U.S. patent application number 15/388050 was filed with the patent office on 2018-05-10 for kinase inhibitors.
This patent application is currently assigned to CHIESI FARMACEUTICI S.P.A.. The applicant listed for this patent is CHIESI FARMACEUTICI S.P.A.. Invention is credited to Elisabetta ARMANI, Carmelida CAPALDI, Christopher HURLEY, Andrew Steven Robert JENNINGS.
Application Number | 20180127410 15/388050 |
Document ID | / |
Family ID | 55024003 |
Filed Date | 2018-05-10 |
United States Patent
Application |
20180127410 |
Kind Code |
A9 |
CAPALDI; Carmelida ; et
al. |
May 10, 2018 |
KINASE INHIBITORS
Abstract
Compounds of formula (I) defined herein are p38 MAPK inhibitors
and are useful as anti-inflammatory agents in the treatment of,
inter alia, diseases of the respiratory tract.
Inventors: |
CAPALDI; Carmelida; (Parma,
IT) ; ARMANI; Elisabetta; (Parma, IT) ;
JENNINGS; Andrew Steven Robert; (Harlow, GB) ;
HURLEY; Christopher; (Harlow, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CHIESI FARMACEUTICI S.P.A. |
Parma |
|
IT |
|
|
Assignee: |
CHIESI FARMACEUTICI S.P.A.
Parma
IT
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20170183343 A1 |
June 29, 2017 |
|
|
Family ID: |
55024003 |
Appl. No.: |
15/388050 |
Filed: |
December 22, 2016 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 11/0020180101; C07D
471/04 20130101; A61P 11/06 20180101 |
International
Class: |
C07D 471/04 20060101
C07D471/04 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 23, 2015 |
EP |
15202346.1 |
Claims
1. A compound of formula (I): ##STR00031## wherein R.sub.1 is a
group of one of the following formulae: ##STR00032## or a
pharmaceutically acceptable salt thereof.
2. A compound or pharmaceutically acceptable salt according to
claim 1, wherein said compound is an isolated diastereomer of
formula (IA): ##STR00033## or a mixture of diastereoisomers.
3. A compound or pharmaceutically acceptable salt according to
claim 1, wherein said compound is an isolated diastereomer of
formula (IB): ##STR00034## or a mixture of diastereoisomers.
4. A compound or pharmaceutically acceptable salt according to
claim 1, which is a compound selected from the group consisting of:
N-[5-tert-Butyl-3-(3-{(1S,4R)-4-[3-(1-dimethyl
amino-1-methyl-ethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetr-
ahydro-naphthalen-1-yl}-ureido)-2-methoxy-phenyl]-methanesulfonamide;
N-[5-tert-Butyl-2-methoxy-3-(3-{(1
S,4R)-4-[3-((S)-1-methyl-piperidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6--
yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureido)-phenyl]-methanesulfonam-
ide; N-[5-tert-Butyl-3-(3-{(1
S,4R)-4-[3-((S)-1,2-dimethyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyrid-
in-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureido)-2-methoxy-phenyl]--
methanesulfonamide; N-[5-tert-Butyl-3-(3-{(1
S,4R)-4-[3-((S)-1-isopropyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridi-
n-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureido)-2-methoxy-phenyl]-m-
ethanesulfonamide hydrochloride salt; N-[5-tert-Butyl-3-(3-{(1
S,4R)-4-[3-((S)-1-dimethylamino-2-methyl-propyl)-[1,2,4]triazolo[4,3-a]py-
ridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureido)-2-methoxy-pheny-
l]-methanesulfonamide;
N-[5-tert-Butyl-3-(3-{(1S,4R)-4-[3-((R)-1,2-dimethyl-pyrrolidin-2-yl)-[1,-
2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ur-
eido)-2-methoxy-phenyl]-methanesulfonamide;
N-[5-tert-Butyl-3-(3-{(1S,4R)-4-[3-((2S,5S)-1,5-dimethyl-pyrrolidin-2-yl)-
-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl-
}-ureido)-2-methoxy-phenyl]-methanesulfonamide;
N-[5-tert-Butyl-3-(3-{(1S,4S)-4-[3-((2S,5S)-1,5-dimethyl-pyrrolidin-2-yl)-
-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl-
}-ureido)-2-methoxy-phenyl]-methanesulfonamide; and
N-[5-tert-Butyl-3-(3-{(1S,4S)-4-[3-((S)-1,2-dimethyl-pyrrolidin-2-yl)
[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl-
}ureido) 2-methoxy-phenyl]-methanesulfonamide or a pharmaceutically
acceptable salt of said compound.
5. A pharmaceutical composition, comprising a compound or
pharmaceutically acceptable salt according to claim 1 and one or
more pharmaceutically acceptable carriers.
6. A method of treating a disease or condition in a human subject
which benefits from inhibition of p38 MAP kinase activity, said
method comprising administering to a subject in need thereof an
effective amount of a compound or pharmaceutically acceptable salt
according to claim 1.
7. A method according to claim 6, wherein said disease or condition
is chronic eosinophilic pneumonia, asthma, COPD, adult respiratory
distress syndrome, exacerbation of airways hyper-reactivity
consequent to other drug therapy, or airways disease that is
associated with pulmonary hypertension.
8. A method of treating a disease or condition in a human subject
which benefits from inhibition of p38 MAP kinase activity, said
method comprising administering to a subject in need thereof an
effective amount of a compound or pharmaceutically acceptable salt
according to claim 2.
9. A method according to claim 8, wherein said disease or condition
is chronic eosinophilic pneumonia, asthma, COPD, adult respiratory
distress syndrome, exacerbation of airways hyper-reactivity
consequent to other drug therapy, or airways disease that is
associated with pulmonary hypertension.
10. A method of treating a disease or condition in a human subject
which benefits from inhibition of p38 MAP kinase activity, said
method comprising administering to a subject in need thereof an
effective amount of a compound or pharmaceutically acceptable salt
according to claim 3.
11. A method according to claim 10, wherein said disease or
condition is chronic eosinophilic pneumonia, asthma, COPD, adult
respiratory distress syndrome, exacerbation of airways
hyper-reactivity consequent to other drug therapy, or airways
disease that is associated with pulmonary hypertension.
12. A method of treating a disease or condition in a human subject
which benefits from inhibition of p38 MAP kinase activity, said
method comprising administering to a subject in need thereof an
effective amount of a compound or pharmaceutically acceptable salt
according to claim 4.
13. A method according to claim 12, wherein said disease or
condition is chronic eosinophilic pneumonia, asthma, COPD, adult
respiratory distress syndrome, exacerbation of airways
hyper-reactivity consequent to other drug therapy, or airways
disease that is associated with pulmonary hypertension.
Description
CROSS REFERENCES TO RELATED APPLICATIONS
[0001] This application claims priority to European Patent
Application No. 15202346.1 filed on Dec. 23, 2015, which is
incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] Field of the Invention
[0003] The present invention relates to compounds and compositions
that are p38 MAPK inhibitors and are useful as anti-inflammatory
agents in the treatment of, inter alia, diseases of the respiratory
tract.
[0004] Discussion of the Background
[0005] Mitogen activated protein kinases (MAPK) constitute a family
of proline-directed serine/threonine kinases that activate their
substrates by dual phosphorylation. There are four known human
isoforms of p38 MAP kinase, p38.alpha., p38.beta., p38.gamma., and
p38.delta.. The p38 kinases, which are also known as cytokine
suppressive anti-inflammatory drug binding proteins (CSBP), stress
activated protein kinases (SAPK) and RK, are responsible for
phosphorylating (see Stein et al., Ann. Rep. Med Chem., 1996, 31,
289-298, which is incorporated herein by reference in its entirety)
and activating transcription factors (such as ATF-2, MAX, CHOP and
C/ERPb) as well as other kinases (such as MAPKAP-K2/3 or MK2/3),
and are themselves activated by physical and chemical stress (e.g.
UV, osmotic stress), pro-inflammatory cytokines and bacterial
lipopolysaccharide (LPS) (see Herlaar E. & Brown Z., Molecular
Medicine Today, 1999, 5, 439-447, which is incorporated herein by
reference in its entirety). The products of p38 phosphorylation
have been shown to mediate the production of inflammatory
cytokines, including tumor necrosis factor alpha (TNF .alpha.) and
interleukin-(IL)-1, and cyclooxygenase-2 (COX-2). IL-1 and
TNF.alpha. are also known to stimulate the production of other
proinflammatory cytokines such as IL-6 and IL-8.
[0006] IL-1 and TNF.alpha. are biological substances produced by a
variety of cells, such as monocytes or macrophages. IL-1 has been
demonstrated to mediate a variety of biological activities thought
to be important in immunoregulation and other physiological
conditions such as inflammation (see, e.g. Dinarello et al., Rev.
Infect. Disease, 1984, 6, 51, which is incorporated herein by
reference in its entirety). Excessive or unregulated TNF production
(particularly TNF.alpha.) has been implicated in mediating or
exacerbating a number of diseases, and it is believed that TNF can
cause or contribute to the effects of inflammation in general. IL-8
is a chemotactic factor produced by several cell types including
mononuclear cells, fibroblasts, endothelial cells, and
keratinocytes. Its production from endothelial cells is induced by
IL-1, TNF, or lipopolysaccharide (LPS). IL-8 stimulates a number of
functions in vitro. It has been shown to have chemoattractant
properties for neutrophils, T-lymphocytes and basophils. Increase
in IL-8 production is also responsible for chemotaxis of
neutrophils into the inflammatory site in vivo.
[0007] Inhibition of signal transduction via p38, which in addition
to IL-1, TNF and IL-8 described above is also required for the
synthesis and/or action of several additional pro-inflammatory
proteins (e.g., IL-6, GM-CSF, COX-2, collagenase and stromelysin),
is expected to be a highly effective mechanism for regulating the
excessive and destructive activation of the immune system. This
expectation is supported by the potent and diverse
anti-inflammatory activities described for p38 kinase inhibitors
(see Badger et al., J. Pharm. Exp. Thera., 1996, 279, 1453-1461;
Griswold et al, Pharmacol. Comm., 1996, 7, 323-229, both of which
are incorporated herein by reference in their entireties). In
particular, p38 kinase inhibitors have been described as potential
agents for treating rheumatoid arthritis. In addition to the links
between p38 activation and chronic inflammation and arthritis,
there is also data implicating a role for p38 in the pathogenesis
of airway diseases in particular COPD and asthma. Stress stimuli
(including tobacco smoke, infections or oxidative products) can
cause inflammation within the lung environment Inhibitors of p38
have been shown to inhibit LPS and ovalbumin induced airway
TNF-.alpha. IL-1.beta., IL-6, IL-4, IL-5 and IL-13 (see Haddad et
al, Br. J. Pharmacol., 2001, 132 (8), 1715-1724; Underwood et al,
Am. J. Physiol. Lung Cell. Mol. 2000, 279, 895-902; Duan et al.,
2005 Am. J. Respir. Crit. Care Med., 171, 571-578; Escott et al Br.
J. Pharmacol., 2000, 131, 173-176; Underwood et al., J. Pharmacol.
Exp. Ther. 2000, 293, 281-288, all of which are incorporated herein
by reference in their entireties). Furthermore, they significantly
inhibit neutrophilia and the release of MMP-9 in LPS, ozone or
cigarette smoke animal models. There is also a significant body of
preclinical data highlighting the potential benefits of inhibition
of the p38 kinase that could be relevant in the lung (see Lee et
al., Immunopharmacology, 2000, 47, 185-200, which is incorporated
herein by reference in its entirety). Thus, therapeutic inhibition
of p38 activation may be important in the regulation of airway
inflammation.
