U.S. patent application number 15/608331 was filed with the patent office on 2018-01-18 for novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders (gpr84 antagonists).
This patent application is currently assigned to GALAPAGOS NV. The applicant listed for this patent is GALAPAGOS NV. Invention is credited to Luke Jonathan ALVEY, Stephen Robert FLETCHER, Frederic Gilbert LABEGU RE, Gregory John Robert NEWSOME, Laurent Raymond Maurice SANI RE.
Application Number | 20180016275 15/608331 |
Document ID | / |
Family ID | 49841660 |
Filed Date | 2018-01-18 |
United States Patent
Application |
20180016275 |
Kind Code |
A1 |
LABEGU RE; Frederic Gilbert ;
et al. |
January 18, 2018 |
NOVEL DIHYDROPYRIMIDINOISOQUINOLINONES AND PHARMACEUTICAL
COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS
(GPR84 ANTAGONISTS)
Abstract
A compound according to Formula Ia: ##STR00001## wherein Cy,
L.sub.1, G, and R.sup.1 are as described herein. The present
invention relates to novel compounds according to Formula I that
antagonize GPR84, a G-protein-coupled receptor that is involved in
inflammatory conditions, and methods for the production of these
novel compounds, pharmaceutical compositions comprising these
compounds, and methods for the prevention and/or treatment of
inflammatory conditions (for example inflammatory bowel diseases
(IBD), rheumatoid arthritis, vasculitis), lung diseases (e.g.
chronic obstructive pulmonary disease (COPD) and lung interstitial
diseases (e.g. idiopathic pulmonary fibrosis (IPF))),
neuroinflammatory conditions, infectious diseases, autoimmune
diseases, endocrine and/or metabolic diseases, and/or diseases
involving impairment of immune cell functions by administering a
compound of the invention.
Inventors: |
LABEGU RE; Frederic Gilbert;
(Gagny, FR) ; NEWSOME; Gregory John Robert;
(Neuilly Plaisance, FR) ; ALVEY; Luke Jonathan;
(Versailles, FR) ; SANI RE; Laurent Raymond Maurice;
(Montesson, FR) ; FLETCHER; Stephen Robert;
(Bishops Stortford, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GALAPAGOS NV |
Mechelen |
|
BE |
|
|
Assignee: |
GALAPAGOS NV
Mechelen
BE
|
Family ID: |
49841660 |
Appl. No.: |
15/608331 |
Filed: |
May 30, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14653323 |
Jun 18, 2015 |
9708312 |
|
|
PCT/EP2013/076818 |
Dec 17, 2013 |
|
|
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15608331 |
|
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61740028 |
Dec 20, 2012 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 19/02 20180101;
C07D 471/04 20130101; A61P 29/00 20180101; A61P 43/00 20180101;
A61P 11/06 20180101; A61P 1/04 20180101; A61K 31/5377 20130101;
A61K 31/519 20130101; C07D 519/00 20130101; A61P 17/06 20180101;
A61P 11/00 20180101 |
International
Class: |
C07D 471/04 20060101
C07D471/04; A61K 31/519 20060101 A61K031/519; A61K 31/5377 20060101
A61K031/5377; C07D 519/00 20060101 C07D519/00 |
Claims
1. A compound according to Formula Ia: ##STR00295## wherein Cy is
##STR00296## wherein X is O or S; Y is --CH.sub.2--, or S; Z is
--CH.sub.2--; each of the subscript n, m, or p is independently
selected from 0, and 1; and A is phenyl, or 5-6-membered heteroaryl
comprising one or two N-atoms; optionally substituted with one or
more independently selected R.sup.5 groups; any one of Cy1 and Cy2
is optionally substituted by one or more independently selected
C.sub.1-4 alkyl groups; R.sup.1 is H, Me, or halo; L.sub.1 is
absent or is --O--, --S--, or --NR.sup.4a--; G is R.sup.2
--W-L.sub.2-R.sup.2, or --W-L.sub.3-R.sup.3 W is C.sub.1-4
alkylene, C.sub.2-4 alkenylene having one double bond, or C.sub.2-4
alkynylene having one triple bond; L.sub.2 is absent or is --O--;
R.sup.2 is H, C.sub.1-8 alkyl optionally substituted with one to
three groups independently selected from OH, halo, CN, C.sub.1-6
alkoxy, C.sub.3-7 cycloalkyl, 4-6 membered heterocycloalkyl
(comprising one to three heteroatoms independently selected from S,
and O), 5-6 membered heteroaryl (comprising one to three
heteroatoms independently selected from N, S, and O), and phenyl,
C.sub.4-7 cycloalkenyl comprising one double bond, 5-7 membered
heterocycloalkenyl comprising one double bond, and one to three
heteroatoms independently selected from O, and S, C.sub.3-7
cycloalkyl (optionally substituted with one or more independently
selected R.sup.6 groups), 4-10 membered heterocycloalkyl comprising
one to two heteroatoms independently selected from S, and O,
(optionally substituted with one to three independently selected
R.sup.6 groups), 5-10 membered heteroaryl comprising one to three
heteroatoms independently selected from N, S, and O (optionally
substituted with one to three independently selected R.sup.7
groups), or C.sub.6-10 aryl (optionally substituted with one or
more independently selected R.sup.7 groups); L.sub.3 is
--NR.sup.4b; R.sup.3 is C.sub.1-4 alkyl substituted with C.sub.6-10
aryl (optionally substituted with one or more independently
selected R.sup.8 groups), or 5-10 membered heteroaryl (optionally
substituted with one or more independently selected R.sup.8 groups)
comprising one to three heteroatoms independently selected from N,
S, and O, 5-10 membered heteroaryl comprising one to three
heteroatoms independently selected from N, S, and O, (optionally
substituted with one or more independently selected R.sup.8
groups), or C.sub.6-10 aryl (optionally substituted with one or
more independently selected R.sup.8 groups); Each R.sup.4a and
R.sup.4b is independently selected from H, C.sub.1-4 alkyl, and
C.sub.3-7 cycloalkyl; R.sup.5 is halo, C.sub.1-4 alkyl or C.sub.1-4
alkoxy; R.sup.6 is oxo or R.sup.7; R.sup.7 is OH, halo, --NO.sub.2,
C.sub.1-6 alkyl (optionally substituted with one to three groups
independently selected from halo, and OH), C.sub.1-6 alkoxy
(optionally substituted with one to three groups independently
selected from halo, and OH), C.sub.3-7 cycloalkyl,
--C(.dbd.O)OR.sup.9, --C(.dbd.O)NR.sup.10R.sup.11,
--NHC(.dbd.O)--C.sub.1-4 alkyl, --CN, phenyl, --O-phenyl, 4-7
membered heterocycloalkyl comprising one to three heteroatoms
independently selected from N, O, and S, or 5-6 membered heteroaryl
comprising one to three heteroatoms independently selected from N,
O, and S; (optionally substituted with one or more independently
selected C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CN, halo, and
--C(.dbd.O)OR.sup.12); R.sup.8 is C.sub.1-4 alkyl, or halo; each of
R.sup.9, R.sup.10, R.sup.11 and R.sup.12, is independently selected
from H and C.sub.1-4 alkyl, or a pharmaceutically acceptable salt,
or a solvate, or a solvate of the pharmaceutically acceptable
salts.
2. A compound or pharmaceutically acceptable salt thereof,
according to claim 1, wherein R.sup.1 is H.
3. A compound or pharmaceutically acceptable salt thereof,
according to claim 1, wherein the compound is according to Formula
IIa-IIi: ##STR00297## ##STR00298## ##STR00299## wherein L.sub.1, W,
L.sub.2, R.sup.2, L.sub.3 and R.sup.3 are as described in claim
1.
4. A compound or pharmaceutically acceptable salt thereof,
according to claim 3, wherein the compound is according to Formula
IIa-IIf, and wherein L.sub.1 is absent.
5. A compound or pharmaceutically acceptable salt thereof,
according to claim 3, wherein the compound is according to Formula
IId-IIf, and wherein L.sub.1 is absent, or is --O--; W is C.sub.1-4
alkylene, or C.sub.2-4 alkenylene having one double bond.
6. A compound or pharmaceutically acceptable salt thereof,
according to claim 3, wherein the compound is according to Formula
IId-IIf, and wherein L.sub.1 is absent; W is C.sub.2-4 alkynylene
having one triple bond.
7. A compound or pharmaceutically acceptable salt thereof,
according to claim 5, wherein the compound is according to Formula
IId-IIf, and wherein L.sub.2 is absent or is --O--.
8. A compound or pharmaceutically acceptable salt thereof,
according to claim 4, wherein the compound is according to Formula
IId-IIf, and wherein -L.sub.1-W-L.sub.2- is selected from
--CH.sub.2--CH.sub.2--, --O--CH.sub.2--, --O--CH.sub.2--CH.sub.2--,
--O--CH.sub.2--CH.sub.2--O--, --C.ident.C--, and
--C.ident.C--CH.sub.2--.
9. A compound or pharmaceutically acceptable salt thereof,
according to claim 2, wherein R.sup.2 is 5-10 membered heteroaryl
comprising one to three heteroatoms independently selected from N,
S, and O, or C.sub.6-10 aryl each of which is optionally
substituted with one to three independently selected R.sup.7
groups.
10. A compound or pharmaceutically acceptable salt thereof,
according to claim 9, wherein each R.sup.7 group is independently
selected from halo, CN, C.sub.1-6 alkyl, --CF.sub.3, --NH.sub.2
(optionally substituted with one or two independently selected
C.sub.1-4 alkyl, and --C(.dbd.O)--C.sub.1-4 alkyl),
--C(.dbd.O)NH.sub.2 (optionally substituted with one or two
independently selected C.sub.1-4 alkyl), C.sub.3-7 cycloalkyl and
4-7 membered heterocycloalkyl comprising one to three heteroatoms
independently selected from N, O, and S).
11. A compound or pharmaceutically acceptable salt thereof,
according to claim 3, wherein R.sup.2 is C.sub.1-6 alkyl optionally
substituted with one to three groups independently selected from
OH, halo, CN, phenyl, C.sub.1-6 alkoxy, and C.sub.3-7
cycloalkyl.
12. A compound or pharmaceutically acceptable salt thereof,
according to claim 3, wherein R.sup.2 is C.sub.3-7 cycloalkyl.
13. A compound or pharmaceutically acceptable salt thereof,
according to claim 3, wherein R.sup.2 is 4-10 membered
heterocycloalkyl comprising one to three heteroatoms independently
selected from N, S, and O; optionally substituted with one to three
independently selected R.sup.6 groups.
14. A compound or pharmaceutically acceptable salt thereof,
according to claim 13, wherein each R.sup.6 group is independently
selected from oxo and R.sup.7; wherein R.sup.7 is OH, or C.sub.1-6
alkyl.
15. A compound or pharmaceutically acceptable salt thereof,
according to claim 1, wherein the compound is selected from:
9-Methoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]iso-
quinolin-4-one,
2-(Chroman-2-ylmethoxy)-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin--
4-one,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-methoxy-6,7-dihydro--
pyrimido[6,1-a]isoquinolin-4-one,
9-Allyloxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]is-
oquinolin-4-one,
2-(2,3-Dihydro-benzofuran-2-ylmethoxy)-9-methoxy-6,7-dihydro-pyrimido[6,1-
-a]isoquinolin-4-one,
9-Hydroxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]iso-
quinolin-4-one,
9-Benzyloxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]i-
soquinolin-4-one,
9-(Pyridin-3-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one,
[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]iso-
quinolin-9-yloxy]-acetonitrile,
9-Butoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoq-
uinolin-4-one,
9-Cyclopropylmethoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one,
9-Phenethyloxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1--
a]isoquinolin-4-one,
9-(Pyridin-4-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one,
9-(Pyridin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one,
9-(Pyridin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one,
9-(2-Phenoxy-ethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one,
9-Methoxy-2-(tetrahydro-pyran-4-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]iso-
quinolin-4-one,
9-Methoxy-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]iso-
quinolin-4-one,
9-Methoxy-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]iso-
quinolin-4-one,
4-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzonitrile,
4-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzonitrile,
9-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
3-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzonitrile,
2-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzonitrile,
9-(4-Chloro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one,
9-(3-Chloro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one,
9-(2-Chloro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one,
9-(4-Fluoro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one,
9-(2-Nitro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one,
4-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzoic acid methyl ester,
3-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzoic acid methyl ester,
3-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzoic acid methyl ester,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(pyridin-2-ylmethoxy)-6,7--
dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimi-
do[6,1-a]isoquinolin-9-yloxy]-acetic acid tert-butyl ester,
2,9-Bis-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-6,7-dihydro-pyrimido[6-
,1-a]isoquinolin-4-one,
[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimi-
do[6,1-a]isoquinolin-9-yloxy]-acetic acid,
9-(3-Nitro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one,
9-(3-Nitro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one,
9-(4-Nitro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one,
9-(3-Methyl-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one,
9-(4-Methyl-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one,
9-(4-Methoxy-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one,
9-(Naphthalen-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one,
9-(Naphthalen-1-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one,
9-(2-Methyl-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one,
9-[2-(2-Methoxy-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dih-
ydro-pyrimido[6,1-a]isoquinolin-4-one,
9-[2-(3-Methoxy-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dih-
ydro-pyrimido[6,1-a]isoquinolin-4-one,
9-[2-(4-Methoxy-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dih-
ydro-pyrimido[6,1-a]isoquinolin-4-one,
9-[2-(2-Chloro-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihy-
dro-pyrimido[6,1-a]isoquinolin-4-one,
9-[2-(3-Chloro-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihy-
dro-pyrimido[6,1-a]isoquinolin-4-one,
9-[2-(4-Chloro-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihy-
dro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-morpholin-4-yl-2-oxo-et-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-morpholin-4-yl-2-oxo-et-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-morpholin-4-yl-2-oxo-et-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-morpholin-4-yl-2-oxo-et-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-acetamide,
2-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-N,N-dimethyl-acetamide,
9-(2,2-Dimethoxy-ethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyr-
imido[6,1-a]isoquinolin-4-one,
2-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-2-methyl-propionamide,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(1,1-dimethyl-2-morpholin--
4-yl-2-oxo-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(2-Benzyloxy-ethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one,
2,9-Bis-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquin-
olin-4-one,
9-(6-Phenyl-pyridin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dih-
ydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(tetrahydro-furan-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-[6-(1-Methyl-1H-pyrazol-4-yl)-pyridin-2-ylmethoxy]-2-(tetrahydro-furan--
2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(6-Furan-3-yl-pyridin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(6-Pyrimidin-5-yl-pyridin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-
-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(1-Cyclopropyl-1H-tetrazol-5-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy-
)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxy]-acetamide,
N,N-Diethyl-2-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-acetamide,
N,N-Dimethyl-2-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyr-
imido[6,1-a]isoquinolin-9-yloxy]-acetamide,
N-Isopropyl-N-methyl-2-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydr-
o-4H-pyrimido[6,1-a]isoquinolin-9-yloxy]-acetamide,
2-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxy]-N-phenyl-acetamide,
9-(1-Propyl-1H-tetrazol-5-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(Oxazol-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one,
2-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-N,N-diethyl-acetamide,
2-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-N-isopropyl-N-methyl-acetamide,
2-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-N-phenyl-acetamide,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(1-propyl-1H-tetrazol-5-yl-
methoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(1-Butyl-1H-tetrazol-5-ylmethoxy)-2-(2,3-dihydro-benzo[1,4]dioxin-2-ylm-
ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-morpholin-4-yl-ethoxy)--
6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimi-
do[6,1-a]isoquinolin-9-yloxy]-acetonitrile,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(oxazol-2-ylmethoxy)-6,7-d-
ihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-oxo-2-pyrrolidin-1-yl-e-
thoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(1-Cyclopropyl-1H-tetrazol-5-ylmethoxy)-2-(2,3-dihydro-benzo[1,4]dioxin-
-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(1H-tetrazol-5-ylmethoxy)--
6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-Allyloxy-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-6,7-dih-
ydro-pyrimido[6,1-a]isoquinolin-4-one,
N-Benzyl-2-[2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydr-
o-4H-pyrimido[6,1-a]isoquinolin-9-yloxy]-acetamide,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-pyrrolidin-1-yl-ethoxy)-
-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-piperidin-1-yl-ethoxy)--
6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(3-piperidin-1-yl-propoxy)-
-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(3-dimethylamino-propoxy)--
6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-[2-(1-methyl-pyrrolidin-2--
yl)-ethoxy]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-[3-(4-methyl-piperazin-1-y-
l)-propoxy]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
5-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxymethyl]-furan-2-carboxylic acid ethyl
ester,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(oxazol-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(oxazol-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(oxazol-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(oxazol-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(5-tert-Butyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-(tetrahydro-furan-2-ylmet-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(5-Phenyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy-
)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro-
-4H-pyrimido[6,1-a]isoquinolin-9-yloxy]-acetonitrile,
[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro-
-4H-pyrimido[6,1-a]isoquinolin-9-yloxy]-acetonitrile,
[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro-
-4H-pyrimido[6,1-a]isoquinolin-9-yloxy]-acetonitrile,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-morpholin-4-y-
l-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(pyridin-2-ylmet-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-[2-(1-methyl-pyr-
rolidin-2-yl)-ethoxy]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1H-tetrazol-5-y-
lmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-Pyridin-3-yl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1--
a]isoquinolin-4-one,
3-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzonitrile,
9-Phenyl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoq-
uinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyridin-4-yl-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
3-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-benzonitrile,
9-(2-Methoxy-phenyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one,
9-(3-Methoxy-phenyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one,
9-(4-Methoxy-phenyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one,
4-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzonitrile,
3-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzoic acid,
4-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzoic acid,
9-(4-Dimethylamino-phenyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one,
4-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzamide,
2-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzonitrile,
9-(1-Methyl-1H-pyrazol-4-yl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-
-pyrimido[6,1-a]isoquinolin-4-one,
N,N-Dimethyl-3-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyr-
imido[6,1-a]isoquinolin-9-yl]-benzamide,
9-(6-Methoxy-pyridin-3-yl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one,
9-(2,6-Dimethyl-phenyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one,
9-(3,5-Dimethyl-isoxazol-4-yl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihyd-
ro-pyrimido[6,1-a]isoquinolin-4-one,
9-Naphthalen-2-yl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6-
,1-a]isoquinolin-4-one,
9-Naphthalen-1-yl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6-
,1-a]isoquinolin-4-one,
9-Pyrimidin-5-yl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,-
1-a]isoquinolin-4-one,
9-(5-Chloro-thiophen-2-yl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one,
2-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-pyrrole-1-carboxylic acid tert-butyl ester,
Trifluoro-methanesulfonic acid
4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,
1-a]isoquinolin-9-yl ester,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(6-methoxy-pyrid-
in-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-Cyclopropylethynyl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one,
9-(3,3-Dimethyl-but-1-ynyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro--
pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(pyridin-4-ylmet-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyridin-3-yl-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-benzonitrile,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-methoxy-pheny-
l)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1H-indazol-5-yl-
)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyrimidin-5-yl-6-
,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
3-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-benzamide,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-dimethylamino-
-phenyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyridin-3-ylethy-
nyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-methoxy-prop--
1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(4-hydroxy-but-1-
-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1,5-dimethyl-1H-
-pyrazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-methyl-[1,2,4-
]oxadiazol-5-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-3-met-
hyl-but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyridin-4-ylethy-
nyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-prop--
1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(6-methyl-pyridi-
n-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(5-methoxy-pyrid-
in-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-Cyclopropylethynyl-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethox-
y)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-Cyclopropylethynyl-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethox-
y)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1-hydroxy-cyclo-
pentylethynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
5-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-pent-4-ynenitrile,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3,3-dimethyl-bu-
t-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-methoxy-pyrid-
in-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one,
5-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-pyridine-2-carboxylic acid
methylamide,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-furan-3-yl-6,7-d-
ihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1-methyl-1H-pyr-
azol-4-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-morpholin-4-ylme-
thyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro-
-4H-pyrimido[6,1-a]isoquinolin-9-ylamino]-acetonitrile,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro--
4H-pyrimido[6,1-a]isoquinoline-9-carbonitrile,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-[(oxazol-2-ylmet-
hyl)-amino]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(5-methyl-[1,2,4-
]oxadiazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(5-ethyl-[1,2,4]-
oxadiazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(5-Cyclopropyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-(2,3-dihydro-[1,4]dioxin-
o[2,3-b]pyridin-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(5-isopropyl-[1,-
2,4]oxadiazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(5-tert-Butyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-(2,3-dihydro-[1,4]dioxino-
[2,3-b]pyridin-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-methyl-isoxaz-
ol-5-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(3-Chloro-2-methoxy-pyridin-4-yl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyr-
idin-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3,6-dihydro-2H--
pyran-4-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
5-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-pyridine-2-carbonitrile,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-ethoxy-pyridi-
n-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(6-ethoxy-pyridi-
n-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(6-morpholin-4-y-
l-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-methoxy-pyrim-
idin-5-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2,3-dimethoxy-p-
henyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2,5-dimethoxy-p-
henyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-3-phe-
nyl-prop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
3-{3-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-di-
hydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-prop-2-ynyloxy}-propionitrile,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-methylamino-p-
rop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-dimethylamino-
-prop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-[3-(Benzyl-methyl-amino)-prop-1-ynyl]-2-(2,3-dihydro-[1,4]dioxino[2,3-b-
]pyridin-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-[3-(1,1-dioxo-th-
iomorpholin-4-yl)-prop-1-ynyl]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-on-
e,
{3-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-di-
hydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-prop-2-ynyl}-urea,
1-{3-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-di-
hydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-prop-2-ynyl}-imidazolidine-2,4-d-
ione,
9-(3-Diethylamino-prop-1-ynyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyr-
idin-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(3-Amino-3-methyl-but-1-ynyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-
-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(tetrahydro-pyra-
n-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1H-pyrazol-4-yl-
)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-but-1-
-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-pent--
1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-hex-1-
-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(1-Amino-cyclohexylethynyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-
-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-5-met-
hyl-hex-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-ethyl-3-hydro-
xy-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-3-phe-
nyl-but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-4-met-
hyl-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-[(R)-1-(2,3-Dihydro-[1,4]dioxin[2,3-b]pyridin-2-yl)methoxy]-9-(oxazol-2-
-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-[(R)-1-(2,3-Dihydro-[1,4]dioxin[2,3-b]pyridin-2-yl)methoxy]-9-(oxazol-2-
-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-[(S)-1-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-yl)methoxy]-9-(oxazol--
2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(3-Butylamino-prop-1-ynyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2--
ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-morpholin-4-y-
l-ethoxymethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(3-Benzylamino-prop-1-ynyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-
-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-phenylamino-p-
rop--ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro--
4H-pyrimido[6,1-a]isoquinoline-9-carboxylic acid
(tetrahydro-pyran-4-yl)-amide,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro--
4H-pyrimido[6,1-a]isoquinoline-9-carboxylic acid
(oxetan-3-ylmethyl)-amide,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyrrolidin-1-ylm-
ethyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(tert-Butylamino-methyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-yl-
methoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-piperidin-1-ylme-
thyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-methyl-oxetan-
-3-ylmethoxymethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-methyl-oxetan-
-3-ylmethoxymethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(oxetan-3-yloxym-
ethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-Cyclopropylethynyl-2-(4-isopropyl-oxetan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one, and
9-Cyclopropylethynyl-2-((R)-4-isopropyl-oxetan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one.
16. A pharmaceutical composition comprising a compound or
pharmaceutically acceptable salt thereof, according to claim 1, and
a pharmaceutically acceptable carrier.
17. The pharmaceutical composition according to claim 16 comprising
a further therapeutic agent.
18. (canceled)
19. (canceled)
20. A method for the treatment or prophylaxis of inflammatory
conditions, comprising administering a prophylactically or
therapeutically effective amount of a compound according to claim
1, or a pharmaceutically acceptable salt, solvate, or solvate of a
pharmaceutically acceptable salt thereof.
21. The method according to claim 20, wherein the compound, or a
pharmaceutically acceptable salt thereof, is administered in
combination with a further therapeutic agent.
22. The method according to claim 20, wherein the inflammatory
condition is rheumatoid arthritis, chronic obstructive pulmonary
disease, asthma, idiopathic pulmonary fibrosis, psoriasis, Crohn's
disease, and/or ulcerative colitis.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to novel compounds that
antagonize GPR84, a G-protein-coupled receptor that is involved in
inflammatory conditions.
[0002] The present invention also provides methods for the
production of these novel compounds, pharmaceutical compositions
comprising these compounds, and methods for the prevention and/or
treatment of inflammatory conditions (e.g. inflammatory bowel
diseases (IBD), rheumatoid arthritis, vasculitis), lung diseases
(e.g. chronic obstructive pulmonary disease (COPD) and lung
interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))),
neuroinflammatory conditions, infectious diseases, autoimmune
diseases, endocrine and/or metabolic diseases, and/or diseases
involving impairment of immune cell functions by administering a
compound of the invention.
BACKGROUND OF THE INVENTION
[0003] GPR84 was recently isolated and characterized from human B
cells (Wittenberger et al., 2001, J Mol Biol, 307, 799-813) as the
result of an expressed sequence tag data mining strategy, and also
using a degenerate primer reverse transcriptase-polymerase chain
reaction (RT-PCR) approach aimed to identify novel chemokine
receptors expressed in neutrophils (Yousefi S et al. 2001 J Leukoc
Biol; 69, 1045-52).
[0004] GPR84 (also known as EX33) remained an orphan GPCR until the
identification of medium-chain FFAs with carbon chain lengths of
9-14 as ligands for this receptor (Wang et al. (2006) J. Biol.
Chem. 281:3457-64). GPR84 was described to be activated by capric
acid (C10:0), undecanoic acid (C11:0) and lauric acid (C12:0) with
potencies of 5 .mu.M, 9 .mu.M and 11 .mu.M, respectively. Three
small molecules were also described to have some GPR84 agonist
activity: 3,3'-diindolylmethane (DIM) (Wang et al. (2006) J. Biol.
Chem. 281:3457-64), embelin (WO 2007/027661) and
6-n-octylaminouracil (6-OAU) (Suzuki et al. (2013) J. Biol Chem.
288:10684-91).
[0005] GPR84 has been shown to be expressed in immune cells at
least but not limited to polymorphonuclear leukocytes (PMN),
neutrophils, monocytes, T cells and B cells. (Wang et al. (2006) J.
Biol. Chem. 281:3457-64, Yousefi S et al. 2001 J Leukoc Biol; 69,
1045-52, Venkataraman and Kuo, 2005, Immunology Letters, 101,
144-153, WO2007/027661). Higher levels of GPR84 were measured in
neutrophils and eosinophils than in T-cells and B-cells. GPR84
expression was demonstrated in tissues that may play a role in the
propagation of the inflammatory response such as lung, spleen, bone
marrow.
[0006] For example, in a recent review, Du Bois reported the
current status of therapies for lung interstitial diseases, such as
idiopathic pulmonary fibrosis (IPF). There are almost 300 distinct
injurious or inflammatory causes of interstitial lung disease that
can result in diffuse lung scarring, and the initial stages of the
IPF pathology are very likely to involve inflammation (Du Bois,
2010, Nat Rev, Drug Discovery, 9, 129), and combination therapies
involving anti-inflammatory treatment could be advantageously
used.
[0007] The expression of GPR84 was highly up-regulated in
monocytes/macrophages upon LPS stimulation (Wang et al. (2006) J.
Biol. Chem. 281:3457-64).
[0008] GPR84 knock-out (KO) mice are viable and indistinguishable
from wild-type littermate controls (Venkataraman and Kuo, 2005,
Immunology Letters, 101, 144-153). The proliferation of T and B
cells in response to various mitogens is reported to be normal in
GPR84-deficient mice (Venkataraman and Kuo, 2005, Immunology
Letters, 101, 144-153). T helper 2 (Th2) differentiated T cells
from GPR84 KO secreted higher levels of IL4, IL5, IL13, the 3 major
Th2 cytokines, compared to wild-type littermate controls. In
contrast, the production of the Th1 cytokine, INF.gamma., was
similar in Th1 differentiated T cells from GPR84 KO and wild-type
littermate (Venkataraman and Kuo, 2005, Immunology Letters, 101,
144-153).
[0009] In addition, capric acid, undecanoic acid and lauric acid
dose dependently increased the secretion of interleukin-12 p40
subunit (IL-12 p40) from RAW264.7 murine macrophage-like cells
stimulated with LPS. The pro-inflammatory cytokine IL-12 plays a
pivotal role in promoting cell-mediated immunity to eradicate
pathogens by inducing and maintaining T helper 1 (T.sub.h1)
responses and inhibiting T helper 2 (T.sub.h2) responses.
Medium-chain FFAs, through their direct actions on GPR84, may
affect T.sub.h1/T.sub.h2 balance.
[0010] Berry et al. identified a whole-blood 393-gene
transcriptional signature for active tuberculosis (TB) (Berry et
al., 2010, Nature, 466, 973-979). GPR84 was part of this
whole-blood 393-gene transcriptional signature for active TB
indicating a potential role for GPR84 in infectious diseases.
[0011] GPR84 expression was also described in microglia, the
primary immune effector cells of the central nervous system (CNS)
from myeloid-monocytic origin (Bouchard et al., 2007, Glia,
55:790-800). As observed in peripheral immune cells, GPR84
expression in microglia was highly inducible under inflammatory
conditions such as TNFa and IL1 treatment but also notably
endotoxemia and experimental autoimmune encephalomyelitis (EAE),
suggesting a role in neuro-inflammatory processes. Those results
suggest that GPR84 would be up-regulated in CNS not only during
endotoxemia and multiple sclerosis, but also in all neurological
conditions in which TNF.alpha. or IL1b pro-inflammatory cytokines
are produced, including brain injury, infection, Alzheimer's
disease (AD), Parkinson's disease (PD).
[0012] GPR84 expression was also observed in adipocytes and shown
to be enhanced by inflammatory stimuli (Nagasaki et al., 2012, FEBS
Letters, 586, 368-372). The results suggest that GPR84 emerges in
adipocytes in response to TNF.alpha. from infiltrating macrophages
and exacerbates the vicious cycle between adiposity and diabesity,
and therefore the inhibition of GPR84 activity might be beneficial
for the treatment of endocrine and/or metabolic diseases.
[0013] Therefore, the present invention provides novel compounds,
processes for their preparation and their use in the preparation of
a medicament for the treatment of inflammatory conditions (e.g.
inflammatory bowel diseases (IBD), rheumatoid arthritis,
vasculitis), lung diseases (e.g. chronic obstructive pulmonary
disease (COPD) and lung interstitial diseases (e.g. idiopathic
pulmonary fibrosis (IPF))), neuroinflammatory conditions,
infectious diseases, autoimmune diseases, endocrine and/or
metabolic diseases, and/or diseases involving impairment of immune
cell functions.
SUMMARY OF THE INVENTION
[0014] The present invention relates to novel
dihydropyrimidinoisoquinolinone compounds that antagonize GPR84,
and that are potentially useful for the treatment of inflammatory
conditions (e.g. inflammatory bowel diseases (IBD), rheumatoid
arthritis, vasculitis), lung diseases (e.g. chronic obstructive
pulmonary disease (COPD) and lung interstitial diseases (e.g.
idiopathic pulmonary fibrosis (IPF))), neuroinflammatory
conditions, infectious diseases, autoimmune diseases, endocrine
and/or metabolic diseases, and/or diseases involving impairment of
immune cell functions.
[0015] The present invention also provides methods for the
production of these compounds, pharmaceutical compositions
comprising these compounds and methods for treating inflammatory
conditions (e.g. inflammatory bowel diseases (IBD), rheumatoid
arthritis, vasculitis), lung diseases (e.g. chronic obstructive
pulmonary disease (COPD) and lung interstitial diseases (e.g.
idiopathic pulmonary fibrosis (IPF))), neuroinflammatory
conditions, infectious diseases, autoimmune diseases, endocrine
and/or metabolic diseases, and/or diseases involving impairment of
immune cell functions.
[0016] Accordingly, in a first aspect of the invention, a compound
of the invention is disclosed having a Formula Ia:
##STR00002## [0017] wherein [0018] Cy is
[0018] ##STR00003## [0019] wherein [0020] X is O or S; [0021] Y is
--CH.sub.2--, or S; [0022] Z is --CH.sub.2--; [0023] each of the
subscript n, m, or p is independently selected from 0, and 1; and A
is phenyl, or 5-6-membered heteroaryl comprising one or two
N-atoms; optionally substituted with one or more independently
selected R.sup.5 groups; [0024] any one of Cy1 and Cy2 is
optionally substituted by one or more independently selected
C.sub.1-4 alkyl groups; [0025] R.sup.1 is H, Me, or halo; [0026]
L.sub.1 is absent or is --O--, --S--, or --NR.sup.4a--; [0027] G is
[0028] R.sup.2, [0029] --W-L.sub.2-R.sup.2, or [0030]
--W-L.sub.3-R.sup.3; [0031] W is C.sub.1-4 alkylene, C.sub.2-4
alkenylene having one double bond, or C.sub.2-4 alkynylene having
one triple bond; [0032] L.sub.2 is absent or is --O--; [0033]
R.sup.2 is [0034] H, [0035] C.sub.1-8 alkyl optionally substituted
with one to three groups independently selected from [0036] OH,
[0037] halo, [0038] CN, [0039] C.sub.1-6 alkoxy, [0040] C.sub.3-7
cycloalkyl, [0041] 4-6 membered heterocycloalkyl (comprising one to
three heteroatoms independently selected from S, and O), [0042] 5-6
membered heteroaryl (comprising one to three heteroatoms
independently selected from N, S, and O), and [0043] phenyl, [0044]
C.sub.4-7 cycloalkenyl comprising one double bond, [0045] 5-7
membered heterocycloalkenyl comprising one double bond, and one to
three heteroatoms independently selected from O, and S, [0046]
C.sub.3-7 cycloalkyl (optionally substituted with one or more
independently selected R.sup.6 groups), [0047] 4-10 membered
heterocycloalkyl comprising one to two heteroatoms independently
selected from S, and O, (optionally substituted with one to three
independently selected R.sup.6 groups), [0048] 5-10 membered
heteroaryl comprising one to three heteroatoms independently
selected from N, S, and O (optionally substituted with one to three
independently selected R.sup.7 groups), or [0049] C.sub.6-10 aryl
(optionally substituted with one or more independently selected
R.sup.7 groups); [0050] L.sub.3 is --NR.sup.4b--; [0051] R.sup.3 is
[0052] C.sub.1-4 alkyl substituted with C.sub.6-10 aryl (optionally
substituted with one or more independently selected R.sup.8
groups), or 5-10 membered heteroaryl comprising one to three
heteroatoms independently selected from N, S, and O, (optionally
substituted with one or more independently selected R.sup.8
groups), [0053] 5-10 membered heteroaryl comprising one to three
heteroatoms independently selected from N, S, and O, (optionally
substituted with one or more independently selected R.sup.8
groups), or [0054] C.sub.6-10 aryl (optionally substituted with one
or more independently selected R.sup.8 groups); [0055] each
R.sup.4a and R.sup.4b is independently selected from H, C.sub.1-4
alkyl, and C.sub.3-7 cycloalkyl; [0056] R.sup.5 is halo, C.sub.1-4
alkyl or C.sub.1-4 alkoxy; [0057] R.sup.6 is oxo or R.sup.7; [0058]
R.sup.7 is [0059] OH, [0060] halo, [0061] --NO.sub.2, [0062]
C.sub.1-6 alkyl (optionally substituted with one to three groups
independently selected from halo, and OH), [0063] C.sub.1-6 alkoxy
(optionally substituted with one to three groups independently
selected from halo, and OH), [0064] C.sub.3-7 cycloalkyl, [0065]
--C(.dbd.O)OR.sup.9, [0066] --C(.dbd.O)NR.sup.10R.sup.11, [0067]
--NHC(.dbd.O)--C.sub.1i4 alkyl, [0068] --CN, [0069] phenyl, [0070]
--O-phenyl, [0071] 4-7 membered heterocycloalkyl comprising one to
three heteroatoms independently selected from N, O, and S, or
[0072] 5-6 membered heteroaryl comprising one to three heteroatoms
independently selected from N, O, and S; (optionally substituted
with one or more independently selected C.sub.1-4 alkyl, C.sub.1-4
alkoxy, CN, halo, and --C(.dbd.O)OR.sup.12); [0073] R.sup.8 is
C.sub.1-4 alkyl, or halo; and [0074] each of R.sup.9, R.sup.10,
R.sup.11 and R.sup.12, is independently selected from H and
C.sub.1-4 alkyl.
[0075] Accordingly, in another aspect of the invention, a compound
of the invention is disclosed having a Formula Ia:
##STR00004## [0076] wherein [0077] Cy is
[0077] ##STR00005## [0078] wherein [0079] X is is O or S; [0080] Y
is is --CH.sub.2--, or S; [0081] Z is is --CH.sub.2--; [0082] each
of the subscript n, m, or p is independently selected from 0, and 1
and [0083] A is phenyl, or 5-6-membered heteroaryl comprising one
or two N-atoms; optionally substituted with one or more
independently selected R.sup.5 groups; [0084] R.sup.1 is H, Me, or
halo; [0085] L.sub.1 is absent or is --O--, --S--, or
--NR.sup.4a--; [0086] G is [0087] R.sup.2 [0088]
--W-L.sub.2-R.sup.2, or [0089] --W-L.sub.3-R.sup.3; [0090] W is
C.sub.1-4 alkylene, C.sub.2-4 alkenylene having one double bond, or
C.sub.2-4 alkynylene having one triple bond; [0091] L.sub.2 is
absent or is --O--; [0092] R.sup.2 is [0093] H, [0094] C.sub.1-8
alkyl optionally substituted with one to three groups independently
selected from [0095] OH, [0096] halo, [0097] CN, [0098] C.sub.1-6
alkoxy, [0099] C.sub.3-7 cycloalkyl, [0100] 4-6 membered
heterocycloalkyl (comprising one to three heteroatoms independently
selected from S, and O), [0101] 5-6 membered heteroaryl (comprising
one to three heteroatoms independently selected from N, S, and O),
and [0102] phenyl, [0103] C.sub.4-7 cycloalkenyl comprising one
double bond, [0104] 5-7 membered heterocycloalkenyl comprising one
double bond, and one to three heteroatoms independently selected
from O, and S, [0105] C.sub.3-7 cycloalkyl (optionally substituted
with one or more independently selected R.sup.6 groups), [0106]
4-10 membered heterocycloalkyl comprising one to two heteroatoms
independently selected from S, and O, (optionally substituted with
one to three independently selected R.sup.6 groups), [0107] 5-10
membered heteroaryl comprising one to three heteroatoms
independently selected from N, S, and O (optionally substituted
with one to three independently selected R.sup.7 groups), or [0108]
C.sub.6-10 aryl (optionally substituted with one or more
independently selected R.sup.7 groups); [0109] L.sub.3 is
--NR.sup.4b--; [0110] R.sup.3 is [0111] C.sub.1-4 alkyl substituted
with C.sub.6-10 aryl (optionally substituted with one or more
independently selected R.sup.8 groups), or 5-10 membered heteroaryl
comprising one to three heteroatoms independently selected from N,
S, and O, (optionally substituted with one or more independently
selected R.sup.8 groups), [0112] 5-10 membered heteroaryl
comprising one to three heteroatoms independently selected from N,
S, and O, (optionally substituted with one or more independently
selected R.sup.8 groups), or [0113] C.sub.6-10 aryl (optionally
substituted with one or more independently selected R.sup.8
groups); [0114] each R.sup.4a and R.sup.4b is independently
selected from H, C.sub.1-4 alkyl, and C.sub.3-7 cycloalkyl; [0115]
R.sup.5 is halo, C.sub.1-4 alkyl or C.sub.1-4 alkoxy; [0116]
R.sup.6 is oxo or R.sup.7; [0117] R.sup.7 is [0118] OH, [0119]
halo, [0120] --NO.sub.2, [0121] C.sub.1-6 alkyl (optionally
substituted with one to three groups independently selected from
halo, and OH), [0122] C.sub.1-6 alkoxy (optionally substituted with
one to three groups independently selected from halo, and OH),
[0123] C.sub.3-7 cycloalkyl, [0124] --C(.dbd.O)OR.sup.9, [0125]
--C(.dbd.O)NR.sup.10R.sup.11, [0126] --NHC(.dbd.O)--C.sub.1-4
alkyl, [0127] --CN, [0128] phenyl, [0129] --O-phenyl, [0130] 4-7
membered heterocycloalkyl comprising one to three heteroatoms
independently selected from N, O, and S, or [0131] 5-6 membered
heteroaryl comprising one to three heteroatoms independently
selected from N, O, and S; (optionally substituted with one or more
independently selected C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CN, halo,
and --C(.dbd.O)OR.sup.12); [0132] R.sup.8 is C.sub.1-4 alkyl, or
halo; and [0133] each of R.sup.9, R.sup.10, R.sup.11 and R.sup.12,
is independently selected from H and C.sub.1-4 alkyl.
[0134] In a further aspect, the present invention provides
pharmaceutical compositions comprising a compound of the invention,
and a pharmaceutical carrier, excipient or diluent. Moreover, a
compound of the present invention useful in the pharmaceutical
compositions and treatment methods disclosed herein, is
pharmaceutically acceptable as prepared and used. In this aspect of
the invention, the pharmaceutical composition may additionally
comprise further active ingredients suitable for use in combination
with a compound of the invention.
[0135] In another aspect of the invention, this invention provides
novel compounds of the invention for use in therapy.
[0136] In a further aspect of the invention, this invention
provides a method of treating a mammal susceptible to or afflicted
with a condition from among those listed herein, and particularly,
such condition as may be associated with aberrant activity of GPR84
and/or aberrant GPR84 expression and/or aberrant GPR84
distribution, for example inflammatory conditions (e.g.
inflammatory bowel diseases (IBD), rheumatoid arthritis,
vasculitis), lung diseases (e.g. chronic obstructive pulmonary
disease (COPD) and lung interstitial diseases (e.g. idiopathic
pulmonary fibrosis (IPF))), neuroinflammatory conditions,
infectious diseases, autoimmune diseases, endocrine and/or
metabolic diseases, and/or diseases involving impairment of immune
cell functions, which method comprises administering a
therapeutically effective amount of a compound of the invention, or
one or more of the pharmaceutical compositions herein
described.
[0137] In a further aspect, the present invention provides a
compound of the invention for use in the treatment or prevention of
a condition selected from those listed herein, particularly such
conditions as may be associated with aberrant activity of GPR84
and/or aberrant GPR84 expression and/or aberrant GPR84 distribution
expression such as inflammatory conditions (e.g. inflammatory bowel
diseases (IBD), rheumatoid arthritis, vasculitis), lung diseases
(e.g. chronic obstructive pulmonary disease (COPD) and lung
interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))),
neuroinflammatory conditions, infectious diseases, autoimmune
diseases, endocrine and/or metabolic diseases, and/or diseases
involving impairment of immune cell functions.
[0138] In additional aspects, this invention provides methods for
synthesizing a compound of the invention, with representative
synthetic protocols and pathways disclosed herein.
[0139] Accordingly, it is a principal object of this invention to
provide a compound of the invention, which can modify the activity
of GPR84 and thus prevent or treat any conditions that may be
causally related thereto.
[0140] It is further an object of this invention to provide a
compound of the invention that can treat or alleviate conditions or
diseases or symptoms of same, such as inflammatory conditions (e.g.
inflammatory bowel diseases (IBD), rheumatoid arthritis,
vasculitis), lung diseases (e.g. chronic obstructive pulmonary
disease (COPD) and lung interstitial diseases (e.g. idiopathic
pulmonary fibrosis (IPF))), neuroinflammatory conditions,
infectious diseases, autoimmune diseases, endocrine and/or
metabolic diseases, and/or diseases involving impairment of immune
cell functions, that may be causally related to the activity and/or
expression and/or distribution of GPR84.
[0141] A still further object of this invention is to provide
pharmaceutical compositions that may be used in the treatment or
prevention of a variety of disease states, including the diseases
associated with aberrant activity of GPR84 and/or aberrant GPR84
expression and/or aberrant GPR84 distribution such as inflammatory
conditions (e.g. inflammatory bowel diseases (IBD), rheumatoid
arthritis, vasculitis), lung diseases (e.g. chronic obstructive
pulmonary disease (COPD) and lung interstitial diseases (e.g.
idiopathic pulmonary fibrosis (IPF))), neuroinflammatory
conditions, infectious diseases, autoimmune diseases, endocrine
and/or metabolic diseases, and/or diseases involving impairment of
immune cell functions.
[0142] Other objects and advantages will become apparent to those
skilled in the art from a consideration of the ensuing detailed
description.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0143] The following terms are intended to have the meanings
presented therewith below and are useful in understanding the
description and intended scope of the present invention.
[0144] When describing the invention, which may include compounds,
pharmaceutical compositions containing such compounds and methods
of using such compounds and compositions, the following terms, if
present, have the following meanings unless otherwise indicated. It
should also be understood that when described herein any of the
moieties defined forth below may be substituted with a variety of
substituents, and that the respective definitions are intended to
include such substituted moieties within their scope as set out
below. Unless otherwise stated, the term `substituted` is to be
defined as set out below. It should be further understood that the
terms `groups` and `radicals` can be considered interchangeable
when used herein.
[0145] The articles `a` and `an` may be used herein to refer to one
or to more than one (i.e. at least one) of the grammatical objects
of the article. By way of example `an analogue` means one analogue
or more than one analogue.
[0146] `Alkyl` means straight or branched aliphatic hydrocarbon
having the specified number of carbon atoms. Particular alkyl
groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched
means that one or more alkyl groups such as methyl, ethyl or propyl
is attached to a linear alkyl chain. Particular alkyl groups are
methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl,
n-pentyl, n-hexyl, and 1,2-dimethylbutyl. Particular alkyl groups
have between 1 and 4 carbon atoms.
[0147] `Alkylene` refers to divalent alkane radical groups having
the number of carbon atoms specified, in particular 1 to 6 carbon
atoms and more particularly 1 to 4 carbon atoms which can be
straight-chained or branched. This term is exemplified by groups
such as methylene (--CH.sub.2--), ethylene
(--CH.sub.2--CH.sub.2--), the propylene isomers (e.g.,
--CH.sub.2--CH.sub.2--CH.sub.2-- and --CH(CH.sub.3)--CH.sub.2--)
and the like.
[0148] `Alkenylene` refers to divalent alkene radical groups having
the number of carbon atoms and the number of double bonds
specified, in particular 2 to 6 carbon atoms and more particularly
2 to 4 carbon atoms which can be straight-chained or branched. This
term is exemplified by groups such as --CH.dbd.CH--,
--CH.sub.2--CH.dbd.CH--, --C(CH.sub.3).dbd.CH--,
--C(CH.sub.3).dbd.CH--CH.sub.2--, --C(CH.sub.3).dbd.C(CH.sub.3)--,
and --CH.sub.2--C(CH.sub.3).dbd.CH--.
[0149] `Alkynylene` refers to divalent alkyne radical groups having
the number of carbon atoms and the number of triple bonds
specified, in particular 2 to 6 carbon atoms and more particularly
2 to 4 carbon atoms which can be straight-chained or branched. This
term is exemplified by groups such as --C.ident.C--,
--CH.sub.2--C.ident.C--, and --C(CH.sub.3)H--C.ident.CH--.
[0150] `Alkoxy` refers to the group O-alkyl, where the alkyl group
has the number of carbon atoms specified. In particular the term
refers to the group --O--C.sub.1-C.sub.6 alkyl. Particular alkoxy
groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and
1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e.
with between 1 and 6 carbon atoms. Further particular alkoxy groups
have between 1 and 4 carbon atoms.
[0151] `Amino` refers to the radical --NH.sub.2.
[0152] `Aryl` refers to a monovalent aromatic hydrocarbon group
derived by the removal of one hydrogen atom from a single carbon
atom of a parent aromatic ring system. In particular aryl refers to
an aromatic ring structure, mono-cyclic or poly-cyclic that
includes the number of ring members specified. Particular aryl
groups have from 6 to 10 ring members. Where the aryl group is a
monocyclic ring system it preferentially contains 6 carbon atoms.
Particularly aryl groups include phenyl, naphthyl, indenyl, and
tetrahydronaphthyl.
[0153] `Carboxy` refers to the radical --C(O)OH.
[0154] `Cycloalkyl` refers to cyclic non-aromatic hydrocarbyl
groups having the number of carbon atoms specified. Particular
cycloalkyl groups have from 3 to 7 carbon atoms. Such cycloalkyl
groups include, by way of example, single ring structures such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and
cycloheptyl.
[0155] `Cyano` refers to the radical --CN.
[0156] `Halo` or `halogen` refers to fluoro (F), chloro (Cl), bromo
(Br) and iodo (I). Particular halo groups are either fluoro or
chloro.
[0157] `Hetero` when used to describe a compound or a group present
on a compound means that one or more carbon atoms in the compound
or group have been replaced by a nitrogen, oxygen, or sulfur
heteroatom. Hetero may be applied to any of the hydrocarbyl groups
described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g.
heterocycloalkyl, aryl, e.g. heteroaryl, and the like having from 1
to 5, and particularly from 1 to 3 heteroatoms.
[0158] `Heteroaryl` means an aromatic ring structure, mono-cyclic
or polycyclic, that includes one or more heteroatoms and the number
of ring members specified. Particular heteraryl groups have 5 to 10
ring members, or 5 to 6 ring members. The heteroaryl group can be,
for example, a five membered or six membered monocyclic ring or a
bicyclic structure formed from fused five and six membered rings or
two fused six membered rings or, by way of a further example, two
fused five membered rings. Each ring may contain up to four
heteroatoms typically selected from nitrogen, sulphur and oxygen.
Typically the heteroaryl ring will contain up to 4 heteroatoms,
more typically up to 3 heteroatoms, more usually up to 2, for
example a single heteroatom. In one embodiment, the heteroaryl ring
contains at least one ring nitrogen atom. The nitrogen atoms in the
heteroaryl rings can be basic, as in the case of an imidazole or
pyridine, or essentially non-basic as in the case of an indole or
pyrrole nitrogen. In general the number of basic nitrogen atoms
present in the heteroaryl group, including any amino group
substituents of the ring, will be less than five. Examples of five
membered monocyclic heteroaryl groups include but are not limited
to pyrrole, furan, thiophene, imidazole, furazan, oxazole,
oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole,
pyrazole, triazole and tetrazole groups. Examples of six membered
monocyclic heteroaryl groups include but are not limited to
pyridine, pyrazine, pyridazine, pyrimidine and triazine. Particular
examples of bicyclic heteroaryl groups containing a five membered
ring fused to another five membered ring include but are not
limited to imidazothiazole and imidazoimidazole. Particular
examples of bicyclic heteroaryl groups containing a six membered
ring fused to a five membered ring include but are not limited to
benzfuran, benzthiophene, benzimidazole, benzoxazole,
isobenzoxazole, benzisoxazole, benzthiazole, benzisothiazole,
isobenzofuran, indole, isoindole, isoindolone, indolizine,
indoline, isoindoline, purine (e.g., adenine, guanine), indazole,
pyrazolopyrimidine, triazolopyrimidine, benzodioxole and
pyrazolopyridine groups. Particular examples of bicyclic heteroaryl
groups containing two fused six membered rings include but are not
limited to quinoline, isoquinoline, chroman, thiochroman, chromene,
isochromene, chroman, isochroman, benzodioxan, quinolizine,
benzoxazine, benzodiazine, pyridopyridine, quinoxaline,
quinazoline, cinnoline, phthalazine, naphthyridine and pteridine
groups. Particular heteroaryl groups are those derived from
thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine,
quinoline, imidazole, oxazole and pyrazine.
[0159] Examples of representative heteroaryls include the
following:
##STR00006##
wherein each Y is selected from >C.dbd.O, NH, O and S.
[0160] As used herein, the term `heterocycloalkyl` refers to a
stable heterocyclic non-aromatic ring and/or rings containing one
or more heteroatoms independently selected from N, O and S, fused
thereto wherein the group contains the number of ring members
specified. Particular heterocycloalkyl groups have 4-10 ring
members or 5 to 7 ring members, or 5 to 6 ring members. The
heterocycloalkyl group can be, for example, a five membered or six
membered monocyclic ring or a bicyclic structure formed from fused
five and six membered rings or two fused six membered rings or, by
way of a further example, two fused five membered rings. Each ring
may contain up to four heteroatoms typically selected from
nitrogen, sulphur and oxygen. Typically the heterocycloalkyl ring
will contain up to 4 heteroatoms, more typically up to 3
heteroatoms, more usually up to 2, for example a single heteroatom.
In one embodiment, the heterocycloalkyl ring contains at least one
ring nitrogen atom. A fused heterocyclic ring system may include
carbocyclic rings and need only include one heterocyclic ring.
Examples of heterocyclic rings include, but are not limited to,
morpholine, piperidine (e.g. 1-piperidinyl, 2-piperidinyl,
3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 1-pyrrolidinyl,
2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, pyran (2H-pyran or
4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran,
dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane,
tetrahydropyran (e.g. 4-tetrahydro pyranyl), imidazoline,
imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine,
piperazine, and N-alkyl piperazines such as N-methyl piperazine.
Further examples include thiomorpholine and its S-oxide and
S,S-dioxide (particularly thiomorpholine). Still further examples
include azetidine, piperidone, piperazone, and N-alkyl piperidines
such as N-methyl piperidine. Particular examples of
heterocycloalkyl groups are shown in the following illustrative
examples:
##STR00007##
wherein each W is selected from CH.sub.2, NH, O and S; and each Y
is selected from NH, O, CO, SO.sub.2, and S.
[0161] `Hydroxy` refers to the radical --OH.
[0162] `Nitro` refers to the radical --NO.sub.2.
[0163] `Substituted` refers to a group in which one or more
hydrogen atoms are each independently replaced with the same or
different substituent(s).
[0164] `Thiol` refers to the group --SH.
[0165] `Thioalkoxy` refers to the group --SR.sup.10 where R.sup.10
is an alkyl group with the number of carbon atoms specified. In
particular thioalkoxy groups where R.sup.10 is a C.sub.1-C.sub.6
alkyl. Particular thioalkoxy groups are thiomethoxy, thioethoxy,
n-thiopropoxy, thioisopropoxy, n-thiobutoxy, tert-thiobutoxy,
sec-thiobutoxy, n-thiopentoxy, n-thiohexoxy, and
1,2-dimethylthiobutoxy. Particular thioalkoxy groups are lower
thioalkoxy, i.e. with between 1 and 6 carbon atoms. Further
particular thioalkoxy groups have between 1 and 4 carbon atoms.
[0166] As used herein, the term `substituted with one or more`
refers to one to four substituents. In one embodiment it refers to
one to three substituents. In further embodiments it refers to one
or two substituents. In a yet further embodiment it refers to one
substituent.
[0167] One having ordinary skill in the art of organic synthesis
will recognize that the maximum number of heteroatoms in a stable,
chemically feasible heterocyclic ring, whether it is aromatic or
non aromatic, is determined by the size of the ring, the degree of
unsaturation and the valence of the heteroatoms. In general, a
heterocyclic ring may have one to four heteroatoms so long as the
heteroaromatic ring is chemically feasible and stable.
[0168] `Pharmaceutically acceptable` means approved or approvable
by a regulatory agency of the Federal or a state government or the
corresponding agency in countries other than the United States, or
that is listed in the U.S. Pharmacopoeia or other generally
recognized pharmacopoeia for use in animals, and more particularly,
in humans.
[0169] `Pharmaceutically acceptable salt` refers to a salt of a
compound that is pharmaceutically acceptable and that possesses the
desired pharmacological activity of the parent compound. In
particular, such salts are non-toxic may be inorganic or organic
acid addition salts and base addition salts. Specifically, such
salts include: (1) acid addition salts, formed with inorganic acids
such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid, and the like; or formed with organic acids
such as acetic acid, propionic acid, hexanoic acid,
cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic
acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric
acid, tartaric acid, citric acid, benzoic acid,
3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic
acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
4-toluenesulfonic acid, camphorsulfonic acid,
4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic
acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary
butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic
acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic
acid, and the like; or (2) salts formed when an acidic proton
present in the parent compound either is replaced by a metal ion,
e.g., an alkali metal ion, an alkaline earth ion, or an aluminum
ion; or coordinates with an organic base such as ethanolamine,
diethanolamine, triethanolamine, N-methylglucamine and the like.
Salts further include, by way of example only, sodium, potassium,
calcium, magnesium, ammonium, tetraalkylammonium, and the like; and
when the compound contains a basic functionality, salts of non
toxic organic or inorganic acids, such as hydrochloride,
hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the
like. The term `pharmaceutically acceptable cation` refers to an
acceptable cationic counter-ion of an acidic functional group. Such
cations are exemplified by sodium, potassium, calcium, magnesium,
ammonium, tetraalkylammonium cations, and the like.
[0170] `Pharmaceutically acceptable vehicle` refers to a diluent,
adjuvant, excipient or carrier with which a compound of the
invention is administered.
[0171] `Prodrugs` refers to compounds, including derivatives of the
compounds of the invention, which have cleavable groups and become
by solvolysis or under physiological conditions the compounds of
the invention which are pharmaceutically active in vivo. Such
examples include, but are not limited to, choline ester derivatives
and the like, N-alkylmorpholine esters and the like.
[0172] `Solvate` refers to forms of the compound that are
associated with a solvent, usually by a solvolysis reaction. This
physical association includes hydrogen bonding. Conventional
solvents include water, ethanol, acetic acid and the like. The
compounds of the invention may be prepared e.g. in crystalline form
and may be solvated or hydrated. Suitable solvates include
pharmaceutically acceptable solvates, such as hydrates, and further
include both stoichiometric solvates and non-stoichiometric
solvates. In certain instances the solvate will be capable of
isolation, for example when one or more solvent molecules are
incorporated in the crystal lattice of the crystalline solid.
`Solvate` encompasses both solution-phase and isolable solvates.
