U.S. patent application number 13/751459 was filed with the patent office on 2013-06-06 for compounds and their use as ikach blockers.
This patent application is currently assigned to ASTRAZENECA AB. The applicant listed for this patent is AstraZeneca AB. Invention is credited to Jonas Bostrom, Hans Emtenas, Kenneth Granberg, Antonio Llinas, Mickael Mogemark.
Application Number | 20130143858 13/751459 |
Document ID | / |
Family ID | 46162787 |
Filed Date | 2013-06-06 |
United States Patent
Application |
20130143858 |
Kind Code |
A1 |
Bostrom; Jonas ; et
al. |
June 6, 2013 |
COMPOUNDS AND THEIR USE AS IKACH BLOCKERS
Abstract
The invention relates to compounds according to Formula I:
##STR00001## or a pharmaceutically acceptable salt thereof, wherein
m, n, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, x and y are as
defined herein. Compounds according to Formula I are
pharmacologically effective as potassium channel inhibitors, in
particular inhibitors of the acetylcholine operated inward
rectifying potassium channel current (i.e. IKACh blockers), and are
believed to be useful in the treatment of cardiac arrhythmias, in
particular supraventricular tacharrhythmias, such as atrial
fibrillation and atrial flutter.
Inventors: |
Bostrom; Jonas; (Molndal,
SE) ; Emtenas; Hans; (Molndal, SE) ; Granberg;
Kenneth; (Molndal, SE) ; Llinas; Antonio;
(Molndal, SE) ; Mogemark; Mickael; (Molndal,
SE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AstraZeneca AB; |
Sodertalje |
|
SE |
|
|
Assignee: |
ASTRAZENECA AB
Sodertalje
SE
|
Family ID: |
46162787 |
Appl. No.: |
13/751459 |
Filed: |
January 28, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13306499 |
Nov 29, 2011 |
8361998 |
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13751459 |
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61417996 |
Nov 30, 2010 |
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Current U.S.
Class: |
514/210.01 ;
514/327; 514/331; 514/424; 514/425; 514/428 |
Current CPC
Class: |
A61P 7/02 20180101; C07D
295/13 20130101; C07D 205/04 20130101; C07D 211/46 20130101; C07D
207/12 20130101; A61P 11/00 20180101; A61P 9/00 20180101; C07D
211/38 20130101; A61P 9/04 20180101; C07D 207/08 20130101; A61P
9/06 20180101; C07D 211/62 20130101 |
Class at
Publication: |
514/210.01 ;
514/428; 514/327; 514/425; 514/424; 514/331 |
International
Class: |
A61K 31/445 20060101
A61K031/445; C07D 295/13 20060101 C07D295/13; C07D 205/04 20060101
C07D205/04; C07D 207/12 20060101 C07D207/12; C07D 211/38 20060101
C07D211/38; C07D 211/46 20060101 C07D211/46; C07D 207/08 20060101
C07D207/08; A61K 31/40 20060101 A61K031/40; A61K 31/397 20060101
A61K031/397 |
Claims
1-11. (canceled)
12. A method of treating a disease, disorder and/or condition which
is affected and/or mediated by IKACh and where treatment by IKACh
blockade is beneficial to a patient in need of such treatment,
wherein: the method comprises administering a therapeutically
effective amount of a compound or pharmaceutically acceptable salt
to the patient; and the compound corresponds in structure to
Formula I: ##STR00063## wherein: each R.sup.5 is independently
selected from fluoro, nitrile, hydroxy, oxo, C.sub.1-5 alkyl,
C.sub.3-5 cycloalkyl, C.sub.1-5 alkoxy or C.sub.1-5 alkoxyalkyl,
wherein: any alkyl, cycloalkyl or alkoxy group is substituted by 0,
1 or 2 substituents independently selected from fluoro, nitrile or
hydroxy, R.sup.1 is selected from C.sub.1-6 alkyl, C.sub.3-6
cycloalkyl or C.sub.1-6 alkoxyalkyl, wherein: any alkyl, cycloalkyl
or alkoxy group is substituted by 0, 1 or 2 substituents
independently selected from fluoro or nitrile, R.sup.2 is selected
from hydrogen or C.sub.1-3 alkyl; R.sup.3 is selected from
C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl or C.sub.1-6 alkoxyalkyl,
wherein: any alkyl or cycloalkyl group is substituted by 0, 1 or 2
substituents independently selected from fluoro, nitrile or
hydroxy; each R.sup.4 is independently selected from halo, nitrile,
hydroxy, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkoxyalkyl
or C.sub.1-3 alkylsulfide, wherein: any alkyl or alkoxy group is
substituted by 0, 1, 2 or 3 substituents independently selected
from halo, nitrile or hydroxy; m is selected from 1, 2 or 3; n is
selected from 1 or 2; x is selected from 0, 1, 2, or 3; and y is
selected from 0, 1, 2 or 3.
13. A method of treating cardiac arrhythmias or a complication
associated with cardiac arrhythmias in a patient in need of such
treatment, wherein: the method comprises administering a
therapeutically effective amount of a compound or pharmaceutically
acceptable salt to the patient; and the compound corresponds in
structure to Formula I: ##STR00064## wherein: each R.sup.5 is
independently selected from fluoro, nitrile, hydroxy, oxo,
C.sub.1-5 alkyl, C.sub.3-5 cycloalkyl, C.sub.1-5 alkoxy or
C.sub.1-5 alkoxyalkyl, wherein: any alkyl, cycloalkyl or alkoxy
group is substituted by 0, 1 or 2 substituents independently
selected from fluoro, nitrile or hydroxy, R.sup.1 is selected from
C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl or C.sub.1-6 alkoxyalkyl,
wherein: any alkyl, cycloalkyl or alkoxy group is substituted by 0,
1 or 2 substituents independently selected from fluoro or nitrile,
R.sup.2 is selected from hydrogen or C.sub.1-3 alkyl; R.sup.3 is
selected from C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl or C.sub.1-6
alkoxyalkyl, wherein: any alkyl or cycloalkyl group is substituted
by 0, 1 or 2 substituents independently selected from fluoro,
nitrile or hydroxy; each R.sup.4 is independently selected from
halo, nitrile, hydroxy, C.sub.1-3 alkyl, C.sub.1-3 alkoxy,
C.sub.1-3 alkoxyalkyl or C.sub.1-3 alkylsulfide, wherein: any alkyl
or alkoxy group is substituted by 0, 1, 2 or 3 substituents
independently selected from halo, nitrile or hydroxy; m is selected
from 1, 2 or 3; n is selected from 1 or 2; x is selected from 0, 1,
2, or 3; and y is selected from 0, 1, 2 or 3.
14. A method of restoring and/or maintaining sinus rhythm in a
patient in need of such treatment, wherein: the method comprises
administering a therapeutically effective amount of a compound or
pharmaceutically acceptable salt to the patient; and the compound
corresponds in structure to Formula I: ##STR00065## wherein: each
R.sup.5 is independently selected from fluoro, nitrile, hydroxy,
oxo, C.sub.1-5 alkyl, C.sub.3-5 cycloalkyl, C.sub.1-5 alkoxy or
C.sub.1-5 alkoxyalkyl, wherein: any alkyl, cycloalkyl or alkoxy
group is substituted by 0, 1 or 2 substituents independently
selected from fluoro, nitrile or hydroxy, R.sup.1 is selected from
C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl or C.sub.1-6 alkoxyalkyl,
wherein: any alkyl, cycloalkyl or alkoxy group is substituted by 0,
1 or 2 substituents independently selected from fluoro or nitrile,
R.sup.2 is selected from hydrogen or C.sub.1-3 alkyl; R.sup.3 is
selected from C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl or C.sub.1-6
alkoxyalkyl, wherein: any alkyl or cycloalkyl group is substituted
by 0, 1 or 2 substituents independently selected from fluoro,
nitrile or hydroxy; each R.sup.4 is independently selected from
halo, nitrile, hydroxy, C.sub.1-3 alkyl, C.sub.1-3 alkoxy,
C.sub.1-3 alkoxyalkyl or C.sub.1-3 alkylsulfide, wherein: any alkyl
or alkoxy group is substituted by 0, 1, 2 or 3 substituents
independently selected from halo, nitrile or hydroxy; m is selected
from 1, 2 or 3; n is selected from 1 or 2; x is selected from 0, 1,
2, or 3; and y is selected from 0, 1, 2 or 3.
15-16. (canceled)
Description
TECHNICAL FIELD
[0001] The present invention relates to a novel class of compounds
which are pharmacologically effective as potassium channel
inhibitors, in particular inhibitors of the acetylcholine operated
inward rectifying potassium channel current, i.e. IKACh
blockers.
[0002] The invention also relates to processes for preparing such
compounds, to pharmaceutical compositions containing them, to the
use of such compounds and to methods for their therapeutic use,
particularly in the treatment of cardiac arrhythmias.
BACKGROUND
[0003] The normal electrophysiologic behaviour of the heart is
determined by ordered propagation of excitatory stimuli that result
in rapid depolarization of the cardiac cell, followed by a slower
repolarization. The sum of these events creates the cardiac action
potential in individual myocytes. Cardiac rhythm disturbances can
be caused by abnormalities of impulse generation, propagation or
the duration and configuration of such individual cardiac action
potentials. The action potentials are generated by the integrated
activity of specific ion currents through various transmembrane
spanning ion channels with specific selectivity for individual ions
(e.g. potassium, sodium, calcium, see Grant AO. Circ. Arrhythmia
Electrophysiol. 2009; 2:185-194). The majority of these ion
channels have been cloned and thus, their molecular components are
known. This knowledge has enabled a more effective search for
selective ion channel blockers, as specific ion channel targets can
be recombinantly over-expressed in mammalian cells and be used for
high capacity screening.
[0004] Electrophysiological studies in the early 1950s showed the
importance of the movement of K.sup.+ out of the cell to produce
repolarization after the rapid depolarizing spike. Over the last 60
years, the introduction of single channel recording techniques and
molecular cloning has resulted in a deeper understanding of cardiac
repolarization and of the different potassium channels involved.
Potassium channels are divided into:
[0005] a. Voltage gated channels (K.sub.V 1-9)
[0006] b. Calcium activated channels (K.sub.Ca)
[0007] c. Inward rectifier channels (K.sub.ir 1-6)
[0008] d. Tandem pore domain channels (TWIK, TREK, TASK, TRAAK)
[0009] The pharmacology of cardiac potassium channels is disclosed
in Tamargo et al., Cardiovascular Research (2004), 62, 9-33.
[0010] The expression of all these channels differs in various part
of the cardiac muscle. Some channels are rather homogenously
expressed, whereas some channels have a more chamber specific
expression. Thus, the ultra rapid delayed rectifier (K.sub.v1.5)
and the acetylcholine operated inward rectifier (K.sub.ir
3.1/K.sub.ir3.4) are shown to be rather atrial selective in their
expression (Wang Z et al. Circ. Res. (1993); 73:1061-1076 and
Schram G et al. Circ. Res. (2002); 90:939-50).
[0011] Compounds that block outwardly directed repolarizing
potassium current will prolong the cardiac action potential
duration (APD). An increase of APD prolongs the corresponding
effective refractory period (ERP), the time period during which the
cell can not be re-exited to generate a new action potential (the
so-called Class III antiarrhythmic action, see Singh B N et al. Br.
J. Pharmacol. (1970); 39:675-689). As a group, such Class III
compounds prevent cardiac tachyarrhythmia, such as atrial
fibrillation (AF) based on so-called re-entrant mechanisms. In the
normal myocardium, pacemaker cells of the sino-atrial node initiate
the cardiac impulse. The cardiac impulse is then propagated to
neighbouring excitable cells, and in this way depolarization
spreads across the atria, through the atrioventricular node, and to
the ventricles in a co-ordinated fashion. The impulse is
unidirectional because of the refractoriness to depolarization of
the preceding myocardial tissue. However, atrial re-entry circuits
occur when the propagating impulse does not die out because it
continues to encounter excitable atrial tissue, which it can
depolarize. This occurs where there is an area of atrial refractory
tissue encountered by the impulse that blocks its progress as a
wave front. Following its circuit around this central area, the
wave front may return to its point of origin after the ERP has
finished and re-exited the atrial tissue, thereby forming a
re-entrant circuit (Waldo A L. Lancet (1993); 341:1189-1193). Drugs
that prolong the atrial ERP thus will minimize the risk for such
re-excitation.
[0012] However, drugs that cause ERP prolongation by block of
potassium current that exists in both atria and ventricle will
prolong APD in both kind of myocardial tissue. Excessive APD
prolongation in the ventricle or in the specialised conduction
tissue, the so-called Purkinje Fibres, may increase the risk for a
proarrhythmic event, i.e. the antiarrhythmic action is replaced by
a situation in which arrhythmias may be created. A typical
proarrhythmia caused by delay of ventricular repolarization is
Torsades de pointes (TdP), which is a life threatening
proarrhythmia, limiting the use of antiarrhythmic compounds of the
Class III type. TdP is caused by so called early after
depolarizations (EADs) defined as single or repetitive
depolarizations originating from the AP plateau and which can
propagate to and excite surrounding cardiac tissue. TdP is a
life-threatening ventricular arrhythmia as it sometimes can
transfer into ventricular fibrillation. Thus, the use of compounds
which as antiarrhythmic mechanism delay cardiac repolarization in
the ventricle, always carry a risk for such dangerous
proarrhythmias and as a consequence, the development of several
such compounds has been halted and some compounds which have
reached the market have been withdrawn (Redfern W S et al.
Cardiovasc. Res. (2003); 58:32-45).
[0013] AF is the most common sustained cardiac arrhythmia and in
2008 10 million patients world-wide suffered from AF and this is
estimated to grow to 13 million by 2020. The presence of AF is
associated with a significant increase in the risk of adverse
cardiovascular events and is an independent predictor of stroke and
congestive heart failure (Estes N A et al. J. Am. Coll. Cardiol.
(2008); 51:865-884; Fang M C et al. J. Am. Coll. Cardiol. (2008);
51:810-815). Moreover, patients quality of life is greatly reduced
as a result of symptoms such as dizziness, palpitations, and
reduced exercise capacity (Thrall G et al. Am. J. Med. (2006);
119:448e1-448e19).
[0014] The therapeutic goals in patients with AF are to reduce
thromboembolic risk, to restore and maintain normal sinus rhythm
and to control ventricular rate during AF. Thromboembolic risk is
mostly reduced by anticoagulation therapy. Restoration and
maintenance of sinus rhythm is obtained by using electrical or
pharmacological cardioversion, or by ablation or surgery, followed
by pharmacological control of sinus rhythm to prevent AF relapse.
When AF is permanent and cardioversion is undoable, the arrhythmia
has to be accepted and the main therapy is to control ventricular
rate predominantly by drugs that delay AV nodal conduction, but
also in some cases by AV nodal ablation and pacemaker implantation
(Markides V et al. Heart 2003; 89:939-943).
[0015] Pharmacological therapy for atrial fibrillation is described
in Expert Opin. Investig. Drugs (2009) 18(4), 417-431. However,
there is currently no optimal drug treatment for sinus rhythm
maintenance available, and a novel compound with better efficacy
for sinus rhythm maintenance and without limiting unacceptable
ventricular side effects is urgently needed.
[0016] The parasympathetic nervous system acts through the vagus
nerve to regulate the heart rate and the conduction properties of
atrial, atrioventricular and ventricular tissue. In animal models,
parasympathetic stimulation has been shown to predispose the atria
to AF and attenuation of vagal effects has been shown to prevent AF
induction (Chiou C W et al. Circulation (1997); 95:2573-2584).
Parasympathetic effects to the heart are largely mediated through
interaction with the acetylcholine operated inward rectifier
channel (i.e. the KACh channel). The cardiac KACh channel is
comprised of two homologous transmembrane spanning proteins--GIRK1
and GIRK 4 (K.sub.ir3.1 and K.sub.ir3.4) (Krapivinsky is G et al.
Nature (1995); 374:135-141), and both homomers are needed to build
the functional channel. Increased activity of the KACh channel
results in shortening of the atrial APD and ERP, thus favouring AF
based on the re-entry mechanism. An interesting finding is that one
of the pore forming homomers are prominently expressed in atrial
muscle but are largely absent in ventricles (Dobyzynski H et al. J.
Histochem. Cytochem. (2001); 49:1221-1234). This finding explain
the fact that vagal stimulation in anaesthetized animals (dog,
rabbit) causes substantial ERP shortening in the atria, whereas no
such effects are noted in the ventricles, thus confirming the
atrial selectivity of the KACh channel. Advantages of atrial
selectivity in antiarrhythmic drug treatment of AF are discussed in
Li et al., Cardiovascular & Hematological Agents in Medicinal
Chemistry (2009), 7(1), 64-75.
[0017] Another important finding is ionic remodelling induced by
atrial pacing and induction of AF also results in increased
constitutively active KACh channels by enhancing spontaneous
channel openings, even in the absence of acetylcholine (Cha T J et
al. Circulation (2006); 113:1730-1737). This finding also is shown
in atrial muscle from AF patients (Dobra D et al. Circulation
(2005); 112:3697-3706). Thus, block of IKACh will lead to atrial
ERP prolongation in all AF patients, not only so in patients with
AF of vagal origin. Ehrlich in J. Cardiovasc describes IKACh as a
potential target for treatment of AF. Pharmacol. (2008), 52(2),
129-135.
SUMMARY
[0018] It is an object of the present invention to provide novel
compounds that are useful for the treatment (including prophylaxis)
of diseases, disorders and/or conditions which is affected and/or
mediated (fully or partially) by IKACh and where treatment by IKACh
blockade is beneficial, in particular cardiac arrhythmias, and more
specifically supraventricular tacharrhythmias, such as atrial
fibrillation and atrial flutter; and therewith associated
complications, such as congestive heart failure, ventricular
fibrillation, and thromboembolic events.
[0019] According to a first aspect, the invention provides a
compound of Formula I:
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein m, n,
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, x and y, are as
defined hereinafter.
[0020] It has been found that this group of compounds exhibit
electrophysiological activity, in particular IKACh blocking
activity. Thus, the compounds of the invention can be used as a
medicament, and in particular the compounds are expected to be
useful in the treatment of cardiac arrhythmias and therewith
associated complications in a patient in need thereof (i.e. a
person suffering from or susceptible to such a condition). The
patient may be a human or non-human animal, in particular a
human.
[0021] Compounds according to the invention are believed to be
useful for restoration and maintenance of sinus rhythm, in
particular maintenance of sinus rhythm. Compounds of the invention
may have advantageous properties compared to compounds of the prior
art, in particular enhanced potency, enhanced selectivity, and/or
reduction of total clearance. These advantages may provide for
corresponding useful properties in practice. For example, when used
as pharmaceutical agents, compounds of the present invention may
have a lower daily clinical dose, longer duration of action, and/or
an improved side effect profile. In particular, the compounds
according to the invention are atrial vs. ventricular selective
inhibitors of the potassium channel function.
[0022] Compounds of the invention may also have the advantage that
they may be more efficacious than, be less toxic than, have a
broader range of activity than, be more potent than, be longer
acting than, produce fewer side effects (including a lower
incidence of proarrhythmias such as TdP and CNS effects) than, be
more easily absorbed than, or that they may have other useful
pharmacological properties than compounds known in the prior
art.
[0023] According to a second aspect of the invention, there is
provided a method of treating cardiac arrhythmias and/or cardiac
diseases, disorders and/or conditions associated therewith by
administering a therapeutically effective amount of a compound of
the invention to a patient in need thereof.
[0024] According to a third aspect, there is provided a
pharmaceutical composition comprising a compound of Formula I and a
pharmaceutically acceptable carrier.
[0025] According to a fourth aspect of the invention, there is
provided a process for preparing the compounds of the Formula I and
salts thereof.
[0026] Other features and advantages of the present invention will
become apparent from the following description of the
invention.
BRIEF DESCRIPTION OF DRAWINGS
[0027] FIG. 1 shows the X-ray powder diffraction pattern for
(S)-2-Chloro-4-fluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)-
benzamide (Example 1.17).
[0028] FIG. 2 shows the X-ray powder diffraction pattern for
(S)-1-(2-(4-Bromo-N-methylbenzamido)-3-methylbutyl)azetidinium
sulfate (Example 5.2B).
[0029] FIG. 3 shows the X-ray powder diffraction pattern for
(S)-1-(2-(4-Bromo-N-methylbenzamido)-3-methylbutyl)azetidinium
2,3-dihydroxysuccinate (Example 5.2C).
[0030] FIG. 4 shows the X-ray powder diffraction pattern for
(S)-4-Fluoro-N-(1-(3-hydroxyazetidin-1-yl)-3-methylbutan-2-yl)-N,3-dimeth-
ylbenzamide (Example 6.1).
[0031] FIG. 5 shows the X-ray powder diffraction pattern for
(S)-4-Chloro-N-(1-(3-hydroxyazetidin-1-yl)-3-methylbutan-2-yl)-N-methylbe-
nzamide (Example 6.2).
[0032] FIG. 6 shows the X-ray powder diffraction pattern for
(S)-4-Chloro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N-methylbenzamide
hydrochloride (Example 8.2 B).
[0033] FIG. 7 shows the X-ray powder diffraction pattern for
(S)-4-Chloro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N-methylbenzamide
tartrate (Example 8.2 C).
[0034] FIG. 8 shows the X-ray powder diffraction pattern for
(S)-4-Fluoro-N,3-dimethyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)benza-
mide-dihydroxysuccinate (Example 12.1).
[0035] FIG. 9 shows the X-ray powder diffraction pattern for
(S)-1-(2-(3-Chloro-4-fluoro-N-methylbenzamido)-3-methylbutyl)pyrrolidiniu-
m chloride (Example 16.55B).
[0036] FIG. 10 shows the X-ray powder diffraction pattern for
(S)-1-(2-(4-Chloro-N-methylbenzamido)-3-methylbutyl)pyrrolidinium
chloride (Example 18).
DETAILED DESCRIPTION
[0037] The present invention relates to compounds of Formula I:
##STR00003##
or a pharmaceutically acceptable salt thereof, wherein
[0038] each optional R.sup.5 is independently selected from fluoro,
nitrile, hydroxy, oxo, C.sub.1-5 alkyl, C.sub.3-5 cycloalkyl,
C.sub.1-5 alkoxy or C.sub.1-5 alkoxyalkyl, wherein [0039] any
alkyl, cycloalkyl or alkoxy group is substituted by 0, 1 or 2
substituents independently selected from fluoro, nitrile or
hydroxy;
[0040] R.sup.1 is selected from C.sub.1-6 alkyl, C.sub.3-6
cycloalkyl or C.sub.1-6 alkoxyalkyl, wherein [0041] any alkyl,
cycloalkyl or alkoxy group is substituted by 0, 1 or 2 substituents
independently selected from fluoro or nitrile;
[0042] R.sup.2 is selected from hydrogen or C.sub.1-3 alkyl;
[0043] R.sup.3 is selected from C.sub.1-6 alkyl, C.sub.3-6
cycloalkyl or C.sub.1-6 alkoxyalkyl, wherein [0044] any alkyl or
cycloalkyl group in these substituents is substituted by 0, 1 or 2
substituents independently selected from fluoro, nitrile or
hydroxy;
[0045] each optional R.sup.4 is independently selected from halo,
nitrile, hydroxy, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3
alkoxyalkyl or C.sub.1-3 alkylsulfide, wherein [0046] any alkyl or
alkoxy group in these substituents is substituted by 0, 1, 2 or 3
substituents independently selected from halo, nitrile or
hydroxy;
[0047] m is selected from 1, 2 or 3 (thus forming azetidinyl,
pyrrolidinyl or piperidinyl);
[0048] n is selected from 1 or 2;
[0049] x is selected from 0, 1, 2, or 3; and
[0050] y is selected from 0, 1, 2 or 3.
[0051] It may be noted that, as known to persons skilled in the
art, an aliphatic carbon atom adjacent to a nitrogen atom, a
sulphur atom or an oxygen atom is in general preferably not
substituted with a hydroxy due to the potential chemical
instability of such compounds.
[0052] Different isomers may have different biological activity. It
may be the case that different compounds of Formula I may show the
highest biological activity with different configurations.
[0053] In a particular embodiment of the invention, the compounds
are represented by Formula Ia, or a pharmaceutically acceptable
salt thereof, wherein m, n, R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5, x and y, are as defined above.
##STR00004##
[0054] In an embodiment of the invention, the compounds are
represented by Formula I, or a pharmaceutically acceptable salt
thereof, wherein y is 0, 1 or 2, and each R.sup.5 is independently
selected from fluoro, nitrile, hydroxy, C.sub.1-5 alkyl, C.sub.3-5
cycloalkyl, C.sub.1-5 alkoxy or C.sub.1-5 alkoxyalkyl, wherein
[0055] any alkyl, cycloalkyl or alkoxy group is substituted by 0, 1
or 2 substituents independently selected from fluoro, nitrile or
hydroxy,
[0056] It shall be noted that R.sup.5 may be linked to any of the
ring carbon atoms of the N-containing heterocyclyl of Formula I,
i.e. the azetidinyl, pyrrolidinyl or piperidinyl of Formula I.
Moreover, two R.sup.5 (same or different) may also be linked to the
same ring carbon atom.
[0057] In a particular embodiment of the invention, the compounds
are represented by Formula I, or a pharmaceutically acceptable salt
thereof, wherein y is 0, 1 or 2, and each R.sup.5 is independently
selected from fluoro, nitrile, hydroxy, (unsubstituted) C.sub.1-3
alkyl, (unsubstituted) cyclopropyl, (unsubstituted) C.sub.1-3
alkoxy or (unsubstituted) C.sub.1-3 alkoxyalkyl.
[0058] Non-limiting examples of R.sup.5 are fluoro, nitrile,
hydroxy, methyl, cyclopropyl, methoxy, ethoxy, 1-methylethoxy,
cyanomethoxy or methoxymethyl.
[0059] In still another embodiment of the invention, the compounds
are represented by Formula I, or a pharmaceutically acceptable salt
thereof, wherein y is selected from 0, 1 or 2.
[0060] In a specific embodiment of the invention, the compounds are
represented by Formula I, or a pharmaceutically acceptable salt
thereof, wherein y is 1 and R.sup.5 is hydroxy.
[0061] In another embodiment of the invention, the compounds are
represented by Formula I, or a pharmaceutically acceptable salt
thereof, wherein n is 1.
[0062] In a particular embodiment of the invention, the compounds
are represented by Formula Ib, or a pharmaceutically acceptable
salt thereof, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, and x are
as defined above.
##STR00005##
[0063] In an embodiment of the invention, the compounds are
represented by Formula I (or Formula Ib) or a pharmaceutically
acceptable salt thereof, wherein R.sup.1 is selected from
(unsubstituted) C.sub.1-6 alkyl, (unsubstituted) C.sub.1-6
alkoxyalkyl or (unsubstituted) C.sub.3-6 cycloalkyl.
[0064] Non-limiting examples of R.sup.1 are methyl, ethyl, propyl,
isopropyl, butyl, 1-methyl-propyl, 2-methyl-propyl, 1-methoxyethyl,
1-(1,1-dimethylethoxy)-ethyl, 1,1-dimethylethyl, cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl.
[0065] In a further embodiment of the invention, the compounds are
represented by Formula I (or Formula Ib), or a pharmaceutically
acceptable salt thereof, wherein R.sup.1 is selected from
(unsubstituted) C.sub.1-4 alkyl, (unsubstituted) C.sub.1-4
alkoxyalkyl, (unsubstituted) cyclopropyl or (unsubstituted)
cyclobutyl, in particular (unsubstituted) C.sub.1-4 alkyl,
(unsubstituted) cyclopropyl or (unsubstituted) cyclobutyl, and more
specifically (unsubstituted) C.sub.2-4 alkyl (such as ethyl, propyl
and isopropyl), cyclopropyl or cyclobutyl.
[0066] In a particular embodiment of the invention, the compounds
are represented by Formula I (or Formula Ib), or a pharmaceutically
acceptable salt thereof, wherein R.sup.2 is selected from hydrogen
or methyl, in particular hydrogen.
[0067] In a further embodiment of the invention, the compounds are
represented by Formula I (or Formula Ib), or a pharmaceutically
acceptable salt thereof, wherein R.sup.3 is selected from
(unsubstituted) C.sub.1-6 alkyl, (unsubstituted) C.sub.1-6
alkoxyalkyl or (unsubstituted) C.sub.3-6 cycloalkyl.
[0068] Non-limiting examples of R.sup.3 are methyl, ethyl,
isopropyl, butyl, cyclopentyl, 2-methoxyethyl and
1-methyl-2-methoxyethyl.
[0069] In a particular embodiment of the invention, the compounds
are represented by Formula I (or Formula Ib), or a pharmaceutically
acceptable salt thereof, wherein R.sup.3 is selected from
(unsubstituted) C.sub.1-3 alkyl or (unsubstituted) C.sub.1-3
alkoxyalkyl, in particular (unsubstituted) C.sub.1-3 alkyl, such as
methyl.
[0070] In another embodiment of the invention, the compounds are
represented by Formula I (or Formula Ib), or a pharmaceutically
acceptable salt thereof, wherein x is 0, 1, 2 or 3 (in particular
0, 1 or 2) and each R.sup.4 is independently selected from chloro,
fluoro, bromo, nitrile, C.sub.1-3 alkyl, C.sub.1-3 alkoxy or
C.sub.1-3 alkylsulfide, wherein [0071] any alkyl or alkoxy group in
these substituents is substituted by 0, 1, 2 or 3 substituents
selected from fluoro or nitrite.
[0072] In still another embodiment of the invention, the compounds
are represented by Formula I (or Formula Ib), or a pharmaceutically
acceptable salt thereof, wherein x is 0, 1, 2 or 3 (in particular
0, 1 or 2) and each R.sup.4 is independently selected from chloro,
fluoro, bromo, nitrile, C.sub.1-3 alkyl or C.sub.1-3 alkoxy,
wherein [0073] any alkyl or alkoxy group in these substituents is
substituted by 0, 1, 2 or 3 substituents selected from fluoro or
nitrile.
[0074] Non-limiting examples of R.sup.4 are chloro, fluoro, bromo,
nitrile, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl,
methoxy, hydroxy, difluoromethoxy, trifluoromethoxy,
cyano-isopropyl and methylsulfide.
[0075] It shall be noted that R.sup.4 may be linked to any of the
ring carbon atoms of the phenyl group of Formula 1.
[0076] In still another embodiment of the invention, the compounds
are represented by Formula I (or Formula Ib), or a pharmaceutically
acceptable salt thereof, wherein x is selected from 0, 1 or 2, in
particular 1 or 2.
[0077] In still another embodiment of the invention, the compounds
are represented by Formula I (or Formula Ib), or a pharmaceutically
acceptable salt thereof, wherein x is 1 or 2 and R.sup.4 is
selected from chloro, fluoro, bromo, nitrile, methyl, ethyl,
isopropyl, difluoromethyl, trifluoromethyl, methoxy, hydroxy,
difluoromethoxy, trifluoromethoxy, cyano-isopropyl or
methylsulfide, in particular chloro, fluoro, bromo, nitrile or
methyl.
[0078] In a particular embodiment of the invention, the compounds
are represented by Formula Ic, or a pharmaceutically acceptable
salt thereof, wherein R.sup.1, R.sup.4, and x are as defined
above.
##STR00006##
[0079] One or more of the above embodiments may be combined to
provide further specific embodiments of the invention.
[0080] Examples of specific compounds according to Formula I of the
invention are: [0081]
(S)-N-(1-(Azetidin-1-yl)pentan-2-yl)-2,4-dichloro-N-methylbenzamide;
[0082]
(S)-N-(1-(Azetidin-1-yl)pentan-2-yl)-4-chloro-N-methylbenzamide;
[0083]
(S)-N-(1-(Azetidin-1-yl)pentan-2-yl)-4-bromo-N-methylbenzamide;
[0084]
(S)-N-(1-(Azetidin-1-yl)pentan-2-yl)-4-fluoro-N,3-dimethylbenzamid-
e; [0085]
(S)-4-Fluoro-N-(1-(3-fluoroazetidin-1-yl)-3-methylbutan-2-yl)-N,-
3-dimethylbenzamide; [0086]
(S)-4-Chloro-N-(1-(3-fluoroazetidin-1-yl)-3-methylbutan-2-yl)-N-methylben-
zamide; [0087] (S)-4-Bromo-N-(1-(3-fluoro
azetidin-1-yl)-3-methylbutan-2-yl)-N-methylbenzamide; [0088]
(S)-3-Chloro-4-fluoro-N-(1-(3-fluoroazetidin-1-yl)-3-methylbutan-2-yl)-N--
methylbenzamide; [0089]
(S)-4-Fluoro-N-(1-(3-fluoroazetidin-1-yl)-3-methylbutan-2-yl)-N-methyl-3--
(trifluoromethyl)benzamide; [0090]
(S)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-4-fluoro-N,3-dimethylbenzami-
de; [0091]
(S)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-4-fluoro-N-methyl--
3-(trifluoromethyl)benzamide; [0092]
(S)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-3-chloro-4-fluoro-N-methylbe-
nzamide;
[0093]
(S)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-3-chloro-N-methylbenza-
mide; [0094]
(S)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-N-methylbenzamide;
[0095]
(S)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-N-methyl-3-(trifluoromethyl)-
benzamide; [0096]
(S)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-N,3-dimethylbenzamide;
[0097]
(S)-2-Chloro-4-fluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)buta-
n-2-yl)benzamide; [0098]
(S)-3,4-Dichloro-N-(3,3-dimethyl-1-(pyrrolidin-1-yl)butan-2-yl)-N-methylb-
enzamide; [0099]
(S)-4-Bromo-N-(3,3-dimethyl-1-(pyrrolidin-1-yl)butan-2-yl)-N-methylbenzam-
ide; [0100]
4-Chloro-N-methyl-N-((2S,3S)-3-methyl-1-(pyrrolidin-1-yl)pentan-2-yl)benz-
amide; [0101]
4-Bromo-N-methyl-N-((2S,3S)-3-methyl-1-(pyrrolidin-1-yl)pentan-2-yl)benza-
mide; [0102]
4-Fluoro-N,3-dimethyl-N-((2S,3S)-3-methyl-1-(pyrrolidin-1-yl)pentan-2-yl)-
benzamide; [0103]
2,4-Dichloro-N-methyl-N-((2S,3S)-3-methyl-1-(pyrrolidin-1-yl)pentan-2-yl)-
benzamide; [0104]
4-Fluoro-N-((2R,3R)-3-methoxy-1-(pyrrolidin-1-yl)butan-2-yl)-N,3-dimethyl-
benzamide; [0105]
N-((2R,3R)-3-Methoxy-1-(pyrrolidin-1-yl)butan-2-yl)-N,3-dimethylbenzamide
[0106]
3-Chloro-4-fluoro-N-((2R,3R)-3-methoxy-1-(pyrrolidin-1-yl)butan-2--
yl)-N-methylbenzamide; [0107]
4-Bromo-N-((2R,3R)-3-methoxy-1-(pyrrolidin-1-yl)butan-2-yl)-N-methylbenza-
mide; [0108]
4-Chloro-N-((2R,3R)-3-methoxy-1-(pyrrolidin-1-yl)butan-2-yl)-N-methylbenz-
amide; [0109]
(S)-4-Bromo-N-(1-(4-methoxypiperidin-1-yl)-3-methylbutan-2-yl)-N-methylbe-
nzamide; [0110]
(S)-4-Chloro-N-(1-(4-methoxypiperidin-1-yl)-3-methylbutan-2-yl)-N-methylb-
enzamide; [0111]
(S)-4-Fluoro-N-(1-(4-methoxypiperidin-1-yl)-3-methylbutan-2-yl)-N,3-dimet-
hylbenzamide; [0112]
(S)-3-Chloro-4-fluoro-N-(1-(4-methoxypiperidin-1-yl)-3-methylbutan-2-yl)--
N-methylbenzamide; [0113]
(S)-N-(1-(4-Methoxypiperidin-1-yl)-3-methylbutan-2-yl)-N,3-dimethylbenzam-
ide; [0114]
(S)-3-Methoxy-N-(1-(4-methoxypiperidin-1-yl)-3-methylbutan-2-yl)-N,4-dime-
thylbenzamide; [0115]
(S)-N-(1-(4-Methoxypiperidin-1-yl)-3-methylbutan-2-yl)-N,3,4-trimethylben-
zamide; [0116]
(S)-N-(1-Cyclopropyl-2-(pyrrolidin-1-yl)ethyl)-4-fluoro-N,3-dimethylbenza-
mide; [0117]
(S)-4-Chloro-N-(1-cyclopropyl-2-(pyrrolidin-1-yl)ethyl)-N-methylbenzamide-
; [0118]
(S)-4-Bromo-N-(1-cyclopropyl-2-(pyrrolidin-1-yl)ethyl)-N-methylbe-
nzamide; [0119]
(S)-N-(1-Cyclopropyl-2-(pyrrolidin-1-yl)ethyl)-3,4-difluoro-N-methylbenza-
mide; [0120]
(S)-N-(1-Cyclopropyl-2-(pyrrolidin-1-yl)ethyl)-N,3-dimethylbenzamide;
[0121]
4-Methoxy-N-((S)-1-((S)-2-(methoxymethyl)pyrrolidin-1-yl)-3-methyl-
butan-2-yl)-N-methylbenz amide; [0122]
4-Chloro-N-((S)-1-(S)-2-(methoxymethyl)pyrrolidin-1-yl)-3-methylbutan-2-y-
l)-N-methylbenzamide; [0123]
4-Bromo-N-((S)-1-((S)-2-(methoxymethyl)pyrrolidin-1-yl)-3-methylbutan-2-y-
l)-N-methylbenzamide; [0124]
(S)-N-(2-(Azetidin-1-yl)-1-cyclopropylethyl)-4-fluoro-N,3-dimethylbenzami-
de; [0125]
(S)-N-(2-(Azetidin-1-yl)-1-cyclopropylethyl)-4-chloro-N-methylb-
enzamide; [0126]
(S)-N-(2-(Azetidin-1-yl)-1-cyclopropylethyl)-4-bromo-N-methylbenzamide;
[0127]
(S)-4-Bromo-N-(1-cyclopropyl-2-(3-hydroxyazetidin-1-yl)ethyl)-N-me-
thylbenzamide [0128]
(S)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-4-chloro-N-methylbenzamide;
[0129]
(S)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-4-bromo-N-methylbenza-
mide; [0130]
(S)-4-Fluoro-N-(1-(3-hydroxyazetidin-1-yl)-3-methylbutan-2-yl)-N,3-dimeth-
ylbenzamide; [0131]
(S)-4-Chloro-N-(1-(3-hydroxyazetidin-1-yl)-3-methylbutan-2-yl)-N-methylbe-
nzamide; [0132]
(S)-4-Bromo-N-(1-(3-hydroxyazetidin-1-yl)-3-methylbutan-2-yl)-N-methylben-
zamide; [0133]
(S)-N-(1-Cyclopropyl-2-(3-hydroxyazetidin-1-yl)ethyl)-4-fluoro-N,3-dimeth-
ylbenzamide; [0134]
(S)-4-Chloro-N-(1-cyclopropyl-2-(3-hydroxyazetidin-1-yl)ethyl)-N-methylbe-
nzamide; [0135]
(S)-3-Chloro-N-(1-cyclopropyl-2-(3-hydroxyazetidin-1-yl)ethyl)-4-fluoro-N-
-methylbenzamide; [0136]
(S)-N-(1-Cyclopropyl-2-(3-hydroxyazetidin-1-yl)ethyl)-4-fluoro-N-methylbe-
nzamide; [0137]
(S)-N-(1-Cyclopropyl-2-(3-hydroxyazetidin-1-yl)ethyl)-4-fluoro-N-methyl-3-
-(trifluoromethyl)benzamide; [0138]
(S)-3,4-Difluoro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N-methylbenzam-
ide; [0139]
(S)-4-Chloro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N-methylbenzamide;
[0140]
(S)-3-Chloro-4-fluoro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N--
methylbenzamide; [0141]
(S)-4-Chloro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N,3-dimethylbenzam-
ide; [0142]
(S)-4-Fluoro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N-methyl-3-(triflu-
oromethyl)benzamide; [0143]
(S)-4-Fluoro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N-methylbenzamide;
[0144]
(S)-4-Bromo-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N-methylbenz-
amide; [0145]
(S)-N-(1-(3-Hydroxyazetidin-1-yl)pentan-2-yl)-N-methyl-3-(trifluoro-methy-
l)benzamide; [0146]
(S)-4-Cyano-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N-methylbenzamide;
[0147]
(S)-N-(1-(3-Hydroxyazetidin-1-yl)pentan-2-yl)-N,3-dimethylbenzamid-
e; [0148]
(S)-4-Fluoro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N,3-dimet-
hylbenzamide; [0149]
N-((S)-1-((3S,4S)-3,4-Dihydroxypyrrolidin-1-yl)-3-methylbutan-2-yl)-4-flu-
oro-N,3-dimethylbenzamide; [0150]
4-Chloro-N-((S)-1-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-3-methylbutan-2--
yl)-N,3-dimethylbenzamide; [0151]
4-Chloro-N-((S)-1-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-3-methylbutan-2--
yl)-N-methylbenzamide; [0152]
4-Chloro-N-((S)-1-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-3-methylbutan-2--
yl)-3-fluoro-N-methylbenzamide; [0153]
4-Chloro-N-((S)-1-((3R,4R)-3,4-dihydroxypyrrolidin-1-yl)-3-methylbutan-2--
yl)-N,3-dimethylbenzamide; [0154]
(S)-4-Fluoro-N-(1-(3-hydroxyazetidin-1-yl)butan-2-yl)-N,3-dimethylbenzami-
de; [0155]
(S)-N-(1-Cyclopropyl-2-(3-cyclopropyl-3-hydroxyazetidin-1-yl)et-
hyl)-4-fluoro-N,3-dimethylbenzamide; [0156]
(S)-3-Chloro-N-(1-cyclopropyl-2-(3-cyclopropyl-3-hydroxyazetidin-1-yl)eth-
yl)-4-fluoro-N-methylbenzamide; [0157]
(S)-N-(1-Cyclopropyl-2-(3-cyclopropyl-3-hydroxyazetidin-1-yl)ethyl)-3,4-d-
ifluoro-N-methylbenzamide; [0158]
(S)-4-Cyano-N-(1-cyclopropyl-2-(3-cyclopropyl-3-hydroxyazetidin-1-yl)ethy-
l)-N-methylbenzamide; [0159]
(S)-N-(1-Cyclopropyl-2-(3-cyclopropyl-3-hydroxyazetidin-1-yl)ethyl)-N,3,4-
-trimethylbenzamide; [0160]
(S)-4-Bromo-N-(1-(3-hydroxy-3-methylazetidin-1-yl)-3-methylbutan-2-yl)-N--
methylbenzamide; [0161]
(S)-4-Chloro-N-(1-(3-hydroxy-3-methylazetidin-1-yl)-3-methylbutan-2-yl)-N-
-methylbenzamide; [0162]
(S)-4-Fluoro-N-(1-(3-hydroxy-3-methylazetidin-1-yl)-3-methylbutan-2-yl)-N-
-methyl-3-(trifluoromethyl)benzamide; [0163]
(S)-N-(1-Cyclopropyl-2-(3-hydroxyazetidin-1-yl)ethyl)-3,4-difluoro-N-meth-
ylbenzamide; [0164]
N-[(1S)-2-(azetidin-1-yl)-1-cyclopropylethyl]-N,3,4-trimethylbenzamide;
[0165]
(S)-N-(2-(Azetidin-1-yl)-1-cyclopropylethyl)-3,4-difluoro-N-methyl-
benzamide; [0166]
2-Chloro-4-fluoro-N-((S)-1-((S)-3-hydroxypyrrolidin-1-yl)-3-methylbutan-2-
-yl)-N-methylbenzamide; [0167]
4-Chloro-N-((S)-1-((S)-3-hydroxypyrrolidin-1-yl)-3-methylbutan-2-yl)-N-me-
thylbenzamide; [0168]
(S)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-4-chloro-N-ethylbenzamide;
[0169]
(S)-4-Fluoro-N,3-dimethyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-y-
l)benzamide; [0170]
(S)-N,3-Dimethyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)benzamide;
[0171]
(S)-3-Chloro-N-(1-cyclopropyl-2-(pyrrolidin-1-yl)ethyl)-4-fluoro-N-
-methyl-benzamide; [0172]
(S)-N-(1-Cyclopropyl-2-(pyrrolidin-1-yl)ethyl)-N,3,4-trimethylbenzamide;
[0173]
(R)-3-Chloro-N-methyl-N-(4-methyl-1-(pyrrolidin-1-yl)pentan-3-yl)b-
enzamide; [0174]
(R)-4-Fluoro-N,3-dimethyl-N-(4-methyl-1-(pyrrolidin-1-yl)pentan-3-yl)benz-
amide; [0175]
N-((2R,3R)-3-Tert-butoxy-1-(pyrrolidin-1-yl)butan-2-yl)-4-fluoro-N,3-dime-
thylbenzamide; [0176]
(S)-4-Bromo-N-ethyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)benzamide;
[0177]
(S)-N-Ethyl-4-fluoro-3-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-
-2-yl)benzamide; [0178]
(S)-4-Chloro-N-ethyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)benzamide;
[0179]
(S)-4-Chloro-N-(2-methoxyethyl)-N-(3-methyl-1-(pyrrolidin-1-yl)but-
an-2-yl)benzamide; [0180]
(S)-4-Bromo-N-(2-methoxyethyl)-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)-
benzamide; [0181]
(S)-3-Chloro-N-(1-(3,3-difluoropiperidin-1-yl)-3-methylbutan-2-yl)-4-fluo-
ro-N-methylbenzamide; [0182]
(S)-N-(1-(3,3-Difluoropiperidin-1-yl)-3-methylbutan-2-yl)-4-fluoro-N-meth-
yl-3-(trifluoromethyl)benzamide; [0183]
(S)-N-(1-(3,3-Difluoropiperidin-1-yl)-3-methylbutan-2-yl)-N,3,4-trimethyl-
benzamide; [0184]
(S)-N-(1-(3,3-Difluoropiperidin-1-yl)-3-methylbutan-2-yl)-3-methoxy-N,4-d-
imethylbenzamide; [0185]
(S)-4-Bromo-N-(1-(3,3-difluoropiperidin-1-yl)-3-methylbutan-2-yl)-N-methy-
l-benzamide; [0186]
4-Chloro-N-methyl-N-(2-methyl-1-(pyrrolidin-1-yl)propan-2-yl)benzamide;
[0187]
4-Bromo-N-methyl-N-(2-methyl-1-(pyrrolidin-1-yl)propan-2-yl)benzam-
ide; [0188]
(S)-3-Fluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)-5-(trifl-
uoromethyl)benzamide; [0189]
(S)-2,3,5-Trifluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)be-
nzamide; [0190]
(S)-N-Methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)-3-(tri-fluorometh-
yl)benzamide; [0191]
(S)-4-Fluoro-3-methoxy-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl-
)benzamide; [0192]
(S)-3,5-Difluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)benza-
mide; [0193]
(S)-3-Fluoro-N,2-dimethyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)benza-
mide; [0194]
(S)-N,4-Dimethyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)benzamide;
[0195]
(S)-N-Methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)-4-(tri-flu-
oromethoxy)benzamide; [0196]
(S)-N-Methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)-3-(tri-fluorometh-
oxy)benz amide; [0197]
(S)-3-Chloro-2-fluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)-
benzamide; [0198]
(S)-2-Fluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)benzamide-
; [0199]
(S)-2-Fluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)--
6-(trifluoromethyl)benzamide; [0200]
(S)-N-Methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)-2-(trifluoromethy-
l)benzamide; [0201]
(S)-3,4,5-Trifluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)be-
nzamide; [0202]
(S)-2,5-Difluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)benza-
mide; [0203]
(S)-4-Fluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)-2-(trifl-
uoromethyl)benzamide; [0204]
2,6-Difluoro-N-methyl-N-[(1S)-2-methyl-1-(pyrrolidin-1-ylmethyl)propyl]be-
nzamide; [0205]
4-Chloro-N,3-dimethyl-N-[(1S)-2-methyl-1-(piperidin-1-ylmethyl)propyl]ben-
zamide; [0206]
2-Chloro-4-fluoro-N-methyl-N-[(1S)-2-methyl-1-(piperidin-1-yl-methyl)prop-
yl]benzamide; [0207]
4-Bromo-N-methyl-N-[(1S)-2-methyl-1-(piperidin-1-ylmethyl)propyl]benzamid-
e; [0208]
3,4-Dichloro-N-methyl-N-[(1S)-2-methyl-1-(piperidin-1-ylmethyl)p-
ropyl]benzamide; [0209]
N,3-Dimethyl-N-[(1S)-2-methyl-1-(piperidin-1-ylmethyl)propyl]benzamide;
[0210]
2,4-Dichloro-N-methyl-N-[(1S)-2-methyl-1-(piperidin-1-ylmethyl)pro-
pyl]benzamide; [0211]
4-Chloro-2-fluoro-N-methyl-N-[(1S)-2-methyl-1-(piperidin-1-ylmethyl)propy-
l]-benzamide; [0212]
N-Methyl-N-[(1S)-2-methyl-1-(piperidin-1-ylmethyl)propyl]-3-(trifluoromet-
hyl)-benzamide; [0213]
3-Chloro-4-fluoro-N-methyl-N-[(1S)-2-methyl-1-(piperidin-1-ylmethyl)propy-
l]-benzamide; [0214]
4-Chloro-N-methyl-N-[(1S)-2-methyl-1-(piperidin-1-ylmethyl)propyl]benzami-
de; [0215]
(S)-3-Bromo-N-methyl-N-(3-methyl-1-(piperidin-1-yl)butan-2-yl)b-
enzamide; [0216]
(S)-4-Bromo-3-fluoro-N-methyl-N-(3-methyl-1-(piperidin-1-yl)butan-2-yl)be-
nzamide; [0217]
(S)-3-Chloro-N-methyl-N-(3-methyl-1-(piperidin-1-yl)butan-2-yl)benzamide;
[0218]
(S)-3-Fluoro-N,2-dimethyl-N-(3-methyl-1-(piperidin-1-yl)butan-2-yl-
)benzamide; [0219]
3-Chloro-2-fluoro-N-[(1S)-1-{[(3S)-3-hydroxypyrrolidin-1-yl]methyl}-2-met-
hylpropyl]-N-methylbenzamide; [0220]
4-Fluoro-N-[(1S)-1-{[(3S)-3-hydroxypyrrolidin-1-yl]methyl}-2-methylpropyl-
]-N,3-dimethylbenzamide; [0221]
N-[(1S)-1-{[(3S)-3-Hydroxypyrrolidin-1-yl]methyl}-2-methylpropyl]-N-methy-
l-4-(trifluoromethoxy)benzamide; [0222]
N-[(1S)-1-{[(3S)-3-Hydroxypyrrolidin-1-yl]methyl}-2-methylpropyl]-N-methy-
l-3-(tri-fluoromethoxy)benzamide; [0223]
N-[(1S)-1-{[(3S)-3-Hydroxypyrrolidin-1-yl]methyl}-2-methylpropyl]-N,4-s
dimethylbenzamide; [0224]
3-Fluoro-N-[(1S)-1-{[(3S)-3-hydroxypyrrolidin-1-yl]methyl}-2-methylpropyl-
]-N-methyl-5-(trifluoromethyl)benzamide; [0225]
3-Fluoro-N-((S)-1-((S)-3-hydroxypyrrolidin-1-yl)-3-methylbutan-2-yl)-N,2--
dimethylbenzamide; [0226]
4-Fluoro-N-((S)-1-((S)-3-hydroxypyrrolidin-1-yl)-3-methylbutan-2-yl)-N-me-
thyl-2-(trifluoromethyl)benzamide; [0227]
(S)-2,4-Dichloro-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)benza-
mide; [0228]
(S)-3-Chloro-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)benzamide-
; [0229]
(S)-4-Isopropyl-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-y-
l)benzamide; [0230]
(S)-4-Chloro-N,3-dimethyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)benza-
mide; [0231]
(S)-3,4-Dichloro-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)benza-
mide; [0232]
(S)-4-Bromo-3-fluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)b-
enzamide; [0233]
(S)-4-Chloro-2-fluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)-
benzamide; [0234]
(S)-2-(Difluoromethoxy)-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-y-
l)benzamide; [0235]
(S)-3-Chloro-4-fluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)-
benzamide; [0236]
(R)-3,4-Dichloro-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)benza-
mide; [0237]
(R)-4-Bromo-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)benzamide;
[0238]
(R)-2,4-Dichloro-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-y-
l)benzamide; [0239]
(R)-4-Chloro-2-fluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)-
benzamide; [0240]
(R)-4-Bromo-3-fluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)b-
enzamide; [0241]
(S)-4-Bromo-N-methyl-N-(1-(pyrrolidin-1-yl)butan-2-yl)benzamide;
[0242]
(S)-3,4-Dichloro-N-methyl-N-(1-(pyrrolidin-1-yl)butan-2-yl)benzamide;
[0243]
4-Fluoro-N-((S)-1-((R)-3-hydroxypyrrolidin-1-yl)-3-methylbutan-2-y-
l)-N,3-dimethylbenzamide; [0244]
4-Chloro-N-((S)-1-((R)-3-hydroxypyrrolidin-1-yl)-3-methylbutan-2-yl)-N-me-
thylbenzamide; [0245]
4-Bromo-N-((S)-1-((R)-3-hydroxypyrrolidin-1-yl)-3-methylbutan-2-yl)-N-met-
hylbenzamide; [0246]
3-Chloro-4-fluoro-N-((S)-1-((R)-3-hydroxypyrrolidin-1-yl)-3-methylbutan-2-
-yl)-N-methylbenzamide; [0247]
4-Fluoro-N-((S)-1-((R)-3-hydroxypyrrolidin-1-yl)-3-methylbutan-2-yl)-N-me-
thyl-3-(trifluoromethyl)benzamide; [0248]
(S)-4-Chloro-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)benzamide-
; [0249]
(S)-4-Bromo-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)be-
nzamide; [0250]
(S)-4-Chloro-N-cyclopentyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)benz-
amide; [0251]
(S)-N-(1-(3,3-Difluoropyrrolidin-1-yl)-3-methylbutan-2-yl)-N,3,4-trimethy-
lbenzamide; [0252]
(S)-4-Fluoro-N-(1-(3-hydroxyazetidin-1-yl)-2,3-dimethylbutan-2-yl)-N,3-di-
methylbenzamide; [0253]
(S)-N-(1-(3-Hydroxyazetidin-1-yl)pentan-2-yl)-N,3,4-trimethylbenzamide;
[0254]
(S)-4-Fluoro-N-(1-(4-hydroxypiperidin-1-yl)-3-methylbutan-2-yl)-N,-
3-dimethylbenzamide; [0255]
(R)-4-Fluoro-N-(1-(4-hydroxypiperidin-1-yl)-3-methylbutan-2-yl)-N,3-dimet-
hylbenzamide; [0256]
(S)-N-(1-(4-Cyanopiperidin-1-yl)-3-methylbutan-2-yl)-4-fluoro-N,3-dimethy-
lbenzamide; [0257]
(S)-4-Chloro-N-(1-(4-hydroxypiperidin-1-yl)-3-methylbutan-2-yl)-N-methylb-
enzamide;
[0258]
(S)-3,4-Difluoro-N-(1-(3-(methoxymethyl)azetidin-1-yl)-3-methylbut-
an-2-yl)-N-methylbenzamide; [0259]
3,4-Difluoro-N-((2S,3S)-1-(3-hydroxyazetidin-1-yl)-3-methylpentan-2-yl)-N-
-methylbenzamide; [0260]
4-Chloro-N-((2S,3S)-1-(3-hydroxyazetidin-1-yl)-3-methylpentan-2-yl)-N-met-
hylbenzamide; [0261]
4-Ethyl-N-((2S,3S)-1-(3-hydroxyazetidin-1-yl)-3-methylpentan-2-yl)-N-meth-
ylbenzamide; [0262]
N-((2S,3S)-1-(3-Hydroxyazetidin-1-yl)-3-methylpentan-2-yl)-N-methylbenzam-
ide; [0263]
4-Cyano-N-((2S,3S)-1-(3-hydroxyazetidin-1-yl)-3-methylpentan-2-yl)-N-meth-
ylbenzamide; [0264]
N-((2S,3S)-1-(3-Hydroxyazetidin-1-yl)-3-methylpentan-2-yl)-4-methoxy-N-me-
thylbenzamide; [0265]
4-Cyano-2-fluoro-N-((2S,3S)-1-(3-hydroxyazetidin-1-yl)-3-methylpentan-2-y-
l)-N-methylbenzamide; [0266]
N-((2S,3S)-1-(3-Hydroxyazetidin-1-yl)-3-methylpentan-2-yl)-2-methoxy-N,5--
dimethylbenzamide; [0267]
5-Chloro-N-((2S,3S)-1-(3-hydroxyazetidin-1-yl)-3-methylpentan-2-yl)-2-met-
hoxy-N-methylbenzamide; [0268]
4-Chloro-N-((2R,3R)-1-(3-hydroxyazetidin-1-yl)-3-methoxybutan-2-yl)-N-met-
hylbenzamide; [0269]
(S)-4-Chloro-N-(1-(3-ethoxyazetidin-1-yl)pentan-2-yl)-N-methylbenzamide;
[0270]
(S)-4-Chloro-N-(1-(3-methoxyazetidin-1-yl)pentan-2-yl)-N-methylben-
zamide; [0271]
4-Chloro-N-{(2S)-1-[3-(cyanomethoxy)azetidin-1-yl]pentan-2-yl}-N-methylbe-
nzamide; [0272]
4-Chloro-N-methyl-N-{(2S)-1-[3-(propan-2-yloxy)azetidin-1-yl]pentan-2-yl}-
benzamide; [0273]
(R)-N-(1-Cyclopentyl-2-(3-hydroxyazetidin-1-yl)ethyl)-3,4-difluoro-N-meth-
ylbenzamide; [0274]
(S)-N-(1-Cyclopentyl-2-(3-hydroxyazetidin-1-yl)ethyl)-3,4-difluoro-N-meth-
ylbenzamide; [0275]
(R)-N-[1-Cyclopentyl-2-(3-hydroxyazetidin-1-yl)ethyl]-4-methoxy-N-methylb-
enzamide; [0276]
(S)-N-[1-Cyclopentyl-2-(3-hydroxyazetidin-1-yl)ethyl]-4-methoxy-N-methylb-
enzamide; [0277]
(R)-4-Chloro-N-[1-cyclopentyl-2-(3-hydroxyazetidin-1-yl)ethyl]-N-methylbe-
nzamide; [0278]
(S)-4-Chloro-N-[1-cyclopentyl-2-(3-hydroxyazetidin-1-yl)ethyl]-N-methylbe-
nzamide; [0279]
(R)-N-[1-Cyclopentyl-2-(3-hydroxyazetidin-1-yl)ethyl]-4-fluoro-N,3-dimeth-
ylbenzamide; [0280]
(S)-N-[1-Cyclopentyl-2-(3-hydroxyazetidin-1-yl)ethyl]-4-fluoro-N,3-dimeth-
ylbenzamide; [0281]
(R)-4-Cyano-N-[1-cyclopentyl-2-(3-hydroxyazetidin-1-yl)ethyl]-N-methylben-
zamide; [0282]
(S)-4-Cyano-N-[1-cyclopentyl-2-(3-hydroxyazetidin-1-yl)ethyl]-N-methylben-
zamide; [0283]
(R)-2-Chloro-N-[1-cyclopentyl-2-(3-hydroxyazetidin-1-yl)ethyl]-4-fluoro-N-
-methylbenzamide; [0284]
(S)-2-Chloro-N-[1-cyclopentyl-2-(3-hydroxyazetidin-1-yl)ethyl]-4-fluoro-N-
-methylbenzamide; [0285]
(R)-3-Chloro-N-[1-cyclopentyl-2-(3-hydroxyazetidin-1-yl)ethyl]-4-fluoro-N-
-methylbenzamide; [0286]
(S)-3-Chloro-N-[1-cyclopentyl-2-(3-hydroxyazetidin-1-yl)ethyl]-4-fluoro-N-
-methylbenzamide; [0287]
(S)-4-Chloro-N-(1-(3-hydroxyazetidin-1-yl)hexan-2-yl)-N-methylbenzamide;
[0288]
3,4-Difluoro-N-[(2S)-1-(3-hydroxyazetidin-1-yl)hexan-2-yl]-N-methy-
lbenzamide; [0289]
4-Cyano-2-fluoro-N-[(2S)-1-(3-hydroxyazetidin-1-yl)hexan-2-yl]-N-methylbe-
nzamide; [0290]
4-Cyano-N-[(2S)-1-(3-hydroxyazetidin-1-yl)hexan-2-yl]-N-methylbenzamide;
[0291]
N-[(2S)-1-(3-Hydroxyazetidin-1-yl)hexan-2-yl]-N-methylbenzamide;
[0292]
4-Hydroxy-N-[(2S)-1-(3-hydroxyazetidin-1-yl)hexan-2-yl]-N-methylbe-
nzamide; [0293]
4-Fluoro-N-[(2S)-1-(3-hydroxyazetidin-1-yl)hexan-2-yl]-N-methylbenzamide;
[0294]
3-Chloro-4-fluoro-N-[(2S)-1-(3-hydroxyazetidin-1-yl)hexan-2-yl]-N--
methylbenzamide; [0295]
2,5-Difluoro-N-[(2S)-1-(3-hydroxyazetidin-1-yl)hexan-2-yl]-N-methylbenzam-
ide; [0296]
3-(Difluoromethyl)-N-[(2S)-1-(3-hydroxyazetidin-1-yl)hexan-2-yl]-N-methyl-
benzamide; [0297]
4-Chloro-N-[(2S)-1-(3-hydroxyazetidin-1-yl)pentan-2-yl]-N-(propan-2-yl)be-
nzamide; [0298]
3,4-Difluoro-N-[(2S)-1-(3-hydroxyazetidin-1-yl)pentan-2-yl]-N-(propan-2-y-
l)benzamide; [0299]
4-Chloro-N-[(1R)-1-cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]-N-methylbe-
nzamide; [0300]
4-Cyano-N-[(1R)-1-cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]-N-methylben-
zamide; [0301]
N-[(1R)-1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]-4-(difluoromethoxy)-
-N-methylbenzamide; [0302]
N-[(1R)-1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]-4-fluoro-N,3-dimeth-
ylbenzamide; [0303]
N-[(1R)-1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]-4-fluoro-N-methylbe-
nzamide; [0304]
2-Chloro-N-[(1R)-1-cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]-4-fluoro-N-
-methylbenzamide; [0305]
N-[(1R)-1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]-3,4-difluoro-N-meth-
ylbenzamide; [0306]
N-[(1R)-1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]-3-(difluoromethyl)--
N-methylbenzamide; [0307]
3-Cyano-N-[(1R)-1-cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]-4-fluoro-N--
methylbenzamide; [0308]
N-[(1R)-1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]-2,4-difluoro-N-meth-
ylbenzamide; [0309]
3-Chloro-N-[(1R)-1-cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]-2-fluoro-N-
-methylbenzamide; [0310]
N-[(1R)-1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]-2-fluoro-4-methoxy--
N-methylbenzamide; [0311]
N-[(1R)-1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]-3-fluoro-4-methoxy--
N-methylbenzamide; [0312]
N-[(1R)-1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]-N-methylbenzamide;
[0313]
4-Cyano-N-[(1S)-1-cyclohexyl-2-(3-hydroxyazetidin-1-yl)ethyl]-N-me-
thylbenzamide; [0314]
4-Chloro-N-[(1S)-1-cyclohexyl-2-(3-hydroxyazetidin-1-yl)ethyl]-N-methylbe-
nzamide; [0315]
3-Cyano-N-[(1S)-1-cyclohexyl-2-(3-hydroxyazetidin-1-yl)ethyl]-N-methylben-
zamide; [0316]
4-Cyano-N-[(1S)-1-cyclohexyl-2-(3-hydroxyazetidin-1-yl)ethyl]-2-fluoro-N--
methylbenzamide; [0317]
4-(2-Cyanopropan-2-yl)-N-[(1S)-1-cyclohexyl-2-(3-hydroxyazetidin-1-yl)eth-
yl]-N-methylbenzamide; [0318]
3-Cyano-N-[(1S)-1-cyclohexyl-2-(3-hydroxyazetidin-1-yl)ethyl]-5-fluoro-N--
methylbenzamide; [0319]
N-[(1S)-1-Cyclohexyl-2-(3-hydroxyazetidin-1-yl)ethyl]-4-fluoro-N-methylbe-
nzamide; [0320]
N-[(1S)-1-Cyclohexyl-2-(3-hydroxyazetidin-1-yl)ethyl]-N-methylbenzamide;
[0321]
4-Chloro-N-[(2R)-1-(3-hydroxyazetidin-1-yl)pentan-2-yl]-N-methylbe-
nzamide; [0322]
3,4-Difluoro-N-[(2S)-1-(3-hydroxyazetidin-1-yl)-4-methylpentan-2-yl]-N-me-
thylbenzamide; [0323]
4-Chloro-N-[(2S)-1-(3-hydroxyazetidin-1-yl)-4-methylpentan-2-yl]-N-methyl-
benzamide; [0324]
4-Ethyl-N-[(2S)-1-(3-hydroxyazetidin-1-yl)-4-methylpentan-2-yl]-N-methylb-
enzamide; [0325]
3-(Difluoromethyl)-N-[(2S)-1-(3-hydroxyazetidin-1-yl)-4-methylpentan-2-yl-
]-N-methylbenzamide; [0326]
4-Fluoro-N-[(2S)-1-(3-hydroxyazetidin-1-yl)-4-methylpentan-2-yl]-3-methox-
y-N-methylbenzamide; [0327]
4-Cyano-2-fluoro-N-[(2S)-1-(3-hydroxyazetidin-1-yl)-4-methylpentan-2-yl]--
N-methylbenzamide; [0328]
4-Chloro-N-[(2S)-1-(3-hydroxyazetidin-1-yl)-4-methylpentan-2-yl]-2-methox-
y-N-methylbenzamide; [0329]
N-[(2S)-1-(3-Hydroxyazetidin-1-yl)-4-methylpentan-2-yl]ethyl-4-(methylsul-
fanyl)benzamide; [0330]
(S)-2-chloro-N-(1-cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-4-fluoro-N--
methylbenzamide; [0331]
(S)-4-Cyano-N-(1-cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-N-methylbenz-
amide; [0332]
(S)-N-(1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-3,4-difluoro-N-methy-
lbenzamide; [0333]
(S)-N-(1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-2,4-difluoro-N-methy-
lbenzamide; [0334]
(S)-N-(1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-2-fluoro-4-methoxy-N-
-methylbenzamide; [0335]
(S)-N-(1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-3-fluoro-4-methoxy-N-
-methylbenzamide; [0336]
(S)-N-(1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-N-methylbenzamide;
[0337]
(S)-N-(1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-N-methyl-4-(t-
rifluoromethyl)benzamide; [0338]
(S)-N-(1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-4-methoxy-N,3-dimeth-
ylbenzamide; [0339]
(S)-N-(1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-2-fluoro-N,5-dimethy-
lbenzamide; [0340]
(S)-4-Chloro-3-fluoro-N-(1-(3-hydroxyazetidin-1-yl)butan-2-yl)-N-methylbe-
nzamide; [0341]
(S)-4-Chloro-N-(1-(3-hydroxyazetidin-1-yl)butan-2-yl)-N-methylbenzamide;
[0342]
(S)-N-(1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-4-fluoro-N-me-
thylbenzamide; [0343]
(S)-4-Chloro-N-(1-cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-N-methylben-
zamide; [0344]
(S)-N-(1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-3-(difluoromethyl)-N-
-methylbenzamide; [0345]
(S)-N-(1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-4-fluoro-N,3-dimethy-
lbenzamide [0346]
(S)-4-Chloro-N-(1-(3-hydroxyazetidin-1-yl)propan-2-yl)-N-methylbenzamide;
[0347]
(S)-N-(1-(3-Hydroxyazetidin-1-yl)propan-2-yl)-N,3,4-trimethylbenza-
mide; [0348]
(S)-4-Chloro-3-fluoro-N-(1-(3-hydroxyazetidin-1-yl)propan-2-yl)-N-methylb-
enzamide; [0349]
(S)-4-Chloro-N-(1-(3-hydroxyazetidin-1-yl)propan-2-yl)-N,3-dimethylbenzam-
ide; [0350]
(S)-4-Bromo-N-(1-(3-hydroxyazetidin-1-yl)propan-2-yl)-N-methylbenzamide;
[0351]
(S)-4-Bromo-N-(1-(3-hydroxyazetidin-1-yl)butan-2-yl)-N-methylbenza-
mide; [0352]
4-Chloro-N-((S)-1-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)pentan-2-yl)-N-
-methylbenzamide; [0353]
4-Chloro-N-((S)-1-((2R,3S)-3-hydroxy-2-methylazetidin-1-yl)pentan-2-yl)-N-
-methylbenzamide; [0354]
4-Fluoro-N-((S)-1-((2R*,3S*)-3-hydroxy-2-methylazetidin-1-yl)pentan-2-yl)-
-N-methylbenzamide; [0355]
3,4-Difluoro-N-((S)-1-((2R*,3S*)-3-hydroxy-2-methylazetidin-1-yl)pentan-2-
-yl)-N-methylbenzamide; [0356]
4-Chloro-N-((S)-1-((2S,3S)-3-hydroxy-2-methylazetidin-1-yl)pentan-2-yl)-N-
-methylbenzamide; [0357]
4-Chloro-N-((S)-1-((2R,3R)-3-hydroxy-2-methylazetidin-1-yl)pentan-2-yl)-N-
-methylbenzamide; [0358]
3,4-Difluoro-N-((S)-1-((2S,3S)-3-hydroxy-2-methylazetidin-1-yl)pentan-2-y-
l)-N-methylbenzamide; [0359]
3,4-Difluoro-N-((S)-1-((2R,3R)-3-hydroxy-2-methylazetidin-1-yl)pentan-2-y-
l)-N-methylbenzamide; [0360]
4-Fluoro-N-((S)-1-((2S,3S)-3-hydroxy-2-methylazetidin-1-yl)pentan-2-yl)-N-
-methylbenzamide; [0361]
4-Fluoro-N-((S)-1-((2R,3R)-3-hydroxy-2-methylazetidin-1-yl)pentan-2-yl)-N-
-methylbenzamide; [0362]
(S)-4-Chloro-N-(1-(4-hydroxypiperidin-1-yl)pentan-2-yl)-N-methylbenzamide-
; [0363]
(S)-4-Chloro-N-(1-(4-methoxypiperidin-1-yl)pentan-2-yl)-N-methylb-
enzamide; [0364]
4-Cyano-N-((S)-1-((S)-3-hydroxypyrrolidin-1-yl)pentan-2-yl)-N-methylbenza-
mide; [0365]
4-Chloro-N-((S)-1-((S)-3-hydroxypyrrolidin-1-yl)pentan-2-yl)-N-methylbenz-
amide, or a pharmaceutically acceptable salt of any of the forgoing
compounds. It shall be noted that any one or more of these specific
compounds may be disclaimed from any of the herein mentioned
embodiments of the invention.
