U.S. patent application number 15/948299 was filed with the patent office on 2018-08-09 for novel inhibitor compounds of phosphodiesterase type 10a.
The applicant listed for this patent is AbbVie Deutschland GmbH & Co. KG, AbbVie Inc.. Invention is credited to Berthold Behl, Jurgen Dinges, Karla Drescher, Herve Geneste, Clarissa Jakob, Katja Jantos, Loic Laplanche, Michael Ochse.
Application Number | 20180222905 15/948299 |
Document ID | / |
Family ID | 46456562 |
Filed Date | 2018-08-09 |
United States Patent
Application |
20180222905 |
Kind Code |
A1 |
Geneste; Herve ; et
al. |
August 9, 2018 |
NOVEL INHIBITOR COMPOUNDS OF PHOSPHODIESTERASE TYPE 10A
Abstract
The present invention relates to novel carboxamide compounds,
pharmaceutical compositions containing them, and their use in
therapy. The compounds possess valuable therapeutic properties and
are particularly suitable for treating or controlling medical
disorders selected from neurological disorders and psychiatric
disorders, for ameliorating the symptoms associated with such
disorders and for reducing the risk of such disorders.
Inventors: |
Geneste; Herve;
(Ludwigshafen, DE) ; Ochse; Michael;
(Ludwigshafen, DE) ; Drescher; Karla;
(Ludwigshafen, DE) ; Behl; Berthold;
(Ludwigshafen, DE) ; Laplanche; Loic;
(Ludwigshafen, DE) ; Dinges; Jurgen; (North
Chicago, IL) ; Jakob; Clarissa; (North Chicago,
IL) ; Jantos; Katja; (Ludwigshafen, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AbbVie Deutschland GmbH & Co. KG
AbbVie Inc. |
Wiesbaden
North Chicago |
IL |
DE
US |
|
|
Family ID: |
46456562 |
Appl. No.: |
15/948299 |
Filed: |
April 9, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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13534127 |
Jun 27, 2012 |
9938269 |
|
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15948299 |
|
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61503040 |
Jun 30, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 25/00 20180101;
A61P 43/00 20180101; C07D 409/14 20130101; A61P 25/28 20180101;
C07D 413/14 20130101; A61P 25/14 20180101; C07D 405/14 20130101;
A61P 25/16 20180101; A61P 3/04 20180101; C07D 471/04 20130101; C07D
403/14 20130101; A61P 25/22 20180101; A61P 25/24 20180101; A61P
25/18 20180101 |
International
Class: |
C07D 471/04 20060101
C07D471/04; C07D 413/14 20060101 C07D413/14; C07D 403/14 20060101
C07D403/14; C07D 405/14 20060101 C07D405/14; C07D 409/14 20060101
C07D409/14 |
Claims
1. A compound of formula (I) ##STR00030## wherein X.sup.1 is
C--R.sup.1, X.sup.2 is N or C--R.sup.2, X.sup.3 is N or C--R.sup.3,
X.sup.4 is C--R.sup.4, provided that 0, 1 or 2 of the moieties
X.sup.1, X.sup.2, X.sup.3 or X.sup.4 is N; A is selected from the
group consisting of O, S, S(.dbd.O), S(.dbd.O).sub.2, NR.sup.5a and
CR.sup.5R.sup.6; Het is selected from the group consisting of i.
monocyclic hetaryl having 1 or 2 nitrogen atoms and optionally a
further heteroatom selected from O, S and N as ring members, which
is unsubstituted or may carry 1, 2, 3 or 4 identical or different
substituents R.sup.x, ii. fused bicyclic hetaryl having 1 or 2
nitrogen atoms and optionally a further heteroatom selected from O,
S and N as ring members, benzothienyl or benzofuryl, where bicyclic
hetaryl, benzothienyl and benzofuryl are, independently of each
other, unsubstituted or may carry 1, 2, 3 or 4 identical or
different substituents R.sup.x, and iii. phenyl, which carries a
monocyclic hetaryl radical having 1 or 2 nitrogen atoms and
optionally a further heteroatom selected from O, S and N as ring
members, which in addition to monocyclic hetaryl, may carry 1, 2 or
3 identical or different substituents R.sup.x, where R.sup.x is
selected from the group consisting of H, halogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy
C.sub.1-C.sub.4-fluoroalkyl, C.sub.1-C.sub.4-fluoroalkoxy,
C.sub.3-C.sub.6-cycloalkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkoxy,
C.sub.1C.sub.4-alkoxy-C.sub.1C.sub.4-alkyl, OH,
hydroxy-C.sub.1-C.sub.4-alkyl, O--C.sub.3-C.sub.6-cycloalkyl,
benzyloxy, C(O)O--(C.sub.1-C.sub.4-alkyl),
O--(C.sub.1-C.sub.4-alkyl)-CO.sub.2H, N(R.sup.x1)(R.sup.x2)
C(O)N(R.sup.x1)(R.sup.x2),
C.sub.1-C.sub.4-alkyl-N(R.sup.x1)(R.sup.x2),
--NR.sup.x3--C(O)--N(R.sup.x1)(R.sup.x2),
NR.sup.x3--C(O)O--(C.sub.1-C.sub.4-alkyl),
--N(R.sup.x3)--SO.sub.2--R.sup.x4, phenyl, CN, --SF.sub.5,
--OSF.sub.5, --SO.sub.2R.sup.x4, --SR.sup.x4 and trimethylsilyl,
where R.sup.x1, R.sup.x2, R.sup.x3 and R.sup.x4, independently of
each other are selected from the group consisting of hydrogen,
C.sub.1-C.sub.4-alkyl C.sub.1-C.sub.4-fluoroalkyl and
C.sub.3-C.sub.6-cycloalkyl or R.sup.x1 and R.sup.x2 form together
with the N atom to which they are attached a 3- to 7-membered,
nitrogen heterocycle which may have 1, 2 or 3 further different or
identical heteroatoms or heteroatom containing groups selected from
the group consisting of O, N, S, SO and SO.sub.2 as ring members
and which may carry 1, 2, 3, 4, 5 or 6 C.sub.1-C.sub.4-alkyl
substituents; R.sup.1, is selected from the group consisting of
hydrogen, halogen, OH, C.sub.1-C.sub.4-alkyl, trimethylsilyl,
C.sub.1-C.sub.4-alkylsulfanyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkylsulfanyl-C.sub.1-C.sub.4-alkoxy,
C.sub.2-C.sub.4-alkenyloxy, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.1-C.sub.4-fluoroalkoxy, cyclopropyl, optionally substituted
by 1, 2 or 3 methyl groups, fluorinated cyclopropyl, CN,
NR.sup.x1R.sup.x2 and NR.sup.x1R.sup.x2-C.sub.1-C.sub.4-alkoxy;
R.sup.2, R.sup.3 independently of each other, are selected from the
group consisting of hydrogen, halogen, OH, C.sub.1-C.sub.4-alkyl,
trimethylsilyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4alkoxy-C.sub.1-C.sub.4-alkoxy,
C.sub.2-C.sub.4-alkenyloxy, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.1-C.sub.4-fluoroalkoxy, cyclopropyl, optionally substituted
by 1, 2 or 3 methyl groups, fluorinated cyclopropyl, CN and
NR.sup.x1R.sup.x2 ; R.sup.4 is Y-Cyc; R.sup.5, R.sup.6
independently of each other are selected from the group consisting
of hydrogen, OH, halogen, C.sub.1-C.sub.4-alkyl, trimethylsilyl,
C.sub.1-C.sub.4-fluoroalkyl, C.sub.1-C.sub.4-fluoroalkoxy,
C.sub.3-C.sub.6-cycloalkyl, optionally substituted by 1, 2 or 3
methyl groups, and fluorinated C.sub.3-C.sub.6-cycloalkyl or the
radicals R.sup.5, R.sup.6 together with the carbon atom to which
they are bound form a carbonyl group or a saturated 3- to
6-membered carbocycle or a saturated 3- to 6-membered heterocycle
having 1 or 2 non-adjacent heteroatoms as ring members, where the
carbocycle and the heterocycle are unsubstituted or may carry 1, 2,
3 or 4 substituents selected from the group consisting of fluorine
and methyl; R.sup.5a is selected from the group consisting of from
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-fluoroalkyl, C.sub.1-C.sub.4-fluoroalkoxy,
C.sub.3-C.sub.6-cycloalkyl, optionally substituted by 1, 2 or 3
methyl groups, fluorinated C.sub.3-C.sub.6-cycloalkyl, phenyl,
benzyl, 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms
selected from the group consisting of O, S and N as ring members,
and 5- or 6-membered hetarylmethyl having 1, 2 or 3 heteroatoms
selected from the group consisting of O, S and N as ring members,
where the rings in the last four mentioned radicals are
unsubstituted or carry 1, 2, 3 or 4 substituents selected from the
group consisting of fluorine, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-fluoroalkyl, C.sub.1-C.sub.4-alkoxy and
C.sub.1-C.sub.4-fluoroalkoxy; R.sup.7, R.sup.8, R.sup.9, R.sup.10
independently of each other are selected from the group consisting
of hydrogen, halogen, C.sub.1-C.sub.4-alkyl, trimethylsilyl,
C.sub.1-C.sub.4-fluoroalkyl, C.sub.1-C.sub.4-fluoroalkoxy, and
C.sub.3-C.sub.6-cycloalkyl, or the radicals together with the
carbon atoms to which they are bound form a saturated 3- to
6-membered carbocycle or a saturated 3- to 6-membered heterocycle
having 1 or 2 non-adjacent heteroatoms as ring members, where the
carbocycle and the heterocycle are unsubstituted or may carry 1, 2,
3 or 4 substituents selected from the group consisting of fluorine
and methyl or either the radicals R.sup.7, R.sup.8 or the radicals
R.sup.9, R.sup.10 together with the carbon atom to which they are
bound form a saturated 3- to 6-membered carbocycle or a saturated
3- to 6-membered heterocycle having 1 or 2 non-adjacent heteroatoms
as ring members, where the carbocycle and the heterocycle are
unsubstituted or may carry 1, 2, 3 or 4 substituents selected from
the group consisting of fluorine and methyl; Y is a chemical bond,
CH.sub.2, O, O--CH.sub.2, NR.sup.y, NR.sup.y--CH.sub.2,
NR.sup.y--S(O).sub.2, S, S(O), S(O).sub.2, 1,2-ethandiyl,
1,2-ethendiyl, or 1,2-ethyndiyl, where R.sup.y is selected from the
group consisting of hydrogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkylcarbonyl, C.sub.1-C.sub.4-alkylsulfonyl,
C.sub.1-C.sub.4-fluoroalkylsulfonyl; Cyc is a radical selected from
the group consisting of 4- to 8-membered saturated or partially
unsaturated monocarbocyclic radicals, 7- to 10-membered saturated
or partially unsaturated bicarbocyclic radicals, 4- to 8-membered
saturated or partially unsaturated heteromonocyclic radicals,
saturated or partially unsaturated 7- to 10 membered heterobicyclic
radicals, where the saturated or partially unsaturated
heteromonocyclic and heterobicyclic radicals have 1, 2, 3 or 4
heteroatoms or heteroatom containing groups as ring members, which
are selected from the group consisting of O, S, SO, SO.sub.2 and N,
where the saturated or partially unsaturated mono- and
bicarbocyclic radicals, the heteromonocyclic and heterobicyclic
radicals and the mono and bicyclic heteroaromatic radicals are
unsubstituted or carry 1, 2, 3, 4 or 5 radicals R.sup.C1 or one
radical Y'--R.sup.C2 and 0, 1, 2, 3 or 4 radicals R.sup.C1; where
R.sup.C1 is selected from the group consisting of hydrogen,
halogen, OH, CN, NO.sub.2, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-alkylsulfanyl,
hydroxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkoxy,
cyano-C.sub.1-C.sub.4-alky, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.1-C.sub.4-fluoroalkoxy, C.sub.1-C.sub.4-alkylsulfonyl,
C(O)R.sup.a, Z--C(O)OR.sup.b, Z--C(O)NR.sup.cR.sup.d,
S(O).sub.2NR.sup.cR.sup.d and Z--NR.sup.eR.sup.f, where R.sup.a is
selected from the group consisting of C.sub.1-C.sub.4-alkyl and
C.sub.1-C.sub.4-fluoroalkyl, R.sup.b is selected from the group
consisting of hydrogen, C.sub.1-C.sub.4-alkyl,
C.sub.2-C.sub.4-alkenyl and C.sub.1-C.sub.4-fluoroalkyl, R.sup.c,
R.sup.d is selected from the group consisting of hydrogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-fluoroalkoxy, R.sup.e,
R.sup.f is selected from the group consisting of hydrogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-fluoroalkoxy, Z is a
covalent bond or C.sub.1-C.sub.4-alkandiyl, or two radicals
R.sup.C1 which are bound at adjacent carbon atoms may form a fused
5- or 6-membered carbocyclic radical or a fused 5- or 6-membered
heterocyclic radical having 1, 2 or 3 heteroatoms as ring members,
which are selected from the group consisting of O, S and N; or two
radicals R.sup.C1 which are bound at the same carbon atom may form
a spiro 5- or 6-membered carbocyclic radical or a spiro 5- or
6-membered heterocyclic radical having 1 or 2 heteroatoms as ring
members, which are selected from the group consisting of O, S and
N, or two radicals R.sup.C1 which are bound at the same carbon atom
may form an oxygen atom, where the fused and the spiro radicals are
unsubstituted or carry 1, 2, 3 or 4 radicals R.sup.C3; Y' is a
chemical bond, CH.sub.2, O, O--CH.sub.2, S(O).sub.2, NR.sup.Y',
NR.sup.y'--CH.sub.2 or NR.sup.y'--S(O).sub.2, where R.sup.y' is
selected from the group consisting of hydrogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4alkylcarbonyl,
C.sub.1-C.sub.4-alkylsulfonyl, C.sub.1-C.sub.4-fluoroalkylsulfonyl;
R.sup.C2 is a carbocyclic or heterocyclic radical selected from the
group consisting of phenyl, 3- to 7-membered saturated or partially
unsaturated monocarbocyclic radicals, 3- to 7-membered saturated or
partially unsaturated heteromonocyclic radicals, having 1, 2 or 3
heteroatoms as ring members, which are selected from the group
consisting of O, S and N, and 5- or 6-membered heteroaromatic
radicals, having 1, 2 or 3 heteroatoms as ring members, which are
selected from the group consisting of O, S and. N, where the
carbocyclic and the heterocyclic radical is unsubstituted or
carries 1, 2, 3, 4 or 5 radicals R.sup.C3; R.sup.C3 is selected
from the group consisting of hydrogen, halogen, OH, CN,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy,
hydroxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl ,
cyano-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.1-C.sub.4-fluoroalkoxy, C.sub.2-C.sub.6-alkenyl, C(O)R.sup.a,
Z--C(O)OR.sup.b, Z--C(O)NR.sup.cR.sup.d, S(O).sub.2NR.sup.cR.sup.d
and Z--NR.sup.eR.sup.f, where, Z, R.sup.a, R.sup.b, R.sup.c,
R.sup.d, R.sup.e and R.sup.f are as defined above or two radicals
R.sup.C3 which are bound at the same atom may form an oxygen atom;
or an N-oxide, prodrug, tautomer, or hydrate thereof; or a
pharmaceutically acceptable salt thereof.
2. (canceled)
3. The compound of claim 1, where X.sup.2 is C--R.sup.2 and X.sup.3
is C--R.sup.3.
4.-6. (canceled)
7. The compound of claim 1, where R.sup.1, R.sup.2 and R.sup.3, if
present, are selected, independently of each other, from the group
consisting of hydrogen, fluorine, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.2-fluoroalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.2-fluoroalkoxy, cyclopropyl, optionally substituted
by 1, 2 or 3 methyl groups, and fluorinated cyclopropyl.
8.-10. (canceled)
11. The compound of claim 1, where A is a radical
CR.sup.5R.sup.6.
12. The compound of claim 1, which is of the formula (I-A)
##STR00031##
13. The compound of claim 12, where R.sup.4 is a radical Y-Cyc and
X.sup.1 is C--R.sup.1, where R.sup.1 is selected from the group
consisting of hydrogen, fluorine, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.2-fluoroalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.2-fluoroalkoxy, cyclopropyl, optionally substituted
by 1, 2 or 3 methyl groups, and fluorinated cyclopropyl.
14. The compound of claim 11, where R.sup.5 and R.sup.6 are,
independently of each other, selected from the group consisting of
hydrogen, fluorine and methyl.
15. The compound of claim 1, where Het is selected from the group
consisting of C-bound 6-membered monocyclic hetaryl, which has 1 or
2 nitrogen atoms as ring members, benzofuryl and C-bound, fused
bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members
and optionally a further heteroatom selected from the group
consisting of O, S and N as ring member; where monocyclic hetaryl,
benzofuryl and bicyclic hetaryl may be unsubstituted or may carry
1, 2, 3 or 4 substituents R.sup.x.
16. The compound of claim 15, where Het has at least one
imino-nitrogen as ring member, which located in the position
adjacent to carbon atom bound to the group CR.sup.9R.sup.10.
17. The compound of claim 15, where Het is selected from the group
consisting of 2-benzofuryl, 2-pyridyl, 3-pyridazinyl,
2-pyrimidinyl, 2-quinolinyl, 2-quinazolinyl, 2-quinoxalinyl,
benzimidazol-2-yl, 1-methylbenzimidazol-2-yl, benzothiazolyl,
imidazo[1,2-a]pyridine-2-yl, thieno[3,2-b]pyridine-5-yl,
imidazo-[2,1-b]-thiazol-6-yl and
1,2,4-triazolo[1,5-a]pyridine-2-yl, where the aforementioned
radicals may carry 1, 2 or 3 radicals selected from fluorine,
chlorine, C.sub.1-C.sub.4-alkyl, fluoromethyl, difluoromethyl,
trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy,
trifluoromethoxy, cyclopropyl, optionally substituted by 1, 2 or 3
methyl groups, and fluorinated cyclopropyl.
18. The compound of claim 1, where R.sup.7 and R.sup.8 are,
independent from each other selected from the group consisting of
hydrogen and fluorine.
19. The compound of claim 1, which is of the formulae (I-Aa) or
(I-Ab) ##STR00032##
20. The compound of claim 1, which is of the formula (I-Ac)
##STR00033## where Q is S or N--CH.sub.3; and R.sup.xx is hydrogen,
fluorine or CH.sub.3
21. The compound of claim 1, which is of the formula (I-Ad)
##STR00034## where q is 0 or 1; and R.sup.x is selected from the
group consisting of C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.1-C.sub.4-fluoroalkoxy, cyclopropyl, which is optionally
substituted by 1, 2 or 3 methyl groups, and fluorinated
cyclopropyl.
22. The compound of claim 19, where R.sup.1 is selected from the
group consisting of hydrogen, fluorine, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.2-fluoroalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.2-fluoroalkoxy, cyclopropyl, optionally substituted
by 1, 2 or 3 methyl groups, and fluorinated cyclopropyl.
23. The compound of claim 19, where R.sup.5 and R.sup.6 are,
independently of each other, selected from the group consisting of
hydrogen, fluorine and methyl.
24. The compound of claim 1, where Y is selected from the group
consisting o chemical bond, O and NH.
25. (canceled)
26. The compound of claim 1, where Cyc is a saturated 4-, 5-, 6-,
7- or 8-membered heteromonocycle or a saturated 7-, 8-, 9- or
10-membered heterobicycle, where the heteromonocycle and the
heterobicycle have one nitrogen or oxygen atom as ring member and
may have one further heteroatom or heteroatom group as ring member,
which is selected from the group consisting of O, S, S(.dbd.O),
S(.dbd.O).sub.2 and N, where the saturated heteromonocycle and the
saturated heterobicycle are unsubstituted or carry 1, 2, 3, 4 or 5
radicals R.sup.C1 or one radical Y'--R.sup.C2 and 0, 1, 2, 3 or 4
radicals R.sup.C1.
27. The compound of claim 1, where Y-Cyc is selected from the group
consisting of 1-piperidinyl, 4,4-difluoro-1-piperidinyl,
4-piperidinyl, 1-methyl-4-piperidinyl, 1-piperazinyl,
4-methyl-1-piperazinyl, morpholin-4-yl,
2-oxa-6-azaspiro-[3,4]octyl, 2,5-diazabicyclo[2.2.1]heptan-2-yl,
3,8-diazabicyclo[3.2.1]octan-8-yl, thiomorpholin-4-yl,
1-oxothiomorpholin-4-yl, N-(oxetan-3-yl)amino,
1,1-dioxothiomorpholin-4-yl and oxetan-3-ylamino.
28. -29. (canceled)
30. The compound of claim 1, where R.sup.9 and R.sup.10 are,
independent from each other, selected from the group consisting of
hydrogen and fluorine.
31. The compound of claim 1, which is selected from the group
consisting of
7-Morpholin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
7-[4-(4-Methyl-piperazin-1-yl)-piperidin-1-yl]-2-(2-quinolin-2-yl-ethyl)--
2,3-dihydro-isoindol-1-one,
7-(1S,4S)-2,5-Diaza-bicyclo[2.2.1]hept-2-yl-2-(2-quinolin-2-yl-ethyl)-2,3-
-dihydro-isoindol-1-one,
7-Piperazin-1-yl-2-(2-quinolin-2-yl-dihydro-isoindol-1-one,
7-(3,8-Diaza-bicyclo[3.2.1]oct-8-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydr-
o-isoindol-1-one,
7-(1,1-Dioxo-1-thiomorpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro--
isoindol-1-one,
7-[4-(1-Methyl-piperidin-4-yl)-piperazin-1-yl]-2-(2-quinolin-2-yl-ethyl)--
2,3-dihydro-isoindol-1-one,
7-(4-Pyridin-4-yl-piperazin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-i-
soindol-1-one,
7-(4-Methyl-piperazin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindo-
l-1-one,
7-(3-Phenyl-piperidin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-
-isoindol-1-one,
7-(3-Phenoxy-piperidin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoind-
ol-1-one,
7-[1,4]Oxazepan-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoin-
dol-1-one, 7-(7-nitro-3,4-dihydroisoquinolin-2
(1H)-yl)-2-(2-(quinolin-2-yl)ethyl)isoindolin-1-one,
7-(7-amino-3,4-dihydroisoquinolin-2
(1H)-yl)-2-(2-(quinolin-2-yl)ethyl)isoindolin-1-one,
4-Chloro-N-{2-[3-oxo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-1H-isoindol-4--
yl]-1,2,3,4-tetrahydro-isoquinolin-7-yl}-benzenesulfonamide,
4-Isopropyl-N-{2-[3-oxo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-1H-isoindol-
-4-yl]-2,3,4-tetrahydro-isoquinolin-7-yl}-benzenesulfonamide,
2-[2-(6-Fluoro-quinolin-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro-isoindo-
l-1-one,
2-[2-(6-Methoxy-quinolin-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydr-
o-isoindol-1-one,
2-[2-(4-Chloro-quinolin-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro-isoindo-
l-1-one,
2-[2-(8-Chloro-quinolin-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro-
-isoindol-1-one,
7-Morpholino-2-(3-(pyrimidin-2-yl)phenethyl)isoindolin-1-one,
7-[8-(4-Methyl-piperazine-1-sulfonyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2--
(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
7-[8-(Morpholine-4-sulfonyl)-3
4-dihydro-1H-isoquinolin-2-yl]-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoi-
ndol-1-one,
7-(2-Oxa-6-aza-spiro[3.4]oct-6-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro--
isoindol-1-one,
7-(1-Oxo-thiomorpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoind-
ol-1-one,
7-(2-Oxa-6-aza-spiro[3,5]non-6-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-
-dihydro-isoindol-1-one, 7-(3-Amino-azetidin-1-yl)
-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
7-(5,5-Difluoro-hexahydro-cyclopenta[c]pyrrol-2-yl)-2-(2-quinolin-2-yl-et-
hyl-)2,3-dihydro-isoindol-1-one,
7-(4,4-Difluoro-piperidin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-iso-
indol-1-one,
7-(Azetidin-3-ylamino)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-o-
ne,
7-[(3S,4S)-4-(2-Fluoro-4-trifluoromethoxy-phenyl)-3-methyl-piperidin-1-
-yl]-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
2-(2-Quinolin-2-yl-ethyl)-7-thiomorpholin-4-yl-2,3-dihydro-isoindol-1-one-
,
7-(8-Methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-2-(2-quinolin-2-yl-ethyl)--
2,3-dihydro-isoindol-1-one,
7-(3-Methyl-3,8-diaza-bicyclo[3.2.1]oct-8-yl)-2-(2-quinolin-2-yl-ethyl)-2-
,3-dihydro-isoindol-1-one,
2-[2-(1-Methyl-1H-benzoimidazol-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro-
-isoindol-1-one,
7-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-(2-quinolin-2-yl-ethyl-
)-2,3-dihydro-isoindol-1-one,
7-[4-(4-Ethyl-piperazin-1-yl)piperidin-1-yl]-2-(2-quinolin-2-yl-ethyl)-2,-
3-dihydro-isoindol-1-one,
2-(2-Quinolin-2-yl-ethyl)-7-(3,4,5,6-tetrahydro-2H-[4,4']bipyridinyl-1-yl-
)-2,3-dihydro-isoindol-1-one,
7-(4-Pyridin-3-yl-piperazin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-i-
soindol-1-one,
7-(3-Amino-4-methyl-piperidin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-
-isoindol -1-one,
2-[2-(1H-Benzoimidazol-2-yl)-ethyl]-7-(1,1-dioxothiomorpholin-4-yl)-2,3-d-
ihydro-isoindol-1-one,
7-[(1S,4S)-5-(4-Chloro-phenyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-2-(2-qu-
inolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
7-(4-Methyl-piperazin-1-ylmethyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-i-
soindol-1-one,
7-Morpholin-4-ylmethyl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-o-
ne
7-(1,1-Dioxo-thiomorpholin-4-yl)-2-[2-(1-methyl-1H-benzoimidazol-2-yl)--
ethyl]-2,3-dihydro-isoindol-1-one,
7-(1,1-Dioxo-thiomorpholin-4-yl)-4-methoxy-2-(2-quinolin-2-yl-ethyl)-2,3--
dihydro-isoindol-1-one,
7-(1,1-Dioxo-tetrahydrothiophen-3-ylamino)-2-(2-quinolin-2-yl-ethyl)-2,3--
dihydro-isoindol-1-one,
7-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dih-
ydro-isoindol-1-one,
7-(4-Pyrrolidin-1-yl-piperidin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydr-
o-isoindol-1-one,
7-[1,4']Bipiperidinyl-1'-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindo-
l-1-one,
7-(1S,5S)-3,6-Diaza-bicyclo[3.2.0]hept-3-yl-2-(2-quinolin-2-yl-et-
hyl)-2,3dihydro-isoindol-1-one,
7-(3aR,7aS)-Octahydro-pyrrolo-[3,2-c]pyridin-5-yl-2-(2-quinolin-2-yl-ethy-
l)-2,3-dihydro-isoindol-1-one,
7-((R)-3-Amino-pyrrolidin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-iso-
indol-1-one,
7-(2-Methyl-morpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindo-
l-1-one,
7-(2-Dimethylaminomethyl-morpholin-4-yl)-2-(2-quinolin-2-yl-ethyl-
)-2,3-dihydro-isoindol-1-one,
7-Morpholin-4-yl-2-(2-[1,2,4]triazolo[1,5-a]pyridin-2-yl-ethyl)-2,3-dihyd-
ro-isoindol-1-one,
7-(1,1-Dioxo-thiomorpholin-4-yl)-2-(2-[1,2,4]triazolo[1,5-a]pyridin-2-yl--
ethyl)-2,3-dihydro-isoindol-1-one,
7-(4-Methyl-piperazin-1-yl)-2-(2-[1,2,4]triazolo[1,5-a]pyridin-2-yl-ethyl-
)-2,3-dihydro-isoindol-1-one,
7-(1,1-Dioxo-thiomorpholin-4-yl)-2-(2-imidazo[1,2-a]pyridin-2-yl-ethyl.)--
2,3-dihydro-isoindol-1-one,
4-Methoxy-7-morpholin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one,
4-(1,1-Dioxothiomorpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-isoindol-
e-1,3-dione, 7-(2-Ethyl
-morpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
2-[2-(1-Methyl-1H-benzoimidazol-2-yl)-ethyl]-7-(4-methyl-piperazin-1-yl)--
2,3-dihydro-isoindol-1-one,
7-(2,6-Dimethyl-morpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-iso-
indol-1-one,
6-(2-Quinolin-2-yl-ethyl)-4-(tetrahydro-furo[3,4-c]pyrrol-5-yl)-6,7-dihyd-
ro-pyrrolo[3,4-b]pyridin-5-one,
4-Methoxy-7-(4-methyl-piperazin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihyd-
ro-isoindol-1-one,
2-[2-(5-Fluoro-1-methyl-1H-benzoimidazol-2-yl)-ethyl]-7-morpholin-4-yl-2,-
3-dihydro-isoindol-1-one,
2-(2-Benzothiazol-2-yl-ethyl)-7-morpholin4-yl-2,3-dihydro-isoindol-1-one,
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)4-methoxy-7-morpholin-4-yl-2,3-dihy-
dro-isoindol-1-one,
4-Methoxy-7-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-(2-quinolin-2--
yl-ethyl)-2,3-dihydro-isoindol-1-one,
4-Morpholin-4-yl-2-(2-quinolin-2-yl-ethyl)-isoindole-1,3-dione,
7-(Oxetan-3-ylamino)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one-
,
4-(Oxetan-3-ylamino)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b-
]pyridin-5-one,
7-(2-Ethyl-6-methyl-morpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-
-isoindol-1-one,
2-[2-(1-Ethyl-1H-benzoimidazol-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro--
isoindol-1-one,
7-(Octahydro-[1,5]naphthyridin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydr-
o-isoindol-1-one,
4-Fluoro-2-(2-imidazo[1,2-a]pyridin-2-yl-ethyl)-7-morpholin-4-yl-2,3-dihy-
dro-isoindol-1-one,
7-(2-Methoxymethyl-morpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro--
isoindol-1-one,
2-[2-(1-Isopropyl-1H-benzoimidazol-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihy-
dro-isoindol-1-one,
7-Morpholin-4-yl-2-[2-(1-propyl-1H-benzoimidazol-2-yl)-ethyl]-2,3-dihydro-
-isoindol-1-one,
2-[2-(1,5-Dimethyl-1H-benzoimidazol-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dih-
ydro-isoindol-1-one,
2-[2-(4-Fluoro-1-methyl-1H-benzoimidazol-2-yl)-ethyl]-7-morpholin-4-yl-2
3-dihydro-isoindol-1-one,
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-7-morpholin-4-yl-2,3-dihydro-isoin-
dol-1-one,
7-(3aS,8aR)-Octahydro-pyrrolo[3,4-c]azepin-2-yl-2-(2-quinolin-2-
-yl-ethyl)-2,3-dihydro-isoindol-1-one,
7-(3aS,8aS)-Octahydro-pyrrolo[3,4-c]azepin-2-yl-2-(2-quinolin-2-yl-ethyl)-
-2,3-dihydro-isoindol-1-one,
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-methoxy-7-(oxetan-3-ylamino)-2,3-
-dihydro-isoindol-1-one, and
4-Methoxy-2-[2-(1-methyl-1H-benzoimidazol-2-yl)-ethyl]-7-morpholin-4-yl-2-
,3-dihydro-isoindol-1-one, or an N-oxide, prodrug, tautomer, or
hydrate thereof, or a pharmaceutically acceptable salt thereof.
32. The compound of claim 1, which is selected from the group
consisting of
4-Methoxy-2-[2-(1-methyl-1H-benzoimidazol-2-yl)-ethyl]-7-(oxetan-3-yla-
mino)-2,3-dihydro-isoindol-1-one,
4-Fluoro-7-(oxetan-3-ylamino)-2-[2-(2-quinolyl-ethyl]isoindolin-1-one,
4-Fluoro 7-morpholino-2-[2-(2 quinolyl)ethyl]isoindolin 1 one,
2-[2-(1-Difluoromethyl-1H-benzoimidazol-2-yl)-ethyl]-7-morpholin-4-yl-2,3-
-dihydro-isoindol-1-one,
7-Morpholino-2-(2-quinoxalin-2-ylethyl)isoindolin-1-one,
4-Fluoro-2-(2-imidazo[1,2-a]pyridin-2-ylethyl)-7-(oxetan-3-ylamino)isoind-
olin-1-one, and
7-Morpholino--2-(2-thieno[3,2-b]pyridin-5-ylethyl)isoindolin-1-one,
or an N-oxide, prodrug, tautomer or hydrate thereof; or a
pharmaceutically acceptable salt thereof.
33. (canceled)
34. A pharmaceutical composition comprising at least one compound
of claim 1 and at least one excipient.
35.-44. (canceled)
45. A method for treating a medical disorder, selected from
neurological and psychiatric disorders which can be treated by
inhibition of phosphodiesterase type 10A, said method comprising
administering an effective amount of at least one compound of claim
1 to a subject in need thereof.
46. The compound of claim 1, which is
4-Fluoro-2-(2-imidazo[1,2-a]pyridin-2-yl-ethyl)-7-morpholin-4-yl-2,3-dihy-
dro-isoindol-1-one, an N-oxide, a tautomer, a hydrate; or a
pharmaceutically acceptable salt thereof.
47. The method of claim 45, where the medical disorder is a CNS
disorder.
48. The method of claim 45, where the medical disorder is selected
from the group consisting of schizophrenia, bipolar disorders,
depression, cognitive dysfunction associated with Alzheimer's
disease, diet-induced obesity Huntington's disease and anxiety.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This claims priority to U.S. Provisional Patent Application
No. 61/503,040, filed on Jun. 30, 2011, the contents of which are
herein fully incorporated by reference.
[0002] The present invention relates to novel compounds which are
inhibitors of phosphodiesterase type 10A and to their use for the
manufacture of a medicament and which thus are suitable for
treating or controlling of medical disorders selected from
neurological disorders and psychiatric disorders, for ameliorating
the symptoms associated with such disorders and for reducing the
risk of such disorders.
BACKGROUND OF THE INVENTION
[0003] Phosphodiesterase type 10A (hereinafter PDE10A) is a
dual-substrate phosphodiesterase that can convert both cAMP to AMP
and cGMP to GMP. PDE10A is highly prominent in the mammalian brain.
In the rat, as well as in other mammalian species, PDE10A and the
mRNA of PDE10A are highly enriched in the GAB Aergic medium spiny
projection neurons (MSNs) of the striatal complex (caudate nucleus,
nucleus accumbens, and olfactory tubercle) where the output is
regulated by the effect of PDE10A on cAMP and cGMP signalling
cascades (see e.g. C. J. Schmidt et al, The Journal of Pharmacology
and Experimental Therapeutics 325 (2008) 681-690, A. Nishi, The
Journal of Neuroscience 2008, 28, 10450-10471).
[0004] MSNs express two functional classes of neurons: the D.sub.1
class expressing D.sub.1 dopamine receptors and the D.sub.2 class
expressing D.sub.2 dopamine receptors. The D.sub.1 class of neurons
is part of the `direct` striatal output pathway, which broadly
functions to facilitate behavioral responses. The D.sub.2 class of
neurons is part of the `indirect` striatal output pathway, which
functions to suppress behavioral responses that compete with those
being facilitated by the `direct` pathway. PDE10A regulation of
cAMP and/or cGMP signaling in the dendritic compartment of these
neurons may be involved in filtering the cortico/thalamic input
into the MSN. Furthermore, PDE10A may be involved in the regulation
of GABA release in the substantia nigra and globus pallidus
(Seeger, T. F. et al. Brain Research, 2003, 985, 1 13-126).
Inhibition of PDE10A results in striatal activation and behavioral
suppression such as dampened locomotion, inhibition of conditioned
avoidance response (CAR), and activity in the rat auditory gating
model, suggesting that inhibitors of phosphodiesterase type 10A
represent a novel class of antipsychotic agents.
[0005] The hypotheses around the physiological role of PDE10A and
the therapeutic utility of PDE10A inhibitors derive in part from
studies with papaverine (J. A. Siuciak et al. loc. cit.), the first
extensively profiled pharmacological tool compound for this target.
The PDE10A inhibitor papaverine was shown to be active in several
antipsychotic models. Papaverine potentiated the cataleptic effect
of the D.sub.2 receptor antagonist haloperidol in rats, but did not
cause catalepsy on its own (WO 03/093499). Papaverine reduced
hyperactivity in rats induced by PCP, while reduction of
amphetamine-induced hyperactivity was insignificant (WO 03/093499).
These models suggest that PDE10A inhibition has the classic
antipsychotic potential that would be expected from theoretical
considerations. Papaverine, however has significant limitations in
this regard with relatively poor potency and selectivity and a very
short exposure half-life after systemic administration. It was
found that inhibition of PDE10A reverses subchronic PCP-induced
deficits in attentional set-shifting in rats suggesting that PDE10A
inhibitors might alleviate cognitive deficits associated with
schizophrenia. (Rodefer et al., Eur. J. Neurosci., 4 (2005)
1070-1076).
[0006] The discovery of a new class of PDE10A inhibitors with
improved potency, selectivity, and pharmacokinetic properties,
provided an opportunity to further explore the physiology of PDE10A
and the potential therapeutic utility of inhibiting this enzyme.
The new class of inhibitors are exemplified by MP-10 (PF-2545920:
2-{
4-[1-methylpyridine-4-yl-1-H-pyrazol-3-31y]phenoxymethyl}-quinoline)
and TP-10, i.e.
2-{4-[pyridine-4-yl-1-(2,2,2-trifluoroethyl)-1-H-pyrazol-3-31y]phenoxymet-
hyl}-quinoline. The compounds offer a therapeutic approach to the
treatment of schizophrenia (see C. J. Schmidt et al., loc cit.; S.
M. Grauer et al., Journal of Pharmacology and Experimental
Therapeutics, fast forward DOI 10.1124 JPET 109.155994). Positive
signals in rodent models of schizophrenia include the: attenuation
of conditioned avoidance response (CAR), inhibition of
hyperactivity caused by amphetamine-induced dopamine release or
phencyclidine (PCP) mediated NMDA receptor blockade, attenuation of
pharmacologically impaired social or object recognition, and
antagonism of apomorphine-induced climbing. Taken together, these
data suggest a broad suppression of all 3 symptoms clusters
(positive symptoms, negative symptoms & cognitive dysfunctions)
linked to schizophrenia (see C. J. Schmidt et al., loc cit.; S. M.
Grauer et al., loc. cit).
[0007] Beyond schizophrenia, selective PDE10 inhibitiors may have
the potential for the treatment of Huntington's disease (S. H.
Francis et al., Physiol. Rev., 91 (2011) 651-690) and they may be
an therapeutic option for substance abuse disorders (F. Sotty et
al., J. Neurochem., 109 (2009) 766-775). Furthermore, it has been
suggested that PDE10A inhibitors may be useful for treatment of
obesity and non-insulin dependent diabetes (see e.g. WO
2005/120514, WO 2005/012485, Cantin et al, Bioorganic &
Medicinal Chemistry Letters 17 (2007) 2869-2873).
[0008] In summary, inhibitors of PDE10A offer a promising
therapeutic approach to the treatment or prevention of neurological
and psychiatric disorders, in particular schizophrenia and related
disorders, including symptoms linked to schizophrenia such as
cognitive dysfunction.
[0009] Several classes of compounds which are inhibitors of PDE10A
have been described in the art, the recent compound groups are:
[0010] Pyridol3,2-c-elpyridazines--see WO 2007/137819, WO
2007/137820, WO 2009/068246, WO 2009/068320, WO 2009/070583 and WO
2009/070584;
[0011] 4-substiuted phthalazines and quinazolines WO 2007/085954,
WO 2007/022280, WO 2007/096743, WO 2007/103370, WO 2008/020302, WO
2008/006372 and WO 2009/036766;
[0012] 4-substiuted cinnazolines--see WO 2006/028957, WO
2007/098169, WO 2007/098214, WO 2007/103554, WO 2009/025823 and WO
2009/025839;
[0013] Isoquinolines and isoquinolinones - see WO 2007/100880 and
WO 2009/029214
[0014] MP10 and MP10 like componds: US 2007/0155779, WO 2008/001182
and WO 2008/004117; and
[0015] zodiazepines--see WO 2007/082546.
[0016] For a further review see also T. Chappie et al. Current
Opinion in Drug Discovery & Development 12(4), (2009) 458-467)
and the literature cited therein.
[0017] Although some of the compounds of prior art are known to
inhibit PDE10A effectively having IC.sub.50 values of less than 50
nM, there is still an ongoing need for compounds which inhibit
PDE10A. In particular, there is an ongoing need for compounds which
have one of the following characteristics: [0018] i. Selective
inhibition of PDE10A, in particular vis-a-inhibition of other
phosphodisesterases such as PDE3 or PDE4; [0019] ii. metabolic
stability, in particular microsomal stability, e.g. measured in
vitro, in liver microsomes from various species (e.g. rat or human)
in human cells, such as hepatocytes; [0020] iii. no or only low
inhibition of cytochrome P450 (CYP) enzymes: cytochrome P450 (CYP)
is the name for a superfamily of heme proteins having enzymatic
activity (oxidase). They are also particularly important for the
degradation (metabolism) of foreign substances such as drugs or
xenobiotics in mammalian organisms. The principal representatives
of the types and subtypes of CYP in the human body are: CYP 1A2,
CYP 2C9, CYP 2D6 and CYP 3A4. If CYP 3A4 inhibitors (e.g.
grapefruit juice, cimetidine, erythromycin) are used at the same
time as medicinal substances which are degraded by this enzyme
system and thus compete for the same binding site on the enzyme,
the degradation thereof may be slowed down and thus effects and
side effects of the administered medicinal substance may be
undesirably enhanced; [0021] iv. a suitable solubility in water (in
mg/ml); [0022] v. suitable pharmacokinetics (time course of the
concentration of the compound of the invention in plasma or in
tissue, for example brain). The pharmacokinetics can be described
by the following parameters: half-life, volume of distribution (in
lkg.sup.-1), plasma clearance (in lh.sup.-1kg.sup.-1), AUC (area
under the curve, area under the concentration-time curve (in
nghl.sup.-1), oral bioavailability, (the dose-normalized ratio of
AUC after oral administration and AUC after intravenous
administration), the so-called brain-plasma ratio (the ratio of AUC
in brain tissue and AUC in plasma); [0023] vi. no or only low
blockade of the hERG channel: compounds which block the hERG
channel may cause a prolongation of the QT interval and thus lead
to serious disturbances of cardiac rhythm (for example so-called
"torsade de pointes"). The potential of compounds to block the hERG
channel can be determined by means of the displacement assay with
radiolabelled dofetilide which is described in the literature (G.
J. Diaz et al., Journal of Pharmacological and Toxicological
Methods, 50 (2004), 187-199). A smaller IC50 in this dofetilide
assay means a greater probability of potent hERG blockade. In
addition, the blockade of the hERG channel can be measured by
electrophysiological experiments on cells which have been
transfected with the hERG channel, by so-called whole-cell patch
clamping (G. J. Diaz et al., Journal of Pharmacological and
Toxicological Methods, 50 (2004), 187-199). [0024] vii. high free
fraction in brain, i.e. the fraction of the compound bound to
proteins should be low. [0025] viii. low lipophilicity.
BRIEF DESCRIPTION OF THE INVENTION
[0026] The present invention is thus based on the object of
providing compounds which inhibit PDE10A at low concentrations.
[0027] The compounds are further intended to display at least one
of the properties i. to viii. mentioned above, in particular high
selectivity with regard to inhibition of PDE10A, high selectivity
vis-a-vis other phosphodiesterases such as, enhanced metabolic
stability, in particular microsomal and/or cytosolic stability, low
affinity to the HERG receptor, low inhibition of cytochrome P450
(CYP) enzymes, suitable solubility in water and suitable
pharmacokinetics.
[0028] This object and further objects are achieved by the
compounds of the general formula I described below, the N-oxides,
the prodrugs, the hydrates and the tautomers thereof and the
pharmaceutically suitable salts thereof:
##STR00001##
[0029] wherein
[0030] X.sup.1 is N or C--R.sup.1
[0031] X.sup.2 is N or C--R.sup.2
[0032] X.sup.3 is N or C--R.sup.3
[0033] X.sup.4 is N or C--R.sup.4
[0034] provided that 0, 1 or 2 of the moieties X.sup.1, X.sup.2,
X.sup.3 or X.sup.4 is N;
[0035] A is selected from the group consisting of O, S, S(.dbd.O),
S(.dbd.O).sub.2, NR.sup.5a and CR.sup.5R.sup.6; [0036] Het is
selected from [0037] i. monocyclic hetaryl having 1 or 2 nitrogen
atoms and optionally a further heteroatom selected from O, S and N
as ring members, which is unsubstituted or may carry 1, 2, 3 or 4
identical or different substituents R.sup.x, [0038] ii. fused
bicyclic hetaryl having 1 or 2 nitrogen atoms and optionally a
further heteroatom selected from O, S and N as ring members,
benzothienyl or benzofuryl, where bicyclic hetaryl, benzothienyl
and benzofuryl are, independently of each other, unstubstituted or
may carry 1, 2, 3 or 4 identical or different substituents R.sup.x,
and [0039] iii. phenyl, which carries a monocyclic hetaryl radical
having 1 or 2 nitrogen atoms and optionally a further heteroatom
selected from O, S and N as ring members, which in addition to
monocyclic hetaryl, may carry 1, 2 or 3 identical or different
substituents R.sup.x, [0040] where [0041] R.sup.x is selected from
the group consisting of H, halogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.1-C.sub.4-fluoroalkoxy, C.sub.3-C.sub.6-cycloalkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, OH,
hydroxy-C.sub.1-C.sub.4-alkyl, O--C.sub.3-C.sub.6-cycloalkyl,
benzyloxy, C(O)O--(C.sub.1-C.sub.4-alkyl),
O--(C.sub.1-C.sub.4-alkyl)--CO.sub.2H, N(R.sup.x1)(R.sup.x2),
C(O)N(R.sup.x1)(R.sup.x2)
C.sub.1-C.sub.4-alkyl-N(R.sup.x1)(R.sup.x2),
--NR.sup.x3--C(O)--N(R.sup.x1)(R.sup.x2),
NR.sup.x3--C(O)O--(C.sub.1-C.sub.4-alkyl),
--N(R.sup.x3)--SO.sub.2--R.sup.x4, phenyl, CN, --SF.sub.5,
--SOF.sub.5, --SO.sub.2R.sup.x4, --SR.sup.x4 and trimethylsilyl,
where R.sup.x1, R.sup.x2, R.sup.x3 and R.sup.x4, independently of
each other are selected from the group consisting of hydrogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-fluoroalkyl and
C.sub.3-C.sub.6-cycloalkyl or R.sup.x1 and R.sup.x2 form together
with the N atom to which they are attached a 3- to 7-membered,
nitrogen heterocycle which may have 1, 2 or 3 further different or
identical heteroatoms or heteroatom containing groups selected from
the group of O, N, S, SO and SO.sub.2 as ring members and which may
carry 1, 2, 3, 4, 5 or 6 substituents selected from
C.sub.1-C.sub.4-alkyl;
[0042] R.sup.1, R.sup.4 independently of each other, are selected
from the group consisting of hydrogen, halogen, OH,
C.sub.1-C.sub.4-alkyl, trimethylsilyl,
C.sub.1-C.sub.4-alkylsulfanyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkylsulfanyl-C.sub.1-C.sub.4-alkoxy,
C.sub.2-C.sub.4-alkenyloxy, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.1-C.sub.4-fluoroalkoxy, cyclopropyl, optionally substituted
by 1, 2 or 3 methyl groups, fluorinated cyclopropyl, CN,
NR.sup.x1R.sup.x2, NR.sup.x1R.sup.x2--C.sub.1-C.sub.4-alkoxy and
the moiety Y-Cyc; [0043] R.sup.2, R.sup.3 independently of each
other, are selected from the group consisting of hydrogen, halogen,
OH, C.sub.1-C.sub.4-alkyl, trimethylsilyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkoxy,
C.sub.2-C.sub.4-alkenyloxy, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.1-C.sub.4-fluoroalkoxy, cyclopropyl, optionally substituted
by 1, 2 or 3 methyl groups, fluorinated cyclopropyl, CN,
NR.sup.x1R.sup.x2 and the moiety Y-Cyc; [0044] provided that one or
two or the radicals R.sup.1, R.sup.2, R.sup.3, R.sup.4 are a moiety
Y-Cyc; [0045] R.sup.5, R.sup.6 independently of each other are
selected from the group consisting of hydrogen, OH, halogen,
C.sub.1-C.sub.4-alkyl, trimethylsilyl, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.1-C.sub.4-fluoroalkoxy, C.sub.3-C.sub.6-cycloalkyl,
optionally substituted by 1, 2 or 3 methyl groups, and fluorinated
C.sub.3-C.sub.6-cycloalkyl or the radicals R.sup.5, R.sup.6
together with the carbon atom to which they are bound form a
carbonyl group or a saturated 3- to 6-membered carbocycle or a
saturated 3- to 6-membered heterocycle having 1 or 2 non-adjacent
heteroatoms as ring members, where the carbocycle and the
heterocycle are unsubstituted or may carry 1, 2, 3 or 4
substituents selected from fluorine and methyl; [0046] R.sup.5a is
selected from the group consisting of from C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.1-C.sub.4-fluoroalkoxy, C.sub.3-C.sub.6-cycloalkyl,
optionally substituted by 1, 2 or 3 methyl groups, fluorinated
C.sub.3-C.sub.6-cycloalkyl, phenyl, benzyl, 5- or 6-membered
hetaryl having 1, 2 or 3 heteroatoms selected from O, S and N as
ring members, and 5- or 6-membered hetarylmethyl having 1, 2 or 3
heteroatoms selected from O, S and N as ring members, where the
rings in the last four mentioned radicals are unsubstituted or
carry 1, 2, 3 or 4 substituents selected from fluorine,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-fluoroalkoxy; [0047]
R.sup.7, R.sup.8, R.sup.9, R.sup.10 independently of each other are
selected from the group consisting of hydrogen, halogen,
C.sub.1-C.sub.4-alkyl, trimethylsilyl, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.1-C.sub.4-fluoroalkoxy, C.sub.3-C.sub.6-cycloalkyl, or the
radicals together with the carbon atoms to which they are bound
form a saturated 3- to 6-membered carbocycle or a saturated 3- to
6-membered heterocycle having 1 or 2 non-adjacent heteroatoms as
ring members, where the carbocycle and the heterocycle are
unsubstituted or may carry 1, 2, 3 or 4 substituents selected from
fluorine and methyl or either the radicals R.sup.7, R.sup.8 or the
radicals R.sup.9, o R.sup.10 together with the carbon atom to which
they are bound form a saturated 3- to 6-membered carbocycle or a
saturated 3- to 6-membered heterocycle having 1 or 2 non-adjacent
heteroatoms as ring members, where the carbocycle and the
heterocycle are unsubstituted or may carry 1, 2, 3 or 4
substituents selected from fluorine and methyl; [0048] Y is a
chemical bond, CH.sub.2, O, O--CH.sub.2, NR.sup.y,
NR.sup.y--CH.sub.2, NR.sup.y--S(O).sub.2, S, S(O), S(O).sub.2,
1,2-ethandiyl, 1,2-ethendiyl or 1,2-ethyndiyl, where R.sup.y is
selected from the group consisting of hydrogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkylcarbonyl,
C.sub.1-C.sub.4-alkylsulfonyl, C.sub.1-C.sub.4-fluoroalkylsulfonyl;
[0049] Cyc is a radical selected from the group consisting of
phenyl, naphthyl, 4- to 8-membered saturated or partially
unsaturated monocarbocyclic radicals, 7- to 10-membered saturated
or partially unsaturated bicarbocyclic radicals, 4- to 8-membered
saturated or partially unsaturated heteromonocyclic radicals,
saturated or partially unsaturated 7- to 10 membered heterobicyclic
radicals, 5- or 6-membered monocyclic hetaryl, and 8- to 10
membered bicyclic hetaryl, where the saturated or partially
unsaturated heteromonocyclic and heterobicyclic radicals have 1, 2,
3 or 4 heteroatoms or heteroatom containing groups as ring members,
which are selected from O, S, SO, SO.sub.2 and N, and where the 5-
or 6-membered monocyclic hetaryl and the 8- to 10-membered bicyclic
hetaryl have 1, 2, 3 or 4 heteroatoms as ring members, which are
selected from O, S and N, [0050] where phenyl, naphthyl, the
saturated or partially unsaturated mono- and bicarbocyclic
radicals, the heteromonocyclic and heterobicyclic radicals and the
mono and bicyclic heteroaromatic radicals are unsubstituted or
carry 1, 2, 3, 4 or 5 radicals R.sup.C1 or one radical Y'--R.sup.C2
and 0, 1, 2, 3 or 4 radicals R.sup.C1; where [0051] R.sup.C1 is
selected from hydrogen, halogen, OH, CN, NO.sub.2,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkylsulfanyl, hydroxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkoxy,
cyano-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.1-C.sub.4-fluoroalkoxy, C.sub.1-C.sub.4-alkylsulfonyl,
C(O)R.sup.a, Z--C(O)OR.sup.b, Z--C(O)NR.sup.cR.sup.d,
S(O).sub.2NR.sup.cR.sup.d and Z--NR.sup.eR.sup.f, where [0052]
R.sup.a is selected from the group consisting of
C.sub.1-C.sub.4-alkyl and C.sub.1-C.sub.4-fluoroalkyl, [0053]
R.sup.b is selected from the group consisting of hydrogen,
C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl and
C.sub.1-C.sub.4-fluoroalkyl, [0054] R.sup.c, R.sup.d is selected
from the group consisting of hydrogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-fluoroalkyl, C.sub.1-C.sub.4-alkoxy and
C.sub.1-C.sub.4-fluoroalkoxy, [0055] R.sup.e, R.sup.f is selected
from the group consisting of hydrogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-fluoroalkyl, C.sub.1-C.sub.4-alkoxy and
C.sub.1-C.sub.4-fluoroalkoxy, [0056] Z is a covalent bond or
C.sub.1-C.sub.4-alkandiyl, [0057] or two radicals R.sup.C1 which
are bound at adjacent carbon atoms may form a fused 5- or
6-membered carbocyclic radical or a fused 5- or 6-membered
heterocyclic radical having 1, 2 or 3 heteroatoms as ring members,
which are selected from O, S and N; [0058] or two radicals R.sup.C1
which are bound at the same carbon atom may form a spiro 5- or
6-membered carbocyclic radical or a spiro 5- or 6-membered
heterocyclic radical having 1 or 2 heteroatoms as ring members,
which are selected from O, S and N, [0059] or two radicals R.sup.C1
which are bound at the same carbon atom may form an oxygen atom,
[0060] where the fused and the spiro radicals are unsubstituted or
carry 1, 2, 3 or 4 radicals R.sup.C3; [0061] Y' is a chemical bond,
CH.sub.2, O, O--CH.sub.2, S(O).sub.2, NR.sup.y, NR.sup.y,
--CH.sub.2 or NR.sup.y'--S(O).sub.2, where R.sup.y' is selected
from the group consisting of hydrogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkylc arbonyl, C.sub.1-C.sub.4-alkylsulfonyl,
C.sub.1-C.sub.4-fluoroalkylsulfonyl ; [0062] R.sup.C2 is a
carbocyclic or heterocyclic radical selected from the group
consisting of phenyl, 3- to 7-membered saturated or partially
unsaturated monocarbocyclic radicals, 3- to 7-membered saturated or
partially unsaturated heteromonocyclic radicals, having 1, 2 or 3
heteroatoms as ring members, which are selected from O, S and N,
and 5- or 6-membered heteroaromatic radicals, having 1, 2 or 3
heteroatoms as ring members, which are selected from O, S and N,
where the carbocyclic and the heterocyclic radical is unsubstituted
or carries 1, 2, 3, 4 or 5 radicals R.sup.C3; [0063] R.sup.C3 is
selected from hydrogen, halogen, OH, CN, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy, hydroxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
cyano-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.1-C.sub.4-fluoroalkoxy, C.sub.2-C.sub.6-alkenyl, C(O)R.sup.a,
Z--C(O)OR.sup.b, Z--C(O)NR.sup.cR.sup.d, S(O).sub.2NR.sup.cR.sup.d
and Z--NR.sup.eR.sup.f, where, Z, R.sup.a, R.sup.b, R.sup.c,
R.sup.d, R.sup.e and R.sup.f are as defined above or two radicals
R.sup.C3 which are bound at the same atom may form an oxygen
atom.
[0064] The present invention therefore relates to the compounds of
the general formula I, their tautomers, the hydrates thereof, the
pharmaceutically suitable salts of the compounds of formula I, the
prodrugs of the compounds of formula I and the pharmaceutically
suitable salts of said prodrugs, tautomers or hydrates of the
compounds of formula I.
[0065] The compounds of the formula I, their salts, their prodrugs,
their hydrates and their tautomers effectively inhibit PDE10A even
at low concentrations. They are additionally distinguished by a
high selectivity in relation to the inhibition of the PDE10A
vis-a-vis inhibition of other phosphodiesterease, such as PDE3 or
PDE4. The compounds of the invention may additionally have one or
more of the properties ii. to viii. mentioned above.
[0066] The compounds of the formula I, their salts, their prodrugs,
their hydrates and their tautomers are therefore particularly
suitable for treating disorders and conditions in creatures,
especially human creatures, which can be treated or controlled by
inhibition of phosphodiesterase type 10A.
[0067] The invention therefore also relates to the use of
carboxamide compounds of the formula I, their tautomers, their
hydrates and their pharmaceutically suitable salts for the
manufacture of a medicament, in particular of a medicament which is
suitable for the treatment of a disorder or a condition which can
be treated by inhibition of phosphodiesterase type 10A.
[0068] The invention further relates to a medicament, in particular
a medicament which is suitable for the treatment of a disorder or a
condition which can be treated by inhibition of phosphodiesterase
type 10A. The medicament comprises at least one compound of the
formula I, as described herein, or a tautomer, or a hydrate or a
prodrug of said compound I, or a pharmaceutically suitable salt of
the compound of the formula I or a pharmaceutically suitable salt
of the tautomer, the hydrate or the prodrug of compound of the
formula I.
DETAILED DESCRIPTION OF THE INVENTION
[0069] The terms "compound of the formula I" and "compounds I" are
used as synonyms. The term "prodrugs" means compounds which are
metabolized in vivo to the compounds I of the invention. Typical
examples of prodrugs are described in C. G. Wermuth (editor): The
Practice of Medicinal Chemistry, Academic Press, San Diego, 1996,
pages 671-715. These include for example phosphates, carbamates,
amino acids, esters, amides, peptides, ureas and the like. Suitable
prodrugs in the present case may be for example derivatives of
those compounds I carrying an OH or NH.sub.2-group, where the OH or
NH.sub.2-group forms an ester/amide/peptide linkage, i.e. where one
of the hydrogen atoms of the OH or NH.sub.2-group is substituted by
a C.sub.1-C.sub.4-alkylcarbonyl group, e.g. by acetyl, propionyl,
n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl or
tert-butylcarbonyl (pivaloyl), by benzoyl, or by an acyl group
derived from an amino acid, e.g. glycine, alanine, serine,
phenylalanine and the like, which is linked to the oxygen or
nitrogen of the OH or NH.sub.2-group via the carbonyl group of the
amino acid. Further suitable prodrugs are alkylcarbonyloxyalkyl
carbonates or carbamates of compounds I carrying an OH- or
NH.sub.2-group in which one of the hydrogen atoms of the OH- or
NH.sub.2-group has been replaced by a group of the formula
--C(.dbd.O)--O--CHR.sup.p--O--C(.dbd.O)--R.sup.q in which R.sup.p
and R.sup.q are independently of one another C.sub.1-C.sub.4-alkyl.
Such carbonates and carbamates are described for example in J.
Alexander, R. Cargill, S. R. Michelson, H. Schwam, J. Medicinal
Chem. 1988, 31(2), 318-322. These groups can then be eliminated
under metabolic conditions and result in compounds I. Therefore,
said prodrugs and their pharmaceutically acceptable salts are also
part of the invention.
[0070] The term "pharmaceutically acceptable salts" refers to
cationic or anionic salts compounds, wherein the counter ion is
derived from pharmaceutically acceptable non-toxic bases or acids
including inorganic or organic bases and inorganic or organic
acids.
[0071] When the compound of formula I or its prodrug or N-oxide is
acidic, salts may be prepared from pharmaceutically acceptable
non-toxic bases, including inorganic and organic bases. Salts
derived from inorganic bases include salts, wherein the counter ion
is aluminium, ammonium, calcium, copper, ferric, ferrous, lithium,
magnesium, manganic, manganous, potassium, sodium, zinc ion and the
like. Particularly preferred are the ammonium, calcium, magnesium,
potassium, and sodium ions. Salts derived from pharmaceutically
acceptable organic non-toxic bases include salts of primary,
secondary, and tertiary amines, substituted amines including
naturally occurring substituted amines, cyclic amines, and basic
ion exchange resins, such as arginine, betaine, caffeine, choline,
dibenzylethylene-diamine, diethylamine, 2-diethylamino-ethanol,
2-dimethylaminoethanol, ethanolamine, ethylenediamine,
N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine,
histidine, hydrabamine, isopropylamine, lysine, methylglucamine,
morpholine, piperazine, piperidine, polyamine resins, procaine,
purines, theobromine, triethylamine, trimethylamine,
tripropylamine, tromethamine, and the like.
[0072] When the compound of formula I or its prodrug or N-oxide is
basic, salts may be prepared from pharmaceutically acceptable
non-toxic acids, including inorganic and organic acids. Such acids
include acetic, trifluoroacetic acid, benzenesulfonic, benzoic,
camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,
glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic,
malic, mandelic, methanesulfonic, mucic, nitric, pamoic,
pantothenic, phosphoric, succinic, sulfuric, tartaric,
p-toluenesulfonic acid, and the like. Particularly preferred are
citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric,
fumaric, and tartaric acids. It will be understood that, as used
herein, references to the compounds of formula I are meant to also
include the pharmaceutically acceptable salts.
[0073] The compounds of the invention may be in the form of a
mixture of diastereomers, or of a mixture of diastereomers in which
one of the two diastereomers is enriched, or of essentially
diastereomerically pure compounds (diastereomeric excess
de>90%). The compounds are preferably in the form of essentially
diastereomerically pure compounds (diastereomeric excess
de>90%). The compounds I of the invention may furthermore be in
the form of a mixture of enantiomers (for example as racemate), of
a mixture of enantiomers in which one of the two enantiomers is
enriched, or essentially in enantiomerically pure compounds
(enantiomeric excess ee>90%). However, the compounds of the
invention are frequently prone to racemization in relation to the
stereochemistry of the carbon atom which carries the radical
R.sup.1, so that mixtures are frequently obtained in relation to
this carbon atom, or compounds which exhibit a uniform
stereochemistry in relation to this C atom form mixtures under
physiological conditions. However, in relation to other
stereocenters and the occurrence, associatied therewith, of
enantiomers and diastereomers, it is preferred to employ the
compounds enantiomerically pure or diastereomerically pure.
[0074] The present invention moreover relates to compounds as
defined herein, wherein one or more of the atoms depicted in
formula I have been replaced by its stable, preferably
non-radioactive isotope (e.g., hydrogen by deuterium, .sup.12C by
.sup.13C, .sup.14N by .sup.15N, .sup.16O by .sup.18O) and
preferably wherein at least one hydrogen atom has been replaced by
a deuterium atom. Of course, the compounds according to the
invention contain more of the respective isotope than this
naturally occurs and thus is anyway present in the compounds I.
[0075] The compounds of the formula I and their salts in the solid
form may exist in more than one crystal structure (polymorphism),
and may also be in the form of hydrates or other solvates. The
present invention includes any polymorph of the compound I or its
salt as well as any hydrate or other solvate.
[0076] In the context of the present description, unless stated
otherwise, the terms "alkyl", "alkenyl", "alkoxy", "alkenyloxy",
"fluoroalkyl", "fluoroalkoxy", "cycloalkyl", "fluorinated
cycloalkyl", "alkylene", "alkandiyl", "hetaryl" and radicals
derived therefrom, such as "alkylcarbonyl", "alkylsulfanyl",
"alkylsulfonyl", "fluoroalkylsulfonyl", "hydroxylalkyl",
"cyanoalkyl", "alkoxylalkyl", "alkoxyalkoxy", "alkylsulfanylalkyl",
"alkylsulfanylalkoxy" and "hetarylmethyl" represent groups of
individual radicals. The groups of noncyclic radicals "alkyl",
"alkenyl", "alkoxy", "alkenyloxy", "fluoroalkyl", "fluoroalkoxy",
"alkylene", "alkandiyl", and the groups of radicals derived
therefrom always include both unbranched and branched "alkyl",
"alkenyl", "alkoxy", "alkenyloxy", "fluoroalkyl", "fluoroalkoxy",
"alkylene" and "alkandiyl", respectively.
[0077] The prefix C.sub.n-C.sub.m-indicates the respective number
of carbons in the hydrocarbon unit. Unless indicated otherwise,
fluorinated substituents preferably have one to five identical or
different fluorine atoms.
[0078] The term "halogen" designates in each case, fluorine,
bromine, chlorine or iodine, specifically fluorine, chlorine or
bromine.
[0079] Examples of other meanings are:
[0080] Alkyl, and the alkyl moieties for example in alkylcarbonyl,
alkylsulfanyl, alkylsulfonyl, alkylsulfanylalkyl and
alkylsulfaylalkoxy: saturated, straight-chain or branched
hydrocarbon radicals having one or more C atoms, e.g. 1 to 4 carbon
atoms, e.g. C.sub.1-C.sub.4-alkyl such as methyl, ethyl, propyl,
1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl and
1,1-dimethylethyl.
[0081] Fluoroalkyl and the fluoroalkyl moieties for example in
fluoroalkylsulfonyl: an alkyl radical having ordinarily 1 to 4 C
atoms, in particular 1 or 2C-atoms (C.sub.1-C.sub.2-fluoroalkyl) as
mentioned above, whose hydrogen atoms are partly or completely
replaced by fluorine atoms such as fluoromethyl, difluoromethyl,
trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoroethyl, pentafluoroethyl, 2-fluoro-1-methylethyl,
2,2-difluoro-1-methylethyl, 2,2-trifluoro-1-methylethyl,
2-fluoropropyl, 3-fluoropropyl, 2,2-difluoropropyl,
2,3-difluoropropyl, 3,3,3-trifluoropropyl,
2,3,3,3-pentafluoropropyl, heptafluoropropyl,
1-(fluoromethyl)-2-fluoroethyl, 4-fluorobutyl, and
nonafluorobutyl.
[0082] Cycloalkyl, and the cycloalkyl moieties for example in
cycloalkoxy or cycloalkyl-C.sub.1-C.sub.4-alkyl: monocyclic,
saturated hydrocarbon groups having three or more C atoms, e.g. 3,
4, 5, 6 or 7 carbon ring members, such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl and cycloheptyl.
[0083] Fluorinated cycloalkyl: monocyclic, saturated hydrocarbon
groups having three or more C atoms, e.g. 3, 4, 5, 6 or 7 carbon
ring members, such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and cycloheptyl, wherein at least one, e.g. 1, 2, 3, 4,
5 or 6 of the hydrogen atoms are replaced by fluorine atoms,
examples including 1-fluorocyclopropyl, 2-fluorocyclopropyl,
2,2-difluorocyclopropyl, 1,2-difluorocyclopropyl,
2,3-difluorocyclopropyl, etc.
[0084] Cycloalkoxy: a cycloalkyl radical as defined above which is
linked via an oxygen atom, e.g. cyclopropyloxy, cyclobutyloxy,
cyclopentyloxy or cyclohexyloxy.
[0085] Cycloalkylalkyl: a cycloalkyl radical as defined above which
is linked via an alkylene group, in particular via a methylene,
1,1-ethylene or 1,2-ethylene group, e.g. cyclopropylmethyl,
cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.
[0086] Alkenyl, and alkenyl moieties for example in alkenyloxy:
monounsaturated, straight-chain or branched hydrocarbon radicals
having two or more C atoms, e.g. 2 to 4 carbon atoms and one
C.dbd.C-double bond in any position, e.g. C.sub.2-C.sub.4-alkenyl
such as ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl,
1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl,
2-methyl-1-propenyl, 1-methyl-2-propenyl and
2-methyl-2-propenyl.
[0087] Alkoxy or alkoxy moieties for example in alkoxyalkyl and
alkoxyalkoxy:
[0088] an alkyl radical as defined above having preferably 1 to 4 C
atoms, which is connected to the remainder of the molecule via an O
atom: e.g. methoxy, ethoxy, n-propoxy, 1-methylethoxy, butoxy,
1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy.
[0089] Fluoroalkoxy: alkoxy as described above, in which the
hydrogen atoms of these groups are partly or completely replaced by
fluorine atoms, i.e. for example C.sub.1-C.sub.4-fluoroalkoxy, in
particular C.sub.1-C.sub.2-fluoroalkoxy, such as fluoromethoxy,
difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy,
2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy,
2-fluoropropoxy, 3-fluoropropoxy, 2,2-difluoropropoxy,
2,3-difluoropropoxy, 3,3,3-trifluoropropoxy,
2,2,3,3,3-pentafluoropropoxy, heptafluoropropoxy,
1-(fluoromethyl)-2-fluoroethoxy, specifically fluoromethoxy,
difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, or
2,2,2-trifluoroethoxy.
[0090] Hydroxyalkyl: an alkyl radical ordinarily having 1 to 4 C
atoms, in which one hydrogen atom is replaced by an OH radical.
Examples thereof are CH.sub.2-OH, 1-hydroxyethyl, 2-hydroxyethyl,
1-hydroxypropyl, 2-hydroxypropyl, 1-methyl-1-hydroxyethyl,
1-methyl-2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxybutyl,
3-hydroxybutyl, 4-hydroxybutyl, 1-methyl-2-hydroxypropyl,
1,1-dimethyl-2-hydroxyetyl, 1-methyl-1-hydroxypropyl etc.
[0091] Cyanoalkyl: an alkyl radical ordinarily having 1 to 4 C
atoms, in which one hydrogen atom is replaced by a CN radical.
Examples thereof are CH.sub.2--CN, 1-cyanoethyl, 2-cyanoethyl,
1-cyanopropyl, 2-cyanopropyl, 1-methyl-1-cyanoethyl,
1-methyl-2-cyanoethyl, 3-cyanopropyl, 2-cyanobutyl, 3-cyanobutyl,
4-cyanobutyl, 1-methyl-2-cyanopropyl, 1,1-dimethyl-2-cyanoetyl,
1-methyl-1-cyanopropyl etc.
[0092] Alkoxyalkyl: an alkyl radical ordinarily having 1 to 4 C
atoms, in which one hydrogen atom is replaced by an alkoxy radical
ordinarily having 1 to 4 C atoms. Examples thereof are
CH.sub.2-OCH.sub.3, CH.sub.2-OC.sub.2H.sub.5, n-propoxymethyl,
CH.sub.2-OCH(CH.sub.3).sub.2, n-butoxymethyl,
(1-methylpropoxy)methyl, (2-methylpropoxy)methyl,
CH.sub.2--OC(CH.sub.3).sub.3, 2-(methoxy)ethyl, 2-(ethoxy)ethyl,
2-(n-propoxy)ethyl, 2-(1-methylethoxy)ethyl, 2-(n-butoxy)ethyl,
2-(1-methylpropoxy)ethyl, 2-(2-methylpropoxy)ethyl,
2-(1,1-dimethylethoxy)ethyl, 2-(methoxy)propyl, 2-(ethoxy)propyl,
2-(n-propoxy)propyl, 2-(1-methylethoxy)propyl, 2-(n-butoxy)propyl,
2-(1-methylpropoxy)propyl, 2-(2-methylpropoxy)propyl,
2-(1,1-dimethylethoxy)propyl, 3-(methoxy)propyl, 3-(ethoxy)propyl,
3-(n-propoxy)propyl, 3-(1-methylethoxy)propyl, 3-(n-butoxy)propyl,
3-(1-methylpropoxy)propyl, 3-(2-methylpropoxy)propyl,
3-(1,1-dimethylethoxy)propyl, 2-(methoxy)butyl, 2-(ethoxy)butyl,
2-(n-propoxy)butyl, 2-(1-methylethoxy)butyl, 2-(n-butoxy)butyl,
2-(1-methylpropoxy)butyl, 2-(2-methylpropoxy)butyl,
2-(1,1-dimethylethoxy)butyl, 3-(methoxy)butyl, 3-(ethoxy)butyl,
3-(n-propoxy)butyl, 3-(1-methylethoxy)butyl, 3-(n-butoxy)butyl,
3-(1-methylpropoxy)butyl, 3-(2-methylpropoxy)butyl,
3-(1,1-dimethylethoxy)butyl, 4-(methoxy)butyl, 4-(ethoxy)butyl,
4-(n-propoxy)butyl, 4-(1-methylethoxy)butyl, 4-(n-butoxy)butyl,
4-(1-methylpropoxy)butyl, 4-(2-methylpropoxy)butyl,
4-(1,1-dimethylethoxy)butyl, etc.
[0093] Alkoxyalkoxy: an alkoxyalkyl radical as defined above
ordinarily having 1 to 4 C atoms both in the alkoxy and the alkyl
moiety which is connected to the remainder of the molecule via an O
atom: Examples thereof are OCH.sub.2-OCH.sub.3,
OCH.sub.2-OC.sub.2H.sub.5, n-propoxymethoxy,
OCH.sub.2-OCH(CH.sub.3).sub.2, n-butoxymethoxy,
(1-methylpropoxy)methoxy, (2-methylpropoxy)methoxy,
OCH.sub.2--OC(CH.sub.3).sub.3, 2-(methoxy)ethoxy, 2-(ethoxy)ethoxy,
2-(n-propoxy)ethoxy, 2-(1-methylethoxy)ethoxy, 2-(n-butoxy)ethoxy,
2-(1-methylpropoxy)ethoxy, 2-(2-methylpropoxy)ethoxy,
2-(1,1-dimethyl-ethoxy)ethoxy, etc.
[0094] Alkylcarbonyl: alkyl as defined above preferably having 1 to
4 C atoms, which is connected via a carbonyl group to the remainder
of the molecule, e.g. acetyl, propionyl, butyryl, isobutyryl,
pentanoyl, pivaloyl and the like.
[0095] Alkylsulfanyl and the alkylsulfanyl radicals in
alkylsulfanylalkyl and alkylsulfanylalkoxy: alkyl as defined above
preferably having 1 to 4 C atoms, which is connected via an S atom
to the remainder of the molecule, e.g. methylsulfanyl,
ethylsulfanyl, n-propylsulfanyl and the like.
[0096] Alkylsulfonyl: alkyl as defined above preferably having 1 to
4 C atoms, which is connected via an SO.sub.2 group to the
remainder of the molecule, e.g. methylsulfonyl, ethylsulfonyl,
n-propylsulfonyl and the like.
[0097] Fluoroalkylsulfanyl: fluoroalkyl as defined above preferably
having 1 to 4 C atoms, which is connected via an S atom to the
remainder of the molecule, e.g. fluoromethylsulfanyl,
difluoromethylsulfanyl, trifluoromethylsulfanyl,
2-fluoroethylsulfanyl, 2,2-difluoroethylsulfanyl,
2,2,2-trifluoroethylsulfanyl, pentafluoroethylsulfanyl,
2-fluoropropylsulfanyl, 3-fluoropropylsulfanyl,
2,2-difluoropropylsulfanyl, 2,3-difluoropropylsulfanyl, and
heptafluoropropylsulfanyl.
[0098] Fluoroalkylsulfonyl: fluoroalkyl as defined above preferably
having 1 to 4 C atoms, which is connected via an SO.sub.2 group to
the remainder of the molecule, e.g. fluoromethylsulfonyl,
difluoromethylsulfonyl, trifluoromethylsulfonyl,
2-fluoroethylsulfonyl, 2,2-difluoroethylsulfonyl,
2,2,2-trifluoroethylsulfonyl, pentafluoroethylsulfonyl,
2-fluoropropylsulfonyl, 3-fluoropropylsulfonyl,
2,2-difluoropropylsulfonyl, 2,3-difluoropropylsulfonyl, and
heptafluoropropylsulfonyl.
[0099] Alkylsulfanylalkyl: an alkyl radical ordinarily having 1 to
4 C atoms, in which one hydrogen atom is replaced by an
alkylsulfanyl radical ordinarily having 1 to 4 C atoms. Examples
thereof are CH.sub.2-SCH.sub.3, CH.sub.2-SC.sub.2H.sub.5,
n-propylsulfanylmethyl, CH.sub.2--SCH(CH.sub.3).sub.2,
n-butylsulfanylmethyl, (1-methylpropsulfanyl)methyl,
(2-methylpropsulfanyl)methyl, CH.sub.2--OC(CH.sub.3).sub.3,
2-(methylsulfanyl)ethyl, 2-(ethylsulfanyl)ethyl,
2-(n-propylsulfanyl)ethyl, 2-(1-methylethylsulfanyl)ethyl,
2-(n-butylsulfanyl)ethyl, 2-(1-methylpropylsulfanyl)ethyl,
2-(2-methylpropylsulfanyl)ethyl,
2-(1,1-dimethylethylsulfanyl)ethyl, 2-(methylsulfanyl)propyl,
2-(ethylsulfanyl)propyl, 2-(n-propylsulfanyl)propyl,
2-(1-methylethylsulfanyl)propyl, 2-(n-butylsulfanyl)propyl,
2-(1-methylpropylsulfanyl)propyl, 2-(2-methylpropylsulfanyl)propyl,
2-(1,1-dimethylethylsulfanyl)propyl, 3-(methylsulfanyl)propyl,
3-(ethylsulfanyl)propyl, 3-(n-propylsulfanyl)propyl,
3-(1-methylethylsulfanyl)propyl, 3-(n-butylsulfanyl)propyl,
3-(1-methylpropylsulfanyl)propyl, 3-(2-methylpropylsulfanyl)propyl,
3-(1,1-dimethylethylsulfanyl)propyl, 2-(methylsulfanyl)butyl,
2-(ethylsulfanyl)butyl, 2-(n-propylsulfanyl)butyl,
2-(1-methylethylsulfanyl)butyl, 2-(n-butylsulfanyl)butyl,
2-(1-methylpropylsulfanyl)butyl, 2-(2-methylpropylsulfanyl)butyl,
2-(1,1-dimethylethylsulfanyl)butyl, 3-(methylsulfanyl)butyl,
3-(ethylsulfanyl)butyl, 3-(n-propylsulfanyl)butyl,
3-(1-methylethylsulfanyl)butyl, 3-(n-butylsulfanyl)butyl,
3-(1-methylpropylsulfanyl)butyl, 3-(2-methylpropylsulfanyl)butyl,
3-(1,1-dimethyl-ethylsulfanyl)butyl, 4-(methylsulfanyl)butyl,
4-(ethylsulfanyl)butyl, 4-(n-propylsulfanyl)butyl,
4-(1-methylethylsulfanyl)butyl, 4-(n-butylsulfanyl)butyl,
4-(1-methylpropylsulfanyl)butyl, 4-(2-methylpropylsulfanyl)butyl,
4-(1,1-dimethylethylsulfanyl)butyl, etc.
[0100] "Alkylen" or "Alkandiyl": a saturated hydrocarbon chain
having ordinarily from 1 to 4 carbon atoms, such as methylen
(--CH.sub.2--), 1,2-ethylen (--CH.sub.2CH.sub.2--), 1,1-ethandiyl
(--CH(CH.sub.3)--), 1,2-propandiyl, 1,3-propandiyl, 1,4-butandiyl,
1,2-butandiyl, 1,3-butandiyl, 1-methyl-1,2-propandiyl,
2-methyl-1,3-propandiyl, 1-methyl-1,1-ethandiyl,
1-methyl-1,2-propandiyl etc.
[0101] Saturated or partially unsaturated 4 to 7-membered
monocarbocyclic radicals include cycloalkyl as defined above and
cycloalkenyl having ordinarily from 4 to 7 carbon atoms as ring
members, e.g. 1-cyclobuten-1-yl, 2-cyclobutenyl, 1-cyclopentenyl,
2-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl,
1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl.
[0102] Saturated or partially unsaturated 7 to 10-membered
bicarbocyclic radicals include bicyclic carbocyclic radicals which
ordinarily have from 7 to 10 carbon atoms as ring members and which
are saturated or which have one or more, e.g. one or two C.dbd.C
double bonds, or which include a monounsaturated carbocycle where
the double bond is part of a fused benzene ring, e.g.
bicyclo[2,2,1]-1-heptyl, bicyclo[2,2,1]-2-heptyl,
bicyclo[2,2,1]-7-heptyl, bicyclo[3,3,0]-1-octyl,
bicyclo[3,3,0]-2-octyl, bicyclo[3,3,0]-3-octyl,
bicyclo[2,2,2]-1-octyl, bicyclo[2,2,2]-2-octyl,
bicyclo[3,2,1]-1-octyl, bicyclo[3,2,1]-2-octyl,
bicyclo[3,2,1]-6-octyl, bicyclo[3,2,1]-8-octyl,
bicyclo[4,3,0]-1-nonyl, bicyclo[4,3,0]-2-nonyl,
bicyclo[4,3,0]-3-nonyl, bicyclo[4,3,0]-7-nonyl,
bicyclo[4,3,0]-8-nonyl, bicyclo[4,4,0]-1-decyl,
bicyclo[4,4,0]-2-decyl, bicyclo[4,4,0]-3-decyl,
bicyclo[2,2,1]-hept-2-en-1-yl, bicyclo[2,2,1]-hept-2-en-2-yl,
bicyclo[2,2,1]-hept-2-en-5-yl, bicyclo[2,2,1]-hept-2-en-7-yl,
bicyclo[2,2,2]-oct-2-en-1-yl, bicyclo[2,2,2]-oct-2-en-2-yl,
bicyclo[2,2,2]-oct-2-en-5-yl, bicyclo[2,2,2]-oct-2-en-7-yl,
bicyclo[3,3,0]-2-octen-1-yl, bicyclo[3,3,0]-2-octen-2-yl,
bicyclo[3,3,0]-2-octen-3-yl, bicyclo[3,3,0]-2-octen-4-yl,
bicyclo[3,3,0]-2-octen-5-yl, bicyclo[3,3,0]-2-octen-6-yl,
bicyclo[3,3,0]-2-octen-7-yl, bicyclo[3,3,0]-2-octen-8-yl,
inden-1-yl, inden-2-yl, inden-4-yl, inden-6-yl,
tetrahydro-1-naphthyl, tetrahydro-2-naphthyl,
tetrahydro-5-naphthyl, tetrahydro-6-naphthyl, etc.
[0103] Heterocyclyl: a heterocyclic radical which may be saturated
or partly unsaturated and which may be a monocyclic heterocyclic
radical ordinarily having 3, 4, 5, 6, 7 or 8 ring atoms or a
heterobicyclic radical ordinarily having 7, 8, 9 or 10 ring atoms,
where ordinarily 1, 2, 3 or 4, in particular 1, 2 or 3, of the ring
atoms are heteroatoms such as N, S or O, or heteroatom groups such
as S(.dbd.O) or S(.dbd.O).sub.2 besides carbon atoms as ring
members.
[0104] Examples of saturated heteromonocycles are in particular:
[0105] Saturated heteromonocyclic radical which ordinarily has 3,
4, 5, 6 or 7 ring atoms, where ordinarily 1, 2 or 3 of the ring
atoms are heteroatoms such as N, S or O, besides carbon atoms as
ring members. These include for example: [0106] C-bonded, 3- or
4-membered saturated rings such as [0107] 2-oxiranyl, 2-oxetanyl,
3-oxetanyl, 2-aziridinyl, 3-thiethanyl, 1-azetidinyl, 2-azetidinyl.
[0108] C-bonded, 5-membered saturated rings such as [0109]
tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,
tetrahydrothien-3-yl, tetrahydropyrrol-2-yl, tetrahydropyrrol-3-yl,
tetrahydropyrazol-3-yl, tetrahydropyrazol-4-yl,
tetrahydroisoxazol-3-yl, tetrahydroisoxazol-4-yl,
tetrahydroisoxazol-5-yl, 1,2-oxathiolan-3-yl, 1,2-oxathiolan-4-yl,
1,2-oxathiolan-5-yl, tetrahydroisothiazol-3-yl,
tetrahydroisothiazol-4-yl, tetrahydroisothiazol-5-yl,
1,2-dithiolan-3-yl, 1,2-dithiolan-4-yl, tetrahydroimidazol-2-yl,
tetrahydroimidazol-4-yl, tetrahydrooxazol-2-yl,
tetrahydrooxazol-4-yl, tetrahydrooxazol-5-yl,
tetrahydrothiazol-2-yl, tetrahydrothiazol-4-yl,
tetrahydrothiazol-5-yl, 1,3-dioxolan-2-yl, 1,3-dioxolan-4-yl,
1,3-oxathiolan-2-yl, 1,3-oxathiolan-4-yl, 1,3-oxathiolan-5-yl,
1,3-dithiolan-2-yl, 1,3-dithiolan-4-yl, 1,3,2-dioxathiolan-4-yl.
