U.S. patent application number 17/291694 was filed with the patent office on 2022-09-08 for compounds and compositions for the treatment of respiratory diseases.
The applicant listed for this patent is THE UNIVERSITY OF MELBOURNE. Invention is credited to Zalihe Hakki, Alastair Stewart, Spencer Williams.
Application Number | 20220281846 17/291694 |
Document ID | / |
Family ID | 1000006322004 |
Filed Date | 2022-09-08 |
United States Patent
Application |
20220281846 |
Kind Code |
A1 |
Stewart; Alastair ; et
al. |
September 8, 2022 |
COMPOUNDS AND COMPOSITIONS FOR THE TREATMENT OF RESPIRATORY
DISEASES
Abstract
The present invention relates to new compounds that are useful
in the prevention or treatment of respiratory diseases, such as
asthma, acute and chronic inflammatory conditions, and fibrotic
diseases or conditions in which fibrosis contributes to the
pathology of the condition. The invention also relates to the
preparation of the compounds, and to compositions including the
compounds. The present invention also relates to the use of the
compounds, as well as compositions including the compounds, in
treating or preventing respiratory diseases, acute and chronic
inflammatory conditions, and fibrotic diseases or conditions in
which fibrosis contributes to the pathology of the condition.
Inventors: |
Stewart; Alastair;
(Melbourne, AU) ; Williams; Spencer; (Melbourne,
AU) ; Hakki; Zalihe; (Melbourne, AU) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
THE UNIVERSITY OF MELBOURNE |
Victoria |
|
AU |
|
|
Family ID: |
1000006322004 |
Appl. No.: |
17/291694 |
Filed: |
November 7, 2019 |
PCT Filed: |
November 7, 2019 |
PCT NO: |
PCT/AU2019/051224 |
371 Date: |
May 6, 2021 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 405/14 20130101;
A61P 11/00 20180101; C07D 409/14 20130101; C07D 403/04
20130101 |
International
Class: |
C07D 403/04 20060101
C07D403/04; C07D 405/14 20060101 C07D405/14; C07D 409/14 20060101
C07D409/14; A61P 11/00 20060101 A61P011/00 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 7, 2018 |
AU |
2018904241 |
Nov 7, 2018 |
AU |
2018904242 |
Claims
1. A compound of formula (I) or a salt, solvate, N-oxide, tautomer,
stereoisomer, polymorph and/or prodrug thereof: ##STR00148##
wherein: R.sub.1 is selected from the group consisting of H,
C.sub.2-6alkyl, hydroxyC.sub.1-6alkyl, C.sub.1alkylC.sub.6aryl,
C.sub.1alkylC.sub.12aryl, C.sub.1alkylC.sub.6arylhalo,
C.sub.1alkyl(C.sub.1alkyl)C.sub.6aryl, C.sub.3-6cycloalkyl,
haloC.sub.3-6cycloalkyl, hydroxyC.sub.3-6cycloalkyl, and
C.sub.3-5heterocyclyl; R.sub.2 is H; R.sub.3 is selected from the
group consisting of F, Cl and CH.sub.3; R.sub.4 is selected from
the group consisting of C.sub.0-3alkylC.sub.3-12cycloalkyl,
C.sub.0-3alkylC.sub.3-12cycloalkylhalo, C.sub.1-12alkyl and
haloC.sub.1-12alkyl; wherein each of R.sub.1, R.sub.2, R.sub.3 and
R.sub.4 is optionally substituted, wherein when R.sub.1 is H,
R.sub.4 is selected from the group consisting of
C.sub.0-3alkylC.sub.4-12cycloalkyl and C.sub.1-12alkyl, wherein
when R.sub.4 is C.sub.6cycloalkyl, R.sub.4 is substituted by one or
more groups selected from C.sub.1-6alkyl, C.sub.1-6haloalkyl, aryl,
heteroaryl, and halo, and when R.sub.4 is C.sub.1-3alkyl, R.sub.4
is substituted by one or more halo groups, and when R.sup.1 is
C.sub.3cycloalkyl, C.sub.1alkylC.sub.6aryl or
C.sub.1alkyl(C.sub.1alkyl)C.sub.6aryl, R.sup.4 is selected from
haloC.sub.1-12alkyl and C.sub.0-3alkylC.sub.3-12cycloalkyl.
2. A compound according to claim 1, or a salt, solvate, N-oxide,
tautomer, stereoisomer, polymorph and/or prodrug thereof, wherein
the compound is not selected from the list of compounds in FIG.
1.
3. A compound according to claim 1, or a salt, solvate, N-oxide,
tautomer, stereoisomer, polymorph and/or prodrug thereof, wherein
the compound is not selected from the list of compounds in FIG.
3.
4. A compound according to claim 1, or a salt, solvate, N-oxide,
tautomer, stereoisomer, polymorph and/or prodrug thereof, wherein
R.sub.1 is selected from C.sub.2-3alkyl, hydroxyC.sub.2-3alkyl,
C.sub.3-6cycloalkyl, haloC.sub.3-6cycloalkyl,
hydroxyC.sub.3-6cycloalkyl, C.sub.3-6heterocyclyl,
C.sub.1alkylC.sub.6aryl, C.sub.1alkylC.sub.12aryl,
C.sub.1alkylC.sub.6arylhalo and
C.sub.1alkyl(C.sub.1alkyl)C.sub.6aryl.
5-7. (canceled)
8. A compound according to claim 4, or a salt, solvate, N-oxide,
tautomer, stereoisomer, polymorph and/or prodrug thereof, wherein
R.sub.1 is selected from cyclobutyl, cyclopentyl and cyclohexyl,
each of which being optionally substituted with one or more groups
selected from hydroxy and halo.
9. A compound according to claim 8, or a salt, solvate, N-oxide,
tautomer, stereoisomer, polymorph and/or prodrug thereof, wherein
the one or more halo groups are one or more fluoro groups.
10. (canceled)
11. (canceled)
12. A compound according to claim 4, or a salt, solvate, N-oxide,
tautomer, stereoisomer, polymorph and/or prodrug thereof, wherein
R.sub.1 is C.sub.1alkylC.sub.6aryl or
C.sub.1alkylC.sub.6arylhalo.
13. A compound according to claim 1, or a salt, solvate, N-oxide,
tautomer, stereoisomer, polymorph and/or prodrug thereof, wherein
R.sub.1 is H.
14. A compound according to claim 1, or a salt, solvate, N-oxide,
tautomer, stereoisomer, polymorph and/or prodrug thereof, wherein
R.sub.3 is F.
15. A compound according to claim 1, or a salt, solvate, N-oxide,
tautomer, stereoisomer, polymorph and/or prodrug thereof, wherein
R.sub.4 is selected from C.sub.0-3alkylC.sub.3-12cycloalkyl,
C.sub.0-3alkylC.sub.3-12cycloalkylhalo, C.sub.1-12alkyl and
haloC.sub.1-12alkyl.
16. A compound according to claim 15, or a salt, solvate, N-oxide,
tautomer, stereoisomer, polymorph and/or prodrug thereof, wherein
R.sub.4 is selected from C.sub.1-2alkylC.sub.3-12cycloalkyl and
C.sub.1-2alkylC.sub.3-12cycloalkylhalo.
17. A compound according to claim 15, or a salt, solvate, N-oxide,
tautomer, stereoisomer, polymorph and/or prodrug thereof, wherein
R.sub.4 is selected from C.sub.3-12cycloalkyl and
C.sub.3-12cycloalkylhalo.
18. A compound according to claim 15, or a salt, solvate, N-oxide,
tautomer, stereoisomer, polymorph and/or prodrug thereof, wherein
R.sub.4 is selected from C.sub.0-3alkylC.sub.3-7cycloalkyl and
C.sub.0-3alkylC.sub.3-7cycloalkylhalo.
19. A compound according to claim 18, or a salt, solvate, N-oxide,
tautomer, stereoisomer, polymorph and/or prodrug thereof, wherein
R.sub.4 is C.sub.0-3alkylC.sub.3-7 cycloalkylhalo and wherein
C.sub.3-7cycloalkyl moiety is substituted by the one or more halo
groups.
20. (canceled)
21. A compound according to claim 1, or a salt, solvate, N-oxide,
tautomer, stereoisomer, polymorph and/or prodrug thereof, wherein
R.sub.4 is a methyl, ethyl, propyl or butyl group, each optionally
substituted by one or more halo groups.
22. A compound according to claim 15, or a salt, solvate, N-oxide,
tautomer, stereoisomer, polymorph and/or prodrug thereof, wherein
R.sub.4 comprises a branched alkyl group.
23. A compound selected from Table 1, or a pharmaceutically
acceptable salt, solvate, N-oxide, tautomer, stereoisomer, prodrug
and/or polymorph thereof.
24. A pharmaceutical composition comprising a compound of formula
(I) according to claim 1, or a pharmaceutically acceptable salt,
solvate, N-oxide, tautomer, stereoisomer, prodrug and/or polymorph
thereof, and a pharmaceutically acceptable excipient.
25. A method of treating or preventing a respiratory disease in a
subject in need thereof, the method comprising administering to the
subject a therapeutically effective amount of a compound of formula
(I) or a salt, solvate, N-oxide, tautomer, stereoisomer, polymorph
and/or prodrug thereof: ##STR00149## wherein: R.sub.1 and R.sub.2
are each independently selected from the group consisting of H,
C.sub.1-6alkyl, C.sub.1alkylC.sub.6aryl, C.sub.3-6cycloalkyl and
C.sub.3-5heterocyclyl; R.sub.3 is selected from the group
consisting of F, Cl and CH.sub.3; R.sub.4 is selected from the
group consisting of C.sub.0-3alkylC.sub.3-12cycloalkyl and
C.sub.1-12alkyl; wherein each of R.sub.1, R.sub.2, R.sub.3 and
R.sub.4 is optionally substituted, thereby treating or preventing
the respiratory disease in the subject.
26. The method according to claim 25, or a salt, solvate, N-oxide,
tautomer, stereoisomer, polymorph and/or prodrug thereof, wherein
the compound of formula (I) is as defined in claim 1.
Description
[0001] This application is a .sctn. 371 national stage filing of
International Application No. PCT/AU2019/051224, filed on Nov. 7,
2019, which claims priority to AU2018904241 and AU2018904242, filed
on 7 Nov. 2018. The entire contents of each of the aforementioned
applications are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention provides imidazole-based compounds
that show potential in the treatment of respiratory diseases, such
as asthma and related conditions, acute and chronic inflammatory
conditions, and fibrotic diseases or conditions in which fibrosis
contributes to the pathology of the condition.
BACKGROUND OF THE INVENTION
[0003] Asthma is a syndrome that encompasses various different
types of diseases, which vary in their severity and in their causes
and triggers. The common features of the asthma syndrome are
reversible airway obstruction, airway hyper-responsiveness and
airway inflammation, with infiltration of the airway wall by
eosinophils and T lymphocytes the most prominent features in
addition to activation of mast cells.
[0004] Current asthma medications include short- and long-acting
.beta..sub.2-adrenoceptor selective agonists (SABA and LABA) and
inhaled corticosteroids (ICS). Ultra-LABA are now also available.
Short and long-acting muscarinic receptor antagonists (SAMA and
LAMA) are used in some patients, usually in combination with other
bronchodilators and anti-inflammatory drugs, especially ICS.
Leukotriene receptor antagonists (LTRA) may also be added to
different therapeutic regimens. More recently, the monoclonal
antibody mepolizumab, which neutralises a chemoattractant for
eosinophils, interleukin-5, has been shown to have benefit
additional to the ICS and LABA combinations in selected patients.
Nevertheless, for severe asthma in particular, patients are still
symptomatic and have periodic worsening of disease, referred to as
exacerbations. There is a considerable unmet need in the drug
treatment of severe asthma. In the majority of cases these asthma
exacerbations are considered to be caused by respiratory viral
infection of the lower respiratory tract. The viruses that cause
these exacerbations include respiratory syncytial virus, influenza
virus and rhinoviruses, which infect the respiratory epithelium.
The epithelium of asthmatic individuals is considered to be
especially susceptible to such infections and is implicated in the
worsening of the inflammatory response.
[0005] Research has shown that TGF-.beta. is able to compromise the
effectiveness of ICS. Furthermore, the inventors have demonstrated
that viral infection of the airway epithelium compromises ICS
activity through induction of TGF-.beta. activity. Drug targeting
of TGF-.beta. carries risk of autoimmune and mitral valve defects.
The inventors surprisingly identified casein kinase
1.delta./.epsilon. as a mediator of TGF-.beta. induced ICS
insensitivity, using the compound PF670462 (WO2016/149756), and
demonstrated the utility of this agent to reverse steroid
insensitivity.
[0006] It would be useful to develop further compounds that can
prevent or treat respiratory diseases, acute and chronic
inflammatory conditions, and fibrotic diseases or conditions in
which fibrosis contributes to the pathology of the condition.
SUMMARY OF THE INVENTION
[0007] Described herein is a compound of formula (I) or a salt,
solvate, N-oxide, tautomer, stereoisomer, polymorph and/or prodrug
thereof:
##STR00001##
wherein: R.sub.1 and R.sub.2 are each independently selected from
the group consisting of H, C.sub.1-6alkyl, C.sub.1alkylC.sub.6aryl,
C.sub.3-6cycloalkyl and C.sub.3-6heterocyclyl; R.sub.3 is selected
from the group consisting of F, Cl and CH.sub.3; R.sub.4 is
selected from the group consisting of
C.sub.0-3alkylC.sub.3-12cycloalkyl and C.sub.1-12alkyl; wherein
each of R.sub.1, R.sub.2, R.sub.3 and R.sub.4 is optionally
substituted.
[0008] In some embodiments, the invention provides a compound of
formula (I), or salt, solvate, N-oxide, tautomer, stereoisomer,
polymorph and/or prodrug thereof,
wherein R.sub.1 is selected from the group consisting of H,
C.sub.2-6alkyl, hydroxyC.sub.1-6alkyl, C.sub.1alkylC.sub.6aryl,
C.sub.1alkylC.sub.12aryl, C.sub.1alkylC.sub.6arylhalo,
C.sub.1alkyl(C.sub.1alkyl)C.sub.6aryl, C.sub.3-6cycloalkyl,
haloC.sub.3-6cycloalkyl, hydroxyC.sub.3-6cycloalkyl, and
C.sub.3-5heterocyclyl;
R.sub.2 is H;
[0009] R.sub.3 is selected from the group consisting of F, Cl and
CH.sub.3; R.sub.4 is selected from the group consisting of
C.sub.0-3alkylC.sub.3-12cycloalkyl,
C.sub.0-3alkylC.sub.3-12cycloalkylhalo, C.sub.1-12alkyl and
haloC.sub.1-12alkyl; wherein each of R.sub.1, R.sub.2, R.sub.3 and
R.sub.4 is optionally substituted; and wherein when R.sub.1 is H,
R.sub.4 is selected from the group consisting of
C.sub.0-3alkylC.sub.4-12cycloalkyl and C.sub.1-12alkyl, wherein
when R.sub.4 is C.sub.6cycloalkyl, R.sub.4 is substituted by one or
more groups selected from C.sub.1-6alkyl, C.sub.1-6haloalkyl, aryl,
heteroaryl, and halo, and when R.sub.4 is C.sub.1-3alkyl, R.sub.4
is substituted by one or more halo groups, and when R.sub.1 is
C.sub.3cycloalkyl, C.sub.1alkylC.sub.6aryl or
C.sub.1alkyl(C.sub.1alkyl)C.sub.6aryl, R.sub.4 is selected from
haloC.sub.1-12alkyl, C.sub.0-3alkylC.sub.3-12cycloalkyl, and
C.sub.0-3alkylC.sub.3-12cycloalkylhalo.
[0010] In another aspect, there is provided a method of treating or
preventing a respiratory disease in a subject in need thereof, the
method comprising administering to the subject a therapeutically
effective amount of a compound of formula (I) or a salt, solvate,
N-oxide, tautomer, stereoisomer, polymorph and/or prodrug thereof,
thereby treating or preventing the respiratory disease in the
subject.
[0011] There is further provided a compound of formula (I) or a
salt, solvate, N-oxide, tautomer, stereoisomer, polymorph and/or
prodrug thereof for use in the treatment or prevention of a
respiratory disease in a subject.
[0012] The respiratory disease may be selected from asthma, chronic
obstructive pulmonary disease, interstitial lung diseases (such as
idiopathic pulmonary fibrosis) and other conditions relating to
tissue remodelling, primary or secondary lung tumour, hayfever,
chronic and acute sinusitis, and chronic and acute viral, fungal
and bacterial infections of the respiratory tract.
[0013] In another aspect, there is provided a method of improving
respiratory function in a subject in need thereof, the method
comprising administering to the subject a therapeutically effective
amount of a compound of formula (I) or a salt, solvate, N-oxide,
tautomer, stereoisomer, polymorph and/or prodrug thereof, thereby
improving respiratory function of the subject.
[0014] There is further provided a compound of formula (I) or a
salt, solvate, N-oxide, tautomer, stereoisomer, polymorph and/or
prodrug thereof for use in improving respiratory function in a
subject.
[0015] The improvement in respiratory function may be selected from
a decrease in the level of constriction of the lungs, a decrease in
the elastic stiffness of the respiratory system, and/or an increase
in the ease with which the respiratory system can be extended.
Preferably, the improvement is selected from a decrease in the
level of constriction of the lungs, and a decrease in the elastic
stiffness of the respiratory system. In yet another aspect, there
is provided a composition comprising a compound according to
formula (I) or a salt, solvate, N-oxide, tautomer, stereoisomer,
polymorph and/or prodrug thereof, and a pharmaceutically acceptable
excipient.
[0016] The composition may be formulated for oral administration or
administration by inhalation or injection.
[0017] Use of a compound of the invention, or a salt, solvate,
N-oxide, tautomer, stereoisomer, polymorph and/or prodrug thereof,
or composition of the invention in the preparation of medicaments
for the treatment or prevention of a respiratory disease in a
subject is also described.
[0018] As used herein, except where the context requires otherwise,
the term "comprise" and variations of the term, such as
"comprising", "comprises" and "comprised", are not intended to
exclude further additives, components, integers or steps.
[0019] Reference to any prior art in the specification is not an
acknowledgment or suggestion that this prior art forms part of the
common general knowledge in any jurisdiction or that this prior art
could reasonably be expected to be understood, regarded as
relevant, and/or combined with other pieces of prior art by a
skilled person in the art.
[0020] Further aspects of the present invention and further
embodiments of the aspects described in the preceding paragraphs
will become apparent from the following description, given by way
of example and with reference to the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] FIG. 1. Defines a number of known compounds.
[0022] FIG. 2. .sub.PIC.sub.50 values (the negative log of the
concentration suppressing IL-11 level by 50%) for inhibition of
TGF-.beta.-induced IL-11 (interpolated from the linear regression
of log concentration small molecule versus IL-11 level).
[0023] FIG. 3. Defines compounds disclosed in WO2018/201192.
[0024] FIG. 4. Plasma concentrations over time following IV or oral
administration of PF670462 (A) and ZH3-138 (B) to male C57BL/6
mice.
[0025] FIG. 5. Comparison of PF670462 and ZH3-138 for inhibition of
TGF-.beta.-induced IL-11 levels (A--a chart of concentration of
IL-11 in supernatant taken from MRC5 cells following exposure to
vehicle, PF670462 and ZH3-138 at 0.1 .mu.M, 1 .mu.M and 10 .mu.M;
B--a chart of IL-11 concentration in supernatant of A549 cells
treated with various concentrations of PF670462 or ZH3-138 30
minutes prior to TGF-.beta. for 24 h).
[0026] FIG. 6. Effects of ZH3-126 on TGF-.beta.-induced IL-11
concentration in supernatant taken from MRC5 cells at 0.1 .mu.M, 1
.mu.M and 10 .mu.M compared to vehicle.
[0027] FIG. 7. Comparison of effects of PF670462 and compounds of
the invention (ZH3-126 and ZH3-138) on supernatant concentrations
of various inflammatory biomarkers (A: IL-6; B: IL-8; C: GM-CSF)
across a range of concentrations.
DETAILED DESCRIPTION
[0028] It will be understood that the invention disclosed and
defined in this specification extends to all alternative
combinations of two or more of the individual features mentioned or
evident from the text or drawings. All of these different
combinations constitute various alternative aspects of the
invention.
[0029] Reference will now be made in detail to certain embodiments
of the invention. While the invention will be described in
conjunction with the embodiments, it will be understood that the
intention is not to limit the invention to those embodiments. On
the contrary, the invention is intended to cover all alternatives,
modifications, and equivalents, which may be included within the
scope of the present invention as defined by the claims.
[0030] One skilled in the art will recognize many methods and
materials similar or equivalent to those described herein, which
could be used in the practice of the present invention. The present
invention is in no way limited to the methods and materials
described. It will be understood that the invention disclosed and
defined in this specification extends to all alternative
combinations of two or more of the individual features mentioned or
evident from the text or drawings. All of these different
combinations constitute various alternative aspects of the
invention.
[0031] All of the patents and publications referred to herein are
incorporated by reference in their entirety.
[0032] For purposes of interpreting this specification, terms used
in the singular will also include the plural and vice versa.
[0033] The present invention provides a compound of formula (I) or
a salt, solvate, N-oxide, tautomer, stereoisomer, polymorph and/or
prodrug thereof:
##STR00002##
wherein: R.sub.1 and R.sub.2 are each independently selected from
the group consisting of H, C.sub.1-6alkyl, C.sub.1alkylC.sub.6aryl,
C.sub.3-6cycloalkyl and C.sub.3-6heterocyclyl; R.sub.3 is selected
from the group consisting of F, Cl and CH.sub.3; R.sub.4 is
selected from the group consisting of
C.sub.0-3alkylC.sub.3-12cycloalkyl and C.sub.1-12alkyl; wherein
each of R.sub.1, R.sub.2, R.sub.3 and R.sub.4 is optionally
substituted.
[0034] In some embodiments, the invention provides a compound of
formula (I),
wherein R.sub.1 is selected from the group consisting of H,
C.sub.2-6alkyl, hydroxyC.sub.1-6alkyl, C.sub.1alkylC.sub.6aryl,
C.sub.1alkylC.sub.12aryl, C.sub.1alkylC.sub.6arylhalo,
C.sub.1alkyl(C.sub.1alkyl)C.sub.6aryl, C.sub.3-6cycloalkyl,
haloC.sub.3-cycloalkyl, hydroxyC.sub.3-6cycloalkyl, and
C.sub.3-5heterocyclyl;
R.sub.2 is H;
[0035] R.sub.3 is selected from the group consisting of F, Cl and
CH.sub.3; R.sub.4 is selected from the group consisting of
C.sub.0-3alkylC.sub.3-12cycloalkyl,
C.sub.0-3alkylC.sub.3-12cycloalkylhalo, C.sub.1-12alkyl and
haloC.sub.1-12alkyl; wherein each of R.sub.1, R.sub.2, R.sub.3 and
R.sub.4 is optionally substituted wherein when R.sub.1 is H,
R.sup.4 is selected from the group consisting of
C.sub.0-3alkylC.sub.4-12cycloalkyl and C.sub.1-12alkyl, wherein
when R.sup.4 is C.sub.6cycloalkyl, R.sup.4 is substituted by one or
more groups selected from C.sub.1-6alkyl, C.sub.1-6haloalkyl, aryl,
heteroaryl, and halo, and when R.sup.4 is C.sub.1-3alkyl, R.sup.4
is substituted by one or more halo groups, and when R.sup.1 is
C.sub.3cycloalkyl, C.sub.1alkylC.sub.6aryl or
C.sub.1alkyl(C.sub.1alkyl)C.sub.6aryl, R.sup.4 is selected from
haloC.sub.1-12alkyl and C.sub.0-3alkylC.sub.3-12cycloalkyl.
[0036] The inventors found that the compounds of Formula (I) are
inhibitors of CK1.delta.. Advantageously, at least preferred
embodiments of these compounds are selective inhibitors of
CK1.delta. compared with other kinases. Selective CK1.delta.
inhibitors may avoid undesired effects associated with the activity
of the other kinases (ie the kinases for which the CK1.delta.
inhibitors select against). Also advantageously, at least preferred
embodiments provided lower clearance rates following administration
(eg IV or oral administration) compared to known CK1.delta.
inhibitors, such as PF670462.
[0037] In any one of the embodiments, the present invention
provides a compound of formula (I) provided that the compound is
not selected from the list of compounds in FIGS. 1 and/or 3.
Various compounds are also described in Keenan, et al. Frontiers in
Pharmacology, 2018, vol 9, article 738; WO2016/149756A1;
WO1996/021654A1; WO1999/032121A1; WO1997/035856A1; Kim, D-K., et
al. Bioorganic & Medicinal Chemistry Letters, 2008, 18,
4006-4010; WO1999/001136A1; U.S. Pat. No. 6,369,068B1; and
WO2018/201192A1. In some embodiments, any specific compound
described in one or more of these documents may be excluded by way
of proviso.
[0038] In any one of the embodiments, R.sub.1 is C.sub.2-6alkyl,
preferably C.sub.2-3alkyl. When R.sub.1 is C.sub.2-3alkyl, R.sub.2
may be H. R.sub.1 may be C.sub.1-3alkyl substituted with one or
more hydroxyl groups.
[0039] In any one of the embodiments, R.sub.1 may be
hydroxyC.sub.1-6alkyl. In some embodiments, the
hydroxyC.sub.1-6alkyl comprises one hydroxyl substituent.
[0040] In any one of the embodiments, the present invention
provides a compound of formula (I) wherein R.sub.2 is H.
[0041] In any one of the embodiments, R.sub.1 is
C.sub.3-6cycloalkyl. R.sub.1 may be selected from cyclobutyl,
cyclopentyl and cyclohexyl. When R.sub.1 is C.sub.3-6cycloalkyl,
R.sub.1 may be substituted or unsubstituted. When substituted, the
substituent may be selected from one or more OH groups and/or one
or more halo groups. When R.sub.1 is C.sub.3-6cycloalkyl, R.sub.2
may be H.
[0042] In any one of the embodiments, R.sub.1 is
haloC.sub.3-6cycloalkyl. In these embodiments, R.sub.1 may comprise
1 or 2 halo groups, which may be the same or different. In some
embodiments, R.sub.1 comprises 2 halo groups, which may be attached
to the same carbon atom. In some embodiments, the
haloC.sub.3-6cycloalkyl is a fluoroC.sub.3-6cycloalkyl. Typically,
the halo group is in a para position relative to the point of
attachment of R.sub.1 to the pyrimidyl amine of formula (I).
[0043] In any one of the embodiments, R.sub.1 is
hydroxyC.sub.3-6cycloalkyl. In these embodiments, R.sub.1 may
comprise 1 hydroxy group. Typically, the hydroxy group is in a para
position relative to the point of attachment to the pyrimidyl amine
of formula (I).
[0044] In any one of the embodiments, R.sub.1 is
C.sub.3-6heterocyclyl. R.sub.1 may be selected from an
oxygen-containing heterocyclyl group, a nitrogen-containing
heterocyclyl group, or a sulphur-containing heterocyclyl group, or
a heterocyclyl group containing a combination of two or more
oxygen, nitrogen and sulphur atoms. In some embodiments, R.sub.1 is
an optionally substituted 4-7 membered heterocyclyl or a 4-6
membered heterocyclyl. In some embodiments, R.sub.1 is selected
from oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl,
imidazolidinyl, terahydrofuranyl, 1,3-dioxolanyl,
tetrahydropyranyl, tetrahydrothipheneyl, and 1,2- and
1,3-oxathiolanyl groups. In one embodiment, when R.sub.1 is
C.sub.3-5heterocyclyl, R.sub.2 is H.
[0045] In any one of the embodiments, the present invention
provides a compound of formula (I) wherein R.sub.1 and R.sub.2 are
both the same. For example, R.sub.1 and R.sub.2 may both be H, or
R.sub.1 and R.sub.2 may both be C.sub.1-6alkyl (e.g. methyl, ethyl,
propyl or butyl).