[0366] In a further specific embodiment of the invention, the
compounds are represented by Formula I, or a pharmaceutically
acceptable salt thereof, wherein each optional R.sup.5 is
independently selected from fluoro, nitrile, hydroxy, C.sub.1-3
alkyl, cyclopropyl, C.sub.1-3 alkoxy or C.sub.1-3 alkoxyalkyl;
[0367] R.sup.1 is selected from C.sub.1-6 alkyl, C.sub.1-6
alkoxyalkyl or C.sub.3-6 cycloalkyl;
[0368] R.sup.2 is hydrogen;
[0369] R.sup.3 is selected from C.sub.1-6 alkyl, C.sub.1-6
alkoxyalkyl or C.sub.3-6 cycloalkyl;
[0370] each R.sup.4 is independently selected from chloro, fluoro,
bromo, nitrile, C.sub.1-3 alkyl, C.sub.1-3 alkoxy or C.sub.1-3
alkylsulfide, wherein [0371] any alkyl or alkoxy group in these
substituents is substituted by 0, 1, 2 or 3 substituents
independently selected from fluoro or nitrile;
[0372] m is selected from 1, 2 or 3;
[0373] n is 1;
[0374] y is selected from 0, 1 or 2; and
[0375] x is selected from 1 or 2.
[0376] In a still further specific embodiment of the invention, the
compounds are represented by Formula I, or a pharmaceutically
acceptable salt thereof, wherein R.sup.5 is hydroxy;
[0377] R.sup.1 is selected from C.sub.1-6 alkyl, C.sub.1-6
alkoxyalkyl or C.sub.3-6 cycloalkyl;
[0378] R.sup.2 is hydrogen;
[0379] R.sup.3 is selected from C.sub.1-6 alkyl, C.sub.1-6
alkoxyalkyl or C.sub.3-6 cycloalkyl;
[0380] each R.sup.4 is independently selected from chloro, fluoro,
bromo, nitrile, methyl, difluoromethyl, trifluoromethyl, methoxy,
hydroxy, difluoromethoxy, trifluoromethoxy or methylsulfide;
[0381] m is 1 (thus forming azetidinyl);
[0382] n is 1;
[0383] y is selected from 0, 1 or 2; and
[0384] x is selected from 1 or 2.
[0385] In a still further specific embodiment of the invention, the
compounds are represented by Formula Ic, or a pharmaceutically
acceptable salt thereof, wherein
##STR00007##
[0386] R.sup.1 is selected from C.sub.1-6 alkyl, C.sub.1-6
alkoxyalkyl or C.sub.3-6 cycloalkyl;
[0387] each R.sup.4 is independently selected from chloro, fluoro,
bromo, nitrile, methyl, difluoromethyl, trifluoromethyl or methoxy,
in particular chloro, fluoro, bromo, nitrile or methyl; and
[0388] x is selected from 0, 1 or 2.
[0389] In a further specific embodiment of the invention, the
compounds are represented by Formula Ic, or a pharmaceutically
acceptable salt thereof, wherein
[0390] R.sup.1 is selected from C.sub.2-4 alkyl or C.sub.3-6
cycloalkyl, such as ethyl, propyl, isopropyl, butyl,
1-methyl-propyl, 2-methyl-propyl, cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl;
[0391] each R.sup.4 is independently selected from chloro, fluoro,
bromo, nitrile, methyl, difluoromethyl, trifluoromethyl or methoxy;
and
[0392] x is selected from 0, 1 or 2.
[0393] In a more specific embodiment of the invention, the
compounds are represented by Formula Ic, or a pharmaceutically
acceptable salt thereof, wherein
[0394] R.sup.1 is selected from C.sub.2-4 alkyl or C.sub.3-6
cycloalkyl, such as ethyl, propyl, isopropyl, butyl,
1-methyl-propyl, 2-methyl-propyl, cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl;
[0395] each R.sup.4 is independently selected from chloro, fluoro,
bromo, nitrile or methyl; and
[0396] x is selected from 1 or 2.
[0397] In a further specific embodiment of the invention, the
compounds are represented by Formula Id, or a pharmaceutically
acceptable salt thereof, wherein
##STR00008##
[0398] R.sup.1 is selected from ethyl, propyl, isopropyl, butyl,
1-methyl-propyl, 2-methyl-propyl, cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl;
[0399] R.sup.6 is selected from hydrogen, chloro, fluoro or methyl;
and
[0400] R.sup.7 is selected from chloro, fluoro, bromo, nitrile or
methyl, in particular chloro, fluoro, bromo or nitrile.
[0401] Examples of specific compounds according to Formula Id of
the invention are: [0402]
4-Bromo-N-(1-cyclopropyl-2-(3-hydroxyazetidin-1-yl)ethyl)-N-methylbenzami-
de; [0403]
4-Fluoro-N-(1-(3-hydroxyazetidin-1-yl)-3-methylbutan-2-yl)-N,3--
dimethylbenzamide; [0404]
4-Chloro-N-(1-(3-hydroxyazetidin-1-yl)-3-methylbutan-2-yl)-N-methylbenzam-
ide; [0405]
4-Bromo-N-(1-(3-hydroxyazetidin-1-yl)-3-methylbutan-2-yl)-N-methylbenzami-
de; [0406]
N-(1-Cyclopropyl-2-(3-hydroxyazetidin-1-yl)ethyl)-4-fluoro-N,3--
dimethylbenzamide; [0407]
4-Chloro-N-(1-cyclopropyl-2-(3-hydroxyazetidin-1-yl)ethyl)-N-methylbenzam-
ide; [0408]
3-Chloro-N-(1-cyclopropyl-2-(3-hydroxyazetidin-1-yl)ethyl)-4-fluoro-N-met-
hylbenzamide; [0409]
N-(1-Cyclopropyl-2-(3-hydroxyazetidin-1-yl)ethyl)-4-fluoro-N-methylbenzam-
ide; [0410]
3,4-Difluoro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N-methylbenzamide;
[0411]
4-Chloro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N-methylbenzami-
de; [0412]
3-Chloro-4-fluoro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N-m-
ethylbenzamide; [0413]
4-Chloro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N,3-dimethylbenzamide;
[0414]
4-Fluoro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N-methylbenzami-
de; [0415]
4-Bromo-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N-methylbenza-
mide; [0416]
4-Cyano-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N-methylbenzamide;
[0417]
4-Fluoro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N,3-dimethylben-
zamide; [0418]
4-Fluoro-N-(1-(3-hydroxyazetidin-1-yl)butan-2-yl)-N,3-dimethylbenzamide;
[0419]
N-(1-Cyclopropyl-2-(3-hydroxyazetidin-1-yl)ethyl)-3,4-difluoro-N-m-
ethylbenzamide; [0420]
N-(1-(3-Hydroxyazetidin-1-yl)pentan-2-yl)-N,3,4-trimethylbenzamide;
[0421]
3,4-Difluoro-N-(1-(3-hydroxyazetidin-1-yl)-3-methylpentan-2-yl)-N--
methylbenzamide; [0422]
4-Chloro-N-(1-(3-hydroxyazetidin-1-yl)-3-methylpentan-2-yl)-N-methylbenza-
mide; [0423]
4-Cyano-N-(1-(3-hydroxyazetidin-1-yl)-3-methylpentan-2-yl)-N-methylbenzam-
ide; [0424]
N-(1-Cyclopentyl-2-(3-hydroxyazetidin-1-yl)ethyl)-3,4-difluoro-N-methylbe-
nzamide; [0425]
4-chloro-N-[1-cyclopentyl-2-(3-hydroxyazetidin-1-yl)ethyl]-N-methylbenzam-
ide; [0426]
N-[1-cyclopentyl-2-(3-hydroxyazetidin-1-yl)ethyl]-4-fluoro-N,3-dimethylbe-
nzamide; [0427]
4-cyano-N-[1-cyclopentyl-2-(3-hydroxyazetidin-1-yl)ethyl]-N-methylbenzami-
de; [0428]
3-chloro-N-[1-cyclopentyl-2-(3-hydroxyazetidin-1-yl)ethyl]-4-fl-
uoro-N-methylbenzamide; [0429]
4-chloro-N-(1-(3-hydroxyazetidin-1-yl)hexan-2-yl)-N-methylbenzamide;
[0430]
3,4-Difluoro-N-[1-(3-hydroxyazetidin-1-yl)hexan-2-yl]-N-methylbenz-
amide; [0431]
4-Cyano-N-[1-(3-hydroxyazetidin-1-yl)hexan-2-yl]-N-methylbenzamide;
[0432]
4-Fluoro-N-[1-(3-hydroxyazetidin-1-yl)hexan-2-yl]-N-methylbenzamid-
e; [0433]
3-Chloro-4-fluoro-N-[1-(3-hydroxyazetidin-1-yl)hexan-2-yl]-N-met-
hylbenzamide; [0434]
4-Chloro-N-[1-cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]-N-methylbenzami-
de; [0435]
4-Cyano-N-[1-cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]-N-meth-
ylbenzamide; [0436]
N-[1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]-4-fluoro-N,3-dimethylben-
zamide; [0437]
N-[1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]-4-fluoro-N-methylbenzami-
de; [0438]
N-[1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]-3,4-difluoro-N-
-methylbenzamide; [0439]
4-cyano-N-[1-cyclohexyl-2-(3-hydroxyazetidin-1-yl)ethyl]-N-methylbenzamid-
e; [0440]
4-Chloro-N-[1-cyclohexyl-2-(3-hydroxyazetidin-1-yl)ethyl]-N-meth-
ylbenzamide; [0441]
N-[1-Cyclohexyl-2-(3-hydroxyazetidin-1-yl)ethyl]-4-fluoro-N-methylbenzami-
de; [0442]
4-Chloro-N-[1-(3-hydroxyazetidin-1-yl)pentan-2-yl]-N-methylbenz-
amide; [0443]
3,4-Difluoro-N-[1-(3-hydroxyazetidin-1-yl)-4-methylpentan-2-yl]-N-methylb-
enzamide; [0444]
4-Chloro-N-[1-(3-hydroxyazetidin-1-yl)-4-methylpentan-2-yl]-N-methylbenza-
mide; [0445]
4-Cyano-N-(1-cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-N-methylbenzamid-
e; [0446]
N-(1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-3,4-difluoro-N--
methylbenzamide; [0447]
4-Chloro-3-fluoro-N-(1-(3-hydroxyazetidin-1-yl)butan-2-yl)-N-methylbenzam-
ide; [0448]
4-Chloro-N-(1-(3-hydroxyazetidin-1-yl)butan-2-yl)-N-methylbenzamide;
[0449]
N-(1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-4-fluoro-N-methyl-
benzamide; [0450]
4-Chloro-N-(1-cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-N-methylbenzami-
de; [0451]
N-(1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-4-fluoro-N,3-d-
imethylbenzamide; [0452]
4-Bromo-N-(1-(3-hydroxyazetidin-1-yl)butan-2-yl)-N-methylbenzamide;
or a pharmaceutically acceptable salt of any of the foregoing
compounds.
[0453] In a further specific embodiment of the invention, the
compounds are represented by Formula Id, or a pharmaceutically
acceptable salt thereof, wherein
[0454] R.sup.1 is selected from ethyl, propyl, isopropyl,
cyclopropyl or cyclobutyl;
[0455] R.sup.6 is selected from hydrogen, chloro, fluoro or methyl;
and
[0456] R.sup.7 is selected from chloro, fluoro, bromo or
nitrile.
[0457] In a still further specific embodiment of the invention, the
compounds are represented by Formula Ie, or a pharmaceutically
acceptable salt thereof, wherein
##STR00009##
[0458] R.sup.1 is selected from ethyl, propyl, isopropyl, butyl,
1-methyl-propyl, 2-methyl-propyl, cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl, in particular ethyl, propyl, isopropyl,
cyclopropyl or cyclobutyl; and
[0459] R.sup.7 is selected from chloro, fluoro, bromo, nitrile or
methyl.
[0460] In a still further specific embodiment of the invention, the
compounds are represented by Formula Ie, or a pharmaceutically
acceptable salt thereof, wherein
[0461] R.sup.1 is selected from ethyl, propyl, isopropyl, butyl,
1-methyl-propyl, 2-methyl-propyl, in particular ethyl, propyl or
isopropyl; and
[0462] R.sup.7 is selected from chloro, fluoro, bromo or
nitrile.
[0463] In a still further specific embodiment of the invention, the
compounds are represented by Formula Ie, or a pharmaceutically
acceptable salt thereof, wherein
[0464] R.sup.1 is selected from cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl, in particular cyclopropyl or cyclobutyl;
and
[0465] R.sup.7 is selected from chloro, fluoro, bromo or
nitrile.
[0466] It shall be understood that as used herein all references to
compounds according to the invention, including a specific chemical
formula or name, are intended to include all pharmaceutically
acceptable salts, co-crystals, solvates, hydrates, polymorphs,
stereoisomers, and tautomeric isomers thereof.
[0467] The following definitions shall apply throughout the
specification and the appended claims.
[0468] As used herein "pharmaceutically acceptable salt", where
such salts are possible, includes salts prepared from
pharmaceutically acceptable non-toxic inorganic or organic bases or
acids, i.e. pharmaceutically acceptable acid and base addition
salts (see "Handbook of Pharmaceutical Salts: Properties, Selection
and Use", P. H. Stahl, P. G. Wermuth, IUPAC, Wiley-VCH, 2002).
[0469] Acid addition salts are formed from inorganic or organic
acids. Examples of suitable non-toxic acid addition salts are
acetate, adipate, aspartate, benzoate, besylate,
bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate,
citrate, cyclamate, edisylate, esylate, formate, fumarate,
gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate,
hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide,
isethionate, lactate, malate, maleate, malonate, mesylate,
methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate,
orotate, oxalate, palmitate, pamoate, phosphate/hydrogen
phosphate/dihydrogen phosphate, pyroglutamate, saccharate,
stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate
and xinofoatc salts. Hemisalts of the acids may also be formed, for
example, hemisulphate.
[0470] Base-addition salts are formed from inorganic or organic
bases. Examples of suitable non-toxic base-addition salts are salts
derived from aluminum, ammonium, calcium, copper, ferric, ferrous,
lithium, magnesium, manganic salts, manganous, potassium, sodium,
zinc, primary, secondary, and tertiary amines, substituted amines
including naturally occurring substituted amines, cyclic amines,
and basic ion exchange resins, such as arginine, betaine, caffeine,
choline, N,N'-dibenzylethylenediamine, diethylamine,
2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,
ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine,
glucosamine, histidine, hydrabamine, isopropylamine, lysine,
methylglucamine, morpholine, piperazine, piperidine, polyamine
resins, procaine, purines, theobromine, TEA, trimethylamine,
tripropylamine, and tromethamine.
[0471] In a salt, proton transfer occurs between the compound of
Formula I and the counter ion of the salt. However, in some cases
there is no or only partial proton transfer and the solid is
therefore not a true salt. It is accepted that the proton transfer
is in fact a continuum, and can change with temperature, and
therefore the point at which a salt is better described as a
"co-crystal" may be subjective. The term "co-crystal" as used
herein refers to a multicomponent system in which there exist a
host API (active pharmaceutical ingredient) molecule or molecules
and a guest (or co-former) molecule or molecules. The guest or
co-former is defined as existing as a solid at room temperature in
order to distinguish the co-crystal from solvates (including
hydrates). However, a co-crystal may itself form solvates
(including hydrates). In a co-crystal there is generally
predominance for interaction through non-ionic forces such as
hydrogen bonding.
[0472] It is also to be understood that certain compounds of the
Formula I can exist in solvated forms, including solvates of the
free compounds or solvates of a salt of the compound, as well as
unsolvated forms.
[0473] The term "solvate" is used herein to describe a molecular
complex comprising the compound of the invention and one or more
pharmaceutically acceptable solvent molecules, for example,
ethanol. The term "hydrate" is employed when said solvent is
water.
[0474] The compounds of the invention may exist in a continuum of
solid states ranging from fully amorphous to fully crystalline.
Thus, it is to be understood that all polymorphs, including
mixtures of different polymorphs, are included within the scope of
the claimed compounds.
[0475] Throughout the specification and the appended claims, a
given chemical formula or name shall encompass, where possible, all
stereoisomers and tautomeric isomers thereof, including compounds
exhibiting more than one type of isomerism, and mixtures of one or
more thereof.
[0476] The compounds of the invention include, where possible, all
stereoisomers, such as diastereomers (including cis-trans isomers,
formerly called `geometric isomers`), enantiomers (optical
isomers), including racemates as well as mixtures in different
proportions of the separate enantiomers, and conformational isomers
(including rotamers). Stereoisomers may be separated using
conventional techniques, e.g. chromatography or fractional
crystallisation. The enantiomers may be isolated by separation of
racemate for example by fractional crystallisation with a chiral
counterion, resolution or chiral HPLC. The diastereomers may be
isolated by separation of isomer mixtures for instance by
fractional crystallisation, fractional salt crystallisation, chiral
HPLC and/or achiral HPLC or flash chromatography. Alternatively the
stereoisomers may be made by chiral synthesis from chiral starting
materials under conditions that will not cause racemisation or
epimerisation, or by derivatisation, with a chiral reagent.
[0477] The compounds of the invention also include, where possible,
all tautomeric isomers thereof, such as prototropic tautomerism
(e.g. hydroxypyridine-pyridone, ketone-enol, amide-imidic acid,
amine-imine), annular tautomerism, ring-chain tautomerism and
valence tautomerism.
[0478] The compounds of the invention also encompasses
isotopically-labelled compounds of Formula I wherein one or more
atoms are replaced by atoms having the same atomic number, but 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 include isotopes of hydrogen, carbon, nitrogen and
oxygen, such as .sup.2H, .sup.3H, .sup.14C, .sup.13C, .sup.11C,
.sup.15N, .sup.18O, .sup.17O or .sup.19F. The invention also
encompasses the use of these isotopically labelled compounds for
pharmacological and metabolic studies. Without being bound by any
theory, substitution with heavier isotopes, such as substitution of
one or more hydrogen atoms with deuterium (.sup.2H), might provide
pharmacological advantages in some instances, such as increased
metabolic stability.
[0479] In addition, compounds of Formula I may be administered in
the form of a prodrug. A prodrug is a compound, which may have
little or no pharmacological activity itself, but when such a
compound is administered into or onto the body, it is converted
into a compound of Formula I having the desired activity. Various
prodrugs are known within the art (see Rautio et al, "Prodrugs:
design and clinical applications", Nature Reviews, Drug Discovery,
255, vol 7, March 2008).
[0480] Also included within the scope of the invention are
metabolites of compounds of Formula I, that is compounds formed in
vivo upon administration of the drug.
[0481] As used herein, the term "leaving group" refers to a moiety
that can be displaced by another moiety, such as by nucleophilic
attack, during a chemical reaction. Leaving groups are well known
in the art and include, for example, halogen, hydroxy, alkoxy,
--O(C.dbd.O)R.sub.a, --OSO.sub.2--R.sub.b, and --OSi(R.sub.c).sub.3
wherein R.sub.a can be C.sub.1-8 alkyl, C.sub.3-7 cycloalkyl, aryl,
heteroaryl, or heterocycloalkyl, wherein R.sub.b can be C.sub.1-8
alkyl, aryl, or heteroaryl, and wherein R.sub.c can be C.sub.1-8
alkyl. Examples of leaving groups include, but are not limited to,
fluoro, chloro, bromo, 4-nitrophenyloxy, mesylate, tosylate,
trimethylsilyloxy, and the like.
[0482] As used herein, the terms "treating", "treat", or
"treatment" are intended to embrace therapeutic (curative),
prophylactic (preventing), controlling and palliative treatment of
the indicated diseases, disorders and/or conditions.
[0483] As used herein, the term "IC.sub.50" refers to the
effectiveness of a compound in inhibiting a biological or
biochemical function. IC.sub.50 represents the concentration of a
drug that is required for 50% inhibition in vitro.
[0484] As used herein, the term "pharmacologically effective
amount" (including "therapeutically effective amount") means an
amount of a compound or pharmaceutical composition according to the
invention that is sufficient to induce the desired therapeutic or
biological effect.
[0485] As used herein, the term "alkyl" means a straight or
branched chain saturated aliphatic hydrocarbon group. C.sub.1-6
alkyl means an alkyl having from 1 to 6 carbon atoms. Non-limiting
examples of C.sub.1-6 alkyl are methyl, ethyl, n-propyl, isopropyl,
2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,
3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,
2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,
2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,
2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,
iso-butyl, t-butyl, pentyl, iso-pentyl, neo-pentyl, hexyl, isohexyl
and the like.
[0486] As used herein, the term "cycloalkyl" represents a saturated
monocyclic aliphatic ring system containing from 3 to 7 ring carbon
atoms. Examples of 3 to 6-membered cycloalkyl include, but are not
limited to cyclopropyl, cyclobutyl, cyclohexyl, and
cyclopentyl.
[0487] As used herein, the term "alkoxy" denotes --O-alkyl wherein
alkyl is as defined above. C.sub.1-6 alkoxy includes an alkyl
having from 1 to 6 carbon atoms. Non-limiting examples of
C.sub.1---6 alkoxy are methoxy, ethoxy, n-propyloxy, iso-propyloxy,
2-methyl-1-propyloxy, 2-methyl-2-propyloxy, 2-methyl-1-butyloxy,
3-methyl-1-butyloxy, 2-methyl-3-butyloxy, 2,2-dimethyl-1-propyloxy,
2-methyl-1-pentyloxy, 3-methyl-1-pentyloxy, 4-methyl-1-pentyloxy,
2-methyl-2-pentyloxy, 3-methyl-2-pentyloxy, 4-methyl-2-pentyloxy,
2,2-dimethyl-1-butyloxy, 3,3-dimethyl-1-butyloxy,
2-ethyl-1-butyloxy, butyloxy, iso-butyloxy, t-butyloxy, pentyloxy,
iso-pentyloxy, neo-pentyloxy, hexyloxy, and the like.
[0488] As used herein, the term "alkoxyalkyl" means -alkyl-O-alkyl,
wherein alkyl is as defined above. C.sub.1-6 alkoxyalkyl includes a
total of from 1 to 6 carbon atoms.
[0489] As used herein, the term "alkylsulfide" denotes --S-alkyl,
wherein alkyl is as defined above. C.sub.1-3 alkylsulfide includes
an alkyl having from 1 to 3 carbon atoms. Non-limiting examples of
C.sub.1-3 alkylsulfide are methylsulfide, ethylsulfide and
propylsulfide.
[0490] As used herein, the term "halo" refers to fluoro, chloro,
bromo and iodo.
[0491] As used herein, the term "hydroxy" refers to --OH.
[0492] As used herein, the term "carboxy" refers to --COOH.
[0493] As used herein, the term "nitrile" (sometimes also called
"cyano") refers to --CN.
[0494] As used herein, the term "oxo" refers to .dbd.O.
[0495] Unless otherwise indicated, the term "substituted" means
substituted by one or more defined groups.
[0496] As used herein, the term "protecting group" means temporary
substituents which protect a potentially reactive functional group
from undesired chemical transformations. Protecting groups may also
be used to obtain a certain selectivity in a reaction. Examples of
such protecting groups include esters of carboxylic acids, silyl
ethers of alcohols, and acetals and ketals of aldehydes and ketones
respectively (see "Protective Groups in Organic Synthesis", 4th
edition, T. W. Greene & P. G. M Wutz, Wiley-Interscince
(2007)). The protecting groups may be removed at any convenient
stage in the synthesis using conventional techniques well known in
the art.
[0497] Certain of the above defined terms may occur more than once
in the foi iulae herein and upon such occurrence each term shall be
defined independently of the other.
Pharmacological Properties
[0498] Compounds of Formula I have been found to exhibit potassium
channel inhibiting activity, especially inhibiting activity of the
acetylcholine operated inward rectifying potassium channel, for
example as demonstrated in the test described below. In particular,
compounds of Formula I are believed to be useful in treating
cardiac arrhythmias, in particular supraventricular
tacharrhythmias, such as atrial fibrillation and atrial flutter,
and therewith associated complications (e.g. congestive heart
failure, ventricular fibrillation, and thromboembolic events).
[0499] According to a further aspect of the invention, there is
provided a compound of Formula I as previously defined for use as a
medicament.
[0500] In another aspect, the invention provides the use of a
compound of Formula I for treatment of cardiac arrhythmias and
therewith associated complications.
[0501] In a further aspect, the invention provides the use of a
compound of Formula I in the preparation of a medicament for
treatment of cardiac arrhythmias, and more specifically
supraventricular tacharrhythmias, such as atrial fibrillation and
atrial flutter, and therewith associated complications, such as
congestive heart failure, ventricular fibrillation, and
thromboembolic events.
[0502] In a still further aspect, the invention provides a method
of treating diseases, disorders and/or conditions which is affected
and/or mediated (fully or partially) by IKACh and where treatment
by IKACh blockade is beneficial, in particular cardiac arrhythmias
and therewith associated complications, comprising administering a
pharmacologically effective amount of a compound of Formula I to a
patient in need thereof.
[0503] It is believed that compounds of Formula I may possess
satisfactory pharmacological profile and promising
biopharmaceutical properties, such as toxicological profile,
metabolism and pharmacokinetic properties, solubility, and
permeability, in particular for providing a satisfactory
bioavailability upon oral administration of a pharmacologically
effective amount of the compound. It will be understood that
determination of appropriate biopharmaceutical properties is within
the knowledge of a person skilled in the art.
[0504] It is further believed that compounds of Formula I may also
possess satisfactory selectivity profile over other ion channels as
exemplified by, but not limited to, Nav1.2, Nav1.3, Nav1.7, Nav1.5,
Kv1.5, hERG, Kv4.3, KvLQT1, Cav1.2, Cav3.2 and HCN4.
Pharmaceutical Compositions
[0505] The compounds of the invention can be administered to a
non-human or human mammal, in particular man, via any route
possible, such as the oral, topical, intradermal, transdermal,
parenteral (including intravenous, intraarterial, intraperitoneal,
intrathecal, intraventricular, intraurethral, intrasternal,
intracranial, intramuscular, intrasynovial and subcutaneous),
ocular (ophthalmic), buccal, lingual, sublingual, rectal, vaginal,
pulmonary (nasal or buccal inhalation) and/or intranasal route, in
the form of a pharmaceutical composition comprising (a
pharmacologically effective amount of) the active compound
according to the invention and one or more pharmaceutically
acceptable carrier.
[0506] When formulated with a pharmaceutically acceptable carrier,
the compound of the invention may be present in the pharmaceutical
composition in a concentration from 0.1 to 99.5%, such as from 0.5
to 95%, by weight of the total composition.
[0507] The choice of carrier is within the knowledge of a person
skilled in the art and depends on, for instance, the mode of
administration, the dosage form, and the physical properties of the
active compound, such as solubility and stability. The term
"carrier" as used herein relates to a therapeutically inactive
ingredient.
[0508] The dosage form may be a solid, semi-solid or liquid system.
The formulation may be an immediate and/or modified release,
including delayed-, sustained-, pulsed-, controlled-, targeted and
programmed release formulation.
[0509] Examples of dosage forms are tablets, pills, troches,
powders, granules, dispersions, suspensions, solutions, capsules
(containing particulates, powders, or liquids), gels, creams,
lotions, ointments, aerosols, suppository, pessary, enema, and the
like. Since tablets, pills and capsules are easy to administer,
these dosage forms generally represent the most advantageous oral
delivery forms.
[0510] Examples of carriers are pharmaceutically acceptable
diluents, bulking agents, binders, disintegrating agents,
lubricants, anti-oxidants, preservatives, coatings, surface active
agents, sweetening and flavoring agents, taste-masking agents,
colorants, emollients, anti-foaming agents, adjuvants, enhancers,
and other excipients.
[0511] Thus, according to a further aspect of the invention there
is also provided a pharmaceutical composition comprising a compound
of Formula I as an active therapeutic ingredient and a
pharmaceutically acceptable carrier. The composition of the
invention may optionally also contain one or more other therapeutic
ingredients as described hereinafter.
[0512] The compositions of the invention may be administered at
varying doses of active compound depending upon the particular
compound employed, the route of administration, the patient
(including weight, sex, health condition, and diet), drug mixing,
and the condition being treated and the severity thereof.
[0513] Suitable doses of the compounds of the invention in the
treatment of humans are believed to be from about 0.001 to about
1000 mg/kg, such as from about 0.01 to about 100 mg/kg, body
weight, given in a single dose or in divided daily doses. The
dosage regimen may be adjusted to provide the optimal therapeutic
response.
Combination Therapy
[0514] One or more compounds of the invention may be combined with
at least one other pharmacologically active agent that is useful in
the treatment of cardiac arrhythmias and/or any other
cardiovascular disorders.
[0515] According to an additional aspect of the invention there is
provided a combination treatment comprising the administration of a
pharmacologically effective amount of a compound of Formula I, or a
pharmaceutically acceptable salt thereof, optionally together with
a pharmaceutically acceptable diluent or carrier, with the
simultaneous, sequential or separate administration of one or more
of the following agents: [0516] any other antiarrhythmic agent,
such as Class I agents (e.g. quinidine, lidocaine, and
propafenone), Class II agents (e.g. propranolol), Class III agents
(e.g. sotalol, dofetilide, amiodarone, dronedarone, budiodarone,
azimilide and ibutilide), Class IV agents (e.g. diltiazem and
verapamil), "Class V agents" (e.g. adenosine), and cardiac
glycosides (e.g. digitalis and ouabain); [0517] haemostasis
modulators, including antithrombotics such as activators of
fibrinolysis; thrombin inhibitors; factor VIIa inhibitors;
anticoagulants, such as vitamin K antagonists (e.g. warfarin),
heparin and low molecular weight analogues thereof (e.g.
dalteparin), factor Xa inhibitors (e.g. rivaroxaban and apixaban),
and direct thrombin inhibitors (e.g. argatroban); antiplatelet
agents, such as cyclooxygenase inhibitors (e.g. aspirin and
NSAIDs), adenosine diphosphate (ADP) receptor inhibitors (e.g.
clopidogrel), phosphodiesterase inhibitors (e.g. cilostazol),
glycoprotein IIB/IIA inhibitors (e.g. tirofiban), and adenosine
reuptake inhibitors (e.g. dipyridamole); [0518] anti-dyslipidemia
agents, such as HMG-CoA reductase inhibitors (statins) and other
cholesterol-lowering agents; PPAR.alpha. agonists (fibrates, e.g.
gemfibrozil and fenofibrate); bile acid sequestrants (e.g.
cholestyramine); cholesterol absorption inhibitors (e.g. plant
sterols (i.e. phytosterols), synthetic inhibitors); cholesteryl
ester transfer protein (CETP) inhibitors; inhibitors of the ileal
bile acid transport system (IBAT inhibitors); bile acid binding
resins; nicotinic acid (niacin) and analogues thereof;
anti-oxidants; and omega-3 fatty acids; [0519] antihypertensive
agents, including adrenergic receptor antagonists, such as beta
blockers (e.g. atenolol), alpha blockers (e.g. doxazosin), and
mixed alpha/beta blockers (e.g. labetalol); adrenergic receptor
agonists, including alpha-2 agonists (e.g. clonidine); angiotensin
converting enzyme (ACE) inhibitors (e.g. lisinopril), calcium
channel blockers, such as dihydropyridines (e.g. nifedipine),
phenylalkylamines (e.g. verapamil), and benzothiazepines (e.g.
diltiazem); angiotensin II receptor antagonists (e.g. losartan);
aldosterone receptor antagonists (e.g. eplerenone); centrally
acting adrenergic drugs, such as central alpha agonists (e.g.
clonidine); and diuretic agents (e.g. furosemide); [0520]
anti-obesity agents, such as appetite suppressant (e.g. ephedrine),
including noradrenergic agents (e.g. phentermine) and serotonergic
agents (e.g. sibutramine), pancreatic lipase inhibitors (e.g.
orlistat), microsomal transfer protein (MTP) modulators, diacyl
glycerolacyltransferase (DGAT) inhibitors, and cannabinoid (CB1)
receptor antagonists (e.g. rimonabant); [0521] insulin and insulin
analogues; [0522] insulin secretagogues, including sulphonylureas
(e.g. glipizide) and prandial glucose regulators (sometimes called
"short-acting secretagogues"), such as meglitinides (e.g.
repaglinide and nateglinide); [0523] agents that improve incretin
action, for example dipeptidyl peptidase IV (DPP-4) inhibitors
(e.g. vildagliptin, and sitagliptin), and glucagon-like peptide-1
(GLP-1) agonists (e.g. exenatide); [0524] insulin sensitising
agents including peroxisome proliferator activated receptor gamma
(PPAR.gamma.) agonists, such as thiazolidinediones (e.g.
pioglitazone and rosiglitazone), and agents with any combination of
PPAR alpha, gamma and delta activity; [0525] agents that modulate
hepatic glucose balance, for example biguanides (e.g. metformin),
fructose 1,6-bisphosphatase inhibitors, glycogen phopsphorylase
inhibitors, glycogen synthase kinase inhibitors, and glucokinase
activators; [0526] agents designed to reduce/slow the absorption of
glucose from the intestine, such as alpha-glucosidase inhibitors
(e.g. miglitol and acarbose); [0527] agents which antagonise the
actions of or reduce secretion of glucagon, such as amylin
analogues (e.g. pramlintide); [0528] agents that prevent the
reabsorption of glucose by the kidney, such as sodium-dependent
glucose transporter 2 (SGLT-2) inhibitors; or a pharmaceutically
acceptable salt, solvate, solvate of such a salt or a prodrug
thereof, optionally together with a pharmaceutically acceptable
carrier to a mammal, such as man, in need of such therapeutic
treatment.
[0529] In an additional aspect of the invention, there is provided
a method of treating cardiac arrhythmias and therewith associated
complications in a mammal, such as man, in need of such treatment
which comprises administering to said animal a pharmacologically
effective amount of a compound of Formula I, or a pharmaceutically
acceptable salt thereof, optionally together with a
pharmaceutically acceptable carrier, in simultaneous, sequential or
separate administration with a pharmacologically effective amount
of a compound from one of the other classes of compounds described
in this combination section, or a is pharmaceutically acceptable
salt, solvate, solvate of such a salt or a prodrug thereof,
optionally together with a pharmaceutically acceptable carrier.
[0530] According to a further aspect of the invention there is
provided a pharmaceutical composition which comprises a compound of
Formula I, or a pharmaceutically acceptable salt thereof, and a
compound from one of the other classes of compounds described in
this combination section or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof, in
association with a pharmaceutically acceptable carrier.
[0531] According to a further aspect of the present invention there
is provided a kit comprising a compound of Formula I, or a
pharmaceutically acceptable salt thereof, and a compound from one
of the other classes of compounds described in this combination
section or a pharmaceutically acceptable salt, solvate, solvate of
such a salt or a prodrug thereof.
[0532] According to a further aspect of the present invention there
is provided a kit comprising:
[0533] a) a compound of Formula I, or a pharmaceutically acceptable
salt thereof, together with a pharmaceutically acceptable carrier,
in a first unit dosage form;
[0534] b) a compound from one of the other classes of compounds
described in this combination section or a pharmaceutically
acceptable salt, solvate, solvate of such a salt or a prodrug
thereof, together with a pharmaceutically acceptable carrier, in a
second unit dosage form; and
[0535] c) container means for containing said first and second
dosage forms.
[0536] According to another aspect of the invention there is
provided the use of a compound of the Formula I, or a
pharmaceutically acceptable salt thereof, and one of the other
compounds described in this combination section, or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof, (in the manufacture of a medicament for use)
in the treatment of cardiac arrhythmias and/or its associated
complications in a mammal, such as man.
[0537] According to a further aspect of the present invention there
is provided a combination treatment comprising the administration
of a pharmacologically effective amount of a compound of the
Formula I, or a pharmaceutically acceptable salt thereof,
optionally together with a pharmaceutically acceptable carrier,
with the simultaneous, sequential or separate administration of a
pharmacologically effective amount of one of the other compounds
described in this combination section, or a pharmaceutically
acceptable salt, solvate, solvate of such a salt or a prodrug
thereof, optionally together with a pharmaceutically acceptable
carrier to a mammal, such as man in need of such therapeutic
treatment.
[0538] Compounds in the invention can also be administered as the
sole active ingredient but in combination with the use of a
pacemaker or defribillator device.
Preparation of the Compounds
[0539] The compounds of Formula I and their salts can be prepared
according to the any one more of procedures of the following
schemes and examples or any process known to be applicable to the
preparation of chemically related compounds. Those skilled in the
art will readily understand that known variations of the conditions
and processes of the following preparative procedures can be used
to prepare these compounds.
[0540] Compounds of Formula I may be prepared by the following
processes a1) to a4).
a1) Compounds of Formula If (i.e. compounds according to Formula I
wherein R.sub.3 is methyl) in which R.sub.1, R.sub.2, R.sub.4 and
R.sub.5 are defined as above and i is 0 or 1 may be prepared
according to Scheme 1.
##STR00010##
[0541] Carboxylic acids of Formula II can be transformed into
amides of Formula III by reacting with the appropriate amine and a
coupling reagent. One skilled in the art understands that there
exists a multitude of suitable methods for this type of conversion.
In one such method carboxylic acids of Formula II are first
activated with a coupling reagent such as TBTU, EDC or HATU, in the
presence of a suitable base, for example NMM, DIPEA or TEA in a
solvent such as DCM or DMF. The activated acid may then be reacted
with the appropriate amine to give amides of Formula III.
[0542] Amides of Formula III can be transformed into amines of
Formula IV using, for example, a reducing agent such as LAH in a
suitable solvent such as THF, dioxane or diethyl ether at either rt
or an elevated temperature. Amines of Formula IV may be converted
into compounds of Formula If by reacting the amine, carboxylic acid
and a coupling reagent such as TBTU, EDC or HATU, in the presence
of a base such as NMM, DIPEA or TEA in a solvent such as DCM or
DMF. An alternative route to obtain amides of Formula If is via
acylation of amines of Formula IV with a suitable acid chloride in
the presence of a base, for example NMM, DIPEA or TEA in a solvent
such as DCM or DMF.
a2) Compounds of Formula I may also be prepared according to Scheme
2, wherein i represents 0 or 1.
##STR00011##
[0543] The t-butoxycarbonyl group of compounds of Formula III may
be removed, for example, by treatment with a suitable acid such as
hydrochloric, sulphuric or phosphoric acid or TFA to form amines of
Formula VI. Compounds of Formula VI can be transformed into amines
of Formula VII using, for example, a reducing agent such as LAH in
a suitable solvent such as THF, dioxane or diethyl ether at either
rt or at an elevated temperature. To convert amines of Formula VII
to compounds of Formula VIII, one skilled in the art can understand
there exists a large variety of suitable methods for such
transformations. For example, reductive amination were the amines
of Formula VII are reacted with the appropriate aldehyde in the
presence of a suitable reducing agent, for example NaBH.sub.4,
NaBH.sub.3CN or NaBH(OCOCH.sub.3).sub.3, in the presence or absence
of a base or acid may give compounds of Formula VIII.
Alternatively, alkylation of amines of Formula VII through
treatment with a base, for example TEA, and addition of an
appropriate electrophile, for example alkyl halides or acyl halides
may give compounds of Formula VIII. Amines of Formula VIII may be
transformed into amides of Formula I by reacting the amines with
suitable carboxylic acids and a coupling reagent such as TBTU, EDC
or HATU, in the presence of a suitable base, for example NMM, DIPEA
or TEA in a solvent such as DCM or DMF. An alternative route to
obtain amides of Formula I may be through acylation of an amine of
Formula VIII with the appropriate acid chloride in the presence of
a base, for example NMM, DIPEA or TEA, in a solvent such as DCM or
DMF.
a3) Compounds of Formula I may also be prepared according to Scheme
3.
##STR00012##
[0544] Those skilled in the art will readily understand that there
exists a multitude of suitable methods for the formation of amides
of Formula X. Compounds of Formula X can, for example be obtained
by reacting amines of Formula IX with the appropriate acid chloride
in the presence of a base, for example NMM, DIPEA or TEA in a
solvent such as DCM or DMF. Alternatively, amides of Formula X may
be formed through activation of the appropriate carboxylic acid
with a coupling reagent such as TBTU, EDC or HATU, in the presence
of a base such as NMM, DIPEA or TEA in a solvent such as DCM or
DMF. The activated acid can then be reacted with a suitable amine
(of Formula IX) to form amides of Formula X. Alkylation of amides
of Formula X may be performed by treatment with a base, for example
NaH, and addition of the appropriate electrophile, for example
alkyl halides or acyl halides to give compounds of Formula I.
a4) Compounds of Formula If (i.e. compounds according to Formula I
wherein R.sub.3 is methyl), wherein i represents 0 or 1, may also
be prepared according to Scheme 4.
##STR00013##
[0545] Treatment of amines of Formula XI with a reducing agent such
as LAH can in a suitable solvent such as THF, dioxane or diethyl
ether at either rt or an elevated temperature give compounds of
Formula XII. Compounds of Formula XIII may be obtained by reacting
the appropriate amine (Formula XII), carboxylic acid and a coupling
reagent such as TBTU, EDC or HATU, in the presence of a base such
as NMM, DIPEA or TEA in a solvent such as DCM or DMF. One skilled
in the art understands that there exists a multitude of suitable
methods for the formation of aldehydes of Formula XIV. In one such
method alcohols of Formula XIII may be transformed in to aldehydes
of Formula XIV by treatment with Dess-Martin periodinane. An
alternative route to obtain aldehydes of Formula XIV may be through
Swern oxidation of alcohols of Formula XIII using, for example
oxalylchloride or trifluoroacetic anhydride together with DMSO in
the presence of a base such as TEA or DIPEA. Reacting the
appropriate amine with aldehydes of Formula XIV in the presence of
a suitable reducing agent, for example NaBH.sub.4, NaBH.sub.3CN or
NaBH(OCOCH.sub.3).sub.3, in the presence or absence of a base or
acid can give compounds of is Formula I.
[0546] During the amide formation step in Scheme 1-4, diacylation
may occur in reactions where a hydroxyl group are present in the
reacting amine. To obtain the monoacylated product hydrolysis of
the formed ester may be performed using, for example NaOH in a
solvent such as MeOH or H.sub.2O.
