U.S. patent application number 16/217190 was filed with the patent office on 2019-06-20 for imidazo[4,5-c]quinolin-2-one compounds and their use in treating cancer.
The applicant listed for this patent is AstraZeneca AB. Invention is credited to Bernard Christophe BARLAAM, Kurt Gordon PIKE.
Application Number | 20190185468 16/217190 |
Document ID | / |
Family ID | 53264681 |
Filed Date | 2019-06-20 |
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United States Patent
Application |
20190185468 |
Kind Code |
A1 |
BARLAAM; Bernard Christophe ;
et al. |
June 20, 2019 |
Imidazo[4,5-c]quinolin-2-one Compounds and Their Use in Treating
Cancer
Abstract
The specification generally relates to compounds of Formula (I):
##STR00001## and pharmaceutically acceptable salts thereof, where
Q, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have any of the
meanings defined herein. The specification also relates to the use
of such compounds and salts thereof to treat or prevent ATM kinase
mediated disease, including cancer. The specification further
relates to crystalline forms of compounds of
imidazo[4,5-c]quinolin-2-one compounds and pharmaceutically
acceptable salts thereof; pharmaceutical compositions comprising
such compounds and salts; kits comprising such compounds and salts;
methods of manufacture of such compounds and salts; intermediates
useful in the manufacture of such compounds and salts; and to
methods of treating ATM kinase mediated disease, including cancer,
using such compounds and salts.
Inventors: |
BARLAAM; Bernard Christophe;
(Cambridge, GB) ; PIKE; Kurt Gordon; (Cambridge,
GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AstraZeneca AB |
Sodertalje |
|
SE |
|
|
Family ID: |
53264681 |
Appl. No.: |
16/217190 |
Filed: |
December 12, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15785974 |
Oct 17, 2017 |
10189834 |
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16217190 |
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15217079 |
Jul 22, 2016 |
9822111 |
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15785974 |
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14704031 |
May 5, 2015 |
9428503 |
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15217079 |
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61990232 |
May 8, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 471/04 20130101;
A61K 31/4545 20130101; A61K 31/502 20130101; A61K 31/4745 20130101;
A61P 35/00 20180101; A61P 43/00 20180101; A61K 45/06 20130101; A61K
31/444 20130101 |
International
Class: |
C07D 471/04 20060101
C07D471/04; A61K 31/502 20060101 A61K031/502; A61K 31/4745 20060101
A61K031/4745; A61K 31/444 20060101 A61K031/444; A61K 45/06 20060101
A61K045/06; A61K 31/4545 20060101 A61K031/4545 |
Claims
1-15. (canceled)
16. A method for treating cancer in a warm-blooded animal in need
of such treatment, which comprises administering to said
warm-blooded animal a therapeutically effective amount of a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof, ##STR00202## where: Q is a cyclobutyl or cyclopentyl ring,
each of which is optionally substituted by one hydroxy or methoxy
group, or Q is an oxetanyl, tetrahydrofuranyl or oxanyl ring, each
of which is optionally substituted by one methyl group; R.sup.1 is
methyl; R.sup.2 is hydrogen or methyl; or R.sup.1 and R.sup.2
together form an azetidinyl, pyrrolidinyl or piperidinyl ring;
R.sup.3 is hydrogen or fluoro; R.sup.4 is hydrogen or methyl; and
R.sup.5 is hydrogen or fluoro.
17. The method according to claim 16, wherein said cancer is
selected form the group consisting of gastric cancer, diffuse large
B-cell lymphoma, chronic lymphocytic leukaemia, acute myeloid
leukaemia, head and neck squamous cell carcinoma, hepatocellular
carcinoma, small cell lung cancer and non-small cell lung
cancer.
18. The method according to claim 16, where Q is cyclobutyl,
1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl,
3-methoxycyclopent-1-yl, oxetan-3-yl, tetrahydrofuran-3-yl,
oxan-3-yl, oxan-4-yl or 4-methyloxan-4-yl.
19. The method according to claim 16, where Q is
1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl or oxan-4-yl.
20. The method according to claim 16, where R.sup.1 is methyl and
R.sup.2 is hydrogen or methyl.
21. The method according to claim 16, where R.sup.3 and R.sup.5 are
both hydrogen.
22. The method according to claim 16, where R.sup.4 is methyl.
23. The method according to claim 16 where: Q is
1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl,
3-methoxycyclopent-1-yl, oxetan-3-yl, oxan-3-yl, oxan-4-yl or
4-methyloxan-4-yl; R.sup.1 is methyl; R.sup.2 is hydrogen or
methyl; or R.sup.1 and R.sup.2 together form an azetidinyl,
pyrrolidinyl or piperidinyl ring; R.sup.3 is hydrogen or fluoro;
R.sup.4 is hydrogen or methyl; and R.sup.5 is hydrogen or
fluoro.
24. The method according to claim 16, wherein the compound of
Formula (I) is
8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imida-
zo[5,4-c]quinolin-2-one.
25. The method according to claim 16, wherein the compound of
Formula (I) is a pharmaceutically acceptable salt of
8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[-
5,4-c]quinolin-2-one.
26. The method according to claim 16, where the compound of Formula
(I), or a pharmaceutically acceptable salt thereof, is administered
in combination with radiotherapy.
27. The method according to claim 16, where the compound of Formula
(I), or a pharmaceutically acceptable salt thereof, is administered
in combination with at least one additional anti-tumour substance
selected from the group consisting of cisplatin, oxaliplatin,
carboplatin, valrubicin, idarubicin, doxorubicin, pirarubicin,
irinotecan, topotecan, amrubicin, epirubicin, etoposide, mitomycin,
bendamustine, chlorambucil, cyclophosphamide, ifosfamide,
carmustine, melphalan, bleomycin, olaparib, MEDI4736, AZD1775 and
AZD6738.
28. A compound of Formula (IV), or a salt thereof, ##STR00203##
where: Q is a cyclobutyl or cyclopentyl ring, each of which is
optionally substituted by one hydroxy or methoxy group, or Q is an
oxetanyl, tetrahydrofuranyl or oxanyl ring, each of which is
optionally substituted by one methyl group; R.sup.4 is hydrogen or
methyl; R.sup.5 is hydrogen or fluoro; and X.sup.1 is a leaving
group.
29. The compound of Formula (IV), or a salt thereof as claimed in
claim 28, wherein X.sup.1 is an iodine, bromine, or chlorine atom
or a triflate group.
30. The compound of Formula (IV), or a salt thereof as claimed in
claim 28, where the compound is
8-bromo-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one.
Description
FIELD OF INVENTION
[0001] The specification generally relates to substituted
imidazo[4,5-c]quinolin-2-one compounds and pharmaceutically
acceptable salts thereof. These compounds and their
pharmaceutically acceptable salts selectively modulate ataxia
telangiectasia mutated ("ATM") kinase, and the specification
therefore also relates to the use of such compounds and salts
thereof to treat or prevent ATM kinase mediated disease, including
cancer. The specification further relates to crystalline forms of
compounds of substituted imidazo[4,5-c]quinolin-2-one compounds and
pharmaceutically acceptable salts thereof; pharmaceutical
compositions comprising such compounds and salts; kits comprising
such compounds and salts; methods of manufacture of such compounds
and salts; intermediates useful in the manufacture of such
compounds and salts; and to methods of treating ATM kinase mediated
disease, including cancer, using such compounds and salts.
BACKGROUND
[0002] ATM kinase is a serine threonine kinase originally
identified as the product of the gene mutated in ataxia
telangiectasia. Ataxia telangiectasia is located on human
chromosome 11q22-23 and codes for a large protein of about 350 kDa,
which is characterized by the presence of a phosphatidylinositol
("PI") 3-kinase-like serine/threonine kinase domain flanked by
FRAP-ATM-TRRAP and FATC domains which modulate ATM kinase activity
and function. ATM kinase has been identified as a major player of
the DNA damage response elicited by double strand breaks. It
primarily functions in S/G2/M cell cycle transitions and at
collapsed replication forks to initiate cell cycle checkpoints,
chromatin modification, HR repair and pro-survival signalling
cascades in order to maintain cell integrity after DNA damage
(Lavin, 2008).
[0003] ATM kinase signalling can be broadly divided into two
categories: a canonical pathway, which signals together with the
Mre11-Rad50-NBS1 complex from double strand breaks and activates
the DNA damage checkpoint, and several non-canonical modes of
activation, which are activated by other forms of cellular stress
(Cremona et al., 2013).
[0004] ATM kinase is rapidly and robustly activated in response to
double strand breaks and is reportedly able to phosphorylate in
excess of 800 substrates (Matsuoka et al., 2007), coordinating
multiple stress response pathways (Kurz and Lees Miller, 2004). ATM
kinase is present predominantly in the nucleus of the cell in an
inactive homodimeric form but autophosphorylates itself on Ser1981
upon sensing a DNA double strand break (canonical pathway), leading
to dissociation to a monomer with full kinase activity (Bakkenist
et al., 2003). This is a critical activation event, and ATM
phospho-Ser1981 is therefore both a direct pharmacodynamic and
patient selection biomarker for tumour pathway dependency.
[0005] ATM kinase responds to direct double strand breaks caused by
common anti-cancer treatments such as ionising radiation and
topoisomerase-II inhibitors (doxorubicin, etoposide) but also to
topoisomerase-I inhibitors (for example irinotecan and topotecan)
via single strand break to double strand break conversion during
replication. ATM kinase inhibition can potentiate the activity of
any these agents, and as a result ATM kinase inhibitors are
expected to be of use in the treatment of cancer, for example as
rational combination partners for existing therapies.
[0006] CN102372711A reports certain imidazo[4,5-c]quinolin-2-one
compounds which are mentioned to be dual inhibitors of PI 3-kinase
a and mammalian target of rapamycin ("mTOR") kinase. Among the
compounds reported in CN102372711A are the following:
##STR00002##
Certain Compounds Reported in CN102372711A
[0007] CN102399218A reports certain imidazo[4,5-c]quinolin-2-one
compounds which are mentioned to be PI 3-kinase a inhibitors. Among
the compounds reported in CN102399218A are the following:
##STR00003##
Certain Compounds Reported in CN102399218A
[0008] While the compounds or CN102372711A and CN102399218A are
reported to possess activity against PI 3-kinase a and in some
cases mTOR kinase, there remains a need to develop new compounds
that are more effective against different kinase enzymes, such as
ATM kinase. There further exists a need for new compounds which act
against certain kinase enzymes, like ATM kinase, in a highly
selective fashion (i.e. by modulating ATM more effectively than
other biological targets).
[0009] As demonstrated elsewhere in the specification (for example
in the cell based assays described in the experimental section),
the compounds of the present specification generally possess very
potent ATM kinase inhibitory activity, but much less potent
activity against other tyrosine kinase enzymes, such as PI 3-kinase
a, mTOR kinase and ataxia telangiectasia and Rad3-related protein
("ATR") kinase. As such, the compounds of the present specification
not only inhibit ATM kinase, but can be considered to be highly
selective inhibitors of ATM kinase.
[0010] As a result of their highly selective nature, the compounds
of the present specification are expected to be particularly useful
in the treatment of diseases in which ATM kinase is implicated (for
example, in the treatment of cancer), but where it is desirable to
minimise off-target effects or toxicity that might arise due to the
inhibition of other tyrosine kinase enzymes, such as class PI
3-kinase a, mTOR kinase and ATR kinase.
SUMMARY OF INVENTION
[0011] Briefly, this specification describes, in part, a compound
of Formula (I):
##STR00004##
[0012] or a pharmaceutically acceptable salt thereof, where:
[0013] Q is a cyclobutyl or cyclopentyl ring, each of which is
optionally substituted by one hydroxy or methoxy group, or Q is an
oxetanyl, tetrahydrofuranyl or oxanyl ring, each of which is
optionally substituted by one methyl group;
[0014] R.sup.1 is methyl;
[0015] R.sup.2 is hydrogen or methyl; or R.sup.1 and R.sup.2
together form an azetidinyl, pyrrolidinyl or piperidinyl ring;
[0016] R.sup.3 is hydrogen or fluoro;
[0017] R.sup.4 is hydrogen or methyl; and
[0018] R.sup.5 is hydrogen or fluoro.
[0019] This specification also describes, in part, a pharmaceutical
composition which comprises a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, and at least one
pharmaceutically acceptable diluent or carrier.
[0020] This specification also describes, in part, a compound of
formula (I), or a pharmaceutically acceptable salt thereof, for use
in therapy.
[0021] This specification also describes, in part, a compound of
formula (I), or a pharmaceutically acceptable salt thereof, for use
in the treatment of cancer.
[0022] This specification also describes, in part, a compound of
formula (I), or a pharmaceutically acceptable salt thereof, for the
manufacture of a medicament for the treatment of cancer.
[0023] This specification also describes, in part, a method for
treating cancer in a warm blooded animal in need of such treatment,
which comprises administering to said warm-blooded animal a
therapeutically effective amount of a compound of Formula (I), or a
pharmaceutically acceptable salt thereof.
BRIEF DESCRIPTION OF THE FIGURES
[0024] FIG. 1: X-Ray Powder Diffraction Pattern of Form A of
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[-
5,4-c]quinolin-2-one.
[0025] FIG. 2: DSC Thermogram of Form A of
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[-
5,4-c]quinolin-2-one.
[0026] FIG. 3: Tumour Growth Inhibition in the Mouse Xenograft
Model by
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3--
methylimidazo[4,5-c]quinolin-2-one (Example 2) in Combination with
Irinotecan.
[0027] FIG. 4: Tumour Growth Inhibition in the Mouse Xenograft
Model by
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[-
5,4-c]quinolin-2-one (Example 1) in Combination with
Irinotecan.
[0028] FIG. 5: Tumour Growth Inhibition in the Mouse Xenograft
Model by
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[-
5,4-c]quinolin-2-one (Example 1) in Combination with Olaparib.
DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0029] Many embodiments of the invention are detailed throughout
the specification and will be apparent to a reader skilled in the
art. The invention is not to be interpreted as being limited to any
particular embodiment(s) thereof.
[0030] In the first embodiment there is provided a compound of
Formula (I):
##STR00005##
[0031] or a pharmaceutically acceptable salt thereof, where:
[0032] Q is a cyclobutyl or cyclopentyl ring, each of which is
optionally substituted by one hydroxy or methoxy group, or Q is an
oxetanyl, tetrahydrofuranyl or oxanyl ring, each of which is
optionally substituted by one methyl group;
[0033] R.sup.1 is methyl;
[0034] R.sup.2 is hydrogen or methyl; or R.sup.1 and R.sup.2
together form an azetidinyl, pyrrolidinyl or piperidinyl ring;
[0035] R.sup.3 is hydrogen or fluoro;
[0036] R.sup.4 is hydrogen or methyl; and
[0037] R.sup.5 is hydrogen or fluoro.
[0038] The terms "cyclobutyl ring" and "cyclopentyl ring" refer to
carbocyclic rings containing no heteroatoms. 1-methoxycyclobut-3-yl
groups and 3-methoxycyclobut-1-yl groups have the same structure,
as shown below.
##STR00006##
[0039] A cis-1-methoxy-cyclobut-3-yl group is equivalent to a
cis-3-methoxy-cyclobut-1-yl and has the following structure:
##STR00007##
[0040] The same conventions apply to other cyclobutyl groups, for
example 1-hydroxycyclobut-3-yl groups and 3-hydroxycyclobut-1-yl
groups.
[0041] In a similar fashion, 1-methoxycyclopent-3-yl groups and
3-methoxycyclopent-1-yl groups have the same structure, as shown
below.
##STR00008##
[0042] The term "oxetanyl ring" includes oxetan-2-yl and
oxetan-3-yl groups, the structures of which are shown below.
##STR00009##
[0043] The term "tetrahydrofuranyl ring" includes
tetrahydrofuran-2-yl and tetrahydrofuran-3-yl groups, the
structures of which are shown below.
##STR00010##
[0044] The term "oxanyl ring" includes oxan-2-yl, oxan-3-yl, and
oxan-4-yl groups, the structures of which are shown below.
##STR00011##
[0045] In the above structures the dashed line indicates the
bonding position of the relevant group.
[0046] An oxanyl ring may also be referred to as a
tetrahydropyranyl ring. Similarly, an oxan-4-yl ring may be
referred to as a tetrahydropyran-4-yl ring; an oxan-3-yl ring may
be referred to as a tetrahydropyran-3-yl ring, and an oxan-2-yl
ring may be referred to as a tetrahydropyran-2-yl ring.
[0047] Where it is mentioned that "R.sup.1 and R.sup.2 together
form an azetidinyl, pyrrolidinyl or piperidinyl ring", this means
the R.sup.1 and R.sup.2 groups are joined via a carbon-carbon
covalent bond to form an unsubstituted alkylene chain of the
appropriate length for the corresponding ring. For example, when
R.sup.1 and R.sup.2 together form a pyrrolidinyl ring, R.sup.1 and
R.sup.2 together represent an unsubstituted butylene chain which is
attached to the relevant nitrogen atom in Formula (I) at both
terminal carbons.
[0048] Where the term "optionally" is used, it is intended that the
subsequent feature may or may not occur. As such, use of the term
"optionally" includes instances where the feature is present, and
also instances where the feature is not present. For example, a
group "optionally substituted by one methoxy group" includes groups
with and without a methoxy substituent.
[0049] The term "substituted" means that one or more hydrogens (for
example 1 or 2 hydrogens, or alternatively 1 hydrogen) on the
designated group is replaced by the indicated substituent(s) (for
example 1 or 2 substituents, or alternatively 1 substituent),
provided that any atom(s) bearing a substituent maintains a
permitted valency. Substituent combinations encompass only stable
compounds and stable synthetic intermediates. "Stable" means that
the relevant compound or intermediate is sufficiently robust to be
isolated and have utility either as a synthetic intermediate or as
an agent having potential therapeutic utility. If a group is not
described as "substituted", or "optionally substituted", it is to
be regarded as unsubstituted (i.e. that none of the hydrogens on
the designated group have been replaced).
[0050] The term "pharmaceutically acceptable" is used to specify
that an object (for example a salt, dosage form, diluent or
carrier) is suitable for use in patients. An example list of
pharmaceutically acceptable salts can be found in the Handbook of
Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl
and C. G. Wermuth, editors, Weinheim/Zurich:Wiley-VCH/VHCA, 2002. A
suitable pharmaceutically acceptable salt of a compound of Formula
(I) is, for example, an acid-addition salt. An acid addition salt
of a compound of Formula (I) may be formed by bringing the compound
into contact with a suitable inorganic or organic acid under
conditions known to the skilled person. An acid addition salt may
for example be formed using an inorganic acid selected from the
group consisting of hydrochloric acid, hydrobromic acid, sulphuric
acid and phosphoric acid. An acid addition salt may also be formed
using an organic acid selected from the group consisting of
trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic
acid, formic acid, benzoic acid, fumaric acid, succinic acid,
tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid,
benzenesulfonic acid and para-toluenesulfonic acid.
[0051] Therefore, in one embodiment there is provided a compound of
Formula (I) or a pharmaceutically acceptable salt thereof, where
the pharmaceutically acceptable salt is a hydrochloric acid,
hydrobromic acid, sulphuric acid, phosphoric acid, trifluoroacetic
acid, citric acid, maleic acid, oxalic acid, acetic acid, formic
acid, benzoic acid, fumaric acid, succinic acid, tartaric acid,
lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic
acid or para-toluenesulfonic acid salt. In one embodiment there is
provided a compound of Formula (I) or a pharmaceutically acceptable
salt thereof, where the pharmaceutically acceptable salt is a
trifluoroacetic acid, formic acid or methanesulfonic acid salt. In
one embodiment there is provided a compound of Formula (I) or a
pharmaceutically acceptable salt thereof, where the
pharmaceutically acceptable salt is a trifluoroacetic acid or
methanesulfonic acid salt. In one embodiment there is provided a
compound of Formula (I) or a pharmaceutically acceptable salt
thereof, where the pharmaceutically acceptable salt is a
methanesulfonic acid salt. In one embodiment there is provided a
compound of Formula (I) or a pharmaceutically acceptable salt
thereof, where the pharmaceutically acceptable salt is a
mono-methanesulfonic acid salt, i.e. the stoichiometry of the
compound of the compound of Formula (I) to methanesulfonic acid is
1:1.
[0052] A further embodiment provides any of the embodiments defined
herein (for example the embodiment of claim 1) with the proviso
that one or more specific Examples (for instance one, two or three
specific Examples) selected from the group consisting of Examples
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,
20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,
37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53,
54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70
and 71 is individually disclaimed.
[0053] Some values of variable groups in Formula (I) are as
follows. Such values may be used in combination with any of the
definitions, claims (for example claim 1), or embodiments defined
herein to provide further embodiments. [0054] a) Q is a cyclobutyl
or cyclopentyl ring, each of which is substituted by one hydroxy or
methoxy group, or Q is an oxetanyl, tetrahydrofuranyl or oxanyl
ring, each of which is optionally substituted by one methyl group.
[0055] b) Q is a cyclobutyl ring substituted by one hydroxy or
methoxy group, or Q is an oxetanyl or oxanyl ring, each of which is
optionally substituted by one methyl group. [0056] c) Q is a
cyclobutyl ring substituted by one hydroxy or methoxy group, or Q
is an oxetanyl or oxanyl ring. [0057] d) Q is cyclobutyl,
1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl,
3-methoxycyclopent-1-yl, oxetan-3-yl, tetrahydrofuran-3-yl,
oxan-3-yl, oxan-4-yl or 4-methyloxan-4-yl. [0058] e) Q is
1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl,
3-methoxycyclopent-1-yl, oxetan-3-yl, oxan-3-yl, oxan-4-yl or
4-methyloxan-4-yl. [0059] f) Q is 1-methoxy-cyclobut-3-yl,
1-hydroxy-cyclobut-3-yl or oxan-4-yl. [0060] g) Q is
cis-1-methoxy-cyclobut-3-yl or oxan-4-yl. [0061] h) Q is a
cyclobutyl or cyclopentyl ring, each of which is optionally
substituted by one hydroxy or methoxy group. [0062] i) Q is a
cyclobutyl or cyclopentyl ring, each of which is optionally
substituted by one methoxy group. [0063] j) Q is a cyclobutyl ring
substituted by one hydroxy or methoxy group. [0064] k) Q is
cyclobutyl, 1-hydroxy-cyclobut-3-yl or 1-methoxy-cyclobut-3-yl.
[0065] l) Q is cyclobutyl. [0066] m) Q is a cyclopentyl ring
substituted by one hydroxy or methoxy group. [0067] n) Q is a
cyclopentyl ring substituted by one methoxy group. [0068] o) Q is
3-methoxycyclopent-1-yl. [0069] p) Q is 1-hydroxy-cyclobut-3-yl or
1-methoxy-cyclobut-3-yl. [0070] q) Q is cis-1-hydroxy-cyclobut-3-yl
or cis-1-methoxy-cyclobut-3-yl. [0071] r) Q is
cis-1-methoxy-cyclobut-3-yl. [0072] s) Q is an oxetanyl,
tetrahydrofuranyl or oxanyl ring, each of which is optionally
substituted by one methyl group. [0073] t) Q is an oxetanyl or
oxanyl ring, each of which is optionally substituted by one methyl
group. [0074] u) Q is an oxetanyl or tetrahydrofuranyl ring. [0075]
v) Q is an oxetanyl ring. [0076] w) Q is oxetan-3-yl. [0077] x) Q
is a tetrahydrofuranyl ring. [0078] y) Q is tetrahydrofuran-3-yl.
[0079] z) Q is an oxanyl ring optionally substituted by one methyl
group. [0080] aa) Q is an oxanyl ring. [0081] bb) Q is oxan-4-yl.
[0082] cc) R.sup.1 is methyl. [0083] dd) R.sup.2 is methyl. [0084]
ee) R.sup.2 is hydrogen. [0085] ff) R.sup.1 is methyl and R.sup.2
is hydrogen or methyl. [0086] gg) R.sup.1 and R.sup.2 are both
methyl; or R.sup.1 and R.sup.2 together form a pyrrolidinyl ring.
[0087] hh) R.sup.1 and R.sup.2 are both methyl. [0088] ii) R.sup.1
and R.sup.2 together form an azetidinyl, pyrrolidinyl or
piperidinyl ring. [0089] jj) R.sup.1 and R.sup.2 together form an
azetidinyl ring. [0090] kk) R.sup.1 and R.sup.2 together form a
pyrrolidinyl ring. [0091] ll) R.sup.1 and R.sup.2 together form a
piperidinyl ring. [0092] mm) R.sup.3 and R.sup.5 are both hydrogen.
[0093] nn) R.sup.3 is hydrogen. [0094] oo) R.sup.3 is fluoro.
[0095] pp) R.sup.4 is hydrogen. [0096] qq) R.sup.4 is methyl.
[0097] rr) R.sup.5 is hydrogen. [0098] ss) R.sup.5 is fluoro.
[0099] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, where:
[0100] Q is cyclobutyl, 1-methoxy-cyclobut-3-yl,
1-hydroxy-cyclobut-3-yl, 3-methoxycyclopent-1-yl, oxetan-3-yl,
tetrahydrofuran-3-yl, oxan-3-yl, oxan-4-yl or
4-methyloxan-4-yl;
[0101] R.sup.1 is methyl;
[0102] R.sup.2 is hydrogen or methyl; or R.sup.1 and R.sup.2
together form an azetidinyl, pyrrolidinyl or piperidinyl ring;
[0103] R.sup.3 is hydrogen or fluoro;
[0104] R.sup.4 is hydrogen or methyl; and
[0105] R.sup.5 is hydrogen or fluoro.
[0106] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, where:
[0107] Q is 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl,
3-methoxycyclopent-1-yl, oxetan-3-yl, oxan-3-yl, oxan-4-yl or
4-methyloxan-4-yl;
[0108] R.sup.1 is methyl;
[0109] R.sup.2 is hydrogen or methyl; or R.sup.1 and R.sup.2
together form an azetidinyl, pyrrolidinyl or piperidinyl ring;
[0110] R.sup.3 is hydrogen or fluoro;
[0111] R.sup.4 is hydrogen or methyl; and
[0112] R.sup.5 is hydrogen or fluoro.
[0113] In one embodiment there is provided a compound of Formula
(I), where:
[0114] Q is 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl or
3-methoxycyclopent-1-yl;
[0115] R.sup.1 is methyl;
[0116] R.sup.2 is hydrogen or methyl; or R.sup.1 and R.sup.2
together form an azetidinyl, pyrrolidinyl or piperidinyl ring;
[0117] R.sup.3 is hydrogen or fluoro;
[0118] R.sup.4 is hydrogen or methyl; and
[0119] R.sup.5 is hydrogen or fluoro.
[0120] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, where:
[0121] Q is oxetan-3-yl, oxan-3-yl, oxan-4-yl or
4-methyloxan-4-yl;
[0122] R.sup.1 is methyl;
[0123] R.sup.2 is hydrogen or methyl; or R.sup.1 and R.sup.2
together form an azetidinyl, pyrrolidinyl or piperidinyl ring;
[0124] R.sup.3 is hydrogen or fluoro;
[0125] R.sup.4 is hydrogen or methyl; and
[0126] R.sup.5 is hydrogen or fluoro.
[0127] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, where:
[0128] Q is cis-1-methoxy-cyclobut-3-yl or oxan-4-yl;
[0129] R.sup.1 is methyl;
[0130] R.sup.2 is methyl or hydrogen;
[0131] R.sup.3 is hydrogen;
[0132] R.sup.4 is methyl or hydrogen; and
[0133] R.sup.5 is hydrogen.
[0134] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, wherein the
compound is selected from the group consisting of: [0135]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[-
5,4-c]quinolin-2-one; [0136]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3--
methylimidazo[4,5-c]quinolin-2-one; [0137]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-(4-methylo-
xan-4-yl)imidazo[5,4-c]quinolin-2-one; [0138]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxetan-3-yl)imidaz-
o[5,4-c]quinolin-2-one; [0139]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-hydroxycyclobutyl)-3--
methylimidazo[4,5-c]quinolin-2-one; [0140]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-1-(cis-3-methoxycyclo-
butyl)-3-methylimidazo[4,5-c]quinolin-2-one; [0141]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(4-methyloxan-4-yl)-
imidazo[5,4-c]quinolin-2-one; [0142]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-(oxan-4-yl-
)imidazo[5,4-c]quinolin-2-one; [0143]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-(oxetan-3--
yl)imidazo[5,4-c]quinolin-2-one; [0144]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-[(3R)-oxan-
-3-yl]imidazo[5,4-c]quinolin-2-one; [0145]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-[(3
S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one; [0146]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3H-
-imidazo[4,5-c]quinolin-2-one; [0147]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-(oxan-4-yl)-3H-imidazo[4,5-c-
]quinolin-2-one; [0148]
8-[6-[3-(Azetidin-1-yl)propoxy]pyridin-3-yl]-1-(cis-3-hydroxycyclobutyl)--
3-methylimidazo[4,5-c]quinolin-2-one; [0149]
1-(3-cis-Hydroxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)pyrid-
in-3-yl]imidazo[4,5-c]quinolin-2-one; [0150]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-[(3R)-oxan-3-yl]imi-
dazo[5,4-c]quinolin-2-one; [0151]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-[(3
S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one; [0152]
8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-1-(cis-3-methoxycyclo-
butyl)-3-methylimidazo[4,5-c]quinolin-2-one; [0153]
8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-7-fluoro-1-(cis-3-met-
hoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one; [0154]
8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-3-methyl-1-[(3
S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one; [0155]
8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-3-methyl-1-(oxan-4-yl-
)imidazo[5,4-c]quinolin-2-one; [0156]
8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-3-methyl-1-[(3R)-oxan-
-3-yl]imidazo[5,4-c]quinolin-2-one; [0157]
7-Fluoro-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-1-[(3S)-tetr-
ahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one; [0158]
7-Fluoro-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-1-[(3
S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one; [0159]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-[(1R,3R)-3-methoxycyclopenty-
l]-3-methylimidazo[4,5-c]quinolin-2-one; [0160]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-[(1S,3S)-3-methoxycyclopenty-
l]-3-methylimidazo[4,5-c]quinolin-2-one; [0161]
7-Fluoro-1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidin-1-ylprop-
oxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one; [0162]
1-(cis-3-Methoxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)pyrid-
in-3-yl]imidazo[4,5-c]quinolin-2-one; [0163]
3-Methyl-1-[(3S)-oxan-3-yl]-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]i-
midazo[5,4-c]quinolin-2-one; [0164]
3-Methyl-1-(oxan-4-yl)-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidaz-
o[5,4-c]quinolin-2-one; [0165]
3-Methyl-1-[(3S)-oxan-3-yl]-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]im-
idazo[5,4-c]quinolin-2-one; [0166]
3-Methyl-1-[(3R)-oxan-3-yl]-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]im-
idazo[5,4-c]quinolin-2-one; [0167]
1-(cis-3-Methoxycyclobutyl)-3-methyl-8-[6-(3-piperidin-1-ylpropoxy)pyridi-
n-3-yl]imidazo[4,5-c]quinolin-2-one; [0168]
8-[6-[3-(Azetidin-1-yl)propoxy]pyridin-3-yl]-3-methyl-1-[(3R)-oxan-3-yl]i-
midazo[5,4-c]quinolin-2-one; [0169]
1-(cis-3-Methoxycyclobutyl)-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]--
3H-imidazo[4,5-c]quinolin-2-one; [0170]
1-(Oxan-4-yl)-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]-3H-imidazo[4,5--
c]quinolin-2-one; [0171]
3-Methyl-1-(oxan-4-yl)-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo-
[5,4-c]quinolin-2-one; [0172]
8-[6-[3-(Azetidin-1-yl)propoxy]pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)--
3-methylimidazo[4,5-c]quinolin-2-one; [0173]
8-[6-[3-(Azetidin-1-yl)propoxy]pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidaz-
o[5,4-c]quinolin-2-one; [0174]
3-Methyl-8-[6-(3-methylaminopropoxy)pyridin-3-yl]-1-(oxan-4-yl)imidazo[5,-
4-c]quinolin-2-one; [0175]
3-Methyl-8-[6-(3-methylaminopropoxy)pyridin-3-yl]-1-[(3S)-oxan-3-yl]imida-
zo[5,4-c]quinolin-2-one; and [0176]
1-(cis-3-Methoxycyclobutyl)-3-methyl-8-[6-(3-methylaminopropoxy)pyridin-3-
-yl]imidazo[4,5-c]quinolin-2-one; [0177]
3-Methyl-8-[6-[3-(methylamino)propoxy]-3-pyridyl]-1-[(3R)-tetrahydropyran-
-3-yl]imidazo[4,5-c]quinolin-2-one; [0178]
8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-3-methyl-1-[(3R)-tetrahydrofur-
an-3-yl]imidazo[4,5-c]quinolin-2-one; [0179]
8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-3-methyl-1-[(3
S)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinolin-2-one; [0180]
1-Cyclobutyl-8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-3-methyl-imidazo[-
4,5-c]quinolin-2-one; [0181]
7-Fluoro-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-[(3
S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one; [0182]
8-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-7-fluoro-3-methyl-1-[-
(3 S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one; [0183]
8-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3-methyl-1-[(3
S)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinolin-2-one; [0184]
8-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3-methyl-1-[(3R)-tetr-
ahydrofuran-3-yl]imidazo[4,5-c]quinolin-2-one; [0185]
1-Cyclobutyl-8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3-methyl-
-imidazo[4,5-c]quinolin-2-one; [0186]
8-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3-methyl-1-(oxetan-3--
yl)imidazo[4,5-c]quinolin-2-one; [0187]
7-Fluoro-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-tetrahydropy-
ran-4-yl-imidazo[4,5-c]quinolin-2-one [0188]
3-Methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-[(3R)-tetrahydrofuran-
-3-yl]imidazo[4,5-c]quinolin-2-one; [0189]
3-Methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-[(3
S)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinolin-2-one; [0190]
3-Methyl-1-(oxetan-3-yl)-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[-
4,5-c]quinolin-2-one; [0191]
1-Cyclobutyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-
-c]quinolin-2-one; [0192]
1-Cyclobutyl-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]imidazo[4-
,5-c]quinolin-2-one; [0193]
3-Methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-1-[(3R)-tetrahydropyr-
an-3-yl]imidazo[4,5-c]quinolin-2-one; [0194]
8-[6-[3-(Azetidin-1-yl)propoxy]-3-pyridyl]-3-methyl-1-[(3
S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one; [0195]
8-[2-Fluoro-6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-3-methyl-1-[(3S)-tetr-
ahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one; [0196]
8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1R,3R)-3-methoxyc-
yclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one; [0197]
8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1S,3S)-3-methoxyc-
yclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one; [0198]
1-[(1R,3R)-3-Methoxycyclopentyl]-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-
-pyridyl]imidazo[4,5-c]quinolin-2-one; [0199]
1-[(1S,3S)-3-Methoxycyclopentyl]-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-
-pyridyl]imidazo[4,5-c]quinolin-2-one; [0200]
1-[(1S,3S)-3-Methoxycyclopentyl]-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-
-3-pyridyl]imidazo[4,5-c]quinolin-2-one; [0201]
1-[(1R,3R)-3-Methoxycyclopentyl]-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-
-3-pyridyl]imidazo[4,5-c]quinolin-2-one; [0202]
8-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-1-[(1R,3R)-3-methoxyc-
yclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one; [0203]
8-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-1-[(1S,3S)-3-methoxyc-
yclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one; [0204]
8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1R,3S)-3-methoxyc-
yclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one; and [0205]
8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1S,3R)-3-methoxyc-
yclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one.