[0046] In any one of the embodiments, R.sub.1 is
C.sub.1alkylC.sub.6aryl. The C.sub.1alkylC.sub.6aryl group may be
substituted. The substituents may be selected from one or more
alkyl groups, one or more hydroxyl groups and one or more halo
groups. The aryl group may be substituted. The alkyl group may be
substituted.
[0047] In any one of the embodiments, R.sub.1 is
C.sub.1alkylC.sub.12aryl. Typically, the C.sub.12aryl is biphenyl.
In some embodiments, the covalent bond between the phenyl rings is
para relative to the C.sub.1alkyl moiety. Typically, the
C.sub.1alkylC.sub.12aryl group is connected to the pyrimidyl amine
through the C.sub.1alkyl moiety.
[0048] In any one of the embodiments, R.sub.1 is
C.sub.1alkylC.sub.6arylhalo. Typically, the halo moiety is a
substituent of the C.sub.6aryl ring. The halo group may be at any
one or more of ortho, meta or para position(s) relative to the
C.sub.1alkyl moiety. Typically, the C.sub.1alkylC.sub.6arylhalo is
a C.sub.1alkylC.sub.6arylfluoro. Typically, the
C.sub.1alkylC.sub.6arylhalo group is connected to the pyrimidyl
amine through the C.sub.1alkyl moiety.
[0049] In any one of the embodiments, R.sub.1 is
C.sub.1alkyl(C.sub.1alkyl)C.sub.6aryl. Typically, the
C.sub.1alkyl(C.sub.1alkyl)C.sub.6aryl group is connected to the
pyrimidyl amine through the C.sub.1alkyl moiety, which may be
denoted as --C.sub.1alkyl(C.sub.1alkyl)C.sub.6aryl.
[0050] In any one of the embodiments, R.sub.1 is selected from H,
ethyl, hydroxyethyl, halobenzyl, hydroxypropyl, cyclopropyl,
cyclobutyl, oxetanyl, halocyclobutyl (eg difluorocyclobutyl),
hydroxycyclobutyl, cyclopentyl, cyclohexyl, halocyclohexyl (eg
difluorocyclohexyl), pyranyl and S,S-dioxythianyl.
[0051] In any one of the embodiments, R.sub.3 is CH.sub.3. In any
one of the embodiments, R.sub.3 is F or Cl. Preferably, R.sub.3 is
F.
[0052] In any one of the embodiments, R.sub.4 is
C.sub.0-3alkylC.sub.3-12cycloalkyl. R.sub.4 may be
C.sub.0-3alkylC.sub.3-12cycloalkyl, wherein the
C.sub.3-12cycloalkyl group is selected from cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. In a preferred
form, R.sub.4 is C.sub.3-12cycloalkyl. More preferably, R.sub.4 is
selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
cycloheptyl.
[0053] In any one of the embodiments, R.sub.4 is
C.sub.1-2alkylC.sub.3-12cycloalkyl. R.sub.4 may be
C.sub.1alkylC.sub.3-12cycloalkyl. The C.sub.3-12cycloalkyl group
may be selected from cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and cycloheptyl.
[0054] In any one of the embodiments, where R.sub.4 is
C.sub.0-3alkylC.sub.3-12cycloalkyl, R.sub.4 may be substituted. The
substituent may be selected from one or more OH groups, one or more
C.sub.1-6alkyl groups, and one or more halo groups.
[0055] In any one of the embodiments, R.sub.4 is selected from
C.sub.0-3alkylC.sub.4-12cycloalkyl and C.sub.3cycloalkyl and
C.sub.2-3alkylC.sub.3cycloalkyl, each of which may be optionally
substituted.
[0056] In any one of the embodiments, R.sub.4 is
C.sub.0-3alkylC.sub.3-12cycloalkylhalo. Typically the halo is a
substituent of the cycloalkyl moiety. The group may comprise 1 or 2
halo groups. In embodiments comprising 2 halo groups, these may be
attached to the same carbon atom. Typically, the halo substituent
is attached to a position of the cycloalkyl group para to the
C.sub.0-3alkyl moiety or the point of attachment to the imidazole
of formula (I). The C.sub.3-12cycloalkyl and/or C.sub.0-3alkyl
moiety of the C.sub.0-3alkylC.sub.3-12cycloalkylhalo group may be
any of the preferred C.sub.0-3alkyl and/or C.sub.3-12cycloalkyl
groups described for any embodiment of R.sub.4. Preferred groups
include dihalocyclobutyl (eg 3,3-difluorocyclobut-1-yl),
dihalocyclobutylmethyl (eg 3,3-difluorocyclobutyl-1-methyl),
dihalocyclohexyl (eg 4,4-difluorocyclohex-1-yl) and
dihalocyclohexylmethyl (eg 4,4-difluorocyclohexyl-1-methyl).
Preferably, the halo is fluoro. Typically, the
C.sub.0-3alkylC.sub.3-12cycloalkylhalo is connected to the
imidazole nitrogen through the C.sub.0-3alkyl moiety (when present)
which may be denoted as --C.sub.0-3alkylC.sub.3-12cycloalkyl.
[0057] In any one of the embodiments, R.sub.4 is C.sub.1-12alkyl.
R.sub.4 may be a methyl, ethyl, propyl or butyl group. R.sub.4 may
be a branched C.sub.1-12alkyl group, such as a branched C.sub.3,
C.sub.4 or C.sub.5 alkyl group. R.sub.4 may be substituted by one
or more groups selected from halo and OH. For example, R.sub.4 may
be substituted by one, two, or more halo groups.
[0058] In any one of the embodiments, R.sub.4 is
haloC.sub.1-12alkyl. In some embodiments, R.sub.4 is a
haloC.sub.1-6alkyl or a haloC.sub.1-4alkyl. The group may comprise
1, 2 or 3 halo groups. In embodiments comprising 2 or more halo
groups, these may be attached to the same carbon atom. Typically,
the halo group is attached the carbon atom distal from the point of
attachment to the imidazole moiety of formula (I). Preferably, the
halo is fluoro. In some embodiments, R.sub.4 is selected from
trihalomethyl, trihaloethyl (eg 2,2,2-trifluoroeth-1-yl),
dihalomethyl (eg difluoromethyl), halomethyl (eg fluoromethyl),
dihaloethyl (eg 2,2-difluoroeth-1-yl), hexahalopropyl (eg
1,1,1,3,3,3-hexafluoroprop-2-yl), trihalopropyl (eg
3,3,3-trifluoroprop-1-yl and 1,1,1-trifluoroprop-2-yl), halopropyl
(eg 2-fluoroprop-2-yl), dihalopropyl (eg 3,3-difluoroprop-1-yl),
haloethyl (eg 2-fluoroeth-1-yl).
[0059] In some embodiments, R.sub.4 is selected from ethyl, pentyl,
cyclopentyl, cyclohexyl, halocyclohexylmethyl, halocyclohexyl and
haloethyl. In some embodiments, R.sub.4 is selected from ethyl,
pentyl, cyclopentyl, cyclohexyl, difluorocyclohexyl (eg
4,4-diflurocyclohex-1-yl), difluorocyclohexylmethyl (eg
4,4-diflurocyclohexyl-1-methyl) and trifluoroethyl (eg
2,2,2-trifluoroeth-1-yl).
[0060] In any one of the embodiments, when R.sup.1 is H, R.sup.4 is
selected from the group consisting of
C.sub.0-3alkylC.sub.4-12cycloalkyl and C.sub.1-12alkyl. In these
embodiments, when R.sup.4 is C.sub.6cycloalkyl, R.sup.4 is
substituted by one or more groups selected from C.sub.1-6alkyl,
C.sub.1-6haloalkyl, aryl, heteroaryl, and halo, preferably halo (eg
fluoro); and when R.sup.4 is C.sub.1-3alkyl, R.sup.4 is substituted
by one or more halo groups.
[0061] In any one of the embodiments, when R.sup.1 is
C.sub.3cycloalkyl, C.sub.1alkylC.sub.6aryl or
C.sub.1alkyl(C.sub.1alkyl)C.sub.6aryl, R.sup.4 is selected from
haloC.sub.1-12alkyl and C.sub.0-3alkylC.sub.3-12cycloalkyl.
[0062] In any one of the embodiments, R.sub.1, R.sub.2, R.sub.3 and
R.sub.4 are optionally substituted by one or more groups selected
from OH, C.sub.1-6alkoxy, halo, amino, mercapto and C.sub.1-6alkyl.
In some embodiments, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are
unsubstituted.
[0063] As used herein the term "C.sub.1-12alkyl" refers to a
straight or branched chain hydrocarbon radical having from one to
twelve carbon atoms, or any range between, i.e. it contains 1, 2,
3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. The alkyl group is
optionally substituted with substituents, multiple degrees of
substitution being allowed. Examples of "C.sub.1-12alkyl" as used
herein include, but are not limited to, methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl,
neopentyl and the like.
[0064] "C.sub.1-3alkyl", "C.sub.1-4alkyl" and "C.sub.1-6alkyl" are
preferred. These groups refer to an alkyl group containing 1-3, 1-4
or 1-6 carbon atoms, respectively, or any range in between (e.g.
alkyl groups containing 2-5 carbon atoms, i.e. 2, 3, 4 or 5 carbon
atoms, are also within the range of C.sub.1-6). Where the term
"C.sub.0-2 alkyl", or the like, is used, there may be no alkyl
group, or an alkyl group containing 1 or 2 carbon atoms.
[0065] The term "C.sub.2-6alkenyl" refers to optionally substituted
straight chain or branched chain hydrocarbon groups having at least
one double bond of either E or Z stereochemistry where applicable
and 2 to 6 carbon atoms. Examples include vinyl, 1-propenyl, 1- and
2-butenyl and 2-methyl-2-propenyl. Unless the context requires
otherwise, the term "C.sub.2-6alkenyl" also encompasses alkenyl
groups containing one less hydrogen atom such that the group is
attached via two positions i.e. divalent. "C.sub.2-4alkenyl" and
"C.sub.2-3alkenyl" including ethenyl, propenyl and butenyl are
preferred with ethenyl being particularly preferred.
[0066] The term "C.sub.2-6alkynyl" refers to optionally substituted
straight chain or branched chain hydrocarbon groups having at least
one triple bond and 2 to 6 carbon atoms. Examples include ethynyl,
1-propynyl, 1- and 2-butynyl, 2-methyl-2-propynyl, 2-pentynyl,
3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and
5-hexynyl and the like. Unless the context indicates otherwise, the
term "C.sub.2-6alkynyl" also encompasses alkynyl groups containing
one less hydrogen atom such that the group is attached via two
positions i.e. divalent. C.sub.2-3alkynyl is preferred.
[0067] As used herein, the term "halogen" refers to fluorine (F),
chlorine (Cl), bromine (Br), or iodine (I) and the term "halo"
refers to the halogen radicals fluoro (--F), chloro (--Cl), bromo
(--Br), and iodo (--I). Preferably, `halo` is fluoro.
[0068] As used herein, the term "cycloalkyl" refers to a
non-aromatic cyclic hydrocarbon ring. The term
"C.sub.3-7cycloalkyl" refers to a non-aromatic cyclic hydrocarbon
ring having from three to seven carbon atoms, or any range of
integers in between. For example, the C.sub.3-7cycloalkyl group
would also include cycloalkyl groups containing 4 to 6 (i.e. 4, 5
or 6) carbon atoms. The alkyl group is as defined above, and may be
substituted. Exemplary "C.sub.3-7cycloalkyl" groups useful in the
present invention include, but are not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
[0069] Cycloalkyl groups may optionally be fused to one or more
heterocyclic or cycloalkyl rings. Cycloalkyl rings may be
substituted at any of the carbon atoms on the ring with another
cycloalkyl or heterocyclic moiety to form a spirocycloalkyl or
spiroheteroalkyl compound.
[0070] Two non-adjacent atoms on the cycloalkyl group may be
bridged by an alkyl or heteroalkyl group to form a bridged system.
Preferably, the bridging group is 1-3 atoms in length.
[0071] As used herein, the terms "heterocyclic" or "heterocyclyl"
refer to a non-aromatic heterocyclic ring, being saturated or
having one or more degrees of unsaturation, containing one or more
heteroatom substitution selected from S, S(O), S(O).sub.2, O, or N.
The term "C.sub.3-7heterocyclyl" refers to a non-aromatic cyclic
hydrocarbon ring having from three to seven carbon atoms (i.e. 3,
4, 5, 6 or 7 carbon atoms) containing one or more heteroatom
substitutions as referred to herein. The heterocyclic moiety may be
substituted, multiple degrees of substitution being allowed. The
term "C.sub.3-7 heterocyclyl" also includes heterocyclyl groups
containing C.sub.4-5, C.sub.5-7, C.sub.6-7, C.sub.4-7, C.sub.4-6
and C.sub.5-6 carbon atoms. Preferably, the heterocyclic ring
contains four to six carbon atoms and one or two heteroatoms. More
preferably, the heterocyclic ring contains five carbon atoms and
one heteroatom, or four carbon atoms and two heteroatom
substitutions, or five carbon atoms and one heteroatom. The
heterocyclyl groups may be 3 to 10-membered ring systems, which
denotes the total number of atoms (carbon atoms and heteroatoms)
contained within the ring system. In this context, the prefixs 3-,
4-, 5-, 6-, 7-, 8-, 9- and 10-membered denote the number of ring
atoms, or range of ring atoms, whether carbon atoms or heteroatoms.
For example, the term "3-10 membered heterocylyl", as used herein,
pertains to a heterocyclyl group having 3, 4, 5, 6, 7, 8, 9 or 10
ring atoms. Examples of heterocylyl groups include 5-6-membered
monocyclic heterocyclyls and 9-10 membered fused bicyclic
heterocyclyls. Accordingly, heterocyclyl heterocyclyl rings may be
optionally fused to one or more other "heterocyclic" ring(s),
cycloalkyl ring(s), aryl ring(s) or heteroaryl ring(s). Examples of
"heterocyclic" moieties include, but are not limited to,
tetrahydrofuran, pyran, oxetane, 1,4-dioxane, 1,3-dioxane,
piperidine, piperazine, N-methylpiperazinyl, 2,4-piperazinedione,
pyrrolidine, imidazolidine, pyrazolidine, morpholine,
thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, and the
like.
[0072] Heterocyclic groups may be substituted at any of the carbons
on the ring with another heterocyclic or cycloalkyl moiety to form
a spirocycloalkyl or spiroheterocyclyl compound.
[0073] Two non-adjacent atoms on the heterocyclic group may further
be bridged by an alkyl or heteroalkyl group to form a bridged
system. Preferably, the bridging group is 1-3 atoms in length.
[0074] As an example of substituted heterocyclic groups, the term
"C.sub.0-2alkylC.sub.3-7heterocyclyl" includes heterocyclyl groups
containing either no alkyl group as a linker between the compound
and the heterocycle, or an alkyl group containing 1 or 2 carbon
atoms as a linker between the compound and the heterocycle (i.e.
heterocycle, --CH.sub.2-heterocycle or
--CH.sub.2CH.sub.2-heterocycle). These heterocycles may be further
substituted.
[0075] Substituted cycloalkyl and heterocyclyl groups may be
substituted with any suitable substituent as described below.
[0076] As used herein, the term "aryl" refers to an optionally
substituted benzene ring or to an optionally substituted benzene
ring system fused to one or more optionally substituted benzene
rings to form, for example, anthracene, phenanthrene, or
naphthalene ring systems. Examples of "aryl" groups include, but
are not limited to, phenyl, 2-naphthyl, 1-naphthyl, biphenyl, as
well as substituted derivatives thereof.
[0077] Preferred substituted aryl groups include arylamino,
arylalkyl, arylalkylhalo, arylhalo, and aralkoxy groups.
[0078] As used herein, the term "heteroaryl" refers to a monocyclic
five, six or seven membered aromatic ring, or to a fused bicyclic
or tricyclic aromatic ring system comprising at least one
monocyclic five, six or seven membered aromatic ring. These
heteroaryl rings contain one or more nitrogen, sulfur, and/or
oxygen heteroatoms, and may be optionally substituted with up to
three members. N-containing heteroaryls may be in the form of an
N-oxide and S-containing heteroaryls may be in the form of sulfur
oxides and dioxides. Examples of "heteroaryl" groups used herein
include furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl,
triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl,
oxadiazolyl, oxo-pyridyl, thiadiazolyl, isothiazolyl, pyridyl,
pyridazyl, pyrazinyl, pyrimidyl, quinolinyl, isoquinolinyl,
benzofuranyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl,
and substituted versions thereof.
[0079] The terms "hydroxy" and "hydroxyl" refer to the group
--OH.
[0080] The term "oxo" refers to the group .dbd.O.
[0081] The term "C.sub.1-6alkoxy" refers to an alkyl group as
defined above covalently bound via an O linkage containing 1 to 6
carbon atoms, such as methoxy, ethoxy, propoxy, isoproxy, butoxy,
tert-butoxy and pentoxy. "C.sub.1-4alkoxy" and "C.sub.1-3alkoxy"
including methoxy, ethoxy, propoxy and butoxy are preferred with
methoxy being particularly preferred.
[0082] The terms "haloC.sub.1-6alkyl" and "C.sub.1-6alkylhalo"
refer to a C.sub.1-6alkyl which is substituted with one or more
halogens. HaloC.sub.1-3alkyl groups are preferred, such as for
example, --CH.sub.2CF.sub.3, and --CF.sub.3.
[0083] The terms "haloC.sub.1-6alkoxy" and "C.sub.1-6alkoxyhalo"
refer to a C.sub.1-6alkoxy which is substituted with one or more
halogens. C.sub.1-3alkoxyhalo groups are preferred, such as for
example, --OCF.sub.3.
[0084] The term "carboxylate" or "carboxyl" refers to the group
--COO-- or --COOH.
[0085] The term "ester" refers to a carboxyl group having the
hydrogen replaced with, for example a C.sub.1-6alkyl group
("carboxylC.sub.1-6alkyl" or "alkylester"), an aryl or aralkyl
group ("arylester" or "aralkylester") and so on.
CO.sub.2C.sub.1-3alkyl groups are preferred, such as for example,
methylester (CO.sub.2Me), ethylester (CO.sub.2Et) and propylester
(CO.sub.2Pr) and includes reverse esters thereof (e.g. --OC(O)Me,
--OC(O)Et and --OC(O)Pr).
[0086] The terms "cyano" and "nitrile" refer to the group --CN.
[0087] The term "nitro" refers to the group --NO.sub.2.
[0088] The term "amino" refers to the group --NH.sub.2.
[0089] The term "substituted amino" or "secondary amino" refers to
an amino group having a hydrogen replaced with, for example a
C.sub.1-6alkyl group ("C.sub.1-6alkylamino"), an aryl or aralkyl
group ("arylamino", "aralkylamino") and so on. C.sub.1-3alkylamino
groups are preferred, such as for example, methylamino (NHMe),
ethylamino (NHEt) and propylamino (NHPr).
[0090] The term "disubstituted amino" or "tertiary amino" refers to
an amino group having the two hydrogens replaced with, for example
a C.sub.1-6alkyl group, which may be the same or different
("dialkylamino"), an aryl and alkyl group ("aryl(alkyl)amino") and
so on. Di(C.sub.1-3alkyl)amino groups are preferred, such as for
example, dimethylamino (NMe.sub.2), diethylamino (NEt.sub.2),
dipropylamino (NPr.sub.2) and variations thereof (e.g. N(Me)(Et)
and so on).
[0091] The term "aldehyde" refers to the group --C(.dbd.O)H.
[0092] The term "acyl" refers to the group --C(O)CH.sub.3.
[0093] The term "ketone" refers to a carbonyl group which may be
represented by --C(O)--.
[0094] The term "substituted ketone" refers to a ketone group
covalently linked to at least one further group, for example, a
C.sub.1-6alkyl group ("C.sub.1-6alkylacyl" or "alkylketone" or
"ketoalkyl"), an aryl group ("arylketone"), an aralkyl group
("aralkylketone) and so on. C.sub.1-3alkylacyl groups are
preferred.
[0095] The term "amido" or "amide" refers to the group
--C(O)NH.sub.2.
[0096] The term "substituted amido" or "substituted amide" refers
to an amido group having a hydrogen replaced with, for example a
C.sub.1-6alkyl group ("C.sub.1-6alkylamido" or
"C.sub.1-6alkylamide"), an aryl ("arylamido"), aralkyl group
("aralkylamido") and so on. C.sub.1-3alkylamide groups are
preferred, such as for example, methylamide (--C(O)NHMe),
ethylamide (--C(O)NHEt) and propylamide (--C(O)NHPr) and includes
reverse amides thereof (e.g. --NHMeC(O)--, --NHEtC(O)-- and
--NHPrC(O)--).
[0097] The term "disubstituted amido" or "disubstituted amide"
refers to an amido group having the two hydrogens replaced with,
for example a C.sub.1-6alkyl group ("di(C.sub.1-6alkyl)amido" or
"di(C.sub.1-6alkyl)amide"), an aralkyl and alkyl group
("alkyl(aralkyl)amido") and so on. Di(C.sub.1-3alkyl)amide groups
are preferred, such as for example, dimethylamide
(--C(O)NMe.sub.2), diethylamide (--C(O)NEt.sub.2) and dipropylamide
((--C(O)NPr.sub.2) and variations thereof (e.g. --C(O)N(Me)Et and
so on) and includes reverse amides thereof.
[0098] The term "thiol" refers to the group --SH.
[0099] The term "C.sub.1-6alkylthio" refers to a thiol group having
the hydrogen replaced with a C.sub.1-6alkyl group.
C.sub.1-3alkylthio groups are preferred, such as for example,
thiolmethyl, thiolethyl and thiolpropyl.
[0100] The terms "thioxo" refer to the group .dbd.S.
[0101] The term "sulfinyl" refers to the group --S(.dbd.O)H.
[0102] The term "substituted sulfinyl" or "sulfoxide" refers to a
sulfinyl group having the hydrogen replaced with, for example a
C.sub.1-6alkyl group ("C.sub.1-6alkylsulfinyl" or
"C.sub.1-6alkylsulfoxide"), an aryl ("arylsulfinyl"), an aralkyl
("aralkyl sulfinyl") and so on. C1-3alkylsulfinyl groups are
preferred, such as for example, --SOmethyl, --SOethyl and
--SOpropyl.
[0103] The term "sulfonyl" refers to the group --SO.sub.2H.
[0104] The term "substituted sulfonyl" refers to a sulfonyl group
having the hydrogen replaced with, for example a C.sub.1-6alkyl
group ("sulfonylC.sub.1-6alkyl"), an aryl ("arylsulfonyl"), an
aralkyl ("aralkylsulfonyl") and so on. SulfonylC.sub.1-3alkyl
groups are preferred, such as for example, --SO.sub.2Me,
--SO.sub.2Et and --SO.sub.2Pr.
[0105] The term "sulfonylamido" or "sulfonamide" refers to the
group --SO.sub.2NH.sub.2.
[0106] The term "substituted sulfonamido" or "substituted
sulphonamide" refers to an sulfonylamido group having a hydrogen
replaced with, for example a C.sub.1-6alkyl group
("sulfonylamidoC.sub.1-6alkyl"), an aryl ("arylsulfonamide"),
aralkyl ("aralkylsulfonamide") and so on.
SulfonylamidoC.sub.1-3alkyl groups are preferred, such as for
example, --SO.sub.2NHMe, --SO.sub.2NHEt and --SO.sub.2NHPr and
includes reverse sulfonamides thereof (e.g. --NHSO.sub.2Me,
--NHSO.sub.2Et and --NHSO.sub.2Pr).
[0107] The term "disubstituted sufonamido" or "disubstituted
sulphonamide" refers to an sulfonylamido group having the two
hydrogens replaced with, for example a C.sub.1-6alkyl group, which
may be the same or different ("sulfonylamidodi(C.sub.1-6alkyl)"),
an aralkyl and alkyl group ("sulfonamido(aralkyl)alkyl") and so on.
Sulfonylamidodi(C.sub.1-3alkyl) groups are preferred, such as for
example, --SO.sub.2NMe.sub.2, --SO.sub.2NEt.sub.2 and
--SO.sub.2NPr.sub.2 and variations thereof (e.g. --SO.sub.2N(Me)Et
and so on) and includes reserve sulfonamides thereof (e.g.
--N(Me)SO.sub.2Me and so on).
[0108] The term "sulfate" refers to the group OS(O).sub.2OH and
includes groups having the hydrogen replaced with, for example a
C.sub.1-6alkyl group ("alkylsulfates"), an aryl ("arylsulfate"), an
aralkyl ("aralkylsulfate") and so on. C.sub.1-3sulfates are
preferred, such as for example, OS(O).sub.2OMe, OS(O).sub.2OEt and
OS(O).sub.2OPr.
[0109] The term "sulfonate" refers to the group SO.sub.3H and
includes groups having the hydrogen replaced with, for example a
C.sub.1-6alkyl group ("alkylsulfonate"), an aryl ("arylsulfonate"),
an aralkyl ("aralkylsulfonate") and so on. C.sub.1-3sulfonates are
preferred, such as for example, SO.sub.3Me, SO.sub.3Et and
SO.sub.3Pr.
[0110] A "substituent" as used herein, refers to a molecular moiety
that is covalently bonded to an atom within a molecule of interest.
For example, a "ring substituent" may be a moiety such as a
halogen, alkyl group, or other substituent described herein that is
covalently bonded to an atom, preferably a carbon or nitrogen atom,
that is a ring member. The term "substituted," as used herein,
means that any one or more hydrogens on the designated atom is
replaced with a selection from the indicated substituents, provided
that the designated atom's normal valence is not exceeded, and that
the substitution results in a stable compound, i.e., a compound
that can be isolated, characterized and tested for biological
activity.
[0111] The terms "optionally substituted" or "may be substituted"
and the like, as used throughout the specification, denotes that
the group may or may not be further substituted or fused (so as to
form a polycyclic system), with one or more non-hydrogen
substituent groups. Suitable chemically viable substituents for a
particular functional group will be apparent to those skilled in
the art. In some embodiments, an optionally substituted moiety may
or may not be further substituted with 1, 2, 3, 4 or more groups,
preferably 1, 2 or 3, more preferably 1 or 2 groups.
[0112] Examples of substituents include but are not limited to:
[0113] C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.1-6 haloalkoxy,
C.sub.1-6hydroxyalkyl, C.sub.3-7heterocyclyl, C.sub.3-7cycloalkyl,
C.sub.1-6alkoxy, C.sub.1-6alkylsulfanyl, C.sub.1-6alkylsulfenyl,
C.sub.1-6alkylsulfonyl, C.sub.1-6alkylsulfonylamino,
arylsulfonoamino, alkylcarboxy, alkylcarboxyamide, oxo, hydroxy,
mercapto, amino, acyl, carboxy, carbamoyl, aryl, aryloxy,
heteroaryl, aminosulfonyl, aroyl, aroylamino, heteroaroyl, acyloxy,
aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halo,
ureido, C.sub.1-6perfluoroalkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6alkoxyaryl, esters, substituted amino,
disubstituted amino, acyl, ketones, substituted ketones, amides,
aminoacyl, substituted amides, disubstituted amides, thiol,
alkylthio, thioxo, sulfates, sulfonates, sulfinyl, substituted
sulfinyl, sulfonyl, substituted sulfonyl, sulfonylamides,
substituted sulfonamides, disubstituted sulfonamides,
arylC.sub.1-6alkyl, heterocyclylC.sub.1-6alkyl, and
C.sub.3-7cycloalkylC.sub.1-6alkyl wherein each alkyl, alkenyl,
alkynyl, cycloalkyl, aryl and heterocyclyl and groups containing
them may be further optionally substituted. In some embodiments, a
moiety may be optionally substituted by any subset of optional
substituents selected from those described above.