Representative solvates include hydrates, ethanolates and
methanolates.
[0173] `Subject` includes humans. The terms `human`, `patient` and
`subject` are used interchangeably herein.
[0174] `Effective amount` means the amount of a compound of the
invention that, when administered to a subject for treating a
disease, is sufficient to effect such treatment for the disease.
The "effective amount" can vary depending on the compound, the
disease and its severity, and the age, weight, etc., of the subject
to be treated.
[0175] `Preventing` or `prevention` refers to a reduction in risk
of acquiring or developing a disease or disorder (i.e., causing at
least one of the clinical symptoms of the disease not to develop in
a subject that may be exposed to a disease-causing agent, or
predisposed to the disease in advance of disease onset.
[0176] The term `prophylaxis` is related to `prevention`, and
refers to a measure or procedure the purpose of which is to
prevent, rather than to treat or cure a disease. Non-limiting
examples of prophylactic measures may include the administration of
vaccines; the administration of low molecular weight heparin to
hospital patients at risk for thrombosis due, for example, to
immobilization; and the administration of an anti-malarial agent
such as chloroquine, in advance of a visit to a geographical region
where malaria is endemic or the risk of contracting malaria is
high.
[0177] `Treating` or `treatment` of any disease or disorder refers,
in one embodiment, to ameliorating the disease or disorder (i.e.,
arresting the disease or reducing the manifestation, extent or
severity of at least one of the clinical symptoms thereof). In
another embodiment `treating` or `treatment` refers to ameliorating
at least one physical parameter, which may not be discernible by
the subject. In yet another embodiment, `treating` or `treatment`
refers to modulating the disease or disorder, either physically,
(e.g., stabilization of a discernible symptom), physiologically,
(e.g., stabilization of a physical parameter), or both. In a
further embodiment, "treating" or "treatment" relates to slowing
the progression of the disease.
[0178] As used herein the term `inflammatory condition(s)` refers
to the group of conditions including, rheumatoid arthritis,
osteoarthritis, juvenile idiopathic arthritis, vasculitis,
psoriasis, gout, allergic airway disease (e.g. asthma, rhinitis),
inflammatory bowel diseases (e.g. Crohn's disease, ulcerative
colitis), and endotoxin-driven disease states (e.g. complications
after bypass surgery or chronic endotoxin states contributing to
e.g. chronic cardiac failure). Particularly the term refers to
rheumatoid arthritis, allergic airway disease (e.g. asthma) and
inflammatory bowel diseases.
[0179] As used herein, the term `infectious diseases` refers to
bacterial infectious diseases and includes but is not limited to
conditions such as sepsis, septicemia, endotoxemia, systemic
inflammatory response syndrome (SIRS), gastritis, enteritis,
enterocolitis, tuberculosis, and other infections involving, for
example, Yersinia, Salmonella, Chlamydia, Shigella, or
enterobacteria species.
[0180] As used herein the term `autoimmune disease(s)` refers to
the group of diseases including obstructive airways disease
(including conditions such as COPD (chronic obstructive pulmonary
disease)), psoriasis, asthma (e.g intrinsic asthma, extrinsic
asthma, dust asthma, infantile asthma) particularly chronic or
inveterate asthma (for example late asthma and airway
hyperreponsiveness), bronchitis, including bronchial asthma,
systemic lupus erythematosus (SLE), multiple sclerosis, type I
diabetes mellitus and complications associated therewith, atopic
eczema (atopic dermatitis), contact dermatitis and further
eczematous dermatitis, vasculitis, inflammatory bowel disease (e.g.
Crohn's disease and ulcerative colitis), atherosclerosis and
amyotrophic lateral sclerosis. Particularly the term refers to
COPD, asthma, psoriasis, systemic lupus erythematosis, type I
diabetes mellitus, vasculitis and inflammatory bowel disease.
[0181] As used herein the term `endocrine and/or metabolic
disease(s)` refers to the group of conditions involving the body's
over- or under-production of certain hormones, while metabolic
disorders affect the body's ability to process certain nutrients
and vitamins. Endocrine disorders include hypothyroidism,
congenital adrenal hyperplasia, diseases of the parathyroid gland,
diabetes mellitus, diseases of the adrenal glands (including
Cushing's syndrome and Addison's disease), and ovarian dysfunction
(including polycystic ovary syndrome), among others. Some examples
of metabolic disorders include cystic fibrosis, phenylketonuria
(PKU), diabetes, hyperlipidemia, gout, and rickets.
[0182] As used herein, the term `diseases involving impairment of
immune cell functions` includes conditions with symptoms such as
recurrent and drawn out viral and bacterial infections, and slow
recovery. Other invisible symptoms may be the inability to kill off
parasites, yeasts and bacterial pathogens in the intestines or
throughout the body.
[0183] As used herein the term `neuroinflammatory conditions`
refers to diseases or disorders characterized by abrupt neurologic
deficits associated with inflammation, demyelination, and axonal
damage, and includes but is not limited to conditions such as
Guillain-Barre syndrome (GBS), multiple sclerosis, axonal
degeneration, and autoimmune encephalomyelitis.
[0184] `Compound(s) of the invention`, and equivalent expressions,
are meant to embrace compounds of the Formula(e) as herein
described, which expression includes the pharmaceutically
acceptable salts, and the solvates, e.g., hydrates, and the
solvates of the pharmaceutically acceptable salts where the context
so permits. Similarly, reference to intermediates, whether or not
they themselves are claimed, is meant to embrace their salts, and
solvates, where the context so permits.
[0185] When ranges are referred to herein, for example but without
limitation, C.sub.1-6 alkyl, the citation of a range should be
considered a representation of each member of said range.
[0186] Other derivatives of the compounds of this invention have
activity in both their acid and acid derivative forms, but in the
acid sensitive form often offers advantages of solubility, tissue
compatibility, or delayed release in the mammalian organism (see,
Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier,
Amsterdam 1985). Prodrugs include acid derivatives well know to
practitioners of the art, such as, for example, esters prepared by
reaction of the parent acid with a suitable alcohol, or amides
prepared by reaction of the parent acid compound with a substituted
or unsubstituted amine, or acid anhydrides, or mixed anhydrides.
Simple aliphatic or aromatic esters, amides and anhydrides derived
from acidic groups pendant on the compounds of this invention are
particularly useful prodrugs. In some cases it is desirable to
prepare double ester type prodrugs such as (acyloxy)alkyl esters or
((alkoxycarbonyl)oxy)alkylesters. Particular such prodrugs are the
C.sub.1 to C.sub.8 alkyl, and substituted or
unsubstitutedC.sub.6-10 aryl, esters of the compounds of the
invention.
[0187] As used herein, the term `isotopic variant` refers to a
compound that contains unnatural proportions of isotopes at one or
more of the atoms that constitute such compound For example, an
`isotopic variant` of a compound can contain one or more
non-radioactive isotopes, such as for example, deuterium (.sup.2H
or D), carbon-13 (.sup.13C), nitrogen-15 (.sup.15N), or the like.
It will be understood that, in a compound where such isotopic
substitution is made, the following atoms, where present, may vary,
so that for example, any hydrogen may be .sup.2H/D, any carbon may
be .sup.13C, or any nitrogen may be .sup.15N, and that the presence
and placement of such atoms may be determined within the skill of
the art. Likewise, the invention may include the preparation of
isotopic variants with radioisotopes, in the instance for example,
where the resulting compounds may be used for drug and/or substrate
tissue distribution studies. The radioactive isotopes tritium, i.e.
.sup.3H, and carbon-14, i.e. .sup.14C, are particularly useful for
this purpose in view of their ease of incorporation and ready means
of detection. Further, compounds may be prepared that are
substituted with positron emitting isotopes, such as .sup.11C,
.sup.8F, .sup.15O and .sup.13N, and would be useful in Positron
Emission Topography (PET) studies for examining substrate receptor
occupancy.
[0188] All isotopic variants of the compounds provided herein,
radioactive or not, are intended to be encompassed within the scope
of the invention.
[0189] It is also to be understood that compounds that have the
same molecular formula but differ in the nature or sequence of
bonding of their atoms or the arrangement of their atoms in space
are termed `isomers`. Isomers that differ in the arrangement of
their atoms in space are termed `stereoisomers`.
[0190] Stereoisomers that are not mirror images of one another are
termed `diastereomers` and those that are non-superimposable mirror
images of each other are termed `enantiomers`. When a compound has
an asymmetric center, for example, it is bonded to four different
groups, a pair of enantiomers is possible. An enantiomer can be
characterized by the absolute configuration of its asymmetric
center and is described by the R- and S-sequencing rules of Cahn
and Prelog, or by the manner in which the molecule rotates the
plane of polarized light and designated as dextrorotatory or
levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral
compound can exist as either individual enantiomer or as a mixture
thereof. A mixture containing equal proportions of the enantiomers
is called a `racemic mixture`.
[0191] `Tautomers` refer to compounds that are interchangeable
forms of a particular compound structure, and that vary in the
displacement of hydrogen atoms and electrons. Thus, two structures
may be in equilibrium through the movement of .pi. electrons and an
atom (usually H). For example, enols and ketones are tautomers
because they are rapidly interconverted by treatment with either
acid or base. Another example of tautomerism is the aci- and
nitro-forms of phenylnitromethane, that are likewise formed by
treatment with acid or base.
[0192] Tautomeric forms may be relevant to the attainment of the
optimal chemical reactivity and biological activity of a compound
of interest.
[0193] The compounds of the invention may possess one or more
asymmetric centers; such compounds can therefore be produced as
individual (R)- or (S)-stereoisomers or as mixtures thereof.
[0194] Unless indicated otherwise, the description or naming of a
particular compound in the specification and claims is intended to
include both individual enantiomers and mixtures, racemic or
otherwise, thereof. The methods for the determination of
stereochemistry and the separation of stereoisomers are well-known
in the art.
[0195] It will be appreciated that compounds of the invention may
be metabolized to yield biologically active metabolites.
The Compounds
[0196] The present invention relates to novel compounds that
antagonize GPR84 and that may be useful for the treatment of
inflammatory conditions (e.g. inflammatory bowel diseases (IBD),
rheumatoid arthritis, vasculitis), lung diseases (e.g. chronic
obstructive pulmonary disease (COPD) and lung interstitial diseases
(e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory
conditions, infectious diseases, autoimmune diseases, endocrine
and/or metabolic diseases, and/or diseases involving impairment of
immune cell functions.
[0197] The present invention also provides methods for the
production of the compounds of the invention, pharmaceutical
compositions comprising the compounds of the invention and methods
for treating inflammatory conditions (e.g. inflammatory bowel
diseases (IBD), rheumatoid arthritis, vasculitis), lung diseases
(e.g. chronic obstructive pulmonary disease (COPD) and lung
interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))),
neuroinflammatory conditions, infectious diseases, autoimmune
diseases, endocrine and/or metabolic diseases, and/or diseases
involving impairment of immune cell functions, by administering a
compound of the invention. A compound of the invention is an
inhibitor of GPR84.
[0198] Accordingly, in a first aspect of the invention, a compound
of the invention is disclosed having a Formula Ia:
##STR00008## [0199] wherein [0200] Cy is
[0200] ##STR00009## [0201] wherein [0202] X is O or S; [0203] Y is
--CH.sub.2--, or S; [0204] Z is --CH.sub.2--; [0205] each of the
subscripts n, m, or p is independently selected from 0, and 1; and
A is phenyl, or 5-6-membered heteroaryl comprising one or two
N-atoms; optionally substituted with one or more independently
selected R.sup.5 groups; [0206] any one of Cy1 and Cy2 is
optionally substituted by one or more independently selected
C.sub.1-4 alkyl groups; [0207] R.sup.1 is H, Me, or halo; [0208]
L.sub.1 is absent or is --O--, --S--, or --NR.sup.4a--; [0209] G is
[0210] R.sup.2 [0211] --W-L.sub.2-R.sup.2, or [0212]
--W-L.sub.3-R.sup.3; [0213] W is C.sub.1-4 alkylene, C.sub.2-4
alkenylene having one double bond, or C.sub.2-4 alkynylene having
one triple bond; [0214] L.sub.2 is absent or is --O--; [0215]
R.sup.2 is [0216] H, [0217] C.sub.1-8 alkyl optionally substituted
with one to three groups independently selected from [0218] OH,
[0219] halo, [0220] CN, [0221] C.sub.1-6 alkoxy, [0222] C.sub.3-7
cycloalkyl, [0223] 4-6 membered heterocycloalkyl (comprising one to
three heteroatoms independently selected from S, and O), [0224] 5-6
membered heteroaryl (comprising one to three heteroatoms
independently selected from N, S, and O), and [0225] phenyl, [0226]
C.sub.4-7 cycloalkenyl comprising one double bond, [0227] 5-7
membered heterocycloalkenyl comprising one double bond, and one to
three heteroatoms independently selected from O, and S, [0228]
C.sub.3-7 cycloalkyl (optionally substituted with one or more
independently selected R.sup.6 groups), [0229] 4-10 membered
heterocycloalkyl comprising one to two heteroatoms independently
selected from S, and O, (optionally substituted with one to three
independently selected R.sup.6 groups), [0230] 5-10 membered
heteroaryl comprising one to three heteroatoms independently
selected from N, S, and O (optionally substituted with one to three
independently selected R.sup.7 groups), or [0231] C.sub.6-10 aryl
(optionally substituted with one or more independently selected
R.sup.7 groups); [0232] L.sub.3 is --NR.sup.4b--; [0233] R.sup.3 is
[0234] C.sub.1-4 alkyl substituted with C.sub.6-10 aryl (optionally
substituted with one or more independently selected R.sup.8
groups), or 5-10 membered heteroaryl comprising one to three
heteroatoms independently selected from N, S, and O, (optionally
substituted with one or more independently selected R.sup.8
groups), [0235] 5-10 membered heteroaryl comprising one to three
heteroatoms independently selected from N, S, and O, (optionally
substituted with one or more independently selected R.sup.8
groups), or [0236] C.sub.6-10 aryl (optionally substituted with one
or more independently selected R.sup.8 groups); each R.sup.4a and
R.sup.4b is independently selected from H, C.sub.1-4 alkyl, and
C.sub.3-7 cycloalkyl; [0237] R.sup.5 is halo, C.sub.1-4 alkyl or
C.sub.1-4 alkoxy; [0238] R.sup.6 is oxo or R.sup.7; [0239] R.sup.7
is [0240] OH, [0241] halo, [0242] --NO.sub.2, [0243] C.sub.1-6
alkyl (optionally substituted with one to three groups
independently selected from halo, and OH), [0244] C.sub.1-6 alkoxy
(optionally substituted with one to three groups independently
selected from halo, and OH), [0245] C.sub.3-7 cycloalkyl, [0246]
--C(.dbd.O)OR.sup.9, [0247] --C(.dbd.O)NR.sup.10R.sup.11, [0248]
--NHC(.dbd.O)--C.sub.1i4 alkyl, [0249] --CN, [0250] phenyl, [0251]
--O-phenyl, [0252] 4-7 membered heterocycloalkyl comprising one to
three heteroatoms independently selected from N, O, and S, or
[0253] 5-6 membered heteroaryl comprising one to three heteroatoms
independently selected from N, O, and S; (optionally substituted
with one or more independently selected C.sub.1-4 alkyl, C.sub.1-4
alkoxy, CN, halo, and --C(.dbd.O)OR.sup.12); [0254] R.sup.8 is
C.sub.1-4 alkyl, or halo; and [0255] each of R.sup.9, R.sup.10,
R.sup.11 and R.sup.12, is independently selected from H and
C.sub.1-4 alkyl.
[0256] In one embodiment, each Cy1 or Cy2 is substituted with one
or more independently selected C.sub.1-4 alkyl. In a particular
embodiment, each Cy1 or Cy2 is substituted with one or two
independently selected C.sub.1-4 alkyl. In a more particular
embodiment, each Cy1 or Cy2 is substituted with one C.sub.1-4
alkyl. In a most particular embodiment, each C.sub.1-4 alkyl is
selected from Me, Et, i-Pr, and t-Bu. In a further most particular
embodiment, the C.sub.1-4 alkyl is i-Pr.
[0257] Accordingly, in another aspect of the invention, a compound
of the invention is disclosed having a Formula Ia:
##STR00010## [0258] wherein [0259] Cy is
[0259] ##STR00011## [0260] wherein [0261] X is is O or S; [0262] Y
is is --CH.sub.2--, or S; [0263] Z is is --CH.sub.2--; [0264] each
of the subscripts n, m, or p is independently selected from 0, and
1 and [0265] A is phenyl, or 5-6-membered heteroaryl comprising one
or two N-atoms; optionally substituted with one or more
independently selected R.sup.5 groups; [0266] R.sup.1 is H, Me, or
halo; [0267] L.sub.1 is absent or is --O--, --S--, or
--NR.sup.4a--; [0268] G is [0269] R.sup.2 [0270]
--W-L.sub.2-R.sup.2, or [0271] --W-L.sub.3-R.sup.3; [0272] W is
C.sub.1-4 alkylene, C.sub.2-4 alkenylene having one double bond, or
C.sub.2-4 alkynylene having one triple bond; [0273] L.sub.2 is
absent or is --O--; [0274] R.sup.2 is [0275] H, [0276] C.sub.1-8
alkyl optionally substituted with one to three groups independently
selected from [0277] OH, [0278] halo, [0279] CN, [0280] C.sub.1-6
alkoxy, [0281] C.sub.3-7 cycloalkyl, [0282] 4-6 membered
heterocycloalkyl (comprising one to three heteroatoms independently
selected from S, and O), [0283] 5-6 membered heteroaryl (comprising
one to three heteroatoms independently selected from N, S, and O),
and [0284] phenyl, [0285] C.sub.4-7 cycloalkenyl comprising one
double bond, [0286] 5-7 membered heterocycloalkenyl comprising one
double bond, and one to three heteroatoms independently selected
from O, and S, [0287] C.sub.3-7 cycloalkyl (optionally substituted
with one or more independently selected R.sup.6 groups), [0288]
4-10 membered heterocycloalkyl comprising one to two heteroatoms
independently selected from S, and O, (optionally substituted with
one to three independently selected R.sup.6 groups), [0289] 5-10
membered heteroaryl comprising one to three heteroatoms
independently selected from N, S, and O (optionally substituted
with one to three independently selected R.sup.7 groups), or [0290]
C.sub.6-10 aryl (optionally substituted with one or more
independently selected R.sup.7 groups); [0291] L.sub.3 is
--NR.sup.4b--; [0292] R.sup.3 is [0293] C.sub.1-4 alkyl substituted
with C.sub.6-10 aryl (optionally substituted with one or more
independently selected R.sup.8 groups), or 5-10 membered heteroaryl
comprising one to three heteroatoms independently selected from N,
S, and O, (optionally substituted with one or more independently
selected R.sup.8 groups), [0294] 5-10 membered heteroaryl
comprising one to three heteroatoms independently selected from N,
S, and O, (optionally substituted with one or more independently
selected R.sup.8 groups), or [0295] C.sub.6-10 aryl (optionally
substituted with one or more independently selected R.sup.8
groups); [0296] Each R.sup.4a and R.sup.4b is independently
selected from H, C.sub.1-4 alkyl, and C.sub.3-7 cycloalkyl; [0297]
R.sup.5 is halo, C.sub.1-4 alkyl or C.sub.1-4 alkoxy; [0298]
R.sup.6 is oxo or R.sup.7; [0299] R.sup.7 is [0300] OH, [0301]
halo, [0302] --NO.sub.2, [0303] C.sub.1-6 alkyl (optionally
substituted with one to three groups independently selected from
halo, and OH), [0304] C.sub.1-6 alkoxy (optionally substituted with
one to three groups independently selected from halo, and OH),
[0305] C.sub.3-7 cycloalkyl, [0306] --C(.dbd.O)OR.sup.9, [0307]
--C(.dbd.O)NR.sup.10R.sup.11, [0308] --NHC(.dbd.O)--C.sub.1i4
alkyl, [0309] --CN, [0310] phenyl, [0311] --O-phenyl, [0312] 4-7
membered heterocycloalkyl comprising one to three heteroatoms
independently selected from N, O, and S, or [0313] 5-6 membered
heteroaryl comprising one to three heteroatoms independently
selected from N, O, and S; (optionally substituted with one or more
independently selected C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CN, halo,
and --C(.dbd.O)OR.sup.12); [0314] R.sup.8 is C.sub.1-4 alkyl, or
halo; and [0315] each of R.sup.9, R.sup.10, R.sup.11 and R.sup.12,
is independently selected from H and C.sub.1-4 alkyl.
[0316] In one embodiment, the compound of the invention is
according to Formula Ib:
##STR00012##
wherein Cy, R.sup.1, L.sub.1 and G are as previously described.
[0317] In another embodiment, the compound of the invention is
according to Formula Ic:
##STR00013##
wherein Cy, R.sup.1, L.sub.1 and G are as previously described.
[0318] In one embodiment, the compound of the invention is
according to Formula Ia, Ib, or Ic, wherein Cy is Cy1, and wherein
X, the subscript n, and the ring A are as described above. In a
particular embodiment, the subscript n is 0, or the subscript n is
1 and X is O. In a more particular embodiment, the subscript n is 1
and X is O.
[0319] In another particular embodiment, the compound of the
invention is according to Formula Ia, Ib, or Ic, wherein Cy is Cy1,
wherein the subscript n is 0, or the subscript n is 1 and X is O,
and the ring A is phenyl. In a more particular embodiment, the
subscript n is 1 and X is O, and the ring A is phenyl.
[0320] In yet another particular embodiment, the compound of the
invention is according to Formula Ia, Ib, or Ic, wherein Cy is Cy1,
wherein the subscript n is 0, or the subscript n is 1 and X is O,
and the ring A is pyridinyl. In a more particular embodiment, the
subscript n is 1 and X is O, and the ring A is pyridinyl.
[0321] In one embodiment, the compound of the invention is
according to Formula Ia, Ib, or Ic, wherein Cy is Cy2, wherein Z,
Y, the subscript m, and the subscript p are as described above. In
a particular embodiment, the subscript m is 0, the subscript p is 1
and Y is --CH.sub.2--. In another particular embodiment, the
subscript m is 1, Z is --CH.sub.2--, the subscript p is 1 and Y is
--CH.sub.2--. In yet another particular embodiment, the subscript m
is 1, Z is --CH.sub.2--, the subscript p is 1 and Y is S. In a
further particular embodiment, the subscript m and the subscript p
are both 0.
[0322] In one embodiment, the compound of the invention is
according to Formula Ia, Ib, or Ic, wherein R.sup.1 is Me, F, or
Cl.
[0323] In one embodiment, the compound of the invention is
according to Formula Ia, Ib, or Ic, wherein R.sup.1 is H.
[0324] In one embodiment, the compound of the invention is
according to any one of Formulae IIa-IIi:
##STR00014## ##STR00015## ##STR00016##
wherein L.sub.1, W, L.sub.2, L.sub.3, R.sup.2 and R.sup.3 are as
described previously.
[0325] In one embodiment, the compound of the invention is
according to any one of Formulae IIIa-Illi:
##STR00017## ##STR00018## ##STR00019##
wherein L.sub.1, W, L.sub.2, L.sub.3, R.sup.2 and R.sup.3 are as
described previously.
[0326] In one embodiment, the compound of the invention is
according to any one of Formulae IVa-IVi:
##STR00020## ##STR00021## ##STR00022##
wherein L.sub.1, W, L.sub.2, L.sub.3, R.sup.2 and R.sup.3 are as
described previously.
[0327] In one embodiment, the compound of the invention is
according to any one of Formulae Ia-IVi, wherein L.sub.1 is absent,
or is --O--. In a preferred embodiment, L.sub.1 is absent.
[0328] In another embodiment, the compound of the invention is
according to any one of Formulae Ia-IVi, wherein L.sub.1 is
--NR.sup.4a--, wherein R.sup.4a is as described previously. In a
preferred embodiment, R.sup.4a is H, Me, Et, or cyclopropyl. In a
more preferred embodiment, R.sup.4a is H.
[0329] In one embodiment, the compound of the invention is
according to any one of Formulae Ia-Ic, IId-IIi, IIId-IIIi, or
IVd-IVi, wherein W is C.sub.1-4 alkylene. In a preferred
embodiment, W is --CH.sub.2--, --CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--CH(CH.sub.3)--,
--CH.sub.2--CH(--CH.sub.2--CH.sub.3)--,
--CH.sub.2--C(CH.sub.3).sub.2--, or
--CH.sub.2--CH.sub.2--CH.sub.2--. In a more preferred embodiment, W
is --CH.sub.2--. In another more preferred embodiment, W
is-CH.sub.2--CH.sub.2--.
[0330] In one embodiment, the compound of the invention is
according to any one of Formulae Ia-Ic, IId-IIi, IIId-IIIi, or
IVd-IVi, wherein W is C.sub.2-4 alkenylene having one double bond.
In a preferred embodiment, W is --CH.dbd.CH--,
--CH.sub.2--CH.dbd.CH--, or --CH.dbd.CH--CH.sub.2. In a more
preferred embodiment, W is --CH.dbd.CH--. In another more preferred
embodiment, W is --CH.sub.2--CH.dbd.CH--.
[0331] In one embodiment, the compound of the invention is
according to any one of Formulae Ia-Ic, IId-IIi, IIId-IIIi, or
IVd-IVi, wherein W is C.sub.2-4 alkynylene having one triple bond.
In a preferred embodiment, W is --C.ident.C--,
--CH.sub.2--C.ident.C--, or --C.ident.C--CH.sub.2. In a more
preferred embodiment, W is --C.ident.C--. In another more preferred
embodiment, W is --CH.sub.2--C.ident.C--.
[0332] In one embodiment, the compound of the invention is
according to any one of Formulae Ia-Ic, IId, IIe, IIf, IIId, IIIe,
IIIf, IVd, IVe, or IVf, wherein L.sub.2 is absent. In another
embodiment, L.sub.2 is --O--.
[0333] In one embodiment, the compound of the invention is
according to any one of Formulae Ia-Ic, IId, IIe, IIf, IIId, IIIe,
IIIf, IVd, We, or IVf, wherein L.sub.1 is absent or is --O--, W is
C.sub.1-4 alkylene; and L.sub.2 and R.sup.2 are as described
previously. In a preferred embodiment, W is --CH.sub.2--,
--CH.sub.2--CH.sub.2--, or --CH.sub.2--CH.sub.2--CH.sub.2--. In a
more preferred embodiment, W is --CH.sub.2--. In another preferred
embodiment, W is-CH.sub.2--CH.sub.2--.
[0334] In another embodiment, the compound of the invention is
according to any one of Formulae Ia-Ic, IId, IIe, IIf, IIId, IIIe,
IIf, IVd, IVe, or IVf, wherein L.sub.1 is absent or is --O--, W is
C.sub.2-4 alkenylene having one double bond; and L.sub.2 and
R.sup.2 are as described previously. In a preferred embodiment, W
is --CH.dbd.CH--, --CH.sub.2--CH.dbd.CH--, or
--CH.dbd.CH--CH.sub.2. In a more preferred embodiment, W is
--CH.dbd.CH--. In another more preferred embodiment, W is
--CH.sub.2--CH.dbd.CH--.
[0335] In yet another embodiment, the compound of the invention is
according to any one of Formulae Ia-Ic, IId, IIe, IIf, IIId, IIIe,
IIIf, IVd, IVe, or IVf, wherein L.sub.1 is absent, W is C.sub.2-4
alkynylene having one triple bond; and L.sub.2 and R.sup.2 are as
described previously. In a preferred embodiment, W is
--C.ident.C--, --CH.sub.2--C.ident.C--, or --C.ident.C--CH.sub.2.
In a more preferred embodiment, W is --C.ident.C--. In another more
preferred embodiment, W is --CH.sub.2--C.ident.C--.
[0336] In one embodiment, the compound of the invention is
according to any one of Formulae Ia-Ic, IId, IIe, IIf, IIId, IIIe,
IIf, IVd, IVe, or IVf, wherein L.sub.1 and L.sub.2 are absent, W is
C.sub.1-4 alkylene; and R.sup.2 is as described previously. In a
preferred embodiment, W is --CH.sub.2--, --CH.sub.2--CH.sub.2--, or
--CH.sub.2--CH.sub.2--CH.sub.2--. In a more preferred embodiment, W
is --CH.sub.2--. In another more preferred embodiment, W is
--CH.sub.2--CH.sub.2--.
[0337] In another embodiment, the compound of the invention is
according to any one of Formulae Ia-Ic, IId, IIe, IIf, IIId, IIIe,
IIIf, IVd, IVe, or IVf, wherein L.sub.1 and L.sub.2 are absent, W
is C.sub.2-4 alkenylene having one double bond; and R.sup.2 is as
described previously. In a preferred embodiment, W is
--CH.dbd.CH--, --CH.sub.2--CH.dbd.CH--, or --CH.dbd.CH--CH.sub.2.
In a more preferred embodiment, W is --CH.dbd.CH--. In another more
preferred embodiment, W is --CH.sub.2--CH.dbd.CH--.
[0338] In yet another embodiment, the compound of the invention is
according to any one of Formulae Ia-Ic, IId, IIe, IIf, IIId, IIIe,
IIIf, IVd, IVe, or IVf, wherein L.sub.1 and L.sub.2 are absent, W
is C.sub.2-4 alkynylene having one triple bond; and R.sup.2 is as
described previously. In a preferred embodiment, W is
--C.ident.C--, --CH.sub.2--C.ident.C--, or --C.ident.C--CH.sub.2.
In a more preferred embodiment, W is --C.ident.C--. In another more
preferred embodiment, W is --CH.sub.2--C.ident.C--.
[0339] In yet another embodiment, the compound of the invention is
according to any one of Formulae Ia-Ic, IId, IIe, IIf, IIId, IIIe,
IIIf, IVd, IVe, or IVf, wherein L.sub.1 is absent, L.sub.2 is
--O--, W is C.sub.2-4 alkynylene having one triple bond; and
R.sup.2 is as described previously. In a preferred embodiment, W is
--C.ident.C--, --CH.sub.2--C.ident.C--, or --C.ident.C--CH.sub.2.
In a more preferred embodiment, W is --C.ident.C--. In another more
preferred embodiment, W is --CH.sub.2--C.ident.C--.
[0340] In yet a further embodiment, the compound of the invention
is according to any one of Formulae Ia-Ic, IId, IIe, IIf, IIId,
IIIe, IIIf, IVd, IVe, or IVf, and wherein -L.sub.1-W-L.sub.2- is
selected from --CH.sub.2--CH.sub.2--, --O--CH.sub.2--,
--O--CH.sub.2--CH.sub.2--, --O--CH.sub.2--CH.sub.2--O--,
--C.ident.C--, --C.ident.C--CH.sub.2--.
[0341] In one embodiment, the compound of the invention is
according to any one of Formulae Ia-IIf, IIIa-IIIf, or IVa-IVf,
wherein R.sup.2 is H.
[0342] In another embodiment, the compound of the invention is
according to any one of Formulae Ia-IIf, IIIa-IIIf, or IVa-IVf,
wherein R.sup.2 is C.sub.1-8 alkyl. In a preferred embodiment,
R.sup.2 is Me, Et, n-Pr, i-Pr, i-Bu, or t-Bu. In a more preferred
embodiment, R.sup.2 is Me, Et, i-Pr or t-Bu. In a more preferred
embodiment, R.sup.2 is t-Bu.
[0343] In one embodiment, the compound of the invention is
according to any one of Formulae Ia-IIf, IIIa-IIIf, or IVa-IVf,
wherein R.sup.2 is C.sub.1-8 alkyl substituted with one to three
groups selected from OH, halo, CN, C.sub.1-6 alkoxy, C.sub.3-7
cycloalkyl, 4-6 membered heterocycloalkyl (comprising one to three
heteroatoms independently selected from S, and O), 5-6 membered
heteroaryl (comprising one to three heteroatoms independently
selected from N, S, and O), and phenyl. In a preferred embodiment,
R.sup.2 is Me, Et, n-Pr, i-Pr, i-Bu, or t-Bu substituted with one
to three groups selected from OH, halo, CN, C.sub.1-6 alkoxy,
C.sub.3-7 cycloalkyl, 4-6 membered heterocycloalkyl (comprising one
to three heteroatoms independently selected from S, and O), 5-6
membered heteroaryl (comprising one to three heteroatoms
independently selected from N, S, and O), and phenyl. In another
preferred embodiment, is C.sub.1-8 alkyl substituted with one to
three groups selected from OH, F, Cl, CN, --OMe, --OEt, Oi-Pr,
cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl,
tetrahydropyranyl, pyrralolyl, imidazolyl, triazolyl, oxazolyl,
thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and phenyl. In a more
preferred embodiment, R.sup.2 is Me, Et, n-Pr, i-Pr, i-Bu, or t-Bu
substituted with one to three groups selected from OH, F, Cl, CN,
--OMe, --OEt, --Oi-Pr, cyclopropyl, cyclobutyl, oxetanyl,
tetrahydrofuranyl, tetrahydropyranyl, pyrralolyl, imidazolyl,
triazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl
and phenyl.
[0344] In another embodiment, the compound of the invention is
according to any one of Formulae Ia-IIf, IIIa-IIIf, or IVa-IVf,
wherein R.sup.2 is C.sub.1-8 alkyl substituted with one group
selected from OH, halo, CN, C.sub.1-6 alkoxy, C.sub.3-7 cycloalkyl,
4-6 membered heterocycloalkyl (comprising one to three heteroatoms
independently selected from S, and O), 5-6 membered heteroaryl
(comprising one to three heteroatoms independently selected from N,
S, and O), and phenyl. In a preferred embodiment, R.sup.2 is Me,
Et, n-Pr, i-Pr, i-Bu, or t-Bu substituted with one group selected
from OH, halo, CN, C.sub.1-6 alkoxy, C.sub.3-7 cycloalkyl, 4-6
membered heterocycloalkyl (comprising one to three heteroatoms
independently selected from S, and O), 5-6 membered heteroaryl
(comprising one to three heteroatoms independently selected from N,
S, and O), and phenyl. In another preferred embodiment, R.sup.2 is
C.sub.---8 alkyl substituted with one group selected from OH, F,
Cl, CN, --OMe, --OEt, --Oi-Pr, cyclopropyl, cyclobutyl, oxetanyl,
tetrahydrofuranyl, tetrahydropyranyl, pyrralolyl, imidazolyl,
triazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,
and phenyl. In a more preferred embodiment, R.sup.2 is Me, Et,
n-Pr, i-Pr, i-Bu, or t-Bu substituted with one group selected from
OH, F, Cl, CN, --OMe, --OEt, --Oi-Pr, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl,
tetrahydropyranyl, pyrralolyl, imidazolyl, triazolyl, oxazolyl,
thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and phenyl. In a most
preferred embodiment, R.sup.2 is --CH.sub.2--OH,
--C(CH.sub.3).sub.2--OH, --CH(OH)CH.sub.3,
--CH(OH)--C.sub.2H.sub.5, --CH(OH)--C.sub.3H.sub.7,
--C(OH)(C.sub.2H.sub.5).sub.2, --C(OH)H--CH(CH.sub.3).sub.2,
--C(OH)H--CH.sub.2--CH(CH.sub.3).sub.2,
--C(OH)H--C(CH.sub.3).sub.3, --CH.sub.2--CN, --CH.sub.2--OCH.sub.3,
--CH.sub.2--CH.sub.2--OCH.sub.3, --CH(OCH.sub.3)--CH.sub.3,
--C(OCH.sub.3)H--CH(CH.sub.3).sub.2, --CH.sub.2--F,
--CH.sub.2--CH.sub.2--F, --CH.sub.2-cyclopropyl,
--CH.sub.2-cyclopentyl, --CH.sub.2-oxetanyl,
--CH.sub.2-tetrahydrofuranyl, or --CH.sub.2-tetrahydropyranyl.
[0345] In one embodiment, the compound of the invention is
according to any one of Formulae Ia-IIf, IIIa-IIIf, or IVa-IVf,
wherein R.sup.2 is C.sub.4-7 cycloalkenyl comprising one double
bond. In a preferred embodiment, R.sup.2 is cyclohexenyl.
[0346] In one embodiment, the compound of the invention is
according to any one of Formulae Ia-IIf, IIIa-IIIf, or IVa-IVf,
wherein R.sup.2 is 5-7 membered heterocycloalkenyl comprising one
double bond, and one to three heteroatoms independently selected
from N, O, and S. In a preferred embodiment, R.sup.2 is
dihydropyranyl.
[0347] In one embodiment, the compound of the invention is
according to any one of Formulae Ia-IIf, IIIa-IIIf, or IVa-IVf,
wherein R.sup.2 is unsubstituted C.sub.3-7 cycloalkyl. In a
preferred embodiment, R.sup.2 is cyclopropyl, cyclobutyl,
cyclopentyl, or cyclohexyl. In a more preferred embodiment, R.sup.2
is cyclopropyl.
[0348] In another embodiment, the compound of the invention is
according to any one of Formulae Ia-IIf, IIIa-IIIf, or IVa-IVf,
wherein R.sup.2 is C.sub.3-7 cycloalkyl substituted with one to
three independently selected R.sup.6 groups. In a preferred
embodiment, R.sup.2 is C.sub.3-7 cycloalkyl substituted with one
R.sup.6 group. In a more preferred embodiment, R.sup.2 is
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which
is substituted with one R.sup.6 group. In another more preferred
embodiment, R.sup.2 is C.sub.3-7 cycloalkyl substituted with one
R.sup.6 group, wherein R.sup.6 is oxo, or R.sup.7, and R.sup.7 is
OH, or C.sub.1-6 alkyl. In a most preferred embodiment, R.sup.2 is
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which
is substituted with one R.sup.6 group, wherein R.sup.6 is oxo, or
R.sup.7 and R.sup.7 is OH, or C.sub.1-6 alkyl. In a further most
preferred embodiment, R.sup.2 is cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl, each of which is substituted with one
R.sup.6 group, wherein R.sup.6 is R.sup.7 and R.sup.7 is OH.
[0349] In one embodiment, the compound of the invention is
according to any one of Formulae Ia-IIf, IIIa-IIIf, or IVa-IVf,
wherein R.sup.2 is 4-10 membered heterocycloalkyl comprising one to
two heteroatoms independently selected from S, and O. In a
preferred embodiment, R.sup.2 is oxetanyl, tetrahydrofuranyl,
tetrahydropyranyl, or dioxanyl.
[0350] In another embodiment, the compound of the invention is
according to any one of Formulae Ia-IIf, IIIa-IIIf, or IVa-IVf,
R.sup.2 is 4-10 membered heterocycloalkyl comprising one to two
heteroatoms independently selected from S, and O, substituted with
one to three independently selected R.sup.6 groups. In a preferred
embodiment, R.sup.2 is 4-10 membered heterocycloalkyl comprising
one to two heteroatoms independently selected from S, and O,
substituted with one R.sup.6 group. In a more preferred embodiment,
R.sup.2 is 4-10 membered heterocycloalkyl comprising one to two
heteroatoms independently selected from S, and O, substituted with
one R.sup.6 group, wherein R.sup.6 is selected from oxo, and
R.sup.7, and R.sup.7 is OH, or C.sub.1-6 alkyl. In another more
preferred embodiment, R.sup.2 is oxetanyl, tetrahydrofuranyl,
tetrahydropyranyl, or dioxanyl, each of which is substituted with
one R.sup.6 group. In a most preferred embodiment, R.sup.2 is
oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl, each
of which is substituted with one R.sup.6 group, wherein R.sup.6 is
selected from oxo, and R.sup.7, and R.sup.7 is OH, or C.sub.1-6
alkyl,
[0351] In one embodiment, the compound of the invention is
according to any one of Formulae Ia-IIf, IIIa-IIIf, or IVa-IVf,
R.sup.2 is 5-10 membered heteroaryl comprising one to three
heteroatoms independently selected from N, S, and O. In a preferred
embodiment, R.sup.2 is furanyl, thienyl, oxazolyl, thiazolyl,
oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl,
pyrazinyl, pyrimidinyl, indanyl, or indazolyl.
[0352] In another embodiment, the compound of the invention is
according to any one of Formulae Ia-IIf, IIIa-IIIf, or IVa-IVf,
R.sup.2 is 5-10 membered heteroaryl comprising one to three
heteroatoms independently selected from N, S, and O, substituted
with one to three independently selected R.sup.7 groups. In a
preferred embodiment, R.sup.2 is 5-10 membered heteroaryl
comprising one to three heteroatoms independently selected from N,
S, and O, substituted substituted with one or two independently
selected R.sup.7 groups. In a more preferred embodiment, R.sup.2 is
furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl,
imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl,
or indazolyl, substituted with one or two independently selected
R.sup.7 groups. In another more preferred embodiment, R.sup.2 is
5-10 membered heteroaryl comprising one to three heteroatoms
independently selected from N, S, and O, substituted with one or
two independently selected R.sup.7 groups, wherein each R.sup.7 is
independently selected from OH, halo, C.sub.1-6 alkyl, C.sub.1-6
alkyl substituted with one or more halo, C.sub.1-6 alkoxy, --CN,
C.sub.3-7 cycloalkyl, 4-7 membered heterocycloalkyl comprising one
to three heteroatoms independently selected from N, O, and S, and
phenyl. In most preferred embodiment, R.sup.2 is furanyl, thienyl,
oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl,
triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or
indazolyl, each of which is substituted with one or two
independently selected R.sup.7 groups, wherein each R.sup.7 is
independently selected from OH, halo, C.sub.1-6 alkyl, C.sub.1-6
alkyl substituted with one or more halo, C.sub.1-6 alkoxy, --CN,
C.sub.3-7 cycloalkyl, 4-7 membered heterocycloalkyl comprising one
to three heteroatoms independently selected from N, O, and S, and
phenyl. In another most preferred embodiment, R.sup.2 is 5-10
membered heteroaryl comprising one to three heteroatoms
independently selected from N, S, and O, substituted with one or
two independently selected R.sup.7 groups, wherein each R.sup.7 is
independently selected from OH, F, Cl, Me, Et, Pr, i-Pr, t-Bu,
--CF.sub.3, --OMe, --OEt, Oi-Pr, --CN, cyclopropyl, pyrrolidinyl,
morpholinyl, piperidinyl, or phenyl. In further most preferred
embodiment, R.sup.2 is furanyl, thienyl, oxazolyl, thiazolyl,
oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl,
pyrazinyl, pyrimidinyl, indanyl, or indazolyl, each of which is
substituted with one or two independently selected R.sup.7 groups,
wherein each R.sup.7 is independently selected from OH, F, Cl, Me,
Et, Pr, i-Pr, t-Bu, --CF.sub.3, --OMe, --OEt, --Oi-Pr, --CN,
cyclopropyl, pyrrolidinyl, morpholinyl, piperidinyl, and
phenyl.
[0353] In another embodiment, the compound of the invention is
according to any one of Formulae Ia-IIf, IIIa-IIIf, or IVa-IVf,
R.sup.2 is C.sub.6-10 aryl. In a preferred embodiment, R.sup.2 is
phenyl.
[0354] In another embodiment, the compound of the invention is
according to any one of Formulae Ia-IIf, IIIa-IIIf, or IVa-IVf,
R.sup.2 is C.sub.6-10 aryl substituted with one or more
independently selected R.sup.7 groups. In a preferred embodiment,
R.sup.2 is C.sub.6-10 aryl substituted with one or two
independently selected R.sup.7 groups. In a more preferred
embodiment, R.sup.2 is C.sub.6-10 aryl substituted with one or two
independently selected R.sup.7 groups, wherein each R.sup.7 group
is selected from halo, CN, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or
--NHC(.dbd.O)--C.sub.1-4 alkyl. In another more preferred
embodiment, R.sup.2 is C.sub.6-10 aryl substituted with one or two
independently selected R.sup.7 groups, wherein each R.sup.7 group
is selected from --C(.dbd.O)NR.sup.10R.sup.11, and each R.sup.10
and R.sup.11 is independently selected from from H and C.sub.1-4
alkyl. In yet another more preferred embodiment, R.sup.2 is phenyl
substituted with one or two independently selected R.sup.6 groups.
In a most preferred embodiment, R.sup.2 is phenyl substituted with
one or two independently selected R.sup.7 groups, wherein each
R.sup.7 group is selected from halo, CN, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, and --NHC(.dbd.O)--C.sub.1-4 alkyl. In another most
preferred embodiment, R.sup.2 is phenyl substituted with one or two
independently selected R.sup.7 groups, wherein each R.sup.7 group
is selected from --C(.dbd.O)NR.sup.10R.sup.11, and each R.sup.10
and R.sup.11 is independently selected from from H and C.sub.1-4
alkyl. In a further most preferred embodiment R.sup.2 is phenyl
substituted with one or two independently selected R.sup.7 groups,
wherein each R.sup.7 group is selected from F, Cl, CN, Me, --OMe,
--OEt, and --NHC(.dbd.O)Me. In another further most preferred
embodiment R.sup.2 is phenyl substituted with one or two
independently selected R.sup.7 groups, wherein each R.sup.7 group
is selected from --C(.dbd.O)NH.sub.2, and --C(.dbd.O)NHMe.
[0355] In another embodiment, the compound of the invention is
according to any one of Formulae Ia-Ic, IIg-IIi, IIIg-IIIi, or
IVg-IVi, wherein L.sub.3 is --NR.sup.4b-, and L.sub.1, W and
R.sup.4b are as described previously. In a preferred embodiment,
R.sup.4b is H, Me, Et, or cyclopropyl. In a more preferred
embodiment, R.sup.4a is H.
[0356] In another embodiment, the compound of the invention is
according to any one of Formulae Ia-Ic, IIg-IIi, IIIg-IIIi, or
IVg-IVi, wherein L.sub.1, W and L.sub.3 are as described
previously, and R.sup.3 is C.sub.1-4 alkyl substituted with
C.sub.6-10 aryl optionally substituted with one or more
independently selected R.sup.7 groups, or 5-10 membered heteroaryl
comprising one to three heteroatoms independently selected from N,
S, and O, optionally substituted with one or more independently
selected R.sup.8 groups. In a preferred embodiment, R.sup.3 is Me
or Et, each of which is substituted with C.sub.6-10 aryl optionally
substituted with one or more independently selected R.sup.8
groups), or 5-10 membered heteroaryl comprising one to three
heteroatoms independently selected from N, S, and O, optionally
substituted with one or more independently selected R.sup.8 groups.
In another preferred embodiment, R.sup.3 is C.sub.1-4 alkyl
substituted with phenyl, or pyridinyl, each of which is optionally
substituted with one or more independently selected R.sup.8 groups.
In a more preferred embodiment, R.sup.3 is C.sub.1-4 alkyl
substituted with phenyl, or pyridinyl. In a more preferred
embodiment, R.sup.3 is C.sub.1-4 alkyl substituted with phenyl, or
pyridinyl, each of which is substituted with Me, Et, F, or Cl. In a
most preferred embodiment, R.sup.3 is Me or Et, each of which is
substituted with phenyl, or pyridinyl. In a more preferred
embodiment, R.sup.3 is Me or Et, each of which is substituted with
phenyl, or pyridinyl, each of which is substituted with Me, Et, F,
or Cl.
[0357] In one embodiment, the compound of the invention is
according to any one of Formulae Ia-Ic, IIg-IIi, IIIg-IIIi, or
IVg-IVi, wherein L.sub.1, W and L.sub.3 are as described
previously, and R.sup.3 is 5-10 membered heteroaryl comprising one
to three heteroatoms independently selected from N, S, and O. In a
preferred embodiment, R.sup.3 is pyridinyl.
[0358] In one embodiment, the compound of the invention is
according to any one of Formulae Ia-Ic, IIg-IIi, IIIg-IIIi, or
IVg-IVi, wherein L.sub.1, W and L.sub.3 are as described
previously, and R.sup.3 is 5-10 membered heteroaryl comprising one
to three heteroatoms independently selected from N, S, and O,
substituted with one or more independently selected R.sup.8 groups,
wherein each R.sup.8 group is as described previously. In a
preferred embodiment, R.sup.3 is pyridinyl, substituted with one or
more independently selected R.sup.8 groups, wherein each R.sup.8
group is as described previously. In another preferred embodiment,
R.sup.3 is 5-10 membered heteroaryl comprising one to three
heteroatoms independently selected from N, S, and O, substituted
with one or more independently selected R.sup.8 groups, wherein
each R.sup.8 group is selected from Me, Et, F, and Cl. In a more
preferred embodiment, R.sup.3 is pyridinyl substituted with one or
more independently selected R.sup.8 groups, wherein each R.sup.8
group is selected from Me, Et, F, and Cl. In a most preferred
embodiment, R.sup.3 is pyridinyl substituted with one R.sup.8 group
selected from Me, Et, F, and Cl.
[0359] In one embodiment, the compound of the invention is
according to one of Formulae I or IIg-IIi, wherein L.sub.1, W and
L.sub.3 are as described previously, and R.sup.3 is C.sub.6-10
aryl. In a preferred embodiment, R.sup.3 is phenyl.
[0360] In one embodiment, the compound of the invention is
according to any one of Formulae Ia-Ic, IIg-IIi, IIIg-IIIi, or
IVg-IVi, wherein L.sub.1, W and L.sub.3 are as described
previously, and R.sup.3 is C.sub.6-10 aryl substituted with one or
more independently selected R.sup.8 groups, wherein each R.sup.8
group is as described previously. In a preferred embodiment,
R.sup.3 is phenyl, substituted with one or more independently
selected R.sup.8 groups, wherein each R.sup.8 group is as described
previously. In another preferred embodiment, R.sup.3 is C.sub.6-10
aryl substituted with one or more independently selected R.sup.8
groups, wherein each R.sup.8 group is selected from Me, Et, F, and
Cl. In a more preferred embodiment, R.sup.3 is phenyl substituted
with one or more independently selected R.sup.8 groups, wherein
each R.sup.8 group is selected from Me, Et, F, and Cl. In a most
preferred embodiment, R.sup.3 is phenyl substituted with one
R.sup.8 group selected from Me, Et, F, and Cl.
[0361] In one embodiment, the compound of the invention according
to any one of Formulae Va-Vh:
##STR00023## ##STR00024## ##STR00025##
wherein R.sup.2 is as described previously.
[0362] In one embodiment, the compound of the invention is
according to any one of Formulae VIa-VIh:
##STR00026## ##STR00027##
wherein R.sup.2 is as described previously.
[0363] In one embodiment, the compound of the invention is
according to any one of Formulae VIIa-VIIh:
##STR00028## ##STR00029## ##STR00030##
wherein R.sup.2 is as described previously.
[0364] In one embodiment, the compound of the invention is
according to any one of Formulae Va, Vb, Ve, Vf, VIa, VIb, VIe,
VIf, VIIa, VIIb, VIIle, or VIIf, wherein R.sup.2 is unsubstituted
C.sub.3-7 cycloalkyl. In a preferred embodiment, R.sup.2 is
cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In a more
preferred embodiment, R.sup.2 is cyclopropyl.
[0365] In another embodiment, the compound of the invention is
according to any one of Formulae Va, Vb, Ve, Vf, VIa, VIb, VIe,
VIf, VIIa, VIIb, VIIe, or VIIf, wherein R.sup.2 is C.sub.3-7
cycloalkyl substituted with one to three independently selected
R.sup.6 groups. In a preferred embodiment, R.sup.2 is C.sub.3-7
cycloalkyl substituted with one R.sup.6 group. In a more preferred
embodiment, R.sup.2 is cyclopropyl, cyclobutyl, cyclopentyl or
cyclohexyl, each of which is substituted with one R.sup.6 group. In
another more preferred embodiment, R.sup.2 is C.sub.3-7 cycloalkyl
substituted with one R.sup.6 group, wherein R.sup.6 is oxo, or
R.sup.7, and R.sup.7 is OH, or C.sub.1-6 alkyl. In a most preferred
embodiment, R.sup.2 is cyclopropyl, cyclobutyl, cyclopentyl or
cyclohexyl, each of which is substituted with one R.sup.6 group,
wherein R.sup.6 is oxo, or R.sup.7, and R.sup.7 is OH, or C.sub.1-6
alkyl. In a further most preferred embodiment, R.sup.2 is
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which
is substituted with one R.sup.6 group, wherein R.sup.6 is R.sup.7,
and R.sup.7 is is OH.
[0366] In one embodiment, the compound of the invention is
according to any one of Formulae Vc, Vd, Vg, Vh, VIc, VId, VIg,
VIh, VIIc, VIId, VIIg, or VIIh, wherein R.sup.2 is 5-10 membered
heteroaryl comprising one to three heteroatoms independently
selected from N, S, and O. In a preferred embodiment, R.sup.2 is
furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl,
imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl,
or indazolyl.
[0367] In another embodiment, the compound of the invention is
according to any one of Formulae Vc, Vd, Vg, Vh, VIc, VId, VIg,
VIh, VIIc, VIId, VIIg, or VIIh, wherein R.sup.2 is 5-10 membered
heteroaryl comprising one to three heteroatoms independently
selected from N, S, and O, substituted with one to three
independently selected R.sup.7 groups. In a preferred embodiment,
R.sup.2 is 5-10 membered heteroaryl comprising one to three
heteroatoms independently selected from N, S, and O, substituted
with one or two independently selected R.sup.7 groups. In a more
preferred embodiment, R.sup.2 is furanyl, thienyl, oxazolyl,
thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl,
pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl,
substituted with one or two independently selected R.sup.7 groups.
In another more preferred embodiment, R.sup.2 is 5-10 membered
heteroaryl comprising one to three heteroatoms independently
selected from N, S, and O, substituted with one or two
independently selected R.sup.7 groups, wherein each R.sup.7 is
independently selected from OH, halo, C.sub.1-6 alkyl, C.sub.1-6
alkyl substituted with one or more halo, C.sub.1-6 alkoxy, --CN,
C.sub.3-7 cycloalkyl, 4-7 membered heterocycloalkyl comprising one
to three heteroatoms independently selected from N, O, and S, and
phenyl. In a most preferred embodiment, R.sup.2 is furanyl,
thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl,
imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl,
or indazolyl, each of which is substituted with one or two
independently selected R.sup.7 groups, wherein each R.sup.7 is
independently selected from OH, halo, C.sub.1-6 alkyl, C.sub.1-6
alkyl substituted with one or more halo, C.sub.1-6 alkoxy, --CN,
C.sub.3-7 cycloalkyl, 4-7 membered heterocycloalkyl comprising one
to three heteroatoms independently selected from N, O, and S, and
phenyl. In another most preferred embodiment, R.sup.2 is 5-10
membered heteroaryl comprising one to three heteroatoms
independently selected from N, S, and O, substituted with one or
two independently selected R.sup.7 groups, wherein each R.sup.7 is
independently selected from OH, F, Cl, Me, Et, Pr, i-Pr, t-Bu,
--CF.sub.3, --OMe, --OEt, Oi-Pr, --CN, cyclopropyl, pyrrolidinyl,
morpholinyl, piperidinyl, and phenyl. In a further most preferred
embodiment, R.sup.2 is furanyl, thienyl, oxazolyl, thiazolyl,
oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl,
pyrazinyl, pyrimidinyl, indanyl, or indazolyl, each of which is
substituted with one or two independently selected R.sup.7 groups,
wherein each R.sup.7 is independently selected from OH, F, Cl, Me,
Et, Pr, i-Pr, t-Bu, --CF.sub.3, --OMe, --OEt, --Oi-Pr, --CN,
cyclopropyl, pyrrolidinyl, morpholinyl, piperidinyl, and
phenyl.
[0368] In another embodiment, the compound of the invention is
according to any one of Formulae Vc, Vd, Vg, Vh, VIc, VId, VIg,
VIh, VIIc, VIId, VIIg, or VIIh, wherein R.sup.2 is C.sub.6-10 aryl.
In a preferred embodiment, R.sup.2 is phenyl.
[0369] In another embodiment, the compound of the invention is
according to any one of Formulae Vc, Vd, Vg, Vh, VIc, VId, VIg,
VIh, VIIc, VIId, VIIg, or VIIh, wherein R.sup.2 is C.sub.6-10 aryl
substituted with one or more independently selected R.sup.7 groups.
In a preferred embodiment, R.sup.2 is C.sub.6-10 aryl substituted
with one or two independently selected R.sup.7 groups. In a more
preferred embodiment, R.sup.2 is C.sub.6-10 aryl substituted with
one or two independently selected R.sup.7 groups, wherein each
R.sup.7 group is selected from halo, CN, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, and --NHC(.dbd.O)--C.sub.1-4 alkyl. In another more
preferred embodiment, R.sup.2 is C.sub.6-10 aryl substituted with
one or two independently selected R.sup.7 groups, wherein each
R.sup.7 group is --C(.dbd.O)NR.sup.9R.sup.10, and each R.sup.10 and
R.sup.11 is independently selected from from H and C.sub.1-4 alkyl.
In another more preferred embodiment, R.sup.2 is phenyl substituted
with one or two independently selected R.sup.7 groups. In a most
preferred embodiment, R.sup.2 is phenyl substituted with one or two
independently selected R.sup.6 groups, wherein each R.sup.7 group
is selected from halo, CN, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and
--NHC(.dbd.O)--C.sub.1-4 alkyl. In another most preferred
embodiment, R.sup.2 is phenyl substituted with one or two
independently selected R.sup.7 groups, wherein each R.sup.7 group
is --C(.dbd.O)NR.sup.10R.sup.11, and each R.sup.10 and R.sup.11 is
independently selected from from H and C.sub.1-4 alkyl. In a
further most preferred embodiment R.sup.2 is phenyl substituted
with one or two independently selected R.sup.7 groups, wherein each
R.sup.7 group is selected from F, Cl, CN, Me, --OMe, --OEt,- and
--NHC(.dbd.O)Me. In a further most preferred embodiment R.sup.2 is
phenyl substituted with one or two independently selected R.sup.7
groups, wherein each R.sup.7 group is selected from
C(.dbd.O)NH.sub.2, and --C(.dbd.O)NHMe.