[0008] The implication of the p38MAPK pathway in various diseases
has been reviewed by P. Chopra et al. (Expert Opinion on
Investigational Drugs, 2008, 17(10), 1411-1425, which is
incorporated herein by reference in its entirety). It is believed
that the compounds of the present invention can be used to treat
p38 mediated diseases such as: chronic obstructive pulmonary
disease (COPD), asthma, chronic or acute bronchoconstriction,
bronchitis, acute lung injury and bronchiectasis, pulmonary artery
hypertension, tuberculosis, lung cancer, inflammation generally
(e.g. inflammatory bowel disease), arthritis, neuroinflammation,
pain, fever, fibrotic diseases, pulmonary disorders and diseases
(e.g., hyperoxic alveolar injury), cardiovascular diseases,
post-ischemic reperfusion injury and congestive heart failure,
cardiomyopathy, stroke, ischemia, reperfusion injury, renal
reperfusion injury, brain edema, neurotrauma and brain trauma,
neurodegenerative disorders, central nervous system disorders,
liver disease and nephritis, gastrointestinal conditions,
ulcerative diseases, Crohn's disease, ophthalmic diseases,
ophthalmological conditions, glaucoma, acute injury to the eye
tissue and ocular traumas, diabetes, diabetic nephropathy,
skin-related conditions, myalgias due to infection, influenza,
endotoxic shock, toxic shock syndrome, autoimmune disease, graft
rejection, bone resorption diseases, multiple sclerosis, psoriasis,
eczema, disorders of the female reproductive system, pathological
(but non-malignant) conditions, such as hemangiomas, angiofibroma
of the nasopharynx, and avascular necrosis of bone, benign and
malignant tumors/neoplasia including cancer, leukaemia, lymphoma,
systemic lupus erythematosus (SLE), angiogenesis including
neoplasia, haemorrhage, coagulation, radiation damage, and/or
metastasis. Chronic release of active TNF can cause cachexia and
anorexia, and TNF can be lethal. TNF has also been implicated in
infectious diseases. These include, for example, malaria,
mycobacterial infection and meningitis. These also include viral
infections, such as HIV, influenza virus, and herpes virus,
including herpes simplex virus type-1 (HSV-1), herpes simplex virus
type-2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus
(VZV), Epstein-Barr virus, human herpes virus-6 (HHV-6), human
herpesvirus-7 (HHV7), human herpesvirus-8 (HHV-8), pseudorabies and
rhinotracheitis, among others.
[0009] Known P38 kinase inhibitors have been reviewed by G. J.
Hanson (Expert Opinions on Therapeutic Patents, 1997, 7, 729-733,
which is incorporated herein by reference in its entirety) J Hynes
et al. (Current Topics in Medicinal Chemistry, 2005, 5, 967-985,
which is incorporated herein by reference in its entirety), C.
Dominguez et al (Expert Opinions on Therapeutics Patents, 2005, 15,
801-816, which is incorporated herein by reference in its
entirety), and L. H. Pettus & R. P. Wurtz (Current Topics in
Medicinal Chemistry, 2008, 8, 1452-1467, which is incorporated
herein by reference in its entirety).
[0010] WO 2013/083604, which is incorporated herein by reference in
its entirety, describes potent p38 MAP Kinase inhibitors.
[0011] However, there remains a need for improved compounds and
compositions that are p38 MAPK inhibitors and are useful as
anti-inflammatory agents in the treatment of, inter alia, diseases
of the respiratory tract.
SUMMARY OF THE INVENTION
[0012] Accordingly, it is one object of the present invention to
provide novel kinase inhibitors.
[0013] It is another object of the present invention to provide
novel compounds which are p38 MAPK inhibitors and are useful as
anti-inflammatory agents in the treatment of, inter alia, diseases
of the respiratory tract.
[0014] It is another object of the present invention to provide
novel compounds which are p38 MAPK inhibitors and are useful as
anti-inflammatory agents in the treatment of, inter alia, diseases
of the respiratory tract.
[0015] It is another object of the present invention to provide
novel pharmaceutical compositions which contain such a
compound.
[0016] It is another object of the present invention to provide
novel methods for the treatment of, inter alia, diseases of the
respiratory tract.
[0017] These and other objects, which will become apparent during
the following detailed description, have been achieved by the
inventors' discovery of compounds of formula (I) described
below.
[0018] Thus, the compounds of the present invention are inhibitors
of p38 mitogen activated protein kinase ("p38 MAPK," "p38 kinase,"
or "p38"), including p38.alpha. kinase, and are inhibitors of
cytokine and chemokine production including TNF.alpha. and IL-8
production. They have a number of therapeutic applications, in the
treatment of inflammatory diseases, particularly allergic and
non-allergic airways diseases, more particularly obstructive or
inflammatory airways diseases such as chronic obstructive pulmonary
disease ("COPD") and asthma. They are therefore particularly suited
for pulmonary delivery, by inhalation by nose or mouth.
[0019] Thus, another object of the present invention is to identify
more potent anti-inflammatory agents to be used in the treatment of
diseases of the respiratory tract.
[0020] Surprisingly, the compounds of the present invention show a
higher potency in BEAS-2B test than the compounds described in WO
2013/083604, which is incorporated herein by reference in its
entirety.
[0021] The BEAS-2B cells are Bronchial Epithelial cells and it is
known in the literature that this cell line releases IL-8 upon
stimulation with TNF.alpha. (see Chmura K, Bai X, Nakamura M,
Kandasamy P, McGibney M, Kuronuma K, Mitsuzawa H, Voelker D R, Chan
E D. Am J Physiol Lung Cell Mol Physiol. 2008; 295(1):L220-30; King
E M, Holden N S, Gong W, Rider C F, Newton R. J Biol Chem. 2009;
284(39):26803-15; Carta S, Silvestri M, and Giovanni A Ital J
Pediatr. 2013; 39: 29) and p38 inhibitors inhibit the release of
IL-8 in TNF.alpha. stimulated BEAS-2B cells (King E M, Holden N S,
Gong W, Rider C F, Newton R. J Biol Chem. 2009; 284(39):26803-15,
all of which are incorporated herein by reference in their
entireties).
[0022] Another object of the present invention is to identify novel
potent p38 mitogen activated protein kinase inhibitors which show
an appropriate developability profile on inhalatory administration
to effectively treat respiratory obstructive or inflammatory
diseases. It is to be understood that such profile may be achieved
in a number of different ways by modulation of specific properties;
by way of example, it could be achieved by administration of a low
effective dose of the drug thus limiting side effects or via a long
duration of action in the lungs which may reduce the frequency of
administration.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0023] Thus, the present invention provides compounds of formula
(I):
##STR00001##
wherein
[0024] R.sub.1 is selected from the group consisting of
##STR00002##
and pharmaceutically acceptable salts thereof.
[0025] In another aspect, the present invention provides
pharmaceutical compositions comprising a compound of the invention,
together with one or more pharmaceutically acceptable carriers
and/or excipients. Particularly preferred are compositions adapted
for inhalation for pulmonary administration.
[0026] In another aspect, the present invention provides the use of
a compound of the invention for the treatment of diseases or
conditions which benefit from inhibition of p38 MAP kinase
activity. The treatment of obstructive or inflammatory airways
diseases is a preferred use. All forms of obstructive or
inflammatory airways diseases are potentially treatable with the
compounds of the present invention, in particular an obstructive or
inflammatory airways disease that is a member selected from the
group consisting of chronic eosinophilic pneumonia, asthma, COPD,
COPD that includes chronic bronchitis, pulmonary emphysema or
dyspnea associated or not associated with COPD, COPD that is
characterized by irreversible, progressive airways obstruction,
adult respiratory distress syndrome (ARDS), exacerbation of airways
hyper-reactivity consequent to other drug therapy and airways
disease that is associated with pulmonary hypertension, chronic
inflammatory diseases including cystic fibrosis, bronchiectasis and
pulmonary fibrosis (Idiopathic). Efficacy is anticipated when p38
kinase inhibitors are administered either locally to the lung (for
example by inhalation and intranasal delivery) or via systemic
routes (for example, oral, intravenous and subcutaneous
delivery).
[0027] Compounds of the invention may exist in one or more
geometrical, optical, enantiomeric, diastereomeric and tautomeric
forms, including but not limited to cis- and trans-forms, E- and
Z-forms, R-, S- and meso-forms, keto-, and enol-forms. Unless
otherwise stated a reference to a particular compound includes all
such isomeric forms, including racemic and other mixtures thereof.
Where appropriate such isomers can be separated from their mixtures
by the application or adaptation of known methods (e.g.
chromatographic techniques and recrystallization techniques). Where
appropriate such isomers may be prepared by the application of
adaptation of known methods (e.g. asymmetric synthesis).
[0028] Throughout the specification the use of an asterisk "*" in
the definition of a structural formula, indicates the point of
attachment for the radical group to the rest of the molecule.
[0029] It is expected that compounds of the invention may be
prepared in the form of hydrates, and solvates. Any reference
herein, including the claims herein, to "compounds with which the
invention is concerned" or "compounds of the invention" or "the
present compounds", and the like, includes reference to salts
hydrates, and solvates of such compounds. The term `solvate` is
used herein to describe a molecular complex comprising the compound
of the invention and a stoichiometric amount of one or more
pharmaceutically acceptable solvent molecules, for example,
ethanol. The term `hydrate` is employed when said solvent is
water.
[0030] Individual compounds of the invention may exist in several
polymorphic forms and may be obtained in different crystal or
co-crystal habits, and they are intended to be included within the
meaning of the term "compounds of the invention".
[0031] The compounds may also be administered in the form of
prodrugs thereof. Thus certain derivatives of the compounds which
may be active in their own right or may have little or no
pharmacological activity themselves can, when administered into or
onto the body, be converted into compounds of the invention having
the desired activity, for example, by hydrolytic cleavage. Such
derivatives are referred to as `prodrugs`. Further information on
the use of prodrugs may be found in Pro-drugs as Novel Delivery
Systems, Vol. 14, ACS Symposium Series (T. Higuchi and V. J.
Stella) and Bioreversible Carriers in Drug Design, Pergamon Press,
1987 (ed. E. B. Roche, American Pharmaceutical Association; C. S.
Larsen and J. Ostergaard, Design, In Textbook of Drug Design and
Discovery, 3.sup.rd Edition, 2002, Taylor and Francis, all of which
are incorporated herein by reference in their entireties, and
application of prodrugs).
[0032] Prodrugs in accordance with the present invention can, for
example, be produced by replacing appropriate functionalities
present in the compounds of formula (I) with certain moieties known
to those skilled in the art as `pro-moieties` as described, for
example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985,
which is incorporated herein by reference in its entirety). Such
examples could be a prodrug of a carboxyl group (such as
--CO--O--CH.sub.2--O--CO-tBu as used in the pivampicillin prodrug
of ampicillin), an amide (--CO--NH--CH.sub.2--NAlk.sub.2) or an
amidine (--C(.dbd.N--O--CH.sub.3)--NH.sub.2).
[0033] In one embodiment, a compound of formula (I) is present in
diastereomeric forms (IA) and (IB), depicted below:
##STR00003##
and mixtures thereof.
