U.S. patent application number 11/466828 was filed with the patent office on 2006-12-21 for [1,8]naphthyridin-2-ones and related compounds for the treatment of schizophrenia.
This patent application is currently assigned to Warner-Lambert Company LLC. Invention is credited to Jerry D. Clark, Jamie M. Davis, David Favor, Lorraine K. Fay, Lloyd Franklin, Kevin E. Henegar, Douglas S. Johnson, Brian J. Nichelson, Ligong Ou, Joseph Thomas Repine, Michael A. Walters, Andrew David White, Zhijian Zhu.
Application Number | 20060287310 11/466828 |
Document ID | / |
Family ID | 34216117 |
Filed Date | 2006-12-21 |
United States Patent
Application |
20060287310 |
Kind Code |
A1 |
Clark; Jerry D. ; et
al. |
December 21, 2006 |
[1,8]NAPHTHYRIDIN-2-ONES AND RELATED COMPOUNDS FOR THE TREATMENT OF
SCHIZOPHRENIA
Abstract
This invention relates to compounds of the formula 1 ##STR1##
wherein G, D, A, Z, Q, X, Y, R.sup.1, and R.sup.4 through R.sup.7
are defined as in the specification, processes for preparing the
same and intermediates used in making the same, and pharmaceutical
compositions containing such compounds and their use in the
treatment of central nervous system disorders and other
disorders.
Inventors: |
Clark; Jerry D.; (Brighton,
MI) ; Davis; Jamie M.; (Ann Arbor, MI) ;
Favor; David; (Ypsilanti, MI) ; Fay; Lorraine K.;
(Ypsilanti, MI) ; Franklin; Lloyd; (Howell,
MI) ; Henegar; Kevin E.; (Ann Arbor, MI) ;
Johnson; Douglas S.; (Dexter, MI) ; Nichelson; Brian
J.; (Hudson, MI) ; Ou; Ligong; (Edmonton,
CA) ; Repine; Joseph Thomas; (Ann Arbor, MI) ;
Walters; Michael A.; (Ann Arbor, MI) ; White; Andrew
David; (Pinckney, MI) ; Zhu; Zhijian;
(Farmington Hills, MI) |
Correspondence
Address: |
WARNER-LAMBERT COMPANY
2800 PLYMOUTH RD
ANN ARBOR
MI
48105
US
|
Assignee: |
Warner-Lambert Company LLC
|
Family ID: |
34216117 |
Appl. No.: |
11/466828 |
Filed: |
August 24, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10900210 |
Jul 28, 2004 |
|
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11466828 |
Aug 24, 2006 |
|
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60497370 |
Aug 22, 2003 |
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Current U.S.
Class: |
514/230.5 ;
514/251; 514/253.04; 514/262.1; 514/264.1; 514/300; 544/105;
544/257; 544/262; 544/279; 544/362; 546/122 |
Current CPC
Class: |
A61P 25/16 20180101;
A61P 25/28 20180101; A61P 25/24 20180101; A61P 25/20 20180101; A61P
1/14 20180101; A61P 25/14 20180101; A61P 27/06 20180101; A61P 25/30
20180101; A61P 25/34 20180101; A61P 25/18 20180101; A61P 3/04
20180101; A61P 25/00 20180101; A61P 27/02 20180101; A61P 25/22
20180101; A61P 25/32 20180101; C07D 471/04 20130101; A61P 25/36
20180101; A61P 31/18 20180101; A61P 43/00 20180101 |
Class at
Publication: |
514/230.5 ;
514/264.1; 514/262.1; 514/251; 514/300; 514/253.04; 544/105;
544/262; 544/279; 544/362; 546/122; 544/257 |
International
Class: |
A61K 31/5383 20060101
A61K031/5383; A61K 31/519 20060101 A61K031/519; A61K 31/496
20060101 A61K031/496; A61K 31/4745 20060101 A61K031/4745; C07D
471/02 20060101 C07D471/02; C07D 491/02 20060101 C07D491/02; C07D
487/02 20060101 C07D487/02 |
Claims
1. A compound of formula 1 ##STR26## A is
--(CH.sub.2).sub.mCH.sub.2--, --(CH.sub.2).sub.mO--, or
--(CH.sub.2).sub.mNH--, wherein m is an integer from 2 to 5 and
wherein one or two of the carbon or nitrogen atoms of
--(CH.sub.2).sub.mCH.sub.2--, --(CH.sub.2).sub.mO-- and
--(CH.sub.2).sub.mNH-- can be substituted, optionally and
independently, with one or two substituents that are selected,
independently, from fluoro and methyl, or with two substituents
attached to the same carbon atom that form, together with the
carbon to which they are attached, a spirocyclopropyl or
spirocyclobutyl ring; D is N, C, or CH, provided that when D is N
each carbon atom covalently attached to D is attached through a
single bond; Z and Q are independently N, C, or CH, provided that
at least one of Z and Q is N; --XY-- is --CH.sub.2--CH.sub.2--,
--CH.dbd.CH--, --CH.sub.2--NH--, --NH--CH.sub.2--, --N.dbd.CH--,
--CH.dbd.N--, --O--CH.sub.2--, or --CH.sub.2--O--, wherein --XY--
can optionally be substituted, at any available bonding site, by
one to four substituents R.sup.2, R.sup.2', R.sup.3 and R.sup.3'; V
and W are independently N, C, or CH; ring AA is a saturated or
unsaturated 5- 6- or 7-membered carbocyclic ring wherein one, two
or three of the carbon atoms of ring AA that are not shared with
the benzo ring of group (ii) can be replaced, optionally and
independently, by a nitrogen, oxygen or sulfur atom; R.sup.1 is
hydrogen, --C(.dbd.O)CH.sub.3, or (C.sub.1-C.sub.3)alkyl; R.sup.2,
R.sup.2', R.sup.3 and R.sup.3' are independently selected from
hydrogen, halo, cyano, oxo, hydroxy, --C(.dbd.O)CH.sub.3,
(C.sub.1-C.sub.4)alky, and (C.sub.1-C.sub.4)alkoxy, wherein the
alkyl moieties of the (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy, and --C(.dbd.O)CH.sub.3 groups can be
optionally substituted with from one to three fluoro atoms and can
also be optionally substituted with an amino or hydroxy
substituent; R.sup.4 and R.sup.5 are independently selected from
hydrogen, halo, cyano, hydroxy, --C(.dbd.O)CH.sub.3,
(C.sub.1-C.sub.4)alkyl, and (C.sub.1-C.sub.4)alkoxy, wherein the
alkyl moieties of the (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy, and --C(.dbd.O)CH.sub.3 groups can be
optionally substituted with from one to three fluoro atoms and can
also be optionally substituted with an amino or hydroxy
substituent; R.sup.6 and R.sup.7 are selected, independently, from
hydrogen and methyl; R.sup.8, R.sup.9, R.sup.10, R.sup.11, and
R.sup.12 are independently selected from hydrogen, halo,
--C(.dbd.O)CH.sub.3, (C.sub.1-C.sub.4)alkyl, and
(C.sub.1-C.sub.4)alkoxy, aryl, and aryloxy, wherein the alkyl
moieties of the (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy,
and --C(.dbd.O)CH.sub.3 groups and the aryl and aryoxy moieties can
be optionally substituted with from one to three fluoro atoms and
can also be optionally substituted with an amino or hydroxy
substituent; R.sup.13 and R.sup.14 are independently selected from
hydrogen, halo, cyano, oxo, hydroxy, --C(.dbd.O)CH.sub.3,
(C.sub.1-C.sub.4)alkyl, and (C.sub.1-C.sub.4)alkoxy, wherein the
alkyl moieties of the (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy, and --C(.dbd.O)CH.sub.3 groups can be
optionally substituted with from one to three fluoro atoms and can
also be optionally substituted with an amino or hydroxy
substituent; and the pharmaceutically acceptable salts of such
compounds.
2. The compound or salt of claim 1, wherein Q is N and Z is CH.
3. The compound or salt of claim 1, wherein Q and Z are both N.
4. The compound or salt of claim 1, wherein W is CH.
5. The compound or salt of claim 1, wherein --XY-- is
--CH.sub.2--CH.sub.2--.
6. The compound or salt of claim 1, wherein --XY-- is
--CH.dbd.CH--.
7. The compound or salt of claim 1, wherein D is N.
8. The compound or salt of claim 1, wherein R.sup.4 and R.sup.5 are
hydrogen.
9. The compound or salt of claim 1, wherein --XY-- is
--CH.sub.2NH--.
10. The compound or salt of claim 1, wherein D is N, Q is N, Z is
CH, --XY-- is --CH.sub.2--CH.sub.2-- or --CH.dbd.CH--, and R.sup.1,
R.sup.4, and R.sup.5 are hydrogen.
11. The compound or salt of claim 1, wherein W and V are C or CH,
or only one of W or V is N.
12. The compound or salt of claim 1, wherein G is naphthyl, and
R.sup.13 and R.sup.14 are independently hydrogen or flouro.
13. The compound or salt of claim 1, wherein at least one of
R.sup.13 or R.sup.14 is flouro or methoxy.
14. The compound or salt of claim 1, wherein G is a group of
formula: ##STR27##
15. The compound or salt of claim 1, wherein G is the group of
formula (ii) and all atoms in ring AA are carbon atoms.
16. The compound or salt of claim 15, wherein ring AA is benzo.
17. The compound or salt of claim 1, wherein G is a group of the
formula (ii) and one, two, or three carbons of the ring AA that are
not shared by the benzo group of formula (ii) have been replaced by
a nitrogen, oxygen or sulfur atom.
18. The compound or salt of claim 1, wherein the compound or salt
has a D.sub.2 intrinsic activity of about 20% to about 60%.
19. The compound or salt of claim 1, selected from the group
consisting of:
7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]-
naphthyridin-2-one;
7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-on-
e;
7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-
-1H-[1,8]naphthyridin-2-one;
7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one;
7-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one;
7-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one;
7-{4-[4-(2-Methoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H--
[1,8]naphthyridin-2-one;
7-{4-[4-(2-Methoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthy-
ridin-2-one;
2-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-py-
rido[2,3-d]pyrimidin-7-one;
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8-
]naphthyridin-2-one;
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridi-
n-2-one;
7-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-but-
oxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;
7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyrid-
in-2-one;
7-{4-[4-(6,7-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}--
3,4-dihydro-1H-[1,8]naphthyridin-2-one;
7-{4-[4-(6,7-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]na-
phthyridin-2-one;
4-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyr-
idin-2-one;
4,4-Dimethyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro--
1H-[1,8]naphthyridin-2-one;
5-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[-
1,8]naphthyridin-2-one;
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-5-methyl-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one;
6-Fluoro-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[-
1,8]naphthyridin-2-one;
7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8-
]naphthyridin-2-one;
7-[4-(4-Benzo[1,2,5]thiadiazol-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1-
H-[1,8]naphthyridin-2-one;
7-[4-(4-Benzo[1,2,5]thiadiazol-4-yl-piperazin-1-yl)-butoxy]-1H-[1,8]napht-
hyridin-2-one;
7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-pyrido[2,3-
-d]pyrimidin-2-one;
3-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-p-
yrido[2,3-d]pyrimidin-2-one;
7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-pyrido[2,3-d]pyrimidin-2-one;
7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,6]naphthyridin-2-one;
2-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3--
d]pyrimidin-7-one; and
6-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4H-pyrido[3,2--
b][1,4]oxazin-3-one.
20. A pharmaceutical composition for treating a disorder or
condition selected from single episodic or recurrent major
depressive disorders, dysthymic disorders, depressive neurosis and
neurotic depression, melancholic depression including anorexia,
weight loss, insomnia, early morning waking or psychomotor
retardation; atypical depression (or reactive depression) including
increased appetite, hypersomnia, psychomotor agitation or
irritability, seasonal affective disorder and pediatric depression;
bipolar disorders or manic depression, for example, bipolar I
disorder, bipolar II disorder and cyclothymic disorder; conduct
disorder; disruptive behavior disorder; attention deficit
hyperactivity disorder (ADHD); behavioral disturbances associated
with mental retardation, autistic disorder, and conduct disorder;
anxiety disorders such as panic disorder with or without
agoraphobia, agoraphobia without history of panic disorder,
specific phobias, for example, specific animal phobias, social
anxiety, social phobia, obsessive-compulsive disorder, stress
disorders including post-traumatic stress disorder and acute stress
disorder, and generalized anxiety disorders; borderline personality
disorder; schizophrenia and other psychotic disorders, for example,
schizophreniform disorders, schizoaffective disorders, delusional
disorders brief psychotic disorders, shared psychotic disorders,
psychotic disorders with delusions or hallucinations, psychotic
episodes of anxiety, anxiety associated with psychosis, psychotic
mood disorders such as severe major depressive disorder; mood
disorders associated with psychotic disorders such as acute mania
and depression associated with bipolar disorder; mood disorders
associated with schizophrenia; delirium, dementia, and amnestic and
other cognitive or neurodegenerative disorders, such as Parkinson's
disease (PD), Huntington's disease (HD), Alzheimer's disease,
senile dementia, dementia of the Alzheimer's type, memory
disorders, loss of executive function, vascular dementia, and other
dementias, for example, due to HIV disease, head trauma,
Parkinson's disease, Huntington's disease, Pick's disease,
Creutzfeldt-Jakob disease, or due to multiple etiologies; movement
disorders such as akinesias, dyskinesias, including familial
paroxysmal dyskinesias, spasticities, Tourette's syndrome, Scott
syndrome, PALSYS and akinetic-rigid syndrome; extra-pyramidal
movement disorders such as medication-induced movement disorders,
for example, neuroleptic-induced Parkinsonism, neuroleptic
malignant syndrome, neuroleptic-induced acute dystonia,
neuroleptic-induced acute akathisia, neuroleptic-induced tardive
dyskinesia and medication-induced postural tremour; chemical
dependencies and addictions (e.g., dependencies on, or addictions
to, alcohol, heroin, cocaine, benzodiazepines, nicotine, or
phenobarbitol) and behavioral addictions such as an addiction to
gambling; and ocular disorders such as glaucoma and ischemic
retinopathy in a mammal, including a human, comprising: an amount
of a compound according to claim 1, or a pharmaceutically
acceptable salt thereof, that is effective in treating such
disorder or condition, and a pharmaceutically acceptable
carrier.
21. A method for treating a disorder or condition selected from
single episodic or recurrent major depressive disorders, dysthymic
disorders, depressive neurosis and neurotic depression, melancholic
depression including anorexia, weight loss, insomnia, early morning
waking or psychomotor retardation; atypical depression (or reactive
depression) including increased appetite, hypersomnia, psychomotor
agitation or irritability, seasonal affective disorder and
pediatric depression; bipolar disorders or manic depression, for
example, bipolar I disorder, bipolar II disorder and cyclothymic
disorder; conduct disorder; disruptive behavior disorder; attention
deficit hyperactivity disorder (ADHD); behavioral disturbances
associated with mental retardation, autistic disorder, and conduct
disorder; anxiety disorders such as panic disorder with or without
agoraphobia, agoraphobia without history of panic disorder,
specific phobias, for example, specific animal phobias, social
anxiety, social phobia, obsessive-compulsive disorder, stress
disorders including post-traumatic stress disorder and acute stress
disorder, and generalized anxiety disorders; borderline personality
disorder; schizophrenia and other psychotic disorders, for example,
schizophreniform disorders, schizoaffective disorders, delusional
disorders brief psychotic disorders, shared psychotic disorders,
psychotic disorders with delusions or hallucinations, psychotic
episodes of anxiety, anxiety associated with psychosis, psychotic
mood disorders such as severe major depressive disorder; mood
disorders associated with psychotic disorders such as acute mania
and depression associated with bipolar disorder; mood disorders
associated with schizophrenia; delirium, dementia, and amnestic and
other cognitive or neurodegenerative disorders, such as Parkinson's
disease (PD), Huntington's disease (HD), Alzheimer's disease,
senile dementia, dementia of the Alzheimer's type, memory
disorders, loss of executive function, vascular dementia, and other
dementias, for example, due to HIV disease, head trauma,
Parkinson's disease, Huntington's disease, Pick's disease,
Creutzfeldt-Jakob disease, or due to multiple etiologies; movement
disorders such as akinesias, dyskinesias, including familial
paroxysmal dyskinesias, spasticities, Tourette's syndrome, Scott
syndrome, PALSYS and akinetic-rigid syndrome; extra-pyramidal
movement disorders such as medication-induced movement disorders,
for example, neuroleptic-induced Parkinsonism, neuroleptic
malignant syndrome, neuroleptic-induced acute dystonia,
neuroleptic-induced acute akathisia, neuroleptic-induced tardive
dyskinesia and medication-induced postural tremour; chemical
dependencies and addictions (e.g., dependencies on, or addictions
to, alcohol, heroin, cocaine, benzodiazepines, nicotine, or
phenobarbitol) and behavioral addictions such as an addiction to
gambling; and ocular disorders such as glaucoma and ischemic
retinopathy in a mammal, including a human, comprising:
administering to a mammal in need of such treatment an amount of a
compound of claim 1, or a pharmaceutically acceptable salt thereof,
that is effective in treating the disorder or condition.
22. The method of claim 21, wherein the disorder or condition that
is being treated is selected from the group consisting of: major
depression, single episode depression, recurrent depression, child
abuse induced depression, postpartum depression, dysthymia,
cyclothymia and bipolar disorder.
23. The method of claim 21, wherein the disorder or condition that
is being treated is selected from the group consisting of:
schizophrenia, schizoaffective disorder, delusional disorder,
substance-induced psychotic disorder, brief psychotic disorder,
shared psychotic disorder, psychotic disorder due to a general
medical condition, and schizophreniform disorder.
24. The method of claim 21, wherein the disorder or condition that
is being treated is selected from autism, pervasive development
disorder, and attention deficit hyperactivity disorder.
25. The method of claim 21, wherein the disorder or condition that
is being treated is selected from generalized anxiety disorder,
panic disorder, obsessive-compulsive disorder, post-traumatic
stress disorder, and phobias, including social phobia, agoraphobia,
and specific phobias.
26. The method of claim 21, wherein the compound according to claim
1 is administered to a human for the treatment of any two or more
comorbid disorders or conditions selected from those disorders and
conditions referred to in any of the above methods.
27. The method of claim 21, wherein the disorder or condition being
treated is schizophrenia with concomitant depression.
28. The method of claim 21, wherein the disorder or condition being
treated is schizophrenia with concomitant anxiety.
29. A method of treating a disorder or condition selected from
single episodic or recurrent major depressive disorders, dysthymic
disorders, depressive neurosis and neurotic depression, melancholic
depression including anorexia, weight loss, insomnia, early morning
waking or psychomotor retardation; atypical depression (or reactive
depression) including increased appetite, hypersomnia, psychomotor
agitation or irritability, seasonal affective disorder and
pediatric depression; bipolar disorders or manic depression, for
example, bipolar I disorder, bipolar II disorder and cyclothymic
disorder; conduct disorder; disruptive behavior disorder; attention
deficit hyperactivity disorder (ADHD); behavioral disturbances
associated with mental retardation, autistic disorder, and conduct
disorder; anxiety disorders such as panic disorder with or without
agoraphobia, agoraphobia without history of panic disorder,
specific phobias, for example, specific animal phobias, social
anxiety, social phobia, obsessive-compulsive disorder, stress
disorders including post-traumatic stress disorder and acute stress
disorder, and generalized anxiety disorders; borderline personality
disorder; schizophrenia and other psychotic disorders, for example,
schizophreniform disorders, schizoaffective disorders, delusional
disorders, brief psychotic disorders, shared psychotic disorders,
psychotic disorders with delusions or hallucinations, psychotic
episodes of anxiety, anxiety associated with psychosis, psychotic
mood disorders such as severe major depressive disorder; mood
disorders associated with psychotic disorders such as acute mania
and depression associated with bipolar disorder; mood disorders
associated with schizophrenia; delirium, dementia, and amnestic and
other cognitive or neurodegenerative disorders, such as Parkinson's
disease (PD), Huntington's disease (HD), Alzheimer's disease,
senile dementia, dementia of the Alzheimer's type, memory
disorders, loss of executive function, vascular dementia, and other
dementias, for example, due to HIV disease, head trauma,
Parkinson's disease, Huntington's disease, Pick's disease,
Creutzfeldt-Jakob disease, or due to multiple etiologies; movement
disorders such as akinesias, dyskinesias, including familial
paroxysmal dyskinesias, spasticities, Tourette's syndrome, Scott
syndrome, PALSYS and akinetic-rigid syndrome; extra-pyramidal
movement disorders such as medication-induced movement disorders,
for example, neuroleptic-induced Parkinsonism, neuroleptic
malignant syndrome, neuroleptic-induced acute dystonia,
neuroleptic-induced acute akathisia, neuroleptic-induced tardive
dyskinesia and medication-induced postural tremour; chemical
dependencies and addictions (e.g., dependencies on, or addictions
to, alcohol, heroin, cocaine, benzodiazepines, nicotine, or
phenobarbitol) and behavioral addictions such as an addiction to
gambling; and ocular disorders such as glaucoma and ischemic
retinopathy in a mammal, including a human, comprising
administering to said mammal: active agent (a), a compound of claim
1, or a pharmaceutically acceptable salt thereof; and active agent
(b), another pharmaceutically active compound that is an
antidepressant or an anti-anxiety agent, or a pharmaceutically
acceptable salt thereof; wherein the active agents (a) and (b) are
present in amounts that render the combination effective in
treating such disorder or condition.
30. A pharmaceutical composition for treating a disorder or
condition selected from single episodic or recurrent major
depressive disorders, dysthymic disorders, depressive neurosis and
neurotic depression, melancholic depression including anorexia,
weight loss, insomnia, early morning waking or psychomotor
retardation; atypical depression (or reactive depression) including
increased appetite, hypersomnia, psychomotor agitation or
irritability, seasonal affective disorder and pediatric depression;
bipolar disorders or manic depression, for example, bipolar I
disorder, bipolar II disorder and cyclothymic disorder; conduct
disorder; disruptive behavior disorder; attention deficit
hyperactivity disorder (ADHD); behavioral disturbances associated
with mental retardation, autistic disorder, and conduct disorder;
anxiety disorders such as panic disorder with or without
agoraphobia, agoraphobia without history of panic disorder,
specific phobias, for example, specific animal phobias, social
anxiety, social phobia, obsessive-compulsive disorder, stress
disorders including post-traumatic stress disorder-and acute stress
disorder, and generalized anxiety disorders; borderline personality
disorder; schizophrenia and other psychotic disorders, for example,
schizophreniform disorders, schizoaffective disorders, delusional
disorders brief psychotic disorders, shared psychotic disorders,
psychotic disorders with delusions or hallucinations, psychotic
episodes of anxiety, anxiety associated with psychosis, psychotic
mood disorders such as severe major depressive disorder; mood
disorders associated with psychotic disorders such as acute mania
and depression associated with bipolar disorder; mood disorders
associated with schizophrenia; delirium, dementia, and amnestic and
other cognitive or neurodegenerative disorders, such as Parkinson's
disease (PD), Huntington's disease (HD), Alzheimer's disease,
senile dementia, dementia of the Alzheimer's type, memory
disorders, loss of executive function, vascular dementia, and other
dementias, for example, due to HIV disease, head trauma,
Parkinson's disease, Huntington's disease, Pick's disease,
Creutzfeldt-Jakob disease, or due to multiple etiologies; movement
disorders such as akinesias, dyskinesias, including familial
paroxysmal dyskinesias, spasticities, Tourette's syndrome, Scott
syndrome, PALSYS and akinetic-rigid syndrome; extra-pyramidal
movement disorders such as medication-induced movement disorders,
for example, neuroleptic-induced Parkinsonism, neuroleptic
malignant syndrome, neuroleptic-induced acute dystonia,
neuroleptic-induced acute akathisia, neuroleptic-induced tardive
dyskinesia and medication-induced postural tremour; chemical
dependencies and addictions (e.g., dependencies on, or addictions
to, alcohol, heroin, cocaine, benzodiazepines, nicotine, or
phenobarbitol) and behavioral addictions such as an addiction to
gambling; and ocular disorders such as glaucoma and ischemic
retinopathy in a mammal comprising: active agent (a), a compound
according to claim 1, or a pharmaceutically acceptable salt
thereof; active agent (b), another pharmaceutically active agent
that is an antidepressant or an anti-anxiety agent; and a
pharmaceutically acceptable carrier.
31. The method of claim 30, wherein the disorder or condition being
treated is schizophrenia.
32. The method of claim 30, wherein the disorder or condition that
is being treated is selected from schizophrenia, schizoaffective
disorder, delusional disorder, substance-induced psychotic
disorder, brief psychotic disorder, shared psychotic disorder,
psychotic disorder due to a general medical condition, and
schizophreniform disorder.
33. The method of claim 30, wherein the disorder or condition that
is being treated is selected from autism, pervasive development
disorder, and attention deficit hyperactivity disorder.
34. The method of claim 30, wherein the disorder or condition that
is being treated is selected from generalized anxiety disorder,
panic disorder, obsessive-compulsive disorder, post-traumatic
stress disorder, and phobias, including social phobia, agoraphobia,
and specific phobias.
35. The method of claim 30, wherein the active agent (a) and the
active agent (b) are administered to a human for the treatment of
any two or more comorbid disorders or conditions selected from
those disorders and conditions referred to in any of the above
methods.
36. The method of claim 30, wherein the disorder or condition being
treated is schizophrenia with concomitant depression.
37. The method of claim 30, wherein the disorder or condition being
treated is schizophrenia with concomitant anxiety.
38. A pharmaceutical composition for treating a disorder or
condition selected from single episodic or recurrent major
depressive disorders, dysthymic disorders, depressive neurosis and
neurotic depression, melancholic depression including anorexia,
weight loss, insomnia, early morning waking or psychomotor
retardation; atypical depression (or reactive depression) including
increased appetite, hypersomnia, psychomotor agitation or
irritability, seasonal affective disorder and pediatric depression;
bipolar disorders or manic depression, for example, bipolar I
disorder, bipolar II disorder and cyclothymic disorder; conduct
disorder; disruptive behavior disorder; attention deficit
hyperactivity disorder (ADHD); behavioral disturbances associated
with mental retardation, autistic disorder, and conduct disorder;
anxiety disorders such as panic disorder with or without
agoraphobia, agoraphobia without history of panic disorder,
specific phobias, for example, specific animal phobias, social
anxiety, social phobia, obsessive-compulsive disorder, stress
disorders including post-traumatic stress disorder and acute stress
disorder, and generalized anxiety disorders; borderline personality
disorder; schizophrenia and other psychotic disorders, for example,
schizophreniform disorders, schizoaffective disorders, delusional
disorders brief psychotic disorders, shared psychotic disorders,
psychotic disorders with delusions or hallucinations, psychotic
episodes of anxiety, anxiety associated with psychosis, psychotic
mood disorders such as severe major depressive disorder; mood
disorders associated with psychotic disorders such as acute mania
and depression associated with bipolar disorder; mood disorders
associated with schizophrenia; delirium, dementia, and amnestic and
other cognitive or neurodegenerative disorders, such as Parkinson's
disease (PD), Huntington's disease (HD), Alzheimer's disease,
senile dementia, dementia of the Alzheimer's type, memory
disorders, loss of executive function, vascular dementia, and other
dementias, for example, due to HIV disease, head trauma,
Parkinson's disease, Huntington's disease, Pick's disease,
Creutzfeldt-Jakob disease, or due to multiple etiologies; movement
disorders such as akinesias, dyskinesias, including familial
paroxysmal dyskinesias, spasticities, Tourette's syndrome, Scott
syndrome, PALSYS and akinetic-rigid syndrome; extra-pyramidal
movement disorders such as medication-induced movement disorders,
for example, neuroleptic-induced Parkinsonism, neuroleptic
malignant syndrome, neuroleptic-induced acute dystonia,
neuroleptic-induced acute akathisia, neuroleptic-induced tardive
dyskinesia and medication-induced postural tremour; chemical
dependencies and addictions (e.g., dependencies on, or addictions
to, alcohol, heroin, cocaine, benzodiazepines, nicotine, or
phenobarbitol) and behavioral addictions such as an addiction to
gambling; and ocular disorders such as glaucoma and ischemic
retinopathy in a mammal, including a human, comprising an amount of
a compound according to claim 19, or a pharmaceutically acceptable
salt thereof, that is effective in treating such disorder or
condition, and a pharmaceutically acceptable carrier.
39. A method for treating a disorder or condition selected from
single episodic or recurrent major depressive disorders, dysthymic
disorders, depressive neurosis and neurotic depression, melancholic
depression including anorexia, weight loss, insomnia, early morning
waking or psychomotor retardation; atypical depression (or reactive
depression) including increased appetite, hypersomnia, psychomotor
agitation or irritability, seasonal affective disorder and
pediatric depression; bipolar disorders or manic depression, for
example, bipolar I disorder, bipolar II disorder and cyclothymic
disorder; conduct disorder; disruptive behavior disorder; attention
deficit hyperactivity disorder (ADHD); behavioral disturbances
associated with mental retardation, autistic disorder, and conduct
disorder; anxiety disorders such as panic disorder with or without
agoraphobia, agoraphobia without history of panic disorder,
specific phobias, for example, specific animal phobias, social
anxiety, social phobia, obsessive-compulsive disorder, stress
disorders including post-traumatic stress disorder and acute stress
disorder, and generalized anxiety disorders; borderline personality
disorder; schizophrenia and other psychotic disorders, for example,
schizophreniform disorders, schizoaffective disorders, delusional
disorders brief psychotic disorders, shared psychotic disorders,
psychotic disorders with delusions or hallucinations, psychotic
episodes of anxiety, anxiety associated with psychosis, psychotic
mood disorders such as severe major depressive disorder; mood
disorders associated with psychotic disorders such as acute mania
and depression associated with bipolar disorder; mood disorders
associated with schizophrenia; delirium, dementia, and amnestic and
other cognitive or neurodegenerative disorders, such as Parkinson's
disease (PD), Huntington's disease (HD), Alzheimer's disease,
senile dementia, dementia of the Alzheimer's type, memory
disorders, loss of executive function, vascular dementia, and other
dementias, for example, due to HIV disease, head trauma,
Parkinson's disease, Huntington's disease, Pick's disease,
Creutzfeldt-Jakob disease, or due to multiple etiologies; movement
disorders such as akinesias, dyskinesias, including familial
paroxysmal dyskinesias, spasticities, Tourette's syndrome, Scott
syndrome, PALSYS and akinetic-rigid syndrome; extra-pyramidal
movement disorders such as medication-induced movement disorders,
for example, neuroleptic-induced Parkinsonism, neuroleptic
malignant syndrome, neuroleptic-induced acute dystonia,
neuroleptic-induced acute akathisia, neuroleptic-induced tardive
dyskinesia and medication-induced postural tremour; chemical
dependencies and addictions (e.g., dependencies on, or addictions
to, alcohol, heroin, cocaine, benzodiazepines, nicotine, or
phenobarbitol) and behavioral addictions such as an addiction to
gambling; and ocular disorders such as glaucoma and ischemic
retinopathy in a mammal, including a human, comprising
administering to a mammal in need of such treatment an amount of a
compound according to claim 19, or a pharmaceutically acceptable
salt thereof, that is effective in treating such disorder or
condition.
40. The method of claim 39, wherein the disorder or condition that
is being treated is selected from major depression, single episode
depression, recurrent depression, child abuse induced-depression,
postpartum depression, dysthymia, cyclothymia and bipolar
disorder.
41. The method of claim 39, wherein the disorder or condition that
is being treated is selected from schizophrenia, schizoaffective
disorder, delusional disorder, substance-induced psychotic
disorder, brief psychotic disorder, shared psychotic disorder,
psychotic disorder due to a general medical condition, and
schizophreniform disorder.
42. The method of claim 39, wherein the disorder or condition that
is being treated is selected from autism, pervasive development
disorder, and attention deficit hyperactivity disorder (ADHD).
43. The method of claim 39, wherein the disorder or condition that
is being treated is selected from generalized anxiety disorder,
panic disorder, obsessive-compulsive disorder, post-traumatic
stress disorder, and phobias, including social phobia, agoraphobia,
and specific phobias.
44. The method of claim 39, wherein the compound of claim 8 is
administered to a human for the treatment of any two or more
comorbid disorders or conditions selected from those disorders and
conditions referred to in any of the above methods.
45. The method of claim 39, wherein the disorder or condition being
treated is schizophrenia with concomitant depression.
46. The method of claim 39, wherein the disorder or condition being
treated is schizophrenia with concomitant anxiety.
47. A method of treating a disorder or condition selected from
single episodic or recurrent major depressive disorders, dysthymic
disorders, depressive neurosis and neurotic depression, melancholic
depression including anorexia, weight loss, insomnia, early morning
waking or psychomotor retardation; atypical depression (or reactive
depression) including increased appetite, hypersomnia, psychomotor
agitation or irritability, seasonal affective disorder and
pediatric depression; bipolar disorders or manic depression, for
example, bipolar I disorder, bipolar II disorder and cyclothymic
disorder; conduct disorder; disruptive behavior disorder; attention
deficit hyperactivity disorder (ADHD); behavioral disturbances
associated with mental retardation, autistic disorder, and conduct
disorder; anxiety disorders such as panic disorder with or without
agoraphobia, agoraphobia without history of panic disorder,
specific phobias, for example, specific animal phobias, social
anxiety, social phobia, obsessive-compulsive disorder, stress
disorders including post-traumatic stress disorder and acute stress
disorder, and generalized anxiety disorders; borderline personality
disorder; schizophrenia and other psychotic disorders, for example,
schizophreniform disorders, schizoaffective disorders, delusional
disorders, brief psychotic disorders, shared psychotic disorders,
psychotic disorders with delusions or hallucinations, psychotic
episodes of anxiety, anxiety associated with psychosis, psychotic
mood disorders such as severe major depressive disorder; mood
disorders associated with psychotic disorders such as acute mania
and depression associated with bipolar disorder; mood disorders
associated with schizophrenia; delirium, dementia, and amnestic and
other cognitive or neurodegenerative disorders, such as Parkinson's
disease (PD), Huntington's disease (HD), Alzheimer's disease,
senile dementia, dementia of the Alzheimer's type, memory
disorders, loss of executive function, vascular dementia, and other
dementias, for example, due to HIV disease, head trauma,
Parkinson's disease, Huntington's disease, Pick's disease,
Creutzfeldt-Jakob disease, or due to multiple etiologies; movement
disorders such as akinesias, dyskinesias, including familial
paroxysmal dyskinesias, spasticities, Tourefte's syndrome, Scott
syndrome, PALSYS and akinetic-rigid syndrome; extra-pyramidal
movement disorders such as medication-induced movement disorders,
for example, neuroleptic-induced Parkinsonism, neuroleptic
malignant syndrome, neuroleptic-induced acute dystonia,
neuroleptic-induced acute akathisia, neuroleptic-induced tardive
dyskinesia and medication-induced postural tremour; chemical
dependencies and addictions (e.g., dependencies on, or addictions
to, alcohol, heroin, cocaine, benzodiazepines, nicotine, or
phenobarbitol) and behavioral addictions such as an addiction to
gambling; and ocular disorders such as glaucoma and ischemic
retinopathy in a mammal, including a human, comprising
administering to said mammal: active compound (a), a compound
according to claim 19 or a pharmaceutically acceptable salt
thereof; and active compound (b), another pharmaceutically active
compound that is an antidepressant or an anti-anxiety agent, or a
pharmaceutically acceptable salt thereof; wherein the active agent
(a) and the active agent (b) are present in amounts that render the
combination effective in treating such disorder or condition.
48. A pharmaceutical composition for treating a disorder or
condition selected from single episodic or recurrent major
depressive disorders, dysthymic disorders, depressive neurosis and
neurotic depression, melancholic depression including anorexia,
weight loss, insomnia, early morning waking or psychomotor
retardation; atypical depression (or reactive depression) including
increased appetite, hypersomnia, psychomotor agitation or
irritability, seasonal affective disorder and pediatric depression;
bipolar disorders or manic depression, for example, bipolar I
disorder, bipolar II disorder and cyclothymic disorder; conduct
disorder; disruptive behavior disorder; attention deficit
hyperactivity disorder (ADHD); behavioral disturbances associated
with mental retardation, autistic disorder, and conduct disorder;
anxiety disorders such as panic disorder with or without
agoraphobia, agoraphobia without history of panic disorder,
specific phobias, for example, specific animal phobias, social
anxiety, social phobia, obsessive-compulsive disorder, stress
disorders including post-traumatic stress disorder and acute stress
disorder, and generalized anxiety disorders; borderline personality
disorder; schizophrenia and other psychotic disorders, for example,
schizophreniform disorders, schizoaffective disorders, delusional
disorders brief psychotic disorders, shared psychotic disorders,
psychotic disorders with delusions or hallucinations, psychotic
episodes of anxiety, anxiety associated with psychosis, psychotic
mood disorders such as severe major depressive disorder; mood
disorders associated with psychotic disorders such as acute mania
and depression associated with bipolar disorder; mood disorders
associated with schizophrenia; delirium, dementia, and amnestic and
other cognitive or neurodegenerative disorders, such as Parkinson's
disease (PD), Huntington's disease (HD), Alzheimer's disease,
senile dementia, dementia of the Alzheimer's type, memory
disorders, loss of executive function, vascular dementia, and other
dementias, for example, due to HIV disease, head trauma,
Parkinson's disease, Huntington's disease, Pick's disease,
Creutzfeldt-Jakob disease, or due to multiple etiologies; movement
disorders such as akinesias, dyskinesias, including familial
paroxysmal dyskinesias, spasticities, Tourette's syndrome, Scott
syndrome, PALSYS and akinetic-rigid syndrome; extra-pyramidal
movement disorders such as medication-induced movement disorders,
for example, neuroleptic-induced Parkinsonism, neuroleptic
malignant syndrome, neuroleptic-induced acute dystonia,
neuroleptic-induced acute akathisia, neuroleptic-induced tardive
dyskinesia and medication-induced postural tremour; chemical
dependencies and addictions (e.g., dependencies on, or addictions
to, alcohol, heroin, cocaine, benzodiazepines, nicotine, or
phenobarbitol) and behavioral addictions such as an addiction to
gambling; and ocular disorders such as glaucoma and ischemic
retinopathy in a mammal comprising: active agent (a), a compound
according to claim 19 or a pharmaceutically acceptable salt
thereof; active agent (b), another pharmaceutically active agent
that is an antidepressant or an anti-anxiety agent; and a
pharmaceutically acceptable carrier.
49. The method of claim 48, wherein the disorder or condition being
treated is schizophrenia.
50. The method of claim 48, wherein the disorder or condition that
is being treated is selected from schizophrenia, schizoaffective
disorder, delusional disorder, substance-induced psychotic
disorder, brief psychotic disorder, shared psychotic disorder,
psychotic disorder due to a general medical condition, and
schizophreniform disorder.
51. The method of claim 48, wherein the disorder or condition that
is being treated is selected from autism, pervasive development
disorder, and attention deficit hyperactivity disorder.
52. The method of claim 48, wherein the disorder or condition that
is being treated is selected from generalized anxiety disorder,
panic disorder, obsessive-compulsive disorder, post-traumatic
stress disorder, and phobias, including social phobia, agoraphobia,
and specific phobias.
53. The method of claim 48, wherein the active agents (a) and (b)
are administered to a human for the treatment of any two or more
comorbid disorders or conditions selected from those disorders and
conditions referred to in any of the above methods.
54. The method of claim 48, wherein the disorder or condition being
treated is schizophrenia with concomitant depression.
55. The method of claim 48, wherein the disorder or condition being
treated is schizophrenia with concomitant anxiety.
56. A process for preparing a compound of formula 6: ##STR28##
wherein P is H or a protecting group n is an integer from 1 to 4;
and Z, Q, X, Y, R.sup.1, R.sup.4, R.sup.5 are defined as claim 1;
comprising, reacting a compound of formula 5: ##STR29## wherein Q,
Z, X, Y, R', R.sup.4, and R.sup.5 are defined as above; and
R.sup.13 is Cl, F, Br, S(O)Me, SO.sub.2Me, or OSO.sub.2CF.sub.3
with a compound of formula: PO(CH.sub.2).sub.nCH.sub.2OH, wherein P
is defined as above, in the presence of a base and a phase transfer
catalyst.
57. The process of claim 56, wherein the protecting group is
benzyl.
58. The process of claim 56, wherein the protecting group is a
substituted benzyl.
59. The process of claim 56, wherein the substituted benzyl is
selected from the group consisting of 2-, 3-, or
4-monomethoxybenzyl; 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or
3,5-dimethoxybenzyl; 2,4,6-, or 3,4,5-trimethoxybenzyl; mono
C-1,6-, n-, iso-, or branched-alkylbenzyl; 1-phenethyl;
2-phenethyl; mono F-, Cl-, or Br-benzyl; 2- or 4-methoxyphenyl;
2,4- or 2,6-dimethoxyphenyl; a benzyl substituted with
diphenylmethyl-, trityl-, or trialkylsilyl- of the formula
R.sub.15R.sub.16R.sub.17Si, where R.sub.15, R.sub.16, and R.sub.17
are independently C.sub.1 to C.sub.6, or n-, iso-, branched-alkyl-,
or phenyl.
60. The process of claim 56, wherein the protecting group is an
acetal.
61. The process of claim 60, wherein the acetal is selected from
the group consisting of: tetrahydropyranyl and acetals of the
general formula CHR.sub.18OR.sub.19, where R.sub.18 is H, phenyl,
benzyl, or C.sub.1 to C.sub.6, n, iso, or branched alkyl, and
R.sub.19 is C.sub.1 to C.sub.6, n, iso, or branched alkyl, phenyl,
or benzyl; 2-(trimethylsilyl)methyxomethyl, 2-methoxyethoxymethyl,
and trichloroethyoxymethyl acetals.
62. The process of claim 56, wherein the protecting group is
selected from the group consisting of p-methoxybenzyl,
tert-butyldimethylsilyl, and tetryhydropyranyl.
63. The process of claim 56, wherein the phase transfer catalyst is
selected from the group consisting of a tetraalkyl or
benzalkylammonium chloride or bromide of the general formula
R.sub.20R.sub.21R.sub.22R.sub.23NX, where X is independently Cl or
Br, and R.sub.20, R.sub.21, R.sub.22, and R.sub.23 are each
independently C.sub.1 through C.sub.18, normal, iso, or branched
chain alkyl, benzyl, or mono or multiply C.sub.1 through C.sub.18,
normal, iso, or branched chain alkyl substituted benzyl, or singly
or multiply halogen or alkoxy substituted benzyl.
64. The process of claim 56, wherein the phase transfer catalyst is
selected from the group consisting of: tetra n-butylammonium
chloride or bromide, benzyltrimethylammonium bromide or chloride,
methyltrioctylammonium chloride or bromide, and
tributylmethylammonium chloride or bromide.
65. The process of claim 56, wherein the phase transfer catalyst is
tetrabutyl ammonium chloride or bromide.
66. The process of claim 56, wherein the base is selected from the
group consisting of sodium hydride, potassium hydride, lithium
t-butoxide, sodium t-butoxide, potassium t-butoxide, lithium
t-amylate, sodium t-amylate, and potassium t-amylate.
67. The process of claim 56, wherein the base is potassium
t-butoxide or sodium t-butoxide.
68. The process of claim 56, wherein the reaction of the compound
of formula 5 is further carried out in the presence of a reaction
solvent.
69. The process of claim 68, wherein the reaction solvent has a
reflux temperature, and reaction is carried out at a reaction
temperature of about 25.degree. C. to the reflux temperature of the
reaction solvent.
70. The process of claim 69, wherein the reaction temperature is
about 25.degree. C.
71. The process of claim 69, where in the reaction solvent is
selected from the group consisting of: tetrahydrafuran,
N-methyl-2-pyrrolidinone, N,N-dimethylacetamide,
N,N-dimethylformamide, dimethylsulfite, acetonitrile,
propionitrile, isobutyronitrile, 1,2-dimethyoxethane,
diethyleneglycoldimethyl ether, 1,4-dioxane,
2-methyltetrahydrofuran, 2,5 dimethyltetrahydrofuran, methyl
t-butylether, and anisole.
72. The process of claim 68, where in the reaction solvent is
tetrahydrafuran.
73. The process of claim 56, wherein R.sup.13 of formula 5 is
F.
74. The process of claim 73, wherein --XY-- is CH.dbd.CH or
CH.sub.2--CH.sub.2.
75. A process for preparing the compound of claim 1, wherein A of
formula 1 is --(CH.sub.2).sub.mO-- and m is an integer from 2 to 5,
the process comprising reacting a compound of formula 4a: ##STR30##
wherein n is an integer from 1 to 4, Q, Z, --XY--, R.sup.1,
R.sup.4, and R.sup.5 are defined as in claim 1, with a compound of
the following formula, in the presence of a base: ##STR31## wherein
G and D are defined as in claim 1.
76. The process of claim 75, wherein the base does not react with
the compound of formula 4a, and is sufficiently basic to absorb HCl
produced in the reaction.
77. The process of claim 75 where the base is selected from the
group consisting of: diisopropylethylamine,
diisopropylisobutylamine, 4-diisopropylmorpholine,
N,N,-diisopropylaniline, 2,6-diisopropylpyridine,
2,6-di-t-butylpyridine, 2,6-di-t-butyl-4-methylpyridine, lithium
carbonate, sodium carbonate, potassium carbonate, rubidium
carbonate, cesium carbonate, calcium carbonate, magnesium
carbonate, lithium bicarbobate, sodium bicarbonate, potassium
bicarbonate, rubidium bicarbonate, cesium bicarbonate, calcium
oxide, calcium hydroxide, magnesium hydroxide, magnesium oxide, and
potassium phosphate.
78. The process of claim 75, wherein the base is selected from the
group consisting of diisopropylethylamine, potassium carbonate, and
sodium carbonate.
79. The process of claim 75, wherein the reaction is carried out in
the presence of a reaction solvent.
80. The process of claim 79, wherein the reaction solvent is
selected from the group consisting of acetonitrile, propionitrile,
isobutyronitrile, 2-methoxyethanol, tetrahydrofuran, 1,4-dioxane,
2-methyltetrahydofuran, 1,2-dimethoxyethane, diethyleneglycol
dimethyl ether, water, and dichloromethane.
81. The process of claim 79, wherein the reaction solvent is
water.
82. The process of claim 81, wherein the reaction is carried out at
a reaction temperature from about 25.degree. C. to about the reflux
temperature of water.
83. The process of claim 82, wherein the reaction is carried out at
about the reflux temperature of water.
84. The process of claim 75, wherein n is 3.
85. A process for preparing the compound of claim 1, comprising
reacting a compound of formula 3: ##STR32## wherein n is an integer
from 1 to 4; and Z, Q, X, Y, R.sup.1, R.sup.4, R.sup.5 are defined
as in claim 1; with a compound of the following formula, ##STR33##
wherein G and D are defined as in claim 1, in a reductive amination
reaction.
86. The process of claim 85, further comprising an oxidation step,
wherein the compound of formula 3 used in the reductive amination
reaction is produced by oxidizing a compound of formula 2:
##STR34## wherein n, Z, Q, X, Y, R.sup.1, R.sup.4, and R.sup.5 are
defined as claim 84; in the presence of an oxidant.
87. The process of claim 86, wherein the oxidant is selected from
the group consisting of: a Dess Martin oxidant, periodinane,
iodoxybenzoic acid, activated dimethylsulfite, pyridinium
chlorochromate, and tetra n-propylruthenate-4-N-methylmorpholine-N
oxide.
88. The process of claim 86, wherein the oxidant is a combination
of 2,2,6,6-tetramethyl-1-piperidinyloxide (TEMPO) or a substituted
TEMPO reagent and a stoichiometeric oxidant, wherein the
stoichiometeric oxidant is selected from the group consisting of
sodium hypochlorite, trichloroisocyanuric acid, iodobenzene
diacetate, N-chlorosuccinimide, N-bromosuccinimide,
dimethyldichlorohydantoin, and dimethyldibromohydantoin.
89. The process of claim 86, wherein the oxidant is 2-iodoxybenzoic
acid.
90. The process of claim 86, wherein the oxidation step is carried
out in the presence of a solvent.
91. The process of claim 90, wherein the solvent is selected from
the group consisting of dichloromethane, 1,2-dichloroethane,
ethylacetate, tetrahydrofuran, acetonitrile, dimethylsulfite, and a
combination of two or more of these solvents.
92. The process of claim 90 where the solvent is
dimethylsulfite.
93. The process of claim 86, wherein the oxidation step is carried
out using a process selected from the group consisting of a Dess
Martin oxidation reaction, a Swern oxidation reaction, and a Moffat
oxidation reaction.
94. The process of claim 85, further comprising using a catalytic
hydrogenation process in the reductive amination step, using
molecular hydrogen and a metal catalyst.
95. The process of claim 94, wherein the metal catalyst is selected
from the group consisting of a platinum catalyst, a palladium
catalyst, and a Raney nickel group catalyst.
96. The process of claim 94, wherein a hydride donor is used in the
catalytic hydrogenation process.
97. The process of claim 96, wherein the hydride donor is selected
from the group consisting of formic acid, triethylammonium formate,
cyclohexene or substituted cyclohexenes, and cyclohexadiene or
substituted cyclohexadienes.
98. The process of claim 85, wherein a hydride reducing agent is
used in the reductive amination reaction.
99. The process of claim 98, wherein the hydride reducing agent is
selected from the group consisting of sodium triacetoxyborohydride,
sodium cyanoborohydride, and sodium borohydride.
100. The process of claim 85, wherein the reductive amination
reaction is carried out in the presence of a base.
101. The process of claim 100, wherein the base is selected from
the group consisting of triethylamine, diisopropylethylamine,
diisopropylisobutylamine, sodium acetate, potassium acetate,
lithium acetate, cesium acetate, rubidium acetate, trifluroacetate,
and hydrobromide.
102. The process of claim 100, wherein the base is
triethylamine.
103. The process of claim 102, wherein a hydrochloride salt of the
compound of formula ##STR35## is used, wherein G and D are defined
as in claim 85.
104. The process of claim 85, wherein the reductive amination
reaction is carried out in the presence of a solvent selected from
the group consisting of: dichloromethane, 1,2-dichloroethane,
N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran,
2,-methyltetrahydrofuran, 2,5-dimethyltetrahydrofuran,
1,2-dimethoxyethane, 1,4-dioxane, methyltertbutylether, chloroform,
and acetonitrile.
Description
BACKGROUND OF THE INVENTION
[0001] This invention relates to [1,8]naphthyridin-2-ones and
related compounds, methods of making such compounds, pharmaceutical
compositions containing them, and their use for the treatment of
schizophrenia and other central nervous system (CNS).
[0002] The [1,8]naphthyridin-2-ones and related compounds of this
invention bind to dopamine D.sub.2 receptors. Some exhibit activity
as partial agonists of D.sub.2 receptors, while others exhibit
activity as antagonists of such receptors.
[0003] Other heterocyclic derivatives that are useful for the
treatment of schizophrenia are referred to in U.S. Pat. No.
5,350,747, which issued on Sep. 27, 1994, and in U.S. Pat. No.
6,127,357, which issued on Oct. 3, 2000. These patents are
incorporated herein by reference in their entireties.
[0004] Other heterocyclic derivatives that have been stated to be
useful as antipsychotic agents are those referred to in PCT patent
publication WO 93/04684, which published on Mar. 18, 1993, and
European patent application EP 402644A, which was published on Dec.
19, 1990. These patent applications are incorporated herein by
reference in their entireties.
SUMMARY OF THE INVENTION
[0005] The present invention relates to compounds of the formula 1
##STR2##
[0006] A is --(CH.sub.2).sub.mCH.sub.2--, --(CH.sub.2).sub.mO--, or
--(CH.sub.2).sub.mNH--, wherein m is an integer from 2 to 5 and
wherein one or two of the carbon or nitrogen atoms of
--(CH.sub.2).sub.mCH.sub.2--, --(CH.sub.2).sub.mO-- and
--(CH.sub.2).sub.mNH-- can be substituted, optionally and
independently, with one or two substituents that are selected,
independently, from fluoro and methyl, or with two substituents
attached to the same carbon atom that form, together with the
carbon to which they are attached, a spirocyclopropyl or
spirocyclobutyl ring;
[0007] D is N, C, or CH, provided that when D is N each carbon atom
covalently attached to D is attached through a single bond;
[0008] Z and Q are independently N, C, or CH, provided that at
least one of Z and Q is N;
[0009] --XY-- is --CH.sub.2--CH.sub.2--, --CH.dbd.CH--,
--CH.sub.2--NH--, --NH--CH.sub.2--, --N.dbd.CH--, --CH.dbd.N--,
--O--CH.sub.2--, or --CH.sub.2--O--, wherein --XY-- can optionally
be substituted, at any available bonding site, by one to four
substituents R.sup.2, R.sup.2', R.sup.3 and R.sup.3';
[0010] V and W are independently N, C, or CH;
[0011] ring AA is a saturated or unsaturated 5- 6- or 7-membered
carbocyclic ring wherein one, two or three of the carbon atoms of
ring AA that are not shared with the benzo ring of group (ii) can
be replaced, optionally and independently, by a nitrogen, oxygen or
sulfur atom;
[0012] R.sup.1 is hydrogen, --C(.dbd.O)CH.sub.3, or
(C.sub.1-C.sub.3)alkyl;
[0013] R.sup.2, R.sup.2', R.sup.3 and R.sup.3' are independently
selected from hydrogen, halo, cyano, oxo, hydroxy,
--C(.dbd.O)CH.sub.3, (C.sub.1-C.sub.4)alkyl, and
(C.sub.1-C.sub.4)alkoxy, wherein the alkyl moieties of the
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy, and
--C(.dbd.O)CH.sub.3 groups can be optionally substituted with from
one to three fluoro atoms and can also be optionally substituted
with an amino or hydroxy substituent;
[0014] R.sup.4 and R.sup.5 are independently selected from
hydrogen, halo, cyano, hydroxy, --C(.dbd.O)CH.sub.3,
(C.sub.1-C.sub.4)alkyl, and (C.sub.1-C.sub.4)alkoxy, wherein the
alkyl moieties of the (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy, and --C(.dbd.O)CH.sub.3 groups can be
optionally substituted with from one to three fluoro atoms and can
also be optionally substituted with an amino or hydroxy
substituent;
[0015] R.sup.6 and R.sup.7 are selected, independently, from
hydrogen and methyl;
[0016] R.sup.8, R.sup.9, R.sup.10, R.sup.11, and R.sup.12 are
independently selected from hydrogen, halo, --C(.dbd.O)CH.sub.3,
(C.sub.1-C.sub.4)alkyl, and (C.sub.1-C.sub.4)alkoxy, aryl, and
aryloxy, wherein the alkyl moieties of the (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy, and --C(.dbd.O)CH.sub.3 groups and the
aryl and aryloxy moieties can be optionally substituted with from
one to three fluoro atoms and can also be optionally substituted
with an amino or hydroxy substituent;
[0017] R.sup.13 and R.sup.14 are independently selected from
hydrogen, halo, cyano, oxo, hydroxy, --C(.dbd.O)CH.sub.3,
(C.sub.1-C.sub.4)alky, and (C.sub.1-C.sub.4)alkoxy, wherein the
alkyl moieties of the (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy, and --C(.dbd.O)CH.sub.3 groups can be
optionally substituted with from one to three fluoro atoms and can
also be optionally substituted with an amino or hydroxy
substituent;
[0018] and the pharmaceutically acceptable salts of such
compounds.
[0019] This invention also relates to a pharmaceutical composition
comprising a therapeutically effective amount of a compound of the
formula 1, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.
[0020] The compounds of formula 1 have useful pharmaceutical and
medicinal properties.
[0021] This invention also relates to a method of treating a
disorder or condition selected from the group consisting of single
episodic or recurrent major depressive disorders, dysthymic
disorders, depressive neurosis and neurotic depression, melancholic
depression including anorexia, weight loss, insomnia, early morning
waking or psychomotor retardation; atypical depression (or reactive
depression) including increased appetite, hypersomnia, psychomotor
agitation or irritability, seasonal affective disorder and
pediatric depression; bipolar disorders or manic depression, for
example, bipolar I disorder, bipolar II disorder and cyclothymic
disorder; conduct disorder; disruptive behavior disorder; attention
deficit hyperactivity disorder (ADHD); behavioral disturbances
associated with mental retardation, autistic disorder, and conduct
disorder; anxiety disorders such as panic disorder with or without
agoraphobia, agoraphobia without history of panic disorder,
specific phobias, for example, specific animal phobias, social
anxiety, social phobia, obsessive-compulsive disorder, stress
disorders including post-traumatic stress disorder and acute stress
disorder, and generalized anxiety disorders; borderline personality
disorder; schizophrenia and other psychotic disorders, for example,
schizophreniform disorders, schizoaffective disorders, delusional
disorders, brief psychotic disorders, shared psychotic disorders,
psychotic disorders with delusions or hallucinations, psychotic
episodes of anxiety, anxiety associated with psychosis, psychotic
mood disorders such as severe major depressive disorder; mood
disorders associated with psychotic disorders such as acute mania
and depression associated with bipolar disorder; mood disorders
associated with schizophrenia; delirium, dementia, and amnestic and
other cognitive or neurodegenerative disorders, such as Parkinson's
disease (PD), Huntington's disease (HD), Alzheimer's disease,
senile dementia, dementia of the Alzheimer's type, memory
disorders, loss of executive function, vascular dementia, and other
dementias, for example, due to HIV disease, head trauma,
Parkinson's disease, Huntington's disease, Pick's disease,
Creutzfeldt-Jakob disease, or due to multiple etiologies; movement
disorders such as akinesias, dyskinesias, including familial
paroxysmal dyskinesias, spasticities, Tourette's syndrome, Scott
syndrome, PALSYS and akinetic-rigid syndrome; extra-pyramidal
movement disorders such as medication-induced movement disorders,
for example, neuroleptic-induced Parkinsonism, neuroleptic
malignant syndrome, neuroleptic-induced acute dystonia,
neuroleptic-induced acute akathisia, neuroleptic-induced tardive
dyskinesia and medication-induced postural tremor; chemical
dependencies and addictions (e.g., dependencies on, or addictions
to, alcohol, heroin, cocaine, benzodiazepines, nicotine, or
phenobarbitol) and behavioral addictions such as an addiction to
gambling; and ocular disorders such as glaucoma and ischemic
retinopathy in a mammal, including a human, comprising
administering to a mammal in need of such treatment an amount of a
compound of the formula 1, or a pharmaceutically acceptable salt
thereof, that is effective in treating such disorder or
condition.
[0022] This invention also relates to a pharmaceutical composition
for treating any disorder or condition listed immediately above,
the pharmaceutical composition comprising an amount of a compound
of the formula 1, or a pharmaceutically acceptable salt thereof,
that is effective in treating such disorder or condition, and a
pharmaceutically acceptable carrier.
[0023] This invention also relates to a process for preparing a
compound of formula 2, below. The compound of formula 2 is suitable
for use as an intermediate in synthesis of compounds of formula 1:
##STR3## wherein [0024] P is H, benzyl, p-methyoxybenzyl,
tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or
tetrahydropyranyl; [0025] n is an integer from 1 to 4; [0026] Q, Z,
--XY--, R.sup.1, R.sup.4, and R.sup.5 are the same as defined for
formula 1, above. The process of making a compound of formula 2,
comprising reacting a compound of formula 3, below: ##STR4##
wherein [0027] O, Z, X, Y, R.sup.1, R.sup.4, and R.sup.5 are
defined as in formula 1 above; and [0028] R.sup.13 is Cl, F, Br,
S(O)Me, or SO.sub.2Me, with a compound of formula:
PO(CH.sub.2).sub.mCH.sub.2OH in the presence of a base and a phase
transfer catalyst.
[0029] This invention also relates to a process for preparing the
compound of formula 1, wherein A is --(CH2).sub.mO-- and m is an
integer from 2 to 5, the process comprising reacting a compound of
formula 4a: ##STR5## [0030] wherein O, Z, --XY--, R.sup.1, R.sup.4,
and R.sup.5 are defined as in formula 1, and n is an integer from 1
to 4, with a compound of the following formula in the presence of a
base: ##STR6## wherein G is defined as in formula 1, above. In this
process, G is preferably a structure of the following formula:
##STR7## wherein [0031] AA is a 6-membered saturated or unsaturated
carbon ring; and R.sup.13 and R.sup.14 are independently selected
from hydrogen, halo, cyano, oxo, hydroxy, --C(.dbd.O)CH.sub.3,
(C.sub.1-C.sub.4)alkyl, and (C.sub.1-C.sub.4)alkoxy. [Add
Description of Reductive Amination (New Independent Claim)]
[0032] The term "alkyl", as used herein, unless otherwise
indicated, includes saturated monovalent hydrocarbon radicals
having straight, branched or cyclic moieties or combinations
thereof. Examples of "alkyl" groups include, but are not limited
to, methyl, ethyl, propyl, isopropyl, butyl, iso- sec- and
tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and
the like.
[0033] The term "alkoxy", as used herein, unless otherwise
indicated, means "alkyl-O--", wherein "alkyl" is as defined above.
Examples of "alkoxy" groups include, but are not limited to,
methoxy, ethoxy, propoxy, butoxy and pentoxy.
[0034] The term "aryl", as used herein, unless otherwise indicated,
refers to an aromatic 5- or 6-membered carbocyclic ring wherein one
carbon of the ring is covalently attached to another subunit of a
compound.
[0035] The term "aryloxy" as used herein, refers to an aryl wherein
one carbon of the aromatic ring is covalently attached to another
subunit of a compound through an --O--, oxy, or
(C.sub.1-C.sub.4)alkoxy residue.
[0036] The term "one or more substituents", as used herein, refers
to a number of substituents that equals from one to the maximum
number of substituents possible based on the number of available
bonding sites.
[0037] The terms "halo" and "halogen", as used herein, unless
otherwise indicated, include, fluoro, chloro, bromo and iodo.
[0038] The term "treating", as used herein, refers to reversing,
alleviating, inhibiting the progress of, or preventing the disorder
or condition to which such term applies, or preventing one or more
symptoms of such condition or disorder.
[0039] The term "treatment", as used herein, refers to the act of
treating, as "treating" is defined immediately above.
[0040] The compounds of formula 1, and the pharmaceutically
acceptable salts of these compounds are referred to herein,
collectively, as the "novel compounds of this invention" and the
"active compounds of this invention".
DETAILED DESCRIPTION OF THE INVENTION
[0041] Preferred embodiments of this invention relate to compounds
of the formula 1, and their pharmaceutically acceptable salts,
wherein G is a group of the formula ii and ring AA is a benzo
ring.
[0042] Other preferred embodiments of this invention relate to
compounds of the formula 1, and their pharmaceutically acceptable
salts, wherein --XY-- is --CH.sub.2--NH--.
[0043] Other preferred embodiments of this invention relate to
compounds of formula 1 and their pharmaceutically acceptable salts,
wherein G is naphthyl, and R.sup.13 and R.sup.14 are independently
hydrogen or flouro.
[0044] Other preferred embodiments of this invention relate to
compounds of formula 1 and their pharmaceutically acceptable salts,
wherein at least one of R.sup.13 or R.sup.14 is flouro or
methoxy.
[0045] Other preferred embodiments of this invention relate to
compounds of the formula 1, and their pharmaceutically acceptable
salts, wherein G is a group of a formula selected from:
##STR8##
[0046] Other preferred embodiments of this invention relate to
compounds of the formula 1, and their pharmaceutically acceptable
salts, wherein G is 2,3-dichlorophenyl.
[0047] Other preferred embodiments of this invention relate to
compounds of the formula 1, and their pharmaceutically acceptable
salts, wherein W and V are C or CH.
[0048] Other preferred embodiments of this invention relate to
compounds of formula 1 and their pharmaceutically acceptable salts,
wherein D is N, Q is N, Z is CH, --XY-- is --CH.sub.2--CH.sub.2--
or --CH.dbd.CH--, and R.sup.1, R.sup.4, and R.sup.5 are
hydrogen.
[0049] Other preferred embodiments of this invention relate to
compounds of formula 1 and their pharmaceutically acceptable salts,
wherein W and V are C or CH, or wherein only one of W or V is
N.
[0050] Other preferred embodiments of this invention relate to
compounds of formula 1 and their pharmaceutically acceptable salts,
wherein Q and Z are both N.
[0051] Other preferred embodiments of this invention relate to
compounds of the formula 1, and their pharmaceutically acceptable
salts, wherein R.sup.4 and R.sup.5 are hydrogen.
[0052] Other preferred embodiments of this invention relate to
compounds of the formula 1, and their pharmaceutically acceptable
salts, wherein D is N.
[0053] Other preferred embodiments of this invention relate to
compounds of the formula 1, and their pharmaceutically acceptable
salts, wherein A is --(CH.sub.2).sub.4O--.
[0054] Other preferred embodiments of this invention relate to
compounds of the formula 1, and their pharmaceutically acceptable
salts, wherein Q is N and Z is C or CH.
[0055] Other preferred embodiments of this invention relate to
compounds of the formula 1, and their pharmaceutically acceptable
salts, wherein Q is N and Z is N.
[0056] Other preferred embodiments of this invention relate to
compounds of the formula 1, and their pharmaceutically acceptable
salts, wherein --XY-- is --CH.sub.2--CH.sub.2-- or
--CH.dbd.CH--.
[0057] Other preferred embodiments of this invention relate to
compounds of the formula 1, and their pharmaceutically acceptable
salts, wherein R.sup.1 is hydrogen.
[0058] Other embodiments of this invention relate to compounds of
the formula 1, and their pharmaceutically acceptable salts, wherein
Q is C or CH, and Z is N.
[0059] Other embodiments of this invention relates to compounds of
the formula 1, and their pharmaceutically acceptable salts, wherein
--XY-- is --O--CH.sub.2--.
[0060] Other embodiments of this invention relates to compounds of
the formula 1, and their pharmaceutically acceptable salts, wherein
--XY-- is --CH.sub.2--O--.
[0061] Other embodiments of this invention relate to compounds of
the formula 1, and their pharmaceutically acceptable salts, wherein
A is --(CH.sub.2).sub.m--CH.sub.2-- wherein m is 3 or 4.
[0062] Other embodiments of this invention relate to compounds of
the formula 1 and their pharmaceutically acceptable salts, wherein
G is a group of the formula (i) and W and V are both N, or W is N
and V is C or CH.
[0063] One set of specific embodiments of the invention relate to
compounds of formula 1 and their pharmaceutically acceptable salts,
wherein all of the atoms of the carbocyclic ring AA are carbon
atoms. These embodiments include the following compounds and their
pharmaceutically acceptable salts. Procedures for synthesis of each
of these compounds are illustrated in the Examples section, below.
[0064]
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8-
]naphthyridin-2-one; [0065]
7-{4-[4-(2-Chloro-3-methyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0066]
7-{4-[4-(3-Chloro-2-methyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0067]
7-{4-[4-(2,3-Dimethyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8-
]naphthyridin-2-one; [0068]
7-{4-[4-(2-Chloro-3-fluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0069]
7-{4-[4-(3-Chloro-2-fluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0070]
7-{4-[4-(2-Chloro-3-trifluoromethyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-d-
ihydro-1H-[1,8]naphthyridin-2-one; [0071]
7-{4-[4-(2,3-Dichloro-4-fluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one; [0072]
7-{4-[4-(2-Chloro-4-fluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0073]
7-{4-[4-(2-Chloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]nap-
hthyridin-2-one; [0074]
7-[4-(4-Biphenyl-2-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthy-
ridin-2-one; [0075]
7-{4-[4-(2,5-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8-
]naphthyridin-2-one; [0076]
7-{4-[4-(2-Chloro-4-fluoro-5-methyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-d-
ihydro-1H-[1,8]naphthyridin-2-one; [0077]
7-{4-[4-(5-Chloro-2-methyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0078]
7-{4-[4-(2-Chloro-4-fluoro-3-methyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-d-
ihydro-1H-[1,8]naphthyridin-2-one; [0079]
7-{4-[4-(3-Ethyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naph-
thyridin-2-one; [0080]
7-{4-[4-(3-Chloro-2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1-
H-[1,8]naphthyridin-2-one; [0081]
7-{4-[4-(3-Methyl-2-phenoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1-
H-[1,8]naphthyridin-2-one; [0082]
7-{4-[4-(2,3-Dimethoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,-
8]naphthyridin-2-one; [0083]
7-{4-[4-(2-Ethoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]nap-
hthyridin-2-one; [0084]
7-{4-[4-(2-Chloro-3-ethoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0085]
7-{4-[4-(2-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1-
H-[1,8]naphthyridin-2-one; [0086]
7-{4-[4-(2-Chloro-3-isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one; [0087]
7-{4-[4-(3-Methoxy-2-methyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1-
H-[1,8]naphthyridin-2-one; [0088]
7-{4-[4-(5-Chloro-2-isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one; [0089]
7-{4-[4-(2-Isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8-
]naphthyridin-2-one; [0090]
7-{4-[4-(2-Isobutoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]-
naphthyridin-2-one; [0091]
7-{4-[4-(2-Acetyl-3-chloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0092]
7-{4-[4-(3-Chloro-2-ethyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H--
[1,8]naphthyridin-2-one; [0093]
7-{4-[4-(2-Acetyl-3-fluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0094]
7-{4-[4-(2-Ethyl-3-fluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H--
[1,8]naphthyridin-2-one; [0095]
7-{4-[4-(3-Acetyl-2-chloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0096]
7-{4-[4-(3-Acetyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]nap-
hthyridin-2-one; [0097]
7-{4-[4-(2-Acetyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]nap-
hthyridin-2-one; [0098]
7-{4-[4-(2-Ethyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naph-
thyridin-2-one; [0099]
7-[4-(4-o-Tolyl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin--
2-one; [0100]
7-{4-[4-(2-Trifluoromethyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0101]
7-{4-[4-(3-Trifluoromethyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0102]
7-[4-(4-Phenyl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-
-one; [0103]
7-{4-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]nap-
hthyridin-2-one; [0104]
7-{4-[4-(2,4-Difluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8-
]naphthyridin-2-one; [0105]
7-(4-{4-[2-(1,1-Difluoro-ethyl)-phenyl]-piperazin-1-yl}-butoxy)-3,4-dihyd-
ro-1H-[1,8]naphthyridin-2-one; [0106]
7-[4-(4-Pyridin-2-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyr-
idin-2-one; [0107]
7-{4-[4-(6-Methyl-pyridin-2-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1-
,8]naphthyridin-2-one; [0108]
7-{4-[4-(6-Ethyl-pyridin-2-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,-
8]naphthyridin-2-one; [0109]
7-{4-[4-(6-Cyclopropyl-pyridin-2-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro--
1H-[1,8]naphthyridin-2-one; [0110]
7-{4-[4-(4-Methyl-pyrimidin-2-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H--
[1,8]naphthyridin-2-one; [0111]
7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]napht-
hyridin-2-one; [0112]
7-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4--
dihydro-1H-[1,8]naphthyridin-2-one; [0113]
7-{4-[4-(3-Fluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-but-
oxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0114]
7-{4-[4-(8-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy-
}-3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0115]
7-{4-[4-(7,7-Dimethyl-8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-
-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0116]
7-{4-[4-(7,7-Difluoro-8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-
-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0117]
7-{4-[4-(7,7-Difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-
-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0118]
7-{4-[4-(7-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy-
}-3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0119]
7-{4-[4-(7-Hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-bu-
toxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0120]
7-{4-[4-(5-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy-
}-3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0121]
7-{4-[4-(5,5-Difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-
-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0122]
7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyrid-
in-2-one; [0123]
7-{4-[4-(2-Oxo-indan-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]na-
phthyridin-2-one; [0124]
7-{4-[4-(2,2-Difluoro-indan-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H--
[1,8]naphthyridin-2-one; [0125]
7-{4-[4-(6,7,8,9-Tetrahydro-5H-benzocyclohepten-1-yl)-piperazin-1-yl]-but-
oxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0126]
7-[4-(4-Naphthalen-1-yl-piperidin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]napht-
hyridin-2-one [0127]
7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0128]
7-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0129]
7-{4-[4-(6-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0130]
7-{4-[4-(5-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0131]
7-{4-[4-(4-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0132]
7-{4-[4-(3-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0133]
7-{4-[4-(2-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0134]
7-{4-[4-(6,7-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one; [0135]
7-{4-[4-(7-Methoxy-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1-
H-[1,8]naphthyridin-2-one; [0136]
7-{4-[4-(7-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0137]
7-{4-[4-(5-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0138]
7-{4-[4-(6-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0139]
7-{4-[4-(8-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0140]
7-{4-[4-(7-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0141]
7-{4-[4-(6-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0142]
7-{4-[4-(5-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0143]
7-{4-[4-(4-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0144]
7-{4-[4-(2-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0145]
8-{4-[4-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyl]-piper-
azin-1-yl}-naphthalene-2-carbonitrile;
[0146]
N-(8-{4-[4-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-bu-
tyl]-piperazin-1-yl}-naphthalen-2-yl)-acetamide; [0147]
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridi-
n-2-one; [0148]
7-{4-[4-(2-Chloro-3-trifluoromethyl-phenyl)-piperazin-1-yl]-butoxy}-1H-[1-
,8]naphthyridin-2-one; [0149]
7-{4-[4-(2-Acetyl-3-chloro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0150]
7-{4-[4-(3-Chloro-2-ethyl-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthy-
ridin-2-one; [0151]
7-{4-[4-(2-Acetyl-3-fluoro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0152]
7-{4-[4-(3-Acetyl-2-chloro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0153]
7-{4-[4-(2-Chloro-4-fluoro-5-methyl-phenyl)-piperazin-1-yl]-butoxy}-1H-[1-
,8]naphthyridin-2-one; [0154]
7-{4-[4-(2-Chloro-4-fluoro-3-methyl-phenyl)-piperazin-1-yl]-butoxy}-1H-[1-
,8]naphthyridin-2-one; [0155]
7-{4-[4-(5-Chloro-2-isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]na-
phthyridin-2-one; [0156]
7-{4-[4-(2-Isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridi-
n-2-one; [0157]
7-{4-[4-(2-Isobutoxy-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-
-2-one; [0158]
7-[4-(4-o-Tolyl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one
[0159]
7-{4-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthy-
ridin-2-one; [0160]
7-{4-[4-(3-Chloro-4-fluoro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0161]
7-{4-[4-(3-Trifluoromethyl-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0162]
7-{4-[4-(2-Trifluoromethyl-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0163]
7-(4-{4-[2-(1,1-Difluoro-ethyl)-phenyl]-piperazin-1-yl}-butoxy)-1H-[1,8]n-
aphthyridin-2-one; [0164]
7-{4-[4-(2-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]napht-
hyridin-2-one; [0165]
7-{4-[4-(2-Chloro-3-ethoxy-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0166]
7-{4-[4-(2-Chloro-3-isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]na-
phthyridin-2-one; [0167]
7-{4-[4-(3-Methyl-2-phenoxy-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]napht-
hyridin-2-one; [0168]
7-{4-[4-(3-Chloro-2-fluoro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0169]
7-{4-[4-(2-Chloro-4-fluoro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0170]
7-{4-[4-(2,3-Dichloro-4-fluoro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]na-
phthyridin-2-one; [0171]
7-{4-[4-(2-Chloro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2--
one; [0172]
7-[4-(4-Biphenyl-2-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one;
[0173]
7-{4-[4-(3-Methoxy-2-methyl-phenyl)-piperazin-1-yl]-butoxy}-1H-[-
1,8]naphthyridin-2-one; [0174]
7-{4-[4-(2-Chloro-3-fluoro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0175]
7-{4-[4-(6-Cyclopropyl-pyridin-2-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naph-
thyridin-2-one; [0176]
7-[4-(4-Pyrimidin-2-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one-
; [0177]
7-{4-[4-(4-Methoxy-pyrimidin-2-yl)-piperazin-1-yl]-butoxy}-1H-[-
1,8]naphthyridin-2-one; [0178]
7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one
[0179]
7-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-buto-
xy}-1H-[1,8]naphthyridin-2-one; [0180]
7-{4-[4-(3-Fluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-but-
oxy}-1H-[1,8]naphthyridin-2-one; [0181]
7-{4-[4-(8-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy-
}-1H-[1,8]naphthyridin-2-one; [0182]
7-{4-[4-(7,7-Dimethyl-8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-
-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one; [0183]
7-{4-[4-(7,7-Dimethyl-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-
-butoxy}-1H-[1,8]naphthyridin-2-one; [0184]
7-{4-[4-(7,7-Difluoro-8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-
-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one; [0185]
7-{4-[4-(7,7-Difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-
-butoxy}-1H-[1,8]naphthyridin-2-one; [0186]
7-{4-[4-(7-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy-
}-1H-[1,8]naphthyridin-2-one; [0187]
7-{4-[4-(7-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy-
}-1H-[1,8]naphthyridin-2-one; [0188]
7-{4-[4-(7-Hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-bu-
toxy}-1H-[1,8]naphthyridin-2-one; [0189]
7-{4-[4-(5-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy-
)-1H-[1,8]naphthyridin-2-one; [0190]
7-{4-[4-(5,5-Difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-
-butoxy}-1H-[1,8]naphthyridin-2-one; [0191]
7-{4-[4-(3-Oxo-indan-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-
-one; [0192]
7-{4-[4-(2-Oxo-indan-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-
-one; [0193]
7-{4-[4-(2,2-Difluoro-indan-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthy-
ridin-2-one; [0194]
7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-on-
e; [0195]
7-{4-[4-(6-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0196]
7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0197]
7-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0198]
7-{4-[4-(5-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0199]
7-{4-[4-(4-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0200]
7-{4-[4-(3-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0201]
7-{4-[4-(2-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0202]
7-{4-[4-(6,7-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]na-
phthyridin-2-one; [0203]
7-{4-[4-(7-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0204]
7-{4-[4-(6-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0205]
7-{4-[4-(5-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0206]
7-{4-[4-(8-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0207]
7-{4-[4-(7-Methoxy-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]napht-
hyridin-2-one; [0208]
7-{4-[4-(6-Methoxy-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]napht-
hyridin-2-one; [0209]
7-{4-[4-(7-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0210]
7-{4-[4-(6-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0211]
7-{4-[4-(5-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0212]
7-{4-[4-(4-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0213]
7-{4-[4-(2-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0214]
8-{4-[4-(7-Oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyl]-piperazin-1--
yl}-naphthalene-2-carbonitrile; [0215]
1-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyr-
idin-2-one; [0216]
7-{3-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-propoxy}-1H-[1,8]naphthyrid-
in-2-one; [0217]
7-[3-(4-Naphthalen-1-yl-piperazin-1-yl)-propoxy]-1H-[1,8]naphthyridin-2-o-
ne; [0218]
7-[3-(4-Naphthalen-1-yl-piperazin-1-yl)-propoxy]-3,4-dihydro-1H-[1,8]naph-
thyridin-2-one; [0219]
7-{2-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-ethoxy}-1H-[1,8]naphthyridi-
n-2-one; [0220]
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-1-methyl-butoxy}-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one; [0221]
7-[1-Methyl-4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[-
1,8]naphthyridin-2-one; [0222]
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-1,1-dimethyl-butoxy}-3,4-di-
hydro-1H-[1,8]naphthyridin-2-one; [0223]
7-[1,1-Dimethyl-4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro--
1H-[1,8]naphthyridin-2-one; [0224]
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-[1,8-
]naphthyridin-2-one; [0225]
7-{5-[4-(2-Chloro-3-methyl-phenyl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0226]
7-{5-[4-(2,3-Dichloro-4-fluoro-phenyl)-piperazin-1-yl]-pentyl}-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one; [0227]
7-{5-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-pentyl}-3,4--
dihydro-1H-[1,8]naphthyridin-2-one; [0228]
7-[5-(4-Naphthalen-1-yl-piperazin-1-yl)-pentyl]-3,4-dihydro-1H-[1,8]napht-
hyridin-2-one; [0229]
7-{5-[4-(2-Chloro-4-fluoro-phenyl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0230]
7-{5-[4-(2-Chloro-4-fluoro-3-methyl-phenyl)-piperazin-1-yl]-pentyl}-3,4-d-
ihydro-1H-[1,8]naphthyridin-2-one; [0231]
7-{5-[4-(6-Methyl-pyridin-2-yl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-[1-
,8]naphthyridin-2-one; [0232]
7-{5-[4-(6-Ethyl-pyridin-2-yl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-[1,-
8]naphthyridin-2-one; [0233]
7-{5-[4-(6-Cyclopropyl-pyridin-2-yl)-piperazin-1-yl]-pentyl}-3,4-dihydro--
1H-[1,8]naphthyridin-2-one; [0234]
7-{5-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1-
H-[1,8]naphthyridin-2-one; [0235]
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-1H-[1,8]naphthyridi-
n-2-one; [0236]
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-4-methyl-1H-[1,8]na-
phthyridin-2-one; [0237]
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-4-methyl-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one; [0238]
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-4-methyl-1H-[1,8]na-
phthyridin-2-one; [0239]
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3-methyl-1H-[1,8]na-
phthyridin-2-one; [0240]
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-3-methyl-1H-[1,8]na-
phthyridin-2-one; [0241]
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3-methyl-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one; [0242]
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dimethyl-1H-[1,-
8]naphthyridin-2-one; [0243]
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-3,4-dimethyl-1H-[1,-
8]naphthyridin-2-one; [0244]
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3-fluoro-1H-[1,8]na-
phthyridin-2-one; [0245]
3-Fluoro-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyr-
idin-2-one; [0246]
7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-3-(2,2,2-trifluoro-ethyl)-
-1H-[1,8]naphthyridin-2-one; [0247]
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,3-dimethyl-3,4-di-
hydro-1H-[1,8]naphthyridin-2-one; [0248]
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,3-dimethyl-1H-[1,-
8]naphthyridine-2,4-dione; [0249]
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-4-hydroxy-3,3-dimet-
hyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0250]
4,4-Dimethyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro--
1H-[1,8]naphthyridin-2-one; [0251]
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3,4-di-
hydro-1H-[1,8]naphthyridin-2-one; [0252]
4,4-Dimethyl-7-{4-[4-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-
-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0253]
7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-4,4-dimethyl-3,4-dihydro-1H-[1-
,8]naphthyridin-2-one; [0254]
7-{4-[4-(2-Chloro-3-methyl-phenyl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3-
,4-dihydro-1H-[1,8]naphthyridin-2-one; [0255]
7-{4-[4-(3-Chloro-2-methyl-phenyl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3-
,4-dihydro-1H-[1,8]naphthyridin-2-one; [0256]
7-{4-[4-(6-Cyclopropyl-pyridin-2-yl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-
-3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0257]
7-{4-[4-(2-Ethyl-phenyl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3,4-dihydro-
-1H-[1,8]naphthyridin-2-one; [0258]
7-{4-[4-(2-Isobutoxy-phenyl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3,4-dih-
ydro-1H-[1,8]naphthyridin-2-one; [0259]
7-{4-[4-(2-Isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3,4-di-
hydro-1H-[1,8]naphthyridin-2-one; [0260]
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-6-methyl-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one; [0261]
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-6-methyl-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one; [0262]
6-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[-
1,8]naphthyridin-2-one; [0263]
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-6-fluoro-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one; [0264]
6-Fluoro-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[-
1,8]naphthyridin-2-one; [0265]
6-Fluoro-7-[4-(4-indan-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]n-
aphthyridin-2-one; [0266]
6-Chloro-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[-
1,8]naphthyridin-2-one; [0267]
6-Bromo-7-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-
-1H-[1,8]naphthyridin-2-one; [0268]
6-Bromo-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1-
,8]naphthyridin-2-one; [0269]
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-5-methyl-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one; [0270]
5-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[-
1,8]naphthyridin-2-one; [0271]
5-Methyl-7-{4-[4-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-but-
oxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0272]
7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-5-methyl-3,4-dihydro-1H-[1,8]n-
aphthyridin-2-one; [0273]
7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-5-trifluoromethyl-3,4-dihydro--
1H-[1,8]naphthyridin-2-one; [0274]
7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-5-trifluoromethyl-3,4-dih-
ydro-1H-[1,8]naphthyridin-2-one; [0275]
7-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-5-tr-
ifluoromethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0276]
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-pyri-
do[2,3-d]pyrimidin-2-one; [0277]
7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-pyrido[2,3-
-d]pyrimidin-2-one; [0278]
7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-pyrido[2,3-d]py-
rimidin-2-one; [0279]
7-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4--
dihydro-1H-pyrido[2,3-d]pyrimidin-2-one; [0280]
7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-pyrido[2,3-d]pyrimidin-2-one; [0281]
8-{4-[4-(2-Oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-7-yloxy)-butyl]--
piperazin-1-yl}-naphthalene-2-carbonitrile; [0282]
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3-methyl-3,4-dihydr-
o-1H-pyrido[2,3-d]pyrimidin-2-one; [0283]
3-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-p-
yrido[2,3-d]pyrimidin-2-one; [0284]
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-4,4-dimethyl-1,4-di-
hydro-pyrido[2,3-d][1,3]oxazin-2-one; [0285]
6-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-4H-pyrido[3,2-b][1,-
4]oxazin-3-one; [0286]
6-{5-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-pentyl}-4H-p-
yrido[3,2-b][1,4]oxazin-3-one; [0287]
6-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-4H-pyrido[3,2-b][1,-
4]oxazin-3-one; [0288]
6-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-4H-pyrido[3,2-b][1,4]oxazin-3--
one; [0289]
6-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-4H-pyrido[3,2-b][1,4]oxaz-
in-3-one; [0290]
6-{4-[4-(6-Methoxy-pyridin-2-yl)-piperazin-1-yl]-butoxy}-4H-pyrido[3,2-b]-
[1,4]oxazin-3-one;
[0291]
6-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4H-pyr-
ido[3,2-b][1,4]oxazin-3-one; [0292]
6-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4H-p-
yrido[3,2-b][1,4]oxazin-3-one; [0293]
2-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]pyr-
imidin-7-one; [0294]
2-{4-[4-(2-Isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]pyr-
imidin-7-one; [0295]
2-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-on-
e; [0296]
2-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-8H-pyrido[2,3-d]pyrimidin-
-7-one; [0297]
6-Fluoro-4-methyl-2-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-8H-pyri-
do[2,3-d]pyrimidin-7-one; [0298]
2-{4-[4-(6-Isopropyl-pyridin-2-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-py-
rido[2,3-d]pyrimidin-7-one; [0299]
2-{4-[4-(6-Ethyl-pyridin-2-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-pyrido-
[2,3-d]pyrimidin-7-one; [0300]
2-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-4-methyl-8H-pyrido[2,3-d]pyrim-
idin-7-one; [0301]
4-Methyl-2-{4-[4-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-but-
oxy}-8H-pyrido[2,3-d]pyrimidin-7-one; [0302]
2-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-py-
rido[2,3-d]pyrimidin-7-one; [0303]
2-{4-[4-(7-Methoxy-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-p-
yrido[2,3-d]pyrimidin-7-one; [0304]
4-Methyl-2-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-8H-pyrido[2,3-d]-
pyrimidin-7-one; [0305]
2-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4,8-dimethyl-8-
H-pyrido[2,3-d]pyrimidin-7-one; [0306]
2-{4-[4-(7-Methoxy-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4,8-dimethyl--
8H-pyrido[2,3-d]pyrimidin-7-one; [0307]
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-[1,6-
]naphthyridin-2-one; [0308]
7-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4--
dihydro-1H-[1,6]naphthyridin-2-one; [0309]
7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,6]napht-
hyridin-2-one; [0310]
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,6-
]naphthyridin-2-one; [0311]
7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,6]naphthyrid-
in-2-one; [0312]
7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,6]naphthyridin-2-one; [0313]
8-Bromo-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1-
,6]naphthyridin-2-one; [0314]
8-Bromo-7-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-
-1H-[1,6]naphthyridin-2-one; [0315]
8-Chloro-7-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydr-
o-1H-[1,6]naphthyridin-2-one; [0316]
8-Chloro-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[-
1,6]naphthyridin-2-one; [0317]
7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-2-oxo-1,2,3,4-tetrahydro--
[1,6]naphthyridine-8-carboxylic acid methyl ester; [0318]
8-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[-
1,6]naphthyridin-2-one; [0319]
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,6]naphthyridi-
n-2-one; [0320]
7-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[-
1,6]naphthyridin-2-one; [0321]
7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-1H-[1,6]naphthyridin-2-one;
[0322]
7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-1H-[1,6]naphthyri-
din-2-one; [0323]
7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,6]naphth-
yridin-2-one; [0324]
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butylamino}-1H-[1,6]naphthy-
ridin-2-one; and [0325]
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-4,4-dimethyl-1,4-di-
hydro-pyrido[4,3-d][1,3]oxazin-2-one.
[0326] This same set of specific embodiments further includes the
following compounds and their pharmaceutically acceptable salts:
[0327]
7-{4-[4-(7-Trifluoromethyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-d-
ihydro-1H-[1,8]naphthyridin-2-one; [0328]
7-{4-[4-(7-Trifluoromethyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1-
,8]naphthyridin-2-one; [0329]
7-(4-{4-[7-(2-Hydroxy-ethoxy)-naphthalen-1-yl]-piperazin-1-yl}-butoxy)-3,-
4-dihydro-1H-[1,8]naphthyridin-2-one; [0330]
7-(4-{4-[7-(2-Methoxy-ethoxy)-naphthalen-1-yl]-piperazin-1-yl}-butoxy)-3,-
4-dihydro-1H-[1,8]naphthyridin-2-one; [0331]
7-(4-{4-[7-(2-Amino-ethoxy)-naphthalen-1-yl]-piperazin-1-yl}-butoxy)-3,4--
dihydro-1H-[1,8]naphthyridin-2-one; [0332]
7-(4-{4-[7-(2-Dimethylamino-ethoxy)-naphthalen-1-yl]-piperazin-1-yl}-buto-
xy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0333]
7-(4-{4-[7-(2-Hydroxy-ethoxy)-naphthalen-1-yl]-piperazin-1-yl}-butoxy)-1H-
-[1,8]naphthyridin-2-one; [0334]
7-(4-{4-[7-(2-Methoxy-ethoxy)-naphthalen-1-yl]-piperazin-1-yi}-butoxy)-1H-
-[1,8]naphthyridin-2-one; [0335]
7-(4-{4-[7-(2-Amino-ethoxy)-naphthalen-1-yl]-piperazin-1-yl}-butoxy)-1H-[-
1,8]naphthyridin-2-one; [0336]
7-(4-{4-[7-(2-Dimethylamino-ethoxy)-naphthalen-1-yl]-piperazin-1-yl}-buto-
xy)-1H-[1,8]naphthyridin-2-one; [0337]
7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperidin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0338]
7-{4-[4-(2-Chloro-3-ethyl-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthy-
ridin-2-one; [0339]
7-{4-[4-(7,8-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one; [0340]
7-{4-[4-(7,8-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]na-
phthyridin-2-one; [0341]
7-{4-[4-(6,8-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one; [0342]
7-{4-[4-(6,8-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]na-
phthyridin-2-one; [0343]
7-{4-[4-(5,7-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one; [0344]
7-{4-[4-(5,7-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]na-
phthyridin-2-one; [0345]
7-{4-[4-(8-Trifluoromethyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-d-
ihydro-1H-[1,8]naphthyridin-2-one; [0346]
7-{4-[4-(8-Trifluoromethyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1-
,8]naphthyridin-2-one; [0347]
7-{4-[4-(2,2-Dimethyl-indan-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H--
[1,8]naphthyridin-2-one; [0348]
7-{4-[4-(2,2-Dimethyl-indan-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthy-
ridin-2-one; [0349]
7-{4-[4-(2,2-Difluoro-3-oxo-indan-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihyd-
ro-1H-[1,8]naphthyridin-2-one; [0350]
7-{4-[4-(2,2-Difluoro-3-oxo-indan-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]n-
aphthyridin-2-one; [0351]
7-{4-[4-(2,2-Dimethyl-3-oxo-indan-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihyd-
ro-1H-[1,8]naphthyridin-2-one; [0352]
7-{4-[4-(2,2-Dimethyl-3-oxo-indan-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]n-
aphthyridin-2-one; [0353]
7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-5-methyl-3,4-d-
ihydro-1H-[1,8]naphthyridin-2-one; [0354]
7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-5-methyl-1H-[1-
,8]naphthyridin-2-one; [0355]
7-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-5-methyl-3,4-d-
ihydro-1H-[1,8]naphthyridin-2-one; [0356]
7-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-5-methyl-1H-[1-
,8]naphthyridin-2-one; [0357]
6-Fluoro-7-{4-[4-(7-fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-d-
ihydro-1H-[1,8]naphthyridin-2-one; [0358]
6-Fluoro-7-{4-[4-(7-fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1-
,8]naphthyridin-2-one; [0359]
6-Fluoro-7-{4-[4-(8-fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-d-
ihydro-1H-[1,8]naphthyridin-2-one; [0360]
6-Fluoro-7-{4-[4-(8-fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1-
,8]naphthyridin-2-one; [0361]
7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3-
,4-dihydro-1H-[1,8]naphthyridin-2-one; [0362]
2-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3--
d]pyrimidin-7-one; [0363]
2-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3--
d]pyrimidin-7-one; [0364]
2-{4-[4-(7-Methoxy-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-
-d]pyrimidin-7-one; [0365]
2-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-5,8-dihydro-6H-
-pyrido[2,3-d]pyrimidin-7-one; [0366]
2-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-5,8-dihydro-6H-
-pyrido[2,3-d]pyrimidin-7-one; [0367]
2-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-py-
rido[2,3-d]pyrimidin-7-one; [0368]
2-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-4-methyl-8H-pyrido[-
2,3-d]pyrimidin-7-one; [0369]
2-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4-methyl-5,8-d-
ihydro-6H-pyrido[2,3-d]pyrimidin-7-one; [0370]
2-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-6-fluoro-4-methyl-8-
H-pyrido[2,3-d]pyrimidin-7-one; [0371]
6-Fluoro-2-{4-[4-(7-fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4-met-
hyl-8H-pyrido[2,3-d]pyrimidin-7-one; [0372]
6-Fluoro-2-{4-[4-(8-fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4-met-
hyl-8H-pyrido[2,3-d]pyrimidin-7-one; [0373]
4,4-Dimethyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-1,4-dihydro--
pyrido[2,3-d][1,3]oxazin-2-one; [0374]
6-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-4H-pyrido[2,3-b]pyrazin-3-
-one; [0375]
6-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-1,4-dihydro-2H-pyrido[2,3-
-b]pyrazin-3-one; [0376]
7-{3-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-propoxy}-3,4-dihydro-1-
H-[1,8]naphthyridin-2-one; [0377]
7-{3-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-propoxy}-1H-[1,8]napht-
hyridin-2-one; and [0378]
7-[5-(4-Naphthalen-1-yl-piperazin-1-yl)-pentyloxy]-3,4-dihydro-1H-[1,8]na-
phthyridin-2-one.
[0379] Another set of specific embodiments of the invention relate
to compounds of formula 1 and their pharmaceutically acceptable
salts, wherein at least one of the carbon atoms of the carbocyclic
ring AA that are not shared with the benzo ring of group (ii) has
been replaced, independently, by a nitrogen, oxygen, or sulfur
atom. These embodiments include the following compounds and their
pharmaceutically acceptable salts. Procedures for synthesis of each
of these compounds are illustrated in the Examples, below. [0380]
7-{4-[4-(2-Oxo-2,3-dihydro-benzooxazol-7-yl)-piperazin-1-yl]-butoxy}-3,4--
dihydro-1H-[1,8]naphthyridin-2-one; [0381]
7-{4-[4-(2,3-Dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-
-1H-[1,8]naphthyridin-2-one; [0382]
7-{4-[4-(2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy-
}-3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0383]
7-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyr-
idin-2-one; [0384]
7-{4-[4-(2,2-Dimethyl-2H-chromen-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one; [0385]
7-{4-[4-(2,2-Dimethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1-
H-[1,8]naphthyridin-2-one; [0386]
7-{4-[4-(Spiro[chromene-2,1'-cyclopentan]-8-yl)-piperazin-1-yl]-butoxy}-3-
,4-dihydro-1H-[1,8]naphthyridin-2-one; [0387]
7-{4-[4-(3,4-Dihydrospiro[chromene-2,1'-cyclopentan]-8-yl)-piperazin-1-yl-
]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0388]
7-{4-[4-(2-Methyl-2H-chromen-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0389]
7-{4-[4-(2-Methyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1-
,8]naphthyridin-2-one; [0390]
7-{4-[4-(2,3-Dihydro-benzofuran-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-
-1H-[1,8]naphthyridin-2-one; [0391]
7-{4-[4-(1,3-Dihydro-isobenzofuran-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihy-
dro-1H-[1,8]naphthyridin-2-one; [0392]
7-[4-(4-Chroman-5-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyr-
idin-2-one; [0393]
7-[4-(4-Isochroman-5-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]napht-
hyridin-2-one; [0394]
7-[4-(4-Isochroman-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]napht-
hyridin-2-one; [0395]
7-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-3,4-d-
ihydro-1H-[1,8]naphthyridin-2-one; [0396]
7-{4-[4-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-piperazin-1-yl]-butox-
y}-3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0397]
7-{4-[4-(2,2,3,3-Tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-
-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0398]
7-{4-[4-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-piperazin-1-yl]-butoxy}-3,4--
dihydro-1H-[1,8]naphthyridin-2-one; [0399]
7-{4-[4-(4-Oxo-chroman-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]-
naphthyridin-2-one; [0400]
7-{4-[4-(3,3-Dimethyl-4-oxo-chroman-8-yl)-piperazin-1-yl]-butoxy}-3,4-dih-
ydro-1H-[1,8]naphthyridin-2-one; [0401]
7-{4-[4-(3,3-Dimethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1-
H-[1,8]naphthyridin-2-one; [0402]
7-[4-(4-Benzofuran-7-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]napht-
hyridin-2-one; [0403]
7-{4-[4-(1H-Indol-7-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]napht-
hyridin-2-one; [0404]
7-{4-[4-(1H-Indol-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]napht-
hyridin-2-one; [0405]
7-{4-[4-(1-Methyl-1H-indol-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[-
1,8]naphthyridin-2-one; [0406]
7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8-
]naphthyridin-2-one; [0407]
7-[4-(4-Benzo[1,2,5]oxadiazol-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0408]
7-[4-(4-Benzo[1,2,5]thiadiazol-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1-
H-[1,8]naphthyridin-2-one; [0409]
7-{4-[4-(2-Trifluoromethyl-3H-benzoimidazol-4-yl)-piperazin-1-yl]-butoxy}-
-3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0410]
7-{4-[4-(1-Methyl-1,2,3,4-tetrahydro-quinolin-5-yl)-piperazin-1-yl]-butox-
y}-3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0411]
7-{4-[4-(1-Ethyl-1,2,3,4-tetrahydro-quinolin-5-yl)-piperazin-1-yl]-butoxy-
}-3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0412]
7-[4-(4-Quinolin-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthy-
ridin-2-one; [0413]
7-[4-(4-Quinolin-5-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthy-
ridin-2-one; [0414]
7-[4-(4-Isoquinolin-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naph-
thyridin-2-one; [0415]
7-[4-(4-Isoquinolin-5-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naph-
thyridin-2-one; [0416]
7-{4-[4-(3-Fluoro-quinolin-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[-
1,8]naphthyridin-2-one; [0417]
7-{4-[4-(3-Fluoro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[-
1,8]naphthyridin-2-one; [0418]
7-{4-[4-(2-Methyl-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[-
1,8]naphthyridin-2-one; [0419]
7-{4-[4-(2-Methoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H--
[1,8]naphthyridin-2-one; [0420]
7-{4-[4-(2-Ethoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[-
1,8]naphthyridin-2-one; [0421]
7-{4-[4-(2-Methoxy-quinolin-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H--
[1,8]naphthyridin-2-one; [0422]
7-[4-(4-Quinoxalin-5-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]napht-
hyridin-2-one; [0423]
7-{4-[4-(2-Dimethylamino-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihyd-
ro-1H-[1,8]naphthyridin-2-one; [0424]
7-{4-[4-(2-Methylamino-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-
-1H-[1,8]naphthyridin-2-one; [0425]
7-{4-[4-(2-Oxo-1,2-dihydro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dih-
ydro-1H-[1,8]naphthyridin-2-one; [0426]
7-{4-[4-(2-Oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazin-1-yl]-butoxy}--
3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0427]
7-{4-[4-(1-Methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazin-1-yl]-
-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0428]
7-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one;
[0429]
7-{4-[4-(2,2-Dimethyl-2H-chromen-8-yl)-piperazin-1-yl]-butoxy}-1H-
-[1,8]naphthyridin-2-one; [0430]
7-{4-[4-(2,2-Dimethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]napht-
hyridin-2-one; [0431]
7-{4-[4-(2-Methyl-2H-chromen-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0432]
7-{4-[4-(2-Methyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyri-
din-2-one; [0433]
7-{4-[4-(Spiro[chromene-2,1'-cyclopentan]-8-yl)-piperazin-1-yl]-butoxy}-1-
H-[1,8]naphthyridin-2-one; [0434]
7-{4-[4-(3,4-Dihydrospiro[chromene-2,1'-cyclopentan]-8-yl)-piperazin-1-yl-
]-butoxy}-1H-[1,8]naphthyridin-2-one; [0435]
7-{4-[4-(2,3-Dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]nap-
hthyridin-2-one; [0436]
7-{4-[4-(2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy-
}-1H-[1,8]naphthyridin-2-one; [0437]
7-[4-(4-Chroman-5-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one;
[0438]
7-{4-[4-(2,3-Dihydro-benzofuran-4-yl)-piperazin-1-yl]-butoxy}-1H--
[1,8]naphthyridin-2-one; [0439]
7-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-1H-[1-
,8]naphthyridin-2-one; [0440]
7-{4-[4-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-piperazin-1-yl]-butoxy}-1H-[-
1,8]naphthyridin-2-one; [0441]
7-{4-[4-(1,3-Dihydro-isobenzofuran-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]-
naphthyridin-2-one; [0442]
7-{4-[4-(4-Oxo-chroman-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-
-2-one; [0443]
7-{4-[4-(3,3-Dimethyl-4-oxo-chroman-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8-
]naphthyridin-2-one; [0444]
7-{4-[4-(3,3-Dimethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]napht-
hyridin-2-one; [0445]
7-[4-(4-Isochroman-5-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-on-
e; [0446]
7-[4-(4-Isochroman-8-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-on-
e; [0447]
7-{4-[4-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-piperazin-1-yl]-butox-
y}-1H-[1,8]naphthyridin-2-one; [0448]
7-[4-(4-Quinolin-8-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one;
[0449]
7-[4-(4-Quinolin-5-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyrid-
in-2-one; [0450]
7-[4-(4-Quinoxalin-5-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-on-
e; [0451]
7-{4-[4-(1H-Indol-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-on-
e; [0452]
7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridi-
n-2-one; [0453]
7-[4-(4-Benzofuran-7-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-on-
e; [0454]
7-{4-[4-(1-Acetyl-1,2,3,4-tetrahydro-quinolin-5-yl)-piperazin-1-yl]-butox-
y}-1H-[1,8]naphthyridin-2-one; [0455]
7-{4-[4-(1-Methyl-1,2,3,4-tetrahydro-quinolin-5-yl)-piperazin-1-yl]-butox-
y}-1H-[1,8]naphthyridin-2-one; [0456]
7-{4-[4-(1-Ethyl-1,2,3,4-tetrahydro-quinolin-5-yl)-piperazin-1-yl]-butoxy-
}-1H-[1,8]naphthyridin-2-one; [0457]
7-{4-[4-(2-Methoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthy-
ridin-2-one; [0458]
7-{4-[4-(2-Ethoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyr-
idin-2-one; [0459]
7-{4-[4-(2-Dimethylamino-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]n-
aphthyridin-2-one; [0460]
7-{4-[4-(2-Methylamino-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]nap-
hthyridin-2-one; [0461]
7-{4-[4-(3-Fluoro-quinolin-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyr-
idin-2-one; [0462]
7-{4-[4-(3-Fluoro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyr-
idin-2-one; [0463]
7-{4-[4-(2-Oxo-1,2-dihydro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8-
]naphthyridin-2-one; [0464]
7-{4-[4-(2-Oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazin-1-yl]-butoxy}--
1H-[1,8]naphthyridin-2-one; [0465]
7-{4-[4-(1-Methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazin-1-yl]-
-butoxy}-1H-[1,8]naphthyridin-2-one; [0466]
7-[4-(4-Benzo[1,2,5]oxadiazol-4-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphth-
yridin-2-one; [0467]
7-[4-(4-Benzo[1,2,5]thiadiazol-4-yl-piperazin-1-yl)-butoxy]-1H-[1,8]napht-
hyridin-2-one; [0468]
7-{4-[4-(2-Trifluoromethyl-3H-benzoimidazol-4-yl)-piperazin-1-yl]-butoxy}-
-1H-[1,8]naphthyridin-2-one; [0469]
4,4-Dimethyl-7-[4-(4-quinolin-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0470]
7-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-4,4-d-
imethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0471]
4,4-Dimethyl-7-{4-[4-(2-oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazin-1-
-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0472]
4,4-Dimethyl-7-{4-[4-(2-oxo-1,2-dihydro-quinolin-8-yl)-piperazin-1-yl]-bu-
toxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0473]
7-[4-(4-Benzofuran-7-yl-piperazin-1-yl)-butoxy]-4,4-dimethyl-3,4-dihydro--
1H-[1,8]naphthyridin-2-one; [0474]
7-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-4,4-dimethyl-3,4-dihydro-1H--
[1,8]naphthyridin-2-one; [0475]
6-Fluoro-7-[4-(4-quinolin-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,-
8]naphthyridin-2-one; [0476]
6-Fluoro-7-[4-(4-isoquinolin-5-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H--
[1,8]naphthyridin-2-one; [0477]
7-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-1H-pyrido[2,3-d]pyrimidin-2--
one; [0478]
7-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-pyrido[2,3-d]-
pyrimidin-2-one; [0479]
7-{4-[4-(2,3-Dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-
-1H-pyrido[2,3-d]pyrimidin-2-one; [0480]
7-{4-[4-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-piperazin-1-yl]-butox-
y}-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one; [0481]
6-{4-[4-(2-Methyl-quinolin-8-yl)-piperazin-1-yl]-butoxy}-4H-pyrido[3,2-b]-
[1,4]oxazin-3-one; [0482]
6-[4-(4-Quinolin-8-yl-piperazin-1-yl)-butoxy]-4H-pyrido[3,2-b][1,4]oxazin-
-3-one; [0483]
6-{4-[4-(2-Oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazin-1-yl]-butoxy}--
4H-pyrido[3,2-b][1,4]oxazin-3-one; [0484]
6-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-4H-pyrido[3,2-b][1,4]oxazin--
3-one; [0485]
6-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-4H-py-
rido[3,2-b][1,4]oxazin-3-one; [0486]
2-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-8H-py-
rido[2,3-d]pyrimidin-7-one; [0487]
2-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7--
one; [0488]
2-[4-(4-Quinolin-8-yl-piperazin-1-yl)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-
-one; [0489]
2-{4-[4-(2,3-Dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2-
,3-d]pyrimidin-7-one; [0490]
2-{4-[4-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-piperazin-1-yl]-butox-
y}-8H-pyrido[2,3-d]pyrimidin-7-one; [0491]
2-{4-[4-(2,2-Dimethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-
-d]pyrimidin-7-one; [0492]
2-{4-[4-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-piperazin-1-yl]-butoxy}-8H-p-
yrido[2,3-d]pyrimidin-7-one; [0493]
2-{4-[4-(2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy-
}-8H-pyrido[2,3-d]pyrimidin-7-one; [0494]
2-{4-[4-(2-Methyl-quinolin-8-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]-
pyrimidin-7-one; [0495]
2-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-4-met-
hyl-8H-pyrido[2,3-d]pyrimidin-7-one; [0496]
2-{4-[4-(2,3-Dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-
-pyrido[2,3-d]pyrimidin-7-one; [0497]
2-[4-(4-Benzofuran-7-yl-piperazin-1-yl)-butoxy]-4-methyl-8H-pyrido[2,3-d]-
pyrimidin-7-one; [0498]
2-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-4-methyl-8H-pyrido[2,3-d]pyr-
imidin-7-one; [0499]
4-Methyl-2-{4-[4-(2-oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazin-1-yl]-
-butoxy}-8H-pyrido[2,3-d]pyrimidin-7-one; [0500]
4-Methyl-2-[4-(4-quinolin-8-yl-piperazin-1-yl)-butoxy]-8H-pyrido[2,3-d]py-
rimidin-7-one; [0501]
7-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,6]naphthyr-
idin-2-one; [0502]
7-{4-[4-(2,3-Dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-
-1H-[1,6]naphthyridin-2-one; [0503]
7-{4-[4-(2,2,3,3-Tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-
-1-yl]-butoxy}-3,4-dihydro-1H-[1,6]naphthyridin-2-one; [0504]
7-{4-[4-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-piperazin-1-yl]-butoxy}-3,4--
dihydro-1H-[1,6]naphthyridin-2-one; [0505]
7-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-3,4-d-
ihydro-1H-[1,6]naphthyridin-2-one; [0506]
7-{4-[4-(2,3-Dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-1H-[1,6]nap-
hthyridin-2-one; [0507]
7-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-1H-[1-
,6]naphthyridin-2-one; [0508]
7-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-1H-[1,6]naphthyridin-2-one;
and [0509]
7-{4-[4-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-piperazin-1-yl]-butoxy}-1H-[-
1,6]naphthyridin-2-one.