[0114] Optional substituents in the case of heterocycles
(heterocyclyl and heteroaryl groups) containing N may also include
but are not limited to C.sub.1-6alkyl i.e. N--C.sub.1-3alkyl, more
preferably methyl particularly N-methyl.
[0115] In one embodiment, cyclic or heterocyclic substituents may
form a spirocycloalkyl or spiroheteroalkyl substituent with a
carbon in the moiety from which the cyclic or heterocyclic group is
substituted. In another embodiment, cyclic or heterocyclic
substituents may be bridged.
[0116] For optionally substituted "C.sub.1-6alkyl",
"C.sub.2-6alkenyl" and "C.sub.2-6alkynyl", the optional substituent
or substituents are preferably selected from halo, aryl,
heterocyclyl, C.sub.3-8cycloalkyl, C.sub.1-6alkoxy, hydroxyl, oxo,
aryloxy, haloC.sub.1-6alkyl, haloC.sub.1-6alkoxyl and carboxyl. In
some embodiments, the optionally substituted "C.sub.1-6alkyl",
"C.sub.2-6alkenyl" and "C.sub.2-6alkynyl" may be optionally
substituted by any subset of optional substituents selected from
those described above.
[0117] Any of these groups may be further substituted by any of the
above-mentioned groups, where appropriate. For example, alkylamino,
or dialkylamino, C.sub.1-6alkoxy, etc.
[0118] Examples of compounds of the present invention are given
below in Table 1.
TABLE-US-00001 TABLE 1 Examples of compounds of the present
invention. Number Structure 10 (ZH3-114) ##STR00003## 11 (ZH3-118)
##STR00004## 5 (ZH3-122) ##STR00005## 6 (ZH3-126) ##STR00006## 25
(ZH2-66) ##STR00007## 16 (ZH2-114) ##STR00008## 17 (ZH2-118)
##STR00009## 18 (ZH2-122) ##STR00010## 20 (ZH2-146) ##STR00011## 21
(ZH2-38) ##STR00012## 22 (ZH2-46) ##STR00013## 23 (ZH2-54)
##STR00014## 24 (ZH2-58) ##STR00015## 26 (ZH2-78) ##STR00016## 29
(ZH3-50) ##STR00017## 30 (ZH3-62) ##STR00018## 31 (ZH3-70)
##STR00019## 33 (ZH3-86) ##STR00020## ZH3-134 ##STR00021## 42
(ZH3-58) ##STR00022## 45 (ZH3-138) ##STR00023## 48 (ZH3-130)
##STR00024## 51 (ZH3-78) ##STR00025## 68 ##STR00026## 69
##STR00027## 70 ##STR00028## 71 ##STR00029## 72 ##STR00030## 73
##STR00031## 56 (ZH5-38) ##STR00032## 59 (ZH4-174) ##STR00033## 57
(ZH5-6) ##STR00034## 58 (ZH4-154) ##STR00035## 74 ##STR00036## 75
##STR00037## 76 ##STR00038## 77 ##STR00039## 78 ##STR00040## 79
##STR00041## 80 ##STR00042## 81 ##STR00043## 82 ##STR00044## 83
##STR00045## 84 ##STR00046## 85 ##STR00047## 86 ##STR00048## 87
##STR00049## 88 ##STR00050## 89 ##STR00051## 90 ##STR00052## 91
##STR00053## 92 ##STR00054## 93 ##STR00055## 94 ##STR00056## 95
##STR00057## 96 ##STR00058## 97 ##STR00059## 98 ##STR00060## 99
##STR00061## 100 ##STR00062## 101 ##STR00063## 102 ##STR00064## 103
##STR00065## 104 ##STR00066## 105 ##STR00067## 106 ##STR00068## 107
##STR00069## 108 ##STR00070## 109 ##STR00071## 110 ##STR00072## 111
##STR00073## 112 ##STR00074## 113 ##STR00075## 114 ##STR00076## 115
##STR00077## 116 ##STR00078## 117 ##STR00079## 118 ##STR00080## 119
##STR00081## 120 ##STR00082## 121 ##STR00083## 122 ##STR00084## 123
##STR00085## 124 ##STR00086## 125 ##STR00087## 126 ##STR00088## 127
##STR00089## 128 ##STR00090## 129 ##STR00091## 130 ##STR00092## 131
##STR00093## 132 ##STR00094## 133 ##STR00095## 134 ##STR00096## 135
##STR00097## 136 ##STR00098## 137 ##STR00099## 138 ##STR00100## 139
##STR00101## 140 ##STR00102## 141 ##STR00103## 142 ##STR00104## 143
##STR00105## 144 ##STR00106## 145 ##STR00107## 146 ##STR00108## 147
##STR00109## 148 ##STR00110## 149 ##STR00111## 150 ##STR00112## 151
##STR00113## 152 ##STR00114## 153 ##STR00115## 55 (ZH4-186)
##STR00116## 60 (ZH5-30 (cis)) 61 (ZH5-34 (trans)) ##STR00117## 62
(ZH5-10) ##STR00118## 63 (ZH5-2) ##STR00119## 64 (ZH5-14)
##STR00120## 65 (ZH4-170) ##STR00121## 154 ##STR00122## 155
##STR00123## 156 ##STR00124## 157 ##STR00125##
158 ##STR00126## 159 ##STR00127## 160 ##STR00128## 161 ##STR00129##
162 ##STR00130## 163 ##STR00131## 164 ##STR00132## 165 ##STR00133##
166 ##STR00134## 66 (ZH4-146) ##STR00135## 67 (ZH4-150)
##STR00136## 37 (ZH2-142) ##STR00137##
[0119] The salts of the compounds of formula (I) are preferably
pharmaceutically acceptable, but it will be appreciated that
non-pharmaceutically acceptable salts also fall within the scope of
the present disclosure, since these may be useful as intermediates
in the preparation of pharmaceutically acceptable salts.
[0120] The term "pharmaceutically acceptable" may be used to
describe any pharmaceutically acceptable salt, solvate, tautomer,
N-oxide, stereoisomer polymorph and/or prodrug, or any other
compound which upon administration to a subject, is capable of
providing (directly or indirectly) a compound of formula (I), or an
active metabolite or residue thereof and typically that is not
deleterious to the subject.
[0121] Suitable pharmaceutically acceptable salts include, but are
not limited to, salts of pharmaceutically acceptable inorganic
acids such as hydrochloric, sulphuric, phosphoric, nitric,
carbonic, boric, sulfamic, and hydrobromic acids, or salts of
pharmaceutically acceptable organic acids such as acetic,
propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric,
malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic,
phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic,
salicylic, sulphanilic, aspartic, glutamic, edetic, stearic,
palmitic, oleic, lauric, pantothenic, tannic, ascorbic, valeric and
xinafoic acids.
[0122] Base salts include, but are not limited to, those formed
with pharmaceutically acceptable cations, such as sodium,
potassium, lithium, calcium, magnesium, zinc, ammonium,
alkylammonium such as salts formed from triethylamine,
alkoxyammonium such as those formed with ethanolamine and salts
formed from ethylenediamine, choline or amino acids such as
arginine, lysine or histidine.
[0123] General information on types of pharmaceutically acceptable
salts and their formation is known to those skilled in the art and
is as described in general texts such as "Handbook of
Pharmaceutical salts" P. H. Stahl, C. G. Wermuth, 1st edition,
2002, Wiley-VCH.
[0124] Basic nitrogen-containing groups may be quarternised with
such agents as lower alkyl halide, such as methyl, ethyl, propyl,
and butyl chlorides, bromides and iodides; dialkyl sulfates like
dimethyl and diethyl sulfate; and others.
[0125] A "prodrug" is a compound that may not fully satisfy the
structural requirements of the compounds provided herein, but is
modified in vivo, following administration to a subject or patient,
to produce a compound of formula (I) provided herein. For example,
a prodrug may be an acylated derivative of a compound as provided
herein. Prodrugs include compounds wherein hydroxy, carboxy, amine
or sulfhydryl groups are bonded to any group that, when
administered to a mammalian subject, cleaves to form a free
hydroxy, carboxy, amino, or sulfhydryl group, respectively.
Examples of prodrugs include, but are not limited to, acetate,
formate, phosphate and benzoate derivatives of alcohol and amine
functional groups within the compounds provided herein. Prodrugs of
the compounds provided herein may be prepared by modifying
functional groups present in the compounds in such a way that the
modifications are cleaved in vivo to generate the parent
compounds.
[0126] Prodrugs include compounds wherein an amino acid residue, or
a polypeptide chain of two or more (e.g., two, three or four) amino
acid residues which are covalently joined to free amino and/or
amido groups of compounds of formula (I). The amino acid residues
include the 20 naturally occurring amino acids commonly designated
by three letter symbols and also include, 4-hydroxyproline,
hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvlin,
beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine,
homoserine, ornithine and methionine sulfone. Prodrugs also include
compounds wherein carbonates, carbamates, amides and alkyl esters
which are covalently bonded to the above substituents of formula
(I) through the carbonyl carbon prodrug sidechain. Prodrugs can
include covalent irreversible and reversible inhibitors.
[0127] In the case of compounds that are solids, it will be
understood by those skilled in the art that the inventive
compounds, agents and salts may exist in different crystalline or
polymorphic forms, all of which are intended to be within the scope
of the present invention and specified formulae.
[0128] The invention includes all crystalline forms of a compound
of Formula (I) including anhydrous crystalline forms, hydrates,
solvates and mixed solvates. If any of these crystalline forms
demonstrates polymorphism, all polymorphs are within the scope of
this invention.
[0129] Formula (I) is intended to cover, where applicable, solvated
as well as unsolvated forms of the compounds. Thus, Formula (I)
includes compounds having the indicated structures, including the
hydrated or solvated forms, as well as the non-hydrated and
non-solvated forms.
[0130] The compounds of Formula (I) or salts, tautomers, N-oxides,
polymorphs or prodrugs thereof may be provided in the form of
solvates. Solvates contain either stoichiometric or
non-stoichiometric amounts of a solvent, and may be formed during
the process of crystallization with pharmaceutically acceptable
solvents such as water, alcohols such as methanol, ethanol or
isopropyl alcohol, DMSO, acetonitrile, dimethyl formamide (DMF),
acetic acid, and the like with the solvate forming part of the
crystal lattice by either non-covalent binding or by occupying a
hole in the crystal lattice. Hydrates are formed when the solvent
is water, alcoholates are formed when the solvent is alcohol.
Solvates of the compounds of the present invention can be
conveniently prepared or formed during the processes described
herein. In general, the solvated forms are considered equivalent to
the unsolvated forms for the purposes of the invention.
[0131] The compound of Formula (I) or salts, tautomers, N-oxides,
solvates and/or prodrugs thereof that form crystalline solids may
demonstrate polymorphism. All polymorphic forms of the compounds,
salts, tautomers, N-oxides, solvates and/or prodrugs are within the
scope of the invention.
[0132] The compound of Formula (I) may demonstrate tautomerism.
Tautomers are two interchangeable forms of a molecule that
typically exist within an equilibrium. Any tautomers of the
compounds of Formula (I) are to be understood as being within the
scope of the invention.
[0133] The compound of Formula (I) may contain one or more
stereocentres. All stereoisomers of the compounds of formula (I)
are within the scope of the invention. Stereoisomers include
enantiomers, diastereomers, geometric isomers (E and Z olephinic
forms and cis and trans substitution patterns) and atropisomers. In
some embodiments, the compound is a stereoisomerically enriched
form of the compound of formula (I) at any stereocentre. The
compound may be enriched in one stereoisomer over another by at
least about 60, 70, 80, 90, 95, 98 or 99%.
[0134] The compound of Formula (I) or its salts, tautomers,
solvates, N-oxides, and/or stereoisomers, may be isotopically
enriched with one or more of the isotopes of the atoms present in
the compound. For example, the compound may be enriched with one or
more of the following minor isotopes: .sup.2H, .sup.3H, .sup.13C,
.sup.14C .sup.15N and/or .sup.17O. An isotope may be considered
enriched when its abundance is greater than its natural
abundance.
[0135] In some embodiments, the compounds of formula (I) or a salt,
solvate, N-oxide, tautomer, stereoisomer, polymorph and/or prodrug
thereof have a pIC.sub.50 of at least 7 M. The inhibitory activity
can be determined using a kinase assay. Such assays are well-known
to a person skilled in the art, and an example of a suitable assay
is that described in the Examples.
[0136] In yet another aspect, there is provided a composition
comprising a compound according to formula (I) or a salt, solvate,
N-oxide, tautomer, stereoisomer, polymorph and/or prodrug thereof,
and a pharmaceutically acceptable excipient.
[0137] An appropriate dosage level will generally be about 0.01 to
500 mg per kg patient body weight per day which can be administered
in single or multiple doses. Preferably, the dosage level will be
about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to
about 100 mg/kg per day. A suitable dosage level may be about 0.01
to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1
to 50 mg/kg per day. Within this range the dosage may be 0.05 to
0.5, 0.5 to 5, or 5 to 50 mg/kg per day. For oral administration,
the compositions are preferably provided in the form of tablets
containing 1.0 to 1000 milligrams of the active ingredient,
particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0,
150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0,
900.0, and 1000.0 milligrams of the active ingredient for the
symptomatic adjustment of the dosage to the patient to be treated.
The compounds may be administered on a regimen of 1 to 4 times per
day, preferably once or twice per day. It will be understood,
however, that the specific dose level and frequency of dosage for
any particular patient may be varied and will depend upon a variety
of factors including the activity of the specific compound
employed, the metabolic stability and length of action of that
compound, the age, body weight, general health, sex, diet, mode and
time of administration, rate of excretion, drug combination, the
severity of the particular condition, and the host undergoing
therapy. The amount of a compound of the present invention in the
composition will also depend upon the particular compound in the
composition.
[0138] In the case of inhaled products, the typical inhalation dose
is less than with other forms of dosing starting at 1 microgram and
rising to 1000 microgram for a single puff. In a preferred form,
the dose ranges from 25 microgram to 250 microgram per puff. In
another preferred form, the dosage ranges from 500 to 1000
micrograms per puff. In another form, the dosage is selected from
the group consisting of 1, 2.5, 10.0, 25.0, 50.0, 75.0, 100.0,
150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0,
900.0, and 1000.0 micrograms per puff or any range in between and
including two of these values. The medication may be one puff per
day or increase up to two puffs four times a day.
[0139] The pharmaceutical composition may further comprise other
therapeutically active compounds which are usually applied in the
treatment of the disclosed disorders or conditions. Selection of
the appropriate agents for use in combination therapy may be made
by one of ordinary skill in the art, according to conventional
pharmaceutical principles. The combination of therapeutic agents
may act synergistically to effect the treatment or prevention of
the various disorders or conditions disclosed herein. Using this
approach, one may be able to achieve therapeutic efficacy with
lower dosages of each agent, thus reducing the potential for
adverse side effects.
[0140] Compounds and compositions of the invention may be
formulated for any appropriate route of administration including,
for example, topical (for example, transdermal or ocular),
pulmonary, oral, buccal, nasal, vaginal, rectal or parenteral
administration. The term parenteral as used herein includes
subcutaneous, intradermal, intravascular (for example,
intravenous), intramuscular, spinal, intracranial, intrathecal,
intraocular, periocular, intraorbital, intrasynovial and
intraperitoneal injection, as well as any similar injection or
infusion technique. In certain embodiments, compositions in a form
suitable for oral use or parenteral use are preferred. Suitable
oral forms include, for example, tablets, troches, lozenges,
aqueous or oily suspensions, dispersible powders or granules,
emulsions, hard or soft capsules, or syrups or elixirs. Within yet
other embodiments, compositions provided herein may be formulated
as a lyophilizate.
[0141] In a preferred form, the composition is suitable for
administration to the respiratory tract. In another form, the
composition is suitable for oral administration.
[0142] The various dosage units are each preferably provided as a
discrete dosage tablet, capsules, lozenge, dragee, gum, or other
type of solid formulation. Capsules may encapsulate a powder,
liquid, or gel. The solid formulation may be swallowed, or may be
of a suckable or chewable type (either frangible or gum-like). The
present invention contemplates dosage unit retaining devices other
than blister packs; for example, packages such as bottles, tubes,
canisters, packets. The dosage units may further include
conventional excipients well-known in pharmaceutical formulation
practice, such as binding agents, gellants, fillers, tableting
lubricants, disintegrants, surfactants, and colorants; and for
suckable or chewable formulations.
[0143] Compositions intended for oral use may further comprise one
or more components such as sweetening agents, flavouring agents,
colouring agents and/or preserving agents in order to provide
appealing and palatable preparations. Tablets contain the active
ingredient in admixture with physiologically acceptable excipients
that are suitable for the manufacture of tablets. Such excipients
include, for example, inert diluents such as calcium carbonate,
sodium carbonate, lactose, calcium phosphate or sodium phosphate,
granulating and disintegrating agents such as corn starch or
alginic acid, binding agents such as starch, gelatine or acacia,
and lubricating agents such as magnesium stearate, stearic acid or
talc. The tablets may be uncoated or they may be coated by known
techniques to delay disintegration and absorption in the
gastrointestinal tract and thereby provide a sustained action over
a longer period. For example, a time delay material such as
glyceryl monosterate or glyceryl distearate may be employed.
[0144] Formulations for oral use may also be presented as hard
gelatine capsules wherein the active ingredient is mixed with an
inert solid diluent such as calcium carbonate, calcium phosphate or
kaolin, or as soft gelatine capsules wherein the active ingredient
is mixed with water or an oil medium such as peanut oil, liquid
paraffin or olive oil.
[0145] Aqueous suspensions contain the active ingredient(s) in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients include suspending agents such as
sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing
or wetting agents such as naturally-occurring phosphatides (for
example, lecithin), condensation products of an alkylene oxide with
fatty acids such as polyoxyethylene stearate, condensation products
of ethylene oxide with long chain aliphatic alcohols such as
heptadecaethyleneoxycetanol, condensation products of ethylene
oxide with partial esters derived from fatty acids and a hexitol
such as polyoxyethylene sorbitol mono-oleate, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and hexitol anhydrides such as polyethylene sorbitan
monooleate. Aqueous suspensions may also comprise one or more
preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one
or more colouring agents, one or more flavouring agents, and one or
more sweetening agents, such as sucrose or saccharin.
[0146] Oily suspensions may be formulated by suspending the active
ingredients in a vegetable oil such as arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent such
as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such
as those set forth above, and/or flavouring agents may be added to
provide palatable oral preparations. Such suspensions may be
preserved by the addition of an antioxidant such as ascorbic
acid.
[0147] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, such as sweetening,
flavouring and colouring agents, may also be present.
[0148] Pharmaceutical compositions may also be in the form of
oil-in-water emulsions. The oily phase may be a vegetable oil such
as olive oil or arachis oil, a mineral oil such as liquid paraffin,
or a mixture thereof. Suitable emulsifying agents include
naturally-occurring gums such as gum acacia or gum tragacanth,
naturally-occurring phosphatides such as soy bean lecithin, and
esters or partial esters derived from fatty acids and hexitol,
anhydrides such as sorbitan monoleate, and condensation products of
partial esters derived from fatty acids and hexitol with ethylene
oxide such as polyoxyethylene sorbitan monoleate. An emulsion may
also comprise one or more sweetening and/or flavouring agents.
[0149] Syrups and elixirs may be formulated with sweetening agents,
such as glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also comprise one or more demulcents,
preservatives, flavouring agents and/or colouring agents.
[0150] Compositions of the invention may be formulated for local or
topical administration, such as for topical application to the
skin. Formulations for topical administration typically comprise a
topical vehicle combined with active agent(s), with or without
additional optional components.
[0151] Suitable topical vehicles and additional components are well
known in the art, and it will be apparent that the choice of a
vehicle will depend on the particular physical form and mode of
delivery. Topical vehicles include organic solvents such as
alcohols (for example, ethanol, iso-propyl alcohol or glycerine),
glycols such as butylene, isoprene or propylene glycol, aliphatic
alcohols such as lanolin, mixtures of water and organic solvents
and mixtures of organic solvents such as alcohol and glycerine,
lipid-based materials such as fatty acids, acylglycerols including
oils such as mineral oil, and fats of natural or synthetic origin,
phosphoglycerides, sphingolipids and waxes, protein-based materials
such as collagen and gelatine, silicone-based materials (both
nonvolatile and volatile), and hydrocarbon-based materials such as
microsponges and polymer matrices.
[0152] A composition may further include one or more components
adapted to improve the stability or effectiveness of the applied
formulation, such as stabilizing agents, suspending agents,
emulsifying agents, viscosity adjusters, gelling agents,
preservatives, antioxidants, skin penetration enhancers,
moisturizers and sustained release materials. Examples of such
components are described in Martindale--The Extra Pharmacopoeia
(Pharmaceutical Press, London 1993) and Martin (ed.), Remington's
Pharmaceutical Sciences. Formulations may comprise microcapsules,
such as hydroxymethylcellulose or gelatine-microcapsules,
liposomes, albumin microspheres, microemulsions, nanoparticles or
nanocapsules.
[0153] A topical formulation may be prepared in a variety of
physical forms including, for example, solids, pastes, creams,
foams, lotions, gels, powders, aqueous liquids, emulsions, sprays
and skin patches. The physical appearance and viscosity of such
forms can be governed by the presence and amount of emulsifier(s)
and viscosity adjuster(s) present in the formulation. Solids are
generally firm and non-pourable and commonly are formulated as bars
or sticks, or in particulate form. Solids can be opaque or
transparent, and optionally can contain solvents, emulsifiers,
moisturizers, emollients, fragrances, dyes/colorants, preservatives
and other active ingredients that increase or enhance the efficacy
of the final product. Creams and lotions are often similar to one
another, differing mainly in their viscosity. Both lotions and
creams may be opaque, translucent or clear and often contain
emulsifiers, solvents, and viscosity adjusting agents, as well as
moisturizers, emollients, fragrances, dyes/colorants, preservatives
and other active ingredients that increase or enhance the efficacy
of the final product. Gels can be prepared with a range of
viscosities, from thick or high viscosity to thin or low viscosity.
These formulations, like those of lotions and creams, may also
contain solvents, emulsifiers, moisturizers, emollients,
fragrances, dyes/colorants, preservatives and other active
ingredients that increase or enhance the efficacy of the final
product. Liquids are thinner than creams, lotions, or gels, and
often do not contain emulsifiers. Liquid topical products often
contain solvents, emulsifiers, moisturizers, emollients,
fragrances, dyes/colorants, preservatives and other active
ingredients that increase or enhance the efficacy of the final
product.
[0154] Emulsifiers for use in topical formulations include, but are
not limited to, ionic emulsifiers, cetearyl alcohol, non-ionic
emulsifiers like polyoxyethylene oleyl ether, PEG-40 stearate,
ceteareth-12, ceteareth-20, ceteareth-30, ceteareth alcohol,
PEG-100 stearate and glyceryl stearate. Suitable viscosity
adjusting agents include, but are not limited to, protective
colloids or nonionic gums such as hydroxyethylcellulose, xanthan
gum, magnesium aluminum silicate, silica, microcrystalline wax,
beeswax, paraffin, and cetyl palmitate. A gel composition may be
formed by the addition of a gelling agent such as chitosan, methyl
cellulose, ethyl cellulose, polyvinyl alcohol, polyquaterniums,
hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, carbomer or ammoniated
glycyrrhizinate. Suitable surfactants include, but are not limited
to, nonionic, amphoteric, ionic and anionic surfactants. For
example, one or more of dimethicone copolyol, polysorbate 20,
polysorbate 40, polysorbate 60, polysorbate 80, lauramide DEA,
cocamide DEA, and cocamide MEA, oleyl betaine, cocamidopropyl
phosphatidyl PG-diimonium chloride, and ammonium laureth sulfate
may be used within topical formulations.
[0155] Preservatives include, but are not limited to,
antimicrobials such as methylparaben, propylparaben, sorbic acid,
benzoic acid, and formaldehyde, as well as physical stabilizers and
antioxidants such as vitamin E, sodium ascorbate/ascorbic acid and
propyl gallate. Suitable moisturizers include, but are not limited
to, lactic acid and other hydroxy acids and their salts, glycerine,
propylene glycol, and butylene glycol. Suitable emollients include
lanolin alcohol, lanolin, lanolin derivatives, cholesterol,
petrolatum, isostearyl neopentanoate and mineral oils. Suitable
fragrances and colours include, but are not limited to, FD&C
Red No. 40 and FD&C Yellow No. 5. Other suitable additional
ingredients that may be included in a topical formulation include,
but are not limited to, abrasives, absorbents, anticaking agents,
antifoaming agents, antistatic agents, astringents (such as witch
hazel), alcohol and herbal extracts such as chamomile extract,
binders/excipients, buffering agents, chelating agents, film
forming agents, conditioning agents, propellants, opacifying
agents, pH adjusters and protectants.
[0156] Typical modes of delivery for topical compositions include
application using the fingers, application using a physical
applicator such as a cloth, tissue, swab, stick or brush, spraying
including mist, aerosol or foam spraying, dropper application,
sprinkling, soaking, and rinsing. Controlled release vehicles can
also be used, and compositions may be formulated for transdermal
administration (for example, as a transdermal patch).
[0157] Pharmaceutical compositions may be formulated as sustained
release formulations such as a capsule that creates a slow release
of modulator following administration. Such formulations may
generally be prepared using well-known technology and administered
by, for example, oral, rectal or subcutaneous implantation, or by
implantation at the desired target site. Carriers for use within
such formulations are biocompatible, and may also be biodegradable.
Preferably, the formulation provides a relatively constant level of
modulator release. The amount of modulator contained within a
sustained release formulation depends upon, for example, the site
of implantation, the rate and expected duration of release and the
nature of the disorder to be treated or prevented.
[0158] A pharmaceutical composition may be formulated as inhaled
formulations, including sprays, mists, or aerosols. For example,
for administration to the respiratory tract. This may be
particularly preferred for treatment of a respiratory disease, a
condition of the airway or lung involving fibrosis as described
herein. The inhaled formulation may be for application to the upper
(including the nasal cavity, pharynx and larynx) and lower
respiratory tract (including trachea, bronchi and lungs). For
inhalation formulations, the composition or combination provided
herein may be delivered via any inhalation methods known to a
person skilled in the art. Such inhalation methods and devices
include, but are not limited to, metered dose inhalers with
propellants such as HFA or propellants that are physiologically and
environmentally acceptable. Other suitable devices are breath
operated inhalers, multidose dry powder inhalers and aerosol
nebulizers. Aerosol formulations for use in the subject method
typically include propellants, surfactants and co-solvents and may
be filled into conventional aerosol containers that are closed by a
suitable metering valve. Different devices and excipients can be
used depending on whether the application is to the upper
(including the nasal cavity, pharynx and larynx) or lower
respiratory tract (including trachea, bronchi and lungs) and can be
determined by those skilled in the art. Further, processes for
micronisation and nanoparticle formation for the preparation of
compounds described herein for use in an inhaler, such as a dry
powder inhaler, are also known by those skilled in the art.
[0159] Inhalant compositions may comprise liquid or powdered
compositions containing the active ingredient that are suitable for
nebulization and intrabronchial use, or aerosol compositions
administered via an aerosol unit dispensing metered doses. Suitable
liquid compositions comprise the active ingredient in an aqueous,
pharmaceutically acceptable inhalant solvent such as isotonic
saline or bacteriostatic water. The solutions are administered by
means of a pump or squeeze-actuated nebulized spray dispenser, or
by any other conventional means for causing or enabling the
requisite dosage amount of the liquid composition to be inhaled
into the patient's lungs. Suitable formulations, wherein the
carrier is a liquid, for administration, as for example, a nasal
spray or as nasal drops, include aqueous or oily solutions of the
active ingredient. Examples of inhalation drug delivery devices are
described in Ibrahim et al. Medical Devices: Evidence and Research
2015:8 131-139, are contemplated for use in the present
invention.