[0110] C-bonded, 6-membered saturated rings such as: [0111]
tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl,
piperidin-2-yl, piperidin-3-yl, piperidin-4-yl,
tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl,
tetrahydrothiopyran-4-yl, 1,3-dioxan-2-yl, 1,3-dioxan-4-yl,
1,3-dioxan-5-yl, 1,4-dioxan-2-yl, 1,3-dithian-2-yl,
1,3-dithian-4-yl, 1,3-dithian-5-yl, 1,4-dithian-2-yl,
1,3-oxathian-2-yl, 1,3-oxathian-4-yl, 1,3-oxathian-5-yl,
1,3-oxathian-6-yl, 1,4-oxathian-2-yl, 1,4-oxathian-3-yl,
1,2-dithian-3-yl, 1,2-dithian-4-yl, hexahydropyrimidin-2-yl,
hexahydropyrimidin-4-yl, hexahydropyrimidin-5-yl,
hexahydropyrazin-2-yl, hexahydropyridazin-3-yl,
hexahydropyridazin-4-yl, tetrahydro-1,3-oxazin-2-yl,
tetrahydro-1,3-oxazin-4-yl, tetrahydro-1,3-oxazin-5-yl,
tetrahydro-1,3-oxazin-6-yl, tetrahydro-1,3-thiazin-2-yl,
tetrahydro-1,3-thiazin-4-yl, tetrahydro-1,3-thiazin-5-yl,
tetrahydro-1,3-thiazin-6-yl, tetrahydro-1,4-thiazin-2-yl,
tetrahydro-1,4-thiazin-3-yl, tetrahydro-1,4-oxazin-2-yl,
tetrahydro-1,4-oxazin-3-yl, tetrahydro-1,2-oxazin-3-yl,
tetrahydro-1,2-oxazin-4-yl, tetrahydro-1,2-oxazin-5-yl,
tetrahydro-1,2-oxazin-6-yl. [0112] N-bonded, 5-membered saturated
rings such as: [0113] tetrahydropyrrol-1-yl,
tetrahydropyrazol-1-yl, tetrahydroisoxazol-2-yl,
tetrahydroisothiazol-2-yl, tetrahydroimidazol-1-yl,
tetrahydrooxazol-3-yl, tetrahydrothiazol-3-yl. [0114] N-bonded,
6-membered saturated rings such as: [0115] piperidin-1-yl,
hexahydropyrimidin-1-yl, hexahydropyrazin-1-yl,
hexahydro-pyridazin-1-yl, tetrahydro-1,3-oxazin-3-yl,
tetrahydro-1,3-thiazin-3-yl, tetrahydro-1,4-thiazin-4-yl,
tetrahydro-1,4-oxazin-4-yl, tetrahydro-1,2-oxazin-2-yl. [0116]
Unsaturated heteromonocyclic radicals which ordinarily have 4, 5, 6
or 7 ring atoms, where ordinarily 1, 2 or 3 of the ring atoms are
heteroatoms such as N, S or O, besides carbon atoms as ring
members. These include for example: [0117] C-bonded, 5-membered,
partially unsaturated rings such as: [0118] 2,3-dihydrofuran-2-yl,
2,3-dihydrofuran-3-yl, 2,5-dihydrofuran-2-yl,
2,5-dihydrofuran-3-yl, 4,5-dihydrofuran-2-yl,
4,5-dihydrofuran-3-yl, 2,3-dihydrothien-2-yl,
2,3-dihydrothien-3-yl, 2,5-dihydrothien-2-yl,
2,5-dihydrothien-3-yl, 4,5-dihydrothien-2-yl,
4,5-dihydrothien-3-yl, 2,3-dihydro-1H-pyrrol-2-yl,
2,3-dihydro-1H-pyrrol-3-yl, 2,5-dihydro-1H-pyrrol-2-yl,
2,5-dihydro-1H-pyrrol-3-yl, 4,5-dihydro-1H-pyrrol-2-yl,
4,5-dihydro-1H-pyrrol-3-yl, 3,4-dihydro-2H-pyrrol-2-yl,
3,4-dihydro-2H-pyrrol-3-yl, 3,4-dihydro-5H-pyrrol-2-yl,
3,4-dihydro-5H-pyrrol-3-yl, 4,5-dihydro-1H-pyrazol-3-yl,
4,5-dihydro-1H-pyrazol-4-yl, 4,5-dihydro-1H-pyrazol-5-yl,
2,5-dihydro-1H-pyrazol-3-yl, 2,5-dihydro-1H-pyrazol-4-yl,
2,5-dihydro-1H-pyrazol-5-yl, 4,5-dihydroisoxazol-3-yl,
4,5-dihydroisoxazol-4-yl, 4,5-dihydroisoxazol-5-yl,
2,5-dihydroisoxazol-3-yl, 2,5-dihydroisoxazol-4-yl,
2,5-dihydroisoxazol-5-yl, 2,3-dihydroisoxazol-3-yl,
2,3-dihydroisoxazol-4-yl, 2,3-dihydroisoxazol-5-yl,
4,5-dihydroisothiazol-3-yl, 4,5-dihydroisothiazol-4-yl,
4,5-dihydroisothiazol-5-yl, 2,5-dihydroisothiazol-3-yl,
2,5-dihydroisothiazol-4-yl, 2,5-dihydroisothiazol-5-yl,
2,3-dihydroisothiazol-3-yl, 2,3-dihydroisothiazol-4-yl,
2,3-dihydroisothiazol-5-yl, 4,5-dihydro-1H-imidazol-2-yl,
4,5-dihydro-1H-imidazol-4-yl, 4,5-dihydro-1H-imidazol-5-yl,
2,5-dihydro-1H-imidazol-2-yl, 2,5-dihydro-1H-imidazol-4-yl,
2,5-dihydro-1H-imidazol-5-yl, 2,3-dihydro-1H-imidazol-2-yl,
2,3-dihydro-1H-imidazol-4-yl, 4,5-dihydrooxazol-2-yl,
4,5-dihydrooxazol-4-yl, 4,5-dihydrooxazol-5-yl,
2,5-dihydrooxazol-2-yl, 2,5-dihydrooxazol-4-yl,
2,5-dihydrooxazol-5-yl, 2,3-dihydrooxazol-2-yl,
2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl,
4,5-dihydrothiazol-2-yl, 4,5-dihydrothiazol-4-yl,
4,5-dihydrothiazol-5-yl, 2,5-dihydrothiazol-2-yl,
2,5-dihydrothiazol-4-yl, 2,5-dihydrothiazol-5-yl,
2,3-dihydrothiazol-2-yl, 2,3-dihydrothiazol-4-yl,
2,3-dihydrothiazol-5-yl, 1,3-dioxo1-2-yl, 1,3-dioxo1-4-yl,
1,3-dithiol-2-yl, 1,3-dithiol-4-yl, 1,3-oxathiol-2-yl,
1,3-oxathiol-4-yl, 1,3-oxathiol-5-yl. [0119] C-bonded, 6-membered,
partially unsaturated rings such as: [0120]
2H-3,4-dihydropyran-6-yl, 2H-3,4-dihydropyran-5-yl,
2H-3,4-dihydropyran-4-yl, 2H-3,4-dihydropyran-3-yl,
2H-3,4-dihydropyran-2-yl, 2H-3,4-dihydrothiopyran-6-yl,
2H-3,4-dihydrothiopyran-5-yl, 2H-3,4-dihydrothiopyran-4-yl,
2H-3,4-dihydrothiopyran-3-yl, 2H-3,4-dihydrothiopyran-2-yl,
1,2,3,4-tetrahydropyridin-6-yl, 1,2,3,4-tetrahydropyridin-5-yl,
1,2,3,4-tetrahydropyridin-4-yl, 1,2,3,4-tetra-hydropyridin-3-yl,
1,2,3,4-tetrahydropyridin-2-yl, 2H-5,6-dihydropyran-2-yl,
2H-5,6-dihydropyran-3-yl, 2H-5,6-dihydropyran-4-yl,
2H-5,6-dihydropyran-5-yl, 2H-5,6-dihydropyran-6-yl,
2H-5,6-dihydrothiopyran-2-yl, 2H-5,6-dihydrothiopyran-3-yl,
2H-5,6-dihydrothiopyran-4-yl, 2H-5,6-dihydrothiopyran-5-yl,
2H-5,6-dihydrothiopyran-6-yl, 1,2,5,6-tetrahydropyridin-2-yl,
1,2,5,6-tetrahydropyridin-3-yl, 1,2,5,6-tetrahydropyridin-4-yl,
1,2,5,6-tetrahydropyridin-5-yl, 1,2,5,6-tetra-hydropyridin-6-yl,
2,3,4,5-tetrahydropyridin-2-yl, 2,3,4,5-tetrahydropyridin-3-yl,
2,3,4,5-tetrahydropyridin-4-yl, 2,3,4,5-tetrahydropyridin-5-yl,
2,3,4,5-tetrahydropyridin-6-yl, 4H-pyran-2-yl, 4H-pyran-3-yl,
4H-pyran-4-yl, 4H-thiopyran-2-yl, 4H-thiopyran-3-yl,
4H-thiopyran-4-yl, 1,4-dihydropyridin-2-yl,
1,4-dihydropyridin-3-yl, 1,4-dihydropyridin-4-yl, 2H-pyran-2-yl,
2H-pyran-3-yl, 2H-pyran-4-yl, 2H-pyran-5-yl, 2H-pyran-6-yl,
2H-thiopyran-2-yl, 2H-thiopyran-3-yl, 2H-thiopyran-4-yl,
2H-thiopyran-5-yl, 2H-thiopyran-6-yl, 1,2-dihydropyridin-2-yl,
1,2-dihydropyridin-3-yl, 1,2-dihydropyridin-4-yl,
1,2-dihydropyridin-5-yl, 1,2-dihydropyridin-6-yl,
3,4-dihydropyridin-2-yl, 3,4-dihydropyridin-3-yl,
3,4-dihydropyridin-4-yl, 3,4-dihydropyridin-5-yl,
3,4-dihydropyridin-6-yl, 2,5-dihydropyridin-2-yl,
2,5-dihydropyridin-3-yl, 2,5-dihydropyridin-4-yl,
2,5-dihydropyridin-5-yl, 2,5-dihydropyridin-6-yl,
2,3-dihydropyridin-2-yl, 2,3-dihydropyridin-3-yl,
2,3-dihydropyridin-4-yl, 2,3-dihydropyridin-5-yl,
2,3-dihydropyridin-6-yl, 2H-5,6-dihydro-1,2-oxazin-3-yl,
2H-5,6-dihydro-1,2-oxazin-4-yl, 2H-5,6-dihydro-1,2-oxazin-5-yl,
2H-5,6-dihydro-1,2-oxazin-6-yl, 2H-5,6-dihydro-1,2-thiazin-3-yl,
2H-5,6-dihydro-1,2-thiazin-4-yl, 2H-5,6-dihydro-1,2-thiazin-5-yl,
2H-5,6-dihydro-1,2-thiazin-6-yl, 4H-5,6-dihydro-1,2-oxazin-3-yl,
4H-5,6-dihydro-1,2-oxazin-4-yl, 4H-5,6-dihydro-1,2-oxazin-5-yl,
4H-5,6-dihydro-1,2-oxazin-6-yl, 4H-5,6-dihydro-1,2-thiazin-3-yl,
4H-5,6-dihydro-1,2-thiazin-4-yl, 4H-5,6-dihydro-1,2-thiazin-5-yl,
4H-5,6-dihydro-1,2-thiazin-6-yl, 2H-3,6-dihydro-1,2-oxazin-3-yl,
2H-3,6-dihydro-1,2-oxazin-4-yl, 2H-3,6-dihydro-1,2-oxazin-5-yl,
2H-3,6-dihydro-1,2-oxazin-6-yl, 2H-3,6-dihydro-1,2-thiazin-3-yl,
2H-3,6-dihydro-1,2-thiazin-4-yl, 2H-3,6-dihydro-1,2-thiazin-5-yl,
2H-3,6-dihydro-1,2-thiazin-6-yl, 2H-3,4-dihydro-1,2-oxazin-3-yl,
2H-3,4-dihydro-1,2-oxazin-4-yl, 2H-3,4-dihydro-1,2-oxazin-5-yl,
2H-3,4-dihydro-1,2-oxazin-6-yl, 2H-3,4-dihydro-1,2-thiazin-3-yl,
2H-3,4-dihydro-1,2-thiazin-4-yl, 2H-3,4-dihydro-1,2-thiazin-5-yl,
2H-3,4-dihydro-1,2-thiazin-6-yl, 2,3,4,5-tetrahydropyridazin-3-yl,
2,3,4,5-tetrahydropyridazin-4-yl, 2,3,4,5-tetrahydropyridazin-5-yl,
2,3,4,5-tetrahydropyridazin-6-yl, 3,4,5,6-tetrahydropyridazin-3-yl,
3,4,5,6-tetrahydropyridazin-4-yl, 1,2,5,6-tetrahydropyridazin-3-yl,
1,2,5,6-tetrahydropyridazin-4-yl, 1,2,5,6-tetrahydropyridazin-5-yl,
1,2,5,6-tetrahydropyridazin-6-yl, 1,2,3,6-tetrahydropyridazin-3-yl,
1,2,3,6-tetrahydropyridazin-4-yl, 4H-5,6-dihydro-1,3-oxazin-2-yl,
4H-5,6-dihydro-1,3-oxazin-4-yl, 4H-5,6-dihydro-1,3-oxazin-5-yl,
4H-5,6-dihydro-1,3-oxazin-6-yl, 4H-5,6-dihydro-1,3-thiazin-2-yl,
4H-5,6-dihydro-1,3-thiazin-4-yl, 4H-5,6-dihydro-1,3-thiazin-5-yl,
4H-5,6-dihydro-1,3-thiazin-6-yl, 3,4,5-6-tetrahydropyrimidin-2-yl,
3,4,5,6-tetrahydropyrimidin-4-yl,
3,4,5,6-tetra-hydropyrimidin-5-yl,
3,4,5,6-tetrahydropyrimidin-6-yl, 1,2,3,4-tetrahydropyrazin-2-yl,
1,2,3,4-tetrahydropyrazin-5-yl, 1,2,3,4-tetrahydropyrimidin-2-yl,
1,2,3,4-tetrahydropyrimidin-4-yl, 1,2,3,4-tetrahydropyrimidin-5-yl,
1,2,3,4-tetrahydropyrimidin-6-yl, 2,3-dihydro-1,4-thiazin-2-yl,
2,3-dihydro-1,4-thiazin-3-yl, 2,3-dihydro-1,4-thiazin-5-yl,
2,3-dihydro-1,4-thiazin-6-yl, 2H-1,3-oxazin-2-yl,
2H-1,3-oxazin-4-yl, 2H-1,3-oxazin-5-yl, 2H-1,3-oxazin-6-yl,
2H-1,3-thiazin-2-yl, 2H-1,3-thiazin-4-yl, 2H-1,3-thiazin-5-yl,
2H-1,3-thiazin-6-yl, 4H-1,3-oxazin-2-yl, 4H-1,3-oxazin-4-yl,
4H-1,3-oxazin-5-yl, 4H-1,3-oxazin-6-yl, 4H-1,3-thiazin-2-yl,
4H-1,3-thiazin-4-yl, 4H-1,3-thiazin-5-yl, 4H-1,3-thiazin-6-yl,
6H-1,3-oxazin-2-yl, 6H-1,3-oxazin-4-yl, 6H-1,3-oxazin-5-yl,
6H-1,3-oxazin-6-yl, 6H-1,3-thiazin-2-yl, 6H-1,3-oxazin-4-yl,
6H-1,3-oxazin-5-yl, 6H-1,3-thiazin-6-yl, 2H-1,4-oxazin-2-yl,
2H-1,4-oxazin-3-yl, 2H-1,4-oxazin-5-yl, 2H-1,4-oxazin-6-yl,
2H-1,4-thiazin-2-yl, 2H-1,4-thiazin-3-yl, 2H-1,4-thiazin-5-yl,
2H-1,4-thiazin-6-yl, 4H-1,4-oxazin-2-yl, 4H-1,4-oxazin-3-yl,
4H-1,4-thiazin-2-yl, 4H-1,4-thiazin-3-yl,
1,4-dihydropyridazin-3-yl, 1,4-dihydropyridazin-4-yl,
1,4-dihydropyridazin-5-yl, 1,4-dihydropyridazin-6-yl,
1,4-dihydropyrazin-2-yl, 1,2-dihydropyrazin-2-yl,
1,2-dihydropyrazin-3-yl, 1,2-dihydropyrazin-5-yl,
1,2-dihydropyrazin-6-yl, 1,4-dihydropyrimidin-2-yl,
1,4-dihydropyrimidin-4-yl, 1,4-dihydropyrimidin-5-yl,
1,4-dihydropyrimidin-6-yl, 3,4-dihydropyrimidin-2-yl,
3,4-dihydropyrimidin-4-yl, 3,4-dihydropyrimidin-5-yl or
3,4-dihydropyrimidin-6-yl. [0121] N-bonded, 5-membered, partially
unsaturated rings such as: [0122] 2,3-dihydro-1H-pyrrol-1-yl, 2,
5-dihydro-1H-pyrrol-1-yl, 4, 5-dihydro-1H-pyrazol-1-yl,
2,5-dihydro-1H-pyrazol-1-yl, 2,3-dihydro-1H-pyrazol-1-yl,
2,5-dihydroisoxazol-2-yl, 2,3-dihydroisoxazol-2-yl,
2,5-dihydroisothiazol-2-yl, 2,3-dihydroisoxazol-2-yl,
4,5-dihydro-1H-imidazol-1-yl, 2,5-dihydro-1H-imidazol-1-yl,
2,3-dihydro-1H-imidazol-1-yl, 2,3-dihydrooxazol-3-yl,
2,3-dihydrothiazol-3-yl. [0123] N-bonded, 6-membered, partially
unsaturated rings such as: [0124] 1,2,3,4-tetrahydropyridin-1-yl,
1,2,5,6-tetrahydropyridin-1-yl, 1,4-dihydropyridin-1-yl,
1,2-dihydropyridin-1-yl, 2H-5,6-dihydro-1,2-oxazin-2-yl,
2H-5,6-dihydro-1,2-thiazin-2-yl, 2H-3,6-dihydro-1,2-oxazin-2-yl,
2H-3,6-dihydro-1,2-thiazin-2-yl, 2H-3,4-dihydro-1,2-oxazin-2-yl,
2H-3,4-dihydro-1,2-thiazin-2-yl, 2,3,4,5-tetrahydropyridazin-2-yl,
1,2,5,6-tetrahydropyridazin-1-yl, 1,2,5,6-tetrahydropyridazin-2-yl,
1,2,3,6-tetrahydropyridazin-1-yl, 3,4,5,6-tetrahydropyrimidin-3-yl,
1,2,3,4-tetrahydropyrazin-1-yl, 1,2,3 ,4-tetrahydropyrimidin-1-yl,
1,2,3 ,4-tetrahydro-pyrimidin-3-yl, 2,3-dihydro-1,4-thiazin-4-yl,
2H-1,2-oxazin-2-yl, 2H-1,2-thiazin-2-yl, 4H-1,4-oxazin-4-yl,
4H-1,4-thiazin-4-yl, 1,4-dihydropyridazin-1-yl,
1,4-dihydropyrazin-1-yl, 1,2-dihydropyrazin-1-yl,
1,4-dihydropyrimidin-1-yl or 3,4-dihydropyrimidin-3-yl.
[0125] Examples of saturated or partially unsaturated
heterobicycles are in particular radicals corresponding to
saturated or partially unsaturated bicarbocyclic radicals, wherein
1, 2 or 3 CH or CH.sub.2 moieties have been replaced by N, NH, O,
S, S(.dbd.O) or S(.dbd.O).sub.2, such as
2-oxa-6-azaspiro-[3,4]octyl, 2-azabicyclo[2.2.1]heptyl,
5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl,
3-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl,
3,8-diazabicyclo[3.2.1]octyl, dihydroindolyl, dihydroindolizynyl,
dihydroisoindolyl, dihydroquinolinyl, dihydroisoquinolinyl,
chromenyl and chromanyl.
[0126] Hetaryl: a 5- or 6-membered aromatic heteromonocyclic
radical (also termed 5- or 6-membered monocyclic hetaryl) which
ordinarily has 1, 2, 3 or 4 heteroatoms as ring members, which are
selected from O, S and N, and which has in particular 1, 2, 3 or 4
nitrogen atoms or a heteroatom selected from oxygen and sulfur and,
if appropriate, 1 or 2 nitrogen atoms as ring members besides
carbon atoms as ring members and a 8- to 10-membered aromatic
heterobicyclic radical (also termed 8- to 10-membered bicyclic
hetaryl) which ordinarily has 1, 2, 3 or 4 heteroatoms as ring
members, which are selected from O, S and N, and which has in
particular 1, 2, 3 or 4 nitrogen atoms or a heteroatom selected
from oxygen and sulfur and, if appropriate, 1 or 2 nitrogen atoms
as ring members besides carbon atoms as ring members: for example
[0127] C-bonded, 5-membered monocyclic hetaryl having 1, 2 or 3 or
4 nitrogen atoms or a heteroatom selected from oxygen and sulfur
and, if appropriate, having 1, 2 or 3 nitrogen atoms as ring
members, such as: [0128] 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,
pyrrol-2-yl, pyrrol-3-yl, pyrazol-3-yl, pyrazol-4-yl,
isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, isothiazol-3-yl,
isothiazol-4-yl, isothiazol-5-yl, imidazol-2-yl, imidazol-4-yl,
oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl,
thiazol-5-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl,
1,2,4-oxadiazol-3-yl, 1,2,4,-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,
1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl,
1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl,
1,3,4-thiadiazolyl-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl,
tetrazol-5-yl. [0129] C-bonded, 6-membered monocyclic hetaryl
having 1, 2 or 3 nitrogen atoms as ring members, such as: [0130]
pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl,
pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl,
pyrazin-2-yl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl,
1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1,2,4,5-tetrazin-3-yl.
[0131] N-bonded, 5-membered heteroaromatic radicals having 1, 2, 3
or 4 nitrogen atoms as ring members, such as: [0132] pyrrol-1-yl,
pyrazol-1-yl, imidazol-1-yl, 1,2,3-triazol-1-yl,
1,2,4-triazol-1-yl, tetrazol-1-yl. [0133] bicyclic 8 to 10-membered
hetaryl, hetaryl which has one of the aforementioned 5- or
6-membered heteroaromatic rings and a further aromatic carbocycle
or 5- or 6-membered heterocycle fused thereto, for example a fused
benzene, thiophene, furane, pyrrole, pyrazole, imidazole, pyridine
or pyrimidine ring. These bicyclic hetaryl include for example
quinolinyl, isoquinolinyl, cinnolinyl, indolyl, indolizynyl,
isoindolyl, indazolyl, benzofuryl, benzothienyl, benzo[b]thiazolyl,
benzoxazolyl, benzthiazolyl, benzimidazolyl,
imidazo[1,2-a]pyridine-2-yl, thieno[3,2-b]pyridine-5-yl,
imidazo-[2,1-b]-thiazol-6-yl and
1,2,4-triazolo[1,5-a]pyridine-2-yl.
[0134] Hetarylalkyl: a hetaryl radical as defined above which is
linked via an alkylene group, in particular via a methylene,
1,1-ethylene or 1,2-ethylene group, to the remainder of the
molecule.
[0135] The expression "optionally substituted" in the context of
the present invention means that the respective moiety is
unsubstituted or has 1, 2 or 3, in particular 1, substituents which
are selected from halogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, OH, SH, CN, CF.sub.3, O--CF.sub.3, COOH,
O--CH.sub.2--COOH, C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.4-haloalkoxy, C.sub.1-C.sub.6-alkylthio,
C.sub.3-C.sub.7-cycloalkyl, COO--C.sub.1-C.sub.6-alkyl, CONH.sub.2,
CONH--C.sub.1-C.sub.6-alkyl, SO.sub.2NH--C.sub.1-C.sub.6-alkyl,
CON--(C.sub.1-C.sub.6-alkyl).sub.2,
SO.sub.2N--(C.sub.1-C.sub.6-alky).sub.2,
NH--SO.sub.2--C.sub.1-C.sub.6-alkyl, NH--CO--C.sub.1-C.sub.6-alkyl,
SO.sub.2--C.sub.1-C.sub.6-alkyl, O-phenyl, O--CH.sub.2-phenyl,
CONH-phenyl, SO.sub.2NH-phenyl, CONH-hetaryl, SO.sub.2NH-hetaryl,
SO.sub.2-phenyl, NH--SO.sub.2-phenyl, NH--CO-phenyl,
NH--SO.sub.2-hetaryl and NH--CO-hetaryl, where phenyl and hetaryl
in the last 11 radicals mentioned are unsubstituted or may have 1,
2 or 3 substituents which are selected from halogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy.
[0136] In relation to their use as inhibitors of PDE10A, the
variables Het, X.sup.1, X.sup.2, X.sup.3, X.sup.4, A, R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.5a, R.sup.6, R.sup.7,
R.sup.8, R.sup.9, R.sup.10, Y, Cyc and Z preferably have the
following meanings, where these represent, both considered on their
own and in combination with at least one other or all, special
configurations of the compounds of the formula I:
[0137] Het is preferably selected from the group consisting of
C-bound 6-membered monocyclic hetaryl, which has 1 or 2 nitrogen
atoms as ring members, benzofuryl and C-bound, fused bicyclic
hetaryl, which has 1 or 2 nitrogen atoms as ring members and
optionally a further heteroatom selected from O, S and N as ring
member, where monocyclic hetaryl, benzofuryl and bicyclic hetaryl
may be unsubstituted or may carry 1, 2, 3 or 4 substituents
R.sup.x, in particular 0, 1 or 2 substituents R.sup.x. In this
regard, R.sup.x is preferably selected from halogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.2-fluoroalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.2-fluoralkoxy, phenyl,
C.sub.3-C.sub.6-cycloalkyl, optionally substituted by 1, 2 or 3
methyl groups, and fluorinated C.sub.3-C.sub.6-cycloalkyl. In this
regard, R.sup.x is in particular selected from fluorine, chlorine,
methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,
fluoromethoxy, difluoromethoxy, trifluoromethoxy, phenyl,
cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, and
fluorinated cyclopropyl.
[0138] In a particular embodiment of the invention, Het is selected
from fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as
ring members and optionally a further heteroatom selected from O, S
and N as ring member and which may be unsubstituted or may carry 1,
2, 3 or 4 substituents R.sup.x, in particular 0, 1 or 2
substituents R.sup.x. In this regard, R.sup.x is preferably
selected from halogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.2-fluoroalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.2-fluoralkoxy, C.sub.3-C.sub.6-cycloalkyl, optionally
substituted by 1, 2 or 3 methyl groups, and fluorinated
C.sub.3-C.sub.6-cycloalkyl. In this regard, R.sup.x is in
particular selected from fluorine, chlorine, methyl, fluoromethyl,
difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, cyclopropyl, optionally
substituted by 1, 2 or 3 methyl groups, and fluorinated
cyclopropyl.
[0139] In another particular embodiment of the invention, Het is
selected from 6-membered monocyclic hetaryl, which may be
unsubstituted or may carry 1, 2, 3 or 4 substituents R.sup.x, in
particular 0, 1 or 2 substituents R.sup.x. In this regard, R.sup.x
is preferably selected from halogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.2-fluoroalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.2-fluoralkoxy, phenyl, C.sub.3-C.sub.6-cycloalkyl,
optionally substituted by 1, 2 or 3 methyl groups, and fluorinated
C.sub.3-C.sub.6-cycloalkyl. In this regard, R.sup.x is in
particular selected from fluorine, chlorine, methyl, fluoromethyl,
difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, cyclopropyl, optionally
substituted by 1, 2 or 3 methyl groups, and fluorinated cyclopropyl
or one R.sup.x may also be phenyl.
[0140] Particular preference is given to those Het radicals, which
have at least one imino-nitrogen as ring member, which is located
in the position adjacent to carbon atom bound to the group
CR.sup.9R.sup.10. Particular preference is given to those Het
radicals, which have at least one imino-nitrogen as ring member,
which is located in the position adjacent to carbon atom bound to
the group CR.sup.9R.sup.10 and which are selected from the group
consisting of C-bound 6-membered monocyclic hetaryl, which has 1 or
2 nitrogen atoms as ring members, benzofuryl and C-bound, fused
bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members
and optionally a further heteroatom selected from O, S and N as
ring member, where monocyclic hetaryl, benzofuryl and bicyclic
hetaryl may be unsubstituted or may carry 1, 2, 3 or 4 substituents
R.sup.x, in particular 0, 1 or 2 substituents R.sup.x. In this
regard, R.sup.x is preferably selected from halogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.2-fluoroalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.2-fluoralkoxy, phenyl,
C.sub.3-C.sub.6-cycloalkyl, optionally substituted by 1, 2 or 3
methyl groups, and fluorinated C.sub.3-C.sub.6-cycloalkyl. In this
regard, R.sup.x is in particular selected from fluorine, chlorine,
methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,
fluoromethoxy, difluoromethoxy, trifluoromethoxy, phenyl,
cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, and
fluorinated cyclopropyl. Particular examples of Het are selected
from the group consisting of 2-benzofuryl, 2-pyridyl,
3-pyridazinyl, 2-pyrimidinyl, 2-quinolinyl, 2-quinazolinyl,
2-quinoxalinyl, benzimidazol-2-yl, 1-methylbenzimidazol-2-yl,
benzothiaozo-2-yl, imidazo[1,2-a]pyridine-2-yl,
thieno[3,2-b]pyridine-5-yl, imidazo-[2,1-b]-thiazol-6-yl and
1,2,4-triazolo[1,5-a]pyridine-2-yl, where the aforementioned
radicals are unsubstituted or may carry 1, 2 or 3 radicals R.sup.x
as defined above, which are in particular selected from the group
consisting of fluorine, chlorine, methyl, fluoromethyl,
difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, cyclopropyl, optionally
substituted by 1, 2 or 3 methyl groups, and fluorinated
cyclopropyl.
[0141] In a particular embodiment of the invention, Het has at
least one imino-nitrogen as ring member, which is located in the
position adjacent to carbon atom bound to the group
CR.sup.9R.sup.10 and Het is selected from the group consisting of
fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring
members and optionally a further heteroatom selected from O, S and
N as ring member, where bicyclic hetaryl may be unsubstituted or
may carry 1, 2, 3 or 4 substituents R.sup.x, in particular 0, 1 or
2 substituents R.sup.x. In this regard, R.sup.x is preferably
selected from halogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.2-fluoroalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.2-fluoralkoxy, C.sub.3-C.sub.6-cycloalkyl, optionally
substituted by 1, 2 or 3 methyl groups, and fluorinated
C.sub.3-C.sub.6-cycloalkyl. In this regard, R.sup.x is in
particular selected from fluorine, chlorine, methyl, fluoromethyl,
difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, cyclopropyl, optionally
substituted by 1, 2 or 3 methyl groups, and fluorinated
cyclopropyl. Particular examples of Het of this embodiment are
2-quinolinyl, 2-quinazolinyl, 2-quinoxalinyl, benzimidazol-2-yl,
1-methylbenzimidazol-2-yl, benzothiaozo-2-yl,
imidazo[1,2-a]pyridine-2-yl, thieno[3,2-b]pyridine-5-yl,
imidazo-[2,1-b]-thiazol-6-yl and
1,2,4-triazolo[1,5-a]pyridine-2-yl, where the aforementioned
radicals are unsubstituted or may carry 1, 2 or 3 radicals R.sup.x
as defined above, which are in particular selected from the group
consisting of fluorine, chlorine, methyl, fluoromethyl,
difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, cyclopropyl, optionally
substituted by 1, 2 or 3 methyl groups, and fluorinated
cyclopropyl.
[0142] Particular preference is given to compounds of the formula
I, where Het is 2-quinolinyl or imidazo[1,2-a]pyridine-2-yl, where
these radicals are unsubstituted or may carry 1, 2 or 3 radicals
R.sup.x as defined above, which are in particular selected from the
group consisting of fluorine, chlorine, methyl, fluoromethyl,
difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, cyclopropyl, optionally
substituted by 1, 2 or 3 methyl groups, and fluorinated
cyclopropyl.
[0143] Particular preference is given to compounds of the formula
I, where Het is 1-methylbenzimidazol-2-yl or benzothiazol-2-yl,
where these radicals are unsubstituted or may carry 1, 2 or 3
radicals R.sup.x as defined above, which are in particular selected
from the group consisting of fluorine, chlorine, methyl,
fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,
fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl,
optionally substituted by 1, 2 or 3 methyl groups, and fluorinated
cyclopropyl.
[0144] Particular preference is given to compounds of the formula
I, where Het is 2-pyridyl, where 2-pyridyl unsubstituted or may
carry 1, 2 or 3 radicals R.sup.x as defined above, which are in
particular selected from the group consisting of halogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkyoxy, cyclopropyl,
optionally substituted by 1, 2 or 3 methyl groups, and fluorinated
cyclopropyl, such as fluorine, chlorine, methyl, ethyl, isopropyl,
fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,
fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl,
1-methylcyclopropyl, 1-fluorocyclopropyl and
2-fluorocyclopropyl.
[0145] X.sup.1 is preferably N or CR.sup.1.
[0146] X.sup.2 is preferably CR.sup.2.
[0147] X.sup.3 is preferably CR.sup.3.
[0148] X.sup.4 is preferably CR.sup.4.
[0149] In this regard, those radicals R.sup.1, R.sup.2, R.sup.3 and
R.sup.4, which are different from Y-Cyc, are in particular
selected, independently of each other, from the group consisting of
hydrogen, fluorine, C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.4-alkoxy, fluorinated
C.sub.1-C.sub.2-alkoxy, cyclopropyl, optionally substituted by 1, 2
or 3 methyl groups, and fluorinated cyclopropyl. In particular
R.sup.2 and R.sup.3 are both hydrogen.
[0150] In a particular group of embodiments of the invention,
X.sup.1 is N, X.sup.2 is C--R.sup.2, X.sup.3 is C--R.sup.3 and
X.sup.4 is C--R.sup.4, where R.sup.2, R.sup.3 and R.sup.4 are as
defined above. In another particular group of embodiments of the
invention, X.sup.1 is C--R.sup.1, X.sup.2 is C--R.sup.2, X.sup.3 is
C--R.sup.3 and X.sup.4 is C--R.sup.4.
[0151] In preferred embodiments of the invention, either R.sup.1 or
R.sup.4 is a radical Y-Cyc and R.sup.2 and R.sup.3, if present,
have a meaning different from Y-Cyc. Amongst these, a particular
embodiment relates to those compounds of the formula I, where
X.sup.4 is C--R.sup.4 and R.sup.4 is a radical Y-Cyc. Amongst
these, another particular embodiment relates to those compounds of
the formula I, where X.sup.1 is C--R.sup.1 and R.sup.1 is a radical
Y-Cyc.
[0152] In particular embodiments of the invention, X.sup.4 is
C--R.sup.4 and R.sup.4 is a radical Y-Cyc, while X.sup.1 is N or
C--R.sup.1, X.sup.2 is C--R.sup.2 and X.sup.3 is C--R.sup.3, where
R.sup.1, if present, R.sup.2 and R.sup.3 have a meaning different
from Y-Cyc. In this regard, R.sup.1, R.sup.2 and R.sup.3 are as
defined above and preferably selected, independently of each other,
from the group consisting of hydrogen, fluorine,
C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.2-alkyl,
C.sub.1-C.sub.4-alkoxy, fluorinated C.sub.1-C.sub.2-alkoxy,
cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, and
fluorinated cyclopropyl. In particular R.sup.2 and R.sup.3 are both
hydrogen.
[0153] In other particular embodiments of the invention, X.sup.1 is
C--R.sup.1 and R.sup.1 is a radical Y-Cyc, while X.sup.4 is N or
C--R.sup.4, X.sup.2 is C--R.sup.2 and X.sup.3 is C--R.sup.3, where
R.sup.4, if present, R.sup.2 and R.sup.3 have a meaning different
from Y-Cyc. In this regard, R.sup.2, R.sup.3 and R.sup.4, if
present, are as defined above and preferably selected,
independently of each other, from the group consisting of hydrogen,
fluorine, C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.2-alkyl,
C.sub.1-C.sub.4-alkoxy, fluorinated C.sub.1-C.sub.2-alkoxy,
cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, and
fluorinated cyclopropyl. In particular R.sup.2 and R.sup.3 are both
hydrogen.
[0154] In special embodiments of the invention, X.sup.4 is
C--R.sup.4 and R.sup.4 is a radical Y-Cyc, while X.sup.1 is N,
X.sup.2 is C--R.sup.2 and X.sup.3 is C--R.sup.3, where R.sup.2 and
R.sup.3 have a meaning different from Y-Cyc.
[0155] In other special embodiment of the invention, X.sup.4 is
C--R.sup.4 and R.sup.4 is a radical Y-Cyc, while X.sup.1 is
C--R.sup.1, X.sup.2 is C--R.sup.2 and X.sup.3 is C--R.sup.3, where
R.sup.1, R.sup.2 and R.sup.3 have a meaning different from
Y-Cyc.
[0156] In further special embodiments of the invention, X.sup.1 is
C--R.sup.1 and R.sup.1 is a radical Y-Cyc, while X.sup.4 is N,
X.sup.2 is C--R.sup.2 and X.sup.3 is C--R.sup.3, where R.sup.2 and
R.sup.3 have a meaning different from Y-Cyc.
[0157] In further special embodiments of the invention, X.sup.1 is
C--R.sup.1 and R.sup.1 is a radical Y-Cyc, while X.sup.4 is
C--R.sup.4, X.sup.2 is C--R.sup.2 and X.sup.3 is C--R.sup.3, where
R.sup.4, R.sup.2 and R.sup.3 have a meaning different from
Y-Cyc.
[0158] In the aforementioned special embodiments, those R.sup.1,
R.sup.2, R.sup.3 and R.sup.4, if present, which are different from
Y-Cyc are preferably selected, independently of each other, from
the group consisting of hydrogen, fluorine, C.sub.1-C.sub.4-alkyl,
fluorinated C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.4-alkoxy,
fluorinated C.sub.1-C.sub.2-alkoxy, cyclopropyl, optionally
substituted by 1, 2 or 3 methyl groups, and fluorinated
cyclopropyl. In particular R.sup.2 and R.sup.3 are both
hydrogen.
[0159] In the moieties Y-Cyc, Y is preferably selected from O, NH
and a chemical bond. In particular embodiments of the invention Y
is a chemical bond.
[0160] Preferably, Cyc is selected from the groups of
[0161] (i) saturated 4-, 5-, 6- or 7-membered heteromonocycles or a
saturated 7-, 8-, 9- or 10-membered heterobicycle, where the
heteromonocycle and the heterobicycle have one nitrogen or oxygen
atom as ring member and may have one further heteroatom or
heteroatom group as ring member, which is selected from the group
consisting of O, S, S(.dbd.O), S(.dbd.O).sub.2 and N, where the
saturated heteromonocycle and the saturated heterobicycle are
unsubstituted or carry 1, 2, 3, 4 or 5, in particular 1, 2, or 3
radicals R.sup.C1 or one radical Y'-R.sup.C2 and 0, 1, 2, 3 or 4,
in particular 0, 1 or 2 radicals R.sup.C1, where R.sup.C1, R.sup.C2
and Y' are as defined herein and where Y', if present, is
preferably a chemical bond or O; and
[0162] (ii) phenyl or a 5- or 6 membered hetaryl, which has one
heteroatom, selected from O, S and N as ring member and optionally
one or two further heteroatoms as ring members, and which is in
particular selected from the group consisting of pyridyl,
pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,
oxazolyl and thiazolyl, where phenyl and the 5- or 6 membered
hetaryl are unsubstituted or carry 1, 2, 3, 4 or 5, in particular
1, 2, or 3 radicals R.sup.C1 or one radical Y'-R.sup.C2 and 0, 1,
2, 3 or 4, in particular 0, 1 or 2 radicals R.sup.C1, where
R.sup.C1, R.sup.C2 and Y' are as defined herein and where Y', if
present, is preferably a chemical bond or O.
[0163] In this regard, R.sup.C1 is preferably selected from the
group consisting of fluorine, chlorine, CN, methyl, difluoromethyl,
trifluoromethyl, methoxy and NH.sub.2, or, if Cyc is phenyl, two
radicals R.sup.C1 which are bound to adjacent carbon atoms,
together with the phenyl ring to which they are bound, form a
bicyclic heterocyclic radical, which is selected from 5- or
6-indolyl, 5- or 6-benzimidazolyl, 5- or 6-benzopyrazolyl, 5- or
6-benzotriazolyl, 5- or 6-benzofuranyl, 2,3-dihydrobenzofuran-5-yl,
2,3-dihydrobenzofuran-6-yl, 1,3-dihydroindol-2-on-5-yl,
1,3-dihydroindol-2-on-6-yl, 5- or 6-quinolinyl, 5- or
6-isoquinolinyl, 5- or 6-quinazolinyl, 2-amino-5-quinazolinyl, and
2-amino-6-quinazolinyl.
[0164] In this regard, R.sup.C2 is preferably selected from the
group consisting of phenyl, C.sub.3-C.sub.6-cycloalkyl, optionally
substituted by 1, 2, or 3 methyl groups, fluorinated
C.sub.3-C.sub.6-cycloalkyl, and 5- or 6-membered saturated
heteromonocyclic radicals, having 1, 2 or 3 heteroatoms as ring
members, which are selected from O, S and N, where phenyl the
saturated heteromonocyclic radical is unsubstituted or carries 1, 2
or 3 radicals R.sup.C3, which are preferably selected from
fluorine, chlorine, CN, methyl, difluoromethyl, trifluoromethyl,
methoxy and NH.sub.2.
[0165] In particular, Cyc is selected from the groups of
[0166] (i) saturated 4-, 5-, 6- or 7-membered heteromonocycles,
where the heteromonocycle has one nitrogen or oxygen atom as ring
member and may have one further heteroatom or heteroatom group as
ring member, which is selected from the group consisting of O, S,
S(.dbd.O), S(.dbd.O).sub.2 and N, where the saturated
heteromonocycle and the saturated heterobicycle are unsubstituted
or carry 1, 2, or 3 radicals R.sup.C1, where R.sup.C1 is as defined
herein; and
[0167] (ii) phenyl or a 5- or 6 membered hetaryl, selected from
pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl,
pyrazolyl, oxazolyl and thiazolyl, where phenyl and the 5- or 6
membered hetaryl are unsubstituted or carry 1, 2, 3, 4 or 5, in
particular 1, 2, or 3 radicals R.sup.C1 or one radical Y'--R.sup.C2
and 0, 1, 2, 3 or 4, in particular 0, 1 or 2 radicals R.sup.C1,
where R.sup.C1, R.sup.C2 and Y' are as defined herein and where Y',
if present, is preferably a chemical bond or O.
[0168] In particular embodiments of the invention, Cyc is selected
from the group consisting of saturated 4-, 5-, 6- or 7-membered
heteromonocycles or a saturated 7-, 8-, 9- or 10-membered
heterobicycle, where the heteromonocycle and the heterobicycle have
one nitrogen or oxygen atom as ring member and may have one further
heteroatom or heteroatom group as ring member, which is selected
from the group consisting of O, S, S(=O), S(.dbd.O).sub.2 and N,
where the saturated heteromonocycle and the saturated heterobicycle
are unsubstituted or carry 1, 2, 3, 4 or 5, in particular 1, 2, or
3 radicals R.sup.C1 or one radical Y'-R.sup.C2 and 0, 1, 2, 3 or 4,
in particular 0, 1 or 2 radicals R.sup.C1, where R.sup.C1, R.sup.C2
and Y' are as defined herein and where Y', if present, is
preferably a chemical bond or O.
[0169] In special embodiments of the invention, Cyc is selected
from the group consisting of saturated 4-, 5-, 6- or 7-membered
heteromonocycles, where the heteromonocycle has one nitrogen or
oxygen atom as ring member and may have one further heteroatom or
heteroatom group as ring member, which is selected from the group
consisting of O, S, S(.dbd.O), S(.dbd.O).sub.2 and N, where the
saturated heteromonocycle and the saturated heterobicycle are
unsubstituted or carry 1, 2, or 3 radicals R.sup.C1, where R.sup.C1
is as defined herein.
[0170] In this particular and special embodiments Y is preferably
selected from O, NH and a chemical bond, with particular preference
given to Y being a chemical bond.
[0171] In this particular and special embodiments Y-Cyc is e.g.
selected from the group consisting of 1-piperidinyl,
4,4-difluoro-1-piperidinyl, 4-piperidinyl, 1-methyl-4-piperidinyl,
1-piperazinyl, 4-methyl-1-piperazinyl, morpholin-4-yl,
2-oxa-6-azaspiro-[3,4]octyl, 2,5-diazabicyclo[2.2.1]heptan-2-yl,
3,8-diazabicyclo[3.2.1]octan-8-yl, thiomorpholin-4-yl,
1-oxothiomorpholin-4-yl, N-(oxetan-3-yl)amino,
1,1-dioxothiomorpholin-4-yl and oxetan-3-ylamino and especially
from the group consisting of 1-piperidinyl,
4,4-difluoro-1-piperidinyl, 4-piperidinyl, 1-methyl-4-piperidinyl,
1-piperazinyl, 4-methyl-1-piperazinyl, morpholin-4-yl,
thiomorpholin-4-yl, 1-oxothiomorpholin-4-yl, N-(oxetan-3-yl)amino,
1,1-dioxothiomorpholin-4-yl and oxetan-3-ylamino.
[0172] In other particular embodiments of the invention, Cyc is
phenyl or a 5- or 6 membered heteroaromatic radical, which has one
heteroatom, selected from O, S and N as ring member and optionally
one or two further heteroatoms as ring members, and which is in
particular selected from the group consisting of pyridyl,
pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,
oxazolyl and thiazolyl, where phenyl and the 5- or 6 membered
heteroaromatic radical are unsubstituted or either carry,
independently of each other, carry 1, 2, 3, 4 or 5, in particular
1, 2, or 3 radicals R.sup.C1 or one radical Y'-R.sup.C2 and 0, 1,
2, 3 or 4, in particular 0, 1 or 2 radicals R.sup.C1, where
R.sup.C1, R.sup.C2 and Y' are as defined herein and where Y', if
present, is preferably a chemical bond or O.
[0173] In other special embodiments of the invention, Cyc is
selected from the group consisting of phenyl or a 5- or 6 membered
hetaryl, selected from pyridyl, pyrimidinyl, furyl, thienyl,
pyrrolyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl, where
phenyl and the 5- or 6 membered hetaryl are unsubstituted or carry
1, 2, 3, 4 or 5, in particular 1, 2, or 3 radicals R.sup.C1 or one
radical Y'-R.sup.C2 and 0, 1, 2, 3 or 4, in particular 0, 1 or 2
radicals R.sup.C1, where R.sup.C1, R.sup.C2 and Y' are as defined
herein and where Y', if present, is preferably a chemical bond or
O. In particular Cyc is selected from the group consisting of
phenyl and 5- or 6-membered hetaryl selected from the group
consisting of pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl,
imidazolyl, pyrazolyl, oxazolyl and thiazolyl, where phenyl and
hetaryl are unsubstituted or carry 1, 2 or 3 radicals R.sup.C1
which are selected from the group consisting of fluorine, chlorine,
CN, methyl, difluoromethyl, trifluoromethyl, methoxy and NH.sub.2,
or, if Cyc is phenyl, two radicals R.sup.C1 which are bound to
adjacent carbon atoms, together with the phenyl ring to which they
are bound, form a bicyclic heterocyclic radical, which is selected
from 5- or 6-indolyl, 5- or 6-benzimidazolyl, 5- or
6-benzopyrazolyl, 5- or 6-benzotriazolyl, 5- or 6-benzofuranyl,
2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl,
1,3-dihydroindol-2-on-5-yl, 1,3-dihydroindol-2-on-6-yl, 5- or
6-quinolinyl, 5- or 6-isoquinolinyl, 5- or 6-quinazolinyl,
2-amino-5-quinazolinyl, and 2-amino-6-quinazolinyl. Amongst these,
particular preference is given to compounds, where Y is a chemical
bond. Amongst these, particular preference is given to compounds,
where Cyc is selected from the group consisting of phenyl and 5- or
6-membered hetaryl selected from the group consisting of pyridyl,
pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,
oxazolyl and thiazolyl, where phenyl and hetaryl are unsubstituted
or carry 1, 2 or 3 radicals R.sup.C1 which are selected from the
group consisting of fluorine, chlorine, CN, methyl, difluoromethyl,
trifluoromethyl, methoxy and NH.sub.2.
[0174] With regard to these particular or special embodiments,
R.sup.C1 is preferably selected from the group consisting of
fluorine, chlorine, CN, methyl, difluoromethyl, trifluoromethyl,
methoxy and NH.sub.2, or, if Cyc is phenyl, two radicals
R.sup.C1which are bound to adjacent carbon atoms, together with the
phenyl ring to which they are bound, form a bicyclic heterocyclic
radical, which is selected from 5- or 6-indolyl, 5- or
6-benzimidazolyl, 5- or 6-benzopyrazolyl, 5- or 6-benzotriazolyl,
5- or 6-benzofuranyl, 2,3-dihydrobenzofuran-5-yl,
2,3-dihydrobenzofuran-6-yl, 1,3-dihydroindol-2-on-5-yl,
1,3-dihydroindol-2-on-6-yl, 5- or 6-quinolinyl, 5- or
6-isoquinolinyl, 5- or 6-quinazolinyl, 2-amino-5-quinazolinyl, and
2-amino-6-quinazolinyl.
[0175] With regard to these particular or special embodiments,
R.sup.C2 is preferably selected from the group consisting of
phenyl, C.sub.3-C.sub.6-cycloalkyl, optionally substituted by 1, 2,
or 3 methyl groups, fluorinated C.sub.3-C.sub.6-cycloalkyl, and 5-
or 6-membered saturated heteromonocyclic radicals, having 1, 2 or 3
heteroatoms as ring members, which are selected from O, S and N,
where phenyl the saturated heteromonocyclic radical is
unsubstituted or carries 1, 2 or 3 radicals R.sup.C3, which are
preferably selected from fluorine, chlorine, CN, methyl,
difluoromethyl, trifluoromethyl, methoxy and NH.sub.2.
[0176] In particular embodiments of the invention A is a radical
CR.sup.5R.sup.6. In these particular embodiments, R.sup.5 and
R.sup.6 are as defined above and in particular, independently of
each other, selected from the group consisting of hydrogen,
fluorine and C.sub.1-C.sub.4-alkyl, especially hydrogen, fluorine
or methyl.
[0177] In other particular embodiments of the invention A is a
radical O.
[0178] In further particular embodiments of the invention A is a
radical N--R.sup.5a. In these particular embodiments, R.sup.5a is
as defined above and in particular selected from the group
consisting of hydrogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.2-fluoroalkyl, cyclopropyl, optionally substituted by
1, 2 or 3 methyl groups, fluorinated cyclopropyl, phenyl and
benzyl, where the rings of phenyl and benzyl are unsubstituted or
carry 1, 2 or 3 substituents selected from fluorine, methyl,
C.sub.1-fluoroalkyl, methoxy and C.sub.1- fluoroalkoxy, especially
from methyl.
[0179] In a group of embodiments, A is different from CH.sub.2, if
X.sup.1 is C--R.sup.1, X.sup.2 is N or C--R.sup.2, X.sup.3 is
C--R.sup.3 and X.sup.4 C--R.sup.4.
[0180] Preference is given to compounds of the formula I, where
R.sup.7, R.sup.8 are selected from hydrogen and fluorine and in
particular to those compounds, where both R.sup.7 and R.sup.8 are
hydrogen.
[0181] Preference is given to compounds of the formula I, where
R.sup.9, R.sup.10 are selected from hydrogen and fluorine and in
particular to those compounds, where both R.sup.9 and R.sup.10 are
hydrogen.
[0182] A particular preferred embodiment of the invention relates
to the compounds of formula I-A, described below, to the N-oxides,
the prodrugs, the hydrates and the tautomers thereof and to the
pharmaceutically suitable salts thereof:
##STR00002## [0183] where Het, X.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.10 are as
defined here and in the claims.
[0184] In the compounds of formula I-A, R.sup.5 and R.sup.6 are as
defined above and in particular, independently of each other,
selected from the group consisting of hydrogen, fluorine and
C.sub.1-C.sub.4-alkyl, especially hydrogen, fluorine or methyl. In
another embodiment of the compounds of formula I-A, the radicals
R.sup.5 and R.sup.6 together with the carbon atom to which they are
bound form a carbonyl group.
[0185] Another particular preferred embodiment of the invention
relates to the compounds of formula I-B, described below, to the
N-oxides, the prodrugs, the hydrates and the tautomers thereof and
to the pharmaceutically suitable salts thereof:
##STR00003## [0186] where Het, X.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.7, R.sup.8, R.sup.9 and R.sup.10 are as defined here and in
the claims.
[0187] Another particular preferred embodiment of the invention
relates to the compounds of formula I-C, described below, to the
N-oxides, the prodrugs, the hydrates and the tautomers thereof and
to the pharmaceutically suitable salts thereof:
##STR00004## [0188] where Het, X.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5a, R.sup.7, R.sup.8, R.sup.9 and R.sup.10 are as defined
here and in the claims.
[0189] In the compounds of formula I-C, R.sup.5a is in particular
selected from the group consisting of hydrogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.2-fluoroalkyl, cyclopropyl,
optionally substituted by 1, 2 or 3 methyl groups, fluorinated
cyclopropyl, phenyl and benzyl, where the rings of phenyl and
benzyl are unsubstituted or carry 1, 2 or 3 substituents selected
from fluorine, methyl, C.sub.1-fluoroalkyl, methoxy and C.sub.1-
fluoroalkoxy, especially from methyl.
[0190] In relation to their use as inhibitors of PDE10A, the
variables Het, X.sup.1, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.7, R.sup.8, R.sup.9, R.sup.10, Y and Cyc in formulae I-A, I-B
and I-C have the meanings given above, in particular the following
meanings, where these represent, both considered on their own and
in combination with at least one other or all, special
configurations of the compounds of the formula I-A, I-B and
I-C:
[0191] In formulae I-A, I-B and I-C, R.sup.4 is preferably a
radical Y-Cyc and X.sup.1 is N or C-- R.sup.1, where R.sup.1 is as
defined above and preferably has a meaning different from Y-Cyc. In
formulae I-A, I-B and I-C, R.sup.1 is in particular selected from
the group consisting of hydrogen, fluorine, C.sub.1-C.sub.4-alkyl,
fluorinated C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.4-alkoxy,
fluorinated C.sub.1-C.sub.2-alkoxy, cyclopropyl, optionally
substituted by 1, 2 or 3 methyl groups, and fluorinated
cyclopropyl.
[0192] In formulae I-A, I-B and I-C, the variables R.sup.2 and
R.sup.3 preferably have a meaning different from Y-Cyc. In this
regard, R.sup.2 and R.sup.3 are as defined above and preferably
selected, independently of each other, from the group consisting of
hydrogen, fluorine, C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.4-alkoxy, fluorinated
C.sub.1-C.sub.2-alkoxy, cyclopropyl, optionally substituted by 1, 2
or 3 methyl groups, and fluorinated cyclopropyl. In particular
R.sup.2 and R.sup.3 are both hydrogen.
[0193] Preference is given to compounds of the formulae I-A, I-B
and I-C, where R.sup.7, R.sup.8 are selected from hydrogen and
fluorine and in particular to those compounds, where both R.sup.7
and R.sup.8 are hydrogen.
[0194] Preference is given to compounds of the of the formulae I-A,
I-B and I-C, where R.sup.9, R.sup.10 are selected from hydrogen and
fluorine and in particular to those compounds, where both R.sup.9
and R.sup.10 are hydrogen.
[0195] In the compounds of formulae I-A, I-B and I-C, Het is
preferably selected from the group consisting of C-bound 6-membered
monocyclic hetaryl, which has 1 or 2 nitrogen atoms as ring
members, benzofuryl and C-bound, fused bicyclic hetaryl, which has
1 or 2 nitrogen atoms as ring members and optionally a further
heteroatom selected from O, S and N as ring member, where
monocyclic hetaryl, benzofuryl and bicyclic hetaryl may be
unsubstituted or may carry 1, 2, 3 or 4 substituents R.sup.x, in
particular 0, 1 or 2 substituents R.sup.x. In this regard, R.sup.x
is preferably selected from halogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.2-fluoroalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.2-fluoralkoxy, phenyl, C.sub.3-C.sub.6-cycloalkyl,
optionally substituted by 1, 2 or 3 methyl groups, and fluorinated
C.sub.3-C.sub.6-cycloalkyl. In this regard, R.sup.x is in
particular selected from fluorine, chlorine, methyl, fluoromethyl,
difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, phenyl, cyclopropyl, optionally
substituted by 1, 2 or 3 methyl groups, and fluorinated
cyclopropyl.
[0196] In a particular embodiment of the compounds of the formulae
I-A, I-B and I-C, Het is selected from fused bicyclic hetaryl,
which has 1 or 2 nitrogen atoms as ring members and optionally a
further heteroatom selected from O, S and N as ring member and
which may be unsubstituted or may carry 1, 2, 3 or 4 substituents
R.sup.x, in particular 0, 1 or 2 substituents R.sup.x. In this
regard, R.sup.x is preferably selected from halogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.2-fluoroalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.2-fluoralkoxy,
C.sub.3-C.sub.6-cycloalkyl, optionally substituted by 1, 2 or 3
methyl groups, and fluorinated C.sub.3-C.sub.6-cycloalkyl. In this
regard, R.sup.x is in particular selected from fluorine, chlorine,
methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,
fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl,
optionally substituted by 1, 2 or 3 methyl groups, and fluorinated
cyclopropyl.
[0197] In another particular embodiment of the compounds of the
formulae I-A, I-B and I-C, Het is selected from 6-membered
monocyclic hetaryl, which may be unsubstituted or may carry 1, 2, 3
or 4 substituents R.sup.x, in particular 0, 1 or 2 substituents
R.sup.x. In this regard, R.sup.x is preferably selected from
halogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.2-fluoroalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.2-fluoralkoxy, phenyl,
C.sub.3-C.sub.6-cycloalkyl, optionally substituted by 1, 2 or 3
methyl groups, and fluorinated C.sub.3-C.sub.6-cycloalkyl. In this
regard, R.sup.x is in particular selected from fluorine, chlorine,
methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,
fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl,
optionally substituted by 1, 2 or 3 methyl groups, and fluorinated
cyclopropyl or one R.sup.x may also be phenyl.
[0198] In the compounds of formulae I-A, I-B and I-C, particular
preference is given to those Het radicals, which have at least one
imino-nitrogen as ring member, which is located in the position
adjacent to carbon atom bound to the group CR.sup.9R.sup.10.
Particular preference is given to those Het radicals, which have at
least one imino-nitrogen as ring member, which is located in the
position adjacent to carbon atom bound to the group
CR.sup.9R.sup.10 and which are selected from the group consisting
of C-bound 6-membered monocyclic hetaryl, which has 1 or 2 nitrogen
atoms as ring members, benzofuryl and C-bound, fused bicyclic
hetaryl, which has 1 or 2 nitrogen atoms as ring members and
optionally a further heteroatom selected from O, S and N as ring
member, where monocyclic hetaryl, benzofuryl and bicyclic hetaryl
may be unsubstituted or may carry 1, 2, 3 or 4 substituents
R.sup.x, in particular 0, 1 or 2 substituents R.sup.x. In this
regard, R.sup.x is preferably selected from halogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.2-fluoroalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.2-fluoralkoxy, phenyl,
C.sub.3-C.sub.6-cycloalkyl, optionally substituted by 1, 2 or 3
methyl groups, and fluorinated C.sub.3-C.sub.6-cycloalkyl. In this
regard, R.sup.x is in particular selected from fluorine, chlorine,
methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,
fluoromethoxy, difluoromethoxy, trifluoromethoxy, phenyl,
cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, and
fluorinated cyclopropyl. Particular examples of Het are selected
from the group consisting of 2-benzofuryl, 2-pyridyl,
3-pyridazinyl, 2-pyrimidinyl, 2-quinolinyl, 2-quinazolinyl,
2-quinoxalinyl, benzimidazol-2-yl, 1-methylbenzimidazol-2-yl,
imidazo[1,2-]pyridine-2-yl, thieno[3,2-b]pyridine-5-yl,
imidazo-[2,1-b]-thiazol-6-yl and
1,2,4-triazolo[1,5-a]pyridine-2-yl, where the aforementioned
radicals are unsubstituted or may carry 1, 2 or 3 radicals R.sup.x
as defined above, which are in particular selected from the group
consisting of fluorine, chlorine, methyl, fluoromethyl,
difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, cyclopropyl, optionally
substituted by 1, 2 or 3 methyl groups, and fluorinated
cyclopropyl.
[0199] In a particular embodiment of the compounds of the formulae
I-A, I-B and I-C, Het has at least one imino-nitrogen as ring
member, which is located in the position adjacent to carbon atom
bound to the group CR.sup.9R.sup.10 and Het is selected from the
group consisting of fused bicyclic hetaryl, which has 1 or 2
nitrogen atoms as ring members and optionally a further heteroatom
selected from O, S and N as ring member, where bicyclic hetaryl may
be unsubstituted or may carry 1, 2, 3 or 4 substituents R.sup.x, in
particular 0, 1 or 2 substituents R.sup.x. In this regard, R.sup.x
is preferably selected from halogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.2-fluoroalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.2-fluoralkoxy, C.sub.3-C.sub.6-cycloalkyl, optionally
substituted by 1, 2 or 3 methyl groups, and fluorinated
C.sub.3-C.sub.6-cycloalkyl. In this regard, R.sup.x is in
particular selected from fluorine, chlorine, methyl, fluoromethyl,
difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, cyclopropyl, optionally
substituted by 1, 2 or 3 methyl groups, and fluorinated
cyclopropyl. Particular examples of Het of this embodiment are
2-quinolinyl, 2-quinazolinyl, 2-quinoxalinyl, benzimidazol-2-yl,
1-methylbenzimidazol-2-yl, benzothiazol-2-yl,
imidazo[1,2-a]pyridine-2-yl, thieno[3,2-b]pyridine-5-yl,
imidazo-[2,1-b]-thiazol-6-yl and
1,2,4-triazolo[1,5-a]pyridine-2-yl, where the aforementioned
radicals are unsubstituted or may carry 1, 2 or 3 radicals R.sup.x
as defined above, which are in particular selected from the group
consisting of fluorine, chlorine, methyl, fluoromethyl,
difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, cyclopropyl, optionally
substituted by 1, 2 or 3 methyl groups, and fluorinated
cyclopropyl.
[0200] Particular preference is given to compounds of the formulae
I-A, I-B and I-C, where Het is 2-quinolinyl or
imidazo[1,2-a]pyridine-2-yl, where these radicals are unsubstituted
or may carry 1, 2 or 3 radicals R.sup.x as defined above, which are
in particular selected from the group consisting of fluorine,
chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl,
methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy,
cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, and
fluorinated cyclopropyl.
[0201] Particular preference is also given to compounds of the
formulae I-A, I-B and I-C, where Het is 1-methylbenzimidazol-2-yl
or benzothiazol-2-yl, where these radicals are unsubstituted or may
carry 1, 2 or 3 radicals R.sup.x as defined above, which are in
particular selected from the group consisting of fluorine,
chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl,
methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy,
cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, and
fluorinated cyclopropyl.
[0202] Particular preference is given to compounds of the formulae
I-A, I-B and I-C, where Het is 2-pyridyl, where 2-pyridyl
unsubstituted or preferably carries 1, 2 or 3 radicals R.sup.x as
defined above, which are in particular selected from the group
consisting of halogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-haloalkyoxy, cyclopropyl, optionally substituted by
1, 2 or 3 methyl groups, and fluorinated cyclopropyl, such as
fluorine, chlorine, methyl, ethyl, isopropyl, fluoromethyl,
difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, cyclopropyl,
1-methylcyclopropyl, 1-fluorocyclopropyl and
2-fluorocyclopropyl.
[0203] An especially preferred embodiment of the invention relates
to the compounds of formulae I-Aa, I-Ab, I-Ac and I-Ad, described
below, to the N-oxides, the prodrugs, the hydrates and the
tautomers thereof and to the pharmaceutically suitable salts
thereof:
##STR00005## [0204] where X.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.9 and R.sup.10 are as defined here and in
the claims.
[0205] In formula I-Ac, R is H, F or CH.sub.3 and Q is S, O or in
particular N--CH.sub.3.
[0206] In formula I-Ad, q is 0 or in particular 1 and R.sup.x is
selected from the group consisting of C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-fluoroalkyl, C.sub.1-C.sub.4-fluoroalkoxy,
cyclopropyl, which is optionally substituted by 1, 2 or 3 methyl
groups, and fluorinated cyclopropyl.
[0207] In the compounds of formulae I-Aa, I-Ab, I-Ac and I-Ad,
R.sup.5 and R.sup.6 are as defined above and in particular,
independently of each other, selected from the group consisting of
hydrogen, fluorine and C.sub.1-C.sub.4-alkyl, especially hydrogen,
fluorine or methyl. In another embodiment of the compounds of
formulae I-Aa, I-Ab, I-Ac and I-Ad, the radicals R.sup.5 and
R.sup.6 together with the carbon atom to which they are bound form
a carbonyl group.
[0208] Another especially preferred embodiment of the invention
relates to the compounds of formulae I-B a, I-Bb, I-Bc and I-Bd,
described below, to the N-oxides, the prodrugs, the hydrates and
the tautomers thereof and to the pharmaceutically suitable salts
thereof:
##STR00006## [0209] where X.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.9 and R.sup.10 are as defined here and in the claims.
[0210] In formula I-Bc, R is H, F or CH.sub.3 and Q is S, O or in
particular N--CH.sub.3.
[0211] In formula I-Bd, q is 0 or or in particular 1 and R.sup.x is
selected from the group consisting of C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-fluoroalkyl, C.sub.1-C.sub.4-fluoroalkoxy,
cyclopropyl, which is optionally substituted by 1, 2 or 3 methyl
groups, and fluorinated cyclopropyl.
[0212] Another especially preferred embodiment of the invention
relates to the compounds of formulae I-Ca, I-Cb, I-Cc and I-Cd,
described below, to the N-oxides, the prodrugs, the hydrates and
the tautomers thereof and to the pharmaceutically suitable salts
thereof:
##STR00007## [0213] where X.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.5a, R.sup.6, R.sup.9 and R.sup.10 are as defined
here and in the claims.
[0214] In formula I-Cc, R is H, F or CH.sub.3 and Q is S, 0 or in
particular N--CH.sub.3.
[0215] In formula I-Cd, q is 0 or or in particular 1 and R.sup.x is
selected from the group consisting of C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-fluoroalkyl, C.sub.1-C.sub.4-fluoroalkoxy,
cyclopropyl, which is optionally substituted by 1, 2 or 3 methyl
groups, and fluorinated cyclopropyl.
[0216] In the compounds of formulae I-Ca, I-Cb, I-Cc and I-Cd,
R.sup.5a is in particular selected from the group consisting of
hydrogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.2-fluoroalkyl,
cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups,
fluorinated cyclopropyl, phenyl and benzyl, where the rings of
phenyl and benzyl are unsubstituted or carry 1, 2 or 3 substituents
selected from fluorine, methyl, C.sub.1-fluoroalkyl, methoxy and
C.sub.1-fluoroalkoxy, especially from methyl.
[0217] In relation to their use as inhibitors of PDE10A, the
variables X.sup.1, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.9,
R.sup.10, Y and Cyc in formulae I-Aa, I-Ab, I-Ac, I-Ad, I-Ba, I-Bb,
I-Bc, I-Bd, I-Ca, I-Cb, I-Cc and I-Cd have the meanings given
above, in particular the meanings given for formulae I-A, I-B and
I-C and the meanings give below, where these represent, both
considered on their own and in combination with at least one other
or all, special configurations of the compounds of the formula
I-Aa, I-Ab, I-Ac, I-Ad, I-B a, I-Bb, I-Bc, I-Bd, I-Ca, I-Cb, I-Cc
and I-Cd.
[0218] In formulae I-Aa, I-Ab, I-Ac, I-Ad, I-Ba, I-Bb, I-Bc, I-Bd,
I-Ca, I-Cb, I-Cc and I-Cd, R.sup.4 is preferably a radical Y-Cyc
and X.sup.1 is N or C--R.sup.1, where R.sup.1 is as defined above
and preferably has a meaning different from Y-Cyc. In formulae
I-Aa, I-Ab, I-Ac, I-Ad, I-Ba, I-Bb, I-Bc, I-Bd, I-Ca, I-Cb, I-Cc
and I-Cd, where X.sup.1 is C--R.sup.1, R.sup.1 is in particular
selected from the group consisting of hydrogen, fluorine,
C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.2-alkyl,
C.sub.1-C.sub.4-alkoxy, fluorinated C.sub.1-C.sub.2-alkoxy,
cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, and
fluorinated cyclopropyl.
[0219] A particular group of embodiments relates to compounds of
formulae I-A, I-B and I-C and likewise to compounds of the formulae
I-Aa, I-Ab, I-Ac, I-Ad, I-Ba, I-Bb, I-Bc, I-Bd, I-Ca, I-Cb, I-Cc,
as well as to the N-oxides, the prodrugs, the tautomers and the
hydrates thereof, and to the pharmaceutically acceptable salts
thereof, where X.sup.1 is N.
[0220] In formulae I-Aa, I-Ab, I-Ac, I-Ad, I-Ba, I-Bb, I-Bc, I-Bd,
I-Ca, I-Cb, I-Cc and I-Cd, the variables R.sup.2 and R.sup.3
preferably have a meaning different from Y-Cyc. In this regard,
R.sup.2 and R.sup.3 are as defined above and preferably selected,
independently of each other, from the group consisting of hydrogen,
fluorine, C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.2-alkyl,
C.sub.1-C.sub.4-alkoxy, fluorinated C.sub.1-C.sub.2-alkoxy,
cyclopropyl, optionally substituted by 1, 2 or 3 methyl groups, and
fluorinated cyclopropyl. In particular R.sup.2 and R.sup.3 are both
hydrogen.
[0221] Preference is given to compounds of the of the formulae
I-Aa, I-Ab, I-Ac, I-Ad, I-Ba, I-Bb, I-Bc, I-Bd, I-Ca, I-Cb, I-Cc
and I-Cd, where R.sup.9, R.sup.10 are selected from hydrogen and
fluorine and in particular to those compounds, where both R.sup.9
and R.sup.10 are hydrogen.
[0222] In the compounds of formulae I-A, I-B and I-C, and likewise
in the compounds of formulae I-Aa, I-Ab, I-Ac, I-Ac, I-Ad, I-Ba,
I-Bb, I-Bc, I-Bd, I-Ca, I-Cb, I-Cc and I-Cd, Y in the moieties
Y-Cyc is preferably selected from 0, NH and a chemical bond. In
particular embodiments of the compounds of formulae I-A, I-B and
I-C, and likewise of the compounds of formulae I-Aa, I-Ab, I-Ac,
I-Ac, I-Ad, I-Ba, I-Bb, I-Bc, I-Bd, I-Ca, I-Cb, I-Cc and I-Cd Y is
a chemical bond.
[0223] In the compounds of formulae I-A, I-B and I-C, and likewise
in the compounds of formulae I-Aa, I-Ab, I-Ac, I-Ac, I-Ad, I-Ba,
I-Bb, I-Bc, I-Bd, I-Ca, I-Cb, I-Cc and I-Cd, Cyc is preferably
selected from the groups of
[0224] (i) saturated 4-, 5-, 6- or 7-membered heteromonocycles or a
saturated 7-, 8-, 9- or 10-membered heterobicycle, where the
heteromonocycle and the heterobicycle have one nitrogen or oxygen
atom as ring member and may have one further heteroatom or
heteroatom group as ring member, which is selected from the group
consisting of O, S, S(.dbd.O), S(.dbd.O).sub.2 and N, where the
saturated heteromonocycle and the saturated heterobicycle are
unsubstituted or carry 1, 2, 3, 4 or 5, in particular 1, 2, or 3
radicals R.sup.C1 or one radical Y'-R.sup.C2 and 0, 1, 2, 3 or 4,
in particular 0, 1 or 2 radicals R.sup.C1, where R.sup.C1, R.sup.C2
and Y' are as defined herein and where Y', if present, is
preferably a chemical bond or O; and
[0225] (ii) phenyl or a 5- or 6 membered hetaryl, which has one
heteroatom, selected from O, S and N as ring member and optionally
one or two further heteroatoms as ring members, and which is in
particular selected from the group consisting of pyridyl,
pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,
oxazolyl and thiazolyl, where phenyl and the 5- or 6 membered
hetaryl are unsubstituted or carry 1, 2, 3, 4 or 5, in particular
1, 2, or 3 radicals R.sup.C1 or one radical Y'-R.sup.C2 and 0, 1,
2, 3 or 4, in particular 0, 1 or 2 radicals R.sup.C1, where
R.sup.C1, R.sup.C2 and Y' are as defined herein and where Y', if
present, is preferably a chemical bond or O.
[0226] In this regard, R.sup.C1 is preferably selected from the
group consisting of fluorine, chlorine, CN, methyl, difluoromethyl,
trifluoromethyl, methoxy and NH.sub.2, or, if Cyc is phenyl, two
radicals R.sup.C1 which are bound to adjacent carbon atoms,
together with the phenyl ring to which they are bound, form a
bicyclic heterocyclic radical, which is selected from 5- or
6-indolyl, 5- or 6-benzimidazolyl, 5- or 6-benzopyrazolyl, 5- or
6-benzotriazolyl, 5- or 6-benzofuranyl, 2,3-dihydrobenzofuran-5-yl,
2,3-dihydrobenzofuran-6-yl, 1,3-dihydroindol-2-on-5-yl,
1,3-dihydroindol-2-on-6-yl, 5- or 6-quinolinyl, 5- or
6-isoquinolinyl, 5- or 6-quinazolinyl, 2-amino-5-quinazolinyl, and
2-amino-6-quinazolinyl.
[0227] In this regard, R.sup.C2 is preferably selected from the
group consisting of phenyl, C.sub.3-C.sub.6-cycloalkyl, optionally
substituted by 1, 2, or 3 methyl groups, fluorinated
C.sub.3-C.sub.6-cycloalkyl, and 5- or 6-membered saturated
heteromonocyclic radicals, having 1, 2 or 3 heteroatoms as ring
members, which are selected from O, S and N, where phenyl the
saturated heteromonocyclic radical is unsubstituted or carries 1, 2
or 3 radicals R.sup.C3, which are preferably selected from
fluorine, chlorine, CN, methyl, difluoromethyl, trifluoromethyl,
methoxy and NH.sub.2.
[0228] In the compounds of formulae I-A, I-B and I-C, and likewise
in the compounds of formulae I-Aa, I-Ab, I-Ac, I-Ac, I-Ad, I-Ba,
I-Bb, I-Bc, I-Bd, I-Ca, I-Cb, I-Cc and I-Cd, Cyc is in particular
selected from the groups of
[0229] (i) saturated 4-, 5-, 6- or 7-membered heteromonocycles,
where the heteromonocycle has one nitrogen or oxygen atom as ring
member and may have one further heteroatom or heteroatom group as
ring member, which is selected from the group consisting of O, S,
S(.dbd.O), S(.dbd.O).sub.2 and N, where the saturated
heteromonocycle and the saturated heterobicycle are unsubstituted
or carry 1, 2, or 3 radicals R.sup.C1, where R.sup.C1 is as defined
herein; and
[0230] (ii) phenyl or a 5- or 6 membered hetaryl, selected from
pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl,
pyrazolyl, oxazolyl and thiazolyl, where phenyl and the 5- or 6
membered hetaryl are unsubstituted or carry 1, 2, 3, 4 or 5, in
particular 1, 2, or 3 radicals R.sup.C1 or one radical Y''R.sup.C2
and 0, 1, 2, 3 or 4, in particular 0, 1 or 2 radicals R.sup.C1,
where R.sup.C1, R.sup.C2 and Y' are as defined herein and where Y',
if present, is preferably a chemical bond or O.
[0231] In particular embodiments of the compounds of formulae I-A,
I-B and I-C, and likewise of the compounds of formulae I-Aa, I-Ab,
I-Ac, I-Ac, I-Ad, I-Ba, I-Bb, I-Bc, I-Bd, I-Ca, I-Cb, I-Cc and
I-Cd, Cyc is selected from the group consisting of saturated 4-,
5-, 6- or 7-membered heteromonocycles or a saturated 7-, 8-, 9- or
10-membered heterobicycle, where the heteromonocycle and the
heterobicycle have one nitrogen or oxygen atom as ring member and
may have one further heteroatom or heteroatom group as ring member,
which is selected from the group consisting of O, S, S(.dbd.O),
S(.dbd.O).sub.2 and N, where the saturated heteromonocycle and the
saturated heterobicycle are unsubstituted or carry 1, 2, 3, 4 or 5,
in particular 1, 2, or 3 radicals R.sup.C1 or one radical
Y'-R.sup.C2 and 0, 1, 2, 3 or 4, in particular 0, 1 or 2 radicals
R.sup.C1, where R.sup.C1, R.sup.C2 and Y' are as defined herein and
where Y', if present, is preferably a chemical bond or O.
[0232] In special embodiments of the compounds of formulae I-A, I-B
and I-C, and likewise of the compounds of formulae I-Aa, I-Ab,
I-Ac, I-Ac, I-Ad, I-Ba, I-Bb, I-Bc, I-Bd, I-Ca, I-Cb, I-Cc and
I-Cd, Cyc is selected from the group consisting of saturated 4-,
5-, 6- or 7-membered heteromonocycles, where the heteromonocycle
has one nitrogen or oxygen atom as ring member and may have one
further heteroatom or heteroatom group as ring member, which is
selected from the group consisting of O, S, S(.dbd.O),
S(.dbd.O).sub.2 and N, where the saturated heteromonocycle and the
saturated heterobicycle are unsubstituted or carry 1, 2, or 3
radicals R.sup.C1, where R.sup.C1 is as defined herein.
[0233] In these particular and special embodiments Y is preferably
selected from O, NH and a chemical bond, with particular preference
given to Y being a chemical bond.
[0234] In these particular and special embodiments Y-Cyc is e.g.
selected from the group consisting of 1-piperidinyl,
4,4-difluoro-1-piperidinyl, 4-piperidinyl, 1-methyl-4-piperidinyl,
1-piperazinyl, 4-methyl-1-piperazinyl, morpholin-4-yl,
2-oxa-6-azaspiro-[3,4]octyl, 2,5-diazabicyclol[2.2.1]heptan-2-yl,
3,8-diazabicyclol[3.2.1]octan-8-yl, thiomorpholin-4-yl,
1-oxothiomorpholin-4-yl, N-(oxetan-3-yl)amino,
1,1-dioxothiomorpholin-4-yl and oxetan-3-ylamino and especially
from the group consisting of 1-piperidinyl,
4,4-difluoro-1-piperidinyl, 4-piperidinyl, 1-methyl-4-piperidinyl,
1-piperazinyl, 4-methyl-1-piperazinyl, morpholin-4-yl,
thiomorpholin-4-yl, 1-oxothiomorpholin-4-yl, N-(oxetan-3-yl)amino,
1,1-dioxothiomorpholin-4-yl and oxetan-3-ylamino.
[0235] In other particular embodiments of the compounds of formulae
I-A, I-B and I-C, and likewise of the compounds of formulae I-Aa,
I-Ab, I-Ac, I-Ac, I-Ad, I-B a, I-Bb, I-Bc, I-Bd, I-Ca, I-Cb, I-Cc
and I-Cd, Cyc is phenyl or a 5- or 6 membered heteroaromatic
radical, which has one heteroatom, selected from O, S and N as ring
member and optionally one or two further heteroatoms as ring
members, and which is in particular selected from the group
consisting of pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl,
imidazolyl, pyrazolyl, oxazolyl and thiazolyl, where phenyl and the
5- or 6 membered heteroaromatic radical are unsubstituted or either
carry, independently of each other, carry 1, 2, 3, 4 or 5, in
particular 1, 2, or 3 radicals R.sup.C1 or one radical Y'-R.sup.C2
and 0, 1, 2, 3 or 4, in particular 0, 1 or 2 radicals R.sup.C1,
where R.sup.C1, R.sup.C2 and Y' are as defined herein and where Y',
if present, is preferably a chemical bond or O.
[0236] In other special embodiments of the compounds of formulae
I-A, I-B and I-C, and likewise of the compounds of formulae I-Aa,
I-Ab, I-Ac, I-Ac, I-Ad, I-Ba, I-Bb, I-Bc, I-Bd, I-Ca, I-Cb, I-Cc
and I-Cd, Cyc is selected from the group consisting of phenyl or a
5- or 6 membered hetaryl, selected from pyridyl, pyrimidinyl,
furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl and
thiazolyl, where phenyl and the 5- or 6 membered hetaryl are
unsubstituted or carry 1, 2, 3, 4 or 5, in particular 1, 2, or 3
radicals R.sup.C1or one radical Y'--R.sup.C2 and 0, 1, 2, 3 or 4,
in particular 0, 1 or 2 radicals R.sup.C1, where R.sup.C1, R.sup.C2
and Y' are as defined herein and where Y', if present, is
preferably a chemical bond or O. In particular Cyc is selected from
the group consisting of phenyl and 5- or 6-membered hetaryl
selected from the group consisting of pyridyl, pyrimidinyl, furyl,
thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl,
where phenyl and hetaryl are unsubstituted or carry 1, 2 or 3
radicals R.sup.C1 which are selected from the group consisting of
fluorine, chlorine, CN, methyl, difluoromethyl, trifluoromethyl,
methoxy and NH.sub.2, or, if Cyc is phenyl, two radicals R.sup.C1
which are bound to adjacent carbon atoms, together with the phenyl
ring to which they are bound, form a bicyclic heterocyclic radical,
which is selected from 5- or 6-indolyl, 5- or 6-benzimidazolyl, 5-
or 6-benzopyrazolyl, 5- or 6-benzotriazolyl, 5- or 6-benzofuranyl,
2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl,
1,3-dihydroindol-2-on-5-yl, 1,3-dihydroindol-2-on-6-yl, 5- or
6-quinolinyl, 5- or 6-isoquinolinyl, 5- or 6-quinazolinyl,
2-amino-5-quinazolinyl, and 2-amino-6-quinazolinyl. Amongst these,
particular preference is given to compounds, where Y is a chemical
bond. Amongst these, particular preference is given to compounds,
where In particular Cyc is selected from the group consisting of
phenyl and 5- or 6-membered hetaryl selected from the group
consisting of pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl,
imidazolyl, pyrazolyl, oxazolyl and thiazolyl, where phenyl and
hetaryl are unsubstituted or carry 1, 2 or 3 radicals R.sup.C1
which are selected from the group consisting of fluorine, chlorine,
CN, methyl, difluoromethyl, trifluoromethyl, methoxy and
NH.sub.2.
[0237] With regard to these particular or special embodiments of
the compounds of formulae I-A, I-B and I-C, and likewise of the
compounds of formulae I-Aa, I-Ab, I-Ac, I-Ac, I-Ad, I-Ba, I-Bb,
I-Bc, I-Bd, I-Ca, I-Cb, I-Cc and I-Cd, R.sup.C1 is preferably
selected from the group consisting of fluorine, chlorine, CN,
methyl, difluoromethyl, trifluoromethyl, methoxy and NH.sub.2, or,
if Cyc is phenyl, two radicals R.sup.C1 which are bound to adjacent
carbon atoms, together with the phenyl ring to which they are
bound, form a bicyclic heterocyclic radical, which is selected from
5- or 6-indolyl, 5- or 6-benzimidazolyl, 5- or 6-benzopyrazolyl, 5-
or 6-benzotriazolyl, 5- or 6-benzofuranyl,
2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl,
1,3-dihydroindol-2-on-5-yl, 1,3-dihydroindol-2-on-6-yl, 5- or
6-quinolinyl, 5- or 6-isoquinolinyl, 5- or 6-quinazolinyl,
2-amino-5-quinazolinyl, and 2-amino-6-quinazolinyl.
