benzene is
used in step 3 instead of
2-(4-(chloromethyl)phenyl)-6-fluoropyridine. MS (ESI) m/z 471.2
[M+H].sup.+.
Example 20
6-(4-(1H-1,2,4-triazol-1-yl)benzyl)-1-isobutyl-3,7-dimethyl-5-(phenylamino-
)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
##STR00069##
[0914] The synthetic procedure of this compound is analogous to
EXAMPLE 11 wherein 1-(4-(bromomethyl)phenyl)-1H-1,2,4-triazole is
used in step 2 instead of 1-(chloromethyl)-4-methoxybenzene, and
NCS chlorination method is used in step 3 instead of the
hexachloroethane and LiHMDS method. MS (ESI) m/z 484.3
[M+H].sup.+.
Example 21
6-(4-(1H-pyrazol-1-yl)benzyl)-1-isobutyl-3-methyl-5-(phenylamino)-1H-pyrro-
lo[3,4-d]pyrimidine-2,4(3H,6H)-dione
##STR00070##
[0916] The synthetic procedure of this compound is analogous to
EXAMPLE 6 wherein 1-(4-(bromomethyl)phenyl)-1H-pyrazole is used in
step 2 instead of 2-(4-(chloromethyl)phenyl)pyridine. MS (ESI) m/z
469.3 [M+H].sup.+.
Example 22
6-(4-(1H-imidazol-1-yl)benzyl)-1-isobutyl-3-methyl-5-(methyl(phenyl)amino)-
-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
##STR00071##
[0918] The synthetic procedure of this compound is analogous to
EXAMPLE 6 wherein 1-(4-(chloromethyl)phenyl)-1H-imidazole is used
in step 2 instead of 2-(4-(chloromethyl)phenyl)pyridine, and
N-methylbenzenamine is used in step 3 instead of aniline. MS (ESI)
m/z 483.3 [M+H].sup.+.
Example 23
Measurement of PDE1B Inhibition In Vitro Using IMAP
Phosphodiesterase Assay Kit
[0919] Phosphodiesterase 1B (PDE1B) is a calcium/calmodulin
dependent phosphodiesterase enzyme that converts cyclic guanosine
monophosphate (cGMP) to 5'-guanosine monophosphate (5'-GMP). PDE1B
can also convert a modified cGMP substrate, such as the fluorescent
molecule cGMP-fluorescein, to the corresponding GMP-fluorescein.
The generation of GMP-fluorescein from cGMP-fluorescein can be
quantitated, using, for example, the IMAP (Molecular Devices,
Sunnyvale, Calif.) immobilized-metal affinity particle reagent.
[0920] Briefly, the IMAP reagent binds with high affinity to the
free 5'-phosphate that is found in GMP-fluorescein and not in
cGMP-fluorescein. The resulting GMP-fluorescein--IMAP complex is
large relative to cGMP-fluorescein. Small fluorophores that are
bound up in a large, slowly tumbling, complex can be distinguished
from unbound fluorophores, because the photons emitted as they
fluoresce retain the same polarity as the photons used to excite
the fluorescence.
[0921] In the phosphodiesterase assay, cGMP-fluorescein, which
cannot be bound to IMAP, and therefore retains little fluorescence
polarization, is converted to GMP-fluorescein, which, when bound to
IMAP, yields a large increase in fluorescence polarization
(.DELTA.mp). Inhibition of phosphodiesterase, therefore, is
detected as a decrease in .DELTA.mp.
[0922] Enzyme Assay
Materials: All chemicals are available from Sigma-Aldrich (St.
Louis, Mo.) except for IMAP reagents (reaction buffer, binding
buffer, FL-GMP and IMAP beads), which are available from Molecular
Devices (Sunnyvale, Calif.). Assay:
3',5'-cyclic-nucleotide-specific bovine brain phosphodiesterase
(Sigma, St. Louis, Mo.) is reconstituted with 50% glycerol to 2.5
U/ml. One unit of enzyme will hydrolyze 1.0 .mu.mole of 3',5'-cAMP
to 5'-AMP per min at pH 7.5 at 30.degree. C. One part enzyme is
added to 1999 parts reaction buffer (30 .mu.M CaCl.sub.2, 10 U/ml
of calmodulin (Sigma P2277), 10 mM Tris-HCl pH 7.2, 10 mM
MgCl.sub.2, 0.1% BSA, 0.05% NaN.sub.3) to yield a final
concentration of 1.25 mU/ml. 99 .mu.l of diluted enzyme solution is
added into each well in a flat bottom 96-well polystyrene plate to
which 1 .mu.l of test compound dissolved in 100% DMSO is added.
Selected Compounds of the Invention are mixed and pre-incubated
with the enzyme for 10 min at room temperature.
[0923] The FL-GMP conversion reaction is initiated by combining 4
parts enzyme and inhibitor mix with 1 part substrate solution
(0.225 .mu.M) in a 384-well microtiter plate. The reaction is
incubated in dark at room temperature for 15 min. The reaction is
halted by addition of 60 .mu.l of binding reagent (1:400 dilution
of IMAP beads in binding buffer supplemented with 1:1800 dilution
of antifoam) to each well of the 384-well plate. The plate is
incubated at room temperature for 1 hour to allow IMAP binding to
proceed to completion, and then placed in an Envision multimode
microplate reader (PerkinElmer, Shelton, Conn.) to measure the
fluorescence polarization (.DELTA.mp).
[0924] A decrease in GMP concentration, measured as decreased
.DELTA.mp, is indicative of inhibition of PDE activity. IC.sub.50
values are determined by measuring enzyme activity in the presence
of 8 to 16 concentrations of compound ranging from 0.0037 nM to
80,000 nM and then plotting drug concentration versus .DELTA.mP,
which allows IC.sub.50 values to be estimated using nonlinear
regression software (XLFit; IDBS, Cambridge, Mass.).
[0925] The Compounds of the Invention are selected and tested in
this assay to show PDE1 inhibitory activity. Exemplified compounds
of the invention generally have IC.sub.50 values of 25 .mu.M, some
less than 1 .mu.M, some less than 500 nM, some less than 200 nM,
some with PDE1A activities, e.g., Examples 1-3, 5 and 6 are shown
to have an IC.sub.50 of less than 200 nM.
Example 24
PDE1 Inhibitor Effect on Sexual Response in Female Rats
[0926] The effect of PDE1 inhibitors on Lordosis Response in female
rats is measured as described in Mani, et al., Science (2000) 287:
1053. Ovariectomized and cannulated wild-type rats are primed with
2 .mu.g estrogen followed 24 hours later by intracerebroventricular
(icv) injection of progesterone (2 .mu.g), PDE1 inhibitors of the
present invention (0.1 mg, 1.0 mg or 2.5 mg) or sesame oil vehicle
(control). The rats are tested for lordosis response in the
presence of male rats. Lordosis response is quantified by the
lordosis quotient (LQ=number of lordosis/10 mounts.times.100). The
LQ for estrogen-primed female rats receiving Compounds of the
Invention, at 0.1 mg, will likely be similar to estrogen-primed
rats receiving progesterone and higher than for estrogen-primed
rats receiving vehicle.
* * * * *