[0547] After completion of any one of processes a1) to a4), if
necessary, one or more of the following may be performed: [0548]
converting a compound of Formula I into another compound of Formula
I; [0549] removing any protecting groups, and/or; [0550] forming a
pharmaceutically acceptable salt or a prodrug thereof
[0551] For the avoidance of doubt it is to be understood that where
in this specification a group is qualified by "defined as above"
the said group encompasses the first occurring and broadest
definition as well as each and all of the particular definitions
for that group.
[0552] The compounds of Formula I prepared by the process of the
invention can be converted to its salts by conventional method.
[0553] The compounds of the invention and intermediates may be
isolated from their reaction mixtures, and if necessary further
purified, by using standard technique, for example, chromatography,
recrystallization, etc.
[0554] Intermediate compounds may also exist in enantiomeric forms
and may be used as purified enantiomers, diastereomers, racemates
or mixtures.
[0555] If not commercially available, the necessary starting
materials for the procedures such as those described above may be
made by procedures which are selected from standard organic
chemical techniques, techniques which are analogous to the
synthesis of known, structurally similar compounds, techniques
which are described or illustrated in the references given above,
or techniques which are analogous to the above described procedure
or the procedures described in the examples.
[0556] Persons skilled in the art will appreciate that, in order to
obtain compounds of the invention in an alternative, and on some
occasions, more convenient manner, the individual process steps
mentioned hereinbefore may be performed in different order, and/or
the individual reactions may be performed at a different stage in
the overall route (i.e. substituents may be added to and/or
chemical transformations performed upon, different intermediates to
those mentioned hereinbefore in conjunction with a particular
reaction). This may negate, or render necessary, the need for
protecting groups.
[0557] It will be appreciated that certain of the various ring
substituents in the compounds of the present invention may be
introduced by standard aromatic substitution reactions or generated
by conventional functional group modifications either prior to or
immediately following the processes mentioned above, and as such
are included in the process aspect of the invention. Such reactions
and modifications include, for example, introduction of a
substituent by means of an aromatic substitution reaction,
reduction of substituents, alkylation of substituents and oxidation
of substituents. The reagents and reaction conditions for such
procedures are well known in the chemical art.
[0558] Further features of the invention are the compounds
obtainable by the processes disclosed herein.
[0559] The naming of compounds in this patent application was made
using the software package ACD/Name 10.06 (or 12.01) from ACD/Labs
or a Struct=Name Pro 9.0.7 (or 11.0.1 or 11.0.2) software package
from Cambridgesoft.
[0560] The invention will now be illustrated by means of
non-limiting examples, in which the following general experimental
procedures were used: [0561] (i) Phase Separators used in the
experimental are ISOLUTE.RTM. Phase Separator Columns. [0562] (ii)
Straight phase flash chromatography was performed using SP1.TM.
Purification System from Biotage.TM. using normal phase silica
FLASH+.TM. (40M, 25M or 12M) or SNAP.TM. KP-Sil Cartridges (340,
100, 50 or 10). [0563] (iii) Purification by preparative
reverse-phase HPLC was preformed using one of the following
methods: [0564] (iv) Method A: Purification by preparative
reverse-phase HPLC with mass triggered fraction collector, equipped
with a XBridge Prep C18 5 .mu.m OBD 150.times.19 mm column, using a
gradient of MeCN in H.sub.2O/MeCN/NH.sub.3 95/5/0.2, pH 10 as
mobile phase. Method B: Purification by preparative reverse-phase
HPLC using XBridge Prep C18 10 .mu.m OBD 250.times.19 mm column,
using a gradient of MeCN in H.sub.2O/MeCN/NH.sub.3 95/5/0.2, pH 10
as mobile phase. Method C: Purification by preparative
reverse-phase HPLC using XBridge Prep C18 10 .mu.M 250.times.50 mm
column, using a gradient of MeCN in H.sub.2O/MeCN/NH.sub.3
95/5/0.2, pH 10 as mobile phase. Method D: Purification by
preparative reverse-phase HPLC with mass triggered fraction
collector, equipped with a Gemini-NX prep C18 5 .mu.m 110A AXIA
21.2.times.150 mm column, using a linear gradient of 5-95% MeCN in
H.sub.2O/MeCN/NH.sub.3 95/5/0.2, pH 10 as mobile phase. Method E:
Purification by preparative reverse-phase HPLC with mass triggered
fraction collector, equipped with a Sunfire Prep C18 5 .mu.m OBD
19.times.150 mm column, using a linear gradient of 5-95% MeCN in
H.sub.2O/MeCN/FA 95/5/0.2, pH 3 as mobile phase. Method F:
Purification by preparative reverse-phase HPLC using Kromasil Prep
C8 10 .mu.m OBD 250.times.20 mm column, using a gradient of MeCN in
H.sub.2O/MeCN/HOAc 95/5/0.2, pH 4 as mobile phase. Method G:
Purification by preparative reverse-phase HPLC using Kromasil Prep
C8 10 .mu.m 250.times.50 mm column, using a gradient of McCN in
H.sub.2O/MeCN/HOAc 95/5/0.2, pH 4 as mobile phase. [0565] (v)
.sup.1H NMR measurements were performed on Varian INOVA 400, 500
and 600 spectrometers or Bruker Avance 400, 500 and 600
spectrometers, operating at .sup.1H frequencies of 400, 500 and 600
MHz respectively. Chemical shifts are given in ppm with the solvent
as internal standard unless noted. Protons on heteroatoms such as
NH and OH protons are only reported when detected in NMR. The NMR
experiments were performed at a temperature of 25.degree. C. [0566]
(vi) .sup.#WET1D experiments: The solutions for the .sup.1H NMR
spectra are taken from a concentrated sample dissolved in
(CH.sub.3).sub.2SO and are diluted with (CD.sub.3).sub.2SO. Since a
substantial amount of (CH.sub.3).sub.2SO is present in the sample,
first a pre-scan is run and analysed to automatically suppress the
(CH.sub.3).sub.2SO (2.54 ppm) and H.sub.2O (3.3 ppm) peaks. This
means that the intensity of peaks that reside in these areas around
3.3 ppm and 2.54 ppm is reduced. Furthermore impurities are seen in
the spectrum which gives rise to a triplet at 1.12 ppm, a singlet
at 2.96 ppm and two multiplets between 2.76-2.70 ppm and 2.61-2.55
ppm. Most probably these impurities are dimethylsulfone and
diethylsulfoxide. Because of that some signals from the compound
around these frequencies may have been omitted and the omitted area
is indicated in the NMR report. [0567] (vii) Mass spectra were
recorded on a Water SQD mass spectormeter equipped with acquity
UPLC and an electrospray interface (LC-MS) or LC-MS system
consisting of a Waters ZQ or 3100 using a LC-Agilent 1100/1200 LC
system. [0568] (viii) Accurate mass (HRMS) spectral data were
obtained using TOF-MS on a Waters LCT, Waters LCTP, Agilent 6530
QTOF system, Waters Xevo QTOF or Waters QTOF Micro. [0569] (ix)
Syringe filter from Advantec MFS Inc. with a pore size of 0.5 .mu.m
was used. [0570] (x) The X-ray diffraction analysis was performed
according to standard methods, which can be found in e.g.
Kitaigorodsky, A. I. (1973), Molecular Crystals and Molecules,
Academic Press, New York; Bunn, C. W. (1948), Chemical
Crystallography, Clarendon Press, London; or Klug, H. P. &
Alexander, L. E. (1974), X-ray Diffraction Procedures, John Wiley
& Sons, New York. X-ray powder diffraction data were measured
without any internal reference. The X-ray powder diffraction
(referred to herein as XRPD) pattern was determined by mounting a
sample on a zero background holder, single silicon crystal, and
spreading out the sample into a thin layer. Using a Bruker D8
Advance theta-2 theta diffractometer with a Position sensitive
detector (PSD), LynxEye, the sample was spun (to improve counting
statistics) and irradiated with X-rays generated by a copper tube
operated at 30 kV and 50 mA with a wavelength of 1.5406 angstroms.
Automatic variable divergence slits were used. The X-ray powder
diffraction (XRPD) patterns in this were obtained in Bragg-Brentano
geometry. Persons skilled in the art of X-ray powder diffraction
will realise that the relative intensity of peaks can be affected
by, for example, grains above 30 microns in size and non-unitary
aspect ratios that may affect analysis of samples. The skilled
person will also realise that the position of reflections can be
affected by the precise height at which the sample sits in the
diffractometer and the zero calibration of the diffractometer. The
surface planarity of the sample may also have a small effect. Hence
the diffraction pattern data presented are not to be taken as
absolute values. It is known that an X-ray powder diffraction
pattern may be obtained which has one or more measurement errors
depending on measurement conditions (such as equipment or machine
used). In particular, it is generally known that intensities in an
X-ray powder diffraction pattern may fluctuate depending on
measurement conditions. (Jenkins, R & Snyder, R. L.
`Introduction to X-Ray Powder Diffractometry` John Wiley & Sons
1996; Bunn, C. W. (1948), Chemical Crystallography, Clarendon
Press, London; Klug, H. P. & Alexander, L. E. (1974), X-Ray
Diffraction Procedures). Generally, a measurement error of a
diffraction angle in an X-ray powder diffractogram may be
approximately plus or minus 0.2.degree. 2-theta, and such a degree
of a measurement error should be taken into account when
considering the X-ray powder diffraction data. Furthermore, it
should be understood that intensities might fluctuate depending on
experimental conditions and sample preparation (e.g. preferred
orientation).
[0571] The following definitions have been used for the relative
intensity (%): 81-100%, vs (very strong); 41-80%, str (strong);
21-40%, med (medium); 10-20%, w (weak); 1-9%, vw (very weak).
[0572] (xi) Yields, where present, are not necessarily the maximum
attainable. [0573] (xii) The following abbrevations are used:
[0574] C Celsius [0575] DCE 1,2-dichloroethane [0576] DCM
dichloromethane [0577] DIPEA N,N-diisopropylethylamine [0578] DMF
N,N'-dimethylformamide [0579] DMSO dimethylsulfoxide [0580] EDC
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine
hydrochloride [0581] Ee enantiomeric excess [0582] ESI electrospray
ionization [0583] ES electrospray [0584] EtOAc ethyl acetate [0585]
EtOH ethanol [0586] Et.sub.2O diethylether [0587] FA formic acid
[0588] HATU
2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate) [0589] HPLC high performance liquid
chromatography [0590] HRMS high resolution mass spectrometry [0591]
IPA 2-propanol [0592] LAH lithium aluminium hydride [0593] LC
liquid chromatography [0594] MeCN acetonitrile [0595] MeI
iodomethane [0596] MeOH methanol [0597] M molar [0598] MS mass
spectroscopy [0599] MTBE 2-methoxy-2-methylpropane [0600] NMM
N-methyl morpholine [0601] NMR nuclear magnetic resonance [0602]
TBTU 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyliso
uronium tetrafluoroborate [0603] TEA triethylamine [0604] TFA
trifluoroacetic acid [0605] THF tetrahydrofuran [0606] TOF time of
flight [0607] QTOF quadropole time of flight [0608] aq aqueous
[0609] rt room temperature [0610] h hour(s) [0611] min minutes
[0612] br broad [0613] s singlet [0614] d doublet [0615] t triplet
[0616] m multiplet [0617] dd double doublet [0618] td triple
doublet
[0619] It will be understood that those chemicals referred to below
for which no manufacturing process are disclosed are either common
chemicals which are commercially available or may easily be
prepared by a person skilled in the art from commercially available
chemicals.
[0620] Intermediates described hereinafter were used in the
Examples below. These intermediates may be prepared by using the
reactions described below, but other procedures and reactions may
be used as well as appreciated by those skilled in the art.
Compound A1
(S)-Tert-butyl
1-(3-hydroxyazetidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate
[0621] (S)-2-(Tert-butoxycarbonylamino)-3-methylbutanoic acid
(30.00 g, 138.08 mmol), which is commercially available, and TBTU
(48.8 g, 151.9 mmol) was mixed in DCM (400 mL). The mixture was
cooled to 0.degree. C. and NMM (45.5 mL, 414.2 mmol) and DMF (100
mL) was added. After 30 min at rt was azetidin-3-ol hydrochloride
(18.15 g, 165.7 mmol) added. The resultant mixture was stirred at
rt over night. The mixture was washed with NaHCO.sub.3 (saturated,
2.times.300 mL) and brine (300 mL), filtered through a phase
separator and concentrated under reduced pressure to give the title
compound (35 g, 93%). The obtained crude product was used without
further purification. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
0.74-1.10, 1.45, 1.67-2.14, 3.58-3.91, 3.92-4.34, 4.37-4.52,
4.52-4.72. Total no of protons: 23. LCMS (M+H).sup.+: 273.
[0622] In a similar manner the following compound was
synthesized:
TABLE-US-00001 Com- pound Name .sup.1H NMR Yield A2 (S)-Tert-butyl
.sup.1H NMR (600 MHz, DMSO-d6) .delta. 3.97 g 1-(3- 0.89-0.96,
1.26-1.62, 3.66- 96% hydroxyazetidin- 3.80, 3.92-4.24, 4.38-4.44,
4.52- 1-yl)-1- 4.63. Total no of protons: 22 oxopentan-
2-ylcarbamate
Compound B1
(S)-Tert-butyl
2-(azetidin-1-yl)-1-cyclopropyl-2-oxoethylcarbamate
[0623] (S)-2-(Tert-butoxycarbonylamino)-2-cyclopropylacetic acid
(2.0 g, 9.30 mmol), which is commercially available, and NMM (3.07
mL, 27.9 mmol) was mixed in DMF (20 mL). The mixture was cooled to
0.degree. C. and TBTU (3.34 g, 10.42 mmol) was added. After 10 min
at rt was azetidine (1.6 mL, 23.7 mmol) added. The resultant
mixture was stirred at rt over night. The mixture was concentrated
and the residue dissolved in DCM (300 mL). The organic phase was
washed with NaHCO.sub.3 (saturated, 150 mL) and brine (150 mL),
filtered through a phase separator and concentrated under reduced
pressure to give the title compound (2.04 g, 86%). The obtained
crude product was used without further purification. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 0.39, 0.44-0.63, 1.09, 1.43, 2.31,
3.84, 3.93-4.46, 5.30. Total no of protons: 22.
[0624] In a similar manner the following compound was
synthesized:
TABLE-US-00002 Com- pound Name .sup.1H NMR Yield B2 (S)-Tert-butyl
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 1.18 g, 1-cyclo-
0.28-0.68, 1.09, 1.24, 82% propyl-2-(3- 1.43, 3.74-3.84, 3.88,
cyclopropyl-3- 3.95-4.09, 4.17, 5.25. hydroxyazetidin- Total no of
protons: 24 1-yl)-2- oxoethylcarbamate B3 Tert-butyl (S)-1- 1H NMR
(400 MHz, CD.sub.3OD) .delta. 2.70 g, ((3R,4R)-3,4-di- 0.91-1.02,
1.4-1.49, 1.92- 97%, hydroxypyrrolidin- 2.04, 3.47-3.6, 3.89-3.95,
76% 1-yl)-3-methyl-1- 4.05-4.17. pure oxobutan- Total number of
protons: 23. 2-ylcarbamate
Compound C1
(S)-Tert-butyl
1-(3-hydroxy-3-methylazetidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate
[0625] (S)-2-(Tert-butoxycarbonylamino)-3-methylbutanoic acid (5.30
g, 24.4 mmol), and TBTU (9.40 g, 29.3 mmol) was mixed in DMF (50
mL). To the mixture was NMM (6.70 mL, 60.99 mmol) added. After 30
min at rt was 3-methylazetidin-3-ol hydrochloride (3.01 g, 24.39
mmol) added. The resultant mixture was stirred at rt over night.
The mixture was concentrated and the residue dissolved in DCM (200
mL). The organic phase was washed with NaHCO.sub.3 (saturated,
2.times.150 mL) and brine (150 mL), filtered through a phase
separator and concentrated under reduced pressure to give the title
compound (7.00 g, quant. yield). The obtained crude product was
used without further purification. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 0.76-1.07, 1.31-1.56, 1.78-2.04, 2.55-2.73,
3.64-3.98, 4.04-4.42, 6.52-6.84.
[0626] In a similar manner the following compounds were
synthesized:
TABLE-US-00003 Com- pound Name .sup.1H NMR and LCMS Yield C2
(S)-Tert-butyl .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.79 g
1-cyclo- 0.16-0.76, 0.92-1.19, 1.20- 89% propyl-2-(3- 1.69, 2.44,
3.34-4.80. hydroxyazetidin- LCMS (M + H).sup.+: 271.
1-yl)-2-oxoethyl- carbamate C3 (S)-Tert-butyl .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 6.0 g 1-(3-fluoro- 0.75-1.09, 1.44, 1.80-2.11,
quant. azetidin-1- 3.56-4.79, 5.14-5.46. yield yl)-3-methyl-1-
Total no of protons: 22. oxobutan-2-yl- LCMS (M + H).sup.+: 275.
carbamate C4 Tert-butyl(S)-1- Mixture of rotamers: 208 mg,
((3S,4S)-3,4-di- (400 MHz, CD.sub.3OD) .delta. 0.91-1, 75%
hydroxypyrrolidin- 1.41-1.49, 1.91-2.01, 3.39- 1-yl)-3-methyl-1-
3.45, 3.59-3.66, 3.7-3.83, oxobutan- 4.05-4.15. LCMS 2-ylcarbamate
(M + H).sup.+: 303.
Compound D
(S)-Tert-butyl
1-(azetidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate
[0627] (S)-2-(Tert-butoxycarbonylamino)-3-methylbutanoic acid (50.0
g, 230.1 mmol), EDC hydrochloride (52.9 g, 276.2 mmol) and
1-hydroxypyrrolidine-2,5-dione (39.7 g, 345.2 mmol) was mixed in
DCM (180 mL). The mixture was cooled to 0.degree. C. and DIPEA (160
mL, 920.6 mmol) was added. After 1 h at 0.degree. C. was azetidine
(18.62 mL, 276.2 mmol) added. The resultant mixture was stirred at
rt over night. The mixture was concentrated and the residue
dissolved in DCM (200 mL). The organic phase was washed with
NaHCO.sub.3 (saturated, 2.times.150 mL), HCl (1M aq. solution,
2.times.200 mL) and brine (150 mL), filtered through a phase
separator and concentrated under reduced pressure to give the title
compound (42 g, 71%). The obtained crude product was used without
further purification. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
0.86, 1.75-1.90, 1.94-2.18, 2.18-2.36, 2.38, 2.99-3.29. Total no of
protons: 19. LCMS (M+H).sup.+: 257.
Compound E
(S)-Tert-butyl 1-(azetidin-1-yl)-1-oxopentan-2-ylcarbamate
[0628] (S)-2-(Tert-butoxycarbonylamino)pentanoic acid (17.0 g,
78.25 mmol), which is commercially available, and EDC hydrochloride
(18.00 g, 93.90 mmol) was mixed in DCM (300 mL). To the mixture was
NMM (20.65 mL, 187.79 mmol) added. The mixture was cooled to
0.degree. C. and azetidine (6.33 mL, 93.90 mmol) was added. The
resultant mixture was stirred at 0.degree. C. for 30 min. and at rt
over night. The reaction mixture was washed with NaHCO.sub.3
(saturated, 2.times.300 mL) and brine (300 mL), filtered through a
phase separator and concentrated under reduced pressure. The
residue was purified via Biotage (gradient; DCM/iso-propanol, 99:1
to 90:10, KP-SIL 340 g column). The solvent was removed under
reduced pressure to give the title compound (12.0 g, 60%). .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 0.92, 1.20-1.76, 2.30, 3.89-4.26,
4.26-4.46, 5.16. LCMS (M+H).sup.+: 257.
Compound F1
(S)-Tert-butyl
3,3-dimethyl-1-oxo-1-(pyrrolidin-1-yl)butan-2-ylcarbamate
[0629] (S)-2-(Tort-butoxycarbonylamino)-3-methylbutanoic acid (7.00
g, 30.3 mmol) and TBTU (9.72 g, 30.27 mmol) was mixed in DMF (70
mL). The mixture was cooled to 0.degree. C. and NMM (3.99 mL, 36.3
mmol) was added. After 10 min was pyrrolidine (3.00 mL, 36.32 mmol)
added. The resultant mixture was stirred at 0.degree. C. for 30
min. and at rt over night. The mixture was concentrated and the
residue dissolved in DCM (250 mL). The organic phase was washed
with NaHCO.sub.3 (saturated, 2.times.200 mL) and brine (200 mL),
filtered through a phase separator and concentrated under reduced
pressure. The residue was purified via Biotage (gradient;
DCM/iso-propanol, 99:1 to 90:10, KP-SIL 340 g column). The solvent
was removed under reduced pressure to give the title compound (6.4
g, 74%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.99, 1.43,
1.80-2.01, 3.31-3.45, 3.47-3.59, 3.67-3.79, 4.29, 5.28. Total no of
protons: 27. LCMS (M+H).sup.+: 285.
[0630] In a similar manner the following compounds were
synthesized:
TABLE-US-00004 Com- pound Name .sup.1H NMR and LCMS Yield F2
Tert-butyl (2S,3S)- .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.72
g 3-methyl-1-oxo-1- 0.76-0.95, 0.97-1.14, 1.40, 93% (pyrrolidin-1-
1.48-1.61, 1.63-1.76, 1.77- yl)pentan-2-yl- 2.00, 3.32-3.58,
3.60-3.76, carbamate 4.18-4.31, 5.23. Total no of protons: 28. LCMS
(M + H).sup.+: 285. F3 (S)-Tert-butyl .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 1.51 g 1-cyclo- 0.25-0.60, 1.15, 1.43, 1.81-
96% propyl-2-oxo-2- 2.03, 3.34-3.58, 3.64, 4.27, (pyrrolidin-1-
5.42. Total no of protons: 24. yl)ethylcarbamate F4 Tert-butyl (S)-
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 4.2 g 1-((R)-3-
0.85-1.04, 1.43, 1.80-2.21, quant. hydroxypyrrolidin- 3.36-3.80,
3.83-4.21, 4.29- yield 1-yl)- 4.50, 6.36-6.74. 3-methyl-1-
oxobutan- 2-ylcarbamate F5 Tert-butyl .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 5.08 g 2-methyl-1-oxo- 1.42, 1.50, 1.84, 3.54,
4.51, 79% 1-(pyrrolidin-1- 5.17. Total no of protons: yl)-propan-
24. LCMS (M + H).sup.+: 257. 2-ylcarbamate F6 (S)-Tert-butyl
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.88 g 1-oxo-1- 0.92,
1.41, 1.48-1.64, 1.65- 67% (pyrrolidin- 2.06, 3.32-3.46, 3.46-3.56,
3.56- 1-yl)butan- 3.72, 4.34, 5.34. 2-ylcarbamate Total no of
protons: 24. LCMS (M + H).sup.+: 257. F7 Tert-butyl(S)- LCMS (M +
H).sup.+: 315. 2.25 g 1-((S)-2- 49% (methoxy- methyl)pyrrolidin-
1-yl)-3-methyl-1- oxo-butan- 2-ylcarbamate F8 (R)-Tert-butyl
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.40 g 4-methyl-1-oxo-
0.90, 0.93, 1.42, 1.79-1.88, 92% 1-(pyrrolidin-1- 1.90-2.07,
2.40-2.60, 3.38- yl)pentan-3- 3.50, 3.54-3.71, 5.51-5.63.
ylcarbamate Total no of protons: 28. LCMS (M + H).sup.+: 285.
Compound G1
Tert-butyl
(2S,3R)-3-methoxy-1-oxo-1-(pyrrolidin-1-yl)butan-2-ylcarbamate
[0631] (2S,3R)-2-(Tert-butoxycarbonylamino)-3-methoxybutanoic acid
(643 mg, 2.76 mmol), which is commercially available, and D1PEA
(1.440 mL, 8.27 mmol) was mixed in DCM (10 mL). The mixture was
cooled to 0.degree. C. TBTU (974 mg, 3.03 mmol) was added and the
mixture stirred at rt for 10 min. Pyrrolidine (0.274 mL, 3.31 mmol)
was added and the resultant mixture was stirred at rt for 16 h. The
mixture was diluted with DCM (10 mL). The organic phase was washed
with NaHCO.sub.3 (8% in aq. solution) and brine, filtered through a
phase separator and concentrated under reduced pressure. The
residue was purified via Biotage (gradient; DCM/iso-propanol, 99:1
to 95:5, KP-SIL 340 g column). The solvent was removed under
reduced pressure to give the title compound (0.704 g, 95%). .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 1.15, 1.44, 1.82-2.05, 3.33,
3.35-3.52, 3.54-3.65, 3.66-3.79, 4.36. Total no of protons: 25.
LCMS (M+H).sup.+: 287.
[0632] In a similar manner the following compound was
synthesized:
TABLE-US-00005 Com- pound Name .sup.1H NMR Yield G2 Tert-butyl
(2S,3R)- .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.60 g
3-tert-butoxy-1- 1.12, 1.19, 1.43, 1.80-1.98, quant.
oxo-1-(pyrrolidin- 3.36-3.45, 3.48-3.61, 3.74, yield
1-yl)butan-2-yl- 3.82-3.90, 4.39. carbamate Total no of protons:
31
Compound H
(S)-Tert-butyl
1-(3,3-difluoropyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate
[0633] (S)-2-(Tert-butoxycarbonylamino)-3-methylbutanoic acid (1.1
g, 5.06 mmol), which is commercially available, and TBTU (1.63 g,
5.06 mmol) was mixed in DMF (10 mL). The mixture was cooled to
0.degree. C. and TEA (2.105 mL, 15.19 mmol) was added. After 10 min
was 3,3-difluoropyrrolidine hydrochloride (0.872 g, 6.08 mmol)
added. The resultant mixture was stirred at rt over night. The
mixture was concentrated and the residue dissolved in DCM (50 mL).
The organic phase was washed with HCl (1M aq. solution, 100 mL),
NaHCO.sub.3 (saturated, 2.times.100 mL) and brine (100 mL),
filtered through a phase separator and concentrated under reduced
pressure to give the title compound (1.54 g, is 99%). The obtained
crude product was used without further purification. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 0.77-1.09, 1.21, 1.43, 1.84-2.08,
2.22-2.69, 3.52-4.40. Total no of protons: 24. LCMS (M+H).sup.+:
307.
Compound I1
(S)-Tert-butyl
1-(4-methoxypiperidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate
[0634] (S)-2-(Tert-butoxycarbonylamino)-3-methylbutanoic acid (2.0
g, 9.21 mmol) and
[0635] TBTU (2.96 g, 9.21 mmol) were mixed in DMF (20 mL). The
mixture was cooled to 0.degree. C. and NMM (1.518 mL, 13.81 mmol)
was dropwise added. After stirring for 10 min was
4-methoxypiperidine (1.272 g, 11.05 mmol) added. The resultant
mixture was stirred at rt over night. The mixture was concentrated
and the residue dissolved in DCM (50 mL). The organic layer was
washed with HCl (1M aq. solution, 100 mL), NaHCO.sub.3 (saturated,
2.times.100 mL) and brine (100 mL), filtered through a phase
separator and concentrated under reduced pressure. The residue was
purified via Biotage (isocratic; DCM/MeOH, 95:5, KP-SIL 100 g
column). The solvent was removed under reduced pressure to give the
title compound (1.75 g, 60%). .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 0.69-1.09, 1.24-1.71, 1.72-2.10, 3.09-3.27, 3.36,
3.39-3.60, 3.60-4.15, 4.20-4.49. Total no of protons: 30.
[0636] In a similar manner the following compound was
synthesized:
TABLE-US-00006 Com- pound Name .sup.1H NMR and LCMS Yield I2
(S)-Tert-butyl 1-(3, .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 3.40
g 3-difluoropiperidin- 0.79-1.05, 1.46, 1.56-2.23, quant.
1-yl)-3-methyl-1- 3.45-4.04, 4.21-4.42. yield oxobutan-2-yl- Total
no of protons: 25. carbamate LCMS (M + H).sup.+: 321.
Compound J1
(S)-1-(Azetidin-1-yl)-N-methylpentan-2-amine
[0637] To a 1M solution of LAH in THF (31.2 mL, 31.2 mmol) was
(S)-tert-butyl (azetidin-1-yl)-1-oxopentan-2-ylcarbamate (Compound
E) (2.0 g, 7.80 mmol) dropwise added (over approximately 60 min) as
a solution in THF (40 mL) under a nitrogen atmosphere. The
resultant mixture was stirred at rt for 30 min and heated at
55.degree. C. over night. The reaction mixture was cooled to
0.degree. C. Water (1.5 mL) was slowly added, followed by THF (10
mL), 15% aq. NaOH (1.5 mL) and additional water (4 mL). The
reaction mixture was warmed to rt and stirred for 1 h. The mixture
was filtered and the solid was washed with THF. The filtrate was
dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure to
give the title compound (1.22 g, quant. yield). The obtained crude
product was used without further purification. .sup.1H NMR (400
MHz, CH.sub.3OD) .delta. 0.90, 1.13-1.41, 2.04, 2.23-2.43,
3.08-3.24. Total no of protons: 19. LCMS (M+H).sup.+: 157.
[0638] In a similar manner the following compounds were
synthesized:
TABLE-US-00007 Com- pound Name .sup.1H NMR and LCMS Yield J2
(S)-3-Methyl-1- .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 4.25 g
(3-methyl-2- 0.76-1.02, 1.44, 1.70-1.98, 2.12- 93% (methylamino)-
2.20, 2.29-2.50, 2.83-3.09, butyl)azetidin- 3.22-3.31. Total no of
protons: 3-ol 20. J3 (S)-1-(2- .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 1.30 g Cyclopropyl- 0.07-0.68, 1.47-1.60, 2.41, 2.47- 74%
2-(methyl- 2.70, 2.74-3.00, 3.56-3.76, amino)eth- 4.20-4.37.
yl)azetidin-3-ol J4 (S)-1-(2-(Methyl- .sup.1H NMR (600 MHz,
CD.sub.3OD) .delta. 1.89 g amino)- 0.87-0.96, 1.23-1.43, 2.24- 76%
pentyl)azetidin- 2.35, 2.31, 2.37-2.47, 2.77- 3-ol 2.82, 2.85-2.92,
3.54-3.67, 4.29. Total no of protons: 18. J5 (S)-1-(3-Fluoro-
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 2.60 g azetidin-
0.57-1.12, 1.79-1.94, 2.11- 66% 1-yl)-N,3- 2.21, 2.31-2.39,
2.41-2.55, 2.99- dimethylbutan- 3.27, 3.47-3.84, 4.96-5.33. 2-amine
LCMS (M + H).sup.+: 175 J6 (S)-1-(2- 1H NMR (400 MHz, CDCl3)
.delta. 2.63 g (Methyl- 0.85-0.94, 1.12-1.38, 1.39-1.60, 71%
amino)pentyl)pi- 1.77-2.01, 2.17-2.26, 2.36-2.40, peridin-4-ol
2.40-2.53, 2.56-2.65, 2.74-2.82, 3.23-3.30, 3.58-3.69, 3.69-3.76.
J7 (S)-1-((S)-2- 1H NMR (400 MHz, DMSO-d6) .delta. 4.6 g (Methyl-
0.65-0.77, 1.03-1.26, 1.31-1.41, 89% amino)pentyl)pyr- 1.47,
1.74-1.86, 1.98-2.09, 2.11, rolidin-3-ol 2.14-2.27, 2.34-2.37,
2.40-2.47, 2.51-2.62, 3.02-3.34, 3.95-4.08, 4.50. J8
(3S,4S)-1-((S)-3- 1H NMR (400 MHz, CD3OD) .delta. 108 mg Methyl-
0.84-0.99, 1.85-1.96, 2.28-2.35, 69% 2-(methylamino) 2.37-2.43,
2.48-2.55, 2.8-2.87, butyl)pyrrolidine- 3.96-4.04. 3,4-diol
Compound K1
(S)-1-(Azetidin-1-yl)-N,3-dimethylbutan-2-amine
[0639] A solution of (S)-tert-butyl
1-(azetidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (Compound D)
(20 g, 78 mmol) in THF (200 mL) was dropwise charged (over
approximately 90 min) to a jacketed reactor containing a 1M
solution of LAH in THF (200 mL, 200 mmol) under a nitrogen
atmosphere. The resultant mixture was heated at 60.degree. C. over
night. The reaction was cooled to -5.degree. C. and H.sub.2O (7.6
mL) was slowly added. The mixture was diluted with THF (200 mL). A
15% aq. NaOH (7.6 mL) solution and additional H.sub.2O (22.8 mL)
were added. The mixture was warmed to 25.degree. C. and stirred for
1 h. The slurry was filtered and solids were washed with THF. The
filtrate was concentrated under reduced pressure to give the title
compound (1.7 g, 79%). The obtained crude product was used without
further purification. .sup.1H NMR (400 MHz, CH.sub.3OD) .delta.
0.86, 1.75-1.90, 1.94-2.18, 2.18-2.36, 2.38, 2.99-3.29. Total no of
protons: 19.
[0640] In a similar manner the following compound was
synthesized:
TABLE-US-00008 Com- pound Name .sup.1H NMR and LCMS Yield K2
(S)-1-(3-Methyl- .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 20.20 g
2-(methyl- 0.66-1.06, 1.74-2.02, 2.06- 80% amino)butyl)- 2.26,
2.41, 2.65-3.02, 3.52- azetidin-3-ol 3.73, 4.17-4.46. Total no of
protons: 18.
Compound L1
(S)-2-(Azetidin-1-yl)-1-cyclopropyl-N-methylethanamine
[0641] To a solution of (S)-tert-butyl
2-(azetidin-1-yl)-1-cyclopropyl-2-oxoethylcarbamate (Compound B1)
(1.4 g, 5.50 mmol) in THF (40 mL) was a 1M solution of LAH in THF
(16 mL, 16.0 mmol) dropwise added (over approximately 10 min) at
-20.degree. C. under a nitrogen atmosphere. The resultant mixture
was stirred at rt for 1 h and heated at 60.degree. C. over night.
The reaction was cooled to -5.degree. C. and
Na.sub.2SO.sub.4.times.10 H.sub.2O (ca 5 g) and NaOH (2M, 2 mL) was
added. The mixture was diluted with EtOH (100 mL) and the resultant
mixture was warmed to rt and stirred for 1 h. The mixture was
filtered and the solid was washed with THF. The filtrate was
concentrated under reduced pressure to give the title compound
(0.31 g, 37%). The obtained crude product was used without further
purification. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.03, 0.26,
0.33-0.46, 0.50-0.64, 1.51, 2.00-2.12, 2.42-2.48, 2.49, 2.56, 3.19.
Total no of protons: 17. LCMS (M+H).sup.+: 155.
[0642] In a similar manner the following compounds were
synthesized:
TABLE-US-00009 Com- pound Name .sup.1H NMR and LCMS Yield L2 (S)-3-
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 0.73 g Cyclopropyl-1-
0.02, 0.26, 0.32-0.64, 1.08- 91% (2-cyclopropyl-2- 1.22, 1.47,
2.43-2.55, 2.62, (methylamino)eth- 2.94, 3.05, 3.16.
yl)azetidin-3-ol Total no of protons: 20. LCMS (M + H).sup.+:
211
Compound M1
(S)-N,3,3-Trimethyl-1-(pyrrolidin-1-yl)butan-2-amine
[0643] To a 1M solution of LAH in THF (28.1 mL, 28.1 mmol) was
(S)-tert-butyl
3,3-dimethyl-1-oxo-1-(pyrrolidin-1-yl)butan-2-ylcarbamate (Compound
F1) (2.0 g, 7.03 mmol) dropwise added (over approximately 60 min)
as a solution in THF (40 mL) under a nitrogen atmosphere. The
resultant mixture was stirred at rt for 30 min and heated at
55.degree. C. over night. The reaction mixture was cooled to
0.degree. C. Water (1.5 mL) was slowly added, followed by THF (10
mL), 15% aq. NaOH (1.5 mL) and additional water (4 mL). The
reaction mixture was warmed to rt and stirred for 1 h. The mixture
was filtered and the solid was washed with THF. The filtrate was
dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure to
give the title compound (1.24 g, 96%). The obtained crude product
was used without further purification. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 0.90, 1.72-1.81, 2.08, 2.26, 2.32-2.48, 2.50,
2.53-2.68. Total no of protons: 23. LCMS (M+H).sup.+: 185.
[0644] In a similar manner the following compounds were
synthesized:
TABLE-US-00010 Com- pound Name .sup.1H NMR and LCMS Yield M2
(2S,3S)-N,3- .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.24 g
Dimethyl-1- 0.82, 0.92, 1.10-1.26, 1.26-1.40, 95% (pyrrolidin-1-
1.53-1.66, 1.69-1.77, 2.04- yl)pentan-2-amine 2.16, 2.29-2.47,
2.47-2.61. Total no of protons: 23. M3 (S)-1- .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 0.83 g Cyclopropyl-N- 0.03, 0.31, 0.41,
0.52-0.67, 94% methyl-2- 1.62-1.82, 2.38, 2.48-2.64, 2.72-
(pyrrolidin-1- 2.85. Total no of protons: 19. yl)ethanamine LCMS (M
+ H).sup.+: 169. M4 (R)-1-((S)-3- .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 1.87 g Methyl-2-(methyl- 0.80-1.03, 1.60-1.76, 1.80-2.00,
68.4% amino)butyl)- 2.05-2.42, 2.44-2.79, 4.19-4.40.
pyrrolidin-3-ol LCMS (M + H).sup.+: 187. M5 (S)-N-Methyl- .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 1.11 g 1-(pyrrolidin-1- 0.88,
1.18-1.39, 1.45-1.62, 1.69- 91% yl)butan-2-amine 1.81, 2.14-2.31,
2.31-2.47, 2.47-2.62. Total no of protons: 19. M6 (2R,3R)-3-
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 0.42 g Methoxy-N-methyl-
1.12, 1.83-1.73, 2.63-2.38, 3.33, 92% 1-(pyrrolidin-1- 3.41-3.34.
Total no of yl)butan-2-amine protons: 21 M7 (2R,3R)-3-Tert- .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 1.49 g butoxy-N-methyl- 1.06,
1.20, 1.71-1.85, 2.43, 83% 1-(pyrrolidin-1- 2.43-2.63, 3.81-3.88.
Total yl)butan-2-amine no of protons: 27 LCMS (M + H).sup.+: 229 M8
(S)-1-((S)-2- (The obtained crude product was 0.27 g (Methoxy- used
in the next step without 17% methyl)pyr- characterization.)
rolidin-1-yl)-N, 3-dimethylbutan- 2-amine M9 (R)-N,4- .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 2.1 g Dimethyl-1- 0.88, 1.44-1.55,
1.57-1.66, 1.72- 93% (pyrrolidin-1- 1.88, 2.19-2.25, 2.39,
2.41-2.59. yl)pentan-3-amine Total no of protons: 23. M10 (R)-N,3-
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 0.68 g Dimethyl-1- 0.85,
0.90, 1.69-1.91, 2.13-2.19, 53% (pyrrolidin-1- 2.29-2.42,
2.46-2.57. Total no of yl)butan-2-amine protons: 22. M11 (S)-1-(2-
(The obtained crude product was 1.80 g (Methylamino)pro- used in
the next step without 71%, pyl)azetidin-3-ol characterization.) 50%
pure M12 (S)-1-(2- .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 1.80 g
(Methylamino)bu- 0.87-0.95, 1.30-1.56, 2.23-2.30, 71%,
tyl)azetidin-3-ol 2.33, 2.42-2.49, 2.78-2.85, 2.88- 50% 2.93,
3.59-3.68, 4.29-4.39. Total pure no of protons: 16. M13
(3R,4R)-1-((S)-3- .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 0.61 g
Methyl-2-(methyl- 0.87, 0.95, 1.84-1.96, 2.33-2.52, 36%,
amino)butyl)pyr- 2.96-3.05, 3.96-4.01. Total no of 80%
rolidine-3,4-diol protons: 19. pure
Compound N
N,2-Dimethyl-1-(pyrrolidin-1-yl)propan-2-amine
[0645] To a solution of tert-butyl
2-methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-ylcarbamate (Compound
F5) (2.696 g, 10.52 mmol) in THF (20 mL) was a 1M LAH in THF (42.1
mL, 42.07 mmol) solution dropwise added (over approximately 10 min)
at 0.degree. C. under a nitrogen atmosphere. The resultant mixture
was stirred at rt for 1 h and heated at 40.degree. C. over night.
The reaction was cooled to 0.degree. C. and
Na.sub.2SO.sub.4.times.10 H.sub.2O followed by NaOH (2M, 2 mL) was
added. The mixture was diluted with Et.sub.2O (100 mL) and the
resultant mixture was filtered. The solids were washed with
Et.sub.2O (3.times.50 mL). To the filtrate was HCl (1.25 N aq.
solution, 15 mL) in EtOH added. The filtrate was concentrated and
the residue mixed with EtOH (60 mL). The EtOH was removed under
reduced pressure. IPA (30 mL) was added and the mixture sonicated
for 2 min. After filtration was the title compound (1.89 g, 96%)
obtained as a HCl salt. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
1.00, 1.71, 2.29, 2.41, 2.63. Total no of protons: 19.
Compound O
(S)-1-(3,3-Difluoropyrrolidin-1-yl)-3-methylbutan-2-amine
[0646] To a 1M solution of LAH in THF (9.89 mL, 9.89 mmol) was
(S)-2-amino-1-(3,3-difluoropyrrolidin-1-yl)-3-methylbutan-1-one
(1.02 g, 4.95 mmol) dropwise added (over approximately 60 min) as a
solution in THF under a nitrogen atmosphere. The mixture was
stirred at rt for 30 min and heated at 70.degree. C. over night.
The reaction was cooled to 0.degree. C. Water (0.5 mL) was slowly
added, followed by 15% aq. NaOH (0.5 mL), THF (10 mL) and
additional water (2 mL). The reaction mixture was warmed to rt and
stirred for 1 h. The mixture was filtered and the solid washed with
THF. The filtrate was dried (Na.sub.2SO.sub.4) and concentrated
under reduced pressure to give the title compound (0.67 g, 70.6%).
The obtained crude product was used without further purification.
.sup.1H NMR (400 MHz, CH.sub.3OD) .delta. 0.87-0.99, 1.52-1.65,
2.12-2.48, 2.59-2.87, 2.92-3.07, 3.31-3.67. Total no of protons:
16. LCMS (M+H).sup.+: 193.
Compound P
(S)-N-(1-(3,3-Difluoropyrrolidin-1-yl)-3-methylbutan-2-yl)-3,4-dimethylben-
zamide
[0647] 3,4-Dimethylbenzoic acid (130 mg, 0.87 mmol) and TBTU (279
mg, 0.87 mmol) was mixed in DMF (1.5 mL). The mixture was cooled to
0.degree. C. and NMM (0.287 mL, 2.61 mmol) was dropwise added.
After 10 min at 0.degree. C. was
(S)-1-(3,3-difluoropyrrolidin-1-yl)-3-methylbutan-2-amine (Compound
O) (167 mg, 0.87 mmol) added. The resultant mixture was stirred at
rt over night. The mixture was concentrated and the residue
dissolved in DCM (5 mL). The organic phase was washed with HCl (1M
aq. solution, 5 mL), NaHCO.sub.3 (saturated, 2.times.5 mL) and
brine (5 mL), and filtered through a phase separator and
concentrated under reduced pressure. The residue was purified by
preparative HPLC to give the title compound (143 mg, 51%). .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 0.65-1.03, 1.61-1.92, 2.00-2.21,
2.23, 2.53-3.03, 3.66-4.22, 7.19, 7.55, 7.61, 7.87. Total no of
protons: 26.
[0648] LCMS (M+H).sup.+: 325
Compound Q
(S)-4-Chloro-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)benzamide
[0649] 4-Chlorobenzoic acid (1.061 g, 6.78 mmol), TBTU (2.25 g,
7.01 mmol) and D1PEA (20.3 mmol) was mixed in DMF (25 mL). After 10
min was (S)-3-methyl-1-(pyrrolidin-1-yl)butan-2-amine (0.962 g,
6.16 mmol), which is commercially available, added. The resultant
mixture was stirred at rt over night. The mixture was concentrated
and the residue was purified by preparative HPLC to give the title
compound (1.48 g, 82%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
0.97, 1.80, 1.94-2.32, 2.47-2.76, 2.80-3.01, 4.13, 6.66, 7.41,
7.80. Total no of protons: 23. LCMS (M+H).sup.+: 295.
Compound R
(S)-N-(2-Methoxyethyl)-3-methyl-1-(pyrrolidin-1-yl)butan-2-amine
[0650] (S)-3-Methyl-1-(pyrrolidin-1-yl)butan-2-amine (0.24 g, 1.54
mmol), which is commercially available, and potassium carbonate
(0.139 mL, 2.30 mmol) was slurried in MeCN. 1-Bromo-2-methoxyethane
(0.147 mL, 1.54 mmol) was added and the reaction was stirred at rt
for 2 h. LMCS showed only traces of the desired product. DIPEA
(0.535 mL, 3.07 mmol) was added and the resultant mixture was
stirred at rt over night and heated at 60.degree. C. for 4 h. The
mixture was cooled to rt and diluted with water (50 mL) and DCM (50
mL). The two layers were separated and the water layer was
extracted with DCM (3.times.100 mL). The organic layers were
combined and washed with brine (100 mL), passed through phase
separator and concentrated under reduced pressure to give the title
compound (0.31 g, 97%). The obtained crude product was used without
further purification. LCMS (M+H).sup.+: 215.
Compound S1
(S)-1-(4-Methoxypiperidin-1-yl)-N,3-dimethylbutan-2-amine
[0651] To a 1M solution of LAH in THF (22.26 mL, 22.26 mmol) was
(S)-tert-butyl
1-(4-methoxypiperidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate
(Compound I1) (1.75 g, 5.57 mmol) dropwise added (over
approximately 60 min) as a solution in THF (20 mL) under a nitrogen
atmosphere. The resultant mixture was stirred at rt for 30 min and
heated at 70.degree. C. over night. The reaction was cooled to
0.degree. C. Water (1 mL) was slowly added, followed by 15% aq.
NaOH (1 mL), THF (20 mL) and additional water (2 mL). The reaction
mixture was warmed to rt and stirred for 1 h. The mixture was
filtered and the solid was washed with THF. The filtrate was dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure to give
the title compound (0.95 g, 80%). The obtained crude product was
used without further purification. .sup.1H NMR (400 MHz,
CH.sub.3OD) .delta. 0.90, 1.44-1.69, 1.74-1.98, 1.98-2.12, 2.32,
2.53-2.71, 2.71-2.93, 3.15-3.29, 3.30. LCMS (M+H).sup.+: 215.
[0652] In a similar manner the following compound was
synthesized:
TABLE-US-00011 Com- pound Name .sup.1H NMR and LCMS Yield S2
(S)-1-(3,3-Difluoro- .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 1.65
g piperidin-1-yl)- 0.83-0.98, 1.63-2.00, 2.14- 71%
N,3-dimethylbutan- 2.63, 2.66-2.81, 3.35-3.81. 2-amine Total no of
protons: 21. LCMS (M + H).sup.+: 221
Compound T
(S)-2-Amino-1-(azetidin-1-yl)-3-methylbutan-1-one
[0653] (S)-Tert-butyl
1-(azetidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (Compound D)
(23.56 g, 90.07 mmol) was stirred in 4M HCl in dioxane (56.3 mL,
225 mmol) for 30 min. Additional dioxane and MeOH was added until
the reaction mixture became a clear solution. The solvent was
removed under reduced pressure and cone. HCl (3.00 mL, 30.4 mmol)
was added. The mixture was stirred for 5 h before the solvent was
removed. The residue was purified via Biotage (gradient;
EtOAc:MeOH(2% TEA), 99:1 to 90:10, then EtOAc:MeOH(2% TEA) 90:10 to
0/100 KP-SIL 340 g. The solvent was removed under reduced pressure
to give the title compound (10.3 g, 70.3%). .sup.1H NMR (600 MHz,
CH.sub.3OD) .delta. 1.03, 1.06, 2.07-2.16, 2.33-2.41, 3.71,
3.99-4.07, 4.07-4.14, 4.25-4.33, 4.33-4.41. Total no of protons:
14. LCMS (M+H).sup.+: 157.
Compound U
(S)-1-(Azetidin-1-yl)-3-methylbutan-2-amine
[0654] To a 1M solution of LAH in THF (19.2 mL, 19.2 mmol) was
(S)-2-amino-1-(azetidin-1-yl)-3-methylbutan-1-one (Compound T) (2
g, 12.8 mmol) in THF (12.8 mL) added (over approximately 30 min) at
0.degree. C. under a nitrogen atmosphere. The resultant mixture was
stirred at rt for 1 h and heated at 60.degree. C. for 6 h. The
reaction was cooled to 0.degree. C. Water (0.73 mL) was slowly
added, followed by 15% aq. NaOH (0.73 mL) and additional water (2.2
mL). The reaction mixture was warmed to rt and stirred for 1 h.
Celite and Na.sub.2SO.sub.4 were added. The mixture was filtered
and the filtrate concentrated under reduced pressure to give the
title compound (1.14 g, 63%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 3.29-3.04, 2.51-2.39, 2.37-2.21, 2.14-1.96, 1.60-1.47,
1.34, 0.94-0.76. Total no of protons: 18.
Compound V
(S)-1-(Azetidin-1-yl)-N-ethyl-3-methylbutan-2-amine
[0655] (S)-1-(Azetidin-1-yl)-3-methylbutan-2-amine (Compound U)
(0.420 g, 2.95 mmol) and acetaldehyde (0.166 mL, 2.95 mmol) was
mixed in DCM (10 mL). Sodium triacetoxyhydroborate (0.813 g, 3.84
mmol) was added in small portions and the resultant mixture was
stirred at rt for 5 h. Water was added and the pH was adjusted to
pH9. The water phase was extracted with DCM (4.times.50 mL). The
combined organic layers were combined and washed with brine, passed
through phase separator and evaporated under reduced pressure to
give the title compound (0.1 g, 20%). The obtained crude product
was used without further purification. LCMS (M+H).sup.+: 171.
Compound X
(S)-Tert-butyl
1-(3-hydroxyazetidin-1-yl)-2,3-dimethyl-1-oxobutan-2-ylcarbamate
[0656] HATU (1.854 g, 4.88 mmol) and azetidin-3-ol hydrochloride
(0.534 g, 4.88 mmol) was added to
(S)-2-(tert-butoxycarbonylamino)-2,3-dimethylbutanoic acid (0.94 g,
4.06 mmol), which is commercially available, and DIPEA (2 mL, 11.45
mmol) in DMF (10 mL). The resultant mixture was stirred at rt over
night. The mixture was concentrated and the residue dissolved in
DCM. The organic phase was washed with NaHCO.sub.3 (saturated) and
brine (200 mL). The filtrate was dried (Na.sub.2SO.sub.4) and
concentrated under reduced pressure. The residue was purified via
Biotage (gradient; DCM/MeOH, 98:2 to 90:10, KP-SIL 100 g column) to
give the title compound (1.1 g, 93%).
Compound Y
(S)-1-(2,3-Dimethyl-2-(methylamino)butyl)azetidin-3-ol
[0657] To a solution of (S)-tert-butyl
1-(3-hydroxyazetidin-1-yl)-2,3-dimethyl-1-oxobutan-2-ylcarbamate
(Compound X) (1.07 g, 3.74 mmol) in THF (50 mL) was a 1M solution
of LAH in THF (16 ml, 16.00 mmol) dropwise added (over
approximately 2 min) at -20.degree. C. under a nitrogen atmosphere.
The resultant mixture was stirred at rt for 30 min and heated at
60.degree. C. over night. Additional LAH in THF (1M solution, 2 mL,
2 mmol) was added and the mixture was heated at 70.degree. C. over
night. The solvent was removed. 1,4-Dioxane (60 mL) and a 0.5M
solution of LAH in ethylene glycol dimethyl ether (10 mL) was added
to the residue. The resultant mixture was heated at 100.degree. C.
over night. The mixture was diluted with diethyl ether (150 mL) and
the reaction was quenched with Na.sub.2SO.sub.4.times.10 H.sub.2O.
The mixture was filtered and the filtrate was concentrated under
reduced pressure to give the title compound (0.8 g, quant.yield).
The obtained crude product was used without further purification.
LCMS (M+H).sup.+: 187.
Compound Z
(S)-4-Fluoro-N-(1-hydroxy-3-methylbutan-2-yl)-N,3-dimethylbenzamide
[0658] TEA (1.774 mL, 12.80 mmol) was added to
(S)-3-methyl-2-(methylamino)butan-1-ol (Compound B2.1) (0.5 g, 4.3
mmol) in DCM (5 mL). The mixture was cooled on an ice-bath and
4-fluoro-3-methylbenzoyl chloride (1.27 mL, 8.96 mmol) in DCM (5
mL) was dropwise (over 5 min) added. The resultant mixture was
stirred at rt over night. Additional TEA (0.414 mL, 2.99 mmol) and
4-fluoro-3-methylbenzoyl chloride (0.368 g, 2.13 mmol) was added
and the stirring was continued for 3 h. Water (12 mL) was added to
the mixture. The organic layer was dried though a phase separator
and concentrated. THF (15 mL) and NaOH was added to the residue and
the resulting mixture was stirred over night. The mixture was
neutralized by the addition of acetic acid. The solvent was removed
and DCM (50 mL) was added. The organic phase was washed with
Na.sub.2CO.sub.3 (saturated, 2.times.30 mL) and brine (30 mL),
filtered through a phase separator and concentrated under reduced
pressure to give the title compound (0.91 g, 85%). The obtained
crude product was used without further purification. Mixture of
rotamers: (600 MHz, CD.sub.3OD) .delta. 0.77-0.82, 0.95, 1.02,
1.74-1.83, 1.89-1.97, 2.23-2.31, 2.83, 2.92, 3.37-3.44, 3.58-3.74,
3.79-3.86, 4.23-4.31, 7.01-7.11, 7.18-7.36. Ratio major:minor:
1:0.6. Total no of protons: 19.
Compound A2.1
(S)-4-Fluoro-N,3-dimethyl-N-(3-methyl-1-oxobutan-2-yl)benzamide
[0659] Dess-Martin periodinane (0.25 g, 0.59 mmol) was added to
(S)-4-fluoro-N-(1-hydroxy-3-methylbutan-2-yl)-N,3-dimethylbenzamide
(Compound Z) (0.1 g, 0.39 mmol) in DCM (3 mL) at rt. The resultant
mixture was stirred at rt for 2 h. An aqueous NaHCO.sub.3 (8 wt %)
solution containing sodium pyrosulphite (0.059 mL, 0.43 mmol) was
added and the resultant mixture was stirred vigorously for 15 min.
The organic phases was washed with Na.sub.2CO.sub.3 (8 wt %),
filtered through a phase separator and dried using
Na.sub.2SO.sub.4. The solvent was removed under reduced pressure to
give the title compound (93 mg, 94%). The obtained crude product
was used without further purification. LCMS (M+H).sup.+: 252.
[0660] The following compounds were prepared, in a manner
essentially similar to that described for A2.1:
TABLE-US-00012 Exam- ple Name .sup.1H NMR and/or LCMS Yield A2.2
(S)-4-Chloro-N- LCMS (M + H).sup.+: 254. 0.86 g,
methyl-N-(3-methyl- 96% 1-oxobutan-2- yl)benzamide A2.3
(S)-3,4-Difluoro- LCMS (M + H).sup.+: 256. 2.17 g, N-methyl-N-(3-
quant. methyl-1-oxobutan- yield 2-yl)benzamide
Compound B2.1
(S)-3-Methyl-2-(methylamino)butan-1-ol
[0661] A 1M solution of LAH in THF (16 mL, 16.0 mmol) was heated to
55.degree. C. (S)-2-(Tert-butoxycarbonylamino)-3-methylbutanoic
acid (14 g, 64.4 mmol), which is commercially available, dissolved
in THF (30 mL) was added (over approximately 45 min). The resultant
mixture was stirred at 55.degree. C. Additional LAH in THF (1M
solution, 40 mL, 2 mmol) was added and the stirring was continued
for 4 h. The reaction was quenched with Na.sub.2SO.sub.4.times.10
H.sub.2O and celite and the resultant mixture was stirred for 2
days. The mixture was filtered and the filtrate was concentrated
under reduced pressure to give the title compound (7.0 g, 93%). The
obtained crude product was used without further purification.
[0662] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 0.87-0.99,
1.81-1.94, 2.28, 2.38, 3.46, 3.62. Total no of protons: 13.