[0238] With regard to these particular or special embodiments of
the compounds of formulae I-A, I-B and I-C, and likewise in the
compounds of formulae I-Aa, I-Ab, I-Ac, I-Ac, I-Ad, I-Ba, I-Bb,
I-Bc, I-Bd, I-Ca, I-Cb, I-Cc and I-Cd, R.sup.C2 is preferably
selected from the group consisting of phenyl,
C.sub.3-C.sub.6-cycloalkyl, optionally substituted by 1, 2, or 3
methyl groups, fluorinated C.sub.3-C.sub.6-cycloalkyl, and 5- or
6-membered saturated heteromonocyclic radicals, having 1, 2 or 3
heteroatoms as ring members, which are selected from O, S and N,
where phenyl the saturated heteromonocyclic radical is
unsubstituted or carries 1, 2 or 3 radicals R.sup.C3, which are
preferably selected from fluorine, chlorine, CN, methyl,
difluoromethyl, trifluoromethyl, methoxy and NH.sub.2.
[0239] Particular embodiment of the invention relates to the
compounds of formula I, to the N-oxides, the prodrugs, the hydrates
and the tautomers thereof and to the pharmaceutically suitable
salts thereof, where the compounds of the formula I are selected
from the group consisting of: [0240]
4-Pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-1,2-dihydro-pyrrolo[3,4-c-
]pyridin-3-one, [0241]
7-Pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-pyrrolo[3,4-c]pyridi-
n-1-one, [0242]
4-Pyridin-4-yl-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]pyridi-
n-5-one, [0243]
3,3-Difluoro-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindo-
l-1-one, [0244]
7-Pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
l-one, [0245]
3,3-Dimethyl-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro--
isoindol-1-one, [0246]
6-[3-Oxo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-1H-isoindol-4-yl]-1H-quina-
zolin-4-one, [0247]
7-(3-Methyl-3H-benzoimidazol-5-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro--
isoindol-1-one, [0248]
5-[3-Oxo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-1H-isoindol-4-yl]-1,3-dihy-
dro-benzoimidazol-2-one, [0249]
7-(3H-Benzotriazol-5-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-
-one, [0250]
7-(3H-Benzoimidazol-5-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol--
1-one, [0251]
7-(2-Amino-quinazolin-6-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindo-
l-1-one, [0252]
2-(2,2-Difluoro-2-quinolin-2-yl-ethyl)-7-pyridin-4-yl-2,3-dihydro-isoindo-
l-1-one, [0253]
6-Fluoro-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1--
one, [0254]
5-Fluoro-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1--
one, [0255]
4-Fluoro-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1--
one, [0256]
1-Methyl-4-(pyridin-4-yl)-2-(2-(quinolin-2-yl)ethyl)-1,2-dihydroindazol-3-
-one, [0257]
4-Pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-benzo[d]isoxazol-3-one,
[0258]
7-Pyridin-4-yl-2-(2-thieno[3,2-b]pyridin-5-yl-ethyl)-2,3-dihydro-isoindol-
-1-one, [0259]
2-(2-Imidazo[1,2-]pyridin-2-yl-ethyl)-7-pyridin-4-yl-2,3-dihydro-isoindol-
-1-one, [0260]
7-Phenyl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
[0261]
7-(4-Fluoro-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
[0262]
7-(4-Methoxy-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindo-
l-1-one, [0263]
2-(2-Quinolin-2-yl-ethyl)-7-thiophen-2-yl-2,3-dihydro-isoindol-1-one,
[0264]
2-(2-Quinolin-2-yl-ethyl)-7-thiophen-3-yl-2,3-dihydro-isoindol-1-o-
ne, [0265]
7-(3-Methoxy-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoi-
ndol-1-one, [0266]
7-(3-Fluoro-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
[0267]
7-(2-Methoxy-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindo-
l-1-one, [0268]
7-(2-Fluoro-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
[0269]
7-Pyridin-3-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
l-one, [0270]
7-Furan-2-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
[0271]
7-(3-Fluoro-4-methoxy-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoin-
dol-1-one, [0272]
7-(3,4-Difluoro-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1--
one, [0273]
7-Benzo[1,3]dioxol5-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-o-
ne, [0274]
7-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-2-(2-quinolin-2-yl-ethyl)-
-2,3-dihydro-isoindol-1-one, [0275]
7-(3,4-Dimethoxy-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-
-one, [0276]
7-(2,4-Dimethoxy-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-
-one, [0277]
7-(4-Dimethylamino-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one, [0278]
7-(4-Methoxy-pyridin-3-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one, [0279]
7-(3,5-Difluoro-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1--
one, [0280]
7-(2,5-Dimethoxy-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-
-one, [0281]
2-[3-Oxo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-1H-isoindol-4-yl]-pyrrole--
1-carboxylic acid tert-butyl ester, [0282]
7-(3-Dimethylamino-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one, [0283]
7-(2-Dimethylamino-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one, [0284]
7-(2,4-Difluoro-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1--
one, [0285]
7-Furan-3-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
[0286]
7-(1H-Indo1-5-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
[0287]
7-(4-Methyl-thiophen-2-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-i-
soindol-1-one, [0288] {
4-[3-Oxo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-1H-isoindol-4-yl]-phenyl}--
acetonitrile, [0289]
7-(2,3-Difluoro-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1--
one, [0290]
7-(2,5-Difluoro-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1--
one, [0291]
7-(5-Fluoro-2-methoxy-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoin-
dol-1-one, [0292]
7-(1H-Pyrazol-3-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
[0293]
7-(6-Methoxy-pyridin-3-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-i-
soindol-1-one, [0294]
7-(2-Fluoro-3-methoxy-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoin-
dol-1-one, [0295]
7-(2,3-Dihydro-benzofuran-5-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-iso-
indol-1-one, [0296]
7-(2,3-Dimethoxy-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-
-one, [0297]
7-Pyrimidin-5-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
[0298]
7-(6-Morpholin-4-yl-pyridin-3-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-di-
hydro-isoindol-1-one, [0299]
7-(3-Methanesulfonyl-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoind-
ol-1-one, [0300]
7-(2-Methoxy-pyrimidin-5-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoind-
ol-1-one, [0301]
7-Quinolin-5-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
[0302]
7-(1H-Indo1-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-
-one, [0303]
7-(1H-Indo1-6-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
[0304]
7-(2-Methyl-pyridin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-is-
oindol-1-one, [0305]
7-(2-Methoxy-pyridin-3-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one, [0306]
7-(3-Methoxymethyl-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one, [0307]
7-Isoquinolin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
[0308]
7-(5-Methoxy-pyridin-3-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-i-
soindol-1-one, [0309]
7-(1-Methyl-1H-pyrazol-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoind-
ol-1-one, [0310]
7-Isoquinolin-5-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
[0311]
7-Benzofuran-5-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-
-one, [0312]
7-(4-Methyl-thiophen-3-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one, [0313]
7-(2-Methyl-2H-pyrazol-3-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoind-
ol-1-one, [0314]
7-Quinolin-6-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
[0315]
7-(3-Fluoro-5-methoxy-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydr-
o-isoindol-1-one, [0316]
7-(5-Fluoro-pyridin-3-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol--
1-one, [0317]
7-(1H-Pyrazol-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
[0318]
7-(5-Methanesulfonyl-pyridin-3-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-d-
ihydro-isoindol-1-one, [0319]
7-(3-Morpholin-4-yl-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindo-
l-1-one, [0320]
{3-[3-Oxo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-1H-isoindol-4-yl]-phenyl}-
-acetonitrile, [0321]
2-(2-Quinolin-2-yl-ethyl)-7-thiazol-2-yl-2,3-dihydro-isoindol-1-one,
[0322]
7-Pyrimidin-2-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1--
one, [0323]
7-(3H-Imidazol-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one-
, [0324]
2-(2-Quinolin-2-yl-ethyl)-7-(5-trifluoromethyl-pyridin-2-yl)-2,3--
dihydro-isoindol-1-one, [0325]
7-(2-Methyl-pyridin-3-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol--
1-one, [0326]
7-(5-Methyl-pyridin-2-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol--
1-one, [0327]
7-(5-Fluoro-pyridin-2-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol--
1-one, [0328]
7-(3-Methyl-pyridin-2-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol--
1-one, [0329]
5-[3-Oxo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-1H-isoindol-4-yl]-1,3-dihy-
dro-indol-2-one, [0330]
7-(6-Methyl-pyridin-3-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol--
1-one, [0331]
7-(1H-Indo1-7-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
[0332]
7-(1H-Indazol-5-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one, [0333]
7-(3-Methyl-3H-imidazol-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoin-
dol-1-one, [0334]
7-(1-Methyl-1H-imidazol-2-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoin-
dol-1-one, [0335]
6-[3-Oxo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-1H-isoindol-4-yl]-1,3-dihy-
dro-indol-2-one, [0336]
7-(1H-Indazol-6-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
[0337]
2-(2-Quinolin-2-yl-ethyl)-7-(6-trifluoromethyl-pyridin-3-yl)-2,3-d-
ihydro-isoindol-1-one, [0338]
7-Morpholin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
[0339]
7-[4-(4-Methyl-piperazin-1-yl)-piperidin-1-yl]-2-(2-quinolin-2-yl--
ethyl)-2,3-dihydro-isoindol-1-one, [0340]
7-(1S,4S)-2,5-Diaza-bicyclo[2.2.1]hept-2-yl-2-(2-quinolin-2-yl-ethyl)-2,3-
-dihydro-isoindol-1-one, [0341]
7-Piperazin-1-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
[0342] 7-(3
,8-Diaza-bicyclo[3.2.1]oct-8-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-is-
oindol-1-one, [0343] 7-(1
,1-Dioxo-1-thiomorpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoi-
ndol-1-one, [0344]
7-[4-(1-Methyl-piperidin-4-yl)-piperazin-1-yl]-2-(2-quinolin-2-yl-ethyl)--
2,3-dihydro-isoindol-1-one, [0345]
7-(4-Pyridin-4-yl-piperazin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-i-
soindol-1-one, [0346]
7-(4-Methyl-piperazin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindo-
l-1-one, [0347]
7-(3-Phenyl-piperidin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindo-
l-1-one, [0348]
7-(3-Phenoxy-piperidin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoind-
ol-1-one, [0349]
7-[1,4]Oxazepan-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one-
, [0350] 7-(7-nitro-3,4-dihydroisoquinolin-2
(1H)-yl)-2-(2-(quinolin-2-yl)ethyl)isoindolin-1-one, [0351]
7-(7-amino-3,4-dihydroisoquinolin-2
(1H)-yl)-2-(2-(quinolin-2-yl)ethyl)isoindolin-1-one, [0352]
4-Chloro-N-{2-[3-oxo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-1H-isoindol-4--
yl]-1,2,3,4-tetrahydro-isoquinolin-7-yl}-benzenesulfonamide, [0353]
4-Isopropyl-N-{2-[3-oxo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-1H-isoindol-
-4-yl]-,2,3,4-tetrahydro-isoquinolin-7-yl}-benzenesulfonamide,
[0354]
2-[2-(6-Fluoro-quinolin-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro-isoindo-
l-1-one, [0355]
2-[2-(6-Methoxy-quinolin-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro-isoind-
ol-1-one, [0356]
2-[2-(4-Chloro-quinolin-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro-isoindo-
l-1-one, [0357]
2-[2-(8-Chloro-quinolin-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro-isoindo-
l-1-one, [0358]
4-Morpholin-4-yl-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]pyri-
din-5-one, [0359]
7-Morpholino-2-(3-(pyrimidin-2-yl)phenethyl)isoindolin-1-one,
[0360]
7-(Pyridin-4-yl)-2-(3-(pyrimidin-2-yl)phenethyl)isoindolin-1-one,
[0361]
(2-(2-Phenylpyrimidin-4-yl)ethyl)-7-(pyridin-4-yl)isoindolin-1-one,
[0362] Pyridine-3-sulfonic acid
[3-oxo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-1H-isoindol-4-yl]-amide
, [0363] 7-1
(Pyridin-2-ylmethyl)-amino1-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindo-
l-1-one, [0364] 7-1
(Pyridin-4-ylmethyl)-amino1-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindo-
l-1-one, [0365] 7-1
(Pyridin-3-ylmethyl)-amino1-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindo-
l-1-one, [0366]
7-(Pyridin-3-ylmethoxy)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1--
one, [0367]
7-(Pyridin-4-ylmethoxy)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1--
one, [0368]
7-(Pyridin-2-ylmethoxy)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1--
one, [0369]
4-Morpholin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
[0370]
4-(1,1-Dioxo-1-thiomorpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-d-
ihydro-isoindol-1-one, [0371]
7-[8-(4-Methyl-piperazine-1-sulfonyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2--
(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one, [0372]
7-[8-(Morpholine-4-sulfonyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-(2-quinol-
in-2-yl-ethyl)-2,3-dihydro-isoindol-1-one, [0373]
7-(2-Oxa-6-aza-spiro[3.4]oct-6-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro--
isoindol-1-one, [0374]
7-(1Oxo-thiomorpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindo-
l-1-one, [0375]
7-(2-Oxa-6-aza-spiro[3.5]non-6-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro--
isoindol-1-one, [0376]
4-(1,1-Dioxo-thiomorpholin-4-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-py-
rrolo[3,4-b]pyridin-5-one, [0377]
4-(4-Methyl-piperazin-1-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo-
[3,4-b]pyridin-5-one, [0378]
7-(3-Amino-azetidin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol--
1-one, [0379]
7-[4-(4-Methoxy-benzyloxy)-phenyl]-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro--
isoindol-1-one, [0380]
4-Piperazin-1-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
[0381]
7-(5,5-Difluoro-hexahydro-cyclopenta[c]pyrrol-2-yl)-2-(2-quinolin--
2-yl-ethyl)-2,3-dihydro-isoindol-1-one, [0382]
7-(4,4-Difluoro-piperidin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-iso-
indol-1-one, [0383]
4-(4-Methyl-piperazin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindo-
l-1-one, [0384]
7-(Azetidin-3-ylamino)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-o-
ne, [0385]
7-[4-(4-Isopropenyl-phenoxy)-phenyl]-2-(2-quinolin-2-yl-ethyl)--
2,3-dihydro-isoindol-1-one, [0386] 7-[(3S
,4S)-4-(2-Fluoro-4-trifluoromethoxy-phenyl)-3-methyl-piperidin-1-yl]-2-(2-
-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one, [0387]
7-[4-(2,6-Dimethyl-pyridin-3-yloxy)-3-fluoro-phenyl]-2-(2-quinolin-2-yl-e-
thyl)-2,3-dihydro-isoindol-1-one, [0388]
7-(1-Pyridin-4-ylmethyl-1H-indol-5-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihy-
dro-isoindol-1-one, [0389]
2-(2-Quinolin-2-yl-ethyl)-7-thiomorpholin-4-yl-2,3-dihydro-isoindol-1-one-
, [0390]
7-(8-Methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-2-(2-quinolin-2-yl--
ethyl)-2,3-dihydro-isoindol-1-one, [0391]
7-(3-Methyl-3,8-diaza-bicyclo[3.2.1]oct-8-yl)-2-(2-quinolin-2-yl-ethyl)-2-
,3-dihydro-isoindol-1-one, [0392]
2-[2-(1-Methyl-1H-benzoimidazol-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro-
-isoindol-1-one, [0393]
7-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-(2-quinolin-2-yl-ethyl-
)-2,3-dihydro-isoindol-1-one, [0394]
7-[3-Chloro-4-(4-hydroxy-4-methyl-cyclohexylamino)-phenyl]-2-(2-quinolin--
2-yl-ethyl)-2,3-dihydro-isoindol-1-one, [0395]
4-(1H-Pyrazol-4-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]p-
yridin-5-one, [0396]
7-[4-(4-Ethyl-piperazin-1-yl)-piperidin-1-yl]-2-(2-quinolin-2-yl-ethyl)-2-
,3-dihydro-isoindol-1-one, [0397] 2-(2-Quinolin-2-yl-ethyl)-7-(3
,4,5 ,
6-tetrahydro-2H-[4,4']bipyridinyl-1-yl)-2,3-dihydro-isoindol-1-one,
[0398]
7-(4-Pyridin-3-yl-piperazin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-di-
hydro-isoindol-1-one, [0399]
4-(4-Fluoro-phenyl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]p-
yridin-5-one, [0400]
4-(4-Methoxy-phenyl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]-
pyridin-5-one, [0401]
4-(2-Methyl-2H-pyrazol-3-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrol-
o[3,4-b]pyridin-5-one, [0402]
4-Piperazin-1-yl-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]pyri-
din-5-one,
[0403]
4-(2-Oxo-2,3-dihydro-1H-indol-6-yl)-6-(2-quinolin-2-yl-ethyl)-6,7--
dihydro-pyrrolo[3,4-b]pyridin-5-one, [0404]
4-Pyrimidin-5-yl-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]pyri-
din-5-one, [0405]
7-[4-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-2-(2-quinolin-2-yl-ethyl)-2,-
3-dihydro-isoindol-1-one, [0406]
7-(4-Morpholin-4-ylmethyl-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-i-
soindol-1-one, [0407]
7-(3-Methoxy-pyridin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one, [0408]
7-(3-Chloro-pyridin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol--
1-one, [0409]
7-(2-Chloro-pyridin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol--
1-one, [0410]
7-(6-Methyl-pyridin-3-ylmethoxy)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-is-
oindol-1-one, [0411]
7-(3-Fluoro-pyridin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol--
1-one, [0412]
7-(3-Amino-4-methyl-piperidin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-
-isoindol-1-one, [0413]
2-[2-(1H-Benzoimidazol-2-yl)-ethyl]-7-(1,1-dioxothiomorpholin-4-yl)-2,3-d-
ihydro-isoindol-1-one, [0414] 7-[ (1S
,4S)-5-(4-Chloro-phenyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-2-(2-quinolin-
-2-yl-ethyl)-2,3-dihydro-isoindol-1-one, [0415]
7-(4-Methyl-piperazin-1-ylmethyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-i-
soindol-1-one, [0416]
7-Morpholin-4-ylmethyl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-o-
ne, [0417]
7-(2-Methyl-pyridin-3-ylmethoxy)-2-(2-quinolin-2-yl-ethyl)-2,3--
dihydro-isoindol-1-one, [0418]
4-Methoxy-7-(1H-pyrazol-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoin-
dol-1-one, [0419]
4-Pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
[0420]
7-(2-Methoxy-pyridin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-i-
soindol-1-one, [0421]
4-Methoxy-7-pyrimidin-5-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one, [0422]
7-(1,1-Dioxo-thiomorpholin-4-yl)-2-[2-(1-methyl-1H-benzoimidazol-2-yl)-et-
hyl]-2,3-dihydro-isoindol-1-one, [0423]
4-Methoxy-7-pyridin-3-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-
-one, [0424]
4-Methoxy-7-(4-methoxy-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoi-
ndol-1-one, [0425]
7-(4-Fluoro-phenyl)-4-methoxy-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoin-
dol-1-one, [0426]
7-(4-Dimethylaminomethyl-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-is-
oindol-1-one, [0427]
7-(1,1-Dioxo-thiomorpholin-4-yl)-4-methoxy-2-(2-quinolin-2-yl-ethyl)-2,3--
dihydro-isoindol-1-one, [0428]
7-(1,1-Dioxo-tetrahydrothiophen-3-ylamino)-2-(2-quinolin-2-yl-ethyl)-2,3--
dihydro-isoindol-1-one, [0429]
7-(6-Fluoro-pyridin-3-ylmethoxy)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-is-
oindol-1-one, [0430]
7-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dih-
ydro-isoindol-1-one, [0431]
7-(4-Aminomethyl-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-
-one, [0432]
7-(4-Methylaminomethyl-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoi-
ndol-1-one, [0433]
2-[2-(1-Methyl-1H-benzoimidazol-2-yl)-ethyl]-7-pyridin-4-yl-2,3-dihydro-i-
soindol-1-one, [0434]
2-[2-(1-Methyl-1H-benzoimidazol-2-yl)-ethyl]-7-pyridin-3-yl-2,3-dihydro-i-
soindol-1-one, [0435]
2-[2-(1-Methyl-1H-benzoimidazol-2-yl)-ethyl]-7-pyrimidin-5-yl-2,3-dihydro-
-isoindol-1-one, [0436]
4-Hydroxy-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-
-one, [0437]
4-Ethoxy-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1--
one, [0438]
4-(1H-Pyrazol-3-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
[0439]
4-Pyridin-3-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-on-
e, [0440]
4-(2-Methyl-2H-pyrazol-3-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihyd-
ro-isoindol-1-one, [0441]
4-(4-Methoxy-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one-
, [0442]
4-(3-Methoxy-propoxy)-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,-
3-dihydro-isoindol-1-one, [0443]
4-Isopropoxy-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindo-
l-1-one, [0444]
7-(4-Pyrrolidin-1-yl-piperidin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydr-
o-isoindol-1-one, [0445]
7-[1,4']Bipiperidinyl-1'-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindo-
l-1-one, [0446]
4-Pyrimidin-5-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
[0447]
7-(4-Methoxy-phenyl)-2-[2-(1-methyl-1H-benzoimidazol-2-yl)-ethyl]--
2,3-dihydro-isoindol-1-one, [0448]
4-Methoxy-7-(2-methyl-2H-pyrazol-3-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihy-
dro-isoindol-1-one, [0449]
7-(4-Fluoro-phenyl)-2-[2-(1-methyl-1H-benzoimidazol-2-yl)-ethyl]-2,3-dihy-
dro-isoindol-1-one, [0450]
4-(4-Fluoro-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
[0451] 4-(2-Methyl-2H-pyrazol-3-yl)-6-(2-[1,2,4]triazolo
[1,5-a]pyridin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one,
[0452]
6-[2-(1-Methyl-1H-benzoimidazol-2-yl)-ethyl]-4-(2-methyl-2H-pyrazo-
l-3-yl)-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one, [0453]
4-Pyrimidin-5-yl-6-(2-[1,2,4]triazolo
[1,5-a]pyridin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one,
[0454]
6-[2-(1-Methyl-1H-benzoimidazol-2-yl)-ethyl]-4-morpholin-4-yl-6,7--
dihydro-pyrrolo[3,4-b]pyridin-5-one, [0455] 2-(2-Imidazo
[1,2-a]pyridin-2-yl-ethyl)-4-methoxy-7-pyrimidin-5-yl-2,3-dihydro-isoindo-
l-1-one, [0456]
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-methoxy-7-pyridin-3-yl-2,3-dihyd-
ro-isoindol-1-one, [0457] 7-(1S,5S)-3,6-Diaza-bicyclo
[3.2.0]hept-3-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
[0458]
7-(3aR,7aS)-Octahydro-pyrrolo[3,2-c]pyridin-5-yl-2-(2-quinolin-2-y-
l-ethyl)-2,3-dihydro-isoindol-1-one, [0459]
2-[2-(5-Fluoro-1-methyl-1H-benzoimidazol-2-yl)-ethyl]-7-pyridin-4-yl-2,3--
dihydro-isoindol-1-one, [0460]
2-[2-(1-Ethyl-1H-benzoimidazol-2-yl)-ethyl]-7-pyridin-4-yl-2,3-dihydro-is-
oindol-1-one, [0461]
2-(2-Benzothiazol-2-yl-ethyl)-7-pyridin-4-yl-2,3-dihydro-isoindol-1-one,
[0462]
7-((R)-3-Amino-pyrrolidin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihy-
dro-isoindol-1-one, [0463]
4-(1H-Pyrazol-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
[0464]
6-[2-(1-Methyl-1H-benzoimidazol-2-yl)-ethyl]-4-(4-methyl-piperazin-
-1-yl)-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one, [0465]
4-Morpholin-4-yl-6-(2-[1,2,4]triazolo
[1,5-a]pyridin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one,
[0466]
7-(2-Methyl-morpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro--
isoindol-1-one, [0467]
7-(2-Dimethylaminomethyl-morpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-di-
hydro-isoindol-1-one, [0468]
7-Pyridin-4-yl-2-(2-[1,2,4]triazolo[1,5-a]pyridin-2-yl-ethyl)-2,3-dihydro-
-isoindol-1-one, [0469]
7-Morpholin-4-yl-2-(2-[1,2,4]triazolo[1,5-a]pyridin-2-yl-ethyl)-2,3-dihyd-
ro-isoindol-1-one, [0470]
7-(1,1-Dioxo-thiomorpholin-4-yl)-2-(2-[1,2,4]triazolo[1,5-a]pyridin-2-yl--
ethyl)-2,3-dihydro-isoindol-1-one, [0471]
7-(4-Methyl-piperazin-1-yl)-2-(2-[1,2,4]triazolo[1,5-a]pyridin-2-yl-ethyl-
)-2,3-dihydro-isoindol-1-one, [0472]
7-(1,1-Dioxo-thiomorpholin-4-yl)-2-(2-imidazo[1,2-a]pyridin-2-yl-ethyl)-2-
,3-dihydro-isoindol-1-one, [0473]
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-7-pyridin-3-yl-2,3-dihydro-isoindo-
l-1-one, [0474]
7-(4-Fluoro-phenyl)-2-(2-imidazo[1,2-a]pyridin-2-yl-ethyl)-2,3-dihydro-is-
oindol-1-one, [0475]
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-7-(4-methoxy-phenyl)-2,3-dihydro-i-
soindol-1-one, [0476]
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-7-pyrimidin-5-yl-2,3-dihydro-isoin-
dol-1-one, [0477]
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-7-(2-methyl-2H-pyrazol-3-yl)-2,3-d-
ihydro-isoindol-1-one, [0478]
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-7-(2-methyl-pyridin-3-yl)-2,3-dihy-
dro-isoindol-1-one, [0479]
6-[2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-3-oxo-2,3-dihydro-1H-isoindol-4-
-yl]-1,3-dihydro-indol-2-one, [0480]
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-7-(1H-pyrazol-4-yl)-2,3-dihydro-is-
oindol-1-one, [0481]
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-7-(1H-indazol-6-yl)-2,3-dihydro-is-
oindol-1-one, [0482] 7-(3H-Benzoimidazol-5-yl)-2-(2-imidazo
[1,2-a]pyridin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one, [0483]
5-[2-(2-Imidazo
[1,2-a]pyridin-2-yl-ethyl)-3-oxo-2,3-dihydro-1H-isoindol-4-yl]-1,3-dihydr-
o-benzoimidazol-2-one, [0484]
4-(Pyridin-3-ylmethoxy)-2-(2-quinolin-2-yl-ethyl)-isoindole-1,
3-dione, [0485]
4-(Pyridin-4-ylmethoxy)-2-(2-quinolin-2-yl-ethyl)-isoindole-1,
3-dione, [0486]
4-Methoxy-7-morpholin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one, [0487]
4-Pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-isoindole-1,3-dione [0488]
4-(1,1-Dioxothiomorpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-isoindole-1,3-d-
ione [0489]
7-(2-Methoxy-pyridin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one, [0490]
7-(2-Ethyl-morpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one, [0491]
2-[2-(1H-Imidazo[4,5-b]pyridin-2-yl)-ethyl]-7-pyridin-3-yl-2,3-dihydro-is-
oindol-1-one, [0492]
2-[2-(1-Methyl-1H-benzoimidazol-2-yl)-ethyl]-7-(4-methyl-piperazin-1-yl)--
2,3-dihydro-isoindol-1-one, [0493] 6-(2-Imidazo
[1,2-a]pyridin-2-yl-ethyl)-4-(2-methyl-2H-pyrazol-3-yl)-6,7-dihydro-pyrro-
lo[3,4-b]pyridin-5-one, [0494] 6-(2-Imidazo
[1,2-a]pyridin-2-yl-ethyl)-4-pyrimidin-5-yl-6,7-dihydro-pyrrolo[3,4-b]pyr-
idin-5-one, [0495]
4-(2-Oxa-6-aza-spiro[3.4]oct-6-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro--
pyrrolo[3,4-b]pyridin-5-one, [0496]
4-(4,4-Difluoro-piperidin-1-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyr-
rolo[3,4-b]pyridin-5-one, [0497]
7-(2,6-Dimethyl-morpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-iso-
indol-1-one, [0498]
6-(2-Quinolin-2-yl-ethyl)-4-(tetrahydro-furo[3,4-c]pyrrol-5-yl)-6,7-dihyd-
ro-pyrrolo[3,4-b]pyridin-5-one, [0499]
4-Methoxy-7-(4-methyl-piperazin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihyd-
ro-isoindol-1-one, [0500]
2-[2-(5-Fluoro-1-methyl-1H-benzoimidazol-2-yl)-ethyl]7-morpholin-4-yl-2,3-
-dihydro-isoindol-1-one, [0501]
2-(2-Benzothiazol-2-yl-ethyl)-7-morpholin-4-yl-2,3-dihydro-isoindol-1-one-
, [0502]
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-methoxy-7-morpholin-4-yl-
-2,3-dihydro-isoindol-1-one, [0503]
4-(3,6-Dihydro-2H-pyran-4-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrro-
lo[3,4-b]pyridin-5-one, [0504]
4-(4,5-Dihydro-furan-3-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[-
3,4-b]pyridin-5-one, [0505]
4-Methylsulfanylmethoxy-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihy-
dro-isoindol-1-one, [0506]
4-Difluoromethoxy-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-is-
oindol-1-one, [0507]
4-Methoxy-7-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-(2-quinolin-2--
yl-ethyl)-2,3-dihydro-isoindol-1-one, [0508]
6-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-morpholin-4-yl-6,7-dihydro-pyrro-
lo[3,4-b]pyridin-5-one, [0509]
4-Pyridin-3-yl-2-(2-quinolin-2-yl-ethyl)-isoindole-1,3-dione,
[0510]
4-Morpholin-4-yl-2-(2-quinolin-2-yl-ethyl)-isoindole-1,3-dione,
[0511]
6-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-(4-methyl-piperazin-1-yl)-6,7-di-
hydro-pyrrolo[3,4-b]pyridin-5-one, [0512]
7-(Oxetan-3-ylamino)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one-
, [0513]
4-(Oxetan-3-ylamino)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrol-
o[3,4-b]pyridin-5-one, [0514]
4-Methylaminomethoxy-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-
-isoindol-1-one, [0515]
7-(2-Ethyl-6-methyl-morpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-
-isoindol-1-one, [0516]
2-[2-(1-Ethyl-1H-benzoimidazol-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro--
isoindol-1-one, [0517]
7-(Octahydro-[1,5]naphthyridin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydr-
o-isoindol-1-one, [0518]
4-Fluoro-2-(2-imidazo[1,2-a]pyridin-2-yl-ethyl)-7-pyridin-4-yl-2,3-dihydr-
o-isoindol-1-one, [0519]
5-[3-Oxo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-1H-isoindol-4-yl]-thiophen-
e-2-carbonitrile, [0520]
7-[2-(4-Methyl-piperazin-1-yl)-pyrimidin-5-yl]-2-(2-quinolin-2-yl-ethyl)--
2,3-dihydro-isoindol-1-one, [0521]
7-(2-Ethoxy-pyrimidin-5-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindo-
l-1-one, [0522]
7-(5-Pyrrolidin-1-ylmethyl-thiophen-2-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-d-
ihydro-isoindol-1-one, [0523]
7-(2-Dimethylamino-pyrimidin-5-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro--
isoindol-1-one, [0524]
7-(5-Piperidin-1-ylmethyl-thiophen-2-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-di-
hydro-isoindol-1-one, [0525]
7-(3-Chloro-thiophen-2-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one, [0526]
3-Methyl-5-[3-oxo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-1H-isoindol-4-yl]-
-thiophene-2-carbonitrile, [0527]
7-(2-Chloro-thiophen-3-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one, [0528]
7-(2-Cyclopropyl-pyridin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoi-
ndol-1-one, [0529]
7-(3,6-Dimethoxy-pyridazin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-is-
oindol-1-one, [0530]
2-{2-[1-(2-Morpholin-4-yl-ethyl)-1H-benzoimidazol-2-yl]-ethyl
}-7-pyridin-4-yl-2,3-dihydro-isoindol-1-one, [0531]
2-{2-[1-(2-Dimethylamino-ethyl)-1H-benzoimidazol-2-yl]-ethyl}-7-pyridin-4-
-yl-2,3-dihydro-isoindol-1-one, [0532]
2-{2-[1-(3-Dimethylamino-propyl)-1H-benzoimidazol-2-yl]-ethyl}-7-pyridin--
4-yl-2,3-dihydro-isoindol-1-one, [0533]
4-Fluoro-2-(2-imidazo[1,2-a]pyridin-2-yl-ethyl)-7-morpholin-4-yl-2,3-dihy-
dro-isoindol-1-one, [0534]
1-Oxy-4-pyrimidin-5-yl-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4--
b]pyridin-5-one, [0535]
6-(2-Quinolin-2-yl-ethyl)-4-(tetrahydro-pyran-4-yl)-6,7-dihydro-pyrrolo[3-
,4-b]pyridin-5-one, [0536]
7-(2-Methoxymethyl-morpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro--
isoindol-1-one, [0537]
4-Fluoromethoxy-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoi-
ndol-1-one, [0538]
2-[2-(4-Fluoro-1-methyl-1H-benzoimidazol-2-yl)-ethyl]-7-pyridin-4-yl-2,3--
dihydro-isoindol-1-one, [0539]
2-[2-(1,5-Dimethyl-1H-benzoimidazol-2-yl)-ethyl]-7-pyridin-4-yl-2,3-dihyd-
ro-isoindol-1-one, [0540]
2-[2-(1-Propyl-1H-benzoimidazol-2-yl)-ethyl]-7-pyridin-4-yl-2,3-dihydro-i-
soindol-1-one, [0541]
2-[2-(1-Isopropyl-1H-benzoimidazol-2-yl)-ethyl]-7-pyridin-4-yl-2,3-dihydr-
o-isoindol-1-one, [0542]
2-[2-(1-Isopropyl-1H-benzoimidazol-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihy-
dro-isoindol-1-one, [0543]
7-Morpholin-4-yl-2-[2-(1-propyl-1H-benzoimidazol-2-yl)-ethyl]-2,3-dihydro-
-isoindol-1-one, [0544]
2-[2-(1,5-Dimethyl-1H-benzoimidazol-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dih-
ydro-isoindol-1-one, [0545]
2-[2-(4-Fluoro-1-methyl-1H-benzoimidazol-2-yl)-ethyl]-7-morpholin-4-yl-2,-
3-dihydro-isoindol-1-one, [0546]
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-morpholin-4-yl-2,3-dihydro-isoin-
dol-1-one, [0547]
6-(2-Quinolin-2-yl-ethyl)-4-(tetrahydro-furan-3-yl)-6,7-dihydro-pyrrolo[3-
,4-b]pyridin-5-one, [0548]
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-7-morpholin-4-yl-2,3-dihydro-isoin-
dol-1-one, [0549]
2-[2-(1H-Benzoimidazol-2-yl)-ethyl]-7-(4-fluoro-phenyl)-2,3-dihydro-isoin-
dol-1-one, [0550]
2-[2-(1H-Benzoimidazol-2-yl)-ethyl]-7-pyrimidin-5-yl-2,3-dihydro-isoindol-
-1-one, [0551]
2-[2-(1H-Benzoimidazol-2-yl)-ethyl]-7-(2-methyl-2H-pyrazol-3-yl)-2,3-dihy-
dro-isoindol-1-one, [0552]
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-(1H-pyrazol-3-yl)-2,3-dihydro-is-
oindol-1-one, [0553]
6-[2-(5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-ethyl]-4-pyridin-
-4-yl-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one, [0554]
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-pyridin-4-yl-2,3-dihydro-isoindo-
l-1-one, [0555]
7-(3aS,8aR)-Octahydro-pyrrolo[3,4-c]azepin-2-yl-2-(2-quinolin-2-yl-ethyl)-
-2,3-dihydro-isoindol-1-one, [0556]
7-(3aS,8aS)-Octahydro-pyrrolo[3,4-c]azepin-2-yl-2-(2-quinolin-2-yl-ethyl)-
-2,3-dihydro-isoindol-1-one, [0557]
1-[5-Oxo-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-
-yl]-piperidine-4-carboxylic acid ethyl ester,
[0558]
4-[8-(Morpholine-4-sulfonyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-(2-
-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one, [0559]
4-[8-(4-Methyl-piperazine-1-sulfonyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2--
(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one, [0560]
4-(3-Methyl-pyridin-4-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3-
,4-b]pyridin-5-one, [0561]
4-(1H-Pyrazol-3-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]p-
yridin-5-one, [0562]
4-(3,6-dimethoxypyridazin-4-yl)-6-(2-(quinolin-2-yl)ethyl)-6,7-dihydro-5H-
-pyrrolo[3,4-b]pyridin-5-one, [0563]
4-(2-Dimethylamino-pyrimidin-5-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro--
pyrrolo[3,4-b]pyridin-5-one, [0564]
4-(2-Methyl-thiazol-5-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3-
,4-b]pyridin-5-one, [0565]
4-(2-Ethoxy-pyrimidin-5-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo-
[3,4-b]pyridin-5-one, [0566]
4-(2-Methoxy-pyridin-4-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[-
3,4-b]pyridin-5-one, [0567]
4-Pyridin-3-yl-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]pyridi-
n-5-one, [0568]
6-(2-Quinolin-2-yl-ethyl)-4-thiophen-3-yl-6,7-dihydro-pyrrolo[3,4-b]pyrid-
in-5-one, [0569]
4-Furan-3-yl-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]pyridin--
5-one, [0570]
4-(1,5-Dimethyl-1H-pyrazol-4-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-py-
rrolo[3,4-b]pyridin-5-one, [0571]
4-(1-Ethyl-1H-pyrazol-4-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo-
[3,4-b]pyridin-5-one, [0572]
4-(2,5-Dimethyl-2H-pyrazol-3-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-py-
rrolo[3,4-b]pyridin-5-one, [0573] 4-(3
,5-Dimethyl-isoxazol-4-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[-
3,4-b]pyridin-5-one, [0574]
4-(3-Methyl-thiophen-2-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[-
3,4-b]pyridin-5-one, [0575]
4-(1-Methyl-1H-pyrrol-3-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo-
[3,4-b]pyridin-5-one, [0576]
4-Pyridazin-4-yl-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]pyri-
din-5-one, [0577]
4-(2-Cyclopropyl-pyridin-4-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrr-
olo[3,4-b]pyridin-5-one, [0578]
6-(2-Quinolin-2-yl-ethyl)-4-thiazol-4-yl-6,7-dihydro-pyrrolo[3,4-b]pyridi-
n-5-one, [0579] 4-(2-Dimethylamino-pyrimidin-5-yl)-2-(2-quinolin-2-
yl-ethyl)-2,3-dihydro-isoindol-1-one, [0580]
4-(2-Methyl-thiazol-5-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol--
1-one, [0581]
4-(2-Ethoxy-pyrimidin-5-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindo-
l-1-one, [0582]
4-(2-Methoxy-pyridin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one, [0583]
2-(2-Quinolin-2-yl-ethyl)-4-thiophen-3-yl-2,3-dihydro-isoindol-1-one,
[0584]
4-Furan-3-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
[0585]
4-(1-Ethyl-1H-pyrazol-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro--
isoindol-1-one, [0586]
4-(2,5-Dimethyl-2H-pyrazol-3-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-is-
oindol-1-one, [0587]
4-(3,5-Dimethyl-isoxazol-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoi-
ndol-1-one, [0588]
4-(5-Methyl-pyrazin-2-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol--
1-one, [0589]
4-(3-Methyl-thiophen-2-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one, [0590]
4-(1-Methyl-1H-pyrrol-3-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindo-
l-1-one, [0591]
4-Pyridazin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one,
[0592]
4-(2-Cyclopropyl-pyridin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihyd-
ro-isoindol-1-one, [0593]
2-(2-Quinolin-2-yl-ethyl)-4-thiazol-4-yl-2,3-dihydro-isoindol-1-one,
[0594]
4-(6-Methoxy-pyrazin-2-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-i-
soindol-1-one, [0595]
4-(3-Phenyl-piperidin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindo-
l-1-one, [0596]
6-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-pyridin-3-yl-6,7-dihydro-pyrrolo-
[3,4-b]pyridin-5-one, [0597]
6-[2-(1-Methyl-1H-benzoimidazol-2-yl)-ethyl]-4-(oxetan-3-ylamino)-6,7-dih-
ydro-pyrrolo[3,4-b]pyridin-5-one, [0598]
6-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-(oxetan-3-ylamino)-6,7-dihydro-p-
yrrolo[3,4-b]pyridin-5-one, [0599]
4-(3-Phenoxy-piperidin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoind-
ol-1-one, [0600]
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-methoxy-7-(oxetan-3-ylamino)-2,3-
-dihydro-isoindol-1-one, [0601]
4-(4-Dimethylamino-piperidin-1-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro--
pyrrolo[3,4-b]pyridin-5-one, [0602]
6-[2-(1-Methyl-1H-benzoimidazol-2-yl)-ethyl]-4-pyrimidin-5-yl-6,7-dihydro-
-pyrrolo[3,4-b]pyridin-5-one, [0603]
6-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-(1H-pyrazol-4-yl)-6,7-dihydro-py-
rrolo[3,4-b]pyridin-5-one, [0604]
1-[5-Oxo-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-
-yl]-piperidine-4-carboxylic acid, [0605]
6-[2-(1-Methyl-1H-benzoimidazol-2-yl)-ethyl]-4-pyridin-4-yl-6,7-dihydro-p-
yrrolo[3,4-b]pyridin-5-one, [0606]
6-[2-(1-Methyl-1H-benzoimidazol-2-yl)-ethyl]-4-pyridin-3-yl-6,7-dihydro-p-
yrrolo[3,4-b]pyridin-5-one, [0607]
6-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-pyridin-4-yl-6,7-dihydro-pyrrolo-
[3,4-b]pyridin-5-one, [0608]
4-Methoxy-2-[2-(1-methyl-1H-benzoimidazol-2-yl)-ethyl]-7-pyridin-4-yl-2,3-
-dihydro-isoindol-1-one, [0609]
4-Methoxy-2-[2-(1-methyl-1H-benzoimidazol-2-yl)-ethyl]-7-morpholin-4-yl-2-
,3-dihydro-isoindol-1-one, [0610]
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-methoxy-7-(1H-pyrazol-4-yl)-2,3--
dihydro-isoindol-1-one, [0611]
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-methoxy-7-(2-methyl-2H-pyrazol-3-
-yl)-2,3-dihydro-isoindol-1-one, [0612]
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-methoxy-7-pyridin-4-yl-2,3-dihyd-
ro-isoindol-1-one, [0613]
6-(2-Benzothiazol-2-yl-ethyl)-4-pyridin-4-yl-6,7-dihydro-pyrrolo[3,4-b]py-
ridin-5-one, [0614]
6-(2-Benzothiazol-2-yl-ethyl)-4-(oxetan-3-ylamino)-6,7-dihydro-pyrrolo[3,-
4-b]pyridin-5-one, [0615]
6-(2-Benzothiazol-2-yl-ethyl)-4-morpholin-4-yl-6,7-dihydro-pyrrolo[3,4-b]-
pyridin-5-one, [0616]
4-Fluoro-2-(2-imidazo[1,2-a]pyridin-2-yl-ethyl)-7-pyridin-3-yl-2,3-dihydr-
o-isoindol-1-one, [0617]
4-Fluoro-7-(4-fluoro-phenyl)-2-(2-imidazo[1,2-a]pyridin-2-yl-ethyl)-2,3-d-
ihydro-isoindol-1-one, [0618]
4-Fluoro-2-(2-imidazo[1,2-a]pyridin-2-yl-ethyl)-7-(4-methoxy-phenyl)-2,3--
dihydro-isoindol-1-one, [0619]
4-Fluoro-2-(2-imidazo[1,2-a]pyridin-2-yl-ethyl)-7-pyrimidin-5-yl-2,3-dihy-
dro-isoindol-1-one, [0620]
4-Fluoro-2-(2-imidazo[1,2-a]pyridin-2-yl-ethyl)-7-(2-methyl-2H-pyrazol-3--
yl)-2,3-dihydro-isoindol-1-one, [0621]
4-Fluoro-2-(2-imidazo[1,2-a]pyridin-2-yl-ethyl)-7-(1H-pyrazol-4-yl)-2,3-d-
ihydro-isoindol-1-one, [0622]
4-[3-(Fluoromethyl)pyrrolidin-1-yl]-6-(2-imidazo[1,2-a]pyridin-2-ylethyl)-
-7H-pyrrolo[3,4-b]pyridin-5-one, [0623]
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-[3-(difluoromethyl)pyrrolidin-1-yl]--
7H-pyrrolo[3,4-b]pyridin-5-one, [0624]
4-[3-(Difluoromethyl)pyrrolidin-1-yl]-6-(2-imidazo[1,2-a]pyridin-2-ylethy-
l)-7H-pyrrolo[3,4-b]pyridin-5-one, [0625]
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-[3-(fluoromethyl)pyrrolidin-1-yl]-7H-
-pyrrolo[3,4-b]pyridin-5-one, [0626]
4-(3-Methoxy-4-pyridyl)-2-[2-(2-quinolyl)ethyl]isoindolin-1-one,
[0627]
4-(3-Methoxy-4-pyridyl)-6-[2-(2-quinolyl)ethyl]-7H-pyrrolo[3,4-b]pyridin--
5-one, [0628]
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(1,1-dioxo-1,4-thiazinan-4-yl)-7H-py-
rrolo[3,4-b]pyridin-5-one trifluoroacetate, [0629]
6-[2-(Benzofuran-2-yl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-one-
, [0630]
6-[2-(7-Methyl-2-quinolyl)ethyl]-4-morpholino-7H-pyrrolo[3,4-b]py-
ridin-5-one, [0631]
6-[2-(Benzothiophen-2-yl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4-b]pyridin-5--
one, [0632]
6-[2-(7-Methyl-2-quinolyl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-
-one trifluoroacetate, [0633]
6-[2-(Benzothiophen-2-yl)ethyl]-4-morpholino-7H-pyrrolo[3,4-b]pyridin-5-o-
ne trifluoroacetate, [0634]
2-[2-(1,3-Benzothiazol-2-yl)ethyl]-7-methoxy-4-(4-pyridyl)isoindolin-1-on-
e, [0635]
6-[2-(Benzofuran-2-yl)ethyl]-4-morpholino-7H-pyrrolo[3,4-b]pyrid-
in-5-one, [0636]
6-[2-(5-Isopropyl-2-pyridyl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4-b]pyridin-
-5-one, [0637]
2-[2-(1,3-Benzothiazol-2-yl)ethyl]-7-methoxy-4-(2-methylpyrazol-3-yl)isoi-
ndolin-1-one, [0638]
2-[2-(1,3-Benzothiazol-2-yl)ethyl]-7-methoxy-4-(1H-pyrazol-3-yl)isoindoli-
n-1-one, [0639]
6-[2-(5-Isopropyl-2-pyridyl)ethyl]-4-morpholino-7H-pyrrolo[3,4-b]pyridin--
5-one, [0640]
6-[2-(6-Fluoro-1,3-benzothiazol-2-yl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4--
b]pyridin-5-one, [0641]
6-[2-(6-Chloro-1,3-benzothiazol-2-yl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4--
b]pyridin-5-one, [0642]
6-[2-(6-Chloro-1,3-benzothiazol-2-yl)ethyl]-4-morpholino-7H-pyrrolo[3,4-b-
]pyridin-5-one, [0643]
6-[2-(6-Fluoro-1,3-benzothiazol-2-yl)ethyl]-4-morpholino-7H-pyrrolo[3,4-b-
]pyridin-5-one, [0644]
6-[2-(6-Methyl-2-quinolyl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-
-one, [0645]
6-[2-(4-Ethylthiazol-2-yl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-
-one, [0646]
6-[244,5-Dimethylthiazol-2-yl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4-b]pyrid-
in-5-one, [0647]
6-[2-(3-Methyl-2-pyridyl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4-b]pyridin-5--
one, [0648]
6-[2-(4-Methyl-2-pyridyl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4-b]pyridin-5--
one, [0649]
4-Methoxy-2-[2-(1-methyl-1H-benzoimidazol-2-yl)-ethyl]-7-(oxetan-3-ylamin-
o)-2,3-dihydro-isoindol-1-one, [0650]
4-(3-Fluoro-pyridin-4-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3-
,4-b]pyridin-5-one, [0651]
6-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-(1H-pyrazol-3-yl)-6,7-dihydro-py-
rrolo[3,4-b]pyridin-5-one, [0652]
4-Furan-3-yl-6-(2-imidazo[1,2-a]pyridin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3-
,4-b]pyridin-5-one, [0653]
6-[2-(1,5-Dimethyl-1H-benzoimidazol-2-yl)-ethyl]-4-morpholin-4-yl-6,7-dih-
ydro-pyrrolo[3,4-b]pyridin-5-one, [0654]
6-[2-(1,5-Dimethyl-1H-benzoimidazol-2-yl)-ethyl]-4-(oxetan-3-ylamino)-6,7-
-dihydro-pyrrolo[3,4-b]pyridin-5-one, [0655]
6-[2-(1,3-Benzoxazol-2-yl)ethyl]-4-morpholino-7H-pyrrolo[3,4-b]pyridin-5--
one, [0656]
6-[2-(1,3-Benzoxazol-2-yl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-
-one, [0657]
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(4-methylpiperazin-1-yl)-7H-pyrrolo[-
3,4-b]pyridin-5-one, [0658]
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(2,3-dihydrofuran-4-yl)-7H-pyrrolo[3-
,4-b]pyridin-5-one trifluoroacetate, [0659]
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(2-fluoro-4-pyridyl)-7H-pyrrolo[3,4--
b]pyridin-5-one trifluoroacetate, [0660]
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(3-furyl)-7H-pyrrolo[3,4-b]pyridin-5-
-one trifluoroacetate, [0661]
6-(2-Imidazo[2,1-b]thiazol-6-ylethyl)-4-(4-pyridyl)-7H-pyrrolo[3,4-b]pyri-
din-5-one trifluoroacetate, [0662]
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(2-oxa-7-azaspiro[3.4]octan-7-yl)-7H-
-pyrrolo[3,4-b]pyridin-5-one, [0663]
6-(2-Imidazo[2,1-b]thiazol-6-ylethyl)-4-morpholino-7H-pyrrolo[3,4-b]pyrid-
in-5-one, [0664]
4-(1,3,3a,4,6,6a-Hexahydrofuro[3,4-c]pyrrol-5-yl)-6-[2-(1,3-benzothiazol--
2-yl)ethyl]-7H-pyrrolo[3,4-b]pyridin-5-one, [0665]
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(4-piperidyloxy)-7H-pyrrolo[3,4-b]py-
ridin-5-one trifluoroacetate, [0666]
2-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(1H-pyrazol-3-yl)isoindolin-1-one,
[0667]
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(1H-pyrazol-3-yl)-7H-pyrrolo[-
3,4-b]pyridin-5-one, [0668]
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(3-pyridyl)-7H-pyrrolo[3,4-b]pyridin-
-5-one trifluoroacetate, [0669]
2-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(4-pyridyl)isoindolin-1-one,
[0670]
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(2-methylpyrazol-3-yl)-7H-pyrrolo[3,-
4-b]pyridin-5-one trifluoroacetate, [0671]
2-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-morpholino-isoindolin-1-one,
[0672]
4-[3-(Difluoromethyl)pyrrolidin-1-yl]-6-[2-(2-quinolyl)ethyl]-7H-pyrrolo[-
3,4-b]pyridin-5-one, [0673]
4-[3-(Fluoromethyl)pyrrolidin-1-yl]-6-[2-(2-quinolyflethyl]-7H-pyrrolo[3,-
4-b]pyridin-5-one, [0674]
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-thiazol-4-yl-7H-pyrrolo[3,4-b]pyridi-
n-5-one, [0675]
4-Fluoro-7-(oxetan-3-ylamino)-2-[2-(2-quinolyl)ethyl]isoindolin-1-one,
[0676]
4-fluoro-7-(3-pyridyl)-2-[2-(2-quinolyl)ethyl]isoindolin-1-one,
[0677]
4-Fluoro-7-(2-methylpyrazol-3-yl)-2-[2-(2-quinolyl)ethyl]isoindoli-
n-1-one, [0678]
4-Fluoro-7-morpholino-2-[2-(2-quinolyl)ethyl]isoindolin-1-one,
[0679]
4-Fluoro-7-(4-methoxyphenyl)-2-[2-(2-quinolyl)ethyl]isoindolin-1-one,
[0680]
4-Fluoro-7-(1H-pyrazol-4-yl)-2-[2-(2-quinolyl)ethyl]isoindolin-1-o-
ne trifluoroacetate, [0681]
4-Fluoro-7-pyrimidin-5-yl-2-[2-(2-quinolyl)ethyl]isoindolin-1-one
trifluoroacetate, [0682]
4-Fluoro-7-(4-fluorophenyl)-2-[2-(2-quinolyl)ethyl]isoindolin-1-one,
[0683]
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(2-methylpyrimidin-5-yl)-7H-p-
yrrolo[3,4-b]pyridin-5-one, [0684]
1-[5-oxo-6-[2-(2-quinolyl)ethyl]-7H-pyrrolo[3,4-b]pyridin-4-yl]azetidine--
3-carboxylic acid [0685]
4-(oxetan-3-yloxy)-6-[2-(2-quinolyl)ethyl]-7H-pyrrolo[3,4-b]pyridin-5-one-
, [0686]
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-7-methoxy-4-pyridin-4-yl-2-
,3-dihydro-isoindol-1-one trifluoroacetate, [0687]
2-[2-(1-Difluoromethyl-1H-benzoimidazol-2-yl)-ethyl]-7-morpholin-4-yl-2,3-
-dihydro-isoindol-1-one trifluoroacetate, [0688]
2-[2-(1-Difluoromethyl-1H-benzoimidazol-2-yl)-ethyl]-7-pyridin-4-yl-2,3-d-
ihydro-isoindol-1-one trifluoroacetate, [0689]
4-Pyridin-4-yl-6-(2-quinolin-2-yl-ethyl)-5,6-dihydro-pyrrolo[3,4-b]pyridi-
n-7-one [0690]
6-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-pyridin-4-yl-5,6-dihydro-pyrrolo-
[3,4-b]pyridin-7-one [0691]
6-(2-Quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one
trifluoroacetate, [0692]
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-7-methoxy-4-(1H-pyrazol-3-yl)-2,3--
dihydro-isoindol-1-one, [0693]
2-[2-(1H-Imidazo[4,5-b]pyridin-2-yl)-ethyl]-7-pyridin-4-yl-2,3-dihydro-is-
oindol-1-one, [0694]
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-7-methoxy-4-pyridin-3-yl-2,3-dihyd-
ro-isoindol-1-one trifluoroacetate, [0695]
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-7-methoxy-4-(4-methoxy-phenyl)-2,3-
-dihydro-isoindol-1-one trifluoroacetate, [0696]
4-(4-Methoxy-phenyl)-6-(2-quinolin-2-yl-ethyl)-5,6-dihydro-pyrrolo[3,4-b]-
pyridin-7-one trifluoroacetate, [0697]
4-(2-Methyl-2H-pyrazol-3-yl)-6-(2-quinolin-2-yl-ethyl)-5,6-dihydro-pyrrol-
o[3,4-b]pyridin-7-one trifluoroacetate, [0698]
6-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-pyridin-3-yl-5,6-dihydro-pyrrolo-
[3,4-b]pyridin-7-one trifluoroacetate, [0699]
6-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-(4-methoxy-phenyl)-5,6-dihydro-p-
yrrolo[3,4-b]pyridin-7-one trifluoroacetate, [0700]
6-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-(2-methyl-2H-pyrazol-3-yl)-5,6-d-
ihydro-pyrrolo[3,4-b]pyridin-7-one trifluoroacetate, [0701]
4-Pyridin-3-yl-6-(2-quinolin-2-yl-ethyl)-5,6-dihydro-pyrrolo[3,4-b]pyridi-
n-7-one trifluoroacetate, [0702]
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-7-methoxy-4-(2-methyl-2H-pyrazol-3-
-yl)-2,3-dihydro-isoindol-1-one trifluoroacetate, [0703]
4-(4-Pyridyl)-6-(2-quinoxalin-2-ylethyl)-7H-pyrrolo[3,4-b]pyridin-5-one,
[0704]
6-[2-(6-Methyl-2-pyridyl)ethyl]-4-morpholino-7H-pyrrolo[3,4-b]pyri-
din-5-one, [0705]
4-Pyrimidin-5-yl-6-[2-(2-quinolyl)ethyl]-5H-pyrrolo[3,4-b]pyridin-7-one
[0706]
6-[2-(5-Methyl-2-pyridyl)ethyl]-4-morpholino-7H-pyrrolo[3,4-b]pyri-
din-5-one, hydrochloride [0707]
6-[2-(1-Methylimidazol-2-yl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4-b]pyridin-
-5-one trifluoroacetate, [0708]
6-[2-(6-Methyl-2-pyridyl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4-b]pyridin-5--
one trifluoroacetate, [0709]
4-(4-Pyridyl)-6-[2-(2-pyridyl)ethyl]-7H-pyrrolo[3,4-b]pyridin-5-one
trifluoroacetate, [0710]
4-(4-Pyridyl)-6-(2-thieno[3,2-b]pyridin-5-ylethyl)-7H-pyrrolo[3,4-b]pyrid-
in-5-one,
[0711]
6-[2-(3,5-Dimethyl-2-pyridyl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4-b-
]pyridin-5-one, [0712]
6-[2-(5,6-Dimethyl-2-pyridyl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4-b]pyridi-
n-5-one trifluoroacetate, [0713]
2-[2-[4-(3-Pyridyl)-5,7-dihydropyrrolo[3,4-b]pyridin-6-yl]ethyl]imidazo[1-
,2-a]pyridine trifluoroacetate, [0714]
6-[2-(5-Methyl-2-pyridyl)ethyl]-4-(3-pyridyl)-7H-pyrrolo[3,4-b]pyridin-5--
one trifluoroacetate, [0715]
2-[2-[4-(2-Methylpyrazol-3-yl)-5,7-dihydropyrrolo[3,4-b]pyridin-6-yl]ethy-
l]imidazo[1,2-a]pyridine trifluoroacetate, [0716]
2-[2-[4-(4-Methoxyphenyl)-5,7-dihydropyrrolo[3,4-b]pyridin-6-yl]ethyl]imi-
dazo[1,2-a]pyridine trifluoroacetate, [0717]
4-(1,1-Dioxo-1,4-thiazinan-4-yl)-6-[2-(5-methyl-2-pyridyl)ethyl]-7H-pyrro-
lo[3,4-b]pyridin-5-one trifluoroacetate, [0718]
6-[2-(5-Methyl-2-pyridyl)ethyl]-4-pyrimidin-5-yl-7H-pyrrolo[3,4-b]pyridin-
-5-one trifluoroacetate, [0719]
6-[2-(5-Methyl-2-pyridyl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4-b]pyridin-5--
one trifluoroacetate, [0720]
7-Morpholino-2-(2-quinoxalin-2-ylethyl)isoindolin-1-one, [0721]
6-[2-(6-Methoxy-2-pyridyl)ethyl]-4-morpholino-7H-pyrrolo[3,4-b]pyridin-5--
one, [0722]
4-(4-Pyridyl)-6-[2-[4-(4-pyridyl)-2-quinolyl]ethyl]-7H-pyrrolo[3,4-b]pyri-
din-5-one, [0723]
4-(2,2,3,3,5,5,6,6-Octadeuteriomorpholin-4-yl)-6-[2-(2-quinolyl)ethyl]-7H-
-pyrrolo[3,4-b]pyridin-5-one, [0724]
4-Morpholino-6-[2-(5-phenyl-2-pyridyl)ethyl]-7H-pyrrolo[3,4-b]pyridin-5-o-
ne, [0725]
6-[2-(1-Methylimidazol-4-yl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4-
-b]pyridin-5-one trifluoroacetate, [0726]
6-[2-(5-Phenyl-2-pyridyl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4-b]pyridin-5--
one trifluoroacetate, [0727] 6-[2-(3
,5-Dimethyl-2-pyridyl)ethyl]-4-morpholino-7H-pyrrolo[3,4-b]pyridin-5-one,
[0728]
6-[2-(5-Methyl-2-pyridyl)ethyl]-4-(oxetan-3-ylamino)-7H-pyrrolo[3,-
4-b]pyridin-5-one, [0729]
4-Morpholino-6-(2-thieno[3,2-b]pyridin-5-ylethyl)-7H-pyrrolo[3,4-b]pyridi-
n-5-one, [0730]
6-[2-(6-Fluoroimidazo[1,2-a]pyridin-2-yl)ethyl]-4-morpholino-7H-pyrrolo[3-
,4-b]pyridin-5-one, hydrochloride [0731]
6-[2-(6-Fluoroimidazo[1,2-a]pyridin-2-yl)ethyl]-4-morpholino-7H-pyrrolo[3-
,4-b]pyridin-5-one trifluoroacetate, [0732]
6-[2-(6-Fluoroimidazo[1,2-a]pyridin-2-yl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[-
3,4-b]pyridin-5-one trifluoroacetate,
[0733]
4-Morpholino-6-(2-quinoxalin-2-ylethyl)-7H-pyrrolo[3,4-b]pyridin-5--
one trifluoroacetate, [0734]
6-[2-(8-Methylimidazo[1,2-a]pyridin-2-yl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[-
3,4-b]pyridin-5-one trifluoroacetate, [0735]
6-[2-(5-Fluoro-2-pyridyl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4-b]pyridin-5--
one trifluoroacetate, [0736]
6-[2-(5-Fluoro-2-pyridyl)ethyl]-4-morpholino-7H-pyrrolo[3,4-b]pyridin-5-o-
ne trifluoroacetate, [0737]
6-[2-(5-Ethyl-2-pyridyl)ethyl]-4-morpholino-7H-pyrrolo[3,4-b]pyridin-5-on-
e trifluoroacetate, [0738]
4-Morpholino-6-[2-[5-(trifluoromethyl)-2-pyridyl]ethyl]-7H-pyrrolo[3,4-b]-
pyridin-5-one trifluoroacetate, [0739]
6-[2-(5-Ethyl-2-pyridyl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-o-
ne trifluoroacetate, [0740]
6-[2-(5-Chloro-2-pyridyl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4-b]pyridin-5--
one trifluoroacetate, [0741]
6-[2-(6-Methoxy-2-pyridyl)ethyl]-4-(3-pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-
-one trifluoroacetate, [0742] 6-[2-(5
,6-Dimethyl-2-pyridyl)ethyl]-4-(oxetan-3-
ylamino)-7H-pyrrolo[3,4-b]pyridin-5-one trifluoroacetate, [0743]
6-[2-(5-Chloro-2-pyridyl)ethyl]-4-morpholino-7H-pyrrolo[3,4-b]pyridin-5-o-
ne, [0744] 4-(4-Pyridyl)-6-[2-[5-(trifluoromethyl)-2-pyridyl]
ethyl]-7H-pyrrolo[3,4-b]pyridin-5-one trifluoroacetate, [0745]
6-[2-(4,5-Dimethyl-2-pyridyl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4-b]pyridi-
n-5-one trifluoroacetate, [0746]
4-Fluoro-2-(2-imidazo[1,2-a]pyridin-2-ylethyl)-7-(oxetan-3-ylamino)isoind-
olin-1-one trifluoroacetate, [0747]
6-[2-(6-Methoxy-2-pyridyl)ethyl]-4-(oxetan-3-
ylamino)-7H-pyrrolo[3,4-b]pyridin-5-one, [0748]
2,3,7,7-Tetradeuterio-6-[1,1-dideuterio-2-(3,4,5
,6,7,8-hexadeuterio-2-quinolyl)ethyl]-4-(2,2,3,3,5,5,6,6-octadeuteriomorp-
holin-4- yl)pyrrolo[3,4-b]pyridin-5-one, [0749]
6-(2-Imidazo[1,2-a]pyridin-2-
yl-1-methyl-ethyl)-4-morpholino-7H-pyrrolo[3,4-b]pyridin-5-one
trifluoroacetate, [0750]
6-[2-(1,5-Naphthyridin-2-yl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4-b]pyridin-
-5-one, [0751]
2,3,7,7-Tetradeuterio-6-[2,2-dideuterio-2-(3,4,5,6,7,8-hexadeuterio-2-qui-
nolyl)ethyl]-4-morpholino-pyrrolo[3,4]pyridin-5-one, [0752]
4-Morpholino-6-[2-(1,5-naphthyridin-2-yl)ethyl]-7H-pyrrolo[3,4-b]pyridin--
5-one, [0753]
6-[2-(3-Methoxy-2-pyridyl)ethyl]-4-[2-(3-methoxy-2-pyridyl)ethylamino]-7H-
-pyrrolo[3,4-b]pyridin-5-one, [0754]
6-[2-(4-Ethylthiazol-2-yl)ethyl]-4-morpholino-7H-pyrrolo[3,4-b]pyridin-5--
one, [0755]
6-[2-(4-Cyclopropylthiazol-2-yl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4-b]pyr-
idin-5-one, [0756]
6-[2-(4-Cyclopropylthiazol-2-yl)ethyl]-4-morpholino-7H-pyrrolo[3,4-b]pyri-
din-5-one, [0757]
6-[2-(4,5-Dimethylthiazol-2-yl)ethyl]-4-morpholino-7H-pyrrolo[3,4-b]pyrid-
in-5-one, [0758]
6-[2-(4,5-Dimethyl-2-pyridyl)ethyl]-4-morpholino-7H-pyrrolo[3,4-b]pyridin-
-5-one, [0759]
6-[2-(4-Methyl-2-pyridyl)ethyl]-4-morpholino-7H-pyrrolo[3,4-b]pyridin-5-o-
ne, [0760]
6-[2-(3-Methyl-2-pyridyl)ethyl]-4-morpholino-7H-pyrrolo[3,4-b]p-
yridin-5-one, [0761]
6-(2-Imidazo[1,2-a]pyridin-2-ylethyl)-4-(3-thienyl)-7H-pyrrolo[3,4-b]pyri-
din-5-one, [0762]
6-(2-Imidazo[1,2-a]pyridin-2-ylethyl)-4-(2-methyl-3-furyl)-7H-pyrrolo[3,4-
-b]pyridin-5-one, [0763]
6-(2-Imidazo[1,2-a]pyridin-2-ylethyl)-4-(5-methyl-2-furyl)-7H-pyrrolo[3,4-
-b]pyridin-5-one, [0764]
6-[2-(6-Fluoroimidazo[1,2-a]pyridin-2-yl)ethyl]-4-(3-furyl)-7H-pyrrolo[3,-
4-b]pyridin-5-one, [0765]
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(4,4-difluoro-1-piperidyl)-7H-pyrrol-
o[3,4-b]pyridin-5-one trifluoroacetate, [0766]
4-Methoxy-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-o-
ne, [0767]
4-(2-Dimethylamino-ethoxy)-7-pyridin-4-yl-2-(2-quinolin-2-yl-et-
hyl)-2,3-dihydro-isoindol-1-one, [0768]
4-(4-Hydroxy-piperidin-1-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrol-
o[3,4-b]pyridin-5-one trifluoroacetate, [0769]
1-[3-Oxo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-1H-isoindol-4-ylmethyl]-az-
etidine-3-carboxylic acid methyl ester [0770]
4-(2-Fluoro-ethoxy)-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-isoindole-1,-
3-dione [0771]
4-(2-Fluoro-ethoxy)-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro--
isoindol-1-one, [0772]
4-(3-Fluoro-pyridin-4-yl)-6-(2-imidazo[1,2-a]pyridin-2-yl-ethyl)-6,7-dihy-
dro-pyrrolo[3,4-b]pyridin-5-one, [0773]
6-[2-(1,5-Dimethyl-1H-benzoimidazol-2-yl)-ethyl]-4-pyrimidin-5-yl-6,7-dih-
ydro-pyrrolo[3,4-b]pyridin-5-one, [0774]
6-[2-(1,5-Dimethyl-1H-benzoimidazol-2-yl)-ethyl]-4-pyridin-4-yl-6,7-dihyd-
ro-pyrrolo[3,4-b]pyridin-5-one, [0775]
2-(2-Imidazo[1,2-a]pyridin-2-ylethyl)-4-thiazol-4-yl-isoindolin-1-one,
[0776]
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(1H-pyrazol-4-yl)-7H-pyrrolo[-
3,4-b]pyridin-5-one trifluoroacetate, [0777]
6-[2-(1,5-Dimethylbenzimidazol-2-yl)ethyl]-4-(3-pyridyl)-7H-pyrrolo[3,4-b-
]pyridin-5-one, [0778]
6-[2-(1,5-Dimethylbenzimidazol-2-yl)ethyl]-4-(2-methylpyrazol-3-yl)-7H-py-
rrolo[3,4-b]pyridin-5-one [0779]
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(4-methoxyphenyl)-7H-pyrrolo[3,4-b]p-
yridin-5-one trifluoroacetate, [0780]
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(4-fluorophenyl)-7H-pyrrolo[3,4-b]py-
ridin-5-one trifluoroacetate, [0781]
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(3 ,
6-dihydro-2H-pyran-4-yl)-7H-pyrrolo[3,4-b]pyridin-5-one [0782]
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-pyrimidin-5-yl-7H-pyrrolo[3,4-b]pyri-
din-5-one, [0783]
4-(Fluoromethoxy)-2-(2-imidazo[1,2-a]pyridin-2-ylethyl)-7-pyrimidin-5-yl--
isoindoline-1,3-dione [0784] 4-(6-Fluoro-1
,4-diazepan-1-yl)-6-[2-(2-quinolyl)ethyl]-7H-pyrrolo[3,4-b]pyridin-5-one,
[0785]
4-(4-Pyridyl)-6-[2-(4-quinolyl)ethyl]-7H-pyrrolo[3,4-b]pyridin-5-o-
ne trifluoroacetate, [0786]
4-Morpholino-6-[2-(4-quinolyl)ethyl]-7H-pyrrolo[3,4-b]pyridin-5-one,
[0787]
7-(4-Fluorophenyl)-2-(2-thieno[3,2-b]pyridin-5-ylethyl)isoindolin--
1-one, [0788]
7-Pyrimidin-5-yl-2-(2-thieno[3,2-b]pyridin-5-ylethyl)isoindolin-1-one,
[0789]
7-(4-Methoxyphenyl)-2-(2-thieno[3,2-b]pyridin-5-ylethyl)isoindolin-
-1-one, [0790]
7-(1H-Pyrazol-5-yl)-2-(2-thieno[3,2-b]pyridin-5-ylethyl)isoindolin-1-one,
[0791]
7-Morpholino-2-(2-thieno[3,2-b]pyridin-5-ylethyl)isoindolin-1-one,
[0792]
7-(1H-Pyrazol-4-yl)-2-(2-thieno[3,2-b]pyridin-5-ylethyl)isoindolin-
-1-one, [0793]
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-7-methoxy-4-pyrimidin-5-yl-2,3-dih-
ydro-isoindol-1-one trifluoroacetate, [0794]
4-Morpholino-6-[2-(2-pyridyl)ethyl]-7H-pyrrolo[3,4-b]pyridin-5-one,
[0795]
6-[2-(5-Methyl-2-pyridyl)ethyl]-4-morpholino-7H-pyrrolo[3,4-b]pyri-
din-5-one, [0796]
6-[2-(7-Ethylimidazo[1,2-a]pyridin-2-yl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3-
,4-b]pyridin-5-one, [0797]
6-[2-(6-Methoxy-2-pyridyl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-
-one, [0798]
6-[2-(5,6-Dimethyl-2-pyridyl)ethyl]-4-morpholino-7H-pyrrolo[3,4-b]pyridin-
-5-one, and [0799]
6-[2-(7-Ethylimidazo[1,2-a]pyridin-2-yl)ethyl]-4-morpholino-7H-pyrrolo[3,-
4-b]pyridin-5-one.
[0800] The compounds of the invention of the general formula I and
the starting materials used to prepare them can be prepared in
analogy to known processes of organic chemistry as are described in
standard works of organic chemistry, e.g. Houben-Weyl, "Methoden
der Organischen Chemie", Thieme-Verlag, Stuttgart, Jerry March
"Advanced Organic Chemistry", 5.sup.th edition, Wiley & Sons
and the literature cited therein, and R. Larock, "Comprehensive
Organic Transformations", 2.sup.nd edition, Weinheim, 1999 and the
literature cited therein. The compounds of the invention of the
general formula I are advantageously prepared by the methods
described below and/or in the experimental section.
[0801] Compounds of the formula I can be prepared e.g. by reacting
a compound of the formula II
##STR00008## [0802] wherein [0803] X.sup.1a is N or C--R.sup.1a
[0804] X.sup.2a is N or C--R.sup.2a [0805] X.sup.3a is N or
C--R.sup.3a [0806] X.sup.4a is N or C--R.sup.4a [0807] provided
that 0, 1 or 2 of the moieties X.sup.1a, X.sup.2a, X.sup.3a or
X.sup.4a is N;
[0808] Het, A, R.sup.7, R.sup.8, R.sup.9 and R.sup.10 are as
defined for formulae I, I-A, I-B or I-C;
[0809] R.sup.1a, R.sup.4a independently of each other, are selected
from the group consisting of hydrogen, halogen,
C.sub.1-C.sub.4-alkyl, trimethylsilyl,
C.sub.1-C.sub.4-alkylsulfanyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkylsulfanyl-C.sub.1-C.sub.4-alkoxy,
C.sub.2-C.sub.4-alkenyloxy, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.1-C.sub.4-fluoroalkoxy, CN, NR.sup.x1R.sup.x2,
NR.sup.x1R.sup.x2--C.sub.1C.sub.4- alkoxy; [0810] R.sup.2a,
R.sup.3a independently of each other, are selected from the group
consisting of hydrogen, halogen, C.sub.1-C.sub.4-alkyl,
trimethylsilyl, C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkoxy,
C.sub.2-C.sub.4-alkenyloxy, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.1-C.sub.4-fluoroalkoxy, CN and NR.sup.x1R.sup.x2; [0811]
provided that 1 or 2 of the radicals R.sup.1a, R.sup.2a, R.sup.3a
and R.sup.4a, in particular exactly one of these radicals is
bromine or iodine, while the others are different from bromine or
iodine; [0812] with a compound of formula III,
[0812] M-Y-Cyc (III) [0813] where Y and Cyc are as defined herein
and wherein [0814] M is a Li, B(OR.sup.B1)(OR.sup.B2) radical or an
Sn(R.sup.Sn).sub.3 radical, where R.sup.B1 and R.sup.B2 are,
independently of each other, hydrogen or C.sub.1-C.sub.4-alkyl or
R.sup.B1 and R.sup.B2 together form a C.sub.2-C.sub.6-alkandiyl
moietyl, e.g. ethan-1,2-diyl, propan-1,3-diyl or
1,1,2,2-tetramethylethan-1,2-diyl, and wherein R.sup.Sn is
C.sub.1-C.sub.6-alkyl or C.sub.3-C.sub.6-cycloalkyl or phenyl.
[0815] Amongst the compounds of formula III, where Y is a chemical
bond, particular preference is given to the compounds of formula
IIIa and, if R.sup.B1 and R.sup.B2 are hydrogen, the trimers
thereof.
##STR00009##
[0816] The reaction of the compound II with the compound III can be
performed by analogy to known coupling reactions in the presence of
suitable transition metal catalysts, in particular palladium
catalysts. Typical reactions conditions are those of Stille
coupling (see e.g. Stille et al. Angew. Chem. Int. Ed. Engl. 1986,
25,508; J. Eluguero et al.; Synthesis 1997, 5, 563-566) or Suzuki
coupling (see e.g. A. Suzuki et al, Chem. Rev. 1995, 95, 2457-2483,
N. Zhe et al.; J. Med. Chem. 2005, 48 (5), 1569-1609; Young et al.;
J. Med. Chem. 2004, 47 (6), 1547-1552; C. Slee et al.; Bioorg. Med.
Chem. Lett. 2001, 9, 3243-3253).
[0817] Compounds of the formula I can also be prepared e.g. by
reacting a compound of the formula IIa
##STR00010## [0818] wherein [0819] X.sup.2b is N or C--R.sup.1b
[0820] X.sup.2b is N or C--R.sup.2b [0821] X.sup.3b is N or
C--R.sup.3b [0822] X.sup.4b is N or C--R.sup.4b [0823] provided
that 0, 1 or 2 of the moieties X.sup.1b; X.sup.2b, X.sup.3b or
X.sup.4b is N; [0824] Het, A, R.sup.7, R.sup.8, R.sup.9 and
R.sup.10 are as defined for formulae I, I-A, I-B or I-C; [0825]
t.sup.1b, R.sup.4b independently of each other, are selected from
the group consisting of hydrogen, C.sub.1-C.sub.4-alkyl,
trimethylsilyl, C.sub.1-C.sub.4-alkylsulfanyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkylsulfanyl-C.sub.1-C.sub.4-alkoxy,
C.sub.2-C.sub.4-alkenyloxy, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.1-C.sub.4-fluoroalkoxy, CN, NR.sup.x1R.sup.x2,
NR.sup.x1R.sup.x2--C.sub.1C.sub.4-alkoxy or a moiety M; [0826]
R.sup.2b, R.sup.3b independently of each other, are selected from
the group consisting of hydrogen, C.sub.1-C.sub.4-alkyl,
trimethylsilyl, C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkoxy,
C.sub.2-C.sub.4-alkenyloxy, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.1-C.sub.4-fluoroalkoxy, CN and NR.sup.x1R.sup.x2, or a moiety
M; [0827] provided that 1 or 2 of the radicals R.sup.1b, R.sup.2b,
R.sup.3b and R.sup.4b, in particular exactly one of these radicals
is moiety M, while the others are different from M, where M is as
defined for formual III and in particular a B(OR.sup.B1)(OR.sup.B2)
radical; [0828] with a compound of formula IIIb,
[0828] Hal-Y-Cyc (IIIb) [0829] where Y and Cyc are as defined
herein and wherein Hal is bromine or iodine.
[0830] The reaction of the compound IIa with the compound IIIa can
be performed by analogy tot the reaction of compound II with
compound III.
[0831] The compounds II, IIa, III, IIIa and IIIb are known or can
be prepared by standard methods of organic chemistry.
[0832] Compounds of the formula I, where Y-Cyc is a N-bound radical
can be obtained by a coupling reaction between the compound II and
the corresponding amine in the presence of a palladium catalyst in
terms of a Buchwald-Hartwig reaction. Suitable palladium catalyst
are for example tris-(dibenzylideneacetone)dipalladium(0)
(Pd.sub.2(dba).sub.3),[1,1-bis(diphenylphosphino)ferrocene]dichloropallad-
ium(II) (PdCl.sub.2(dppf)) or palladium acetate (Pd(OAc).sub.2).
The reaction is usually carried out in the presence of a
tri(substituted)phosphine, e.g. a triarylphosphine such as
triphenylphosphine, tritolylphosphine or
2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (BINAP),
tri(cyclo)alkylphosphine such as tris-n-butylphosphine,
tris(tert-butyl)phosphine or tris(cyclohexylphosphine), or
dicyclohexyl-(2',4',6'-tri-iso-propyl-biphenyl-2-yl)-phosphane
(X-Phos). Usually, the reaction is performed in the presence of a
base such as an alkaline alkoxide, earth alkine alkoxide, alkaline
carbonate or earth alkaline carbonate such as or sodium
tert-butoxide or cesium carbonate.
[0833] E.g. compounds of the formula I (or likewise the compounds
II), where A is CR.sup.5R.sup.6 can be prepared according to the
following reaction schemes 1 and 2:
##STR00011##
##STR00012##
[0834] In schemes 1 and 2,X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.1a, X.sup.2a, X.sup.3a, X.sup.4a, R.sup.5, R.sup.6, R.sup.7,
R.sup.8, R.sup.9, R.sup.10 and Het are as defined above, R.sup.v is
C.sub.1-C.sub.4-alkoxy, e.g. methoxy or ethoxy, and L is a suitable
leaving group, e.g. chlorine, bromine, alkylsulfonyloxy such as
methan-sulfonyloxy or arylsulfonyloxy such as phenylsulfonyloxy or
p-tolylsulfonyloxy. L may also be OH or C.sub.1-C.sub.4-alkoxy, if
CR.sup.5R.sup.6 represents a carbonyl group.
[0835] Compounds of the formula I (or likewise the compounds II),
where A is O can be prepared according to the following reaction
schemes 3 and 4by reacting a compound of the formulae VII or VIIa,
respectively, with a suitable hydroxylamine compound VI, to give an
amide compound VIII and VIIIa, respectively, and subsequent
cyclisation (J. Med. Chem, 51(12), 3357-9 (2008).
##STR00013##
##STR00014##
[0836] In schemes 3 and 4, X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.1a, X.sup.2a, X.sup.3a, X.sup.4a, R.sup.7, R.sup.8, R.sup.9,
R.sup.10 and Het are as defined above, and Hal' is a suitable
leaving group, e.g. fluorine. The reaction of the carboxylic acid
VII and VIIa, respectively, with a hydroxylamine compound VI is
usually carried out in the presence of an activating agent of
carboxylic acids, e.g. carbodiimides such as
dicyclohexylcarbodiimide or diisopropylcarbodiimide or triazoles
such as 1-hydroxybenzotriazole, 1-hydroxy-7-aza-benzotriazole,
benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate
or benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium
hexafluorophosphate.
[0837] Compounds of the formula I (or likewise the compounds II),
where A is NR.sup.5a can be prepared according to the following
reaction schemes 5 and 6 by successively reacting compounds of the
formulae X or Xa, respectively with a suitable hydroxy compound IX,
in terms of a Mitsunobu reaction.
##STR00015##
##STR00016##
[0838] In schemes 5 and 6, X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.1a, X.sup.2a, X.sup.3a, X.sup.4a, R.sup.5a, R.sup.6, R.sup.7,
R.sup.8, R.sup.9, R.sup.10 and Het are as defined above. Compounds
of the formulae X and Xa, respectively, can be prepared in analogy
to known methods, e.g. as described in J. Heterocycl. Chem. 26,
257-64 (1989), WO 2004/037814 or WO 2006/056873
[0839] Apart from that, compounds of the formula I and likewise
compounds of the formula II, where A is CF.sub.2 can be prepared by
successively reacting compounds of the formulae I and II, where A
is C.dbd.O with a suitable sulfurizing agent, such as Lawenson's
reagent or P.sub.2S.sub.5, obtain a compound of the formula I and
then reacting the obtained thio-compound with a suitable
fluorinating agent, e.g. HF or HF adduct of tetraalkyl-amonium
fluoride in the presence of N-bromosuccinimid [Tet. Lett. 35(23),
3983-4 (1994)].
[0840] The N-oxides of compound I may be prepared from the
compounds of formula I according to conventional oxidation methods,
for example by treating said compounds with an organic peracid;
such as metachloroperbenzoic acid or 3-chloroperbenzoic acid
[Journal of Medicinal Chemistry 38(11), 1892-1903 (1995), WO
03/64572]; or with inorganic oxidizing agents; such as hydrogen
peroxide [cf. Journal of Heterocyclic Chemistry 18 (7), 1305-1308
(1981)] or oxone [cf. Journal of the American Chemical Society
123(25), 5962-5973 (2001)]. The oxidation may lead to pure
mono-N-oxides or to a mixture of different N-oxides, which can be
separated by conventional methods; such as chromatography.
Compounds of the formula IIa can be prepared from compounds of the
formula II by suitable metal-halogen exchange reactions.
[0841] The compounds of the formulae III, IV, VI and VIII as well
as the compounds of the formulae V, Va, VII, VIIa, X and Xa are
well known in the art or can be prepared by anology to well
established reactions of organic synthetic chemistry or by analogy
to the methods as described in standard works of organic chemistry,
e.g. Houben-Weyl, "Methoden der Organischen Chemie", Thieme-Verlag,
Stuttgart, Jerry March "Advanced Organic Chemistry", 5.sup.th
edition, Wiley & Sons and the literature cited therein, and R.
Larock, "Comprehensive Organic Transformations", 2.sup.nd edition,
Weinheim, 1999 and the literature cited therein.
[0842] The reactions are usually performed in an organic solvent,
including aprotic organic solvent, e.g. substituted amides,
lactames and ureas; such as dimethylformamide, dimethylacetamide,
N-methylpyrrolidone, tetramethyl urea, cyclic ethers; such as
dioxane, tetrahydrofurane, halogenated hydrocarbons; such as
dichloromethane, and mixtures thereof as well as mixtures thereof
with C.sub.1-C.sub.6-alkanols and/or water.
[0843] The reactions described above will be usually performed at
temperatures ranging from -10.degree. C. to 100.degree. C.,
depending on the reactivity of the used compounds.
[0844] The reaction mixtures are worked up in a conventional way,
e.g. by mixing with water, separating the phases and, where
appropriate, purifying the crude products by chromatography. The
intermediates and final products in some cases result in the form
of colorless or pale brownish, viscous oils which are freed of
volatiles or purified under reduced pressure and at moderately
elevated temperature. If the intermediates and final products are
obtained as solids, the purification can also take place by
recrystallization or digestion.