[0370] In one embodiment, the compound of the invention is selected
from: [0371]
9-Methoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,-
1-a]isoquinolin-4-one, [0372]
2-(Chroman-2-ylmethoxy)-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin--
4-one, [0373]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-methoxy-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one, [0374]
9-Allyloxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]is-
oquinolin-4-one, [0375]
2-(2,3-Dihydro-benzofuran-2-ylmethoxy)-9-methoxy-6,7-dihydro-pyrimido[6,1-
-a]isoquinolin-4-one, [0376]
9-Hydroxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]iso-
quinolin-4-one, [0377]
9-Benzyloxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]i-
soquinolin-4-one, [0378]
9-(Pyridin-3-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one, [0379]
[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]iso-
quinolin-9-yloxy]-acetonitrile, [0380]
9-Butoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoq-
uinolin-4-one, [0381]
9-Cyclopropylmethoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one, [0382]
9-Phenethyloxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1--
a]isoquinolin-4-one, [0383]
9-(Pyridin-4-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one, [0384]
9-(Pyridin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one, [0385]
9-(Pyridin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one, [0386]
9-(2-Phenoxy-ethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one, [0387]
9-Methoxy-2-(tetrahydro-pyran-4-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]iso-
quinolin-4-one, [0388]
9-Methoxy-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]iso-
quinolin-4-one, [0389]
9-Methoxy-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]iso-
quinolin-4-one, [0390]
4-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzonitrile, [0391]
4-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzonitrile, [0392]
9-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0393]
9-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0394]
3-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzonitrile, [0395]
2-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzonitrile, [0396]
9-(4-Chloro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one, [0397]
9-(3-Chloro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one, [0398]
9-(2-Chloro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one, [0399]
9-(4-Fluoro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one, [0400]
9-(2-Nitro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one, [0401]
4-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzoic acid methyl ester, [0402]
3-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzoic acid methyl ester, [0403]
3-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzoic acid methyl ester, [0404]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(pyridin-2-ylmethoxy)-6,7--
dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0405]
[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimi-
do[6,1-a]isoquinolin-9-yloxy]-acetic acid tert-butyl ester, [0406]
2,9-Bis-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-6,7-dihydro-pyrimido[6-
,1-a]isoquinolin-4-one, [0407]
[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimi-
do[6,1-a]isoquinolin-9-yloxy]-acetic acid, [0408]
9-(3-Nitro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one, [0409]
9-(3-Nitro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one, [0410]
9-(4-Nitro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one, [0411]
9-(3-Methyl-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one, [0412]
9-(4-Methyl-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one, [0413]
9-(4-Methoxy-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one, [0414]
9-(Naphthalen-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one, [0415]
9-(Naphthalen-1-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one, [0416]
9-(2-Methyl-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one, [0417]
9-[2-(2-Methoxy-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dih-
ydro-pyrimido[6,1-a]isoquinolin-4-one, [0418]
9-[2-(3-Methoxy-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dih-
ydro-pyrimido[6,1-a]isoquinolin-4-one, [0419]
9-[2-(4-Methoxy-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dih-
ydro-pyrimido[6,1-a]isoquinolin-4-one, [0420]
9-[2-(2-Chloro-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihy-
dro-pyrimido[6,1-a]isoquinolin-4-one, [0421]
9-[2-(3-Chloro-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihy-
dro-pyrimido[6,1-a]isoquinolin-4-one, [0422]
9-[2-(4-Chloro-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihy-
dro-pyrimido[6,1-a]isoquinolin-4-one, [0423]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-morpholin-4-yl-2-oxo-et-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0424]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-morpholin-4-yl-2-oxo-et-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0425]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-morpholin-4-yl-2-oxo-et-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0426]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-morpholin-4-yl-2-oxo-et-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0427]
2-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-acetamide, [0428]
2-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-N,N-dimethyl-acetamide, [0429]
9-(2,2-Dimethoxy-ethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyr-
imido[6,1-a]isoquinolin-4-one, [0430]
2-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-2-methyl-propionamide, [0431]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(1,1-dimethyl-2-morpholin--
4-yl-2-oxo-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0432]
9-(2-Benzyloxy-ethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one, [0433]
2,9-Bis-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquin-
olin-4-one, [0434]
9-(6-Phenyl-pyridin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dih-
ydro-pyrimido[6,1-a]isoquinolin-4-one, [0435]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(tetrahydro-furan-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0436]
9-[6-(1-Methyl-1H-pyrazol-4-yl)-pyridin-2-ylmethoxy]-2-(tetrahydro-furan--
2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0437]
9-(6-Furan-3-yl-pyridin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0438]
9-(6-Pyrimidin-5-yl-pyridin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-
-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0439]
9-(1-Cyclopropyl-1H-tetrazol-5-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy-
)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0440]
2-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxy]-acetamide, [0441]
N,N-Diethyl-2-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-acetamide, [0442]
N,N-Dimethyl-2-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyr-
imido[6,1-a]isoquinolin-9-yloxy]-acetamide, [0443]
N-Isopropyl-N-methyl-2-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydr-
o-4H-pyrimido[6,1-a]isoquinolin-9-yloxy]-acetamide, [0444]
2-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxy]-N-phenyl-acetamide, [0445]
9-(1-Propyl-1H-tetrazol-5-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0446]
9-(Oxazol-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one, [0447]
2-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-N,N-diethyl-acetamide, [0448]
2-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-N-isopropyl-N-methyl-acetamide,
[0449]
2-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-N-phenyl-acetamide, [0450]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(1-propyl-1H-tetrazol-5-yl-
methoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0451]
9-(1-Butyl-1H-tetrazol-5-ylmethoxy)-2-(2,3-dihydro-benzo[1,4]dioxin-2-ylm-
ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0452]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-morpholin-4-yl-ethoxy)--
6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0453]
[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimi-
do[6,1-a]isoquinolin-9-yloxy]-acetonitrile, [0454]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(oxazol-2-ylmethoxy)-6,7-d-
ihydro-pyrimido[6,1-a]isoquinolin-4-one, [0455]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-oxo-2-pyrrolidin-1-yl-e-
thoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0456]
9-(1-Cyclopropyl-1H-tetrazol-5-ylmethoxy)-2-(2,3-dihydro-benzo[1,4]dioxin-
-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0457]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(1H-tetrazol-5-ylmethoxy)--
6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0458]
9-Allyloxy-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-6,7-dih-
ydro-pyrimido[6,1-a]isoquinolin-4-one, [0459]
N-Benzyl-2-[2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydr-
o-4H-pyrimido[6,1-a]isoquinolin-9-yloxy]-acetamide, [0460]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-pyrrolidin-1-yl-ethoxy)-
-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0461]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-piperidin-1-yl-ethoxy)--
6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0462]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(3-piperidin-1-yl-propoxy)-
-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0463]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(3-dimethylamino-propoxy)--
6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0464]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-[2-(1-methyl-pyrrolidin-2--
yl)-ethoxy]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0465]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-[3-(4-methyl-piperazin-1-y-
l)-propoxy]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0466]
5-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxymethyl]-furan-2-carboxylic acid ethyl
ester, [0467]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(oxazol-2-
-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0468]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(oxazol-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0469]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(oxazol-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0470]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(oxazol-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0471]
9-(5-tert-Butyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-(tetrahydro-furan-2-ylmet-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0472]
9-(5-Phenyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy-
)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0473]
[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro-
-4H-pyrimido[6,1-a]isoquinolin-9-yloxy]-acetonitrile, [0474]
[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro-
-4H-pyrimido[6,1-a]isoquinolin-9-yloxy]-acetonitrile, [0475]
[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro-
-4H-pyrimido[6,1-a]isoquinolin-9-yloxy]-acetonitrile, [0476]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-morpholin-4-y-
l-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0477]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(pyridin-2-ylmet-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0478]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-[2-(1-methyl-pyr-
rolidin-2-yl)-ethoxy]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0479]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1H-tetrazol-5-y-
lmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0480]
9-Pyridin-3-yl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1--
a]isoquinolin-4-one, [0481]
3-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzonitrile, [0482]
9-Phenyl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoq-
uinolin-4-one, [0483]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyridin-4-yl-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0484]
3-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-benzonitrile, [0485]
9-(2-Methoxy-phenyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one, [0486]
9-(3-Methoxy-phenyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one, [0487]
9-(4-Methoxy-phenyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one, [0488]
4-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzonitrile, [0489]
3-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzoic acid, [0490]
4-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzoic acid, [0491]
9-(4-Dimethylamino-phenyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one, [0492]
4-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzamide, [0493]
2-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzonitrile, [0494]
9-(1-Methyl-1H-pyrazol-4-yl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-
-pyrimido[6,1-a]isoquinolin-4-one, [0495]
N,N-Dimethyl-3-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyr-
imido[6,1-a]isoquinolin-9-yl]-benzamide,
[0496]
9-(6-Methoxy-pyridin-3-yl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-di-
hydro-pyrimido[6,1-a]isoquinolin-4-one, [0497]
9-(2,6-Dimethyl-phenyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one, [0498]
9-(3,5-Dimethyl-isoxazol-4-yl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihyd-
ro-pyrimido[6,1-a]isoquinolin-4-one, [0499]
9-Naphthalen-2-yl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6-
,1-a]isoquinolin-4-one, [0500]
9-Naphthalen-1-yl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6-
,1-a]isoquinolin-4-one, [0501]
9-Pyrimidin-5-yl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,-
1-a]isoquinolin-4-one, [0502]
9-(5-Chloro-thiophen-2-yl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one, [0503]
2-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-pyrrole-1-carboxylic acid tert-butyl ester, [0504]
Trifluoro-methanesulfonic acid
4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]isoq-
uinolin-9-yl ester, [0505]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(6-methoxy-pyrid-
in-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0506]
9-Cyclopropylethynyl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one, [0507]
9-(3,3-Dimethyl-but-1-ynyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro--
pyrimido[6,1-a]isoquinolin-4-one, [0508]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(pyridin-4-ylmet-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0509]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyridin-3-yl-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0510]
2-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-benzonitrile, [0511]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-methoxy-pheny-
l)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0512]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1H-indazol-5-yl-
)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0513]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyrimidin-5-yl-6-
,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0514]
3-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-benzamide, [0515]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-dimethylamino-
-phenyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0516]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyridin-3-ylethy-
nyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0517]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-methoxy-prop--
1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0518]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(4-hydroxy-but-1-
-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0519]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1,5-dimethyl-1H-
-pyrazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0520]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-methyl-[1,2,4-
]oxadiazol-5-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0521]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydrox-
y-3-methyl-but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0522]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyridin-4-
-ylethynyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0523]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-prop--
1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0524]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(6-methyl-pyridi-
n-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0525]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(5-methoxy-pyrid-
in-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0526]
9-Cyclopropylethynyl-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethox-
y)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0527]
9-Cyclopropylethynyl-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethox-
y)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0528]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1-hydroxy-cyclo-
pentylethynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0529]
5-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-pent-4-ynenitrile, [0530]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3,3-dimethyl-bu-
t-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0531]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-methoxy-pyrid-
in-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0532]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one, [0533]
5-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-pyridine-2-carboxylic acid
methylamide, [0534]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-furan-3-yl-6,7-d-
ihydro-pyrimido[6,1-a]isoquinolin-4-one, [0535]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1-methyl-1H-pyr-
azol-4-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0536]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-morpholin-4-ylme-
thyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0537]
[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro-
-4H-pyrimido[6,1-a]isoquinolin-9-ylamino]-acetonitrile, [0538]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro--
4H-pyrimido[6,1-a]isoquinoline-9-carbonitrile, [0539]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-[(oxazol-2-ylmet-
hyl)-amino]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0540]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(5-methyl-[1,2,4-
]oxadiazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0541]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(5-ethyl--
[1,2,4]oxadiazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one-
, [0542]
9-(5-Cyclopropyl-[12,4]oxadiazol-3-ylmethoxy)-2-(2,3-dihydro-[1,4-
]dioxino[2,3-b]pyridin-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-
-4-one, [0543]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(5-isopropyl-[1,-
2,4]oxadiazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0544]
9-(5-tert-Butyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-(2,3-dihydro-[1,4]-
dioxino[2,3-b]pyridin-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin--
4-one, [0545]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-methyl-isoxaz-
ol-5-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0546]
9-(3-Chloro-2-methoxy-pyridin-4-yl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyr-
idin-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0547]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3,6-dihydro-2H--
pyran-4-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0548]
5-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-pyridine-2-carbonitrile,
[0549]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-ethoxy-pyridi-
n-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0550]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(6-ethoxy-pyridi-
n-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0551]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(6-morpholin-4-y-
l-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0552]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-methoxy-pyrim-
idin-5-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0553]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2,3-dimethoxy-p-
henyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0554]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2,5-dimethoxy-p-
henyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0555]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-3-phe-
nyl-prop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0556]
3-{3-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-di-
hydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-prop-2-ynyloxy}-propionitrile,
[0557]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-methyl-
amino-prop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0558]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-dimethylamino-
-prop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0559]
9-[3-(Benzyl-methyl-amino)-prop-1-ynyl]-2-(2,3-dihydro-[1,4]dioxino[2,3-b-
]pyridin-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0560]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-[3-(1,1-dioxo-th-
iomorpholin-4-yl)-prop-1-ynyl]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-on-
e, [0561]
{3-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-
-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-prop-2-ynyl}-urea,
[0562]
1-{3-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-di-
hydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-prop-2-ynyl}-imidazolidine-2,4-d-
ione, [0563]
9-(3-Diethylamino-prop-1-ynyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin--
2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0564]
9-(3-Amino-3-methyl-but-1-ynyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-
-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0565]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(tetrahydro-pyra-
n-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0566]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1H-pyrazol-4-yl-
)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0567]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-but-1-
-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0568]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-pent--
1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0569]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-hex-1-
-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0570]
9-(1-Amino-cyclohexylethynyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-
-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0571]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-5-met-
hyl-hex-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0572]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-ethyl-3-hydro-
xy-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0573]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-3-phe-
nyl-but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0574]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-4-met-
hyl-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0575]
2-[(R)-1-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-yl)methoxy]-9-(oxazol--
2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0576]
2-[(R)-1-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-yl)methoxy]-9-(oxazol--
2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0577]
2-[(S)-1-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-yl)methoxy]-9-(oxazol--
2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0578]
9-(3-Butylamino-prop-1-ynyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2--
ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0579]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-morpholin-4-y-
l-ethoxymethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0580]
9-(3-Benzylamino-prop-1-ynyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-
-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0581]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-phenylamino-p-
rop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0582]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro--
4H-pyrimido[6,1-a]isoquinoline-9-carboxylic acid
(tetrahydro-pyran-4-yl)-amide, [0583]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro--
4H-pyrimido[6,1-a]isoquinoline-9-carboxylic acid
(oxetan-3-ylmethyl)-amide, [0584]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyrrolidin-1-ylm-
ethyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0585]
9-(tert-Butylamino-methyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-yl-
methoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0586]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-piperidin-1-ylme-
thyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0587]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-methyl-oxetan-
-3-ylmethoxymethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0588]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-methyloxy)-9--
(3-methyl-oxetan-3-ylmethoxymethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-
-4-one, [0589]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(oxetan-3-yloxym-
ethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0590]
9-Cyclopropylethynyl-2-(4-isopropyl-oxetan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one, and [0591]
9-Cyclopropylethynyl-2-((R)-4-isopropyl-oxetan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one.
[0592] In one embodiment a compound of the invention is not an
isotopic variant.
[0593] In one aspect a compound of the invention is present as the
free base.
[0594] In one aspect a compound of the invention is a
pharmaceutically acceptable salt.
[0595] In one aspect a compound of the invention is present as the
free base or a pharmaceutically acceptable salt.
[0596] In one aspect a compound of the invention is a solvate.
[0597] In one aspect a compound of the invention is a solvate of a
pharmaceutically acceptable salt of the compound.
[0598] In certain aspects, the present invention provides prodrugs
and derivatives of a compound of the invention according to the
formula above. Prodrugs are derivatives of a compound of the
invention, which have metabolically cleavable groups and become by
solvolysis or under physiological conditions the compounds of the
invention, which are pharmaceutically active, in vivo. Such
examples include, but are not limited to, choline ester derivatives
and the like, N-alkylmorpholine esters and the like.
[0599] Other derivatives of the compounds of this invention have
activity in both their acid and acid derivative forms, but the acid
sensitive form often offers advantages of solubility, tissue
compatibility, or delayed release in the mammalian organism (see,
Bundgard, H. Design of Prodrugs, pp. 7-9, 21-24, Elsevier,
Amsterdam 1985). Prodrugs include acid derivatives well know to
practitioners of the art, such as, for example, esters prepared by
reaction of the parent acid with a suitable alcohol, or amides
prepared by reaction of the parent acid compound with a substituted
or unsubstituted amine, or acid anhydrides, or mixed anhydrides.
Simple aliphatic or aromatic esters, amides and anhydrides derived
from acidic groups pendant on the compounds of this invention are
preferred prodrugs. In some cases it is desirable to prepare double
ester type prodrugs such as (acyloxy)alkyl esters or
((alkoxycarbonyl)oxy)alkylesters. Particularly useful are the
C.sub.1 to C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, aryl,
C.sub.7-C.sub.12 substituted aryl, and C.sub.7-C.sub.12 arylalkyl
esters of the compounds of the invention.
[0600] While specified groups for each embodiment have generally
been listed above separately, a compound of the invention includes
one in which several or each embodiment in the above Formula, as
well as other formulae presented herein, is selected from one or
more of particular members or groups designated respectively, for
each variable. Therefore, this invention is intended to include all
combinations of such embodiments within its scope.
[0601] While specified groups for each embodiment have generally
been listed above separately, a compound of the invention may be
one for which one or more variables (for example, R groups) is
selected from one or more embodiments according to any of the
Formula(e) listed above. Therefore, the present invention is
intended to include all combinations of variables from any of the
disclosed embodiments within its scope.
[0602] Alternatively, the exclusion of one or more of the specified
variables from a group or an embodiment, or combinations thereof is
also contemplated by the present invention.
Clauses
[0603] 1. A compound according to Formula Ia:
[0603] ##STR00031## [0604] wherein [0605] Cy is
[0605] ##STR00032## [0606] wherein [0607] X is O or S; [0608] Y is
--CH.sub.2--, or S; [0609] Z is --CH.sub.2--; [0610] each of the
subscript n, m, or p is independently selected from 0, and 1; and A
is phenyl, or 5-6-membered heteroaryl comprising one or two
N-atoms; optionally substituted with one or more independently
selected R.sup.5 groups; [0611] any one of Cy1 and Cy2 is
optionally substituted by one or more independently selected
C.sub.1-4 alkyl groups; [0612] R.sup.1 is H, Me, or halo; [0613]
L.sub.1 is absent or is --O--, --S--, or --NR.sup.4a--; [0614] G is
[0615] R.sup.2, [0616] --W-L.sub.2-R.sup.2, or [0617]
--W-L.sub.3-R.sup.3; [0618] W is C.sub.1-4 alkylene, C.sub.2-4
alkenylene having one double bond, or C.sub.2-4 alkynylene having
one triple bond; [0619] L.sub.2 is absent or is --O--; [0620]
R.sup.2 is [0621] H, [0622] C.sub.1-8 alkyl (optionally substituted
with one to three groups independently selected from [0623] OH,
[0624] halo, [0625] CN, [0626] C.sub.1-6 alkoxy, [0627] C.sub.3-7
cycloalkyl, [0628] 4-6 membered heterocycloalkyl (comprising one to
three heteroatoms independently selected from S, and O), [0629] 5-6
membered heteroaryl (comprising one to three heteroatoms
independently selected from N, S, and O), and [0630] phenyl, [0631]
C.sub.4-7 cycloalkenyl comprising one double bond, [0632] 5-7
membered heterocycloalkenyl comprising one double bond, and one to
three heteroatoms independently selected from 0, and S, [0633]
C.sub.3-7 cycloalkyl (optionally substituted with one or more
independently selected R.sup.6 groups), [0634] 4-10 membered
heterocycloalkyl comprising one to two heteroatoms independently
selected from S, and O, (optionally substituted with one to three
independently selected R.sup.6 groups), [0635] 5-10 membered
heteroaryl comprising one to three heteroatoms independently
selected from N, S, and O (optionally substituted with one to three
independently selected R.sup.7 groups), or C.sub.6-10 aryl
(optionally substituted with one or more independently selected
R.sup.7 groups); [0636] L.sub.3 is --NR.sup.4b--; [0637] R.sup.3 is
[0638] C.sub.1-4 alkyl substituted with C.sub.6-10 aryl (optionally
substituted with one or more independently selected R.sup.8
groups), or 5-10 membered heteroaryl comprising one to three
heteroatoms independently selected from N, S, and O, (optionally
substituted with one or more independently selected R.sup.8
groups), [0639] 5-10 membered heteroaryl comprising one to three
heteroatoms independently selected from N, S, and O, (optionally
substituted with one or more independently selected R.sup.8
groups), or [0640] C.sub.6-10 aryl (optionally substituted with one
or more independently selected R.sup.8 groups); [0641] Each
R.sup.4a and R.sup.4b is independently selected from H, C.sub.1-4
alkyl, or C.sub.3-7 cycloalkyl; [0642] R.sup.5 is halo, C.sub.1-4
alkyl or C.sub.1-4 alkoxy; [0643] R.sup.6 is oxo or R.sup.7; [0644]
R.sup.7 is [0645] OH, [0646] halo, [0647] --NO.sub.2, [0648]
C.sub.1-6 alkyl (optionally substituted with one to three groups
independently selected from halo, and OH), [0649] C.sub.1-6 alkoxy
(optionally substituted with one to three groups independently
selected from halo, and OH), [0650] C.sub.3-7 cycloalkyl, [0651]
--C(.dbd.O)OR.sup.9, [0652] --C(.dbd.O)NR.sup.10R.sup.11, [0653]
--NHC(.dbd.O)--C.sub.1i4 alkyl, [0654] --CN, [0655] phenyl, [0656]
--O-phenyl, [0657] 4-7 membered heterocycloalkyl comprising one to
three heteroatoms independently selected from N, O, and S, or
[0658] 5-6 membered heteroaryl comprising one to three heteroatoms
independently selected from N, O, and S; (optionally substituted
with one or more independently selected C.sub.1-4 alkyl, C.sub.1-4
alkoxy, CN, halo, and --C(.dbd.O)OR.sup.12); [0659] R.sup.8 is
C.sub.1-4 alkyl, or halo; and [0660] each of R.sup.9, R.sup.10,
R.sup.11 and R.sup.12, is independently selected from H and
C.sub.1-4 alkyl. [0661] or a pharmaceutically acceptable salt, or a
solvate, or a solvate of the pharmaceutically acceptable salts.
[0662] 2. A compound according to Formula Ia:
[0662] ##STR00033## [0663] wherein [0664] Cy is
[0664] ##STR00034## [0665] wherein [0666] X is is O or S; [0667] Y
is is --CH.sub.2--, or S; [0668] Z is is --CH.sub.2--; [0669] each
of the subscript n, m, or p is independently selected from 0, and
1; and [0670] A is phenyl, or 5-6-membered heteroaryl comprising
one or two N-atoms; optionally substituted with one or more
independently selected R.sup.5 groups; [0671] R.sup.1 is H, Me, or
halo; [0672] L.sub.1 is absent or is --O--, --S--, or
--NR.sup.4a--; [0673] G is [0674] R.sup.2, [0675]
--W-L.sub.2-R.sup.2, or [0676] --W-L.sub.3-R.sup.3; [0677] W is
C.sub.1-4 alkylene, C.sub.2-4 alkenylene having one double bond, or
C.sub.2-4 alkynylene having one triple bond; [0678] L.sub.2 is
absent or is --O--; [0679] R.sup.2 is [0680] H, [0681] C.sub.1-8
alkyl (optionally substituted with one to three groups
independently selected from [0682] OH, [0683] halo, [0684] CN,
[0685] C.sub.1-6 alkoxy, [0686] C.sub.3-7 cycloalkyl, [0687] 4-6
membered heterocycloalkyl (comprising one to three heteroatoms
independently selected from S, and O), [0688] 5-6 membered
heteroaryl (comprising one to three heteroatoms independently
selected from N, S, and O), and [0689] phenyl, [0690] C.sub.4-7
cycloalkenyl comprising one double bond, [0691] 5-7 membered
heterocycloalkenyl comprising one double bond, and one to three
heteroatoms independently selected from O, and S, [0692] C.sub.3-7
cycloalkyl (optionally substituted with one or more independently
selected R.sup.6 groups), [0693] 4-10 membered heterocycloalkyl
comprising one to two heteroatoms independently selected from S,
and O, (optionally substituted with one to three independently
selected R.sup.6 groups), [0694] 5-10 membered heteroaryl
comprising one to three heteroatoms independently selected from N,
S, and O (optionally substituted with one to three independently
selected R.sup.7 groups), or [0695] C.sub.6-10 aryl (optionally
substituted with one or more independently selected R.sup.7
groups); [0696] L.sub.3 is --NR.sup.4b--; [0697] R.sup.3 is [0698]
C.sub.1-4 alkyl substituted with C.sub.6-10 aryl (optionally
substituted with one or more independently selected R.sup.8
groups), or 5-10 membered heteroaryl comprising one to three
heteroatoms independently selected from N, S, and O, (optionally
substituted with one or more independently selected R.sup.8
groups), [0699] 5-10 membered heteroaryl comprising one to three
heteroatoms independently selected from N, S, and O, (optionally
substituted with one or more independently selected R.sup.8
groups), or [0700] C.sub.6-10 aryl (optionally substituted with one
or more independently selected R.sup.8 groups); [0701] Each
R.sup.4a and R.sup.4b is independently selected from H, C.sub.1-4
alkyl, or C.sub.3-7 cycloalkyl; [0702] R.sup.5 is halo, C.sub.1-4
alkyl or C.sub.1-4 alkoxy; [0703] R.sup.6 is oxo or R.sup.7; [0704]
R.sup.7 is [0705] OH, [0706] halo, [0707] --NO.sub.2, [0708]
C.sub.1-6 alkyl (optionally substituted with one to three groups
independently selected from halo, and OH), [0709] C.sub.1-6 alkoxy
(optionally substituted with one to three groups independently
selected from halo, and OH), [0710] C.sub.3-7 cycloalkyl, [0711]
--C(.dbd.O)OR.sup.9, [0712] --C(.dbd.O)NR.sup.10R.sup.11, [0713]
--NHC(.dbd.O)--C.sub.1i4 alkyl, [0714] --CN, [0715] phenyl, [0716]
--O-phenyl, [0717] 4-7 membered heterocycloalkyl comprising one to
three heteroatoms independently selected from N, O, and S, or
[0718] 5-6 membered heteroaryl comprising one to three heteroatoms
independently selected from N, O, and S; (optionally substituted
with one or more independently selected C.sub.1-4 alkyl, C.sub.1-4
alkoxy, CN, halo, and --C(.dbd.O)OR.sup.12); [0719] R.sup.8 is
C.sub.1-4 alkyl, or halo; and [0720] each of R.sup.9, R.sup.10,
R.sup.11 and R.sup.12, is independently selected from H and
C.sub.1-4 alkyl. [0721] or a pharmaceutically acceptable salt, or a
solvate, or a solvate of the pharmaceutically acceptable salts.
[0722] 3. A compound or pharmaceutically acceptable salt thereof,
according to clause 1 or 2, wherein the compound is according to
Formula Ib:
[0722] ##STR00035## [0723] wherein Cy, R.sup.1, L.sub.1 and G are
as previously described. [0724] 4. A compound or pharmaceutically
acceptable salt thereof, according to clause 1 or 2, wherein the
compound is according to Formula Ic:
[0724] ##STR00036## [0725] wherein Cy, R.sup.1, L.sub.1 and G are
as previously described. [0726] 5. A compound or pharmaceutically
acceptable salt thereof, according to any one of clauses 1-4,
wherein Cy is Cy1. [0727] 6. A compound or pharmaceutically
acceptable salt thereof, according to clause 5, wherein the
subscript n is 0. [0728] 7. A compound or pharmaceutically
acceptable salt thereof, according to clause 5, wherein the
subscript n is 1 and X is O. [0729] 8. A compound or
pharmaceutically acceptable salt thereof, according to any one of
clauses 5-6, wherein the ring A is phenyl. [0730] 9. A compound or
pharmaceutically acceptable salt thereof, according to any one of
clauses 5-6, wherein the ring A is pyridinyl. [0731] 10. A compound
or pharmaceutically acceptable salt thereof, according to any one
of clauses 1-4, wherein Cy is Cy2. [0732] 11. A compound or
pharmaceutically acceptable salt thereof, according to clause 10,
wherein the subscript m is 0, the subscript p is 1 and Y is
--CH.sub.2--. [0733] 12. A compound or pharmaceutically acceptable
salt thereof, according to clause 10, wherein, the subscript m is
1, Z is --CH.sub.2--, the subscript p is 1 and Y is --CH.sub.2--.
[0734] 13. A compound or pharmaceutically acceptable salt thereof,
according to clause 10, wherein the subscript m is 1, Z is
--CH.sub.2--, the subscript p is 1 and Y is S. [0735] 14. A
compound or pharmaceutically acceptable salt thereof, according to
clause 10, wherein the subscript m and p are both 0. [0736] 15. A
compound or pharmaceutically acceptable salt thereof, according to
any one of clauses 1-14, wherein R.sup.1 is Me, F, or Cl. [0737]
16. A compound or pharmaceutically acceptable salt thereof,
according to any one of clauses 1-4, or 10, wherein R.sup.1 is H.
[0738] 17. A compound or pharmaceutically acceptable salt thereof,
according to clause 1 or 2, wherein the compound is according to
any one of Formulae IIa-IIc:
[0738] ##STR00037## [0739] wherein L.sub.1, and R.sup.2 are as
described in clause 1 or 2. [0740] 18. A compound or
pharmaceutically acceptable salt thereof, according to clause 1 or
2, wherein the compound is according to any one of Formulae
IId-IIf:
[0740] ##STR00038## [0741] wherein L.sub.1, W, L.sub.2, and R.sup.2
are as described in clause 1 or 2. [0742] 19. A compound or
pharmaceutically acceptable salt thereof, according to clause 1 or
2, wherein the compound is according to any one of Formulae
IIg-IIi:
[0742] ##STR00039## [0743] wherein L.sub.1, W, L.sub.3, and R.sup.3
are as described in clause 1 or 2. [0744] 20. A compound or
pharmaceutically acceptable salt thereof, according to any one of
clauses 1-19, wherein L.sub.1 is absent. [0745] 21. A compound or
pharmaceutically acceptable salt thereof, according to any one of
clauses 1-19, wherein L.sub.1 is --O--. [0746] 22. A compound or
pharmaceutically acceptable salt thereof, according to any one of
clauses 1-19, wherein L.sub.1 is --NR.sup.4a--, and R.sup.4a is H,
Me, Et, or cyclopropyl. [0747] 23. A compound or pharmaceutically
acceptable salt thereof, according to clause 22 wherein R.sup.4a is
H. [0748] 24. A compound or pharmaceutically acceptable salt
thereof, according to any one of clauses 1-16, or 18-23 wherein W
is C.sub.1-4 alkylene. [0749] 25. A compound or pharmaceutically
acceptable salt thereof, according to clause 24, wherein W is
--CH.sub.2--, --CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--CH(CH.sub.3)--,
--CH.sub.2--CH(--CH.sub.2--CH.sub.3)--,
--CH.sub.2--C(CH.sub.3).sub.2-, or
--CH.sub.2--CH.sub.2--CH.sub.2--. [0750] 26. A compound or
pharmaceutically acceptable salt thereof, according to clause 25,
wherein W is-CH.sub.2--CH.sub.2--. [0751] 27. A compound or
pharmaceutically acceptable salt thereof, according to any one of
clauses 1-16, or 18-23, wherein W is C.sub.2-4 alkenylene having
one double bond. [0752] 28. A compound or pharmaceutically
acceptable salt thereof, according to clause 27, wherein W is
--CH.dbd.CH--, --CH.sub.2--CH.dbd.CH--, or --CH.dbd.CH--CH.sub.2.
[0753] 29. A compound or pharmaceutically acceptable salt thereof,
according to clause 28, wherein W is --CH.dbd.CH--. [0754] 30. A
compound or pharmaceutically acceptable salt thereof, according to
any one of clauses 1-16, or 18-23, wherein W is C.sub.2-4
alkynylene having one triple bond. [0755] 31. A compound or
pharmaceutically acceptable salt thereof, according to clause 30,
wherein W is --C.ident.C--, --CH.sub.2--C.ident.C--, or
--C.ident.C--CH.sub.2--. [0756] 32. A compound or pharmaceutically
acceptable salt thereof, according to clause 31, wherein W is
--C.ident.C-- [0757] 33. A compound or pharmaceutically acceptable
salt thereof, according to any one of clauses 1-16, 18, or 20-32,
wherein L.sub.2 is --O--. [0758] 34. A compound or pharmaceutically
acceptable salt thereof, according to any one of clauses 1-16, 18,
or 20-32, wherein L.sub.2 is absent. [0759] 35. A compound or
pharmaceutically acceptable salt thereof, according to any one of
clauses 1-16 or 18, wherein L.sub.1 and L.sub.2 are absent, and W
is --CH.sub.2--, --CH.sub.2--CH.sub.2--, or
--CH.sub.2--CH.sub.2--CH.sub.2--. [0760] 36. A compound or
pharmaceutically acceptable salt thereof, according to any one of
clauses 1-16 or 18, wherein L.sub.1 and L.sub.2 are absent, and W
is --CH.dbd.CH--, --CH.sub.2--CH.dbd.CH--, or
--CH.dbd.CH--CH.sub.2--. [0761] 37. A compound or pharmaceutically
acceptable salt thereof, according to any one of clauses 1-16 or
18, wherein L.sub.1 and L.sub.2 are absent, and W is --C.ident.C--,
--CH.sub.2--C.ident.C--, or --C.ident.C--CH.sub.2--. [0762] 38. A
compound or pharmaceutically acceptable salt thereof, according to
any one of clauses 1-18, or 20-37, wherein R.sup.2 is H. [0763] 39.
A compound or pharmaceutically acceptable salt thereof, according
to any one of clauses 1-18, or 20-37, wherein R.sup.2 is C.sub.1-8
alkyl. [0764] 40. A compound or pharmaceutically acceptable salt
thereof, according to any one of clauses 1-18, or 20-37, wherein
R.sup.2 is C.sub.1-8 alkyl substituted with one group selected from
OH, halo, CN, C.sub.1-6 alkoxy, C.sub.3-7 cycloalkyl, 4-6 membered
heterocycloalkyl (comprising one to three heteroatoms independently
selected from S, and O), 5-6 membered heteroaryl (comprising one to
three heteroatoms independently selected from N, S, and O), and
phenyl. [0765] 41. A compound or pharmaceutically acceptable salt
thereof, according to clause 39 or 40, wherein R.sup.2 is Me, Et,
n-Pr, i-Pr, i-Bu, or t-Bu. [0766] 42. A compound or
pharmaceutically acceptable salt thereof, according to clause 40,
wherein R.sup.2 is C.sub.1-8 alkyl substituted with one group
selected from OH, F, Cl, CN, --OMe, --OEt, --Oi-Pr, cyclopropyl,
cyclobutyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,
pyrralolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, pyridinyl,
pyrimidinyl, pyrazinyl, and phenyl. [0767] 43. A compound or
pharmaceutically acceptable salt thereof, according to any one of
clauses 1-18, or 20-37, wherein R.sup.2 is C.sub.4-7 cycloalkenyl
comprising one double bond. [0768] 44. A compound or
pharmaceutically acceptable salt thereof, according to clause 43,
wherein R.sup.2 is cyclohexenyl. [0769] 45. A compound or
pharmaceutically acceptable salt thereof, according to any one of
clauses 1-18, or 20-37, wherein R.sup.2 is 5-7 membered
heterocycloalkenyl comprising one double bond, and one to three
heteroatoms independently selected from N, O, and S. [0770] 46. A
compound or pharmaceutically acceptable salt thereof, according to
clause 45, wherein R.sup.2 is dihydropyranyl. [0771] 47. A compound
or pharmaceutically acceptable salt thereof, according to any one
of clauses 1-18, or 20-37, wherein R.sup.2 is C.sub.3-7 cycloalkyl.
[0772] 48. A compound or pharmaceutically acceptable salt thereof,
according to any one of clauses 1-18, or 20-37, wherein R.sup.2 is
C.sub.3-7 cycloalkyl substituted with one R.sup.6 group. [0773] 49.
A compound or pharmaceutically acceptable salt thereof, according
to clause 48, wherein R.sup.6 is oxo, or R.sup.7, and R.sup.7 is
OH, or C.sub.1-6 alkyl. [0774] 50. A compound or pharmaceutically
acceptable salt thereof, according to clause 47, 48 or 49, wherein
R.sup.2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
[0775] 51. A compound or pharmaceutically acceptable salt thereof,
according to any one of clauses 1-18, or 20-37, wherein R.sup.2 is
4-10 membered heterocycloalkyl comprising one to two heteroatoms
independently selected from S, and O. [0776] 52. A compound or
pharmaceutically acceptable salt thereof, according to any one of
clauses 1-18, or 20-37, wherein R.sup.2 is 4-10 membered
heterocycloalkyl comprising one to two heteroatoms independently
selected from S, and O, substituted with one R.sup.6 group. [0777]
53. A compound or pharmaceutically acceptable salt thereof,
according to clause 52, wherein R.sup.6 is oxo, or R.sup.7, and
R.sup.7 is OH, or C.sub.1-6 alkyl. [0778] 54. A compound or
pharmaceutically acceptable salt thereof, according to clause 50,
51 or 52, wherein R.sup.2 is oxetanyl, tetrahydrofuranyl,
tetrahydropyranyl, or dioxanyl. [0779] 55. A compound or
pharmaceutically acceptable salt thereof, according to any one of
clauses 1-18, or 20-37, wherein R.sup.2 is 5-10 membered heteroaryl
comprising one to three heteroatoms independently selected from N,
S, and O. [0780] 56. A compound or pharmaceutically acceptable salt
thereof, according to any one of clauses 1-18, or 20-37, wherein
R.sup.2 is 5-10 membered heteroaryl comprising one to three
heteroatoms independently selected from N, S, and O, substituted
with one or two independently selected R.sup.7 groups. [0781] 57. A
compound or pharmaceutically acceptable salt thereof, according to
clause 56, wherein each R.sup.7 is independently selected from OH,
halo, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with one or more
halo, C.sub.1-6 alkoxy, --CN, C.sub.3-7 cycloalkyl, 4-7 membered
heterocycloalkyl comprising one to three heteroatoms independently
selected from N, O, and S, and phenyl. [0782] 58. A compound or
pharmaceutically acceptable salt thereof, according to clause 55,
56 or 57, wherein R.sup.2 is furanyl, thienyl, oxazolyl, thiazolyl,
oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl,
pyrazinyl, pyrimidinyl, indanyl, or indazolyl. [0783] 59. A
compound or pharmaceutically acceptable salt thereof, according to
any one of clauses 1-18, or 20-37, wherein R.sup.2 is C.sub.6-10
aryl. [0784] 60. A compound or pharmaceutically acceptable salt
thereof, according to any one of clauses 1-18, or 20-37, wherein
R.sup.2 is C.sub.6-10 aryl, substituted with one or two
independently selected R.sup.7 groups. [0785] 61. A compound or
pharmaceutically acceptable salt thereof, according to clause 60,
wherein R.sup.7 is selected from halo, CN, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, --NHC(.dbd.O)--C.sub.1-4 alkyl, and
--C(.dbd.O)NR.sup.10R.sup.11, wherein each R.sup.10 and R.sup.11 is
independently selected from from H and C.sub.1-4 alkyl. [0786] 62.
A compound or pharmaceutically acceptable salt thereof, according
to clause 59, 60 or 61, wherein R.sup.2 is phenyl. [0787] 63. A
compound or pharmaceutically acceptable salt thereof, according to
any one of clauses 1-16, or 19-32, wherein L.sub.3 is
--NR.sup.4b--, and R.sup.4b is H, Me, Et, or cyclopropyl. [0788]
64. A compound or pharmaceutically acceptable salt thereof,
according to any one of clauses 1-16, 19-32, or 63, wherein R.sup.3
is C.sub.1-4 alkyl substituted with phenyl, or pyridyl. [0789] 65.
A compound or pharmaceutically acceptable salt thereof, according
to any one of clauses 1-16, 19-32, or 63, wherein R.sup.3 is
C.sub.1-4 alkyl substituted with phenyl, or pyridyl, each of which
is substituted with Me, Et, F, or Cl. [0790] 66. A compound or
pharmaceutically acceptable salt thereof, according to any one of
clauses 1-16, 19-32, or 63, wherein R.sup.3 is 5-10 membered
heteroaryl comprising one to three heteroatoms independently
selected from N, S, and O. [0791] 67. A compound or
pharmaceutically acceptable salt thereof, according to any one of
clauses 1-16, 19-32, or 63, wherein R.sup.3 is 5-10 membered
heteroaryl comprising one to three heteroatoms independently
selected from N, S, and O, substituted with one or more
independently selected R.sup.8 groups. [0792] 68. A compound or
pharmaceutically acceptable salt thereof, according to clause 67
wherein R.sup.8 is selected from Me, Et, F, and Cl. [0793] 69. A
compound or pharmaceutically acceptable salt thereof, according to
clause 66, 67, or 68 wherein R.sup.3 is pyridyl. [0794] 70. A
compound or pharmaceutically acceptable salt thereof, according to
any one of clauses 1-16, 19-32, or 63, wherein R.sup.3 is
C.sub.6-10 aryl. [0795] 71. A compound or pharmaceutically
acceptable salt thereof, according to any one of clauses 1-16,
19-32, or 63, wherein R.sup.3 is C.sub.6-10 aryl, substituted with
one or more independently selected R.sup.8 groups. [0796] 72. A
compound or pharmaceutically acceptable salt thereof, according to
clause 71, wherein R.sup.8 is selected from Me, Et, F, and Cl.
[0797] 73. A compound or pharmaceutically acceptable salt thereof,
according to clause 70, 71, or 72, wherein R.sup.3 is phenyl.
[0798] 74. A compound or pharmaceutically acceptable salt thereof,
according to clause 1 or 2, wherein the compound is according to
Formulae Va, VIa, or VIIa:
[0798] ##STR00040## [0799] wherein R.sup.2 is are as described in
clause 1 or 2. [0800] 75. A compound or pharmaceutically acceptable
salt thereof, according to clause 1 or 2, wherein the compound is
according to Formulae Vb, VIb, or VIIb:
[0800] ##STR00041## [0801] wherein R.sup.2 is are as described in
clause 1 or 2. [0802] 76. A compound or pharmaceutically acceptable
salt thereof, according to clause 1 or 2, wherein the compound is
according to Formulae Vc, VIc, or VIIc:
[0802] ##STR00042## [0803] wherein R.sup.2 is are as described in
clause 1 or 2. [0804] 77. A compound or pharmaceutically acceptable
salt thereof, according to clause 1 or 2, wherein the compound is
according to Formulae Vd, VId, or VIId:
[0804] ##STR00043## [0805] wherein R.sup.2 is are as described in
clause 1 or 2. [0806] 78. A compound or pharmaceutically acceptable
salt thereof, according to clause 74 or 75, wherein R.sup.2 is
C.sub.3-7 cycloalkyl. [0807] 79. A compound or pharmaceutically
acceptable salt thereof, according to clause 74 or 75, wherein
R.sup.2 is C.sub.3-7 cycloalkyl substituted with one R.sup.6 group.
[0808] 80. A compound or pharmaceutically acceptable salt thereof,
according to clause 79, wherein R.sup.6 is oxo, or R.sup.7, and
R.sup.7 is OH, or C.sub.1-6 alkyl. [0809] 81. A compound or
pharmaceutically acceptable salt thereof, according to clause 78,
79 or 80, wherein R.sup.2 is cyclopropyl, cyclobutyl, cyclopentyl
or cyclohexyl. [0810] 82. A compound or pharmaceutically acceptable
salt thereof, according to clause 76 or 77, wherein R.sup.2 is 5-10
membered heteroaryl comprising one to three heteroatoms
independently selected from N, S, and O. [0811] 83. A compound or
pharmaceutically acceptable salt thereof, according to clause 76 or
77, wherein R.sup.2 is 5-10 membered heteroaryl comprising one to
three heteroatoms independently selected from N, S, and O,
substituted with one or two independently selected R.sup.7 groups.
[0812] 84. A compound or pharmaceutically acceptable salt thereof,
according to clause 83, wherein R.sup.7 is selected from OH, halo,
C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with one or more halo,
C.sub.1-6 alkoxy, --CN, C.sub.3-7 cycloalkyl, 4-7 membered
heterocycloalkyl comprising one to three heteroatoms independently
selected from N, O, and S, and phenyl. [0813] 85. A compound or
pharmaceutically acceptable salt thereof, according to clause 82,
83 or 84, wherein R.sup.2 is furanyl, thienyl, oxazolyl, thiazolyl,
oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl,
pyrazinyl, pyrimidinyl, indanyl, or indazolyl. [0814] 86. A
compound or pharmaceutically acceptable salt thereof, according to
clause 76 or 77, wherein R.sup.2 is C.sub.6-10 aryl. [0815] 87. A
compound or pharmaceutically acceptable salt thereof, according to
clause 76 or 77, wherein R.sup.2 is C.sub.6-10 aryl substituted
with one or two independently selected R.sup.7 groups. [0816] 88. A
compound or pharmaceutically acceptable salt thereof, according to
clause 87, wherein R.sup.7 is selected from halo, CN, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, --NHC(.dbd.O)--C.sub.1-4 alkyl, and
--C(.dbd.O)NR.sup.10R.sup.11, and each R.sup.10 and R.sup.11 is
independently selected from from H and C.sub.1-4 alkyl. [0817] 89.
A compound or pharmaceutically acceptable salt thereof, according
to clause 86, 87 or 88, wherein R.sup.2 is phenyl.
Pharmaceutical Compositions
[0818] When employed as a pharmaceutical, a compound of the
invention is typically administered in the form of a pharmaceutical
composition. Such compositions can be prepared in a manner well
known in the pharmaceutical art and comprise at least one active
compound. Generally, a compound of the invention is administered in
a pharmaceutically effective amount. The amount of a compound
actually administered will typically be determined by a physician,
in the light of the relevant circumstances, including the condition
to be treated, the chosen route of administration, the actual
compound-administered, the age, weight, and response of the
individual patient, the severity of the patient's symptoms, and the
like.
[0819] The pharmaceutical compositions of the invention can be
administered by a variety of routes including oral, rectal,
transdermal, subcutaneous, intra-articular, intravenous,
intramuscular, intranasal and inhalation. Depending on the intended
route of delivery, a compound of this invention is preferably
formulated as either injectable or oral compositions or as salves,
as lotions or as patches all for transdermal administration.
[0820] The compositions for oral administration can take the form
of bulk liquid solutions or suspensions, or bulk powders. More
commonly, however, the compositions are presented in unit dosage
forms to facilitate accurate dosing. The term "unit dosage forms"
refers to physically discrete units suitable as unitary dosages for
human subjects and other mammals, each unit containing a
predetermined quantity of active material calculated to produce the
desired therapeutic effect, in association with a suitable
pharmaceutical excipient, vehicle or carrier. Typical unit dosage
forms include prefilled, premeasured ampules or syringes of the
liquid compositions or pills, tablets, capsules or the like in the
case of solid compositions. In such compositions, a compound of the
invention is usually a minor component (from about 0.1 to about 50%
by weight or preferably from about 1 to about 40% by weight) with
the remainder being various vehicles or carriers and processing
aids helpful for forming the desired dosing form.
[0821] Liquid forms suitable for oral administration may include a
suitable aqueous or nonaqueous vehicle with buffers, suspending and
dispensing agents, colorants, flavors and the like. Solid forms may
include, for example, any of the following ingredients, or
compounds of a similar nature: a binder such as microcrystalline
cellulose, gum tragacanth or gelatin; an excipient such as starch
or lactose, a disintegrating agent such as alginic acid, Primogel,
or corn starch; a lubricant such as magnesium stearate; a glidant
such as colloidal silicon dioxide; a sweetening agent such as
sucrose or saccharin; or a flavoring agent such as peppermint,
methyl salicylate, or orange flavoring.
[0822] Injectable compositions are typically based upon injectable
sterile saline or phosphate-buffered saline or other injectable
carriers known in the art. As before, the active compound in such
compositions is typically a minor component, often being from about
0.05 to 10% by weight with the remainder being the injectable
carrier and the like.
[0823] Transdermal compositions are typically formulated as a
topical ointment or cream containing the active ingredient(s),
generally in an amount ranging from about 0.01 to about 20% by
weight, preferably from about 0.1 to about 20% by weight,
preferably from about 0.1 to about 10% by weight, and more
preferably from about 0.5 to about 15% by weight. When formulated
as a ointment, the active ingredients will typically be combined
with either a paraffinic or a water-miscible ointment base.
Alternatively, the active ingredients may be formulated in a cream
with, for example an oil-in-water cream base. Such transdermal
formulations are well-known in the art and generally include
additional ingredients to enhance the dermal penetration of
stability of the active ingredients or the formulation. All such
known transdermal formulations and ingredients are included within
the scope of this invention.
[0824] A compound of the invention can also be administered by a
transdermal device. Accordingly, transdermal administration can be
accomplished using a patch either of the reservoir or porous
membrane type, or of a solid matrix variety.
[0825] The above-described components for orally administrable,
injectable or topically administrable compositions are merely
representative. Other materials as well as processing techniques
and the like are set forth in Part 8 of Remington's Pharmaceutical
Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pa.,
which is incorporated herein by reference.
[0826] A compound of the invention can also be administered in
sustained release forms or from sustained release drug delivery
systems. A description of representative sustained release
materials can be found in Remington's Pharmaceutical Sciences.
[0827] The following formulation examples illustrate representative
pharmaceutical compositions that may be prepared in accordance with
this invention. The present invention, however, is not limited to
the following pharmaceutical compositions.
Formulation 1--Tablets
[0828] A compound of the invention may be admixed as a dry powder
with a dry gelatin binder in an approximate 1:2 weight ratio. A
minor amount of magnesium stearate may be added as a lubricant. The
mixture may be formed into 240-270 mg tablets (80-90 mg of active
amide compound per tablet) in a tablet press.
Formulation 2--Capsules
[0829] A compound of the invention may be admixed as a dry powder
with a starch diluent in an approximate 1:1 weight ratio. The
mixture may be filled into 250 mg capsules (125 mg of active amide
compound per capsule).
Formulation 3--Liquid
[0830] A compound of the invention (125 mg), may be admixed with
sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture
may be blended, passed through a No. 10 mesh U.S. sieve, and then
mixed with a previously made solution of microcrystalline cellulose
and sodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium
benzoate (10 mg), flavor, and color may be diluted with water and
added with stirring. Sufficient water may then be added with
stirring. Sufficient water may be then added to produce a total
volume of 5 mL.
Formulation 4--Tablets
[0831] A compound of the invention may be admixed as a dry powder
with a dry gelatin binder in an approximate 1:2 weight ratio. A
minor amount of magnesium stearate may be added as a lubricant. The
mixture is formed into 450-900 mg tablets (150-300 mg of active
amide compound) in a tablet press.
Formulation 5--Injection
[0832] A compound of the invention may be dissolved or suspended in
a buffered sterile saline injectable aqueous medium to a
concentration of approximately 5 mg/mL.
Formulation 6--Topical
[0833] Stearyl alcohol (250 g) and a white petrolatum (250 g) may
be melted at about 75.degree. C. and then a mixture of a compound
of the invention (50 g) methylparaben (0.25 g), propylparaben (0.15
g), sodium lauryl sulfate (10 g), and propylene glycol (120 g)
dissolved in water (about 370 g) may be added and the resulting
mixture may be stirred until it congeals.
Methods of Treatment
[0834] A compound of the invention may be used as a therapeutic
agent for the treatment of conditions in mammals that are causally
related or attributable to aberrant activity of GPR84 and/or
aberrant GPR84 expression and/or aberrant GPR84 distribution.
[0835] Accordingly, a compound and pharmaceutical compositions of
the invention find use as therapeutics for the prophylaxis and/or
treatment of inflammatory conditions (e.g. inflammatory bowel
diseases (IBD), rheumatoid arthritis, vasculitis), lung diseases
(e.g. chronic obstructive pulmonary disease (COPD) and lung
interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))),
neuroinflammatory conditions, infectious diseases, autoimmune
diseases, endocrine and/or metabolic diseases, and/or diseases
involving impairment of immune cell functions, in mammals including
humans.
[0836] Accordingly, in one aspect, the present invention provides
the compound of the invention, or a pharmaceutical composition
comprising the compound of the invention for use as a
medicament.
[0837] In another aspect, the present invention provides the
compound of the invention, or a pharmaceutical composition
comprising the compound of the invention for use in the manufacture
of a medicament.
[0838] In yet another aspect, the present invention provides a
method of treating a mammal having, or at risk of having a disease
disclosed herein. In a particular aspect, the present invention
provides a method of treating a mammal having, or at risk of having
inflammatory conditions (e.g. inflammatory bowel diseases (IBD),
rheumatoid arthritis, vasculitis), lung diseases (e.g. chronic
obstructive pulmonary disease (COPD) and lung interstitial diseases
(e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory
conditions, infectious diseases, autoimmune diseases, endocrine
and/or metabolic diseases, and/or diseases involving impairment of
immune cell functions, in mammals including humans, said method
comprising administering an effective amount of a compound of the
invention, or one or more of the pharmaceutical compositions herein
described.
[0839] In one aspect, the present invention provides the compound
of the invention, or a pharmaceutical composition comprising the
compound of the invention for use in the prophylaxis and/or
treatment of inflammatory conditions. In a specific embodiment, the
inflammatory condition is selected from inflammatory bowel disease
(IBD), rheumatoid arthritis, vasculitis, chronic obstructive
pulmonary disease (COPD), and idiopathic pulmonary fibrosis
(IPF).
[0840] In another aspect, the present invention provides the
compound of the invention, or a pharmaceutical composition
comprising the compound of the invention for use in the manufacture
of a medicament for the prophylaxis and/or treatment of
inflammatory conditions. In a specific embodiment, the inflammatory
condition is selected from inflammatory bowel disease (IBD),
rheumatoid arthritis, vasculitis, chronic obstructive pulmonary
disease (COPD), and idiopathic pulmonary fibrosis (IPF).
[0841] In another aspect, the present invention provides a method
of treating a mammal having, or at risk of having a disease
selected from inflammatory conditions (for example inflammatory
bowel diseases (IBD), rheumatoid arthritis, vasculitis), lung
diseases (e.g. chronic obstructive pulmonary disease (COPD) and
lung interstitial diseases (e.g. idiopathic pulmonary fibrosis
(IPF))), neuroinflammatory conditions, infectious diseases,
autoimmune diseases, endocrine and/or metabolic diseases, and/or
diseases involving impairment of immune cell functions, which
method comprises administering an effective amount of a compound of
the invention, or one or more of the pharmaceutical compositions
herein described.
[0842] In additional method of treatment aspects, this invention
provides methods of treatment and/or prophylaxis of a mammal
susceptible to or afflicted with inflammatory conditions, which
method comprises administering an effective amount of a compound of
the invention, or one or more of the pharmaceutical compositions
herein described. In a specific embodiment, the inflammatory
condition is selected from inflammatory bowel disease (IBD),
rheumatoid arthritis, vasculitis, chronic obstructive pulmonary
disease (COPD), and idiopathic pulmonary fibrosis (IPF).
[0843] In one aspect, the present invention provides a compound of
the invention, or a pharmaceutical composition comprising the
compound of the invention for use in the prophylaxis and/or
treatment of neuroinflammatory conditions, Guillain-Barre syndrome
(GBS), multiple sclerosis, axonal degeneration, autoimmune
encephalomyelitis.
[0844] In another aspect, the present invention provides a compound
of the invention, or a pharmaceutical composition comprising the
compound of the invention for use in the manufacture of a
medicament for the prophylaxis and/or treatment of
neuroinflammatory conditions, Guillain-Barre syndrome (GBS),
multiple sclerosis, axonal degeneration, autoimmune
encephalomyelitis.
[0845] In additional method of treatment aspects, this invention
provides methods of treatment and/or prophylaxis of a mammal
susceptible to or afflicted with neuroinflammatory conditions,
Guillain-Barre syndrome (GBS), multiple sclerosis, axonal
degeneration, autoimmune encephalomyelitis, which method comprises
administering an effective amount of a compound of the invention,
or one or more of the pharmaceutical compositions herein
described.
[0846] In one aspect, the present invention provides a compound of
the invention, or a pharmaceutical composition comprising the
compound of the invention for use in the prophylaxis and/or
treatment of infectious disease(s). In a specific embodiment, the
infectious disease(s) is selected from sepsis, septicemia,
endotoxemia, systemic inflammatory response syndrome (SIRS),
gastritis, enteritis, enterocolitis, tuberculosis, and other
infections involving, for example, Yersinia, Salmonella, Chlamydia,
Shigella, enterobacteria species.
[0847] In another aspect, the present invention provides a compound
of the invention, or a pharmaceutical composition comprising the
compound of the invention for use in the manufacture of a
medicament for the prophylaxis and/or treatment of infectious
disease(s). In a specific embodiment, the infectious disease(s) is
selected from sepsis, septicemia, endotoxemia, systemic
inflammatory response syndrome (SIRS), gastritis, enteritis,
enterocolitis, tuberculosis, and other infections involving, for
example, Yersinia, Salmonella, Chlamydia, Shigella, enterobacteria
species.
[0848] In additional method of treatment aspects, this invention
provides methods of treatment and/or prophylaxis of a mammal
susceptible to or afflicted with infectious disease(s), which
method comprises administering an effective amount of a compound of
the invention, or one or more of the pharmaceutical compositions
herein described. In a specific embodiment, the infectious disease
is selected from sepsis, septicemia, endotoxemia, systemic
inflammatory response syndrome (SIRS), gastritis, enteritis,
enterocolitis, tuberculosis, and other infections involving, for
example, Yersinia, Salmonella, Chlamydia, Shigella, enterobacteria
species.