[0034] In one embodiment, a compound of formula (I) is selected
from the group consisting of: [0035] N-[5-tert-Butyl-3-(3-{(1
S,4R)-4-[3-(1-dimethylamino-1-methyl-ethyl)-[1,2,4]triazolo[4,3-a]pyridin-
-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureido)-2-methoxy-phenyl]-me-
thanesulfonamide; [0036] N-[5-tert-Butyl-2-methoxy-3-(3-{(1
S,4R)-4-[3-((S)-1-methyl-piperidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6--
yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureido)-phenyl]-methanesulfonam-
ide; [0037] N-[5-tert-Butyl-3-(3-{(1
S,4R)-4-[3-((S)-1,2-dimethyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyrid-
in-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureido)-2-methoxy-phenyl]m-
ethanesulfonamide; [0038]
N-[5-tert-Butyl-3-(3-{(1S,4R)-4-[3-((S)-1-isopropyl-pyrrolidin-2-yl)-[1,2-
,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ure-
ido)-2-methoxy-phenyl]-methanesulfonamide hydrochloride salt;
[0039]
N-[5-tert-Butyl-3-(3-{(1S,4R)-4-[3-((S)-1-dimethylamino-2-methyl-propyl)--
[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-
-ureido)-2-methoxy-phenyl]-methanesulfonamide; [0040]
N-[5-tert-Butyl-3-(3-{(1S,4R)-4-[3-((R)-1,2-dimethyl-pyrrolidin-2-yl)-[1,-
2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ur-
eido)-2-methoxy-phenyl]-methanesulfonamide; [0041]
N-[5-tert-Butyl-3-(3-{(1S,4R)-4-[3-((2S,5S)-1,5-dimethyl-pyrrolidin-2-yl)-
-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl-
}-ureido)-2-methoxy-phenyl]-methanesulfonamide; [0042]
N-[5-tert-Butyl-3-(3-{(1S,4S)-4-[3-((2S,5S)-1,5-dimethyl-pyrrolidin-2-yl)-
-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl-
}-ureido)-2-methoxy-phenyl]-methanesulfonamide; and [0043]
N-[5-tert-Butyl-3-(3-{(1S,4S)-4-[3-((S)-1,2-dimethyl-pyrrolidin-2-yl)
[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl-
}ureido) 2-methoxy-phenyl]-methanesulfonamide, and pharmaceutically
acceptable salts thereof.
[0044] As mentioned above the compounds of the invention are
p38MAPK inhibitors, and thus may have utility for the treatment of
diseases or conditions which benefit from inhibition of the p38
enzyme. Such diseases and conditions are known from the literature
and several have been mentioned above. However, the compounds are
generally of use as anti-inflammatory agents, particularly for use
in the treatment of respiratory disease. In particular, the
compounds may be used in the treatment of chronic obstructive
pulmonary disease (COPD), chronic bronchitis, lung fibrosis,
pneumonia, acute respiratory distress syndrome (ARDS), pulmonary
emphysema, or smoking-induced emphysema, intrinsic (non-allergic
asthma and extrinsic (allergic) asthma, mild asthma, moderate
asthma, severe asthma, steroid resistant asthma, neutrophilic
asthma, bronchitic asthma, exercise induced asthma, occupational
asthma and asthma induced following bacterial infection, cystic
fibrosis, pulmonary fibrosis and bronchiectasis.
[0045] The present invention provides the use of the compounds of
the invention for the prevention and/or treatment of any disease or
condition which benefit from inhibition of the p38 enzyme.
[0046] In a further aspect the present invention provides the use
of compounds of the invention for the preparation of a medicament
for the prevention and/or treatment of any disease or condition
which benefit from inhibition of the p38 enzyme.
[0047] Moreover the present invention provides a method for
prevention and/or treatment of any disease which benefit from
inhibition of the p38 enzyme, said method comprises administering
to a patient in need of such treatment a therapeutically effective
amount of a compound of the invention.
[0048] As mentioned above, the compounds with which the invention
is concerned are p38 kinase inhibitors, and are useful in the
treatment of several diseases for example inflammatory diseases of
the respiratory tract. Examples of such diseases are referred to
above, and include asthma, rhinitis, allergic airway syndrome,
bronchitis and chronic obstructive pulmonary disease.
[0049] It will be understood that the specific dose level for any
particular patient will depend upon a variety of factors including
the activity of the specific compound employed, the age, body
weight, general health, sex, diet, time of administration, route of
administration, rate of excretion, drug combination and the
severity of the particular disease undergoing treatment. Optimum
dose levels and frequency of dosing will be determined by clinical
trial, as is required in the pharmaceutical art. In general, the
daily dose range for oral administration will lie within the range
of from about 0.001 mg to about 100 mg per kg body weight of a
human, often 0.01 mg to about 50 mg per kg, for example 0.1 to 10
mg per kg, in single or divided doses. In general, the daily dose
range for inhaled administration will lie within the range of from
about 0.1 .mu.g to about 1 mg per kg body weight of a human,
preferably 0.1 .mu.g to 50 .mu.g per kg, in single or divided
doses. On the other hand, it may be necessary to use dosages
outside these limits in some cases. For the purpose of the
invention, inhaled administration is preferred.
[0050] The compounds with which the invention is concerned may be
prepared for administration by any route consistent with their
pharmacokinetic properties. Orally administrable compositions may
be in the form of tablets, capsules, powders, granules, lozenges,
liquid or gel preparations, such as oral, topical, or sterile
parenteral solutions or suspensions. Tablets and capsules for oral
administration may be in unit dose presentation form, and may
contain conventional excipients such as binding agents, for example
syrup, acacia, gelatin, sorbitol, tragacanth, or
polyvinyl-pyrrolidone; fillers for example lactose, sugar,
maize-starch, calcium phosphate, sorbitol or glycine; tabletting
lubricant, for example magnesium stearate, talc, polyethylene
glycol or silica; disintegrants for example potato starch, or
acceptable wetting agents such as sodium lauryl sulfate. The
tablets may be coated according to methods well known in normal
pharmaceutical practice. Oral liquid preparations may be in the
form of, for example, aqueous or oily suspensions, solutions,
emulsions, syrups or elixirs, or may be presented as a dry product
for reconstitution with water or other suitable vehicle before use.
Such liquid preparations may contain conventional additives such as
suspending agents, for example sorbitol, syrup, methyl cellulose,
glucose syrup, gelatin hydrogenated edible fats; emulsifying
agents, for example lecithin, sorbitan monooleate, or acacia;
non-aqueous vehicles (which may include edible oils), for example
almond oil, fractionated coconut oil, oily esters such as
glycerine, propylene glycol, or ethyl alcohol; preservatives, for
example methyl or propyl p-hydroxybenzoate or sorbic acid, and if
desired conventional flavouring or colouring agents.
[0051] For topical application to the skin, the drug may be made up
into a cream, lotion or ointment. Cream or ointment formulations
which may be used for the drug are conventional formulations well
known in the art, for example as described in standard textbooks of
pharmaceutics such as the British Pharmacopoeia, which is
incorporated herein by reference in its entirety.
[0052] The active ingredient may also be administered parenterally
in a sterile medium. Depending on the vehicle and concentration
used, the drug can either be suspended or dissolved in the vehicle.
Advantageously, adjuvants such as a local-anaesthetic, preservative
and buffering agents can be dissolved in the vehicle.
[0053] However, for treatment of an inflammatory disease of the
respiratory tract, compounds of the invention may also be
formulated for inhalation, for example as a nasal spray, or dry
powder or aerosol inhalers. For delivery by inhalation, the active
compound is preferably in the form of microparticles. They may be
prepared by a variety of techniques, including spray-drying,
freeze-drying and micronization. Aerosol generation can be carried
out using, for example, pressure-driven jet atomizers or ultrasonic
atomizers, preferably using propellant-driven metered aerosols or
propellant-free administration of micronized active compounds from,
for example, inhalation capsules or other "dry powder" delivery
systems.
[0054] By way of example, a composition of the invention may be
prepared as a suspension for delivery from a nebulizer or as an
aerosol in a liquid propellant, for example for use in a
pressurised metered dose inhaler (PMDI). Propellants suitable for
use in a PMDI are known to the skilled person, and include CFC-12,
HFA-134a, HFA-227, HCFC-22 and HFA-152.
[0055] In a preferred embodiment of the invention, a composition of
the invention is in dry powder form, for delivery using a dry
powder inhaler (DPI). Microparticles for delivery by administration
may be formulated with excipients that aid delivery and release.
For example, in a dry powder formulation, microparticles may be
formulated with large carrier particles that aid flow from the DPI
into the lung. Suitable carrier particles are known, and include
lactose particles; they may have a mass median aerodynamic diameter
of greater than 90 .mu.m.
[0056] In the case of an aerosol-based formulation, an example
is:
TABLE-US-00001 Compound of the invention 24 mg/canister Lecithin,
NF Liq. Conc. 1.2 mg/canister Trichlorofluoromethane, NF 4.025
g/canister Dichlorodifluoromethane, NF 12.15 g/canister.
[0057] The active compounds may be dosed as described depending on
the inhaler system used. In addition to the active compounds, the
administration forms may additionally contain excipients, such as,
for example, propellants (e.g. Frigen in the case of metered
aerosols), surface-active substances, emulsifiers, stabilizers,
preservatives, flavorings, fillers (e.g. lactose in the case of
powder inhalers) or, if appropriate, further active compounds.
[0058] For the purposes of inhalation, a large number of systems
are available with which aerosols of optimum particle size can be
generated and administered, using an inhalation technique which is
appropriate for the patient. In addition to the use of adaptors
(spacers, expanders) and pear-shaped containers (e.g.
Nebulator.RTM., Volumatic.RTM.), and automatic devices emitting a
puffer spray (Autohaler.RTM.), for metered aerosols, in particular
in the case of powder inhalers, a number of technical solutions are
available (e.g. Diskhaler.RTM., Rotadisk.RTM., Turbohaler.RTM. or
the inhalers for example as described EP-A-0 505 321, which is
incorporated herein by reference in its entirety). Additionally,
compounds of the invention may be delivered in multi-chamber
devices thus allowing for delivery of combination agents.
[0059] Other compounds may be combined with compounds with which
the invention is concerned for the prevention and treatment of
inflammatory diseases, in particular respiratory diseases. Thus the
present invention is also concerned with pharmaceutical
compositions comprising a therapeutically effective amount of a
compound of the invention and one or more other therapeutic agents.