[0510] This same set of specific embodiments further includes the
following compounds and their pharmaceutically acceptable salts:
[0511]
7-(4-{4-[2-(2-Hydroxy-ethoxy)-quinolin-8-yl]-piperazin-1-yl}-butoxy)-3,4--
dihydro-1H-[1,8]naphthyridin-2-one; [0512]
7-(4-{4-[2-(2-Methoxy-ethoxy)-quinolin-8-yl]-piperazin-1-yl}-butoxy)-3,4--
dihydro-1H-[1,8]naphthyridin-2-one; [0513]
7-(4-{4-[2-(2-Amino-ethoxy)-quinolin-8-yl]-piperazin-1-yl}-butoxy)-3,4-di-
hydro-1H-[1,8]naphthyridin-2-one; [0514]
7-(4-{4-[2-(2-Dimethylamino-ethoxy)-quinolin-8-yl]-piperazin-1-yl}-butoxy-
)-3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0515]
7-(4-{4-[2-(2-Hydroxy-ethoxy)-quinolin-8-yl]-piperazin-1-yl}-butoxy)-1H-[-
1,8]naphthyridin-2-one; [0516]
7-(4-{4-[2-(2-Methoxy-ethoxy)-quinolin-8-yl]-piperazin-1-yl}-butoxy)-1H-[-
1,8]naphthyridin-2-one; [0517]
7-(4-{4-[2-(2-Amino-ethoxy)-quinolin-8-yl]-piperazin-1-yl}-butoxy)-1H-[1,-
8]naphthyridin-2-one; [0518]
7-(4-{4-[2-(2-Dimethylamino-ethoxy)-quinolin-8-yl]-piperazin-1-yl}-butoxy-
)-1H-[1,8]naphthyridin-2-one; [0519]
7-{4-[4-(2-Hydroxymethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one; [0520]
7-{4-[4-(2-Aminomethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro--
1H-[1,8]naphthyridin-2-one; [0521]
7-{4-[4-(3-Hydroxy-2,2-dimethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-3,4-
-dihydro-1H-[1,8]naphthyridin-2-one; [0522]
7-{4-[4-(2,2-Dimethyl-3-oxo-chroman-8-yl)-piperazin-1-yl]-butoxy}-3,4-dih-
ydro-1H-[1,8]naphthyridin-2-one; [0523]
7-{4-[4-(2-Hydroxymethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]na-
phthyridin-2-one; [0524]
7-{4-[4-(2-Aminomethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naph-
thyridin-2-one; [0525]
7-{4-[4-(3-Hydroxy-2,2-dimethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-1H--
[1,8]naphthyridin-2-one; [0526]
7-{4-[4-(2,2-Dimethyl-3-oxo-chroman-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8-
]naphthyridin-2-one; [0527]
7-{4-[4-(3-Methyl-chroman-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1-
,8]naphthyridin-2-one; [0528]
7-{4-[4-(3-Hydroxymethyl-chroman-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one; [0529]
7-{4-[4-(3-Aminomethyl-chroman-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro--
1H-[1,8]naphthyridin-2-one; [0530]
5-{4-[4-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyl]-piper-
azin-1-yl}-chroman-3-carbonitrile; [0531]
7-{4-[4-(3,3-Dimethyl-4-oxo-chroman-5-yl)-piperazin-1-yl]-butoxy}-3,4-dih-
ydro-1H-[1,8]naphthyridin-2-one; [0532]
7-{4-[4-(3,3-Dimethyl-chroman-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1-
H-[1,8]naphthyridin-2-one; [0533]
7-{4-[4-(4-Methyl-chroman-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1-
,8]naphthyridin-2-one; [0534]
7-{4-[4-(3-Methyl-chroman-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyri-
din-2-one; [0535]
7-{4-[4-(3-Hydroxymethyl-chroman-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]na-
phthyridin-2-one; [0536]
7-{4-[4-(3-Aminomethyl-chroman-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naph-
thyridin-2-one; [0537]
5-{4-[4-(7-Oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyl]-piperazin-1--
yl}-chroman-3-carbonitrile; [0538]
7-{4-[4-(3,3-Dimethyl-4-oxo-chroman-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,8-
]naphthyridin-2-one; [0539]
7-{4-[4-(3,3-Dimethyl-chroman-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]napht-
hyridin-2-one; [0540]
7-{4-[4-(4-Methyl-chroman-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyri-
din-2-one; [0541]
7-[3-(4-Chroman-8-yl-piperazin-1-yl)-propoxy]-3,4-dihydro-1H-[1,8]naphthy-
ridin-2-one; [0542]
7-[3-(4-Chroman-8-yl-piperazin-1-yl)-propoxy]-1H-[1,8]naphthyridin-2-one;
[0543]
7-{4-[4-(1,2,3,4-Tetrahydro-isoquinolin-8-yl)-piperazin-1-yl]-bu-
toxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one; [0544]
7-{4-[4-(1,2,3,4-Tetrahydro-isoquinolin-8-yl)-piperazin-1-yl]-butoxy}-1H--
[1,8]naphthyridin-2-one; [0545]
7-{4-[4-(1,2,3,4-Tetrahydro-isoquinolin-5-yl)-piperazin-1-yl]-butoxy}-3,4-
-dihydro-1H-[1,8]naphthyridin-2-one; [0546]
7-{4-[4-(1,2,3,4-Tetrahydro-isoquinolin-5-yl)-piperazin-1-yl]-butoxy}-1H--
[1,8]naphthyridin-2-one; [0547]
7-{4-[4-(2-Ethyl-2,3-dihydro-1H-isoindol-4-yl)-piperazin-1-yl]-butoxy}-3,-
4-dihydro-1H-[1,8]naphthyridin-2-one; [0548]
8-{4-[4-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyl]-piper-
azin-1-yl}-quinoline-2-carbonitrile; [0549]
8-{4-[4-(7-Oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyl]-piperazin-1--
yl}-quinoline-2-carbonitrile; [0550]
7-{4-[4-(3-Methoxy-isoquinolin-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro--
1H-[1,8]naphthyridin-2-one; [0551]
7-{4-[4-(3-Methoxy-isoquinolin-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naph-
thyridin-2-one; [0552]
5-{4-[4-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyl]-piper-
azin-1-yl}-quinoline-3-carbonitrile; [0553]
5-{4-[4-(7-Oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyl]-piperazin-1--
yl}-quinoline-3-carbonitrile; [0554]
7-{4-[4-(3-Chloro-quinolin-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[-
1,8]naphthyridin-2-one; and [0555]
7-{4-[4-(3-Chloro-quinolin-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyr-
idin-2-one.
[0556] The following compounds and their pharmaceutically
acceptable salts are preferred embodiments of the compound of
formula 1: [0557]
7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]napht-
hyridin-2-one; [0558]
7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-on-
e; [0559]
7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0560]
7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0561]
7-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0562]
7-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0563]
7-{4-[4-(2-Methoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H--
[1,8]naphthyridin-2-one; [0564]
7-{4-[4-(2-Methoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthy-
ridin-2-one; [0565]
2-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-py-
rido[2,3-d]pyrimidin-7-one; [0566]
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8-
]naphthyridin-2-one; [0567]
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridi-
n-2-one; [0568]
7-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4--
dihydro-1H-[1,8]naphthyridin-2-one; [0569]
7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyrid-
in-2-one; [0570]
7-{4-[4-(6,7-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one; [0571]
7-{4-[4-(6,7-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]na-
phthyridin-2-one; [0572]
4-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyr-
idin-2-one; [0573]
4,4-Dimethyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro--
1H-[1,8]naphthyridin-2-one; [0574]
5-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[-
1,8]naphthyridin-2-one; [0575]
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-5-methyl-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one; [0576]
6-Fluoro-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[-
1,8]naphthyridin-2-one; [0577]
7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8-
]naphthyridin-2-one; [0578]
7-[4-(4-Benzo[1,2,5]thiadiazol-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1-
H-[1,8]naphthyridin-2-one; [0579]
7-[4-(4-Benzo[1,2,5]thiadiazol-4-yl-piperazin-1-yl)-butoxy]-1H-[1,8]napht-
hyridin-2-one; [0580]
7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-pyrido[2,3-
-d]pyrimidin-2-one; [0581]
3-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-p-
yrido[2,3-d]pyrimidin-2-one; [0582]
7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-pyrido[2,3-d]pyrimidin-2-one; [0583]
7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,6]naphthyridin-2-one; [0584]
2-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3--
d]pyrimidin-7-one; and [0585]
6-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4H-pyrido[3,2--
b][1,4]oxazin-3-one
[0586] The following compounds and their pharmaceutically
acceptable salts are particularly preferred embodiments of the
compound of formula 1: [0587]
7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]napht-
hyridin-2-one; [0588]
7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-on-
e; [0589]
7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0590]
7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0591]
7-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one; [0592]
7-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one; [0593]
7-{4-[4-(2-Methoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H--
[1,8]naphthyridin-2-one; [0594]
7-{4-[4-(2-Methoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthy-
ridin-2-one; and [0595]
2-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-py-
rido[2,3-d]pyrimidin-7-one.
[0596] Compounds of the formula 1 may contain chiral centers and
therefore may exist in different enantiomeric and diastereomeric
forms. This invention relates to all optical isomers and all
stereoisomers of compounds of the formula 1, both as racemic
mixtures and as individual enantiomers and diastereoisomers of such
compounds, and mixtures thereof, and to all pharmaceutical
compositions and methods of treatment defined above that contain or
employ them, respectively. Individual isomers can be obtained by
known methods, such as optical resolution, fractional
crystallization, optically selective reaction, or chromatographic
separation in the preparation of the final product or its
intermediate. Individual enantiomers of the compounds of formula 1
may have advantages, as compared with the racemic mixtures of these
compounds, in the treatment of various disorders or conditions.
[0597] In so far as the compounds of formula 1 are basic compounds,
they are all capable of forming a wide variety of different salts
with various inorganic and organic acids. Although such salts must
be pharmaceutically acceptable for administration to animals, it is
often desirable in practice to initially isolate the base compound
from the reaction mixture as a pharmaceutically unacceptable salt
and then simply convert to the free base compound by treatment with
an alkaline reagent and thereafter convert the free base to a
pharmaceutically acceptable acid addition salt. The acid addition
salts of the base compounds of this invention are readily prepared
by treating the base compound with a substantially equivalent
amount of the chosen mineral or organic acid in an aqueous solvent
or in a suitable organic solvent, such as methanol or ethanol. Upon
careful evaporation of the solvent, the desired solid salt is
readily obtained. The acids which are used to prepare the
pharmaceutically acceptable acid addition salts of the
aforementioned base compounds of this invention are those which
form non-toxic acid addition salts, i.e., salts containing
pharmaceutically acceptable anions, such as the hydrochloride,
hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate
or acid phosphate, acetate, lactate, citrate or acid citrate,
tartrate or bi-tartrate, succinate, maleate, fumarate, gluconate,
saccharate, benzoate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
[0598] The present invention also includes isotopically labeled
compounds, which are identical to those of formula 1, but for the
fact that one or more atoms are replaced by an atom having an
atomic mass or mass number different from the atomic mass or mass
number usually found in nature. Examples of isotopes that can be
incorporated into compounds of the present invention include
isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,
sulfur, fluorine and chlorine, such as .sup.2H, .sup.3H, .sup.13C,
.sup.11C, .sup.14C, .sup.15N, .sup.18O, .sup.17O, .sup.31P,
.sup.32P, .sup.35S, .sup.18F, and .sup.36Cl, respectively.
Compounds of the present invention, prodrugs thereof, and
pharmaceutically acceptable salts of said compounds or of said
prodrugs which contain the aforementioned isotopes and/or other
isotopes of other atoms are within the scope of this invention.
Certain isotopically labeled compounds of the present invention,
for example those into which radioactive isotopes such as .sup.3H
and .sup.14C are incorporated, are useful in drug and/or substrate
tissue distribution assays. Tritiated, i.e., .sup.3H, and
carbon-14, i.e., .sup.14C, isotopes are particularly preferred for
their ease of preparation and detectability. Further, substitution
with heavier isotopes such as deuterium, i.e., .sup.2H, can afford
certain therapeutic advantages resulting from greater metabolic
stability, for example increased in vivo half-life or reduced
dosage requirements and, hence, may be preferred in some
circumstances. Isotopically labeled compounds of formula 1 and
prodrugs thereof can generally be prepared by carrying out the
procedures disclosed in the Schemes and/or in the Examples below,
by substituting a readily available isotopically labeled reagent
for a non-isotopically labeled reagent.
[0599] In one specific embodiment of the method of the present
invention of treating a disorder or condition, the disorder or
condition that is being treated is selected from major depression,
single episode depression, recurrent depression, child abuse
induced depression, postpartum depression, dysthymia, cyclothymia
and bipolar disorder.
[0600] Another more specific embodiment of this invention relates
to the above method wherein the disorder or condition that is being
treated is selected from schizophrenia, schizoaffective disorder,
delusional disorder, substance-induced psychotic disorder, brief
psychotic disorder, shared psychotic disorder, psychotic disorder
due to a general medical condition, and schizophreniform
disorder.
[0601] Another more specific embodiment of this invention relates
to the above method wherein the disorder or condition that is being
treated is selected from autism, pervasive development disorder,
speech impediments such as stuttering, and attention deficit
hyperactivity disorder.
[0602] Another more specific embodiment of this invention relates
to the above method wherein the disorder or condition that is being
treated is selected from generalized anxiety disorder, panic
disorder, obsessive-compulsive disorder, post-traumatic stress
disorder, and phobias, including social phobia, agoraphobia, and
specific phobias.
[0603] Another more specific embodiment of this invention relates
to the above method wherein the disorder or condition that is being
treated is selected from movement disorders such as akinesias,
dyskinesias, including familial paroxysmal dyskinesias,
spasticities, Tourette's syndrome, Scott syndrome, PALSYS and
akinetic-rigid syndrome; and extra-pyramidal movement disorders
such as medication-induced movement disorders, for example,
neuroleptic-induced Parkinsonism, neuroleptic malignant syndrome,
neuroleptic-induced acute dystonia, neuroleptic-induced acute
akathisia, neuroleptic-induced tardive dyskinesia and
medication-induced postural tremor.
[0604] Another more specific embodiment of this invention relates
to the above method wherein the disorder or condition that is being
treated is selected from delirium, dementia, and amnestic and other
cognitive or neurodegenerative disorders, such as Parkinson's
disease (PD), Huntington's disease (HD), Alzheimer's disease,
senile dementia, dementia of the Alzheimer's type, memory disorder,
vascular dementia, and other dementias, for example, due to HIV
disease, head trauma, Parkinson's disease, Huntington's disease,
Pick's disease, Creutzfeldt-Jakob disease, or due to multiple
etiologies.
[0605] Another more specific embodiment of this invention relates
to the above method wherein the compound of formula 1 is
administered to a human for the treatment of any two or more
comorbid disorders or conditions selected from those disorders and
conditions referred to in any of the above methods.
[0606] For the treatment of depression, anxiety, schizophrenia or
any of the other disorders and conditions referred to above in the
descriptions of the methods and pharmaceutical compositions of this
invention, the novel compounds of this invention can be used in
conjunction with one or more other antidepressants or anti-anxiety
agents. Examples of classes of antidepressants that can be used in
combination with the active compounds of this invention include
norepinephrine reuptake inhibitors, selective serotonin reuptake
inhibitors (SSRIs), NK-1 receptor antagonists, monoamine oxidase
inhibitors (MAOs), reversible inhibitors of monoamine oxidase
(RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs),
corticotropin releasing factor (CRF) antagonists,
.alpha.-adrenoreceptor antagonists, and atypical antidepressants.
Suitable norepinephrine reuptake inhibitors include tertiary amine
tricyclics and secondary amine tricyclics. Suitable tertiary amine
tricyclics and secondary amine tricyclics include amitriptyline,
clomipramine, doxepin, imipramine, trimipramine, dothiepin,
butripyline, iprindole, lofepramine, nortriptyline, protriptyline,
amoxapine, desipramine and maprotiline. Suitable selective
serotonin reuptake inhibitors include fluoxetine, fluvoxamine,
paroxetine and sertraline. Examples of monoamine oxidase inhibitors
include isocarboxazid, pheneizine, and tranylcyclopramine. Suitable
reversible inhibitors of monoamine oxidase include moclobemide.
Suitable serotonin and noradrenaline reuptake inhibitors of use in
the present invention include venlafaxine. Suitable CRF antagonists
include those compounds described in International Patent
Application Nos. WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676
and WO 94/13677. Suitable atypical anti-depressants include
bupropion, lithium, nefazodone, trazodone and viloxazine. Suitable
NK-1 receptor antagonists include those referred to in World Patent
Publication WO 01/77100.
[0607] Suitable classes of anti-anxiety agents that can be used in
combination with the active compounds of this invention include
benzodiazepines and serotonin 1A (5-HT.sub.1A) agonists or
antagonists, especially 5-HT.sub.1A partial agonists, and
corticotropin releasing factor (CRF) antagonists. Suitable
benzodiazepines include alprazolam, chlordiazepoxide, clonazepam,
chlorazepate, diazepam, halazepam, lorazepam, oxazepam, and
prazepam. Suitable 5-HT.sub.1A receptor agonists or antagonists
include buspirone, flesinoxan, gepirone and ipsapirone.
[0608] This invention also relates to a method of treating a
disorder or condition selected from single episodic or recurrent
major depressive disorders, dysthymic disorders, depressive
neurosis and neurotic depression, melancholic depression including
anorexia, weight loss, insomnia, early morning waking or
psychomotor retardation; atypical depression (or reactive
depression) including increased appetite, hypersomnia, psychomotor
agitation or irritability, seasonal affective disorder and
pediatric depression; bipolar disorders or manic depression, for
example, bipolar I disorder, bipolar II disorder and cyclothymic
disorder; conduct disorder; disruptive behavior disorder; attention
deficit hyperactivity disorder (ADHD); behavioral disturbances
associated with mental retardation, autistic disorder, and conduct
disorder; anxiety disorders such as panic disorder with or without
agoraphobia, agoraphobia without history of panic disorder,
specific phobias, for example, specific animal phobias, social
anxiety, social phobia, obsessive-compulsive disorder, stress
disorders including post-traumatic stress disorder and acute stress
disorder, and generalized anxiety disorders; borderline personality
disorder; schizophrenia and other psychotic disorders, for example,
schizophreniform disorders, schizoaffective disorders, delusional
disorders, brief psychotic disorders, shared psychotic disorders,
psychotic disorders with delusions or hallucinations, psychotic
episodes of anxiety, anxiety associated with psychosis, psychotic
mood disorders such as severe major depressive disorder; mood
disorders associated with psychotic disorders such as acute mania
and depression associated with bipolar disorder; mood disorders
associated with schizophrenia; delirium, dementia, and amnestic and
other cognitive or neurodegenerative disorders, such as Parkinson's
disease (PD), Huntington's disease (HD), Alzheimer's disease,
senile dementia, dementia of the Alzheimer's type, memory
disorders, loss of executive function, vascular dementia, and other
dementias, for example, due to HIV disease, head trauma,
Parkinson's disease, Huntington's disease, Pick's disease,
Creutzfeldt-Jakob disease, or due to multiple etiologies; movement
disorders such as akinesias, dyskinesias, including familial
paroxysmal dyskinesias, spasticities, Toureffe's syndrome, Scott
syndrome, PALSYS and akinetic-rigid syndrome; extra-pyramidal
movement disorders such as medication-induced movement disorders,
for example, neuroleptic-induced Parkinsonism, neuroleptic
malignant syndrome, neuroleptic-induced acute dystonia,
neuroleptic-induced acute akathisia, neuroleptic-induced tardive
dyskinesia and medication-induced postural tremor; chemical
dependencies and addictions (e.g., dependencies on, or addictions
to, alcohol, heroin, cocaine, benzodiazepines, nicotine, or
phenobarbitol) and behavioral addictions such as an addiction to
gambling; and ocular disorders such as glaucoma and ischemic
retinopathy in a mammal in need of such treatment, including a
human, comprising administering to said mammal:
[0609] (a) a compound of the formula 1, or a pharmaceutically
acceptable salt thereof; and
[0610] (b) another pharmaceutically active compound that is an
antidepressant or anti-anxiety agent, or a pharmaceutically
acceptable salt thereof;
[0611] wherein the active compounds "a" and "b" are present in
amounts that render the combination effective in treating such
disorder or condition.
[0612] A more specific embodiment of this invention relates to the
above method wherein the disorder or condition that is being
treated is selected from major depression, single episode
depression, recurrent depression, child abuse induced depression,
postpartum depression, dysthymia, cyclothymia and bipolar
disorder.
[0613] Another more specific embodiment of this invention relates
to the above method wherein the disorder or condition that is being
treated is selected from schizophrenia, schizoaffective disorder,
delusional disorder, substance-induced psychotic disorder, brief
psychotic disorder, shared psychotic disorder, psychotic disorder
due to a general medical condition, and schizophreniform
disorder.
[0614] Another more specific embodiment of this invention relates
to the above method wherein the disorder or condition that is being
treated is selected from autism, pervasive development disorder,
and attention deficit hyperactivity disorder (ADHD).
[0615] Another more specific embodiment of this invention relates
to the above method wherein the disorder or condition that is being
treated is selected from generalized anxiety disorder, panic
disorder, obsessive-compulsive disorder, post-traumatic stress
disorder, and phobias, including social phobia, agoraphobia, and
specific phobias.
[0616] Another more specific embodiment of this invention relates
to the above method wherein the disorder or condition that is being
treated is selected from movement disorders such as akinesias,
dyskinesias, including familial paroxysmal dyskinesias,
spasticities, Tourette's syndrome, Scott syndrome, PALSYS and
akinetic-rigid syndrome; and extra-pyramidal movement disorders
such as medication-induced movement disorders, for example,
neuroleptic-induced Parkinsonism, neuroleptic malignant syndrome,
neuroleptic-induced acute dystonia, neuroleptic-induced acute
akathisia, neuroleptic-induced tardive dyskinesia and
medication-induced postural tremor.
[0617] Another more specific embodiment of this invention relates
to the above method wherein the disorder or condition that is being
treated is selected from delirium, dementia, and amnestic and other
cognitive or neurodegenerative disorders, such as Parkinson's
disease (PD), Huntington's disease (HD), Alzheimer's disease,
senile dementia, dementia of the Alzheimer's type, memory
disorders, loss of executive function, vascular dementia, and other
dementias, for example, due to HIV disease, head trauma,
Parkinson's disease, Huntington's disease, Pick's disease,
Creutzfeldt-Jakob disease, or due to multiple etiologies.
[0618] Another more specific embodiment of this invention relates
to the above method wherein the compound of formula 1 and the
additional antidepressant or anti-anxiety agent are administered to
a human for the treatment of any two or more comorbid disorders or
conditions selected from those disorders and conditions referred to
in any of the above methods.
[0619] This invention also relates to a pharmaceutical composition
for treating a disorder or condition selected from single episodic
or recurrent major depressive disorders, dysthymic disorders,
depressive neurosis and neurotic depression, melancholic depression
including anorexia, weight loss, insomnia, early morning waking or
psychomotor retardation; atypical depression (or reactive
depression) including increased appetite, hypersomnia, psychomotor
agitation or irritability, seasonal affective disorder and
pediatric depression; bipolar disorders or manic depression, for
example, bipolar I disorder, bipolar II disorder and cyclothymic
disorder; conduct disorder; disruptive behavior disorder; attention
deficit hyperactivity disorder (ADHD); behavioral disturbances
associated with mental retardation, autistic disorder, and conduct
disorder; anxiety disorders such as panic disorder with or without
agoraphobia, agoraphobia without history of panic disorder,
specific phobias, for example, specific animal phobias, social
anxiety, social phobia, obsessive-compulsive disorder, stress
disorders including post-traumatic stress disorder and acute stress
disorder, and generalized anxiety disorders; borderline personality
disorder; schizophrenia and other psychotic disorders, for example,
schizophreniform disorders, schizoaffective disorders, delusional
disorders, brief psychotic disorders, shared psychotic disorders,
psychotic disorders with delusions or hallucinations, psychotic
episodes of anxiety, anxiety associated with psychosis, psychotic
mood disorders such as severe major depressive disorder; mood
disorders associated with psychotic disorders such as acute mania
and depression associated with bipolar disorder; mood disorders
associated with schizophrenia; delirium, dementia, and amnestic and
other cognitive or neurodegenerative disorders, such as Parkinson's
disease (PD), Huntington's disease (HD), Alzheimer's disease,
senile dementia, dementia of the Alzheimer's type, memory
disorders, loss of executive function, vascular dementia, and other
dementias, for example, due to HIV disease, head trauma,
Parkinson's disease, Huntington's disease, Pick's disease,
Creutzfeldt-Jakob disease, or due to multiple etiologies; movement
disorders such as akinesias, dyskinesias, including familial
paroxysmal dyskinesias, spasticities, Tourette's syndrome, Scott
syndrome, PALSYS and akinetic-rigid syndrome; extra-pyramidal
movement disorders such as medication-induced movement disorders,
for example, neuroleptic-induced Parkinsonism, neuroleptic
malignant syndrome, neuroleptic-induced acute dystonia,
neuroleptic-induced acute akathisia, neuroleptic-induced tardive
dyskinesia and medication-induced postural tremor; chemical
dependencies and addictions (e.g., dependencies on, or addictions
to, alcohol, heroin, cocaine, benzodiazepines, nicotine, or
phenobarbitol) and behavioral addictions such as an addiction to
gambling; and ocular disorders such as glaucoma and ischemic
retinopathy in a mammal in need of such treatment, including a
human, comprising:
[0620] (a) a compound of the formula 1, or a pharmaceutically
acceptable salt thereof;
[0621] (b) another pharmaceutically active compound that is an
antidepressant or anti-anxiety agent, or a pharmaceutically
acceptable salt thereof; and
[0622] (c) a pharmaceutically acceptable carrier;
[0623] wherein the active compounds "a" and "b" are present in
amounts that render the composition effective in treating such
disorder or condition.
[0624] The active compounds of this invention may be prepared as
described below. Unless otherwise indicated, in the reaction
schemes and discussion that follow, A, Z, D, W, Q, ring AA, G, X,
Y, R.sup.1 through R.sup.14, formula 1, the dotted line connecting
X and Y, and groups of the formulas (i) and (ii) are defined as
above. ##STR9##
[0625] Scheme A illustrates a method for preparing compounds of the
formula 1 wherein A is --(CH.sub.2).sub.mO--, optionally
substituted as indicated in the definition of formula 1 above (also
referred to as compounds of the formula 1A). This method involves
oxidation of a compound of the formula 2 with Dess-Martin
Periodinane or another suitable oxidizing agent such as IBX
(o-iodoxybenzoic acid), oxalyl chloride in dimethyl sulfoxide
(DMSO) (Swern oxidation) or PCC (pyridinium chlorochromate) to form
the corresponding aldehyde of formula 3. This reaction may be
carried out in dichloromethane (CH.sub.2Cl.sub.2), tetrahydrofuran
(THF), dimethyl sulfoxide (DMSO) or a combination of two or more of
these solvents. Reductive amination of a G-substituted piperidine
or piperizine, as shown in Scheme A, using methods well known to
those of skill in the art, with a compound of formula 3 yields the
corresponding compound of formula 1A. The reductive amination can
be performed, for example, utilizing catalytic hydrogenation
methods or using a hydride reducing agent such as sodium
triacetoxyborohydride or sodium cyanoborohydride. The reaction
solvent can be 1,2-dichloroethane, tetrahydrofuran, acetonitrile,
dimethylformamide or a combination of two or more of these
solvents, with the optional addition of 1-10 equivalents of acetic
acid. When the piperazine or piperidine hydrochloride or
hydrobromide salt is used, a base such as triethylamine is
typically added. ##STR10##
[0626] Alternatively, compounds of the formula 1A can be prepared
according to Scheme B. The hydroxy group of the compound of formula
2 is converted into a leaving group (L) using conventional methods
to provide the corresponding compound of formula 4 wherein L is
mesylate (OMs), tosylate (OTs) or a halogen such as bromide, iodide
or chloride. L is preferably chlorine. The resulting compound of
formula 4 is then reacted with a G-substituted piperazine or
piperidine, as depicted in Scheme B, to yield the desired compound
of formula 1A. This reaction is preferably run in the presence of a
base such as potassium carbonate, sodium carbonate, cesium
carbonate, triethylamine or diisopropylethylamine. The solvent used
may be acetonitrile, water, tetrahydrofuran, dioxane, acetone,
methyl isobutyl ketone, benzene or toluene, or a combination of two
or more of these solvents. Inorganic salts such as sodium or
potassium iodide may be employed as catalysts in the reaction. The
temperature of the reaction may vary from about ambient temperature
to about the reflux temperature of the solvent used. The reaction
may also be conducted under microwave irradiation. ##STR11##
[0627] Scheme C illustrates a method for preparing compounds of the
formula 2A (wherein X is double bonded to Y) and 2B (wherein X is
single bonded to Y). Addition of 2 to 20 equivalents of a diol of
the formula HOCH.sub.2(CH.sub.2).sub.nOH, wherein n is an integer
from 1 to 4, or 1 to 4 equivalents of a suitably mono-protected
diol of the formula POCH.sub.2(CH.sub.2).sub.nOH, wherein n is an
integer between 1 and 4 and P is tetrahydropyranyl (THP), benzyl
(Bn), p-methoxybenzyl, tert-butyldimethysilyl (TBS), or
tert-butyldiphenylsilyl (TBDPS), to a compound of the formula 5,
wherein R.sup.13 is chloro, fluoro, bromo, S(O)CH.sub.3 or
SO.sub.2CH.sub.3, provides the corresponding compound of formula 6
(or 2A when the unprotected diol reactant is used). R.sup.13 is
most preferably fluoro. This reaction is conducted in the presence
of a base such as potassium tert-butoxide, sodium tert-butoxide,
sodium hydride, potassium hydride, lithium diisopropylamide,
lithium bis(trimethylsilyl)amide, potassium
bis(trimethylsilyl)amide, or sodium bis(trimethylsilyl)amide.
Suitable solvents for this reaction include tetrahydrofuran (THF),
dioxane, ethylene glycol dimethylether, dimethylformamide (DMF),
N-methylpyrrolidinone (NMP), or dimethylsulfoxide (DMSO), or a
combination of two or more of these solvents. The temperature of
the reaction may vary from about ambient temperature to about the
reflux temperature of the solvent used.
[0628] The reaction of the compound of formula 5 with the 2 to 20
equivalents of the diol of the formula
HOCH.sub.2(CH.sub.2).sub.nOH, wherein n is an integer from 1 to 4,
or the 1 to 4 equivalents of the mono-protected diol of the formula
POCH.sub.2(CH.sub.2).sub.nOH to yield the compound of formula 6, as
described above, is preferably conducted in the presence of a
catalytic amount of a phase transfer catalyst, such as tetrabutyl
ammonium chloride or bromide. The use of a phase transfer catalyst
accelerates the rate of the coupling, and allows one to carry out
the reaction at a lower temperature than would be possible without
the catalyst. Use of the phase transfer catalyst also significantly
reduces the formation of dimeric by-products.
[0629] Compounds of the formula 6 where, P is tetrahydropyranyl
(THP), can be deprotected using conventional methods such as
treatment with PPTS (pyridinium p-tolunesulfonate) or
ptoluenesulfonic acid in ethanol to give the corresponding
compounds of formula 2A. Compounds of the formula 6 wherein P is
tert-butyldimethysilyl or tert-butyldiphenylsilyl can be
deprotected using conventional methods such as treatment with
tetrabutylammonium fluoride in tetrahydrofuran to yield compounds
of the formula 2A.
[0630] Compounds of the formula 2A or compounds of the formula 6
wherein P is H or benzyl can be reduced using catalytic
hydrogenation methods to provide the corresponding compounds of
formula 2B. For example, the hydrogenation can be conducted using 5
to 20% palladium on activated carbon in a solvent such as methanol,
ethanol, tetrahydrofuran, acetic acid, dimethylformamide, or a
combination of two or more of these solvents for a period of about
5 hours to about 48 hours, preferably for about 24 hours, under a
hydrogen pressure from about 1 to about 5 atmosphere, preferably
about 1 atmosphere.
[0631] Alternatively, compounds of the formula 2B can be prepared
by hydrogenating, using methods well known to those of skill in the
art, such as those described above, compounds of the formula 8,
depicted below, ##STR12## which are identical to compounds of the
formula 6, wherein P is benzyl, but wherein the oxo substituent is
replaced by a benzyloxy substituent.
[0632] Compounds of the formula 2B can be prepared, alternatively,
by first deprotecting and then hydrogenating the corresponding
compounds of formula 8, using methods well known to those of skill
in the art, such as those described above. Compounds of the formula
8 can be prepared by a method analogous to that used to prepare
compounds of the formula 6 in Scheme C, but wherein the reactant of
formula 5 is replaced by a compound having formula 7, as depicted
below. ##STR13##
[0633] Compounds of the formula 7 can be prepared by reacting the
corresponding compounds of formula 5A wherein R.sup.13 is chloro
with benzyl bromide and silver carbonate in refluxing toluene.
Compounds of the formula 7 wherein Z is CR.sup.5 can be prepared,
alternatively, by reacting the 2,7-dichloro-[1,8]naphthyridine with
one equivalent of benzyl alcohol in the presence of a base such as
such as potassium tert-butoxide, sodium tert-butoxide, sodium
hydride, potassium hydride, lithium diisopropylamide, lithium
bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, or
sodium bis(trimethylsilyl)amide. Suitable solvents for this
reaction include tetrahydrofuran (THF), dioxane, ethylene glycol
dimethylether, dimethylformamide (DMF), N-methylpyrrolidinone
(NMP), or dimethylsulfoxide (DMSO), or a combination of two or more
of these solvents. The temperature of the reaction may vary from
about -20.degree. C. to ambient temperature. ##STR14##
[0634] Scheme D illustrates another method for preparing compounds
of the formula 1A. Addition of a compound of the formula 9 to a
compound of the formula 7 provides the corresponding compound of
formula 10. This reaction is generally conducted in the presence of
a base such as potassium tert-butoxide, sodium tert-butoxide,
sodium hydride, potassium hydride, lithium diisopropylamide,
lithium bis(trimethylsilyl)amide, potassium
bis(trimethylsilyl)amide, or sodium bis(trimethylsilyl)amide.
Suitable solvents for this reaction include THF, dioxane, ethylene
glycol dimethylether, DMF, NMP, and DMSO, or a combination of two
or more of these solvents. The reaction temperature can range from
about -78.degree. C. to about ambient temperature, and is
preferably from about -20.degree. to about 0.degree. C. Compounds
of the formula 10 can be debenzylated using mild catalytic
hydrogenation methods to provide the corresponding compounds of
formula 1A(1). For example, the hydrogenation can be conducted
using 5% palladium on activated carbon in a solvent such as
methanol, ethanol, or THF, or a combination of two or more of these
solvents, for a period of about 1 hour. More exhaustive catalytic
hydrogenation of compounds of the formula 10 or 1A (when G is
compatible with the hydrogenation conditions) provides compounds of
formula 1A(2). For example, the hydrogenation can be conducted
using 5 to 20% palladium on activated carbon in a solvent such as
methanol, ethanol, THF, acetic acid, or DMF, or a combination of
two or more of these solvents, for a period of about 5 hours to
about 48 hours, preferably for about 12 to 24 hours.
[0635] Compounds of the formula 1A wherein D is N can also be
prepared by reacting a compound of the formula 11, depicted below
##STR15## wherein n is an integer from 1 to 4, with a compound of
the formula G-L.sup.2, wherein L.sup.2 is bromo, iodo, chloro or
triflate (OTf), under Buchwald palladium catalyzed amination
conditions, as described in J. Org. Chem., 2000, 65, 1158). For
example, the coupling can be conducted using a catalytic amount of
palladium acetate (Pd(OAc).sub.2) or
tris(dibenzylideneacetone)dipalladium(0) (Pd.sub.2(dba).sub.3) and
a phosphine ligand such as
2-dicyclohexylphosphino-2'(N,N-dimethylamino)biphenyl,
2-(dicyclohexylphosphino)biphenyl,
2-(di-tert-butylphosphino)biphenyl or
2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (BINAP) in the
presence of a base such as cesium carbonate, sodium tert-butoxide
or potassium phosphate (K.sub.3PO.sub.4), in a solvent such as
toluene, dioxane, or ethylene glycol dimethyl ether (DME). The
temperature of the reaction may vary from about ambient temperature
to about the reflux temperature of the solvent used. ##STR16##
[0636] Scheme E illustrates a method for preparing compounds of the
formula 1 wherein A is --(CH.sub.2).sub.mCH.sub.2--, optionally
substituted as described in the definition of formula 1 above,
(compounds of the formula 1B). Referring to Scheme E, compounds of
the formula 5 can be reacted with a chloroalkenylboronic acid of
the formula Cl(CH.sub.2).sub.nCH.dbd.CHB(OH).sub.2, wherein n is an
integer from 1 to 4, under palladium-catalyzed Suzuki
cross-coupling conditions (Chem. Rev. 1995, 95, 2457), to give the
corresponding compounds of formula 12. For example, the coupling
can be conducted using a catalytic amount of
tetrakis(triphenylphosphine)-palladium(0) in the presence of a base
such as aqueous sodium carbonate, sodium hydroxide, or sodium
ethoxide, in a solvent such as THF, dioxane, ethylene glycol
dimethylether, ethanol (EtOH) or benzene. The temperature of the
reaction may vary from about ambient temperature to about the
reflux temperature of the solvent used. The resulting compounds of
the formula 12 are then reacted with a G-substituted piperazine or
piperidine, as depicted in Scheme E, to yield the corresponding
compounds of formula 13. This reaction is typically run in the
presence of a base such as potassium carbonate, sodium carbonate,
cesium carbonate, triethylamine or diisopropylethylamine. Typical
solvents include acetonitrile, water, THF, dioxane, acetone, methyl
isobutyl ketone, benzene or toluene, or a combination of two or
more of these solvents. Inorganic salts such as sodium or potassium
iodide may be employed as catalysts in the reaction. The
temperature of the reaction can range from about ambient
temperature to about the reflux temperature of the solvent. The
reaction may also be conducted under microwave irradiation.
Hydrogenation of compounds of the formula 13, using methods well
known to those of skill in the art, yields the desired compounds of
formula 1B. For example, the hydrogenation reaction can be
conducted using catalytic Raney-nickel in a solvent such as
ethanol, methanol, or THF, or a combination of two or more of these
solvents, at a hydrogen pressure from about 1 atmosphere to about 5
atmospheres, preferably at about 1 atmosphere.
[0637] Compounds of the formula 5 wherein R.sup.13 is chloro,
fluoro or bromo, and X is double bonded to Y can be prepared by
diazotization of the analogous compounds wherein R.sup.13 is
replaced by an amino group with sodium nitrite, followed by in situ
trapping of the diazonium ion with a halogen source such as
hydrogen fluoride, hydrogen bromide tetrafluoroboric acid
(HBF.sub.4), hydrogen chloride, copper(I) chloride, hydrogen
bromide or copper(I) bromide. For example, the reaction to form a
compound of the formula 5 wherein R.sup.13 is chloro can be
conducted in concentrated hydrochloric acid with the optional
addition of copper(I) chloride at a temperature of about
-20.degree. C. to about ambient temperature. In the case of
deaminative fluorinations, the reaction can be enhanced by
employing a base such as pyridine, as described in Tetrahedron,
1996, 52, 23. Compounds of the formula 5 wherein R.sup.13 is
chloro, fluoro or bromo, and X is single bonded to Y can be
prepared using a similar method wherein the aminated starting
material described above is first subjected to hydrogenation using
methods well known to those of skill in the art, for example, using
5 to 20% palladium on activated carbon in a solvent such as acetic
acid, 1N to 6N hydrochloric acid, or DMF, for a period from about
12 hours to about 24 hours.
[0638] Compounds of the formula 5 wherein R.sup.1 is other than
hydrogen can be prepared from the analogous compounds wherein
R.sup.1 is hydrogen by reacting such analogous compounds with a
compound of the formula R.sup.1 Br in the presence of a base such
as potassium t-butoxide, sodium hydride, lithium diisopropylamide
or lithium bis(trimethylsilyl)amide, in a solvent such as THF,
dioxane, ethylene glycol dimethylether, DMF, or DMSO, or a
combination of two or more of these solvents. Suitable temperatures
for this reaction range from about 0.degree. C. to about the reflux
temperature of the solvent. ##STR17##
[0639] Scheme F illustrates an alternative method for preparing
compounds of the formula 5A(1) (J. Org. Chem. 1990, 55, 4744).
(Compounds of the formula 5A(1) are compounds of the formula 5
wherein X is CR.sup.3, Y is CR.sup.2 and there is a double bond
between X and Y). Ortho metalation of compounds of the formula 14
and subsequent treatment with electrophiles having the formula
shown in Scheme F results in compounds of the formula 15.
Condensation of compounds of the formula 15 with the enolates of
the alkyl esters having the formula shown in Scheme F provides the
corresponding compounds of formula 16. Refluxing compounds of the
formula 16 in aqueous acid such as 3N hydrochloric acid, with the
optional use of a co-solvent such as dioxane, generates the
corresponding compounds of formula 5A(1). ##STR18##
[0640] Scheme G illustrates another method for preparing compounds
of the formula 2A-1. Addition of a suitably mono-protected diol,
where n is an integer between 1 and 4 and P is tetrahydropyranyl
(THP), benzyl, or tert-butyldimethysilyl, to compounds of the
formula 17 provides compounds of the formula 18. The reaction is
conducted in the presence of a base such as potassium
tert-butoxide, sodium tert-butoxide, sodium hydride, potassium
hydride, lithium diisopropylamide, lithium
bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, or
sodium bis(trimethylsilyl)amide. The solvents used may be THF,
dioxane, ethylene glycol dimethylether, DMF, NMP, or DMSO or a
combination of two or more of these solvents. The temperature of
the reaction may vary from about 0.degree. C. to about the reflux
temperature of the solvent.
[0641] Alternatively, compounds of the formula 18 can be prepared
from compounds of the formula 17 according to the method described
in Scheme F for the preparation of compounds of the formula 15.
[0642] Condensation of compounds of the formula 18 with the
enolates of the esters having the formula shown in Scheme G
provides .alpha.,.beta.-hydroxy ester intermediates, which are
treated with an aqueous acid such as 3N hydrochloric acid, with the
optional use of a co-solvent such as dioxane, at temperatures
varying from about ambient temperature to about the reflux
temperature of the solvent, to generate compounds of the formula
2A-1.
[0643] Alternatively, Horner-Wadsworth-Emmons reaction of compounds
of the formula 18 with ketophosphonates having the formula shown in
Scheme G, in the presence of a base such as sodium hydride, sodium
ethoxide, or butyl lithium, in a solvent such as THF, DMSO,
dioxane, ethylene glycol dimethylether, ethanol, or benzene, or a
combination of two or more of these solvents, to give the
corresponding intermediate .alpha.,.beta.-unsaturated esters. This
reaction can also be conducted using lithium chloride and a base,
such as DBU (1,8-diazabicyclo[5,4,0]undec-7-ene) or triethylamine,
in a solvent such as acetonitrile or THF. The intermediate
.alpha.,.beta.-unsaturated esters are then treated with aqueous
hydrochloric acid with the optional use of a co-solvent such as
dioxane to provide the desired compounds of the formula 2A-1. The
temperature of this reaction may vary from about ambient
temperature to about the reflux temperature of the solvent.
##STR19##
[0644] Scheme H illustrates a method for preparing compounds of the
formula 5B-1, 5B-2 and 5B-3. Ortho metalation of compounds of the
formula 14, as described in Scheme F, and subsequent treatment with
3-oxopropionic acid esters of the formula shown in Scheme H above
provides the corresponding compounds of formula 19. The reaction
can be conducted in a solvent such as tetrahydrofuran at
temperatures ranging from about -78.degree. C. to about ambient
temperature, preferably from about -78.degree. C. to about
-20.degree. C. Refluxing compounds of the formula 19 in an aqueous
acid such as 3N hydrochloric acid, with the optional use of a
co-solvent such as dioxane, generates the corresponding compounds
of formula 5B-1. Compounds of the formula 5B-2 can be prepared by
treating the corresponding compounds of the formula 5B-1 with
triethylsilane in trifluoroacetic acid at a temperature from about
room temperature to the reflux temperature of the solvent.
Compounds of the formula 5B-3 can be prepared by treating compounds
of the formula 5B-1 with an oxidizing agent such as Dess Martin
periodinane, IBX or PCC at about ambient temperature in a solvent
such as dichloromethane, dichloroethane, THF or DMSO, or a
combination of two or more of these solvents. ##STR20##
[0645] Scheme I illustrates a method for preparing compounds of the
formula 5B (4) (see PCT Patent Application WO 02/056882).
Alkylation of compounds of the formula 20 with an ester of the
formula shown in Scheme I (L=Br, I, Cl, OMs, OTs) yields the
corresponding compounds of formula 21. This reaction is typically
run in the presence of a base such as potassium carbonate or sodium
hydride, in a solvent such as acetonitrile, THF, dioxane, acetone,
methyl isobutyl ketone, benzene, toluene or DMF, or a combination
of two or more of these solvents. The temperature of the reaction
may vary from about ambient temperature to about the reflux
temperature of the solvent. The nitro group of compounds of the
formula 21 can be reduced with iron powder and acetic acid, with or
without the addition of a solvent such methanol or water, at
temperatures from about room temperature to about the reflux
temperature of the solvent mixture used. These conditions also
result in ring closure to yield compounds of the formula 5B (4).
##STR21##
[0646] Scheme K illustrates a method for preparing compounds of the
formula 5B-5. Compounds of the formula 22 can be heated with liquid
ammonia in a sealed reaction vessel at temperatures of about
40.degree. C. to about 100.degree. C., in a solvent such as THF, to
yield compounds of the formula 23. Reduction of the ester of
compound 23 to the corresponding alcohol, using lithium aluminum
hydride, under conventional conditions well known to those of skill
in the art, followed by oxidation of the alcohol with an oxidizing
agent such as barium manganate, manganese dioxide, IBX, Dess Martin
periodinane, or PCC, in a solvent such as dichloromethane, THF, or
DMSO, or a combination of two or more of these solvents, yields the
corresponding aldehydes of formula 24. Compounds of the formula 24
can then be reacted with (carbethoxymethylene)triphenylphosphorane
or a similar Wittig reagent in a solvent such as dichloromethane,
chloroform, THF, benzene or toluene, at a temperature from about
room temperature to about the reflux temperature of the solvent, to
give the corresponding compounds of formula 25. In the case of
barium manganate, the oxidation and the Wittig reaction can be
carried out using a one-pot procedure (J. Org. Chem. 1998, 63,
4489). Hydrogenation of compounds of the formula 25, using methods
known to those skilled in the art, for example, as described above,
preferably using palladium on barium sulfate in a solvent such as
THF, provides the corresponding amino esters. The resulting amino
esters can be cyclized to give compounds of the formula 5B(5) by
heating at a temperature from about 50.degree. C. to about the
reflux temperature of the solvent, in a solvent such as ethanol,
methanol or isopropanol, preferably with a catalytic amount of acid
(i.e., TsOH) or base (i.e., DBU). ##STR22##
[0647] Scheme L illustrates an alternative method for preparing
compounds of the formula 2A-2 and 2B-1. Compounds of the formula 26
can be prepared by reacting compounds of the formula 5A-2 with
benzyl alcohol in the presence of a base such as such as potassium
tert-butoxide, sodium tert-butoxide, sodium hydride, potassium
hydride, lithium diisopropylamide, lithium
bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, or
sodium bis(trimethylsilyl)amide. The solvents used may be
tetrahydrofuran, dioxane, ethylene glycol dimethylether,
dimethylformamide, N-methylpyrrolidinone, dimethylsulfoxide, or a
combination of two of the formerly mentioned solvents. The
temperature of the reaction may vary from ambient to the reflux
temperature of the solvent used. Compounds of the formula 26 can be
reacted with a suitably mono-protected diol, preferably P=Bn, under
Mitsunobo conditions to give compounds of the formula 27. Typical
reaction conditions employ diethyldiazodicarboxylate (DEAD) and
triphenylphosphine in a solvent such as tetrahydrofuran. Compounds
of the formula 27 can be hydrogenated to give compounds of the
formula 2A-2 and 2B-1 following methods described in Scheme C for
the hydrogenation of compounds of the formula 8. ##STR23##
[0648] Scheme M illustrates an alternative method for preparing
compounds of the formula 2B-2. Addition of a suitably
mono-protected diol, where n is an integer between 1 and 4 and P is
tetrahydropyranyl (THP), benzyl, or tert-butyldimethysilyl (TBS),
to compounds of the formula 28 provides the corresponding compounds
of formula 29. This reaction is typically conducted in the presence
of a base such as potassium tert-butoxide, sodium tert-butoxide,
sodium hydride, lithium diisopropylamide, lithium
bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, or
sodium bis(trimethylsilyl)amide, in a solvent such as THF, dioxane,
or ethylene glycol dimethylether, preferably THF. The temperature
of the reaction may vary from about -78.degree. C. to about room
temperature. Compounds of the formula 29 can be reacted with sodium
azide in solvents such as DMF, NMP or DMSO, or a combination of two
or more of these solvents, to provide compounds of the formula 30.
The temperature of the reaction may vary from about room
temperature to about the reflux temperature of the solvent, and is
preferably about 70.degree. C. The azide of compounds of the
formula 30 can be reduced to an amine using conventional reducing
agents known to those skilled in the art, preferably using
hexamethyldisilthiane [(Me.sub.3Si).sub.2S] in a solvent such as
methanol or ethanol. Subsequent reduction of the cyano group to an
aldehyde using diisobutylaluminum hydride in a solvent such as THF
at about 0.degree. C. provides compounds of the formula 31.
Compounds of the formula 31 can be reacted with
(carbethoxymethylene)triphenylphosphorane or a similar Wittig
reagent in a solvent such as dichloromethane, chloroform, THF,
benzene or toluene, or a mixture of two or more of these solvents,
at about room temperature to about the reflux temperature of the
solvent, to give compounds of the formula 32. Compounds of the
formula 32 can be hydrogenated using methods known to those skilled
in the art, using, for example, palladium on activated carbon,
palladium on barium sulfate, or Raney-nickel, in a solvent such as
methanol, ethanol, THF, or a combination of two of the formerly
mentioned solvents. The resulting amino esters can be cyclized to
give the corresponding compounds of the formula 2B-2 by heating at
a temperature from about 50.degree. C. to about the reflux
temperature of the solvent, in a solvent such as ethanol, methanol
or isopropanol, or a mixture of two or more of these solvents.
Preferably, a catalytic amount of acid (i.e., TsOH) or base (i.e.,
DBU) is used. ##STR24##
[0649] Scheme N illustrates a method for preparing compounds of the
formula 2B(3). The corresponding compounds of formula 2B are
halogenated regioselectively with N-bromosuccinamide,
N-chlorosuccinamide, or N-iodosuccinamide in DMF at temperatures
from about room temperature to about 80.degree. C. to provide
compounds of the formula 2B-3 (J. Med. Chem. 2003, 46, 702).
##STR25##
[0650] Scheme O illustrates a method for preparing compounds of the
formula IB-2. Compounds of the formula 15 can be reacted with
chloro-alkenylboronic acids (n=1 to 3) under palladium-catalyzed
Suzuki cross-coupling conditions as described in Scheme E to give
compounds of the formula 33. Subsequent reaction with the
G-substituted piperazines or piperidines of the formula shown in
Scheme O according to the methods described in Scheme E provide the
corresponding compounds of formula 34. Compounds of the formula 34
may be hydrogenated in the presence of a catalyst such as
Raney-nickel in a solvent such as ethanol, methanol,
tetrahydrofuran, or a combination of two of the formerly mentioned
solvents. Subsequent removal of the pivaloyl group under acidic
conditions, preferably with 3N aqueous hydrochloric acid at
temperatures of about room temperature to about the reflux
temperature of the solvent provides compounds of the formula 35.
Compounds of the formula 35 can be reacted with Grignard reagents
such as alky magnesium bromides in solvents such as
tetrahydrofuran, diethyl ether, toluene, or a combination of two of
the formerly mentioned solvents at temperatures of about
-78.degree. C. to room temperature to give the corresponding
alcohols. Subsequent treatment with reagents such as phosgene,
carbonyldiimidazole (CDI), 4-nitrophenyl chloroformate, methyl
chloroformate, or phenyl chloroformate, with or without a base such
as triethylamine, pyridine, potassium bicarbonate, or potassium
carbonate in solvents such as tetrahydrofuran, methyl tert-butyl
ether (MTBE), water, toluene, hexanes, heptane or a combination of
two of the formerly mentioned solvents gives compounds of the
formula IB-2 (J. Org. Chem. 1998, 63, 8536).
[0651] The preparation of other compounds of the formula 1 not
specifically described in the foregoing experimental section can be
accomplished using combinations of the reactions described above
that will be apparent to those skilled in the art.
[0652] In each of the reactions discussed or illustrated above,
pressure is not critical unless otherwise indicated. Pressures from
about 0.5 atmospheres to about 5 atmospheres are generally
acceptable, and ambient pressure, i.e., about 1 atmosphere, is
preferred as a matter of convenience.
[0653] The compounds of the formula 1 and the intermediates shown
in the above reaction schemes can be isolated and purified by
conventional procedures, such as recrystallization or
chromatographic separation.
[0654] The compounds of the formula 1 and their pharmaceutically
acceptable salts, can be administered to mammals via either the
oral, parenteral (such as subcutaneous, intravenous, intramuscular,
intrasternal and infusion techniques), rectal, buccal or intranasal
routes. In general, these compounds are most desirably administered
in doses ranging from about 3 mg to about 600 mg per day, in single
or divided doses (ie., from 1 to 4 doses per day), although
variations will necessarily occur depending upon the species,
weight and condition of the patient being treated and the patient's
individual response to said medicament, as well as on the type of
pharmaceutical formulation chosen and the time period and interval
at which such administration is carried out. However, a dosage
level that is in the range of about 10 mg to about 100 mg per day
is most desirably employed. In some instances, dosage levels below
the lower limit of the aforesaid range may be more than adequate,
while in other cases still larger doses may be employed without
causing any harmful side effects, provided that such higher dose
levels are first divided into several small doses for
administration throughout the day.
[0655] The novel compounds of the present invention may be
administered alone or in combination with pharmaceutically
acceptable carriers or diluents by any of the routes previously
indicated, and such administration may be carried out in single or
multiple doses. More particularly, the novel therapeutic agents of
this invention can be administered in a wide variety of different
dosage forms, i.e., they may be combined with various
pharmaceutically acceptable inert carriers in the form of tablets,
capsules, lozenges, troches, hard candies, suppositories, jellies,
gels, pastes, ointments, aqueous suspensions, injectable solutions,
elixirs, syrups, and the like. Such carriers include solid diluents
or fillers, sterile aqueous media and various non-toxic organic
solvents, etc. Moreover, oral pharmaceutical compositions can be
suitably sweetened and/or flavored. In general, the weight ratio of
the novel compounds of this invention to the pharmaceutically
acceptable carrier will be in the range from about 1:6 to about
2:1, and preferably from about 1:4 to about 1:1.
[0656] For oral administration, tablets containing various
excipients such as microcrystalline cellulose, sodium citrate,
calcium carbonate, dicalcium phosphate and glycine may be employed
along with various disintegrants such as starch (and preferably
corn, potato or tapioca starch), alginic acid and certain complex
silicates, together with granulation binders like
polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,
lubricating agents such as magnesium stearate, sodium lauryl
sulfate and talc are often very useful for tabletting purposes.
Solid compositions of a similar type may also be employed as
fillers in gelatin capsules; preferred materials in this connection
also include lactose or milk sugar as well as high molecular weight
polyethylene glycols. When aqueous suspensions and/or elixirs are
desired for oral administration, the active ingredient may be
combined with various sweetening or flavoring agents, coloring
matter or dyes, and, if so desired, emulsifying and/or suspending
agents as well, together with such diluents as water, ethanol,
propylene glycol, glycerin and various like combinations
thereof.
[0657] For parenteral administration, solutions of a compound of
the present invention in either sesame or peanut oil or in aqueous
propylene glycol may be employed. The aqueous solutions should be
suitably buffered (preferably pH greater than 8) if necessary and
the liquid diluent first rendered isotonic. These aqueous solutions
are suitable for intravenous injection purposes. The oily solutions
are suitable for intra-articular, intra-muscular and subcutaneous
injection purposes. The preparation of all these solutions under
sterile conditions is readily accomplished by standard
pharmaceutical techniques well known to those skilled in the
art.
[0658] This invention relates to methods of treating anxiety,
depression, schizophrenia and the other disorders referred to in
the description of the methods of the present invention, wherein a
novel compound of this invention and one or more of the other
active agents referred to above (e.g., an NK1 receptor antagonist,
tricyclic antidepressant, 5HT1D receptor antagonist, or serotonin
reuptake inhibitor) are administered together, as part of the same
pharmaceutical composition, as well as to methods in which such
active agents are administered separately as part of an appropriate
dose regimen designed to obtain the benefits of the combination
therapy. The appropriate dose regimen, the amount of each dose of
an active agent administered, and the specific intervals between
doses of each active agent will depend upon the subject being
treated, the specific active agent being administered and the
nature and severity of the specific disorder or condition being
treated. In general, the novel compounds of this invention, when
used as a single active agent or in combination with another active
agent, will be administered to an adult human in an amount from
about 3 mg to about 300 mg per day, in single or divided doses,
preferably from about 10 to about 100 mg per day. Such compounds
may be administered on a regimen of up to 6 times per day,
preferably 1 to 4 times per day, especially 2 times per day and
most especially once daily. Variations may nevertheless occur
depending upon the species of animal being treated and its
individual response to said medicament, as well as on the type of
pharmaceutical formulation chosen and the time period and interval
at which such administration is carried out. In some instances,
dosage levels below the lower limit of the aforesaid range may be
more than adequate, while in other cases still larger doses may be
employed without causing any harmful side effect, provided that
such larger doses are first divided into several small doses for
administration throughout the day.
[0659] A proposed daily dose of a 5HT reuptake inhibitor,
preferably sertraline, in the combination methods and compositions
of this invention, for oral, parenteral or buccal administration to
the average adult human for the treatment of the conditions
referred to above, is from about 0.1 mg to about 2000 mg,
preferably from about 1 mg to about 200 mg of the 5HT reuptake
inhibitor per unit dose, which could be administered, for example,
1 to 4 times per day. A proposed daily dose of a 5HT1D receptor
antagonist in the combination methods and compositions of this
invention, for oral, parenteral, rectal or buccal administration to
the average adult human for the treatment of the conditions
referred to above, is from about 0.01 mg to about 2000 mg,
preferably from about 0.1 mg to about 200 mg of the 5HT1D receptor
antagonist per unit dose, which could be administered, for example,
1 to 4 times per day.
[0660] For intranasal administration or administration by
inhalation, the novel compounds of the invention are conveniently
delivered in the form of a solution or suspension from a pump spray
container that is squeezed or pumped by the patient or as an
aerosol spray presentation from a pressurized container or a
nebulizer, with the use of a suitable propellant, e.g.,
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
the case of a pressurized aerosol, the dosage unit may be
determined by providing a valve to deliver a metered amount. The
pressurized container or nebulizer may contain a solution or
suspension of the active compound. Capsules and cartridges (made,
for example, from gelatin) for use in an inhaler or insufflator may
be formulated containing a powder mix of a compound of the
invention and a suitable powder base such as lactose or starch.
Formulations of the active compounds of this invention for
treatment of the conditions referred to above in the average adult
human are preferably arranged so that each metered dose or "puff"
of aerosol contains 20 .mu.g to 1000 .mu.g of active compound. The
overall daily dose with an aerosol will be within the range 100
.mu.g to 10 mg. Administration may be several times daily, for
example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses
each time.
[0661] The ability of the novel compounds of this invention to bind
to the dopamine D.sub.2 receptor can be determined using
conventional radioligand receptor binding assays. All receptors can
be heterologously expressed in cell lines and experiments conducted
in membrane preparations from the cell lines using procedures
outlined below. IC.sub.50 concentrations can be determined by
nonlinear regression of concentration-dependent reduction in
specific binding. The Cheng-Prussoff equation can be used to
convert the IC.sub.50 to Ki concentrations.
Dopamine D.sub.2 Receptor Binding Assay:
[0662] [.sup.3H]Spiperone binding to a membrane preparation from
CHO-hD.sub.2L cells is carried out in 250 .mu.l of 50 mM Tris-HCl
buffer containing 100 mM NaCl, 1 mM MgCl.sub.2 and 1% DMSO at pH
7.4. Duplicate samples containing (in order of addition) the test
compounds, 0.4 nM [.sup.3H]spiperone and approximately 12 .mu.g
protein are incubated for 120 minutes at room temperature. Bound
radioligand is separated by rapid filtration under reduced pressure
through Whatman GF/B glass fiber filters previously treated with
0.3% polyethyleneimine. Radioactivity retained on the filter is
determined by liquid scintillation spectrophotometry.
[0663] Title compounds of the Examples, below, were tested using
the above assay, in which specific binding determined in the
presence of 1 mM haloperidol was 95%. All of the title compounds
exhibited Ki values less than or equal to 75 nM (see Tables 1 and
2, below). Preferred embodiments of compounds of the present
invention preferably exhibit Ki values of no more than 100 nM, more
preferably no more than 50 nM, even more preferably no more than 25
nM, most preferably no more than 10 nM.
[0664] D.sub.2 intrinsic activity of title compounds of the
Examples, below, was determined using the [.sup.3H]thymidine uptake
assay described below.
[.sup.3H]Thymidine Uptake Assay for D.sub.2 Intrinsic Activity
[0665] Cells are serum deprived by washing twice with 200 .mu.l of
serum-free media. 90 .mu.l serum-free media was added to each well.
The plates ware incubated for two to three hours. 10 .mu.l of
serum-containing media, as a positive control, vehicle (serum-free
media), negative control (an antagonist) or test compounds and
standards (10 .mu.l of a 10 .mu.M solution for a final
concentration of 1 .mu.M) in serum-free media were added to wells.
The plates are returned to the incubator. Eighteen hours later
[.sup.3H]thymidine is added (0.5 .mu.C/well in 10 .mu.l of
serum-free media) and the plates are returned to the incubator.
Four hours later trypsin (0.25%) is added (100 .mu.l/well). The
plates are returned to the incubator, once again. One hour later
the assay is terminated by rapid filtration through Whatman GF/C
glass fiber filters. Filters are washed four times with 500 ml of
50 mM Tris-HCl pH 7.0 buffer, for example, using a Brandel MLR-96T
cell harvester. Radioactivity remaining on the filters are
estimated, for example, with a Wallac 1205 Betaplate liquid
scintillation counter (50% efficiency). Intrinsic activity is
defined as total uptake (1 .mu.M Quinpirole) minus serum-free media
(no uptake). Test compounds are compared to 1 .mu.M Quinpirole
(full DA agonist), which was classified as 100% intrinsic activity.
All assays are preferably performed in triplicate, with each drug
occupying one full column (8 wells) per plate.
[0666] Compounds of the present invention preferably exhibit at
least 1% to up to 90% intrinsic activity, more prefeferably at
least 10% to up to 90% activity, more preferably at least 10% to up
to 80% activity, more preferably at least 20% to up to 60%
intrinsic activity, even more preferably at least 30% to up to 50%
intrinsic activity.
[0667] Each of the title compounds produced as described in the
Examples, below, were also tested using the above assay. All of the
title compounds tested in this assay exhibited an intrinsic
activity between 2 and 83 percent. See Tables 1 and 2, below, for
results obtained from each of the compounds tested. TABLE-US-00001
TABLE 1 Example D.sub.2 Ki (nM) D.sub.2 Intrinsic Activity (%) A1
1.0 30 A2 1.0 29 A3 3.0 35 A4 2.5 28 A5 2.5 29 A6 1.0 31 A7 1.0 15
A8 10.0 7 A9 5.5 9 A10 5.7 31 A11 6.5 6 A12 2.0 11 A13 11.4 21 A14
5.5 7 A15 4.5 4 A16 3.5 16 A17 1.0 15 A18 7.7 NOT TESTED A19 19.5
10 A20 0.7 19 A21 6.7 NOT TESTED A22 4.5 36 A23 14.9 NOT TESTED A24
16.5 40 A25 1.0 27 A26 1.0 33 A27 1.4 38 A28 3.5 2 A29 2.5 20 A30
15.5 11 A31 2.0 26 A32 2.0 7 A33 15.5 31 A34 0.5 8 A35 0.3 24 A36
5.0 38 A37 2.2 46 A38 6.0 23 A39 7.9 56 A40 12.0 32 A41 9.1 28 A42
4.9 28 A43 52.0 75 A44 22.2 51 A45 2.8 34 A46 2.0 41 A47 75.9 NOT
TESTED A48 0.8 34 A49 1.4 21 A50 0.8 14 A51 0.4 20 A52 2.0 32 A53
5.3 NOT TESTED A54 0.6 NOT TESTED A55 0.2 NOT TESTED A56 2.5 29 A57
9.4 NOT TESTED A58 30.4 48 A59 4.5 30 A60 1.0 18 A61 2.2 NOT TESTED
A62 0.9 27 A63 35.0 4 A64 3.5 36 A65 1.0 36 A66 2.0 49 A67 1.0 19
A68 6.0 17 A69 2.0 10 A70 1.1 14 A71 1.6 3 A72 3.5 NOT TESTED A73
1.0 23 A74 4.0 37 A75 23.8 36 A76 8.7 16 A77 10.8 36 A78 1.4 24 A79
15.0 24 A80 23.5 30 A81 24.7 4 A82 28.1 27 A83 2.5 36 A84 3.0 11 B1
1.0 19 B2 2.5 22 B3 3.9 8 B4 1.4 22 B5 3.0 2 B6 1.0 16 B7 5.0 28 B8
2.0 17 B9 1.7 23 B10 1.2 34 B11 1.4 31 B12 4.9 38 B13 11.2 45 B14
6.5 37 B15 2.5 17 B16 2.5 41 B17 1.7 43 B18 3.0 32 B19 4.6 NOT
TESTED B20 13.0 NOT TESTED B21 6.7 NOT TESTED B22 1.0 36 B23 2.5 15
B24 4.6 10 B25 2.2 43 B26 11.5 23 B27 9.8 47 B28 1.4 31 B29 1.0 32
B30 28.0 83 B31 69.5 76 B32 <2 19 B33 2.0 26 B34 0.7 14 B35 0.4
20 B36 3.0 39 B37 4.0 NOT TESTED B38 0.6 NOT TESTED B39 1.0 NOT
TESTED B40 1.4 36 B41 4.2 NOT TESTED B42 8.5 37 B43 3.0 18 B44 0.7
27 B45 0.6 NOT TESTED B46 1.0 29 B47 0.3 44 B48 1.0 19 B49 0.9 50
B50 1.0 51 B51 3.5 36 B52 3.5 17 B53 1.1 26 B54 2.8 15 B55 1.0 NOT
TESTED B56 2.0 28 B57 4.1 21 B58 12.5 42 B59 5.1 37 B60 1.6 28 B61
23.9 18 B62 1.0 21 B63 47.9 18 B64 17.0 27 B65 9.2 10 B66 29.2 33
B67 2.5 39 B68 4.5 17 C1 6.6 43 C2 4.7 24 C3 6.8 22 C4 54.1 2 C5
1.4 40 C6 2.0 44 C7 2.0 46 C8 1.4 33 C9 2.6 34 C10 7.0 5 C11 16.4 7
C12 13.5 12 C13 2.0 14 C14 65.5 10 C15 32.0 8 C16 46.7 34 C17 20.5
21 C18 7.1 34 C19 10.4 13 C20 2.0 33 D1 1.0 31 D2a 2.9 20 D2b 2.0
24 D3 4.5 15 D4 2.0 16 D5 1.8 15 D6a 2.5 17 D6b 3.0 24 D7 3.0 15 D8
2.2 8 D9 1.0 15 D10 0.9 22 D11 1.4 30 D12 5.0 3 D13 2.8 19 D14 0.4
3 D15 0.6 25 D16 3.0 31 D17 3.9 29 D18 4.7 37 D19 3.2 39 D20 2.0 44
D21 12.5 24 D22 5.2 42 D23 6.9 33 D24 13.4 32 D25 1.6 31 E1 2.0 32
E2 1.3 22 E3 1.0 31 E4 2.2 38 E5 2.0 21 E6 3.5 32 E7 6.3 19 E8 1.4
26 E9 1.4 34 E10 1.0 31 E11 1.0 19 E12 1.0 39 E13 5.0 11 E14 28.5
36 E15 39.8 20 F1 0.6 8 F2 1.0 30 F3 0.8 15 F4 1.4 23 F5 1.0 32 F6
0.6 37 F7 0.5 11 F8 1.0 15 F9 3.9 11 G1 7.5 27 G2 3.9 6 G3 1.4 25
G4 0.7 NOT TESTED G5 0.6 NOT TESTED G6 66.7 NOT TESTED G7 0.8 NOT
TESTED G8 1.0 NOT TESTED H1 1.0 28 H2 1.0 22 H3 1.8 25 H4 4.9 38 H5
3.0 34 H6 1.0 42 H7 8.8 46 H8 1.3 NOT TESTED H9 1.0 NOT TESTED
H10 3.0 44 H11 0.4 23 H12 1.0 34 H13 15.4 36 H14 9.3 33 I1 5.0 17
I2 9.0 37 I3 14.5 33 I4 NOT TESTED NOT TESTED I5 13.9 23 I6 1.0 24
I7 7.4 37 I8 5.9 25 I9 4.5 19 I10 9.5 21 I11 8.7 19 I12 NOT TESTED
NOT TESTED I13 2.0 19 I14 3.5 24 I15 2.5 20 I16 2.1 27 I17 1.0 32
I18 1.6 54 I19 7.5 22
[0668] TABLE-US-00002 TABLE 2 Example D.sub.2 Ki (nM) D.sub.2
Intrinsic Activity (%) A1' 0.4 73 A2' 1.4 21 A3' 1.0 37 A4' 1.0 18
A5' 2.2 31 A6' 2.0 42 A7' 4.0 34 A8' 1.4 30 A9' 1.0 30 A10' 0.4 NOT
TESTED A11' 3.0 17 A12' 2.8 NOT TESTED A13' 0.7 14 A14' 3.0 NOT
TESTED A15' NOT TESTED NOT TESTED A16' 2.5 15 A17' 1.0 15 A18' 1.4
13 A19' 1.4 40 A20' 65.1 NOT TESTED A21' 1.0 24 A22' 0.7 NOT TESTED
A23' 1.1 39 A24' 2.0 6 A25' 1.4 36 A26' 12.5 12 A27' 0.5 21 A28'
0.3 21 A29' 7.4 33 A30' 8.9 41 A31' 0.6 NOT TESTED A32' 28.0 27
A33' 17.3 18 A34' 1.0 38 A35' 1.4 20 A36' 0.6 62 A37' 1.6 45 A38'
1.0 20 A39' 0.4 NOT TESTED A40' 1.0 30 A41' 1.0 32 A42' 0.7 NOT
TESTED A43' 25.2 32 A44' 18.6 29 A45' 4.2 NOT TESTED A46' 3.2 NOT
TESTED A47' 15.9 32 A48' 7.4 34 A49' 7.5 38 B1' 1.0 22 B2' 1.0 33
B3' 2.0 50 B4' 1.0 28 B5' 0.3 NOT TESTED B6' 1.0 33 B7' 1.0 48 B8'
1.0 21 B9' 1.0 40 B10' 1.0 22 B11' 1.0 21 B12' 2.0 24 B13' 2.0 33
B14' 2.0 NOT TESTED B15' 9.4 NOT TESTED B16' 1.1 4 B17' 1.4 NOT
TESTED B18' 1.4 NOT TESTED B19' 1.0 NOT TESTED B20' 1.0 16 B21' 1.0
18 B22' 1.0 12 B23' 5.5 21 B24' 0.8 42 B25' 1.0 21 B26' 1.2 26 B27'
17.9 34 B28' 7.5 44 B29' 31.9 26 B30' 1.0 42 B31' 0.6 NOT TESTED
B32' 1.4 NOT TESTED B33' 4.2 NOT TESTED B34' 0.7 35 B35' 0.4 NOT
TESTED B36' 12.9 36 B37' 3.2 39 B38' 3.0 46 B39' 5.7 29 B40' 3.9 49
B41' 0.8 NOT TESTED C1' 6.2 38 C2' 1.9 22 C3' 7.0 19 C4' 18.4 21
C5' 3.0 23 C6' 1.4 24 D1' 2.0 24 D2' 5.0 40 E1' 1.0 12 E2' 0.5 9
E3' 0.7 8 E4' 0.4 26 F1' 0.7 NOT TESTED F2' 2.4 NOT TESTED F3' 10.1
NOT TESTED F4' 1.0 NOT TESTED F5' 0.8 NOT TESTED G1' 10.0 20 G2'
3.5 21 G3' 17.6 28 G4' 9.0 13 G5' 8.5 7 G6' 0.7 17 G7' 1.4 38 G8'
2.5 32 G9' 5.5 21 G10' 1.0 18 G11' 2.0 39 G12' 3.0 36 G13' 2.5 NOT
TESTED G14' 15.0 44 G15' 3.4 41 H1' 4.9 22 H2' 6.9 15 H3' 2.0 22
H4' 0.6 21 H5' 5.5 14 H6' 6.5 21 H7' 3.9 17 H8' 3.5 32 H9' 0.6
31
[0669] The following Examples illustrate the preparation of several
compounds of the present invention. Melting points are uncorrected.
NMR data are reported in parts per million and are referenced to
the deuterium lock signal from the sample solvent. Any reference to
a "title compound" in an example, below, refers to the compound
named in the title of that particular example.
EXAMPLES
Example A1
Synthesis of
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8-
]naphthyridin-2-one
[0670] A first intermediate compound,
2-Benzyloxy-7-chloro-[1,8]naphthyridine, was produced, as follows.
To a solution of benzyl alcohol (5.0 mL, 48.0 mmol) in THF (50 mL)
cooled to 0.degree. C. was added KOtBu (1M in THF, 46 mL, 46.0
mmol). The solution was stirred at 0.degree. C. for 20 min and then
added via cannula to a suspension of
2,7-dichloro-[1,8]naphthyridine (10.0 g, 50.2 mmol, J. Org. Chem.
1981, 46, 833) in DMF (50 mL) and THF (50 mL) cooled to 0.degree.
C. The orange suspension was stirred at 0.degree. C. for 15 min and
at room temperature for 30 min. The reaction was quenched with
saturated NH.sub.4Cl and H.sub.2O. The mixture was extracted with
EtOAc. The organic layer was filtered through celite to remove an
orange clay-like precipitate. The organic layer was washed with
H.sub.2O and brine, and concentrated to give an orange solid. The
solid was absorbed onto SiO.sub.2 and purified by liquid
chromatography (2% EtOAc/48% Hexanes/50% CH.sub.2Cl.sub.2) to give
the first intermediate compound as a white solid (6.37 g, 23.5
mmol, 51%). MS: APCI: M+1: 271.0 (Exact Mass: 270.06).
[0671] A second intermediate compound,
2-Benzyloxy-7-(4-benzyloxy-butoxy)-[1,8]naphthyridine, was
produced, as follows. To a solution of 4-benzyloxy-1-butanol (4.9
mL, 28.2 mmol, 1.2 equiv) in THF (20 mL) cooled to 0.degree. C. was
added KO.sup.tBu (1M in THF, 27 mL, 27 mmol, 1.15 equiv). The
solution was stirred at 0.degree. C. for 20 min and then added via
cannula to a suspension of 2-benzyloxy-7-chloro-[1,8]naphthyridine
(6.35 g, 23.5 mmol), produced as described above, in THF (70 mL),
and cooled to 0.degree. C. The reaction became homogenous. After 30
min at 0.degree. C., saturated NH.sub.4Cl and H.sub.2O were added
to quench the reaction. The mixture was extracted with EtOAc. The
organic layer was washed with saturated NaHCO.sub.3, H.sub.2O and
brine, dried over Na.sub.2SO.sub.4 and concentrated. The crude was
absorbed onto SiO.sub.2 and purified by liquid chromatography
(10-15% EtOAc/Hexanes) to give the second intermediate compound as
a yellow oil (4.64 g, 11.19 mmol, 48%). MS: APCI: M+1: 415.2 (Exact
Mass: 414.19).
[0672] A third intermediate compound,
7-(4-Hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one, was
produced, as follows. To a solution of
2-benzyloxy-7-(4-benzyloxy-butoxy)-[1,8]naphthyridine (4.64 g,
11.19 mmol) in MeOH (100 mL) was added 20% Pd/C (1.5 g) and the
mixture was hydrogenated for 22 h. The reaction was filtered,
concentrated and purified by liquid chromatography (5% MeOH/CH2Cl2)
to give the title compound as a white solid (2.44 g, 10.33 mmol,
92%). MS: APCI: M+1: 237.1 (Exact Mass: 236.12).
[0673] The third intermediate compound was also prepared by
hydrogenation of 7-(4-hydroxy-butoxy)-1H-[1,8]naphthyridin-2-one
(an intermediate in Example B1, below).
[0674] A fourth intermediate compound,
4-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde,
was produced using either a Dess-Martin oxidation reaction or a
Swern oxidation reaction, as described below.
[0675] Dess-Martin oxidation: To a cloudy solution of the
Dess-Martin periodinane (2.80 g, 6.60 mmol, 1.5 equiv) in
CH.sub.2Cl.sub.2 (13 mL) was added a solution of
7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one (1.04
g, 4.40 mmol) in CH.sub.2Cl.sub.2 (25 mL) via cannula. The reaction
was stirred at room temperature for 5 h and stored in the freezer
overnight. A 1:1 mixture of saturated Na.sub.2S.sub.2O.sub.3 and
saturated NaHCO.sub.3 (50 mL) was added followed by Et.sub.2O. The
mixture was stirred for 10 min and then extracted with
Et.sub.2O/EtOAc (2:1). The organic layer was washed with saturated
NaHCO.sub.3 and brine, dried over Na.sub.2SO.sub.4 and concentrated
to give the fourth intermediate compound as a pale yellow oil (1.06
g, used crude in next reaction). MS: APCI: M+1: 235.1 (Exact Mass:
234.10).
[0676] Swern oxidation: A solution of oxalyl chloride (9.97 mL, 112
mmol) in CH.sub.2Cl.sub.2 was cooled to -70.degree. C. and DMSO
(15.6 mL, 220 mmol) was carefully added. The solution was stirred
at -60.degree. C. for 10 min and then a solution of
7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one (23 g,
97.5 mmol) in DMSO (70 mL) was added dropwise at
-50.about.-60.degree. C. The reaction mixture was stirred at
-60.degree. C. for 20 min and then triethylamine (72 mL, 0.513 mol)
was added dropwise. The reaction was warmed to room temp and
stirred for 30 min. The mixture was poured into ice-water and the
organic phase was separated. The aqueous phase was extracted with
CH.sub.2Cl.sub.2, combined with the organic phase, washed with
brine, dried over Na.sub.2SO.sub.4, and concentrated under vacuum
to give the crude product. Purification by column chromatography
(hexane:ethyl acetate 2:1) followed by recrystallization provided
the fourth intermediate compound (12.7 g, 54.3 mmol, 56%).
[0677] In the final step of the synthesis reaction, the title
compound,
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8-
]naphthyridin-2-one was produced as follows: To a solution of
4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
(1.06 g, crude from previous reaction) was added a solution of
2,3-dichlorophenylpiperazine (1.02 g, 4.40 mmol) in dichloroethane
(5 mL). The solution was stirred for 15 min and NaBH(OAc).sub.3
(1.21 g, 5.72 mmol, 1.3 equiv) was added as a powder. The reaction
was stirred at room temperature for 3 h and quenched with saturated
NaHCO.sub.3 and H.sub.2O. The mixture was extracted with EtOAc. The
organic layer was washed with saturated NaHCO.sub.3, H.sub.2O and
brine, dried over Na.sub.2SO.sub.4 and concentrated to give a
yellow foam/oil. Purification by liquid chromatography (4%
MeOH/CH.sub.2Cl.sub.2) afforded the title compound as a white foam
(1.20 g, 2.67 mmol, 61% over 2 steps). The HCl salt was formed by
dissolving the title compound (800 mg, 1.78 mmol) in Et.sub.2O (20
mL) and CH.sub.2Cl.sub.2 (2 mL) followed by the addition of 1N HCl
in Et.sub.2O (1.75 mL). The resulting white precipitate was
collected by filtration, washed with Et.sub.2O and dried to give a
white solid (801 mg). MS: APCI: M+1: 449.1 (Exact Mass:
448.14).
[0678] A variation of this same method was used to produce other
compounds as described in examples below, wherein other compounds
were substituted for 2,3-dichlorophenylpiperazine in the final step
of the synthesis procedure.
Example A2
Synthesis of
7-{4-[4-(2-Chloro-3-methyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one
[0679]
7-{4-[4-(2-Chloro-3-methyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dih-
ydro-1H-[1,8]naphthyridin-2-one was produced according to a process
similar to that described in Example A1, except that in the final
step of the synthesis procedure, 2-chloro-3-methylphenylpiperazine
hydrochloride (506 mg, 2.05 mmol) was added to a solution of
4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
(approx. 1.9 mmol) in dichloroethane (10 mL), followed by the
addition of Et.sub.3N (0.53 mL, 3.76 mmol, 2 equiv).
NaBH(OAc).sub.3 (557 mg, 2.63 mmol, 1.4 equiv) was added as a
powder. The reaction was stirred at room temperature (about
25.degree. C.) for 4 hours and worked up as in Example A1.
[0680] Purification by liquid chromatography (3-4%
MeOH/CH.sub.2Cl.sub.2) gave the title compound, as a white foam
(430 mg, 1.00 mmol, 53% from the alcohol). The foam was dissolved
in Et.sub.2O and a white solid crystallized (337 mg). MS: APCI:
M+1: 429.2 (Exact Mass: 428.20).
Example A3
Synthesis of
7-{4-[4-(3-Chloro-2-methyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one
[0681] The reductive amination procedure from Example A1 was
followed, except that 2-chloro-3-methylphenylpiperazine was
substituted for 2,3-dichlorophenylpiperazine in the final stage of
the procedure.
[0682] Purification by liquid chromatography (3-4%
MeOH/CH.sub.2Cl.sub.2) gave the title compound as a white foam (558
mg, 1.30 mmol). The foam was dissolved in Et.sub.2O and 1 N HCl in
Et.sub.2O (1.3 mL) was added. The resulting white precipitate was
collected by filtration, washed with Et.sub.2O and dried to give a
white solid (538 mg). MS: APCI: M+1: 429.2 (Exact Mass:
428.20).
Example A4
Synthesis of
7-{4-[4-(2,3-Dimethyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8-
]naphthyridin-2-one
[0683] The reductive amination procedure from Example A1 was
followed using 1-(2,3-dimethyl-phenyl)-piperazine to give the title
compound. MS: APCI: M+1: 409.2 (Exact Mass: 408.25).
Example A5
Synthesis of
7-{4-[4-(2-Chloro-3-fluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one
[0684] The reductive amination procedure from Example A1 was
followed using 1-(2-chloro-3-fluoro-phenyl)-piperazine to give the
title compound (296 mg, 53%). MS: APCI: M+1: 433.2 (Exact Mass:
432.17).
Example A6
Synthesis of
7-{4-[4-(3-Chloro-2-fluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one
[0685] The reductive amination procedure from Example A1 was
followed, using 1-(3-chloro-2-fluoro-phenyl)-piperazine to give the
title compound. MS: APCI: M+1: 433.2 (Exact mass: 432.17).
Example A7
Synthesis of
7-{4-[4-(2-Chloro-3-trifluoromethyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-d-
ihydro-1H-[1,8]naphthyridin-2-one
[0686] An intermediate,
1-(2-Chloro-3-trifluoromethyl-phenyl)-piperazine was produced as
follows: To a stirred solution of trifluoro-methanesulfonic acid
2-chloro-3-trifluoromethyl-phenyl ester (5.0 g, 15.20 mmol) in
toluene (50 mL) at room temperature, was added 1-boc-piperazine
(3.39 g, 18.20 mmol), tris-(dibenzylideneacetone)dipalladium(0)
(Pd.sub.2(dba).sub.3) (3.49 g, 38.10 mmol),
tert-2,2'-bis(diphenyl)phosphino-1,1'-binaphthyl (BINAP) (4.27 g,
68.60 mmol) and sodium tert-butoxide (2.04 g, 21.30 mmol). The
mixture was degassed, filled with N.sub.2, degassed and heated at
80.degree. C. for 1.5 h. The mixture was diluted with ethyl
acetate, celite was added and the mixture was stirred at room
temperature for 15 min. It was filtered through a pad of silica gel
and the pad was washed with additional amounts of ethyl acetate,
The combined solvent was removed in vacuo and the residue was
purified on a silica gel column using hexanes-ethyl acetate (5:1)
as eluent to give
4-(2-chloro-3-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid
tert-butyl ester (2.30 g, 42%) as an oil. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 7.35 (m, 2H), 7.22 (d, 1H), 3.62 (br s, 4H),
3.05 (br s, 4H), 1.55 (s, 9H).
[0687] To a stirred solution of
4-(2-chloro-3-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid
tert-butyl ester (2.0 g, 5.49 mmol) in dichloromethane (15 mL)
cooled to 0.degree. C., was added trifluoroacetic acid (6.26 g,
54.90 mmol). The resulting mixture was stirred at room temperature
overnight and the solvent was removed in vacuo. Ether was added to
the residue and the solid formed was filtered to give the
intermediate compound (1.1 g, 55%) named immediately above. .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta. 9.85 (br s, 1H), 7.55 (d, 1H),
7.40 (d, 1H), 7.30 (m, 1H), 7.25 (s, 4H), 7.20 (s, 4H).
[0688] The reductive amination procedure from Example A1 was
followed using 1-(2-chloro-3-trifluoromethyl-phenyl)-piperazine,
the intermediate compound, to give the title compound (0.65 g,
71%). .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.65 (s, 1H),
7.40-7.20 (m, 3H), 6.40 (d, 1H), 4.25 (t, 2H), 3.15 (br s, 4H),
2.85 (t, 2H), 2.70 (br s, 4H), 2.45 (t, 2H), 1.80 (m, 2H), 1.65 (m,
2H). MS ES: m/z 483.01 (M+H).sup.+ (Exact mass: 482.17).
Example A8
Synthesis of
7-{4-[4-(2,3-Dichloro-4-fluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one
[0689] The reductive amination procedure from Example A1 was
followed using 1-(2,3-dichloro-4-fluoro-phenyl)-piperazine to give
the title compound. MS: APCI: M+1: 467.1 (Exact mass: 466.13).
Example A9
Synthesis of
7-{4-[4-(2-Chloro-4-fluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one
[0690] The reductive amination procedure from Example A1 was
followed using 1-(2-chloro-4-fluoro-phenyl)-piperazine to give the
title compound. MS: APCI: M+1: 433.2 (Exact mass: 432.17).
Example A10
Synthesis of
7-{4-[4-(2-Chloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]nap-
hthyridin-2-one
[0691] The reductive amination procedure from Example A1 was
followed using 1-(2-chloro-phenyl)-piperazine to give the title
compound. MS: APCI: M+1: 415.2 (Exact mass: 414.18).
Example A11
Synthesis of
7-[4-(4-Biphenyl-2-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthy-
ridin-2-one
[0692] The reductive amination procedure from Example A1 was
followed using 1-biphenyl-2-yl-piperazine to give the title
compound. MS: APCI: M+1: 457.3 (Exact mass: 456.25).
Example A12
Synthesis of
7-{4-[4-(2,5-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8-
]naphthyridin-2-one
[0693] The reductive amination procedure from Example A1 was
followed using 1-(2,5-dichloro-phenyl)-piperazine to give the title
compound (0.399 g, 82%). MS: APCI: M+1: 449.1 (Exact mass:
448.14).
Example A13
Synthesis of
7-{4-[4-(2-Chloro-4-fluoro-5-methyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-d-
ihydro-1H-[1,8]naphthyridin-2-one
[0694] The reductive amination procedure from Example A1 was
followed using 1-(2-chloro-4-fluoro-5-methyl-phenyl)-piperazine
hydrochloride to give the title compound (0.277 g, 57%). MS: APCI:
M+1: 447.2 (Exact mass: 446.19).
Example A14
Synthesis of
7-{4-[4-(5-Chloro-2-methyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one
[0695] The reductive amination procedure from Example A1 was
followed using 1-(5-chloro-2-methyl-phenyl)-piperazine to give the
title compound (0.358 g, 77%). MS: APCI: M+1: 429.2 (Exact mass:
428.20).
Example A15
Synthesis of
7-{4-[4-(2-Chloro-4-fluoro-3-methyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-d-
ihydro-1H-[1,8]naphthyridin-2-one
[0696] The reductive amination procedure from Example A1 was
followed using 1-(2-chloro-4-fluoro-3-methyl-phenyl)-piperazine
hydrochloride to give the title compound (0.463 g, 96%). MS: APCI:
M+1: 447.2 (Exact mass: 446.19).
Example A16
Synthesis of
7-{4-[4-(3-Ethyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naph-
thyridin-2-one
[0697] The reductive amination procedure from Example A1 was
followed using 1-(3-ethyl-phenyl)-piperazine to give the title
compound. MS: APCI: M+1: 409.2 (Exact mass: 408.25).
Example A17
Synthesis of
7-{4-[4-(3-Chloro-2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1-
H-[1,8]naphthyridin-2-one
[0698] An intermediate compound
1-(3-Chloro-2-methoxy-phenyl)-piperazine, was produced as follows.
A solution of 2,6-dichloroanisole (1.55 mL, 11.30 mmol) in dry
toluene (40 mL) was degassed for 10 min by blowing nitrogen into
the solution. This solution was then added via cannula to a flask
containing Boc-piperazine 3.16 g, 16.90 mmol), Cs.sub.2CO.sub.3
(5.15 g, 15.80 mmol), Pd.sub.2(dba).sub.3 (414 mg, 0.452 mmol, 4
mol %) and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl
(356 mg, 0.904 mmol, 8 mol %) under nitrogen. The reaction mixture
was heated at 100.degree. C. overnight (16 h). MS showed a small
product peak and a large Boc-piperazine peak. TLC (10% EtOAc/Hex)
showed a product spot. The reaction was allowed to cool to room
temperature and Et.sub.2O was added. The mixture was filtered
through Celite washing with Et.sub.2O. The filtrate was washed 3
times with 0.5 M citric acid (to remove excess Boc-piperazine) and
once with brine, dried over MgSO.sub.4 and concentrated to give a
brown oil. Purification by SiO.sub.2 chromatography (10%
EtOAC/Hexanes) gave
4-(3-chloro-2-methoxy-phenyl)-piperazine-1-carboxylic acid
tert-butyl ester as a pale yellow solid (278 mg, 8%).
[0699] To a solution of
4-(3-chloro-2-methoxy-phenyl)-piperazine-1-carboxylic acid
tert-butyl ester (273 mg, 0.835 mmol) in CH.sub.2Cl.sub.2 (4 mL)
was added TFA (4 mL) at RT. The reaction was stirred at room
temperature for 1 hour and concentrated to give a reddish brown
oil. Purification by SiO.sub.2 chromatography (10%
MeOH/CH.sub.2Cl.sub.2 with 1% NH.sub.4OH) gave
1-(3-Chloro-2-methoxy-phenyl)-piperazine as a pale yellow solid/oil
(137 mg, 0.604 mmol, 72%). MS: APCI: M+1: 227.1 (Exact Mass:
226.09).
[0700] The reductive amination procedure from Example A1 was
followed using 1-(3-chloro-2-methoxy-phenyl)-piperazine to give the
title compound. MS: APCI: M+1: 445.2 (Exact Mass: 444.19).
Example A18
Synthesis of
7-{4-[4-(3-Methyl-2-phenoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1-
H-[1,8]naphthyridin-2-one
[0701] The reductive amination procedure from Example A1 was
followed using 1-(3-methyl-2-phenoxy-phenyl)-piperazine to give the
title compound. MS: APCI: M+1: 487.2 (Exact Mass: 486.26).
Example A19
Synthesis of
7-{4-[4-(2,3-Dimethoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,-
8]naphthyridin-2-one
[0702] The reductive amination procedure from Example A1 was
followed using 1-(2,3-dimethoxy-phenyl)-piperazine to give the
title compound. MS: APCI: M+1: 441.6 (Exact Mass: 440.24).
Example A20
Synthesis of
7-{4-[4-(2-Ethoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]nap-
hthyridin-2-one
[0703] The reductive amination procedure from Example A1 was
followed using 1-(2-ethoxy-phenyl)-piperazine to give the title
compound (475 mg, 87%). MS: APCI: M+1: 425.2 (Exact Mass:
424.25).
Example A21
Synthesis of
7-{4-[4-(2-Chloro-3-ethoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one
[0704] A first intermediate, 2-Chloro-3-ethoxy-nitro-benzene, was
produced as follows: A slurry of 2-chloro-3-nitrophenol (5 g, 28.8
mmol), potassium carbonate (4.0 g, 28.8 mmol), and iodoethane (4.8
mL, 60 mmol) in acetonitrile (100 mL) was heated under reflux for 6
h. After cooling, the salts were removed by filtration and the
filtrate concentrated to a solid. The solid was triturated in
diethyl ether (100 mL). The triturant was concentrated to provide
the first intermediate compound (6.5 g). Proton NMR indicated a
spectrum consistent with that of the structure of the compound.
[0705] A second intermediate compound, 2-Chloro-3-ethoxy-aniline,
was produced as follows: To a solution of
2-chloro-3-ethoxy-nitro-benzene (6.5 g, 28.8 mmol), water (50 mL),
and glacial acetic acid (16.5 mL) in methanol (200 mL) was added Fe
dust (16.1 g, 28.8 mmol). The slurry was heated under reflux for 90
minutes, cooled, and filtered. The filtrate was concentrated in
vacuo to a solid which was triturated in water (.about.100 mL) to
provide the acetate salt of the desired product. This salt, which
was only sparingly soluble in water, was converted to the free base
with NaHCO.sub.3 and extracted into CHCl.sub.3, dried over
Na.sub.2SO.sub.4, and concentrated to provide the second
intermediate compound (5 g). MS: APCI: M+1: 171.9 (Exact Mass:
171.05).
[0706] A third intermediate compound,
1-(2-Chloro-3-ethoxy-phenyl)-piperazine, was produced as follows: A
mixture of 2-chloro-3-ethoxy-aniline (3.0 g, 17.5 mmol) and
bis(2-chloroethyl)amine hydrochloride (3.12 g, 17.5 mmol) was
heated under reflux in chlorobenzene (20 mL) for 48 h. Diethyl
ether (200 mL) was added to the cooled solution to provide a
crunchy solid that was collected by filtration. An aqueous solution
of this material was treated with saturated NaHCO3, extracted into
CHCl3, dried over Na2SO4, and concentrated to an oil which was
purified by chromatography (MPLC, elution with 15% MeOH in CHCl3)
to provide the third intermediate compound (3.5 g, 14.6 mmol, 83%)
as an oil. MS: APCI: M+1: 241.1 (Exact Mass: 240.10).
[0707] Finally, a solution of
4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
(0.4 g, 1.17 mmol) and 1-(2-chloro-3-ethoxy-phenyl)-piperazine
(0.445 g, 1.85 mmol) in 1,2-dichloroethane (30 mL) was stirred for
15 min before NaBH(OAc).sub.3 (0.46 g, 2.17 mmol) was added as a
powder. The reaction was stirred at room temperature for 18 h and
quenched with saturated NaHCO.sub.3 and H.sub.2O. The mixture was
extracted with CHCl.sub.3. The organic layer was washed with
saturated NaHCO.sub.3, H.sub.2O and brine, dried over
Na.sub.2SO.sub.4 and concentrated to afford an oil. Purification by
liquid chromatography (1% MeOH/CH.sub.2Cl.sub.2) gave the product
as a white foam. Trituration of this foam in a minimal amount of
diethyl ether provided the title compound as white crystals (300
mg, 0.655 mmol, 56%). mp 110-112.degree. C. MS: APCI: M+1: 459.2
(Exact Mass: 458.21).
Example A22
Synthesis of
7-{4-[4-(2-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1-
H-[1,8]naphthyridin-2-one
[0708] 1-(2-Chloro-3-methoxy-phenyl)-piperazine was prepared
according to the procedure for
1-(2-chloro-3-ethoxy-phenyl)-piperazine in Example A21.
[0709] The reductive amination procedure from Example A21 was
followed using the 1-(2-chloro-3-methoxy-phenyl)-piperazine to give
the title compound. MS: APCI: M+1: 445.6 (Exact Mass: 444.19).
Example A23
Synthesis of
7-{4-[4-(2-Chloro-3-isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one
[0710] 1-(2-Chloro-3-isopropoxy-phenyl)-piperazine was prepared
according to the procedure for
1-(2-chloro-3-ethoxy-phenyl)-piperazine in Example A21.
[0711] The reductive amination procedure from Example A21 was
followed using 1-(2-chloro-3-isopropoxy-phenyl)-piperazine to give
the title compound. MS: APCI: M+1: 473.2 (Exact Mass: 472.22).
Example A24
Synthesis of
7-{4-[4-(3-Methoxy-2-methyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1-
H-[1,8]naphthyridin-2-one
[0712] The reductive amination procedure from Example A1 was
followed using 1-(3-methoxy-2-methyl-phenyl)-piperazine to give the
title compound. MS: APCI: M+1: 425.2 (Exact Mass: 424.25).
Example A25
Synthesis of
7-{4-[4-(5-Chloro-2-isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one
[0713] To a suspension of
4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
(0.241 g, 1.02 mmol, 1 eq) and
1-(5-chloro-2-isopropoxy-phenyl)-piperazine (0.382 g, 1.13 mmol,
1.1 eq) in dichloroethane (5 mL) was added NaBH(OAc).sub.3 (0.583
g, 2.75 mmol, 2.67 eq). The slurry was allowed to stir overnight at
room temperature (18 h). Analysis by HPLC showed reaction mostly
complete. The mixture was diluted with EtOAc and quenched with
saturated NaHCO.sub.3. The organic phase was then washed with
brine, dried over Na.sub.2SO.sub.4, filtered and evaporated in
vacuo. Purification by silica gel chromatography (100% EtOAc)
followed by formation of the HCl salt using 1N HCl in ether
provided the title compound (0.219 g, 25%). MS: APCI: M+1: 473.2
(Exact Mass: 472.22).
Example A26
Synthesis of
7-{4-[4-(2-Isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8-
]naphthyridin-2-one
[0714] The above reductive amination procedure in Example A25 using
1-(2-isopropoxy-phenyl)-piperazine provided the title compound
(0.152 g, 32%). CHN found: C, 67.72; H, 7.81; N, 12.55. This
calculates out for C.sub.25H.sub.34N.sub.4O.sub.3 plus 0.13H.sub.2O
(residual solvent).
Example A27
Synthesis of
7-{4-[4-(2-Isobutoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]-
naphthyridin-2-one
[0715] The above reductive amination procedure in Example A25 using
1-(2-isobutoxy-phenyl)-piperazine provided the title compound
(0.177 g, 37%). CHN found: C, 63.22; H, 7.65; N, 11.19. This
calculates out for
C.sub.26H.sub.36N.sub.4O.sub.3.times.1.05HCl.
Example A28
Synthesis of
7-{4-[4-(2-Acetyl-3-chloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one
[0716] An intermediate compound,
1-(2-Chloro-6-piperazin-1-yl-phenyl)-ethanone, was produced as
follows: To a 250 mL flask was added piperazine (72 g, 0.834 mol)
and 1-(2-chloro-6-fluoro-phenyl)-ethanone (24 g, 0.139 mol)
followed by heating to 120.degree. C. for 2 hours. Excess
piperazine was then distilled from the flask under vacuum leaving a
brown oil which solidified. This oil (10 g) was purified by
chromatography on silica gel (dichloromethane/methanol 98:2) to
give the intermediate compound (4.89 g).
[0717] In a manner similar to that of other examples, above,
1-(2-chloro-6-piperazin-1-yl-phenyl)-ethanone was coupled by
reductive amination to
4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
followed by typical workup and purification to give the title
compound, mp 115.degree. C. MS: APCI: M+1: 457.2 (Exact Mass:
456.19).
Example A29
Synthesis of
7-{4-[4-(3-Chloro-2-ethyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H--
[1,8]naphthyridin-2-one
[0718] An intermediate compound,
1-(3-Chloro-2-ethyl-phenyl)-piperazine hydrochloride, was produced
as follows: To 1-(2-chloro-6-piperazin-1-yl-phenyl)-ethanone (2.45
g, 10.3 mmol) was added trifluoroacetic acid (18 g) and
triethylsilane (18 g) followed by heating to reflux for 5 hours.
Upon cooling, the solution was evaporated and the residue suspended
in water. The pH was adjusted to 13 by addition of 4N NaOH followed
by extraction with diethyl ether. The organic layer was dried over
magnesium sulfate and evaporated to give a yellow oil which was
distilled and crystallized as the hydrochloride salt from an ether
solution by addition of ethereal HCl.
[0719] In a manner similar to that of other examples above,
1-(3-chloro-2-ethyl-phenyl)-piperazine hydrochloride was coupled by
reductive amination to
4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
followed by typical workup and purification to give the title
compound. MS: APCI: M+1: 443.2 (Exact Mass: 442.21).
Example A30
Synthesis of
7-{4-[4-(2-Acetyl-3-fluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one
[0720] A first intermediate compound,
4-(2-Acetyl-3-fluoro-phenyl)-piperazine-1-carboxylic acid
tert-butyl ester, was produced as follows: To acetonitrile (100 mL)
was added boc-piperazine (28.63 g, 0.153 mol),
2,6-difluoroacetophenone (24 g, 0.154 mol), potassium carbonate (53
g, 0.384 mol) and potassium fluoride (8.93 g, 0.154 mol) followed
by heating to 100.degree. C. for 24 hours. Concentration of the
solution in vacuo gave a mixture of solids which were isolated by
filtration. The first intermediate compound was obtained by
recrystallization from ethyl acetate, mp 88.degree. C.
[0721] A second intermediate compound,
1-(2-Fluoro-6-piperazin-1-yl-phenyl)-ethanone, was produced as
follows: To dichloromethane (10 mL) was added
4-(2-acetyl-3-fluoro-phenyl)-piperazine-1-carboxylic acid
tert-butyl ester giving a solution. Trifluoroacetic acid (2.12 g)
was added followed by stirring at 25.degree. C. for 3 hours. The
mixture was evaporated and the residue taken up into diethyl ether
and water. The pH was then adjusted to 13 by addition of 4N NaOH
and the ether phase was decanted. The ether phase was dried over
magnesium sulfate, filtered and concentrated in vacuo to give the
title compound as a white solid (1.09 g), mp 64.degree. C.
[0722] In a manner similar to that of other examples above,
1-(2-fluoro-6-piperazin-1-yl-phenyl)-ethanone was coupled by
reductive amination to
4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
followed by typical workup and purification to give the title
compound. MS: APCI: M+1: 441.3 (Exact Mass: 440.22).
Example A31
Synthesis of
7-{4-[4-(2-Ethyl-3-fluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H--
[1,8]naphthyridin-2-one
[0723] An intermediate compound,
1-(2-Ethyl-3-fluoro-phenyl)-piperazine hydrochloride, was produced
as follows: To 4-(2-acetyl-3-fluoro-phenyl)-piperazine-1-carboxylic
acid tert-butyl ester (2.0 g, 6.2 mmol) was added trifluoroacetic
acid (10.6 g) and triethylsilane (7.2 g) followed by heating to
reflux for 5 hours. Upon cooling, the solution was evaporated and
the residue suspended in water. The pH was adjusted to 13 by
addition of 4N NaOH followed by extraction with diethyl ether. The
organic layer was dried over magnesium sulfate and evaporated to
give a yellow oil which was distilled and crystallized as the
hydrochloride salt from an ether solution by addition of ethereal
HCl giving the intermediate compound (0.907 g).
[0724] In a manner similar to that of other examples above,
1-(2-ethyl-3-fluoro-phenyl)-piperazine hydrochloride was coupled by
reductive amination to
4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
followed by typical workup and purification to give the title
compound. MS: APCI: M+1: 427.2 (Exact Mass: 426.24).
Example A32
Synthesis of
7-{4-[4-(3-Acetyl-2-chloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one
[0725] A first intermediate compound,
1-(3-Amino-2-chloro-phenyl)-ethanone, was produced as follows: To
THF (400 mL) was added 1-(2-chloro-3-nitro-phenyl)-ethanone (13.1
g, 065.6 mmol, European Journal of Medicinal Chemistry, 1989, 24,
479-84) followed by Raney Nickel (2.0 g) and pressurization to 25
psi with hydrogen gas over 24 hours. The mixture was filtered and
evaporated to an oil. The oil was resuspended in water and diethyl
ether, filtered and the organic phase decanted. Addition of hexane
gave a crystalline solid, which was filtered and dried in vacuo to
give the first intermediate compound as a solid (9.3 g).
[0726] A second intermediate compound,
4-(3-Acetyl-2-chloro-phenyl)-piperazine-1-carboxylic acid
tert-butyl ester, was produced as follows: In a manner similar to
the preparation of
1-(6,7,8,9-tetrahydro-5H-benzocyclohepten-1-yl)-piperazine,
1-(3-amino-2-chloro-phenyl)-ethanone was converted to crude
1-(2-chloro-3-piperazin-1-yl-phenyl)-ethanone (8.51 g, 35.6 mmol)
to which was added di-t-butyloxycarbonate (7.78 g, 35.6 mmol) as a
solution in dichloromethane (40 mL). After 2 hours the mixture was
concentrated and purified by chromatography on silica gel eluting
with dichloromethane and ethyl acetate to give the second
intermediate compound as an oil (4.96 g).
[0727] A third intermediate compound,
1-(2-Chloro-3-piperazin-1-yl-phenyl)-ethanone trifluoroacetate, was
produced as follows: To dichloromethane (10 mL) was added
4-(3-acetyl-2-chloro-phenyl)-piperazine-1-carboxylic acid
tert-butyl ester (1.01 g, 2.98 mmol) followed by trifluoroacetic
acid (0.5 mL). The mixture was stirred at 25.degree. C. for 2
hours, and the solvent removed by evaporation to give third
intermediate compound as an oil.
[0728] In a manner similar to that of other examples above,
1-(2-chloro-3-piperazin-1-yl-phenyl)-ethanone trifluoroacetate was
coupled by reductive amination to
4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
followed by typical workup and purification to give the title
compound, mp 138-139.degree. C. MS: APCI: M+1: 457.2 (Exact Mass:
456.19).
Example A33
Synthesis of
7-{4-[4-(3-Acetyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]nap-
hthyridin-2-one
[0729] The reductive amination procedure from Example A1 was
followed using 1-(3-piperazin-1-yl-phenyl)-ethanone to give the
title compound. MS: APCI: M+1: 423.2 (Exact Mass: 422.23).
Example A34
Synthesis of
7-{4-[4-(2-Acetyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]nap-
hthyridin-2-one
[0730] The reductive amination procedure from Example A1 was
followed using 1-(2-piperazin-1-yl-phenyl)-ethanone to give the
title compound. MS: APCI: M+1: 423.3 (Exact Mass: 422.23).
Example A35
Synthesis of
7-{4-[4-(2-Ethyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naph-
thyridin-2-one
[0731] The reductive amination procedure from Example A1 was
followed using 1-(2-ethyl-phenyl)-piperazine to give the title
compound. MS: APCI: M+1: 409.2 (Exact Mass: 408.25).
Example A36
Synthesis of
7-[4-(4-o-Tolyl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin--
2-one
[0732] The reductive amination procedure from Example A1 was
followed using 1-(2-methyl-phenyl)-piperazine to give the title
compound. MS: APCI: M+1: 395.2 (Exact Mass: 394.24).
Example A37
Synthesis of
7-{4-[4-(2-Trifluoromethyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one
[0733] The reductive amination procedure from Example A1 was
followed using 1-(2-trifluoromethyl-phenyl)-piperazine to give the
title compound. MS: APCI: M+1: 449.2 (Exact Mass: 448.21).
Example A38
Synthesis of
7-{4-[4-(3-Trifluoromethyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one
[0734] The reductive amination procedure from Example A1 was
followed using 1-(3-trifluoromethyl-phenyl)-piperazine to give the
title compound. MS: APCI: M+1: 449.3 (Exact Mass: 448.21).
Example A39
Synthesis of
7-[4-(4-Phenyl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-
-one
[0735] The reductive amination procedure from Example A1 was
followed using 1-phenyl-piperazine to give the title compound. MS:
APCI: M+1: 381.1 (Exact Mass: 380.22).
Example A40
Synthesis of
7-{4-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]nap-
hthyridin-2-one
[0736] The reductive amination procedure from Example A1 was
followed using 1-(4-fluoro-phenyl)-piperazine to give the title
compound. MS: APCI: M+1: 399.4 (Exact Mass: 398.21).
Example A41
Synthesis of
7-{4-[4-(2,4-Difluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8-
]naphthyridin-2-one
[0737] The reductive amination procedure from Example A1 was
followed using 1-(2,4-difluoro-phenyl)-piperazine to give the title
compound. MS: APCI: M+1: 417.2 (Exact Mass: 416.20).
Example A42
Synthesis of
7-(4-{4-[2-(1,1-Difluoro-ethyl)-phenyl]-piperazin-1-yl}-butoxy)-3,4-dihyd-
ro-1H-[1,8]naphthyridin-2-one
[0738] A first intermediate compound,
1-Bromo-2-(1,1-difluoro-ethyl)-benzene, was produced as follows: A
solution of 1-(2-bromo-phenyl)-ethanone (3.98 g, 20 mmol) in DAST
(5.3 mL, 40 mmol) was heated at 55.degree. C. for 48 h, cooled to
RT, diluted with CCl.sub.4 (20 mL) and poured into ice (100 g). The
mixture was extracted with CCl.sub.4 (2.times.40 mL). The combined
organic phases were dried, concentrated, and purified by
chromatography on silica gel to give the first intermediate
compound (2.2 g, 50%). .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
7.60 (m, 2H), 7.45 (t, 1H), 7.20 (m, 1H), 2.05 (t, 3H).
[0739] A second intermediate compound,
1-[2-(1,1-Difluoro-ethyl)-phenyl]-piperazine, was produced as
follows: To a mixture of 1-bromo-2-(1,1-difluoro-ethyl)-benzene
(1.3 g, 5.91 mmol), piperazine (0.64 g, 7.39 mmol),
Pd.sub.2(dba).sub.3 (1.30 g, 1.42 mmol), BINAP (0.82 g, 2.63 mmol),
NaOtBu (0.80 g, 8.30 mmol) in toluene (40 mL) was bubbled N.sub.2
gas for 10 min. The mixture was then heated at 110.degree. C. for 2
h, cooled to RT, diluted with EtOAc (300 mL), filtered through a
pad of celite and concentrated. The residue was treated with 1 N
HCl to pH=2 and washed with ether (2.times.50 mL). The aqueous
phase was basified with K.sub.2CO.sub.3 to pH=11 and extracted with
CH.sub.2Cl.sub.2 (3.times.50 mL). The combined organic phases were
dried and concentrated to give the second intermediate compound
(0.80 g, 60%). .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.60 (m,
1H), 7.40 (m, 1H), 7.38 (m, 1H), 7.20 (m, 1H), 3.00 (m, 4H), 2.90
(m, 4H), 2.10 (t, 3H).