[0849] In one aspect, the present invention provides the compound
of the invention, or a pharmaceutical composition comprising the
compound of the invention for use in the prophylaxis and/or
treatment of autoimmune diseases, and/or diseases involving
impairment of immune cell functions. In a specific embodiment, the
autoimmune diseases and/or diseases involving impairment of immune
cell functions is selected from COPD, asthma, psoriasis, systemic
lupus erythematosis, type I diabetes mellitus, vasculitis and
inflammatory bowel disease.
[0850] In another aspect, the present invention provides the
compound of the invention, or a pharmaceutical composition
comprising the compound of the invention for use in the manufacture
of a medicament for the prophylaxis and/or treatment of autoimmune
diseases and/or diseases involving impairment of immune cell
functions. In a specific embodiment, the autoimmune diseases,
and/or diseases involving impairment of immune cell functions is
selected from COPD, asthma, psoriasis, systemic lupus
erythematosis, type I diabetes mellitus, vasculitis and
inflammatory bowel disease.
[0851] In additional method of treatment aspects, this invention
provides methods of treatment and/or prophylaxis of a mammal
susceptible to or afflicted with autoimmune diseases and/or
diseases involving impairment of immune cell functions, which
method comprises administering an effective amount of a compound of
the invention, or one or more of the pharmaceutical compositions
herein described. In a specific embodiment, the autoimmune diseases
and/or diseases involving impairment of immune cell functions is
selected from COPD, asthma, psoriasis, systemic lupus
erythematosis, type I diabetes mellitus, vasculitis and
inflammatory bowel disease.
[0852] In one aspect, the present invention provides the compound
of the invention, or a pharmaceutical composition comprising the
compound of the invention for use in the prophylaxis and/or
treatment of endocrine and/or metabolic diseases. In a specific
embodiment, the endocrine and/or metabolic diseases is selected
from hypothyroidism, congenital adrenal hyperplasia, diseases of
the parathyroid gland, diabetes mellitus, diseases of the adrenal
glands (including Cushing's syndrome and Addison's disease),
ovarian dysfunction (including polycystic ovary syndrome), cystic
fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout,
and rickets.
[0853] In another aspect, the present invention provides the
compound of the invention, or a pharmaceutical composition
comprising the compound of the invention for use in the manufacture
of a medicament for the prophylaxis and/or treatment of endocrine
and/or metabolic diseases. In a specific embodiment, the endocrine
and/or metabolic diseases is selected from hypothyroidism,
congenital adrenal hyperplasia, diseases of the parathyroid gland,
diabetes mellitus, diseases of the adrenal glands (including
Cushing's syndrome and Addison's disease), ovarian dysfunction
(including polycystic ovary syndrome), cystic fibrosis,
phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and
rickets.
[0854] In additional method of treatment aspects, this invention
provides methods of treatment and/or prophylaxis of a mammal
susceptible to or afflicted with endocrine and/or metabolic
diseases, which method comprises administering an effective amount
of a compound of the invention, or one or more of the
pharmaceutical compositions herein described. In a specific
embodiment, the endocrine and/or metabolic diseases is selected
from hypothyroidism, congenital adrenal hyperplasia, diseases of
the parathyroid gland, diabetes mellitus, diseases of the adrenal
glands (including Cushing's syndrome and Addison's disease),
ovarian dysfunction (including polycystic ovary syndrome), cystic
fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout,
and rickets.
[0855] As a further aspect of the invention there is provided a
compound of the invention for use as a medicament especially in the
treatment or prevention of the aforementioned conditions and
diseases. Also provided herein is the use of the compound in the
manufacture of a medicament for the treatment or prevention of one
of the aforementioned conditions and diseases.
[0856] A particular regimen of the present method comprises the
administration to a subject in suffering from an inflammatory
condition, of an effective amount of a compound of the invention
for a period of time sufficient to reduce the level of inflammation
in the subject, and preferably terminate, the processes responsible
for said inflammation. A special embodiment of the method comprises
administering of an effective amount of a compound of the invention
to a subject suffering from or susceptible to the development of
inflammatory condition, for a period of time sufficient to reduce
or prevent, respectively, inflammation of said patient, and
preferably terminate, the processes responsible for said
inflammation.
[0857] Injection dose levels range from about 0.1 mg/kg/h to at
least 10 mg/kg/h, all for from about 1 to about 120 h and
especially 24 to 96 h. A preloading bolus of from about 0.1 mg/kg
to about 10 mg/kg or more may also be administered to achieve
adequate steady state levels. The maximum total dose is not
expected to exceed about 2 g/day for a 40 to 80 kg human
patient.
[0858] Transdermal doses are generally selected to provide similar
or lower blood levels than are achieved using injection doses.
[0859] When used to prevent the onset of a condition, a compound of
the invention will be administered to a patient at risk for
developing the condition, typically on the advice and under the
supervision of a physician, at the dosage levels described above.
Patients at risk for developing a particular condition generally
include those that have a family history of the condition, or those
who have been identified by genetic testing or screening to be
particularly susceptible to developing the condition.
[0860] A compound of the invention can be administered as the sole
active agent or it can be administered in combination with other
therapeutic agents, including other compounds that demonstrate the
same or a similar therapeutic activity, and that are determined to
be safe and efficacious for such combined administration. In a
specific embodiment, co-administration of two (or more) agents
allows for significantly lower doses of each to be used, thereby
reducing the side effects seen.
[0861] In one embodiment, a compound of the invention is
co-administered with another therapeutic agent for the treatment
and/or prevention of an inflammatory condition; particular agents
include, but are not limited to, immunoregulatory agents e.g.
azathioprine, corticosteroids (e.g. prednisolone or dexamethasone),
cyclophosphamide, cyclosporin A, tacrolimus, Mycophenolate Mofetil,
muromonab-CD3 (OKT3, e.g. Orthocolone.RTM.), ATG, aspirin,
acetaminophen, ibuprofen, naproxen, and piroxicam.
[0862] In one embodiment, a compound of the invention is
co-administered with another therapeutic agent for the treatment
and/or prevention of arthritis (e.g. rheumatoid arthritis);
particular agents include but are not limited to analgesics,
non-steroidal anti-inflammatory drugs (NSAIDS), steroids, synthetic
DMARDS (for example but without limitation methotrexate,
leflunomide, sulfasalazine, auranofin, sodium aurothiomalate,
penicillamine, chloroquine, hydroxychloroquine, azathioprine, and
cyclosporin), and biological DMARDS (for example but without
limitation Infliximab, Etanercept, Adalimumab, Rituximab,
Golimumab, Certolizumab pegol, Tocilizumab, Interleukin 1 blockers
and Abatacept).
[0863] In one embodiment, a compound of the invention is
co-administered with another therapeutic agent for the treatment
and/or prevention of autoimmune diseases; particular agents include
but are not limited to: glucocorticoids, cytostatic agents (e.g.
purine analogs), alkylating agents, (e.g nitrogen mustards
(cyclophosphamide), nitrosoureas, platinum compounds, and others),
antimetabolites (e.g. methotrexate, azathioprine and
mercaptopurine), cytotoxic antibiotics (e.g. dactinomycin
anthracyclines, mitomycin C, bleomycin, and mithramycin),
antibodies (e.g., anti-CD20, anti-CD25 or anti-CD3 (OTK3)
monoclonal antibodies, Atgam.RTM. and Thymoglobuline.RTM.),
cyclosporin, tacrolimus, rapamycin (sirolimus), interferons (e.g.
IFN-.beta.), TNF binding proteins (e.g. infliximab (Remicade.TM.),
etanercept (Enbrel.TM.), or adalimumab (Humira.TM.)),
mycophenolate, Fingolimod, and Myriocin.
[0864] In one embodiment, a compound of the invention is
co-administered with another therapeutic agent for the treatment
and/or prevention of infectious diseases; particular agents include
but are not limited to antibiotics. In a particular embodiment, a
compound of the invention is co-administered with another
therapeutic agent for the treatment and/or prevention of infections
of any organ of the human body; particular agents include but are
not limited to: aminoglycosides, ansamycins, carbacephem,
carbapenems, cephalosporins, glycopeptides, lincosamides,
macrolides, monobactams, nitrofurans, penicillins, polypeptides,
quinolones, sulfonamides, tetracyclins, anti-mycobacterial agents,
as well as chloramphenicol, fosfomycin, linezolid, metronidazole,
mupirocin, rifamycin, thiamphenicol and tinidazole.
[0865] In one embodiment, a compound of the invention is
co-administered with another therapeutic agent for the treatment
and/or prevention of vasculitis, particular agents include but are
not limited to steroids (for example prednisone, prednisolone),
cyclophosphamide and eventually antibiotics in case of cutaneous
infections (for example cephalexin)
[0866] In one embodiment, a compound of the invention is
co-administered with another therapeutic agent for the treatment
and/or prevention of IPF, particular agents include but are not
limited to pirfenidone and bosentan.
[0867] In one embodiment, a compound of the invention is
co-administered with another therapeutic agent for the treatment
and/or prevention of asthma and/or rhinitis and/or COPD; particular
agents include but are not limited to: beta.sub.2-adrenoceptor
agonists (e.g. salbutamol, levalbuterol, terbutaline and
bitolterol), epinephrine (inhaled or tablets), anticholinergics
(e.g. ipratropium bromide), glucocorticoids (oral or inhaled)
Long-acting .beta..sub.2-agonists (e.g. salmeterol, formoterol,
bambuterol, and sustained-release oral albuterol), combinations of
inhaled steroids and long-acting bronchodilators (e.g.
fluticasone/salmeterol, budesonide/formoterol), leukotriene
antagonists and synthesis inhibitors (e.g. montelukast, zafirlukast
and zileuton), inhibitors of mediator release (e.g. cromoglycate
and ketotifen), phosphodiesterase-4 inhibitors (e.g. Roflumilast),
biological regulators of IgE response (e.g. omalizumab),
antihistamines (e.g. ceterizine, cinnarizine, fexofenadine), and
vasoconstrictors (e.g. oxymethazoline, xylomethazoline, nafazoline
and tramazoline).
[0868] Additionally, a compound of the invention may be
administered in combination with emergency therapies for asthma
and/or COPD, such therapies include oxygen or heliox
administration, nebulized salbutamol or terbutaline (optionally
combined with an anticholinergic (e.g. ipratropium), systemic
steroids (oral or intravenous, e.g. prednisone, prednisolone,
methylprednisolone, dexamethasone, or hydrocortisone), intravenous
salbutamol, non-specific beta-agonists, injected or inhaled (e.g.
epinephrine, isoetharine, isoproterenol, metaproterenol),
anticholinergics (IV or nebulized, e.g. glycopyrrolate, atropine,
ipratropium), methylxanthines (theophylline, aminophylline,
bamiphylline), inhalation anesthetics that have a bronchodilatory
effect (e.g. isoflurane, halothane, enflurane), ketamine, and
intravenous magnesium sulfate.
[0869] In one embodiment, a compound of the invention is
co-administered with another therapeutic agent for the treatment
and/or prevention of inflammatory bowel disease (IBD); particular
agents include but are not limited to: glucocorticoids (e.g.
prednisone, budesonide) synthetic disease modifying,
immunomodulatory agents (e.g. methotrexate, leflunomide,
sulfasalazine, mesalazine, azathioprine, 6-mercaptopurine and
ciclosporin) and biological disease modifying, immunomodulatory
agents (infliximab, adalimumab, rituximab, and abatacept).
[0870] By co-administration is included any means of delivering two
or more therapeutic-agents to the patient as part of the same
treatment regime, as will be apparent to the skilled person. Whilst
the two or more agents may be administered simultaneously in a
single formulation this is not essential. The agents may be
administered in different formulations and at different times.
General Synthetic Procedures
General
[0871] A compound of the invention can be prepared from readily
available starting materials using the following general methods
and procedures. It will be appreciated that where typical or
preferred process conditions (i.e., reaction temperatures, times,
mole ratios of reactants, solvents, pressures, etc.) are given,
other process conditions can also be used unless otherwise stated.
Optimum reaction conditions may vary with the particular reactants
or solvent used, but such conditions can be determined by one
skilled in the art by routine optimization procedures.
[0872] Additionally, as will be apparent to those skilled in the
art, conventional protecting groups may be necessary to prevent
certain functional groups from undergoing undesired reactions. The
choice of a suitable protecting group for a particular functional
group as well as suitable conditions for protection and
deprotection are well known in the art. For example, numerous
protecting groups, and their introduction and removal, are
described in T. W. Greene and P. G. M. Wuts, Protecting Groups in
Organic Synthesis, Wiley-Blackwell; 4th Revised edition edition
(2006), and references cited therein.
[0873] The following methods are presented with details as to the
preparation of representative
6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one compounds that have
been listed hereinabove. A compound of the invention may be
prepared from known or commercially available starting materials
and reagents by one skilled in the art of organic synthesis.
[0874] All reagents were of commercial grade and were used as
received without further purification, unless otherwise stated.
Commercially available anhydrous solvents were used for reactions
conducted under inert atmosphere. Reagent grade solvents were used
in all other cases, unless otherwise specified. Column
chromatography was performed on silica standard (30-70 .mu.m). Thin
layer chromatography was carried out using pre-coated silica gel 60
F-254 plates (thickness 0.25 mm). .sup.1H NMR spectra were recorded
on a Bruker Advance 400 NMR spectrometer (400 MHz) or a Bruker
Advance 300 NMR spectrometer (300 MHz). Chemical shifts (.delta.)
for 1H NMR spectra are reported in parts per million (ppm) relative
to tetramethylsilane (.delta. 0.00) or the appropriate residual
solvent peak as internal reference. Multiplicities are given as
singlet (s), doublet (d), doublet of doublet (dd), triplet (t),
quartet (q), multiplet (m) and broad (br). Electrospray MS spectra
were obtained either on a Waters platform LC/MS spectrometer or on
an Agilent 1100 Series LC/MSD. Analytic LCMS: Columns used, Waters
Acquity UPLC BEH C18 1.7 m, 2.1 mm ID.times.50 mm L or Waters
Acquity UPLC BEH C18 1.7 m, 2.1 mm ID.times.30 mm L or Waters
XBridge C18 3.5 .mu.m, 2.1 mm ID.times.50 mm L. All the methods are
using MeCN/H.sub.2O gradients. MeCN and H.sub.2O contain either
0.1% Formic Acid or NH.sub.3 (10 mM). Preparative LCMS: Column
used, Waters XBridge Prep C18 5 .mu.m ODB 30 mm ID.times.100 mm L.
All the methods are using either MeOH/H.sub.2O or MeCN/H.sub.2O
gradients. MeOH, MeCN and H.sub.2O contain either 0.1% Formic Acid
or 0.1% Diethylamine. Analytic chiral LC: Column used, Chiralpak IA
5 .mu.m 250.times.4.6 mm. Microwave heating was performed with a
Biotage Initiator.
TABLE-US-00001 TABLE I List of abbreviations used in the
experimental section: .mu.L microliter AcOH Acetic acid Aq. aqueous
ATP Adenosine 5'-Triphosphate BINAP
2,2'-bis(diphenylphosphino)-1,1'- binaphthyl Boc
tert-Butyloxy-carbonyl Boc.sub.2O Di-tert-butyl dicarbonate br s
broad singlet Calcd calculated Cat. Catalytic amount D doublet Dd
Doublet of doublet DCC N,N'-Dicyclohexylcarbodiimide DCE
1,2-Dichloroethane DCM Dichloromethane DIAD Diisopropyl
azodicarboxylate DIPEA N,N-diisopropylethylamine DMAP
4-Dimethylaminopyridine DME Dimethoxyethane DMF
N,N-dimethylformamide DMSO Dimethylsulfoxide DPBS Dulbecco's
Phosphate-Buffered Saline DPPF 1,1'-
Bis(diphenylphosphino)ferrocene EtOAc Ethyl acetate Et.sub.2O
Diethyl ether eq. equivalent g gram GTP.gamma.S guanosine
5'-O-[gamma- thio]triphosphate h hour H Heptane HPLC
High-performance liquid chromatography iPrOH isopropanol iPr.sub.2O
Diisopropyl ether KHMDS Potassium hexamethyldisilazane LCMS Liquid
Chromatography-Mass Spectrometry L Liter M multiplet MeOH Methanol
MeCN Acetonitrile MeI Methyl iodide MEK Methyl ethyl ketone Mg
milligram Min minute mL milliliter Mmol millimole MS mass
spectrometry MW Molecular weight MW Molecular weight observed (obs)
MW Molecular weight calculated (calc) NADP Nicotinamide adenine
dinucleotide phosphate NEAA Non-Essential Amino Acid NMP
N-Methyl-2-pyrrolidone NMR Nuclear Magnetic Resonnance obsd
observed Pd(OAc).sub.2 Palladium(II)acetate Pd(PPh.sub.3).sub.4
Tetrakis(triphenylphosphine)palladium (0) Pd/C Palladium on Carbon
10% ppm part-per-million q quadruplet rpm revolutions per minute RT
Room temperature Rt retention time RuPhos
2-Dicyclohexylphosphino-2',6'- di-i-propoxy-1,1'-biphenyl s singlet
SM Starting material spA Scintillation proximity assay SPE Solid
phase extraction STAB sodiumtriacetoxyborohydride t triplet TBAF
Tetra-n-butylammonium fluoride TEA Triethylamine TFA
Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer
chromatography
General Synthetic Method
[0875] Intermediates to prepare the compounds according to the
invention can be produced according to the following schemes.
##STR00044##
Intermediate 1: [2-(3-methoxy-phenyl)-ethyl]-urea
[0876] A solution of 3-methoxyphenethylamine (100 g, 661.3 mmol, 1
eq.), urea (157.3 g, 2619.0 mmol, 4 eq.), AcOH (36 mL) and aq. HCl
(12 mL) in H.sub.2O (800 mL) was heated under reflux for 5 days.
The reaction mixture was cooled to room temperature, the solid was
filtered off, washed with water and dried to afford intermediate
1.
[0877] (.sup.1H, CDCl.sub.3) .delta. (ppm): 7.24 (1H, t), 6.82-6.77
(3H, m), 5.10 (1H, br s), 4.52 (2H, br), 3.81 (1H, s), 3.42 (2H, br
t), 2.80 (2H, t).
Intermediate 2: [2-(3-hydroxy-phenyl)-ethyl]-urea
[0878] A solution of intermediate 1 (72 g, 370.7 mmol) in
concentrated HBr (500 mL) was heated under reflux overnight. The
reaction mixture was basified with the addition of NaHCO.sub.3 and
extracted with EtOAc. The organic layer was dried over MgSO.sub.4
and concentrated under vacuum to afford intermediate 2.
[0879] (.sup.1H, MeOD-d4) .delta. (ppm): 7.15 (1H, t), 6.76-6.68
(3H, m), 3.40-3.36 (2H, t), 2.77-2.74 (2H, t).
Intermediate 3: [2-(3-allyloxy-phenyl)-ethyl]-urea
[0880] To a solution of intermediate 2 (45 g, 249.7 mmol, 1 eq.)
and K.sub.2CO.sub.3 (103.5 g, 749.1 mmol, 3 eq.) in dry DMF (300
mL) under nitrogen, was added allylbromide (50.5 mL, 499.4 mmol, 2
eq.). The reaction mixture was stirred for 2.5 days, then DMF was
evaporated to dryness. The residue was dissolved in EtOAc, washed
with a saturated solution of Na.sub.2CO.sub.3, brine, dried over
MgSO.sub.4 and concentrated under vacuum to afford intermediate
3.
[0881] (.sup.1H, MeOD-d4) .delta. (ppm): 7.24 (1H, t), 6.87-6.81
(3H, m), 6.16-6.06 (1H, m), 5.45 (1H, dd), 5.29 (1H, dd), 4.59-4.57
(2H, m), 3.38 (2H, t), 2.80 (2H, t)
Intermediate 4:
1-[2-(3-allyloxy-phenyl)-ethyl]-pyrimidine-2,4,6-trione
[0882] Sodium (20.06 g, 872 mmol, 1 eq.) was dissolved in EtOH (1.4
L). Diethyl malonate (132.4 mL, 872 mmol, 1 eq.) was added and the
reaction mixture was heated under reflux for 1 h. Intermediate 3
(96 g, 436 mmol, 0.5 eq.) in EtOH (300 mL) was added and the
reaction mixture was heated under reflux for 12 h. The reaction was
cooled to room temperature, IN aq. HCl was added and the
precipitate was filtered off, washed with water and dried to afford
intermediate 4.
[0883] (.sup.1H, CDCl.sub.3) .delta. (ppm): 8.40 (1H, br s), 7.25
(1H, t), 6.88-6.82 (3H, m), 6.14-6.04 (1H, m), 5.45 (1H, dd), 5.32
(1H, dd), 4.58-4.56 (2H, m), 4.13 (2H, t), 3.64 (2H, s), 2.92 (2H,
t)
[0884] MW (calcd): 288.3; MW (obsd): 289.3 (M+1)
Intermediate 5:
9-allyloxy-2-chloro-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[0885] A solution of intermediate 4 (20 g, 69.4 mmol, 1 eq.) in
POCl.sub.3 (150 mL) was stirred at 50.degree. C. for 3 days.
POCl.sub.3 was evaporated under vacuum and the residue was
dissolved in DCM and quenched with a saturated solution of
NaHCO.sub.3. The organic layer was washed with water, dried over
MgSO.sub.4 and concentrated to afford intermediate 5.
[0886] (.sup.1H, CDCl.sub.3) .delta. (ppm): 7.71 (2H, d), 6.97 (1H,
dd), 6.86 (1H, d), 6.71 (1H, s), 6.13-6.04 (1H, m), 5.47 (1H, dd),
5.36 (1H, dd), 4.67-4.65 (2H, m), 4.27 (2H, t), 3.05 (2H, t)
[0887] MW (calcd): 288.7; MW (obsd): 289.3 (M+1)
Intermediate 6:
1-[2-(3-methoxy-phenyl)-ethyl]-pyrimidine-2,4,6-trione
[0888] Sodium (2.96 g, 128.7 mmol, 2.5 eq.) was dissolved in EtOH
(200 mL), diethyl malonate (11.73 mL, 77.2 mmol, 1.5 eq.) was added
and the reaction was heated under reflux for 1 h. Intermediate 1
(10 g, 51.5 mmol, 1 eq.) was then added and the reaction mixture
was heated under reflux for 48 h. The reaction was cooled to RT,
conc. HCl was added and the mixture was concentrated to dryness.
The residue was dissolved in brine and extracted with AcOEt. The
organic layer was dried over MgSO.sub.4 and concentrated to afford
intermediate 6.
[0889] (.sup.1H, DMSO) .delta. (ppm): 9.34 (1H, s), 7.20 (1H, t),
6.80-6.75 (3H, m), 6.14-6.04 (1H, m), 3.99 (1H, s), 3.83 (2H, t),
3.74 (3H, s), 2.70 (2H, t)
Intermediate 7:
9-allyloxy-2-chloro-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[0890] A round bottom flask was charged with intermediate 6 (6.21
g, 23.67 mmol, 1 eq.) and POCl.sub.3 (71 mL) and heated at
80.degree. C. for 1.5 days. The volatiles were then removed under
vacuum, the residue was dissolved in H.sub.2O and the pH was
adjusted to pH 7 with solid NaHCO.sub.3. The mixture was extracted
with DCM, which was washed with H.sub.2O, brine and dried over
MgSO.sub.4. Upon filtration, volatiles were removed under vacuum,
and the residue was purified by flash chromatography on silica gel
eluting with 5% iPrOH/DCM to give intermediate 7.
[0891] (.sup.1H, DMSO-d.sub.6) 8.00-7.86 (1H, t), 7.89-7.83 (1H,
d), 7.00-6.82 (1H, m), 6.08 (1H, s), 3.95-3.82 (4H, m)
General Method a for Intermediates A:
##STR00045##
[0893] To a solution of NaH (60% in mineral oil) or tBuOK (2 eq.)
in dry DCM at 0.degree. C., is added the appropriate alcohol
(R--OH) (2 eq.), after 15 min, intermediate 5 (1 eq.) is added at
0.degree. C., and the reaction is stirred at room temperature until
full completion. The reaction mixture is quenched with a saturated
solution of NH.sub.4Cl, the organic layer is washed with water,
dried over MgSO.sub.4 and concentrated. Intermediate A is purified
by flash chromatography on silica gel.
Illustrative Synthesis of General Method A:
Intermediate A1:
9-allyloxy-2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one
##STR00046##
[0895] To a solution of
(2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanol (8.63 g, 51.9 mmol,
1.5 eq.) and tBuOK (7.76 g, 69.2 mmol, 2 eq.) in dry DCM (150 mL)
was added intermediate 5 (10 g, 34.6 mmol, 1 eq.) at 0.degree. C.
The reaction mixture was stirred at room temperature for 1 h, then
the organic layer was washed with water, dried over MgSO.sub.4 and
evaporated to dryness. The crude product was purified by flash
chromatography on silica gel eluting with 5% MeOH/DCM to afford
intermediate A1.
[0896] (.sup.1H, CDCl.sub.3) .delta. (ppm): 7.68 (1H, d), 6.98-6.84
(6H, m), 6.31 (1H, s), 6.13-6.06 (1H, m), 5.50-5.34 (2H, m),
4.17-4.59 (5H, m), 4.41-4.13 (4H, m), 3.02 (2H, t)
[0897] MW (calcd): 418.5; MW (obsd): 419 (M+1)
Intermediate A2:
9-allyloxy-2-[(R)-1-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-yl)methoxy]-
-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
##STR00047##
[0899] Intermediate A2 is prepared using general method A with
intermediate 5 and
(S)-1-(2,3-dihydro-1,4]dioxino[2,3-b]pyridin-2-yl)-methanol.
[0900] (.sup.1H, CDCl.sub.3) .delta. (ppm): 7.87 (1H, dd), 7.69
(1H, d), 7.30-7.28 (1H, m), 6.97-6.93 (2H, m), 6.85-6.84 (1H, m),
6.30 (1H, s), 6.14-6.04 (1H, m), 5.47 (1H, dd), 5.38 (1H, dd),
4.73-4.72 (2H, m), 4.66-4.58 (4H, m), 4.40-4.34 (1H, m), 4.25 (2H,
t), 3.00 (2H, t)
[0901] MW (calcd): 419.4; MW (obsd): 420 (M+1)
Intermediate A3:
9-allyloxy-2-[(S)-1-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-yl)methoxy]-
-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
##STR00048##
[0903] Intermediate A3 is prepared using general method A with
intermediate 5 and
(R)-1-(2,3-dihydro-1,4]dioxino[2,3-b]pyridin-2-yl)-methanol.
[0904] (S)-1-(2,3-Dihydro-1,4]dioxino[2,3-b]pyridin-2-yl)-methanol
and (R)-1-(2,3-dihydro-1,4]dioxino[2,3-b]pyridin-2-yl)-methanol can
be prepared according to following publication [Bolchi et al.,
Tetrahedron: Asymmetry 16(20), (2005) 3380-3384]
[0905] (.sup.1H, CDCl.sub.3) .delta. (ppm): 7.87 (1H, dd), 7.67
(1H, d), 7.28-7.26 (1H, m), 6.97-6.91 (2H, m), 6.85-6.82 (1H, m),
6.30 (1H, s), 6.14-6.04 (1H, m), 5.47 (1H, dd), 5.37 (1H, dd),
4.73-4.71 (2H, m), 4.66-4.57 (4H, m), 4.39-4.33 (1H, m), 4.26 (2H,
t), 3.01 (2H, t)
General Method B for Intermediates B:
##STR00049##
[0907] To a suspension of intermediate A (1 eq.) in a mixture of
DCM/MeOH (1/1) is added K.sub.2CO.sub.3 (2 eq.) and
Pd(PPh.sub.3).sub.4 (0.05 eq.). The reaction mixture is degassed
before stirring at room temperature. After full completion, water
is added to the reaction mixture and the aqueous layer is
separated. The pH of the aqueous solution is adjusted to pH 1 with
2M aq. HCl. The precipitate is filtered off, washed with water and
dried to afford intermediate B.
Illustrative Synthesis of General Method B:
Intermediate B1:
2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-hydroxy-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one
##STR00050##
[0909] To a suspension of intermediate A1 (1.04 g, 2.49 mmol, 1
eq.) in a mixture of DCM/MeOH (1/1, 60 mL) was added
K.sub.2CO.sub.3 (0.75 g, 5.47 mmol, 2.2 eq.) and
Pd(PPh.sub.3).sub.4 (144 mg, 0.12 mmol, 0.05 eq.). The reaction
mixture was stirred at room temperature for 2 h. The reaction was
evaporated to dryness and the residue was purified by flash
chromatography on silica gel eluting with 5% MeOH/DCM to afford
intermediate B1.
[0910] (.sup.1H, DMSO-d.sub.6) .delta. 7.84 ppm (1H, d), 6.83-6.94
(4H, m), 6.71-6.80 (2H, m), 6.50 (1H, s), 4.38-4.62 (4H, m),
4.07-4.16 (1H, m), 4.00 (2H, t), 2.91 (2H, t)
[0911] MW (calcd): 378.4; MW (obsd): 379.1 (M+1)
Intermediate B2:
2-[(R)-1-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-yl)methoxy]-9-hydroxy--
6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
##STR00051##
[0913] Intermediate B2 was prepared using general method B starting
from intermediate A2.
[0914] (.sup.1H, DMSO-d.sub.6) .delta. ppm 7.75-7.90 (2H, m), 7.37
(1H, dd), 6.93-7.03 (2H, m), 6.72-6.83 (2H, m), 4.41-4.68 (4H, m),
4.24-4.37 (1H, m), 4.01 (2H, t), 2.87-2.98 (2H, m)
[0915] MW (calcd): 379.4; MW (obsd): 380.1 (M+1)
Intermediate B3:
2-[(S)-1-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-yl)methoxy]-9-hydroxy--
6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
##STR00052##
[0917] Intermediate B3 was prepared using general method B starting
from intermediate A3.
[0918] (.sup.1H, DMSO-d.sub.6) .delta. ppm 7.84 (1H, d), 7.77 (1H,
dd), 7.36 (1H, dd), 6.97 (1H, dd), 6.73-6.81 (2H, m), 6.49 (1H, s),
4.47-4.67 (4H, m), 4.26-4.35 (1H, m), 3.97-4.03 (2H, m), 2.88-2.95
(2H, m)
[0919] MW (calcd):379.4; MW (obsd): 380.3 (M+1)
Intermediate B4:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-hydroxy-6,7-dihy-
dro-pyrimido[6,1-a]isoquinolin-4-one
##STR00053##
[0921] Intermediate B4 was prepared using general method B starting
from compound 77.
[0922] (.sup.1H, DMSO-d.sub.6) .delta. ppm 7.84 (1H, d), 7.77 (1H,
dd), 7.33-7.38 (1H, m), 6.94-6.99 (1H, m), 6.71-6.80 (2H, m), 6.49
(1H, s), 4.46-4.67 (4H, m), 4.26-4.34 (1H, m), 4.00 (2H, s),
2.87-2.95 (2H, m)
General Method C for Intermediate C:
##STR00054##
[0924] A solution of intermediate B (1 eq.),
N-phenyl-bis(trifluoromethanesulfonimide) (1.2 eq.) and Et.sub.3N
(1.3 eq.) in DCM under nitrogen is stirred at room temperature
until full completion. The reaction mixture is concentrated and the
crude is purified by crystallization from iPrOH to afford
intermediate C.
Illustrative Synthesis of General Method C:
Intermediate C1: methanesulfonic acid
4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]isoq-
uinolin-9-yl ester
##STR00055##
[0926] A solution of compound 6 (117 mg, 0.37 mmol, 1 eq.),
N-phenyl-bis(trifluoromethanesulfonimide) (146 mg, 0.41 mmol, 1.1
eq.) and Et.sub.3N (0.093 mL, 0.67 mmol, 1.8 eq.) in DCM (4 mL)
under a nitrogen atmosphere is stirred at room temperature for 2 h.
The reaction mixture is concentrated under vacuum and the residue
is purified by flash chromatography on silica gel eluting with 4%
MeOH/DCM to afford intermediate C1.
[0927] (.sup.1H, CDCl.sub.3) .delta. ppm 7.76-7.82 (1H, m),
7.28-7.36 (1H, m), 7.26 (1H, s), 6.38 (1H, s), 4.53-4.63 (1H, m),
4.25 (4H, d), 3.80-3.99 (2H, m), 3.04-3.12 (2H, m), 1.87-2.14 (2H,
m), 1.61-1.71 (2H, m)
Intermediate C2: methanesulfonic acid
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro--
4H-pyrimido[6,1-a]isoquinolin-9-yl ester
##STR00056##
[0929] A solution of intermediate B4 (150 mg, 0.40 mmol, 1 eq.),
N-phenyl-bis(trifluoromethanesulfonimide) (155 mg, 0.43 mmol, 1.1
eq.) and Et.sub.3N (0.1 mL, 0.71 mmol, 1.8 eq.) in DCM (5 mL) under
a nitrogen atmosphere is stirred at room temperature overnight. The
reaction mixture is concentrated under vacuum and the residue is
purified by flash chromatography on silica gel eluting with 4%
MeOH/DCM to afford intermediate C2.
[0930] (.sup.1H, CDCl.sub.3) .delta. ppm 7.76-7.85 (2H, m),
7.23-7.33 (2H, m), 7.20 (1H, dd), 6.86 (1H, dd), 6.35 (1H, s), 4.66
(2H, d), 4.48-4.60 (2H, m), 4.30 (1H, dd), 4.18-4.25 (2H, m), 3.07
(2H, t)
General Method D:
##STR00057##
[0932] A vial is charged with intermediate B (1 eq.), tBuOK (2.4
eq.), the appropriate alkylating agent (2.7 eq.) in dry DCM. After
16 h, the mixture is partitioned between DCM and H.sub.2O. The
organic phase is collected and washed with H.sub.2O, brine and
dried over MgSO.sub.4. After evaporation, the crude product is
purified by flash chromatography on silica gel to give clean
product.
Illustrative Synthesis of General Method D:
Compound 7:
9-benzyloxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]i-
soquinolin-4-one
##STR00058##
[0934] A vial was charged with compound 6 (9.1 mg, 0.029 mmol, 1
eq.), tBuOK (7.7 mg, 0.007 mmol, 2.4 eq.), benzyl bromide (0.0095
mL, 0.008 mmol, 2.7 eq.) and dry DCM (0.5 mL). After 16 h, the
mixture was partitioned between DCM and H.sub.2O. The organic phase
was collected and washed with H.sub.2O, brine and dried over
MgSO.sub.4. After evaporation, the crude product was purified by
flash chromatography eluting with EtOAc/DCM/iPrOH (10/10/1) to give
compound 7.
[0935] (.sup.1H, CDCl.sub.3) .delta. ppm 7.63 (1H, d), 7.33-7.48
(5H, m), 6.91-7.01 (1H, m), 6.82-6.89 (1H, m), 6.29 (1H, s), 5.14
(2H, s), 4.51-4.61 (1H, m), 4.15-4.33 (4H, m), 3.90-3.98 (1H, m),
3.79-3.89 (1H, m), 2.97 (2H, t), 2.01-2.11 (1H, m), 1.86-2.00 (2H,
m), 1.58-1.73 (1H, m).
General Method E:
##STR00059##
[0937] A solution of intermediate B (1 eq.), the appropriate
alkylating agent (1.5 eq.), K.sub.2CO.sub.3 (2 eq.), KI or NaI (1
eq.) in MEK is heated at 80.degree. C. When the reaction has
reached completion, the volatiles are evaporated to dryness and the
product is then obtained after purification by either flash
chromatography on silica gel, preparative TLC or preparative
HPLC-MS.
Illustrative Synthesis of General Method E:
Compound 18:
9-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
##STR00060##
[0939] A solution of compound 6 (122 mg, 0.39 mmol, 1 eq.),
2-bromomethyl-2,3-dihydro-benzo[1,4]dioxine (409 mg, 1.79 mmol, 4.6
eq.), K.sub.2CO.sub.3 (520 mg, 3.76 mmol, 9.7 eq.), NaI (157 mg,
1.05 mmol, 2.7 eq.) in MEK (3.5 mL) was heated at 80.degree. C. for
16 h. The reaction was evaporated to dryness and the residue was
purified by flash chromatography on silica gel, eluting with 4%
MeOH/DCM to give compound 18.
[0940] (.sup.1H, CDCl.sub.3) .delta. ppm 7.64 (1H, d), 6.85-6.96
(5H, m), 6.83 (1H, d), 6.29 (1H, s), 4.51-4.65 (2H, m), 4.36-4.44
(1H, m), 4.16-4.35 (7H, m), 3.89-3.99 (1H, m), 3.79-3.88 (1H, m),
2.97 (2H, t), 2.00-2.13 (1H, m), 1.85-2.00 (2H, m), 1.58-1.72 (1H,
m).
General Method F:
##STR00061##
[0942] A vial is charged with intermediate C (1 eq.), the
appropriate boronic acid, boronic ester or potassium
trifluoroborate (3 eq.), Cs.sub.2CO.sub.3 (3.5 eq.),
(DPPF)PdCl.sub.2.DCM (0.05 eq.), in 1,4-dioxane/H.sub.2O (10/1,
v/v), and the mixture is degassed with N.sub.2. The vial is sealed
and heated at 80.degree. C. When the reaction has reached full
completion, the vial is cooled to room temperature and the reaction
is either worked up or volatiles are evaporated under vacuum. The
product is then obtained after purification by either flash
chromatography on silica gel, preparative TLC or preparative
HPLC-MS.
Illustrative Synthesis of General Method F:
Compound 94:
9-pyridin-3-yl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1--
a]isoquinolin-4-one
##STR00062##
[0944] A vial was charged with intermediate C1 (56 mg, 0.13 mmol, 1
eq.), pyridine-3-boronic acid (65 mg, 0.53 mmol, 4.2 eq.),
Cs.sub.2CO.sub.3 (143 mg, 0.44 mmol, 3.5 eq.), (DPPF)PdCl.sub.2.DCM
(5 mg, 0.0063 mmol, 0.05 eq.), in 1,4-dioxane (2 mL) and H.sub.2O
(0.2 mL), and the mixture was degassed with N.sub.2. The vial was
sealed and heated at 80.degree. C. After 2 h, the vial was cooled
to room temperature and volatiles were evaporated under vacuum. The
residue was then purified by preparative HPLC-MS to afford compound
94.
[0945] (.sup.1H, CDCl.sub.3) .delta. ppm 8.89 (1H, d), 8.66 (1H,
d), 7.88-7.96 (1H, m), 7.77-7.84 (1H, m), 7.58-7.64 (1H, m),
7.49-7.54 (1H, m), 7.39-7.45 (1H, m), 6.44 (1H, s), 4.53-4.63 (1H,
m), 4.23-4.34 (4H, m), 3.94 (1H, dt), 3.81-3.89 (1H, m), 3.10 (2H,
t), 2.02-2.13 (1H, m), 1.89-2.01 (2H, m), 1.61-1.72 (1H, m).
[0946] MW (calcd): 375.4; MW (obsd): 376.3 (M+1)
General Method G:
##STR00063##
[0948] Intermediate C (1 eq.) is dissolved in DMF, the appropriate
alkyne (3 eq.) is added followed by TEA or iPr.sub.2NH (3.5 eq.),
and the mixture is degassed. Pd(PPh.sub.3).sub.3Cl.sub.2 (0.05 eq.)
is added with CuI (0.2 eq.) and the reaction mixture is heated at
80.degree. C. When the reaction is gone to completion, it is cooled
to room temperature and either worked up or volatiles are
evaporated to dryness. The product is then obtained after
purification by either flash chromatography on silica gel,
preparative TLC or preparative HPLC-MS.
Illustrative Synthesis of General Method G:
Compound 119:
9-cyclopropylethynyl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one
##STR00064##
[0950] Intermediate C1 (40 mg, 0.089 mmol, 1 eq.) was dissolved in
DMF (2 mL), ethynyl-cyclopropane (18 mg, 0.27 mmol, 3 eq.) was
added followed by TEA (0.044 mL, 0.31 mmol, 3 eq.). The mixture was
degassed and Pd(PPh.sub.3).sub.3Cl.sub.2 (3 mg, 0.0045 mmol, 0.05
eq.) was added with CuI (3.3 mg, 0.018 mmol, 0.2 eq.). The reaction
mixture was heated at 80.degree. C. for 2 days. The reaction was
cooled to room temperature and evaporated to dryness. The crude
product was then purified by preparative HPLC-MS to give compound
119.
[0951] (.sup.1H, CDCl.sub.3) .delta. ppm 7.57 (1H, d), 7.32 (1H,
dd), 7.27 (1H, s), 6.33 (1H, s), 4.48-4.59 (1H, m), 4.09-4.31 (4H,
m), 3.87-3.96 (1H, m), 3.78-3.86 (1H, m), 2.95 (2H, t), 1.84-2.11
(3H, m), 1.57-1.70 (1H, m), 1.39-1.53 (1H, m), 0.77-0.96 (4H,
m).
[0952] MW (calcd): 362.4; MW (obsd): 363.4 (M+1)
General Method H:
##STR00065##
[0954] A vial is charged with intermediate C2 (1 eq.), the
corresponding potassium trifluoroborate (1 eq.), Cs.sub.2CO.sub.3
(3 eq.), Pd(OAc).sub.2 (0.03 eq.) and XPhos (0.06 eq.) in a mixture
of THF/H.sub.2O (10/1, v/v), then the mixture is degassed with
N.sub.2. The vial is sealed and heated at 80.degree. C. for 16 h.
The vial is then cooled to room temperature, the reaction is
quenched with brine, extracted with EtOAc and dried over
MgSO.sub.4. After evaporation to dryness, clean product is obtained
by preparative HPLC-MS.
Illustrative Synthesis of General Method H
Compound 197:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyrrolidin-1-ylm-
ethyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
##STR00066##
[0956] A vial was charged with intermediate C2 (80 mg, 0.157 mmol,
1 eq.), potassium [(pyrrolidin-1-yl)methyl]trifluoroborate (30 mg,
0.157 mmol, 1 eq.), Cs.sub.2CO.sub.3 (153 mg, 0.471 mmol, 3 eq.),
Pd(OAc).sub.2 (1 mg, 0.0047 mmol, 0.03 eq.) and XPhos (5 mg, 0.0094
mmol, 0.06 eq.) in a mixture of THF/H.sub.2O (3 mL, 10/1, v/v),
then the mixture was degassed with N.sub.2. The vial was sealed and
heated at 80.degree. C. for 16 h. The vial was then cooled to room
temperature, the reaction was quenched with brine, extracted with
EtOAc and dried over MgSO.sub.4. After evaporation to dryness,
compound 197 was obtained by preparative HPLC-MS.
[0957] (.sup.1H, CDCl.sub.3) .delta. ppm 7.84 (1H, dd), 7.66 (1H,
d), 7.35 (1H, m), 7.31 (1H, s), 7.23 (1H, dd), 6.89 (1H, dd), 6.35
(1H, s), 4.68 (2H, d), 4.52-4.61 (2H, m), 4.33 (1H, dd), 4.18-4.25
(2H, m), 3.66 (2H, s), 3.01 (2H, t), 2.49-2.57 (4H, m), 1.81 (4H,
m).
[0958] MW (calcd): 446.1; MW (obsd): 447.1 (M+1)
Compounds of the Invention
Compound 1:
9-methoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]iso-
quinolin-4-one
[0959] This compound is prepared via general method A using
intermediate 7 and (tetrahydro-furan-2-yl)-methanol.
Compound 2:
2-(chroman-2-ylmethoxy)-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin--
4-one
[0960] This compound is prepared via general method A using
intermediate 7 and chroman-2-yl-methanol.
Compound 3:
2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-methoxy-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one
[0961] This compound is prepared via general method A using
intermediate 7 and
(2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanol.
Compound 4:
9-allyloxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]is-
oquinolin-4-one
[0962] This compound is prepared via general method A using
intermediate 5 and (tetrahydro-furan-2-yl)-methanol.
Compound 5:
2-(2,3-dihydro-benzofuran-2-ylmethoxy)-9-methoxy-6,7-dihydro-pyrimido[6,1-
-a]isoquinolin-4-one
[0963] This compound is prepared via general method A using
intermediate 7 and (2,3-dihydro-benzofuran-2-yl)-methanol.
Compound 6:
9-hydroxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]iso-
quinolin-4-one
[0964] This compound is prepared via general method B using
compound 4.
Compound 7:
9-benzyloxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]i-
soquinolin-4-one
[0965] Synthesis fully described above.
Compound 8:
9-(pyridin-3-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one
[0966] This compound is prepared via general method D using
compound 6 and 3-bromomethyl-pyridine.
Compound 9:
[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]iso-
quinolin-9-yloxy]-acetonitrile
[0967] This compound is prepared via general method D using
compound 6 and bromo-acetonitrile.
Compound 10:
9-butoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoq-
uinolin-4-one
[0968] This compound is prepared via general method D using
compound 6 and 1-bromo-butane.
Compound 11:
9-cyclopropylmethoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one
[0969] This compound is prepared via general method D using
compound 6 and bromomethyl-cyclopropane.
Compound 12:
9-phenethyloxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1--
a]isoquinolin-4-one
[0970] This compound is prepared via general method D using
compound 6 and (2-bromo-ethyl)-benzene.
Compound 13:
9-(pyridin-4-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one
[0971] This compound is prepared via general method D using
compound 6 and 4-chloromethyl-pyridine hydrochloride.
Compound 14:
9-(pyridin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one
[0972] This compound is prepared via general method D using
compound 6 and 2-chloromethyl-pyridine hydrochloride.
Compound 15:
9-(2-phenoxy-ethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one
[0973] This compound is prepared via general method D using
compound 6 and (2-bromo-ethoxy)-benzene.
Compound 16:
9-methoxy-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]iso-
quinolin-4-one
[0974] This compound is prepared via general method A using
intermediate 7 and (tetrahydro-pyran-2-yl)-methanol.
Compound 17:
4-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzonitrile
[0975] This compound is prepared via general method E using
compound 6 and 4-bromomethyl-benzonitrile.
Compound 18:
9-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[0976] Synthesis fully described above.
Compound 19:
3-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzonitrile
[0977] This compound is prepared via general method E using
compound 6 and 3-bromomethyl-benzonitrile.
Compound 20:
2-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzonitrile
[0978] This compound is prepared via general method E using
compound 6 and 2-bromomethyl-benzonitrile.
Compound 21:
9-(4-chloro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one
[0979] This compound is prepared via general method E using
compound 6 and 1-chloro-4-chloromethyl-benzene.
Compound 22:
9-(3-chloro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one
[0980] This compound is prepared via general method E using
compound 6 and 1-bromomethyl-3-chloro-benzene.
Compound 23:
9-(2-lhloro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one
[0981] This compound is prepared via general method E using
compound 6 and 1-bromomethyl-2-chloro-benzene.
Compound 24:
9-(4-fluoro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one
[0982] This compound is prepared via general method E using
compound 6 and 1-chloromethyl-4-fluoro-benzene.
Compound 25:
9-(2-nitro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one
[0983] This compound is prepared via general method E using
compound 6 and 1-chloromethyl-2-nitro-benzene.
Compound 26:
4-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzoic acid methyl ester
[0984] This compound is prepared via general method E using
compound 6 and 4-bromomethyl-benzoic acid methyl ester.
Compound 27:
3-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzoic acid methyl ester
[0985] This compound is prepared via general method E using
compound 6 and 3-bromomethyl-benzoic acid methyl ester.
Compound 28:
2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(pyridin-2-ylmethoxy)-6,7--
dihydro-pyrimido[6,1-a]isoquinolin-4-one
[0986] This compound is prepared via general method E using
intermediate B1 and 2-chloromethyl-pyridine.
Compound 29:
[2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimi-
do[6,1-a]isoquinolin-9-yloxy]-acetic acid tert-butyl ester
[0987] This compound is prepared via general method E using
intermediate B1 and bromo-acetic acid tert-butyl ester.
Compound 30:
2,9-bis-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-6,7-dihydro-pyrimido[6-
,1-a]isoquinolin-4-one
[0988] This compound is prepared via general method E using
intermediate B1 and
2-bromomethyl-2,3-dihydro-benzo[1,4]dioxine.
Compound 31:
[2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimi-
do[6,1-a]isoquinolin-9-yloxy]-acetic acid
##STR00067##
[0990] Compound 29 (33 mg, 0.06 mmol, 1 eq.) was dissolved in
dioxane (0.4 mL), conc. HCl (51 .mu.L, 10 eq.) was added and the
reaction was stirred until full completion. The white precipitate
was filtered and dried to obtain compound 31.
Compound 32:
9-(3-nitro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one
[0991] This compound is prepared via general method E using
compound 6 and 1-bromomethyl-3-nitro-benzene.
Compound 33:
9-(4-nitro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one
[0992] This compound is prepared via general method E using
compound 6 and 1-chloromethyl-4-nitro-benzene.
Compound 34:
9-(3-methyl-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one
[0993] This compound is prepared via general method E using
compound 6 and 1-bromomethyl-3-methyl-benzene.
Compound 35:
9-(4-methyl-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one
[0994] This compound is prepared via general method E using
compound 6 and 1-bromomethyl-4-methyl-benzene.
Compound 36:
9-(2-methoxy-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one
[0995] This compound is prepared via general method E using
compound 6 and 1-chloromethyl-4-methoxy-benzene.
Compound 37:
9-(naphthalen-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one
[0996] This compound is prepared via general method E using
compound 6 and 2-chloromethyl-naphthalene.
Compound 38:
9-(naphthalen-1-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one
[0997] This compound is prepared via general method E using
compound 6 and 1-chloromethyl-naphthalene.
Compound 39:
9-(2-methyl-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one
[0998] This compound is prepared via general method E using
compound 6 and 1-chloromethyl-2-methyl-benzene.
Compound 40:
9-[2-(2-methoxy-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dih-
ydro-pyrimido[6,1-a]isoquinolin-4-one
[0999] This compound is prepared via general method E using
compound 6 and 1-(2-bromo-ethoxy)-2-methoxy-benzene.
Compound 41:
9-[2-(3-methoxy-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dih-
ydro-pyrimido[6,1-a]isoquinolin-4-one
[1000] This compound is prepared via general method E using
compound 6 and 1-(2-bromo-ethoxy)-3-methoxy-benzene.
Compound 42:
9-[2-(4-methoxy-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dih-
ydro-pyrimido[6,1-a]isoquinolin-4-one
[1001] This compound is prepared via general method E using
compound 6 and 1-(2-bromo-ethoxy)-4-methoxy-benzene.
Compound 43:
9-[2-(2-chloro-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihy-
dro-pyrimido[6,1-a]isoquinolin-4-one
[1002] This compound is prepared via general method E using
compound 6 and 1-(2-bromo-ethoxy)-2-chloro-benzene.
Compound 44:
9-[2-(3-chloro-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihy-
dro-pyrimido[6,1-a]isoquinolin-4-one
[1003] This compound is prepared via general method E using
compound 6 and 1-(2-bromo-ethoxy)-3-chloro-benzene.
Compound 45:
9-[2-(4-chloro-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihy-
dro-pyrimido[6,1-a]isoquinolin-4-one
[1004] This compound is prepared via general method E using
compound 6 and 1-(2-bromo-ethoxy)-4-chloro-benzene.
Compound 46:
2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-morpholin-4-yl-2-oxo-et-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
##STR00068##
[1006] A vial was charged with compound 31 (50 mg, 0.11 mmol, 1
eq.), morpholine (12 .mu.L, 0.14 mmol, 1.2 eq.), EDC (33 mg, 0.17
mmol, 1.5 eq.) and DMAP (28 mg, 0.23 mmol, 2 eq.) in DMF (1 mL).
The vial was sealed and the reaction was stirred for 16 h. The
reaction was evaporated to dryness then the residue was dissolved
in DCM and washed with a saturated solution of NaHCO.sub.3. After
evaporation of the organic phase under vacuum, the crude product
was purified by flash chromatography on silica gel eluting with 5%
MeOH/DCM to give compound 46.
Compound 47:
2-[2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-acetamide
##STR00069##
[1008] Compound 31 (50 mg, 0.11 mmol, 1 eq.), isobutyl
chloroformate (16.5 .mu.L, 0.13 mmol, 1.1 eq.) and NMM (15 .mu.L,
0.14 mmol, 1.2 eq.) were dissolved in DCM (1 mL) at 0.degree. C.
After 5 min, 20% aq. NH.sub.3 (50 .mu.L, 0.57 mmol, 5 eq.) was
added and the reaction was stirred for 16 h. The reaction was
evaporated to dryness, the residue was dissolved in DCM and washed
with aq. HCl (1 N). The DCM layer was dried over MgSO.sub.4, and
evaporated to dryness to recover compound 47.
Compound 48:
2-[2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-N,N-dimethyl-acetamide
##STR00070##
[1010] A vial was charged with compound 31 (50 mg, 0.11 mmol, 1
eq.), dimethylamine hydrochloride (11 mg, 0.14 mmol, 1.2 eq.), EDC
(33 mg, 0.17 mmol, 1.5 eq.), DIEA (57 .mu.L, 0.34 mmol, 3 eq.) and
DMAP (28 mg, 0.23 mmol, 2 eq.) in DMF (1 mL). The vial was sealed
and the reaction was stirred for 16 h. The reaction was evaporated
to dryness then the residue was dissolved in DCM and washed with a
saturated solution of NaHCO.sub.3. After evaporation of the organic
phase under vacuum, the crude product was purified by flash
chromatography on silica gel eluting with 5% MeOH/DCM to give
compound 48.
Compound 49:
2-[2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-2-methyl-propionamide
##STR00071## ##STR00072##
[1011] Step 1: 2-[2-(2,
3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,
7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yloxy]-2-methyl-propionic
acid tert-butyl ester (intermediate 8)
[1012] Intermediate 8 is prepared via general method F using
intermediate B1 and 2-bromo-2-methyl-propionic acid tert-butyl
ester.
[1013] (.sup.1H, CDCl.sub.3) .delta. ppm 7.54 (1H, d), 6.67-6.89
(4H, m), 6.64 (1H, d), 6.16-6.26 (2H, m), 4.57 (2H, dd), 4.43-4.51
(2H, m), 4.27 (2H, dd), 4.00-4.15 (3H, m), 1.56 (6H, s), 1.37 (9H,
s)
Step 2: 2-[2-(2, 3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,
7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yloxy]-2-methyl-propionic
acid (intermediate 9)
[1014] Intermediate 8 (203 mg, 0.39 mmol, 1 eq.) was dissolved in
dioxane (6 mL), TFA (300 .mu.L, 3.9 mmol, 10 eq.) was added and the
reaction was heated at 85.degree. C. After full completion, the
reaction was evaporated to dryness, the residue was then purified
on SPX cartridge to give intermediate 9.
[1015] (.sup.1H, CDCl.sub.3) .delta. ppm 7.43-7.77 (2H, m), 6.84
(4H, d), 6.50 (2H, br. s.), 4.47-4.78 (1H, m), 4.03-4.38 (3H, m),
3.64-3.90 (4H, m), 2.86-3.14 (2H, m), 1.70 (6H, br. s.)
[1016] MW (calcd): 464.5; MW (obsd): 465.8 (M+1)
Step 3: 2-[2-(2, 3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,
7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yloxy]-2-methyl-propionamide
(compound 49)
[1017] Intermediate 9 (28 mg, 0.06 mmol, 1 eq.), isobutyl
chloroformate (8.7 .mu.L, 0.7 mmol, 1.1 eq.) and NMM (8 .mu.L, 0.7
mmol, 1.2 eq.) were dissolved in DCM (1 mL) at 0.degree. C. After 5
min, 20% aq. NH.sub.3 (26 .mu.L, 0.30 mmol, 5 eq.) was added and
the reaction was stirred for 16 h. The reaction was evaporated to
dryness, the residue was purified by flash chromatography on silica
gel eluting with 5% MeOH/DCM to recover compound 49.
Compound 50:
2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(1,1-dimethyl-2-morpholin--
4-yl-2-oxo-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
##STR00073##
[1019] A vial was charged with intermediate 9 (28 mg, 0.06 mmol, 1
eq.), morpholine (7 .mu.L, 0.08 mmol, 1.3 eq.), EDC (17 mg, 0.09
mmol, 1.5 eq.) and DMAP (15 mg, 0.12 mmol, 2 eq.) in DMF (1 mL).
The vial was sealed and the reaction was stirred for 16 h. The
reaction was evaporated to dryness then the crude product was
purified by flash chromatography on silica gel eluting with 5%
MeOH/DCM to give compound 50.
Compound 51:
9-(2-benzyloxy-ethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one
[1020] This compound is prepared via general method E using
compound 6 and (2-bromo-ethoxymethyl)-benzene.
Compound 52:
2,9-bis-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquin-
olin-4-one
[1021] This compound is prepared via general method E using
compound 6 and 2-bromomethyl-tetrahydro-furan.
Compound 53:
9-(6-phenyl-pyridin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dih-
ydro-pyrimido[6,1-a]isoquinolin-4-one
##STR00074##
[1022] Step 1:
9-(6-bromo-pyridin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,
7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (intermediate 10)
[1023] Intermediate 10 is prepared via general method E using
compound 6 and 2-bromo-6-bromomethyl-pyridine.
[1024] (.sup.1H, CDCl.sub.3) .delta. ppm 7.49-7.60 (2H, m), 7.39
(2H, s), 6.83-6.93 (1H, m), 6.76-6.83 (1H, m), 6.21 (1H, s), 5.15
(2H, s), 4.38-4.55 (1H, m), 4.04-4.29 (4H, m), 3.68-3.94 (2H, m),
2.82-2.99 (2H, m), 1.74-2.08 (3H, m), 1.46-1.67 (1H, m)
Step 2:
9-(6-phenyl-pyridin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)--
6, 7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (compound 53)
[1025] This compound is prepared via general method F using
intermediate 10 and phenylboronic acid.