[0663] The following compound was prepared, in a manner essentially
similar to that is described for B2.1:
TABLE-US-00013 Exam- ple Name .sup.1H NMR and/or LCMS Yield B2.2
(1-((2R,3R)-3- .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 0.72 g,
Methoxy-2- 1.10, 2.31-2.36, 2.41, 2.43-2.47, 72% (methylamino)bu-
2.84-2.89, 2.89-2.97, 3.32, 3.33- tyl)azetidin-3-ol 3.38,
3.55-3.67, 4.33-4.45.
Compound C2.1
(S)-2-(4-Chloro-N-methylbenzamido)-3-methylbutyl
4-chlorobenzoate
[0664] TEA (4.73 mL, 34.1 mmol) was added to
(S)-3-methyl-2-(methylamino)butan-1-ol (Compound B2.1) (1 g, 8.5
mmol) in DCM (10 mL). The mixture was cooled on an ice-bath and
4-chlorobenzoyl chloride (3.14 g, 17.9 mmol) in DCM (10 mL) was
dropwise (over 10 min) added. The resultant mixture was stirred at
rt for 2 h. The organic phase was washed with Na.sub.2CO.sub.3 (8
wt %, 40 mol) and concentrated under reduced pressure to give the
title compound (3.3 g, 98%). The obtained crude product was used
without further purification. LCMS (M+H).sup.+: 394. Mixture of
rotamers: .sup.1H NMR (600 MHz, CD.sub.3OD) .delta. 0.93-1.04 (m),
1.13 (d), 1.98-2.13 (m), 2.87 (s), 3.02 (s), 3.60-3.74 (m),
4.43-4.73 (m), 7.16-7.64 (m), 7.87-8.19 (m). Total number of
protons: 21.
[0665] The following compound was prepared, in a manner essentially
similar to that described for C2.1:
TABLE-US-00014 Exam- ple Name .sup.1H NMR and/or LCMS Yield C2.2
(S)-2-(3,4- Mixture of rotamers: 4.05 g, Difluoro-N- .sup.1H NMR
(600 MHz, CD.sub.3OD) .delta. quant. methylbenzamido)- 0.95-0.98
(m), 1.02 (d), 1.14 yield 3-methylbutyl 3,4- (d), 2.01-2.14 (m),
2.89 (s), difluorobenzoate 3.02 (s), 3.64-3.74 (m), 4.46-4.72 (m),
7.04-7.56 (m), 7.83-7.95 (m), 8.00-8.12 (m). Total no of protons:
19 LCMS (M + H).sup.+: 398.
Compound D2.1
(S)-4-Chloro-N-(1-hydroxy-3-methylbutan-2-yl)-N-methylbenzamide
[0666] NaOH (2.35 ml, 8.93 mmol) was added to
(S)-2-(4-chloro-N-methylbenzamido)-3-methylbutyl 4-chlorobenzoate
(Compound C2.1) (3.2 g, 8.12 mmol) in MeOH. The resultant mixture
was stirred at rt for 20 min. Additional NaOH (1.07 ml, 4.06 mmol)
was added and the stirring continued for 1 h. To the mixture was
water (5 mol) added and the resultant mixture was stirred for 2 h.
The mixture was neutralized by the addition of acetic acid. The
solvent was removed and DCM (50 mL) was added. The organic phase
was washed with NaHCO.sub.3 (saturated, 3.times.50 mL), filtered
through a phase separator and concentrated under reduced pressure
to give the title compound (1.47 g, 71%). The obtained crude
product was used without further purification. Mixture of rotamers:
(600 MHz, CD.sub.3OD) .delta. 0.78-0.85, 0.95-0.99, 1.02-1.07,
1.78-1.86, 1.90-1.98, 2.84, 2.95, 3.35-3.40, 3.59-3.66, 3.68-3.77,
3.83-3.88, 4.28-4.34, 7.39-7.48. Total no of protons: 17. LCMS
(M+H).sup.+: 256.
Compound E2.1
(S)-3,4-Difluoro-N-(1-hydroxy-3-methylbutan-2-yl)-N-methylbenzamide
[0667] LiOH (25.7 mL, 12.83 mmol) was added to
(S)-2-(3,4-difluoro-N-methylbenzamido)-3-methylbutyl
3,4-difluorobenzoate (Compound C2.2) (4 g, 8.56 mmol) in MeOH (40
mL). The resultant mixture was stirred at rt over night. Additional
LiOH (10.27 mL, 10.27 mmol) was added and the stirring continued
for 2 h. The mixture was neutralized by the addition of acetic
acid. The solvent was removed and DCM (50 mL) was added. The
organic phase was washed with NaHCO.sub.3 (saturated, 1.times.50
mol, 2.times.30 mL), dried (Na.sub.2SO.sub.4) and concentrated
under reduced pressure to give the title compound (2.18 g, 99%).
The obtained crude product was used without further
purification.
[0668] Mixture of rotamers: .sup.1H NMR (600 MHz, CD.sub.3OD)
.delta. 0.78-0.84 (m), 0.97 (d), 1.04 (d), 1.77-1.86 (m), 1.90-1.98
(m), 2.85 (s), 2.94 (s), 3.34-3.40 (m), 3.60-3.66 (m), 3.70-3.76
(m), 3.83-3.88 (m), 4.26-4.33 (m), 7.22-7.44 (m). Total no of
protons: 16. LCMS (M+H).sup.+: 258.
Compound F2.1
Tert-butyl
(2S,3S)-1-(3-hydroxyazetidin-1-yl)-3-methyl-1-oxopentan-2-ylcar-
bamate
[0669] NMM (6.12 mL, 55.6 mmol) in DMF (5 mL) was added to
(2S,3S)-2-(tert-butoxycarbonylamino)-3-methylpentanoic acid (4.15
g, 17.9 mmol), which is commercially available, in DCM (45 mL)
under a nitrogen atmosphere. TBTU was added portionwise and the
resultant mixture was stirred at rt for 15 min. Azetidin-3-ol
hydrochloride (2.359 g, 21.53 mmol) was added and the stirring
continued for 20 h. The mixture was diluted with DCM, washed with
NaHCO.sub.3 and brine, filtered through a phase separator and
concentrated under reduced pressure. The residue was dissolved in
Et.sub.2O, washed with water, filtered through a phase separator
and concentrated under reduced pressure to give the title compound
(5 g, 97%). The obtained crude product was used without further
purification. .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 0.81-0.95,
1.04-1.16, 1.35-1.48, 1.48-1.70, 3.79-4.09, 4.14-4.24, 4.25-4.42,
4.52-4.74, 5.05-5.16.
[0670] The following compounds were prepared, in a manner
essentially similar to that described for Compound F2.1:
TABLE-US-00015 Exam- ple Name .sup.1H NMR and/or LCMS Yield F2.2
Tert-butyl (2S,3R)- .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 1.93
g, 1-(3- 1.10, 2.31-2.36, 2.41, 2.43- 84% hydroxyazetidin- 2.47,
2.84-2.89, 2.89-2.97, 1-yl)-3-methoxy-1- 3.32, 3.33-3.38,
3.55-3.67, oxobutan-2- 4.33-4.45. ylcarbamate F2.3 (S)-Tert-butyl
1-(3- LCMS (M + H).sup.+: 287 10.34 g, hydroxyazetidin-1- 77%
yl)-1-oxohexan-2- ylcarbamate F2.4 (S)-Tert-butyl 1- .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 11.30 g, cyclohexyl-2-(3- 0.86-1.32
(m, 5H), 1.43 121% hydroxyazetidin- (s, 9H), 1.50-1.90 (m, 6H),
1-yl)-2- 3.70-3.89 (m, 2H), 3.98-4.06 oxoethylcarbamate (m, 1H),
4.11-4.26 (m, 1H), 4.45 (t, 1H), 4.49-4.65 (m, 2H). LCMS (M +
H).sup.+: 313.5 F2.5 (S)-Tert-butyl .sup.1H NMR (600 MHz,
CDCl.sub.3) .delta. 24.7 g, 1-(3- 0.92, 1.30-1.53, 1.65, 2.63, 100%
hydroxyazetidin- 3.83, 3.91, 4.00, 4.14-4.38, 1-yl)-4-methyl-1-
4.53-4.74, 5.04. oxopentan-2- ylcarbamate F2.6 (R)-Tert-butyl
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.050 g, 1-(3- 0.80,
1.02-1.62, 2.10-2.26, 44.1% hydroxyazetidin- 2.29-2.46, 3.72, 3.80,
3.89, 1-yl)-1-oxopentan- 3.95-4.15, 4.15-4.32, 4.36- 2-ylcarbamate
4.48, 4.49-4.70, 4.99. F2.7 (R)-Tert-butyl 1- LCMS (M + H).sup.+:
285. 7.5 g, cyclobutyl-2-(3- 121%, hydroxyazetidin- 69% 1-yl)-2-
pure oxoethylcarbamate
Compound G2.1
1-((2S,3S)-3-Methyl-2-(methylamino)pentyl)azetidin-3-ol
[0671] To LAH (1 M solution in THF) (69.8 mL, 69.84 mmol) was added
a solution of tert-butyl
(2S,3S)-1-(3-hydroxyazetidin-1-yl)-3-methyl-1-oxopentan-2-ylcarbamate
(Compound F2.1) (5 g, 17.5 mmol) in anhydrous THF (24 mL) dropwise
(1 h) under nitrogen. The reaction mixture was stirred at rt for 1
h and then heated at 60.degree. C. over night. The reaction mixture
was cooled to 0.degree. C. Water (3.5 ml) was added dropwise,
followed by 15% aq. NaOH (3.5 ml), THF (50 ml) and water (7.5 ml).
The mixture was allowed to reach rt and stirred for 30 min. The
solids were filtered off and washed with THF. The filtrate was
dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure
to give the title compound as colorless oil (2.8 g, 86%). The
product was used in the next step without further purification.
.sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 0.80 (d, 3H), 0.91 (t,
3H), 1.10-1.23 (m, 1H), 1.25-1.38 (m, 1H), 1.53-1.63 (m, 1H),
2.15-2.30 (m, 3H), 2.36 (s, 3H), 2.38-2.47 (m, 2H), 2.77-2.84 (m,
1H), 2.89-2.97 (m, 1H), 3.50-3.64 (m, 2H), 4.33-4.44 (m, is
1H).
[0672] The following compounds were prepared, in a manner
essentially similar to that described for Compound G2.1:
TABLE-US-00016 Exam- ple Name .sup.1H NMR and/or LCMS Yield G2.2
(S)-1-(2- Mixture of rotamers: 5.04 g, (Methyl- .sup.1H NMR (600
MHz, CD.sub.3OD) .delta. 77%, amino)hexyl)- 0.87-0.97 (m, 3H),
1.23-1.50 89% azetidin-3-ol (m, 7H), 2.27-2.37 (m, 4H), pure
2.39-2.49 (m, 2H), 2.79-2.84 (m, 1H), 2.88-2.94 (m, 1H), 3.56-3.67
(m, 2H), 4.26-4.36 (m, 1H). Total number of protons in spectrum: 20
G2.3 (S)-1-(2- .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 5.40 g,
Cyclohexyl-2- 0.94-1.34, 1.45-1.82, 2.10-2.18, 70%, (methyl- 2.34,
2.40-2.47, 2.75-2.82, 2.85- 75% amino)ethyl)- 2.93, 3.54-3.66,
4.24-4.36. pure azetidin-3-ol G2.4 (S)-1-(4- .sup.1H NMR (600 MHz,
CD.sub.3OD) .delta. 12.8 g, Methyl-2- 0.89-0.94, 1.11-1.18,
1.26-1.32, 80%, (methyl- 1.63-1.71, 2.32, 2.35-2.49, 2.82, 90%
amino)pentyl)- 2.91, 3.59-3.66, 4.28-4.34. Total pure azetidin-3-ol
number of protons: 20 (expected 22, NH and OH protons exchanged
with solvent). LCMS (M + H).sup.+: 187. G2.5 (R)-1-(2- .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 0.586 g, (Methyl- 0.87-1.00,
1.16-1.51, 1.94-2.13, 88% amino)pentyl)- 2.25-2.54, 2.80-2.90,
2.90-2.98, azetidin-3-ol 3.60-3.77, 4.39-4.50. Total number of
protons: 20. G2.6 (R)-1-(2- .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 3.85 g, Cyclobutyl-2- 1.76-2.00, 2.06-2.18, 2.23-2.44, 93%,
(methyl- 2.37-2.40, 2.80-2.98, 3.57-3.71, 52% amino)ethyl)-
4.30-4.40. pure azetidin-3-ol
Compound H2.1
2-Cyclopentyl-3-ethoxy-3-oxopropanoic acid
[0673] KOH (3.42 g, 61.0 mmol) in water (10 mL) was slowly added
(over 1 h) to diethyl 2-cyclopentylmalonate (12.12 g, 53.09 mmol)
in ethanol (30 mL) at 0.degree. C. The resultant mixture was
stirred at 0.degree. C. for 2 h and at rt over night. The mixture
was freezing-dried, and the residue partitioned between Et.sub.2O
and water. The aqueous layer was washed with Et.sub.2O. The
combined organic layers were washed with brine, dried
(Na.sub.2SO.sub.4) and concentrated under reduce pressure to
recover unreacted diethyl cyclopentylmalonate (1.94 g, 8.5 mmol).
The aqueous layer was cooled to -10.degree. C. and the pH was
adjusted to 1 using HCl (conc.). The water layer was extracted with
Et.sub.2O (6.times.50 mL), dried (MgSO.sub.4) and concentrated
under reduce pressure to give the title compound (10.2 g, 96%). The
obtained crude product was used without further purification.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.21-1.38, 1.47-1.75,
1.76-1.97, 2.37-2.55, 3.24, 4.14-4.31. Total no of protons: 15.
Compound I2.1
Ethyl 2-cyclopentyl-2-(methoxycarbonylamino)acetate
[0674] TEA (5.74 mL, 41.2 mmol) was added to
2-cyclopentyl-3-ethoxy-3-oxopropanoic acid (Compound H2.1) (7.5 g,
37.46 mmol) and diphenyl phosphorazidate (9.42 mL, 43.7 mmol) in
toluene (25 mL) at rt under a nitrogen atmosphere. The mixture was
heated at 80.degree. C. for 30 min. The temperature was adjusted to
75.degree. C. and MeOH (50.0 mL) was added. The resultant mixture
was heated at 75.degree. C. for 5 h and in a microwave reactor at
100.degree. C. for 10 min. The solvent was removed under reduced
pressure. The residue was diluted with EtOAc and the organic phase
was washed with 5% citric acid, NaHCO.sub.3 (saturated) and NaCl
(saturated). The organic phase was dried (MgSO.sub.4), filtered and
concentrated under reduce pressure. The residue was purified via
Biotage (DCM/MeOH, KP-SIL 100 g column) to give the title product
(8.14 g, 95%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.28,
1.31-1.46, 1.46-1.81, 2.21, 3.68, 4.13-4.24, 4.24-4.33, 5.15. Total
no of protons: 19.
Compound J2.1
2-Cyclopentyl-2-(methoxycarbonylamino)acetic acid
[0675] KOH (3.87 g, 69.0 mmol) in water (50 mL) was added to ethyl
2-cyclopentyl-2-(methoxycarbonylamino)acetate (Compound I2.1) (7.6
g, 33.2 mmol) in ethanol (20 mL). The resultant mixture was stirred
at rt for 5 h. Part of the solvent was removed under reduce
pressure. The remaining mixture was extracted with Et.sub.2O
(2.times.50 mL). The pH of the water layer was acidified by
additions of HCl (1N, 20 mL) and the resultant mixture was
extracted with DCM (3.times.50 mL), dried (MgSO.sub.4) and
concentrated under reduce pressure. The residue was purified via
Biotage (gradient: 10-80% of DCM/MeOH/HOAc (1:0.05:0.01) in DCM,
KP-SIL 340 g column), KP-SIL 340 g column) to give the title
product (5.95 g, 85%). .sup.1H NMR (600 MHz, CDCl.sub.3) 1.26-1.48,
1.49-1.68, 1.68-1.85, 2.28, 3.69, 4.31, 5.12. Total no of protons:
14.
Compound K2.1
Methyl
1-cyclopentyl-2-(3-hydroxyazetidin-1-yl)-2-oxoethylcarbamate
[0676] TBTU (0.373 g, 1.16 mmol) was added to azetidin-3-ol
hydrochloride (1.960 g, 17.89 mmol),
2-cyclopentyl-2-(methoxycarbonylamino)acetic acid (Compound J2.1)
(3 g, 14.91 mmol) and DIPEA (10 mL, 57.3 mmol) in DCM (60 mL) at
rt. The resultant mixture was stirred for 2 h. Additional
azetidin-3-ol hydrochloride (0.45 g, 4.11 mmol) was added and the
mixture was heated at 50.degree. C. for 1.5 h. The mixture was
cooled to rt and the pH was adjusted to 2 using KHSO.sub.4 (1.5 M).
The mixture was extracted with DCM and the combined DCM layers were
washed with brine and concentrated under reduced pressure. The
residue was diluted with MeOH (15 mL) and KOH (1.56 g) in water (30
mL) was added. The resultant mixture was stirred at rt for 5 h.
Part of the solvent was removed under reduce pressure. The
remaining mixture was diluted with water and extracted with DCM.
The organic layer was washed with brine, dried (MgSO.sub.4) and
concentrated under reduce pressure. The residue was purified via
Biotage (gradient: 10-100% of DCM/MeOH (1:0.05) in DCM, KP-SIL 100
g column) to give the title product (5.95 g, 50%). .sup.1H NMR (600
MHz, CDCl.sub.3) 1.15-1.40, 1.45-1.81, 2.04-2.20, 2.33, 2.50, 3.65,
3.84, 3.92, 4.04, 4.14-4.28, 4.32, 4.37-4.44, 4.65, 5.25. Total no
of protons: 20.
Compound L2.1
1-(2-Cyclopentyl-2-(methylamino)ethyl)azetidin-3-ol
[0677] To a solution of methyl
1-cyclopentyl-2-(3-hydroxyazetidin-1-yl)-2-oxoethylcarbamate
(Compound K2.1) (1.89 g, 7.37 mmol) in THF (50 mL) was a 1M
solution of LAH in THF (30 mL, 30.0 mmol) dropwise added (over
approximately 5 min) at rt under a nitrogen atmosphere. The
resultant mixture was stirred at rt for 30 min and heated at
45.degree. C. over night. Additional LAH in THF (1M solution, 10
mL) was added and the mixture was heated at 65.degree. C. for 1
day. The mixture was diluted with Et.sub.2O (150 mL) and the
reaction was quenched with Na.sub.2SO.sub.4.times.10 H.sub.2O. The
mixture was filtered and a HCl solution in EtOH was added (1.25N,
15 mL) to the filtrate. The filtrate was concentrated under reduced
pressure and the residue was co-evaporated with MeOH to give the
title compound (1.5 g, 75.0%). The obtained crude product was used
without further purification. LCMS (M+H).sup.+: 199.
Compound M2.1
(S)-2-Amino-1-(3-hydroxyazetidin-1-yl)pentan-1-one
[0678] To a solution of (S)-tert-butyl
1-(3-hydroxyazetidin-1-yl)-1-oxopentan-2-ylcarbamate (Compound A2)
(3.5 g, 12.8 mmol) in anhydrous DCM (50 mL) was added TFA (18 mL,
242 mmol) dropwise at 0.degree. C. under N.sub.2(g). The reaction
mixture was stirred at r.t for 2 h and then concentrated under
reduced pressure. The residue was dissolved in DCM and concentrated
under reduced pressure to remove the residue of TFA. This procedure
was repeated twice with DCM and twice with McOH. To the residue was
added diethyl ether and decanted (.times.2). The crude product was
dried in vacuo give the title compound (3.88 g) used in the next
step without further purification. LCMS (M+H).sup.+: 173.1
Compound N2.1
(S)-1-(3-Hydroxyazetidin-1-yl)-2-(propan-2-ylideneamino)pentan-1-one
[0679] A solution of
(S)-2-amino-1-(3-hydroxyazetidin-1-yl)pentan-1-one (Compound M2.1)
(1.9 g, 11.0 mmol) in propan-2-one (40 mL, 544 mmol) was stirred at
rt for 48 h. The reaction mixture was then concentrated in vacuo
until 10 mL remained. To the mixture was added Me-THF (40 mL) and
then mixture was again reduced in vacuo until 10 mL remained. This
procedure was repeated three times and the remaining mixture (11
mL) was used in the next step without further treatment. LCMS
(M+H).sup.+: 213.1.
Compound O2.1
(S)-1-(2-(Isopropylamino)pentyl)azetidin-3-ol
[0680] A solution of
(S)-1-(3-hydroxyazetidin-1-yl)-2-(propan-2-ylideneamino)pentan-1-one
(Compound N2.1) (2.34 g, 11.0 mmol) in Me-THF (11 M1) was added to
aluminum(III) lithium hydride (1.0 M solution in THF) (44.0 mL,
44.00 mmol) dropwise under N.sub.2. The reaction mixture was
stirred at rt for 40 min and then heated at 60.degree. C.
overnight. The reaction mixture was cooled to 0.degree. C. Water
(2.25 mL) was added dropwise, followed by 15% aq. NaOH (2.25 mL),
THF (35 mL) and water (4.82 mL). The mixture was allowed to reach
rt and stirred for 30 min. The mixture was filtered and the solid
washed with THF and the filtrate was dried over Na2SO4 and
concentrated in vacuo to give the title compound (2.8 g), which was
used in the next step without further purification. LCMS
(M+H).sup.+: 201.1
Compound S2.1
(2S,3R)-1-Benzhydryl-2-methylazetidin-3-yl benzoate and
(2R,3S)-1-benzhydryl-2-methylazetidin-3-yl benzoate
[0681] Benzoic anhydride (1.61 g, 7.11 mmol) was added to a stirred
mixture of (2S,3R)-1-benzhydryl-2-methylazetidin-3-ol and
(2R,3S)-1-benzhydryl-2-methylazetidin-3-ol (1.2 g, 4.74 mmol) and
N,N-dimethylpyridin-4-amine (1.16 g, 9.47 mmol) in DCM (25 mL), and
the resulting mixture was stirred over the weekend. 8% NaHCO.sub.3
(25 mL) was added and the stirring continued for 30 min. Phases
were separated on a phase separator and the aqueous layer extracted
with DCM (25 mL). The combined organic layers were concentrated and
purified on a 20 g Isolute Flash Si column eluted with
heptane/EtOAc 6:1 to yield the title compound (1.69 g, 100%).
[0682] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.88, 2.83, 3.36,
3.84, 4.43, 4.89, 7.16-7.33, 7.39-7.49, 7.56, 8.02. Total no of
protons: 23. LCMS (M+H).sup.+: 358.3.
Compound T2.1
(2S,3R)-2-Methylazetidin-3-ylbenzoate and
(2R,3S)-2-methylazetidin-3-yl benzoate
[0683] (2S,3R)-1-Benzhydryl-2-methylazetidin-3-yl benzoate and
(2R,3S)-1-benzhydryl-2-methylazetidin-3-yl benzoate (Compound S2.1)
(1.69 g, 4.73 mmol) was dissolved in EtOH (25 mL) and added to
Pd(OH).sub.2 (20% wt Pd, 50% wet, 200 mg). The mixture was
hydrogenated at 8 bar pressure over night. The catalyst was
filtered off and washed with EtOH, and the combined filtrates were
concentrated to yield the title compound as a 1:1 mixture of title
compound and diphenylmethane (1.54 g, 90%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 1.41, 3.64, 3.81, 4.06, 5.06, 7.46, 7.58, 8.06.
Total no of protons: 12. LCMS (M+H).sup.+: 192.1.
Compound U2.1
(2S,3R)-1-((S)-2-(Tert-butoxycarbonylamino)pentanoyl)-2-methylazetidin-3-y-
l benzoate and
(2R,3S)-1-(S)-2-(tert-butoxycarbonylamino)pentanoyl)-2-methylazetidin-3-y-
l benzoate
[0684] NMM (0.939 mL, 8.54 mmol) and TBTU (2.06 g, 6.40 mmol) were
added to a stirred solution of
(S)-2-(tert-butoxycarbonylamino)pentanoic acid (1.21 g, 5.55 mmol),
which is commercially available, and (2S,3R)-2-methylazetidin-3-yl
benzoate and (2R,35)-2-methylazetidin-3-yl benzoate (Compound T2.1)
(1.54 g, 53% purity, 4.27 mmol) in DCM (15 mL), and the resulting
mixture was stirred for 2 h. 8% NaHCO.sub.3 (20 mL) was added and
the phases separated on a phase separator. The aqueous layer was
extracted with DCM (20 mL) and the combined organic layers washed
with 8% NaHCO.sub.3 (2.times.20 mL). The organic layer was passed
through a phase separator and concentrated. The residue was
purified by preparative HPLC to yield the title compound as a 1:1
mixture of
(2S,3R)-1-((S)-2-(tert-butoxycarbonylamino)pentanoyl)-2-methylazetidin-3--
yl benzoate and
(2R,3S)-1-(S)-2-(tert-butoxycarbonylamino)pentanoyl)-2-methylazetidin-3-y-
l benzoate (1.40 g, 84%). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
0.89-1.00, 1.27-1.78, 3.88-4.88, 4.95-5.05, 7.50, 7.64, 8.05. Total
no of protons: 29. LCMS (M+H).sup.+: 391.3.
[0685] The following Compound U2.2 was prepared, in a manner
essentially similar to that described for Compound U2.1
TABLE-US-00017 Exam- ple Name .sup.1H NMR and/or LCMS Yield U2.2
Tert-butyl(S)-1-((S)-3- LCMS (M + H).sup.+: 287. 9.11 g,
hydroxypyrrolidin-1-yl)-1- quant. oxopentan-2-ylcarbamate yield
Compound V2.1
(2S,3R)-2-Methyl-1-((S)-2-(methylamino)pentyl)azetidin-3-ol and
(2R,3S)-2-methyl-1-((S)-2-(methylamino)pentyl)azetidin-3-ol
[0686] A solution of a 1:1 mixture of
(2S,3R)-1-(S)-2-(tert-butoxycarbonylamino)-pentanoyl)-2-methylazetidin-3--
yl benzoate and
(2R,3S)-1-(S)-2-(tert-butoxycarbonyl-amino)pentanoyl)-2-methylazetidin-3--
yl benzoate (Compound U2.1) (1.40 g, 3.58 mmol) in dry THF (15 mL)
was added dropwise to a stirred solution of 1M LiAlH.sub.4 in THF
(21.5 mL, 21.5 mmol) under a N.sub.2 atmosphere. The reaction
mixture was stirred at room temperature for 30 min, and at
60.degree. C. over night. The mixture was cooled to 0.degree. C. in
an ice-bath and aqueous NaHCO.sub.3 (8%, 5.1 mL) was added dropwise
(10 mL THF was added to facilitate stirring), and the stirring was
continued for an additional 1 h at rt. The mixture was diluted with
DCM, the white precipitate filtered off and washed with DCM. The
filtrate was concentrated to yield the title compound as a 1:1
mixture of
(2S,3R)-2-methyl-1-((S)-2-(methylamino)pentyl)azetidin-3-ol and
(2R,3S)-2-methyl-1-((S)-2-(methylamino)pentyl)azetidin-3-ol,
containing 1 eq of BnOH (1.00 g, 95%). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 0.94, 1.14-1.53, 2.28-2.43, 2.48-2.61, 2.68,
2.88, 3.65, 3.77. Total no of protons: 20. LCMS (M+H).sup.+:
187.2.
Compound X2.1
(2S,3S)-2-Methyl-1-((S)-2-(methylamino)pentyl)azetidin-3-ol and
(2R,3R)-2-methyl-1-((S)-2-(methylamino)pentyl)azetidin-3-ol
[0687] A 1:1 mixture of
(2S,3S)-2-methyl-1-((S)-2-(methylamino)pentyl)azetidin-3-ol and
(2R,3R)-2-methyl-1-((S)-2-(methylamino)pentyl)azetidin-3-ol,
containing 1 eq of BnOH (728 mg, 60%) was prepared from
(2S,3S)-1-benzhydryl-2-methylazetidin-3-ol and
(2R,3R)-1-benzhydryl-2-methylazetidin-3-ol (1.05 g, 4.14 mmol) in 4
steps by the same method as for Compound V2.1. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 0.93, 1.10, 1.15, 1.18-1.51, 2.21-2.58,
3.02, 3.17-3.31 (partially obscured by solvent peak), 4.26. Total
no of protons: 20. LCMS (M+H).sup.+: 187.2.
Compound Y2.1
(S)-Tert-butyl
1-cyclobutyl-2-(3-hydroxyazetidin-1-yl)-2-oxoethylcarbamate
[0688] NMM (4.26 mL, 38.8 mmol) was added to a mixture of
(S)-2-(tert-butoxycarbonylamino)-2-cyclobutylacetic acid (4.04 g,
17.6 mmol), which is commercially available, in DCM (45 mL) and DMF
(14 mL). The mixture was cooled to 0.degree. C. and TBTU (5.66 g,
17.6 mmol) was added. After 10 min was azetidin-3-ol hydrochloride
(2.40 g, 21.9 mmol) added. The resultant mixture was stirred at rt
over night. The mixture was washed with NaHCO.sub.3 (8% aq., 30
mL). A second wash with NaHCO.sub.3 (8% aq., 30 mL) resulted in an
emulsion. The emulsion was diluted with DCM (50 mL) and NaHCO.sub.3
(8% aq., 30 mL), mixed well and left to separate. The organic layer
was dried (Na.sub.2SO.sub.4) and concentrated under reduced
pressure. The residue was co-evaporated with toluene to give the
title compound (4.10 g, 82%) as a solid. The obtained crude product
was used without further purification. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 1.44 (9H), 1.76-2.09 (6H), 2.51-2.65 (1H),
3.67-3.82 (1H), 3.97-4.27 (3H), 4.45-4.69 (2H). Expected Number of
protons: 24. OH- and NH-protons are exchanged with CD.sub.3OD.
Compound Z2.1
(S)-1-(2-Cyclobutyl-2-(methylamino)ethyl)azetidin-3-ol
[0689] A 1 M solution of LAH in THF (66.8 mL, 66.8 mmol) under
nitrogen was heated to 45.degree. C. A solution of (S)-tert-butyl
1-cyclobutyl-2-(3-hydroxyazetidin-1-yl)-2-oxoethylcarbamate
(Compound Y2.1) (3.80 g, 13.4 mmol) in THF (20 mL) was added
dropwise over 30 min. The resultant mixture was stirred at
47.degree. C. over night. The mixture was cooled on an ice-bath and
NaHCO.sub.3 (8% aq., 16 mL) was carefully added dropwise. The
stirring was continued for 2 h at rt. The precipitate was filtered
off and washed with DCM. The filtrate was concentrated and the
residue dissolved in DCM and filtered through a 0.45 .mu.m syringe
filter. The filtrate was concentrated to give the title compound
(2.23 g, 91%, 92% pure) as an oil. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 1.69-2.13 (6H), 2.2-2.38 (7H), 2.79 (1H), 2.89
(1H), 3.56-3.66 (2H), 4.26-4.34 (1H). Expected Number of protons:
20. OH- and NH-protons are exchanged with CD.sub.3OD.
Compound A3.1
(S)-Tert-butyl 1-(3-hydroxyazetidin-1-yl)-1-oxopropan-2-yl
carbamate
[0690] DIPEA (8.53 mL, 49.0 mmol) was added to a mixture of
(S)-2-(tert-butoxycarbonylamino)propanoic acid (3.089 g, 16.33
mmol), which is commercially available, and TBTU (5.24 g, 16.33
mmol) in DCM (30 mL). Upon stirring at rt the mixture gradually
became a clear solution. Azetidin-3-ol hydrochloride (2.68 g, 24.5
mmol) was added and the mixture was stirred over night. NaHCO.sub.3
(8% aq., 20 mL) was added. The organic layer was washed with
NaHCO.sub.3 (8% aq., 3.times.60 mL). DCM (100 mL) was used for
backextraction of the combined aqueous phases. Toluene was added
and the combined organic layers were concentrated on the rotavapor
over night (45.degree. C. in waterbath) to give the title product
(3.35 g, 84%,) as a transparent oil which solidified upon standing.
Mixture of rotamers: .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.
1.21-1.27, 1.41-1.49, 3.7-3.83, 3.98-4.27, 4.41-4.47,
4.56-4.64.
[0691] The following Compound A3.2 was prepared in a manner
essentially similar to that described for Compound A3.1.
TABLE-US-00018 Exam- ple Name .sup.1H NMR and/or LCMS Yield A3.2
(S)-Tert-butyl 1-(3- .sup.1H NMR (400 MHz, 8.08 g,
hydroxyazetidin-1-yl)-1- CD.sub.3OD) .delta.0.9-1, 110%.
oxobutan-2-ylcarbamate 1.4-1.5, 1.52-1.74, 61% 3.7-4.05, 4.13-4.28,
pure 4.41-4.48, 4.53-4.65.
Compound B3.1
Tert-butyl
1,1,1-trifluoro-3-(3-hydroxyazetidin-1-yl)-3-oxopropan-2-ylcarb-
amate
[0692] TBTU (6.87 g, 21.4 mmol) was added to a stirred suspension
of 2-(tert-butoxycarbonylamino)-3,3,3-trifluoropropanoic acid,
which is commercially available, in DCM (50 mL). NMM (4.4 mL, 40
mmol) and 3-hydroxyazetidinol hydrochloride (2.48 g, 22.6 mmol)
were added. The mixture was stirred at rt for 4 h. The turbid
solution was diluted with DCM (70 mL) and washed with NaHCO.sub.3
solution (saturated, 1.times.100, 2.times.20 mL). After drying
(Na.sub.2SO.sub.4) the solvent was evaporated under reduced
pressure. The residue was stirred at rt with isohexanes (60 mL) to
yield the title product (3.97 g, 97%) as a colourless powder.
.sup.1H NMR (500 MHz, DMSO-d6) .delta. 7.86-8.05 (1H), 5.71-5.87
(1H), 4.86-5.03 (1H), 4.27-4.54 (2H), 4.04-4.15 (1H), 3.78-3.97
(1H), 3.56-3.68 (1H), 1.38-1.4 (9H). Ratio of rotamers
.about.6:4.
Compound C3.1
1-(3,3,3-Trifluoro-2-(methylamino)propyl)azetidin-3-ol
[0693] Tert-butyl
1,1,1-trifluoro-3-(3-hydroxyazetidin-1-yl)-3-oxopropan-2-ylcarbamate
(Compound B3.1) (3.97 gg, 13.3 mmol) was added under argon in
portions to 1M solution of LAH in THF (53 mL, 53 mmol) over 15 min.
The mixture was heated under argon to reflux for 7 h. After
additional standing for 15 h at rt EtOAc (10 mL) was added dropwise
under ice cooling, followed by addition of water/THF (1:1, 12 mL).
The mixture was diluted with DCM (120 mL). Celite was added and the
suspension was stirred for 10 min. The mixture was filtered, the
solids washed with DCM (2.times.50 mL). The combined filtrates were
dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure to
give the title compound (2.39 g, 91%). The obtained crude product
was used in the next step without characterization.
Compound D3.1
1-(3,3,3-Trifluoro-2-(methylamino)propyl)azetidin-3-yl benzoate
[0694] A solution of benzoyl fluoride (1.37 mL, 12.6 mmol) in DCM
(5 mL) was added dropwise under argon to an ice cooled solution of
1-(3,3,3-trifluoro-2-(methylamino)propyl)azetidin-3-ol (Compound
C3.1) (2.28 g, 11.5 mmol) and TEA (3.21 mL, 23 mmol) in DCM (45
mL). The stirring was continued at rt for 2.5 h. NaHCO.sub.3
(saturated, 20 mL) was added and the mixture was stirred vigorously
for 40 min. The layers were separated, the aqueous layer was
extracted with DCM, and the combined organic layers were washed
with NaHCO.sub.3 (saturated), dried (Na.sub.2SO.sub.4) and
concentrated under reduced pressure. The residue was purified by
preparative HPLC. After concentrating the fractions to
approximately 30 mL the aqueous emulsion was extracted DCM
(.times.2). The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure to give
the title product (1.54 g, 44%.) as a colourless oil. .sup.1H NMR
(500 MHz, DMSO-d6) .delta. 7.97 (2H), 7.67 (1H), 7.53 (2H), 5.16
(1H), 3.7-3.79 (2H), 3.25 (1H), 3.18 (1H), 2.92-3.02 (1H), 2.66
(1H), 2.59 (1H), 2.38 (3H), 1.99-2.06 (1H).
Compound E3.1
(S)-Tert-butyl
1-(4-hydroxypiperidin-1-yl)-1-oxopentan-2-ylcarbamate
[0695] TBTU (7.09 g, 22.09 mmol) was added to a solution of
(S)-2-(tert-butoxycarbonylamino)pentanoic acid (4 g, 18.41 mmol),
which is commercially available, and piperidin-4-ol (2.235 g, 22.09
mmol) in DCM (50 mL). The reaction was stirred for 3 h and was then
quenched by addition of NaHCO3(aq., 8%, 25 mL). The aqueous phase
was extracted with DCM. The organic phases were combined, dried
(MgSO.sub.4), filtered and evaporated. The residue was added
H.sub.3PO.sub.4(aq) (1 M, 25 mL) and the aqueous phase was
extracted with Et.sub.2O. The organic phases were pooled, dried
(MgSO.sub.4), filtered and evaporated to give the title product
(5.86 g, 106%) as a yellow oil. The obtained crude product was used
in the next step without characterization.
[0696] It may be noted that certain intermediates disclosed herein
for preparation of compounds of Formula I are believed to be novel
and therefore comprise an independent aspect of the invention.
[0697] It shall be noted that if the intermediate/compound was
prepared as a specific isomer (e.g. 3R,4S), the chemical name of
the intermediate/compound reflects that.
Example 1.1
(S)-N-(1-(Azetidin-1-yl)pentan-2-yl)-2,4-dichloro-N-methylbenzamide
##STR00014##
[0699] 2,4-Dichlorobenzoic acid (92 mg, 0.48 mmol) and TBTU (162
mg, 0.50 mmol) was mixed in DMF (1.5 mL). The mixture was cooled to
0.degree. C. and NMM (0.063 mL, 0.58 mmol) was dropwise added.
After 10 min at 0.degree. C. was
(S)-1-(azetidin-1-yl)-N-methyl-pentan-2-amine (Compound J1) (75 mg,
0.48 mmol) added. The resultant mixture was stirred at 0.degree. C.
for 30 min and at rt for 16 h. The mixture was concentrated and the
residue dissolved in DCM (5 mL). The organic phase was washed with
NaHCO.sub.3 (saturated, 2.times.5 mL), filtered through a phase
separator and concentrated under reduced pressure. The residue was
purified by preparative HPLC to give the title compound (98 mg,
62%).
[0700] Mixture of rotamers: .sup.1H NMR (400 MHz, DMSO-d6):
0.59-0.87, 0.90, 0.98-1.66, 1.72-2.11, 2.22-2.47, 2.5, 2.78,
4.26-4.70, 7.24-7.36, 7.43-7.64, 7.65-7.79. Total no of protons:
22. HRMS (M+H).sup.+: calculated 329.1187; found 329.1161
[0701] The compounds according to Examples 1.2-1.17 were prepared,
from appropriate intermediates, by analogy with the method
described for Example 1.1 hereinbefore.
TABLE-US-00019 Example Name Yield 1.2
(S)-N-(1-(Azetidin-1-yl)pentan-2-yl)-4-chloro-N- 87 mg,
methylbenzamide 62% .sup.1H NMR Mixture of rotamers: (400 MHz,
DMSO-d6) .delta. 0.62-1.11, 1.15-1.80, 2.41, and 3.00-3.22, 3.3
(overlaps with the H.sub.2O peak), 3.42-3.73, 4.55-4.76, 7.10- HRMS
7.71. Ratio major:minor: 3:2. Total no of protons: 23. HRMS (M +
H).sup.+: calculated 295.1577; found 295.1563. The compound was
found to be amorphous by XRPD. 1.3
(S)-N-(1-(Azetidin-1-yl)pentan-2-yl)-4-bromo-N- 88 mg,
methylbenzamide 54% .sup.1H NMR Mixture of rotamers: (400 MHz,
DMSO-d6) .delta. 0.58-0.98, 0.93-1.65, 1.79- and 1.98, 2.20-2.37,
2.5 (overlaps with the DMSO peak), 2.56-2.79, 2.83- HRMS 3.03,
3.03-3.17, 3.3 (overlaps with the H.sub.2O peak), 4.46, 7.12-7.72.
Ratio major:minor: 7:3. Total no of protons: 23. HRMS (M +
H).sup.+: calculated 339.1072; found 339.1067 1.4
(S)-N-(1-(Azetidin-1-yl)pentan-2-yl)-4-fluoro-N,3-dimethyl- 77 mg,
benzamide 55% .sup.1H NMR Mixture of rotamers: (400 MHz, DMSO-d6)
.delta. 0.47-1.65, 1.74-2.01, 2.26, and 2.30-2.41, 2.5 (overlaps
with the DMSO peak), 2.67, 2.86-3.06, 3.05- HRMS 3.21, 3.36-3.54,
4.47, 6.82-7.56. Total no of protons: 25. HRMS (M + H).sup.+:
calculated 293.2029; found 293.2017 1.5
(S)-4-Fluoro-N-(1-(3-fluoroazetidin-1-yl)-3-methylbutan-2-yl)- 35
mg, N,3-dimethylbenzamide 20% .sup.1H NMR Mixture of rotamers: (400
MHz, CD.sub.3OD) .delta. 0.75-1.13, 1.65-1.99, 2.30, and 2.55-2.98,
3.05-3.29, 3.39-3.80, 4.28, 4.95-5.28, 7.03-7.16, 7.21- HRMS 7.52.
Total no of protons: 24. HRMS (M + H).sup.+: calculated 311.1935;
found 311.1930 1.6
(S)-4-Chloro-N-(1-(3-fluoroazetidin-1-yl)-3-methylbutan-2-yl)- 36
mg, N-methylbenzamide 20% .sup.1H NMR Mixture of rotamers: (400
MHz, CD.sub.3OD) .delta. 0.74-1.13, 1.66-1.96, 2.51- and 3.00,
3.05-3.27, 3.42-3.82, 4.29, 4.95-5.28, 7.31-7.63. Total no of HRMS
protons: 22. HRMS (M + H).sup.+: calculated 313.1483; found
313.1486 1.7
(S)-4-Bromo-N-(1-(3-fluoroazetidin-1-yl)-3-methylbutan-2-yl)- 41
mg, N-methylbenzamide 20% .sup.1H NMR Mixture of rotamers: (400
MHz, CD.sub.3OD) .delta. 0.77-1.11, 1.66-1.99, 2.56- and 2.80,
2.81-2.97, 3.06-3.28, 3.38-3.76, 4.28, 4.94-5.26, 7.30-7.51, HRMS
7.54-7.68. Total no of protons: 22. HRMS (M + H).sup.+: calculated
357.0978; found 357.0975 1.8
(S)-3-Chloro-4-fluoro-N-(1-(3-fluoroazetidin-1-yl)-3- 34 mg,
methylbutan-2-yl)-N-methylbenzamide 18% .sup.1H NMR NMR (400 MHz,
CD.sub.3OD) .delta. 0.60-1.27, 1.61-2.01, 2.44-3.01, 3.04- and
3.42, 3.43-3.82, 4.07-4.44, 4.94-5.30, 7.23-7.85. Total no of
protons: HRMS 21. HRMS (M + H).sup.+: calculated 331.1389; found
331.1394 1.9
(S)-4-Fluoro-N-(1-(3-fluoroazetidin-1-yl)-3-methylbutan-2-yl)- 31
mg, N-methyl-3-(trifluoromethyl)benzamide 15% .sup.1H NMR NMR (400
MHz, CD.sub.3OD) .delta. 0.56-1.27, 1.61-2.02, 2.48-3.06, 3.09- and
3.41, 3.43-3.97, 4.16-4.41, 4.97-5.32, 7.27-7.57, 7.63-8.17. Total
no HRMS of protons: 21. HRMS (M + H).sup.+: calculated 365.1652;
found 365.1658 1.10
(S)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-4-fluoro-N,3- 47 mg,
dimethylbenzamide 53%, .sup.1H NMR Mixture of rotamers: (600 MHz,
DMSO-d6) .delta. 0.70, 0.81, 0.93, 1.57-1.79, and 1.84-1.99, 2.23,
2.14-2.69 (omitted signals), 2.70, 2.92-3.17, 3.3-3.4 HRMS (omitted
signals), 7.11-7.19, 7.23, 7.33, 7.39. HRMS (M + H).sup.+:
calculated 293.2029; found 293.1999 1.11
(S)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-4-fluoro-N- 39 mg,
methyl-3-(trifluoromethyl)benzamide 17% .sup.1H NMR Mixture of
rotamers: (400 MHz, CD.sub.3OD) .delta. 0.47-1.22, 1.67-1.94, 1.96-
and 2.25, 2.50-2.68, 2.72, 2.87, 3.04-3.24, 3.25-3.40, 4.29,
7.28-7.57, 7.59- HRMS 8.05, 8.04-8.26. Ratio major:minor: 7:3.
Total no of protons: 22. HRMS (M + H).sup.+: calculated 347.1747;
found 347.1757 1.12
(S)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-3-chloro-4-fluoro- 28
mg, N-methylbenzamide 14% HRMS HRMS (M + H).sup.+: calculated
313.1483; found 313.1473 1.13
(S)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-3-chloro-N- 23 mg,
methylbenzamide 12% HRMS HRMS (M + H).sup.+: calculated 295.1577;
found 295.1592 1.14 (S)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-N-
1.8 mg, methylbenzamide 1% HRMS HRMS (M + H).sup.+: calculated
261.1967; found 261.1958 1.15
(S)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-N-methyl-3- 3.8 mg,
(trifluoromethyl)benzamide 1.8% HRMS HRMS (M + H).sup.+: calculated
329.1841; found 329.1832 1.16
(S)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-N,3-dimethyl- 3.8 mg,
benzamide 1.8% HRMS HRMS (M + H).sup.+: calculated 275.2123; found
275.2113 1.17
(S)-2-Chloro-4-fluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1- 2.62 g,
yl)butan-2-yl)benzamide 89% .sup.1H NMR. Mixture of rotamers: (400
MHz, CD.sub.3OD) .delta. 0.70-1.19, 1.52-2.03, 2.21- HRMS 3.21,
4.25-4.62, 6.99-7.46, 7.62-7.77. Total no of protons: 24. and HRMS
(M + H).sup.+: calculated 327.1639; found 327.1629. XRPD XRPD
pattern d (.ANG.) 8.9 (vs), 7.5 (vw), 6.6 (vw), 5.2 (vw), 5.0 (vw),
4.84 (vw), 4.56 (vw), 3.63 (vw), 3.31 (vw), 2.90 (vw))
Example 2.1
(S)-3,4-Dichloro-N-(3,3-dimethyl-1-(pyrrolidin-1-yl)butan-2-yl)-N-methylbe-
nzamide
##STR00015##
[0703] To a solution of
(S)-N,3,3-trimethyl-1-(pyrrolidin-1-yl)butan-2-amine (Compound M1)
(75 mg, 0.41 mmol) in DMF (1.5 mL) was NMM (0.049 mL, 0.45 mmol)
and 3,4-dichlorobenzoyl chloride (0.074 mL, 0.53 mmol) added. The
resultant mixture was stirred at rt overnight. The mixture was
concentrated and the residue dissolved in DCM (5 mL). The organic
phase was washed with NaHCO.sub.3 (saturated, 5 mL), filtered
through a phase separator and concentrated under reduced pressure.
The residue was purified by preparative HPLC to give the title
compound (109 mg, 75%). Mixture of rotamers: .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 0.97, 1.35-1.99, 2.07-2.43, 2.52-2.73, 2.93-3.18,
4.57, 6.86-7.18, 7.18-7.37, 7.37-7.61, 7.61-7.88. Total no of
protons: 26. HRMS (M+H).sup.+: calculated 357.1500; found
357.1470.
[0704] The compounds according to Examples 2.2-2.6 were prepared,
from appropriate intermediates, by analogy with the method
described for Example 2.1 hereinbefore.
TABLE-US-00020 Example Name Yield 2.2
(S)-4-Bromo-N-(3,3-dimethyl-1-(pyrrolidin-1-yl)butan-2-yl)-N- 78
mg, methylbenzamide 52% .sup.1H NMR Mixture of rotamers: (400 MHz,
DMSO-d6) .delta. 0.90, 1.55-1.76, 2.16-2.43, and 2.71, 2.87,
2.93-3.11, 3.34-3.44, 4.48-4.72, 7.23-7.32, 7.35-7.43, 7.43-7.53.
HRMS Ratio major:minor: 7:3. Total no of protons: 27. HRMS (M +
H).sup.+: calculated 367.1385; found 367.1376 2.3
4-Chloro-N-methyl-N-((2S,3S)-3-methyl-1-(pyrrolidin-1- 74 mg,
yl)pentan-2-yl)benzamide 56% .sup.1H NMR Mixture of rotamers: (400
MHz, CD.sub.3OD) .delta. 0.71-1.09, 1.10-1.30, 1.41-1.97, and
2.32-3.05, 3.37-3.52, 4.40-4.71, 7.14-7.76. Total no of protons:
27. HRMS HRMS (M + H).sup.+: calculated 323.1890; found 323.1984
2.4 4-Bromo-N-methyl-N-((2S,3S)-3-methyl-1-(pyrrolidin-1- 64 mg,
yl)pentan-2-yl)benzamide 43% .sup.1H NMR Mixture of rotamers: (400
MHz, CD.sub.3OD) .delta. 0.65-1.08, 1.06-1.31, 1.37-1.59, and
1.59-1.97, 2.34-3.03, 3.36-3.46, 4.31-4.71, 7.16-7.45, 7.45-7.76.
HRMS Total no of protons: 27. HRMS (M + H).sup.+: calculated
367.1385; found 367.1360 2.5
4-Fluoro-N,3-dimethyl-N-((2S,3S)-3-methyl-1-(pyrrolidin-1- 87 mg,
yl)pentan-2-yl)benzamide 67% .sup.1H NMR Mixture of rotamers: (400
MHz, CD.sub.3OD) .delta. 0.59-1.09, 1.08-1.30, 1.37-1.97, and
2.07-3.05, 3.42-3.63, 4.40-4.70, 6.96-7.19, 7.19-7.51. Total no of
HRMS protons: 29. HRMS (M + H).sup.+: calculated 321.2342; found
321.2343 2.6
2,4-Dichloro-N-methyl-N-((2S,3S)-3-methyl-1-(pyrrolidin-1- 68 mg,
yl)pentan-2-yl)benzamide 47% .sup.1H NMR Mixture of rotamers: (400
MHz, CD.sub.3OD) .delta. 0.71-1.13, 1.11-1.34, 1.77, and 2.24-2.59,
2.59-2.79, 2.79-3.03, 4.28-4.71, 7.12-7.74. Total no of HRMS
protons: 26. HRMS (M + H).sup.+: calculated 357.1500; found
357.1473
Example 3.1
4-Fluoro-N-((2R,3R)-3-methoxy-1-(pyrrolidin-1-yl)butan-2-yl)-N,3-dimethylb-
enzamide
##STR00016##
[0706] To a solution of
(2R,3R)-3-methoxy-N-methyl-1-(pyrrolidin-1-yl)butan-2-amine
(Compound M6) (80 mg, 0.43 mmol) in DCM (1.5 mL) was DIPEA (0.090
mL, 0.52 mmol) and 4-fluoro-3-methylbenzoyl chloride (0.061 mL,
0.43 mmol) added. The resultant mixture was stirred at rt
overnight. The mixture was diluted with DCM (5 mL), washed with
NaHCO3 (saturated, 5 mL), filtered through a phase separator and
concentrated under reduced pressure. The residue was purified by
preparative HPLC to give the title compound (102 mg, 74%).
[0707] Mixture of rotamers: .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 1.09, 1.22, 1.53-1.94, 2.17-2.40, 2.40-2.49, 2.50-2.63,
2.63-2.76, 2.76-2.86, 2.89, 2.97, 3.19, 3.31, 3.37-3.44, 3.52-3.66,
3.65-3.81, 6.87-7.15, 7.17-7.57. Ratio major:minor: 3:2. Total no
of protons in spectrum: 27. HRMS (M+H).sup.+: calculated 323.2135;
found 323.2139.
[0708] The compounds according to Examples 3.2-3.20 were prepared,
from appropriate intermediates, by analogy with the method
described for Example 3.1 hereinbefore.
TABLE-US-00021 Example Name Yield 3.2
N-((2R,3R)-3-Methoxy-1-(pyrrolidin-1-yl)butan-2-yl)-N,3- 84 mg,
dimethylbenzamide 64% .sup.1H NMR Mixture of rotamers: (400 MHz,
CD.sub.3OD) .delta. 1.08, 1.25, 1.55-2.03, 2.17-2.42, and
2.42-2.53, 2.53-2.64, 2.65-2.76, 2.76-2.84, 2.84, 3.01, 3.14-3.24,
HRMS 3.34, 3.36-3.46, 3.54-3.67, 3.67-3.79, 7.01-7.55. Ratio
major:minor: 3:2. Total no of protons: 28. HRMS (M + H).sup.+:
calculated 305.2229; found 305.2216 3.3
3-Chloro-4-fluoro-N-((2R,3R)-3-methoxy-1-(pyrrolidin-1- 79 mg,
yl)butan-2-yl)-N-methylbenzamide 53% .sup.1H NMR Mixture of
rotamers: (400 MHz, CD.sub.3OD) .delta. 1.09, 1.24, 1.50-2.02,
2.22-2.50, and 2.48-2.65, 2.65-2.80, 2.79, 3.19-3.28, 3.34,
3.37-3.46, 3.50-3.76, HRMS 7.23-7.38, 7.38-7.52, 7.54-7.71. Ratio
major:minor: 55:45. Total no of protons: 24. HRMS (M + H).sup.+:
calculated 343.1588; found 343.1567 3.4
4-Bromo-N-((2R,3R)-3-methoxy-1-(pyrrolidin-1-yl)butan-2-yl)- 101
mg, N-methylbenzamide 64% .sup.1H NMR Mixture of rotamers: (400
MHz, CD.sub.3OD) .delta. 0.95-1.37, 1.60-1.93, 2.24-2.38, and
2.38-2.49, 2.49-2.64, 2.64-2.77, 2.77-2.87, 2.90, 2.97, 3.16-3.25,
HRMS 3.34, 3.40, 3.51-3.72, 7.28-7.50, 7.60. Ratio major:minor:
3:2. Total no of protons: 25. HRMS (M + H).sup.+: calculated
369.1177; found 369.1188 3.5
4-Chloro-N-((2R,3R)-3-methoxy-1-(pyrrolidin-1-yl)butan-2-yl)- 73
mg, N-methylbenzamide 53% .sup.1H NMR Mixture of rotamers: (400
MHz, CD.sub.3OD) .delta. 1.09, 1.22, 1.56-2.03, 2.21-2.38, and
2.38-2.50, 2.50-2.62, 2.64-2.76, 2.78-2.87, 2.88, 2.98, 3.20, 3.34,
HRMS 3.40, 3.53-3.72, 7.21-7.65. Ratio major:minor: 3:2. Total no
of protons: 25. HRMS (M + H).sup.+: calculated 325.1683; found
325.1672 3.6
(S)-4-Bromo-N-(1-(4-methoxypiperidin-1-yl)-3-methylbutan-2- 132 mg,
yl)-N-methylbenzamide 75% .sup.1H NMR Mixture of rotamers: (400
MHz, CD.sub.3OD) .delta. 0.69-1.19, 1.33-1.66, 1.66-2.08, and
2.11-2.22, 2.24-2.51, 2.51-2.71, 2.72, 2.91, 2.93-3.07, 3.12-3.27,
HRMS 3.33, 4.49, 7.25-7.38, 7.37-7.56, 7.56-7.79. Ratio
major:minor: 7:3. Total no of protons: 29. HRMS (M + H).sup.+:
calculated 397.1490; found 397.1479 3.7
(S)-4-Chloro-N-(1-(4-methoxypiperidin-1-yl)-3-methylbutan-2- 108
mg, yl)-N-methylbenzamide 69% .sup.1H NMR Mixture of rotamers: (400
MHz, CD.sub.3OD) .delta. 0.70-1.15, 1.35-1.66, 1.68-2.07, and
2.11-2.22, 2.23-2.51, 2.51-2.70, 2.74, 2.91, 2.94-3.05, 3.12-3.28,
HRMS 3.33, 4.49, 7.29-7.43, 7.43-7.53. Ratio major:minor: 7:3.