[0740] The reductive amination procedure from Example A1 was
followed using 1-[2-(1,1-difluoro-ethyl)-phenyl]-piperazine to give
the title compound (0.48 g, 91%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 10.40 (s, 1H), 10.20 (s, 1H), 7.50 (m, 4H),
7.35 (m, 1H), 6.40 (d, 1H), 4.20 (s, 2H), 3.60 (m, 2H), 3.30-3.00
(m, 8H), 2.80 (m, 2H), 2.50 (m, 2H), 2.10 (t, 3H), 1.90-1.70 (m,
4H).
Example A43
Synthesis of
7-[4-(4-Pyridin-2-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyr-
idin-2-one
[0741] The reductive amination procedure from Example A1 was
followed using 1-pyridin-2-yl-piperazine to give the title
compound. MS: APCI: M+1: 382.1 (Exact Mass: 381.22).
Example A44
Synthesis of
7-{4-[4-(6-Methyl-pyridin-2-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1-
,8]naphthyridin-2-one
[0742] To a suspension of 1-(6-methyl-pyridin-2-yl)-piperazine
bishydrochloride (0.77 g, 3.08 mmol) in dichloroethane (10 mL) was
added Et.sub.3N (1.0 mL, 7.17 mmol) and the mixture was stirred for
30 min.
4-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
(0.85 g, 3.63 mmol) was added as a solution in dichloroethane (3
mL) and the mixture was stirred at room temperature for 15 min.
NaBH(OAc).sub.3 (1.1 g, 5.2 mmol) was added as a solid and the
mixture was stirred at room temperature for 3 h. The reaction was
poured into EtOAc and washed with saturated NaHCO.sub.3 and brine,
dried over MgSO.sub.4 and concentrated. The residue was partitioned
between EtOAc and pH 4.5 aqueous citric acid. The product went into
the aqueous layer selectively over the impurities. The aqueous
layer was neutralized with solid NaHCO.sub.3 to pH 8 and extracted
with EtOAc. The organic layer was washed with brine, dried over
MgSO.sub.4 and concentrated to give the title compound as a sticky
foam (0.77 g). The foam was dissolved in Et.sub.2O and treated with
anhydrous HCl gas to give a white precipitate. The mixture was
filtered, washed with Et.sub.2O and hexanes, and dried to give a
white solid (616 mg). MS: APCI: M+1: 396.1 (Exact Mass:
395.23).
Example A45
Synthesis of
7-{4-[4-(6-Ethyl-pyridin-2-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,-
8]naphthyridin-2-one
[0743] To a solution of 1-(6-ethyl-pyridin-2-yl)-piperazine (0.41
g, 2.13 mmol) in dichloroethane (15 mL) was added Et.sub.3N (0.22
g, 2.13 mmol) and the mixture was stirred for 5 min.
4-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
(0.50 g, 2.13 mmol) was added as a solution in dichloroethane (3
mL) and the mixture was stirred at room temperature for 15 min.
NaBH(OAc).sub.3 (0.63 g, 3.00 mmol) was added as a solid and the
reaction was stirred at room temperature for 2 h. The reaction was
quenched with saturated NaHCO.sub.3 and extracted with EtOAc. The
organic layer was washed with brine, dried over MgSO.sub.4 and
concentrated. Purification by liquid chromatography (Biotage 40M,
gradient elution 100% CH.sub.2Cl.sub.2 to 99%
CH.sub.2Cl.sub.2/MeOH) afforded the title compound as a sticky
white foam (413 mg, 1.01 mmol, 47%). The foam was dissolved in
Et.sub.2O and treated with anhydrous HCl gas to give a white
precipitate. The mixture was filtered and dried to give a white
powder (287 mg). MS: APCI: M+1: 410.3 (Exact Mass: 409.25).
Example A46
Synthesis of
7-{4-[4-(6-Cyclopropyl-pyridin-2-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro--
1H-[1,8]naphthyridin-2-one
[0744] A mixture of
4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
(0.47 g, 2.0 mmol) and 1-(6-cyclopropyl-pyridin-2-yl)-piperazine
(0.41 g, 2.0 mmol) in dichloroethane (12 mL) was stirred for 20 min
and NaBH(OAc).sub.3 (0.55 g, 2.6 mmol) was added. The reaction was
stirred at room temperature for 2.5 h. The reaction was quenched
with saturated NaHCO.sub.3 and extracted with Et.sub.2O. The
organic layer was washed with brine, dried over MgSO.sub.4 and
concentrated. Purification by liquid chromatography (Biotage 12M,
eluted with CHCl.sub.3) gave the title compound as an oil. The oil
was dissolved in Et.sub.2O and treated with anhydrous HCl gas to
give a precipitate. The mixture was filtered, washed with Et.sub.2O
and hexanes and dried to give a white solid (121 mg). MS: APCI:
M+1: 422.3 (Exact Mass: 421.25).
Example A47
Synthesis of
7-{4-[4-(4-Methyl-pyrimidin-2-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H--
[1,8]naphthyridin-2-one
[0745] In a manner similar to that of other examples above,
4-methyl-2-piperazin-1-yl-pyrimidine hydrochloride (U.S. Pat. No.
6,303,603) was coupled by reductive amination to
4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
followed by typical workup and purification to give the title
compound. MS: APCI: M+1: 397.2 (Exact Mass: 396.23).
Example A48
Synthesis of
7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]napht-
hyridin-2-one
[0746] The procedure in Example A1 was followed using
1-naphthalen-1-yl-piperazine hydrochloride. Purification by liquid
chromatography (4% MeOH/CH.sub.2Cl.sub.2) gave the title compound
as a white foam (595 mg, 1.38 mmol). The foam was dissolved in
Et.sub.2O and 1 N HCl in Et.sub.2O (1.4 mL) was added. The
resulting white precipitate was collected by filtration, washed
with Et.sub.2O and dried to give a white solid (600 mg). .sup.1H
NMR (400 MHz, d.sub.6-dmso) .delta. 10.69 (bs, 1H), 10.26 (s, 1H),
8.10 (m, 1H), 7.88 (m, 1H), 7.63 (d, 1H), 7.52-7.41 (m, 4H), 7.14
(d, 1H), 6.34 (d, 1H), 4.20 (t, 2H), 3.59 (m, 2H), 3.39 (m, 4H),
3.22 (m, 4H), 2.75 (t, 2H), 2.44 (t, 2H), 1.87 (bm, 2H), 1.75 (m,
2H). MS: APCI: M+1: 431.2 (Exact Mass: 430.24).
Example A49
Synthesis of
7-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4--
dihydro-1H-[1,8]naphthyridin-2-one
[0747] The procedure in Example A1 was followed using
1-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine. Purification by
liquid chromatography (0-5% MeOH/CH.sub.2Cl.sub.2) gave the title
compound as a white foam (668 mg, 1.53 mmol). The foam was
dissolved in CH.sub.3CN and a solid crashed out, which was
collected by filtration, washed with Et.sub.2O and dried to give a
white solid (657 mg, 1.51 mmol, 52%). MS: APCI: M+1: 435.2 (Exact
Mass: 434.27).
Example A50
Synthesis of
7-{4-[4-(3-Fluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-but-
oxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one
[0748] The reductive amination procedure from Example A1 was
followed using
1-(3-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine to give
the title compound (0.461 g; 72%). MS: APCI: M+1: 453.3 (Exact
mass: 452.26).
Example A51
Synthesis of
7-{4-[4-(8-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy-
}-3,4-dihydro-1H-[1,8]naphthyridin-2-one
[0749] A first intermediate compound,
8-Hydroxy-3,4-dihydro-2H-naphthalen-1-one, was produced as follows:
A solution of naphthalene-1,8-diol (1.00 g, 6.24 mmol, J. Org.
Chem. 2002, 67, 5190) in ethanol (100 mL) was treated with 10% Pd/C
(wet, 0.342 g), then hydrogenated at 50 psi H.sub.2 for 3 hours.
The mixture was filtered through a Celite pad and the pad was
rinsed with ethanol. The filtrate was concentrated under vacuum to
give a brown oil. The oil was purified by column chromatography
(hexanes/ethyl acetate, 7:1) to afford the first intermediate
compound (0.760 g, 78%) as a yellow liquid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.44 (s, 1H), 7.46 (t, 1H), 6.80 (d, 1H),
6.77 (d, 1H), 2.90 (t, 2H), 2.69 (t, 2H), 2.05-1.98 (m, 2H).
[0750] A second intermediate compound, trifluoro-methanesulfonic
acid 8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl ester, was produced
as follows: An ice-cold brown solution of
8-hydroxy-3,4-dihydro-2H-naphthalen-1-one (0.76 g, 4.68 mmol) in
dichloromethane (25 mL) was treated with lithium chloride (0.20 g,
4.72 mmol), followed by triethylamine (0.65 mL, 4.66 mmol).
Trifluoromethanesulfonic anhydride (0.8 mL, 4.76 mmol) was added
dropwise to the mixture. After the exothermic reaction subsided,
the resulting mixture was stirred at 0.degree. C. for 1 hour, then
quenched with water and extracted with dichloromethane. The
extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under vacuum to give a brown oil. The oil was purified
by column chromatography (hexanes/ethyl acetate, 4:1) to afford the
second intermediate compound (1.164 g, 84%) as a yellow liquid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.52 (t, 1H), 7.33 (d,
1H), 7.13 (d, 1H), 3.04 (t, 2H), 2.72 (t, 2H), 2.20-2.10 (m,
2H).
[0751] A third intermediate compound,
4-(8-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine-1-carboxylic
acid tert-butyl ester, was produced as follows: Tetrahydrofuran (20
mL) was degassed with nitrogen for 15 minutes, then treated with
2-(di-tert-butylphosphino)biphenyl (0.304 g, 1.02 mmol) and
degassed for another 5 minutes. To this mixture was added
trifluoro-methanesulfonic acid
8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl ester (3.00 g, 10.20
mmol), Boc-piperazine (2.279 g, 12.20 mmol), and potassium
phosphate (3.03 g, 14.27 mmol) followed by palladium acetate (0.228
g, 1.02 mmol) and the resulting mixture was degassed with nitrogen
for 5 minutes. The brown suspension was heated at 80.degree. C. for
3 days, then cooled to room temperature and diluted with ethyl
acetate. The suspension was filtered through a Celite pad and the
pad was rinsed with ethyl acetate. The filtrate was concentrated in
vacuo to give a brown oil. The oil was purified by column
chromatography (hexanes/ethyl acetate, 7:1 to 3:1 gradient) to
afford the third intermediate compound (1.237 g, 37%) as a brown
oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.34 (t, 1H), 6.86
(t, 2H), 3.70-3.62 (m, 4H), 3.06-2.96 (m, 4H), 2.94 (t, 2H), 2.62
(t, 2H), 2.10-2.00 (m, 2H), 1.48 (s, 9H).
[0752] A fourth intermediate compound,
8-Piperazin-1-yl-3,4-dihydro-2H-naphthalen-1-one, was produced as
follows: A brown solution of
4-(8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine-1-carboxylic
acid tert-butyl ester (1.089 g, 3.30 mmol) in dichloromethane (10
mL) was treated with trifluoroacetic acid (5 mL, 64.9 mmol). The
resulting mixture was stirred at room temperature for 1.5 hours.
The dark brown solution was concentrated under vacuum to afford the
fourth intermediate compound (1.03 g, quantitative) as a brown oil.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.69 (br s, 2H), 7.43
(t, 1H), 6.96 (d, 2H), 3.31-3.23 (m, 4H), 3.16-3.11 (m, 4H), 2.91
(t, 2H), 2.54 (t, 2H), 1.99-1.91 (m, 2H).
[0753] The reductive amination procedure from Example A1 was
followed using 8-piperazin-1-yl-3,4-dihydro-2H-naphthalen-1-one to
give the title compound (0.411 g, 61%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.53 (br s, 1H), 7.36 (d, 1H), 7.32 (d, 1H),
6.88 (d, 1H), 6.81 (d, 1H), 6.35 (d, 1H), 4.22 (d, 2H), 3.14-3.05
(m, 4H), 2.92 (d, 2H), 2.85 (d, 2H), 2.75-2.67 (m, 4H), 2.67-2.59
(m, 4H), 2.49 (t, 2H), 2.08-2.00 (m, 2H), 1.84-1.75 (m, 2H),
1.75-1.66 (m, 2H). MS ES: 449.26 (M+H).sup.+ (Exact mass:
448.25).
Example A52
Synthesis of
7-{4-[4-(7,7-Dimethyl-8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-
-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one
[0754] A first intermediate compound,
4-(7,7-Dimethyl-8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine-1-ca-
rboxylic acid tert-butyl ester, was produced as follows: To a
stirred solution of compound
4-(8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine-1-carboxylic
acid tert-butyl ester (1.25 g, 4.1 mmol) in anhydrous THF (20 mL)
was added MeI (2.33 g, 16.4 mmol, 4.0 equiv). The reaction mixture
was cooled to 0.degree. C. and potassium tert-butoxide (1.4 g, 12.3
mmol, 3.0 equiv) was added. The reaction mixture was warmed to room
temperature and stirred for 30 min. TLC indicated that the reaction
was incomplete. Excess MeI (1.0 mL) was added and the stirring was
continued at room temperature for an additional hour. The reaction
mixture was quenched with water and extracted with ethyl acetate.
The extracts were dried over Na.sub.2SO.sub.4 and concentrated to
afford the first intermediate compound (1.20 g, 88%) as dark yellow
thick oil which was carried to the next step without further
purification. .sup.1H NMR: .delta. (CDCl.sub.3, 400 MHz) 7.30 (t,
1H), 6.90 (m, 2H), 3.70 (m, 4H), 3.00 (br s, 4H), 3.95 (t, 2H),
1.90 (t, 2H), 1.50 (s, 9H), 1.20 (s, 6H); ESMS: 359.23 (Exact mass:
358.23).
[0755] A second intermediate compound,
2,2-Dimethyl-8-piperazin-1-yl-3,4-dihydro-2H-naphthalen-1-one, was
produced as follows: An ice cold solution of
4-(7,7-dimethyl-8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine-1-ca-
rboxylic acid tert-butyl ester (0.60 g, 1.8 mmol) in
dichloromethane (10.0 mL) was treated with TFA (5.0 mL) and stirred
for 2 h at room temperature. The solvents were removed under
reduced pressure and purified by column chromatography eluting with
5% methanol in dichloromethane to afford the second intermediate
compound (0.50 g, 77%) as yellow solid. .sup.1H NMR: .delta.
(CDCl.sub.3, 400 MHz) 9.80 (br s, 2H), 7.30 (t, 1H), 6.90 (m, 2H),
3.50 (br s, 4H), 3.30 (br s, 4H), 3.00 (t, 2H), 1.90 (t, 3H), 1.20
(s, 6H); ESMS: 259.14 (Exact mass: 258.17).
[0756] The reductive amination procedure from Example A1 was
followed using
2,2-dimethyl-8-piperazin-1-yl-3,4-dihydro-2H-naphthalen-1-one to
give the title compound (0.20 g, 60%). .sup.1H-NMR: .delta.
(CDCl.sub.3, 400 MHz) 7.80 (br s, 1H), 7.40-7.20 (m, 2H), 6.90 (d,
1H), 6.85 (d, 1H), 6.40 (d, 2H), 4.30 (m, 2H), 3.10 (br s, 4H),
3.00-2.80 (m, 4H), 2.80-2.60 (m, 6H), 2.50 (t, 2H), 1.90-1.60 (m,
6H), 1.15-1.05 (m, 6H); ESMS: 477.25 (Exact mass: 476.28).
Example A53
Synthesis of
7-{4-[4-(7,7-Dimethyl-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-
-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one
[0757] An intermediate compound,
1-(7,7-Dimethyl-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine, was
produced as follows:
2,2-Dimethyl-8-piperazin-1-yl-3,4-dihydro-2H-naphthalen-1-one (0.60
g, 1.8 mmol) was taken up in BF.sub.3-OEt.sub.2 (6.0 mL) and
triethyl silane (1.8 mL, 10.8 mmol, 6.0 equiv) was added. The
reaction mixture was heated in a sealed tube at 90.degree. C. for 6
h. The sealed tube was cooled and excess ether was added to the
reaction mixture. A white precipitate was formed which was
collected by filtration. The intermediate compound product (0.40 g,
quantitative) was used in the next step without purification.
.sup.1H-NMR: .delta. (CDCl.sub.3, 400 MHz) 7.60 (d, 1H), 7.20 (m,
2H), 4.00 (m, 2H), 3.80 (m, 2H), 3.45 (m, 2H), 3.10 (m, 2H), 2.90
(t, 2H), 2.65 (s, 2H), 1.60 (t, 2H). ESMS: 245.17 (Exact mass:
244.19).
[0758] The reductive amination procedure from Example A1 was
followed using
1-(7,7-dimethyl-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine to
give the title compound. .sup.1H NMR: .delta. (CDCl.sub.3, 400 MHz)
7.80 (br s, 1H), 7.40 (d, 1H), 7.10 (t, 1H), 6.90 (m, 2H), 6.40 (d,
1H), 4.15 (t, 2H), 2.95-2.45 (m, 16H), 1.80-1.70 (m, 4H), 1.50 (t,
2H), 1.25 (t, 2H), 1.00 (s, 6H). ESMS: 463.28 (Exact mass:
462.30).
Example A54
Synthesis of
7-{4-[4-(7,7-Difluoro-8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-
-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one
[0759] A first intermediate compound,
4-(7,7-Difluoro-8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine-1-ca-
rboxylic acid tert-butyl ester, was produced as follows: 1M LiHMDS
in THF (38.5 mL, 38.5 mmol) was cooled to -78.degree. C. and
4-(8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine-1-carboxylic
acid tert-butyl ester (3.64 g, 11 mmol) in THF (8 mL) was added
dropwise. The reaction mixture was stirred at 0.degree. C. for 2.5
h and re-cooled to -78.degree. C. N-fluorobenzenesulfonimide (12.14
g, 38.5 mmol) in THF (25 mL) was added dropwise and the reaction
was stirred overnight at room temperature. Saturated NH.sub.4Cl
solution was added and the mixture was extracted with Et.sub.2O.
Column chromatography of the orange oily material, eluting with
EtOAc:Hex (2:8) and then changing to (2.5:7.5) gave the first
intermediate compound (0.42 g) as a thick orange oil, along with a
mixture of the title compound with monofluorinated compound (1.69
g). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.42 (t, 1H), 6.91
(d, 1H), 6.83 (d, 1H), 3.72 (m, 4H), 3.16 (t, 2H), 3.11-2.96 (br s,
4H), 2.56-2.42 (m, 2H), 1.43 (s, 9H).
[0760] A second intermediate compound,
2,2-Difluoro-8-piperazin-1-yl-3,4-dihydro-2H-naphthalen-1-one, was
produced as follows: To a solution of
4-(7,7-difluoro-8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine-1-ca-
rboxylic acid tert-butyl ester (0.42, 1.14 mmol) in methanol (10
mL) was added dropwise acetyl chloride (0.8 mL, 11.46 mmol). The
reaction mixture was stirred overnight at room temperature. The
solvent was evaporated under vacuum, and trituration with diethyl
ether yielded the second intermediate compound (0.31 g, quant) as
yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.58 (t,
1H), 7.06 (d, 1H), 7.03 (d, 1H), 3.34 (m, 6H), 3.21 (m, 4H), 3.11
(m, 2H).
[0761] The reductive amination procedure from Example A1 was
followed using
2,2-difluoro-8-piperazin-1-yl-3,4-dihydro-2H-naphthalen-1-one to
give the title compound. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. 10.24 (s, 1H), 7.61 (t, 1H), 7.56 (d, 1H), 7.08 (d, 1H),
7.06 (d, 1H), 6.38 (d, 1H), 4.22 (t, 2H), 3.62 (m, 2H), 3.41-3.03
(m, 11), 2.78 (t, 2H), 2.62-2.42 (m, 4H) 1.98-1.74 (m, 4H).
Example A55
Synthesis of
7-{4-[4-(7,7-Difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-
-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one
[0762] A first intermediate compound,
4-(7,7-Difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine-1-carboxyl-
ic acid tert-butyl ester, was produced as follows: An ice-cold
solution of
4-(7-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine-1-carboxylic
acid tert-butyl ester (0.720 g, 2.20 mmol) in dichloromethane (10
mL) was treated with bis(2-methoxyethyl)aminosulfur trifluoride (1
mL, 5.40 mmol). The dark brown solution was warmed to room
temperature and stirred overnight. The mixture was carefully
diluted with water and extracted with dichloromethane. The extracts
were dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under vacuum to give a brown oil. The oil was purified
by column chromatography (hexanes/ethyl acetate, 10:1) to afford
the first intermediate compound (0.172 g, 22%) as a white solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.19 (t, 1H), 6.98-6.92
(m, 2H), 3.66-3.40 (m, 4H), 3.24 (t 2H), 3.02 (t, 2H), 2.88-2.74
(m, 4H), 2.28-2.14 (m, 2H), 1.49 (s, 9H).
[0763] A second intermediate compound,
1-(7,7-Difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine, was
produced as follows: An ice-cold solution of methanol (3 mL) was
treated with acetyl chloride (0.6 mL), then stirred at 0.degree. C.
for 15 minutes.
4-(7,7-Difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine-1-
-carboxylic acid tert-butyl ester (0.172 g, 0.49 mmol) was added
giving a clear yellow solution, which slowly clouded over time.
After stirring at room temperature for 1.5 hours, the suspension
was diluted with diethyl ether and the second intermediate compound
(0.141 g, quantitative) was collected by vacuum filtration as a
white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.04 (br
s, 2H), 7.21 (t, 1H), 7.02-6.97 (m, 2H), 3.34-3.20 (m, 6H),
3.06-2.92 (m, 6H), 2.30-2.14 (m, 2H).
[0764] The reductive amination procedure from Example A1 was
followed using
1-(7,7-difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine to
give the title compound (0.271 g, 92%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.57 (br s, 1H), 7.36 (d, 1H), 7.17 (t, 1H),
7.00 (d, 1H), 6.92 (d, 1H), 6.36 (d, 1H), 4.23 (t, 2H), 3.22 (t,
2H), 3.01 (t, 2H), 2.95-2.83 (m, 6H), 2.70-2.58 (m, 6H), 2.49 (t,
2H), 2.26-2.13 (m, 2H), 1.86-1.75 (m, 2H), 1.74-1.64 (m, 2H). ES
MS: 471.26 (M+1).sup.+ (Exact mass: 470.25).
Example A56
Synthesis of
7-{4-[4-(7-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy-
}-3,4-dihydro-1H-[1,8]naphthyridin-2-one
[0765] A first intermediate compound,
1-(7-Methoxy-5,8-dihydro-naphthalen-1-yl)-piperazine, was produced
as follows: Ammonia (30 mL) was collected in a 3-neck 125 mL round
bottom flask at -78.degree. C. To this was added sequentially
isopropanol (7 mL), 1-(7-methoxy-naphthalen-1-yl)-piperazine (3.0
g, 8.43 mmol), and tetrahydrofuran (7 mL). To the dark brown
solution was added metallic sodium (795 mg, 35 mmol) portionwise
over 10 minutes. The blue solution was stirred at -78.degree. C.
for 1 hour, then warmed to room temperature over 2 hours. Water
(150 mL) was added and the mixture was stirred 10 minutes and the
grey precipitate was filtered off and rinsed with water (2.times.20
mL) to yield the first intermediate compound (1.47 g, 71%) as a
grey solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.22 (t,
1H), 6.80-6.65 (m, 2H), 4.63 (t, 1H), 3.55 (s, 3H), 3.80-3.70 (m,
2H), 3.65-3.55 (m, 3H), 2.86 (t, 4H), 2.70 (t, 4H).
[0766] A second intermediate compound,
7-{4-[4-(7-Methoxy-5,8-dihydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3-
,4-dihydro-1H-[1,8]naphthyridin-2-one, was produced as follows:
1-(7-Methoxy-5,8-dihydro-naphthalen-1-yl)-piperazine (329 mg, 1.35
mmol) and
4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
(300 mg, 1.28 mmol) were dissolved in dichloroethane (10 mL).
Triethylamine (329 mg, 3.85 mmol) was added and the mixture was
stirred for 10 minutes. Sodium triacetoxyborohydride (285 mg, 1.35
mmol) was added and the mixture was stirred for 1 hour. The mixture
was quenched with water (20 mL) and extracted with dichloromethane
(20 mL). The organic layer was washed with brine (20 mL), dried
over anhydrous sodium sulfate, filtered and evaporated. The crude
solid was purified by column chromatography (5:95 methanol/ethyl
acetate) to yield the second intermediate compound (330 mg, 56%) as
a white foam. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.55 (s,
1H), 7.36 (d, 1H), 7.17 (t, 1H), 7.00-6.85 (m, 2H), 6.38 (d, 1H),
4.80 (t, 1H), 4.20 (t, 2H), 3.60 (s, 3H), 3.50-3.45 (m, 2H),
3.44-3.38 (m, 2H), 3.00-2.90 (m, 4H), 2.88 (t, 2H), 2.70-2.50 (m,
6H), 2.50-2.40 (m, 2H), 1.85-1.55 (m, 4H).
[0767]
7-{4-[4-(7-Methoxy-5,8-dihydro-naphthalen-1-yl)-piperazin-1-yl]-bu-
toxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one (325 mg, 0.704 mmol)
was dissolved in ethanol (5 mL) and 10% HCl (1 mL). The mixture was
stirred at room temperature for 2 hours then quenched with
saturated sodium bicarbonate (10 mL) and extracted with ethyl
acetate (20 mL). The organic layer was washed with brine (20 mL),
dried over anhydrous sodium sulfate, filtered and evaporated. The
crude solid was purified by column chromatography (2:98
methanol/ethyl acetate) to yield the title compound (180 mg, 57%)
as a white foam. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.60 (s,
1H), 7.38 (d, 1H), 7.20 (t, 1H), 7.02-6.96 (m, 2H), 6.36 (d, 1H),
4.20 (t, 2H), 3.60 (s, 2H), 2.06 (t, 2H), 3.00-2.80 (m, 6H),
2.80-2.40 (m, 10H), 1.80-1.60 (4H); MS ES+ 449.06 (M+H).sup.+
(Exact mass: 448.25).
Example A57
Synthesis of
7-{4-[4-(7-Hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-bu-
toxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one
[0768] To a solution of
7-{4-[4-(7-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy-
}-3,4-dihydro-1H-[1,8]naphthyridin-2-one (0.24 g, 0.54 mmol) in
methanol (5 mL) was added portionwise NaBH.sub.4 (0.081 g, 2.14
mmol). The reaction mixture was stirred at room temperature for 30
min and quenched with saturated NH.sub.4Cl solution and the
compound was extracted with CH.sub.2Cl.sub.2 (2.times.20 mL). The
organic layer was washed with brine (20 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and evaporated. The crude product was
purified by column chromatography (10% methanol in ethyl acetate)
to afford compound the title compound (0.16 g, 67%) as a white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.54 (s, 1H), 7.36
(d, 1H), 7.12 (t, 1H), 6.93-6.85 (m, 2H), 6.35 (d, 1H), 4.23 (t,
2H), 4.14-4.09 (m, 1H), 3.20-3.19 (m, 1H), 3.02-2.83 (m, 8H),
2.66-2.47 (m 10H), 1.83-1.67 (m, 6H). ES MS: 451.27 (M+H).sup.+
(Exact mass: 450.26).
Example A58
Synthesis of
7-{4-[4-(5-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy-
}-3,4-dihydro-1H-[1,8]naphthyridin-2-one
[0769] A first intermediate compound,
5-Amino-3,4-dihydro-2H-naphthalen-1-one, was produced as follows:
5-Nitro-3,4-dihydro-2H-naphthalen-1-one (Chem. Pharm. Bull. 1988,
36, 481) was dissolved in THF (400 mL) and RaNi (3 g) was added,
followed by pressurization of the reaction vessel to 100 psi with
hydrogen gas. Upon completion, the solution was evaporated in vacuo
giving a solid, which was crystallized from dichloromethane/hexane
to yield the first intermediate compound (16.54 g). mp
118-120.degree. C.
[0770] A second intermediate compound,
3-[2-(5-Oxo-5,6,7,8-tetrahydro-naphthalen-1-ylamino)-ethyl]-oxazolidin-2--
one, was produced as follows: According to a method described in
the literature (Tetrahedron Lett. 1994, 35, 7331), to acetonitrile
(300 mL) was added 5-amino-3,4-dihydro-2H-naphthalen-1-one (10 g),
cesium carbonate (30.0 g) and toluene-4-sulfonic acid
2-(2-oxo-oxazolidin-3-yl)-ethyl ester (34 g) under nitrogen
followed by heating at 100.degree. C. for 48 hours. The solvent was
removed in vacuo, and the residue was taken up in dichloromethane
and diluted with brine. The dichloromethane phase was dried over
sodium sulfate and charcoal. The filtrate was evaporated to an oil
(17.7 g), which crystallized upon standing. Repeated trituration
with diethyl ether selectively removed excess reagents and
impurities. The remaining solid was dissolved in dichloromethane
and chromatographed on silica gel (dichloromethane with a gradient
to 4% methanol). The second intermediate compound crystallized from
diethyl ether/dichloromethane (8.8 g).
[0771] A third intermediate compound,
5-Piperazin-1-yl-3,4-dihydro-2H-naphthalen-1-one, was produced as
follows:
3-[2-(5-Oxo-5,6,7,8-tetrahydro-naphthalen-1-ylamino)-ethyl]-oxaz-
olidin-2-one (8.6 g) was dissolved in 200 mL dichloromethane. The
solution was sparged with anhydrous HBr gas, precipitating a
yellow-green oil. The solution was evaporated to a yellow brittle
foam. The foam was heated by oil bath to 175.degree. C. for 1.5
hours. The foam melted and re-expanded as a brittle foam with
off-gassing. This foam again melted and solidified. The residue was
taken up into 200 mL of a 50:50 water:dichloromethane mixture. The
solution was filtered, agitated and the dichloromethane phase was
decanted. The pH of the aqueous phase was adjusted to 14 with 4N
NaOH and the mixture was extracted with dichloromethane. The
dichloromethane solution was dried over sodium sulfate and filtered
thru a short plug of silica gel. The filtrate was evaporated to an
oil (7.7 g). This was suspended in diethyl ether, filtered to
remove minor insoluble material and sparged with anhydrous HCl gas
to yield a solid precipitate. The suspension was filtered, washed
with ether and dried in vacuo to give the third intermediate
compound as the hydrochloride salt (5.55 g, 66%).
[0772] In a manner similar to that of other examples above,
5-piperazin-1-yl-3,4-dihydro-2H-naphthalen-1-one was coupled by
reductive amination to
4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
followed by typical workup and purification to give the title
compound, mp 169-170.degree. C. MS: APCI: M+1: 449.2 (Exact Mass:
448.25).
Example A59
Synthesis of
7-{4-[4-(5,5-Difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-
-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one
[0773] A first intermediate compound,
5-Bromo-1,1-difluoro-1,2,3,4-tetrahydro-naphthalene, was produced
as follows: A solution of 5-bromo-3,4-dihydro-2H-naphthalen-1-one
(4.02 g, 17.86 mmol) and bis-(2-methoxyethyl)aminosulfur
trifluoride (6.5 mL, 35.25 mmol) in a sealed plastic bottle was
heated at 65.degree. C. overnight. The brown solution was diluted
with dichloromethane and washed with saturated sodium bicarbonate
solution. The organic extract was dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under vacuum to a brown
oil. The oil was purified by column chromatography (hexane) to
afford the first intermediate compound (1.749 g, 40%) as a yellow
liquid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.78 (d, 1H),
7.68-7.60 (m, 1H), 7.18 (t, 1H), 2.85-2.79 (m, 2H), 2.31-2.19 (m,
2H), 2.06-1.98 (m, 2H).
[0774] A second intermediate compound,
1-(5,5-Difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine, was
produced as follows: A yellow solution of
5-bromo-1,1-difluoro-1,2,3,4-tetrahydro-naphthalene (1.024 g, 4.14
mmol) in toluene (20 mL) was degassed with nitrogen for 30 minutes.
The solution was treated with 2-(dicyclohexylphosphino)biphenyl
(0.145 g, 0.41 mmol) followed by piperazine (0.393 g, 4.56 mmol),
sodium tert-butoxide (0.600 g, 6.22 mmol) and palladium acetate
(0.093 g, 0.41 mmol). The resulting brown solution was degassed
with nitrogen for 10 minutes, then heated at 110.degree. C. for 1.5
hours. The mixture was cooled to room temperature, then filtered
through a Celite pad. The pad was rinsed with dichloromethane and
the filtrate was concentrated in vacuo to a brown liquid. The
liquid was diluted with 3N HCl to pH 1 and then extracted with
dichloromethane. The organic layer was discarded and the aqueous
layer was basified with 2N KOH solution to pH 12. The aqueous layer
was extracted with dichloromethane and the extracts were dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to
afford the second intermediate compound (0.310 g, 30%) as a brown
oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.43 (d, 1H), 7.30
(t, 1H), 7.11 (d, 1H), 3.06-2.97 (m, 4H), 2.97-2.88 (m, 6H),
2.36-2.22 (m, 2H), 2.00-1.90 (m, 2H).
[0775] The reductive amination procedure from Example A1 was
followed using
1-(5,5-difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine to
give the title compound (0.310 g, 60%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.58 (br s, 1H), 7.44 (d, 1H), 7.36 (d, 1H),
7.30 (t, 1H), 7.12 (d, 1H), 6.36 (d, 1H), 4.20 (t, 2H), 2.92 (t,
4H), 2.86 (t, 2H), 2.82-2.76 (m, 2H), 2.70-2.52 (m, 6H), 2.48 (t,
2H), 2.34-2.22 (m, 2H), 2.00-1.90 (m, 2H), 1.84-1.76 (m, 2H),
1.74-1.65 (m, 2H). ES MS: 471.12 (M+H).sup.+ (Exact mass:
470.25).
Example A60
Synthesis of
7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyrid-
in-2-one
[0776] The procedure in Example A1 was followed using
1-indan-4-yl-piperazine. Purification by liquid chromatography
(0-5% MeOH/CH.sub.2Cl.sub.2) gave the title compound as a white
foam (545 mg, 1.29 mmol, 48%). The foam was dissolved in Et.sub.2O
and 1 N HCl in Et.sub.2O (1.3 mL) was added. The resulting white
precipitate was collected by filtration, washed with Et.sub.2O and
dried to give a white solid (563 mg). MS: APCI: M+1: 421.5 (Exact
Mass: 420.25).
Example A61
Synthesis of
7-{4-[4-(2-Oxo-indan-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]na-
phthyridin-2-one
[0777] A first intermediate compound,
4'-Bromo-1',3'-dihydro-spiro[[1,3]dioxolane-2,2'-indene], was
produced as follows: To a stirred solution of 4-bromo-indan-2-one
(2.20 g, 10.40 mmol) in benzene (60 mL) was added ethylene glycol
and para-toluene sulfonic acid monohydrate (200 mg). The resulting
mixture was heated at 110.degree. C. for 40 h using Dean-Stark
apparatus. The solvent was removed in vacuo, ethyl acetate was
added and the solution was washed with saturated sodium bicarbonate
solution, water and brine. It was dried (Na.sub.2SO.sub.4) and the
solvent was removed in vacuo to give the title compound (2.40 g,
90%) as a liquid. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.22 (d, 1H),
7.15 (d, 1H), 6.95 (m, 1H) 3.95 (s, 4H), 3.20 (s, 2H), 3.15 (s,
2H).
[0778] A second intermediate compound,
4-(1',3'-Dihydro-spiro[[1,3]dioxolane-2,2'-inden]-4'-yl)-piperazine-1-car-
boxylic acid tert-butyl ester, was produced as follows: To a
stirred solution of
4'-bromo-1',3'-dihydro-spiro[[1,3]dioxolane-2,2'-indene] (2.12 g,
8.35 mmol) in toluene (40 mL) at room temperature, was added
1-boc-piperazine (1.86 g, 10.0 mmol),
tris-(dibenzylideneacetone)di-palladium(0) (Pd.sub.2(dba).sub.3,
1.91 g, 2.08 mmol),
tert-2,2'-bis(diphenyl)phosphino-1,1'-binaphthyl (BINAP, 2.34 g,
3.76 mmol) and cesium carbonate (4.08 g, 12.52 mmol). The resulting
mixture was degassed, filled with N.sub.2, degassed and heated at
100.degree. C. overnight. The mixture was diluted with ethyl
acetate and filtered through a pad of celite. The filtrate was
concentrated and the residue was purified by chromatography on
silica (4:1 hexanes-ethyl acetate) to give the second intermediate
compound (1.60 g, 40%) as an oil. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta.: 7.18 (m, 1H), 6.90 (d, 1H), 6.75 (d, 1H),
4.05 (s, 4H), 3.58 (m, 4H), 3.20 (s, 2H), 3.10 (s, 2H), 2.95 (m,
4H), 1.50 (s, 9H).
[0779] A third intermediate compound, 4-Piperazin-1-yl-indan-2-one,
was produced as follows: Trifluoroacetic acid-water (9:1, 50 mL)
was added to
4-(1',3'-dihydro-spiro[[1,3]dioxolane-2,2'-inden]-4'-yl)-piperazine-1-car-
boxylic acid tert-butyl ester (1.65 g, 4.58 mmol) cooled to
0.degree. C. The resulting mixture was stirred at 0.degree. C. for
3 h and the solvent was removed in vacuo. Ether was added to the
residue and the solid formed was filtered to give the third
intermediate compound (1.20 g, 75%). .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta.: 7.30 (t, 1H), 7.15 (d, 1H), 7.05 (d, 1H),
3.58 (s, 2H), 3.55 (s, 2H), 3.30 (m, 4H), 3.20 (m, 4H).
[0780] The reductive amination procedure from Example A1 was
followed using 4-piperazin-1-yl-indan-2-one to give the title
compound. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.55 (br s,
1H), 7.42 (d, 1H), 7.25 (t, 1H), 6.98 (d, 1H), 6.85 (d, 1H), 6.38
(d, 1H), 4.25 (t, 2H), 3.58 (s, 2H), 3.50 (s, 2H), 3.15 (br s, 4H),
2.90 (t, 2H), 2.60 (m, 6H), 2.45 (m, 2H), 1.80 (m, 2H), 1.65 (m,
2H). MS ES: m/z 435.19 (M+1).sup.+ (Exact mass: 434.23).
Example A62
Synthesis of
7-{4-[4-(2,2-Difluoro-indan-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H--
[1,8]naphthyridin-2-one
[0781] A first intermediate compound, 4-Bromo-2,2-difluoro-indan,
was produced as follows: To a stirred solution of
4-bromo-indan-2-one (5.0 g, 23.70 mmol) in dichloromethane (20 mL)
cooled to 0.degree. C. was added (diethylamino)sulfur trifluoride
(DAST) (9.55 g, 59.30 mmol). The resulting mixture was stirred at
room temperature overnight, diluted with additional dichloromethane
(50 mL) and quenched with ice-water. The organic layer was
separated, washed with saturated sodium bicarbonate solution,
water, brine and dried (Na.sub.2SO.sub.4). The solvent was removed
in vacuo and the residue was purified on a silica gel column using
hexanes as eluent to give the first intermediate compound (2.54 g,
46%) as an oil. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.40 (d, 1H),
7.15 (m, 2H), 3.49 (m, 4H).
[0782] A second intermediate compound,
4-(2,2-Difluoro-indan-4-yl)-piperazine-1-carboxylic acid tert-butyl
ester, was produced as follows: To a stirred solution of
4-bromo-2,2-difluoro-indan (2.41 g, 10.34 mmol) in toluene (65 mL)
at room temperature, was added 1-boc-piperazine (2.31 g, 12.42
mmol), tris-(dibenzylideneacetone)dipalladium(0)
[Pd.sub.2(dba).sub.3] (2.37 g, 2.58 mmol),
tert-2,2'-bis(diphenyl)phosphino-1,1'-binaphthyl (BINAP) (2.90 g,
4.66 mmol) and cesium carbonate (4.77 g, 14.63 mmol). The mixture
was degassed, filled with N.sub.2, degassed and heated at
80.degree. C. for 24 h. The mixture was diluted with ethyl acetate,
filtered through a pad of silica gel and the pad was washed with
additional amount of ethyl acetate. The combined solvent was
removed in vacuo and the residue was purified on a silica gel
column using hexanes:ethyl acetate (4:1) as eluent to give the
title compound (1.40 g, 40%) as an oil. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta.: 7.25 (m, 1H), 6.95 (d, 1H), 6.85 (d, 1H),
3.60 (m, 4H), 3.35 (m, 4H), 2.95 (m, 4H), 1.45 (s, 9H).
[0783] A third intermediate compound,
1-(2,2-Difluoro-indan-4-yl)-piperazine, was produced as follows: A
solution of 4-(2,2-difluoro-indan-4-yl)-piperazine-1-carboxylic
acid tert-butyl ester (0.10 g, 0.29 mmol) in methanol (30 mL) was
added to a solution of acetyl chloride (0.35 g, 4.44 mmol) in
methanol (50 mL), cooled to 0.degree. C. The resulting mixture was
stirred at room temperature overnight and the solvent was removed
in vacuo. Diethyl ether was added to the residue and the resulting
solid was filtered to give the title compound (0.07 g, 87%). 1H NMR
(400 MHz, CD.sub.3OD): .delta.: 7.50 (t, 1H), 7.15 (d, 1H), 6.90
(d, 1H), 3.45 (m, 4H), 3.35 (m, 4H), 3.15 (m, 4H).
[0784] The reductive amination procedure from Example A1 was
followed using 1-(2,2-difluoro-indan-4-yl)-piperazine to give the
title compound (0.360 g, 69%). .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta.: 7.60 (br s, 1H), 7.39 (d, 1H), 7.25 (t, 1H), 6.96 (d, 1H),
6.85 (d, 1H), 6.39 (d, 1H), 4.26 (t, 2H), 3.35 (m, 4H), 3.15 (br s,
4H), 2.85 (m, 4H), 2.65 (m, 6H), 2.45 (m, 2H), 1.85 (m, 1H), 1.65
(m, 1H). MS ES: m/z 457.10 (M+H).sup.+ (Exact mass: 456.23).
Example A63
Synthesis of
7-{4-[4-(6,7,8,9-Tetrahydro-5H-benzocyclohepten-1-yl)-piperazin-1-yl]-but-
oxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one
[0785] A first intermediate compound,
1-Nitro-6,7,8,9-tetrahydro-benzocyclohepten-5-one, was produced as
follows: To 250 g (1.56 mmol) of 1-benzosubersone in 5000-mL 4-neck
round bottom flask with nitrogen inlet, mechanical stirring, and
thermocouple was added 1560 mL of chloroform and 125 g (1.56 mmol)
of ammonium nitrate. After the solution was cooled to -15.degree.
C., 780 mL (1160 g, 5.52 mmol) of trifluoroacetic anhydride was
added dropwise keeping the temperature below -15.degree. C. A white
suspension formed. The reaction was stirred at -15.degree. C. for 1
h and then allowed to warm to room temperature and stir for 16 h.
The clear orange solution was poured over 7.8 L of water and then
extracted with two 4000-mL portions of dichloromethane. The
combined organic layers were washed with 4000 mL of saturated
aqueous sodium bicarbonate and 4000 mL of brine, dried
(Na.sub.2SO.sub.4), and concentrated in vacuo to give a mixture of
C-8 nitration/C-6 nitration/starting material--3:1:1. This material
was combined with material from 64-g and 250-g runs was taken up in
approximately 2.5 L of heptane and brought to near reflux. The
solid product became an oil on heating. Enough ethyl acetate was
added to get the oil into solution. The solution was allowed to
cool to room temperature and sit overnight. Crystals, which formed
on the sides of the flasks, were determined to be mainly the C-8
isomer. The mother liquor was separated and concentrated in vacuo
to give C-8 nitration/C-6 nitration/starting material--1:1:0.7. The
residual solid was purified by flash column chromatography on 3000
g of silica (loaded with dichloromethane and eluted with 15% ethyl
acetate-heptane) to give 82.9 g of product. This material was
recrystallized with heptane-ethyl acetate (just enough ethyl
acetate to keep the product from oiling out) to give 51.0 g of the
title compound as pale yellow needles. The material obtained from
the mother liquor was then recrystallized to give another 7.1 g of
the title compound as yellow needles.
[0786] A second intermediate compound,
6,7,8,9-Tetrahydro-5H-benzocyclo-hepten-1-ylamine, was produced, as
follows: TFA (10 mL) was added to a 50 mL flask and cooled in a
CO.sub.2/acetone bath.
1-Nitro-6,7,8,9-tetrahydro-benzocyclohepten-5-one (1.8 g) was added
followed by triethylsilane (10 mL). The mixture was warmed to
55.degree. C. After 5 hours, the mixture was evaporated to a
residue under high vacuum at 70.degree. C. The residue was taken up
into hexane, filtered and washed with 2N HCl. The hexane layer was
washed with brine, dried over sodium sulfate and evaporated to an
oil (2.7 g), which contained a mixture of products. This material
was dissolved in methanol and 10% Pd/C (0.6 g) was added. The
mixture was pressurized to 50 psi with hydrogen gas for 2 hours,
after which the mixture was filtered and evaporated to an oil (2.46
g). The oil was chromatographed on silica gel (gradient of 100%
hexane to 60% ethyl acetate) to give the second intermediate
compound as an oil which was crystallized from ether (0.66 g), mp
107-111.degree. C.
[0787] A third intermediate compound,
1-(6,7,8,9-Tetrahydro-5H-benzocyclo-hepten-1-yl)-piperazine, was
produced as follows:
6,7,8,9-Tetrahydro-5H-benzocyclohepten-1-ylamine (0.617 g) and
bis-dichloroethyl amine HCl (1.3 g) were added to a sealable tube.
Chlorobenzene (3 mL), hexanol (1 mL) and diisopropylethylamine (2
mL) were added. The solution was warmed to 45.degree. C. for 3
hours, then warmed to 95.degree. C. overnight. The mixture was
evaporated to give a syrup, which was taken up into dichloromethane
and washed twice with water. The dichloromethane layer was dried
over sodium sulfate and evaporated to an oil (0.88 g). The oil was
chromatographed on silica gel and recrystallized from
dichloromethane and ether to give the title compound (0.183 g).
[0788] In a manner similar to that of other examples above,
6,7,8,9-tetrahydro-5H-benzocyclohepten-1-ylamine (0.178 g) was
coupled by reductive amination to
4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
followed by typical workup and purification to give the title
compound as the hydrochloride salt (0.109 g). MS: APCI: M+1: 449.3
(Exact Mass: 448.26).
Example A64
Synthesis of
7-[4-(4-Naphthalen-1-yl-piperidin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]napht-
hyridin-2-one
[0789]
7-[4-(4-Naphthalen-1-yl-piperidin-1-yl)-butoxy]-3,4-dihydro-1H-[1,-
8]naphthyridin-2-one was produced according to a process similar to
that described in Example A1, using 4-naphthalen-1-yl-piperidine
hydrochloride. Purification by liquid chromatography (5%
MeOH/CH.sub.2Cl.sub.2 with 0.8% NH.sub.4OH) gave the title compound
as a white foam (474 mg, 1.10 mmol). The foam was dissolved in
Et.sub.2O/CH.sub.2Cl.sub.2 and 1 N HCl in Et.sub.2O (1.1 mL) was
added. The resulting white precipitate was collected by filtration,
washed with Et.sub.2O and dried to give a white solid (466 mg). MS:
APCI: M+1: 430.4 (Exact Mass: 429.24).
Example A65
Synthesis of
7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one
[0790] A first intermediate compound, Trifluoro-methanesulfonic
acid 7-fluoro-3,4-dihydro-naphthalen-1-yl ester, was produced as
follows: 7-Fluoro-1-tetralone (1.0 g, 6.10 mmol, prepared according
to J. Am. Chem. Soc. 1967, 89, 386) was dissolved in
tetrahydrofuran (20 mL) then cooled to -78.degree. C. To this
solution was added lithium hexamethyldisilazane (7.32 mL, 7.32
mmol, 1.0 M in tetrahydrofuran) over 5 minutes. The mixture was
stirred at -78.degree. C. for 1 hour, and then N-phenyl triflamide
(2.62 g, 7.32 mmol) was added in one portion. The mixture was
allowed to warm to room temperature and stirred for 2 hours. The
mixture was evaporated, dissolved in ethyl acetate (20 mL) and
washed with 1N sodium hydroxide (20 mL), water (20 mL), and brine
(20 mL). The organic layer was dried over anhydrous sodium sulfate,
filtered and evaporated in vacuo. The crude oil was filtered
through a short plug of silica gel, eluting with 9:1 hexanes/ethyl
acetate to yield the first intermediate compound (2.06 g crude,
quant.) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.20-7.10 (m, 1H), 7.04 (d, 1H), 6.98-6.90 (m, 1H), 6.05 (d, 1H),
2.82 (t, 2H), 2.58-2.46 (m, 2H).
[0791] A second intermediate compound, Trifluoro-methanesulfonic
acid 7-fluoro-naphthalen-1-yl ester, was produced as follows:
Trifluoro-methanesulfonic acid 7-fluoro-3,4-dihydro-naphthalen-1-yl
ester (2.06 g, 6.96 mmol) was dissolved in dioxane (20 mL) and
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (2.37 g, 10.44 mmol) was
added. The mixture was refluxed for 36 hours and then cooled to
room temperature. The mixture was evaporated in vacuo to a solid
and purified by column chromatography (hexanes) to yield the title
compound (1.48 g, 72%) as a red solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.98-7.82 (m, 2H), 7.66 (d, 1H), 7.56-7.40 (m,
3H).
[0792] A third intermediate compound,
4-(7-Fluoro-naphthalen-1-yl)-piperazine-1-carboxylic acid
tert-butyl ester, was produced as follows:
Trifluoro-methanesulfonic acid 7-fluoro-naphthalen-1-yl ester (1.48
g, 5.03 mmol) and 1-Boc-piperazine (1.13 g, 6.04 mmol) were
dissolved in toluene (10 mL) and the mixture was degassed for 30
minutes. To this was added 2-(dicyclohexylphosphino)-biphenyl (176
mg, 0.50 mmol), palladium acetate (113 mg, 0.50 mmol), and sodium
tert-butoxide (677 mg, 7.04 mmol). The mixture was stirred at
80.degree. C. for 16 hours and then cooled to room temperature. The
mixture was washed with water (20 mL) and brine (20 mL), dried over
anhydrous sodium sulfate, filtered and concentrated in vacuo. The
crude oil was filtered through a short plug of silica gel, eluting
with 3:1 hexanes/ethyl acetate to yield the title compound (900 mg,
54%) as a brown oil.
[0793] A fourth intermediate compound,
1-(7-Fluoro-naphthalen-1-yl)-piperazine, was produced as follows:
4-(7-Fluoro-naphthalen-1-yl)-piperazine-1-carboxylic acid
tert-butyl ester (900 mg, 2.73 mmol) was dissolved in
dichloromethane (10 mL) and trifluoroacetic acid (2 mL). The
mixture was stirred at room temperature for 3 hours then diluted
with diethyl ether. The solid was filtered off and washed with
diethyl ether (2.times.20 mL) to yield the title compound as the
TFA salt (415 mg, 1.21 mmol, 44%) as a grey powder. .sup.1NMR (400
MHz, dmso-d.sub.6) .delta. 8.80 (s, 1H), 8.04 (t, 1H), 7.82 (d,
1H), 7.58 (d, 1H), 7.44 (t, 2H), 7.24 (d, 1H), 3.40-3.30 (m, 4H),
3.20-3.00 (m, 4H).
[0794] The reductive amination procedure from Example A1 was
followed using 1-(7-fluoro-naphthalen-1-yl)-piperazine to give the
title compound. .sup.1NMR (400 MHz, dmso-d.sub.6) .delta. 10.25 (s,
1H), 8.00 (t, 1H), 7.80-7.60 (m, 2H), 7.46-7.40 (m, 3H), 7.20 (d,
1H), 6.38 (d, 1H), 4.20 (t, 2H), 3.06-2.90 (m, 4H), 2.80 (t, 2H),
2.80-2.60 (m, 4H), 2.50-2.40 (m, 4H), 1.80-1.70 (m, 2H), 1.64-1.55
(m, 2H), MS ES+ 449.31 (M+1).sup.+ (Exact mass: 448.23).
Example A66
Synthesis of
7-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one
[0795] A first intermediate compound, 8-Bromo-naphthalen-1-ylamine,
was produced as follows: 8-Bromo-naphthalene-1-carboxylic acid
(10.0 g, 39.8 mmol) was taken up in CHCl.sub.3 (60 mL) and conc.
H.sub.2SO.sub.4 (20 mL) were added. The mixture was stirred at
45.degree. C. until all the compound was dissolved. NaN.sub.3
(15.52 g, 240.0 mmol, 6.0 equiv) was then added in portions, each
successive portion was added after the effervescence resulting from
the previous addition had subsided. The mixture was stirred for 2 h
at 45.degree. C. and added to water (100 mL). The mixture was made
alkaline with aqueous ammonia and extracted with dichloromethane
(4.times.30 mL). The combined extracts were dried over
Na.sub.2SO.sub.4 and evaporated to give the title compound as a
dark crystalline solid (8.5 g, 96%). .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 7.70 (d, 1H), 7.65 (d, 1H), 7.30 (d, 2H), 7.05
(t, 1H), 6.65 (m, 1H), 5.20 (br s, 2H). MS (ES+): 221.99 (M.sup.+),
223.99 (M.sup.+2).
[0796] A second intermediate compound,
1-Bromo-8-fluoro-naphthalene, was produced as follows: To a cooled
solution of 8-bromo-naphthalen-1-ylamine (8.0 g, 36.0 mmol) in THF
(10 mL) was added 48% HBF.sub.4 (50 mL) at 0.degree. C. and the
mixture was stirred for 10 min. A solution of NaNO.sub.2 (7.5 g,
108.1 mmol, 3.0 equiv) in water (20 mL) was added and the stirring
was continued for 1 h at 0.degree. C., then NaBF.sub.4 (20.0 g,
180.0 mmol, 5.0 equiv) was added. The mixture was allowed to warm
to room temperature and stir for 1 h. The reaction was filtered and
the solid was washed with ether and dried overnight under high
vacuum to give a gray solid. This solid was taken up in
chlorobenzene (30 mL) and refluxed for 3 h. The solvent was removed
under reduced pressure and the dark residue was triturated with
hexane. The yellow colored hexane layer was decanted and
trituration with hexane was repeated several times until the hexane
layer became colorless. The combined hexane portions were
concentrated to give the second intermediate compound as a dark
yellow oil (5.6 g, 69%). .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
7.78 (m, 2H), 7.60 (d, 1H), 7.35-7.15 (m, 3H).
[0797] A third intermediate compound,
1-(8-Fluoro-naphthalen-1-yl)-piperazine, was produced as follows: A
solution of Pd(OAc).sub.2 (0.25 g, 1.11 mmol, 0.1 equiv)) and
dicyclohexylphosphino-biphenyl (0.39 g, 1.11 mmol, 0.1 equiv) in
toluene (20 mL) was degassed by bubbling N.sub.2 gas for 1 h.
1-Bromo-8-fluoro-naphthalene (2.5 g, 11.1 mmol) in toluene (10 mL)
and 1-Boc-piperazine (2.5 g, 13.3 mmol, 1.2 equiv) were added
followed by NaO.sup.tBu (1.6 g, 16.66 mmol, 1.5 equiv). The mixture
was stirred at 80.degree. C. for 18 h. The solvent was removed
under reduced pressure and the residue was taken in dichloromethane
and filtered through a celite pad. The celite was rinsed with
dichloromethane and the combined filtrates were concentrated. The
residue was purified by silica gel chromatography (20% ethyl
acetate in hexane) to give
4-(8-fluoro-naphthalen-1-yl)-piperazine-1-carboxylic acid
tert-butyl ester as a dark oil (1.4 g, 38%). .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 7.60 (d, 1H), 7.50 (d, 1H), 7.40 (m, 1H), 7.10
(m, 2H), 6.95 (d, 1H), 4.50-4.00 (br s, 2H), 3.40-3.20 (m, 4H),
2.80-2.60 (m, 2H), 1.50 (s, 9H). MS (ES+): 331.08 (M+H).sup.+.
[0798] 4-(8-Fluoro-naphthalen-1-yl)-piperazine-1-carboxylic acid
tert-butyl ester (1.4 g, 4.2 mmol) was dissolved in dichloromethane
(10 mL) and TFA (10 mL) was added at 0.degree. C. The mixture was
allowed to warm to room temperature and stir for 1 h. The solvents
were removed under reduced pressure and the residue was purified by
silica gel chromatography (5% methanol in dichloromethane) to give
the third intermediate compound as a TFA salt (1.3 g, 89%). .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta. 7.65-7.58 (m, 2H), 7.40 (m, 2H),
7.10-7.00 (m, 2H), 3.60-3.40 (m, 6H), 3.40-3.20 (m, 2H). MS (ES+):
231.11 (M+H).sup.+.
[0799] The reductive amination procedure from Example A1 was
followed using 1-(8-fluoro-naphthalen-1-yl)-piperazine. 1H NMR (400
MHz, CDCl3): .delta. 7.60 (m, 2H), 7.50 (m, 1H), 7.40 (m, 3H),
7.10-7.00 (m, 2H), 6.28 (d, 1H), 4.25 (t, 2H), 3.40-3.30 (m, 2H),
3.05-2.80 (m, 6H), 2.65 (t, 2H), 2.60-2.40 (m, 4H), 1.80-1.60 (m,
4H). MS (ES+): 449.19 (M+H).sup.+ (Exact mass: 448.23).
Example A67
Synthesis of
7-{4-[4-(6-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one
[0800] A first intermediate compound, 6-Fluoro-1-tetralone, was
produced as follows: 6-Amino-3,4-dihydro-2H-naphthalen-1-one (6.45
g, 40.1 mmol) was dissolved in a mixture of hydrochloric acid (9
mL) and water (6 mL) and cooled to 0.degree. C. A solution of
sodium nitrite (2.90 g, 42.0 mmol) in water (4 mL) was added
dropwise to the mixture and tetrafluoroboric acid (8.0 g, 44.0
mmol, 5.71 mL, 48% in water) was added. The mixture was allowed to
stand at 0.degree. C. for 30 minutes and then cooled to -30.degree.
C. The precipitate was filtered off and rinsed with cold methanol
(10 mL), and then with cold diethyl ether (10 mL) to yield the
diazonium salt (6.0 g, 58%) as a brown solid. .sup.1H NMR (400 MHz,
dmso-d.sub.6) .delta. 8.70 (s, 1H), 8.59 (d, 1H), 8.30 (d, 1H),
3.10 (t, 2H), 2.78 (t, 2H), 2.20-2.06 (m, 2H).
[0801] The diazonium salt (6.0 g, 23.3 mmol) was dried overnight in
vacuo, then suspended in toluene (60 mL) and stirred at 110.degree.
C. for 1 hour. The mixture was cooled to room temperature and the
liquid was decanted from the insoluble tar. The organic mixture was
washed with water (20 mL), 1 N sodium hydroxide (20 mL), and water
(20 mL). The organic layer was dried over anhydrous magnesium
sulfate, filtered and concentrated in vacuo. The crude oil was
purified by column chromatography (8:1, hexanes/ethyl acetate) to
yield the first intermediate compound (2.87 g, 76%) as a light red
oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.04 (t, 1H),
7.00-6.84 (m, 2H), 2.95 (t, 2H), 2.62 (t, 2H), 2.20-2.02 (m,
2H).
[0802] A second intermediate compound, Trifluoro-methanesulfonic
acid 6-fluoro-3,4-dihydro-naphthalen-1-yl ester, was produced as
follows: 6-Fluoro-1-tetralone (1.00 g, 6.10 mmol) was dissolved in
tetrahydrofuran (20 mL) and cooled to -78.degree. C. Lithium
hexamethyldisilazane (7.32 mmol, 7.32 mL, 1.0 M solution in
tetrahydrofuran) was added dropwise and the mixture was stirred at
-78.degree. C. for 1 hour. N-Phenyl triflamide (2.62 g, 7.32 mmol)
in tetrahydrofuran (5 mL) was added and the mixture was allowed to
warm to room temperature over 1.5 hours and then was poured into
water (20 mL). The mixture was extracted with ethyl acetate (20 mL)
and the organic layer was washed with water (2.times.20 mL), 1 N
sodium hydroxide (20 mL), and brine (20 mL). The organic layer was
dried over anhydrous sodium sulfate, filtered and concentrated in
vacuo. The crude oil was filtered through a short plug of silica
gel, eluting with hexanes to yield the second intermediate compound
(1.69 g, 94%) as a light brown oil. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.38-7.28 (m, 1H), 7.00-6.84 (m, 2H), 5.99 (t,
1H), 2.84 (t, 2H), 2.60-2.50 (m, 2H).
[0803] A third intermediate compound, Trifluoro-methanesulfonic
acid 6-fluoro-naphthalen-1-yl ester, was produced as follows:
Trifluoro-methanesulfonic acid 6-fluoro-3,4-dihydro-naphthalen-1-yl
ester (1.69 g, 5.72 mmol) was dissolved in dioxane (20 mL) and
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.95 g, 8.57 mmol) was
added. The mixture was heated at reflux for 36 hours and then
additional 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (649 mg, 2.86
mmol) was added and the mixture refluxed for another 6 hours. The
mixture was cooled to room temperature, evaporated to a solid and
loaded onto a short plug of silica gel, eluting with hexanes to
yield the first intermediate compound (1.24 g, 74%) as a yellow
semi-solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.10-8.05 (m,
1H), 7.80 (d, 1H), 7.60-7.45 (m, 2H), 7.45-7.38 (m, 2H).
[0804] A fourth intermediate compound,
1-(6-Fluoro-naphthalen-1-yl)-piperazine, was produced as follows:
Trifluoro-methanesulfonic acid 6-fluoro-naphthalen-1-yl ester (1.24
g, 4.23 mmol) and 1-Boc-piperazine (946 mg, 5.08 mmol) were
dissolved in toluene (15 mL) and the mixture was degassed for 30
minutes. To this was added 2-(dicyclohexylphosphino)-biphenyl (148
mg, 0.42 mmol), palladium acetate (95 mg, 0.42 mmol), and sodium
tert-butoxide (569 mg, 5.92 mmol). The mixture was stirred at
80.degree. C. for 30 minutes, then cooled to room temperature,
washed with water (20 mL) and brine (20 mL), dried over anhydrous
sodium sulfate, filtered and concentrated in vacuo. The crude oil
was filtered through a short plug of silica gel, eluting with 3:1
hexanes/ethyl acetate to yield crude
4-(6-fluoro-naphthalen-1-yl)-piperazine-1-carboxylic acid
tert-butyl ester as a brown oil. The crude oil was dissolved in a
mixture of dichloromethane (5 mL) and trifluoroacetic acid (5 mL)
and stirred at room temperature for 4 hours. The mixture was
evaporated in vacuo and diethyl ether (30 mL) was added. The grey
precipitate was filtered off and rinsed with diethyl ether (20 mL)
to yield the fourth intermediate compound as the TFA salt (755 mg,
52%) as a grey solid. .sup.1H NMR (400 MHz, dmso-d.sub.6) .delta.
8.80 (s, 1H), 8.24-8.18 (m, 1H), 7.72 (d, 1H), 7.68 (d, 1H), 7.50
(t, 1H), 7.40 (t, 1H), 7.18 (d, 1H), 3.40-3.10 (m, 8H).
[0805] The reductive amination procedure from Example A1 was
followed using 1-(6-fluoro-naphthalen-1-yl)-piperazine to give the
title compound. .sup.1H NMR (400 MHz, dmso-d.sub.6) .delta. 10.20
(s, 1H), 8.22-7.98 (m, 1H), 7.75 (d, 1H), 7.65 (d, 1H), 7.54-7.48
(m, 2H), 7.44 (t, 1H), 7.20 (d, 1H), 6.40 (d, 1H), 4.24 (t, 2H),
3.70-3.10 (m, 10H), 2.80 (t, 2H), 2.44 (t, 2H), 1.95-1.76 (m, 4H),
MS ES+ 449.25 (M+H).sup.+ (Exact mass: 448.23).
Example A68
Synthesis of
7-{4-[4-(5-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one
[0806] A first intermediate compound,
5-Bromo-naphthalene-1-carboxylic acid, was produced, as follows: To
a suspension of naphthalene-1-carboxylic acid (20.14 g, 0.12 mmol)
in HOAc (100 mL) was added Br.sub.2 (6.60 mL, 0.13 mmol). The
mixture was heated at 110.degree. C. for 48 h and cooled to room
temperature. It was filtered, the pad was washed with hexane and
dried to give the first intermediate compound (18.0 g) as a grey
solid in 62%. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 13.40 (br
s, 1H), 8.90 (d, J=6.0 Hz, 1H), 8.42 (d, J=6.0 Hz, 1H), 8.25 (d,
J=5.0 Hz, 1H), 8.00 (d, J=5.0 Hz, 1H), 7.80 (m, 1H), 7.60 (m,
1H).
[0807] A second intermediate compound,
5-Bromo-naphthalen-1-ylamine, was produced as follows: To a
solution of 5-bromo-naphthalene-1-carboxylic acid (10 g, 40 mmol)
in t-BuOH (150 mL) was added Et.sub.3N (13.6 mL, 80 mmol) and DPPA
(10.5 mL, 48 mmol) successively. After the mixture was stirred at
room temperature for 1 h, it was refluxed for 16 h. The solvent was
then removed and the residue was purified by chromatography on
silica gel to give (5-bromo-naphthalen-1-yl)-carbamic acid
tert-butyl ester (8.4 g, 65%) as a white solid. .sup.1H NMR (400
MHz, CDCl.sub.3): .delta. 8.60 (d, J=6.0 Hz, 1H), 8.55 (d, J=6.0
Hz, 1H), 8.50 (d, J=6.0 Hz, 1H), 8.40 (d, J=6.0 Hz, 1H), 8.20 (t,
J=6.0 Hz, 1H), 8.10 (t, J=6.0 Hz, 1H).
[0808] The material obtained in the last step was dissolved in
dichloromethane (150 mL) and trifluoroacetic acid (15 mL) was
added. The resulting mixture was stirred under reflux for 2 h. The
solvent was removed. The residue was washed with hexane to give a
white solid, which was suspended in dichloromethane (150 mL) and
treated with aqueous KOH (50 mL containing 15 g KOH). The mixture
was stirred at room temperature for 30 min. The organic layer was
separated and the aqueous layer was extracted with dichloromethane
(2.times.50 mL). The combined organic phases were dried over
Na.sub.2SO.sub.4 and concentrated to give the second intermediate
compound (5.13 g, 85%) as a purple solid. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 8.80 (m, 2H), 7.70 (d, J=7.0 Hz, 2H), 7.40 (t,
J=6.2 Hz, 1H), 7.20 (t, J=6.0 Hz, 1H), 6.80 (d, J=6.0 Hz, 1H).
[0809] A third intermediate compound, 1-Bromo-5-fluoro-naphthalene.
Was produced as follows: To a cooled (0.degree. C.) solution of
5-bromo-naphthalen-1-ylamine (1.0 g, 4.52 mmol) in THF (1 mL) was
added 48% HBF.sub.4 (10 mL) followed by a solution of NaNO.sub.2
(0.49 g, 13.58 mmol, 3 eq) in water (2 mL). After the addition was
over, the mixture was kept stirring at 0.degree. C. for 1 h and
NaBF.sub.4 (2.49 g, 22.6 mmol, 5 eq) was added. The mixture was
allowed to warm up to room temperature and filtered. The solid was
washed with ether and dried overnight under high vacuum to give a
green solid, which was suspended in xylene (5 mL) and refluxed for
1 h. The resulting mixture was subjected to chromatography on
silica gel to give the third intermediate compound (480 mg) as a
yellow solid in 47% yield for two steps. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 8.17 (d, J=7.0 Hz, 1H), 8.10 (d, J=7.0 Hz 1H),
7.90 (d, J=6.0 Hz, 1H), 7.55 (m, 1H), 7.40 (t, J=6.0 Hz, 1H), 7.20
(m, 1H).
[0810] A fourth intermediate compound,
1-(5-Fluoro-naphthalen-1-yl)-piperazine, was produced as follows: A
solution of Pd(OAc).sub.2 (0.31 mg, 1.38 mmol) and
dicyclohexylphosphrous-diphenyl (0.48 mg, 1.38 mmol) was degassed
by bubbling N.sub.2 for 20 min. 1-Bromo-5-fluoro-naphthalene (3.10
g, 13.8 mmol) and 1-Boc-piperazine (3.08 g, 16.6 mmol) were added
followed by NaOt-Bu (1.86 g, 19.3 mmol). The mixture was warmed up
to 80.degree. C. and kept at this temperature for 16 h. The solvent
was removed under reduced pressure and the residue was dissolved in
6 N HCl (60 mL) and washed with ether (3.times.50 mL). The aqueous
phase was basified with solid KOH to pH=11, it was then extracted
with EtOAc (3.times.100 mL). The combined organic phases were dried
over Na.sub.2SO.sub.4 and concentrated to give the fourth
intermediate compound (2.10 g, 66%) as a brown oil. .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. 8.00 (d, J=6.0 Hz, 1H), 7.80 (d,
J=6.0 Hz, 1H), 7.45 (m, 1H), 7.40 (m, 1H), 7.10 (m, 2H), 3.40-3.10
(m, 8H).
[0811] The reductive amination procedure from Example A1 was
followed using 1-(5-fluoro-naphthalen-1-yl)-piperazine to give the
first intermediate compound. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 8.00 (d, J=6.0 Hz, 1H), 7.80 (d, J=6.0 Hz, 1H), 7.60 (br s,
1H), 7.55 (t, J=7.0 Hz, 1H), 7.42 (m, 2H), 7.10 (m, 2H), 6.40 (d,
J=6.0 Hz, 1H), 4.25 (t, J=4.0 Hz, 2H), 3.20 (br s, 4H), 2.90-2.40
(m, 10H), 1.90 -1.70 (m, 4H). Elemental Analysis: calculated for
C.sub.26H.sub.29FN.sub.402-0.5H.sub.2O: C, 68.27; H, 6.35; N,
12.25. Found: C, 68.22; H, 6.50; N, 11.85.
Example A69
Synthesis of
7-{4-[4-(4-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one
[0812] A first intermediate compound,
1-(4-Fluoro-naphthalen-1-yl)-piperazine, was produced as follows: A
mixture of dicyclohexylphosphino biphenyl (0.155 g, 0.444 mmol, 0.1
mmol) and palladium acetate (0.099 g, 0.444 mmol, 0.1 equiv) in dry
toluene (15 mL) was bubbled with N.sub.2 gas for two hours. To the
resultant clear solution was added 1-bromo-4-fluoro naphthalene
(1.0 g, 4.44 mmol, 1.0 equiv) followed by 1-Boc-piperazine (1.0 g,
5.33 mmol, 1.2 equiv). To this mixture was added NaO.sup.tBu (0.600
g, 6.22 mmol, 1.4 equiv) and the reaction mixture was stirred at
80.degree. C. overnight. The reaction mixture was cooled to room
temperature, and the solvent was removed under reduced pressure.
The residue was taken up in CH.sub.2Cl.sub.2, filtered through a
celite bed, and then rinsed with CH.sub.2Cl.sub.2. The combined
filtrates were concentrated and purified by column chromatography
on silica (20% EtOAc in hexane).
4-(4-Fluoro-naphthalen-1-yl)-piperazine-1-carboxylic acid
tert-butyl ester (1.4 g, impure) was obtained as a dark viscous
liquid, which was used in the next step without further
purification. .sup.1H NMR: (400 MHz, CDCl.sub.3) .delta. 8.25 (m,
1H), 8.05 (m, 1H), 7.55 (m, 2H), 7.05-6.80 (m, 2H), 4.00 (br s,
4H), 3.00 (br s, 4H), 1.45 (s, 9H). MS: ES+ 331.13 (M+H).sup.+
(Exact mass: 330.17).
[0813] To a solution of
4-(4-fluoro-naphthalen-1-yl)-piperazine-1-carboxylic acid
tert-butyl ester (1.1 g, 3.33 mmol) in CH.sub.2Cl.sub.2 (10 mL) was
added TFA (10 mL) at 0.degree. C. The reaction mixture was warmed
to room temperature and stirred for one hour. Solvents were removed
and the residue was purified by column chromatography on silica
(10% MeOH in CH.sub.2Cl.sub.2) to afford the first intermediate
compound (0.90 g, 78%) as a pale brown crystalline solid. .sup.1H
NMR: (400 MHz, DMSO-d.sub.6) .delta. 9.0 (br s, 2H), 8.28 (m, 1H),
8.08 (m, 1H), 7.65 (m, 2H), 7.30 (m, 1H), 7.08 (m, 1H), 3.45 (br s,
4H), 3.20 (br s, 4H). MS: ES+ 231.09 (M+H).sup.+ (Exact mass:
230.12).
[0814] The reductive amination procedure from Example A1 was
followed using 1-(4-fluoro-naphthalen-1-yl)-piperazine to give the
title compound. .sup.1H NMR: (400 MHz, CDCl.sub.3) .delta. 8.25 (m,
1H), 8.10 (m, 1H), 7.65 (br s, 1H), 7.55 (m, 2H), 7.38 (d, 1H),
7.10-6.95 (m, 2H), 6.35 (d, 1H), 4.25 (t, 2H), 3.10-3.00 (br s,
4H), 2.90-2.40 (m, 10H), 1.85-1.55 (m, 4H). MS: ES+ 449.18
(M+H).sup.+ (Exact mass: 448.23).
Example A70
7-{4-[4-(3-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H--
[1,8]naphthyridin-2-one
[0815] A first intermediate, 3-Fluoro-naphthalene-1-carboxylic acid
methyl ester, was produced as follows: An ice-cold mixture of
3-amino-naphthalene-1-carboxylic acid methyl ester (1.76 g, 8.75
mmol) in tetrahydrofuran (2 mL) was treated with 48%
tetrafluoroboric acid (20 mL) followed by sodium nitrite (1.81 g,
26.20 mmol) in water (4 mL). The suspension was stirred for 1 hour
at 0.degree. C., then sodium tetrafluoroborate (4.80 g, 43.70 mmol)
was added. The suspension was warmed to room temperature and
stirred for 30 minutes. The green diazonium salt was collected by
vacuum filtration, rinsed with diethyl ether and dried under high
vacuum overnight. The solid was diluted with chlorobenzene (10 mL)
and then refluxed for 1 hour. The brown solution was cooled to room
temperature, quenched with water and extracted with
dichloromethane. The extracts were dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to a brown
oil. The oil was purified by column chromatography (5:1,
hexanes/ethyl acetate) to afford the first intermediate compound
(0.892 g, 50%) as a yellow liquid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.89 (d, 1H), 8.00-7.94 (m, 1H), 7.85-7.78 (m,
1H), 7.70-7.62 (m, 1H), 7.60-7.52 (m, 2H), 4.00 (s, 3H).
[0816] A second intermediate compound,
(3-Fluoro-naphthalen-1-yl)-carbamic acid tert-butyl ester, was
produced as follows: A mixture of 3-fluoro-naphthalene-1-carboxylic
acid methyl ester (4.47 g, 21.90 mmol) in 2N KOH (15 mL, 30 mmol)
and methanol (60 mL) was refluxed for 2 hours. The solution was
cooled, then concentrated under reduced pressure. The residue was
diluted with water and acidified to pH 1 with 3N HCl. A solid
precipitated out of solution and the suspension was diluted with
ethyl acetate. The organic layer was separated and the aqueous
layer was extracted with ethyl acetate. The combined extracts were
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo to afford the carboxylic acid (4.08 g, 98%) as a yellow
solid.
[0817] A mixture of 3-fluoro-naphthalene-1-carboxylic acid (3.98 g,
21 mmol) in dry tert-butanol (80 mL) was treated with triethylamine
(6.2 mL, 44 mmol) followed by diphenylphosphoryl azide (5.60 mL, 26
mmol). The yellow solution was refluxed overnight, then cooled and
concentrated under vacuum. The residue was purified by column
chromatography (7:1, hexanes/ethyl acetate) to afford the second
intermediate compound (4.78 g, 87%) as a yellow solid. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.96-7.87 (m, 1H), 7.84-7.75 (m, 2H),
7.56-7.43 (m, 2H), 7.21 (d, 1H), 7.03 (br s, 1H), 1.48 (s, 9H).
[0818] A third intermediate compound,
1-(3-Fluoro-naphthalen-1-yl)-piperazine, was produced as follows: A
solution of (3-fluoro-naphthalen-1-yl)-carbamic acid tert-butyl
ester (4.78 g, 18.30 mmol) in dichloromethane (30 mL) and
trifluoroacetic acid (10 mL) was refluxed for 2 hours. The mixture
was diluted with diethyl ether and the solid that precipitated out
was collected by vacuum filtration as the TFA salt (2.137 g). The
filtrate was neutralized with 2N KOH and extracted with
dichloromethane. The extracts were dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated to a brown residue. The
residue was purified by column chromatography (5:1, hexanes/ethyl
acetate) to afford 3-fluoro-naphthalen-1-ylamine (0.967 g, 33%).
The TFA salt (2.137 g) was stirred in a heterogeneous solution of
2N KOH (10 mL) in dichloromethane (20 mL). The organic layer was
separated and the aqueous layer was extracted with dichloromethane.
The combined extracts were dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated to afford an additional amount of
3-fluoro-naphthalen-1-ylamine (1.193 g, 40%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.78-7.64 (m, 2H), 7.48-7.42 (m, 1H), 7.41-7.34
(m, 1H), 6.90 (d, 1H), 6.54 (d, 1H), 4.30 (br s, 2H).
[0819] A solution of 3-fluoro-naphthalen-1-ylamine (1.00 g, 6.20
mmol), sodium iodide (0.465 g, 3.10 mmol), diisopropylethylamine
(0.30 mL, 3.10 mmol) and bis(2-chloroethyl)amine hydrochloride
(1.218 g, 6.82 mmol) in chlorobenzene (10 mL) and 1-hexanol (1 mL)
was heated at 150.degree. C. overnight. The solvent was removed
from the brown solution by vacuum distillation and the residue was
cooled to room temperature. The residue was diluted with
hexanes/diethyl ether (1:1) and then the solvent was decanted. This
was repeated, then the solid was collected by vacuum filtration.
The brown solid was diluted with methanoychloroform and absorbed
onto SiO.sub.2, then loaded onto a column for chromatography
(methanol/ammonium hydroxide/chloroform, 8:1:91) to afford a brown
oil. The oil was triturated with diethyl ether to afford the third
intermediate compound (0.173 g, 12%), as a brown solid. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.20 (br s, 1H), 8.10 (d, 1H), 7.88
(d, 1H), 7.60-7.41 (m, 2H), 7.02 (d, 1H), 3.20 (br s, 4H), 3.05 (br
s, 4H).
[0820] The reductive amination procedure from Example A1 was
followed using 1-(3-fluoro-naphthalen-1-yl)-piperazine to give the
title compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.12 (d,
1H), 7.74 (d, 1H), 7.55 (br s, 1H), 7.50-7.39 (m, 2H), 7.37 (d,
1H), 7.14 (dd, 1H), 6.86 (dd, 1H), 6.36 (d, 1H), 4.24 (t, 2H), 3.16
(br s, 4H), 2.87 (t, 2H), 2.75 (br s, 4H), 2.64 (t 2H), 2.54 (t,
2H), 1.88-1.78 (m, 2H), 1.78-1.68 (m, 2H); ES MS: 449.12
(M+H).sup.+ (Exact mass: 448.23).
Example A71
Synthesis of
7-{4-[4-(2-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one
[0821] A first intermediate, 1-Bromo-naphthalen-2-ylamine, was
produced as follows: To a solution of naphthalen-2-ylamine (1.03 g,
7.2 mmol) in DMF was added NBS (1.54 g, 8.6 mmol, 1.2 eq). The
mixture was heated at 110.degree. C. for 2 h, cooled to room
temperature, taken up in EtOAc (150 mL) and washed with water
(3.times.50 mL). The organic phase was dried over Na.sub.2SO.sub.4
and concentrated. The residue was purified by chromatography on
silica gel to give compound the first intermediate compound (1.12
g, 70%) as a red solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
8.05 (d, J=5.0 Hz, 1H), 7.70 (d, J=6.0 Hz, 1H), 7.65 (d, J=6.0 Hz,
1H), 7.58 (t, J=5.0 Hz, 1H), 7.30 (t, J=5.0 Hz, 1H), 7.00 (d, J=6.0
Hz, 1H), 4.40 (br s, 2H).
[0822] A second intermediate compound,
1-Bromo-2-fluoro-naphthalene, was produced as follows: To a cooled
(0.degree. C.) solution of 1-bromo-naphthalen-2-ylamine (1.0 g,
4.52 mmol) in THF (1 mL) was added 48% HBF.sub.4 (10 mL) followed
by a solution of NaNO.sub.2 (0.49 g, 13.58 mmol, 3 eq) in water (2
mL). After the addition was over, the mixture was kept stirring at
0.degree. C. for 1 h and NaBF.sub.4 (2.49 g, 22.6 mmol, 5 eq) was
added. The mixture was allowed to warm to room temperature and was
filtered. The solid was washed with ether and dried overnight under
high vacuum to give the diazonium salt as a green solid, which was
used in the next step. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
8.60 (d, J=6.8 Hz, 1H), 8.55 (d, J=6.0 Hz, 1H), 8.50 (d, J=6.0 Hz,
1H), 8.40 (d, J=6.0 Hz, 1H), 8.20 (t, J=6.0 Hz, 1H), 8.10 (t, J=6.0
Hz, 1H).
[0823] The material obtained in the last step was suspended in
xylene (5 mL) and refluxed for 1 h. The resulting mixture was
subjected to chromatography on silica gel to give the second
intermediate compound (480 mg, 47%) as a yellow solid for two
steps. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.22 (d, J=7.0
Hz, 1H), 7.80 (m, 2H), 7.60 (t, J=6.0 Hz, 1H), 7.50 (t, J=6.0 Hz,
1H), 7.30 (t, J=7.0 Hz, 1H).
[0824] A third intermediate compound,
1-(2-Fluoro-naphthalen-1-yl)-piperazine, was produced as follows: A
solution of Pd(OAc).sub.2 (44.8 mg, 0.2 mmol) and
2-(dicyclohexylphosphino)biphenyl (70.0 mg, 0.2 mmol) was degassed
by bubbling N.sub.2 for 20 min. 1-Bromo-2-fluoro-naphthalene (0.448
g, 2 mmol) and 1-Boc-piperazine (0.446 g, 2.4 mmol) were added
followed by the addition of NaO.sup.tBu (0.27 g, 2.8 mmol). The
mixture was warmed up to 80.degree. C. and kept at this temperature
for 16 h. The solvent was removed under reduced pressure and the
residue was purified by chromatography on silica gel to give
4-(2-fluoro-naphthalen-1-yl)-piperazine-1-carboxylic acid
tert-butyl ester (0.24 g, 40%).
[0825] A mixture of
4-(2-fluoro-naphthalen-1-yl)-piperazine-1-carboxylic acid
tert-butyl ester (1.05 g, 2.83 mmol) and TFA (1 mL) in
dichloromethane (10 ml) was refluxed for 2 h. The solvent was
removed under reduced pressure to give a black solid (1.05 g),
which was dissolved in dichloromethane (2 mL) and ether was added
to precipitate the third intermediate compound (0.36 g) as the TFA
salt. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.75 (d, J=6.0 Hz,
1H), 8.00 (d, J=6.0 Hz, 1H), 7.90 (m, 1H), 7.62 (m, 1H), 7.58 (m,
1H), 7.42 (t, J=6.0 Hz, 1H), 3.60-3.10 (m, 8H).
[0826] The reductive amination procedure from Example A1 was
followed using 1-(2-fluoro-naphthalen-1-yl)-piperazine to give the
title compound. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.40 (d,
J=6.0 Hz, 1H), 7.80 (d, J=6.0 Hz, 1H), 7.60 (m, 1H), 7.55 (m, 2H),
7.42 (m, 1H), 7.37 (d, J=5.0 Hz, 1H), 7.20 (m, 1H), 6.35 (d, J=6.0
Hz, 1H), 4.25 (t, J=4.0 Hz, 2H), 3.50 (m, 2H), 3.10 (m, 1H), 2.95
(m, 2H), 2.85 (t, J=6.0 Hz, 2H), 2.65 (t, J=7.0 Hz, 2H), 2.50 (m,
2H), 2.40 (m, 2H), 1.85 (m, 2H), 1.75 (m, 2H).
Example A72
Synthesis of
7-{4-[4-(6,7-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one
[0827] A first intermediate compound, Trifluoro-methanesulfonic
acid 6,7-difluoro-3,4-dihydro-naphthalen-1-yl ester, was produced
as follows: To a cooled (-78.degree. C.) solution of
6,7-difluoro-3,4-dihydro-2H-naphthalen-1-one (3.64 g, 20 mmol,
Tetrahedron Lett. 2003, 44,4007) in THF (40 mL) was added LiHMDS
(24 mL, 24 mmol) over 10 min. The resulting mixture was stirred at
-78.degree. C. for 1 h and a solution of
N-phenyltrifluoromethanesulfonimide (8.59 g, 24 mmol) in THF (20
mL) was added. The mixture was stirred at -78.degree. C. for
another 3 h, quenched with H.sub.2O and extracted with EtOAc
(3.times.50 mL). The combined organic phases were dried and
concentrated to give the first intermediate compound (6.28 g,
100%). .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.20 (m, 1H),
7.00 (m, 1H), 6.05 (t, 1H), 2.80 (m, 2H), 2.50 (m, 2H).
[0828] A second intermediate compound, Trifluoro-methanesulfonic
acid 6,7-difluoro-naphthalen-1-yl ester, was produced as follows: A
mixture of trifluoro-methanesulfonic acid
6,7-difluoro-3,4-dihydro-naphthalen-1-yl ester (6.28 g, 20 mmol)
and DDQ (9.08 g, 40 mmol) in dioxane (60 mL) was refluxed for 24 h
and then cooled to RT. The reaction mixture was partitioned between
hexanes and water. The organic layer was washed with water, dried
and concentrated. The residue was passed through a pad of celite
eluting with hexane which gave the second intermediate compound
(4.38 g, 70%) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 7.80 (m, 2H), 7.70 (m, 1H), 7.50 (m, 2H).
[0829] A third intermediate compound,
1-(6,7-Difluoro-naphthalen-1-yl)-piperazine, was produced as
follows: Nitrogen gas was bubbled through a solution of
trifluoro-methanesulfonic acid 6,7-difluoro-naphthalen-1-yl ester
(4.38 g, 14.04 mmol), 1-Boc-piperazine (3.18 g, 16.85 mmol),
Pd(OAc).sub.2 (0.31 g, 1.4 mmol) and 2-dicyclohexylphosphino
biphenyl (0.49 g, 1.4 mmol) in toluene (40 mL) for 10 min. NaOtBu
(1.89 g, 19.66 mmol) was added. The resulting mixture was heated at
80.degree. C. for 2 h, cooled to RT, diluted with EtOAC (40 mL) and
filtered through a pad of celite. The filtrate was concentrated and
the residue was purified by chromatography on silica gel to give
4-(6,7-difluoro-naphthalen-1-yl)-piperazine-1-carboxylic acid
tert-butyl ester.
[0830] To a solution of the
4-(6,7-difluoro-naphthalen-1-yl)-piperazine-1-carboxylic acid
tert-butyl ester (1.15 g) in MeOH (10 mL) was added conc. HCl (4
mL). The resulting mixture was stirred at room temperature for 16 h
and concentrated under vacuum. The solid obtained was washed with a
small amount of MeOH and ether and dried to give the third
intermediate compound (0.43 g, 11% in two steps). .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 9.30 (br s, 2H), 8.10 (m, 2H), 7.70 (d,
1H), 7.50 (t, 1H), 7.30 (d, 1H), 3.40 (br s, 4H), 3.20 (br s,
4H).
[0831] The reductive amination procedure from Example A1 was
followed using 1-(6,7-difluoro-naphthalen-1-yl)-piperazine to give
the title compound (0.25 g, 75%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 10.30 (br s, 2H), 8.05 (m, 2H), 7.70 (d,
1H), 7.50 (m, 2H), 7.26 (d, 1H), 6.40 (d, 1H), 4.22 (t, 2H),
3.60-3.10 (m, 10H), 2.80 (m, 2H), 2.50 (m, 2H), 1.90-1.70 (m,
4H).
Example A73
Synthesis of
7-{4-[4-(7-Methoxy-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1-
H-[1,8]naphthyridin-2-one
[0832] A first intermediate compound,
4-(7-Methoxy-naphthalen-1-yl)-piperazine-1-carboxylic acid
tert-butyl ester, was produced as follows:
4-(7-Hydroxy-naphthalen-1-yl)-piperazine-1-carboxylic acid
tert-butyl ester (2.0 g, 6.10 mmol) was dissolved in
dimethylsulfoxide (7 mL) and sodium hydroxide (366 mg, 9.14 mmol)
was added. The mixture was stirred for 5 minutes and then methyl
iodide (1.73 g, 0.76 mL, 12.20 mmol) was added. The reaction was
stirred at room temperature for 3 hours, quenched with water (20
mL) and extracted with ethyl acetate (20 mL). The organic layer was
washed with water (2.times.20 mL) and brine (20 mL), dried over
anhydrous sodium sulfate, filtered and concentrated in vacuo to
yield the first intermediate compound (1.91 g, 92%) as a yellow
oil. MS: ES+ 343.20 (M+1).sup.+.
[0833] A second intermediate compound,
1-(7-Methoxy-naphthalen-1-yl)-piperazine, was produced as follows:
4-(7-Methoxy-naphthalen-1-yl)-piperazine-1-carboxylic acid
tert-butyl ester (1.70 g, 4.97 mmol) was dissolved in
dichloromethane (10 mL) and trifluoroacetic acid (2 mL). The
mixture was stirred at room temperature for 24 hours and then
diluted with hexanes (50 mL). The solids were collected by vacuum
filtration and rinsed with hexanes (2.times.30 mL) to yield the
second intermediate compound (2.18 g, quant.) as a purple powder.
.sup.1H NMR (400 MHz, dmso-d.sub.6) .delta. 8.90 (s, 2H), 7.80 (d,
1H), 7.60 (d, 1H), 7.40 (s, 1H), 7.30 (t, 1H), 7.20-7.10 (m, 2H),
3.95 (s, 3H), 3.80-3.40 (m, 8H).
[0834] The reductive amination procedure from Example A1 was
followed using 1-(7-methoxy-naphthalen-1-yl)-piperazine to give the
title compound. .sup.1H NMR (400 MHz, dmso-d.sub.6) .delta. 10.22
(s, 1H), 7.80 (d, 1H), 7.55-7.42 (m, 2H), 7.40 (s, 1H), 7.26 (t,
1H), 7.18 (d, 1H), 7.10 (d, 1H), 6.40 (d, 1H), 4.20 (t, 2H), 3.84
(s, 3H), 3.15-2.90 (m, 4H), 2.80-2.55 (m, 6H), 2.44-2.40 (m, 4H),
1.80-1.50 (m, 4H), MS ES+ 461.22 (M+1).sup.+.
Example A74
Synthesis of
7-{4-[4-(7-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one
[0835] A first intermediate compound, Trifluoro-methanesulfonic
acid 7-chloro-3,4-dihydro-naphthalen-1-yl ester, was produced as
follows: To a stirred solution of 7-chloro-1-tetralone (6 g, 33.33
mmol) in dry THF (140 mL) at -78.degree. C. was added 1M solution
of lithium bis(trimethylsilyl)amide in THF (40 mL, 40 mmol) over 5
min under N.sub.2. The reaction mixture was stirred for 1 h and
N-phenyltrifluoromethanesulfonimide (14.44 g, 40 mmol) was added in
one portion. The reaction mixture was allowed to warm to room
temperature and stirred for 2 h. The solvent was removed in vaccuo
and the residue was dissolved in EtOAc (200 mL), and washed
successively with 2M NaOH, H.sub.2O and brine. Drying over
Na.sub.2SO.sub.4 and evaporation under vaccuo yielded a brown oil.
Purification by chromatography on silica gel (10% EtOAc:hexanes)
gave the first intermediate compound as an oil (9.78 g, 95%).
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.32 (d, 1H), 7.24 (dd,
1H), 7.12 (d, 1H), 6.06 (t, 1H), 2.84 (t, 2H), 2.53 (m, 2H).
[0836] A second intermediate compound, Trifluoro-methanesulfonic
acid 7-chloro-naphthalen-1-yl ester, was produced as follows: To a
stirred solution of trifluoro-methanesulfonic acid
7-chloro-3,4-dihydro-naphthalen-1-yl ester (9.0 g, 28.8 mmol) in
dioxane (150 mL) was added
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (13.0 g, 57.7 mmol). The
reaction mixture was refluxed for 24 h, and the solvent was removed
under vaccuo. EtOAc (250 mL) was added, the mixture was washed with
H.sub.2O and brine, and dried over Na.sub.2SO.sub.4. Evaporation
under vaccuo and column chromatography of the resulting dark brown
oil on silica gel, eluting with hexanes, yielded the second
intermediate compound as an oil (6.2 g, 55%). .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 8.04 (d, 1H), 7.83 (m, 2H), 7.58-7.48 (m,
3H).
[0837] A third intermediate compound,
4-(7-Chloro-naphthalen-1-yl)-piperazine-1-carboxylic acid
tert-butyl ester, was produced as follows: To an oven dried flask
was added 1-boc-piperazine (3.48 g, 19.34 mmol), K.sub.3PO.sub.4
(4.78 g, 22.56 mmol), Pd(OAc).sub.2 (0.361 g, 1.61 mmol),
2-(di-tert-butylphosphino)binaphthyl (0.64 g, 1.61 mmol), THF (40
mL) and trifluoro-methanesulfonic acid 7-chloro-naphthalen-1-yl
ester (5 g, 16.12 mmol). While stirring the reaction mixture at
room temperature, the air in the flask was removed and refilled
with N.sub.2. This process was repeated three times. The reaction
was heated at 80.degree. C. for 16 h. Diethyl ether was added at
room temperature and the mixture was filtered through a pad of
silica gel. The brown oil was chromatographed on silica gel eluting
with hexanes:chloroform (1:1) and then changing to chloroform
(100%) to yield the third intermediate compound (3.65 g, 63%) as a
brown oil. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 8.16 (d,
1H), 7.96 (d, 1H), 7.68 (d, 1H), 7.55 (d, 1H), 7.52 (t, 1H), 7.21
(d, 1H), 3.61 (s, 4H), 2.98 (s, 4H), 1.42 (s, 9H).
[0838] A fourth intermediate compound,
1-(7-Chloro-naphthalen-1-yl)-piperazine, was produced as follows:
To a solution of
4-(7-chloro-naphthalen-1-yl)-piperazine-1-carboxylic acid
tert-butyl ester (2.4 g, 6.89 mmol) in CH.sub.2Cl.sub.2 (20 mL) at
0.degree. C. was added dropwise trifluoroacetic acid (5.24 mL,
68.96 mmol). The reaction mixture was stirred at room temperature
for 2 h and the solvent was evaporated. Addition of Et.sub.2O gave
the fourth intermediate compound as a white amorphous TFA salt (1.8
g, 73%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 8.82 (s, 2H),
8.19 (d, 1H), 7.98 (d, 1H), 7.73 (d, 1H), 7.57 (m, 2H), 7.24 (d,
1H), 3.54-3.11 (m, 8H).
[0839] The reductive amination procedure from Example A1 was
followed using 1-(7-chloro-naphthalen-1-yl)-piperazine to give the
title compound. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 10.28
(s, 2H), 8.12 (d, 1H), 7.98 (d, 1H), 7.74 (d, 1H), 7.58-7.49 (m,
3H), 7.28 (d, 1H), 6.38 (d, 1H), 4.24 (t, 2H), 3.64 (m, 2H),
3.50-3.14 (m, 8H), 2.78 (t, 2H), 2.48 (m, 2H), 1.96-1.75 (m,
4H).
Example A75
Synthesis of
7-{4-[4-(5-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one
[0840] A first intermediate compound, 5-Chloro-naphthalen-1-ol, was
produced as follows: To a cold solution of 5-amino-naphthalen-1-ol
in conc. HCl (100 mL) and H.sub.2O (100 mL) at 0.degree. C. was
added dropwise a solution of NaNO.sub.2 (12.36 g, 190 mmol) in
H.sub.2O (20 mL). Freshly prepared CuCl (17.75 g, 190 mmol) was
dissolved in conc. HCl (20 ml) and added to the reaction mixture.
The reaction mixture became very thick and black foamy material
resided on the top of the reaction mixture. CH.sub.3CN (50 ml) was
added to make the reaction mixture homogenous. The reaction was
brought to room temperature and stirred at 65.degree. C. for 20
min. Ethyl acetate (500 mL) was added and the organic layer was
separated and washed with H.sub.2O (3.times.100 mL), brine, dried
over Na.sub.2SO.sub.4 and evaporated under vaccuo. The dark black
material was chromatographed on a silica column, eluting with
CHCl.sub.3 and then changing to CHCl.sub.3:MeOH (98:2), to yield
compound the first intermediate compound as an oil (4.16 g, 19%).
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.18 (d, 1H), 7.82 (d,
1H), 7.59 (d, 1H), 7.42-7.37 (m, 2H), 6.86 (d, 1H), 5.96 (s,
1H).
[0841] A second intermediate compound, Trifluoro-methanesulfonic
acid 5-chloro-naphthalen-1-yl ester, was produced as follows: To a
cold solution of 5-chloro-naphthalen-1-ol (3.7 g, 20.78 mmol) in
CH.sub.2Cl.sub.2 (50 mL) at 0.degree. C. was added dropwise
Et.sub.3N (5.78 mL, 41.6 mmol), followed by
trifluoromethanesulfonic anhydride (5.24 mL, 31.2 mmol). The
reaction mixture was stirred at 0-5.degree. C. for 30 min and
saturated NaHCO.sub.3 (50 mL) was added. The organic layer was
separated and washed with saturated NH.sub.4Cl solution, brine and
dried over Na.sub.2SO.sub.4. Evaporation under vaccuo and
purification by chromatography on silica (3:1 Et.sub.2O/hexanes)
yielded the second intermediate compound as a colorless oil (5.5 g,
85%). .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.38 (d, 1H), 8.02
(d, 1H), 7.71 (d, 1H), 7.60 (m, 2H), 7.58 (d, 1H).
[0842] A third intermediate compound,
4-(5-Chloro-naphthalen-1-yl)-piperazine-1-carboxylic acid
tert-butyl ester, was produced as follows: To an oven dried flask,
1-boc-piperazine (2.95 g, 15.87 mmol), K.sub.3PO.sub.4 (3.92 g,
18.5 mmol), Pd(OAc).sub.2 (0.296 g, 1.32 mmol),
2-(Di-tert-butylphosphino)binaphthyl (0.525 g, 1.32 mmol), THF (40
mL) and trifluoro-methanesulfonic acid 5-chloro-naphthalen-1-yl
ester (4.1 g, 13.22 mmol) were added. While stirring the reaction
mixture at room temperature, the air in the flask was removed and
refilled with N.sub.2. This process was repeated three times. The
reaction temperature was brought to 80.degree. C. and stirred for
18 h. Diethyl ether was added at room temperature and the mixture
was filtered through a pad of silica gel. The brown oily material
was purified by chromatography on silica column eluting with
hexanes:chloroform (1:1) and then changing to chloroform (100%) to
yield the third intermediate compound (1.75 g, 41%) as a brown oil.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 8.18 (d, 1H), 7.90 (d,
1H), 7.68 (d, 1H), 7.58 (t, 1H), 7.53 (t, 1H), 7.22 (d, 1H), 3.61
(s, 4H), 2.97 (s, 4H), 1.42 (s, 9H).
[0843] A fourth intermediate compound,
1-(5-Chloro-naphthalen-1-yl)-piperazine, was produced as follows:
To a solution of
4-(5-chloro-naphthalen-1-yl)-piperazine-1-carboxylic acid
tert-butyl ester (1.85 g, 5.35 mmol) in CH.sub.2Cl.sub.2 (10 ml) at
0.degree. C. was added dropwise trifluoromethanesulfonic acid (4.1
ml, 53.5 mmol).The reaction mixture was stirred at room temperature
for 2 h and the solvent was evaporated under vaccuo. Addition of
Et.sub.2O gave the fourth intermediate compound as a white
amorphous solid (1.5 g, 80%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.84 (s, 2H), 8.19 (d, 1H), 7.97 (d, 1H), 7.74 (d, 1H),
7.64 (t, 1H), 7.54 (t, 1H), 7.34 (d, 1H), 3.54-3.11 (m, 8H).
[0844] The reductive amination procedure from Example A1 was
followed using 1-(5-chloro-naphthalen-1-yl)-piperazine to give the
title compound. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 10.76
(s, 1H), 10.29 (s, 1H), 8.21 (d, 1H), 7.98 (d, 1H), 7.74 (d, 1H),
7.68 (t, 1H), 7.54 (m, 2H), 7.36 (d, 1H), 6.37 (d, 1H), 4.24 (t,
2H), 3.63 (m, 2H), 3.52-3.13 (m, 10H), 2.78 (t, 2H), 1.98-1.68 (m,
4H).
Example A76
7-{4-[4-(6-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H--
[1,8]naphthyridin-2-one
[0845] An intermediate compound,
1-(6-Chloro-naphthalen-1-yl)-piperazine, was produced as follows:
The intermediate compound was prepared from 6-amino-naphthalen-1-ol
according to the route described in Example A75 above. .sup.1H-NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.91 (s, 2H), 8.18 (d, 1H), 8.03
(d, 1H), 7.66 (d, 1H), 7.52 (m, 2H), 7.22 (d, 1H), 3.41 (s, 4H),
3.21 (s, 4H).
[0846] The reductive amination procedure from Example A1 was
followed using 1-(6-chloro-naphthalen-1-yl)-piperazine to give the
title compound (0.50 g, 60%), mp. 215-216.degree. C. .sup.1H-NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.66 (s, 1H), 10.22 (s, 1H), 8.18
(d, 1H), 8.03 (d, 1H), 7.64 (d, 1H), 7.58 (m, 3H), 7.22 (d, 1H),
6.38 (d, 1H), 4.22 (t, 2H), 3.62 (m, 2H), 3.51-3.09 (m, 10H), 2.78
(t, 2H), 1.98-1.72 (m, 4H).
Example A77
7-{4-[4-(8-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H--
[1,8]naphthyridin-2-one
[0847] A first intermediate compound, 8-Bromo-naphthalen-1-ylamine,
was produced as follows: Sodium azide (7.81 g, 120 mmol) was added
portionwise to a suspension of 8-bromo-naphthalene-1-carboxylic
acid (5 g, 19.92 mmol) in conc. H.sub.2SO.sub.4 (17.5 mL) and
CHCl.sub.3 (17.5 mL) at 45.degree. C. The reaction mixture was
stirred for 1.5 h and water (150 mL) was added at room temperature.
The mixture was made alkaline with ammonium hydroxide and extracted
with CHCl.sub.3. The organic layer was dried over Na.sub.2SO.sub.4
and evaporated to give the first intermediate compound as a brown
oil (4.48 g, 99%). .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.68
(dd, 1H), 7.62 (dd, 1H), 7.24 (m, 2H), 7.13 (t, 1H), 6.74 (q, 1H),
5.20 (s, 2H).
[0848] A second intermediate compound,
1-Bromo-8-chloro-naphthalene, was produced as follows: To a cold
solution of 8-bromo-naphthalen-1-ylamine (4.48 g, 20 mmol) in conc.
HCl (30 mL) and H.sub.2O (25 mL) at 0.degree. C. was added dropwise
a solution of NaNO.sub.2 (3.45 g, 50 mmol) in H.sub.2O (10 mL).
Freshly prepared CuCl (13.86 g, 140 mmol) was dissolved in conc.
HCl (15 ml) and was added to the reaction mixture. The reaction was
brought to room temperature and stirred at 65.degree. C. for 30
min. Ethyl acetate (250 mL) was added and the organic layer was
separated and washed with H.sub.2O (3.times.100 mL), brine, dried
over Na.sub.2SO.sub.4 and evaporated under vaccuo. The dark black
material was purified by chromatography on silica, eluting with
CHCl.sub.3 and then changing to CHCl.sub.3:MeOH (98:2), to yield
the second intermediate compound as an oil (2.95 g, 72%). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.92 (dd, 1H), 7.82-7.75 (m, 2H),
7.65 (dd, 1H), 7.36 (t, 1H), 7.26 (q, 1H).
[0849] A third intermediate compound,
1-(8-Chloro-naphthalen-1-yl)-piperazine, was produced as follows:
To an oven dried flask, 1-boc-piperazine (1.2 g, 6.47 mmol), NaOtBu
(0.724 g, 7.54 mmol), Pd(OAc).sub.2 (0.12 g, 0.539 mmol),
2-(di-cyclohexylphosphino)biphenyl (0.12 g, 0.539 mmol), toluene
(15 mL) and 1-bromo-8-chloro-naphthalene (1.3 g, 5.39 mmol) were
added. While stirring the reaction mixture at room temperature, the
air in the flask was removed and refilled with N.sub.2. This
process was repeated three times. The reaction mixture was stirred
for 3 h at 80-90.degree. C. Diethyl ether was added at room
temperature and the mixture was filtered through a pad of silica
gel. The brown oily material was purified by chromatography on
silica, eluting with hexanes:chloroform (1:1) and then changing to
100% chloroform, to give
4-(8-chloro-naphthalen-1-yl)-piperazine-1-carboxylic acid
tert-butyl ester as an oil (1.35 g, 72%). .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 7.73 (dd, 1H), 7.56 (dd, 1H), 7.52 (dd, 1H),
7.42 (t, 1H), 7.34 (t, 1H), 7.18 (dd, 1H), 4.16 (s, 2H), 3.38 (s,
2H), 3.22 (m, 2H), 2.76 (m, 2H), 1.45 (s, 9H).
[0850] To a solution of
4-(8-chloro-naphthalen-1-yl)-piperazine-1-carboxylic acid
tert-butyl ester (1.34 g, 3.87 mmol) in CH.sub.2Cl.sub.2 (10 mL) at
0.degree. C. was added dropwise trifluoroacetic acid (2.94 mL, 38.7
mmol). The reaction mixture was stirred at room temperature for 1.5
h and the solvent was evaporated under vaccuo. Addition of
Et.sub.2O gave the third intermediate compound as a white amorphous
solid (1.03 g, 74%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
8.92 (s, 1H), 8.71 (s, 1H), 7.92 (dd, 1H), 7.76 (d, 1H), 7.62 (dd,
1H), 7.54 (t, 1H), 7.46 (m, 1H), 7.33 (dd, 1H), 3.44-3.27 (m, 4H),
3.20-2.91 (m, 4H).
[0851] The reductive amination procedure from Example A1 was
followed using 1-(8-chloro-naphthalen-1-yl)-piperazine to give the
title compound (0.303 g, 48%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. 10.31 (s, 1H), 10.21 (s, 1H), 7.94 (dd, 1H), 7.76 (d, 1H),
7.62 (dd, 1H), 7.54 (m, 2H), 7.46 (t, 1H), 7.32 (d, 1H), 6.38 (d,
1H), 4.22 (t, 2H), 3.62 (m, 2H), 3.44-3.22 (m, 8H), 3.08 (m, 2H),
2.79 (m, 2H), 1.92-1.72 (m, 4H).
Example A78
7-{4-[4-(7-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H--
[1,8]naphthyridin-2-one
[0852] A first intermediate compound,
4-(7-Trifluoromethanesulfonyloxy-naphthalen-1-yl)-piperazine-1-carboxylic
acid tert-butyl ester, was produced as follows:
4-(7-Hydroxy-naphthalen-1-yl)-piperazine-1-carboxylic acid
tert-butyl ester (2.00 g, 6.09 mmol) was dissolved in
dichloromethane (30 mL) and triethylamine (1.23 g, 1.70 mL, 12.2
mmol) were added. The mixture was cooled to 0.degree. C. and
trifluoromethanesulfonic anhydride (2.58 g, 1.54 mL, 9.15 mmol) was
added dropwise. The mixture was stirred at 0.degree. C. for 30
minutes and water (20 mL) was added. The organic layer was washed
with saturated sodium bicarbonate (20 mL) and brine (20 mL), dried
over anhydrous magnesium sulfate, filtered and concentrated in
vacuo. The crude oil was purified by column chromatography (5:1,
hexanes/ethyl acetate) to yield the first intermediate compound
(2.50 g, 89%) as an orange oil that solidified. .sup.1H NMR (400
MHz, dmso-d.sub.6) .delta. 8.20-8.10 (m, 2H), 7.78 (d, 1H),
7.65-7.50 (m, 2H), 7.30 (d, 1H), 3.80-3.40 (m, 4H), 3.05-2.90 (m,
4H), 1.40 (s, 9H).
[0853] A second compound,
1-(8-Piperazin-1-yl-naphthalen-2-yl)-ethanone, was produced as
follows:
4-(7-Trifluoromethanesulfonyloxy-naphthalen-1-yl)-piperazine-1-carboxylic
acid tert-butyl ester (2.50 g, 5.44 mmol) was dissolved in
dimethylformamide (15 mL) and the solution was degassed for 30
minutes. Triethylamine (1.10 g, 1.52 mL, 10.87 mmol), butyl vinyl
ether (2.72 g, 3.50 mL, 27.17 mmol), palladium acetate (61 mg, 0.27
mmol), and 1,3-bis(diphenylphosphino)-propane (112 mg, 0.27 mmol)
were added sequentially and the mixture was heated to 80.degree. C.
and stirred for 3 hours at this temperature, then the temperature
was lowered to 40.degree. C. and stirred for an additional 15
hours, then cooled to room temperature. The mixture was extracted
with dichloromethane (30 mL), and the organic layer was washed with
water (3.times.30 mL) and brine (30 mL), dried over anhydrous
magnesium sulfate, filtered and concentrated in vacuo. The crude
oil was filtered through a short plug of silica gel, eluting with
3:1 hexanes/ethyl acetate to yield a mixture of
4-[7-(1-butoxy-vinyl)-naphthalen-1-yl]-piperazine-1-carboxylic acid
tert-butyl ester and
4-(7-acetyl-naphthalen-1-yl)-piperazine-1-carboxylic acid
tert-butyl ester (2.14 g).