[0845] Due to their capability of inhibiting PDE10A at low
concentrations, the compounds of the formula I, their N-oxides,
their hydrates, their tautomers and their prodrugs and the
pharmaceutically acceptable salts thereof, are particularly
suitable for treating disorders or conditions, which can be treated
by inhibition of phosphodiesterase type 10A. The terms "treating"
and "treatment" in terms of the present invention have to be
understood to include both curative treatment of the cause of a
disease or disorder, the treatment of the symptoms associated with
a disease or disorder, i.e. controlling the disease or disorder or
ameliorating the conditions or symptoms associated with a disease
or disorder, and prophylactic treatment, i.e. a treatment for
reducing the risk of a disease or disorder.
[0846] Neurological and psychiatric disorders or conditions which
can be treated by inhibition of PDE10A, including curative
treatment, control or amelioration and prophylaxis, include CNS
disorders, in particular schizophrenia, depression, bipolar
disorders, cognitive dysfunctions associated with schizophrenia,
cognitive dysfunctions associated with Alzheimer's disease,
Huntington's disease (Huntington chorea), anxiety and
substance-related disorders, especially substance use disorder,
substance tolerance conditions associated with substance
withdrawal. Disorders or conditions which can be treated by
inhibition of PDE10A, including curative treatment, control or
amelioration and prophylaxis, also include treatment of diet
induced obesity.
[0847] Thus, the invention relates to the use of compounds of
formula I, their N-oxides, their hydrates, their tautomers and
their prodrugs and the pharmaceutically acceptable salts thereof,
for treatment of disorders or conditions, which can be treated by
inhibition of phosphodiesterase type 10A, i.e. the invention
relates to the use of such compounds for curative treatment of such
a disease or disorder, controlling such a disease or disorder,
ameliorating the symptoms associated with such a disease or
disorder and reducing the risk for such a disease or disorder.
[0848] The present invention also relates to a method for the
treatment of a medical disorder, selected from neurological and
psychiatric disorders which can be treated by inhibition of
phosphodiesterase type 10A, said method comprising administering an
effective amount of at least one compound, selected from the group
of compounds of formula I, their N-oxides, their hydrates, their
tautomers, their prodrugs and the pharmaceutically acceptable salts
thereof, to a mammal in need thereof.
[0849] The present invention in particular relates to: [0850] a
method for treating, controlling, ameliorating or reducing the risk
of schizophrenia in a mammalian; [0851] a method for treating,
controlling, ameliorating or reducing the risk of cognitive
disturbances associated with schizophrenia in a mammalian; [0852] a
method for treating, controlling, ameliorating or reducing the risk
of depression in a mammalian; [0853] a method for treating,
controlling, ameliorating or reducing the risk of bipolar disorders
in a mammalian; [0854] a method for treating or ameliorating the
symptoms associated with substance use disorders in a mammalian;
[0855] a method for treating or ameliorating the symptoms
associated with diet-induced obesity in a mammalian; [0856] a
method for treating, controlling, ameliorating or reducing the risk
of cognitive disturbances associated with Alzheimer's disease in a
mammalian; [0857] a method for treating, controlling, ameliorating
or reducing the risk of behavioral symptoms in Alzheimer's disease;
[0858] a method for treating, controlling, ameliorating or reducing
the risk of anxiety in a mammalian; [0859] a method for treating,
controlling, ameliorating or reducing the risk of
[0860] Huntington's disease in a mammalian;
[0861] which methods comprising administering an effective amount
of at least one compound, selected from the group of compounds of
formula I, their N-oxides, their hydrates, their tautomers, their
prodrugs and the pharmaceutically acceptable salts thereof, to a
mammal in need thereof.
[0862] The subject treated in the present methods is generally a
mammal, preferably a human being, male or female, in whom
inhibition of PDE10A is desired. The terms "effective amount" and
"therapeutically effective amount" mean the amount of the subject
compound that will elicit the biological or medical response of a
tissue, system, animal or human that is being sought by the
researcher, veterinarian, medical doctor or other clinician. It is
recognized that one skilled in the art may affect the neurological
and psychiatric disorders by treating a patient presently afflicted
with the disorders or by prophylactically treating a patient
afflicted with the disorders with an effective amount of the
compound of the present invention. As used herein, the terms
"treatment" and "treating" refer to all processes, wherein there
may be a slowing, interrupting, arresting, controlling, or stopping
of the progression of the disorders described herein, but does not
necessarily indicate a total elimination of all disorder symptoms,
as well as the prophylactic therapy of the mentioned conditions,
particularly in a patient who is predisposed to such disease or
disorder. The term "composition" as used herein is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combination of the specified ingredients in the
specified amounts. Such term in relation to pharmaceutical
composition, is intended to encompass a product comprising the
active ingredient(s), and the inert ingredient(s) that make up the
carrier, as well as any product which results, directly or
indirectly, from combination, complexation or aggregation of any
two or more of the ingredients, or from dissociation of one or more
of the ingredients, or from other types of reactions or
interactions of one or more of the ingredients. Accordingly, the
pharmaceutical compositions of the present invention encompass any
composition made by admixing a compound of the present invention
and a pharmaceutically acceptable carrier. By "pharmaceutically
acceptable" it is meant the carrier, diluent or excipient must be
compatible with the other ingredients of the formulation and not
deleterious to the recipient thereof.
[0863] The terms "administration of and or "administering a"
compound should be understood to mean providing a compound of the
invention or a prodrug of a compound of the invention to the
individual in need of treatment.
[0864] A preferred embodiment of the present invention provides a
method for treating schizophrenia, comprising: administering to a
patient in need thereof an effective amount of at least one
compound, selected from the group of compounds of formula I, their
N-oxides, their hydrates, their tautomers, their prodrugs and the
pharmaceutically acceptable salts thereof.
[0865] In another preferred embodiment, the present invention
provides a method for treating cognitive disturbances associated
with schizophrenia, comprising: administering to a patient in need
thereof an effective amount of at least one compound, selected from
the group of compounds of formula I, their N-oxides, their
hydrates, their tautomers, their prodrugs and the pharmaceutically
acceptable salts thereof.
[0866] At present, the fourth edition of the Diagnostic and
Statistical Manual of Mental Disorders (DSM-IV) (1994, American
Psychiatric Association, Washington, D.C.), provides a diagnostic
tool including schizophrenia and other psychotic disorders. These
include: disorders having psychotic symptoms as the defining
feature. The term psychotic refers to delusions, prominent
hallucinations, disorganized speech, disorganized or catatonic
behavior. The disorder includes: paranoid, disorganized, catatonic,
undifferentiated, and residual schizophrenia, schizophreniform
disorder, schizoaffective disorder, delusional disorder, brief
psychotic disorder, shared psychotic disorder, psychotic disorder
due to a general medical condition, substance-induced psychotic
disorder, and psychotic disorder not otherwise specified. The
skilled artisan will recognize that there are alternative
nomenclatures, nosologies, and classification systems for
neurological and psychiatric disorders, and particular
schizophrenia, and that these systems evolve with medical
scientific progress. Thus, the term "schizophrenia" is intended to
include like disorders that are described in other diagnostic
sources.
[0867] In another preferred embodiment, the present invention
provides a method for treating substance-related disorders,
comprising: administering to a patient in need thereof an effective
amount of at least one compound, selected from the group of
compounds of formula I, their N-oxides, their hydrates, their
tautomers, their prodrugs and the pharmaceutically acceptable salts
thereof.
[0868] In another preferred embodiment, the present invention
provides a method for treating anxiety, comprising: administering
to a patient in need thereof an effective amount of at least one
compound, selected from the group of compounds of formula I, their
N-oxides, their hydrates, their tautomers, their prodrugs and the
pharmaceutically acceptable salts thereof. At present, the fourth
edition of the Diagnostic and Statistical Manual of Mental
Disorders (DSM-IV) (1994, American Psychiatric Association,
Washington, D.C.), provides a diagnostic tool including anxiety and
related disorders. These include: panic disorder with or without
agoraphobia, agoraphobia without history of panic disorder,
specific phobia, social phobia, obsessive-compulsive disorder,
post-traumatic stress disorder, acute stress disorder, generalized
anxiety disorder, anxiety disorder due to a general medical
condition, substance-induced anxiety disorder and anxiety disorder
not otherwise specified. As used herein the term "anxiety" includes
treatment of those anxiety disorders and related disorder as
described in the DSM-IV. The skilled artisan will recognize that
there are alternative nomenclatures, nosologies, and classification
systems for neurological and psychiatric disorders, and particular
anxiety, and that these systems evolve with medical scientific
progress. Thus, the term "anxiety" is intended to include like
disorders that are described in other diagnostic sources.
[0869] In another preferred embodiment, the present invention
provides a method for treating depression, comprising:
administering to a patient in need thereof an effective amount of
at least one compound, selected from the group of compounds of
formula I, their N-oxides, their hydrates, their tautomers, their
prodrugs and the pharmaceutically acceptable salts thereof. At
present, the fourth edition of the Diagnostic and Statistical
Manual of Mental Disorders (DSM-IV) (1994, American Psychiatric
Association, Washington, D.C.), provides a diagnostic tool
including depression and related disorders. Depressive disorders
include, for example, single episodic or recurrent major depressive
disorders, and dysthymic disorders, depressive neurosis, and
neurotic depression; melancholic depression including anorexia,
weight loss, insomnia and early morning waking, and psychomotor
retardation; atypical depression (or reactive depression) including
increased appetite, hypersomnia, psychomotor agitation or
irritability, anxiety and phobias; seasonal affective disorder; or
bipolar disorders or manic depression, for example, bipolar I
disorder, bipolar II disorder and cyclothymic disorder. As used
herein the term "depression" includes treatment of those depression
disorders and related disorder as described in the DSM-1V.
[0870] In another preferred embodiment, the present invention
provides a method for treating substance-related disorders,
especially substance dependence, substance abuse, substance
tolerance, and substance withdrawal, comprising: administering to a
patient in need thereof an effective amount at least one compound,
selected from the group of compounds of formula I, their N-oxides,
their hydrates, their tautomers, their prodrugs and the
pharmaceutically acceptable salts thereof. At present, the fourth
edition of the Diagnostic and Statistical Manual of Mental
Disorders (DSM-IV) (1994, American Psychiatric Association,
Washington, D.C.), provides a diagnostic tool including disorders
related to taking a drug of abuse (including alcohol), to the side
effects of a medication, and to toxin exposure. Substances include
alcohol, amphetamine and similarly acting sympathomimetics,
caffeine, cannabis, cocaine, hallucinogens, inhalants, nicotine,
opioids, phencyclidine (PCP) or similarly acting
arylcyclohexylamines, and sedatives, hypnotics, or anxiolytics.
Also, polysubstance dependence and other unknown substance-related
disorders are included. The skilled artisan will recognize that
there are alternative nomenclatures, nosologies, and classification
systems for neurological and psychiatric disorders, and particular
substance-related disorders, and that these systems evolve with
medical scientific progress. Thus, the term "substance-related
disorder" is intended to include like disorders that are described
in other diagnostic sources.
[0871] In the treatment, prevention, control, amelioration, or
reduction of risk of conditions which require inhibition of PDE10A
an appropriate dosage level will generally be about 0.01 to 500 mg
per kg patient body weight per day which can be administered in
single or multiple doses. Preferably, the dosage level will be
about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to
about 100 mg/kg per day. A suitable dosage level may be about 0.01
to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1
to 50 mg/kg per day. Within this range the dosage may be 0.05 to
0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration,
the compositions are preferably provided in the form of tablets
containing 1.0 to 1000 milligrams of the active ingredient,
particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0,
150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0,
900.0, and 1000.0 milligrams of the active ingredient for the
symptomatic adjustment of the dosage to the patient to be treated.
The compounds may be administered on a regimen of 1 to 4 times per
day, preferably once or twice per day. When treating, preventing,
controlling, ameliorating, or reducing the risk of neurological and
psychiatric disorders or other diseases for which compounds of the
present invention are indicated, generally satisfactory results are
obtained when the compounds of the present invention are
administered at a daily dosage of from about 0.1 milligram to about
100 milligram per kilogram of animal body weight, preferably given
as a single daily dose or in divided doses two to six times a day,
or in sustained release form. For most large mammals, the total
daily dosage is from about 1.0 milligrams to about 1000 milligrams,
preferably from about 1 milligram to about 50 milligrams, in the
case of a 70 kg adult human, the total daily dose will generally be
from about 7 milligrams to about 350 milligrams. This dosage
regimen may be adjusted to provide the optimal therapeutic
response. It will be understood, however, that the specific dose
level and frequency of dosage for any particular patient may be
varied and will depend upon a variety of factors including the
activity of the specific compound employed, the metabolic stability
and length of action of that compound, the age, body weight,
general health, sex, diet, mode and time of administration, rate of
excretion, drug combination, the severity of the particular
condition, and the host undergoing therapy.
[0872] The compounds of the present invention may be administered
by conventional routes of administration, including parenteral
(e.g., intramuscular, intrapentoneal, intravenous, ICV,
intracisternal injection or infusion, subcutaneous injection, or
implant), oral, by inhalation spray, nasal, vaginal, rectal,
sublingual, or topical routes of administration.
[0873] The compounds according to the present invention are further
useful in a method for the prevention, treatment, control,
amelioration, or reduction of risk of the aforementioned diseases,
disorders and conditions in combination with other agents.
[0874] The compounds of the present invention may be used in
combination with one or more other drugs in the treatment,
prevention, control, amelioration, or reduction of risk of diseases
or conditions for which compounds of Formula I or the other drugs
may have utility, where the combination of the drugs together are
safer or more effective than either drug alone. Such other drug(s)
may be administered, by a route and in an amount commonly used
therefore, contemporaneously or sequentially with a compound of
Formula I. When a compound of formula I is used contemporaneously
with one or more other drugs, a pharmaceutical composition in unit
dosage form containing such other drugs and the compound of formula
I is preferred. However, the combination therapy may also include
therapies in which the compound of formula I and one or more other
drugs are administered on different overlapping schedules. It is
also contemplated that when used in combination with one or more
other active ingredients, the compounds of the present invention
and the other active ingredients may be used in lower doses than
when each is used singly. Accordingly, the pharmaceutical
compositions of the present invention include those that contain
one or more other active ingredients, in addition to a compound of
formula I. The above combinations include combinations of a
compound of the present invention not only with one other active
compound, but also with two or more other active compounds.
[0875] Likewise, compounds of the present invention may be used in
combination with other drugs that are used in the prevention,
treatment, control, amelioration, or reduction of risk of the
diseases or conditions for which compounds of the present invention
are useful. Such other drugs may be administered, by a route and in
an amount commonly used therefore, contemporaneously or
sequentially with a compound of the present invention. When a
compound of the present invention is used contemporaneously with
one or more other drugs, a pharmaceutical composition containing
such other drugs in addition to the compound of the present
invention is preferred. Accordingly, the pharmaceutical
compositions of the present invention include those that also
contain one or more other active ingredients, in addition to a
compound of the present invention.
[0876] The weight ratio of the compound of the compound of the
present invention to the second active ingredient may be varied and
will depend upon the effective dose of each ingredient. Generally,
an effective dose of each will be used. Thus, for example, when a
compound of the present invention is combined with another agent,
the weight ratio of the compound of the present invention to the
other agent will generally range from about 1000:1 to about 1:1000,
preferably about 200:1 to about 1:200. Combinations of a compound
of the present invention and other active ingredients will
generally also be within the aforementioned range, but in each
case, an effective dose of each active ingredient should be used.
In such combinations the compound of the present invention and
other active agents may be administered separately or in
conjunction. In addition, the administration of one element may be
prior to, concurrent to, or subsequent to the administration of
other agent(s).
[0877] The present invention also relates to pharmaceutical
compositions (i.e. medicaments) which comprise at least one
compound of the present invention and, where appropriate, one or
more suitable excipients.
[0878] These excipients/drug carriers are chosen according to the
pharmaceutical form and the desired mode of administration.
[0879] The compounds of the present invention can be used to
manufacture pharmaceutical compositions for parenteral (e.g.,
intramuscular, intrapentoneal, intravenous, ICV, intracisternal
injection or infusion, subcutaneous injection, or implant), oral,
sublingual, intratracheal, intranasal, topical, transdermal,
vaginal or rectal administration, and be administered to animals or
humans in unit dose forms, mixed with conventional pharmaceutical
carriers, for the prophylaxis or treatment of the above impairments
or diseases.
[0880] In the pharmaceutical compositions, the at least one
compound of the present invention may be formulated alone or
together with further active compounds, in suitable dosage unit
formulations containing conventional excipients, which generally
are non-toxic and/or pharmaceutically acceptable. Carriers or
excipients can be solid, semisolid or liquid materials which serve
as vehicles, carriers or medium for the active compound. Suitable
excipients are listed in the specialist medicinal monographs. In
addition, the formulations can comprise pharmaceutically acceptable
carriers or customary auxiliary substances, such as glidants;
wetting agents; emulsifying and suspending agents; preservatives;
antioxidants; antiirritants; chelating agents; coating auxiliaries;
emulsion stabilizers; film formers; gel formers; odor masking
agents; taste corrigents; resin; hydrocolloids; solvents;
solubilizers; neutralizing agents; diffusion accelerators;
pigments; quaternary ammonium compounds; refatting and overfatting
agents; raw materials for ointments, creams or oils; silicone
derivatives; spreading auxiliaries; stabilizers; sterilants;
suppository bases; tablet auxiliaries, such as binders, fillers,
glidants, disintegrants or coatings; propellants; drying agents;
opacifiers; thickeners; waxes; plasticizers and white mineral oils.
A formulation in this regard is based on specialist knowledge as
described, for example, in Fiedler, H. P., Lexikon der Hilfsstoffe
fur Pharmazie, Kosmetik and angrenzende Gebiete [Encyclopedia of
auxiliary substances for pharmacy, cosmetics and related fields],
4.sup.th edition, Aulendorf: ECV-Edition-Kantor-Verlag, 1996.
[0881] Suitable unit dose forms include forms for oral
administration, such as tablets, gelatin capsules, powders,
granules and solutions or suspensions for oral intake, forms for
sublingual, buccal, intratracheal or intranasal administration,
aerosols, implants, forms of subcutaneous, intramuscular or
intravenous administration and forms of rectal administration.
[0882] The compounds of the invention can be used in creams,
ointments or lotions for topical administration.
[0883] If a solid composition is prepared in the form of tablets,
the main ingredient is mixed with a pharmaceutical carrier such as
gelatin, starch, lactose, magnesium stearate, talc, silicon dioxide
or the like.
[0884] The tablets may be coated with sucrose, a cellulose
derivative or another suitable substance or be treated otherwise in
order to display a prolonged or delayed activity and in order to
release a predetermined amount of the active basic ingredient
continuously.
[0885] A preparation in the form of gelatin capsules is obtained by
mixing the active ingredient with an extender and taking up the
resulting mixture in soft or hard gelatin capsules.
[0886] A preparation in the form of a syrup or elixir or for
administration in the form of drops may comprise active ingredients
together with a sweetener, which is preferably calorie-free,
methylparaben or propylparaben as antiseptics, a flavoring and a
suitable coloring.
[0887] The water-dispersible powders or granules may comprise the
active ingredients mixed with dispersants, wetting agents or
suspending agents such as polyvinylpyrrolidones, and sweeteners or
taste improvers.
[0888] Rectal administration is achieved by the use of
suppositories which are prepared with binders which melt at the
rectal temperature, for example cocobutter or polyethylene glycols.
Parenteral administration is effected by using aqueous suspensions,
isotonic salt solutions or sterile and injectable solutions which
comprise pharmacologically suitable dispersants and/or wetting
agents, for example propylene glycol or polyethylene glycol.
[0889] The active basic ingredient may also be formulated as
microcapsules or liposomes/centrosomes, if suitable with one or
more carriers or additives.
[0890] In addition to the compounds of the general formula I, their
prodrugs, their N-oxides, their tautomers, their hydrates or their
pharmaceutically suitable salts, the compositions of the invention
may comprise further active basic ingredients which may be
beneficial for the treatment of the impairments or diseases
indicated above.
[0891] The present invention thus further relates to pharmaceutical
compositions in which a plurality of active basic ingredients are
present together, where at least one thereof is a compound of the
invention.
[0892] When producing the pharmaceutical compositions, the
compounds according to the invention are optionally mixed or
diluted with one or more carriers.
[0893] The following examples are intended for further illustration
of the present invention.
[0894] Abbreviations which have been used in the descriptions of
the schemes and the Examples that follow are:
[0895] AIBN for azobisisobutyronitrile; BINAP for 2,2'-bis
(diphenylphosphino)-1,1'-binaphthyl; BOC for tert-butyloxycarbonyl;
DCM for dichloromethane; DEAD for diethyl azodicarboxylate; DIAD
for diisopropyl azodicarboxylate; DIPEA for
N,N-diisopropylethylamine; DMF for dimethylformamide; DMSO for
dimethyl sulfoxide; EA or EtOAc for ethyl acetate (ethyl
ethanoate); Et for ethyl; EtOH for ethanol; HOAc or AcOH for acetic
acid; LDA for lithium diisopropylamide; LiHMDS for lithium bis
(trimethylsilyl)amide; Me for methyl; MeOD or MeOD-d.sub.4 for
deuterated methanol; MeOH for methanol; NBS for N-bromosuccinimde;
n-Bu for n-butyl; NIS for N-iodosuccinimde; OAc for acetate;
Pd.sub.2(dba).sub.3 for tris (dibenzylideneacetone)dipalladium(0):
PdCl.sub.2(dppf) for 1,1'-bis
(diphenylphosphino)ferrocene-palladium (II)-dichloride; PE for
petroleum ether; PyBOP for
benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate;
Raney-Ni for Raney nickel; R.sub.t for retension time; TBAI for
tetrabutylammonium iodide; TFA for trifluoroacetic acid; THF for
tetrahydrofuran; TMSCl for trimethylsilyl chloride; X-PHOS for
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.
[0896] LC-MS was recorded on Agilent 1200 HPLC/6110 SQ system.
[0897] The compounds I of the invention were purified in some cases
by preparative HPLC. The compounds I then result as the salts.
PREPARATION EXAMPLES
I. Preparation of Intermediates
[0898] The starting materials used in the examples are either
commercially available or can be synthesized by the average skilled
person trained in organic chemistry following routine laboratory
practice as outlined, for example in the examples below.
a) Preparation of Compounds of the General Formula IV (Compounds
Het-CR.sup.9R.sup.10--CR.sup.7R.sup.8-NH.sub.2)
a1) 2-Quinolin-2-yl-ethylamine (also referred to as
2-(quinolin-2-yl)ethanamine)
##STR00017##
[0899] Route a)
a1.1a) Quinolin-2-yl-acetic acid ethyl ester
[0900] To a suspension of vacuum dried Zn dust (6.0 g, 93.8 mmol)
in dry THF (100 mL) was added TMSCl (0.5 mL) dropwise over 5 min.
under N.sub.2 atmosphere and under stiffing. The mixture was
stirred for 30 min. and warmed to 45.degree. C. Ethyl bromoacetate
(5.2 mL, 46.9 mmol) was added dropwise via a syringe. After
addition, the mixture was stirred at the same temperature for 1 h.
After sedation at room temperature for 2 h, a clear orange solution
was formed. The orange solution (50 mL) was carefully sucked into a
syringe through a long needle and added to a mixture of
2-bromoquinoline (2.0 g, 9.6 mmol) and PdCl.sub.2(dppf) (200 mg,
0.27 mmol) in a three-neck flask. The mixture was refluxed under
N.sub.2 for 3 h. The reaction was monitored with LCMS. Ethyl
acetate (200 mL) was added to dilute the mixture and water (50 mL)
was added to quench the reaction. The mixture was filtered through
a celite pad. The filtration was partitioned between brine and
ethyl acetate. The organic layer was separated, washed with brine
(100 mL), dried over sodium sulfate and concentrated. The residue
was purified with silica column (PE/EA=3:1) to give the title
compound as orange oil (1.0 g, 48%). LCMS (ESI+): m/z 216
(M+H).sup.+, R.sub.t: 0.62 min.
a1.2a) 2-Quinolin-2-yl-ethanol
[0901] To a cold (0.degree. C.) solution of the compound from
Example a1.1a (10 g, 45 mmol) in THF (200 mL) was added LiAlH.sub.4
(2.65 mg, 70 mmol) in small portions over a period of 5 min. The
resulting mixture was stirred for 1 h. Water was added dropwise
very slowly. Then more water and EA were added. The organic phase
was collected, dried and concentrated. The residue was purified by
silica gel chromatography (PE/EA=2: 1) to give the title compound
as a yellow solid (2.5 g, 30%). LCMS (ESI+): m/z 174 (M+H).sup.+,
R.sub.t:0.75 min
a1.3a) 1-(2-Quinolin-2-yl-ethyl)pyrrolidine-2,5-dione
[0902] 2-Quinolin-2-yl-ethanol from Example a1.2a (2.5 g, 15 mmol),
pyrrolidine-2,5-dione (2 g, 20 mmol) and triphenylphosphine (5.25
g, 20 mmol) were dissolved in THF (50 mL). DEAD (6.1 g, 35 mmol)
was then added. The resultant mixture was stirred at room
temperature overnight. The solvent was evaporated and the residue
was purified by silica gel chromatography (PE/EA=2/1) to give the
title compound as a yellow oil (2.5 g, 66%). LCMS (ESI+): m/z 255
(M+H).sup.+, R.sub.t: 1.15 min
a1.4a) 2-Quinolin-2-yl-ethylamine
[0903] A flask was charged with
1-(2-quinolin-2-yl-ethyl)pyrrolidine-2,5-dione from Example a1.3a
(2.5 g, 20 mmol) and methanol (50 mL). Aqueous NH.sub.2NH.sub.2
(85%, 25 mL) was added. The solution was stirred at reflux
overnight. The solvent was evaporated and the residue was purified
by silica gel chromatography (DCM/MeOH.dbd.10/1) to give the title
compound as a yellow solid (1.5 g, 43%). LCMS (ESI+): m/z 173
(M+H).sup.+, R.sub.t: 1.42min.
Route b)
a1.1b) 2-(Chloromethyl)quinoline
[0904] To a suspension of 2-(chloromethyl)quinoline hydrochloride
(30 g, 0.14 mol) in EtOAc/H.sub.2O (400 mL: 200 mL) was added
NaHCO.sub.3 powder portionwise until no gas evolved. The organic
layer was collected, washed with brine (3*50 mL), dried over sodium
sulfate and concentrated. The residue was used in next step without
further purification (25 g, 100%).
a1.2b) Quinolin-2-yl-acetonitrile
[0905] 2-(Chloromethyl)quinoline (25 g, 0.14 mol) was dissolved in
a mixture of EtOH/H.sub.2O (200 mL: 100 mL). Sodium cyanide (7.5 g,
0.15 mol) was added. The mixture was heated to 50.degree. C. and
stirred overnight. Ethanol was removed under reduced pressure. The
residue was extracted with EtOAc (3*200 mL). The remaining aqueous
phase was treated with 1M FeSO.sub.4 solution (200 mL). The
combined organic layer was washed with water (3*50 mL), dried over
sodium sulfate and concentrated. The residue was purified with
silica column (PE/EA=5:1). The waste water phase was treated with
1M FeSO.sub.4 solution (50 mL).
a1.3b) 2-Quinolin-2-yl-ethylamine
[0906] To a solution of quinolin-2-yl-acetonitrile (19 g, 0.11 mol)
in EtOH (400 mL) was added Raney-Ni (1.0 g) and NH.sub.3-H.sub.2O
(conc., 100 mL). The mixture was hydrogenated with H.sub.2 (2 atm)
overnight. The mixture was filtered and concentrated. The residue
was dissolved in water (200 mL). HCl (3 M, 20 mL) was added. The
aqueous solution was washed with EtOAc (3*100 mL) and adjusted to
pH=6 with NaHCO.sub.3. The resulting aqueous solution was washed
with DCM (2*100 mL). The aqueous phase was freeze-dried to give a
yellow solid. DCM (300 mL) was added to the solid. The mixture was
stirred at room temperature for half an hour. The filtrate was
concentrated in vacuo to give the title compound as a yellow solid
(7.3 g, 36.5%).
a2) 2-(8-Chloro-quinolin-2-yl)-ethylamine
[0907] According to route a) starting from
2-bromo-8-chloro-quinoline
a3) 2-(7-Fluoro-quinolin-2-yl)-ethylamine
[0908] According to route a) starting from
2-bromo-7-fluoro-quinoline
a4) 2-(6-Methoxy-quinolin-2-yl)-ethylamine
[0909] According to route b) starting from
2-chloromethyl-6-methoxy-quinoline
a5) 2-(6-Fluoro-quinolin-2-yl)-ethylamine
[0910] according to route b) starting from
2-chloromethyl-6-fluoro-quinoline
a6) 2-(4-Chloro-quinolin-2-yl)-ethylamine
[0911] According to route b) starting from
4-chloro-2-chloromethyl-quinoline
a7) 2-(3-Fluoro-quinolin-2-yl)-ethylamine
[0912] According to route b) starting from
3-fluoro-2-chloromethyl-quinoline
[0913] They were used in the next step without purification.
b1) 2,2-Difluoro-2-quinolin-2-yl-ethylamine
##STR00018##
[0914] b1.1) Difluoroquinolin-2-yl acetic acid ethyl ester
[0915] 2-Bromoquinoline (5.0 g, 24.0 mmol), ethyl
2-bromodifluoroacetate (5.8 g, 28.8 mmol) and copper powder (3.5 g,
55.2 mmol) in DMSO (20 mL) were stirred at 55.degree. C. for 5
hours. The solid was filtered off, water (100 mL) and EA (150 mL)
were added. The organic layer was separated, dried over sodium
sulfate and concentrated to give the title compound as a yellow oil
(4.2 g, 70%), which was used in the next step without further
purification. LCMS (ESI+): m/z 252 (M+H).sup.+, R.sub.t: 0.934
min
b1.2) 2,2-Difluoro-2-quinolin-2-ylethanol
[0916] To a solution of difluoroquinolin-2-yl acetic acid ethyl
ester (2 g, 7.9 mmol) in ethanol (20 mL) was added NaBH.sub.4 (317
mg, 1.0 mmol) at 0.degree. C. under N.sub.2. The mixture was
stirred for 1 hour and then at room temperature for 1.5 hours. The
solution was quenched with dilute HCl (0.1 N, 20 mL). The mixture
was neutralized with saturated NaHCO.sub.3 solution and extracted
with EtOAc (3*100 mL). The combined organic layer was dried over
sodium sulfate. The solvent was evaporated and the residue was
purified by column chromatography on silica gel (PE:EA=10:1) to
give the title compound as a yellow solid (0.7 g, 44%). LCMS
(ESI+): m/z 210 (M+H).sup.+, R.sub.t: 0.747 min.
b1.3) Trifluoromethanesulfonic acid 2,2-difluoro-2-quinolin-2-yl
ethyl ester
[0917] To a solution of 2,2-difluoro-2-quinolin-2-ylethanol (300
mg, 1.4 mmol) and triethylamine (217 mg, 2.1 mmol) in anhydrous DCM
(5 mL) was added dropwise trifluoromethanesulphonic anhydride (606
mg, 2.1 mmol) at -70.degree. C. The reaction mixture was stirred
for 1 hour. The resulting solution was warmed slowly to room
temperature and stirred for 1 hour. The solid was removed by
filtration. Water (5 mL) and DCM (30 mL) were added, the organic
layer was separated, dried over sodium sulfate and evaporated to
give the crude title compound as an orange oil (450 mg, 92%), which
was used in the next step without further purification. LCMS
(ESI+): m/z 342 (M+H).sup.+, R.sub.t: 1.006 min
b1.4) 2,2-Difluoro-2-quinolin-2-yl-ethyl azide
[0918] A mixture of trifluoromethanesulfonic acid
2,2-difluoro-2-quinolin-2-yl ethyl ester (500 mg, 1.7 mmol) and
sodium azide (450 mg, 6.9 mmol) in DMF (5 mL) was stirred at
60.degree. C. for 12 hours. Water (20 mL) and EA (100 mL) were
added. The organic layer was separated, dried over sodium sulfate
and concentrated to give the crude title compound as a yellow oil
(300 mg, 74%), which was used in the next step without further
purification. LCMS (ESI+): m/z 235 (M+H).sup.+, R.sub.t: 0.943
min
b1.5) 2,2-Difluoro-2-quinolin-2-yl-ethylamine
[0919] A mixture of 2,2-difluoro-2-quinolin-2-yl-ethyl azide (300
mg, 1.2 mmol) and Pd/C (100 mg) in EA (10 mL) was stirred at room
temperature for 2 hours under H.sub.2 (1.5 atm). The catalyst Pd/C
was filtered off, the filtrate was concentrated to give the crude
title compound as white solid (240 mg, 90%), which was used in the
next step without further purification. LCMS (ESI+): m/z 209
(M+H).sup.+, R.sub.t: 0.610 min
c1) 2- Thieno13,2-bl pyridin-5-yl-ethylamine
##STR00019##
[0920] c1.1) Compound (2)
[0921] To a suspension of LiAlH.sub.4 (1.39 g, 36.58 mmol) in
anhydrous THF (30 mL) was added a solution of methyl
3-aminothiophene 2-carboxylate (compound 1, 5.00 g, 31.81 mmol)
dropwise at 0.degree. C. The reaction mixture was stirred at room
temperature overnight. Water (4 mL) was added dropwise to quench
the reaction. The mixture was stirred for 30 min. and then more
water was added (10 mL). The solid was filtered off and then washed
with NaOH solution (50 mL, 5 N). The filtrate was concentrated in
vacuo and the residue was dissolved in EtOAc (200 mL). The solution
was dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The crude solid was used in the next step without further
purification (2.71 g, yield 66%). LCMS (ESI+): m/z 130 (M+H).sup.+,
R.sub.t: 1.57 min
c1.2) Compound (3)
[0922] A mixture of compound 2 (8.14 g, 63.00 mmol) and MnO.sub.2
(32.8 g, 0.378 mol) in EtOAc (100 mL) was stirred at 30.degree. C.
for 48 h. The mixture was filtered and the filtrate was
concentrated in vacuo. The residue was used in the next step
without further purification (6.82 g, yield 85%). LCMS (ESI+): m/z
128 (M+H).sup.+, R.sub.t: 1.55 min
c1.3) Compound (4)
[0923] To a solution of compound 3 (6.82 g, 53.62 mmol) in EtOH (70
mL) was added a mixture of pyruvic acid (9.44 g, 0.107 mol) and
NaOH (10.7 g, 0.268 mol) in H.sub.2O (70 mL) in one portion. The
mixture was heated at 60.degree. C. for 2 h, then cooled and
extracted with Et.sub.2O/EtOAc (1:1, 30 mL). The aqueous layer was
acidified with HCl (2 N) to pH=3 at 0.degree. C. and the water was
removed under reduced pressure. The residue was co-evaporated with
toluene (50 mL.times.3) and then used in the next step without
further purification. LCMS (ESI+): m/z 180 (M+H).sup.+, R.sub.t:
1.50 min
c1.4) Compound (5)
[0924] To a mixture of crude compound 4 (7 g, 39 mmol) in methanol
(60 mL) was added thionyl chloride (10 mL) dropwise at 0.degree. C.
The reaction mixture was then heated at 65.degree. C. for 3 h. The
excess of solvent was removed under reduced pressure. The residue
was diluted with EtOAc (100 mL) and washed with saturated
NaHCO.sub.3 aqueous solution (30 mL.times.4) and brine (30 mL). The
organic layer was dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The residue was purified on a silica column
(PE/EtOAc=5:1, v/v) to afford the title product as an off-white
solid (715 mg, total yield 9.5%). LCMS (ESI+): m/z 194 (M+H).sup.+,
R.sub.t: 1.78 min
c1.5) Compound (6)
[0925] To a solution of compound 5 (100 mg, 0.52 mmol) in THF (2
mL) was added LiBH.sub.4 (11 mg) in one portion. The mixture was
allowed to stir at room temperature overnight. The reaction was
quenched with saturated NH.sub.4Cl solution, then extracted with
EtOAc (20 mL). The organic layer was washed with brine (10 mL),
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
The yellow residue was used in the next step without further
purification. LCMS (ESI+): m/z 166 (M+H).sup.+, R.sub.t: 1.44
min
c1.6) Compound (7)
[0926] A mixture of compound 6 (100 mg, crude) and thionyl chloride
(1 mL) in DCM (3 mL) was stirred at room temperature for 3 h. The
mixture was concentrated in vacuo. The residue was diluted with
EtOAc (20 mL) and washed with saturated NaHCO.sub.3 solution (6
mL.times.4) and brine (6 mL). The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The red
residue was used in the next step without further purification.
LCMS (ESI+): m/z 184 (M+H).sup.+, R.sub.t: 1.88 min
c1.7) Compound (8)
[0927] A mixture of compound 7 (580 mg, 3.157 mmol) and NaCN (170
mg, 3.473 mmol) in EtOH (12 mL) and H.sub.2O (4 mL) was stirred at
50.degree. C. for 60 h. The mixture was diluted with EtOAc (50 mL)
and washed with brine (15 mL.times.4). The organic layer was dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The
residue was purified on a silica column (PE/EtOAc=10:1, v/v) to
afford the title product as an off-white solid (280 mg, yield 51%).
LCMS (ESI+): m/z 175 (M+H).sup.+, R.sub.t: 1.89 min
c1.8) 2-Thieno[3,2-b]pyridin-5-yl-ethylamine (9)
[0928] A mixture of compound 8 (283 mg, 1.624 mmol) and Raney-Ni in
MeOH (12 mL) and ammonium hydroxide (2 mL) was stirred at room
temperature under hydrogen atmosphere (1.5 atm) overnight. The
mixture was then filtered and the filtrate was concentrated in
vacuo. The yellow residue was used in the next step without further
purification (183 mg, yield 63%). LCMS (ESI+): m/z 179 (M+H).sup.+,
R.sub.t: 1.47 min
c2) Methyl 2-bromo-6-methylbenzoate (10)
##STR00020##
[0930] The compound 9 (40 g, 186 mmol) was dissolved in SOCl.sub.2
(54.3 ml, 744 mmol), stirred and heated to about 80.degree. C. for
about 3 h in a 500 mL pear flask. The MeOH (200 ml) was added
dropwise via dropping funnel to the solution in an ice bath. The
resulting solution was stirred at about 80.degree. C. for about 30
min. The reaction mixture was diluted with ethyl acetate. Washed
with sat NaHCO.sub.3, water, and sat NaCl. The combined organic
layers were dried with Na.sub.2SO.sub.4, filtered and concentrated
to give it asmethyl 2-bromo-6-methylbenzoate (40 g, 175 mmol, 94%
yield).
[0931] LC-MS: m/z 229 (M+H) RT=2.05 min/3 min
c3) Methyl 2-bromo-6-(bromomethyl)benzoate (11)
##STR00021##
[0933] A mixture of compound 10 (2.50 g, 9.05 mmol),
N-bromosuccinimide (1.93 g, 10.86 mmol) and azobisisbutyronitrile
(0.669 g, 4.07 mmol) in tetrachloromethane (20 mL) was stirred at
reflux overnight. The mixture was concentrated in vacuo. The
residue was purified on a silica column (PE/EtOAc=200:1, v/v) to
afford the title product as a white solid as a white solid (1.62 g,
yield 50%).
[0934] LC-MS: m/z 355 (M+H) RT=2.33 min/3 min
c4)
7-Bromo-2-(2-(thieno[3,2-b]pyridin-5-yl)ethyl)isoindolin-1-one
##STR00022##
[0936] A mixture of compound 9 (183 mg, 1.06 mmol) and 11 (364 mg,
1.06 mmol) in ethanol (5 mL) was stirred at reflux overnight. The
mixture was concentrated in vacuo and purified on a silica column
(pet. ether/EtOAc=1:1, v/v) to afford the title product as a white
solid (178 mg, yield 41%).
[0937] LC-MS: m/z 421 (M+H) RT=1.91 min/3 min
[0938] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.=8.11 (d, J=8.4
Hz, 1H), 7.75 (d, J=5.6 Hz, 1H), 7.58-7.56 (m, 1H), 7.51 (d, J=5.6
Hz, 1H), 7.33 (t, J=3.0 Hz, 1H), 7.25 (t, J=6.4 Hz, 1H), 4.26 (s,
2H), 4.09 (t, J=7.2 Hz, 2H), 3.33 (t, J=7.2 Hz, 2H).
d1) 2-(Imidazo[1,2-a]pyridin-2-yl)ethylamine
##STR00023##
[0939] Route a)
d1.1a) Imidazo[1,2-a]pyridin-2-yl-acetic acid ethyl ester
[0940] A mixture of 2-aminopyridine (15 g, 159 mmol) and ethyl
4-chloro-3-oxobutanoate (compound 1, 26.2 g, 159 mmol) in THF (100
mL) was heated to reflux for 16 h. The mixture was concentrated and
the residue was purified by silica gel chromatography (PE:EA=1:1)
to afford the title compound as a yellow oil (5.0 g, 15%). LCMS
(ESI+): m/z 205 (M+H).sup.+, R.sub.t: 1.61 min
d1.2a) Imidazol[1,2-a]pyridin-2-yl-acetamide
[0941] A mixture of the compound from Example d1.1a) (600 mg, 2.94
mmol) in ammonium hydroxide (15 mL, 385 mmol) was heated to
90.degree. C. for 3 h. The solvent was removed under reduced
pressure. The residue was purified by plate-TLC (DCM: MeOH=10:1) to
give the title compound as a yellow solid (230 mg, 45% yield). LCMS
(ESI+): m/z 176 (M+H).sup.+, R.sub.t: 1.03 min
d1.3a) 2-Imidazo[1,2-a]pyridin-2-ylethylamine (4)
[0942] Borane tetrahydrofuran complex BH.sub.3.THF (10 mL, 10.0
mmol) was added to a mixture of the compound from Example d1.2a
(200 mg, 1.142 mmol) in THF (3 mL) at 0.degree. C. The mixture was
stirred at 35.degree. C. for 16 h. After cooling to room
temperature, MeOH (2 mL) and HCl (6N, 2 mL) were added. The mixture
was stirred at room temperature for 2 h. The mixture was adjusted
to pH=9 by NaOH (10%). The solvent was removed under reduced
pressure. The residue was dissolved in MeOH (10 mL). The solid was
removed by filtration. The filtrate was concentrated to give the
crude title compound as a yellow solid (120 mg, 65%), which was
directly taken to the next step without purification. LCMS (ESI+):
m/z 162 (M+H).sup.+, R.sub.t: 0.36 min
Route b)
d1.1b) 2-(Chloromethyl)imidazo[1,2-a]pyridine
[0943] To a solution of 1,3-dichloro-2-propanone (67.45 g, 531.3
mmol) in 1,2-dimethoxyethane (200 mL) was added 2-aminopyridine (50
g, 531.3 mmol) and the mixture was stirred at room temperature for
2 hours. During this time a thick precipitate was formed, which was
collected by filtration. The precipitate was refluxed in absolute
ethanol for 2 hours after which volatiles were removed by
evaporation. The residue was dissolved in water (150 mL) and solid
NaHCO.sub.3 was added to neutralize the mixture. A white
precipitate formed, and this was collected by filtration, washed
with water and vacuum dried to yield the title compound pure as a
cream white solid (60 g, 67.8%).
[0944] LC-MS: m/z 167 (M+H); R.sub.t=0.28 min
d1.2b) 2-(Imidazol[1,2-a]pyridin-2-yl)acetonitrile
[0945] A mixture of 2-(chloromethyl)imidazol[1,2-a]pyridine (30 g,
180 mmol) and sodium cyanide (8 g, 163 mmol) in water (100 mL) and
ethanol (100 mL) was heated and stirred for one night at 60.degree.
C. After cooling, the mixture was extracted with DCM (3.times.150
mL).The organic layers was washed with water, dried and evaporated
under reduced pressure. The residue was purified by chromatography
column on silica gel (eluted with PE/EA, 1:1) to give the title
compound (16 g, yield: 50.4%) as a yellow solid. LC-MS: m/z 158.2
(M+H); R.sub.t=0.62 min.
d1.3b) 2-(Imidazol[1,2-a]pyridin-2-yl)ethylamine
[0946] To a solution of 2-(imidazol[1,2-a]pyridin-2-yl)acetonitrile
(13 g, 82.7 mmol) in THF (100 mL), BH.sub.3THF (450 mL, 450 mmol)
was added dropwise at 0.degree. C. After 30 min., the mixture was
allowed to stir at 60.degree. C. for one night. The reaction was
quenched with MeOH (150 mL) and 6N aq.HCl (100 mL).The resulting
mixture was refluxed for 2 hours. The solvent was distilled under
reduced pressure. Aq.Na.sub.2CO.sub.3 was added to neutralize the
mixture and the mixture was evaporated. The residue was purified by
chromatography column (eluted with DCM/MeOH from 20:1 to 10:1) to
give the title compound (10 g, yield: 75%) as a white solid. LC-MS:
m/z 162.1 (M+H); R.sub.t=0.73 min
e1) 2-(3-(Pyrimidin-2-yl)phenyl)ethylamine
##STR00024##
[0947] e1.1) 2-m-Tolylpyrimidine
[0948] A mixture of 3-methylboronic acid (2 g, 14.71 mmol),
2-bromopyrimidine (2.13 g, 13.37 mmol), K.sub.2CO.sub.3 (5.54 g,
40.1 mmol) and PdCl.sub.2(dppf) (.sub.0.98 g, 1.34 mmol) in dioxane
(30 mL) and H.sub.2O (10 mL) was stirred at 100.degree. C. under
nitrogen for 2 h. The mixture was concentrated and the residue was
purified by silica gel column chromatography, eluting with PE/EA
(10:1) to give the title compound as a white solid (1.9 g, 82%).
LCMS (ESI+): m/z 171 (M+H).sup.+, R.sub.t: 0.86 min
e1.2) 2-(3-(Bromomethyl)phenyl)pyrimidine
[0949] A mixture of 2-m-tolylpyrimidine (1.00 g, 5.88 mmol), NBS
(1.26 g, 7.05 mmol) and AIBN (0.43g, 2.64 mmol) in CCl.sub.4 (30
mL) was stirred at 90.degree. C. overnight. The mixture was
concentrated and the residue was purified by silica gel column,
eluting with PE:EA (50: 1) to give the title compound as a white
solid (1.2 g, 81%). LCMS (ESI+): m/z 249 (M+H).sup.+, R.sub.t: 0.89
min
e1.3) 2-(3-(Pyrimidin-2-yl)phenyl)acetonitrile
[0950] A mixture of 2-(3-(bromomethyl)phenyl)pyrimidine (100 mg,
0.4 mmol), NaCN (20 mg, 0.4 mmol) and TBAI (148 mg, 0.4 mmol) in
toluene/H.sub.2O (10 mL: 3 mL) was stirred at 60.degree. C.
overnight. Then the mixture was poured into a mixture of 0.5 g
FeSO.sub.4 in 2 mL water and extracted with EA (50 mL). The organic
layer was dried over sodium sulfate, concentrated and the residue
was purified by silica gel column (PE:EA=2:1) to give the title
compound as a white solid (70 mg, 89%). LCMS (ESI+): m/z 196
(M+H).sup.+, R.sub.t: 0.75 min
e1.4) 2-(3-(Pyrimidin-2-yl)phenyl)ethylamine
[0951] A mixture of 2-(3-(pyrimidin-2-yl)phenyl)acetonitrile (1.15
g, 5.89 mmol) and Raney-Ni (0.6 g) in NH.sub.3.H.sub.2O (3 mL) and
MeOH (30 mL) was stirred at room temperature under H.sub.2 (1.5
atm) overnight. The mixture was filtered. The filtrate was
concentrated to afford the title compound as a yellow oil (0.95 g,
65%). LCMS (ESI+): m/z 200 (M+H).sup.+, R.sub.t: 0.57 min
f1) 2-(2-Phenylpyrimidin-4-yl)ethylamine
##STR00025##
[0952] f1.1) (E)-N'-Hydroxybenzimidamide
[0953] Benzonitrile (5.0 g, 48.5 mmol) was dissolved in 50 mL of
methanol, potassium carbonate (13.4 g, 97.1 mmol) was added and
hydroxylamine hydrochloride (5.1 g, 72.8 mmol) dissolved in 100 mL
of methanol was added subsequently in small portions. The reaction
mixture was refluxed for 5 h, then the solvent was evaporated and
the residue was taken up in a 1:4 mixture of water (100 mL) and DCM
(500 mL). The organic layer was separated, washed twice with water
(100 mL), dried with magnesium sulfate, filtered and evaporated to
afford the title compound as a white solid (4.9 g, 74.3%), which
was used without further purification. LCMS (ESI+): m/z 137
(M+H).sup.+, R.sub.t: 0.29 min
f1.2) 6-Methyl-2-phenylpyrimidine 1-oxide
[0954] To a solution of (E)-N'-hydroxybenzimidamide (5.0 g, 36.8
mmol) and 4,4-dimethoxybutan-2-one (5.3 g, 40.4 mmol) in
iso-propanol (100 mL) was added TFA (4.6 g, 40.4 mmol) dropwise.
The mixture was stirred at 100.degree. C. overnight, concentrated
to give the title compound as a yellow solid (5.3 g, 77.4%). LCMS
(ESI+): m/z 187 (M+H).sup.+, R.sub.t: 0.639 min
f1.3) 4-(Chloromethyl)-2-phenylpyrimidine
[0955] To a solution of 6-methyl-2-phenylpyrimidine 1-oxide (5.3 g,
28.5 mmol) in 1,4-dioxane (100 mL) was added POCl.sub.3 (44 g, 285
mmol) dropwise at room temperature. The mixture stirred at
100.degree. C. for 2 h, then cooled to room temperature and poured
into ice water, extracted with EA (200 mL.times.2), concentrated
and the residue was purified by silica gel column (PE:EA=50: 1) to
obtain the title compound as a yellow solid (2 g, 34.3%). LCMS
(ESI+): m/z 205 (M+H).sup.+, R.sub.t: 0.93 min
f1.4) 2-(2-Phenylpyrimidin-4-yl)acetonitrile
[0956] A mixture of 4-(chloromethyl)-2-phenylpyrimidine (3.7 g,
18.1 mmol) and NaCN (1.0 g, 19.9 mmol) in EtOH/H.sub.2O
(150mL/50mL) was stirred at 50.degree. C. overnight. Then the
mixture was poured into FeSO.sub.4/H.sub.2O and extracted with EA
(300 mL), concentrated and the residue was purified by silica gel
column (PE:EA=10:1) to give the title compound as a yellow solid
(0.78 g, 22%). LCMS (ESI+): m/z 196 (M+H).sup.+, R.sub.t: 0.82
min.
f1.5) 2-(2-Phenylpyrimidin-4-yl)ethylamine
[0957] A mixture of the compound from Example f1.4) (0.78 g, 4
mmol) and Raney-Ni (0.50 g) in NH.sub.3.H.sub.2O (3 mL) and MeOH
(30 mL) was stirred at room temperature under H.sub.2 (1.5 atm)
overnight. The mixture was filtered and concentrated to afford the
title compound as a yellow oil (0.61 g, 76.6%). LCMS (ESI+): m/z
200 (M+H).sup.+, R.sub.t: 0.61 min. .sup.1H NMR (400 MHz, MeOD):
.delta. 2.99-3.00 (m, 2H), 3.12-3.17 (m, 2H), 4.1 (s, 2H), 7.36 (d,
J=4.4 Hz, 1H), 7.53 (s, 3H), 8.41 (s, 2H), 8.79 (d, J=4.4 Hz,
1H).
g1) 2-[1,2,4]Triazolo[1,5-]pyridin-2-yl-ethylamine
##STR00026##
[0958] g1.1) 2-Iminopyridin-1(2H)-amine hydroiodide
[0959] A solution of aminooxysulfonic acid (84 g, 0.744 mol) and
potassium hydroxide (41.7 g, 0.744 mol) in 150 mL of H.sub.2O
(prepared at 0.degree. C.) was added dropwise to a solution at
40.degree. C. of 2-aminopyridine (70 g, 0.744 mol) in 100 mL
H.sub.2O within 15 min The reaction mixture was stirred at
55.degree. C. for 2 h. To this solution was added dropwise a
solution of potassium carbonate (51.4 g, 0.372 mol) in 150 mL of
H.sub.2O and then, about half of the volume was evaporated in
vacuo. The reaction mixture was diluted with 2-3-fold (v) of EtOH.
The precipitate was filtered and the mother liquor evaporated to
about 20% of its volume. Hydrogen iodide (95 g, 744 mmol) was added
to the suspension. The reaction mixture was evaporated in vacuo.
The residue was triturated with EtOH and the solid was filtrated to
give the title compound (40 g, yield: 22.7%) as a white solid.
LC-MS: m/z 110 (M+H) R.sub.t=1.44 min. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta.=8.28 (s, 2H), 8.04 (d, J=6 Hz, 1H),
7.84-7.80 (m, 1H), 7.09-7.06 (m, 1H), 6.87-6.83 (m, 1H).
g1.2) 2-([1,2,4]Triazolo[1,5-a]pyridin-2-yl)acetonitrile
[0960] To a mixture of 2-iminopyridin-1(2H)-amine hydroiodide e (40
g, 169 mmol) and ethyl 2-cyanoacetate (38.2 g, 337 mmol) in ethanol
(40 mL) sodium hydroxide (6.75 g, 169 mmol) was added. The reaction
mixture was stirred at reflux overnight. Upon cooling a precipitate
formed. The solid was filtered off, washed with a small amount of
cool ethanol, dried and purified by column chromatography on silica
gel (eluted with PE/EA from 3:1 to 1:1) to give the title compound
(13 g, yield: 46.6%) as a white solid.
[0961] LC-MS: m/z 159 (M+H) R.sub.t=1.15 min. .sup.1H NMR (400 MHz,
d6-DMSO): .delta.=8.94 (d, J=6.8 Hz, 1H), 7.81 (d, J=7.2 Hz, 1H),
7.70 (t, J=8.0 Hz, 1H), 7.23 (t, J=6.8 Hz, 1H), 4.40 (s, 2H).
g1.3) 2-([1,2,4]Triazolo[1,5-a]pyridin-2-yl)ethylamine
[0962] To a solution of
2-([1,2,4]triazolo[1,5-a]pyridin-2-yl)acetonitrile (7 g, 44.3 mmol)
in THF (100 mL) was added BH.sub.3.THF (221 mL, 221 mmol) dropwise
at 0.degree. C. After 30 min., the mixture was allowed to stir at
refluxed for 3 hours. The reaction was monitored by LCMS. The
reaction was quenched with MeOH (150 mL) and the resulting mixture
was refluxed for 2 hours. The solvent was distilled off under
reduced pressure. The residue was purified by chromatography column
(eluted with DCM/MeOH from 20:1 to 10:1) to give a crude product,
which was recrystallized from PE/EA (10:1) to give the title
compound (2.8 g, yield: 39%) as a light yellow solid. LC-MS: m/z
163 (M+H) R.sub.t=0.57 min. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta.=8.53 (d, J=6.8 Hz, 1H), 7.69 (d, J=9.2 Hz, 1H), 7.52-7.48
(m, 1H), 7.01-6.97 (m, 1H), 3.24 (t, J=6.4 Hz, 2H), 3.09 (t, J=6.4
Hz, 2H).
[0963] The compounds of the following Preparation Examples can be
prepared using the standard operation procedures described
above.
Preparation Example 1
6-[2-(Benzofuran-2-yl)ethyl]-4-bromo-7H-pyrrolo[3,4-b]pyridin-5-one
[0964] ESI-MS: [M+Na+]=379,00, [M+H+]=357,95
Preparation Example 2
6-[2-(Benzothiophen-2-yl)ethyl]-4-bromo-7H-pyrrolo[3,4-b]pyridin-5-one
Preparation Example 3
4-Bromo-6-[2-(7-methyl-2-quinolyl)ethyl]-7H-pyrrolo[3,4-b]pyridin-5-one
[0965] ESI-MS: 384,00, [M+H+]=383,05
Preparation Example 4
4-Bromo-6-[2-(5-isopropyl-2-pyridyl)ethyl]-7H-pyrrolo[3,4-b]pyridin-5-one
[0966] ESI-MS: 362,10, [M+H+]=361,05
Preparation Example 5
2-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-bromo-7-methoxy-isoindolin-1-one
[0967] ESI-MS: 405,00, [M+H+]=404,00
Preparation Example 6
4-Bromo-6-[2-(6-chloro-1,3-benzothiazol-2-yl)ethyl]-7H-pyrrolo[3,4-b]pyrid-
in-5-one
[0968] ESI-MS: [M+Na+]=431,90, [M+H+]=409,90
Preparation Example 7
4-Bromo-6-[2-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]-7H-pyrrolo[3,4-b]pyrid-
in-5-one
[0969] ESI-MS: [M+Na+]=415,85, [M+H+]=392,95
Preparation Example 8
4-Bromo-6-[2-(6-methyl-2-quinolyl)ethyl]-7H-pyrrolo[3,4-b]pyridin-5-one
[0970] ESI-MS: 384,00, [M+]=382,00
Preparation Example 9
4-Bromo-6-[2-(4,5-dimethylthiazol-2-yl)ethyl]-7H-pyrrolo[3,4-b]pyridin-5-o-
ne
[0971] ESI-MS: [M+Na+]=375,95, 355,00, [M+H+]=353,00
Preparation Example 10
4-Bromo-6-[2-(4-methyl-2-pyridyl)ethyl]-7H-pyrrolo[3,4-b]pyridin-5-one
[0972] ESI-MS: [2M+Na+]=688,10, 335,00, [M+H+]=333,05
Preparation Example 11
4-Bromo-6-[2-(3-methyl-2-pyridyl)ethyl]-7H-pyrrolo[3,4-b]pyridin-5-one
[0973] ESI-MS: [M+H+]=333,00
Preparation Example 12
4-Bromo-6-[2-(4-ethylthiazol-2-yl)ethyl]-7H-pyrrolo[3,4-b]pyridin-5-one
[0974] ESI-MS: [M+Na+]=376,00, 355,00, [M+H+]=353,00
Preparation Example 13
2-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-bromo-isoindolin-1-one
[0975] ESI-MS: [M+]=373,00
Preparation Example 14
4-[(Z)-2-(Diisopropylamino)vinyl]-6-[2-(2-quinolyl)ethyl]-7H-pyrrolo[3,4-b-
]pyridin-5-one
[0976] ESI-MS: 416,20, [M+H+]=415,20
Preparation Example 15
4-Chloro-6-(2-quinolin-2-yl-ethyl)-5,6-dihydro-pyrrolo[3,4-b]pyridin-7-one
[0977] ESI-MS: [M+H+]=324.10
Preparation Example 16
4-Chloro-6-(2-imidazo[1,2-a]pyridin-2-yl-ethyl)-5,6-dihydro-pyrrolo[3,4-b]-
pyridin-7-one
[0978] ESI-MS: [M+H+]=313.10
Preparation Example 17
4-Bromo-6-[2-(5-methyl-pyridin-2-yl)-ethyl]-6,7-dihydro-pyrrolo[3,4-b]pyri-
din-5-one
[0979] ESI-MS: [M+H+]=333.00
Preparation Example 18
4-Bromo-6-(2-pyridin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one
[0980] ESI-MS: [M+Na+]=341.95, [M+H+]=319.00
Preparation Example 19
4-Bromo-6-[2-(5-phenyl-pyridin-2-yl)-ethyl]-6,7-dihydro-pyrrolo[3,4-b]pyri-
din-5-one
[0981] ESI-MS: [M+H+]=395.00
Preparation Example 20
4-Bromo-6-[2-(6-methyl-pyridin-2-yl)-ethyl]-6,7-dihydro-pyrrolo[3,4-b]pyri-
din-5-one
[0982] ESI-MS: [M+H+]=333.00
Preparation Example 21
4-Bromo-6-[2-(1-methyl-1H-imidazol-2-yl)-ethyl]-6,7-dihydro-pyrrolo[3,4-b]-
pyridin-5-one
[0983] ESI-MS: [M+H+]=322.05
Preparation Example 22
4-Bromo-6-[2-(1-methyl-1H-imidazol-4-yl)-ethyl]-6,7-dihydro-pyrrolo[3,4-b]-
pyridin-5-one
[0984] ESI-MS: [M+H+]=322.00
Preparation Example 23
7-Bromo-2-(2-quinoxalin-2-ylethyl)isoindolin- l-one
[0985] ESI-MS: [M+H+]=369.00
Preparation Example 24
4-Bromo-6-[2-(5,6-dimethyl-2-pyridyl)ethyl]-7H-pyrrolo[3,4-b]pyridin-5-one
[0986] ESI-MS: [M+H+]=347.10
Preparation Example 25
4-Bromo-6-[2-(7-ethylimidazo[1,2-a]pyridin-2-yl)ethyl]-7H-pyrrolo[3,4-b]py-
ridin-5-one
[0987] ESI-MS: [M+H+]=386.10
Preparation Example 26
4-Bromo-6-[2-(6-methoxy-2-pyridyl)ethyl]-7H-pyrrolo[3,4-b]pyridin-5-one
[0988] ESI-MS: [M+]=348.10
Preparation Example 27
4-Bromo-6-[2-(3,5-dimethyl-2-pyridyl)ethyl]-7H-pyrrolo[3,4-b]pyridin-5-one
[0989] ESI-MS: [M+H+]=347.00
Preparation Example 28
4-Bromo-6-[2-(6-fluoroimidazo[1,2-a]pyridin-2-yl)ethyl]-7H-pyrrolo[3,4-b]p-
yridin-5-one
[0990] ESI-MS: 377.00 (M+H+), [M+H+]=376.00
Preparation Example 29
4-Bromo-6-[2-(4-cyclopropylthiazol-2-yl)ethyl]-7H-pyrrolo[3,4-b]pyridin-5--
one
[0991] ESI-MS: [M+H+]=365.00
II. Preparation of Compounds of the Formula I
[0992] II.1 Preparation of Compounds of the Formula I in which
X.sup.3 is N
Example 1
4-Pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-1,2-dihydro-pyrrolo[3,4-c]pyridin-
-3-one; compound with trifluoro-acetic acid
1.1 2-Cyano-3-methyl-but-2-enoic acid methyl ester
[0993] A suspension of cyanoacetic acid methyl ester (56.60 g, 0.57
mol), acetone (39.80 g, 0.68 mol), HOAc (6.0 g, 0.10 mol) and
NH.sub.4OAc (4.0 g, 0.05 mol) in toluene (500 mL) was heated at
reflux overnight with removal of water in a Dean-Stark trap. After
cooling, the solvent was removed under reduced pressure and the
residue was purified by column chromatography on silica using
PE:EA=3: 1 to give the title compound (40.30 g, 50.8%). .sup.1H-NMR
(400 MHz, CDCl.sub.3): .delta. 3.82 (s, 3H), 2.42 (s, 3H), 2.32 (s,
3H), LCMS (ESI+): m/z 140 (M+H).sup.+, R.sub.t: 0.72 min
1.2 2-Cyano-5-dimethylamino-3-methyl-penta-2,4-dienoic acid methyl
ester
[0994] N,N-Dimethylformamide dimethyl acetal (34.85 g, 0.29 mol)
was added dropwise to a solution of 2-cyano-3-methyl-but-2-enoic
acid methyl ester (40.30 g, 0.29 mol) in absolute EtOH (200 mL).
After the addition, the solution was heated at reflux overnight and
then concentrated to yield the crude title compound (36.80 g,
65.3%) which was used in the next step without further
purification. LCMS (ESI+): m/z 195 (M+H).sup.+, R.sub.t: 1.64
min
1.3 2-Bromo-4-methyl-nicotinic acid methyl ester
[0995] The compound from example 1.2 (36.80 g, 0.19 mol) was
dissolved in AcOH (150 mL) and the mixture was heated to 40.degree.
C. A solution of 30% HBr-AcOH (250 mL) was added dropwise and then
the mixture was heated to 55.degree. C. with stirring. After
heating for 3 hours, the solution was concentrated, poured into
water (200 mL), neutralized with solid Na.sub.2CO.sub.3, extracted
with DCM (3.times.300 mL) and dried over Na.sub.2SO.sub.4. The
organic phase was concentrated to dryness and the residue was
purified by column chromatography on silica using PE:EA=5:1 to give
the title compound as an off-white solid (34.68 g, 79.3%).
.sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 8.26-8.25 (m, 1H),
7.15-7.14 (m, 1H), 3.98 (s, 3H), 2.34 (s, 3H). LCMS (ESI+): m/z 232
(M+2).sup.+, R.sub.t: 1.97 min.
1.4 4-Methyl-[2,4']bipyridinyl-3-carboxylic acid methyl ester
[0996] Dioxane (70 mL) and 2N aqueous Cs.sub.2CO.sub.3 (38 mL,
0.076 mol) were added to a flask containing the compound from
Example 1.3 (4.35 g, 0.019 mol), pyridine-4-boronic acid (2.80 g,
0.023 mol) and PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 (1.55 g, 0.0019
mol) under N.sub.2 atmosphere. The reaction mixture was then heated
to 95.degree. C. and stirred overnight. The reaction mixture was
cooled to room temperature and then filtered through Celite, the
solvent was removed and the crude was purified with silica gel
column chromatography (PE:EA=3/1 to 1/5) to give the crude title
compound as an off-white solid (2.89 g, 66.7%)..sup.1H-NMR (400
MHz, CDCl.sub.3): .delta. 8.71-8.69 (m, 2H), 8.63-8.61 (m, 1H),
7.50-7.51 (m, 2H), 7.27-7.24 (m, 1H), 3.69 (s, 3H), 2.45 (s, 3H).
LCMS (ESI+): m/z 229 (M+H).sup.+, R.sub.t: 1.65 min
1.5
4-Pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-1,2-dihydro-pyrrolo[3,4-c]pyr-
idin-3-one
[0997] To a solution of diisopropylamine (7.4 mL, 52.8 mmol) in THF
(20 mL) was added dropwise n-BuLi (2.5 M solution in hexane, 20 mL,
52.8 mmol) at -78.degree. C. The mixture was allowed to warm to
0.degree. C. in 30 minutes. The compound from Example 1.4 (0.50 g,
2.2 mmol) was added dropwise to the above prepared LDA solution (5
mL) at -30.degree. C., then the mixture was warmed to 0.degree. C.
slowly and stirred at this temperature for 30 minutes. A solution
of BrCCl.sub.2CCl.sub.2Br (1.72 g, 5.28 mmol) in THF (5 mL) was
added dropwise to the reaction mixture at -30.degree. C., and the
mixture was stirred at 0.degree. C. for 2 h. After that, a
suspension of 2-quinolin-2-yl-ethylamine from Example a1 (0.50 g,
3.0 mmol) in THF (20 mL) was added to the mixture and the reaction
was stirred at room temperature overnight. The crude product was
purified by Prep-HPLC to get the title compound (53 mg, 13.3%) as a
white solid. .sup.1H-NMR (400 MHz, MeOD): .delta. 9.00 (d, J=8.4
Hz, 1H), 8.91 (dm, J=5.2 Hz, 1H), 8.81 (dm, J=5.6 Hz, 2H), 8.39 (d,
J=6.0 Hz, 2H), 8.24 (m, 2H), 8.00 (m, 2H), 7.89-7.83 (m, 2H), 4.85
(s, 2H), 4.23 (t, J=6.8 Hz, 2H), 3.72 (t, J=6.8 Hz, 2H); LCMS
(ESI+): m/z 367 (M+H).sup.+, R.sub.t: 1.46 min
II.2 Preparation of Compounds of the Formula I in Which X.sup.2 is
N
Example 2
7-Pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-pyrrolo[3,4-c]pyridin-
-1-one
2.1 3-Bromo-5-methyl-pyridin-4-ylamine
[0998] To a solution of 4-amino-3-picoline (10 g, 0.092 mmol) and
HBr (50 mL) heated to 70.degree. C. was added 15% H.sub.2O.sub.2
(16 mL) over one h. The reaction mixture was stirred for an
additional hour and poured into ice (100 g). The pH of the solution
was adjusted to about 5 with 50% NaOH and the resulting red
precipitate was filtered. The pH was raised to about 9 and the
resulting white precipitate was collected by filtration to afford
the title compound (13.5 g, 78%).
2.2 5-Methyl-[3,4']bipyridinyl-4-ylamine
[0999] A mixture of 3-bromo-5-methyl-pyridin-4-ylamine (1.00 g,
5.347 mmol), pyridin-4-yl boronic acid (0.65 g, 5.347 mmol),
K.sub.2CO.sub.3 (2.22 g, 16.04 mmol) and Pd(dppf)Cl.sub.2 (436 mg,
0.5347 mmol) in water (3 mL) and 1,4-dioxane (15 mL) was stirred at
105.degree. C. overnight. The mixture was diluted with EtOAc (100
mL) and washed with brine (30 mL.times.4). The organic layer was
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
The residue was purified on a silica column (EtOAc) to afford the
title product as a white solid (554 mg, yield 56%). LCMS (ESI+):
m/z 186 (M+H).sup.+, R.sub.t: 1.16 min
2.3 4-Bromo-5-methyl-[3,4']bipyridinyl
[1000] To a cooled (0.degree. C.) suspension of the compound from
Example 2.2 (270 mg, 1.458 mmol) and CuBr (839 mg, 5.832 mmol) in
75% H.sub.2SO.sub.4 (5 mL) was added dropwise a solution of
NaNO.sub.2 (332 mg, 4.811 mmol) in water (2 mL). The mixture was
stirred at 0.degree. C. for 3 h and then neutralized with NaOH (2
N) at 0.degree. C. The precipitates were filtered off, and the
filtrate was extracted with EtOAc (50 mL.times.3). The organic
layer was dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The residue was purified on a silica column (EtOAc) to
afford the title product as an off-white solid (230 mg, yield 63%).
.sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta. 8.73 (s, 2H), 8.46
(s, 1H,), 8.29 (s, 1H), 7.35-7.40 (m, 2H), 2.49 (s, 3H); LCMS
(ESI+): m/z 249 (M+H).sup.+, R.sub.t: 1.70 min
2.4 5-Methyl-[3,4']bipyridinyl-4-carboxylic acid methyl ester
[1001] A mixture of 4-bromo-5-methyl-[3,4']bipyridinyl (3 g, 12.04
mmol), PdCl.sub.2(dppf) (8.81 g, 12.04 mmol) and triethylamine
(1.219 g, 12.04 mmol) in methanol (50 mL) was heated under CO
atmosphere (10 atm) to 100.degree. C. for about 8 h in a 100 mL
pressure reaction vessel. The solution was concentrated to dryness
to give a brown oil. The residue was purified by silica column (5:
1=PE:EA). Collected fractions were concentrated to afford the title
compound as an off-white solid (1.5 g, 42.6%). LCMS (ESI+): m/z 229
(M+H).sup.+, R.sub.t: 0.52 min.
2.5
7-Pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-pyrrolo[3,4-c]pyr-
idin-1-one
[1002] To a solution of diisopropylamine (7.4 mL, 52.8 mmol) in THF
(20 mL) was added dropwise n-BuLi (2.5 M solution in hexane, 20 mL,
52.8 mmol) in THF (5 mL) at -78.degree. C. The mixture was allowed
to warm to 0.degree. C. in 30 minutes. The compound from Example
2.4 (0.10 g, 0.44 mmol) was added dropwise to the above prepared
LDA solution (1 mL) at -78.degree. C., then the mixture was warmed
to -30.degree. C. slowly and stirred at this temperature for 30
minutes. A solution of Freon 113 (0.23 g, 1.05 mmol) in THF (5 mL)
was added dropwise to the reaction mixture at -30.degree. C., and
the mixture was stirred at 0.degree. C. for 2 h. After that, a
suspension of 2-(quinolin-2-yl)ethylamine from Example a1 (0.07 g,
0.45 mmol) in dry THF (2 mL) was added to the mixture. TBAI (10 mg,
0.04 mmol) was added. The reaction mixture was stirred at room
temperature overnight. The crude product was purified by plate-TLC
using CH.sub.2Cl.sub.2: MeOH=10:1 and then by prep-HPLC to get the
title compound (27 mg, 12.5%) as a yellow oil. LCMS (ESI+): m/z 367
(M+H).sup.+, R.sub.t: 1.16 mM..sup.1H-NMR (400 MHz, MeOD): .delta.
3.70 (t, J=6.4 Hz, 2H), 4.24 (t, J=6.4Hz, 2H), 4.88 (s, 2H), 7.93
(t, J=7.6 Hz, 1H), 8.02-8.05 (dm, J=8.0 Hz, 1H), 8.10-8.13 (m, 3H),
8.21 (d, J=8.8 Hz, 1H), 8.28 (d, J=6.4 Hz, 1H), 8.83 (br, 3H), 8.99
(d, J=8.8 Hz, 1H), 9.09 (br,1H).
11.3 Preparation of Compounds of the Formula I in Which X.sup.1 is
N
Example 3
4-Pyridin-4-yl-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]pyridin-
-5-one
3.1 3-(2-Ethoxycarbonyl-ethylamino)-but-2-enoic acid ethyl
ester
[1003] A mixture of 3-aminopropionic acid ethyl ester hydrochloride
(53.12 g, 0.35 mmol), 3-oxobutyric acid ethyl ester (43.70 mL, 0.35
mol) and anhydrous potassium carbonate (116.10 g, 0.84 mol) in 600
mL of toluene was refluxed in an equipment with a Dean-Stark trap
overnight. The reaction mixture was cooled and diluted with EtOAc
(300 mL) and CH.sub.2Cl.sub.2 (200 mL), filtered, and the obtained
solution was concentrated under reduced pressure, yielding the
crude title compound (76.2 g, 94.3%) which was used in the next
step without further purification. LCMS (ESI+): m/z 230
(M+H).sup.+, R.sub.t: 1.80 min
3.2 2-Methyl-4-oxo-1,4,5,6-tetrahydropyridine-3-carboxylic acid
ethyl ester
[1004] A solution of the compound from Example 3.1 (76.2 g, 0.33
mol) in 600 mL of toluene was supplied with sodium hydride (24 g of
a 50% dispersion in oil, 0.50 mol) and the resulting yellow
suspension was stirred and heated at reflux overnight. After the
mixture had been cooled to room temperature, the reaction was
quenched with water (300 mL) and the organic solvent was removed in
vacuum. The obtained alkaline, aqueous solution was treated with
15% hydrochloric acid (200 mL), and then washed with Et.sub.2O
(3.times.300 mL). The aqueous phase was basified with NaHCO.sub.3
and extracted with CH.sub.2Cl.sub.2 solution (3.times.300 mL). The
combined organic layer was dried over Na.sub.2SO.sub.4, and
concentrated to give the crude title compound (20.0 g, 33.3%) as a
pale yellow solid which was used in the next step without further
purification. LCMS (ESI+): m/z 184 (M+H).sup.+, R.sub.t: 1.34
min
3.3 2-Methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid ethyl
ester
[1005] A mixture of the compound from Example 3.2 (20.0 g, 0.11
mol) and lead tetraacetate (146.2 g, 0.33 mol) in 250 mL of acetic
acid was heated under reflux with stirring overnight. Next, the
solvent was removed under diminished pressure and the dark yellow,
oily residue was dissolved in EtOH/CH.sub.2Cl.sub.2 (1: 10, 500
mL). The resulting suspension was filtered through a pad of silica
gel (200 g), and the filtrate was concentrated to afford the crude
title compound (16.8 g, 84.0%). .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. 11.57 (s, 1H), 7.56 (s, 1H), 6.07 (s,1H),
4.22-4.16 (m, 2H), 3.34 (s, 3H), 2.18 (s, 3H), 1.25-1.22 (m, 3H).
LCMS (ESI+): m/z 182 (M+H).sup.+, R.sub.t: 1.24 min
3.4 4-Chloro-2-methyl-nicotinic acid ethyl ester
[1006] The compound from Example 3.3 (16.8 g, 0.092 mol) in 150 mL
of POCl.sub.3 was stirred at reflux overnight. The reaction mixture
was poured into ice, adjusted to pH=7-8 with solid NaOH, and then
extracted with EtOAc (3.times.300 mL). The organic phase was washed
with sat. NaHCO.sub.3 and sat. NaCl solution, then the solvent was
removed under reduced pressure and the residue was purified by
column chromatography on silica gel using PE:EA=5: 1 to get the
title compound (4.2 g, 26.0%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6):
.delta. 8.53-8.52 (m, 1H), 7.54-7.52 (m, 1H), 6.07 (s,1H),
4.43-4.41 (m, 2H), 2.52-2.44 (m, 3H), 1.36-1.32 (m, 3H). LCMS
(ESI+): m/z 200 (M+H).sup.+, R.sub.t: 1.83 min.
3.5 2-Methyl-[4,4']bipyridinyl-3-carboxylic acid ethyl ester
[1007] Dioxane (50 mL) and 2N aqueous Cs.sub.2CO.sub.3 (42 mL,
0.084 mol) were added to a flask containing the compound from
Example 3.4 (4.20 g, 0.021 mol), pyridin-4-ylboronic acid (3.10 g,
0.025 mol) and PdCl.sub.2(dppf)CH.sub.2Cl.sub.2 (1.71 g, 0.0021
mol) under N.sub.2 atmosphere. The reaction mixture was then heated
to 95.degree. C. and stirred overnight. After the reaction mixture
was cooled to room temperature and filtered over Celite, the
solvent was removed and the crude compound was purified by silica
gel column chromatography (PE:EA=3/1 to 1/5) to give the title
compound (3.46 g, 68.1%). .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta.:8.69-8.63 (m, 3H), 8.63-8.61 (m, 1H), 7.31-7.26 (m, 2H),
7.15-7.14 (m, 1H), 4.15-4.13 (m, 2H), 2.67 (s, 3H), 1.06-1.02 (m,
3H). LCMS (ESI+): m/z 243 (M+H).sup.+, R.sub.t: 1.70 min
3.6
4-Pyridin-4-yl-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolol[3,4-b]py-
ridin-5-one
[1008] To a solution of diisopropylamine (7.4 mL, 52.8 mmol) in THF
(20 mL) was added dropwise n-BuLi (2.5 M solution in hexane, 20
mL,52.8 mmol) at -78.degree. C. The mixture was allowed to warm to
0.degree. C. in 30 minutes. The compound from Example 3.5 (0.50 g,
2.0 mmol) was added dropwise to the above prepared LDA solution (5
mL) at -30.degree. C., then the mixture was warmed to 0.degree. C.
slowly and stirred at this temperature for 30 minutes. A solution
of Freon 113 (562 mg, 3.0 mmol) in THF (5 mL) was added dropwise to
the reaction mixture at -30.degree. C., and the mixture was stirred
at 0.degree. C. for 2 h. After that, a suspension of
2-(quinolin-2-yl)ethylamine from Example a1 (0.50 g, 3.0 mmol) in
DMF (2 mL) was added to the mixture and then TBAI (50 mg, 0.2
mmol). The reaction mixture was heated to 40.degree. C. for 2 h.
The crude product was first purified by plate-TLC using
CH.sub.2Cl.sub.2: MeOH=10:1 to get the crude title compound (20 mg,
2.7%) which was then further purified by prep-HPLC. .sup.1H-NMR
(400 MHz, MeOD): .delta. 8.79 (d, J=5.2 Hz, 1H), 8.57-8.55 (m, 2H),
8.29 (d, J=8.4 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.85 (d, J=8.8 Hz,
1H), 7.73-7.69 (m, 1H), 7.60-7.47 (m, 5H), 4.62 (s, 2H), 4.13 (t,
J=6.8 Hz, 2H), 3.40-3.37 (t, J=6.8 Hz, 2H). LCMS (ESI+): m/z 367
(M+H).sup.+, R.sub.t: 1.75 min
II.4 Preparation of Compounds of the Formula I in Which A is
CR5R6
Example 4
3,3-Difluoro-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one
4.1 3-Bromophthalic acid
[1009] KOH (1 g, 0.019 mol) was added to a solution of
1-bromo-2,3-dimethylbenzene (5 g, 0.027 mol) in water (200 mL).
Then a solution of KMnO.sub.4 (20 g, 0.13 mol) in water (100 mL)
was added dropwise. After addition, the mixture was heated at
reflux for 16 h. EtOH was added to reduce excessive KMnO.sub.4 and
the mixture was filtered. The filtrate was acidified with conc. HCl
to pH=3, concentrated to 50 mL and then extracted with EA (200 mL).
The organic layer was washed with water (50 mL) and dried over
Na.sub.2SO.sub.4, and evaporated to afford the title compound as a
white solid (4.5 g, 68%). LCMS (ESI+): m/z 245 (M+H).sup.+,
R.sub.t: 0.31 min.
4.2 4-Bromo-2-(2-quinolin-2-yl-ethyl)-isoindole-1,3-dione
[1010] A mixture of 3-bromophthalic acid (0.8 g, 3.3 mmol),
2-(quinolin-2-yl)ethanamine from Example a1 (1.1 g, 6.6 mmol) and
AcONa (406 mg, 5.0 mmol) in AcOH (15 mL) was heated at reflux for 2
h. The solvent was evaporated under reduced pressure. The residue
was dissolved in EA (15 mL) and washed with saturated
Na.sub.2CO.sub.3 solution (10 mL) and water (10 mL) in sequence.
The organic layer was dried over Na.sub.2SO.sub.4 and concentrated.
The residue solid was washed with CH.sub.3OH to give the title
compound as a brown solid (400 mg, 32%). LCMS (ESI+): m/z 381
(M+H).sup.+, R.sub.t: 1.58 min.
4.3
7-Bromo-2-(2-quinolin-2-yl-ethyl)-3-thioxo-2,3-dihydroisoindol-1-one
[1011] A mixture of the compound from Example 4.2 (0.35 g, 0.92
mmol) and Lawenson's reagent (409 mg, 1.01 mmol) in toluene (15 mL)
was heated to reflux for 16 h. The solvent was removed under
reduced pressure. The residue was purified by plate-TLC (DCM: PE=2:
1) to give the title compound as a yellow solid (200 mg, 55%). LCMS
(ESI+): m/z 397 (M+H).sup.+, R.sub.t: 2.39 min
4.4
7-Bromo-3,3-difluoro-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1--
one
[1012] NBS (99 mg, 0.56 mmol) was added to a solution of the
compound from Example 4.3 (100 mg, 0.25 mmol) and
n-Bu.sub.4NH.sub.2F.sub.3 (226 mg, 0.75 mmol) in DCM (10 mL) at
0.degree. C. The reaction mixture was stirred at room temperature
for 1 h. The mixture was poured into aqueous
NaHSO.sub.3-NaHCO.sub.3 solution (0.1 M-0.1 M, 20 mL). The organic
layer was dried over Na.sub.2SO.sub.4 and evaporated under reduced
pressure. The residue was purified by plate-TLC (PE:EA=3:1) to give
the title compound as a brown solid (50 mg, 50%). LCMS (ESI+): m/z
403 (M+H).sup.+, R.sub.t: 2.29 min
4.5 3,3-Difluoro-7-pyridin-4- y1-2-(2-quinolin-2- yl-ethyl)-2
,3-dihydro-isoindol-1-one
[1013] A mixture of the compound from Example 4.4 (50 mg, 0.12
mmol), PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (13 mg, 0.016
mmol), pyridin-4-boronic acid (17 mg, 0.14 mmol) and
K.sub.2CO.sub.3 (50 mg, 0.36 mmol) in dioxane/water (3:1, 20 mL)
was heated to 100.degree. C. for 30 min. The solvent was removed
under reduced pressure. The residue was dissolved in DCM (10 mL),
washed with water (5 mL*2). The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated. The residue oil was purified by
silica gel chromatography (PE:EA=2:1) to give the title compound as
a white solid (40 mg, 80%). LCMS (ESI+): m/z 402 (M+H).sup.+,
R.sub.t: 2.12 min. .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 3.41
(t, J=7.8 Hz, 2H), 4.10 (t, J=8 Hz, 2H), 7.35 (d, J=8.4 Hz, 1H),
7.42 (d, J=5.2 Hz, 2H), 7.52-7.513 (m, 2H), 7.702-7.805 (m, 4H),
8.047-8.102 (m, 2H), 8.69 (s, 2H).
Example 5
7-Pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
5.1 2-Bromo-6-methylbenzoic acid
[1014] A solution of CuBr (45 g, 316 mmol) in HBr (80 mL) and
H.sub.2O (80 mL) was stirred at room temperature (the solution
1).
[1015] 2-Amino-6-methylbenzoic acid (20 g, 132 mmol) was dissolved
in HBr (80 mL) and H.sub.2O (80 mL). The solution was cooled to
0.degree. C. Aq. NaNO.sub.2 (11 g, 160 mmol, in 20 mL water) was
added dropwise while the temperature was maintained at 0-10.degree.
C. The mixture was stirred for 20 min. (the solution 2).
[1016] The solution 1 was added dropwise to the solution 2. Then
the mixture was stirred at room temperature for 2 h. The solid was
filtered to give the title compound as a yellow solid (16 g, 56%).