[0160] In another aspect, there is provided a method of treating or
preventing a respiratory disease in a subject in need thereof, the
method comprising administering to the subject a therapeutically
effective amount of a compound of formula (I) or a salt, solvate,
N-oxide, tautomer, stereoisomer, polymorph and/or prodrug thereof,
thereby treating or preventing a respiratory disease in a
subject.
[0161] There is further provided a compound of formula (I) or a
salt, solvate, N-oxide, tautomer, stereoisomer, polymorph and/or
prodrug thereof for use in the treatment or prevention of a
respiratory disease in a subject in need thereof.
[0162] Use of a compound of formula (I) or a salt, solvate,
N-oxide, tautomer, stereoisomer, polymorph and/or prodrug thereof
in the preparation of a medicament for the treatment or prevention
of a respiratory disease in a subject in need thereof is also
described.
[0163] As used herein, `preventing` or `prevention` is intended to
refer to at least the reduction of likelihood of the risk of (or
susceptibility to) acquiring a disease or disorder (i.e., causing
at least one of the clinical symptoms of the disease not to develop
in a patient that may be exposed to or predisposed to the disease
but does not yet experience or display symptoms of the disease).
Biological and physiological parameters for identifying such
patients are provided herein and are also well known by
physicians.
[0164] The terms `treatment` or `treating` of a subject includes
the application or administration of a compound of the invention to
a subject (or application or administration of a compound of the
invention to a cell or tissue from a subject) with the purpose of
delaying, slowing, stabilizing, curing, healing, alleviating,
relieving, altering, remedying, lessening, worsening, ameliorating,
improving, or affecting the disease or condition, the symptom of
the disease or condition, or the risk of (or susceptibility to) the
disease or condition. The term `treating` refers to any indication
of success in the treatment or amelioration of an injury, pathology
or condition, including any objective or subjective parameter such
as abatement; remission; lessening of the rate of worsening;
lessening severity of the disease; stabilization, diminishing of
symptoms or making the injury, pathology or condition more
tolerable to the subject; slowing in the rate of degeneration or
decline; making the final point of degeneration less debilitating;
or improving a subject's physical or mental well-being.
[0165] The term `antagonizing` used herein is intended to mean
`decreasing` or `reducing`. A sufficient period of time can be
during one week, or between 1 week to 1 month, or between 1 to 2
months, or 2 months or more. For chronic conditions, the compound
of the present invention can be advantageously administered for
life time period.
[0166] The term `respiratory` refers to the process by which oxygen
is taken into the body and carbon dioxide is discharged, through
the bodily system including the nose, throat, larynx, trachea,
bronchi and lungs.
[0167] The term `respiratory disease` or `respiratory condition`
refers to any one of several ailments that may involve inflammation
and/or tissue remodelling affecting a component of the respiratory
system including the upper (including the nasal cavity, pharynx and
larynx) and lower respiratory tract (including trachea, bronchi and
lungs). Such ailments include pulmonary fibrosis (interstitial lung
diseases), rhino sinusitis, influenza, sarcoidosis, bronchial
carcinoma (including but not limited to non-small cell and small
cell carcinoma of the lung, and lung metastases from tumours of
other organs), silicosis, pneumoconiosis, acute lung injury,
ventilation-induced lung injury, congenital emphysema,
bronchopulmonary dysplasia, bronchiectasis, atelectasis, nasal
polyps, asbestosis, mesothelioma, pulmonary eosinophilia, diffuse
pulmonary haemorrhage syndromes, bronchiolitis obliterans, alveolar
proteinosis, collagen and vascular disorders affecting the lung,
and cough. Preferably, the respiratory disease is an obstructive
airway disease, such ailments include asthmatic conditions
including hay fever, allergen-induced asthma, exercise-induced
asthma, pollution-induced asthma, cold-induced asthma,
stress-induced asthma and viral-induced-asthma, obesity-related
asthma, occupational asthma, thunderstorm-induced asthma, asthma
COPD overlap syndrome (ACOS) chronic obstructive pulmonary diseases
including chronic bronchitis with normal airflow, chronic
bronchitis with airway obstruction (chronic obstructive
bronchitis), emphysema, asthmatic bronchitis, and bullous disease,
and other pulmonary diseases involving inflammation including
cystic fibrosis, pigeon fancier's disease, farmer's lung, acute
respiratory distress syndrome, pneumonia of fungal, viral,
bacterial, mixed or unknown aetiology, aspiration or inhalation
injury, fat embolism in the lung, acidosis inflammation of the
lung, acute pulmonary edema, acute mountain sickness, post-cardiac
surgery, acute pulmonary hypertension, persistent pulmonary
hypertension of the newborn, perinatal aspiration syndrome, hyaline
membrane disease, acute pulmonary thromboembolism,
heparin-protamine reactions, sepsis, status asthmaticus and
hypoxia. The inflammation in the upper and lower respiratory tract
may be associated with or caused by viral infection or an allergen.
It is expected that the anti-inflammatory activity of the compounds
either alone or when co-administered with a glucocorticoid would
make them particularly suitable for treatment of these disease or
conditions.
[0168] The respiratory disease or condition may be associated with
or caused by an allergen, such as house dust mite. The respiratory
disease or condition may be the result of an allergen-induced
inflammation. The present invention finds particular application to
allergic disease of the airway or lung and exacerbations of that
disease, such as exacerbations resulting from viral infection (e.g.
RSV infection).
[0169] A symptom of respiratory disease may include cough, excess
sputum production, a sense of breathlessness or chest tightness
with audible wheeze. Exercise capacity may be quite limited. In
asthma the FEV1.0 (forced expiratory volume in one second) as a
percentage of that predicted nomographically based on weight,
height and age, may be decreased as may the peak expiratory flow
rate in a forced expiration. In COPD the FEV1.0 as a ratio of the
forced vital capacity (FVC) is typically reduced to less than 0.7.
In IPF there is a progressive fall in FVC. The impact of each of
these conditions may also be measured by days of lost work/school,
disturbed sleep, requirement for bronchodilator drugs, requirement
for glucocorticoids including oral glucocorticoids. Further
measures of the impact of these conditions include validated
health-related quality of life measurements. Medical imaging
procedures including but not limited to X-ray, high resolution
computed tomography, magnetic resonance imaging, positron emission
tomography, ultra sound, optical coherence tomography and
fluoroscopy may also be used to assess disease and therapeutic
response.
[0170] The existence of, improvement in, treatment of or prevention
of a respiratory disease may be by any clinically or biochemically
relevant method of the subject or a biopsy therefrom. For example,
a parameter measured may be the presence or degree of lung
function, signs and symptoms of obstruction; exercise tolerance;
night time awakenings; days lost to school or work; bronchodilator
usage; ICS dose; oral GC usage; need for other medications; need
for medical treatment; hospital admission.
[0171] As used herein, the term `asthma` refers to a respiratory
disorder characterized by episodic difficulty in breathing brought
on by any one or a combination of three primary factors including:
1) bronchospasm (i.e., variable and reversible airway obstruction
due to airway muscle contraction), 2) inflammation of the airway
lining, and 3) bronchial hyper-responsiveness resulting in
excessive mucous in the airways, which may be triggered by exposure
to an allergen or combination of allergens (i.e., dust mites and
mold), viral or bacterial infection (i.e., common cold virus),
environmental pollutants (i.e., chemical fumes or smoke), physical
exertion (i.e., during exercise), stress, or inhalation of cold
air. The term `asthmatic condition,` as used herein, refers to the
characteristic of an individual to suffer from an attack of asthma
upon exposure to any one or a number of asthma triggers for that
individual. An individual may be characterized as suffering from,
for example, allergen-induced asthma, exercise-induced asthma,
pollution-induced asthma, viral-induced asthma, or cold-induced
asthma.
[0172] The efficacy of a treatment for asthma may be measured by
methods well-known in the art, for example, increase in pulmonary
function (spirometry), decrease in asthma exacerbations, increase
in morning peak expiratory flow rate, decrease in rescue medication
use, decrease in daytime and night-time asthma symptoms, increase
in asthma-free days, increase in time to asthma exacerbation, and
increase in forced expiratory volume in one second (FEV1.0).
[0173] The terms `chronic obstructive pulmonary disease` and `COPD`
as used interchangeably herein refers to a chronic disorder or
combination of disorders characterized by reduced maximal
expiratory flow and slow forced emptying of the lungs that does not
change markedly over several months and is not, or is only
minimally, reversible with traditional bronchodilators. Most
commonly, COPD is a combination of chronic bronchitis, i.e. the
presence of cough and sputum for more than three months for about
two consecutive years, and emphysema, i.e. alveolar damage.
However, COPD can involve chronic bronchitis with normal airflow,
chronic bronchitis with airway obstruction (chronic obstructive
bronchitis), emphysema, asthmatic bronchitis, and bullous disease,
and combinations thereof. Chronic obstructive pulmonary disease is
a condition usually but not exclusively resulting from chronic lung
damage induced by exposure to tobacco smoke. Other noxious airborne
pollutants, such as indoor cooking exhaust and car exhaust may over
the long-term cause or increase the risk of COPD, as does
ageing.
[0174] The phrase `a condition of the airway or lung involving
fibrosis` or `a condition of the airway or lung having a fibrotic
component` includes any disease or condition where there is the
formation or development of excess fibrous connective tissue
(fibrosis) in the airway or lung thereby resulting in the
development of scarred (fibrotic) tissue. This includes
interstitial lung diseases such as pulmonary fibrosis, lung
fibrosis or Idiopathic pulmonary fibrosis (IPF). More precisely,
pulmonary fibrosis is a chronic disease that causes swelling and
scarring of the alveoli and interstitial tissues of the lungs. The
scar tissue replaces healthy tissue and causes inflammation. This
damage to the lung tissue causes stiffness of the lungs which
subsequently makes breathing more and more difficult. Lung fibrosis
may result from radiation injury or from exposure to therapeutic
agents such as bleomycin.
[0175] `Idiopathic pulmonary fibrosis (IPF)` is a specific
manifestation of idiopathic interstitial pneumonia (IIP), a type of
interstitial lung disease. Interstitial lung disease, also known as
diffuse parenchymal lung disease (DPLD), refers to a group of lung
diseases affecting the interstitium. Microscopically, lung tissue
from IPF patients shows a characteristic set of histological
features known as usual interstitial pneumonia (UIP). UIP is
therefore the pathologic presentation of IPF.
[0176] The existence of, improvement in, treatment of or prevention
of a condition of the airway or lung involving fibrosis,
particularly pulmonary fibrosis/lung fibrosis or Idiopathic
pulmonary fibrosis may be by any clinically or biochemically
relevant method of the subject or a biopsy therefrom. For example,
the rate of decline in FVC or the appearance of high resolution
computed tomographic images of the lung may be useful in diagnosing
IPF. Further, a parameter measured may be the presence or degree of
fibrosis, the content of collagen, fibronectin, or another
extracellular matrix protein, the proliferation rate of the cells
or any extracellular matrix components in the cells or
transdifferentiation of the cells to myofibroblasts.
[0177] In one embodiment, the respiratory disease is selected from
asthma, chronic obstructive pulmonary disease, interstitial lung
diseases (such as idiopathic pulmonary fibrosis) and other
conditions relating to tissue remodelling, primary or secondary
lung tumour, hayfever, chronic and acute sinusitis, and chronic and
acute viral, fungal and bacterial infections of the respiratory
tract.
[0178] In one embodiment, the improvement in respiratory function
may be selected from a decrease in the level of constriction of the
lungs, a decrease in the elastic stiffness of the respiratory
system, and/or an increase in the ease with which the respiratory
system can be extended. Preferably, the improvement is selected
from a decrease in the level of constriction of the lungs, and a
decrease in the elastic stiffness of the respiratory system. In yet
another aspect, there is provided a composition comprising a
compound according to formula (I) or a salt, solvate, N-oxide,
tautomer, stereoisomer, polymorph and/or prodrug thereof, and a
pharmaceutically acceptable excipient.
[0179] The therapeutically effective amount of the formulation
depends on the severity of the specific respiratory disease
indication (e.g. severe chronic asthma), the patient's clinical
history and response, and the discretion of the attending
physician. The formulation may be administered to the patient at
one time or over a series of treatments. An initial candidate
dosage may be administered to a patient and the proper dosage and
treatment regimen established by monitoring the progress of this
patient using conventional techniques well known to those of
ordinary skill in the art. Preferably, the therapeutically
effective concentration of the active compound will be in the range
0.1 nM to 100 .mu.M. More preferably the range will be 0.1-10
.mu.M. However, it will be appreciated that delivery by inhalation
can result in cells within the airway being exposed for short
periods of time to concentrations exceeding those quoted above, for
a period of time whilst the drug is being diluted in the airway
surface fluid and also being absorbed from the airway and lung
surfaces.
[0180] In one aspect, the method of treatment of the present
invention further comprises administering a concomitant medication
for the target disease indication. For example, concomitant asthma
medications (for both chronic and acute) that may be used with the
method of the present invention include but are not limited to:
inhaled and oral steroids (e.g. beclomethasone, budesonide,
flunisolide, fluticasone, triamcinolone, mometasone); systemic
corticosteroids (e.g. methylprednisolone, prednisolone, prednisone,
dexamethasone, and deflazacort); inhaled or oral
.beta..sub.2-adrenoceptor agonists (e.g. salmeterol, formoterol,
bitolterol, pirbuterol, vilanterol, terbutaline, bambuterol and
albuterol); cromolyn and nedocromil; anti-allergic opthalmic
medications (e.g. dexamethasone); agents that modulate the
production and action of transforming growth factor-beta, including
pirfenidone and nintedanib; methylxanthines and other
phosphodiesterase inhibitors (e.g. theophylline and
mepyramine-theophylline acetate, roflumilast); leukotriene
modifying agents (e.g. zafirlukast, zileuton, montekulast and
pranlukast); anticholinergics (e.g. ipatropium bromide); other
therapeutic antibodies of any format (e.g. antibodies directed
against interleukin 5, such as mepolizumab, or against IgE, such as
omalizumab, those antibodies in monoclonal form, Fab, scFV,
multivalent compositions, xenoantibodies etc.), natural or
engineered antibody mimetics (e.g. anticalin) or natural,
engineered or synthetic peptides; thromboxane A.sub.2 synthetase
inhibitors; thromboxane prostanoid receptor antagonists; other
eicosanoid modifiers (e.g. alprostadil vs. PGE.sub.1, dinoprostone
vs. PGE.sub.2, epoprostenol vs. prostacyclin and PGI.sub.2
analogues (e.g. PG1.sub.2 beraprost), seratrodast,
phosphodiesterase 4 isoenzyme inhibitors, thromboxane A.sub.2
synthetase inhibitors (e.g. ozmagrel, dazmegrel or ozagrel); ditec
(low dose disodium cromoglycate and fenoterol); platelet activating
factor receptor antagonists; antihistamines or histamine
antagonists: promethazine, chlorpheniramine, loratadine,
cetirazine, azelastine; thromboxane A.sub.2 receptor antagonists;
bradykinin receptor antagonists (e.g. icatibant); agents that
inhibit activated eosinophils and T-cell recruitment (e.g.
ketotifen), IL-13 blockers (e.g. soluble IL-13 receptor fragments),
IL-4 blockers (e.g. soluble IL-4 receptor fragments); ligands that
bind and block the activity of IL-13 or IL-4, and xanthine
derivatives (e.g. pentoxifylline); chemokine receptor antagonists
and antagonists of the CRTH2 receptor.
[0181] In certain embodiments, the method of treatment of the
present invention includes the concomitant provision to the subject
of inhibitory RNA molecules (RNA interference molecules), for the
purpose of reducing, inhibiting or preventing the expression of
genes which encode target proteins. For example, the inhibitory RNA
molecules may be used for reducing or inhibiting the expression of
one or more of: proteins associated with pathogens (viral,
bacterial, fungal) or mammalian cells, including but not limited to
casein kinase 1 isoforms and other components of the CLOCK
regulatory network (eg ARNT1, period 1-3) and other proteins that
contribute to the inflammatory response in the respiratory system
such as interleukin-5 and the NALP inflammasome.
[0182] The skilled person will be familiar with various means for
utilising inhibitory RNA molecules for the purpose of interfering
with gene expression in the subject. For example, the inhibitory
RNA molecules may be any one of: short interfering RNA (siRNA),
microRNA mimetic (miRNA), short hairpin RNA (shRNA) or long double
stranded RNA (long dsRNA) molecules. The inhibitory RNA molecule
may be administered directly to the subject requiring treatment
(for example by inhalation, intratracheal, oral or nasal
administration or by parenteral administration), or alternatively,
be formed in the subject receiving treatment, following the
administration of a polynucleotide (vector) construct which encodes
a double stranded RNA (dsRNA) molecule which is capable of forming
an inhibitory RNA molecule. The skilled person will also be
familiar with various methods known in the art for formulating
inhibitory RNA molecules for administration (for example, in
liposomes, nanoparticles and the like). The invention also includes
the administration of an inhibitor of casein kinase 1 and a
medication for the target disease indication as described above
where either or both are administered by inhalation or formulated
for oral administration.
[0183] Although the invention finds application in humans, the
invention is also useful for therapeutic veterinary purposes. The
invention is useful for domestic or farm animals such as cattle,
sheep, horses and poultry; for companion animals such as cats and
dogs; and for zoo animals.
[0184] As used herein, a `subject` refers to an animal, such as a
mammalian or an avian species, including a human, an ape, a horse,
a cow, a sheep, a goat, a dog, a cat, a guinea pig, a rat, a mouse,
a chicken etc.
[0185] CK1.delta. homologues are ubiquitious in nature, including
in protozoa such as malaria, and in funghi and bacteria. Therefore,
it is envisioned that the compounds of this invention may be used
in any application requiring inhibition of CK1.delta. homologues.
Such uses may include administration of a compound of the invention
to a subject suffering from a disease, condition and/or disorder
associated with infection and/or infestation with protozoa, fungii
and/or bacteria.
[0186] In another aspect, the present invention provides a method
of inhibiting casein kinase 1.delta. (CK1.delta.), comprising
contacting a cell with an effective amount of a compound of formula
(I) as defined herein, or a salt, solvate, N-oxide, tautomer,
stereoisomer, polymorph and/or prodrug thereof.
[0187] Surprisingly, the compounds of the present invention or a
salt, solvate, N-oxide, tautomer, stereoisomer, polymorph and/or
prodrug thereof may serve as a selective inhibitor of CK1.delta..
The compounds of the invention in any of their disclosed forms, may
selectively inhibit CK1.delta. compared to one or more other
kinases, such as ERBB4/HER4, MINK/MINK1 and the like. In some
embodiments, the compounds of the invention may be selective for
CK1.delta. over at least one kinase by at least about 1, 5, 10 or
100-fold.
[0188] In another aspect the present invention provides a kit or
article of manufacture including a compound of formula (I) or
pharmaceutical compositions including a compound of formula (I) as
described herein.
[0189] In other embodiments there is provided a kit for use in a
therapeutic or prophylactic application mentioned herein, the kit
including: a container holding a compound of formula (I) or
pharmaceutical composition including a compound of formula (I); and
a label or package insert with instructions for use.
[0190] The kit or `article of manufacture` may comprise a container
and a label or package insert on or associated with the container.
Suitable containers include, for example, bottles, vials, syringes,
blister pack(s), etc. The containers may be formed from a variety
of materials such as glass or plastic. The container holds a
compound of formula (I), or composition which is effective for
treating the condition and may have a sterile access port (for
example the container may be an intravenous solution bag or a vial
having a stopper pierceable by a hypodermic injection needle). The
label or package insert indicates that the composition is used for
treating a disorder. In one embodiment, the label or package insert
includes instructions for use and indicates that the therapeutic or
prophylactic composition can be used to treat a disorder described
herein.
[0191] The kit may comprise (a) a therapeutic or prophylactic
composition; and (b) a second container with a second active
principle or ingredient contained therein. The kit in this
embodiment of the invention may further comprise a package insert
indicating the composition and other active principle can be used
to treat a disorder or prevent a complication stemming from a
disorder described herein. Alternatively, or additionally, the kit
may further comprise a second (or third) container comprising a
pharmaceutically-acceptable buffer, such as bacteriostatic water
for injection (BWFI), phosphate-buffered saline, Ringer's solution
and dextrose solution. It may further include other materials
desirable from a commercial and user standpoint, including other
buffers, diluents, filters, needles, and syringes.
[0192] In certain embodiments the therapeutic composition may be
provided in the form of a device, disposable or reusable, including
a receptacle for holding the compound of formula (I) or therapeutic
or prophylactic pharmaceutical composition including a compound of
formula (I). In one embodiment, the device is a syringe. The
therapeutic or prophylactic composition may be provided in the
device in a state that is ready for use or in a state requiring
mixing or addition of further components.
EXAMPLES
[0193] In Vitro Assays
[0194] Kinase Inhibition Assay
[0195] The assay used was the HotSpot assay (Reaction Biology
Corp).
[0196] Compounds were tested in 10-dose IC.sub.50 mode with a
3-fold serial dilution starting at 10 .mu.M. Control Compound,
D4476, was tested in 10-dose IC.sub.50 mode with 4-fold serial
dilution starting at 20 .mu.M. Reactions were carried out at 10
.mu.M ATP.
[0197] Reagents
[0198] Base Reaction buffer; 20 mM Hepes (pH 7.5), 10 mM
MgCl.sub.2, 1 mM EGTA, 0.02% Brij35, 0.02 mg/mL BSA, 0.1 mM
Na.sub.3VO.sub.4, 2 mM DTT, 1% DMSO.
*Required cofactors are added individually to each kinase
reaction
[0199] Reaction Procedure [0200] 1. The peptide substrate was
freshly prepared in Base Reaction Buffer [0201] 2. Any required
cofactors were delivered to the substrate solution above [0202] 3.
The human recombinant Casein kinase 18 was delivered into the
substrate solution and gently mixed [0203] 4. The compounds in DMSO
were delivered into the kinase reaction mixture by Acoustic
technology (Echo550; nanoliter range), and incubated for 20 minutes
at room temperature [0204] 5. .sup.33P-ATP (specific activity 10
mCi/mL) together with ATP (10 .mu.M) was delivered into the
reaction mixture to initiate the reaction. [0205] 6. The kinase
reaction was incubated for 2 hours at room temperature [0206] 7.
The reaction mixtures were spotted onto P81 ion exchange paper
[0207] 8. The kinase activity was detected by measuring
.sup.33P-ATP-labelled product peptide using a filter-binding
method. The results of the assay (conducted on casein kinase 18)
are given below in Table 2 (PIC.sub.50) and Table 3
(IC.sub.50).
TABLE-US-00002 [0207] TABLE 2 Inhibitory activity of a number of
compounds of the present invention Compound pIC.sub.50 ZH3-114 8.93
ZH3-118 8.67 ZH3-122 8.38 ZH3-126 9.19 ZH2-114 8.44 ZH2-118 8.02
ZH2-122 8.29 ZH2-146 8.31 ZH2-38 8.74 ZH2-46 8.30 ZH2-54 8.76
ZH2-58 7.71 ZH2-78 8.33 ZH3-50 8.87 ZH3-62 8.88 ZH3-70 9.00 ZH3-86
8.12 ZH3-134 8.94 ZH3-58 8.08 ZH3-130 8.21 ZH3-138 8.03 ZH3-78 7.23
D4476 6.67
TABLE-US-00003 TABLE 3 IC.sub.50 for various compounds for
CK1.delta., ERBB4/HER4 and MINK/MINK1 Compound IC.sub.50 (M)
Compound ID CK1.delta. ERBB4/HER4 MINK/MINK1 ZH3-114 1.17 .times.
10.sup.-9 3.00 .times. 10.sup.-6 9.44 .times. 10.sup.-8 ZH3-118
2.13 .times. 10.sup.-9 5.13 .times. 10.sup.-7 1.97 .times.
10.sup.-7 ZH3-122 4.16 .times. 10.sup.-9 4.42 .times. 10.sup.-6
1.83 .times. 10.sup.-8 ZH3-126 .sup. 6.38 .times. 10.sup.-10 9.52
.times. 10.sup.-6 1.99 .times. 10.sup.-7 ZH2-114 3.67 .times.
10.sup.-9 {circumflex over ( )} 3.33 .times. 10.sup.-8 ZH2-118 9.60
.times. 10.sup.-9 3.66 .times. 10.sup.-6 4.21 .times. 10.sup.-8
ZH2-122 5.07 .times. 10.sup.-9 {circumflex over ( )} 1.95 .times.
10.sup.-8 ZH2-146 4.93 .times. 10.sup.-9 {circumflex over ( )} 1.10
.times. 10.sup.-7 ZH2-38 1.82 .times. 10.sup.-9 3.12 .times.
10.sup.-6 4.16 .times. 10.sup.-8 ZH2-46 4.99 .times. 10.sup.-9 9.01
.times. 10.sup.-6 6.69 .times. 10.sup.-8 ZH2-54 1.73 .times.
10.sup.-9 {circumflex over ( )} 1.70 .times. 10.sup.-7 ZH2-58 1.95
.times. 10.sup.-8 >1.00 .times. 10.sup.-5 2.36 .times. 10.sup.-7
ZH2-78 4.70 .times. 10.sup.-9 7.50 .times. 10.sup.-7 2.26 .times.
10.sup.-8 ZH3-50 1.36 .times. 10.sup.-9 4.41 .times. 10.sup.-6 1.73
.times. 10.sup.-8 ZH3-62 1.31 .times. 10.sup.-9 >1.00 .times.
10.sup.-5 7.53 .times. 10.sup.-9 ZH3-70 1.00 .times. 10.sup.-9
{circumflex over ( )} 2.16 .times. 10.sup.-8 ZH3-86 7.59 .times.
10.sup.-9 1.48 .times. 10.sup.-6 1.06 .times. 10.sup.-8 ZH3-134
1.15 .times. 10.sup.-9 {circumflex over ( )} 3.77 .times. 10.sup.-8
ZH3-58 8.33 .times. 10.sup.-9 1.39 .times. 10.sup.-6 2.17 .times.
10.sup.-7 ZH3-130 6.13 .times. 10.sup.-9 1.42 .times. 10.sup.-6
8.90 .times. 10.sup.-7 ZH3-138 9.32 .times. 10.sup.-9 9.98 .times.
10.sup.-6 1.15 .times. 10.sup.-6 ZH3-78 5.93 .times. 10.sup.-8 8.35
.times. 10.sup.-6 8.09 .times. 10.sup.-7 Notes: {circumflex over (
)} no inhibition or compound activity could not be fit to an IC50
curve
[0208] Human Parenchymal Fibroblast Cell Assay
[0209] Primary human parenchymal fibroblast cells (pFbs) were
cultured from parenchyma of lung resection specimens and from
non-transplanted lungs of donors without chronic respiratory
disease. pFbs were passaged in Dulbecco's Modified Eagle's Media
(DMEM) containing 10% (v/v) heat-inactivated fetal calf serum
(FCS), 15 mM HEPES, 0.2% (v/v) sodium bicarbonate, 2 mM
L-glutamine, 1% (v/v) non-essential amino acids, 1% (v/v) sodium
pyruvate, 2.5 .mu.g/mL amphotericin, 5 IU/mL penicillin and 50
.mu.g/mL streptomycin. In some experiments the human lung
fibroblast cell line, MRC5 (sourced from ATTC) was used as
indicated. The MRC5 line was maintained under the same conditions
as described for the pFb.
[0210] Prior to experimentation, pFb were incubated in serum-free
DMEM containing 0.25% bovine serum albumin (BSA) and
insulin-transferrin-selenium-containing supplement (Monomed A; CSL,
Parkville, Melbourne, Australia). The cells were incubated with
small molecular CK1.delta. inhibitors (0.1-10 .mu.M) for 30 min
prior to 100 .mu.M TGF-.beta..sub.1 (R&D Systems, Minneapolis,
Minn.) and the incubation continued for 16-24 hours prior to
harvest of supernatant for detection of immunoreactive IL-11. Stock
solutions were made as 10 mM in 100% DMSO and diluted to the
required concentration in medium containing 0.1% DMSO (final
concentration).