[0854] This mixture (2.14 g) was dissolved in a mixture of
dichloromethane (4 mL), trifluoroacetic acid (3 mL) and water (1
mL) and stirred at room temperature for 4 hours. The mixture was
evaporated in vacuo and hexanes (30 mL) were added. The precipitate
was filtered off and washed with hexanes (20 mL) to yield the
second intermediate compound (2.1 g, quant.) as an orange solid.
.sup.1H NMR (400 MHz, dmso-d6) .delta. 8.95 (s, 1H), 8.70 (s, 1H),
8.05-7.98 (m, 2H), 7.76 (d, 1H), 7.60 (t, 1H), 7.30 (d, 1H),
3.50-3.30 (m, 4H), 3.30-3.10 (m, 4H), 2.75 (s, 3H).
[0855] The reductive amination procedure from Example A1 was
followed using 1-(8-piperazin-1-yl-naphthalen-2-yl)-ethanone to
give the title compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.85 (s, 1H), 8.00 (d, 1H), 7.85 (d, 1H), 7.60-7.50 (m, 3H), 7.38
(d, 1H), 7.18 (d, 1H), 4.24 (t, 2H), 3.25-3.10 (m, 4H), 2.86 (t,
2H), 2.85-2.76 (m, 4H), 2.75 (s, 3H), 2.64 (t, 2H), 2.55 (t, 2H),
1.90-1.70 (m, 4H), MS ES+ 473.24 (M+H).sup.+.
Example A79
Synthesis of
7-{4-[4-(6-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one
[0856] An intermediate compound,
1-(5-Piperazin-1-yl-naphthalen-2-yl)-ethanone, was produced as
follows: The intermediate compound was prepared from
4-(6-hydroxy-naphthalen-1-yl)-piperazine-1-carboxylic acid
tert-butyl ester according to the route described in Example A78.
.sup.1H NMR (400 MHz, dmso-d.sub.6) .delta. 8.90 (s, 1H), 8.65 (s,
1H), 8.20 (d, 1H), 7.98 (d, 1H), 7.86 (d, 1H), 7.60 (t, 1H), 7.36
(d, 1H), 3.60-3.18 (m, 8H), 2.70 (s, 3H).
[0857] The reductive amination procedure from Example A1 was
followed using 1-(5-piperazin-1-yl-naphthalen-2-yl)-ethanone to
give the title compound (366 mg, 83%). .sup.1H NMR (400 MHz,
dmso-d.sub.6) .delta. 10.30 (s, 1H), 8.70 (s, 1H), 8.20 (d, 1H),
7.99 (d, 1H), 7.88 (d, 1H), 7.60 (t, 1H), 7.54 (d, 1H), 7.36 (d,
1H), 6.40 (d, 1H), 4.20 (t, 2H), 3.80-3.60 (m, 6H), 3.40 (t, 2H),
3.30-3.10 (m, 4H), 2.80 (t, 2H), 2.70 (s, 3H), 1.96-1.70 (m, 4H),
MS ES+ 473.19 (M+H).sup.+ (Exact mass: 472.25).
Example A80
Synthesis of
7-{4-[4-(5-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one
[0858] An intermediate compound,
1-(5-Piperazin-1-yl-naphthalen-1-yl)-ethanone, was produced as
follows: The intermediate compound was prepared from
4-(5-hydroxy-naphthalen-1-yl)-piperazine-1-carboxylic acid
tert-butyl ester according to the route described in Example A78.
.sup.1H-NMR (400 MHz, CDCl3): 8.80 (br s, 2H), 8.42 (d, J=7.0 Hz,
1H), 8.35 (d, J=7.0 Hz, 1H), 8.12 (d, J=7.0 Hz, 1H), 7.65 (m, 1H),
7.57 (m, 1H), 7.25 (d, J=6.0 Hz, 1H), 3.60-3.10 (m, 8H).
[0859] The reductive amination procedure from Example A1 was
followed using 1-(5-piperazin-1-yl-naphthalen-1-yl)-ethanone to
give the title compound (0.41 g, 76%). .sup.1H-NMR (400 MHz,
CDCl.sub.3): 10.05 (s, 1H), 8.40 (d, J=7.0 Hz, 1H), 8.30 (d, J=7.0
Hz, 1H), 8.13 (d, J=6.0 Hz, 1H), 7.70-7.50 (m, 3H), 7.30 (d, J=6.5
Hz, 1H), 6.40 (d, J=7.0 Hz, 1H), 4.30 (t, J=3.0 Hz, 2H), 3.70 (m,
2H), 3.60-3.20 (m, 8H), 2.80 (t, J=8 Hz, 2H), 2.70 (s, 3H), 2.50
(m, 2H), 2.00-1.80 (m, 4H).
Example A81
Synthesis of
7-{4-[4-(4-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one
[0860] An intermediate compound,
1-(4-Piperazin-1-yl-naphthalen-1-yl)-ethanone, was produced as
follows: The intermediate compound was prepared from
4-(4-bromo-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butyl
ester according to the route described in Example A78. .sup.1H-NMR
(400 MHz, DMSO-d.sub.6): .delta. 8.90 (s, 2H), 8.80 (d, 1H), 8.20
(d, 1H), 8.10 (d, 1H), 7.60 (m, 2H), 7.20 (d, 1H), 3.45 (s, 4H),
3.25 (s, 4H), 2.65 (s, 3H).
[0861] The reductive amination procedure from Example A1 was
followed using 1-(4-piperazin-1-yl-naphthalen-1-yl)-ethanone to
give the title compound (0.40 g, 80%). .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta.: 10.40 (s, 1H), 10.25 (s, 1H), 8.80 (d, 1H),
8.20 (m, 2H), 7.60 (m, 2H), 7.50 (d, 1H), 7.20 (d, 1H), 6.40 (d,
1H), 4.23 (m, 2H), 3.80-3.20, 1OH), 2.80 (m, 2H), 2.70 (s, 3H),
2.50 (m, 2H), 2.00-1.75 (m, 4H).
Example A82
Synthesis of
7-{4-[4-(2-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one
[0862] An intermediate compound,
1-(1-Piperazin-1-yl-naphthalen-2-yl)-ethanone, was produced as
follows: The intermediate compound was prepared from
4-(2-hydroxy-naphthalen-1-yl)-piperazine-1-carboxylic acid
tert-butyl ester according to the route described in Example A78.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.: 8.35 (m, 1H), 8.00
(m, 1H), 7.80 (m, 1H), 7.60 (m, 3H), 3.40-3.20 (m, 8H), 2.70 (s,
3H).
[0863] The reductive amination procedure from Example A1 was
followed using 1-(1-piperazin-1-yl-naphthalen-2-yl)-ethanone to
give the title compound. .sup.1H-NMR (400 MHz, DMSO-d.sub.6):
.delta.: 12.90 (s, 1H), 8.30 (s, 1H), 7.90 (m, 2H), 7.80 (m, 1H),
7.70-7.50 (m, 3H), 7.45 (m, 2H), 6.40 (d, J=6.0 Hz, 1H), 4.40-4.10
(m, 4H), 3.70 (m, 2H), 3.40-3.00 (m, 6H), 2.90 (m, 2H), 2.67 (m,
5H), 2.40-1.90 (m, 4H).
Example A83
Synthesis of
8-{4-[4-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyl]-piper-
azin-1-yl}-naphthalene-2-carbonitrile
[0864] A first intermediate compound,
(7-Cyano-naphthalen-1-yl)-carbamic acid benzyl ester, was produced
as follows: Tris(dibenzylideneacetone)dipalladium(0)-chloroform
adduct (0.24 g, 0.23 mmol), 1,1'-bis(diphenylphosphino)-ferrocene
(1.04 g, 1.87 mmol), KCN (3.05 g, 47.0 mmol),
trifluoro-methanesulfonic acid
8-benzyloxycarbonylamino-naphthalen-2-yl ester (10 g, 23.52 mmol),
and NMP (20 mL) were combined sequentially and stirred at room
temperature for 20 minutes until a yellow reaction complex was
formed. The reaction mixture was stirred for 1 h at 80.degree. C.
and then cooled to room temperature. The dark brown reaction
mixture was purified by chromatography on silica, eluting with
hexanes:EtOAc (8.5:1.5) and then changing to hexanes:EtOAc (8:2),
to give the first intermediate compound (5.81 g, 82%) as a brown
oil which solidified upon standing at room temperature. .sup.1H-NMR
(400 MHz, CDCl.sub.3) .delta. 8.34 (s, 1H), 7.93 (d, 2H), 7.70 (d,
1H), 7.62 (m, 2H), 7.46-7.32 (m, 5H), 5.24 (s, 2H).
[0865] A second intermediate compound,
8-Amino-naphthalene-2-carbonitrile, was produced as follows: To
(7-cyano-naphthalen-1-yl)-carbamic acid benzyl ester (5.81 g, 19.23
mmol) was added 33% HBr in HOAc (35 mL) and the mixture was stirred
at room temperature for 6 h. Et.sub.2O was added and the product
was crystallized as a yellow solid. The solid was washed three
times with Et.sub.2O to give the second intermediate compound (4.22
g, 88%) as yellow solid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.68 (s, 1H), 8.16 (d, 1H), 7.86 (m, 2H), 7.69 (t, 1H),
7.49 (d, 1H).
[0866] A third intermediate compound,
8-Piperazin-1-yl-naphthalene-2-carbonitrile, was produced as
follows: A mixture of 8-amino-naphthalene-2-carbonitrile (1 g, 4.03
mmol), bis-(2-chloroethyl)amine hydrochloride (0.778 g, 4.4 mmol),
NaI (0.299 g, 2.01 mmol), and 1-hexanol (1 mL) in chlorobenzene was
heated at 140.degree. C. for 20 h. The reaction mixture was
concentrated and the residue was stirred with Et.sub.2O:hexanes
(1:1) and the solvent was decanted. The brown material was purified
by chromatography on silica, eluting with MeOH:CHCl.sub.3 (3:97)
and then changed to MeOH:CHCl.sub.3:NH.sub.3 (10:89:1), to yield
the third intermediate compound (0.75 g, 79%) as a light yellow
oil. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.79 (s, 1H), 8.64
(s, 1H), 8.13 (d, 1H), 7.80 (m, 2H), 7.64 (t, 1H), 7.37 (d, 1H),
3.62 (m, 2H), 3.42 (m, 2H), 3.12-3.05 (m, 4H).
[0867] The reductive amination procedure from Example A1 was
followed using 8-piperazin-1-yl-naphthalene-2-carbonitrile to give
the title compound (0.245 g, 37%). .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.21 (s, 1H), 8.64 (s, 1H), 8.14 (d, 1H),
7.82 (m, 2H), 7.69 (t, 1H), 7.52 (d, 1H), 7.36 (d, 1H), 6.38 (d,
1H), 4.22 (t, 2H), 3.82-3.15 (m, 12H), 2.79 (m, 2H), 1.96-1.76 (m,
4H).
Example A84
Synthesis of
N-(8-{4-[4-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyl]-pi-
perazin-1-yl}-naphthalen-2-yl)-acetamide
[0868] The reductive amination procedure from Example A1 was
followed using N-(8-piperazin-1-yl-naphthalen-2-yl)-acetamide to
give the title compound. MS: APCI: M+1: 488.2 (Exact Mass:
487.26).
Example A85
Synthesis of
7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)butoxy]-3,4-dihydro-1H-[1,8]naphth-
yridin-2-one
[0869] A first intermediate compound,
7-(4-benzyloxybutoxy)-[1,8]naphthyridin-2-one, was produced
according to the reaction summarized below, as follows.
7-Fluoro-1H-[1,8]naphthyridin-2-one (210 g, 1.28 moles),
tetrabutylammonium bromide (20 g, 0.064 mole), 4-benzyloxybutanol
(235.8 mL, 1.34 mole), and THF (2.5 L) were charged to a 12 L
three-neck round bottom flask equipped with a mechanical stirrer,
an addition funnel, and inerted with nitrogen (g). The suspension
was stirred at 25.degree. C. for 30 minutes. An ice bath was used
to cool the reaction mixture and 1 M potassium tert-butoxide in THF
(2.87 L, 2.87 mole) was added via addition funnel at a rate to keep
the internal temperature below 30.degree. C. Upon complete
addition, the thick slurry became a solution and was stirred at
25.degree. C. for 4 hours or until the reaction was complete by
LC/MS analysis. 1N HCl (1.6 L, 1.6 mole) was added slowly to keep
the reaction temperature below 30.degree. C. and stirred for 30
minutes. THF was removed using a rotoevaporator and 7 L of ethyl
acetate was added to form a biphasic mixture. The mixture was
transferred to a separatory funnel, where the aqueous layer was
collected and reextracted with 1 L of ethyl acetate. The ethyl
acetate layers were combined, filtered through Celite, washed with
water, then with brine, and collected. MgSO.sub.4 was added, then
filtered, and product was concentrated under vacuum to a yellow
solid (405 g, 1.25 mole, 97.8%). MS: APCI: M+1: 325.1 (Exact Mass:
324.15). .sup.1H NMR (CDCl.sub.3).
[0870] A second intermediate compound,
7-(4-Hydroxybutoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one, was
produced according to the reaction summarized below, as follows.
The first intermediate compound,
7-(4-Benzyloxybutoxy)-1H-[1,8]naphthyridin-2-one (132.4 g, 0.408
mole), and MeOH (1.3 L) were charged to a pressure reactor with 20%
Palladium on Carbon (20.0 g, 50% water-wet) and hydrogenated for 48
hours at 45.degree. C. and 50 psi. The reaction was monitored by
mass spectroscopy or HPLC. Upon completion, the palladium catalyst
was filtered and the filtrate was concentrated to an off-white
solid. Yield=96.3 g, Quantitative. MS: APCI: M+1: 237.1. .sup.1H
NMR (CDCl.sub.3).
[0871] A third intermediate compound,
7-(4-chlorobutoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one, was
produced according to the reaction summarized below, as follows.
The second intermediate compound,
7-(4-Hydroxybutoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one (121 g,
0.515 mole), was stirred with THF (1.2 L) in a 3 L round-bottom
flask equipped with an addition funnel, thermocouple, and inerted
with nitrogen. Methane sulfonyl chloride (48 mL, 0.618 mole) was
added and the reaction was cooled to -11.degree. C. with an
acetone/ice bath. Triethylamine (100 mL, 0.721 mole) was added via
addition funnel at a rate to keep the internal temperature below
0.degree. C. Following complete addition, the reaction was warmed
to ambient temperature. TLC (50% CH.sub.2Cl.sub.2-Ethyl Acetate)
showed the reaction was complete. LiCl (43.6 g, 1.03 mole) was
added to the reaction suspension and refluxed for 12 hours. TLC
showed the reaction was complete. THF was removed via vacuum
distillation and Ethyl Acetate (1.2 L) was added. The organic layer
was washed with water (500 mL), sat. NaHCO.sub.3 (500 mL), and
brine. MgSO.sub.4 was used to dry the organic solution, which was
filtered, concentrated, and dried to a solid that stuck tightly to
the walls of the flask. Yield=120 g, 92%. MS: APCI: M+1: 255.0.
.sup.1H NMR (CDCl.sub.3).
[0872] Finally,
7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)butoxy]-3,4-dihydro-1H-[1,8]naphth-
yridin-2-one was produced according to the following reaction, as
described below. The third intermediate compound,
7-(4-Chlorobutoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one (119 g,
0.469 mole), 1-naphthalen-1-yl-piperazine hydrochloride (110.7 g,
0.446 mole), and potassium carbonate (185 g, 1.339 mole) were
charged to a 2 L round bottomed flask equipped with mechanical
stirring and a condenser. Water (1.2 L) was added and the reaction
was refluxed for 12 hours under nitrogen gas. The reaction was
cooled to ambient temperature and the water was decanted, leaving a
clump of tan solids. Ethyl acetate (1.2 L) was added, along with
water (500 mL), and the solids were stirred for 30 minutes to form
a bi-layer. Water (500 mL) was added to the ethyl acetate layer for
another wash, followed by a wash with brine (500 mL). MgSO.sub.4
was added to the ethyl acetate, which was then filtered and
concentrated to a brown solid. Yield=164 g, 85%. MS: APCI: M+1:
431.2. .sup.1H NMR (CDCl.sub.3).
[0873] The resulting product was recrystallized from acetitrile (7
mL/g) by heating the acetonitrile slurry to 60.degree. C., where a
solution developed. The solution was then cooled at a rate of
-3.degree. C./hr to get to ambient temperature. The recrystallized
slurry was then cooled to 0.degree. C. with an ice-bath, filtered
cold, and dried to give the purified material in greater than 97%
HPLC purity (294 nm). Recrystallization yield=80-85%.
Example B1
Synthesis of
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridi-
n-2-one
[0874] A first intermediate compound,
2-Benzyloxy-7-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-[1,8]naphthyridine,
was produced as follows: To a solution of
4-(tetrahydro-pyran-2-yloxy)-1-butanol (3.27 g, 18.8 mmol, 1.2
equiv) in THF (20 mL) cooled to 0.degree. C. was added KO.sup.tBu
(1M in THF, 18 mL, 18 mmol, 1.15 equiv). The solution was stirred
at 0.degree. C. for 20 min and then added via cannula to a
suspension of 2-benzyloxy-7-chloro-[1,8]naphthyridine (4.24 g,
15.66 mmol) in THF (50 mL) cooled to 0.degree. C. The reaction
turned orange and became homogenous. After 30 min at 0.degree. C.,
saturated NH.sub.4Cl and H.sub.2O were added to quench the
reaction. The mixture was extracted with EtOAc. The organic layer
was washed with saturated NaHCO.sub.3, H.sub.2O and brine, dried
over Na.sub.2SO.sub.4 and concentrated. The crude was absorbed onto
SiO.sub.2 and purified by liquid chromatography (20-30%
EtOAc/Hexanes) to give the first intermediate compound as a pale
yellow oil (3.71 g, 9.08 mmol, 58%). MS: APCI: M+1: 409.2 (Exact
Mass: 408.20).
[0875] A third intermediate compound,
7-(4-Hydroxy-butoxy)-1H-[1,8]naphthyridin-2-one, was produced as
follows:
2-Benzyloxy-7-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-[1,8]naphthyridine
(620 mg, 1.52 mmol) was hydrogenated using 5% Pd/C in MeOH for 40
min. The reaction was filtered and concentrated. The residue was
dissolved in EtOH (5 mL) and PPTS (25 mg, 0.10 mmol) was added. The
mixture was heated at 60.degree. C. overnight. The reaction was
concentrated and purified by liquid chromatography (6%
MeOH/CH.sub.2Cl.sub.2) to give the third intermediate compound as a
white solid (282 mg, 1.20 mmol, 79%). MS: APCI: M+1: 235.1 (Exact
Mass: 234.10).
[0876] This intermediate was also prepared using the following
procedure:
[0877] To a suspension of 60% NaH (83.6 g, 2.09 mol) in NMP (1 L)
was added dry 1,4-butanediol (300 mL, 3.39 mol, concentrated from
toluene) dropwise to control foaming. The reaction temperature
increased to 50.degree. C. and the mixture was stirred at
60.degree. C. for 15 min. 7-Chloro-1H-[1,8]naphthyridin-2-one (146
g, 0.813 mol) was added with stirring and the reaction was heated
at 68.degree. C. for 20 h. CH.sub.3CN (5 L) was added and the
mixture was filtered and the filter cake was washed with CH.sub.3CN
(500 mL) and THF (500 mL). The filter cake was reslurried with THF
(3 L) and 3N HCl in MeOH (290 mL, 0.870 mol) was added. The mixture
was heated at 60.degree. C. for 1 h and then filtered through
celite washing with THF (1 L). The filtrate was concentrated to a
volume of 500 mL and THF (1.5 L), Darco (10 g) and magnesol (100
mL) was added. The mixture was stirred at 40.degree. C. for 30 min
and then filtered washing with THF (500 mL). The filtrate was
concentrated to 500 mL, CH.sub.3CN was added and the mixture was
concentrated to 1 L. The resulting solid was filtered, washed with
CH.sub.3CN (200 mL) and Et.sub.2O (300 mL) and dried at 50.degree.
C. to yield the title compound (101 g, 53%). The filtrate upon
standing gave additional crystals, which were collected by
filtration, washed and dried as before to give additional title
compound (17 g, total yield of 62%).
[0878] A fourth intermediate compound,
4-(7-Oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde, was
produced as follows: Using Swern oxidation: To a solution of oxalyl
chloride (0.12 mL, 1.32 mmol, 1.1 equiv) in CH.sub.2Cl.sub.2 (2.5
mL) cooled to -78.degree. C. was added DMSO (0.18 mL, 2.6 mmol).
The reaction was stirred for 5 min and then
7-(4-hydroxy-butoxy)-1H-[1,8]naphthyridin-2-one (282 mg, 1.20 mmol)
was added as a solution in CH.sub.2Cl.sub.2 (4.5 mL) and DMSO (1.2
mL) via cannula over 5 min. The DMSO was necessary to dissolve the
alcohol. The reaction was stirred for 15 min and Et.sub.3N (0.83
mL, 6.0 mmol, 5 equiv) was added. The reaction turned cloudy. The
reaction was allowed to stir at -78.degree. C. for 10 min and then
warmed to RT. After 30 min at RT, H.sub.2O was added and the
mixture was extracted with CH.sub.2Cl.sub.2. The organic layer was
washed with brine, dried over MgSO.sub.4 and concentrated to give
the fourth intermediate compound as a light brown oil (340 mg),
which was used in the next reaction. MS: APCI: M+1: 233.1 (Exact
Mass: 232.08).
[0879] Using IBX oxidation: To a solution of
7-(4-hydroxy-butoxy)-1H-[1,8]naphthyridin-2-one (223 mg, 0.952
mmol) in DMSO (3 mL) was added a solution of IBX (400 mg, 1.43
mmol) in DMSO (4.8 mL, 0.3 M). The reaction was stirred at room
temperature for 6 h, cooled to 0.degree. C. and quenched with 5%
NaHCO3. The mixture was extracted with CH2Cl2 (4.times.). The
organic layer was washed with 5% NaHCO3, dried over MgSO.sub.4 and
concentrated to give the title compound as a pale yellow solid (175
mg, 0.754 mmol, 79%). MS: APCI: M+1: 233.1 (Exact Mass:
232.08).
[0880] To a solution of
4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
(crude from previous reaction) in dichloroethane (6 mL) was added
2,3-dichlorophenylpiperazine hydrochloride (321 mg, 1.20 mmol)
followed by Et.sub.3N (0.34 mL, 2.40 mmol, 2 equiv). The resulting
suspension was stirred for 5 min and NaBH(OAc).sub.3 (356 mg, 1.68
mmol, 1.4 equiv) was added as a powder. The reaction was stirred at
room temperature for 2 h. The reaction was quenched with saturated
NaHCO.sub.3 and H.sub.2O and the mixture was extracted with EtOAc.
The organic layer was washed with saturated NaHCO.sub.3 and brine,
dried over Na.sub.2SO.sub.4 and concentrated. Purification by
liquid chromatography (4-5% MeOH/CH.sub.2Cl.sub.2) gave the title
compound as a white foam (378 mg, 0.845 mmol, 70% over 2 steps).
The foam was dissolved in Et.sub.2O/CH.sub.2Cl.sub.2 and 1N HCl in
Et.sub.2O (0.82 mL) was added. The resulting white precipitate was
collected by filtration, washed with Et.sub.2O and dried to give a
white solid (355 mg). MS: APCI: M+1: 447.1 (Exact Mass:
446.13).
Example B2
Synthesis of
7-{4-[4-(2-Chloro-3-trifluoromethyl-phenyl)-piperazin-1-yl]-butoxy}-1H-[1-
,8]naphthyridin-2-one
[0881] The reductive amination procedure from Example B1 was
followed using 1-(2-chloro-3-trifluoromethyl-phenyl)-piperazine to
give the title compound (0.55 g, 60%). .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 9.45 (s, 1H), 7.75 (d, 1H), 7.65 (d, 1H), 7.35
(m, 3H), 6.60 (d, 1H), 6.55 (d, 1H), 4.40 (t, 2H), 3.15 (br s, 4H),
2.65 (br s, 4H), 2.50 (m, 2H), 1.85 (m, 2H), 1.75 (m, 2H). MS ES:
m/z 480.93 (M+H).sup.+ (Exact mass: 480.15).
Example B3
Synthesis of
7-{4-[4-(2-Acetyl-3-chloro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one
[0882] In a manner similar to that of other examples above,
1-(2-chloro-6-piperazin-1-yl-phenyl)-ethanone was coupled by
reductive amination to
4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
followed by typical workup and purification to give the title
compound. MS: APCI: M+1: 455.2 (Exact Mass: 454.18).
Example B4
Synthesis of
7-{4-[4-(3-Chloro-2-ethyl-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthy-
ridin-2-one
[0883] In a manner similar to that of other examples above,
1-(3-chloro-2-ethyl-phenyl)-piperazine hydrochloride was coupled by
reductive amination to
4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
followed by typical workup and purification to give the title
compound. MS: APCI: M+1: 441.2 (Exact Mass: 440.20).
Example B5
Synthesis of
7-{4-[4-(2-Acetyl-3-fluoro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one
[0884] In a manner similar to that of other examples above,
1-(2-fluoro-6-piperazin-1-yl-phenyl)-ethanone was coupled by
reductive amination to
4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
followed by typical workup and purification to give the title
compound. MS: APCI: M+1: 439.2 (Exact Mass: 438.21).
Example B6
Synthesis of
7-{4-[4-(3-Acetyl-2-chloro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one
[0885] In a manner similar to that of other examples above,
1-(2-chloro-3-piperazin-1-yl-phenyl)-ethanone trifluoroacetate was
coupled by reductive amination to
4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
followed by typical workup and purification to give the title
compound, mp 108-110.degree. C. MS: APCI: M+1: 455.2 (Exact Mass:
454.18).
Example B7
Synthesis of
7-{4-[4-(2-Chloro-4-fluoro-5-methyl-phenyl)-piperazin-1-yl]-butoxy}-1H-[1-
,8]naphthyridin-2-one
[0886] The reductive amination procedure from Example B1 was
followed using 1-(2-chloro-4-fluoro-5-methyl-phenyl)-piperazine
hydrochloride to give the title compound (0.246 g, 51%). MS: APCI:
M+1: 445.2 (Exact mass: 444.17).
Example B8
Synthesis of
7-{4-[4-(2-Chloro-4-fluoro-3-methyl-phenyl)-piperazin-1-yl]-butoxy}-1H-[1-
,8]naphthyridin-2-one
[0887] The reductive amination procedure from Example B1 was
followed using 1-(2-chloro-4-fluoro-3-methyl-phenyl)-piperazine
hydrochloride to give the title compound (0.223 g, 46%). MS: APCI:
M+1: 445.2 (Exact mass: 444.17).
Example B9
Synthesis of
7-{4-[4-(5-Chloro-2-isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]na-
phthyridin-2-one
[0888] To a suspension of
4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
(0.206 g, 0.887 mmol, 1 eq) and
1-(5-chloro-2-isopropoxy-phenyl)-piperazine (0.328 g, 0.977 mmol,
1.1 eq) in dichloroethane (5 mL) was added NaBH(OAc).sub.3 (0.535
g, 2.524 mmol, 2.84 eq). The slurry was allowed to stir overnight
at room temperature (18 h). Analysis by HPLC showed reaction mostly
complete. The mixture was diluted with Ethyl Acetate and quenched
with saturated NaHCO.sub.3. The organic phase was washed with
brine, dried over Na.sub.2SO.sub.4, filtered and evaporated in
vacuo. Purification by silica gel chromatography (2%
MeOH/CH.sub.2Cl.sub.2) followed by formation of the HCl salt using
1N HCl in ether provided the title compound (0.164 g, 39%). MS:
APCI: M+1: 471.2 (Exact Mass: 470.21).
Example B10
Synthesis of
7-{4-[4-(2-Isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridi-
n-2-one
[0889] The above reductive amination procedure using
1-(2-isopropoxy-phenyl)-piperazine afforded the title compound. MS:
APCI: M+1: 437.3 (Exact Mass: 436.25).
Example B11
Synthesis of
7-{4-[4-(2-Isobutoxy-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-
-2-one
[0890] The above reductive amination procedure using
1-(2-isobutoxy-phenyl)-piperazine afforded the title compound. MS:
APCI: M+1: 451.2 (Exact Mass: 450.26).
Example B12
Synthesis of
7-[4-(4-o-Tolyl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one
[0891] The reductive amination procedure from Example B1 was
followed using 1-o-tolyl-piperazine to give the title compound. MS:
APCI: M+1: 393.2 (Exact mass: 392.22).
Example B13
Synthesis of
7-{4-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2--
one
[0892] The reductive amination procedure from Example B1 was
followed using 1-(4-fluoro-phenyl)-piperazine to give the title
compound. MS: APCI: M+1: 397.1 (Exact mass: 396.20).
Example B14
Synthesis of
7-{4-[4-(3-Chloro-4-fluoro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one
[0893] The reductive amination procedure from Example B1 was
followed using 1-(3-chloro-4-fluoro-phenyl)-piperazine to give the
title compound. MS: APCI: M+1: 431.2 (Exact mass: 430.16).
Example B15
Synthesis of
7-{4-[4-(3-Trifluoromethyl-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one
[0894] The reductive amination procedure from Example B1 was
followed using 1-(3-trifluoromethyl-phenyl)-piperazine to give the
title compound. MS: APCI: M+1: 447.2 (Exact mass: 446.19).
Example B16
Synthesis of
7-{4-[4-(2-Trifluoromethyl-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one
[0895] The reductive amination procedure from Example B1 was
followed using 1-(2-trifluoromethyl-phenyl)-piperazine to give the
title compound. MS: APCI: M+1: 447.2 (Exact mass: 446.19).
Example B17
Synthesis of
7-(4-{4-[2-(1,1-Difluoro-ethyl)-phenyl]-piperazin-1-yl}-butoxy)-1H-[1,8]n-
aphthyridin-2-one
[0896] The reductive amination procedure from Example B1 was
followed using 1-[2-(1,1-difluoro-ethyl)-phenyl]-piperazine to give
the title compound (0.45 g, 79%). .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. 12.00 (s, 1H), 10.65 (s, 1H), 8.00 (d, 1H),
7.81 (d, 1H), 7.58 (m, 2H), 7.50 (m 1H), 7.30 (m 1H), 6.70 (d, 1H),
6.40 (d, 1H), 4.40 (t, 2H), 3.60 (m, 2H), 3.30-3.00 (m, 8H), 2.10
(t, 3H), 2.00-1.70 (m, 4H).
Example B18
Synthesis of
7-{4-[4-(2-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]napht-
hyridin-2-one
[0897] The reductive amination procedure from Example B1 was
followed using 1-(2-chloro-3-methoxy-phenyl)-piperazine to give the
title compound. MS: APCI: M+1: 443.3 (Exact mass: 442.18).
Example B19
Synthesis of
7-{4-[4-(2-Chloro-3-ethoxy-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one
[0898] The reductive amination procedure from Example B1 was
followed using 1-(2-chloro-3-ethoxy-phenyl)-piperazine to give the
title compound. MS: APCI: M+1: 457.2 (Exact mass: 456.19).
Example B20
Synthesis of
7-{4-[4-(2-Chloro-3-isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]na-
phthyridin-2-one
[0899] The reductive amination procedure from Example B1 was
followed using 1-(2-chloro-3-isopropoxy-phenyl)-piperazine to give
the title compound. MS: APCI: M+1:471.2 (Exact mass: 470.21).
Example B21
Synthesis of
7-{4-[4-(3-Methyl-2-phenoxy-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]napht-
hyridin-2-one
[0900] The reductive amination procedure from Example B1 was
followed using 1-(3-methyl-2-phenoxy-phenyl)-piperazine to give the
title compound. MS: APCI: M+1: 485.2 (Exact mass: 484.25).
Example B22
Synthesis of
7-{4-[4-(3-Chloro-2-fluoro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one
[0901] The reductive amination procedure from Example B1 was
followed using 1-(3-chloro-2-fluoro-phenyl)-piperazine to give the
title compound. MS: APCI: M+1: 431.2 (Exact mass: 430.16).
Example B23
Synthesis of
7-{4-[4-(2-Chloro-4-fluoro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one
[0902] The reductive amination procedure from Example B1 was
followed using 1-(2-chloro-4-fluoro-phenyl)-piperazine to give the
title compound. MS: APCI: M+1: 431.2 (Exact mass: 430.16).
Example B24
Synthesis of
7-{4-[4-(2,3-Dichloro-4-fluoro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]na-
phthyridin-2-one
[0903] The reductive amination procedure from Example B1 was
followed using 1-(2,3-dichloro-4-fluoro-phenyl)-piperazine to give
the title compound. MS: APCI: M+1: 465.1 (Exact mass: 464.12).
Example B25
Synthesis of
7-{4-[4-(2-Chloro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2--
one
[0904] The reductive amination procedure from Example B1 was
followed using 1-(2-chloro-phenyl)-piperazine to give the title
compound. MS: APCI: M+1: 413.1 (Exact mass: 412.17).
Example B26
Synthesis of
7-[4-(4-Biphenyl-2-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one
[0905] The reductive amination procedure from Example B1 was
followed using 1-biphenyl-2-yl-piperazine to give the title
compound. MS: APCI: M+1: 455.0 (Exact mass: 454.24).
Example B27
Synthesis of
7-{4-[4-(3-Methoxy-2-methyl-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]napht-
hyridin-2-one
[0906] The reductive amination procedure from Example B1 was
followed using 1-(3-methoxy-2-methyl-phenyl)-piperazine to give the
title compound. MS: APCI: M+1: 423.2 (Exact mass: 422.23).
Example B28
Synthesis of
7-{4-[4-(2-Chloro-3-fluoro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one
[0907] The reductive amination procedure from Example B1 was
followed using 1-(2-chloro-3-fluoro-phenyl)-piperazine to give the
title compound. MS: APCI: M+1: 431.2 (Exact mass: 430.16).
Example B29
Synthesis of
7-{4-[4-(6-Cyclopropyl-pyridin-2-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naph-
thyridin-2-one
[0908] The reductive amination procedure from Example B1 was
followed using 1-(6-cyclopropyl-pyridin-2-yl)-piperazine to give
the title compound. MS: APCI: M+1: 420.2 (Exact mass: 419.23).
Example B30
Synthesis of
7-[4-(4-Pyrimidin-2-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one
[0909] In a manner similar to that of other examples above,
2-piperazin-1-yl-pyrimidine hydrobromide was coupled by reductive
amination to
4-(7-Oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
followed by typical workup and purification to give the title
compound, MS: APCI: M+1: 381.1 (Exact Mass: 380.20).
Example B31
Synthesis of
7-{4-[4-(4-Methoxy-pyrimidin-2-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one
[0910] In a manner similar to that of other examples above,
4-methoxy-2-piperazin-1-yl-pyrimidine hydrochloride (U.S. Pat. No.
6,303,603) was coupled by reductive amination to
4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
followed by typical workup and purification to give the title
compound. MS: APCI: M+1: 411.2 (Exact Mass: 410.21).
Example B32
Synthesis of
7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one
[0911] The reductive amination procedure from Example B1 was
followed using 1-indan-4-yl-piperazine to give the title compound.
MS: APCI: M+1: 419.2 (Exact mass: 418.24).
Example B33
Synthesis of
7-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[-
1,8]naphthyridin-2-one
[0912] The reductive amination procedure from Example B1 was
followed using 1-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine to
give the title compound. MS: APCI: M+1: 433.3 (Exact mass:
432.25).
Example B34
Synthesis of
7-{4-[4-(3-Fluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-but-
oxy}-1H-[1,8]naphthyridin-2-one
[0913] The reductive amination procedure from Example B1 was
followed using
1-(3-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine to give
the title compound (0.364 g; 54%). MS: APCI: M+1: 451.3 (Exact
mass: 450.24).
Example B35
Synthesis of
7-{4-[4-(8-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy-
}-1H-[1,8]naphthyridin-2-one
[0914] The reductive amination procedure from Example B1 was
followed using 8-piperazin-1-yl-3,4-dihydro-2H-naphthalen-1-one to
give the title compound (0.391 g, 59%). .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 8.89 (br s, 1H), 7.71 (d, 1H), 7.63 (d, 1H),
7.33 (t, 1H), 6.90 (d, 1H), 6.82 (d, 1H), 6.60 (d, 1H), 6.51 (d,
1H), 4.38 (t, 2H), 3.16-3.04 (m, 4H), 2.93 (t, 2H), 2.78-2.68 (m,
4H), 2.63 (t, 2H), 2.56-2.48 (m, 2H), 2.10-2.00 (m, 2H), 1.88-1.79
(m, 2H), 1.79-1.67 (m, 2H). MS ES: 447.26 (M+H).sup.+ (Exact mass:
446.23).
Example B36
Synthesis of
7-{4-[4-(7,7-Dimethyl-8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-
-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one
[0915] The reductive amination procedure from Example B1 was
followed using
2,2-dimethyl-8-piperazin-1-yl-3,4-dihydro-2H-naphthalen-1-one to
give the title compound. .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta.
9.15 (brs, 1H), 7.75 (d, 1H), 7.70 (d, 1H), 7.30 (m, 2H), 6.65 (d,
1H), 6.55 (d, 1H), 6.60 (d, 1H), 6.50 (d, 1H), 4.40 (t, 2H), 3.10
(br s, 4H), 2.90 (t, 2H), 2.60 (br s, 4H), 2.50 (br s, 2H), 1.90
(t, 2H), 1.90-1.60 (m, 4H), 1.20 (s, 6H). ESMS: 475.26 (Exact mass:
474.26).
Example B37
Synthesis of
7-{4-[4-(7,7-Dimethyl-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-
-butoxy}-1H-[1,8]naphthyridin-2-one
[0916] The reductive amination procedure from Example B1 was
followed using
1-(7,7-dimethyl-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine to
give the title compound. .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta.
9.30 (br s, 1H), 7.75 (d, 1H), 7.65 (d, 1H), 7.10 (t, 1H), 6.90 (m,
2H), 6.60 (d, 1H), 6.50 (d, 1H), 4.40 (t, 2H), 2.95-2.40 (m, 14H),
1.90 (m, 2H), 1.70 (m, 2H), 1.50 (m, 2H), 1.00 (s, 6H). ESMS:
461.29 (Exact mass: 460.28).
Example B38
Synthesis of
7-{4-[4-(7,7-Difluoro-8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-
-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one
[0917] The reductive amination procedure from Example B1 was
followed using
2,2-difluoro-8-piperazin-1-yl-3,4-dihydro-2H-naphthalen-1-one to
give the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 12.03 (s, 1H), 8.02 (s, 1H), 7.84 (d, 1H), 7.60 (t, 1H),
7.09 (d, 1H), 7.06 (d, 1H), 6.64 (d, 1H), 6.38 (d, 1H), 4.20 (t,
2H), 3.61 (m, 2H), 3.98-3.03 (m, 13), 1.98-1.78 (m, 4H).
Example B39
Synthesis of
7-{4-[4-(7,7-Difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-
-butoxy}-1H-[1,8]naphthyridin-2-one
[0918] The reductive amination procedure from Example B1 was
followed using
1-(7,7-difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine to
give the title compound (0.329 g, 78%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 9.02 (br s, 1H), 7.72 (d, 1H), 7.62 (d, 1H),
7.18 (t, 1H), 6.99 (d, 1H), 6.92 (d, 1H), 6.60 (d, 1H), 6.52 (d,
1H), 4.39 (t, 2H), 3.23 (t, 2H), 3.01 (t, 2H), 2.95-2.84 (m, 4H),
2.74-2.56 (m, 4H), 2.54-2.46 (m, 2H), 2.28-2.13 (m, 2H), 1.90-1.81
(m, 2H), 1.79-1.68 (m, 2H). ES MS: 469.27 (M+1).sup.+ (Exact mass:
468.23).
Example B40
Synthesis of
7-{4-[4-(7-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy-
}-1H-[1,8]naphthyridin-2-one
[0919] An intermediate compound,
7-{4-[4-(7-Methoxy-5,8-dihydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1-
H-[1,8]naphthyridin-2-one, was produced as follows:
[0920] 1-(7-Methoxy-5,8-dihydro-naphthalen-1-yl)-piperazine (578
mg, 2.37 mmol) and
4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (500
mg, 2.16 mmol) were dissolved in dichloroethane (10 mL).
Triethylamine (655 mg, 6.47 mmol) was added and the mixture was
stirred for 10 minutes. Sodium triacetoxyborohydride (548 mg, 2.59
mmol) was added and the mixture was stirred for 1.5 hours. The
mixture was quenched with water (20 mL) and extracted with
dichloromethane (20 mL). The organic layer was washed with brine
(20 mL), dried over anhydrous sodium sulfate, filtered and
evaporated. The crude solid was purified by column chromatography
(5:95 triethylamine/ethyl acetate) to yield the intermediate
compound (589 mg, 59%) as a white foam. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 9.40 (s, 1H), 7.75 (d, 1H), 7.60 (d, 1H), 7.18
(t, 1H), 7.00-6.90 (m, 2H), 6.60 (d, 1H), 6.54 (d, 1H), 4.80 (t,
1H), 4.40 (t, 2H), 3.60 (s, 3H), 3.50-3.48 (m, 2H), 3.44-3.38 (m,
2H), 2.95 (t, 4H), 2.80-2.50 (m, 4H), 2.44 (t, 2H), 1.90-1.65 (m,
4H).
[0921]
7-{4-[4-(7-Methoxy-5,8-dihydro-naphthalen-1-yl)-piperazin-1-yl]-bu-
toxy}-1H-[1,8]naphthyridin-2-one (360 mg, 0.78 mmol) was dissolved
in a mixture of ethanol (6 mL) and tetrahydrofuran (2 mL). To this
was added 10% hydrochloric acid (1.5 mL) and the mixture was
stirred at room temperature for 15 minutes, then quenched with
saturated sodium bicarbonate (10 mL). The mixture was extracted
with ethyl acetate (20 mL) and the organic layer was washed with
brine (20 mL), dried over anhydrous sodium sulfate, filtered and
evaporated. The crude solid was purified by column chromatography
(6:94 triethylamine/ethyl acetate) to yield the title compound (263
mg, 75%) as a white foam. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
9.15 (s, 1H), 7.76 (d, 1H), 7.60 (d, 1H), 7.20 (t, 1H), 7.00-6.95
(m, 2H), 6.60 (d, 1H), 6.50 (d, 1H), 4.40 (t, 2H), 3.60 (s, 2H),
3.04 (t, 2H), 2.90-2.80 (m, 4H), 2.80-2.40 (m, 8H), 1.90-1.60 (m,
4H), MS ES+ 447.05 (M+H).sup.+ (Exact mass: 446.23).
Example B41
Synthesis of
7-{4-[4-(7-Hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-bu-
toxy}-1H-[1,8]naphthyridin-2-one
[0922] To a solution of
7-{4-[4-(7-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy-
}-1H-[1,8]naphthyridin-2-one (1.20 g, 2.69 mmol) in methanol (10
mL) was added portionwise NaBH.sub.4 (0.41 g, 10.76 mmol). The
reaction mixture was stirred at room temperature for 30 min and
quenched with saturated NH.sub.4Cl solution and the compound was
extracted with CH.sub.2Cl.sub.2 (2.times.20 mL). The organic layer
was washed with brine (20 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and evaporated. The crude product was
purified by column chromatography (10% methanol in ethyl acetate)
to afford the title compound (0.60 g, 50%), as a white solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.25 (s, 1H), 7.72 (d,
1H), 7.63 (d, 1H), 7.12 (t, 1H), 6.91 (d, 1H), 6.85 (d, 1H), 6.59
(d, 1H), 6.52 (d, 1H), 4.23 (t, 2H), 4.13-4.08 (m, 1H), 3.25-3.20
(m, 1H), 3.02-2.83 (m, 6H), 2.61-2.47 (m 6H), 1.88-1.71 (m, 6H). ES
MS: 449.26 (M+1).sup.+ (Exact mass: 448.25).
Example B42
Synthesis of 7-{4-[4-(5-Oxo-5,6,7
8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridi-
n-2-one
[0923] In a manner similar to that of other examples above,
5-piperazin-1-yl-3,4-dihydro-2H-naphthalen-1-one was coupled by
reductive amination to
4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
followed by typical workup and purification to give the title
compound, mp 158-160.degree. C. MS: APCI: M+1: 447.3 (Exact Mass:
446.23).
Example B43
Synthesis of
7-{4-[4-(5,5-Difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-
-butoxy}-1H-[1,8]naphthyridin-2-one
[0924] The reductive amination procedure from Example B1 was
followed using
1-(5,5-difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine to
give the title compound (0.227 g, 37%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 9-00 (br s, 1H), 7.72 (d, 1H), 7.64 (d, 1H),
7.44 (d, 1H), 7.30 (t, 1H), 7.12 (d, 1H), 6.60 (d, 1H), 6.52 (d,
1H), 4.40 (t, 2H), 2.98-2.88 (m, 4H), 2.82-2.76 (m, 2H), 2.70-2.54
(m, 4H), 2.48 (t, 2H), 2.36-2.22 (m, 2H), 2.00-1.91 (m, 2H),
1.89-1.80 (m, 2H), 1.77-1.66 (m, 2H). ES MS: 469.03 (M+H).sup.+
(Exact mass: 468.23).
Example B44
Synthesis of
7-{4-[4-(3-Oxo-indan-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-
-one
[0925] The reductive amination procedure from Example B1 was
followed using 7-piperazin-1-yl-indan-1-one to give the title
compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.92 (br s,
1H), 7.72 (d, 1H), 7.64 (d, 1H), 7.45 (t, 1H), 6.97 (d, 1H), 6.77
(d, 1H), 6.60 (d, 1H), 6.52 (d, 1H), 4.38 (t, 2H), 3.32-3.16 (m,
4H), 3.10-3.02 (m, 2H), 2.80-2.66 (m, 4H), 2.66-2.62 (m, 2H),
2.58-2.46 (m, 2H), 1.92-1.80 (m, 2H), 1.80-1.66 (m, 2H). ES MS:
432.94 (M+1).sup.+ (Exact mass: 432.22).
Example B45
Synthesis of
7-{4-[4-(2-Oxo-indan-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-
-one
[0926] The reductive amination procedure from Example B1 was
followed using 4-piperazin-1-yl-indan-2-one to give the title
compound. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.: 9.20 (br s,
1H), 7.75 (d, 1H), 7.65 (d, 1H), 7.25 (t, 1H), 7.05 (d, 1H), 6.90
(d, 1H), 4.40 (t, 2H), 3.55 (s, 2H), 3.45 (s, 2H), 3.05 (br s, 4H),
2.70 (br s, 4H), 2.45 (t, 2H), 1.85 (m, 2H), 1.65 (m, 2H). MS ES:
m/z 433.21 (M+H).sup.+ (Exact mass: 432.22).
Example B46
Synthesis of
7-{4-[4-(2,2-Difluoro-indan-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthy-
ridin-2-one
[0927] The reductive amination procedure from Example B1 was
followed using 1-(2,2-difluoro-indan-4-yl)-piperazine to give the
title compound (0.208 g, 40%). .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta.: 9.15 (br s, 1H), 7.75 (d, 1H), 7.65 (d, 1H), 7.25 (t, 1H),
6.90 (d, 1H), 6.85 (d, 1H), 6.65 (d, 1H), 6.50 (d, 1H), 4.40 (t,
2H), 3.35 ( m, 4H), 3.05 (br s, 4H), 2.75 (br s, 4H), 2.50 (m, 2H),
1.90 (m, 2H), 1.75 (m, 2H). MS ES: m/z 455.11 (M+H).sup.+ (Exact
mass: 454.22).
Example B47
Synthesis of
7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-on-
e
[0928] To a mixture of
4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (175
mg, 0.754 mmol) and 1-naphthalen-1-yl-piperazine hydrochloride (206
mg, 0.829 mmol) in DCE (4 mL) was added Et.sub.3N (0.23 mL, 1.66
mmol). The mixture was stirred for 10 min and NaBH(OAc).sub.3 (224
mg, 1.06 mmol) was added as a powder. The reaction was stirred at
room temperature for 2 h and then quenched with saturated
NaHCO.sub.3. The mixture was extracted with EtOAc. The organic
layer was washed with saturated NaHCO.sub.3 and brine, dried over
Na.sub.2SO.sub.4 and concentrated to give a white foam.
Purification by liquid chromatography (5% MeOH/CH.sub.2Cl.sub.2)
gave the title compound as a white foam (260 mg, 0.607 mmol, 80%).
The foam was dissolved in a minimal amount of CH.sub.2Cl.sub.2 and
Et.sub.2O was added. 1M HCl in Et.sub.2O (0.6 mL) was added and a
white precipitate formed. The solid was collected by filtration,
washed with Et.sub.2O and dried to give a white fluffy solid (257
mg). MS: APCI: M+1: 429.2 (Exact Mass: 428.22).
Example B48
Synthesis of
7-{4-[4-(6-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one
[0929] The reductive amination procedure from Example B1 was
followed using 1-(6-fluoro-naphthalen-1-yl)-piperazine to give the
title compound (195 mg, 72%). .sup.1H NMR (400 MHz, dmso-d.sub.6)
.delta. 12.00 (s, 1H), 8.20-8.15 (m, 1H), 8.10 (d, 1H), 7.80 (d,
1H), 7.76-7.60 (m, 2H), 7.60-7.40 (m, 2H), 7.20 (d, 1H), 6.65 (d,
1H), 6.40 (d, 1H), 4.40 (t, 2H), 3.70-3.20 (m, 10H), 2.00-1.80 (m,
4H), MS ES+ 447.18 (M+H).sup.+ (Exact mass: 446.21).
Example B49
Synthesis of
7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one
[0930] The reductive amination procedure from Example B1 was
followed using 1-(7-fluoro-naphthalen-1-yl)-piperazine to give the
title compound (250 mg, 85%). .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 9.02 (s, 1H), 7.82-7.79 (m, 2H), 7.75 (d, 1H), 7.62 (d,
1H), 7.58 (d, 1H), 7.36 (t, 1H), 7.30-7.20 (m, 1H), 7.18 (d, 1H),
6.60 (d, 1H), 6.56 (d, 1H), 4.40 (t, 2H), 3.20-3.00 (m, 4H),
2.90-2.60 (m, 4H), 2.60 (t, 2H), 1.96-1.70 (m, 4H). MS ES+ 447.17
(M+1).sup.+ (Exact mass: 446.21).
Example B50
Synthesis of
7-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one
[0931] The reductive amination procedure from Example B1 was
followed using 1-(8-fluoro-naphthalen-1-yl)-piperazine to give the
title compound (0.32 g, 42%). .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 9.20 (br s, 1H), 7.75 (d, 1H), 7.60 (m, 2H), 7.45 (d, 1H),
7.40-7.30 (m, 2H), 7.15-7.05 (m, 2H), 6.60 (d, 1H), 6.48 (d, 1H),
4.40 (t, 2H), 3.40-3.25 (m, 2H), 3.05-2.80 (m, 4H), 2.60-2.40 (m,
4H), 1.90-1.65 (m, 4H). MS (ES+): 447.17 (M+H).sup.+ (Exact mass:
446.21).
Example B51
Synthesis of
7-{4-[4-(5-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one
[0932] The reductive amination procedure from Example B1 was
followed using 1-(5-fluoro-naphthalen-1-yl)-piperazine to give the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 12.00
(s, 1H), 8.03 (d, J=6.0 Hz, 1H), 7.97 (d, J=6.0 Hz, 1H), 7.85 (d,
J=6.0 Hz, 1H), 7.75 (d, J=5.0 Hz, 1H), 7.50 (m, 2H), 7.35 (m, 1H),
7.22 (d, J=5.0 Hz, 1H), 6.68 (d, J=6.0 Hz, 1H), 6.40 (d, J=6.70 Hz,
1H), 4.40 (t, J=3.0 Hz, 2H), 3.00 (s, 4H), 2.70 (s, 4H), 2.50 (br
s, 2H), 1.80 (m, 2H), 1.60 (m, 2H).
Example B52
Synthesis of
7-{4-[4-(4-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one
[0933] The reductive amination procedure from Example B1 was
followed using 1-(4-fluoro-naphthalen-1-yl)-piperazine to give the
title compound. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 9.20 (br
s, 1H), 8.25 (m, 1H), 8.10 (m, 1H), 7.75 (d, 1H), 7.62 (d, 1H),
7.58 (dd, 2H), 7.10-6.95 (m, 2H), 6.60 (d, 1H), 6.45 (d, 1H), 4.40
(t, 2H), 3.22-3.00 (br s, 4H), 2.85-2.60 (br s, 4H), 2.55 (m, 2H),
1.95-1.65 (m, 4H). MS: ES+ 447.23 (M+H).sup.+ (Exact mass:
446.21).
Example B53
Synthesis of
7-{4-[4-(3-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one
[0934] The reductive amination procedure from Example B1 was
followed using 1-(3-fluoro-naphthalen-1-yl)-piperazine to give the
title compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.00 (br
s, 1H), 8.12 (d, 1H), 7.78-7.70 (m, 2H), 7.64 (d, 1H), 7.50-7.38
(m, 2H), 7.14 (dd, 1H), 6.86 (dd, 1H), 6.62 (d, 1H), 6.52 (d, 1H),
4.40 (t, 2H), 3.15 (brs, 4H), 2.76 (brs, 4H), 2.56 (t, 2H),
1.94-1.84 (m, 2H), 1.81-1.70 (m, 2H). MS (ES+): 447.05 (M+H).sup.+
(Exact mass: 446.21).
Example B54
Synthesis of
7-{4-[4-(2-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one
[0935] The reductive amination procedure from Example B1 was
followed using 1-(2-fluoro-naphthalen-1-yl)-piperazine to give the
title compound (175 mg, 43%). .sup.1H-NMR (400 MHz, DMSO-d.sub.6):
.delta.: 12.00 (s, 1H), 8.30 (d, J=6.0 Hz, 1H), 7.97 (m, 2H), 7.83
(m, 2H), 7.60-7.30 (m, 3H), 6.65 (d, J=8.0 Hz, 1H), 6.40 (d, J=8.0
Hz, 1H), 4.40 (m, 2H), 4.00 (br s, 4H), 3.40-3.10 (m, 6H),
2.00-1.77 (m, 4H).
Example B55
Synthesis of
7-{4-[4-(6,7-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]na-
phthyridin-2-one
[0936] The reductive amination procedure from Example B1 was
followed using 1-(6,7-difluoro-naphthalen-1-yl)-piperazine to give
the title compound (0.25 g, 70%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 12.30 (s, 1H), 10.55 (br s, 1H), 8.03 (m,
3H), 7.80 (d, 1H), 7.70 (d, 1H), 7.55 (t, 1H), 7.22 (d, 1H), 6.65
(d, 1H), 6.40 (d, 1H), 4.40 (t, 2H), 3.70-3.10 (m, 10H), 1.90-1.70
(m, 4H).
Example B56
Synthesis of
7-{4-[4-(7-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one
[0937] The reductive amination procedure from Example B1 was
followed using 1-(7-chloro-naphthalen-1-yl)-piperazine to give the
title compound (0.373 g, 45%). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 12.01 (s, 1H), 10.78 (s, 1H), 8.12 (d, 1H), 8.01 (t, 2H),
7.85 (d, 1H), 7.74 (d, 1H), 7.58-7.48 (m, 2H), 7.28 (d, 1H), 6.68
(d, 1H), 6.37 (d, 1H), 4.40 (t, 2H), 3.64 (m, 2H), 3.48-3.19 (m,
8H), 1.98-1.81 (m, 4H).
Example B57
Synthesis of
7-{4-[4-(6-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one
[0938] The reductive amination procedure from Example B1 was
followed using 1-(6-chloro-naphthalen-1-yl)-piperazine to give the
title compound (0.403 g, 48%). mp. 208-209.degree. C. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 12.01 (s, 1H), 8.16 (d, 1H), 8.06
(d, 1H), 8.02 (d, 1H), 7.83 (d, 1H), 7.64 (d, 1H), 7.55 (m, 2H),
7.22 (d, 1H), 6.64 (d, 1H), 6.39 (d, 1H), 4.40 (t, 2H), 3.62 (m,
2H), 3.53-3.09 (m, 8H), 1.98-1.73 (m, 4H).
Example B58
Synthesis of
7-{4-[4-(5-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one
[0939] The reductive amination procedure from Example B1 was
followed using 1-(5-chloro-naphthalen-1-yl)-piperazine to give the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.01
(s, 1H), 8.18 (d, 1H), 8.01 (d, 1H), 7.98 (d, 1H), 7.83 (d, 1H),
7.77 (d, 1H), 7.63 (t, 1H), 7.54 (t, 1H), 7.32 (d, 1H), 6.68 (d,
1H), 6.38 (dd, 1H), 4.40 (t, 2H), 3.64 (m, 2H), 3.48-3.15 (m, 8H),
1.98-1.81 (m, 4H).
Example B59
Synthesis of
7-{4-[4-(8-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one
[0940] The reductive amination procedure from Example B1 was
followed using 1-(8-chloro-naphthalen-1-yl)-piperazine to give the
title compound (0.257 g, 41%). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 12.04 (s, 1H), 8.02 (d, 1H), 7.92 (dd, 1H), 7.84 (d, 1H),
7.76 (d, 1H), 7.62 (dd, 1H), 7.54 (t, 1H), 7.46 (t, 1H), 7.32 (dd,
1H), 6.66 (d, 1H), 6.38 (d, 1H), 4.38 (t, 2H), 3.62 (m, 2H),
3.55-3.24 (m, 6H), 3.12 (m, 2H), 1.96-1.78 (m, 4H).
Example B60
Synthesis
7-{4-[4-(7-Methoxy-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[-
1,8]naphthyridin-2-one
[0941] The reductive amination procedure from Example B1 was
followed using 1-(7-methoxy-naphthalen-1-yl)-piperazine to give the
title compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.90 (s,
1H), 7.78-7.74 (m, 2H), 7.62 (d, 1H), 7.60-7.40 (m, 2H), 7.26-7.24
(m, 1H), 7.18-7.06 (m, 2H), 6.60 (d, 1H), 6.50 (d, 1H), 4.40 (t,
2H), 3.90 (s, 3H), 3.30-2.80 (m, 8H), 2.60 (t, 2H), 1.90-1.65 (m,
4H). MS ES+ 459.21 (M+1).sup.+ (Exact mass: 458.23).
Example B61
Synthesis of
7-{4-[4-(6-Methoxy-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]napht-
hyridin-2-one
[0942] The reductive amination procedure from Example B1 was
followed using 1-(6-methoxy-naphthalen-1-yl)-piperazine to give the
title compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.90 (s,
1H), 8.10 (d, 1H), 7.74 (d, 1H), 7.60 (d, 1H), 7.40 (d, 1H), 7.38
(t, 1H), 7.18-7.10 (m, 2H), 6.98 (d, 1H), 6.60 (d, 1H), 6.50 (d,
1H), 4.40 (t, 2H), 3.90 (s, 3H), 3.20-2.80 (m, 8H), 2.58 (t, 2H),
1.90-1.65 (m, 4H). MS ES+ 459.20 (M+H).sup.+ (Exact mass:
458.23).
Example B62
Synthesis of
7-{4-[4-(7-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one
[0943] The reductive amination procedure from Example B1 was
followed using 1-(8-piperazin-1-yl-naphthalen-2-yl)-ethanone to
give the title compound (400 mg, 83%). .sup.1H NMR (400 MHz,
dmso-d.sub.6) .delta. 12.00 (s, 1H), 8.70 (s, 1H), 8.10-8.00 (m,
3H), 7.85 (d, 1H), 7.80 (d, 1H), 7.60 (t, 1H), 7.30 (d, 1H), 6.65
(d, 1H), 6.40 (d, 1H), 4.40 (t, 2H) 3.70-3.60 (m, 2H), 3.60-3.20
(m, 8H), 2.80 (s, 3H), 2.00-1.80 (m, 4H), MS ES+ 471.23 (M+H).sup.+
(Exact mass: 470.23).
Example B63
Synthesis of
7-{4-[4-(6-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one
[0944] The reductive amination procedure from Example B1 was
followed using 1-(5-piperazin-1-yl-naphthalen-2-yl)-ethanone to
give the title compound (300 mg, 85%). .sup.1H NMR (400 MHz,
dmso-d.sub.6) .delta. 12.00 (s, 1H), 8.64 (s, 1H), 8.20 (d, 1H),
8.05-7.95 (m, 2H), 7.90-7.80 (m, 2H), 7.60 (t, 1H), 7.36 (d, 1H),
6.64 (d, 1H), 6.40 (d, 1H), 4.40 (t, 2H), 3.70-3.60 (m, 2H),
3.50-3.32 (m, 4H), 3.30-3.10 (m, 4H), 2.70 (s, 3H), 2.00-1.80 (m,
4H), MS ES+ 471.17 (M+H).sup.+ (Exact mass: 470.23).
Example B64
Synthesis of
7-{4-[4-(5-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one
[0945] The reductive amination procedure from Example B1 was
followed using 1-(5-piperazin-1-yl-naphthalen-1-yl)-ethanone to
give the title compound (0.39 g, 77%). .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 8.45 (d, J=7.0 Hz, 1H), 8.30 (d, J=7.6 Hz,
1H), 7.90 (d, J=5.0 Hz, 1H), 7.75 (m, 2H), 7.55 (m, 2H), 7.30 (d,
J=6.0 Hz, 1H), 6.70 (m, 2H), 4.50 (t, J=3.0 Hz, 2H), 4.00-3.60 (m,
4H), 3.40-3.10 (m, 4H), 2.80 (s, 3H), 2.30 (m, 2H), 2.00 (m,
4H).
Example B65
Synthesis of
7-{4-[4-(4-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one
[0946] The reductive amination procedure from Example B1 was
followed using 1-(4-piperazin-1-yl-naphthalen-1-yl)-ethanone to
give the title compound (0.42 g, 69%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 12.00 (s, 1H), 10.60 (s, 1H), 8.80 (d, 1H),
8.15 (m, 2H), 8.00 (d, 1H), 7.80 (d, 1H), 7.60 (m, 2H), 7.20 (d,
1H), 6.63 (d, 1H), 6.40 (d, 1H), 4.40 (m, 2H), 3.80-3.20 (m, 10H),
2.70 (s, 3H), 2.00-1.80 (m, 4H).
Example B66
Synthesis of
7-{4-[4-(2-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one
[0947] The reductive amination procedure from Example B1 was
followed using 1-(1-piperazin-1-yl-naphthalen-2-yl)-ethanone to
give the title compound. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
12.00 (s, 1H), 8.37 (m, 1H), 7.80 (m, 2H), 7.60 (m, 3H), 6.70 (d,
J=8.0 Hz, 1H), 6.40 (d, J=8.0 Hz, 1H), 4.40 (m, 2H), 3.60-3.40 (m,
10H), 2.66 (s, 3H), 1.90 (m, 4H).
Example B67
Synthesis of
8-{4-[4-(7-Oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyl]-piperazin-1--
yl}-naphthalene-2-carbonitrile
[0948] The reductive amination procedure from Example B1 was
followed using 8-piperazin-1-yl-naphthalene-2-carbonitrile to give
the title compound (0.341 g, 24%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.03 (s, 1H), 11.24 (s, 1H), 8.63 (s, 1H),
8.13 (d, 1H), 8.20 (d, 1H), 7.83 (m, 2H), 7.70 (t, 1H), 7.37 (d,
1H), 6.68 (d, 1H), 6.38 (d, 1H), 4.40 (t, 2H), 3.68-3.21 (m, 16H),
2.40-1.90 (m, 4H).
Example B68
Synthesis of
1-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyr-
idin-2-one
[0949] An intermediate compound,
7-Chloro-1-methyl-1H-[1,8]naphthyridin-2-one, was produced as
follows: To a suspension of 7-chloro-1H-[1,8]naphthyridin-2-one
(1.17 g, 6.49 mmol) in THF (32 mL) cooled to 0.degree. C. was added
potassium tert-butoxide (1 M in THF, 9.7 mL, 9.7 mmol). After
stirring for 15 min, MeI (0.81 mL, 13.0 mmol) was added. The
reaction was stirred at 0.degree. C. for 1 h and at room
temperature for 5 h. The reaction was quenched with saturated
NH.sub.4Cl and H.sub.2O. The mixture was extracted with EtOAc. The
organic layer was washed with saturated NaHCO.sub.3 and brine,
dried over Na.sub.2SO.sub.4 and concentrated. Purification by
liquid chromatography (Analogix, RS-120, 10-50% EtOAc/Hexanes) gave
the intermediate compound as a white solid (0.88 g, 4.52 mmol,
70%). MS: APCI: M+1: 195.0 (Exact Mass: 194.02).
[0950] To a solution of
4-(4-naphthalen-1-yl-piperazin-1-yl)-butan-1-ol (422 mg, 1.48 mmol)
in THF (5 mL) cooled to 0.degree. C. was added
7-chloro-1-methyl-1H-[1,8]naphthyridin-2-one (303 mg, 1.56 mmol) as
a solution in THF (9 mL) via cannula. The reaction was stirred for
about 2 h at 0.degree. C. The reaction was quenched with saturated
NH.sub.4Cl and the mixture was extracted with EtOAc. The organic
layer was washed with saturated NaHCO.sub.3 and brine, dried over
Na.sub.2SO.sub.4 and concentrated. Purification by LC (4%
MeOH/CH.sub.2Cl.sub.2) gave the title compound as a white foam (507
mg, 1.15 mmol, 77%). A portion of the title compound (243 mg, 0.549
mmol) was dissolved in Et.sub.2O and 1 N HCl in Et.sub.2O (0.55 mL)
was added. The resulting white precipitate was collected by
filtration, washed with Et.sub.2O and dried to give a white solid
(248 mg). MS: APCI: M+1: 443.3 (Exact Mass: 442.24).
Example C1
Synthesis of
7-{3-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-propoxy}-1H-[1,8]naphthyrid-
in-2-one
[0951] An intermediate compound,
2-Benzyloxy-7-{3-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-propoxy}-[1,8]n-
aphthyridine, was produced as follows: To a suspension of
3-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-propan-1-ol
hydrochloride (400 mg, 1.23 mmol) in THF (5 mL) cooled to
-40.degree. C. was added KO.sup.tBu (1 M in THF, 2.3 mL, 2.3 mmol,
1.9 equiv). The mixture became a cloudy solution. After stirring
for 20 min at -40.degree. C.,
2-benzyloxy-7-chloro-[1,8]naphthyridine (333 mg, 1.23 mmol) was
added as a solution in THF (8 mL) via cannula. The reaction was
allowed to warm to 0.degree. C. slowly over 1 h. The reaction was
quenched with saturated NH.sub.4Cl and H.sub.2O and extracted with
EtOAc. The organic layer was washed with saturated NaHCO.sub.3 and
brine, dried over Na.sub.2SO.sub.4 and concentrated. Purification
by liquid chromatography (CH.sub.2Cl.sub.2 to 2%
MeOH/CH.sub.2Cl.sub.2) gave the title compound as a clear oilfoam
(367 mg, 0.701 mmol, 57%). MS: APCI: M+1: 523.0 (Exact Mass:
522.16).
[0952]
2-Benzyloxy-7-{3-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-propoxy}-
-[1,8]naphthyridine (367 mg, 0.701 mmol) was hydrogenated using 5%
Pd/C (0.1 g) in MeOH (50 mL) for 1 h. The reaction was filtered and
concentrated. Purification by liquid chromatography (4-5%
MeOH/CH.sub.2Cl.sub.2) gave the title compound as a white foam (181
mg, 0.418 mmol, 60%). MS: APCI: M+1: 433.1 (Exact Mass:
432.11).
Example C2
Synthesis of
7-[3-(4-Naphthalen-1-yl-piperazin-1-yl)-propoxy]-1H-[1,8]naphthyridin-2-o-
ne
[0953] A first intermediate compound,
4-(3-Hydroxy-propyl)-piperazine-1-carboxylic acid tert-butyl ester,
was produced as follows: A 12 L, 4-necked RB flask, equipped with a
mechanical stirrer, thermometer, nitrogen inlet and an addition
funnel is charged with a solution of N-boc-piperazine, (600 g,
3.225 mol) in DMF (3.9 L) followed by anhydrous potassium carbonate
(666 g, 4.82 mol) then sodium iodide (72.5 g, 1.25 mol). The
reaction mixture is stirred at .about.80.degree. C. for 16 h,
cooled to room temperature, filtered, washed with DMF (2.times.200
mL) and evaporated to a thick mass, which is set aside for a day at
.about.5.degree. C. The solids are filtered, washed with hexanes
(3.times.300 mL) and dried in vacuum at -50.degree. C. to get 438 g
crude as a white powder. The crude compound is dissolved in 10%
methanol in ether (2.5 L) and passed through a small silica gel
column (previously washed with ether containing 2% triethylamine).
The filtrates are evaporated to thick liquid and added to a mixture
of hexanes-ether (2:1, 2.5 L) while stirring and continued the
stirring for 12 h at .about.5.degree. C., filtered, washed with
hexanes and dried the product to give the title compound, as a
white crystalline solid (308 g, 39%).
[0954] A second intermediate compound,
4-[3-(7-Benzyloxy-[1,8]naphthyridin-2-yloxy)-propyl]-piperazine-1-carboxy-
lic acid tert-butyl ester, was produced as follows: A 5 L 4-necked
flask, equipped with a mechanical stirrer, thermometer, nitrogen
inlet and an addition funnel is charged with a solution of
4-(3-hydroxy-propyl)-piperazine-1-carboxylic acid tert-butyl ester,
(129 g, 0.528 mol) in anhydrous THF (1.6 L) and cooled to
-40.degree. C. To this potassium tert-butoxide solution (580 mL, 1M
in THF, 0.58 mol) is added drop-wise during 1 h, and stirred
further for 30 min. 2-Benzyloxy-7-chloro-[1,8]naphthyridine (130 g,
0.48 mol) is added to the reaction mixture in portions at
-40.degree. C. during 1 h. The reaction is stirred for 4 h to bring
to 0.degree. C., then quenched with saturated ammonium chloride
solution (1.5 L) and extracted with ethyl acetate (2 L and 1 L).
The combined organic extracts are washed with brine (1 L), dried
over anhydrous sodium sulfate and concentrated to afford the crude
as a dark brown thick paste. The crude is purified by silica gel
chromatography using 20-25% ethyl acetate in hexanes for elution to
give the second intermediate compound as a thick almost colorless
thick paste (126 g, 49.8%).
[0955] A third intermediate compound,
4-[3-(7-Oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-propyl]-piperazine-1-c-
arboxylic acid tert-butyl ester, was produced as follows: To a
solution of
4-[3-(7-benzyloxy-[1,8]naphthyridin-2-yloxy)-propyl]-piperazine-1-carboxy-
lic acid tert-butyl ester (62 g, 0.129 mol) in methanol (600 mL)
and THF (150 mL) is added 10% Pd/C (6 g) and the mixture is
hydrogenated at atmospheric pressure at room temperature for 20 h.
The reaction mixture is filtered, washed with methanol,
concentrated and vacuum dried at -50.degree. C. to afford the third
intermediate compound as a pale yellow thick gummy solid (48.8 g,
94%).
[0956] A fourth intermediate compound,
7-(3-Piperazin-1-yl-propoxy)-1H-[1,8]naphthyridin-2-one, was
produced as follows: A 2 L, 3-necked RB flask, equipped with
mechanical stirrer and a nitrogen inlet is charged with a solution
of
4-[3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-propyl]-piperaz-
ine-1-carboxylic acid tert-butyl ester (43.4 g, 0.111 mol) in
dichloromethane (500 mL) followed by trifluoroacetic acid (187 mL)
at room temperature. The reaction mixture is stirred at room
temperature by occasionally evacuating the reaction flask with
vacuum. After ensuring the absence of starting material by TLC (10%
methanol in CH.sub.2Cl.sub.2), the solvents are removed by
co-distilling with toluene (3.times.). The residue is triturated in
ether to obtain 62 g of the crude as a TFA salt. The crude TFA salt
is suspended in water (50 mL), basified with 4N NaOH (100 mL),
stirred, washed with CH.sub.2Cl.sub.2 and passed through a column
of HP-20 (300 mL) previously washed with methanol followed by
water. The column is thoroughly washed with water to eliminate any
basic impurities and eluted with methanol. The methanol solution
thus obtained is evaporated and the residue is triturated in ether
to afford the fourth intermediate compound as an off-white powder
(33 g, 100%), m.p. 192-195.degree. C.
[0957] 7-(3-Piperazin-1-yl-propoxy)-1H-[1,8]naphthyridin-2-one (1.5
g, 4.2 mmol) was placed in a 25 mL flask with 15 mL toluene and
azeotroped to dryness. The mixture was cooled to 25.degree. C. and
1-bromo-naphthalene (4.45 g, 21 5 mmol) was added. In a separate
flask, Pd(OAc).sub.2 (0.073 g, 0.325 mmol) and
2-dicyclohexylphosphino biphenyl (0.180 g, 0.514 mmol) were
dissolved in degassed anhydrous toluene (3 mL). This solution was
then added to the suspension of the two reactants via syringe.
Sodium tert-butoxide, (0.8 g, 8.32 mmol) was added which gave a
suspension upon stirring. After the mixture had been heated to
reflux overnight, the mixture was evaporated and the residue was
taken up into dichloromethane and water. The pH was adjusted to 4.5
with 1N citric acid followed by separation of the aqueous phase.
The organic phase was washed with water and the pH adjusted to 12
by addition of 1N sodium hydroxide and brine. The organic phase was
separated, dried over sodium sulfate, filtered and evaporated to an
oil with suspended solids. The residue was purified by
chromatography on silica gel eluting with dichloromethane and then
a gradient to 20% methanol in ethyl acetate. The title compound was
recovered as a crystalline solid (0.262 g). MS: APCI: M+1: 415.5
(Exact Mass: 414.21).
Example C3
Synthesis of
7-[3-(4-Naphthalen-1-yl-piperazin-1-yl)-propoxy]-3,4-dihydro-1H-[1,8]naph-
thyridin-2-one
[0958] A first intermediate compound,
4-[3-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-propyl]-piperaz-
ine-1-carboxylic acid tert-butyl ester, was produced as follows: To
a solution of
4-[3-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-propyl]-piperazine-1-c-
arboxylic acid tert-butyl ester (62 g, 0.129 mol) in methanol (600
mL) and THF (150 mL) is added 10% Pd/C (6 g) and the mixture is
hydrogenated at atmospheric pressure at room temperature for 20 h.
The reaction mixture is filtered, washed with methanol,
concentrated and vacuum dried at .about.50.degree. C. to afford 43
g of a pale yellow thick gummy solid. It is again subjected to
hydrogenation by dissolving in DMF-dioxane-ethanol (0.3 L:1 L:0.2
L) and adding fresh Pd/C (8 g). After a similar workup, the first
intermediate compound was obtained as a thick gum (37 g,
73.5%).
[0959] A second intermediate,
7-(3-Piperazin-1-yl-propoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one,
was produced as follows: A 2 L, 3-necked RB flask, equipped with a
mechanical stirrer, and a nitrogen inlet is charged with a solution
of
4-[3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-propyl]-piperaz-
ine-1-carboxylic acid tert-butyl ester (35 g, 0.089 mol) in
dichloromethane (500 mL) followed by trifluoroacetic acid (150 mL)
at room temperature. The reaction mixture is stirred at room
temperature by occasionally evacuating the reaction flask with
vacuum. After ensuring the absence of starting material by TLC (10%
methanol in CH.sub.2Cl.sub.2), the solvents are removed by
co-distilling with toluene (3.times.) to get the crude TFA salt as
a light brown thick paste. The crude material is suspended in water
(50 mL), basified with 4N NaOH (100 mL), stirred, filtered, washed
thoroughly with water followed by ether and dried under vacuum over
P.sub.2O.sub.5 at .about.50.degree. C. to afford the second
intermediate compound as an off-white powder (24.4 g, 93%), m.p.
142-46.degree. C.
[0960] In a similar manner to the example shown above,
7-(3-piperazin-1-yl-propoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one
was coupled to 1-bromo-naphthalene to give the title compound
(0.189 g). MS: APCI: M+1: 417.2 (Exact Mass: 416.22).
Example C4
Synthesis of
7-{2-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-ethoxy}-1H-[1,8]naphthyridi-
n-2-one
[0961] An intermediate compound,
2-Benzyloxy-7-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethoxy}-[1,8]na-
phthyridine, was produced as follows: To a solution of
2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethanol (1.0 g, 3.63
mmol) in THF (6 mL) cooled to -20.degree. C. was added 1M
KO.sup.tBU in THF (3.6 mL, 3.6 mmol). After 15 min, a solution of
2-benzyloxy-7-chloro-[1,8]naphthyridine (1.18 g, 4.35 mmol, 1.2
equiv) in THF (25 mL) was added quickly via cannula. The reaction
became a brown solution. The reaction was slowly allowed to warm to
0.degree. C. over 90 min and then quenched with saturated
NH.sub.4Cl and H.sub.2O. The mixture was extracted with EtOAc. The
organic layer was washed with saturated NaHCO.sub.3 and brine,
dried over Na.sub.2SO.sub.4 and concentrated. Purification by
liquid chromatography (CH.sub.2Cl.sub.2 to 2%
MeOH/CH.sub.2Cl.sub.2) gave the product with some lower Rf
impurities. Further purification by liquid chromatography (75%
EtOAc/Hexanes) afforded the intermediate compound as a clear
oil/white foam (1.36 g, 2.67 mmol, 74%). MS: APCI: M+1: 509.0
(Exact Mass: 508.14).
[0962]
2-Benzyloxy-7-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethoxy}--
[1,8]naphthyridine (1.30 g, 2.55 mmol) was hydrogenated using 5%
Pd/C (0.4 g) in MeOH (100 mL) for 40 min. The reaction was filtered
and concentrated. Purification by liquid chromatography (2-3%
MeOH/EtOAc with 1% NH.sub.4OH) gave the title compound as a white
foam (600 mg, 1.43 mmol, 56%). The HCl salt was prepared using 1N
HCl in Et.sub.2O to give a white solid. MS: APCI: M+1: 419.1 (Exact
Mass: 418.10).
Example C5
Synthesis of
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-1-methyl-butoxy}-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one
[0963] A first intermediate compound,
2-Benzyloxy-7-[4-(tert-butyl-dimethyl-silanyloxy)-1-methyl-butoxy]-[1,8]n-
aphthyridine, was produced as follows: To a solution of the
5-(tert-butyl-dimethyl-silanyloxy)-pentan-2-ol (1.61 g, 7.39 mmol,
Tetrahedron Lett. 1979, 99) in THF (7 mL) cooled to -30.degree. C.
was added 1M KOtBu in THF (7.4 mL, 7.4 mmol). The solution was
stirred for 15 min and 2-benzyloxy-7-chloro-[1,8]naphthyridine (2.0
g, 7.39 mmol) was added as a solution in THF (40 mL). The reaction
was allowed to warm to room temperature over 6 h. The reaction was
quenched with saturated NH4Cl and H2O and extracted with EtOAc. The
organic layer was washed with saturated NaHCO.sub.3 and brine,
dried over Na2SO4 and concentrated. Purification by liquid
chromatography (5% EtOAc/Hexanes) gave the first intermediate
compound as a clear oil (1.77 g, 3.91 mmol, 53%). MS: APCI: M+1:
453.2 (Exact Mass: 452.25).
[0964] A second intermediate compound,
4-(7-Benzyloxy-[1,8]naphthyridin-2-yloxy)-pentan-1-ol, was produced
as follows: To a solution of
2-benzyloxy-7-[4-(tert-butyl-dimethyl-silanyloxy)-1-methyl-butoxy]-[1,8]n-
aphthyridine (1.77 g, 3.91 mmol) in THF (8 mL) was added 1 M TBAF
in THF (7.8 mL, 7.8 mmol). The reaction turned purple instantly.
The reaction was stirred at room temperature for 1 h. Saturated
NaHCO.sub.3 was added and the mixture was extracted with EtOAc. The
organic layer was washed with H.sub.2O and brine, dried over
Na.sub.2SO.sub.4 and concentrated to give a pale brown oil.
Purification by liquid chromatography (35-40% EtOAc/Hexanes) gave
the second intermediate compound as a clear oil (1.29 g, 3.81 mmol,
97%).
[0965] A third intermediate compound,
7-(4-Hydroxy-1-methyl-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one,
was produced as follows:
4-(7-Benzyloxy-[1,8]naphthyridin-2-yloxy)-pentan-1-ol (1.29 g, 3.81
mmol) was hydrogenated using 20% Pd/C (0.35 g) in MeOH (50 mL) for
18 h. The reaction was filtered and concentrated. Purification by
liquid chromatography (5% MeOH/CH.sub.2Cl.sub.2) gave the third
intermediate compound as a clear oil (0.898 g, 3.59 mmol, 94%).
[0966] A fourth intermediate compound,
4-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-pentanal,
was produced as follows: To a cloudy solution of the Dess-Martin
reagent (2.28 g, 5.38 mmol) in CH.sub.2Cl.sub.2 (10 mL) was added
7-(4-hydroxy-1-methyl-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one
(0.895 g, 3.59 mmol) as a solution in CH.sub.2Cl.sub.2 (10 mL). The
reaction turned clear and then became pale yellow. The reaction was
stirred at room temperature for 6 h. Saturated NaHCO.sub.3 and
saturated Na.sub.2S.sub.2O.sub.3 (1:1) was added and the mixture
was stirred for 10 min. The mixture was extracted with
EtOAc/Et.sub.2O (2.times.). The organic layer was washed with
saturated NaHCO.sub.3, H.sub.2O and brine, dried over MgSO.sub.4
and concentrated to give a brown oil (901 mg, used crude in
subsequent reductive aminations). MS: APCI: M+1: 249.1 (Exact Mass:
248.12).
[0967] To a solution of
4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-pentanal
(450 mg, crude) in DCE (10 mL) was added
2,3-dichlorophenyl-piperazine hydrochloride (495 mg, 1.85 mmol)
followed by Et.sub.3N (0.55 mL, 3.96 mmol). The mixture was stirred
for 10 min and then powdered NaBH(OAc).sub.3 (534 mg, 2.52 mmol)
was added. The reaction was stirred at room temperature for 2 h and
then quenched with saturated NaHCO.sub.3. The mixture was extracted
with EtOAc (2.times.). The organic layer was washed with saturated
NaHCO.sub.3 and brine, dried over Na.sub.2SO.sub.4 and concentrated
to give a foam. Purification by liquid chromatography (4%
MeOH/CH.sub.2Cl.sub.2) gave the title compound as a white foam (507
mg, 1.09 mmol, 61%). MS: APCI: M+1: 463.1 (Exact Mass: 462.16). The
enantiomers were separated by chiral HPLC (Chiralcel OD).
Example C6
Synthesis of
7-[1-Methyl-4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[-
1,8]naphthyridin-2-one
[0968] The procedure above was followed using
1-naphthalen-1-yl-piperazine hydrochloride (460 mg, 1.85 mmol).
Purification by liquid chromatography (4% MeOH/CH.sub.2Cl.sub.2)
gave the title compound as a white foam (539 mg, 1.21 mmol, 67%).
MS: APCI: M+1: 445.2 (Exact Mass: 444.25).
[0969] The enantiomers were separated by chiral HPLC (Chiralcel
OD).
Example C7
Synthesis of
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-1,1-dimethyl-butoxy}-3,4-di-
hydro-1H-[1,8]naphthyridin-2-one
[0970] A first intermediate compound,
2-Benzyloxy-7-[4-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-butoxy]-[1-
,8]naphthyridine, was produced as follows: To a mixture of the
5-(tert-butyl-dimethyl-silanyloxy)-2-methyl-pentan-2-ol (3.0 g,
12.91 mmol, J. Org. Chem. 1997, 62, 3153 and Tetrahedron Lett.
1979, 99) and 2-benzyloxy-7-chloro-[1,8]naphthyridine (3.49 g,
12.91 mmol) in THF (100 mL) cooled to 0.degree. C. was added KHMDS
(0.5 M in toluene, 25.8 mL, 12.91 mmol). The reaction turned dark
green. After 30 min at 0.degree. C., the ice bath was removed and
the reaction was stirred for 2 h at RT. Saturated NH.sub.4Cl was
added and the mixture was extracted with CH.sub.2Cl.sub.2
(2.times.). The organic layer was washed with saturated NH.sub.4Cl
and concentrated to give a dark orange oil. Purification by liquid
chromatography (5% EtOAc/Hexanes) gave the first intermediate
compound as a clear oil (1.64 g, 3.51 mmol, 27%). MS: APCI: M+1:
467.1, fragment: 253.1 (Exact Mass: 466.27).
[0971] A second intermediate compound,
7-(4-Hydroxy-1,1-dimethyl-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one,
was produced as follows:
2-Benzyloxy-7-[4-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-butoxy]-[1-
,8]naphthyridine (1.64 g, 3.51 mmol) was hydrogenated using 20%
Pd/C (0.5 g) in MeOH (50 mL) for 22 h. The TBS group was removed
under the reaction conditions. The reaction was filtered and
concentrated. The residue was dissolved in EtOAc and washed with
saturated NaHCO.sub.3 and brine. The organics were concentrated and
purified by liquid chromatography (5% MeOH/CH.sub.2Cl.sub.2) to
give the second intermediate compound as a clear oil which
solidified under vacuum to give a white solid (648 mg, 2.45 mmol,
70%). MS: APCI: M+1: 265.1 (Exact Mass: 264.15).
[0972] A third intermediate compound,
4-Methyl-4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-pentanal,
was produced as follows: To a cloudy solution of the Dess-Martin
reagent (1.66 g, 3.92 mmol) in CH.sub.2Cl.sub.2 (10 mL) was added
7-(4-hydroxy-1,1-dimethyl-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one
(648 mg, 2.45 mmol) as a solution in CH.sub.2Cl.sub.2 (5 mL). The
reaction was stirred at room temperature for 5 h. Saturated
NaHCO.sub.3 and saturated Na.sub.2S.sub.2O.sub.3 (1:1) was added
and the mixture was stirred for 10 min. The mixture was extracted
with EtOAc/Et.sub.2O (2.times.). The organic layer was washed with
saturated NaHCO.sub.3, H.sub.2O and brine, dried over MgSO.sub.4
and concentrated to give a yellow solid/oil (679 mg, used crude in
subsequent reductive aminations). MS: APCI: M+1: 263.1 (Exact Mass:
262.13).
[0973] To a solution of
4-methyl-4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-pentanal
(335 mg, crude) in DCE (6 mL) was added
2,3-dichlorophenyl-piperazine hydrochloride (335 mg, 1.25 mmol)
followed by Et.sub.3N (0.35 mL, 2.50 mmol). The mixture was stirred
for 10 min and then powdered NaBH(OAc).sub.3 (365 mg, 1.72 mmol)
was added. The reaction was stirred at room temperature for 2 h and
then quenched with saturated NaHCO.sub.3. The mixture was extracted
with EtOAc (2.times.). The organic layer was washed with saturated
NaHCO.sub.3, H.sub.2O and brine, dried over Na.sub.2SO.sub.4 and
concentrated. Purification by liquid chromatography (4%
MeOH/CH.sub.2Cl.sub.2) gave the title compound as a white foam (395
mg, 0.827 mmol, 67% over 2 steps). The foam was dissolved in
Et.sub.2O and 1N HCl in Et.sub.2O (0.85 mL) was added. The
resulting white precipitate was collected by filtration, washed
with Et.sub.2O and dried to give a white solid (386 mg). MS: APCI:
M+1: 477.1 (Exact Mass: 476.17).
Example C8
Synthesis of
7-[1,1-Dimethyl-4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro--
1H-[1,8]naphthyridin-2-one
[0974] The procedure above was followed using
1-naphthalen-1-yl-piperazine hydrochloride (311 mg, 1.25 mmol).
Purification by liquid chromatography (4% MeOH/CH.sub.2Cl.sub.2)
gave the title compound as a white foam (384 mg, 0.837 mmol, 68%
over 2 steps). The HCl salt was prepared as above to give a white
solid (385 mg). MS: APCI: M+1: 459.2 (Exact Mass: 458.27).
Example C9
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-[1,8]-
naphthyridin-2-one
[0975] A first intermediate compound,
7-Amino-3,4-dihydro-1H-[1,8]naphthyridin-2-one, was produced as
follows: A solution of
7-amino-[1,8]naphthyridin-2-ol.H.sub.2SO.sub.4 (36.0 g, 139 mmol,
J. Org. Chem. 1981, 46, 833) in 6 N HCl (600 mL) was hydrogenated
using 20% Pd/C for 2 d. The reaction was filtered and then cooled
to -50.degree. C. A thick white precipitate formed which was
filtered and washed with Et.sub.2O. The resulting solid was
slurried with Et.sub.2O, filtered and dried to give the first
intermediate compound as the hydrochloride salt (21.5 g, 108 mmol,
78%). MS: APCI: M+1: 164.0 (Exact Mass: 163.07).
[0976] A second intermediate compound,
7-Chloro-3,4-dihydro-1H-[1,8]naphthyridin-2-one, was produced as
follows: To concentrated HCl (80 mL) cooled to -5.degree. C. and
saturated with HCl gas was added
7-amino-3,4-dihydro-1H-[1,8]naphthyridin-2-one (9.0 g, 55.0 mmol)
to give a solution. A solution of NaNO.sub.2 (9.6 g, 137.0 mmol) in
H.sub.2O (15 mL) was added subsurface via a syringe pump over 20
min. The temperature was between -5 to -7.degree. C. The mixture
was a yellow-orange suspension during the addition and turned dark
green after the addition. The reaction was poured into saturated
NaHCO.sub.3 (500 mL) at 10.degree. C. and additional solid
NaHCO.sub.3 was added to bring pH to 7. The mixture was extracted
with EtOAc. The organic layer was dried over MgSO.sub.4 and
concentrated. The residue was dissolved in warm EtOAc (125 mL) and
the insoluble material was filtered off. The filtrate was washed
with saturated Na.sub.2CO.sub.3, dried over MgSO.sub.4 and
concentrated to a smaller volume. The resulting solid was filtered
and dried to give the second intermediate compound (4.4 g, 24.2
mmol, 44%). MS: APCI: M+1: 183.0 (Exact Mass: 182.02).
[0977] A third intermediate compound,
7-(5-Chloro-pent-1-enyl)-3,4-dihydro-1H-[1,8]naphthyridin-2-one,
was produced as follows: To a solution of
7-chloro-3,4-dihydro-1H-[1,8]naphthyridin-2-one (9.0 g, 49.0 mmol)
in dimethoxyethane (160 mL) was added Pd(PPh3)4 (1.60 g, 1.48 mmol)
followed by a slurry of 5-chloro-1-pentenyl boronic acid (10.97 g,
74.0 mmol) in dimethoxyethane (20 mL). A solution of Na2CO3 (10.7
g) in H2O (50 mL) was added and the mixture was heated overnight at
85.degree. C. More Pd(PPh3)4 (0.44 g) was added and the reaction
was heated at 104.degree. C. overnight. The reaction was complete.
The reaction was cooled to room temperature and the organic layer
was separated. The organic layer was cooled to -10.degree. C. and a
precipitate formed. The solid was filtered off and the filtrate was
concentrated to give a brown oil. The oil was dissolved in Et2O,
washed with 2N NaOH and brine, dried over MgSO4 and concentrated to
give a solid. Et2O (450 mL) was added and a yellow solid remained
insoluble which was filtered off. The filtrate was treated with
charcoal and concentrated to give a solid. The solid was washed
with cold Et2O and dried to give the third intermediate compound as
a white solid (7.97 g, 49.0 mmol, 71%). mp 70-73.degree. C. MS:
APCI: M+1: 251.1 (Exact Mass: 250.09).
[0978] A fourth intermediate compound,
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one, was produced as follows: To a mixture of
2,3-dichlorophenylpiperazine (2.2 g, 9.52 mmol) and
7-(5-chloro-pent-1-enyl)-3,4-dihydro-1H-[1,8]naphthyridin-2-one
(2.15 g, 8.58 mmol) in CH.sub.3CN (20 mL) was added a solution of
K.sub.2CO.sub.3 (2.5 g, 18.1 mmol) in H.sub.2O (10 mL) followed by
KI (0.1 g). The reaction was heated at 78.degree. C. for 3 d. The
reaction was about 50% complete so it was heated by microwave at
120.degree. C. for 90 min. The reaction was allowed to cool to room
temperature and solids precipitated. The mixture was cooled in the
refrigerator. The solids were collected by filtration and washed
with H.sub.2O and brine. The solids were dissolved in EtOAc, washed
with saturated NaHCO.sub.3 and brine, and dried over MgSO.sub.4.
The solution was concentrated to a reduced volume and the resulting
white precipitate was filtered and washed with Et.sub.2O to give a
white solid. Recrystallization from CH.sub.3CN gave the fourth
intermediate compound as a white solid (2.08 g, 4.57 mmol, 54%).
MS: APCI: M+1: 445.1 (Exact Mass: 444.15).
[0979]
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dih-
ydro-1H-[1,8]naphthyridin-2-one (1.85 g, 4.16 mmol) was
hydrogenated using Ra-Ni (1 g) in EtOH/THF (50 mL) for 1.4 h. The
reaction was filtered and concentrated to give a solid.
Recrystallization from hot CH.sub.3CN gave the title compound as a
white solid (1.58 g, 3.54 mmol, 85%). MS: APCI: M+1: 447.1 (Exact
Mass: 446.16).
Example C10
Synthesis of
7-{5-[4-(2-Chloro-3-methyl-phenyl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one
[0980] An intermediate compound,
7-{5-[4-(2-Chloro-3-methyl-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihyd-
ro-1H-[1,8]naphthyridin-2-one, was produced as follows: To a
solution of Na.sub.2CO.sub.3 (0.28 g, 2.6 mmol) in H.sub.2O (2 mL)
was added 2-chloro-3-methylphenylpiperazine hydrochloride (0.311 g,
1.26 mmol) and
7-(5-chloro-pent-1-enyl)-3,4-dihydro-1H-[1,8]naphthyridin-2-one
(0.30 g, 1.20 mmol) followed by a catalytic amount of NaI. The
mixture was heated at 95.degree. C. overnight. After cooling to RT,
the solid was washed several times with H.sub.2O and dried over a
stream of N.sub.2. Purification by liquid chromatography
(SiO.sub.2, 5% EtOH/CH.sub.2Cl.sub.2 to 5% MeOH/CH.sub.2Cl.sub.2)
gave the intermediate compound (471 mg, 1.11 mmol, 92%). MS: APCI:
M+1: 425.2 (Exact Mass: 424.20).
[0981]
7-{5-[4-(2-Chloro-3-methyl-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,-
4-dihydro-1H-[1,8]naphthyridin-2-one (0.322 g, 0.758 mmol) was
hydrogenated using Ra-Ni (0.5 g) in 1:1 EtOH/THF (50 mL) for 21 h.
The reaction was filtered and concentrated. Purification by liquid
chromatography (SiO.sub.2, 5% MeOH/CH2Cl2 to 7% MeOH/CH2Cl2) gave
the title compound as a light yellow foam (282 mg, 0.660 mmol,
87%). MS: APCI: M+1: 427.3 (Exact Mass: 426.22).
Example C11
Synthesis of
7-{5-[4-(2,3-Dichloro-4-fluoro-phenyl)-piperazin-1-yl]-pentyl}-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one
[0982] An intermediate compound,
7-{5-[4-(2,3-Dichloro-4-fluoro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-d-
ihydro-1H-[1,8]naphthyridin-2-one, was produced as follows: To a
mixture of
7-(5-chloro-pent-1-enyl)-3,4-dihydro-1H-[1,8]naphthyridin-2-one
(500 mg, 1.99 mmol) and 4-fluoro-2,3-dichlorophenylpiperazine
bishydrochloride (805 mg, 2.50 mmol, 1.25 equiv) in CH.sub.3CN (10
mL) was added K.sub.2CO.sub.3 (1.10 g, 7.98 mmol, 4 equiv) followed
by KI (66 mg, 0.40 mmol, 0.2 equiv). The reaction was refluxed for
2 d. H.sub.2O was added to dissolve the salts and the mixture was
extracted with EtOAc. The organic layer was washed with saturated
NaHCO.sub.3 and brine, dried over Na.sub.2SO.sub.4 and
concentrated. Purification by liquid chromatography (4%
MeOH/CH.sub.2Cl.sub.2) gave the intermediate compound as a white
foam (768 mg, 1.66 mmol, 83%). MS: APCI: M+1: 463.1 (Exact Mass:
462.14).
[0983]
7-{5-[4-(2,3-Dichloro-4-fluoro-phenyl)-piperazin-1-yl]-pent-1-enyl-
}-3,4-dihydro-1H-[1,8]naphthyridin-2-one (633 mg, 1.37 mmol) was
hydrogenated using Ra-Ni (0.65 g) in 1:1 EtOH/THF (50 mL) for 21 h.
The reaction was filtered and concentrated. Purification by liquid
chromatography (4% MeOH/CH.sub.2Cl.sub.2) gave a white foam (425
mg). The foam was dissolved in CH.sub.3CN and the compound
crystallized. The solid was collected by filtration, washed with
Et.sub.2O and dried to give the title compound as a white solid
(366 mg, 0.786 mmol, 57%). MS: APCI: M+1: 465.1 (Exact Mass:
464.15).
Example C12
Synthesis of
7-15-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-pentyl}-3,4--
dihydro-1H-[1,8]naphthyridin-2-one
[0984] A first intermediate compound,
1-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazine, was produced as
follows: To a reaction flask containing a solution of
5,6,7,8-tetrahydro-naphthalen-1-ylamine (10.0 g, 67.9 mmol) in
chlorobenzene (10 mL), was added bis-(2-chloro-ethyl)-amine
hydrochoride (12.12 g, 67.92 mmol). The reaction was refluxed for
14 hours. The reaction was cooled and the precipitate was filtered.
The filtrate was partitioned between ethyl acetate and water. The
organic layer was washed with brine, dried over Na.sub.2SO.sub.4,
and concentrated. Purification by chromatography on silica gel
(0-40% MeOH/CH.sub.2Cl.sub.2) afforded the first intermediate
compound as a grayish white solid (8.25 g, 56%). MS: APCI: M+1:
217.2 (Exact Mass: 216.16).
[0985] A second intermediate compound,
7-{5-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-pent-1-enyl}-
-3,4-dihydro-1H-[1,8]naphthyridin-2-one, was produced as follows:
To a flask containing a solution of
7-(5-chloro-pent-1-enyl)-3,4-dihydro-1H-[1,8]naphthyridin-2-one
(0.330 g, 1.19 mmol) in CH.sub.3CN (8 ml) was added
1-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine (0.388 g, 1.79
mmol), followed by K.sub.2CO.sub.3 (0.328 g, 2.38 mmol) and KI
(0.039 g, 0.238 mmol). The reaction was refluxed for 18 hours. The
reaction was cooled to room temperature and partitioned between
EtOAc and aqueous NaHCO.sub.3. The organic layer was washed with
brine, dried over Na.sub.2SO.sub.4 and concentrated to give an oil.
Purification by chromatography on silica gel (0-10% MeOH/EtOAc)
afforded the second intermediate compound as a white foam (0.308 g,
60%). A small portion (81 mg) was then dissolved in Et.sub.2O and
1M HCl in Et.sub.2O (1 equiv) was added. A precipitate formed and
was filtered. The product was a white solid (90 mg). MS: APCI: M+1:
431.3 (Exact Mass: 430.27).
[0986]
7-{5-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-pent--
1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one (0.225 g, 0.523
mmol) was hydrogenated using Ra-Ni (0.25 g) in THF for 16 hours.
The reaction was filtered and concentrated to give a foam. This was
dissolved in Et.sub.2O and 1M HCl in Et.sub.2O (1 equiv) was added.
The precipitate was filtered and dried to give the title compound
as a white solid (0.157 g, 70%). MS: APCI: M+1: 433.4 (Exact Mass:
432.29).
Example C13
Synthesis of
7-[5-(4-Naphthalen-1-yl-piperazin-1-yl)-pentyl]-3,4-dihydro-1H-[1,8]napht-
hyridin-2-one
[0987] An intermediate compound,
7-[5-(4-Naphthalen-1-yl-piperazin-1-yl)-pent-1-enyl]-3,4-dihydro-1H-[1,8]-
naphthyridin-2-one, was produced as follows: Reaction of
7-(5-chloro-pent-1-enyl)-3,4-dihydro-1H-[1,8]naphthyridin-2-one
with 1-naphthalen-1-yl-piperazine according to the procedure in
Example C9 gave the intermediate compound (0.340 g, 0.80 mmol,
50%). MS: APCI: M+1: 427.2 (Exact Mass: 426.24).
[0988] Hydrogenation of
7-[5-(4-naphthalen-1-yl-piperazin-1-yl)-pent-1-enyl]-3,4-dihydro-1H-[1,8]-
naphthyridin-2-one according to the procedure in Example C9 gave
the title compound (0.250 g, 0.48 mmol, 75%). MS: APCI: M+1: 429.3
(Exact Mass: 428.26).
Example C14
Synthesis of
7-{5-[4-(2-Chloro-4-fluoro-phenyl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one
[0989] An intermediate compound,
7-{5-[4-(2-Chloro-4-fluoro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihyd-
ro-1H-[1,8]naphthyridin-2-one, was produced as follows: To a flask
containing a solution of
7-(5-chloro-pent-1-enyl)-3,4-dihydro-1H-[1,8]naphthyridin-2-one
(0.300 g, 1.19 mmol) in CH.sub.3CN (8 mL) and H.sub.2O (3 mL), was
added 1-(2-chloro-4-fluoro-phenyl)-piperazine (0.516 g, 1.79 mmol),
followed by K.sub.2CO.sub.3 (0.493 g, 3.57 mmol) and KI (0.027 g,
0.238 mmol). The reaction was refluxed for 12 hours. The reaction
was cooled to room temperature, diluted with EtOAc and washed with
NaHCO.sub.3 and brine. The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated to give an oil. Purification by
chromatography on silica gel (0-10% MeOH/EtOAc) afforded the
intermediate compound as a white foam (0.363 g, 71%). A small
portion (93 mg) was then dissolved in Et.sub.2O and 1M HCl in
Et.sub.2O (1 equiv) was added. A precipitate formed which was
filtered and dried to give a white solid (97 mg). MS: APCI: M+1:
429.2 (Exact Mass: 428.18).
[0990]
7-{5-[4-(2-Chloro-4-fluoro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,-
4-dihydro-1H-[1,8]naphthyridin-2-one (0.268 g, 0.623 mmol) was
hydrogenated using Ra-Ni (0.2 g) in THF for 13 hours. The reaction
was filtered and concentrated to give an oil. Et.sub.2O was added
and the product crashed out. The mixture was filtered and dried to
give the title compound as a white solid (0.214 g, 80%). MS: APCI:
M+1: 431.3 (Exact Mass: 430.19).
Example C15
Synthesis
7-{5-[4-(2-Chloro-4-fluoro-3-methyl-phenyl)-piperazin-1-yl]-pent-
yl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one of
[0991] An intermediate compound,
7-{5-[4-(2-Chloro-4-fluoro-3-methyl-phenyl)-piperazin-1-yl]-pent-1-enyl}--
3,4-dihydro-1H-[1,8]naphthyridin-2-one, was produced as follows: To
a solution of Na.sub.2CO.sub.3 (93 mg, 0.88 mmol) in H.sub.2O (2
mL) was added 2-chloro-4-fluoro-3-methylphenylpiperazine
hydrochloride (106 mg, 0.40 mmol) and
7-(5-chloro-pent-1-enyl)-3,4-dihydro-1H-[1,8]naphthyridin-2-one
(100 mg, 0.40 mmol) followed by a catalytic amount of NaI. The
mixture was heated at 95.degree. C. overnight. After cooling to RT,
the solid was washed several times with H.sub.2O and dried over a
stream of N.sub.2. Purification by liquid chromatography
(SiO.sub.2, 5% EtOH/CH.sub.2Cl.sub.2 to 5% MeOH/CH.sub.2Cl.sub.2)
gave the intermediate compound (134 mg, 0.303 mmol, 76%). MS: APCI:
M+1: 443.2 (Exact Mass: 442.19).
[0992]
7-{5-[4-(2-Chloro-4-fluoro-3-methyl-phenyl)-piperazin-1-yl]-pent-1-
-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one (0.382 g, 0.862 mmol)
was hydrogenated using Ra-Ni (0.5 g) in 1:1 EtOH/THF (50 mL) for 12
h. The reaction was filtered and concentrated. Purification by
liquid chromatography (SiO.sub.2, 5% MeOH/CH2Cl2 to 7% MeOH/CH2Cl2)
gave the title compound as a light yellow foam (342 mg, 0.769 mmol,
89%). MS: APCI: M+1: 445.2 (Exact Mass: 444.21).
Example C16
Synthesis of
7-{5-[4-(6-Methyl-pyridin-2-yl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-[1-
,8]naphthyridin-2-one
[0993] An intermediate compound,
7-{5-[4-(6-Methyl-pyridin-2-yl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro--
1H-[1,8]naphthyridin-2-one, was produced as follows:
[0994] To a solution of K.sub.2CO.sub.3 (1.16 g, 8.38 mmol) in
H.sub.2O (3 mL) was added CH.sub.3CN (9 mL),
1-(6-methyl-pyridin-2-yl)-piperazine (0.84 g, 3.35 mmol) and
7-(5-chloro-pent-1-enyl)-3,4-dihydro-1H-[1,8]naphthyridin-2-one
(0.70 g, 2.80 mmol) followed by a catalytic amount of KI (8 mg).
The mixture was stirred for 15 min and then heated in a microwave
(300 W) at 120.degree. C. for 150 min. After cooling to RT,
saturated NaHCO.sub.3 was added and the mixture was extracted with
EtOAC. The organic layer was washed with brine, dried over
MgSO.sub.4 and concentrated to give a yellow oil. Purification by
liquid chromatography (40M Biotage SiO.sub.2 column,
CH.sub.2Cl.sub.2 to 2% MeOH/CH.sub.2Cl.sub.2) gave the intermediate
compound as a foam (426 mg, 1.09 mmol, 39%). MS: APCI: M+1: 392.1
(Exact Mass: 391.24).
[0995]
7-{5-[4-(6-Methyl-pyridin-2-yl)-piperazin-1-yl]-pent-1-enyl}-3,4-d-
ihydro-1H-[1,8]naphthyridin-2-one (0.343 g, 0.876 mmol) was
hydrogenated using 20% Pd/C in EtOH for 103 h. The reaction was
filtered and concentrated. Purification by liquid chromatography
(Biotage 12 SiO.sub.2 column, CH.sub.2Cl.sub.2 to 1%
MeOH/CH.sub.2Cl.sub.2) followed by recrystallization from Et.sub.2O
gave the title compound as a white powder (42 mg, 0.01 mmol, 12%).
MS: APCI: M+1: 394.2 (Exact Mass: 393.25).
Example C17
Synthesis of
7-{5-[4-(6-Ethyl-pyridin-2-yl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-[1,-
8]naphthyridin-2-one
[0996] An intermediate compound,
7-{5-[4-(6-Ethyl-pyridin-2-yl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1-
H-[1,8]naphthyridin-2-one, was produced as follows: To a solution
of K.sub.2CO.sub.3 (1.16 g, 8.38 mmol) in H.sub.2O (3 mL) was added
CH.sub.3CN (9 mL), 1-(6-ethyl-pyridin-2-yl)-piperazine (0.64 g,
3.36 mmol) and
7-(5-chloro-pent-1-enyl)-3,4-dihydro-1H-[1,8]naphthyridin-2-one
(0.70 g, 2.80 mmol) followed by a catalytic amount of KI (8 mg).
The mixture was stirred for 15 min and then heated in a microwave
(300 W) at 120.degree. C. for 150 min. After cooling to RT,
saturated NaHCO.sub.3 was added and the mixture was extracted with
EtOAC. The organic layer was washed with brine, dried over
MgSO.sub.4 and concentrated to give a yellow oil. Purification by
liquid chromatography (40M Biotage SiO.sub.2 column,
CH.sub.2Cl.sub.2 to 1% MeOH/CH.sub.2Cl.sub.2) gave the intermediate
compound (845 mg, 2.08 mmol, 74%). MS: APCI: M+1: 406.3 (Exact
Mass: 405.25).
[0997]
7-{5-[4-(6-Ethyl-pyridin-2-yl)-piperazin-1-yl]-pent-1-enyl}-3,4-di-
hydro-1H-[1,8]naphthyridin-2-one (0.515 g, 1.27 mmol) was
hydrogenated using 20% Pd/C in EtOH for 103 h. The reaction was
filtered and concentrated. Purification by liquid chromatography
(Biotage 12 SiO.sub.2 column, CH.sub.2Cl.sub.2 to 1%
MeOH/CH.sub.2Cl.sub.2) followed by recrystallization from Et.sub.2O
gave the title compound as a solid (50 mg, 0.012 mmol, 10%). MS:
APCI: M+1: 408.2 (Exact Mass: 407.27).
Example C18
Synthesis of
7-{5-[4-(6-Cyclopropyl-pyridin-2-yl)-piperazin-1-yl]-pentyl}-3,4-dihydro--
1H-[1,8]naphthyridin-2-one
[0998] An intermediate compound,
7-{5-[4-(6-Cyclopropyl-pyridin-2-yl)-piperazin-1-yl]-pent-1-enyl}-3,4-dih-
ydro-1H-[1,8]naphthyridin-2-one, was produced as follows: To a
solution of K.sub.2CO.sub.3 (1.16 g, 8.38 mmol) in H.sub.2O (6 mL)
was added CH.sub.3CN (9 mL),
1-(6-cyclopropyl-pyridin-2-yl)-piperazine (0.68 g, 3.35 mmol) and
7-(5-chloro-pent-1-enyl)-3,4-dihydro-1H-[1,8]naphthyridin-2-one
(0.70 g, 2.80 mmol). The mixture was stirred for 15 min and then
heated in a microwave (300 W) at 120.degree. C. for 150 min. After
cooling to RT, saturated NaHCO.sub.3 was added and the mixture was
extracted with EtOAC. The organic layer was washed with brine,
dried over MgSO.sub.4 and concentrated to give a yellow oil/foam.