[0206] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, wherein the
compound is selected from the group consisting of: [0207]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[-
5,4-c]quinolin-2-one; [0208]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3--
methylimidazo[4,5-c]quinolin-2-one; [0209]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-(4-methylo-
xan-4-yl)imidazo[5,4-c]quinolin-2-one; [0210]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxetan-3-yl)imidaz-
o[5,4-c]quinolin-2-one; [0211]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-hydroxycyclobutyl)-3--
methylimidazo[4,5-c]quinolin-2-one; [0212]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-1-(cis-3-methoxycyclo-
butyl)-3-methylimidazo[4,5-c]quinolin-2-one; [0213]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(4-methyloxan-4-yl)-
imidazo[5,4-c]quinolin-2-one; [0214]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-(oxan-4-yl-
)imidazo[5,4-c]quinolin-2-one; [0215]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-(oxetan-3--
yl)imidazo[5,4-c]quinolin-2-one; [0216]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-[(3R)-oxan-
-3-yl]imidazo[5,4-c]quinolin-2-one; [0217]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-[(3S)-oxan-
-3-yl]imidazo[5,4-c]quinolin-2-one; [0218]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3H-
-imidazo[4,5-c]quinolin-2-one; [0219]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-(oxan-4-yl)-3H-imidazo[4,5-c-
]quinolin-2-one; [0220]
8-[6-[3-(Azetidin-1-yl)propoxy]pyridin-3-yl]-1-(cis-3-hydroxycyclobutyl)--
3-methylimidazo[4,5-c]quinolin-2-one; [0221]
1-(3-cis-Hydroxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)pyrid-
in-3-yl]imidazo[4,5-c]quinolin-2-one; [0222]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-[(3R)-oxan-3-yl]imi-
dazo[5,4-c]quinolin-2-one; [0223]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-[(3
S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one; [0224]
8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-1-(cis-3-methoxycyclo-
butyl)-3-methylimidazo[4,5-c]quinolin-2-one; [0225]
8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-7-fluoro-1-(cis-3-met-
hoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one; [0226]
8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-3-methyl-1-[(3S)-oxan-
-3-yl]imidazo[5,4-c]quinolin-2-one; [0227]
8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-3-methyl-1-(oxan-4-yl-
)imidazo[5,4-c]quinolin-2-one; [0228]
8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-3-methyl-1-[(3R)-oxan-
-3-yl]imidazo[5,4-c]quinolin-2-one; [0229]
3-Methyl-1-[(3R)-oxan-3-yl]-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]i-
midazo[5,4-c]quinolin-2-one; [0230]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-[(1R,3R)-3-methoxycyclopenty-
l]-3-methylimidazo[4,5-c]quinolin-2-one; [0231]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-[(1S,3S)-3-methoxycyclopenty-
l]-3-methylimidazo[4,5-c]quinolin-2-one; [0232]
7-Fluoro-1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidin-1-ylprop-
oxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one; [0233]
1-(cis-3-Methoxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)pyrid-
in-3-yl]imidazo[4,5-c]quinolin-2-one; [0234]
3-Methyl-1-[(3S)-oxan-3-yl]-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]i-
midazo[5,4-c]quinolin-2-one; [0235]
3-Methyl-1-(oxan-4-yl)-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidaz-
o[5,4-c]quinolin-2-one; [0236]
3-Methyl-1-[(3S)-oxan-3-yl]-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]im-
idazo[5,4-c]quinolin-2-one; [0237] is
3-Methyl-1-[(3R)-oxan-3-yl]-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]im-
idazo[5,4-c]quinolin-2-one; [0238]
1-(cis-3-Methoxycyclobutyl)-3-methyl-8-[6-(3-piperidin-1-ylpropoxy)pyridi-
n-3-yl]imidazo[4,5-c]quinolin-2-one; [0239]
8-[6-[3-(Azetidin-1-yl)propoxy]pyridin-3-yl]-3-methyl-1-[(3R)-oxan-3-yl]i-
midazo[5,4-c]quinolin-2-one; [0240]
1-(cis-3-Methoxycyclobutyl)-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]--
3H-imidazo[4,5-c]quinolin-2-one; [0241]
1-(Oxan-4-yl)-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]-3H-imidazo[4,5--
c]quinolin-2-one; [0242]
3-Methyl-1-(oxan-4-yl)-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo-
[5,4-c]quinolin-2-one; [0243]
8-[6-[3-(Azetidin-1-yl)propoxy]pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)--
3-methylimidazo[4,5-c]quinolin-2-one; [0244]
8-[6-[3-(Azetidin-1-yl)propoxy]pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidaz-
o[5,4-c]quinolin-2-one; [0245]
3-Methyl-8-[6-(3-methylaminopropoxy)pyridin-3-yl]-1-(oxan-4-yl)imidazo[5,-
4-c]quinolin-2-one; [0246]
3-Methyl-8-[6-(3-methylaminopropoxy)pyridin-3-yl]-1-[(3S)-oxan-3-yl]imida-
zo[5,4-c]quinolin-2-one; and [0247]
1-(cis-3-Methoxycyclobutyl)-3-methyl-8-[6-(3-methylaminopropoxy)pyridin-3-
-yl]imidazo[4,5-c]quinolin-2-one.
[0248] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, wherein the
compound is selected from the group consisting of: [0249]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[-
5,4-c]quinolin-2-one; [0250]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3--
methylimidazo[4,5-c]quinolin-2-one; [0251]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-(4-methylo-
xan-4-yl)imidazo[5,4-c]quinolin-2-one; [0252]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxetan-3-yl)imidaz-
o[5,4-c]quinolin-2-one; [0253]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-hydroxycyclobutyl)-3--
methylimidazo[4,5-c]quinolin-2-one; [0254]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-1-(cis-3-methoxycyclo-
butyl)-3-methylimidazo[4,5-c]quinolin-2-one; [0255]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(4-methyloxan-4-yl)-
imidazo[5,4-c]quinolin-2-one; [0256]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-(oxan-4-yl-
)imidazo[5,4-c]quinolin-2-one; [0257]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-(oxetan-3--
yl)imidazo[5,4-c]quinolin-2-one; [0258]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-[(3R)-oxan-
-3-yl]imidazo[5,4-c]quinolin-2-one; [0259]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-[(3S)-oxan-
-3-yl]imidazo[5,4-c]quinolin-2-one; [0260]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3H-
-imidazo[4,5-c]quinolin-2-one; [0261]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-(oxan-4-yl)-3H-imidazo[4,5-c-
]quinolin-2-one; [0262]
8-[6-[3-(Azetidin-1-yl)propoxy]pyridin-3-yl]-1-(cis-3-hydroxycyclobutyl)--
3-methylimidazo[4,5-c]quinolin-2-one; [0263]
1-(3-cis-Hydroxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)pyrid-
in-3-yl]imidazo[4,5-c]quinolin-2-one; [0264]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-[(3R)-oxan-3-yl]imi-
dazo[5,4-c]quinolin-2-one; [0265]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-[(3
S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one; [0266]
8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-1-(cis-3-methoxycyclo-
butyl)-3-methylimidazo[4,5-c]quinolin-2-one; [0267]
8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-7-fluoro-1-(cis-3-met-
hoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one; [0268]
8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-3-methyl-1-[(3S)-oxan-
-3-yl]imidazo[5,4-c]quinolin-2-one; [0269]
8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-3-methyl-1-(oxan-4-yl-
)imidazo[5,4-c]quinolin-2-one; [0270]
8-[6-(3-Dimethylaminopropoxy)-2-fluoropyridin-3-yl]-3-methyl-1-[(3R)-oxan-
-3-yl]imidazo[5,4-c]quinolin-2-one; [0271]
3-Methyl-1-[(3R)-oxan-3-yl]-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]i-
midazo[5,4-c]quinolin-2-one; [0272]
7-Fluoro-1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidin-1-ylprop-
oxy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one; [0273]
1-(cis-3-Methoxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)pyrid-
in-3-yl]imidazo[4,5-c]quinolin-2-one; [0274]
3-Methyl-1-[(3S)-oxan-3-yl]-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]i-
midazo[5,4-c]quinolin-2-one; [0275]
3-Methyl-1-(oxan-4-yl)-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]imidaz-
o[5,4-c]quinolin-2-one; [0276]
3-Methyl-1-[(3S)-oxan-3-yl]-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]im-
idazo[5,4-c]quinolin-2-one; [0277]
3-Methyl-1-[(3R)-oxan-3-yl]-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]im-
idazo[5,4-c]quinolin-2-one; [0278]
1-(cis-3-Methoxycyclobutyl)-3-methyl-8-[6-(3-piperidin-1-ylpropoxy)pyridi-
n-3-yl]imidazo[4,5-c]quinolin-2-one; [0279]
8-[6-[3-(Azetidin-1-yl)propoxy]pyridin-3-yl]-3-methyl-1-[(3R)-oxan-3-yl]i-
midazo[5,4-c]quinolin-2-one; [0280]
1-(cis-3-Methoxycyclobutyl)-8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-yl]--
3H-imidazo[4,5-c]quinolin-2-one; [0281]
1-(Oxan-4-yl)-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]-3H-imidazo[4,5--
c]quinolin-2-one; [0282]
3-Methyl-1-(oxan-4-yl)-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]imidazo-
[5,4-c]quinolin-2-one; [0283]
8-[6-[3-(Azetidin-1-yl)propoxy]pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)--
3-methylimidazo[4,5-c]quinolin-2-one; [0284]
8-[6-[3-(Azetidin-1-yl)propoxy]pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidaz-
o[5,4-c]quinolin-2-one; [0285]
3-Methyl-8-[6-(3-methylaminopropoxy)pyridin-3-yl]-1-(oxan-4-yl)imidazo[5,-
4-c]quinolin-2-one; [0286]
3-Methyl-8-[6-(3-methylaminopropoxy)pyridin-3-yl]-1-[(3S)-oxan-3-yl]imida-
zo[5,4-c]quinolin-2-one; and [0287]
1-(cis-3-Methoxycyclobutyl)-3-methyl-8-[6-(3-methylaminopropoxy)pyridin-3-
-yl]imidazo[4,5-c]quinolin-2-one. [0288] In one embodiment, there
is provided a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, wherein the compound is selected from the
group consisting of: [0289]
7-Fluoro-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-1-[(3-
S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one; [0290]
7-Fluoro-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-1-[(3R)-tetr-
ahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one; [0291]
3-Methyl-8-[6-[3-(methylamino)propoxy]-3-pyridyl]-1-[(3R)-tetrahydropyran-
-3-yl]imidazo[4,5-c]quinolin-2-one; [0292]
8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-3-methyl-1-[(3R)-tetrahydrofur-
an-3-yl]imidazo[4,5-c]quinolin-2-one; [0293]
8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-3-methyl-1-[(3
S)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinolin-2-one; [0294]
1-Cyclobutyl-8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-3-methyl-imidazo[-
4,5-c]quinolin-2-one; [0295]
7-Fluoro-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-[(3S)-tetrah-
ydropyran-3-yl]imidazo[4,5-c]quinolin-2-one; [0296]
8-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-7-fluoro-3-methyl-1-[-
(3 S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one; [0297]
8-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3-methyl-1-[(3
S)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinolin-2-one; [0298]
8-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3-methyl-1-[(3R)-tetr-
ahydrofuran-3-yl]imidazo[4,5-c]quinolin-2-one; [0299]
1-Cyclobutyl-8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3-methyl-
-imidazo[4,5-c]quinolin-2-one; [0300]
8-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3-methyl-1-(oxetan-3--
yl)imidazo[4,5-c]quinolin-2-one; [0301]
7-Fluoro-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-tetrahydropy-
ran-4-yl-imidazo[4,5-c]quinolin-2-one [0302]
13-Methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-[(3R)-tetrahydrofura-
n-3-yl]imidazo[4,5-c]quinolin-2-one; [0303]
3-Methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-[(3
S)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinolin-2-one; [0304]
3-Methyl-1-(oxetan-3-yl)-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[-
4,5-c]quinolin-2-one; [0305]
1-Cyclobutyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-
-c]quinolin-2-one; [0306]
1-Cyclobutyl-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]imidazo[4-
,5-c]quinolin-2-one; [0307]
3-Methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-1-[(3R)-tetrahydropyr-
an-3-yl]imidazo[4,5-c]quinolin-2-one; [0308]
8-[6-[3-(Azetidin-1-yl)propoxy]-3-pyridyl]-3-methyl-1-[(3
S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one; [0309]
8-[2-Fluoro-6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-3-methyl-1-[(3S)-tetr-
ahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one; [0310]
8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1R,3R)-3-methoxyc-
yclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one; [0311]
8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1S,3S)-3-methoxyc-
yclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one; [0312]
1-[(1R,3R)-3-Methoxycyclopentyl]-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-
-pyridyl]imidazo[4,5-c]quinolin-2-one; [0313]
1-[(1S,3S)-3-Methoxycyclopentyl]-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-
-pyridyl]imidazo[4,5-c]quinolin-2-one; [0314]
1-[(1S,3S)-3-Methoxycyclopentyl]-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-
-3-pyridyl]imidazo[4,5-c]quinolin-2-one; [0315]
1-[(1R,3R)-3-Methoxycyclopentyl]-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-
-3-pyridyl]imidazo[4,5-c]quinolin-2-one; [0316]
8-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-1-[(1R,3R)-3-methoxyc-
yclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one; [0317]
8-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-1-[(1S,3S)-3-methoxyc-
yclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one; [0318]
8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1R,3S)-3-methoxyc-
yclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one; and [0319]
8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1S,3R)-3-methoxyc-
yclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one.
[0320] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, wherein the
compound is selected from the group consisting of: [0321]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-[(1R,3R)-3-methoxycyclopenty-
l]-3-methylimidazo[4,5-c]quinolin-2-one; and [0322]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-[(1S,3S)-3-methoxycyclopenty-
l]-3-methylimidazo[4,5-c]quinolin-2-one.
[0323] In one embodiment there is provided
8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3--
methylimidazo[4,5-c]quinolin-2-one, or a pharmaceutically
acceptable salt thereof.
[0324] In one embodiment there is provided
8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3--
methylimidazo[4,5-c]quinolin-2-one.
[0325] In one embodiment there is provided a pharmaceutically
acceptable salt of
8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclob-
utyl)-3-methylimidazo[4,5-c]quinolin-2-one.
[0326] In one embodiment there is provided
8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[-
5,4-c]quinolin-2-one, or a pharmaceutically acceptable salt
thereof.
[0327] In one embodiment there is provided
8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[-
5,4-c]quinolin-2-one.
[0328] In one embodiment there is provided a pharmaceutically
acceptable salt of
8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)-
imidazo[5,4-c]quinolin-2-one.
[0329] In one embodiment there is provided
1-(cis-3-methoxycyclobutyl)-3-methyl-8-{6-[3-(pyrrolidin-1-yl)propoxy]pyr-
idin-3-yl}-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one, or a
pharmaceutically acceptable salt thereof.
[0330] In one embodiment there is provided
1-(cis-3-methoxycyclobutyl)-3-methyl-8-{6-[3-(pyrrolidin-1-yl)propoxy]pyr-
idin-3-yl}-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one.
[0331] In one embodiment there is provided a pharmaceutically
acceptable salt of
1-(cis-3-methoxycyclobutyl)-3-methyl-8-{6-[3-(pyrrolidin-1-yl)pro-
poxy]pyridin-3-yl}-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one.
[0332] Compounds and salts described in this specification may
exist in solvated forms and unsolvated forms. For example, a
solvated form may be a hydrated form, such as a hemi-hydrate, a
mono-hydrate, a di-hydrate, a tri-hydrate or an alternative
quantity thereof. The invention encompasses all such solvated and
unsolvated forms of compounds of Formula (I), particularly to the
extent that such forms possess ATM kinase inhibitory activity, as
for example measured using the tests described herein.
[0333] Atoms of the compounds and salts described in this
specification may exist as their isotopes. The invention
encompasses all compounds of Formula (I) where an atom is replaced
by one or more of its isotopes (for example a compound of Formula
(I) where one or more carbon atom is an .sup.11C or .sup.13C carbon
isotope, or where one or more hydrogen atoms is a .sup.2H or
.sup.3H isotope, or where one of more fluorine atoms is an .sup.18F
isotope).
[0334] Compounds and salts described in this specification may
exist as a mixture of tautomers. "Tautomers" are structural isomers
that exist in equilibrium resulting from the migration of a
hydrogen atom. The invention includes all tautomers of compounds of
Formula (I) particularly to the extent that such tautomers possess
ATM kinase inhibitory activity.
[0335] Compounds and salts described in this specification may
exist in optically active or racemic forms by virtue of one or more
asymmetric carbon atoms. The invention includes any optically
active or racemic form of a compound of Formula (I) which possesses
ATM kinase inhibitory activity, as for example measured using the
tests described herein. The synthesis of optically active forms may
be carried out by standard techniques of organic chemistry well
known in the art, for example by synthesis using optically active
materials or by resolution of a racemic form.
[0336] Therefore, in one embodiment there is provided a compound of
Formula (I), or a pharmaceutically acceptable salt thereof, which
is a single optical isomer being in an enantiomeric excess (% ee)
of .gtoreq.95%, .gtoreq.98% or .gtoreq.99%. In one embodiment, the
single optical isomer is present in an enantiomeric excess (% ee)
of .gtoreq.99%.
[0337] Compounds and salts described in this specification may be
crystalline, and may exhibit one or more crystalline forms. The
invention encompasses any crystalline or amorphous form of a
compound of Formula (I), or mixture of such forms, which possesses
ATM kinase inhibitory activity.
[0338] It is generally known that crystalline materials may be
characterised using conventional techniques such as X-Ray Powder
Diffraction (XRPD), Differential Scanning calorimetry (DSC),
Thermal Gravimetric Analysis (TGA), Diffuse Reflectance Infrared
Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR)
spectroscopy, solution and/or solid state nuclear magnetic
resonance spectroscopy. The water content of such crystalline
materials may be determined by Karl Fischer analysis.
[0339] The specific solid forms described herein provide XRPD
patterns substantially the same as the XRPD patterns shown in the
Figures, and have the various 2-theta values as shown in the Tables
included herein. One skilled in the art will understand that an
XRPD pattern or diffractogram may be obtained which has one or more
measurement errors depending on the recording conditions, such as
the equipment or machine used. Similarly, it is generally known
that intensities in an XRPD pattern may fluctuate depending on
measurement conditions or sample preparation as a result of
preferred orientation. Persons skilled in the art of XRPD will
further realise that the relative intensity of peaks can also be
affected by, for example, grains above 30 .mu.m in size and
non-unitary aspect ratios. The skilled person understands that the
position of reflections can be affected by the precise height at
which the sample sits in the diffractometer, and also the zero
calibration of the diffractometer. The surface planarity of the
sample may also have a small effect.
[0340] As a result of these considerations, the diffraction pattern
data presented are not to be taken as absolute values (Jenkins, R
& Snyder, R. L. `Introduction to X-Ray Powder Diffractometry`
John Wiley & Sons 1996; Bunn, C. W. (1948), `Chemical
Crystallography`, Clarendon Press, London; Klug, H. P. &
Alexander, L. E. (1974), `X-Ray Diffraction Procedures`). It should
correspondingly be understood that the solid forms are not limited
to the crystals that provide XRPD patterns that are identical to
the XRPD pattern shown in the Figures, and any crystals providing
XRPD patterns substantially the same as those shown in the Figures
fall within the scope of the invention. A person skilled in the art
of XRPD is able to judge the substantial identity of XRPD patterns.
Generally, a measurement error of a diffraction angle in an XRPD is
approximately plus or minus 0.2.degree. 2-theta, and such degree of
a measurement error should be taken into account when considering
the X-ray powder diffraction pattern in the Figures and when
reading data contained in the Tables included herein.
[0341] The compound of Example 1 exhibits crystalline properties,
and one crystalline form has been characterised.
[0342] Therefore, in one embodiment there is provided Form A of
8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[-
5,4-c]quinolin-2-one.
[0343] In one embodiment there is provided a crystalline form, Form
A of
8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[-
5,4-c]quinolin-2-one, which has an X-ray powder diffraction pattern
with at least one specific peak at about 2-theta=3.90.
[0344] In one embodiment there is provided a crystalline form, Form
A of
8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[-
5,4-c]quinolin-2-one, which has an X-ray powder diffraction pattern
with at least one specific peak at about 2-theta=11.6.degree..
[0345] In one embodiment there is provided a crystalline form, Form
A of
8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[-
5,4-c]quinolin-2-one, which has an X-ray powder diffraction pattern
with at least two specific peaks at about 2-theta=3.9 and
11.6.degree..
[0346] In one embodiment there is provided a crystalline form, Form
A of
8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[-
5,4-c]quinolin-2-one, which has an X-ray powder diffraction pattern
with specific peaks at about 2-theta=3.9, 7.7, 10.7, 11.6, 15.4,
16.9, 17.4, 18.4, 21.3 and 22.2.degree..
[0347] In one embodiment there is provided a crystalline form, Form
A of
8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[-
5,4-c]quinolin-2-one which has an X-ray powder diffraction pattern
substantially the same as the X-ray powder diffraction pattern
shown in FIG. 1.
[0348] In one embodiment there is provided a crystalline form, Form
A of
8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[-
5,4-c]quinolin-2-one, which has an X-ray powder diffraction pattern
with at least one specific peak at 2-theta=3.9.degree. plus or
minus 0.2.degree. 2-theta.
[0349] In one embodiment there is provided a crystalline form, Form
A of
8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[-
5,4-c]quinolin-2-one, which has an X-ray powder diffraction pattern
with at least one specific peak at 2-theta=11.6.degree. plus or
minus 0.2.degree. 2-theta.
[0350] In one embodiment there is provided a crystalline form, Form
A of
8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[-
5,4-c]quinolin-2-one, which has an X-ray powder diffraction pattern
with at least two specific peaks at 2-theta=3.9 and 11.6.degree.
plus or minus 0.2.degree. 2-theta.
[0351] In one embodiment there is provided a crystalline form, Form
A of
8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[-
5,4-c]quinolin-2-one, which has an X-ray powder diffraction pattern
with specific peaks at 2-theta=3.9, 7.7, 10.7, 11.6, 15.4, 16.9,
17.4, 18.4, 21.3 and 22.2.degree. plus or minus 0.2.degree.
2-theta.
[0352] DSC analysis of Form A of
8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[-
5,4-c]quinolin-2-one shows a melting endotherm with an onset of
212.3.degree. C. and a peak at 214.1.degree. C. (FIG. 2).
[0353] A person skilled in the art understands that the value or
range of values observed in a particular compound's DSC Thermogram
will show variation between batches of different purities.
Therefore, whilst for one compound the range may be small, for
others the range may be quite large. Generally, a measurement error
of a diffraction angle in DSC thermal events is approximately plus
or minus 5.degree. C., and such degree of a measurement error
should be taken into account when considering the DSC data included
herein.
[0354] Therefore, in one embodiment there is provided a crystalline
form, Form A of
8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-y-
l)imidazo[5,4-c]quinolin-2-one which has a DSC endotherm with an
onset of melting at about 212.3.degree. C. and a peak at about
214.1.degree. C.
[0355] Therefore, in one embodiment there is provided a crystalline
form, Form A of
8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-y-
l)imidazo[5,4-c]quinolin-2-one which has a DSC endotherm with an
onset of melting at 212.3.degree. C. plus or minus 5.degree. C. and
a peak at 214.1.degree. C. plus or minus 5.degree. C.
[0356] In one embodiment there is provided a crystalline form, Form
A of
8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[-
5,4-c]quinolin-2-one which has a DSC endotherm with an onset of
melting at 212.3.degree. C. and a peak at 214.1.degree. C.
[0357] In one embodiment there is provided a crystalline form, Form
A of
8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[-
5,4-c]quinolin-2-one which has a DSC thermogram substantially as
shown in FIG. 2.
[0358] When it is stated that an embodiment relates to a
crystalline form, the degree of crystallinity may be greater than
about 60%. In some embodiments the degree of crystallinity is
greater than about 80%. In some embodiments the degree of
crystallinity is greater than about 90%. In some embodiments the
degree of crystallinity is greater than about 95%. In some
embodiments the degree of crystallinity is greater than about
98%.
[0359] Compounds of Formula (I) may for example be prepared by the
reaction of a compound of Formula (II):
##STR00012##
[0360] Or a salt thereof, where Q, R.sup.3, R.sup.4 and R.sup.5 are
as defined in any of the embodiments herein and X is a leaving
group (for example a halogen atom, or alternatively a fluorine
atom) with a compound of formula (III):
##STR00013##
[0361] Or a salt thereof, where R.sup.1 and R.sup.2 are as defined
in any of the embodiments herein. The reaction is conveniently
performed in a suitable solvent (for example DMF, DMA or THF) and
in the presence of a base (for example sodium hydride) at a
suitable temperature (for example a temperature in the range of
about 20-50.degree. C.).
[0362] Compounds of Formula (II), and salts thereof, are therefore
useful as intermediates in the preparation of the compounds of
Formula (I) and provide a further embodiment.
[0363] In one embodiment there is provided a compound of Formula
(II), or a salt thereof, where:
[0364] Q is a cyclobutyl or cyclopentyl ring, each of which is
optionally substituted by one hydroxy or methoxy group, or Q is an
oxetanyl, tetrahydrofuranyl or oxanyl ring, each of which is
optionally substituted by one methyl group;
[0365] R.sup.3 is hydrogen or fluoro;
[0366] R.sup.4 is hydrogen or methyl;
[0367] R.sup.5 is hydrogen or fluoro; and
[0368] X is a leaving group. In one embodiment X is a halogen atom
or a triflate group. In one embodiment X is a fluorine atom.
[0369] In one embodiment there is provided a compound of Formula
(II), or a salt thereof, where:
[0370] Q is cyclobutyl, 1-methoxy-cyclobut-3-yl,
1-hydroxy-cyclobut-3-yl, 3-methoxycyclopent-1-yl, oxetan-3-yl,
tetrahydrofuran-3-yl, oxan-3-yl, oxan-4-yl or
4-methyloxan-4-yl;
[0371] R.sup.3 is hydrogen or fluoro;
[0372] R.sup.4 is hydrogen or methyl;
[0373] R.sup.5 is hydrogen or fluoro; and
[0374] X is a leaving group. In one embodiment X is a halogen atom
or a triflate group. In one embodiment X is a fluorine atom.
[0375] In one embodiment there is provided a compound of Formula
(II), or a salt thereof, where:
[0376] Q is 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl,
3-methoxycyclopent-1-yl, oxetan-3-yl, oxan-3-yl, oxan-4-yl or
4-methyloxan-4-yl;
[0377] R.sup.3 is hydrogen or fluoro;
[0378] R.sup.4 is hydrogen or methyl;
[0379] R.sup.5 is hydrogen or fluoro; and
[0380] X is a leaving group. In one embodiment X is a halogen atom
or a triflate group. In one embodiment X is a fluorine atom.
[0381] In one embodiment there is provided
8-(6-fluoropyridin-3-yl)-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-o-
ne, or a salt thereof.
[0382] In one embodiment there is provided
8-(6-fluoropyridin-3-yl)-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5--
c]quinolin-2-one, or a salt thereof.
[0383] In any of the embodiments where a compound of Formula (II)
or a salt thereof is mentioned it is to be understood that such
salts do not need to be pharmaceutically acceptable salts. A
suitable salt of a compound of Formula (II) is, for example, an
acid-addition salt. An acid addition salt of a compound of Formula
(II) may be formed by bringing the compound into contact with a
suitable inorganic or organic acid under conditions known to the
skilled person. An acid addition salt may for example be formed
using an inorganic acid selected from the group consisting of
hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric
acid. An acid addition salt may also be formed using an organic
acid selected from the group consisting of trifluoroacetic acid,
citric acid, maleic acid, oxalic acid, acetic acid, formic acid,
benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic
acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid and
para-toluenesulfonic acid.
[0384] Therefore, in one embodiment there is provided a compound of
Formula (II) or a salt thereof, where the salt is a hydrochloric
acid, hydrobromic acid, sulphuric acid, phosphoric acid,
trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic
acid, formic acid, benzoic acid, fumaric acid, succinic acid,
tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid,
benzenesulfonic acid or para-toluenesulfonic acid salt.
[0385] The compounds of Formula (II) may for example be prepared by
the reaction of a compound of Formula (IV):
##STR00014##
[0386] Where Q, R.sup.4 and R.sup.5 are as defined in any of the
embodiments herein and X.sup.1 is a leaving group (for example an
iodine, bromine, or chlorine atom or a triflate group, or
alternatively a bromine atom) with a compound of formula (V):
##STR00015##
[0387] Or a salt thereof, where R.sup.3 and X are as defined in any
of the embodiments herein and Y is a boronic acid, boronic ester or
potassium trifluoroborate group (for example boronic acid, boronic
acid pinacol ester, or potassium trifluoroborate). The reaction may
be performed under standard conditions well known to those skilled
in the art, for example in the presence of a palladium source (for
example tetrakis triphenylphosphine palladium or palladium(II)
acetate), optionally a phosphine ligand (for example Xantphos or
S-phos), and a suitable base (for example cesium carbonate or
triethylamine).