[0211] Supernatants were collected for measurement of IL-11
(R&D DuoSet, DY218) by ELISA following the manufacturers'
instructions. Generally, capture antibodies were initially diluted
to the recommended concentrations using PBS buffer, and then used
to coat the wells of 96-well microplates (Greiner, #655061) by
adding 50 .mu.L/well and incubated overnight at room temperature.
Next day, solutions were discarded and wells were washed 3 times
with wash buffer (PBS containing 0.1% (v/v) Tween-20) prior to the
addition of 200 .mu.L of blocking solution (PBS containing 1% (v/v)
BSA) for 1 hour to block non-specific sites. Plates were then
washed 3 times with wash buffer and 50 .mu.L of samples or
standards were then added to wells and incubated for 2 hours at
room temperature. After the incubation, plates were washed 3 times
with wash buffer and 50 .mu.L of detection antibodies were added to
wells and incubated for 2 hours at room temperature. Plates were
then washed 3 times before adding streptavidin-conjugated
horseradish peroxidase (at the recommended concentrations) for 45
min. Plates were then washed 5 times with wash buffer and 100 .mu.L
TMB substrate solution (equal parts A and B, BD Biosciences) was
added to each well until sufficient signals emerged. The reactions
were inactivated by adding 100 .mu.L sulphuric acid (2M
H.sub.2SO.sub.4). The absorbance was measured at 450 nm using the
Multiskan Ascent.RTM. plate reader. The absorbance of the cytokine
standards was fitted to a logistic equation, allowing the
concentrations of cytokine in samples to be determined.
[0212] .sub.PIC.sub.50 values (the negative log of the
concentration suppressing IL-11 level by 50%) for inhibition of
TGF-.beta.-induced IL-11 were interpolated from the linear
regression of log concentration small molecule versus IL-11 level
(Table 4 and FIG. 2).
TABLE-US-00004 TABLE 4 IL-11 suppression activity of a number of
compounds of the present invention pIC.sub.50 IL-11 Compound
suppression ZH3-114 4.98 ZH3-118 5.08 ZH3-122 6.75 ZH3-126 5.73
ZH2-114 4.00* ZH2-118 5.84 ZH2-122 5.61 ZH2-146 4.94 ZH2-38 4.00*
ZH2-46 4.00* ZH2-54 5.36 ZH2-58 4.53 ZH2-78 6.53 ZH3-50 6.38 ZH3-62
6.00 ZH3-70 4.00* ZH3-86 6.47 ZH3-134 4.00* ZH3-58 6.26 ZH3-130
6.08 ZH3-138 4.70 ZH3-78 5.07 *a value of 4.00 is assigned to the
pIC50 of compounds that failed to cause 50% or more inhibition at
10 mM.
[0213] Cellular Assays (MRC5 and A549) Assessing
TGF-.beta.-Elicited IL-11 Levels Following Exposure to ZH3-138,
ZH3-126 and PF670462
[0214] A further set of experiments to ascertain the potency of
ZH3-138 compared with PF670462 in regulating TGF-.beta.-elicited
IL-11 levels was conducted in MRC5 cells. Data are presented in
FIG. 5A as the means and SEM of 3 replicates.
[0215] A549 cells were treated with various concentrations of
PF670462 or ZH3-138 30 min prior to TGF-b (40 .mu.M) for 24 h.
Supernatant was collected for the determination of IL-11 or PAI-1
by ELISA. Data are presented in FIG. 5B as mean.+-.SEM of three
replicates. A similar experiment assessing the ability of ZH3-126
to effect IL-11 levels following administration was also carried
out. Data from this experiment are presented in FIG. 6 as
mean.+-.SEM of three replicates.
[0216] These examples demonstrate that inhibition of CK1.delta. by
the compounds of the invention is able to lower the levels of
inflammatory biomarkers.
[0217] Cellular Assay (A549 Human Lung Adenocarcinoma Cells)
Assessing Effect of ZH3-138, ZH3-126 and PF670462 Against
IL1.alpha.-Mediated Cytokine Production
[0218] In addition, compounds of the invention (eg ZH3-138 and
ZH3-126) demonstrate the ability to reduce supernatant
concentrations of other inflammatory biomarkers (such as
interleukin-1.alpha. (IL1.alpha.)-mediated cytokine production) in
a dose dependant manner. The anti-inflammatory potential of
selected compounds was examined by establishing the effects on
interleukin-1.alpha. (IL1.alpha.)-mediated cytokine production by
the lung adenocarcinoma cell line A549. Serum starved A549 cells
were treated with various concentrations of the relevant CK1.delta.
inhibitor (PF670462, ZH3-126 and ZH3-138) 30 min prior to
IL-1.alpha. (1 ng/ml) for 24 h. Supernatant was collected and
concentration of IL-6, IL-8 and GM-CSF was detected by ELISA. Data
are presented as mean.+-.SEM across three replicates in FIG. 7 (A:
IL-6; B: IL-8 and C: GM-CSF).
[0219] Human Microsomal Stability of Compounds of the Invention
In Vitro Metabolic Stability
[0220] Incubation: The metabolic stability assay was performed by
incubating each test compound in human liver microsomes at
37.degree. C. and a protein concentration of 0.4 mg/mL. The
metabolic reaction was initiated by the addition of an
NADPH-regenerating system and quenched at various time points over
a 60 minute incubation period by the addition of acetonitrile
containing diazepam as internal standard. Control samples
(containing no NADPH) were included (and quenched at 2, 30 and 60
minutes) to monitor for potential degradation in the absence of
cofactor. The human liver microsomes used in this experiment were
supplied by XenoTech, lot #1410230. Microsomal incubations were
performed at a substrate concentration of 1 .mu.M. Data analysis:
Species scaling factors from Ring et al. (2011) JPharmSci,
100:4090-4110 were used to convert the in vitro CLint
(.mu.L/min/mg) to an in vivo CLint(mL/min/kg). Hepatic blood
clearance and the corresponding hepatic extraction ratio (EH) were
calculated using the well stirred model of hepatic extraction in
each species, according to the "in vitro T1/2" approach described
in Obach (1999) DrugMetab. Dispos. 27:1350-1359. The EH was then
used to classify compounds as low(<0.3), intermediate (0.3-0.7),
high (0.7-0.95) or very high (>0.95) extraction compounds.
Predicted in vivo clearance values have not been corrected for
microsomal or plasma protein binding. Species scaling calculations
are based on two assumptions: 1) NADPH-dependent oxidative
metabolism predominates over other metabolic routes (i.e. direct
conjugative metabolism, reduction, hydrolysis, etc.), and; 2) rates
of metabolism and enzyme activities in vitro are truly reflective
of those that exist in vivo. If significant non-NADPH-mediated
degradation is observed in microsome control samples, then
assumption (1) is invalid and predicted clearance parameters are
therefore not reported.
TABLE-US-00005 TABLE 5 Metabolic evaluation of compounds of the
invention CL.sub.int, in vitro Predicted Predicted Compound
Microsome T.sub.1/2 (.mu.L/min/mg CL.sub.int, in vivo CL.sub.blood
Predicted Clearance ID species (min) protein) (mL/min/kg)
(mL/min/kg) EH classification Notes PF670462 Mouse 4 428 1105 108
0.90 High {circumflex over ( )} PF670462 Human 9 192 158 18 0.88
High {circumflex over ( )} ZH3-126 Human 242 7 6 5 0.22 Low ZH3-138
Human >255 <7 <6 <5 <0.22 Low # Notes: # This
compound showed minimal degradation (<15%) over the course of
the incubation in human microsomes; {circumflex over ( )} obtained
by incubation at a concentration of 1 .mu.M in human or mouse liver
microsomes.
[0221] Pharmacokinetics: PF670462 and a Compound of the
Invention
[0222] PF670462 (2HCl.0.4 mol. eq. isopropanol) and ZH3-138
(unionised) were administered to male C57BL/6 mice by IV (3 mg/kg)
or orally (10 mg/kg). IV administration was achieved by bolus
injection into the tail vein of mice using 1 mL syringe with
25G.times.1'' needle at a volume of 3 mL/kg. Oral administration
was achieved by gavage needle at a volume of 3 mL/kg.
[0223] Blood was collected from mice at 15 min and 1 h post-dose of
each compound for the purposes of determining the whole
blood-to-plasma (B/P) ratio. The apparent whole blood-to-plasma
ratio (B/P) in mouse blood was 1.0 for PF670462 and 0.91 for
ZH3-138, suggesting that all compounds distributed effectively into
red blood cells. No adverse reactions or compound-related side
effects observed in any mice during the 24 h sampling period after
dosing any of the compounds. Plasma samples were also taken from 2
mice that were not administered test compound for use as analytical
tool.
[0224] The experimental protocol is summarised in the following
Table 6
TABLE-US-00006 TABLE 6 Summary of experimental protocol for
pharmacokinetic study STUDY DESIGN Species Male C57BL/6 mice Dose
Route IV and Oral Target Dose IV: 3 mg/kg | Oral: 10 mg/kg Dosing
Details IV: Bolus IV Injection into the tail vein using 1 mL
syringe with 25G x 1'' needle at a volume of 3 mL/kg Oral: Via
gavage needle at a volume of 3 mL/kg Post-dose plasma IV: 1, 2, 5,
15, and 30 min; 1, 2, 4, 7.5, and 24 h collection.sup.b Oral: 15
and 30 min; 1, 2, 4, 7.5, and 24 h FORMULATION Vehicle 5% (v/v)
DMSO in an aqueous solution containing 10% (w/v) Captisol (pH
modified with 1M hydrochloric acid to solubilize ZH3-134 and
ZH3-138) Appearance IV: Clear solution IV: Clear solution IV: Clear
solution (pH 3.0) (pH 3.1) (pH 2.8) Oral: Clear solution Oral:
Clear solution Oral: Clear solution (pH 2.6) (pH 2.5) (pH 3.0)
Concentration IV: 1.00 mg/mL | Oral: 3.33 mg/mL
[0225] Concentration of PF670462 was only measurable up to 4 h
post-dose and the apparent half-life was short (approximately 0.5
h), which is consistent with literature precedent
(Neuropsychopharmacology 2012; 37: 2121-2131 and CPT
Pharmacometrics and Systems Pharmacology 2013; 2: e57). The
apparent blood volume of distribution and the blood clearance
values were moderate for PF670462.
[0226] The concentration-time profile for ZH3-138 was distinctly
different to PF670462 (FIG. 4). Plasma concentrations remained
above the analytical lower limit of quantitation (LLQ) for the
duration of the 24 h sampling period, and the apparent half-life
was approximately 3 h. In addition the concentration-time profile
exhibited an apparent secondary peak at 2 h post-dose; this may be
indicative of enterohepatic recirculation where compound is
excreted in bile (either unchanged, or as a conjugated metabolite)
and then reabsorbed into the systemic circulation from the
gastrointestinal tract. The apparent blood volume of distribution
was moderate and the apparent blood clearance was low for ZH3-138.
Given the possibility contribution of enterohepatic recirculation
to plasma exposure, calculated PK parameters for ZH3-138 should be
viewed as apparent values only. Furthermore, it should be noted
that while secondary peaks were not observed for PF670462, this
does not preclude potential susceptibility of those compounds to
biliary excretion.
[0227] These apparent blood clearance values are consistent with
their relative metabolic stability in mouse liver microsomes, where
the in vivo predicted hepatic extraction ratios were 0.90 for
PF670462 (0.88 for PF670462 in human microsomes and <0.22 for
ZH3-138 in human microsomes (see Table 5 above)).
[0228] Formulation Preparation and Analysis
[0229] Intravenous (IV) and oral formulations were prepared using
the same method. On the day of dosing, each of the solid compound
was dissolved in DMSO to which an aqueous solution containing 10%
Captisol was added. Hydrochloric acid (1 M) was used to modify pH
for the formulation of ZH3-138 with the purpose of solubilising the
compound (see Section B for the final pH of each formulation). The
formulations of each compound were thoroughly vortexed, producing
colourless solutions for all three compounds.
[0230] The IV formulation was filtered through a 0.22 .mu.m syringe
filter prior to IV dosing. The average measured concentration of
compound in aliquots (n=2) of the filtered solution was 0.806 mg/mL
for PF670462 and 0.908 mg/mL for ZH3-138. For the oral formulation,
the average measured concentration of compound in aliquots (n=3) of
the bulk formulation was 3.38 mg/mL (range 3.34-3.45 mg/mL) for
PF670462, and 3.00 mg/mL (range 2.59-3.28 mg/mL) for ZH3-138.
[0231] Mouse Pharmacokinetics
[0232] All animal studies were conducted using established
procedures in accordance with the Australian Code of Practice for
the Care and Use of Animals for Scientific Purposes, and the study
protocols were reviewed and approved by the Monash Institute of
Pharmaceutical Sciences Animal Ethics Committee.
[0233] The systemic exposure of PF670462 and ZH3-138 was studied in
non-fasted male C57BL/6 mice weighing 19.8-26.8 g. Mice had access
to food and water ad libitum throughout the pre- and post-dose
sampling period.
[0234] Compounds were dosed to mice by bolus injection into the
lateral tail vein (3 mL/kg) for IV administration and by gavage (3
mL/kg) for oral administration. Following IV and oral
administration, blood samples were collected up to 24 h (n=3 mice
per time point) with a maximum of three samples from each mouse.
Samples were collected via submandibular bleed (approximately 120
.mu.L; conscious sampling). No urine samples were collected as mice
were housed in bedded cages.
[0235] Blood was collected into polypropylene Eppendorf tubes
containing heparin as anticoagulant and stabilisation cocktail
(containing Complete.RTM. (a protease inhibitor cocktail) and
potassium fluoride) to minimise the potential for ex vivo compound
degradation in blood/plasma samples.
[0236] Once collected, blood samples were centrifuged immediately,
supernatant plasma was removed, and stored at -80.degree. C. until
analysis by LC-MS.
[0237] Plasma samples were quantified against calibration standards
prepared by spiking blank mouse plasma (50 .mu.L) with solution
standards (10 .mu.L) obtained by diluting a stock solution of test
compound (1 mg/mL in DMSO) with 50% acetonitrile in water. Diazepam
(10 .mu.L of 5 .mu.g/mL in 50% acetonitrile/water) was added to all
plasma calibration standards and samples as an internal standard
(IS). The extraction of the test compound and IS from plasma was
conducted using protein precipitation with acetonitrile. Protein
precipitation was carried out by the addition of acetonitrile
followed by vortexing and centrifugation (10,000 rpm) for 3 minutes
to obtain supernatant for analysis using the LC-MS conditions
described in Table 7.
TABLE-US-00007 TABLE 7 Summary of bioanalytical method Instrument
Waters Xevo TQS Micro coupled to a Waters Acquity UPLC Detection
Positive electrospray ionisation multiple-reaction monitoring mode
Column Supelco Ascentis Express RP Amide column (50 .times. 2.1 mm,
2.7 .mu.m) LC conditions Gradient cycle time: 4 min; Injection vol:
3 .mu.L; Flow rate: 0.4 mL/min Mobile phase Acetonitrile-water
gradient with 0.05% formic acid Extraction Protein precipitation
using acetonitrile (2-fold volume ratio) T.sub.R Transition Cone
CID Analyte (min) (m/z) Voltage (V) PF670462 1.63 338.31 >
256.16 40 20 Diazepam 2.32 285.16 > 154.08 40 25 (internal
standard for PF670462) ZH3-138 1.96 374.29 > 256.17 40 30
Diazepam 2.67 285.16 > 154.08 40 25 (internal standard for
ZH3-138)
[0238] Analysis of B/P partitioning samples was conducted similarly
and quantified against calibration standards samples prepared using
a 1:1 v/v mixture of blank mouse blood and plasma. The matrix
matched B/P partitioning samples and standards were processed using
protein precipitation with acetonitrile as described above.
[0239] Formulation aliquots were analysed against standard samples
prepared in 50% acetonitrile/water. Formulation aliquots (50 or 100
.mu.L) were dissolved in DMSO (1 mL final volume) and diluted using
50% acetonitrile/water to be within the calibration range.
[0240] The accuracy and precision of the assays were within the
CDCO's acceptance criteria as summarised in Table 8.
TABLE-US-00008 TABLE 8 Replicate analysis and calibration QC Data
Calibration Data QC Accuracy Precision Range LLQ .sup.a Compound
Matrix{circumflex over ( )} (ng/mL (% bias)* (% RSD) (ng/mL)
R.sup.2 (ng/mL) PF670462 Plasma 50 (n = 7) 1.6 3.2 1-10,000 0.9997
1.0 500 (n = 7) -1.2 6.0 1:1 (v/v) 100 (n = 3) 0.5 3.4 2-1,000
0.9996 2.0 blood:plasma 1000 (n = 3) 1.6 2.7 Solvent 500 (n = 3)
2.5 0.5 2.5-2,500 0.9997 2.5 ZH3-138 Plasma 50 (n = 6) 12.4 4.7
1-10,000 0.9998 1.0 500 (n = 6) 9.3 3.7 1:1 (v/v) 100 (n = 3) 1.8
0.7 1-2,000 1.0000 2.0 blood:plasma 1000 (n = 3) -3.1 3.0 Solvent
500 (n = 3) -1.6 1.5 2.5-5,000 0.9998 2.5
[0241] In Vivo Determination of Whole Blood-to-Plasma Ration
[0242] Blood was collected via cardiac puncture (whilst under
gaseous isoflurane anaesthesia) into tubes containing heparin and
stabilisation cocktail. The haematocrit was determined via
centrifugation (13000.times.g for 4 min using a Clemets.RTM.
Microhematocrit centrifuge and Safecap.RTM. Plain Self-sealing
Mylar Wrapped capillary tubes), and values ranged from 38% to 40%
for PF670462 and 38% to 44% for ZH3-138.
[0243] Aliquots of blood (4.times.25 .mu.L) were collected and
matrix matched with equivalent volumes of blank plasma. The
remainder of the blood samples were centrifuged and 4.times.25
.mu.L plasma aliquots from each mouse were collected and matrix
matched with equivalent volumes of blank blood. Samples were frozen
on dry ice and stored at -80.degree. C. until analysis by
LC-MS.
[0244] The B/P ratio was obtained by dividing the average measured
concentration in blood by the average concentration measured in
plasma following centrifugation of whole blood.
TABLE-US-00009 TABLE 9 Plasma concentrations of PF670462 in male
C57BL/6 mice following IV administration at 2.42 mg/kg Plasma
Concentration (.mu.M) Time (h) Mouse ID Individual Mean SD 0.017 7A
18.4 15.5 4.1 8A 10.9 9A 17.3 0.033 10A 8.83 8.14 0.63 11A 8.03 12A
7.57 0.083 1A 5.58 6.09 0.57 2A 5.99 3A 6.70 0.25 1A 2.38 2.48 0.23
2A 2.32 3A 2.75 0.5 4A 0.900 0.851 0.26 5A 0.566 6A 1.09 1.0 4A
0.193 0.190 0.024 5A 0.165 6A 0.212 2.0 7A 0.0263 0.253 0.0043 8A
0.0207 9A 0.0290 4.0 10A .sup. 0.00222 .sup.a 0.00209 0.0069 11A
.sup. 0.00134 .sup.a 12A .sup. 0.00270 .sup.a 7.5 7A ND -- -- 8A ND
9A ND 24 10A ND -- -- 11A ND 12A ND .sup.a Included in the PK data
analysis as the value is only marginally below the LLQ. ND Not
detected
TABLE-US-00010 TABLE 10 Plasma concentrations of PF670462 in male
C57BL/6 mice following oral administration at 10.1 mg/kg Plasma
Concentration (.mu.M) Time (h) Mouse ID Individual Mean SD 0.25 13A
1.45 1.25 0.33 14A 0.873 15A 1.44 0.50 16A 1.95 0.941 0.886 17A
0.508 18A 0.366 1.0 19A 0.260 0.292 0.042 20A 0.340 21A 0.277 2.0
13A 0.140 0.103 0.038 14A 0.0641 15A 0.104 4.0 16A 0.0318 0.0165
0.013 17A 0.0106 18A 0.00703 7.5 19A ND -- -- 20A ND 21A ND 24 16A
ND -- -- 17A ND 18A ND ND Not detected
TABLE-US-00011 TABLE 11 Plasma concentrations of ZH3-138 in male
C57BL/6 mice following IV administration at 2.69 mg/kg Plasma
Concentration (.mu.M) Time (h) Mouse ID Individual Mean SD 0.017 1
11.1 10.8 0.84 2 11.4 3 9.81 0.033 4 7.86 7.84 1.53 5 6.30 6 9.37
0.083.sup.a 1 5.29 5.73 0.38 2 5.94 3 5.95 0.25 1 5.04 4.65 0.42 2
4.68 3 4.21 0.5 4 4.01 4.14 0.14 5 4.12 6 4.28 1.0 4 2.93 3.12 0.51
5 2.73 6 3.70 2.0 7 4.42 4.55 0.63 8 5.24 9 4.00 4.0 10 3.74 3.63
0.11 11 3.53 12 3.63 7.5 7 1.84 1.72 0.16 8 1.77 9 1.54 24 10
0.0237 0.0245 0.0039 11 0.0287 12 0.0211 .sup.aThe actual sampling
time was 0.10 h.
TABLE-US-00012 TABLE 12 Plasma concentrations of ZH3-138 in male
C57BL/6 mice following oral administration at 8.96 mg/kg Plasma
Concentration (.mu.M) Time (h) Mouse ID Individual Mean SD 0.25 13
12.1 11.9 2.9 14 14.7 15 8.96 0.50 16 13.7 15.8 5.9 17 11.3 18 22.5
1.0 19 13.9 14.8 1.2 20 16.2 21 14.4 2.0 13 13.8 16.3 2.2 14 17.4
15 17.7 4.0 16 11.0 12.1 2.6 17 10.2 18 15.1 7.5 19 6.59 7.09 1.4
20 5.97 21 8.71 24 16 0.0513 0.0557 0.018 17 0.0400 18 0.0758
[0245] Synthesis
[0246] General
[0247] Proton nuclear magnetic resonance spectra (.sup.1H NMR, 400,
600 MHz) and proton decoupled carbon-13 nuclear magnetic resonance
spectra (.sup.13C NMR, 100, 150 MHz) were obtained in deuterated
solvents, with residual protonated solvent as internal standard.
Chemical shifts are followed by multiplicity, coupling constant(s)
(J, Hz), integration and assignments where possible. Flash
chromatography was carried out according to the procedure of Still
et al. using an automated system..sup.1 Analytical thin layer
chromatography (t.l.c.) was conducted on aluminium-backed 2 mm
thick silica gel 60 GF.sub.254 and chromatograms were visualized
under an ultraviolet lamp. High resolution mass spectra (HRMS) were
obtained by ionizing samples using electrospray ionization (ESI)
and a time of flight mass analyzer. Dry THF and CH.sub.2Cl.sub.2
were obtained by the method of Pangborn et al..sup.2 Pet. spirits
refers to petroleum ether, boiling range 40-60.degree. C. All other
commercially available reagents were used as received. [0248] 1 W.
C. Still, M. Kahn and A. M. Mitra, J. Org. Chem., 1978, 43, 2923.
[0249] 2 A. B. Pangborn, M. A. Giardello, R. H. Grubbs, R. K. Rosen
and F. J. Timmers, Organometallics, 1996, 15, 1518.
##STR00138##
[0249] 2-(Methylsulfanyl)pyrimidine-4-carbaldehyde (1)
[0250] Aqueous 4 M HCl (13 mL) was added to a solution of
4-dimethoxymethyl-2-methylsulfanyl-pyrimidine (4.10 g, 20.5 mmol).
The resulting mixture was heated at 50.degree. C. for 18 h. .sup.1H
NMR analysis indicated conversion to the carbaldehyde so the
mixture was cooled to r.t. The reaction mixture was diluted with
EtOAc and neutralized with K.sub.2CO.sub.3 solution. The aqueous
phase was extracted with EtOAc, dried (MgSO.sub.4) and
concentrated. The crude material was used in the next step without
purification (2.74 g, 87%). .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 2.64 (3H, s), 7.44 (1H, d, J=4.8 Hz), 8.77 (1H, d, J=4.8
Hz), 9.96 (1H, s).
N-Ethyl-1-(2-(methylsulfanyl)pyrimidin-4-yl)methanimine (2)
[0251] A solution of 2.0 M ethylamine in THF (1.37 mL, 2.74 mmol)
and 20% aqueous K.sub.2CO.sub.3 (0.230 g, 1.64 mmol) were added to
a solution of the crude aldehyde (0.21 g, 1.37 mmol) in
CH.sub.2Cl.sub.2 (5 mL). The reaction mixture was stirred at r.t.
overnight. .sup.1H NMR analysis indicated complete consumption of
the aldehyde. The reaction mixture containing the imine was used
directly in the next step without isolation.
4-(1-Ethyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-2-(methylsulfanyl)pyrimidi-
ne (3)
[0252] A mixture of
.alpha.-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (0.474 g, 1.64
mmol), 2 (0.248 g, 1.37 mmol) and aq. K.sub.2CO.sub.3 20% w/v (1.13
mL, 1.64 mmol) in CH.sub.2Cl.sub.2 (5 ml) was stirred at r.t. for 5
d. The reaction mixture was diluted with CH.sub.2Cl.sub.2, and
washed with water, dried (MgSO.sub.4), filtered and concentrated.
Flash chromatography of the residue (EtOAc/pet. spirits 20% to 80%)
afforded a light orange oil (0.340 g, 79%). .sup.1H-NMR (400 MHz;
CDCl.sub.3): .delta. 1.33 (3H, t, J=7.2 Hz), 2.53 (3H, s,), 4.32
(2H, q, J=7.2 Hz), 6.75 (1H, d, J=5.2 Hz), 6.97 (2H, t, J=8.6 Hz),
7.40 (2H, dd, J=5.8, 7.9 Hz), 7.63 (1H, s), 8.27 (1H, d, J=5.2 Hz);
.sup.13C-NMR (101 MHz; CDCl.sub.3): .delta. 14.1, 16.7, 42.0,
115.4, 115.6, 116.2, 130.2 (d, J.sub.C-F=8.1 Hz), 130.4 (d,
J.sub.C-F=3.1 Hz), 139.3, 143.8, 156.9, 157.7, 162.5 (d,
J.sub.C-F=247 Hz), 172.8; HRMS (ESI.sup.+) calcd for
C.sub.16H.sub.16FN.sub.4S [M+H].sup.+ 315.1080. Found 315.1075.
4-(1-Ethyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-2-(methylsulfonyl)pyrimidi-
ne (4)
[0253] mCPBA (57-86%) (0.559 g, 3.24 mmol) was added portionwise to
a mixture of sulfide (0.340 g, 1.08 mmol) in CH.sub.2Cl.sub.2 (10
mL) and the mixture was stirred at r.t. overnight. TLC indicated
conversion to a more polar compound. The mixture was quenched with
aq. Na.sub.2CO.sub.3 10% w/v, water, brine, dried (MgSO.sub.4), and
concentrated in vacuum to give the sulfone as a pale yellow oil
(0.294 g, 79%). .sup.1H-NMR (500 MHz; CDCl.sub.3): .delta. 0.97
(3H, t, J=7.2 Hz), 2.88 (3H, s), 3.99 (2H, q, J=7.2 Hz), 6.59 (2H,
t, J=8.7 Hz), 6.81 (1H, d, J=5.4 Hz), 6.96 (3H, m), 8.10 (1H, d,
J=5.4 Hz); .sup.13C-NMR (126 MHz; CDCl.sub.3): .delta. 16.7, 39.1,
42.9, 115.9, 116.1, 122.1, 122.9, 130.1 (d, J.sub.C-F=3.4 Hz),
130.5 (d, J.sub.C-F=8.2 Hz), 140.9, 146.4, 157.4, 159.1, 162.9 (d,
J.sub.C-F=248 Hz), 166.0; HRMS (ESI.sup.+) calcd for
C.sub.16H.sub.16FN.sub.4O.sub.2S [M+H].sup.+ 347.0978. Found
347.0970.