LCMS (ESI+): m/z 215 (M+H).sup.+, R.sub.t: 0.759 min
5.2 2-Bromo-6-methylbenzoic acid methyl ester
[1017] 2-Bromo-6-methylbenzoic acid (16 g, 74 mmol) was dissolved
in SOCl.sub.2 (30 mL). The mixture was stirred at reflux for 4 h.
The solvent was evaporated. The residue was dissolved in methanol
(40 mL) and the resulting solution was stirred at reflux overnight.
Then the solvent was evaporated and the residue was purified by
column chromatography on silica gel (PE:EA=50: 1) to give the title
compound as yellow oil (16 g, 93%). LCMS (ESI+): m/z 229
(M+H).sup.+, R.sub.t: 0.868 min.
5.3 2-Bromo-6-bromomethylbenzoic acid methyl ester
[1018] To a solution of 2-bromo-6-methylbenzoic acid methyl ester
(6 g, 26 mmol) in CCl.sub.4 (40 mL) was added NBS (4.7 g, 26 mmol)
and AIBN (215 mg, 1.3 mmol) under N.sub.2. The mixture was heated
to reflux overnight. The solution was cooled and filtered. The
filtrate was concentrated and purified by column chromatography on
silica gel (PE: EA=100: 1) to give the compound as an off-white
solid (6.2 g, 76%). LCMS (ESI+): m/z 307 (M+H).sup.+, R.sub.t:
0.879 min
5.4
7-Bromo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
[1019] A solution of 2-bromo-6-bromomethylbenzoic acid methyl ester
(300 mg, 0.97 mmol) and 2-quinolin-2-ylethylamine from Example a1
(184 mg, 1.0 mmol) in anhydrous EtOH (10 mL) was stirred at reflux
under N.sub.2 overnight. The solvent was evaporated. The residue
was purified by column chromatography on silica gel (DCM:
CH.sub.3OH=20:1) to give the title compound as a white solid (150
mg, 42%). LCMS (ESI+): m/z 367 (M+H).sup.+, R.sub.t: 0.693 min
5.5
7-Pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
[1020] A mixture of
7-bromo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one (300
mg, 0.8 mmol), pyridine-4-ylboronic acid (151 mg, 1.2 mmol),
Pd(dppf)Cl.sub.2 (66 mg) and Cs.sub.2CO.sub.3 (666 mg, 2.0 mmol) in
DME/EtOH/H.sub.2O (1/1/1, 15 mL) was stirred at 100.degree. C. for
15 min. in a microwave. The solution was concentrated and purified
by plate-TLC (PE/EA=1:2) to give the title compound as white solid
(170 mg, 56%). LCMS (ESI+): m/z 366 (M+H).sup.+, R.sub.t: 1.853
min. .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 8.56 (dd, J=4.4
Hz, 1.6 Hz, 2H), 8.29 (d, J=8.4Hz, 1H), 7.94 (d, J=7.2Hz, 1H), 7.89
(d, J=8.8 Hz, 1H), 7.72-7.65 (m, 3H), 7.56-7.54 (m, 1H), 7.48 (d,
J=8.8 Hz, 1H), 7.40 (dd, J=4.4 Hz, 1.6 Hz, 3H), 4.54 (s, 2H), 3.99
(t, J=7.2 Hz, 2H), 3.27 (t, J=7.4 Hz, 2H)
Example 6
3,3-Dimethyl-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one
[1021] To a solution of the compound from Example 5 (150 mg, 0.4
mmol) in anhydrous THF (15 mL) was added dropwise LiHMDS (1.2 mL,
1.2 mmol) at -70.degree. C. and stirred for 30 min. Then
iodomethane (174 mg, 1.2 mmol) was added dropwise. The resulting
solution was warmed slowly to room temperature and stirred for 1
hour. Water (2 mL) was added and the solvent was evaporated. The
residue was purified by column chromatography on silica gel (DCM:
CH.sub.3OH=20:1) to give compound the title compound as a white
solid (16 mg, 10%). LCMS (ESI+): m/z 394 (M+H).sup.+, R.sub.t:
1.419 min. .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 8.56 (d,
J=5.2 Hz, 2H), 8.29 (d, J=8.4 Hz, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.92
(d, J=8.4Hz, 1H), 7.65-7.79 (m,7H), 7.44 (d, J=8.0 Hz, 1H), 3.91
(t, J=7.2 Hz, 2H), 3.40 (t, J=7.6 Hz, 2H), 1.51 (s, 6H).
Examples 7 to 12 were prepared analogously to the method for
Example 5.
Example 7
6-[3-Oxo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-1H-isoindol-4-yl]-1H-quinaz-
olin-4-one trifluoroacetate
[1022] ESI-MS: [M+Na.sup.+]=456.20, [M+H.sup.+]=433.10.
Example 8
7-(3-Methyl-3H-benzoimidazol-5-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-i-
soindol-1-one trifluoroacetate
[1023] ESI-MS: [M+H.sup.+]=419.20.
Example 9
5-[3-Oxo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-1H-isoindol-4-yl]-1,3-dihyd-
ro-benzoimidazol-2-one trifluoroacetate
[1024] ESI-MS: [M+H].sup.+=421.10.
Example 10
7-(3H-Benzotriazol-5-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1--
one trifluoroacetate
[1025] ESI-MS: [M+H].sup.+=406.10.
Example 11
7-(3H-Benzoimidazol-5-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-
-one trifluoroacetate
[1026] ESI-MS: [M+H].sup.+=405.10.
Example 12
7-(2-Amino-quinazolin-6-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one
[1027] ESI-MS: [M+H].sup.+=432.10.
II.5 Preparation of compounds I, where R.sup.9 and R.sup.10 are
different from H
Example 13
2-(2,2-Difluoro-2-quinolin-2-yl-ethyl)-7-pyridin-4-yl-2,3-dihydro-isoindol-
-1-one
13.1.
7-Bromo-2-(2,2-difluoro-2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol--
1-one
[1028] A solution of 2,2-difluoro-2-quinolin-2-yl-ethylamine from
Example b1(250 mg, 1.2 mmol) and 2-bromo-6-bromomethyl-benzoic acid
methyl ester from Example 5.3 (554 mg, 1.8 mmol) in anhydrous EtOH
(8 mL) was stirred at reflux under N.sub.2 overnight. The solvent
was evaporated. The residue was purified by column chromatography
on silica gel (PE:EA=3:1) to give the title compound as white solid
(150 mg, 31%). LCMS (ESI+): m/z 403 (M+H).sup.+, R.sub.t: 0.937
min.
13.2
2-(2,2-Difluoro-2-quinolin-2-yl-ethyl)-7-pyridin-4-yl-2,3-dihydro-iso-
indol-1-one
[1029] A mixture of
7-bromo-2-(2,2-difluoro-2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
(150 mg, 0.4 mmol), pyridine-4-ylboronic acid (69 mg, 1.5 mmol),
Pd(dppf)Cl.sub.2 (30 mg) and Cs.sub.2CO.sub.3 (303 mg, 2.5 mmol) in
DME/EtOH/H.sub.2O (1/1/1, 5 mL) was stirred at 100.degree. C. for
15 min. in a microwave. The solution was concentrated and purified
by plate-TLC (PE:EA=3:1) to give the title product as white solid
(65 mg, 44%). LCMS (ESI+): m/z 402 (M+H).sup.+, R.sub.t: 2.045
min.
[1030] .sup.1H-NMR (400 MHz, DMSO): .delta. 8.62 (d, J=8.8 Hz, 1H),
8.5 (d, J=6.0 Hz, 2H), 8.12 (d, J=8.0 Hz, 1H), 8.06 (d, J=8.4 Hz,
1H), 7.89-7.86 (m,2H), 7.76-7.72 (m, 3H), 7.46-7.42 (m, 2H), 7.3
(d, J=5.6 Hz, 1H), 4.70 (s, 2H), 4.52 (t, J=7.2 Hz, 2H).
II.6 Preparation of Compounds of the Formula I in Which One of the
Radicals R.sup.1, R.sup.2 or R.sup.3 is different from H
Example 14
6-Fluoro-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-o-
ne
14.1 3-Fluoro-2-iodo-6-methylbenzoic acid
[1031] 5-Fluoro-2-methyl-benzoic acid (3.0 g, 19.5 mmol), NIS (4.8
g, 21.4 mmol), Pd(OAc).sub.2 (448 mg, 2 mmol) in 100 mL of DMF were
stirred at 110.degree. C. for 2 h. After completion of the
reaction, the mixture was cooled to room temperature and poured
into water, the product was extracted with EA, the organic layer
was collected and dried with Na.sub.2SO.sub.4, concentrated and
purified by silica-gel (PE/EA=6/1) to afford the title compound as
an off-white solid (4.9 g, 89.7%). LCMS (ESI+): m/z
(M+H).sup.+281.7, R.sub.t: 1.786 min.
14.2 3-Fluoro-2-iodo-6-methylbenzoic acid ethyl ester
[1032] 3-Fluoro-2-iodo-6-methylbenzoic acid (4.2 g, 15 mmol),
K.sub.2CO.sub.3 (6.7 g, 30 mmol) in 50 mL of DMF were stirred at
room temperature for 20 min. Ethyl iodide (3.04 g, 19.5 mmol) was
added portionwise. The temperature was increased to 50.degree. C.
for 1 h. After the reaction was completed (monitored by TLC),
solvent was evaporated. The residue was washed with water (3*50 mL)
and extracted with EA. The organic layers were combined, dried over
Na.sub.2SO.sub.4 and concentrated to afford the title product as an
orange oil (4.1 g, 88.7%). LCMS (ESI+): m/z (M+H).sup.+309.7,
R.sub.t: 2.306 min.
14.3 6-Bromomethyl-3-fluoro-2-iodobenzoic acid ethyl ester
[1033] 3-Fluoro-2-iodo-6-methylbenzoic acid ethyl ester (2.8 g, 9.1
mmol), NBS (2.43 g, 13.6 mmol), AIBN (89 mg, 0.55 mmol) and 50 mL
of anhydrous CCl.sub.4 were mixed and refluxed under N.sub.2
atmosphere overnight. The reaction mixture was cooled, concentrated
and the residue was purified by plate-TLC (PE/EA=12/1) to give the
title compound as a white solid (2.0 g, 57.1%). LCMS (ESI+): m/z
(M+H).sup.+387.7, R.sub.t: 2.310 min.
14.4
6-Fluoro-7-iodo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
[1034] 6-Bromomethyl-3-fluoro-2-iodobenzoic acid ethyl ester (0.5
g, 1.3 mmol), 2-quinolin-2-yl-ethylamine from Example a1(0.22 g,
1.3 mmol), K.sub.2CO.sub.3 (0.36 g, 2.6 mmol) and 15 mL of EtOH
were mixed and refluxed for 5 h. The reaction mixture was cooled,
concentrated and the residue was purified by plate-TLC (PE/EA=2/1)
to give the title compound as an off-white solid (0.35 g, 62.5%).
LCMS (ESI+): m/z (M+H).sup.+433.7, R.sub.t: 1.615 min
14.5
6-Fluoro-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindo-
l-1-one
[1035] The compound from Example 14.4 (300 mg, 0.69 mmol),
pyridine-4-ylboronic acid (85 mg, 0.69 mmol), Pd(dppf)Cl.sub.2 (30
mg) and K.sub.2CO.sub.3 (192 mg, 1.39 mmol) were dissolved in
dioxane/H.sub.2O (3/1, 6 mL) then the mixture was stirred in
nitrogen atmosphere at 120.degree. C. for 1 h in a microwave tube.
The solution was concentrated and the residue was purified by
plat-TLC (DCM/MeOH=12/1). The crude product was recrystalized from
MeOH to give the title compound as a white solid (71 mg, 26.7%).
LCMS (ESI+): m/z (M+H).sup.+384.7, R.sub.t: 1.273 min. .sup.1H NMR
(DMSO-d.sub.6, 400 MHz): .delta. 8.58 (dd, J=4.4 Hz, 1.6 Hz, 2H),
8.27 (d, J=8.4 Hz, 1H), 7.94 (d, J=7.6 Hz, 1H), 7.88 (d, J=8.0 Hz,
1H), 7.73-7.68 (m, 2H), 7.58-7.54 (m, 2H), 7.45 (d, J=8.8 Hz, 1H),
7.30 (d, J=4.8 Hz, 2H), 4.52 (s, 2H), 3.94 (t, J=7.4 Hz, 2H), 3.25
(t, J=7.2 Hz, 2H).
Example 15
5-Fluoro-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-o-
ne
15.1 4-Fluoro-2-iodo-6-methylbenzoic acid
[1036] The title compound was prepared in analogy to the process
described in Example 14.1 starting from 4-fluoro-2-methyl benzoic
acid. Yield: 69.4%; LCMS (ESI+): m/z (M+H).sup.+281.7, R.sub.t:
1.952 min.
15.2 4-Fluoro-2-iodo-6-methylbenzoic acid ethyl ester
[1037] The title compound was prepared in analogy to the process
described in Example 14.2 starting from the compound from Example
15.1. Yield: 91%. LCMS (ESI+): m/z (M+H).sup.+309.7, R.sub.t: 2.158
min.
15.3 2-Bromomethyl-4-fluoro-6-iodo-benzoic acid ethyl ester
[1038] The title compound was prepared in analogy to the process
described in Example 14.3 starting from the compound from Example
15.2. Yield: 42%; LCMS (ESI+): m/z (M+H).sup.+387.7, R.sub.t: 2.183
min.
15.4
5-Fluoro-7-iodo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
[1039] The title compound was prepared in analogy to the process
described in Example 14.4 starting from the compound from Example
15.3. Yield: 55%; LCMS (ESI+): m/z (M+H).sup.+433.7, R.sub.t: 1.721
min.
15.5
5-Fluoro-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindo-
l-1-one
[1040] The title compound was prepared in analogy to the process
described in Example 14.5 starting from the compound from Example
15.4. Yield: 27%; LCMS (ESI+): m/z (M+H).sup.+384.7, R.sub.t: 1.290
min. ; .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 8.57 (dd, J=4.8
Hz, 2.0 Hz, 2H), 8.28 (d, J=8.0 Hz, 1H), 7.94 (d, J=7.2 Hz, 1H),
7.88 (d, J=8.4 Hz, 1H), 7.73-7.69 (m, 1H), 7.58-7.53 (m, 2H), 7.48
(d, J=8.0 Hz, 1H), 7.42 (dd, J=4.4 Hz, 1.2 Hz, 2H), 7.31 (dd, J=10
Hz, 2.4 Hz, 1H), 4.55 (s, 2H), 3.96 (t, J=7.2 Hz, 2H), 3.28 (t,
J=7.2 Hz, 2H).
Example 16
4-Fluoro-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-o-
ne
16.1 3-Fluoro-6-iodo-2-methylbenzoic acid
[1041] The title compound was prepared in analogy to the process
described in Example 14.1 starting from 3-fluoro-2-methyl benzoic
acid. Yield: 74%; LCMS (ESI+): m/z (M+H).sup.+281.7, R.sub.t: 1.738
min.
16.2 3-Fluoro-6-iodo-2-methylbenzoic acid ethyl ester
[1042] The title compound was prepared in analogy to the process
described in Example 14.2 starting from 3-fluoro-6-iodo-2-methyl
benzoic acid. Yield: 91%. LCMS (ESI+): m/z (M+H).sup.+309.7,
R.sub.t: 2.358 min
16.3 2-Bromomethyl-3-fluoro-6-iodo-benzoic acid ethyl ester
[1043] The title compound was prepared in analogy to the process
described in Example 14.3 starting from the compound of Example
16.2. Yield: 40%; LCMS (ESI+): m/z (M+H).sup.+387.7, R.sub.t: 2.358
min.
16.4
4-Fluoro-7-iodo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
[1044] The title compound was prepared in analogy to the process
described in Example 14.4 starting from the compound from Example
16.3. Yield: 39%; LCMS (ESI+): m/z (M+H).sup.+433.7, R.sub.t: 1.615
min.
16.5 4-Fluoro-7-pyridin-4- y1-2-(2-quinolin-2-
yl-ethyl)-2,3-dihydro-isoindol-1-one
[1045] The title compound was prepared in analogy to the process
described in Example 14.5 starting from the compound of Example
16.4. Yield: 27%; LCMS (ESI+): m/z (M+H).sup.+384.7, R.sub.t: 1.299
min. ; .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 8.55 (dd, J=4.8
Hz, 1.6 Hz, 2H), 8.28 (d, J=8.4 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H),
7.87 (d, J=8.4 Hz, 1H), 7.73-7.69 (m, 1H), 7.57-7.53 (m, 2H), 7.50
(t, J=4.2 Hz, 2H), 7.38-7.36 (dd, J=4.4 Hz, 1.6 Hz, 2H), 4.67 (s,
2H), 3.97 (t, J=7.2 Hz, 2H), 3.29 (t, J=7.2 Hz, 2H).
II.7 Preparation of Compounds of the Formula I in Wwhich A is
NR.sup.5a
Example 17
1-Methyl-4-(pyridin-4-yl)-2-(2-(quinolin-2-yl)ethyl)-1,2-dihydroindazol-3--
one
[1046] 17.1 Ethyl 2-bromo-6-fluorobenzoate
[1047] To a solution of 2-bromo-6-fluoro-benzoic acid (5 g, 22.83
mmol) and Cs.sub.2CO.sub.3 (14.9 g, 45.7 mmol) in CH.sub.3CN (100
mL) was added CH.sub.3CH.sub.2I (7.12 g, 45.7 mmol) dropwise. The
mixture was stirred at 30.degree. C. overnight. The mixture was
filtered and the filtrate was concentrated. The residue was
purified by silica gel column chromatography, eluting with PE/EA
(10:1) to give the title compound as a colorless oil (2 g, 25%).
LCMS (ESI+): m/z 247,249. (M+H)+, R.sub.t: 0.93 min.
17.2 4-Bromo-1-methyl-1,2-dihydroindazol-3-one
[1048] A mixture of the compound from Example 17.1 (1.0 g, 4.0
mmol), acetic acid (290 mg, 4.8 mmol) and methylhydrazine (370 mg,
8.1 mmol) in ethanol (50 mL) was heated to about 80.degree. C.
overnight. The mixture was concentrated and the residue was
purified by silica gel column chromatography, eluting with PE/EA
(5:1) to give the title compound as colorless oil (0.4 g, 44%).
LCMS (ESI+): m/z 227,229. (M+H).sup.+, R.sub.t: 0.73 min.
17.3 1-Methyl-4-(pyridin-4- y1)-1,2-dihydroindazol-3-one
[1049] A mixture of the compound from Example 17.2 (120 mg, 0.528
mmol), pyridin-4-ylboronic acid (65 mg, 0.528 mmol),
K.sub.2CO.sub.3 (219 mg, 1.584 mmol) and PdCl.sub.2(dppf) (39 mg,
0.053 mmol) in 1,4-dioxane (12 mL) and water (4 mL) was heated to
about 100.degree. C. for about 2 h. The reaction mixture was
concentrated and the residue was purified by silica gel column
chromatography, eluting with PE/EA (1:1) to give the title compound
as a yellow solid (80 mg, 54%). LCMS (ESI+): m/z 226. (M+H).sup.+,
R.sub.t: 0.55 min.
17.4
1-Methyl-4-(pyridin-4-yl)-2-(2-(quinolin-2-yl)ethyl)-1,2-dihydroindaz-
ol-3-one
[1050] A mixture of the compound from Example 17.3 (500 mg, 2.22
mmol), 2-quinolin-2-yl-ethanol from Example a1.2a (384 mg, 2.22
mmol), triphenylphosphine (1747 mg, 6.66 mmol) and DIAD (0.863 mL,
4.44 mmol) in CH.sub.2Cl.sub.2 (10 mL) was stirred at 25.degree. C.
over night. The mixture was concentrated and the residue was
purified by silica gel column, eluting with DCM/MeOH (50: 1) to
give the title compound as colorless oil (200 mg, 23%). LCMS
(ESI+): m/z 381. (M+H).sup.+, R.sub.t: 1.37 min.; .sup.1H NMR (400
MHz, MeOD): .delta. 3.16 (t, J=6.0 Hz, 2H), 3.69 (s, 3H), 4.59 (t,
J=6.0 Hz, 2H), 6.74 (dd, J=5.8, 2.0 Hz, 1H), 6.98 (d, J=8.4 Hz,
1H), 7.12-7.14 (m,2H), 7.17-7.19 (m, 2H), 7.34-7.38 (m, 1H),
7.52-7.56 (m, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H),
7.93 (d, J=8.8 Hz, 1H), 8.02-8.04 (m, 2H).
II.8 Preparation of Compounds of the Dormula I in Which A is O
Example 18
4-Pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-benzo[d]isoxazol-3-one
18.1 Vinylboronic acid
[1051] To a rapidly stirred cold (-20.degree. C.) solution of
trimethyl borate (10.4 g, 0.1 mol) in anhydrous THF (100 mL) was
added dropwise vinylmagnesium bromide (100 mL, 1 M in THF
solution). When the addition was completed, the mixture was stirred
at -20.degree. C. for further 30 min. The reaction was then
quenched with HCl (2 N), the mixture was extracted with EtOAc (200
mL) and washed with HCl (2 N) (50 mL.times.2) and brine (50 mL).
The organic layer was dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The crude solid was used in the next step
without further purification (6.8 g, yield 96%).
18.2 2-Vinylquinoline
[1052] A mixture of 2-bromoquinoline (5.00 g, 24.03 mmol),
vinylboronic acid (2.07 g, 28.83 mmol), K.sub.2CO.sub.3 (9.96 g,
72.08 mmol) and Pd(dppf)Cl.sub.2 (1.96 g, 2.403 mmol) in water (10
mL) and 1,4-dioxane (30 mL) was stirred at 105.degree. C.
overnight. The mixture was diluted with EtOAc (100 mL) and washed
with brine (30 mL.times.4). The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
was purified on a silica column (PE/EtOAc=20:1, v/v) to afford the
title product as a light orange oil (2.25 g, yield 60%). LCMS
(ESI+): m/z 156 (M+H).sup.+, R.sub.t: 1.89 min
18.3 N-(2-Quinolin-2-yl-ethyl)-hydroxylamine
[1053] A mixture of 2-vinylquinoline (2.25 g, 14.50 mmol) and
hydroxylamine hydrochloride (10.1 g, 145.0 mmol) in MeOH (30 mL)
was stirred at reflux overnight. The mixture was concentrated in
vacuo. The residue was dissolved in EtOAc (100 mL) and washed with
aqueous saturated NaHCO.sub.3 solution (30 mL.times.5). The organic
layer was dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The residue was then purified on a silica column (DCM/MeOH
=50:1, v/v) to afford the title product as a yellow solid (2.18 g,
yield 80%). LCMS (ESI+): m/z 189 (M+H).sup.+, R.sub.t: 1.59 min
18.4
2-Bromo-6-fluoro-N-hydroxy-N-(2-quinolin-2-yl-ethyl)-benzamide
[1054] A mixture of N-(2-quinolin-2-yl-ethyl)-hydroxylamine (500
mg, 2.657 mmol), 2-bromo-6-fluorobenzoic acid (582 mg, 2.657 mmol),
PyBOP (1.66 g, 3.188 mmol) and DIPEA (412 mg, 3.188 mmol) in DMF
(10 mL) was stirred at room temperature overnight. The mixture was
diluted with EtOAc (50 mL) and washed with brine (15 mL.times.3).
The organic layer was dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The residue was then purified on a silica
column (pet. ether/EtOAc=1:1, v/v) to afford the title product as a
dark oil (crude, 1.01 g, yield 98%). LCMS (ESI+): m/z 389
(M+H).sup.+, R.sub.t: 1.86 min
18.5 4-Bromo-2-(2-quinolin-2-yl-ethyl)-benzo[d]isoxazol-3-one
[1055] A mixture of the compound from Example 18.4 (1.01 g, 2.593
mmol) and Cs.sub.2CO.sub.3 (1.69 g, 5.187 mmol) in DMF (20 mL) was
stirred at 80.degree. C. overnight. The mixture was diluted with
EtOAc (100 mL) and washed with brine (30 mL.times.3). The organic
layer was dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The residue was purified on a silica column (PE/EtOAc=4:1,
v/v) to afford the title product as a white solid (110 mg, yield
11%). LCMS (ESI+): m/z 369 (M+H).sup.+, R.sub.t: 1.90 min.
18.6
4-Pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-benzo[d]isoxazol-3-one
[1056] A mixture of the compound from Example 18.5 (110 mg, 0.2979
mmol), pyridine-4-ylboronic acid (44 mg, 0.3575 mmol),
K.sub.2CO.sub.3 (124 mg, 0.8938 mmol) and Pd(dppf)Cl.sub.2 (24 mg,
0.02979 mmol) in water (1 mL) and 1,4-dioxane (5 mL) was stirred at
105.degree. C. overnight. The mixture was diluted with EtOAc (30
mL) and washed with brine (10 mL.times.4). The organic layer was
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
The residue was purified by pre-TLC (eluent: EtOAc) to afford the
title product as a white solid (68 mg, yield 62%). LCMS (ESI+): m/z
368 (M+H).sup.+, R.sub.t: 1.94 min.; .sup.1H NMR (CDCl.sub.3/TMS,
400 MHz) .delta.: 8.65 (d, J=5.2 Hz, 2H), 8.09 (d, J=8.0 Hz, 1H),
7.88 (d, J=8.4 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.63-7.69 (m, 2H),
7.46-7.52 (m, 3H), 7.33 (d, J=8.8 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H),
7.25-7.27 (m, 1H), 4.57 (t, J=7.2 Hz, 2H), 3.49 (t, J=7.0 Hz,
2H).
II.9 Preparation of Compounds of the Formula I in Which Het is
Different from 2-quinolin-2-yl
Example 19
7-Pyridin-4-yl-2-(2-thieno[3,2-b]pyridin-5-yl-ethyl)-2,3-dihydro-isoindol--
1-one
19.1 2-Iodo-6-methylbenzoic acid
[1057] To a solution of 2-methylbenzoic acid (50 g, 0.36 mol) in
DMF (800 mL) was added Pd(OAc).sub.2 (8 g, 0.036 mmol) and NIS (80
g, 0.36 mol). Then the reaction mixture was heated to 100.degree.
C. for 1.5h. The reaction was monitored by TLC. When the starting
material was consumed, the reaction mixture was cooled,
concentrated in vacuo to remove the excess solvent. The residue was
dissolved in DCM (500 mL), washed with brine (2*200 mL), dried by
Na.sub.2SO.sub.4, filtered, concentrated and purified by silica gel
chromatography, eluting with PE/EA=5:1 to give the title compound
(92 g, 95%) as a white solid. LCMS (ESI+): m/z 263 (M+H).sup.+,
R.sub.t: 1.90 min
19.2 Methyl 2-iodo-6-methylbenzoate
[1058] To a solution of 2-iodo-6-methylbenzoic acid (80 g, 0.31
mol) in DCM (700 mL) was added SOCl.sub.2 (55 g, 0.46 mol) dropwise
at 0.degree. C. After addition, the reaction mixture was stirred at
reflux for 2 hours. The solvent was removed in vacco. The residue
was added dropwise to MeOH (100 mL) at 0.degree. C. The mixture was
then refluxed overnight. The solvent was evaporated under reduce
pressure. The residue was purified by silica gel chromatography
eluting PE/EA=70:1 to give the title compound (43 g, 50%) as a
white solid. LCMS (ESI+): m/z 277 (M+H).sup.+, R.sub.t: 2.17
min
19.3 2-Bromomethyl-6-iodo-benzoic acid methyl ester
[1059] A mixture of 2-iodo-6-methyl-benzoic acid methyl ester (2.50
g, 9.055 mmol), N-bromosuccinimide (1.93 g, 10.86 mmol) and
azobisisbutyronitrile (0.669 g, 4.075 mmol) in tetrachloromethane
(20 mL) was stirred at reflux overnight. The mixture was
concentrated in vacuo and the residue was purified on a silica
column (PE/EtOAc=200:1, v/v) to afford the title product as a white
solid as a white solid (1.62 g, yield 50%). LCMS (ESI+): m/z 355
(M+H).sup.+, R.sub.t: 2.33 min
19.4
7-Iodo-2-(2-thieno[3,2-b]pyridin-5-yl-ethyl)-2,3-dihydro-isoindol-1-o-
ne
[1060] A mixture of 2-thieno[3,2-b]pyridin-5-yl-ethylamine from
Example c1 (183 mg, 1.062 mmol) and the compound from Example 19.3
(364 mg, 1.062 mmol) in ethanol (5 mL) was stirred at reflux
overnight. The mixture was concentrated in vacuo and purified on a
silica column (pet. ether/EtOAc=1:1, v/v) to afford the title
product as a white solid (178 mg, yield 41%). LCMS (ESI+): m/z 421
(M+H).sup.+, R.sub.t: 1.91 min
19.5
7-Pyridin-4-yl-2-(2-thieno[3,2-b]pyridin-5-yl-ethyl)-2,3-dihydro-isoi-
ndol-1-one
[1061] A mixture of the compound from Example 19.4 (178 mg, 0.4235
mmol), pyridine-4-ylboronic acid (63 mg, 0.5082 mmol),
K.sub.2CO.sub.3 (176 mg, 1.271 mmol) and Pd(dppf)Cl.sub.2 (35 mg,
0.04235 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at
105.degree. C. overnight. The mixture was diluted with EtOAc (30
mL) and washed with brine (10 mL.times.4). The organic layer was
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
The residue was purified on a silica column (eluent: EtOAc) to
afford the title product as a white solid (113 mg, yield 72%). LCMS
(ESI+): m/z 372 (M+H).sup.+, R.sub.t: 1.86 min.; .sup.1H NMR
(CDCl.sub.3/TMS, 400 MHz) .delta. 8.67 (d, J=4.8 Hz, 2H), 8.12 (d,
J=8.0 Hz, 1H), 7.76 (d, J=5.6 Hz, 1H), 7.59 (t, J=7.4 Hz, 1H),
7.46-7.51 (m, 4H), 7.36 (d, J=7.6 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H),
4.40 (s, 2H), 4.07 (t, J=7.2 Hz, 2H), 3.31 (t, J=7.2 Hz, 2H).
Example 20
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-7-pyridin-4-yl-2,3-dihydro-isoindol-
-1-one
20.1
7-Bromo-2-(2-imidazo[1,2-a]pyridin-2-yl-ethyl)-2,3-dihydro-isoindol-1-
-one
[1062] A mixture of 2-imidazo[1,2-a]pyridin-2-ylethylamine from
Example d1(120 mg, 0.744 mmol), methyl
2-bromo-6-(bromomethyl)benzoate from Example 5.3 (367 mg, 0.893
mmol) and DIPEA (0.260 mL, 1.489 mmol) in 2-propanol (15 mL) was
heated to 85.degree. C. for 2 h. The solvent was evaporated. The
residue was purified by plate-TLC (DCM: MeOH=10:1) to give the
title compound as a white solid (200 mg, 75%). LCMS (ESI+): m/z 356
(M+H).sup.+, R.sub.t: 1.77 min.
20.2
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-7-pyridin-4-yl-2,3-dihydro-iso-
indol-1-one
[1063] A mixture of
7-bromo-2-(2-imidazo[1,2-a]pyridin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
(200 mg, 0.561 mmol), pyridin-4-ylboronic acid (83 mg, 0.674 mmol),
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (59.6 mg, 0.073 mmol) and
K.sub.2CO.sub.3 (233 mg, 1.684 mmol) in 1,4-dioxane (8 mL) and
water (4.00 mL) was heated to 100.degree. C. for 30 min. The
solvent was evaporated and the residue was dissolved in DCM (10 mL)
and washed with water (10 mL). The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by plate-TLC (DCM: MeOH=10:1) to give 220 mg of a black
solid, which was further purified by reverse phase flash column
(C18, MeOH-0.1% NH.sub.3HCO.sub.3/H.sub.2O=20% 95%) to give the
title compound as an off-white solid (150 mg, 0.423 mmol, 75%).
LCMS (ESI+): m/z 355 (M+H).sup.+, R.sub.t: 1.69 min. .sup.1H NMR
(DMSO-d.sub.6, TMS, 400 MHz): .delta. 3.02 (t, J=7.4 Hz, 2H), 3.85
(t, J=7.2 Hz, 2H), 4.50 (s, 2H), 6.80-6.84 (m, 1H), 7.15-7.19 (m,
1H), 7.41-7.49 (m, 4H), 7.64-7.69 (m, 2H), 7.75 (s, 1H), 8.46 (d,
J=7.2 Hz, 1H), 8.6 (d, J=4 Hz, 2H).
II.10 Preparation of Compounds of the Formula I in Which A is
CH.sub.2
Route a):
##STR00027##
[1064] Step A: 7-Iodo-2-(2-(quinolin-2-yl)ethyl)isoindolin-1-one
(3)
[1065] A mixture of 2-(quinolin-2-yl)ethylamine from Example a1
(compound 1, 7.3 g, 0.042 mol), methyl
2-(bromomethyl)-6-iodobenzoate from Example 19.3 (compound 2, 15 g,
0.042 mol), and Et.sub.3N (4.2 g, 0.042 mol) in dry isopropanol
(100 mL) was refluxed under N.sub.2 overnight. The reaction mixture
was cooled to room temperature, filtered, and concentrated. The
residue was purified with a silica column (PE/EA=3:1) to give the
compound 3 (8.9 g, 50%) as a yellow solid. LCMS (ESI+): m/z 415
(M+H).sup.+, R.sub.t: 1.94 min.
Step B: Compound (4)
[1066] A suspension of compound 3 (60 mg, 0.15 mmol), the
corresponding boronic acid R.sup.1--B(OH).sub.2 (0.17 mmol) and
Pd(dppf)Cl.sub.2 (6 mg) in dioxane (1.5 mL) and H.sub.2O (1.5 mL)
was stirred at room temperature for 2 min. and then heated by
microwave irradiation at 100.degree. C. for 20 min. Upon
completion, the mixture was concentrated and purified by prep-HPLC
to give compound 4.
Step C: 3-Oxo-2-(2-(quinolin-2-yl)ethyl)isoindolin-4-ylboronic acid
(5)
[1067] Compound 3 (1.0 g, 2.4 mmol) and trimethyl borate (0.3 g,
2.9 mmol) were dissolved in dry THF (20 mL) at -78.degree. C.
n-BuLi (1.1 mL, 2.5 M in hexanes, 2.8 mmol) was added dropwise at
-78.degree. C. The mixture was warmed to 0.degree. C. and stirred
for 1 h. Aqueous NaOH (1M, 10 mL) was added. The organic solvent
was removed under reduced pressure. The residue was extracted with
DCM (2*50 mL). The water phase was adjusted to pH=2 by aqueous HCl
(1M). The mixture was condensed under reduced pressure. The residue
was dissolved in DCM/MeOH (10:1, 50 mL). The solid was removed by
filtration. The filtrate was concentrated to give title compound as
off-white solid (0.17 g, 21%). LCMS (ESI+): m/z 333 (M+H).sup.+,
R.sub.t: 1.68 min
Step D: Compound (4)
[1068] A suspension of compound 5 (60 mg, 0.15 mmol), the
corresponding bromide R.sup.1--Br (0.17 mmol), Pd(dppf)Cl.sub.2 (6
mg) in dioxane (1.5 mL) and H.sub.2O (1.5 mL) was stirred at room
temperature for 2 min. and then heated with microwave irradiation
at 100.degree. C. for 20 min. Upon completion, the mixture was
concentrated and the residue was purified by prep-HPLC to give
compound 4.
[1069] The following compounds of the Examples 21 to 98 listed
below were prepared in an analogous manner.
TABLE-US-00001 Ex. IUPAC-Name physico-chemical data 21
7-Phenyl-2-(2- .sup.1H NMR (DMSO-d.sub.6): .delta. 8.29 (d, J = 8.4
Hz, 1H), quinolin-2-yl-ethyl)- 7.94 (d, J = 6.4 Hz, 1H), 7.90 (d, J
= 5.2 Hz, 1H), 7.61 (d, J = 7.2 Hz, 2,3-dihydro-isoindol- 1H), 7.56
(s, 1H), 7.54 (s, 1H), 7.48 (d, J = 8 Hz, 1-one 1H), 7.4 (m, 2H),
7.36 (m, 4H), 4.5 (s, 2H), 3.96 (t, J = 8 Hz, 1H), 3.29 (s, 2H);
LCMS (ESI+): m/z 365 (M + H).sup.+, R.sub.t: 1.72 min. 22
7-(4-Fluoro-phenyl)- .sup.1H NMR (DMSO-d.sub.6): .delta. 8.61 (m,
1H), 8.10 (d, J = 8 Hz, 2-(2-quinolin-2-yl- 1H), 8.0 (d, J = 8.4
Hz, 1H), 7.89 (t, J = 7.2 Hz, ethyl)-2,3-dihydro- 1H), 7.74 (t, J =
7.2 Hz, 2H), 7.63 (d, J = 8 Hz, 1H), isoindol-1-one 7.59 (d, J =
2.8 Hz, 1H), 7.35 (t, J = 9.2 Hz, 3H), 7.1 (t, J = 8.8 Hz, 2H), 4.5
(s, 2H), 3.9 (t, J = 7.2 Hz, 2H), 3.38 (t, J = 8.8 Hz, 2H); LCMS
(ESI+): m/z 383 (M + H).sup.+, R.sub.t: 1.74 min. 23 7-(4-Methoxy-
.sup.1H NMR (DMSO-d.sub.6): .delta. 8.59 (d, J = 4 Hz, 1H), 8.08
(d, phenyl)-2-(2-quinolin- J = 8 Hz, 1H), 8.00 (d, J = 8 Hz, 1H),
7.85 (t, J = 7.2 Hz, 2-yl-ethyl)-2,3- 1H), 7.68 (m, 2H), 7.58 (t, J
= 8 Hz, 1H), 7.56 (d, J = 13.2 Hz, dihydro-isoindol-1- 1H), 7.28
(m, 3H), 6.85 (m, 2H), 4.52 (s, one 2H), 3.98 (t, J = 7.2 Hz, 2H),
3.77 (s, 3H), 3.63 (t, J = 6.8 Hz, 2H); LCMS (ESI+): m/z 395 (M +
H).sup.+, R.sub.t: 1.72 min. 24 2-(2-Quinolin-2-yl- .sup.1H NMR
(MeOD-d.sub.4): .delta. 8.17 (d, J = 8.4 Hz, 1H),
ethyl)-7-thiophen-2- 7.83 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 10.8
Hz, 1H), 7.61 (t, J = 6.8 Hz, yl-2,3-dihydro- 1H), 7.43 (m, 3H),
7.35 (m, 4H), 6.99 (d, J = 4 Hz, isoindol-1-one 1H), 4.35 (s, 2H),
3.98 (t, J = 7.2 Hz, 2H), 3.25 (t, J = 7.2 Hz, 2H); LCMS (ESI+):
m/z 371 (M + H).sup.+, R.sub.t: 1.70 min. 25 2-(2-Quinolin-2-yl-
.sup.1H NMR (DMSO-d.sub.6): .delta. 8.30 (d, J = 6.8 Hz, 1H),
ethyl)-7-thiophen-3- 7.92 (m, 2H), 7.82 (d, J = 1.6 Hz, 1H), 7.71
(t, J = 2 Hz, yl-2,3-dihydro- 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.56
(d, J = 3.6 Hz, 1H), isoindol-1-one 7.51 (m, 4H), 7.39 (d, J = 1.2
Hz, 1H), 4.49 (s, 2H), 3.98 (t, J = 7.2 Hz, 2H), 3.28 (t, J = 8.8
Hz, 2H); LCMS (ESI+): m/z 371 (M + H).sup.+, R.sub.t: 1.70 min. 26
7-(3-Methoxy- .sup.1H NMR (DMSO-d.sub.6): .delta. 8.30 (d, J = 4.8
Hz, 1H), phenyl)-2-(2-quinolin- 7.93 (d, J = 8.4 Hz, 1H), 7.90 (d,
J = 8.8 Hz, 2H), 7.71 (d, J = 1.6 Hz, 2-yl-ethyl)-2,3- 1H), 7.56
(m, 3H), 7.48 (d, J = 8.4 Hz, 1H), dihydro-isoindol-1- 7.35 (d, J =
0.8 Hz, 1H), 7.34 (d, J = 1.2 Hz, 1H), one 7.26 (t, J = 8.4 Hz,
1H), 6.97 (m, 2H), 6.91 (d, J = 1.2 Hz, 1H), 4.51 (s, 2H), 3.96 (d,
J = 6.8 Hz, 2H), 3.72 (s, 3H), 3.26 (t, J = 7.2 Hz, 2H); LCMS
(ESI+): m/z 395 (M + H).sup.+, R.sub.t: 1.71 min. 27
7-(3-Fluoro-phenyl)- .sup.1H NMR (DMSO-d.sub.6): .delta. 8.28 (d, J
= 8.4 Hz, 1H), 2-(2-quinolin-2-yl- 7.94 (d, J = 7.6 Hz, 1H), 7.89
(d, J = 8.4 Hz, 1H), 7.70 (t, J = 6.8 Hz, ethyl)-2,3-dihydro- 1H),
7.60 (m, 2H), 7.54 (t, J = 6.8 Hz, 1H), isoindol-1-one 7.48 (d, J =
8.8 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 6.8 Hz, 1H),
7.24 (s, 1H), 7.22 (d, J = 2.8 Hz, 1H), 7.19 (d, J = 10.8 Hz, 1H),
4.52 (s, 2H), 3.97 (t, J = 6.8 Hz, 2H), 3.27 (t, J = 7.2 Hz, 2H);
LCMS (ESI+): m/z 383 (M + H).sup.+, R.sub.t: 1.74 min. 28
7-(2-Methoxy- .sup.1H NMR (DMSO-d.sub.6): .delta. 8.28 (d, J = 8.4
Hz, 1H), phenyl)-2-(2-quinolin- 7.93 (d, J = 3.6 Hz, 1H), 7.91 (d,
J = 3.6 Hz, 1H), 7.71 (t, J = 7.2 Hz, 2-yl-ethyl)-2,3- 1H), 7.56
(d, J = 6.8 Hz, 1H), 7.51 (t, J = 7.2 Hz, dihydro-isoindol-1- 2H),
7.47 (d, J = 8.4 Hz, 1H), 7.31 (t, J = 4.8 Hz, one 1H), 7.21 (d, J
= 6.4 Hz, 1H), 7.05 (d, J = 7.2 Hz, 1H), 7.01 (d, J = 8 Hz, 1H),
6.92 (t, J = 6.8 Hz, 1H), 4.47 (s, 2H), 3.92 (t, J = 6.8 Hz, 2H),
3.55 (s, 3H), 3.24 (t, J = 7.2 Hz, 2H); LCMS (ESI+): m/z 395 (M +
H).sup.+, R.sub.t: 1.75 min. 29 7-(2-Fluoro-phenyl)- .sup.1H NMR
(DMSO-d.sub.6): .delta. 8.28 (d, J = 8.0 Hz, 1H),
2-(2-quinolin-2-yl- 7.92 (t, J = 8 Hz, 2H), 7.71 (t, J = 7.2, 1H),
7.63 (m, 2H), ethyl)-2,3-dihydro- 7.55 (t, J = 8 Hz, 1H), 7.47 (d,
J = 8.8 Hz, 1H), isoindol-1-one 7.39 (m, 1H), 7.32 (d, J = 6.4 Hz,
1H), 7.31 (d, J = 5.6 Hz, 1H), 7.22 (d, J = 2.8 Hz, 1H), 7.21 (d, J
= 6.4 Hz, 1H), 4.52 (s, 2H), 3.94 (t, J = 7.2 Hz, 2H), 3.25 (t, J =
7.2 Hz, 2H); LCMS (ESI+): m/z 383 (M + H).sup.+, R.sub.t: 1.69 min.
30 7-Pyridin-3-yl-2-(2- .sup.1H NMR (DMSO-d.sub.6): .delta. 8.60
(d, J = 2 Hz, 1H), 8.54 (d, quinolin-2-yl-ethyl)- J = 5.2 Hz, 1H),
8.29 (d, J = 9.2 Hz, 1H), 7.94 (d, J = 6.8 Hz,
2,3-dihydro-isoindol- 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.82 (d, J =
7.2 Hz, 1-one 1H), 7.72 (d, J = 6.8 Hz, 1H), 7.68 (d, J = 3.2 Hz,
1H), 7.66 (d, J = 7.2 Hz, 1H), 7.64 (t, J = 4.8 Hz, 1H), 7.54 (t, J
= 7.2 Hz, 1H), 7.52 (d, J = 160 Hz, 1H), 7.40 (d, J = 5.2 Hz, 1H),
7.39 (d, J = 5.2 Hz, 1H), 4.52 (s, 2H), 3.94 (t, J = 7.2 Hz, 2H),
3.25 (t, J = 7.2 Hz, 2H); LCMS (ESI+): m/z 366 (M + H).sup.+,
R.sub.t: 1.263 min. 31 7-Furan-2-yl-2-(2- .sup.1H NMR
(DMSO-d.sub.6): .delta. 8.30 (d, J = 8.4 Hz, 1H),
quinolin-2-yl-ethyl)- 7.95 (d, J = 3.6 Hz, 1H), 7.94 (s, 1H), 7.92
(s, 1H), 7.84 (d, J = 8.4 Hz, 2,3-dihydro-isoindol- 1H), 7.78 (s,
1H), 7.72 (t, J = 7.6 Hz, 1H), 1-one 7.61 (t, J = 7.6 Hz, 1H), 7.56
(d, J = 8.0 Hz, 1H), 7.53 (d, J = 5.2 Hz, 1H), 7.49 (s, 1H), 7.47
(s, 1H), 7.45 (s, 1H), 4.50 (s, 2H), 4.02 (t, J = 7.2 Hz, 2H), 3.29
(t, J = 7.2 Hz, 2H); LCMS (ESI+): m/z 355 (M + H).sup.+, R.sub.t:
1.68 min. 32 7-(3-Fluoro-4- .sup.1H NMR (DMSO-d.sub.6): .delta.
8.29 (d, J = 8.4 Hz, 1H), methoxy-phenyl)-2- 7.94 (d, J = 7.6 Hz,
1H), 7.89 (d, J = 8.8 Hz, 1H), 7.70 (t, J = 6.8 Hz,
(2-quinolin-2-yl- 1H), 7.61 (d, J = 7.2 Hz, 1H), 7.57 (d, J = 3.6
Hz, ethyl)-2,3-dihydro- 1H), 7.54 (d, J = 6 Hz, 1H), 7.54 (d, J =
8.4 Hz, isoindol-1-one 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.34 (d, J =
6.8 Hz, 1H), 7.29 (d, J = 13.2 Hz, 1H), 7.21 (d, J = 9.2 Hz, 1H),
7.15 (t, J = 8.4 Hz, 1H), 4.50 (s, 2H), 3.97 (t, J = 6.8 Hz, 3.87
(s, 3H), 2H), 3.28 (t, J = 8.8 Hz, 2H); LCMS (ESI+): m/z 413 (M +
H).sup.+, R.sub.t: 1.74 min. 33 7-(3,4-Difluoro- .sup.1H NMR
(DMSO-d.sub.6): .delta. 8.29 (d, J = 8.4 Hz, 1H),
phenyl)-2-(2-quinolin- 7.94 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0
Hz, 1H), 7.70 (t, J = 7.2 Hz, 2-yl-ethyl)-2,3- 1H), 7.62 (t, J =
7.6 Hz, 1H), 7.60 (s, 1H), dihydro-isoindol-1- 7.54 (t, J = 7.6 Hz,
1H), 7.48 (d, J = 8.4 Hz, 1H), one 7.47 (d, J = 8.0 Hz, 1H), 7.43
(d, J = 8.4 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 7.24 (m, 1H), 4.52
(s, 2H), 3.97 (t, J = 7.2 Hz, 2H), 3.27 (t, J = 7.2 Hz, 2H); LCMS
(ESI+): m/z 401 (M + H).sup.+, R.sub.t: 1.77 min. 34
7-Benzo[1,3]dioxol-5- .sup.1H NMR (DMSO-d.sub.6): .delta. 8.29 (d,
J = 8.4 Hz, 1H), yl-2-(2-quinolin-2-yl- 7.94 (d, J = 7.2 Hz, 1H),
7.90 (d, J = 4.8 Hz, 1H), 7.70 (t, J = 7.2 Hz, ethyl)-2,3-dihydro-
1H), 7.58 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 2.4, isoindol-1-one
1H), 7.52 (d, J = 7.2 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.31 (d, J
= 6.8 Hz, 1H), 6.97 (d, J = 1.2 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H),
6.89 (d, J = 1.2 Hz, 1H), 6.87 (d, J = 1.6 Hz, 1H), 4.49 (s, 2H),
3.96 (t, J = 7.2 Hz, 2H), 3.26 (t, J = 7.2 Hz, 2H); LCMS (ESI+):
m/z 409 (M + H).sup.+, R.sub.t: 1.71 min. 35 7-(2,3-Dihydro-benzo-
.sup.1H NMR (DMSO-d.sub.6): .delta. 8.62-8.60 (m, 1H), 8.10 (d, J =
8.4 Hz, [1,4]dioxin-6-yl)-2-(2- 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.88
(t, J = 4.8 Hz, quinolin-2-yl-ethyl)- 1H), 7.73-7.69 (m, 2H), 7.57
(t, J = 7.6 Hz, 1H), 2,3-dihydro-isoindol- 7.52 (d, J = 7.6 Hz,
1H), 7.29 (d, J = 7.2 Hz, 1H), 1-one 6.87 (d, J = 1.2 Hz, 1H), 6.74
(s, 1H), 4.52 (s, 2H), 3.99 (t, J = 7.2 Hz, 2H), 3.38 (t, J = 7.2
Hz, 2H); LCMS (ESI+): m/z 423 (M + H).sup.+, R.sub.t: 1.70 min. 36
7-(3,4-Dimethoxy- .sup.1H NMR (DMSO-d.sub.6): .delta. 8.28 (d, J =
8.4 Hz, 1H), phenyl)-2-(2-quinolin- 7.93 (d, J = 8.0 Hz, 1H), 7.89
(d, J = 8.8 Hz, 1H), 7.70 (t, J = 8.4 Hz, 2-yl-ethyl)-2,3- 1H),
7.57 (t, J = 7.6 Hz, 1H), 7.52 (t, J = 7.6 Hz dihydro-isoindol-1-
2H), 7.48 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 7.6 Hz, one 1H), 7.03
(s, 1H), 6.95 (d, J = 2 Hz, 1H), 6.94 (s, 1H), 4.50 (s, 2H), 3.97
(t, J = 7.2 Hz, 2H), 3.78 (s, 3H), 3.67 (s, 3H), 3.26 (t, J = 7.2
Hz, 2H); LCMS (ESI+): m/z 425 (M + H).sup.+, R.sub.t: 1.66 min. 37
7-(2,4-Dimethoxy- .sup.1H NMR (DMSO-d.sub.6): .delta. 8.28 (d, J =
8.4 Hz, 1H), phenyl)-2-(2-quinolin- 7.93 (d, J = 8.0 Hz, 1H), 7.71
(t, J = 7.2 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2-yl-ethyl)-2,3- 1H),
7.52 (d, J = 7.6 Hz, 1H), 7.47 (s, 1H), dihydro-isoindol-1- 7.45
(s, 1H), 7.18 (d, J = 7.2 Hz, 1H), 6.98 (d, J = 8.4 Hz, one 1H),
6.56 (d, J = 2 Hz, 1H), 6.51 (d, J = 8.4 Hz, 1H), 4.45 (s, 2H),
3.92 (t, J = 7.2 Hz, 2H), 3.79 (s, 3H), 3.54 (s, 3H), 3.24 (t, J =
7.2 Hz, 2H); LCMS (ESI+): m/z 425 (M + H).sup.+, R.sub.t: 1.73 min.
38 7-(4-Dimethylamino- .sup.1H NMR (DMSO-d.sub.6): .delta. 8.29 (d,
J = 8.8 Hz, 1H), phenyl)-2-(2-quinolin- 7.92 (d, J = 8.0 Hz, 1H),
7.71 (t, J = 8.4 Hz, 1H), 2-yl-ethyl)-2,3- 7.56-7.51 (m, 2H), 7.48
(d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.0 Hz, dihydro-isoindol-1- 1H),
7.31-7.27 (m, 3H), 6.71 (d, J = 8.8 Hz, 1H), one 4.47 (s, 2H), 3.96
(t, J = 7.2 Hz, 2H), 3.26 (t, J = 7.2 Hz, 2H), 2.96 (s, 3H); LCMS
(ESI+): m/z 408 (M + H).sup.+, R.sub.t: 1.4 min. 39
7-(4-Methoxy-pyridin- .sup.1H NMR (MeOD-d.sub.4): .delta. 8.30 (d,
J = 4.4 Hz, 1H), 3-yl)-2-(2-quinolin-2- 8.14 (d, J = 8.4 Hz, 1H),
7.99 (s, 1H), 7.82 (d, J = 8.4 Hz, yl-ethyl)-2,3-dihydro- 1H), 7.78
(d, J = 7.6 Hz, 1H), 7.61 (t, J = 6.8 Hz,, 1H), isoindol-1-one 7.50
(t, J = 7.6 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz,
1H), 7.18 (d, J = 7.2 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H), 4.37 (s,
2H), 3.93 (t, J = 7.2 Hz, 2H), 3.55 (s, 3H), 3.21 (t, J = 7.2 Hz,
2H); LCMS (ESI+): m/z 396 (M + H).sup.+, R.sub.t: 1.3 min. 40
7-(3,5-Difluoro- .sup.1H NMR (DMSO-d.sub.6): .delta. 8.29 (d, J =
8.4 Hz, 1H), phenyl)-2-(2-quinolin- 7.93 (d, J = 7.6 Hz, 1H), 7.87
(d, J = 8.0 Hz, 1H), 7.69 (t, J = 7.2 Hz, 2-yl-ethyl)-2,3- 1H),
7.64 (d, J = 2 Hz, 1H), 7.62 (s, 1H), dihydro-isoindol-1- 7.54 (t,
J = 6.8 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.41 (m, one 1H), 7.22
(t, J = 9.6 Hz, 1H), 7.12 (d, J = 2 Hz, 1H), 7.10 (d, J = 2 Hz,
1H), 4.53 (s, 2H), 3.97 (t, J = 7.2 Hz, 2H), 3.27 (t, J = 7.2 Hz,
2H); LCMS (ESI+): m/z 401 (M + H).sup.+, R.sub.t: 1.79 min. 41
7-(2,5-Dimethoxy- .sup.1H NMR (MeOD-d.sub.4): .delta. 8.18 (d, J =
2.2 Hz, 1H), phenyl)-2-(2-quinolin- 7.89 (d, J = 8.4 Hz, 1H), 7.82
(d, J = 8.0 Hz, 1H), 7.66 (t, J = 7.2 Hz, 2-yl-ethyl)-2,3- 1H),
7.48 (t, J = 7.6 Hz, 1H), 7.39 (t, J = 8.8 Hz, dihydro-isoindol-1-
1H), 7.18 (d, J = 7.2 Hz, 1H), 6.82 (s, 2H), 6.61 (s, one 1H), 7.43
(d, J = 8.4 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 7.24 (m, 2H), 4.37
(s, 2H), 3.97 (t, J = 7.2 Hz, 2H), 3.65 (s, 3H), 3.44 (s, 3H), 3.28
(d, J = 11.2 Hz, 2H); LCMS (ESI+): m/z 425 (M + H).sup.+, R.sub.t:
1.71 min. 42 2-[3-Oxo-2-(2- .sup.1H NMR (DMSO-d.sub.6): .delta.
8.29 (d, J = 8.4 Hz, 1H), quinolin-2-yl-ethyl)- 7.94 (s, 1H), 7.92
(s, 1H), 7.72 (t, J = 8.4 Hz, 1H), 2,3-dihydro-1H- 7.57-7.51 (m,
3H), 7.51 (d, J = 6 Hz, 1H), 7.35 (s, 1H), isoindol-4-yl]-pyrrole-
7.31 (d, J = 6 Hz, 1H), 6.23 (t, J = 3.2 Hz, 1H), 1-carboxylic acid
tert- 6.16-6.15 (m, 1H), 4.49 (s, 2H), 3.94 (t, J = 7.2 Hz, 2H),
3.25 (t, J = 7.2 Hz, butyl ester 2H), 1.07 (s, 9H); LCMS (ESI+):
m/z 454 (M + H).sup.+, R.sub.t: 1.86 min. 43 7-(3-Dimethylamino-
.sup.1H NMR (DMSO-d.sub.6): .delta. 8.27 (d, J = 8.4 Hz, 1H),
phenyl)-2-(2-quinolin- 7.93 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.8
Hz, 1H), 7.70 (t, J = 10 Hz, 2-yl-ethyl)-2,3- 1H), 7.59 (d, J = 7.2
Hz, 1H), 7.53 (d, J = 6.8 Hz dihydro-isoindol-1- 1H), 7.47 (d, J =
7.6 Hz, 1H), 7.33 (d, J = 6.4 Hz, one 1H), 7.15 (t, J = 7.6 Hz,
1H), 6.74 (br, 1H), 6.72 (d, J = 2.8 Hz, 1H), 6.69 (d, J = 7.6 Hz,
1H), 4.50 (s, 2H), 3.96 (t, J = 7.2 Hz, 2H), 3.26 (t, J = 7.2 Hz,
2H), 2.85 (br, 6H); LCMS (ESI+): m/z 408 (M + H).sup.+, R.sub.t:
1.4 min. 44 7-(2-Dimethylamino- .sup.1H NMR (DMSO-d.sub.6): .delta.
8.88 (d, J = 8.4 Hz, 1H), phenyl)-2-(2-quinolin- 8.22 (d, J = 8.4
Hz, 1H), 8.10-8.07 (m, 2H), 7.94 (d, J = 8.8 Hz, 2-yl-ethyl)-2,3-
1H), 7.89 (t, J = 6 Hz, 1H), 7.80 (t, J = 2.8 Hz 3H),
dihydro-isoindol-1- 7.62 (t, J = 8.0 Hz, 1H), 7.47 (t, J = 7.6 Hz,
1H),
one 7.43 (t, J = 6 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 4.26 (d, J =
8.0 Hz 1H), 4.06 (d, J = 7.2 Hz 1H), 3.60 (t, J = 6 Hz, 2H), 3.07
(br, 6H); LCMS (ESI+): m/z 408 (M + H).sup.+, R.sub.t: 1.37 min. 45
7-(2,4-Difluoro- .sup.1H NMR (DMSO-d.sub.6): .delta. 8.28 (d, J =
8.4 Hz, 1H), phenyl)-2-(2-quinolin- 7.91 (t, J = 8.4 Hz, 2H), 7.71
(t, J = 7.2 Hz, 1H), 7.64 (d, J = 6 Hz, 2-yl-ethyl)-2,3- 1H), 7.62
(d, J = 6 Hz, 1H), 7.54 (t, J = 7.6 Hz, dihydro-isoindol-1- 1H),
7.47 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 6.4 Hz, 2H), one 7.24 (t, J
= 10 Hz, 1H), 7.10 (t, J = 9.2 Hz, 1H), 4.52 (s, 2H), 3.94 (t, J =
7.2 Hz, 2H), 3.25 (t, J = 7.2 Hz, 2H); LCMS (ESI+): m/z 401 (M +
H).sup.+, R.sub.t: 1.74 min. 46 7-Furan-3-yl-2-(2- .sup.1H NMR
(DMSO-d.sub.6): .delta. 8.14 (d, J = 8.4 Hz, 1H),
quinolin-2-yl-ethyl)- 8.01 (br, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.77
(d, J = 8.4 Hz, 2,3-dihydro-isoindol- 1H), 7.59 (t, J = 6 Hz, 1H),
7.44-7.37 (br, 5H), 7.26 (d, 1-one J = 6.8 Hz 1H), 6.68 (br, 1H),
4.29 (br, 2H), 3.95 (d, J = 7.2 Hz, 2H), 3.23 (t, J = 6.8 Hz, 2H);
LCMS (ESI+): m/z 355 (M + H).sup.+, R.sub.t: 1.65 min. 47
7-(1H-Indol-5-yl)-2- .sup.1H NMR (DMSO-d.sub.6): .delta. 8.29 (d, J
= 8.4 Hz, 1H), (2-quinolin-2-yl- 7.94 (d, J = 8.0 Hz, 1H), 7.88 (d,
J = 8.0 Hz, 1H), 7.70 (t, J = 7.2 Hz, ethyl)-2,3-dihydro- 1H), 7.62
(t, J = 7.6 Hz, 1H), 7.60 (s, 1H), isoindol-1-one 7.54 (t, J = 7.6
Hz, 1H), 7.48 (d, J = 8.4. Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.43
(d, J = 8.4 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 7.24 (m 4.50 (s,
2H), 3.96 (t, J = 7.2 Hz, 2H), 3.26 (t, J = 7.2 Hz, 2H); LCMS
(ESI+): m/z 404 (M + H).sup.+, R.sub.t: 1.68 min. 48
7-(4-Methyl-thiophen- .sup.1H NMR (DMSO-d.sub.6): .delta. 11.08
(br, 1H), 8.29 (d, J = 8.4 Hz, 2-yl)-2-(2-quinolin-2- 1H), 7.94 (d,
J = 8.4 Hz, 1H), 7.91 (d, J = 8.4 Hz, yl-ethyl)-2,3-dihydro- 1H),
7.71 (t, J = 6.4 Hz, 1H), 7.59-7.53 (br, 3H), 7.48 (t,
isoindol-1-one J = 6.8 Hz, 2H), 7.35-7.33 (br, 3H), 7.16 (d, J =
8.0 Hz, 1H), 6.41 (br, 1H), 4.50 (s, 2H), 3.96 (t, J = 7.2 Hz, 2H),
3.29 (br, 3H), 3.26 (t, J = 7.2 Hz, 2H); LCMS (ESI+): m/z 385 (M +
H).sup.+, R.sub.t: 1.78 min. 49 {4-[3-Oxo-2-(2- .sup.1H NMR
(DMSO-d.sub.6): .delta. 8.66 (d, J = 7.2 Hz, 1H),
quinolin-2-yl-ethyl)- 8.13 (d, J = 8.0 Hz, 1H), 8.03 (d, J = 8.0
Hz, 1H), 7.90 (t, J = 7.2 Hz, 2,3-dihydro-1H- 1H), 7.66 (d, J = 3.6
Hz, 1H), 7.73 (d, J = 8.0 Hz, isoindol-4-yl]- 1H), 7.64-7.58 (br,
2H), 7.31 (t, J = 6.8 Hz, 3H), phenyl}-acetonitrile 7.25 (d, J =
8.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H),
7.24 (m, 2H), 4.56 (s, 2H), 4.09 (br, 2H), 3.99 (t, J = 7.2 Hz,
2H), 3.4 (t, J = 7.2 Hz, 2H); LCMS (ESI+): m/z 404 (M + H).sup.+,
R.sub.t: 1.65 min. 50 7-(2,3-Difluoro- .sup.1H NMR (DMSO-d.sub.6):
.delta. 8.28 (d, J = 8.4 Hz, 1H), phenyl)-2-(2-quinolin- 7.92 (d, J
= 8.0 Hz, 1H), 7.90 (d, J = 80 Hz, 1H), 7.71 (t, J = 7.2 Hz,
2-yl-ethyl)-2,3- 1H), 7.69 (d, J = 7.6 Hz, 2H), 7.54 (t, J = 6.8
Hz, dihydro-isoindol-1- 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.35 (t, J =
3.2 Hz, one 1H), 7.25 (t, J = 8.0 Hz, 1H), 7.17-7.13 (br, 1H), 4.53
(s, 2H), 3.95 (t, J = 7.2 Hz, 2H), 3.25 (t, J = 7.2 Hz, 2H); LCMS
(ESI+): m/z 401 (M + H).sup.+, R.sub.t: 1.74 min. 51
7-(2,5-Difluoro- .sup.1H NMR (MeOD-d.sub.4): .delta. 8.27 (d, J =
8.4 Hz, 1H), phenyl)-2-(2-quinolin- 7.91 (t, J = 9.6 Hz, 2H), 7.73
(d, J = 8.0 Hz, 1H), 7.64 (t, J = 7.2 Hz, 2-yl-ethyl)-2,3- 1H),
7.58 (d, J = 7.6 Hz, 2H), 7.50 (d, J = 8.8 Hz, dihydro-isoindol-1-
1H), 7.36 (d, J = 8.4 Hz, 1H), 7.11 (t, J = 6.8 Hz, one 2H), 6.99
(t, J = 3.6 Hz, 1H), 4.06 (t, J = 7.2 Hz, 2H), 3.35 (t, J = 7.2 Hz,
2H); LCMS (ESI+): m/z 401 (M + H).sup.+, R.sub.t: 1.74 min. 52
7-(5-Fluoro-2- .sup.1H NMR (DMSO-d.sub.6): .delta. 8.588 (br, 1H),
8.08 (d, J = 8.4 Hz, methoxy-phenyl)-2- 1H), 8.01 (d, J = 8.0 Hz,
1H), 7.86 (t, J = 7.2 Hz, (2-quinolin-2-yl- 1H), 7.70 (d, J = 7.2
Hz, 1H), 7.57 (t, J = 6 Hz, 1H), ethyl)-2,3-dihydro- 7.25 (d, J =
8.4 Hz, 1H), 7.13 (d, J = 6 Hz, 1H), isoindol-1-one 6.99 (d, J =
9.2 Hz, 1H), 6.86 (d, J = 9.2 Hz, 1H), 4.52 (s, 2H), 3.96 (t, J =
7.2 Hz, 2H), 3.36 (t, J = 7.2 Hz, 2H); LCMS (ESI+): m/z 413 (M +
H).sup.+, R.sub.t: 1.74 min. 53 7-(1H-Pyrazol-3-yl)- .sup.1H NMR
(MeOD-d.sub.4): .delta. 8.17 (d, J = 8.4 Hz, 1H),
2-(2-quinolin-2-yl- 7.85 (d, J = 10.8 Hz, 1H), 7.80 (d, J = 8.0 Hz,
1H), 7.79 (d, J = 7.2 Hz, ethyl)-2,3-dihydro- 1H), 7.60 (t, J = 7.6
Hz, 1H), 7.54 (t, J = 7.6 Hz, isoindol-1-one 1H), 7.45 (br, 1H),
7.44 (s, 1H), 7.42 (s, 1H), 7.37 (d, J = 7.2 Hz, 1H), 6.78 (br,
1H), 4.45 (s, 2H), 4.03 (t, J = 7.2 Hz, 2H), 3.31 (t, J = 7.2 Hz,
2H); LCMS (ESI+): m/z 355 (M + H).sup.+, R.sub.t: 1.47 min. 54
7-(6-Methoxy-pyridin- .sup.1H NMR (DMSO-d.sub.6): .delta. 8.29 (d,
J = 8.4 Hz, 1H), 3-yl)-2-(2-quinolin-2- 8.21 (d, J = 2 Hz, 1H),
7.94 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 4.4 Hz,
yl-ethyl)-2,3-dihydro- 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.70 (t, J =
8.4 Hz, isoindol-1-one 1H), 7.62 (t, J = 8.4 Hz, 1H), 7.58 (d, J =
8.4 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H),
7.37 (d, J = 7.2 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 4.51 (s, 2H),
3.97 (t, J = 7.2 Hz, 2H), 3.89 (br, 3H), 3.27 (t, J = 7.2 Hz, 2H);
LCMS (ESI+): m/z 396 (M + H).sup.+, R.sub.t: 1.55 min. 55
7-(2-Fluoro-3- .sup.1H NMR (DMSO-d.sub.6): .delta. 8.57 (m, 1H),
8.08 (d, J = 8.4 Hz, methoxy-phenyl)-2- 1H), 8.01 (d, J = 80 Hz,
1H), 7.86 (t, J = 4.8 Hz, (2-quinolin-2-yl- 1H), 7.69 (m, 2H), 7.63
(d, J = 7.6 Hz, 1H), 7.63 (br, ethyl)-2,3-dihydro- 1H), 7.31 (d, J
= 8.4 Hz, 1H), 7.13 (t, J = 8.0 Hz, 1H), isoindol-1-one 7.07 (t, J
= 7.2 Hz, 1H), 6.75 (t, J = 8.4 Hz, 1H), 4.55 (s, 2H), 3.96 (t, J =
7.2 Hz, 2H), 3.83 (br, 3H), 3.35 (t, J = 9.2 Hz, 2H); LCMS (ESI+):
m/z 413 (M + H).sup.+, R.sub.t: 1.71 min. 56 7-(2,3-Dihydro-
.sup.1H NMR (DMSO-d.sub.6): .delta. 8.28 (d, J = 8.4 Hz, 1H),
benzofuran-5-yl)-2-(2- 7.94 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.4
Hz, 1H), 7.70 (t, J = 7.2 Hz, quinolin-2-yl-ethyl)- 1H), 7.57 (d, J
= 7.6 Hz, 1H), 7.54 (d, J = 7.2 Hz, 2,3-dihydro-isoindol- 1H), 7.48
(t, J = 8.4 Hz, 2H), 7.28 (d, J = 8.0 Hz, 1-one 1H), 7.24 (br, 1H),
7.14 (d, J = 7.2 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 4.49 (s, 2H),
4.55 (t, J = 7.2 Hz, 2H), 3.96 (t, J = 7.2 Hz, 2H), 3.24 (t, J =
9.2 Hz, 2H), 3.14 (t, J = 8.4 Hz, 2H); LCMS (ESI+): m/z 407 (M +
H).sup.+, R.sub.t: 1.72 min. 57 7-(2,3-Dimethoxy- .sup.1H NMR
(DMSO-d.sub.6): .delta. 8.26 (d, J = 8.4 Hz, 1H),
phenyl)-2-(2-quinolin- 7.90 (t, J = 8.0 Hz, 2H), 7.70 (t, J = 8.0
Hz, 1H), 7.53 (br, 2-yl-ethyl)-2,3- 3H), 7.45 (d, J = 7.6 Hz, 1H),
7.18 (d, J = 7.6 Hz, 1H), dihydro-isoindol-1- 7.03 (d, J = 8.4 Hz,
1H), 6.99 (t, J = 8.4 Hz, 1H), one 6.64 (d, J = 8.4 Hz, 1H), 4.55
(s, 2H), 3.92 (t, J = 7.2 Hz, 2H), 3.81 (br, 3H), 3.30 (br, 3H),
3.26 (t, J = 7.2 Hz, 2H); LCMS (ESI+): m/z 425 (M + H).sup.+,
R.sub.t: 1.67 min. 58 7-Pyrimidin-5-yl-2-(2- .sup.1H NMR
(DMSO-d.sub.6): .delta. 9.13 (br, 1H), 8.78 (br, 1H),
quinolin-2-yl-ethyl)- 8.62 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 8.0
Hz, 1H), 2,3-dihydro-isoindol- 7.99 (d, J = 8.0 Hz, 1H), 7.88 (t, J
= 7.2 Hz, 1H), 7.72 (br, 1-one 4H), 7.50 (d, J = 7.6 Hz, 1H), 4.59
(s, 2H), 4.01 (t, J = 7.2 Hz, 2H), 3.39 (t, J = 7.2 Hz, 2H); LCMS
(ESI+): m/z 367 (M + H).sup.+, R.sub.t: 1.38 min. 59
7-(6-Morpholin-4-yl- .sup.1H NMR (CDCl.sub.3-dl): .delta. 8.73 (d,
J = 8.4 Hz, 1H), pyridin-3-yl)-2-(2- 8.55 (d, J = 8.0 Hz, 1H), 8.38
(d, J = 2 Hz, 1H), 8.06 (d, J = 7.2 Hz, quinolin-2-yl-ethyl)- 1H),
8.04 (d, J = 7.6 Hz, 1H), 8.02 (d, J = 5.6 Hz,
2,3-dihydro-isoindol- 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.82 (d, J =
8.4 Hz, 1-one 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.4 Hz,
1H), 7.34 (d, J = 7.2 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 4.60 (s,
2H), 4.172 (t, J = 7.2 Hz, 2H), 3.90 (br, 5H), 3.76 (br, 6H); LCMS
(ESI+): m/z 451 (M + H).sup.+, R.sub.t: 1.36 min. 60
7-(3-Methanesulfonyl- .sup.1H NMR (DMSO-d.sub.6): .delta. 8.05 (d,
J = 8.4 Hz, 1H), phenyl)-2-(2-quinolin- 7.37 (d, J = 8.0 Hz, 1H),
7.21 (br, 2H), 6.99 (br, 4H), 2-yl-ethyl)-2,3- 6.79 (d, J = 7.6 Hz,
1H), 6.75 (d, J = 7.6 Hz, 1H), 6.67 (s, dihydro-isoindol-1- 1H),
6.63 (d, J = 8.4 Hz, 1H), 6.53 (d, J = 8.0 Hz, 1H), one H), 3.79
(s, 2H), 3.25 (t, J = 7.2 Hz, 2H), 2.718 (t, J = 7.2 Hz, 2H), 2.09
(br, 3H); LCMS (ESI+): m/z 443 (M + H).sup.+, R.sub.t: 1.56 min. 61
7-(2-Methoxy- .sup.1H NMR (DMSO-d.sub.6): .delta. 8.64 (s, 2H),
8.29 (d, J = 8.4 Hz, pyrimidin-5-yl)-2-(2- 1H), 7.93 (d, J = 8 Hz,
1H), 7.67 (br, 3H), 7.54 (t, J = 7.2 Hz, quinolin-2-yl-ethyl)- 1H),
7.45 (t, J = 7.6 Hz, 2H), 4.54 (s, 2H), 2,3-dihydro-isoindol- 3.98
(t, J = 7.2 Hz, 4H), 3.27 (t, J = 7.2 Hz, 2H); LCMS 1-one (ESI+):
m/z 397 (M + H).sup.+, R.sub.t: 1.5 min. 62 7-Quinolin-5-yl-2-(2-
.sup.1H NMR (DMSO-d.sub.6): .delta. 8.85 (d, J = 8.4 Hz, 1H),
quinolin-2-yl-ethyl)- 8.26 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 8.0
Hz, 1H), 7.94 (d, J = 7.2 Hz, 2,3-dihydro-isoindol- 1H), 7.86 (d, J
= 7.6 Hz, 1H), 7.76 (d, J = 6.8 Hz, 1-one 1H), 7.74 (d, J = 7.6 Hz,
1H), 7.70 (br, 3H), 7.68 (d, J = 8.0 Hz, 1H), 7.54 (t, J = 8.4 Hz,
1H), 7.42 (d, J = 7.2 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.37 (d, J
= 8.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 4.67 (q, J = 7.2 Hz, 2H),
3.86 (t, J = 7.2 Hz, 2H), 3.20 (t, J = 7.2 Hz, 2H); LCMS (ESI+):
m/z 416 (M + H).sup.+, R.sub.t: 1.36 min. 63 7-(1H-Indol-4-yl)-2-
.sup.1H NMR (DMSO-d.sub.6): .delta. 11.09 (br, 1H), 8.28 (d, J =
8.4 Hz, (2-quinolin-2-yl- 1H), 7.92 (t, J = 8.0 Hz, 2H), 7.71 (t, J
= 8.0 Hz, ethyl)-2,3-dihydro- 1H), 7.60 (t, J = 7.2 Hz, 1H), 7.56
(t, J = 7.6 Hz, 2H), isoindol-1-one 7.46 (d, J = 8.4 Hz, 1H), 7.42
(d, J = 7.6 Hz, 1H), 7.23 (t, J = 8.4 Hz, 1H), 7.05 (t, J = 8.0 Hz,
1H), 6.91 (d, J = 8.4 Hz, 1H), 6.02 (d, J = 7.2 Hz, 1H), 4.52 (s,
2H), 3.90 (t, J = 7.2 Hz, 2H), 3.24 (t, J = 7.2 Hz, 2H); LCMS
(ESI+): m/z 404 (M + H).sup.+, R.sub.t: 1.65 min. 64
7-(1H-Indol-6-yl)-2- .sup.1H NMR (DMSO-d.sub.6): .delta. 11.11 (br,
1H), 8.29 (d, J = 8.4 Hz, (2-quinolin-2-yl- 1H), 7.92 (t, J = 8.0
Hz, 2H), 7.71 (t, J = 8.0 Hz, ethyl)-2,3-dihydro- 1H), 7.60 (d, J =
7.2 Hz, 1H), 7.56 (d, J = 7.6 Hz, isoindol-1-one 1H), 7.51 (br,
5H), 7.38 (d, J = 7.6 Hz, 2H), 7.07 (d, J = 8.4 Hz, 1H), 6.44 (br,
1H), 4.50 (s, 2H), 3.96 (t, J = 7.2 Hz, 2H), 3.27 (t, J = 7.2 Hz,
2H); LCMS (ESI+): m/z 404 (M + H).sup.+, R.sub.t: 1.72 min. 65
7-(2-Methyl-pyridin- .sup.1H NMR (DMSO-d.sub.6): .delta. 8.40 (d, J
= 8.4 Hz, 1H), 4-yl)-2-(2-quinolin-2- 8.29 (d, J = 8.0 Hz, 1H),
7.94 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 7.2 Hz,
yl-ethyl)-2,3-dihydro- 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.66 (br,
2H), isoindol-1-one 7.55 (t, J = 8.4 Hz, 1H), 7.49 (t, J = 7.6 Hz,
1H), 7.38 (d, J = 8.4 Hz, 1H), 7.21 (br, 1H), 7.18 (d, J = 8.0 Hz,
1H), 4.55 (s, 2H), 3.97 (t, J = 7.2 Hz, 2H), 3.26 (t, J = 7.2 Hz,
2H), 2.46 (br, 3H); LCMS (ESI+): m/z 380 (M + H).sup.+, R.sub.t:
1.28 min. 66 7-(2-Methoxy-pyridin- .sup.1H NMR (DMSO-d.sub.6):
.delta. 8.28 (d, J = 8.4 Hz, 1H), 3-yl)-2-(2-quinolin-2- 8.16 (d, J
= 80 Hz, 1H), 7.92 (t, J = 8.0 Hz, 2H), 7.71 (t, J = 7.2 Hz,
yl-ethyl)-2,3-dihydro- 1H), 7.56 (br, 3H), 7.47 (d, J = 8.4 Hz,
2H), isoindol-1-one 7.28 (d, J = 7.6 Hz, 1H), 7.00 (d, J = 8.4 Hz,
1H), 4.49 (s, 2H), 3.93 (t, J = 7.2 Hz, 2H), 3.67 (br, 3H), 3.24
(t, J = 7.2 Hz, 2H); LCMS (ESI+): m/z 396 (M + H).sup.+, R.sub.t:
1.57 min. 67 7-(3-Methoxymethyl- .sup.1H NMR (DMSO-d.sub.6):
.delta. 8.08 (d, J = 8.4 Hz, 1H), phenyl)-2-(2-quinolin- 7.78 (d, J
= 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 7.2 Hz,
2-yl-ethyl)-2,3- 1H), 7.39 (t, J = 7.6 Hz, 2H), 7.31 (t, J = 7.6
Hz, dihydro-isoindol-1- 2H), 7.15 (br, 5H), 4.30 (s, 4H), 3.88 (t,
J = 7.2 Hz, one 2H), 3.23 (s, 3H), 3.167 (t, J = 7.2 Hz, 2H); LCMS
(ESI+): m/z 409 (M + H).sup.+, R.sub.t: 1.70 min. 68
7-Isoquinolin-4-yl-2- .sup.1H NMR (DMSO-d.sub.6): .delta. 8.92 (d,
J = 8.4 Hz, 1H), (2-quinolin-2-yl- 8.50 (d, J = 8.0 Hz, 1H), 8.42
(br, 1H), 8.28 (d, J = 8.0 Hz, ethyl)-2,3-dihydro- 1H), 8.11 (d, J
= 8.4 Hz, 1H), 8.05 (t, J = 6.8 Hz 1H), isoindol-1-one 7.96-7.844
(br, 5H), 7.63 (d, J = 7.6 Hz, 1H), 7.54 (d, J
= 8.4 Hz, 1H), 4.73 (d, J = 18 Hz, 1H), 4.58 (q, J = 7.6 Hz, 1H),
4.06 (q, J = 7.6 Hz, 1H), 3.63 (t, J = 7.2 Hz, 2H); LCMS (ESI+):
m/z 416 (M + H).sup.+, R.sub.t: 1.35 min. 69 7-(5-Methoxy-pyridin-
.sup.1H NMR (DMSO-d.sub.6): .delta. 8.28 (d, J = 8.4 Hz, 1H),
3-yl)-2-(2-quinolin-2- 8.26 (d, J = 3.2 Hz, 1H), 8.19 (d, J = 1.2
Hz, 1H), 7.93 (d, J = 5.6 Hz, yl-ethyl)-2,3-dihydro- 1H), 7.88 (d,
J = 8.4 Hz, 1H), 7.70 (t, J = 7.6 Hz, isoindol-1-one 1H), 7.65 (d,
J = 6.4 Hz, 1H), 7.64 (s, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.48 (d, J
= 8.4 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.40 (t, J = 2 Hz, 1H),