[0388] Compounds of Formula (IV) are therefore useful as
intermediates in the preparation of the compounds of Formula (I)
and provide a further embodiment.
[0389] In one embodiment there is provided a compound of Formula
(IV), or a salt thereof, where:
[0390] Q is a cyclobutyl or cyclopentyl ring, each of which is
optionally substituted by one hydroxy or methoxy group, or Q is an
oxetanyl, tetrahydrofuranyl or oxanyl ring, each of which is
optionally substituted by one methyl group;
[0391] R.sup.4 is hydrogen or methyl;
[0392] R.sup.5 is hydrogen or fluoro; and
[0393] X.sup.1 is a leaving group. In one embodiment X.sup.1 is an
iodine, bromine, or chlorine atom or a triflate group. In one
embodiment X.sup.1 is a bromine atom.
[0394] In one embodiment there is provided a compound of Formula
(IV), or a salt thereof, where:
[0395] Q is cyclobutyl, 1-methoxy-cyclobut-3-yl,
1-hydroxy-cyclobut-3-yl, 3-methoxycyclopent-1-yl, oxetan-3-yl,
tetrahydrofuran-3-yl, oxan-3-yl, oxan-4-yl or
4-methyloxan-4-yl;
[0396] R.sup.4 is hydrogen or methyl;
[0397] R.sup.5 is hydrogen or fluoro; and
[0398] X.sup.1 is a leaving group. In one embodiment X.sup.1 is an
iodine, bromine, or chlorine atom or a triflate group. In one
embodiment X.sup.1 is a bromine atom.
[0399] In one embodiment there is provided a compound of Formula
(IV), or a salt thereof, where:
[0400] Q is 1-methoxy-cyclobut-3-yl, 1-hydroxy-cyclobut-3-yl,
3-methoxycyclopent-1-yl, oxetan-3-yl, oxan-3-yl, oxan-4-yl or
4-methyloxan-4-yl;
[0401] R.sup.4 is hydrogen or methyl;
[0402] R.sup.5 is hydrogen or fluoro; and
[0403] X.sup.1 is a leaving group. In one embodiment X.sup.1 is an
iodine, bromine, or chlorine atom or a triflate group. In one
embodiment X.sup.1 is a bromine atom.
[0404] In one embodiment there is provided
8-bromo-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one.
[0405] In one embodiment there is provided
8-bromo-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one.
[0406] Compounds of formula (IV) can be prepared by methods similar
to those shown in the Examples section.
[0407] Compounds of Formula (I) may also be prepared by the
reaction of a compound of Formula (IV) as described above with a
compound of formula (VI):
##STR00016##
[0408] Where R.sup.1, R.sup.2 and R.sup.3 are as defined in any of
the embodiments herein and Y is a boronic acid, boronic ester or
potassium trifluoroborate group (for example boronic acid, boronic
acid pinacol ester, or potassium trifluoroborate). The reaction may
be performed under standard conditions well known to those skilled
in the art, for example in the presence of a palladium source (for
example tetrakis triphenylphosphine palladium or palladium(II)
acetate), optionally a phosphine ligand (for example Xantphos or
S-phos), and a suitable base (for example cesium carbonate or
triethylamine).
[0409] Compounds of formula (VI) can be prepared by methods similar
to those shown in the Examples section.
[0410] As a result of their ATM kinase inhibitory activity, the
compounds of Formula (I), and pharmaceutically acceptable salts
thereof are expected to be useful in therapy, for example in the
treatment of diseases or medical conditions mediated at least in
part by ATM kinase, including cancer.
[0411] Where "cancer" is mentioned, this includes both
non-metastatic cancer and also metastatic cancer, such that
treating cancer involves treatment of both primary tumours and also
tumour metastases.
[0412] "ATM kinase inhibitory activity" refers to a decrease in the
activity of ATM kinase as a direct or indirect response to the
presence of a compound of Formula (I), or pharmaceutically
acceptable salt thereof, relative to the activity of ATM kinase in
the absence of compound of Formula (I), or pharmaceutically
acceptable salt thereof. Such a decrease in activity may be due to
the direct interaction of the compound of Formula (I), or
pharmaceutically acceptable salt thereof with ATM kinase, or due to
the interaction of the compound of Formula (I), or pharmaceutically
acceptable salt thereof with one or more other factors that in turn
affect ATM kinase activity. For example, the compound of Formula
(I), or pharmaceutically acceptable salt thereof may decrease ATM
kinase by directly binding to the ATM kinase, by causing (directly
or indirectly) another factor to decrease ATM kinase activity, or
by (directly or indirectly) decreasing the amount of ATM kinase
present in the cell or organism.
[0413] The term "therapy" is intended to have its normal meaning of
dealing with a disease in order to entirely or partially relieve
one, some or all of its symptoms, or to correct or compensate for
the underlying pathology. The term "therapy" also includes
"prophylaxis" unless there are specific indications to the
contrary. The terms "therapeutic" and "therapeutically" should be
interpreted in a corresponding manner.
[0414] The term "prophylaxis" is intended to have its normal
meaning and includes primary prophylaxis to prevent the development
of the disease and secondary prophylaxis whereby the disease has
already developed and the patient is temporarily or permanently
protected against exacerbation or worsening of the disease or the
development of new symptoms associated with the disease.
[0415] The term "treatment" is used synonymously with "therapy".
Similarly the term "treat" can be regarded as "applying therapy"
where "therapy" is as defined herein.
[0416] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, for use in
therapy.
[0417] In one embodiment there is provided the use of the compound
of Formula (I), or a pharmaceutically acceptable salt thereof, for
the manufacture of a medicament.
[0418] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, for use in the
treatment of a disease mediated by ATM kinase. In one embodiment,
said disease mediated by ATM kinase is cancer. In one embodiment,
said cancer is selected from the group consisting of colorectal
cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large
B-cell lymphoma, chronic lymphocytic leukaemia, acute myeloid
leukaemia, head and neck squamous cell carcinoma, breast cancer,
hepatocellular carcinoma, small cell lung cancer and non-small cell
lung cancer. In one embodiment, said cancer is selected from the
group consisting of colorectal cancer, glioblastoma, gastric
cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic
lymphocytic leukaemia, head and neck squamous cell carcinoma and
lung cancer. In one embodiment, said cancer is colorectal
cancer.
[0419] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, for use in the
treatment of cancer.
[0420] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, for use in the
treatment of Huntingdon's disease.
[0421] In one embodiment there is provided the use of the compound
of Formula (I), or a pharmaceutically acceptable salt thereof, for
the manufacture of a medicament for the treatment of a disease
mediated by ATM kinase. In one embodiment, said disease mediated by
ATM kinase is cancer. In one embodiment, said cancer is selected
from the group consisting of colorectal cancer, glioblastoma,
gastric cancer, ovarian cancer, diffuse large B-cell lymphoma,
chronic lymphocytic leukaemia, acute myeloid leukaemia, head and
neck squamous cell carcinoma, breast cancer, hepatocellular
carcinoma, small cell lung cancer and non-small cell lung cancer.
In one embodiment, said cancer is selected from the group
consisting of colorectal cancer, glioblastoma, gastric cancer,
ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic
leukaemia, head and neck squamous cell carcinoma and lung cancer.
In one embodiment, said cancer is colorectal cancer.
[0422] In one embodiment there is provided the use of the compound
of Formula (I), or a pharmaceutically acceptable salt thereof, for
the manufacture of a medicament for the treatment of cancer.
[0423] In one embodiment there is provided a method for treating a
disease in which inhibition of ATM kinase is beneficial in a
warm-blooded animal in need of such treatment, which comprises
administering to said warm-blooded animal a therapeutically
effective amount of a compound of Formula (I), or a
pharmaceutically acceptable salt thereof. In one embodiment, said
disease is cancer. In one embodiment, said cancer is selected from
the group consisting of colorectal cancer, glioblastoma, gastric
cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic
lymphocytic leukaemia, acute myeloid leukaemia, head and neck
squamous cell carcinoma, breast cancer, hepatocellular carcinoma,
small cell lung cancer and non-small cell lung cancer. In one
embodiment, said cancer is selected from the group consisting of
colorectal cancer, glioblastoma, gastric cancer, ovarian cancer,
diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, head
and neck squamous cell carcinoma and lung cancer. In one
embodiment, said cancer is colorectal cancer.
[0424] The term "therapeutically effective amount" refers to an
amount of a compound of Formula (I) as described in any of the
embodiments herein which is effective to provide "therapy" in a
subject, or to "treat" a disease or disorder in a subject. In the
case of cancer, the therapeutically effective amount may cause any
of the changes observable or measurable in a subject as described
in the definition of "therapy", "treatment" and "prophylaxis"
above. For example, the effective amount can reduce the number of
cancer or tumour cells; reduce the overall tumour size; inhibit or
stop tumour cell infiltration into peripheral organs including, for
example, the soft tissue and bone; inhibit and stop tumour
metastasis; inhibit and stop tumour growth; relieve to some extent
one or more of the symptoms associated with the cancer; reduce
morbidity and mortality; improve quality of life; or a combination
of such effects. An effective amount may be an amount sufficient to
decrease the symptoms of a disease responsive to inhibition of ATM
kinase activity. For cancer therapy, efficacy in-vivo can, for
example, be measured by assessing the duration of survival, time to
disease progression (TTP), the response rates (RR), duration of
response, and/or quality of life. As recognized by those skilled in
the art, effective amounts may vary depending on route of
administration, excipient usage, and co-usage with other agents.
For example, where a combination therapy is used, the amount of the
compound of formula (I) or pharmaceutically acceptable salt
described in this specification and the amount of the other
pharmaceutically active agent(s) are, when combined, jointly
effective to treat a targeted disorder in the animal patient. In
this context, the combined amounts are in a "therapeutically
effective amount" if they are, when combined, sufficient to
decrease the symptoms of a disease responsive to inhibition of ATM
activity as described above. Typically, such amounts may be
determined by one skilled in the art by, for example, starting with
the dosage range described in this specification for the compound
of formula (I) or pharmaceutically acceptable salt thereof and an
approved or otherwise published dosage range(s) of the other
pharmaceutically active compound(s).
[0425] "Warm-blooded animals" include, for example, humans.
[0426] In one embodiment there is provided a method for treating
cancer in a warm-blooded animal in need of such treatment, which
comprises administering to said warm-blooded animal a
therapeutically effective amount of a compound of Formula (I), or a
pharmaceutically acceptable salt thereof. In one embodiment, said
cancer is selected from the group consisting of colorectal cancer,
glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell
lymphoma, chronic lymphocytic leukaemia, acute myeloid leukaemia,
head and neck squamous cell carcinoma, breast cancer,
hepatocellular carcinoma, small cell lung cancer and non-small cell
lung cancer. In one embodiment, said cancer is selected from the
group consisting of colorectal cancer, glioblastoma, gastric
cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic
lymphocytic leukaemia, head and neck squamous cell carcinoma and
lung cancer. In one embodiment, said cancer is colorectal
cancer.
[0427] In any embodiment where cancer is mentioned in a general
sense, said cancer may be selected from the group consisting of
colorectal cancer, glioblastoma, gastric cancer, ovarian cancer,
diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, acute
myeloid leukaemia, head and neck squamous cell carcinoma, breast
cancer, hepatocellular carcinoma, small cell lung cancer and
non-small cell lung cancer. Said cancer may also be selected from
the group consisting of colorectal cancer, glioblastoma, gastric
cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic
lymphocytic leukaemia, head and neck squamous cell carcinoma and
lung cancer.
[0428] In any embodiment where cancer is mentioned in a general
sense the following embodiments may apply:
[0429] In one embodiment the cancer is colorectal cancer.
[0430] In one embodiment the cancer is glioblastoma.
[0431] In one embodiment the cancer is gastric cancer.
[0432] In one embodiment the cancer is oesophageal cancer.
[0433] In one embodiment the cancer is ovarian cancer.
[0434] In one embodiment the cancer is endometrial cancer.
[0435] In one embodiment the cancer is cervical cancer.
[0436] In one embodiment the cancer is diffuse large B-cell
lymphoma.
[0437] In one embodiment the cancer is chronic lymphocytic
leukaemia.
[0438] In one embodiment the cancer is acute myeloid leukaemia.
[0439] In one embodiment the cancer is head and neck squamous cell
carcinoma.
[0440] In one embodiment the cancer is breast cancer. In one
embodiment the cancer is triple negative breast cancer.
[0441] "Triple negative breast cancer" is any breast cancer that
does not express the genes for the oestrogen receptor, progesterone
receptor and Her2/neu.
[0442] In one embodiment the cancer is hepatocellular
carcinoma.
[0443] In one embodiment the cancer is lung cancer. In one
embodiment the lung cancer is small cell lung cancer. In one
embodiment the lung cancer is non-small cell lung cancer.
[0444] In one embodiment the cancer is metastatic cancer. In one
embodiment the metastatic cancer comprises metastases of the
central nervous system. In one embodiment the metastases of the
central nervous system comprise brain metastases. In one embodiment
the metastases of the central nervous system comprise
leptomeningeal metastases.
[0445] "Leptomeningeal metastases" occur when cancer spreads to the
meninges, the layers of tissue that cover the brain and the spinal
cord. Metastases can spread to the meninges through the blood or
they can travel from brain metastases, carried by the cerebrospinal
fluid (CSF) that flows through the meninges. In one embodiment the
cancer is non-metastatic cancer. The anti-cancer treatment
described in this specification may be useful as a sole therapy, or
may involve, in addition to administration of the compound of
Formula (I), conventional surgery, radiotherapy or chemotherapy; or
a combination of such additional therapies. Such conventional
surgery, radiotherapy or chemotherapy may be administered
simultaneously, sequentially or separately to treatment with the
compound of Formula (I).
[0446] Radiotherapy may include one or more of the following
categories of therapy: [0447] i. External radiation therapy using
electromagnetic radiation, and intraoperative radiation therapy
using electromagnetic radiation; [0448] ii. Internal radiation
therapy or brachytherapy; including interstitial radiation therapy
or intraluminal radiation therapy; or [0449] iii. Systemic
radiation therapy, including but not limited to iodine 131 and
strontium 89.
[0450] Therefore, in one embodiment there is provided a compound of
Formula (I), or a pharmaceutically acceptable salt thereof, and
radiotherapy, for use in the treatment of cancer. In one embodiment
the cancer is glioblastoma. In one embodiment, the cancer is
metastatic cancer. In one embodiment the metastatic cancer
comprises metastases of the central nervous system. In one
embodiment the metastases of the central nervous system comprise
brain metastases. In one embodiment the metastases of the central
nervous system comprise leptomeningeal metastases.
[0451] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, for use in the
treatment of cancer, where the compound of Formula (I), or a
pharmaceutically acceptable salt thereof, is administered in
combination with radiotherapy. In one embodiment the cancer is
glioblastoma. In one embodiment, the cancer is metastatic cancer.
In one embodiment the metastatic cancer comprises metastases of the
central nervous system. In one embodiment the metastases of the
central nervous system comprise brain metastases. In one embodiment
the metastases of the central nervous system comprise
leptomeningeal metastases.
[0452] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, and
radiotherapy, for use in the simultaneous, separate or sequential
treatment of cancer. In one embodiment the cancer is selected from
glioblastoma, lung cancer (for example small cell lung cancer or
non-small cell lung cancer), breast cancer (for example triple
negative breast cancer), head and neck squamous cell carcinoma,
oesophageal cancer, cervical cancer and endometrial cancer. In one
embodiment the cancer is glioblastoma. In one embodiment, the
cancer is metastatic cancer. In one embodiment the metastatic
cancer comprises metastases of the central nervous system. In one
embodiment the metastases of the central nervous system comprise
brain metastases. In one embodiment the metastases of the central
nervous system comprise leptomeningeal metastases.
[0453] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, for use in the
treatment of cancer, where the compound of Formula (I), or a
pharmaceutically acceptable salt thereof, is administered
simultaneously, separately or sequentially with radiotherapy. In
one embodiment the cancer is selected from glioblastoma, lung
cancer (for example small cell lung cancer or non-small cell lung
cancer), breast cancer (for example triple negative breast cancer),
head and neck squamous cell carcinoma, oesophageal cancer, cervical
cancer and endometrial cancer. In one embodiment the cancer is
glioblastoma. In one embodiment, the cancer is metastatic cancer.
In one embodiment the metastatic cancer comprises metastases of the
central nervous system. In one embodiment the metastases of the
central nervous system comprise brain metastases. In one embodiment
the metastases of the central nervous system comprise
leptomeningeal metastases.
[0454] In one embodiment there is provided a method of treating
cancer in a warm-blooded animal who is in need of such treatment,
which comprises administering to said warm-blooded animal a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof and radiotherapy, wherein the compound of Formula (I), or a
pharmaceutically acceptable salt thereof, and radiotherapy are
jointly effective in producing an anti-cancer effect. In one
embodiment the cancer is selected from glioblastoma, lung cancer
(for example small cell lung cancer or non-small cell lung cancer),
breast cancer (for example triple negative breast cancer), head and
neck squamous cell carcinoma, oesophageal cancer, cervical cancer
and endometrial cancer. In one embodiment the cancer is
glioblastoma. In one embodiment, the cancer is metastatic cancer.
In one embodiment the metastatic cancer comprises metastases of the
central nervous system. In one embodiment the metastases of the
central nervous system comprise brain metastases. In one embodiment
the metastases of the central nervous system comprise
leptomeningeal metastases.
[0455] In one embodiment there is provided a method of treating
cancer in a warm-blooded animal who is in need of such treatment,
which comprises administering to said warm-blooded animal a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof and simultaneously, separately or sequentially
administering radiotherapy, wherein the compound of Formula (I), or
a pharmaceutically acceptable salt thereof, and radiotherapy are
jointly effective in producing an anti-cancer effect. In one
embodiment the cancer is glioblastoma. In one embodiment, the
cancer is metastatic cancer. In one embodiment the metastatic
cancer comprises metastases of the central nervous system. In one
embodiment the metastases of the central nervous system comprise
brain metastases. In one embodiment the metastases of the central
nervous system comprise leptomeningeal metastases.
[0456] In any embodiment the radiotherapy is selected from the
group consisting of one or more of the categories of radiotherapy
listed under points (i)-(iii) above.
[0457] Chemotherapy may include one or more of the following
categories of anti-tumour substance: [0458] i. Antineoplastic
agents and combinations thereof, such as DNA alkylating agents (for
example cisplatin, oxaliplatin, carboplatin, cyclophosphamide,
nitrogen mustards like ifosfamide, bendamustine, melphalan,
chlorambucil, busulphan, temozolamide and nitrosoureas like
carmustine); antimetabolites (for example gemcitabine and
antifolates such as fluoropyrimidines like 5-fluorouracil and
tegafur, raltitrexed, methotrexate, cytosine arabinoside, and
hydroxyurea); anti-tumour antibiotics (for example anthracyclines
like adriamycin, bleomycin, doxorubicin, liposomal doxorubicin,
pirarubicin, daunomycin, valrubicin, epirubicin, idarubicin,
mitomycin-C, dactinomycin, amrubicin and mithramycin); antimitotic
agents (for example vinca alkaloids like vincristine, vinblastine,
vindesine and vinorelbine and taxoids like taxol and taxotere and
polokinase inhibitors); and topoisomerase inhibitors (for example
epipodophyllotoxins like etoposide and teniposide, amsacrine,
irinotecan, topotecan and camptothecin); inhibitors of DNA repair
mechanisms such as CHK kinase; DNA-dependent protein kinase
inhibitors; inhibitors of poly (ADP-ribose) polymerase (PARP
inhibitors, including olaparib); and Hsp90 inhibitors such as
tanespimycin and retaspimycin, inhibitors of ATR kinase (such as
AZD6738); and inhibitors of WEE1 kinase (such as AZD1775/MK-1775);
[0459] ii. Antiangiogenic agents such as those that inhibit the
effects of vascular endothelial growth factor, for example the
anti-vascular endothelial cell growth factor antibody bevacizumab
and for example, a VEGF receptor tyrosine kinase inhibitor such as
vandetanib (ZD6474), sorafenib, vatalanib (PTK787), sunitinib
(SU11248), axitinib (AG-013736), pazopanib (GW 786034) and
cediranib (AZD2171); compounds such as those disclosed in
International Patent Applications WO97/22596, WO 97/30035, WO
97/32856 and WO 98/13354; and compounds that work by other
mechanisms (for example linomide, inhibitors of integrin
.alpha.v.beta.3 function and angiostatin), or inhibitors of
angiopoietins and their receptors (Tie-1 and Tie-2), inhibitors of
PLGF, inhibitors of delta-like ligand (DLL-4); [0460] iii.
Immunotherapy approaches, including for example ex-vivo and in-vivo
approaches to increase the immunogenicity of patient tumour cells,
such as transfection with cytokines such as interleukin 2,
interleukin 4 or granulocyte-macrophage colony stimulating factor;
approaches to decrease T-cell anergy or regulatory T-cell function;
approaches that enhance T-cell responses to tumours, such as
blocking antibodies to CTLA4 (for example ipilimumab and
tremelimumab), B7H1, PD-1 (for example BMS-936558 or AMP-514),
PD-L1 (for example MEDI4736) and agonist antibodies to CD137;
approaches using transfected immune cells such as
cytokine-transfected dendritic cells; approaches using
cytokine-transfected tumour cell lines, approaches using antibodies
to tumour associated antigens, and antibodies that deplete target
cell types (e.g., unconjugated anti-CD20 antibodies such as
Rituximab, radiolabeled anti-CD20 antibodies Bexxar and Zevalin,
and anti-CD54 antibody Campath); approaches using anti-idiotypic
antibodies; approaches that enhance Natural Killer cell function;
and approaches that utilize antibody-toxin conjugates (e.g.
anti-CD33 antibody Mylotarg); immunotoxins such as moxetumumab
pasudotox; agonists of toll-like receptor 7 or toll-like receptor
9; [0461] iv. Efficacy enhancers, such as leucovorin.
[0462] Therefore, in one embodiment there is provided a compound of
Formula (I), or a pharmaceutically acceptable salt thereof, and at
least one additional anti-tumour substance, for use in the
treatment of cancer. In one embodiment there is provided a compound
of Formula (I), or a pharmaceutically acceptable salt thereof, for
use in the treatment of cancer, where the compound of Formula (I),
or a pharmaceutically acceptable salt thereof is administered in
combination with an additional anti-tumour substance. In one
embodiment there is one additional anti-tumour substance. In one
embodiment there are two additional anti-tumour substances. In one
embodiment there are three or more additional anti-tumour
substances.
[0463] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, and at least
one additional anti-tumour substance for use in the simultaneous,
separate or sequential treatment of cancer. In one embodiment there
is provided a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, for use in the treatment of cancer, where
the compound of Formula (I), or a pharmaceutically acceptable salt
thereof, is administered simultaneously, separately or sequentially
with an additional anti-tumour substance.
[0464] In one embodiment there is provided a method of treating
cancer in a warm-blooded animal who is in need of such treatment,
which comprises administering to said warm-blooded animal a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof and at least one additional anti-tumour substance, wherein
the amounts of the compound of Formula (I), or a pharmaceutically
acceptable salt thereof, and the additional anti-tumour substance
are jointly effective in producing an anti-cancer effect.
[0465] In one embodiment there is provided a method of treating
cancer in a warm-blooded animal who is in need of such treatment,
which comprises administering to said warm-blooded animal a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof, and simultaneously, separately or sequentially
administering at least one additional anti-tumour substance to said
warm-blooded animal, wherein the amounts of the compound of Formula
(I), or pharmaceutically acceptable salt thereof, and the
additional anti-tumour substance are jointly effective in producing
an anti-cancer effect.
[0466] In any embodiment the additional anti-tumour substance is
selected from the group consisting of one or more of the
anti-tumour substances listed under points (i)-(iv) above.
[0467] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, and at least
one anti-neoplastic agent for use in the treatment of cancer. In
one embodiment there is provided a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, for use in the treatment
of cancer, where the compound of Formula (I), or a pharmaceutically
acceptable salt thereof, is administered in combination with at
least one anti-neoplastic agent. In one embodiment the
anti-neoplastic agent is selected from the list of antineoplastic
agents in point (i) above.
[0468] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, and at least
one anti-neoplastic agent for use in the simultaneous, separate or
sequential treatment of cancer. In one embodiment there is provided
a compound of Formula (I), or a pharmaceutically acceptable salt
thereof, for use in the treatment of cancer, where the compound of
Formula (I), or a pharmaceutically acceptable salt thereof, is
administered simultaneously, separately or sequentially with at
least one anti-neoplastic agent. In one embodiment the
antineoplastic agent is selected from the list of antineoplastic
agents in point (i) above.
[0469] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, and at least
one additional anti-tumour substance selected from the group
consisting of cisplatin, oxaliplatin, carboplatin, valrubicin,
idarubicin, doxorubicin, pirarubicin, irinotecan, topotecan,
amrubicin, epirubicin, etoposide, mitomycin, bendamustine,
chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan,
bleomycin, olaparib, MEDI4736, AZD1775 and AZD6738, for use in the
treatment of cancer.
[0470] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, and at least
one additional anti-tumour substance selected from the group
consisting of cisplatin, oxaliplatin, carboplatin, doxorubicin,
pirarubicin, irinotecan, topotecan, amrubicin, epirubicin,
etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide,
ifosfamide, carmustine, melphalan, bleomycin, olaparib, AZD1775 and
AZD6738, for use in the treatment of cancer.
[0471] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, for use in the
treatment of cancer, where the compound of Formula (I), or a
pharmaceutically acceptable salt thereof, is administered in
combination with at least one additional anti-tumour substance
selected from the group consisting of cisplatin, oxaliplatin,
carboplatin, valrubicin, idarubicin, doxorubicin, pirarubicin,
irinotecan, topotecan, amrubicin, epirubicin, etoposide, mitomycin,
bendamustine, chlorambucil, cyclophosphamide, ifosfamide,
carmustine, melphalan, bleomycin, olaparib, MEDI4736, AZD1775 and
AZD6738.
[0472] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, and at least
one additional anti-tumour substance selected from the group
consisting of doxorubicin, irinotecan, topotecan, etoposide,
mitomycin, bendamustine, chlorambucil, cyclophosphamide,
ifosfamide, carmustine, melphalan, bleomycin and olaparib for use
in the treatment of cancer.
[0473] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, for use in the
treatment of cancer, where the compound of Formula (I), or a
pharmaceutically acceptable salt thereof, is administered in
combination with at least one additional anti-tumour substance
selected from the group consisting of doxorubicin, irinotecan,
topotecan, etoposide, mitomycin, bendamustine, chlorambucil,
cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin and
olaparib.
[0474] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, and at least
one additional anti-tumour substance selected from the group
consisting of doxorubicin, irinotecan, topotecan, etoposide,
mitomycin, bendamustine, chlorambucil, cyclophosphamide,
ifosfamide, carmustine, melphalan and bleomycin, for use in the
treatment of cancer.
[0475] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, for use in the
treatment of cancer, where the compound of Formula (I), or a
pharmaceutically acceptable salt thereof, is administered in
combination with at least one additional anti-tumour substance
selected from the group consisting of doxorubicin, irinotecan,
topotecan, etoposide, mitomycin, bendamustine, chlorambucil,
cyclophosphamide, ifosfamide, carmustine, melphalan and
bleomycin.
[0476] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, for use in the
treatment of cancer, where the compound of Formula (I), or a
pharmaceutically acceptable salt thereof, is administered in
combination with at least one additional anti-tumour substance
selected from the group consisting of doxorubicin, pirarubicin,
amrubicin and epirubicin. In one embodiment the cancer is acute
myeloid leukaemia. In one embodiment the cancer is breast cancer
(for example triple negative breast cancer). In one embodiment the
cancer is hepatocellular carcinoma.
[0477] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, and irinotecan,
for use in the treatment of cancer. In one embodiment there is
provided a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, for use in the treatment of cancer, where
the compound of Formula (I), or a pharmaceutically acceptable salt
thereof, is administered in combination with irinotecan. In one
embodiment the cancer is colorectal cancer.
[0478] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, and FOLFIRI,
for use in the treatment of cancer. In one embodiment there is
provided a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, for use in the treatment of cancer, where
the compound of Formula (I), or a pharmaceutically acceptable salt
thereof, is administered in combination with FOLFIRI. In one
embodiment the cancer is colorectal cancer.
[0479] FOLFIRI is a dosage regime involving a combination of
leucovorin, 5-fluorouracil and irinotecan.
[0480] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, for use in the
treatment of cancer, where the compound of Formula (I), or a
pharmaceutically acceptable salt thereof, is administered in
combination with olaparib. In one embodiment the cancer is gastric
cancer.
[0481] In one embodiment there is provided a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, for use in the
treatment of cancer, where the compound of Formula (I), or a
pharmaceutically acceptable salt thereof, is administered in
combination with topotecan. In one embodiment the cancer is small
cell lung cancer. In one embodiment there is provided a compound of
Formula (I), or a pharmaceutically acceptable salt thereof, for use
in the treatment of cancer, where the compound of Formula (I), or a
pharmaceutically acceptable salt thereof, is administered in
combination with immunotherapy. In one embodiment the immunotherapy
is one or more of the agents listed under point (iii) above. In one
embodiment the immunotherapy is an anti-PD-L1 antibody (for example
MEDI4736).
[0482] In one embodiment there is provided a pharmaceutical
composition comprising a compound of Formula (I) and at least one
additional anti-tumour substance. In one embodiment the
pharmaceutical composition also comprises at least one
pharmaceutically acceptable diluent or carrier. In one embodiment
the anti-tumour substance is an anti-neoplastic agent.
[0483] In one embodiment there is provided a pharmaceutical
composition comprising a compound of Formula (I) and at least one
additional anti-tumour substance, for use in the treatment of
cancer. In one embodiment the pharmaceutical composition also
comprises at least one pharmaceutically acceptable diluent or
carrier. In one embodiment the anti-tumour substance is an
anti-neoplastic agent.
[0484] According to a further embodiment there is provided a kit
comprising:
[0485] a) A compound of formula (I), or a pharmaceutically
acceptable salt thereof, in a first unit dosage form;
[0486] b) A further additional anti-tumour substance in a further
unit dosage form;
[0487] c) Container means for containing said first and further
unit dosage forms; and optionally
[0488] d) Instructions for use. In one embodiment the anti-tumour
substance comprises an anti-neoplastic agent.
[0489] In any embodiment where an anti-neoplastic agent is
mentioned, the anti-neoplastic agent is one or more of the agents
listed under point (i) above.
[0490] The compounds of Formula (I), and pharmaceutically
acceptable salts thereof, may be administered as pharmaceutical
compositions, comprising one or more pharmaceutically acceptable
diluents or carriers.
[0491] Therefore, in one embodiment there is provided a
pharmaceutical composition comprising a compound of Formula (I), or
a pharmaceutically acceptable salt thereof, and at least one
pharmaceutically acceptable diluent or carrier.
[0492] The compositions may be in a form suitable for oral use (for
example as tablets, lozenges, hard or soft capsules, aqueous or
oily suspensions, emulsions, dispersible powders or granules,
syrups or elixirs), for topical use (for example as creams,
ointments, gels, or aqueous or oily solutions or suspensions), for
administration by inhalation (for example as a finely divided
powder or a liquid aerosol), for administration by insufflation
(for example as a finely divided powder) or for parenteral
administration (for example as a sterile aqueous or oily solution
for intravenous, subcutaneous, intramuscular or intramuscular
dosing), or as a suppository for rectal dosing. The compositions
may be obtained by conventional procedures using conventional
pharmaceutical excipients, well known in the art. Thus,
compositions intended for oral use may contain, for example, one or
more colouring, sweetening, flavouring and/or preservative
agents.
[0493] In one embodiment there is provided a pharmaceutical
composition comprising a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, and at least one
pharmaceutically acceptable diluent or carrier, for use in
therapy.
[0494] In one embodiment there is provided a pharmaceutical
composition comprising a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, and at least one
pharmaceutically acceptable diluent or carrier, for use in the
treatment of cancer. In one embodiment, said cancer is selected
from the group consisting of colorectal cancer, glioblastoma,
gastric cancer, ovarian cancer, diffuse large B-cell lymphoma,
chronic lymphocytic leukaemia, acute myeloid leukaemia, head and
neck squamous cell carcinoma, breast cancer, hepatocellular
carcinoma, small cell lung cancer and non-small cell lung cancer.