Suitable therapeutic agents for a combination therapy with
compounds of the invention include, but are not limited to: (1)
corticosteroids, such as fluticasone propionate, fluticasone
furoate, mometasone furoate, beclometasone dipropionate,
ciclesonide, budesonide, GSK 685698, GSK 870086, QAE 397, QMF 149,
TPI-1020; (2) .beta.2-adrenoreceptor agonists such as salbutamol,
albuterol, terbutaline, fenoterol, and long acting
.beta.2-adrenoreceptor agonists such as salmeterol, indacaterol,
formoterol (including formoterol fumarate), arformoterol,
carmoterol, GSK 642444, GSK 159797, GSK 159802, GSK 597501, GSK
678007, AZD3199; (3) corticosteroid/long acting .beta.2 agonist
combination products such as salmeterol/fluticasone propionate
(Advair/Seretide), formoterol/budesonide (Symbicort),
formoterol/fluticasone propionate (Flutiform),
formoterol/ciclesonide, formoterol/mometasone furoate,
formoterol/beclometasone dipropionate, indacaterol/mometasone
furoate, Indacaterol/QAE 397, GSK 159797/GSK 685698, GSK 159802/GSK
685698, GSK 642444/GSK 685698, GSK 159797/GSK 870086, GSK
159802/GSK 870086, GSK 642444/GSK 870086, arformoterol/ciclesonide;
(4) anticholinergic agents, for example muscarinic-3 (M3) receptor
antagonists such as ipratropium bromide, tiotropium bromide,
Aclidinium (LAS-34273), NVA-237, GSK 233705, Darotropium, GSK
573719, GSK 961081, QAT 370, QAX 028, EP-101; (5) dual pharmacology
M3-anticholinergic/.beta.2-adrenoreceptor agonists such as
GSK961081, AZD2115 and LAS190792; (6) leukotriene modulators, for
example leukotriene antagonists such as montelukast, zafirulast or
pranlukast or leukotriene biosynthesis inhibitors such as Zileuton
or BAY-1005, or LTB4 antagonists such as Amelubant, or FLAP
inhibitors such as GSK 2190914, AM-103; (7) phosphodiesterase-IV
(PDE-IV) inhibitors (oral or inhaled), such as roflumilast,
cilomilast, Oglemilast, ONO-6126, Tetomilast, Tofimilast, UK
500,001, GSK 256066; (8) antihistamines, for example selective
histamine-1 (H1) receptor antagonists, such as fexofenadine,
citirizine, loratidine or astemizole or dual H1/H3 receptor
antagonists such as GSK 835726, GSK 1004723, or selective
histamine-4 (H4) receptor antagonists, such as ZPL3893787; (9)
antitussive agents, such as codeine or dextramorphan; (10) a
mucolytic, for example N acetyl cysteine or fudostein; (11) a
expectorant/mucokinetic modulator, for example ambroxol, hypertonic
solutions (e.g. saline or mannitol) or surfactant; (12) a peptide
mucolytic, for example recombinant human deoxyribonoclease I
(dornase-alfa and rhDNase) or helicidin; (13) antibiotics, for
example azithromycin, tobramycin and aztreonam; (14) non-selective
COX-1/COX-2 inhibitors, such as ibuprofen or ketoprofen; (15) COX-2
inhibitors, such as celecoxib and rofecoxib; (16) VLA-4
antagonists, such as those described in WO97/03094 and WO97/02289,
which are incorporated herein by reference in their entireties;
(17) TACE inhibitors and TNF-.alpha. inhibitors, for example
anti-TNF monoclonal antibodies, such as Remicade and CDP-870 and
TNF receptor immunoglobulin molecules, such as Enbrel; (18)
inhibitors of matrix metalloprotease, for example MMP-12; (19)
human neutrophil elastase inhibitors, such as ONO-6818 or those
described in WO2005/026124, WO2003/053930, and WO06/082412, which
are incorporated herein by reference in their entireties; (20) A2b
antagonists such as those described in WO2002/42298, which is
incorporated herein by reference in its entirety; (21) modulators
of chemokine receptor function, for example antagonists of CCR3 and
CCR8; (22) compounds which modulate the action of other prostanoid
receptors, for example a thromboxane A.sub.2 antagonist; DP1
antagonists such as MK-0524, CRTH2 antagonists such as ODC9101 and
00000459 and AZD1981 and mixed DP1/CRTH2 antagonists such as AMG
009 and AMG853; (23) PPAR agonists including PPAR alpha agonists
(such as fenofibrate), PPAR delta agonists, PPAR gamma agonists
such as Pioglitazone, Rosiglitazone and Balaglitazone; (24)
methylxanthines such as theophylline or aminophylline and
methylxanthine/corticosteroid combinations such as
theophylline/budesonide, theophylline/fluticasone propionate,
theophylline/ciclesonide, theophylline/mometasone furoate and
theophylline/beclometasone dipropionate; (25) A2a agonists such as
those described in EP 1 052 264 and EP 1 241 176, which are
incorporated herein by reference in their entireties; (26) CXCR2 or
IL-8 antagonists such as SCH 527123 or GSK 656933; (27) IL-R
signalling modulators such as kineret and ACZ 885; and (28) MCP-1
antagonists such as ABN-912.
[0060] The present invention is also directed to a kit comprising
the pharmaceutical compositions of compounds of the invention alone
or in combination with or in admixture with one or more
pharmaceutically acceptable carriers and/or excipients and a device
which may be a single- or multi-dose dry powder inhaler, a metered
dose inhaler or a nebulizer.
Methods of Synthesis
[0061] In one aspect of the present invention, a process for the
preparation of compounds of the invention is provided, according to
general synthetic routes described in this section. In the
following reaction schemes, unless otherwise indicated, the groups
mentioned assume the same meaning as those reported for compounds
of formula (I).
[0062] The skilled person may introduce, where appropriate,
suitable variations to the conditions specifically described in the
experimentals in order to adapt the synthetic routes to the
provision of further compounds of the invention. Such variations
may include, but are not limited to, use of appropriate starting
materials to generate different compounds, changes in the solvent
and temperature of reactions, replacements of reactives with
analogous chemical role, introduction or removal of
protection/deprotection stages of functional groups sensitive to
reaction conditions and reagents, as well as introduction or
removal of specific synthetic steps oriented to further
functionalisation of the chemical scaffold.
[0063] Processes which can be used and are described and reported
in the Examples and Schemes, should not be viewed as limiting the
scope of the synthetic methods available for the preparation of the
compounds of the invention.
[0064] The process described is particularly advantageous as it is
susceptible of being properly modulated, through any proper variant
known to the skilled person, so as to obtain any of the desired
compounds of the invention. Such variants are comprised within the
scope of the present invention.
[0065] From all of the above, it should be clear to the skilled
person that any of the described groups may be present as such or
in any properly protected form.
[0066] In particular, functional groups present in the intermediate
and compounds and which could generate unwanted side reaction and
by-products, need to be properly protected before the alkylation,
acylation, coupling or sulfonylation takes place. Likewise,
subsequent deprotection of those same protected groups may follow
upon completion of the said reactions.
[0067] In the present invention, unless otherwise indicated, the
term "protecting group" designates a protective group adapted to
preserve the function of the group it is bound to. Typically,
protective groups are used to preserve amino, hydroxyl, or carboxyl
functions. Appropriate protecting groups may thus include, for
example, benzyl, benzyloxycarbonyl, t-butoxycarbonyl, alkyl or
benzyl esters or the like, which are well known to those skilled in
the art (see, for a general reference, T. W. Green; Protective
Groups in Organic Synthesis (Wiley, N.Y. 1981), which is
incorporated herein by reference in its entirety).
[0068] Likewise, selective protection and deprotection of any of
the said groups, for instance including carbonyl, hydroxyl or amino
groups, may be accomplished according to very well-known methods
commonly employed in organic synthetic chemistry.
[0069] Optional salification of the compounds of formula (I) may be
carried out by properly converting any of the free acidic or amino
groups into the corresponding pharmaceutically acceptable salts. In
this case too, the operative conditions being employed for the
optional salification of the compounds of the invention are all
within the ordinary knowledge of the skilled person.
[0070] From all of the above, it should be clear that the above
process, comprehensive of any variant thereof for the preparation
of suitable compounds of the invention, may be conveniently
modified so that to adapt the reaction conditions to the specific
needs, for instance by choosing appropriate condensing agents,
solvents and protective groups, as the case may be.
[0071] For example compounds of the invention of formula (I) may be
prepared according to the route illustrated in Scheme 1.
##STR00004##
[0072] Compounds of general formula (I) may be prepared from
compounds of general formula (1b), wherein R.sub.1 is as defined
above, by reaction with a compound of general formula (1c1) or
(1c2) in a suitable solvent such as dimethyl sulfoxide,
1,4-dioxane, DMF, 2-methylTHF, THF or acetonitrile, in the absence
of base (for 1c2) or the presence of a base (either 1c1 or 1c2)
such as diisopropylethylamine or sodium hydroxide at a range of
temperatures, preferably between RT and 100.degree. C.
[0073] Compounds of general formula (1c1) and (1c2) are either
known in the literature or may be prepared from amines of general
formula (1d) according to known procedures (e.g. WO 2006/009741, EP
1 609 789, and WO 2008/033999, all of which are incorporated herein
by reference in their entireties).
[0074] Compound (1d) is known in the literature (see WO
2013/083604, which is incorporated herein by reference in its
entirety).
[0075] Compounds of general formula (1b) may be prepared according
to the route illustrated in Scheme 2.
##STR00005##
[0076] Compounds of general formula (1b) may be prepared from
compounds of general formula (2b) by reaction with compound (2a),
wherein G is a suitable chemical group known to those skilled in
the art selected such that it can facilitate a suitable coupling
reaction such as nucleophilic displacement or metal catalysed cross
coupling. For example G may include halogen or a suitable leaving
group such as mesylate or triflate.
[0077] Compounds of general formula (2a), (2b) and (1b) may exist
in one or more geometrical, optical, enantiomeric, diastereomeric
and tautomeric forms, including but not limited to cis- and
trans-forms, E- and Z-forms, R-, S- and meso-forms, keto-, and
enol-forms.
[0078] Examples of the coupling conditions used may include using a
base such as sodium hydride or potassium tert-butoxide and
18-crown-6 or 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone in
a suitable solvent such as N,N-dimethylformamide, 2-methylTHF,
toluene, 1,4-dioxane or acetonitrile at a range of temperatures,
preferably between RT and 150.degree. C.
[0079] Compounds of formula (2b) may be prepared according to the
route in Scheme 3.
##STR00006##
[0080] Compounds of general formula (2b) may be prepared from
compounds of general formula (3e) as above reported using a
suitable oxidant such as chloramine T, lead tetracetate or
phenyliodine(III) diacetate, in a suitable solvent such as
dichloromethane or ethanol at a range of temperatures, preferably
between RT and 100.degree. C., wherein R2 is selected on the group
consisting of
##STR00007##
[0081] Compounds of general formula (3e) may be prepared from
compounds of general formula (3a) by reaction with an aldehyde of
general formula (3c) in a suitable solvent such as ethanol or
tetrahydrofuran at a range of temperatures, preferably between RT
and 80.degree. C.
[0082] Compounds of formula (3a) and (3c) are known in the
literature or may be prepared by literature methods by those
skilled in the art.
[0083] Alternatively, compounds of formula (2b) may be prepared
from compounds of formula (3d) using a suitable dehydrating agent
such as Burgess' reagent, triphenyl phosphine and hexachloroethane,
phosphorus oxychloride, acetic acid or Mitsunobu conditions
(diethylazodicarboxylate/triphenylphosphine/trimethylsilylazide),
in the absence or presence of a suitable solvent such as
tetrahydrofuran, toluene or NMP, at a range of temperatures,
preferably between RT and 120.degree. C.
[0084] Compounds of formula (3d) may be prepared from compounds of
formula (3a) by reaction with a compound of general formula (3b1)
using a suitable acylating/dehydrating agent such as
triphenylphosphine/trichloroacetonitrile/HOBt/2-(7-aza-1H-benzotriazole-1-
-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate or
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide in the presence of a
base such as diisopropylethylamine, in a suitable solvent such as
dichloromethane or acetonitrile, at a range of temperatures,
preferably between RT and 150.degree. C.
[0085] Alternatively, compounds of formula (3d) may be prepared
from compounds of formula (3a) by reaction with a compound of
general formula (3b2) in the presence of a base such as
diisopropylethylamine, in a suitable solvent such as
dichloromethane or THF at a range of temperatures preferably
between -10.degree. C. and the boiling point of the solvent.