4.54 (s, 2H), 3.97 (t, J = 7.2 Hz, 2H), 3.80 (br, 3H), 3.27 (t, J =
7.2 Hz, 2H); LCMS (ESI+): m/z 396 (M + H).sup.+, R.sub.t: 1.34 min.
70 7-(1-Methyl-1H- .sup.1H NMR (DMSO-d.sub.6): .delta. 8.46 (br,
1H), 8.30 (d, J = 8.0 Hz, pyrazol-4-yl)-2-(2- 1H), 7.98 (br, 1H),
7.94 (d, J = 1.6 Hz, 1H), quinolin-2-yl-ethyl)- 7.92 (d, J = 1.6
Hz, 1H), 7.72 (t, J = 6.4 Hz 1H), 7.59 (d, J = 7.6 Hz,
2,3-dihydro-isoindol- 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.51 (d, J =
8.0 Hz, 1-one 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 7.2 Hz,
1H), 4.00 (t, J = 7.2 Hz, 2H), 3.86 (br, 3H), 3.28 (t, J = 7.2 Hz,
2H); LCMS (ESI+): m/z 369 (M + H).sup.+, R.sub.t: 1.46 min. 71
7-Isoquinolin-5-yl-2- .sup.1H NMR (MeOD-d.sub.4): .delta. 9.74 (br,
1H), 8.95 (d, J = 8.4 Hz, (2-quinolin-2-yl- 1H), 8.45 (d, J = 8.0
Hz, 1H), 8.28 (d, J = 8.0 Hz, ethyl)-2,3-dihydro- 1H), 8.25 (d, J =
7.2 Hz, 1H), 8.13 (d, J = 7.6 Hz, 1H), isoindol-1-one 8.09 (t, J =
8.4 Hz, 1H), 7.95-7.90 (br, 4H), 7.85-7.82 (br, 3H), 7.46 (t, J =
8.40 Hz, 1H), 4.10 (t, J = 7.2 Hz, 2H), 3.63 (t, J = 7.2 Hz, 2H);
LCMS (ESI+): m/z 416 (M + H).sup.+, R.sub.t: 1.35 min. 72
7-Benzofuran-5-yl-2- .sup.1H NMR (DMSO-d.sub.6): .delta. 8.95 (d, J
= 8.4 Hz, 1H), (2-quinolin-2-yl- 8.30 (d, J = 8.0 Hz, 1H), 8.11
(br, 1H), 7.95 (d, J = 8.0 Hz, ethyl)-2,3-dihydro- 1H), 7.76 (d, J
= 2 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), isoindol-1-one 7.59 (d, J =
7.2 Hz, 1H), 7.48 (br, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.34 (d, J =
8.0 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.75 (br, 1H), 4.68 (s, 2H),
4.16 (t, J = 7.2 Hz, 2H), 3.61 (t, J = 7.2 Hz, 2H); LCMS (ESI+):
m/z 405 (M + H).sup.+, R.sub.t: 1.76 min. 73 7-(4-Methyl-thiophen-
.sup.1H NMR (DMSO-d.sub.6): .delta. 8.98 (d, J = 8.4 Hz, 1H),
3-yl)-2-(2-quinolin-2- 8.28 (d, J = 8.0 Hz, 1H), 8.12 (br, 2H),
7.99 (d, J = 8.0 Hz, yl-ethyl)-2,3-dihydro- 1H), 7.97 (t, J = 7.2
Hz, 1H), 7.62 (d, J = 7.6 Hz, 2H), isoindol-1-one 7.23 (d, J = 7.2
Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 4.69
(s, 2H), 4.16 (t, J = 7.2 Hz, 2H), 3.63 (t, J = 7.2 Hz, 2H), 1.67
(br, 3H); LCMS (ESI+): m/z 385 (M + H).sup.+, R.sub.t: 1.73 min. 74
7-(2-Methyl-2H- .sup.1H NMR (MeOD-d.sub.4): .delta. 8.24 (d, J =
8.4 Hz, 1H), pyrazol-3-yl)-2-(2- 7.86 (t, J = 8.0 Hz, 2H), 7.64 (t,
J = 8.0 Hz, 2H), 7.53 (q, J = 7.2 Hz, quinolin-2-yl-ethyl)- 2H),
7.48 (d, J = 7.6 Hz, 1H), 7.42 (t, J = 6.8 Hz,
2,3-dihydro-isoindol- 1H), 6.19 (d, J = 8.4 Hz, 1H), 4.58 (s, 2H),
4.06 (t, 1-one J = 7.2 Hz, 2H), 3.33 (t, J = 7.2 Hz, 2H), 3.24 (br,
3H); LCMS (ESI+): m/z 369 (M + H).sup.+, R.sub.t: 1.44 min. 75
7-Quinolin-6-yl-2-(2- .sup.1H NMR (DMSO-d.sub.6): .delta. 8.91 (d,
J = 8.4 Hz, 1H), quinolin-2-yl-ethyl)- 8.34 (d, J = 8.0 Hz, 1H),
8.29 (d, J = 8.0 Hz, 1H), 2,3-dihydro-isoindol- 7.96-7.93 (br, 3H),
7.89 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 8.4 Hz 1-one 1H), 7.70 (t, J
= 6.8 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H),
7.56 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 7.2 Hz, 1H), 7.48 (d, J =
9.2 Hz, 1H), 4.52 (s, 2H), 3.97 (t, J = 7.2 Hz, 2H), 3.75 (br, 3H),
3.27 (t, J = 7.2 Hz, 2H); LCMS (ESI+): m/z 416 (M + H).sup.+,
R.sub.t: 1.37 min. 76 7-(3-Fluoro-5- .sup.1H NMR (DMSO-d.sub.6):
.delta. 8.28 (d, J = 8.4 Hz, 1H), methoxy-phenyl)-2- 7.93 (d, J =
8.0 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 7.2 Hz,
(2-quinolin-2-yl- 2H), 7.55 (t, J = 7.6 Hz, 1H), 7.48 (d, 1H),
ethyl)-2,3-dihydro- 7.54 (t, J = 7.6 Hz, 1H), 7.48 (d, J = 8.4 Hz,
1H), isoindol-1-one 7.38 (d, J = 8.4 Hz, 1H), = 8.0 Hz, 1H), 6.83
(br, 3H), 4.52 (s, 2H), 3.94 (t, J = 7.2 Hz, 2H), 3.25 (t, J = 7.2
Hz, 2H); LCMS (ESI+): m/z 413 (M + H).sup.+, R.sub.t: 1.78 min. 77
7-(5-Fluoro-pyridin-3- .sup.1H NMR (DMSO-d.sub.6): .delta. 8.56 (d,
J = 0.5 Hz, 1H), yl)-2-(2-quinolin-2-yl- 8.48 (br, 1H), 8.29 (d, J
= 8.0 Hz, 1H), 7.85 (t, J = 7.2 Hz, ethyl)-2,3-dihydro- 1H), 7.76
(d, J = 7.6 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), isoindol-1-one 7.68
(d, J = 7.2 Hz, 1H), 7.66 (br, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.49
(d, J = 8.0 Hz, 1H), 7.46 (t, J = 8.4 Hz, 1H), 4.55 (s, 2H), 3.98
(t, J = 7.2 Hz, 2H), 3.29 (t, J = 7.2 Hz, 2H); LCMS (ESI+): m/z 384
(M + H).sup.+, R.sub.t: 1.48 min. 78 7-(1H-Pyrazol-4-yl)- .sup.1H
NMR (DMSO-d.sub.6): .delta. 12.89 (br, 1H), 8.30 (d, J = 8.4 Hz,
2-(2-quinolin-2-yl- 1H), 7.94 (br, 1H), 7.91 (br, 1H), 7.71 (t, J =
8.0 Hz, ethyl)-2,3-dihydro- 1H), 7.62 (d, J = 7.2 Hz, 1H),
7.54-7.48 (m, 3H), isoindol-1-one 7.38 (d, J = 7.6 Hz, 1H), 4.00
(t, J = 7.2 Hz, 2H), 3.29 (t, J = 7.2 Hz, 2H); LCMS (ESI+): m/z 355
(M + H).sup.+, R.sub.t: 1.39 min. 79 7-(5-Methanesulfonyl- .sup.1H
NMR (MeOD-d.sub.4): .delta. 9.02 (br, 1H), 8.97 (d, J = 8.4 Hz,
pyridin-3-yl)-2-(2- 1H), 8.81 (br, 1H), 8.32 (br, 1H), 8.31 (d, J =
8.0 Hz, quinolin-2-yl-ethyl)- 1H), 8.12 (d, J = 5.2 Hz, 1H), 7.98
(d, J = 8.4 Hz, 2,3-dihydro-isoindol- 1H), 7.92 (t, J = 7.6 Hz,
1H), 7.76 (d, J = 7.6 Hz, 1H), 1-one 7.75 (d, J = 8.4 Hz, 1H), 7.55
(d, J = 8.0 Hz, 1H), 4.73 (s, 2H), 4.19 (t, J = 7.2 Hz, 2H), 3.64
(t, J = 7.2 Hz, 2H), 3.13 (br, 3H); LCMS (ESI+): m/z 444 (M +
H).sup.+, R.sub.t: 1.44 min. 80 7-(3-Morpholin-4-yl- .sup.1H NMR
(DMSO-d.sub.6): .delta. 8.28 (d, J = 8.4 Hz, 1H),
phenyl)-2-(2-quinolin- 7.93 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0
Hz, 1H), 2-yl-ethyl)-2,3- 7.60-7.52 (br, 3H), 7.47 (d, J = 7.2 Hz,
1H), 7.34 (d, J = 7.6 Hz, dihydro-isoindol-1- 1H), 7.21 (d, J = 7.2
Hz, 1H), 6.95 (d, J = 8.4 Hz, 2H), one 6.86 (d, J = 8.0 Hz, 1H),
4.55 (s, 2H), 3.96 (t, J = 7.2 Hz, 2H), 3.72 (br, 4H), 3.26 (t, J =
7.2 Hz, 2H), 3.061 (br, 4H); LCMS (ESI+): m/z 450 (M + H).sup.+,
R.sub.t: 1.55 min. 81 {3-[3-Oxo-2-(2- .sup.1H NMR (DMSO-d.sub.6):
.delta. 8.80 (d, J = 8.4 Hz, 1H), quinolin-2-yl-ethyl)- 8.14 (d, J
= 8.0 Hz, 1H), 7.99-7.96 (m, 2H), 7.82 (t, J = 7.2 Hz,
2,3-dihydro-1H- 2H), 7.53 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 7.6 Hz,
isoindol-4-yl]- 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.22 (t, J = 8.0 Hz,
phenyl}-acetonitrile 3H), 7.05 (d, J = 8.4 Hz, 1H), 7.37 (d, J =
7.2 Hz, 1H), 4.55 (s, 2H), 4.03 (t, J = 7.2 Hz, 2H), 3.68 (br, 2H),
3.48 (t, J = 7.2 Hz, 2H); LCMS (ESI+): m/z 404 (M + H).sup.+,
R.sub.t: 1.64 min. 82 2-(2-Quinolin-2-yl- .sup.1H NMR
(MeOD-d.sub.4): .delta. 9.03 (d, J = 8.4 Hz, 1H),
ethyl)-7-thiazol-2-yl- 8.29 (d, J = 8.0 Hz, 1H), 8.21 (d, J = 8.0
Hz, 1H), 8.13 (d, J = 7.2 Hz, 2,3-dihydro-isoindol- 1H), 8.09 (t, J
= 12.0 Hz, 3H), 7.95 (d, J = 7.6 Hz, 1-one 1H), 7.91 (d, J = 4.8
Hz, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.41 Hz, 1H), 7.37
(d, J = 7.2 Hz, 1H), 4.80 (s, 2H), 4.26 (t, J = 7.2 Hz, 2H), 3.71
(t, J = 7.2 Hz, 2H); LCMS (ESI+): m/z 372 (M + H).sup.+, R.sub.t:
1.36 min. 83 7-Pyrimidin-2-yl-2-(2- .sup.1H NMR (MeOD-d.sub.4):
.delta. 8.86 (d, J = 8.8 Hz, 1H), quinolin-2-yl-ethyl)- 8.81 (d, J
= 5.2 Hz, 2H), 8.16 (d, J = 7.2 Hz, 1H), 8.03 (d, J = 8.0 Hz,
2,3-dihydro-isoindol- 1H), 7.99 (t, J = 7.6 Hz, 1H), 7.89 (t, J =
10.8 Hz, 1-one 2H), 7.82 (t, J = 8.4 Hz, 1H), 7.70 (d, J = 8.0 Hz,
2H), 7.50 (t, J = 4.8 Hz, 1H), 4.65 (s, 2H), 4.10 (t, J = 7.2 Hz,
2H), 3.55 (t, J = 7.2 Hz, 2H); LCMS (ESI+): m/z 367 (M + H).sup.+,
R.sub.t: 1.32 min. 84 7-(3H-Imidazol-4-yl)- .sup.1H NMR
(MeOD-d.sub.4): .delta. 8.98 (d, J = 8.4 Hz, 1H),
2-(2-quinolin-2-yl- 8.82 (br, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.20
(br, 1H), ethyl)-2,3-dihydro- 8.19 (d, J = 8.0 Hz, 1H), 8.09 (t, J
= 7.2 Hz, 1H), 7.77 (t, J = 7.6 Hz, isoindol-1-one 1H), 7.70 (d, J
= 7.6 Hz, 1H), 4.80 (s, 2H), 4.30 (t, J = 7.2 Hz, 2H), 3.71 (t, J =
7.2 Hz, 2H); LCMS (ESI+): m/z 355 (M + H).sup.+, R.sub.t: 1.28 min.
85 2-(2-Quinolin-2-yl- .sup.1H NMR (MeOD-d.sub.4): .delta. 8.99 (d,
J = 8.4 Hz, 1H), ethyl)-7-(5- 8.84 (br, 1H), 8.30 (d, J = 8.0 Hz,
1H), 8.13 (d, J = 3.6 Hz, trifluoromethyl- 2H), 7.98 (br, 3H), 7.75
(br, 2H), 7.63 (t, J = 7.2 Hz, pyridin-2-yl)-2,3- 2H), 4.52 (s,
2H), 3.94 (t, J = 7.2 Hz, 2H), 3.25 (t, J = 7.2 Hz,
dihydro-isoindol-1- 2H); one LCMS (ESI+): m/z 434 (M + H).sup.+,
R.sub.t: 1.69 min. 86 7-(2-Methyl-pyridin- .sup.1H NMR
(MeOD-d.sub.4): .delta. 9.00 (d, J = 8.8 Hz, 1H),
3-yl)-2-(2-quinolin-2- 8.66 (d, J = 8.0 Hz, 1H), 8.30 (d, J = 8.4
Hz, 1H), 8.19 (t, J = 8.0 Hz, yl-ethyl)-2,3-dihydro- 2H), 8.13 (t,
J = 7.6 Hz, 1H), 8.01 (d, J = 8.8 Hz, isoindol-1-one 1H), 7.95 (t,
J = 7.2 Hz, 1H), 7.81 (br, 3H), 7.41 (t, J = 4.8 Hz, 1H), 4.19 (q,
J = 6.8 Hz, 2H), 3.65 (t, J = 6.8 Hz, 2H), 2.27 (br, 3H); LCMS
(ESI+): m/z 380 (M + H).sup.+, R.sub.t: 1.26 min. 87
7-(5-Methyl-pyridin- .sup.1H NMR (MeOD-d.sub.4): .delta. 8.96 (d, J
= 8.4 Hz, 1H), 2-yl)-2-(2-quinolin-2- 8.65 (br, 1H), 8.45 (d, J =
8.0 Hz, 1H), 8.35 (d, J = 8.0 Hz, yl-ethyl)-2,3-dihydro- 1H), 8.25
(d, J = 8.4 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H), isoindol-1-one 8.12
(q, J = 4. Hz, 1H), 8.07 (t, J = 7.2 Hz, 1H), 8.03 (d, J = 8.4 Hz,
1H), 7.90 (br, 3H), 4.84 (s, 2H), 4.28 (t, J = 7.2 Hz, 2H), 3.70
(t, J = 7.2 Hz, 2H), 2.59 (br, 3H); LCMS (ESI+): m/z 380 (M +
H).sup.+, R.sub.t: 1.31 min. 88 7-(5-Fluoro-pyridin-2- .sup.1H NMR
(MeOD-d.sub.4): .delta. 8.78 (d, J = 8.4 Hz, 1H),
yl)-2-(2-quinolin-2-yl- 8.26 (br, 1H), 8.10 (d, J = 8.0 Hz, 1H),
7.93 (br, 1H), ethyl)-2,3-dihydro- 7.79 (d, J = 8.4 Hz, 1H), 7.74
(t, J = 7.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, isoindol-1-one 2H), 7.40
(d, J = 8.4 Hz, 1H), 7.30 (q, J = 8.0 Hz, 2H), 4.50 (s, 2H), 3.97
(t, J = 7.2 Hz, 2H), 3.43 (t, J = 7.2 Hz, 2H); LCMS (ESI+): m/z 384
(M + H).sup.+, R.sub.t: 1.48 min. 89 7-(3-Methyl-pyridin- .sup.1H
NMR (MeOD-d.sub.4): .delta. 8.93 (d, J = 8.4 Hz, 1H),
2-yl)-2-(2-quinolin-2- 8.63 (d, J = 6.8 Hz, 1H), 8.43 (d, J = 8.0
Hz, 1H), 8.25 (d, J = 7.2 Hz, yl-ethyl)-2,3-dihydro- 1H), 8.16 (d,
J = 7.6 Hz, 1H), 8.10 (t, J = 7.6 Hz, isoindol-1-one 1H), 7.97-7.85
(br, 5H), 7.61 (d, J = 8.0 Hz, 1H), 4.80 (s, 2H), 4.16 (t, J = 7.2
Hz, 2H), 3.63 (t, J = 7.2 Hz, 2H), 2.11 (br, 3H); LCMS (ESI+): m/z
380 (M + H).sup.+, R.sub.t: 1.27 min. 90 5-[3-Oxo-2-(2- .sup.1H NMR
(MeOD-d.sub.4): .delta. 9.00 (d, J = 8.0 Hz, 1H),
quinolin-2-yl-ethyl)- 8.33 (d, J = 8.0 Hz, 1H), 8.15 (d, J = 8.0
Hz, 2H), 7.99 (t, J = 8.4 Hz, 2,3-dihydro-1H- 2H), 7.64 (d, J = 7.6
Hz, 1H), 7.57 (d, J = 6.8 Hz, isoindol-4-yl]-1,3- 1H), 7.35 (d, J =
8.4 Hz, 1H), 7.08 (d, J = 8.0 Hz, dihydro-indol-2-one 1H), 7.02
(br, 1H), 6.77 (d, J = 8.4 Hz, 1H), 4.69 (s, 2H), 4.17 (t, J = 7.2
Hz, 2H), 3.62 (t, J = 7.2 Hz, 2H), 3.38 (br, 2H); LCMS (ESI+): m/z
420 (M + H).sup.+, R.sub.t: 1.48 min. 91 7-(6-Methyl-pyridin-
.sup.1H NMR (MeOD-d.sub.4): .delta. 8.91 (d, J = 8.4 Hz, 1H),
3-yl)-2-(2-quinolin-2- 8.80 (br, 1H), 8.41 (d, J = 8.4 Hz, 1H),
8.24 (d, J = 8.0 Hz, yl-ethyl)-2,3-dihydro- 1H), 8.14 (d, J = 7.2
Hz, 1H), 8.08 (t, J = 6.8 Hz, 1H), isoindol-1-one 7.95 (d, J = 7.6
Hz, 1H), 7.89 (t, J = 8.4 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.80
(d, J = 6.4 Hz, 2H), 7.56 (d, J = 7.2 Hz, 1H), 4.72 (s, 2H), 4.18
(t, J = 7.2 Hz, 2H), 3.62 (t, J = 7.2 Hz, 2H), 2.82 (br, 3H); LCMS
(ESI+): m/z 380 (M + H).sup.+, R.sub.t: 1.28 min. 92
7-(1H-Indol-7-yl)-2- .sup.1H NMR (MeOD-d.sub.4): .delta. 10.55 (br,
1H), 8.55 (d, J = 12 Hz, (2-quinolin-2-yl- 1H), 8.08 (d, J = 8.0
Hz, 1H), 8.00 (d, J = 8.0 Hz, ethyl)-2,3-dihydro- 1H), 7.85 (t, J =
6.8 Hz, 1H), 7.70-7.60 (m, 5H),
isoindol-1-one 7.51 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H),
7.17 (br, 1H), 6.93 (t, J = 8.4 Hz, 1H), 6.83 (d, J = 6.8 Hz, 1H),
6.43 (br, 1H), 4.55 (s, 2H), 3.95 (t, J = 7.2 Hz, 2H), 3.35 (t, J =
7.2 Hz, 2H); LCMS (ESI+): m/z 404 (M + H).sup.+, R.sub.t: 1.73 min.
93 7-(1H-Indazol-5-yl)-2- .sup.1H NMR (MeOD-d.sub.4): .delta. 8.96
(d, J = 8.4 Hz, 1H), (2-quinolin-2-yl- 8.27 (d, J = 8.0 Hz, 1H),
8.11 (br, 2H), 7.96 (br, 3H), ethyl)-2,3-dihydro- 7.67 (d, J = 7.2
Hz, 1H), 7.59 (t, J = 6.0 Hz, 2H), 7.41 (d, J = 7.6 Hz,
isoindol-1-one 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 8.0 Hz,
1H), 4.69 (s, 2H), 4.15 (t, J = 7.2 Hz, 2H), 3.62 (t, J = 7.2 Hz,
2H); LCMS (ESI+): m/z 405 (M + H).sup.+, R.sub.t: 1.53 min. 94
7-(3-Methyl-3H- .sup.1H NMR (MeOD-d.sub.4): .delta. 8.91 (br, 2H),
8.25 (d, J = 8.0 Hz, imidazol-4-yl)-2-(2- 1H), 8.15 (d, J = 8.0 Hz,
1H), 8.08 (t, J = 7.2 Hz, quinolin-2-yl-ethyl)- 1H), 7.96 (d, J =
7.6 Hz, 1H), 7.92-7.85 (br, 2H), 2,3-dihydro-isoindol- 7.80 (t, J =
7.6 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.47 (br, 1-one 1H), 4.77
(s, 2H), 4.19 (t, J = 7.2 Hz, 2H), 3.62 (t, J = 7.2 Hz, 2H), 3.38
(br, 3H); LCMS (ESI+): m/z 369 (M + H).sup.+, R.sub.t: 1.23 min. 95
7-(1-Methyl-1H- .sup.1H NMR (MeOD-d.sub.4): .delta. 8.71 (d, J =
8.4 Hz, 1H), imidazol-2-yl)-2-(2- 8.14 (d, J = 8.0 Hz, 1H), 8.06
(d, J = 8.0 Hz, 1H), 7.99 (t, J = 7.2 Hz, quinolin-2-yl-ethyl)-
2H), 7.89 (t, J = 7.6 Hz, 1H), 7.83 (d, J = 7.6 Hz,
2,3-dihydro-isoindol- 1H), 7.79 (t, J = 8.4 Hz, 1H), 7.71 (d, J =
8.0 Hz, 1-one 1H), 7.64 (br, 1H), 4.77 (s, 2H), 4.17 (t, J = 7.2
Hz, 2H), 3.55 (t, J = 7.2 Hz, 2H), 3.44 (br, 3H); LCMS (ESI+): m/z
369 (M + H).sup.+, R.sub.t: 1.20 min. 96 6-[3-Oxo-2-(2- .sup.1H NMR
(MeOD-d.sub.4): .delta. 8.99 (d, J = 8.4 Hz, 1H),
quinolin-2-yl-ethyl)- 8.29 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 3.6
Hz, 2H), 7.98 (t, J = 7.2 Hz, 2,3-dihydro-1H- 1H), 7.94 (t, J = 4.0
Hz, 1H), 7.67 (d, J = 7.2 Hz, isoindol-4-yl]-1,3- 1H), 7.60 (d, J =
8.4 Hz, 1H), 7.36 (d, J = 8.0 Hz, dihydro-indol-2-one 1H), 7.10 (d,
J = 8.4 Hz, 1H), 6.88 (br, 1H), 6.81 (d, J = 7.2 Hz, 1H), 4.68 (s,
2H), 4.17 (t, J = 7.2 Hz, 2H), 3.63 (t, J = 7.2 Hz, 2H), 3.53 (br,
2H); LCMS (ESI+): m/z 420 (M + H).sup.+, R.sub.t: 1.5 min. 97
7-(1H-Indazol-6-yl)-2- .sup.1H NMR (MeOD-d.sub.4): .delta. 8.94 (d,
J = 8.4 Hz, 1H), (2-quinolin-2-yl- 8.24 (d, J = 8.0 Hz, 1H), 8.08
(d, J = 3.6 Hz, 2H), 7.96 (br, ethyl)-2,3-dihydro- 1H), 7.94 (d, J
= 7.2 Hz, 1H), 7.89 (q, J = 3.6 Hz, 1H), isoindol-1-one 7.69 (t, J
= 7.6 Hz, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H),
7.47 (br, 1H), 7.42 (d, J = 8.4 Hz, 1H), 6.931 (d, J = 7.2 Hz, 1H),
4.69 (s, 2H), 4.15 (t, J = 7.2 Hz, 2H), 3.61 (t, J = 7.2 Hz, 2H);
LCMS (ESI+): m/z 405 (M + H).sup.+, R.sub.t: 1.54 min. 98
2-(2-Quinolin-2-yl- .sup.1H NMR (MeOD-d.sub.4): .delta. 8.98 (d, J
= 8.4 Hz, 1H), ethyl)-7-(6- 8.62 (br, 1H), 8.29 (d, J = 8.0 Hz,
1H), 8.13 (d, J = 8.0 Hz, trifluoromethyl- 2H), 7.99 (d, J = 7.2
Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H), pyridin-3-yl)-2,3- 7.73 (t, J =
7.6 Hz, 3H), 7.48 (d, J = 6.8 Hz, 1H), dihydro-isoindol-1- 4.73 (s,
2H), 4.17 (t, J = 7.2 Hz, 2H), 3.64 (t, J = 7.2 Hz, one 2H); LCMS
(ESI+): m/z 434 (M + H).sup.+, R.sub.t: 1.73 min. Ex. = EXAMPLE
Example 99
7-Morpholin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
[1070] A 25 mL round-bottomed flask was charged with
7-bromo-2-(2-quinolin-2-yl)-2,3-dihydro-isoindol-1-one from Example
5.4 (100 mg, 0.3 mmol), Pd(OAc).sub.2 (7 mg, 0.03 mmol), BINAP (37
mg, 0.06 mmol) in toluene (3 mL). The reaction mixture was
sequentially treated with sodium t-butoxide (58 mg, 0.6 mmol) and
morpholine (130 mg, 1.5 mmol). The reaction mixture was heated at
80.degree. C. overnight. The solvent was removed under reduced
pressure and the residue was purified by prep-TLC (PE/EA=1/2) to
give the title compound (20 mg, 18%). LCMS (ESI+): m/z 374
(M+H).sup.+, R.sub.t: 1.93 min.; .sup.1H NMR (DMSO-d.sub.6, 400
MHz) .delta.: 8.28 (d, J=8 Hz, 1H), 7.93 (t, J=8.4 Hz, 2H), 7.73
(m, 1H), 7.56 (t, J=7.6 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.43 (t,
J=7.6Hz, 1H), 7.05 (d, J=7.6 Hz, 1H), 6.85 (d, J=8 Hz, 1H), 4.39
(s, 2H), 3.96 (t, J=7.2 Hz, 2H), 3.72 (t, J=4.4 Hz, 4H), 3.26 (t,
J=7.2 Hz, 2H), 3.11 (t, J=4 Hz, 4H).
[1071] Compounds of Examples 100 to 110 were prepared analogously
to the method described for Example 99.
Example 100
7-[4-(4-Methyl-piperazin-1-yl)-piperidin-1-yl]-2-(2-quinolin-2-yl-ethyl)-2-
,3-dihydro-isoindol-1-one trifluoroacetate
[1072] ESI-MS: [M+Na.sup.+]=492.2, [M+H.sup.+]=470.3.
Example 101
7-(1S,4S)-2,5-Diaza-bicyclo[2.2.1]hept-2-yl-2-(2-quinolin-2-yl-ethyl)-2,3--
dihydro-isoindol-1-one
[1073] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta.=9.08 (s br,
1H), 8.77-8.56 (m, 2H), 8.20-8.04 (m, 2H), 7.91 (t, 1H), 7.82-7.68
(m, 2H), 7.37 (t, 1H), 6.90 (d, 1H), 6.69 (d, 1H), 4.74 (s., 1H),
4.44 (q, 2H), 4.33 (s., 1H), 4.09-3.81 (m, 3H), 3.40 (t, 2H), 3.26
(s br., 1H), 3.15 (m, 2H), 1.97 (d., 1H), 1.80 ppm (d., 1H)
Example 102
7-Piperazin-1-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
[1074] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta.=8.92 (s br,
2H), 8.63 (d, 1H), 8.10 (d, 1H), 8.05 (d, 1H), 7.88 (t, 1H), 7.76
(d, 1H), 7.70 (t, 1H), 7.46 (t, 1H), 7.13 (d, 1H), 6.90 (d, 1H),
4.47 (s., 2H), 3.99 (t, 2H), 3.40 (t, 2H), 3.25-3.08 (m, 8H)
Example 103
7-(3,8-Diaza-bicyclo[3.2.1]oct-8-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-
-isoindol-1-one
[1075] ESI-MS: [M+Na.sup.+]=421.20, 400.20, [M+H.sup.+]=399.20.
Example 104
7-(1,1-Dioxo-1-thiomorpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-i-
soindol-1-one
[1076] ESI-MS: [M+Na.sup.+]=444.10, [M+H.sup.+]=422.10.
Ecample 105
7-[4-(1-Methyl-piperidin-4-yl)-piperazin-1-yl]-2-(2-quinolin-2-yl-ethyl)-2-
,3-dihydro-isoindol-1-one
[1077] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta.=8.28 (d, 1H),
7.88-8.60 (m, 2H), 7.72 (t, 1H), 7.57 (t, 1H), 7.49 (d, 1H), 7.40
(t, 1H), 7.00 (d, 1H), 6.82 (d, 1H), 4.39 (s br., 2H), 3.93 (t,
2H), 3.25 (t, 2H), 3.10 (s br., 4H), 2.80 (d, 2H), 2.60 (s br.,
4H), 2.14 (s br., 4H), 1.85 (t, 2H), 1.72 (d., 2H), 1.42 ppm (q,
2H).
Example 106
7-(4-Pyridin-4-yl-piperazin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-is-
oindol-1-one
[1078] ESI-MS: [M+Na.sup.+]=473.1, [M+H.sup.+]=450.2.
Example 107
7-(4-Methyl-piperazin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one
[1079] ESI-MS: [M+Na.sup.+]=409.1, [M+H.sup.+]=387.1.
Example 108
7-(3-Phenyl-piperidin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one
[1080] ESI-MS: [M+Na.sup.+]=470.2, [M+H.sup.+]=448.2.
Example 109
7-(3-Phenoxy-piperidin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindo-
l-1-one
[1081] ESI-MS: [M+Na.sup.+]=486.2, [M+H.sup.+]=464.2.
Example 110
7-[1,4]Oxazepan-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
hydrochloride
[1082] ESI-MS: [M+Na.sup.+]=410.1, [M+H.sup.+]=388.1
Example 111
7-(7-Nitro-3,4-dihydroisoquinolin-2
(1H)-yl)-2-(2-(quinolin-2-yl)ethyl)isoindolin-1-one
[1083] The title compound was prepared in the same manner as the
compound of Example 99 starting from
7-bromo-2-(2-quinolin-2-yl)-2,3-dihydro-isoindol-1-one from Example
5.4 and commercially available
7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (yield 25%).
ESI-MS: [M+Na.sup.+]=487.10, [M+H.sup.+]=465.10
Example 112
7-(7-Amino-3,4-dihydroisoquinolin-2 (1H)-
yl)-2-(2-(quinolin-2-yl)ethyl)isoindolin-1-one
[1084] 7-(7-Nitro-3,4-dihydroisoquinolin-2
(1H)-yl)-2-(2-(quinolin-2- yl)ethyl)isoindolin-1-one from Example
111 (0.14 mmol, 66 mg) was added to tin chloride dihydrate (0.71
mmol, 160 mg) dissolved in concentrated HCl (37%, 2mL) under
vigorous stiffing. The mixture was further stirred for 2 h at
50.degree. C. Upon cooling with an ice bath, the reaction mixture
was basified with aq. NaOH and then extracted with ethyl acetate (3
times). The combined organic phases were washed once with sat. aq.
NaCl, dried (Na.sub.2SO.sub.4), filtered and evaporated. The
residuewas purified on a SiOH Chromabond column, eluted with 0-2%
methanol in CH.sub.2Cl.sub.2. Yield 34 mg (55%). ESI-MS
[M+H.sup.+]=435.20.
Example 113
4-Chloro-N-{2-[3-oxo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-1H-isoindol-4-y-
l]-1,2,3,4-tetrahydro-isoquinolin-7-yl}-benzenesulfonamide
[1085] 4-Chlorobenzene-1-sulfonyl chloride (0.03 mmol, 6 mg) was
added to a cooled solution (4.degree. C.) of
7-(7-amino-3,4-dihydroisoquinolin-2
(1H)-yl)-2-(2-(quinolin-2-yl)ethyl)isoindolin-1-one from Example
112 (0.03 mmol, 11 mg) in pyridine (1 mL). The mixture was then
stirred for 12 h at room temperature, poured into saturated aqueous
NaHCO.sub.3 and extracted twice with ethyl acetate. The combined
organic phases were dried (Na.sub.2SO.sub.4), filtered and
evaporated. The resiude was purified on a SiOH Chromabond column,
eluted with 0-2% methanol in CH.sub.2Cl.sub.2. Yield 5 mg (32%).
ESI-MS: [M+Na.sup.+]=632.20, [M+H.sup.+]=610.20.
Example 114
4-Isopropyl-N-{2-[3-oxo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-1H-isoindol--
4-yl]-,2,3,4-tetrahydro-isoquinolin-7-yl}-benzenesulfonamide
[1086] The title compound was prepared in the same manner as the
compound of Example 113 but using 4-isopropylbenzene-1-sulfonyl
chloride (0.03 mmol, 6 mg).
[1087] Yield 2 mg (13%). ESI-MS: [M+Na].sup.+=639.20,
[M+H.sup.+]=617.30.
Example 115
2-[2(6-Fluoro-quinolin-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro-isoindol--
1-one trifluoroacetate
[1088] The title compound was prepared in the same manner as the
compound of Example 99 but using
2-(6-fluoro-quinolin-2-yl)-ethylamine from Example a5. ESI-MS:
[M+Na.sup.+]=414.1, [M+H.sup.+]=392.1;
Example 116
2-[2-(6-Methoxy-quinolin-2- yl)-ethyl]-7-morpholin-4-
y1-2,3-dihydro-isoindol-1-one hydrochloride
[1089] The title compound was prepared in the same manner as the
compound of Example 99 but using
2-(6-methoxy-quinolin-2-yl)-ethylamine from Example a4. ESI-MS:
[M+Na].sup.+=426.1, [M+H.sup.+]=404.1;
Example 117
2-[2-(4-Chloro-quinolin-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro-isoindol-
-1-one trifluoroacetate
[1090] The title compound was prepared in the same manner as the
compound of Example 99 but using
2-(4-chloro-quinolin-2-yl)-ethylamine from Example a6. ESI-MS:
[M+Na.sup.+]=430.1, 1M+H.sup.+=408.2;
Example 118
2-[2-(8-Chloro-quinolin-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro-isoindol-
-1-one
[1091] The title compound was prepared in the same manner as the
compound of Example 99 but using
2-(8-chloro-quinolin-2-yl)-ethylamine from Example a2. ESI-MS:
[M+Na].sup.+=430.10, 1M+H.sup.+1=408.10.
Example 119
4-Morpholin-4-yl-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]pyrid-
in-5-one
119.1 Ethyl 4-bromo-2-methylnicotinate
[1092] Ethyl 2-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate from
Example 3.3 (8 g, 44 mmol) in 9 mL of POBr.sub.3 was stirred at
100.degree. C. overnight. The reaction mixture was poured into ice,
adjusted to pH=7.about.8 with solid NaHCO.sub.3, and then extracted
with EtOAc (3 times). The organic phase was washed with water,
dried (Na.sub.2SO.sub.4), filtered and evaporated to yield 3 g of
ethyl 4-bromo-2-methylnicotinate (90% pure).
[1093] ESI-MS: [M+H].sup.+=245.90, 244.90, 243.90.
119.2 Ethyl 4-bromo-2-(bromomethyl)nicotinate
[1094] N-Bromosuccinimide (2.46 mmol, 438 mg) and benzoyl peroxide
(0.08 mmol, 20 mg) were added to a solution of ethyl
4-bromo-2-methylnicotinate (90% pure, 500 mg) in CCl.sub.4 (15mL)
and stirred at reflux for 2 d. The solution was evaporated in vacuo
to yield 597 mg of ethyl 4-bromo-2-(bromomethyl)nicotinate (56%
pure).
119.3
4-Bromo-6-(2-(quinolin-2-yl)ethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyri-
din-5-one
[1095] K.sub.2CO.sub.3 (2.07 mmol, 286 mg) was added to a solution
of ethyl 4-bromo-2-(bromomethyl)nicotinate (56% pure, 597 mg) in
DMF (15mL) and stirred for a few minutes.
2-(Quinolin-2-yl)ethylamine from Example a1 (1.04 mmol, 178 mg) was
added and the mixture was further stirred at room temperature for
12 h. The suspension was filtrated and the filtrate evaporated in
vacuo. Water was added and the solution basified with a 5%
K.sub.2CO.sub.3 aqueous solution. The water phase was extracted
with ethyl acetate (3 times); the organic phases were washed with
water, dried (Na.sub.2SO.sub.4), filtered and evaporated. The
residue was passed on a silicagel column eluted with ethyl acetate
to yield 89 mg of
4-bromo-6-(2-(quinolin-2-yl)ethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-
-one. ESI-MS: [M+Na].sup.+=390.00, 371.00, 370.00, 369.05,
[M+H.sup.+]=368.00.
[1096] 119.4
4-Morpholin-4-yl-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]pyri-
din-5-one
[1097] The title compound was prepared in the same manner as the
compound of Example 99 starting from
4-bromo-6-(2-(quinolin-2-yl)ethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-
-one. Yield 3 mg (12%). ESI-MS: [M+Na].sup.+=397.1,
[M+H.sup.+]=375.1.
Example 120
7-Morpholino-2-(3-(pyrimidin-2-yl)phenethyl)isoindolin-1-one
120.1 7-Bromo-2-(3-(pyrimidin-2-yl)phenethyl)isoindolin-1-one
[1098] A mixture of 2-(3-(pyrimidin-2-yl)phenyl)ethanamine from
Example e1(750 mg, 3.76 mmol), 2-bromo-6-bromomethyl-benzoic acid
methyl ester from Example 5.3 (1209 mg, 4.14 mmol) and DIPEA (486
mg, 3.76 mmol) in isopropanol (15 mL) was stirred and refluxed
overnight. The mixture was concentrated and the residue was
purified by silica gel column (PE:EA=1:1) to give the title
compound as a white solid (1.2 g, 80%). LCMS (ESI+): m/z 396
(M+H).sup.+, R.sub.t: 0.87 min
120.2
7-Morpholino-2-(3-(pyrimidin-2-yl)phenethyl)isoindolin-1-one
[1099] A mixture of the compound from example 120.1 (400 mg, 1.02
mmol), morpholine (442 mg, 5.07 mmol), PdCl.sub.2(dppf) (.sub.74
mg, 0.10 mmol) and t-BuONa (195 mg, 2.03 mmol) in toluene (15 mL)
was stirred at 80.degree. C. under N.sub.2 overnight. The mixture
was concentrated and the residue was purified by Prep-HPLC to
obtain the title compound as an off-white gel (60 mg, 14%). LCMS
(ESI+): m/z 401 (M+H).sup.+, R.sub.t: 1.76 min. .sup.1H NMR (400
MHz, MeOD): .delta. 3.00 (t, J=7.2 Hz, 2H), 3.25 (m, 4H), 3.78-3.84
(m, 6H), 4.28 (s, 2H), 7.06-7.09 (m, 1H), 7.13-7.16 (m, 1H), 7.24
(t, J=4.8 Hz, 1H), 7.31 (d, J=5.2 Hz, 2H), 7.44 (t, J=7.8 Hz, 1H),
8.12-8.14 (m, 1H), 8.18 (s, 1H), 8.70 (d, J=4.8 Hz, 2H).
Example 121
7-(Pyridin-4-yl)-2-(3-(pyrimidin-2-yl)phenethyl)isoindolin-1-one
[1100] A mixture of the compound from Example 120.1 (100 mg, 0.25
mmol), pyridin-4-ylboronic acid (34 mg, 0.28 mmol), PdCl.sub.2
(dppf) (.sub.19 mg, 0.03 mmol) and K.sub.2CO.sub.3 (105 mg, 0.76
mmol) in dioxane (12 mL) and H.sub.2O (4 mL) was stirred at
100.degree. C. under N.sub.2 for 2 h. The mixture was concentrated
and the residue was purified by Pre-HPLC to obtain the title
compound as a white solid (50 mg, 51%). LCMS (ESI+): m/z 393
(M+H).sup.+, R.sub.t: 1.94 min. .sup.1H NMR (400 MHz, MeOD):
.delta. 3.02 (t, J=7.2 Hz, 2H), 3.82 (t, J=7.2 Hz, 2H), 4.41 (s,
2H), 7.23 (t, J=4.8 Hz, 1H), 7.31-7.32 (m, 2H), 7.46-7.48 (m, 1H),
7.64-7.66 (m, 2H), 8.06 (d, J=6.4 Hz, 2H), 8.15-8.17 (m, 2H), 8.68
(d, J=4.8 Hz, 2H). 8.74 (d, J=6.4 Hz, 2H).
Example 122
(2-(2-Phenylpyrimidin-4-yl)ethyl)-7-(pyridin-4-yl)isoindolin-1-one
122.1 7-Bromo-2-(2-(2-phenylpyrimidin-4-yl)ethyl)isoindolin-
l-one
[1101] A mixture of the compound from Example f1 (100 mg, 0.50
mmol) and 2-bromo-6-bromomethyl-benzoic acid methyl ester from
Example 5.3 (232 mg, 0.75 mmol) in THF (5 mL) was stirred at
70.degree. C. overnight. The mixture was concentrated and the
residue was purified by Prep-TLC (PE:EA=1:1) to give the title
compound as a white solid (40 mg, 20%). LCMS (ESI+): m/z 394
(M+H).sup.+, R.sub.t: 0.90 min.
122.2
(2-(2-Phenylpyrimidin-4-yl)ethyl)-7-(pyridin-4-yl)isoindolin-1-one
[1102] A mixture of the compound from Example 122.1 (40 mg, 0.10
mmol), pyridin-4-ylboronic acid (14 mg, 0.11 mmol),
PdCl.sub.2(dppf) (8 mg, 0.01 mmol) and K.sub.2CO.sub.3 (41 mg, 0.30
mmol) in dioxane (12 mL) and H.sub.2O (4 mL) was stirred at
100.degree. C. under N.sub.2 for 2 h. The mixture was concentrated
and the residue was purified by Prep-HPLC to obtain the title
compound as a white solid (20 mg, 51%). LCMS (ESI+): m/z 393
(M+H).sup.+, R.sub.t: 1.59 min.; .sup.1H NMR (400 MHz, MeOD):
.delta. 3.10 (t, J=6.2 Hz, 2H), 3.96 (t, J=6.8 Hz, 2H), 4.56 (s,
2H), 7.18-7.31 (m, 7H), 7.58 (d, J=4.8 Hz, 2H), 8.05 (d, J=7.2 Hz,
2H), 8.39 (s, 2H), 8.56 (d, J=4.8 Hz, 1H).
Example 123
Pyridine-3-sulfonic acid
[3-oxo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-1H-isoindol-4-yl]-amide
123.1 7-Nitro-2-(2-(quinolin-2-yl)ethyl)isoindolin-1-one
[1103] Methyl 2-(bromomethyl)-6-nitrobenzoate (1.82 mmol, 500 mg)
was added portionswise to a mixture of K.sub.2CO.sub.3 (4.56 mmol,
630 mg) and 2-(quinolin-2-yl)ethanamine dihydrochloride from
Example a1 (3.04 mmol, 745 mg) in acetonitrile (50mL). The
suspension was then stirred 12 h at room temperature filtrated and
the filtrate evaporated in vacuo. The residue was passed on a
silicagel column eluted with ethyl acetate to yield 353 mg (58%) of
the title compound.
123.2 7-Amino-2-(2-(quinolin-2-yl)ethyl)isoindolin-1-one
[1104] 7-Nitro-2-(2-(quinolin-2-yl)ethyl)isoindolin-1-one from
Example 123.1 (1.04 mmol, 345 mg) was hydrogenated on Pd/C (10%) in
ethanol (50 mL) to give 122 mg (39%) of the title compound. ESI-MS:
[2M+Na].sup.+=629.20, [M+Na].sup.+=326.10, 305.10,
[M+H].sup.+=304.10.
123.3 Pyridine-3-sulfonic acid
[3-oxo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-1H-isoindol-4-yl]-amide
[1105] Pyridine-3-sulfonyl chloride (0.05 mmol, 9 mg) was added
dropwise to a solution of
7-amino-2-(2-(quinolin-2-yl)ethyl)isoindolin-1-one (0.05 mmol, 15
mg) in pyridine (1mL) at 0.degree. C. and the solution was further
stirred 12 h at room temperature. A saturated aqueous solution of
NaHCO.sub.3 was added and the mixture was extracted with EtOAc (3
times). The combined organic phases were washed with water, dried
and evaporated in vacuo. The residue was passed on a silicagel
column eluted with EtOAc: 2M NH.sub.3 in EtOH to give 4 mg (17%) of
the title compound. .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta.=9.92
(s br., 1H), 9.07 (s, 1H), 8.70 (d, 1H), 8.09 (d, 1H), 8.10 (d 1H),
7.99 (d, 1H), 7.80 (d, 1H), 7.70 (t, 1H), 7.59 (d, 1H), 7.51 (t,
1H), 7.41-7.29 (m, 3H), 7.00 (d, 1H), 4.29 (s, 2H), 4.08 (t, 2H),
3.32 (t, 2H).
Example 124
7-[(Pyridin-2-ylmethyl)-amino]-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoin-
dol-1-one
[1106] 7-Amino-2-(2-(quinolin-2-yl)ethyl)isoindolin-1-one from
Example 123.2 (0.07 mmol, 20 mg) and picolinaldehyde (0.07 mmol, 7
mg) were solved in methanol (1 mL) and stirred for 30 min. at room
temperature. Zinc chloride (0.04 mmol, 5 mg) was added and the
mixture was further stirred 30 min. Sodium cyanoborohydride (0.08
mmol, 5 mg) was finally added and the mixture was stirred 12 h at
room temperature. A saturated aqueous solution of NaHCO.sub.3 was
added and the mixture was extracted with EtOAc (3 times). The
joined organic phases were washed with water, dried and evaporated
in vacuo. The residue was passed on a silicagel column eluted with
EtOAc.
[1107] Yield 20 mg (77%). ESI-MS: [M+H].sup.+=395.1.
Example 125
7-[(Pyridin-4-ylmethyl)-amino]-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoin-
dol-1-one
[1108] The title compound was prepared as described for Example 124
using isonicotinaldehyde (0.07 mmol, 7 mg). Yield 10 mg (39%).
ESI-MS: [M+Na.sup.+]=417.1, [M+H.sup.+]=395.1.
Example 126
7-[(Pyridin-3-ylmethyl)-amino]-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoin-
dol-1-one
[1109] The title compound was prepared as described for Example 124
using nicotinaldehyde (0.07 mmol, 7 mg). Yield: 2 mg (7%). .sup.1H
NMR (CDCl.sub.3, 500 MHz): .delta.=8.61 (s, 1H), 8.50 (d, 1H), 8.08
(d, 1H), 8.05 (d 1H), 7.78 (d, 1H), 7.68 (t, 2H), 7.48 (t, 1H),
7.84 (d, 1H), 7.30-7.11 (m, 3H), 6.60 (d, 1H), 6.40 (d, 1H), 4.48
(d, 2H), 4.25 (s, 2H), 4.07 (t, 2H), 3.36 (t, 2H).
Example 127
7-(Pyridin-3-ylmethoxy)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-o-
ne
127.1
7-Methoxy-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
[1110] The title compound was prepared in analogy to the process
described in Example 5.4 starting from
2-bromomethyl-6-methoxy-benzoic acid methyl ester (prepared in
analogy to the method described for 2-bromomethyl-6-bromo-benzoic
acid methyl ester) and 2-quinolin-2-yl-ethylamine from Example a1.
ESI-MS: [2M+Na].sup.+=659.2, [M+H].sup.+=319.1
127.2
7-Hydroxy-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
[1111] Demethylation of
7-methoxy-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
(0.43 mmol, 138 mg) with BBr.sub.3 gave the title compound. Yield
71 mg (54%). ESI-MS: [2M+Na.sup.+]=631.2, [M+Na.sup.+]=327.0,
[M+H.sup.+]=305.1.
127.3
7-(Pyridin-3-ylmethoxy)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoind-
ol-1-one
[1112] 3-(Bromomethyl)pyridine hydrobromide (0.07 mmol, 17 mg) was
added portionswise to
7-hydroxy-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
(0.07 mmol, 20 mg) and cesium carbonate (0.33mo1, 107 mg) in DMF
(15mL). The reaction mixture was further stirred over 12 h at room
temperature under an inert atmosphere of nitrogen. A saturated
aqueous solution of K.sub.2CO.sub.3 was added and the mixture was
extracted with EtOAc (3 times). The joined organic phases were
washed with water, dried and evaporated in vacuo. The residue was
passed on a silicagel column eluted first with EtOAc to elute the
impurity and finally with CH.sub.2Cl.sub.2: MeOH 19: 1. Yield 5 mg
(19%)..sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta.=8.71 (s br.,
1H), 8.54 (s br., 1H), 8.28 (d, 1H), 7.97-7.88 (m, 3H), 7.70 (t,
1H), 7.53 (t, 1H), 7.49 (d, 2H), 7.41 (t, 1H), 7.15-7.05 (m, 2H),
5.27 (s br., 2H), 4.43 (s br., 2H), 3.96 (t, 2H), 3.27 (t, 2H).
Example 128
7-(Pyridin-4-ylmethoxy)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-o-
ne
[1113] The title compound was prepared in analogy to the process
described in Example 127 using 4-(bromomethyl)pyridine hydrobromide
(0.07 mmol, 17 mg). Yield 4 mg (15%). .sup.1H NMR (DMSO-d.sub.6,
500 MHz): .delta.=8.57 (d, 2H), 8.28 (d, 1H), 7.92 (d, 2H), 7.70
(t, 1H), 7.58-7.43 (m, 5H), 7.10 (d, 1H), 7.02 (d, 1H), 5.29 (s,
2H), 4.43 (s, 2H), 3.99 (t, 2H), 3.28 (t, 2H).
Example 129
7-(Pyridin-2-ylmethoxy)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-o-
ne
[1114] The title compound was prepared in analogy to the process
described in Example 127 using 2-(bromomethyl)pyridine hydrobromide
(0.07 mmol, 17 mg). Yield 15 mg (57%). ESI-MS: [M+Na+]=418.1,
[M+H+]=396.1
Example 130
4-Morpholin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one;
compound with trifluoro-acetic acid
130.1 4-Bromo-2-(2-(quinolin-2-yl)ethyl)isoindolin-1-one
[1115] The title compound was prepared in analogy to the process
described in Example 119.3 starting from methyl
3-bromo-2-(bromomethyl)benzoate (1.62 mmol, 500 mg) and
2-(quinolin-2-yl)ethanamine from Example a1.
130.2
4-Morpholin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-on-
e ; compound with trifluoro-acetic acid
[1116] The title compound was prepared in analogy to the process
described in Example 99 starting from the compound of Example 130.1
(0.08 mmol, 30 mg) and morpholine.
[1117] Yield. 15 mg (37%).
Example 131
4-(1,1-Dioxo-1-thiomorpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-i-
soindol-1-one
[1118] The title compound was prepared in analogy to the process
described in Example 99 starting from the compound of Example
130.1. Yield: 7 mg (15%). ESI-MS: [M+Na.sup.+]=444.00,
[M+H.sup.+]=422.10.
[1119] The following compounds of the formula (I) described below
were prepared using the standard operation procedures described
above.
Example 132
7-[8-(4-Methyl-piperazine-1-sulfonyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-(-
2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
trifluoroacetate
Example 133
7-[8-(Morpholine-4-sulfonyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-(2-quinoli-
n-2-yl-ethyl)-2,3-dihydro-isoindol-1-one trifluoroacetate
[1120] .sup.1H NMR (DMSO-d.sub.6, 500 MHz)=8.79 (d, 1H), 8.18 (d,
1H), 8.10 (d, 1H), 7.97 (t, 1H), 7.87 (d, 1H), 7.78 (t, 1H), 7.71
(d, 1H), 7.45 (m, 3H), 7.10 (d, 1H), 6.86 (d, 1H), 4.60 (s, 2H),
4.50 (s, 2H), 4.03 (m +H.sub.2O), 3.61 (s, 4H), 3.46 (t, 2H), 3.32
(br.s., 2H), 3.05 (br. s., 4H), 2.83 (br. s., 2H)
Example 134
7-(2-Oxa-6-aza-spiro[3.4]oct-6-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-i-
soindol-1-one
[1121] ESI-MS: [M+H.sup.+]=400.10.
Example 135
7-(1-Oxo-thiomorpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindo-
l-1-one
[1122] ESI-MS: [M+H.sup.+]=406.10.
Example 136
7-(2-Oxa-6-aza-spiro[3.5]non-6-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-i-
soindol-1-one
[1123] ESI-MS: [M+H.sup.+]=414.10.
Example 137
4-(1,1-Dioxo-thiomorpholin-4-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyr-
rolo[3,4-b]pyridin-5-one
[1124] ESI-MS: [M+Na.sup.+]=445.10, 424.10, [M+H.sup.+]=423.10.
Example 138
4-(4-Methyl-piperazin-1-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[-
3,4-b]pyridin-5-one
[1125] ESI-MS: [M+Na.sup.+]=410.10, 389.15, [M+H.sup.+]=38.20.
Example 139
7-(3-Amino-azetidin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-
-one
[1126] ESI-MS: [M+H.sup.+]=359.10.
Example 140
7-[4-(4-Methoxy-benzyloxy)-phenyl]-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-i-
soindol-1-one
[1127] ESI-MS: 502.20, [M+H.sup.+]=501.20.
Example 141
4-Piperazin-1-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
[1128] ESI-MS: [M+H.sup.+]=373.15;
Example 142
7-(5,5-Difluoro-hexahydro-cyclopenta[c]pyrrol-2-yl)-2-(2-quinolin-2-yl-eth-
yl)-2,3-dihydro-isoindol-1-one
[1129] ESI-MS: [M+H.sup.+]=434.20.
Example 143
7-(4,4-Difluoro-piperidin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoi-
ndol-1-one
[1130] ESI-MS: [M+H.sup.+]=408.10.
Example 144
4-(4-Methyl-piperazin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one
[1131] ESI-MS: [M+H.sup.+]=387.20.
Example 145
7-(Azetidin-3-ylamino)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-on-
e
[1132]
3-[3-Oxo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-1H-isoindol-4-ylamin-
o]-1-carboxylic acid tert-butyl ester was prepared in the same
manner as the compound of Example 99 starting from
7-bromo-2-(2-quinolin-2-yl)-2,3-dihydro-isoindol-1-one from Example
5.4 and commercially available tert-butyl
3-aminoazetidine-1-carboxylate (yield: 63%). The protecting Boc
group was subsequently cleaved using TFA (1 equivalent) by stirring
1 h at room temperature in dichloromethane (yield: 49%).
[1133] ESI-MS: [M+Na.sup.+]=381.10, [M+H.sup.+]=359.10.
Example 146
7-[4-(4-Isopropenyl-phenoxy)-phenyl]-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-
-isoindol-1-one
[1134] ESI-MS: 498.20, [M+H.sup.+]=497.20.
Example 147
7-[(3S
,4S)-4-(2-Fluoro-4-trifluoromethoxy-phenyl)-3-methyl-piperidin-1-yl-
]-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
trifluororacetate
[1135] ESI-MS: 565.20, [M+H.sup.+]=564.20.
Example 148
7-[4-(2,6-Dimethyl-pyridin-3-yloxy)-3-fluoro-phenyl]-2-(2-quinolin-2-yl-et-
hyl)-2,3-dihydro-isoindol-1-one trifluoroacetate
[1136] ESI-MS: 505.20, [M+H.sup.+]=504.20.
Example 149
7-(1-Pyridin-4-ylmethyl-1H-indol-5-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihyd-
ro-isoindol-1-one trifluoroacetate
[1137] ESI-MS: 496.20, [M+H.sup.+]=495.20.
Example 150
2-(2-Quinolin-2-yl-ethyl)-7-thiomorpholin-4-yl-2,3-dihydro-isoindol-1-one
[1138] ESI-MS: [M+Na.sup.+]=412.10, 391.10, [M+H.sup.+]=390.10.
Example 151
7-(8-Methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-2-(2-quinolin-2-yl-ethyl)-2,-
3-dihydro-isoindol-1-one
Example 152
7-(3-Methyl-3,8-diaza-bicyclo[3.2.1]oct-8-yl)-2-(2-quinolin-2-yl-ethyl)-2,-
3-dihydro-isoindol-1-one
[1139] ESI-MS: [M+H.sup.+]=413.20.
Example 153
2-[2-(1-Methyl-1H-benzoimidazol-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro--
isoindol-1-one
[1140] ESI-MS: [M+H.sup.+]=377.20.
Example 154
7-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-(2-quinolin-2-yl-ethyl)-
-2,3-dihydro-isoindol-1-one
[1141] ESI-MS: [M+Na.sup.+]=435.20, [M+H.sup.+]=413.20.
Example 155
7-[3-Chloro-4-(4-hydroxy-4-methyl-cyclohexylamino)-phenyl]-2-(2-quinolin-2-
-yl-ethyl)-2,3-dihydro-isoindol-1-one hydrocloride
[1142] ESI-MS: 529.20, [M+H.sup.+]=527.20, 526.20.
Example 156
4-(1H-Pyrazol-4-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]py-
ridin-5-one
[1143] ESI-MS: [M+Na.sup.+]=378.10, 357.10, [M+H.sup.+]=356.10.
Example 157
7-[4-(4-Ethyl-piperazin-1-yl)-piperidin-1-yl]-2-(2-quinolin-2-yl-ethyl)-2,-
3-dihydro-isoindol-1-one trifluoroacetate
[1144] ESI-MS: [M+H.sup.+]=484.30.
Example 158
2-(2-Quinolin-2-yl-ethyl)-7-(3,4,5,6-tetrahydro-2H-l4,4'bipyridinyl-1-yl)--
2,3-dihydro-isoindol-1-one trifluoroacetate
[1145] ESI-MS: [M+H.sup.+]=449.20.
Example 159
7-(4-Pyridin-3-yl-piperazin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-is-
oindol-1-one trifluoroacetate
[1146] ESI-MS: [M+H.sup.+]=450.20.
Example 160
4-(4-Fluoro-phenyl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]py-
ridin-5-one (di trifluoroacetate)
[1147] ESI-MS: 385.10, [M+H.sup.+]=384.10.
Example 161
4-(4-Methoxy-phenyl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]p-
yridin-5-one
[1148] ESI-MS: 397.10, [M+H.sup.+]=396.10.
Example 162
4-(2-Methyl-2H-pyrazol-3-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo-
[3,4-b]pyridin-5-one hydrochloride
[1149] ESI-MS: [M+Na.sup.+]=392.15, 371.15, [M+H.sup.+]=370.10.
Example 163
4-Piperazin-1-yl-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]pyrid-
in-5-one
[1150] .sup.1H NMR (CDCl.sub.3, 500 MHz)=8.29 (d, 1H), 8.08 (d,
1H), 8.02 (d, 1H), 7.78 (d, 1H), 7.69 (t, 1H), 7.50 (t, 1H), 7.36
(d, 1H), 6.60 (d, 1H), 4.30 (s, 2H), 4.11 (t, 2H), 3.72 (q, 1H),
3.48 (m sym., 4H), 3.35 (t, 2H), 3.07 (m sym., 4H)
Example 165
4-(2-Oxo-2,3-dihydro-1H-indol-6-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro--
pyrrolo[3,4-b]pyridin-5-one
[1151] ESI-MS: 422.10, [M+H.sup.+]=421.10.
Example 166
4-Pyrimidin-5-yl-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]pyrid-
in-5-one
[1152] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta.=9.28 (s, 1H), 8.95
(s, 2H), 8.79 (d, 1H), 8.10 (d, 1H), 7.96 (d, 1H), 7.79 (d, 1H),
7.68 (t, 1H), 7.51 (t, 1H), 7.36 (d, 1H), 7.32 (m sym., 2H), 4.55
(s, 2H), 4.20 (t, 2H), 3.40 (t, 2H).
Example 167
7-[4-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-2-(2-quinolin-2-yl-ethyl)-2,3-
-dihydro-isoindol-1-one trifluoroacetate
[1153] ESI-MS: [M+Na.sup.+]=499.20, [M+H.sup.+]=477.20.
Example 168
7-(4-Morpholin-4-ylmethyl-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-is-
oindol-1-one trifluoroacetate
[1154] ESI-MS: [M+Na.sup.+]=486.20, [M+H.sup.+]=464.20.
Example 169
7-(3-Methoxy-pyridin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol--
1-one trifluoroacetate
[1155] ESI-MS: [M+H].sup.+=396.15;
Example 170
7-(3-Chloro-pyridin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-
-one trifluoroacetate
[1156] ESI-MS: [M+H].sup.+=400.10.
Example 171
7-(2-Chloro-pyridin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-
-one trifluoroacetate
[1157] ESI-MS: [M+H].sup.+=400.10.
Example 172
7-(6-Methyl-pyridin-3-ylmethoxy)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-iso-
indol-1-one
[1158] ESI-MS: 411.20, [M+H].sup.+=410.20.
Example 173
7-(3-Fluoro-pyridin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-
-one
[1159] ESI-MS: [M+H.sup.+]=384.10.
Example 174
7-(3-Amino-4-methyl-piperidin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro--
isoindol-1-one
[1160] ESI-MS: [M+H.sup.+]=401.20.
Example 175
2-[2-(1H-Benzoimidazol-2-yl)-ethyl]-7-(1,1-dioxo-thiomorpholin-4-yl)-2,3-d-
ihydro-isoindol-1-one
[1161] ESI-MS: [M+Na.sup.+]=433.10, [M+H.sup.+]=411.10.
Example 176
7-[(1S,4S)-5-(4-Chloro-phenyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-2-(2-qui-
nolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one trifluoroacetate
[1162] .sup.1H NMR (DMSO-d.sub.6, 500 MHz)=8.76 (d, 1H), 8.19 (d.,
1H), 8.11 (d, 1H), 7.97 (t., 1H), 7.88-7.76 (m, 2H), 7.25 (t., 1H),
7.13 (d, 2H), 6.76 (d, 1H), 6.59 (d, 1H), 6.49 (d, 2H), 4.78 (s.,
1H), 4.45 (br. s., 1H), 4.39 (d, 2H), 3.91 (m sym., 2H), 3.88 (d,
1H), 3.40 (m, 3H), 3.00 (d, 1H), 2.89 (d, 1H), 1.90 (br. s.,
2H)
Example 177
7-(4-Methyl-piperazin-1-ylmethyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-is-
oindol-1-one
[1163] ESI-MS: [M+H.sup.+]=401.25;
Example 178
7-Morpholin-4-ylmethyl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-on-
e
[1164] ESI-MS: [M+H.sup.+]=388.20.
Example 179
7-(2-Methyl-pyridin-3-ylmethoxy)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-iso-
indol-1-one
[1165] ESI-MS: [M+Na.sup.+]=432.20, 411.20, [M+H.sup.+]=410.20.
Example 180
4-Methoxy-7-(1H-pyrazol-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoind-
ol-1-one
[1166] ESI-MS: [M+H.sup.+]=385.20.
Example 181
4-Pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
[1167] ESI-MS: [M+Na.sup.+]=388.10, [M+H.sup.+]=366.15;
Example 182
7-(2-Methoxy-pyridin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol--
1-one trifluoroacetate
[1168] ESI-MS: [M+H.sup.+]=396.20.
Example 183
4-Methoxy-7-pyrimidin-5-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol--
1-one
[1169] ESI-MS: [M+H.sup.+]=397.20.
Example 184
7-(1,1-Dioxothiomorpholin-4-yl)-2-[2-(1-methyl-1H-benzoimidazol-2-yl)-ethy-
l]-2,3-dihydro-isoindol-1-one trifluoroacetate
[1170] ESI-MS: [M+Na.sup.+]=447.15, [M+H.sup.+]=425.20.
Example 185
4-Methoxy-7-pyridin-3-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1--
one trifluoroacetate
[1171] .sup.1H NMR (DMSO-d.sub.6, 500 MHz)=8.90 (s, 1H), 8.79 (d,
1H), 8.70 (d, 1H), 8.34 (d, 1H), 8.13 (d, 1H), 8.05 (d, 1H), 7.91
(t, 1H), 7.86 (t, 1H), 7.79 (d, 1H), 7.72 (t, 1H), 7.55 (d, 1H),
7.38 (d, 1H), 4.54 (s, 2H), 4.03 (t, 2H), 3.96 (s, 3H), 3.45 (t,
2H).
Example 186
4-Methoxy-7-(4-methoxy-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoin-
dol-1-one
[1172] ESI-MS: [M+H.sup.+]=425.20.
Example 187
7-(4-Fluoro-phenyl)-4-methoxy-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoind-
ol-1-one
[1173] ESI-MS: [M+H.sup.+]=413.15;
Example 188
7-(4-Dimethylaminomethyl-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-iso-
indol-1-one (dihydrochloride)
[1174] ESI-MS: [M+Na.sup.+]=444.25, 423.30, [M+H.sup.+]=422.30.
Example 189
7-(1,1-Dioxo-thiomorpholin-4-yl)-4-methoxy-2-(2-quinolin-2-yl-ethyl)-2,3-d-
ihydro-isoindol-1-one
[1175] ESI-MS: [M+Na.sup.+]=474.15, [M+H.sup.+]=452.20.
Example 190
7-(1,1-Dioxo-tetrahydro-thiophen-3-ylamino)-2-(2-quinolin-2-yl-ethyl)-2,3--
dihydro-isoindol-1-one
[1176] ESI-MS: [M+Na.sup.+]=444.15, [M+H.sup.+]=422.15;
Example 191
7-(6-Fluoro-pyridin-3-ylmethoxy)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-iso-
indol-1-one
[1177] ESI-MS: [M+Na.sup.+]=436.20, 415.20, [M+H.sup.+]=414.20.
Example 192
7-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihy-
dro-isoindol-1-one
[1178] ESI-MS: [M+H.sup.+]=399.20.
Example 193
7-(4-Aminomethyl-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1--
one
[1179] ESI-MS: [M+Na.sup.+]=416.10, [M+H.sup.+]=394.20.
Example 194
7-(4-Methylaminomethyl-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoin-
dol-1-one
[1180] ESI-MS: [M+Na.sup.+]=430.20, [M+H.sup.+]=408.30.
Example 195
2-[2-(1-Methyl-1H-benzoimidazol-2-yl)-ethyl]-7-pyridin-4-yl-2,3-dihydro-is-
oindol-1-one
[1181] ESI-MS: 370.10, [M+H.sup.+]=369.10.
Example 196
2-[2-(1-Methyl-1H-benzoimidazol-2-yl)-ethyl]-7-pyridin-3-yl-2,3-dihydro-is-
oindol-1-one
[1182] ESI-MS: 370.10, [M+H.sup.+]=369.10.
Example 197
2-[2-(1-Methyl-1H-benzoimidazol-2-yl)-ethyl]-7-pyrimidin-5-yl-2,3-dihydro--
isoindol-1-one
[1183] ESI-MS: 371.15, [M+H.sup.+]=370.10.
Example 198
4-Hydroxy-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1--
one
[1184] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta.=8.49 (d, 1H),
8.28 (d, 1H), 7.9 (m, 2H), 7.55 (t, 1H), 7.51 (t, 1H), 7.48 (d,
1H), 7.38 (d, 2H), 7.24 (d, 1H), 7.05 (d, 1H), 4.38 (s, 1H), 3.97
(t, 1H), 3.27 (m +H.sub.2O)
Example 199
4-Ethoxy-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-o-
ne
[1185] ESI-MS: [M+H.sup.+]=410.10.
Example 200
4-(1H-Pyrazol-3-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
[1186] A Personal Chemistry Ermy's optimizer microwave was used.
Each microwave tube was charged with 0.1 eq. of
[1,1'-Bis(diphenylphosphino)-ferrocene]dichloro-palladium(II),
complex with dichloromethane (7mg). To the microwave tube, a
solution of 4-bromo-2-(2-(quinolin-2-yl)ethyl)isoindolin-1-one from
Example 130.1 (31 mg, 0.08 mmol) dissolved in dioxane (1.0 mL) was
added, followed by the addition of 1H-pyrazol-3-ylboronic acid
(11.2 mg, 0.1mmol) dissolved in dioxane (0.35 mL). Then, 250 .mu.L
of 1M aqueous solution of Cs.sub.2CO.sub.3 was added and the
resulting mixture was heated in the microwave for 1200 sec at
120.degree. C. The reaction was filtered, checked by LC/MS and
concentrated to dryness. The residues were dissolved in 1:1
DMSO/MeOH. Purification by reverse phase HPLC provided
4-(1H-pyrazol-3-yl)-2-(2-(quinolin-2-yl)ethyl)isoindolin-1-one (2.3
mg, 8%). .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 8.28 (d,
J=8.54 Hz, 1H) 8.01 (d, J=6.41 Hz, 1H) 7.92 (t, J=8.09 Hz, 2H) 7.84
(s, 1H) 7.69-7.74 (m, 1H) 7.50-7.62 (m, 4H) 6.83 (s, 1H) 4.80 (s,
2H) 4.07 (t, J=7.17 Hz, 2H) 3.34 (t, J=7.32 Hz, 2H). MS (APCI) m/z
355 (M+H).sup.+; ESI-MS: 356.10, [M+H.sup.+]=355.10.
Example 201
4-Pyridin-3-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
[1187] Syntheses were performed using a Personal Chemistry Ermy's
optimizer microwave. Each microwave tube was charged with 0.1 eq.
of [1,1'-Bis(diphenylphosphino)-ferrocene]dichloropalladium(II),
complex with dichloromethane (7 mg). To the microwave tube, a
solution of 4-bromo-2-(2-(quinolin-2-yl)ethyl)isoindolin-1-one from
Eample 130.1 (31 mg, 0.08 mmol) dissolved in dioxane (1.0 mL). was
added, followed by pyridin-3-ylboronic acid (12.2mg, 0.1 mmol)
dissolved in dioxane (0.35 mL). Then, 250 uL of 1M aqueous solution
of Cs.sub.2CO.sub.3 was added and the resulting mixture was heated
in the microwave for 1200 sec at 120.degree. C. The reaction was
filtered, checked by LC/MS and concentrated to dryness. The
residues were dissolved in 1:1 DMSO/MeOH. Purification by reverse
phase HPLC provided
4-(pyridin-3-yl)-2-(2-(quinolin-2-yl)ethyl)isoindolin-1-one (14.6
mg, 47%). .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 8.80 (d,
J=1.83 Hz, 1H) 8.65 (dd, J=4.88, 1.53 Hz, 1H) 8.28 (d, J=8.55 Hz,
1H) 8.00-8.06 (m, 1H) 7.91 (dd, J=19.23, 8.24 Hz, 2H) 7.70-7.76 (m,
3H) 7.62-7.66 (m, 1H) 7.49-7.59 (m, 3H) 4.72 (s, 2H) 4.03 (t,
J=7.17 Hz, 2H) 3.31 (t, J=7.32 Hz, 2H); MS (APCI) m/z 366
(M+H).sup.+.
[1188] The following compounds of the formula (I) described below
were prepared using the standard operation procedures described
above.
Example 202
4-(2-Methyl-2H-pyrazol-3-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindo-
l-1-one trifluoroacetate
[1189] ESI-MS: [M+Na.sup.+]=391.10, 370.10, [M+H.sup.+]=369.10.
Example 203
4-(4-Methoxy-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
trifluoroacetate
[1190] ESI-MS: 396.10, [M+H.sup.+]=395.10.
Example 204
4-(3-Methoxy-propoxy)-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-
-isoindol-1-one
[1191] ESI-MS: 455.20, [M+H.sup.+]=454.20.
Example 205
4-Isopropoxy-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one
[1192] ESI-MS: 425.20, [M+H.sup.+]=424.20.
Example 206
7-(4-Pyrrolidin-1-yl-piperidin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-
-isoindol-1-one trifluoroacetate
[1193] ESI-MS: [M+H.sup.+]=441.25.
Example 207
7-[1,4']Bipiperidinyl-1'-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one trifluoroacetate
[1194] ESI-MS: [M+H.sup.+]=455.30.
Example 208
4-Pyrimidin-5-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
[1195] ESI-MS: [M+Na.sup.+]=389.10, 368.10, [M+H.sup.+]=367.10.
Example 209
7-(4-Methoxy-phenyl)-2-[2-(1-methyl-1H-benzoimidazol-2-yl)-ethyl]-2,3-dihy-
dro-isoindol-1-one trifluoroacetate
[1196] ESI-MS: 399.20, [M+H.sup.+]=398.20.
Example 210
4-Methoxy-7-(2-methyl-2H-pyrazol-3-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihyd-
ro-isoindol-1-one
[1197] ESI-MS: 400.15, [M+H.sup.+]=399.10.
Example 211
7-(4-Fluoro-phenyl)-2-[2-(1-methyl-1H-benzoimidazol-2-yl)-ethyl]-2,3-dihyd-
ro-isoindol-1-one trifluoroacetate
[1198] ESI-MS: 387.10, [M+H.sup.+]=386.10.
Example 212
4-(4-Fluoro-phenyl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
trifluoroacetate
[1199] ESI-MS: [M+Na.sup.+]=405.10, 384.10, [M+H.sup.+]=383.10.
Example 213
4-(2-Methyl-2H-pyrazol-3-yl)-6-(2-[1,2,4]triazolo[1,5-a]pyridin-2-yl-ethyl-
)-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one trifluoroacetate
[1200] ESI-MS: 361.10, [M+H.sup.+]=360.10.
Example 214
6-[2-(1-Methyl-1H-benzoimidazol-2-yl)-ethyl]-4-(2-methyl-2H-pyrazol-3-yl)--
6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one
[1201] ESI-MS: 374.15, [M+H.sup.+]=373.10.
Example 215
4-Pyrimidin-5-yl-6-(2-[1,2,4]triazolo[1,5-a]pyridin-2-yl-ethyl)-6,7-dihydr-
o-pyrrolo[3,4-b]pyridin-5-one
[1202] ESI-MS: 359.10, [M+H.sup.+]=358.10.
Example 216
6-[2-(1-Methyl-1H-benzoimidazol-2-yl)-ethyl]-4-morpholin-4-yl-6,7-dihydro--
pyrrolo[3,4-b]pyridin-5-one
[1203] ESI-MS: 379.10, [M+H.sup.+]=378.10.
Example 217
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-methoxy-7-pyrimidin-5-yl-2,3-dihy-
dro-isoindol-1-one trifluoroacetate
[1204] ESI-MS: [M+H.sup.+]1 =386.10.
Example 218
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-methoxy-7-pyridin-3-yl-2,3-dihydr-
o-isoindol-1-one trifluoroacetate
[1205] ESI-MS: [M+H.sup.+]=38510.
Example 219
7-(1S,5S)-3,6-Diaza-bicyclo[3.2.0]hept-3-yl-2-(2-quinolin-2-yl-ethyl)-2,3--
dihydro-isoindol-1-one trifluoroacetate
[1206] ESI-MS: [M+H.sup.+]=385.20.
Example 220
7-(3aR,7aS)-Octahydro-pyrrolo[3,2-c]pyridin-5-yl-2-(2-quinolin-2-yl-ethyl)-
-2,3-dihydro-isoindol-1-one trifluoroacetate
[1207] ESI-MS: [M+H.sup.+]=413.20.
Example 221
2-[2-(5-Fluoro-1-methyl-1H-benzoimidazol-2-yl)-ethyl]-7-pyridin-4-yl-2,3-d-
ihydro-isoindol-1-one trifluoroacetate
[1208] ESI-MS: [M+H.sup.+]=387.10.
Example 222
2-[2-(1-Ethyl-1H-benzoimidazol-2-yl)-ethyl]-7-pyridin-4-yl-2,3-dihydro-iso-
indol-1-one trifluoroacetate
[1209] ESI-MS: [[M+H.sup.+]=383.10.
Example 223
2-(2-Benzothiazol-2-yl-ethyl)-7-pyridin-4-yl-2,3-dihydro-isoindol-1-one
trifluoroacetate
[1210] ESI-MS: M+H .sup.+]=372.10.
Example 224
7-((R)-3-Amino-pyrrolidin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoi-
ndol-1-one trifluoroacetate
[1211] ESI-MS: [M+Na.sup.+]=395.20, [M+H .sup.+]=373.20.
Example 225
4-(1H-Pyrazol-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
[1212] .sup.1H NMR (DMSO-d.sub.6, 500 MHz)=13.20 (br.s., 1H), 8.29
(d, 1H), 8.22 (br.s., 1H), 8.00 (br.s., 1H), 7.93 (m, 2H), 7.85 (m,
1H), 7.72 (t, 1H), 7.55 (t, 1H), 7.50 (m, 3H), 4.75 (s, 2H), 4.05
(t, 2H), 3.35 (m +H.sub.2O)
Example 226
6-[2-(1-Methyl-1H-benzoimidazol-2-yl)-ethyl]-4-(4-methyl-piperazin-1-yl)-6-
,7-dihydro-pyrrolo[3,4-b]pyridin-5-one trifluoroacetate
[1213] ESI-MS: [M+Na.sup.+]=413.20, 392.20, [M+H.sup.+]=391.20.
Example 227
4-Morpholin-4-yl-6-(2-[1,2,4]triazolo[1,5-a]pyridin-2-yl-ethyl)-6,7-dihydr-
o-pyrrolo[3,4-b]pyridin-5-one
[1214] ESI-MS: 366.10, [M+H.sup.+]=365.10.
Example 228
7-(2-Methyl-morpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one trifluoroacetate
[1215] ESI-MS: [M+Na.sup.+]=410.10, 389.20, [M+H.sup.+]=388.20.
Example 229
7-(2-Dimethylaminomethyl-morpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dih-
ydro-isoindol-1-one trifluoroacetate
[1216] ESI-MS: [M+Na.sup.+]=453.20, 432.20, [M+H.sup.+]=431.20.
Example 230
7-Pyridin-4-yl-2-(2-[1,2,4]triazolo[1,5-a]pyridin-2-yl-ethyl)-2,3-dihydro--
isoindol-1-one
230.1 7-Bromo-2-(2-[1,2,4]triazolo
[1,5-a]pyridin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
[1217] In a 20 mL microwave reaction vial,
2-bromo-6-bromomethylbenzoic acid methyl ester from Example 5.3
(3.1 g, 10 mmol), 2-[1,2,4]triazolo[1,5-a]pyridin-2-yl-ethylamine
from Example g1) (1.6 g, 10 mmol) and DIPEA (1.3 g, 10 mmol) were
dissolved in isopropanol (15 mL). The resulted mixture was heated
on microwave at 100.degree. C. for 1.5 h. The solvent was
evaporated under reduced pressure. The residue was chromatographied
on silica gel (solvent: CH.sub.2Cl.sub.2/CH.sub.3OH (10:1; v/v).
The title compound was obtained as a white solid (1.9 g, yield
51%). LC-MS: m/z=359 (M+H.sup.+) R.sub.t=1.60 min. .sup.1H NMR (400
MHz, CDCl.sub.3): .delta.=8.53-8.51 (m, 1H), 7.70-7.68 (m, 1H),
7.60-7.58 (m, 1H), 7.54-7.52 (m, 1H), 7.36-7.34 (m, 2H), 7.03-7.01
(m, 1H), 4.38 (s, 2H), 4.20-4.16 (t, J=6.8 Hz, 2H), 3.36-3.33 (t,
J=6.8 Hz, 2H).
[1218] 230.2
7-Pyridin-4-yl-2-(2-[1,2,4]triazolo[1,5-a]pyridin-2-yl-ethyl)-2,3-dihydro-
-isoindol-1-one
[1219] A 5 mL microwave reaction vial was charged with the compound
from Example 230.1 (96 mg, 0.27 mmol), pyridin-4-ylboronic acid
(39.4 mg, 0.32 mmol) and Cs.sub.2CO.sub.3 (175 mg, 0.54 mmol) in
DMF (3 mL). Pd(dppf)Cl.sub.2 (4.4 mg, 5.4 .mu.mol) was added to
give a suspension. The mixture was purged with argon for 1 min. The
resulting mixture was heated on microwave at 100.degree. C. for 45
min. The reaction mixture was filtered through filter. The filtrate
was purified by Prep-HPLC to give the title compound (40 mg, yield:
40.2%) as a white solid. LC-MS: m/z=356 (M+H).sup.+; R.sub.t=1.63
min.
[1220] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.=8.59-8.58 (m,
2H), 8.44-8.42 (m, 1H), 7.61-7.59 (m, 1H), 7.51-7.49 (m, 1H),
7.43-7.42 (m, 4H), 7.29-7.28 (m, 1H), 6.92-6.91 (m, 1H), 4.37 (s,
2H), 4.08-4.04 (t, J=7.2 Hz, 2H), 3.25-3.21 (t, J=7.2 Hz, 2H).
Example 231
7-Morpholin-4-yl-2-(2-1,2,4triazolo[1,5-a]pyridin-2-yl-ethyl)-2,3-dihydro--
isoindol-1-one
[1221] A 5 mL microwave reaction vial was charged with the compound
from Example 230.1 (96 mg, 0.27 mmol), Cs.sub.2CO.sub.3 (175 mg,
0.54 mmol), Pd.sub.2(dba).sub.3 (5 mg, 2 mol %) and X-PHOS (8 mg, 6
mol %). The solids were purged with argon for at least 5 min. A
separate round bottom flask was charged with DMF (3 mL) and
morpholine (73 mg, 0.54 mmol), degas with argon for at least 10
min. and then transfered to the microwave reaction vial under inert
conditions. The resulting reaction mixture was heated on microwave
at 100.degree. C. for 1 h. The reaction mixture was filtered
through filter. The filtrate was purified by Prep-HPLC to give the
title compound (20 mg, yield: 19.6%) as a white solid. LC-MS:
m/z=364 (M+H.sup.+); R.sub.t=1.65 min. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta.=8.44-8.42 (m, 1H), 7.61-7.59 (m, 1H),
7.42-7.41 (m, 1H), 7.34-7.30 (m, 1H), 6.91-6.87 (m, 2H), 6.79-6.77
(m, 1H), 4.26 (s, 2H), 4.05-4.02 (t, J=6.8 Hz, 2H), 3.88-3.86 (m,
4H), 3.24-3.18 (m, 6H).
Example 232
7-(1,1-Dioxothiomorpholin-4-yl)-2-(2-[1,2,4]triazolo[1,5-a]pyridin-2-yl-et-
hyl)-2,3-dihydro-isoindol-1-one
[1222] The title compound was prepared in analogy to the process
described in example 231. LC-MS: m/z=412 (M+H.sup.+); R.sub.t=1.59
min. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.=8.54-8.52 (m, 1H),
7.72-7.70 (m, 1H), 7.57-7.55 (m, 1H), 7.45-7.41 (m, 1H), 7.06-7.02
(m, 2H), 6.90-6.88 (m, 1H), 4.38 (s, 2H), 4.16-4.12 (t, J=6.8 Hz,
2H), 3.74-3.73 (m, 4H), 3.35-3.31 (m, 6H)
Example 233
7-(4-Methyl-piperazin-1-yl)-2-(2-[1,2,4]triazolol[1,5-a]pyridin-2-yl-ethyl-
)-2,3-dihydro-isoindol-1-one
[1223] The title compound was prepared in analogy to the process
described in example 231. LC-MS: m/z=377 (M+H.sup.+) R.sub.t=1.53
min. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.=8.47 (s, 1H), 7.62
(s, 1H), 7.45 (s, 1H), 7.36-7.33 (m, 1H), 6.98-6.91 (m, 2H),
6.79-6.77 (m, 1H), 4.29 (s, 2H), 4.04 (s, 2H), 3.69-3.66 (m, 2H),
3.55-3.53 (m, 2H), 3.30-3.13 (m, 6H), 2.79 (s, 3H).
Example 234
7-(1,1-Dioxothiomorpholin-4-yl)-2-(2-imidazol[1,2-a]pyridin-2-yl-ethyl)-2,-
3-dihydro-isoindol-1-one
[1224] A mixture of
7-bromo-2-(2-imidazol[1,2-a]pyridin-2-yl-ethyl)-2,3-dihydro-isoindol-1-on-
e from Example 20.1 (100 mg, 0.281 mmol), thiomorpholine
1,1-dioxide (76 mg, 0.561 mmol), CS.sub.2CO.sub.3 (183 mg, 0.561
mmol), dicyclohexyl (2',4',6'-triisopropylbiphenyl-2-yl)phosphine
(13.38 mg, 0.028 mmol) and Pd.sub.2(dba).sub.3 (25.7 mg, 0.028
mmol) in DMF (2 mL) was heated to 100.degree. C. for one hour in a
microwave. The solvent was removed under reduced pressure, and the
residue was purified by pre-HPLC to give the title compound (40 mg,
0.097 mmol, 34.7% yield) as white solid. LC-MS: m/z=411 (M+H.sup.+)
R.sub.t=1.66 min. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.=8.06
(d, J=6.4 Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.46-7.40 (m, 2H), 7.15
(t, J=7.8 Hz, 1H), 7.05 (d, J=7.2 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H),
6.79 (t, J=6.8 Hz, 1H), 4.32 (s, 2H), 4.03 (t, J=7.2 Hz, 2H), 3.76
(s, 4H), 3.36 (s, 4H), 3.19 (t, J=7.2 Hz, 2H).
Example 235
2-(2-Imidazol[1,2-a]pyridin-2-yl-ethyl)-7-pyridin-3-yl-2,3-dihydro-isoindo-
l-1-one
[1225] A mixture of
7-bromo-2-(2-imidazol[1,2-a]pyridin-2-yl-ethyl)-2,3-dihydro-isoindol-1-on-
e from Example 20.1 (100 mg, 0.281 mmol), pyridin-3-ylboronic acid
(51.8 mg, 0.421 mmol), Cs.sub.2CO.sub.3 (137 mg, 0.421 mmol) and
Pd(dppf)Cl.sub.2 (20.54 mg, 0.028 mmol) in DMF (2 mL) was heated in
a Biotage microwave at about 100.degree. C. for about 1 h .The
mixture was purified by pre-HPLC to give the title compound (25.8
mg, 0.073 mmol, 25.9% yield) as a white solid. LC-MS: m/z=355
(M+H.sup.+) R.sub.t=1.70 min
[1226] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=8.67 (s, 1H),
8.66-8.56 (m, 1H), 8.47 (d, J=6.8 Hz 1H), 7.91-7.88 (m, 1H), 7.74
(s, 1H), 7.68-7.61 (m, 2H), 7.47-7.41 (m, 3H), 7.19-7.15 (m, 1H),
6.84-6.80 (m, 1H), 4.5 (s, 2H), 3.36 (s, 4H), 3.87 (t, J=7.4 Hz,
2H), 3.04 (t, J=7.2 Hz, 2H).