Total no of protons: 29. HRMS (M + H).sup.+: calculated 353.1996;
found 353.1976 3.8
(S)-4-Fluoro-N-(1-(4-methoxypiperidin-1-yl)-3-methylbutan-2- 79 mg,
yl)-N,3-dimethylbenzamide 51% .sup.1H NMR Mixture of rotamers: (400
MHz, CD.sub.3OD) .delta. 0.63-1.24, 1.35-1.64, 2.22-2.49, and
2.50-2.81, 2.81-3.06, 3.11-3.28, 3.33, 3.37-3.48, 4.48, 7.00-7.17,
HRMS 7.18-7.44. Ratio major:minor: 7:3. Total no of protons: 31.
HRMS (M + H).sup.+: calculated 351.2448; found 351.2447 3.9
(S)-3-Chloro-4-fluoro-N-(1-(4-methoxypiperidin-1-yl)-3- 107 mg,
methylbutan-2-yl)-N-methylbenzamide 65% .sup.1H NMR Mixture of
rotamers: (400 MHz, CD.sub.3OD) .delta. 0.69-1.17 1.37-1.67,
1.68-2.14, and 2.14-2.25, 2.27-2.55, 2.54-2.71, 2.75, 2.90,
2.93-3.05, 3.17-3.28, HRMS 3.33, 4.46, 7.27-7.42, 7.42-7.49,
7.49-7.58, 7.61-7.71. Ratio major:minor: 7:3. Total no of protons:
28. HRMS (M + H).sup.+: calculated 371.1902; found 371.1882 3.10
(S)-N-(1-(4-Methoxypiperidin-1-yl)-3-methylbutan-2-yl)-N,3- 94 mg,
dimethylbenzamide 64% .sup.1H NMR Mixture of rotamers: (400 MHz,
CD.sub.3OD) .delta. 0.67-1.18, 1.38-1.65, 1.65-2.07, and 2.09-2.20,
2.23-2.51, 2.63, 2.90, 2.94-3.10, 3.17-3.28, 3.33, 3.37-3.47, HRMS
4.50, 7.12-7.22, 7.22-7.37. Ratio major:minor: 7:3. Total no of
protons: 32. HRMS (M + H).sup.+: calculated 333.2542; found
333.2537 3.11
(S)-3-Methoxy-N-(1-(4-methoxypiperidin-1-yl)-3-methylbutan- 124 mg,
2-yl)-N,4-dimethylbenzamide 77% HRMS HRMS (M + H).sup.+: calculated
363.2648; found 363.2641 3.12
(S)-N-(1-(4-Methoxypiperidin-1-yl)-3-methylbutan-2-yl)-N,3,4- 100
mg, trimethylbenzamide 65% HRMS HRMS (M + H).sup.+: calculated
347.2698; found 347.2685 3.13
(S)-N-(1-Cyclopropyl-2-(pyrrolidin-1-yl)ethyl)-4-fluoro-N,3-di- 107
mg, methylbenzamide 59% .sup.1H NMR Mixture of rotamers: (400 MHz,
DMSO-d6) .delta. 0.06-0.63, 0.90-1.03, 1.54-1.72, and 2.13-2.62,
2.70-3.03, 3.82-3.97, 7.07-7.31. Ratio major:minor: 1:0.7. HRMS
Total no of protons: 25. HRMS (M + H).sup.+: calculated 305.2029;
found 305.2014 3.14
(S)-4-Chloro-N-(1-cyclopropyl-2-(pyrrolidin-1-yl)ethyl)-N- 86 mg,
methylbenzamide 47% .sup.1H NMR Mixture of rotamers: (600 MHz,
DMSO-d6) .delta. 0.02-0.72, 0.88-1.09, 1.51-1.80, and 2.06-2.58,
2.70-3.12, 3.78-4.05, 7.24-7.37, 7.38-7.59. Ratio: 1:1. HRMS Total
no of protons: 23 HRMS (M + H).sup.+: calculated 307.1577; found
307.1572 3.15
(S)-4-Bromo-N-(1-cyclopropyl-2-(pyrrolidin-1-yl)ethyl)-N- 81 mg,
methylbenzamide 39% .sup.1H NMR Mixture of rotamers: (400 MHz,
DMSO-d6) .delta. 0.02-0.72, 0.88-1.09, 1.51-1.80, and 2.06-2.58,
2.70-3.12, 3.78-4.05, 7.24-7.37, 7.38-7.59. Ratio: 1:1. HRMS Total
no of protons: 23. HRMS (M + H).sup.+: calculated 351.1072; found
351.1055 3.16
(S)-N-(1-Cyclopropyl-2-(pyrrolidin-1-yl)ethyl)-3,4-difluoro-N- 121
mg, methylbenzamide 66% .sup.1H NMR Mixture of rotamers: (600 MHz,
DMSO-d6) .delta. 0.05-0.68, 0.89-1.08, 1.55-1.76, and 2.12-2.65,
2.69-3.08, 3.78-3.96, 7.12-7.22, 7.31-7.58. Total HRMS no of
protons: 22. HRMS (M + H).sup.+: calculated 309.1778; found
309.1760 3.17
(S)-N-(1-Cyclopropyl-2-(pyrrolidin-1-yl)ethyl)-N,3-dimethyl- 142
mg, benzamide 83% .sup.1H NMR Mixture of rotamers: (600 MHz,
DMSO-d6) .delta. 0.09-0.68, 0.90-1.05, 1.53-1.77, and 2.11-2.63,
2.69-3.04, 3.84-3.98, 6.97-7.38. Ratio major:minor: 1:0.7. HRMS
Total no of protons: 26. HRMS (M + H).sup.+: calculated 287.2123;
found 287.2118 3.18
4-Methoxy-N-((S)-1-((S)-2-(methoxymethyl)pyrrolidin-1-yl)-3- 3.3
mg, methylbutan-2-yl)-N-methylbenzamide 2.7% HRMS HRMS (M +
H).sup.+: calculated 349.2491; found 349.2481 3.19
4-Chloro-N-((S)-1-((S)-2-(methoxymethyl)pyrrolidin-1-yl)-3- 121 mg,
methylbutan-2-yl)-N-methylbenzamide 66% .sup.1H NMR Mixture of
rotamers: (600 MHz, DMSO-d6, (CH.sub.3).sub.2SO#) .delta. 0.74,
0.82, 0.96, and 1.23-1.48, 1.55-1.84, 2.56-2.70, 2.73, 2.8-4.2
(omitted signals), 7.23-7.32, HRMS 7.38-7.51. Ratio major:minor:
3:2. HRMS (M + H).sup.+: calculated 353.1996; found 353.2000 3.20
4-Bromo-N-((S)-1-((S)-2-(methoxymethyl)pyrrolidin-1-yl)-3- 8.8 mg,
methylbutan-2-yl)-N-methylbenzamide 6.3% HRMS HRMS (M + H).sup.+:
calculated 397.1490; found 397.1479
Example 4.1
(S)-N-(2-(Azetidin-1-yl)-1-cyclopropylethyl)-4-fluoro-N,3-dimethylbenzamid-
e
##STR00017##
[0710] To a mixture of 4-fluoro-3-methylbenzoic acid (330 mg, 2.14
mmol) and DIPEA (0.508 mL, 2.92 mmol) in DCM (3 mL) was TBTU (687
mg, 2.14 mmol) added. After 10 min was a solution of
(S)-2-(azetidin-1-yl)-1-cyclopropyl-N-methylethanamine (Compound
L1) (300 mg, 1.94 mmol) in DCM (3 mL) added. The resultant mixture
was stirred at r.t for 6 h. The mixture was washed with NaHCO.sub.3
(8% aq., 5 mL), filtered through a phase separator and concentrated
under reduced pressure. The residue was purified by preparative
HPLC to give the title compound (353 mg, 63%). Mixture of rotamers:
.sup.1H NMR (600 MHz, CD.sub.3OD) .delta. 0.04-0.14, 0.31-0.40,
0.40-0.48, 0.48-0.57, 0.59-0.66, 0.67-0.75, 0.92-1.06, 2.01-2.07,
2.07-2.16, 2.29, 2.30, 2.56-2.65, 2.76-2.88, 2.90, 2.94-3.00, 3.02,
3.09-3.21, 3.26-3.37, 3.80-3.91, 7.04-7.14, 7.22-7.40. Total no of
protons: 23. HRMS (M+H).sup.+: calculated 291.1873; found
291.1865.
[0711] The compounds according to Examples 4.2-4.4 were prepared,
from appropriate intermediates, by analogy with the method
described for Example 4.1 hereinbefore.
TABLE-US-00022 Example Name Yield 4.2
(S)-N-(2-(Azetidin-1-yl)-1-cyclopropylethyl)-4- 77 mg,
chloro-N-methylbenzamide 55% .sup.1H NMR Mixture of rotamers: (400
MHz, CD.sub.3OD) .delta. 0.23-1.11, and 1.82-2.22, 2.78, 3.3,
3.60-3.94, 6.96-7.60. Total no of HRMS protons: 21. HRMS (M +
H).sup.+: calculated 293.1421; found 293.1427 4.3
(S)-N-(2-(Azetidin-1-yl)-1-cyclopropylethyl)-4- 99 mg,
bromo-N-methylbenzamide 60% .sup.1H NMR Mixture of rotamers: (400
MHz, CD.sub.3OD) .delta. 0.04-0.25, and 0.25-0.83, 0.86-1.22,
1.71-2.29, 2.49-2.71, 2.71-3.23, 3.3, HRMS 3.64-4.11, 7.14-7.50,
7.48-7.92. Total no of protons: 21. HRMS (M + H).sup.+: calculated
337.0915; found 337.0898 4.4 (S)-4-Bromo-N-(1-cyclopropyl-2-(3- 670
mg, hydroxyazetidin-1-yl)ethyl)-N-methylbenzamide 43% .sup.1H NMR
Mixture of rotamers: (600 MHz, CD.sub.3OD) .delta. 0.04-0.15, and
0.29-0.76, 0.92-1.07, 2.58-2.66, 2.75-3.08, 3.39-3.45, HRMS
3.51-3.57, 3.64-3.76, 3.81-3.90, 4.24-4.39, 4.24-4.37, 7.32-7.41,
7.58-7.65. Total no of protons: 20. HRMS (M + H).sup.+: calculated
353.0865; found 353.0881
Example 5.1 A
(S)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-4-chloro-N-methylbenz-amide
##STR00018##
[0713] 4-Chlorobenzoic acid (1.300 mL, 12.80 mmol) and TBTU (4.31
g, 13.44 mmol) was mixed in DMF (35 mL). The mixture was cooled to
0.degree. C. and NMM (1.689 mL, 15.36 mmol) was dropwise added.
After 10 min at 0.degree. C. was
(S)-1-(azetidin-1-yl)-N-methylpentan-2-amine (Compound J1) (2 g,
12.80 mmol) added. The resultant mixture was stirred at 0.degree.
C. for 30 min and at rt for 16 h. The mixture was concentrated and
the residue dissolved in DCM (25 mL). The organic phase was washed
with NaHCO.sub.3 (saturated, 2.times.50 mL), and brine (50 mL),
filtered through a phase separator and concentrated under reduced
pressure. The residue was purified by preparative HPLC to give the
title compound (2.49 g, 66%).
[0714] Mixture of rotamers: .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 0.73-1.18, 1.65-1.91, 1.95-2.25, 2.69, 3.04-3.23,
3.23-3.37, 7.27-7.75. Ratio major:minor: 7:3. Total number of
protons: 23. HRMS (M+H).sup.+: calculated 295.1577; found
295.1570.
Example 5.1 B
(S)-1-(2-(4-Chloro-N-methylbenzamido)-3-methylbutyl)azetidinium
2,3-dihydroxysuccinate
[0715] The title compound of Example 5.1 A was dissolved in MeCN
(10 mL) and a solution of DL-tartaric acid (659 mg, 4.39 mmol) in
water (15 mL) was added. The resulting mixture was filtered and the
solution freeze dried in vacuo to give the title product (3.13 g,
66%). Mixture of rotamers: .sup.1H NMR (400 MHz, DMSO-d6) .delta.
0.42-1.25, 1.52-1.86, 1.86-2.01, 2.01-2.24, 2.5-2.54, 2.64, 2.77,
2.84-3.23, 3.40-3.82, 3.95, 4.10-4.35, 7.10-7.71. Ratio
major:minor: 6:4. The compound was found to be amorphous by
XRPD.
[0716] The compound according to Examples 5.2 A --C was prepared,
from appropriate intermediates, by analogy with the methods
described for Examples 5.1 A and 5.1 B hereinbefore.
TABLE-US-00023 Example Name Yield 5.2 A
(S)-1-(2-(4-Bromo-N-methylbenzamido)-3- 4.37 g,
methylbutyl)azetidinium 3-carboxypropanoate 83% .sup.1H NMR,
Mixture of rotamers: (400 MHz, DMSO-d6) .delta. 0.82, HRMS
1.56-1.87, 1.88-2.01, 2.02-2.22, 2.5, 2.64, 2.72, 2.82-3.21, and
3.96, 4.11-4.37, 7.33, 7.41, 7.63. Ratio major:minor: 3:2. XRPD
HRMS (M + H).sup.+: calculated 339.1072; found 339.1055. The
compound was found to be amorphous by XRPD. Example 5.2 B:
(S)-1-(2-(4-Bromo-N-methylbenzamido)-3- methylbutyl)azetidinium
sulfate (S)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-4-bromo-N-
methylbenzamide (95 mg, 0.28 mmol) was mixed in MeCN (0.5 mL) and
water (1 mL). Sulfuric acid (14.30 mg, 0.14 mmol) in water (1 mL)
was dropwise added and the resultant mixture freeze dried in vacuo
to give the title compound (107 mg, 98%). XRPD pattern d (.ANG.)
15.0 (vw), 7.5 (med), 6.4 (vw), 6.1 (vw), 5.4 (vw), 4.99 (med),
4.20 (vw), 3.86 (vw), 3.75 (vs), 3.45 (vw), 2.57 (vw), 2.50 (w),
2.21 (vw). Example 5.2 C: (S)-1-(2-(4-Bromo-N-methylbenzamido)-3-
methylbutyl)azetidinium 2,3-dihydroxysuccinate
(S)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-4-bromo-N-
methylbenzamide (89 mg, 0.26 mmol) was mixed in MeCN (0.5 mL) and
water (1 mL). Succinic acid (15.49 mg, 0.13 mmol) was added and the
resultant mixture freeze dried to give the title compound (119 mg,
99%). XRPD pattern d (.ANG.) 6.4 (med), 5.9 (w), 5.6 (med), 5.2
(w), 4.80 (med), 4.70 (med), 4.25 (w), 4.10 (med), 3.83 (vs), 3.54
(med), 3.33 (med), 3.06 (w), 2.95 (w).
Example 6.1
(S)-4-Fluoro-N-(1-(3-hydroxyazetidin-1-yl)-3-methylbutan-2-yl)-N,3-dimethy-
lbenzamide
##STR00019##
[0718] 4-Fluoro-3-methylbenzoic acid (0.089 g, 0.58 mmol) and TBTU
(0.196 g, 0.61 mmol) was mixed in DMF (1.5 mL). The mixture was
cooled to 0.degree. C. and NMM (0.070 mL, 0.64 mmol) was dropwise
added. After 40 min at 0.degree. C. was
(S)-1-(3-methyl-2-(methylamino)butyl)azetidin-3-ol (Compound K2)
(0.1 g, 0.58 mmol) added. The resultant mixture was stirred at
0.degree. C. for 30 min and at rt for 16 h. NaOH (aq., 3.8 M, 0.5
mL), water (0.5 mL) and dioxane (1 mL) was added and the resultant
mixture was stirred at rt overnight. To the mixture was water (2
mL) and DMSO (4 mL) added. The residue was purified by preparative
HPLC to give the title compound (121 mg, 68%). Mixture of rotamers:
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 0.80-0.87, 0.94, 1.05,
1.68-1.93, 2.25-2.34, 2.54-3.00, 3.26-3.34, 3.39-3.46, 3.55-3.61,
3.62-3.75, 4.19-4.43, 7.02-7.49. Ratio major:minor: 1:0.5. Total no
of protons: 24. HRMS (M+H).sup.+: calculated 309.1978; found
309.1949. XRPD pattern d (.ANG.) 9.3 (vw), 7.8 (w), 7.6 (w), 6.5
(med), 5.7 (vs), 5.3 (str), 4.71 (str), 4.52 (str), 4.40 (med),
4.31 (med), 3.83 (med), 3.30 (med), 3.22 (med). The compound was
found to be a hydrate (most likely a monohydrate).
Example 6.2
(S)-4-Chloro-N-(1-(3-hydroxyazetidin-1-yl)-3-methylbutan-2-yl)-N-methylben-
zamide
##STR00020##
[0720] (S)-1-(3-Methyl-2-(methylamino)butyl)azetidin-3-ol (Compound
K2) (1.0 g, 3.48 mmol) was dissolved in DCM (13.3 mL), DIPEA(1.82
mL, 10.4 mmol), 4-chlorobenzoic acid (0.654 g, 4.18 mmol), and TBTU
(1.45 g, 4.53 mmol) were added. The reaction was stirred for 2 h at
rt whereupon saturated NaHCO.sub.3 (aq.) was added. The organic
layer was separated and evaporated in vacuo. The residue was
redissolved in THF/water and 3.8 M NaOH was added (1.2 mL) the
reaction mixture was stirred for 15 min whereupon water was added
and some of the organics was evaporated. The water phase was
extracted with DCM, separated using a phase-separator and
evaporated. The residue was evaporated and redissolved in DMSO and
purified by preparative HPLC on a XBridge C18 column (10 .mu.m
250.times.50 ID mm) using a gradient of 15-55% Acetonitrile in
H.sub.2O/ACN/NH.sub.3 95/5/0.2 buffer over 30 minutes with a flow
of 100 mL/min. The compounds were detected by UV at 220 nm to give
the target compound pooling of pure fractions and evaporation of
solvents in vacuo gave
(S)-4-chloro-N-(1-(3-hydroxyazetidin-1-yl)-3-methylbutan-2-yl)-N-met-
hylbenzamide (0.67 g, 62%). Mixture of rotamers: .sup.1H NMR (600
MHz, CD.sub.3OD) .delta. 0.81-0.88, 0.99, 1.09, 1.72-2.00, 1.95,
2.63-2.76, 2.80, 2.85-2.97, 3.12-3.19, 3.26-3.35, 3.46-3.67,
4.10-4.19, 4.28-4.56, 7.44-7.54. Ratio major:minor: 1:0.2. Total no
of protons: 27.3 (5.3 from CH.sub.3CO.sub.2H). HRMS (M+H).sup.+:
calculated 311.1526; found 311.1528.
[0721] A solution of
(S)-4-chloro-N-(1-(3-hydroxyazetidin-1-yl)-3-methylbutan-2-yl)-N-methylbe-
nzamide (0.20 g, 0.64 mmol) in ethanol (0.2 mL) was added to water
(1.8 mL) in a test tube containing a broken glass rod. The test
tube was put in a water bath with ultra sonic waves. After
approximately 10 min the milky mixture became white and thick. The
formed crystals were filtered off (P3-filter) and washed with a
cold ethanol (10% in water). The crystals were air dried to give
the product
(S)-4-chloro-N-(1-(3-hydroxyazetidin-1-yl)-3-methylbutan-2-yl)-N-methylbe-
nzamide (0.12 g, 60%) as white crystals. This material was used
further for crystallization experiments.
[0722] To a solution of
(S)-4-chloro-N-(1-(3-hydroxyazetidin-1-yl)-3-methylbutan-2-yl)-N-methylbe-
nzamide (0.040 g, 0.13 mmol) in ethanol (2 mL) in an open test tube
was added water (6 mL). After ten days crystals had formed: [0723]
a) One crystal (approximately 3 mm) was seen at the top of the
solvent and was specifically picked out and analyzed by
thermoanalysis, which showed only one thermal event at high
temperature indicating no solvation that this crystalline form is
likely to be anhydrous. [0724] b) The crystals which precipitated
were filtered off and air-dried before they were further dried
under vacuo over night to give the product
(S)-4-chloro-N-(1-(3-hydroxyazetidin-1-yl)-3-methylbutan-2-yl)-N-methylbe-
nzamide (0.106 g, 44%) as white crystals. The compound was found to
be a monohydrate. XRPD pattern d (.ANG.), 18.0 (w), 9.0 (vw), 7.6
(vw), 6.0 (vw), 5.1 (vw), 4.52 (str), 4.11 (w), 3.78 (vw), 3.62
(vw).
[0725] The compound according to Example 6.3 was prepared, from
appropriate intermediates, by analogy with the method described for
Example 6.1 hereinbefore.
TABLE-US-00024 Example Name Yield 6.3
(S)-4-Bromo-N-(1-(3-hydroxyazetidin-1-yl)-3- 62 mg,
methylbutan-2-yl)-N-methylbenzamide 26% .sup.1H NMR Mixture of
rotamers: (600 MHz, CD.sub.3OD) .delta. 0.79-0.88, 0.98, and 1.08
1.72-1.98, 1.95, 2.61-3.24, 3.37-3.64, 3.95-4.10, HRMS 4.27-4.53,
7.38-7.48, 7.57-7.70. Ratio major:minor: 1:0.3. Total no of
protons: 25 (3 from CH.sub.3CO.sub.2H). HRMS (M + H).sup.+:
calculated 355.1021; found 355.1036
Example 7A
(S)-N-(1-Cyclopropyl-2-(3-hydroxyazetidin-1-yl)-4-fluoro-N,3-dimethylbenza-
mide
##STR00021##
[0727] 4-Fluoro-3-methylbenzoic acid (0.095 g, 0.62 mmol), TBTU
(0.226 g, 0.70 mmol) and 4-methylmorpholine (0.194 mL, 1.76 mmol)
was mixed in DMF (2 mL). After 30 min at rt was
(S)-1-(2-cyclopropyl-2-(methylamino)ethyl)azetidin-3-ol (Compound
J3) (0.1 g, 0.59 mmol) added. The resultant mixture was stirred at
rt overnight. Analysis by LCMS indicated formation of both mono and
diacylated product. Additional TBTU (0.189 g, 0.59 mmol),
4-fluoro-3-methylbenzoic acid (0.091 g, 0.59 mmol) and NMM (0.129
mL, 1.17 mmol) were added to drive the reaction towards the
diacylated product. The resultant mixture was stirred at rt
overnight. The mixture was diluted with DCM (5 mL) and the organic
phase was washed with NaHCO.sub.3 (saturated, 5 mL), filtered
through a phase separator and concentrated under reduced pressure.
The residue was dissolved in a mixture of MeOH (3 mL) and NaOH (aq.
3 mL, 1M) and the resultant mixture stirred at rt for 30 min. The
solvents were evaporated and the crude mixture purified by
preparative HPLC to give the title compound (54 mg, 30%). Mixture
of rotamers: .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. -0.13-1.25,
2.01-2.48, 2.60-2.65, 2.73-3.22, 3.39-4.02, 4.21-4.45, 6.96-7.45.
Total no of protons: 22. HRMS (M+H).sup.+: calculated 307.1822;
found 307.1827.
[0728] The compounds according to Examples 7.2-7.5 were prepared,
from appropriate intermediates, by analogy with the method
described for Example 7.1 hereinbefore.
TABLE-US-00025 Example Name Yield 7.2
(S)-4-Chloro-N-(1-cyclopropyl-2-(3- 27 mg,
hydroxyazetidin-1-yl)ethyl)-N-methylbenzamide 15% .sup.1H NMR
Mixture of rotamers: (400 MHz, CD.sub.3OD) .delta. -0.43-1.29, and
2.43-3.11, 3.30-3.89, 4.10-4.35, 7.14-7.56. HRMS Total number of
protons: 20. HRMS (M + H).sup.+: calculated 309.1370; found
309.1371 7.3 (S)-3-Chloro-N-(1-cyclopropyl-2-(3- 78 mg,
hydroxyazetidin-1-yl)ethyl)-4-fluoro-N- 41% methylbenzamide .sup.1H
NMR Mixture of rotamers: (400 MHz, and CD.sub.3OD) .delta.
-0.42-1.52, 2.57-2.64, 2.76-3.14, HRMS 3.40-3.95, 4.16-4.52,
7.21-7.76. Total number of protons: 19. HRMS (M + H).sup.+:
calculated 327.1275; found 327.1273 7.4
(S)-N-(1-Cyclopropyl-2-(3-hydroxyazetidin- 54 mg,
1-yl)ethyl)-4-fluoro-N-methylbenzamide 31% .sup.1H NMR Mixture of
rotamers: (400 MHz, CD.sub.3OD) .delta. and -0.24-1.27, 2.51-2.73,
2.85, 2.92-3.15, 3.37-4.05, HRMS 4.20-4.50, 6.95-7.70. Total number
of protons: 20. HRMS (M + H).sup.+: calculated 293.1665; found
293.1642 7.5 (S)-N-(1-Cyclopropyl-2-(3-hydroxyazetidin- 88 mg,
1-yl)ethyl)-4-fluoro-N-methyl-3- 42% (trifluoromethyl)benzamide
.sup.1H NMR Mixture of rotamers: (400 MHz, CD.sub.3OD) .delta. and
-0.32-1.42, 2.53-2.64, 2.74-3.16, 3.37-4.07, 4.12-4.49, HRMS
7.20-7.55, 7.61-8.02. Total number of protons: 19. HRMS (M +
H).sup.+: calculated 361.1539; found 361.1533
Example 8.1
(S)-3,4-Difluoro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N-methylbenzami-
de
##STR00022##
[0730] 3,4-Difluorobenzoic acid (0.184 g, 1.16 mmol), TBTU (0.373
g, 1.16 mmol) and
[0731] DIPEA (0.303 mL, 1.74 mmol) was stirred in DCM (2 mL) for 40
min before (S)-1-(2-(methylamino)pentyl)azetidin-3-ol (Compound J4)
(0.1 g, 0.58 mmol) was added. The resultant mixture was stirred at
rt overnight. The solvent was removed under reduced pressure and
the residue dissolved in a mixture of MeOH (3 mL) and NaOH (aq. 1
mL, 1 M). The resultant mixture was stirred at rt for 90 min before
the MeOH was removed on a vacuum centrifuge. The crude product was
extracted with DCM and concentrated under reduced pressure. The
residue was purified by preparative HPLC to give the title compound
(102 mg, 56%). Mixture of rotamers: (600 MHz, DMSO-d6) .delta.
0.67-0.76, 0.79-0.91, 0.92-1.04, 1.06-1.48, 2.30-2.76, 3.23-3.42,
3.43-3.53, 4.05-4.17, 4.37-4.47, 5.17-5.26, 7.14-7.27, 7.36-7.56.
Total no of protons: 22. HRMS (M+H).sup.+: calculated 313.1728;
found 313.1714.
Example 8.2 A
(S)-4-Chloro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N-methyl-benzamide
##STR00023##
[0733] N-ethyl-N-isopropylpropan-2-amine (1.580 mL, 9.07 mmol) was
added to a stirred suspension of 4-chlorobenzoic acid (0.473 g,
3.02 mmol) and TBTU (0.971 g, 3.02 mmol) in DCM (10 mL) at rt. The
suspension was stirred for about 5 min before a solution of
(S)-1-(2-(methylamino)pentyl)azetidin-3-ol (Compound J4) (0.62 g,
3.02 mmol) in DCM (3 mL) was added. The reaction was stirred at rt
overnight. The reaction mixture was washed with an 8% aq. sol. of
NaHCO.sub.3 (20 mL). The organic layer was dried through a phase
separator and concentrated on the rotary evaporator. The residue
was purified by preparative HPLC affording the title compound
(0.760 g, 81%) as an oil. Mixture of rotamers: .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 0.80-0.88, 0.94-1.01, 1.09-1.65,
2.39-2.53, 2.62-2.99, 3.28-3.62, 3.65-3.76, 4.22-4.39, 4.64-4.76,
7.39-7.52. HRMS (M+H).sup.+: calculated 311.1526; found
311.1539.
Example 8.2 B
(S)-4-Chloro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N-methyl-benzamide
hydrochloride
[0734] A solution of hydrochloric acid in MeOH (0.1 M, 0.48 ml) was
added
(S)-4-Chloro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N-methylbenzamide
(Example 8.2A) (15 mg, 48 mmol) and allowed to evaporate. The
product was dissolved in EtOAc (1 mL) and allowed to evaporate
until dry.
[0735] XRPD pattern d (.ANG.) 10.16 (str), 7.88 (str), 6.72 (str),
6.25 (vs), 5.28 (str), 4.9 (str), 4.69 (str), 4.58 (str), 4.26
(str), 4.08 (str), 3.92 (str), 3.85 (vs), 3.54 (str), 3.39 (str),
2.83 (str).
Example 8.2 C
(S)-4-Chloro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N-methyl-benzamide
tartrate
[0736] A solution of tartaric acid in MeOH (0.1 M, 0.48 ml) was
added to
(S)-4-Chloro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N-methylbenzamide
(Example 8.2A) (15 mg, 48 .mu.mol) and allowed to evaporate. The
product was dissolved in EtOAc (1 mL) and allowed to evaporate
until dry.
[0737] XRPD pattern d (.ANG.) 19.7 (vs), 9.95 (str), 9.8 (med),
7.04 (med), 6.25 (med), 5.32 (str), 5.09 (str), 4.97 (med), 4.22
(med).
[0738] The compounds according to Examples 8.3-8.11 were prepared,
from appropriate intermediates, by analogy with the method
described for Example 8.1 hereinbefore.
[0739] The compounds according to Examples 8.12-8.17 were prepared,
from appropriate intermediates, by analogy with the method
described for Example 8.2 A hereinbefore.
TABLE-US-00026 Example Name Yield 8.3
(S)-3-Chloro-4-fluoro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2- 110
mg, yl)-N-methylbenzamide 58% .sup.1H NMR Mixture of rotamers: (600
MHz, DMSO-d6) .delta. 0.66-0.91, 0.92-1.49, 2.30-2.75, and
3.20-3.41, 3.43-3.53, 4.05-4.18, 4.37-4.47, 5.12-5.32, 7.17-7.79.
HRMS Total no of protons: 22. HRMS (M + H).sup.+: calculated
329.1432; found 329.1454 8.4
(S)-4-Chloro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N,3-di- 96
mg, methylbenzamide 51% .sup.1H NMR Mixture of rotamers: (400 MHz,
DMSO-d6) .delta. 0.71-0.78, 0.86-0.92, 0.96-1.50, and 2.32-2.40,
2.47-2.65, 2.68-2.76, 3.25-3.42, 3.46-3.55, 4.06-4.19, HRMS
4.42-4.51, 5.23, 7.12-7.16, 7.19-7.23, 7.28-7.32, 7.35-7.38,
7.43-7.47. Total no of protons: 25. HRMS (M + H).sup.+: calculated
325.1683; found 325.1680 8.5
(S)-4-Fluoro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N- 129 mg,
methyl-3-(trifluoromethyl)benzamide 61% .sup.1H NMR Mixture of
rotamers: (600 MHz, DMSO-d6) .delta. 0.66-0.74, 0.84-0.91,
0.93-1.50, and 2.31-2.39, 2.44-2.76, 3.21-3.42, 3.44-3.53,
4.01-4.20, 4.36-4.52, HRMS 5.15-5.33, 7.47-7.97. Total no of
protons: 22. HRMS (M + H).sup.+: calculated 363.1696; found
363.1686 8.6
(S)-4-Fluoro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N- 96 mg,
methylbenzamide 56% .sup.1H NMR Mixture of rotamers: (600 MHz,
DMSO-d6) .delta. 0.70-0.77, 0.79-0.92, 0.95-1.51, and 2.23-2.75,
3.22-3.56, 4.02-4.19, 4.42-4.52, 5.23, 7.21-7.29, HRMS 7.35-7.48.
Total no of protons: 23. HRMS (M + H).sup.+: calculated 295.1822;
found 295.1844 8.7
(S)-4-Bromo-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N- 105 mg,
methylbenzamide 51% .sup.1H NMR Mixture of rotamers: (600 MHz,
DMSO-d6) .delta. 0.71-0.78, 0.86-0.92, 0.96-1.52, and 2.33-2.39,
2.46-2.64, 2.67-2.75, 3.24-3.41, 3.45-3.54, 4.06-4.19, HRMS
4.43-4.52, 5.23, 7.25-7.29, 7.31-7.35, 7.61-7.65. Total no of
protons: 23. HRMS (M + H).sup.+: calculated 355.1021; found
355.1027 8.8
(S)-N-(1-(3-Hydroxyazetidin-1-yl)pentan-2-yl)-N-methyl-3-(tri- 104
mg, fluoromethyl)benzamide 52% .sup.1H NMR Mixture of rotamers:
(600 MHz, DMSO-d6) .delta. 0.66-0.75, 0.85-0.91, 0.93-1.51, and
2.27-2.79, 3.16-3.56, 4.00-4.21, 4.39-4.53, 5.16-5.30, 7.53-7.87.
HRMS Total no of protons: 23. HRMS (M + H).sup.+: calculated
345.1790; found 345.1768 8.9
(S)-4-Cyano-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N- 90 mg,
methylbenzamide 51% .sup.1H NMR Mixture of rotamers: (600 MHz,
DMSO-d6) .delta. 0.68-0.76, 0.84-0.90, 0.93-1.50, and 2.30-2.79,
3.17-3.55, 4.02-4.22, 4.38-4.53, 5.17-5.27, 7.42-7.58, HRMS
7.82-7.95. Total no of protons: 23. HRMS (M + H).sup.+: calculated
302.1868; found 302.1857 8.10
(S)-N-(1-(3-Hydroxyazetidin-1-yl)pentan-2-yl)-N,3-dimethyl- 95 mg,
benzamide 56% .sup.1H NMR Mixture of rotamers: (600 MHz, DMSO-d6)
.delta. 0.64-1.50, 2.18-2.75, 3.09-3.62, and 4.03-4.17, 4.41-4.52,
5.12-5.30, 6.96-7.38. Total no of protons: HRMS 26. HRMS (M +
H).sup.+: calculated 291.2072; found 291.2053 8.11
(S)-4-Fluoro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N,3-di- 98
mg, methylbenzamide 55% .sup.1H NMR Mixture of rotamers: (600 MHz,
DMSO-d6) .delta. 0.70-0.77, 0.81-0.93, 0.95-1.50, and 2.24,
2.33-2.41, 2.45-2.65, 2.67-2.76, 3.25-3.54, 4.06-4.19, 4.42-4.51,
HRMS 5.20-5.27, 7.13-7.35. Total no of protons: 25. HRMS (M +
H).sup.+: calculated 309.1978; found 309.1996 8.12
N-((S)-1-((3S,4S)-3,4-Dihydroxypyrrolidin-1-yl)-3-methylbutan- 59
mg, 2-yl)-4-fluoro-N,3-dimethylbenzamide 50% .sup.1H NMR Mixture of
rotamers: (600 MHz, DMSO-d6) .delta. 0.73-0.81, 0.88, 0.97,
1.64-1.83, and 2.24-2.27, 2.3-2.37, 2.39-2.54, 2.6-2.82, 3.13-3.24,
3.83-3.9, HRMS 4.2-4.33, 4.85, 4.92, 7.09-7.24, 7.27-7.42. HRMS (M
+ H).sup.+: calculated 339.2084; found 339.2089 8.13
4-Chloro-N-((S)-1-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-3- 84 mg,
methylbutan-2-yl)-N,3-dimethylbenzamide 57% .sup.1H NMR Mixture of
rotamers: (600 MHz, DMSO-d6) .delta. 0.71-0.77, 0.86, 0.95,
1.63-1.79, and 2.28-2.35, 2.37-2.42, 2.43-2.51, 2.57-2.79,
3.08-3.15, 3.81-3.87, HRMS 4.2-4.3, 4.83, 4.91, 7.15-7.19,
7.28-7.32, 7.33-7.36, 7.37-7.44. HRMS (M + H).sup.+: calculated
355.1788; found 355.1795 8.14
4-Chloro-N-((S)-1-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-3- 84 mg,
methylbutan-2-yl)-N-methylbenzamide 59% .sup.1H NMR Mixture of
rotamers: (600 MHz, DMSO-d6) .delta. 0.7-0.77, 0.85, 0.95,
1.63-1.79, and 2.27-2.52, 2.57-2.62, 2.67-2.79, 3.04-3.1,
3.81-3.87, 4.2-4.3, HRMS 4.81, 4.92, 7.34-7.37, 7.4-7.51. HRMS (M +
H).sup.+: calculated 341.1632; found 341.1641 8.15
4-Chloro-N-((S)-1-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-3- 77 mg,
methylbutan-2-yl)-3-fluoro-N-methylbenzamide 52% .sup.1H NMR
Mixture of rotamers: (600 MHz, DMSO-d6) .delta. 0.72-0.79, 0.86,
0.95, 1.65-1.79, and 2.27-2.34, 2.36-2.42, 2.44-2.52, 2.57-2.8,
3.05-3.11, 3.81-3.87, HRMS 4.19-4.27, 4.85, 4.90, 7.18-7.22,
7.35-7.38, 7.39-7.43, 7.45-7.48, 7.55-7.59, 7.6-7.64. HRMS (M +
H).sup.+: calculated 359.1537; found 359.1544 8.16
4-Chloro-N-((S)-1-((3R,4R)-3,4-dihydroxypyrrolidin-1-yl)-3- 3 mg,
methylbutan-2-yl)-N,3-dimethylbenzamide 3% HRMS HRMS (M + H).sup.+:
calculated 355.1788; found 355.1794 8.17
(S)-4-Fluoro-N-(1-(3-hydroxyazetidin-1-yl)butan-2-yl)-N,3- 293 mg,
dimethylbenzamide 88% HRMS HRMS (M + H).sup.+: calculated 295.1822;
found 295.1813
Example 9.1
(S)-N-(1-Cyclopropyl-2-(3-cyclopropyl-3-hydroxyazetidin-1-yl)ethyl)-4-fluo-
ro-N,3-dimethylbenzamide
##STR00024##
[0741] 4-Fluoro-3-methylbenzoic acid (0.102 g, 0.66 mmol), TBTU
(0.248 g, 0.77 mmol) and NMM (0.063 mL, 0.58 mmol) was mixed in DCM
(10 mL). After 10 min at rt was
(S)-3-cyclopropyl-1-(2-cyclopropyl-2-(methylamino)ethyl)azetidin-3-ol
(Compound L2) (0.116 g, 0.55 mmol) added. The resultant mixture was
stirred at rt for 48 h. To the mixture was 1.4 N KOH (5 mL) added.
The organic phase was isolated, filtered through a phase separator
and concentrated under reduced pressure. The residue was purified
by preparative HPLC to give the title compound (96 mg, 50%).
Mixture of rotamers: .sup.1H NMR (600 MHz, DMSO-d6) .delta.
0.09-0.14, 0.22-0.70, 1.01, 1.18, 2.30, 2.52-2.55, 2.72-3.10, 3.20,
3.72, 5.12, 7.15-7.44. Total no of protons: 27. HRMS (M+H).sup.+:
calculated 347.2135; found 347.2124.
[0742] The compounds according to Examples 9.2-9.11 were prepared,
from appropriate intermediates, by analogy with the method
described for Example 9.1 hereinbefore.
TABLE-US-00027 Example Name Yield 9.2
(S)-3-Chloro-N-(1-cyclopropyl-2-(3-cyclopropyl-3- 107 mg,
hydroxyazetidin-1-yl)ethyl)-4-fluoro-N- 53% methylbenzamide .sup.1H
NMR Mixture of rotamers: (600 MHz, DMSO-d6) .delta. -0.03, and
0.14-0.63, 0.92, 1.11, 2.59-3.22, 3.54-3.73, 5.09, 7.23-7.75. HRMS
Total no of protons: 24. HRMS (M + H).sup.+: calculated 367.1588;
found 367.1594 9.3 (S)-N-(1-Cyclopropyl-2-(3-cyclopropyl-3- 104 mg,
hydroxyazetidin-1-yl)ethyl)-3,4-difluoro-N- 54% methylbenzamide
.sup.1H NMR Mixture of rotamers: (600 MHz, DMSO-d6) .delta. 0.08,
and 0.25-0.74, 1.04, 1.20, 2.75-3.11, 3.15-3.35, 3.69, 5.18, 7.29,
HRMS 7.45-7.78. Total no of protons: 23. HRMS (M + H).sup.+:
calculated 351.1884; found 351.1887 9.4
(S)-4-Cyano-N-(1-cyclopropyl-2-(3-cyclopropyl-3- 99 mg,
hydroxyazetidin-1-yl)ethyl)-N-methylbenzamide 53% .sup.1H NMR
Mixture of rotamers: (600 MHz, DMSO-d6) .delta. -0.05-0.15, and
0.19-0.73, 0.90-1.07, 1.10-1.25, 2.60-3.30, 3.64-3.83, 5.13, HRMS
7.43-7.71, 7.87-8.04. Total no of protons: 25. HRMS (M + H).sup.+:
calculated 340.2025; found 340.2035 9.5
(S)-N-(1-Cyclopropyl-2-(3-cyclopropyl-3- 116 mg,
hydroxyazetidin-1-yl)ethyl)-N,3,4- 62% trimethylbenzamide .sup.1H
NMR Mixture of rotamers: (600 MHz, DMSO-d6) .delta. -0.06, and
0.11-0.62, 0.77-1.17, 2.21, 2.55-3.20, 3.64, 5.05, 6.94-7.19. HRMS
Total no of protons: 30 HRMS (M + H).sup.+: calculated 343.2386;
found 343.2390 9.6 (S)-4-Bromo-N-(1-(3-hydroxy-3-methylazetidin-
103 mg, 1-yl)-3-methyl-butan-2-yl)-N-methylbenzamide 52% .sup.1H
NMR Mixture of rotamers: (400 MHz, CD.sub.3OD) .delta. 0.75-1.13,
and 1.46, 1.66-1.96, 2.56-2.64, 2.66-2.70, 2.71-3.16, 3.22-3.28,
HRMS 3.33-3.38, 7.25-7.41, 7.43-7.74. Total no of protons: 24. HRMS
(M + H).sup.+: calculated 369.1177; found 369.1162 9.7
(S)-4-Chloro-N-(1-(3-hydroxy-3-methylazetidin-1- 84 mg,
yl)-3-methyl-butan-2-yl)-N-methylbenzamide 48% .sup.1H NMR Mixture
of rotamers: (400 MHz, CD.sub.3OD) .delta. 0.73-1.12, and 1.46,
1.68-1.95, 2.58-2.64, 2.66-2.70, 2.71-3.17, 3.22-3.29, HRMS
3.32-3.40, 7.30-7.66. Total no of protons: 24. HRMS (M + H).sup.+:
calculated 325.1683; found 325.1692 9.8
(S)-4-Fluoro-N-(1-(3-hydroxy-3-methylazetidin-1- 103 mg,
yl)-3-methyl-butan-2-yl)-N-methyl-3- 51% (trifluoromethyl)benzamide
.sup.1H NMR Mixture of rotamers: (400 MHz, CD.sub.3OD) .delta.
0.65-1.17, and 1.46, 1.68-1.96, 2.55-2.64, 2.67-3.20, 3.21-3.28,
3.33-3.41, HRMS 4.26, 7.28-7.60, 7.67-8.00, 8.03-8.23. Total no of
protons: 24. HRMS (M + H).sup.+: calculated 377.1852; found
377.1874 9.9 (S)-N-(1-Cyclopropyl-2-(3-hydroxyazetidin-1- 31 mg,
yl)ethyl)-3,4-difluoro-N-methylbenzamide 17% .sup.1H NMR Mixture of
rotamers: (600 MHz, DMSO-d6) .delta. -0.18-0.76, and 0.89-1.10,
2.65-3.03, 3.45-3.79, 4.19, 5.31, 7.15-7.39, HRMS 7.40-7.65. Total
no of protons: 20. HRMS (M + H).sup.+: calculated 311.1571; found
311.1557 9.10 N-[(1S)-2-(azetidin-1-yl)-1-cyclopropylethyl]-N,3,4-
3 mg, trimethylbenzamide 2% .sup.1H NMR Mixture of rotamers: (600
MHz, CDCl.sub.3) .delta. 0.07, 0.43, 0.58, and 0.68, 0.84, 0.98,
2.03, 2.30, 2.57, 2.65, 2.77, 2.91, 3.01, HRMS 3.10, 3.25, 3.86,
7.14. Ratio major:minor: 1:0.8. Total no of protons: 26. HRMS (M +
H).sup.+: calculated 287.2123; found 287.2108 9.11
(S)-N-(2-(Azetidin-1-yl)-1-cyclopropylethyl)- 6 mg,
3,4-difluoro-N-methylbenzamide 4% .sup.1H NMR Mixture of rotamers:
(400 MHz, CDCl.sub.3) .delta. 0.16-0.33, and 0.35-0.50, 0.51-0.64,
0.66-0.83, 1.46-1.75, 1.77-2.16, HRMS 2.37-2.71, 2.89-3.07,
3.20-3.48, 3.49-3.61, 3.68, 3.81-3.95, 4.29, 7.05-7.32. Total no of
protons: 20. HRMS (M + H).sup.+: calculated 295.1622; found
295.1611
Example 10.1
(3S)-1-(S)-2-(2-Chloro-4-fluoro-N-methylbenzamido)-3-methylbutyl)-3-hydrox-
ypyrrolidinium 2,3-dihydroxysuccinate
##STR00025##
[0744] To a solution of
(S)-1-((S)-3-methyl-2-(methylamino)butyl)pyrrolidin-3-ol
dihydrochloride (0.30 g, 1.16 mmol), which is commercially
available, in DMF (2 mL) was DIPEA (0.809 mL, 4.63 mmol) and
2-chloro-4-fluorobenzoyl chloride (0.223 g, 1.16 mmol) added. The
resultant mixture was stirred at rt overnight. To the mixture was
added NH.sub.3 in MeOH (1 mL, 2N). The reaction was concentrated
under reduced pressure and the residue purified by preparative HPLC
to give the neutral form of the title compound (280 mg, 58%). The
product was dissolved in MeCN (5 mL) and a solution of DL-tartaric
acid (61 mg, 0.41 mmol) in water (5 mL) was added. The resulting
mixture was freeze dried in vacuo to give the title compound (280
mg, 58%). Mixture of rotamers: .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 0.85-0.93, 1.05, 1.11, 1.93, 2.25, 2.77, 3.14, 3.32-3.51,
4.37, 4.50, 4.66, 7.12-7.28, 7.35. Ratio major:minor: 1:0.05. Total
no of protons: 23 (excluding the tartaric acid peak). HRMS
(M+H).sup.+: calculated 343.1588; found 343.1593.
[0745] The compound according to Example 10.2 was prepared, from
appropriate intermediates, by analogy with the method described for
Example 10.1 hereinbefore.
TABLE-US-00028 Example Name Yield 10.2
4-Chloro-N-((S)-1-((S)-3-hydroxypyrrolidin-1-yl)-3- 345 mg,
methylbutan-2-yl)-N-methylbenzamide hemi tartrate 75% .sup.1H NMR,
Mixture of rotamers: (400 MHz, CD.sub.3OD) .delta. 0.89, 0.93, HRMS
1.02, 1.10, 1.65-1.83, 1.86-2.03, 2.05-2.14, 2.26, 2.86, 2.93, and
3.23, 3.31, 3.37-3.55, 4.35, 4.52, 4.63, 7.50. Ratio XRPD
major:minor: 1:0.15. Total no of protons: 24 (excluding the
tartaric acid peak). HRMS (M + H).sup.+: calculated 325.1683; found
325.1669. The compound was found to be amorphous by XRPD.
Example 11
(S)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-4-chloro-N-ethylbenzamide
##STR00026##
[0747] 4-Chlorobenzoic acid (0.030 mL, 0.29 mmol), TBTU (113 mg,
0.35 mmol) and DIPEA (0.303 mL, 1.74 mmol) was stirred in DMF (2
mL). (S)-1-(azetidin-1-yl)-N-ethyl-3-methylbutan-2-amine (Compound
V) (50 mg, 0.29 mmol) was added and the resultant mixture was
stirred at rt overnight. The reaction mixture was diluted with DCM
(10 mL) and NaHCO.sub.3 (saturated, 10 mL). The organic phase was
isolated, filtered through a phase separator and concentrated under
reduced pressure. The residue was purified by preparative HPLC to
give the title compound (2.2 mg, 2%). Mixture of rotamers: .sup.1H
NMR (600 MHz, DMSO-d6) .delta. 0.63-1.32, 1.60-1.76, 1.82-1.98,
2.0-3.5 (omitted signals), 7.27-7.51. HRMS (M+H).sup.+: calculated
309.1725; found 309.1734.
Example 12.1
(S)-4-Fluoro-N,3-dimethyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)benzam-
ide-dihydroxysuccinate
##STR00027##
[0749] NMM (2.80 mL, 25.5 mmol) was added to a slurry of
(S)-N,3-dimethyl-1-(pyrrolidin-1-yl)butan-2-amine dihydrochloride
(2.0 g, 8.22 mmol) (for synthesis, see e.g. Synthetic
Communications (1994), 24(10), 1475-81) in DMF (20 mL). The mixture
was cooled to 0.degree. C. and 4-fluoro-3-methylbenzoyl chloride
(1.845 g, 10.69 mmol) was added. The resultant mixture was stirred
at rt for 1 h. Additional NMM (1.36 mL, 12.3 mmol) was added and
the resulting mixture was stirred for 2 h. The reaction mixture was
diluted with NaHCO.sub.3 (saturated, 100 mL) and DCM (100 mL). The
organic phase was isolated, filtered through a phase separator and
concentrated under reduced pressure. The residue was purified by
preparative HPLC to give 1.29 g, 51% of neutral form of the title
compound. The material was dissolved in MeCN (10 mL) and a solution
of DL-tartaric acid (0.63 g, 4.2 mmol) in water (5 mL) was added.
The resulting mixture was freeze dried in vacuo to give the title
product (1.93 g, 51%). Mixture of rotamers: .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 0.76-1.20, 1.72-2.15, 2.22-2.65, 2.73-2.98,
3.07-3.28, 3.32-3.64, 4.31, 4.52-4.72, 7.01-7.47. Ratio
major:minor: 8:1. Total no of protons: 27 (excluding the tartaric
acid peak). HRMS (M+H).sup.+: calculated 307.2186; found 307.2163.
XRPD pattern d (.ANG.) 20.1 (vs), 13.1 (str), 11.6 (str), 10.0
(str), 9.6 (str), 8.0 (str), 6.9 (str), 6.7 (str), 6.2 (str), 5.3
(str), 4.96 (str), 4.82 (str), 4.60 (str).
[0750] The compound according to Example 12.2 was prepared, from
appropriate intermediates, by analogy with the method described for
Example 12.1 hereinbefore.
TABLE-US-00029 Example Name Yield 12.2
(S)-1-(2-(N,3-Dimethylbenzamido)- 258 mg,
3-methylbutyl)pyrrolidinium2,3-dihydroxysuccinate 69% .sup.1H NMR
Mixture of rotamers: (400 MHz, DMSO-d6) 0.56-1.22, 1.43- and 1.93,
2.08-2.39, 2.65-2.91, 3.00-3.35, 4.29-4.56, 7.05-7.16, HRMS
7.16-7.38. Ratio major:minor: 65:31:4. HRMS (M + H).sup.+:
calculated 289.2280; found 289.2266
Example 13.1
(S)-3-Chloro-N-(1-cyclopropyl-2-(pyrrolidin-1-yl)ethyl)-4-fluoro-N-methylb-
enzamide
##STR00028##
[0752] 3-Chloro-4-fluorobenzoic acid (0.156 g, 0.89 mmol), TBTU
(0.334 g, 1.04 mmol) and NMM (0.204 mL, 1.86 mmol) was mixed in DCM
(10 mL). After 10 min at rt was
(S)-1-cyclopropyl-N-methyl-2-(pyrrolidin-1-yl)ethanamine (Compound
M3) (0.125 g, 0.74 mmol) added. The resultant mixture was stirred
at rt for 48 h. To the mixture was 1.4 N KOH (5 mL) added. The
organic phase was isolated, filtered through a phase separator and
concentrated under reduced pressure. The residue was purified by
preparative HPLC to give the title compound (130 mg, 54%). Mixture
of rotamers: .sup.1H NMR (600 MHz, DMSO-d6) .delta. 0.03,
0.16-0.62, 0.95, 1.50-1.74, 2.14-2.41, 2.47-2.51, 2.65-3.06, 3.84,
7.29, 7.46. Total no of protons: 22. HRMS (M+H).sup.+: calculated
325.1483; found 325.1475.
[0753] The compounds according to Example 13.2-13.4 were prepared,
from appropriate intermediates, by analogy with the method
described for Example 13.1 hereinbefore.
TABLE-US-00030 Example Name Yield 13.2
(S)-N-(1-Cyclopropyl-2-(pyrrolidin-1-yl)ethyl)- 88 mg,
N,3,4-trimethyl-benzamide 39% .sup.1H NMR Mixture of rotamers: (400
MHz, CDCl.sub.3) .delta. 0.02-0.25, 0.47, and 0.65, 0.89, 1.73,
2.17-3.20, 7.11, 7.17. HRMS (M + H).sup.+: HRMS calculated
301.2280; found 301.227 13.3
(R)-3-Chloro-N-methyl-N-(4-methyl-1-(pyrrolidin- 42 mg,
1-yl)pentan-3-yl)benzamide 34% HRMS HRMS (M + H).sup.+: calculated
323.1890; found 323.1901 13.4
(R)-4-Fluoro-N,3-dimethyl-N-(4-methyl-1- 64 mg,
(pyrrolidin-1-yl)pentan-3-yl)benzamide 52% HRMS HRMS (M + H).sup.+:
calculated 321.2342; found 321.2348
Example 14
N-((2R,3R)-3-Tert-butoxy-1-(pyrrolidin-1-yl)butan-2-yl)-4-fluoro-N,3-dimet-
hylbenzamide
##STR00029##
[0755] 4-Fluoro-3-methylbenzoic acid (101 mg, 0.66 mmol), TBTU (232
mg, 0.72 mmol) and DIPEA (0.172 mL, 0.99 mmol) was stirred in DCM
(2 mL) for 1 h.
(2R,3R)-3-tert-butoxy-N-methyl-1-(pyrrolidin-1-yl)butan-2-amine
(Compound M7) (150 mg, 0.66 mmol) was added and the resultant
mixture was stirred at rt overnight. The reaction mixture was
washed with NaHCO.sub.3 (8% aq., 2 mL), filtered through a phase
separator and concentrated under reduced pressure. The residue was
purified by preparative HPLC to give the title compound (43 mg,
18%). Mixture of rotamers: .sup.1H NMR (600 MHz, DMSO-d6) .delta.
0.94, 1.05-1.15, 1.55-1.72, 2.20, 2.21-2.28, 2.31-2.45, 2.60-2.66,
2.77, 2.83, 2.90, 3.27, 3.44-3.50, 3.70-3.77, 3.87-3.93, 4.51-4.58,
7.08-7.22, 7.23-7.28, 7.37. HRMS (M+H).sup.+: calculated 365.2604;
found 365.2592.
Example 15.1
(S)-4-Bromo-N-ethyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)benzamide
##STR00030##
[0757] To a solution of
(S)-N-ethyl-3-methyl-1-(pyrrolidin-1-yl)butan-2-amine (0.1 g, 0.54
mmol) (for synthesis, see e.g. EP254545) in DCM (2 mL) was TEA
(0.075 mL, 0.54 mmol) and 4-bromobenzoyl chloride (0.119 g, 0.54
mmol) added. The resultant mixture was stirred at rt overnight. The
mixture was washed with H.sub.2O (2 mL), filtered through a phase
separator and concentrated under reduced pressure. The residue was
purified by preparative HPLC to give the title compound (29 mg,
15%). Mixture of rotamers: .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 0.77-1.13, 1.30, 1.66-2.06, 2.26-2.59, 2.62-2.91,
3.00-3.29, 3.43-3.69, 7.27-7.42, 7.52-7.70. Total no of protons:
27. HRMS (M+H).sup.+: calculated 367.1385; found 367.1384.
[0758] The compounds according to Examples 15.2-15.5 were prepared,
from appropriate intermediates, by analogy with the method
described for Example 15.1 hereinbefore.