In one embodiment, said cancer is selected from the group
consisting of colorectal cancer, glioblastoma, gastric cancer,
ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic
leukaemia, head and neck squamous cell carcinoma and lung cancer.
In one embodiment, said cancer is colorectal cancer.
[0495] The compound of Formula (I) will normally be administered to
a warm-blooded animal at a unit dose within the range 2.5-5000
mg/m.sup.2 body area of the animal, or approximately 0.05-100
mg/kg, and this normally provides a therapeutically-effective dose.
A unit dose form such as a tablet or capsule will usually contain,
for example 0.1-250 mg of active ingredient. The daily dose will
necessarily be varied depending upon the host treated, the
particular route of administration, any therapies being
co-administered, and the severity of the illness being treated.
Accordingly the practitioner who is treating any particular patient
may determine the optimum dosage.
EXAMPLES
[0496] The various embodiments are illustrated by the following
Examples. The invention is not to be interpreted as being limited
to the Examples. During the preparation of the Examples, generally:
[0497] i. Operations were carried out at ambient temperature/room
temperature, i.e. in the range of about 17.degree. C. to 30.degree.
C. and under atmospheric conditions unless otherwise stated; [0498]
ii. Evaporations were carried out by rotary evaporation or
utilising Genevac equipment in vacuo and work-up procedures were
carried out after removal of residual solids by filtration; [0499]
iii. Flash chromatography purifications were performed on an
automated Armen Glider Flash: Spot II Ultimate (Armen Instrument,
Saint-Ave, France) or automated Presearch combiflash companions
using prepacked Merck normal phase Si60 silica cartridges
(granulometry: 15-40 or 40-63 .mu.m) obtained from Merck, Darmstad,
Germany, silicycle silica cartridges or graceresolv silica
cartridges; [0500] iv. Preparative chromatography was performed on
a Waters instrument (600/2700 or 2525) fitted with a ZMD or ZQ ESCi
mass spectrometers and a Waters X-Terra or a Waters X-Bridge or a
Waters SunFire reverse-phase column (C-18, 5 microns silica, 19 mm
or 50 mm diameter, 100 mm length, flow rate of 40 mL/minute) using
decreasingly polar mixtures of water (containing 1% ammonia) and
acetonitrile or decreasingly polar mixtures of water (containing
0.1% formic acid) and acetonitrile as eluents. Examples 2, 6-8, 13,
16, 18, 19-22, 27, 29, 34, 39, 59, 60, 70 and 71 were isolated
directly from preparative HPLC solutions containing formic acid.
The material isolated therefore comprises a certain amount of
formic acid; [0501] v. Yields, where present, are not necessarily
the maximum attainable; [0502] vi. Structures of end-products of
Formula (I) were confirmed by nuclear magnetic resonance (NMR)
spectroscopy, with NMR chemical shift values measured on the delta
scale. Proton magnetic resonance spectra were determined using a
Bruker advance 700 (700 MHz), Bruker Avance 500 (500 MHz), Bruker
400 (400 MHz) or Bruker 300 (300 MHz) instrument; 19F NMR were
determined at 282 MHz or 376 MHz; 13C NMR were determined at 75 MHz
or 100 MHz; measurements were taken at around 20-30.degree. C.
unless otherwise specified; the following abbreviations have been
used: s=singlet; d=doublet; t=triplet; q=quartet; p=pentet/quintet;
m=multiplet; dd=doublet of doublets; ddd=doublet of doublet of
doublet; dt=doublet of triplets; td=triplet of doublets; qd=quartet
of doublets; bs=broad signal; [0503] vii. End-products of Formula
(I) were also characterised by mass spectroscopy following liquid
chromatography (LCMS); LCMS was carried out using an Waters
Alliance HT (2790 & 2795) fitted with a Waters ZQ ESCi or ZMD
ESCi mass spectrometer and an X Bridge 5 .mu.m C-18 column
(2.1.times.50 mm) at a flow rate of 2.4 mL/min, using a solvent
system of 95% A+5% C to 95% B+5% C over 4 minutes, where A=water,
B=methanol, C=1:1 methanol:water (containing 0.2% ammonium
carbonate); or by using a Shimadzu UFLC or UHPLC coupled with DAD
detector, ELSD detector and 2020 EV mass spectrometer (or
equivalent) fitted with a Phenomenex Gemini-NX C18 3.0.times.50 mm,
3.0 .mu.m column or equivalent (basic conditions) or a Shim pack
XR--ODS 3.0.times.50 mm, 2.2 .mu.m column or Waters BEH C18
2.1.times.50 mm, 1.7 .mu.m column or equivalent using a solvent
system of 95% D+5% E to 95% E+5% D over 4 minutes, where D=water
(containing 0.05% TFA), E=Acetonitrile (containing 0.05% TFA)
(acidic conditions) or a solvent system of 90% F+10% G to 95% G+5%
F over 4 minutes, where F=water (containing 6.5 mM ammonium
hydrogen carbonate and adjusted to pH10 by addition of ammonia),
G=Acetonitrile (basic conditions); [0504] viii. Intermediates were
not generally fully characterised and purity was assessed by thin
layer chromatographic, mass spectral, HPLC and/or NMR analysis;
[0505] ix. X-ray powder diffraction spectra were determined (using
a Bruker D4 Analytical Instrument) by mounting a sample of the
crystalline material on a Bruker single silicon crystal (SSC) wafer
mount and spreading out the sample into a thin layer with the aid
of a microscope slide. The sample was spun at 30 revolutions per
minute (to improve counting statistics) and irradiated with X-rays
generated by a copper long-fine focus tube operated at 40 kV and 40
mA with a wavelength of 1.5418 angstroms. The collimated X-ray
source was passed through an automatic variable divergence slit set
at V20 and the reflected radiation directed through a 5.89 mm
antiscatter slit and a 9.55 mm detector slit. The sample was
exposed for 0.03 seconds per 0.00570.degree. 2-theta increment
(continuous scan mode) over the range 2 degrees to 40 degrees
2-theta in theta-theta mode. The running time was 3 minutes and 36
seconds. The instrument was equipped with a Position sensitive
detector (Lynxeye). Control and data capture was by means of a Dell
Optiplex 686 NT 4.0 Workstation operating with Diffrac+software;
[0506] x. Differential Scanning Calorimetry was performed on a TA
Instruments Q1000 DSC. Typically, less than 5 mg of material
contained in a standard aluminium pan fitted with a lid was heated
over the temperature range 25.degree. C. to 300.degree. C. at a
constant heating rate of 10.degree. C. per minute. A purge gas
using nitrogen was used at a flow rate 50 ml per minute [0507] xi.
The following abbreviations have been used: h=hour(s); r.t.=room
temperature (.about.17-30.degree. C.); conc.=concentrated;
FCC=flash column chromatography using silica; DCM=dichloromethane;
DIPEA=diisopropylethylamine; DMA=N,N-dimethylacetamide;
DMF=N,N-dimethylformamide; DMSO=dimethylsulfoxide;
Et.sub.2O=diethyl ether; EtOAc=ethyl acetate; EtOH=ethanol;
K.sub.2CO.sub.3=potassium carbonate; MeOH=methanol;
MeCN=acetonitrile; MTBE=Methyltertbutylether; MgSO.sub.4=anhydrous
magnesium sulphate; Na.sub.2SO.sub.4=anhydrous sodium sulphate;
THF=tetrahydrofuran; sat.=saturated aqueous solution; and [0508]
xii. IUPAC names were generated using `SmiToSd`, a proprietary
program built around the OpenEye Lexichem toolkit
(http://www.eyesopen.com/lexichem-tk), or Canvas, a different
proprietary program. `SmiToSd` was used to name Examples 1 to 22
and 25 to 42, and Canvas was used to name Examples 23, 24 and 43 to
71. `SmiToSd` did not automatically recognise stereochemistry of
the 3-substituted cyclobut-1-yl group present in certain of the
Examples, so the names of these Examples were manually edited to
include the correct cyclobutyl stereochemistry. Furthermore, as
stated in the introduction, the compounds comprise an
imidazo[4,5-c]quinolin-2-one core. However, in certain Examples the
IUPAC name describes the core as an imidazo[5,4-c]quinolin-2-one.
The imidazo[4,5-c]quinolin-2-one and imidazo[5,4-c]quinolin-2-one
cores are nevertheless the same, with the naming convention
slightly different because of the peripheral groups.
Example 1
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5-
,4-c]quinolin-2-one
##STR00017##
[0510] Sodium hydride (60% dispersion in mineral oil) (21.14 g,
528.56 mmol) was added portion-wise to 3-(dimethylamino)propan-1-ol
(27.3 g, 264.27 mmol) in DMF (500 mL) at 10.degree. C. over a
period of 20 minutes under nitrogen. The resulting mixture was
stirred at r.t. for 1 h.
8-(6-Fluoropyridin-3-yl)-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-o-
ne (50.0 g, 132.14 mmol) was added portion-wise to the reaction
mixture at 10.degree. C. over a period of 20 minutes under
nitrogen. The resulting mixture was stirred at r.t. for 16 h. The
reaction mixture was diluted with water and the precipitate
collected by filtration, washed with water (300 mL) and dried under
vacuum. The dried solid was triturated with EtOAc (2 L) and
filtered. The crude product was purified by crystallisation from
MeCN to afford the desired product (50.0 g, 82%) as a white solid.
NMR Spectrum: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.90-2.04
(4H, m), 2.29 (6H, s), 2.49 (2H, t), 2.93-3.07 (2H, m), 3.56-3.67
(5H, m), 4.10-4.30 (2H, m), 4.43 (2H, t), 5.10 (1H, t), 6.89 (1H,
d), 7.80 (1H, d), 7.92 (1H, dd), 8.21 (1H, d), 8.40 (1H, s), 8.51
(1H, d), 8.71 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=462.3.
[0511] The title material (49.5 g, 107.25 mmol) was suspended in
MeCN (300 mL) to give a freely stirring thick solution. This
solution was allowed to stir at r.t. overnight giving a thinner
solution. The material was filtered, washed with cold (0.degree.
C.) MeCN (200 mL) and dried overnight in vacuo at 30.degree. C. to
give the title material in crystalline form A (48 g, 97%) as a
white solid. NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta.
1.81-1.99 (4H, m), 2.16 (6H, s), 2.37 (2H, t), 2.73 (2H, qd), 3.51
(3H, s), 3.59 (2H, t), 4.07 (2H, dd), 4.37 (2H, t), 5.14 (1H, ddd),
6.94-7.01 (1H, m), 7.95 (1H, dd), 8.14 (1H, d), 8.18 (1H, dd), 8.43
(1H, s), 8.66 (1H, d), 8.89 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=462.6.
[0512] The slurry filtrate and washings were combined and
evaporated to recover additional title material (580 mg, 1.172%) as
a pale cream solid. The material obtained by the above procedure
was determined to be crystalline form A and was analysed by XRPD to
give an X-Ray diffractogram with the following characteristic
peaks.
TABLE-US-00001 TABLE 1 Characteristic X-Ray powder diffraction
peaks for Form A of 8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-
methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one Angle 2-Theta
(2.theta.) Intensity (%) 3.9 100 11.6 78 21.3 32 22.2 28 10.7 25
7.7 21 15.4 20 16.9 18 17.4 15 18.4 14
[0513]
8-(6-Fluoropyridin-3-yl)-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinol-
in-2-one can be prepared according to the following procedure.
Intermediate A1:
8-(6-Fluoropyridin-3-yl)-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-o-
ne
##STR00018##
[0515] Monopalladium(IV) disodium tetrachloride (0.975 g, 3.31
mmol) was added to
8-bromo-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one (60.0 g,
165.64 mmol), (6-fluoropyridin-3-yl)boronic acid (25.7 g, 182.21
mmol), K.sub.2CO.sub.3 (68.7 g, 496.93 mmol) and
3-(di-tert-butylphosphino)propane-1-sulfonic acid (0.445 g, 1.66
mmol) in 1,4-dioxane (400 mL) and water (100 mL) at r.t. under air.
The resulting mixture was stirred at 80.degree. C. for 16 h. The
reaction mixture was diluted with water and the precipitate
collected by filtration, washed with water (200 mL) and dried under
vacuum. The resulting solid was dissolved with DCM (18 L) and the
mixture filtered through celite to remove Palladium residues. The
solvent was removed under reduced pressure to afford the desired
material (60.0 g, 96%) as a white solid, which was used without
further purification. NMR Spectrum: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 1.85-2.01 (2H, m), 2.86-3.02 (2H, m), 3.57-3.68
(5H, m), 4.16-4.31 (2H, m), 5.11 (1H, t), 6.98-7.19 (1H, m), 7.83
(1H, dd), 8.16 (1H, td), 8.30 (1H, dd), 8.50 (1H, s), 8.60 (1H, s),
8.77 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=379.2.
Intermediate A2:
8-Bromo-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one
##STR00019##
[0517] A solution of sodium hydroxide (10.34 g, 258.48 mmol) in
water (900 mL) was added to a stirred mixture of
8-bromo-1-(oxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-one (60.0 g,
172.32 mmol), iodomethane (48.9 g, 344.63 mmol) and
tetrabutylammonium bromide (5.55 g, 17.23 mmol) in DCM (1500 mL) at
r.t. under air. The resulting mixture was stirred for 16 h then the
DCM removed under reduced pressure. The precipitate was collected
by filtration, washed with water (200 mL) and dried under vacuum to
afford the desired material (58.0 g, 93%) as a brown solid, which
was used without further purification. NMR Spectrum: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 1.81-1.98 (2H, m), 2.82-3.00 (2H, m),
3.60 (3H, s), 3.63 (2H, td), 4.05-4.35 (2H, m), 4.93 (1H, t), 7.69
(1H, dd), 8.03 (1H, d), 8.36 (1H, s), 8.71 (1H, s). Mass Spectrum:
m/z (ES+)[M+H]+=364.
[0518] On a larger scale,
8-bromo-1-(oxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-one (1300 g, 3.73
mol) was charged to the vessel along with tetrabutylammonium
bromide (130 g, 0.40 mol) and 2-MeTHF (20.8 L). A solution of NaOH
(240 g, 6.00 mol) in water (20.8 L) was then added over 5 minutes
with an observed exotherm from 18-24.degree. C. The biphasic
mixture was heated to 42-48.degree. C. before the addition of
methyl iodide (465 mL, 7.47 mol) as a solution in 2-MeTHF (930 mL).
The reaction was stirred at 45.degree. C. for 17 h at which point
HPLC analysis showed 2.9% starting material and 97.1% product. The
reaction mixture was combined with that of the other large scale
batches for concentration in vacuo. The resulting aqueous
suspension was then returned to the vessel and slurried for 1 h
with the product material obtained from the development batches
combined at this point. The product was then isolated by
filtration, washing with water (2.times.12 L) before oven drying
under vacuum at 40.degree. C. In total 3479 g of
8-bromo-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one was
isolated. Analytical data was consistent with that obtained from
previous batches.
Intermediate A3:
8-Bromo-1-(oxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-one
##STR00020##
[0520] Triethylamine (143 mL, 1025.07 mmol) was added to
6-bromo-4-(oxan-4-ylamino)quinoline-3-carboxylic acid (120 g,
341.69 mmol) in DMF (600 mL) at r.t. under air. The resulting
mixture was stirred for 30 minutes then diphenyl phosphorazidate
(113 g, 410.03 mmol) was added. The resulting mixture was stirred
for 30 minutes at r.t. then at 60.degree. C. for 2 h. The solvent
was removed under reduced pressure and the reaction mixture diluted
with water. The precipitate was collected by filtration, washed
with water (250 mL) and dried under vacuum to afford the desired
material (120 g, 101%) as a brown solid, which was used without
further purification.
[0521] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta.
1.72-1.95 (2H, m), 2.59-2.80 (2H, m), 3.58 (2H, td), 3.98-4.11 (2H,
m), 4.75-5.04 (1H, m), 7.75 (1H, dd), 7.97 (1H, d), 8.43 (1H, s),
8.71 (1H, s), 11.71 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=348.
[0522] On a larger scale,
6-bromo-4-(oxan-4-ylamino)quinoline-3-carboxylic acid (2011 g,
(2005 g active), 5.71 mol) was added to the vessel with DMF (18.2
L). Triethylamine (4.7 L, 33.72 mol) was added with an endotherm
observed from 21-18.degree. C. Diphenyl phosphorazidate (1600 mL,
7.42 mol) was added over 10 minutes with an observed exotherm from
21.degree. C. to 23.degree. C. over the addition. The exotherm
continued with the batch reaching 55.degree. C. after 1 h (jacket
held at 30.degree. C.) with gas evolution. The reaction initially
went into solution with a precipitate then forming after .about.30
minutes. Once the temperature had stabilised the batch was analysed
by HPLC showing consumption of starting material and 99% product.
The batch was heated to 60.degree. C. for h with HPLC again
indicating consumption of starting material and 98% product. The
batch was concentrated in vacuo to a minimum volume (.about.3
volumes) and the residue added to water (17 L) rinsing in with a
further portion of water (10 L). The mixture was slurried for 1 h
and filtered, washing with water (2.times.17 L). The solid was then
returned to the vessel and slurried in sat. NaHCO.sub.3 solution
(10 L) and MeOH (495 mL) for 1 h. The solid was collected by
filtration, washing with water (2.times.3.5 L) and then oven dried
in vacuo at 40.degree. C. for 116 h to obtain 2023 g of desired
material. Analytical data was consistent with that obtained from
previous batches.
Intermediate A4: 6-Bromo-4-(oxan-4-ylamino)quinoline-3-carboxylic
acid
##STR00021##
[0524] A solution of sodium hydroxide (79 g, 1977.60 mmol) in water
(1500 mL) was added to a stirred mixture of ethyl
6-bromo-4-(oxan-4-ylamino)quinoline-3-carboxylate (150 g, 395.52
mmol) in MeOH (1500 mL) at r.t. under air. The resulting mixture
was stirred at 70.degree. C. for 2 h then the solvent removed under
reduced pressure. The reaction mixture was adjusted to pH=3 with 2M
hydrochloric acid. The precipitate was collected by filtration,
washed with water (500 mL) and dried under vacuum to afford the
desired material (120 g, 86%) as a white solid, which was used
without further purification. NMR Spectrum: .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 1.75-1.82 (2H, m), 2.05-2.09 (2H, m), 3.85-3.94
(5H, m), 7.95 (1H, d), 8.18 (1H, d), 8.65 (1H, s), 9.01 (1H, s).
Mass Spectrum: m/z (ES+)[M+H]+=351.1.
[0525] On a larger scale, ethyl
6-bromo-4-(oxan-4-ylamino)quinoline-3-carboxylate (1925 g, 5.08
mol) was charged to the vessel with EtOH (12.5 L). 2M NaOH (12.5 L,
25.03 mol) was then added with an exotherm from 22-35.degree. C.
over the 20 minute addition. The batch was heated to 70-80.degree.
C. for 17 h at which point HPLC indicated 98.3% product and <1%
starting material.
[0526] The batch was concentrated in vacuo to remove EtOH and
returned to the vessel. A 2M HCl solution (13 L) was then added
until pH 5-6 was obtained maintaining a batch temperature below
50.degree. C. An exotherm from 20-32.degree. C. was observed over
the 40 minute addition. A precipitate formed which was slurried at
20-25.degree. C. for 1.5 h before filtration, washing with water
until pH neutral (3.times.7 L). The collected solid was dried under
vacuum at 70.degree. C. to give 1794 g of desired material.
Analytical data was consistent with that obtained from previous
batches.
Intermediate A5: Ethyl
6-bromo-4-(oxan-4-ylamino)quinoline-3-carboxylate
##STR00022##
[0528] DIPEA (139 mL, 794.75 mmol) was added to ethyl
6-bromo-4-chloroquinoline-3-carboxylate (100 g, 317.90 mmol) and
tetrahydro-2H-pyran-4-amine (35.4 g, 349.69 mmol) in DMA (1000 mL)
at r.t. under air. The resulting mixture was stirred at 60.degree.
C. for 16 h then the solvent removed under reduced pressure. The
mixture was azeotroped twice with toluene to afford the desired
material (150 g, 124%) as a brown solid, which was used without
further purification.
[0529] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta. 1.36
(3H, t), 1.58-1.75 (2H, m), 1.90-2.02 (2H, m), 3.40 (2H, t),
3.81-3.98 (2H, m), 3.98-4.19 (1H, m), 4.37 (2H, q), 7.82 (1H, d),
7.92 (1H, dd), 8.56 (1H, s), 8.86 (1H, s). Mass Spectrum: m/z
(ES-)[M-H]-=378, 380.
[0530] On a larger scale, ethyl
6-bromo-4-chloroquinoline-3-carboxylate (2196 g, (1976 g active),
6.28 mol) was charged to the vessel with DMA (16 L).
Tetrahydro-2H-pyran-4-amine (1224 g, 12.10 mol) was added over 10
minutes with an observed exotherm of 21-27.degree. C. DIPEA (3.5 L,
20.09 mol) was added with no observed exotherm. The mixture was
heated to 75-85.degree. C. and the resulting solution stirred for
18.5 h at 80.degree. C. HPLC indicated consumption of starting
material and 99.2% product. The reaction was cooled to 50.degree.
C. and then poured into water (50 L). The resulting suspension was
stirred for 2 h at r.t. and the solids isolated by filtration,
washing with water (8 L then 2.times.4 L). The solid was dried
under vacuum at 40.degree. C. for 55 h to give 2307 g of desired
material. Analytical data was consistent with that obtained from
previous batches.
Intermediate A6: Ethyl 6-bromo-4-chloroquinoline-3-carboxylate
##STR00023##
[0532] DMF (0.119 mL, 1.54 mmol) was added to ethyl
6-bromo-1-[(4-methoxyphenyl)methyl]-4-oxoquinoline-3-carboxylate
(160 g, 384.37 mmol) in thionyl chloride (800 mL) at r.t. under
air. The resulting mixture was stirred at 75.degree. C. for 16 h
then the solvent removed under reduced pressure. The resulting
mixture was azeotroped twice with toluene then n-hexane (500 mL)
added. The precipitate was collected by filtration, washed with
n-hexane (200 mL) and dried under vacuum to afford the desired
material (100 g, 83%) as a brown solid. NMR Spectrum: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 1.47 (3H, t), 4.51 (2H, q), 7.95 (1H,
dd), 8.11 (1H, d), 8.60 (1H, d), 9.24 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=314, 316.
[0533] On a larger scale, ethyl
6-bromo-1-[(4-methoxyphenyl)methyl]-4-oxoquinoline-3-carboxylate
(5765 g, 13.85 mol) was charged to the vessel with thionyl chloride
(28.8 L). An exotherm from 20-26.degree. C. was observed. DMF (4.4
mL) was added with no observed exotherm and the batch heated to
75.degree. C. and stirred for 17 h. HPLC showed 1.3% starting
material remained with 98.0% product. The reaction was concentrated
in vacuo and the residue azeotroped with toluene (25 L). The
resulting solid was then slurried in heptane (18.5 L) for 2.5 h,
filtered and washed with heptane (3.times.4 L). The solid was dried
under vacuum at 35.degree. C. to give 4077 g of the desired
material (93% crude yield) which contained .about.5% of ethyl
6-bromo-1-[(4-methoxyphenyl)methyl]-4-oxoquinoline-3-carboxylate in
addition to .about.4% hydrolysis product by HPLC (90% pure). The
crude material (4077 g) was returned to the vessel and reprocessed
with thionyl chloride (14.5 L) and DMF (2.2 mL). The mixture was
heated to 75.degree. C. for 40 h. The thionyl chloride was removed
in vacuo and the residue azeotroped with toluene (10 L). The
residue was slurried in heptane (18 L) for .about.16 h at
20.degree. C. The solid was collected by filtration, one portion
being filtered under nitrogen and washed with heptane (3 L) to
yield 2196 g of desired material (90% NMR assay, 99% by HPLC). The
remainder of the batch was filtered under air and washed with
heptane (3 L) to yield 1905 g of the desired material (88% NMR
assay, 99% by HPLC). The yellow solids were combined for further
processing (4101 g, 3653 g active, 83% yield, 99% by HPLC).
Intermediate A7: Ethyl
6-bromo-1-[(4-methoxyphenyl)methyl]-4-oxoquinoline-3-carboxylate
##STR00024##
[0535] DBU (102 mL, 679.62 mmol) was added drop-wise to ethyl
2-(5-bromo-2-fluorobenzoyl)-3-[(4-methoxyphenyl)methylamino]prop-2-enoate
(296.5 g, 679.62 mmol), in acetone (1.2 L) at r.t. over a period of
2 minutes. The resulting solution was stirred for 16 h then the
solid removed by filtration and washed with MTBE to afford the
desired material (180 g, 64%) as light yellow solid. NMR Spectrum:
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 1.30 (3H, t), 3.71 (3H, s),
4.25 (2H, q), 5.60 (2H, s), 6.90-6.95 (2H, m), 7.12-7.25 (2H, m),
7.67 (1H, d), 7.80-7.90 (1H, m), 8.30 (1H, d), 8.92 (1H, s). Mass
Spectrum: m/z (ES+)[M+H]+=418.
[0536] On a larger scale, ethyl
2-(5-bromo-2-fluorobenzoyl)-3-[(4-methoxyphenyl)methylamino]prop-2-enoate
(8434 g, (7730 g assumed active), 17.71 mol) was charged to the
vessel with acetone (23.2 L) at 15.degree. C. DBU (2.8 L, 18.72
mol) was added over 25 minutes with an observed exotherm from
18-23.degree. C. over the addition. A precipitate formed after
.about.25 minutes and the batch continued to exotherm reaching a
maximum of 37.degree. C. after 1 h. The reaction was stirred at
20.degree. C. for 16.5 h at which point HPLC indicated consumption
of starting material and 96.5% product. The resulting precipitate
was collected by filtration washing with TBME (4.times.3.4 L). The
solid was then dried under vacuum at 40.degree. C. to give 6033 g
of the desired material as a white solid (81.6% yield over 3 steps,
99.8% purity by HPLC). Analytical data was consistent with that
obtained on previous batches.
Intermediate A8: Ethyl
2-(5-bromo-2-fluorobenzoyl)-3-[(4-methoxyphenyl)methylamino]prop-2-enoate
##STR00025##
[0538] (E)-Ethyl 3-(dimethylamino)acrylate (98 g, 685.00 mmol) was
added portion-wise to 5-bromo-2-fluorobenzoyl chloride (163 g, 685
mmol) and DIPEA (120 mL, 685.00 mmol) in toluene (800 mL) at
10.degree. C. over a period of 10 minutes. The resulting solution
was stirred at 70.degree. C. for 16 h then allowed to cool.
(4-Methoxyphenyl)methanamine (94 g, 685 mmol) was added to the
mixture over a period of 20 minutes at r.t. The resulting solution
was stirred for 3 h then the reaction mixture diluted with DCM (4
L), and washed with water (3.times.1 L). The organic phase was
dried over Na.sub.2SO.sub.4, filtered and evaporated to give the
desired material (300 g, 100%) as brown oil, which was used
immediately in the subsequent reaction without further
purification. Mass Spectrum: m/z (ES+)[M+H]+=436.
[0539] On a larger scale, 5-bromo-2-fluorobenzoyl chloride (4318 g,
4205 g active, 17.71 mol) was charged to the vessel as a solution
in toluene (7.5 L). DIPEA (3150 mL, 18.08 mol) was added with no
observed exotherm. Ethyl-3-(dimethylamino)acrylate (2532 g, 17.71
mol) was added portionwise over 30 minutes maintaining a batch
temperature <40.degree. C. An exotherm from 21-24.degree. C. was
noted over the 30 minute addition with a further slow rise to
38.degree. C. over 1 h. The reaction was stirred at 20-30.degree.
C. for 16.5 h. 4-Methoxybenzylamine (2439 g, 17.78 mol) was added
portionwise over 30 mins maintaining a batch temperature
<40.degree. C. An exotherm of 25-30.degree. C. was observed over
the addition with cooling provided by a reduced jacket temperature
of 15.degree. C. The reaction was stirred for 4 h at 20-30.degree.
C. after which HPLC indicated 93.2% of desired material. The batch
was split for workup with each half of the mixture diluted with DCM
(28.6 L) and washed with water (3.times.7.8 L). The organics were
dried over MgSO.sub.4 (.about.550 g) and filtered, washing with DCM
(4 L). The combined organics were then concentrated to give 8444 g
of the desired material as an oil (8434 g, 106% yield, 94.7% purity
by HPLC). Analytical data was consistent with that obtained from
previous batches.
Intermediate A9: 5-Bromo-2-fluorobenzoyl chloride
##STR00026##
[0541] Thionyl chloride (75.0 mL, 1027.36 mmol) was added drop-wise
to 5-bromo-2-fluorobenzoic acid (150 g, 684.91 mmol), in toluene
(1.2 L) and DMF (12 mL) at r.t. over a period of 1 h. The resulting
mixture was stirred at 70.degree. C. for 16 h then the mixture
allowed to cool and concentrated in vacuo to afford the desired
material (160 g, 98%) as light yellow oil, which was used without
further purification. NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 7.26-7.31 (1H, m), 7.83 (1H, dd), 8.02 (1H, d).
[0542] On a larger scale, 3-bromo-6-fluorobenzoic acid (3888 g,
17.75 mol) was charged to the vessel at 20.degree. C. followed by
toluene (29.2 L). Thionyl chloride (1950 ml, 26.88 mol) was added,
followed by DMF (310 mL) with no observed exotherm. The mixture was
heated to 65-75.degree. C. (solution obtained above
.about.45.degree. C.) with no observed exotherm and slight gas
evolution. The reaction was stirred for 40 h at this temperature at
which point HPLC analysis showed 87.6% product, 3.4% starting
material. The reaction was concentrated in vacuo and azeotroped
with toluene (18 L) to give 4328 g of the desired material (103%
yield, 87.3% by HPLC).
[0543]
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)im-
idazo[5,4-c]quinolin-2-one can also be prepared directly from
8-bromo-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one in the
following manner:
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5-
,4-c]quinolin-2-one
##STR00027##
[0545]
Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-
[242'-amino-1,1'-biphenyl)]palladium(II) (0.070 g, 0.09 mmol) was
added to 8-bromo-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one
(3.2 g, 8.83 mmol), K.sub.2CO.sub.3 (3.66 g, 26.50 mmol) and
N,N-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2--
yl]oxypropan-1-amine (3.25 g, 10.60 mmol) in 1,4-dioxane (80 mL)
and water (15 mL) under nitrogen. The resulting mixture was stirred
at 90.degree. C. for 2 h. The reaction mixture was concentrated and
diluted with EtOAc (500 mL) and washed sequentially with water
(2.times.100 mL), and sat. brine (100 mL). The organic layer was
dried over Na.sub.2SO.sub.4, filtered and the volume reduced to
approximately 80 mL in vacuo. The precipitate was collected by
filtration, washed with Et.sub.2O (10 mL) and dried under vacuum to
afford the desired material (2.80 g, 68.7%) as a white solid.
Analytical data consistent with material synthesised by alternate
route.
[0546] On a larger scale,
8-bromo-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one (1700.1
g) was suspended in EtOH (20.4 L) in a 50 L vessel then
K.sub.2CO.sub.3 (1948.7 g) and
N,N-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyr-
idin-2-yl]oxypropan-1-amine (1731.4 g) added. EtOH (6.8 L) and
purified water (5.1 L) were added to the mixture followed by the
addition
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[242'--
amino-1,1'-biphenyl)]palladium(II) (37.3 g). The mixture was heated
to reflux (77-80.degree. C.) and stirred for 30 mins at reflux then
cooled to 20.degree. C. prior to being distilled under reduced
pressure to a volume of 12.6 L. The batch was then cooled to
15-25.degree. C. and purified water (19.9 L) added. The batch was
stirred for 1 h 5 mins, filtered and the filter cake washed with
purified water (3.times.3.7 L) then dried under vacuum at
40.degree. C. to afford crude desired material (1978 g, 91.3%). The
reaction was repeated on a similar scale to deliver a further 2084
g of crude material. The purification of the crude
8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[-
5,4-c]quinolin-2-one (2066.9 g) was carried out in 6 portions of
350 g or less.
[0547] Crude
8-[6-(3-dimethylaminopropoxy)pyridin-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[-
5,4-c]quinolin-2-one (350.1 g) was charged to a 10 L flask with
EtOH (7.7 L) and heated until a solution was formed (68-73.degree.