N-Cyclobutyl-4-(1-ethyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)pyrimidin-2-am-
ine (5; ZH3-122)
[0254] Cyclobutylamine (61.0 .mu.L, 0.854 mmol) was added to a
mixture of 4 (37.0 mg, 0.107 mmol) in THF (5 mL) and the mixture
was stirred at 40.degree. C. for 4 d. The mixture was concentrated
under vacuum and the residue purified by flash chromatography
(EtOAc/pet. spirits 70%) to give a pale orange solid (31.6 mg,
88%). .sup.1H-NMR (500 MHz; CDCl.sub.3): .delta. 1.38 (3H, t, J=7.2
Hz), 1.71-1.82 (2H, m), 1.90-1.9 (2H, m), 2.42 (2H, m), 4.31-4.35
(2H, m), 4.44-4.52 (1H, m), 5.46-5.50 (1H, m), 6.40 (1H, d, J=5.1
Hz), 7.00 (2H, t, J=8.7 Hz), 7.48 (2H, dd, J=5.5, 8.6 Hz), 7.63
(1H, s), 8.11 (1H, m); .sup.13C-NMR (126 MHz; CDCl.sub.3): .delta.
15.2, 16.8, 31.7, 41.8, 46.7, 111.3, 115.3, 115.5, 125.2, 130.20
(d, J.sub.C-F=8.0 Hz), 130.8 (d, J.sub.C-F=2.9 Hz), 138.6, 142.6,
158.0, 158.7, 162.4 (d, J.sub.C-F=247 Hz); HRMS (ESI.sup.+) calcd
for C.sub.21H.sub.21FN.sub.5 [M+H].sup.+ 338.1781. Found
338.1773.
2-((4-(1-Ethyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)pyrimidin-2-yl)amino)et-
han-1-ol (6; ZH3-126)
[0255] Ethanolamine (46.0 .mu.L, 0.762 mmol) was added to a mixture
of 4 (33.0 mg, 0.095 mmol) in THF (5 mL) and the mixture was
stirred at 40.degree. C. for 3 d. The mixture was concentrated
under vacuum and the residue purified by flash chromatography
(EtOAc 100% to MeOH/EtOAc 20%) to give a pale orange oil (24.9 mg,
78%). .sup.1H-NMR (500 MHz; CDCl.sub.3): .delta. 1.36 (3H, t, J=7.2
Hz), 3.60 (2H, m), 3.83 (2H, m), 4.30 (2H, q, J=7.2 Hz), 5.90-5.97
(1H, m), 6.41 (1H, d, J=5.2 Hz), 7.00 (2H, m, J=4.8, 8.7 Hz), 7.45
(2H, m, J=4.9, 5.3 Hz), 7.63 (1H, s), 8.09 (1H, d, J=5.2 Hz);
.sup.13C-NMR (126 MHz; CDCl.sub.3): .delta. 16.8, 41.8, 45.9, 58.4,
111.4, 115.4, 115.6, 125.0, 130.2 (d, J.sub.C-F=8.1 Hz), 130.6 (d,
J.sub.C-F=3.4 Hz), 138.7, 142.6, 158.8, 162.5 (d, J.sub.C-F=247
Hz), 162.8; HRMS (ESI.sup.+) calcd for C.sub.17H.sub.19FN.sub.5O
[M+H].sup.+ 328.1574. Found 328.1570.
##STR00139## ##STR00140##
N-(Cyclohexylmethyl)-1-(2-(methylsulfanyl)pyrimidin-4-yl)methanimine
(7)
[0256] Cyclohexylmethylamine (356 .mu.L, 2.74 mmol) and
K.sub.2CO.sub.3 (0.227 g, 1.64 mmol) were added to a solution of
the crude aldehyde 1 (0.211 g, 1.37 mmol) in CH.sub.2Cl.sub.2 (5
mL). The reaction mixture was stirred at r.t. overnight. .sup.1H
NMR analysis indicated complete consumption of the aldehyde. The
reaction mixture containing the imine was used directly in the next
step without isolation.
4-(1-(Cyclohexylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-2-(methylsulf-
anyl)pyrimidine (8)
[0257] A mixture of
.alpha.-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (0.474 g, 1.64
mmol), 7 (0.342 g, 1.37 mmol) and aq. K.sub.2CO.sub.3 20% w/v (1.13
mL, 1.64 mmol) in CH.sub.2Cl.sub.2 (5 ml) was stirred at r.t. for 5
d. The reaction mixture was diluted with CH.sub.2Cl.sub.2, and
washed with water, dried (MgSO.sub.4), filtered and concentrated.
Flash chromatography of the residue (EtOAc/pet. spirits 50%)
afforded a yellow oil (0.410 g, 78%). .sup.1H-NMR (400 MHz;
CDCl.sub.3): .delta. 0.85 (2H, q, J=10.8 Hz), 1.09 (3H, d, J=8.0
Hz), 1.53-1.65 (6H, m), 2.55 (3H, s), 4.12 (2H, d, J=6.7 Hz), 6.75
(1H, d, J=5.3 Hz), 6.98 (2H, t, J=8.6 Hz), 7.42 (2H, dd, J=5.5, 8.5
Hz), 7.55 (1H, s), 8.28 (1H, d, J=5.2 Hz); .sup.13C-NMR (101 MHz;
CDCl.sub.3): .delta. 14.1, 25.6, 26.1, 30.5, 38.7, 53.1, 115.4,
115.6, 116.3, 124.2, 130.3 (d, J.sub.C-F=7.9 Hz), 130.4 (d,
J.sub.C-F=3.2 Hz), 140.6, 143.7, 156.9, 157.82, 162.5 (d,
J.sub.C-F=248 Hz), 172.8; HRMS (ESI.sup.+) calcd for
C.sub.21H.sub.24FN.sub.4S [M+H].sup.+ 383.1706. Found 383.1698.
4-(1-(Cyclohexylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-2-(methylsulf-
onyl)pyrimidine (9)
[0258] mCPBA (57-86% purity) (0.459 g, 2.66 mmol) was added
portionwise to a mixture of sulfide (0.339 g, 0.886 mmol) in
CH.sub.2Cl.sub.2 (15 mL) and the mixture was stirred at r.t.
overnight. The mixture was quenched with aq. Na.sub.2CO.sub.3,
water, brine, dried (MgSO.sub.4), and concentrated in vacuo to give
the sulfone as a pale yellow solid (0.308 g, 84%). .sup.1H-NMR (400
MHz; CDCl.sub.3): .delta. 0.88-0.96 (2H, m), 1.15 (3H, m), 1.67
(6H, m), 3.36 (3H, s), 4.28 (2H, d, J=6.9 Hz), 7.08 (2H, t, J=8.6
Hz), 7.28 (1H, d, J=5.4 Hz), 7.45 (2H, dd, J=5.4, 8.5 Hz), 7.68
(1H, s), 8.56 (1H, d, J=5.4 Hz); .sup.13C-NMR (101 MHz;
CDCl.sub.3): .delta. 25.6, 26.3, 30.4, 38.7, 39.2, 54.1, 116.1,
116.3, 122.2, 123.2, 130.0 (d, J.sub.C-F=3.0 Hz), 130.7 (d,
J.sub.C-F=8.1 Hz), 142.3, 146.4, 157.4, 159.5, 163.1 (d,
J.sub.C-F=249 Hz), 166.2; HRMS (ESI.sup.+) calcd for
C.sub.21H.sub.24FN.sub.4O.sub.2S [M+H].sup.+ 415.1604. Found
415.1597.
4-(1-(Cyclohexylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(oxetan-3-y-
l)pyrimidin-2-amine (10; ZH3-114)
[0259] 3-Oxetanamine (100 .mu.L, 1.18 mmol) was added to a mixture
of 9 (49.0 mg, 0.118 mmol) in THF (5 mL) and the mixture was
stirred at 40.degree. C. for 5 d. The mixture was concentrated
under vacuum and the residue purified by flash chromatography
(EtOAc/pet. spirits (50% to 100%) to give a pale yellow oil (31.9
mg, 66%). .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 0.85-1.69
(11H, m), 4.10 (2H, d, J=6.8 Hz), 4.63 (2H, t, J=6.3 Hz), 5.00 (2H,
t, J=6.9 Hz), 5.15 (1H, dt, J=6.8, 13.6 Hz), 6.08 (1H, bs), 6.47
(1H, d, J=5.0 Hz), 6.99 (2H, t, J=8.5 Hz), 7.45 (2H, dd, J=5.6, 8.3
Hz), 7.57 (1H, s), 8.15 (1H, d, J=5.1 Hz); .sup.13C-NMR (101 MHz;
CDCl.sub.3): .delta. 25.7, 26.2, 30.7, 38.9, 46.6, 52.8, 79.2,
112.4, 115.4, 115.6, 125.0, 130.2 (d, J.sub.C-F=8.2 Hz), 130.5 (d,
J.sub.C-F=3.2 Hz), 140.0, 142.7, 158.2, 159.1, 161.3, 162.5 (d,
J.sub.C-F=248 Hz).
2-((4-(1-(Cyclohexylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)pyrimidin--
2-yl)amino)ethan-1-ol (11; ZH3-118)
[0260] Ethanolamine (75.0 .mu.L, 1.25 mmol) was added to a mixture
of 9 (52.0 mg, 0.125 mmol) in THF (5 mL) and the mixture was
stirred at 40.degree. C. for 5 d. The mixture was concentrated
under vacuum and the residue purified by flash chromatography
(EtOAc/pet. spirits 70% to 100%) to give a pale yellow foam (41.7
mg, 85%). .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 0.84-1.67
(10H, m), 2.04 (1H, d, J=8.3 Hz), 3.61 (2H, q, J=5.1 Hz), 3.83 (2H,
t, J=4.9 Hz), 4.09 (3H, m, J=6.6 Hz), 5.93 (1H, bs), 6.41 (1H, d,
J=5.1 Hz), 6.99 (2H, t, J=8.6 Hz), 7.45 (2H, dd, J=5.6, 8.4 Hz),
7.56 (1H, s), 8.10 (1H, d, J=4.9 Hz); .sup.13C-NMR (101 MHz;
CDCl.sub.3): .delta. 25.7, 26.2, 30.7, 38.8, 44.4, 52.8, 62.7,
111.6, 115.3, 115.6, 125.2, 130.2 (d, J.sub.C-F=8.0 Hz), 130.5 (d,
J.sub.C-F=3.1 Hz), 140.0, 142.5, 157.8, 159.1, 162.5 (d,
J.sub.C-F=248 Hz), 162.7; HRMS (ESI.sup.+) calcd for
C.sub.22H.sub.27FN.sub.5O [M+H].sup.+ 396.2200. Found 396.2193.
##STR00141## ##STR00142##
4-((Cyclohexylimino)-methyl)-N-methylsulfanylpyrimidin-2-amine
(12)
[0261] Aqueous K.sub.2CO.sub.3 20% w/v (0.55 g, 0.39 mmol) and
cyclohexylamine (2.45 mL, 21.4 mmol) were added to a solution of
the crude aldehyde (2.74 g, 17.8 mmol) in CH.sub.2Cl.sub.2 (15 mL).
The reaction mixture was stirred at r.t. overnight. .sup.1H NMR
analysis indicated complete consumption of the aldehyde. The
reaction mixture containing the imine was used directly in the next
step without isolation.
4-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-2-(methylsulfanyl)pyr-
imidine (13)
[0262] A mixture of
.alpha.-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (5.67 g, 19.6
mmol), 12 (2.74 g, 17.8 mmol) and K.sub.2CO.sub.3 (2.71 g, 19.6
mmol) in CH.sub.2Cl.sub.2 (15 ml) was stirred at r.t. overnight.
The reaction mixture was diluted with CH.sub.2Cl.sub.2, and washed
with water, dried (MgSO.sub.4), filtered and concentrated. Flash
chromatography of the residue (EtOAc/pet. spirits 1:1) afforded a
solid with at which was recrystallized from EtOAc/pet. spirits) to
give the sulfide as pale yellow crystals, (2.32 g, 35%), m.p.
192-195.degree. C. .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta.
1.41-1.19 (3H, m), 1.75-1.59 (3H, m), 1.88 (2H, d, J=13.3 Hz), 2.16
(2H, d, J=11.3 Hz), 2.58 (3H, s), 4.62 (1H, tt, J=11.9, 3.4 Hz),
6.76 (1H, d, J=5.2 Hz), 6.99 (2H, t, J=8.6 Hz), 7.40 (2H, dd,
J=8.5, 5.5 Hz), 7.76 (1H, s), 8.31 (1H, d, J=5.2 Hz); .sup.13C-NMR
(101 MHz; CDCl.sub.3): .delta. 14.2, 25.4, 26.0, 34.7, 55.9, 115.5,
115.71 (s, 1C), 117.2, 124.2, 130.3 (d, J.sub.C-F=8.0 Hz), 130.6
(d, J.sub.C-F=3.2 Hz), 136.6, 143.1, 157.1, 158.2, 162.6 (d,
J.sub.C-F=247 Hz), 173.0; HRMS (ESI.sup.+) calcd for
C.sub.20H.sub.22FN.sub.4S (M+H) 369.1549. Found 369.1545.
4-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-2-methylsulfonylpyrim-
idin-2-amine (14)
[0263] mCPBA (55-86%) (0.569 g, 3.30 mmol) was added portionwise to
a mixture of 13 (0.404 g, 1.10 mmol) in CH.sub.2Cl.sub.2 (20 mL)
and the mixture was stirred at r.t. overnight. The mixture was
quenched with aq. Na.sub.2CO.sub.3, water, brine, dried with
Na.sub.2SO.sub.4, and concentrated in vacuum to give the sulfone as
a colourless solid (0.440 g, 87%), m.p. 196-202.degree. C.
.sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 1.93-1.21 (8H, m), 2.23
(2H, d, J=11.3 Hz), 3.39 (3H, s), 4.85 (1H, tt, J=11.8, 3.4 Hz),
7.08 (2H, t, J=8.6 Hz), 7.27 (1H, m), 7.43 (2H, dd, J=8.5, 5.5 Hz),
7.86 (1H, s), 8.59 (1H, d, J=5.4 Hz); .sup.13C-NMR (101 MHz;
CDCl.sub.3): .delta. 25.5, 25.8, 34.9, 39.2, 56.9, 116.0, 116.3,
123.1, 130.3 (d, J.sub.C-F=3.6 Hz, 1C), 130.7 (d, J.sub.C-F=8.2
Hz), 138.2, 146.0, 157.5, 159.8, 163.1 (d, J.sub.C-F=249 Hz),
166.3; HRMS (ESI.sup.+) calcd for C.sub.20H.sub.22FN.sub.4O.sub.2S
(M+H) 401.1447. Found 401.1444.
4-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluorobenzyl)pyr-
imidin-2-amine (16; ZH2-114)
[0264] 3-Fluorobenzylamine (118 .mu.L, 1.03 mmol) was added to a
solution of 14 (41.3 mg, 0.103 mmol) in THF (5 mL) and the mixture
was stirred at 40.degree. C. for 5 d. The mixture was concentrated
under vacuum and the residue purified by flash chromatography
(EtOAc/pet. spirits 40% to 70%) to give a colourless solid (45.1
mg, 99%). .sup.1H-NMR (500 MHz; CDCl.sub.3): .delta. 1.12-1.20 (3H,
m), 1.55-1.65 (3H, m), 1.79-1.81 (2H, m), 2.09 (2H, m, J=11.8 Hz),
4.47-4.52 (1H, m), 4.71 (2H, d, J=6.2 Hz), 5.90 (1H, s), 6.44 (1H,
d, J=5.1 Hz), 6.94-7.00 (3H, m), 7.06 (1H, d, J=9.8 Hz), 7.13 (1H,
d, J=7.6 Hz), 7.30 (1H, td, J=6.0, 7.9 Hz), 7.42-7.45 (2H, m), 7.71
(1H, s), 8.12-8.13 (1H, m); .sup.13C-NMR (126 MHz; CDCl.sub.3):
.delta. 25.4, 25.7, 34.6, 44.8, 55.5, 112.6, 113.9, 114.1, 114.1,
114.3, 115.3, 115.4, 122.7 (d, J.sub.C-F=2.3 Hz), 125.0, 130.1 (d,
J.sub.C-F=8.0 Hz), 130.3 (d, J.sub.C-F=8.2 Hz), 130.7 (d,
J.sub.C-F=3.2 Hz), 135.9, 141.7, 142.0, 142.1, 158.4, 159.2, 162.4
(d, J.sub.C-F=247 Hz), 162.5, 163.2 (d, J.sub.C-F=247 Hz); HRMS
(ESI.sup.+) calcd for C.sub.26H.sub.26F.sub.2N.sub.5 [M+H].sup.+
446.2156. Found 446.2148.
4-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorobenzyl)pyr-
imidin-2-amine (17; ZH2-118)
[0265] 2-Fluorobenzylamine (87.0 .mu.L, 0.759 mmol) was added to a
solution of 14 (30.4 mg, 0.076 mmol) in THF (5 mL) and the mixture
was stirred at 40.degree. C. for 5 d. The mixture was concentrated
under vacuum and the residue purified by flash chromatography
(EtOAc/pet. spirits 40% to 70%) to give a colourless solid (33.2
mg, 98%). .sup.1H-NMR (500 MHz; CDCl.sub.3): .delta. 1.22-2.14
(10H, m), 4.56 (1H, ddd, J=3.3, 8.7, 11.7 Hz), 4.78 (2H, d, J=6.2
Hz), 5.78 (1H, s), 6.45 (1H, d, J=5.1 Hz), 6.97-7.01 (2H, m),
7.06-7.14 (2H, m), 7.30-7.26 (1H, m), 7.39-7.47 (3H, m), 7.74 (1H,
s), 8.14 (1H, d, J=4.2 Hz); .sup.13C-NMR (126 MHz; CDCl.sub.3):
.delta. 25.4, 25.8, 34.7, 39.5, 55.6, 112.5, 115.3, 115.4, 115.5,
115.7, 124.3, 124.4, 125.1, 126.1, 126.2, 129.2 (d, J.sub.C-F=8.0
Hz), 129.4 (d, J.sub.C-F=2.8 Hz), 130.1 (d, J.sub.C-F=8.1 Hz),
130.8 (d, J.sub.C-F=3.2 Hz), 135.9, 141.7, 158.4, 159.1, 161.1 (d,
J=246 Hz), 162.4 (d, J=247 Hz), 162.5; HRMS (ESI.sup.+) calcd for
C.sub.26H.sub.25F.sub.2N.sub.5 [M+H].sup.+ 446.2156. Found
446.1195.
4-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-fluorobenzyl)pyr-
imidin-2-amine (18; ZH2-122)
[0266] 4-Fluorobenzylamine (79.0 .mu.L, 0.694 mmol) was added to a
solution of 14 (27.8 mg, 0.069 mmol) in THF (5 mL) and the mixture
was stirred at 40.degree. C. for 5 d. The mixture was concentrated
under vacuum and the residue purified by flash chromatography
(EtOAc/pet. spirits 40% to 70%) to give a colourless solid (21.4
mg, 70%). .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 1.22 (3H, m),
1.63 (3H, m), 1.83 (2H, m), 2.12 (2H, m), 4.52 (1H, tt, J=3.3,
11.9, Hz), 4.67 (2H, d, J=6.0 Hz), 5.66 (1H, dd, J=0.7, 1.4 Hz),
6.45 (1H, d, J=5.1 Hz), 7.02 (4H, dt, J=9.0, 18.3, Hz), 7.33 (2H,
dd, J=5.5, 8.2 Hz), 7.45 (2H, dd, J=5.6, 8.4 Hz), 7.76 (1H, s),
8.16 (1H, d, J=4.7 Hz); .sup.13C-NMR (101 MHz; CDCl.sub.3): .delta.
25.4, 25.8, 34.6, 44.8, 55.7, 112.5, 115.3, 115.6 (2C), 115.8,
125.1, 128.9, 129.0 (d, J.sub.C-F=8.1 Hz), 130.1 (d, J.sub.C-F=8.0
Hz), 130.4 (d, J.sub.C-F=3.2 Hz), 134.8 (d, J=3.0 Hz, 1C), 135.8,
141.5, 158.3, 159.0, 162.3 (d, J.sub.C-F=246 Hz), 162.4, 162.5 (d,
J.sub.C-F=247 Hz); HRMS (ESI.sup.+) calcd for
C.sub.26H.sub.26F.sub.2N.sub.5 [M+H].sup.+ 446.2156. Found
446.2147.
4-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4,4-difluorocycloh-
exyl)pyrimidin-2-amine (20; ZH2-146)
[0267] 4,4-Difluorocyclohexan-1-amine (67.0 mg, 0.499 mmol) was
added to a solution of 14 (20.0 mg, 0.050 mmol) in THF (5 mL) and
the mixture was stirred at 40.degree. C. for 3 d. The mixture was
concentrated under vacuum and the residue purified by flash
chromatography (EtOAc/pet. spirits 70% to 100%) to give a pale
orange solid (22.2 mg, 98%). .sup.1H-NMR (500 MHz; CDCl.sub.3):
.delta. 1.27-1.34 (2H, m), 1.63-1.92 (10H, m), 2.12-2.17 (6H, m),
3.96-4.01 (1H, m), 4.48 (1H, tt, J=3.6, 12.0 Hz), 5.21 (1H, s),
6.43 (1H, d, J=5.1 Hz), 6.96-7.01 (2H, m), 7.41-7.45 (2H, m), 7.76
(1H, s), 8.15 (1H, d, J=5.1 Hz); .sup.13C-NMR (126 MHz;
CDCl.sub.3): .delta. 25.4, 26.1, 28.9 (d, J=9.9 Hz), 32.3 (t,
J=24.8 Hz), 34.7, 47.9, 55.6, 112.4, 115.3, 115.5, 120.8, 122.7,
124.6, 125.2, 130.1 (d, J.sub.C-F=8.0 Hz), 130.6 (d, J.sub.C-F=3.3
Hz), 135.9, 141.5, 158.4, 160.0, 161.9. 162.4 (d, J.sub.C-F=247
Hz).
3-((4-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)pyrimidin-2-yl)ami-
no)propan-1-ol (21; ZH2-38)
[0268] 3-Amino-1-propanol (46.0 .mu.L, 0.100 mmol) was added to a
solution of 14 (45.0 mg, 0.600 mmol) in THF (5 mL) and the mixture
was stirred at r.t. for 18 h. The mixture was concentrated under
vacuum and the residue purified by flash chromatography (EtOAc 100%
to EtOAc/MeOH 90%) to give a pale yellow oil (39.0 mg, 99%).
.sup.1H-NMR (500 MHz; CDCl.sub.3): .delta. 1.29-1.39 (2H, m),
1.63-1.83 (8H, m), 2.15-2.17 (2H, m), 3.63 (2H, q, J=6.2 Hz), 3.71
(2H, t, J=5.7 Hz), 4.48-4.55 (1H, m), 5.43 (1H, s), 6.41 (1H, d,
J=5.1 Hz), 6.97-7.01 (2H, m), 7.42-7.46 (2H, m), 7.73 (1H, s), 8.14
(1H, d, J=5.1 Hz); .sup.13C-NMR (126 MHz; CDCl.sub.3): .delta.
25.5, 26.0, 29.9, 33.1, 34.7, 38.1, 55.7, 59.4, 112.0, 115.3,
115.5, 124.9, 130.1 (d, J.sub.C-F=8.0 Hz), 130.7 (d, J.sub.C-F=3.4
Hz), 136.0, 141.9, 158.2, 159.4, 162.4 (d, J.sub.C-F=247 Hz),
163.0; HRMS (ESI.sup.+) calcd for C.sub.22H.sub.27FN.sub.5O
[M+H].sup.+ 396.2200. Found 396.2191.
4-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-cyclopentylpyrimidi-
n-2-amine (22; ZH2-46)
[0269] Cyclopentylamine (110 .mu.L, 1.12 mmol) was added to a
solution of 14 (75.0 mg, 0.187 mmol) in THF (5 mL) and the mixture
was stirred at 40.degree. C. for 4 d. The mixture was concentrated
under vacuum and the residue purified by flash chromatography
(EtOAc/pet. spirits 50% to 70%) to give a colourless solid (75.0
mg, 99%). .sup.1H-NMR (500 MHz; CDCl.sub.3): .delta. 1.23-2.17
(18H, m), 4.32 (1H, q, J=6.8 Hz), 4.61 (1H, s), 5.29 (1H, s), 6.37
(1H, d, J=5.1 Hz), 6.96-6.99 (2H, m), 7.44-7.47 (2H, m), 7.73 (1H,
s), 8.12 (1H, d, J=4.7 Hz); .sup.13C-NMR (126 MHz; CDCl.sub.3):
.delta. 23.6, 25.2, 25.7, 33.4, 34.4, 52.8, 55.2, 111.5, 115.0,
115.1, 125.1, 129.8 (d, J.sub.C-F=8.0 Hz), 130.59 (d, J.sub.C-F=3.1
Hz), 135.5, 141.2, 157.9, 158.8, 162.1, 162.1 (d, J.sub.C-F=247
Hz); HRMS (ESI.sup.+) calcd for C.sub.24H.sub.29FN.sub.5
[M+H].sup.+ 406.2407. Found 406.2403.
4-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(tetrahydro-2H-pyra-
n-4-yl)pyrimidin-2-amine (23; ZH2-54)
[0270] 4-Aminotetrahydropyran (67.0 .mu.L, 0.649 mmol) was added to
a solution of 14 (32.5 mg, 0.081 mmol) in THF (5 mL) and the
mixture was stirred at 40.degree. C. for 6 d. The mixture was
concentrated under vacuum and the residue purified by flash
chromatography (EtOAc/pet. spirits 50% to 100%) to give a
colourless oil (30.9 mg, 91%). .sup.1H-NMR (400 MHz; CDCl.sub.3):
.delta. 1.24-2.19 (14H, m), 3.52 (2H, t, J=11.3 Hz), 4.01-4.15 (3H,
m), 4.51 (1H, ddd, J=3.4, 8.6, 12 Hz), 5.29 (1H, s), 6.42 (1 HM, d,
J=5.1 Hz), 6.99 (2H, t, J=8.7 Hz), 7.44 (2H, dd, J=5.5, 8.6 Hz),
7.76 (1H, s), 8.15 (1H, d, J=5.0 Hz); .sup.13C-NMR (101 MHz;
CDCl.sub.3): .delta. 25.4, 26.1, 33.5, 34.7, 47.4, 55.6, 67.0,
112.2, 115.3, 115.5, 125.2, 130.1 (d, J.sub.C-F=8.1 Hz), 130.6 (d,
J.sub.C-F=3.2 Hz), 135.8, 141.5, 158.4, 159.0, 161.8, 162.4 (d,
J.sub.C-F=248 Hz).
N-Cyclohexyl-4-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)pyrimidin-
-2-amine (24; ZH2-58)
[0271] Cyclohexylamine (75.0 .mu.L, 0.659 mmol) was added to a
solution of 14 (33.0 mg, 0.082 mmol) in THF (5 mL) and the mixture
was stirred at 40.degree. C. for 6 d. The mixture was concentrated
under vacuum and the residue purified by flash chromatography
(EtOAc/pet. spirits 40% to 100%) to give a pale yellow oil (32.7
mg, 95%). .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 1.19-1.43 (6H,
m), 1.60-1.73 (4H, m), 1.73-1.80 (4H, m), 1.87-1.94 (2H, m),
2.05-2.22 (4H, m), 3.82-3.89 (2H, m), 4.54-4.59 (1H, m), 5.25 (1H,
bs, J=0.5 Hz), 6.36 (1H, d, J=5.1 Hz), 6.98 (2H, t, J=8.6 Hz), 7.45
(2H, dd, J=5.5, 8.4 Hz), 7.74 (1H, s), 8.11 (1H, d, J=4.9 Hz);
.sup.13C-NMR (101 MHz; CDCl.sub.3): .delta. 25.1, 25.5, 25.8, 26.0,
33.5, 34.7, 49.9, 55.51, 111.7, 115.2, 115.4, 125.4, 130.1 (d,
J.sub.C-F=8.2 Hz), 130.7 (d, J.sub.C-F=3.1 Hz), 135.8, 141.4,
158.2, 159.0, 161.9, 162.4 (d, J.sub.C-F=247 Hz); HRMS (ESI.sup.+)
calcd for C.sub.25H.sub.31FN.sub.5 [M+H].sup.+ 420.2563. Found
420.2553.