Compounds of formulae (3b1) and (3b2) are known in the literature
or may be prepared by adapting appropriate literature methods by
those skilled in the art.
[0086] Compound (2a) is known in the literature (WO 2013/083604,
which is incorporated herein by reference in its entirety).
[0087] Other features of the invention will become apparent in the
course of the following descriptions of exemplary embodiments which
are given for illustration of the invention and are not intended to
be limiting thereof.
EXAMPLES
[0088] Abbreviations used in the experimental section: [0089]
aq.=aqueous; [0090] DCM=dichloromethane; [0091]
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene; [0092]
DIPEA=diisopropylethylamine; [0093] DMF=N,N-dimethylformamide;
[0094] DMSO=dimethyl sulfoxide; [0095]
EDC=1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride;
[0096] EtOAc=ethyl acetate; [0097] EtOH=ethanol; [0098] FCC=flash
column chromatography; [0099] h=hour; [0100] H.sub.2O=water; [0101]
HOBt=1-hydroxy-benzotriazole; [0102] HPLC=high performance liquid
chromatography; [0103] IMS=Industrial Methylated Spirit; [0104]
LCMS=liquid chromatography mass spectrometry; [0105]
MeCN=acetonitrile; [0106] MeOH=methanol; [0107] min=minutes; [0108]
NH.sub.3=ammonia; [0109] NMR=nuclear magnetic resonance; [0110]
RT=room temperature; [0111] Rt=retention time; [0112]
sat.=saturated; [0113] SCX-2=strong cation exchange chromatography;
[0114] TFA=trifluoroacetic acid; and [0115]
THF=tetrahydrofuran.
[0116] In the procedures that follow, after each starting material,
reference to an Intermediate/Example number is usually provided.
This is provided merely for assistance to the skilled chemist. The
starting material may not necessarily have been prepared from the
batch referred to.
[0117] When reference is made to the use of a "similar" or
"analogous" procedure, as will be appreciated by those skilled in
the art, such a procedure may involve minor variations, for example
reaction temperature, reagent/solvent amount, reaction time,
work-up conditions or chromatographic purification conditions.
[0118] The nomenclature of structures was assigned using Autonom
2000 Name software from MDL Inc. When the nomenclature of
structures could not be assigned using Autonom, ACD/Name software
utility part of the ACD/Labs Release 12.00 Product Version 12.5
(Build 45133, 16 Dec. 2010) was used. Stereochemical assignments of
compounds are based on comparisons with data reported in WO
2008/043019, which is incorporated herein by reference in its
entirety, for key intermediates. All reactions were carried out
under anhydrous conditions and an atmosphere of nitrogen or argon
unless specified otherwise.
[0119] NMR spectra were obtained on a Varian Unity Inova 400
spectrometer with a 5 mm inverse detection triple resonance probe
operating at 400 MHz or on a Bruker Avance DRX 400 spectrometer
with a 5 mm inverse detection triple resonance TXI probe operating
at 400 MHz or on a Bruker Avance DPX 300 spectrometer with a
standard 5 mm dual frequency probe operating at 300 MHz. Shifts are
given in ppm relative to tetramethylsilane (.delta.=0 ppm). J
values are given in Hz through-out. NMR spectra were assigned using
DataChord Spectrum Analyst Version 4.0.b21 or SpinWorks version
3.
[0120] Where products were purified by flash column chromatography,
`flash silica` refers to silica gel for chromatography, 0.035 to
0.070 mm (220 to 440 mesh) (e.g. Fluka silica gel 60), and an
applied pressure of nitrogen up to 10 p.s.i accelerated column
elution or use of the CombiFlash.RTM. Companion purification system
or use of the Biotage SP1 purification system. All solvents and
commercial reagents were used as received.
[0121] Compounds purified by preparative HPLC were purified using a
C18-reverse-phase column (100.times.22.5 mm i.d. Genesis column
with 7 .mu.m particle size), or a Phenyl-Hexyl column
(250.times.21.2 mm i.d. Gemini column with 5 .mu.m particle size),
UV detection between 220-254 nm, flow 5-20 mL/min), eluting with
gradients from 100-0 to 0-100% water/acetonitrile (containing 0.1%
TFA or 0.1% formic acid) or a C18-reverse-phase column
(19.times.250 mm, XBridge OBD, with 5 .mu.m particle size), eluting
with gradients from 100-0 to 0-100% water/acetonitrile (containing
0.1% NH.sub.4OH); or a ChiralPak IC column (10.times.250 mm i.d.,
with 5 .mu.m particle size), unless otherwise indicated. Fractions
containing the required product (identified by LCMS analysis) were
pooled, the organic solvent removed by evaporation, and the
remaining aqueous residue lyophilized, to give the final product.
Products purified by preparative HPLC were isolated as free base,
formate or TFA salts, unless otherwise stated.
[0122] The Liquid Chromatography Mass Spectroscopy LCMS systems
used are:
Method 1
[0123] Waters ZMD quadrupole mass spectrometer with a
C18-reverse-phase column (30.times.4.6 mm Phenomenex Luna 3 .mu.m
particle size), elution with A: water+0.1% formic acid; B:
acetonitrile+0.1% formic acid. Gradient:
TABLE-US-00002 Gradient - Time flow mL/min % A % B 0.00 2.0 95 5
0.50 2.0 95 5 4.50 2.0 5 95 5.50 2.0 5 95 6.00 2.0 95 5
[0124] Detection--MS, ELS, UV (200 .mu.L split to MS with in-line
HP1100 DAD detector). MS ionization method--Electrospray (positive
and negative ion).
Method 2 Acquity i-Class (quaternary pump/PDA detector)+Quattro
Micro Mass Spectrometer with an ACQUITY UPLC BEH C.sub.18 1.7
.mu.m, 100.times.2.1 mm, maintained at 40.degree. C. Elution with
A: water+0.1% formic acid; B: acetonitrile+0.1% formic acid.
Gradient:
TABLE-US-00003 [0125] Gradient - Time flow mL/min % A % B 0.00 0.4
95 5 0.40 0.4 95 5 6.00 0.4 5 95 6.80 0.4 5 95 7.00 0.4 95 5 8.00
0.4 95 5
[0126] Detection--MS, UV PDA. MS ionization method--Electrospray
(positive and negative ion).
Method 3
[0127] Waters micromass ZQ2000 quadrupole mass spectrometer with an
Acquity BEH C18 1.7 um 100.times.2.1 mm, Acquity BEH Shield RP18
1.7 um 100.times.2.1 mm or Acquity HSST3 1.8 um 100.times.2.1 mm,
maintained at 40.degree. C. Elution with A: water+0.1% formic acid;
B: acetonitrile+0.1% formic acid. Gradient:
TABLE-US-00004 Gradient - Time flow mL/min % A % B 0.00 0.4 95 5
0.40 0.4 95 5 6.00 0.4 5 95 6.80 0.4 5 95 7.00 0.4 95 5 8.00 0.4 95
5
[0128] Detection--MS, UV PDA. MS ionization method--Electrospray
(positive and negative ion).
Method 4
[0129] Acquity H-Class (quaternary pump/PDA detector)+QDa Mass
Spectrometer, Acquity UPLC BEH C18 1.7.mu., 50.times.2.1 mm at
50.degree. C. Elution with A: water+0.1% formic acid; B:
acetonitrile+0.1% formic acid. Gradient:
TABLE-US-00005 Gradient - Time flow mL/min % A % B 0.00 1.0 97 3
1.50 1.0 1 99 1.90 1.0 1 99 2.00 1.0 97 3 2.50 1.0 97 3
[0130] Detection--MS, UV diode array 190-450 nm. MS ionization
method--Electrospray (positive and negative ion).
Method 5
[0131] Agilent 1260 infinity purification system. Column: XBridge
Prep C18 OBD, particle size 5 .mu.m, 30.times.150 mm, RT. Elution
with A: water+0.1% ammonia; B: CH.sub.3CN+0.1% ammonia.
Gradient--90% A/10% B to 2% A/95% B over 22 min--flow rate 60
mL/min. Detection--In-line Agilent 6100 series single Quadrupole
LC/MS.
Example 1.
N-[5-tert-Butyl-3-(3-{(1S,4R)-4-[3-(1-dimethylamino-1-methyl-et-
hyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen--
1-yl}-ureido)-2-methoxy-phenyl]-methansulfonamide
##STR00008##
[0132] a.
N-(5-tert-Butyl-3-isocyanato-2-methoxy-phenyl)-methanesulfonamid- e
(Intermediate 1a)
##STR00009##
[0134] To a stirred solution of
N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (WO
2013/083604, which is incorporated herein by reference in its
entirety, 11.0 g, 40.4 mmol) in DCM (595 ml) and saturated aqueous
NaHCO.sub.3 solution (370 ml) at 0.degree. C. was added phosgene
(20% solution in toluene, 63.9 ml, 120 mmol). The reaction mixture
was stirred at 0.degree. C. for 1 hour and then the two phases were
separated. The aqueous phase was extracted with DCM (.times.2) and
the combined organic phases were washed with brine, dried with
Na.sub.2SO.sub.4 and the solvent was removed under reduced
pressure. The resulting solid was triturated with cyclohexane to
give the title compound (11.6 g, 96%).
[0135] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.29 (9H, s), 3.05 (3H,
s), 3.88 (3H, s), 6.77 (1H, br s), 6.85 (1H, d, J=2.2 Hz), 7.41
(1H, d, J=2.2 Hz).
b. Example 1
[0136] To a solution of
(1S,4R)-4-[3-(1-dimethylamino-1-methyl-ethyl)-[1,2,4]triazolo[4,3-a]pyrid-
in-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamine (WO
2013/083604, which is incorporated herein by reference in its
entirety, 600 mg, 1.60 mmol) and DIPEA (0.86 ml, 4.90 mmol) in
2-methyltetrahydrofuran (16 ml) at 0.degree. C. was added
Intermediate 1a (590 mg, 2.00 mmol). The reaction mixture was
stirred at 0.degree. C. for 90 minutes and then it was diluted with
H.sub.2O. The two phases were separated and the aqueous phase was
extracted with EtOAc (.times.2) and the combined organic phases
were washed with brine, dried with Na.sub.2SO.sub.4 and the solvent
was removed under reduced pressure. The crude mixture was purified
by FCC eluting with 0-4% 2M NH.sub.3 in MeOH/DCM. The resulting
foam was triturated with ether and dried at 50.degree. C. in vacuo
to give the title compound (460 mg, 42%).
[0137] LCMS (Method 3): Rt 3.54 min, m/z 664 [MH.sup.+].
[0138] .sup.1H NMR (400 MHz, d.sub.6-DMSO): 1.22 (9H, s), 1.48 (3H,
s), 1.49 (3H, s), 1.83-2.10 (10H, m), 3.02 (3H, s), 3.66 (3H, s),
4.87-4.92 (1H, m), 5.41 (1H, t, J=4.5 Hz), 6.91 (1H, d, J=2.2 Hz),
7.26-7.41 (6H, m), 7.72 (1H, d, J=9.5 Hz), 8.03 (1H, s), 8.16 (1H,
d, J=2.6 Hz), 8.56 (1H, d, J=1.7 Hz), 8.99 (1H, s).
Example 2.