Compound 54:
2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(tetrahydro-furan-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1026] This compound is prepared via general method E using
intermediate B1 and 2-bromomethyl-tetrahydro-furan.
Compound 55:
9-[6-(1-methyl-1H-pyrazol-4-yl)-pyridin-2-ylmethoxy]-2-(tetrahydro-furan--
2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
##STR00075##
[1028] This compound is prepared via general method F using
intermediate 10 and 1-methyl-1H-pyrazole-4-boronic acid pinacol
ester.
Compound 56:
9-(6-furan-3-yl-pyridin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one
##STR00076##
[1030] This compound is prepared via general method F using
intermediate 10 and furan-3-boronic acid.
Compound 57:
9-(6-pyrimidin-5-yl-pyridin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-
-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
##STR00077##
[1032] This compound is prepared via general method F using
intermediate 10 and 5-pyrimidinylboronic acid.
Compound 58:
9-(1-cyclopropyl-1H-tetrazol-5-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy-
)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1033] This compound is prepared via general method E using
compound 6 and 5-chloromethyl-1-cyclopropyl-1H-tetrazole.
Compound 59:
2-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxy]-acetamide
[1034] This compound is prepared via general method E using
compound 6 and 2-bromo-acetamide.
Compound 60:
N,N-diethyl-2-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-acetamide
[1035] This compound is prepared via general method E using
compound 6 and 2-chloro-N,N-diethyl-acetamide.
Compound 61:
N,N-dimethyl-2-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyr-
imido[6,1-a]isoquinolin-9-yloxy]-acetamide
[1036] This compound is prepared via general method E using
compound 6 and 2-chloro-N,N-dimethyl-acetamide.
Compound 62:
N-isopropyl-N-methyl-2-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydr-
o-4H-pyrimido[6,1-a]isoquinolin-9-yloxy]-acetamide
[1037] This compound is prepared via general method E using
compound 6 and 2-bromo-N-isopropyl-N-methyl-acetamide.
Compound 63:
2-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxy]-N-phenyl-acetamide
[1038] This compound is prepared via general method E using
compound 6 and 2-chloro-N-phenyl-acetamide.
Compound 64:
9-(1-propyl-1H-tetrazol-5-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1039] This compound is prepared via general method E using
compound 6 and 5-chloromethyl-1-propyl-1H-tetrazole.
Compound 65:
9-(oxazol-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one
[1040] This compound is prepared via general method E using
compound 6 and 2-chloromethyl-oxazole.
Compound 66:
2-[2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-N,N-diethyl-acetamide
[1041] This compound is prepared via general method E using
intermediate B1 and 2-chloro-N,N-diethyl-acetamide.
Compound 67:
2-[2-(2,3-dihydro-zenzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-N-isopropyl-N-methyl-acetamide
[1042] This compound is prepared via general method E using
intermediate B1 and 2-bromo-N-isopropyl-N-methyl-acetamide.
Compound 68:
2-[2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-N-phenyl-acetamide
[1043] This compound is prepared via general method E using
intermediate B1 and 2-chloro-N-phenyl-acetamide.
Compound 69:
2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(1-propyl-1H-tetrazol-5-yl-
methoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1044] This compound is prepared via general method E using
intermediate B1 and 5-chloromethyl-1-propyl-1H-tetrazole.
Compound 70:
9-(1-butyl-1H-tetrazol-5-ylmethoxy)-2-(2,3-dihydro-benzo[1,4]dioxin-2-ylm-
ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1045] This compound is prepared via general method E using
intermediate B1 and 5-chloromethyl-1-butyl-1H-tetrazole.
Compound 71:
2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-morpholin-4-yl-ethoxy)--
6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1046] This compound is prepared via general method E using
intermediate B1 and 4-(2-chloro-ethyl)-morpholine
hydrochloride.
Compound 72:
[2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimi-
do[6,1-a]isoquinolin-9-yloxy]-acetonitrile
[1047] This compound is prepared via general method E using
intermediate B1 and bromo-acetonitrile.
Compound 73:
2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(oxazol-2-ylmethoxy)-6,7-d-
ihydro-pyrimido[6,1-a]isoquinolin-4-one
[1048] This compound is prepared via general method E using
intermediate B1 and 2-chloromethyl-oxazole.
Compound 74:
2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-oxo-2-pyrrolidin-1-yl-e-
thoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1049] This compound is prepared via general method E using
intermediate B1 and 2-chloro-1-pyrrolidin-1-yl-ethanone.
Compound 75:
9-(1-cyclopropyl-1H-tetrazol-5-ylmethoxy)-2-(2,3-dihydro-benzo[1,4]dioxin-
-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1050] This compound is prepared via general method E using
intermediate B1 and 5-chloromethyl-1-cyclopropyl-1H-tetrazole.
Compound 76:
2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(1H-tetrazol-5-ylmethoxy)--
6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
##STR00078##
[1052] Compound 72 (100 mg, 0.24 mmol, 1 eq.) and Bu.sub.3SnN.sub.3
(131 .mu.L, 0.48 mmol, 2 eq.) were mixed in dioxane (5 mL) and the
reaction was heated to 95.degree. C. for 16 h. The mixture was
evaporated to dryness and the residue was purified by preparative
HPLC to obtain compound 76.
Compound 77:
9-allyloxy-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-6,7-dih-
ydro-pyrimido[6,1-a]isoquinolin-4-one
[1053] This compound is prepared via general method A using
intermediate 5 and
(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-yl)-methanol.
Compound 78:
N-benzyl-2-[2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydr-
o-4H-pyrimido[6,1-a]isoquinolin-9-yloxy]-acetamide
[1054] This compound is prepared via general method E using
intermediate B1 and N-benzyl-2-chloro-acetamide.
Compound 79:
2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-pyrrolidin-1-yl-ethoxy)-
-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1055] This compound is prepared via general method E using
intermediate B1 and 1-(2-chloro-ethyl)-pyrrolidine
hydrochloride.
Compound 80:
2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-piperidin-1-yl-ethoxy)--
6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1056] This compound is prepared via general method E using
intermediate B1 and 1-(2-chloro-ethyl)-piperidine
hydrochloride.
Compound 81:
2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(3-piperidin-1-yl-propoxy)-
-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1057] This compound is prepared via general method E using
intermediate B1 and 1-(3-chloro-propyl)-piperidine
hydrochloride.
Compound 82:
2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(3-dimethylamino-propoxy)--
6,7-dihydro-yrimido[6,1-a]isoquinolin-4-one
[1058] This compound is prepared via general method E using
intermediate B1 and (3-chloro-propyl)-dimethyl-amine
hydrochloride.
Compound 83:
2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-[2-(1-methyl-pyrrolidin-2--
yl)-ethoxy]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1059] This compound is prepared via general method E using
intermediate B1 and 2-(2-chloro-ethyl)-1-methyl-pyrrolidine
hydrochloride.
Compound 84:
2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-[3-(4-methyl-piperazin-1-y-
l)-propoxy]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1060] This compound is prepared via general method E using
intermediate B1 and 1-(3-chloro-propyl)-4-methyl-piperazine
hydrochloride.
Compound 85:
5-[2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxymethyl]-furan-2-carboxylic acid ethyl
ester
[1061] This compound is prepared via general method E using
intermediate B1 and 5-chloromethyl-furan-2-carboxylic acid ethyl
ester hydrochloride.
Compound 86:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(oxazol-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1062] This compound is prepared via general method E using
intermediate B4 and 2-chloromethyl-oxazole.
Compound 87:
9-(5-tert-butyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-(tetrahydro-furan-2-ylmet-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1063] This compound is prepared via general method E using
compound 6 and 5-tert-butyl-3-chloromethyl-[1,2,4]oxadiazole.
Compound 88:
9-(5-phenyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy-
)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1064] This compound is prepared via general method E using
compound 6 and 3-chloromethyl-5-phenyl-[1,2,4]oxadiazole.
Compound 89:
[2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro-
-4H-pyrimido[6,1-a]isoquinolin-9-yloxy]-acetonitrile
[1065] This compound is prepared via general method E using
intermediate B4 and bromo-acetonitrile.
Compound 90:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-morpholin-4-y-
l-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1066] This compound is prepared via general method E using
intermediate B4 and 4-(2-chloro-ethyl)-morpholine.
Compound 91:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(pyridin-2-ylmet-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1067] This compound is prepared via general method E using
intermediate B4 and 2-chloromethyl-pyridine hydrochloride.
Compound 92:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-[2-(1-methyl-pyr-
rolidin-2-yl)-ethoxy]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1068] This compound is prepared via general method E using
intermediate B4 and 2-(2-chloro-ethyl)-1-methyl-pyrrolidine
hydrochloride.
Compound 93:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1H-tetrazol-5-y-
lmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
##STR00079##
[1070] Compound 89 (90 mg, 0.22 mmol, 1 eq.) and Bu.sub.3SnN.sub.3
(118 .mu.L, 0.43 mmol, 2 eq.) were mixed in dioxane (3 mL) and the
reaction was heated to 95.degree. C. for 16 h. The mixture was
evaporated to dryness and the residue was purified by preparative
HPLC to obtain compound 93.
Compound 94:
9-Pyridin-3-yl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1--
a]isoquinolin-4-one
[1071] Synthesis fully described above.
Compound 95:
3-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzonitrile
[1072] This compound is prepared via general method F using
intermediate C1 and 3-cyanophenylboronic acid.
Compound 96:
9-phenyl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoq-
uinolin-4-one
[1073] This compound is prepared via general method F using
intermediate C1 and phenylboronic acid.
Compound 97:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyridin-4-yl-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1074] This compound is prepared via general method F using
intermediate C2 and pyridine-4-boronic acid.
Compound 98:
3-[2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-benzonitrile
[1075] This compound is prepared via general method F using
intermediate C2 and 3-cyanophenylboronic acid.
Compound 99:
9-(2-methoxy-phenyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one
[1076] This compound is prepared via general method F using
intermediate C1 and 2-methoxyphenylboronic acid.
Compound 100:
9-(3-methoxy-phenyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one
[1077] This compound is prepared via general method F using
intermediate C1 and 3-methoxyphenylboronic acid.
Compound 101:
9-(4-methoxy-phenyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one
[1078] This compound is prepared via general method F using
intermediate C1 and 4-methoxyphenylboronic acid.
Compound 102:
4-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzonitrile
[1079] This compound is prepared via general method F using
intermediate C1 and 4-cyanophenylboronic acid.
Compound 103:
3-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzoic acid
[1080] This compound is prepared via general method F using
intermediate C1 and 3-carboxyphenylboronic acid.
Compound 104:
4-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzoic acid
[1081] This compound is prepared via general method F using
intermediate C1 and 4-carboxyphenylboronic acid.
Compound 105:
9-(4-dimethylamino-phenyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one
[1082] This compound is prepared via general method F using
intermediate C1 and 4-(N,N-dimethylamino)phenylboronic acid.
Compound 106:
4-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzamide
[1083] This compound is prepared via general method F using
intermediate C1 and benzamide-4-boronic acid.
Compound 107:
2-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzonitrile
[1084] This compound is prepared via general method F using
intermediate C1 and 2-cyanophenylboronic acid.
Compound 108:
9-(1-methyl-1H-pyrazol-4-yl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-
-pyrimido[6,1-a]isoquinolin-4-one
[1085] This compound is prepared via general method F using
intermediate C1 and
1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyraz-
ole.
Compound 109:
N,N-dimethyl-3-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyr-
imido[6,1-a]isoquinolin-9-yl]-benzamide
[1086] This compound is prepared via general method F using
intermediate C1 and 3-(dimethylcarbamoyl)phenylboronic acid.
Compound 110:
9-(6-methoxy-pyridin-3-yl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one
[1087] This compound is prepared via general method F using
intermediate C1 and 2-methoxy-5-pyridineboronic acid.
Compound 111:
9-(2,6-dimethyl-phenyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one
[1088] This compound is prepared via general method F using
intermediate C1 and 2,6-dimethylphenylboronic acid.
Compound 112:
9-(3,5-dimethyl-isoxazol-4-yl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihyd-
ro-pyrimido[6,1-a]isoquinolin-4-one
[1089] This compound is prepared via general method F using
intermediate C1 and 3,5-dimethylisoxazole-4-boronic acid.
Compound 113:
9-naphthalen-2-yl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6-
,1-a]isoquinolin-4-one
[1090] This compound is prepared via general method F using
intermediate C1 and 2-naphthaleneboronic acid.
Compound 114:
9-naphthalen-1-yl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6-
,1-a]isoquinolin-4-one
[1091] This compound is prepared via general method F using
intermediate C1 and 1-naphthaleneboronic acid.
Compound 115:
9-pyrimidin-5-yl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,-
1-a]isoquinolin-4-one
[1092] This compound is prepared via general method F using
intermediate C1 and 5-pyrimidinylboronic acid.
Compound 116:
9-(5-chloro-thiophen-2-yl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one
[1093] This compound is prepared via general method F using
intermediate C1 and 5-chlorothiophene-2-boronic acid.
Compound 117:
2-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-pyrrole-1-carboxylic acid tert-butyl ester
[1094] This compound is prepared via general method F using
intermediate C1 and 1-tert-butoxycarbonyl-2-pyrrolylboronic
acid.
Compound 118:
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(6-methoxy-pyrid-
in-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1095] This compound is prepared via general method F using
intermediate C2 and 2-methoxy-5-pyridineboronic acid.
Compound 119:
9-cyclopropylethynyl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one
[1096] Synthesis fully described above.
Compound 120:
9-(3,3-dimethyl-but-1-ynyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro--
pyrimido[6,1-a]isoquinolin-4-one
[1097] This compound is prepared via general method G using
intermediate C1 and 3,3-dimethyl-but-1-yne.
Compound 121:
9-(4-methoxy-phenylethynyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro--
pyrimido[6,1-a]isoquinolin-4-one
[1098] This compound is prepared via general method G using
intermediate C1 and 1-ethynyl-4-methoxy-benzene.
Compound 122:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(pyridin-4-ylmet-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1099] This compound is prepared via general method E using
intermediate B4 and 4-chloromethyl-pyridine hydrochloride.
Compound 123:
9-quinoxalin-6-ylethynyl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyr-
imido[6,1-a]isoquinolin-4-one
[1100] This compound is prepared via general method G using
intermediate C1 and 6-ethynyl-quinoxaline.
Compound 124:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyridin-3-yl-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1101] This compound is prepared via general method F using
intermediate C2 and pyridine-3-boronic acid.
Compound 125:
2-[2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-benzonitrile
[1102] This compound is prepared via general method F using
intermediate C2 and 2-cyanophenylboronic acid.
Compound 126:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-methoxy-pheny-
l)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1103] This compound is prepared via general method F using
intermediate C2 and 2-methoxyphenylboronic acid.
Compound 127:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1H-indazol-5-yl-
)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1104] This compound is prepared via general method F using
intermediate C2 and 1H-indazole-5-boronic acid.
Compound 128:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyrimidin-5-yl-6-
,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1105] This compound is prepared via general method F using
intermediate C2 and 5-pyrimidinylboronic acid.
Compound 129:
3-[2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-benzamide
[1106] This compound is prepared via general method F using
intermediate C2 and 3-carbamoylphenylboronic acid.
Compound 130:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-dimethylamino-
-phenyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1107] This compound is prepared via general method F using
intermediate C2 and 2-(dimethylamine) phenylboronic acid.
Compound 131:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyridin-3-ylethy-
nyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1108] This compound is prepared via general method G using
intermediate C2 and 3-ethynyl-pyridine.
Compound 132:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-methoxy-prop--
1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1109] This compound is prepared via general method G using
intermediate C2 and 3-methoxy-propyne.
Compound 133:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(4-hydroxy-but-1-
-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1110] This compound is prepared via general method G using
intermediate C2 and but-3-yn-1-ol.
Compound 134:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1,5-dimethyl-1H-
-pyrazol-3-methoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1111] This compound is prepared via general method E using
intermediate B4 and 3-chloromethyl-1,5-dimethyl-1H-pyrazole.
Compound 135:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-methyl-[1,2,4-
]oxadiazol-5-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1112] This compound is prepared via general method E using
intermediate B4 and 5-chloromethyl-3-methyl-[1,2,4]oxadiazole.
Compound 136:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-3-met-
hyl-but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1113] This compound is prepared via general method G using
intermediate C2 and 2-methyl-but-3-yn-2-ol.
Compound 137:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyridin-4-ylethy-
nyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1114] This compound is prepared via general method G using
intermediate C2 and 4-ethynyl-pyridine.
Compound 138:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-prop--
1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1115] This compound is prepared via general method G using
intermediate C2 and prop-2-yn-1-ol.
Compound 139:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(6-methyl-pyridi-
n-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1116] This compound is prepared via general method F using
intermediate C2 and 6-methylpyridin-3-ylboronic acid.
Compound 140:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(5-methoxy-pyrid-
in-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1117] This compound is prepared via general method F using
intermediate C2 and 3-methoxy-5-pyridineboronic acid pinacol
ester.
Compound 141:
9-cyclopropylethynyl-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethox-
y)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1118] This compound is prepared via general method G using
intermediate C2 and ethynyl-cyclopropane.
Compound 142:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1-hydroxy-cyclo-
pentlethynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1119] This compound is prepared via general method G using
intermediate C2 and 1-ethynyl-cyclopentanol.
Compound 143:
5-[2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-pyrimido[6,1-a]isoquinolin-9-yl]-pent-4-ynenitrile
[1120] This compound is prepared via general method G using
intermediate C2 and pent-4-ynenitrile.
Compound 144:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3,3-dimethyl-bu-
t-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1121] This compound is prepared via general method G using
intermediate C2 and 3,3-dimethyl-but-1-yne.
Compound 145:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-methoxy-pyrid-
in-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1122] This compound is prepared via general method F using
intermediate C2 and 2-methoxy-3-pyridinyl boronic acid.
Compound 146:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one
[1123] This compound is prepared via general method F using
intermediate C2.
Compound 147:
5-[2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-pyridine-2-carboxylic acid
methylamide
[1124] This compound is prepared via general method F using
intermediate C2 and 2-(N-methylaminocarbonyl) pyridine-5-boronic
acid pinacol ester.
Compound 148:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-furan-3-yl-6,7-d-
ihydro-pyrimido[6,1-a]isoquinolin-4-one
[1125] This compound is prepared via general method F using
intermediate C2 and furan-3-boronic acid.
Compound 149:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1-methyl-1H-pyr-
azol-4-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1126] This compound is prepared via general method F using
intermediate C2 and 1-methylpyrazole-4-boronic acid pinacol
ester.
Compound 150:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-morpholin-4-ylme-
thyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1127] This compound is prepared via general method F using
intermediate C2 and potassium (morpholin-4-yl)
methyltrifluoroborate.
Compound 151:
[2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro-
-4H-pyrimido [6,1-a]isoquinolin-9-ylamino]-acetonitrile
##STR00080##
[1129] A vial was charged with intermediate C2 (56 mg, 0.109 mmol,
1 eq.), cyanomethyl-ammonium chloride (68 mg, 0.73 mmol, 7 eq.),
Cs.sub.2CO.sub.3 (75 mg, 0.229 mmol, 2.1 eq.), Pd(OAc).sub.2 (6 mg,
0.028 mmol, 0.26 eq.) and XPhos (13 mg, 0.029 mmol, 0.27 eq.) in
dry toluene (3 mL), the vial was sealed and degazed. The reaction
was heated at 100.degree. C. for 16 h, then the mixture was
filtered through Celite and evaporated to dryness. The residue was
then purified by preparative HPLC to give compound 151.
Compound 152:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro--
4H-pyrimido [6,1-a]isoquinoline-9-carbonitrile
##STR00081##
[1131] A vial was charged with intermediate C2 (56 mg, 0.109 mmol,
1 eq.), cyanomethyl-ammonium chloride (68 mg, 0.73 mmol, 7 eq.),
Cs.sub.2CO.sub.3 (75 mg, 0.229 mmol, 2.1 eq.), Pd(OAc).sub.2 (6 mg,
0.028 mmol, 0.26 eq.) and XPhos (13 mg, 0.029 mmol, 0.27 eq.) in
dry toluene (3 mL), the vial was sealed and degazed. The reaction
was heated at 100.degree. C. for 16 h, then the mixture was
filtered through Celite and evaporated to dryness. The residue was
then purified by preparative HPLC to give compound 152.
Compound 153:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-[(oxazol-2-ylmet-
hyl)-amino]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
##STR00082##
[1133] A vial was charged with intermediate C2 (50 mg, 0.099 mmol,
1 eq.), oxazol-2-ylmethyl-ammonium chloride (45 mg, 0.33 mmol, 3.3
eq.), Cs.sub.2CO.sub.3 (68 mg, 0.208 mmol, 2.1 eq.), Pd(OAc).sub.2
(5.5 mg, 0.025 mmol, 0.26 eq.) and XPhos (13 mg, 0.027 mmol, 0.27
eq.) in dry toluene (3 mL), the vial was sealed and degazed. The
reaction was heated at 100.degree. C. for 16 h, then the mixture
was filtered through Celite and evaporated to dryness. The residue
was then purified by preparative HPLC to give compound 153.
Compound 154:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(5-methyl-[1,2,4-
]oxadiazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1134] This compound is prepared via general method E using
intermediate B4 and 3-chloromethyl-5-methyl-[1,2,4]oxadiazole.
Compound 155:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(5-ethyl-[1,2,4]-
oxadiazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1135] This compound is prepared via general method E using
intermediate B4 and 3-chloromethyl-5-ethyl-[1,2,4]oxadiazole.
Compound 156:
9-(5-cyclopropyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-(2,3-dihydro-[1,4]dioxin-
o[2,3-b]pyridin-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1136] This compound is prepared via general method E using
intermediate B4 and
3-chloromethyl-5-cyclopropyl-[1,2,4]oxadiazole.
Compound 157:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(5-isopropyl-[1,-
2,4]oxadiazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1137] This compound is prepared via general method E using
intermediate B4 and
3-chloromethyl-5-isopropyl-[1,2,4]oxadiazole.
Compound 158:
9-(5-tert-Butyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-(2,3-dihydro-[1,4]dioxino-
[2,3-b]pyridin-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1138] This compound is prepared via general method E using
intermediate B4 and
5-tert-butyl-3-chloromethyl-[1,2,4]oxadiazole.
Compound 159:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-methyl-isoxaz-
ol-5-yl methoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1139] This compound is prepared via general method E using
intermediate B4 and 5-chloromethyl-3-methyl-isoxazole.
Compound 160:
9-(3-chloro-2-methoxy-pyridin-4-yl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyr-
idin-2-yl methoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1140] This compound is prepared via general method F using
intermediate C2 and 3-chloro-2-methoxypyridine-4-boronic acid.
Compound 161:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3,6-dihydro-2H--
pyran-4-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1141] This compound is prepared via general method F using
intermediate C2 and 3,6-dihydro-2H-pyran-4-boronic acid.
Compound 162:
5-[2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-pyrimido [6,1-a]isoquinolin-9-yl]-pyridine-2-carbonitrile
[1142] This compound is prepared via general method F using
intermediate C2 and 2-cyanopyridine-5-boronic acid.
Compound 163:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-ethoxy-pyridi-
n-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1143] This compound is prepared via general method F using
intermediate C2 and 2-ethoxypyridine-3-boronic acid.
Compound 164:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(6-ethoxy-pyridi-
n-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1144] This compound is prepared via general method F using
intermediate C2 and 6-ethoxypyridine-3-boronic acid.
Compound 165:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(6-morpholin-4-y-
l-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1145] This compound is prepared via general method F using
intermediate C2 and 2-morpholino-5-pyridineboronic acid.
Compound 166:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-methoxy-pyrim-
idin-5-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1146] This compound is prepared via general method F using
intermediate C2 and 2-methoxypyrimidine-5-boronic acid.
Compound 167:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2,3-dimethoxy-p-
henyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1147] This compound is prepared via general method F using
intermediate C2 and 2,3-dimethoxyphenylboronic acid.
Compound 168:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2,5-dimethoxy-p-
henyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1148] This compound is prepared via general method F using
intermediate C2 and 2,5-dimethoxyphenylboronic acid.
Compound 169:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-3-phe-
nyl-prop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1149] This compound is prepared via general method G using
intermediate C2 and 1-phenyl-prop-2-yn-1-ol.
Compound 170:
3-{3-[2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-di-
hydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-prop-2-ynyloxy}-propionitrile
[1150] This compound is prepared via general method G using
intermediate C2 and 3-prop-2-ynyloxy-propionitrile.
Compound 171:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-methylamino-p-
rop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1151] This compound is prepared via general method G using
intermediate C2 and methyl-prop-2-ynyl-amine.
Compound 172:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-dimethylamino-
-prop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1152] This compound is prepared via general method G using
intermediate C2 and dimethyl-prop-2-ynyl-amine.
Compound 173:
9-[3-(benzyl-methyl-amino)-prop-1-ynyl]-2-(2,3-dihydro-[1,4]dioxino[2,3-b-
]pyridin-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1153] This compound is prepared via general method G using
intermediate C2 and benzyl-methyl-prop-2-ynyl-amine.
Compound 174:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-[3-(1,1-dioxo-th-
iomorpholin-4-yl)-prop-1-ynyl]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-on-
e
[1154] This compound is prepared via general method G using
intermediate C2 and 4-prop-2-ynyl-thiomorpholine 1,1-dioxide.
Compound 175:
{3-[2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihy-
dro-1H-pyrimido[6,1-a]isoquinolin-9-yl]-prop-2-ynyl}-urea
[1155] This compound is prepared via general method G using
intermediate C2 and prop-2-ynyl-urea.
Compound 176:
1-{3-[2-(2,3-dihydro-[1,4]dioxino[23-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dih-
ydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-prop-2-ynyl}-imidazolidine-2,4-di-
one
[1156] This compound is prepared via general method G using
intermediate C2 and 1-prop-2-ynyl-imidazolidine-2,4-dione.
Compound 177:
9-(3-diethylamino-prop-1-ynyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin--
2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1157] This compound is prepared via general method G using
intermediate C2 and diethyl-prop-2-ynyl-amine.
Compound 178:
9-(3-amino-3-methyl-but-1-ynyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-
-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1158] This compound is prepared via general method G using
intermediate C2 and 1,1-dimethyl-prop-2-ynylamine.
Compound 179:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(tetrahydro-pyra-
n-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1159] This compound is prepared via general method D using
intermediate B4 and 2-(chloromethyl)tetrahydro-2H-pyran.
Compound 180:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1H-pyrazol-4-yl-
)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1160] This compound is prepared via general method F using
intermediate C2 and pyrazole-4-boronic acid.
Compound 181:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-but-1-
-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1161] This compound is prepared via general method G using
intermediate C2 and but-3-yn-2-ol.
Compound 182:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-pent--
1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1162] This compound is prepared via general method G using
intermediate C2 and pent-1-yn-3-ol.
Compound 183:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-hex-1-
-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1163] This compound is prepared via general method G using
intermediate C2 and hex-1-yn-3-ol.
Compound 184:
9-(1-amino-cyclohexylethynyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-
-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1164] This compound is prepared via general method G using
intermediate C2 and 1-ethynyl-cyclohexylamine.
Compound 185:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-5-met-
hyl-hex-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1165] This compound is prepared via general method G using
intermediate C2 and 5-methyl-hex-1-yn-3-ol.
Compound 186:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-ethyl-3-hydro-
xy-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1166] This compound is prepared via general method G using
intermediate C2 and 3-ethyl-pent-1-yn-3-ol.
Compound 187:
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-3-phe-
nyl-but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1167] This compound is prepared via general method G using
intermediate C2 and 2-phenyl-but-3-yn-2-ol.
Compound 188:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-4-met-
hyl-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1168] This compound is prepared via general method G using
intermediate C2 and 4-methyl-pent-1-yn-3-ol.
Compound 189:
2-[(R)-1-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-yl)methoxy]-9-(oxazol--
2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1169] This compound is prepared via general method E using
intermediate B2 and 2-chloromethyl-oxazole.
Compound 190:
2-[(S)-1-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(oxazol-2-
-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1170] This compound is prepared via general method E using
intermediate B3 and 2-chloromethyl-oxazole.
Compound 191:
9-(3-butylamino-prop-1-ynyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2--
ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1171] This compound is prepared via general method G using
intermediate C2 and butyl-prop-2-ynyl-amine.
Compound 192:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-morpholin-4-y-
l-ethoxy methyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1172] This compound is prepared via general method F using
intermediate C2 and potassium
[2-(morpholin-4-yl)ethoxy]methyltrifluoroborate.
Compound 193:
9-(3-benzylamino-prop-1-ynyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-
-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1173] This compound is prepared via general method G using
intermediate C2 and benzyl-prop-2-ynyl-amine.
Compound 194:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-phenylamino-p-
rop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1174] This compound is prepared via general method G using
intermediate C2 and phenyl-prop-2-ynyl-amine.
Compound 195:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro--
4H-pyrimido [6,1-a]isoquinoline-9-carboxylic acid
(tetrahydro-pyran-4-yl)-amide
##STR00083##
[1176] A vial was charged with intermediate C2 (100 mg, 0.196 mmol,
1 eq.), 4-aminotetrahydropyran (40 .mu.L, 0.391 mmol, 2 eq.),
K.sub.2CO.sub.3 (81 mg, 0.587 mmol, 3 eq.),
trans-di-mu-acetatobis[2-(di-otolylphosphino)benzyl] dipalladium
(II) (0.46 mg, 0.489 .mu.mol, 0.0025 eq.), hexacarbonyl molybdene
(53 mg, 0.196 mmol, 1 eq.), XPhos (0.67 mg, 0.00147 mmol, 0.0075
eq.), DMAP (48 mg, 0.391 mmol, 2 eq.) in dry dioxane (2 mL) and the
vial was sealed. The reaction was then irradiated in a microwave at
160.degree. C. for 20 min. The reaction mixture was directly
purified on a preparative TLC to obtain product 195.
Compound 196:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro--
4H-pyrimido [6,1-a]isoquinoline-9-carboxylic acid
(oxetan-3-ylmethyl)-amide
##STR00084##
[1178] A vial was charged with intermediate C2 (100 mg, 0.196 mmol,
1 eq.), oxetan-3-ylmethanamine (40 mg, 0.46 mmol, 2.35 eq.),
K.sub.2CO.sub.3 (81 mg, 0.587 mmol, 3 eq.),
trans-di-mu-acetatobis[2-(di-otolylphosphino)benzyl] dipalladium
(II) (0.46 mg, 0.489 .mu.mol, 0.0025 eq.), hexacarbonyl molybdenum
(53 mg, 0.196 mmol, 1 eq.), XPhos (0.67 mg, 0.00147 mmol, 0.0075
eq.), DMAP (48 mg, 0.391 mmol, 2 eq.) in dry dioxane (2 mL) and the
vial was sealed. The reaction was then irradiated in a microwave at
160.degree. C. for 20 min. The reaction mixture was directly
purified on a preparative TLC to obtain compound 196.
Compound 197:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyrrolidin-1-ylm-
ethyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1179] Synthesis fully described above.
Compound 198:
9-(tert-butylamino-methyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-yl-
methoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1180] This compound is prepared via general method H using
intermediate C2 and potassium (t-butylaminomethyl)
trifluoroborate.
Compound 199:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-piperidin-1-ylme-
thyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
[1181] This compound is prepared via general method H using
intermediate C2 and potassium
trifluoro[(piperidin-1-yl)methyl]borate.
Compound 200:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-methyl-oxetan-
-3-ylmethoxymethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
##STR00085##
[1182] Step 1: potassium
(3-methyl-3-methyloxy-oxetane-methyltrifluoroborate (intermediate
11)
[1183] 3-Methyl-3-oxetanemethanol (305 mg, 2.99 mmol, 2 eq.) was
added to a solution of NaH (120 mg, 2.99 mmol, 2 eq., 60% in
mineral oil) in THF (5 mL) at 0.degree. C. The reaction was warmed
to room temperature for 30 min then cooled again at 0.degree. C.
Bromo methyltrifluoroborate (300 mg, 1.49 mmol, 1 eq.) was added to
the reaction in one portion and the mixture was stirred at room
temperature for 1 day (monitoring by .sup.19F-NMR). The reaction
was quenched with a solution of KHF.sub.2 (3 mL, 1.5 M, 3 eq.) and
the mixture was evaporated to dryness. The residue was suspended in
acetone, the inorganics were filtered off and the filtrate was
evaporated to dryness. The residue was suspended in a minimum
amount of acetone (1.5 mL), and Et.sub.2O (6 mL) was added.
Intermediate 11 was obtained by filtration.
[1184] (.sup.1H, DMSO-d.sub.6) .delta. ppm 4.34 (2H, d), 4.14 (2H,
d), 3.26 (2H, s), 2.59-2.52 (2H, m), 1.19 (3H, s)
Step 2: 2-(2, 3-dihydro-[1,4]dioxino[2,
3-b]pyridin-2-ylmethoxy)-9-(3-methyl-oxetan-3-ylmethoxymethyl)-6,
7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (compound 200)
[1185] This compound is prepared via general method F using
intermediates C2 and 11.
Compound 201:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-ethylamino-ox-
etan-3-ylethynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
##STR00086## ##STR00087##
[1186] Step 1: 2-methyl-propane-2-sulfinicacid{3-[2-(2,
3-dihydro-[1,4]dioxino[2, 3-b]pyridin-2-ylmethoxy)-4-oxo-6,
7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-ylethynyl]-oxetan-3-yl}-amide
(intermediate 12)
[1187] Intermediate 12 is prepared via general method G using
intermediate C2 and 2-methyl-propane-2-sulfinic acid
(3-ethynyl-oxetan-3-yl)-amide.
[1188] (.sup.1H, CDCl.sub.3) .delta. ppm 7.84-7.82 (1H, m),
7.70-7.85 (1H, d), 7.50-7.45 (1H, d), 7.44 (1H, s), 7.27-7.23 (2H,
m), 6.92-6.87 (1H, m), 5.50-5.00 (2H, m), 4.85-4.80 (2H, m),
4.70-4.67 (2H, d), 4.60-4.52 (1H, m), 4.38-4.30 (1H, m), 4.25-4.20
(2H, t), 4.18-4.10 (1H, q), 3.08-3.00 (2H, t), 4.34 (2H, d), 4.14
(2H, d), 3.26 (2H, s), 2.59-2.52 (2H, m), 1.19 (3H, s)
[1189] MW (calcd): 562.6; MW (obsd): 563.3 (M+1)
Step 2: 2-methyl-propane-2-sulfinic acid {3-[2-(2,
3-dihydro-[1,4]dioxino[2, 3-b]pyridin-2-ylmethoxy)-4-oxo-6,
7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-ylethynyl]-oxetan-3-yl}-ethyl-a-
mide (intermediate 13)
[1190] Intermediate 12 (107 mg, 0.190 mmol, 1 eq.) was dissolved in
a mixture of THF/DMF (3 mL/5 mL) at 0.degree. C. and NaH (60% in
mineral oil, 18 mg, 0.456 mmol, 2.4 eq.) was added. After stirring
at room temperature for 2 h, iodoethane (76 .mu.L, 0.951 mmol, 5
eq.) was added and the reaction was stirred for 1 h at room
temperature. The reaction was then quenched with brine and
extracted with EtOAc, and the organic layer was dried over
Na.sub.2SO.sub.4. Crude intermediate 13 was used in the next step
without further purification.
[1191] MW 590.7 (calcd); MW (obsd): 591.3 (M+1)
Step 3: 2-(2, 3-dihydro-[1,4]dioxino[2,
3-b]pyridin-2-ylmethoxy)-9-(3-ethylamino-oxetan-3-ylethynyl)-6,
7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (compound 201)
[1192] HCl (1M in Et.sub.2O, 0.25 mL, 0.25 mmol 2.5 eq.) was added
dropwise at 0.degree. C. to a solution of intermediate 13 (60 mg,
0.102 mmol, 1 eq.) in a mixture of THF/iPr.sub.2O (4 mL, 3/1).
After 10 min, the precipitate was filtered off and washed with
iPr.sub.2O and Et.sub.2O. The solids were purified by preparative
HPLC to give compound 201.
Compound 202:
2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(oxetan-3-yloxym-
ethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one
##STR00088##
[1193] Step 1: potassium 3-oxy-oxetanemethyltrifluoroborate
(intermediate 14)
[1194] Oxetan-3-ol (152 mg, 1.49 mmol, 2 eq.) was added to a
solution of NaH (60 mg, 1.49 mmol, 2 eq., 60% in mineral oil) in
THF (4 mL) at 0.degree. C. The reaction was warmed to room
temperature for 30 min then cooled again at 0.degree. C. Bromo
methyltrifluoroborate (150 mg, 0.75 mmol, 1 eq.) was added to the
reaction in one portion and the mixture was stirred at room
temperature for 1 day (monitoring by .sup.19F-NMR). The reaction
was quenched with a solution of KHF.sub.2 (1.5 mL, 1.5 M, 3 eq.)
and the mixture was evaporated to dryness. The residue was
suspended in acetone, the inorganics were filtered off and the
filtrate was evaporated to dryness. The residue was suspended in a
minimum amount of acetone (1.5 mL), and Et.sub.2O (6 mL) was added.
Intermediate 14 was obtained by filtration.
[1195] (.sup.1H, DMSO-d.sub.6) .delta. ppm 4.56 (2H, s), 4.32 (3H,
d), 2.40 (2H, d)
Step 2: 2-(2, 3-dihydro-[, 4]dioxino[2,
3-b]pyridin-2-ylmethoxy)-9-(oxetan-3-yloxymethyl)-6,
7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (compound 202)
[1196] This compound is prepared via general method F using
intermediates C2 and 14.
Compound 203:
9-cyclopropylethynyl-2-(4-isopropyl-oxetan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one
##STR00089##
[1197] Step 1: 9-allyloxy-2-methoxy-6, 7-dihydro-pyrimido[6,
1-a]isoquinolin-4-one (intermediate 15)
[1198] Intermediate 5 (5 g, 17.32 mmol, 1 eq.) was suspended in dry
MeOH (75 mL) and tBuOK (1.943 g, 17.32 mmol, 1 eq.) was added, the
reaction was stirred at room temperature for 2.5 days. The yellow
precipitate was filtered off to give intermediate 15.
[1199] (.sup.1H, CDCl.sub.3) .delta. ppm 7.70-7.61 (1H, d),
6.95-6.89 (1H, m), 6.80 (1H, s), 6.19 (1H, s), 6.12-5.95 (1H, m),
5.50-5.40 (1H, d), 5.38-5.25 (1H, m), 4.61 (2H, d), 4.24-4.18 (2H,
m), 3.99 (3H, s), 3.00-2.92 (2H, m)
[1200] MW (calcd): 284.3; MW (obsd): 285.2 (M+1)
Step 2: 9-hydroxy-2-methoxy-6,
7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (intermediate 16)
[1201] Intermediate 15 (4.86 g, 17.09 mmol, 1 eq.) was dissolved in
a mixture of THF (60 mL) and MeOH (40 mL), the reaction was degased
then 1,3-dimethylbarbituric acid (4 g, 25.6 mmol, 1.5 eq.) was
added followed by Pd(PPh.sub.3).sub.4 (0.988 g, 0.855 mmol, 0.05
eq.). After 1.5 h of stirring, the precipitate was filtered off and
washed with THF to afford intermediate 16.
[1202] MW (calcd): 244.3; MW (obsd): 245.2 (M+1)
Step 3: trifluoro-methanesulfonic acid 2-methoxy-4-oxo-6,
7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9-yl ester (intermediate
17)
[1203] Intermediate 16 (3.11 g, 12.73 mmol, 1 eq.) and
N-phenyl-bis(trifluoromethanesulfinimide (4.87 g, 43.62 mmol, 1.07
eq.) were suspended in dry DCM (200 mL), TEA (3.55 mL, 25.5 mmol, 2
eq.) was then added and the reaction was stirred for 16 h. The
reaction mixture was directly loaded onto a silica gel column
chromatography eluting with 2% MeOH/DCM to give product 17.
[1204] (.sup.1H, CDCl.sub.3) .delta. ppm 7.85-7.80 (1H, d),
7.44-7.40 (1H, d), 7.29 (1H, m), 6.29 (1H, s), 4.27-4.23 (2H, m),
4.01 (3H, s), 3.10-3.04 (2H, m)
[1205] MW (calcd): 376.3; MW (obsd): 377.0 (M+1)
Step 4: 9-cyclopropylethynyl-2-methoxy-6,
7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (intermediate 18)
[1206] Intermediate 18 was prepared via general method G using
intermediate and ethynyl-cyclopropane.
[1207] (.sup.1H, CDCl.sub.3) .delta. ppm 7.63-7.58 (1H, d),
7.58-7.34 (1H, d), 7.33 (1H, m), 6.25 (1H, s), 4.23-4.16 (2H, m),
3.99 (3H, s), 3.00-2.93 (2H, m), 1.53-1.46 (1H, m); 0.95-0.82 (4H,
m)
[1208] MW (calcd): 292.3; MW (obsd): 293.2 (M+1)
Step 5: 9-cyclopropylethynyl-2-hydroxy-6,
7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (intermediate 19)
[1209] Intermediate 18 (2.25 g, 7.70 mmol, 1 eq.) was dissolved in
THF (90 mL) and H.sub.2O (90 mL), and TFA (2.3 .mu.L, 0.031 mmol,
0.004 eq.) was added, the reaction was then heated to 50.degree. C.
for 2.5 days. The mixture was cooled to room temperature and the
precipitate was filtered off, washed with H.sub.2O to afford
intermediate 19.
[1210] (.sup.1H, CDCl.sub.3) .delta. ppm 8.64 (1H, br. s),
7.62-7.56 (1H, d), 7.38-7.32 (1H, d), 7.28-7.26 (1H, m), 6.12 (1H,
s), 4.10-4.03 (2H, m), 3.00-2.95 (2H, m), 1.51-1.43 (1H, m),
0.95-0.80 (4H, m)
[1211] MW (calcd): 278.3; MW (obsd): 279.2 (M+1)
Step 6: 2-chloro-9-cyclopropylethynyl-6,
7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (intermediate 20)
[1212] Intermediate 19 (0.5 g, 1.8 mmol, 1 eq.) was dissolved in
POCl.sub.3 (8.35 mL) and the reaction was heated to 50.degree. C.
for 3.5 h then for 2.5 days at room temperature. The reaction
mixture was then evaporated to dryness, the residue was dissolved
in a mixture of DCM (5 mL) and a saturated solution of NaHCO.sub.3
(5 mL), and the mixture was stirred for 1 h. The organic layer was
separated, dried over Na.sub.2SO.sub.4, filtered and concentrated
to dryness to a give intermediate 20.
[1213] (.sup.1H, CDCl.sub.3) .delta. ppm 7.66-7.62 (1H, d),
7.40-7.36 (1H, d), 7.32 (1H, m), 6.74 (1H, s), 4.24-4.18 (2H, m),
3.04-2.98 (2H, m), 1.52-1.44 (1H, m), 0.97-0.83 (4H, m)
[1214] MW (calcd): 296.8; MW (obsd): 297.1 (M+1)
Step 7: 9-cyclopropylethynyl-2-(4-isopropyl-oxetan-2-ylmethoxy)-6,
7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (compound 203)
[1215] This compound is prepared via general method A using
intermediate 20 and (4-isopropyl-oxetan-2-yl)-methanol.
Compound 204:
9-cyclopropylethynyl-2-((R)-4-isopropyl-oxetan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one
##STR00090##
[1217] This compound is prepared via general method A using
intermediate 20 and ((S)-4-isopropyl-oxetan-2-yl)-methanol.