Example 236
7-(4-Fluoro-phenyl)-2-(2-imidazol[1,2-a]pyridin-2-yl-ethyl)-2,3-dihydro-is-
oindol-1-one
[1227] The title compound was prepared in analogy to the process
described in example 235. LC-MS: m/z=372 (M+H.sup.+) R.sub.t=1.979
min. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=8.47 (d, J=6.4 Hz
1H), 7.74 (s, 1H), 7.63-7.45 (m, 5H), 7.36 (d, J=7.2 Hz 1H),
7.24-7.16 (m, 3H), 6.84 (t, J=7.2 Hz, 1H), 4.48 (s, 2H), 3.86 (t,
J=7.4 Hz, 2H), 3.04 (t, J=7.2 Hz, 2H)
Example 237
2-(2-Imidazol[1,2-a]pyridin-2-yl-ethyl)-7-(4-methoxy-phenyl)-2,3-dihydro-i-
soindol-1-one
[1228] The title compound was prepared in analogy to the process
described in example 235. LC-MS: m/z=384 (M+H.sup.+) R.sub.t=1.95
min. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=8.47 (d, J=6.8
Hz, 1H), 7.79 (s, 1H), 7.60-7.42 (m, 5H), 7.33-7.31 (m, 1H),
7.20-7.17 (m, 1H), 6.97-6.94 (m, 2H), 6.84-6.80 (m, 1H), 4.46 (s,
2H), 3.86-3.81 (m, 5H), 3.03 (t, J=7.2 Hz, 2H).
Example 238
2-(2-Imidazol[1,2-a]pyridin-2-yl-ethyl)-7-pyrimidin-5-yl-2,3-dihydro-isoin-
dol-1-one
[1229] The title compound was prepared in analogy to the process
described in example 235. LC-MS: m/z=356 (M+H.sup.+) R.sub.t=1.61
min. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=9.18 (s, 1H),
8.92 (s, 1H), 8.46 (d, J=7.2 Hz, 1H), 7.74-7.65 (m, 3H), 7.53-7.50
(m, 1H), 7.46-7.44 (m, 1H), 7.19-7.15 (m, 1H), 6.84-6.80 (m, 1H),
4.52 (s, 2H), 3.88 (t, J=7.6 Hz, 2H), 3.04 (t, J=7.2 Hz, 2H).
Example 239
2-(2-Imidazol[1,2-a]pyridin-2-yl-ethyl)-7-(2-methyl-2H-pyrazol-3-yl)-2,3-d-
ihydro-isoindol-1-one
[1230] The title compound was prepared in analogy to the process
described in example 235. LC-MS: m/z=358 (M+H.sup.+) R.sub.t=1.70
min. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=8.44 (d, J=6.8
Hz, 1H), 7.73 (s, 1H), 7.66-7.61 (m, 2H), 7.43 (d, J=8.0 Hz, 2H),
7.34 (d, J=8.0 Hz, 1H), 7.18-7.14 (m, 1H), 6.83-6.79 (m, 1H), 6.26
(d, J=1.6 Hz, 1H), 4.53 (s, 2H), 3.85 (t, J=7.0 Hz, 2H), 3.46 (s,
3H), 3.02 (t, J=7.0 Hz, 2H).
Example 240
2-(2-Imidazol[1,2-a]pyridin-2-yl-ethyl)-7-(2-methyl-pyridin-3-yl)-2,3-dihy-
dro-isoindol-1-one
[1231] The title compound was prepared in analogy to the process
described in example 235. LC-MS: m/z=369 (M+H.sup.+) R.sub.t=1.73
min. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=8.44-8.42 (m,
2H), 7.71 (s, 1H), 7.63-7.60 (m, 2H), 7.48-7.44 (m, 2H), 7.24-7.22
(m, 2H), 7.18-7.15 (m, 1H), 6.83-6.79 (m, 1H), 4.57-4.45 (m, 2H),
3.83 (t, J=7.2 Hz, 2H), 3.01 (t, J=7.2 Hz, 2H), 2.13 (s, 3H).
Example 241
6-[2-(2-Imidazol[1,2-a]pyridin-2-yl-ethyl)-3-oxo-2,3-dihydro-1H-isoindol-4-
-yl]-1,3-dihydro-indol-2-one
[1232] A 5 mL microwave reaction vial was charged with
7-bromo-2-(2-imidazol[1,2-a]pyridin-2-yl-ethyl)-2,3-dihydro-isoindol-1-on-
e from Example 20.1 (100 mg, 0.281 mmol),
6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (87
mg, 0.337 mmol) and aq.Na.sub.2CO.sub.3 (2 N, 0.5 mL) in dioxane (2
mL). Pd(PPh.sub.3).sub.4 (3.24 mg, 2.81 .mu.mol)was added. The
resulting suspension was heated on microwave at 100.degree. C. for
30 minutes. The solid was filtered. The filtrated was purified by
Prep-HPLC to give the title compound (24.5 mg, 0.060 mmol, 21.37%
yield). LC-MS: m/z=409 (M+H.sup.+); R.sub.t=1.74 min. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta.=10.40 (s, 1H), 8.46 (d, J=6.4 Hz,
1H), 7.62-7.45 (m, 3H), 7.33-7.31 (m, 1H), 7.23-7.16 (m, 2H),
7.01-7.00 (m, 1H), 6.94 (s, 1H), 6.84-6.80 (m, 1H), 4.47 (s, 2H),
3.86 (t, J=6.8 Hz, 2H), 3.52 (s, 2H). 3.03 (t, J=7.2 Hz, 2H).
Example 242
2-(2-Imidazol[1,2-a]pyridin-2-yl-ethyl)-7-(1H-pyrazol-4-yl)-2,3-dihydro-is-
oindol-1-one
[1233] The title compound was prepared in analogy to the process
described in example 241. LC-MS: m/z=344 (M+H.sup.+) R.sub.t=1.64
min. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=12.90 (s, 1H),
8.54 (s, 1H), 6.46 (d, J=6.8 Hz, 1H), 8.01 (s, 1H), 7.76 (s, 1H),
7.64 (d, J=7.2 Hz, 1H), 7.56-7.45 (m, 2H), 7.37 (d, J=7.6 Hz, 1H),
77.17 (t, J=8.4 Hz, 1H), 6.82 (t, J=7.2 Hz, 1H), 4.43 (s, 2H),
3.90-3.85 (m, 2H), 3.03 (t, J=7.4 Hz, 2H).
Example 243
2-(2-Imidazol[1,2-a]pyridin-2-yl-ethyl)-7-(1H-indazol-6-yl)-2,3-dihydro-is-
oindol-1-one
[1234] The title compound was prepared in analogy to the process
described in example 241. LC-MS: m/z=394 (M+H.sup.+) R.sub.t=1.79
min. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.=8.09 (s, 1H), 8.00
(d, J=6.8 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.68 (s, 1H), 7.57-7.52
(m, 2H), 7.42-7.40 (m, 3H), 7.35 (d, J=8.4 Hz, 1H), 7.13 (t, J=7.8
Hz, 1H), 6.72 (t, J=6.6 Hz, 1H), 4.38 (s, 2H), 4.02 (t, J=7.0 Hz,
2H), 3.17 (t, J=7.0 Hz, 2H).
Example 244
7-(3H-Benzoimidazol-5-yl)-2-(2-imidazol[1,2-]pyridin-2-yl-ethyl)-2,3-dihyd-
ro-isoindol-1-one
[1235] The title compound was prepared in analogy to the process
described in example 241. LC-MS: m/z=394 (M+H.sup.+) R.sub.t=1.67
min. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=12.46 (s, 1H),
8.46 (d, J=7.2 Hz, 1H), 7.74 (s, 1H), 7.65-7.60 (m, 2H), 7.53-7.50
(m, 1H), 7.47-7.44 (m, 1H), 7.40-7.38 (m, 1H), 7.33-7.31 (m, 1H),
7.28-7.26 (m, 1H), 7.18-7.15 (m, 1H), 6.83-6.80 (m, 1H), 4.47 (s,
2H), 3.85 (t, J=7.2 Hz, 2H), 3.03 (t, J=7.2 Hz, 2H).
Example 245
5-[2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-3-oxo-2,3-dihydro-1H-isoindol-4--
yl]-1,3-dihydro-benzoimidazol-2-one
[1236] The title compound was prepared in analogy to the process
described in example 241. LC-MS: m/z=410 (M+H.sup.+) R.sub.t=1.67
min. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.=10.71 (s, 1H),
10.05 (s, 1H), 8.09 (s, 1H), 7.62 (s, 1H), 7.47-7.42 (m, 2H),
7.41-7.35 (m, 1H), 7.26-7.23 (m, 1H), 7.00-6.98 (m, 3H), 6.77 (s,
1H), 6.49-6.48 (m, 1H), 4.39 (s, 2H), 4.12 (t, J=6.8 Hz, 2H), 3.27
(t, J=6.8 Hz, 2H).
[1237] The following compounds of the Examples 246 to 250 listed
below were prepared in an analogous manner.
[1238] Example 246
4-(Pyridin-3-ylmethoxy)-2-(2-quinolin-2-yl-ethyl)-isoindole-1,3-dione
[1239] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta.=8.71 (s, 1H),
8.57 (d, 1H), 8.27 (d, 1H), 7.92 (d, 1H), 7.88 (d, 1H), 7.77 (m,
2H), 7.67 (t, 1H), 7.51-7.57 (m, 2H), 7.46 (d, 2H), 7.40 (d, 1H),
5.38 (s, 2H), 4.01 (t, 2H), 3.24 (t, 2H).
Example 247
4-(Pyridin-4-ylmethoxy)-2-(2-quinolin-2-yl-ethyl)-isoindole-1,3-dione
[1240] ESI-MS: [M+Na.sup.+]=432.10, 411.10, [M+H.sup.+]=410.10
Example 248
4-Methoxy-7-morpholin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol--
1-one
[1241] ESI-MS: [M+H.sup.+]=404.10.
Example 249
4-Pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-isoindole-1,3-dione
dihydrochloride
[1242] ESI-MS: [M+Na.sup.+]=402.10, 381.10, [M+H.sup.+]=380.10
Example 250
4-(1,1-Dioxothiomorpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-isoindole-1,3-di-
one
[1243] ESI-MS: [M+Na.sup.+]=458.10, 437.10, [M+H.sup.+]=436.10
Example 251
7-(2-Methoxy-pyridin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol--
1-one
[1244] A Personal Chemistry Ermy's optimizer microwave was used.
Each microwave tube was charged with 0.1 eq. of
[1,1'-Bis(diphenylphosphino)-ferrocene]dichloro-palladium(II),
complex with dichloromethane (7 mg). To the microwave tube, a
solution of 7-bromo-2-(2-(quinolin-2-yl)ethyl)isoindolin-1-one from
Example 5.4 (30 mg, 0.08mmo1) dissolved in dioxane (1.0 mL) was
added, followed by 2-methoxypyridin-4-ylboronic acid (15.2 mg, 0.1
mmol) dissolved in dioxane (0.3 mL). Then, 250 .mu.L of 1M aqueous
solution of Cs.sub.2CO.sub.3 was added and the resulting mixture
was heated in the microwave for 1200 sec at 120.degree. C. The
reaction was filtered, checked by LC/MS and concentrated to
dryness. The residues were dissolved in 1:1 DMSO/MeOH. Purification
by reverse phase HPLC gave
7-(2-methoxypyridin-4-yl)-2-(2-(quinolin-2-yl
ethyl)isoindolin-1-one (13 mg, 40%). .sup.1H NMR (400 MHz,
DMSO/D.sub.2O) .delta. ppm 8.28 (d, J=8.54 Hz, 1H) 8.11 (d, J=5.19
Hz, 1H) 7.91 (dd, J=23.96, 8.39 Hz, 2H) 7.63-7.75 (m, 3H) 7.53-7.59
(m, 1H) 7.48 (d, J=8.24 Hz, 1H) 7.38 (dd, J=6.10, 2.44 Hz, 1H) 6.96
(dd, J=5.34, 1.37 Hz, 1H) 6.80 (s, 1H) 4.54 (s, 2H) 3.97 (t, J=7.17
Hz, 2H) 3.87 (s, 3H) 3.28 (t, J=7.17 Hz, 2H); MS (ESI) m/z 396
(M+H).sup.+.
[1245] The following compounds of the formula (I) described below
were prepared using the standard operation procedures described
above.
Example 252
7-(2-Ethyl-morpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol--
1-one trifluoroacetate
[1246] ESI-MS: [M+Na.sup.+]=424.10, 403.20, [M+H.sup.+]=402.20
Example 253
2-[2-(1H-Imidazo[4,5-b]pyridin-2-yl)-ethyl]-7-pyridin-3-yl-2,3-dihydro-iso-
indol-1-one
[1247] ESI-MS: [M+H.sup.+]=356.10
Example 254
2-[2-(1-Methyl-1H-benzoimidazol-2-yl)-ethyl]-7-(4-methyl-piperazin-1-yl)-2-
,3-dihydro-isoindol-1-one
[1248] ESI-MS: [M+Na.sup.+]=412.10, 391.20, [M+H.sup.+]=390.20.
Example 255
6-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-(2-methyl-2H-pyrazol-3-yl)-6,7-di-
hydro-pyrrolo[3,4-b]pyridin-5-one
[1249] ESI-MS: 360.10, [M+H.sup.+]=359.10.
Example 256
6-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-pyrimidin-5-yl-6,7-dihydro-pyrrol-
o[3,4-b]pyridin-5-one
[1250] ESI-MS: 358.10, [M+H.sup.+]=357.10.
Example 257
4-(2-Oxa-6-aza-spiro[3.4]oct-6-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-p-
yrrolo[3,4-b]pyridin-5-one
[1251] ESI-MS: [M+Na.sup.+]=423.10, 402.20, [M+H.sup.+]=401.15.
Example 258
4-(4,4-Difluoro-piperidin-1-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrr-
olo[3,4-b]pyridin-5-one
[1252] .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta.=8.32 (d, 1H),
8.08 (d, 1H), 8.00 (d, 1H), 7.79 (d, 1H), 7.69 (t, 1H), 7.51 (t,
1H), 7.36 (d, 1H), 6.61 (d, 1H), 4.32 (s, 2H), 4.13 (t, 2 H), 3.60
(br. s., 4H), 3.36 (t, 2H), 2.15-2.22 (m br, 4H).
Example 259
7-(2,6-Dimethyl-morpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoi-
ndol-1-one trifluoroacetate
[1253] ESI-MS: [M+Na.sup.+]=424.10, 403.20, [M+H.sup.+]=402.20.
Example 260
6-(2-Quinolin-2-yl-ethyl)-4-(tetrahydro-furo[3,4-c]pyrrol-5-yl)-6,7-dihydr-
o-pyrrolo[3,4-b]pyridin-5-one
[1254] ESI-MS: [M+Na.sup.+]=423.10, 402.20, [M+H.sup.+]=401.20.
Example 261
4-Methoxy-7-(4-methyl-piperazin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydr-
o-isoindol-1-one di-trifluoroacetate
[1255] ESI-MS: [M+Na.sup.+]=439.15, 418.20, [M+H.sup.+]=417.20.
Example 262
2-[2-(5-Fluoro-1-methyl-1H-benzoimidazol-2-yl)-ethyl]-7-morpholin-4-yl-2,3-
-dihydro-isoindol-1-one
[1256] ESI-MS: [M+Na.sup.+]=417.10, [M+H.sup.+]=380.10
Example 263
2-(2-Benzothiazol-2-yl-ethyl)-7-morpholin-4-yl-2,3-dihydro-isoindol-1-one
trifluoroacetate
[1257] ESI-MS: [M+Na.sup.+]=402.10, [M+H.sup.+]=380.10
Example 264
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-methoxy-7-morpholin-4-yl-2,3-dihy-
dro-isoindol-1-one trifluoroacetate
[1258] ESI-MS: [M+H.sup.+]=393.20.
Example 265:
4-(3,6-Dihydro-2H-pyran-4-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrro-
lo[3,4-b]pyridin-5-one
[1259] ESI-MS: [M+Na.sup.+]=394.10, 373.10, [M+H.sup.+]=372.10.
Example 266
4-(4,5-Dihydro-furan-3-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3-
,4-b]pyridin-5-one
[1260] ESI-MS: 359.10, [M+H.sup.+]=358.10.
Example 267
4-Methylsulfanylmethoxy-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihyd-
ro-isoindol-1-one
[1261] ESI-MS: 443.10, [M+H.sup.+]=442.10.
Example 268
4-Difluoromethoxy-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-iso-
indol-1-one
[1262] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta.=8.56 (d, 2H),
8.28 (d, 1H), 7.93 (d, 1H), 7.86 (d, 1H), 7.70 (t, 1H), 7.29-7.57
(m, 6H), 4.60 (s, 1H), 3.98 (t, 2H), 3.58 (s, 1H), 3.30 (t, 2H),
2.28 (t, 1H).
Example 269
4-Methoxy-7-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-(2-quinolin-2-y-
l-ethyl)-2,3-dihydro-isoindol-1-one di-trifluoroacetate
[1263] ESI-MS: [M+Na].sup.+=522.20, 501.30, [M+H].sup.+=500.30.
Example 270
6-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-morpholin-4-yl-6,7-dihydro-pyrrol-
o[3,4-b]pyridin-5-one di-trifluoroacetate
[1264] ESI-MS: 365.10, [M+H].sup.+=364.10.
Example 271
4-Pyridin-3-yl-2-(2-quinolin-2-yl-ethyl)-isoindole-1,3-dione
Example 272
4-Morpholin-4-yl-2-(2-quinolin-2-yl-ethyl)-isoindole-1,3-dione
[1265] ESI-MS: [M+Na].sup.+=410.10, 389.10, [M+H].sup.+=388.10.
Example 273
6-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-(4-methyl-piperazin-1-yl)-6,7-dih-
ydro-pyrrolo[3,4-b]pyridin-5-one
[1266] .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta.=8.28 (d, 1H),
8.03 (d, 1H), 7.52 (d, 1H), 7.41 (s, 1H), 7.14 (t, 1H), 6.73 (t,
1H), 6.61 (d, 1H), 4.23 (s, 2H), 4.02 (t, 2H), 3.59 (br. s., 4H),
3.15 (t, 2H), 2.64 (br. s., 4H), 2.37 (s, 4H).
Example 274
7-(Oxetan-3-ylamino)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
[1267] ESI-MS: [M+Na].sup.+=382.10, 361.10, [M+H].sup.+=360.10.
Example 275
4-(Oxetan-3-ylamino)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]p-
yridin-5-one
[1268] .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta.=8.20 (d, 1H),
8.09 (d, 1H), 8.02 (d, 1H), 7.79 (d, 1H), 7.69 (t, 1H), 7.51 (t,
1H), 7.36 (d, 1H), 7.20 (m, 1H), 6.19 (d, 1H), 4.98 (t, 2H), 4.64
(t, 2H), 4.29 (s, 2H), 4.12 (t, 2H), 3.36 (t, 3H).
Example 276
4-Methylaminomethoxy-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro--
isoindol-1-one
[1269] .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta.=8.63 (m, 3H),
8.08 (d, 1H), 7.99 (d, 1H), 7.79 (d, 1H), 7.69 (t, 1H), 7.51 (t,
1H), 7.41-7.29 (m, 3H), 7.28 (d, 1H), 5.07 (s, 2H), 4.44 (d, 2H),
4.11 (t, 2H), 3.36 (t, 2H), 2.61 (s, 3H).
Example 277
7-(2-Ethyl-6-methyl-morpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro--
isoindol-1-one
[1270] ESI-MS: [M+Na].sup.+=438.20, 417.20, [M+H].sup.+=416.20.
Example 278
2-[2-(1-Ethyl-1H-benzoimidazol-2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro-i-
soindol-1-one
[1271] ESI-MS: [M+H].sup.+=391.20.
Example 279
7-(Octahydro-[1,5]naphthyridin-1-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-
-isoindol-1-one trifluoroacetate
Example 280
4-Fluoro-2-(2-imidazo[1,2-a]pyridin-2-yl-ethyl)-7-pyridin-4-yl-2,3-dihydro-
-isoindol-1-one
280.1 4-Fluoro-2-(2-imidazo
[1,2-a]pyridin-2-yl-ethyl)-7-iodo-2,3-dihydro-isoindol-1-one
[1272] Et.sub.3N (2.95 ml, 21.19 mmol) and 2-(imidazo
[1,2-a]pyridin-2-yl)ethylamine from Example d1 (4.10 g, 25.4 mmol)
were each added sequentially rapidly to a solution of ethyl
2-(bromomethyl)-3-fluoro-6-iodobenzoate from Example 16.3 (8.2 g,
21.19 mmol) in MeCN (5 mL). The reaction was heated in a microwave
at about 100.degree. C. for about 20 min. The solvent was removed
and the resulting mixture was deposited onto silica gel and loaded
onto a silica gel column and eluted with 50:1
CH.sub.2Cl.sub.2/MeOH.to give the title compound (3.2 g, 7.27 mmol,
34.3% yield). MS (ESI): m/z 422 (M+H).sup.+, R.sub.t: 1.87min.
.sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 3.22 (t, J=7Hz, 2H);
4.08 (t, J=6.8Hz, 2H); 4.29 (s, 2H); 6.76 (t, J=6.8Hz, 1H); 6.94
(t, J=8.4Hz, 1H); 7.14-7.18 (m, 1H); 7.47 (s, 1H); 7.54 (d,
J=8.8Hz, 1H); 7.82-7.85 (m, 1H); 8.06 (d, J=6.8 Hz, 1H).
280.2
4-Fluoro-2-(2-imidazo[1,2-a]pyridin-2-yl-ethyl)-7-pyridin-4-yl-2,3-d-
ihydro-isoindol-1-one
[1273] K.sub.2CO.sub.3 (59.1 mg, 0.427 mmol) and
bis(triphenylphosphin)palladium(II) chloride (10.00 mg, 0.014 mmol)
were each added sequentially rapidly to a suspension of the
compound from Example 280.1 (60 mg, 0.142 mmol) and
pyridin-4-ylboronic acid (19.26 mg, 0.157 mmol) in DMF (1 mL)/water
(0.200 mL).The reaction was heated in a microwave at about
120.degree. C. for about 20 min. The mixture was purified via
waters 2767 PHW003 (20-50% MeCN/water (NH.sub.4OAc buffer) over 15
min; Boston C18 10 um 21*250 mm column) to give the title compound
(28.4 mg, 0.076 mmol, 53.5% yield).
[1274] MS (ESI): m/z 373 (M+H).sup.+, R.sub.t:1.74 min. .sup.1H-NMR
(400 MHz, CDCl.sub.3): .delta. 3.18 (t, J=7.2 Hz, 2H); 4.03 (t,
J=6.8 Hz, 2H); 4.44 (s, 2H); 6.73-6.77 (m, 1H); 7.13-7.17 (m, 1H);
7.24-7.28 (m, 1H); 7.34-7.37 (m, 1H); 7.42-7.45 (m , 3H); 7.52 (d,
J=9.2Hz, 1H); 8.04 (d, J=6.8Hz, 1H); 8.67 (dd, J=4.4Hz, 1H).
Example 281
5-[3-Oxo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-1H-isoindol-4-yl]-thiophene-
-2-carbonitrile
[1275] A Personal Chemistry Ermy's optimizer microwave was used.
Each microwave tube was charged with 0.1 eq. of
[1,1'-Bis(diphenylphosphino)-ferrocene]dichloro-palladium(II),
complex with dichloromethane (7 mg). To the microwave tube, a
solution of 7-bromo-2-(2-(quinolin-2-yl)ethyl)isoindolin-1-one from
Example 5.4 (30 mg, 0.08 mmol) dissolved in dioxane (1.0 mL) was
added, followed by 5-cyanothiophen-2-ylboronic acid (15.3 mg, 0.1
mmol) dissolved in dioxane (0.3 mL). Then, 250 .mu.L of 1M aqueous
solution of Cs.sub.2CO.sub.3 was added and the resulting mixture
was heated in the microwave for 1200 sec at 120.degree. C. The
reaction was filtered, checked by LC/MS and concentrated to
dryness. The residues were dissolved in 1:1 DMSO/MeOH. Purification
by reverse phase HPLC provided
5-(3-oxo-2-(2-(quinolin-2-yl)ethyl)isoindolin-4-yl)thiophene-2-carbonitri-
le (2.7 mg, 8%). .sup.1H NMR (400 MHz, DMSO-d.sub.6/D.sub.2O)
.delta. ppm 8.23-8.31 (m, 1H) 7.85-7.97 (m, 3H) 7.42-7.77 (m, 7H)
4.44-4.57 (m, 2H) 4.00 (t, J=7.17 Hz, 2H) 3.18-3.35 (m, 2H). MS
(ESI) m/z 396 (M+H).sup.+.
Example 282
7-[2-(4-Methyl-piperazin-1-yl)-pyrimidin-5-yl]-2-(2-quinolin-2-yl-ethyl)-2-
,3-dihydro-isoindol-1-one
[1276] The title compound was prepared in analogy to the process
described in Example 281 using
2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-
)pyrimidine (30.4 mg, 0.1 mmol) dissolved in dioxane (0.3 mL)
instead of 5-cyanothiophen-2-ylboronic acid (15.3 mg, 0.1 mmol)
dissolved in dioxane (0.3 mL).
[1277] Yield: 12.4 mg, 32%. .sup.1H NMR (400 MHz,
DMSO-d.sub.6/D.sub.2O) .delta. ppm 8.41 (s, 1H) 8.29 (d, J=8.54 Hz,
1H) 7.86-7.95 (m, 2H) 7.69-7.75 (m, 1H) 7.60-7.65 (m, 1H) 7.52-7.58
(m, 3H) 7.47-7.50 (m, 1H) 7.38 (d, J=7.63 Hz, 1H) 4.52 (s, 2H) 3.98
(t, J=7.17 Hz, 2H) 3.76-3.80 (m, 4H) 3.28 (t, J=7.02 Hz, 2H)
2.37-2.42 (m, 4H) 2.21-2.24 (m, 3H); MS (ESI) m/z 465
(M+H).sup.+.
Example 283
7-(2-Ethoxy-pyrimidin-5-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one
[1278] The title compound was prepared in analogy to the process
described in Example 281 using 2-ethoxypyrimidin-5-ylboronic acid
(16.7 mg, 0.1 mmol) dissolved in dioxane (0.3 mL) instead of
5-cyanothiophen-2-ylboronic acid (15.3 mg, 0.1 mmol) dissolved in
dioxane (0.3 mL). Yield: 10 mg, 29%. .sup.1H NMR (400 MHz,
DMSO/D.sub.2O) .delta. ppm 8.59 (s, 2H) 8.29 (d, J=8.54 Hz, 1H)
7.83-7.96 (m, 2H) 7.62-7.74 (m, 3H) 7.53-7.58 (m, 1H) 7.49 (d,
J=8.54 Hz, 1H) 7.42-7.46 (m, 1H) 4.55 (s, 2H) 4.37-4.44 (m, 2H)
3.98 (t, J=7.17 Hz, 2H) 3.28 (t, J=7.17 Hz, 2H) 1.37 (t, J=7.02 Hz,
3H); MS (ESI) m/z 411 (M+H).sup.+.
Example 284
7-(5-Pyrrolidin-1-ylmethyl-thiophen-2-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-di-
hydro-isoindol-1-one
[1279] The title compound was prepared in analogy to the process
described in Example 281 using
1-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)methyl)p-
yrrolidine (29.3 mg, 0.1 mmol) dissolved in dioxane (0.3 mL)
instead of 5-cyanothiophen-2-ylboronic acid (15.3 mg, 0.1 mmol)
dissolved in dioxane (0.3 mL).
[1280] Yield: 5.5 mg, 15%. .sup.1H NMR (400 MHz, DMSO/D.sub.2O)
.delta. ppm 8.29 (d, J=8.24 Hz, 1H) 7.93 (t, J=8.39 Hz, 2H)
7.69-7.77 (m, 1H) 7.55-7.60 (m, 2H) 7.47-7.53 (m, 4H) 6.92 (d,
J=3.66 Hz, 1H) 4.47-4.53 (m, 2H) 4.00 (t, J=7.17 Hz, 2H) 3.79 (s,
2H) 3.29 (t, J=7.17 Hz, 2H) 2.48 (t, 4H) 1.64-1.89 (m, 4H); MS
(ESI) m/z 454 (M+H).sup.+.
Example 285
7-(2-Dimethylamino-pyrimidin-5-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-i-
soindol-1-one
[1281] The title compound was prepared in analogy to the process
described in Example 281 using
2-(dimethylamino)pyrimidin-5-ylboronic acid (16.7mg, 0.1mmol)
dissolved in dioxane (0.3 mL) instead of
5-cyanothiophen-2-ylboronic acid (15.3 mg, 0.1 mmol) dissolved in
dioxane (0.3 mL). Yield: 9.1 mg, 27%. .sup.1H NMR (400 MHz,
DMSO/D.sub.2O) .delta. ppm 8.40 (s, 2H) 8.29 (d, J=8.24 Hz, 1H)
7.87-7.95 (m, 2H) 7.69-7.75 (m, 1H) 7.60-7.65 (m, 1H) 7.56 (t,
J=7.63 Hz, 2H) 7.49 (d, J=8.54 Hz, 1H) 7.37 (d, J=6.71 Hz, 1H) 4.51
(s, 2H) 3.98 (t, J=7.17 Hz, 2H) 3.28 (t, J=7.17 Hz, 2H) 3.16 (s,
6H); MS (ESI) m/z 410 (M+H).sup.+.
Example 286
7-(5-Piperidin-1-ylmethyl-thiophen-2-yl)-2-(2-quinolin-2-yl-ethyl-2,3-dihy-
dro-isoindol-1-one
[1282] The title compound was prepared in analogy to the process
described in Example 281 using
1-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)methyl)p-
iperidine (30.7 mg, 0.1 mmol) dissolved in dioxane (0.3 mL) instead
of 5-cyanothiophen-2-ylboronic acid (15.3 mg, 0.1 mmol) dissolved
in dioxane (0.3 mL).
[1283] Yield: 9.7 mg, 25%. .sup.1H NMR (400 MHz, DMSO/D.sub.2O)
.delta. ppm 8.29 (d, J=8.24 Hz, 1H) 7.93 (t, J=8.39 Hz, 2H)
7.70-7.77 (m, 1H) 7.47-7.59 (m, 6H) 6.91 (d, J=3.36 Hz, 1H) 4.50
(s, 2H) 4.00 (t, J=7.17 Hz, 2H) 3.63 (s, 2H) 3.29 (t, J=7.17 Hz,
2H) 2.35-2.45 (m, 3H) 1.83-2.04 (m, 2H) 1.46-1.56 (m, 3H) 1.35-1.44
(m, 2H); MS (ESI) m/z 468 (M+H).sup.+.
Example 287
7-(3-Chlorothiophen-2-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-
-one
[1284] The title compound was prepared in analogy to the process
described in Example 281 using 3-chlorothiophen-2-ylboronic acid
(16.2 mg, 0.1 mmol) dissolved in dioxane (0.3 mL) instead of
5-cyanothiophen-2-ylboronic acid (15.3 mg, 0.1 mmol) dissolved in
dioxane (0.3 mL). Yield: 3.8 mg, 11%. .sup.1H NMR (400 MHz,
DMSO/D.sub.2O) .delta. ppm 8.22-8.29 (m, 1H) 7.88-7.95 (m, 2H)
7.70-7.75 (m, 1H) 7.64-7.68 (m, 1H) 7.51-7.58 (m, 2H) 7.51 (dd,
J=7.02, 3.05 Hz, 1H) 7.44-7.49 (m, 1H) 7.36 (dd, J=5.65, 2.90 Hz,
1H) 7.08 (d, J=5.19 Hz, 1H) 4.46-4.56 (m, 2H) 3.96 (t, J=7.17 Hz,
2H) 3.18-3.29 (m, 2H); MS (ESI) m/z 405 (M+H).sup.+.
Example 288
3-Methyl-5-[3-oxo-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-1H-isoindol-4-yl]--
thiophene-2-carbonitrile
[1285] The title compound was prepared in analogy to the process
described in Example 281 using 5-cyano-4-methylthiophen-2-ylboronic
acid (16.6 mg, 0.1 mmol) dissolved in dioxane (0.3 mL) instead of
5-cyanothiophen-2-ylboronic acid (15.3 mg, 0.1 mmol) dissolved in
dioxane (0.3 mL). Yield: 5.4 mg, 16%. .sup.1H NMR (400 MHz,
DMSO/D.sub.2O) .delta. ppm 8.29 (d, J=8.55 Hz, 1H) 7.92-7.95 (m,
1H) 7.87 (d, J=8.54 Hz, 1H) 7.70-7.74 (m, 1H) 7.64-7.67 (m, 2H)
7.53-7.59 (m, 2H) 7.48-7.51 (m, 1H) 7.45 (s, 1H) 4.56 (s, 2H) 4.00
(t, J=7.17 Hz, 2H) 3.29 (t, J=7.17 Hz, 2H) 2.39 (s, 3H); MS (ESI)
m/z 410 (M+H).sup.+.
Example 289
7-(2-Chlorothiophen-3-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-
-one
[1286] The title compound was prepared in analogy to the process
described in Example 281 but using 2-chlorothiophen-3-ylboronic
acid (16.2 mg, 0.1 mmol) dissolved in dioxane (0.3 mL) instead of
5-cyanothiophen-2-ylboronic acid (15.3 mg, 0.1 mmol) dissolved in
dioxane (0.3 mL). Yield: 5.6 mg, 17%. .sup.1H NMR (400 MHz,
DMSO/D.sub.2O) .delta. ppm 8.28 (d, J=8.54 Hz, 1H) 7.91 (dd,
J=19.23, 7.93 Hz, 2H) 7.69-7.75 (m, 1H) 7.35-7.67 (m, 5H) 7.29-7.34
(m, 1H) 6.93 (d, J=5.80 Hz, 1H) 4.53 (s, 2H) 3.96 (t, J=7.17 Hz,
2H) 3.27 (t, J=7.17 Hz, 2H); MS (ESI) m/z 405 (M+H).sup.+.
Example 290
7-(2-Cyclopropyl-pyridin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoin-
dol-1-one
[1287] The title compound was prepared in analogy to the process
described in Example 281 but using 2-cyclopropylpyridin-4-ylboronic
acid (16.2 mg, 0.1 mmol) dissolved in dioxane (0.3 mL) instead of
5-cyanothiophen-2-ylboronic acid (15.3 mg, 0.1 mmol) dissolved in
dioxane (0.3 mL). Yield: 6.4 mg, 19%. .sup.1H NMR (400 MHz,
DMSO/D.sub.2O) .delta. ppm 8.26-8.33 (m, 1H) 7.90 (dd, J=30.36,
8.39 Hz, 2H) 7.65-7.73 (m, 2H) 7.47-7.58 (m, 4H) 7.38 (dd, J=6.10,
2.14 Hz, 1H) 7.18 (s, 1H) 7.07-7.11 (m, 1H) 4.56 (s, 2H) 3.98 (t,
J=7.02 Hz, 2H) 3.28 (t, J=6.87 Hz, 2H) 2.02 (s, 1H) 0.88-1.01 (m,
4H); MS (ESI) m/z 406 (M+H).sup.+.
Example 291
7-(3,6-Dimethoxy-pyridazin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-iso-
indol-1-one
[1288] The title compound was prepared in analogy to the process
described in Example 281 but using
3,6-dimethoxypyridazin-4-ylboronic acid (18.3 mg, 0.1 mmol)
dissolved in dioxane (0.3 mL) instead of
5-cyanothiophen-2-ylboronic acid (15.3 mg, 0.1 mmol) dissolved in
dioxane (0.3 mL). Yield: 9.2 mg, 26%. .sup.1H NMR (400 MHz,
DMSO/D.sub.2O) .delta. ppm 8.28 (d, J=7.94 Hz, 1H) 7.86-7.96 (m,
2H) 7.71-7.76 (m, 1H) 7.61-7.67 (m, 2H) 7.54-7.59 (m, 1H) 7.47 (d,
J=8.24 Hz, 1H) 7.34 (dd, J=5.34, 3.20 Hz, 1H) 6.98 (s, 1H)
4.47-4.58 (m, 2H) 3.90-4.05 (m, 5H) 3.72 (s, 3H) 3.22-3.34 (m, 2H);
MS (ESI) m/z 427 (M+H).sup.+.
[1289] The compounds of the Examples 292 to 294 can be prepared
using the standard operation procedures described above
Example 292
2-{2-[1-(2-Morpholin-4-yl-ethyl)-1H-benzoimidazol-2-yl]-ethyl}-7-pyridin-4-
-yl-2,3-dihydro-isoindol-1-one trifluoroacetate
Example 293
2-{2-[1-(2-Dimethylamino-ethyl)-1H-benzoimidazol-2-yl]-ethyl}-7-pyridin-4--
yl-2,3-dihydro-isoindol-1-one trifluoroacetate
[1290] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta.=8.74 (d, 2H),
7.97 (d, 1H), 7.84-7.72 (m, 5H), 7.53-7.59 (m, 3H), 4.86 (t, 2H),
4.73 (s, 2H), 4.03-4.06 (m, 2H), 3.61 (t, 2H), 3.55 (br. s., 2H),
2.94 (s, 6H).
Example 294
2-{2-[1-(3-Dimethylamino-propyl)-1H-benzoimidazol-2-yl]-ethyl}-7-pyridin-4-
-yl-2,3-dihydro-isoindol-1-one trifluoroacetate
[1291] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta.=9.92 (s br,
1H), 8.68 (d, 2H), 7.98 (d, 1H), 7.82-7-74 (m, 3H), 7.68 (d, 2H),
7.62-7.50 (m, 3H), 4.72 (s, 2H), 4.54 (t, 2H), 3.55 (t, 2H), 3.22
(s br, 2H), 2.75 (s, 6H), 2.22 (m br, 2H).
Example 295
4-Fluoro-2-(2-imidazo[1,2-a]pyridin-2-yl-ethyl)-7-morpholin-4-yl-2,3-dihyd-
ro-isoindol-1-one
[1292] Dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (146 mg,
0.356 mmol), Pd.sub.2dba.sub.3 (65.2 mg, 0.071 mmol) and
K.sub.2CO.sub.3 (295 mg, 2.137 mmol) were each added sequentially
rapidly to a solution of the compound from Example 280.1 (300 mg,
0.712 mmol) and morpholine (186 mg, 2.137 mmol) in DMF (3 mL). The
reaction was heated in a microwave at about 140.degree. C. for
about 20 min. The mixture was purified via Gilson 281(PHG008)
(18-75% MeCN/Water (NH.sub.4OAc buffer) over 15 min; Waters
X-bridge OBD C 18 19*250mm, 10 um) to give the title compound
(15mg, 0.039 mmol, 5.54% yield). MS (ESI): m/z 381 (M+H).sup.+,
R.sub.t: 1.77 min. .sup.1H-NMR (400 MHz, CDCl.sub.3-d): .delta.
3.17 (t, J=7.2Hz, 2H); 3.22 (s, 4H); 3.95 (t, J=4.2Hz, 4H); 4.01
(t, J=7.2Hz, 2H); 4.32 (s, 2H); 6.75 (t, J=6.8Hz, 1H); 6.84 (dd,
J=8.6Hz, 1H); 7.09 (t, J=8.4Hz, 1H); 7.16 (t, J=8Hz, 1H); 7.43 (s,
1H); 7.54 (d, J=9.2Hz, 1H); 8.04 (d, J=6.8Hz, 1H).
[1293] The compounds of the Examples 296 to 309 can be prepared
using the standard operation procedures described above.
TABLE-US-00002 Ex IUPAC-Name physico-chemical data 296
1-Oxy-4-pyrimidin-5-yl-6-(2-quinolin-2-yl- .sup.1H NMR (CDCl.sub.3,
500 MHz): ethyl)-6,7-dihydro-pyrrolo[3,4-b]pyridin-5- .delta. =
9.24 (s, 1 H), 8.88 (s, 2 H), one 8.37 (d, 1 H), 8.13 (d, 1 H),
8.01 (d, 1 H), 7.81 (d, 1 H), 7.69 (t, 1 H), 7.53 (t, 1 H),
7.33-7.37 (m, 2 H), 4.71 (s, 2 H), 4.20 (t, 2 H), 3.43 (t, 2 H) 297
6-(2-Quinolin-2-yl-ethyl)-4-(tetrahydro- ESI-MS: 396.10, [M +
Na.sup.+] = 394.10, pyran-4-yl)-6,7-dihydro-pyrrolo[3,4- 375.10, [M
+ H.sup.+] = 374.15, b]pyridin-5-one 373.10, 372.10 298
7-(2-Methoxymethyl-morpholin-4-yl)-2-(2- ESI-MS: [M + Na.sup.+] =
440.10, quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1- 419.20, [M +
H.sup.+] = 418.20 one 299 4-Fluoromethoxy-7-pyridin-4-yl-2-(2-
.sup.1H NMR (CDCl.sub.3, 500 MHz):
quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1- .delta. = 8.64 (d, 2
H), 8.09 (d, 1 H), one 7.99 (d, 1 H), 7.80 (d, 1 H), 7.69 (t, 1 H),
7.51 (t, 1 H), 7.41 (d, 2 H), 7.36 (d, 2 H), 7.29 (m, 1 H, incl.
CHCl.sub.3), 5.86 (s, 1 H), 5.75 (s, 1 H), 4.45 (s, 2 H), 4.12 (t,
2 H), 3.36 (t, 2 H) 300 2-[2-(4-Fluoro-1-methyl-1H-benzoimidazol-
ESI-MS: [M + H.sup.+] = 387.10
2-yl)-ethyl]-7-pyridin-4-yl-2,3-dihydro- isoindol-1-one
trifluoroacetate 301 2-[2-(1,5-Dimethyl-1H-benzoimidazol-2- ESI-MS:
[M + H.sup.+] = 383.10 yl)-ethyl]-7-pyridin-4-yl-2,3-dihydro-
isoindol-1-one trifluoroacetate 302
2-[2-(1-Propyl-1H-benzoimidazol-2-yl)- ESI-MS: [M + H.sup.+] =
397.20 ethyl]-7-pyridin-4-yl-2,3-dihydro-isoindol- 1-one
trifluoroacetate 303 2-[2-(1-Isopropyl-1H-benzoimidazol-2-yl)-
ESI-MS: [M + H.sup.+] = 397.20
ethyl]-7-pyridin-4-yl-2,3-dihydro-isoindol- 1-one trifluoroacetate
304 2-[2-(1-Isopropyl-1H-benzoimidazol-2-yl)-
ethyl]-7-morpholin-4-yl-2,3-dihydro- isoindol-1-one
trifluoroacetate 305 7-Morpholin-4-yl-2-[2-(1-propyl-1H- ESI-MS: [M
+ Na.sup.+] = 427.15, benzoimidazol-2-yl)-ethyl]-2,3-dihydro- [M +
H.sup.+] = 405.20 isoindol-1-one trifluoroacetate 306
2-[2-(1,5-Dimethyl-1H-benzoimidazol-2- ESI-MS: [M + H.sup.+] =
391.20 yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro- isoindol-1-one
trifluoroacetate 307 2-[2-(4-Fluoro-1-methyl-1H-benzoimidazol-
ESI-MS: [M + Na.sup.+] = 417.10,
2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro- [M + H.sup.+] = 395.15
isoindol-1-one trifluoroacetate 308
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4- ESI-MS: [M + H.sup.+] =
363.10 morpholin-4-yl-2,3-dihydro-isoindol-1-one 309
6-(2-Quinolin-2-yl-ethyl)-4-(tetrahydro-
furan-3-yl)-6,7-dihydro-pyrrolo[3,4- b]pyridin-5-one
Example 310
2-(2-Imidazo [1,2-a]pyridin-2- yl-ethyl)-7-morpholin-4-
yl-2,3-dihydro-isoindol-1-one
[1294] In a 5 mL microwave reaction vial,
7-bromo-2-(2-imidazol[1,2-]pyridin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
from Example 20.1 (100 mg, 0.281 mmol), Cs.sub.2CO.sub.3 (183 mg,
0.561 mmol), Pd.sub.2(dba).sub.3 (25.7 mg, 0.028 mmol) and X-PHOS
(13.38 mg, 0.028 mmol) were added. The solids were purged with
argon for at least 5 min. A separate round bottom flask was charged
with dioxane (3 mL) and morpholine (48 mg, 0.56 mmol), degas with
argon for at least 10 min. and then the solvents were transfered to
the microwave reaction vial under inert conditions. The resulted
mixture was heated on microwave at 110.degree. C. for 1 h. The
reaction mixture was filtered. The filtrate was purified by
Prep-HPLC to give the title compound (25 mg, yield: 24.6%) as a
white solid. LC-MS: m/z 363(M+H.sup.+); R.sub.t=1.71 min. .sup.1H
NMR(400 MHz, CDCl.sub.3): .delta. 8.34 (d, J=6.8 Hz,1H), 7.67 (s,
1H), 7.48-7.44 (m, 2H), 7.28 (t, J=8.8 Hz, 1H), 7.07 (d, J=7.2 Hz,
1H), 6.96 (d, J=8.0 Hz, 1H), 6.89 (t, J=6.4 Hz, 1H), 4.36 (s , 2H),
3.98 (t, J=7.2 Hz, 2H), 3.87-3.85 (m , 4H), 3.17-3.12(m , 6H).
[1295] The compounds of the Examples 311 to 321 can be prepared
using the standard operation procedures described above.
TABLE-US-00003 Ex. IUPAC-Name physico-chemical data 311
2-[2-(1H-Benzoimidazol-2-yl)-ethyl]-7-(4- .sup.1H NMR
(DMSO-d.sub.6, 500 MHz): fluoro-phenyl)-2,3-dihydro-isoindol-1-one
.delta. = 7.79-7.74 (m, 2 H), trifluoroacetate 7.63 (m, 2 H),
7.54-7.47 (m, 2 H), 7.33 (d, 1 H), 7.28 (t, 2 H), 7.04 (t, 2 H),
4.57 (s, 2 H), 3.99 (t, 2 H). 312
2-[2-(1H-Benzoimidazol-2-yl)-ethyl]-7- ESI-MS: [M + H.sup.+] =
356.10 pyrimidin-5-yl-2,3-dihydro-isoindol-1-one trifluoroacetate
313 2-[2-(1H-Benzoimidazol-2-yl)-ethyl]-7-(2- ESI-MS: [M + H.sup.+]
= 358.10 methyl-2H-pyrazol-3-yl)-2,3-dihydro- isoindol-1-one
trifluoroacetate 314 2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-
ESI-MS: [M + H.sup.+] = 344.10
(1H-pyrazol-3-yl)-2,3-dihydro-isoindol-1- one trifluoroacetate 315
6-[2-(5,7-Dimethyl-[1,2,4]triazolo[1,5- .sup.1H NMR (DMSO-d.sub.6,
500 MHz): a]pyrimidin-2-yl)-ethyl]-4-pyridin-4-yl-6,7- .delta. =
8.85 (d, 1H), 8.76 (d, 2 H), dihydro-pyrrolo[3,4-b]pyridin-5-one
7.76 (d, 2 H), 7.57 (d, 1 H), trifluoroacetate 7.12 (s, 1 H), 4.68
(s, 2 H), 3.97 (t, 2 H), 3.21 (t, 2 H), 2.65 (s, 3 H), 2.56 (s, 3
H) 316 2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4- ESI-MS: [M +
H.sup.+] = 355.10 pyridin-4-yl-2,3-dihydro-isoindol-1-one 317
7-(3aS,8aR)-Octahydro-pyrrolo[3,4-c]azepin- ESI-MS: [M + H.sup.+] =
427.20 2-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro- isoindol-1-one
trifluoroacetate 318 7-(3aS,8aS)-Octahydro-pyrrolo[3,4-c]azepin-
ESI-MS: [M + H.sup.+] = 427.20
2-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro- isoindol-1-one
trifluoroacetate 319 1-[5-Oxo-6-(2-quinolin-2-yl-ethyl)-6,7-
ESI-MS: [M + Na.sup.+] = 467.20,
dihydro-5H-pyrrolo[3,4-b]pyridin-4-yl]- 446.20, [M + H.sup.+] =
445.20 piperidine-4-carboxylic acid ethyl ester 320
4-[8-(Morpholine-4-sulfonyl)-3,4-dihydro- ESI-MS: 571.20, 570.20,
1H-isoquinolin-2-yl]-2-(2-quinolin-2-yl- [M + H.sup.+] = 569.20
ethyl)-2,3-dihydro-isoindol-1-one 321
4-[8-(4-Methyl-piperazine-1-sulfonyl)-3,4- ESI-MS: 584.20, 583.20,
dihydro-1H-isoquinolin-2-yl]-2-(2-quinolin- [M + H.sup.+] = 582.20
2-yl-ethyl)-2,3-dihydro-isoindol-1-one
[1296] Example 322
4-(3-Methyl-pyridin-4-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,-
4-b]pyridin-5-one
[1297] A Personal Chemistry Ermy's optimizer microwave was used.
Each microwave tube was charged with 0.1 eq. of
[1,1'-Bis(diphenylphosphino)-ferrocene]dichloro-palladium(II),
complex with dichloromethane (7 mg). To the microwave tube, a
solution of
4-bromo-6-(2-(quinolin-2-yl)ethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-
-one from Example 119.3 (31 mg, 0.08 mmol) dissolved in dioxane
(1.0 mL) was added, followed by 3-methylpyridin-4-ylboronic acid
(13.7 mg, 0.1 mmol) dissolved in dioxane (0.35 mL). Then, 250 .mu.L
of 1M aqueous solution of Cs.sub.2CO.sub.3 was added and the
resulting mixture was heated in the microwave for 1200 sec at
120.degree. C. The reaction was filtered, checked by LC/MS and
concentrated to dryness. The residues were dissolved in 1:1
DMSO/MeOH. Purification by reverse phase HPLC provided the title
compound (10.8 mg, 33%). .sup.1H NMR (500 MHz, DMSO/D.sub.2O)
.delta. ppm 8.79 (d, J=5.19 Hz, 1H) 8.42 (s, 1H) 8.39 (d, J=4.88
Hz, 1H) 8.27 (d, J=8.24 Hz, 1H) 7.93 (d, J=7.32 Hz, 1H) 7.81 (d,
J=8.54 Hz, 1H) 7.68-7.73 (m, 1H) 7.54-7.58 (m, 1H) 7.48 (d, J=8.54
Hz, 1H) 7.30 (d, J=4.88 Hz, 1H) 7.06 (d, J=4.88 Hz, 1H) 4.65 (s,
2H) 3.98 (t, J=6.87 Hz, 2H) 3.29 (t, J=7.02 Hz, 2H) 1.83 (s, 3H);
MS (ESI) m/z 381 (M+H).sup.+.
Example 323
4-(1H-Pyrazol-3-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]py-
ridin-5-one
[1298] The title compound was prepared in analogy to the process
described in Example 322 but using 1H-pyrazol-3-ylboronic acid
(11.2 mg, 0.1 mmol) dissolved in dioxane (0.35 mL) instead of
3-methylpyridin-4-ylboronic acid (13.7 mg, 0.1 mmol) dissolved in
dioxane (0.35 mL). Yield: 6.6 mg, 22%. .sup.1H NMR (500 MHz,
DMSO/D.sub.2O) .delta. ppm 8.73 (s, 1H) 8.30 (d, J=8.24 Hz, 1H)
7.94 (d, J=8.24 Hz, 3H) 7.65-7.78 (m, 2H) 7.55 (t, J=7.63 Hz, 2H)
7.23 (s, 1H) 4.49-4.77 (m, 2H) 4.14 (s, 2H) 3.38 (s, 2H); MS (ESI)
m/z 356 (M+H).sup.+.
Example 324
4-(3,6-dimethoxypyridazin-4-yl)-6-(2-(quinolin-2-yl)ethyl)-6,7-dihydro-5H--
pyrrolo[3,4-b]pyridin-5-one
[1299] The title compound was prepared in analogy to the process
described in Example 322 but using
3,6-dimethoxypyridazin-4-ylboronic acid (18.3 mg, 0.1 mmol)
dissolved in dioxane (0.35 mL) instead of
3-methylpyridin-4-ylboronic acid (13.7 mg, 0.1 mmol) dissolved in
dioxane (0.35 mL). Yield: 3.2 mg, 7%. .sup.1H NMR (500 MHz,
DMSO/D.sub.2O) 6 ppm 8.80 (d, J=5.19 Hz, 1H) 8.29 (d, J=8.54 Hz,
1H) 7.93 (d, J=8.85 Hz, 1H) 7.85 (d, J=8.85 Hz, 1H) 7.69-7.76 (m,
1H) 7.56 (t, J=7.48 Hz, 1H) 7.45-7.51 (m, 2H) 7.11 (s, 1H) 4.62 (s,
2H) 3.99 (s, 2H) 3.98 (s, 3H) 3.74 (s, 3H) 3.29 (t, J=7.02 Hz, 2H);
MS (ESI) m/z 428 (M+H).sup.+.
Example 325
4-(2-Dimethylamino-pyrimidin-5-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-p-
yrrolo[3,4-b]pyridin-5-one
[1300] The title compound was prepared in analogy to the process
described in Example 322 but using
2-(dimethylamino)pyrimidin-5-ylboronic acid (16.7 mg, 0.1 mmol)
dissolved in dioxane (0.35 mL) instead of
3-methylpyridin-4-ylboronic acid (13.7 mg, 0.1 mmol) dissolved in
dioxane (0.35 mL). Yield: 3 mg, 8%. .sup.1H NMR (500 MHz,
DMSO/D.sub.2O) .delta. ppm 8.68 (d, J=5.49 Hz, 1H) 8.59 (s, 2H)
8.29 (d, J=8.54 Hz, 1H) 7.94 (d, J=7.93 Hz, 1H) 7.85 (d, J=8.54 Hz,
1H) 7.68-7.74 (m, 1H) 7.53-7.58 (m, 1H) 7.47-7.53 (m, 2H) 4.56 (s,
2H) 4.03 (t, J=7.02 Hz, 2H) 3.31 (t, J=7.17 Hz, 2H) 3.18 (s, 6H);
MS (ESI) m/z 411 (M+H).sup.+
Example 326
4-(2-Methyl-thiazol-5-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,-
4-b]pyridin-5-one
[1301] The title compound was prepared in analogy to the process
described in Example 322 but using
2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole
(22.5 mg, 0.1 mmol) dissolved in dioxane (0.35 mL) instead of
3-methylpyridin-4-ylboronic acid (13.7 mg, 0.1 mmol) dissolved in
dioxane (0.35 mL). Yield: 4.4 mg, 13%. .sup.1H NMR (500 MHz,
DMSO/D.sub.2O) .delta. ppm 8.67 (d, J=5.49 Hz, 1H) 8.59 (s, 1H)
8.30 (d, J=8.24 Hz, 1H) 7.94 (d, J=7.63 Hz, 1H) 7.87 (d, J=8.54 Hz,
1H) 7.69-7.74 (m, 1H) 7.63 (d, J=5.49 Hz, 1H) 7.51-7.58 (m, 2H)
4.57 (s, 2H) 4.05 (t, J=7.17 Hz, 2H) 3.33 (t, J=7.17 Hz, 2H) 2.70
(s, 3H); MS (ESI) m/z 387 (M+H).sup.+.
Example 327
4-(2-Ethoxy-pyrimidin-5-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[-
3,4-b]pyridin-5-one
[1302] The title compound was prepared in analogy to the process
described in Example 322 but using 2-ethoxypyrimidin-5-ylboronic
acid (16.8 mg, 0.1 mmol) dissolved in dioxane (0.35 mL) instead of
3-methylpyridin-4-ylboronic acid (13.7 mg, 0.1 mmol) dissolved in
dioxane (0.35 mL). Yield: 2.7 mg, 8%. .sup.1H NMR (500 MHz,
DMSO/D.sub.2O) .delta. ppm 8.75-8.79 (m, 3H) 8.29 (d, J=8.24 Hz,
1H) 7.94 (d, J=7.02 Hz, 1H) 7.82 (d, J=8.54 Hz, 1H) 7.68-7.73 (m,
1H) 7.49-7.57 (m, 3H) 4.61 (s, 2H) 4.43 (q, J=7.02 Hz, 2H) 4.03 (t,
J=7.17 Hz, 2H) 3.31 (t, J=7.17 Hz, 2H) 1.37 (t, J=7.02 Hz, 3H); MS
(ESI) m/z 412 (M+H).sup.+.
Example 328
4-(2-Methoxy-pyridin-4-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3-
,4-b]pyridin-5-one
[1303] The title compound was prepared in analogy to the process
described in Example 322 but using 2-methoxypyridin-4-ylboronic
acid (15.3 mg, 0.1 mmol) dissolved in dioxane (0.35 mL) instead of
3-methylpyridin-4-ylboronic acid (13.7 mg, 0.1 mmol) dissolved in
dioxane (0.35 mL). Yield: 4.5 mg, 13%. .sup.1H NMR (500 MHz,
DMSO/D.sub.2O) .delta. ppm 8.78 (d, J=5.19 Hz, 1H) 8.29 (d, J=8.24
Hz, 1H) 8.18-8.21 (m, 1H) 7.94 (d, J=7.93 Hz, 1H) 7.83 (d, J=8.54
Hz, 1H) 7.67-7.75 (m, 1H) 7.54-7.58 (m, 1H) 7.47-7.52 (m, 2H) 7.06
(dd, J=5.19, 1.53 Hz, 1H) 6.94 (s, 1H) 4.61 (s, 2H) 4.01 (t, J=7.32
Hz, 2H) 3.88 (s, 3H) 3.31 (t, J=7.02 Hz, 2H); MS (ESI) m/z 397
(M+H).sup.+.
Example 329
4-Pyridin-3-yl-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]pyridin-
-5-one
[1304] The title compound was prepared in analogy to the process
described in Example 322 but using pyridin-3-ylboronic acid (12.2
mg, 0.1 mmol) dissolved in dioxane (0.35 mL) instead of
3-methylpyridin-4-ylboronic acid (13.7 mg, 0.1 mmol) dissolved in
dioxane (0.35 mL). Yield: 8.7 mg, 28%. .sup.1H NMR (500 MHz,
DMSO/D.sub.2O) .delta. ppm 8.78 (d, J=4.88 Hz, 1H) 8.69 (d, J=1.53
Hz, 1H) 8.62 (dd, J=4.88, 1.53 Hz, 1H) 8.29 (d, J=8.24 Hz, 1H)
7.91-7.97 (m, 2H) 7.83 (d, J=8.54 Hz, 1H) 7.68-7.74 (m, 1H)
7.53-7.59 (m, 1H) 7.50-7.53 (m, 2H) 7.47 (dd, J=7.78, 4.73 Hz, 1H)
4.62 (s, 2H) 4.02 (t, J=7.17 Hz, 2H) 3.31 (t, J=7.17 Hz, 2H); MS
(ESI) m/z 367 (M+H).sup.+.
Example 330
6-(2-Quinolin-2-yl-ethyl)-4-thiophen-3-yl-6,7-dihydro-pyrrolo[3,4-b]pyridi-
n-5-one
[1305] The title compound was prepared in analogy to the process
described in Example 322 but using hiophen-3-ylboronic acid (12.8
mg, 0.1 mmol) dissolved in dioxane (0.35 mL) instead of
3-methylpyridin-4-ylboronic acid (13.7 mg, 0.1 mmol) dissolved in
dioxane (0.35 mL). Yield: 1.9 mg, 6%. .sup.1H NMR (500 MHz,
DMSO/D.sub.2O) .delta. ppm 8.67 (d, J=5.49 Hz, 1H) 8.37 (dd,
J=3.05, 1.22 Hz, 1H) 8.30 (d, J=8.54 Hz, 1H) 7.94 (d, J=7.63 Hz,
1H) 7.87 (d, J=8.54 Hz, 1H) 7.69-7.74 (m, 1H) 7.50-7.66 (m, 5H)
4.56 (s, 2H) 4.05 (t, J=7.17 Hz, 2H) 3.32 (t, J=7.17 Hz, 2H); MS
(ESI) m/z 371 (M+H).sup.+.
Example 331
4-Furan-3-yl-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-
-one
[1306] The title compound was prepared in analogy to the process
described in Example 322 but using furan-3-ylboronic acid (11.1mg,
0.1 mmol) dissolved in dioxane (0.35 mL) instead of
3-methylpyridin-4-ylboronic acid (13.7 mg, 0.1 mmol) dissolved in
dioxane (0.35 mL). Yield: 3.6 mg, 12%. .sup.1H NMR (500 MHz,
DMSO/D.sub.2O) .delta. ppm 8.88 (s, 1H) 8.65 (d, J=5.49 Hz, 1H)
8.30 (d, J=8.24 Hz, 1H) 7.94 (d, J=8.24 Hz, 1H) 7.89 (d, J=7.93 Hz,
1H) 7.78 (t, J=1.68 Hz, 1H) 7.70-7.74 (m, 1H) 7.67 (d, J=5.19 Hz,
1H) 7.51-7.58 (m, 2H) 7.22 (d, J=1.22 Hz, 1H) 4.55 (s, 2H) 4.06 (t,
J=7.17 Hz, 2H) 3.33 (t, J=7.17 Hz, 2H); MS (ESI) m/z 356
(M+H).sup.+.
Example 332
4-(1,5-Dimethyl-1H-pyrazol-4-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyr-
rolo[3,4-b]pyridin-5-one
[1307] The title compound was prepared in analogy to the process
described in Example 322 but using
1,5-dimethyl-1H-pyrazol-4-ylboronic acid (13.9 mg, 0.1 mmol)
dissolved in dioxane (0.35 mL) instead of
3-methylpyridin-4-ylboronic acid (13.7 mg, 0.1 mmol) dissolved in
dioxane (0.35 mL). Yield: 9 mg, 28%. .sup.1H NMR (500 MHz,
DMSO/D.sub.2O) .delta. ppm 8.62 (d, J=5.19 Hz, 1H) 8.28 (d, J=8.54
Hz, 1H) 7.93 (d, J=7.32 Hz, 1H) 7.84 (d, J=8.24 Hz, 1H) 7.69-7.73
(m, 1H) 7.49-7.58 (m, 3H) 7.28 (d, J=5.19 Hz, 1H) 4.54 (s, 2H) 4.02
(t, J=7.02 Hz, 2H) 3.75 (s, 3H) 3.30 (t, J=7.02 Hz, 2H) 2.14 (s,
3H); MS (ESI) m/z 384 (M+H).sup.+.
Example 333
4-(1-Ethyl-1H-pyrazol-4-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[-
3,4-b]pyridin-5-one
[1308] The title compound was prepared in analogy to the process
described in Example 322 but using 1-ethyl-1H-pyrazol-4-ylboronic
acid (13.9 mg, 0.1 mmol) dissolved in dioxane (0.35 mL) instead of
3-methylpyridin-4-ylboronic acid (13.7 mg, 0.1 mmol) dissolved in
dioxane (0.35 mL). Yield: 1.1 mg, 3%. .sup.1H NMR (500 MHz,
DMSO/D.sub.2O) .delta. ppm 8.82 (s, 1H) 8.56 (d, J=5.49 Hz, 1H)
8.28-8.33 (m, 2H) 7.92 (dd, J=21.97, 8.24 Hz, 2H) 7.70-7.74 (m, 1H)
7.67 (d, J=5.19 Hz, 1H) 7.51-7.58 (m, 2H) 4.52 (s, 2H) 4.17 (q,
J=7.32 Hz, 2H) 4.05 (t, J=7.17 Hz, 2H) 3.32 (t, J=7.17 Hz, 2H) 1.40
(t, J=7.32 Hz, 3H); MS (ESI) m/z 384 (M+H).sup.+.
Example 334
4-(2,5-Dimethyl-2H-pyrazol-3-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyr-
rolo[3,4-b]pyridin-5-one
[1309] The title compound was prepared in analogy to the process
described in Example 322 but using
1,3-dimethyl-1H-pyrazol-5-ylboronic acid (13.9 mg, 0.1 mmol)
dissolved in dioxane (0.35 mL) instead of
3-methylpyridin-4-ylboronic acid (13.7 mg, 0.1 mmol) dissolved in
dioxane (0.35 mL). Yield: 3.9 mg, 12%. .sup.1H NMR (500 MHz,
DMSO/D.sub.2O) .delta. ppm 8.76 (d, J=5.19 Hz, 1H) 8.27 (d, J=8.54
Hz, 1H) 7.93 (d, J=7.93 Hz, 1H) 7.81 (d, J=8.54 Hz, 1H) 7.67-7.71
(m, 1H) 7.53-7.58 (m, 1H) 7.50 (d, J=8.24 Hz, 1H) 7.37 (d, J=5.19
Hz, 1H) 6.15 (s, 1H) 4.64 (s, 2H) 4.02 (t, J=6.87 Hz, 2H) 3.30 (t,
J=7.02 Hz, 2H) 3.27 (s, 3H) 2.15 (s, 3H); MS (ESI) m/z 384
(M+H).sup.+.
Example 335
4-(3,5-Dimethyl-isoxazol-4-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrro-
lo[3,4-b]pyridin-5-one
[1310] The title compound was prepared in analogy to the process
described in Example 322 but using 3,5-dimethylisoxazol-4-ylboronic
acid (14.1 mg, 0.1 mmol) dissolved in dioxane (0.35 mL) instead of
3-methylpyridin-4-ylboronic acid (13.7 mg, 0.1 mmol) dissolved in
dioxane (0.35 mL). Yield: 3.6 mg, 11%. .sup.1H NMR (500 MHz,
DMSO/D.sub.2O) .delta. ppm 8.75 (d, J=5.19 Hz, 1H) 8.27 (d, J=8.54
Hz, 1H) 7.92 (d, J=7.02 Hz, 1H) 7.80 (d, J=8.54 Hz, 1H) 7.67-7.72
(m, 1H) 7.48-7.57 (m, 2H) 7.37 (d, J=5.19 Hz, 1H) 4.63 (d, J=4.88
Hz, 2H) 3.97-4.06 (m, 2H) 3.30 (t, J=6.87 Hz, 2H) 2.10 (s, 3H) 1.89
(s, 3H); MS (ESI) m/z 385 (M+H).sup.+.
Example 336
4-(3-Methyl-thiophen-2-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3-
,4-b]pyridin-5-one
[1311] The title compound was prepared in analogy to the process
described in Example 322 but using 3-methylthiophen-2-ylboronic
acid (14.2 mg, 0.1 mmol) dissolved in dioxane (0.35 mL) instead of
3-methylpyridin-4-ylboronic acid (13.7 mg, 0.1 mmol) dissolved in
dioxane (0.35 mL). Yield: 10.2 mg, 37%. .sup.1H NMR (500 MHz,
DMSO/D.sub.2O) .delta. ppm 8.70 (d, J=5.19 Hz, 1H) 8.27 (d, J=8.24
Hz, 1H) 7.92 (d, J=7.93 Hz, 1H) 7.83 (d, J=8.54 Hz, 1H) 7.68-7.73
(m, 1H) 7.53-7.59 (m, 2H) 7.50 (d, J=8.54 Hz, 1H) 7.33 (d, J=4.88
Hz, 1H) 6.96 (d, J=5.19 Hz, 1H) 4.60 (s, 2H) 4.01 (t, J=6.87 Hz,
2H) 3.30 (t, J=7.02 Hz, 2H) 1.86 (s, 3H); MS (ESI) m/z 385
(M+H).sup.+.
Example 337
4-(1-Methyl-1H-pyrrol-3-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[-
3,4-b]pyridin-5-one
[1312] The title compound was prepared in analogy to the process
described in Example 322 but using
1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole
(20.7 mg, 0.1 mmol) dissolved in dioxane (0.35 mL) instead of
3-methylpyridin-4-ylboronic acid (13.7 mg, 0.1 mmol) dissolved in
dioxane (0.35 mL). Yield: 3.8 mg, 12%. .sup.1H NMR (500 MHz,
DMSO/D.sub.2O) .delta. ppm 8.64 (d, J=5.19 Hz, 1H) 8.28 (d, J=8.24
Hz, 1H) 7.93 (d, J=7.93 Hz, 1H) 7.84 (d, J=8.54 Hz, 1H) 7.67-7.73
(m, 1H) 7.52-7.58 (m, 1H) 7.51 (d, J=8.54 Hz, 1H) 7.30 (d, J=5.19
Hz, 1H) 6.87-6.93 (m, 1H) 6.28 (dd, J=3.66, 1.83 Hz, 1H) 6.06-6.11
(m, 1H) 4.57 (s, 2H) 4.02 (t, J=7.02 Hz, 2H) 3.30 (t, J=7.02 Hz,
2H) 3.24-3.27 (m, 3H); MS (ESI) m/z 369 (M+H).sup.+.
Example 338
4-Pyridazin-4-yl-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]pyrid-
in-5-one
[1313] The title compound was prepared in analogy to the process
described in Example 322 but using
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine (20.6 mg,
0.1 mmol) dissolved in dioxane (0.35 mL) instead of
3-methylpyridin-4-ylboronic acid (13.7 mg, 0.1 mmol) dissolved in
dioxane (0.35 mL). Yield: 5 mg, 16%. .sup.1H NMR (500 MHz,
DMSO/D.sub.2O) .delta. ppm 9.30-9.34 (m, 2H) 8.87 (d, J=5.19 Hz,
1H) 8.30 (d, J=8.54 Hz, 1H) 7.94 (d, J=8.24 Hz, 1H) 7.80-7.85 (m,
2H) 7.69-7.73 (m, 1H) 7.62 (d, J=5.19 Hz, 1H) 7.56 (t, J=7.48 Hz,
1H) 7.52 (d, J=8.24 Hz, 1H) 4.66 (s, 2H) 4.03 (t, J=7.17 Hz, 2H)
3.32 (t, J=7.17 Hz, 2H); MS (ESI) m/z 368 (M+H).sup.+.
Example 339
4-(2-Cyclopropyl-pyridin-4-yl)-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-pyrro-
lo[3,4-b]pyridin-5-one
[1314] The title compound was prepared in analogy to the process
described in Example 322 but using 2-cyclopropylpyridin-4-ylboronic
acid (16.3 mg, 0.1 mmol) dissolved in dioxane (0.35 mL) instead of
3-methylpyridin-4-ylboronic acid (13.7 mg, 0.1 mmol) dissolved in
dioxane (0.35 mL). Yield: 3.5 mg, 10%. .sup.1H NMR (500 MHz,
DMSO/D.sub.2O) .delta. ppm 8.79 (d, J=5.19 Hz, 1H) 8.40 (d, J=5.19
Hz, 1H) 8.29 (d, J=8.54 Hz, 1H) 7.94 (d, J=8.24 Hz, 1H) 7.81 (d,
J=8.54 Hz, 1H) 7.68-7.73 (m, 1H) 7.45-7.57 (m, 3H) 7.28 (s, 1H)
7.19 (dd, J=5.03, 1.68 Hz, 1H) 4.63 (s, 2H) 4.02 (t, J=7.02 Hz, 2H)
3.30 (t, J=7.02 Hz, 2H) 2.01-2.07 (m, 1H) 0.88-1.01 (m, 4H); MS
(ESI) m/z 407 (M+H).sup.+.
Example 340
6-(2-Quinolin-2-yl-ethyl)-4-thiazol-4-yl-6,7-dihydro-pyrrolo[3,4-b]pyridin-
-5-one
[1315] The title compound was prepared in analogy to the process
described in Example 322 using thiazol-4-ylboronic acid (12.8 mg,
0.1mmol) dissolved in dioxane (0.35 mL) instead of
3-methylpyridin-4-ylboronic acid (13.7 mg, 0.1 mmol) dissolved in
dioxane (0.35 mL). Yield: 3 mg, 9%. .sup.1H NMR (500 MHz,
DMSO/D.sub.2O) .delta. ppm 9.41 (d, J=1.83 Hz, 1H) 9.21 (d, J=1.83
Hz, 1H) 8.77 (d, J=5.19 Hz, 1H) 8.30 (d, J=8.24 Hz, 1H) 8.19 (d,
J=5.49 Hz, 1H) 7.94 (d, J=7.93 Hz, 1H) 7.88 (d, J=8.24 Hz, 1H)
7.70-7.74 (m, 1H) 7.53-7.57 (m, 2H) 4.60 (s, 2H) 4.09 (t, J=7.17
Hz, 2H) 3.35 (t, J=7.17 Hz, 2H); MS (ESI) m/z 373 (M+H).sup.+.
Example 341
4-(2-Dimethylamino-pyrimidin-5-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-i-
soindol-1-one
[1316] Syntheses were performed using a Personal Chemistry Ermy's
optimizer microwave. Each microwave tube was charged with 0.1 eq.
of [1,1'-Bis(diphenylphosphino)-ferrocene]dichloropalladium(II),
complex with dichloromethane (7 mg). To the microwave tube, a
solution of 4-bromo-2-(2-(quinolin-2-yl)ethyl)isoindolin-1-one from
Example 130.1 (31 mg, 0.08 mmol) dissolved in dioxane (1.0 mL). was
added, followed by 2-(dimethylamino)pyrimidin-5-ylboronic acid
(16.7 mg, 0.1 mmol) dissolved in dioxane (0.35 mL). Then, 250 .mu.L
of 1M aqueous solution of Cs.sub.2CO.sub.3 was added and the
resulting mixture was heated in the microwave for 1200 sec at
120.degree. C. The reaction was filtered, checked by LC/MS and
concentrated to dryness. The residues were dissolved in 1:1
DMSO/MeOH. Purification by reverse phase HPLC provided
4-(2-(dimethylamino)pyrimidin-5-yl)-2-(2-(quinolin-2-yl)ethyl)isoindolin--
1-one (5 mg, 14%). .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm
8.61 (s, 2H) 8.28 (d, J=8.55 Hz, 1H) 7.92 (dd, J=12.97, 8.09 Hz,
2H) 7.49-7.75 (m, 6H) 4.74 (s, 2H) 4.02 (t, J=7.32 Hz, 2H) 3.31 (t,
J=7.32 Hz, 2H) 3.20 (s, 6H); MS (ESI) m/z 410 (M+H).sup.+. MS
(APCI) m/z 410 (M+H).sup.+.
Example 342
4-(2-Methyl-thiazol-5-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-
-one
[1317] The title compound was prepared in analogy to the process
described in Example 341 but using
2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole
(22.5 mg, 0.1mmol) dissolved in dioxane (0.35 mL) instead of
2-(dimethylamino)pyrimidin-5-ylboronic acid (16.7 mg, 0.1 mmol)
dissolved in dioxane (0.35 mL). Yield: 6.4 mg, 20%. .sup.1H NMR
(500 MHz, DMSO/D.sub.2O) .delta. ppm 8.30 (d, J=8.54 Hz, 1H) 8.01
(s, 1H) 7.93 (dd, J=13.73, 7.93 Hz, 2H) 7.81 (d, J=6.71 Hz, 1H)
7.70-7.76 (m, 1H) 7.63-7.66 (m, 1H) 7.50-7.60 (m, 3H) 4.71 (s, 2H)
4.07 (t, J=7.17 Hz, 2H) 3.34 (t, J=7.17 Hz, 2H) 2.71 (s, 3H); MS
(APCI) m/z 386 (M+H).sup.+.
Example 343
4-(2-Ethoxy-pyrimidin-5-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one
[1318] The title compound was prepared in analogy to the process
described in Example 341 but using 2-ethoxypyrimidin-5-ylboronic
acid (16.8 mg, 0.1 mmol) dissolved in dioxane (0.35 mL) instead of
2-(dimethylamino)pyrimidin-5-ylboronic acid (16.7 mg, 0.1 mmol)
dissolved in dioxane (0.35 mL). Yield: 3.2 mg, 9%. .sup.1H NMR (500
MHz, DMSO/D.sub.2O) .delta. ppm 8.85 (s, 2H) 8.28 (d, J=8.24 Hz,
1H) 7.91 (dd, J=15.41, 8.09 Hz, 2H) 7.69-7.76 (m, 3H) 7.63 (t,
J=7.48 Hz, 1H) 7.54-7.59 (m, 1H) 7.51 (d, J=8.24 Hz, 1H) 4.76 (s,
2H) 4.45 (q, J=7.02 Hz, 2H) 4.02 (t, J=7.32 Hz, 2H) 3.30 (t, J=7.32
Hz, 2H) 1.39 (t, J=7.02 Hz, 3H); MS (ESI) m/z 411 (M+H).sup.+. MS
(APCI) m/z 411 (M+H).sup.+.
Example 344
4-(2-Methoxy-pyridin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol--
1-one
[1319] The title compound was prepared in analogy to the process
described in Example 341 but using 2-methoxypyridin-4-ylboronic
acid (15.2 mg, 0.1 mmol) dissolved in dioxane (0.35 mL) instead of
2-(dimethylamino)pyrimidin-5-ylboronic acid (16.7 mg, 0.1 mmol)
dissolved in dioxane (0.35 mL). Yield: 8.8 mg, 26%. .sup.1H NMR
(500 MHz, DMSO/D.sub.2O) .delta. ppm 8.24-8.31 (m, 2H) 7.91 (dd,
J=18.31, 7.93 Hz, 2H) 7.70-7.77 (m, 3H) 7.61-7.66 (m, 1H) 7.56 (t,
J=7.02 Hz, 1H) 7.51 (d, J=8.54 Hz, 1H) 7.19 (dd, J=5.49, 1.53 Hz,
1H) 7.01 (s, 1H) 4.72 (s, 2H) 4.03 (t, J=7.17 Hz, 2H) 3.92 (s, 3H)
3.31 (t, J=7.32 Hz, 2H); MS (ESI) m/z 396 (M+H).sup.+.
Example 345
2-(2-Quinolin-2-yl-ethyl)-4-thiophen-3-yl-2,3-dihydro-isoindol-1-one
[1320] The title compound was prepared in analogy to the process
described in Example 341 but using thiophen-3-ylboronic acid (12.7
mg, 0.1 mmol) dissolved in dioxane (0.35 mL) instead of
2-(dimethylamino)pyrimidin-5-ylboronic acid (16.7 mg, 0.1 mmol)
dissolved in dioxane (0.35 mL). Yield: 15 mg, 48%. .sup.1H NMR (500
MHz, DMSO/D.sub.2O) .delta. ppm 8.28 (s, 1H) 7.41-7.98 (m, 11 H)
4.46-4.81 (m, 2H) 3.97-4.27 (m, 2H) 3.13-3.41 (m, 2H); MS (ESI) m/z
371 (M+H).sup.+.
Example 346
4-Furan-3-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
[1321] The title compound was prepared in analogy to the process
described in Example 341 but using furan-3-ylboronic acid (11.1 mg,
0.1 mmol) dissolved in dioxane (0.35 mL) instead of
2-(dimethylamino)pyrimidin-5-ylboronic acid (16.7 mg, 0.1 mmol)
dissolved in dioxane (0.35 mL). Yield: 11.8 mg, 39%. .sup.1H NMR
(500 MHz, DMSO/D.sub.2O) .delta. ppm 8.29 (d, J=8.54 Hz, 1H) 8.13
(s, 1H) 7.92 (dd, J=10.38, 8.54 Hz, 2H) 7.81-7.86 (m, 2H) 7.68-7.76
(m, 1H) 7.50-7.59 (m, 4H) 7.03 (s, 1H) 4.71 (s, 2H) 4.06 (t, J=7.32
Hz, 2H) 3.36 (t, J=7.32 Hz, 2H); MS (ESI) m/z 355 (M+H).sup.+.
Example 347
4-(1-Ethyl-1H-pyrazol-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one
[1322] The title compound was prepared in analogy to the process
described in Example 341 but using 1-ethyl-1H-pyrazol-4-ylboronic
acid (13.9mg, 0.1 mmol) dissolved in dioxane (0.35 mL) instead of
2-(dimethylamino)pyrimidin-5-ylboronic acid (16.7 mg, 0.1 mmol)
dissolved in dioxane (0.35 mL). Yield: 4.8 mg, 15%. .sup.1H NMR
(500 MHz, DMSO/D.sub.2O) .delta. ppm 8.30 (d, J=8.55 Hz, 1H) 8.18
(s, 1H) 7.89-7.97 (m, 3H) 7.82 (dd, J=6.10, 2.44 Hz, 1H) 7.69-7.76
(m, 1H) 7.47-7.60 (m, 4H) 4.71 (s, 2H) 4.20 (q, J=7.12 Hz, 2H) 4.07
(t, J=7.17 Hz, 2H) 3.36 (t, J=7.32 Hz, 2H) 1.43 (t, J=7.32 Hz, 3H);
MS (ESI) m/z 383 (M+H).sup.+.
Example 348
4-(2,5-Dimethyl-2H-pyrazol-3-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-iso-
indol-1-one
[1323] The title compound was prepared in analogy to the process
described in Example 341 but using
1,3-dimethyl-1H-pyrazol-5-ylboronic acid (13.9mg, 0.1 mmol)
dissolved in dioxane (0.35 mL) instead of
2-(dimethylamino)pyrimidin-5-ylboronic acid (16.7 mg, 0.1 mmol)
dissolved in dioxane (0.35 mL). Yield: 2.3 mg, 7%.
Example 349
4-(3,5-Dimethyl-isoxazol-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoin-
dol-1-one
[1324] The title compound was prepared in analogy to the process
described in Example 341 but using 3,5-dimethylisoxazol-4-ylboronic
acid (14.0mg, 0.1 mmol) dissolved in dioxane (0.35 mL) instead of
2-(dimethylamino)pyrimidin-5-ylboronic acid (16.7 mg, 0.1 mmol)
dissolved in dioxane (0.35 mL). Yield: 13.5 mg, 41%. .sup.1H NMR
(500 MHz, DMSO/D.sub.2O) .delta. ppm 8.28 (d, J=8.54 Hz, 1H) 7.93
(d, J=7.63 Hz, 1H) 7.84 (d, J=8.24 Hz, 1H) 7.68-7.75 (m, 2H)
7.53-7.59 (m, 2H) 7.45-7.51 (m, 2H) 4.24 (s, 2H) 4.01 (t, J=7.17
Hz, 2H) 3.30 (t, J=7.02 Hz, 2H) 2.16 (s, 3H) 2.00 (s, 3H); MS
(APCI) m/z 384 (M+H).sup.+.
Example 350
4-(5-Methyl-pyrazin-2-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-
-one
[1325] The title compound was prepared in analogy to the process
described in Example 341 but using
2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine
(22.0 mg, 0.1 mmol) dissolved in dioxane (0.35 mL) instead of
2-(dimethylamino)pyrimidin-5-ylboronic acid (16.7 mg, 0.1 mmol)
dissolved in dioxane (0.35 mL). Yield: 3.4 mg, 11%. .sup.1H NMR
(500 MHz, DMSO/D.sub.2O) .delta. ppm 9.10 (d, J=1.22 Hz, 1H) 8.58
(s, 1H) 8.29 (d, J=8.24 Hz, 1H) 8.21 (d, J=6.71 Hz, 1H) 7.92 (dd,
J=13.28, 8.09 Hz, 2H) 7.70-7.78 (m, 1H) 7.62-7.67 (m, 1H) 7.54-7.61
(m, 2H) 7.50-7.54 (m, 1H) 4.87 (s, 2H) 4.07 (t, J=7.17 Hz, 2H) 3.33
(t, J=7.17 Hz, 2H) 2.57 (s, 3H); MS (APCI) m/z 381 (M+H).sup.+.
Example 351
4-(3-Methyl-thiophen-2-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol--
1-one
[1326] The title compound was prepared in analogy to the process
described in Example 341 but using 3-methylthiophen-2-ylboronic
acid (14.1mg, 0.1 mmol) dissolved in dioxane (0.35 mL) instead of
2-(dimethylamino)pyrimidin-5-ylboronic acid (16.7 mg, 0.1 mmol)
dissolved in dioxane (0.35 mL). Yield: 16.3 mg, 50%. .sup.1H NMR
(500 MHz, DMSO/D.sub.2O) .delta. ppm 8.28 (d, J=8.54 Hz, 1H) 7.93
(d, J=7.63 Hz, 1H) 7.86 (d, J=8.54 Hz, 1H) 7.65-7.75 (m, 2H)
7.48-7.60 (m, 5H) 7.04 (d, J=4.88 Hz, 1H) 4.41 (s, 2H) 4.02 (t,
J=7.02 Hz, 2H) 3.30 (t, J=7.02 Hz, 2H) 2.07 (s, 3H); MS (ESI) m/z
385 (M+H).sup.+.
Example 352
4-(1-Methyl-1H-pyrrol-3-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-
-1-one
[1327] The title compound was prepared in analogy to the process
described in Example 341 but using
1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole
(20.7 mg, 0.1 mmol) dissolved in dioxane (0.35 mL) instead of
2-(dimethylamino)pyri-midin-5-ylboronic acid (16.7 mg, 0.1 mmol)
dissolved in dioxane (0.35 mL). Yield: 17 mg, 54%. .sup.1H NMR (500
MHz, DMSO/D.sub.2O) .delta. ppm 8.28 (d, J=8.54 Hz, 1H) 7.91 (dd,
J=19.07, 8.09 Hz, 2H) 7.69-7.77 (m, 1H) 7.48-7.62 (m, 5H) 6.87-6.92
(m, 1H) 6.23 (dd, J=3.51, 1.68 Hz, 1H) 6.11-6.14 (m, 1H) 4.51 (s,
2H) 4.02 (t, J=7.17 Hz, 2 H) 3.55 (s, 3H) 3.30 (t, J=7.17 Hz, 2H);
MS (APCI) m/z 368 (M+H).sup.+.