Purification by liquid chromatography (40M Biotage SiO.sub.2
column, CH.sub.2Cl.sub.2 to 2% MeOH/CH.sub.2Cl.sub.2) gave the
intermediate compound as a yellow oil/foam (443 mg, 1.06 mmol,
38%). MS: APCI: M+1: 418.3 (Exact Mass: 417.25).
[0999]
7-{5-[4-(6-Cyclopropyl-pyridin-2-yl)-piperazin-1-yl]-pent-1-enyl}--
3,4-dihydro-1H-[1,8]naphthyridin-2-one (0.347 g, 0.831 mmol) was
hydrogenated using 20% Pd/C in THF for 15 h. The reaction was
filtered and concentrated. Recrystallization from hot CH.sub.3CN
gave the title compound as a white powder (288 mg, 0.686 mmol,
83%). MS: APCI: M+1: 420.3 (Exact Mass: 419.27).
Example C19
Synthesis of
7-{5-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1-
H-[1,8]naphthyridin-2-one
[1000] An intermediate compound,
7-{5-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihy-
dro-1H-[1,8]naphthyridin-2-one, was produced as follows: To a
solution of K.sub.2CO.sub.3 (1.16 g, 8.38 mmol) in H.sub.2O (3 mL)
was added CH.sub.3CN (9 mL),
1-(4,6-dimethyl-pyridin-2-yl)-piperazine (0.909 g, 3.34 mmol) and
7-(5-chloro-pent-1-enyl)-3,4-dihydro-1H-[1,8]naphthyridin-2-one
(0.70 g, 2.80 mmol) followed by a catalytic amount of KI (8 mg).
The mixture was stirred for 15 min and then heated in a microwave
(300 W) at 120.degree. C. for 150 min. After cooling to RT,
saturated NaHCO.sub.3 was added and the mixture was extracted with
EtOAC. The organic layer was washed with brine, dried over
MgSO.sub.4 and concentrated to give a yellow oil/foam. Purification
by liquid chromatography (40M Biotage SiO.sub.2 column, CHCl.sub.3
to 1% MeOH/CHCl.sub.3) gave the intermediate compound as a foam
(540 mg, 1.33 mmol, 48%). MS: APCI: M+1: 406.2 (Exact Mass:
405.25).
[1001]
7-{5-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-pent-1-enyl}-3-
,4-dihydro-1H-[1,8]naphthyridin-2-one (0.54 g, 1.33 mmol) was
hydrogenated using 20% Pd/C in EtOH for 58 h. The reaction was
filtered and concentrated. Purification by liquid chromatography
(Biotage 12 SiO.sub.2 column, CHCl.sub.3 to 1% MeOH/CHCl.sub.3)
followed by recrystallization from Et.sub.2O/hexanes gave the title
compound as an off-white solid (313 mg, 0.761 mmol, 57%). MS: APCI:
M+1: 408.2 (Exact Mass: 407.27).
Example C20
Synthesis of
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-1H-[1,8]naphthyridi-
n-2-one
[1002] A first intermediate compound,
7-Chloro-1H-[1,8]naphthyridin-2-one, was produced as follows: To a
stirred solution of lithium hexamethyldisilazane (26.3 mmol, 1.0 M
in THF) in THF (10 mL) at -78.degree. C. is added t-butyl acetate
(3.53 mL, 26.3 mmol) dropwise. The mixture is stirred at
-78.degree. C. for 30 min and
N-(6-chloro-3-formyl-pyridin-2-yl)-2,2-dimethyl-propionamide (3.00
g, 12.5 mmol) in THF (20 mL) is added dropwise. A yellow
precipitate forms and the mixture is stirred at -78.degree. C. for
30 minutes and warmed to room temperature over 3 hours. H.sub.2O
(10 mL) is added, the mixture stirred for 5 minutes and then
diluted with ethyl acetate (20 mL) and brine (10 mL). The organic
layer is separated, washed with brine (20 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The
compound is recrystallized from ethyl acetate and hexanes to yield
3-[6-chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydroxy-propi-
onic acid tert-butyl ester (3.52 g, 79%); mp 130-132.degree. C.,
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.25 (br s, 1H), 7.76 (d,
1H), 7.16 (d, 1H), 5.05-4.98 (m, 1H), 4.08 (d, 1H), 2.80 (dd, 1H),
2.70 (dd, 1H), 1.41 (s, 9H), 1.36 (s, 9H); MS ES+ 357.03
(M+H).sup.+.
[1003]
3-[6-Chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydrox-
y-propionic acid tert-butyl ester (15.43 g, 43.3 mmol) is dissolved
in dioxane (60 mL) and 3 N HCl (60 mL) is added. The mixture is
refluxed for 4 hours, cooled to room temperature, and poured over
ice. The resulting precipitate is filtered, washed with H.sub.2O
(2.times.20 mL) and dried to afford the first intermediate compound
(7.80 g, >99%); mp 258-259.degree. C., .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.38 (br s, 1H), 8.14 (d, 1H), 7.94 (d, 1H),
7.30 (d, 1H), 6.54 (d, 1H); MS ES+ 180.76 (M.sup.+) (Exact Mass:
180.01).
[1004] A second intermediate compound,
7-(5-Chloro-pent-1-enyl)-1H-[1,8]naphthyridin-2-one, was produced
as follows: 7-Chloro-1H-[1,8]naphthyridin-2-one (0.10 g, 0.56 mmol)
is dissolved in dioxane (4 mL) and Pd(Ph.sub.3P).sub.4 (19 mg, 0.02
mmol) is added. The solution is stirred for 5 minutes at room
temperature and 5-chloro-1-pentenylboronic acid (0.13 g, 0.84 mmol)
is added followed immediately by aqueous Na.sub.2CO.sub.3 (2 mL, 2
M). The mixture is heated at 100.degree. C. for 18 hours. The
mixture is cooled to RT, filtered through Celite and diluted with
ethyl acetate (10 mL). The organic layer is washed with brine (10
mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under
vacuum. The residue was purified by column chromatography (ethyl
acetate) to yield the second intermediate compound (45 mg, 33%); mp
125-127.degree. C., .sup.1H NMR (200 MHz, CDCl.sub.3) .delta. 9.35
(br s, 1H), 7.80 (d, 1H), 7.65 (d, 1H), 7.05 (d, 1H), 6.70 (dt,
1H), 6.60 (d, 1H), 6.55 (d, 1H), 3.60 (t, 2H), 2.60-2.40 (m, 2H),
2.10-1.90 (m, 2H), MS ES+ 248.79 (M.sup.+) (Exact Mass:
248.07).
[1005] A third intermediate compound,
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-1H-[1,8]naphth-
yridin-2-one, was produced as follows: Sodium iodide (2.18 g, 14.52
mmol) is added to a stirred solution of
7-(5-chloro-pent-1-enyl)-1H-[1,8]naphthyridin-2-one (1.8 g, 7.26
mmol) in CH.sub.3CN (40 mL). The mixture is refluxed for 1 hour and
cooled to room temperature. Triethylamine (2.20 g, 21.78 mmol) and
1-(2,3-Dichlorophenyl)piperazine monohydrochloride (2.91 g, 10.9
mmol) are added and the mixture is refluxed for 5 hours and cooled
to RT. The mixture is filtered and the solids are washed with ethyl
acetate (10 mL). The filtrate is diluted with ethyl acetate (20
mL), washed with saturated NH.sub.4Cl (20 mL), saturated
NaHCO.sub.3 (20 mL), water (20 mL), and brine (20 mL). The organic
layer is dried over Na.sub.2SO.sub.4, filtered and concentrated
under vacuum. The crude solid is purified by column chromatography
(triethylamine/CH.sub.2Cl.sub.2, 5:95) to yield the third
intermediate compound as an orange solid (700 mg, 22%). mp
176-178.degree. C. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.98
(s, 1H), 7.80 (d, 1H), 7.66 (d, 1H), 7.20-7.10 (m, 3H), 7.00-6.85
(m, 2H), 6.62 (d, 1H), 6.53 (d, 1H), 3.20-3.00 (m, 4H), 2.76-2.60
(m, 4H), 2.50 (t, 2H), 2.40-2.36 (m, 2H), 1.82-1.75 (m, 2H). MS ES+
443.06 (M.sup.+) (Exact mass: 442.13).
[1006]
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-1H-[1,8-
]naphthyridin-2-one (160 mg, 0.361 mmol) was hydrogenated using
Raney Nickel (0.2 g) in MeOH for 42 h. The reaction was filtered
and concentrated. Purification by liquid chromatography (5%
MeOH/CH.sub.2Cl.sub.2 with 1% NH.sub.4OH) gave the title compound
as a white foam (109 mg, 0.245 mmol, 68%), which was further
purified by HPLC to remove a small amount of over-reduced
side-product. MS: APCI: M-1: 443.1 (Exact Mass: 444.15).
Example D1
Synthesis of
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-4-methyl-1H-[1,8]na-
phthyridin-2-one
[1007] A first intermediate compound,
7-Chloro-4-methyl-1H-[1,8]naphthyridin-2-one, was produced as
follows: A solution of tert-butyl acetate (0.6 mL, 4.45 mmol) is
added dropwise to a solution of lithium bis(trimethylsilyl)amide
(1.0 M in THF, 4.2 mL, 4.2 mmol) in THF (5 mL) at -78.degree. C.
The yellow solution is stirred for 1 hour and
N-(3-acetyl-6-chloro-pyridin-2-yl)-2,2-dimethyl-propionamide (0.503
g, 1.97 mmol) in THF (5 mL) is added dropwise to the mixture. The
yellow suspension is stirred at -78.degree. C. for 30 minutes and
warmed to RT. The suspension clears to a yellow solution and the
mixture is stirred at room temperature for 1.5 hours. The mixture
is quenched with water and extracted with CH.sub.2Cl.sub.2. The
organic extracts are washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to a brown
liquid. The liquid is purified by column chromatography (2:1
hexanes/ethyl acetate) to afford
3-[6-chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydroxy-butyr-
ic acid tert-butyl ester (0.548 g, 75%) as a yellow oil. .sup.1H
NMR (CDCl.sub.3, 400 MHz): .delta. 10.40 (br s, 1H), 7.37 (d, 1H),
6.98 (d, 1H), 5.61 (s, 1H), 3.03 (d, 1H), 2.67 (d, 1H), 1.56 (s,
3H), 1.45 (s, 9H), 1.32 (s, 9H). MS ES: m/z=370.86, 372.56.
[1008] A light yellow solution of
3-[6-chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydroxy-butyr-
ic acid tert-butyl ester (0.473 g, 1.28 mmol) in 3N HCl (10 mL) and
dioxane (10 mL) is refluxed for 1 hour. The yellow mixture is
cooled to room temperature and extracted with Et.sub.2O. The
aqueous layer is separated and neutralized with Na.sub.2CO.sub.3. A
white solid separates out of solution and the solid is collected by
filtration to afford the first intermediate compound (0.232 g, 94%)
as a white solid. mp 238-239.degree. C. .sup.1H NMR (DMSO-d.sub.6,
400 MHz): 6 12.20 (brs, 1H), 8.14 (d, 1H), 7.31 (d, 1H), 6.45 (d,
1H), 2.39 (d, 3H). MS ES: m/z=194.74, 196.62.
[1009] A second intermediate compound,
2-Benzyloxy-7-chloro-4-methyl-[1,8]naphthyridine, was produced as
follows: A mixture of 7-chloro-4-methyl-1H-[1,8]naphthyridin-2-one
(0.208 g, 1.07 mmol), silver carbonate (0.176 g, 0.64 mmol), and
benzyl bromide (0.15 mL, 1.26 mmol) in toluene (5 mL) is heated at
70.degree. C. overnight. The grey suspension is filtered through
Celite and the yellow filtrate is concentrated under vacuum to a
yellow solid. The solid is purified by column chromatography (3:1
hexanes/ethyl acetate) to afford the second intermediate compound
(0.196 g, 64%) as an off-white solid. mp 150-151.degree. C. .sup.1H
NMR (CDCl.sub.3, 400 MHz): .delta. 8.19 (d, 1H), 7.53-7.48 (m, 2H),
7.43-7.34 (m, 4H), 6.92-6.90 (s, 1H), 5.61 (s, 2H), 2.67 (s, 3H).
MS ES: m/z=285.02, 287.03.
[1010] A third intermediate compound,
2-Benzyloxy-7-(4-benzyloxy-butoxy)-4-methyl-[1,8]naphthyridine, was
produced as follows: A mixture of 4-benzyloxy-1-butanol (1.40 mL,
7.96 mmol) in THF (20 mL) is treated with potassium tert-butoxide
(0.892 g, 7.95 mmol). The yellow solution is stirred for 15 minutes
at RT. 2-Benzyloxy-7-chloro-4-methyl-[1,8]naphthyridine (1.84 g,
6.46 mmol) in THF (20 mL) is added to the mixture at -40.degree. C.
The dark red/brown mixture is warmed to room temperature and
stirred for 10 minutes. The mixture is quenched with saturated
NaHCO.sub.3 solution (20 mL) and extracted with ethyl acetate
(3.times.30 mL). The organic extracts are washed with brine (30
mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo to a brown residue. The residue is purified by column
chromatography (5:1 hexanes/ethyl acetate) to afford the third
intermediate compound (1.146 g, 41%) as a yellow liquid. .sup.1H
NMR (CDCl.sub.3, 400 MHz): .delta. 8.08 (d, 1H), 7.54-7.48 (m, 2H),
7.42-7.26 (m, 8H), 6.84 (d, 1H), 6.75 (s, 1H), 5.60 (s, 2H), 4.59
(t, 2H), 4.54 (s, 2H), 3.58 (t, 2H), 2.58 (s, 3H), 2.00-1.90 (m,
2H), 1.90-1.80 (m, 2H). MS ES: m/z=428.92 (MH.sup.+).
[1011] A fourth intermediate compound,
7-(4-Hydroxy-butoxy)-4-methyl-1H-[1,8]naphthyridin-2-one, was
produced as follows: Hydrogen gas (35 psi) is applied to a mixture
of 2-benzyloxy-7-(4-benzyloxy-butoxy)-4-methyl-[1,8]naphthyridine
(1.188 g, 2.77 mmol), 10% Pd/C (wet, 0.364 g) and methanol (160 mL)
in a Parr bottle under agitation for 4.5 hours. The catalyst is
filtered through a pad of Celite and the pad is rinsed with
methanol. The filtrate is concentrated under vacuum to afford the
fourth intermediate compound (0.580 g, 84%) as a white solid. mp
172-173.degree. C. .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta.
11.79 (br s, 1H), 8.02 (d, 1H), 6.65 (d, 1H), 6.25 (s, 1H), 4.47
(t, 1H), 4.33 (t, 2H), 3.45 (q, 2H), 2.36 (s, 3H), 1.82-1.72 (m,
2H), 1.60-1.50 (m, 2H).
[1012] Alternatively, a mixture of 1,4-butanediol (0.177 g, 1.96
mmol) in THF (2 mL) is placed in a sealed glass pressure tube. The
mixture is treated with potassium tert-butoxide (0.252 g, 2.25
mmol) and the cloudy white suspension is stirred at room
temperature for 15 minutes. The suspension is treated with
7-chloro-4-methyl-1H-[1,8]naphthyridin-2-one (0.100 g, 0.51 mmol)
in THF (2 mL). The pressure tube is sealed and heated at
100.degree. C. for 16 hours. The mixture is cooled to room
temperature and diluted with saturated NaHCO.sub.3 solution (10 mL)
and extracted with CH.sub.2Cl.sub.2 (2.times.30 mL). The organic
extracts are washed with brine (20 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under vacuum to a white
residue. The residue is purified by column chromatography (5:95
methanol/chloroform) to afford the fourth intermediate compound
(0.081 g, 63%) as a white solid. mp 172-173.degree. C. .sup.1H NMR
(DMSO-d.sub.6, 400 MHz): .delta. 11.79 (br s, 1H), 8.02 (d, 1H),
6.65 (d, 1H), 6.25 (s, 1H), 4.47 (t, 1H), 4.33 (t, 2H), 3.45 (q,
2H), 2.36 (s, 3H), 1.82-1.72 (m, 2H), 1.60-1.50 (m, 2H). MS ES:
m/z=248.90 (MH.sup.+).
[1013] A fifth intermediate compound,
4-(5-Methyl-7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde,
was produced as follows: A mixture of Dess-Martin periodinane
(1.764 g, 4.16 mmol) in CH.sub.2Cl.sub.2 (30 mL) is treated with
7-(4-hydroxy-butoxy)-4-methyl-1H-[1,8]naphthyridin-2-one (0.798 g,
3.21 mmol) in THF (10 mL) at RT. The slightly cloudy yellow
solution is stirred for 2 hours, diluted with Et.sub.2O and poured
into a solution of aqueous saturated NaHCO.sub.3 solution (20 mL)
containing sodium thiosulfate (3.8 g, 24.0 mmol). The immiscible
solution is stirred for 5 minutes and the organic layer is
separated out. The aqueous layer is extracted with Et.sub.2O. The
combined organic extracts are washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under vacuum to a white
solid. The crude aldehyde is used directly in the next step without
purification.
[1014] The crude
4-(5-methyl-7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
from the previous reaction in 1,2-dichloroethane (30 mL) is treated
with 1-(2,3-dichlorophenyl)piperazine monohydrochloride (1.144 g,
4.20 mmol), followed by triethylamine (0.90 mL, 6.46 mmol) and
sodium triacetoxyborohydride (0.955 g, 4.50 mmol). The cloudy
yellow solution is stirred at room temperature for 1 hour. The
mixture is quenched with H.sub.2O and saturated NaHCO.sub.3
solution and extracted with CH.sub.2Cl.sub.2. The organic extracts
are washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated under vacuum to a yellow oil. The oil is purified by
column chromatography (5:95 methanol/ethyl acetate) to afford the
title compound (0.97 g, 63% over 2 steps) as a white solid. mp
181-182.degree. C. .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 7.57
(br s, 1H), 7.40 (d, 1H), 7.18-7.12 (m, 2H), 7.00-6.94 (m, 1H),
6.38 (d, 1H), 4.23 (t, 2H), 3.16-3.00 (m, 5H), 2.77-2.68 (m, 4H),
2.75-2.56 (m, 1H), 2.52-2.36 (m, 3H), 1.86-1.75 (m, 2H), 1.75-1.64
(m, 2H), 1.28 (d, 3H). MS ES: m/z=460.70, 462.58.
Example D2a and D2b
Synthesis of
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-4-methyl-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one
[1015] A First intermediate compound,
7-(4-Hydroxy-butoxy)-4-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one,
was produced as follows: Hydrogen gas (40 psi) is applied to a
mixture of 7-(4-hydroxy-butoxy)-4-methyl-1H-[1,8]naphthyridin-2-one
(0.640 g, 2.58 mmol), 10% Pd/C (wet, 0.310 g) and methanol (160 mL)
in a Parr bottle under agitation overnight. The catalyst is
filtered through a pad of Celite and the pad is rinsed with
methanol. The filtrate is concentrated under vacuum to a colorless
semi-solid. The semi-solid is purified by column chromatography
(5:95 methanol/chloroform) to afford the first intermediate
compound (0.510 g, 79%) as a white solid. Mp 99-100C. .sup.1H NMR
(CDCl.sub.3, 400 MHz): .delta. 7.60 (br s, 1H), 7.40 (d, 1H), 6.39
(d, 1H), 4.24 (t, 2H), 3.77-3.68 (m, 2H), 3.11-3.00 (m, 2H),
2.77-2.68 (m, 2H), 2.46-2.37 (m, 2H), 1.50 (br s, 1H), 1.24 (d,
3H). MS ES: m/z=250.89 (MH.sup.+).
[1016] A second intermediate compound,
4-(5-Methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyralde-
hyde, was produced as follows: A mixture of Dess-Martin periodinane
(1.511 g, 3.56 mmol) in CH.sub.2Cl.sub.2 (30 mL) is treated with
7-(4-hydroxy-butoxy)-4-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one
(0.742 g, 2.96 mmol) in THF (10 mL) at RT. The slightly cloudy
yellow solution is stirred for 2 hours, diluted with Et.sub.2O and
poured into a solution of aqueous saturated NaHCO.sub.3 (20 mL)
containing sodium thiosulfate (3.5 g, 21.1 mmol). The immiscible
solution is stirred for 5 minutes and the organic layer is
separated out. The aqueous layer is extracted with Et.sub.2O. The
combined organic extracts are washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under vacuum to a
yellow solid. The crude aldehyde is used directly in the next step
without purification.
[1017] The crude
4-(5-methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyralde-
hyde in 1,2-dichloroethane (50 mL) is treated with
1-(2,3-dichlorophenyl)piperazine monohydrochloride (1.104 g, 4.13
mmol), followed by triethylamine (0.80 mL, 5.69 mmol) and sodium
triacetoxyborohydride (0.911 g, 4.30 mmol). The cloudy yellow
solution is stirred at room temperature for 1 hour. The mixture is
quenched with water and saturated NaHCO.sub.3 solution and
extracted with CH.sub.2Cl.sub.2. The organic extracts are washed
with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated
under vacuum to a yellow oil. The oil is purified by column
chromatography (5:95 methanol/ethyl acetate) to afford the title
compound (1.08 g, 79% over 2 steps) as a white solid. Mp
53-54.degree. C. .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 8.94
(br s, 1H), 7.83 (d, 1H), 7.18-7.13 (m, 2H), 6.98-6.94 (m, 1H),
6.62 (d, 1H), 6.38 (d, 1H), 4.38 (t, 2H), 3.16-3.02 (m, 4H),
2.76-2.60 (m, 4H), 2.55-2.46 (m, 2H), 1.90-1.82 (m, 2H), 1.77-1.64
(m, 2H). MS ES: m/Z=462.72, 464.58.
[1018] The enantiomers were separated by chiral HPLC (Chiralcel OD)
to give the enantiomers D2a and D2b.
Example D3
Synthesis of
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-4-methyl-1H-[1,8]na-
phthyridin-2-one
[1019] A first intermediate compound,
7-(5-Chloro-pent-1-enyl)-4-methyl-1H-[1,8]naphthyridin-2-one, was
produced as follows: To a solution of
7-chloro-4-methyl-1H-[1,8]naphthyridin-2-one (1.01 g, 5.20 mmol) in
dioxane was added Pd(PPh.sub.3).sub.4 (234 mg, 0.20 mmol) followed
by 5-chloro-1-pentenyl boronic acid (1.21 g, 8.10 mmol).
Na.sub.2CO.sub.3 (1.21 g, 11.40 mmol) and water (2 mL) were added
and the resulting mixture was refluxed overnight. The orange
heterogeneous mixture was cooled to room temperature and some
crystals precipitated out of solution. The mixture was filtered and
the filtrate was partitioned between EtOAc and water. The organic
layer was dried over Na.sub.2SO.sub.4 and concentrated to give a
yellow solid. Recrystallization from EtOAc/Hexanes afforded the
first intermediate compound as a golden solid (815 mg, 60%). mp
137-138.degree. C.; .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 9.00
(br s, 1H), 7.88 (d, 1H), 7.13 (d, 1H), 6.94-6.82 (m, 1H),
6.58-6.46 (m, 2H), 3.61 (t, 2H), 2.52-2.42 (m, 2H), 2.45 (d, 3H),
2.06-1.98 (m, 2H); MS ES: m/z=263.02, 265.00.
[1020] A second intermediate compound,
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-4-methyl-1H-[1-
,8]naphthyridin-2-one, was produced as follows: A mixture of
7-(5-chloro-pent-1-enyl)-4-methyl-1H-[1,8]naphthyridin-2-one (500
mg, 1.90 mmol) and KI (316 mg, 1.90 mmol) was refluxed for 30 min.
The mixture was cooled to room temperature and then treated with
1-(2,3-dichlorophenyl)piperazine monohydrochloride (630 mg, 2.40
mmol) followed by K.sub.2CO.sub.3 (611 mg, 4.40 mmol). The yellow
suspension was refluxed for 2 d and then quenched with water. The
mixture was extracted with EtOAc. The organic layer was washed with
brine, dried over Na.sub.2SO.sub.4 and concentrated to give a
yellow oil. Purification by column chromatography (5% MeOH/EtOAc)
afforded the second intermediate compound as a yellow solid (371
mg, 42%). mp 198-199.degree. C.; .sup.1H NMR (CDCl.sub.3, 400 MHz):
.delta. 9.03 (brs, 1H), 7.84 (d, 1H), 7.18-7.12 (m, 3H), 7.00-6.92
(m, 2H), 6.59-6.46 (m, 2H), 3.16-3.02 (m, 4H), 2.74-2.60 (m, 4H),
2.54-2.47 (m, 2H), 2,45 (d, 3H), 2.40-2.32 (m, 2H), 1.83-1.72 (m,
2H); MS ES: m/z=457.40, 459.35.
[1021]
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-4-methy-
l-1H-[1,8]naphthyridin-2-one (880 mg, 1.92 mmol) was dissolved in
THF (50 mL) and added to a Parr bottle containing a suspension of
Raney-Nickel (1.5 mL of a settled suspension in water) in EtOH (50
mL). The mixture was hydrogenated at 45 psi for 5.5 h. The reaction
was not complete so additional Raney-Nickel (1 mL of a suspension
in water) was added and the mixture was hydrogenated at 45 psi for
2.5 h. The reaction mixture was filtered through a bed of Celite
and washed with EtOH. The filtrate was concentrated to give a white
solid. Purification by column chromatography (10% MeOH/EtOAc)
afforded the title compound as a white solid (780 mg, 88%). mp
195-196.degree. C.; .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 9.16
(br s, 1H), 7.88 (d, 1H), 7.18-7.12 (m, 2H), 7.06 (d, 1H),
7.00-6.92 (m, 1H), 6.50 (s, 1H), 3.14-3.00 (m, 4H), 2.85 (t, 2H),
2.72-2.54 (m, 4H), 2.46 (d, 3H), 2.42 (t, 2H), 1.85-1.72 (m, 2H),
1.64-1.52 (m, 2H), 1.48-1.36 (m, 2H); MS ES: m/z=459.08,
461.03.
Example D4
Synthesis of
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3-methyl-1H-[1,8]na-
phthyridin-2-one
[1022] A first intermediate compound,
7-Chloro-3-methyl-1H-[1,8]naphthyridin-2-one, was produced as
follows: Diisopropyl amine (freshly distilled over sodium, 12.8 mL,
91.4 mmol, 2.2 equiv.) was dissolved in Et.sub.2O (40 mL) and
cooled to -78.degree. C. Butyl lithium (2.5 M solution in hexane,
37.0 mL, 91.4 mmol, 2.2 equiv.) was added slowly under nitrogen
atmosphere. The mixture was stirred for 15 min and t-butyl
propionate (13.8 mL, 91.4 mmol, 2.2 equiv.) was added as a solution
in dry THF (20 mL). The reaction mixture was stirred for 30 min and
N-(6-chloro-3-formyl-pyridin-2-yl)-2,2-dimethyl-propionamide (10.0
g, 42.0 mmol, 1.0 equiv.) was added as a solution in a minimum
amount of dry THF (35 mL). A bright yellow precipitate was formed
within 10 min and stirring became difficult. The reaction was
allowed to warm up to RT. The reaction mixture turned dark red and
was poured into saturated NH.sub.4Cl (100 mL). The organic layer
was separated and the aqueous layer was extracted with
CH.sub.2Cl.sub.2. The combined organic layers were dried over
Na.sub.2SO.sub.4 and concentrated.
3-[6-Chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydroxy-2-met-
hyl-propionic acid tert-butyl ester was obtained as a yellow thick
syrup which upon drying under high vacuum became a foamy solid
(20.0 g, crude). The product was used in the next step without
further purification.
[1023]
3-[6-Chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydrox-
y-2-methyl-propionic acid tert-butyl ester (20.0 g) was dissolved
in dioxane (100 mL) and 3N HCl (100 mL) was added. The mixture was
stirred under reflux conditions. After 30 min, more dioxane (15 mL)
was added as there was some precipitation in the reaction mixture
and the resultant clear solution was refluxed overnight. The
reaction mixture was cooled in a cold water bath, diluted with 20
mL water and neutralized with saturated K.sub.2CO.sub.3 (80 mL). A
pale yellow precipitate was formed which was separated by
filtration. The precipitate was washed thoroughly with water and
dried under vacuum to give the first intermediate compound as a
pale yellow shiny solid (7.43 g, 38.18 mmol, 93% over 2 steps). mp
259-261.degree. C.; MS: ES+ 194.78, 196.64 (Exact Mass:
194.02).
[1024] A second intermediate compound,
2-Benzyloxy-7-chloro-3-methyl-[1,8]naphthyridine, was produced as
follows: To a mixture of
7-chloro-3-methyl-1H-[1,8]naphthyridin-2-one (0.30 g, 1.54 mmol,
1.0 equiv) and silver carbonate (0.30 g, 1.08 mmol, 0.7 equiv) in
toluene (10 mL) was added benzyl bromide (257 .mu.L, 2.156 mmol,
1.4 equiv). The reaction was stirred at 60.degree. C. overnight.
TLC (50% EtOAc in hexanes) indicated the completion of the
reaction. The reaction mixture was filtered through Celite and
rinsed thoroughly with toluene and CH.sub.2Cl.sub.2. The combined
filtrates were concentrated under reduced pressure and hexane
(20-30 mL) was added to the residue. A white precipitate formed
which was collected by filtration and washed with hexane until all
the yellow color was washed out. The second intermediate compound
was obtained as a white solid (0.24 g, 56%). m.p. 133.degree. C.;
MS: ES+ 284.90, 286.56 (Exact Mass: 284.07).
[1025] A third intermediate compound,
2-Benzyloxy-7-(4-benzyloxy-butoxy)-3-methyl-[1,8]naphthyridine, was
produced ad follows: To a solution of 4-benzyloxy-1-butanol (0.254
g, 1.4 mmol, 2.0 equiv) in anhydrous THF (5.0 mL) cooled to
-40.degree. C. was added potassium tert-butoxide (0.158 g, 1.4
mmol, 2.0 equiv) and the mixture was stirred for 10 min. A solution
of 2-benzyloxy-7-chloro-3-methyl-[1,8]naphthyridine (0.20 g, 0.70
mmol, 1.0 equiv) in anhydrous THF (5.0 mL) was added and the
reaction mixture was allowed to warm to RT. The reaction mixture
was stirred for 10 min at room temperature and quenched with water
(5.0 mL). The organic phase was separated and the aqueous phase was
extracted with ethyl acetate (2.times.10 mL). The combined organic
extracts were dried over Na.sub.2SO.sub.4 and concentrated in vacuo
to give a yellow oily residue which was purified by column
chromatography (silica gel, hexane:EtOAc, 8:1) to afford the third
intermediate compound as a pale yellow oil (0.160 g, 55%). MS: ES+
428.98 (Exact Mass: 428.21).
[1026] A fourth intermediate compound,
7-(4-Hydroxy-butoxy)-3-methyl-1H-[1,8]naphthyridin-2-one, was
produced as follows: To a solution of
2-benzyloxy-7-(4-benzyloxy-butoxy)-3-methyl-[1,8]naphthyridine (1.0
g, 4.2 mmol) in methanol (200 mL) and THF (20 mL) was added 5% Pd/C
(0.3 g) and the mixture was hydrogenated at 35 psi for 4 hours. The
slurry was filtered through a pad of Celite, rinsed with methanol
and the filtrate was concentrated in vacuo to provide the fourth
intermediate compound as a white solid (0.58 g, 98%). .sup.1H NMR
was very clean so the product was used in the next step without
further purification. MS: ES+ 249.03 (Exact Mass: 248.12).
[1027] A fifth intermediate compound,
4-(6-Methyl-7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyd,
was produced as follows: A mixture of pyridinium chlorochromate
(PCC) (1.195 g, 5.5 mmol, 2.5 equiv) and neutral alumina (4.2 g,
3.5 g/ 1.0 g of PCC) in anhydrous CH.sub.2Cl.sub.2 (20 mL) was
stirred for 30 min at RT. A solution of
7-(4-hydroxy-butoxy)-3-methyl-1H-[1,8]naphthyridin-2-one (0.55 g,
2.22 mmol, 1.0 equiv) in CH.sub.2Cl.sub.2 (20 mL) and THF (5 mL)
was added to the reaction mixture and stirred for 2 h. The reaction
mixture was filtered through a pad of silica and rinsed with
CH.sub.2Cl.sub.2 and then 5% MeOH/CH.sub.2Cl.sub.2. The combined
filtrates were concentrated in vacuo to give the fifth intermediate
compound as a dark brown oil (0.65 g) which was used without
purification in the next reaction.
[1028] To a solution of crude
4-(6-methyl-7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
(0.65 g, 2.24 mmol, 1.0 equiv) in anhydrous methanol (40 mL) cooled
to 0.degree. C. was added 2,3-dichlorophenylpiperazine (1.2 g, 4.0
mmol, 2.0 equiv). The mixture was stirred for 5 min and
NaBH(OAc).sub.3 (2.3 g, 11.2 mmol, 5.0 equiv) was added. The
reaction mixture was brought to room temperature and stirred
overnight. The reaction was quenched with water and was
concentrated to remove methanol completely. The resultant pale
green residue was dissolved in ethyl acetate and washed with 0.5 N
HCl (1.times.10 mL), saturated NaHCO.sub.3 solution (1.times.10 mL)
and brine. The organic layer was dried over Na.sub.2SO.sub.4 and
concentrated. The residue was purified by column chromatography
(silica gel, 2% MeOH/CH.sub.2Cl.sub.2) to afford the title compound
as a white foamy solid (0.2 g, 30%). MS: ES+ 461.03, 463.03 (Exact
Mass: 460.14).
Example D5
Synthesis of
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-3-methyl-1H-[1,8]na-
phthyridin-2-one
[1029] A first intermediate compound,
7-(5-Chloro-pent-1-enyl)-3-methyl-1H-[1,8]naphthyridin-2-one, was
produced as follows: To a solution of compound
7-chloro-3-methyl-1H-[1,8]naphthyridin-2-one (0.75 g, 4.11 mmol,
1.0 equiv) in anhydrous dioxane (60 mL) were added
5-chloro-1-pentenylboronic acid (0.92 g, 6.17 mmol, 1.5 equiv),
K.sub.2CO.sub.3 (5.70 g, 41.1 mmol, 10.0 equiv) followed by
Pd(PPh.sub.3).sub.4 (0.19 g, 0.16 mmol, 0.04 equiv). The mixture
was refluxed for 48 h, cooled and filtered through a small celite
bed. The filtrate was concentrated to give a pale yellow residue.
Purification by column chromatography on silica gel
(EtOAc:Hexanes:MeOH, 1:1:0.2) gave the first intermediate compound
as a pale yellow solid (0.70 g, 79%). mp: 128-129.degree. C.;
.sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 9.22 (br s, 1H), 7.75
(d, 1H), 7.50 (s, 1H), 7.10 (d, 1H), 6.90-6.80 (m, 1H), 6.55 (dd,
1H), 3.60 (t, 2H), 2.55-2.45 (m, 2H), 2.25 (s, 3H), 2.10-1.90 (m,
2H); MS: ES+: 263.05 (M+H).sup.+, 265.06, (Exact mass: 262.09)
[1030] A second intermediate compound,
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3-methyl-1H-[1-
,8]naphthyridin-2-one, was produced as follows: KI (0.30 g, 1.79
mmol, 1.0 equiv) was added to a stirred solution of
7-(5-chloro-pent-1-enyl)-3-methyl-1H-[1,8]naphthyridin-2-one (0.47
g, 1.79 mmol, 1.0 equiv) in CH.sub.3CN (25 mL) and stirred for 1 h.
Triethylamine (1 mL), 1-(2,3-dichlorophenyl)piperazine
monohydrochloride (0.47 g, 1.79 mmol, 1.0 equiv) and
K.sub.2CO.sub.3 (1.0 g, 7.16 mmol, 4.0 equiv) were added and the
mixture was refluxed for 48 h. The reaction mixture was cooled to
room temperature and filtered. The solids were washed with EtOAc (5
mL). The filtrate was diluted with EtOAc (20 mL) and washed with
water (20 mL), saturated NaHCO.sub.3 (10 mL) and brine. The organic
layer was dried over Na.sub.2SO.sub.4 and concentrated.
Purification of the residue by column chromatography on silica
(EtOAc:Hexanes:MeOH, 4:4:0.5 to 1:1:0.5) gave the second
intermediate compound as a pale yellow solid (0.28 g, 34%). mp:
82-84.degree. C.; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.40
(br s, 1H), 7.75 (d, 1H), 7.55 (s, 1H), 7.20-7.10 (m, 3H),
6.90-6.88 (m, 2H), 6.50 (dd, 1H), 3.10 (br s, 4H), 2.75 (br s, 4H),
2.52-2.50 (m, 2H), 2.32-2.28 (m, 2H), 2.20 (s, 3H), 1.72-1.68 (m,
2H); MS: ES+: 457.01 (M+H).sup.+, 459.00. (Exact mass: 456.15).
[1031] A solution of
7-{5-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3-methyl-1H-[1-
,8]naphthyridin-2-one (0.43 g, 0.94 mmol) in THF was added to a
slurry of Raney Ni in EtOH. The mixture was hydrogentated for 4 h
at 40 psi. The reaction mixture was filtered through a small celite
bed and rinsed with CH.sub.2Cl.sub.2 and mMeOH. The filtrate was
concentrated and purified by column chromatography on silica (10%
MeOH/EtOAc) to afford the title compound as a pale yellow solid
(0.22 g, 51.4%). mp: 157-158.degree. C.; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 9.00 (br s, 1H), 7.75 (d, 1H), 7.50 (s, 1H),
7.15 (m, 2H), 7.00-6.90 (m, 2H), 3.10 (br s, 4H), 2.80 (t, 2H),
2.60 (br s, 4H), 2.42-2.38 (m, 2H), 2.20 (s, 3H), 1.82-1.80 (m,
2H), 1.70-1.60 (m, 4H); MS: ES+: 459.01 (M+H).sup.+, 460.97 (Exact
mass: 458.16).
Example D6a and D6b
Synthesis of
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3-methyl-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one
[1032] A first intermediate compound,
7-(4-Hydroxy-butoxy)-3-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one,
was produced as follows: A mixture of
2-benzyloxy-7-(4-benzyloxy-butoxy)-3-methyl-[1,8]naphthyridine (1.8
g, 4.2 mmol) and 5% Pd/C (0.5 g) in methanol (250 mL) was
hydrogenated overnight at 35 psi. The slurry was filtered through a
pad of Celite washing with methanol and the filtrate was
concentrated in vacuo to provide a mixture of
7-(4-hydroxy-butoxy)-3-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one
and 7-(4-hydroxy-butoxy)-3-methyl-1H-[1,8]naphthyridin-2-one as a
colorless viscous material (0.9 g). The products were separated by
column chromatography (silica gel, 5% methanol/CH.sub.2Cl.sub.2) to
afford the first intermediate compound (0.45 g, 1.80 mmol, 43%) as
a viscous material and
7-(4-hydroxy-butoxy)-3-methyl-1H-[1,8]naphthyridin-2-one (0.28 g)
as a white powder. The combined yield was 73%. MS: ES+ 251.15
(Exact Mass: 250.13).
[1033] A second intermediate compound,
4-(6-Methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyralde-
hyde, was produced as follows: A mixture of pyridinium
chlorochromate (PCC) (0.13 g, 0.6 mmol, 2.5 equiv) and neutral
alumina (0.45 g, 3.5 g/ 1.0 g of PCC) in anhydrous CH.sub.2Cl.sub.2
(5.0 mL) was stirred for 30 min at RT. A solution of
7-(4-hydroxy-butoxy)-3-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one
(0.06 g, 0.24 mmol, 1.0 equiv) in CH.sub.2Cl.sub.2 (5.0 mL) and THF
(2.0 mL) was added to the reaction mixture and stirred for 2.0 h.
The reaction mixture was filtered through a pad of silica and
rinsed with CH.sub.2Cl.sub.2. The combined filtrates were
concentrated in vacuo to give the second intermediate compound as a
pale yellow oil. The crude (0.05 g) was used in the next step
without purification.
[1034] To a solution of crude
4-(6-methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyralde-
hyde (0.5 g, 2.0 mmol, 1.0 equiv) in anhydrous methanol (40 mL)
cooled to 0.degree. C. was added 2,3-dichlorophenylpiperazine (1.1
g, 4.0 mmol, 2.0 equiv). The mixture was stirred for 5 min and
NaBH(OAc).sub.3 (2.14 g, 10.0 mmol, 5.0 equiv) was added. The
reaction mixture was brought to room temperature and stirred
overnight. TLC indicated a trace amount of aldehyde was still left.
More NaBH(OAc).sub.3 was added and stirring continued for one more
hour. TLC indicated the reaction was complete. The reaction mixture
was concentrated to dryness. The resultant pale green residue was
dissolved in ethyl acetate and washed with 0.5 N HCl (1.times.10
mL), saturated NaHCO.sub.3 solution (1.times.10 mL) and brine. The
organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The
residue was purified by column chromatography (silica gel, 2%
MeOH/CH.sub.2Cl.sub.2) to afford the title compound as a colorless
viscous material (0.63 g, 75% over 2 steps). The enantiomers were
separated by chiral HPLC (Chiralpak AD, 40:60Hexane/EtOH) to give
the enantiomers D6a and D6b. MS: APCI: M+1: 463.1 (Exact Mass:
462.16).
Example D7
Synthesis of
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dimethyl-1H-[1,-
8]naphthyridin-2-one
[1035] A first intermediate compound,
7-Chloro-3,4-dimethyl-1H-[1,8]naphthyridin-2-one, was produced as
follows: To a stirred solution of diisopropylamine (0.60 g, 0.83
mL, 5.9 mmol) in Et.sub.2O (15 mL) at -78.degree. C. is added
n-butyl lithium (2.4 mL, 2.5 M in hexanes, 5.9 mmol). The mixture
is stirred at -78.degree. C. for 30 minutes and t-butyl propionate
(0.77 g, 0.89 mL, 5.9 mmol) is added dropwise. The mixture is
stirred at -78.degree. C. for 30 minutes and
N-(3-acetyl-6-chloro-pyridin-2-yl)-2,2-dimethyl-propionamide (0.50
g, 1.9 mmol) in Et.sub.2O (3 mL) is added dropwise. A yellow
precipitate forms and the mixture is stirred at -78.degree. C. for
30 minutes and warmed to room temperature over 3 hours. Water (10
mL) is added, the mixture stirred for 5 minutes and then diluted
with ethyl acetate (20 mL) and brine (10 mL). The organic layer is
separated, washed with brine (2.times.20 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The crude
oil is recrystallized from hexanes to yield
3-[6-chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydroxy-2-met-
hyl-butyric acid tert-butyl ester (0.48 g, 64%). mp 146-148.degree.
C., .sup.1H NMR (200 MHz, CDCl.sub.3) .delta. 10.50 (br s, 1H),
7.50 (d, 1H), 6.95 (d, 1H), 5.30 (s, 1H), 3.10 (q, 1H), 1.48 (s,
3H), 1.45 (s, 9H), 1.30 (s, 9H), 1.22 (d, 3H), MS ES+ 384.82
(M.sup.+).
[1036] Aqueous 3 N HCl (20 mL) is added to
3-[6-chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydroxy-2-met-
hyl-butyric acid tert-butyl ester (4.5 g, 15.8 mmol) in dioxane (20
mL). The mixture is refluxed for4 hours, cooled to RT, and poured
over ice. The resulting precipitate is filtered, washed with water
(2.times.20 mL) and dried to afford the first intermediate compound
(2.4 g, 96%). mp 239-241.degree. C., .sup.1H NMR (200 MHz,
CDCl.sub.3) .delta. 10.0 (br s, 1H), 7.95 (d, 1H), 7.20 (d, 1H),
2.45 (s, 3H), 2.30 (s, 3H), MS ES+ 208.99 (M+H).sup.+ (Exact Mass:
208.04).
[1037] A second intermediate compound,
2-Benzyloxy-7-chloro-3,4-dimethyl-[1,8]naphthyridine, was produced
as follows: 7-Chloro-3,4-dimethyl-1H-[1,8]naphthyridin-2-one (0.20
g, 0.96 mmol) in toluene (10 mL) is treated with silver carbonate
(0.20 g, 0.73 mmol) followed by benzyl bromide (0.25 g, 0.17 mL,
1.4 mmol). The mixture is stirred at 60.degree. C. for 16 hours.
The mixture is cooled to RT, filtered and concentrated under
vacuum. The crude oil is recrystallized from hexanes to give the
second intermediate compound (87 mg, 30%). mp 140-141.degree. C.,
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.20 (d, 1H), 7.55 (d,
1H), 7.42-7.30 (m, 5H), 5.62 (s, 2H), 2.58 (s, 3H), 2.40 (s, 3H),
MS ES+ 299.04 (M+H).sup.+ (Exact Mass: 298.09).
[1038] A third intermediate compound,
2-Benzyloxy-7-(4-benzyloxy-butoxy)-3,4-dimethyl-[1,8]naphthyridine,
was produced as follows: To a stirred solution of
4-benzyloxy-1-butanol (500 mg, 0.49 mL, 2.77 mmol) in THF (6 mL) at
-45.degree. C. is added potassium tert-butoxide (311 mg, 2.77
mmol). The mixture is stirred at -45.degree. C. for 10 minutes and
then 2-benzyloxy-7-chloro-3,4-dimethyl-[1,8]naphthyridine (661 mg,
2.31 mmol) in THF (5 mL) is added. The solution turns a reddish
color and is allowed to warm to room temperature over 2 hours.
Saturated NH.sub.4Cl (3 mL) is added and the solution is diluted
with ethyl acetate (20 mL) and washed with water (20 mL), brine (20
mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under
vacuum. The crude oil is purified by column chromatography (2:1
hexane/Et.sub.2O) to afford the third intermediate compound (580
mg, 57%) as a clear oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.10 (d, 1H), 7.55-7.50 (m, 2H), 7.40-7.20 (m, 8H), 6.80 (d, 1H),
5.60 (s, 2H), 4.56 (t, 2H), 4.54 (s, 2H), 3.58 (t, 2H), 2.55 (s,
3H), 2.30 (s, 3H), 2.00-1.80 (m, 4H), MS ES+ 442.93 (M.sup.+)
(Exact Mass: 442.23).
[1039] A fourth intermediate compound,
7-(4-Hydroxy-butoxy)-3,4-dimethyl-1H-[1,8]naphthyridin-2-one, was
produced as follows: To a solution of
2-benzyloxy-7-(4-benzyloxy-butoxy)-3,4-dimethyl-[1,8]naphthyridine
(500 mg, 1.1 mmol) in MeOH (20 mL) is added 10% Pd/C (200 mg) and
the mixture is shaken under 45 psi H.sub.2 for 3 hours. The mixture
is then filtered through Celite and concentrated under vacuum to
yield the fourth intermediate compound (272 mg, 92%) as a white
solid. mp 172-174.degree. C., .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 11.80 (s, 1H), 8.02 (d, 1H), 6.61 (d, 1H), 4.42 (t, 1H),
4.34 (t, 2H), 3.45 (t, 2H), 2.34 (s, 3H), 2.04 (s, 3H), 1.80-1.70
(m, 2H), 1.60-1.55 (m, 2H), MS ES+ 263.06 (M+H).sup.+ (Exact Mass:
262.13).
[1040] A fifth intermediate compound,
4-(5,6-Dimethyl-7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyd-
e, was produced as follows: To a stirred solution of Dess-Martin
periodinane (178 mg, 0.42 mmol) in CH.sub.2Cl.sub.2 (10 mL) at room
temperature is added
7-(4-hydroxy-butoxy)-3,4-dimethyl-1H-[1,8]naphthyridin-2-one (100
mg, 0.38 mmol) in THF (6 mL). The resulting mixture is stirred for
1 hour and then Et.sub.2O (10 mL) is added. The resulting
suspension is poured into a mixture of saturated NaHCO.sub.3 (10
mL) and Na.sub.2S.sub.2O.sub.3 (464 mg, 2.94 mmol) and stirred for
10 minutes. The organic layer is separated, washed with saturated
NaHCO.sub.3 (10 mL) and brine (10 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated under vacuum. The crude aldehyde is used
without purification in the next step.
[1041] The crude
4-(5,6-dimethyl-7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyd-
e (100 mg, 0.38 mmol) is dissolved in dichloroethane (7 mL) and
1-(2,3-dichlorophenyl)piperazine monohydrochloride (112 mg, 0.42
mmol) is added, followed by triethylamine (39 mg, 0.05 mL, 1.14
mmol). The mixture is stirred for 5 minutes and NaBH(OAc).sub.3 (81
mg, 0.38 mmol) is added. The mixture is stirred at room temperature
for 1 hour and water (5 mL) is added. The organic layer is
separated, washed with brine (10 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated under vacuum. The crude solid is purified
by column chromatography (1:9 methanol/ethyl acetate) to yield the
title compound (123 mg, 68%) as a white solid. mp 161-163.degree.
C., .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.98 (br s, 1H), 7.80
(d, 1H), 7.20-7.10 (m, 2H), 7.00-6.90 (m, 1H), 6.60 (d, 1H), 4.20
(t, 2H), 3.15-3.00 (m, 4H), 2.75-2.60 (m, 4H), 2.50 (t, 2H), 2.40
(s, 3H), 2.20 (s, 3H), 1.85-1.60 (m, 4H), MS ES+ 474.76 (M).sup.+
(Exact Mass: 474.16).
Example D8
Synthesis of
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-3,4-dimethyl-1H-[1,-
8]naphthyridin-2-one
[1042] A first intermediate compound,
7-(5-Chloro-pent-1-enyl)-3,4-dimethyl-1H-[1,8]naphthyridin-2-one,
was produced as follows: To a stirred solution of
7-chloro-3,4-dimethyl-1H-[1,8]naphthyridin-2-one (2.0 g, 9.6 mmol)
in dioxane (20 mL) was added Pd(PPh.sub.3).sub.4 (334 mg, 0.29
mmol) and the mixture was stirred for 5 min. 5-Chloro-1-pentenyl
boronic acid (2.140 g, 14.42 mmol) was added followed by aqueous
Na.sub.2CO.sub.3 (2 M, 20 mL) and the mixture was heated at
100.degree. C. for 18 h. The mixture was cooled to room temperature
and diluted with water (20 mL) and ethyl acetate (30 mL). The
organic layer was separated and washed with brine (20 mL), dried
over anhydrous Na.sub.2SO.sub.4, filtered and evaporated. The crude
solid was recrystallized from CH.sub.2Cl.sub.2/hexanes to yield the
first intermediate compound as a light yellow solid (1.12 g, 42%).
mp 152-153.degree. C., .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.95 (s, 1H), 7.88 (d, 1H), 7.05 (d, 1H), 6.82 (dt, 1H), 6.50 (d,
1H), 3.60 (t, 2H), 2.46-2.40 (m, 2H), 2.39 (s, 3H), 2.22 (s, 3H),
2.04-1.98 (m, 2H), MS ES+ 277.06 (M+H).sup.+.
[1043] A second intermediate compound,
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dimethyl-1-
H-[1,8]naphthyridin-2-one, was produced as follows: To a stirred
solution of
7-(5-chloro-pent-1-enyl)-3,4-dimethyl-1H-[1,8]naphthyridin-2-one
(500 mg, 1.81 mmol) in CH.sub.3CN (20 mL) were added
1-(2,3-dichlorophenyl) piperazine monohydrochloride (581 mg, 2.17
mmol), KI (361 mg, 2.17 mmol) and K.sub.2CO.sub.3 (1.25 g, 9.05
mmol). The mixture was refluxed for 48 h, cooled to room
temperature, and diluted with water (10 mL) and CH.sub.2Cl.sub.2
(10 mL). The organic layer was separated, washed with water (10 mL)
and brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered
and evaporated in vacuo. The crude solid was purified by column
chromatography (5% MeOH/CH.sub.2Cl.sub.2) to yield the second
intermediate compound as a yellow solid (416 mg, 49%). mp
92-97.degree. C., .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 10.00
(br s, 1H), 7.85 (d, 1H), 7.10-7.03 (m, 3H), 6.98-6.80 (m, 2H),
6.56 (d, 1H), 3.10-3.00 (m, 4H), 2.80-2.60 (m, 4H), 2.50 (t, 2H),
2.40 (s, 3H), 2.38-2.24 (m, 2H), 2.22 (s, 3H), 1.82-1.70 (m, 2H),
MS ES+ 471.02 (M+H).sup.+ (Exact Mass: 470.16).
[1044]
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dim-
ethyl-1H-[1,8]naphthyridin-2-one (80 mg, 0.17 mmol) was dissolved
in a minimal amount of THF (2 mL) and the solution was diluted with
ethanol (10 mL). The solution was treated with Raney Nickel (0.5 mL
slurry in water) and shaken under 45 psi H.sub.2 for 3 h. The
mixture was filtered through celite. The celite pad was washed with
THF (2.times.10 mL), and the filtrate was evaporated in vacuo. The
crude solid was purified by column chromatography (5%
MeOH/CH.sub.2Cl.sub.2) to yield the title compound as a white solid
(64 mg, 80%). mp 202-203.degree. C., .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.98 (br s, 1H) 7.84 (d, 1H), 7.20-7.15 (m,
2H), 7.04 (d, 1H), 6.98-6.95 (m, 1H), 3.15-3.00 (m, 4H), 2.81 (t,
2H), 2.70-2.55 (m, 4H), 2.46-2.36 (m, 5H), 2.22 (s, 3H), 1.82-1.75
(m, 2H), 1.60-1.50 (m, 2H), 1.45-1.36 (m, 2H), MS ES+ 473.00
(M+H).sup.+ (Exact Mass: 472.18).
Example D9
Synthesis of
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3-fluoro-1H-[1,8]na-
phthyridin-2-one
[1045] A first intermediate compound,
N-{3-Formyl-6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridin-2-yl}-2,2-dim-
ethyl-propionamide, was produced as follows: To a cooled
(-78.degree. C.) solution of
2,2-dimethyl-N-{6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridin-2-yl}-pro-
pionamide (7.0 g, 20 mmol) in THF was added n-BuLi (20 mL, 2.5 M in
Hexane, 50 mmol). The mixture was stirred at 0.degree. C. for 3.5 h
and then cooled back to -78.degree. C. DMF (4.6 mL, 60 mmol) was
added dropwise with vigorous stirring. The cooling bath was removed
and the reaction was allowed to warm to 0.degree. C. The reaction
was quenched with saturated aqueous NH.sub.4Cl (20 mL) and
extracted with EtOAc (300 mL). The organic layer was washed with
water (2.times.20 mL) and brine (20 mL), dried over
Na.sub.2SO.sub.4 and concentrated to give an oil which was purified
by column chromatography (20% EtOAc/Hexanes) to give the first
intermediate compound as a pale yellow oil (5.8 g, 77%). .sup.1H
NMR (400 MHz, .delta. ppm): 11.50 (br s, 1H), 9.85 (s, 1H), 7.80
(d, 1H), 6.50 (d, 1H), 4.55 (m, 3H), 3.85 (m, 2H), 3.45 (m, 2H),
2.00-1.50 (m, 10H), 1.40 (s, 9H).
[1046] A second intermediate compound,
3-Fluoro-7-(4-hydroxy-butoxy)-1H-[1,8]naphthyridin-2-one, was
produced as follows: To a mixture of
N-{3-formyl-6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridin-2-yl}-2,2-dim-
ethyl-propionamide (4.10 g, 10.85 mmol),
triethyl-2-fluoro-2-phosphonoacetate (5.30 g, 21.70 mmol, 2 eq) and
LiCl (0.91 g, 21.70 mmol, 2 eq) in CH.sub.3CN was added DBU (3.30
g, 21.70 mmol, 2 eq) dropwise at such a rate that the temperature
of the mixture did not exceed 30.degree. C. The mixture was stirred
at room temperature overnight and quenched with saturated
NH.sub.4Cl (30 mL). The mixture was extracted with EtOAc (200 mL).
The organic layer was washed with water (20 mL) and brine (20 mL),
dried over Na.sub.2SO.sub.4 and concentrated to give a mixture of
cis- and trans-.alpha.,.beta.-unsaturated esters. This mixture was
dissolved in dioxane (40 mL) and 3 N HCl (20 mL) and refluxed for 2
h. The reaction was cooled in an ice-bath and neutralized with
K.sub.2CO.sub.3 (pH 8). The mixture was extracted with THF (250
mL). The organic layer was washed with brine (30 mL), dried over
Na.sub.2SO.sub.4 and concentrated. The residue was purified by
column chromatography (5% MeO/CH.sub.2Cl.sub.2) to give the second
intermediate compound as a pale yellow solid (700 mg, 26%). .sup.1H
NMR (400MHz, .delta. ppm): 7.90 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.0
Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 4.42 (t, J=6.0 Hz, 2H), 3.61 (t,
J=6.0 Hz, 2H), 1.90 (m, 2H), 1.70 (m, 2H).
[1047] To a suspension of Dess-Martin periodinane (1.09 g, 2.56
mmol, 1.2 eq) in CH.sub.2Cl.sub.2 (30 mL) was added a solution of
3-fluoro-7-(4-hydroxy-butoxy)-1H-[1,8]naphthyridin-2-one (0.538 g,
2.13 mmol) in THF (10 mL)/DMSO (2 mL). The mixture was stirred at
room temperature for 1.5 h. The reaction mixture was diluted with
Et.sub.2O (100 mL) and quenched with aqueous NaHCO.sub.3 (30 mL)
containing Na.sub.2S.sub.2O.sub.3 (2.36 g, 14.91 mmol, 7 eq). After
extraction with Et.sub.2O (3.times.50 mL), the combined organic
layer was washed with brine (20 mL), dried over Na.sub.2SO.sub.4
and concentrated to give the crude aldehyde as a pale yellow solid.
To a solution of the aldehyde in 1,2-dichloroethane (40 mL) was
added 1-(2,3-dichlorophenyl)piperazine monohydrochloride (0.803 g,
3.0 mmol, 1.4 eq), Et.sub.3N (0.54 mL, 4.0 mmol, 1.9 eq), and
NaBH(OAc).sub.3 (0.631 g, 3.0 mmol, 1.4 eq). The mixture was
stirred at room temperature for 1 h and then quenched with water
and saturated NaHCO.sub.3. After extraction with CH.sub.2Cl.sub.2
(3.times.50 mL), the combined organic layer was dried over
Na.sub.2SO.sub.4 and concentrated. The residue was purified by
column chromatography (3% MeOH/CH.sub.2Cl.sub.2) to give the title
compound (900 mg, 91% in two steps). .sup.1H NMR (400 MHz, .delta.
ppm): 12.60 (brs, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz,
1H), 7.30 (m, 2H), 7.10 (m, 1H), 6.75 (d, J=8.0 Hz, 1H), 4.40 (t,
J=7.0 Hz, 2H), 3.00 (brs, 4H), 2.50 (brs, 4H), 2.40 (t, J=6.0 Hz,
2H), 1.80 (m, 2H), 1.60 (m, 2H); .sup.19F NMR: -140 ppm; MS: 465
(M+H).sup.+ (Exact Mass: 464.12).
Example D10
Synthesis of
3-Fluoro-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyr-
idin-2-one
[1048] To a suspension of Dess-Martin periodinane (0.79 g, 1.86
mmol, 1.2 eq) in CH.sub.2Cl.sub.2 (20 mL) was added a solution of
3-fluoro-7-(4-hydroxy-butoxy)-1H-[1,8]naphthyridin-2-one (0.39 g,
1.5 mmol) in THF (6 mL)/DMSO (2 mL). The mixture was stirred at
room temperature for 1.5 h. The reaction mixture was diluted with
Et.sub.2O (100 mL) and quenched with aqueous NaHCO.sub.3 (20 mL)
containing Na.sub.2S.sub.2O.sub.3 (1.66 g, 10.5 mmol, 7 eq). After
extraction with Et2O (3.times.40 mL), the combined organic layer
was washed with brine (20 mL), dried over Na.sub.2SO.sub.4 and
concentrated to give the crude aldehyde as a pale yellow solid. To
a solution of the aldehyde in 1,2-dichloroethane (20 mL) was added
1-naphthalen-1-yl-piperazine monohydrochloride (0.522 g, 2.1 mmol,
1.4 eq), Et.sub.3N (0.38 mL, 2.85 mmol, 1.9 eq) and NaBH(OAc).sub.3
(0.445 g, 2.1 mmol, 1.4 eq). The mixture was stirred at room
temperature for 1 h and quenched with water and saturated
NaHCO.sub.3. After extraction with CH.sub.2Cl.sub.2 (3.times.50
mL), the combined organic layer was dried over Na.sub.2SO.sub.4 and
concentrated. The residue was purified by column chromatography (3%
MeOH/CH.sub.2Cl.sub.2) to give the title compound (430 mg, 62% in
two steps). .sup.1H NMR (400 MHz, .delta. ppm): 12.60 (br s, 1H),
8.10 (d, J=6.0 Hz, 1H), 8.00 (d, J=7.0 Hz, 1H), 7.85 (m, 2H), 7.60
(d, J=6.0 Hz, 1H), 7.50 (m, 2H), 7.40 (d, J=6.0 Hz, 1H), 7.10 (d,
J=6.0 Hz, 1H), 6.75 (d, J=7.0 Hz, 1H), 4.35 (t, J=4.0 Hz, 2H), 3.00
(br s, 4H), 2.60 (br s, 4H), 2.40 (t, J=3.0 Hz, 2H), 1.80 (m, 2H),
1.60 (m, 2H); .sup.19F NMR: -140 ppm; MS: 447 (M+H).sup.+ (Exact
Mass: 446.21).
Example D11
Synthesis of
7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-3-(2,2,2-trifluoro-ethyl)-
-1H-[1,8]naphthyridin-2-one
[1049] An intermediate compound,
7-(4-Hydroxy-butoxy)-3-(2,2,2-trifluoro-ethyl)-1H-[1,8]naphthyridin-2-one-
, was produced as follows: To a cooled (-78.degree. C.) solution of
LiHMDS (47.6 mL, 1 M in THF) was added ethyl
4,4,4-trifluorobutyrate (8.10 g, 47.6 mmol) dropwise and the
mixture was stirred for 1 hour. A solution of
N-{3-formyl-6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridin-2-yl}-2,2-dim-
ethyl-propionamide (3.0 g, 7.93 mmol) in THF (15 mL) was added. The
cooling bath was then removed and the reaction was allowed to
gradually warm to 0.degree. C. The reaction was quenched with
aqueous NH.sub.4Cl (30 mL) and the mixture was extracted with
EtOAc. The organic layer was washed with water and brine, dried
over Na.sub.2SO.sub.4 and concentrated to give the condensation
product which was used in the next step without further
purification.
[1050] The crude material obtained in the last step was dissolved
in dioxane (30 mL) and 3 N HCl (15 mL). The resulting solution was
refluxed overnight and neutralized with K.sub.2CO.sub.3 (pH 8)
while cooling with an ice-bath. The mixture was extracted with
EtOAc (3.times.50 mL). The combined organic layers were dried over
Na.sub.2SO.sub.4 and concentrated to give a mixture of the desired
product,
7-(4-hydroxy-butoxy)-3-(2,2,2-trifluoro-ethyl)-1H-[1,8]naphthyridin-2-one-
, and a side-product,
2-[2-amino-6-(4-hydroxy-butoxy)-pyridin-3-ylmethylene]-4,4,4-trifluoro-bu-
tyric acid ethyl ester. The crude mixture was dissolved in MeOH (20
mL) and water (10 mL) and KOH (1.07 g) was added. The resulting
mixture was stirred overnight at RT. The mixture was concentrated
and the residue was extracted with EtOAc (3.times.50 mL). The
combined organic layers were dried over Na.sub.2SO.sub.4 and
concentrated to give an oil which was purified by chromatography on
silica gel (3% MeOH/CH.sub.2Cl.sub.2) to give the intermediate
compound as a yellow solid (260 mg, 10% in three steps). .sup.1H
NMR (400 MHz, .delta. ppm): 9.78 (br s, 1H), 7.75 (d, J=5.0 Hz,
2H), 6.60 (d, J=5.0 Hz), 4.70 (t, J=3.0 Hz), 4.50 (t, J=3.0 Hz),
3.80 (m, 2H), 3.50 (q, J=8 Hz, 2H), 1.60-2.00 (m, 4H). .sup.19F
NMR: -65 ppm, MS: 317 (M.sup.+).
[1051] To a suspension of Dess-Martin periodinane (0.419 g, 0.99
mmol, 1.2 eq) in CH.sub.2Cl.sub.2 (20 mL) was added a solution of
7-(4-hydroxy-butoxy)-3-(2,2,2-trifluoro-ethyl)-1H-[1,8]naphthyridin-2-one
(0.26 g, 0.82 mmol) in THF (8 mL ). The mixture was stirred at room
temperature for 1 h. Et.sub.2O (100 mL) was added to dilute the
reaction mixture. The reaction was quenched with aqueous
NaHCO.sub.3 (20 mL) containing Na.sub.2S.sub.2O.sub.3 (0.91 g, 5.74
mmol, 7 eq). After extraction with Et.sub.2O (3.times.50 mL), the
combined organic layer was washed with brine (20 mL), dried over
Na.sub.2SO.sub.4, and concentrated to give the crude aldehyde as a
pale yellow solid. To a solution of the crude aldehyde in
1,2-dichloroethane (20 mL) was added 1-naphthalen-1-yl-piperazine
monohydrochloride (0.286 g, 1.15 mmol, 1.4 eq), Et.sub.3N (0.21 mL,
1.56 mmol, 1.9 eq) and NaBH(OAc).sub.3 (0.241 g, 1.15 mmol, 1.4
eq). The mixture was stirred at room temperature for 1 h. The
reaction was quenched with water and saturated NaHCO.sub.3. After
extraction with CH.sub.2Cl.sub.2 (3.times.50 mL), the combined
organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The
residue was purified by column chromatography (2%
MeOH/CH.sub.2Cl.sub.2) to give the title compound (200 mg, 50% in
two steps). .sup.1H NMR (400 MHz, .delta. ppm): 9.05 (br s, 1H),
8.20 (d, J=6.0 Hz, 1H), 7.80 (d, J=6.0 Hz, 1H), 7.75 (m, 2H), 7.58
(d, J=6.0 Hz, 1H), 7.50 (m, 2H), 7.40 (t, J=6.0 Hz, 1H), 7.10 (d,
J=5.0 Hz, 1H), 6.40 (d, J=6.0 Hz, 1H), 4.40 (t, J=4.0 Hz, 2H), 3.50
(q, J=7.0 Hz, 2H), 3.20 (br s, 4H), 2.80 (br s, 4H), 2.60 (m, 2H),
1.90 (m, 2H), 1.72 (m, 2H). .sup.19F NMR: -65.6 ppm. MS: 511
(M.sup.+). Elemental Analysis calculated for
C.sub.28H.sub.29F.sub.3N.sub.4O.sub.2: C, 65.88; H, 5.69; N, 10.98.
Found: C, 66.08; H, 5.89; N, 10.67.
Example D12
Synthesis of
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-3,3-dimethyl-3,4-di-
hydro-1H-[1,8]naphthyridin-2-one
[1052] A first intermediate compound,
3-[6-Chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydroxy-2,2-d-
imethyl-propionic acid methyl ester, was produced as follows: To a
stirred solution of oxalyl chloride (11.0 g, 87.0 mmol) in
CH.sub.2Cl.sub.2 (180 mL) at -60.degree. C. was added a solution of
DMSO (12.9 mL, 182 mmol) in CH.sub.2Cl.sub.2 (40 mL), dropwise at a
rapid rate. The resulting solution was stirred for 5 min, then a
solution of methyl-2,2-dimethyl-3-hydroxypropionate (10.0 g, 75.6
mmol) in CH.sub.2Cl.sub.2 (10 mL) was added dropwise over 10 min.
The cloudy mixture was then stirred for 15 min, at which time
triethylamine (52 mL, 380 mmol) was added dropwise, maintaining the
temperature at or below -50.degree. C. After stirring for 5 min,
the mixture was allowed to warm to room temperature and water (200
mL) was then added. The layers were separated and the aqueous layer
extracted with CH.sub.2Cl.sub.2 (2.times.100 mL). The combined
organic layers were washed successively with 1 M HCl (100 mL),
water (100 mL), saturated NaHCO.sub.3 solution (100 mL), water (100
mL) and brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo until only a small volume of CH.sub.2Cl.sub.2
remained, to minimize the loss of the volatile product. The crude
product was purified by vacuum distillation affording the desired
product 2,2-dimethyl-3-oxopropionic acid methyl ester (8.1 g, 83%,
89.degree. C., ca 80 mmHg). .sup.1H NMR (CDCl.sub.3) .delta. 9.67
(s, 1H), 3.76 (s, 3H), 1.36 (s, 6H).
[1053] To a stirred solution of
N-(6-chloro-pyridin-2-yl)-2,2-dimethyl-propionamide (12.0 g, 56.6
mmol) in THF (180 mL) at -78.degree. C., was added dropwise,
n-butyllithium (95.0 mL, 153 mmol, 1.6 M in hexanes). After the
addition was complete, the mixture was warmed to -20.degree. C. and
stirred at this temperature for 3 h. The reaction mixture was then
cooled to -78.degree. C. and added, via cannula, to a stirred
solution of 2,2-dimethyl-3-oxopropionic acid methyl ester (14.7 g,
130 mmol) in THF (50 mL) at -78.degree. C. After stirring for 2 h,
the reaction was quenched by the addition of a saturated NH.sub.4Cl
solution, diluted with ethyl acetate (50 mL) and warmed to RT. The
organic layer was removed and washed with water (50 mL), saturated
NaHCO.sub.3 (50 mL), water (50 mL) and brine (50 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude
product was purified by silica gel chromatography (90:10 to 50:50
hexanes/ethyl acetate) to afford the first intermediate compound
(10.7 g, 55%) as a pale yellow solid. 1H NMR (CDCl.sub.3) .delta.
8.77 (br s, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H),
5.06 (d, J=3.0 Hz, 1H), 3.70 (s, 3H), 3.61 (d, J=3.0 Hz, 1H), 1.33
(s, 9H), 1.24 (s, 3H), 1.21 (s, 3H); MS (ESI) m/z 343
[C.sub.16H.sub.23ClN.sub.2O.sub.4+H].sup.+.
[1054] A second intermediate compound,
7-Chloro-4-hydroxy-3,3-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one,
was produced as follows:
3-[6-Chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydroxy-2,2-d-
imethyl-propionic acid methyl ester (2.0 g, 5.8 mmol) was partially
dissolved in a mixture of 3M HCl and dioxane (1:1, 120 mL). The
mixture was refluxed for 90 min, cooled to room temperature and
concentrated in vacuo. The residue was partitioned between ethyl
acetate (100 mL) and a saturated NaHCO.sub.3 solution (100 mL). The
aqueous layer was removed and extracted with ethyl acetate
(2.times.30 mL). The combined organic layers were washed with brine
(50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated.
The crude residue was purified by silica gel chromatography (80:20
to 40:60 hexanes/ethyl acetate) to afford the second intermediate
compound (0.85 g, 65%) as a pale yellow foamy solid. .sup.1H NMR
(CDCl.sub.3) .delta. 7.78 (br s, 1H), 7.69 (d, J=7.0 Hz, 1H), 7.04
(d, J=7.0 Hz, 1H), 4.53 (d, J=4.0 Hz, 1H), 2.12 (d, J=5.0 Hz, 1H),
1.26 (s, 3H), 1.23 (s, 3H); MS (ESI) m/z 227
[C.sub.10H.sub.11ClN.sub.2O.sub.2+H].sup.+; Anal. Calcd for
C.sub.10H.sub.11ClN.sub.2O.sub.2: C, 52.99; H, 4.89; N, 12.36; Cl,
15.64. Found: C, 53.17; H, 4.88; N, 12.27; Cl, 15.63.
[1055] A third intermediate compound,
7-Chloro-3,3-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one, was
produced as follows: To a solution of
7-chloro-4-hydroxy-3,3-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one
(0.71 g, 3.14 mmol) in TFA (10 mL) was added triethylsilane (1.5
mL, 9.7 mmol, 3.1 equiv). The mixture was heated at reflux for 2 h.
The reaction was cooled to room temperature and concentrated. The
residue was dissolved in CH.sub.2Cl.sub.2, washed with saturated
NaHCO.sub.3 and brine, and concentrated to give a solid. The solid
was triturated with hexanes and filtered to give the third
intermediate compound (520 mg, 80%). MS: ESI: m/z: 210.98 (Exact
Mass: 210.06).
[1056] A fourth intermediate compound,
7-(5-Chloro-pent-1-enyl)-3,3-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2--
one, was produced as follows: A 100 mL round bottom flask was
charged with
7-chloro-3,3-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one (520
mg, 2.47 mmol), 5-chloro-pent-1-enyl-boronic acid (769 mg, 5.2
mmol), Pd(PPh.sub.3).sub.4 (0.14 g, 0.12 mmol, 5 mol %) and
Na.sub.2CO.sub.3 (262 mg, 2.47 mmol). DME (20 mL) and H.sub.2O (5
mL) were added and the reaction was heated at reflux for 11 h. The
reaction was cooled to room temperature and stirred overnight. The
solvents were evaporated and the residue was partitioned between
EtOAc (50 mL) and H.sub.2O (50 mL). The organic layer was washed
with H.sub.2O, saturated NaHCO.sub.3 and brine, dried over
Na.sub.2SO.sub.4 and concentrated. Purification by liquid
chromatography (SiO.sub.2, 5 to 35% EtOAc/Hexanes) afforded the
fourth intermediate compound (560 mg, 82%). MS: ESI: m/z: 279.12
(Exact Mass: 278.12).
[1057] A fifth intermediate compound,
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,3-dimethyl-3-
,4-dihydro-1H-[1,8]naphthyridin-2-one, was produced as follows: To
a solution of
7-(5-chloro-pent-1-enyl)-3,3-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2--
one (0.55 g, 1.98 mmol) in CH.sub.3CN (50 mL) was added
1-(2,3-dichloro-phenyl)-piperazine (0.63 g, 2.37 mmol),
K.sub.2CO.sub.3 (0.87 g, 6.34 mmol) and NaI (0.35 g, 2.37 mmol).
The mixture was heated at reflux for 3 days. The reaction mixture
was poured into H.sub.2O and extracted with CH.sub.2Cl.sub.2. The
organic layer was washed with brine, dried over Na.sub.2SO.sub.4
and concentrated. Purification by liquid chromatography (Biotage
25M, CH.sub.2Cl.sub.2 to 5% MeOH/CH.sub.2Cl.sub.2) gave the product
contaminated with a small amount of starting chloro compound.
Repurification by liquid chromatography (Biotage 25M, EtOAc to 5%
MeOH/EtOAc) afforded the pure fifth intermediate compound (640 mg,
68%). MS: ESI: m/z: 473.34 (Exact Mass: 472.18).
[1058] A Parr shaker was charged with PtO.sub.2 (0.12 g) and EtOAc
(25 mL) was added under N.sub.2. The catalyst was shaken under a
H.sub.2 atmosphere (50 psi) for 10 min and a suspension of
7-{5-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,3-dimethyl-3-
,4-dihydro-1H-[1,8]naphthyridin-2-one (0.54 g, 1.15 mmol) in EtOAc
(125 mL) was added. The mixture was shaken under H.sub.2 (50 psi)
for 1.5 h. The reaction was filtered through Celite washing with
MeOH and the filtrate was concentrated to give an oily residue.
Hexanes was added and the mixture was concentrated to give the
title compound as a white solid (0.54 g, 99%). MS: ESI: m/z: 475.32
(Exact Mass: 474.20).
Example D13
Synthesis of
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,3-dimethyl-3,4-di-
hydro-1H-[1,8]naphthyridin-2-one
[1059] A first intermediate compound,
7-Chloro-3,3-dimethyl-1H-[1,8]naphthyridine-2,4-dione, was produced
as follows: To a suspension of Dess Martin periodinane (5.61 g,
13.23 mmol) in CH.sub.2Cl.sub.2 (25 mL) was added a solution of
7-chloro-4-hydroxy-3,3-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one
(2.0 g, 8.82 mmol) in CH.sub.2Cl.sub.2/THF (40 mL/10 mL) via
cannula. The reaction was stirred at room temperature for 2 hours.
Upon completion, a 1:1 mixture of saturated Na.sub.2S.sub.2O.sub.3
and saturated NaHCO.sub.3 (75 ml) were added, followed by
Et.sub.2O. The mixture was stirred for 20 minutes, and then
extracted with a mixture of EtOAc/Et.sub.2O (1:2). The organic
layer was washed with saturated NaHCO.sub.3 and brine, dried over
Na.sub.2SO.sub.4 and concentrated to give the first intermediate
compound as a pale yellow solid (1.96 g, 98%). MS: APCI: M+1: 225.1
(Exact Mass: 224.04).
[1060] A second intermediate compound,
7-(4-Benzyloxy-butoxy)-3,3-dimethyl-1H-[1,8]naphthyridine-2,4-dione,
was produced as follows: To a solution of 4-benzyloxy-butan-1-ol
(4.7 mL, 26.70 mmol) in dry THF was added KO.sup.tBu (1M in THF,
25.3 mL, 25.34 mmol). The mixture was stirred for 20 minutes and
then added to a solution of
7-chloro-3,3-dimethyl-1H-[1,8]naphthyridine-2,4-dione (1.5 g, 6.67
mmol) in dry THF. The reaction was stirred at room temperature for
1 hour. The reaction was quenched with saturated NH.sub.4Cl and
partitioned between water and EtOAc. The organic layer was washed
with saturated NaHCO.sub.3 and brine, dried over Na.sub.2SO.sub.4
and concentrated. Purification by liquid chromatography on silica
gel (10-40% EtOAc/Hexanes) gave the second intermediate compound as
a colorless oil (2.25 g, 91%). MS: APCI: M+1: 369.5 (Exact Mass:
368.17).
[1061] A third intermediate compound,
7-(4-Hydroxy-butoxy)-3,3-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one,
was produced as follows:
7-(4-Benzyloxy-butoxy)-3,3-dimethyl-1H-[1,8]naphthyridine-2,4-dione
(2.26 g, 6.13 mmol) was hydrogenated using 20% Pd/C (0.25 g) in THF
for 1 h. A mixture of the title compound and
4-hydroxy-7-(4-hydroxy-butoxy)-3,3-dimethyl-3,4-dihydro-1H-[1,8]naphthyri-
din-2-one was obtained. The mixture was filtered and concentrated
to give an oil. Purification by liquid chromatography on silica gel
(50-100% EtOAc/Hexanes) gave the third intermediate compound (0.321
g, 19%). MS: APCI: M+1: 265.1 (Exact Mass: 264.15).
[1062] A fourth intermediate compound,
4-(6,6-Dimethyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyr-
aldehyde, was produced as follows: To a suspension of Dess Martin
periodinane (0.693 g, 1.63 mmol) in dry CH.sub.2Cl.sub.2 (5 mL) was
added a solution of
7-(4-hydroxy-butoxy)-3,3-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one
(0.287 g, 1.08 mmol) in dry CH.sub.2Cl.sub.2 (5 mL) via cannula.
The reaction was stirred at room temperature for 7 hours. A 1:1
mixture of saturated NaHCO.sub.3 and saturated
Na.sub.2S.sub.2O.sub.3 was added (30 mL), followed by Et.sub.2O.
The mixture was stirred for 15 minutes and then extracted with
Et.sub.2O/EtOAc. The organic layer was washed with saturated
NaHCO.sub.3 and brine, dried over Na.sub.2SO.sub.4 and concentrated
to afford the fourth intermediate compound as a white solid (0.268
g, 1.02 mmol, 94%). MS: APCI: M-1: 261.0 (Exact Mass: 262.13).
[1063] To a solution of
4-(6,6-dimethyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyr-
aldehyde (0.250 g, 0.953 mmol) in DCE (6 mL) was added
1-(2,3-dichloro-phenyl)-piperazine hydrochloride (0.255 g, 0.953
mmol) followed by Et.sub.3N (0.27 mL, 1.90 mmol). The mixture was
stirred for 20 minutes at room temperature and NaBH(OAc).sub.3
(0.282 g, 1.33 mmol) was added. The reaction was stirred for 2.5 h
and quenched with saturated NaHCO.sub.3 and water. The mixture was
extracted with EtOAc and the organic layer was washed with
saturated NaHCO.sub.3, water and brine, dried over Na.sub.2SO.sub.4
and concentrated. Purification by liquid chromatography on silica
gel (0-5% MeOH/CH.sub.2Cl.sub.2) gave a foam (0.214 g, 0.443 mmol,
46%). The foam was dissolved in Et.sub.2O and treated with maleic
acid to give a white solid. MS: APCI: M+1: 477.1 (Exact Mass:
476.17).
Example D14
Synthesis of
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,3-dimethyl-1H-[1,-
8]naphthyridine-2,4-dione
[1064] A first intermediate compound,
3,3-Dimethyl-7-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-1H-[1,8]naphthyridin-
e-2,4-dione, was produced as follows: To a solution of
4-(tetrahydro-pyran-2-yloxy)-butan-1-ol (1.93 g, 11.07 mmol) in dry
THF (4 mL) was added KO.sup.tBu (1M in THF, 10.5 mL, 10.5 mmol).
The mixture was stirred for 20 minutes and then added to a solution
of 7-chloro-3,3-dimethyl-1H-[1,8]naphthyridine-2,4-dione (0.621 g,
2.76 mmol) in dry THF (5 mL). The reaction was stirred at room
temperature for 1 hour. The reaction was quenched with saturated
NH.sub.4Cl and partitioned between water and EtOAc. The organic
layer was washed with saturated NaHCO.sub.3 and brine, dried over
Na.sub.2SO.sub.4 and concentrated. Purification by liquid
chromatography on silica gel (10-40% EtOAc/Hexanes) gave the first
intermediate compound as an orange oil (0.89 g, 2.40 mmol, 88%).
MS: APCI: M+1: 363.1 (Exact Mass: 362.18).
[1065] A second intermediate compound,
7-(4-Hydroxy-butoxy)-3,3-dimethyl-1H-[1,8]naphthyridine-2,4-dione,
was produced as follows: To a solution of
3,3-dimethyl-7-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-1H-[1,8]naphthyridin-
e-2,4-dione (1.22 g, 3.37 mmol) in EtOH (15 mL) was added PPTS. The
reaction was heated to 60.degree. C. for 3 hours. The reaction was
cooled and concentrated to give an oil. Purification by liquid
chromatography on silica gel (30-70% EtOAc/Hexanes) gave the second
intermediate compound as a white solid (0.373 g, 40%). MS: APCI:
M+1: 279.1 (Exact Mass: 278.13).
[1066] A third intermediate compound,
4-(6,6-Dimethyl-5,7-dioxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-b-
utyraldehyde, was produced as follows: To a suspension of Dess
Martin periodinane (2.256 g, 5.31 mmol) in dry CH.sub.2Cl.sub.2 (5
mL) was added a solution of
7-(4-hydroxy-butoxy)-3,3-dimethyl-1H-[1,8]naphthyridine-2,4-dione
(0.37 g, 1.30 mmol) in dry CH.sub.2Cl.sub.2 (5 mL) via cannula. The
reaction was stirred at room temperature for 4 hours. A 1:1 mixture
of saturated NaHCO.sub.3 and saturated Na.sub.2S.sub.2O.sub.3 was
added (40 mL), followed by Et.sub.2O. The mixture was stirred for
15 minutes and then extracted with Et.sub.2O/EtOAc. The organic
layer was washed with saturated NaHCO.sub.3 and brine, dried over
Na.sub.2SO.sub.4 and concentrated to afford the third intermediate
compound as a yellow film (0.52 g, 1.22 mmol, 65%). MS: APCI: M+1:
277.1 (Exact Mass: 276.11).
[1067] To a solution of
4-(6,6-dimethyl-5,7-dioxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-b-
utyraldehyde (0.520 g, 1.88 mmol) in DCE (6 mL) was added
1-(2,3-dichloro-phenyl)-piperazine hydrochloride (0.503 g, 1.88
mmol) followed by Et.sub.3N (0.53 mL, 3.76 mmol). The mixture was
stirred for 20 minutes at room temperature and NaBH(OAc).sub.3
(0.56 g, 2.60 mmol) was added. The reaction was stirred for 2.5 h
and quenched with saturated NaHCO.sub.3 and water. The mixture was
extracted with EtOAc and the organic layer was washed with
saturated NaHCO.sub.3, water and brine, dried over Na.sub.2SO.sub.4
and concentrated. Purification by liquid chromatography on silica
gel (0-5% MeOH/CH.sub.2Cl.sub.2) gave a white solid (0.277 g, 0.564
mmol, 30%). MS: APCI: M+1: 491.1 (Exact Mass: 490.15).
Example D15
Synthesis of
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-4-hydroxy-3,3-dimet-
hyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one
[1068] To a solution of
7-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,3-dimethyl-1H-[1,-
8]naphthyridine-2,4-dione (0.132 g, 0.268 mmol) in THF (2 mL),
cooled to 0.degree. C. was added NaBH.sub.4 (0.013 g, 0.335 mmol).
The reaction was warmed to room temperature and stirred for 3
hours. The reaction was quenched with saturated NaHCO.sub.3 and
partitioned between EtOAc and water. The organic layer was washed
with brine, dried over Na.sub.2SO.sub.4 and concentrated to give
the title compound as a white solid (0.095 g, 0.192 mmol, 57%). MS:
APCI: M+1: 493.1 (Exact Mass: 492.17).
Example D16
Synthesis of
4,4-Dimethyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro--
1H-[1,8]naphthyridin-2-one
[1069] A first intermediate compound, 3-Methyl-but-3-enoic acid
(6-amino-pyridin-2-yl)-amide, was produced as follows:
2,5-Diaminopyridine (70 g, 0.641 mol) was dissolved in 2100 mL THF
in a 5 L 4-neck flask equipped with mechanical stirring, N.sub.2
line and a 500 mL addition funnel. Et.sub.3N (447 mL, 5 eq.) was
added to the reaction flask. 3,3-Dimethylacryloyl chloride (76 g,
0.641 mol) was diluted with 700 mL THF and this solution was added
dropwise to the reaction flask. The moderate exotherm observed was
controlled with an ice/water bath to maintain a temperature
<15.degree. C. After the addition was complete, the reaction was
allowed to warm to room temperature and stirred under N.sub.2 for
1.5 h. The reaction mixture was concentrated and CH.sub.2Cl.sub.2
was added. The CH.sub.2Cl.sub.2 solution was washed with H.sub.2O
and the aqueous layer was back extracted with CH.sub.2Cl.sub.2. The
organic layers were combined and dried over Na.sub.2SO.sub.4,
filtered and concentrated to an oil. The crude product was purified
by column chromatography using a gradient mobile phase of 10%-30%
EtOAc in hexanes. All fractions containing the desired product were
pooled and concentrated to an oil. NMR analysis of the product
indicated the product was a 1:1 mixture of 2 isomers, the alpha
beta unsaturated and the beta gamma unsaturated isomer resulting in
first intermediate compound (90.0 g, 0.47 mol, 73%). MS: APCI: M+1:
192.0 (Exact Mass: 191.11).
[1070] A second intermediate compound,
7-Amino-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one, was
produced as follows: 3-Methyl-but-3-enoic acid
(6-amino-pyridin-2-yl)-amide (49.2 g, 0.26 mol) was dissolved in
500 mL CH.sub.2Cl.sub.2 in a 1000 mL 3-neck flask equipped with
mechanical stirring, a 125 mL addition funnel and a thermal couple.
While stirring, MeSO.sub.3H (50 mL, 0.78 mol) was added to the
flask dropwise. The exotherm upon addition was controlled to
maintain a temperature <20.degree. C. by an ice/water bath. The
mixture was allowed to stir for 15 minutes. AlCl.sub.3 (274 g, 2.08
mol) was suspended in 1500 mL CH.sub.2Cl.sub.2 in a 5 L 4-neck
flask equipped with mechanical stirring, 1000 mL addition funnel,
N.sub.2 line and a thermal couple. To this suspension, the amide
solution was added dropwise. The exotherm from the addition was
again controlled to maintain a temperature <20.degree. C. with
an ice/water bath. The reaction was allowed to warm to room
temperature and stir overnight. The reaction had consumed all the
beta gamma unsaturated isomer and was deemed complete. The reaction
mixture was slowly added to ice as an inverse quench. The quenched
mixture was brought to pH 8-10 with 2 N KOH. The salts precipitated
out of solution and saturated the aqueous phase. The suspension was
transferred to a separatory funnel and extracted twice with 100:8:1
CH.sub.2Cl.sub.2:EtOH:NH.sub.4OH. The organic layers were combined,
dried over Na.sub.2SO.sub.4, filtered and concentrated to a crude
solid. The solid was triturated with EtOAc and filtered. The
resulting solids were pure second intermediate compound (22.4 g,
0.117 mol, 46%). MS: APCI: M+1: 192.2 (Exact Mass: 191.11).
[1071] A third intermediate compound,
7-Fluoro-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one, was
produced as follows: HF-pyridine (100 mL) was cooled to -42.degree.
C. in a 1000 mL HDPE bottle using an CH.sub.3CN dry ice bath. While
stirring vigorously,
7-amino-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one (24.6
g, 0.129 mol) was added portionwise to control the exotherm. After
the addition, NaNO.sub.2 (8.9 g, 0.1291 mol) was added portionwise.
Significant exotherms were observed for both additions. The
reaction mixture was then allowed to warm to 0.degree. C. and stir
for 2 h. The reaction mixture was quenched into a 4 L HDPE bottle
full of ice. The aqueous slurry was then neutralized using 2 N KOH.
The resulting aqueous solution was extracted 3 times with
CH.sub.2Cl.sub.2. The organic layers were dried over
Na.sub.2SO.sub.4, filtered and concentrated to dryness. Excess
pyridine was azeotroped with heptane. The product was dried under
vacuum (2 mm Hg) for 3 h. The third intermediate compound was
isolated as a white powder (23.06 g, 0.119 mol, 92%). MS: APCI:
M+1: 195.1 (Exact Mass: 194.09).
[1072] 7-Fluoro-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one
(247 mg, 1.272 mmol),
4-(4-naphthalen-1-yl-piperazin-1-yl)-butan-1-ol (365 mg, 1.285
mmol) and sodium t-butoxide (367 mg, 3.82 mmol) were combined in a
dried flask 3 necked flask under N.sub.2. NMP was added and the
solution was heated in an oil bath to 70.degree. C. for 4 hours.
The reaction was cooled to room temperature and poured into ice
water. The solid that was collected was slurried in
CH.sub.2Cl.sub.2 and ethyl acetate and purified by liquid
chromatography (MPLC, gradient of 100% CH.sub.2Cl.sub.2 to 100%
ethyl acetate) to give the title compound as a foam (280 mg, 0.610
mmol, 48%). MS: APCI: M+1: 459.2 (Exact Mass: 458.27).
Example D17
Synthesis of
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3,4-di-
hydro-1H-[1,8]naphthyridin-2-one
[1073] A first intermediate compound,
7-(4-Hydroxy-butoxy)-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one,
was produced as follows: The
7-fluoro-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one (5.09
g, 26.2 mmol) and butane-1,4-diol (11.81 g, 131.0 mmol) were
combined in a dried 2-necked flask under N.sub.2. NMP (50 mL) was
added and the solution was heated in an oil bath to 70.degree. C.
overnight. The reaction was cooled to room temperature and poured
into ice water. The solid that formed was collected and triturated
in acetonitrile to give the title compound as a tan powder (1.72
g). The mother liquor was extracted with CH.sub.2Cl.sub.2, dried
over Na.sub.2SO.sub.4, filtered and purified by MPLC (gradient of
100% CH.sub.2Cl.sub.2 to 100% ethyl acetate). The compound was
isolated as a mixture with diol byproducts. The title compound was
formed as clear crystals (1.09 g) after recrystallization in
acetonitrile and another 340 mg was obtained from a second
recrystallization. The products were combined to give a total of
3.15 g of the first intermediate compound (11.9 mmol, 45.5%). MS:
APCI: M+1: 265.1 (Exact Mass: 264.15).
[1074] A second intermediate compound,
4-(5,5-Dimethyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyr-
aldehyde, was produced as follows:
7-(4-Hydroxy-butoxy)-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one
(1.72 g, 6.51 mmol) was dissolved in ethyl acetate (50 mL, 0.14 M
solution) and IBX (13 g, 46.4 mmol) was added. The suspension was
immersed in an oil bath set at 80.degree. C. and stirred vigorously
with a condenser. After 1.5 h, the reaction mixture was cooled to
room temperature and filtered. The filtrate was concentrated to
give the second intermediate compound as a tan solid (1.62 g, 6.18
mmol, 95%). MS: APCI: M+1: 263.1 (Exact Mass: 262.13).
[1075] The naphthyridinones of Examples D17-D25 were synthesized in
a combinatorial library format by reductive amination of the
appropriate piperazine starting materials with
4-(5,5-dimethyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyr-
aldehyde following the procedure outlined in Example H7. The final
products were made into hydrochloride salts by treatment with a
solution of saturated HCl in MeOH.
[1076] The title compound was isolated (182 mg, 0.381 mmol, 63.5%).
MS: APCI: M+1: 477.1 (Exact Mass: 476.17).
Example D18
Synthesis of
4,4-Dimethyl-7-{4-[4-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-
-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one
[1077] The title compound was isolated as a hygroscopic foam (149
mg, 0.322 mmol, 53.6%). MS: APCI: M+1: 463.2 (Exact Mass:
462.30).
Example D19
Synthesis of
7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-4,4-dimethyl-3,4-dihydro-1H-[1-
,8]naphthyridin-2-one
[1078] The title compound was isolated as a foam (158 mg, 0.352
mmol, 58.7%). MS: APCI: M+1: 449.2 (Exact Mass: 448.28).
Example D20
Synthesis of
7-{4-[4-(2-Chloro-3-methyl-phenyl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3-
,4-dihydro-1H-[1,8]naphthyridin-2-one
[1079] The title compound was isolated as a hygroscopic foam (159
mg, 0.349 mmol, 58.1%). MS: APCI: M+1: 457.2 (Exact Mass:
456.23).
Example D21
Synthesis of
7-{4-[4-(3-Chloro-2-methyl-phenyl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3-
,4-dihydro-1H-[1,8]naphthyridin-2-one
[1080] The title compound was isolated as a hygroscopic foam (144
mg, 0.315 mmol, 52.5%). MS: APCI: M+1: 457.2 (Exact Mass:
456.23).
Example D22
Synthesis of
7-{4-[4-(6-Cyclopropyl-pyridin-2-yl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-
-3,4-dihydro-1H-[1,8]naphthyridin-2-one
[1081] The title compound was isolated as a foam (143 mg, 0.318
mmol, 53.0%). MS: APCI: M+1: 450.2 (Exact Mass: 449.28).
Example D23
Synthesis of
7-{4-[4-(2-Ethyl-phenyl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3,4-dihydro-
-1H-[1,8]naphthyridin-2-one
[1082] The title compound was isolated as a solid (144 mg, 0.330
mmol, 55%). MS: APCI: M+1: 437.2 (Exact Mass: 436.28).
Example D24
Synthesis of
7-{4-[4-(2-Isobutoxy-phenyl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3,4-dih-
ydro-1H-[1,8]naphthyridin-2-one
[1083] The title compound was isolated as the hydrochloride salt
(237 mg, 0.458 mmol, 60.1%). MS: APCI: M+1: 481.2 (Exact Mass:
480.31).
Example D25
Synthesis of
7-{4-[4-(2-Isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3,4-di-
hydro-1H-[1,8]naphthyridin-2-one
[1084] The title compound was isolated as the hydrochloride salt
(213 mg, 0.423 mmol, 55.5%). MS: APCI: M+1: 467.3 (Exact Mass:
466.29).
Example E1
Synthesis of
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-6-methyl-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one
[1085] A first intermediate compound,
7-Benzyloxy-3-methyl-1H-[1,8]naphthyridin-2-one, was produced, ad
follows: To a solution of benzyl alcohol (4.3 mL, 41.4 mmol, 2.3
equiv) in DMF (15 mL) was added NaH (1.5 g, 54.0 mmol, 3.0 equiv)
in portions. H.sub.2 gas was liberated and the resultant slurry was
stirred for 30 minutes at RT. A solution of
7-chloro-3-methyl-1H-[1,8]naphthyridin-2-one (3.5 g, 18.0 mmol, 1.0
equiv) in DMF (40 mL) was added to the reaction mixture slowly via
a syringe. The reaction mixture was stirred overnight at
100.degree. C., cooled and water was added until all the solids had
precipitated. The precipitate was collected by filtration and dried
to give the first intermediate compound as a pale yellow solid
(3.75 g, 78%). mp: 220-221.degree. C.; .sup.1H NMR: (400 MHz,
CDCl.sub.3) .delta. 9.55 (br s, 1H), 7.70 (d, 1H), 7.45-7.35 (m,
6H), 6.65 (d, 1H), 5.40 (s, 2H), 2.15 (s, 3H). MS: ES+ 267.02
(M+H).sup.+, exact mass: 266.11.
[1086] A second intermediate compound,
7-Benzyloxy-2-(4-benzyloxy-butoxy)-3-methyl-[1,8]naphthyridine, was
produced as follows: To a stirred mixture of
7-benzyloxy-3-methyl-1H-[1,8]naphthyridin-2-one (2.5 g, 9.4 mmol,
1.0 equiv), triphenylphosphine (7.4 g, 28.2 mmol, 3.0 equiv) and
4-benzyloxy butanol (4.9 mL, 28.2 mmol, 3.0 equiv) in THF (250 mL)
was added DEAD (4.5 mL, 28.2 mmol, 3.0 equiv) dropwise under
nitrogen atmosphere. The reaction mixture was stirred for 2 hours
and quenched with MeOH (10 mL). The solvents were evaporated and
the residue was purified by column chromatography (25%
EtOAc/hexanes) to afford the second intermediate compound as a pale
yellow viscous oil (1.27 g, 32%). .sup.1H NMR: (400 MHz,
CDCl.sub.3) .delta. 7.85 (d, 1H), 7.70 (s, 1H), 7.50-7.25 (m, 10H),
6.85 (d, 1H), 5.60 (s, 2H), 4.62 (t, 2H), 4.55 (s, 2H), 3.58 (t,
2H), 2.30 (s, 3H). MS: ES+ 429.07 (M+H).sup.+, exact mass:
428.21.
[1087] A third intermediate compound,
7-(4-Hydroxy-butoxy)-6-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one,
was produced as follows: To a solution of
7-benzyloxy-2-(4-benzyloxy-butoxy)-3-methyl-[1,8]naphthyridine
(1.25 g, 2.92 mmol) in THF (20 mL) and MeOH (100 mL) was added 10%
Pd--C (1.0 g) and the mixture was hydrogenated at 40 psi for 48
hours. The reaction mixture was filtered through a celite bed
rinsing with MeOH and CH.sub.2Cl.sub.2. The filtrate was
concentrated and the residue was purified by column chromatography
(10% MeOH/EtOAc) to afford the third intermediate compound as a
white shiny solid (0.55 g, 76%). mp: 118-119.degree. C.; .sup.1H
NMR: (400 MHz, CDCl.sub.3) .delta. 7.65 (br s, 1H), 7.20 (s, 1H),
4.30 (t, 2H), 3.75 (t, 2H), 2.85 (t, 2H), 2.60 (t, 2H), 2.10 (s,
3H), 1.90-1.85 (m, 2H), 1.78-1.62 (m, 2H). MS: ES+ 251.02
(M+H).sup.+, exact mass: 250.13.
[1088] To a clear solution of the Dess-Martin reagent (0.90 g, 2.12
mmol, 1.3 equiv) in CH.sub.2Cl.sub.2 (40 mL) was added
7-(4-hydroxy-butoxy)-6-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one
(0.40 g, 1.6 mmol, 1.0 equiv) and the mixture was stirred at room
temperature for 3 hours. TLC indicated the presence of a trace
amount of starting material and hence more Dess-Martin reagent (0.1
g) was added and the mixture was stirred for an additional 1 hour.
The reaction mixture was diluted with CH.sub.2Cl.sub.2 and poured
into a saturated solution of NaHCO.sub.3 containing
Na.sub.2S.sub.2O.sub.3 (2.0 g). The layers were separated and the
aqueous layer was extracted with CH.sub.2Cl.sub.2 (2.times.20 mL).
The combined organic layer was dried over Na.sub.2SO.sub.4 and
concentrated. The crude aldehyde was dissolved in DCE and
1-(2,3-dichlorophenyl)piperazine monohydrochloride, Et.sub.3N and
NaBH(OAc).sub.3 were added. The reaction mixture was stirred for 1
hour, diluted with CH.sub.2Cl.sub.2 and washed with saturated
NaHCO.sub.3 and brine. The organic layer was dried over Na.sub.2SO4
and concentrated. Purification of the residue by column
chromatography (10% MeOH/EtOAc) gave the title compound as a white
solid (0.51 g, 54%). mp: 138-139.degree. C.; .sup.1H NMR: (400 MHz,
CDCl.sub.3) .delta. 7.50 (br s, 1H), 7.25-7.15 (m, 3H), 6.95 (m,
1H), 4.25 (t, 2H), 3.10 (br s, 4H), 2.82 (t, 2H), 2.65 (br s, 4H),
2.60 (t, 2H), 2.50 (t, 2H), 2.10 (s, 3H), 1.80-1.60 (m, 4H). MS:
ES+ 463.11 (M+H).sup.+, 465.12, exact mass: 462.16.
Example E2
Synthesis of
6-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[-
1,8]naphthyridin-2-one
[1089] To a clear solution of Dess-Martin reagent (1.40 g, 3.3
mmol, 1.3 equiv) in CH.sub.2Cl.sub.2 (200 mL) was added
7-(4-hydroxy-butoxy)-6-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one
(0.55 g, 2.2 mmol, 1.0 equiv) and the mixture was stirred at room
temperature for 4 hours. TLC confirmed the completion of the
reaction. The reaction mixture was diluted with CH.sub.2Cl.sub.2
and poured into a saturated solution of NaHCO.sub.3 containing
Na.sub.2S.sub.2O.sub.3 (3.0 g). The mixture was stirred and the
organic layer was separated. The aqueous layer was extracted with
CH.sub.2Cl.sub.2 (2.times.30 mL) and the combined organic layer was
dried over Na.sub.2SO.sub.4 and concentrated. The crude aldehyde
was dissolved in DCE and 1-naphthalen-1-yl-piperazine
monohydrochloride (0.76 g, 3.08 mmol, 1.4 equiv), Et.sub.3N (0.5
mL, 1.7 equiv) and NaBH(OAc).sub.3 (0.65 g, 3.08 mmol, 1.4 equiv)
were added. The reaction mixture was stirred for 1 hour, diluted
with CH.sub.2Cl.sub.2 and washed with saturated NaHCO.sub.3 and
brine. The organic layer was dried over Na.sub.2SO.sub.4 and
concentrated. Purification of the residue by column chromatography
(5% MeOH/EtOAc) gave the title compound as a white solid (0.40 g,
41%). mp: 76-78.degree. C.; .sup.1H NMR: (400 MHz, CDCl.sub.3)
.delta. 8.22 (d, 1H), 7.85 (d, 1H), 7.58-7.38 (m, 5H), 7.25 (s,
1H), 7.05 (d, 1H), 4.25 (t, 2H), 3.30-3.10 (br s, 4H), 2.82-2.65
(m, 4H), 2.65-2.45 (m, 4H), 2.15 (s, 3H), 1.88-1.35 (m, 6H). MS:
ES+ 445.41 (M+H).sup.+, exact mass: 444.25.
Example E3
Synthesis of
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-6-fluoro-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one
[1090] A first intermediate compound,
6-(4-Benzyloxy-butoxy)-2-chloro-5-fluoro-nicotinonitrile, was
produced as follows: To a solution of 4-benzyloxy-1-butanol (19.44
g, 108 mmol) in THF (200 mL) cooled to -40.degree. C. was added 1M
KO.sup.tBu in THF (108 mL, 108 mmol). The mixture was stirred for 5
min at -10.degree. C. and then added to a solution of
2,6-dichloro-5-fluoro-nicotinonitrile (20.0 g, 105 mmol) in THF
(300 mL) cooled to -70.degree. C. over 25 min. The mixture turned
brownish yellow with some cloudiness. The reaction was allowed to
warm to room temperature over 2 h. The THF was evaporated and the
residue was diluted with Et.sub.2O. The mixture was washed with
water, brine, 1N citric acid, water and brine, dried over
Na.sub.2SO.sub.4 and concentrated to an oil. The oil was dissolved
in Et2O/hexanes and cooled in the refrigerator overnight. A
crystalline solid formed which was collected by filtration, washed
with hexanes and dried to give the first intermediate compound as a
white solid (17.0 g). The filtrate was concentrated and purified by
silica gel chromatography (Biotage 40L, 0-6% EtOAc/Hexanes) to give
additional first intermediate compound as a white solid (total of
26.9 g, 80.4 mmol, 77%). MS: APCI: M+1: 335.1 (Exact Mass:
334.09).
[1091] A second intermediate compound,
2-Azido-6-(4-benzyloxy-butoxy)-5-fluoro-nicotinonitrile, was
produced as follows: To a solution of
6-(4-benzyloxy-butoxy)-2-chloro-5-fluoro-nicotinonitrile (20.0 g,
60.0 mmol) in DMF (40 mL) was added sodium azide (4.27 g, 65.7
mmol) and the mixture was heated at 70.degree. C. overnight. The
mixture was poured into Et.sub.2O and washed with water and brine.
The Et.sub.2O solution was passed through a silica gel Biotage 12M
column, dried over MgSO.sub.4 and charcoal, and concentrated to
give an oil (19.67 g). Recrystallization from Et.sub.2O/MeOH gave
the second intermediate compound as a solid (17.24 g, 50.5 mmol,
84%). MS: APCI: M+1: (Exact Mass: 341.13).
[1092] A third intermediate compound,
2-Amino-6-(4-benzyloxy-butoxy)-5-fluoro-nicotinonitrile, was
produced as follows: To a solution of
2-azido-6-(4-benzyloxy-butoxy)-5-fluoro-nicotinonitrile (17.2 g,
50.4 mmol) in MeOH (450 mL) was added hexamethyldisilthiane (19.0
g, 106.5 mmol). The reaction gives off a gas and a precipitate
forms after 15 min. The reaction was stirred overnight at room
temperature and then filtered to remove the precipitated sulfur.
The mixture was concentrated and then redissolved in Et.sub.2O. The
mixture was filtered again to remove additional precipitated
sulfur. The filtrate was concentrated and recrystallized from
MeOH/hexanes. The solid was collected by filtration, washed with
hexane/MeOH and dried to give the third intermediate compound
(13.74 g, 43.57 mmol, 86%). MS: APCI: M+1: 316.4 (Exact Mass:
315.14).
[1093] A fourth intermediate compound,
2-Amino-6-(4-benzyloxy-butoxy)-5-fluoro-pyridine-3-carbaldehyde,
was produced as follows: To a solution of
2-amino-6-(4-benzyloxy-butoxy)-5-fluoro-nicotinonitrile (7.25 g,
23.0 mmol) in THF (40 mL) cooled to 0.degree. C. is added DIBALH
(1M in THF, 69 mL, 69 mmol). The reaction was complete after 5 min.
Chilled 2N HCl was added very slowly (strong exotherm) to quench
the reaction. The mixture forms a red gelatinous material.
Et.sub.2O was added and the layers were separated. The organic
layer was washed with brine and saturated NaHCO.sub.3 and then
filtered through Celite. There may still have been some aluminum
complexed product so the organic solution was washed again with 2N
HCl, brine, saturated NaHCO.sub.3 and brine, dried over MgSO.sub.4
and concentrated to give the crude fourth intermediate compound as
an orange oil (5.23 g, 16.4 mmol, 71%). MS: APCI: M+1: 319.2 (Exact
Mass: 318.14).
[1094] A fifth intermediate compound,
3-[2-Amino-6-(4-benzyloxy-butoxy)-5-fluoro-pyridin-3-yl]-acrylic
acid ethyl ester, was produced as follows: To a solution of
2-amino-6-(4-benzyloxy-butoxy)-5-fluoro-pyridine-3-carbaldehyde
(5.23 g, 16.4 mmol, crude from previous reaction) in THF (50 mL)
was added (carbethoxymethylene)triphenylphosphorane (5.72 g. 16.43
mmol) and the solution was heated at 67.degree. C. overnight. The
reaction was concentrated and the residue was purified by liquid
chromatography (Biotage 65M, 0-10% EtOAc/CH.sub.2Cl.sub.2) to give
the fifth compound as a yellow solid (73%). MS: APCI: M+1: 389.4
(Exact Mass: 388.18).
[1095] A sixth intermediate compound,
7-(4-Benzyloxy-butoxy)-6-fluoro-3,4-dihydro-1H-[1,8]naphthyridin-2-one,
was produced as follows:
3-[2-Amino-6-(4-benzyloxy-butoxy)-5-fluoro-pyridin-3-yl]-acrylic
acid ethyl ester (7.18 g, 18.5 mmol) was hydrogenated under an
atmosphere of H.sub.2 (4300 psi) using Ra-Ni (2 g) in MeOH (100
mL). The reaction was filtered and concentrated. MS indicated the
double bond had been reduced and some of the material cyclized. The
material was suspended in .sup.iPrOH and p-toluenesulfonic acid
hydrate (0.41 g) was added. The mixture was heated at 80.degree. C.
for 30 min. Saturated NaHCO.sub.3 was added and the mixture was
concentrated. The residue was partitioned between Et.sub.2O and
water. The organic layer was washed with saturated NaHCO.sub.3 and
brine, dried over MgSO.sub.4 and concentrated to give a yellow oil
which solidified. Recrystallization from Et.sub.2O/hexane afforded
the sixth intermediate compound as a pale yellow solid. MS: APCI:
M+1: 345.1 (Exact Mass: 344.15).