N-[5-tert-Butyl-2-methoxy-3-(3-{(1S,4R)-4-[3-((S)-1-methyl-pipe-
ridin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naph-
thalen-1-yl}-ureido)-phenyl]-methanesulfonamide
##STR00010##
[0140] To a stirred solution of
(1S,4R)-4-[3-((S)-1-methyl-piperidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin--
6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamine (WO 2013/083604,
which is incorporated herein by reference in its entirety, 7.22 g,
19.2 mmol) in 2-methyltetrahydrofuran (300 ml) at 0.degree. C. was
added was added Intermediate 1a (7.13 g, 23.9 mmol). The reaction
mixture was stirred at 0.degree. C. for 1 hour and then it was
diluted with H.sub.2O. The two phases were separated and the
aqueous phase was extracted with EtOAc (.times.2) and the combined
organic phases were dried with Na.sub.2SO.sub.4 and the solvent was
removed under reduced pressure. The crude mixture was purified by
FCC eluting with 0-10% MeOH/EtOAc. The resulting solid was
triturated with ether and dried at 50.degree. C. under vacuum to
give the title compound (9.55 g, 75%).
[0141] LCMS (Method 3): Rt 3.47 min, m/z 676 [MH.sup.+].
[0142] .sup.1H NMR (400 MHz, d.sub.6-DMSO): 1.22 (9H, s), 1.33-1.44
(1H, m), 1.58-2.19 (13H, m), 2.95-3.00 (1H, m), 3.02 (3H, s), 3.66
(3H, s), 3.76 (1H, dd, J=10.0, 3.0 Hz), 4.88-4.93 (1H, m), 5.41
(1H, t, J=4.5 Hz), 6.91 (1H, d, J=2.5 Hz), 7.25-7.41 (6H, m), 7.70
(1H, d, J=10.0 Hz), 8.04 (1H, s), 8.17 (1H, d, J=2.3 Hz), 8.40 (1H,
br s), 8.99 (1H, s).
Example 3. N-[5-tert-Butyl-3-(3-{(1
S,4R)-4-[3-((S)-1,2-dimethyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyrid-
in-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureido)-2-methoxy-phenyl]--
methanesulfonamide
##STR00011##
[0144] The title compound was prepared starting from Intermediate
1a (6.90 g, 23.1 mmol) and
(1S,4R)-4-[3-((S)-1,2-dimethyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyr-
idin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamine (WO
2013/083604, which is incorporated herein by reference in its
entirety, 7.50 g, 19.9 mmol) using the procedure described to make
Example 2. The crude was purified by FCC eluting with EtOAc,
followed by 0-3% MeOH/DCM. The resulting solid was further purified
by FCC eluting with 0-4% 2M NH.sub.3 in MeOH/DCM and triturated
with ether to give the title compound (11.6 g, 76%).
[0145] LCMS (Method 3): Rt 3.49 min, m/z 676 [MH.sup.+].
[0146] .sup.1H NMR (400 MHz, d.sub.6-DMSO): 1.22 (9H, s), 1.49 (3H,
s), 1.77-2.21 (11H, m), 2.65 (1H, t, J=8.8 Hz), 3.02 (3H, s),
3.12-3.19 (1H, m), 3.66 (3H, s), 4.87-4.93 (1H, m), 5.34 (1H, t,
J=4.5 Hz), 6.91 (1H, d, J=2.5 Hz), 7.25-7.41 (6H, m), 7.74 (1H, d,
J=10.0 Hz), 8.03 (1H, s), 8.16 (1H, d, J=2.2 Hz), 8.45 (1H, d,
J=1.8 Hz), 8.99 (1H, s).
Example 4.
N-[5-tert-Butyl-3-(3-{(1S,4R)-4-[3-((S)-1-isopropyl-pyrrolidin--
2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-
-1-yl}-ureido)-2-methoxy-phenyl]-methanesulfonamide hydrochloride
salt
##STR00012##
[0148] The title compound was prepared starting from Intermediate
1a (148 mg, 0.50 mmol) and
(1S,4R)-4-[3-((S)-1-isopropyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyri-
din-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamine (WO
2013/083604, which is incorporated herein by reference in its
entirety, 97 mg, 0.25 mmol) using the procedure described to make
Example 1 (step b). The reaction mixture was poured in a SCX-2 SPE
cartridge, washed with MeOH and the product eluted with 2M NH.sub.3
in MeOH. The resulting product was further purified by HPLC (Gemini
C18, 20-40% MeCN in H.sub.2O, 0.1% HCO.sub.2H). The obtained solid
was dissolved in MeCN (1 ml) and H.sub.2O (1 ml) and an aqueous HCl
solution (1M, 1 eq) was added. The mixture was lyophilized to
afford the title compound (39.6 mg, 22%)
[0149] NB. The hydrochloride salt presented two different
stereoisomers due to formation of a stereogenic centre on the
ammonium and the stereoisomers have been labelled with .sup.#.
[0150] LCMS (Method 3): Rt 3.59 min, m/z 690 [MH.sup.+].
[0151] .sup.1H NMR (400 MHz, d.sub.6-DMSO): 1.11 (1.5H.sup.#, d,
J=5.0 Hz), 1.20-1.26 (13.5H.sup.#, m), 1.83-2.31 (7H, m), 2.57-2.70
(1H, m), 3.02 (3H, s), 3.43 (1H, br s), 3.62 (2H, br s), 3.66 (3H,
s), 4.89-4.94 (1H, m), 5.50-5.61 (1.7H.sup.#, m), 5.87-5.92
(0.3H.sup.#, m), 6.91 (1H, d, J=2.3 Hz), 7.28-7.44 (6H, m),
7.81-7.85 (1H, m), 8.05-8.08 (1H, m), 8.17 (1H, d, J=2.5 Hz), 8.49
(0.7H.sup.#, br s), 8.87 (0.3H.sup.#, br s), 8.99 (1H, s), 10.37
(0.7H.sup.#, br s), 11.86 (0.3H.sup.#, br s).
Example 5.
N-[5-tert-Butyl-3-(3-{(1S,4R)-4-[3-((S)-1-dimethylamino-2-methy-
l-propyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphth-
alen-1-yl}-ureido)-2-methoxy-phenyl]-methanesulfonamide
##STR00013##
[0152] a. (S)-2-Dimethylamino-3-methyl-butyric acid
N'-(5-fluoro-pyridin-2-yl)-hydrazide (Intermediate 5a)
##STR00014##
[0154] A solution of N,N-dimethyl-L-valine (1.39 g, 9.60 mmol) and
(5-fluoro-pyridin-2-yl)-hydrazine (WO 2013/083604, 1.11 g, 8.70
mmol) in DCM (15 ml) was treated with EDC (2.00 g, 10.5 mmol), HOBt
(120 mg, 0.87 mmol) and DIPEA (3.04 ml, 17.4 mmol). The reaction
mixture was stirred overnight at RT. The reaction mixture was
quenched with H.sub.2O and the two phases were separated. The
aqueous phase was extracted with DCM (.times.2) and the combinated
organic phases were washed with a saturated aqueous NaHCO.sub.3
solution and brine, dried with Na.sub.2SO.sub.4 and the solvent was
removed under reduced pressure. The resulting product was
triturated with ether and dried at 50.degree. C. under vacuum to
give the title compound (900 mg, 41%).
[0155] LCMS (Method 1): Rt 0.98 min, m/z 255 [MH.sup.+].
b.
[(S)-1-(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-2-methyl-propyl]-d-
imethyl-amine (Intermediate 5b)
##STR00015##
[0157] Hexachloroethane (2.22 g, 9.40 mmol) was added portion-wise
to a stirred solution of Intermediate 5a (1.19 g, 4.70 mmol),
triphenylphosphine (2.45 g, 9.40 mmol) and DBU (2.80 ml, 18.7 mmol)
in anhydrous THF (47 ml), and the reaction mixture was stirred at
RT for 21 hours. The solvent was removed under reduced pressure and
the residue was dissolved in DCM/H.sub.2O. The two phases were
separated and the aqueous phase was extracted with DCM (.times.2).
The combined organic phases were washed with a saturated
NaHCO.sub.3 aqueous solution and brine, dried with Na.sub.2SO.sub.4
and the solvent was removed under reduced pressure. Purification by
FCC, eluting with 0-2.5% 2M NH.sub.3 in MeOH/DCM afforded the title
compound (740 mg, 67%).
[0158] LCMS (Method 1): Rt 0.79 min, m/z 237 [MH.sup.+].
c.
(1S,4R)-4-[3-((S)-1-Dimethylamino-2-methyl-propyl)-[1,2,4]triazolo[4,3--
a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamine
(Intermediate 5c)
##STR00016##
[0160] To a solution of Intermediate 5b (1.00 g, 4.20 mmol),
(1R,4S)-4-amino-1,2,3,4-tetrahydro-naphthalen-1-ol (WO 2013/083604,
which is incorporated herein by reference in its entirety, 690 mg,
4.20 mmol) and 18-crown-6 (110 mg, 0.42 mmol) in
2-methyltetrahydrofuran (10 ml) at 0.degree. C. under nitrogen was
added potassium tert-butoxide (550 mg, 4.90 mmol). The reaction
mixture was warmed at RT and stirred for 23 hours and then diluted
with H.sub.2O. The two phases were separated and the aqueous phase
was extracted with 2-methyltetrahydrofuran (.times.2). The combined
organic phases were washed with a saturated aqueous NaHCO.sub.3
solution and brine, dried with Na.sub.2SO.sub.4 and the solvent was
removed under reduced pressure. Purification by FCC, eluting with
0-4% 2M NH.sub.3 in MeOH/DCM afforded the title compound (1.20 g,
75%).
[0161] LCMS (Method 1): Rt 0.47 min, m/z 380 [MH.sup.+].
d. Example 5
[0162] The title compound was prepared starting from Intermediate
1a (118 mg, 0.40 mmol) and Intermediate 5c (150 mg, 0.40 mmol)
using the procedure described to make Example 2. The crude mixture
was purified by FCC eluting with 0-5% 2M NH.sub.3 in MeOH/DCM. The
resulting solid was triturated with ether and dried at 50.degree.
C. under vacuum to give the title compound (184 mg, 69%).
[0163] LCMS (Method 2): Rt 3.53 min, m/z 678 [MH.sup.+].
[0164] .sup.1H NMR (400 MHz, d.sub.6-DMSO): 0.65 (3H, d, J=7.0 Hz),
1.11 (3H, d, J=7.0 Hz), 1.25 (9H, s), 1.85-2.14 (10H, m), 2.43-2.48
(1H, m), 3.05 (3H, s), 3.68 (3H, s), 4.11 (1H, d, J=11.0 Hz),
4.90-4.95 (1H, m), 5.58 (1H, t, J=4.8 Hz), 6.94 (1H, d, J=2.4 Hz),
7.17 (1H, dd, J=9.8, 2.0 Hz), 7.28-7.44 (5H, m), 7.73 (1H, d,
J=10.0 Hz), 8.07 (1H, s), 8.19 (1H, d, J=2.3 Hz), 8.51 (1H, d,
J=1.4 Hz), 9.02 (1H, s).
Example 6.
N-[5-tert-Butyl-3-(3-{(1S,4R)-4-[3-((R)-1,2-dimethyl-pyrrolidin-
-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthale-
n-1-yl}-ureido)-2-methoxy-phenyl]-methanesulfonamide
##STR00017##
[0165] a. (R)-1,2-Dimethyl-pyrrolidine-2-carboxylic acid
hydrochloride salt (Intermediate 6a)
##STR00018##
[0167] To a solution of 2-methyl-D-proline hydrochloride salt (10.0
g, 60.4 mmol) in EtOH (150 ml) was added formaldehyde (37% in
water, 12.0 ml, 148 mmol) and palladium on carbon (10%, 1.5 g). The
vessel was evacuated and filled with hydrogen (.times.3) and the
reaction mixture was stirred overnight at RT under hydrogen. The
reaction mixture was filtered through a pad of celite and the
solvent was removed under reduced pressure. The residue was
triturated with ether to give the title compound (10.7 g, 99%).