TABLE-US-00031 Example Name Yield 15.2
(S)-N-Ethyl-4-fluoro-3-methyl-N-(3-methyl-1- 54 mg,
(pyrrolidin-1-yl)butan-2-yl)benzamide 31% .sup.1H NMR Mixture of
rotamers: (400 MHz, CD.sub.3OD) .delta. 0.72-1.15, 1.30, and
1.61-2.07, 2.11-2.59, 2.60-2.93, 2.98-3.29, 3.33-3.42, HRMS
3.46-3.68, 7.00-7.17, 7.20-7.36. Total no of protons: 29. HRMS (M +
H).sup.+: calculated 321.2342; found 321.2365 15.3
(S)-4-Chloro-N-ethyl-N-(3-methyl-1-(pyrrolidin- 69 mg,
1-yl)butan-2-yl)benzamide 40% .sup.1H NMR Mixture of rotamers: (400
MHz, CD.sub.3OD) .delta. 0.75-1.14, and 1.21-1.42, 1.64-2.07,
2.27-2.60, 2.67-2.93, 2.98-3.11, HRMS 3.17-3.29, 3.52-3.64,
7.26-7.59. Total no of protons: 27. HRMS (M + H).sup.+: calculated
323.1890; found 323.1902 15.4
(S)-4-Chloro-N-(2-methoxyethyl)-N-(3-methyl-1- 39 mg,
(pyrrolidin-1-yl)butan-2-yl)benzamide 24% .sup.1H NMR Mixture of
rotamers: (400 MHz, CD.sub.3OD) .delta. 0.73-1.14, and 1.60-2.10,
2.25-2.78, 2.83-3.01, 3.06-3.22, 3.32-3.49, HRMS 3.51-3.86,
7.22-7.61. Ratio major:minor: 1.3:1. Total no of protons: 29. HRMS
(M + H).sup.+: calculated 353.1996; found 353.1974 15.5
(S)-4-Bromo-N-(2-methoxyethyl)-N-(3-methyl-1- 50 mg,
(pyrrolidin-1-yl)butan-2-yl)benzamide 27% .sup.1H NMR Mixture of
rotamers: (400 MHz, CD.sub.3OD) .delta. 0.63-1.18, and 1.62-2.12,
2.25-2.78, 2.81-3.25, 3.32-3.50, 3.56-3.82, HRMS 7.26-7.43,
7.56-7.67. Ratio major:minor: 1.3:1. Total no of protons: 29. HRMS
(M + H).sup.+: calculated 397.1490; found 397.1476
Example 16.1
(S)-3-Chloro-N-(1-(3,3-difluoropiperidin-1-yl)-3-methylbutan-2-yl)-4-fluor-
o-N-methylbenzamide
##STR00031##
[0760] 3-Chloro-4-fluorobenzoic acid (0.087 g, 0.50 mmol), TBTU
(0.175 g, 0.54 mmol) and NMM (0.125 mL, 1.13 mmol) was mixed in DMF
(2 mL). After 10 min at rt was
(S)-1-(3,3-difluoropiperidin-1-yl)-N,3-dimethylbutan-2-amine
(Compound S2) (0.1 g, 0.45 mmol) and additional DMF (1 mL) added.
The resultant mixture was stirred at rt overnight. The mixture was
concentrated and the residue dissolved in DCM (5 mL). The organic
phase was washed with NaHCO.sub.3 (saturated, 5 mL), filtered
through a phase separator and concentrated under reduced pressure.
The residue was purified by preparative HPLC to give the title
compound (80 mg, 47%). HRMS (M+H).sup.+: calculated 377.1607; found
377.1613.
[0761] The compounds according to Examples 16.2-16.60 were
prepared, from appropriate intermediates, by analogy with the
method described for Example 16.1 hereinbefore.
TABLE-US-00032 Example Name Yield 16.2
(S)-N-(1-(3,3-Difluoropiperidin-1-yl)-3-methylbutan-2-yl)-4- 79 mg,
fluoro-N-methyl-3-(trifluoromethyl)benzamide 43% HRMS HRMS (M +
H).sup.+: calculated 411.1871; found 411.1840 16.3
(S)-N-(1-(3,3-Difluoropiperidin-1-yl)-3-methylbutan-2-yl)- 83 mg,
N,3,4-trimethylbenzamide 52% HRMS HRMS (M + H).sup.+: calculated
353.2404; found 353.2394 16.4
(S)-N-(1-(3,3-Difluoropiperidin-1-yl)-3-methylbutan-2-yl)-3- 70 mg,
methoxy-N,4-dimethylbenzamide 42% HRMS HRMS (M + H).sup.+:
calculated 369.2354; found 369.2341 16.5
(S)-4-Bromo-N-(1-(3,3-difluoropiperidin-1-yl)-3-methylbutan-2- 77
mg, yl)-N-methylbenzamide 42% .sup.1H NMR Mixture of rotamers: (600
MHz, DMSO-d6) .delta. 0.58-1.08, 1.41-1.99, 2.08-2.45, and
2.49-2.65, 2.68-2.96, 4.18-4.56, 7.13-7.42, 7.50-7.77. Total HRMS
no of protons: 24. HRMS (M + H).sup.+: calculated 403.1196; found
403.1212 16.6
4-Chloro-N-methyl-N-(2-methyl-1-(pyrrolidin-1-yl)propan-2- 8 mg,
yl)benzamide 9% .sup.1H NMR Mixture of rotamers: (600 MHz, DMSO-d6,
(CH.sub.3).sub.2SO.sup.#) 1.37, 1.63, and 2.14-2.70 (omitted
signals), 2.80, 2.94, 3.3-3.4 (omitted signals), 7.32, 7.45. HRMS
HRMS (M + H).sup.+: calculated 295.1577; found 295.1556 16.7
4-Bromo-N-methyl-N-(2-methyl-1-(pyrrolidin-1-yl)propan-2- 26 mg,
yl)benzamide 23% .sup.1H NMR Mixture of rotamers: (600 MHz,
DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta. 1.37, 1.63, and
2.14-2.70 (omitted signals), 2.80, 2.94, 3.3-3.4 (omitted signals),
7.25, 7.59. HRMS HRMS (M + H).sup.+: calculated 339.1072; found
339.1086 16.8
(S)-3-Fluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2- 4.3
mg, yl)-5-(trifluoromethyl)benzamide 6.0% .sup.1H NMR Mixture of
rotamers: (600 MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta.
0.75-0.79, 0.83-0.8, and 0.92-0.96, 1.57-1.81, 2.01-3.60 (omitted
signals), 4.22-4.35, 7.38-7.55, HRMS 7.73-7.78. HRMS (M + H).sup.+:
calcd 361.1903, found 361.1902 16.9
(S)-2,3,5-Trifluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1- 6.0 mg,
yl)butan-2-yl)benzamide 9.1% .sup.1H NMR Mixture of rotamers: (600
MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta. 0.69-0.83, and
0.85, 0.95, 1.64, 1.72-1.81, 2.01-3.47 (omitted signals),
4.24-4.35, 6.89-7.08, HRMS 7.56-7.62. Ratio major:minor 3:1. HRMS
(M + H).sup.+: calcd 329.1841, found 329.1828 16.10
(S)-N-Methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)-3-(tri-
13.4 mg, fluoromethyl)benzamide 19.6% .sup.1H NMR Mixture of
rotamers: (600 MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta.
0.76, 0.81, 0.87, and 0.96, 1.63, 2.01-3.45 (omitted signals),
4.25-4.35, 7.53-7.69, 7.74-7.80. HRMS Ratio: 1:1. HRMS (M +
H).sup.+: calcd 343.1997, found 343.1991 16.11
(S)-4-Fluoro-3-methoxy-N-methyl-N-(3-methyl-1-(pyrrolidin-1- 22 mg,
yl)butan-2-yl)benzamide 34% .sup.1H NMR Mixture of rotamers: (600
MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta. 0.74-0.80, and
0.83, 0.94, 1.59-1.79, 2.02-3.45 (omitted signals), 3.83, 4.34,
7.06-7.13, HRMS 7.13-7.22. Ratio: 1:1. HRMS (M + H).sup.+: calcd
323.2135, found 323.2137 16.12
(S)-3,5-Difluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1- 3.2 mg,
yl)butan-2-yl)benzamide 5.1% .sup.1H NMR Mixture of rotamers: (600
MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta. 0.73-0.80, and
0.85, 0.94, 1.60-1.80, 1.98-3.49 (omitted signals), 4.21-4.35,
6.92-6.97, HRMS 7.04-7.09, 7.26-7.33. Ratio: 1:1. HRMS (M +
H).sup.+: calcd 311.1935, found 311.1926 16.13
(S)-3-Fluoro-N,2-dimethyl-N-(3-methyl-1-(pyrrolidin-1- 12 mg,
yl)butan-2-yl)benzamide 19% .sup.1H NMR Mixture of rotamers: (600
MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta. 0.87, 0.96,
1.58-1.79, and 1.95-3.47 (omitted signals), 4.32-4.45, 6.76-6.94,
7.11-7.16, HRMS 7.21-7.30. Ratio major:minor 9:1. HRMS (M +
H).sup.+: calcd 307.2186, found 307.2185 16.14
(S)-N,4-Dimethyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2- 15 mg,
yl)benzamide 26% .sup.1H NMR Mixture of rotamers: (600 MHz,
DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta. 0.76, 0.80, 0.84, and
0.95, 1.62, 2.02-3.45 (omitted signals), 4.33, 7.12-7.23. Ratio
HRMS major:minor 5:4. HRMS (M + H).sup.+: calcd 289.2280, found
289.2273 16.15
(S)-N-Methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)-4-(tri- 16
mg, fluoromethoxy)benzamide 23% .sup.1H NMR Mixture of rotamers:
(600 MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta. 0.78, 0.82,
0.85, and 0.95, 1.63, 2.01-3.48 (omitted signals), 4.24-4.36,
7.37-7.46. Ratio HRMS major:minor 3:2. HRMS (M + H).sup.+: calcd
359.1946, found 359.1944 16.16
(S)-N-Methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)-3-(tri- 10
mg, fluoromethoxy)benzamide 14% .sup.1H NMR Mixture of rotamers:
(600 MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta. 0.75, 0.80,
0.85, and 0.96, 1.58-1.80, 2.01-3.89 (omitted signals), 4.22-4.36,
7.17-7.20, 7.28-7.36, HRMS 7.37-7.42, 7.52-7.59. Ratio: 1:1. HRMS
(M + H).sup.+: calcd 359.1946, found 359.1938 16.17
(S)-3-Chloro-2-fluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1- 20 mg,
yl)butan-2-yl)benzamide 31% .sup.1H NMR Mixture of rotamers: (600
MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta. 0.70-0.83, and
0.85, 0.95, 1.54-1.81, 2.01-3.48 (omitted signals), 4.26-4.36,
7.13-7.33, HRMS 7.57-7.64. Ratio major:minor 4:1. HRMS (M +
H).sup.+: calcd 327.1639, found 327.1647 16.18
(S)-2-Fluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2- 18
mg, yl)benzamide 30% .sup.1H NMR Mixture of rotamers: (600 MHz,
DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta. 0.70-0.81, 0.85, and
0.95, 1.55-1.80, 2.01-3.48 (omitted signals), 4.28-4.39, 7.16-7.27,
7.39-7.46. HRMS Ratio major:minor 3:1. HRMS (M + H).sup.+: calcd
293.2029, found 293.2030 16.19
(S)-2-Fluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2- 11
mg, yl)-6-(trifluoromethyl)benzamide 15% .sup.1H NMR Mixture of
rotamers: (600 MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta.
0.85, 0.88, 0.94-0.98, and 1.02, 1.13, 1.60-1.86, 2.02-3.44
(omitted signals), 4.30-4.39, HRMS 7.60-7.69. Ratio major:minor
5:4. HRMS (M + H).sup.+: calcd 361.1903, found 361.1881 16.20
(S)-N-Methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)-2- 17 mg,
(trifluoromethyl)benzamide 25% .sup.1H NMR Mixture of rotamers:
(600 MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta. 0.84, 0.92,
0.93-0.98, and 1.60-1.85, 2.02-3.45 (omitted signals), 4.25-4.37,
7.21-7.32, HRMS 7.57-7.61, 7.69-7.79. Ratio major:minor 2:1. HRMS
(M + H).sup.+: calcd 343.1997, found 343.1988 16.21
(S)-3,4,5-Trifluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1- 10 mg,
yl)butan-2-yl)benzamide 15% .sup.1H NMR Mixture of rotamers: (600
MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta. 0.73, 0.78, 0.84,
and 0.94, 1.59-1.79, 2.01-3.49 (omitted signals), 4.19-4.35, 7.21,
7.35. HRMS Ratio: 1:1. HRMS (M + H).sup.+: calcd 329.1841, found
329.1855 16.22
(S)-2,5-Difluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1- 10 mg,
yl)butan-2-yl)benzamide 16% .sup.1H NMR Mixture of rotamers: (600
MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta. 0.71-0.82, and
0.85, 0.95, 1.59-1.81, 2.00-3.47 (omitted signals), 4.26-4.36,
6.98-7.19, HRMS 7.25-7.36. Ratio major:minor 3:1. HRMS (M +
H).sup.+: calcd 311.1935, found 311.1934 16.23
(S)-4-Fluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2- 15
mg, yl)-2-(trifluoromethyl)benzamide 21% .sup.1H NMR Mixture of
rotamers: (600 MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta.
0.82, 0.88-0.92, and 0.93-0.98, 1.59-1.85, 2.02-3.46 (omitted
signals), 4.22-4.36, 7.24-7.40, HRMS 7.55-7.74. Ratio major:minor
2:1. HRMS (M + H).sup.+: calcd 361.1903, found 361.1900 16.24
2,6-Difluoro-N-methyl-N-[(1S)-2-methyl-1-(pyrrolidin-1- 18 mg,
ylmethyl)propyl]benzamide 28% .sup.1H NMR Mixture of rotamers: (600
MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta. 0.81, 0.85, 0., and
1.52-1.58, 1.58-1.69, 1.69-1.83, 2.07-3.53, 4.27-4.39, 7.11-7.18,
HRMS 7.43-7.51. Ratio major:minor 9:1. HRMS (M + H).sup.+: calcd
311.1935, found 311.1936 16.25
4-Chloro-N,3-dimethyl-N-[(1S)-2-methyl-1-(piperidin-1- 2.4 mg,
ylmethyl)propyl]benzamide 3.6% HRMS HRMS (M + H).sup.+: calcd
337.2047, found 337.2046 16.26
2-Chloro-4-fluoro-N-methyl-N-[(1S)-2-methyl-1-(piperidin-1-yl- 1.2
mg, methyl)propyl]benzamide 1.8% HRMS HRMS (M + H).sup.+: calcd
341.1796, found 341.1797 16.27
4-Bromo-N-methyl-N-[(1S)-2-methyl-1-(piperidin-1-ylmethyl)- 2.2 mg,
propyl]benzamide 3.0% HRMS HRMS (M + H).sup.+: calcd 367.1385,
found 367.1391 16.28
3,4-Dichloro-N-methyl-N-[(1S)-2-methyl-1-(piperidin-1- 2.1 mg,
ylmethyl)propyl]benzamide 2.9% HRMS HRMS (M + H).sup.+: calcd
357.1500, found 357.1506 16.29
N,3-Dimethyl-N-[(1S)-2-methyl-1-(piperidin-1-ylmethyl)- 1.3 mg,
propyl]benzamide 2.1% HRMS HRMS (M + H).sup.+: calcd 303.2436,
found 303.2434 16.30
2,4-Dichloro-N-methyl-N-[(1S)-2-methyl-1-(piperidin-1- 2.4 mg,
ylmethyl)propyl]benzamide 3.4% HRMS HRMS (M + H).sup.+: calcd
357.1500, found 357.1503 16.31
4-Chloro-2-fluoro-N-methyl-N-[(1S)-2-methyl-1-(piperidin-1-yl- 2.1
mg, methyl)propyl]benzamide 3.1% HRMS HRMS (M + H).sup.+: calcd
341.1796, found 341.1810 16.32
N-Methyl-N-[(1S)-2-methyl-1-(piperidin-1-ylmethyl)propyl]-3- 0.5
mg, (trifluoromethyl)benzamide 0.7% HRMS HRMS (M + H).sup.+: calcd
357.2154, found 357.2151 16.33
3-Chloro-4-fluoro-N-methyl-N-[(1S)-2-methyl-1-(piperidin-1-yl- 2.0
mg, methyl)propyl]benzamide 2.9% HRMS HRMS (M + H).sup.+: calcd
341.1796, found 341.1800 16.34
4-Chloro-N-methyl-N-[(1S)-2-methyl-1-(piperidin-1-ylmethyl)- 1.6
mg, propyl]benzamide 2.5% HRMS HRMS (M + H).sup.+: calcd 323.1890,
found 323.1887 16.35
(S)-3-Bromo-N-methyl-N-(3-methyl-1-(piperidin-1-yl)butan-2- 2.3 mg,
yl)benzamide 3.1% HRMS HRMS (M + H).sup.+: calcd 367.1385, found
367.1376 16.36
(S)-4-Bromo-3-fluoro-N-methyl-N-(3-methyl-1-(piperidin-1- 2.2 mg,
yl)butan-2-yl)benzamide 2.9% HRMS HRMS (M + H).sup.+: calcd
385.1291, found 385.302 16.37
(S)-3-Chloro-N-methyl-N-(3-methyl-1-(piperidin-1-yl)butan-2- 2.3
mg, yl)benzamide 3.6% HRMS HRMS (M + H).sup.+: calcd 323.1890,
found 323.1886 16.38
(S)-3-Fluoro-N,2-dimethyl-N-(3-methyl-1-(piperidin-1-yl)butan- 1.5
mg, 2-yl)benzamide 2.3% HRMS HRMS (M + H).sup.+: calcd 321.2342,
found 321.2355 16.39
3-Chloro-2-fluoro-N-[(1S)-1-{[(3S)-3-hydroxypyrrolidin-1-yl]- 31
mg, methyl}-2-methylpropyl]-N-methylbenzamide 45% .sup.1H NMR
Mixture of rotamers: (600 MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#)
.delta. 0.69-0.82, and 0.85, 0.95, 1.45-1.52, 1.63-1.80, 1.90-2.00,
2.10-3.43 (omitted HRMS signals), 4.11-4.17, 4.25-4.34, 4.63-4.71,
7.17-7.30, 7.42-7.51, 7.58-7.65. Ratio major:minor 4:1. HRMS (M +
H).sup.+: calcd 343.1588, found 343.1572 16.40
4-Fluoro-N-[(1S)-1-{[(3S)-3-hydroxypyrrolidin-1-yl]methyl}-2- 24
mg, methylpropyl]-N,3-dimethylbenzamide 37% .sup.1H NMR Mixture of
rotamers: (600 MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta.
0.76, 0.84, 0.94, and 1.44-1.52, 1.64-1.77, 1.89-1.99, 2.18-3.48
(omitted signals), 4.09-4.17, HRMS 4.20-4.32, 4.66, 7.10-7.17,
7.18-7.25, 7.32. Ratio major:minor 3:2. HRMS (M + H).sup.+: calcd
323.2135, found 323.2122 16.41
N-[(1S)-1-{[(3S)-3-Hydroxypyrrolidin-1-yl]methyl}-2-methyl- 31 mg,
propyl]-N-methyl-4-(trifluoromethoxy)benzamide 42% .sup.1H NMR
Mixture of rotamers: (600 MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#)
.delta. 0.76, 0.79, 0.85, and 0.95, 1.43-1.52, 1.64-1.79,
1.87-1.99, 2.16-3.37 (omitted signals), 4.06-4.17, HRMS 4.22-4.32,
4.62-4.68, 7.35-7.44, 7.49. Ratio: 1:1
HRMS (M + H).sup.+: calcd 375.1895, found 375.1890 16.42
N-[(1S)-1-{[(3S)-3-Hydroxypyrrolidin-1-yl]methyl}-2-methyl- 18 mg,
propyl]-N-methyl-3-(trifluoromethoxy)benzamide 24% .sup.1H NMR
Mixture of rotamers: (600 MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#)
.delta. 0.75, 0.78, 0.85, and 0.95, 1.44-1.53, 1.65-1.80,
1.86-1.98, 2.16-2.28, 2.30-3.41 (omitted HRMS signals), 4.07-4.16,
4.21-4.31, 4.66, 7.21, 7.32, 7.34-7.42, 7.50-7.58. Ratio: 1:1. HRMS
(M + H).sup.+: calcd 375.1895, found 375.1890 16.43
N-[(1S)-1-{[(3S)-3-Hydroxypyrrolidin-1-yl]methyl}-2-methyl- 20 mg,
propyl]-N,4-dimethylbenzamide 32% .sup.1H NMR Mixture of rotamers:
(600 MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta. 0.75, 0.78,
0.84, and 0.94, 1.42-1.52, 1.63-1.78, 1.86-1.99, 2.13-2.22,
2.23-3.51 (omitted HRMS signals), 4.07-4.17, 4.23-4.32, 4.63,
4.64-4.67, 7.14-7.22, 7.24. Ratio major:minor 3:2. HRMS (M +
H).sup.+: calcd 305.2229, found 305.2220 16.44
3-Fluoro-N-[(1S)-1-{[(3S)-3-hydroxypyrrolidin-1-yl]methyl}-2- 26
mg, methylpropyl]-N-methyl-5-(trifluoromethyl)benzamide 35% .sup.1H
NMR Mixture of rotamers: (600 MHz, DMSO-d6,
(CH.sub.3).sub.2SO.sup.#) .delta. 0.76, 0.87, 0.95, and 1.45-1.54,
1.66-1.81, 1.88-1.99, 2.17-3.46 (omitted signals), 4.09-4.17, HRMS
4.19-4.29, 4.67, 4.70, 7.43, 7.47-7.52, 7.56-7.63, 7.70-7.78.
Ratio: 1:1. HRMS (M + H).sup.+: calcd 377.1852, found 377.1858
16.45 3-Fluoro-N-((S)-1-((S)-3-hydroxypyrrolidin-1-yl)-3- 10.2 mg,
methylbutan-2-yl)-N,2-dimethylbenzamide 15.9% .sup.1H NMR Mixture
of rotamers: (600 MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta.
0.65-0.69, 0.71-0.76, and 0.81-0.84, 0.86, 0.88-0.92, 0.96,
1.41-1.55, 1.67-1.78, 1.85-1.94, HRMS 2.08-3.48 (omitted signals),
4.06-4.20, 4.27-4.42, 4.57-4.71, 6.85-6.90, 6.90-6.94, 7.10-7.16,
7.18-7.21, 7.22-7.28, 7.30-7.33. HRMS (M + H).sup.+: calcd
323.2135, found 323.2128 16.46
4-Fluoro-N-((S)-1-((S)-3-hydroxypyrrolidin-1-yl)-3- 23.3 mg,
methylbutan-2-yl)-N-methyl-2-(trifluoromethyl)benzamide 30.7%
.sup.1H NMR Mixture of rotamers: (600 MHz, DMSO-d6,
(CH.sub.3).sub.2SO.sup.#) .delta. 0.65-0.68, 0.75-0.78, and 0.82,
0.87-0.92, 0.94, 1.41-1.54, 1.68-1.94, 1.96-2.03, HRMS 2.06-3.51
(omitted signals), 4.09-4.30, 4.56-4.60, 4.67-4.72, 7.35-7.44,
7.55-7.60, 7.67-7.72. HRMS (M + H).sup.+: calcd 377.1852, found
377.1840 16.47
(S)-2,4-Dichloro-N-methyl-N-(3-methyl-1-(pyrrolidin-1- 180 mg,
yl)butan-2-yl)benzamide 67% .sup.1H NMR Mixture of rotamers: (600
MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#)) .delta. 0.77, 0.87, 0.95,
and 1.53-1.81, 2.14-3.32 (omitted signals), 4.25-4.37, 7.07,
7.21-7.30, 7.43-7.54, HRMS 7.63-7.72. HRMS (M + H).sup.+: calcd
343.1344; found 343.1333 16.48
(S)-3-Chloro-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2- 8 mg,
yl)benzamide 13% .sup.1H NMR Mixture of rotamers: (600 MHz,
DMSO-d6, (CH.sub.3).sub.2SO.sup.#)) .delta. 0.77, 0.85, 0.95, and
1.60-1.79, 2.21-3.48 (omitted signals), 4.23-4.32, 7.21, 7.24-7.27,
HRMS 7.36, 7.40-7.49. Ratio 1:1. HRMS (M + H).sup.+: calcd
309.1733; found 309.1741 16.49
(S)-4-Isopropyl-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan- 4
mg, 2-yl)benzamide 6% .sup.1H NMR Mixture of rotamers: (600 MHz,
DMSO-d6, (CH.sub.3).sub.2SO.sup.#)) .delta. 0.77, 0.80, 0.84, and
0.95, 1.18, 1.58-1.78, 2.16-3.46 (omitted signals), 4.27-4.34,
7.18, 7.24, HRMS 7.26. Ratio major:minor: 3:2. HRMS (M + H).sup.+:
calcd 317.2593; found 317.2591 16.50
(S)-4-Chloro-N,3-dimethyl-N-(3-methyl-1-(pyrrolidin-1- 6 mg,
yl)butan-2-yl)benzamide 9% .sup.1H NMR Mixture of rotamers: (600
MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta. 0.78, 0.84, 0.95,
and 1.59-1.79, 2.18-3.47 (omitted signals), 4.25-4.33, 7.08, 7.15,
7.23, 7.29, HRMS 7.43. Ratio major:minor: 3:2. HRMS (M + H).sup.+:
calcd 323.1890; found 323.1890 16.51
(S)-3,4-Dichloro-N-methyl-N-(3-methyl-1-(pyrrolidin-1- 11 mg,
yl)butan-2-yl)benzamide 16% .sup.1H NMR Mixture of rotamers: (600
MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta. 0.77, 0.85, 0.94,
and 1.59-1.79, 2.22-3.47 (omitted signals), 4.22-4.31, 7.25, 7.30,
7.48, 7.59, HRMS 7.68. Ratio 1:1. HRMS (M + H).sup.+: calcd
343.1344; found 343.1353 16.52
(S)-4-Bromo-3-fluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1- 14 mg,
yl)butan-2-yl)benzamide 19% .sup.1H NMR Mixture of rotamers: (600
MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta. 0.76, 0.85, 0.94,
and 1.61-1.79, 2.25-3.48 (omitted signals), 4.19-4.29, 7.13, 7.20,
7.26, 7.38, HRMS 7.60. Ratio 1:1. HRMS (M + H).sup.+: calcd
371.1134; found 371.1144 16.53
(S)-4-Chloro-2-fluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1- 152 mg,
yl)butan-2-yl)benzamide 53% .sup.1H NMR Mixture of rotamers: (600
MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta. 0.71-0.88, and
0.95, 1.56-1.80, 2.15-3.32 (omitted signals), 4.26-4.36, 7.22,
7.31-7.37, HRMS 7.47-7.54. Ratio major:minor: 7:3. HRMS (M +
H).sup.+: calcd 327.1639; found 327.1634 16.54
(S)-2-(Difluoromethoxy)-N-methyl-N-(3-methyl-1-(pyrrolidin- 4 mg,
1-yl)butan-2-yl)benzamide 6% .sup.1H NMR Mixture of rotamers: (600
MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta. 0.75, 0.86, 0.95,
and 1.51-1.76, 2.19-3.49 (omitted signals), 4.30-4.38, 7.07-7.13,
7.15-7.26, HRMS 7.26-7.39, 7.39-7.46. HRMS (M + H).sup.+: calcd
341.2040; found 341.2047 16.55 A
(S)-3-Chloro-4-fluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1- 180 mg,
yl)butan-2-yl)benzamide 63% .sup.1H NMR, Mixture of rotamers: (600
MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta. 0.76, 0.85, 0.95,
HRMS 1.57-1.81, 2.23-2.43, 2.42-2.56 (omitted signals), 2.62, 2.69,
2.75, 2.81, and 3.14, 4.20-4.32, 7.25-7.31, 7.31-7.37, 7.42-7.49,
7.58. Ratio 1:1. XRPD HRMS (M + H).sup.+: calcd 327.1639; found
327.1650. Example 16.55 B:
(S)-1-(2-(3-Chloro-4-fluoro-N-methylbenzamido)-3-
methylbutyl)pyrrolidinium chloride To a mixture of
(S)-3-chloro-4-fluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-
1-yl)butan-2-yl)benzamide (410 mg, 1.25 mmol) in DCM was HCl (1.25N
in MeOH) and Et.sub.2O added. The resultant mixture was
concentrated under reduced pressure and the residue dissolved in
DCM. Et.sub.2O was added and the precipitated solid was collected
to give the title compound (430 mg, 94%). XRPD pattern d (.ANG.)
10.2 (str), 8.6 (str), 6.0 (vs), 5.6 (vs), 5.4 (med), 4.97 (str),
4.64 (str), 4.27 (str), 3.85 (str), 3.51 (vs), 3.05 (med). 16.56
(R)-3,4-Dichloro-N-methyl-N-(3-methyl-1-(pyrrolidin-1- 46 mg,
yl)butan-2-yl)benzamide 66% .sup.1H NMR Mixture of rotamers: (600
MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta. 0.77, 0.85, 0.95,
and 1.58-1.80, 2.24-3.37 (omitted signals), 4.21-4.31, 7.24, 7.30,
7.47, 7.59, HRMS 7.68. Ratio 1:1. HRMS (M + H).sup.+: calcd
343.1344; found 343.1334 16.57
(R)-4-Bromo-N-methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2- 48 mg,
yl)benzamide 68% .sup.1H NMR Mixture of rotamers: (600 MHz,
DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta. 0.76-0.88, and 0.95,
1.58-1.80, 2.17-3.39 (omitted signals), 4.24-4.34, 7.20, 7.27,
7.60. HRMS Ratio major:minor: 3:2. HRMS (M + H).sup.+: calcd
353.1228; found 353.1231 16.58
(R)-2,4-Dichloro-N-methyl-N-(3-methyl-1-(pyrrolidin-1- 46 mg,
yl)butan-2-yl)benzamide 68% .sup.1H NMR Mixture of rotamers: (600
MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta. 0.74-0.81, and
0.87, 0.95, 1.53-1.81, 2.12-3.40 (omitted signals), 4.25-4.36,
7.07, 7.22-7.30, HRMS 7.43-7.54, 7.63-7.72. HRMS (M + H).sup.+:
calcd 343.1344; found 343.1343 16.59
(R)-4-Chloro-2-fluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1- 45 mg,
yl)butan-2-yl)benzamide 69% .sup.1H NMR Mixture of rotamers: (600
MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta. 0.72-0.88, and
0.94, 1.56-1.80, 2.16-3.39 (omitted signals), 4.26-4.37, 7.22,
7.31-7.39, HRMS 7.47-7.55. Ratio major:minor: 4:1. HRMS (M +
H).sup.+: calcd 327.1639; found 327.1630 16.60
(R)-4-Bromo-3-fluoro-N-methyl-N-(3-methyl-1-(pyrrolidin-1- 51 mg,
yl)butan-2-yl)benzamide 68% .sup.1H NMR Mixture of rotamers: (600
MHz, DMSO-d6, (CH.sub.3).sub.2SO.sup.#) .delta. 0.77, 0.85, 0.94,
and 1.58-1.81, 2.27-3.38 (omitted signals), 4.18-4.30, 7.12, 7.20,
7.26, 7.38, HRMS 7.61. Ratio 1:1. HRMS (M + H).sup.+: calcd
371.1134; found 371.1141
Example 17.1
(S)-4-Bromo-N-methyl-N-(1-(pyrrolidin-1-yl)butan-2-yl)benzamide
##STR00032##
[0763] To a solution of
(S)-N-methyl-1-(pyrrolidin-1-yl)butan-2-amine (Compound M5) (75 mg,
0.48 mmol) in DCM (1.5 mL) was NMM (0.058 mL, 0.53 mmol) and
4-bromobenzoyl chloride (137 mg, 0.62 mmol) added. The resultant
mixture was stirred at rt overnight. The mixture was diluted with
DCM (5 mL), washed with NaHCO.sub.3 (saturated, 5 mL), filtered
through a phase separator and concentrated under reduced pressure.
The residue was purified by preparative HPLC to give the title
compound (100 mg, 62%). Mixture of rotamers: .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 0.92, 1.33-1.66, 1.66-1.97, 2.55, 2.94, 3.64,
4.70-4.83, 7.21-7.49, 7.49-7.76. Ratio major:minor: 3:2. Total no
of protons: 23. HRMS (M+H).sup.+: calculated 339.1072; found
339.1061.
[0764] The compounds according to Examples 17.2-17.7 were prepared,
from appropriate intermediates, by analogy with the method
described for Example 17.1 hereinbefore.
TABLE-US-00033 Example Name Yield 17.2
(S)-3,4-Dichloro-N-methyl-N-(1-(pyrrolidin-1-yl)butan-2-yl)- 95 mg,
benzamide 60% .sup.1H NMR Mixture of rotamers: (400 MHz,
CD.sub.3OD) .delta. 0.64-1.19, 1.40-1.98, 2.31- and 2.98, 3.3-3.42,
4.75, 7.12-7.53, 7.53-7.74. Ratio major:minor: 7:3. Total HRMS no
of protons: 22. HRMS (M + H).sup.+: calculated 329.1187; found
329.1195 17.3 4-Fluoro-N-((S)-1-((R)-3-hydroxypyrrolidin-1-yl)-3-
143 mg, methylbutan-2-yl)-N,3-dimethylbenzamide 83% .sup.1H NMR
Mixture of rotamers: (400 MHz, CD.sub.3OD) .delta. 0.63-1.24,
1.59-1.95, 2.03- and 2.18, 2.23-2.64, 2.66-3.01, 4.20-4.57,
6.98-7.47. Total no of protons: HRMS 26. HRMS (M + H).sup.+:
calculated 323.2135; found 323.2134 17.4
4-Chloro-N-((S)-1-((R)-3-hydroxypyrrolidin-1-yl)-3- 107 mg,
methylbutan-2-yl)-N-methylbenzamide 61% .sup.1H NMR Mixture of
rotamers: (400 MHz, CD.sub.3OD) .delta. 0.49-1.41, 1.56-1.94, 1.98-
and 2.64, 2.67-2.84, 2.86-3.04, 4.25-4.56, 7.13-7.68. Total no of
protons: HRMS 24. HRMS (M + H).sup.+: calculated 325.1683; found
325.1657 17.5 4-Bromo-N-((S)-1-((R)-3-hydroxypyrrolidin-1-yl)-3-
120 mg, methylbutan-2-yl)-N-methylbenzamide 61% .sup.1H NMR Mixture
of rotamers: (400 MHz, CD.sub.3OD) .delta. 0.47 1.42, 1.50-1.93,
2.00- and 2.22, 2.25-2.64, 2.66-3.02, 4.18-4.60, 7.17-7.80. Total
no of protons: HRMS 24. HRMS (M + H).sup.+: calculated 369.1177;
found 369.1178 17.6
3-Chloro-4-fluoro-N-((S)-1-((R)-3-hydroxypyrrolidin-1-yl)-3- 122
mg, methylbutan-2-yl)-N-methylbenzamide 66% .sup.1H NMR Mixture of
rotamers: (400 MHz, CD.sub.3OD) .delta. 0.50-1.27, 1.57-1.94, 2.02-
and 2.22, 2.35-2.62, 2.67-3.03, 4.17-4.58, 7.09-7.80. Total no of
protons: HRMS 24. HRMS (M + H).sup.+: calculated 343.1588; found
343.1590 17.7 4-Fluoro-N-((S)-1-((R)-3-hydroxypyrrolidin-1-yl)-3-
51 mg, methylbutan-2-yl)-N-methyl-3-(trifluoromethyl)benzamide 25%
.sup.1H NMR Mixture of rotamers: (400 MHz, CD.sub.3OD) .delta.
0.59-1.38, 1.57-1.95, 1.97- and 2.23, 2.30-2.63, 2.67-3.08,
4.17-4.68, 7.27-7.52, 7.60-8.11. Total no HRMS of protons: 23. HRMS
(M + H).sup.+: calculated 377.1852; found 377.1844
Example 18
(S)-1-(2-(4-Chloro-N-methylbenzamido)-3-methylbutyl)pyrrolidinium
chloride
##STR00033##
[0766] 4-Chlorobenzoic acid (0.470 g, 3 mmol), TBTU (0.963 g, 3
mmol) and NMM (0.330 mL, 3 mmol) was mixed in DMF (10 mL). After 10
min at rt was a solution of
(S)-N,3-dimethyl-1-(pyrrolidin-1-yl)butan-2-amine (0.426 mg, 2.50
mmol) (for synthesis, see e.g. Synthetic Communications (1994),
24(10), 1475-81) and NMM (0.430 mL, 3.9 mmol) in DMF (5 mL) added.
The resultant mixture was stirred at rt for 16 h. The reaction
mixture was washed with Na.sub.2CO.sub.3 (1M, 2 mL) and
concentrated under reduced pressure. The residue was purified by
preparative HPLC to give an oily residue. The residue was dissolved
in EtOH (5 mL). HCl (1.25 N EtOH solution, 10 mL) and H.sub.2O (5
mL) were added and the mixture freezing-dried to give the title
compound (600 mg, 58%).
[0767] Mixture of rotamers: .sup.1H NMR (600 MHz, CD.sub.3OD)
.delta. 1.00, 1.10, 1.86-1.98, 2.11, 2.89, 3.18, 3.41, 3.63-3.79,
3.87, 4.68, 7.46, 7.60. HRMS (M+H).sup.+: calculated 309.1733;
found 309.1750. XRPD pattern d (.ANG.) 8.4 (med), 7.7 (med), 7.4
(med), 5.0 (vs), 4.31 (str), 4.13 (str), 3.84 (str), 3.46 (str),
3.39 (med), 3.17 (med), 3.00 (med), 2.83 (med).
Example 19
(S)-1-(2-(4-bromo-N-methylbenzamido)-3-methylbutyl)pyrrolidinium
3-carboxy-2,3-dihydroxypropanoate
##STR00034##
[0769] At 0.degree. C. was NMM (3 mL, 27.29 mmol) added to a
mixture of (S)-N,3-dimethyl-1-(pyrrolidin-1-yl)butan-2-amine
dihydrochloride (1.18 g, 4.85 mmol) (for synthesis, see e.g.
Synthetic Communications (1994), 24(10), 1475-81) in DMF (12 mL).
After 10 min was 4-bromobenzoyl chloride (1.4 g, 6.38 mmol) and DCM
added (6 mL). The resultant mixture was stirred at rt for 48 h. The
mixture was concentrated and the residue was purified by
preparative HPLC to give the title compound (1.45 g, 85%). The
title compound was dissolved in MeCN (10 mL) and a solution of
DL-tartaric acid (569 mg, 3.79 mmol) in water (20 mL) was added.
The resulting mixture was freeze dried in vacuo to give the title
product (1.85 g, 76%). Mixture of rotamers: .sup.1H NMR (600 MHz,
DMSO-d6) .delta. 0.61-1.10, 1.52-1.95, 2.17-2.41, 2.56-2.84,
2.84-3.43, 3.89-4.19, 4.45, 7.15-7.44, 7.52-7.75. Total no of
protons: 27. HRMS (M+H).sup.+: calculated 353.1228; found 353.1247.
The compound was found to be amorphous by XRPD.
Example 20
(S)-4-Chloro-N-cyclopentyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)benza-
mide
##STR00035##
[0771] Cyclopent-3-enone (57.9 mg, 0.70 mmol) was added to a
mixture of (S)-3-methyl-1-(pyrrolidin-1-yl)butan-2-amine (109 mg,
0.70 mmol), which is commercially available, in THF (1.7 mL). After
10 min was a solution of sodium cyanoborohydride (58 mg, 0.92 mmol)
in THF (0.9 mL) added. The resultant mixture was stirred at rt for
3 h. Acetic acid (0.3 mL, 5.24 mmol) and MeOH (2 mL) was added and
the mixture stirred at rt overnight. The reaction mixture was
concentrated and the residue dissolved in DMF (2.5 mL). DIPEA (0.5
mL, 2.86 mmol) and a solution of 4-chlorobenzoyl chloride (2.2 mL,
1.01 mmol) in DCM (2 mL) was added. The resultant mixture was
stirred at rt overnight. H.sub.2O (0.5 mL) and MeOH (5 mL) were
added and the mixture was stirred for 10 min. The solvent was
removed under reduced pressure and the residue mixed in NaOH (1 N
aq., 10 mL). The water layer was extracted with DCM (3.times.10 mL)
and the combined organic layer were washed with brine (10 mL),
filtered through a phase separator and concentrated under reduced
pressure. The residue was purified by preparative HPLC to give the
title compound (17 mg, 7%).
[0772] Mixture of rotamers: .sup.1H NMR (600 MHz, DMSO-d6) .delta.
0.78, 0.90, 1.38-1.87, 2.03-2.28, 2.69, 3.05, 3.55, 7.24, 7.42.
HRMS (M+H).sup.+: calculated 363.2203; found 363.2216.
Example 21
(S)-N-(1-(3,3-Difluoropyrrolidin-1-yl)-3-methylbutan-2-yl)-N,3,4-trimethyl-
benzamide
##STR00036##
[0774] To a mixture of
(S)-N-(1-(3,3-difluoropyrrolidin-1-yl)-3-methylbutan-2-yl)-3,4-dimethylbe-
nzamide (Compound P) (167 mg, 0.51 mmol) in THF (1 mL) was sodium
hydride (0.024 mL, 0.51 mmol) added. After 30 min was MeI (0.032
mL, 0.51 mmol) added and the resultant mixture was stirred at rt
overnight. Additional sodium hydride (0.013 mL, 0.51 mmol) and MeI
(0.032 mL, 0.51 mmol) was added and the resulting mixture stirred
for 2 h. The reaction was quenched with MeOH (0.5 mL). The solvent
was removed under reduced pressure and the residue dissolved in DCM
(5 mL). The organic phase was washed with NaHCO.sub.3 (saturated, 5
mL), filtered through a phase separator and concentrated under
reduced pressure. The residue was purified by preparative HPLC to
give the title compound (47 mg, 27%). HRMS (M+H).sup.+: calculated
339.2248; found 339.2277.
Example 22
(S)-4-Fluoro-N-(1-(3-hydroxyazetidin-1-yl)-2,3-dimethylbutan-2-yl)-N,3-dim-
ethylbenzamide
##STR00037##
[0776] HATU (0.408 g, 1.07 mmol) was added to a mixture of
4-fluoro-3-methylbenzoic acid (5.34 ml, 1.07 mmol) and DIPEA (2 mL,
11.45 mmol) in DMF (10 mL). After 10 min was
(S)-1-(2,3-dimethyl-2-(methylamino)butyl)azetidin-3-ol (Compound Y)
(0.1 g, 0.54 mmol) in DCM added. The resultant mixture was stirred
at rt over night. The mixture was concentrated and the residue
dissolved in DCM. The organic phase was washed with NaHCO.sub.3
(saturated) and brine. The filtrate was dried (Na.sub.2SO.sub.4)
and concentrated under reduced pressure. MeOH (10 mL) and KOH
(2.221 ml, 3.22 mmol) was added and the resultant mixture was
stirred at rt for 3 days. The solvent was removed and the residue
was purified by preparative HPLC to give the title compound (1.1
mg, 0.5%). Mixture of rotamers: .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 0.91, 1.01, 2.29, 2.34-2.43, 2.81, 2.96, 3.03-3.56,
3.65-3.79, 3.79-3.96, 4.00-4.12, 4.28, 4.43-4.57, 6.92-7.06,
7.16-7.25. Total no of protons: 27. HRMS (M+H).sup.+: calculated
323.2135; found 323.2113.
Example 23
(S)-N-(1-(3-Hydroxyazetidin-1-yl)pentan-2-yl)-N,3,4-trimethylbenzamide
##STR00038##
[0778] 3,4-Dimethylbenzoic acid (0.174 g, 1.16 mmol), TBTU (0.373
g, 1.16 mmol) and
[0779] DIPEA (0.303 mL, 1.74 mmol) was stirred in DCM (2 mL) for 40
min before (S)-1-(2-(methylamino)pentyl)azetidin-3-ol (Compound J4)
(0.1 g, 0.58 mmol) was added. The resultant mixture was stirred at
rt overnight. The solvent was removed under reduced pressure and
the residue dissolved in a mixture of MeOH (3 mL) and NaOH (aq. 1
mL, 1 M). The resultant mixture was stirred at rt for 90 min before
the MeOH was removed on a vacuum centrifuge. The crude product was
extracted with DCM and concentrated under reduced pressure. To the
residue was DMSO (1 mL), DCM (3 mL) and KOH (1M solution, 3 mL)
added. The organic phase was filtered through a phase separator and
concentrated under reduced pressure. The residue was purified by
preparative HPLC. The product containing fractions was
concentrated, water (5 mL) and DCM (5 mL) was added and the pH was
adjusted to 12 using KOH (1M solution). The organic layer was
filtered through a phase separator and the solvent was removed
under reduced pressure to give the title compound (48 mg, 27%).
Mixture of rotamers: (600 MHz, DMSO-d6) .delta. 0.69-0.78,
0.85-0.93, 0.94-1.06, 1.08-1.50, 2.19-2.28, 2.32-2.41, 2.44-2.56,
2.56-2.65, 2.66-2.76, 3.27-3.38, 3.43-3.55, 4.03-4.20, 4.44-4.52,
5.17-5.26, 6.97-7.21. Total no of protons: 28. HRMS (M+H).sup.+:
calculated 305.2229; found 305.2214.
Example 24
(S)-4-Fluoro-N-(1-(4-hydroxypiperidin-1-yl)-3-methylbutan-2-yl)-N,3-dimeth-
ylbenzamide
##STR00039##
[0781] Piperidin-4-ol (0.048 g, 0.48 mmol) and acetic acid (0.032
mL, 0.56 mmol) was added to
(S)-4-fluoro-N,3-dimethyl-N-(3-methyl-1-oxobutan-2-yl)benzamide
(Compound A2.1) (0.1 g, 0.40 mmol) in DCM (3 mL). The resultant
mixture was stirred at rt for 30 min before sodium
triacetoxyhydroborate (0.101 g, 0.48 mmol) was added. The stirring
was continued at rt for 3 h. NaOH (1 N aq.) was added to the
mixture. The organic phase was filtered through a phase separator
and concentrated under reduced pressure. The residue was purified
by preparative HPLC. The product containing fractions was
concentrated and the residue was purified a second time by
preparative HPLC using Chiralpak AD 5 .mu.m 20.times.250 mm column
and Heptan/EtOH/TEA 80/20/0.1, as mobile phase to give the title
compound (29 mg, 22%). Enantiomeric excess: 99.9%. Mixture of
rotamers: (600 MHz, CD.sub.3OD) .delta. 0.82-1.08, 1.43-1.63,
1.71-2.06, 2.12-2.51, 2.54-2.81, 2.89, 2.97-3.09, 3.27-3.46,
3.51-3.65, 4.40-4.59, 7.06-7.14, 7.22-7.37. Total no of protons:
28. HRMS (M+H).sup.+: calculated 337.2291; found 337.2268.
Example 25
(R)-4-Fluoro-N-(1-(4-hydroxypiperidin-1-yl)-3-methylbutan-2-yl)-N,3-dimeth-
ylbenzamide
##STR00040##
[0783] The slower eluting compound in Example 24 was collected and
evaporated to yield the title compound (1.5 mg, 1.5%). Enantiomeric
excess: 92.3%. Mixture of rotamers: (600 MHz, CD.sub.3OD) Mixture
of rotamers: .sup.1H NMR (600 MHz, CD.sub.3OD) .delta. 0.82-1.06,
1.44-1.63, 1.71-2.05, 2.11-2.49, 2.54-2.79, 2.89, 2.98-3.07,
3.25-3.43, 3.51-3.64, 4.42-4.56, 7.07-7.14, 7.21-7.38. Total no of
protons: 28. HRMS (M+H).sup.+: calculated 337.2291; found
337.2290.
Example 26
(S)-N-(1-(4-Cyanopiperidin-1-yl)-3-methylbutan-2-yl)-4-fluoro-N,3-dimethyl-
benzamide
##STR00041##
[0785] TEA (0.552 mL, 3.98 mmol) was added to a mixture of
piperidine-4-carbonitrile (0.132 g, 1.19 mmol) in EtOH (2 mL) and
DCM (3 mL). To the mixture was added
(S)-4-fluoro-N,3-dimethyl-N-(3-methyl-1-oxobutan-2-yl)benzamide
(Compound A2.1) (0.2 g, 0.80 mmol). The resultant mixture was
stirred at rt for 15 min before sodium triacetoxyhydroborate (0.337
g, 1.59 mmol) was added. The stirring was continued at rt over
night. Sodium tetrahydroborate (0.015 g, 0.40 mmol) was added and
the mixture was stirred for 1 h. The solvents were removed on a
vacuum centrifuge. The residue was diluted with DCM and washed with
NaOH (aq., 1M). The organic phase was filtered through a phase
separator and concentrated under reduced pressure. The residue was
purified by preparative HPLC. The product containing fractions was
concentrated and the residue was purified a second time by
preparative HPLC using Chiralpak IC 5 .mu.m 20.times.250 mm column
and Heptan/EtOH/TEA 60/40/0.1, as mobile phase to give the title
compound (11 mg, 4%). Enantiomeric excess: 98.2%. Mixture of
rotamers: (400 MHz, CD.sub.3OD) .delta. 0.85-1.08, 1.69-2.02,
2.12-2.96, 3.37-3.50, 4.41-4.59, 7.07-7.16, 7.19-7.36. Total no of
protons: 28. HRMS (M+H).sup.+: calculated 346.2295; found
346.2289.
Example 27
(S)-4-Chloro-N-(1-(4-hydroxypiperidin-1-yl)-3-methylbutan-2-yl)-N-methylbe-
nzamide
##STR00042##
[0787] (S)-4-Chloro-N-methyl-N-(3-methyl-1-oxobutan-2-yl)benzamide
(Compound A2.2) (0.12 g, 0.47 mmol) dissolved in DCM was added to
piperidin-4-ol (72 mg, 0.71 mmol) and acetic acid (0.135 mL, 2.36
mmol) in MeOH (2 mL). Sodium cyanotrihydroborate (0.059 g, 0.95
mmol) was added and the resultant mixture was stirred at rt over
night. The solvent was removed and the residue diluted with DCM.
The organic phase was washed with LiOH (aq., 3 mL, 1M), filtered
through a phase separator and concentrated under reduced pressure.
The residue was purified by preparative HPLC. The product
containing fractions was concentrated and the residue was purified
a second time by preparative HPLC using Chiralpak IC 5 .mu.m
20.times.250 mm column and Heptan/EtOH/TEA 60/40/0.1, as mobile
phase to give the title compound (4 mg, 2.5%). Enantiomeric excess:
99.8%. Mixture of rotamers: (600 MHz, CD.sub.3OD) .delta. 0.87,
0.92, 0.96, 1.03, 1.42-1.62, 1.71-1.90, 1.92-2.03, 2.14-2.21,
2.26-2.38, 2.42-2.50, 2.55-2.79, 2.88-2.93, 3.01, 3.28-3.38,
3.52-3.64, 4.43-4.56, 7.37-7.41, 7.43-7.52. Total no of protons:
26. HRMS (M+H).sup.+: calculated, 339.1839; found 339.1807.
Example 28
(S)-3,4-Difluoro-N-(1-(3-(methoxymethyl)azetidin-1-yl)-3-methylbutan-2-yl)-
-N-methylbenzamide
##STR00043##
[0789]
(S)-3,4-Difluoro-N-methyl-N-(3-methyl-1-oxobutan-2-yl)benzamide
(Compound A2.3) (0.25 g, 0.98 mmol) in MeOH (1.5 mL) was added to
3-(methoxymethyl)azetidine hydrochloride (0.202 g, 1.47 mmol) and
TEA (0.679 mL, 4.90 mmol) in MeOH (1.5 mL). Sodium
cyanotrihydroborate (0.103 mL, 1.96 mmol) was added and the
resultant mixture was stirred at rt over night. The solvent was
removed and the residue diluted with DCM. The organic phase was
washed with LiOH (aq., 3 mL, 1M), filtered through a phase
separator and concentrated under reduced pressure. The residue was
purified by preparative HPLC. The product containing fractions was
concentrated and the residue was purified a second time by
preparative HPLC using Chiralpak AD 5 .mu.m 20.times.250 mm column
and Heptan/EtOH/TEA 80/20/0.1, as mobile phase to give the title
compound (69 mg, 21%). Enantiomeric excess: 99.9%. Mixture of
rotamers: (400 MHz, CD.sub.3OD) .delta. 0.77-0.86, 0.93, 1.06,
1.70-1.90, 2.57-2.88, 2.94-3.09, 3.22-3.36, 3.40-3.57, 4.18-4.36,
7.23-7.52, 7.63-7.74. Total no of protons: 26. HRMS (M+H).sup.+:
calculated 341.2040; found 341.2051.
Example 29.1
3,4-Difluoro-N-((2S,3S)-1-(3-hydroxyazetidin-1-yl)-3-methylpentan-2-yl)-N--
methylbenzamide
##STR00044##
[0791] DIPEA (0.224 mL, 1.29 mmol) was added to 3,4-difluorobenzoic
acid (0.068 g, 0.43 mmol) and TBTU (0.138 g, 0.43 mmol) in DCM (2
mL). The mixture was stirred at rt for 30 min.
1-((2S,3S)-3-Methyl-2-(methylamino)pentyl)azetidin-3-ol (Compound
G2.1) (0.1 g, 0.43 mmol) in DCM (1 mL) was added and the resultant
mixture was stirred at rt overnight. The mixture was washed with
NaHCO.sub.3, filtered through a phase separator and concentrated
under reduced pressure. The residue was purified by preparative
HPLC to give the title compound (95 mg, 68%). Mixture of rotamers:
.sup.1H NMR (600 MHz, DMSO-d6) .delta. 0.61-0.74, 0.75-0.92,
0.97-1.09, 1.20-1.63, 2.33-2.45, 2.48-2.83, 3.11-3.23, 3.32-3.38,
3.39-3.53, 4.04-4.23, 5.14-5.31, 7.10-7.22, 7.28-7.41, 7.42-7.56,
7.56-7.70. Total number of protons: 24. HRMS (M+H).sup.+:
calculated 327.1884; found 327.1878. The compounds according to
Examples 29.2-29.9 were prepared, from appropriate intermediates,
by analogy with the method described for Example 29.1
hereinbefore.