[1096] A seventh intermediate compound,
6-Fluoro-7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one,
was produced as follows:
7-(4-Benzyloxy-butoxy)-6-fluoro-3,4-dihydro-1H-[1,8]naphthyridin-2-one
(4.79 g, 13.9 mmol) was hydrogenated under an atmosphere of H.sub.2
using 20% Pd/C (1.0 g) in EtOH (100 mL). The reaction was filtered
and concentrated to give a slurry. Et.sub.2O was added and the
solids were filtered. The filtrate was concentrated and the process
was repeated to give the seventh intermediate compound as a solid
(3.2 g, 13.0 mmol, 91%). MS: APCI: M+1: 255.1 (Exact Mass:
254.11).
[1097] An eighth intermediate compound,
4-(3-Fluoro-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyralde-
hyde, was produced as follows: To a solution of oxalyl chloride
(1.78 g, 14.0 mmol) in CH.sub.2Cl.sub.2 (25 mL) cooled to
-70.degree. C. was added a solution of DMSO (2.15 g, 27.6 mmol) in
CH.sub.2Cl.sub.2 (1.5 mL) over 4 min. The mixture was stirred for 5
min and a solution of
6-fluoro-7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one
(3.1 g, 12.0 mmol) in DMSO (4.5 mL) and CH.sub.2Cl.sub.2 (44 mL)
cooled to -50.degree. C. was added over 5 min. The mixture was
stirred for 10 min at -70.degree. C. and it solidified. The
reaction was warmed to -30.degree. C. and triethylamine (8.9 mL,
63.8 mmol) was added resulting in a stirable suspension. The
reaction was warmed to room temperature over 30 min. The mixture
was added to water and the layers were separated. The organic layer
was washed with water and dilute brine, dried over MgSO.sub.4 and
concentrated to give an oil. The residue was partitioned between
Et.sub.2O and aqueous citric acid (pH 4.5). The organic layer was
washed with dilute aqueous NaHCO.sub.3 and brine, dried over
MgSO.sub.4 and concentrated to give the eighth intermediate
compound as a yellow oil (1.89 g) which was used directly in the
next reaction. MS: APCI: M+1: 253.2 (Exact Mass: 252.09).
[1098] To a suspension of 1-(2,3-dichloro-phenyl)-piperazine
hydrochloride (0.80 g, 3.0 mmol) in 1,2-dichloroethane (10 mL) was
added triethylamine (0.61 mL, 6.0 mmol). The mixture was stirred
for 30 min at room temperature and
4-(3-fluoro-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyralde-
hyde (0.76 g, 3.0 mmol) was added as a suspension in
1,2-dichloroethane (5 mL). The mixture was stirred for 30 min and
NaBH(OAc).sub.3 (0.89 g, 4.2 mmol) was added as a solid. The
reaction was stirred at room temperature for 4 h. The mixture was
poured into EtOAc/dichloroethane and washed with saturated
NaHCO.sub.3 and brine. The organic layer was washed with aqueous
citric acid (pH 4.5) and brine, dried over Na.sub.2SO.sub.4 and
concentrated to a slurry. Et.sub.2O was added and the solid was
collected by filtration. Purification by liquid chromatography
(Biotage 40S, gradient of CH.sub.2Cl.sub.2 to 10% MeOH/CHCl.sub.3)
gave the title compound as a white solid (738 mg, 1.58 mmol, 53%).
MS: APCI: M+1: 467.3 (Exact Mass: 466.13).
Example E4
Synthesis of
6-Fluoro-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[-
1,8]naphthyridin-2-one
[1099] The title compound was prepared by reductive amination of
4-(3-fluoro-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyralde-
hyde with 1-naphthalen-1-yl-piperazine hydrochloride according to
the above procedure. MS: APCI: M+1: 449.1 (Exact Mass: 448.23).
Example E5
Synthesis of
6-Fluoro-7-[4-(4-indan-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]n-
aphthyridin-2-one
[1100] The title compound was prepared by reductive amination of
4-(3-fluoro-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyralde-
hyde with 1-indan-4-yl-piperazine according to the above procedure.
MS: APCI: M+1: 439.2 (Exact Mass: 438.24).
Example E6
Synthesis of
6-Chloro-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[-
1,8]naphthyridin-2-one
[1101] A first intermediate compound,
6-Chloro-7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one,
was produced as follows: To a solution of
7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one (2.0 g,
8.46 mmol) in DMF (17 mL) was added NCS (1.24 g, 9.31 mmol). The
solution was stirred at room temperature for 1 hour. There was no
reaction so the mixture was heated at 80.degree. C. for 5 hours.
Water was added and the mixture was extracted with EtOAc. The
organic layer was washed with water and brine, dried over
Na.sub.2SO.sub.4 and concentrated. Purification by liquid
chromatography (0-5% MeOH/CH.sub.2Cl.sub.2) gave the first
intermediate compound as an off-white solid (0.71 g, 2.62 mmol, low
yield was due to chromatography mishap). MS: APCI: M+1: 271.0
(Exact Mass: 270.08).
[1102] A second intermediate compound,
4-(3-Chloro-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyralde-
hyde, was produced as follows: A suspension of the Dess-Martin
reagent (1.67 g, 3.93 mmol) in CH.sub.2Cl.sub.2 (6 mL) was stirred
for 30 min and a solution of
6-chloro-7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one
(0.71 g, 2.62 mmol) in CH.sub.2Cl.sub.2 (5 mL)/THF (15 mL) was
added via cannula. The reaction mixture became homogenous and
turned yellow. The reaction was stirred at room temperature for 6
h. A 1:1 mixture of saturated NaHCO.sub.3 and saturated
Na.sub.2S.sub.2O.sub.3 was added and the mixture was stirred for 15
min. The mixture was extracted with EtOAc (2.times.). The organic
layer was washed with saturated NaHCO.sub.3 and brine, dried over
MgSO.sub.4 and concentrated to give a yellow solid (0.74 g, approx.
80% pure, used crude in the next reaction). MS: APCI: M+1: 269.0
(Exact Mass: 268.06).
[1103] To a solution of
4-(3-chloro-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyralde-
hyde (400 mg, approx. 1.49 mmol, crude from previous reaction) in
DCE (7 mL) was added 1-naphthalen-1-yl-piperazine hydrochloride
(370 mg, 1.49 mmol) followed by Et.sub.3N (0.42 mL, 2.98 mmol). The
solution was stirred for 15 min and NaBH(OAc).sub.3 (410 mg, 1.94
mmol) was added as a powder. The reaction was stirred at room
temperature for 2 h and quenched with saturated NaHCO.sub.3 and
H.sub.2O. The mixture was extracted with EtOAc. The organic layer
was washed with saturated NaHCO.sub.3, H.sub.2O and brine, dried
over Na.sub.2SO.sub.4 and concentrated. Purification by liquid
chromatography (0-3% MeOH/CH.sub.2Cl.sub.2) afforded the title
compound as an off-white foam (324 mg, 0.697 mmol, 47%). Et.sub.2O
was added and the foam turned into a white solid after 5 minutes of
stirring. The solid was collected by filtration, washed with
Et.sub.2O and dried to give a white solid. MS: APCI: M+1: 465.2
(Exact Mass: 464.20).
Example E7
Synthesis of
6-Bromo-7-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-
-1H-[1,8]naphthyridin-2-one
[1104] A first intermediate compound,
6-Bromo-7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one,
was produced as follows: To a solution of
7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one (2.0 g,
8.46 mmol) in DMF (18 mL) was added NBS (1.70 g, 9.30 mmol). The
solution was stirred at room temperature overnight. Within 2 hours,
the reaction had turned purple. Water was added and the mixture was
extracted with EtOAc. The organic layer was washed with water and
brine, dried over Na.sub.2SO.sub.4 and concentrated to give a brown
oil. Purification by liquid chromatography (0-5%
MeOH/CH.sub.2Cl.sub.2) gave the first intermediate compound as an
off-white solid (2.13, 6.76 mmol, 80%). MS: APCI: M+1: 315.0, 317.0
(Exact Mass: 314.03).
[1105] A second intermediate compound,
4-(3-Bromo-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldeh-
yde, was produced as follows: A suspension of the Dess-Martin
reagent (3.28 g, 7.74 mmol) in CH.sub.2Cl.sub.2 (15 mL) was stirred
for 30 min and a solution of
6-bromo-7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one
(1.524 g, 4.84 mmol) in CH.sub.2Cl.sub.2 (5 mL)/THF (20 mL) was
added via cannula. The reaction mixture became homogenous and
turned yellow. The reaction was stirred at room temperature for 6 h
and then stored in the refrigerator overnight. A 1:1 mixture of
saturated NaHCO.sub.3 and saturated Na.sub.2S.sub.2O.sub.3 was
added and the mixture was stirred for 15 min. The mixture was
extracted with EtOAc (2.times.). The organic layer was washed with
saturated -NaHCO.sub.3 and brine, dried over Na.sub.2SO.sub.4 and
concentrated to give a yellow solid/oil (1.51 g, used crude in the
next reaction). MS: APCI: M+1: 313.0, 315.0 (Exact Mass:
312.01).
[1106] To a solution of
4-(3-bromo-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldeh-
yde (0.43 g, approx. 1.37 mmol, crude from previous reaction) in
DCE (6 mL) was added 1-(2,3-dichloro-phenyl)-piperazine
hydrochloride (367 mg, 1.37 mmol) followed by Et.sub.3N (0.38 mL,
2.75 mmol). The solution was stirred for 15 min and NaBH(OAc).sub.3
(407 mg, 1.92 mmol) was added as a powder. The reaction was stirred
at room temperature for 2 h and quenched with saturated NaHCO.sub.3
and H.sub.2O. The mixture was extracted with EtOAc. The organic
layer was washed with saturated NaHCO.sub.3, H.sub.2O and brine,
dried over Na.sub.2SO.sub.4 and concentrated. Purification by
liquid chromatography (4% MeOH/CH.sub.2Cl.sub.2) afforded the title
compound as a white foam (497 mg, 0.941 mmol, 69%). MS: APCI: M+1:
527.0, 529.0, 531.0 (Exact Mass: 526.05).
Example E8
Synthesis of
6-Bromo-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1-
,8]naphthyridin-2-one
[1107] To a solution of
4-(3-bromo-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldeh-
yde (1.11 g, approx. 3.54 mmol, crude) in DCE (17 mL) was added
1-naphthalen-1-yl-piperazine hydrochloride (0.882 g, 3.54 mmol)
followed by Et.sub.3N (1.0 mL, 7.1 mmol). The solution was stirred
for 15 min and NaBH(OAc).sub.3 (1.05 g, 4.96 mmol) was added as a
powder. The reaction was stirred at room temperature for 2 h and
quenched with saturated NaHCO.sub.3 and H.sub.2O. The mixture was
extracted with EtOAc. The organic layer was washed with saturated
NaHCO.sub.3, H.sub.2O and brine, dried over Na.sub.2SO.sub.4 and
concentrated. Purification by liquid chromatography (4%
MeOH/CH.sub.2Cl.sub.2) afforded the title compound as an off-white
foam (1.37 g, 2.69 mmol, 76%). The HCl salt was formed by
dissolving the title compound (138 mg, 0.27 mmol) in
Et.sub.2O/CH.sub.2Cl.sub.2 followed by the addition of 1N HCl in
Et.sub.2O (0.3 mL). The resulting white precipitate was collected
by filtration, washed with Et.sub.2O and dried to give a white
solid (125 mg). MS: APCI: M+1: 509.1, 511.1 (Exact Mass:
508.15).
Example E9
Synthesis of
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-5-methyl-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one
[1108] A first intermediate compound,
N-(7-Hydroxy-5-methyl-[1,8]naphthyridin-2-yl)-acetamide, was
produced as follows: A suspension of
7-amino-4-methyl-[1,8]naphthyridin-2-ol (25.6 g, 146 mmol) in
acetic anhydride (375 mL) was heated at reflux for 4.5 hours. The
mixture was filtered hot and washed with acetic anhydride and
Et.sub.2O. The resulting solid was dried to give the first
intermediate product (28.8 g, 132.6 mmol, 91%, >95% purity).
Calcd for C.sub.11H.sub.11N.sub.3O.sub.2: C, 60.82, H, 5.10, N,
19.34; Found C, 60.88, H, 5.03, N, 19.39.
[1109] A second intermediate compound,
N-(7-Chloro-5-methyl-[1,8]naphthyridin-2-yl)-acetamide, was
produced as follows:
N-(7-Hydroxy-5-methyl-[1,8]naphthyridin-2-yl)-acetamide (28.5 g,
131.2 mmol) was suspended in POCl.sub.3 (280 mL) and heated to
reflux for 90 min giving a dark solution. The reaction was quenched
by slowly adding it to a 3 L flask containing ice with mechanical
stirring (total volume of 1 L). The mixture was cooled and
neutralized to pH 6.5 using 15% to 50% aqueous NaOH to give a
precipitate. The mixture was filtered overnight, washed with
H.sub.2O and dried to give a light brown solid (36 g, contains
product and deacetylated compound). The solid was suspended in
refluxing toluene and the mixture was filtered while hot. The
insoluble solids were mostly more polar side products. The filtrate
was cooled to give a precipitate which was collected by filtration
and washed with toluene to give material that was enriched in the
desired product. This solid was suspended in CH.sub.2Cl.sub.2 and
the insoluble material was collected by filtration to give pure
second intermediate compound. Several additional crops were
collected (total of 18.5 g, 78.5 mmol, 60%). MS: APCI: M+1: 236.1,
238.1 (Exact Mass: 235.05).
[1110] A third intermediate compound,
7-Chloro-5-methyl-[1,8]naphthyridin-2-ylamine, was produced as
follows: N-(7-Chloro-5-methyl-[1,8]naphthyridin-2-yl)-acetamide
(11.5 g, 48.8 mmol) was suspended in 10% H.sub.2SO.sub.4 (180 mL).
The mixture was heated at 110.degree. C. for 2 h and filtered hot
to remove the minor insoluble solids. H.sub.2O (180 mL) was added
to the filtrate and a precipitate formed. The mixture was heated
again to give a solution. The heating was removed and concentrated
NH.sub.4OH was added with rapid stirring until the mixture was at
pH 10. The mixture was cooled and the precipitate was collected by
filtration, washed with H.sub.2O and dried to give the third
intermediate compound as a pale yellow solid (9.24 g, 47.7 mmol,
98%). mp 264-266.degree. C. MS: APCI: M+1: 194.0, 196.0 (Exact
Mass: 193.04).
[1111] A fourth intermediate compound,
7-Chloro-5-methyl-1H-[1,8]naphthyridin-2-one, was produced as
follows: To a mixture of
7-chloro-5-methyl-[1,8]naphthyridin-2-ylamine (13.7 g, 70.7 mmol)
in concentrated H.sub.2SO.sub.4 (55 mL) cooled to 0.degree. C. was
added a solution of NaNO.sub.2 (6.3 g, 92.0 mmol) in H.sub.2O (25
mL) dropwise. Additional H.sub.2O was added and the mixture was
stirred at 20.degree. C. for 1 h. The mixture was poured into ice.
The resulting precipitate was filtered, washed with H.sub.2O, EtOH
and Et.sub.2O and dried to give the fourth intermediate compound as
a powder (13.45 g, 69.1 mmol, 98%).
[1112] A fifth intermediate compound,
7-(4-Benzyloxy-butoxy)-5-methyl-1H-[1,8]naphthyridin-2-one, was
produced as follows: To a suspension of 60% NaH (5.7 g, 144 mmol,
washed with THF to remove the oil) in DMF (80 mL) was added
4-benzyloxy-1-butanol (25.0 g, 137 mmol) slowly. The mixture was
warmed to 70.degree. C. and then cooled to RT. This mixture was
added to a suspension of
7-chloro-5-methyl-1H-[1,8]naphthyridin-2-one (12.7 g, 65.3 mmol) in
DMF (40 mL) to give a brown solution. The mixture was heated at
90.degree. C. for 30 min and at 120.degree. C. for 2 h. The
reaction was allowed to cool to room temperature and stir
overnight. The reaction was poured into a separatory funnel and
Et.sub.2O was added followed by a minimal amount of H.sub.2O. The
ether phase contained excess 4-benzyloxy-1-butanol. The pH of the
DMF/aqueous layer was adjusted to 11.5 by adding 1 N citric acid
and a precipitate formed. The precipitate was filtered and washed
with Et.sub.2O. The solid was resuspended in H.sub.2O (100 mL) and
EtOH (200 mL) was added to dissolve the solid. The mixture was
filtered through celite to remove the insoluble solids. The
filtrate was diluted with H.sub.2O (700 mL) and a pale yellow solid
precipitated. The solid was collected by filtration, washed with
H.sub.2O and dried to give the fifth intermediate compound as a
solid (7.38 g, 21.8 mmol, 33%). MS: APCI: M+1: 339.2 (Exact Mass:
338.16).
[1113] A sixth intermediate compound,
7-(4-Hydroxy-butoxy)-5-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one,
was produced as follows:
7-(4-Benzyloxy-butoxy)-5-methyl-1H-[1,8]naphthyridin-2-one (7.31 g,
21.6 mmol) was hydrogenated using 20% Pd/C (1.0 g) in EtOH (100
mL). The product precipitated out of solution before the double
bond was reduced. DMF (75 mL) was added and the mixture was heated
to dissolve the solids. More 20% Pd/C (1.0 g) was added and the
hydrogenation was continued, however the double bond was resistant
to further hydrogenation under these conditions. The reaction
mixture was filtered and the solvent was concentrated to give a
slurry. Et.sub.2O was added and the solid was collected by
filtration and dried to give
7-(4-hydroxy-butoxy)-5-methyl-1H-[1,8]naphthyridin-2-one (4.37 g,
17.6 mmol, 81%).
[1114] 7-(4-Hydroxy-butoxy)-5-methyl-1H-[1,8]naphthyridin-2-one
(3.0 g, 12.08 mmol) was hydrogenated using 20% Pd/C in acetic acid
( mL) for x h. The reaction mixture was filtered and concentrated
to give a mixture of the sixth intermediate compound and the
corresponding acetylated compound. The mixture was suspended in
MeOH (30 mL) and H.sub.2O (10 mL) and the pH was adjusted to 14 by
addition of 50% aqueous NaOH. The mixture was warmed to 45.degree.
C. Glacial acetic acid was added to bring the pH to 7.5 and the
MeOH was removed under reduced pressure. The resulting solid was
filtered, washed with H.sub.2O and dried to give the sixth
intermediate compound as a solid (2.78 g, 11.1 mmol, 92%). MS:
APCI: M+1: 251.1 (Exact Mass: 250.13).
[1115] A seventh intermediate compound,
4-(4-Methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyralde-
hyde, was produced as follows: To a solution of oxalyl chloride
(1.57 g, 12.4 mmol) in CH.sub.2Cl.sub.2 (20 mL) cooled to
-70.degree. C. was added a solution of DMSO (1.90 g, 24.38 mmol) in
CH.sub.2Cl.sub.2 (4 mL) over 4 min. The mixture was stirred for 5
min and a solution of
7-(4-hydroxy-butoxy)-5-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one
(2.70 g, 11.0 mmol) in DMSO (8 mL) and CH.sub.2Cl.sub.2 (40 mL) was
added over 5 min. The reaction was stirred at -70.degree. C. for 10
min and a solid precipitated. The mixture was warmed to -50.degree.
C. for 5 min and recooled to -70.degree. C. Et.sub.3N (7.9 mL, 56.4
mmol) was added and the mixture was warmed to room temperature over
30 min. The reaction mixture was added to H.sub.2O and the layers
were separated. The organic layer was washed with H.sub.2O, 1N
citric acid (2.times.) and saturated NaHCO.sub.3, dried over
Na.sub.2SO.sub.4 and concentrated to a slurry. Et.sub.2O was added
and the solid was collected by filtration to give the seventh
intermediate compound (2.38 g, 9.59 mmol, 89%). MS: APCI: M+1:
249.2 (Exact Mass: 248.12).
[1116] To a suspension of 1-(2,3-dichloro-phenyl)-piperazine
hydrochloride (0.93 g, 3.48 mmol) in dichloroethane (10 mL) was
added Et.sub.3N (0.96 mL, 6.92 mmol). The mixture was stirred for
15 min and a suspension of
4-(4-methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyralde-
hyde (0.86 g, 3.46 mmol) in dichloroethane (5 mL) was added. After
20 min at RT, NaBH(OAc).sub.3 (1.03 g, 4.85 mmol) was added and the
reaction was stirred at room temperature for 4 h. The reaction
mixture was poured into CH.sub.2Cl.sub.2 and washed with H.sub.2O,
1N citric acid, saturated NaHCO.sub.3 and brine, dried over
Na.sub.2SO.sub.4 and concentrated to an oil. Et.sub.2O was added
and the organics were decanted from an insoluble gum. The filtrate
yielded a crystalline solid, which was collected by filtration and
dried. Purification by liquid chromatography (gradient elution,
100% CHCl.sub.3 to 2% MeOH/CHCl.sub.3, Biotage 40m column) provided
the title compound as a white solid (1.12 g, 2.44 mmol, 70%). MS:
APCI: M+1: 463.1 (Exact Mass: 462.16).
Example E10
Synthesis of
5-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[-
1,8]naphthyridin-2-one
[1117] The title compound was prepared by reductive amination of
4-(4-methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyralde-
hyde with 1-naphthalen-1-yl-piperazine hydrochloride according to
the above procedure. MS: APCI: M+1: 445.2 (Exact Mass: 444.25).
Example E11
Synthesis of
5-Methyl-7-{4-[4-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-but-
oxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one
[1118] The title compound was prepared by reductive amination of
4-(4-methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyralde-
hyde with 1-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine
according to the above procedure. MS: APCI: M+1: 450.0 (Exact Mass:
448.28).
Example E12
Synthesis of
7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-5-methyl-3,4-dihydro-1H-[1,8]n-
aphthyridin-2-one
[1119] The title compound was prepared by reductive amination of
4-(4-methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyralde-
hyde with 1-indan-4-yl-piperazine according to the above procedure.
MS: APCI: M+1: 435.6 (Exact Mass: 434.27).
Example E13
Synthesis of
7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-5-trifluoromethyl-3,4-dihydro--
1H-[1,8]naphthyridin-2-one
[1120] A first intermediate compound,
6-(4-Benzyloxy-butoxy)-2-chloro-4-trifluoromethyl-nicotinonitrile,
was produced as follows: A solution of
2,6-dichloro-4-(trifluoromethyl)niconitrile (20 g, 83 mmol) in THF
(200 mL) was cooled to -70.degree. C. Separately, a solution of
4-benzyloxy-1-butanol (15.41 g, 85.5 mmol) in THF (150 mL) was
cooled to -40.degree. C. and 1M potassium t-butoxide in THF (85.5
mL) was added dropwise and the temperature was allowed to reach
10.degree. C. over 15 minutes. The solution thus prepared was added
to the solution of 2,6-dichloro-4-(trifluoromethyl)niconitrile at
-70.degree. C. over 2 hours, followed by warming to 25.degree. C.
for 16 hours. The THF was removed in vacuo and the residue was
partitioned between ether and water. The ether phase was washed
with 1N citric acid, brine, dried over magnesium sulfate and
filtered. The filtrate was evaporated to an oil, which was
sufficiently pure to be used in the next step.
[1121] A second intermediate compound,
2-Azido-6-(4-benzyloxy-butoxy)-4-trifluoromethyl-nicotinonitrile,
was produced as follows: To DMF (60 mL) was added
6-(4-benzyloxy-butoxy)-2-chloro-4-trifluoromethyl-nicotinonitrile
(32 g, 83.1 mmol) and sodium azide (5.9 g, 91 mmol) followed by
heating at 70.degree. C. for 16 hours. The mixture was partitioned
between water and ether. The ether phase was washed with brine,
dried over magnesium sulfate, filtered and evaporated to give the
second intermediate compound as an oil (30.7 g) of sufficient
purity to be used in the next step.
[1122] A third intermediate compound,
2-Amino-6-(4-benzyloxy-butoxy)-4-trifluoromethyl-nicotinonitrile,
was produced as follows: To a solution of
2-azido-6-(4-benzyloxy-butoxy)-4-trifluoromethyl-nicotinonitrile
(30.7 g, 78.5 mmol) in methanol (150 mL) cooled to 0.degree. C. was
added 1,1,1,3,3,3-hexamethyl-disilathiane (28.02 g, 157 mmol). The
reaction was exothermic and off-gassing occurred over 3 hours. A
minor amount of precipitate was filtered off and the filtrate was
refrigerated giving a solid precipitate. The solid was filtered,
washed with hexane and dried to a weight of 19.7 g. The solid was
purified by chromatography on silica gel eluting with
dichloromethane to give the third intermediate compound as a solid
(6.08 g), mp 94-96.degree. C.
[1123] A fourth intermediate compound,
2-Amino-6-(4-benzyloxy-butoxy)-4-trifluoromethyl-pyridine-3-carbaldehyde,
was produced as follows: To solution of
2-amino-6-(4-benzyloxy-butoxy)-4-trifluoromethyl-nicotinonitrile
(8.76 g, 24 mmol) in THF (40 mL) cooled to 0.degree. C. was added
1M DIBAL in THF (96 mL). After warming to 25.degree. C. for 1 hour,
the mixture was quenched by addition of a solution of cold 2N HCl
(200 mL). After stirring and warming to 25.degree. C., the mixture
was neutralized to pH 7 by addition of potassium carbonate and the
mixture extracted with diethyl ether. The ether washings were dried
over magnesium sulfate, filtered and evaporated to give the fourth
intermediate compound as an oil (7.5 g).
[1124] A fifth intermediate compound,
3-[2-Amino-6-(4-benzyloxy-butoxy)-4-trifluoromethyl-pyridin-3-yl]-acrylic
acid ethyl ester, was produced as follows: To a solution of
2-amino-6-(4-benzyloxy-butoxy)-4-trifluoromethyl-pyridine-3-carbaldehyde
(4.66 g, 10.6 mmol) in methanol (100 mL) was added
(triphenylphosphanylidene) acetic acid ethyl ester (7.09 g, 20.4
mmol). The mixture was heated to 67.degree. C. for 16 hours and
evaporated to an oil. Purification by chromatography on silica gel
eluting with hexane/ethyl acetate provided the fifth intermediate
compound as an oil (4.66 g).
[1125] A sixth intermediate compound,
7-(4-Benzyloxy-butoxy)-5-trifluoromethyl-3,4-dihydro-1H-[1,8]naphthyridin-
-2-one, was produced as follows: To a solution of
3-[2-amino-6-(4-benzyloxy-butoxy)-4-trifluoromethyl-pyridin-3-yl]-acrylic
acid ethyl ester (7.5 g, 20 mmol) in THF (70 mL) was added Raney
Nickel (1.5 g). The reaction was pressurized to 50 psi with
hydrogen gas for 16 hours. The mixture was filtered, evaporated to
an oil, redissolved in isopropanol (20 mL) and p-toluene sulfonic
acid (0.24 g) was added. The mixture was heated at reflux for 45
minutes. The mixture was poured into a mixture of saturated sodium
carbonate and diethyl ether and the ether phase was separated. The
ether layer was washed with brine, dried over anhydrous magnesium
sulfate, filtered and evaporated to give the sixth intermediate
compound as an oil (3.29 g).
[1126] A seventh intermediate compound,
7-(4-Hydroxy-butoxy)-5-trifluoromethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-
-one, was produced as follows: To a 50:50 mixture of THF/methanol
(50 mL) was added
7-(4-benzyloxy-butoxy)-5-trifluoromethyl-3,4-dihydro-1H-[1,8]na-
phthyridin-2-one (3.29 g, 8.3 mmol) followed by 20% Pd on charcoal
(2.0 g). The reaction was pressurized to 50 psi with hydrogen gas
for 48 hours. The mixture was filtered and evaporated to give the
seventh intermediate compound as a solid (3.29 g).
[1127] An eighth intermediate compound,
4-(7-Oxo-4-trifluoromethyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)--
butyraldehyde, was produced as follows: To a solution of oxallyl
chloride (1.1 g, 8.77 mmol) and DMSO (1.35 g, 17.2 mmol) in
dichloromethane (20 mL) at -70.degree. C. was added a solution of
7-(4-hydroxy-butoxy)-5-trifluoromethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-
-one (2.32 g, 7.62 mmol) in DMSO over 10 minutes. To the mixture
was added triethylamine (4.0 g, 40 mmol) and the reaction was
warmed to 25.degree. C. over 45 minutes. The mixture was washed
consecutively with 1N citric acid, saturated sodium bicarbonate and
brine, followed by drying of the organic phase over magnesium
sulfate and filtration. The filtrate was evaporated to give the
eighth intermediate compound as a solid (2.28 g).
[1128] In a manner similar to that of other examples above,
1-indan-4-yl-piperazine hydrochloride was coupled by reductive
amination to
4-(7-oxo-4-trifluoromethyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-ylox-
y)-butyraldehyde followed by typical workup and purification to
give the title compound. MS: APCI: M+1: 489.4 (Exact Mass:
488.24).
Example E14
Synthesis of
7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-5-trifluoromethyl-3,4-dih-
ydro-1H-[1,8]naphthyridin-2-one
[1129] In a manner similar to that of other examples above,
1-naphthalen-1-yl-piperazine hydrochloride was coupled by reductive
amination to
4-(7-oxo-4-trifluoromethyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)--
butyraldehyde followed by typical workup and purification to give
the title compound. MS: APCI: M+1: 499.1 (Exact Mass: 489.22).
Example E15
Synthesis of
7-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-5-tr-
ifluoromethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one
[1130] In a manner similar to that of other examples above,
1-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine was coupled by
reductive amination to
4-(7-oxo-4-trifluoromethyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)--
butyraldehyde followed by typical workup and purification to give
the title compound. MS: APCI: M+1: 503.1 (Exact Mass: 502.26).
Example F1
Synthesis of
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-pyri-
do[2,3-d]pyrimidin-2-one
[1131] A first intermediate compound,
N-{3-Hydroxymethyl-6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridin-2-yl}--
2,2-dimethyl-propionamide, was produced as follows: An ice-cold
mixture of
N-{3-formyl-6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridin-2-yl}-2,2-dim-
ethyl-propionamide (2.20 g, 5.80 mmol) in methanol (20 mL) was
treated with NaBH.sub.4 (0.394 g, 10.40 mmol) in portions. Bubbles
evolved from the mixture. The mixture was warmed to room
temperature and stirred for 1 hour. The colorless solution was
quenched with water and concentrated under vacuum. The residue was
diluted with water and EtOAc. The organic layer was separated and
the aqueous layer was extracted with EtOAc. The combined organic
extracts were washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated under vacuum to afford the first
intermediate compound as a yellow oil (2.21 g, quantitative).
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.69 (d, 1H), 7.68 (br
s, 1H), 6.62 (d, 1H), 4.62-4.58 (m, 1H), 4.38 (d, 2H), 4.26 (t,
2H), 4.04-3.96 (m, 1H), 3.92-3.77 (m, 2H), 3.55-3.42 (m, 2H),
1.92-1.67 (m, 6H), 1.63-1.48 (m, 4H), 1.36 (s, 9H). MS ES:
m/z=381.10.
[1132] A second intermediate compound,
N-{3-Azidomethyl-6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridin-2-yl}-2,-
2-dimethyl-propionamide, was produced as follows: An ice-cold
mixture of
N-{3-hydroxymethyl-6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridin-2-yl}--
2,2-dimethyl-propionamide (1.00 g, 2.60 mmol) and
diphenylphosphoryl azide (1.44 g, 4.20 mmol) in toluene was treated
with DBU (7.27 g, 4.78 mmol). The reaction mixture was warmed to
room temperature and stirred for 1 hour. The brown mixture was
concentrated under vacuum and diluted with EtOAc and water. The
organic layer was separated and the aqueous layer was extracted
with EtOAc. The combined organic extracts were dried over Na2SO4,
filtered and concentrated under vacuum. The residue was purified by
column chromatography (3:1, hexanes/EtOAc) to afford the second
intermediate compound as a light yellow oil (0.800 g, 75%). .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta. 7.63 (d, 1H), 7.58 (s, 1H), 6.62
(d, 1H), 4.62-4.59 (m, 1H), 4.30 (s, 2H), 4.26 (s, 2H), 3.92-3.77
(m, 2H), 3.54-3.42 (m, 2H), 1.92-1.67 (m, 6H), 1.63-1.46 (m, 4H),
1.35 (s, 9H). MS ES: m/z=406.10.
[1133] A third intermediate compound,
N-[3-Azidomethyl-6-(4-hydroxy-butoxy)-pyridin-2-yl]-2,2-dimethyl-propiona-
mide, was produced as follows: A mixture of
N-{3-azidomethyl-6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridin-2-yl}-2,-
2-dimethyl-propionamide (0.730 g, 1.80 mmol), pyridinium
p-toluenesulphonic acid (0.100 g, 0.40 mmol) in EtOH (50 mL) was
refluxed for 1 hour. The solution was concentrated under vacuum,
then diluted with water and EtOAc. The organic layer was separated
and the aqueous layer was extracted with EtOAc. The combined
organic extracts were dried over Na.sub.2SO.sub.4, filtered and
concentrated under vacuum to afford the third intermediate compound
as a yellow oil (0.570 g, 99%). .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 7.70-7.62 (br s, 1H), 7.63 (d, 1H), 6.63 (d, 1H), 4.31 (s,
2H), 4.29 (t, 2H), 3.73 (t, 2H), 1.92-1.82 (m, 2H), 1.78-1.68 (m,
3H), 1.35 (s, 9H). MS ES: m/z=322.20.
[1134] A fourth intermediate compound,
N-[3-Azidomethyl-6-(4-oxo-butoxy)-pyridin-2-yl]-2,2-dimethyl-propionamide-
, was produced as follows: A solution of Dess-Martin periodinane
(0.982 g, 2.20 mmol) in CH.sub.2Cl.sub.2 (20 mL) was treated with
N-[3-azidomethyl-6-(4-hydroxy-butoxy)-pyridin-2-yl]-2,2-dimethyl-propiona-
mide (0.470 g, 1.46 mmol) in CH.sub.2Cl.sub.2 (5 mL) at RT. The
yellow mixture was stirred for 1.5 hours, then diluted with
Et.sub.2O and poured into saturated NaHCO.sub.3 containing
Na.sub.2S.sub.2O.sub.3 (2.50 g, 15.80 mmol). The mixture was
stirred for 10 minutes and the organic layer was separated. The
aqueous layer was extracted with Et.sub.2O and the combined organic
extracts were washed with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated under vacuum to afford the crude
aldehyde, which was used in the next step without further
purification.
[1135] A fifth intermediate compound,
N-(3-Azidomethyl-6-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-py-
ridin-2-yl)-2,2-dimethyl-propionamide, was produced as follows: To
a solution of
N-[3-azidomethyl-6-(4-oxo-butoxy)-pyridin-2-yl]-2,2-dimethyl-propionamide
in DCE (50 mL) was added 1-(2,3-dichlorophenyl)piperazine (0.553 g,
2.10 mmol), Et.sub.3N (0.295 g, 2.90 mmol) and NaBH(OAc).sub.3
(0.433 g, 2.00 mmol). The mixture was stirred at room temperature
for 1 hour, then quenched with water and saturated NaHCO.sub.3. The
mixture was extracted with CH.sub.2Cl.sub.2 and the combined
extracts were washed with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The residue was purified by
column chromatography (10% MeOH/EtOAc) to afford the fifth
intermediate compound as a yellow oil (0.455 g, 58%). .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. 7.62 (d, 1H), 7.61-7.55 (br s, 1H),
7.20-7.14 (m, 2H), 7.00-6.92 (m, 1H), 6.61 (d, 1H), 4.33 (s, 2H),
4.27 (t, 2H), 3.18-3.00 (m, 4H), 2.78-2.58 (m, 4H), 2.47-2.41 (m,
2H), 1.89-1.62 (m, 4H), 1.36 (s, 9H). MS ES: m/z=534.09,
536.04.
[1136] A sixth intermediate compound,
[6-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-2-(2,2-dimethyl-pr-
opionylamino)-pyridin-3-ylmethyl]-carbamic acid tert-butyl ester,
was produced as follows: A mixture of
N-(3-azidomethyl-6-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-py-
ridin-2-yl)-2,2-dimethyl-propionamide (0.808 g, 1.51 mmol) and
di-tert-butyl dicarbonate (0.326 g, 1.54 mmol) in EtOH (40 mL) was
treated with Raney-Nickel (2 mL suspension in water). The mixture
was shaken under 45 psi of H.sub.2 for 3 hours. The suspension was
filtered through Celite and the Celite pad was washed with EtOH.
The filtrate was concentrated in vacuo. The residue was purified by
column chromatography (10% MeOH/EtOAc) to afford the sixth
intermediate compound as a white solid (0.619 g, 67%). mp
143-144.degree. C.; .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
8.12-8.04 (brs, 1H), 7.67 (d, 1H), 7.18-7.12 (m, 2H), 7.00-6.92 (m,
1H), 6.58 (d, 1H), 5.64-5.50 (br s, 1H), 4.24 (t, 2H), 4.08 (d,
2H), 3.15-3.01 (m, 4H), 2.70-2.59 (m, 4H), 2.48 (t, 2H), 1.85-1.64
(m, 4H), 1.43 (s, 9H), 1.35 (s, 9H). MS ES: m/z=608.22, 610.17.
[1137] A seventh intermediate compound,
3-Aminomethyl-6-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-pyrid-
in-2-ylamine, was produced as follows: A mixture of
[6-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-2-(2,2-dimethyl-pr-
opionylamino)-pyridin-3-ylmethyl]-carbamic acid tert-butyl ester
(0.557 g, 0.91 mmol) in 2 N aqueous KOH (5 mL) and EtOH (20 mL) was
refluxed for 5 hours. The reaction was not complete (judged by
.sup.1H NMR), so an additional amount of 2 N KOH (5 mL) was added
and the resulting mixture was refluxed overnight. The mixture was
cooled to RT, then diluted with water and extracted with EtOAc. The
organic extracts were dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to afford a brown oil, which was used in the
next step without further purification. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 7.20-7.10 (m, 3H), 7.00-6.92 (m, 1H), 5.98 (s,
1H), 5.17-5.00 (br s, 2H), 4.82-4.71 (br s, 2H), 4.18 (t, 2H), 4.14
(d, 2H), 3.19-2.97 (m, 4H), 2.78-2.50 (m, 4H), 2.45 (t, 2H),
1.85-1.62 (m, 4H), 1.44 (s, 9H).
[1138] To a solution of crude
(2-amino-6-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-pyridin-3--
ylmethyl)-carbamic acid tert-butyl ester in dioxane (15 mL) was
added 3 N HCl (15 mL). The resulting mixture was refluxed for 2
hours, cooled to RT, then neutralized with saturated
Na.sub.2CO.sub.3. The neutralized solution was extracted with EtOAc
and the organic extracts were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford the
title compound as a brown oil (0.367 g, 94% over two steps).
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.21-7.10 (m, 3H),
7.00-6.91 (m, 1H), 6.00 (d, 1H), 5.40-5.21 (br s, 2H), 4.12 (t,
2H), 3.82 (s, 2H), 3.71 (s, 2H), 3.19-2.98 (m, 4H), 2.81-2.55 (m,
4H), 2.50 (t, 2H), 1.91-1.43 (m, 4H). MS ES: m/z=424.00,
425.99.
[1139] A mixture of
3-aminomethyl-6-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-pyrid-
in-2-ylamine (0.260 g, 0.61 mmol) in THF (10 mL) was treated with
4-nitrophenyl chloroformate (0.160 g, 0.79 mmol). The mixture was
stirred at room temperature for 30 minutes, then cooled to
0.degree. C. and treated with LDA (0.9 mL, 3.8 mmol, 2.0 M in
heptane/THF/ethylbenzene). The brown mixture was stirred at room
temperature for 1 hour, then quenched with water and extracted with
EtOAc. The organic extracts were washed with water and brine, dried
over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The
residue was purified by preparative thin layer chromatography (10%
MeOH/EtOAc) to afford the title compound as a light yellow solid
(0.071 g, 25%). mp 166-167.degree. C.; 1H NMR (400 MHz,
CDCl.sub.3): .delta. 7.25 (s, 1H), 7.19-7.14 (m, 2H), 7.14-7.09 (br
s, 1H), 6.99-6.94 (m, 1H), 6.32 (d, 1H), 5.57-5.51 (br s, 1H), 4.45
(s, 2H), 4.24 (t, 2H), 3.16-3.02 (m, 4H), 2.75-2.58 (m, 4H), 2.49
(t, 2H), 1.84-1.64 (m, 4H). MS ES: m/z=450.03, 452.02.
Example F2
Synthesis of
7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-pyrido[2,3-
-d]pyrimidin-2-one
[1140] A first intermediate compound,
N-{3-Azidomethyl-6-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-pyridin--
2-yl}-2,2-dimethyl-propionamide, was produced as follows: To a
solution of
N-[3-azidomethyl-6-(4-oxo-butoxy)-pyridin-2-yl]-2,2-dimethyl-propionamide
in DCE (250 mL) was added 1-naphthalen-1-yl-piperazine
monohydrochloride (2.81 g, 11.30 mmol), Et.sub.3N (2.00 g, 19.80
mmol) and NaBH(OAc).sub.3 (2.38 g, 11.20 mmol). The mixture was
stirred at room temperature for 1 hour, then quenched with water
and saturated NaHCO.sub.3. The mixture was extracted with
CH.sub.2Cl.sub.2 and the combined extracts were washed with brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
The residue was purified by column chromatography (1:19,
Et.sub.3N/EtOAc) to afford the first intermediate compound as a
brown oil (2.36 g, 59%). .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
8.26-8.17 (m, 1H), 7.85-7.80 (m, 1H), 7.64 (d, 1H), 7.60 (s, 1H),
7.55 (d, 1H), 7.50-7.44 (m, 2H), 7.41 (t, 1H), 7.10 (d, 1H), 6.64
(d, 1H), 4.31 (s, 2H), 4.28 (t, 2H), 3.25-3.05 (m, 4H), 2.90-2.62
(m, 4H), 2.55 (t, 2H), 1.90-1.68 (m, 4H), 1.35 (s, 9H). MS ES:
m/z=516.20.
[1141] A second intermediate compound,
{2-(2,2-Dimethyl-propionylamino)-6-[4-(4-naphthalen-1-yl-piperazin-1-yl)--
butoxy]-pyridin-3-ylmethyl}-carbamic acid tert-butyl ester, was
produced as follows: A mixture of
N-{3-azidomethyl-6-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-pyridin--
2-yl}-2,2-dimethyl-propionamide (2.36 g, 4.60 mmol) and
di-tert-butyl dicarbonate (1.035 g, 4.74 mmol) in EtOH (80 mL) was
treated with Palladium on charcoal (10% wet, 1.254 g). The mixture
was shaken under 45 psi of H.sub.2 for 3.5 hours. The suspension
was filtered through Celite and the Celite pad was washed with
EtOH. The filtrate was concentrated in vacuo to afford the second
intermediate compound as a white solid (2.64 g, 97%). mp
80-82.degree. C. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
8.24-8.16 (m, 1H), 8.00 (br s, 1H), 7.86-7.80 (m, 1H), 7.66 (d,
1H), 7.55 (d, 1H), 7.50-7.42 (m, 2H), 7.40 (t, 1H), 7.10 (d, 1H),
6.59 (d, 1H), 5.45 (br s, 1H), 4.28 (t, 2H), 4.09 (d, 2H),
3.25-3.05 (m, 4H), 2.85-2.60 (m, 4H), 2.60-2.50 (m, 2H), 1.89-1.60
(m, 4H), 1.42 (s, 9H), 1.35 (s, 9H). MS ES: m/z=590.33.
[1142] A third intermediate compound,
{2-Amino-6-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-pyridin-3-ylmeth-
yl}-carbamic acid tert-butyl ester, was produced as follows: A
mixture of
{2-(2,2-dimethyl-propionylamino)-6-[4-(4-naphthalen-1-yl-piperazin-1-yl)--
butoxy]-pyridin-3-ylmethyl}-carbamic acid tert-butyl ester (2.64 g,
4.48 mmol) in 2 N aqueous. KOH (40 mL) and EtOH (40 mL) was
refluxed overnight. The mixture was cooled to RT, then diluted with
water and extracted with EtOAc. The organic extracts were dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The
residue was purified by column chromatography (2.5%
Et.sub.3N/EtOAc) to afford the third intermediate compound as a
white solid (1.30 g, 58%). mp 67-68.degree. C. .sup.1H NMR (400
MHz, CDCl.sub.3): .delta. 8.42-8.30 (m, 1H), 7.85-7.60 (m, 1H),
7.55 (d, 1H), 7.51-7.40 (m, 2H), 7.39 (t, 1H), 7.16 (d, 1H), 7.08
(d, 1H), 6.00 (d, 1H), 5.13-5.00 (br s, 2H), 4.85-4.70 (br s, 1H),
4.20 (t, 2H), 4.14 (d, 2H), 3.28-3.04 (m, 4H), 2.90-2.62 (m, 4H),
2.54 (t, 2H), 1.88-1.66 (m, 4H), 1.54 (s, 9H). MS ES:
m/z=506.19.
[1143] A fourth intermediate compound,
3-Aminomethyl-6-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-pyridin-2-y-
lamine, was produced as follows: To a solution of
{2-amino-6-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-pyridin-3-ylmeth-
yl}-carbamic acid tert-butyl ester (1.17 g, 2.31 mmol) in dioxane
(10 mL) was added 3 N HCl (10 mL). The resulting mixture was
refluxed for 1 hour, cooled to RT, then neutralized with saturated
Na.sub.2CO.sub.3. The neutralized solution was extracted with EtOAc
and the organic extracts were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford the
fourth intermediate compound as a brown oil (0.92 g, 98%). .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta. 8.22-8.15 (m, 1H), 7.85-7.78 (m,
1H), 7.55 (d, 1H), 7.50-7.40 (m, 2H), 7.40 (t, 1H), 7.18 (d, 1H),
7.09 (d, 1H), 6.00 (d, 1H), 5.30 (br s, 2H), 4.20 (t, 2H), 3.79 (s,
2H), 3.71 (s, 2H), 3.28-3.06 (m, 4H), 2.96-2.64 (m, 4H), 2.56 (t,
2H), 1.88-1.68 (m, 4H). MS ES: m/z=406.10.
[1144] A mixture of
3-aminomethyl-6-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-pyridin-2-y-
lamine (0.92 g, 2.27 mmol) in THF (25 mL) was treated with phenyl
chloroformate (0.40 mL, 3.18 mmol) followed by Et.sub.3N (0.46 g,
4.54 mmol). The mixture was stirred at room temperature for 1 hour,
then cooled to 0.degree. C. and treated with LDA (5.6 mL, 11.20
mmol, 2.0 M in heptane/THF/ethylbenzene). The brown mixture was
stirred at room temperature for 1 hour, then quenched with water
and extracted with EtOAc. The organic extracts were washed with
water, and brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo. The residue was purified by column
chromatography (2.5% Et.sub.3N/EtOAc) to afford the title compound
as a light yellow solid (0.204 g, 21%). mp 136-138; .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. 8.24-8.16 (m, 1H), 7.85-7.78 (m,
1H), 7.55 (d, 1H), 7.50-7.42 (m, 2H), 7.40 (t, 1H), 7.25 (d, 1H),
7.09 (d, 1H), 6.84 (br s, 1H), 6.34 (d, 1H), 5.05 (br s, 1H), 4.48
(s, 2H), 4.45 (t, 2H), 3.30-2.05 (m, 4H), 2.93-2.60 (m, 4H), 2.55
(t, 2H), 1.90-1.70 (m, 4H). MS ES: m/z=432.11.
Example F3
Synthesis of
7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-pyrido[2,3-d]py-
rimidin-2-one
[1145] A first intermediate compound,
2-Amino-6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridine-3-carbaldehyde,
was produced as follows: A mixture of
N-{3-formyl-6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridin-2-yl}-2,2-dim-
ethyl-propionamide (9.8 g, 25.9 mmol), 2 N KOH (35 mL) and EtOH (40
mL) was heated at 80.degree. C. for 2 h. Ethanol was removed under
reduced pressure and the residue was extracted with EtOAc
(3.times.100 mL). The combined organic phases were washed with
H.sub.2O (40 mL) and brine (40 mL), dried over Na.sub.2SO.sub.4,
and concentrated to give the first intermediate compound as an oil
which was used in the next step without further purification.
.sup.1H NMR (400 MHz, CDCl3): .delta. 9.70 (s, 1H), 7.62 (d, 1H),
6.17 (d, 1H), 4.60 (m, 1H), 4.40 (m, 2H), 3.90 (m, 2H), 3.50 (m,
2H), 2.00-1.50 (m, 10H).
[1146] A second intermediate compound,
7-[4-(Tetrahydro-pyran-2-yloxy)-butoxy]-1H-pyrido[2,3-d]pyrimidin-2-one,
was produced as follows: To a solution of
2-amino-6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridine-3-carbaldehyde
obtained in the last step in CH.sub.2Cl.sub.2 (50 mL) was added
trichloroacetyl isocyanate (5.85 g, 31.08 mmol) dropwise. After the
addition was over, the mixture was stirred at room temperature for
1 h. To this mixture, MeOH (50 mL) and 1 N NaOH (40 mL) were added
successively. The mixture thus obtained was kept stirring at room
temperature for another 1 h. The solvent was then removed under
reduced pressure and the residue was extracted with
CH.sub.2Cl.sub.2 (3.times.100 mL). The combined organic phases were
washed with brine, dried and concentrated. The residue was
crystallized from ether to give the second intermediate compound
(6.6 g, 79% in two steps) as a pale yellow solid. .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 9.00 (s, 1H), 8.00 (d, 1H), 6.60 (d,
1H), 4.60 (m, 1H), 4.40 (m, 2H), 3.70 (m, 2H), 3.40 (m, 2H),
1.90-1.30 (m, 10H).
[1147] A third intermediate,
7-(4-Hydroxy-butoxy)-1H-pyrido[2,3-d]pyrimidin-2-one, was produced
as follows: A mixture of
7-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-1H-pyrido[2,3-d]pyrimidin-2-one
(4.9 g, 15 mmol), MeOH (30 mL), THF (15 mL) and 3 N HCl (7.5 mL)
was stirred at room temperature for 1 h. The mixture was
concentrated under reduced pressure. The residue was dissolved in
H.sub.2O (30 mL) and neutralized carefully with saturated
NaHCO.sub.3. The mixture was extracted with THF (5.times.100 mL).
The combined organic phases were washed with brine, dried and
concentrated to give the third intermediate compound (3.3 g, 90%)
which was used in the next step without further purification.
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.03 (s, 1H), 8.17 (d,
1H), 6.67 (d, 1H), 4.50 (m, 1H), 4.40 (m, 2H), 3.50 (m, 3H), 1.80
(m, 2H), 1.55 (m, 2H).
[1148] A fourth intermediate compound,
4-(2-Oxo-1,2-dihydro-pyrido[2,3-d]pyrimidin-7-yloxy)-butyraldehyde,
was produced as follows: A mixture of
7-(4-hydroxy-butoxy)-1H-pyrido[2,3-d]pyrimidin-2-one (0.512 g, 2.18
mmol) and IBX (1.9 g, 6.6 mmol) in CH.sub.3CN (40 mL) was heated at
87.degree. C. for 7 h. It was cooled to RT, diluted with EtOAc (80
mL) and filtered. The pad was washed thoroughly with EtOAc. The
combined filtrate was concentrated to give the fourth intermediate
compound as a solid which was contaminated with some byproduct from
the reaction. This solid was used in the next step without further
purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 12.18
(s, 1H), 9.77 (s, 1H), 8.20 (d, 1H), 6.70 (d, 1H), 4.40 (m, 2H),
2.70 (m, 2H), 2.00 (m, 2H).
[1149] To a mixture of
4-(2-oxo-1,2-dihydro-pyrido[2,3-d]pyrimidin-7-yloxy)-butyraldehyde,
1-indan-4-yl-piperazine (0.581 g, 2.44 mmol), Et.sub.3N (1.70 mL,
12.2 mmol) in 1-methyl-2-pyrrolidinone (20 mL) was added
NaBH(OAc).sub.3 (0.65 g, 3.05 mmol) in portions over 20 min. After
the addition was over, the mixture was left stirring overnight.
After quenching with H.sub.2O (50 mL), the reaction mixture was
extracted with CH.sub.2Cl.sub.2 (3.times.100 mL). The combined
organic phases were washed with brine (100 mL), dried and
concentrated. The residue was purified by chromatography on silica
gel to give a gum (350 mg). To a solution of this gum in THF (6 mL)
and MeOH (2 mL) was added NaBH.sub.4 (63 mg) in portions. After the
addition was over, the mixture was kept stirring overnight. The
reaction was quenched with H.sub.2O. The mixture was extracted with
CH.sub.2Cl.sub.2 (3.times.50 mL). The combined organic phases were
dried over Na.sub.2SO.sub.4 and concentrated. The residue was
purified by chromatography on silica gel to give a semi-solid which
was converted to its HCl salt by treating with 1 equivalent of 1 N
HCl in a mixed solvent of THF and Et.sub.2O to give the title
compound (176 mg) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 10.2 (s, 1H), 9.30 (s, 1H), 7.40 (d, 1H),
7.10 (t, 1H), 6.95 (m, 2H), 6.77 (d, 1H), 6.30 (d, 1H), 4.25 (m,
4H), 4.00 (m, 2H), 3.60 (m, 2H), 3.30-3.00 (m, 6H), 2.80 (m, 4H),
2.00-1.70 (m, 6H).
Example F4
Synthesis of
7-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4--
dihydro-1H-pyrido[2,3-d]pyrimidin-2-one
[1150] The procedure from Example F3 was followed using
1-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine to give the title
compound. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 10.20 (s,
1H), 9.22 (s, 1H), 7.40 (d, 1H), 7.10 (m, 1H), 6.95 (s, 1H), 6.85
(m 2H), 6.30 (d, 1H), 4.30 (m, 4H), 3.70-3.00 (m, 10H), 2.80-2.60
(m, 4H), 1.90-1.60 (m, 8H).
Example F5
Synthesis of
7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl-butoxy}-3,4-dihydro-1H--
pyrido[2,3-d]pyrimidin-2-one
[1151] The procedure from Example F3 was followed using
1-(7-fluoro-naphthalen-1-yl)-piperazine to give the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.25 (s, 1H), 8.00 (m,
1H), 7.80 (m, 1H), 7.75 (m, 1H), 7.40 (m, 3H), 7.20 (d, 1H), 6.95
(s, 1H), 6.30 (d, 1H), 4.23 (m, 4H), 3.70-3.10 (m, 10H), 1.90-1.70
(m, 4H).
Example F6
Synthesis of
8-{4-[4-(2-Oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-7-yloxy)-butyl]--
piperazin-1-yl}-naphthalene-2-carbonitrile
[1152] The procedure from Example F3 was followed using
8-piperazin-1-yl-naphthalene-2-carbonitrile to give the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.25 (s, 1H), 8.60
(s, 1H), 8.10 (d, 1H), 7.80 (m, 1H), 7.70 (m, 1H), 7.45-7.30 (m,
2H), 6.90 (s, 1H), 6.30 (d, 1H), 4.25 (m, 4H), 3.80-3.10 (m, 10H),
1.90-1.70 (m, 4H).
Example F7
Synthesis of
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3-methyl-3,4-dihydr-
o-1H-pyrido[2,3-d]pyrimidin-2-one
[1153] A first intermediate compound,
N-[6-(4-Benzyloxy-butoxy)-3-formyl-pyridin-2-yl]-2,2-dimethyl-propionamid-
e, was produced as follows: To a stirred solution of
4-benzyloxy-1-butanol (300 mg, 1.66 mmol) in DMF (5 mL) at
0.degree. C. was added NaH (50 mg, 2.08 mmol). The resulting grey
slurry was stirred at 0.degree. C. for 15 minutes and
N-(6-chloro-3-formyl-pyridin-2-yl)-2,2-dimethyl-propionamide (200
mg, 0.83 mmol) was added portionwise. The mixture became a light
orange color and bubbles were evolved. The orange mixture was
allowed to warm to room temperature over 1 hour. Water (10 mL) was
added and the mixture was diluted with EtOAc (20 mL). The organic
layer was separated, washed with water (2.times.10 mL) and brine
(20 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated in
vacuo. The residual oil was purified by column chromatography (3:1,
hexane/EtOAc) to yield the first intermediate compound as a clear
oil (266 mg, 83%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 11.55
(s, 1H), 9.75 (s, 1H), 7.80 (d, 1H), 7.40-7.20 (m, 5H), 6.44 (d,
1H), 4.60-4.44 (m, 4H), 3.50 (t, 2H), 1.95-1.70 (m, 4H), 1.36 (s,
9H).
[1154] A second intermediate compound,
N-[6-(4-Benzyloxy-butoxy)-3-methylaminomethyl-pyridin-2-yl]-2,2-dimethyl--
propionamide, was produced as follows: To a stirred solution of
N-[6-(4-benzyloxy-butoxy)-3-formyl-pyridin-2-yl]-2,2-dimethyl-propionamid-
e (1.40 g, 3.65 mmol) in EtOH (20 mL) at room temperature was added
methylamine monohydrochloride (295 mg, 4.37 mmol) and Et.sub.3N
(443 mg, 0.61 mL, 4.37 mmol). The mixture was stirred for 24 hours
and then cooled to 0.degree. C. NaBH.sub.4 (138 mg, 3.65 mmol) was
added and the mixture was warmed to room temperature over 1 hour,
then heated at 50.degree. C. for 3 hours. The mixture was cooled to
RT, water (20 mL) was added, and the mixture was extracted with
EtOAc (30 mL). The organic layer was separated, washed with water
(20 mL) and brine (20 mL), dried over Na.sub.2SO.sub.4, filtered,
and concentrated in vacuo. The impure oil was purified by column
chromatography (5% MeOH/CH.sub.2Cl.sub.2) to yield the second
intermediate compound as a clear oil (1.22 g, 84%). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 10.55 (s, 1H), 7.38-7.22 (m, 6H),
6.39 (d, 1H), 4.46 (s, 2H), 4.38 (t, 2H), 3.64 (s, 2H), 3.53 (t,
2H), 2.42 (s, 3H), 1.90-1.75 (m, 4H), 1.58 (br s, 1H), 1.36 (s,
9H).
[1155] A third intermediate compound,
[6-(4-Benzyloxy-butoxy)-2-(2,2-dimethyl-propionylamino)-pyridin-3-ylmethy-
l]-methyl-carbamic acid tert-butyl ester, was produced as follows:
N-[6-(4-Benzyloxy-butoxy)-3-methylaminomethyl-pyridin-2-yl]-2,2-dimethyl--
propionamide (1.22 g, 3.06 mmol) was dissolved in MeOH (20 mL) and
di-tert-butyl dicarbonate (701 mg, 3.21 mmol) was added. The
mixture was stirred at room temperature overnight and water (10 mL)
was added. The mixture was extracted with EtOAc (20 mL). The
organic layer was washed with water (20 mL) and brine (20 mL),
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to
yield the third intermediate compound as a clear oil (1.48 g, 97%).
.sup.1H NMR (200 MHz, DMSO-d.sub.6) .delta. 9.55 (s, 1H), 7.44 (d,
1H), 7.40-7.20 (m, 5H), 6.72 (d, 1H), 4.48 (s, 2H), 4.25 (t, 2H),
4.15 (s, 2H), 3.50 (t, 2H), 2.70 (s, 3H), 1.90-1.60 (m, 4H), 1.45
(s, 9H), 1.25 (s, 9H).
[1156] A fourth intermediate compound,
[2-(2,2-Dimethyl-propionylamino)-6-(4-hydroxy-butoxy)-pyridin-3-ylmethyl]-
-methyl-carbamic acid tert-butyl ester, was produced as follows:
[6-(4-Benzyloxy-butoxy)-2-(2,2-dimethyl-propionylamino)-pyridin-3-ylmethy-
l]-methyl-carbamic acid tert-butyl ester (1.48 g, 2.96 mmol) was
dissolved in MeOH (20 mL) and treated with 10% palladium on
charcoal (400 mg). The mixture was shaken under an atmosphere of
H.sub.2 (45 psi) for 3 hours, filtered through celite and the
celite was washed with EtOAc (2.times.20 mL). The filtrate was
concentrated in vacuo to yield the fourth intermediate compound as
a clear oil (1.21 g, 99%). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 9.60 (s, 1H), 7.42 (d, 1H), 6.68 (d, 1H), 4.42 (t, 1H),
4.21 (t, 2H), 4.15 (s, 2H), 3.44-3.41 (m, 2H), 2.70 (s, 3H),
1.80-1.70 (m, 2H), 1.60-1.54 (m, 2H), 1.40 (s, 9H), 1.20 (s,
9H).
[1157] A fifth intermediate compound,
[6-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-2-(2,2-dimethyl-pr-
opionylamino)-pyridin-3-ylmethyl]-methyl-carbamic acid tert-butyl
ester, was produced as follows: To a stirred solution of
Dess-Martin periodinane (926 mg, 2.18 mmol) in CH.sub.2Cl.sub.2 (20
mL) was added
[2-(2,2-dimethyl-propionylamino)-6-(4-hydroxy-butoxy)-pyridin-3-ylmethyl]-
-methyl-carbamic acid tert-butyl ester (746 mg, 1.82 mmol) in
CH.sub.2Cl.sub.2 (3 mL). The mixture was stirred at room
temperature for 3.5 hours, then poured into a solution of saturated
NaHCO.sub.3 (20 mL) containing Na.sub.2S.sub.2O.sub.3 (2.01 g, 12.7
mmol). The biphasic mixture was stirred vigorously for 15 minutes
and the organic layer was separated. The organic layer was washed
with saturated NaHCO.sub.3 (20 mL) and brine (20 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to yield the
crude aldehyde (920 mg, 99%). The aldehyde (920 mg, 1.82 mmol) was
dissolved in 1,2-dichloroethane (20 mL) and 1-(2,3-dichlorophenyl)
piperazine monohydrochloride (536 mg, 2.00 mmol), Et.sub.3N (553
mg, 0.76 mL, 5.46 mmol), and NaBH(OAc).sub.3 (540 mg, 2.55 mmol)
were added. The mixture was stirred at room temperature for 3 hours
and water (10 mL) was added. The organic layer was washed with
water (20 mL) and brine (20 mL), dried over Na.sub.2SO.sub.4,
filtered, and concentrated in vacuo. The crude oil was purified by
column chromatography (5% MeOH/CH.sub.2Cl.sub.2) to yield the fifth
intermediate compound as a foam (686 mg, 61%). mp 57-59.degree. C.;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.56 (s, 1H), 7.44 (d,
1H), 7.38-7.25 (m, 2H), 7.18-7.14 (m, 1H), 6.78 (d, 1H), 4.24 (t,
2H), 4.15 (s, 2H), 3.00-2.95 (m, 4H), 2.64 (s, 3H), 2.60-2.56 (m,
4H), 2.39 (t, 2H), 1.80-1.75 (m, 2H), 1.63-1.55 (m, 2H), 1.40 (s,
9H), 1.20 (s, 9H).
[1158] A sixth intermediate compound,
6-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3-methylaminomethyl-
-pyridin-2-ylamine, was produced as follows:
[1159]
[6-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-2-(2,2-dime-
thyl-propionylamino)-pyridin-3-ylmethyl]-methyl-carbamic acid
tert-butyl ester (686 mg, 1.11 mmol) was dissolved in dioxane (4
mL) and 3 N HCl (4 mL) was added. The solution was heated at
60.degree. C. for 15 hours. The solution was cooled to room
temperature and neutralized with saturated Na.sub.2CO.sub.3. The
mixture was diluted with water (20 mL) and EtOAc (20 mL). The
organic layer was washed with water (2.times.20 mL) and brine (20
mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo to yield the sixth intermediate compound as a brown powder
(458 mg, 95%). mp 119-121.degree. C.; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.20-7.03 (m, 3H), 7.00-6.95 (m, 1H), 5.97 (d,
1H), 5.20 (br s, 2H), 4.18 (t, 2H), 3.65 (s, 2H), 3.25 (br s, 1H),
3.15-3.00 (m, 4H), 2.80-2.58 (m, 4H), 2.45 (t, 2H), 2.40 (s, 3H),
1.83-1.63 (m, 4H).
[1160] To a stirred solution of
6-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-3-methylaminomethyl-
-pyridin-2-ylamine (203 mg, 0.47 mmol) in THF (10 mL) at 0.degree.
C. was added 4-nitrobenzyl chloroformate (105 mg, 0.49 mmol). The
mixture was stirred at 0.degree. C. for 45 minutes and LDA (1.16
mL, 2.32 mmol, 2.0 M solution in heptane/THF/ethylbenzene) was
added dropwise. The mixture was stirred for 1.5 hours at 0.degree.
C. and then poured over ice. EtOAc (30 mL) was added to the
quenched mixture and the organic layer was separated. The organic
layer was washed with water (20 mL) and brine (20 mL), dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude
oil was purified by preparative TLC (6% MeOH/EtOAc) to yield the
title compound as a light orange foam (66 mg, 31%). .sup.1H NMR
(400 MHz, CDCl3) .delta. 7.22 (d, 1H), 7.19-7.10 (m, 2H), 7.00-6.92
(m, 1H), 6.76 (s, 1H), 6.34 (d, 1H), 4.38 (s, 2H), 4.22 (t, 2H),
3.14-3.00 (m, 4H), 3.00 (s, 3H), 2.77-2.58 (m, 4H), 2.44 (t, 2H),
1.83-1.60 (m, 4H).
Example F8
Synthesis of
3-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-p-
yrido[2,3-d]pyrimidin-2-one
[1161] A first intermediate compound,
{2-(2,2-Dimethyl-propionylamino)-6-[4-(4-naphthalen-1-yl-piperazin-1-yl)--
butoxy]-pyridin-3-ylmethyl}-methyl-carbamic acid tert-butyl ester,
was produced as follows: To a stirred solution of Dess-Martin
periodinane (3.10 g, 7.32 mmol) in CH.sub.2Cl.sub.2 (40 mL) was
added
[2-(2,2-dimethyl-propionylamino)-6-(4-hydroxy-butoxy)-pyridin-3-ylmethyl]-
-methyl-carbamic acid tert-butyl ester (2.00 g, 4.88 mmol) in
CH.sub.2Cl.sub.2 (5 mL). The mixture was stirred at room
temperature for 3.5 hours and then poured into a solution of
saturated NaHCO.sub.3 (40 mL) containing Na.sub.2S.sub.2O.sub.3
(5.40 g, 34.2 mmol). The biphasic mixture was stirred vigorously
for 20 minutes and the organic layer was separated, washed with
saturated NaHCO.sub.3 (30 mL) and brine (30 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to yield the
crude aldehyde (1.95 g, 99%). The aldehyde (1.95 g, 4.88 mmol) was
dissolved in 1,2-dichloroethane (40 mL) and
1-naphthalen-1-yl-piperazine monohydrochloride (1.34 g, 5.39 mmol),
Et.sub.3N (1.49 g, 2.05 mL, 5.46 mmol), and NaBH(OAc).sub.3 (1.45
g, 6.86 mmol) were added. The mixture was stirred at room
temperature for 3 hours and water (20 mL) was added. The organic
layer was washed with water (30 mL) and brine (30 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude oil
was purified by column chromatography (5% MeOH/CH.sub.2Cl.sub.2) to
yield the first intermediate compound as a foam (1.39 g, 47%). mp
69-71.degree. C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.58
(s, 1H), 8.15 (d, 1H), 7.85 (d, 1H), 7.60 (d, 1H), 7.56-7.40 (m,
4H), 7.10 (d, 1H), 6.77 (d, 1H), 4.22 (t, 2H), 4.10 (s, 2H),
3.08-2.98 (m, 4H), 2.70 (s, 3H), 2.70-2.58 (m, 4H), 2.45 (t, 2H),
1.85-1.70 (m, 2H), 1.70-1.58 (m, 2H), 1.40 (s, 9H), 1.20 (s,
9H).
[1162] A second intermediate compound,
3-Methylaminomethyl-6-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-pyrid-
in-2-ylamine, was produced as follows:
{2-(2,2-Dimethyl-propionylamino)-6-[4-(4-naphthalen-1-yl-piperazin-1-yl)--
butoxy]-pyridin-3-ylmethyl}-methyl-carbamic acid tert-butyl ester
(1.39 g, 3.31 mmol) was dissolved in dioxane (6 mL) and 3 N HCl (6
mL) was added. The solution was heated at 60.degree. C. for 8
hours. The solution was cooled to room temperature and neutralized
with saturated Na.sub.2CO.sub.3. The mixture was diluted with water
(30 mL) and EtOAc (30 mL). The organic layer was washed with water
(2.times.30 mL) and brine (30 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo to yield the second intermediate
compound as a brown oil (709 mg, 73%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.20 (d, 1H), 7.80 (d, 1H), 7.60-7.40 (m, 4H),
7.20 (d, 1H), 7.10 (d, 1H), 6.00 (d, 1H), 5.40 (s, 2H), 4.20 (t,
2H), 3.60 (s, 2H), 3.24-3.00 (m, 4H), 2.90-2.60 (m, 4H), 2.57 (t,
2H), 2.40 (s, 3H), 1.85-1.65 (m, 4H), 1.44 (s, 1H).
[1163]
3-Methylaminomethyl-6-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy-
]-pyridin-2-ylamine (709 mg, 1.69 mmol) was dissolved in THF (10
mL) and cooled to 0.degree. C. Phenyl chloroformate (291 mg, 0.23
mL, 1.86 mmol) was added dropwise followed by Et.sub.3N (342 mg,
0.47 mL, 3.38 mmol). The mixture was allowed to warm to room
temperature for 45 minutes. Water (20 mL) and EtOAc (20 mL) were
added. The organic layer was separated, washed with water
(2.times.20 mL) and brine (20 mL), dried over Na2SO4, filtered and
concentrated in vacuo to give a yellow foam (850 mg, 93%). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.23-8.18 (m, 1H), 7.81 (d, 1H),
7.60-7.04 (m, 11H), 6.02 (d, 1H), 5.24 (s, 2H), 4.38 (s, 2H), 4.20
(t, 2H), 3.24-3.00 (m, 4H), 2.99 (s, 3H), 2.95-2.64 (m, 4H),
2.60-2.50 (m, 2H), 1.90-1.70 (m, 4H).
[1164] The foam (850 mg, 1.57 mmol) was dissolved in THF (20 mL)
and the solution was cooled to 0.degree. C. LDA (3.94 mL, 7.89
mmol, 2.0 M solution in heptane/THF/ethylbenzene) was added
dropwise and the mixture became a dark orange color. The mixture
was allowed to warm to room temperature over 1 hour and water (10
mL) and EtOAc (20 mL) were added. The organic layer was separated,
washed with water (2.times.20 mL) and brine (20 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residual
oil was purified by column chromatography (6% MeOH/EtOAc) to yield
the title compound as a light yellow powder (308 mg, 41%). mp
180-182.degree. C.; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.20
(d, 1H), 7.82 (d, 1H), 7.60-7.40 (m, 4H), 7.23-7.20 (m, 1H), 7.10
(d, 1H), 6.75 (s, 1H), 6.30 (d, 1H), 4.39 (s, 2H), 4.23 (t, 2H),
3.24 (m, 4H), 3.02 (s, 3H), 2.84-2.60 (m, 4H), 2.80-2.70 (m, 2H),
1.85-1.64 (m, 4H).
Example F9
Synthesis of
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-4,4-dimethyl-1,4-di-
hydro-pyrido[2,3-d][1,3]oxazin-2-one
[1165] A first intermediate compound,
N-[3-Acetyl-6-(5-chloro-pent-1-enyl)-pyridin-2-yl]-2,2-dimethyl-propionam-
ide, was produced as follows: To a solution of
N-(3-acetyl-6-chloro-pyridin-2-yl)-2,2-dimethyl-propionamide (7.0
g, 27.5 mmol) in DME (110 mL) purged and degassed with N.sub.2 was
added Pd(Ph.sub.3P).sub.4 (953 mg, 0.83 mmol, 3 mol %, Strem).
5-Chloro-1-pentenyl boronic acid (6.12 g, 41.2 mmol, 1.5 equiv) was
added followed by 2M Na.sub.2CO.sub.3 (6.12 g, 57.8 mmol in 28 mL
of H.sub.2O). The mixture was refluxed overnight. The reaction was
concentrated and then diluted with THF (100 mL) and sonicated for 3
min. A white sticky precipitate formed. The mixture was filtered
and washed with THF. The filtrate was concentrated and absorbed
onto SiO.sub.2. Purification by liquid chromatography (20-25%
EtOAc/Hexanes) gave the product as a yellow solid.
Recrystallization from Et.sub.2O/Hexanes gave the first
intermediate compound as a pale yellow crystalline solid (6.49 g,
20.1 mmol, 73%). MS: APCI: M+1: 323.2 (Exact Mass: 322.14).
[1166] A second intermediate compound,
N-(3-Acetyl-6-{5-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-py-
ridin-2-yl)-2,2-dimethyl-propionamid, was produced as follows: To a
mixture of
N-[3-acetyl-6-(5-chloro-pent-1-enyl)-pyridin-2-yl]-2,2-dimethyl-propionam-
ide (6.34 g, 19.7 mmol) and 2,3-dichlorophenylpiperazine
hydrochloride (6.35 g, 23.75 mmol, 1.2 equiv) in CH.sub.3CN (100
mL) was added K.sub.2CO.sub.3 (8.2 g, 59.4 mmol, 3 equiv) followed
by KI (332 mg, 2 mmol, 0.1 equiv). The mixture was refluxed for 2
days. H.sub.2O was added to dissolve the salts and the mixture was
extracted with EtOAc. The organic layer was washed with saturated
NaHCO.sub.3 and brine, dried over Na.sub.2SO.sub.4 and concentrated
to give a dark brown oil. Purification by liquid chromatography (5%
EtOAc/CH.sub.2Cl.sub.2 to 4% MeOH/CH.sub.2Cl.sub.2) gave a light
brown foam (5.0 g). Recrystallization from CH.sub.3CN gave the
second intermediate compound as a light tan solid (2.45 g, 4.73
mmol, 24%). The filtrate was concentrated and purified by liquid
chromatography (3-4% MeOH/CH.sub.2Cl.sub.2) to give additional
product as a yellow foam (1.27 g, 2.45 mmol, 12%). MS: APCI: M+1:
517.1 (Exact Mass: 516.21).
[1167] A third intermediate compound,
N-(3-Acetyl-6-{5-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-pentyl}-pyridin-
-2-yl)-2,2-dimethyl-propionamide, was produced as follows:
N-(3-Acetyl-6-{5-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-py-
ridin-2-yl)-2,2-dimethyl-propionamide (2.40 g, 4.62 mmol) was
hydrogenated using Ra-Ni (0.3 g) in 1:1 EtOH/THF (50 mL) for 2 h.
The reaction was filtered and concentrated. Purification by liquid
chromatography (4% MeOH/CH.sub.2Cl.sub.2) gave the third
intermediate compound as a yellow oil (2.09 g, 4.02 mmol, 87%). MS:
APCI: M+1: 519.2 (Exact Mass: 518.22).
[1168] A fourth intermediate compound,
1-(2-Amino-6-{5-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-pentyl}-pyridin--
3-yl)-ethanone, was produced as follows: A solution of
N-(3-acetyl-6-{5-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-pentyl}-pyridin-
-2-yl)-2,2-dimethyl-propionamide (2.08 g, 4.00 mmol) in 3N HCl (50
mL) was refluxed overnight. The reaction was cooled to room
temperature and a precipitate formed. The solid was collected by
filtration, washed with H.sub.2O and dried to give the title
compound as a yellow solid (HCl salt, 1.15 g, 2.44 mmol, 61%). The
filtrate was made basic with 6N NaOH and extracted with
CH.sub.2Cl.sub.2 (4.times.). The organic layer was washed with
brine, dried over Na.sub.2SO.sub.4 and concentrated to give
additional fourth intermediate compound (582 mg, 1.34 mmol, 33%)
which looked clean by NMR and was used in the next step without
purification. MS: APCI: M+1: 435.2 (Exact Mass: 434.16).
[1169] A fifth intermediate compound,
2-(2-Amino-6-{5-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-pentyl}-pyridin--
3-yl)-propan-2-ol, was produced as follows: To a solution of
1-(2-amino-6-{5-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-pentyl}-pyridin--
3-yl)-ethanone (575 mg, 1.32 mmol) in THF (8 mL) cooled to
0.degree. C. was added MeMgBr (3M in Et.sub.2O, 2.2 mL, 6.60 mmol,
5 equiv) slowly. The reaction was exothermic and turned orange and
then a precipitate formed. The reaction was stirred at 0.degree. C.
for 15 min and at room temperature for 2 h. The reaction was
quenched with careful addition of saturated NH.sub.4Cl and
H.sub.2O. The mixture was extracted with EtOAc. The organic layer
was washed with H.sub.2O and brine, dried over Na.sub.2SO.sub.4 and
concentrated. Purification by liquid chromatography (6%
MeOH/CH.sub.2Cl.sub.2 with 1% NH.sub.4OH) gave a white crystalline
solid (490 mg, 1.09 mmol, 82%). MS: APCI: M+1: 451.2 (Exact Mass:
450.20).
[1170] To a solution of
2-(2-amino-6-{5-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-pentyl}-pyridin--
3-yl)-propan-2-ol (442 mg, 0.98 mmol) in THF (4 mL) and toluene (1
mL) was added Et.sub.3N (0.30 mL, 2.15 mmol, 2.2 equiv). The
mixture was cooled to 0.degree. C. and phosgene (20% in toluene,
0.65 mL, 1.3 mmol) was added. A precipitate formed. The reaction
was stirred at 0.degree. C. for 15 min and at room temperature for
2 h. MeOH was added to quench the excess phosgene. Saturated
NaHCO.sub.3 and H.sub.2O were added and the mixture was extracted
with EtOAc. The organic layer was washed with H.sub.2O and brine,
dried over Na.sub.2SO.sub.4 and concentrated. Purification by
liquid chromatography (3.5% MeOH/CH.sub.2Cl.sub.2) gave the title
compound as a white foam (411 mg, 0.861 mmol, 88%). The foam was
dissolved in Et.sub.2O/CH.sub.2Cl.sub.2 and 1M HCl in Et.sub.2O
(0.86 mL) was added. The resulting white precipitate was collected
by filtration, washed with Et.sub.2O and dried to give a fluffy
white solid (400 mg). MS: APCI: M+1: 477.1 (Exact Mass:
476.17).
Example G1
Synthesis of
6-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-4H-pyrido[3,2-b][1,-
4]oxazin-3-one
[1171] A first intermediate compound,
6-(5-Chloro-pent-1-enyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one, was
produced as follows: To a solution of
6-bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one (2.0 g, 8.73 mmol, WO
02/056882) in DME (45 mL) was added 5-chloro-pent-1-enyl-boronic
acid (1.94 g, 13.09 mmol), followed by Pd(PPh.sub.3).sub.4 (0.252
g, 0.218 mmol) and 2M Na.sub.2CO.sub.3 (1.855 g in 8.7 mL
H.sub.2O). The reaction was refluxed for 14 hours. The reaction was
cooled, and partitioned between ethyl acetate and water. The
organic layer was washed with brine, dried over Na.sub.2SO.sub.4
and concentrated. Purification by chromatography on silica gel
(0-40% EtOAc/Hexanes) gave the first intermediate compound as a
white solid (1.935 g, 88%). MS: APCI: M+1: 253.1 (Exact Mass:
252.07).
[1172] A second intermediate compound,
6-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-4H-pyrido[3,2--
b][1,4]oxazin-3-one, was produced as follows: To a solution of
6-(5-chloro-pent-1-enyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one (0.710
g, 2.80 mmol) in CH.sub.3CN (10 mL) was added
1-(2,3-dichloro-phenyl)-piperazine (0.974 g, 4.21 mmol), followed
by potassium carbonate (0.77 g, 5.6 mmol) and potassium iodide
(0.092 g, 0.56 mmol). The reaction was refluxed for 14 hours. The
reaction was cooled to room temperature and partitioned between
EtOAc and H.sub.2O. The organic layer was washed with saturated
NaHCO.sub.3 and brine, dried over Na.sub.2SO.sub.4 and concentrated
to give an oil. Purification by chromatography on silica gel (0-7%
MeOH/EtOAc) afforded the second intermediate compound as a white
solid (0.903 g, 72%). MS: APCI: M+1: 447.1 (Exact Mass:
446.13).
[1173]
6-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-4H-pyri-
do[3,2-b][1,4]oxazin-3-one (0.774 g, 1.73 mmol) was hydrogenated
using Ra-Ni (0.25 g) in THF for 16 hours. The reaction was filtered
and concentrated to give an oil. Ethyl acetate was added and the
product crashed out. The precipitate was filtered and dried to give
the title compound as a white solid (0.645 g, 83%). MS: APCI: M+1:
449.1 (Exact Mass: 448.14).
Example G2
Synthesis of
6-{5-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-pentyl}-4H-p-
yrido[3,2-b][1,4]oxazin-3-one
[1174] An intermediate compound,
6-{5-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-pent-1-enyl}-
-4H-pyrido[3,2-b][1,4]oxazin-3-one, was produced as follows: To a
solution of
6-(5-chloro-pent-1-enyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one (0.408
g, 1.61 mmol) in CH.sub.3CN (7 mL) was added
1-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine (0.523 g, 2.41
mmol), followed by potassium carbonate (0.445 g) and potassium
iodide (0.053 g, 0.322 mmol). The reaction was refluxed for 14
hours. The reaction was cooled to room temperature and partitioned
between EtOAc and H.sub.2O. The organic layer was washed with
saturated NaHCO.sub.3 and brine, dried over Na.sub.2SO.sub.4 and
concentrated to give an oil. Purification by chromatography on
silica gel (0-5% MeOH/EtOAc) afforded the first intermediate
compound as a yellow solid (0.172 g, 72%). MS: APCI: M+1: 433.2
(Exact Mass: 432.25).
[1175]
6-{5-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-pent--
1-enyl}-4H-pyrido[3,2-b][1,4]oxazin-3-one (0.098 g, 0.226 mmol) was
hydrogenated using Ra-Ni in THF for 16 hours. The reaction was
filtered and concentrated to give an oil. Purification by
chromatography on silica gel (0-5% MeOH/EtOAc) afforded the title
compound as a film (0.059 g, 61%). This was dissolved in Et.sub.2O
and 1M HCl in Et.sub.2O (1 equivalent) was added. The resulting
precipitate was filtered and dried to give a white solid. MS: APCI:
M+1: 435.5 (Exact Mass: 434.27).
Example G3
Synthesis of
6-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-4H-pyrido[3,2-b][1,-
4]oxazin-3-one
[1176] A first intermediate compound,
6-Amino-4H-pyrido[3,2-b][1,4]oxazin-3-one, was produced as follows:
A mixture of 6-nitro-4H-pyrido[3,2-b][1,4]oxazin-3-one (34.23 g,
0.1755 mol), 20% Pd--C (3.0 g, 50% H.sub.2O) and DMF (1 L) was
hydrogentated at 20 psi H.sub.2 pressure. After 2 h, uptake of
H.sub.2 ceased with 141 psi of H.sub.2 being absorbed. The reaction
mixture was filtered through a pad of Celite.RTM., washing with DMF
(500 mL). The filtrate was diluted with cold H.sub.2O (2 L) to give
a solid. The solid was collected, washed with H.sub.2O, slurried in
EtOH (150 mL), collected, washed with heptane and dried to give the
first intermediate compound (23.60 g, 81%) as a gray-tan solid.
[1177] A second intermediate compound,
6-Fluoro-4H-pyrido[3,2-b][1,4]oxazin-3-one, was produced as
follows: A 1 gallon Nalgene jar (with openings in the top for a
N.sub.2 inlet and addition of solids) was cooled in an ice/salt
bath and hydrogen fluoride-pyridine (500 g) was added. With
magnetic stirring and under a stream of N.sub.2,
6-amino-4H-pyrido[3,2-b][1,4]oxazin-3-one (88.48 g, 0.5362 mol, 1.0
equiv) was added slowly portion-wise. When addition was complete,
the red-brown mixture was stirred for 0.25 h to ensure complete
solution. Sodium nitrite (44.40 g, 0.6435 mol, 1.2 equiv) was added
cautiously portion-wise over 0.5 hr. Each addition was exothermic
and accompanied by the evolution of HF and N.sub.2. When addition
was complete the reaction mixture was stirred in the ice/salt bath
for 1 h. The reaction was quenched by the slow, careful addition of
ice-cold H.sub.2O (2 L). The resulting solid was collected, washed
with H.sub.2O, resuspended in H.sub.2O (3.times.1 L), collected,
washed with H.sub.2O and dried on the filter for 1 h. The solid was
washed with heptane and dried under a N.sub.2 stream for 2 h. Final
drying in a vacuum oven for 24 h at -40.degree. C. gave the second
intermediate compound (69.03 g, 76%) as an orange-brown solid. Mp
179.9-181.20.
[1178] A third intermediate compound,
6-(4-Benzyloxy-butoxy)-4H-pyrido[3,2-b][1,4]oxazin-3-one, was
produced as follows: A solution of 4-benzyloxy-butan-1-ol 1 (34.31
g, 33.37 mL, 190.3 mmol) and potassium t-butoxide (1M solution; 181
mL) in THF (60 mL) was prepared and stirred at room temperature for
20 min. A suspension of 6-fluoro-4H-pyrido[3,2-b][1,4]oxazin-3-one
(8 g, 48 mmol) in THF (100 mL) was prepared, and the alcohol/base
solution was added to this solution via canula. The reaction was
heated at reflux for 25 hours. The reaction was quenched with
saturated NH.sub.4Cl and water. The solution was brought to a pH of
8 and extracted with ethyl acetate. The organic layer was washed
with brine and concentrated to give a solid. Purification by
SiO.sub.2 chromatography (0-70% EtOAc/hexanes) gave the third
intermediate compound as a white solid (6.6 g, 42%). MS: APCI: M+1:
329.2 (Exact Mass: 328.14).
[1179] A fourth intermediate compound,
6-(4-Hydroxy-butoxy)-4H-pyrido[3,2-b][1,4]oxazin-3-one, was
produced as follows: To a solution of
6-(4-benzyloxy-butoxy)-4H-pyrido[3,2-b][1,4]oxazin-3-one (6.4 g, 19
mmol) in MeOH/THF (100 mL) was added 20% Pd/C (1.5 g) and the
mixture was hydrogenated for 12 h. The reaction was filtered,
concentrated and purified by liquid chromatography (0-10%
MeOH/CH.sub.2Cl.sub.2) to give the fourth intermediate compound as
a white solid (4.3 g, 18 mmol, 93%). MS: APCI: M+1: 239.1 (Exact
Mass: 238.10).
[1180] A fifth intermediate compound,
4-(3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yloxy)-butyraldehyde,
was produced as follows: To a suspension of
6-(4-hydroxy-butoxy)-4H-pyrido[3,2-b][1,4]oxazin-3-one (4.3 g,
18.02 mmol) in dichloroethane (30 mL) was added IBX (15 g, 54
mmol). This mixture was heated at 80.degree. C. for 5 hours. The
reaction was cooled and stirred, and then filtered. The filter cake
was washed with CH.sub.2Cl.sub.2 until the product was removed. The
filtrate was concentrated to give a red oil, which was purified by
SiO.sub.2 chromatography (0-7% MeOH/CH.sub.2Cl.sub.2) to give the
fifth intermediate compound as a red oil (3.90 g, 16.5 mmol, 92%).
MS: APCI: M+1: 237.1 (Exact Mass: 236.08).
[1181] To a solution of
4-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yloxy)-butyraldehyde
(0.325 g, 1.37 mmol) in dichloroethane (6 mL) was added a solution
of 1-(2,3-dichloro-phenyl)-piperazine (0.318 g, 1.37 mmol) in
dichloroethane (3 mL) via cannula. The mixture was stirred for 20
minutes at room temperature and NaBH(OAc).sub.3 (0.377 g, 1.78
mmol) was added. The reaction was stirred for 2.5 h and quenched
with saturated NaHCO.sub.3 and water. The mixture was extracted
with EtOAc and the organic layer was washed with saturated
NaHCO.sub.3, water and brine, dried over Na.sub.2SO.sub.4 and
concentrated. Purification by chromatography on silica gel (0-5%
MeOH/CH.sub.2Cl.sub.2) gave a foam. Et.sub.2O was added and product
crashed out. The precipitate was filtered and dried to give the
title compound as a white solid (0.386 g, 0.854 mmol, 63%). MS:
APCI: M+1: 451.1 (Exact Mass: 450.12).
Example G4
Synthesis of
6-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-4H-pyrido[3,2-b][1,4]oxazin-3--
one
[1182] The reductive amination procedure from Example G3 was
followed using 1-indan-4-yl-piperazine to give the title compound
(0.24 g; 69%). MS: APCI: M+1: 423.3 (Exact Mass: 422.23).
Example G5
Synthesis of
6-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-4H-pyrido[3,2-b][1,4]oxaz-
in-3-one
[1183] The reductive amination procedure from Example G3 was
followed using 1-naphthalen-1-yl-piperazine to give the title
compound (0.24 g, 56%). MS: APCI: M+1: 433.1 (Exact Mass:
432.22).
Example G6
Synthesis of
6-{4-[4-(6-Methoxy-pyridin-2-yl)-piperazin-1-yl]-butoxy}-4H-pyrido[3,2-b]-
[1,4]oxazin-3-one
[1184] The reductive amination procedure from Example G3 was
followed using 1-(6-methoxy-pyridin-2-yl)-piperazine to give the
title compound (0.21 g, 62%). MS: APCI: M+1: 414.2 (Exact Mass:
413.21).
Example G7
Synthesis of
6-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4H-pyrido[3,2--
b][1,4]oxazin-3-one
[1185] The reductive amination procedure from Example G3 was
followed using 1-(7-fluoro-naphthalen-1-yl)-piperazine to give the
title compound (0.31 g, 64%). MS: APCI: M+1: 451.3 (Exact Mass:
450.21).
Example G8
Synthesis of
6-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4H-p-
yrido[3,2-b][1,4]oxazin-3-one
[1186] The reductive amination procedure from Example G3 was
followed using 1-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine to
give the title compound (0.23 g, 65%). MS: APCI: M+1: 437.3 (Exact
Mass: 436.25).
Example H1
Synthesis of
2-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]pyr-
imidin-7-one
[1187] A first intermediate compound,
2-Methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one, was produced as
follows: To a suspension of
2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (5.0 g, 25.9 mmol)
in CH.sub.2Cl.sub.2 (100 mL), CHCl.sub.3 (50 mL) and MeOH (10 mL,
the starting material still did not dissolve) was added the
oxaziridine (8.11 g, 31.05 mmol, 1.2 equiv) as a solid. The
reaction became homogenous after 3 h and was stirred overnight at
RT. The reaction was concentrated and CH.sub.2Cl.sub.2/MeOH was
added to dissolve the residue. Much of the solid did not dissolve
so the mixture was filtered to give an off-white solid which was
the first intermediate compound (2.31 g, 11.04 mmol, 43%). MS:
APCI: M+1: 210.1 (Exact Mass: 209.03).
[1188] A second intermediate compound,
2-[4-(Tetrahydro-pyran-2-yloxy)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-one,
was produced as follows: To a solution of
4-(tetrahydro-pyran-2-yloxy)-1-butanol (4.45 g, 25.3 mmol, 2.5
equiv) in THF (20 mL) cooled to 0.degree. C. was added 1M KOtBu in
THF (25 mL, 25 mmol). The solution was stirred at 0.degree. C. for
20 min and then added to a suspension of
2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (2.12 g, 10.13
mmol) in DMF (30 mL) at RT. The reaction became homogenous and was
stirred at room temperature for 1 h. Saturated NH4Cl and H2O were
added to quench the reaction. The mixture was extracted with EtOAc.
The organic layer was washed with H2O and brine, dried over Na2SO4
and concentrated. Purification by liquid chromatography (70%
EtOAc/Hexanes to 100% EtOAc) gave the second intermediate compound
as a white solid (1.95 g, 6.11 mmol, 60%). MS: APCI: M+1: 320.2
(Exact Mass: 319.15).
[1189] A third intermediate compound,
2-(4-Hydroxy-butoxy)-8H-pyrido[2,3-d]pyrimidin-7-one, was produced
as follows: To a suspension of
2-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-one
(1.95 g, 6.11 mmol) in EtOH (30 mL) and CH.sub.2Cl.sub.2 (2 mL,
added to help dissolve the starting material) was added PPTS (151
mg, 0.6 mmol). The solution was stirred overnight at room
temperature and then heated at 60.degree. C. for 5 h. The reaction
was concentrated to give a white solid. Purification by liquid
chromatography (6% MeOH/CH2Cl2) gave the third intermediate
compound as a white solid (1.22 g, 5.19 mmol, 85%). MS: APCI: M+1:
236.1 (Exact Mass: 235.10).
[1190] A fourth intermediate compound,
4-(7-Oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)-butyraldehyde,
was produced as follows: To a solution of
2-(4-hydroxy-butoxy)-8H-pyrido[2,3-d]pyrimidin-7-one (251 mg, 1.07
mmol) in DMSO (3 mL) was added a solution of IBX (597 mg, 2.13
mmol) in DMSO (7 mL, 0.3 M). The reaction was stirred at room
temperature for 90 min, cooled to 0.degree. C. and quenched with 5%
NaHCO.sub.3. The mixture was extracted with CH.sub.2Cl.sub.2
(4.times.). The organic layer was washed with 5% NaHCO.sub.3 and
brine, dried over Na.sub.2SO.sub.4 and concentrated to give the
fourth intermediate compound as a white solid (171 mg, 0.733 mmol,
69%). MS: APCI: M+1: 234.1 (Exact Mass: 233.08).
[1191] To a suspension of
4-(7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)-butyraldehyde
(235 mg, 1.01 mmol) in dichloroethane (5 mL) was added
1-(2,3-dichloro-phenyl)-piperazine hydrochloride (270 mg, 1.01
mmol) followed by Et3N (0.28 mL, 2.0 mmol, 2 equiv). After 10 min
at RT, NaBH(OAc)3 (297 mg, 1.4 mmol) was added as a powder. The
reaction was stirred for 2 h at room temperature and quenched with
saturated NaHCO3 and H2O. The mixture was extracted with EtOAc
(with a little MeOH to help dissolve the solids). The organic layer
was washed with brine and concentrated. Purification by liquid
chromatography (5% MeOH/CH2Cl2 with 1% NH4OH) gave the title
compound as a white solid (375 mg, 0.836 mmol, 83%). MS: APCI: M+1:
448.1 (Exact Mass: 447.12).
[1192] The pyrimidines of Examples H2 and H3 were synthesized in a
combinatorial library format by reductive amination of the
appropriate piperazine starting materials with
4-(7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)-butyraldehyde
using the procedure outlined in Example H1.
Example H2
Synthesis of
2-{4-[4-(2-Isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]pyr-
imidin-7-one
[1193] The title compound was isolated as a white solid (223 mg,
0.510 mmol, 59.4%). MS: APCI: M+1: 438.1 (Exact Mass: 437.24).
Example H3
Synthesis of
2-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-on-
e
[1194] The title compound was isolated as a white solid (270 mg,
0.643 mmol, 75.1%). MS: APCI: M+1: 420.3 (Exact Mass: 419.23).
Example H4
Synthesis of
2-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-8H-pyrido[2,3-d]pyrimidin-
-7-one
[1195] Following the same procedure as in Example H12 and starting
from 2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (300 mg,
1.332 mmol, U.S. Pat. No. 6,498,163) and
4-(4-naphthalen-1-yl-piperazin-1-yl)-butan-1-ol (416 mg, 1.465
mmol), the title compound was made as a solid (300 mg, 0.683 mmol,
51.3%). MS: APCI: M+1: 430.2 (Exact Mass: 429.22).
Example H5
Synthesis of
6-Fluoro-4-methyl-2-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-8H-pyri-
do[2,3-d]pyrimidin-7-one
[1196] Following the same procedure as in Example H12 and starting
from
6-fluoro-2-methanesulfonyl-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one
(300 mg, 1.166 mmol, U.S. Pat. No. 6,498,163) and
4-(4-naphthalen-1-yl-piperazin-1-yl)-butan-1-ol (331 mg, 1.166
mmol), the title compound was made as a solid (323 mg, 0.684 mmol,
58.7%). MS: APCI: M+1: 462.1 (Exact Mass: 461.22).
Example H6
Synthesis of
2-{4-[4-(6-Isopropyl-pyridin-2-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-py-
rido[2,3-d]pyrimidin-7-one
[1197] A first intermediate compound,
2-Methanesulfonyl-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one, was
produced as follows: A solution of
4-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (24 g,
0.1158 mol, U.S. Pat. No. 6,498,163) in a mixture of
CH.sub.2Cl.sub.2 (1.9 L) and methanol (300 mL) is treated with
m-chloroperbenzoic acid (103 g, 60%, 0.345 mol) in portions at room
temperature. The mixture is stirred for 24 h, cooled to
.about.5.degree. C. and quenched with saturated sodium bicarbonate
solution. The solids are filtered, washed thoroughly with water
followed by ether and dried in vacuum to give the first compound as
a solid (10 g, 0.042 mol, 36%). MS: APCI: M+1: 240.0 (Exact Mass:
239.04).
[1198] A second intermediate compound,
4-Methyl-2-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-8H-pyrido[2,3-d]pyrimidi-
n-7-one, was produced as follows: To a ice bath cooled solution of
4-(tetrahydro-pyran-2-yloxy)-butan-1-ol (27.3 g, 0.1567 mol) in dry
THF (125 mL) is added drop wise a solution of KOtBu (1M, 155 mL,
0.155 mol) in THF within 15 min. The mixture is then stirred at
0.degree. C. for 2 h. To this mixture is added a suspension of
2-methanesulfonyl-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (15 g,
0.0627 mol) in DMF (225 mL) at room temperature within 15 min. The
orange red colored reaction mixture is stirred at room temperature
for 1.5 h, cooled and quenched with saturated NH.sub.4Cl solution
(150 mL) and water (2 L). The mixture is extracted with ethyl
acetate (2.times.0.75 L) and the organic layer is washed with brine
(300 mL), dried over anhydrous sodium sulfate, filtered through a
small bed of silica gel eluting with 5% methanol in ethyl acetate
(750 mL) and concentrated. The residue is then triturated with
hexane, filtered and dried to give the second intermediate compound
as a white solid (16.5 g, 0.0495 mol 78%). MS: APCI: M+1: 334.0
(Exact Mass: 333.17).
[1199] A third intermediate compound,
2-(4-Hydroxy-butoxy)-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one, was
produced as follows: A mixture of
4-methyl-2-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-8H-pyrido[2,3-d]pyrimidi-
n-7-one (16.5 g, 0.049 mol) and PPTS (1.24 g, 0.0049 mol) in
ethanol (250 mL) and CH.sub.2Cl.sub.2 (20 mL) is stirred at room
temperature for 16 h, followed by heating at reflux
(.about.90.degree. C.) for 3 h. The cloudy reaction mixture is
evaporated under vacuum and the residue is triturated in
hexane-ethyl acetate (150 mL, 1:1) and dried to give the third
intermediate compound as a yellow powder (12.5 g, 0.049 mol, 100%).
MS: APCI: M+1: 250.0 (Exact Mass: 249.11).
[1200] A fourth intermediate compound,
4-(4-Methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)-butyraldehy-
de, was produced as follows: A stirred solution of IBX (26 g, 0.092
mol) in DMSO (220 ml) is treated with
2-(4-hydroxy-butoxy)-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (11
g, 0.0467 mol) portion wise while stirring at room temperature
during 30 min and the reaction is stirred at room temperature for
an additional 2 h. The mixture is cooled and treated with saturated
NaHCO.sub.3 (150 mL) and extracted with chloroform (4.times.0.5 L).
The combined organic layer is washed with brine/ice (2.times.),
dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue
is stirred with ether, filtered, washed with ether and dried to
give 6 g of the crude, which shows it to be a mixture. The ether
filtrate residue also shows some product, but mostly starting
material. The residue from the filtrate and the crude (11 g) are
subjected to re-oxidation as above using fresh IBX (15.5 g, 0.055
mol) in DMSO (150 mL), but stirred at 30.degree. C. for 3 h. Workup
as above yielded the fourth intermediate compound as an off-white
powder (8.3 g, 0.057 mol, 66.8%). MS: APCI: M+1: 248.0 (Exact Mass:
247.10).
4-(4-Methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)-butyraldehy-
de (74.2 mg, 0.3 mmol) and 1-(6-isopropyl-pyridin-2-yl)-piperazine
(62.8 mg, 0.306 mmol) were combined in methylene chloride and
stirred in a vial over sieves for 10 min. Sodium
triacetoxyborohydride (89 mg, 0.42 mmol) was added and the reaction
was stirred overnight. The reaction was quenched by slowly adding
water and then the mixture was filtered. The residue was
partitioned between CH.sub.2Cl.sub.2 and water and the organic
layer was concentrated. Purification by liquid chromatography
(MPLC, gradient of 100% CH.sub.2Cl.sub.2 to 100% of a 10% MeOH in
CH.sub.2Cl.sub.2 solution) gave the title compound as a low melting
solid (55 mg, 0.126 mmol, 42%). MS: APCI: M+1: 437.3 (Exact Mass:
436.26).
[1201] The pyrimidines of Examples H6-H11 were synthesized in
combinatorial library format by reductive amination of the
appropriate piperazine starting materials with
4-(4-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)-butyraldehy-
de following the procedure outlined in Example H7.
Example H7
Synthesis of
2-{4-[4-(6-Ethyl-pyridin-2-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-pyrido-
[2,3-d]pyrimidin-7-one
[1202] The title compound was isolated as a low melting solid (87
mg, 0.206 mmol, 68.6%). MS: APCI: M+1: 423.3 (Exact Mass:
422.24).
Example H8
Synthesis of
2-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-4-methyl-8H-pyrido[2,3-d]pyrim-
idin-7-one
[1203] The title compound was isolated as a white powder (66 mg,
0.152 mmol, 50.74%). MS: APCI: M+1: 434.2 (Exact Mass: 433.25).
Example H9
Synthesis of
4-Methyl-2-{4-[4-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-but-
oxy}-8H-pyrido[2,3-d]pyrimidin-7-one
[1204] The title compound was isolated as a white powder (75 mg,
0.167 mmol, 55.86%). MS: APCI: M+1: 448.3 (Exact Mass: 447.26).
Example H10
Synthesis of
2-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-py-
rido[2,3-d]pyrimidin-7-one
[1205] The title compound was isolated as a solid (61 mg, 0.132
mmol, 44.06%). MS: APCI: M+1: 462.2 (Exact Mass: 461.22).
Example H11
Synthesis of
2-{4-[4-(7-Methoxy-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-p-
yrido[2,3-d]pyrimidin-7-one
[1206] The title compound was isolated as a solid (43 mg, 0.09
mmol, 30.3%). MS: APCI: M+1: 474.3 (Exact Mass: 473.24).
Example H12
Synthesis of
4-Methyl-2-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-8H-pyrido[2,3-d]-
pyrimidin-7-one
[1207] 2-Methanesulfonyl-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one
(300 mg, 1.245 mmol, U.S. Pat. No. 6,498,163),
4-(4-naphthalen-1-yl-piperazin-1-yl)-butan-1-ol (392 mg, 1.379
mmol) and sodium t-butoxide (362 mg, 3.76 mmol) were combined in a
vial. Dioxane (10 mL) was added and the solution was stirred for 1
h. The reaction mixture was concentrated and then partitioned
between ethyl acetate and water. The organic layer was washed with
water, dried over Na.sub.2SO.sub.4, filtered and concentrated.
Purification by liquid chromatography (MPLC, gradient of 100%
CH.sub.2Cl.sub.2 to 100% of 100:8:1
CH.sub.2Cl.sub.2:EtOH:NH.sub.4OH solution) gave the title compound
as a solid (220 mg, 0.485 mmol, 38%). MS: APCI: M+1: 444.2 (Exact
Mass: 443.23).
Example H13
Synthesis of
2-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4,8-dimethyl-8-
H-pyrido[2,3-d]pyrimidin-7-one
[1208] A first intermediate compound,
2-Methanesulfonyl-4,8-dimethyl-8H-pyrido[2,3-d]pyrimidin-7-one, was
produced as follows: A solution of
4,8-dimethyl-2-methylthio-8-hydropyridino[2,3-d]pyrimidin-7-one
(48.0 g, 0.216 mol) in a mixture of CH.sub.2Cl.sub.2 (2.8 L) and
methanol (410 mL) is treated with m-chloroperbenzoic acid (100 g,
57-86%) in portions at room temperature. The mixture is stirred for
24 h, filtered and the filtrate is concentrated. The residue is
dissolved in chloroform, washed with saturated NaHCO.sub.3
(2.times.300 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated to give the crude which upon purification by column
chromatography (EtOAc/Hexanes) gave the first intermediate compound
as white solid (38 g, mmol, 0.150 mol, 69%). MS: APCI: M+1: 254.0
(Exact Mass: 253.05).
[1209] A second intermediate compound
4,8-Dimethyl-2-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-8H-pyrido[2,3-d]pyri-
midin-7-one, was produced as follows: To a solution of
4-(tetrahydro-pyran-2-yloxy)-butan-1-ol (82.3 g, 0.472 mol) in dry
THF (450 mL) cooled to 0.degree. C. is added drop-wise a solution
of KOtBu (1M in THF, 473 mL, 0.472 mol) within 1 h. The mixture is
stirred at 0.degree. C. for 1 h and then a solution of
2-methanesulfonyl-4,8-dimethyl-8H-pyrido[2,3-d]pyrimidin-7-one (38
g, 0.15 mol) in DMF (475 mL) is added at room temperature within 15
min. The mixture is stirred at room temperature for 1 h, cooled and
quenched with saturated NH.sub.4Cl (300 mL) followed by water (2 L)
and extracted with EtOAc (3.times.1 L). The organic layer is washed
with brine (3.times.500 mL), dried over MgSO.sub.4, filtered and
concentrated. The residue is purified by column chromatography
(EtOAc/Hexane, 70%-100%) to afford the second intermediate compound
as an oil (24.6 g, 0.071 mol, 47.2%). MS: APCI: M+1: 348.0 (Exact
Mass: 347.18).
[1210] A third intermediate compound,
2-(4-Hydroxy-butoxy)-4,8-dimethyl-8H-pyrido[2,3-d]pyrimidin-7-one,
was produced as follows: A mixture of
4,8-dimethyl-2-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-8H-pyrido[2,3-d]pyri-
midin-7-one (24 g, 0.069 mol) and PPTS (1.9 g, 0.0075 mol) in
ethanol (200 mL) is heated to -65.degree. C. overnight. The mixture
is evaporated under vacuum. The residue is dissolved in
CH.sub.2Cl.sub.2 (500 mL), washed with water (3.times.100 mL),
NaHCO.sub.3 solution (2.times.100 mL), dried over MgSO.sub.4,
filtered and evaporated under vacuum. The residue obtained is
stirred in ether, filtered, washed with ether and dried to give the
third intermediate compound as an off-white solid (9.5 g, 0.361
mol, 52.5%). MS: APCI: M+1: 264.0 (Exact Mass: 263.13).
[1211] A fourth intermediate compound,
4-(4,8-Dimethyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)-butyral-
dehyde, was produced as follows: A stirred solution of
2-(4-hydroxy-butoxy)-4,8-dimethyl-8H-pyrido[2,3-d]pyrimidin-7-one
(9.26 g, 0.0351 mol) in DMSO (180 mL) is treated with IBX (19.7 g,
0.070 mol) and the mixture is stirred at room temperature for 1.5
h. The mixture is cooled to 0.degree. C., treated with saturated
NaHCO.sub.3 (400 mL) and extracted with CH.sub.2Cl.sub.2
(4.times.200 mL). The combined organic layer is washed with 15%
NaHCO.sub.3 brine/ice (2.times.100 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue obtained
is stirred with ether, filtered, washed with ether and dried to
give the fourth intermediate compound as a cream white solid (6.9
g, 0.026 mol, 75.2%). MS: APCI: M+1: 262.0 (Exact Mass:
261.11).
[1212]
4-(4,8-dimethyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)--
butyraldehyde (78.4 mg, 0.30 mmol) and
1-(7-fluoro-naphthalen-1-yl)-piperazine trifluoroacetic acid (105
mg, 0.306 mmol) were combined in methylene chloride and
triethylamine (63 mg, 0.63 mmol) was added. The mixture was stirred
in a vial over sieves for 10 min. Sodium triacetoxyborohydride (89
mg, 0.420 mmol) was added and the reaction was stirred overnight.
The reaction was quenched slowly with water and the mixture was
filtered. The residue was partitioned between CH.sub.2Cl.sub.2 and
water. The organic layer was washed with water and concentrated.
Purification by liquid chromatography (MPLC, gradient of 100%
CH.sub.2Cl.sub.2 to 100% of a 10% MeOH in CH.sub.2Cl.sub.2
solution) gave the title compound as a white foam (89 mg, 0.187
mmol, 62.4%). MS: APCI: M+1: 476.2 (Exact Mass: 475.24).
Example H14
Synthesis of
2-{4-[4-(7-Methoxy-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4,8-dimethyl--
8H-pyrido[2,3-d]pyrimidin-7-one
[1213] The title compound was prepared as described above using
1-(7-methoxy-naphthalen-1-yl)-piperazine to give a pale yellow foam
(91 mg, 0.186 mmol, 62.2%). MS: APCI: M+1: 488.2 (Exact Mass:
487.26).
Example I1
Synthesis of
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-[1,6-
]naphthyridin-2-one
[1214] A first intermediate compound,
(4-Amino-6-chloro-pyridin-3-yl)-methanol, was produced as follows:
To a suspension of LiAlH.sub.4 (2.20 g, 58 mmol) in THF (100 mL)
was added a solution of 4-amino-6-chloro-nicotinic acid ethyl ester
(8.0 g, 36.2 mmol) via cannula. After 90 minutes, H.sub.2O (2.2 mL)
was added slowly and the mixture was stirred for 20 minutes. 3M
NaOH (2.2 mL) was added, followed by H.sub.2O (6.6 mL) and the
mixture was stirred for 1 hour. The precipitate was filtered. The
organic layer was washed with saturated NaHCO.sub.3 and brine,
dried over Na.sub.2SO.sub.4 and concentrated to give the first
intermediate compound as a yellow solid (6.39 g, 69%). MS: APCI:
M+1: 159.1 (Exact Mass: 158.03).