TABLE-US-00002 TABLE II Mass spectral data of the Compounds of the
Invention Cpd MW MW # Structures Name (calc) (obsd) 1 ##STR00091##
9-Methoxy-2-(tetrahydro-furan- 2-ylmethoxy)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 328 329 2 ##STR00092##
2-(Chroman-2-ylmethoxy)-9- methoxy-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 390 391.3 3 ##STR00093##
2-(2,3-Dihydro- benzo[1,4]dioxin-2-ylmethoxy)-
9-methoxy-6,7-dihydro- pyrimido[6,1-a]isoquinolin-4- one 392 393.2
4 ##STR00094## 9-Allyloxy-2-(tetrahydro-furan-
2-ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin-4- one 354 --
5 ##STR00095## 2-(2,3-Dihydro-benzofuran-2-
ylmethoxy)-9-methoxy-6,7- dihydro-pyrimido[6,1-a] isoquinolin-4-one
376 377.3 6 ##STR00096## 9-Hydroxy-2-(tetrahydro-furan-
2-ylmethoxy)-6,7-dihydro- pyrimido[6,7-a]isoquinolin-4- one 314 --
7 ##STR00097## 9-Benzyloxy-2-(tetrahydro- furan-2-ylmethoxy)-6,7-
dihydro-pyrimido[6,1-a] isoquinolin-4-one 298 -- 8 ##STR00098##
9-(Pyridin-3-ylmethoxy)-2- (tetrahydro-furan-2-ylmethoxy)-
6,7-dihydro-pyrimido[6,1-a] isoquinolin-4-one 405 -- 9 ##STR00099##
[4-Oxo-2-(tetrahydro-furan-2- ylmethoxy)-6,7-dihydro-4H-
pyrimido[6,1-a]isoquinolin-9- yloxy]-acetonitrile 353 -- 10
##STR00100## 9-Butoxy-2-(tetrahydro-furan-2-
ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin-4- one 370 -- 11
##STR00101## 9-Cyclopropylmethoxy-2-
(tetrahydro-furan-2-ylmethoxy)- 6,7-dihydro-pyrimido[6,1-
a]isoquinolin-4-one 368 -- 12 ##STR00102##
9-Phenethyloxy-2-(tetrahydro- furan-2-ylmethoxy)-6,7-
dihydro-pyrimido[6,1- a]isoquinolin-4-one 418 -- 13 ##STR00103##
9-(Pyridin-4-ylmethoxy)-2- (tetrahydro-furan-2-ylmethoxy)-
6,7-dihydro-pyrimido[6,1-a] isoquinolin-4-one 405 -- 14
##STR00104## 9-(Pyridin-2-ylmethoxy)-2-
(tetrahydro-furan-2-ylmethoxy)- 6,7-dihydro-pyrimido[6,1-a]
isoquinolin-4-one 405 406.3 15 ##STR00105## 9-(2-Phenoxy-ethoxy)-2-
(tetrahydro-furan-2-ylmethoxy)- 6,7-dihydro-pyrimido[6,1-a]
isoquinolin-4-one 434 -- 16 ##STR00106##
9-Methoxy-2-(tetrahydro-pyran- 2-ylmethoxy)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 342 343.1 17 ##STR00107##
4-[4-Oxo-2-(tetrahydro-furan-2- ylmethoxy)-6,7-dihydro-4H-
pyrimido[6,1-a]isoquinolin-9- yloxymethyl]-benzonitrile 429 -- 18
##STR00108## 9-(2,3-Dihydro- benzo[1,4]dioxin-2-ylmethoxy)-
2-(tetrahydro-furan-2- ylmethoxy)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 463 -- 19 ##STR00109##
3-[4-Oxo-2-(tetrahydro-furan-2- ylmethoxy)-6,7-dihydro-4H-
pyrimido[6,1-a]isoquinolin-9- yloxymethyl]-benzonitrile 429 430.2
20 ##STR00110## 2-[4-Oxo-2-(tetrahydro-furan-2-
ylmethoxy)-6,7-dihydro-4H- pyrimido[6,1-a]isoquinolin-9-
yloxymethyl]-benzonitrile 429 430.3 21 ##STR00111##
9-(2-Chloro-benzyloxy)-2- (tetrahydro-furan-2-ylmethoxy)-
6,7-dihydro-pyrimido[6,1-a] isoquinolin-4-one 439 439.2 22
##STR00112## 9-(3-Chloro-benzyloxy)-2-
(tetrahydro-furan-2-ylmethoxy)- 6,7-dihydro-pyrimido[6,1-
a]isoquinolin-4-one 439 439.2 23 ##STR00113##
9-(2-Chloro-benzyloxy)-2- (tetrahydro-furan-2-ylmethoxy)-
6,7-dihydro-pyrimido[6,1-a] isoquinolin-4-one 439 439.2 24
##STR00114## 9-(4-Fluoro-benzyloxy)-2-
(tetrahydro-furan-2-ylmethoxy)- 6,7-dihydro-pyrimido[6,7-
a]isoquinolin-4-one 422 423.3 25 ##STR00115##
9-(2-Nitro-benzyloxy)-2- (tetrahydro-furan-2-ylmethoxy)-
6,7-dihydro-pyrimido[6,1-a] isoquinolin-4-one 449 450.2 26
##STR00116## 4-[4-Oxo-2-(tetrahydro-furan-2-
ylmethoxy)-6,7-dihydro-4H- pyrimido[6,1-a]isoquinolin-9-
yloxymethyl]-benzoic acid methyl ester 463 463.3 27 ##STR00117##
3-[4-Oxo-2-(tetrahydro-furan-2- ylmethoxy)-6,7-dihydro-4H-
pyrimido[6,1-a]isoquinolin-9- yloxymethyl]-benzoic acid methyl
ester 463 463.2 28 ##STR00118## 2-(2,3-Dihydro-
benzo[1,4]dioxin-2-ylmethoxy)- 9-(pyridin-2-ylmethoxy)-6,7-
dihydro-pyrimido[6,1-a] isoquinolin-4-one 470 470.0 29 ##STR00119##
[2-(2,3-Dihydro- benzo[1,4]dioxin-2-ylmethoxy)-
4-oxo-6,7-dihydro-4H- pyrimido[6,1-a]isoquinolin-9- yloxy]-acetic
acid tert-butyl ester 493 -- 30 ##STR00120## 2,9-Bis-(2,3-dihydro-
benzo[1,4]dioxin-2-ylmethoxy)- 6,7-dihydro-pyrimido[6,1-a]
isoquinolin-4-one 527 -- 31 ##STR00121## [2-(2,3-Dihydro-
benzo[1,4]dioxin-2-ylmethoxy)- 4-oxo-6,7-dihydro-4H-
pyrimido[6,1-a]isoquinolin-9- yloxy]-acetic acid 436 437.1 32
##STR00122## 9-(3-Nitro-benzyloxy)-2-
(tetrahydro-furan-2-ylmethoxy)- 6,7-dihydro-pyrimido[6,1-a]
isoquinolin-4-one 449 450.1 33 ##STR00123##
9-(4-Nitro-benzyloxy)-2- (tetrahydro-furan-2-ylmethoxy)-
6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 449 450.1 34
##STR00124## 9-(3-Methyl-benzyloxy)-2-
(tetrahydro-furan-2-ylmethoxy)- 6,7-dihydro-pyrimido[6,1-
a]isoquinolin-4-one 418 419.1 35 ##STR00125##
9-(4-Methyl-benzyloxy)-2- (tetrahydro-furan-2-ylmethoxy)-
6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 418 419.1 36
##STR00126## 9-(4-Methoxy-benzyloxy)-2-
(tetrahydro-furan-2-ylmethoxy)- 6,7-dihydro-pyrimido[6,1-
a]isoquinolin-4-one 434 435.2 37 ##STR00127##
9-(Naphthalen-2-ylmethoxy)-2- (tetrahydro-furan-2-ylmethoxy)-
6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 455 455.2 38
##STR00128## 9-(Naphthalen-1-ylmethoxy)-2-
(tetrahydro-furan-2-ylmethoxy)- 6,7-dihydro-pyrimido[6,1-
a]isoquinolin-4-one 455 455.1 39 ##STR00129##
9-(2-Methyl-benzyloxy)-2- (tetrahydro-furan-2-ylmethoxy)-
6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 434 435.2 40
##STR00130## 9-[2-(2-Methoxy-phenoxy)-
ethoxy]-2-(tetrahydro-furan-2- ylmethoxy)-6,7-dihydro-
pyrimido[6,1- a]isoquinolin-4-one 465 464.9 41 ##STR00131##
9-[2-(3-Methoxy-phenoxy)- ethoxy]-2-(tetrahydro-furan-2-
ylmethoxy)-6,7-dihydro- pyrimido[6,1- a]isoquinolin-4-one 465 -- 42
##STR00132## 9-[2-(4-Methoxy-phenoxy)-
ethoxy]-2-(tetrahydro-furan-2- ylmethoxy)-6,7-dihydro-
pyrimido[6,1- a]isoquinolin-4-one 465 465.3 43 ##STR00133##
9-[2-(2-Chloro-phenoxy)- ethoxy]-2-(tetrahydro-furan-2-
ylmethoxy)-6,7-dihydro- pyrimido[6,1- a]isoquinolin-4-one 469 469.2
44 ##STR00134## 9-[2-(3-Chloro-phenoxy)-
ethoxy]-2-(tetrahydro-furan-2- ylmethoxy)-6,7-dihydro-
pyrimido[6,1- a]isoquinolin-4-one 469 469.2 45 ##STR00135##
9-[2-(4-Chloro-phenoxy)- ethoxy]-2-(tetrahydro-furan-2-
ylmethoxy)-6,7-dihydro- pyrimido[6,1- a]isoquinolin-4-one 469 469.2
46 ##STR00136## 2-(2,3-Dihydro- benzo[1,4]dioxin-2-ylmethoxy)-
9-(2-morpholin-4-yl-2-oxo- ethoxy)-6,7-dihydro- pyrimido[6,1-
a]isoquinolin-4-one 506 506.0 47 ##STR00137## 2-[2-(2,3-Dihydro-
benzo[1,4]dioxin-2-ylmethoxy)- 4-oxo-6,7-dihydro-4H- pyrimido[6,1-
a]isoquinolin-9-yloxy]- acetamide 435 435.9 48 ##STR00138##
2-[2-(2,3-Dihydro- benzo[1,4]dioxin-2-ylmethoxy)-
4-oxo-6,7-dihydro-4H- pyrimido[6,1-a]isoquinolin-9-
yloxy]-N,N-dimethyl-acetamide 463 464.0 49 ##STR00139##
2-[2-(2,3-Dihydro- benzo[1,4]dioxin-2-ylmethoxy)-
4-oxo-6,7-dihydro-4H- pyrimido[6,1-a]isoquinolin-9-
yloxy]-2-methyl-propionamide 463 -- 50 ##STR00140## 2-(2,3-Dihydro-
benzo[1,4]dioxin-2-ylmethoxy)- 9-(1,1-dimethyl-2-morpholin-4-
yl-2-oxo-ethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin-4- one 534
-- 51 ##STR00141## 9-(2-Benzyloxy-ethoxy)-2-
(tetrahydro-furan-2-ylmethoxy)- 6,7-dihydro-pyrimido[6,1-
a]isoquinolin-4-one 449 449.1 52 ##STR00142##
2,9-Bis-(tetrahydro-furan-2- ylmethoxy)-6,7-dihydro- pyrimido[6,1-
a]isoquinolin-4-one 398 399.1 53 ##STR00143##
9-(6-Phenyl-pyridin-2- ylmethoxy)-2-(tetrahydro-furan-
2-ylmethoxy)-6,7-dihydro- pyrimido[6,1- a]isoquinolin-4-one 482
482.1 54 ##STR00144## 2-(2,3-Dihydro-
benzo[1,4]dioxin-2-ylmethoxy)- 9-(tetrahydro-furan-2-
ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 463 463.0
55 ##STR00145## 9-[6-(1-Methyl-1H-pyrazol-4-
yl)-pyridin-2-ylmethoxy]-2- (tetrahydro-furan-2-ylmethoxy)-
6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 486 486.1 56
##STR00146## 9-(6-Furan-3-yl-pyridin-2-
ylmethoxy)-2-(tetrahydro-furan- 2-ylmethoxy)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin- 4-one 472 472.1 57 ##STR00147##
9-(6-Pyrimidin-5-yl-pyridin-2- ylmethoxy)-2-(tetrahydro-furan-
2-ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 484
484.1 58 ##STR00148## 9-(1-Cyclopropyl-1H-tetrazol-
5-ylmethoxy)-2-(tetrahydro- furan-2-ylmethoxy)-6,7-
dihydro-pyrimido[6,1-a] isoquinolin-4-one 436 437.1 59 ##STR00149##
2-[4-Oxo-2-(tetrahydro-furan-2- ylmethoxy)-6,7-dihydro-4H-
pyrimido[6,1-a]isoquinolin- 9-yloxy]-acetamide 371 372.1 60
##STR00150## N,N-Diethyl-2-[4-oxo-2-
(tetrahydro-furan-2-ylmethoxy)- 6,7-dihydro-4H-pyrimido[6,1-
a]isoquinolin-9-yloxy]- acetamide 428 428.1 61 ##STR00151##
N,N-Dimethyl-2-[4-oxo-2- (tetrahydro-furan-2-ylmethoxy)-
6,7-dihydro-4H-pyrimido[6,1- a]isoquinolin-9-yloxy]- acetamide 399
400.0 62 ##STR00152## N-Isopropyl-N-methyl-2-[4-
oxo-2-(tetrahydro-furan-2- ylmethoxy)-6,7-dihydro-4H-
pyrimido[6,1-a]isoquinolin-9- yloxy]-acetamide 428 428.1 63
##STR00153## 2-[4-Oxo-2-(tetrahydro-furan-2-
ylmethoxy)-6,7-dihydro-4H- pyrimido[6,1-a]isoquinolin-9-
yloxy]-N-phenyl-acetamide 447 448.0 64 ##STR00154##
9-(1-Propyl-1H-tetrazol-5- ylmethoxy)-2-(tetrahydro-furan-
2-ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin-4- one 438
439.1 65 ##STR00155## 9-(Oxazol-2-ylmethoxy)-2-
(tetrahydro-furan-2-ylmethoxy)- 6,7-dihydro-pyrimido[6,1-a]
isoquinolin-4-one 395 396.0 66 ##STR00156## 2-[2-(2,3-Dihydro-
benzo[1,4]dioxin-2-ylmethoxy)- 4-oxo-6,7-dihydro-4H-
pyrimido[6,1-a]isoquinolin-9- yloxy]-N,N-diethyl-acetamide 492
492.0
67 ##STR00157## 2-[2-(2,3-Dihydro- benzo[1,4]dioxin-2-ylmethoxy)-
4-oxo-6,7-dihydro-4H- pyrimido[6,1-a]isoquinolin-9-
yloxy]-N-isopropyl-N-methyl- acetamide 492 492.0 68 ##STR00158##
2-[2-(2,3-Dihydro- benzo[1,4]dioxin-2-ylmethoxy)-
4-oxo-6,7-dihydro-4H- pyrimido[6,1-a]isoquinolin-9-
yloxy]-N-phenyl-acetamide 512 512.0 69 ##STR00159## 2-(2,3-Dihydro-
benzo[1,4]dioxin-2-ylmethoxy)- 9-(1-propyl-1H-tetrazol-5-
ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin-4- one 503 503.0
70 ##STR00160## 9-(1-Butyl-1H-tetrazol-5-
ylmethoxy)-2-(2,3-dihydro- benzo[1,4]dioxin-2-ylmethoxy)-
6,7-dihydro-pyrimido[6,1-a] isoquinolin-4-one 517 517.0 71
##STR00161## 2-(2,3-Dihydro- benzo[1,4]dioxin-2-ylmethoxy)-
9-(2-morpholin-4-yl-ethoxy)- 6,7-dihydro-pyrimido[6,1-a]
isoquinolin-4-one 492 492.0 72 ##STR00162## [2-(2,3-Dihydro-
benzo[1,4]dioxin-2-ylmethoxy)- 4-oxo-6,7-dihydro-4H-
pyrimido[6,1-a]isoquinolin-9- yloxy]-acetonitrile 417 418.0 73
##STR00163## 2-(2,3-Dihydro- benzo[1,4]dioxin-2-ylmethoxy)-
9-(oxazol-2-ylmethoxy)-6,7- dihydro-pyrimido[6,1-a]
isoquinolin-4-one 459 460.0 74 ##STR00164## 2-(2,3-Dihydro-
benzo[1,4]dioxin-2-ylmethoxy)- 9-(2-oxo-2-pyrrolidin-1-yl-
ethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin-4- one 490 490.0 75
##STR00165## 9-(1-Cyclopropyl-1H-tetrazol-
5-ylmethoxy)-2-(2,3-dihydro- benzo[1,4]dioxin-2-ylmethoxy)-
6,7-dihydro-pyrimido[6,1-a] isoquinolin-4-one 501 501.1 76
##STR00166## 2-(2,3-Dihydro- benzo[1,4]dioxin-2-ylmethoxy)-
9-(1H-tetrazol-5-ylmethoxy)- 6,7-dihydro-pyrimido[6,1-a]
isoquinolin-4-one 460 461.0 77 ##STR00167##
9-Allyloxy-2-(2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin-4- one 419 420.0
78 ##STR00168## N-Benzyl-2-[2-(2,3-dihydro-
benzo[1,4]dioxin-2-ylmethoxy)- 4-oxo-6,7-dihydro-4H-
pyrimido[6,1-a]isoquinolin-9- yloxy]-acetamide 526 526.0 79
##STR00169## 2-(2,3-Dihydro- benzo[1,4]dioxin-2-ylmethoxy)-
9-(2-pyrrolidin-1-yl-ethoxy)- 6,7-dihydro-pyrimido[6,1-
a]isoquinolin-4-one 476 476.1 80 ##STR00170## 2-(2,3-Dihydro-
benzo[1,4]dioxin-2-ylmethoxy)- 9-(2-piperidin-1-yl-ethoxy)-6,7-
dihydro-pyrimido[6,1-a] isoquinolin-4-one 490 490.1 81 ##STR00171##
2-(2,3-Dihydro- benzo[1,4]dioxin-2-ylmethoxy)-
9-(3-piperidin-1-yl-propoxy)- 6,7-dihydro-pyrimido[6,1-a]
isoquinolin-4-one 504 504.1 82 ##STR00172## 2-(2,3-Dihydro-
benzo[1,4]dioxin-2-ylmethoxy)- 9-(3-dimethylamino-propoxy)-
6,7-dihydro-pyrimido[6,1-a] isoquinolin-4-one 464 464.1 83
##STR00173## 2-(2,3-Dihydro- benzo[1,4]dioxin-2-ylmethoxy)-
9-[2-(1-methyl-pyrrolidin-2-yl)- ethoxy]-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 490 490.1 84 ##STR00174##
2-(2,3-Dihydro- benzo[1,4]dioxin-2-ylmethoxy)-
9-[3-(4-methyl-piperazin-1-yl)- propoxy]-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 519 519.1 85 ##STR00175##
5-[2-(2,3-Dihydro- benzo[1,4]dioxin-2-ylmethoxy)-
4-oxo-6,7-dihydro-4H- pyrimido[6,1-a]isoquinolin-9-
yloxymethyl]-furan-2- carboxylic acid ethyl ester 531 531.3 86
##STR00176## 2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(oxazol-2- ylmethoxy)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 460 461.3 87 ##STR00177##
9-(5-tert-Butyl- [1,2,4]oxadiazol-3-ylmethoxy)-
2-(tetrahydro-furan-2- ylmethoxy)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 453 453.4 88 ##STR00178##
9-(5-Phenyl-[1,2,4]oxadiazol-3- ylmethoxy)-2-(tetrahydro-furan-
2-ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin-4- one 473
473.4 89 ##STR00179## [2-(2,3-Dihydro-
[1,4]dioxino[2,3-b]pyridin-2- ylmethoxy)-4-oxo-6,7-dihydro-
4H-pyrimido[6,1-a]isoquinolin- 9-yloxy]-acetonitrile 418 419.3 90
##STR00180## 2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(2-morpholin-4- yl-ethoxy)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 493 493.2 91 ##STR00181##
2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(pyridin-2- ylmethoxy)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 470 471.3 92 ##STR00182##
2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-[2-(1-methyl- pyrrolidin-2-yl)-ethoxy]-6,7-
dihydro-pyrimido[6,1-a] isoquinolin-4-one 491 491.3 93 ##STR00183##
2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(1H-tetrazol-5- ylmethoxy)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 461 462.3 94 ##STR00184##
9-Pyridin-3-yl-2-(tetrahydro- furan-2-ylmethoxy)-6,7-
dihydro-pyrimido[6,1-a] isoquinolin-4-one 375 376.3 95 ##STR00185##
3-[4-Oxo-2-(tetrahydro-furan-2- ylmethoxy)-6,7-dihydro-4H-
pyrimido[6,1-a]isoquinolin-9- yl]-benzonitrile 399 400.3 96
##STR00186## 9-Phenyl-2-(tetrahydro-furan-2-
ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin-4- one 374 375.3
97 ##STR00187## 2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-pyridin-4-yl-6,7- dihydro-pyrimido[6,1-a]
isoquinolin-4-one 440 441.4 98 ##STR00188## 3-[2-(2,3-Dihydro-
[1,4]dioxino[2,3-b]pyridin-2- ylmethoxy)-4-oxo-6,7-dihydro-
4H-pyrimido[6,1-a]isoquinolin- 9-yl]-benzonitrile 464 465.4 99
##STR00189## 9-(2-Methoxy-phenyl)-2-
(tetrahydro-furan-2-ylmethoxy)- 6,7-dihydro-pyrimido[6,1-
a]isoquinolin-4-one 404 405.4 100 ##STR00190##
9-(3-Methoxy-phenyl)-2- (tetrahydro-furan-2-ylmethoxy)-
6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 404 405.4 101
##STR00191## 9-(4-Methoxy-phenyl)-2-
(tetrahydro-furan-2-ylmethoxy)- 6,7-dihydro-pyrimido[6,1-a]
isoquinolin-4-one 404 405.4 102 ##STR00192##
4-[4-Oxo-2-(tetrahydro-furan-2- ylmethoxy)-6,7-dihydro-4H-
pyrimido[6,1-a]isoquinolin-9- yl]-benzonitrile 399 400.4 103
##STR00193## 3-[4-Oxo-2-(tetrahydro-furan-2-
ylmethoxy)-6,7-dihydro-4H- pyrimido[6,1-a]isoquinolin-9-
yl]-benzoic acid 418 419.4 104 ##STR00194##
4-[4-Oxo-2-(tetrahydro-furan-2- ylmethoxy)-6,7-dihydro-4H-
pyrimido[6,1-a]isoquinolin-9- yl]-benzoic acid 418 419.4 105
##STR00195## 9-(4-Dimethylamino-phenyl)-2-
(tetrahydro-furan-2-ylmethoxy)- 6,7-dihydro-pyrimido[6,1-a]
isoquinolin-4-one 418 418.5 106 ##STR00196##
4-[4-Oxo-2-(tetrahydro-furan-2- ylmethoxy)-6,7-dihydro-4H-
pyrimido[6,1-a]isoquinolin-9- yl]-benzamide 417 418.5 107
##STR00197## 2-[4-Oxo-2-(tetrahydro-furan-2-
ylmethoxy)-6,7-dihydro-4H- pyrimido[6,1-a]isoquinolin-9-
yl]-benzonitrile 399 400.5 108 ##STR00198##
9-(1-Methyl-1H-pyrazol-4-yl)- 2-(tetrahydro-furan-2-
ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin-4- one 378 379.4
109 ##STR00199## N,N-Dimethyl-3-[4-oxo-2-
(tetrahydro-furan-2-ylmethoxy)- 6,7-dihydro-4H-pyrimido[6,1-a]
isoquinolin-9-yl]-benzamide 446 446.5 110 ##STR00200##
9-(6-Methoxy-pyridin-3-yl)-2- (tetrahydro-furan-2-ylmethoxy)-
6,7-dihydro-pyrimido[6,1-a] isoquinolin-4-one 405 406.5 111
##STR00201## 9-(2,6-Dimethyl-phenyl)-2-
(tetrahydro-furan-2-ylmethoxy)- 6,7-dihydro-pyrimido[6,1-a]
isoquinolin-4-one 402 403.4 112 ##STR00202##
9-(3,5-Dimethyl-isoxazol-4-yl)- 2-(tetrahydro-furan-2-
ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin- 4-one 393 394.5
113 ##STR00203## 9-Naphthalen-2-yl-2-
(tetrahydro-furan-2-ylmethoxy)- 6,7-dihydro-pyrimido[6,1-a]
isoquinolin-4-one 425 425.5 114 ##STR00204## 9-Naphthalen-1-yl-2-
(tetrahydro-furan-2-ylmethoxy)- 6,7-dihydro-pyrimido[6,1-a]
isoquinolin-4-one 425 425.5 115 ##STR00205##
9-Pyrimidin-5-yl-2-(tetrahydro- furan-2-ylmethoxy)-6,7-
dihydro-pyrimido[6,1-a] isoquinolin-4-one 376 377.4 116
##STR00206## 9-(5-Chloro-thiophen-2-yl)-2-
(tetrahydro-furan-2-ylmethoxy)- 6,7-dihydro-pyrimido[6,1-a]
isoquinolin-4-one 415 415.4 117 ##STR00207##
2-[4-Oxo-2-(tetrahydro-furan-2- ylmethoxy)-6,7-dihydro-4H-
pyrimido[6,1-a]isoquinolin-9- yl]-pyrrole-1-carboxylic acid
tert-butyl ester 464 464.5 118 ##STR00208## 2-(2,3-Dihydro-
[1,4]dioxino[2,3-b]pyridin-2- ylmethoxy)-9-(6-methoxy-
pyridin-3-yl)-6,7-dihydro- pyrimido[6,1-a]isoquinolin-4- one 470
471.5 119 ##STR00209## 9-Cyclopropylethynyl-2-
(tetrahydro-furan-2-ylmethoxy)- 6,7-dihydro-pyrimido[6,1-a]
isoquinolin-4-one 362 363.4 120 ##STR00210##
9-(3,3-Dimethyl-but-1-ynyl)-2- (tetrahydro-furan-2-ylmethoxy)-
6,7-dihydro-pyrimido[6,1-a] isoquinolin-4-one 378 379.5 121
##STR00211## 9-(4-Methoxy-phenylethynyl)- 2-(tetrahydro-furan-2-
ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin-4- one 428 429.5
122 ##STR00212## 2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(pyridin-4- ylmethoxy)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 470 471.4 123 ##STR00213##
9-Quinoxalin-6-ylethynyl- 2(tetrahydro-furan-2-
ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin-4- one 450 451.5
124 ##STR00214## 2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-pyridin-3-yl-6,7- dihydro-pyrimido[6,1-a]
isoquinolin-4-one 440 441.4 125 ##STR00215## 2-[2-(2,3-Dihydro-
[1,4]dioxino[2,3-b]pyridin-2- ylmethoxy)-4-oxo-6,7-dihydro-
4H-pyrimido[6,1-a]isoquinolin- 9-yl]-benzonitrile 464 465.4 126
##STR00216## 2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(2-methoxy- phenyl)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 470 470.4 127 ##STR00217##
2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(1H-indazol-5- yl)-6,7-dihydro-pyrimido[6,1-
a]isoquinolin-4-one 480 480.4 128 ##STR00218## 2-(2,3-Dihydro-
[1,4]dioxino[2,3-b]pyridin-2- ylmethoxy)-9-pyrimidin-5-yl-
6,7-dihydro-pyrimido[6,1-a] isoquinolin-4-one 441 442.4 129
##STR00219## 3-[2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-4-oxo-6,7-dihydro- 4H-pyrimido[6,1-a]isoquinolin-
9-yl]-benzonitrile 483 483.4 130 ##STR00220## 2-(2,3-Dihydro-
[1,4]dioxino[2,3-b]pyridin-2- ylmethoxy)-9-(2-
dimethylamino-phenyl)-6,7- dihydro-pyrimido[6,1-a]
isoquinolin-4-one 483 483.4 131 ##STR00221## 2-(2,3-Dihydro-
[1,4]dioxino[2,3-b]pyridin-2- ylmethoxy)-9-pyridin-3-
ylethynyl-6,7-dihydro- pyrimido[6,1-a]isoquinolin-4- one 464 465.4
132 ##STR00222## 2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(3-methoxy-prop- 1-ynyl)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 431 --
133 ##STR00223## 2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(4-hydroxy-but- 1-ynyl)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 431 432.4 134 ##STR00224##
2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(1,5-dimethyl- 1H-pyrazol-3-ylmethoxy)-6,7-
dihydro-pyrimido[6,1-a] isoquinolin-4-one 488 488.4 135
##STR00225## 2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(3-methyl- [1,2,4]oxadiazol-5-ylmethoxy)-
6,7-dihydro-pyrimido[6,1-a] isoquinolin-4-one 475 476.4 136
##STR00226## 2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(3-hydroxy-3- methyl-but-1-ynyl)-6,7-
dihydro-pyrimido[6,1-a] isoquinolin-4-one 445 446.4 137
##STR00227## 2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-pyridin-4- ylethynyl-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 464 465.4 138 ##STR00228##
2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(3-hydroxy-prop- 1-ynyl)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 417 418.4 139 ##STR00229##
2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(6-methyl- pyridin-3-yl)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 454 455.4 140 ##STR00230##
2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(5-methoxy- pyridin-3-yl)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 470 471.4 141 ##STR00231##
9-Cyclopropylethynyl-2-(2,3- dihydro-[1,4]dioxino[2,3-
b]pyridin-2-ylmethoxy)-6,7- dihydro-pyrimido[6,1-
a]isoquinolin-4-one 427 428.4 142 ##STR00232## 2-(2,3-Dihydro-
[1,4]dioxino[2,3-b]pyridin-2- ylmethoxy)-9-(1-hydroxy-
cyclopentylethynyl)-6,7- dihydro-pyrimido[6,1- a]isoquinolin-4-one
472 472.4 143 ##STR00233## 5-[2-(2,3-Dihydro-
[1,4]dioxino[2,3-b]pyridin-2- ylmethoxy)-4-oxo-6,7-dihydro-
4H-pyrimido[6,1-a]isoquinolin- 9-yl]-pent-4-ynenitrile 440 441.4
144 ##STR00234## 2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(3,3-dimethyl- but-1-ynyl)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 444 444.4 145 ##STR00235##
2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(2-methoxy- pyridin-3-yl)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 470 -- 146 ##STR00236##
2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin-4- one 363 --
147 ##STR00237## 5-[2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-4-oxo-6,7-dihydro- 4H-pyrimido[6,1-a]isoquinolin-
9-yl]-pyridine-2-carboxylic acid methylamide 498 498.4 148
##STR00238## 2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-furan-3-yl-6,7- dihydro-pyrimido[6,1-a]
isoquinolin-4-one 429 430.4 149 ##STR00239## 2-(2,3-Dihydro-
[1,4]dioxino[2,3-b]pyridin-2- ylmethoxy)-9-(1-methyl-1H-
pyrazol-4-yl)-6,7-dihydro- pyrimido[6,1-a]isoquinolin-4- one 443
444.4 150 ##STR00240## 2-(2,3-Dihydro-
[1,4]dioxino[2,3-b]pyridin-2- ylmethoxy)-9-morpholin-4-
ylmethyl-6,7-dihydro- pyrimido[6,1-a]isoquinolin-4- one 463 463.4
151 ##STR00241## [2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-4-oxo-6,7-dihydro- 4H-pyrimido[6,1-a]isoquinolin-
9-ylamino]-acetonitrile 417 418.4 152 ##STR00242## 2-(2,3-Dihydro-
[1,4]dioxino[2,3-b]pyridin-2- ylmethoxy)-4-oxo-6,7-dihydro-
4H-pyrimido[6,1-a] isoquinoline-9-carbonitrile 388 389.3 153
##STR00243## 2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-[(oxazol-2- ylmethyl)-amino]-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 459 460.4 154 ##STR00244##
2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(5-methyl- [1,2,4]oxadiazol-3-ylmethoxy)-
6,7-dihydro-pyrimido[6,1-a] isoquinolin-4-one 475 476.4 155
##STR00245## 2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(5-ethyl- [1,2,4]oxadiazol-3-ylmethoxy)-
6,7-dihydro-pyrimido[6,1-a] isoquinolin-4-one 489 490.4 156
##STR00246## 9-(5-Cyclopropyl- [1,2,4]oxadiazol-3-ylmethoxy)-
2-(2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin-4- one 502 502.4
157 ##STR00247## 2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(5-isopropyl- [1,2,4]oxadiazol-3-ylmethoxy)-
6,7-dihydro-pyrimido[6,1-a] isoquinolin-4-one 504 504.4 158
##STR00248## 9-(5-tert-Butyl- [1,2,4]oxadiazol-3-ylmethoxy)-
2-(2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin-4- one 518 518.4
159 ##STR00249## 2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(3-methyl- isoxazol-5-ylmethoxy)-6,7-
dihydro-pyrimido[6,1- a]isoquinolin-4-one 474 475.3 160
##STR00250## 9-(3-Chloro-2-methoxy- pyridin-4-yl)-2-(2,3-dihydro-
[1,4]dioxino[2,3-b]pyridin-2- ylmethoxy)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 505 505.4 161 ##STR00251##
2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(3,6-dihydro-2H- pyran-4-yl)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 445 446.4 162 ##STR00252##
5-[2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-4-oxo-6,7-dihydro- 4H-pyrimido[6,1-a]isoquinolin-
9-yl]-pyridine-2-carbonitrile 465 466.4 163 ##STR00253##
2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(2-ethoxy- pyridin-3-yl)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 485 485.4 164 ##STR00254##
2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(6-ethoxy- pyridin-3-yl)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 485 485.4 165 ##STR00255##
2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(6-morpholin-4- yl-pyridin-3-yl)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 526 526.5 166 ##STR00256##
2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(2-methoxy- pyrimidin-5-yl)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 471 472.4 167 ##STR00257##
2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(2,3-dimethoxy- phenyl)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 500 500.4 168 ##STR00258##
2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(2,5-dimethoxy- phenyl)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 500 500.4 169 ##STR00259##
2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(3-hydroxy-3- phenyl-prop-1-ynyl)-6,7-
dihydro-pyrimido[6,1- a]isoquinolin-4-one 494 494.4 170
##STR00260## 3-{3-[2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-4-oxo-6,7-dihydro- 4H-pyrimido[6,1-a]isoquinolin-
9-yl]-prop-2-ynyloxy}- propionitrile 470 471.4 171 ##STR00261##
2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(3-methylamino- prop-1-ynyl)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 430 431.4 172 ##STR00262##
2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2- ylmethoxy)-9-(3-
dimethylamino-prop-1-ynyl)- 6,7-dihydro-pyrimido[6,1-a]
isoquinolin-4-one 444 445.4 173 ##STR00263##
9-[3-(Benzyl-methyl-amino)- prop-1-ynyl]-2-(2,3-dihydro-
[1,4]dioxino[2,3-b]pyridin-2- ylmethoxy)-6,7-dihydro
pyrimido[6,1-a]isoquinolin-4- one 521 521.4 174 ##STR00264##
2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-[3-(1,1-dioxo- thiomorpholin-4-yl)-prop-1-
ynyl]-6,7-dihydro- pyrimido[6,1-a]isoquinolin-4- one 535 535.4 175
##STR00265## {3-[2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-4-oxo-6,7-dihydro- 4H-pyrimido[6,1-a]isoquinolin-
9-yl]-prop-2-ynyl}-urea 459 460.4 176 ##STR00266##
1-{3-[2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-4-oxo-6,7-dihydro- 4H-pyrimido[6,1-a]isoquinolin-
9-yl]-prop-2-ynyl}- imidazolidine-2,4-dione 499 500.4 177
##STR00267## 9-(3-Diethylamino-prop-1- ynyl)-2-(2,3-dihydro-
[1,4]dioxino[2,3-b]pyridin-2- ylmethoxy)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 473 473.4 178 ##STR00268##
9-(3-Amino-3-methyl-but-1- ynyl)-2-(2,3-dihydro-
[1,4]dioxino[2,3-b]pyridin-2- ylmethoxy)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 444 445.4 179 ##STR00269##
2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(tetrahydro- pyran-2-ylmethoxy)-6,7-
dihydro-pyrimido[6,1- a]isoquinolin-4-one 478 478.4 180
##STR00270## 2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(1H-pyrazol-4- yl)-6,7-dihydro-pyrimido[6,1-
a]isoquinolin-4-one 429 430.3 181 ##STR00271## 2-(2,3-Dihydro-
[1,4]dioxino[2,3-b]pyridin-2- ylmethoxy)-9-(3-hydroxy-but-
1-ynyl)-6,7-dihydro- pyrimido[6,1-a]isoquinolin-4- one 431 432.2
182 ##STR00272## 2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(3-hydroxy-pent- 1-ynyl)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 445 446.2 183 ##STR00273##
2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(3-hydroxy-hex- 1-ynyl)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 460 460.2 184 ##STR00274##
9-(1-Amino- cyclohexylethynyl)-2-(2,3- dihydro-[1,4]dioxino[2,3-
b]pyridin-2-ylmethoxy)-6,7- dihydro-pyrimido[6,1-
a]isoquinolin-4-one 485 485.2 185 ##STR00275## 2-(2,3-Dihydro-
[1,4]dioxino[2,3-b]pyridin-2- ylmethoxy)-9-(3-hydroxy-5-
methyl-hex-1-ynyl)-6,7- dihydro-pyrimido[6,1- a]isoquinolin-4-one
474 474.2 186 ##STR00276## 2-(2,3-Dihydro-
[1,4]dioxino[2,3-b]pyridin-2- ylmethoxy)-9-(3-ethyl-3-
hydroxy-pent-1-ynyl)-6,7- dihydro-pyrimido[6,1- a]isoquinolin-4-one
474 474.2 187 ##STR00277## 2-(2,3-Dihydro-
[1,4]dioxino[2,3-b]pyridin-2- ylmethoxy)-9-(3-hydroxy-3-
phenyl-but-1-ynyl)-6,7-dihydro- pyrimido[6,1-a]isoquinolin-4- one
508 508.2 188 ##STR00278## 2-(2,3-Dihydro-
[1,4]dioxino[2,3-b]pyridin-2- ylmethoxy)-9-(3-hydroxy-4-
methyl-pent-1-ynyl)-6,7- dihydro-pyrimido[6,1- a]isoquinolin-4-one
460 460.2 189 ##STR00279## 2-[(R)-1-(2,3-Dihydro-
[1,4]dioxino[2,3-b]pyridin-2- yl)methoxy]-9-(oxazol-2-
ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin-4- one 460 461.2
190 ##STR00280## 2-[(S)-1-(2,3-Dihydro-
[1,4]dioxino[2,3-b]pyridin-2- yl)methoxy]-9-(oxazol-2-
ylmethoxy)-6,7-dihydro- pyrimido[6,1-a]isoquinolin-4- one 460 461.4
191 ##STR00281## 9-(3-Butylamino-prop-1-ynyl)- 2-(2,3-dihydro-
[1,4]dioxino[2,3-b]pyridin-2- ylmethoxy)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 473 473.2 192 ##STR00282##
2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(2-morpholin-4- yl-ethoxymethyl)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 507 507.2 193 ##STR00283##
9-(3-Benzylamino-prop-1- ynyl)-2-(2,3-dihydro-
[1,4]dioxino[2,3-b]pyridin-2- ylmethoxy)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 507 507.2 194 ##STR00284##
2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(3-phenylamino- prop-1-ynyl)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 493 493.2 195 ##STR00285##
2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-4-oxo-6,7-dihydro- 4H-pyrimido[6,1-
a]isoquinoline-9-carboxylic acid (tetrahydro-pyran-4-yl)- amide 491
491.2
196 ##STR00286## 2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-4-oxo-6,7-dihydro- 4H-pyrimido[6,1-a]
isoquinoline-9-carboxylic acid (oxetan-3-ylmethyl)-amide 476 477.0
197 ##STR00287## 2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-pyrrolidin-1- ylmethyl-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 447 447.1 198 ##STR00288##
9-(tert-Butylamino-methyl)-2- (2,3-dihydro-[1,4]dioxino[2,3-
b]pyridin-2-ylmethoxy)-6,7- dihydro-pyrimido[6,1-
a]isoquinolin-4-one 449 449.2 199 ##STR00289## 2-(2,3-Dihydro-
[1,4]dioxino[2,3-b]pyridin-2- ylmethoxy)-9-piperidin-1-
ylmethyl-6,7-dihydro- pyrimido[6,1-a]isoquinolin-4- one 461 461.2
200 ##STR00290## 2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(3-methyl- oxetan-3-ylmethoxymethyl)-
6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 478 478.4 201
##STR00291## 2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(3-ethylamino- oxetan-3-ylethynyl)-6,7-
dihydro-pyrimido[6,1- a]isoquinolin-4-one 486 487.3 202
##STR00292## 2-(2,3-Dihydro- [1,4]dioxino[2,3-b]pyridin-2-
ylmethoxy)-9-(oxetan-3- yloxymethyl)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin-4- one 449 450.4 203 ##STR00293##
9-Cyclopropylethynyl-2-(4- isopropyl-oxetan-2-ylmethoxy)-
6,7-dihydro-pyrimido[6,1- a]isoquinolin-4-one 390 391.2 204
##STR00294## 9-Cyclopropylethynyl-2-((R)-4-
isopropyl-oxetan-2-ylmethoxy)- 6,7-dihydro-pyrimido[6,1-
a]isoquinolin-4-one 390 391.2 MW: Molecular weight calc: calculated
obs: observed
TABLE-US-00003 TABLE III NMR Data of the Compounds of the Invention
Cpd# NMR data (.delta.) 1 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.60
(1 H, d), 6.87 (1 H, dd), 6.76 (1 H, d), 6.25 (1 H, s), 4.47-4.57
(1 H, m), 4.13-4.29 (4 H, m), 3.87-3.94 (1 H, m), 3.77-3.86 (4 H,
m), 2.95 (2 H, t), 1.98-2.08 (1 H, m), 1.83-1.98 (2 H, m),
1.57-1.68 (1 H, m). 2 (.sup.1H, MeOD-d.sub.4) .delta. ppm 8.03-8.09
(1 H, m), 7.27 (2 H, s), 7.13-7.21 (2 H, m), 7.01-7.08 (1 H, m),
6.96-7.01 (1 H, m), 6.76 (1 H, s), 4.72-4.83 (2 H, m), 4.60 (2 H,
m), 4.34-4.40 (2 H, m), 4.09-4.13 (3 H, m), 3.23-3.29 (3 H, m),
3.08-3.15 (1 H, m), 3.03-3.07 (1 H, m) 3 (.sup.1H, CDCl.sub.3)
.delta. ppm: 7.66 (1 H, d), 6.78-6.95 (6 H, m), 6.28 (1 H, s),
4.64-4.72 (2 H, m), 4.53-4.61 (1 H, m), 4.36 (1 H, dd), 4.19-4.25
(2 H, m), 4.11-4.19 (1 H, m), 3.88 (3 H, s), 3.00 (1 H, t) 4
(.sup.1H, CDCl.sub.3) .delta. ppm: 7.62 (1 H, d), 6.91 (1 H, dd),
6.80 (1 H, d), 6.28 (1 H, s), 5.97-6.13 (1 H, m), 5.39-5.48 (1 H,
m), 5.31-5.37 (1 H, m), 4.52-4.63 (3 H, m), 4.15-4.32 (4 H, m),
3.89-3.97 (1 H, m), 3.79-3.88 (1 H, m), 2.97 (2 H, t), 2.00-2.11 (1
H, m), 1.87-2.00 (2 H, m), 1.59-1.72 (1 H, m). 5 (.sup.1H,
CDCl.sub.3) .delta. ppm: 7.64 (1 H, d), 7.17-7.22 (1 H, m),
7.10-7.16 (1 H, m), 6.81-6.93 (3 H, m), 6.77-6.81 (1 H, m), 6.30 (1
H, s), 5.10-5.20 (1 H, m), 4.76 (1 H, dd), 4.51 (1 H, dd),
4.19-4.25 (2 H, m), 3.88 (3 H, s), 3.36 (1 H, dd), 2.95-3.08 (3 H,
m). 6 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.45 (1 H, d), 6.88-6.92
(1 H, m), 6.76 (1 H, d), 6.04 (1 H, s), 4.53 (1 H, dd), 4.05-4.41
(4 H, m), 3.87-4.02 (2 H, m), 2.89 (2 H, t), 1.90-2.15 (3 H, m),
1.59-1.73 (1 H, m). 7 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.63 (1 H,
d), 7.33-7.48 (5 H, m), 6.91-7.01 (1 H, m), 6.82-6.89 (1 H, m),
6.29 (1 H, s), 5.14 (2 H, s), 4.51-4.61 (1 H, m), 4.15-4.33 (4 H,
m), 3.90-3.98 (1 H, m), 3.79-3.89 (1 H, m), 2.97 (2 H, t),
2.01-2.11 (1 H, m), 1.86-2.00 (2 H, m), 1.58-1.73 (1 H, m). 8
(.sup.1H, CDCl.sub.3) .delta. ppm: 8.73 (1 H, br. s.), 8.64 (1 H,
m), 7.84 (1 H, d), 7.65 (1 H, d), 7.38-7.45 (1 H, m), 6.95-7.02 (1
H, m), 6.83-6.93 (1 H, m), 6.30 (1 H, s), 5.17 (2 H, s), 4.52-4.60
(1 H, m), 4.18-4.32 (4 H, m), 3.93 (1 H, m), 3.80-3.88 (1 H, m),
2.99 (2 H, t), 2.02-2.10 (1 H, m), 1.87-2.01 (2 H, m), 1.60-1.71 (1
H, m). 9 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.70 (1 H, d), 7.00 (1
H, dd), 6.91 (1 H, d), 6.32 (1 H, s), 4.86 (2 H, s), 4.51-4.60 (1
H, m), 4.12-4.33 (4 H, m), 3.82-3.99 (2 H, m), 3.03 (2 H, t),
2.03-2.14 (1 H, m), 1.86-2.02 (2 H, m), 1.59-1.73 (1 H, m). 10
(.sup.1H, CDCl.sub.3) .delta. ppm: 7.62 (1 H, d), 6.82-6.96 (1 H,
m), 6.73-6.81 (1 H, m), 6.28 (1 H, s), 4.50-4.63 (1 H, m),
4.25-4.33 (2 H, m), 4.15-4.24 (2 H, m), 4.02 (1 H, t), 3.79-3.98 (3
H, m), 2.95 (2 H, t), 2.00-2.13 (1 H, m), 1.88-1.99 (2 H, m),
1.74-1.86 (1 H, m), 1.56-1.72 (3 H, m), 1.44-1.56 (1 H, m), 0.99 (3
H, t) 11 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.62 (1 H, d),
6.85-6.94 (1 H, m), 6.73-6.82 (1 H, m), 6.28 (1 H, s), 4.50-4.61 (1
H, m), 4.23-4.34 (2 H, m), 4.15-4.24 (2 H, m), 3.78-3.98 (3 H, m),
2.86-3.03 (2 H, m), 1.94 (3 H, d), 1.62 (1 H, d), 1.28 (1 H, d),
0.64-0.74 (2 H, m), 0.31-0.43 (1 H, m) 12 (.sup.1H, CDCl.sub.3)
.delta. ppm: 7.61 (1 H, d), 7.24-7.38 (5 H, m), 6.88 (1 H, dd),
6.77 (1 H, d), 6.28 (1 H, s), 4.51-4.60 (1 H, m), 4.15-4.32 (6 H,
m), 3.78-3.97 (2 H, m), 3.13 (2 H, t), 2.91-2.99 (2 H, m),
2.01-2.11 (1 H, m), 1.85-2.00 (2 H, m), 1.61-1.70 (1 H, m). 13
(.sup.1H, CDCl.sub.3) .delta. ppm: 8.67 (2 H, d), 7.65 (1 H, d),
7.42 (2 H, d), 6.96 (1 H, dd), 6.86 (1 H, d), 6.30 (1 H, s), 5.19
(2 H, s), 4.55 (1 H, s), 4.17-4.32 (4 H, m), 3.93 (1 H, m),
3.80-3.89 (1 H, m), 2.98 (2 H, t), 2.01-2.12 (1 H, m), 1.88-2.00 (2
H, m), 1.60-1.71 (1 H, m). 14 (.sup.1H, CDCl.sub.3) .delta. ppm:
8.62 (1 H, d), 7.70-7.81 (1 H, m), 7.58-7.67 (1 H, m), 7.45-7.55 (1
H, m), 7.23-7.31 (1 H, m), 6.94-7.05 (1 H, m), 6.83-6.92 (1 H, m),
6.28 (1 H, s), 5.27 (2 H, s), 4.50-4.61 (1 H, m), 4.15-4.34 (4 H,
m), 3.77-4.00 (2 H, m), 2.90-3.03 (2 H, m), 1.78-2.13 (3 H, m),
1.56-1.74 (1 H, m). 15 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.64 (1
H, d), 7.32 (2 H, t), 6.90-7.06 (4 H, m), 6.85 (1 H, br. s.), 6.30
(1 H, s), 4.52-4.61 (1 H, m), 4.33-4.43 (4 H, m), 4.15-4.33 (4 H,
m), 3.94 (1 H, q), 3.85 (1 H, q), 2.94-3.02 (2 H, m), 1.88-2.11 (3
H, m), 1.60-1.72 (1 H, m). 16 (.sup.1H, CDCl.sub.3) .delta. ppm:
7.63 (1 H, d), 6.86-6.93 (1 H, m), 6.75-6.81 (1 H, m), 6.31 (1 H,
s), 4.50 (1 H, dd), 4.28 (1 H, dd), 4.15-4.23 (2 H, m), 4.02-4.10
(1 H, m), 3.87 (3 H, s), 3.66-3.75 (1 H, m), 3.44-3.54 (1 H, m),
2.97 (2 H, t), 1.84-1.95 (1 H, m), 1.31-1.67 (5 H, m). 17 (.sup.1H,
CDCl.sub.3) .delta. ppm: 7.69-7.74 (2 H, m), 7.65 (1 H, d), 7.56 (2
H, d), 6.95 (1 H, dd), 6.85 (1 H, d), 6.30 (1 H, s), 5.20 (2 H, s),
4.53-4.61 (1 H, m), 4.18-4.32 (4 H, m), 3.94 (1 H, dt), 3.80-3.88
(1 H, m), 2.98 (2 H, t), 2.01-2.12 (1 H, m), 1.88-2.00 (2 H, m),
1.63-1.71 (1 H, m). 18 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.64 (1
H, d), 6.85-6.96 (5 H, m), 6.83 (1 H, d), 6.29 (1 H, s), 4.51-4.65
(2 H, m), 4.36-4.44 (1 H, m), 4.16-4.35 (7 H, m), 3.89-3.99 (1 H,
m), 3.79-3.88 (1 H, m), 2.97 (2 H, t), 2.00-2.13 (1 H, m),
1.85-2.00 (2 H, m), 1.58-1.72 (1 H, m). 19 (.sup.1H, CDCl.sub.3)
.delta. ppm: 7.72-7.79 (1 H, m), 7.62-7.70 (3 H, m), 7.46-7.59 (1
H, m), 6.85-7.03 (2 H, m), 6.31 (1 H, s), 5.15-5.34 (2 H, m),
4.52-4.63 (1 H, m), 4.18-4.35 (4 H, m), 3.89-3.99 (1 H, m),
3.81-3.89 (1 H, m), 2.95-3.04 (2 H, m), 2.01-2.15 (1 H, m),
1.86-2.00 (2 H, m), 1.64-1.75 (1 H, m). 20 .sup.1H, CDCl.sub.3)
.delta. ppm: 7.75 (1 H, d), 7.68 (3 H, d), 7.44-7.55 (1 H, m),
6.97-7.06 (1 H, m), 6.91 (1 H, s), 6.23-6.38 (1 H, m), 5.33 (2 H,
s), 4.16-4.38 (3 H, m), 3.90-4.00 (1 H, m), 3.77-3.90 (1 H, m),
2.94-3.08 (2 H, m), 2.01-2.11 (1 H, m), 1.86-2.01 (1 H, m),
1.46-1.73 (4 H, m) 21 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.64 (1 H,
d), 7.35-7.42 (4 H, m), 6.95 (1 H, d), 6.85 (1 H, d), 6.30 (1 H,
s), 5.10 (2 H, s), 4.52-4.62 (1 H, m), 4.17-4.33 (4 H, m),
3.90-3.98 (1 H, m), 3.81-3.89 (1 H, m), 2.98 (2 H, t), 2.01-2.11 (1
H, m), 1.88-2.00 (2 H, m), 1.63-1.71 (1 H, m). 22 (.sup.1H,
CDCl.sub.3) .delta. ppm: 7.66 (1 H, d), 7.44 (1 H, s), 7.28-7.38 (3
H, m), 6.93-6.99 (1 H, m), 6.86 (1 H, d), 6.31 (1 H, s), 5.11 (2 H,
s), 4.52-4.62 (1 H, m), 4.18-4.34 (4 H, m), 3.90-3.99 (1 H, m),
3.80-3.89 (1 H, m), 2.99 (2 H, t), 2.02-2.13 (1 H, m), 1.88-2.01 (2
H, m), 1.61-1.70 (1 H, m). 23 (.sup.1H, CDCl.sub.3) .delta. ppm:
7.65 (1 H, d), 7.51-7.55 (1 H, m), 7.41-7.46 (1 H, m), 7.29-7.34 (2
H, m), 6.95-7.01 (1 H, m), 6.88 (1 H, d), 6.30 (1 H, s), 5.24 (2 H,
s), 4.52-4.61 (1 H, m), 4.16-4.32 (4 H, m), 3.94 (1 H, m),
3.80-3.88 (1 H, m), 2.99 (2 H, t), 2.02-2.11 (1 H, m), 1.87-2.01 (2
H, m), 1.58-1.69 (1 H, m). 24 (.sup.1H, CDCl.sub.3) .delta. ppm:
7.64 (1 H, d), 7.38-7.44 (2 H, m), 7.07-7.14 (2 H, m), 6.96 (1 H,
dd), 6.85 (1 H, d), 6.30 (1 H, s), 5.09 (2 H, s), 4.52-4.61 (1 H,
m), 4.16-4.32 (4 H, m), 3.89-3.97 (1 H, m), 3.81-3.88 (1 H, m),
2.98 (2 H, t), 2.01-2.11 (1 H, m), 1.87-2.01 (2 H, m), 1.60-1.65 (1
H, m). 25 (.sup.1H, CDCl.sub.3) .delta. ppm: 8.21 (1 H, dd), 7.86
(1 H, d), 7.72 (1 H, td), 7.66 (1 H, d), 7.51-7.57 (1 H, m), 7.00
(1 H, dd), 6.90 (1 H, d), 6.30 (1 H, s), 5.56 (2 H, s), 4.50-4.59
(1 H, m), 4.17-4.33 (4 H, m), 3.90-3.98 (1 H, m), 3.79-3.89 (1 H,
m), 3.00 (2 H, t), 2.01-2.12 (1 H, m), 1.86-2.01 (2 H, m),
1.60-1.75 (1 H, m). 26 (.sup.1H, CDCl.sub.3) .delta. ppm: 8.06-8.13
(2 H, m), 7.64 (1 H, d), 7.47-7.53 (2 H, m), 6.96 (1 H, dd), 6.86
(1 H, d), 6.29 (1 H, s), 5.20 (2 H, s), 4.52-4.60 (1 H, m),
4.18-4.33 (4 H, m), 3.91-3.96 (4 H, m), 3.81-3.89 (1 H, m), 2.98 (2
H, t), 2.03-2.12 (1 H, m), 1.88-2.01 (2 H, m), 1.63-1.73 (1 H, m).
27 (.sup.1H, CDCl.sub.3) .delta. ppm: 8.12 (1 H, br. s), 8.04 (1 H,
d), 7.64 (2 H, d), 7.50 (1 H, t), 6.97 (1 H, dd), 6.87 (1 H, d),
6.30 (1 H, s), 5.18 (2 H, s), 4.53-4.61 (1 H, m), 4.17-4.32 (4 H,
m), 3.90-3.98 (4 H, m), 3.81-3.88 (1 H, m), 2.98 (2 H, t),
2.02-2.11 (1 H, m), 1.88-2.01 (2 H, m), 1.67-1.73 (1 H, m). 28
(.sup.1H, CDCl.sub.3) .delta. ppm: 8.57-8.67 (1 H, m), 7.75 (1 H,
td), 7.66 (1 H, d), 7.48-7.54 (1 H, m), 7.24-7.30 (1 H, m), 7.00 (1
H, dd), 6.83-6.96 (5 H, m), 6.28 (1 H, s), 5.28 (2 H, s), 4.63-4.72
(2 H, m), 4.52-4.60 (1 H, m), 4.31-4.41 (1 H, m), 4.18-4.25 (2 H,
m), 4.11-4.18 (1 H, m), 2.94-3.03 (2 H, m). 29 (.sup.1H,
CDCl.sub.3) .delta. ppm: 7.66 (1 H, d), 6.82-6.94 (5 H, m),
6.76-6.80 (1 H, m), 6.27 (1 H, s), 4.62-4.70 (2 H, m), 4.58 (2 H,
s), 4.52-4.57 (1 H, m), 4.32-4.38 (1 H, m), 4.17-4.23 (2 H, m),
4.10-4.17 (1 H, m), 2.93-3.02 (2 H, m), 1.50 (9 H, s). 30 (.sup.1H,
CDCl.sub.3) .delta. ppm: 7.67 (1 H, d), 6.81-6.99 (10 H, m), 6.29
(1 H, s), 4.67 (2 H, m), 4.54-4.65 (2 H, m), 4.29-4.43 (3 H, m),
4.11-4.28 (5 H, m), 2.99 (2 H, t). 31 (.sup.1H, DMSO-d.sub.6)
.delta. ppm: 7.96 (1 H, d), 6.80-6.99 (6 H, m), 6.60 (1 H, s), 4.80
(2 H, s), 4.46-4.62 (3 H, m), 4.37-4.45 (1 H, m), 4.08-4.17 (1 H,
m), 4.02 (2 H, t), 2.97 (2 H, t). 32 (.sup.1H, CDCl.sub.3) .delta.
ppm: 8.37 (1H, s), 8.27 (1H, d), 7.82-6.81 (1H, d), 7.70 (1H, d),
7.65 (1H, t), 7.01 (1H, dd), 6.92 (1H, d), 6.34 (1H, s), 5.27 (2H,
s), 4.63-4.57 (1H, m), 4.33-4.20 (4H, m), 3.97 (1H, q), 3.88 (1H,
q), 3.03 (2H, t), 2.14-1.94 (3H, m), 1.72-1.65 (1H, m). 33
(.sup.1H, CDCl.sub.3) .delta. ppm: 8.32 (2H, dt), 7.69 (1H, d),
7.65 (2H, d), 7.0 (1H, dd), 6.90 (1H, d), 6.33 (1H, s), 6.28 (2H,
s), 4.61-4.59 (1H, m), 4.32-4.18 (4H, m), 3.97 (1H, q), 3.88 (1H,
q) 3.02 (2H, t), 2.12-1.92 (3H, m), 1.71-1.66 (1H, m). 34 (.sup.1H,
CDCl.sub.3) .delta. ppm: 7.67 (1H, d), 7.35-7.25 (3H, m), 7.21 (1H,
d), 7.0 (1H, dd), 6.90 (1H, d), 6.32 (1H, s), 5.13 (2H, s), 4.60
(1H, m), 4.34-4.30 (2H, m), 4.26-4.22 (2H, m), 3.97 (1H, q), 3.88
(1H, q) 3.01 (2H, t), 2.42 (3H, s), 2.12-1.92 (3H, m), 1.72-1.63
(1H, m). 35 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.66 (1H, d), 7.30
(4H, dd), 6.99 (1H, dd), 6.89 (1H, d), 6.32 (1H, s), 5.12 (2H, s),
4.60 (1H, dt), 4.34-4.28 (2H, m), 4.26-4.21 (2H, m), 3.97 (1H, q),
3.88 (1H, q), 3.00 (2H, t), 2.41 (3H, s), 2.12-2.05 (1H, m),
2.03-1.92 (2H, m), 1.73-1.63 (1H, m). 36 (.sup.1H, CDCl.sub.3)
.delta. ppm: 7.65 (1H, d), 7.45 (1H, dd), 7.36 (1H, dt), 7.04-6.99
(2H, m), 6.97 (1H, d), 6.91 (1H, d), 6.31 (1H, s), 5.21 (2H, s),
4.58 (1H, dt), 4.33-4.28 (2H, m), 4.27-4.18 (2H), 3.99-3.93 (1H,
m), 3.91 (3H, s), 3.90-3.84 (1H, q), 3.00 (2H, t), 2.13-2.05 (1H,
m), 2.02-1.91 (2H, m), 1.71-1.64 (1H, m). 37 (.sup.1H, CDCl.sub.3)
.delta. ppm: 7.94-7.88 (4H, m), 7.67 (1H, d), 7.58-7.53 (3H, m),
7.05 (1H, dd), 6.94 (1H, d), 6.32 (1H, s), 5.34 (2H, s), 4.59 (1H,
dt), 4.34-4.27 (2H, m), 4.29-4.18 (2H, m), 3.97 (1H, q), 3.87 (1H,
q), 3.01 (2H, t), 2.14-1.92 (3H, m), 1.72-1.65 (1H, m).
38 (.sup.1H, CDCl.sub.3) .delta. ppm: 8.07-8.05 (1H, m), 7.97-7.92
(2H, m), 7.69 (1H, d), 7.64-7.51 (4H, m), 7.09 (1H, dd), 6.98 (1H,
d), 6.34 (1H, s), 5.60 (2H, s), 4.63-4.47 (1H, m), 4.34-4.29 (2H,
m), 4.28-4.21 (2H, m), 3.97 (2H, q), 3.88 (2H, q), 3.02 (2H, t),
2.14-1.92 (3H, m), 1.74-1.65 (1H, m). 39 (.sup.1H, CDCl.sub.3)
.delta. ppm: 7.68 (1H, d), 7.42 (1H, d), 7.35-7.31 (1H, m),
7.29-7.25 (2H, m), 7.02 (1H, dd), 6.91 (1H, d), 6.33 (1H, s), 5.14
(2H, s), 4.60 (1H, dt), 4.35-4.29 (2H, m), 4.28-4.21 (2H, m),
4.0-3.94 (1H, m), 3.90-9.85 (1H, m), 3.02 (2H, t), 2.42 (3H, s),
2.14-1.92 (3H, m), 1.74-1.67 (1H, m). 40 (.sup.1H, CDCl.sub.3)
.delta. ppm: 7.63 (1 H, d), 6.88-7.01 (5 H, m), 6.85 (1 H, d), 6.29
(1 H, s), 4.48-4.61 (1 H, m), 4.37-4.45 (4 H, m), 4.16-4.31 (4 H,
m), 3.89-3.97 (1 H, m), 3.79-3.88 (4 H, m), 2.97 (2 H, t),
2.00-2.09 (1 H, m), 1.88-1.99 (2 H, m), 1.59-1.71 (1 H, m). 41
(.sup.1H, CDCl.sub.3) .delta. ppm: 7.59-7.67 (1 H, m), 7.16-7.23 (1
H, m), 6.94 (1 H, dd), 6.83 (1 H, d), 6.49-6.58 (3 H, m), 6.28 (1
H, s), 4.50-4.59 (1 H, m), 4.31-4.40 (4 H, m), 4.15-4.29 (4 H, m),
3.75-3.96 (5 H, m), 2.96 (2 H, t), 2.00-2.10 (1 H, m), 1.87-2.00 (2
H, m), 1.59-1.69 (1 H, m). 42 (.sup.1H, CDCl.sub.3) .delta. ppm:
7.63 (1 H, d), 6.80-7.00 (6 H, m), 6.29 (1 H, s), 4.50-4.60 (1 H,
m), 4.16-4.44 (8 H, m), 3.89-3.97 (1 H, m), 3.80-3.89 (1 H, m),
3.73-3.79 (3 H, m), 2.97 (2 H, t), 2.00-2.11 (1 H, m), 1.84-1.99 (2
H, m), 1.58-1.71 (1 H, m). 43 (.sup.1H, CDCl.sub.3) .delta. ppm:
7.63 (1 H, d), 7.37 (1 H, dd), 7.20-7.26 (1 H, m), 6.91-7.03 (3 H,
m), 6.88 (1 H, d), 6.29 (1 H, s), 4.50-4.60 (1 H, m), 4.37-4.48 (4
H, m), 4.16-4.32 (4 H, m), 3.89-3.97 (1 H, m), 3.79-3.88 (1 H, m),
2.97 (2 H, t), 2.00-2.11 (1 H, m), 1.88-1.99 (2 H, m), 1.59-1.70 (1
H, m). 44 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.61-7.68 (1 H, m),
7.17-7.26 (1 H, m), 6.90-7.01 (3 H, m), 6.79-6.88 (2 H, m), 6.29 (1
H, s), 4.51-4.62 (1 H, m), 4.16-4.42 (8 H, m), 3.89-3.98 (1 H, m),
3.79-3.88 (1 H, m), 2.98 (2 H, t), 2.01-2.12 (1 H, m), 1.88-2.00 (2
H, m), 1.57-1.70 (1 H, m). 45 (.sup.1H, CDCl.sub.3) .delta. ppm:
7.64 (1 H, d), 7.23-7.28 (2 H, m), 6.94 (1 H, dd), 6.85-6.91 (2 H,
m), 6.83 (1 H, d), 6.29 (1 H, s), 4.51-4.60 (1 H, m), 4.16-4.40 (8
H, m), 3.89-3.97 (1 H, m), 3.80-3.88 (1 H, m), 2.97 (2 H, t),
2.01-2.10 (1 H, m), 1.86-1.99 (2 H, m), 1.59-1.70 (1 H, m). 46
(.sup.1H, CDCl.sub.3) .delta. ppm: 7.65 (1 H, d), 6.79-6.98 (6 H,
m), 6.26 (1 H, s), 4.77 (2 H, s), 4.64 (2 H, m), 4.51-4.58 (1 H,
m), 4.30-4.38 (1 H, m), 4.16-4.23 (2 H, m), 4.08-4.16 (1 H, m),
3.53-3.73 (8 H, m), 2.97 (2 H, t). 47 (.sup.1H, CDCl.sub.3) .delta.