TABLE-US-00034 Example Name Yield 29.2
4-Chloro-N-((2S,3S)-1-(3-hydroxyazetidin-1-yl)-3- 105 mg,
methylpentan-2-yl)-N-methylbenzamide 75% .sup.1H NMR Mixture of
rotamers: .sup.1H NMR (600 MHz, DMSO-d6) .delta. 0.60-0.76, 0.76-
and 0.93, 0.97-1.09, 1.24-1.47, 1.49-1.62, 2.32-2.43, 2.49-2.78,
3.09-3.19, HRMS 3.37-3.54, 4.02-4.26, 5.15-5.27, 7.26-7.34,
7.41-7.54. Total number of protons: 25. HRMS (M + H).sup.+:
calculated 325.1683; found 325.1673 29.3
4-Ethyl-N-((2S,3S)-1-(3-hydroxyazetidin-1-yl)-3-methylpentan- 98
mg, 2-yl)-N-methylbenzamide 71% .sup.1H NMR Mixture of rotamers:
.sup.1H NMR (600 MHz, DMSO-d6) .delta. 0.63-0.76, 0.78- and 0.85,
0.85-0.92, 0.96-1.08, 1.12-1.19, 1.25-1.45, 1.47-1.62, 2.32-2.53,
HRMS 2.54-2.76, 3.21-3.29, 3.39-3.53, 4.06-4.26, 5.12-5.26,
7.15-7.28, 7.29- 7.38. Total number of protons: 30. HRMS (M +
H).sup.+: calculated 319.2386; found 3 19.2372 29.4
N-((2S,3S)-1-(3-Hydroxyazetidin-1-yl)-3-methylpentan-2-yl)-N- 103
mg, methylbenzamide 83% .sup.1H NMR Mixture of rotamers: .sup.1H
NMR (600 MHz, DMSO-d6) .delta. 0.62-0.79, 0.80- and 0.86,
0.85-0.92, 0.99-1.08, 1.25-1.46, 1.51-1.62, 2.33-2.53, 2.56-2.77,
HRMS 3.14-3.24, 3.38-3.55, 4.06-4.28, 5.14-5.25, 7.21-7.29,
7.32-7.47. Total number of protons: 26. HRMS (M + H).sup.+:
calculated 291.2072; found 291.2072 29.5
4-Cyano-N-((2S,3S)-1-(3-hydroxyazetidin-1-yl)-3-methylpentan- 66
mg, 2-yl)-N-methylbenzamide 49% .sup.1H NMR Mixture of rotamers:
.sup.1H NMR (600 MHz, DMSO-d6) .delta. 0.62-0.77, 0.79- and 0.93,
0.97-1.09, 1.26-1.48, 1.51-1.62, 2.33-2.60, 2.61-2.78, 2.98-3.07,
HRMS 2.97-3.09, 3.22-3.29, 3.38-3.53, 4.07-4.26, 5.16-5.27,
7.41-7.50, 7.55- 7.63, 7.80-7.95. Total number of protons: 25. HRMS
(M + H).sup.+: calculated 316.2025; found 316.2022 29.6
N-((2S,3S)-1-(3-Hydroxyazetidin-1-yl)-3-methylpentan-2-yl)-4- 99
mg, methoxy-N-methylbenzamide 72% .sup.1H NMR Mixture of rotamers:
.sup.1H NMR (600 MHz, DMSO-d6) .delta. 0.62-0.75, 0.76- and 0.91,
0.97-1.07, 1.24-1.46, 1.49-1.60, 2.33-2.44, 2.49-2.55, 2.56-2.77,
HRMS 3.20-3.38, 3.39-3.53, 3.70-3.79, 4.05-4.26, 5.13-5.25,
6.87-7.01, 7.19- 7.30, 7.39-7.50. Total number of protons: 28. HRMS
(M + H).sup.+: calculated 321.2178; found 321.2172 29.7
4-Cyano-2-fluoro-N-((2S,3S)-1-(3-hydroxyazetidin-1-yl)-3- 38 mg,
methylpentan-2-yl)-N-methylbenzamide 26% .sup.1H NMR Mixture of
rotamers: .sup.1H NMR (600 MHz, DMSO-d6) .delta. 0.63-0.85, 0.85-
and 0.92, 0.93-1.09, 1.13-1.67, 2.25-2.44, 2.48-2.60, 2.60-2.79,
2.82-2.94, HRMS 3.37-3.54, 4.00-4.29, 5.09-5.31, 7.38-7.52,
7.65-7.80, 7.84-8.01. Total number of protons: 24. HRMS (M +
H).sup.+: calculated 334.1931; found 334.1949 29.8
N-((2S,3S)-1-(3-Hydroxyazetidin-1-yl)-3-methylpentan-2-yl)-2- 66
mg, methoxy-N,5-dimethylbenzamide 46% .sup.1H NMR Mixture of
rotamers: .sup.1H NMR (600 MHz, DMSO-d6) .delta. 0.62-0.90, 0.92-
and 1.08, 1.23-1.42, 1.43-1.67, 1.98-2.25, 2.26-2.80, 2.88-3.02,
3.09-3.26, HRMS 3.33-3.58, 3.59-3.77, 3.98-4.19, 4.19-4.33,
5.11-5.25, 6.74-6.95, 7.01- 7.19. Total number of protons: 30. HRMS
(M + H).sup.+: calculated 335.2335; found 335.2311 29.9
5-Chloro-N-((2S,3S)-1-(3-hydroxyazetidin-1-yl)-3- 110 mg,
methylpentan-2-yl)-2-methoxy-N-methylbenzamide 72% .sup.1H NMR
Mixture of rotamers: .sup.1H NMR (600 MHz, DMSO-d6) .delta.
0.63-0.92, 0.94- and 1.09, 1.25-1.68, 2.25-2.81, 2.88, 3.11-3.27,
3.37-3.57, 3.64-3.84, 3.99- HRMS 4.18, 4.17-4.30, 5.14-5.29,
6.97-7.12, 7.29-7.45. Total number of protons: 27. HRMS (M +
H).sup.+: calculated 355.1788; found 355.1789
Example 30
4-Chloro-N-((2R,3R)-1-(3-hydroxyazetidin-1-yl)-3-methoxybutan-2-yl)-N-meth-
ylbenzamide
##STR00045##
[0793] To 4-chlorobenzoic acid (65.7 mg, 0.42 mmol) and DIPEA
(0.365 mL, 2.10 mmol) in DCM (0.7 mL) was TBTU (148 mg, 0.46 mmol)
added 1-((2R,3R)-3-Methoxy-2-(methylamino)butyl)azetidin-3-ol
(Compound B2.2) (79 mg, 0.42 mmol) in DCM (0.7 mL) was added and
the resultant mixture stirred at rt for 2 h. NaHCO.sub.3 was added
and the stirring continued for 30 min. The layers were separated
and the organic phase concentrated under reduced pressure. The
residue was dissolved in THF/MeOH/water (3:1:1) and a small amount
of NaOH (3.8M) was added. The resultant mixture was stirred for 30
min. The mixture was diluted with water and the organic solvent was
removed. The water layer was extracted with DCM. The combined
organic layers were filtered through a phase separator and
concentrated. The residue was purified by preparative HPLC to give
the title compound (39 mg, 28%). Mixture of rotamers: .sup.1H NMR
(600 MHz, DMSO-d6) .delta. 0.92, 1.08, 2.34-2.40, 2.52-2.59, 2.63,
2.69, 2.70-2.76, 2.77, 3.18-3.23, 3.34-3.39, 3.44-3.48, 3.48-3.54,
4.04-4.10, 4.11-4.16, 4.40, 5.16-5.24, 7.31, 7.40, 7.43-7.50. Total
of protons in spectrum: 22. Ratio major:minor: 3:2. HRMS
(M+H).sup.+: calculated 327.1475; found 327.1476.
Example 31.1
(S)-4-Chloro-N-(1-(3-ethoxyazetidin-1-yl)pentan-2-yl)-N-methylbenzamide
##STR00046##
[0795] To
(S)-4-chloro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N-methylb-
enzamide (Example 8.2 A) (85 mg, 0.27 mmol) in dry THF (3 mL) was
NaH (60% in mineral oil) (16.41 mg, 0.41 mmol) added carefully. The
mixture was stirred at rt for 30 minutes then iodoethane (0.023 mL,
0.29 mmol) was added in one portion. The mixture was left standing
at rt on. NaHCO.sub.3 and DCM were added and the two layers were
separated using a phase separator. The organic phase was
concentrated and the residue was purified by preparative HPLC to
give the title compound (36 mg, 39%). Mixture of rotamers: .sup.1H
NMR (600 MHz, DMSO-d6) .delta. 0.71, 0.86, 0.93-1.08, 1.08-1.32,
1.33-1.49, 2.36, 2.49-2.53, 2.54-2.61, 2.66, 2.70, 2.72-2.80,
3.19-3.32, 3.48, 3.96, 7.32, 7.38, 7.47. HRMS (M+H).sup.+:
calculated 339.1839; found 339.1840.
[0796] The compounds according to Example 31.2-31.4 were prepared,
from appropriate intermediates, by analogy with the method
described for Example 31.1 hereinbefore.
TABLE-US-00035 Example Name Yield 31.2
(S)-4-Chloro-N-(1-(3-methoxyazetidin-1-yl)pentan-2-yl)-N- 15 mg,
methylbenzamide 14% .sup.1H NMR Mixture of rotamers: .sup.1H NMR
(600 MHz, DMSO-d6) .delta. 0.71-0.77, 0.86- and 0.92, 0.96-1.06,
1.10-1.50, 2.35-2.43, 2.46-2.63, 2.68-2.75, 2.77- HRMS 2.83,
3.10-3.14, 3.28-3.42, 3.46-3.52, 3.86-3.96, 4.45-4.52, 7.33- 7.36,
7.39-7.42, 7.47-7.51. Total no of protons: 25 HRMS (M + H).sup.+:
calculated 325.1683; found 325.1674 31.3
4-chloro-N-{(2S)-1-[3-(cyanomethoxy)azetidin-1-yl]pentan-2- 34.2
mg, yl}-N-methylbenzamide 30.4% .sup.1H NMR .sup.1H NMR (400 MHz,
DMSO) .delta. 0.59 (t, 1H), 0.74 (t, 1H), 0.80-1.43 (m, and 3H),
2.20-2.56 (m, 10H), 2.58 (s, 1H), 2.63-2.83 (m, 1H), 3.13-3.33 (m,
HRMS 3H), 3.40 (q, 1H), 3.96-4.13 (m, 1H), 4.29 (dd, 1H), 7.16-7.31
(m, 1H), 7.35 (d, 1H). HRMS (M + H).sup.+: calculated 350.164;
found 350.1645. 31.4
4-chloro-N-methyl-N-{(2S)-1-[3-(propan-2-yloxy)azetidin-1- (12 mg,
yl]pentan-2-yl}benzamide 10%) .sup.1H NMR Mixture of rotamers:
.sup.1H NMR (600 MHz, DMSO-d6) .delta. 0.72, 0.87, 0.94- and 1.07,
1.07-1.33, 1.33-1.48, 2.30-2.43, 2.53-2.67, 2.67-2.79, 3.36, HRMS
3.50, 3.91-4.09, 7.32, 7.39, 7.47. Total of protons in spectrum:
29. HRMS (M + H).sup.+: calculated 353.1996; found 353.2004.
Example 32.1
(R)- and
(S)-N-(1-Cyclopentyl-2-(3-hydroxyazetidin-1-yl)ethyl)-3,4-difluor-
o-N-methylbenzamide
##STR00047##
[0798] TBTU (0.534 g, 1.66 mmol) was added to
1-(2-cyclopentyl-2-(methylamino)ethyl)azetidin-3-ol dihydrochloride
(dihydrochloride of Compound L2.1) (0.22 g, 0.81 mmol),
3,4-difluorobenzoic acid (0.283 g, 1.79 mmol) and DIPEA (2.5 mL,
14.31 mmol) in DCM (20 mL) at rt. The mixture was stirred for 3 h.
The mixture was concentrated under reduced pressure. To the residue
was added KOH (6 mL, 6.00 mmol), water (6 mL) and MeOH (20 mL). The
resultant mixture was stirred at rt for 5 min. Part of the solvent
was removed and the remaining mixture was diluted with water and
extracted with DCM. The combined DCM layers were washed with brine,
KHSO.sub.4 (0.1M) and NaHCO.sub.3 (saturated), dried (MgSO.sub.4)
and concentrated under reduce pressure. The residue was purified by
preparative HPLC. The product containing fractions were
concentrated in vacuo. The enantiomers were separated by chiral
preparative HPLC using Chiralpak AD 5 .mu.m 20.times.250 mm column
and Heptan/EtOH/TEA 80/20/0.1, as mobile phase. The enantiomers are
given in order of elution:
[0799] Isomer 1: (90 mg, 33%), ee: 99.9%. Mixture of rotamers: (600
MHz, CDCl.sub.3) .delta. 0.74-1.98, 2.33-2.61, 2.60-3.02,
3.25-3.90, 4.20-4.53, 6.98-7.22, 7.22-7.39, 7.55. Total no of
protons: 24. HRMS (M+H).sup.+: calculated 339.1884; found
339.1901.
[0800] Isomer 2: (90 mg, 33%), ee: 98.8%. Mixture of rotamers: (600
MHz, CDCl.sub.3) .delta. 0.73-2.05, 2.31-3.02, 3.05-3.80,
4.10-4.69, 6.99-7.23, 7.22-7.44, 7.55. Total no of protons: 24.
HRMS (M+H).sup.+: calculated 339.1884; found 339.1862.
[0801] The compounds according to Examples 32.2-32.7 were prepared,
from appropriate intermediates, by analogy with the method
described for Example 32.1 hereinbefore.
TABLE-US-00036 Example Name Yield/ee 32.2 (R)- and
(S)-N-[1-cyclopentyl-2-(3- Isomer 1: 35.6 mg, 99.9% ee
hydroxyazetidin-1-yl)ethyl]-4-methoxy-N- Isomer 2: 35.7 mg, 99.9%
ee methylbenzamide .sup.1H NMR Isomer 1: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 0.70-1.03, 1.05-2.01, 2.28- and 2.88,
3.28-3.63, 3.69, 4.09-4.52, 6.76, 7.22, 7.41. HRMS (M + H).sup.+:
HRMS calculated 333.2178; found 333.218. Isomer 2: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 0.73-1.04, 1.05-2.08, 2.26- 2.90,
3.27-3.61, 3.69, 4.25, 6.75, 7.22, 7.41. HRMS (M + H).sup.+:
calculated 333.2178; found 333.2187. 32.3 (R)- and
(S)-4-chloro-N-[1-cyclopentyl-2- Isomer 1: 29.2 mg, 99.9%
(3-hydroxyazetidin-1-yl)ethyl]-N- Isomer 2: 31.5 mg, 99.9% ee
methylbenzamide .sup.1H NMR Isomer 1: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 0.68-0.86, 0.86-1.01, 1.05- and 1.91,
1.92-2.27, 2.30-2.49, 2.51-2.90, 3.25, 3.35, 3.45-3.62, 4.08- HRMS
4.51, 7.16-7.31, 7.39. HRMS (M + H).sup.+: calculated 337.1683;
found 337.1684. Isomer 2: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
0.69-0.85, 0.86-1.02, 1.03- 1.92, 2.26-2.51, 2.51-2.89, 3.14-3.42,
3.43-3.65, 4.05-4.55, 7.16- 7.28, 7.39. HRMS (M + H).sup.+:
calculated 337.1683; found 337.1679. 32.4 (R)- and
(S)-N-[1-cyclopentyl-2-(3- Isomer 1: 29.9 mg, >99.9% ee
hydroxyazetidin-1-yl)ethyl]-4-fluoro-N,3- Isomer 2: 32.2 mg, 97.7%
ee dimethylbenzamide .sup.1H NMR Isomer 1: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 0.63-1.91, 2.16, 2.24-2.88, and 3.18-3.40,
3.41-3.66, 4.09-4.51, 6.87, 6.97-7.11, 7.20-7.32. HRMS HRMS (M +
H).sup.+: calculated 335.2135; found 335.2147. Isomer 2: .sup.1H
NMR (400 MHz, CDCl3) .delta. 0.57-2.01, 2.15, 2.24-2.90, 3.30,
3.42-3.64, 4.04-4.51, 6.86, 7.00-7.11, 7.26. HRMS (M + H).sup.+:
calculated 335.2135; found 335.2141. 32.5 (R)- and
(S)-4-cyano-N-[1-cyclopentyl-2- Isomer 1: 19.5 mg, >99.9% ee
(3-hydroxyazetidin-1-yl)ethyl]-N- Isomer 2: 20.1 mg, 99.2% ee
methylbenzamide .sup.1H NMR Isomer 1: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 0.67-0.97, 0.97-1.93, 2.22- and 2.51,
2.51-2.92, 3.11, 3.26-3.39, 3.44-3.66, 4.12-4.42, 7.27-7.46, HRMS
7.56. HRMS (M + H).sup.+: calculated 328.2025; found 328.2026.
Isomer 2: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.65-0.99,
1.05-1.92, 2.25- 2.50, 2.53-2.68, 2.69-2.92, 3.12, 3.33, 3.46-3.65,
4.18-4.42, 7.13, 7.37, 7.51-7.63. HRMS (M + H).sup.+: calculated
328.2025; found 328.2018. 32.6 (R)- and
(S)-2-chloro-N-[1-cyclopentyl-2- Isomer 1: 14 mg, 98% ee
(3-hydroxyazetidin-1-yl)ethyl]-4-fluoro-N- Isomer 2: 14 mg, 99.4%
ee methylbenzamide .sup.1H NMR Isomer 1:.sub.--.sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 0.60-2.28 (m), 2.28-3.26 (m), and
3.29-3.68 (m), 4.06-4.57 (m), 6.81-7.24 (m), 7.55-7.70 (m). HRMS
HRMS (M + H).sup.+: calculated 355.1588; found 355.1604 Isomer 2:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.63-2.02 (m), 2.03-3.25
(m), 3.30-3.84 (m), 3.98-4.65 (m), 6.76-7.26 (m), 7.58-7.69 (m)
HRMS (M + H).sup.+: calculated 355.1588; found 355.1588 32.7 (R)-
and (S)-3-chloro-N-[1-cyclopentyl-2-(3- 37.5 mg, >99.9% ee
hydroxyazetidin-1-yl)ethyl]-4-fluoro-N- 28.1 mg, 97.6% ee
methylbenzamide .sup.1H NMR Isomer 1: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 0.71-1.00, 1.03-1.95, 2.00- and 2.89, 3.22,
3.39, 3.46-3.66, 4.10-4.44, 6.93-7.10, 7.10-7.22, 7.26- HRMS 7.45,
7.66. HRMS (M + H).sup.+: calculated 355.1588; found 355.1592
Isomer 2: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.71-0.98,
1.02-1.94, 2.39, 2.54-2.89, 3.22, 3.39, 3.48-3.69, 4.27, 6.88-7.09,
7.10-7.23, 7.25- 7.44, 7.66. HRMS (M + H).sup.+: calculated
355.1588; found 355.1594
Example 33.1
(S)-4-chloro-N-(1-(3-hydroxyazetidin-1-yl)hexan-2-yl)-N-methylbenzamide
##STR00048##
[0803] DIPEA (0.275 mL, 1.58 mmol) was added to a stirred
suspension of 4-chlorobenzoic acid (0.082 g, 0.53 mmol) and TBTU
(0.169 g, 0.53 mmol) in DCM (1 mL) at rt. The suspension was
stirred for 5 min. A solution of
(S)-1-(2-(methylamino)hexyl)azetidin-3-ol (Compound G2.2) (0.11 g,
0.53 mmol) in DCM (1 mL) was added and the reaction was stirred at
rt overnight. The reaction mixture was washed with an 8% aq. sol.
of NaHCO.sub.3 (2 mL). The organic layer was dried through a phase
separator and the solvent was removed in vacuo. Purification by
preparative HPLC afforded the title compound (51 mg, 30%). Mixture
of rotamers: .sup.1H NMR (600 MHz, DMSO-d6) .delta. 0.75-0.80,
0.82-0.87, 0.91-0.99, 1.02-1.46, 2.31-2.39, 2.44-2.62, 2.65-2.73,
3.16-3.53, 3.99-4.17, 4.36-4.48, 5.23, 7.30-7.33, 7.35-7.39,
7.45-7.49. Total number of protons in spectrum: 25. HRMS
(M+H).sup.+: calculated 325.1683; found 325.169
[0804] The compounds according to Examples 33.2-33.10 were
prepared, from appropriate intermediates, by analogy with the
method described for Example 33.1 hereinbefore.
TABLE-US-00037 Example Name Yield 33.2
3,4-Difluoro-N-[(2S)-1-(3-hydroxyazetidin-1-yl)hexan-2-yl]-N- 75
mg, methylbenzamide 44% .sup.1H NMR Mixture of rotamers: 1H NMR
(600 MHz, DMSO-d6) .delta. 0.74-0.88, 0.90- and 1.51, 2.30-2.42,
2.45-2.76, 3.19-3.53, 4.03-4.18, 4.34-4.45, 5.17- HRMS 5.30,
7.11-7.28, 7.32-7.54. HRMS (M + H).sup.+: calculated 327.1884;
found 327.1885 33.3
4-Cyano-2-fluoro-N-[(2S)-1-(3-hydroxyazetidin-1-yl)hexan-2- 93 mg,
yl]-N-methylbenzamide 53% .sup.1H NMR Mixture of rotamers: 1H NMR
(600 MHz, DMSO-d6) .delta. 0.74-0.88, 0.93- and 1.52, 2.32-2.79,
3.00-3.60, 3.99-4.17, 4.41-4.51, 5.19-5.31, 7.42- HRMS 8.00. HRMS
(M + H).sup.+: calculated 334.1931; found 334.1928 33.4
4-Cyano-N-[(2S)-1-(3-hydroxyazetidin-1-yl)hexan-2-yl]-N- 78 mg,
methylbenzamide 47% .sup.1H NMR Mixture of rotamers: .sup.1H NMR
(600 MHz, DMSO-d6) .delta. 0.76-0.87, 0.90- and 1.47, 2.30-2.39,
2.44-2.79, 3.18-3.54, 4.03-4.17, 4.39-4.48, 5.23, 7.42- HRMS 7.56,
7.84-7.94. HRMS (M + H).sup.+: calculated 316.2025; found 316.2025
33.5 N-[(2S)-1-(3-Hydroxyazetidin-1-yl)hexan-2-yl]-N- 68 mg,
methylbenzamide 45% .sup.1H NMR Mixture of rotamers: .sup.1H NMR
(600 MHz, DMSO-d6) .delta. 0.72-0.88, 0.91- and 1.47, 2.32-2.74,
3.19-3.53, 4.02-4.17, 4.41-4.50, 5.16-5.25, 7.23- HRMS 7.46. HRMS
(M + H).sup.+: calculated 291.2072; found 291.2075 33.6
4-Hydroxy-N-[(2S)-1-(3-hydroxyazetidin-1-yl)hexan-2-yl]-N- 39 mg,
methylbenzamide 24% .sup.1H NMR Mixture of rotamers: .sup.1H NMR
(600 MHz, DMSO-d6) .delta. 0.70-1.55, 2.13- and 2.79, 3.09-3.63,
4.00-4.17, 4.33-4.45, 5.11-5.35, 6.68-6.79, 7.11-7.23. HRMS HRMS (M
+ H).sup.+: calculated 307.2021; found 307.2027 33.7
4-Fluoro-N-[(2S)-1-(3-hydroxyazetidin-1-yl)hexan-2-yl]-N- 77 mg,
methylbenzamide 47.5% .sup.1H NMR Mixture of rotamers: .sup.1H NMR
(600 MHz, DMSO-d6) .delta. 0.73-0.87, 0.90- and 0.99, 1.02-1.47,
2.31-2.73, 3.20-3.54, 4.03-4.17, 4.38-4.48, 5.22, 7.12- HRMS 7.27,
7.32-7.45. HRMS (M + H).sup.+: calculated 309.1978; found 309.1980
33.8 3-Chloro-4-fluoro-N-[(2S)-1-(3-hydroxyazetidin-1-yl)hexan-2-
82 mg, yl]-N-methylbenzamide 45.5% .sup.1H NMR Mixture of rotamers:
.sup.1H NMR (600 MHz, DMSO-d6) .delta. 0.73-0.88, 0.90- and 0.99,
1.02-1.48, 2.30-2.40, 2.44-2.75, 3.21-3.52, 4.05-4.17, 4.34-4.44,
HRMS 5.19-5.29, 7.30-7.35, 7.37-7.41, 7.43-7.49, 7.50-7.54,
7.61-7.65. HRMS (M + H).sup.+: calculated 343.1588; found 343.1592
33.9 2,5-Difluoro-N-[(2S)-1-(3-hydroxyazetidin-1-yl)hexan-2-yl]-N-
76 mg, methylbenzamide 44% .sup.1H NMR Mixture of rotamers: .sup.1H
NMR (600 MHz, DMSO-d6) .delta. 0.72-0.86, 0.93- and 1.62,
2.30-2.82, 3.33, 4.01-4.17, 4.38-4.48, 5.17-5.30, 7.10-7.40. HRMS
HRMS (M + H).sup.+: calculated 327.1884; found 327.1882 33.10
3-(Difluoromethyl)-N-[(2S)-1-(3-hydroxyazetidin-1-yl)hexan-2- 92
mg, yl]-N-methylbenzamide 51% .sup.1H NMR Mixture of rotamers:
.sup.1H NMR (600 MHz, DMSO-d6) .delta. 0.73-0.89, 0.92- and 1.01,
1.03-1.48, 2.29-2.41, 2.42-2.64, 2.65-2.77, 3.18-3.37, 3.44-3.54,
HRMS 4.03-4.17, 4.40-4.52, 5.18-5.26, 6.93-6.98, 7.01-7.09,
7.11-7.18, 7.43- 7.65. HRMS (M + H).sup.+: calculated 341.204;
found 341.2037
Example 34.1
4-Chloro-N-[(2S)-1-(3-hydroxyazetidin-1-yl)pentan-2-yl]-N-(propan-2-yl)ben-
zamide
##STR00049##
[0806] To a mixture of 4-chlorobenzoic acid (0.067 g, 0.43 mmol)
and TBTU (0.137 g, 0.43 mmol) in DCM (2 mL) was added
N-ethyl-N-isopropylpropan-2-amine (0.222 mL, 1.28 mmol). The
suspension was stirred at rt for 30 min. A solution of
(S)-1-(2-(isopropylamino)pentyl)azetidin-3-ol (Compound O2.1)
(0.142 g, 0.43 mmol) in DCM (1 mL) was added and the reaction
mixture was stirred at rt overnight. The reaction was washed with
saturated NaHCO.sub.3 solution (2 ml). The organic phase was
concentrated using a vacuum centrifuge. The residue was dissolved
in MeOH (2 ml) and 1M NaOH(aq., 0.5 ml) was added. The mixture was
stirred at rt for 1.5 h. Acetic acid (110 mg) was added and the
mixture was concentrated. The residue was dissolved in DCM (3.5 ml)
and washed with saturated NaHCO.sub.3 solution (2 ml). The organic
phase was concentrated using a vacuum centrifuge and the residue
purified by preparative HPLC affording the title compound (20 mg,
14%). Mixture of rotamers: .sup.1H NMR (600 MHz, DMSO-d6) d
0.62-0.78, 0.76-0.93, 0.93-1.14, 1.14-1.54, 1.67-1.93, 2.24-2.40,
2.41-2.77, 2.76-2.97, 2.96-3.15, 3.16-3.45, 3.45-3.75, 3.96-4.20,
5.12-5.31, 7.17-7.35, 7.38-7.52. Number of protons: 27. HRMS
(M+H).sup.+: calculated 339.1839; found 339.1866
[0807] The compound according to Examples 34.2 was prepared, from
appropriate intermediates, by analogy with the method described for
Example 34.1 hereinbefore.
TABLE-US-00038 Example Name Yield 34.2
3,4-Difluoro-N-[(2S)-1-(3-hydroxyazetidin-1- 14 mg,
yl)pentan-2-yl]-N-(propan-2-yl)benzamide 10% .sup.1H NMR Mixture of
rotamers: .sup.1H NMR (600 MHz, DMSO-d6) .delta. 0.59- and 0.77,
0.80-0.92, 0.95-1.13, 1.13-1.53, 1.67-1.94, 2.30-2.39, HRMS
2.42-2.61, 2.61-2.76, 2.88, 2.99-3.16, 3.16-3.33, 3.36-3.75,
4.00-4.22, 5.12-5.31, 7.04-7.17, 7.30-7.56. Number of protons: 26.
HRMS (M + H).sup.+: calculated 341.2041; found 341.2041
Example 35.1
4-Chloro-N-[(1R)-1-cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]-N-methylben-
zamide
##STR00050##
[0809] DIPEA (0.275 mL, 1.57 mmol) was added to a suspension of
4-chlorobenzoic acid (82 mg, 0.52 mmol) and TBTU (168 mg, 0.52
mmol) in DCM (1 mL) at rt. The reaction mixture was stirred for 45
min before a solution of
(R)-1-(2-cyclobutyl-2-(methylamino)ethyl)azetidin-3-ol (Compound
G2.6) (184 mg, 0.52 mmol) in NMP (1.000 mL) was added. The reaction
mixture was stirred at rt over the weekend. The reaction mixture
was washed with NaHCO.sub.3 (8% aq. 2 mL). The organic layer was
passed through a phase separator and the solvent was removed in
vacuo. The residue was purified by preparative HPLC to give the
title compound (88 mg, 52%). .sup.1H NMR (600 MHz, DMSO-d6) .delta.
1.38-1.52, 1.55-1.62, 1.64-1.95, 2.00-2.06, 2.21-2.25, 2.27-2.33,
2.36-2.43, 2.55-2.62, 2.64-2.68, 2.70-2.72, 2.73-2.79, 3.23-3.26,
3.40-3.44, 3.54-3.57, 4.11-4.18, 4.43-4.51, 5.20-5.27, 7.29-7.35,
7.47-7.54. HRMS (M+H).sup.+: calculated 323.1526; found
323.1535
[0810] The compounds according to Examples 35.2-35.14 were
prepared, from appropriate intermediates, by analogy with the
method described for Example 35.1 hereinbefore.
TABLE-US-00039 Example Name Yield 35.2
4-Cyano-N-[(1R)-1-cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]- 73
mg, N-methylbenzamide 44% .sup.1H NMR .sup.1H NMR (600 MHz,
DMSO-d6) .delta. 1.35-1.63, 1.68-1.97, 2.00-2.07, 2.20- and 2.29,
2.36-2.49, 2.55-2.58, 2.64-2.71, 2.72-2.74, 3.17-3.28, 3.41- HRMS
3.54, 4.11. 4.17, 4.43-4.51, 5.21-5.26, 7.45-7.47, 7.60-7.63,
7.89-7.95. HRMS (M + H).sup.+: calculated 314.1868; found 314.1876
35.3 N-[(1R)-1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]-4- 80
mg, (difluoromethoxy)-N-methylbenzamide 43% .sup.1H NMR .sup.1H NMR
(600 MHz, DMSO-d6) .delta. 1.35-1.94, 1.99-2.04, 2.17-2.41, 2.55-
and 2.78, 3.16-3.26, 3.38-3.65, 4.08-4.15, 4.36-4.52, 5.19-5.27,
7.08-7.42, HRMS 7.49-7.52. HRMS (M + H).sup.+: calculated 355.1833;
found 355.1836 35.4
N-[(1R)-1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]-4-fluoro-
77.7 mg N,3-dimethylbenzamide 46% .sup.1H NMR .sup.1H NMR (600 MHz,
DMSO-d6) .delta. 1.34-1.59, 1.62-1.92, 1.98-2.04, 2.11- and 2.28,
2.31-2.43, 2.51-2.59, 2.64-2.75, 3.20-3.24, 3.35-3.41, 3.46-3.60,
HRMS 4.08-4.14, 4.40-4.50, 5.19-5.24, 7.07-7.23, 7.27-7.42. HRMS (M
+ H).sup.+: calculated 321.1978; found 321.1988 35.5
N-[(1R)-1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]-4-fluoro- 81
mg, N-methylbenzamide 50% .sup.1H NMR .sup.1H NMR (600 MHz,
DMSO-d6) .delta. 1.31-1.60, 1.65-2.05, 2.17-2.41, 2.51- and 2.75,
3.20-3.25, 3.36-3.50, 4.11, 4.44, 5.19, 7.19-7.35, 7.49. HRMS HRMS
(M + H).sup.+: calculated 307.1822; found 307.1829 35.6
2-Chloro-N-[(1R)-1-cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]- 30
mg, 4-fluoro-N-methylbenzamide 17% .sup.1H NMR .sup.1H NMR (600
MHz, DMSO-d6) .delta. 1.35-2.06, 2.20-2.42, 2.55-2.77, 2.99- and
3.24, 3.44-3.54, 3.55-3.74, 4.01-4.19, 4.38-4.56, 4.66, 5.16-5.28,
7.21- HRMS 7.43, 7.47-7.58, 7.60-7.63. HRMS (M + H).sup.+:
calculated 341.1432; found 341.1436 35.7
N-[(1R)-1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]-3,4- 2 mg,
difluoro-N-methylbenzamide 2.4% HRMS HRMS (M + H).sup.+: calculated
325.1728; found 325.1722 35.8
N-[(1R)-1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]-3- 2.8 mg,
(difluoromethyl)-N-methylbenzamide 3.5% HRMS HRMS (M + H).sup.+:
calculated 339.1884; found 339.1890 35.9
3-Cyano-N-[(1R)-1-cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]- 64
mg, 4-fluoro-N-methylbenzamide 37% .sup.1H NMR .sup.1H NMR (600
MHz, DMSO-d6) .delta. 1.37-1.46, 1.52-1.59, 1.61-2.04, 2.19- and
2.27, 2.31-2.46, 2.55-2.62, 2.63-2.77, 3.21-3.25, 3.41-3.52,
4.06-4.19, HRMS 4.37. 4.49, 5.16-5.30, 7.53-7.65, 7.66-7.73,
7.84-7.91, 8.04-8.10. HRMS (M + H).sup.+: calculated 332.1774;
found 332.1781 35.10
N-[(1R)-1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]-2,4- 73 mg,
difluoro-N-methylbenzamide 43% .sup.1H NMR .sup.1H NMR (600 MHz,
DMSO-d6) .delta. 1.35-2.09, 2.14-2.46, 2.61-2.73, 3.09- and 3.23,
3.35-3.51, 4.05-4.16, 4.36-4.56, 5.16-5.23, 7.11-7.20, 7.28-7.54.
HRMS HRMS (M + H).sup.+: calculated 325.1728; found 325.173 35.11
3-Chloro-N-[(1R)-1-cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]- 58
mg, 2-fluoro-N-methylbenzamide 33% .sup.1H NMR .sup.1H NMR (600
MHz, DMSO-d6) .delta. 1.43-2.04 (m), 2.16-2.38 (m), 2.61- and 2.77
(m), 3.07-3.22 (m), 3.44-3.67 (m), 4.04-4.16 (m), 4.35-4.56 (m),
HRMS 5.15-5.25 (m), 7.16-7.33 (m), 7.47-7.66 (m). HRMS (M +
H).sup.+: calculated 341.1432; found 341.1439 35.12
N-[(1R)-1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]-2-fluoro- 72
mg, 4-methoxy-N-methylbenzamide 41% .sup.1H NMR .sup.1H NMR (600
MHz, DMSO-d6) .delta. 1.33-2.02, 2.15-2.47, 2.56-2.71, 3.15- and
3.26, 3.37-3.42, 3.45-3.50, 3.70-3.81, 4.03-4.14, 4.38-4.54, 5.19,
6.65- HRMS 6.92, 7.11-7.20, 7.27-7.38. HRMS (M + H).sup.+:
calculated 337.1927; found 337.1928 35.13
N-[(1R)-1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]-3-fluoro- 89
mg, 4-methoxy-N-methylbenzamide 50% .sup.1H NMR .sup.1H NMR (600
MHz, DMSO-d6) .delta. 1.36-1.47, 1.51-1.59, 1.62-1.94, 1.97- and
2.05, 2.20-2.27, 2.30-2.44, 2.56-2.73, 3.39-3.53, 3.76-3.88,
4.09-4.14, HRMS 4.37-4.45, 5.16-5.26, 7.07-7.39. HRMS (M +
H).sup.+: calculated 337.1927; found 337.1935 35.14
N-[(1R)-1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl]-N- 68 mg,
methylbenzamide 45% .sup.1H NMR .sup.1H NMR (600 MHz, DMSO-d6)
.delta. 1.33-1.40, 1.47-1.61, 1.68-1.96, 2.00- and 2.06, 2.25,
2.33-2.41, 2.46, 2.58, 2.65, 2.67-2.75, 3.24, 3.40-3.44, 3.52, HRMS
4.10-4.16, 4.49, 5.23, 7.25-7.28, 7.40-7.46. HRMS (M + H).sup.+:
calculated 289.1916; found 289.1921
Example 36.1
4-cyano-N-[(1S)-1-cyclohexyl-2-(3-hydroxyazetidin-1-yl)ethyl]-N-methylbenz-
amide
##STR00051##
[0812] 4-cyanobenzoic acid (65.0 mg, 0.44 mmol) in DCM (2 mL) was
treated with DIPEA (0.231 mL, 1.32 mmol) and TBTU (142 mg, 0.44
mmol) and the suspension was stirred for 10 min. A 125 mg/mL
solution of (S)-1-(2-cyclohexyl-2-(methylamino)ethyl)azetidin-3-ol
(Compound G2.3) (125 mg, 0.44 mmol) in DCM (1 mL) was added and the
reaction was stirred at ambient temperature overnight. The reaction
was washed with 8% aq. sol. of NaHCO.sub.3 and concentrated. The
residue was dissolved in DMSO (0.4 mL) and filtered through a
syringe filter. The residue was purified by HPLC to give the title
compound (73.6 mg, 49%). Mixture of rotamers. .sup.1H NMR (600 MHz,
DMSO-d6) .delta. 0.53-0.70, 0.89-1.81, 2.43-2.59, 2.64-2.78, 3.03,
3.28-3.31, 3.43-3.54, 4.11-4.30, 5.23, 5.26, 7.48, 7.61, 7.87-7.94.
HRMS (M+H).sup.+: calculated 342.2181; found 342.2193
[0813] The compounds according to Examples 36.2-36.8 were prepared,
from appropriate intermediates, by analogy with the method
described for Example 36.1 hereinbefore
TABLE-US-00040 Example Name Yield 36.2
4-Chloro-N-[(1S)-1-cyclohexyl-2-(3-hydroxyazetidin-1-yl)ethyl]- 76
mg, N-methylbenzamide 49% .sup.1H NMR Mixture of rotamers: .sup.1H
NMR (600 MHz, DMSO-d6) .delta. 0.58-0.69, 0.90- and 1.05,
1.07-1.25, 1.33-1.81, 2.44-2.58, 2.61, 2.65, 2.69-2.76, 3.15, 3.42-
HRMS 3.48, 3.48-3.53, 4.11-4.29, 5.22, 5.25, 7.31-7.34, 7.45-7.51.
HRMS (M + H).sup.+: calculated 351.184; found 351.1856 36.3
3-Cyano-N-[(1S)-1-cyclohexyl-2-(3-hydroxyazetidin-1-yl)ethyl]- 76
mg, N-methylbenzamide 50% .sup.1H NMR Mixture of rotamers: .sup.1H
NMR (600 MHz, DMSO-d6) .delta. 0.56-0.66, 0.99, and 1.06-1.26,
1.35-1.82, 2.44-2.53, 2.54-2.60, 2.61, 2.64-2.72, 2.72-2.78, HRMS
3.05, 3.44-3.54, 4.11-4.32, 5.22, 5.29, 7.62-7.68, 7.75-7.80,
7.87-7.92, 7.93-7.96. HRMS (M + H).sup.+: calculated 342.218; found
342.2196 36.4
4-Cyano-N-[(1S)-1-cyclohexyl-2-(3-hydroxyazetidin-1-yl)ethyl]- 50
mg, 2-fluoro-N-methylbenzamide 31.5% .sup.1H NMR Mixture of
rotamers: .sup.1H NMR (600 MHz, DMSO-d6) .delta. 0.53-0.74, 0.86-
and 1.26, 1.35-1.80, 2.45-2.53, 2.57, 2.64-2.67, 2.74, 2.78,
2.84-2.90, 3.41- HRMS 3.54, 4.08-4.32, 5.24, 7.46-7.50, 7.72-7.80,
7.92-8.00. HRMS (M + H).sup.+: calculated 360.209; found 360.2105
36.5 4-(2-Cyanopropan-2-yl)-N-[(1S)-1-cyclohexyl-2-(3- 99.7 mg,
hydroxyazetidin-1-yl)ethyl]-N-methylbenzamide 59% .sup.1H NMR
Mixture of rotamers: .sup.1H NMR (600 MHz, DMSO-d6) .delta.
0.54-0.72, 0.91- and 1.06, 1.06-1.33, 1.30-1.68, 1.69-1.73,
1.75-1.82, 2.45-2.53, 2.58, 2.61- HRMS 2.63, 2.64-2.77, 3.19-3.25,
3.29-3.37, 3.44-3.49, 3.49-3.54, 4.11-4.32, 5.22, 5.25, 7.35-7.39,
7.50-7.53, 7.54-7.60. HRMS (M + H).sup.+: calculated 384.265; found
384.2674 36.6
3-Cyano-N-[(1S)-1-cyclohexyl-2-(3-hydroxyazetidin-1-yl)ethyl]- 53
mg, 5-fluoro-N-methylbenzamide 33% .sup.1H NMR Mixture of rotamers:
.sup.1H NMR (600 MHz, DMSO-d6) .delta. 0.54-0.70, 0.88- and 1.25,
1.35-1.81, 2.44-2.48, 2.51-2.58, 2.59-2.64, 2.64-2.71, 2.72-2.79,
HRMS 3.05, 3.28-3.38, 3.45-3.53, 4.13-4.23, 5.23, 5.31, 7.52-7.58,
7.67, 7.76, 7.84, 7.90-7.96. HRMS (M + H).sup.+: calculated
360.209; found 360.2105 36.7
N-[(1S)-1-Cyclohexyl-2-(3-hydroxyazetidin-1-yl)ethyl]-4-fluoro- 93
mg, N-methylbenzamide 63% .sup.1H NMR Mixture of rotamers: .sup.1H
NMR (600 MHz, DMSO-d6) .delta. 0.57-0.68 (m), 0.88- and 1.24 (m),
1.33-1.82 (m), 2.44-2.59 (m), 2.61 (s), 2.63-2.76 (m), 3.20 HRMS
(td), 3.29-3.36 (m), 3.42-3.48 (m), 3.48-3.53 (m), 4.11-4.31 (m),
5.22 (d), 5.25 (d), 7.22-7.28 (m), 7.34-7.39 (m), 7.49-7.54 (m).
HRMS (M + H).sup.+: calculated 335.214; found 335.215 36.8
N-[(1S)-1-Cyclohexyl-2-(3-hydroxyazetidin-1-yl)ethyl]-N- 87 mg,
methylbenzamide .sup.1H NMR Mixture of rotamers: .sup.1H NMR (600
MHz, DMSO-d6) .delta. 0.53-0.71, 0.90- and 1.25, 1.33-1.42,
1.42-1.82, 2.45-2.56, 2.59-2.77, 3.21, 3.29-3.34, 3.43- HRMS 3.54,
4.10-4.36, 5.22, 5.24, 7.26-7.46. HRMS (M + H).sup.+: calculated
317.223; found 317.2244
Example 37
4-Chloro-N-[(2R)-1-(3-hydroxyazetidin-1-yl)pentan-2-yl]-N-methylbenzamide
##STR00052##
[0815] 4-chlorobenzoic acid (0.527 g, 3.37 mmol) and DIPEA (1.176
mL, 6.73 mmol) were mixed in DCM (20 mL) at 0.degree. C. After
stirring for 10 min, TBTU (1.103 g, 3.43 mmol) was added to the
reaction mixture. The mixture was stirred at 0.degree. C. for 20
min. The above mixture was added in three portions to a solution of
(R)-1-(2-(methylamino)pentyl)-azetidin-3-ol (Compound G2.5) (0.58
g, 3.37 mmol) in DCM (20 mL) within 10 min at 0.degree. C. The
mixture was stirred at 0.degree. C. for 2.5 h, then warmed to rt
and the mixture was stirred overnight. The mixture was concentrated
to dryness. To the residue was added aq KOH (30 mL, 15.00 mmol) and
methanol (15 mL)/THF (15 mL). The reaction mixture was stirred at
rt for 2.5 h. The mixture was concentrated and extracted with DCM
(30 mL.times.2). The DCM layers were combined, evaporated in vacuo
to an oil residue. The crude was purified by preparative HPLC to
afford the title compound (0.766 g, 73.2%). Mixture of
rotamers:
[0816] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 0.87, 0.99,
1.11-1.70, 2.49, 2.64-3.04, 3.40-3.66, 3.67-3.81, 4.34, 4.63-4.79,
7.30-7.70. Total number of protons: 22 (proton from hydroxyl group
missing). HRMS (M+H).sup.+: calculated 311.153; found 311.1529
Example 38.1
3,4-Difluoro-N-[(2S)-1-(3-hydroxyazetidin-1-yl)-4-methylpentan-2-yl]-N-met-
hylbenzamide
##STR00053##
[0818] DIPEA (0.252 mL, 1.45 mmol) was added to a stirred
suspension of 3,4-difluorobenzoic acid (76 mg, 0.48 mmol) and TBTU
(155 mg, 0.48 mmol) in DCM (2 mL) at rt. The suspension was stirred
for 3 min. A solution of
(S)-1-(4-methyl-2-(methylamino)pentyl)azetidin-3-ol (Compound G2.4)
(100 mg, 0.48 mmol) in DCM (1 mL) was added and the reaction was
stirred at rt overnight. The reaction was washed with an 8% aq.
solution of NaHCO.sub.3 (1.5 mL). The organic layer was
concentrated and purified by preparative HPLC affording the title
compound (102 mg, 65%). Mixture of rotamers:
[0819] .sup.1H NMR (600 MHz, DMSO-d6) .delta. 0.56, 0.75,
0.82-0.92, 1.14-1.25, 1.29-1.41, 1.44-1.58, 2.35, 2.44, 2.52-2.57,
2.62, 2.65-2.75, 3.34, 3.44-3.54, 4.11-4.18, 4.50-4.58, 5.25, 5.28,
7.16-7.21, 7.29-7.35, 7.39-7.45, 7.46-7.56, 7.59-7.66. HRMS
(M+H).sup.+: calculated 327.1884; found 327.1881.
[0820] The compounds according to Examples 38.2-38.8 were prepared,
from appropriate intermediates, by analogy with the method
described for Example 38.1 hereinbefore.
TABLE-US-00041 Example Name Yield 38.2
4-Chloro-N-[(2S)-1-(3-hydroxyazetidin-1-yl)-4-methylpentan-2- 88
mg, yl]-N-methylbenzamide 56% .sup.1H NMR Mixture of rotamers:
.sup.1H NMR (600 MHz, DMSO) .delta. 0.56, 0.75, 0.83-0.93, and
1.17-1.25, 1.29-1.39, 1.44-1.56, 2.35, 2.43, 2.51-2.53, 2.61, 2.65,
2.69- HRMS 2.76, 3.30-3.38, 3.42-3.54, 4.10-4.19, 4.52-4.61,
5.21-5.30, 7.31-7.37, 7.43-7.53. HRMS (M + H).sup.+: calculated
325.168; found 325.1707 38.3
4-Ethyl-N-[(2S)-1-(3-hydroxyazetidin-1-yl)-4-methylpentan-2- 97 mg,
yl]-N-methylbenzamide 63% .sup.1H NMR Mixture of rotamers: .sup.1H
NMR (600 MHz, DMSO) .delta. 0.54, 0.75, 0.90, 1.15- and 1.25,
1.28-1.39, 1.44-1.57, 2.36, 2.44, 2.48-2.53, 2.59-2.66, 2.69-2.75,
HRMS 3.30-3.38, 3.48-3.58, 4.08-4.19, 4.53-4.62, 5.24, 7.21-7.28,
7.33. HRMS (M + H).sup.+: calculated 319.239; found 319.2357 38.4
3-(Difluoromethyl)-N-[(2S)-1-(3-hydroxyazetidin-1-yl)-4- 103 mg,
methylpentan-2-yl]-N-methylbenzamide 63% .sup.1H NMR Mixture of
rotamers: .sup.1H NMR (600 MHz, DMSO) .delta. 0.55, 0.74,
0.80-0.94, and 1.17-1.26, 1.29-1.41, 1.43-1.58, 2.34-2.44,
2.48-2.58, 2.59-2.66, 2.70- HRMS 2.77, 3.29-3.45, 3.53, 4.09-4.19,
4.55-4.65, 5.25, 6.99, 7.08, 7.18, 7.47- 7.52, 7.56-7.67. HRMS (M +
H).sup.+: calculated 341.204; found 341.2024 38.5
4-Fluoro-N-[(2S)-1-(3-hydroxyazetidin-1-yl)-4-methylpentan-2- 109
mg, yl]-3-methoxy-N-methylbenzamide 67% .sup.1H NMR Mixture of
rotamers: .sup.1H NMR (600 MHz, DMSO) .delta. 1.31, 1.42, 1.52,
1.56, and 1.60-1.75, 1.93-2.44, 3.12-3.46, 3.48-3.56, 3.89-4.21,
4.27-4.38, 4.48- HRMS 4.64, 4.83-5.00, 5.27-5.66, 5.99-6.07,
7.45-7.65, 7.67-8.09. HRMS (M + H).sup.+: calculated 339.208; found
339.2089 38.6
4-Cyano-2-fluoro-N-[(2S)-1-(3-hydroxyazetidin-1-yl)-4- 94 mg,
methylpentan-2-yl]-N-methylbenzamide 58% .sup.1H NMR Mixture of
rotamers: .sup.1H NMR (600 MHz, DMSO-d6) .delta. 0.61, 0.75, 0.80-
and 0.94, 1.17-1.54, 2.34-2.75, 2.79, 3.05-3.42, 3.48-3.56,
4.03-4.20, 4.53- HRMS 4.62, 5.22-5.31, 7.48-7.58, 7.68-7.85,
7.93-8.05. HRMS (M + H).sup.+: calculated 334.1931; found 334.1962
38.7 4-Chloro-N-[(2S)-1-(3-hydroxyazetidin-1-yl)-4-methylpentan-2-
112 mg, yl]-2-methoxy-N-methylbenzamide 65% .sup.1H NMR 1H NMR (600
MHz, dmso) .delta. 0.52, 0.62, 0.72, 0.76, 0.80-0.93, 1.11-1.64,
and 2.30-2.66, 2.73, 3.33, 3.46-3.58, 3.68-3.86, 4.04-4.19,
4.42-4.85, 5.20- HRMS 5.27, 6.98-7.20, 7.26. HRMS (M + H).sup.+:
calculated 355.1788; found 355.1809 38.8
N-[(2S)-1-(3-Hydroxyazetidin-1-yl)-4-methylpentan-2-yl]-N- 105 mg,
methyl-4-(methylsulfanyl)benzamide 65% Mixture of rotamers: 1H NMR
(600 MHz, DMSO-d6) .delta. 0.56 (d), 0.76 (d), 0.82-0.93 (m),
1.16-1.25 (m), 1.27-1.40 (m), 1.43-1.57 (m), 2.33-2.39 (m),
2.41-2.56 (m), 2.62-2.76 (m), 3.30-3.39 (m), 3.48-3.59 (m), 4.09-
4.19 (m), 4.52-4.61 (m), 5.21-5.27 (m), 7.23-7.31 (m), 7.38 (d).
Some signals overlap with solvent/water. HRMS (M + H).sup.+:
calculated 337.1950; found 337.1962
Example 39.1
(S)-2-chloro-N-(1-cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-4-fluoro-N-m-
ethylbenzamide
##STR00054##
[0822] DIPEA (0.183 mL, 1.05 mmol) was added to a stirred
suspension of 2-chloro-4-fluorobenzoic acid (55 mg, 0.31 mmol) and
TBTU (0.101 g, 0.31 mmol) in DCM (1 mL) at rt. The suspension was
stirred for 5 min before it was cooled on an ice-bath. A solution
of (S)-1-(2-cyclobutyl-2-(methylamino)ethyl)azetidin-3-ol (Compound
Z2.1) (0.07 g, 0.35 mmol) in DCM (1 mL) was added over 3 min. The
ice-bath was removed and the reaction was stirred at rt for 2 h.
The reaction mixture was washed with NaHCO.sub.3 (8% aq., 3 mL),
filtered through a phase separator and concentrated under reduced
pressure. The residue was purified by preparative HPLC to give the
title compound (54 mg, 45%). Mixture of rotamers: .sup.1H NMR (600
MHz, DMSO-d6) .delta. 1.41-2.1, 2.22-2.85, 3.06-3.59, 4.02-4.23,
4.46-4.60, 5.17-5.35, 7.23-7.72. HRMS (M+H).sup.+: calculated
341.1432; found 341.1442.
Example 39.2
(S)-4-Cyano-N-(1-cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-N-methylbenza-
mide
##STR00055##
[0824] DIPEA (2.504 mL, 14.38 mmol) was added to a stirred
suspension of 4-cyanobenzoic acid (0.670 g, 4.55 mmol) and TBTU
(1.462 g, 4.55 mmol) in DCM (10 mL) at rt. The suspension was
stirred for 5 min before it was cooled on an ice-bath. A solution
of (S)-1-(2-cyclobutyl-2-(methylamino)ethyl)azetidin-3-ol (Compound
Z2.1) (0.960 g, 4.79 mmol) in DCM (10 mL) was added over 5 min. The
ice-bath was removed after 10 min and the reaction was stirred at
rt for 3 h. The reaction mixture was diluted with DCM (20 mL),
washed with NaHCO.sub.3 (8% aq., 35 mL), filtered through a phase
separator and concentrated under reduced pressure. The residue was
purified by preparative HPLC. The selected fractions were
concentrated and NaHCO.sub.3 (saturated, 40 mL) was added. The
water layer was extracted with DCM (3.times.75 mL) and the combined
organic layers were filtered through a phase separator and
concentrated under reduced pressure to give the title compound
(0.925 g, 62%). Mixture of rotamers: .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 1.32-1.62, 1.65-1.97, 1.97-2.08, 2.17-2.28, 2.32-2.60,
2.62-2.74, 3.16-3.27, 3.39-3.45, 3.46-3.52, 4.07-4.18, 4.40-4.52,
5.19-5.24, 7.42-7.46, 7.57-7.62, 7.87-7.95. HRMS (M+H).sup.+:
calculated 314.1868; found 314.1870
[0825] The compounds according to Examples 39.3-39.16 were
prepared, from appropriate intermediates, by analogy with the
method described for Example 39.1 hereinbefore.
TABLE-US-00042 Example Name Yield 39.3
(S)-N-(1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-3,4- 82 mg,
difluoro-N-methylbenzamide 72% .sup.1H NMR Mixture of rotamers:
(600 MHz, DMSO-d6) .delta. 1.39-2.09, 2.16-2.78, 3.26- and 3.56,
4.10-4.22, 4.40-4.54, 5.20-5.42, 7.13-7.22, 7.30-7.67. HRMS HRMS (M
+ H).sup.+: calculated 325.1728; found 325.1752 39.4
(S)-N-(1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-2,4- 74 mg,
difluoro-N-methylbenzamide 65% .sup.1H NMR Mixture of rotamers:
(600 MHz, DMSO-d6) .delta. 1.42-2.1, 2.21-2.8, 3.12- and 3.75,
4.07-4.22, 4.41-4.56, 5.28, 6.98-7.58. HRMS (M + H).sup.+:
calculated HRMS 325.1683; found 325.1680 39.5
(S)-N-(1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-2-fluoro- 60
mg, 4-methoxy-N-methylbenzamide 51% .sup.1H NMR Mixture of
rotamers: (600 MHz, DMSO-d6) .delta. 1.44-2.08, 2.22-2.77, 3.18-
and 3.87, 4.06-4.21, 4.41-4.58, 5.28, 6.67-6.96, 7.14-7.25,
7.3-7.43. HRMS HRMS (M + H).sup.+: calculated 337.1927; found
337.1944 39.6
(S)-N-(1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-3-fluoro- 79
mg, 4-methoxy-N-methylbenzamide 67% .sup.1H NMR Mixture of
rotamers: (600 MHz, DMSO-d6) .delta. 1.35-1.5, 1.54-2.06, 2.22- and
2.77, 3.27-3.6, 3.79-3.98, 4.09-4.22, 4.38-4.51, 5.24-5.36, 7.05-
HRMS 7.48. HRMS (M + H).sup.+: calculated 337.1927; found 337.1939
39.7 (S)-N-(1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-N- 70 mg,
methylbenzamide 70% .sup.1H NMR Mixture of rotamers: (600 MHz,
DMSO-d6) .delta. 1.32-1.42, 1.48-1.62, 1.69- and 2.09, 2.22-2.81,
3.22-3.28, 3.36-3.58, 4.08-4.21, 4.45-4.57, 5.28, HRMS 7.24-7.51.
HRMS (M + H).sup.+: calculated 289.1916; found 289.1927 39.8
(S)-N-(1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-N-methyl- 69
mg, 4-(trifluoromethyl)benzamide 55% .sup.1H NMR Mixture of
rotamers: (600 MHz, DMSO-d6) .delta. 1.37-1.46, 1.49-2.08, 2.2- and
2.77, 3.18-3.58, 4.1-4.21, 4.45-4.57, 5.30, 7.43-7.78, 7.78-7.9.
HRMS HRMS (M + H).sup.+: calculated 357.1790; found 357.1795 39.9
(S)-N-(1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-4- 63 mg,
methoxy-N,3-dimethylbenzamide 54% .sup.1H NMR Mixture of rotamers:
(600 MHz, DMSO-d6) .delta. 1.36-1.53, 1.56-1.98, 2.01- and 2.78,
3.27-3.61, 3.71-3.89, 4.1-4.19, 4.43-4.55, 5.22-5.33, 6.92- HRMS
7.05, 7.07-7.19, 7.25-7.37. HRMS (M + H).sup.+: calculated
333.2178; found 333.2195 39.10
(S)-N-(1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-2-fluoro- 78
mg, N,5-dimethylbenzamide 70% .sup.1H NMR Mixture of rotamers: (600
MHz, DMSO-d6) .delta. 1.38-1.5, 1.54-2.09, 2.15- and 2.79,
3.11-3.73, 4.08-4.2, 4.46-4.79, 5.2-5.41, 7.02-7.34. HRMS HRMS (M +
H).sup.+: calculated 321.1978; found 321.1988 39.11
(S)-4-Chloro-3-fluoro-N-(1-(3-hydroxyazetidin-1-yl)butan-2-yl)-
1.30 g, N-methylbenzamide 76% .sup.1H NMR Mixture of rotamers: (500
MHz, CD.sub.3OD) .delta. 0.82, 0.96, 1.43-1.67, 2.39- and 2.55,
2.65-3.04, 3.43-3.59, 3.67-3.81, 4.24-4.45, 4.52-4.67, 7.24- HRMS
7.37, 7.38-7.51, 7.55-7.67. HRMS (M + H).sup.+: calculated
315.1275; found 315.1284 39.12
(S)-4-Chloro-N-(1-(3-hydroxyazetidin-1-yl)butan-2-yl)-N- 275 mg,
methylbenzamide 83% .sup.1H NMR Mixture of rotamers: (400 MHz,
CD.sub.3OD) .delta. 0.82, 0.95, 1.47-1.62, 2.41- and 2.52,
2.62-2.99, 3.28-3.54, 3.65-3.76, 4.22-4.39, 4.53-4.64, 7.41-7.53.