4-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-ethylpyrimidin-2-am-
ine (26; ZH2-78)
[0272] Ethylamine solution (2.0 M in THF) (377 .mu.L, 0.754 mmol)
was added to a solution of 14 (30.2 mg, 0.075 mmol) in THF (5 mL)
and the mixture was stirred at 40.degree. C. for 3 d. The mixture
was concentrated under vacuum and the residue purified by flash
chromatography (EtOAc/pet. spirits 50%) to give a pale yellow solid
(29.1 mg, 98%). .sup.1H-NMR (500 MHz; CDCl.sub.3): .delta.
1.32-2.19 (13H, m), 3.49 (2H, qd, J=7.2, 5.7 Hz), 4.59 (1H, m),
5.25 (1H, t, J=0.6 Hz), 6.39 (1H, d, J=5.1 Hz), 6.96-7.00 (2H, m),
7.46 (2H, ddd, J=2.7, 5.4, 9.3 Hz), 7.73 (1H, s, 1H), 8.13 (1H, d,
J=4.8 Hz); .sup.13C-NMR (126 MHz; CDCl.sub.3): .delta. 15.3, 25.5,
26.0, 34.7, 36.4, 55.6, 111.9, 115.2, 115.4, 125.3, 130.1 (d,
J.sub.C-F=8.0 Hz), 130.8 (d, J.sub.C-F=3.2 Hz), 135.8, 141.5,
158.2, 159.0, 162.4 (d, J.sub.C-F=247 Hz), 162.5; HRMS (ESI.sup.+)
calcd for C.sub.21H.sub.25FN.sub.5 [M+H].sup.+ 366.2094. Found
366.2087.
trans-3-((4-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)pyrimidin-2--
yl)amino)cyclobutan-1-ol (29; ZH3-50)
[0273] trans-3-Amino-cyclobutanol (29.0 mg, 0.328 mmol) was added
to a solution of 14 (26.3 mg, 0.066 mmol) in THF (5 mL) and the
mixture was stirred at r.t. for 5 d. The mixture was concentrated
under vacuum and the residue purified by flash chromatography
(EtOAc/pet. spirits 80% to 10%) to give a pale yellow solid (26.5
mg, 99%). .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 1.21-1.41 (5H,
m), 1.59-1.75 (3H, m), 1.87-1.91 (2H, m), 2.31-2.45 (4H, m),
4.51-4.63 (4H, m), 6.38 (1H, d, J=5.1 Hz), 6.98 (2H, t, J=8.6 Hz),
7.42 (2H, dd, J=5.5, 8.4 Hz), 7.80 (1H, s), 8.07 (1H, d, J=4.5 Hz);
.sup.13C-NMR (126 MHz; CDCl.sub.3): .delta. 25.4, 26.0, 34.6, 40.5,
42.9, 55.9, 65.2, 112.1, 115.5, 115.7, 125.1, 129.9 (d,
J.sub.C-F=2.0 Hz), 130.3 (d, J.sub.C-F=8.1 Hz), 135.9, 157.2,
159.2, 161.4, 162.7 (d, J.sub.C-F=247 Hz).
cis-3-((4-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)pyrimidin-2-yl-
)amino)cyclobutan-1-ol (30; ZH3-62)
[0274] cis-3-Amino-cyclobutanol (20.0 mg, 0.226 mmol) was added to
a solution of 14 (22.7 mg, 0.057 mmol) in THF (4 mL) and the
mixture was stirred at 40.degree. C. for 7 d. The mixture was
concentrated under vacuum and the residue purified by flash
chromatography (EtOAc/pet. spirits 80% to 100%) to give a pale
yellow solid (26.5 mg, 91%). .sup.1H-NMR (400 MHz; CD.sub.3OD):
.delta. 1.29-1.41 (3H, m), 1.76 (3H, m), 1.89-1.96 (4H, m), 2.12
(2H, m), 2.74-2.81 (2H, m), 4.01 (2H, m), 4.58-4.64 (1H, m), 6.36
(1H, d, J=5.1 Hz), 7.06 (2H, t, J=8.6 Hz), 7.39 (2H, dd, J=5.5, 8.4
Hz), 8.01 (1H, s), 8.13 (1H, d, J=4.8 Hz); .sup.13C-NMR (101 MHz;
CD.sub.3OD): .delta. 26.3, 26.9, 35.3, 38.9, 42.1, 57.0, 61.5,
112.6, 116.1, 116.4, 131.3 (d, J.sub.C-F=8.3 Hz), 131.6 (d,
J.sub.C-F=2.7 Hz), 137.4, 159.5, 163.2, 163.8 (d, J.sub.C-F=247
Hz); HRMS (ESI.sup.+) calcd for C.sub.23H.sub.27FN.sub.5O
[M+H].sup.+ 408.2200. Found 408.2187.
4-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,3-difluorocyclob-
utyl)pyrimidin-2-amine (31; ZH3-70)
[0275] 3,3-Difluorocyclobutanamine hydrochloride (67.0 mg, 0.469
mmol) and K.sub.2CO.sub.3 (65.0 mg, 0.469 mmol) was added to a
solution of 14 (47.0 mg, 0.117 mmol) in THF/H.sub.2O (5:1, 6 mL)
and the mixture was stirred at 40.degree. C. for 5 d. The mixture
was concentrated under vacuum and the residue purified by flash
chromatography (EtOAc/pet. spirits 30% to 100%) to give a
colourless solid (32.2 mg, 64%). .sup.1H-NMR (500 MHz; CDCl.sub.3):
.delta. 1.25-1.37 (3H, m), 1.62-1.78 (3H, m), 1.91-1.93 (2H, m),
2.15-2.17 (2H, m), 2.51-2.61 (2H, m), 3.03-3.11 (2H, m), 4.35-4.41
(1H, m), 4.52-4.57 (1H, m), 5.71 (1H, bs), 6.48 (1H, d, J=5.1 Hz),
7.00 (2H, t, J=8.7 Hz), 7.43 (2H, dd, J=5.5, 8.6 Hz), 7.78 (1H, s),
8.16 (1H, d, J=5.0 Hz); .sup.13C-NMR (126 MHz; CDCl.sub.3): .delta.
22.8, 25.4, 26.0, 29.4-29.8 (m), 32.1, 34.7, 36.5-36.7 (m),
43.6-43.9 (m), 55.7, 113.0, 115.4, 115.5, 116.7, 118.9, 118.9,
121.1, 125.0, 130.2 (d, J.sub.C-F=8.0 Hz), 130.5 (d, J.sub.C-F=3.0
Hz), 136.0, 141.8, 158.2, 159.2, 161.8, 162.5 (d, J.sub.C-F=247
Hz); HRMS (ESI.sup.+) calcd for C.sub.23H.sub.25F.sub.3N.sub.5
[M+H].sup.+ 428.2062. Found 428.2056.
4-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-cyclopropylpyrimidi-
n-2-amine (33; ZH3-86)
[0276] Cyclopropyl amine (34.0 mg, 0.599 mmol) was added to a
solution of 14 (24.0 mg, 0.060 mmol) in THF (5 mL) and the mixture
was stirred at 40.degree. C. for 3 d. The mixture was concentrated
under vacuum and the residue purified by flash chromatography
(EtOAc/pet. spirits 50% to 80%) to give a pale yellow solid (11.8
mg, 51%). .sup.1H-NMR (400 MHz; CDCl.sub.3): 50.59-0.63 (2H, m),
0.80-0.90 (2H, m), 1.19-1.41 (3H, m), 1.59-1.75 (3H, m), 1.87-1.90
(2H, m), 2.16-2.19 (2H, t, J=12.0 Hz), 2.82 (1H, qd, J=3.5, 6.5
Hz), 4.67-4.73 (1H, m), 5.58 (1H, d, J=13.9 Hz), 6.45 (1H, d, J=5.1
Hz), 6.99 (2H, t, J=8.6 Hz), 7.41-7.48 (2H, m), 7.78 (1H, s), 8.17
(1H, d, J=3.9 Hz); .sup.13C-NMR (101 MHz; CDCl.sub.3): .delta. 7.7,
24.2, 25.5, 26.0, 34.6, 55.6, 112.5, 115.3, 115.5, 125.3, 130.2 (d,
J.sub.C-F=8.0 Hz), 130.5 (d, J.sub.C-F=2.2 Hz), 135.9, 141.7,
158.0, 159.1, 161.2, 162.5 (d, J.sub.C-F=248 Hz); HRMS (ESI.sup.+)
calcd for C.sub.22H.sub.25FN.sub.5 [M+H].sup.+ 378.2094. Found
378.2086.
4-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(tetrahydro-2H-thio-
pyran-4-yl)pyrimidin-2-amine (37; ZH2-142)
[0277] Tetrahydrothiopyran-4-ylamine (57.0 mg, 0.486 mmol) was
added to a solution of 14 (29.9 mg, 0.075 mmol) in THF (5 mL) and
the mixture was stirred at 40.degree. C. for 3 d. The mixture was
concentrated under vacuum and the residue purified by flash
chromatography (EtOAc/pet. spirits 50% to 70%) to give a pale
yellow solid (27.0 mg, 83%). .sup.1H-NMR (500 MHz; CDCl.sub.3):
.delta. 1.27-1.33 (2H, m), 1.62-1.76 (6H, m), 1.90-1.93 (2H, m),
2.15-2.18 (2H, m), 2.35-2.38 (2H, m), 2.69-2.79 (4H, m), 3.87-3.90
(1H, m), 4.46-4.51 (1H, m), 5.29 (1H, bs), 6.41 (1H, d, J=5.1 Hz),
6.97-7.01 (2H, m), 7.42-7.45 (2H, m), 7.76 (1H, s), 8.14 (1H, d,
J=5.1 Hz); .sup.13C-NMR (126 MHz; CDCl.sub.3): .delta. 25.4, 26.1,
28.0, 34.5, 34.7, 49.3, 55.6, 112.2, 115.3, 115.5, 125.2, 130.1 (d,
J.sub.C-F=8.0 Hz), 130.5 (d, J.sub.C-F=3.2 Hz), 135.8, 141.5,
158.3, 159.1, 161.6, 162.4 (d, J.sub.C-F=248 Hz); HRMS (ESI.sup.+)
calcd for C.sub.24H.sub.29FN.sub.5 [M+H].sup.+ HRMS (ESI.sup.+)
calcd for C.sub.27H.sub.35FN.sub.5 [M+H].sup.+ 438.2128. Found
438.2119.
##STR00143##
4-((4-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)pyrimidin-2-yl)am-
ino)tetrahydro-2H-thiopyran 1,1-dioxide (38; ZH3-134)
[0278] mCPBA (57-86%) (32.0 mg, 0.185 mmol) was added to a mixture
of ZH2-142 (27.0 mg, 0.062 mmol) in CH.sub.2Cl.sub.2 (10 mL) and
the mixture was stirred at r.t. overnight. The mixture was quenched
with aq. NaHCO.sub.3, water, brine, dried (MgSO.sub.4). The residue
was purified by flash chromatography (EtOAc/pet. spirits 50% to
100%) to give the sulfone as a yellow oil (12.0 mg, 41%).
.sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 1.24-1.31 (3H, m),
1.64-1.77 (4H, m), 1.93 (2H, m), 2.14-2.30-2.14 (5H, m), 2.44 (2H,
m), 3.05-3.18 (4H, m), 4.13 (1H, m), 4.39-4.45 (1H, m), 5.40 (1H,
bs), 6.50 (1H, d, J=5.0 Hz), 6.99 (2H, t, J=8.5 Hz), 7.42 (2H, dd,
J=5.6, 8.0 Hz), 7.81 (1H, s), 8.19 (1H, d, J=4.9 Hz); .sup.13C-NMR
(101 MHz; CDCl.sub.3): .delta. 25.3, 26.1, 29.9, 34.7, 47.0, 49.6,
55.8, 112.9, 115.4, 115.6, 130.1 (d, J.sub.C-F=8.0 Hz), 136.0,
158.3, 159.2, 161.5, 162.5 (d, J.sub.C-F=248 Hz); HRMS (ESI.sup.+)
calcd for C.sub.24H.sub.29FN.sub.5O.sub.2S [M+H].sup.+ 470.2026.
Found 470.2014.
##STR00144##
Benzyl 4-formylpyrimidin-2-ylcarbamate hydrochloride (39)
[0279] Aqueous 4 M HCl (2 ml) was added to a solution of dimethyl
acetal (0.133 g, 0.438 mmol) in THF (1 mL). The resulting mixture
was heated to 40.degree. C. overnight and then cooled r.t. The
reaction mixture containing the hydrochloride salt of the aldehyde
was used directly in the next step without isolation.
Benzyl (4-((cyclopentylimino)methyl)pyrimidin-2-yl)carbamate
hydrochloride (40)
[0280] 45% aq. KOH (0.449 g, 8.00 mmol) was added to an ice-cold
solution of crude aldehyde 39 (0.113 g, 0.438 mmol) in aq. HCl (2
ml, 8.00 mmol), while the temperature was maintained below
15.degree. C. To the neutralized solution, CH.sub.2Cl.sub.2 (5 ml)
and K.sub.2CO.sub.3 (0.073 g, 0.523 mmol) were added followed by
cyclopentylamine (87.0 .mu.L, 0.877 mmol). The reaction mixture was
gradually warmed to room temperature and stirring was continued for
18 h. .sup.1H NMR analysis of the reaction mixture showed complete
consumption of the aldehyde. The crude material was used in the
next step without isolation.
Benzyl
(4-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)pyrimidin-2-y-
l)carbamate (41)
[0281] A mixture of
.alpha.-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (0.152 g,
0.526 mmol), 40 (0.142 g, 0.438 mmol) and aq. K.sub.2CO.sub.3 20%
w/v (0.365 mL, 0.526 mmol) in CH.sub.2Cl.sub.2 (10 mL) was stirred
at r.t. for 3 d. The reaction mixture was diluted with
CH.sub.2Cl.sub.2, and washed with water, dried (MgSO.sub.4),
filtered and concentrated. Flash chromatography of the residue
(EtOAc/pet. spirits 20% to 80%) afforded a mixture of inseparable
components (137 mg).
4-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)pyrimidin-2-amine
(42; ZH3-58)
[0282] 20 wt % Pd(OH).sub.2/C (33.0 mg) was added to a solution of
difluorocyclohexyl carbamate (25.0 mg, 0.135 mmol) in THF/MeOH 5:3
(8 mL). The resulting mixture was stirred under an atmosphere of
hydrogen at 200 psi for 2 h. The mixture was filtered through
Celite, concentrated and the residue was purified by flash
chromatography (EtOAc/pet. spirits 80% to 100%) to afford a pale
yellow solid (29.8 mg, 21% over 3 steps). .sup.1H-NMR (500 MHz;
CDCl.sub.3): .delta. 1.69-1.75 (2H, m), 1.82-1.89 (4H, m),
2.11-2.17 (2H, m), 4.98-5.04 (1H, m), 5.20 (2H, s), 6.52 (1H, d,
J=5.1 Hz), 6.98-7.02 (2H, m), 7.44-7.47 (2H, m), 7.81 (1H, s), 8.20
(1H, d, J=5.1 Hz); .sup.13C-NMR (126 MHz; CDCl.sub.3): .delta.
24.1, 33.9, 57.8, 113.2, 115.5, 115.7, 125.6, 129.7 (d,
J.sub.C-F=1.4 Hz), 130.0 (d, J.sub.C-F=8.2 Hz), 135.7, 141.3,
158.3, 159.4, 162.6 (d, J.sub.C-F=248 Hz), 163.0; HRMS (ESI.sup.+)
calcd for C.sub.18H.sub.19FN.sub.5 [M+H].sup.+ 324.1624. Found
324.1620.
Benzyl
(4-(((4,4-difluorocyclohexyl)imino)methyl)pyrimidin-2-yl)carbamate
(43)
[0283] Aqueous KOH 45% w/v (0.449 g, 8.00 mmol) was added to an
ice-cold solution of crude aldehyde 39 (0.116 g, 0.451 mmol) in aq.
HCl (2 ml, 8.00 mmol), while the temperature was maintained below
15.degree. C. To the neutralized solution, CH.sub.2Cl.sub.2 (5 mL)
and K.sub.2CO.sub.3 (0.075 g, 0.541 mmol) were added followed by
difluorocyclohexyl amine (125 .mu.L, 0.901 mmol). The reaction
mixture was gradually warmed to room temperature and stirring was
continued for 18 h. .sup.1H NMR analysis of the reaction mixture
showed complete consumption of the aldehyde. The crude material was
used in the next step without isolation.
Benzyl
(4-(1-(4,4-difluorocyclohexyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-
pyrimidin-2-yl)carbamate (44)
[0284] A mixture of
.alpha.-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (0.156 g,
0.541 mmol), 43 (0.142 g, 0.451 mmol) and aq. K.sub.2CO.sub.3 20%
w/v (0.374 mL, 0.541 mmol) in CH.sub.2Cl.sub.2 (5 mL) was stirred
at r.t. for 2 d. The reaction mixture was diluted with
CH.sub.2Cl.sub.2, and washed with water, dried (MgSO.sub.4),
filtered and concentrated. Flash chromatography of the residue
(EtOAc/pet. spirits 20% to 100%), followed by recrystallization
from Et.sub.2O/pet. spirits afforded the difluorocyclohexyl
carbamate as colourless crystals (30.4 mg, 13%), m.p.
224-231.degree. C. .sup.1H-NMR (500 MHz; CDCl.sub.3): .delta.
1.98-2.20 (8H, m), 5.24 (2H, s), 5.87-5.90 (1H, m), 6.78 (1H, d,
J=5.3 Hz), 7.06-7.09 (2H, m), 7.34-7.48 (7H, m), 7.99 (1H, s), 8.08
(1H, s), 8.29 (1H, d, J=5.3 Hz); .sup.13C-NMR (126 MHz;
CDCl.sub.3): .delta. 30.1, 30.2, 32.7 (m), 53.4, 67.8, 116.1 (m),
124.1, 128.8, 128.9, 130.9 (d, J=8.3 Hz), 135.5, 136.3, 151.4,
157.3, 158., 163.2 (d, J=248 Hz).
4-(1-(4,4-Difluorocyclohexyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)pyrimidi-
n-2-amine (45; ZH3-138)
[0285] 20 wt % Pd(OH).sub.2/C (9.00 mg) was added to a solution of
the difluorocyclohexyl carbamate 44 (25.0 mg, 0.135 mmol) in
THF/MeOH 2:1 (6 mL). The resulting mixture was stirred under an
atmosphere of hydrogen at 200 psi for 3 h. The mixture was filtered
through Celite, concentrated and the residue was purified by flash
chromatography (EtOAc/pet. spirits 50% to 100%) to afford a pale
yellow solid (29.8 mg, 82%). .sup.1H-NMR (500 MHz; CDCl.sub.3):
.delta. 1.80-1.93 (2H, m), 2.00-2.07 (2H, m), 2.20-2.28 (4H, m),
4.68-4.74 (1H, m), 5.34 (2H, bs), 6.48 (1H, d, J=5.2 Hz), 6.99-7.02
(2H, m), 7.41-7.44 (2H, m), 7.78 (1H, s), 8.14 (1H, d, J=5.2 Hz);
.sup.13C-NMR (126 MHz; CDCl.sub.3): .delta. 29.9, 29.9, 32.8-33.2
(m), 53.6, 112.8, 115.4, 115.6, 119.9, 121.8, 123.7, 124.6, 130.0
(d, J.sub.C-F=3.1 Hz), 130.2 (d, J.sub.C-F=8.1 Hz), 135.8, 142.4,
158.1, 159.1, 162.6 (d, J.sub.C-F=248 Hz), 162.8; HRMS (ESI.sup.+)
calcd for C.sub.19H.sub.19F.sub.3N.sub.5 [M+H].sup.+ 374.1593.
Found 374.1587.
Benzyl
(4-((((4,4-difluorocyclohexyl)methyl)imino)methyl)pyrimidin-2-yl)ca-
rbamate (46)
[0286] 45% aq. KOH (0.449 g, 8.00 mmol) was added to an ice-cold
solution of crude aldehyde 39 (0.101 g, 0.393 mmol) in aq. HCl (2
ml, 8.00 mmol), while the temperature was maintained below
15.degree. C. To the neutralized solution, CH.sub.2Cl.sub.2 (5 mL)
and K.sub.2CO.sub.3 (0.119 g, 0.786 mmol) were added followed by
4,4-difluorocyclohexylmethanamine hydrochloride (146 mg, 0.786
mmol). The reaction mixture was gradually warmed to room
temperature and stirring was continued for 18 h. .sup.1H NMR
analysis of the reaction mixture showed complete consumption of the
aldehyde. The crude material was used in the next step without
isolation.
Benzyl
(4-(1-((4,4-difluorocyclohexyl)methyl)-4-(4-fluorophenyl)-1H-imidaz-
ol-5-yl)pyrimidin-2-yl)carbamate (47)
[0287] A mixture of
.alpha.-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (0.137 g,
0.472 mmol), 46 (0.153 g, 0.393 mmol) and aq. 20% K.sub.2CO.sub.3
(0.326 mL, 0.472 mmol) in CH.sub.2Cl.sub.2 (5 mL) was stirred at
r.t. for 4 d. The reaction mixture was diluted with
CH.sub.2Cl.sub.2, and washed with water, dried (MgSO.sub.4),
filtered and concentrated. Flash chromatography of the residue
(EtOAc/pet. spirits 30% to 100%) afforded a mixture of inseparable
components (97.2 mg), which was used in the next step.
4-(1-((4,4-Difluorocyclohexyl)methyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-
pyrimidin-2-amine (48; ZH3-130)
[0288] 20 wt % Pd(OH)2/C (65.0 mg) was added to a solution of the
difluorocyclohexylmethyl carbamate (90.0 mg, 0.173 mmol) in
THF/MeOH 5:3 (8 mL). The resulting mixture was stirred under an
atmosphere of hydrogen at 200 psi for 2 h. The mixture was filtered
through Celite, concentrated and the residue was purified by flash
chromatography (EtOAc/pet. spirits 80% to 100%) to afford a pale
yellow solid (45.3 mg, 30% over 3 steps). 1H-NMR (400 MHz; CD3OD):
.delta. 1.25-1.35 (2H, m), 1.59-1.71 (4H, m), 1.97-1.99 (2H, m),
4.33 (2H, d, J=7.1 Hz), 6.40 (1H, d, J=4.6 Hz), 7.09 (2H, t, J=8.4
Hz), 7.44 (2H, t, J=6.6 Hz), 7.87 (1H, bs), 8.12 (1H, bs); 13C-NMR
(126 MHz; CD3OD): .delta. 27.4, 27.5, 33.6-34.0 (m), 38.0, 52.3,
116.3, 116.5, 124.4, 131.5 (d, J.sub.C-F=8.2 Hz), 159.3, 161.9,
164.0 (d, J.sub.C-F=248 Hz), 164.9; HRMS (ESI.sup.+) calcd for
C.sub.20H.sub.21F.sub.3N.sub.5 [M+H].sup.+ 388.1749. Found
388.1742.
Benzyl (4-((neopentylimino)methyl)pyrimidin-2-yl)carbamate (49)
[0289] 45% aq. KOH (0.449 g, 8.00 mmol) was added to an ice-cold
solution of crude aldehyde 39 (0.155 g, 0.603 mmol) in aq. HCl (2
ml, 8.00 mmol), while the temperature was maintained below
15.degree. C. To the neutralized solution, CH.sub.2Cl.sub.2 (5 mL)
and K.sub.2CO.sub.3 (0.100 g, 0.724 mmol) were added followed by
neopentyl amine (105 mg, 1.21 mmol). The reaction mixture was
gradually warmed to room temperature and stirring was continued for
18 h. .sup.1H NMR analysis of the reaction mixture showed complete
consumption of the aldehyde. The crude material was used in the
next step without isolation.
Benzyl
(4-(4-(4-fluorophenyl)-1-neopentyl-1H-imidazol-5-yl)pyrimidin-2-yl)-
carbamate (50)
[0290] A mixture of
.alpha.-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (0.209 g,
0.724 mmol), 49 (0.197 g, 0.603 mmol) and aq. 20% K.sub.2CO.sub.3
(0.500 mL, 0.724 mmol) in CH.sub.2Cl.sub.2 (5 mL) was stirred at
r.t. for 3 d. The reaction mixture was diluted with
CH.sub.2Cl.sub.2, and washed with water, dried (MgSO.sub.4),
filtered and concentrated. Flash chromatography of the residue
(EtOAc/pet. spirits 30% to 100%) afforded a mixture of inseparable
components (185 mg), which was used in the next step.
4-(4-(4-Fluorophenyl)-1-neopentyl-1H-imidazol-5-yl)pyrimidin-2-amine
(51; ZH3-78)
[0291] 20% wt Pd(OH).sub.2/C (52.0 mg) was added to a solution of
the impure neopentyl carbamate (109 mg) in THF/MeOH 5:1 (6 mL). The
resulting mixture was stirred under an atmosphere of hydrogen at
200 psi for 18 h. The mixture was filtered through Celite,
concentrated and the residue was purified by flash chromatography
(EtOAc/pet. spirits 50% to 100%), followed by recrystallization
from toluene to afford pale yellow crystals (29.3 mg, 15% over 3
steps). .sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 0.78 (9H, s,)
4.22 (2H, s), 5.32 (2H, bs), 6.48 (1H, d, J=5.1 Hz), 6.99 (2H, t,
J=8.6 Hz), 7.45 (2H, dd, J=5.6, 8.4 Hz), 7.58 (1H, s), 8.15 (1H, d,
J=5.1 Hz); .sup.13C-NMR (101 MHz; CDCl.sub.3): .delta. 27.8, 33.3,
53.5, 56.7, 102.4, 108.9, 113.1, 115.3, 115.5, 125.5, 130.2 (d,
J.sub.C-F=8.2 Hz), 130.5 (d, J.sub.C-F=3.2 Hz), 140.5, 141.9,
158.4, 159.2, 159.9, 162.5 (d, J.sub.C-F=248 Hz), 163.1; HRMS
(ESI.sup.+) calcd for C.sub.18H.sub.21FN.sub.5 [M+H].sup.+
326.1781. Found 326.1775.
##STR00145## ##STR00146##
2-(Methylthio)pyrimidine-4-carbaldehyde (1)
[0292] Aqueous 4 M HCl (13 mL) was added to a solution of
4-dimethoxymethyl-2-methylsulfanyl-pyrimidine (2.42 g, 12.1 mmol).
The resulting mixture was heated at 50.degree. C. for 18 h. .sup.1H
NMR analysis indicated conversion to the carbaldehyde so the
mixture was cooled to r.t. The reaction mixture was diluted with
EtOAc and neutralized with 45% KOH solution. The aqueous phase was
extracted with EtOAc, dried with MgSO.sub.4 and concentrated. The
crude material was used in the next step without purification (2.74
g, 87%). .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 2.64 (3H, s),
7.44 (1H, d, J=4.8 Hz), 8.77 (1H, d, J=4.8 Hz), 9.96 (1H, s).
1-(2-(Methylthio)pyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)methanimine
(52)
[0293] 2,2,2-Trifluoroethylamine hydrochloride (1.96 g, 14.5 mmol)
and K.sub.2CO.sub.3 (3.68 g, 26.6 mmol) were added to a solution of
the crude aldehyde (1.87 g, 12.1 mmol) in CH.sub.2Cl.sub.2 (20 mL).