ppm: 7.68 (1 H, d), 6.79-6.97 (6 H, m), 6.57 (1 H, br. s.), 6.32 (1
H, br. s.), 6.28 (1 H, s), 4.61-4.67 (2 H, m), 4.53-4.58 (3 H, m),
4.34 (1 H, dd), 4.07-4.24 (3 H, m), 2.99 (2 H, t). 48 (.sup.1H,
CDCl.sub.3) .delta. ppm: 7.65 (1 H, d), 6.82-6.97 (6 H, m), 6.27 (1
H, s), 4.78 (2 H, s), 4.66 (2 H, dd), 4.52-4.60 (1 H, m), 4.32-4.38
(1 H, m), 4.17-4.23 (2 H, m), 4.10-4.17 (1 H, m), 3.10 (3 H, s),
2.96-3.02 (5 H, m). 49 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.62 (1
H, d), 6.78-6.97 (6 H, m), 6.43 (1 H, br. s), 6.28 (1 H, s), 5.73
(1 H, br. s), 4.60-4.72 (2 H, m), 4.52-4.60 (1 H, m), 4.31-4.39 (1
H, m), 4.09-4.23 (3 H, m), 2.96 (2 H, t), 1.62 (6 H, s). 50
(.sup.1H, CDCl.sub.3) .delta. ppm: 7.61 (1 H, d), 6.80-6.97 (5 H,
m), 6.72-6.79 (1 H, m), 6.27 (1 H, s), 4.64-4.69 (2 H, m),
4.52-4.60 (1 H, m), 4.32-4.38 (1 H, m), 4.17-4.23 (2 H, m), 4.14 (1
H, dd), 3.74-3.83 (2 H, m), 3.55-3.70 (6 H, m), 2.95 (2 H, t), 1.69
(6 H, s). 51 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.62 (1 H, d),
7.28-7.38 (5 H, m), 6.91 (1 H, dd), 6.81 (1 H, d), 6.28 (1 H, s),
4.62-4.67 (2 H, m), 4.52-4.60 (1 H, m), 4.14-4.32 (6 H, m),
3.75-3.98 (4 H, m), 2.92-2.99 (2 H, m), 1.88-2.12 (3 H, m),
1.59-1.71 (1 H, m). 52 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.61 (1
H, d), 6.92 (1 H, dd), 6.81 (1 H, d), 6.28 (1 H, s), 4.49-4.60 (1
H, m), 4.14-4.34 (5 H, m), 4.00-4.07 (2 H, m), 3.78-3.99 (4 H, m),
2.92-3.00 (2 H, m), 1.85-2.18 (6 H, m), 1.53-1.84 (2 H, m). 53
(.sup.1H, CDCl.sub.3) .delta. ppm: 7.96-8.04 (2 H, m), 7.74-7.82 (1
H, m), 7.58-7.70 (2 H, m), 7.38-7.52 (4 H, m), 7.00 (1 H, dd), 6.91
(1 H, d), 6.27 (1 H, s), 5.33 (2 H, s), 4.49-4.60 (1 H, m),
4.14-4.32 (4 H, m), 3.76-3.97 (2 H, m), 2.95 (2 H, t), 1.84-2.10 (3
H, m), 1.57-1.70 (1 H, m). 54 (.sup.1H, CDCl.sub.3) .delta. ppm:
7.65 (1 H, d), 6.74-7.01 (6 H, m), 6.28 (1 H, s), 4.48-4.73 (3 H,
m), 4.25-4.40 (2 H, m), 4.21 (3 H, s), 4.01-4.06 (2 H, m),
3.80-4.00 (2 H, m), 2.98 (2 H, t), 1.90-2.26 (3 H, m), 1.67-1.88 (1
H, m) 55 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.95 (2 H, d),
7.53-7.75 (1 H, m), 7.34-7.45 (1 H, m), 7.22-7.30 (1 H, m),
6.93-7.05 (1 H, m), 6.89 (1 H, d), 6.27 (1 H, s), 5.25 (2 H, s),
4.54 (1 H, m), 4.22-4.31 (2 H, m), 4.12-4.22 (2 H, m), 3.96 (3 H,
s), 3.90 (2 H, s), 2.95 (2 H, t), 1.87-2.12 (2 H, m), 1.54-1.76 (2
H, m) 56 (.sup.1H, CDCl.sub.3) .delta. ppm: 8.04 (1 H, s),
7.67-7.76 (1 H, m), 7.63 (1 H, d), 7.51 (1 H, t), 7.40 (1 H, d),
7.33 (1 H, d), 7.00 (1 H, dd), 6.88-6.93 (2 H, br s), 6.28 (1 H,
s), 5.28 (2 H, s), 4.48-4.60 (1 H, m), 4.14-4.33 (4 H, m), 4.02 (1
H, quin), 3.77-3.97 (2 H, m), 2.96 (2 H, t), 1.98-2.12 (1 H, m),
1.84-1.98 (2 H, m), 1.56-1.71 (1 H, m). 57 (.sup.1H, CDCl.sub.3)
.delta. ppm: 9.36 (2 H, s), 9.28 (1 H, s), 7.85-7.94 (1 H, m), 7.74
(1 H, d), 7.65 (1 H, d), 7.57 (1 H, d), 7.02 (1 H, dd), 6.92 (1 H,
d), 6.29 (1 H, s), 5.35 (2 H, s), 4.49-4.61 (1 H, m), 4.14-4.33 (4
H, m), 3.77-3.99 (2 H, m), 2.98 (2 H, t), 1.85-2.12 (3 H, m),
1.57-1.72 (1 H, m). 58 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.64 (1
H, d), 7.02 (1 H, dd), 6.94 (1 H, d), 6.27 (1 H, s), 5.50 (2 H, s),
4.47-4.56 (1 H, m), 4.20-4.28 (2 H, m), 4.11-4.19 (2 H, m),
3.86-3.94 (1 H, m), 3.77-3.85 (1 H, m), 3.69-3.77 (1 H, m), 2.97 (2
H, t), 1.84-2.09 (3 H, m), 1.57-1.68 (1 H, m), 1.33-1.42 (2 H, m),
1.21-1.32 (2 H, m). 59 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.65 (1
H, d), 6.92 (1 H, dd), 6.82 (1 H, d), 6.58 (1 H, br. s), 6.29 (1 H,
s), 6.20 (1 H, br. s), 4.48-4.59 (3 H, m), 4.12-4.29 (4 H, m),
3.87-3.95 (1 H, m), 3.79-3.86 (1 H, m), 2.98 (2 H, t), 2.00-2.10 (1
H, m), 1.85-2.00 (2 H, m), 1.58-1.69 (1 H, m). 60 (.sup.1H,
CDCl.sub.3) .delta. ppm: 7.58 (1 H, d), 6.85-6.93 (1 H, m),
6.75-6.83 (1 H, m), 6.23 (1 H, s), 4.72 (2 H, s), 4.45-4.56 (1 H,
m), 4.19-4.27 (2 H, m), 4.09-4.17 (2 H, m), 3.84-3.92 (1 H, m),
3.74-3.83 (1 H, m), 3.27-3.44 (4 H, m), 2.92 (2 H, t), 1.96-2.06 (1
H, m), 1.82-1.95 (2 H, m), 1.54-1.67 (1 H, m), 1.20 (3 H, t), 1.10
(3 H, t). 61 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.59 (1 H, d), 6.90
(1 H, dd), 6.80 (1 H, d), 6.25 (1 H, s), 4.75 (2 H, s), 4.47-4.56
(1 H, m), 4.19-4.29 (2 H, m), 4.10-4.19 (2 H, m), 3.85-3.93 (1 H,
m), 3.76-3.84 (1 H, m), 3.07 (3 H, s), 2.97 (3 H, s), 2.94 (2 H,
t), 1.97-2.09 (1 H, m), 1.84-1.96 (2 H, m), 1.55-1.69 (1 H, m). 62
(.sup.1H, CDCl.sub.3) .delta. ppm: 7.57 (1 H, d), 6.84-6.94 (1 H,
m), 6.75-6.82 (1 H, m), 6.23 (1 H, s), 4.68-4.82 (2.5 H, m),
4.43-4.55 (1 H, m), 4.17-4.27 (2 H, m), 4.00-4.17 (2.5, m),
3.84-3.92 (1 H, m), 3.73-3.83 (1 H, m), 2.88-2.97 (2 H, m),
2.75-2.87 (3 H, m), 1.95-2.07 (1 H, m), 1.79-1.95 (2 H, m),
1.51-1.70 (1 H, m), 1.19 (3 H, d), 1.07 (3 H, d). 63 (.sup.1H,
CDCl.sub.3) .delta. ppm: 8.27 (1 H, br. s), 7.66-7.71 (1 H, m),
7.58-7.62 (2 H, m), 7.34-7.39 (2 H, m), 7.14-7.21 (1 H, m), 7.00 (1
H, dd), 6.90 (1 H, d), 6.31 (1 H, s), 4.69 (2 H, s), 4.51-4.59 (1
H, m), 4.15-4.31 (4 H, m), 3.89-3.96 (1 H, m), 3.81-3.88 (1 H, m),
3.00 (2 H, t), 1.99-2.12 (1 H, m), 1.85-1.99 (2 H, m), 1.59-1.70 (1
H, m). 64 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.64 (1 H, d), 7.00 (1
H, dd), 6.92 (1 H, d), 6.27 (1 H, s), 5.47 (2 H, s), 4.48-4.58 (1
H, m), 4.41 (2 H, t), 4.11-4.29 (4 H, m), 3.87-3.95 (1 H, m),
3.78-3.86 (1 H, m), 2.98 (2 H, t), 1.83-2.10 (5 H, m), 1.56-1.68 (1
H, m), 0.99 (3 H, t). 65 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.70 (1
H, d), 7.61 (1 H, d), 7.15 (1 H, d), 6.99 (1 H, dd), 6.90 (1 H, d),
6.26 (1 H, s), 5.20 (2 H, s), 4.47-4.56 (1 H, m), 4.20-4.29 (2 H,
m), 4.11-4.20 (2 H, m), 3.86-3.94 (1 H, m), 3.77-3.86 (1 H, m),
2.95 (2 H, t), 1.98-2.08 (1 H, m), 1.85-1.97 (2 H, m), 1.56-1.68 (1
H, m). 66 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.64 (1 H, d),
6.77-6.99 (6 H, m), 6.25 (1 H, s), 4.76 (2 H, s), 4.61-4.66 (2 H,
m), 4.51-4.58 (1 H, m), 4.34 (1 H, dd), 4.16-4.21 (2 H, m), 4.13 (1
H, dd), 3.32-3.44 (4 H, m), 2.96 (2 H, t), 1.24 (3 H, t), 1.14 (3
H, t). 67 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.63 (1 H, d),
6.76-6.98 (6 H, m), 6.25 (1 H, s), 4.76-4.85 (1.5 H, m), 4.74 (1 H,
s), 4.64 (2 H, dd), 4.54 (1 H, m), 4.33 (1 H, dd), 4.09-4.21 (3.5
H, m), 2.96 (2 H, t), 2.79-2.89 (3 H, m), 1.23 (3 H, d), 1.11 (3 H,
d). 68 (.sup.1H, CDCl.sub.3) .delta. ppm: 8.23 (1 H, br. s), 7.72
(1 H, d), 7.57-7.64 (2 H, m), 7.33-7.42 (2 H, m), 7.14-7.22 (1 H,
m), 6.98-7.07 (1 H, m), 6.82-6.96 (5 H, m), 6.31 (1 H, s), 4.69 (2
H, s), 4.66 (2 H, t), 4.53-4.60 (1 H, m), 4.35 (1 H, dd), 4.19-4.25
(2 H, m), 4.14 (1 H, dd), 3.02 (2 H, t). 69 (.sup.1H, CDCl.sub.3)
.delta. ppm: 7.67 (1 H, d), 7.02 (1 H, dd), 6.78-6.97 (5 H, m),
6.27 (1 H, s), 5.48 (2 H, s), 4.64 (2 H, t), 4.54 (1 H, m), 4.42 (2
H, t), 4.34 (1 H, dd), 4.15-4.20 (2 H, m), 4.12 (1 H, dd), 2.99 (2
H, t), 2.00 (2 H, s.times.t), 0.98 (3 H, t). 70 (.sup.1H,
CDCl.sub.3) .delta. ppm: 7.68 (1 H, d), 7.02 (1 H, dd), 6.79-6.96
(5 H, m), 6.28 (1 H, s), 5.48 (2 H, s), 4.65 (2 H, t), 4.55 (1 H,
m), 4.45 (2 H, t), 4.34 (1 H, dd), 4.16-4.21 (2 H, m), 4.13 (1 H,
dd), 3.00 (2 H, t), 1.89-1.99 (2 H, m), 1.39 (2 H, m), 0.96 (3 H,
t). 71 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.64 (1 H, d), 6.77-6.95
(6 H, m), 6.26 (1 H, s), 4.61-4.68 (2 H, m), 4.54 (1 H, m), 4.34 (1
H, dd), 4.09-4.22 (5 H, m), 3.70-3.76 (4 H, m), 2.96 (2 H, t), 2.82
(2 H, t), 2.54-2.60 (4 H, m). 72 (.sup.1H, CDCl.sub.3) .delta. ppm:
7.74 (1 H, d), 7.01 (1 H, dd), 6.81-6.96 (5 H, m), 6.32 (1 H, s),
4.86 (2 H, s), 4.68 (2 H, t), 4.54-4.61 (1 H, m), 4.36 (1 H, dd),
4.20-4.26 (2 H, m), 4.15 (1 H, dd), 3.04 (2 H, t). 73 (.sup.1H,
CDCl.sub.3) .delta. ppm: 7.70 (1 H, d), 7.64 (1 H, d), 7.14-7.18 (1
H, m), 7.00 (1 H, dd), 6.78-6.93 (5 H, m), 6.25 (1 H, s), 5.21 (2
H, s), 4.63 (2 H, m), 4.49-4.57 (1 H, m), 4.32 (1 H, dd), 4.15-4.20
(2 H, m), 4.11 (1 H, dd), 2.96 (2 H, t). 74 (.sup.1H, CDCl.sub.3)
.delta. ppm: 7.63 (1 H, d), 6.75-6.97 (6 H, m), 6.25 (1 H, s), 4.69
(2 H, s), 4.63 (2 H, dd), 4.49-4.57 (1 H, m), 4.33 (1 H, dd), 4.17
(2 H, t), 4.12 (1 H, dd), 3.50 (4 H, q), 2.96 (2 H, t), 1.99 (2 H,
q), 1.86 (2 H, q). 75 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.69 (1 H,
d), 7.04 (1 H, dd), 6.96 (1 H, d), 6.81-6.94 (4 H, m), 6.28 (1 H,
s), 5.52 (2 H, s), 4.66 (2 H, t), 4.52-4.59 (1 H, m), 4.35 (1 H,
dd), 4.19 (2 H, t), 4.14 (1 H, dd), 3.74 (1 H, m), 3.00 (2 H, t),
1.37-1.45 (2 H, m),
1.25-1.32 (2 H, m). 76 (.sup.1H, DMSO-d.sub.6) .delta. ppm: 8.01 (1
H, d), 7.12 (1 H, d), 7.09 (1 H, dd), 6.82-6.93 (4 H, m), 6.63 (1
H, s), 5.60 (2 H, s), 4.46-4.63 (3 H, m), 4.42 (1 H, dd), 4.13 (1
H, dd), 4.03 (2 H, t), 3.00 (2 H, t). 77 (.sup.1H, DMSO-d.sub.6)
.delta. ppm: 7.95 (1 H, d), 7.75-7.81 (1 H, m), 7.36 (1 H, dd),
6.87-7.06 (3 H, m), 6.57 (1 H, s), 5.96-6.14 (1 H, m), 5.42 (1 H,
dd), 5.29 (1 H, dd), 4.45-4.70 (6 H, m), 4.31 (1 H, dd), 4.02 (2 H,
t), 2.97 (2 H, t). 78 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.67 (1 H,
d), 7.27-7.37 (5 H, m), 6.79-6.96 (7 H, m), 6.28 (1 H, s), 4.65 (2
H, t), 4.61 (2 H, s), 4.52-4.59 (3 H, m), 4.34 (1 H, dd), 4.18 (2
H, t), 4.13 (1 H, dd), 2.97 (2 H, t). 79 (.sup.1H, CDCl.sub.3)
.delta. ppm: 7.64 (1 H, d), 6.82-6.94 (5 H, m), 6.78-6.82 (1 H, m),
6.26 (1 H, s), 4.65 (2 H, dd), 4.55 (1 H, m), 4.34 (1 H, dd),
4.10-4.23 (5 H, m), 2.97 (2 H, t), 2.93 (2 H, t), 2.61-2.67 (4 H,
m), 1.78-1.85 (4 H, m). 80 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.62
(1 H, d), 6.80-6.92 (5 H, m), 6.78 (1 H, d), 6.24 (1 H, s), 4.63 (2
H, dd), 4.53 (1 H, dtd), 4.33 (1 H, dd), 4.08-4.21 (5 H, m), 2.95
(2 H, t), 2.77 (2 H, t), 2.42-2.54 (4 H, m), 1.59 (4 H, quin),
1.38-1.48 (2 H, m). 81 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.62 (1
H, d), 6.80-6.95 (5 H, m), 6.78 (1 H, d), 6.25 (1 H, s), 4.62-4.67
(2 H, m), 4.50-4.58 (1 H, m), 4.34 (1 H, dd), 4.19 (2 H, t), 4.12
(1 H, dd), 4.07 (2 H, t), 2.96 (2 H, t), 2.46 (2 H, t), 2.33-2.43
(4 H, br m), 1.99 (2 H, quin), 1.58 (4 H, quin), 1.44 (2 H, m). 82
(.sup.1H, CDCl.sub.3) .delta. ppm: 7.64 (1 H, d), 6.82-6.94 (5 H,
m), 6.80 (1 H, d), 6.27 (1 H, s), 4.66 (2 H, dd), 4.56 (1 H, m),
4.35 (1 H, dd), 4.18-4.23 (2 H, m), 4.14 (1 H, dd), 4.09 (2 H, t),
2.97 (2 H, t), 2.48 (2 H, t), 2.28 (6 H, s), 1.99 (2 H, quin). 83
(.sup.1H, CDCl.sub.3) .delta. ppm: 7.64 (1 H, m), 6.71-6.95 (6 H,
m), 6.22-6.31 (1 H, m), 4.66 (2 H, dd), 4.56 (1 H, m), 4.35 (1 H,
dd), 4.03-4.24 (4 H, m), 2.93-3.16 (2 H, m), 2.52-2.80 (2 H, m),
1.51-2.44 (11 H, m). 84 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.63 (1
H, d), 6.81-6.94 (5 H, m), 6.78 (1 H, d), 6.26 (1 H, s), 4.65 (2 H,
dd), 4.54 (1 H, m), 4.34 (1 H, dd), 4.19 (2 H, t), 4.13 (1 H, dd),
4.07 (2 H, t), 2.96 (2 H, t), 2.34-2.59 (10 H, m), 2.28 (3 H, s),
1.99 (2 H, quin). 85 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.65 (1 H,
d), 7.13-7.19 (1 H, m), 6.93-6.98 (1 H, m), 6.81-6.93 (5 H, m),
6.53-6.58 (1 H, m), 6.27 (1 H, s), 5.12 (2 H, s), 4.65 (2 H, dd),
4.55 (1 H, m), 4.36 (1 H, q), 4.31-4.36 (2 H, m), 4.16-4.23 (2 H,
m), 4.13 (1 H, dd), 2.98 (2 H, t), 1.37 (3 H, t). 86 (.sup.1H,
CDCl.sub.3) .delta. ppm: 7.82 (1 H, dd), 7.71 (1 H, s), 7.66 (1 H,
d), 7.22 (1 H, dd), 7.17 (1 H, s), 7.01 (1 H, dd), 6.93 (1 H, d),
6.88 (1 H, dd), 6.26 (1 H, s), 5.22 (2 H, s), 4.66 (2 H, d),
4.50-4.59 (2 H, m), 4.31 (1 H, m), 4.19 (2 H, t), 2.98 (2 H, t). 87
(.sup.1H, CDCl.sub.3) .delta. ppm: 7.61 (1 H, d), 6.98 (1 H, dd),
6.89 (1 H, d), 6.25 (1 H, s), 5.18 (2 H, s), 4.45-4.55 (1 H, m),
4.11-4.27 (4 H, m), 3.84-3.92 (1 H, m), 3.75-3.83 (1 H, m), 2.95 (2
H, t), 1.96-2.08 (1 H, m), 1.82-1.96 (2 H, m), 1.55-1.67 (1 H, m),
1.42 (9 H, s). 88 (.sup.1H, CDCl.sub.3) .delta. ppm: 8.12-8.18 (2
H, m), 7.58-7.67 (2 H, m), 7.49-7.57 (2 H, m), 7.04 (1 H, dd), 6.95
(1 H, d), 6.28 (1 H, s), 5.31 (2 H, s), 4.50-4.57 (1 H, m),
4.23-4.30 (2 H, m), 4.14-4.23 (2 H, m), 3.91 (1 H, m), 3.78-3.86 (1
H, m), 2.98 (2 H, t), 1.99-2.10 (1 H, m), 1.84-1.98 (2 H, m),
1.58-1.69 (1 H, m). 89 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.85 (1
H, dd), 7.74 (1 H, d), 7.25 (1 H, dd), 7.01 (1 H, dd), 6.88-6.93 (2
H, m), 6.30 (1 H, s), 4.87 (2 H, s), 4.70 (2 H, d), 4.53-4.62 (2 H,
m), 4.30-4.38 (1 H, m), 4.21-4.27 (2 H, m), 3.04 (2 H, t). 90
(.sup.1H, CDCl.sub.3) .delta. ppm: 7.84 (1 H, dd), 7.65 (1 H, d),
7.24 (1 H, dd), 6.86-6.94 (2 H, m), 6.81 (1 H, d), 6.27 (1 H, s),
4.65-4.71 (2 H, m), 4.52-4.61 (2 H, m), 4.29-4.36 (1 H, m),
4.17-4.25 (4 H, m), 3.74-3.80 (4 H, m), 2.98 (2 H, t), 2.88 (2 H,
t), 2.58-2.69 (4 H, m). 91 (.sup.1H, CDCl.sub.3) .delta. ppm: 8.62
(1 H, d), 7.83 (1 H, dd), 7.74 (1 H, td), 7.62-7.68 (1 H, m), 7.49
(1 H, d), 7.19-7.31 (2 H, m), 6.99 (1 H, dd), 6.84-6.92 (2 H, m),
6.26 (1 H, s), 5.26 (2 H, s), 4.64-4.70 (2 H, m), 4.49-4.61 (2 H,
m), 4.27-4.37 (1 H, m), 4.20 (2 H, t), 2.97 (2 H, t). 92 (.sup.1H,
CDCl.sub.3) .delta. ppm: 7.83 (1 H, dd), 7.61-7.68 (1 H, m), 7.23
(1 H, dd), 6.84-6.92 (2 H, m), 6.74-6.81 (1 H, m), 6.22-6.30 (1 H,
m), 4.73-4.82 (1 H, m), 4.67 (2 H, d), 4.50-4.61 (2 H, m),
4.28-4.37 (1 H, m), 4.20 (2 H, t), 2.92-3.38 (6 H, m), 2.71-2.78 (3
H, m), 2.39-2.52 (1 H, m), 1.87-2.28 (5 H, m). 93 (.sup.1H,
CDCl.sub.3) .delta. ppm: 7.78 (1 H, d), 7.57 (1 H, d), 7.19 (1 H,
d), 6.98 (1 H, d), 6.92 (1 H, br. s.), 6.85 (1 H, dd), 6.21 (1 H,
s), 5.39 (2 H, br. s.), 4.59 (2 H, d), 4.49 (2 H, m), 4.21-4.31 (1
H, m), 4.11 (2 H, t), 2.92 (2 H, m). 94 (.sup.1H, CDCl.sub.3)
.delta. ppm: 8.89 (1 H, d), 8.66 (1 H, d), 7.88-7.96 (1 H, m),
7.77-7.84 (1 H, m), 7.58-7.64 (1 H, m), 7.49-7.54 (1 H, m),
7.39-7.45 (1 H, m), 6.44 (1 H, s), 4.53-4.63 (1 H, m), 4.23-4.34 (4
H, m), 3.94 (1 H, dt), 3.81-3.89 (1 H, m), 3.10 (2 H, t), 2.02-2.13
(1 H, m), 1.89-2.01 (2 H, m), 1.61-1.72 (1 H, m). 95 (.sup.1H,
CDCl.sub.3) .delta. ppm: 7.74-7.95 (3 H, m), 7.44-7.73 (4 H, m),
6.42 (1 H, br. s.), 4.55 (1 H, d), 4.17-4.35 (4 H, m), 3.76-3.98 (2
H, m), 3.01-3.15 (2 H, m), 2.01-2.12 (1 H, m), 1.94 (2 H, m),
1.57-1.72 (1 H, m). 96 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.75 (1
H, d), 7.56-7.65 (3 H, m), 7.44-7.53 (3 H, m), 7.37-7.44 (1 H, m),
6.41 (1 H, s), 4.53-4.61 (1 H, m), 4.20-4.33 (4 H, m), 3.89-3.97 (1
H, m), 3.81-3.88 (1 H, m), 3.07 (2 H, t), 2.01-2.11 (1 H, m),
1.87-2.00 (2 H, m), 1.60-1.71 (1 H, m). 97 (.sup.1H, CDCl.sub.3)
.delta. ppm: 8.94 (2H, br. s), 7.78-7.88 (2 H, m), 7.54-7.70 (4 H,
m), 7.23 (1 H, dd), 6.88 (1 H, dd), 6.42 (1 H, s), 4.69 (2 H, d),
4.51-4.61 (2 H, m), 4.33 (1 H, dd), 4.26 (2 H, t), 3.12 (2 H, t).
98 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.88-7.91 (1 H, m), 7.81-7.87
(3 H, m), 7.70 (1 H, dt), 7.57-7.63 (2 H, m), 7.52 (1 H, d), 7.24
(1 H, dd), 6.86-6.91 (1 H, m), 6.42 (1 H, s), 4.70 (2 H, d),
4.53-4.62 (2 H, m), 4.33 (1 H, dd), 4.24-4.29 (2 H, m), 3.11 (2 H,
t). 99 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.72 (1 H, d), 7.55 (1 H,
d), 7.46 (1 H, br. s.), 7.29-7.41 (2 H, m), 6.97-7.10 (2 H, m),
6.42 (1 H, br. s.), 4.57 (1 H, m), 4.19-4.34 (4 H, m), 3.94 (1 H,
m), 3.84 (4 H, m), 3.00-3.10 (2 H, m), 2.02-2.12 (1 H, m),
1.89-2.01 (2 H, m), 1.61-1.72 (1 H, m). 100 (.sup.1H, CDCl.sub.3)
.delta. ppm: 7.74 (1 H, d), 7.58 (1 H, dd), 7.49 (1 H, br. s),
7.35-7.41 (1 H, m) 7.19 (1 H, d), 7.11-7.14 (1 H, m), 6.94 (1 H,
dd), 6.40 (1 H, s), 4.51-4.60 (1 H, m), 4.20-4.33 (4 H, m),
3.89-3.97 (1 H, m), 3.79-3.88 (4 H, m), 3.06 (2 H, t), 2.01-2.11 (1
H, m), 1.87-2.00 (2 H, m), 1.60-1.70 (1 H, m). 101 (.sup.1H,
CDCl.sub.3) .delta. ppm: 7.73 (1 H, d), 7.54-7.60 (3 H, m), 7.47 (1
H, br. s), 7.01 (2 H, d) 6.41 (1 H, s), 4.53-4.61 (1 H, m),
4.20-4.33 (4 H, m), 3.90-3.98 (1 H, m), 3.81-3.89 (4 H, m), 3.06 (2
H, t), 2.01-2.12 (1 H, m), 1.88-2.01 (2 H, m), 1.61-1.71 (1 H, m).
102 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.76-7.85 (3 H, m),
7.71-7.76 (2 H, m), 7.62 (1 H, dd), 7.54 (1 H, s), 6.45 (1 H, s),
4.55-4.63 (1 H, m), 4.24-4.35 (4 H, m), 3.91-3.99 (1 H, m),
3.82-3.90 (1 H, m), 3.11 (2 H, t), 2.04-2.14 (1 H, m), 1.89-2.02 (2
H, m), 1.62-1.73 (1 H, m). 103 (.sup.1H, DMSO-d.sub.6) .delta. ppm:
8.27 (1 H, s), 8.13 (1 H, d), 8.00 (2 H, t), 7.79 (1 H, s), 7.74 (1
H, dd), 7.64 (1 H, t), 6.69 (1 H, s), 4.27-4.32 (1 H, m), 4.13-4.26
(2 H, m), 4.07 (2 H, t), 3.76-3.83 (1 H, m), 3.65-3.71 (1 H, m),
3.11 (2 H, t), 1.77-2.04 (3 H, m), 1.60-1.70 (1 H, m). 104
(.sup.1H, DMSO-d.sub.6) .delta. ppm: 8.11 (1 H, d), 8.00 (2 H, d),
7.80 (3 H, d), 7.75 (1 H, dd), 6.69 (1 H, s), 4.27-4.32 (1 H, m),
4.13-4.26 (2 H, m), 4.07 (2 H, m), 3.76-3.83 (1 H, m), 3.64-3.71 (1
H, m), 3.09 (2 H, t), 1.79-2.04 (3 H, m), 1.60-1.71 (1 H, m). 105
(.sup.1H, CDCl.sub.3) .delta. ppm: 7.70 (1 H, d), 7.52-7.59 (3 H,
m), 7.46 (1 H, d), 6.78-6.82 (2 H, m), 6.39 (1 H, s), 4.53-4.61 (1
H, m), 4.20-4.34 (4 H, m), 3.90-3.98 (1 H, m), 3.81-3.88 (1 H, m),
3.01-3.08 (8 H, m), 2.01-2.12 (1 H, m), 1.89-2.01 (2 H, m),
1.61-1.72 (1 H, m). 106 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.94 (2
H, d), 7.80 (1 H, d), 7.72 (2 H, d), 7.64 (1 H, dd), 7.56 (1 H, s),
6.44 (1 H, s), 6.18 (1H, br. s), 5.71 (1H, br. s), 4.54-4.63 (1 H,
m), 4.22-4.35 (4 H, m), 3.91-3.99 (1 H, m), 3.81-3.90 (1 H, m),
3.10 (2 H, t), 1.89-2.12 (3 H, m), 1.64-1.72 (1 H, m). 107
(.sup.1H, CDCl.sub.3) .delta. ppm 7.78-7.86 (2 H, m), 7.66-7.75 (1
H, m), 7.47-7.62 (4 H, m), 6.45 (1 H, s), 4.53-4.63 (1 H, m),
4.20-4.37 (4 H, m), 3.81-4.00 (2 H, m), 3.06-3.16 (2 H, m), 1.96 (3
H, m), 1.61-1.75 (1 H, m). 108 (.sup.1H, MeOD-d.sub.4) .delta. ppm
8.02 (1 H, s), 7.87 (1 H, s), 7.75 (1 H, d), 7.46-7.54 (2 H, m),
6.43-6.49 (1 H, m), 4.28-4.38 (1 H, m), 4.17-4.27 (2 H, m), 4.09 (2
H, t), 3.85-3.95 (4 H, m), 3.75-3.84 (1 H, m), 2.96-3.03 (2 H, m),
1.85-2.14 (3 H, m), 1.63-1.77 (1 H, m). 109 (.sup.1H, CDCl.sub.3)
.delta. ppm 7.75 (1 H, d), 7.55-7.68 (3 H, m), 7.38-7.54 (3 H, m),
6.40 (1 H, s), 4.49-4.60 (1 H, m), 4.15-4.34 (4 H, m), 3.77-3.96 (2
H, m), 2.94-3.20 (7 H, m), 1.83-2.13 (4 H, m), 1.58-1.72 (1 H, m).
110 .sup.1H NMR (MeOD-d.sub.4)) .delta. ppm 8.45-8.51 (1 H, m),
7.93-8.06 (2 H, m), 7.61-7.69 (2 H, m), 6.91 (1 H, d), 6.63 (1 H,
s), 4.37-4.46 (1 H, m), 4.23-4.35 (2 H, m), 4.15-4.24 (2 H, m),
3.76-4.01 (5 H, m), 3.13 (2 H, t), 1.84-2.17 (3 H, m), 1.67-1.84 (1
H, m) 111 (.sup.1H, CDCl.sub.3) .delta. ppm 7.76 (1 H, d),
7.07-7.23 (5 H, m), 6.43 (1 H, s), 4.58 (1 H, m), 4.30 (4 H, s),
3.80-3.99 (2 H, m), 3.00-3.10 (2 H, m), 1.86-2.15 (9 H, m),
1.60-1.73 (1 H, m). 112 (.sup.1H, CDCl.sub.3) .delta. ppm 7.77 (1
H, d), 7.27-7.31 (1 H, m), 7.18-7.22 (1 H, m), 6.42 (1 H, s),
4.55-4.63 (1 H, m), 4.20-4.35 (4 H, m), 3.81-3.99 (2 H, m), 3.07 (2
H, t), 2.46 (3 H, s), 2.32 (3 H, s), 1.89-2.14 (3 H, m), 1.60-1.74
(1 H, m). 113 (.sup.1H, CDCl.sub.3) .delta. ppm 7.43-8.14 (10 H,
m), 6.44 (1 H, s), 4.52-4.68 (1 H, m), 4.18-4.38 (4 H, m),
3.79-4.03 (2 H, m), 3.03-3.18 (2 H, m), 1.84-2.20 (3 H, m),
1.59-1.78 (1 H, m). 114 (.sup.1H, CDCl.sub.3) .delta. ppm 7.76-7.96
(4 H, m), 7.37-7.58 (6 H, m), 6.46 (1 H, s), 4.54-4.65 (1 H, m),
4.30 (4 H, s), 3.80-4.00 (2 H, m), 3.08 (2 H, t), 1.83-2.15 (3 H,
m), 1.59-1.75 (1 H, m). 115 (.sup.1H, CDCl.sub.3) .delta. ppm 9.27
(1 H, s), 9.00 (2 H, s), 7.84 (1 H, s), 7.59-7.65 (1 H, m),
7.51-7.55 (1 H, m), 6.45 (1 H, s), 4.54-4.63 (1 H, m), 4.21-4.34 (4
H, m), 3.80-3.98 (2 H, m), 3.08-3.17 (2 H, m), 1.85-2.13 (3 H, m),
1.61-1.72 (1 H, m). 116 (.sup.1H, CDCl.sub.3) .delta. ppm 7.70 (1
H, d), 7.52 (1 H, d), 7.42 (1 H, s), 7.20 (1 H, d), 6.95 (1 H, d),
6.39 (1 H, s), 4.52-4.63 (1 H, m), 4.19-4.35 (4 H, m), 3.79-4.00 (2
H, m), 3.05 (2 H, m), 1.90-2.12 (3 H, m), 1.60-1.72 (1 H, m).
117 (.sup.1H, CDCl.sub.3) .delta. ppm 7.66 (1 H, d), 7.33-7.39 (2
H, m), 7.27-7.30 (1 H, m), 6.39 (1 H, s), 6.22-6.29 (2 H, m),
4.50-4.61 (1 H, m), 4.16-4.34 (4 H, m), 3.77-3.97 (2 H, m), 3.01 (2
H, t), 1.91 (3 H, s), 1.58-1.73 (1 H, m), 1.42 (9 H, s). 118
(.sup.1H, CDCl.sub.3) .delta. ppm 8.45 (1 H, d), 7.76-7.88 (3 H,
m), 7.53-7.60 (1 H, m), 7.44-7.49 (1 H, m), 7.22-7.27 (1 H, m),
6.83-6.94 (2 H, m), 6.40 (1 H, s), 4.70 (2 H, d), 4.53-4.64 (2 H,
m), 4.31-4.39 (1 H, m), 4.23-4.31 (2 H, m), 4.01 (3 H, s),
3.07-3.14 (2 H, m). 119 (.sup.1H, CDCl.sub.3) .delta. ppm 7.57 (1
H, d), 7.32 (1 H, dd), 7.27 (1 H, s), 6.33 (1 H, s), 4.48-4.59 (1
H, m), 4.09-4.31 (4 H, m), 3.87-3.96 (1 H, m), 3.78-3.86 (1 H, m),
2.95 (2 H, t), 1.84-2.11 (3 H, m), 1.57-1.70 (1 H, m), 1.39-1.53 (1
H, m), 0.77-0.96 (4 H, m). 120 (.sup.1H, CDCl.sub.3) .delta. ppm
7.59 (1 H, d), 7.32-7.39 (1 H, m), 7.30 (1 H, s), 6.34 (1 H, s),
4.54 (1 H, m), 4.12-4.33 (4 H, m), 3.77-3.96 (2 H, m), 2.95 (2 H,
t), 1.84-2.13 (3 H, m), 1.57-1.72 (1 H, m), 1.32 (9 H, s). 121
(.sup.1H, CDCl.sub.3) .delta. ppm 7.64 (1 H, d), 7.48 (3 H, d),
7.42 (1 H, s), 6.89 (2 H, d), 6.37 (1 H, s), 4.54 (1 H, s), 4.27 (4
H, s), 3.87-3.97 (1 H, m), 3.83 (3 H, s), 2.94-3.05 (2 H, m),
1.82-2.12 (4 H, m), 1.57-1.72 (1 H, m) 122 (.sup.1H, CDCl.sub.3)
.delta. ppm 8.65 (2 H, d), 7.84 (1 H, dd), 7.68 (1 H, d), 7.36 (2
H, d), 7.24 (1 H, dd), 6.96 (1 H, dd), 6.84-6.92 (2 H, m), 6.27 (1
H, s), 5.17 (2 H, s), 4.67 (2 H, d), 4.50-4.61 (2 H, m), 4.28-4.37
(1 H, m), 4.16-4.25 (2 H, m), 2.99 (2 H, t). 123 (.sup.1H,
CDCl.sub.3) .delta. ppm 8.88 (2 H, d), 8.28-8.34 (1 H, m), 8.12 (1
H, d), 7.90 (1 H, d), 7.72 (1 H, s), 7.55 (2 H, s), 6.42 (1 H, s),
4.58 (1 H, d), 4.30 (4 H, s), 3.79-4.00 (2 H, m), 3.01-3.11 (2 H,
m), 1.88-2.14 (2 H, m), 1.63-1.75 (2 H, m) 124 (.sup.1H,
CDCl.sub.3) .delta. ppm: 8.93 (1H, s), 8.70 (1H, br.s), 7.96 (1H,
dd), 7.88-7.86 (2H, m), 7.65 (1H, d), 7.57 (1H, s), 7.48-7.45 (1H,
m), 7.28 (1H, dd), 6.93 (1H, dd), 6.45 (1H, s), 4.75-4.73 (2H, m),
4.65-4.58 (2H, m), 4.38 (1H, dd), 4.31 (2H, t), 3.15 (2H, t). 125
(.sup.1H, CDCl.sub.3) .delta. ppm: 7.90-7.88 (2H, d), 7.74 (1H,
dt), 7.65-7.54 (4H, m), 7.31-7.28 (1H, m), 6.94 (1H, dd), 6.47 (1H,
s), 4.74 (2H, d), 4.66-4.58 (2H, m), 4.39 (1H, dd), 4.32 (2H, t),
3.53 (1H, s), 3.16 (2H, t). 126 (.sup.1H, CDCl.sub.3) .delta. ppm:
7.87 (1H, dd), 7.77 (1H, d), 7.59 (1H, dd), 7.51 (1H, dd), 7.41
(1H, dt), 7.35 (1H, dd), 7.27 (1H, dd), 7.09 (1H, dd), 7.05 (1H,
d), 6.92 (1H, dd), 6.42 (1H, s), 7.73-7.72 (2H, m), 4.64-4.57 (2H,
m), 4.37 (1H, dd), 4.29 (2H, t), 3.87 (3H, s), 3.09 (2H, t). 127
(.sup.1H, CDCl.sub.3) .delta. ppm: 7.98 (1H, m), 7.83 (1H, t), 7.67
(1H, dd), 7.62 (1H, d), 7.54-7.44 (3H, m), 7.40 (1H, m), 7.08 (1H,
s), 7.06 (1H, dd), 6.72 (1H, dd), 6.23 (1H, s), 4.54-4.52 (2H, m),
4.45-4.35 (2H, m), 4.16 (1H, dd), 4.11 (2H, t), 2.93 (2H, t). 128
(.sup.1H, CDCl.sub.3) .delta. ppm: 9.30 (1H, s), 9.03 (2H, s),
7.93-7.90 (1H, m), 7.88 (1H, dd), 7.66 (1H, dd), 7.58 (1H, m), 7.28
(1H, dd), 6.93 (1H, dd), 6.46 (1H, s), 4.75-4.74 (2H, m), 4.66-4.57
(2H, m), 4.38 (1H, dd), 4.32 (2H, t), 3.17 (2H, t). 129 (.sup.1H,
CDCl.sub.3) .delta. ppm: 8.09 (1H, s), 7.79-7.70 (3H, m), 7.60-7.35
(4H, m), 7.19 (1H, d), 6.84 (1H, dd), 6.37 (1H, s), 4.61-4.59 (2H,
m), 4.51-4.48 (2H, m), 4.27 (1H, dd), 4.16 (2H, t), 3.02 (2H, t).
130 (1H, CDCl.sub.3) .delta. ppm: 7.87 (1H, dd), 7.77 (1H, d), 7.68
(1H, dd), 7.56 (1H, dd), 7.35 (1H, dt), 7.27 (1H, dd), 7.26 (1H,
t), 7.10 (1H, d), 7.07 (1H, dt), 6.92 (1H, dd), 6.43 (1H, s),
7.74-7.73 (2H, m), 4.65-4.57 (2H, m), 4.37 (1H, dd), 4.30 (2H, t),
3.09 (2H, t), 2.60 (6H, s). 131 (.sup.1H, CDCl.sub.3) .delta. ppm:
8.61-8.41 (2H, m), 7.63-7.61 (1H, m), 7.52 (1H, d), 7.50-7.42 (1H,
m), 7.36-7.32 (1H, dd), 7.12 (1H, m), 7.05 (1H, s), 7.03 (1H, dd),
6.68 (1H, dd), 6.17 (1H, s), 4.49-4.48 (2H, m), 4.41-4.32 (2H, m),
4.12 (1H, dd), 4.03 (2H, t), 2.83 (2H, t). 132 (.sup.1H,
CDCl.sub.3) .delta. ppm: 7.87 (1H, dd), 7.70 (1H, d), 7.48 (1H,
dd), 7.42 (1H, s), 7.26 (1H, dd), 6.92 (1H, dd), 6.38 (1H, s),
4.73-4.71 (2H, m), 4.63-4.56 (2H, m), 4.37 (3H, s), 4.24 (2H, t),
3.49 (3H, s), 3.03 (2H, t). 133 (.sup.1H, CDCl.sub.3) .delta. ppm:
7.86 (1H, dd), 7.66 (1H, d), 7.42 (1H, dd), 7.37 (1H, br.s), 7.26
(1H, dd), 6.91 (1H, dd), 6.36 (1H, s), 4.71-4.69 (2H, m), 4.62-4.55
(2H, m), 4.35 (1H, dd), 4.22 (2H, t), 3.88 (2H, t), 3.00 (2H, t),
2.75 (2H, t), 2.19 (1H, br.s). 134 (.sup.1H, CDCl.sub.3) .delta.
ppm: 8.17 (1 H, br. s), 7.84 (1 H, dd), 7.64 (1 H, d), 7.25 (1 H,
dd), 7.00 (1 H, dd), 6.94-6.84 (1 H, m), 6.22-6.29 (1 H, m),
6.09-6.14 (1 H, m), 5.07 (2 H, br. s), 4.63-4.70 (1 H, m),
4.50-4.60 (2 H, m), 4.32 (1 H, dd), 4.19 (2 H, t), 3.78 (3 H, s),
3.48 (1 H, s), 2.91-3.02 (2 H, m), 2.27 (3 H, s) 135 (.sup.1H,
CDCl.sub.3) .delta. ppm: 7.84 (1 H, dd), 7.71 (1 H, d), 7.25 (1 H,
dd), 7.01 (1 H, dd), 6.93-6.89 (2 H, m), 6.29 (1 H, s), 5.36 (2 H,
s), 4.70 (2 H, s), 4.0-4.54 (2 H, m), 4.32 (1 H, dd), 4.21 (2 H,
t), 3.03 (2 H, t), 2.46 (3 H, s) 136 (.sup.1H, CDCl.sub.3) .delta.
ppm: 7.82 (1 H, dd), 7.63 (1 H, d), 7.39 (1 H, d), 7.31-7.36 (1 H,
m), 7.22 (1 H, dd), 6.84-6.92 (1 H, m), 6.33 (1 H, br. s),
4.63-4.70 (2 H, m), 4.49-4.58 (1 H, m), 4.26-4.37 (1 H, m),
4.14-4.23 (2 H, m), 3.43-3.49 (1 H, m), 2.91-3.02 (1 H, m),
2.61-2.67 (1 H, m), 1.62 (6 H, s) 137 (.sup.1H, CDCl.sub.3) .delta.
ppm: 8.65 (1 H, br. s), 7.86 (1 H, dd), 7.75 (1 H, d), 7.57 (1 H,
d), 7.51 (1 H, br. s), 7.38-7.44 (2 H, m), 7.25 (2 H, dd), 6.91 (1
H, dd), 6.39 (1 H, s), 4.71 (2 H, d), 4.52-4.65 (2 H, m), 4.35 (1
H, dd), 4.25 (2 H, t), 3.00-3.11 (2 H, m) 138 (.sup.1H, CDCl.sub.3)
.delta. ppm 7.83 (1 H, dd), 7.63 (1 H, d), 7.37-7.43 (1 H, m), 7.35
(1 H, s), 7.23 (1 H, dd), 6.90 (1 H, dd), 6.33 (1 H, s), 4.65-4.70
(2 H, m), 4.50-4.61 (4 H, m), 4.32 (1 H, dd), 4.19 (2 H, t), 2.97
(2 H, t). 139 (.sup.1H, CDCl.sub.3) .delta. ppm 8.83 (1 H, d), 7.93
(1 H, s), 7.83 (2 H, m), 7.63 (1 H, m), 7.54 (1 H, s), 7.35 (1 H,
d), 7.27 (1 H, s), 6.92 (1 H, dd), 6.43 (1 H, s), 4.71 (2 H, d),
4.54-4.64 (2 H, m), 4.36 (1 H, dd), 4.28 (2 H, t), 3.12 (2 H, t),
2.67 (3 H, s). 140 (.sup.1H, CDCl.sub.3) .delta. ppm 8.36 (2 H, br.
d), 7.83 (2 H, m), 7.57-7.63 (1 H, m), 7.53 (1 H, s), 7.39 (1 H,
s), 7.24 (1 H, dd), 6.85-6.92 (1 H, m), 6.41 (1 H, s), 4.67-4.74 (2
H, m), 4.51-4.63 (2 H, m), 4.26 (3 H, m), 3.94 (3 H, s), 3.07-3.16
(2 H, m). 141 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.87 (1H, dd),
7.64 (1H, d), 7.38 (1H, dd), 7.33 (1H, br.s), 7.27 (1H, dd), 6.93
(1H, dd), 6.36 (1H, s), 4.71-4.70 (2H, m), 4.63-4.56 (2H, m), 4.35
(1H, dd), 4.23 (2H, t), 3.00 (2H, t), 1.54-1.47 (1H, m), 0.98-0.85
(4H, m). 142 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.87 (1H, dd), 7.68
(1H, d), 7.44 (1H, dd), 7.39 (1H, m), 7.27 (1H, dd), 6.92 (1H, dd),
6.37 (1H, s), 4.72-4.71 (2H, m), 4.63-4.56 (2H, m), 4.36 (1H, dd),
4.24 (2H, t), 3.02 (2H, t), 2.15-2.08 (5H, m), 1.96-179 (4H, m).
143 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.86 (1H, dd), 7.68 (1H, d),
7.44 (1H, dd), 7.39 (1H, br.s), 7.26 (1H, dd), 6.91 (1H, dd), 6.37
(1H, s), 4.72-4.70 (2H, m), 4.63-4.55 (2H, m), 4.35 (1H, dd), 4.23
(2H, t), 4.02 (2H, t), 2.85 (2H, t), 2.71 (2H, t). 144 (.sup.1H,
CDCl.sub.3) .delta. ppm: 7.86 (1H, dd), 7.65 (1H, d), 7.40 (1H,
dd), 7.35 (1H, m), 7.26 (1H, dd), 6.91 (1H, dd), 6.36 (1H, s),
4.71-4.70 (2H, m), 4.62-4.55 (2H, m), 4.35 (1H, dd), 4.22 (2H, t),
3.00 (2H, t), 1.35 (9H, s). 145 (.sup.1H, CDCl.sub.3) .delta. ppm:
8.15 (1H, dd), 7.77 (1H, d), 7.70 (1H, d), 7.56 (1H, dd), 7.53-7.51
(1H, m), 7.45 (1H, s), 7.18 (1H, d), 6.95 (1H, dd), 6.83 (1H, dd),
6.33 (1H, s), 4.64-4.63 (2H, m), 4.55-4.48 (2H, m), 4.27 (1H, dd),
4.19 (2H, t), 3.93 (3H, s), 3.01 (2H, t). 146 (.sup.1H, CDCl.sub.3)
.delta. ppm: 7.78 (1H, dt), 7.66 (1H, d), 7.45-7.30 (2H, m), 7.25
(1H, d), 7.19 (1H, dd), 6.84 (1H, dd), 6.30 (1H, s), 4.64-4.62 (2H,
m), 4.55-4.47 (2H, m), 4.27 (1H, dd), 4.16 (2H, t), 2.96 (2H, t).
147 (.sup.1H, CDCl.sub.3) .delta. ppm: 8.83 (1H, d), 8.34 (1H, dd),
8.10 (1H, dd), 8.06 (1H, d), 7.090-7.86 (2H, m), 6.67 (1H, dd),
7.60 (1H, d), 7.27 (1H, dd), 6.93 (1H, dd), 6.45 (1H, s), 4.74-4.73
(2H, m), 4.65-4.57 (2H, m), 4.37 (1H, dd), 3.31 (2H, t), 3.16 (2H,
t), 3.10 (3H, d). 148 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.88-7.87
(2H, m), 7.75 (1H, d), 7.56 (1H, t), 7.53 (1H, dd), 7.45 (H, br.s),
7.28 (1H, dd), 6.99 (1H, dd), 6.77 (1H, m), 6.39 (1H, s), 4.73-4.72
(2H, m), 4.64-4.58 (2H, m), 4.37 (1H, dd), 4.27 (2H, t), 3.08 (2H,
t). 149 ((.sup.1H, CDCl.sub.3) .delta. ppm: 7.86 (1H, dd), 7.85
(1H, s), 7.74-7.72 (2H, m), 7.50 (1H, dd), 7.42 (1H, d), 7.26 (1H,
dd), 6.92 (1H, dd), 6.37 (1H, s), 4.72-4.71 (2H, m), 4.63-4.56 (2H,
m), 4.36 (1H, dd), 4.26 (2H, t), 4.00 (3H, s), 3.06 (2H, t). 150
(.sup.1H, CDCl.sub.3) .delta. ppm: 7.81-7.89 (1 H, m), 7.64-7.72 (1
H, m), 7.29-7.42 (1 H, m), 7.24 (1 H, dd), 6.90 (1 H, dd), 6.35 (1
H, s), 4.70 (1 H, d), 4.50-4.63 (1 H, m), 4.28-4.40 (1 H, m), 4.22
(1 H, t), 3.74 (4 H, br. s), 3.55 (1 H, br. s), 3.03 (1 H, t), 2.48
(4 H, br. s) 151 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.80-7.89 (1 H,
m), 7.53 (1 H, d), 7.22-7.25 (1 H, m), 6.90 (1 H, dd), 6.63 (1 H,
dd), 6.52 (1 H, d), 6.20 (1 H, s), 4.64-4.74 (3 H, m), 4.49-4.61 (3
H, m), 4.29-4.38 (1 H, m), 4.14-4.25 (3 H, m), 2.91 (2 H, t) 152
(.sup.1H, CDCl.sub.3) .delta. ppm: 7.80-7.88 (2 H, m), 7.63-7.73 (2
H, m), 7.24 (1 H, dd), 6.91 (1 H, dd), 6.41 (1 H, s), 4.71 (2 H,
d), 4.51-4.64 (2 H, m), 4.29-4.39 (1 H, m), 4.20-4.29 (2 H, m),
3.04-3.14 (2 H, m) 153 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.85 (1
H, dd), 7.66 (1 H, s), 7.55 (1 H, d), 7.22-7.26 (1 H, m), 7.12 (1
H, s), 6.89 (1 H, dd), 6.67 (1 H, dd), 6.54 (1 H, d), 6.20 (1 H,
s), 4.65-4.71 (2 H, m), 4.50-4.61 (4 H, m), 4.28-4.40 (1 H, m),
4.20 (2 H, t), 2.94 (2 H, t) 154 (.sup.1H, CDCl.sub.3) .delta. ppm:
7.80-7.87 (1 H, m), 7.67 (1 H, d), 7.24 (1 H, dd), 7.02 (1 H, dd),
6.83-6.95 (2 H, m), 6.27 (1 H, s), 5.23 (2 H, br. s), 4.68 (2 H,
d), 4.50-4.61 (2 H, m), 4.27-4.38 (1 H, m), 4.21 (2 H, t), 2.99 (2
H, t), 2.59-2.68 (3 H, m) 155 (.sup.1H, CDCl.sub.3) .delta. ppm:
7.84 (1 H, dd), 7.67 (1 H, d), 7.24 (1 H, dd), 7.03 (1 H, dd),
6.85-6.96 (2 H, m), 6.27 (1 H, s), 5.23 (2 H, s), 4.68 (2 H, m),
4.50-4.61 (2 H, m), 4.32 (1 H, dd), 4.21 (2 H, t), 2.89-3.05 (4 H,
m), 1.40 (3 H, t) 156 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.79-7.87
(1 H, m), 7.65 (1 H, d), 7.24 (1 H, dd), 7.01 (1 H, dd), 6.82-6.95
(2 H, m), 6.27 (1 H, s), 5.18 (2 H, s), 4.64-4.72 (2 H, m),
4.49-4.61 (2 H, m), 4.28-4.38 (1 H, m), 4.21 (2 H, t), 2.99 (2 H,
t), 2.15-2.30 (1 H, m), 1.16-1.31 (4 H, m) 157 (.sup.1H,
CDCl.sub.3) .delta. ppm: 7.77-7.87 (1 H, m), 7.68 (1 H, d), 7.23 (1
H, dd), 7.02 (1 H, dd), 6.92-6.95 (1 H, m), 6.86-6.91 (1 H, m),
6.26 (1 H, s), 5.23 (2 H, s), 4.63-4.72 (2 H, m), 4.50-4.61 (2 H,
m), 4.32 (1 H, dd), 4.21 (2 H, t), 3.25 (1 H, spt), 2.99 (2 H, t),
1.43 (6 H, d) 158 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.79-7.87 (1
H, m), 7.67 (1 H, d), 7.24 (1 H, dd), 7.03 (1 H, dd), 6.94 (1 H,
d), 6.89 (1 H, dd), 6.27 (1 H, s), 5.22 (2 H, s), 4.64-4.71 (2 H,
m), 4.47-4.60 (2 H, m), 4.32 (1 H, dd), 4.20 (2 H, t), 3.00 (2 H,
t), 1.44 (9
H, s) 159 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.84 (1 H, dd), 7.68
(1 H, d), 7.24 (1 H, dd), 6.96 (1 H, dd), 6.82-6.92 (2 H, m), 6.27
(1 H, s), 6.20 (1 H, s), 5.19 (2 H, s), 4.64-4.73 (2 H, m),
4.48-4.62 (2 H, m), 4.33 (1 H, dd), 4.19 (1 H, t), 3.00 (2 H, t),
2.31 (3 H, s) 160 (.sup.1H, CDCl.sub.3) .delta. ppm: 8.09 (1 H, d),
7.75-7.88 (2 H, m), 7.45-7.53 (1 H, m), 7.40 (1 H, br. s),
7.20-7.26 (1 H, m), 6.84-6.93 (2 H, m), 6.42 (1 H, s), 4.71 (2 H,
m), 4.50-4.65 (2 H, m), 4.31-4.37 (1 H, m), 4.28 (2 H, t), 4.08 (3
H, s), 3.10 (2 H, t) 161 (.sup.1H, CDCl.sub.3) .delta. ppm:
7.78-7.88 (1 H, m), 7.68 (1 H, d), 7.38-7.46 (1 H, m), 7.32 (1 H,
br. s), 7.24 (1 H, dd), 6.89 (1 H, dd), 6.35 (1 H, s), 6.29 (1 H,
br. s.), 4.69 (2 H, m), 4.50-4.63 (2 H, m), 4.29-4.40 (3 H, m),
4.23 (2 H, t), 3.95 (2 H, t), 3.04 (2 H, m), 2.54 (2 H, m) 162
(.sup.1H, CDCl.sub.3) .delta. ppm: 9.01 (1H, d), 8.09 (1H, dd),
7.92 (1H, dd), 7.88-7.85 (2H, m), 7.67 (1H, dd), 7.60 (1H, d), 7.27
(1h, dd), 6.93 (1h, dd), 6.47 (1H, s), 4.74-4.73 (2H, m), 4.65-4.57
(2H, m), 3.37 (1H, dd), 3.34 (2H, t), 3.17 (2H, t). 163 (.sup.1H,
CDCl.sub.3) .delta. ppm: 8.22 (1H, dd), 7.87 (1H, dd), 7.80 (1H,
d), 7.67 (2H, dt), 7.57 (1H, d), 7.27 (1H, dd), 7.02 (1H, dd), 6.93
(1H, dd), 6.44 (1H, s), 4.74-4.73 (2H, m), 4.65-4.57 (2H, m), 4.49
(2H, q), 4.37 (1H, dd), 3.30 (2H, t), 3.11 (2H, t), 1.42 (3H, t).