HRMS HRMS (M + H).sup.+: calculated 297.1370; found 297.1369 39.13
(S)-N-(1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-4-fluoro- 72
mg, N-methylbenzamide 67% .sup.1H NMR Mixture of rotamers: (600
MHz, DMSO-d6) .delta. 1.34-2.08, 2.2-2.8, 3.21- and 3.58,
4.09-4.21, 4.42-4.55, 5.21-5.31, 7.08-7.43, 7.47-7.58. HRMS HRMS (M
+ H).sup.+: calculated 307.1822; found 307.1825 39.14
(S)-4-Chloro-N-(1-cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)- 69
mg, N-methylbenzamide 61% .sup.1H NMR Mixture of rotamers: (600
MHz, DMSO-d6) .delta. 1.36-2.1, 2.21-2.77, 3.2- and 3.57, 4.1-4.2,
4.43-4.53, 5.23-5.28, 7.31-7.35, 7.45-7.58. HRMS HRMS (M +
H).sup.+: calculated 323.1526; found 323.1539 39.15
(S)-N-(1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-3- 62 mg,
(difluoromethyl)-N-methylbenzamide 52% .sup.1H NMR Mixture of
rotamers: (400 MHz, CD.sub.3OD) 1.42-2.98, 3.47-3.84, 4.23- and
4.42, 4.64-4.78, 6.58-6.87, 6.93-7.04, 7.4-7.79. HRMS (M +
H).sup.+: HRMS calculated 339.1884; found 339.1900 39.16
(S)-N-(1-Cyclobutyl-2-(3-hydroxyazetidin-1-yl)ethyl)-4-fluoro- 61
mg, N,3-dimethylbenzamide 55% .sup.1H NMR Mixture of rotamers: (600
MHz, DMSO-d6) 1.37-1.53, 1.56-1.98, 2.01- and 2.08, 2.16-2.76,
3.24-3.56, 4.11-4.2, 4.41-4.55, 5.22-5.32, 7.13-7.44. HRMS HRMS (M
+ H).sup.+: calculated 321.1978; found 321.1983
Example 40.1
(S)-4-Chloro-N-(1-(3-hydroxyazetidin-1-yl)propan-2-yl)-N-methylbenzamide
##STR00056##
[0827] DIPEA (0.200 mL, 1.15 mmol) was added to a stirred
suspension of 4-chlorobenzoic acid (0.06 g, 0.38 mmol) and TBTU
(0.123 g, 0.38 mmol) in DCM (2 mL) at rt. The suspension was
stirred for 5 min before it was cooled on an ice-bath. A solution
of (S)-1-(2-(methylamino)propyl)azetidin-3-ol (Compound M11) (0.06
g, 0.42 mmol) in THF (1.5 mL) was added over 10 min. The ice-bath
was removed and the reaction was stirred at rt over night. DCM (3
mL) was added and the mixture was washed with NaHCO.sub.3 (8% aq.,
3 mL), filtered through a phase separator and concentrated under
reduced pressure. The residue was dissolved in MeOH (2 mL) and NaOH
(aq., 2M) was added. The resulting mixture was stirred at rt for 3
h, then concentrated under reduced pressure. DCM (5 mL) and
NaHCO.sub.3, (aq., 8%, 5 mL) was added. The organic phase was
collected and the solvents were removed under reduced pressure. The
residue was purified by preparative HPLC to give the title compound
(17 mg, 16%). Mixture of rotamers: .sup.1H NMR (600 MHz, DMSO-d6)
.delta. 0.99-1.12, 2.18-2.23, 2.33-2.79, 3.15-3.56, 4.03-4.18,
4.44-4.54, 5.16-5.28, 7.32-7.55. Some signals overlap with solvent.
HRMS (M+H).sup.+: calculated 283.1213; found 283.1219.
[0828] The compounds according to Examples 40.2-40.12 were
prepared, from appropriate intermediates, by analogy with the
method described for Example 40.1 hereinbefore.
TABLE-US-00043 Example Name Yield 40.2
(S)-N-(1-(3-Hydroxyazetidin-1-yl)propan-2-yl)-N,3,4- 13 mg,
trimethylbenzamide 11% .sup.1H NMR Mixture of rotamers: (600 MHz,
DMSO-d6) .delta. 0.99-1.09, 2.15-2.26, 2.34- and 2.40, 2.46-2.77,
3.18-3.61, 4.03-4.18, 4.44-4.51, 5.19-5.30, 7.04, HRMS 7.09-7.11,
7.16. HRMS (M + H).sup.+: calculated 277.1916; found 277.1926 40.3
(S)-4-Chloro-3-fluoro-N-(1-(3-hydroxyazetidin-1-yl)propan-2- 12 mg,
yl)-N-methylbenzamide 10% .sup.1H NMR Mixture of rotamers: (600
MHz, DMSO-d6) .delta. 1.01-1.10, 2.19-2.26, 2.33- and 2.39,
2.46-2.80, 3.18-3.57, 4.04-4.19, 4.42-4.51, 5.22-5.30, 7.19- HRMS
7.26, 7.40-7.49, 7.62-7.68. HRMS (M + H).sup.+: calculated
301.1119; found 301.1119 40.4
(S)-4-Chloro-N-(1-(3-hydroxyazetidin-1-yl)propan-2-yl)-N,3- 7 mg,
dimethylbenzamide 6% .sup.1H NMR Mixture of rotamers: (600 MHz,
DMSO-d6) .delta. 1.02-1.09, 2.18-2.39, 2.45- and 2.78, 3.17-3.56,
4.03-4.19, 4.43-4.52, 5.19-5.31, 7.15-7.21, 7.33, 7.45. HRMS HRMS
(M + H).sup.+: calculated 297.1370; found 297.1381
Example 41
(S)-4-Bromo-N-(1-(3-hydroxyazetidin-1-yl)propan-2-yl)-N-methylbenzamide
##STR00057##
[0830] D1PEA (0.217 mL, 1.25 mmol) was added to a stirred
suspension of 4-bromobenzoic acid (0.075 g, 0.37 mmol) and TBTU
(0.120 g, 0.37 mmol) in DCM (2 mL) at rt. The suspension was
stirred for 20 min before it was cooled on an ice-bath. A solution
of (S)-1-(2-(methylamino)propyl)azetidin-3-ol (Compound M11) (0.06
g, 0.42 mmol) in THF (1.5 mL) was added over 10 min. The ice-bath
was removed and the reaction was stirred at rt over night. DCM (3
mL) was added and the mixture was washed with NaHCO.sub.3 (8% aq.,
3 mL). The aqueous layer was extracted with DCM (2.times.3 mL). The
combined organic layers were filtered through a phase separator and
concentrated under reduced pressure. The residue was purified by
preparative HPLC to give the title compound (23 mg, 17%). Mixture
of rotamers: .sup.1H NMR (600 MHz, DMSO-d6) .delta. 1.01-1.11,
2.17-2.24, 2.33-2.38, 2.45-2.77, 3.15-3.56, 4.03-4.20, 4.44-4.53,
5.18-5.28, 7.27-7.34, 7.59-7.66. Some signals overlap with solvent.
HRMS (M+H).sup.+: calculated 327.0708; found 327.0722.
Example 42
(S)-4-Bromo-N-(1-(3-hydroxyazetidin-1-yl)butan-2-yl)-N-methylbenzamide
##STR00058##
[0832] DIPEA (0.52 mL, 3.0 mmol) was added to a stirred suspension
of 4-bromobenzoic acid (462 mg, 3.0 mmol) and TBTU (963 mg, 3.0
mmol) in THF (15 mL) at rt. After 10 min was
(S)-1-(2-(methylamino)butyl)azetidin-3-ol (Compound M12) (475 mg,
3.0 mmol) added, followed by addition of DIPEA (0.52 mL, 3.0 mmol).
The reaction was stirred at rt for 4 h. The mixture was
concentrated under reduced pressure and the residue dissolved in
DCM (60 mL). The organic phase was washed with NaHCO.sub.3 (aq., 60
mL). The aqueous layer was extracted with DCM (15 mL). The combined
organic layers were washed with NaHCO.sub.3 (8% aq., 60 mL), dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure. The
residue was purified by preparative HPLC to give the title compound
(577 mg, 56%). Mixture of rotamers: .sup.1H NMR (500 MHz, DMSO-d6)
.delta. 0.82, 1.43-1.54, 2.43, 2.54-2.62, 2.70-2.80, 3.39-3.51,
4.18, 4.88, 7.33, 7.63. Total number of protons: 20. There is one
additional very broad proton signal between 4.2 and 3.1 ppm. HRMS
(M+H).sup.+: calculated 341.0865; found 341.0870.
Example 43.1
4-Chloro-N4S)-1-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)pentan-2-yl)-N-me-
thylbenzamide and
4-chloro-N-((S)-1-((2R,3S)-3-hydroxy-2-methylazetidin-1-yl)pentan-2-yl)-N-
-methylbenzamide
##STR00059##
[0834] D1PEA (0.198 mL, 1.14 mmol), 4-chlorobenzoic acid (0.107 g,
0.68 mmol) and TBTU (0.292 g, 0.91 mmol) were added to a stirred
solution of a 1:1 mixture of
(2S,3R)-2-methyl-1-((S)-2-(methylamino)pentyl)azetidin-3-ol and
(2R,3S)-2-methyl-1-((S)-2-(methylamino)pentyl)azetidin-3-ol
(Compound V2.1) (0.200 g, 63% purity, 0.68 mmol) in DCM (5 mL). The
resulting mixture was stirred over night. DCM (5 mL) and 8%
NaHCO.sub.3 (10 mL) were added, and the phases were separated on a
phase separator. The organic layer was concentrated, the residue
dissolved in THF (20 mL) and 1M NaOH (10 mL) was added. The
resulting mixture was stirred over the weekend at rt. Phases were
separated and the organic layer was concentrated. The residue was
purified by preparative HPLC to yield the isomers. The
diastereomers are given in order of elution:
[0835] Isomer 1: (76 mg, 35%) Mixture of rotamers: .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 0.87, 0.98, 1.05, 1.12-1.64, 2.26-2.39,
2.43, 2.63, 2.68-2.98, 3.54, 3.65-3.76, 3.80, 4.74, 7.38-7.52.
Ratio major:minor: 6:5. Total no of protons: 24. HRMS (M+H).sup.+:
calculated 325.1683; found 325.1685.
[0836] Isomer 2: (76 mg, 35%) Mixture of rotamers: .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 0.81, 0.98, 1.02-1.65, 2.46, 2.53,
2.60-2.77, 2.79, 2.84-2.98, 3.50, 3.61-3.84, 4.68, 7.38-7.57. Ratio
major:minor: 1:1. Total no of protons: 24. HRMS (M+H).sup.+:
calculated 325.1683; found 325.1691.
[0837] The compounds according to Examples 43.2-43.6 were prepared,
from appropriate intermediates, by analogy with the method
described for Example 43.1 hereinbefore. The isomers in Example
43.6 were separated by HPLC on a CelluCoat column (250.times.50
mm), using heptane/1PA/TEA 90:10:0.1 as mobile phase.
TABLE-US-00044 Example Name Yield 43.2
4-Fluoro-N-((S)-1-((2R*,3S*)-3-hydroxy-2-methylazetidin-1- 61 mg,
24% yl)pentan-2-yl)-N-methylbenzamide, isomer 2 .sup.1H NMR Mixture
of rotamers: (400 MHz, CD.sub.3OD) .delta. 0.80, 0.98, 1.01-1.64,
2.46, and 2.52, 2.61-2.76, 2.79, 2.84-2.97, 3.49, 3.64-3.84, 4.67,
7.14-7.23, 7.46, HRMS 7.58. Ratio major:minor: 1:1. Total no of
protons: 24. HRMS (M + H).sup.+: 309.1978; found 309.1986 43.3
3,4-Difluoro-N-((S)-1-((2R*,3S*)-3-hydroxy-2-methylazetidin- 73 mg,
33% 1-yl)pentan-2-yl)-N-methylbenzamide, isomer 2 .sup.1H NMR
Mixture of rotamers: (400 MHz, CD.sub.3OD) .delta. 0.80, 0.98,
1.01-1.62, 2.48, and 2.56, 2.63, 2.68-2.77, 2.79, 2.87, 2.88-2.98,
3.54, 3.66-3.84, 4.66, 7.22- HRMS 7.29, 7.30-7.44, 7.69. Ratio
major:minor: 1:1. Total no of protons: 23. HRMS (M + H).sup.+:
calculated 327.1884; found 327.1878 43.4
4-Chloro-N-((S)-1-((2S,3S)-3-hydroxy-2-methylazetidin-1- Isomer 1:
yl)pentan-2-yl)-N-methylbenzamide and 4-chloro-N-((S)- 33 mg, 13%
1-((2R,3R)-3-hydroxy-2-methylazetidin-1-yl)pentan-2-yl)- Isomer 2:
N-methylbenzamide 19 mg, 7% .sup.1H NMR Isomer 1: Mixture of
rotamers: 400 MHz, CD.sub.3OD) .delta. 0.85, 0.93-1.02, 1.09- and
1.62, 2.33-2.42, 2.67-2.75, 2.82, 2.87, 2.98, 3.07, 3.15-3.40
(partially HRMS obscured by solvent peak), 3.48, 4.23, 4.29, 4.67,
7.41-7.50. Ratio major:minor: 1:1. Total no of protons: 24. HRMS (M
+ H).sup.+: calculated 325.1683; found 325.1678. Isomer 2: Mixture
of rotamers: .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 0.81, 0.97,
1.01-1.62, 2.50, 2.55-2.65, 2.70, 2.77, 2.86, 3.01, 3.10, 3.24-3.34
(partially obscured by solvent peak), 3.39, 3.61, 4.26, 4.32, 4.62,
7.40-7.49, 7.54-7.60. Ratio major:minor: 1:1. Total no of protons:
24. HRMS (M + H).sup.+: calculated 325.1683; found 325.1701. 43.5
3,4-Difluoro-N-((S)-1-((2S,3S)-3-hydroxy-2-methylazetidin- Isomer
1: 1-yl)pentan-2-yl)-N-methylbenzamide and 3,4-Difluoro-N- 76 mg,
30% ((S)-1-((2R,3R)-3-hydroxy-2-methylazetidin-1-yl)pentan-2-
Isomer 2: yl)-N-methylbenzamide 64 mg, 25% .sup.1H NMR Isomer 1:
Mixture of rotamers: (400 MHz, CD.sub.3OD) .delta. 0.85, 0.97,
1.02, 1.09- and 1.62, 2.31-2.43, 2.68-2.90, 3.01, 3.08, 3.17,
3.22-3.40 (partially HRMS obscured by solvent peak), 3.49, 4.25,
4.29, 4.65, 7.25-7.51. Ratio major:minor: 8:7. Total no of protons:
23. HRMS (M + H).sup.+: calculated 327.1884; found 327.1885 Isomer
2: Mixture of rotamers: (400 MHz, CD.sub.3OD) .delta. 0.80, 0.97,
1.00- 1.61, 2.49-2.76, 2.78, 2.85, 3.04, 3.14, 3.25-3.44 (partially
obscured by solvent peak), 3.65, 4.27, 4.33, 4.61, 7.23-7.48, 7.73.
Ratio major:minor: 1:1. Total no of protons: 23. HRMS (M +
H).sup.+: calculated 327.1884; found 327.1897 43.6
4-Fluoro-N-((S)-1-((2S,3S)-3-hydroxy-2-methylazetidin-1- Isomer 1:
yl)pentan-2-yl)-N-methylbenzamide and 4-fluoro-N-((S)-1- 54 mg, 22%
((2R,3R)-3-hydroxy-2-methylazetidin-1-yl)pentan-2-yl)-N- Isomer 2:
methylbenzamide 60 mg, 25% .sup.1H NMR Isomer 1: Mixture of
rotamers: (400 MHz, CD.sub.3OD) .delta. 0.84, 0.94-1.02, and
1.08-1.62, 2.34-2.43, 2.72, 2.74, 2.83, 2.87, 2.99, 3.07, 3.16-3.42
HRMS (partially obscured by the solvent peak), 3.51, 4.22, 4.30,
4.67, 7.15-7.23, 7.47-7.54. Ratio major:minor: 8:7. Total no of
protons: 24. HRMS (M + H).sup.+: calculated 309.1978; found
309.1980. Isomer 2: Mixture of rotamers: (400 MHz, CD.sub.3OD)
.delta. 0.80, 0.97, 1.00- 1.63, 2.51, 2.58-2.67, 2.72, 2.78, 2.86,
3.01, 3.10, 3.27-3.36 (partially obscured by the solvent peak),
3.43, 3.64, 4.25, 4.33, 4.63, 7.14-7.23, 7.48, 7.62. Ratio
major:minor: 8:7. Total no of protons: 24. HRMS (M + H).sup.+:
309.1978; found 309.1991
Example 44
(S)-4-Chloro-N-(1-(4-hydroxypiperidin-1-yl)pentan-2-yl)-N-methylbenzamide
##STR00060##
[0839] 4-Chlorobenzoyl chloride (1.683 mL, 13.12 mmol) was added to
a solution of (S)-1-(2-(methylamino)pentyl)piperidin-4-ol (Compound
J6) (2.629 g, 13.12 mmol) and TEA (3.66 mL, 26.25 mmol) in DCM (25
mL) at 0.degree. C. A white slurry was formed. The reaction was
stirred for 45 min at 0.degree. C. and was then allowed to attain
rt. The reaction was stirred overnight and was then quenched by
addition of NaHCO.sub.3(8% aq., 25 mL). The aqueous phase was
extracted with DCM. The organic phases were pooled, dried
(MgSO.sub.4), filtered and evaporated under reduced pressure. The
crude product was chromatographed to give the title product (3.13
g, 70.3%) as a colourless glue. .sup.1H NMR (400 MHz, CD.sub.3OD)
0.87, 0.99, 1.17-1.33, 1.35-1.63, 1.71-1.90, 1.95-2.15, 2.15-2.36,
2.43-2.51, 2.52-2.68, 2.71-2.80, 2.89, 2.99-3.08, 3.51-3.64,
3.68-3.77, 4.87-4.97, 7.08-7.24, 7.37-7.51. HRMS (M+H).sup.+:
calculated 339.1839; found 339.1827.
Example 45
(S)-4-Chloro-N-(1-(4-methoxypiperidin-1-yl)pentan-2-yl)-N-methylbenzamide
##STR00061##
[0841] NaH (21.24 mg, 0.89 mmol) was added to a solution of
(S)-4-chloro-N-(1-(4-hydroxypiperidin-1-yl)pentan-2-yl)-N-methylbenzamide
(Example 44) (200 mg, 0.59 mmol) in dry THF (10 mL) at room
temperature under N.sub.2. After 5 min was MeI (0.037 mL, 0.59
mmol) added. The reaction was stirred overnight and was then
quenched by addition of NH.sub.3 saturated H.sub.2O (2 mL). The
resulting solution was evaporated and the remainder was dissolved
in EtOAc and poured on an SCX-2 column (5 g). The column was washed
with MeOH and the product was eluted by NH.sub.3 saturated MeOH.
The crude product was purified by preparative HPLC to yield the
title product (106 mg, 51.0%). .sup.1H NMR (600 MHz, DMSO-d6)
.delta. 0.78, 0.91, 1.05-1.51, 1.70-1.84, 1.91-2.03, 2.09-2.13,
2.17-2.23, 2.33-2.39, 2.41-2.54, 2.58-2.64, 2.76, 2.82, 3.12,
3.19-3.22, 3.53-3.59, 4.71-4.79, 7.31-7.35, 7.36-7.40, 7.47-7.53.
HRMS (M+H).sup.+: calculated 353.1996; found 353.2006.
Example 46.1
4-Cyano-N4S)-1-((S)-3-hydroxypyrrolidin-1-yl)pentan-2-yl)-N-methylbenzamid-
e
##STR00062##
[0843] 4-Cyanobenzoyl chloride (0.800 g, 4.83 mmol) was added to a
solution of (S)-1-((S)-2-(methylamino)pentyl)pyrrolidin-3-ol
(Compound J7) (1 g, 5.37 mmol) and TEA (1.496 mL, 10.74 mmol) in
DCM (25 mL) at 0.degree. C. The reaction was stirred for 30 min and
was then allowed to attain rt. After 1.5 h the reaction was
quenched with K.sub.2CO.sub.3 (1 M aq., 25 mL) and the aqueous
phase was extracted with DCM. The organic phases were pooled, dried
(MgSO.sub.4), filtered and evaporated. The residue was dissolved in
EtOAc and poured on an SCX-2 column (10 g). The column was washed
with EtOAc and MeOH, The product was eluted with NH.sub.3 saturated
MeOH. The crude product (1.200 g, 70.9%) was obtained as a yellow
oil. A fraction of the crude material was purified by preparative
HPLC to yield 31 mg of the title product with a purity of 99.5%.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 0.85-1.09, 1.14-1.75,
2.03-2.23, 2.29-2.61, 2.66-2.76, 2.82-3.00, 4.24-4.39, 5.49,
7.57-7.65, 7.80-7.85. HRMS (M+H).sup.+: calculated 316.2025; found
316.2038.
[0844] The compounds according to Example 46.2 was prepared, from
appropriate is intermediates, by analogy with the method described
for Example 46.1 hereinbefore.
TABLE-US-00045 Example Name Yield 46.2
4-Chloro-N-((S)-1-((S)-3-hydroxypyrrolidin-1- 1.24 g,
yl)pentan-2-yl)-N-methylbenzamide 71% crude yield .sup.1H NMR
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 0.87, 0.99, 1.14-1.75,
and 2.02-2.20, 2.29-2.39, 2.42-2.60, 2.64-2.71, 2.76, HRMS
2.82-2.98, 3.66-3.75, 4.23-4.38, 7.38-7.50. HRMS (M + H).sup.+:
calculated 325.1683; found 325.1653
Example 47
Additional Compounds
[0845] The following compounds were prepared in similar manners as
described for the preparation of the compounds above.
TABLE-US-00046 Name HRMS (M + H)+
(S)-3-Cyano-N-methyl-N-(3-methyl-1-(pyrrolidin-1- Calc. 375.2059,
yl)butan-2-yl)benzamide found 375.2063
2-Fluoro-N-methyl-N-[(1S)-2-methyl-1-(pyrrolidin-1- Calc. 300.2076,
ylmethyl)propyl]-5-(trifluoromethyl)benzamide found 300.2081
(S)-4-Fluoro-N-methyl-N-(3-methyl-1-(piperidin-1- Calc. 375.2059,
yl)butan-2-yl)-2-(trifluoromethyl)benzamide found 375.2063
2-Fluoro-N-methyl-N-[(1S)-2-methyl-1-(pyrrolidin-1- Calc. 375.2059,
ylmethyl)propyl]-5-(trifluoromethyl)benzamide found 375.2059
(S)-N-Methyl-N-(3-methyl-1-(piperidin-1-yl)butan-2-yl)-3- Calc.
373.2103, (trifluoromethoxy)benzamide found 373.2115
(S)-4-Fluoro-N,3-dimethyl-N-(3-methyl-1-(piperidin-1- Calc.
321.2342, yl)butan-2-yl)benzamide found 321.234
(S)-4-(Difluoromethoxy)-N-methyl-N-(3-methyl-1- Calc. 341.204,
(pyrrolidin-1-yl)butan-2-yl)benzamide found 341.2032
(S)-4-Cyano-N-(1-(4-methoxypiperidin-1-yl)-3- Calc. 344.2338,
methylbutan-2-yl)-N-methylbenzamide found 344.2331
(S)-3,4-Difluoro-N-(1-(4-methoxypiperidin-1-yl)-3- Calc. 355.2197,
methylbutan-2-yl)-N-methylbenzamide found 355.2201
(S)-N-(3,3-Dimethyl-1-(pyrrolidin-1-yl)butan-2-yl)-4- Calc.
321.2342, fluoro-N,3-dimethylbenzamide found 321.2333
(S)-4-Chloro-N-(3,3-dimethyl-1-(pyrrolidin-1-yl)butan-2- Calc.
323.189, yl)-N-methylbenzamide found 323.1898
(S)-N-(1-(Azetidin-1-yl)pentan-2-yl)-4-fluoro-N,2- Calc. 293.2029,
dimethylbenzamide found 293.2023
(R)-3-Bromo-N-methyl-N-(3-methyl-1-(pyrrolidin-1- Calc. 353.1228,
yl)butan-2-yl)benzamide found 353.1222
(R)-N-Methyl-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)- Calc.
359.1946, 4-(trifluoromethoxy)benzamide found 359.1945
(S)-3-Bromo-N-methyl-N-(3-methyl-1-(pyrrolidin-1- Calc. 353.1228,
yl)butan-2-yl)benzamide found 353.1226
N,2-Dimethyl-N-[(1S)-2-methyl-1-(pyrrolidin-1- Calc. 289.228,
ylmethyl)propyl]benzamide found 289.2278
(S)-N-(1-(4,4-difluoropiperidin-1-yl)-3-methylbutan-2-yl)- Calc.
353.2404, N,3,4-trimethylbenzamide found 353.2385
(S)-4-Chloro-N-(1-(4,4-difluoropiperidin-1-yl)-3- Calc. 359.1702,
methylbutan-2-yl)-N-methylbenzamide found 359.1696
(S)-4-Bromo-N-(1-(4,4-difluoropiperidin-1-yl)-3- Calc. 403.1196,
methylbutan-2-yl)-N-methylbenzamide found 403.1196
(R)-3-Chloro-4-fluoro-N-methyl-N-(4-methyl-1- Calc. 341.1796,
(pyrrolidin-1-yl)pentan-3-yl)benzamide found 341.1797
(R)-N,3,4-Trimethyl-N-(4-methyl-1-(pyrrolidin-1- Calc. 317.2593,
yl)pentan-3-yl)benzamide found 317.2598
(R)-4-Chloro-N,2-dimethyl-N-(4-methyl-1-(pyrrolidin-1- Calc.
337.2047, yl)pentan-3-yl)benzamide found 337.2036
(R)-3,4-Difluoro-N-methyl-N-(4-methyl-1-(pyrrolidin-1- Calc.
325.2091, yl)pentan-3-yl)benzamide found 325.2099
(R)-2-Chloro-4-fluoro-N-methyl-N-(4-methyl-1- Calc. 341.1796,
(pyrrolidin-1-yl)pentan-3-yl)benzamide found 341.1819
(R)-4-Bromo-N-methyl-N-(4-methyl-1-(pyrrolidin-1- Calc. 367.1385,
yl)pentan-3-yl)benzamide found 367.139
(S)-4-Cyano-N-(1-cyclopropyl-2-(pyrrolidin-1-yl)ethyl)-N-
methylbenzamide
(S)-N-(1-Cyclopropyl-2-(pyrrolidin-1-yl)ethyl)-4-fluoro-N- Calc.
291.1873, methylbenzamide found 291.1862
(S)-4-Cyano-N-(1-(3,3-difluoropiperidin-1-yl)-3- Calc. 350.2044,
methylbutan-2-yl)-N-methylbenzamide found 350.2049
(S)-N-(1-(3,3-Difluoropiperidin-1-yl)-3-methylbutan-2-yl)- Calc.
339.2248, N,3-dimethylbenzamide found 339.2238
(S)-N-(1-(3,3-Difluoropiperidin-1-yl)-3-methylbutan-2-yl)- Calc.
357.2154, 4-fluoro-N,3-dimethylbenzamide found 357.2145
(S)-4-Chloro-N-(1-(3,3-difluoropiperidin-1-yl)-3- Calc. 359.1702,
methylbutan-2-yl)-N-methylbenzamide found 359.1702
(S)-3,4-Difluoro-N-(1-(3-fluoroazetidin-1-yl)-3- Calc. 315.1684,
methylbutan-2-yl)-N-methylbenzamide found 315.1683
(S)-N-(1-(3-Fluoroazetidin-1-yl)-3-methylbutan-2-yl)- Calc.
307.2186, N,3,4-trimethylbenzamide found 307.2157
(S)-N-(1-(3-Fluoroazetidin-1-yl)-3-methylbutan-2-yl)-3- Calc.
323.2135, methoxy-N,4-dimethylbenzamide found 323.2136
(R)-2,4-Dichloro-N-methyl-N-(4-methyl-1-(pyrrolidin-1- Calc.
357.15, yl)pentan-3-yl)benzamide found 357.1511
(R)-N,3-Dimethyl-N-(4-methyl-1-(pyrrolidin-1-yl)pentan- Calc.
303.2436, 3-yl)benzamide found 303.2443
(R)-4-Chloro-N-methyl-N-(4-methyl-1-(pyrrolidin-1- Calc. 323.189,
yl)pentan-3-yl)benzamide found 323.1874
(S)-4-Fluoro-N,3-dimethyl-N-(1-(pyrrolidin-1-yl)butan-2- Calc.
293.2029, yl)benzamide found 293.2036
(S)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-4-bromo-N- Calc.
353.1228, ethylbenzamide found 353.1202
(S)-4-Fluoro-N-(2-methoxyethyl)-3-methyl-N-(3-methyl-1- Calc.
351.2448, (pyrrolidin-1-yl)butan-2-yl)benzamide found 351.2429
(R)-4-Fluoro-N-(1-(3-hydroxyazetidin-1-yl)-3- Calc. 309.1978,
methylbutan-2-yl)-N,3-dimethylbenzamide found 309.1976
(S)-N-(1-(3-Hydroxy-3-methylazetidin-1-yl)-3- Calc. 305.2229,
methylbutan-2-yl)-N,3-dimethylbenzamide found 305.2238
(S)-3-Chloro-4-fluoro-N-(1-(3-hydroxy-3-methylazetidin- Calc.
343.1588, 1-yl)-3-methylbutan-2-yl)-N-methylbenzamide found
343.1606 (S)-4-Fluoro-N-(1-(3-hydroxy-3-methylazetidin-1-yl)-3-
Calc. 323.2135, methylbutan-2-yl)-N,3-dimethylbenzamide found
323.2114 (S)-N-(2-(Azetidin-1-yl)-1-cyclopropylethyl)-3-chloro-4-
Calc. 311.1326, fluoro-N-methylbenzamide found 311.1316
N-((S)-1-((S)-2-(Methoxymethyl)pyrrolidin-1-yl)-3- Calc. 333.2542,
methylbutan-2-yl)-N,4-dimethylbenzamide found 333.2542
(S)-4-Chloro-N-isopropyl-N-(3-methyl-1-(pyrrolidin-1- Calc.
337.2047, yl)butan-2-yl)benzamide found 337.2032
(S)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-4-fluoro- Calc.
293.2029, N,2-dimethylbenzamide found 293.203
(S)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-4-cyano-2- Calc.
304.1825, fluoro-N-methylbenzamide found 304.1819
(S)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-3-methoxy- Calc.
291.2072, N-methylbenzamide found 291.2072
(S)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-3,4-difluoro- Calc.
297.1778, N-methylbenzamide found 297.1787
(S)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-3-chloro-5- Calc.
313.1483, fluoro-N-methylbenzamide found 313.147
3-fluoro-N-methyl-N-[(1S)-2-methyl-1-(pyrrolidin-1- Calc. 293.2029,
ylmethyl)propyl]benzamide found 293.2033
4-Chloro-N-{(1S)-1-[(2,5-dimethylpyrrolidin-1-yl)methyl]- Calc.
337.2047, 2-methylpropyl}-N-methylbenzamide found 337.2052
5-Fluoro-N,2-dimethyl-N-[(1S)-2-methyl-1-(pyrrolidin-1- Calc.
307.2186, ylmethyl)propyl]benzamide found 307.2178
(S)-4-Chloro-N-methyl-N-(1-(pyrrolidin-1-yl)butan-2- yl)benzamide
N-[(2S)-1-(3-Hydroxyazetidin-1-yl)pentan-2-yl]-N- Calc. 305.2229;
(propan-2-yl)benzamide found 305.2239
4-Cyano-N-[(2S)-1-(3-hydroxyazetidin-1-yl)pentan-2-yl]- Calc.
330.2181; N-(propan-2-yl)benzamide found 330.2195
4-Cyano-N-[(1S)-1-cyclobutyl-2-(3-hydroxyazetidin-1- Calc.
332.1774; yl)ethyl]-2-fluoro-N-methylbenzamide found 332.178
4-Chloro-N-((S)-1-((3R,4R)-3,4-dihydroxypyrrolidin-1-yl)- Calc.
359.1537; 3-methylbutan-2-yl)-3-fluoro-N-methylbenzamide found
359.1555 4-Fluoro-N-((S)-1-((2S*,3R*)-3-hydroxy-2- Calc. 309.1978;
methylazetidin-1-yl)pentan-2-yl)-N-methylbenzamide found 309.1982
3,4-Difluoro-N-((2R,3R)-1-(3-hydroxyazetidin-1-yl)-3- Calc.
329.1677; methoxybutan-2-yl)-N-methylbenzamide found 329.1675
(S)-N-(1-(3-Hydroxyazetidin-1-yl)-4-methylpentan-2-yl)- Calc.
335.2335; 2-methoxy-N,5-dimethylbenzamide found 335.2319
3,4-Difluoro-N-((S)-1-((R)-2-(hydroxymethyl)azetidin-1- Calc.
327.1884; yl)-3-methylbutan-2-yl)-N-methylbenzamide found
327.1888
Pharmacological Activity, In Vitro
[0846] Human KCNJ3 encoding Kir3.1 (Genbank acc. No.
NM.sub.--002239) was inserted between EcoRI and NotI in the
pIRESneo3 vector (Clontech Laboratories, Inc. CA, USA). Human KCNJ5
encoding Kir3.4 (Genbank Acc. No. BC069482) was inserted between
EcoRI and NotI in the pIRESpuro3 vector (Clontech Laboratories,
Inc. CA, USA). A Kozak sequence (GCCACC) was introduced before the
start codon ATG of both constructs. Chinese Hamster Ovary K1,
CHO-FLP/IN, cells (Invitrogen Corporation, Paisley, UK) were
transfected simultaneously using Lipofectamine 2000 reagent
(Invitrogen Corporation, Paisley, UK). Geneticin 600 .mu.g/mL
(Invitrogen Corporation, Paisley, UK) and puromycin 3 .mu.g/mL (BD
Bioscience) were added to the cell culture medium 3 days after
transfection. Two weeks after transfection, colonies had appeared
and were manually picked and sorted to one cell per well in a
96-well plate. Cells were then tested for Kir3.1 and Kir3.4
expression using membrane potential assay, Western Blot and
Immunocytochemistry. The resulting clone was transfected with human
CHRM2 construct encoding Muscarinic 2 receptor (Genbank acc. No.
NM.sub.--001006630) using the FLP/IN technology (Invitrogen
Corporation, Paisley, UK) and resulted in a stable
CHO-FLP/IN-hKCNJ3/KCNJ5/CHRM2 cell line. The cell line was
re-sorted by flow cytometry and resulting clones were assayed
electrophysiologically using IonWorks (Molecular Devices) and later
validated on the Q-Patch (Sophion A/S).
[0847] The stable cell line was cultured in DMEM/F12 with Glutamax
1 (Invitrogen Corporation, Paisley, UK), supplemented with foetal
bovine scrum 10%, puromycin 3 .mu.g/mL, hygromycin 300 .mu.g/mL and
geneticin 600 .mu.g/mL (Invitrogen Corporation, Paisley, UK). Care
was taken not to seed cells at too low density and cells were
passaged at approximately 70-80% confluency. Cells used for
patch-clamp experiments were prepared by washing using PBS (--Mg,
--Ca.sup.2+), 2 times, detached using Accutase (Sigma). For Q-Patch
measurements, storage medium was prepared fresh by adding 1.25 mL
of 1M Hepes (GibcoBRL) to 50 mL CHO-SFM II medium (GibcoBRL) and
detached cells were diluted to 2 million cells/mL in this medium.
Frozen (Cryopreserved) cells were used for Atomic Absorption
Screening (AAS) and plated poly-D-lysine 384-well plates (Greiner)
at a density of 11,000-13,000 cells/well, the day before assay.
[0848] The blocking effects of compounds on the human cardiac ion
channel proteins hKir3.1/Kir3.4 were assessed in CHO-K1 cells
stably expressing the channel proteins using Atomic Absorption
Screening (AAS). Cells were washed and then loaded with 25 .mu.L
Rb-loading buffer for three hours at 37.degree. C. After that, the
cells were washed again and 25 .mu.L of diluted compound was
transferred to the cell plate, incubated for 5 min in RT, and then
25 .mu.L of Carbachol/high K+(10 .mu.M carbachol and 20 mM KCl
final concentration) buffer added to stimulate the cells and open
the Kir3.1/Kir3.4 channel. After 10 min stimulation, 60 .mu.L of
the supernatant was transferred to a new microplate, 45 .mu.L
washing buffer added to the supernatant and the level of Rb in the
supernatant was then measured using an Aurora ICR 8000. Compounds
were studied at concentrations ranging from 0.003 to 67 .mu.mol/L
(dilutions by three, 10-pt CR) or from 0.037 to 27 .mu.mol/L
(dilutions by three, 7-pt CR).
[0849] Currents were recorded at room temperature (RT, 22.degree.
C.) by using the whole-cell configuration of the patch-clamp
technique and Q-Patch (Sophion). The inward currents of
hKir3.1/Kir3.4, in transfected cells together with human muscarinic
receptor 2 (hM2), were activated by the addition of 10 .mu.M
carbachol and by increasing the extracellular potassium
concentration to 50 mM. The hKir3.1/Kir3.4 currents were clamped at
-90 mV, incubated with compound for 90-120 s and stimulated by
carbachol/high K.sup.+ and the current level was measured at the
end of the sweep. Compounds were studied at concentrations ranging
from 0.12 to 30 .mu.mol/L (dilutions by three, 6-pt CR).
[0850] Stock solutions of compounds were prepared in DMSO 10 mM and
stored at RT. Buffers used for AAS contained (in mM): HEPES 20,
NaCl 150, MgCl.sub.2 1.0, CaCl.sub.2 2.0 and NaH.sub.2PO.sub.4 0.8
and Glucose 10 (wash 1) or KCl 5 and Glucose 5 (wash 2) or KCl 5
(dilution buffer). The High K.sup.+ channel opener buffer contained
(in mM): HEPES 20, NaCl 130, MgCl.sub.2 1.0, CaCl.sub.2 2.0 and
NaH.sub.2PO.sub.4 0.8 together with KCl 20. Solutions used for
Q-Patch (extracellular) in mM: NaCl 145, KCl 4, CaCl.sub.2 2.0,
MgCl.sub.2 1.0, HEPES 10 and glucose 10. The high K.sup.+ extra
cellular solution used for Q-Patch in mM: NaCl 96.7, KCl 50.7,
CaCl.sub.2 2.0, MgCl.sub.2 1.0, HEPES 10 and glucose 10 while the
intra cellular solution used was (in mM): KCl 120, CaCl.sub.2
5.374, MgCl.sub.2 1.75, EGTA 10, KOH 3.125, HEPES 10, Na.sub.2ATP
4.
[0851] Results are given as mean IC.sub.50 of >4 replicates
(10-pt CR, AAS) or >3 replicates (7-pt CR, AAS). Some of the
data in Table 1 are mean values of two or more runs. Data was
analyzed using H-base calculation method "EC50 main method" (sample
based) for AAS experiments.
[0852] The title compounds of the Examples 1.1-46.2 were tested in
the biological test described above, and these compounds were found
to exhibit an IC.sub.50 of <20 .mu.M.
TABLE-US-00047 TABLE 1 IKACh IC.sub.50 IKACh IC.sub.50 10-pt CR,
7-pt CR, Example AAS [.mu.M] AAS [.mu.M] 1.1 2.3 1.2 3.6 1.3 3.1
1.4 3.7 1.5 12 1.6 6.7 1.7 5.0 1.8 11 1.9 3.6 1.10 6.9 1.11 1.2
1.12 2.9 1.13 12 1.14 6.6 1.15 2.3 1.16 17 1.17 4.2 2.8 2.1 11 2.2
14 2.3 1.6 2.4 1.8 2.5 2.7 2.6 2.0 3.1 7.4 3.2 20 3.3 7.2 3.4 2.2
3.5 7.2 3.6 3.2 3.7 1.3 3.8 4.8 3.9 3 3.10 14 3.11 7.2 3.12 2.5
3.13 3.6 3.14 5.7 3.15 3.8 3.16 13 3.17 9.3 3.18 1.9 3.19 6.0 3.20
8.4 4.1 5.9 4.2 2.8 4.3 6.8 4.4 0.59 5.1 6 5.2 1.8 6.1 1.5 6.2 2.6
6.3 2.5 7.1 1.3 7.2 1.8 7.3 1.9 7.4 9.8 7.5 1.8 8.1 1.7 8.2 0.88
8.3 0.8 8.4 0.2 8.5 0.58 8.6 8.5 8.7 1.7 8.8 2.4 8.9 8.6 8.10 4.3
8.11 0.84 8.12 4.3 8.13 1.9 8.14 5.8 8.15 4.5 8.16 16 8.17 2.0 9.1
2.6 9.2 1.2 9.3 3.1 9.4 14 9.5 1.3 9.6 2.8 9.7 8.6 9.8 5.3 9.9 11
9.10 2.1 9.11 12 10.1 6.1 3.7 10.2 5.1 2.0 11 5.6 12.1 15 1.4 12.2
16 5.8 13.1 2.5 13.2 3.9 13.3 19 13.4 19 14 16 15.1 11 15.2 18 15.3
7.4 15.4 5.7 15.5 2.3 16.1 17 16.2 15 16.3 11 16.4 18 16.5 11 16.6
20 16.7 14 16.8 8.0 16.9 14 3.9 16.10 2.6 16.11 11 16.12 15 23
16.13 14 5.3 16.14 6.7 16.15 2.5 16.16 2.6 16.17 1.2 16.18 11 16.19
14 16.20 14 16.21 12 16.22 18 16.23 6.7 16.24 9.8 >27 16.25 2.8
16.26 4.8 16.27 4.0 16.28 0.84 16.29 9.3 8.8 16.30 1.7 16.31 2.4
16.32 4.0 16.33 6.7 16.34 4.3 16.35 12 16.36 11 16.37 15 14 16.38
17 16.39 3.9 16.40 3.2 16.41 6.8 16.42 3.9 16.43 5.5 16.44 8.4
16.45 16 16.46 19 16.47 0.56 16.48 4.2 16.49 9.7 7.1 16.50 0.42
16.51 0.46 16.52 3.2 16.53 0.9 16.54 9.1 6.0 16.55 1.9 1.4 16.56
3.6 16.57 8.8 11 16.58 5.8 16.59 18 16.60 16 17.1 12 17.2 1.4 17.3
11 17.4 17 17.5 2.7 17.6 12 17.7 3.6 18 6.8 1.2 19 4.6 0.82 20 11
21 19 22 19 23 0.44 24 4.0 25 17 26 7.0 27 1.1 28 19 29.1 9.3 29.2
0.16 29.3 0.22 29.4 12 29.5 12 29.6 1.6 29.7 3.5 29.8 11 29.9 16 30
6.3 31.1 0.43 31.2 5.9 31.3 1.7 31.4 0.33 32.1, isomer 0.26; 2.3 1
and 2 32.2, isomer 0.58; 15 1 and 2 32.3, isomer 0.055; 0.30 1 and
2 32.4, isomer 0.034; 0.98 1 and 2 32.5, isomer 0.34; 7.5 1 and 2
32.6, isomer 1.1; 2.3 1 and 2 32.7, isomer 0.075; 0.16 1 and 2 33.1
0.12 33.2 0.32 33.3 0.84 33.4 1.1 33.5 1.0 33.6 11 33.7 0.55 33.8
0.16 33.9 4.3 33.10 1.1 34.1 3.3 34.2 11 35.1 3.4 35.2 14 35.3 8.7
35.4 0.66 35.5 11 35.6 4.6 35.7 3.9 35.8 8.0 35.9 4.6 35.10 15
35.11 4.8 35.12 16 35.13 11 35.14 13 36.1 0.41 36.2 0.049 36.3 0.92
36.4 0.33 36.5 1.9 36.6 1.9 36.7 1.4 36.8 1.1 37 9.7 38.1 1.3 38.2
0.11
38.3 2.1 38.4 0.77 38.5 4.2 38.6 3.4 38.7 0.47 38.8 0.83 39.1 1.1
39.2 0.49 39.3 0.41 39.4 7.8 39.5 1.1 39.6 0.48 39.7 1.4 39.8 0.23
39.9 0.34 39.10 0.81 39.11 1.6 39.12 3.9 39.13 0.16 39.14 0.072
39.15 0.25 39.16 0.078 40.1 9.7 40.2 8.5 40.3 9.4 40.4 6.1 41 7.3
42 4.0 43.1, isomer 1.3; 3.0 1 and 2 43.2 9.1 43.3 2.7 43.4, isomer
1.7; 0.72 1 and 2 43.5, isomer 8.4; 2.7 1 and 2 43.6, isomer 9.5;
9.0 1 and 2 44 0.81 45 0.68 46.1 8.0 46.2 5.5
[0853] It has been shown that compounds according to the invention
possess promising potency as IKACh blockers and the compounds are
thus believed to be useful for treatment of cardiac
arrhythmias.
[0854] It may be noted that the following compounds were found to
have an IC.sub.50 of >67 .mu.M in the above described 10-pt CR
assay or IC.sub.50>27 .mu.M in the above described 7-pt CR
assay:
TABLE-US-00048
3-Chloro-N-methyl-N-(1-methyl-2-pyrrolidin-1-ylethyl)benzamide
(S)-N-(1-(3,3-Difluoropiperidin-1-yl)-3-methylbutan-2-yl)-3,4-difluoro-N-
methylbenzamide
(S)-4-Cyano-2-fluoro-N-(1-(3-fluoroazetidin-1-yl)-3-methylbutan-2-yl)-N-
methylbenzamide
(S)-N-(1-(3-Fluoroazetidin-1-yl)-3-methylbutan-2-yl)-3-methoxy-N-methylben-
zamide
(S)-N-(1-(4,4-Difluoropiperidin-1-yl)-3-methylbutan-2-yl)-4-fluoro-N,3-
dimethylbenzamide
(S)-N-(1-(3,3-Difluoropyrrolidin-1-yl)-3-methylbutan-2-yl)-4-fluoro-N,3-
dimethylbenzamide
(S)-4-Bromo-N-(1-(3,3-difluoropyrrolidin-1-yl)-3-methylbutan-2-yl)-N-
methylbenzamide
(R)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-4-bromo-N-methylbenzamide
4-Chloro-2-fluoro-N-methyl-N-[(1R)-2-methyl-1-(2-pyrrolidin-1-
ylethyl)propyl]benzamide
N-Methyl-N-[(1R)-2-methyl-1-(2-pyrrolidin-1-ylethyl)propyl]benzamide
2-Chloro-N-methyl-N-[(1R)-2-methyl-1-(2-pyrrolidin-1-ylethyl)propyl]benzam-
ide
(S)-N-(3,3-Dimethyl-1-(pyrrolidin-1-yl)butan-2-yl)-4-fluoro-N,2-dimethylbe-
nzamide
(S)-N-(1-(3-Hydroxy-3-methylazetidin-1-yl)-3-methylbutan-2-yl)-N-methylben-
zamide
(S)-3,4-Difluoro-N-(1-(3-hydroxy-3-methylazetidin-1-yl)-3-methylbutan-2-yl-
)-N- methylbenzamide
(S)-4-Fluoro-N-(1-(3-hydroxy-3-methylazetidin-1-yl)-3-methylbutan-2-yl)-N-
methylbenzamide
N-Methyl-N-[(1S)-2-methyl-1-(pyrrolidin-1-ylmethyl)propyl]benzamide
(S)-4-Chloro-N-(1-(3,3-difluoropyrrolidin-1-yl)-3-methylbutan-2-yl)-N-
methylbenzamide
3-Chloro-4-fluoro-N-methyl-N-[(1R)-2-methyl-1-(pyrrolidin-1-
ylmethyl)propyl]benzamide
N-Methyl-N-[(1R)-2-methyl-1-(pyrrolidin-1-ylmethyl)propyl]-2-
(trifluoromethoxy)benzamide
3-Cyano-N-methyl-N-[(1R)-2-methyl-1-(pyrrolidin-1-ylmethyl)propyl]benzamid-
e
2,3,5-Trifluoro-N-methyl-N-[(1S)-2-methyl-1-(piperidin-1-ylmethyl)propyl]b-
enzamide
(S)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-3-fluoro-4-methoxy-N-methylbe-
nzamide
(S)-N-(1-(Azetidin-1-yl)-3-methylbutan-2-yl)-4-cyano-N-methylbenzamide
N-Methyl-N-[(1S)-2-methyl-1-(piperidin-1-ylmethyl)propyl]-4-
(trifluoromethoxy)benzamide
3-Cyano-N-methyl-N-[(1S)-2-methyl-1-(piperidin-1-ylmethyl)propyl]benzamide
2,3,5-Trifluoro-N-[(1S)-1-{[(3S)-3-hydroxypyrrolidin-1-yl]methyl}-2-methyl-
propyl]- N-methylbenzamide
2-Fluoro-N-[(1S)-1-{[(3S)-3-hydroxypyrrolidin-1-yl]methyl}-2-methylpropyl]-
-N- methyl-5-(trifluoromethyl)benzamide
N-[(1S)-1-{[(3S)-3-Hydroxypyrrolidin-1-yl]methyl}-2-methylpropyl]-N,3-
dimethylbenzamide
3-Cyano-N-[(1S)-1-{[(3S)-3-hydroxypyrrolidin-1-yl]methyl}-2-methylpropyl]--
N- methylbenzamide
4-Fluoro-N-methyl-N-[(1S)-2-methyl-1-(pyrrolidin-1-ylmethyl)propyl]benzami-
de
4-Bromo-N-methyl-N-[(1S)-1-methyl-2-pyrrolidin-1-ylethyl]benzamide
4-Fluoro-N,3-dimethyl-N-(2-methyl-1-(pyrrolidin-1-yl)propan-2-yl)benzamide
4-Fluoro-N-[(1S)-1-[(3-hydroxyazetidin-1-yl)methyl]-2-methyl-propyl]-3-
(hydroxymethyl)-N-methyl-benzamide
N-[(1S)-2-(Azetidin-1-yl)-1-cyclopropyl-ethyl]-4-cyano-N-methyl-benzamide
N-[(1S)-1-[(3,3-Difluoro-1-piperidyl)methyl]-2-methyl-propyl]-3-methoxy-N--
methyl- benzamide
(S)-3,4-Difluoro-N-(1-(3-fluoro-3-(hydroxymethyl)azetidin-1-yl)-3-methylbu-
tan-2-yl)- N-methylbenzamide
3,4-Difluoro-N-((S)-1-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)pentan-2-yl-
)-N- methylbenzamide
4-Cyano-N-((S)-1-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-3-methylbutan-2-yl-
)-N- methylbenzamide
N-((S)-1-((3R,4R)-3,4-Dihydroxypyrrolidin-1-yl)-3-methylbutan-2-yl)-4-fluo-
ro-N,3- dimethylbenzamide
4-Chloro-N-((S)-1-((3R,4R)-3,4-dihydroxypyrrolidin-1-yl)-3-methylbutan-2-y-
l)-N- methylbenzamide
4-Cyano-N-((S)-1-((3R,4R)-3,4-dihydroxypyrrolidin-1-yl)-3-methylbutan-2-yl-
)-N- methylbenzamide
[0855] Inhibition of the human ether-a-go-go-related gene
(hERG)-encoded K.sup.+ channel was determined using hERG-expressing
Chinese hamster ovary K.sub.1 (CHO) cells on a IonWorks.TM. HT
assay platform as described by M. H. Bridgland-Taylor et al. J. of
Pharmacological and Toxicological Methods (2006); 54:189-199. The
results for some compounds according to the invention are presented
in Table 2.
TABLE-US-00049 TABLE 2 Example hERG IC.sub.50 [.mu.M] 1.2 20 1.4
>33 1.17 >100 4.1 >33 4.4 >33 5.1 76 5.2 34 6.1 >100
6.2 >53 7.1 >33 7.2 >33 7.3 >33 8.1 >100 8.2 >57
8.6 >33 10.2 >33 12.1 >100 12.2 >33 16.55 >31 18
>30 19 17 29.7 >33 33.4 18 33.7 79 38.1 >33 38.2 >33
38.6 >33 39.2 80 39.12 >33 39.14 >33 39.16 >33
Pharmacological Activity In Vivo Rabbit
[0856] Efficacy in an in vivo pharmacodynamic (PD) model was
demonstrated using a model in anaesthetized rabbits subjected to
vagal stimulation. Rabbits were anaesthetized using ketalar and
domitor (2.5 and 0.07 mg/kg, respectively) as an i.v. bolus
followed by a maintenance i.v. infusion (11 and 0.33 mg/kg/h,
respectively) and ventilated with room air. Two percutaneous
polyethylene catheter (Venflon 0.8 mm, Viggo, Helsingborg, Sweden)
for administration of anaesthetics and drug infusions,
respectively, were inserted into marginal veins on the right and
left ear. A polyethylene catheter (Intramedic PE 160 Clay Adams,
Becton Dickinson, Sparks, Md., USA) was inserted into the left
carotid artery and advanced to the level of the aortic arch for
blood pressure recording (by means of a pressure transducer, Peter
von Berg Medizintechnik Gmbh, Kirchseeon/Englharting, Germany) and
for blood sampling. For recording of right atrial electrogram and
for atrial pacing, a 4F quadripolar electrophysiological recording
catheters (Electrophysiology catheter--Deflectable tip, Biosense
Webster Inc, Johnson & Johnson, Diamond Bar, Calif., USA) was
advanced into the right jugular vein and positioned high up in the
right atrium (HRA). Electrodes were advanced via introducers (4F
Fast-Cath haemostasis introducer, ST. Jude Medical, DAIG Division,
Inc. Minnetonka, Minn., USA) correctly positioned through
fluoroscopic guidance. The effective refractory period in the right
atrium (RAERP) was determined at a stimulation current strength
approximately 20% above the threshold for pacing the atria. A
custom-made PC-based (AstraZeneca R&D, Molndal, Sweden)
programmable stimulator and constant current pulse generator (WPI
Stimulus Isolator, World Precision Instruments, Sarasota, Fla.,
USA) were used for stimulation at one or two predefined basic cycle
lengths (S1) of for example 200 and 300 ms. A premature extra
stimulus (S2) was introduced after every 10th paced basic beat with
increments of 2 ms until capture. The RAERP was defined as the
longest S1 S2 interval at which S2 failed to capture. For vagal
stimulation, both vagal nerves were ligated and cut in the cervical
region and propranolol (0.5 mg/kg) was administrated as an i.v.
infusion to decrease sympathetic influence. Electrodes were
inserted in the middle of the right vagal nerve to stimulate the
efferent vagi. The RAERP was determined without or with vagal
stimulation at 50% of maximal vagal response. Subsequent infusion
of compound aimed to increase the RAERP with 20 ms during the first
dose of two consecutive doses. The drug infusion was followed by a
washout period of approximately 30-60 min. QT prolongation was
recorded from surface electrocardiography (ECG). The effect on
RAERP was measured several times during infusion and washout and
blood samples were taken at each measurements. Effect and plasma
concentration data was analysed accounting for a
concentration-effect-time delay and the unbound plasma
concentration (Ceu) increasing the RAERP by 20 ms was
calculated.
[0857] The results for some compounds according to the invention
are presented in Table 3.
TABLE-US-00050 TABLE 3 Example C.sub.eu 20 ms [.mu.M] 1.2 0.40 1.4
0.60 1.17 1.40 4.1 0.74 4.4 0.75 5.1 1.00 5.2 0.60 6.1 0.54 6.2
0.40 7.1 5.40 7.2 1.00 7.3 2.10 8.1 0.87 8.2 0.34 8.6 2.50 10.2
1.40 12.1 0.68 12.2 2.20 16.55 0.60 18 0.70 19 0.34 29.7 0.79 33.4
0.52 33.7 0.80 38.1 0.34 38.2 0.38 38.6 0.72 39.2 0.28 39.12 2.06
39.14 0.10 39.16 0.24
[0858] While the invention has been described in detail and with
reference to specific embodiments thereof, it will be apparent for
one skilled in the art that various changes and modifications can
be made therein without departing from the spirit and scope
thereof.
* * * * *