[0168] .sup.1H NMR (300 MHz, d.sub.6-DMSO): 1.54 (3H, br s),
1.86-2.14 (3H, m), 2.28 (1H, br s), 2.76 (3H, s), 3.22-3.64 (3H,
m).
b. (R)-1,2-Dimethyl-pyrrolidine-2-carboxylic acid
N'-(5-Fluoro-pyridine-2-yl)-hydrazide (Intermediate 6b)
##STR00019##
[0170] The title compound was prepared starting from Intermediate
6a (10.6 g, 59.1 mmol) and (5-fluoro-pyridin-2-yl)-hydrazine (WO
2013/083604, which is incorporated herein by reference in its
entirety, 7.50 g, 59.1 mmol) using the procedure described to make
Intermediate 5a. The crude was purified by FCC eluting with DCM,
followed by 10% acetone/DCM and 0-5% 2M NH.sub.3 in MeOH/DCM. The
resulting solid was triturated with petroleum ether to give the
title compound (7.60 g, 51%).
[0171] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.24 (3H, s), 1.73-1.92
(3H, m), 2.12-2.30 (1H, m), 2.38 (3H, s), 2.50-2.63 (1H, m),
3.07-3.18 (1H, m), 6.53 (1H, br s), 6.60 (1H, dd, J=9.0, 3.6 Hz),
7.22-7.33 (1H, m), 8.03 (1H, d, J=2.7 Hz), 9.33 (1H, br s).
c.
3-((R)-1,2-Dimethyl-pyrrolidin-2-yl)-6-fluoro-[1,2,4]triazolo[4,3-a]pyr-
idine (Intermediate 6c)
##STR00020##
[0173] Hexachloroethane (2.22 g, 9.40 mmol) was added portionwise
to a stirred solution of Intermediate 6b (7.50 g, 29.8 mmol),
triphenylphosphine (15.6 g, 59.5 mmol) and TEA (16 ml, 118.9 mmol)
in 2-methyltetrahydrofuran (150 ml) and the reaction mixture was
stirred at 80.degree. C. for 1 hour. The reaction mixture was
cooled at RT, diluted with H.sub.2O and the two phases were
separated. The organic phase was washed with H.sub.2O and extracted
with a 0.5M aqueous solution of citric acid. The aqueous phase was
washed with 2-methyltetrahydrofuran and then basified with solid
K.sub.2CO.sub.3. The resulting aqueous phase was extracted with DCM
(.times.3) and the combined organic phases were dried with
Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure
to afford the title compound (6.74 g, 97%).
[0174] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.65 (3H, s), 1.85-2.28
(7H, m), 2.74 (1H, q, J=8.7 Hz), 3.20-3.30 (1H, m), 7.17 (1H, ddd,
J=9.9, 7.3, 2.1 Hz), 7.73 (1H, dd, J=9.9, 5.0 Hz), 8.82 (1H,
m).
d.
(1S,4R)-4-[3-((R)-1,2-Dimethyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]p-
yridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamine
(Intermediate 6d)
##STR00021##
[0176] The title compound was prepared starting from Intermediate
6c (6.50 g, 27.8 mmol) and
(1R,4S)-4-amino-1,2,3,4-tetrahydro-naphthalen-1-ol (WO 2013/083604,
which is incorporated herein by reference in its entirety, 4.53 g,
27.8 mmol) using the procedure described to make Intermediate 5c to
give the title compound (8.32 g, 79%).
[0177] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.65 (3H, s), 1.84-2.13
(10H, m), 2.18-2.39 (2H, m), 2.73 (1H, q, J=8.9 Hz), 3.11-3.21 (1H,
m), 3.98 (1H, dd, J=8.4, 5.1 Hz), 5.17 (1H, t, J=4.5 Hz), 7.11 (1H,
dd, J=9.9, 2.3 Hz), 7.29 (1H, d, J=7.2 Hz), 7.33-7.43 (2H, m), 7.60
(1H, d, J=7.7 Hz), 7.68 (1H, dd, J=9.9, 0.8 Hz), 8.57 (1H, d, J=2.2
Hz) plus one proton obscured by water.
e. Example 6
[0178] The title compound was prepared starting from Intermediate
1a (395 mg, 1.30 mmol) and Intermediate 6d (500 mg, 1.30 mmol)
using the procedure described to make Example 2. The crude mixture
was purified by FCC eluting with 25% acetone/DCM, followed by 5% 2M
NH.sub.3 in MeOH/DCM to give the title compound (790 mg, 88%).
[0179] LCMS (Method 3): Rt 3.69 min, m/z 676 [MH.sup.+].
[0180] .sup.1H NMR (400 MHz, d.sub.6-DMSO): 1.25 (9H, s), 1.52 (3H,
s), 1.80-2.28 (11H, m), 2.67 (1H, q, J=9.0 Hz), 3.04 (3H, s), 3.18
(1H, dt, J=8.7, 3.5 Hz), 3.68 (3H, s), 4.89-4.94 (1H, m), 5.42 (1H,
t, J=4.6 Hz), 6.94 (1H, d, J=2.4 Hz), 7.30-7.46 (6H, m), 7.76 (1H,
d, J=9.8 Hz), 8.06 (1H, s), 8.18 (1H, d, J=2.3 Hz), 8.50 (1H, d,
J=1.7 Hz), 9.03 (1H, br s).
Example 7.
N-[5-tert-Butyl-3-(3-{(1S,4R)-4-[3-((2S,5S)-1,5-dimethyl-pyrrol-
idin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-napht-
halen-1-yl}-ureido)-2-methoxy-phenyl]-methanesulfonamide
##STR00022##
[0181] a.
(2S,5S)-2-[N'-(5-Fluoro-pyridin-2-yl)-hydrazinocarbonyl]-5-methy- l
pyrrolidine-1-carboxylic acid tert-butyl ester (Intermediate
7a)
##STR00023##
[0183] A solution of (2S,5S)-5-methyl-pyrrolidine-1,2-dicarboxylic
acid 1-tert-butyl ester (5.0 g, 21.80 mmol) and
(5-fluoro-pyridin-2-yl)-hydrazine (WO 2014/195402, 2.8 g, 21.80
mmol) in DCM (60 ml) was treated with EDC (5.00 g, 24.00 mmol),
HOBt (298 mg, 2.20 mmol) and DIPEA (4.60 ml, 17.4 mmol). The
reaction mixture was stirred overnight at RT. The reaction mixture
was quenched with H.sub.2O and the two phases were separated. The
aqueous phase was extracted with DCM (.times.2) and the combinated
organic phases were washed with a saturated aqueous NaHCO.sub.3
solution and brine, dried with Na.sub.2SO.sub.4 and the solvent was
removed under reduced pressure. The resulting product was
triturated with DCM/ether and dried at 50.degree. C. under vacuum
to give the title compound (4.5 g, 65%).
[0184] LCMS (Method 4): Rt 1.04 min, m/z 339 [MH.sup.+].
b.
(2S,5S)-2-(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-5-methyl-pyrrol-
idine-1-carboxylic acid tert-butylester (Intermediate 7b)
##STR00024##
[0186] Hexachloroethane (2.22 g, 9.40 mmol) was added portion-wise
to an ice cold stirred solution of Intermediate 7a (4.50 g, 13.30
mmol), triphenylphosphine (3.50 g, 26.60 mmol) and TEA (7.40 ml,
53.20 mmol) in anhydrous 2-methyltetrahydrofuran (80 ml) and the
reaction mixture was stirred at RT for 3 hours. The reaction was
partitioned with H.sub.2O and diluted with EtOAc. The two phases
were separated and the aqueous phase was extracted with EtOAc
(.times.2). The combined organic phases were washed with a
saturated NaHCO.sub.3 aqueous solution and brine, dried with
Na.sub.2SO.sub.4 and the solvent was removed under reduced
pressure. Purification by FCC, eluting with 100% EtOAc afforded the
title compound (4.25 g, 99%).
[0187] LCMS (Method 4): Rt 1.05 min, m/z 321 [MH.sup.+].
c.
(6-Fluoro-3-((2S,5S)-5-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]py-
ridine (Intermediate 7c)
##STR00025##
[0189] A solution of Intermediate 7b (4.25 g, 13.30 mmol) in DCM
(15 mL) was treated with TFA (10 mL) and the reaction mixture was
stirred at RT for 2 hours. The solvent was evaporated under reduced
pressure and the residue was taken up in HCl 1M and the solution
washed with EtOAc (.times.2). The aqueous was basified with
Na.sub.2CO.sub.3 and extracted with DCM (.times.2) and
2-methyltetrahydrofuran (.times.2). The combined organic layers
were evaporated under reduced pressure to afford the title compound
(1.85 g, 65%).
[0190] LCMS (Method 4): Rt 0.43 min, m/z 221 [MH.sup.+].
d.
3-((2S,5S)-1,5-Dimethyl-pyrrolidin-2-yl)-6-fluoro-[1,2,4]triazolo[4,3-a-
]pyridine (Intermediate 7d)
##STR00026##
[0192] A solution of Intermediate 7c (1.85 g, 8.39 mmol) in IMS (25
mL) was treated with paraformaldehyde (756 mg, 25.20 mmol). The
reaction mixture was stirred at RT for 3 hours and then treated
with Na(OAc).sub.3BH. The resulting reaction mixture was stirred at
RT for 21 hour. The reaction mixture was quenched with H.sub.2O and
the solvent was removed under reduced pressure. Purification by
FCC, eluting with MeOH/DCM 0-10% afforded the title compound (1.96
g, 99%).
[0193] LCMS (Method 4): Rt 0.17 min, m/z 235 [MH.sup.+].
e.
(1S,4R)-4-[3-((2S,5S)-1,5-Dimethyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-
-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamine and
(1S,4S)-4-[3-((2S,5S)-1,5-dimethyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a-
]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamine
(Intermediate 7e)
##STR00027##
[0195] To a solution of Intermediate 7d (1.30 g, 5.50 mmol),
(1R,4S)-4-amino-1,2,3,4-tetrahydro-naphthalen-1-ol (WO 2014/195402,
which is incorporated herein by reference in its entirety, 900 mg,
5.50 mmol) and 18-crown-6 (1.93 g, 7.30 mmol) in
2-methyltetrahydrofuran (30 ml) at 0.degree. C. under nitrogen was
added potassium tert-butoxide (1.96 g, 17.50 mmol). The reaction
mixture was warmed at RT and stirred for 23 hours and then diluted
with H.sub.2O. The two phases were separated and the aqueous phase
was extracted with 2-methyltetrahydrofuran (.times.2). The combined
organic phases were washed with a saturated aqueous NaHCO.sub.3
solution and brine, dried with Na.sub.2SO.sub.4 and the solvent was
removed under reduced pressure. Purification by FCC, eluting with
0-4% 2M NH.sub.3 in MeOH/DCM afforded the title compound (1.20 g,
60%).
[0196] LCMS (Method 4): Rt 0.17 min, m/z 378 [MH.sup.+].
f.