C.). Activated charcoal (35 g) was added and the solution stirred
at 70-75.degree. C. for 1 h. The hot solution was filtered using a
porosity 3 sinter funnel through a celite pad (.about.40 g) in
small portions to ensure the product stayed in solution. The celite
pad was washed with hot EtOH (2 L) to remove any residual product
on the celite and the initial filtrate charged to the vessel and
the wash filtrate was stored in a carboy. This process was repeated
with the remaining portions of crude material. After completion of
the 6 hot filtrations carried out over 2 days the filtrate in the
vessel was distilled under reduced pressure until the remaining
filtrate (held in a carboy) could be added. The batch was then
heated until a solution was formed (69.degree. C.) and the
distillation was then continued until the volume in the vessel was
equal to 5 volumes of the input material (maximum distillation
batch temperature=55.degree. C.). The distillation was stopped and
the batch cooled to 5-15.degree. C., filtered, washed with EtOH
(2.3 L) and dried to give the pure desired product (1926 g, 93.2%
yield).
[0548] Analytical data consistent with material synthesised by
alternate routes/different scales.
[0549] Intermediate A3,
8-Bromo-1-(oxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-one can also be
prepared in the following manner:
Intermediate A3:
8-Bromo-1-(oxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-one
##STR00028##
[0551] 1,3,5-Trichloro-1,3,5-triazinane-2,4,6-trione (18.9 g, 81.9
mmol) was added portionwise to a mixture of
6-bromo-4-(oxan-4-ylamino)quinoline-3-carboxamide (57.3 g, 163.7
mmol) and DBU (54.7 g, 360.1 mmol) in MeOH (500 mL) at 0.degree. C.
The resulting mixture was allowed to warm and stirred at r.t. for
30 minutes. The resulting mixture was evaporated to dryness and the
residue triturated with a mixture of petroleum ether/EtOAc (5:1,
1000 mL) to afford the desired material (46.0 g, 81%) as a yellow
solid. NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta.
1.55-1.64 (2H, m), 1.87-1.98 (2H, m), 3.28-3.42 (2H, m), 3.79-3.89
(2H, m), 3.95-3.98 (1H, m), 7.62 (1H, bs), 7.70-7.85 (2H, m), 7.89
(1H, d), 8.12 (1H, bs), 8.60 (1H, s), 8.71 (1H, s).
Intermediate A10:
6-bromo-4-(oxan-4-ylamino)quinoline-3-carboxamide
##STR00029##
[0553] A mixture of 6-bromo-4-chloroquinoline-3-carboxamide (50 g,
175.4 mmol), tetrahydro-2H-pyran-4-amine (26.2 g, 193 mmol) and
DIPEA (56.13 mL, 438.5 mmol) in DMA (500 mL) was stirred at
90.degree. C. overnight. The mixture was allowed to cool and poured
into water (1500 mL).
[0554] The precipitate was filtered, washed with water (2.times.200
mL) and dried under reduced pressure to afford the desired material
(57.3 g, 93%) as a white solid. NMR Spectrum: .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 2.88-1.92 (2H, m), 2.59-2.78 (2H, m), 3.50-3.62
(3H, m), 3.96-4.08 (2H, m), 4.92-4.98 (1H, m), 7.80 (1H, m), 7.99
(1H, dd), 8.46 (1H, d), 8.74 (1H, s).
Intermediate A11: 6-Bromo-4-chloroquinoline-3-carboxamide
##STR00030##
[0556] DMF (1.506 mL, 19.37 mmol) was added to
6-bromo-4-oxo-1H-quinoline-3-carboxylic acid (51.93 g, 193.72 mmol)
and thionyl chloride (353 mL, 4843.07 mmol) at r.t. and the
resulting solution stirred at 70.degree. C. for 2 h under an inert
atmosphere. The resulting solution was evaporated to dryness and
the residue azeotroped with toluene to afford
6-bromo-4-chloroquinoline-3-carbonyl chloride (62.13 g). The
6-bromo-4-chloroquinoline-3-carbonyl chloride was dissolved in DCM
(420 mL) and added portionwise to ammonium hydroxide (251 mL,
1937.23 mmol) at 0.degree. C. over 15 minutes. The organic solvent
was removed under reduced pressure and the solid collected by
filtration, washed with water, Et.sub.2O and then dried to afford
the desired material (52.8 g, 95%) as a white solid. NMR Spectrum:
.sup.1H NMR (500 MHz, DMSO-d6) .delta. 8.00-8.11 (3H, m), 8.24 (1H,
s), 8.45 (1H, s), 8.92 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=287.
Intermediate A12: 6-Bromo-4-oxo-1H-quinoline-3-carboxylic acid
##STR00031##
[0558] 2N Sodium hydroxide (506 mL, 1011.43 mmol) was added to a
stirred suspension of ethyl
6-bromo-4-oxo-1H-quinoline-3-carboxylate (59.9 g, 202.29 mmol) in
EtOH (590 mL) and the resulting solution stirred at 75.degree. C.
for 1.5 h. Water was added and the mixture cooled to 0.degree. C.
The pH of the solution was adjusted to 3 using hydrochloric acid
and the precipitate collected by filtration. The solid was washed
with water, EtOH/water (1:1) then Et.sub.2O before being dried to
afford the desired material (51.9 g, 96%) as a beige solid. NMR
Spectrum: .sup.1H NMR (500 MHz, DMSO-d6) .delta. 7.80 (1H, d), 8.05
(1H, d), 8.37 (1H, s), 8.93 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=270.
Intermediate A13: Ethyl
6-bromo-4-oxo-1H-quinoline-3-carboxylate
##STR00032##
[0560] Diphenyl ether (870 mL) was heated to 240.degree. C. then
diethyl 2-[[(4-bromophenyl)amino]methylidene]propanedioate (75 g,
219.18 mmol) added portionwise. The mixture was stirred at
240.degree. C. for 60 minutes in a flask fitted with dean-stark
apparatus. After cooling (25.degree. C.) a crystallized solid was
formed. The mixture was diluted with Et.sub.2O and the solid was
collected by filtration, washed with Et.sub.2O and dried to afford
the desired material (59.9 g) as a beige crystallized solid, which
was used without purification or characterisation.
Intermediate A14: Diethyl
2-[[(4-bromophenyl)amino]methylidene]propanedioate
##STR00033##
[0562] Diethyl 2-(ethoxymethylene)malonate (71.5 mL, 354.02 mmol)
was added to 4-bromoaniline (42 g, 244.15 mmol) in EtOH (420 mL)
and the resulting mixture stirred at 78.degree. C. overnight. After
cooling to 10.degree. C. the white solid was collected by
filtration, washed with heptane and dried to afford the desired
material (75 g, 90%) as a white crystallized solid. NMR Spectrum:
.sup.1H NMR (500 MHz, DMSO-d6) .delta. 1.25 (6H, s), 4.10-4.27 (4H,
m), 7.38 (2H, d), 7.57 (2H, d), 8.37 (1H, bs). Mass Spectrum: m/z
(ES+)[M+H]+=344.
[0563] The preparation of
N,N-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2--
yl]oxypropan-1-amine is described below.
N,N-Dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-y-
l]oxypropan-1-amine
##STR00034##
[0565] Butyllithium (2.5N, 4.8 mL, 50.96 mmol) was added to a
solution of 3-(5-bromopyridin-2-yl)oxy-N,N-dimethylpropan-1-amine
(2.07 g, 7.99 mmol) and
4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane (2.79 g,
15.00 mmol) in THF (20 mL) at -78.degree. C. over 10 minutes under
an inert atmosphere. The resulting solution was stirred for 4 h at
18.degree. C. The reaction was then quenched by the addition of a
sat. aqueous solution of ammonium chloride then partitioned between
EtOAc (100 mL) and water (100 mL). The organic layer was
concentrated in vacuo and the residue purified by FCC, eluting with
EtOAc/petroleum ether (1:3) to afford the desired material (270 mg,
11%) as a yellow solid. Mass Spectrum: m/z (ES+)[M+H]+=225.
3-(5-Bromopyridin-2-yl)oxy-N,N-dimethylpropan-1-amine
##STR00035##
[0567] 3-(Dimethylamino)propan-1-ol (3.09 g, 29.95 mmol) was added
to a mixture of sodium hydride (2.4 g, 60.00 mmol) in DMF (50 mL)
over a period of 20 min at r.t. 5-Bromo-2-fluoropyridine (5.81 g,
33.01 mmol) was added and the resulting solution stirred for 4 h at
30.degree. C. The reaction was then quenched by the addition of a
sat. aqueous solution of ammonium chloride and the resulting
mixture concentrated under vacuum. The residue was purified by FCC,
eluting with DCM/MeOH in Et.sub.2O (10:1) to afford the desired
material (5.2 g, 67%) as yellow oil. Mass Spectrum: m/z
(ES+)[M+H]+=259.
Example 2
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-(cis-3-methoxycyclobutyl)-3-m-
ethylimidazo[4,5-c]quinolin-2-one
##STR00036##
[0569] Pd(Ph.sub.3P).sub.4 (2.074 g, 1.79 mmol) was added to a
mixture of
8-bromo-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one
(13 g, 35.89 mmol),
N,N-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2--
yl]oxypropan-1-amine (13.15 g, 43.07 mmol) and cesium carbonate
(23.39 g, 71.78 mmol) in 1,4-dioxane (200 mL) and water (40 mL)
under nitrogen. The resulting mixture was stirred at 90.degree. C.
for 3 h before being allowed to cool. The reaction mixture was
concentrated and diluted with EtOAc (750 mL), and washed
sequentially with water (2.times.150 mL), and sat. brine (150 mL).
The organic layer was dried over Na.sub.2SO.sub.4, filtered and
evaporated to afford crude product. The crude product was purified
by FCC, elution gradient 0 to 10% MeOH in DCM, to afford the
desired material (12.50 g, 75%) as a white solid. NMR Spectrum:
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 1.90 (2H, q), 2.16 (6H, s),
2.37 (2H, t), 2.72-2.92 (2H, m), 3.01 (2H, d), 3.21 (3H, s), 3.50
(3H, s), 3.79-3.95 (1H, m), 4.37 (2H, t), 5.12 (1H, t), 6.97 (1H,
d), 7.82-7.98 (1H, m), 8.11 (1H, d), 8.19 (2H, dd), 8.42 (1H, s),
8.67 (1H, d), 8.87 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=462.
Intermediate B1:
8-Bromo-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinolin-2-one
##STR00037##
[0571] Methyl iodide (11.49 mL, 183.81 mmol) was added to a mixture
of
8-bromo-1-(cis-3-methoxycyclobutyl)-3H-imidazo[4,5-c]quinolin-2-one
(32 g, 91.90 mmol), sodium hydroxide (5.51 g, 137.85 mmol) and
tetrabutylammonium bromide (2.94 g, 9.19 mmol) in DCM (400 mL) and
water (300 mL) and the resulting mixture stirred at r.t. for 12 h.
The DCM was removed in vacuo and the precipitate collected by
filtration, washed with water (200 mL) and dried under vacuum to
afford the desired material (25.00 g, 75%) as a pale yellow solid.
NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta. 2.72-2.86 (2H,
m), 2.9-3.08 (2H, m), 3.22 (3H, s), 3.49 (3H, s), 3.85-3.89 (1H,
m), 4.88-5.06 (1H, m), 7.74 (1H, dd), 7.98 (1H, d), 8.50 (1H, d),
8.92 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=362, 364.
Intermediate B2:
8-Bromo-1-(cis-3-methoxycyclobutyl)-3H-imidazo[4,5-c]quinolin-2-one
##STR00038##
[0573] Triethylamine (39.3 mL, 281.89 mmol) was added to
6-bromo-4-[(cis-3-methoxycyclobutyl)amino]quinoline-3-carboxylic
acid (33 g, 93.96 mmol) in DMF (200 mL) at r.t. After stirring for
30 minutes diphenyl phosphorazidate (28.4 g, 103.36 mmol) was added
and the resulting mixture stirred at 60.degree. C. for 2 h. The
reaction mixture was poured into water (500 mL), the precipitate
collected by filtration, washed with water (200 mL) and dried under
vacuum to afford the desired material (32.0 g, 98%) as a yellow
solid, which was used without further purification. NMR Spectrum:
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 2.75-2.82 (2H, m), 2.9-3.05
(2H, m), 3.22 (3H, s), 3.80-3.90 (1H, m), 4.85-4.99 (1H, m), 7.71
(1H, dd), 7.94 (1H, d), 8.48 (1H, d), 8.69 (1H, s), 10.42 (1H, s).
Mass Spectrum: m/z (ES+)[M+H]+=348, 350.
Intermediate B3:
6-Bromo-4-[(cis-3-methoxycyclobutyl)amino]quinoline-3-carboxylic
acid
##STR00039##
[0575] Sodium hydroxide (190 mL, 379.70 mmol) was added to ethyl
6-bromo-4-[(cis-3-methoxycyclobutyl)amino]quinoline-3-carboxylate
(36 g, 94.92 mmol) in a mixture of MeOH (120 mL) and THF (120 mL)
and the resulting mixture stirred at 60.degree. C. for 3 h. The
solvent was removed under reduced pressure and the mixture adjusted
to pH 3 with 2M hydrochloric acid. The precipitate was collected by
filtration, washed with water (300 mL) and dried under vacuum to
afford the desired material (33.0 g, 99%) as a pale yellow solid,
which was used without further purification. Mass Spectrum: m/z
(ES+)[M+H]+=351.
Intermediate B4: Ethyl
6-bromo-4-[(cis-3-methoxycyclobutyl)amino]quinoline-3-carboxylate
##STR00040##
[0577] DIPEA (41.6 mL, 238.43 mmol) was added to ethyl
6-bromo-4-chloroquinoline-3-carboxylate (30 g, 95.37 mmol) and
3-methoxycyclobutan-1-amine hydrochloride (15.75 g, 114.44 mmol) in
DMA (100 mL) and the resulting mixture stirred at 75.degree. C. for
5 h. The solvent was removed under reduced pressure to afford the
desired material (36.0 g, 100%) as a yellow solid, which was used
without further purification. NMR Spectrum: .sup.1H NMR (300 MHz,
DMSO-d6) .delta. 1.38 (3H, t), 1.85-1.98 (2H, m), 2.75-7.89 (2H,
m), 3.17 (3H, s), 3.65-3.78 (1H, m), 3.98-4.05 (1H, m), 4.35 (2H,
q), 7.60 (1H, d), 7.70 (1H, dd), 8.40 (1H, d), 8.84-8.85 (1H, m).
Mass Spectrum: m/z (ES+)[M+H]+=379.
[0578] Intermediate B2:
8-Bromo-1-(cis-3-methoxycyclobutyl)-3H-imidazo[4,5-c]quinolin-2-one,
can also be prepared in the following manner.
##STR00041##
[0579] DBU (5.36 mL, 35.86 mmol) was added in one portion to a
mixture of
6-bromo-4-[(cis-3-methoxycyclobutyl)amino]quinoline-3-carboxamide
(6.28 g, 17.93 mmol) and
1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (1.667 g, 7.17 mmol)
in MeOH (65 mL). The resulting mixture was stirred at r.t. for 18
h. The resulting mixture was evaporated to dryness and the residue
was purified by FCC, elution gradient 0 to 10% MeOH in DCM, to
afford the desired material (6.48 g, 104%). Data consistent with
material produced from alternate synthesis described earlier.
Intermediate B5:
6-Bromo-4-[(cis-3-methoxycyclobutyl)amino]quinoline-3-carboxamide
##STR00042##
[0581] DIPEA (13.76 mL, 78.80 mmol) was added to a mixture of
6-bromo-4-chloroquinoline-3-carboxamide (7.5 g, 26.27 mmol) and
3-methoxycyclobutan-1-amine hydrochloride (3.98 g, 28.89 mmol) in
DMA (35 mL) and the resulting mixture stirred at 100.degree. C. for
18 h. The reaction mixture was diluted with water (250 mL) and the
precipitate was collected by filtration, washed with water (50 mL)
and dried under vacuum to afford the desired material (6.28 g,
68.3%) as a tan solid, which was used without further purification.
NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta. 2.45-2.55 (2H,
m), 2.76-2.88 (2H, m), 3.17 (3H, s), 3.66 (1H, q), 4-4.16 (1H, m),
7.67 (1H, s), 7.80 (1H, dd), 7.93 (1H, dd), 8.15 (1H, s), 8.59 (1H,
s), 8.69 (1H, s), 9.34 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=350,
352.
Example 3
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-7-fluoro-3-methyl-1-(4-methylox-
an-4-yl)imidazo[5,4-c]quinolin-2-one
##STR00043##
[0583]
8-Bromo-7-fluoro-3-methyl-1-(4-methyloxan-4-yl)imidazo[5,4-c]quinol-
in-2-one (0.13 g, 0.33 mmol) was added to
N,N-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2--
yl]oxypropan-1-amine (0.121 g, 0.40 mmol), cesium carbonate (0.322
g, 0.99 mmol) and Pd(Ph.sub.3P).sub.4 (0.038 g, 0.03 mmol) in
1,4-dioxane (5 mL) and water (1 mL) under nitrogen. The resulting
mixture was stirred at 80.degree. C. for 2 h. The crude product was
purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5
.mu.m silica, 19 mm diameter, 100 mm length), using decreasingly
polar mixtures of water (containing 0.1% NH3) and MeCN as eluents.
Fractions containing the desired compound were evaporated to
dryness to afford the desired material (0.050 g, 30.8%) as a white
solid. NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta.
1.82-2.10 (7H, m), 2.18 (6H, s), 2.35-2.50 (2H, m), 3.0-3.1 (2H,
m), 3.31-3.39 (2H, m), 3.35 (3H, s), 3.61-3.74 (2H, m), 4.36 (2H,
t), 6.99 (1H, d), 7.97 (1H, d), 8.01 (1H, dt), 8.39 (1H, d), 8.45
(1H, d), 8.97 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=494.
[0584] The following compounds were synthesised in an analogous
fashion using the appropriate boronic ester and the appropriate
bromide:
TABLE-US-00002 Example Structure Name 4* ##STR00044##
8-[6-(3-dimethylaminopropoxy)pyridin- 3-yl]-3-methyl-1-(oxetan-3-
yl)imidazo[5,4-c]quinolin-2-one methanesulfonic acid salt 5**
##STR00045## 8-[6-(3-dimethylaminopropoxy)pyridin-
3-yl]-1-(cis-3-hydroxycyclobutyl)-3-
methylimidazo[4,5-c]quinolin-2-one 6 ##STR00046##
8-[6-(3-dimethylaminopropoxy)pyridin- 3-yl]-7-fluoro-1-(cis-3-
methoxycyclobutyl)-3- methylimidazo[4,5-c]quinolin-2-one 7
##STR00047## 8-[6-(3-dimethylaminopropoxy)pyridin-
3-yl]-3-methyl-1-(4-methyloxan-4- yl)imidazo[5,4-c]quinolin-2-one
8** ##STR00048## 8-[6-(3-dimethylaminopropoxy)pyridin-
3-yl]-7-fluoro-3-methyl-1-(oxan-4- yl)imidazo[5,4-c]quinolin-2-one
9** ##STR00049## 8-[6-(3-dimethylaminopropoxy)pyridin-
3-yl]-7-fluoro-3-methyl-1-(oxetan-3-
yl)imidazo[5,4-c]quinolin-2-one 10*** ##STR00050##
8-[6-(3-dimethylaminopropoxy)pyridin-
3-yl]-7-fluoro-3-methyl-1-[(3R)-oxan-3-
yl]imidazo[5,4-c]quinolin-2-one 11*** ##STR00051##
8-[6-(3-dimethylaminopropoxy)pyridin-
3-yl]-7-fluoro-3-methyl-1-[(3S)-oxan-3-
yl]imidazo[5,4-c]quinolin-2-one 12** ##STR00052##
8-[6-(3-dimethylaminopropoxy)pyridin-
3-yl]-1-(cis-3-methoxycyclobutyl)-3H- imidazo[4,5-c]quinolin-2-one
13**** ##STR00053## 8-[6-(3-dimethylaminopropoxy)pyridin-
3-yl]-1-(oxan-4-yl)-3H-imidazo[4,5- c]quinolin-2-one 14**
##STR00054## 8-[6-[3-(azetidin-1-yl)propoxy]pyridin-
3-yl]-1-(cis-3-hydroxycyclobutyl)-3-
methylimidazo[4,5-c]quinolin-2-one 15** ##STR00055##
1-(cis-3-hydroxycyclobutyl)-3-methyl-8-
[6-(3-pyrrolidin-1-ylpropoxy)pyridin-3-
yl]imidazo[4,5-c]quinolin-2-one 16***** ##STR00056##
8-[6-(3-dimethylaminopropoxy)pyridin-
3-yl]-3-methyl-1-[(3R)-oxan-3- yl]imidazo[5,4-c]quinolin-2-one
17***** ##STR00057## 8-[6-(3-dimethylaminopropoxy)pyridin-
3-yl]-3-methyl-1-[(3S)-oxan-3- yl]imidazo[5,4-c]quinolin-2-one 18
##STR00058## 8-[6-(3-dimethylaminopropoxy)-2-
fluoropyridin-3-yl]-1-(cis-3- methoxycyclobutyl)-3-
methylimidazo[4,5-c]quinolin-2-one 19 ##STR00059##
8-[6-(3-dimethylaminopropoxy)-2-
fluoropyridin-3-yl]-7-fluoro-1-(cis-3- melhoxycyclobutyl)-3-
mcthylimidazo[4,5-c]quinolin-2-one 20 ##STR00060##
8-[6-(3-dimethylaminopropoxy)-2-
fluoropyridin-3-yl]-3-methyl-1-[(3S)-
oxan-3-yl]imidazo[5,4-c]quinolin-2-one 21 ##STR00061##
8-[6-(3-dimethylaminopropoxy)-2-
fluoropyridin-3-yl]-3-methyl-1-(oxan-4-
yl)imidazo[5,4-c]quinolin-2-one 22 ##STR00062##
8-[6-(3-dimethylaminopropoxy)-2-
fluoropyridin-3-yl]-3-methyl-1-[(3R)-
oxan-3-yl]imidazo[5,4-c]quinolin-2-one 23****** ##STR00063##
7-fluoro-3-methyl-8-[6-(3-pyrrolidin-1-
ylpropoxy)-3-pyridyl]-1-[(3S)- tetrahydropyran-3-yl]imidazo[4,5-
c]quinolin-2-one 24****** ##STR00064##
7-fluoro-3-methyl-8-[6-(3-pyrrolidin-1-
ylpropoxy)-3-pyridyl]-1-[(3R)- tetrahydropyran-3-yl]imidazo[4,5-
c]quinolin-2-one *Reaction stirred for 18 h at 80.degree. C. This
compound can also be isolated as the methanesulfonic acid salt by
dissolving the free base in DCM, treating with methanesulfonic acid
(~1.1 equiv), concentrating in vacuo and triturating the residue
with Et.sub.2O. **Reaction stirred for 2 h at 90.degree. C.
***Reaction stirred for 75 mins at 120.degree. C. ****The reaction
used starting material tert-butyl
8-bromo-1-(oxan-4-yl)-2-oxoimidazo[5,4-c]quinoline-3-carboxylate
and was stirred at 90.degree. C for 2 h. The crude material was
purified by prep HPLC using decreasingly polar mixtures of water
(containing 0.3% formic acid) and MeCN as eluents. No additional
deprotection step was required. *****Reaction performed using
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-bipheny1)]palladium(II) as the catalyst and stirred at
100.degree. C for 3 h. ******Reaction stirred for 1 h at
100.degree. C.
Example 4
[0585] NMR Spectrum (free base): .sup.1H NMR (500 MHz, DMSO-d6)
.delta. 1.90 (2H, p), 2.18 (6H, s), 2.35-2.43 (2H, m), 3.55 (3H,
s), 4.37 (2H, t), 5.07 (2H, dd), 5.28 (2H, t), 6.13-6.24 (1H, m),
6.97 (1H, d), 7.98 (1H, dd), 8.15 (1H, d), 8.17-8.27 (1H, m), 8.50
(1H, d), 8.69 (1H, d), 8.94 (1H, s). NMR Spectrum (methanesulfonic
acid salt): .sup.1H NMR (500 MHz, DMSO-d6) .delta. 2.06 (2H, dt),
2.31 (3H, s), 2.59 (6H, s), 2.79-3.05 (2H, m), 3.55 (3H, s), 4.40
(2H, t), 5.07 (2H, dd), 5.27 (2H, t), 6.14-6.24 (1H, m), 6.99 (1H,
dd), 7.99 (1H, dd), 8.15 (1H, d), 8.25 (1H, dd), 8.53 (1H, d), 8.70
(1H, dd), 8.94 (1H, s), 9.35 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=433.6.
Example 5
[0586] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta.
1.87-1.92 (2H, m), 2.15 (6H, s), 2.38 (2H, t), 2.78-2.98 (4H, m),
3.50 (3H, s), 4.01-4.19 (1H, m), 4.40 (2H, t), 4.92 (1H, p), 5.26
(1H, d), 6.97 (1H, d), 7.92 (1H, dd), 8.11 (1H, d), 8.20 (1H, dd),
8.41 (1H, s), 8.67 (1H, d), 8.85 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=462.3.
Example 6
[0587] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta. 1.93
(2H, t), 2.22 (6H, s), 2.48 (2H, t), 2.77-2.79 (2H, m), 2.93-3.02
(2H, m), 3.10 (3H, s), 3.49 (3H, s), 3.69-3.9 (1H, m), 4.37 (2H,
t), 5.06 (1H, p), 6.98 (1H, d), 7.90 (1H, d), 8.04 (1H, dd), 8.37
(1H, d), 8.50 (1H, d), 8.91 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=480.
Example 7
[0588] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta.
1.92-1.98 (2H, m), 2.00 (3H, s), 2.01-2.07 (2H, m), 2.28 (6H, s),
2.50-2.54 (2H, m), 3.11 (2H, d), 3.36 (2H, t), 4.35-4.38 (2H, m),
3.51 (3H, s), 4.36 (2H, t), 6.97 (1H, d), 7.90 (1H, dd), 8.11-8.15
(2H, m), 8.47 (1H, s), 8.57 (1H, d), 8.95 (1H, s). Mass Spectrum:
m/z (ES+)[M+H]+=476.
Example 8
[0589] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta.
1.92-1.96 (4H, m), 2.23 (6H, s), 2.49-2.51 (2H, m), 2.62-2.75 (2H,
m), 3.33-3.57 (5H, m), 4.05 (2H, dd), 4.37 (2H, t), 5.03-5.11 (1H,
m), 6.98 (1H, d), 7.94 (1H, d), 8.08 (1H, dd), 8.34 (1H, d), 8.54
(1H, s), 8.93 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=480.
Example 9
[0590] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta.
1.85-1.91 (2H, m), 2.16 (6H, s), 2.37 (2H, t), 3.53 (3H, s), 4.36
(2H, t), 5.01 (2H, t), 5.24 (2H, t), 6.13 (1H, p), 6.98 (1H, d),
7.93 (1H, d), 8.05 (1H, dd), 8.43 (1H, d), 8.50 (1H, s), 8.97 (1H,
s). Mass Spectrum: m/z (ES+)[M+H]+=452.
Example 10
[0591] NMR Spectrum: .sup.1H NMR (500 MHz, DMSO-d6) .delta. 1.78
(2H, dd), 1.90 (2H, p), 2.17 (7H, s), 2.38 (2H, t), 2.66 (1H, qd),
3.38 (1H, td), 3.49 (3H, s), 3.91 (1H, d), 4.12 (1H, dd), 4.21 (1H,
t), 4.38 (2H, t), 4.91 (1H, ddd), 7.01 (1H, d), 7.93 (1H, d), 8.06
(1H, dt), 8.26 (1H, d), 8.51 (1H, s), 8.92 (1H, s). Mass Spectrum:
m/z (ES+)[M+H]+=479.
Example 11
[0592] NMR Spectrum: .sup.1H NMR (500 MHz, DMSO-d6) .delta. 1.80
(2H, d), 1.90 (2H, p), 2.17 (7H, s), 2.38 (2H, t), 2.61-2.73 (1H,
m), 3.38 (1H, td), 3.50 (3H, s), 3.91 (1H, d), 4.12 (1H, dd), 4.21
(1H, t), 4.38 (2H, t), 4.86-4.98 (1H, m), 7.01 (1H, d), 7.94 (1H,
d), 8.06 (1H, dt), 8.27 (1H, d), 8.52 (1H, s), 8.92 (1H, s). Mass
Spectrum: m/z (ES+)[M+H]+=479
Example 12
[0593] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta.
1.89-1.91 (2H, m), 2.15 (6H, s), 2.35 (2H, t), 2.78-2.83 (2H, m),
2.96-3.303 (2H, m), 3.19 (3H, s), 3.83 (1H, p), 4.36 (2H, t), 5.09
(1H, p), 6.97 (1H, d), 7.91 (1H, dd), 8.08 (1H, d), 8.20 (1H, dd),
8.43 (1H, d), 8.65 (1H, d), 8.87 (1H, s), 11.54 (1H, bs). Mass
Spectrum: m/z (ES+)[M+H]+=448.
Example 13
[0594] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
1.85-1.92 (4H, m), 2.19 (6H, s), 2.40 (2H, t), 2.69-2.75 (2H, m),
3.57 (2H, t), 4.04-4.09 (2H, m), 4.36 (2H, t), 5.08 (1H, p), 6.98
(1H, d), 7.94 (1H, dd), 8.10-8.21 (2H, m), 8.42 (1H, s), 8.65 (1H,
s), 8.66 (1H, s), 11.57 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=448.
Example 14
[0595] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
1.77-1.90 (2H, m), 1.90-1.99 (2H, m), 2.47-2.51 (2H, m), 2.72-2.91
(4H, m), 3.09 (4H, t), 3.50 (3H, s), 4.04-4.08 (1H, m), 4.33 (2H,
t), 4.94 (1H, p), 5.24 (1H, d), 6.95 (1H, d), 7.92 (1H, dd), 8.11
(1H, d), 8.20 (1H, dd), 8.41 (1H, d), 8.66 (1H, d), 8.87 (1H, s).
Mass Spectrum: m/z (ES+)[M+H]+=460.
Example 15
[0596] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
1.67-1.70 (4H, m), 1.88-1.97 (2H, m), 2.44-2.51 (4H, m), 2.54-2.56
(2H, m), 2.79-2.95 (4H, m), 3.49 (3H, s), 4.05-4.11 (1H, m), 4.37
(2H, t), 4.93 (1H, p), 5.24 (1H, d), 6.96 (1H, d), 7.92 (1H, dd),
8.11 (1H, d), 8.20 (1H, dd), 8.40 (1H, d), 8.66 (1H, d), 8.87 (1H,
s). Mass Spectrum: m/z (ES+)[M+H]+=474.
Example 16
[0597] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
1.75-1.97 (4H, m), 2.10-2.22 (1H, d), 2.24 (6H, s), 2.42-2.55 (2H,
m), 2.62-2.77 (1H, m), 3.34-3.45 (1H, m), 3.50 (3H, s), 3.92 (1H,
d), 4.10-4.26 (2H, m), 4.35 (2H, t), 4.89-5.02 (1H, m), 6.98 (1H,
d), 7.92 (1H, dd), 8.12-8.19 (2H, m), 8.33 (1H, s), 8.62 (1H, d),
8.89 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=462.25.
Example 17
[0598] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
1.75-1.97 (4H, m), 2.10-2.28 (7H, m), 2.40 (2H, t), 2.62-2.77 (1H,
m), 3.33-3.47 (1H, m), 3.50 (3H, s), 3.93 (1H, d), 4.10-4.26 (2H,
m), 4.35 (2H, t), 4.91-5.05 (1H, m), 6.98 (1H, d), 7.95 (1H, dd),
8.12-8.19 (1H, m), 8.35 (1H, s), 8.62 (1H, d), 8.89 (1H, s). Mass
Spectrum: m/z (ES+)[M+H]+=462.25.