[1215] A second intermediate compound,
3-(4-Amino-6-chloro-pyridin-3-yl)-acrylic acid ethyl ester, was
produced as follows: To a suspension of
(4-amino-6-chloro-pyridin-3-yl)-methanol (6.39 g, 40.29 mmol) in
CH.sub.2Cl.sub.2, was added barium manganate (17.55 g, 68.49 mmol),
followed by (carbethoxymethylene)triphenylphosphorane (19.71 g,
52.37 mmol). The reaction was refluxed for 5 hours and then stirred
at room temperature for 14 hours. The reaction was filtered through
Celite, washed with CH.sub.2Cl.sub.2 and the filtrate was
concentrated. Et.sub.2O was added and the mixture was stirred for
14 hours. The precipitate (Ph.sub.3PO) was filtered off and the
filtrate was concentrated. Purification by liquid chromatography
(30-50% EtOAc/Hexanes) gave the second intermediate compound as a
white solid (5.85 g, 64%). MS: APCI: M+1: 227.2 (Exact Mass:
226.05).
[1216] A third intermediate compound,
3-(4-Amino-6-chloro-pyridin-3-yl)-propionic acid ethyl ester, was
produced as follows: 3-(4-Amino-6-chloro-pyridin-3-yl)-acrylic acid
ethyl ester (2.51 g, 11.0 mmol) was hydrogenated using 5%
Pd/BaSO.sub.4 in THF (100 mL) for 28 hours. The reaction was
filtered and concentrated to give a yellow oil. Purification by
liquid chromatography (20-40% EtOAc/Hexanes) afforded the third
intermediate compound as a colorless oil (1.191 g, 48%). MS: APCI:
M+1: 229.0 (Exact Mass: 228.05).
[1217] A fourth intermediate compound,
7-Chloro-3,4-dihydro-1H-[1,6]naphthyridin-2-one, was produced as
follows: To a solution of
3-(4-amino-6-chloro-pyridin-3-yl)-propionic acid ethyl ester (1.034
g, 4.53 mmol) in ethanol, was added DBU. The reaction was heated to
70.degree. C. and stirred for 20 hours. The reaction was cooled and
concentrated. Purification by liquid chromatography (20-50%
EtOAc/Hexanes) gave the fourth intermediate compound as a white
solid (0.794 g, 96%). MS: APCI: M+1: 183.0 (Exact Mass:
182.02).
[1218] A fifth intermediate compound,
7-(5-Chloro-pent-1-enyl)-3,4-dihydro-1H-[1,6]naphthyridin-2-one,
was produced as follows: To a solution of
7-chloro-3,4-dihydro-1H-[1,6]naphthyridin-2-one (0.908 g, 4.97
mmol) in DME (20 mL) was added 5-chloro-pent-1-enyl-boronic acid
(1.475 g, 9.94 mmol), followed by Pd(PPh.sub.3).sub.4 (0.144 g,
0.124 mmol) and 2M Na.sub.2CO.sub.3 (1.053 g in 5.0 mL H.sub.2O).
The reaction was refluxed for 14 hours. The reaction was cooled,
and partitioned between EtOAc and water. The organic layer was
washed with brine, dried over Na.sub.2SO.sub.4 and concentrated.
Purification by chromatography on silica gel (0-40% EtOAc/Hexanes)
gave the fifth intermediate compound as a white solid (0.763 g,
61%). MS: APCI: M+1: 253.1 (Exact Mass: 252.10).
[1219] A sixth intermediate compound,
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-
-[1,6]naphthyridin-2-one, was produced as follows: To a solution of
7-(5-chloro-pent-1-enyl)-3,4-dihydro-1H-[1,6]naphthyridin-2-one
(0.72 g, 2.87 mmol) in CH.sub.3CN (10 mL) was added
1-(2,3-dichloro-phenyl)-piperazine (0.994 g, 4.30 mmol), followed
by K.sub.2CO.sub.3 (0.793 g, 5.74 mmol) and KI (0.095 g, 0.574
mmol). The reaction was refluxed for 14 hours. The reaction was
cooled to room temperature and partitioned between EtOAc and
H.sub.2O. The organic layer was washed with saturated NaHCO.sub.3
and brine, dried over Na.sub.2SO.sub.4 and concentrated to give an
oil. Purification by chromatography on silica gel (10-40%
MeOH/EtOAc) afforded the sixth intermediate compound as a white
solid (0.903 g, 72%). MS: APCI: M+1: 445.1 (Exact Mass:
444.15).
[1220]
7-{5-(4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dih-
ydro-1H-[1,6]naphthyridin-2-one (0.417 g, 0.937 mmol) was
hydrogenated using Ra-Ni (0.25 g) in THF for 2 hours. The reaction
was filtered and concentrated to give a white solid. EtOAc was
added and the product crashed out. The precipitate was filtered and
dried to give the title compound as a white solid (0.391 g, 93%).
MS: APCI: M+1: 447.2 (Exact Mass: 446.16).
Example I2
Synthesis of
7-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4--
dihydro-1H-[1,6]naphthyridin-2-one
[1221] The first intermediate compound,
3-(4,6-Diamino-pyridin-3-yl)-acrylic acid ethyl ester, was produced
as follows: A mixture of (carbethoxymethylene)triphenylphosphorane
(436 g, 1.25 mol) and 4,6-diaminopyridine-3-carbaldehyde (131.8 g,
0.96 mol) in 1,4-dioxane (2.0 L) was refluxed for 2.0 h. The
mixture was cooled and filtered through silica gel (800 g) eluting
with 0-10% MeOH/EtOAc. The filtrate was concentrated and the
residue (.about.580 g) was used in the next step without further
purification.
[1222] A second intermediate compound,
7-Amino-1H-[1,6]naphthyridin-2-one, was produced as follows: The
residue obtained from the above procedure was refluxed in conc. HCl
(1.5 L) for 1.5 h. The mixture was cooled and diluted with water
(2.5 L). At 35-40.degree. C., the mixture was washed with EtOAc
(3.times.). The aqueous layer was made basic with 50% NaOH to
pH>10 while cooling with a cold water bath. The resulting solid
was collected via filtration, rinsed with water, methanol, and oven
dried to afford the second intermediate compound (106 g, 68% for
two steps) as off-white crystals.
[1223] A third intermediate compound,
7-Fluoro-1H-[1,6]naphthyridin-2-one, was produced as follows: To a
stirred mixture of HF-pyridine (660 g) and
7-amino-1H-[1,6]naphthyridin-2-one (58 g, 0.36 mol) in a plastic
bottle was added NaNO.sub.2 (39.7 g, 0.57 mol) in small portions
over 30-40 min while cooled with a cold (.about.10.degree. C.)
water bath in order to keep the internal temperature at around RT.
After the addition, the mixture was further stirred at room
temperature for 20 min before it was poured into water (2.6 L) and
stirred for 3.0 h. The resulting solid was collected via
filtration, rinsed with water (2.times.), EtOAc-heptane (1:1,
2.times.), and oven dried to afford the third intermediate compound
(48.6 g, 82%) as pale solid.
[1224] A fourth intermediate compound,
7-(4-Benzyloxy-butoxy)-1H-[1,6]naphthyridin-2-one, was produced as
follows: A solution of 4-benzyloxy-butan-1-ol (35.98 g,199.6 mmol)
and potassium t-butoxide (21 g,188 mmol) in THF (60 mL) was
prepared and stirred at room temperature for 20 min. A suspension
of 7-fluoro-1H-[1,6]naphthyridin-2-one (8.1 g, 49 mmol) in THF (100
mL) was prepared, and the alcohol solution was added to this
solution via canula. The reaction was stirred at 80.degree. C.
overnight. MS showed mostly product. So reaction quenched with
saturated NH.sub.4Cl and water. The solution was brought to a pH of
8 and extracted with ethyl acetate. The organic layer was washed
with brine and concentrated to give a silky solid. EtOAc was added
and the mixture was filtered to give a beige solid. The NMR
indicated that it was the product and it was recrystallized from
acetonitrile to give clean product. (9.70 g). The filtrate was
concentrated and filtered to give more precipitate (0.788 g). The
filtrate was concentrated and purified by chromatography (0-70%
EtOAc/hexanes) to give additional product as a beige solid (2.716
g). (Total Product: 13.21 g, 82%). MS: APCI: M+1: 325.2 (Exact
Mass: 324.15).
[1225] A fifth intermediate compound,
7-(4-Hydroxy-butoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one, was
produced as follows: To a solution of
7-(4-benzyloxy-butoxy)-1H-[1,6]naphthyridin-2-one (7.92 g, 24.4
mmol) in MeOH/THF (100 mL) was added 20% Pd/C (1.5 g) and the
mixture was hydrogenated for 59 h. The reaction was filtered,
concentrated and purified by liquid chromatography (0-10%
MeOH/CH2Cl2) to give the fifth intermediate compound as a white
solid (4.11 g, 17.4 mmol, 71%). MS: APCI: M+1: 237.1 (Exact Mass:
236.12).
[1226] A sixth intermediate compound,
4-(2-Oxo-1,2,3,4-tetrahydro-[1,6]naphthyridin-7-yloxy)-butyraldehyde,
was produced as follows: To a suspension of
7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one (2.0 g,
8.5 mmol) in dichloroethane (20 mL) was added IBX (7 g, 25 mmol).
This was heated at 80.degree. C. for 5 hours. The reaction was
cooled and then filtered. The filter cake was washed with
CH.sub.2CH.sub.2 until the product was removed. The filtrate was
concentrated to give a yellow solid (1.88 g, used crude in next
reaction). MS: APCI: M+1: 235.1 (Exact Mass: 234.10).
[1227] A reductive amination procedure similar to Example A1 was
followed using 1-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine to
give the title compound (0.33 g; 56%). MS: APCI: M+1: 435.2 (Exact
Mass: 434.27).
Example I3
Synthesis of
7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,6]napht-
hyridin-2-one
[1228] A reductive amination procedure similar to Example A1 was
followed using 1-naphthalen-1-yl-piperazine to give the title
compound (0.480 g, 87%). MS: APCI: M+1: 431.2 (Exact Mass:
430.24).
Example I4
Synthesis of
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,6-
]naphthyridin-2-one
[1229] A reductive amination procedure similar to Example A1 was
followed using 1-(2,3-dichloro-phenyl)-piperazine to give the title
compound (0.48 g; 81%). MS: APCI: M+1: 449.1 (Exact Mass:
448.14).
Example I5
Synthesis of
7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,6]naphthyrid-
in-2-one
[1230] A reductive amination procedure similar to Example A1 was
followed using 1-indan-4-yl-piperazine to give the title compound
(0.36 g; 66%). MS: APCI: M+1: 421.2 (Exact Mass: 420.25).
Example I6
Synthesis of
7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,6]naphthyridin-2-one
[1231] A reductive amination procedure similar to Example A1 was
followed using 1-(7-fluoro-naphthalen-1-yl)-piperazine to give the
title compound (0.31 g; 68%). MS: APCI: M+1: 449.3 (Exact Mass:
448.23).
Example I7
Synthesis of
8-Bromo-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1-
,6]naphthyridin-2-one
[1232] The first intermediate compound,
8-Bromo-7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one,
was produced as follows: To a solution of
7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one (1.1 g,
4.7 mmol) in DMF (10 mL) was added NBS (0.91 g, 5.1 mmol). The
solution was stirred at room temperature for 2.5 h. The reaction
turned a deeper yellow color. H.sub.2O was added and the mixture
was extracted with EtOAc. The organic layer was washed with
H.sub.2O, and brine, dried over MgSO.sub.4 and concentrated.
Purification by SiO.sub.2 chromatography (0-7%
MeOH/CH.sub.2Cl.sub.2) gave the first intermediate compound as an
off-white solid (1.16 g, 3.69 mmol, 79%). MS: APCI: M+1: 315.0
(Exact Mass: 314.03).
[1233] A second intermediate compound,
4-(8-Bromo-2-oxo-1,2,3,4-tetrahydro-[1,6]naphthyridin-7-yloxy)-butyraldeh-
yde, was produced as follows: To a suspension of
8-bromo-7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one
(1.1 g, 3.5 mmol) in dichloroethane (20 mL) was added IBX (3 g, 10
mmol). This was heated at 80.degree. C. for 5 hours. The reaction
was cooled and then filtered. The filter cake was washed with
CH.sub.2CH.sub.2 until the product was removed. The filtrate was
concentrated to give a yellow oil. Purification by SiO.sub.2
chromatography (0-7% MeOH/CH.sub.2Cl.sub.2) gave the second
intermediate compound as a yellow solid (1.01 g). MS: APCI: M+1:
313.1 (Exact Mass: 312.01).
[1234] A reductive amination procedure similar to Example A1 was
followed using 1-naphthalen-1-yl-piperazine to give the title
compound (0.62 g; 76%). MS: APCI: M+1: 509.4 (Exact Mass:
508.15).
Example I8
Synthesis of
8-Bromo-7-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-
-1H-[1,6]naphthyridin-2-one
[1235] A reductive amination procedure similar to Example A1 was
followed using 1-(2,3-dichloro-phenyl)-piperazine to give the title
compound (0.43 g; 51%). MS: APCI: M+1: 527.0 (Exact Mass:
526.05).
Example I9
Synthesis of
8-Chloro-7-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydr-
o-1H-[1,6]naphthyridin-2-one
[1236] A first intermediate compound,
8-Chloro-7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one,
was produced as follows: To a solution of
7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one (2.0 g,
8.46 mmol) in DMF (23 mL) was added NCS (1.2 g, 9.3 mmol). The
solution was stirred at room temperature for 2 hours and there was
no reaction. The reaction was heated to 80.degree. C. overnight and
it went from a colorless solution to a dark brown solution. The
reaction was cooled and then water was added. The mixture was
extracted with EtOAc (3.times.). The organic layer was washed with
H.sub.2O and brine, dried over Na.sub.2SO.sub.4 and concentrated to
give a brown oil. Purification by SiO.sub.2 chromatography (0-10%
MeOH/CH.sub.2Cl.sub.2) gave the first intermediate compound as a
yellow solid (1.10 g, 48%). MS: APCI: M+1: 271.0 (Exact Mass:
270.08).
[1237] A second intermediate compound,
4-(8-Chloro-2-oxo-1,2,3,4-tetrahydro-[1,6]naphthyridin-7-yloxy)-butyralde-
hyd, was produced as follows: To a solution of
8-chloro-7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one
(1.05 g, 3.88 mmol) in DCE (25 mL) was added IBX (3.0 g, 12 mmol).
The reaction was heated at 80.degree. C. for 4.5 h. The reaction
was cooled and filtered. The filter cake was washed with
CH.sub.2Cl.sub.2 until all product washed off. The filtrate was
concentrated to give a yellow oil, which solidified on the pump.
Purification by SiO.sub.2 chromatography (0-10%
MeOH/CH.sub.2Cl.sub.2) gave a mixture of spots. The second
intermediate compound was obtained in low yield (0.128 g, 12%). MS:
APCI: M+1: 269.0 (Exact Mass: 268.06).
[1238] A reductive amination procedure similar to Example A1 was
followed using 1-(2,3-dichloro-phenyl)-piperazine to give the title
compound. MS: APCI: M+1: 483.1 (Exact Mass: 482.10).
Example I10
Synthesis of
8-Chloro-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[-
1,6]naphthyridin-2-one
[1239] A reductive amination procedure similar to Example A1 was
followed using 1-naphthalen-1-yl-piperazine to give the title
compound (0.041 g; 38%). MS: APCI: M+1: 465.2 (Exact Mass:
464.20).
Example I11
Synthesis of
7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-2-oxo-1,2,3,4-tetrahydro--
[1,6]naphthyridine-8-carboxylic acid methyl ester
[1240] A first intermediate compound,
8-Bromo-7-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-3,4-dihydro-1H-[1,6]napht-
hyridin-2-one, was produced as follows: To a solution of
8-bromo-7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one
(1.24 g, 3.93 mmol) in dry CH.sub.2Cl.sub.2 was added dihydropyran
(0.49 g, 5.9 mmol), followed by pyridinium p-toluenesulfonate
(0.099 g, 0.39 mmol). The reaction was stirred at room temperature
for 2 days. The reaction mixture was partitioned between ether and
brine. The organic layer was dried over MgSO.sub.4 and
concentrated. The residue solidified in the refrigerator to give
the first intermediate compound as a white solid (1.57 g). MS:
APCI: M+1: 399.1 (Exact Mass: 398.08).
[1241] A second intermediate compound,
7-(4-Hydroxy-butoxy)-2-oxo-1,2,3,4-tetrahydro-[1,6]naphthyridine-8-carbox-
ylic acid methyl ester, was produced as follows: A 300 mL high
pressure reaction vessel was charged with
8-bromo-7-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-3,4-dihydro-1H-[1,6]napht-
hyridin-2-one (0.70 g 1.75 mmol), DPPF (0.149 g, 0.175 mmol, 0.1
eq), Et.sub.3N (0.29 mL, 2.10 mmol, 1.2 eq), and MeOH (100 mL). The
vessel was purged and charged to 400 psi with CO. The reaction was
heated and stirred at 100.degree. C. for 60 hours. The mixture was
filtered and concentrated to give a pink solid. Purification by
SiO.sub.2 chromatography (0-20% MeOH/CH.sub.2Cl.sub.2) gave the
second intermediate compound as a solid (0.381 g, 74%). MS: APCI:
M+1: 295.1 (Exact Mass: 294.12).
[1242] A third intermediate compound,
2-Oxo-7-(4-oxo-butoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine-8-carboxylic
acid methyl ester, was produced as follows: To a suspension of
7-(4-hydroxy-butoxy)-2-oxo-1,2,3,4-tetrahydro-[1,6]naphthyridine-8-carbox-
ylic acid methyl ester (0.340 g, 1.15 mmol) in dichloroethane (6
mL) was added IBX (1.0 g, 3 mmol). This was heated at 80.degree. C.
for 5 hours. The reaction was cooled and stirred, and then
filtered. The filter cake was washed with CH.sub.2Cl.sub.2 until
the product was removed. The filtrate was concentrated to give the
third intermediate compound as a yellow solid (0.327 g, 97%). MS:
APCI: M+1: 293.0 (Exact Mass: 292.11).
[1243] A reductive amination procedure similar to Example A1 was
followed using 1-naphthalen-1-yl-piperazine to give the title
compound (0.219 g; 40%). MS: APCI: M+1: 489.1 (Exact Mass:
488.24).
Example I12
Synthesis of
8-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[-
1,6]naphthyridin-2-one
[1244] A first intermediate compound,
7-(4-Hydroxy-butoxy)-8-methyl-3,4-dihydro-1H-[1,6]naphthyridin-2-one,
was produced as follows: To a solution of
8-bromo-7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one
(0.1 g, 0.3 mmol) in DME (5 mL) was added methylboronic acid (28
mg, 0.48 mmol), followed by Pd(PPh.sub.3).sub.4 (9 mg, 2.5 mol %),
and 2M Na.sub.2CO.sub.3. The reaction was heated at 90.degree. C.
for 2 days. The reaction was cooled and extracted with EtOAc
(3.times.), dried over MgSO.sub.4 and concentrated. Purification by
SiO.sub.2 chromatography (0-20% MeOH/CH.sub.2Cl.sub.2) gave the
first intermediate compound (0.036 g, 23%). MS: APCI: M+1: 251.1
(Exact Mass: 250.13)
[1245] A second intermediate compound,
4-(8-Methyl-2-oxo-1,2,3,4-tetrahydro-[1,6]naphthyridin-7-yloxy)-butyralde-
hyde, was produced as follows: To a suspension of
7-(4-hydroxy-butoxy)-8-methyl-3,4-dihydro-1H-[1,6]naphthyridin-2-one
(60 mg, 18.02 mmol) in dichloroethane (6 mL) was added IBX (15 g,
54 mmol). The mixture was heated at 80.degree. C. for 5 hours. The
reaction was cooled and stirred, and then filtered. The filter cake
was washed with CH.sub.2Cl.sub.2 until the product was removed. The
filtrate was concentrated to give a red oil. Purification by
SiO.sub.2 chromatography (0-7% MeOH/CH.sub.2Cl.sub.2) gave the
second intermediate compound as a yellow solid (50 mg, 84%). MS:
APCI: M+1: 249.1 (Exact Mass: 248.12).
[1246] A reductive amination procedure similar to Example A1 was
followed using 1-naphthalen-1-yl-piperazine to give the title
compound. MS: APCI: M+1: 445.3 (Exact Mass: 444.25).
Example I13
Synthesis of
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,6]naphthyridi-
n-2-one
[1247] A first intermediate compound,
7-(4-Hydroxy-butoxy)-1H-[1,6]naphthyridin-2-one, was produced as
follows: Butane-1,4-diol (8.24 g, 8.12 mL, 91.3 mmol) was added to
solid KOtBu (6 g, 55 mmol). The very viscous mixture was stirred
for 15 min before adding 7-fluoro-1H-[1,6]naphthyridin-2-one (3 g,
18 mmol). NMP (60 mL) was then added and the reaction was heated at
70.degree. C. overnight. The reaction was cooled and poured into
ice water. No precipitate formed, so the mixture was extracted with
EtOAc. The organic layer was washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated. Purification by SiO.sub.2
chromatography (0-50% EtOAc/Hex) gave the first intermediate
compound (2.36 g, 55%). MS: APCI: M+1: 235.0 (Exact Mass:
234.10).
[1248] A second intermediate compound,
4-(2-Oxo-1,2-dihydro-[1,6]naphthyridin-7-yloxy)-butyraldehyde, was
produced as follows: To a suspension of
7-(4-hydroxy-butoxy)-1H-[1,6]naphthyridin-2-one (2.33 g, 9.95 mmol)
in dichloroethane (30 mL) was added IBX (8 g, 30 mmol). The mixture
was heated at 80.degree. C. for 5 hours. The reaction was cooled
and stirred, and then filtered. The filter cake was washed with
CH.sub.2Cl.sub.2 until the product was removed. The filtrate was
concentrated to give the second intermediate compound as a yellow
solid (2.45 g). MS: APCI: M+1: 233.1 (Exact Mass: 232.08).
[1249] A reductive amination procedure similar to Example A1 was
followed using 1-(2,3-dichloro-phenyl)-piperazine to give the title
compound. MS: APCI: M+1: 447.1 (Exact Mass: 446.13).
Example I14
Synthesis of
7-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[-
1,6]naphthyridin-2-one
[1250] A reductive amination procedure similar to Example A1 was
followed using 1-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine to
give the title compound (0.37 g, 66%). MS: APCI: M+1: 433.3 (Exact
Mass: 432.25).
Example I15
Synthesis of
7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-1H-[1,6]naphthyridin-2-one
[1251] A reductive amination procedure similar to Example A1 was
followed using 1-indan-4-yl-piperazine to give the title compound
(0.206 g, 57%). MS: APCI: M+1: 419.2 (Exact Mass: 418.24).
Example I16
Synthesis of
7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-1H-[1,6]naphthyridin-2-on-
e
[1252] A reductive amination procedure similar to Example A1 was
followed using 1-naphthalen-1-yl-piperazine to give the title
compound (0.18 g, 56%). MS: APCI: M+1: 429.2 (Exact Mass:
428.22).
Example I17
Synthesis of
7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,6]naphth-
yridin-2-one
[1253] A reductive amination procedure similar to Example A1 was
followed using 1-(7-fluoro-naphthalen-1-yl)-piperazine to give the
title compound (0.31 g, 65%). MS: APCI: M+1: 447.3 (Exact Mass:
446.21).
Example I18
Synthesis of
7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butylamino}-1H-[1,6]naphthy-
ridin-2-one
[1254] To a mixture of
4-(4-naphthalen-1-yl-piperazin-1-yl)-butylamine (1.00 g, 3.31 mmol)
and 7-fluoro-1H-[1,6]naphthyridin-2-one (517 mg, 3.15 mmol) in
xylenes (6 mL) was added Et.sub.3N (0.7 mL, 4.8 mmol). The mixture
was heated at 140.degree. C. for 2 days. The reaction was
partitioned between CH.sub.2Cl.sub.2 and water. The solubility of
the compound in CH.sub.2Cl.sub.2 is poor so some MeOH was added.
The organic layer was washed with saturated NaHCO.sub.3 and brine,
dried over Na.sub.2SO.sub.4 and concentrated. Purification by
liquid chromatography (6-8% MeOH/CH.sub.2Cl.sub.2 with 1%
NH.sub.4OH) gave the title compound as a pale yellow solid (252 mg,
0.565 mmol, 18%). MS: APCI: M+1: 446.1 (Exact Mass: 445.14).
Example I19
Synthesis of
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-4,4-dimethyl-1,4-di-
hydro-pyrido[4,3-d][1,3]oxazin-2-one
[1255] A first intermediate compound, 4-Amino-6-chloro-nicotinic
acid ethyl ester, was produced as follows: To a solution of
4,6-dichloro-nicotinic acid ethyl ester (15.0 g, 68.2 mmol) in THF
was added liquid NH.sub.3. The bomb was sealed and heated at
65.degree. C. overnight. The reaction was concentrated and
partitioned between EtOAc and water. The aqueous layer was
extracted with EtOAc. The combined organic layer was washed with
saturated NaHCO.sub.3 and brine, dried over Na.sub.2SO.sub.4 and
concentrated to give a solid. Recrystallization from EtOAc/Hexanes
gave an off-white solid (1 g) which was not product. The filtrate
was concentrated, absorbed onto SiO.sub.2 and purified by liquid
chromatography (20-25% EtOAc/Hexanes) to give the first
intermediate compound as a white crystalline solid (10.20 g, 50.8
mmol, 75%). The structure was confirmed by NMR and mass
spectrometry. MS: APCI: M+1: 201.0 (Exact Mass: 200.04).
[1256] A second intermediate compound,
2-(4-Amino-6-chloro-pyridin-3-yl)-propan-2-ol, was produced as
follows: A solution of 4-amino-6-chloro-nicotinic acid ethyl ester
(2.50 g, 12.5 mmol) in Et.sub.2O (20 mL) and THF (10 mL) was added
via cannula to a solution of MeMgBr (3M in Et.sub.2O, 20 mL, 60
mmol) in Et.sub.2O (10 mL) cooled to 0.degree. C. The reaction was
allowed to warm to room temperature and stir overnight. A thick
green precipitate formed on the bottom of the flask. The reaction
was quenched by slow addition of water and 1N HCl. The precipitate
dissolved and the green color disappeared. The mixture was
extracted with Et.sub.2O. The organic layer was washed with brine,
dried over Na.sub.2SO.sub.4 and concentrated to give the second
intermediate compound as a white solid (2.13 g, 11.41 mmol, 91%).
The structure was confirmed by NMR and mass spectrometry. MS: APCI:
M+1: 187.0 (Exact Mass: 186.06).
[1257] A third intermediate compound,
7-Chloro-4,4-dimethyl-1,4-dihydro-pyrido[4,3-d][1,3]oxazin-2-one,
was produced as follows: To a solution of
2-(4-amino-6-chloro-pyridin-3-yl)-propan-2-ol (500 mg, 2.68 mmol)
in toluene (2 mL) and THF (4 mL) was added triethylamine (0.82 mL,
5.90 mmol). The reaction was cooled to 0.degree. C. and a 20%
solution of phosgene in toluene (1.5 mL, 3.21 mmol) was added. The
reaction was allowed to warm to room temperature and stir for 4 h.
MeOH was added to quench excess phosgene. Dilute aqueous
NaHCO.sub.3 was added and the mixture was extracted with EtOAc. The
organic layer was washed with saturated NaHCO.sub.3 and brine,
dried over Na.sub.2SO.sub.4 and concentrated. Purification by
liquid chromatography (30-35% EtOAc/Hexanes) afforded the third
intermediate compound as a white solid (0.43 g, 2.02 mmol, 75%).
The structure was confirmed by NMR and mass spectrometry. MS: APCI:
M+1: 213.0 (Exact Mass: 212.04).
[1258] A fourth intermediate compound,
7-(5-Chloro-pent-1-enyl)-4,4-dimethyl-1,4-dihydro-pyrido[4,3-d][1,3]oxazi-
n-2-one, was produced as follows: To a solution of
7-chloro-4,4-dimethyl-1,4-dihydro-pyrido[4,3-d][1,3]oxazin-2-one
(444 mg, 2.09 mmol) in dimethoxyethane (10 mL) was added
Pd(Ph.sub.3P).sub.4 (72 mg, 0.063 mmol, 3 mol %).
5-Chloro-1-pentenyl boronic acid (700 mg, 4.72 mmol) was added as a
slurry in DME (2 mL) via a pipet, followed by 2M Na.sub.2CO.sub.3
(465 mg in 2.2 mL H.sub.2O, 4.39 mmol). The reaction was refluxed
overnight. The reaction was concentrated and THF was added. The
mixture was sonicated for 2 min and the resulting suspension was
filtered through Celite. The filtrate was concentrated and purified
by liquid chromatography (50-60% EtOAc/Hexanes) to give the fourth
intermediate compound as a white solid (440 mg, 1.57 mmol, 75%).
The structure was confirmed by NMR and mass spectrometry. MS: APCI:
M+1: 281.0 (Exact Mass: 280.10).
[1259] A fifth intermediate compound,
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-4,4-dimethyl-1-
,4-dihydro-pyrido[4,3-d][1,3]oxazin-2-one, was produced as follows:
To a mixture of
7-(5-chloro-pent-1-enyl)-4,4-dimethyl-1,4-dihydro-pyrido[4,3-d][1,3]oxazi-
n-2-one (435 mg, 1.55 mmol) in CH.sub.3CN was added a solution of
1-(2,3-dichloro-phenyl)-piperazine (620 mg, 2.68 mmol) in
CH.sub.3CN (5 mL) via cannula. K.sub.2CO.sub.3 (428 mg, 3.1 mmol)
and KI (52 mg, 0.31 mmol) were added and the reaction was refluxed
for 40 h. The mixture was filtered and washed with CH.sub.3CN. The
filtrate was concentrated and partitioned between EtOAc and water.
The organic layer was washed with saturated NaHCO.sub.3 and brine,
dried over Na.sub.2SO.sub.4 and concentrated. Purification by
liquid chromatography (5% MeOH/CH.sub.2Cl.sub.2 with 0.5%
NH.sub.4OH) afforded the fourth intermediate compound as a
pinkish-white foam (558 mg, 1.17 mmol, 76%). MS: APCI: M+1: 475.1
(Exact Mass: 474.16).
[1260]
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-4,4-dim-
ethyl-1,4-dihydro-pyrido[4,3-d][1,3]oxazin-2-one (452 mg, 0.95
mmol) was hydrogentated using Ra-Ni in EtOH/THF. The reaction was
filtered and concentrated. Purification by liquid chromatography
(5% MeOH/CH.sub.2Cl.sub.2 with 0.5% NH.sub.4OH) gave a white foam
(385 mg, 85% pure). The foam was dissolved in a minimal amount of
EtOAc and, upon standing, a white precipitate formed. The
precipitate was filtered and washed with Et.sub.2O to give the
title compound as a white solid (200 mg, 0.42 mmol, 44%). MS: APCI:
M+1: 477.1 (Exact Mass: 476.17).
EXAMPLES SET 3
Example A1'
Synthesis of
7-{4-[4-(2-Oxo-2,3-dihydro-benzooxazol-7-yl)-piperazin-1-yl]-butoxy}-3,4--
dihydro-1H-[1,8]naphthyridin-2-one
[1261] A first intermediate compound,
2-Benzyloxy-7-chloro-[1,8]naphthyridine, was produced as follows:
To a solution of benzyl alcohol (5.0 mL, 48.0 mmol) in THF (50 mL)
cooled to 0.degree. C. was added KO.sup.tBu (1M in THF, 46 mL, 46.0
mmol). The solution was stirred at 0.degree. C. for 20 min and then
added via cannula to a suspension of
2,7-dichloro-[1,8]naphthyridine (10.0 g, 50.2 mmol, J. Org. Chem.
1981, 46, 833) in DMF (50 mL) and THF (50 mL) cooled to 0.degree.
C. The orange suspension was stirred at 0.degree. C. for 15 min and
at room temperature for 30 min. The reaction was quenched with
saturated NH.sub.4Cl and H.sub.2O. The mixture was extracted with
EtOAc. The organic layer was filtered through celite to remove an
orange clay-like precipitate. The organic layer was washed with
H.sub.2O and brine, and concentrated to give an orange solid. The
solid was absorbed onto SiO.sub.2 and purified by liquid
chromatography (2% EtOAc/48% Hexanes/50% CH.sub.2Cl.sub.2) to give
the first intermediate compound as a white solid (6.37 g, 23.5
mmol, 51%). MS: APCI: M+1: 271.0 (Exact Mass: 270.06).
[1262] A second intermediate compound,
2-Benzyloxy-7-(4-benzyloxy-butoxy)-[1,8]naphthyridine, was produced
as follows: To a solution of 4-benzyloxy-1-butanol (4.9 mL, 28.2
mmol, 1.2 equiv) in THF (20 mL) cooled to 0.degree. C. was added
KO.sup.tBU (1M in THF, 27 mL, 27 mmol, 1.15 equiv). The solution
was stirred at 0.degree. C. for 20 min and then added via cannula
to a suspension of 2-benzyloxy-7-chloro-[1,8]naphthyridine (6.35 g,
23.5 mmol) in THF (70 mL) cooled to 0.degree. C. The reaction
became homogenous. After 30 min at 0.degree. C., saturated
NH.sub.4Cl and H.sub.2O were added to quench the reaction. The
mixture was extracted with EtOAc. The organic layer was washed with
saturated NaHCO.sub.3, H.sub.2O and brine, dried over
Na.sub.2SO.sub.4 and concentrated. The crude was absorbed onto
SiO.sub.2 and purified by liquid chromatography (10-15%
EtOAc/Hexanes) to give the second intermediate compound as a yellow
oil (4.64 g, 11.19 mmol, 48%). MS: APCI: M+1: 415.2 (Exact Mass:
414.19).
[1263] A third intermediate compound,
7-(4-Hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one, was
produced as follows: To a solution of
2-benzyloxy-7-(4-benzyloxy-butoxy)-[1,8]naphthyridine (4.64 g,
11.19 mmol) in MeOH (100 mL) was added 20% Pd/C (1.5 g) and the
mixture was hydrogenated for 22 h. The reaction was filtered,
concentrated and purified by liquid chromatography (5% MeOH/CH2Cl2)
to give the third intermediate compound as a white solid (2.44 g,
10.33 mmol, 92%). MS: APCI: M+1: 237.1 (Exact Mass: 236.12).
[1264] 7-(4-Hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one
was also prepared by hydrogenation of
7-(4-hydroxy-butoxy)-1H-[1,8]naphthyridin-2-one (intermediate in
Example B1).
[1265] A fourth intermediate compound,
4-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
was produced by oxidizing the third intermediate compound using
either a Dess-Martin oxidation reaction or a Swern oxidation
reaction, as follows:
[1266] Dess-Martin oxidation: To a cloudy solution of Dess-Martin
periodinane (2.80 g, 6.60 mmol, 1.5 equiv) in CH.sub.2Cl.sub.2 (13
mL) was added a solution of
7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one (1.04
g, 4.40 mmol) in CH.sub.2Cl.sub.2 (25 mL) via cannula. The reaction
was stirred at room temperature for 5 h and stored in the freezer
overnight. A 1:1 mixture of saturated Na.sub.2S.sub.2O.sub.3 and
saturated NaHCO.sub.3 (50 mL) was added followed by Et.sub.2O. The
mixture was stirred for 10 min and then extracted with
Et.sub.2O/EtOAc (2:1). The organic layer was washed with saturated
NaHCO.sub.3 and brine, dried over Na.sub.2SO.sub.4 and concentrated
to give the fourth intermediate compound as a pale yellow oil (1.06
g, used crude in next reaction). MS: APCI: M+1: 235.1 (Exact Mass:
234.10).
[1267] Swern oxidation: A solution of oxalyl chloride (9.97 mL, 112
mmol) in CH.sub.2Cl.sub.2 was cooled to -70.degree. C. and DMSO
(15.6 mL, 220 mmol) was carefully added. The solution was stirred
at -60.degree. C. for 10 min and then a solution of
7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one (23 g,
97.5 mmol) in DMSO (70 mL) was added dropwise at
-50.about.-60.degree. C. The reaction mixture was stirred at
-60.degree. C. for 20 min and then triethylamine (72 mL, 0.513 mol)
was added dropwise. The reaction was warmed to room temp and
stirred for 30 min. The mixture was poured into ice-water and the
organic phase was separated. The aqueous phase was extracted with
CH.sub.2Cl.sub.2, combined with the organic phase, washed with
brine, dried over Na.sub.2SO.sub.4, and concentrated under vacuum
to give the crude product. Purification by column chromatography
(hexane:ethyl acetate 2:1) followed by recrystallization provided
the fourth intermediate compound (12.7 g, 54.3 mmol, 56%).
[1268] To a solution of
4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
(300 mg, 1.28 mmol) in DCE (6 mL) was added
7-piperazin-1-yl-3H-benzooxazol-2-one (309 mg, 1.41 mmol, prepared
according to EP 0189612 and/or EP 0138280; Drugs of the Future,
2001, 26, 128). The piperazine did not dissolve so DMF (1 mL) was
added. The reaction was stirred for 10 min and NaBH(OAc)3 (380 mg,
1.79 mmol) was added. The reaction was stirred for 2 h at RT.
Saturated NaHCO3 was added and the mixture was extracted with EtOAc
(along with a little MeOH). The organic layer was washed with H2O
and brine, and concentrated to give a light brown solid. The solid
was dissolved in CH2Cl2/MeOH, absorbed onto SiO2 and purified by
liquid chromatography (AnaLogix, RS-40, 0-5% MeOH/CH2Cl2) to give a
white solid. Et2O was added and the solid was collected by
filtration and dried to give the product as a white solid (360 mg,
0.823 mmol, 64%). MS: APCI: M+1: 438.2 (Exact Mass: 437.21).
[1269] A variation of this same method was used to produce other
compounds as described in examples below, wherein other compounds
were substituted for 7-piperazin-1-yl-3H-benzooxazol-2-one in the
final step of the synthesis procedure.
Example A2'
Synthesis of
7-{4-[4-(2,3-Dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-
-1H-[1,8]naphthyridin-2-one
[1270] A first intermediate compound
4-(2,3-Dihydro-benzofuran-7-yl)-piperazine-1-carboxylic acid
tert-butyl ester, was produced as follows: A solution of
bis-(dibenzylideneacetone)palladium(0) (4.92 g, 0.16 mol) and
toluene (2500 ml) was degassed with nitrogen for 15 minutes. (Note:
Degassing was continued during each addition. Time between
additions was 15 minutes.) Then added was tri-o-tolylphosphine
(4.92 g, 0.16 mol) then sodium t-butoxide (53.8 g, 0.56 mol) then
Boc-piperazine (86.8 g, 0.47 mol) then a solution of
7-bromo-2,3-dihydro-benzofuran (79.6 g, 0.40 mol, prepared
according to Tetrahedron Lett. 1998, 39, 2219) in toluene (100 ml).
The reaction mixture was stirred at reflux for 16 h. By TLC, all
starting material had been consumed. The cooled reaction mixture
was filtered over a pad of Celite. The filtrate was concentrated
under reduced pressure and the residue was triturated with ethyl
acetate in heptane (50%). The insoluble material was filtered off
and that filtrate was concentrated under reduced pressure. The
crude residue was purified by flash column chromatography using
ethyl acetate in heptane (50%) to give 46.4 g (38% yield) of the
first intermediate compound as a tan solid.
[1271] A second intermediate compound,
1-(2,3-Dihydro-benzofuran-7-yl)-piperazine dihydrochloride, was
produced as follows: A solution of
4-(2,3-dihydro-benzofuran-7-yl)-piperazine-1-carboxylic acid
tert-butyl ester (42.3 g, 0.139 mol) in ethyl acetate (420 ml) was
cooled in an ice bath to 0.degree. C. HCl in ethyl acetate (3 M,
1.05 mol, 350 ml) was added dropwise. The reaction mixture was
stirred at 0.degree. C. for 1 h, at ambient temperature for 6 h, at
50.degree. C. for 2 h, at ambient temperature for 16 h, and at
50.degree. C. for 2 h. The resulting suspension was cooled and the
resulting solid was collected and washed with ethyl acetate then
dried in a vacuum oven at 70.degree. C. to give 32.76 g (79% yield
as the di-HCl salt) of the second intermediate compound as a tan
solid. Mp: decomposition at 200.degree. C.
[1272] A reductive amination procedure similar to Example A1' was
followed using 1-(2,3-dihydro-benzofuran-7-yl)-piperazine
dihydrochloride to give the title compound. MS: APCI: M+1: 423.2
(Exact Mass: 422.23).
Example A3'
Synthesis of
7-{4-[4-(2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy-
}-3,4-dihydro-1H-[1,8]naphthyridin-2-one
[1273] A first intermediate compound
2,2-Dimethyl-2,3-dihydro-benzofuran-7-ylamine, was produced as
follows: To a mixture of
2,2-dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid (Maybridge,
6.15 g, 32.0 mmol) in dry tert-butanol (100 mL) was added Et.sub.3N
(8.9 mL, 64.0 mmol) and the mixture became homogenous. DPPA (8.3
mL, 38.4 mmol) was added and the reaction was refluxed overnight.
The reaction was concentrated and diluted with EtOAc. The organics
were washed with water (2.times.) and brine, dried over
Na.sub.2SO.sub.4 and concentrated. Purification by SiO.sub.2
chromatography (AnaLogix RS-120, 2-25% EtOAc/Hex) gave
(2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-carbamic acid tert-butyl
ester as a clear oil (6.33 g, 24.0 mmol, 75%).
[1274] To a solution of
(2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-carbamic acid tert-butyl
ester (6.33 g, 24.0 mmol) in CH.sub.2Cl.sub.2 (30 mL) was added TFA
(25 mL). The reaction bubbled for about 5 minutes and was stirred
at room temperature for 1 h. The reaction was concentrated. The
crude material was partitioned between EtOAc and aqueous
NaHCO.sub.3. The organic layer was washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated to give the first intermediate
compound as a light brown liquid (3.83 g, 23.5 mmol, 97%). MS:
APCI: M+1: 164.1 (Exact Mass: 163.10).
[1275] A second intermediate compound,
1-(2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl)-piperazine, was
produced as follows: A mixture of
2,2-dimethyl-2,3-dihydro-benzofuran-7-ylamine (3.83 g, 23.5 mmol),
bis-(2-chloroethyl)amine hydrochloride (4.61 g, 25.8 mmol), NaI
(1.76 g, 11.7 mmol) and hexyl alcohol (3 mL) in chlorobenzene (60
mL) was heated at 140.degree. C. overnight. The mixture was
concentrated and the residue was stirred 2.times. with 50%
Et.sub.2O/Hexanes. The solvent was decanted and a light brown solid
remained in the flask. The residue was dissolved in
MeOH/CH.sub.2Cl.sub.2 and absorbed onto SiO.sub.2. Purification by
SiO.sub.2 chromatography (8% MeOH/CH.sub.2Cl.sub.2 with 1%
NH.sub.4OH) gave the second intermediate compound as a light brown
oil which partially solidified on the pump (5.05 g, 21.7 mmol,
93%). The gooey solid was triturated with ether to give an
off-white solid which was filtered, washed with ether and dried.
MS: APCI: M+1: 233.2 (Exact Mass: 232.16).
[1276] A reductive amination procedure similar to Example A1' was
followed using
1-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-piperazine to give the
title compound. MS: APCI: M+1: 451.2 (Exact Mass: 450.26).
Example A4'
Synthesis of
7-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyr-
idin-2-one
[1277] A first intermediate compound
4-Chroman-8-yl-piperazine-1-carboxylic acid tert-butyl ester, was
produced as follows: The reaction was done in two batches on the
following scale: A suspension of Pd.sub.2(dba).sub.3 (0.48 g, 0.53
mmol) in toluene (500 mL) was purged/degassed with N.sub.2
(directly into the solution). To this was charged rac-BINAP (0.99
g, 1.6 mmol), sodium t-butoxide (28.4 g, 0.30 mol), Boc-piperazine
(46 g, 0.247 mol) and lastly 8-bromo-chroman (45 g, 0.21 mol,
prepared according to Tetrahedron Lett. 1998, 39, 2219) after which
time the purge line was removed and the reaction continued under an
atmosphere of N.sub.2. The reaction was heated to 80-85.degree. C.
over .about.16 h (monitor by TLC, 9:1 heptane:EtOAc, UV, I.sub.2).
After cooling the two batches were filtered through Celite,
combined and the solvent evaporated. Chromatography (3:1
heptane:EtOAc) and trituration of the resulting solid gave 98.6 g
(74%) of the first intermediate compound in two crops.
[1278] A second intermediate compound, 1-Chroman-8-yl-piperazine
dihydrochloride, was produced as follows: A solution of
4-chroman-8-yl-piperazine-1-carboxylic acid tert-butyl ester (75.0
g, 0.236 mol) and ethyl acetate (590 ml) was cooled in an ice bath
to 0.degree. C. HCl in ethyl acetate (3 M; 1.77 mol; 590 ml) was
added dropwise. The reaction mixture was stirred at 0.degree. C.
for 1 h, at ambient temperature for 20 h and at 50.degree. C. for 6
h (monitor by LCMS). The resulting suspension was cooled and the
solid was collected, washed with ethyl acetate then dried in a
vacuum oven at 70.degree. C. to give 67.41 g (94% yield as the
di-HCl salt) of the second intermediate compound as a white
solid.
[1279] A reductive amination procedure similar to Example A1' was
followed using 1-chroman-8-yl-piperazine dihydrochloride to give
the title compound. MS: APCI: M+1: 437.2 (Exact Mass: 436.25).
Example A5'
Synthesis of
7-{4-[4-(2,2-Dimethyl-2H-chromen-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydr-
o-1H-[1,8]naphthyridin-2-one
[1280] A first intermediate compound
1-Bromo-2-(1,1-dimethyl-prop-2-ynyloxy)-benzene, was produced as
follows: To a solution of 2-methyl-3-butyn-2-ol (4.47 g, 53.2 mmol)
in CH.sub.3CN (30 mL) cooled to 0.degree. C. was added DBU (10.4
mL, 1.5 eq), followed by dropwise addition of trifluoroacetic acid
anhydride (7.5 mL, 53.2 mmol) over 20 min. The resultant yellow
solution was stirred at 0.degree. C. for 40 min.
[1281] In a separate flask, a solution of 2-bromophenol (8.00 g,
46.2 mmol) in CH.sub.3CN (30 mL) cooled to 0.degree. C. was treated
with DBU (9.0 mL, 1.3 eq), followed by CuCl.sub.2 (17 mg). To this
green solution was added the above 2-methyl-3-butyn-2-ol
trifluoroacetate solution via cannula over 20 min at 0.degree. C.
The reaction was stirred to 2 h at 0.degree. C. and then stored in
the refrigerator overnight. The reaction was concentrated and then
partitioned between hexanes and water. The aqueous layer was
extracted with hexanes. The combined organic layer was washed with
1N HCl, 1N NaOH (2.times.) and brine, dried over MgSO.sub.4 and
concentrated to give the first intermediate compound as a clear oil
(8.25 g, 34.5 mmol, 75%). Crude NMR looked clean.
[1282] A second intermediate compound,
8-Bromo-2,2-dimethyl-2H-chromene, was produced as follows: To 20 mL
of N,N-diethylaniline at 180.degree. C. was added
1-bromo-2-(1,1-dimethyl-prop-2-ynyloxy)-benzene (8.0 g, 33.5 mmol)
via syringe under nitrogen. The solution was heated at 190.degree.
C. overnight (22 h). The reaction is difficult to follow by TLC.
The reaction was allowed to cool and then poured into a mixture of
hexanes and 1N HCl. The organic layer was washed with 1N HCl
(2.times.) and brine, dried over MgSO.sub.4 and concentrated to
give the second intermediate compound as a yellow liquid (7.40 g,
30.9 mmol, 92%). Crude NMR looks good.
[1283] A third intermediate compound,
4-(2,2-Dimethyl-2H-chromen-8-yl)-piperazine-1-carboxylic acid
tert-butyl ester, was produced as follows: A solution of
8-bromo-2,2-dimethyl-2H-chromene (7.22 g, 30.2 mmol) in dry toluene
(60 mL) was degassed for 10 min by blowing nitrogen into the
solution. This solution was then added via cannula to a flask
containing Pd.sub.2(dba).sub.3 (360 mg, 0.393 mmol, 2.5 mol % in
Pd), di-tert-butylphosphino biphenyl (451 mg, 1.51 mmol, 5 mol %),
NaOtBu (4.06 g, 42.3 mmol) and Boc-piperazine (6.75 g, 36.2 mmol)
under nitrogen. The reaction mixture was heated at 80.degree. C.
overnight (17 h). MS showed a large product peak. The reaction was
allowed to cool to room temperature and Et.sub.2O was added. The
mixture was filtered through Celite washing with Et.sub.2O. The
filtrate was washed with 0.5 M citric acid (3.times., to remove
excess Boc-piperazine) and once with brine, dried over
Na.sub.2SO.sub.4 and concentrated to give a dark red oil (approx.
10 g). Purification by SiO.sub.2 chromatography (10% EtOAc/Hexanes)
gave the third intermediate compound as a yellow oil which
partially solidified under vacuum (4.94 g, 14.3 mmol, 48%). MS:
APCI: M+1: 345.2 (Exact Mass: 344.21).
[1284] A fourth intermediate compound,
1-(2,2-Dimethyl-2H-chromen-8-yl)-piperazine, was produced as
follows: To a solution of
4-(2,2-dimethyl-2H-chromen-8-yl)-piperazine-1-carboxylic acid
tert-butyl ester (2.43 g, 7.05 mmol) in CH2Cl2 (15 mL) was added
TFA (12 mL). The reaction turned brown and was stirred at room
temperature for 2 h. The reaction was concentrated 2.times. from
CH2Cl2. The residue was taken up in 5% MeOH/CH2Cl2 with 1% NH4OH
and the mixture smoked. The solution was concentrated to give a
brown oil. Purification by SiO2 chromatography (8% MeOH/CH2Cl2 with
1% NH4OH) gave the fourth intermediate compound as pale brown oil
which solidified to give a tan solid (1.19 g, 4.87 mmol, 69%).
[1285] A reductive amination procedure similar to Example A1' was
followed using 1-(2,2-dimethyl-2H-chromen-8-yl)-piperazine to give
the title compound. MS: APCI: M+1: 463.2 (Exact Mass: 462.26).
Example A6'
Synthesis of
7-{4-[4-(2,2-Dimethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1-
H-[1,8]naphthyridin-2-one
[1286] A first intermediate compound
4-(2,2-Dimethyl-chroman-8-yl)-piperazine-1-carboxylic acid
tert-butyl ester, was produced as follows:
4-(2,2-Dimethyl-2H-chromen-8-yl)-piperazine-1-carboxylic acid
tert-butyl ester (2.50 g, 7.26 mmol) was hydrogenated in the HPL
using 10% Pd/C (1.0 g) in MeOH (50 mL) for 1.5 h. The reaction was
filtered and concentrated to give a yellow oil. The crude oil was
absorbed onto SiO.sub.2 and purified by chromatography (10%
EtOAC/Hexanes) to give the first intermediate compound as a clear
oil which solidified to give a white solid (1.92 g, 5.54 mmol,
76%). MS: APCI: M+1: 347.1 (Exact Mass: 346.23).
[1287] A second intermediate compound,
1-(2,2-Dimethyl-chroman-8-yl)-piperazine, was produced as follows:
To a solution of
4-(2,2-dimethyl-chroman-8-yl)-piperazine-1-carboxylic acid
tert-butyl ester (1.90 g, 5.48 mmol) in CH.sub.2Cl.sub.2 (10 mL)
cooled to 0.degree. C. was added TFA (10 mL). The ice bath was
removed and the solution was stirred at room temperature for 1 h.
The reaction was concentrated 2.times. from CH.sub.2Cl.sub.2 to
give a light brown oil which solidified on the pump to give the
second intermediate compound as a white solid as the tris-TFA salt
(3.12 g, 5.30 mmol, 97%). MS: APCI: M+1: 247.2 (Exact Mass:
246.17).
[1288] A reductive amination procedure similar to Example A1' was
followed using 1-(2,2-dimethyl-chroman-8-yl)-piperazine to give the
title compound. MS: APCI: M+1: 465.2 (Exact Mass: 464.28).
Example A7'
Synthesis of
7-{4-[4-(Spiro[chromene-2,1'-cyclopentan]-8-yl)-piperazin-1-yl]-butoxy}-3-
,4-dihydro-1H-[1,8]naphthyridin-2-one
[1289] An intermediate compound,
1-Spiro[chromene-2,1'-cyclopentan]-8-ylpiperazine was produced as
follows: The procedures in Example A5' were followed starting from
1-ethynyl-cyclopentanol to give the intermediate compound. MS:
APCI: M+1: 271.0 (Exact Mass: 270.17).
[1290] A reductive amination procedure similar to Example A1' was
followed using 1-spiro[chromene-2,1'-cyclopentan]-8-ylpiperazine to
give the title compound. MS: APCI: M+1: 489.3 (Exact Mass:
488.28).
Example A8'
Synthesis of
7-{4-[4-(3,4-Dihydrospiro[chromene-2,1'-cycloyentan]-8-yl)-piperazin-1-yl-
]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one
[1291] An intermediate compound
1-(3,4-Dihydrospiro[chromene-2,1'-cyclopentan]-8-yl)piperazine, was
produced as follows: The procedure in Example A6' was followed to
give the intermediate compound. MS: APCI: M+1: 273.1 (Exact Mass:
272.19).
[1292] A reductive amination procedure similar to Example A1' was
followed using
1-(3,4-dihydrospiro[chromene-2,1'-cyclopentan]-8-yl)piperazine to
give the title compound. MS: APCI: M+1: 491.3 (Exact Mass:
490.29).
Example A9'
Synthesis of
7-{4-[4-(2-Methyl-2H-chromen-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one
[1293] An intermediate compound
1-(2-Methyl-2H-chromen-8-yl)-piperazine, was produced as follows:
The procedures in Example A5' were followed starting from
but-3-yn-2-ol to give the intermediate compound. MS: APCI: M+1:
231.1 (Exact Mass: 230.14).
[1294] A reductive amination procedure similar to Example A1' was
followed using 1-(2-methyl-2H-chromen-8-yl)-piperazine to give the
title compound. MS: APCI: M+1: 449.3 (Exact Mass: 448.25).
Example A10'
Synthesis of
7-{4-[4-(2-Methyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1-
,8]naphthyridin-2-one
[1295] An intermediate compound,
1-(2-Methyl-chroman-8-yl)-piperazine, was produced as follows: The
procedure in Example A6' was followed to give the intermediate
compound. MS: APCI: M+1: 233.1 (Exact Mass: 232.16).
[1296] A reductive amination procedure similar to Example A1' was
followed using 1-(2-methyl-chroman-8-yl)-piperazine to give the
title compound. MS: APCI: M+1: 451.3 (Exact Mass: 450.26).
Example A11'
Synthesis of
7-{4-[4-(2,3-Dihydro-benzofuran-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-
-1H-[,8]naphthyridin-2-one
[1297] An intermediate compound,
1-(2,3-Dihydro-benzofuran-4-yl)-piperazine, was produced as
follows: A 1 L, 3-necked flask equipped with a mechanical stirrer,
thermometer and a nitrogen inlet was charged with a solution of
2,3-dihydro-benzofuran-4-ylamine (12.5 g, 0.092 mol, J.
Heterocyclic Chem. 1980, 17, 1333) in chlorobenzene (220 mL) and
1-hexanol (10 mL). The mixture was treated with
diisopropylethylamine (8.2 g, 0.063 mol), stirred for 10 min, and
then NaI was added (4.4 g, 0.029 mol), followed by
bis-(2-chloroethyl)amine hydrochloride (16.9 g, 0.094 mol). The
mixture was refluxed for 16 h at an external temperature of
140.degree. C. The reaction mixture was cooled to room temperature,
evaporated under vacuum and the dark thick liquid was dissolved in
chloroform-methanol (9:1) containing a few drops of ammonia,
absorbed onto silica gel and purified by silica gel chromatography,
using 5% methanol in chloroform for elution. The product was
obtained as a thick paste after evaporation of the main fractions,
which upon trituration with CH.sub.2Cl.sub.2 gave the intermediate
compound as white powder (8.0 g, 38%).
[1298] A reductive amination procedure similar to Example A1' was
followed using 1-(2,3-dihydro-benzofuran-4-yl)-piperazine to give
the title compound. MS: APCI: M+1: (Exact Mass: 422.23).
Example A12'
Synthesis of
7-{4-[4-(1,3-Dihydro-isobenzofuran-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihy-
dro-1H-[1,8]naphthyridin-2-one
[1299] A first intermediate compound
1,2-Bis-bromomethyl-3-nitro-benzene, was produced as follows: To a
dry flask under an inert atmosphere containing
1,2-dimethyl-3-nitro-benzene (17.00 g, 112.4 mmol, 1 eq) in 70 mL
of CCl.sub.4 was added NBS (43.06 g, 241.9 mmol, 2.1 eq) and
benzoyl peroxide (0.274 g, 1.131 mmol, 0.01 eq). The orange colored
suspension was refluxed for two hours before an additional 1.074 g
benzoyl peroxide was added. The reaction was refluxed for two hours
and then cooled to room temperature. The reaction mixture was
filtered and washed with CCl.sub.4 to remove a white solid. The
yellow filtrate was concentrated to give the first intermediate
compound as a crude oil (30.954 g, 89%).
[1300] A second intermediate compound,
4-Nitro-1,3-dihydro-isobenzofuran, was produced as follows: To a
flask containing 1,2-bis-bromomethyl-3-nitro-benzene (1.129 g,
3.655 mmol, 1 eq) was added alumina (15 g, 147 mmol, 40 eq) and
toluene (10 mL) and the mixture was heated at 120.degree. C. for
two hours. The reaction mixture was filtered to remove the alumina
and washed with ethyl acetate. The filtrate was concentrated to
give a yellow solid which was purified by chromatography on silica
gel (0-10% EtOAc:hexane) to afford the second intermediate compound
(0.546 g, 90%). MS: APCI: M-1: 164.9 (Exact Mass: 165.04).
[1301] A third intermediate compound,
1,3-Dihydro-isobenzofuran-4-ylamine, was produced as follows: A
solution of 4-nitro-1,3-dihydro-isobenzoturan (5.976 g, 36.19 mmol)
in 100 mL of THF was hydrogenated using Ra/Ni. The reaction was
filtered and then concentrated to obtain the third intermediate
compound (4.996 g, 100%). MS: APCI: M+1: 136.2 (Exact Mass:
135.07).
[1302] A fourth intermediate compound,
1-(1,3-Dihydro-isobenzofuran-4-yl)-piperazine, was produced as
follows: To a reaction flask containing a solution of
1,3-dihydro-isobenzofuran-4-ylamine (0.488 g, 3.610 mmol, 1 eq) in
chlorobenzene (6 mL), was added bis-(2-chloro-ethyl)-amine
hydrochloride (0.907 g, 4.260 mmol, 1.18 eq) and diisopropylethyl
amine (0.297 g, 2.30 mmol, 0.64 eq). The reaction was refluxed for
14 hours. The reaction was cooled and concentrated. Purification by
chromatography on silica gel (0-40% MeOH/NH4OH:CH2Cl2) afforded the
fourth intermediate compound (0.400 g, 54%). MS: APCI: M+1: 205.1
(Exact Mass: 204.13).
[1303] To a suspension of
4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
(0.278 g, 1.186 mmol, 1.1 eq) and
1-(1,3-dihydro-isobenzofuran-4-yl)-piperazine (0.217 g, 1.064 mmol,
1 eq) in dichloroethane (5 mL) was added NaBH(OAc).sub.3 (0.469 g,
4.425 mmol, 3.73 eq). The slurry was allowed to stir overnight at
room temperature (18 h). The mixture was diluted with EtOAc and
quenched with saturated NaHCO.sub.3. The organic phase was then
washed with brine, dried over Na.sub.2SO.sub.4, filtered and
evaporated in vacuo. Purification by silica gel chromatography (2%
MeOH/CH.sub.2Cl.sub.2) followed by formation of the HCl salt using
1N HCl in ether provided the title compound (0.143 g, 26%). CHN
Found: C, 64.37; H, 6.54; N, 12.13. This calculates out for
C24H30N4O3.times.1.00HCl.
Example A13'
Synthesis of
7-[4-(4-Chroman-5-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyr-
idin-2-one
[1304] A first intermediate compound 3-Nitro-2-vinyl-phenol, was
produced as follows: To a degassed solution of
2-bromo-3-nitro-phenol (3.00 g, 13.8 mmol) and tributylvinyltin
(4.4 mL, 15.1 mmol) in toluene (70 mL) was added
tetrakis(triphenylphosphine)palladium(0) (1.59 g, 1.38 mmol, 10 mol
%). The reaction was refluxed overnight. The mixture was filtered
through celite washing with EtOAc. The solvent was removed and the
residue was purified by SiO.sub.2 chromatography (AnaLogix RS-120,
10-30% EtOAc/Hexanes) to give the first intermediate compound as a
yellowish orange solid (1.00 g, 6.06 mmol, 44%). MS: APCI: M-1:
163.9 (Exact Mass: 165.04).
[1305] A second intermediate compound,
1-Allyloxy-3-nitro-2-vinyl-benzene, was produced as follows: To a
solution of 3-nitro-2-vinyl-phenol (1.0 g, 6.1 mmol) in acetone (20
mL). was added allyl bromide (1.05 mL, 12.1 mmol, 2 eq) followed by
K.sub.2CO.sub.3 (1.67 g, 12.1 mmol, 2 eq). The mixture was refluxed
for 30 min and stirred at room temperature overnight. The reaction
mixture was filtered washing with acetone and then concentrated.
Purification by SiO.sub.2 chromatography (AnaLogix RS-40, 2-5%
EtOAc/Hexanes) gave the second intermediate compound as an orange
oil (1.00 g, 4.87 mmol, 80%).
[1306] A third intermediate compound, 5-Nitro-2H-chromene, was
produced as follows: To a solution of
1-allyloxy-3-nitro-2-vinyl-benzene (1.0 g, 4.9 mmol) in
CH.sub.2Cl.sub.2 (25 mL) was added the 2nd generation Grubbs
catalyst (207 mg, 5 mol %). The reaction was stirred at room
temperature for 3 h. The mixture was concentrated and purified by
SiO.sub.2 chromatography (AnaLogix RS-40, 2-5% EtOAc/Hexanes) to
give the third intermediate compound as a yellow solid (852 mg,
4.81 mmol, 98%). MS: APCI: M-1: 175.9 (Exact Mass: 177.04).
[1307] A fourth intermediate compound, Chroman-5-ylamine, was
produced as follows: 5-Nitro-2H-chromene (800 mg, 4.52 mmol) was
hydrogenated using 10% Pd/C in MeOH (50 mL) for 4.6 h. The yellow
solution turned clear. The reaction mixture was concentrated to
give the fourth intermediate compound as a light brown oil which
looked pure by NMR and TLC (679 mg, quant). MS: APCI: M+1: 150.3
(Exact Mass: 149.08).
[1308] A fifth intermediate compound, 1-Chroman-5-yl-piperazine,
was produced as follows: To a solution of chroman-5-ylamine (679
mg, 4.55 mmol) in chlorobenzene (12 mL) and hexanol (0.6 mL) was
added bis(2-chloroethyl)amine hydrochloride (894 mg, 5.01 mmol),
NaI (341 mg, 2.28 mmol) and diisopropylethylamine (0.44 mL, 2.50
mmol). The reaction was refluxed at 140.degree. C. for 20 h. A tan
ppt formed. The reaction was allowed to cool to room temperature
and hexanes was added. The mixture was filtered and washed with
hexanes. The solid was dissolved in MeOH/CH.sub.2Cl.sub.2 and
absorbed onto SiO.sub.2. Purification by SiO.sub.2 chromatography
(8-10% MeOH/CH.sub.2Cl.sub.2 with 1% NH.sub.4OH) gave the fifth
intermediate compound as a light tan solid (548 mg, 2.51 mmol,
55%). MS: APCI: M+1: 219.1 (Exact Mass: 218.14).
[1309] A reductive amination procedure similar to Example A1' was
followed using 1-chroman-5-yl-piperazine to give the title
compound. MS: APCI: M+1: 437.3 (Exact Mass: 436.25).
Example A14'
Synthesis of
7-[4-(4-Isochroman-5-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]napht-
hyridin-2-one
[1310] A first intermediate compound
1-Bromo-2-[2-(2-methoxy-ethoxymethoxy)-ethyl]-benzene, was produced
as follows: To a solution of 2-(2-bromo-phenyl)-ethanol (7.8 g,
38.8 mmol) and diisopropylethylamine (8.02 g, 62 mmol) in 50 mL of
dry CH.sub.2Cl.sub.2 was added MEM chloride (6.26 g, 50.4 mmol)
dropwise at 0.degree. C. The resulting mixture was stirred at the
same temperature for 2 h and treated with 1 N HCl and
CH.sub.2Cl.sub.2. The organic layer was washed with H.sub.2O, dried
over Na.sub.2SO.sub.4, concentrated under vacuum. The residue was
purified by chromatography (25% EtOAc/hexanes) to give the first
intermediate compound (9.0 g, 80%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.53 (dd, J=1.0 Hz, J=7.0 Hz, 1H), 7.29-7.23
(m, 2H), 7.09-7.05 (m, 1H), 4.71 (s, 2H), 3.80 (t, J=7.0 Hz, 2H),
3.62-3.60 (m, 2H), 3.51-3.49 (m, 2H), 3.37 (s, 3H), 3.04 (t, J=7.0
Hz, 4H).
[1311] A second intermediate compound, 5-Bromo-isochroman, was
produced as follows: To a solution of
1-bromo-2-[2-(2-methoxy-ethoxymethoxy)-ethyl]-benzene (4.5 g, 15.56
mmol) in 100 mL of CH.sub.2Cl.sub.2 was added a solution of
TiCl.sub.4 in CH.sub.2Cl.sub.2 dropwise at 0.degree. C. The
resulting mixture was stirred at the same temperature for 1 h and
treated with H.sub.2O and CH.sub.2Cl.sub.2. The organic layer was
washed with H.sub.2O, dried over Na.sub.2SO.sub.4, and concentrated
under vacuum. The residue was purified by chromatography (25%
EtOAc/hexanes) to give the second intermediate compound (2.7 g,
82%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.43 (d, J=7.0 Hz,
1H), 7.05 (t, J=7.0 Hz, 1H), 6.95 (d, J=7.0 Hz, 1H), 4.73 (s, 2H),
4.00 (t, J=5.0 Hz, 2H), 3.82 (t, J=5.0 Hz, 2H).
[1312] A third intermediate compound, 1-Isochroman-5-yl-piperazine,
was produced as follows: To a mixture of 5-bromo-isochroman (1 g,
4.69 mmol), 1-boc-piperazine (1.05 g, 5.6 mmol),
2-dicyclohexylphosphino biphenyl (0.066 g, 0.19 mmol), and
Pd(OAc).sub.2 (0.42 g, 0.19 mmol) in 10 mL of dry degassed
C.sub.6H.sub.5CH.sub.3 was added NaOtBu (0.63 g, 6.6 mmol) at room
temperature. The resulting mixture was stirred at 80-90.degree. C.
for 1 h, cooled and passed through a pad of celite and the filtrate
was concentrated under vacuum. The residue was purified by
chromatography (25-50% EtOAc/hexanes) to give
4-isochroman-5-yl-piperazine-1-carboxylic acid tert-butyl ester
(0.89 g, 60%). MS (ES) m/z 319.19 [M+1]. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.16 (t, J=7.0 Hz, 1H), 6.88 (d, J=7.0 Hz, 1H),
6.75 (d, J=7.0 Hz, 1H), 4.79 (s, 2H), 3.94 (t, J=5.0 Hz, 2H), 3.55
(br s, 4H), 2.86-2.80 (m, 4H), 1.49 (s, 9H).
[1313] To a solution of 4-isochroman-5-yl-piperazine-1-carboxylic
acid tert-butyl ester (0.5 g, 1.57 mmol) in dry CH.sub.2Cl.sub.2
was added 3 mL of TFA at 0.degree. C. dropwise. The resulting
mixture was stirred at room temperature for 2 h. The evaporation of
the solvent gave the third intermediate compound (0.52 g,
quantitative). MS (ES) m/z: 219.12 [M+1]. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.12 (br s, 1H), 7.19 (t, J=7.0 Hz, 1H), 6.95
(d, J=7.0 Hz, 1H), 6.82 (d, J=7.0 Hz, 1H), 4.82 (s, 2H), 3.98 (t,
J=5.0 Hz, 2H), 3.54 (br s, 4H), 3.21-3.19 (m, 4H), 2.80 (t, J=5.0
Hz, 2H).
[1314] A reductive amination procedure similar to Example A1' was
followed using 1-isochroman-5-yl-piperazine to give the title
compound (0.40 g, 58%). MS (ES) m/z: 437.26 [M+1] (Exact mass:
436.25). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.69 (br s, 1H),
7.36 (d, J=8.0 Hz, 1H), 7.63 (d, J=7.0 Hz, 1H), 7.18 (t, J=7.0 Hz,
1H), 6.92 (d, J=7.0 Hz, 1H), 6.72 (d, J=7.0 Hz, 1H), 6.36 (d, J=7.3
Hz, 1H), 4.80 (s, 2H), 4.22 (t, J=6.0 Hz, 2H), 3.93 (t, J=5.0 Hz,
2H), 2.95 (t, J=4.0 Hz, 4H), 2.88-2.80 (m, 4H), 2.67-2.63 (m, 4H),
2.47 (t, J=7.0 Hz, 4H), 1.82-1.78 (m, 2H), 1.72-1.69 (m, 2H).
Example A15'
Synthesis of
7-[4-(4-Isochroman-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]napht-
hyridin-2-one
[1315] A first intermediate compound 8-Bromo-isochroman and
6-Bromo-isochroman, was produced as follows: To a solution of
1-bromo-3-[2-(2-methoxy-ethoxymethoxy)-ethyl]-benzene (2.8 g, 9.7
mmol) in 50 mL of CH.sub.2Cl.sub.2 was added a solution of
TiCl.sub.4 (14.5 mmol) in CH.sub.2Cl.sub.2 dropwise at 0.degree. C.
The resulting mixture was stirred at the same temperature for 1 h
and treated with H.sub.2O and CH.sub.2Cl.sub.2. The organic layer
was washed with H.sub.2O, dried over Na.sub.2SO.sub.4 and
concentrated under vacuum. The residue was purified by
chromatography (25% EtOAc/hexanes) to give 1.8 g of a mixture of
the first intermediate compounds, 8-bromo-isochroman and
6-bromo-isochroman (.about.1:4 by HPLC) in 90% yield.
[1316] A second intermediate compound,
4-Isochroman-8-yl-piperazine-1-carboxylic acid tert-butyl ester,
was produced as follows: To a mixture of 8-bromo-isochroman and
6-bromo-isochroman (1.8 g, 8.4 mmol), 1-boc-piperazine (1.9 g,
10.15 mmol), 2-dicyclohexylphosphino biphenyl (0.12 g, 0.34 mmol),
and Pd(OAc).sub.2 (0.076 g, 0.34 mmol) in 15 mL of dry degassed
toluene was added NaOtBu (1.13 g, 11.8 mmol) at room temperature.
The resulting mixture was stirred at 80-90.degree. C. for 1 h,
cooled and passed through a pad of celite and the filtrate was
concentrated under vacuum. The residue was subjected to
chromatography (10% EtOAc/hexanes) to give 0.2 g of the second
intermediate compound, 4-isochroman-8-yl-piperazine-1-carboxylic
acid tert-butyl ester, and 0.8 g of the regioisomer,
4-isochroman-6-yl-piperazine-1-carboxylic acid tert-butyl ester, in
37% yield. Second intermediate compound: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.17 (t, J=7.0 Hz, 1H), 6.90 (d, J=7.0 Hz, 2H),
4.80 (s, 2H), 3.96 (t, J=5.0 Hz, 2H), 3.53 (br s, 4H), 2.87 (t,
J=5.0 Hz, 4H), 2.80 (t, J=4.0 Hz, 4H), 1.48 (s, 9H). MS (ES) m/z:
319.19 [M+1] (Exact mass: 318.19).
[1317] A third intermediate compound, 1-Isochroman-8-yl-piperazine,
was produced as follows: To a solution of
4-isochroman-8-yl-piperazine-1-carboxylic acid tert-butyl ester
(0.9 g, 2.8 mmol) in 30 mL of dry CH2Cl2 was added 5 mL of TFA at
0.degree. C. dropwise. The resulting mixture was stirred at room
temperature for 2 h. The evaporation of the solvent gave 0.92 g of
the third intermediate compound in 98% yield. 1H NMR (400 MHz,
CDCl3) .delta. 8.18 (br s, 1H), 7.25 (t, J=8.0 Hz, 1H), 7.02 (d,
J=8.0 Hz, 2H), 4.89 (s, 2H), 4.07 (t, J=6.0 Hz, 2H), 3.46 (br s,
4H), 3.18-3.15 (m, 4H), 2.94 (t, J=6.0 Hz, 2H). MS (ES) m/z: 219.13
[M+1] (Exact mass: 218.14).
[1318] A reductive amination procedure similar to Example A1' was
followed using 1-isochroman-8-yl-piperazine to give the title
compound (0.6 g, 65%). MS (ES) m/z: 437.26 [M+1] (Exact mass:
436.25). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.69 (brs, 1H),
7.35 (d, J=7.0 Hz, 1H), 7.16 (t, J=7.0 Hz, 1H), 6.95 (d, J=7.0 Hz,
1H), 6.88 (d, J=7.0 Hz, 1H), 6.35 (d, J=8.0 Hz, 1H), 4.78 (s, 2H),
4.22 (t, J=6.0 Hz, 2H), 3.94 (t, J=5.0 Hz, 2H), 2.93 (t, J=4.0 Hz,
4H), 2.88-2.84 (m, 4 H), 2.70-2.62 (m, 6H), 2.55 (t, J=7.0 Hz, 2H),
1.82-1.77 (m, 2H), 1.75-1.72 (m, 2H).
Example A16'
Synthesis of
7-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl-piperazin-1-yl]-butoxy}-3,4-di-
hydro-1H-[1,8]naphthyridin-2-one
[1319] A reductive amination procedure similar to Example A1' was
followed using 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine (WO
97/03067) to give the title compound. MS: APCI: M+1: 439.3 (Exact
Mass: 438.23).
Example A17'
Synthesis of
7-{4-[4-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-piperazin-1-yl]-butox-
y}-3,4-dihydro-1H-[1,8]naphthyridin-2-one
[1320] In a manner similar to that of other examples above,
1-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-piperazine
hydrochloride (J. Med. Chem. 1988, 31, 1934-1940) was coupled by
reductive amination to
4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
followed by typical workup and purification to give the
intermediate compound. MS: APCI: M+1: 453.6 (Exact Mass:
452.55).
Example A18'
Synthesis of
7-{4-[4-(2,2,3,3-Tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-
-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one
[1321] An intermediate compound,
1-(2,2,3,3-Tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine,
was produced as follows: To the mixture of
2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-ylamine (8.9 g,
40 mmol) and bis-(2-chloro-ethyl)-carbamic acid tert-butyl ester
(14.5 g, 60 mmol) in DMF (200 mL) was added NaH (3.2 g, 60% oil
dispersion, 80 mmol) at 0.degree. C. and the resulting mixture was
stirred at the same temperature for 1.0 h. No reaction was observed
by TLC. The mixture was further stirred at room temperature for 4.0
h until LCMS indicated the starting material disappeared. The
reaction was quenched with aq. NH.sub.4Cl, extracted with EtOAc,
washed with brine, dried and concentrated. The residue was purified
by flash chromatography (Et.sub.3N:EtOAc:heptane/1:10:100) to
afford
4-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine-1-ca-
rboxylic acid tert-butyl ester (5.2 g, 33%) as colorless
crystals.
[1322] A solution of
4-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine-1-ca-
rboxylic acid tert-butyl ester (12.5 g, 0.0319 mol) in 1,4-dioxane
(150 mL) was treated with 4 N HCl in 1,4-dioxane (100 mL) and the
mixture was stirred at room temperature for 16 h, and then
35.degree. C. for 2.0 h until LCMS indicated completion. The
resulting solid was collected via filtration, rinsed with
1,4-dioxane, ether, and oven-dried to afford the title compound as
the hydrochloride salt (8.9 g, 85%) as an off-white powder.
[1323] A reductive amination procedure similar to Example A1' was
followed using
1-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine
hydrochloride to give the title compound. MS: APCI: M+1: 511.1
(Exact Mass: 510.19).
Example A19'
Synthesis of
7-{4-[4-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-piperazin-1-yl]-butoxy}-3,4--
dihydro-1H-[1,8]naphthyridin-2-one
[1324] An intermediate compound,
1-(2,2-Difluoro-benzo[1,3]dioxol4-yl)-piperazine, was produced as
follows: To the mixture of 2,2-difluoro-benzo[1,3]dioxol-4-ylamine
(27 g, 0.156 mol) and bis-(2-chloro-ethyl)-carbamic acid tert-butyl
ester (75.5 g, 0.31 mol) in DMF (500 mL) was added NaH (15.6 g, 60%
oil dispersion, 0.39 mol) at 0.degree. C. and the resulting mixture
was stirred at room temperature for 24 h until LCMS indicated the
starting material disappeared. The reaction was quenched with aq.
NH4Cl, extracted with EtOAc, washed with brine, dried and
concentrated. The residue was purified by flash chromatography
(Et3N:EtOAc:heptane/1:10:100) to afford
4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-piperazine-1-carboxylic acid
tert-butyl ester (12.0 g, 22%) as colorless crystals.
[1325] A solution of
4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-piperazine-1-carboxylic acid
tert-butyl ester (9.9 g, 0.029 mol) in 1,4-dioxane (100 ml) was
treated with 4 N HCl in 1,4-dioxane (75 mL) and the mixture was
stirred at room temperature for 20 h, and then 35-40.degree. C. for
2.0 h until LCMS indicated completion. The resulting solid was
collected via filtration, rinsed with ether, and oven-dried to
afford the intermediate compound as the hydrochloride salt (7.8 g,
97%) as white powder.
[1326] A reductive amination procedure similar to Example A1' was
followed using 1-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-piperazine
hydrochloride to give the title compound. MS: APCI: M+1: 461.2
(Exact Mass: 460.19).
Example A20'
Synthesis of
7-{4-[4-(4-Oxo-chroman-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]-
naphthyridin-2-one
[1327] A first intermediate compound
8-Bromo-2,3-dihydrospiro[chromene-4,2'-[1,3]dioxolane], was
produced as follows: A mixture of 8-bromo-chroman-4-one (0.87 g,
3.8 mmol), ethylene glycol (0.23 g, 3.8 mmol) and TsOH in benzene
(50 mL) was refluxed using a Dean-Stark apparatus for 16 h. It was
cooled to RT, diluted with EtOAc (50 mL), washed with aqueous
NaHCO.sub.3, dried and concentrated to give the first intermediate
compound (1.05 g). .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.50
(d, 1H), 7.40 (d, 1H), 6.90 (t, 1H), 4.30 (m, 2H), 4.10 (m, 2H),
4.10 (m, 2H), 2.20 (m, 2H).
[1328] A second intermediate compound,
4-(2,3-Dihydrospiro[chromene-4,2'-[1,3]dioxolan-8-yl])-piperazine-1-carbo-
xylic acid tert-butyl ester, was produced as follows: Nitrogen gas
was bubbled through a solution of
8-bromo-2,3-dihydrospiro[chromene-4,2'-[1,3]dioxolane] (1.05 g,
3.89 mmol), 1-Boc-piperazine (0.86 g, 4.67 mmol), Pd(OAc).sub.2 (88
mg) and 2-dicyclohexylphosphino biphenyl (0.14 g) in toluene (40
mL) for 10 min. NaOtBu (0.52 g, 5.45 mmol) was added and the
resulting mixture was heated at 110.degree. C. for 3 h. The mixture
was cooled to RT, diluted with EtOAC (40 mL) and filtered through a
pad of celite. The filtrate was concentrated and the residue was
purified by chromatography on silica gel to give the second
intermediate compound (0.55 g, 38%). .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 7.15 (m, 1H), 6.90 (m, 2H), 4.47 (m, 2H), 4.22
(m, 2H), 4.10 (m, 2H), 3.60 (m, 4H), 3.00 (m, 4H), 2.20 (m, 2H),
1.44 (s, 9H).
[1329] A third intermediate compound,
8-Piperazin-1-yl-chroman-4-one, was produced as follows: To a
solution of
4-(2,3-dihydrospiro[chromene4,2'-[1,3]dioxolan-8-yl])-piperazine-1-carbox-
ylic acid tert-butyl ester (0.55 g, 1.46 mmol) in MeOH (10 mL) was
added conc. HCl (4 mL). The resulting mixture was stirred at room
temperature for 16 h and concentrated under vacuum. The solid
obtained was washed with a small amount of MeOH and ether and dried
to give the third intermediate compound (0.31 g, 69%).
[1330] A reductive amination procedure similar to Example A1' was
followed using 8-piperazin-1-yl-chroman-4-one to give the title
compound (0.32 g, 83%). .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
7.60 (d, 1H), 7.56 (d, 1H), 7.10 (d, 1H), 6.96 (t, 1H), 6.39 (d,
1H) 4.60 (t, 2H), 4.22 (t, 2H), 3.10 (br s, 4H), 2.85 (m, 4H), 2.70
(m, 6H), 2.46 (m, 2H), 1.85-1.60 (m, 4H).
Example A21'
Synthesis of
7-{4-[4-(3,3-Dimethyl-4-oxo-chroman-8-yl)-piperazin-1-yl]-butoxy}-3,4-dih-
ydro-1H-[1,8]naphthyridin-2-one
[1331] A first intermediate compound
3-(2-Bromo-phenoxy)-2,2-dimethyl-propionic acid, was produced as
follows: To a mixture of
3-methanesulfonyloxy-2,2-dimethyl-propionic acid methyl ester
(20.00 g, 95.23 mmol) and 2-bromophenol (16.48 g, 95.23 mmol) in
acetonitrile (200 mL) was added Cs.sub.2CO.sub.3 (46.50 g, 142.80
mmol) and the mixture was heated at 100.degree. C. in a sealed
flask overnight. The resulting suspension was filtered. The solvent
was evaporated and the crude material was partitioned between
dichloromethane (100 mL) and water (100 mL). The organic layer was
separated and the aqueous layer was extracted with dichloromethane
(50 mL), dried over Na.sub.2SO.sub.4 and evaporation of the solvent
gave 3-(2-bromo-phenoxy)-2,2-dimethyl-propionic acid methyl ester
(19.00 g, 70%) as a colorless oil. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 7.55 (d, 1H), 7.26-7.22 (m, 1H), 6.87-6.80 (m,
2H), 4.02 (s, 2H), 3.72 (s, 3H), 1.40 (s, 6H).
[1332] To a solution of the methyl ester (19.00 g, 66.20 mmol) in
THF:H.sub.2O (4:1, 50 mL) was added LiOH-H.sub.2O (8.34 g, 198.60
mmol) and the mixture was stirred at room temperature overnight.
The organic solvent was evaporated, and the aqueous layer was
diluted with water (10 mL). The pH of the reaction mixture was
adjusted to 3 using 1N HCl. The compound was extracted with
dichloromethane (2.times.100 mL). The organic layer was dried over
Na.sub.2SO.sub.4 and evaporation of the solvent gave the first
intermediate compound (18.00 g, quantitative) as a colorless solid.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.52-7.50 (m, 1H),
7.26-7.22 (m, 1H), 6.89-6.80 (m, 2H), 4.03 (s, 2H), 1.41 (s,
6H).
[1333] A second intermediate compound,
8-Bromo-3,3-dimethyl-chroman-4-one, was produced as follows: To a
solution of 3-(2-bromo-phenoxy)-2,2-dimethyl-propionic acid (6.00
g, 21.98 mmol) in chlorobenzene (150 mL) was added Yb(OTf).sub.3
(1.36 g, 2.20 mmol) and the mixture was heated at 190.degree. C. in
a sealed flask overnight. The resulting suspension was filtered.
The solvent was evaporated and the crude material was partitioned
between diethyl ether (100 mL) and water (50 mL). The organic layer
was separated and the aqueous layer was extracted with diethyl
ether (50 mL), dried over Na.sub.2SO.sub.4 and evaporation of the
solvent gave the second intermediate compound (4.00 g, 71%) as a
pale yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.89
(d, 1H), 6.75 (d, 1H), 6.90-6.81 (m, 1H), 4.25 (s, 2H), 1.20 (s,
6H).
[1334] A third intermediate compound,
4-(3,3-Dimethyl-4-oxo-chroman-8-yl)-piperazine-1-carboxylic acid
tert-butyl ester, was produced as follows: To a mixture of
8-bromo-3,3-dimethyl-chroman-4-one (1.60 g, 6.27 mmol) and
Boc-piperazine (1.40 g, 7.53 mmol) in degassed toluene (30 mL) was
added palladium acetate (0.14 g, 0.63 mmol),
2-(di-tert-butylphosphino)biphenyl (0.37 g, 1.25 mmol) and sodium
t-butoxide (0.84 g, 8.78 mmol). The reaction mixture was heated
overnight at 100.degree. C. The solvent was removed, and the
compound was purified by flash column chromatography using 10%
ethyl acetate in hexanes to give the third intermediate compound
(1.30 g, 58%). .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.60 (d,
1H), 7.10 (br d, 1H), 6.95-6.90 (m, 1H), 4.20 (s, 2H), 3.63-3.60
(m, 4H), 3.04-3.00 (m, 4H), 1.50 (s, 9H), 1.21 (s, 6H).
[1335] A fourth intermediate compound,
3,3-Dimethyl-8-piperazin-1-yl-chroman-4-one, was produced as
follows: A solution of
4-(3,3-dimethyl-4-oxo-chroman-8-yl)-piperazine-1-carboxylic acid
tert-butyl ester (1.30 g, 3.61 mmol) in dichloromethane (10 mL) was
treated with trifluoroacetic acid (10 mL). The resulting mixture
was stirred at room temperature for 2 h. The brown solution was
concentrated under vacuum and diluted with water (20 mL) and pH was
adjusted to 7 using saturated NaHCO.sub.3 solution. The compound
was extracted with dichloromethane (2.times.40 mL). The organic
layer was dried over Na.sub.2SO.sub.4 and evaporation of the
solvent gave the fourth intermediate compound (0.77 g, 83%) as a
colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.62 (d,
1H), 7.11 (br d, 1H), 7.00-6.95 (m, 1H), 4.20 (s, 2H), 3.25-3.19
(m, 8H), 1.22 (s, 6H).
[1336] A reductive amination procedure similar to Example A1' was
followed using 3,3-dimethyl-8-piperazin-1-yl-chroman-4-one to give
the title compound (0.41 g, 51%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.73 (br s, 1H), 7.60-7.58 (d, 1H), 7.37-7.35 (m, 1H),
7.11-7.09 (m, 1H), 6.99-6.95 (m, 1H), 6.35 (d, 1H), 4.24-4.21 (m,
4H), 3.11 (br, 4H), 2.87 (t, 2H), 2.69-2.63 (m, 6H), 2.49 (t, 2H),
1.82-1.67 (m, 8H).
Example A22'
Synthesis of
7-{4-[4-(3,3-Dimethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1-
H-[1,8]naphthyridin-2-one
[1337] A first intermediate compound 8-Bromo-3,3-dimethyl-chroman,
was produced as follows: To a solution of
8-bromo-3,3-dimethyl-chroman-4-one (1.90 g, 7.45 mmol) in
BF.sub.3-Et.sub.2O (6 mL) was added Et.sub.3SiH (5.19 g, 44.71
mmol) and the mixture was heated at 90.degree. C. in a sealed tube
overnight. The solvent was evaporated and the crude material was
partitioned between CH.sub.2Cl.sub.2 (20 mL) and water (20 mL). The
organic layer was separated and the aqueous layer was extracted
with CH.sub.2Cl.sub.2 (20 mL), dried over Na.sub.2SO.sub.4 and
evaporation of the solvent gave the first intermediate compound
(1.10 g, 61%) as an oil. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
7.34 (d, 1H), 6.96 (d, 1H), 6.74-6.70 (m, 1H), 3.86 (s, 2H), 2.57
(s, 2H), 1.03 (s, 6H).
[1338] A second intermediate compound,
4-(3,3-Dimethyl-chroman-8-yl)-piperazine-1-carboxylic acid
tert-butyl ester, was produced as follows: To a mixture of
8-bromo-3,3-dimethyl-chroman (0.90 g, 3.73 mmol) and Boc-piperazine
(0.83 g, 4.48 mmol) in degassed toluene (20 mL) was added palladium
acetate (0.08 g, 0.37 mmol), 2-(di-tert-butylphosphino)biphenyl
(0.22 g, 0.75 mmol) and sodium t-butoxide (0.50 g, 5.23 mmol). The
reaction mixture was heated overnight at 100.degree. C. The solvent
was removed, and the compound was purified by flash column
chromatography using 10% ethyl acetate in hexanes to give the
second intermediate compound (0.65 g, 50%). .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 6.83-6.71 (m, 3H), 3.83 (s, 2H), 3.62-2.96 (br
m, 4H), 2.99-2.96 (br m, 4H), 2.55 (s, 2H), 1.48 (s, 9H), 1.03 (s,
6H).
[1339] A third intermediate compound,
1-(3,3-Dimethyl-chroman-8-yl)-piperazine, was produced as follows:
A solution of 4-(3,3-dimethyl-chroman-8-yl)-piperazine-1-carboxylic
acid tert-butyl ester (0.65 g, 1.88 mmol) in dichloromethane (5 mL)
was treated with trifluoroacetic acid (5 mL). The resulting mixture
was stirred at room temperature for 1 h. The brown solution was
concentrated under vacuum and diluted with water (20 mL) and the pH
was adjusted to 7 using saturated NaHCO.sub.3 solution. The
compound was extracted with dichloromethane (2.times.40 mL). The
organic layer was dried over Na.sub.2SO.sub.4 and evaporation of
the solvent gave the third intermediate compound (0.55 g, quant.)
as a colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
6.84-6.74 (m, 3H), 3.81 (s, 2H), 3.30-3.22 (m, 8H), 2.55 (s, 2H),
1.03 (s, 6H).
[1340] A reductive amination procedure similar to Example A1' was
followed using 1-(3,3-dimethyl-chroman-8-yl)-piperazine to give the
title compound (0.25 g, 53%). .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 7.56 (br s, 1H), 7.39 (d, 1H), 6.82-6.78 (m, 2H), 6.70 (br
s, 1H), 6.36 (d, 1H), 4.21 (m, 2H), 3.81 (s, 2H), 3.20-3.00 (br s,
3H), 2.82 (t, 2H), 2.70-2.60 (m, 6H), 2.55 (s, 2H), 2.30-2.20 (br
t, 2H), 1.82-1.63 (m, 4H), 1.03 (s, 6H).
Example A23'
Synthesis of
7-[4-(4-Benzofuran-7-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]napht-
hyridin-2-one
[1341] A reductive amination procedure similar to Example A1' was
followed using 1-benzofuran-7-yl-piperazine to give the title
compound. MS: APCI: M+1: 421.2 (Exact Mass: 420.22).
Example A24'
Synthesis of
7-{4-[4-(1H-Indol-7-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]napht-
hyridin-2-one
[1342] A reductive amination procedure similar to Example A1' was
followed using 7-piperazin-1-yl-1H-indole to give the title
compound. MS: APCI: M+1: 420.2 (Exact Mass: 419.23).
Example A25'
Synthesis of
7-{4-[4-(1H-Indol-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]napht-
hyridin-2-one
[1343] A reductive amination procedure similar to Example A1' was
followed using 4-piperazin-1-yl-1H-indole. Purification by liquid
chromatography (0-7% MeOH/CH.sub.2Cl.sub.2) gave the title compound
as a foam. The foam was dissolved in Et.sub.2O and a solid crashed
out (305 mg, 0.727 mmol, 43%). MS: APCI: M+1: 420.2 (Exact Mass:
419.23).
Example A26'
Synthesis of
7-{4-[4-(1-Methyl-1H-indol-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[-
1,8]naphthyridin-2-one
[1344] A reductive amination procedure similar to Example A1' was
followed using 1-methyl-4-piperazin-1-yl-1H-indole. MS: APCI: M+1:
(Exact Mass: 433.25).
Example A27'
Synthesis of
7-{4-[4-(2-Methyl-1H-indol-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[-
1,8]naphthyridin-2-one
[1345] A reductive amination procedure similar to Example A1' was
followed using 2-methyl-4-piperazin-1-yl-1H-indole. Purification by
liquid chromatography (6% MeOH/CH.sub.2Cl.sub.2) gave the title
compound as a tan foam (618 mg, 1.43 mmol, 83%). MS: APCI: M+1:
434.2 (Exact Mass: 433.25).
Example A28'
Synthesis of
7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8-
]naphthyridin-2-one
[1346] A reductive amination procedure similar to Example A1' was
followed using 1-benzo[b]thiophen-4-yl-piperazine. Purification by
liquid chromatography (0-10% MeOH/CH.sub.2Cl.sub.2) gave the title
compound as an oil. Et.sub.2O was added and a solid crashed out to
give a yellow solid (241 mg, 0.552 mmol, 89%). MS: APCI: M+1: 437.2
(Exact Mass: 436.19).
Example A29'
Synthesis of
7-[4-(4-Benzo[1,2,5]oxadiazol-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one
[1347] A reductive amination procedure similar to Example A1' was
followed using 4-piperazin-1-yl-benzo[1,2,5]oxadiazole
hydrochloride (Vogel, Martin; Karst, Uwe. (2001), DE 19936731) to
give the title compound (0.395 g; 74%). MS: APCI: M+1: 423.2 (Exact
mass: 422.21).
Example A30'
Synthesis of
7-[4-(4-Benzo[1,2,5]thiadiazol-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1-
H-[1,8]naphthyridin-2-one
[1348] A reductive amination procedure similar to Example A1' was
followed using 4-piperazin-1-yl-benzo[1,2,5]thiadiazole (Lowe, John
A., Ill.; Nagel, Arthur A. (1989), U.S. Pat. No. 4,831,031) to give
the title compound (0.336 g; 60%). MS: APCI: M+1: 439.2 (Exact
mass: 438.18).
Example A31'
Synthesis of
7-{4-[4-(2-Trifluoromethyl-3H-benzoimidazol-4-yl)-piperazin-1-yl]-butoxy}-
-3,4-dihydro-1H-[1,8]naphthyridin-2-one
[1349] A first intermediate compound,
4-Nitro-2-trifluoromethyl-1H-benzoimidazole, was produced as
follows: To a chilled flask containing 3-nitro-benzene-1,2-diamine
(3.454 g, 22.557 mmol, 1 eq) was added trifluoroacetic anhydride
(19.33 g, 92.04 mmol, 4 eq) drop wise. The suspension was stirred
for two hours and then the light brown solid was filtered off. To
the solid was added toluene (55 mL) and p-toluenesulfonic acid
(10.13 g, 53.25 mmol, 2.361 eq) and the mixture was heated at
120.degree. C. for two hours. The reaction was cooled to room
temperature and diluted with ethyl acetate. The solution was washed
with 1 N NaOH and then brine. The organic solution was concentrated
to provide the first intermediate compound as a brown solid (4.622
g, 88%). MS: APCI: M+1: 232.0 (Exact Mass: 231.03).
[1350] A second intermediate compound,
2-Trifluoromethyl-1H-benzoimidazol-4-ylamine, was produced as
follows: A solution of 4-nitro-2-trifluoromethyl-1H-benzoimidazole
(3.73 g, 16.1 mmol) in 100 mL (1:1 THF:methanol) was hydrogenated
using Ra/Ni. The reaction was filtered and then concentrated to
obtain second intermediate compound (3.527 g, 100%). MS: APCI: M+1:
202.0 (Exact Mass: 201.05).
[1351] A third intermediate compound,
4-Piperazin-1-yl-2-trifluoromethyl-1H-benzoimidazole, was produced
as follows: To a reaction flask containing a mixture of
2-trifluoromethyl-1H-benzoimidazol-4-ylamine (0.325 g, 1.618 mmol,
1 eq) and alumina (3.27 g, 32.1 mmol, 19.8 eq) was added
bis-(2-chloro-ethyl)-amine hydrochloride (0.600 g, 3.363 mmol, 2.1
eq). The reaction was heated to 140.degree. C. for 6 hours. The
reaction was cooled and treated with 10 mL of 1 N NaOH (1 mL) in
methanol. The mixture was filtered and concentrated. Purification
by chromatography on silica gel (0-40%
MeOH/NH.sub.4OH:CH.sub.2Cl.sub.2) afforded the third intermediate
compound (0.181 g, 41%). MS: APCI: M+1: 271.0 (Exact Mass:
270.11).
[1352] To a suspension of
4-(7-oxo-5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yloxy)-butyraldehyde
(0.297 g, 1.266 mmol, 1.32 eq) and
4-piperazin-1-yl-2-trifluoromethyl-1H-benzoimidazole (0.258 g,
0.953 mmol, 1 eq) in dichloroethane (5 mL) was added
NaBH(OAc).sub.3 (0.723 g, 3.413 mmol, 3.58 eq). The slurry was
allowed to stir overnight at room temperature (18 h). Analysis by
HPLC showed reaction mostly complete. The mixture was diluted with
Ethyl Acetate and quenched with saturated NaHCO.sub.3. The organic
phase was then washed with brine, dried over Na.sub.2SO.sub.4,
filtered and evaporated in vacuo. Purification by silica gel
chromatography (2% MeOH/CH.sub.2Cl.sub.2) followed by formation of
the HCl salt using 1N HCl in ether provided the title compound
(0.166 g, 35%). MS: APCI: M+1: 489.2 (Exact Mass: 488.21).
Example A32'
Synthesis of
7-{4-[4-(1-Methyl-1,2,3,4-tetrahydro-quinolin-5-yl)-piperazin-1-yl]-butox-
y}-3,4-dihydro-1H-[1,8]naphthyridin-2-one
[1353] An intermediate compound,
1-Methyl-5-piperazin-1-yl-1,2,3,4-tetrahydro-quinoline, was
produced as follows: To a stirred solution of
4-(1,2,3,4-tetrahydro-quinolin-5-yl)-piperazine-1-carboxylic acid
tert-butyl ester (1.30 g, 4.10 mmol) in THF-DMF (1:1, 40 mL) was
added NaH (60% dispersion in oil, 0.58 g, 24.16 mmol) at room
temperature. The resulting mixture was stirred at room temperature
for 1 h, cooled to 0.degree. C. and iodomethane (1.75 g, 12.30
mmol) was added. The mixture was stirred at room temperature
overnight and diluted with ethyl acetate. Water was added and the
organic layer was separated. The aqueous layer was extracted with
ethyl acetate. The combined organic extracts were washed with
water, brine, dried (Na.sub.2SO.sub.4) and the solvent was removed
in vacuo. The residue was purified on a silica gel column using
hexanes-ethyl acetate (3:1) as eluent to give
4-(1-methyl-1,2,3,4-tetrahydro-quinolin-5-yl)-piperazine-1-carboxylic
acid tert-butyl ester (0.90 g, 66%) as a liquid. .sup.1H NMR (400
MHz, CDCl.sub.3): .delta. 7.10 (t, 1H), 6.40 (m, 2H), 3.50 (br s ,
4H), 3.25 (t, 2H), 2.90 (s, 3H), 2.80 (br s, 4H), 2.75 (t, 2H),
1.90 (t, 3H), 1.45 (s, 9H).
[1354] To a stirred solution of
4-(1-methyl-1,2,3,4-tetrahydro-quinolin-5-yl)-piperazine-1-carboxylic
acid tert-butyl ester (0.90 g, 2.72 mmol) in dichloromethane (15
mL) cooled to 0.degree. C., was added trifluoroacetic acid (3.10 g,
27.20 mmol). The resulting mixture was stirred at room temperature
overnight and the solvent was removed in vacuo to give the
intermediate compound (0.90 g, 97%) as a foam. .sup.1H NMR (400
MHz, CDCl.sub.3): .delta. 9.60 (br s, 1H), 7.25 (d, 1H), 6.90 (d,
1H), 6.79 (d, 1H), 3.39 (t, 2H), 3.30 (br s, 4H), 3.19 (br s, 4H),
3.10 (s, 3H), 2.78 (t, 2H), 2.15 (t, 2H), 1.65 (t, 2H). MS ES: m/z
232.12 (M+H).sup.+ (Exact mass: 231.17).
[1355] A reductive amination procedure similar to Example A1' was
followed using
1-methyl-5-piperazin-1-yl-1,2,3,4-tetrahydro-quinoline to give the
title compound. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 12.95
(br s, 1H), 7.80 (br s, 1H), 7.42 (d, 1H), 7.30 (d, 1H), 7.15 (d,
1H), 6.39 (d, 1H), 4.28 (t, 2H), 3.80-3.60 (br, 4H), 3.45 (br s,
2H), 3.18 (s, 3H), 3.15 (br, 6H), 2.85 (br s, t, 4H), 2.65 (t, 2H),
2.18 (br, 4H), 1.85 (t, 2H). MS ES: m/z 450.13 (M+H).sup.+ (Exact
mass: 449.28).
Example A33'
Synthesis of
7-{4-[4-(1-Ethyl-1,2,3,4-tetrahydro-quinolin-5-yl)-piperazin-1-yl]-butoxy-
}-3,4-dihydro-1H-[1,8]naphthyridin-2-one
[1356] A reductive amination procedure similar to Example A1' was
followed using
1-ethyl-5-piperazin-1-yl-1,2,3,4-tetrahydro-quinoline to give the
title compound. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.50 (s,
1H), 7.35 (d, 1H), 7.00 (t, 1H), 6.28 (m, 2H), 4.30 (t, 2H),
3.60-2.20 (m, 8H), 2.95-2.40 (m, 12H), 1.95-1.75 (m, 4H), 1.05 (t,
3H). MS ES: m/z 464.18 (M+H).sup.+ (Exact mass: 463.29).
Example A34'
Synthesis of
7-[4-(4-Quinolin-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthy-
ridin-2-one
[1357] A reductive amination procedure similar to Example A1' was
followed using 8-piperazin-1-yl-quinoline. Purification by liquid
chromatography (0-10% MeOH/CH.sub.2Cl.sub.2) gave the title
compound as a foam (460 mg, 1.06 mmol, 62%). MS: APCI: M+1: 432.2
(Exact Mass: 431.23).
Example A35'
Synthesis of
7-[4-(4-Quinolin-5-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthy-
ridin-2-one
[1358] A reductive amination procedure similar to Example A1' was
followed using 5-piperazin-1-yl-quinoline. Purification by liquid
chromatography (0-10% MeOH/CH.sub.2Cl.sub.2) gave the title
compound as a white solid (517 mg, 1.20 mmol, 70%). MS: APCI: M+1:
432.2 (Exact Mass: 431.23).
Example A36'
Synthesis of
7-[4-(4-Isoquinolin-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naph-
thyridin-2-one
[1359] A reductive amination procedure similar to Example A1' was
followed using 8-piperazin-1-yl-isoquinoline to give the title
compound as a yellow foam. MS: APCI: M+1: 432.5 (Exact Mass:
431.23).
Example A37'
Synthesis of
7-[4-(4-Isoquinolin-5-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naph-
thyridin-2-one
[1360] A reductive amination procedure similar to Example A1' was
followed using 5-piperazin-1-yl-isoquinoline to give the title
compound as a yellow foam which was recrystallized from Et.sub.2O
to give a yellow solid. MS: APCI: M+1:432.2 (Exact Mass:
431.23).
Example A38'
Synthesis of
7-{4-[4-(3-Fluoro-quinolin-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[-
1,8]naphthyridin-2-one
[1361] A first intermediate compound, 3-Fluoro-quinolin-5-ylamine
and 3-Fluoro-quinolin-8-ylamine, was produced as follows:
3-Fluoro-quinoline (2.808 g, 19.10 mmol) was cooled to 0.degree. C.
and sulfuric acid (15 mL) was added. To the mixture was added
fuming nitric acid (1.21 mL, 1.81 g, 29.0 mmol) dropwise. The
mixture was warmed to room temperature and stirred for 1 hour. The
mixture was poured into 200 mL ice, quenched with NaOH until basic
and extracted with ethyl acetate (2.times.30 mL). The organic
layers were combined and washed with brine (30 mL), dried over
anhydrous sodium sulfate, filtered and concentrated in vacuo to
give a mixture of 3-fluoro-5-nitro-quinoline and
3-fluoro-8-nitro-quinoline (3.50 g, 95%) as a yellow solid.
[1362] The mixture of nitroquinolines was dissolved in ethyl
acetate (40 mL) and 5% palladium on charcoal (800 mg) was added.
The mixture was placed in a Parr apparatus and shaken under 40 psi
hydrogen atmosphere for 1.5 h. The mixture was filtered through
celite, evaporated in vacuo and the residue purified by column
chromatography (gradient elution 3:1 to 1:1, hexanes/ethyl acetate)
to yield 3-fluoro-quinolin-5-ylamine (1.79 g, 61%) as a brown solid
[.sup.1H NMR (400 MHz, dmso-d.sub.6) .delta. 8.80 (d, 1H), 8.40 (d,
1H), 7.40 (t, 1H), 7.20 (d, 1H), 6.78 (d, 1H), 6.00 (s, 2H)] and
3-fluoro-quinolin-8-ylamine (726 mg, 25%) [.sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.60 (s, 1H), 7.64 (d, 1H), 7.38 (t, 1H), 7.10
(d, 1H), 6.84 (d, 1H), 4.99 (s, 2H)].
[1363] A second intermediate compound,
3-Fluoro-5-piperazin-1-yl-quinoline, was produced as follows:
3-Fluoro-quinolin-5-ylamine (400 mg, 2.47 mmol),
bis(2-chloroethyl)amine hydrochloride (485 mg, 2.72 mmol), sodium
iodide (185 mg, 1.24 mmol) and diisopropylethylamine (0.22 mL, 160
mg, 1.24 mmol) were all dissolved in a mixture of chlorobenzene (6
mL) and 1-hexanol (1 mL). The mixture was heated at 140.degree. C.
overnight. The mixture was cooled and concentrated in vacuo. The
residue was loaded onto silica gel and purified by column
chromatography (1:10:89, ammonium
hydroxide/methanol/dichloromethane) to yield the second
intermediate compound (301 mg, 53%) as a brown solid. .sup.1H NMR
(400 MHz, dmso-d.sub.6) .delta. 9.00 (s, 1H), 8.20 (d, 1H), 7.80
(d, 1H), 7.65 (t, 1H), 7.24 (d, 1H), 3.30 (s, 1H), 3.20 (t, 4H),
3.05-3.00 (m, 4H).
[1364] A reductive amination procedure similar to Example A1' was
followed using 3-fluoro-5-piperazin-1-yl-quinoline to give the
title compound (273 mg, 57%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.80 (s, 1H), 8.15 (d, 1H), 7.80 (d, 1H), 7.62-7.50 (m,
2H), 7.40 (d, 1H), 7.20 (d, 1H), 6.40 (d, 1H), 4.24 (t, 2H),
3.20-3.00 (m, 4H), 2.80 (t, 2H), 2.78-2.60 (m, 4H), 2.60 (t, 2H),
2.56 (t, 2H), 1.80-1.64 (m, 4H); MS ES+ 450.32 (M+H).sup.+ (Exact
mass: 449.22).
Example A39'
Synthesis of
7-{4-[4-(3-Fluoro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[-
1,8]naphthyridin-2-one
[1365] An intermediate compound,
3-Fluoro-8-piperazin-1-yl-quinoline, was produced as follows:
3-Fluoro-quinolin-8-ylamine (1.15 g, 7.10 mmol, see previous
example), bis(2-chloroethyl)amine hydrochloride (1.39 g, 7.81
mmol), sodium iodide (532 mg, 3.55 mmol) and diisopropylethylamine
(0.62 mL, 459 mg, 3.55 mmol) were all dissolved in a mixture of
chlorobenzene (15 mL) and 1-hexanol (2.5 mL). The mixture was
heated at 140.degree. C. for 48 hours. The mixture was cooled and
concentrated in vacuo. The residue was loaded onto silica gel and
purified by column chromatography (1:10:89,
NH.sub.4OH/methanol/dichloromethane) to yield the first
intermediate compound (1.37 g, 83%) as a brown solid. .sup.1H NMR
(400 MHz, dmso-d.sub.6) .delta. 8.84 (s, 1H), 8.20 (d, 1H),
7.60-7.52 (m, 2H), 7.15-7.10 (m, 1H), 3.60-3.20 (m, 5H), 3.18-3.04
(m, 4H).
[1366] A reductive amination procedure similar to Example A1' was
followed using 3-fluoro-8-piperazin-1-yl-quinoline to give the
title compound (426 mg, 66%). .sup.1H NMR (400 MHz, dmso-d.sub.6)
.delta. 10.25 (s, 1H), 8.84 (s, 1H), 8.20 (d, 1H), 7.54-7.40 (m,
3H), 7.14-7.00 (m, 1H), 6.40 (d, 1H), 4.20 (t, 2H), 2.78 (t, 2H),
2.64-2.60 (m, 4H), 2.60-2.39 (m, 8H), 1.80-1.70 (m, 2H), 1.70-1.58
(m, 2H), MS ES+ 450.22 (M+H).sup.+ (Exact mass: 449.22).
Example A40'
Synthesis of
7-{4-[4-(2-Methyl-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[-
1,8]naphthyridin-2-one
[1367] A reductive amination procedure similar to Example A1' was
followed using 2-methyl-8-piperazin-1-yl-quinoline. Purification by
liquid chromatography (0-10% MeOH/CH.sub.2Cl.sub.2) gave the title
compound as a foam (530 mg, 1.19 mmol, 60% mmol). MS: APCI: M+1:
446.2 (Exact Mass: 445.25).