N-[5-tert-Butyl-3-(3-{(1S,4R)-4-[3-((2S,5S)-1,5-dimethyl-pyrrolidin-2-y-
l)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1--
yl}-ureido)-2-methoxy-phenyl]-methanesulfonamide (Example 7)
[0197] The title compound was prepared starting from Intermediate
1a (96 mg, 0.32 mmol) and Intermediate 7e (110 mg, 0.30 mmol) using
the procedure described to make Example 2. The crude mixture was
purified by MDAP (Method 5) followed by SFC (LUX CELLULOSE-3 10/90
MeOH (0.1% DEA)/CO2, 100 ml/min, 120 bar, 40.degree. C., GLS 40
psi, SYSTEM 3150 PSI, DROP 94 Bar, DAD 220 nm) to separate the two
different diastereisomers (CIS and TRANS) across the
tetrahydronaphtalene. The resulting solid was triturated with ether
and dried at 50.degree. C. under vacuum to give the title compound
(28 mg, 13%).
[0198] LCMS (Method 3): Rt 3.54 min, m/z 676 [MH.sup.+].
[0199] .sup.1H NMR (400 MHz, d.sub.6-DMSO): 1.19 (3H, d, J=5.5 Hz),
1.25 (9H, s), 2.18 (3H, s), 2.43-2.50 (4H, m, partially obscured by
solvent peak), 3.05 (3H, s), 3.28-3.32 (4H, m, partially obscured
by solvent peak), 3.68 (3H, s), 4.06 (1H, t, J=8.4 Hz), 4.90-4.95
(1H, m), 5.34 (1H, t, J=4.5 Hz), 5.74 (1H, s), 6.86 (1H, s), 6.94
(1H, d, J=2.6 Hz), 7.28-7.44 (2H, m), 7.35-7.48 (3H, m), 7.74 (1H,
d, J=7.75 Hz), 8.04 (1H, s), 8.18 (1H, d, J=2.3 Hz), 8.40 (1H, d,
J=1.4 Hz), 9.02 (1H, s).
Example 8.
N-[5-tert-Butyl-3-(3-{(1S,4S)-4-[3-((2S,5S)-1,5-dimethyl-pyrrol-
idin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-napht-
halen-1-yl}-ureido)-2-methoxy-phenyl]-methanesulfonamide
##STR00028##
[0201] The title compound was prepared starting from Intermediate
1a (96 mg, 0.32 mmol) and Intermediate 7e (110 mg, 0.30 mmol) using
the procedure described to make Example 2. The crude mixture was
purified by MDAP (Method 5) followed by SFC (LUX CELLULOSE-3 10/90
MeOH (0.1% DEA)/CO2, 100 ml/min, 120 bar, 40.degree. C., GLS 40
psi, SYSTEM 3150 PSI, DROP 94 Bar, DAD 220 nm) to separate the two
different diastereisomers (CIS and TRANS) across the tetrahydro
naphtalene. The resulting solid was triturated with ether and dried
at 50.degree. C. under vacuum to give the title compound (30 mg,
14%).
[0202] LCMS (Method 3): Rt 3.54 min, m/z 676 [MH.sup.+].
[0203] .sup.1H NMR (400 MHz, d.sub.6-DMSO): 1.19 (3H, d, J=5.5 Hz),
1.25 (9H, s), 2.18 (3H, s), 2.43-2.51 (4H, m, partially obscured by
solvent peak), 3.02 (3H, s), 3.28-3.32 (4H, m, partially obscured
by solvent peak), 3.65 (3H, s), 4.05 (1H, t, J=9.6 Hz), 4.95-5.0
(1H, m), 5.50 (1H, t, J=4.3 Hz), 5.75 (1H, s), 6.86 (1H, s), 6.94
(1H, d, J=2.6 Hz), 7.28-7.44 (2H, m), 7.35-7.48 (3H, m), 7.74 (1H,
d, J=7.75 Hz), 8.04 (1H, s), 8.18 (1H, d, J=2.3 Hz), 8.38 (1H, d,
J=1.4 Hz), 9.02 (1H, s).
Example 9.
N-[5-tert-Butyl-3-(3-{(1S,4S)-4-[3-((S)-1,2-dimethyl-pyrrolidin-
-2-yl)[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-
-1-yl}ureido) 2-methoxy-phenyl]-methanesulfonamide
##STR00029##
[0204] a.
(1S,4S)-4-[3-((S)-1,2-Dimethyl-pyrrolidin-2-yl)-[1,2,4]triazolo[-
4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamine
(Intermediate 10a)
##STR00030##
[0206] The title compound (145 mg, 55%) was prepared starting from
Intermediate 1a (165 mg, 0.70 mmol) and
(1S,4S)-4-amino-1,2,3,4-tetrahydro-naphthalen-1-ol (WO 2013/83206,
which is incorporated herein by reference in its entirety) (114 mg,
0.70 mmol) using the procedure described to make Intermediate
5c.
[0207] LCMS (Method 4): Rt 0.22 min, m/z 378 [MH.sup.+].
b.
N-[5-tert-Butyl-3-(3-{(1S,4S)-4-[3-((S)-1,2-dimethyl-pyrrolidin-2-yl)[1-
,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}ur-
eido) 2-methoxy-phenyl]-methanesulfonamide (Example 9)
[0208] To a solution of Intermediate 10a (145 mg, 0.38 mmol) in
2-methyltetrahydrofuran (4 ml) was added DIPEA (0.1 ml, 0.57 mmol)
followed by
5-tert-butyl-3-methane-sulfonamide-2-methoxyphenyl-isocyanate (115
mg, 0.38 mmol). The reaction mixture was stirred at room
temperature for 2 hours. The reaction mixture was washed with
H.sub.2O, diluted with EtOAc and the solvent was removed under
reduced pressure. Purification by MDAP (Method 5) afforded the
title compound (194 mg, 75%).
[0209] LCMS (Method 3): Rt 3.53 min, m/z 676 [MH.sup.+].
[0210] .sup.1H NMR (400 MHz, d-.sub.6-DMSO): 1.24 (9H, s), 1.50
(3H, s), 1.76-1.86 (2H, m), 1.96-2.26 (9H, m), 2.65 (1H, q, J=8.9
Hz), 3.01 (3H, s), 3.13-3.19 (1H, m), 3.66 (3H, s), 4.98-5.03 (1H,
m), 5.49-5.52 (1H, m), 6.93 (1H, d, J=2.3 Hz), 7.28-7.44 (6H, m),
7.75 (1H, d, J=9.8 Hz), 8.02 (1H, s), 8.16 (1H, br s), 8.43 (1H, d,
J=1.8 Hz), 9.00 (1H, br s).
Biological Assays
P38alpha Enzyme Inhibition Assay
[0211] The inhibitory activity of compounds was determined using an
Alphascreen.RTM. (Perkin Elmer) based kinase activity assay. Kinase
reactions consisted of 25 mM HEPES pH 7.5, 10 mM MgCl.sub.2, 100
.mu.M Na.sub.3VO.sub.4, 2 mM DTT, 0.05 mg/ml Tween 20, 100 pM
p38alpha (Invitrogen, PV3304), 1% DMSO and 0.3 .mu.g/ml ATF-2
fusion protein (New England Biolabs, 9224). Compounds were
incubated under these conditions for 2 hours, at 25.degree. C.,
prior to the initiation of the kinase activity by the addition of
the 250 .mu.M ATP. Reaction volumes were 20 uL. After 1 hour at
25.degree. C., reactions were stopped by the adding 10 uL of 25 mM
HEPES pH 7.5 containing 62.5 mM EDTA, 0.05% Triton X-100, 10% BSA
and 0.83 ng/uL anti-phospho-ATF2 antibody (Abcam, ab28812).
Detection was performed by measuring luminescence following the
addition of Alphascreen Donor beads (Perkin Elmer 6765300) and
Protein A Alphascreen Acceptor beads (Perkin Elmer 6760137), both
at a final concentration of 20 ug/ml. IC.sub.50 values were
determined from concentration--response curves.
[0212] The compounds of the invention show p38.alpha. potencies
(IC.sub.50 values)<5 nM
LPS-Stimulated PBMC TNF.alpha. Release Assay
[0213] Peripheral Blood Mononuclear Cells (PBMCs) were isolated
from healthy human volunteer blood using a standard density
gradient centrifugation technique. Citrated blood was placed onto
Histopaque.TM. and centrifuged. The PBMCs were removed from the
density gradient interface and washed in phosphate buffered saline
(PBS). The PBMCs were suspended in RPMI 1640 medium (without
serum), dispensed into a 96-well plate and incubated at 37.degree.
C. for 3 hours in a humidified incubator. After incubation, the
medium was replaced (with medium containing 1% foetal bovine serum)
and the plate incubated at 37.degree. C., for 1 hour, in the
presence of test compound or the appropriate vehicle. LPS (10
ng/ml), or an appropriate vehicle control, was then added to the
cells and the plate returned to the incubator for 18 hours.
Cell-free supernatants were removed and assayed for TNF.alpha.
levels using MSD plates on the Sector Imager 6000 (MesoScale).
[0214] A dose response curve to each test compound was performed
and the effect of compound in each experiment was expressed as a
percentage inhibition of the control TNF.alpha. release. Dose
response curves were plotted and compound potency (IC.sub.50) was
determined. Compounds were tested in at least three separate
experiments.
[0215] The compounds of the invention show human PBMC potencies
(IC.sub.50 values)<2 nM.
TNF.alpha.-Stimulated BEAS-2B IL-8 Release Assay
[0216] Human bronchial epithelial cell line BEAS-2B was purchased
from Sigma (St. Louis, Mo.). BEAS-2B cells were cultured in
Bronchial Epithelial cell Growth Medium (BEGM), prepared by
supplementing Bronchial Epithelial Basal Medium with
SingleQuotes.TM. (Lonza, Switzerland), which contains retinoic
acid, epidermal growth factor, epinephrine, transferrin,
triiodothyronin, insulin, hydrocortisone, antimicrobial agents, and
bovine pituitary extract. In addition, BEGM medium was supplemented
with 2 mM glutamine, 100 U penicillin and 100 .mu.g/ml streptomycin
(Life Technologies), in an atmosphere of 95% air and 5% CO2 at
37.degree. C.
[0217] BEAS-2B were seeded in 48-well plates at the density of
3.times.104 cells per well, grown to approximately 80-90%
confluence. Cells were pre-incubated with p38 inhibitors for 1 hour
and then stimulated with TNF-.alpha. (10 ng/ml) for 18 hours at
37.degree. C. with 5% CO2. Subsequently, supernatants were
collected and used for measuring IL-8 levels using a paired
antibody quantitative ELISA kit purchased from Life Technologies
(detection limit: 5 pg/ml). All the treatments were performed at
least in quadruplicate.
[0218] A concentration-response curve to each test compound was
performed and the effect of compound in each experiment was
expressed as a percentage inhibition of the control IL-8 release.
Compound potency (IC.sub.50) was calculated by the analysis of the
sigmoidal dose-response curve (variable slope) elaborated by Graph
Pad PRISM4 program.
[0219] The compounds of the invention show BEAS-2B potencies
(IC.sub.50 values)<0.5 nM.
[0220] Where a numerical limit or range is stated herein, the
endpoints are included. Also, all values and subranges within a
numerical limit or range are specifically included as if explicitly
written out.
[0221] As used herein the words "a" and "an" and the like carry the
meaning of "one or more."
[0222] Obviously, numerous modifications and variations of the
present invention are possible in light of the above teachings. It
is therefore to be understood that, within the scope of the
appended claims, the invention may be practiced otherwise than as
specifically described herein.
[0223] All patents and other references mentioned above are
incorporated in full herein by this reference, the same as if set
forth at length.
* * * * *