Example 18
[0599] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
1.85-2.00 (2H, m), 2.21 (6H, s), 2.46 (2H, t), 2.74-2.87 (2H, m),
2.91-3.07 (2H, m), 3.18 (3H,$), 3.50 (3H, s), 3.75-3.89 (1H, m),
4.32 (2H, t), 4.91-5.08 (1H, m), 6.94 (1H, d), 7.78 (1H, dd), 8.10
(1H, d), 8.16-8.27 (1H, m), 8.45 (1H, s), 8.90 (1H, s); .sup.19F
NMR (300 MHz, DMSO-d6) .delta. 73.62. Mass Spectrum: m/z
(ES+)[M+H]+=480.
Example 19
[0600] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
1.88-2.00 (2H, m), 2.23 (6H, s), 2.41-2.50 (2H, m), 2.71-2.83 (2H,
m), 2.89-3.03 (1H, m), 3.15 (3H, s), 3.49 (3H, s), 3.71-3.86 (1H,
m), 4.33 (2H, t), 4.91-5.08 (1H, m), 6.97 (1H, d), 7.90 (1H, d),
8.12 (1H, dt), 8.43 (1H, dd), 8.92 (1H, s). .sup.19F NMR (300 MHz,
DMSO-d6) .delta. 71.56 ppm, 116.913 ppm. Mass Spectrum: m/z
(ES+)[M+H]+=498.
Example 20
[0601] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
1.79-1.90 (2H, m), 2.10-2.25 (3H, m), 2.60-2.72 (1H, m), 2.73 (6H,
s), 3.10-3.20 (2H, m), 3.30-3.47 (4H, m), 3.91 (1H, d), 4.10 (1H,
d), 4.28 (1H, t), 4.39 (2H, t), 4.81-4.96 (1H, m), 6.99 (1H, d),
7.85 (1H, d), 8.14 (1H, d), 8.30 (1H, dd), 8.41 (1H, s), 8.91 (1H,
s). Mass Spectrum: m/z (ES+)[M+H]+=480.
Example 21
[0602] NMR Spectrum: .sup.1H NMR (300 MHz, MeOD) .delta. 1.94-204
(2H, m), 2.20-2.30 (2H, m), 2.82 (6H, s), 2.82-3.00 (2H, m),
3.18-3.35 (2H, m), 3.62 (3H, s), 3.62-3.71 (2H, m), 4.20 (2H, dd),
4.50 (2H, t), 5.12-5.25 (1H, m), 6.95 (1H, d), 7.91 (1H, d), 8.19
(2H, m), 8.64 (1H, d), 8.87 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=480.
Example 22
[0603] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
1.75-1.99 (4H, m), 2.10-2.24 (7H, m), 2.35-2.47 (2H, m), 2.55-2.69
(1H, m), 3.34-3.46 (1H, m), 3.92 (1H, d), 4.03 (1H, d), 4.24-4.97
(3H, m), 4.81-4.99 (1H, m), 6.97 (1H, d), 7.84 (1H, d), 8.13 (1H,
d), 8.24 (1H, dd), 8.40 (1H, s), 8.90 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=480.
Example 23
[0604] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta. 1.71
(4H, p), 1.78 (2H, d), 1.95 (2H, p), 2.14 (1H, d), 2.53-2.74 (6H,
m), 3.38 (2H, td), 3.49 (3H, s), 3.91 (1H, d), 4.12 (1H, dd), 4.21
(1H, t), 4.40 (2H, t), 4.91 (1H, t), 7.01 (1H, d), 7.94 (1H, d),
8.06 (1H, dt), 8.26 (1H, d), 8.51 (1H, s), 8.92 (1H, s). Mass
Spectrum: m/z (ES+)[M+H]+=506.
Example 24
[0605] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta.
1.64-1.74 (4H, m), 1.78 (2H, d), 1.94 (2H, p), 2.14 (1H, d), 2.46
(4H, d), 2.54-2.6 (1H, m), 2.61-2.73 (1H, m), 3.34-3.43 (2H, m),
3.49 (3H, s), 3.91 (1H, d), 4.07-4.17 (1H, m), 4.21 (1H, t), 4.40
(2H, t), 4.84-4.98 (1H, m), 6.98-7.04 (1H, m), 7.93 (1H, d), 8.06
(1H, dt), 8.26 (1H, d), 8.51 (1H, s), 8.92 (1H, s); Mass Spectrum:
m/z (ES+)[M+H]+=506.
[0606] The preparations for the bromo intermediates required for
the synthesis of Examples 3-24 have either already been described
or were carried out in the following manner by methylation of the
corresponding 3H-imidazo[4,5-c]quinolin-2-one intermediates.
Intermediate C1:
8-Bromo-7-fluoro-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinol-
in-2-one
##STR00065##
[0608] A solution of sodium hydroxide (4 g, 100 mmol) in water (240
mL) was added to a solution of
8-bromo-7-fluoro-1-(cis-3-methoxycyclobutyl)-3H-imidazo[4,5-c]quinolin-2--
one (23 g, 62.81 mmol), methyl iodide (13.41 g, 94.48 mmol) and
tetrabutylammonium bromide (2 g, 6.21 mmol) in DCM (400 mL) and the
resulting solution stirred at r.t. overnight. The mixture was
concentrated under vacuum and the solids collected by filtration.
The crude product was re-crystallized from DCM:EtOAc in the ratio
of 1:2 and the solid dried in an oven under reduced pressure to
afford the desired material (18 g, 75%) as an off-white solid. NMR
Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta. 2.70-2.85 (2H, m),
2.93-3.07 (2H, m), 3.22 (3H, s), 3.48 (3H, s), 3.73-4.00 (1H, m),
4.86-5.15 (1H, m), 7.75-8.07 (1H, d), 8.52-8.73 (1H, d), 8.93 (1H,
s). Mass Spectrum: m/z (ES+)[M+H]+=380.
[0609] The following intermediates were prepared in an analogous
fashion from the appropriate 3H-imidazo[4,5-c]quinolin-2-one
intermediate:
TABLE-US-00003 Intermediate Structure Name Intermediate D1
##STR00066## 8-bromo-3-methyl-1-[(3S)-oxan-3-
yl]imidazo[5,4-c]quinolin-2-one Intermediate E1* ##STR00067##
8-bromo-3-methyl-1-[(3R)-oxan-3- yl]imidazo[5,4-c]quinolin-2-one
Intermediate F1 ##STR00068## 8-bromo-7-fluoro-3-methyl-1-(oxan-
4-yl)imidazo[5,4-c]quinolin-2-one Intermediate G1 ##STR00069##
8-bromo-7-fluoro-3-methyl-1-(oxetan-
3-yl)imidazo[5,4-c]quinolin-2-one Intermediate H1* ##STR00070##
8-bromo-3-methyl-1-(oxetan-3- yl)imidazo[5,4-c]quinolin-2-one
Intermediate I1 ##STR00071## 8-bromo-7-fluoro-3-methyl-1-(4-
methyloxan-4-yl)imidazo[5,4- c]quinolin-2-one Intermediate J1
##STR00072## 8-bromo-1-(cis-3- hydroxycyclobutyl)-3-
methylimidazo[4,5-c]quinolin-2- one Intermediate K1** ##STR00073##
8-bromo-7-fluoro-3-methyl-1-[(3S)-
oxan-3-yl]imidazo[5,4-c]quinolin-2- one Intermediate L1
##STR00074## 8-bromo-7-fluoro-3-methyl-1-[(3R)-
oxan-3-yl]imidazo[5,4-c]quinolin-2- one *The reaction had not
proceeded to completion so additional methyl iodide, sodium
hydroxide and tetrabutylammonium bromide were added and the
reaction stirred a further 16-18 h. **The reaction was stirred for
72 h at ambient temperature.
Intermediate D1
[0610] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
1.82-1.88 (2H, m), 2.09-2.15 (1H, m), 2.55-2.78 (1H, m), 3.30-3.47
(1H, m) 3.48 (3H, s), 3.92 (1H, d), 4.02-4.22 (2H, m), 4.68-4.88
(1H, m), 7.75 (1H, d), 7.99 (1H, d), 8.35 (1H, s), 8.92 (1H, s).
Mass Spectrum: m/z (ES+)[M+H]+=362.2.
Intermediate E1
[0611] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
1.80-1.86 (2H, m), 2.07-2.12 (1H, m), 2.61-2.75 (1H, m), 3.32-3.46
(1H, m), 3.47 (3H, s), 3.92-3.98 (1H, m), 4.01-4.20 (2H, m),
4.72-4.83 (1H, m), 7.76 (1H, dd), 8.00 (1H, d), 8.34 (1H, d), 8.92
(1H, s). Mass Spectrum: m/z (ES+)[M+H]+=362, 364.
Intermediate F1
[0612] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6, 100.degree. C.)
.delta. 1.88 (2H, d), 2.59-2.84 (2H, m), 3.50 (3H, s), 3.60 (2H,
t), 4.06 (2H, d), 4.95 (1H, s), 7.90 (1H, d), 8.56 (1H, d), 8.89
(1H, s). Mass Spectrum: m/z (ES+)[M+H]+=381.96.
Intermediate G1
[0613] Mass Spectrum: m/z (ES+)[M+H]+=352.
Intermediate H1
[0614] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta. 3.53
(3H, s), 5.01 (2H, dd), 5.22 (2H, t), 6-6.18 (1H, m), 7.77 (1H,
dd), 8.00 (1H, d), 8.51 (1H, d), 8.97 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=334, 336.
Intermediate H
[0615] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6, 100.degree. C.)
.delta. 1.99 (3H, s), 2.00-2.04 (2H, m), 2.98 (1H, d), 3.13-3.16
(1H, m), 3.32-3.38 (2H, m), 3.53 (3H, s), 3.66-3.70 (2H, m), 7.99
(1H, d), 8.63 (1H, d), 9.00 (1H, s) Mass Spectrum: m/z
(ES+)[M+H]+=394, 396.
Intermediate J1
[0616] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta.
2.65-2.72 (2H, m), 2.85-2.93 (2H, m), 3.51 (3H, s), 4.02-4.09 (1H,
m), 4.78 (1H, m), 5.26 (1H, d), 7.73 (1H, dd), 7.97 (1H, d), 8.45
(1H, d), 8.92 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=348.
Intermediate K1
[0617] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta.
1.88-190 (2H, m), 2.09 (1H, d), 2.70 (1H, ddd), 3.36-3.44 (1H, m),
3.47 (3H, s), 3.94 (1H, d), 4.07 (1H, dd), 4.15 (1H, t), 4.79 (1H,
ddd), 7.97 (1H, d), 8.48 (1H, d), 8.93 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=380, 382.
Intermediate L1
[0618] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta. 1.86
(2H, dd), 2.11 (1H, d), 2.69 (1H, ddd), 3.37-3.45 (1H, m), 3.48
(3H, s), 3.95 (1H, d), 4.08 (1H, dd), 4.18 (1H, t), 4.80 (1H, ddd),
7.98 (1H, d), 8.50 (1H, d), 8.94 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=380, 382.
[0619] Intermediate M1,
8-bromo-3-methyl-1-(4-methyloxan-4-yl)imidazo[5,4-c]quinolin-2-one,
was prepared in the following manner:
##STR00075##
[0620] 1,1-Dimethoxy-N,N-dimethylmethanamine (1.663 mL, 12.42 mmol)
was added to a stirred suspension of
8-bromo-1-(4-methyloxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-one (0.9
g, 2.48 mmol) in DMF (8.28 mL) under an inert atmosphere and the
reaction heated at 80.degree. C. overnight. The reaction mixture
was evaporated to dryness and the crude product was dry-loaded onto
silica and purified by FCC, elution gradient 2 to 10% MeOH in DCM,
to afford the desired material (0.591 g, 63.2%) as a yellow solid.
NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta. 1.92 (3H, s),
2.02 (2H, ddd), 2.95-3.03 (2H, m), 3.36 (2H, td), 3.50 (3H, s),
3.68 (2H, dt), 7.72 (1H, dd), 8.00 (1H, d), 8.49 (1H, d), 8.98 (1H,
s). Mass Spectrum: m/z (ES+)[M+H]+=376.4.
[0621] The required 3H-imidazo[4,5-c]quinolin-2-one intermediates
were prepared by cyclisation of the appropriate acid intermediate
as follows:
Intermediate C2:
8-Bromo-7-fluoro-1-(cis-3-methoxycyclobutyl)-3H-imidazo[4,5-c]quinolin-2--
one
##STR00076##
[0623] A solution of
6-bromo-7-fluoro-4-[(cis-3-methoxycyclobutyl)amino]quinoline-3-carboxylic
acid (5.90 g, 15.98 mmol), and triethylamine (9.72 g, 96.06 mmol)
in DMF (100 mL) was stirred at ambient temperature for 2 h then
diphenyl phosphorazidate (11.02 g, 40.04 mmol) added The resulting
solution was stirred at 60.degree. C. for 2 h before being
concentrated in vacuo. The residue was diluted with water (80 mL)
and the solids collected by filtration and dried in an oven under
reduced pressure to afford the desired material (4.5 g, 77%) as a
white solid. NMR Spectrum: .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 2.75 (2H, m), 2.95 (2H, m), 3.25 (3H, s), 3.85 (1H, m),
4.75 (1H, m), 8.00 (1H, d), 8.62-8.58 (2H, t). Mass Spectrum: m/z
(ES+)[M+H]+=366.
[0624] The following 3H-imidazo[4,5-c]quinolin-2-one intermediates
were prepared in a similar fashion from the appropriate carboxylic
acid intermediates:
TABLE-US-00004 Intermediate Structure Name Intermediate D2*
##STR00077## 8-bromo-1-[(3S)-oxan-3-yl]-3H-
imidazo[4,5-c]quinolin-2-one Intermediate E2* ##STR00078##
8-bromo-1-[(3R)-oxan-3-yl]-3H- imidazo[4,5-c]quinolin-2-one
Intermediate F2 ##STR00079## 8-bromo-7-fluoro-1-(oxan-4-yl)-3H-
imnidazo[4,5-c]quinolin-2-one Intermediate G2* ##STR00080##
8-bromo-7-fluoro-1-(oxetan-3-yl)-3H- imnidazo[4,5-c]quinolin-2-one
Intermediate J2* ##STR00081## 8-bromo-1-(cis-3-hydroxycyclobutyl)-
3H-imidazo[4,5-c]quinolin-2-one *The reaction was stirred at
60.degree. C. for 1 h.
Intermediate D2
[0625] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
1.84-2.11 (3H, m), 2.62-2.76 (1H, m), 3.35-3.44 (1H, m), 3.92-4.22
(3H, m), 4.71-4.80 (1H, m), 7.76 (1H, dd), 7.98 (2H, d), 8.32 (1H,
dd), 8.71 (1H, s), 11.85 (1H, bs). Mass Spectrum: m/z
(ES+)[M+H]+=350.
Intermediate E2
[0626] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
1.82-2.11 (3H, m), 2.61-2.75 (1H, m), 3.34-3.43 (1H, m), 3.91-4.21
(3H, m), 4.69-4.78 (1H, m), 7.75 (1H, dd), 7.99 (2H, d), 8.33 (1H,
dd), 8.69 (1H, s), 11.70 (1H, bs). Mass Spectrum: m/z
(ES+)[M+H]+=350.
Intermediate F2
[0627] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6, 100.degree. C.)
.delta. 1.88 (2H, dd), 2.71 (2H, qd), 3.59 (2H, td), 4.06 (2H, dd),
4.92 (1H, tt), 7.92 (1H, d), 8.57 (1H, d), 8.72 (1H, s), 11.43 (1H,
s). Mass Spectrum: m/z (ES+)[M+H]+=367.92.
Intermediate G2
[0628] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta. 5.01
(2H, t), 5.20 (2H, t), 6.08 (1H, m), 7.96 (1H, d), 8.70-8.73 (1H,
m), 8.74 (1H, s), 11.80 (1H, bs). Mass Spectrum: m/z
(ES+)[M+H]+=338.
Intermediate J2
[0629] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta.
2.70-2.76 (2H, m), 2.81-2.90 (2H, m), 4.04-4.08 (1H, m), 4.75 (1H,
p), 7.74 (1H, dd), 7.95 (1H, d), 8.45 (1H, d), 8.68 (1H, s), 11.62
(1H, bs). Mass Spectrum: m/z (ES+)[M+H]+=334, 336.
[0630] The above acid intermediates were prepared from the
corresponding ester intermediate as follows:
Intermediate C3:
6-Bromo-7-fluoro-4-[(cis-3-methoxycyclobutyl)amino]quinoline-3-carboxylic
acid
##STR00082##
[0632] A solution of sodium hydroxide (8 g, 200 mmol) in water (100
mL) was added to a solution of ethyl
6-bromo-7-fluoro-4-[(cis-3-methoxycyclobutyl)amino]quinoline-3-carboxylat-
e (6.0 g, 15.10 mmol) in MeOH (300 mL) and the resulting solution
stirred overnight at ambient temperature. The temperature was
increased to 40.degree. C. for a further 2 h. The pH value of the
solution was adjusted to 5 with 1.5M hydrochloric acid and the
solids collected by filtration and dried in an oven under reduced
pressure to afford the desired material (5.6 g) as a white solid
which was used without further purification. NMR Spectrum: .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 1.98-1.91 (2H, m), 2.88-2.84 (2H,
m), 3.17 (1H, s), 3.77-3.70 (1H, t), 4.22-4.19 (1H, t), 7.73 (1H,
d), 8.44 (1H, d), 8.88 (1H, s), 13.27 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=369.
[0633] The following carboxylic acid intermediates were prepared in
a similar fashion from the appropriate ester precursor:
TABLE-US-00005 Intermediate Structure Name Intermediate D3*
##STR00083## 6-bromo-4-[[(3S)-oxan-3-
yl]amino]quinoline-3-carboxylic acid Intermediate E3* ##STR00084##
6-bromo-4-[[(3R)-oxan-3- yl]amino]quinoline-3-carboxylic acid
Intermediate F3** ##STR00085## 6-bromo-7-fluoro-4-(oxan-4-
ylamino)quinoline-3-carboxylic acid Intermediate G3*** ##STR00086##
6-bromo-7-fluoro-4-(oxetan-3- ylamino)quinoline-3-carboxylic acid
Intermediate J3* ##STR00087## 6-bromo-4-[(cis-3-
hydroxycyclobutyl)amino] quinoline-3-carboxylic acid *The reaction
was stirred between 60-70.degree. C. for 1-3 h. **The reaction was
stirred at ambient temperature overnight. ***The reaction was
performed using a mixture of THF and water as the solvent and was
heated at 65.degree. C. for 3 h.
Intermediate D3
[0634] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
1.50-1.57 (1H, m), 1.61-1.82 (2H, m), 1.98-2.13 (1H, m), 3.48-3.72
(3H, m), 3.89 (1H, d), 4.15-4.26 (1H, m), 7.77 (1H, dd), 7.95 (1H,
d), 8.31 (1H, d), 8.90 (1H,$), 13.38 (1H, bs). Mass Spectrum: m/z
(ES+)[M+H]+=351.
Intermediate E3
[0635] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
1.50-1.56 (1H, m), 1.62-1.83 (2H, m), 1.99-2.12 (1H, m), 3.50-3.71
(3H, m), 3.89 (1H, d), 4.16-4.28 (1H, m), 7.78 (1H, dd), 7.94 (1H,
d), 8.30 (1H, d), 8.94 (1H,$), 13.50 (1H, bs). Mass Spectrum: m/z
(ES+)[M+H]+=351.
Intermediate F3
[0636] Mass Spectrum: m/z (ES+)[M+H]+=369.
Intermediate G3
[0637] Mass Spectrum: m/z (ES+)[M+H]+=341.
Intermediate J3
[0638] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
2.03-2.07 (2H, m), 2.85-2.93 (2H, m), 4.00-4.04 (1H, t), 4.21-4.35
(2H, m), 7.95 (1H, d), 8.16 (1H, dd), 8.58 (1H, s), 8.99 (1H, s),
11.02 (1H, bs). Mass Spectrum: m/z (ES+)[M+H]+=337, 339.
[0639] The above ester intermediates were prepared from the
appropriate ethyl 4-chloroquinoline-3-carboxylate intermediates as
follows:
Intermediate C4: Ethyl
6-bromo-7-fluoro-4-[(cis-3-methoxycyclobutyl)amino]quinoline-3-carboxylat-
e
##STR00088##
[0641] A solution of ethyl
6-bromo-4-chloro-7-fluoroquinoline-3-carboxylate (7.5 g, 22.55
mmol), 3-methoxycyclobutan-1-aminehydrochloride (3.41 g, 24.78
mmol) and DIPEA (14.61 g, 113.04 mmol) in DMA (25 mL) was stirred
at 85.degree. C. for 3 h. The reaction mixture was cooled and the
solids collected by filtration, washed with water (3.times.20 mL)
and dried in an oven under reduced pressure to afford the desired
material (6.9 g, 77%) as a white solid which was used without
further purification. NMR Spectrum: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 1.44-1.41 (3H, t), 2.21-2.14 (2H, m), 3.05-2.98
(2H, m), 3.30 (3H, s), 3.94-3.75 (1H, m), 4.11-4.06 (1H, m),
4.43-4.37 (2H, d), 7.70 (1H, d), 8.29 (1H, d), 9.07 (1H, d), 9.69
(1H, s). Mass Spectrum: m/z (ES+)[M+H]+=397.
[0642] The following ester intermediates were prepared in an
analogous fashion from the appropriate amine and either ethyl
6-bromo-4-chloro-7-fluoroquinoline-3-carboxylate or ethyl
6-bromo-4-chloroquinoline-3-carboxylate:
TABLE-US-00006 Intermediate Structure Name Intermediate D4*
##STR00089## ethyl 6-bromo-4-[[(3S)-oxan-3-
yl]amino]quinoline-3-carboxylate Intermediate E4* ##STR00090##
ethyl 6-bromo-4-[[(3R)-oxan-3- yl]amino]quinoline-3-carboxylate
Intermediate F4** ##STR00091## ethyl 6-bromo-7-fluoro-4-(oxan-4-
ylamino)quinoline-3-carboxylate Intermediate G4** ##STR00092##
ethyl 6-bromo-7-fluoro-4-(oxetan- 3-ylamino)quinoline-3-
carboxylate Intermediate J4** ##STR00093## ethyl 6-bromo-4-[(cis-3-
hydroxycyclobutyl)amino] quinoline-3-carboxylate *The reaction was
stirred at 80.degree. C. for 16 h. **The reaction was stirred at
90.degree. C. for 1-3 h.
Intermediate D4
[0643] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta. 1.36
(3H, t), 1.70-1.74 (1H, m), 1.75-1.77 (2H, m), 2.03-2.05 (1H, m),
3.58-3.61 (3H, m), 3.80-3.85 (1H, m), 4.01-4.03 (1H, m), 4.35 (2H,
q), 7.80 (1H, d), 7.89 (1H, dd), 8.58 (1H, s), 8.67 (1H, d), 8.93
(1H, s). Mass Spectrum: m/z (ES+)[M+H]+=380.8.
Intermediate E4
NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta. 1.50-1.56 (1H,
m), 1.62-1.84 (2H, m), 1.99-2.13 (1H, m), 3.51-3.73 (3H, m), 3.89
(1H, d), 4.12-4.22 (1H, m), 7.77 (1H, d), 7.90 (1H, d), 8.31 (1H,
s), 8.94 (1H, s), 13.41 (1H, bs). Mass Spectrum: m/z
(ES+)[M+H]+=379
Intermediate F4
[0644] Mass Spectrum: m/z (ES+)[M+H]+=397.
Intermediate G4
[0645] Mass Spectrum: m/z (ES+)[M+H]+=369.
Intermediate J4
[0646] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta. 1.35
(3H, t), 1.91-1.95 (2H, m), 2.77-2.81 (2H, m), 3.91-3.95 (2H, m),
4.35 (2H, q), 5.28 (1H, d), 7.78 (1H, d), 7.85 (1H, dd), 8.37 (1H,
d), 8.85 (1H, s), 8.89 (1H, d). Mass Spectrum: m/z (ES+)[M+H]+=365,
367.
[0647] The preparation of ethyl
6-bromo-4-chloroquinoline-3-carboxylate has been described earlier.
The preparation of ethyl
6-bromo-4-chloro-7-fluoroquinoline-3-carboxylate is described
below:
Intermediate C5: Ethyl
6-bromo-4-chloro-7-fluoroquinoline-3-carboxylate
##STR00094##
[0649] Thionyl chloride (150 mL, 2.08 mol) was added to a solution
of ethyl 6-bromo-7-fluoro-4-oxo-1H-quinoline-3-carboxylate (25 g,
79.59 mmol) in DMF (50 mL) and the solution stirred at 80.degree.
C. for 4 h. The mixture was concentrated under vacuum and quenched
by the addition of ice/water. The reaction mixture was extracted
with DCM (8.times.100 mL), the organic extracts combined and the
mixture adjusted to pH=7 by the addition of 1.5M ammonium hydrogen
carbonate. The resulting mixture was washed with water (3.times.100
mL), the organics dried over Na.sub.2SO.sub.4 and concentrated in
vacuo to afford the desired material (20 g, 76%) as a light yellow
solid which was used without further purification.
[0650] NMR Spectrum: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
1.49-1.42 (3H, m), 4.54-4.82 (2H, q), 7.86 (1H, d), 8.69 (1H, d),
9.23 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=334.
Intermediate C6: Ethyl
6-bromo-7-fluoro-4-oxo-1H-quinoline-3-carboxylate
##STR00095##
[0652] A solution of diethyl
2-[[(4-bromo-3-fluorophenyl)amino]methylidene]propanedioate (90 g,
249.88 mmol) in diphenyl ether (600 mL, 3.79 mol) was stirred at
240.degree. C. for 2.5 h. The mixture was allowed to cool to
70.degree. C., the solids collected by filtration and dried in a
vacuum oven to afford the desired material (50 g, 64%) as a white
solid which was used without further purification. NMR Spectrum:
.sup.1H NMR (500 MHz, DMSO-d6, (100.degree. C.)) .delta. 1.26-1.33
(3H, m), 4.25 (2H, q), 7.52 (1H, d), 8.37 (1H, d), 8.48 (1H, s),
12.05 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=314.
Intermediate C7: Diethyl
2-[[(4-bromo-3-fluorophenyl)amino]methylidene]propanedioate
##STR00096##
[0654] A solution of 4-bromo-3-fluoroaniline (56.6 g, 297.87 mmol)
and 1,3-diethyl 2-(ethoxymethylidene)propanedioate (72.45 g, 335.06
mmol) in EtOH (560 mL) was stirred at 80.degree. C. for 4 h. The
reaction mixture was allowed to cool, the solids collected by
filtration and dried in an oven to afford the desired material (90
g, 84%) as an off-white solid which was used without further
purification. NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta.
1.26 (6H, q), 4.14 (2H, q), 4.22 (2H, q), 7.18-7.25 (1H, m), 7.57
(1H, dd), 7.64-7.7 (1H, m), 8.33 (1H, d), 10.62 (1H, d). Mass
Spectrum: m/z (ES+)[M+H]+=360.
[0655] The required 3H-imidazo[4,5-c]quinolin-2-one intermediates
were prepared by cyclisation of the appropriate carboxamide
intermediates as follows:
Intermediate H2:
8-Bromo-1-(oxetan-3-yl)-3H-imidazo[4,5-c]quinolin-2-one
##STR00097##
[0657] DBU (2.34 mL, 15.64 mmol) was added to
6-bromo-4-(oxetan-3-ylamino)quinoline-3-carboxamide (2.52 g, 7.82
mmol) and 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (0.727 g,
3.13 mmol) in MeOH (35 mL) and the resulting mixture stirred at
ambient temperature overnight. The mixture was evaporated to
dryness and the residue purified by FCC, elution gradient 0 to 20%
MeOH in DCM, to afford the desired material (0.485 g, 19.37%) as a
cream solid. NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta.
5.00 (2H, dd), 5.21 (2H, t), 5.87-6.15 (1H, m), 7.75 (1H, dd), 7.97
(1H, d), 8.51 (1H, d), 8.72 (1H, s), 11.73 (1H, s). Mass Spectrum:
m/z (ES+)[M+H]+=320, 322.
[0658] The following 3H-imidazo[4,5-c]quinolin-2-one intermediates
were prepared in an analogous fashion:
TABLE-US-00007 Intermediate Structure Name Intermediate K2 *
##STR00098## 8-bromo-7-fluoro-1-[(3S)-oxan-3-
yl]-3H-imidazo[4,5-c]quinolin-2- one Intermediate L2 ##STR00099##
8-bromo-7-fluoro-1-[(3R)-oxan-3- yl]-3H-imidazo[4,5-c]quinolin-2-
one *The reaction was stirred at ambient temperature for 70 h but
was still incomplete and so additional DBU and
1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione and the mixture
stirred at ambient temperature for a further 3 h.
Intermediate K.sub.2
[0659] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta.
1.77-1.93 (2H, m), 2.10 (1H, d), 2.68 (1H, qd), 3.34-3.44 (1H, m),
3.94 (1H, d), 4.08 (1H, dd), 4.18 (1H, t), 4.75 (1H, ddd), 7.94
(1H, d), 8.48 (1H, d), 8.69 (1H, s), 11.63 (1H, s). Mass Spectrum:
m/z (ES+)[M+H]+=366, 368.
Intermediate L2
[0660] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta.
1.7-1.93 (2H, m), 2.10 (1H, d), 2.63-2.75 (1H, m), 3.49-3.61 (1H,
m), 3.84-4.03 (1H, m), 4.08 (1H, dd), 4.19 (1H, t), 4.76 (1H, t),
7.95 (1H, d), 8.49 (1H, d), 8.70 (1H, s), 11.66 (1H, s). m/z:
ES+[M+H]+ 366, 368 Mass Spectrum: m/z (ES+)[M+H]+=366, 368.
[0661] The appropriate carboxamide intermediates were prepared as
follows:
Intermediate H3:
6-Bromo-4-(oxetan-3-ylamino)quinoline-3-carboxamide
##STR00100##
[0663] Oxetan-3-amine (0.614 g, 8.41 mmol) was added to
6-bromo-4-chloroquinoline-3-carboxamide (2 g, 7.00 mmol) and DIPEA
(2.440 mL, 14.01 mmol) in DMA (24 mL) and the resulting mixture
stirred at 100.degree. C. for 18 h. The crude product was purified
by ion exchange chromatography, using an SCX column and eluting
with 7M NH.sub.3/MeOH, to afford the desired material (2.52 g,
112%) as a dark brown solid which was used without further
purification. NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta.
4.06-4.15 (2H, m), 4.16-4.20 (2H, m), 5.63-5.96 (1H, m), 7.16-7.2
(3H, m), 7.22-7.26 (2H, m), 7.32 (1H, d), 7.93 (1H, d). Mass
Spectrum: m/z (ES+)[M+H]+=322, 324.
[0664] The following intermediates were prepared in an analogous
fashion from 6-bromo-4-chloro-7-fluoroquinoline-3-carboxamide:
TABLE-US-00008 Intermediate Structure Name Intermediate K3 *
##STR00101## 6-bromo-7-fluoro-4-[[(3S)-oxan-3-
yl]amino]quinoline-3-carboxamide Intermediate L3 ##STR00102##
6-bromo-7-fluoro-4-[[(3R)-oxan-3- yl]amino]quinoline-3-carboxamide
*The reaction was stirred at 80.degree. C. overnight.
Intermediate K.sub.3
[0665] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta. 1.52
(1H, td), 1.59-1.79 (2H, m), 2.02 (1H, d), 3.32-3.48 (2H, m), 3.68
(1H, dd), 3.87 (1H, dd), 3.9-4.01 (1H, m), 7.56 (1H, s), 7.71 (1H,
d), 8.10 (1H, s), 8.20 (1H, d), 8.62 (2H, d). Mass Spectrum: m/z
(ES-)[M-H]-=366.
Intermediate L3
[0666] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta. 1.52
(1H, td), 1.67 (2H, ddd), 2.02 (1H, d), 3.32-3.5 (2H, m), 3.68 (1H,
dd), 3.87 (1H, dd), 3.91-4.02 (1H, m), 7.56 (1H, s), 7.71 (1H, d),
8.10 (1H, s), 8.20 (1H, d), 8.62 (2H, d). Mass Spectrum: m/z
(ES+)[M+H]+=368, 370.
[0667] The preparation of 6-bromo-4-chloroquinoline-3-carboxamide
has been described earlier. The preparation of
6-bromo-4-chloro-7-fluoroquinoline-3-carboxamide is described
below.