The reaction mixture was stirred at r.t. overnight. .sup.1H NMR
analysis indicated complete consumption of the aldehyde. The
reaction mixture containing the imine was used directly in the next
step without isolation.
4-(4-(4-Fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)-2-(methyl-
thio)pyrimidine (53)
[0294] A mixture of
.alpha.-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (3.33 g, 11.5
mmol), 2 (2.26 g, 9.60 mmol) and 20% aq. K.sub.2CO.sub.3 (8.00 mL,
11.5 mmol) in CH.sub.2Cl.sub.2 (50 mL) was stirred at r.t. for 5
days. The reaction mixture was diluted with CH.sub.2Cl.sub.2, and
washed with water, dried (MgSO.sub.4), filtered and concentrated.
Flash chromatography of the residue (EtOAc/pet. spirits 10% to 50%)
afforded a mixture of inseparable products (3.04 g crude).
4-(4-(4-Fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)-2-(methyl-
sulfonyl)pyrimidine (54)
[0295] mCPBA (57-86%) (4.27 g, 24.7 mmol) was added portionwise to
a mixture of the crude sulfide (3.04 g, 8.24 mmol) in
CH.sub.2Cl.sub.2 (20 mL) and the mixture was stirred at r.t.
overnight. The mixture was quenched with aq. Na.sub.2CO.sub.3,
water, brine, dried with MgSO.sub.4, and concentrated under vacuum.
The residue was purified by flash chromatography (EtOAc/pet.
spirits 50%) and concentrated to afford the sulfone as a yellow
solid (0.438 g, 9% over 4 steps). .sup.1H-NMR (400 MHz;
CDCl.sub.3): .delta. 3.37 (3H, s), 5.41 (2H, q, J=8.4 Hz), 7.13
(2H, t, J=8.5 Hz), 7.32 (1H, d, J=5.4 Hz), 7.49 (2H, dd, J=8.4, 5.4
Hz), 7.87 (1H, s), 8.65 (1H, d, J=5.4 Hz).
N-Ethyl-4-(4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)py-
rimidin-2-amine (55; ZH4-186)
[0296] Ethylamine solution (2.0 M) in THF (115 .mu.L, 0.230 mmol)
was added to a mixture of sulfone (22.5 mg, 0.057 mmol) in THF (5
mL) and the mixture was stirred at 40.degree. C. for 24 h. The
mixture was concentrated under vacuum and the compound purified by
flash chromatography (EtOAc/pet. spirits 30% to 50%) to afford a
pale yellow solid (15.0 mg, 72%). .sup.1H-NMR (400 MHz;
CDCl.sub.3): .delta. 1.28 (3H, t, J=7.2 Hz), 3.48 (2H, m), 5.22
(2H, d, J=8.3 Hz), 6.40 (1H, d, J=5.1 Hz), 7.04 (2H, t, J=8.7 Hz),
7.49 (2H, dd, J=5.5, 8.6 Hz), 7.70 (1H, s), 8.13 (1H, d, J=4.9 Hz);
.sup.13C-NMR (101 MHz; CDCl.sub.3): .delta. 15.1, 36.5, 46.7 (q,
J.sub.C-F=35.4 Hz), 111.0, 115.5, 115.7, 121.8, 124.5, 125.1, 130.1
(d, J.sub.C-F=3.0 Hz), 130.5 (d, J.sub.C-F=8.2 Hz), 140.1, 143.2,
157.6, 158.7, 162.3, 162.8 (d, J.sub.C-F=248 Hz). HRMS (ESI.sup.+)
calcd for C.sub.17H.sub.16F.sub.4N.sub.5 (M+H) 366.1342. Found
366.1337.
2-((4-(4-(4-Fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)pyrimi-
din-2-yl)amino)ethan-1-ol (56; ZH5-38)
[0297] Ethanolamine (8.00 .mu.L, 0.130 mmol) was added to a mixture
of sulfone (13.0 mg, 0.032 mmol) in THF (5 mL) and the mixture was
stirred at r.t. for 48 h. The mixture was concentrated under vacuum
and the compound purified by flash chromatography (EtOAc/pet.
spirits 50% to 100%) to afford an oil (8.10 mg, 66%). .sup.1H-NMR
(400 MHz; CDCl.sub.3): .delta. 3.66 (2H, q, J=5.1 Hz), 3.88 (2H, t,
J=4.9 Hz), 5.20 (2H, q, J=8.5 Hz), 6.46 (1H, d, J=5.3 Hz), 7.05
(2H, t, J=8.6 Hz), 7.48 (2H, dd, J=5.5, 8.4 Hz), 7.74 (1H, s), 8.08
(1H, s). HRMS (ESI.sup.+) calcd for C.sub.17H.sub.16F.sub.4N.sub.5O
(M+H) 382.1291. Found 382.1284.
3-((4-(4-(4-Fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)pyrimi-
din-2-yl)amino)propan-1-ol (57; ZH5-6)
[0298] 3-Amino-1-propanol (18.0 .mu.L, 0.237 mmol) was added to a
mixture of sulfone (23.7 mg, 0.059 mmol) in THF (5 mL) and the
mixture was stirred at 40.degree. C. for 48 h. The mixture was
concentrated under vacuum and the compound purified by flash
chromatography (EtOAc/pet. spirits 20% to 100%) to afford a pale
yellow oil (15.3 mg, 66%). .sup.1H-NMR (500 MHz; CDCl.sub.3):
.delta. 1.81-1.86 (2H, m), 3.62 (2H, q, J=6.2 Hz), 3.73 (2H, t,
J=5.5 Hz), 5.17 (2H, q, J=8.5 Hz), 5.50 (1H, s), 6.41 (1H, d, J=5.2
Hz), 7.02-7.06 (2H, m), 7.46-7.50 (2H, m), 7.70 (1H, s), 8.12 (1H,
d, J=5.2 Hz); .sup.13C-NMR (126 MHz; CDCl.sub.3): .delta. 32.8,
38.4, 46.8 (q, J.sub.C-F=35.4 Hz), 59.5, 107.9, 111.2, 115.6,
115.8, 119.8, 122.0, 124.2, 124.9, 126.5, 130.0 (d, J.sub.C-F=3.3
Hz), 130.5 (d, J.sub.C-F=8.0 Hz), 140.3, 143.4, 158.0, 158.4,
162.7, 162.8 (d, J.sub.C-F=248 Hz). HRMS (ESI.sup.+) calcd for
C.sub.18H.sub.18F.sub.4N.sub.5O (M+H) 396.1447. Found 396.1443.
N-Cyclopropyl-4-(4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-5-
-yl)pyrimidin-2-amine (58; ZH4-154)
[0299] Cyclopropylamine (14.0 .mu.L, 0.252 mmol) was added to a
mixture of sulfone (25.2 mg, 0.063 mmol) in THF (5 mL) and the
mixture was stirred at 50.degree. C. for 48 h. The mixture was
concentrated under vacuum and the compound purified by flash
chromatography (EtOAc/pet. spirits 30% to 40%) to afford a pale
yellow solid (18.8 mg, 79%). .sup.1H-NMR (400 MHz; CDCl.sub.3):
.delta. 0.58-0.62 (2H, m), 0.79-0.87 (2H, m), 2.78 (1H, m),
5.34-5.42 (2H, m), 5.57-5.62 (1H, m), 6.46 (1H, d, J=5.1 Hz), 7.05
(2H, t, J=8.7 Hz), 7.47-7.52 (2H, m), 7.71 (1H, s), 8.13 (1H, d,
J=4.8 Hz); .sup.13C-NMR (101 MHz; CDCl.sub.3): .delta. 7.47, 24.1,
46.8 (q, J.sub.C-F=35.2 Hz), 111.2, 115.6, 115.8, 121.9, 122.1,
124.6, 124.9, 130.2 (d, J.sub.C-F=3.2 Hz), 130.7 (d, J.sub.C-F=8.3
Hz), 140.5, 143.7, 157.7, 158.4, 162.9 (d, J.sub.C-F=248 Hz),
163.2. HRMS (ESI.sup.+) calcd for C.sub.18H.sub.16F.sub.4N.sub.5
(M+H) 378.1342. Found 378.1336.
N-Cyclobutyl-4-(4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-5--
yl)pyrimidin-2-amine (59; ZH4-174)
[0300] Cyclobutylamine (20.0 .mu.L, 0.236 mmol) was added to a
mixture of sulfone (23.6 mg, 0.059 mmol) in THF (5 mL) and the
mixture was stirred at 40.degree. C. for 72 h. The mixture was
concentrated under vacuum and the compound purified by flash
chromatography (EtOAc/pet. spirits 20% to 60%) to afford a pale
yellow solid (17.3 mg, 75%). .sup.1H-NMR (400 MHz; CDCl.sub.3):
.delta. 1.76-1.88 (2H, m), 1.94-2.11 (2H, m), 2.43-2.49 (2H, m),
4.47 (1H, q, J=7.8 Hz), 5.23-5.25 (2H, m), 5.59 (1H, s), 6.43 (1H,
d, J=5.1 Hz), 7.06 (2H, t, J=8.6 Hz), 7.51 (2H, dd, J=5.5, 8.5 Hz),
7.73 (1H, s), 8.13 (1H, d, J=4.6 Hz); .sup.13C-NMR (101 MHz;
CDCl.sub.3): .delta. 15.3, 31.6, 47.2-46.2, 111.1, 115.6, 115.8,
121.8, 124.5, 125.0, 130.1 (d, J.sub.C-F=3.5 Hz), 130.6 (d,
J.sub.C-F=8.3 Hz), 140.2, 143.5, 157.9, 158.2, 161.1, 162.8 (d,
J.sub.C-F=248 Hz). HRMS (ESI.sup.+) calcd for
C.sub.19H.sub.18F.sub.4N.sub.5 (M+H) 392.1498. Found 392.1493.
Cis-3-((4-(4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)py-
rimidin-2-yl)amino)cyclobutan-1-ol (60; ZH5-30)
[0301] Cis-3-amincyclobutanol (17.0 .mu.L, 0.190 mmol) was added to
a mixture of sulfone (19.1 mg, 0.047 mmol) in THF (5 mL) and the
mixture was stirred at 40.degree. C. for 72 h. The mixture was
concentrated under vacuum and the compound purified by flash
chromatography (EtOAc/pet. spirits 50% to 100%) to afford a pale
yellow oil (15.8 mg, 83%). .sup.1H-NMR (500 MHz; CDCl.sub.3):
.delta. 1.90-1.95 (2H, m), 2.87-2.93 (2H, m), 3.99-4.04 (1H, m),
4.15 (1H, quintet, J=7.1 Hz), 5.16-5.19 (2H, m), 5.38 (1H, s), 6.42
(1H, d, J=5.1 Hz), 7.02-7.05 (2H, m), 7.48 (2H, td, J=2.7, 6.0 Hz),
7.70 (1H, s), 8.13 (1H, d, J=5.1 Hz); .sup.13C-NMR (126 MHz;
CDCl.sub.3): .delta. 38.0, 42.1, 46.7 (q, J.sub.C-F=35.4 Hz), 61.3,
111.5), 115.6, 115.8, 119.8, 122.0, 124.2, 125.0, 126.5, 130.0 (d,
J.sub.C-F=3.2 Hz), 130.5 (d, J.sub.C-F=8.2 Hz), 140.1, 143.3,
157.7, 158.7, 161.5, 162.8 (d, J.sub.C-F=248 Hz). HRMS (ESI.sup.+)
calcd for C.sub.19H.sub.18F.sub.4N.sub.5O (M+H) 408.1447. Found
408.1442.
Trans-3-((4-(4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)-
pyrimidin-2-yl)amino)cyclobutan-1-ol (61; ZH5-34)
[0302] Trans-3-amincyclobutanol (19.0 .mu.L, 0.214 mmol) was added
to a mixture of sulfone (21.4 mg, 0.053 mmol) in THF (5 mL) and the
mixture was stirred at 40.degree. C. for 72 h. The mixture was
concentrated under vacuum and the compound purified by flash
chromatography (EtOAc/pet. spirits 50% to 100%) to afford a pale
yellow oil (4.1 mg, 20%). .sup.1H-NMR (500 MHz; CDCl.sub.3):
.delta. 2.32-2.36 (2H, m), 2.43-2.48 (2H, m), 4.51 (1H, m), 4.62
(1H, m)), 5.23 (2H, m), 5.40 (1H, bs), 6.44 (1H, d, J=5.1 Hz), 7.04
(2H, t, J=8.8 Hz), 7.47-7.50 (2H, m), 7.70 (1H, s), 8.13 (1H, dd,
J=4.8 Hz); .sup.13C-NMR (126 MHz; CDCl.sub.3): .delta. 40.5, 42.7,
46.7 (q, J.sub.C-F=35.3 Hz), 65.3, 111.5, 115.6, 115.8, 122.0,
124.3, 125.0, 130.1 (d, J.sub.C-F=2.9 Hz), 130.6 (d, J.sub.C-F=8.2
Hz), 140.3, 143.5, 157.7, 158.6, 161.7, 162.9 (d, J.sub.C-F=248
Hz). HRMS (ESI.sup.+) calcd for C.sub.19H.sub.18F.sub.4N.sub.5O
(M+H) 408.1447. Found 408.1436.
N-(3,3-Difluorocyclobutyl)-4-(4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)--
1H-imidazol-5-yl)pyrimidin-2-amine (62; ZH5-10)
[0303] 3,3-Difluorocyclobutanamine hydrochloride (30.0 mg, 0.206
mmol) was added to a mixture of sulfone (20.6 mg, 0.051 mmol) and
aq. 20% K.sub.2CO.sub.3 (140 .mu.L, 0.206 mmol) in THF (5 mL) and
the mixture was stirred at r.t. for 48 h. The mixture was
concentrated under vacuum and the compound purified by flash
chromatography (EtOAc/pet. spirits 20% to 40%) to afford a pale
yellow solid (11.2 mg, 51%). .sup.1H-NMR (400 MHz; CDCl.sub.3):
.delta. 2.51-2.64 (2H, m), 3.09 (2H, m), 4.33-4.37 (1H, m), 5.18
(2H, q, J=8.5 Hz), 6.49 (1H, d, J=5.2 Hz), 7.04 (2H, t, J=8.6 Hz),
7.48 (2H, dd, J=5.5, 8.6 Hz), 7.73 (1H, s), 8.14 (1H, d, J=5.1 Hz).
HRMS (ESI.sup.+) calcd for C.sub.19H.sub.16F.sub.6N.sub.5 (M+H)
428.1310. Found 428.1305.
N-Cyclopentyl-4-(4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-5-
-yl)pyrimidin-2-amine (63; ZH5-2)
[0304] Cyclopentylamine (24.0 .mu.L, 0.242 mmol) was added to a
mixture of sulfone (24.2 mg, 0.060 mmol) in THF (5 mL) and the
mixture was stirred at r.t. for 48 h. The mixture was concentrated
under vacuum and the compound purified by flash chromatography
(EtOAc/pet. spirits 10% to 50%) to afford an oil (17.7 mg, 73%).
.sup.1H-NMR (400 MHz; CDCl.sub.3): .delta. 1.49-1.81 (8H, m), 2.06
(2H, m), 4.28 (1H, dq, J=6.6, 13 Hz), 5.23 (3H, m), 6.39 (1H, d,
J=5.1 Hz), 7.04 (2H, t, J=8.7 Hz), 7.50 (2H, dd, J=8.6, 5.5 Hz),
7.70 (1H, s), 8.12 (1H, d, J=4.9 Hz); .sup.13C-NMR (101 MHz;
CDCl.sub.3): .delta. 23.9, 33.6, 46.7 (q, J.sub.C-F=35.4 Hz), 53.1,
110.9, 115.5, 115.7, 119.0, 121.8, 124.6, 125.1, 127.3, 130.2 (d,
J.sub.C-F=3.2 Hz), 130.5 (d, J.sub.C-F=8.2 Hz), 140.1, 143.2,
157.6, 158.7, 162.0, 162.8 (d, J.sub.C-F=248 Hz). HRMS (ESI.sup.+)
calcd for C.sub.20H.sub.19F.sub.4N.sub.5 (M+H) 406.1655. Found
406.1651.
4-(4-(4-Fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)-N-(tetrah-
ydro-2H-pyran-4-yl)pyrimidin-2-amine (64; ZH5-14)
[0305] 4-Aminotetrahydropyran (17 mg, 0.170 mmol) was added to a
mixture of sulfone (17.8 mg, 0.042 mmol) in THF (5 mL) and the
mixture was stirred at 40.degree. C. for 48 h. The mixture was
concentrated under vacuum and the compound purified by flash
chromatography (EtOAc/pet. spirits 50% to 70%) to afford a pale
yellow oil (13.1 mg, 74%). .sup.1H-NMR (400 MHz; CDCl.sub.3):
.delta. 1.59-1.67 (2H, m), 2.04 (2H, d, J=11.0 Hz), 3.51-3.57 (2H,
m), 4.04 (3H, m), 5.16 (3H, dt, J=7.6, 16.1 Hz), 6.43 (1H, d, J=5.1
Hz), 7.04 (2H, t, J=8.7 Hz), 7.49 (2H, dd, J=5.5, 8.6 Hz), 7.71
(1H, s), 8.14 (1H, d, J=5.1 Hz); .sup.13C-NMR (101 MHz;
CDCl.sub.3): .delta. 33.5, 46.7 (q, J.sub.C-F=35.4 Hz), 47.5, 66.9,
111.4, 115.6, 115.8, 121.8, 124.5, 125.0, 127.3, 130.1 (d,
J.sub.C-F=3.5 Hz), 130.5 (d, J.sub.C-F=8.0 Hz), 140.1, 143.4,
156.2, 157.7, 158.8, 162.5 (d, J.sub.C-F=248 Hz). HRMS (ESI.sup.+)
calcd for C.sub.20H.sub.20F.sub.4N.sub.5O (M+H) 422.1604. Found
422.1600.
N-(4,4-Difluorocyclohexyl)-4-(4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)--
1H-imidazol-5-yl)pyrimidin-2-amine (65; ZH4-170)
[0306] 4,4-Difluorocyclohexanamine (40.0 .mu.L, 0.301 mmol) was
added to a mixture of sulfone (30.0 mg, 0.075 mmol) in THF (5 mL)
and the mixture was stirred at 40.degree. C. for 48 h. The mixture
was concentrated under vacuum and the compound purified by flash
chromatography (EtOAc/pet. spirits 20% to 50%) to afford a pale
yellow solid (27.4 mg, 80%). .sup.1H-NMR (400 MHz; CDCl.sub.3):
.delta. 1.63-1.71 (2H, m), 1.83-1.99 (2H, m), 2.15 (4H, m),
3.94-4.01 (1H, m), 5.16 (3H, m, J=8.5 Hz), 6.44 (1H, d, J=5.1 Hz),
7.04 (2H, t, J=8.6 Hz), 7.49 (2H, dd, J=5.5, 8.5 Hz), 7.71 (1H, s),
8.14 (1H, d, J=5.1 Hz); .sup.13C-NMR (101 MHz; CDCl.sub.3): .delta.
28.9 (d, J.sub.C-F=9.9 Hz), 32.3 (t, J.sub.C-F=24.9 Hz), 46.7 (q,
J.sub.C-F=35.3 Hz), 48.0, 111.5, 115.6, 115.8, 116.3, 116.5, 120.3,
121.8, 122.7, 124.5, 125.0, 125.1, 130.1 (d, J.sub.C-F=3.2 Hz),
130.5 (d, J.sub.C-F=8.1 Hz), 140.2, 143.4, 157.8, 158.7, 161.7,
162.8 (d, J.sub.C-F=248 Hz). HRMS (ESI.sup.+) calcd for
C.sub.21H.sub.20F.sub.6N.sub.5 (M+H) 456.1623 Found 456.1619.
N-(2-Fluorobenzyl)-4-(4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imida-
zol-5-yl)pyrimidin-2-amine (66; ZH4-146)
[0307] 2-Fluorobenzylamine (28.0 .mu.L, 0.247 mmol) was added to a
mixture of sulfone (24.7 mg, 0.062 mmol) in THF (5 mL) and the
mixture was stirred at 40.degree. C. for 48 h. The mixture was
concentrated under vacuum and the compound purified by flash
chromatography (EtOAc/pet. spirits 10% to 80%) to afford a pale
yellow oil (24.7 mg, 89%). .sup.1H-NMR (400 MHz; CDCl.sub.3):
.delta. 4.74 (2H, d, J=6.1 Hz), 4.96 (2H, bs), 5.69 (1H, bs), 6.46
(1H, d, J=5.1 Hz), 7.01-7.14 (4H, m), 7.26-7.29 (1H, m), 7.38 (1H,
t, J=7.3 Hz), 7.46-7.50 (2H, m), 7.66 (1H, s), 8.17 (1H, d, J=5.1
Hz). HRMS (ESI.sup.+) calcd for C.sub.22H.sub.17F.sub.5N.sub.5
(M+H) 446.1404. Found 446.1401.
N-(4-Fluorobenzyl)-4-(4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-imida-
zol-5-yl)pyrimidin-2-amine (67; ZH4-150)
[0308] 4-Fluorobenzylamine (28.0 .mu.L, 0.244 mmol) was added to a
mixture of sulfone (24.4 mg, 0.061 mmol) in THF (5 mL) and the
mixture was stirred at 40.degree. C. for 48 h. The mixture was
concentrated under vacuum and the compound purified by flash
chromatography (EtOAc/pet. spirits 30% to 80%) to afford a pale
yellow oil (24.4 mg, 90%). .sup.1H-NMR (400 MHz; CDCl.sub.3):
.delta. 4.64 (2H, d, J=5.9 Hz), 4.87 (2H, s), 5.76 (1H, s), 6.46
(1H, d, J=5.1 Hz), 7.04 (4H, m), 7.33 (2H, dd, J=5.4, 8.2 Hz), 7.48
(2H, dd, J=5.5, 8.5 Hz), 7.64 (1H, s), 8.16 (1H, d, J=5.0 Hz);
.sup.13C-NMR (101 MHz; CDCl.sub.3): .delta. 44.9, 46.4 (q,
J.sub.C-F=35.9 Hz), 111.8, 115.5, 115.7, 115.8, 115.9, 121.6,
124.4, 125.0, 128.6, 130.0 (d, J.sub.C-F=3.2 Hz), 130.5 (d,
J.sub.C-F=8.0 Hz), 134.8 (d, J.sub.C-F=3.2 Hz), 140.2, 143.3,
157.8, 158.8, 161.0, 162.2, 162.3 (d, J.sub.C-F=247 Hz), 162.8 (d,
J.sub.C-F=249 Hz). HRMS (ESI.sup.+) calcd for
C.sub.22H.sub.17F.sub.5N.sub.5 (M+H) 446.1404. Found 446.1397.
[0309] Other compounds described herein may be prepared by methods
similar to those described above.
[0310] Also described herein are the following embodiments:
1. A compound of formula (I) or a salt, solvate, N-oxide, tautomer,
stereoisomer, polymorph and/or prodrug thereof:
##STR00147##
wherein: R.sub.1 and R.sub.2 are each independently selected from
the group consisting of H, C.sub.1-6alkyl, C.sub.1alkylC.sub.6aryl,
C.sub.3-6cycloalkyl and C.sub.3-5heterocyclyl; R.sub.3 is selected
from the group consisting of F, Cl and CH.sub.3; R.sub.4 is
selected from the group consisting of
C.sub.0-3alkylC.sub.3-12cycloalkyl and C.sub.1-12alkyl; wherein
each of R.sub.1, R.sub.2, R.sub.3 and R.sub.4 is optionally
substituted. 2. A compound according to embodiment 1, wherein the
compound is not selected from the list of compounds in FIG. 1. 3. A
compound according to any one of the preceding embodiments, wherein
R.sub.1 is C.sub.1-3alkyl. 4. A compound according to embodiment 3,
wherein R.sub.1 is substituted. 5. A compound according to
embodiment 4, wherein the substituent is selected from one or more
hydroxyl groups. 6. A compound according to embodiment 1, wherein
R.sub.1 is C.sub.3-6cycloalkyl. 7. A compound according to
embodiment 6, wherein R.sub.1 is selected from cyclobutyl,
cyclopentyl and cyclohexyl. 8. A compound according to embodiment 6
or embodiment 7, wherein R.sub.1 is substituted. 9. A compound
according to embodiment 8, wherein the substituent is selected from
one or more OH groups and/or one or more halo groups. 10. A
compound according to embodiment 1, wherein R.sub.1 is
C.sub.3-6heterocyclyl. 11. A compound according to any one of
embodiments 1 to 9, wherein R.sub.1 is C.sub.1alkylC.sub.6aryl. 12.
A compound according to embodiment 11, wherein the C.sub.1alkyl
group is substituted. 13. A compound according to embodiment 12,
wherein the substituent is selected from one or more alkyl groups,
one or more hydroxyl groups and/or one or more halo groups. 14. A
compound according to any one of embodiments 11 to 13, wherein the
C.sub.6aryl group is substituted. 15. A compound according to
embodiment 14, wherein the substituent is selected from one or more
alkyl groups, one or more hydroxyl groups and/or one or more halo
groups. 16. A compound according to any one of the preceding
embodiments, wherein R.sub.2 is H. 17. A compound according to
embodiment 1, wherein R.sub.1 and R.sub.2 are both the same. 18. A
compound according to any one of the preceding embodiments, wherein
R.sub.3 is CH.sub.3. 19. A compound according to any one of
embodiments 1 to 17, wherein R.sub.3 is F or C.sub.1. 20. A
compound according to any one of the preceding embodiments, wherein
R.sub.4 is C.sub.0-3alkylC.sub.3-12cycloalkyl. 21. A compound
according to embodiment 20, wherein R.sub.4 is
C.sub.1-2alkylC.sub.3-12cycloalkyl. 22. A compound according to
embodiment 20, wherein R.sub.4 is C.sub.3-12cycloalkyl. 23. A
compound according to any one of embodiments 20 to 22, wherein the
C.sub.3-12cycloalkyl group is selected from cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. 24. A compound
according to any one of embodiments 20 to 23, wherein R.sub.4 is
substituted on the C.sub.1-3alkyl group. 25. A compound according
to any one of embodiments 20 to 24, wherein R.sub.4 is substituted
on the C.sub.3-12cycloalkyl group. 26. A compound according to
embodiment 24 or embodiment 25, wherein the substituent is selected
from one or more C.sub.1-6alkyl groups, one or more OH groups and
one or more halo groups. 27. A compound according to any one of
embodiments 1 to 19, wherein R.sub.4 is C.sub.1-12alkyl. 28. A
compound according to embodiment 27, wherein R.sub.4 is a methyl,
ethyl, propyl or butyl group. 29. A compound according to
embodiment 27, wherein R.sub.4 is a branched alkyl group. 30. A
compound according to any one of embodiments 27 to 29, wherein
R.sub.4 is substituted. 31. A compound according to embodiment 30,
wherein by the substituent is selected from one or more OH groups
and/or one or more halo groups. 32. A compound according to any one
of the preceding embodiments, wherein R.sub.1, R.sub.2, R.sub.3 and
R.sub.4 are optionally substituted by one or more groups selected
from OH, C.sub.1-6alkoxy, halo, amino, mercapto and C.sub.1-6alkyl.
33. A method of treating or preventing a respiratory disease in a
subject in need thereof, the method comprising administering to the
subject a therapeutically effective amount of a compound of formula
(I) according to any one of embodiments 1 to 32, thereby treating
or preventing a respiratory disease in a subject. 34. A compound of
formula (I) according to any one of embodiments 1 to 32 for use in
the treatment or prevention of a respiratory disease in a subject.
35. A composition comprising a compound of formula (I) according to
any one of embodiments 1 to 32, and a pharmaceutically acceptable
excipient. 36. Use of a compound according to any one of
embodiments 1 to 32, or a composition according to embodiment 35,
in the preparation of a medicament for the treatment or prevention
of a respiratory disease in a subject.
* * * * *