Example A41'
Synthesis of
7-{4-[4-(2-Methoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H--
[1,8]naphthyridin-2-one
[1368] A first intermediate compound 8-Chloro-2-methoxy-quinoline,
was produced as follows: To a suspension of 2,8-dichloro-quinoline
(1.98 g, 10.00 mmol) in methanol (20 mL) was added NaOMe (0.81 g,
15.00 mmol) and the reaction mixture was heated under reflux
overnight. The solvent was evaporated and the residue was dissolved
in ethyl acetate (50 mL) and washed with water (2.times.50 mL). The
organic layer was dried (Na.sub.2SO.sub.4) and evaporated, and the
crude product was purified by chromatography (10% EtOAc/Hexane) to
give the first intermediate compound as a colorless oil (1.93 g,
99%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 8.00 (d, 2H), 7.70
(d, 1H), 7.60 (d, 1H), 7.28 (t, 1H), 6.98 (d, 1H), 4.10 (s,
3H).
[1369] A second intermediate compound,
4-(2-Methoxy-quinolin-8-yl)-piperazine-1-carboxylic acid tert-butyl
ester, was produced as follows: To an oven-dried flask, under
nitrogen, was added Pd(OAc).sub.2 (0.04 g, 0.20 mmol) and
2-(dicyclohexylphosphino)biphenyl (0.072 g, 0.20 mmol). The flask
was evacuated, filled with nitrogen, and then the following
materials were added in this order: degassed toluene (10 mL),
8-chloro-2-methoxy-quinoline (1.00 g, 5.14 mmol), 1-Boc-piperazine
(1.15 g, 6.18 mmol), and NaOtBu (0.69 g, 7.21 mmol). The mixture
was stirred at 80.degree. C. for 1.5 h. After cooling to room
temperature, the mixture was diluted with ethyl acetate and
filtered through a bed of celite. The filtrate was concentrated in
vacuo. The crude material was purified by chromatography on silica
gel (10% EtOAc/Hexane) to give the second intermediate compound as
a yellow oil (1.00 g, 56%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 7.98 (d, 2H), 7.40 (d, 1H), 7.30 (t, 1H), 7.10 (d, 1H),
6.90 (d, 1H), 4.05 (s, 3H), 3.75 (t, 4H), 3.38 (t, 4H), 1.50 (s,
9H).
[1370] A third intermediate compound,
2-Methoxy-8-piperazin-1-yl-quinoline, was produced as follows: To a
solution of 4-(2-methoxy-quinolin-8-yl)-piperazine-1-carboxylic
acid tert-butyl ester (1.00 g, 2.90 mmol) in dichloromethane (20
mL) was added trifluoroacetic acid (4 mL) at 0.degree. C. The
reaction mixture was stirred at this temperature for 3 h, and then
allowed to warm to room temperature. The mixture was basified by
addition of saturated NaHCO.sub.3 and extracted with
dichloromethane (3.times.20 mL). The combined organic layer was
dried (Na.sub.2SO.sub.4) and evaporated to give the third
intermediate compound (0.70 g, 99%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 7.98 (d, 2H), 7.40 (d, 1H), 7.30 (t, 1H), 7.10
(d, 1H), 6.90 (d, 1H), 4.05 (s, 3H), 3.50 (m, 4H), 3.30 (m,
4H).
[1371] A reductive amination procedure similar to Example A1' was
followed using 2-methoxy-8-piperazin-1-yl-quinoline to give the
title compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.98 (d,
2H), 7.58 (br s, 1H), 7.38 (d, 1H), 7.30 (t, 1H), 7.12 (d, 1H),
6.90 (d, 1H), 6.38 (d, 1H), 4.22 (t, 2H), 4.05 (s, 3H), 2.82 (m,
6H), 2.62 (t, 2H), 2.50 (dd, 2H), 1.82 (m, 2H), 1.78 (m, 2H).
Example A42'
Synthesis of
7-{4-[4-(2-Ethoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[-
1,8]naphthyridin-2-one
[1372] An intermediate compound,
2-Ethoxy-8-piperazin-1-yl-quinoline, was produced as follows: The
title compound was prepared according to the procedure detailed for
2-methoxy-8-piperazin-1-yl-quinoline above in Example A41'. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 9.30 (brs, 2H), 8.05 (d, 1H),
7.55 (d, 1H), 7.40 (t, 1H), 7.30 (d, 1H), 6.96 (d, 1H), 4.50 (q,
2H), 3.80 (m, 4H), 3.60 (m, 4H), 1.50 (t, 3H).
[1373] A reductive amination procedure similar to Example A1' was
followed using 2-ethoxy-8-piperazin-1-yl-quinoline to give the
title compound (0.27 g, 80%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.98 (d, 1H), 7.60 (brs, 1H), 7.38 (m, 2H), 7.30 (t, 1H),
7.10 (d, 1H), 6.86 (d, 1H), 6.38 (d, 1H), 4.58 (t, 2H), 4.28 (t,
2H), 3.50 (brs, 4H), 2.90 (t, 2H), 2.82 (m, 4H), 2.62 (t, 2H), 2.58
(t, 2H), 1.90 (m, 2H), 1.80 (m, 2H), 1.50 (t, 3H); MS (ES): m/z:
476.25 (M+H).sup.+ (Exact mass: 475.26).
Example A43'
Synthesis of
7-{4-[4-(2-Methoxy-quinolin-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H--
[1,8]naphthyridin-2-one
[1374] A first intermediate compound 5-Bromo-2-chloro-quinoline,
was produced as follows: To a solution of 5-bromoquinoline (8.13 g,
39.27 mmol) in chloroform (70 mL) was added peroxyacetic acid and
the mixture was refluxed for 3 hours. After cooling down, the
mixture was poured into ice-water and basified by the addition of
4N NaOH aqueous solution to a final pH of 10. The N-oxide was
extracted with ethyl. acetate and dried (Na.sub.2SO4). The solvent
was evaporated to give the crude N-oxide as a white solid (6.61 g).
To the N-oxide (5.20 g, 23.31 mmol) at -10.degree. C. was carefully
added POCl.sub.3 (40 mL, highly exothermic). The mixture was then
stirred at room temperature for 10 min and heated at 100.degree. C.
for 3 hours. The excess of POCl.sub.3 was removed under vacuum. The
residue was dissolved in dichloromethane, poured into ice-water,
and the pH was adjusted to 8. The aqueous layer was extracted with
dichloromethane. The combined organic layers were dried and
evaporated. The crude product was purified by chromatography (5%
EtOAc/Hexane) to give the first intermediate compound as a white
solid (1.70 g, 30%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.:
8.50 (d, 1H), 8.05 (d, 1H), 7.85 (d, 1H), 7.60 (dd, 1H), 7.50 (d,
1H).
[1375] A second intermediate compound, 5-Bromo-2-methoxy-quinoline,
was produced as follows: To a suspension of
5-bromo-2-chloro-quinoline (0.99 g, 4.10 mmol) in methanol (20 mL)
was added NaOMe (0.27 g, 4.73 mmol) and the reaction mixture was
heated under reflux overnight. The solvent was evaporated and the
residue was dissolved in ethyl acetate (50 mL). The organics were
washed with water (2.times.50 mL), dried (Na.sub.2SO.sub.4) and
evaporated. The crude product was purified by chromatography (5%
EtOAc/Hexane) to give the second intermediate compound as white
crystals (0.79 g, 82%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.:
8.40 (d, 1H), 7.85 (d, 1H), 7.65 (d, 1H), 7.45 (dd, 1H), 7.00 (d,
1H), 4.10 (s, 3H).
[1376] A third intermediate compound,
2-Methoxy-5-piperazin-1-yl-quinoline, was produced as follows: To
an oven-dried flask, under nitrogen, was added Pd(OAc).sub.2 (0.03
g, 0.13 mmol) and 2-(dicyclohexylphosphino)biphenyl (0.045 g, 0.13
mmol). The flask was evacuated and refilled with nitrogen. The
following materials were added in the following order: degassed
toluene (10 mL), 5-bromo-2-methoxy-quinoline (0.76 g, 3.23 mmol),
1-Boc-piperazine (0.72 g, 3.87 mmol), and NaOtBu (0.43 g, 4.52
mmol). The mixture was stirred at 80.degree. C. for 1.5 h. After
cooling to room temperature, the mixture was diluted with ethyl
acetate and filtered through celite. The filtrate was concentrated
in vaccuo and purified by chromatography on silica gel (10%
EtOAc/Hexane) to give
4-(2-methoxy-quinolin-5-yl)-piperazine-1-carboxylic acid tert-butyl
ester as a yellowish solid (0.73 g, 66%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 8.35 (d, 1H), 7.60 (m, 2H), 7.00 (d, 1H), 6.90
(d, 1H), 4.05 (s, 3H), 3.75 (m, 4H), 3.00 (m, 4H), 1.50 (s,
9H).
[1377] To a solution of
4-(2-methoxy-quinolin-5-yl)-piperazine-1-carboxylic acid tert-butyl
ester (0.73 g, 2.14 mmol) in dichloromethane (4.0 mL) was added
trifluoroacetic acid (16 mL) at 0.degree. C. The reaction mixture
was stirred for 3 h, and was allowed to warm to room temperature
during this time. The mixture was evaporated and the residue was
treated with diethyl ether. The precipitate was filtered and washed
with ether to give the title compound (0.75 g, 95%). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta.: 9.90 (br.s, 2H), 8.25 (d, 1H), 7.65
(d, 1H), 7.58 (t, 1H), 7.10 (d, 1H), 6.90 (d, 1H), 4.05 (s, 3H),
3.50 (m, 4H), 3.35 (m, 4H).
[1378] A reductive amination procedure similar to Example A1' was
followed using 2-methoxy-5-piperazin-1-yl-quinoline to give the
title compound (0.38 g, 99%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 8.35 (d, 1H), 7.60 (br.s,1H), 7.55 (dd, 1H), 7.40 (d, 1H),
7.00 (d, 1H), 6.85 (d, 1H), 6.38 (d, 1H), 4.25 (t, 2H), 4.05 (s,
3H), 3.10 (br.s, 4H), 2.90 (t, 2H), 2.80 (br.s, 4H), 2.70 (t, 2H),
2.55 (t, 2H), 1.82 (m, 2H), 1.78 (m, 2H).
Example A44'
Synthesis of
7-[4-(4-Quinoxalin-5-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]napht-
hyridin-2-one
[1379] A first intermediate compound Trifluoro-methanesulfonic acid
quinoxalin-5-yl ester, was produced as follows: To a solution of
quinoxalin-5-ol (3.97 g, 27.2 mmol, prepared according to J. Org.
Chem. 1951, 16, 438-442) in CH.sub.2Cl.sub.2 (110 mL) cooled to
0.degree. C. was added Et.sub.3N (7.6 mL, 54.3 mmol) followed by
trifluoromethanesulfonic anhydride (6.0 mL, 35.4 mmol). The rxn
smoked briefly and was stirred at 0.degree. C. for 1 h. The
reaction was quenched with sat. NaHCO.sub.3 at 0.degree. C. and
warmed to RT. The layers were separated and the aqueous layer was
extracted with CH2Cl2. The combined organic layer was washed with
water and brine, dried over Na.sub.2SO.sub.4 and concentrated to
give an organic brown solid. The crude material was absorbed onto
SiO.sub.2 and purified by LC (20% EtOAc/Hexanes) to give the first
intermediate compound as a light orange solid (6.51 g, 23.4 mmol,
86%). MS: APCI: M+1: 279.0 (Exact Mass: 278.00).
[1380] A second intermediate compound,
4-Quinoxalin-5-yl-piperazine-1-carboxylic acid tert-butyl ester,
was produced as follows: A solution of trifluoro-methanesulfonic
acid quinoxalin-5-yl ester (4.23 g, 15.2 mmol) in dry DME (30 mL)
was degassed for 10 min by blowing nitrogen into the solution. This
solution was then added via cannula to a flask containing
Boc-piperazine (3.54 9,19.00 mmol), K.sub.3PO.sub.4 (4.52 g, 21.3
mmol), Pd.sub.2(dba).sub.3 (348 mg, 0.380 mmol, 2.5 mol %) and
2-(di-t-butylphosphino)biphenyl (227 mg, 0.760 mmol, 5 mol %) under
nitrogen. The reaction mixture was heated at 80.degree. C.
overnight (20 h). MS showed a large product peak. The reaction was
allowed to cool to room temperature and Et.sub.2O was added. The
mixture was filtered through Celite washing with Et.sub.2O. The
filtrate was washed with 0.5 M citric acid (2.times., to remove
excess Boc-piperazine) and once with brine, dried over
Na.sub.2SO.sub.4 and concentrated to give a dark red oil.
Purification by LC (40% EtOAc/Hexanes) gave the product as a red
oil which foamed on the pump (2.68 g, 8.52 mmol, 56%). MS: APCI:
M+1: 315.2 (Exact Mass: 314.17).
[1381] A third intermediate compound, 5-Piperazin-1-yl-quinoxaline,
was produced as follows: To a solution of
4-quinoxalin-5-yl-piperazine-1-carboxylic acid tert-butyl ester
(2.65 g, 8.43 mmol) in CH.sub.2Cl.sub.2 (15 mL) cooled to 0.degree.
C. was added TFA (15 mL). The reaction was warmed to room
temperature and stirred for 90 min. The mixture was concentrated
and the remaining TFA was neutralized by adding 10% MeOH/CH2Cl2
with 1% NH.sub.4OH. SiO.sub.2 was added and the mixture was
concentrated. Purification by LC (10% MeOH/CH.sub.2Cl.sub.2 with 1%
NH.sub.4OH) gave the third intermediate compound as an orange solid
(1.65 g, 7.70 mmol, 91%). MS: APCI: M+1: 215.2 (Exact Mass:
214.12).
[1382] A reductive amination procedure similar to Example A1' was
followed using 5-piperazin-1-yl-quinoxaline to give the title
compound. MS: APCI: M+1: 433.3 (Exact Mass: 432.23).
Example A45'
Synthesis of
7-{4-[4-(2-Dimethylamino-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihyd-
ro-1H-[1,8]naphthyridin-2-one
[1383] A first intermediate compound
(8-Chloro-quinolin-2-yl)-dimethyl-amine, was produced as follows:
To a suspension of 2,8-dichloro-quinoline (5.00 g, 25.2 mmol) in a
water/dioxane solution (69 mL, 10:1) was added an aqueous solution
of Na.sub.2CO.sub.3 (2N, 38 mL, 76 mmol) and dimethylamine
hydrochloride (4.12 g, 50.5 mmol). The reaction mixture was heated
at 160.degree. C. for 1.5 h in a microwave. The reaction was
extracted with CH.sub.2Cl.sub.2 (2.times.), dried
(Na.sub.2SO.sub.4) and evaporated, and the crude product was
purified by chromatography (2-20% EtOAc/Hexane) to give the first
intermediate compound as a faint yellow solid (4.22 g, 81%). MS:
APCI: M+1: 207.0 (Exact mass: 206.06).
[1384] A second intermediate compound,
4-(2-Dimethylamino-quinolin-8-yl)-piperazine-1-carboxylic acid
tert-butyl ester, was produced as follows: To an oven-dried flask,
under nitrogen, was added Pd.sub.2 (dba).sub.3 (0.111 g, 0.121
mmol) and (2'-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine
(0.190 g, 0.484 mmol). The flask was evacuated, filled with
nitrogen, and then the following materials were added in this
order: degassed toluene (14 mL),
(8-chloro-quinolin-2-yl)-dimethyl-amine (1.00 g, 5.14 mmol),
1-Boc-piperazine (1.80 g, 9.68 mmol), and Cs.sub.2CO.sub.3 (2.21 g,
6.77 mmol). The mixture was stirred at 105.degree. C. for 19 h.
Another 5 mol % of the catalyst was added and heating was continued
for an additional 18 h. After cooling to room temperature, the
mixture was diluted and filtered through a bed of celite. The
filtrate was concentrated in vacuo. The crude material was purified
by chromatography on silica gel (3-40% EtOAc/Hexane) to give the
second intermediate compound as yellow foam (1.26 g, 73%). MS:
APCI: M+1: 357.2 (Exact mass: 356.22).
[1385] A third intermediate compound,
Dimethyl-(8-piperazin-1-yl-quinolin-2-yl)-amine, was produced as
follows: To a solution of
4-(2-dimethylamino-quinolin-8-yl)-piperazine-1-carboxylic acid
tert-butyl ester (1.244 g, 3.63 mmol) in dichloromethane (35 mL)
was added trifluoroacetic acid (10 mL) at 0.degree. C. The reaction
mixture was stirred at this temperature for 1.5 h, and then allowed
to warm to room temperature. The volatiles were removed in vacuo
and the crude oil was taken up in CH.sub.2Cl.sub.2, and washed with
2N KOH, dried (Na.sub.2SO.sub.4) and evaporated to give the third
intermediate compound (0.895 g, >99%). MS: APCI: M+1: 257.1
(Exact mass: 256.17).
[1386] A reductive amination procedure similar to Example A1' was
followed using dimethyl-(8-piperazin-1-yl-quinolin-2-yl)-amine to
give the title compound (0.314 g; 79%). MS: APCI: M+1: 475.2 (Exact
mass: 474.27).
Example A46'
Synthesis of
7-{4-[4-(2-Methylamino-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-
-1H-[1,8]naphthyridin-2-one
[1387] A first intermediate compound
(8-Chloro-quinolin-2-yl)-methyl-amine, was produced as follows: To
a suspension of 2,8-dichloro-quinoline (5.00 g, 25.2 mmol) in a
water/dioxane solution (69 mL, 10:1) was added an aqueous solution
of Na.sub.2CO.sub.3 (2N, 25.2 mL, 50.5 mmol) and aqueous
methylamine (40% w/w, 5.4 g, 63 mmol). The reaction mixture was
heated at 160.degree. C. for 1.5 h in a microwave. The reaction was
extracted with CH.sub.2Cl.sub.2 (2.times.), dried
(Na.sub.2SO.sub.4) and evaporated, and the crude product was
purified by chromatography (2-20% EtOAc/Hexane) to give the first
intermediate compound as a light yellow solid (3.69 g, 76%). MS:
APCI: M+1: 193.0 (Exact mass: 192.05).
[1388] A second intermediate compound,
4-(2-methylamino-quinolin-8-yl)-piperazine-1-carboxylic acid
tert-butyl ester, was produced as follows: To an oven-dried flask,
under nitrogen, was added Pd.sub.2(dba).sub.3 (0.238 g, 0.260 mmol)
and (2'-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (0.409
g, 1.04 mmol). The flask was evacuated, filled with nitrogen, and
then the following materials were added in this order: degassed
toluene (30 mL), (8-chloro-quinolin-2-yl)-methyl-amine (2.00 g,
10.4 mmol), 1-Boc-piperazine (3.87 g, 20.8 mmol), and
Cs.sub.2CO.sub.3 (4.74 g, 14.5 mmol). The mixture was stirred at
105.degree. C. for 19 h. After cooling to room temperature, the
mixture was diluted and filtered through a bed of celite. The
filtrate was concentrated in vacuo. The crude material was purified
by chromatography on silica gel (3-50% EtOAc/Hexane) to give the
second intermediate compound as light orange oil (0.751 g, 21%).
MS: APCI: M+1: 343.3 (Exact mass: 342.21).
[1389] A third intermediate compound,
Dimethyl-(8-piperazin-1-yl-quinolin-2-yl)-amine, was produced as
follows: To a solution of
4-(2-methylamino-quinolin-8-yl)-piperazine-1-carboxylic acid
tert-butyl ester (0.751 g, 2.19 mmol) in dichloromethane (29 mL)
was added trifluoroacetic acid (10 mL) at 0.degree. C. The reaction
mixture was stirred at this temperature for 1 h, and then allowed
to warm to room temperature. The volatiles were removed in vacuo
and the crude oil was taken up in CH.sub.2Cl.sub.2, and washed with
2N KOH, dried (Na.sub.2SO.sub.4) and evaporated to give the third
intermediate compound (0.510 g, 96%). MS: APCI: M+1: 243.1 (Exact
mass: 242.15).
[1390] A reductive amination procedure similar to Example A1' was
followed using methyl-(8-piperazin-1-yl-quinolin-2-yl)-amine to
give the title compound (0.081 g; 28%). MS: APCI: M+1: 461.3 (Exact
mass: 460.26).
Example A47'
Synthesis of
7-{4-[4-(2-Oxo-1,2-dihydro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dih-
ydro-1H-[1,8]naphthyridin-2-one
[1391] In a manner similar to that of other examples above,
8-piperazin-1-yl-1H-quinolin-2-one hydrochloride (Chem. Pharm.
Bull. 1984, 32, 2100-2110) was coupled by reductive amination to
4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
followed by typical workup and purification to give the title
compound. MS: APCI: M+1: 448.2 (Exact Mass: 447.23).
Example A48'
Synthesis of
7-{4-[4-(2-Oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazin-1-yl]-butoxy}--
3,4-dihydro-1H-[1,8]naphthyridin-2-one
[1392] In a manner similar to that of other examples above,
8-piperazin-1-yl-3,4-dihydro-1H-quinolin-2-one hydrochloride (Chem.
Pharm. Bull. 1984, 32, 2100-2110) was coupled by reductive
amination to
4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
followed by typical workup and purification to give the title
compound. MS: APCI: M+1: 450.2 (Exact Mass: 449.24).
Example A49'
Synthesis of
7-{4-[4-(1-Methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazin-1-yl]-
-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one
[1393] A first intermediate compound,
4-(2-Oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazine-1-carboxylic
acid tert-butyl ester, was produced as follows: To dichloromethane
(75 mL) was added 8-piperazin-1-yl-3,4-dihydro-1H-quinolin-2-one
hydrochloride (10.8 mmol), diisopropylethylamine (1.95 mL, 11.2
mmol) and di-t-butylcarbonate (9.20 g, 9.33 mmol) followed by
stirring for 16 hours at 25.degree. C. The mixture was washed
consecutively with 1N citric acid, saturated sodium bicarbonate and
brine. The organic phase was dried over sodium sulfate, filtered
and evaporated to give the first intermediate compound (2.78 g), mp
117-178.degree. C.
[1394] A second intermediate compound,
1-Methyl-8-piperazin-1-yl-3,4-dihydro-1H-quinolin-2-one
hydrochloride, was produced as follows: To a solution of
4-(2-oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazine-1-carboxylic
acid tert-butyl ester (2.5 g, 7.54 mmol) in THF (45 mL) cooled to
-50.degree. C. was added a solution of potassium t-butoxide, 1M in
THF (8.3 mL, 8.30 mmol). After stirring for 15 minutes, methyl
iodide (0.47 mL, 7.54 mmol) was added followed by stirring for 16
hours at 25.degree. C. The mixture was evaporated and the residue
was taken up into dichloromethane. The solution was washed
consecutively with 1N citric acid, saturated sodium bicarbonate and
brine. The organic phase was dried over sodium sulfate, filtered
and evaporated to give a white foam, which was purified by
chromatography on silica gel eluting with a gradient of
dichloromethane and ethyl acetate. Evaporation of the appropriate
fractions gave
4-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazine-1-carboxyl-
ic acid tert-butyl ester (2.1 g).
[1395] To a mixture of dichloromethane (45 mL) and diethyl ether (5
mL) was added
4-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazine--
1-carboxylic acid tert-butyl ester (2.1 g, 6.08 mmol), followed by
purging with anhydrous HCl gas intermittently over several hours
until the starting material was consumed. The mixture was
evaporated to a solid, triturated with diethyl ether and dried in
vacuo to give the second intermediate compound as a pale yellow
solid (1.75 g).
[1396] In a manner similar to that of other examples above,
1-methyl-8-piperazin-1-yl-3,4-dihydro-1H-quinolin-2-one
hydrochloride was coupled by reductive amination to
4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
followed by typical workup and purification to give the title
compound. MS: APCI: M+1: 464.6 (Exact Mass: 463.26).
Example B1'
Synthesis of
7-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one
[1397] A first intermediate compound,
2-Benzyloxy-7-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-[1,8]naphthyridine,
was produced as follows: To a solution of
4-(tetrahydro-pyran-2-yloxy)-1-butanol (3.27 g, 18.8 mmol, 1.2
equiv) in THF (20 mL) cooled to 0.degree. C. was added KO.sup.tBu
(1M in THF, 18 mL, 18 mmol, 1.15 equiv). The solution was stirred
at 0.degree. C. for 20 min and then added via cannula to a
suspension of 2-benzyloxy-7-chloro-[1,8]naphthyridine (4.24 g,
15.66 mmol) in THF (50 mL) cooled to 0.degree. C. The reaction
turned orange and became homogenous. After 30 min at 0.degree. C.,
saturated NH.sub.4Cl and H.sub.2O were added to quench the
reaction. The mixture was extracted with EtOAc. The organic layer
was washed with saturated NaHCO.sub.3, H.sub.2O and brine, dried
over Na.sub.2SO.sub.4 and concentrated. The crude was absorbed onto
SiO.sub.2 and purified by liquid chromatography (20-30%
EtOAc/Hexanes) to give the first intermediate compound as a pale
yellow oil (3.71 g, 9.08 mmol, 58%). MS: APCI: M+1: 409.2 (Exact
Mass: 408.20).
[1398] A second intermediate compound,
7-(4-Hydroxy-butoxy)-1H-[1,8]naphthyridin-2-one, was produced as
follows:
2-Benzyloxy-7-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-[1,8]naphthyridine
(620 mg, 1.52 mmol) was hydrogenated using 5% Pd/C in MeOH for 40
min. The reaction was filtered and concentrated. The residue was
dissolved in EtOH (5 mL) and PPTS (25 mg, 0.10 mmol) was added. The
mixture was heated at 60.degree. C. overnight. The reaction was
concentrated and purified by liquid chromatography (6%
MeOH/CH.sub.2Cl.sub.2) to give the second intermediate compound as
a white solid (282 mg, 1.20 mmol, 79%). MS: APCI: M+1: 235.1 (Exact
Mass: 234.10).
[1399] This intermediate was also prepared using the following
procedure: To a suspension of 60% NaH (83.6 g, 2.09 mol) in NMP (1
L) was added dry 1,4-butanediol (300 mL, 3.39 mol, concentrated
from toluene) dropwise to control foaming. The reaction temperature
increased to 50.degree. C. and the mixture was stirred at
60.degree. C. for 15 min. 7-Chloro-1H-[1,8]naphthyridin-2-one (146
g, 0.813 mol) was added with stirring and the reaction was heated
at 68.degree. C. for 20 h. CH.sub.3CN (5 L) was added and the
mixture was filtered and the filter cake was washed with CH.sub.3CN
(500 mL) and THF (500 mL). The filter cake was reslurried with THF
(3 L) and 3N HCl in MeOH (290 mL, 0.870 mol) was added. The mixture
was heated at 60.degree. C. for 1 h and then filtered through
celite washing with THF (1 L). The filtrate was concentrated to a
volume of 500 mL and THF (1.5 L), Darco (10 g) and magnesol (100
mL) was added. The mixture was stirred at 40.degree. C. for 30 min
and then filtered washing with THF (500 mL). The filtrate was
concentrated to 500 mL, CH.sub.3CN was added and the mixture was
concentrated to 1 L. The resulting solid was filtered, washed with
CH.sub.3CN (200 mL) and Et.sub.2O (300 mL) and dried at 50.degree.
C. to yield the second intermediate compound (101 g, 53%). The
filtrate upon standing gave additional crystals, which were
collected by filtration, washed and dried as before to give
additional second intermediate compound (17 g, total yield of
62%).
[1400] A third intermediate compound,
4-(7-Oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde, was
produced as follows: Using Swern oxidation: To a solution of oxalyl
chloride (0.12 mL, 1.32 mmol, 1.1 equiv) in CH2Cl2 (2.5 mL) cooled
to -78.degree. C. was added DMSO (0.18 mL, 2.6 mmol). The reaction
was stirred for 5 min and then
7-(4-hydroxy-butoxy)-1H-[1,8]naphthyridin-2-one (282 mg, 1.20 mmol)
was added as a solution in CH2Cl2 (4.5 mL) and DMSO (1.2 mL) via
cannula over 5 min. The DMSO was necessary to dissolve the alcohol.
The reaction was stirred for 15 min and Et3N (0.83 mL, 6.0 mmol, 5
equiv) was added. The reaction turned cloudy. The reaction was
allowed to stir at -78.degree. C. for 10 min and then warmed to RT.
After 30 min at RT, H2O was added and the mixture was extracted
with CH2Cl2. The organic layer was washed with brine, dried over
MgSO4 and concentrated to give the third intermediate compound as a
light brown oil (340 mg), which was used in the next reaction. MS:
APCI: M+1: 233.1 (Exact Mass: 232.08).
[1401] Using IBX oxidation: To a solution of
7-(4-hydroxy-butoxy)-1H-[1,8]naphthyridin-2-one (223 mg, 0.952
mmol) in DMSO (3 mL) was added a solution of IBX (400 mg, 1.43
mmol) in DMSO (4.8 mL, 0.3 M). The reaction was stirred at room
temperature for 6 h, cooled to 0.degree. C. and quenched with 5%
NaHCO.sub.3. The mixture was extracted with CH2Cl2 (4.times.). The
organic layer was washed with 5% NaHCO3, dried over MgSO4 and
concentrated to give the third intermediate compound as a pale
yellow solid (175 mg, 0.754 mmol, 79%). MS: APCI: M+1: 233.1 (Exact
Mass: 232.08).
[1402] A mixture of
4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (300
mg, 1.29 mmol) and 1-chroman-8-yl-piperazine bishydrochloride (395
mg, 1.36 mmol) were suspended in DCE (8 mL)/DMF (1 mL) and Et3N
(0.54 mL, 3.88 mmol) was added. After about 10 min, NaBH(OAc)3 (356
mg, 1.68 mmol) was added and the reaction was stirred at room
temperature for 2 h. The reaction was quenched with saturated
NaHCO.sub.3 and extracted with EtOAc. The organic layer was washed
with saturated NaHCO3 and brine, dried over Na2SO4 and
concentrated. Purification by liquid chromatography (5% MeOH/CH2Cl2
with 0.5% NH4OH) gave the title compound as a white foam (364 mg,
0.838 mmol, 65%). The foam was dissolved in THF/Et2O and 1N HCl in
Et2O (0.84 mL) was added. The resulting precipitate was collected
by filtration, washed with Et.sub.2O and dried to give a white
solid (368 mg). MS: APCI: M+1: 435.2 (Exact mass: 434.23).
Example B2'
Synthesis of
7-{4-[4-(2,2-Dimethyl-2H-chromen-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]na-
phthyridin-2-one
[1403] The reductive amination procedure from Example B1' was
followed using 1-(2,2-dimethyl-2H-chromen-8-yl)-piperazine to give
the title compound. MS: APCI: M+1: 461.2 (Exact mass: 460.25).
Example B3'
Synthesis of
7-{4-[4-(2,2-Dimethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]napht-
hyridin-2-one
[1404] The reductive amination procedure from Example B1' was
followed using 1-(2,2-dimethyl-chroman-8-yl)-piperazine to give the
title compound. MS: APCI: M+1: 463.2 (Exact mass: 462.26).
Example B4'
Synthesis of
7-{4-[4-(2-Methyl-2H-chromen-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphth-
yridin-2-one
[1405] The reductive amination procedure from Example B1' was
followed using 1-(2-methyl-2H-chromen-8-yl)-piperazine to give the
title compound. MS: APCI: M+1: 447.3 (Exact mass: 446.23).
Example B5'
Synthesis of
7-{4-[4-(2-Methyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyri-
din-2-one
[1406] The reductive amination procedure from Example B1' was
followed using 1-(2-methyl-chroman-8-yl)-piperazine to give the
title compound. MS: APCI: M+1: 449.3 (Exact mass: 448.25).
Example B6'
Synthesis of
7-{4-[4-(Spiro[chromene-2,1'-cyclopentan]-8-yl)-piperazin-1-yl]-butoxy}-1-
H-[1,8]naphthyridin-2-one
[1407] The reductive amination procedure from Example B1' was
followed using 1-spiro[chromene-2,1'-cyclopentan]-8-ylpiperazine to
give the title compound. MS: APCI: M+1: 487.2 (Exact mass:
486.26).
Example B7'
Synthesis of
7-{4-[4-(3,4-Dihydrospiro[chromene-2,1'-cyclopentan]-8-yl)-piperazin-1-yl-
]-butoxy}-1H-[1,8]naphthyridin-2-one
[1408] The reductive amination procedure from Example B1' was
followed using
1-(3,4-dihydrospiro[chromene-2,1'-cyclopentan]-8-yl)piperazine to
give the title compound. MS: APCI: M+1: 489.3 (Exact mass:
488.28).
Example B8'
Synthesis of
7-{4-[4-(2,3-Dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]nap-
hthyridin-2-one
[1409] The reductive amination procedure from Example B1' was
followed using 1-(2,3-dihydro-benzofuran-7-yl)-piperazine to give
the title compound. MS: APCI: M+1: 421.2 (Exact mass: 420.22).
Example B9'
Synthesis of
7-{4-[4-(2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy-
}-1H-[1,8]naphthyridin-2-one
[1410] The reductive amination procedure from Example B1' was
followed using
1-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-piperazine to give the
title compound. MS: APCI: M+1: 449.2 (Exact mass: 448.25).
Example B10'
Synthesis of
7-[4-(4-Chroman-5-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one
[1411] The reductive amination procedure from Example B1' was
followed using 1-chroman-5-yl-piperazine to give the title
compound. MS: APCI: M+1: 435.3 (Exact mass: 434.23).
Example B 11'
Synthesis of
7-{4-[4-(2,3-Dihydro-benzofuran-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]nap-
hthyridin-2-one
[1412] The reductive amination procedure from Example B1' was
followed using 1-(2,3-dihydro-benzofuran-4-yl)-piperazine to give
the title compound. MS: APCI: M+1: 421.2 (Exact mass: 420.22).
Example B12'
Synthesis of
7-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-1H-[1-
,8]naphthyridin-2-one
[1413] The reductive amination procedure from Example B1' was
followed using 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine to
give the title compound. MS: APCI: M+1: 437.2 (Exact mass:
436.21).
Example B13'
Synthesis of
7-{4-[4-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-piperazin-1-yl]-butoxy}-1H-[-
1,8]naphthyridin-2-one
[1414] The reductive amination procedure from Example B1' was
followed using 1-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-piperazine to
give the title compound. MS: APCI: M+1: 459.2 (Exact mass:
458.18).
Example B14'
Synthesis of
7-{4-[4-(1,3-Dihydro-isobenzofuran-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]-
naphthyridin-2-one
[1415] To a suspension of
4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
(0.257 g, 1.107 mmol, 1.1 eq) and
1-(1,3-dihydro-isobenzofuran-4-yl)-piperazine (0.204 g, 0.998 mmol,
1 eq) in dichloroethane (5 mL) was added NaBH(OAc).sub.3 (0.433 g,
2.043 mmol, 1.84 eq). The slurry was allowed to stir overnight at
room temperature (18 h). The mixture was diluted with EtOAc and
quenched with saturated NaHCO.sub.3. The organic phase was then
washed with brine, dried over Na.sub.2SO.sub.4, filtered and
evaporated in vacuo. Purification by silica gel chromatography (2%
MeOH/CH.sub.2Cl.sub.2) followed by formation of the HCl salt using
1N HCl in ether provided the title compound (0.064 g, 12%). CHN
Found: C, 64.37; H, 6.54; N, 12.13. This calculates out for
C.sub.24H.sub.28N.sub.4O.sub.30.74HCl.
Example B15'
Synthesis of
7-{4-[4-(4-Oxo-chroman-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-
-2-one
[1416] The reductive amination procedure from Example B1' was
followed using 8-piperazin-1-yl-chroman-4-one to give the title
compound (0.22 g, 48%). .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
9.00 (br s, 1H), 7.75 (d, 1H), 7.60 (m, 2H), 7.10 (d, 1H), 7.00 (t,
1H), 6.60 (d, 1H), 6.50 (d, 1H), 4.60 (t, 2H), 4.40 (t, 2H), 3.10
(br s, 4H), 2.80-2.40 (m, 8H), 1.90-1.70 (m, 4H).
Example B16'
Synthesis of
7-{4-[4-(3,3-Dimethyl-4-oxo-chroman-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8-
]naphthyridin-2-one
[1417] The reductive amination procedure from Example B1' was
followed using 3,3-dimethyl-8-piperazin-1-yl-chroman-4-one to give
the title compound (0.30 g, 55%). .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 9.90 (br s, 1H), 7.71 (d, 1H), 7.63 (d, 1H),
7.60-7.58 (m, 1H), 7.10 (d, 1H), 6.98-6.94 (m, 1H), 6.60 (d, 1H),
6.54 (d, 1H), 4.20 (t, 2H), 4.22 (s, 2H), 3.12 (br s, 4H), 2.72 (br
s, 4H), 2.52 (t, 2H), 1.87-1.71 (m, 4H), 1.21 (s, 6H).
Example B1 7'
Synthesis of
7-{4-[4-(3.3-Dimethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]napht-
hyridin-2-one
[1418] The reductive amination procedure from Example B1' was
followed using 1-(3,3-dimethyl-chroman-8-yl)-piperazine to give the
title compound (0.30 g, 54%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.39 (br s, 1H), 7.71 (d, 1H), 7.63 (d, 1H), 6.80-6.78 (m,
2H), 6.71-6.69 (m, 1H), 6.58 (d, 1H), 6.52 (d, 1H), 4.38 (t, 2H),
3.82 (s, 2H), 3.09 (br s, 4H), 2.69 (br s, 4H), 2.55 (s, 2H), 2.48
(t, 2H), 1.86-1.66 (m, 6H), 1.02 (s, 6H).
Example B18'
Synthesis of
7-[4-(4-Isochroman-5-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-on-
e
[1419] The reductive amination procedure from Example B1' was
followed using 1-isochroman-5-yl-piperazine to give the title
compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.05 (br s,
1H), 7.72 (d, J=8.0 Hz, 1H), 7.63 (d, J=9.0 Hz, 1H), 7.16 (t, J=7.0
Hz, 1H), 6.92 (d, J=7.0 Hz, 1H), 6.72 (d, J=7.0 Hz, 1H), 6.60 (dd,
J=1.0 Hz, J=8.0 Hz, 1H), 6.52 (d, J=9.0 Hz, 1H), 4.80 (s, 2H), 4.39
(t, J=6.0 Hz, 2H), 3.93 (t, J=5.0 Hz, 2H), 2.96 (br s, 4H), 2.81
(t, J=5.0 Hz, 2 H), 2.63 (br s, 2H), 2.49 (s, 2H), 1.87-1.82 (m,
2H), 1.72-1.61 (m, 2H). MS (ES) m/z. 435.23 (M+1).sup.+ (Exact
mass: 434.23).
Example B19'
Synthesis of
7-[4-(4-Isochroman-8-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-on-
e
[1420] The reductive amination procedure from Example B1' was
followed using 1-isochroman-8-yl-piperazine to give the title
compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.14 (br s,
1H), 7.72 (d, J=8.0 Hz, 1H), 7.63 (d, J=9.0 Hz, 1H), 7.16 (t, J=7.0
Hz, 1H), 6.94 (d, J=7.0 Hz, 1H), 6.88 (d, J=7.0 Hz, 1H), 6.60 (d,
J=8.0 Hz, 1H), 6.52 (d, J=9.0 Hz, 1H), 4.78 (s, 2H), 4.39 (t, J=6.0
Hz, 2 H), 3.96 (t, J=5.0 Hz, 2H), 2.91-2.86 (m, 4H), 2.61 (br s,
2H), 2.50 (t, J=7.8 Hz, 2H), 1.88-1.81 (m, 2H), 1.75-1.68 (m, 2H).
MS (ES) m/z: 435.23 (M+1).sup.+ (Exact mass: 434.23).
Example B20'
Synthesis of
7-{4-[4-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-piperazin-1-yl]-butox-
y}-1H-[1,8]naphthyridin-2-one
[1421] In a manner similar to that of other examples above,
1-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-piperazine
hydrochloride (J. Med. Chem. 1988, 31, 1934-1940) was coupled by
reductive amination to
4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
followed by typical workup and purification to give the title
compound. MS: APCI: M+1: 451.2 (Exact Mass: 450.23).
Example B21'
Synthesis of
7-[4-(4-Quinolin-8-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one
[1422] The reductive amination procedure from Example B1' was
followed using 8-piperazin-1-yl-quinoline to give the title
compound. MS: APCI: M+1: 430.3 (Exact mass: 429.22).
Example B22'
Synthesis of
7-[4-(4-Quinolin-5-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one
[1423] The reductive amination procedure from Example B1' was
followed using 5-piperazin-1-yl-quinoline to give the title
compound. MS: APCI: M+1: 430.2 (Exact mass: 429.22).
Example B23'
Synthesis of
7-[4-(4-Quinoxalin-5-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-on-
e
[1424] The reductive amination procedure from Example B1' was
followed using 5-piperazin-1-yl-quinoxaline to give the title
compound. MS: APCI: M+1: 431.2 (Exact mass: 430.21).
Example B24'
Synthesis of
7-{4-[4-(1H-Indol-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-on-
e
[1425] The reductive amination procedure from Example B1' was
followed using 4-piperazin-1-yl-1H-indole to give the title
compound. MS: APCI: M+1: 418.2 (Exact mass: 417.22).
Example B25'
Synthesis of
7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridi-
n-2-one
[1426] The reductive amination procedure from Example B1' was
followed using 1-benzo[b]thiophen-4-yl-piperazine to give the title
compound. MS: APCI: M+1: 435.2 (Exact mass: 434.18).
Example B26'
Synthesis of
7-[4-(4-Benzofuran-7-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-on-
e
[1427] The reductive amination procedure from Example B1' was
followed using 1-benzofuran-7-yl-piperazine to give the title
compound. MS: APCI: M+1: 419.2 (Exact mass: 418.20).
Example B27'
Synthesis of
7-{4-[4-(1-Acetyl-1,2,3,4-tetrahydro-quinolin-5-yl)-piperazin-1-yl]-butox-
y}-1H-[1,8]naphthyridin-2-one
[1428] A first intermediate compound
4-(1,2,3,4-Tetrahydro-quinolin-5-yl)-piperazine-1-carboxylic acid
tert-butyl ester, was produced as follows: To a stirred solution of
compound 4-quinolin-5-yl-piperazine-1-carboxylic acid tert-butyl
ester (3.0 g, 9.58 mmol) in methanol (60 mL) cooled to -5.degree.
C., was added nickel chloride hexahydrate (2.28 g, 9.58 mmol) and
sodium borohydride (1.45 g, 38.3 mmol). The resulting mixture was
stirred at room temperature overnight and quenched with saturated
ammonium chloride solution. Ethyl acetate (100 mL) was added and
the organic layer was separated. The aqueous layer was re-extracted
with ethyl acetate (2.times.100 mL). The combined organic extracts
were washed with brine, dried (Na.sub.2SO.sub.4) and the solvent
was removed in vacuo. The residue was purified by SiO.sub.2
chromatography using hexanes-ethyl acetate (2:1) as eluent to give
the first intermediate compound (1.82 g, 53%) as a solid. .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta. 6.95 (m, 1H), 6.38 (d, 1H), 6.25
(d, 1H), 3.58 (br s, 4H), 3.30 (t, 2H), 2.84 (br s, 4H), 2.72 (t,
2H), 1.88 (m, 2H), 1.45 (s, 9H).
[1429] A second intermediate compound,
4-(1-Acetyl-1,2,3,4-tetrahydro-quinolin-5-yl)-piperazine-1-carboxylic
acid tert-butyl ester, was produced as follows: To a stirred
solution of
4-(1,2,3,4-tetrahydro-quinolin-5-yl)-piperazine-1-carboxylic acid
tert-butyl ester (1.38 g, 4.35 mmol) in dichloromethane (30 mL) at
0.degree. C., was added triethylamine (0.79 g, 7.83 mmol) and
acetic anhydride (0.67 g, 6.53 mmol). The resulting mixture was
stirred at room temperature overnight and diluted with additional
dichloromethane (50 mL). Water was added and the organic layer was
separated. The aqueous layer was re-extracted with dichloromethane.
The combined organic extracts were washed brine, dried
(Na.sub.2SO.sub.4) and the solvent was removed in vacuo. The
residue was purified by silica gel chromatography using
hexanes-ethyl acetate (1:2) as eluent to give the second
intermediate compound (1.50 g, 97%) as a foam. .sup.1H NMR (400
MHz, CDCl.sub.3): .delta. 7.20 (m, 1H), 6.83 (br, 1H), 6.80 (d,
1H), 3.80 (t, 2H), 3.50 (br s, 4H), 2.85 (br s, 4H), 2.62 (t, 2H),
2.25 (s, 3H), 1.90 (t, 2H), 1.50 (s, 9H).
[1430] A third intermediate compound,
1-(5-Piperazin-1-yl-3,4-dihydro-2H-quinolin-1-yl)-ethanone, was
produced as follows: To a stirred solution of
4-(1-acetyl-1,2,3,4-tetrahydro-quinolin-5-yl)-piperazine-1-carboxylic
acid tert-butyl ester (0.90 g, 2.51 mmol) in dichloromethane (15
mL) cooled to 0.degree. C., was added trifluoroacetic acid (2.86 g,
25.08 mmol). The resulting mixture was stirred at room temperature
overnight and the solvent was removed in vacuo. The solid formed
upon addition of diethyl ether was filtered to give the third
intermediate compound (0.82 g, 88%). .sup.1H NMR (400 MHz,
DMSO-d6): .delta. 8.84 (br s, 1H), 7.20 (br s, 2H), 6.82 (d, 2H),
3.64 (t, 2H), 3.24 (br s, 4H), 3.08 (br s, 4H), 2.64 (t, 2H), 2.20
(s, 3H), 1.80 (t, 2H). MS ES: m/z 260.15 (M+H).sup.+ (Exact mass:
259.17).
[1431] The reductive amination procedure from Example B1' was
followed using
1-(5-piperazin-1-yl-3,4-dihydro-2H-quinolin-1-yl)-ethanone to give
the title compound. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.92
(s, 1H), 7.75 (d, 1H), 7.65 (d, 1H), 7.18 (m, 1H), 6.90 (m, 2H),
6.60 (d, 1H), 6.50 (d, 1H), 4.40 (t, 2H), 3.75 (t, 2H), 2.95 (br s,
4H), 2.65 (br s, 4H), 2.50 (t, 2H), 2.20 (s, 3H), 1.90 (m, 4H),
1.70 (m, 2H). MS ES: m/z 476.2 (M+H).sup.+ (Exact mass:
475.26).
Example B28'
Synthesis of
7-{4-[4-(1-Methyl-1,2,3,4-tetrahydro-quinolin-5-yl)-piperazin-1-yl]-butox-
y}-1H-[1,8]naphthyridin-2-one
[1432] The reductive amination procedure from Example B1' was
followed using
1-methyl-5-piperazin-1-yl-1,2,3,4-tetrahydro-quinoline to give the
title compound. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 9.75 (br
s, 1H), 7.70 (d, 1H), 7.65 (d, 1H) 7.05 (t, 1H), 6.62 (d, 1H), 6.58
(d, 1H), 6.42 (2H), 4.40 (t, 2H), 3.22 (t, 2H), 2.95 (br s, 4H),
2.85 (s, 3H), 2.80-2.45 (m, 8H), 1.95-1.65 (6H). MS ES: m/z 448.12
(M+H).sup.+ (Exact mass: 447.26).
Example B29'
Synthesis of
7-{4-[4-(1-Ethyl-1,2,3,4-tetrahydro-quinolin-5-yl)-piperazin-1-yl]-butoxy-
}-1H-[1,8]naphthyridin-2-one
[1433] The reductive amination procedure from Example B1' was
followed using
1-ethyl-5-piperazin-1-yl-1,2,3,4-tetrahydro-quinoline to give the
title compound. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 12.80
(br s, 1H), 7.70 (d, 1H), 7.65 (d, 1H), 7.25 (m, 2H), 7.05 (br s,
1H) 6.62 (d, 1H), 6.59 (d, 1H), 4.40 (m, 2H), 3.65 (m, 4H), 3.45
(m, 4H), 3.25-3.00 (m, 8H), 2.80 (m, 2H), 2.25-1.85 (m, 4H), 1.30
(t, 3H). MS ES: m/z 462.12 (M+H).sup.+ (Exact mass: 461.28).
Example B30'
Synthesis of
7-{4-[4-(2-Methoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthy-
ridin-2-one
[1434] The reductive amination procedure from Example B1' was
followed using 2-methoxy-8-piperazin-1-yl-quinoline to give the
title compound (0.73 g, 92%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.00 (br. s, 1H), 7.98 (d, 1H), 7.75 (d, 1H), 7.62 (d, 1H),
7.38 (d, 1H), 7.30 (t, 1H), 7.10 (d, 1H), 6.90 (d, 1H), 6.60 (d,
1H), 6.50 (d, 1H), 4.40 (t, 2H), 4.05 (s, 3H), 3.50 (br. s, 4H),
2.82 (m, 6H), 2.68 (t, 2H), 2.50 (dd, 2H), 1.82 (m, 2H), 1.78 (m,
2H).
Example B31'
Synthesis of
7-{4-[4-(2-Ethoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyr-
idin-2-one
[1435] The reductive amination procedure from Example B1' was
followed using 2-ethoxy-8-piperazin-1-yl-quinoline to give the
title compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.06
(brs, 1H), 7.98 (d, 1H), 7.75 (d, 1H), 7.62 (d, 1H), 7.38 (d, 1H),
7.30 (t, 1H), 7.10 (d, 1H), 6.90 (d, 1H), 6.65 (d, 1H), 6.55 (d,
1H), 4.58 (t, 2H), 4.40 (t, 2H), 3.50 (brs, 4H), 2.82 (m, 4H), 2.58
(t, 2H), 1.90 (m, 2H), 1.80 (m, 2H), 1.60 (t, 3H); MS (ES): m/z:
474.26 (M+H).sup.+ (Exact mass: 473.24).
Example B32'
Synthesis of
7-{4-[4-(2-Dimethylamino-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]n-
aphthyridin-2-one
[1436] The reductive amination procedure from Example B1' was
followed using dimethyl-(8-piperazin-1-yl-quinolin-2-yl)-amine to
give the title compound (0.144 g; 51%). MS: APCI: M+1: 473.2 (Exact
mass: 472.26).
Example B33'
Synthesis of
7-{4-[4-(2-Methylamino-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]nap-
hthyridin-2-one
[1437] The reductive amination procedure from Example B1' was
followed using methyl-(8-piperazin-1-yl-quinolin-2-yl)-amine to
give the title compound (0.282 g; 70%). MS: APCI: M+1: 459.3 (Exact
mass: 458.24).
Example B34'
Synthesis of
7-{4-[4-(3-Fluoro-quinolin-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyr-
idin-2-one
[1438] The reductive amination procedure from Example B1' was
followed using 3-fluoro-5-piperazin-1-yl-quinoline to give the
title compound (433 mg, 66%). .sup.1H NMR (400 MHz, dmso-d.sub.6)
.delta. 12.00 (s, 1H), 8.90 (s, 1H), 8.05 (d, 1H), 8.00 (d, 1H),
7.80 (d, 1H), 7.76 (d, 1H), 7.64 (t, 1H), 7.24 (d, 1H), 6.62 (d,
1H), 6.38 (s, 1H), 4.40 (t, 2H), 3.05-2.90 (m, 4H), 2.80-2.60 (m,
4H), 2.44 (t, 2H), 1.82-1.70 (m, 2H), 1.70-1.60 (m, 2H), MS ES+
448.23 (M+1).sup.+ (Exact mass: 447.21).
Example B35'
Synthesis of
7-{4-[4-(3-Fluoro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyr-
idin-2-one
[1439] The reductive amination procedure from Example B1' was
followed using 3-fluoro-8-piperazin-1-yl-quinoline to give the
title compound (420 mg, 66%). MS ES+ 448.16 (M+1).sup.+ (Exact
mass: 447.21).
Example B36'
Synthesis of
7-{4-[4-(2-Oxo-1,2-dihydro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8-
]naphthyridin-2-one
[1440] In a manner similar to that of other examples above,
8-piperazin-1-yl-1H-quinolin-2-one hydrochloride (Chem. Pharm.
Bull. 1984, 32, 2100-2110) was coupled by reductive amination to
4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
followed by typical workup and purification to give the title
compound. MS: APCI: M+1: 446.2 (Exact Mass: 445.21).
Example B37'
Synthesis of
7-{4-[4-(2-Oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazin-1-yl]-butoxy}--
1H-[1,8]naphthyridin-2-one
[1441] In a manner similar to that of other examples above,
8-piperazin-1-yl-3,4-dihydro-1H-quinolin-2-one hydrochloride (Chem.
Pharm. Bull. 1984, 32, 2100-2110) was coupled by reductive
amination to
4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
followed by typical workup and purification to give the title
compound. MS: APCI: M+1: 448.3 (Exact Mass: 447.23).
Example B38'
Synthesis of
7-{4-[4-(1-Methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazin-1-yl]-
-butoxy}1H-[1,8]naphthyridin-2-one
[1442] In a manner similar to that of other examples above,
1-methyl-8-piperazin-1-yl-3,4-dihydro-1H-quinolin-2-one
hydrochloride was coupled by reductive amination to
4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
followed by typical workup and purification to give the title
compound. MS: APCI: M+1: 462.2 (Exact Mass: 461.24).
Example B39'
Synthesis of
7-[4-(4-Benzo[1,2,5]oxadiazol-4-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphth-
yridin-2-one
[1443] The reductive amination procedure from Example B1' was
followed using 4-piperazin-1-yl-benzo[1,2,5]oxadiazole
hydrochloride (Vogel, Martin; Karst, Uwe. (2001) DE 19936731) to
give the title compound (0.161 g; 45%). MS: APCI: M+1: 421.2 (Exact
mass: 420.19).
Example B40'
Synthesis of
7-[4-(4-Benzo[1,2,5]thiadiazol-4-yl-piperazin-1-yl)-butoxy]-1H-[1,8]napht-
hyridin-2-one
[1444] The reductive amination procedure from Example B1' was
followed using 4-piperazin-1-yl-benzo[1,2,5]thiadiazole (Lowe, John
A., Ill.; Nagel, Arthur A. (1989), U.S. Pat. No. 4,831,031) to give
the title compound (0.336 g; 60%). MS: APCI: M+1: 439.2 (Exact
mass: 438.17).
Example B41'
Synthesis of
7-{4-[4-(2-Trifluoromethyl-3H-benzoimidazol-4-yl)-piperazin-1-yl]-butoxy}-
-1H-[1,8]naphthyridin-2-one
[1445] To a suspension of
4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde
(0.211 g, 0.908 mmol, 1.29 eq) and
4-piperazin-1-yl-2-trifluoromethyl-1H-benzoimidazole (0.190 g,
0.703 mmol, 1 eq) in dichloroethane (5 mL) was added
NaBH(OAc).sub.3 (0.558 g, 2.631 mmol, 3.74 eq). The slurry was
allowed to stir overnight at room temperature (18 h). The mixture
was diluted with EtOAc and quenched with saturated NaHCO.sub.3. The
organic phase was then washed with brine, dried over
Na.sub.2SO.sub.4, filtered and evaporated in vacuo. Purification by
silica gel chromatography (2% MeOH/CH.sub.2Cl.sub.2) followed by
formation of the HCl salt using 1N HCl in ether provided the title
compound (0.230 g, 62%). MS: APCI: M+1: 487.1 (Exact Mass:
486.20).
Example C1'
Synthesis of
4,4-Dimethyl-7-[4-(4-quinolin-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-
-[1,8]naphthyridin-2-one
[1446] A first intermediate compound 3-Methyl-but-3-enoic acid
(6-amino-pyridin-2-yl)-amide, was produced as follows:
2,5-Diaminopyridine (70 g, 0.641 mol) was dissolved in 2100 mL THF
in a 5 L 4-neck flask equipped with mechanical stirring, N.sub.2
line and a 500 mL addition funnel. Et.sub.3N (447 mL, 5 eq.) was
added to the reaction flask. 3,3-Dimethylacryloyl chloride (76 g,
0.641 mol) was diluted with 700 mL THF and this solution was added
dropwise to the reaction flask. The moderate exotherm observed was
controlled with an ice/water bath to maintain a temperature
<15.degree. C. After the addition was complete, the reaction was
allowed to warm to room temperature and stirred under N.sub.2 for
1.5 h. The reaction mixture was concentrated and CH.sub.2Cl.sub.2
was added. The CH.sub.2Cl.sub.2 solution was washed with H.sub.2O
and the aqueous layer was back extracted with CH.sub.2Cl.sub.2. The
organic layers were combined and dried over Na.sub.2SO.sub.4,
filtered and concentrated to an oil. The crude product was purified
by column chromatography using a gradient mobile phase of 10%-30%
EtOAc in hexanes. All fractions containing the desired product were
pooled and concentrated to an oil. NMR analysis of the product
indicated the product was a 1:1 mixture of 2 isomers, the alpha
beta unsaturated and the beta gamma unsaturated isomer resulting in
first intermediate compound (90.0 g, 0.47 mol, 73%). MS: APCI: M+1:
192.0 (Exact Mass: 191.11).
[1447] A second intermediate compound,
7-Amino-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one, was
produced as follows: 3-Methyl-but-3-enoic acid
(6-amino-pyridin-2-yl)-amide (49.2 g, 0.26 mol) was dissolved in
500 mL CH.sub.2Cl.sub.2 in a 1000 mL 3-neck flask equipped with
mechanical stirring, a 125 mL addition funnel and a thermal couple.
While stirring, MeSO.sub.3H (50 mL, 0.78 mol) was added to the
flask dropwise. The exotherm upon addition was controlled to
maintain a temperature <20.degree. C. by an ice/water bath. The
mixture was allowed to stir for 15 minutes. AlCl.sub.3 (274 g, 2.08
mol) was suspended in 1500 mL CH.sub.2Cl.sub.2 in a 5 L 4-neck
flask equipped with mechanical stirring, 1000 mL addition funnel,
N.sub.2 line and a thermal couple. To this suspension, the amide
solution was added dropwise. The exotherm from the addition was
again controlled to maintain a temperature <20.degree. C. with
an ice/water bath. The reaction was allowed to warm to room
temperature and stir overnight. The reaction had consumed all the
beta gamma unsaturated isomer and was deemed complete. The reaction
mixture was slowly added to ice as an inverse quench. The quenched
mixture was brought to pH 8-10 with 2 N KOH. The salts precipitated
out of solution and saturated the aqueous phase. The suspension was
transferred to a separatory funnel and extracted twice with 100:8:1
CH.sub.2Cl.sub.2:EtOH:NH.sub.4OH. The organic layers were combined,
dried over Na.sub.2SO.sub.4, filtered and concentrated to a crude
solid. The solid was triturated with EtOAc and filtered. The
resulting solids were pure second intermediate compound (22.4 g,
0.117 mol, 46%). MS: APCI: M+1: 192.2 (Exact Mass: 191.11).
[1448] A third intermediate compound,
7-Fluoro-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one, was
produced as follows: HF-pyridine (100 mL) was cooled to -42.degree.
C. in a 1000 mL HDPE bottle using an CH.sub.3CN dry ice bath. While
stirring vigorously,
7-amino-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one (24.6
g, 0.129 mol) was added portionwise to control the exotherm. After
the addition, NaNO.sub.2 (8.9 g, 0.1291 mol) was added portionwise.
Significant exotherms were observed for both additions. The
reaction mixture was then allowed to warm to 0.degree. C. and stir
for 2 h. The reaction mixture was quenched into a 4 L HDPE bottle
full of ice. The aqueous slurry was then neutralized using 2 N KOH.
The resulting aqueous solution was extracted 3 times with
CH.sub.2Cl.sub.2. The organic layers were dried over
Na.sub.2SO.sub.4, filtered and concentrated to dryness. Excess
pyridine was azeotroped with heptane. The product was dried under
vacuum (2 mm Hg) for 3 h. The third intermediate compound was
isolated as a white powder (23.06 g, 0.119 mol, 92%). MS: APCI:
M+1: 195.1 (Exact Mass: 194.09).
[1449] A fourth intermediate compound,
7-(4-Hydroxy-butoxy)-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one,
was produced as follows: The
7-fluoro-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one (5.09
g, 26.2 mmol) and butane-1,4-diol (11.81 g, 131.0 mmol) were
combined in a dried 2-necked flask under N.sub.2. NMP (50 mL) was
added and the solution was heated in an oil bath to 70.degree. C.
overnight. The reaction was cooled to room temperature and poured
into ice water. The solid that formed was collected and triturated
in acetonitrile to give the fourth intermediate compound as a tan
powder (1.72 g). The mother liquor was extracted with
CH.sub.2Cl.sub.2, dried over Na.sub.2SO.sub.4, filtered and
purified by MPLC (gradient of 100% CH.sub.2Cl.sub.2 to 100% ethyl
acetate). The compound was isolated as a mixture with diol
byproducts. The fourth intermediate compound was formed as clear
crystals (1.09 g) after recrystallization in acetonitrile and
another 340 mg was obtained from a second recrystallization. The
products were combined to give a total of 3.15 g of the fourth
intermediate compound (11.9 mmol, 45.5%). MS: APCI: M+1: 265.1
(Exact Mass: 264.15).
[1450] A fifth intermediate compound,
4-(5,5-Dimethyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyr-
aldehyde, was produced as follows:
7-(4-Hydroxy-butoxy)-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one
(1.72 g, 6.51 mmol) was dissolved in ethyl acetate (50 mL, 0.14 M
solution) and IBX (13 g, 46.4 mmol) was added. The suspension was
immersed in an oil bath set at 80.degree. C. and stirred vigorously
with a condenser. After 1.5 h, the reaction mixture was cooled to
room temperature and filtered. The filtrate was concentrated to
give the fifth intermediate compound as a tan solid (1.62 g, 6.18
mmol, 95%). MS: APCI: M+1: 263.1 (Exact Mass: 262.13).
[1451] The naphthyridinones of Examples C1'-C6' were synthesized in
a combinatorial library format by reductive amination of the
appropriate piperazine starting materials with
4-(5,5-dimethyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyr-
aldehyde using the following general procedure.
[1452] The aldehyde (0.3 mmol) and the piperazine (60.306 mmol)
were combined in methylene chloride and stirred in a vial over
sieves for 10 min. Sodium triacetoxyborohydride (0.42 mmol) was
added and the reaction was stirred overnight. The reaction was
quenched by slowly adding water and then the mixture was filtered.
The residue was partitioned between CH.sub.2Cl.sub.2 and water and
the organic layer was concentrated. Purification by liquid
chromatography (MPLC, gradient of 100% CH.sub.2Cl.sub.2 to 100% of
a 10% MeOH in CH.sub.2Cl.sub.2 solution) gave the title compound.
The final products were made into hydrochloride salts by treatment
with a solution of saturated HCl in MeOH.
[1453] The title compound was isolated as a foam (207 mg, 0.451
mmol, 75.1%). MS: APCI: M+1: 460.2 (Exact Mass: 459.26).
Example C2'
Synthesis of
7-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-4,4-d-
imethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one
[1454] The title compound was isolated as a white solid (91 mg,
0.195 mmol, 39.2%). MS: APCI: M+1: 467.2 (Exact Mass: 466.26).
Example C3'
Synthesis of
4,4-Dimethyl-7-{4-[4-(2-oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazin-1-
-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one
[1455] The title compound was isolated as the hydrochloride salt
(101 mg, 0.196 mmol, 25.7%). MS: APCI: M+1: 478.3 (Exact Mass:
477.27).
Example C4'
Synthesis of
4,4-Dimethyl-7-{4-[4-(2-oxo-1,2-dihydro-quinolin-8-yl)-piperazin-1-yl]-bu-
toxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one
[1456] The title compound was isolated as the hydrochloride salt
(140 mg, 0.273 mmol, 35.8%). MS: APCI: M+1: 476.2 (Exact Mass:
475.26).
Example C5'
Synthesis of
7-[4-(4-Benzofuran-7-yl-piperazin-1-yl)-butoxy]-4,4-dimethyl-3,4-dihydro--
1H-[1,8]naphthyridin-2-one
[1457] The title compound was isolated as the hydrochloride salt
(105 mg, 0.216 mmol, 28.4%). MS: APCI: M+1: 449.3 (Exact Mass:
448.25).
Example C6'
Synthesis of
7-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-4,4-dimethyl-3,4-dihydro-1H--
[1,8]naphthyridin-2-one
[1458] The title compound was isolated as a white solid (221 mg,
0.476 mmol, 56.7%). MS: APCI: M+1: 465.2 (Exact Mass: 464.28).
Example D1'
Synthesis of
6-Fluoro-7-[4-(4-quinolin-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,-
8]naphthyridin-2-one
[1459] A first intermediate compound
6-(4-Benzyloxy-butoxy)-2-chloro-5-fluoro-nicotinonitrile, was
produced as follows: To a solution of 4-benzyloxy-1-butanol (19.44
g, 108 mmol) in THF (200 mL) cooled to -40.degree. C. was added 1M
KO.sup.tBu in THF (108 mL, 108 mmol). The mixture was stirred for 5
min at -10.degree. C. and then added to a solution of
2,6-dichloro-5-fluoro-nicotinonitrile (20.0 g, 105 mmol) in THF
(300 mL) cooled to -70.degree. C. over 25 min. The mixture turned
brownish yellow with some cloudiness. The reaction was allowed to
warm to room temperature over 2 h. The THF was evaporated and the
residue was diluted with Et.sub.2O. The mixture was washed with
water, brine, 1N citric acid, water and brine, dried over
Na.sub.2SO.sub.4 and concentrated to an oil. The oil was dissolved
in Et2O/hexanes and cooled in the refrigerator overnight. A
crystalline solid formed which was collected by filtration, washed
with hexanes and dried to give the first intermediate compound as a
white solid (17.0 g). The filtrate was concentrated and purified by
silica gel chromatography (Biotage 40L, 0-6% EtOAc/Hexanes) to give
additional first intermediate compound as a white solid (total of
26.9 g, 80.4 mmol, 77%). MS: APCI: M+1: 335.1 (Exact Mass:
334.09).
[1460] A second intermediate compound,
2-Azido-6-(4-benzyloxy-butoxy)-5-fluoro-nicotinonitrile, was
produced as follows: To a solution of
6-(4-benzyloxy-butoxy)-2-chloro-5-fluoro-nicotinonitrile (20.0 g,
60.0 mmol) in DMF (40 mL) was added sodium azide (4.27 g, 65.7
mmol) and the mixture was heated at 70.degree. C. overnight. The
mixture was poured into Et.sub.2O and washed with water and brine.
The Et.sub.2O solution was passed through a silica gel Biotage 12M
column, dried over MgSO.sub.4 and charcoal, and concentrated to
give an oil (19.67 g). Recrystallization from Et.sub.2O/MeOH gave
the second intermediate compound as a solid (17.24 g, 50.5 mmol,
84%). MS: APCI: M+1: (Exact Mass: 341.13).
[1461] A third intermediate compound,
2-Amino-6-(4-benzyloxy-butoxy)-5-fluoro-nicotinonitrile, was
produced as follows: To a solution of
2-azido-6-(4-benzyloxy-butoxy)-5-fluoro-nicotinonitrile (17.2 g,
50.4 mmol) in MeOH (450 mL) was added hexamethyldisilthiane (19.0
g, 106.5 mmol). The reaction gives off a gas and a precipitate
forms after 15 min. The reaction was stirred overnight at room
temperature and then filtered to remove the precipitated sulfur.
The mixture was concentrated and then redissolved in Et.sub.2O. The
mixture was filtered again to remove additional precipitated
sulfur. The filtrate was concentrated and recrystallized from
MeOH/hexanes. The solid was collected by filtration, washed with
hexane/MeOH and dried to give the third intermediate compound
(13.74 g, 43.57 mmol, 86%). MS: APCI: M+1: 316.4 (Exact Mass:
315.14).
[1462] A fourth intermediate compound,
2-Amino-6-(4-benzyloxy-butoxy)-5-fluoro-pyridine-3-carbaldehyde,
was produced as follows: To a solution of
2-amino-6-(4-benzyloxy-butoxy)-5-fluoro-nicotinonitrile (7.25 g,
23.0 mmol) in THF (40 mL) cooled to 0.degree. C. is added DIBALH
(1M in THF, 69 mL, 69 mmol). The reaction was complete after 5 min.
Chilled 2N HCl was added very slowly (strong exotherm) to quench
the reaction. The mixture forms a red gelatinous material.
Et.sub.2O was added and the layers were separated. The organic
layer was washed with brine and saturated NaHCO.sub.3 and then
filtered through Celite. There may still have been some aluminum
complexed product so the organic solution was washed again with 2N
HCl, brine, saturated NaHCO.sub.3 and brine, dried over MgSO.sub.4
and concentrated to give the crude fourth intermediate compound as
an orange oil (5.23 g, 16.4 mmol, 71%). MS: APCI: M+1: 319.2 (Exact
Mass: 318.14).
[1463] A fifth intermediate compound,
3-[2-Amino-6-(4-benzyloxy-butoxy)-5-fluoro-pyridin-3-yl]-acrylic
acid ethyl ester, was produced as follows: To a solution of
2-amino-6-(4-benzyloxy-butoxy)-5-fluoro-pyridine-3-carbaldehyde
(5.23 g, 16.4 mmol, crude from previous reaction) in THF (50 mL)
was added (carbethoxymethylene)triphenylphosphorane (5.72 g. 16.43
mmol) and the solution was heated at 67.degree. C. overnight. The
reaction was concentrated and the residue was purified by liquid
chromatography (Biotage 65M, 0-10% EtOAc/CH.sub.2Cl.sub.2) to give
the fifth intermediate compound as a yellow solid (73%). MS: APCI:
M+1: 389.4 (Exact Mass: 388.18).
[1464] A sixth intermediate compound,
7-(4-Benzyloxy-butoxy)-6-fluoro-3,4-dihydro-1H-[1,8]naphthyridin-2-one,
was produced as follows:
3-[2-Amino-6-(4-benzyloxy-butoxy)-5-fluoro-pyridin-3-yl]-acrylic
acid ethyl ester (7.18 g, 18.5 mmol) was hydrogenated under an
atmosphere of H.sub.2 (4300 psi) using Ra-Ni (2 g) in MeOH (100
mL). The reaction was filtered and concentrated. MS indicated the
double bond had been reduced and some of the material cyclized. The
material was suspended in .sup.iPrOH and p-toluenesulfonic acid
hydrate (0.41 g) was added. The mixture was heated at 80.degree. C.
for 30 min. Saturated NaHCO.sub.3 was added and the mixture was
concentrated. The residue was partitioned between Et.sub.2O and
water. The organic layer was washed with saturated NaHCO.sub.3 and
brine, dried over MgSO.sub.4 and concentrated to give a yellow oil
which solidified. Recrystallization from Et.sub.2O/hexane afforded
the sixth intermediate compound as a pale yellow solid. MS: APCI:
M+1: 345.1 (Exact Mass: 344.15).
[1465] A seventh intermediate compound,
6-Fluoro-7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one,
was produced as follows:
7-(4-Benzyloxy-butoxy)-6-fluoro-3,4-dihydro-1H-[1,8]naphthyridin-2-one
(4.79 g, 13.9 mmol) was hydrogenated under an atmosphere of H.sub.2
using 20% Pd/C (1.0 g) in EtOH (100 mL). The reaction was filtered
and concentrated to give a slurry. Et.sub.2O was added and the
solids were filtered. The filtrate was concentrated and the process
was repeated to give the seventh intermediate compound as a solid
(3.2 g, 13.0 mmol, 91%). MS: APCI: M+1: 255.1 (Exact Mass:
254.11).
[1466] A eighth intermediate compound,
4-(3-Fluoro-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyralde-
hyde, was produced as follows: To a solution of oxalyl chloride
(1.78 g, 14.0 mmol) in CH.sub.2Cl.sub.2 (25 mL) cooled to
-70.degree. C. was added a solution of DMSO (2.15 g, 27.6 mmol) in
CH.sub.2Cl.sub.2 (1.5 mL) over 4 min. The mixture was stirred for 5
min and a solution of
6-fluoro-7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one
(3.1 g, 12.0 mmol) in DMSO (4.5 mL) and CH.sub.2Cl.sub.2 (44 mL)
cooled to -50.degree. C. was added over 5 min. The mixture was
stirred for 10 min at -70.degree. C. and it solidified. The
reaction was warmed to -30.degree. C. and triethylamine (8.9 mL,
63.8 mmol) was added resulting in a stirable suspension. The
reaction was warmed to room temperature over 30 min. The mixture
was added to water and the layers were separated. The organic layer
was washed with water and dilute brine, dried over MgSO.sub.4 and
concentrated to give an oil. The residue was partitioned between
Et.sub.2O and aqueous citric acid (pH 4.5). The organic layer was
washed with dilute aqueous NaHCO.sub.3 and brine, dried over
MgSO.sub.4 and concentrated to give the eighth intermediate
compound as a yellow oil (1.89 g) which was used directly in the
next reaction. MS: APCI: M+1: 253.2 (Exact Mass: 252.09).
[1467] The title compound was prepared by reductive amination of
4-(3-fluoro-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyralde-
hyde with 8-piperazin-1-yl-quinoline using a procedure similar to
Example A1'. MS: APCI: M+1: 450.2 (Exact Mass: 449.22).
Example D2'
Synthesis of
6-Fluoro-7-[4-(4-isoquinolin-5-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H--
[1,8]naphthyridin-2-one
[1468] The title compound was prepared by reductive amination of
4-(3-fluoro-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyralde-
hyde with 5-piperazin-1-yl-isoquinoline using a procedure similar
to Example A1'. MS: APCI: M+1: 450.2 (Exact Mass: 449.22).
Example E1'
Synthesis of
7-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-1H-pyrido[2,3-d]pyrimidin-2--
one
[1469] A first intermediate compound
2-Amino-6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridine-3-carbaldehyde,
was produced as follows: A mixture of
N-{3-formyl-6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridin-2-yl}-2,2-dim-
ethyl-propionamide (9.8 g, 25.9 mmol), 2 N KOH (35 mL) and EtOH (40
mL) was heated at 80.degree. C. for 2 h. Ethanol was removed under
reduced pressure and the residue was extracted with EtOAc
(3.times.100 mL). The combined organic phases were washed with
H.sub.2O (40 mL) and brine (40 mL), dried over Na.sub.2SO.sub.4,
and concentrated to give the first intermediate compound as an oil
which was used in the next step without further purification.
.sup.1H NMR (400 MHz, CDCl3): .delta. 9.70 (s, 1H), 7.62 (d, 1H),
6.17 (d, 1H), 4.60 (m, 1H), 4.40 (m, 2H), 3.90 (m, 2H), 3.50 (m,
2H), 2.00-1.50 (m, 10H).
[1470] A second intermediate compound,
7-[4-(Tetrahydro-pyran-2-yloxy)-butoxy]-1H-pyrido[2,3-d]pyrimidin-2-one,
was produced as follows: To a solution of
2-amino-6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridine-3-carbaldehyde
obtained in the last step in CH.sub.2Cl.sub.2 (50 mL) was added
trichloroacetyl isocyanate (5.85 g, 31.08 mmol) dropwise. After the
addition was over, the mixture was stirred at room temperature for
1 h. To this mixture, MeOH (50 mL) and 1 N NaOH (40 mL) were added
successively. The mixture thus obtained was kept stirring at room
temperature for another 1 h. The solvent was then removed under
reduced pressure and the residue was extracted with
CH.sub.2Cl.sub.2 (3.times.100 mL). The combined organic phases were
washed with brine, dried and concentrated. The residue was
crystallized from ether to give the second intermediate compound
(6.6 g, 79% in two steps) as a pale yellow solid. .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 9.00 (s, 1H), 8.00 (d, 1H), 6.60 (d,
1H), 4.60 (m, 1H), 4.40 (m, 2H), 3.70 (m, 2H), 3.40 (m, 2H),
1.90-1.30 (m, 10H).
[1471] A third intermediate compound,
7-(4-Hydroxy-butoxy)-1H-pyrido[2,3-d]pyrimidin-2-one, was produced
as follows: A mixture of
7-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-1H-pyrido[2,3-d]pyrimidin-2-one
(4.9 g, 15 mmol), MeOH (30 mL), THF (15 mL) and 3 N HCl (7.5 mL)
was stirred at room temperature for 1 h. The mixture was
concentrated under reduced pressure. The residue was dissolved in
H.sub.2O (30 mL) and neutralized carefully with saturated
NaHCO.sub.3. The mixture was extracted with THF (5.times.100 mL).
The combined organic phases were washed with brine, dried and
concentrated to give the third intermediate compound (3.3 g, 90%)
which was used in the next step without further purification.
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.03 (s, 1H), 8.17 (d,
1H), 6.67 (d, 1H), 4.50 (m, 1H), 4.40 (m, 2H), 3.50 (m, 3H), 1.80
(m, 2H), 1.55 (m, 2H).
[1472] A fourth intermediate compound,
4-(2-Oxo-1,2-dihydro-pyrido[2,3-d]pyrimidin-7-yloxy)-butyraldehyde,
was produced as follows: A mixture of
7-(4-hydroxy-butoxy)-1H-pyrido[2,3-d]pyrimidin-2-one (0.512 g, 2.18
mmol) and IBX (1.9 g, 6.6 mmol) in CH.sub.3CN (40 mL) was heated at
87.degree. C. for 7 h. It was cooled to RT, diluted with EtOAc (80
mL) and filtered. The pad was washed thoroughly with EtOAc. The
combined filtrate was concentrated to give the fourth intermediate
compound as a solid which was contaminated with some byproduct from
the reaction. This solid was used in the next step without further
purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 12.18
(s, 1H), 9.77 (s, 1H), 8.20 (d, 1H), 6.70 (d, 1H), 4.40 (m, 2H),
2.70 (m, 2H), 2.00 (m, 2H).
[1473] To a mixture of
4-(2-oxo-1,2-dihydro-pyrido[2,3-d]pyrimidin-7-yloxy)-butyraldehyde
obtained in the last step, 1-chroman-8-yl-piperazine hydrochloride
(0.634 g, 2.18 mmol), Et.sub.3N (0.73 mL, 5.23 mmol) in
1-methyl-2-pyrrolidinone (20 mL) was added NaBH(OAc).sub.3 (0.514
g, 2.62 mmol) in portions over 20 min. The mixture was stirred
overnight. After quenching with H.sub.2O (50 mL), the reaction
mixture was extracted with CH.sub.2Cl.sub.2 (3.times.100 mL). The
combined organic phases were washed with brine (100 mL), dried and
concentrated. The residue was purified by chromatography on silica
gel to give a gum (520 mg). To a solution of this gum (200 mg) in
THF (2 mL) was added 1 N HCl (0.43 mL) in Et.sub.2O. The mixture
was stirred at room temperature for 30 min and filtered. The solid
was washed with Et.sub.2O and dried under vacuum to give the title
compound (190 mg) as a yellow solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): 6 12.30 (s, 1H), 9.20 (s, 1H), 8.20 (d, 1H), 7.80
(m, 4H), 4.45 (m, 2H), 4.20 (m, 2H), 3.60 (m, 4H), 3.20 (m, 2H),
3.00 (m, 2H), 2.00-1.70 (m, 6H).
Example E2'
Synthesis of
7-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-pyrido[2
3-d]pyrimidin-2-one
[1474] To a solution of
7-[4-(4-chroman-8-yl-piperazin-1-yl)-butoxy]-1H-pyrido[2,3-d]pyrimidin-2--
one (320 mg) in THF (6 mL) and MeOH (2 mL) was added NaBH.sub.4 (54
mg) in portions. After the addition was over, the mixture was kept
stirring overnight. The reaction was quenched with H.sub.2O. The
mixture was extracted with CH.sub.2Cl.sub.2 (3.times.50 mL). The
combined organic phases were dried over Na.sub.2SO.sub.4 and
concentrated. The residue was purified by chromatography on silica
gel to give a semi-solid which was converted to its HCl salt by
treating with 1 equivalent of 1 N HCl in a mixed solvent of THF and
Et.sub.2O to give the title compound (147 mg) as a white solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.20 (s, 1H), 7.40 (d,
1H), 6.98 (s, 1H), 7.70 (m, 3H), 6.25 (d, 1H), 4.30-4.06 (m, 6H),
3.60-3.30 (m, 4H), 3.15 (m, 4H), 3.00-2.70 (, 4H), 2.00-1.60 (m,
6H).
Example E3'
Synthesis of
7-{4-[4-(2,3-Dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-
-1H-pyrido[2,3-d]pyrimidin-2-one
[1475] To a mixture of
4-(2-oxo-1,2-dihydro-pyrido[2,3-d]pyrimidin-7-yloxy)-butyraldehyde,
1-(2,3-dihydro-benzofuran-7-yl)-piperazine hydrochloride (0.76 g,
2.58 mmol), Et.sub.3N (2.15 mL, 15.5 mmol) in
1-methyl-2-pyrrolidinone (20 mL) was added NaBH(OAc).sub.3 (0.76 g,
3.61 mmol) in portions over 20 min. After the addition was over,
the mixture was left stirring overnight. After quenching with
H.sub.2O (50 mL), the reaction mixture was extracted with
CH.sub.2Cl.sub.2 (3.times.100 mL). The combined organic layer was
washed with brine (100 mL), dried and concentrated. The residue was
purified by chromatography on silica gel to give a gum (290 mg). To
a solution of this gum in THF (6 mL) and MeOH (2 mL) was added
NaBH.sub.4 (63 mg) in portions. After the addition was over, the
mixture was kept stirring overnight. The reaction was quenched with
H.sub.2O. The mixture was extracted with CH.sub.2Cl.sub.2
(3.times.50 mL). The combined organic phases were dried over
Na.sub.2SO.sub.4 and concentrated. The residue was purified by
chromatography on silica gel to give a semi-solid which was
converted to the HCl salt by treating with 1 equivalent of 1 M HCl
in a mixed solvent of THF and Et.sub.2O to give the title compound
(147 mg) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 9.20 (s, 1H), 7.40 (d, 1H), 7.00 (s, 1H), 6.95 (d, 1H),
6.80 (m, 1H), 6.70 (d, 1H), 6.30 (d, 1H), 4.50 (t, 2H), 4.20 (m,
4H), 3.80-3.40 (m, 4H), 3.20-2.90 (m, 8H), 1.90-1.60 (m, 4H).
Example E4'
Synthesis of
7-{4-[4-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-piperazin-1-yl]-butox-
y}-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one
[1476] The procedure from Example E3' was followed using
1-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-piperazine to give
the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.25 (s, 1H), 7.40 (d, 1H), 6.90 (s, 1H), 6.80 (m, 1H), 6.60 (m,
2H), 6.25 (d, 1H), 4.30-4.00 (m, 8H), 3.60-3.40 (4H), 3.20-3.00 (m,
6H), 2.10 (m, 2H), 1.90-1.60 (m, 4H).
Example F1'
Synthesis of
6-{4-[4-(2-Methyl-quinolin-8-yl)-piperazin-1-yl]-butoxy}-4H-pyrido[3,2-b]-
[1,4]oxazin-3-one
[1477] A first intermediate compound
6-Amino-4H-pyrido[3,2-b][1,4]oxazin-3-one, was produced as follows:
A mixture of 6-nitro-4H-pyrido[3,2-b][1,4]oxazin-3-one (34.23 g,
0.1755 mol), 20% Pd--C (3.0 g, 50% H.sub.2O) and DMF (1 L) was
hydrogentated at 20 psi H.sub.2 pressure. After 2 h, uptake of
H.sub.2 ceased with 141 psi of H.sub.2 being absorbed. The reaction
mixture was filtered through a pad of Celite.RTM., washing with DMF
(500 mL). The filtrate was diluted with cold H.sub.2O (2 L) to give
a solid. The solid was collected, washed with H.sub.2O, slurried in
EtOH (150 mL), collected, washed with heptane and dried to give the
first intermediate compound (23.60 g, 81%) as a gray-tan solid.
[1478] A second intermediate compound,
6-Fluoro-4H-pyrido[3,2-b][1,4]oxazin-3-one, was produced as
follows: A 1 gallon Nalgene jar (with openings in the top for a
N.sub.2 inlet and addition of solids) was cooled in an ice/salt
bath and hydrogen fluoride-pyridine (500 g) was added. With
magnetic stirring and under a stream of N.sub.2,
6-amino-4H-pyrido[3,2-b][1,4]oxazin-3-one (88.48 g, 0.5362 mol, 1.0
equiv) was added slowly portion-wise. When addition was complete,
the red-brown mixture was stirred for 0.25 h to ensure complete
solution. Sodium nitrite (44.40 g, 0.6435 mol, 1.2 equiv) was added
cautiously portion-wise over 0.5 hr. Each addition was exothermic
and accompanied by the evolution of HF and N.sub.2-When addition
was complete the reaction mixture was stirred in the ice/salt bath
for 1 h. The reaction was quenched by the slow, careful addition of
ice-cold H.sub.2O (2 L). The resulting solid was collected, washed
with H.sub.2O, resuspended in H.sub.2O (3.times.1 L), collected,
washed with H.sub.2O and dried on the filter for 1 h. The solid was
washed with heptane and dried under a N.sub.2 stream for 2 h. Final
drying in a vacuum oven for 24 h at -40.degree. C. gave the second
intermediate compound (69.03 g, 76%) as an orange-brown solid. Mp
179.9181.20.
[1479] A third intermediate compound,
6-(4-Benzyloxy-butoxy)-4H-pyrido[3,2-b][1,4]oxazin-3-one, was
produced as follows: A solution of 4-benzyloxy-butan-1-ol 1 (34.31
g, 33.37 mL, 190.3 mmol) and potassium t-butoxide (1M solution; 181
mL) in THF (60 mL) was prepared and stirred at room temperature for
20 min. A suspension of 6-fluoro-4H-pyrido[3,2-b][1,4]oxazin-3-one
(8 g, 48 mmol) in THF (100 mL) was prepared, and the alcohol/base
solution was added to this solution via canula. The reaction was
heated at reflux for 25 hours. The reaction was quenched with
saturated NH.sub.4Cl and water. The solution was brought to a pH of
8 and extracted with ethyl acetate. The organic layer was washed
with brine and concentrated to give a solid. Purification by
SiO.sub.2 chromatography (0-70% EtOAc/hexanes) gave the third
intermediate compound as a white solid (6.6 g, 42%). MS: APCI: M+1:
329.2 (Exact Mass: 328.14).
[1480] A fourth intermediate compound,
6-(4-Hydroxy-butoxy)-4H-pyrido[3,2-b][1,4]oxazin-3-one, was
produced as follows: To a solution of
6-(4-benzyloxy-butoxy)-4H-pyrido[3,2-b][1,4]oxazin-3-one (6.4 g, 19
mmol) in MeOH/THF (100 mL) was added 20% Pd/C (1.5 g) and the
mixture was hydrogenated for 12 h. The reaction was filtered,
concentrated and purified by liquid chromatography (0-10%
MeOH/CH.sub.2Cl.sub.2) to give the fourth intermediate compound as
a white solid (4.3 g, 18 mmol, 93%). MS: APCI: M+1: 239.1 (Exact
Mass: 238.10).
[1481] A fifth intermediate compound,
4-(3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yloxy)-butyraldehyde,
was produced as follows: To a suspension of
6-(4-hydroxy-butoxy)-4H-pyrido[3,2-b][1,4]oxazin-3-one (4.3 g,
18.02 mmol) in dichloroethane (30 mL) was added IBX (15 g, 54
mmol). This mixture was heated at 80.degree. C. for 5 hours. The
reaction was cooled and stirred, and then filtered. The filter cake
was washed with CH.sub.2Cl.sub.2 until the product was removed. The
filtrate was concentrated to give a red oil, which was purified by
SiO.sub.2 chromatography (0-7% MeOH/CH.sub.2Cl.sub.2) to give the
fifth intermediate compound as a red oil (3.90 g, 16.5 mmol, 92%).
MS: APCI: M+1: 237.1 (Exact Mass: 236.08).
[1482] A reductive amination procedure similar to Example A1' was
followed using 2-methyl-8-piperazin-1-yl-quinoline to give the
title compound (0.19 g, 51%). MS: APCI: M+1: 448.3 (Exact Mass:
447.23).
Example F2'
Synthesis of
6-[4-(4-Quinolin-8-yl-piperazin-1-yl)-butoxy]-4H-pyrido[3,2-b][1,4]oxazin-
-3-one
[1483] A reductive amination procedure similar to Example A1' was
followed using 8-piperazin-1-yl-quinoline to give the title
compound (0.18 g, 64%). MS: APCI: M+1: 434.3 (Exact Mass:
433.21).
Example F3'
Synthesis of
6-{4-[4-(2-Oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazin-1-yl]-butoxy}--
4H-pyrido[3,2-b][1,4]oxazin-3-one
[1484] A reductive amination procedure similar to Example A1' was
followed using 8-piperazin-1-yl-3,4-dihydro-1H-quinolin-2-one to
give the title compound (0.20 g, 66%). MS: APCI: M+1: 452.3 (Exact
Mass: 451.22).
Example F4'
Synthesis of
6-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-4H-pyrido[3,2-b][1,4]oxazin--
3-one
[1485] A reductive amination procedure similar to Example A1' was
followed using 1-chroman-8-yl-piperazine to give the title compound
(0.29 g, 79%). MS: APCI: M+1: 439.3 (Exact Mass: 438.23).
Example F5'
Synthesis of
6-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-4H-py-
rido[3,2-b][1,4]oxazin-3-one
[1486] A reductive amination procedure similar to Example A1' was
followed using 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine to
give the title compound (0.22 g, 67%). MS: APCI: M+1: 441.1 (Exact
Mass: 440.21).
Example G1'
Synthesis of
2-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-8H-py-
rido[2,3-d]pyrimidin-7-one
[1487] A first intermediate compound
2-Methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one, was produced as
follows: To a suspension of
2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (5.0 g, 25.9 mmol)
in CH.sub.2Cl.sub.2 (100 mL), CHCl.sub.3 (50 mL) and MeOH (10 mL,
the starting material still did not dissolve) was added the
oxaziridine (8.11 g, 31.05 mmol, 1.2 equiv) as a solid. The
reaction became homogenous after 3 h and was stirred overnight at
RT. The reaction was concentrated and CH.sub.2Cl.sub.2/MeOH was
added to dissolve the residue. Much of the solid did not dissolve
so the mixture was filtered to give an off-white solid which was
the first intermediate compound (2.31 g, 11.04 mmol, 43%). MS:
APCI: M+1: 210.1 (Exact Mass: 209.03).
[1488] A second intermediate compound,
2-[4-(Tetrahydro-pyran-2-yloxy)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-one,
was produced as follows: To a solution of
4-(tetrahydro-pyran-2-yloxy)-1-butanol (4.45 g, 25.3 mmol, 2.5
equiv) in THF (20 mL) cooled to 0.degree. C. was added 1M KOtBu in
THF (25 mL, 25 mmol). The solution was stirred at 0.degree. C. for
20 min and then added to a suspension of
2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (2.12 g, 10.13
mmol) in DMF (30 mL) at RT. The reaction became homogenous and was
stirred at room temperature for 1 h. Saturated NH4Cl and H2O were
added to quench the reaction. The mixture was extracted with EtOAc.
The organic layer was washed with H2O and brine, dried over Na2SO4
and concentrated. Purification by liquid chromatography (70%
EtOAc/Hexanes to 100% EtOAc) gave the second intermediate compound
as a white solid (1.95 g, 6.11 mmol, 60%). MS: APCI: M+1: 320.2
(Exact Mass: 319.15).
[1489] A third intermediate compound,
2-(4-Hydroxy-butoxy)-8H-pyrido[2,3-d]pyrimidin-7-one, was produced
as follows: To a suspension of
2-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-one
(1.95 g, 6.11 mmol) in EtOH (30 mL) and CH2Cl2 (2 mL, added to help
dissolve the starting material) was added PPTS (151 mg, 0.6 mmol).
The solution was stirred overnight at room temperature and then
heated at 60.degree. C. for 5 h. The reaction was concentrated to
give a white solid. Purification by liquid chromatography (6%
MeOH/CH2Cl2) gave the third intermediate compound as a white solid
(1.22 g, 5.19 mmol, 85%). MS: APCI: M+1: 236.1 (Exact Mass:
235.10).
[1490] A fourth intermediate compound,
4-(7-Oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)-butyraldehyde,
was produced as follows: To a solution of
2-(4-hydroxy-butoxy)-8H-pyrido[2,3-d]pyrimidin-7-one (251 mg, 1.07
mmol) in DMSO (3 mL) was added a solution of IBX (597 mg, 2.13
mmol) in DMSO (7 mL, 0.3 M). The reaction was stirred at room
temperature for 90 min, cooled to 0.degree. C. and quenched with 5%
NaHCO3. The mixture was extracted with CH2Cl2 (4.times.). The
organic layer was washed with 5% NaHCO3 and brine, dried over
Na2SO4 and concentrated to give the fourth intermediate compound as
a white solid (171 mg, 0.733 mmol, 69%). MS: APCI: M+1: 234.1
(Exact Mass: 233.08).
[1491] The pyrimidines of Examples G1'-G9' were synthesized in a
combinatorial library format by reductive amination of the
appropriate piperazine starting materials with
4-(7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)-butyraldehyde
using the procedure outlined in Example C1'.
[1492] The title compound was isolated as white solid (292 mg,
0.637 mmol, 74.3%). MS: APCI: M+1: 438.1 (Exact Mass: 437.21).
Example G2'
Synthesis of
2-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7--
one
[1493] The title compound was isolated as a white solid (258 mg,
0.564 mmol, 65.8%). MS: APCI: M+1: 436.1 (Exact Mass: 435.23).
Example G3'
Synthesis of
2-[4-(4-Quinolin-8-yl-piperazin-1-yl)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-
-one
[1494] The title compound was isolated as a yellow solid (225 mg,
0.522 mmol, 61%). MS: APCI: M+1: 431.1 (Exact Mass: 430.21).
Example G4'
Synthesis of
2-{4-[4-(2,3-Dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2-
,3-d]pyrimidin-7-one
[1495] The title compound was isolated as a white solid (118 mg,
0.280 mmol, 32.7%). MS: APCI: M+1: 422.1 (Exact Mass: 421.21).
Example G5'
Synthesis of
2-{4-[4-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-piperazin-1-yl]-butox-
y}-8H-pyrido[2,3-d]pyrimidin-7-one
[1496] The title compound was isolated as a white solid (117 mg,
0.259 mmol, 30.2%). MS: APCI: M+1: 452.3 (Exact Mass: 451.22).
Example G6'
Synthesis of
2-{4-[4-(2,2-Dimethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-
-d]pyrimidin-7-one
[1497] The title compound was isolated as a white solid (202 mg,
0.435 mmol, 50.8%). MS: APCI: M+1: 464.3 (Exact Mass: 463.26).
Example G7'
Synthesis of
2-{4-[4-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-piperazin-1-yl]-butoxy}-8H-p-
yrido[2,3-d]pyrimidin-7-one
[1498] The title compound was isolated as a white foam (249 mg,
0.541 mmol, 63.2%). MS: APCI: M+1: 460.2 (Exact Mass: 459.17).
Example G8'
Synthesis of
2-{4-[4-(2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy-
}-8H-pyrido[2,3-d]pyrimidin-7-one
[1499] The title compound was isolated as an off white foam (188
mg, 0.418 mmol, 48.8%). MS: APCI: M+1: 450.1 (Exact Mass:
449.24).
Example G9'
Synthesis of
2-{4-[4-(2-Methyl-quinolin-8-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]-
pyrimidin-7-one
[1500] The title compound was isolated as tan crystals (93 mg,
0.209 mmol, 24.4%). MS: APCI: M+1: 445.1 (Exact Mass: 444.23).
Example G1'
Synthesis of
2-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-4-met-
hyl-8H-pyrido[2,3-d]pyrimidin-7-one
[1501] A first intermediate compound
2-Methanesulfonyl-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one, was
produced as follows: A solution of
4-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (24 g,
0.1158 mol, U.S. Pat. No. 6,498,163) in a mixture of
CH.sub.2Cl.sub.2 (1.9 L) and methanol (300 mL) is treated with
m-chloroperbenzoic acid (103 g, 60%, 0.345 mol) in portions at room
temperature. The mixture is stirred for 24 h, cooled to -5.degree.
C. and quenched with saturated sodium bicarbonate solution. The
solids are filtered, washed thoroughly with water followed by ether
and dried in vacuum to give the first intermediate compound as a
solid (10 g, 0.042 mol, 36%). MS: APCI: M+1: 240.0 (Exact Mass:
239.04).
[1502] A second intermediate compound,
4-Methyl-2-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-8H-pyrido[2,3-d]pyrimidi-
n-7-one, was produced as follows: To a ice bath cooled solution of
4-(tetrahydro-pyran-2-yloxy)-butan-1-ol (27.3 g, 0.1567 mol) in dry
THF (125 mL) is added drop wise a solution of KOtBu (1M, 155 mL,
0.155 mol) in THF within 15 min. The mixture is then stirred at
0.degree. C. for 2 h. To this mixture is added a suspension of
2-methanesulfonyl-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (15 g,
0.0627 mol) in DMF (225 mL) at room temperature within 15 min. The
orange red colored reaction mixture is stirred at room temperature
for 1.5 h, cooled and quenched with saturated NH.sub.4Cl solution
(150 mL) and water (2 L). The mixture is extracted with ethyl
acetate (2.times.0.75 L) and the organic layer is washed with brine
(300 mL), dried over anhydrous sodium sulfate, filtered through a
small bed of silica gel eluting with 5% methanol in ethyl acetate
(750 mL) and concentrated. The residue is then triturated with
hexane, filtered and dried to give the second intermediate compound
as a white solid (16.5 g, 0.0495 mol 78%). MS: APCI: M+1: 334.0
(Exact Mass: 333.17).
[1503] A third intermediate compound,
2-(4-Hydroxy-butoxy)-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one, was
produced as follows: A mixture of
4-methyl-2-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-8H-pyrido[2,3-d]pyrimidi-
n-7-one (16.5 g, 0.049 mol) and PPTS (1.24 g, 0.0049 mol) in
ethanol (250 mL) and CH.sub.2Cl.sub.2 (20 mL) is stirred at room
temperature for 16 h, followed by heating at reflux
(.about.90.degree. C.) for 3 h. The cloudy reaction mixture is
evaporated under vacuum and the residue is triturated in
hexane-ethyl acetate (150 mL, 1:1) and dried to give the third
intermediate compound as a yellow powder (12.5 g, 0.049 mol, 100%).
MS: APCI: M+1: 250.0 (Exact Mass: 249.11).
[1504] A fourth intermediate compound,
4-(4-Methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)-butyraldehy-
de, was produced as follows: A stirred solution of IBX (26 g, 0.092
mol) in DMSO (220 ml) is treated with
2-(4-hydroxy-butoxy)-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (11
g, 0.0467 mol) portion wise while stirring at room temperature
during 30 min and the reaction is stirred at room temperature for
an additional 2 h. The mixture is cooled and treated with saturated
NaHCO.sub.3 (150 mL) and extracted with chloroform (4.times.0.5 L).
The combined organic layer is washed with brine/ice (2.times.),
dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue
is stirred with ether, filtered, washed with ether and dried to
give 6 g of the crude, which shows it to be a mixture. The ether
filtrate residue also shows some product, but mostly starting
material. The residue from the filtrate and the crude (11 g) are
subjected to re-oxidation as above using fresh IBX (15.5 g, 0.055
mol) in DMSO (150 mL), but stirred at 30.degree. C. for 3 h. Workup
as above yielded the fourth intermediate compound as an off-white
powder (8.3 g, 0.057 mol, 66.8%). MS: APCI: M+1: 248.0 (Exact Mass:
247.10).
[1505] The pyrimidines of Examples G10'-G15' were synthesized in
combinatorial library format by reductive amination of the
appropriate piperazine starting materials with
4-(4-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)-butyraldehy-
de following the general procedure outlined in Example C1'.
[1506] The title compound was isolated as a solid (81 mg, 0.179
mmol, 59.8%). MS: APCI: M+1: 452.3 (Exact Mass: 451.22).
Example G11'
Synthesis of
2-{4-[4-(2,3-Dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-
-pyrido[2,3-d]pyrimidin-7-one
[1507] The title compound was isolated as a solid (56 mg, 0.128
mmol, 42.86%). MS: APCI: M+1: 436.3 (Exact Mass: 435.23).
Example G12'
Synthesis of
2-[4-(4-Benzofuran-7-yl-piperazin-1-yl)-butoxy]-4-methyl-8H-pyrido[2,3-d]-
pyrimidin-7-one
[1508] The title compound was isolated as a white solid (56 mg,
0.129 mmol, 43.06%). MS: APCI: M+1: 434.1 (Exact Mass: 433.21).
Example G13'
Synthesis of
2-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-4-methyl-8H-pyrido[2,3-d]pyr-
imidin-7-one
[1509] The title compound was isolated as a white powder (53 mg,
0.117 mmol, 39.3%). MS: APCI: M+1: 450.2 (Exact Mass: 449.24).
Example G14'
Synthesis of
4-Methyl-2-{4-[4-(2-oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazin-1-yl]-
-butoxy}-8H-pyrido[2,3-d]pyrimidin-7-one
[1510] The title compound was isolated as a solid (58 mg, 0.125
mmol, 41.8%). MS: APCI: M+1: 463.2 (Exact Mass: 462.24).
Example G15'
Synthesis of
4-Methyl-2-[4-(4-quinolin-8-yl-piperazin-1-yl)-butoxy]-8H-pyrido[2,3-d]py-
rimidin-7-one
[1511] The title compound was isolated as a brown solid (44 mg,
0.099 mmol, 32.9%). MS: APCI: M+1: 445.3 (Exact Mass: 444.23).
Example H1'
Synthesis of
7-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,6]naphthyr-
idin-2-one
[1512] A first intermediate compound
3-(4,6-Diamino-pyridin-3-yl)-acrylic acid ethyl ester, was produced
as follows: A mixture of (carbethoxymethylene)triphenylphosphorane
(436 g, 1.25 mol) and 4,6-diaminopyridine-3-carbaldehyde (131.8 g,
0.96 mol) in 1,4-dioxane (2.0 L) was refluxed for 2.0 h. The
mixture was cooled and filtered through silica gel (800 g) eluting
with 0-10% MeOH/EtOAc. The filtrate was concentrated and the
residue (.about.580 g) was used in the next step without further
purification.
[1513] A second intermediate compound,
7-Amino-1H-[1,6]naphthyridin-2-one, was produced as follows: The
residue obtained from the above procedure was refluxed in conc. HCl
(1.5 L) for 1.5 h. The mixture was cooled and diluted with water
(2.5 L). At 35-40.degree. C., the mixture was washed with EtOAc
(3.times.). The aqueous layer was made basic with 50% NaOH to
pH>10 while cooling with a cold water bath. The resulting solid
was collected via filtration, rinsed with water, methanol, and oven
dried to afford the second intermediate compound (106 g, 68% for
two steps) as off-white crystals.
[1514] A third intermediate compound,
7-Fluoro-1H-[1,6]naphthyridin-2-one, was produced as follows: To a
stirred mixture of HF-pyridine (660 g) and
7-amino-1H-[1,6]naphthyridin-2-one (58 g, 0.36 mol) in a plastic
bottle was added NaNO.sub.2 (39.7 g, 0.57 mol) in small portions
over 30-40 min while cooled with a cold (.about.10.degree. C.)
water bath in order to keep the internal temperature at around RT.
After the addition, the mixture was further stirred at room
temperature for 20 min before it was poured into water (2.6 L) and
stirred for 3.0 h. The resulting solid was collected via
filtration, rinsed with water (2.times.), EtOAc-heptane (1:1,
2.times.), and oven dried to afford the third intermediate compound
(48.6 g, 82%) as pale solid.
[1515] A fourth intermediate compound,
7-(4-Benzyloxy-butoxy)-1H-[1,6]naphthyridin-2-one, was produced as
follows: A solution of 4-benzyloxy-butan-1-ol (35.98 g,199.6 mmol)
and potassium t-butoxide (21 g,188 mmol) in THF (60 mL) was
prepared and stirred at room temperature for 20 min. A suspension
of 7-fluoro-1H-[1,6]naphthyridin-2-one (8.1 g, 49 mmol) in THF (100
mL) was prepared, and the alcohol solution was added to this
solution via canula. The reaction was stirred at 80.degree. C.
overnight. MS showed mostly product. So reaction quenched with
saturated NH.sub.4Cl and water. The solution was brought to a pH of
8 and extracted with ethyl acetate. The organic layer was washed
with brine and concentrated to give a silky solid. EtOAc was added
and the mixture was filtered to give a beige solid. The NMR
indicated that it was the product and it was recrystallized from
acetonitrile to give clean product. (9.70 g). The filtrate was
concentrated and filtered to give more precipitate (0.788 g). The
filtrate was concentrated and purified by chromatography (0-70%
EtOAc/hexanes) to give additional product as a beige solid (2.716
g). (Total Product: 13.21 g, 82%). MS: APCI: M+1: 325.2 (Exact
Mass: 324.15).
[1516] A fifth intermediate compound,
7-(4-Hydroxy-butoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one, was
produced as follows: To a solution of
7-(4-benzyloxy-butoxy)-1H-[1,6]naphthyridin-2-one (7.92 g, 24.4
mmol) in MeOH/THF (100 mL) was added 20% Pd/C (1.5 g) and the
mixture was hydrogenated for 59 h. The reaction was filtered,
concentrated and purified by liquid chromatography (0-10%
MeOH/CH2Cl2) to give the fifth intermediate compound as a white
solid (4.11 g, 17.4 mmol, 71%). MS: APCI: M+1: 237.1 (Exact Mass:
236.12).
[1517] A sixth intermediate compound,
4-(2-Oxo-1,2,3,4-tetrahydro-[1,6]naphthyridin-7-yloxy)-butyraldehyde,
was produced as follows: To a suspension of
7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one (2.0 g,
8.5 mmol) in dichloroethane (20 mL) was added IBX (7 g, 25 mmol).
This was heated at 80.degree. C. for 5 hours. The reaction was
cooled and then filtered. The filter cake was washed with
CH.sub.2CH.sub.2 until the product was removed. The filtrate was
concentrated to give a yellow solid (1.88 g, used crude in next
reaction). MS: APCI: M+1: 235.1 (Exact Mass: 234.10).
[1518] A reductive amination procedure similar to Example A1' was
followed using 1-chroman-8-yl-piperazine (0.24 g; 69%). MS: APCI:
M+1: 437.2 (Exact Mass: 436.25).
Example H2'
Synthesis of
7-{4-[4-(2,3-Dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-
-1H-[1,6]naphthyridin-2-one
[1519] A reductive amination procedure similar to Example A1' was
followed using 1-(2,3-dihydro-benzofuran-7-yl)-piperazine to give
the title compound (0.32 g, 50%). MS: APCI: M+1: 423.2 (Exact Mass:
422.23).
Example H3'
Synthesis of
7-{4-[4-(2,2,3,3-Tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-
-1-yl]-butoxy}-3,4-dihydro-1H-[1,6]naphthyridin-2-one
[1520] A reductive amination procedure similar to Example A1' was
followed using
1-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine
to give the title compound (0.21 g, 27%). MS: APCI: M+1: 511.1
(Exact Mass: 510.19).
Example H4'
Synthesis of
7-{4-[4-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-piperazin-1-yl]-butoxy}-3,4--
dihydro-1H-[1,6]naphthyridin-2-one
[1521] A reductive amination procedure similar to Example A1' was
followed using 1-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-piperazine to
give the title compound (0.40 g, 56%). MS: APCI: M+1: 461.2 (Exact
Mass: 460.19).
Example H5'
Synthesis of
7-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-3,4-d-
ihydro-1H-[1,6]naphthyridin-2-one
[1522] A reductive amination procedure similar to Example A1' was
followed using 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine to
give the title compound (0.22 g, 50%). MS: APCI: M+1: 439.3 (Exact
Mass: 438.23).
Example H6'
Synthesis of
7-{4-[4-(2,3-Dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-1H-[1,6]nap-
hthyridin-2-one
[1523] A first intermediate compound
7-(4-Hydroxy-butoxy)-1H-[1,6]naphthyridin-2-one, was produced as
follows: Butane-1,4-diol (8.24 g, 8.12 mL, 91.3 mmol) was added to
solid KOtBu (6 g, 55 mmol). The very viscous mixture was stirred
for 15 min before adding 7-fluoro-1H-[1,6]naphthyridin-2-one (3 g,
18 mmol). NMP (60 mL) was then added and the reaction was heated at
70.degree. C. overnight. The reaction was cooled and poured into
ice water. No precipitate formed, so the mixture was extracted with
EtOAc. The organic layer was washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated. Purification by SiO.sub.2
chromatography (0-50% EtOAc/Hex) gave the first intermediate
compound (2.36 g, 55%). MS: APCI: M+1: 235.0 (Exact Mass:
234.10).
[1524] A second intermediate compound,
4-(2-Oxo-1,2-dihydro-[1,6]naphthyridin-7-yloxy)-butyraldehyde, was
produced as follows: To a suspension of
7-(4-hydroxy-butoxy)-1H-[1,6]naphthyridin-2-one (2.33 g, 9.95 mmol)
in dichloroethane (30 mL) was added IBX (8 g, 30 mmol). The mixture
was heated at 80.degree. C. for 5 hours. The reaction was cooled
and stirred, and then filtered. The filter cake was washed with
CH.sub.2Cl.sub.2 until the product was removed. The filtrate was
concentrated to give the second intermediate compound as a yellow
solid (2.45 g). MS: APCI: M+1: 233.1 (Exact Mass: 232.08).
[1525] A reductive amination procedure similar to Example A1' was
followed using 1-(2,3-dihydro-benzofuran-7-yl)-piperazine to give
the title compound (0.225 g, 59%). MS: APCI: M+1: 421.2 (Exact
Mass: 420.22).
Example H7'
Synthesis of
7-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-1H-[1-
,6]naphthyridin-2-one
[1526] A reductive amination procedure similar to Example A1' was
followed using 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine to
give the title compound (0.22 g, 60%). MS: APCI: M+1: 437.2 (Exact
Mass: 436.21).
Example H8'
Synthesis of
7-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-1H-[1,6]naphthyridin-2-one
[1527] A reductive amination procedure similar to Example A1' was
followed using 1-chroman-8-yl-piperazine to give the title compound
(0.23 g, 62%). MS: APCI: M+1: 435.2 (Exact Mass: 434.23).
Example H9'
Synthesis of
7-{4-[4-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-piperazin-1-yl]-butoxy}-1H-[-
1,6]naphthyridin-2-one
[1528] A reductive amination procedure similar to Example A1' was
followed using 1-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-piperazine to
give the title compound (0.26 g, 66%). MS: APCI: M+1: 459.2 (Exact
Mass: 458.18).
* * * * *