164 (.sup.1H, CDCl.sub.3) .delta. ppm: 8.45 (1H, d), 7.88-7.81 (3H,
m), 7.58 (1H, dd), 7.50 (1H, dd), 7.28 (1H, dd), 6.93 (1H, dd),
6.86 (1H, d), 6.42 (1H, s), 4.74-4.73 (2H, m), 4.65-4.57 (2H, m),
4.45 (2H, q), 4.37 (1H, dd), 3.30 (2H, t), 3.12 (2H, t), 1.46 (3H,
t). 165 (.sup.1H, CDCl.sub.3) .delta. ppm: 8.50 (1 H, d), 7.84 (1
H, dd), 7.74-7.80 (2 H, m), 7.55 (1 H, dd), 7.46 (1 H, d), 7.24 (1
H, dd), 6.89 (1 H, dd), 6.73 (1 H, d), 6.38 (1 H, s), 4.70 (2 H,
d), 4.52-4.63 (2 H, m), 4.34 (1 H, dd), 4.26 (2 H, t), 3.80-3.89 (4
H, m), 3.54-3.64 (4 H, m), 3.08 (2 H, t) 166 (.sup.1H, CDCl.sub.3)
.delta. ppm: 8.77 (2 H, s), 7.84 (2 H, m), 7.52-7.60 (1 H, m), 7.48
(1 H, s), 7.20-7.26 (1 H, m), 6.88 (1 H, dd), 6.41 (1 H, s),
4.66-4.74 (2 H, m), 4.51-4.63 (2 H, m), 4.34 (1 H, dd), 4.27 (2 H,
t), 4.05-4.12 (3 H, m), 3.11 (2 H, t) 167 (.sup.1H, CDCl.sub.3)
.delta. ppm: 7.84 (1 H, dd), 7.76 (1 H, d), 7.59 (1 H, dd),
7.47-7.52 (1 H, m), 7.25 (1 H, dd), 7.10-7.18 (1 H, m), 6.96 (2 H,
m), 6.90 (1 H, dd), 6.41 (1 H, s), 4.71 (2 H, d), 4.51-4.64 (2 H,
m), 4.30-4.39 (1 H, m), 4.26 (2 H, t), 3.93 (3 H, s), 3.64 (3 H,
s), 3.07 (2 H, t) 168 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.84 (1 H,
dd), 7.75 (1 H, d), 7.56 (1 H, dd), 7.45-7.51 (1 H, m), 7.25 (1 H,
dd), 6.85-6.99 (4 H, m), 6.39 (1 H, s), 4.68-4.72 (2 H, m),
4.51-4.63 (2 H, m), 4.30-4.39 (1 H, m), 4.21-4.29 (2 H, m), 3.82 (3
H, s), 3.79 (3 H, s), 3.07 (2 H, t) 169 (.sup.1H, CDCl.sub.3)
.delta. ppm: 8.02 (2 H, d), 7.80-7.87 (1 H, m), 7.77 (1 H, t),
7.47-7.70 (5 H, m), 7.20-7.26 (1 H, m), 6.89 (1 H, dd), 6.40 (1 H,
s), 4.65-4.73 (2 H, m), 4.51-4.62 (2 H, m), 4.33 (1 H, dd),
4.18-4.28 (2 H, m), 4.01 (2 H, m), 3.02-3.12 (2 H, m) 170 (.sup.1H,
CDCl.sub.3) .delta. ppm: 7.76-7.93 (1 H, m), 7.68 (1 H, d), 7.46 (1
H, dd), 7.40 (1 H, s), 7.24 (1 H, d), 6.90 (1 H, br. s.), 6.36 (1
H, s), 4.69 (2 H, d), 4.51-4.62 (2 H, m), 4.47 (2 H, s), 4.28-4.38
(1 H, m), 4.21 (2 H, t), 3.83 (2 H, t), 3.01 (2 H, t), 2.64-2.73 (2
H, m) 171 (.sup.1H, CDCl.sub.3) .delta. ppm: 8.43 (1 H, br. s),
7.85 (1 H, dd), 7.66 (1 H, d), 7.43 (2 H, dd), 7.19-7.26 (1 H, m),
6.84-6.94 (1 H, m), 6.35 (1 H, br. s), 4.70 (2 H, d), 4.50-4.63 (2
H, m), 4.29-4.38 (1 H, m), 4.15-4.27 (2 H, m), 3.65-3.71 (1 H, m),
2.97-3.04 (3 H, m), 2.62 (1 H, s), 2.58 (2 H, s) 172 (.sup.1H,
CDCl.sub.3) .delta. ppm: 7.78-7.89 (1 H, m), 7.66 (1 H, d), 7.44 (1
H, d), 7.39 (1 H, s), 7.23 (1 H, dd), 6.84-6.93 (1 H, m), 6.35 (1
H, s), 4.68 (2 H, m), 4.50-4.62 (2 H, m), 4.28-4.37 (1 H, m), 4.19
(2 H, t), 3.64 (2 H, s), 3.00 (2 H, t), 2.50 (6 H, br. s) 173
(.sup.1H, CDCl.sub.3) .delta. ppm: 7.78-7.86 (1 H, m), 7.65-7.73 (1
H, m), 7.48 (1 H, dd), 7.31-7.45 (5 H, m), 7.24 (1 H, dd), 6.89 (1
H, dd), 6.38 (1 H, s), 4.66 (2 H, m), 4.53 (2 H, dd), 4.31 (1 H,
dd), 4.21 (2 H, t), 3.94 (2 H, s), 3.77 (2 H, s), 3.02 (2 H, t),
2.60 (3 H, s) 174 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.78-7.90 (1
H, m), 7.66 (1 H, d), 7.42 (1 H, dd), 7.37 (1 H, br. s), 7.23 (1 H,
dd), 6.83-6.94 (1 H, m), 6.36 (1 H, s), 4.64-4.71 (2 H, m),
4.48-4.61 (2 H, m), 4.28-4.37 (1 H, m), 4.20 (2 H, t), 3.69 (2 H,
s), 3.47 (2 H, s), 3.15 (6 H, s), 3.01 (2 H, t) 175 (.sup.1H,
MeOD-d.sub.4) .delta. ppm: 8.20 (1 H, br. s), 8.07 (1 H, d),
7.79-7.85 (1 H, m), 7.74-7.78 (2 H, m), 7.63-7.71 (1 H, m),
7.51-7.60 (1 H, m), 7.39-7.47 (1 H, m), 7.28-7.37 (1 H, m), 7.18 (1
H, d), 7.10-7.14 (2 H, m), 7.03 (1 H, dd), 6.81 (1 H, s), 6.65-6.73
(1 H, m), 6.11-6.20 (1 H, m), 5.03-5.12 (2 H, m), 4.91-5.03 (2 H,
m), 4.70-4.80 (1 H, m), 4.59 (4 H, s), 4.41-4.47 (2 H, m),
4.26-4.38 (2 H, m), 4.06-4.19 (1 H, m), 3.89-3.95 (2 H, m),
3.76-3.81 (1 H, m), 3.34-3.46 (2 H, m), 3.11-3.17 (1 H, m),
2.70-2.84 (2 H, m) 176 (.sup.1H, MeOD-d.sub.4) .delta. ppm:
7.00-7.08 (1 H, m), 6.88-6.97 (1 H, m), 6.61-6.72 (2 H, m), 6.49 (1
H, dd), 6.16 (1 H, dd), 5.65 (1 H, s), 3.89-3.95 (2 H, m),
3.76-3.86 (2 H, m), 3.69 (2 H, s), 3.53-3.63 (1 H, m), 3.38-3.48 (2
H, m), 3.27-3.34 (1 H, m), 2.63 (1 H, dt), 2.23-2.28 (2 H, m) 177
(.sup.1H, CDCl.sub.3) .delta. ppm: 7.78-7.85 (1 H, m), 7.63 (1 H,
d), 7.38-7.43 (1 H, m), 7.31-7.36 (1 H, m), 7.21 (1 H, dd), 6.86 (1
H, dd), 6.33 (1 H, s), 4.67 (2 H, d), 4.49-4.61 (2 H, m), 4.27-4.37
(1 H, m), 4.19 (2 H, t), 3.62-3.69 (2 H, m), 2.97 (2 H, t), 2.62 (4
H, q), 1.11 (6 H, t) 178 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.83 (1
H, br. s.), 7.51-7.66 (1 H, m), 7.36 (2 H, br. s), 7.18-7.25 (1 H,
m), 6.89 (1 H, br. s.), 6.44-6.69 (1 H, m), 6.32 (1 H, s),
5.26-5.33 (1 H, m), 4.71-4.63 (2 H, m), 4.47-4.60 (2 H, m),
4.25-4.39 (1 H, m), 4.07-4.22 (2 H, m), 2.89-2.99 (2 H, m), 1.67 (6
H, br. s) 179 (.sup.1H, CDCl.sub.3) .delta. ppm: 7.81-7.88 (1 H,
m), 7.68-7.74 (1 H, m), 7.65 (1 H, d), 7.49-7.57 (1 H, m), 7.25 (1
H, dd), 6.86-6.97 (2 H, m), 6.80-6.85 (1 H, m), 6.26 (1 H, s), 5.31
(2 H, s), 4.63-4.71 (2 H, m), 4.52-4.62 (2 H, m), 4.28-4.38 (1 H,
m), 4.16-4.25 (3 H, m), 4.00-4.12 (2 H, m), 3.91-3.99 (1 H, m),
3.68-3.79 (1 H, m), 3.46-3.58 (1 H, m), 2.98 (2 H, t) 180 .sup.1H,
MeOD-d.sub.4) .delta. ppm: 8.51 (1 H, br. s.), 8.45-8.53 (1 H, m),
8.39-8.45 (1 H, m), 8.20-8.26 (1 H, m), 8.12-8.17 (1 H, m), 8.01 (4
H, s), 7.92-7.99 (1 H, m), 7.81-7.87 (1 H, m), 7.72-7.80 (1 H, m),
7.54-7.65 (2 H, m), 7.46-7.53 (1 H, m), 7.36 (4 H, s), 7.06-7.12 (1
H, m), 6.96 (1 H, dd), 6.89-7.00 (1 H, m), 6.44 (1 H, s), 6.38-6.50
(1 H, m), 5.23-5.41 (3 H, m), 4.98-5.09 (1 H, m), 4.85-4.95 (1 H,
m), 4.73 (2 H, m), 4.62 (2 H, d), 4.33-4.44 (1 H, m), 4.26 (2 H,
br. s.), 4.07 (1 H, br. s.), 3.96 (25 H, br. s.), 3.70-3.81 (2 H,
m), 3.42 (1 H, br. s.), 3.10 (1 H, br. s.), 2.71 (2 H, s),
2.63-2.77 (1 H, m), 2.07 (1 H, br. s.), 2.06 (6 H, s) 181 (.sup.1H
DMSO-d.sub.6) .delta. ppm 8.02 (1 H, d), 7.77 (1 H, d), 7.47 (1 H,
s), 7.32-7.45 (2 H, m), 6.92-7.04 (1 H, m), 6.73 (1 H, s), 5.56 (1
H, d), 4.45-4.70 (5 H, m), 4.25-4.37 (1 H, m), 4.03 (2 H, t), 3.00
(2 H, t), 1.40 (3 H, m). 182 (.sup.1H DMSO-d.sub.6) .delta. ppm
8.02 (1 H, d), 7.77 (1 H, d), 7.47 (1 H, s), 7.32-7.45 (2 H, m),
6.92-7.04 (1 H, m), 6.73 (1 H, s), 5.54 (1 H, d), 4.45-4.70 (4 H,
m), 4.35-4.43 (1 H, m), 4.25-4.34 (1 H, m), 4.03 (2 H, t), 3.01 (2
H, t), 1.60-1.75 (2 H, m), 1.00 (3 H, m). 183 (.sup.1H
DMSO-d.sub.6) .delta. ppm 8.02 (1 H, d), 7.77 (1 H, d), 7.47 (1 H,
s), 7.32-7.45 (2 H, m), 6.92-7.04 (1 H, m), 6.73 (1 H, s), 5.54 (1
H, d), 4.41-4.70 (5 H, m), 4.25-4.35 (1 H, m), 4.02 (2 H, t), 3.01
(2 H, t), 1.55-1.72 (2 H, m), 1.38-1.53 (2 H, m), 0.92 (3 H, m).
184 (.sup.1H DMSO-d.sub.6) .delta. ppm 8.02 (1 H, d), 7.77 (1 H,
d), 7.47 (1 H, s), 7.32-7.45 (2 H, m), 6.92-7.04 (1 H, m), 6.73 (1
H, s), 4.48-4.70 (4 H, m), 4.25-4.35 (1 H, m), 4.02 (2 H, t), 3.01
(2 H, t), 2.05-2.42 (2 H, br. s), 1.75-1.90 (2 H, m), 1.30-1.70 (7
H, m), 1.10-1.28 (1 H, m). 185 (.sup.1H DMSO-d.sub.6) .delta. ppm
8.02 (1 H, d), 7.77 (1 H, d), 7.47 (1 H, s), 7.32-7.45 (2 H, m),
6.92-7.04 (1 H, m), 6.73 (1 H, s), 5.54 (1 H, d), 4.45-4.70 (5 H,
m), 4.25-4.35 (1 H, m), 4.02 (2 H, t), 3.01 (2 H, t), 1.75-1.80 (1
H, m), 1.45-1.65 (2 H, m), 0.92 (6 H, m). 186 (.sup.1H
DMSO-d.sub.6) .delta. ppm 8.02 (1 H, d), 7.77 (1 H, d), 7.47 (1 H,
s), 7.32-7.45 (2 H, m), 6.92-7.04 (1 H, m), 6.73 (1 H, s), 5.28 (1
H, s), 4.45-4.70 (4 H, m), 4.25-4.35 (1 H, m), 4.02 (2 H, t), 3.01
(2 H, t), 1.55-1.75 (4 H, m), 1.00 (6 H, m). 187 (.sup.1H
DMSO-d.sub.6) .delta. ppm 8.03 (1 H, d), 7.77 (1 H, m), 7.65 (2 H,
m), 7.52 (1 H, s), 7.43-7.47 (1 H, m), 7.34-7.41 (3 H, m),
7.25-7.32 (1 H, m), 6.94-7.01 (1 H, m), 6.74 (1 H, s), 6.32 (1 H,
s), 4.48-4.70 (4 H, m), 4.25-4.35 (1 H, m), 4.02 (2 H, t), 3.01 (2
H, t), 1.72 (6 H, m). 188 (.sup.1H DMSO-d.sub.6) .delta. ppm 8.02
(1 H, d), 7.77 (1 H, d), 7.47 (1 H, s), 7.32-7.45 (2 H, m),
6.92-7.04 (1 H, m), 6.73 (1 H, s), 5.56 (1 H, d), 4.45-4.70 (5 H,
m), 4.25-4.37 (1 H, m), 4.03 (2 H, t), 3.00 (2 H, t), 1.75-1.92 (1
H, m), 0.95-1.05 (6 H, m). 189 (.sup.1H, CDCl.sub.3) .delta. ppm
7.84 (1 H, dd), 7.72 (1 H, d), 7.67 (1 H, d), 7.24 (1 H, dd), 7.18
(1 H, d), 7.03 (1 H, dd), 6.94 (1 H, d), 6.89 (1 H, dd), 6.26 (1 H,
s), 5.23 (2 H, s), 4.66-4.70 (2 H, m), 4.52-4.61 (2 H, m), 4.32 (1
H, dd), 4.17-4.24 (2 H, m), 2.99 (2 H, t). 190 (.sup.1H,
CDCl.sub.3) .delta. ppm: 7.85 (1H, dd), 7.74 (1H, d), 7.69 (1H, d),
7.25 (1H, dd), 7.20-7.19 (1H, m), 7.04 (1H, dd), 6.96 (1H, d), 6.90
(1H, dd), 6.28 (1H, s), 5.25 (2H, s), 4.70-4.69 (2H, m), 4.61-4.54
(2H, m), 4.34 (1H, dd), 4.22 (2H, t), 3.01 (2H, t). 191 (.sup.1H
DMSO-d.sub.6) .delta. ppm 8.00 (1 H, d), 7.77 (1 H, m), 7.32-7.55
(3 H, m), 6.92-7.04 (1 H, m), 6.72 (1 H, s), 4.45-4.72 (4 H, m),
4.25-4.40 (1 H, m), 4.02 (2 H, m), 3.57 (2 H, s), 3.00 (2 H, m),
2.50-2.70 (2 H, m), 1.85-2.10 (1 H, br. s), 1.15-1.53 (4 H, m),
0.88 (3 H, m). 192 (.sup.1H, CDCl.sub.3) .delta. ppm 7.83 (1 H,
dd), 7.69 (1 H, d), 7.33-7.37 (1 H, m), 7.29 (1 H, br. s), 7.22 (1
H, dd), 6.89 (1 H, dd), 6.35 (1 H, s), 4.66-4.70 (2 H, m),
4.50-4.62 (5 H, m), 4.32 (1 H, dd), 4.18-4.24 (2 H, m), 3.73 (4 H,
t), 3.65 (2 H, t), 3.02 (2 H, t), 2.66 (2 H, t), 2.49-2.58 (3 H,
m). 193 (.sup.1H DMSO-d.sub.6) .delta. ppm 8.01 (1 H, d), 7.77 (1
H, m), 7.18-7.51 (9 H, m), 6.97 (1 H, m), 6.72 (1 H, s), 4.45-4.70
(4 H, m), 4.25-4.35 (1 H, m), 4.05 (2 H, m), 3.81 (2 H, s), 3.56 (2
H, s), 2.92-3.10 (2 H, m). 194 (.sup.1H DMSO-d.sub.6) .delta. ppm
7.98 (1 H, d), 7.77 (1 H, m), 7.42 (1 H, s), 7.35 (2 H, m),
7.10-7.20 (2 H, m), 6.90-7.02 (1 H, m), 6.65-6.75 (3 H, m),
6.55-6.65 (1
H, m), 6.11 (1 H, s), 4.45-4.70 (4 H, m), 4.25-4.35 (1 H, m), 4.15
(2 H, d), 4.00 (2 H, m), 3.00 (2 H, t). 195 (.sup.1H, CDCl.sub.3)
.delta. ppm 7.85 (1 H, d), 7.70-7.82 (3 H, m), 7.20-7.25 (1 H, m),
6.85-6.92 (1 H, m), 6.41 (1 H, s), 6.11 (1 H, d), 4.70 (2 H, d),
4.50-4.62 (2 H, m), 4.31-4.40 (1 H, m), 4.15-4.30 (3 H, m), 4.00 (2
H, m), 3.45-3.62 (2 H, m), 3.05 (2 H, m), 1.95-2.10 (2 H, m),
1.55-1.65 (2 H, m). 196 (.sup.1H, CDCl.sub.3) .delta. ppm 7.70-7.90
(4 H, m), 7.22 (1 H, m), 6.90 (1 H, m), 6.45 (1 H, m), 6.41 (1 H,
s), 4.82-4.95 (2 H, m), 4.70 (2 H, m), 4.45-4.62 (4 H, m),
4.28-4.40 (1 H, m), 4.15-4.30 (2 H, m), 3.78 (2 H, m), 3.25-3.40 (1
H, m), 3.02-3.15 (2 H, m). 197 (.sup.1H, CDCl.sub.3) .delta. ppm
7.84 (1 H, dd), 7.66 (1 H, d), 7.35 (1 H, m), 7.31 (1 H, s), 7.23
(1 H, dd), 6.89 (1 H, dd), 6.35 (1 H, s), 4.68 (2 H, d), 4.52-4.61
(2 H, m), 4.33 (1 H, dd), 4.18-4.25 (2 H, m), 3.66 (2 H, s), 3.01
(2 H, t), 2.49-2.57 (4 H, m), 1.81 (4 H, m). 198 (.sup.1H,
CDCl.sub.3) .delta. ppm 7.84 (1 H, dd), 7.66 (1 H, d), 7.33-7.41 (2
H, m), 7.24 (1 H, dd), 6.89 (1 H, dd), 6.34 (1 H, s), 4.69 (2 H,
d), 4.52-4.62 (2 H, m), 4.33 (1 H, dd), 4.20 (2 H, t), 3.81 (2 H,
s), 2.98-3.04 (2 H, m), 1.20 (9 H, s). 199 (.sup.1H, CDCl.sub.3)
.delta. ppm 7.85 (1 H, dd), 7.68 (1 H, d), 7.32-7.42 (2 H, m), 7.25
(1 H, dd), 6.90 (1 H, dd), 6.35 (1 H, s), 4.70 (2 H, d), 4.53-4.63
(2 H, m), 4.34 (1 H, dd), 4.19-4.26 (2 H, t) 3.60 (2 H, s),
2.99-3.06 (2 H, t), 2.44-2.55 (4 H, m), 1.66 (4 H, m), 1.49 (2 H,
m). 200 (.sup.1H, CDCl.sub.3) .delta. ppm 7.84 (1 H, m), 7.71 (1 H,
d), 7.36 (1 H, d), 7.30 (1 H, s), 7.24 (1 H, m), 6.89 (1 H, dd),
6.36 (1 H, s), 4.69 (2 H, d), 4.51-4.65 (6 H, m), 4.40 (2 H, d),
4.32 (1 H, dd), 4.23 (2 H, t), 3.59 (2 H, s), 3.00-3.07 (2 H, m),
1.36 (3 H, s). 201 (.sup.1H, CDCl.sub.3) .delta. ppm 7.85 (1 H, m),
7.67 (1 H, d), 7.38-7.47 (2 H, m), 7.21-7.25 (1 H, m), 6.89 (1 H,
m), 6.36 (1 H, s), 4.89 (2 H, d), 4.69 (2 H, m), 4.52-4.64 (4 H,
m), 4.30-4.37 (1 H, m), 4.19-4.25 (2 H, m), 3.00 (2 H, m),
2.75-2.83 (2 H, m), 1.17-1.26 (3 H, m). 202 (.sup.1H, CDCl.sub.3)
.delta. ppm 7.84 (1 H, dd), 7.71 (1 H, d), 7.29-7.39 (2 H, m), 7.24
(1 H, dd), 6.89 (1 H, dd), 6.36 (1 H, s), 4.74-4.83 (2 H, m),
4.63-4.72 (5 H, m), 4.51-4.62 (2 H, m), 4.49 (2 H, s), 4.32 (1 H,
dd), 4.18-4.26 (2 H, m), 3.03 (2 H, t). 203 (.sup.1H, CDCl.sub.3)
.delta. ppm 7.60 (1 H, d), 7.35 (1 H, d), 7.30 (1 H, s), 6.35 (1 H,
s), 4.78-4.90 (1 H, m), 4.60 (2 H, m), 4.40-4.28 (1 H, m),
4.25-4.15 (2 H, m), 3.00-2.85 (2 H, m), 2.50-2.35 (2 H, m),
2.00-1.85 (1 H, m), 1.50-1.38 (1 H, m), 1.00-0.80 (10 H, m) 204
(.sup.1H, CDCl.sub.3) .delta. ppm 7.65 (1 H, d), 7.38 (1 H, d),
7.30 (1 H, s), 6.33 (1 H, s), 5.05-4.90 (1 H, m), 4.60-4.40 (2 H,
m), 4.40-4.25 (1 H, m), 4.25-4.15 (2 H, m), 3.05-2.90 (2 H, m),
2.60-2.55 (1 H, m), 2.22-2.10 (1 H, m), 1.95-1.75 (1 H, m),
1.55-1.40 (1 H, m), 1.00-0.80 (10 H, m)
Biological Examples
1. In Vitro Assays
[1218] 1.1. Cell Based Assay: GTp-.gamma.S Binding Assay.
[1219] The following assay can be used for determination of GPR84
activation. The [.sup.35S]GTP.gamma.S binding assay measures the
level of G protein activation following agonist occupation of a
GPCR, by determining the binding of the non-hydrolysable analog
[.sup.35S]GTP.gamma.S to G.alpha. subunits.
[1220] 1.1.1 HEPES Buffer Assay
[1221] The assay is performed in a 96 well plate where the
following reagents are added. First 50 .mu.L compound is added into
the assay plate, followed by addition of 20 .mu.L 3,3' di
indolylmethane at EC.sub.80 concentration (concentration which
gives 80% of the activity of GPR84). In a last step, 30 .mu.L of a
mixture consisting of membranes-GTP.gamma.S-SpA beads is added
[mixture consists of 20 .mu.g/well membranes derived from stable
cell line over expressing GPR84 (membranes are pre-incubated with
0.1 .mu.M GDP for 15 min at 4.degree. C.), 0.1 nM
[.sup.35S]GTP.gamma.S (Perkin Elmer, NEG030) and 0.5 mg/well
PVT-WGA SpA beads (Perkin Elmer, RPNQ0001)]. All components are
diluted in assay buffer containing 20 mM HEPES pH 7.4; 5 mM
MgCl.sub.2; 250 mM NaCl; 0.05% BSA; 75 ug/mL saponin. Reactions are
incubated for 90 min at room temperature followed by centrifugation
at 2000 rpm during 15 min. Plates are read on a Topcount reader
(Perkin Elmer) immediately after centrifugation (readout time, 1
min/well).
TABLE-US-00004 TABLE IV GPR84 assay GTP.gamma.S IC.sub.50 of
selected Compounds of the invention. Cpd# GPR84 1 * 2 * 3 **** 4 *
5 ** 6 * 7 **** 8 *** 9 * 10 *** 11 *** 12 *** 13 *** 14 *** 15
**** 16 **** 17 **** 18 **** 19 *** 20 **** 21 **** 22 **** 23 ***
24 *** 25 **** 26 *** 27 **** 28 **** 29 **** 30 **** 31 *** 32
**** 33 **** 35 **** 36 **** 37 **** 39 **** 40 **** 41 **** 42
**** 43 **** 44 **** 45 **** 46 **** 47 **** 48 **** 49 **** 50 **
51 **** 52 ** 53 * 54 **** 55 *** 56 **** 57 *** 58 *** 59 * 60 *
61 * 62 * 63 **** 64 *** 65 ** 66 *** 67 **** 68 **** 69 **** 70
**** 71 **** 72 **** 73 *** 74 *** 75 **** 76 **** 77 *** 78 ****
79 *** 80 *** 81 *** 82 ** 83 *** 84 *** 85 **** 86 **** 87 **** 88
**** 89 **** 90 *** 91 **** 92 *** 93 **** 94 ** 95 *** 96 *** 97
**** 98 **** 99 *** 100 *** 101 *** 102 * 103 ** 104 * 105 *** 106
*** 107 ** 108 **** 136 **** 140 **** 141 **** 145 **** 146 ****
147 **** 148 **** 149 **** 150 **** 151 *** 152 *** 153 **** 154
**** 155 **** 156 **** 157 **** 158 **** 159 **** 160 **** 161 ****
162 **** 163 **** 164 **** 165 **** 166 **** 167 **** 168 **** 169
**** 170 **** 171 ** 172 **** 173 *** 174 *** 175 **** 176 *** 177
*** 178 *** 179 **** 180 **** 181 **** 182 **** 183 **** 184 ***
185 **** 186 **** 187 **** 188 **** 189 **** 190 *** 191 *** 192
**** 193 **** 194 **** 195 *** 196 * 197 *** 198 * 199 **** 200
**** 201 *** 202 **** 203 ** 204 * N/A: not active * >1000 nM **
>500-1000 nM *** >100-500 nM **** 0.01-100 nM
[1222] 1.1.2 Tris Buffer Assay
[1223] Alternatively, the assay is performed in a 96 well plate
where the following reagents are added. First 50 .mu.L compound is
added into the assay plate, followed by addition of 20 .mu.L 3,3'
di indolylmethane at EC.sub.80 concentration (concentration which
gives 80% of the activity of GPR84). In a last step, 30 .mu.L of a
mixture consisting of membranes-GTP.gamma.S-SpA beads is added
[mixture consists of 20 .mu.g/well membranes derived from stable
cell line over expressing GPR84 (membranes are pre-incubated with
0.1 .mu.M GDP for 15 min at 4.degree. C.), 0.1 nM
[.sup.35S]GTP.gamma.S (Perkin Elmer, NEG030) and 0.5 mg/well
PVT-WGA SpA beads (Perkin Elmer, RPNQ0001)]. All components are
diluted in assay buffer containing 20 mM Tris pH 7.5; 5 mM
MgCl.sub.2; 250 mM NaCl; 0.05% BSA; 75 ug/mL saponin. Reactions are
incubated for 90 min at room temperature followed by centrifugation
at 2000 rpm during 15 min. Plates are read on a Topcount reader
(Perkin Elmer) immediately after centrifugation (readout time, 1
min/well).
TABLE-US-00005 TABLE V Alternative GPR84 assay GTP.gamma.S
IC.sub.50 of selected Compounds of the invention. Cpd# GPR84-2 34
*** 38 ** 109 * 110 *** 111 * 112 *** 113 **** 114 ** 115 * 116 **
117 * 118 **** 119 *** 120 ** 122 **** 124 **** 125 *** 126 *** 127
**** 128 **** 129 **** 130 *** 131 *** 132 *** 133 **** 134 ****
135 **** 137 **** 138 **** 139 **** 142 **** 143 **** 144 **** N/A:
not active * >1000 nM ** >500-1000 nM *** >100-500 nM ****
0.01-100 nM
2. Cellular Assays
2.1. Human Neutrophil Migration Assay
[1224] We have established that GPR84 agonists (MCFA such as
sodiumdecanoate, 3,3' di indolylmethane and Embelin induce
neutrophil chemotaxis and that GPR84 antagonists could block GPR84
agonist-induced chemotaxis but not IL8-induced chemotaxis,
indicating that G Protein-Coupled Receptor 84 (GPR84) is an
essential player in the process of neutrophil recruitment.
[1225] The effect of agonists or antagonists for GPR84 can
therefore be assayed in a neutrophil migration test. In the
neutrophil migration assay, neutrophils, freshly isolated from
buffy coats from human volunteers, are treated with a compound for
30 min. Subsequently, the neutrophils are transferred to the upper
wells of a Corning HTS transwell 96 permeable support system, of
which the lower wells are filled with a embelin solution at
EC.sub.80 (concentration which gives 80% of the activity of GPR84).
After 1 h of incubation, migration of the neutrophils towards
embelin in the lower compartment can be quantified by measuring the
ATP-content of the lower wells using the ATPlite luminescence ATP
detection assay system (Perkin Elmer, Cat. N.degree..: 436110).
2.1.1 Isolation of Neutrophils from Human Buffy Coat
[1226] A human buffy coat is diluted with an equal volume of ice
cold DPBS. 20 mL of the diluted buffy coat is gently mixed with 4
mL of ACD buffer (140 mM citric acid, 200 mM sodium citrate and 220
mM dextrose). Then, 12 mL of the 6% dextran/0.9% NaCl solution (15
g dextran T2000 and 2.25 g NaCl dissolved in 250 mL H.sub.2O) is
added to the mixture and the samples are inverted gently up to 20
times. The total volume was transferred to a new recipient and
incubated at room temperature for 1 h for complete separation of
the two phases to occur. The yellowish supernatant is then
transferred to a clean centrifugation tube and centrifuged for 12
min at 1300 rpm and 4.degree. C. After centrifugation, the
supernatant is discarded and the remaining cell pellet is rapidly
resuspended in 12 mL of ice-cold H.sub.2O for red blood cell lysis
to occur. After 20 seconds, 4 mL of ice-cold 0.6 M KCl is added.
Samples are mixed carefully and centrifuged for 6 min at 1300 rpm,
4.degree. C. The supernatant is discarded and the red blood cell
lysis procedure is repeated one more time. Subsequently, the cell
pellet is resuspended in 4 mL of DPBS and layered over 5 mL of
Lymphoprep (Nycomed Pharma, Cat. No.: 1114545) in a 15 mL
centrifuge tube. After centrifugation for 12 min at 1300 rpm,
4.degree. C., the supernatant is removed and the cell pellet,
containing the neutrophils, is resuspended in 25 mL chemotaxis
buffer (RPMI 1640 medium, supplemented with 10 mM HEPES; freshly
made for each experiment)
2.1.2 Migration Assay
[1227] A cell suspension of 8.9.times.10.sup.6 cells per milliliter
is prepared. 20 .mu.L of compound solution in chemotaxis buffer is
added to 180 .mu.L cell suspension. The mixture is incubated at
37.degree. C. for 30 min with intermediate resuspension of the
cells after 15 min. Following this, 70 .mu.L cell suspension is
transferred to the upper compartment of a Corning HTS transwell 96
permeable support system with 5.0 .mu.m pore size polycarbonate
membrane (Corning, Cat.N.degree..: 3387). The receiver well of the
transwell system is then filled with 200 .mu.L chemotaxis buffer
containing compound and chemotactic agent (embelin). After
incubation at 37.degree. C. in 5% CO.sub.2 for 1 h, the upper plate
of the transwell system is removed and the cell suspension in the
receiver plate is transferred to a 96-well V-bottom plate. 50 .mu.L
of DPBS is added to the receiver plate to prevent remaining cells
from drying out. The V-bottom plate is centrifuged for 6 min at
1500 rpm. The supernatant is removed and the cells are resuspended
in 50 .mu.L DPBS. The cells are then transferred back to the
receiver plate of the transwell system. After this, 100 .mu.L
ATPlite solution (Perkin Elmer, Cat. N.degree.: 436110) was added
to the cells. The plate is incubated for 10 min in the dark, while
shaking. 170 .mu.L of cell lysate is then transferred to a white
96-well plate and luminescence is measured. The detected
luminescent signal is considered as linearely related to the number
of cells having migrated from the upper well to the receiver
well.
TABLE-US-00006 TABLE VI human neutrophil migration IC.sub.50 of
selected Compounds of the invention. Cpd# Neutrophils Cpd#
Neutrophils 15 **** 15 **** 18 **** 136 **** 32 **** 137 **** 46
**** 139 **** 57 *** 142 **** 74 **** 180 **** 76 **** 181 **** 86
**** 182 **** 89 **** 183 **** 91 **** 188 **** 93 *** 189 **** 118
**** 190 **** 122 **** 192 **** 125 **** 193 **** 131 **** 199 ****
132 **** 200 **** 134 **** 202 **** * >1000 nM ** >500-1000
nM *** >100-500 nM **** 0.01-100 nM
2.2. Rat Neutrophil Migration Assay
[1228] We have established that GPR84 agonists (MCFA such as
sodiumdecanoate, 3,3' di indolylmethane and Embelin induce
neutrophil chemotaxis and that GPR84 antagonists could block GPR84
agonist-induced chemotaxis but not IL8-induced chemotaxis,
indicating that G Protein-Coupled Receptor 84 (GPR84) is an
essential player in the process of neutrophil recruitment.
[1229] The effect of agonists or antagonists for GPR84 can
therefore be assayed in a neutrophil migration test. In the rat
neutrophil migration assay, neutrophils, freshly isolated from rat
after intraperitoneal injection of glycogen (0.1%, w/v), are
treated with a compound for 30 min. Subsequently, the neutrophils
are transferred to the upper wells of a Corning HTS transwell 96
permeable support system, of which the lower wells are filled with
a embelin solution at EC.sub.80 (concentration which give 80% of
the activity of the GPR84). After 1 h of incubation, migration of
the neutrophils towards embelin in the lower compartment can be
quantified by measuring the ATP-content of the lower wells using
the Cell Titer Glow Substrate assay system (Promega,
Cat.N.degree..: G755B).
2.2.1. Isolation of Neutrophils from Rats
[1230] 24 h after intraperitoneal injection of glycogen (0.1%,
w/v), cells are harvested by peritoneal lavage with 25 mL HBSS then
centrifuged for 12 min at 1300 rpm and 4.degree. C. After
centrifugation, the supernatant is discarded and the remaining cell
pellet is rapidly resuspended in 12 mL of ice-cold H.sub.2O for red
blood cell lysis to occur. After 20 seconds, 4 mL of ice-cold 0.6 M
KCl is added. Samples are mixed carefully and centrifuged for 6 min
at 1300 rpm, 4.degree. C. The supernatant is discarded and the cell
pellet is resuspended in 4 mL of DPBS and layered over 5 mL of
Lymphoprep (Axis Shield, Cat. No.: 1114544) in a 15 mL centrifuge
tube. After centrifugation for 30 min at 1500 rpm, 4.degree. C.,
the supernatant is removed and the cell pellet, containing the
neutrophils, is resuspended in 5 mL chemotaxis buffer (RPMI 1640
medium, supplemented with 10 mM HEPES; freshly made for each
experiment).
2.2.2. Migration Assay
[1231] A cell suspension of 8.9.times.106 cells per milliliter is
prepared. 10 .mu.L of compound solution in chemotaxis buffer is
added to 90 .mu.L cell suspension. The mixture is incubated at
37.degree. C. for 30 min with intermediate resuspension of the
cells after 15 min. Following this, 75 .mu.L cell suspension is
transferred to the upper compartment of a Corning HTS transwell 96
permeable support system with 5.0 .mu.m pore size polycarbonate
membrane (Corning, Cat.N.degree..: 3387). The receiver well of the
transwell system is then filled with 200 .mu.L chemotaxis buffer
containing compound and chemotactic agent (embelin). After
incubation at 37.degree. C. in 5% CO2 for 1 h, the upper plate of
the transwell system is removed and 70 .mu.L Cell Titer Glow
Substrate (Promega, Cat.N.degree..: G755B) are added in the
receiver plate. The receiver plate is incubated for 10 min in the
dark, while shaking. 180 .mu.L of cell lysate is then transferred
to a white 96-well plate and luminescence is measured. The detected
luminescent signal is considered as linearely related to the number
of cells having migrated from the upper well to the receiver
well.
3. ADME, PK and Safety Models
[1232] 3.1 Aqueous Solubility
[1233] Starting from a 10 mM Stock in DMSO, a Serial Dilution of
the Compound is Prepared in DMSO. The dilution series is
transferred to a 96 NUNC Maxisorb plate F-bottom and 0.1M phosphate
buffer pH 7.4 or 0.1M citrate buffer pH3.0 at room temperature is
added.
[1234] The final concentrations range from 18.75 to 300 .mu.M in 5
equal dilution steps. The final DMSO concentration does not exceed
3%.
[1235] 200 .mu.M Pyrene is added to the corner points of each 96
well plate and serves as a reference point for calibration of
Z-axis on the microscope.
[1236] The assay plates are sealed and incubated for 1 h at
37.degree. C. while shaking at 230 rpm. The plates are then scanned
under a white light microscope, yielding individual pictures of the
precipitate per concentration. The precipitate is analyzed and
converted into a number by a custom-developed software tool. The
first concentration at which the compound appears completely
dissolved is the concentration reported, however the true
concentration lies somewhere between this concentration and one
dilution step higher.
[1237] Solubility values are reported in M and in g/mL.
[1238] 3.2. Thermodynamic Solubility
[1239] Two individual solutions of 2 mg/mL of compound are prepared
in a 0.1 M phosphate buffer pH 7.4 or a 0.1 M citrate buffer pH 3.0
at room temperature in a 2 mL glass vial.
[1240] After addition of a magnetic stir, the samples are stirred
at room temperature for 24 h.
[1241] After 24 h, the vials are centrifuged 10 min at 1400 rpm.
The supernatant of the sample is then transferred to a MultiscreenR
Solubility Plate (Millipore, MSSLBPC50) and filtered (10-12'' Hg)
with the aid of a vacuum manifold into a clean Greiner
polypropylene V-bottom 96 well plate. Per sample, two dilutions
(factor 10 and 100) are made in DMSO. Other dilutions can be made
if the acquired peak area is not within the standard curve.
[1242] A 10 mM DMSO stock, made from dry matter, is used to make a
200 .mu.g/mL working stock. The standard curve for the compound is
prepared in DMSO starting from the 200 .mu.g/mL working stock.
Eight concentrations and two quality control samples (QC) are made
in 2 mL tubes. The first 3 concentrations (50, 35 and 15 .mu.g/mL)
and the first QC sample (20 .mu.g/mL) are made starting with the
200 .mu.g/mL working stock. The 4.sup.th concentration (5 .mu.g/mL)
is made with the 50 .mu.g/mL solution and the 5.sup.th
concentration (1 g/mL) with the 15 .mu.g/mL. The last three
concentrations (0.2, 0.1 and 0.05 .mu.g/mL) are made with the 1
.mu.g/mL solution. The second QC sample (0.5 .mu.g/mL) is made with
the first QC sample.
[1243] Of every step of the dilution series, quality control and
sample dilutions, a volume is transferred to a 96-well Deepwell
plate. The samples are injected on a LC-MS/MS system (API2000 from
Applied Biosystems).
[1244] The samples are analyzed on LC-MS/MS with a flow rate of 0.5
mL/min. Solvent A is 0.1% Formic Acid in water and solvent B is
0.1% Formic Acid in methanol. The sample is run under positive ion
spray on a Pursuit 5 C18 2.0 mm column (Varian). The solvent
gradient has a total run time of 1.4 min and ranges from 10% B to
100% B.
[1245] The thermodynamic solubility samples are analyzed with the
aid of QuanLynx software. For the standard curve a linear or
quadratic curve can be used in the analysis. Samples of the
standard curve that have more than 15% deviation are excluded; the
lowest concentrations of the curve may vary up to 20%. Peak areas
of the samples are plotted against the standard curve to obtain the
solubility of the compound.
[1246] Solubility values are reported in .mu.M or g/mL.
[1247] 3.3 Microsomal Stability
[1248] A 10 mM stock solution of compound in DMSO is 1,668 fold
diluted in a 105 mM phosphate buffer pH 7.4. Of this compound
dilution, 50 .mu.L is transferred in two 96 assay plates: one for
time point 0 min (T0 plate) and one for time point 30 min (T30
plate) and pre-warmed at 37.degree. C.
[1249] In the time zero reference sample (T0 plate), 100 .mu.L MeOH
(1:1) is added to the wells. In each assay plate (T0 and T30 min),
50 .mu.L of microsomal mix is then added.
[1250] Final reaction concentrations are: 3 .mu.M compound, 0.5
mg/mL microsomes, 0.4 U/mL GDPDH, 3.3 mM MgCl.sub.2, 3.3 mM
glucose-6-phosphate and 1.3 mM NADP.sup.+.
[1251] The T30 plate is incubated at 37.degree. C., 300 rpm and
after 30 min of incubation the reaction is stopped with MeOH (1:1).
The samples are mixed, centrifuged and the supernatant is harvested
for analysis on LC-MS/MS (API2000 from Applied Biosystems).
[1252] The samples are analyzed on LC-MS/MS with a flow rate of 0.5
mL/min. Solvent A is 0.1% Formic Acid in water and solvent B is
0.1% Formic Acid in methanol. The sample is run under positive ion
spray on a Pursuit 5 C18 2.0 mm column (Varian). The solvent
gradient has a total run time of 1.4 min and ranges from 10% B to
100% B.Peak area from the parent compound at time 0 is considered
to be 100% remaining. The percentage remaining after 30 min
incubation is calculated from time 0. The solubility of the
compound in the final test concentration in buffer is inspected by
microscope and results are also reported.
[1253] 3.4 Hepatocyte Stability.
[1254] Test compounds (1 .mu.M initial concentration, n=2) are
incubated in Williams' Medium E, containing 4 mM L-gutamine and 2
mM magnesium sulphate, with pooled cryopreserved hepatocytes
(Celsis International) in suspension at cell densities of 0.25-0.5
million viable cells/mL. The incubations are performed at
37.degree. C. in a shaking water bath with 100 .mu.L samples taken
from the incubation at 0, 10, 20, 45 and 90 min, and reactions
terminated by addition of 100 .mu.L of acetonitrile containing
carbamazepine as analytical internal standard. Samples are
centrifuged and the supernatant fractions analysed by LC-MS/MS. The
instrument responses (i.e. peak heights) are referenced to the zero
time-point samples (as 100%) in order to determine the percentage
of compound remaining. Ln plots of the % remaining for each
compound are used to determine the half-life for the hepatocyte
incubations. Half-life values are calculated from the relationship:
T.sub.1/2 (min)=-0.693/.lamda., where .lamda. is the slope of the
Ln concentration vs time curve. Standard compounds testosterone,
midazolam, and 4-methylumbelliferone are included in the assay
design.
[1255] 3.5 Plasma Protein Binding (Equilibrium Dialysis)
[1256] A 10 mM stock solution of the compound in DMSO is diluted
with a factor 10 in DMSO. This solution is further diluted in
freshly thawed human, rat, mouse or dog plasma (BioReclamation INC)
with a final concentration of 5 .mu.M and final DMSO concentration
of 0.5%.
[1257] A Pierce Red Device plate with inserts (ThermoScientific) is
prepared and filled with 450 .mu.L PBS in the buffer chamber and
300 .mu.L of the spiked plasma in the plasma chamber. The plate is
incubated for 4 h at 37.degree. C. while shaking at 100 rpm. After
incubation, 120 .mu.L of both chambers is transferred to 480 .mu.L
methanol in a 96-well round bottom, PP deep-well plates (Nunc) and
sealed with an aluminum foil lid. The samples are mixed and
immediately centrifuged 30 min at 1400 rcf at 4.degree. C. and the
supernatant is transferred to a 96 v-bottom PP plate (Greiner,
651201) for analysis on LC-MS/MS (API2000 from Applied
Biosystems).
[1258] The samples are analyzed on LC-MS/MS with a flow rate of 0.5
mL/min. Solvent A is 0.1% Formic Acid in water and solvent B is
0.1% Formic Acid in methanol. The sample is run under positive ion
spray on a Pursuit 5 C18 2.0 mm column (Varian). The solvent
gradient has a total run time of 1.4 min and ranges from 10% B to
100% B.
[1259] Peak area from the compound in the buffer chamber and the
plasma chamber are considered to be 100% compound. The percentage
bound to plasma is derived from these results and is reported as
percentage bound to plasma.
[1260] The solubility of the compound in the final test
concentration in PBS is inspected by microscope to indicate whether
precipitation is observed or not.
[1261] 3.6 Caco2 Permeability
[1262] Bi-directional Caco-2 assays are performed as described
below. Caco-2 cells are obtained from European Collection of Cell
Cultures (ECACC, cat 86010202) and used after a 21 day cell culture
in 24-well Transwell plates (Corning, cell growth area: 0.33
cm.sup.2, Membrane pore size: 0.4 .mu.M, membrane diameter: 6.5
mm).
[1263] 2.times.10.sup.5 cells/well are seeded in plating medium
consisting of DMEM+GlutaMAX.TM.-I+1% NEAA+10% FBS (FetalClone
II)+1% Pen/Strep. The medium is changed every 2-3 days.
[1264] Test and reference compounds (propranolol and rhodamine 123
or vinblastine, all purchased from Sigma) are prepared in Hanks'
Balanced Salt Solution containing 25 mM HEPES (pH7.4) and added to
either the apical (125 .mu.L) or basolateral (600 .mu.L) chambers
of the Transwell plate assembly at a concentration of 10 .mu.M with
a final DMSO concentration of 0.25%.
[1265] 50 .mu.M Lucifer Yellow (Sigma) is added to the donor buffer
in all wells to assess integrity of the cell layers by monitoring
Lucifer Yellow permeation. As Lucifer Yellow (LY) cannot freely
permeate lipophilic barriers, a high degree of LY transport
indicates poor integrity of the cell layer.
[1266] After a 1 h incubation at 37.degree. C. while shaking at an
orbital shaker at 150 rpm, 70 .mu.L aliquots are taken from both
apical (A) and basal (B) chambers and added to 100 .mu.L 50:50
acetonitrile:water solution containing analytical internal standard
(0.5 .mu.M carbamazepine) in a 96 well plate.
[1267] Lucifer yellow is measured with a Spectramax Gemini XS (Ex
426 nm and Em 538 nm) in a clean 96 well plate containing 150 .mu.L
of liquid from basolateral and apical side.
[1268] Concentrations of compound in the samples are measured by
high performance liquid-chromatography/mass spectroscopy
(LC-MS/MS).
[1269] Apparent permeability (P.sub.app) values are calculated from
the relationship:
P.sub.app=[compound].sub.acceptor
final.times.V.sub.acceptor/([compound].sub.donor
initial.times.V.sub.donor)/T.sub.inc.times.V.sub.donor/surface
area.times.60.times.10.sup.-6 cm/s
V=chamber volume T.sub.inc=incubation time. Surface area=0.33
cm.sup.2
[1270] The Efflux ratios, as an indication of active efflux from
the apical cell surface, are calculated using the ratio of
P.sub.app B>A/P.sub.app A>B.
[1271] The following assay acceptance criteria are used:
Propranolol: P.sub.app (A>B) value.gtoreq.20(.times.10.sup.-6
cm/s) Rhodamine 123 or Vinblastine: P.sub.app (A>B) value<5
(.times.10.sup.-6 cm/s) with Efflux ratio.gtoreq.5. Lucifer yellow
permeability: .ltoreq.100 nm/s
[1272] 3.7 Liability for QT Prolongation
[1273] Potential for QT prolongation is assessed in the hERG manual
patch clamp assay.
[1274] 3.7.1 Conventional Whole-Cell Patch-Clamp
[1275] Whole-cell patch-clamp recordings are performed using an
EPC10 amplifier controlled by Pulse v8.77 software (HEKA). Series
resistance is typically less than 10 MR and compensated by greater
than 60%, recordings are not leak subtracted. Electrodes are
manufactured from GC150TF pipette glass (Harvard).
[1276] The external bathing solution contains: 135 mM NaCl, 5 mM
KCl, 1.8 mM CaCl.sub.2, 5 mM Glucose, 10 mM HEPES, pH 7.4.
[1277] The internal patch pipette solution contains: 100 mM
Kgluconate, 20 mM KCl, 1 mM CaCl.sub.2, 1 mM MgCl.sub.2, 5 mM
Na.sub.2ATP, 2 mM Glutathione, 11 mM EGTA, 10 mM HEPES, pH 7.2.
[1278] Drugs are perfused using a Biologic MEV-9/EVH-9 rapid
perfusion system.
[1279] All recordings are performed on HEK293 cells stably
expressing hERG channels. Cells are cultured on 12 mm round
coverslips (German glass, Bellco) anchored in the recording chamber
using two platinum rods (Goodfellow). hERG currents are evoked
using an activating pulse to +40 mV for 1000 ms followed by a tail
current pulse to -50 mV for 2000 ms, holding potential is -80 mV.
Pulses are applied every 20s and all experiments are performed at
room temperature.
[1280] 3.7.2 Data Analysis
[1281] IC.sub.50 values are calculated for each compound tested.
The fold difference between the IC.sub.50 in the manual hERG patch
clamp and the unbound IC.sub.50 in the whole blood assay is
calculated.
[1282] For the concentration response curves, peak tail current
amplitude is measured during the voltage step to -50 mV.
Curve-fitting of concentration-response data is performed using the
equation:
y=a+[(b-a)/(1+10 ((log c-x)d)]
[1283] where a is minimum response, b is maximum response and d is
Hill slope, this equation can be used to calculate both IC.sub.50
(where y=50 and c is the IC.sub.50 value) and IC.sub.20 (where y=20
and c is the IC.sub.20 value). GraphPad.RTM. Prism.RTM.
(Graphpad.RTM. Software Inc.) software is used for all curve
fitting. A difference of 100 fold or greater indicates a low
potential for QT prolongation.
[1284] 3.8 Pharmacokinetic Study
[1285] 3.8.1 Single Dose Pharmacokinetic Study in Rats
[1286] Compounds are formulated in PEG200/physiological saline
mixtures for the intravenous route and in PEG400/0.5%
methylcellulose (10/90 v/v) for the oral route. Test compounds are
orally dosed as a single esophageal gavage at 5-10 mg/kg and
intravenously dosed as a bolus via the caudal vein at 1 mg/kg to
male Sprague-Dawley rats. Each group consists of 3 rats. Blood
samples are collected either via the jugular vein using cannulated
rats or at the retro-orbital sinus with lithium heparin as
anti-coagulant at the time points in the following range: 0.05 to 8
h (intravenous route), and 0.25 to 6 or 24 h (oral route). Whole
blood samples are centrifuged at 5000 rpm for 10 min and the
resulting plasma samples are stored at -20.degree. C. pending
analysis.
[1287] 3.8.2 Multiple Dose Pharmacokinetic Study in Rats
[1288] Compounds are formulated in PEG400/0.5% methylcellulose
(10/90 v/v) for the oral route. Test compounds are orally dosed as
an esophageal daily gavage at 30 or 300 mg/kg to male
Sprague-Dawley rats for 14 days. Each group consists of 3 rats.
Blood samples are collected via the tail vein with lithium heparin
as anti-coagulant at the following time points on day 1, 7 and 14:
0.25, 1, 4, 8 and 24 h. In addition, on day 2 blood samples are
taken at 0.25, 1 and 4 h and at day 4 and 11 at 0.25 h. Whole blood
samples are centrifuged at 5000 rpm for 10 min and the resulting
plasma samples are stored at -20.degree. C. pending analysis.
[1289] 3.8.3 Quantification of Compound Levels in Plasma
[1290] Plasma concentrations of each test compound are determined
by an LC-MS/MS method in which the mass spectrometer is operated in
positive or negative electrospray mode.
[1291] 3.8.4 Determination of Pharmacokinetic Parameters
[1292] Pharmacokinetic parameters are calculated using
Winnonlin.RTM. (Pharsight.RTM., US).
[1293] 3.9 7-Day Rat Toxicity Study
[1294] A 7-day oral toxicity study with test compounds is performed
in Sprague-Dawley male rats to assess their toxic potential and
toxicokinetics, at daily doses of 100, 300 and 1000 mg/kg/day, by
gavage, at the constant dosage-volume of 10 mL/kg/day.
[1295] The test compounds are formulated in PEG400/0.5%
methylcellulose (10/90, v/v). Each group includes 6 principal male
rats as well as 3 satellite animals for toxicokinetics. A fourth
group is given PEG400/0.5% methylcellulose (10/90, v/v) only, at
the same frequency, dosage volume and by the same route of
administration, and acts as the vehicle control group.
[1296] The goal of the study is to determine the lowest dose that
results in no adverse events being identified (no observable
adverse effect level--NOAEL).
[1297] 3.10 Cytochrome P450 Inhibition
[1298] Reversible CYP inhibition and time-dependent CYP3A4
inhibition is determined in human liver microsomes and specific
probe substrates.
[1299] 3.10.1 P450 Inhibition in Human Liver Microsomes, Reversible
Inhibition
[1300] The inhibitory potential of a test compound is assessed for
human cytochrome P450 isoenzymes CYP1A2, 2C8, 2C9, 2C19, 2D6 and
3A4.
[1301] A 10 mM stock solution of the test compound is prepared in
DMSO, serially diluted in Tris buffer (100 mM pH 7.4) and added to
hepatic microsomes (Xenotech LLC) and NADPH at 37.degree. C. in a
shaking water bath. Seven different test compounds concentrations
(0.05 to 100 .mu.M), 1% DMSO and 1 mM NADPH are obtained to
react.
[1302] After 15 or 30 min reactions are terminated by addition of
100 .mu.L of acetonitrile containing carbamazepine as analytical
internal standard. Samples are centrifuged and the supernatant
fractions analysed by LC-MS/MS. For each isoform, the instrument
responses (peak heights) are referenced to those for DMSO controls
(considered as 100%) in order to determine the percentage reduction
in probe metabolism, using midazolam and testosterone as probe
substrate. Percentage inhibition of probe metabolism and Log [test
compound concentration] are plotted using Graphpad Prism software.
The sigmoidal dose response model is fitted to the data in order to
determine the IC.sub.50.
[1303] Inhibition of CYP3A4 using nifedipine and atorvastatin as
probe substrate is carried out as follows.
[1304] A 1.67 mM stock solution of test compound is prepared in
methanol, serially diluted 1:3 in 50 mM potassium phosphate buffer
pH7.4 and added to human hepatic microsomes (BD Gentest) and probe
substrate. Seven different test compounds concentrations
(0.045-33.3 .mu.M), 2% methanol, 0.1 mg/mL microsomes, 10 .mu.M
atorvastatin or 5 .mu.M nifedipine. After pre-warming 5 min at
37.degree. C., the reaction was started by adding cofactor mix
(7.65 mg/mL glucose-6-phosphate, 1.7 mg/mL NADP, 6 U/mL of
glucose-6-phosphate dehydrogenase).
[1305] After 5 min (nifedipine) or 10 min (atorvastatin) at
37.degree. C., the reaction (50 .mu.L) is terminated with 150 .mu.L
acetonitrile:methanol (2:1) solution with internal standard
(Warfarin). Samples are centrifuged and the supernatant fractions
analyzed by LC-MS/MS. The instrument responses (ratio of test
compound/internal standard peak areas) are referenced to those for
solvent controls (assumed as 100%) in order to determine the
percentage reduction in probe metabolism. Percent of control
activity vs concentration plots are generated and fitted using
GraphPad Prism software to generate IC.sub.50.
[1306] 3.10.2 CYP3A4 Inhibition in Human Liver Microsomes,
Time-Dependent
[1307] The time-dependent inhibitory potential of a test compound
is assessed for human cytochrome P450 isoenzyme 3A4. The compound
is pre-incubated with the human liver microsomes before addition of
the probe substrates. The result is compared to the condition where
the compound is not pre-incubated with the human liver microsomes
to see if there was a shift in IC.sub.50, indicating time-dependent
inhibition.
[1308] A 10 mM stock solution of test compound is prepared in DMSO
and diluted 1:20 with Tris buffer (100 mM pH 7.4) and further
serially diluted in Tris buffer/5% DMSO,
[1309] The cofactor, NADPH, and each test compound dilution is
mixed in two separate plates for 0 and 30 min pre-incubation. Human
hepatic microsomes (Xenotech LLC) are added only to the "30 min
pre-incubation" plate and both plates are then incubated for 30 min
at 37.degree. C. in a shaking water bath. Following the
pre-incubation, microsomes are added to the "0 min" plate and
appropriate probe substrates (in 0.5% DMSO) are added to both
plates. Plates are then returned to the water bath for a further
incubation.
[1310] In total, six different test compound concentrations (1.6 to
50 .mu.M) are assessed. Reactions are terminated with 100 .mu.L of
acetonitrile containing carbamazepine as analytical internal
standard. Samples are centrifuged and the supernatant fractions
analysed by LC-MS/MS. For each isoform, the instrument responses
(peak height ratio with internal standard) are referenced to those
for DMSO controls (considered as 100%) in order to determine the
percentage reduction in probe metabolism. Percentage inhibition of
probe metabolism and Log [Test Compound concentration] are plotted
using Graphpad Prism software. The sigmoidal dose response model is
fitted to the data in order to determine the IC.sub.50.
4. In-Vivo Studies
[1311] The in-vivo activity of the compounds of the invention may
be demonstrated in the following in vivo efficacy inflammation
models.
[1312] 4.1 Inflammatory Bowel Disease (Mice).
[1313] The mouse chronic DSS-induced inflammatory bowel disease
model (IBD) is a well validated disease model for inflammatory
bowel disease (Wirtz S. et al., 2007 Nature Protocols 2, 541-546;
Sina et al., 2009 J. Immunol. 183 7514-7522).
[1314] To induce a chronic colitis, female BALB/c mice are fed with
4% dextran sodium sulfate (DSS) dissolved in drinking water for 4
days, followed by 3 days of regular drinking water. This cycle is
repeated three times. This protocol allows inducing a strong
colitis while avoiding high mortality rates. Animals are divided
into several groups:
[1315] a. intact water; vehicle alone, n=10),
[1316] b. diseased (DSS; vehicle alone, n=10),
[1317] c. sulfazalazine used as reference (DSS; 20 mg/kg/day, p.o.,
n=10) and
[1318] d. the tested compound (DSS; 1, 3, 10, 30 mg/kg/day, p.o.,
n=10).
[1319] Clinical parameters are measured every other day. The
disease activity index (DAI) is a composite measure combining of
the individual scores for weight loss, stool consistency and rectal
bleeding. Mice are sacrificed at day 20 of the experiment according
to the protocol introduced by Sina et al. (2009). At sacrifice
time, the complete colon is removed and rinsed with sterile PBS.
Segments of the distal colon are dissected for histological
analysis, gene expression and protein level measurement.
[1320] 4.2 Collagen-Induced Arthritis (Mice).
[1321] The mouse collagen-induced arthritis (CIA) is the gold
standard rheumatoid arthritis model (Brand, et al., 2007 Nature
Protocols 2, 1269-1275, Lin et al., 2007 Br J Pharmacol 1,
829-831). DBA1//J male mice are injected with a collagen II
solution (Completed Freund's adjuvant). Immune reaction is boosted
by a second injection (incomplete Freund's adjuvant) 21 days later.
At day 31, arthritis is scored according to the method of
Khachigian et al. (Khachigian et al., 2006 Nature Protocols 1,
2512-2516) and animals are randomized to reach an average clinical
score of 2 per group. Animals are divided into several groups:
intact (no treatment, n=5), diseased (vehicle alone, n=10),
Enbrel.RTM. as reference (10 mg/kg, 3.times. week, i.p., n=10), and
the tested compound (3, 10 or 30 mg/kg/day, p.o., n=10).
Therapeutic dosing lasted from day 31 to day 46 and the arthritis
is scored every day. Mice are sacrificed at day 46, X-ray photos
are taken of the hind paws of each individual animal and the
severity of bone erosion is ranked with the radiological Larsen's
score (Salvemini et al., 2001 Arthritis Rheum 44, 2909-2921).
[1322] 4.3 Tabacco Smoke Model (Mice)
[1323] Daily exposures of female inbred C57BL/6J mice to tobacco
smoke (TS) for 11 consecutive days result in pulmonary
inflammation, as indicated by an increase in the total number of
cells recovered in the bronchoalveolar lavage (BAL), when compared
with a similarly treated air-exposed group, 24 h after the final
exposure. The exposure period to TS is increased initially from 25
min at the start of the study (day 1) to a maximum of 45 min on day
3 until day 11. Animals are divided into several groups: intact (no
treatment, n=5), diseased (vehicle alone, n=10), Roflumilast as
reference (5 mg/kg/day p.o., n=10), and the tested compounds (10 or
30 mg/kg/bid, p.o., n=10). At the end of 11 days, the numbers of
macrophages, epithelial cells, neutrophils and lymphocytes are
counted in the BAL. BAL is further analysed for gene expression and
protein level. Lung tissue is dissected for histological analysis,
gene expression and protein level measurement.
[1324] It will be appreciated by those skilled in the art that the
foregoing descriptions are exemplary and explanatory in nature, and
intended to illustrate the invention and its preferred embodiments.
Through routine experimentation, an artisan will recognise apparent
modifications and variations that may be made without departing
from the spirit of the invention. All such modifications coming
within the scope of the appended claims are intended to be included
therein. Thus, the invention is intended to be defined not by the
above description, but by the following claims and their
equivalents.
[1325] All publications, including but not limited to patents and
patent applications, cited in this specification are herein
incorporated by reference as if each individual publication were
specifically and individually indicated to be incorporated by
reference herein as though fully set forth.
[1326] It should be understood that factors such as the
differential cell penetration capacity of the various compounds can
contribute to discrepancies between the activity of the compounds
in the in vitro biochemical and cellular assays.
[1327] At least some of the chemical names of compound of the
invention as given and set forth in this application, may have been
generated on an automated basis by use of a commercially available
chemical naming software program, and have not been independently
verified. Representative programs performing this function include
the Lexichem naming tool sold by Open Eye Software, Inc. and the
Autonom Software tool sold by MDL, Inc. In the instance where the
indicated chemical name and the depicted structure differ, the
depicted structure will control.
[1328] Chemical structures shown herein were prepared using either
ChemDraw.RTM. or ISIS.RTM./DRAW. Any open valency appearing on a
carbon, oxygen or nitrogen atom in the structures herein indicates
the presence of a hydrogen atom. Where a chiral center exists in a
structure but no specific stereochemistry is shown for the chiral
center, both enantiomers associated with the chiral structure are
encompassed by the structure.
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