Intermediate K4:
6-Bromo-4-chloro-7-fluoroquinoline-3-carboxamide
##STR00103##
[0669] DMF (0.5 mL) was added to a stirred suspension of
6-bromo-7-fluoro-4-oxo-1H-quinoline-3-carboxylic acid (22.5 g,
78.66 mmol) in thionyl chloride (140 g, 1179.85 mmol) and the
mixture heated to reflux for 2 h. The reaction was allowed to cool,
concentrated in vacuo and the residue azeotroped twice with toluene
to afford a yellow solid. This solid was added portionwise to a
solution of ammonium hydroxide (147 mL, 1179.85 mmol) at 0.degree.
C. The white suspension was stirred for 15 minutes then the solid
filtered, washed with water and dried under vacuum to afford the
desired material (23.80 g, 100%) as a white powder.
[0670] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.92
(1H, s), 8.59 (1H, d), 8.21 (1H, s), 8.09 (1H, d), 7.98 (1H, s).
Mass Spectrum: m/z (ES+)[M+H]+=304.8.
Intermediate K5: 6-Bromo-7-fluoro-4-oxo-1H-quinoline-3-carboxylic
acid
##STR00104##
[0672] A solution of sodium hydroxide (18.34 g, 458.44 mmol) in
water (100 mL) was added to a stirred suspension of ethyl
6-bromo-7-fluoro-4-oxo-1H-quinoline-3-carboxylate (28.8 g, 91.69
mmol) in EtOH (500 mL) at ambient temperature. The reaction mixture
was then stirred at 75.degree. C. for 2 h, allowed to cool and the
pH adjusted to 4 using 2N hydrochloric acid. The precipitate was
collected by filtration, washed with water and dried under vacuum
to afford the desired material (23.30 g, 89%) as a white powder.
NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta. 14.78 (1H, s),
13.45 (1H, s), 8.93 (1H, s), 8.46 (1H, d), 7.70 (1H, d). Mass
Spectrum: m/z (ES+)[M+H]+=287.8.
[0673] The preparation of ethyl
6-bromo-7-fluoro-4-oxo-1H-quinoline-3-carboxylate has already been
described.
[0674] The required 3H-imidazo[4,5-c]quinolin-2-one intermediates
were prepared by cyclisation of the appropriate amino intermediates
as follows:
Intermediate 12:
8-Bromo-7-fluoro-1-(4-methyloxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-one
##STR00105##
[0676] 6-Bromo-7-fluoro-/V-(4-methyloxan-4-yl)quinoline-3,4-diamine
(1.1 g, 3.11 mmol) was added to bis(trichloromethyl)carbonate
(0.553 g, 1.86 mmol) in DCM (20 mL) and the resulting mixture
stirred at 30.degree. C. for 2 h. The crude product was purified by
FCC, elutiongradient 0 to 5% MeOH in DCM, to afford the desired
material (0.950 g, 80%) as a brown solid which was used without
further purification.
[0677] The following intermediate was prepared in an analogous
fashion from the appropriate precursor:
TABLE-US-00009 Intermediate Structure Name Intermediate M2 *
##STR00106## 8-bromo-1-(4-methyloxan-4-yl)-
3H-imidazo[4,5-c]quinolin-2-one *Triethylamine (1.2 equivalents)
was added to the reaction mixture and the reaction proceeded at
ambient temperature over 2 h. The reaction mixture was purified
using an SCX column with the desired material eluted with 7M
ammonia in MeOH.
Intermediate M2
[0678] Mass Spectrum: m/z (ES-)[M-H]-=362.39.
[0679] The preparation of the appropriate amino intermediates is
described below:
Intermediate 13:
6-Bromo-7-fluoro-N'-(4-methyloxan-4-yl)quinoline-3,4-diamine
##STR00107##
[0681]
6-Bromo-7-fluoro-N-(4-methyloxan-4-yl)-3-nitroquinolin-4-amine
(1.215 g, 3.16 mmol) was added to iron powder (1.8 g) in acetic
acid (15 mL). The mixture was stirred and heated gently with a hot
air gun (approximately 60.degree. C.) to initiate reaction. The
heat source was removed and the resulting mixture was stirred for 1
h. The reaction mixture was diluted with water and the solids
removed by filtration and discarded. The filtrate was concentrated
in vacuo, diluted with water and extracted with EtOAc. The organics
were dried over Na.sub.2SO.sub.4 and concentrated in vacuo to
afford the desired material (1.10 g, 98%) as a brown solid which
was used without further purification.
Intermediate 14:
6-Bromo-7-fluoro-N-(4-methyloxan-4-yl)-3-nitroquinolin-4-amine
##STR00108##
[0683] 6-Bromo-4-chloro-7-fluoro-3-nitroquinoline (1 g, 3.27 mmol)
was added to a solution of 4-methyltetrahydro-2H-pyran-4-amine
hydrochloride (0.596 g, 3.93 mmol) and DIPEA (1.715 mL, 9.82 mmol)
in DMA (10 mL) and the resulting mixture stirred at 100.degree. C.
for 4 h. The reaction mixture was diluted with water and the solid
collected by filtration and dried to afford the desired material
(1.215 g, 97%) as a brown solid which was used without further
purification.
[0684] The synthesis of 6-bromo-4-chloro-7-fluoro-3-nitroquinoline
has been reported in the literature (e.g. Garcia-Echeverria, C. et
al., WO2006122806) and is available as a commercial reagent (e.g.
Aces Pharma, Inc--order number 74244).
[0685] 6-Bromo-N-(4-methyloxan-4-yl)quinoline-3,4-diamine was
prepared as follows:
Intermediate M3:
6-Bromo-N'-(4-methyloxan-4-yl)quinoline-3,4-diamine
##STR00109##
[0687] Water (8.35 mL) was added to a stirred mixture of
6-bromo-N-(4-methyloxan-4-yl)-3-nitroquinolin-4-amine (1.07 g, 2.92
mmol), iron (0.979 g, 17.53 mmol) and ammonia hydrochloride (0.109
g, 2.05 mmol) in EtOH (50.1 mL) and the resulting slurry heated to
105.degree. C. for 2 h. The reaction was filtered warm through a
pad of celite, washing with MeOH, and the filtrate evaporated to
dryness. The crude solid was dissolved in DCM (10 mL) and washed
with a sat. aqueous solution of NaHCO.sub.3 (10 mL) and sat. brine
(10 mL). The organic layer was dried over MgSO.sub.4, filtered and
evaporated to afford the desired material (0.850 g, 87%) as a pale
orange solid. This was used without further purification. NMR
Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta. 1.19 (3H, s), 1.51
(2H, d), 1.76 (2H, td), 3.43 (2H, td), 3.73 (2H, dt), 4.15 (1H, s),
5.45 (2H, s), 7.39 (1H, dd), 7.67 (1H, d), 8.22 (1H, d), 8.51 (1H,
s). Mass Spectrum: m/z (ES+)[M+H]+=336, 338.
Intermediate M4:
6-Bromo-N-(4-methyloxan-4-yl)-3-nitroquinolin-4-amine
##STR00110##
[0689] A solution of 6-bromo-4-chloro-3-nitroquinoline (1 g, 3.48
mmol), 4-methyltetrahydro-2H-pyran-4-amine hydrochloride (1.055 g,
6.96 mmol) and triethylamine (1.939 mL, 13.91 mmol) in DMF (10 mL)
was heated to 100.degree. C. for 1 h in a sealed tube in the
microwave reactor. The mixture was allowed to cool then poured into
stirred water (50 mL) and the resulting yellow precipitate was
collected by filtration and dried under vacuum to afford the
desired material (1.070 g, 84%) as a yellow solid. This was used
without further purification. NMR Spectrum: .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 1.40 (3H, s), 1.78 (2H, dt), 1.89 (2H, ddd),
3.51-3.64 (4H, m), 7.80 (1H, s), 7.91 (1H, d), 8.01 (1H, dd), 8.48
(1H, d), 9.18 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=366, 368.
[0690] The synthesis of 6-bromo-4-chloro-3-nitroquinoline has been
reported in the literature (e.g. Garcia-Echeverria, C. et al.,
WO2005054238) and is available as a commercial reagent (e.g. Aces
Pharma, Inc--order number 74381).
[0691] Intermediate N1, tert-butyl
8-bromo-1-(oxan-4-yl)-2-oxoimidazo[5,4-c]quinoline-3-carboxylate,
used for the preparation of example 13 was prepared as described
below:
Intermediate N1: tert-Butyl
8-bromo-1-(oxan-4-yl)-2-oxoimidazo[5,4-c]quinoline-3-carboxylate
##STR00111##
[0693] Di-tert-butyl dicarbonate (376 mg, 1.72 mmol) was added to a
mixture of 8-bromo-1-(oxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-one
(300 mg, 0.86 mmol) and triethylamine (0.240 mL, 1.72 mmol) in DCM
(20 mL). The resulting solution was stirred at ambient temperature
for 4 h then concentrated in vacuo. The crude product was purified
by FCC, elution gradient 0 to 60% MeOH in DCM, to afford the
desired material (310 mg, 80%) as a white solid.
[0694] NMR Spectrum: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.72
(9H, s), 1.81-1.95 (2H, m), 2.92-3.03 (2H, m), 3.57-3.65 (2H, m),
4.26 (2H, dd), 4.89-4.94 (1H, m), 7.82 (1H d), 8.32-8.35 (1H, m),
8.39 (1H, s), 9.49 (1H, m). Mass Spectrum: m/z (ES+)[M+H]+=448.
[0695]
2-[3-(Azetidin-1-yl)propoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)pyridine,
2-(3-pyrrolidin-1-ylpropoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl)pyridine and
3-[6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]o-
xy-N,N-dimethylpropan-1-amine were prepared as follows:
2-[3-(Azetidin-1-yl)propoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y-
l)pyridine
##STR00112##
[0697] n-Butyl lithium (4.65 mL, 11.62 mmol) was added to
2-[3-(azetidin-1-yl)propoxy]-5-bromopyridine (2.1 g, 7.74 mmol) and
2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.161 g,
11.62 mmol) in THF (50 mL) at -78.degree. C. over a period of 10
minutes and the resulting solution stirred at -78.degree. C. for 1
h. The reaction was quenched with sat. Na.sub.2SO.sub.4 (10 mL) and
the solvent removed in vacuo. The residue was dissolved in DCM (100
mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to afford
the desired material (2.00 g, 81%) as a white solid. Mass Spectrum:
m/z (ES+)[M+H]+=319.
2-[3-(Azetidin-1-yl)propoxy]-5-bromopyridine
##STR00113##
[0699] Sodium hydride (1.364 g, 56.82 mmol) was added to
3-(azetidin-1-yl)propan-1-ol (2.62 g, 22.73 mmol) in THF (20 mL) at
ambient temperature under an inert atmosphere and the reaction
stirred for 10 minutes. 5-Bromo-2-fluoropyridine (2.0 g, 11.36
mmol) was added and the resulting solution stirred for 1 h before
being quenched with water (20 mL) and extracted with EtOAc
(5.times.50 mL). The organics were combined, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford the
desired material (3.75 g, 122%) as a white solid. NMR Spectrum:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.80 (2H, m), 2.11 (2H,
m), 2.55 (2H, t), 3.18 (4H, t), 4.328 (2H, t), 6.64 (1H, d), 7.62
(1H, dd), 8.16 (1H, d). Mass Spectrum: m/z (ES+)[M+H]+=271.
3-(Azetidin-1-yl)propan-1-ol
##STR00114##
[0701] A solution of lithium aluminium hydride (2.0 M in THF) (8.38
mL, 16.76 mmol) diluted in further THF (20 mL) was added to a
mixture of methyl 3-(azetidin-1-yl)propanoate (2 g, 13.97 mmol) in
THF (5 mL) dropwise at 0.degree. C. under an inert atmosphere. The
resulting solution was stirred at 0.degree. C. for 1 h then the
reaction mixture treated with sodium sulphate decahydrate and
stirred for 30 minutes. The solid was removed by filtration and
discarded and the filtrate evaporated to afford the desired
material (1.240 g, 77%) as a colourless oil.
[0702] NMR Spectrum: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
1.51-1.57 (2H, m), 2-2.07 (2H, m), 2.6-2.66 (2H, m), 3.20 (4H, t),
3.7-3.76 (2H, m).
Methyl 3-(azetidin-1-yl)propanoate
##STR00115##
[0704] Methyl acrylate (2.082 mL, 23.12 mmol) was added to a
solution of azetidine (1.2 g, 21.02 mmol) in DCM and the resulting
solution stirred at ambient temperature, under an inert atmosphere
for 16 h. The reaction mixture was evaporated and the crude product
purified by FCC, eluted with 25% EtOAc in DCM, to afford the
desired material (2.0 g, 66.5%) as a colourless oil. NMR Spectrum:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.97-2.1 (2H, m), 2.33
(2H, d), 2.67 (2H, d), 3.18 (4H, t), 3.67 (3H, s).
2-(3-Pyrrolidin-1-ylpropoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y-
l)pyridine
##STR00116##
[0706] n-Butyllithium (5.68 mL, 14.20 mmol) was added dropwise to a
mixture of 5-bromo-2-(3-pyrrolidin-1-ylpropoxy)pyridine (2.7 g,
9.47 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(2.64 g, 14.20 mmol) in THF (20 mL) at -78.degree. C. over a period
of 10 minutes under an inert atmosphere. The resulting mixture was
allowed to warm to ambient temperature and stirred for 12 h. The
reaction mixture was quenched by the addition of a sat. aqueous
solution of ammonium chloride, extracted with EtOAc (2.times.50 mL)
and the organic layer dried over Na.sub.2SO.sub.4, filtered and
evaporated to afford the desired material (3.10 g, 99%) as a yellow
oil. The product was used in the next step directly without further
purification. NMR Spectrum: .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 1.26-1.41 (12H, m), 1.77-1.80 (4H, m), 1.95-2.04 (2H, m),
2.50-2.58 (4H, m), 2.62 (2H, t), 4.37 (2H, t), 6.69 (1H, d), 7.91
(1H, d), 8.52 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=251.
5-bromo-2-(3-pyrrolidin-1-ylpropoxy)pyridine
##STR00117##
[0708] Sodium hydride (0.591 g, 14.77 mmol) was added portionwise
to a solution of 3-(pyrrolidin-1-yl)propan-1-ol (1.615 g, 12.50
mmol) in THF (20 mL) at to 0.degree. C. then stirred at ambient
temperature for 30 minutes. 5-Bromo-2-fluoropyridine (2 g, 11.36
mmol) was added and the resulting mixture stirred at ambient
temperature for 2 h before being quenched by the addition of a sat.
aqueous solution of ammonium chloride. The moisture was extracted
with EtOAc (2.times.100 mL), the organic layer dried over
Na.sub.2SO.sub.4, filtered and evaporated to afford pale yellow
solid. The crude product was purified by FCC, elution gradient 0 to
10% MeOH in DCM, to afford the desired material (2.70 g, 83%) as a
yellow solid.
[0709] Mass Spectrum: m/z (ES+)[M+H]+=285.
3-[6-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]ox-
y-N,N-dimethylpropan-1-amine
##STR00118##
[0711] A solution of n-butyllithium (0.693 g, 10.83 mmol) in
n-hexane (4.33 mL) was added to a stirred mixture of
3-(5-bromo-6-fluoropyridin-2-yl)oxy-N,N-dimethylpropan-1-amine (2
g, 7.22 mmol) and
2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.014 g,
10.83 mmol) in THF (20 mL) at -78.degree. C. over a period of 20
minutes under an inert atmosphere. The resulting mixture was
allowed to warm to ambient temperature and stirred for 2 h. The
reaction mixture was quenched with sat. NaHCO.sub.3 solution and
concentrated in vacuo. The crude product was purified by FCC,
elution gradient 0 to 10% MeOH in DCM, to afford the desired
material (2.50 g, 107%). Mass Spectrum: m/z (ES+)[M+H]+=325.
3-(5-Bromo-6-fluoropyridin-2-yl)oxy-N,N-dimethylpropan-1-amine
##STR00119##
[0713] (E)-Diisopropyl diazene-1,2-dicarboxylate (15.80 g, 78.13
mmol) was added dropwise to 3-(dimethylamino)propan-1-ol (8.06 g,
78.13 mmol), 5-bromo-6-fluoropyridin-2-ol (10 g, 52.09 mmol) and
triphenylphosphine (20.49 g, 78.13 mmol) in DCM (150 mL) cooled to
0-5.degree. C. under an inert atmosphere. The resulting solution
was stirred at ambient temperature for 16 h then the solvent
removed under reduced pressure. The residue was diluted with EtOAc
(50 mL) and the solid removed by filtration and discarded. The
filtrate was acidified with hydrogen chloride in dioxane. The solid
was collected by filtration then dissolved in a sat. aqueous
solution of Na.sub.2CO.sub.3 (200 mL) and extracted with EtOAc
(3.times.100 mL). The combined organic layers were washed with
water, brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo
to afford the desired material (9.00 g, 62.3%). NMR Spectrum:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.89-1.98 (2H, m), 2.26
(6H, s), 2.34 (2H, t), 4.30 (2H, t), 6.53 (1H, d), 7.74 (1H, t).
Mass Spectrum: m/z (ES+)[M+H]+=277.
5-Bromo-6-fluoropyridin-2-ol
##STR00120##
[0715] A solution of sodium nitrite (21.67 g, 314.13 mmol) in water
(150 mL) was added dropwise to a stirred mixture of
5-bromo-6-fluoropyridin-2-amine (50 g, 261.78 mmol) and sulphuric
acid (1.2 mL, 22.51 mmol) in water (750 mL) at 0-5.degree. C. The
resulting suspension was stirred for 48 h at ambient temperature
then the precipitate collected by filtration, washed with water
(200 mL) and dried under vacuum to afford the desired material
(40.0 g, 80%) as a pale yellow solid, which was used without
further purification. NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6)
.delta. 6.55 (1H, d), 8.00 (1H, t), 11.71 (1H, bs). Mass Spectrum:
m/z (ES+)[M+H]+=192.
5-bromo-6-fluoropyridin-2-amine
##STR00121##
[0717] NBS (50.0 g, 280.99 mmol) was added slowly to
6-fluoropyridin-2-amine (30 g, 267.61 mmol) in MeCN (300 mL) cooled
to 10-20.degree. C. over a period of 30 minutes. The resulting
solution was stirred at ambient temperature for 60 minutes then the
solvent removed under reduced pressure. The residue was diluted
with water, the precipitate collected by filtration, washed with
water (200 mL) and dried under vacuum to afford the desired
material (50.0 g, 98%) as a white solid, which was used without
further purification. NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6)
.delta. 6.29 (1H, d), 6.57 (2H, bs), 7.65 (1H, t). Mass Spectrum:
m/z (ES+)[M+H]+=191.
Examples 25 & 26
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-[(1R,3R)-3-methoxycyclopentyl-
]-3-methylimidazo[4,5-c]quinolin-2-one and
8-[6-(3-Dimethylaminopropoxy)pyridin-3-yl]-1-[(1S,3S)-3-methoxycyclopenty-
l]-3-methylimidazo[4,5-c]quinolin-2-one
##STR00122##
[0719]
Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-
[2-(2'-amino-1,1'-biphenyl)]palladium(II) (26.1 mg, 0.03 mmol) was
added to
8-bromo-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinoli-
n-2-one:
8-bromo-1-[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]qu-
inolin-2-one (1:1 mixture) (250 mg, 0.66 mmol),
N,N-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2--
yl]oxypropan-1-amine (244 mg, 0.80 mmol) and Cs.sub.2CO.sub.3 (433
mg, 1.33 mmol) in 1,4-dioxane (20 mL) and water (5 mL) and the
resulting mixture stirred at 100.degree. C. for 2 h. The reaction
mixture was poured into water (25 mL), extracted with DCM
(2.times.50 mL), the organic layer dried over Na.sub.2SO.sub.4,
filtered and evaporated to afford yellow residue. The crude product
was purified by preparative HPLC (XSelect CSH Prep C18 OBD column,
5.mu. silica, 19 mm diameter, 150 mm length), using decreasingly
polar mixtures of water (containing 0.1% Formic acid) and MeCN as
eluents. Fractions containing the desired compound were evaporated
to dryness to afford the desired material as a racemic mixture (175
mg, 53.3%) as a white solid. Optimisation on the Agilent 1100, AD
column, (20 micron .mu.m silica, 4.6 mm diameter, 250 mm length)
showed that MeCN/MeOH/TEA, 95/05/0.1 would give the best
separation. This method was used for the preparative HPLC
purification. The racemic mixture (130 mg, 0.27 mmol) was dissolved
in EtOH (10 mL) and separated using preparative HPLC on AD column
(20 .mu.m silica, 50 mm diameter, 250 mm length), two injections
were required in order to prep the entire sample. Mixed fractions
were subjected to a second separation using the above method and
fractions containing the desired pure enantiomers were evaporated
to afford the desired materials. This method gave mixed fractions
which were repurified using the same conditions. Fractions
containing the separated isomers were evaporated to dryness:
Example 25: Isomer 1 (58 mg)
[0720] NMR Spectrum: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
1.87-1.98 (1H, m), 2.04 (3H, dt), 2.33 (8H, s), 2.47-2.64 (3H, m),
2.72 (1H, ddd), 3.36 (3H, s), 3.59 (3H, s), 4.09-4.21 (1H, m), 4.43
(2H, t), 5.59 (1H, q), 6.88 (1H, d), 7.80 (1H, dd), 7.92 (1H, dd),
8.22 (1H, d), 8.33 (1H, d), 8.50 (1H, d), 8.70 (1H, s). Mass
Spectrum: m/z (ES+)[M+H]+=476.
Example 26: Isomer 2 (58 mg)
[0721] NMR Spectrum: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.94
(1H, m), 1.99-2.11 (3H, m), 2.32 (8H, s), 2.46-2.64 (3H, m),
2.66-2.83 (2H, m), 3.36 (3H, s), 3.59 (3H, s), 4.17 (1H, m), 4.43
(2H, t), 5.44-5.72 (1H, m), 6.88 (1H, d), 7.80 (1H, dd), 7.91 (1H,
dd), 8.22 (1H, d), 8.33 (1H, d), 8.50 (1H, d), 8.70 (1H, s). Mass
Spectrum: m/z (ES+)[M+H]+=476.
[0722] The preparation of
8-bromo-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-
-one:
8-bromo-1-[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quino-
lin-2-one (1:1 mixture) is described below:
Intermediate O1:
8-bromo-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-
-one:
8-bromo-1-[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quino-
lin-2-one (1:1 Mixture)
##STR00123##
[0724] A mixture of
6-bromo-4-[[(1R,3R)-3-methoxycyclopentyl]amino]quinoline-3-carboxylic
acid:
6-bromo-4-[[(1S,3S)-3-methoxycyclopentyl]amino]quinoline-3-carboxyl-
ic acid (1:1 mixture) (13 g, 35.8 mmol), tetrabutylammonium bromide
(1.16 g, 3.60 mmol), iodomethane (7.645 g, 53.86 mmol) and sodium
hydroxide (2.15 g, 53.75 mmol) in DCM (600 mL) and water (380 mL)
was stirred at ambient temperature overnight. The resulting
solution was concentrated under vacuum to remove the organics and
the solids collected by filtration, washed with water (5.times.10
mL) and dried in a vacuum oven to afford the desired material
(racemic mixture) (9.8 g, 73%) as a off-white solid. NMR Spectrum:
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 1.81-1.87 (1H, m), 2.33-2.51
(4H, m), 2.45-2.51 (1H, m), 3.28 (3H, s), 3.49 (3H, s), 4.02-4.21
(1H, m), 5.40 (1H, p), 7.73 (1H, dd), 7.98 (1H, d), 8.35 (1H, d),
8.91 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=375.9.
Intermediate O2:
8-bromo-1-[(1R,3R)-3-methoxycyclopentyl]-3H-imidazo[4,5-c]quinolin-2-one:
8-bromo-1-[(1S,3S)-3-methoxycyclopentyl]-3H-imidazo[4,5-c]quinolin-2-one
(1:1 Mixture)
##STR00124##
[0726] A mixture of
6-bromo-4-[[(1R,3R)-3-methoxycyclopentyl]amino]quinoline-3-carboxylic
acid:
6-bromo-4-[[(1S,3S)-3-methoxycyclopentyl]amino]quinoline-3-carboxyl-
ic acid (1:1 mixture) (17 g, 46.54 mmol), triethylamine (14.1 g,
139.34 mmol) in DMF (270 mL) was stirred at ambient temperature for
1 h. Diphenyl phosphorazidate (25.6 g, 93.02 mmol) was added
dropwise with stirring and the solution stirred at ambient
temperature for a further 20 minutes before being heated to
60.degree. C. for 1 h. The reaction was allowed to cool and
concentrated under vacuum. The residue was diluted with water (300
mL), the solids collected by filtration and dried in an oven under
reduced pressure to afford the desired material (as a racemic
mixture) (13 g, 77%) as a off-white solid. Mass Spectrum: m/z
(ES+)[M+H]+=362.2.
Intermediate O3:
6-bromo-4-[[(1R,3R)-3-methoxycyclopentyl]amino]quinoline-3-carboxylic
acid:
6-bromo-4-[[(1S,3S)-3-methoxycyclopentyl]amino]quinoline-3-carboxyl-
ic acid (1:1 Mixture)
##STR00125##
[0728] 2N Sodium hydroxide (150 mL) was added to a mixture of ethyl
6-bromo-4-[[(1R,3R)-3-methoxycyclopentyl]amino]quinoline-3-carboxylate:
ethyl
6-bromo-4-[[(1S,3S)-3-methoxycyclopentyl]amino]quinoline-3-carboxyl-
ate (1:1 mixture) (18.6 g, 47.2 mmol) in MeOH (500 mL) and water
(100 mL) and the resulting solution stirred for 15 h at ambient
temperature. The mixture was concentrated under vacuum and the
residue diluted with water (300 mL). The pH value of the solution
was adjusted to 5 with 2N hydrochloric acid, the solids collected
by filtration and dried in an oven under reduced pressure to afford
the desired material (as a racemic mixture) (17.1 g) as a off-white
solid. NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta.
1.60-1.71 (2H, m), 1.81-1.88 (1H, m), 1.96-2.02 (1H, m), 2.03-2.10
(2H, m), 3.21 (3H, s), 3.91-3.96 (1H, m), 4.51-4.72 (1H, m), 7.77
(1H, d), 7.93 (1H, d), 8.45 (1H, d), 8.85 (1H, s), 13.30 (1H, bs).
Mass Spectrum: m/z (ES+)[M+H]+=365.2.
Intermediate O4: Ethyl
6-bromo-4-[[(1R,3R)-3-methoxycyclopentyl]amino]quinoline-3-carboxylate:
ethyl
6-bromo-4-[[(1S,3S)-3-methoxycyclopentyl]amino]quinoline-3-carboxyl-
ate (1:1 Mixture)
##STR00126##
[0730] A mixture of ethyl 6-bromo-4-chloroquinoline-3-carboxylate
(15 g, 47.69 mmol), (trans)-3-methoxycyclopentan-1-amine (racemic
mixture) (8.09 g, 26.68 mmol) and DIPEA (19.68 g, 152.27 mmol) in
DMA (100 mL) was stirred at 80.degree. C. for 4 h under an inert
atmosphere. The reaction was quenched by the addition of water (500
mL), the solids collected by filtration and dried in an oven under
reduced pressure to afford the desired material (as a racemic
mixture) (18.6 g) as a light brown solid. Mass Spectrum: m/z
(ES+)[M+H]+=393, 395.
[0731] The preparation of ethyl
6-bromo-4-chloroquinoline-3-carboxylate has been described
earlier.
Example 27
7-Fluoro-1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidin-1-ylpropo-
xy)pyridin-3-yl]imidazo[4,5-c]quinolin-2-one
##STR00127##
[0733] 3-(Pyrrolidin-1-yl)propan-1-ol (46.9 mg, 0.36 mmol) was
added to sodium hydride (29.1 mg, 1.21 mmol) in THF (4 mL) at
ambient temperature over a period of 20 minutes.
7-Fluoro-8-(6-fluoropyridin-3-yl)-1-(cis-3-methoxycyclobutyl)-3-methylimi-
dazo[4,5-c]quinolin-2-one (120 mg, 0.30 mmol) was added. The
resulting mixture was stirred at ambient temperature for 2 h. The
reaction mixture was quenched with water and the crude product
purified by FCC, elution gradient 0 to 5% MeOH in DCM. The crude
product was purified by preparative HPLC (Waters XBridge Prep C18
OBD column, 5.mu. silica, 19 mm diameter, 100 mm length), using
decreasingly polar mixtures of water (containing 0.1% formic acid)
and MeCN as eluents. Fractions containing the desired compound were
evaporated to dryness to afford the desired material (60.0 mg,
38.7%) as a off-white solid. NMR Spectrum: .sup.1H NMR (300 MHz,
MeOD) .delta. 1.90-2.00 (4H, m), 2.10-2.20 (2H, m), 2.81-3.00 (8H,
m), 3.04-3.17 (2H, m), 3.28 (3H, s), 3.6 (3H, s), 3.85-3.96 (1H,
m), 4.48 (2H, t), 5.00-5.13 (1H, m), 6.88 (1H, d), 7.82 (1H, d),
8.05 (1H, d), 8.43-8.50 (2H, m), 8.83 (1H, s)
[0734] Mass Spectrum: m/z (ES+)[M+H]+=506.
[0735] The following compounds were prepared in an analogous
fashion using the appropriate alcohol and the appropriate pyridyl
fluoro intermediate.
TABLE-US-00010 Example Structure Name 28* ##STR00128##
l-(cis-3-methoxycyclobutyl)-3-methyl-
8-[6-(3-pyrrolidin-1-ylpropoxy)pyridin-
3-yl]imidazo[4,5-c]quinolin-2-one 29 ##STR00129##
3-methyl-1-[(3S)-oxan-3-yl]-8-[6-(3-
pyrrolidin-1-ylpropoxy)pyridin-3- yl]imidazo[5,4-c]quinolin-2-one
30 ##STR00130## 3-methyl-1-(oxan-4-yl)-8-[6-(3-
pyrrolidin-1-ylpropoxy)pyridin-3- yl]imidazo[5,4-c]quinolin-2-one
31 ##STR00131## 3-methyl-1-[(3S)-oxan-3-yl]-8-[6-
(3-piperidin-1-ylpropoxy)pyridin- 3-yl]imidazo[5,4-c]quinolin-2-one
32 ##STR00132## 3-methyl-1-[(3R)-oxan-3-yl]-8-[6-
(3-piperidin-1-ylpropoxy)pyridin- 3-yl]imidazo[5,4-c]quinolin-2-one
33* ##STR00133## 1-(cis-3-methoxycyclobutyl)-3-methyl-
8-[6-(3-piperidin-1-ylpropoxy)pyridin-
3-yl]imidazo[4,5-c]quinolin-2-one 34 ##STR00134##
8-[6-[3-(azetidin-1-yl)propoxy]pyridin-
3-yl]-3-methyl-1-[(3R)-oxan-3- yl]imidazo[5,4-c]quinolin-2-one 35**
##STR00135## 1-(cis-3-methoxycyclobutyl)-8-[6-(3-
pyrrolidin-1-ylpropoxy)pyridin-3-yl]-
3H-imidazo[4,5-c]quinolin-2-one 36* ##STR00136##
1-(oxan-4-yl)-8-[6-(3-piperidin-1- ylpropoxy)pyridin-3-yl]-3H-
imidazo[4,5-c]quinolin-2-one 37** ##STR00137##
3-methyl-1-(oxan-4-yl)-8-[6-(3- piperidin-1-ylpropoxy)pyridin-3-
yl]imidazo[5,4-c]quinolin-2-one 38** ##STR00138##
8-[6-[3-(azetidin-1-yl)propoxy]pyridin-
3-yl]-1-(cis-3-methoxycyclobutyl)-3-
methylimidazo[4,5-c]quinolin-2-one 39* ##STR00139##
8-[6-[3-(azetidin-1-yl)propoxy]pyridin-
3-yl]-3-methyl-1-(oxan-4-yl)imidazo- [5,4-c]quinolin-2-one *The
reaction was performed in DMF between 0.degree. C. and ambient
temperature. **The reaction was performed in DMA at 50.degree.
C.
Example 28
[0736] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta.