Example 353
4-Pyridazin-4-yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1-one
[1328] The title compound was prepared in analogy to the process
described in Example 341 but using
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine (20.6 mg,
0.1 mmol) dissolved in dioxane (0.35 mL) instead of
2-(dimethylamino)pyrimidin-5-ylboronic acid (16.7 mg, 0.1 mmol)
dissolved in dioxane (0.35 mL). Yield: 6.2 mg, 20%. .sup.1H NMR
(500 MHz, DMSO/D.sub.2O) .delta. ppm 9.50-9.57 (m, 1H) 9.32-9.37
(m, 1H) 8.28 (d, J=8.24 Hz, 1H) 7.86-7.98 (m, 4H) 7.81 (d, J=6.71
Hz, 1H) 7.68-7.75 (m, 2H) 7.49-7.60 (m, 2H) 4.85 (s, 2H) 4.04 (t,
J=7.32 Hz, 2H) 3.31 (t, J=7.32 Hz, 2H); MS (APCI) m/z 367
(M+H).sup.+.
Example 354
4-(2-Cyclopropyl-pyridin-4-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoin-
dol-1-one
[1329] The title compound was prepared in analogy to the process
described in Example 341 but using 2-cyclopropylpyridin-4-ylboronic
acid (16.2 mg, 0.1 mmol) dissolved in dioxane (0.35 mL) instead of
2-(dimethylamino)pyrimidin-5-ylboronic acid (16.7 mg, 0.1 mmol)
dissolved in dioxane (0.35 mL). Yield: 14.2 mg, 41%. .sup.1H NMR
(500 MHz, DMSO/D.sub.2O) .delta. ppm 8.44-8.53 (m, 1H) 8.29 (d,
J=8.54 Hz, 1H) 7.92 (dd, J=17.09, 7.93 Hz, 2H) 7.71-7.76 (m, 2H)
7.61-7.70 (m, 2H) 7.54-7.59 (m, 1H) 7.50-7.53 (m, 1H) 7.45 (s, 1H)
7.31 (dd, J=5.19, 1.83 Hz, 1H) 4.71 (s, 2H) 4.04 (t, J=7.17 Hz, 2H)
3.31 (t, J=7.32 Hz, 2H) 2.11-2.24 (m, 1H) 0.95-1.02 (m, 4H); MS
(ESI) m/z 406 (M+H).sup.+.
Example 355
2-(2-Quinolin-2-yl-ethyl)-4-thiazol-4-yl-2,3-dihydro-isoindol-1-one
[1330] The title compound was prepared in analogy to the process
described in Example 341 but using thiazol-4-ylboronic acid (12.9
mg, 0.1 mmol) dissolved in dioxane (0.35 mL) instead of
2-(dimethylamino)pyrimidin-5-ylboronic acid (16.7 mg, 0.1 mmol)
dissolved in dioxane (0.35 mL). Yield: 4.6 mg, 15%. .sup.1H NMR
(500 MHz, DMSO/D.sub.2O) .delta. ppm 9.24 (d, J=1.83 Hz, 1H) 8.29
(d, J=8.24 Hz, 1H) 8.22 (d, J=1.83 Hz, 1H) 8.18 (d, J=6.71 Hz, 1H)
7.89-7.95 (m, 2H) 7.70-7.75 (m, 1H) 7.65-7.68 (m, 1H) 7.50-7.62 (m,
3H) 4.88 (s, 2H) 4.08 (t, J=7.32 Hz, 2H) 3.35 (t, J=7.32 Hz, 2H);
MS (ESI) m/z 372 (M+H).sup.+.
Example 356
4-(6-Methoxy-pyrazin-2-yl)-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro-isoindol--
1-one
[1331] The title compound was prepared in analogy to the process
described in Example 341 but using
2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine
(23.6 mg, 0.1 mmol) dissolved in dioxane (0.35 mL) instead of
2-(dimethylamino)pyrimidin-5-ylboronic acid (16.7 mg, 0.1 mmol)
dissolved in dioxane (0.35 mL). Yield: 3.5 mg, 10%. .sup.1H NMR
(500 MHz, DMSO/D.sub.2O) .delta. ppm 8.83 (s, 1H) 8.23-8.31 (m, 3H)
7.91 (dd, J=18.16, 7.78 Hz, 2H) 7.79 (d, J=7.02 Hz, 1H) 7.70-7.75
(m, 1H) 7.66 (t, J=7.63 Hz, 1H) 7.53-7.59 (m, 1H) 7.51 (d, J=8.54
Hz, 1H) 4.87 (s, 2H) 4.06-4.14 (m, 2H) 3.79 (s, 3H) 3.33 (t, J=7.02
Hz, 2H); MS (APCI) m/z 397 (M+H).sup.+.
[1332] The compounds of the Examples 357 to 377 can be prepared
using the standard operation procedures described above.
TABLE-US-00004 Ex. IUPAC-Name physico-chemical data 357
4-(3-Phenyl-piperidin-1-yl)-2-(2-quinolin-2-yl- ESI-MS: 449.20,
ethyl)-2,3-dihydro-isoindol-1-one trifluoroacetate [M + H.sup.+] =
448.20 358 6-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-pyridin-3-
ESI-MS: 357.10, yl-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one [M +
H.sup.+] = 356.10 359
6-[2-(1-Methyl-1H-benzoimidazol-2-yl)-ethyl]-4- ESI-MS: [M +
H.sup.+] = 364.10 (oxetan-3-ylamino)-6,7-dihydro-pyrrolo[3,4-
b]pyridin-5-one 360
6-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-(oxetan-3- ESI-MS: 351.10,
ylamino)-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one [M + H.sup.+] =
350.10 361 4-(3-Phenoxy-piperidin-1-yl)-2-(2-quinolin-2-yl- ESI-MS:
465.20, ethyl)-2,3-dihydro-isoindol-1-one [M + H.sup.+] = 464.20
362 2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-methoxy- ESI-MS:
380.10, 7-(oxetan-3-ylamino)-2,3-dihydro-isoindol-1-one [M +
H.sup.+] = 379.10 363
4-(4-Dimethylamino-piperidin-1-yl)-6-(2-quinolin- ESI-MS: 417.20,
2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one [M + H.sup.+] =
416.20 hydrochloride 364
6-[2-(1-Methyl-1H-benzoimidazol-2-yl)-ethyl]-4- ESI-MS: 372.10,
pyrimidin-5-yl-6,7-dihydro-pyrrolo[3,4-b]pyridin-5- [M + H.sup.+] =
371.10 one 365 6-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-(1H-
ESI-MS: [M + H.sup.+] = 345.10
pyrazol-4-yl)-6,7-dihydro-pyrrolo[3,4-b]pyridin-5- one 366
1-[5-Oxo-6-(2-quinolin-2-yl-ethyl)-6,7-dihydro-5H- ESI-MS: 418.10,
pyrrolo[3,4-b]pyridin-4-yl]-piperidine-4-carboxylic [M + H.sup.+] =
417.10 acid 367 6-[2-(1-Methyl-1H-benzoimidazol-2-yl)-ethyl]-4-
ESI-MS: 371.10, pyridin-4-yl-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-
[M + H.sup.+] = 370.10 one 368
6-[2-(1-Methyl-1H-benzoimidazol-2-yl)-ethyl]-4- ESI-MS: 371.10,
pyridin-3-yl-6,7-dihydro-pyrrolo[3,4-b]pyridin-5- [M + H.sup.+] =
370.10 one 369 6-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-pyridin-4-
ESI-MS: 357.10, yl-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one [M +
H.sup.+] = 356.10 370 4-Methoxy-2-[2-(1-methyl-1H-benzoimidazol-2-
ESI-MS: 400.20,
yl)-ethyl]-7-pyridin-4-yl-2,3-dihydro-isoindol-1-one [M + H.sup.+]
= 399.20 371 4-Methoxy-2-[2-(1-methyl-1H-benzoimidazol-2- ESI-MS:
[M + Na.sup.+] = 429.20,
yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro-isoindol-1- 408.20, [M +
H.sup.+] = 407.20 one 372
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-methoxy- .sup.1H NMR
(CDCl.sub.3, 500 MHz):
7-(1H-pyrazol-4-yl)-2,3-dihydro-isoindol-1-one .delta. = 8.24 (s
br, 2 H), 8.03 (d, 1 H), 7.58-7.50 (m, 2 H), 7.46 (s, 1 H), 7.14 (m
sym, 1 H), 7.00 (d, 1 H), 6.73 (t, 1 H), 4.29 (s, 2 H), 4.13 (q, 1
H), 4.04 (t, 2 H), 3.88 (s, 3 H), 3.20 (t, 2 H) 373
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-methoxy- ESI-MS: 389.20,
7-(2-methyl-2H-pyrazol-3-yl)-2,3-dihydro-isoindol- [M + H.sup.+] =
388.20 1-one 374 2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-methoxy-
ESI-MS: 386.20, 7-pyridin-4-yl-2,3-dihydro-isoindol-1-one [M +
H.sup.+] = 385.20 375
6-(2-Benzothiazol-2-yl-ethyl)-4-pyridin-4-yl-6,7- ESI-MS: 374.10,
dihydro-pyrrolo[3,4-b]pyridin-5-one [M + H.sup.+] = 373.10 376
6-(2-Benzothiazol-2-yl-ethyl)-4-(oxetan-3- ESI-MS: [M + Na.sup.+] =
389.10, ylamino)-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one 368.10, [M
+ H.sup.+] = 367.10 377
6-(2-Benzothiazol-2-yl-ethyl)-4-morpholin-4-yl-6,7- ESI-MS: [M +
Na.sup.+] = 403.10, dihydro-pyrrolo[3,4-b]pyridin-5-one 382.10, [M
+ H.sup.+] = 381.10
Example 378
4-Fluoro-2-(2-imidazol[1,2-]pyridin-2-yl-ethyl)-7-pyridin-3-yl-2,3-dihydro-
-isoindol-1-one
[1333] K.sub.2CO.sub.3 (98 mg, 0.712 mmol) and
Pd(PPh.sub.3).sub.2Cl.sub.2 (16.66 mg, 0.024 mmol) were each added
sequentially rapidly to a suspension of
4-fluoro-2-(2-(imidazol[1,2-]pyridin-2-yl)ethyl)-7-iodoisoindolin-1-one
from Example 280.1 (100.00 mg, 0.237 mmol) and pyridin-3-ylboronic
acid (32.1 mg, 0.261 mmol) in DMF (5 ml)/water (1 ml).The reaction
was heated in a Biotage microwave at about 120.degree. C. for 20
min. The mixture was purified by Prep-HPLC to give the title
compound (70 mg, 0.188 mmol, 79% yield) as white solid. LC-MS: m/z
373 (M+H) R.sub.t=1.74 min/3min. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta.=8.69 (d, J=2.0 Hz, 1H), 8.63 (m, 1H), 8.04 (d, J=6.8 Hz,
1H), 7.90-7.93 (m, 1H), 7.52 (d, J=9.2Hz, 1H), 7.42 (s, 1H),
7.34-7.38 (m, 2H), 7.24-7.28 (m, 1H), 7.12 (t, J=8.4 Hz, 1H), 6.74
(t, J=6.8 Hz, 1H), 4.43 (s, 2H), 4.03 (t, J=7.0 Hz, 2H), 3.18 (t,
J=7.2 Hz, 2H).
Example 379
4-Fluoro-7-(4-fluoro-phenyl)-2-(2-imidazol[1,2-]pyridin-2-yl-ethyl)-2,3-di-
hydro-isoindol-1-one
[1334] The title compound was prepared in analogy to the method
described in Example 378. LC-MS: m/z 390 (M+H) RT=2.02 min/3min.
.sup.1H NMR (400 MHz, CDCl.sub.3):.delta.=8.03 (d, J=6.8 Hz, 1H),
7.52 (d, J=8.8 Hz, 1H), 7.46.about.7.5 (m, 2H), 7.41 (s, 1H),
7.29.about.7.3 (m, 1H), 7.11 (t, J=8.4 Hz, 1H), 7.09.about.7.15(m,
3H), 6.74 (t, J=6.8 Hz, 1H), 4.40 (s, 2H), 4.02 (t, J=7.0 Hz, 2H),
3.17(t, J=7.2 Hz, 2H).
Example 380
4-Fluoro-2-(2-imidazol[1,2-]pyridin-2-yl-ethyl)-7-(4-methoxy-phenyl)-2,3-d-
ihydro-isoindol-1-one
[1335] The title compound was prepared in analogy to the method
described in Example 378. LC-MS: m/z 402 (M+H); R.sub.t=2.01
min/3min. .sup.1H NMR (400 MHz, CDCl.sub.3):.delta.=8.02 (d, J=6.8
Hz, 1H), 7.52 (d, J=9.2 Hz, 1H), 7.46.about.7.47 (m, 2H), 7.41 (s,
1H), 7.30.about.7.33 (m, 2H), 7.27 (m, 1H), 7.11.about.7.21 (m,
2H), 6.96.about.6.98 (m, 2H), 6.73.about.6.75 (m, 1H), 4.44 (s,
2H), 4.02 (t, J=7.2 Hz, 2H), 3.86(s, 3H) , 3.17 (t, J=7.2 Hz,
2H).
Example 381
4-Fluoro-2-(2-imidazol[1,2-]pyridin-2-yl-ethyl)-7-pyrimidin-5-yl-2,3-dihyd-
ro-isoindol-1-one
[1336] The title compound was prepared in analogy to the method
described in Example 378. LC-MS: m/z 374 (M+H); R.sub.t=1.65
min/3min. .sup.1H NMR (400 MHz, CDCl.sub.3):.delta.=9.23 (s, 1H),
8.88(s, 2H), 8.05 (d, J=6.8 Hz, 1H), 7.52 (d, J=9.2 Hz, 1H), 7.41
(s, 1H), 7.31.about.7.35 (m, 2H), 7.15 (t, J=8.4 Hz, 1H), 6.51 (t,
J=6.8 Hz, 1H), 4.46 (s, 2H), 4.04 (t, J=7.2 Hz, 2H), 3.19 (t, J=7.2
Hz, 2H).
Example 382
4-Fluoro-2-(2-imidazol[1,2-]pyridin-2-yl-ethyl)-7-(2-methyl-2H-pyrazol-3-y-
l)-2,3-dihydro-isoindol-1-one
[1337] The title compound was prepared in analogy to the method
described in Example 378. LC-MS: m/z 376 (M+H) RT=1.88 min/3min.
.sup.1H NMR (400 MHz, CDCl.sub.3):.delta.=8.03 (d, J=6.8 Hz, 1H),
7.54 (d, J=1.6 Hz 1H), 7.50 (d, J=10 Hz, 1H), 7.45 (s, 1H),
7.31.about.7.34 (m, 2H), 7.24 (t, J=8.0 Hz, 1H), 7.12.about.7.14
(m, 1H), 6.72.about.6.76(m, 1H), 6.28(d, J=1.6 Hz 1H), 4.46 (s,
2H), 4.02 (t, J=7.0 Hz, 2H), 3.65(s, 3H),3.18(t, J=7.2 Hz, 2H).
Example 383
4-Fluoro-2-(2-imidazol[1,2-]pyridin-2-yl-ethyl)-7-(1H-pyrazol-4-yl)-2,3-di-
hydro-isoindol-1-one
[1338] The title compound was prepared in analogy to the method
described in Example 378. LC-MS: m/z 362 (M+H); R.sub.t=1.69
min/3min. .sup.1H NMR (400 MHz, MeOD):.delta.=8.23 (d, J=6.8 Hz,
1H), 8.00 (brs, 2H), 7.58 (s, 1H), 7.49.about.7.52 (m, 1H),
7.35.about.7.37 (m, 1H), 7.17.about.7.21 (m, 2H), 6.74.about.6.78
(m, 1H), 4.36 (s, 2H), 3.89 (t, J=7.0 Hz, 2H), 3.06(t, J=7.2 Hz,
2H).
[1339] The compounds of the Examples 384 to 555 can be prepared
using the standard operation procedures described above.
TABLE-US-00005 Ex. IUPAC name physico-chemical data 384
4-[3-(Fluoromethyl)pyrrolidin-1-yl]-6-(2- ESI-MS: [M + Na+] =
402.20, imidazo[1,2-a]pyridin-2-ylethyl)-7H- [M + H+] = 380.2
pyrrolo[3,4-b]pyridin-5-one 385
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-[3- ESI-MS: [M + Na+] =
437.10, (difluoromethyl)pyrrolidin-1-yl]-7H- [M + H+] = 415.10
pyrrolo[3,4-b]pyridin-5-one 386
4-[3-(Difluoromethyl)pyrrolidin-1-yl]-6-(2- ESI-MS: [M + Na+] =
420.10, imidazo[1,2-a]pyridin-2-ylethyl)-7H- [M + H+] = 398.10
pyrrolo[3,4-b]pyridin-5-one 387
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-[3- ESI-MS: [M + Na+] =
419.00, (fluoromethyl)pyrrolidin-1-yl]-7H- [M + H+] = 397.10
pyrrolo[3,4-b]pyridin-5-one 388 4-(3-Methoxy-4-pyridyl)-2-[2-(2-
ESI-MS: [M + Na+] = 418.10, quinolyl)ethyl]isoindolin-1-one [M +
H+] = 396.10 389 4-(3-Methoxy-4-pyridyl)-6-[2-(2- ESI-MS: [M + K+]
= 435.10, quinolyl)ethyl]-7H-pyrrolo[3,4-b]pyridin-5- [M + Na+] =
419.05, [M + H+] = 397.10 one 390
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(1,1- ESI-MS: [M + K+] =
467.15, dioxo-1,4-thiazinan-4-yl)-7H-pyrrolo[3,4- [M + Na+] =
451.10, [M + H+] = 429.05 b]pyridin-5-one trifluoroacetate 391
6-[2-(Benzofuran-2-yl)ethyl]-4-(4-pyridyl)- ESI-MS: [M + K+] =
394.10, 7H-pyrrolo[3,4-b]pyridin-5-one [M + Na+] = 378.10, [M + H+]
= 356.10 392 6-[2-(7-Methyl-2-quinolyl)ethyl]-4- ESI-MS: [M + Na+]
= 411.10, morpholino-7H-pyrrolo[3,4-b]pyridin-5-one [M + H+] =
389.15 393 6-[2-(Benzothiophen-2-yl)ethyl]-4-(4- ESI-MS: [M + K+] =
410.10, pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-one [M + Na+] = 394.1,
[M + H+] = 372.10 394 6-[2-(7-Methyl-2-quinolyl)ethyl]-4-(4-
ESI-MS: [M + K+] = 419.10, pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-one
[M + H+] = 381.10 trifluoroacetate 395
6-[2-(Benzothiophen-2-yl)ethyl]-4- ESI-MS: [M + K+] = 418.10,
morpholino-7H-pyrrolo[3,4-b]pyridin-5-one [M + Na+] = 402.10, [M +
H+] = 380.10 trifluoroacetate 396
2-[2-(1,3-Benzothiazol-2-yl)ethyl]-7- ESI-MS: [M + H+] = 402.10
methoxy-4-(4-pyridyl)isoindolin-1-one 397
6-[2-(Benzofuran-2-yl)ethyl]-4-morpholino- ESI-MS: [M + H+] =
364.10 7H-pyrrolo[3,4-b]pyridin-5-one 398
6-[2-(5-Isopropyl-2-pyridyl)ethyl]-4-(4- ESI-MS: [M + H+] = 359.20
pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-one 399
2-[2-(1,3-Benzothiazol-2-yl)ethyl]-7- ESI-MS: [M + K+] = 443.05,
methoxy-4-(2-methylpyrazol-3- [M + Na+] = 427.10, [M + H+] = 405.10
yl)isoindolin-1-one 400 2-[2-(1,3-Benzothiazol-2-yl)ethyl]-7-
ESI-MS: [M + H+] = 391.10 methoxy-4-(1H-pyrazol-3-yl)isoindolin-1-
one 401 6-[2-(5-Isopropyl-2-pyridyl)ethyl]-4- ESI-MS: [M + H+] =
367.20 morpholino-7H-pyrrolo[3,4-b]pyridin-5-one 402
6-[2-(6-Fluoro-1,3-benzothiazol-2-yl)ethyl]- ESI-MS: [M + K+] =
429.00, 4-(4-pyridyl)-7H-pyrrolo[3,4-b]pyridin-5- [M + Na+] =
413.05, [M + H+] = 391.10 one 403
6-[2-(6-Chloro-1,3-benzothiazol-2- ESI-MS: [M + H+] = 407.10
yl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4- b]pyridin-5-one 404
6-[2-(6-Chloro-1,3-benzothiazol-2- ESI-MS: [M + Na+] = 437.00,
yl)ethyl]-4-morpholino-7H-pyrrolo[3,4- [M + H+] = 415.10
b]pyridin-5-one 405 6-[2-(6-Fluoro-1,3-benzothiazol-2-yl)ethyl]-
ESI-MS: [M + Na+] = 421.10,
4-morpholino-7H-pyrrolo[3,4-b]pyridin-5- [M + H+] = 399.10 one 406
6-[2-(6-Methyl-2-quinolyl)ethyl]-4-(4- ESI-MS: [M + K+] = 419.05,
pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-one [M + H+] = 381.10 407
6-[2-(4-Ethylthiazol-2-yl)ethyl]-4-(4- ESI-MS: [M + Na+] = 373.10,
pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-one [M + H+] = 351.10 408
6-[2-(4,5-Dimethylthiazol-2-yl)ethyl]-4-(4- ESI-MS: [M + H+] =
351.10 pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-one 409
6-[2-(3-Methyl-2-pyridyl)ethyl]-4-(4- ESI-MS: [M + H+] = 331.10
pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-one 410
6-[2-(4-Methyl-2-pyridyl)ethyl]-4-(4- ESI-MS: [M + H+] = 331.10
pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-one 411
4-Methoxy-2-[2-(1-methyl-1H- ESI-MS: [M + Na+] = 415.20,
benzoimidazol-2-yl)-ethyl]-7-(oxetan-3- 394.20, [M + H+] = 393.20
ylamino)-2,3-dihydro-isoindol-1-one 412
4-(3-Fluoro-pyridin-4-yl)-6-(2-quinolin-2- ESI-MS: 386.10, [M + H+]
= 385.10 yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]pyridin- 5-one 413
6-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4- ESI-MS: 346.10, [M + H+]
= 345.10 (1H-pyrazol-3-yl)-6,7-dihydro-pyrrolo[3,4- b]pyridin-5-one
414 4-Furan-3-yl-6-(2-imidazo[1,2-a]pyridin-2- ESI-MS: 346.10, [M +
H+] = 345.10 yl-ethyl)-6,7-dihydro-pyrrolo[3,4-b]pyridin- 5-one 415
6-[2-(1,5-Dimethyl-1H-benzoimidazol-2- ESI-MS: 393.20, [M + H+] =
392.20 yl)-ethyl]-4-morpholin-4-yl-6,7-dihydro-
pyrrolo[3,4-b]pyridin-5-one 416
6-[2-(1,5-Dimethyl-1H-benzoimidazol-2- ESI-MS: 379.20, [M + H+] =
378.20 yl)-ethyl]-4-(oxetan-3-ylamino)-6,7-dihydro-
pyrrolo[3,4-b]pyridin-5-one 417 6-[2-(1,3-Benzoxazol-2-yl)ethyl]-4-
ESI-MS: [M + Na+] = 387.10,
morpholino-7H-pyrrolo[3,4-b]pyridin-5-one 366.10, [M + H+] = 365.10
418 6-[2-(1,3-Benzoxazol-2-yl)ethyl]-4-(4- ESI-MS: 358.10, [M + H+]
= 357.10 pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-one 419
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(4- ESI-MS: [M + Na+] =
416.15, methylpiperazin-1-yl)-7H-pyrrolo[3,4- 395.15, [M + H+] =
394.15 b]pyridin-5-one 420
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(2,3- ESI-MS: 365.10, [M + H+]
= 364.10 dihydrofuran-4-yl)-7H-pyrrolo[3,4- b]pyridin-5-one
trifluoroacetate 421 6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(2-
ESI-MS: 392.10, [M + H+] = 391.10
fluoro-4-pyridyl)-7H-pyrrolo[3,4-b]pyridin- 5-one trifluoroacetate
422 6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(3- ESI-MS: [M + Na+] =
384.19, furyl)-7H-pyrrolo[3,4-b]pyridin-5-one 363.10, [M + H+] =
362.10 trifluoroacetate 423
6-(2-Imidazo[2,1-b]thiazol-6-ylethyl)-4-(4- ESI-MS: 363.10, [M +
H+] = 362.10 pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-one
trifluoroacetate 424 6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(2-
ESI-MS: [M + Na+] = 429.10, oxa-7-azaspiro[3.4]octan-7-yl)-7H-
408.15, [M + H+] = 407.10 pyrrolo[3,4-b]pyridin-5-one 425
6-(2-Imidazo[2,1-b]thiazol-6-ylethyl)-4- ESI-MS: 371.10, [M + H+] =
370.10 morpholino-7H-pyrrolo[3,4-b]pyridin-5-one 426
4-(1,3,3a,4,6,6a-Hexahydrofuro[3,4- ESI-MS: [M + Na+] = 429.10,
c]pyrrol-5-yl)-6-[2-(1,3-benzothiazol-2- 408.15, [M + H+] = 407.10
yl)ethyl]-7H-pyrrolo[3,4-b]pyridin-5-one 427
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(4- ESI-MS: [M + Na+] =
417.10, piperidyloxy)-7H-pyrrolo[3,4-b]pyridin-5- 396.10, [M + H+]
= 395.10 one trifluoroacetate 428
2-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(1H- ESI-MS: [M + H+] = 361.10
pyrazol-3-yl)isoindolin-1-one 429
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(1H- ESI-MS: 363.10, [M + H+]
= 362.10 pyrazol-3-yl)-7H-pyrrolo[3,4-b]pyridin-5- one 430
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(3- ESI-MS: 374.10, [M + H+] =
373.10 pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-one trifluoroacetate 431
2-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(4- ESI-MS: [M + H+] = 372.10
pyridyl)isoindolin-1-one 432
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(2- ESI-MS: [M + Na+] =
398.10, methylpyrazol-3-yl)-7H-pyrrolo[3,4- 377.10, [M + H+] =
376.10 b]pyridin-5-one trifluoroacetate 433
2-[2-(1,3-Benzothiazol-2-yl)ethyl]-4- ESI-MS: [M + H+] = 380.10
morpholino-isoindolin-1-one 434
4-[3-(Difluoromethyl)pyrrolidin-1-yl]-6-[2- ESI-MS: [M + Na+] =
431.20, (2-quinolyl)ethyl]-7H-pyrrolo[3,4-b]pyridin- 410.20, [M +
H+] = 409.20 5-one 435 4-[3-(Fluoromethyl)pyrrolidin-1-yl]-6-[2-(2-
ESI-MS: [M + Na+] = 413.20,
quinolyl)ethyl]-7H-pyrrolo[3,4-b]pyridin-5- 392.20, [M + H+] =
391.20 one 436 6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4- ESI-MS:
402.00, [M + Na+] = 401.00,
thiazol-4-yl-7H-pyrrolo[3,4-b]pyridin-5-one 381.05, 380.05, [M +
H+] = 379.00 437 4-Fluoro-7-(oxetan-3-ylamino)-2-[2-(2- ESI-MS:
379.15, [M + H+] = 378.20 quinolyl)ethyl]isoindolin-1-one 438
4-fluoro-7-(3-pyridyl)-2-[2-(2- ESI-MS: 385.10, [M + H+] = 384.10
quinolyl)ethyl]isoindolin-1-one 439
4-Fluoro-7-(2-methylpyrazol-3-yl)-2-[2-(2- ESI-MS: 388.10, [M + H+]
= 387.10 quinolyl)ethyl]isoindolin-1-one 440
4-Fluoro-7-morpholino-2-[2-(2- ESI-MS: [M + Na+] = 414.10,
quinolyl)ethyl]isoindolin-1-one 393.20, [M + H+] = 392.20 441
4-Fluoro-7-(4-methoxyphenyl)-2-[2-(2- ESI-MS: 414.15, [M + H+] =
413.20 quinolyl)ethyl]isoindolin-1-one 442
4-Fluoro-7-(1H-pyrazol-4-yl)-2-[2-(2- ESI-MS: 374.10, [M + H+] =
373.10 quinolyl)ethyl]isoindolin-1-one trifluoroacetate 443
4-Fluoro-7-pyrimidin-5-yl-2-[2-(2- ESI-MS: 386.10, [M + H+] =
385.10 quinolyl)ethyl]isoindolin-1-one trifluoroacetate 444
4-Fluoro-7-(4-fluorophenyl)-2-[2-(2- ESI-MS: [M + Na+] = 423.10,
quinolyl)ethyl]isoindolin-1-one 402.10, [M + H+] = 401.10 445
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(2- ESI-MS: [M + Na+] =
410.10, methylpyrimidin-5-yl)-7H-pyrrolo[3,4- 389.10, [M + H+] =
388.10 b]pyridin-5-one 446 1-[5-oxo-6-[2-(2-quinolyl)ethyl]-7H-
ESI-MS: 390.20, [M + H+] = 389.10
pyrrolo[3,4-b]pyridin-4-yl]azetidine-3- carboxylic acid 447
4-(oxetan-3-yloxy)-6-[2-(2-quinolyl)ethyl]- ESI-MS: [M + H+] =
362.10 7H-pyrrolo[3,4-b]pyridin-5-one 448
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-7- ESI-MS: [M + H+] = 385.10
methoxy-4-pyridin-4-yl-2,3-dihydro- isoindol-1-one trifluoroacetate
449 2-[2-(1-Difluoromethyl-1H-benzoimidazol- ESI-MS: [M + Na+] =
435.10, 2-yl)-ethyl]-7-morpholin-4-yl-2,3-dihydro- [M + H+] =
413.10 isoindol-1-one trifluoroacetate 450
2-[2-(1-Difluoromethyl-1H-benzoimidazol- ESI-MS: [M + H+] = 405.10
2-yl)-ethyl]-7-pyridin-4-yl-2,3-dihydro- isoindol-1-one
trifluoroacetate 451 4-Pyridin-4-yl-6-(2-quinolin-2-yl-ethyl)-
ESI-MS: [M + H+] = 367.10 5,6-dihydro-pyrrolo[3,4-b]pyridin-7-one
452 6-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4- ESI-MS: [M + H+] =
356.10 pyridin-4-yl-5,6-dihydro-pyrrolo[3,4- b]pyridin-7-one 453
6-(2-Quinolin-2-yl-ethyl)-6,7-dihydro- ESI-MS: [M + Na+] = 312.10,
pyrrolo[3,4-b]pyridin-5-one trifluoroacetate [M + H+] = 290.10 454
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-7- ESI-MS: [M + H+] = 374.10
methoxy-4-(1H-pyrazol-3-yl)-2,3-dihydro- isoindol-1-one 455
2-[2-(1H-Imidazo[4,5-b]pyridin-2-yl)- ESI-MS: [M + Na+] = 378.10,
ethyl]-7-pyridin-4-yl-2,3-dihydro-isoindol-1- [M + H+] = 356.10 one
456 2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-7- ESI-MS: [M + H+] =
385.10 methoxy-4-pyridin-3-yl-2,3-dihydro- isoindol-1-one
trifluoroacetate 457 2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-7-
ESI-MS: [M + H+] = 414.20 methoxy-4-(4-methoxy-phenyl)-2,3-dihydro-
isoindol-1-one trifluoroacetate 458
4-(4-Methoxy-phenyl)-6-(2-quinolin-2-yl- ESI-MS: [M + H+] = 396.20
ethyl)-5,6-dihydro-pyrrolo[3,4-b]pyridin-7- one trifluoroacetate
459 4-(2-Methyl-2H-pyrazol-3-yl)-6-(2- ESI-MS: [M + H+] = 370.10
quinolin-2-yl-ethyl)-5,6-dihydro- pyrrolo[3,4-b]pyridin-7-one
trifluoroacetate 460 6-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-
ESI-MS: [M + H+] = 356.10 pyridin-3-yl-5,6-dihydro-pyrrolo[3,4-
b]pyridin-7-one trifluoroacetate 461
6-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-(4- ESI-MS: [M + H+] =
385.10 methoxy-phenyl)-5,6-dihydro-pyrrolo[3,4- b]pyridin-7-one
trifluoroacetate 462 6-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-4-(2-
ESI-MS: [M + H+] = 359.10 methyl-2H-pyrazol-3-yl)-5,6-dihydro-
pyrrolo[3,4-b]pyridin-7-one trifluoroacetate 463
4-Pyridin-3-yl-6-(2-quinolin-2-yl-ethyl)- ESI-MS: [M + H+] = 367.10
5,6-dihydro-pyrrolo[3,4-b]pyridin-7-one trifluoroacetate 464
2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-7- ESI-MS: [M + H+] = 388.20
methoxy-4-(2-methyl-2H-pyrazol-3-yl)-2,3- dihydro-isoindol-1-one
trifluoroacetate
465 4-(4-Pyridyl)-6-(2-quinoxalin-2-ylethyl)- ESI-MS: [M + K+] =
406.10, 7H-pyrrolo[3,4-b]pyridin-5-one [M + Na+] = 390.10, [M + H+]
= 368.10 466 6-[2-(6-Methyl-2-pyridyl)ethyl]-4- ESI-MS: [M + Na+] =
361.10, morpholino-7H-pyrrolo[3,4-b]pyridin-5-one [M + H+] = 339.20
467 4-Pyrimidin-5-yl-6-[2-(2-quinolyl)ethyl]- ESI-MS: [M + H+] =
368.10 5H-pyrrolo[3,4-b]pyridin-7-one 468
6-[2-(5-Methyl-2-pyridyl)ethyl]-4- ESI-MS: [M + Na+] = 361.20,
morpholino-7H-pyrrolo[3,4-b]pyridin-5-one [M + H+] = 339.20
hydrochloride 469 6-[2-(1-Methylimidazol-2-yl)ethyl]-4-(4- ESI-MS:
[M + H+] = 320.10 pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-one
trifluoroacetate 470 6-[2-(6-Methyl-2-pyridyl)ethyl]-4-(4- ESI-MS:
[M + H+] = 331.15 pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-one
trifluoroacetate 471 4-(4-Pyridyl)-6-[2-(2-pyridyl)ethyl]-7H-
ESI-MS: [M + H+] = 317.10 pyrrolo[3,4-b]pyridin-5-one
trifluoroacetate 472 4-(4-Pyridyl)-6-(2-thieno[3,2-b]pyridin-5-
ESI-MS: [M + H+] = 373.10 ylethyl)-7H-pyrrolo[3,4-b]pyridin-5-one
473 6-[2-(3,5-Dimethyl-2-pyridyl)ethyl]-4-(4- ESI-MS: [M + H+] =
345.15 pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-one 474
6-[2-(5,6-Dimethyl-2-pyridyl)ethyl]-4-(4- ESI-MS: [M + H+] = 345.20
pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-one trifluoroacetate 475
2-[2-[4-(3-Pyridyl)-5,7-dihydropyrrolo[3,4- ESI-MS: [M + H+] =
342.20 b]pyridin-6-yl]ethyl]imidazo[1,2-a]pyridine trifluoroacetate
476 6-[2-(5-Methyl-2-pyridyl)ethyl]-4-(3- ESI-MS: [2M + Na+] =
683.30, pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-one [M + H+] = 331.10
trifluoroacetate 477 2-[2-[4-(2-Methylpyrazol-3-yl)-5,7- ESI-MS: [M
+ H+] = 345.20 dihydropyrrolo[3,4-b]pyridin-6-
yl]ethyl]imidazo[1,2-a]pyridine trifluoroacetate 478
2-[2-[4-(4-Methoxyphenyl)-5,7- ESI-MS: [M + H+] = 371.15
dihydropyrrolo[3,4-b]pyridin-6- yl]ethyl]imidazo[1,2-a]pyridine
trifluoroacetate 479 4-(1,1-Dioxo-1,4-thiazinan-4-yl)-6-[2-(5-
ESI-MS: [M + Na+] = 409.10, methyl-2-pyridyl)ethyl]-7H-pyrrolo[3,4-
[M + H+] = 387.10 b]pyridin-5-one trifluoroacetate 480
6-[2-(5-Methyl-2-pyridyl)ethyl]-4- ESI-MS: [M + H+] = 332.10
pyrimidin-5-yl-7H-pyrrolo[3,4-b]pyridin-5- one trifluoroacetate 481
6-[2-(5-Methyl-2-pyridyl)ethyl]-4-(4- ESI-MS: [M + K+] = 369.10,
pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-one [M + H+] = 331.10
trifluoroacetate 482 7-Morpholino-2-(2-quinoxalin-2- ESI-MS: [M +
H+] = 375.10 ylethyl)isoindolin-1-one 483
6-[2-(6-Methoxy-2-pyridyl)ethyl]-4- ESI-MS: [M + H+] = 355.10
morpholino-7H-pyrrolo[3,4-b]pyridin-5-one 484
4-(4-Pyridyl)-6-[2-[4-(4-pyridyl)-2- ESI-MS: [M + H+] = 444.20
quinolyl]ethyl]-7H-pyrrolo[3,4-b]pyridin-5- one 485
4-(2,2,3,3,5,5,6,6-Octadeuteriomorpholin-4- ESI-MS: [M + H+] =
383.20 yl)-6-[2-(2-quinolyl)ethyl]-7H-pyrrolo[3,4- b]pyridin-5-one
486 4-Morpholino-6-[2-(5-phenyl-2- ESI-MS: [M + H+] = 401.20
pyridyl)ethyl]-7H-pyrrolo[3,4-b]pyridin-5- one 487
6-[2-(1-Methylimidazol-4-yl)ethyl]-4-(4- ESI-MS: [M + H+] = 320.10
pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-one trifluoroacetate 488
6-[2-(5-Phenyl-2-pyridyl)ethyl]-4-(4- ESI-MS: [M + H+] = 393.20
pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-one trifluoroacetate 489
6-[2-(3,5-Dimethyl-2-pyridyl)ethyl]-4- ESI-MS: [M + H+] = 353.20
morpholino-7H-pyrrolo[3,4-b]pyridin-5-one 490
6-[2-(5-Methyl-2-pyridyl)ethyl]-4-(oxetan- ESI-MS: [M + H+] =
325.10 3-ylamino)-7H-pyrrolo[3,4-b]pyridin-5-one 491
4-Morpholino-6-(2-thieno[3,2-b]pyridin-5- ESI-MS: [M + H+] = 381.10
ylethyl)-7H-pyrrolo[3,4-b]pyridin-5-one 492
6-[2-(6-Fluoroimidazo[1,2-a]pyridin-2- ESI-MS: [M + H+] = 382.10
yl)ethyl]-4-morpholino-7H-pyrrolo[3,4- b]pyridin-5-one
hydrochloride 493 6-[2-(6-Fluoroimidazo[1,2-a]pyridin-2- ESI-MS: [M
+ H+] = 382.10 yl)ethyl]-4-morpholino-7H-pyrrolo[3,4-
b]pyridin-5-one trifluoroacetate 494
6-[2-(6-Fluoroimidazo[1,2-a]pyridin-2- ESI-MS: [M + H+] = 374.10
yl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4- b]pyridin-5-one
trifluoroacetate 495 4-Morpholino-6-(2-quinoxalin-2-ylethyl)-
ESI-MS: [M + H+] = 376.15 7H-pyrrolo[3,4-b]pyridin-5-one
trifluoroacetate 496 6-[2-(8-Methylimidazo[1,2-a]pyridin-2- ESI-MS:
[M + H+] = 370.15 yl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4-
b]pyridin-5-one trifluoroacetate 497
6-[2-(5-Fluoro-2-pyridyl)ethyl]-4-(4- ESI-MS: [M + H+] = 335.10
pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-one trifluoroacetate 498
6-[2-(5-Fluoro-2-pyridyl)ethyl]-4- ESI-MS: [M + Na+] = 365.10,
morpholino-7H-pyrrolo[3,4-b]pyridin-5-one [M + H+] = 343.10
trifluoroacetate 499 6-[2-(5-Ethyl-2-pyridyl)ethyl]-4- ESI-MS: [M +
H+] = 353.2 morpholino-7H-pyrrolo[3,4-b]pyridin-5-one
trifluoroacetate 500 4-Morpholino-6-[2-[5-(trifluoromethyl)-2-
ESI-MS: [M + Na+] = 415.10,
pyridyl]ethyl]-7H-pyrrolo[3,4-b]pyridin-5- [M + H+] = 393.10 one
trifluoroacetate 501 6-[2-(5-Ethyl-2-pyridyl)ethyl]-4-(4- ESI-MS:
[M + H+] = 345.20 pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-one
trifluoroacetate 502 6-[2-(5-Chloro-2-pyridyl)ethyl]-4-(4- ESI-MS:
[M + H+] = 351.10 pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-one
trifluoroacetate 503 6-[2-(6-Methoxy-2-pyridyl)ethyl]-4-(3- ESI-MS:
[M + Na+] = 369.10, pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-one [M +
H+] = 347.10 trifluoroacetate 504
6-[2-(5,6-Dimethyl-2-pyridyl)ethyl]-4- ESI-MS: 357.10 (M + 18),
(oxetan-3-ylamino)-7H-pyrrolo[3,4- [M + H+] = 339.10
b]pyridin-5-one trifluoroacetate 505
6-[2-(5-Chloro-2-pyridyl)ethyl]-4- ESI-MS: [M + Na+] = 381.10,
morpholino-7H-pyrrolo[3,4-b]pyridin-5-one [M + H+] = 359.10 506
4-(4-Pyridyl)-6-[2-[5-(trifluoromethyl)-2- ESI-MS: [M + H+] =
385.10 pyridyl]ethyl]-7H-pyrrolo[3,4-b]pyridin-5- one
trifluoroacetate 507 6-[2-(4,5-Dimethyl-2-pyridyl)ethyl]-4-(4-
ESI-MS: [M + H+] = 345.10 pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-one
trifluoroacetate 508 4-Fluoro-2-(2-imidazo[1,2-a]pyridin-2- ESI-MS:
[M + H+] = 367.10 ylethyl)-7-(oxetan-3-ylamino)isoindolin-1- one
trifluoroacetate 509 6-[2-(6-Methoxy-2-pyridyl)ethyl]-4- ESI-MS: [M
+ Na+] = 363.10, (oxetan-3-ylamino)-7H-pyrrolo[3,4- [M + H+] =
341.10 b]pyridin-5-one 510
2,3,7,7-Tetradeuterio-6-[1,1-dideuterio-2- ESI-MS: [M + H+] =
395.20 (3,4,5,6,7,8-hexadeuterio-2-quinolyl)ethyl]-
4-(2,2,3,3,5,5,6,6-octadeuteriomorpholin-4-
yl)pyrrolo[3,4-b]pyridin-5-one 511
6-(2-Imidazo[1,2-a]pyridin-2-yl-1-methyl- ESI-MS: [M + H+] = 378.20
ethyl)-4-morpholino-7H-pyrrolo[3,4- b]pyridin-5-one
trifluoroacetate 512 6-[2-(1,5-Naphthyridin-2-yl)ethyl]-4-(4-
ESI-MS: [M + H+] = 368.10 pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-one
513 2,3,7,7-Tetradeuterio-6-[2,2-dideuterio-2- ESI-MS: [M+] =
386.20 (3,4,5,6,7,8-hexadeuterio-2-quinolyl)ethyl]-
4-morpholino-pyrrolo[3,4-b]pyridin-5-one 514
4-Morpholino-6-[2-(1,5-naphthyridin-2- ESI-MS: [M + Na+] = 398.10,
yl)ethyl]-7H-pyrrolo[3,4-b]pyridin-5-one [M + H+] = 376.10 515
6-[2-(3-Methoxy-2-pyridyl)ethyl]-4-[2-(3- ESI-MS: [M + H+] = 420.20
methoxy-2-pyridyl)ethylamino]-7H- pyrrolo[3,4-b]pyridin-5-one 516
6-[2-(4-Ethylthiazol-2-yl)ethyl]-4- ESI-MS: [M + H+] = 359.20
morpholino-7H-pyrrolo[3,4-b]pyridin-5-one 517
6-[2-(4-Cyclopropylthiazol-2-yl)ethyl]-4-(4- ESI-MS: [M + Na+] =
385.20, pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-one [M + H+] = 363.20
518 6-[2-(4-Cyclopropylthiazol-2-yl)ethyl]-4- ESI-MS: [M + H+] =
371.10 morpholino-7H-pyrrolo[3,4-b]pyridin-5-one 519
6-[2-(4,5-Dimethylthiazol-2-yl)ethyl]-4- ESI-MS: [M + Na+] =
381.10, morpholino-7H-pyrrolo[3,4-b]pyridin-5-one [M + H+] = 359.10
520 6-[2-(4,5-Dimethyl-2-pyridyl)ethyl]-4- ESI-MS: [M + H+] =
353.10 morpholino-7H-pyrrolo[3,4-b]pyridin-5-one 521
6-[2-(4-Methyl-2-pyridyl)ethyl]-4- ESI-MS: [M + H+] = 339.10
morpholino-7H-pyrrolo[3,4-b]pyridin-5-one 522
6-[2-(3-Methyl-2-pyridyl)ethyl]-4- ESI-MS: [M + H+] = 339.20
morpholino-7H-pyrrolo[3,4-b]pyridin-5-one 523
6-(2-Imidazo[1,2-a]pyridin-2-ylethyl)-4-(3- ESI-MS: [M + H+] =
361.10 thienyl)-7H-pyrrolo[3,4-b]pyridin-5-one 524
6-(2-Imidazo[1,2-a]pyridin-2-ylethyl)-4-(2- ESI-MS: [M + H+] =
359.10 methyl-3-furyl)-7H-pyrrolo[3,4-b]pyridin-5- one 525
6-(2-Imidazo[1,2-a]pyridin-2-ylethyl)-4-(5- ESI-MS: [M + H+] =
359.10 methyl-2-furyl)-7H-pyrrolo[3,4-b]pyridin-5- one 526
6-[2-(6-Fluoroimidazo[1,2-a]pyridin-2- ESI-MS: [M + H+] = 363.10
yl)ethyl]-4-(3-furyl)-7H-pyrrolo[3,4- b]pyridin-5-one 527
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(4,4- .sup.1H NMR
(METHANOL-d.sub.4, difluoro-1-piperidyl)-7H-pyrrolo[3,4- 400 MHz):
.delta. = 8.27 (d, H), b]pyridin-5-one trifluoroacetate 7.93 (d, 1
H), 7.87 (d, 1 H), 7.46-7.49 (m, 1 H), 7.37-7.42 (m, 1 H), 6.85 (d,
1 H), 4.40 (s, 2 H), 4.09 (t, 2 H), 3.48-3.58 (m, 6 H), 2.01-2.11
(m, 4 H) 528 4-Methoxy-6-(2-quinolin-2-yl-ethyl)-6,7-
dihydro-pyrrolo[3,4-b]pyridin-5-one 529
4-(2-Dimethylamino-ethoxy)-7-pyridin-4- .sup.1H NMR
(METHANOL-d.sub.4, yl-2-(2-quinolin-2-yl-ethyl)-2,3-dihydro- 400
MHz): .delta. = 8.65 (d, 2 H), isoindol-1-one 8.58 (d, 1 H), 8.08
(d, 1H), 7.99 (d, 1 H), 7.85-7.90 (m, 3 H), 7.71-7.75 (m, 2 H),
7.62 (d, 1 H), 7.43 (d, 1 H), 4.60-4.67 (m, 4 H), 4.14 (t, 2 H),
3.71-3.74 (t, 1 H), 3.51 (t, 2 H), 3.01-3.06 (m, 6 H) 530
4-(4-Hydroxy-piperidin-1-yl)-6-(2-quinolin- .sup.1H NMR
(CHLOROFORM-d, 2-yl-ethyl)-6,7-dihydro-pyrrolo[3,4- 500 MHz):
.delta. = 9.93-10.06 (m, b]pyridin-5-one trifluoroacetate 1 H),
8.79-8.90 (m, 1 H), 8.67 (d, 1 H), 8.56 (d, 1 H), 8.50 (d, 1 H),
8.03 (d, 1 H), 7.98 (t, 1 H), 7.73-7.86 (m, 2 H), 6.80 (d, 1 H),
5.00 (s. Br., 1 H), 4.57 (s, 2 H), 4.12 (t, 2 H), 3.71 (t, 2 H),
3.41 (m br., 2 H), 3.25 (m br., 2 H), 2.29 (t, 3 H) 531
1-[3-Oxo-2-(2-quinolin-2-yl-ethyl)-2,3- .sup.1H NMR (CHLOROFORM-d,
dihydro-1H-isoindol-4-ylmethyl]-azetidine- 500 MHz): .delta. = 8.09
(d, 1 H), 3-carboxylic acid methyl ester 8.00 (d, 1 H), 7.79 (d, 1
H), 7.69 (t, 1 H), 7.36-7.52 (m, 4 H), 4.32 (s, 2 H), 4.27 (s br.,
1 H), 4.12 (t, 2 H), 3.72 (s, 2 H), 3.53-3.70 (m, 2 H), 3.50 (s
br., 1 H), 3.37 (t, 3 H) 532
4-(2-Fluoro-ethoxy)-7-pyridin-4-yl-2-(2- .sup.1H NMR (CHLOROFORM-d,
quinolin-2-yl-ethyl)-isoindole-1,3-dione 400 MHz): .delta. = 8.60
(d, 2 H), 8.09 (d, 1 H), 7.90 (d br., 1 H), 7.79 (d, 1 H), 7.63 (t,
1 H), 7.46-7.57 (m, 2 H), 7.31 (t, 2 H), 7.21-7.28 (m, incl.
CHCl.sub.3), 4.89 (d, 1 H), 4.77 (d, 1 H), 4.53 (m sym., 1 H), 4.47
(m sym., 1 H), 4.14 (t, 2 H), 3.33 (t, 2 H) 533
4-(2-Fluoro-ethoxy)-7-pyridin-4-yl-2-(2- .sup.1H NMR (CHLOROFORM-d,
quinolin-2-yl-ethyl)-2,3-dihydro-isoindol-1- 400 MHz): .delta. =
8.62 (d, 2 H), one 8.09 (d, 1 H), 8.01 (d, 1 H), 7.79 (d, 1 H),
7.69 (t, 1 H), 7.50 (m, 1 H), 7.40 (d, 2 H), 7.30-7.40 (m, 2 H),
7.04 (d, 1 H), 4.84 (d, 1 H), 4.71 (d, 1 H), 4.46 (s, 2 H), 4.39
(d, 1 H), 4.32 (d, 1 H), 4.11 (t, 2 H), 3.37 (t, 2 H) 534
4-(3-Fluoro-pyridin-4-yl)-6-(2-imidazo[1,2- .sup.1H NMR
(CHLOROFORM-d, a]pyridin-2-yl-ethyl)-6,7-dihydro- 500 MHz): .delta.
= 8.77 (d, 1 H), pyrrolo[3,4-b]pyridin-5-one 8.61 (s, 1 H), 8.54
(d, 1 H), 8.03 (d, 1 H), 7.54 (s, 1H), 7.52 (d, 1 H), 7.40-7.43 (m,
2 H), 7.33 (d, 1 H), 7.16 (t, 1 H), 6.75 (t, 1 H), 4.45 (s, 2 H),
4.08 (t, 2 H), 3.20 (t, 2 H) 535
6-[2-(1,5-Dimethyl-1H-benzoimidazol-2- .sup.1H NMR (CHLOROFORM-d,
yl)-ethyl]-4-pyrimidin-5-yl-6,7-dihydro- 500 MHz): .delta. = 9.28
(s, 1 H), pyrrolo[3,4-b]pyridin-5-one 8.96 (s, 2 H), 8.80 (d, 1 H),
7.46 (s, 1 H), 7.32 (d, 1 H), 7.18 (d, 1 H), 7.09 (d, 1 H), 4.69
(s, 2 H), 4.18 (t, 2 H), 3.72 (s, 3 H), 3.31 (t, 2 H), 2.46 (s, 3
H)
536 6-[2-(1,5-Dimethyl-1H-benzoimidazol-2- .sup.1H NMR
(CHLOROFORM-d, yl)-ethyl]-4-pyridin-4-yl-6,7-dihydro- 500 MHz):
.delta. = 8.76 (d, 1 H), pyrrolo[3,4-b]pyridin-5-one 8.70 (d, 2 H),
7.46 (d, 3 H), 7.31 (d, 1 H), 7.18 (d, 1 H), 7.10 (d, 1 H), 4.66
(s, 2 H), 4.16 (t, 2 H), 3.73 (s, 3 H), 3.30 (t, 2 H), 2.46 (s, 3
H) 537 2-(2-Imidazo[1,2-a]pyridin-2-ylethyl)-4- .sup.1H NMR
(CHLOROFORM-d, thiazol-4-yl-isoindolin-1-one 400 MHz): .delta. =
8.87 (s, 1 H), 8.04 (d, 1 H), 7.96 (d, 1 H), 7.85 (d, 1 H),
7.50-7.58 (m, 4 H), 7.14 (t, 1 H), 6.73 (t, 1 H), 4.77 (s, 2 H),
4.12 (t, 2 H), 3.27 (t, 2 H) 538
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(1H- .sup.1H NMR
(DMSO-d.sub.6, pyrazol-4-yl)-7H-pyrrolo[3,4-b]pyridin-5- 500 MHz):
.delta. = 8.70 (s, 2 H), one trifluoroacetate 8.61 (d, 2 H), 8.06
(d, 1 H), 7.95 (d, 1 H), 7.77 (d, 1 H), 7.49 (t, 1 H), 7.41 (t, 1
H), 4.56 (s, 2 H), 4.06 (t, 2 H), 3.54 (t, 2 H) 539
6-[2-(1,5-Dimethylbenzimidazol-2- .sup.1H NMR (CHLOROFORM-d,
yl)ethyl]-4-(3-pyridyl)-7H-pyrrolo[3,4- 500 MHz): .delta. = 8.79
(d, 1 H), b]pyridin-5-one 8.74 (d, 1 H), 8.68 (dd, 1 H), 7.96 (dt,
1 H), 7.48 (s, 1 H), 7.40 (m sym., 1 H), 7.33 (d, 1 H), 7.18 (d, 1
H), 7.09 (d, 1 H), 4.64 (s, 2 H), 4.16 (t, 2 H), 3.72 (s, 3 H),
3.30 (t, 2 H), 2.46 (s, 3 H) 540 6-[2-(1,5-Dimethylbenzimidazol-2-
.sup.1H NMR (CHLOROFORM-d, yl)ethyl]-4-(2-methylpyrazol-3-yl)-7H-
500 MHz): .delta. = 8.73 (d, 1 H), pyrrolo[3,4-b]pyridin-5-one 7.55
(s, 1 H), 7.43 (s, 1 H), 7.24 (d, 1 H), 7.18 (d, 1 H), 7.09 (d, 1
H), 6.40 (s, 1 H), 4.67 (s, 2 H), 4.14 (t, 2 H), 3.75 (s, 3 H),
3.55 (s, 3 H), 3.31 (t, 2 H), 2.45 (s, 3 H) 541
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(4- .sup.1H NMR (DMSO-d.sub.6,
methoxyphenyl)-7H-pyrrolo[3,4-b]pyridin- 500 MHz): .delta. = 8.70
(d, 1 H), 5-one trifluoroacetate 8.06 (d, 1 H), 7.93 (d, 1 H), 7.61
(d, 2 H), 7.49 (t, 1 H), 7.39-7.45 (m, 2 H), 6.99 (d, 2 H), 4.59
(s, 2 H), 4.02 (t, 2 H), 3.82 (s, 3 H), 3.52 (t, 2 H) 542
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(4- .sup.1H NMR (DMSO-d.sub.6,
fluorophenyl)-7H-pyrrolo[3,4-b]pyridin-5- 500 MHz): .delta. = 8.75
(d, 1 H), one trifluoroacetate 8.06 (d, 1 H), 7.92 (d, 1 H),
7.65-7.69 (m, 2 H), 7.46-7.50 (m, 2 H), 7.41 (t, 1 H), 4.62 (s, 2
H), 4.03 (t, 2 H), 3.52 (t, 2 H) 543
6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4-(3,6- .sup.1H NMR
(CHLOROFORM-d, dihydro-2H-pyran-4-yl)-7H-pyrrolo[3,4- 400 MHz):
.delta. = 8.74 (d, 1H), b]pyridin-5-one 7.96 (d, 1H), 7.86 (d, 1H),
7.48 (t, 1H), 7.39 (t, 1H), 7.20 (d, 1H), 6.12 (s, 1H), 4.60 (t,
2H), 4.54 (s, 2H), 4.19 (t, 2H), 3.54 (t, 2H), 2.93 (t, 2H), 1.78
(br. s, 2H) 544 6-[2-(1,3-Benzothiazol-2-yl)ethyl]-4- .sup.1H NMR
(CHLOROFORM-d, pyrimidin-5-yl-7H-pyrrolo[3,4-b]pyridin-5- 400 MHz):
.delta. = 9.29 (s, 1H), one 9.01 (s, 2H), 8.80 (d, 1H), 7.95 (d,
1H), 7.84 (d, 1H), 7.47 (t, 1H), 7.33-7.38 (m, 2H), 4.55 (s, 2H),
4.20 (t, 2H), 3.54 (t, 2H) 545 4-(Fluoromethoxy)-2-(2-imidazo[1,2-
.sup.1H NMR (DMSO-d.sub.6, a]pyridin-2-ylethyl)-7-pyrimidin-5-yl-
500 MHz): .delta. = 9.24 (s, 1 H), isoindoline-1,3-dione 8.98 (s, 2
H), 8.45 (d, 1 H), 7.92 (d, 1 H), 7.77 (s, 1 H), 7.74 (d, 1 H),
7.41 (d, 1 H), 7.16 (dd, 1 H), 6.83 (t, 1 H), 6.18 (s, 1 H), 6.07
(s, 1 H), 3.86 (t, 2 H), 2.99 (t, 2 H) 546
4-(6-Fluoro-1,4-diazepan-1-yl)-6-[2-(2-
quinolyl)ethyl]-7H-pyrrolo[3,4-b]pyridin-5- one 547
4-(4-Pyridyl)-6-[2-(4-quinolyl)ethyl]-7H- .sup.1H NMR
(METHANOL-d.sub.4, pyrrolo[3,4-b]pyridin-5-one trifluoroacetate 500
MHz): .delta. = 9.01 (d, 1 H), 8.88 (d, 1 H), 8.77 (d, 2 H), 8.61
(d, 1 H), 8.21 (d, 1 H), 8.11 (t, 1 H), 7.84-8.00 (m, 4 H), 7.58
(d, 1 H), 4.76 (s, 2 H), 4.11 (t, 2 H), 3.80 (t, 2 H) 548
4-Morpholino-6-[2-(4-quinolyl)ethyl]-7H- .sup.1H NMR (CHLOROFORM-d,
pyrrolo[3,4-b]pyridin-5-one 500 MHz): .delta. = 8.83 (d, 1H), 8.33
(d, 1H), 8.18-8.23 (m, 2H), 7.77 (t, 1H), 7.65 (t, 1H), 7.35 (d,
1H), 6.66 (d, 1H), 4.33 (s, 2H), 3.90-3.99 (m, 6H), 3.53-3.61 (m,
6H) 549 2-(2-Imidazo[1,2-a]pyridin-2-yl-ethyl)-7- .sup.1H NMR
(CHLOROFORM-d, methoxy-4-pyrimidin-5-yl-2,3-dihydro- 500 MHz):
.delta. = 9.27 (s, 1 H), isoindol-1-one trifluoroacetate 8.94 (s,
1H), 8.45 (d, 1 H), 8.06 (s, 1 H), 7.96 (d, 1 H), 7.73 (t, 1 H),
7.55 (d, 1 H), 7.26-7.30 (m, 1 H), 7.06 (d, 1H), 4.62 (s, 2 H),
4.13 (t, 2 H), 3.97 (s, 3 H), 3.42 (m, 2H), 0.00 (s, 2 H) 550
4-Morpholino-6-[2-(2-pyridyl)ethyl]-7H- .sup.1H NMR (CHLOROFORM-d,
pyrrolo[3,4-b]pyridin-5-one 400 MHz): .delta. = 8.56 (d, 1 H), 8.32
(d, 1 H), 7.59 (td, 1 H), 7.20 (d, 1 H), 7.12-7.15 (m, 1 H), 6.61
(d, 1 H), 4.21 (s, 2 H), 4.00 (t, 3 H), 3.89-3.93 (m, 3 H), 3.55
(dd, 4 H), 3.15 (t, 2H) 551 6-[2-(5-Methyl-2-pyridyl)ethyl]-4-
.sup.1H NMR (CHLOROFORM-d,
morpholino-7H-pyrrolo[3,4-b]pyridin-5-one 400 MHz): .delta. = 8.37
(d, 1 H), 8.32 (d, 1 H), 7.39 (dd, 1 H), 7.09 (d, 1 H), 6.60 (d, 1
H), 4.19 (s, 2 H), 3.97 (t, 2H), 3.89-3.94 (m, 4 H), 3.53-3.57 (m,
4 H), 3.11 (t, 2 H), 2.30 (s, 3 H) 552
6-[2-(7-Ethylimidazo[1,2-a]pyridin-2- .sup.1H NMR (DMSO-d.sub.6,
yl)ethyl]-4-(4-pyridyl)-7H-pyrrolo[3,4- 500 MHz): .delta. = 8.81
(br. s., 1 b]pyridin-5-one H), 8.67 (br. s., 2 H), 8.35 (br. s., 1
H), 7.66 (br. s., 1 H), 7.62 (br. s., 2 H), 7.52 (br. s., 1 H),
7.22 (br. s., 1 H), 6.73 (br. s., 1 H), 4.57 (br. s., 2 H), 3.88
(br. s., 2 H), 3.02 (br. s., 2 H), 2.62 (m, 2 H), 1.18-1.22 (m, 3
H) 553 6-[2-(6-Methoxy-2-pyridyl)ethyl]-4-(4- .sup.1H NMR
(DMSO-d.sub.6, pyridyl)-7H-pyrrolo[3,4-b]pyridin-5-one 500 MHz):
.delta. = 8.81 (d, 1H), 8.68 (d, 2 H), 7.58-7.62 (m, 3 H), 7.52 (d,
1 H), 6.89 (d, 1 H), 6.63 (d, 1 H), 4.55 (s, 2 H), 3.91 (t, 2 H),
3.72 (s, 3 H), 3.02 (t, 2 H) 554
6-[2-(5,6-Dimethyl-2-pyridyl)ethyl]-4- .sup.1H NMR (CHLOROFORM-d,
morpholino-7H-pyrrolo[3,4-b]pyridin-5-one 500 MHz): .delta. = 8.32
(d, 1 H), 7.30 (d, 1 H), 6.94 (d, 1 H), 6.61 (d, 1 H), 4.20 (s, 2
H), 3.96 (t, 2 H), 3.90-3.94 (m, 4 H), 3.55 (m, 4 H), 3.08 (t, 2
H), 2.46 (s, 3H), 2.24 (s, 3 H) 555
6-[2-(7-Ethylimidazo[1,2-a]pyridin-2- .sup.1H NMR (CHLOROFORM-d,
yl)ethyl]-4-morpholino-7H-pyrrolo[3,4- 400 MHz): .delta. = 8.31 (d,
1 H), b]pyridin-5-one 7.91 (d, 1 H), 7.32 (s, 2 H), 6.61 (t, 2 H),
4.24 (s, 2 H), 4.01 (t, 2H), 3.90-3.93 (m, 4 H), 3.54-3.57 (m, 4
H), 3.13 (t, 2 H), 2.68 (q, 2 H), 1.27 (t, 3 H)
Example 556
7-Morpholino-2-(2-(thieno[3,2-b]pyridin-5-yl)ethyl)isoindolin-1-one
##STR00028##
[1341]
7-Bromo-2-(2-(thieno[3,2-b]pyridin-5-yl)ethyl)isoindolin-1-one (50
mg, 0.134 mmol) was dissolved in DMF (2 ml) in a 10 mL microwave
reaction vial. The Pd.sub.2(dba).sub.3 (24.53 mg, 0.027 mmol),
Cs.sub.2CO.sub.3 (87 mg, 0.268 mmol),
dicyclohexyl-(2',4',6'-triisopropylbiphenyl-2-yl)-phosphine (38.3
mg, 0.080 mmol) and morpholine (0.035 ml, 0.402 mmol) were each
added sequentially rapidly to the solution. The suspension was
heated in a Biotage microwave at about 110.degree. C. for about 2
h. The resulting mixture was purified via Waters (0-40% MeCN/Water
(NH.sub.4OAc buffer) over 10 min. to give it as
7-morpholino-2-(2-(thieno[3,2-b]pyridin-5-yl)ethyl)isoindolin-1-one
(4 mg, 10.54 .mu.mol, 7.87% yield).
[1342] LC-MS: m/z 379.8 (M+H) RT=1.67 min/3 min
[1343] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.=8.38 (d, J=8.4
Hz, 1H), 8.09 (d, J=5.6 Hz, 1H), 7.48 (d, J=4.8 Hz, 1H), 7.42 (t,
J=7.6 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.06 (d, J=7.6 Hz, 1H), 6.85
(d, J=8.4 Hz, 1H), 4.371, (s, 2H), 4.38 (t, J=7.2 Hz, 2H), 3.72 (t,
J=4.4 Hz, 4H), 3.16 (t, J=7.2 Hz, 2H), 3.11 (t, J=4.2 Hz, 4H).
Example 557
7-(4-Fluorophenyl)-2-(2-(thieno[3,2-b]pyridin-5-yl)ethyl)isoindolin-1-one
##STR00029##
[1345]
7-Bromo-2-(2-(thieno[3,2-b]pyridin-5-yl)ethyl)isoindolin-1-one (50
mg, 0.134 mmol) was dissolved in toluene (2 mL) and water (0.400
mL) in a 10 mL microwave reaction vial. Pd(PPh.sub.3).sub.2Cl.sub.2
(28.2 mg, 0.040 mmol) (SCRC), K.sub.2CO.sub.3 (55.5 mg, 0.404 mmol)
and 4-fluorophenylboronic acid (22.5 mg, 0.161 mmol) were each
added sequentially rapidly to the solution. The suspension was
heated in a Biotage microwave at about 100.degree. C. for about 1
h. The resulting mixture was purified via HPLC: Waters (0-40%
MeCN/Water (NH.sub.4OAc buffer) over 10 min; 12 g Redi-Sep C-18
column). The following fractions were collected to give the title
compound (23 mg, 0.059 mmol, 44.2% yield).
[1346] LC-MS: m/z 388.9 (M+H) RT=1.96 min/3 min
[1347] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.=8.09 (d, J=8.4
Hz, 1H), 7.74 (d, J=5.2 Hz, 1H), 7.51-7.47 (m, 4H), 7.38 (s, 1H),
7.32 (d, J=7.2 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.11 (d, J=8.8 Hz,
2H), 4.34, (s, 2H), 4.04 (t, J=7. 4 Hz, 2H), 3.28 (t, J=7.4 Hz,
2H).
Examples 558-561
The compounds were obtained as the same scheme of example 558. The
LCMS and .sup.1H NMR data of them are listed behind.
TABLE-US-00006 [1348] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) Ex.
IUPAC name .delta.; LCMS (ESI+) 558 7-(4-Methoxyphenyl)-2-(2-
LC-MS: m/z 400.9 (M + H) RT = 1.91 min/ thieno[3,2-b]pyridin-5- 3
min ylethyl)isoindolin-1-one .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. = 8.09 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 5.2 Hz, 1H),
7.50-7.47 (m, 4H), 7.34-7.33 (m, 2H), 7.206 (d, J = 8.4 Hz, 1H),
6.97 (d, J = 8.8 Hz, 1 H), 4.32 (s, 2H), 4.04 (t, J = 7.4 Hz, 2H),
3.85 (s, 3H), 3.29 (t, J = 7.4 Hz, 2H) 559
7-Pyrimidin-5-yl-2-(2-thieno[3,2- LC-MS: m/z 372.9 (M + H) RT =
1.60 min/ b]pyridin-5-ylethyl)isoindolin-1- 3 min one .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. = 9.22 (s, 1H), 8.88 (s, 2H), 8.11
(d, J = 8.4 Hz, 1H), 7.74 (d, J = 5.2 Hz, 1H), 7.62 (t, J = 7.6 Hz,
1H), 7.48 (t, J = 6.4 Hz, 2 H), 7.35 (d, J = 6.4 Hz, 1H), 7.21 (d,
J = 8.0 Hz, 1H), 4.40 (s, 2H), 4.07 (t, J = 7.2 Hz, 2H), 3.30 (t, J
= 7.2 Hz, 2H) 560 7-(1H-Pyrazol-5-yl)-2-(2- LC-MS: m/z 360.8 (M +
H) RT = 1.75 min/ thieno[3,2-b]pyridin-5- 3 min
ylethyl)isoindolin-1-one .sup.1H NMR (400 MHz, MeOD): .delta. =
8.31 (d, J = 8.0 Hz, 1H), 7.95 (t, J = 5.6 Hz, 2H), 7.63 (t, J =
7.8 Hz, 1H), 7.58 (s, 1H), 7.46-7.43 (m, 2H), 6.90 (d, J = 1.6 Hz,
1 H), 4.51 (s, 2H), 4.13 (t, J = 7.0 Hz, 2H), 3.37 (t, J = 7.0 Hz,
2H). 561 7-(1H-Pyrazol-4-yl)-2-(2- LC-MS: m/z 361.1 (M + H) RT =
1.48 min/ thieno[3,2-b]pyridin-5- 3 min ylethyl)isoindolin-1-one
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. = 12.93 (s, 1H), 8.50
(s, 1H), 8.38 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 5.6 Hz, 1H), 8.05
(s, 1H), 7.61 (d, J = 7.6 Hz, 1 H), 7.53-7.49 (m, 2H), 7.37 (d, J =
7.2 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 4.43 (s, 2H), 3.94 (t, J =
7.2 Hz, 2H), 3.21 (t, J = 7.2 Hz, 2H)
Biological Tests
a) Measurement of PDE Activity
[1349] The recombinant PDE proteins are used in in vitro enzymatic
reaction for measurement of PDE activity. These recombinant
proteins, including PDE10A (human, rat and mouse PDE10) and
isoforms of PDEs 1, 3, 4, and 5, were purchased from commercial
vendor BPS Bioscience. The enzymatic activity of PDEs was
determined by cAMP measurement kit from CisBio (IBA) using HTRF
technology.
[1350] The PDE enzymatic reaction was carried out in assay buffer
(20mM Tris-HCl pH7.5, 10 mM MgCl.sub.2, 0.1% bovine serum albumin)
containing enzyme and substrate. The PDE enzymes concentration
ranged from 10 pM-250 pM, depending on each enzyme's specific
activity. The substrate cyclic nucleotide (cAMP or cGMP)
concentration used in the assay was 20 nM for PDE10, and 100 nM for
other PDEs. The inhibitory effect of compound was determined by
incubating various concentration of inhibitor in the enzymatic
assay. Typically, compound was serial diluted in DMSO then further
diluted in assay buffer. Next, the compound at varying
concentration was mixed with PDE enzyme. The reaction was initiated
by addition of cyclic nucleotide substrate, and incubated for 60
minutes at 29C. The reaction was stopped by addition of lysis
buffer from assay kit. The cAMP-d2 and anti-cAMP cryptate in the
lysis buffer detected the level of cAMP left from the PDE
hydrolysis reaction. The PDE activity is reversely correlated with
the amount of cAMP left in the reaction and can be converted to the
percent activity of an uninhibited control (100%). Thus, IC.sub.50
value of inhibitor can be obtained by plotting inhibitor
concentration against PDE activity at that concentration. The
results are shown in Table 1.
TABLE-US-00007 TABLE 1 EXAMPLE IC.sub.50.sup.1) 1 +++ 2 +++ 3 +++ 4
+++ 5 +++ 6 ++ 7 + 8 + 9 +++ 10 +++ 11 +++ 12 +++ 13 +++ 14 +++ 15
+++ 16 +++ 17 +++ 18 +++ 19 +++ 20 +++ 21 ++ 22 +++ 23 +++ 25 ++ 27
++ 29 ++ 30 +++ 31 + 32 + 33 + 34 ++ 43 + 45 ++ 46 +++ 50 + 51 + 53
++ 54 +++ 56 + 58 +++ 61 ++ 64 +++ 65 +++ 70 ++ 72 + 73 + 74 +++ 75
+++ 77 +++ 78 +++ 82 + 84 +++ 86 +++ 88 + 91 +++ 93 + 94 + 96 +++
97 +++ 98 + 99 +++ 101 + 102 + 103 + 104 +++ 105 + 106 + 107 + 110
+++ 115 +++ 116 +++ 117 ++ 119 +++ 120 + 121 + 125 + 126 + 127 ++
130 +++ 131 + 134 +++ 135 +++ 137 +++ 138 +++ 141 + 143 +++ 145 +
150 +++ 153 +++ 156 +++ 160 +++ 161 +++ 162 +++ 163 +++ 165 +++ 166
+++ 169 ++ 170 +++ 171 ++ 173 +++ 175 ++ 179 +++ 180 +++ 181 +++
182 + 183 +++ 184 +++ 185 +++ 186 ++ 187 +++ 188 + 189 +++ 190 ++
193 ++ 194 + 195 +++ 196 +++ 197 +++ 200 +++ 201 +++ 202 +++ 203
+++ 204 +++ 205 +++ 208 +++ 210 +++ 211 + 212 + 214 ++ 215 + 216
+++ 217 +++ 218 +++ 221 +++ 222 +++ 223 +++ 225 +++ 227 +++ 230 +
234 +++ 235 +++ 236 + 238 +++ 239 ++ 240 +++ 241 +++ 242 ++ 243 +++
244 ++ 245 +++ 246 +++ 247 +++ 248 +++ 250 +++ 251 + 253 + 255 ++
256 +++ 257 +++ 258 +++ 260 +++ 261 +++ 262 +++ 263 +++ 264 +++ 265
+++ 266 +++ 267 +++ 268 +++ 270 +++ 271 +++ 274 +++ 275 +++ 276 +++
278 +++ 279 + 280 +++ 281 +++ 292 +++ 293 +++ 294 + 295 +++ 296 +++
297 +++ 299 +++ 300 +++ 301 +++ 302 +++ 303 ++ 304 ++ 305 + 306 +++
307 + 308 ++ 309 +++ 310 +++ 312 +++ 313 + 314 +++ 316 +++ 317 +
319 + 321 + 322 +++ 323 +++ 326 +++ 329 +++ 330 +++ 331 +++ 332 +++
333 ++ 334 ++ 335 + 336 ++ 337 ++ 338 +++ 341 ++ 342 +++ 343 + 344
++ 345 +++ 346 +++ 347 ++ 348 ++ 349 + 350 +++ 351 + 352 ++ 353 ++
354 + 355 +++ 356 + 363 + 364 +++ 365 +++ 366 ++ 367 +++ 368 +++
369 +++ 370 +++ 371 +++ 372 +++ 373 +++ 374 +++ 375 +++
376 +++ 377 +++ 378 +++ 379 ++ 380 + 381 +++ 382 +++ 383 +++ 384
+++ 385 +++ 386 +++ 387 +++ 388 ++ 389 ++ 390 +++ 392 +++ 394 +++
396 +++ 397 +++ 397 + 398 +++ 399 +++ 400 +++ 401 +++ 402 +++ 403
+++ 405 +++ 406 +++ 407 +++ 409 + 409 + 411 +++ 412 +++ 413 +++ 414
+++ 415 +++ 416 +++ 417 ++ 418 + 421 +++ 422 +++ 423 +++ 424 +++
425 +++ 426 +++ 428 +++ 429 +++ 430 +++ 431 ++ 432 ++ 434 +++ 435
+++ 436 + 437 +++ 438 +++ 439 +++ 440 +++ 441 ++ 442 +++ 443 +++
444 +++ 445 ++ 446 ++ 447 +++ 448 +++ 449 + 450 + 451 +++ 452 + 454
++ 456 +++ 457 +++ 458 +++ 459 + 461 ++ 463 ++ 464 +++ 465 +++ 466
++ 467 ++ 472 +++ 473 ++ 474 ++ 479 + 481 + 482 ++ 483 +++ 484 +++
485 +++ 486 +++ 488 + 489 +++ 491 +++ 493 +++ 494 +++ 495 +++ 496
+++ 499 +++ 501 ++ 503 ++ 505 + 507 + 510 +++ 512 +++ 513 +++ 514
+++ 516 +++ 517 +++ 518 +++ 519 +++ 520 ++ 521 + 522 ++ 523 +++ 524
++ 526 +++ 527 +++ 528 +++ 529 +++ 530 +++ 531 +++ 532 +++ 533 +++
534 +++ 535 +++ 536 +++ 537 +++ 538 +++ 539 +++ 540 +++ 541 ++ 542
++ 544 ++ 545 +++ 549 +++ 550 + 551 +++ 552 +++ 553 +++ 554 +++ 555
+++ 556 ++ 559 +++ 560 ++ .sup.1)+++: IC.sub.50 < 100 nM ++: 100
nM .ltoreq. IC.sub.50 .ltoreq. 200 nM +: 200 nM < IC.sub.50 <
500 nM
b) Determination of the Microsomal Half-Life:
[1351] The metabolic stability of the compounds of the invention
was determined in the following assay.
[1352] The test substances were incubated in a concentration of 0.5
.mu.M as follows:
[1353] 0.5 .mu.M test substance are preincubated together with
liver microsomes from different species (from rat, human or other
species) (0.25 mg of microsomal protein/ml) in 0.05 M potassium
phosphate buffer of pH 7.4 in microtiter plates at 37.degree. C.
for 5 min The reaction is started by adding NADPH (1 mg/mL). After
0, 5, 10, 15, 20 and 30 min, 50 .mu.l aliquots are removed, and the
reaction is immediately stopped and cooled with the same volume of
acetonitrile. The samples are frozen until analyzed. The remaining
concentration of undegraded test substance is determined by MSMS.
The half-life (T1/2) is determined from the gradient of the signal
of test substance/unit time plot, it being possible to calculate
the half-life of the test substance, assuming first order kinetics,
from the decrease in the concentration of the compound with time.
The microsomal clearance (mCl) is calculated from
mCl=ln2/T1/2/(content of microsomal protein in mg/ml).times.1000
[ml/min/mg] (modified from references: Di, The Society for
Biomoleculur Screening, 2003, 453-462; Obach, DMD, 1999 vol 27. N
11, 1350-1359). The results are shown in Table 2.
TABLE-US-00008 TABELLE 2 Ex. Rat mCl.sup.2) Human mCl.sup.2) 2 + +
3 + ++ 4 .smallcircle. + 7 + + 8 + .smallcircle. 9 + ++ 10 ++ + 11
++ ++ 12 + + 14 + + 15 .smallcircle. + 19 + .smallcircle. 20 ++ ++
54 + + 58 ++ .smallcircle. 86 .smallcircle. + 91 ++ + 96 + + 98 ++
+ 99 ++ + 100 ++ + 101 .smallcircle. ++ 102 + ++ 103 ++ ++ 104 ++
++ 106 ++ + 107 ++ ++ 110 + .smallcircle. 115 ++ + 116 ++ + 119 ++
++ 120 + + 121 -- + 122 + ++ 128 + .smallcircle. 129 ++ + 130
.smallcircle. + 131 ++ ++ 134 + .smallcircle. 135 ++ ++ 137 ++ ++
138 ++ ++ 144 + ++ 145 ++ ++ 146 + .smallcircle. 147 +
.smallcircle. 153 ++ ++ 154 -.smallcircle. ++ 155 + .smallcircle.
156 + ++ 157 ++ .smallcircle. 159 + .smallcircle. 160 .smallcircle.
+ 161 .smallcircle. + 162 ++ ++ 163 ++ ++ 165 ++ ++ 166 ++ ++ 167 +
.smallcircle. 172 + + 174 + ++ 175 ++ ++ 177 ++ ++ 179 +
.smallcircle. 180 .smallcircle. + 183 + + 184 ++ + 185 +
.smallcircle. 188 + + 189 + + 190 + + 192 .smallcircle. ++ 193 ++
++ 194 + + 195 + .smallcircle. 196 ++ .smallcircle. 197 ++ + 200
.smallcircle. + 202 .smallcircle. + 210 .smallcircle. + 213 ++ ++
214 ++ ++ 215 ++ ++ 216 ++ ++ 217 ++ ++ 218 ++ ++ 220 .smallcircle.
+ 223 ++ ++ 226 ++ ++ 227 ++ ++ 228 + .smallcircle. 229 ++ ++ 230
++ ++ 231 ++ ++ 232 ++ ++ 233 ++ ++ 234 ++ ++ 235 ++ + 236 + + 237
+ + 238 ++ + 239 ++ ++ 240 + ++ 241 ++ ++ 242 + ++ 244 ++ ++ 245 ++
++ 246 .smallcircle. + 248 ++ ++ 249 .smallcircle. + 250
.smallcircle. + 253 ++ ++ 254 ++ ++ 255 ++ ++ 256 ++ ++ 257 + + 261
.smallcircle. ++ 262 ++ + 263 ++ + 264 ++ ++ 265 + + 269 ++ ++ 270
++ ++ 273 ++ ++ 274 + + 275 ++ ++ 278 + + 280 + + 294 ++ + 295 ++
++ 296 ++ ++ 297 + + 298 + + 300 + .smallcircle. 306 ++ + 308 ++ ++
310 ++ ++ 312 ++ ++ 313 ++ ++ 314 ++ ++ 316 + ++ 317 ++ + 318
.smallcircle. + 326 + + 329 + + 332 ++ ++ 334 ++ ++ 335
.smallcircle. + 337 .smallcircle. + 338 ++ ++ 343 .smallcircle. +
353 + ++ 358 ++ ++ 359 ++ ++ 360 ++ ++ 362 ++ ++ 363 ++ ++ 364 ++
++ 365 + ++ 366 ++ ++ 367 ++ ++ 368 ++ ++ 369 ++ ++ 370 ++
.smallcircle. 371 ++ .smallcircle. 372 ++ ++ 373 ++ ++ 374 ++ ++
375 ++ ++ 376 ++ ++ 377 ++ ++ 378 ++ + 379 .smallcircle. + 380
.smallcircle. + 381 ++ + 382 ++ ++ 383 ++ ++ 384 + ++ 385 + + 386 +
++ 387 .smallcircle. + 390 + ++ 391 ++ ++ 394 .smallcircle. ++ 396
+ ++ 397 + -- 398 .smallcircle. + 399 + ++ 400 .smallcircle. ++ 401
+ ++ 402 + + 403 + ++ 405 + .smallcircle. 408 + ++ 409 ++ ++ 411 +
.smallcircle. 413 ++ ++ 414 ++ ++ 415 ++ ++ 416 ++ ++ 417 ++ ++ 418
++ ++ 421 ++ .largecircle. 422 + ++ 424 ++ ++ 425 ++ .largecircle.
426 ++ + 428 .smallcircle. + 429 ++ ++ 430 ++ ++ 431 .smallcircle.
++ 432 ++ ++ 436 ++ ++ 445 ++ ++ 446 ++ ++ 447 + + 448 ++ ++ 449 +
+ 450 + .smallcircle. 451 + ++ 452 ++ ++ 454 ++ ++ 456 + ++ 457 + +
459 ++ ++ 461 .smallcircle. ++ 463 ++ ++ 464 ++ ++ 465 ++ ++ 466
.smallcircle. ++ 467 ++ ++ 472 + + 473 + + 474 + + 479 ++ ++ 481 ++
++ 482 ++ ++ 483 ++ ++ 485 + + 486 .smallcircle. + 488
.smallcircle. + 489 + + 491 + + 493 ++ ++ 494 ++ ++
495 ++ ++ 496 ++ ++ 501 + ++ 503 + + 505 ++ ++ 507 .smallcircle. +
510 .smallcircle. + 512 ++ ++ 513 .smallcircle. + 514 ++ ++ 516 +
++ 518 + ++ 519 .smallcircle. ++ 520 + ++ 521 ++ ++ 522 ++ ++ 524
.smallcircle. + 526 + ++ 528 ++ ++ 529 ++ ++ 530 + ++ 531 ++ ++ 534
++ ++ 535 ++ ++ 536 ++ + 537 + ++ 538 + ++ 539 ++ ++ 540 ++ ++ 541
+ ++ 542 + ++ 544 ++ ++ 545 ++ ++ 549 ++ ++ 550 ++ ++ 551 ++ ++ 552
+ ++ 553 + + 554 + + 555 ++ + 556 + + 559 + .smallcircle. Ex.
Example mCl mikrosomal clearance .sup.2)++: <100 .mu.l
min.sup.-1 mg.sup.-1 +: 100-220 .mu.l min.sup.-1 mg.sup.-1
.smallcircle. not avialable or >220 .mu.l min.sup.-1
mg.sup.-1
* * * * *