1.67-1.96 (6H, m), 2.44-2.55 (6H, m), 2.78-3.03 (4H, m), 3.19 (3H,
s), 3.50 (3H, s), 3.84-3.88 (1H, m), 4.38 (2H, t), 5.13 (1H, p),
6.97 (1H, d), 7.92 (1H, dd), 8.12 (1H, dd), 8.20 (1H, dd), 8.43
(1H, s), 8.67 (1H, d), 8.88 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=488.
Example 29
[0737] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
1.68-1.86 (6H, m), 1.95 (2H, p), 2.10-2.19 (1H, d), 2.51-2.75 (7H,
m), 3.35-3.49 (1H, m), 3.50 (3H, s), 3.92 (1H, d), 4.08-4.18 (1H,
m), 4.22 (1H, t), 4.38 (2H, t), 4.90-5.03 (1H, m), 6.98 (1H, d),
7.92 (1H, dd), 8.15-8.20 (1H, m), 8.25 (1H, s), 8.32 (1H, s), 8.66
(1H, d), 8.90 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=488.
Example 30
[0738] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta.
1.67-1.73 (4H, m), 1.90-1.98 (4H, m), 2.39-2.46 (4H, m), 2.54-2.61
(2H, m), 2.72 (2H, ddd), 3.52 (3H, s), 3.59 (2H, t), 4.06 (2H, dd),
4.38 (2H, t), 5.13-5.16 (1H, m), 6.98 (1H, d), 7.96 (1H, dd), 8.14
(1H, d), 8.20 (1H, dd), 8.45 (1H, s), 8.67 (1H, d), 8.91 (1H, s).
Mass Spectrum: m/z (ES+)[M+H]+=488.
Example 31
[0739] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
1.38-1.50 (6H, m), 1.83-1.95 (4H, m), 2.13-2.18 (1H, m), 2.35-2.43
(6H, m), 2.62-2.75 (1H, m), 3.38-3.44 (1H, m), 3.49 (3H, s), 3.94
(1H, d), 4.13-4.27 (2H, m), 4.35 (2H, t), 4.90-5.02 (1H, m), 6.99
(1H, d), 7.94 (1H, d), 8.13-8.18 (2H, m), 8.34 (1H, s), 8.48 (1H,
d), 8.90 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=502.
Example 32
[0740] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
1.35-1.58 (6H, m), 1.85-1.98 (4H, m), 2.12-2.21 (1H, m), 2.21-2.50
(6H, m), 2.60-2.80 (1H, m), 3.33-3.48 (1H, m), 3.48 (3H, s),
3.89-3.97 (1H, m), 4.10-4.28 (2H, m), 4.30-4.38 (2H, m), 4.90-5.08
(1H, m), 6.98 (1H, d), 7.93-8.0 (1H, m), 8.13-8.22 (2H, m), 8.35
(1H, s), 8.63 (1H, s), 8.94 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=502.3.
Example 33
[0741] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
1.32-1.45 (2H, m), 1.45-1.51 (4H, m), 1.88-1.98 (2H, m), 2.31-2.51
(6H, m), 2.81-2.83 (2H, m), 2.97-3.11 (2H, m), 3.19 (3H, s), 3.50
(3H, s), 3.84-3.91 (1H, m), 4.36 (2H, t), 5.10-5.17 (1H, m), 6.97
(1H, d), 7.93 (1H, d), 8.12 (1H, d), 8.21 (1H, dd), 8.43 (1H, s),
8.68 (1H, d), 8.89 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=502.
Example 34
[0742] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
1.78-1.85 (4H, m), 2.05-2.18 (3H, m), 2.66-2.80 (3H, m), 3.36-3.49
(8H, m), 3.94 (1H, d), 4.12-4.35 (2H, m), 4.38 (2H, t), 4.94-4.98
(1H, m), 7.00 (1H, d), 7.92 (1H, d), 8.13-8.20 (2H, m), 8.33 (1H,
s), 8.63 (1H, s), 8.90 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=474.3.
Example 35
[0743] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta.
1.64-1.75 (4H, m), 1.94 (2H, p), 2.45 (3H, d), 2.53-2.58 (3H, m),
2.75-2.88 (2H, m), 2.94-3.08 (2H, m), 3.21 (3H, s), 3.87 (1H, p),
4.39 (2H, t), 5.08 (1H, p), 6.97 (1H, d), 7.90 (1H, dd), 8.09 (1H,
d), 8.19 (1H, dd), 8.43 (1H, d), 8.65 (1H, s), 8.67 (1H, d), 11.50
(1H, s). m/z: ES+[M+H]+ 474. Mass Spectrum: m/z
(ES+)[M+H]+=474.
Example 36
[0744] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta. 1.38
(2H, d), 1.46-1.53 (4H, m), 1.85-1.92 (4H, m), 2.27-2.42 (6H, m),
2.67-2.80 (2H, m), 3.52 (2H, t), 4.08 (2H, dd), 4.33 (2H, t), 5.10
(1H, p), 6.97 (1H, d), 7.93 (1H, d), 8.09 (1H, d), 8.12 (1H, d),
8.20 (1H, dd), 8.42 (1H, s), 8.65 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=488.
Example 37
[0745] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta. 1.40
(2H, d), 1.50 (4H, q), 1.92 (4H, dq), 2.3-2.45 (6H, m), 2.66-2.8
(2H, m), 3.52 (3H, s), 3.59 (2H, t), 4.07 (2H, dd), 4.37 (2H, t),
5.09-5.2 (1H, m), 6.96-6.99 (1H, d), 7.96 (1H, dd), 8.15 (1H, d),
8.18-8.21 (1H, m), 8.44 (1H, s), 8.66 (1H, d), 8.90 (1H, s). Mass
Spectrum: m/z (ES+)[M+H]+=502.46.
Example 38
[0746] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta. 1.74
(2H, p), 1.96 (2H, p), 2.47 (2H, t), 2.78-2.87 (2H, m), 3.01 (2H,
qd), 3.10 (4H, t), 3.21 (3H, s), 3.51 (3H, s), 3.87 (1H, p), 4.35
(2H, t), 5.08-5.18 (1H, m), 6.93-6.97 (1H, d), 7.92 (1H, dd), 8.12
(1H, d), 8.18-8.21 (1H, d), 8.43 (1H, d), 8.65-8.68 (1H, m), 8.88
(1H, s). Mass Spectrum: m/z (ES+)[M+H]+=474.43.
Example 39
[0747] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
1.74-1.78 (2H, m), 1.81-1.93 (2H, m), 2.00-2.09 (2H, m), 2.65-2.77
(4H, m), 3.31-3.36 (4H, m), 3.51 (3H, s), 3.58 (2H, t), 4.04-4.09
(2H, m), 4.34 (2H, t), 5.14 (1H, p), 6.97 (1H, d), 7.94 (1H, dd),
8.13 (1H, d), 8.20 (1H, dd), 8.22 (1H, s), 8.66 (1H, d), 8.90 (1H,
s). Mass Spectrum: m/z (ES+)[M+H]+=474.
[0748] The required fluoro intermediates for Examples 27-39 have
either already been described or were prepared from the appropriate
bromo intermediates as described below:
Intermediate P:
8-(6-fluoropyridin-3-yl)-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinoli-
n-2-one
##STR00140##
[0750] Pd(Ph.sub.3P).sub.4 (0.160 g, 0.14 mmol) was added to
8-bromo-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one (1
g, 2.76 mmol), (6-fluoropyridin-3-yl)boronic acid (0.506 g, 3.59
mmol) and Cs.sub.2CO.sub.3 (1.799 g, 5.52 mmol) in 1,4-dioxane (23
mL) and water (3 mL) under nitrogen. The resulting mixture was
stirred at 100.degree. C. for 3 h then allowed to cool and the
solvent removed under reduced pressure. The crude product was
purified by FCC, elution gradient 0 to 7% MeOH in DCM to give the
desired material (0.905 g, 87%) as a yellow solid. NMR Spectrum:
.sup.1H NMR (300 MHz, DMSO-d6) .delta. 1.83-1.86 (2H, m), 2.15-2.19
(1H, m), 2.49-2.64 (1H, m), 3.38-3.41 (1H, m), 3.49 (3H, s), 3.93
(1H, d), 4.15-4.26 (2H, m), 4.91-5.10 (1H, m), 7.42 (1H, dd), 7.96
(1H, dd), 8.13 (1H, d), 8.38 (1H,$), 8.44 (1H, td), 8.72 (1H, d),
8.96 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=379.1.
[0751] The following fluoro intermediates were prepared in an
analogous fashion from (6-fluoropyridin-3-yl)boronic acid and the
appropriate bromo intermediates, the synthesis of which has already
been described:
TABLE-US-00011 Intermediate Structure Name Intermediate Q
##STR00141## 8-(6-fluoropyridin-3-yl)-3-methyl-
1-[(3R)-oxan-3-yl]imidazo[5,4-c]- quinolin-2-one Intermediate R *
##STR00142## 7-fluoro-8-(6-fluoropyridin-3-yl)-
1-(cis-3-methoxycyclobutyl)-3- methylimidazo[4,5-c]quinolin-2- one
Intermediate S ** ##STR00143## 8-(6-fluoropyridin-3-yl)-1-(cis-3-
methoxycyclobutyl)-3-methyl- imidazo[4,5-c]quinolin-2-one
Intermediate T ** ##STR00144## 8-(6-fluoropyridin-3-yl)-1-(oxan-
4-yl)-3H-imidazo[4,5-c]quinolin- 2-one Intermediate U ***
##STR00145## 8-(6-fluoropyridin-3-yl)-1-(cis-3-
methoxycyclobutyl)-3H-imidazo- [4,5-c]quinolin-2-one *The reaction
was stirred at 80.degree. C. for 2 h. **The reaction was performed
using
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) as the catalyst and was stirred
at 90.degree. C. for 2 h. ***The reaction was performed with a 1:2
mixture of sodium tetrachloropalladate and
3-(di-tert-butylphosphino)propane-1-sulfonic acid (0.05 M in water)
as the catalyst and ligand and K.sub.2CO.sub.3 as the base. The
reaction was stirred at 80.degree. C. for 3 h.
Intermediate Q
[0752] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
1.80-1.83 (2H, m), 2.15-2.18 (1H, m), 2.49-2.73 (1H, m), 3.37-3.41
(1H, m), 3.49 (3H, s), 3.93 (1H, d), 4.16-4.26 (2H, m), 4.90-5.10
(1H, m), 7.42 (1H, dd), 7.97 (1H, dd), 8.14 (1H, d), 8.38 (1H,$),
8.45 (1H, td), 8.71 (1H, d), 8.95 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=379.
Intermediate R
[0753] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
2.76-2.81 (2H, m), 2.91-3.05 (2H, m), 3.13 (3H, s), 3.49 (3H, s),
3.78-3.82 (1H, m), 5.07-5.10 (1H, m), 7.40 (1H, dd), 7.94 (1H, d),
8.32 (1H, td), 8.45 (d) 8.59 (1H, s), 8.95 (1H, s). Mass Spectrum:
m/z (ES+)[M+H]+=397.
Intermediate S
[0754] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta. 2.83
(2H, s), 3.01 (2H, d), 3.20 (3H, s), 3.51 (3H, s), 3.86 (1H, s),
5.07-5.18 (1H, m), 7.37 (1H, d), 7.96 (1H, d), 8.16 (1H, d), 8.49
(2H, d), 8.75 (1H, s), 8.92 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=379.
Intermediate T
[0755] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
1.90-1.96 (2H, m), 2.65-2.79 (2H, s), 3.65 (2H, t), 4.01-4.11 (2H,
m), 5.06-5.14 (1H, m), 7.40 (1H, dd), 8.02 (1H, dd), 8.15 (1H, d),
8.44-8.50 (2H, m), 8.71 (1H, s), 8.75 (1H, dd), 11.75 (1H, bs).
Mass Spectrum: m/z (ES+)[M+H]+=365.
Intermediate U
[0756] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta.
2.71-2.84 (3H, m), 2.97-3.09 (2H, m), 3.20 (3H, s), 3.86 (1H, p),
5.09 (1H, ddd), 7.35 (1H, dd), 7.83 (1H, dd), 8.07 (1H, d),
8.42-8.5 (2H, m), 8.63 (1H, s), 8.73 (1H, d). Mass Spectrum: m/z
(ES+)[M+H]+=365, 367.
Example 40
3-Methyl-8-[6-(3-methylaminopropoxy)pyridin-3-yl]-1-(oxan-4-yl)imidazo[5,4-
-c]quinolin-2-one
##STR00146##
[0758] Sodium hydride (50.7 mg, 2.11 mmol) was added to tert-butyl
(3-hydroxypropyl)(methyl)carbamate (200 mg, 1.06 mmol) in DMF (5
mL) at ambient temperature under air. The resulting solution was
stirred for 1 h then
8-(6-fluoropyridin-3-yl)-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinoli-
n-2-one (200 mg, 0.53 mmol) was added and the resulting solution
stirred at ambient temperature overnight. The reaction mixture was
quenched with water (20 mL), extracted with EtOAc (5.times.20 mL),
the organic layers combined and washed with water (3.times.50 mL).
The organic layer was dried over Na.sub.2SO.sub.4, filtered and
evaporated to afford a white solid (262 mg, 91%). This material was
dissolved in DCM (10 mL) and TFA (5 mL, 64.90 mmol) added. The
reaction was stirred at ambient temperature for 1 h then the
solvent removed in vacuo. The crude product was purified by
preparative HPLC (XSelect CSH Prep C18 OBD column, 5 .mu.m silica,
19 mm diameter, 150 mm length), using decreasingly polar mixtures
of water (containing 0.1% NH.sub.4HCO.sub.3) and MeCN as eluents.
Fractions containing the desired compound were evaporated to
dryness to afford the desired material (60.0 mg, 27.7%) as a white
solid. NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
1.86-1.94 (4H, m), 2.30 (3H, s), 3.08 (2H, t), 2.71 (2H, dd), 3.52
(3H, s), 3.58 (2H, t), 4.05 (2H, dd), 4.36 (2H, t), 5.15 (1H, p),
6.98 (1H, d), 7.94 (1H, dd), 8.12 (1H, d), 8.20 (1H, dd), 8.42 (1H,
s), 8.65 (1H, d), 8.90 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=448.
[0759] The following compounds were prepared in an analogous
fashion from tert-butyl (3-hydroxypropyl)(methyl)carbamate and the
appropriate fluoro intermediate.
TABLE-US-00012 Example Structure Name 41 ##STR00147##
3-methyl-8-[6-(3-methylaminopropoxy)-
pyridin-3-yl]-1-[(3S)-oxan-3-yl]imidazo- [5,4-c]quinolin-2-one 42
##STR00148## 1-(cis-3-methoxycyclobutyl)-3-methyl-8-
[6-(3-methylaminopropoxy)pyridin-3- yl]imidazo[4,5-c]quinolin-2-one
43* ##STR00149## 3-methyl-8-[6-[3-(methylamino)propoxy]-
3-pyridyl]-1-[(3R)-tetrahydropyran-3-
yl]imidazo[4,5-c]quinolin-2-one *The initial deprotonation and
displacement reaction was performed in THF.
Example 41
[0760] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
1.79-1.84 (2H, m), 2.06-2.21 (3H, m), 2.67 (3H, s), 2.68-2.80 (1H,
m), 3.10 (2H, t), 3.40-3.60 (5H, m), 3.94 (1H, d), 4.12-4.25 (2H,
m), 4.43 (2H, t), 5.20 (1H, p), 7.08 (1H, d), 8.10 (1H, d),
8.19-8.28 (1H, m), 8.40 (1H, s), 8.68 (1H, s), 9.06 (1H, s). Mass
Spectrum: m/z (ES+)[M+H]+=448.2.
Example 42
[0761] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
1.82-1.92 (2H, m), 2.29 (3H, s), 2.62 (2H, t), 2.77-2.88 (2H, m),
3.00 (2H, q), 3.21 (3H, s), 3.50 (3H, s), 3.87 (1H, p), 4.38 (2H,
t), 5.10 (1H, p), 6.98 (1H, d), 7.91 (1H, d), 8.10 (1H, d), 8.21
(1H, dd), 8.42 (1H, s), 8.67 (1H, s), 8.89 (1H, s). Mass Spectrum:
m/z (ES+)[M+H]+=448.
Example 43
[0762] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta. 1.84
(2H, m), 2.10 (3H, m), 2.70 (4H, m), 3.10 (2H, m), 3.40 (1H, m),
3.50 (3H, s), 3.92 (1H, d), 4.18 (2H, m), 4.43 (2H, t), 5.02 (1H,
bs), 7.03 (1H, d), 8.03-9.01 (6H, m). Mass Spectrum: m/z
(ES+)[M+H]+=448.2.
[0763] The preparation of the required fluoro intermediates for
examples 40-43 have already been described.
Example 44
8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-3-methyl-1-[(3R)-tetrahydrofura-
n-3-yl]imidazo[4,5-c]quinolin-2-one methanesulfonic acid salt
##STR00150##
[0765]
N,N-Dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyri-
din-2-yl]oxypropan-1-amine (106 mg, 0.34 mmol), 2M K.sub.2CO.sub.3
(0.718 mL, 1.44 mmol) and
8-bromo-3-methyl-1-[(3R)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinolin-2-on-
e (100 mg, 0.29 mmol) were suspended in dioxane (3 mL) and then
degassed with nitrogen. To this suspension was added
dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II)
(18.72 mg, 0.03 mmol) and the resulting suspension heated in a
sealed microwave vial at 80.degree. C. for 1 h. The reaction was
partitioned between water and DCM and the organic layer
concentrated under reduced pressure. The crude product was purified
by FCC, elution gradient 0 to 10% methanolic ammonia in DCM, to
afford the desired compound (90 mg). The desired material can be
isolated as a methanesulfonic acid salt by dissolving the isolated
material in DCM (10 mL) then adding 1M methanesulfonic acid in DCM
(0.201 mL, 0.20 mmol) and stirring the mixture at room temperature
for 1 h. The solvent was removed in vacuo and the solid was
triturated in Et.sub.2O to afford the methanesulfonic acid salt as
a beige solid (64.0 mg). NMR Spectrum (methanesulfonic acid salt):
.sup.1H NMR (500 MHz, DMSO-d6) .delta. 2.08-2.24 (2H, m), 2.31 (3H,
s), 2.33-2.46 (1H, m), 2.54 (1H, s), 2.83 (6H, s), 3.18-3.29 (2H,
m), 3.55 (3H, s), 3.91 (1H, td), 4.09-4.23 (2H, m), 4.27 (1H, td),
4.42 (2H, t), 5.79-5.9 (1H, m), 7.00 (1H, dd), 7.98 (1H, dd), 8.16
(1H, d), 8.26 (1H, dd), 8.61 (1H, d), 8.71 (1H, dd), 8.94 (1H, s),
9.34 (1H, s).
[0766] Mass Spectrum: m/z (ES+)[M+H]+=448.
[0767] The following compounds were prepared in an analogous
fashion from the appropriate bromo intermediate.
TABLE-US-00013 Example Structure Name 45 ##STR00151##
8-[6-[3-(dimethylamino)propoxy]- 3-pyridyl]-3-methyl-1-[(3S)-tetra-
hydrofuran-3-yl]imidazo[4,5-c]- quinolin-2-one methanesulfonic acid
salt 46 ##STR00152## 1-cyclobutyl-8-[6-[3-(dimethyl-
amino)propoxy]-3-pyridyl]-3- methyl-imidazo[4,5-c]quinolin- 2-one
methanesulfonic acid salt
Example 45
[0768] NMR Spectrum (methanesulfonic acid salt): .sup.1H NMR (500
MHz, DMSO-d6) .delta. 2.11-2.21 (2H, m), 2.29-2.33 (3H, m),
2.32-2.46 (1H, m), 2.52-2.6 (1H, m), 2.83 (6H, s), 3.21-3.28 (2H,
m), 3.55 (3H, s), 3.91 (1H, td), 4.12-4.23 (2H, m), 4.27 (1H, td),
4.42 (2H, t), 5.79-5.9 (1H, m), 7.00 (1H, dd), 7.98 (1H, dd), 8.16
(1H, d), 8.27 (1H, dd), 8.61 (1H, d), 8.71 (1H, d), 8.94 (1H, s),
9.33 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=448.
Example 46
[0769] NMR Spectrum (free base): .sup.1H NMR (500 MHz, DMSO-d6)
.delta. 1.39 (3H, d), 1.92-2.01 (1H, m), 2.01-2.11 (1H, m), 2.34
(6H, s), 2.43 (1H, dd), 2.51-2.61 (2H, m), 2.73 (1H, dd), 3.24 (2H,
pd), 3.58 (3H, s), 5.31-5.41 (1H, m), 5.43-5.53 (1H, m), 6.89 (1H,
dd), 7.78 (1H, dd), 7.89 (1H, dd), 8.18-8.22 (1H, m), 8.32 (1H, d),
8.51 (1H, dd), 8.69 (1H, s). NMR Spectrum (methanesulfonic acid
salt): .sup.1H NMR (500 MHz, DMSO-d6) .delta. 1.76-2.01 (2H, m),
2.08-2.22 (2H, m), 2.31 (3H, s), 2.41-2.49 (2H, m), 2.83 (6H, s),
3.09 (2H, pd), 3.18-3.28 (2H, m), 3.51 (3H, s), 4.42 (2H, t), 5.51
(1H, p), 7.01 (1H, dd), 7.93 (1H, dd), 8.13 (1H, d), 8.24 (1H, dd),
8.42 (1H, d), 8.69 (1H, dd), 8.89 (1H, s), 9.34 (1H, s). Mass
Spectrum: m/z (ES+)[M+H]+=432.
[0770] The bromo intermediates required for the preparation of
examples 44-46 were prepared as described below:
Intermediate V1:
8-Bromo-3-methyl-1-[(3R)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinolin-2-on-
e
##STR00153##
[0772] Tetrabutylammonium bromide (0.222 g, 0.69 mmol) was added to
8-bromo-1-[(3R)-tetrahydrofuran-3-yl]-3H-imidazo[4,5-c]quinolin-2-one
(2.3 g, 6.88 mmol), methyl iodide (1.291 mL, 20.65 mmol) and NaOH
(0.551 g, 13.77 mmol) in DCM (65 mL) and water (39 mL) and the
resulting mixture stirred at ambient temperature overnight. The
solvent was removed under reduced pressure and the crude product
purified by FCC, elution gradient 2 to 5% MeOH in DCM, to afford
the desired material as a yellow solid (1.80 g, 75%). NMR Spectrum:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.41-2.49 (1H, m),
2.59-2.65 (1H, m), 3.62 (3H, s), 4.00-4.06 (1H, m), 4.21-4.48 (2H,
m), 4.49-4.52 (1H, m), 5.69-5.77 (1H, m), 7.69 (1H, d), 8.02 (1H,
d), 8.64 (1H, s), 8.74 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=350.
[0773] The following compounds were prepared in an analogous
fashion from the appropriate intermediate:
TABLE-US-00014 Intermediate Structure Name Intermediate W1
##STR00154## 8-bromo-3-methyl-1-[(3S)-
tetrahydrofuran-3-yl]imidazo- [4,5-c]quinolin-2-one Intermediate X1
##STR00155## 8-bromo-1-cyclobutyl-3-methyl-
imidazo[4,5-c]quinolin-2-one
Intermediate W1
[0774] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta.
2.40-2.48 (1H, m), 2.58-2.67 (1H, m), 3.63 (3H, s), 3.98-4.05 (1H,
m), 4.19-4.28 (2H, m), 4.46-4.51 (1H, td), 5.68-5.76 (1H, m), 7.72
(1H, d), 8.07 (1H, d), 8.67 (1H, d), 8.76 (1H, s). Mass Spectrum:
m/z (ES+)[M+H]+=348.
Intermediate X1
[0775] NMR Spectrum: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
1.95-2.12 (2H, m), 2.52-2.59 (2H, m), 3.17-3.28 (2H, m), 3.59 (3H,
s), 5.18-5.27 (1H, m), 7.8 (1H, d), 8.02 (1H, d), 8.37 (1H, d),
8.70 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=332.
Intermediate V2:
8-Bromo-1-[(3R)-tetrahydrofuran-3-yl]-3H-imidazo[4,5-c]quinolin-2-one
##STR00156##
[0777] Triethylamine (2.60 mL, 18.69 mmol) was added to
6-bromo-4-[[(3R)-tetrahydrofuran-3-yl]amino]quinoline-3-carboxylic
acid (2.1 g, 6.23 mmol) in DMF (30 mL) and the resulting mixture
stirred at ambient temperature for 1 h. Diphenyl phosphorazidate
(3.43 g, 12.46 mmol) was added and the resulting mixture stirred at
60.degree. C. overnight. The reaction mixture was diluted with
water (300 mL) and the solids collected by filtration to afford the
desired material as a yellow solid (2.0 g, 96%). NMR Spectrum:
.sup.1H NMR (300 MHz, DMSO-d6) .delta. 2.42-2.45 (2H, m), 3.85-3.90
(1H, m), 4.05-4.16 (2H, m), 4.16-4.25 (1H, m), 5.62-5.72 (1H, m),
7.16-7.18 (1H, m), 7.74 (1H, d), 7.97 (1H, d), 8.68 (1H, s), 8.73
(1H, s), 11.84 (1H, s).
[0778] Mass Spectrum: m/z (ES+)[M+H]+=334.
[0779] The following compounds were prepared in an analogous
fashion from the appropriate intermediate
TABLE-US-00015 Intermediate Structure Name Intermediate W2
##STR00157## 8-bromo-1-[(3S)-tetrahydrofuran-
3-yl]-3H-imidazo[4,5-c]quinolin- 2-one Intermediate X2 ##STR00158##
8-bromo-1-cyclobutyl-3H- imidazo-[4,5-c]quinolin-2-one
Intermediate W2
[0780] Mass Spectrum: m/z (ES+)[M+H]+=334.
Intermediate X2
[0781] Mass Spectrum: m/z (ES+)[M+H]+=318.
Intermediate V3:
6-Bromo-4-[[(3R)-tetrahydrofuran-3-yl]amino]quinoline-3-carboxylic
acid
##STR00159##
[0783] Sodium hydroxide (0.657 g, 16.43 mmol) was added to ethyl
6-bromo-4-[[(3R)-tetrahydrofuran-3-yl]amino]quinoline-3-carboxylate
(3 g, 8.21 mmol) in THF (60 mL) and water (30 mL) and the resulting
mixture stirred at 60.degree. C. overnight. The aqueous component
was removed under reduced pressure and the remaining solution was
adjusted to pH 6 with 2 M HCl. The solids were collected by
filtration and dried in an oven to afford the desired material as a
white solid (2.1 g, 76%). NMR Spectrum: .sup.1H NMR (300 MHz,
MeOH-d4) .delta. 2.05-2.08 (1H, m), 2.38-2.48 (1H, m), 3.72-3.93
(4H, m), 4.83-5.01 (1H, m) 7.09 (1H, d), 8.04 (1H, d), 8.55 (1H,
s), 8.95 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=339.
[0784] The following compounds were prepared in an analogous
fashion from the appropriate intermediate
TABLE-US-00016 Intermediate Structure Name Intermediate W3
##STR00160## 6-bromo-4-[[(3S')-tetra- hydro-furan-3-yl]amino]-
quinoline-3-carboxylic acid Intermediate X3 ##STR00161##
6-bromo-4-(cyclobutyl- amino)quinoline-3- carboxylic acid
Intermediate W3
[0785] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta.
1.95-2.05 (1H, m), 2.31-2.41 (1H, m), 3.79-3.87 (2H, m), 3.89-3.95
(2H, m), 4.82-4.92 (1H, m), 7.78 (1H, d), 7.92-7.94 (1H, m), 8.44
(1H, d), 8.90 (1H, s), 13.3 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=337.
Intermediate X3
[0786] NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta.
1.81-1.95 (3H, m), 2.01-2.15 (3H, m), 4.53-4.55 (1H, m), 7.74 (1H,
d), 7.88 (1H, d), 8.25 (1H, s), 8.89 (1H, s), 13.27 (1H, s). Mass
Spectrum: m/z (ES+)[M+H]+=321.
Intermediate V4: Ethyl
6-bromo-4-[[(3R)-tetrahydrofuran-3-yl]amino]quinoline-3-carboxylate
##STR00162##
[0788] DIPEA (7.77 mL, 44.51 mmol) was added to ethyl
6-bromo-4-chloroquinoline-3-carboxylate (3.5 g, 11.13 mmol) and
(R)-tetrahydrofuran-3-amine (1.939 g, 22.25 mmol) in DMF (40 mL)
and the resulting mixture stirred at 100.degree. C. overnight. The
reaction mixture was cooled, filtered and the solid dried in an
oven to afford the desired material as a white solid (3.00 g,
73.8%). NMR Spectrum: .sup.1H NMR (300 MHz, MeOH-d4) .delta. 1.35
(3H, t), 1.96-2.01 (1H, m), 2.33-2.38 (1H, m), 3.73 (2H, m), 3.94
(2H, m), 4.67 (1H, m), 7.77-7.89 (2H, m), 8.50 (1H, s), 8.75 (1H,
d), 8.87 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=365.
[0789] The following compounds were prepared in an analogous
fashion from the appropriate intermediate.
TABLE-US-00017 Intermediate Structure Name Intermediate W4
##STR00163## ethyl 6-bromo-4-[[(3S)-tetra- hydrofuran-3-yl]amino]-
quinoline-3-carboxylate Intermediate X4 * ##STR00164## ethyl
6-bromo-4-(cyclobutyl- amino)quinoline-3-carboxylate *The reaction
was stirred at 60.degree. C. for 16 h.
Intermediate W4
[0790] NMR Spectrum: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.45
(3H, t), 2.12-2.19 (1H, m), 2.48-2.55 (1H, m), 3.87-4.04 (2H, m),
4.12 (2H, td), 4.43 (2H, q), 4.76-4.86 (1H, m), 7.80 (1H, dd), 7.95
(1H, d), 8.34 (1H, d), 9.14 (1H, s), 9.64 (1H, s). Mass Spectrum:
m/z (ES+)[M+H]+=365.
Intermediate X4
[0791] NMR Spectrum: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.45
(3H, t), 1.77-2.01 (2H, m), 2.16-2.31 (2H, m), 2.58-2.71 (2H, m),
4.45 (3H, m), 7.74 (1H, dd), 7.82 (1H, d), 8.23 (1H, d), 9.09 (1H,
s), 9.57 (1H, d) Mass Spectrum: m/z (ES+)[M+H]+=349.
[0792] The preparation of ethyl
6-bromo-4-chloroquinoline-3-carboxylate has been described
earlier.
Example 47
7-Fluoro-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-[(3S)-tetrahy-
dropyran-3-yl]imidazo[4,5-c]quinolin-2-one methanesulfonic acid
salt
##STR00165##
[0794] 3-(Piperidin-1-yl)propan-1-ol (43.4 mg, 0.30 mmol) in THF
(0.5 mL) was added dropwise to a stirred suspension of sodium
hydride (24.22 mg, 0.61 mmol) in THF (0.5 mL) at room temperature.
The resulting suspension was stirred for 10 minutes under nitrogen
then 7-fluoro-8-(6-fluoro-3-pyridyl)-3-methyl-1-[(3
S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one (100 mg, 0.25
mmol) in DMF (1.5 mL) added and the reaction mixture stirred at
room temperature overnight. The reaction mixture was diluted with
EtOAc (40 mL), washed twice with water (20 mL), the organic layer
dried over MgSO.sub.4, filtered and evaporated to afford crude
product. The crude product was purified by FCC, elution gradient 0
to 4% 2N methanolic ammonia in DCM, to afford the desired material
as a white solid (80 mg, 61.0%). The isolated material (79 mg) was
dissolved in DCM (2 mL) and methanesulfonic acid (16.07 mg, 0.17
mmol) in DCM added. The solution was evaporated to dryness to
afford the methanesulfonic acid salt of the desired material as a
pale yellow solid (97 mg). NMR Spectrum (methanesulfonic acid
salt): .sup.1H NMR (500 MHz, DMSO-d6) .delta. 1.40 (1H, dd),
1.55-1.92 (6H, m), 2.06-2.26 (3H, m), 2.31 (3H, s), 2.59-2.77 (1H,
m), 2.82-3.03 (2H, m), 3.19-3.29 (2H, m), 3.38 (2H, td), 3.49 (5H,
s), 3.84-3.95 (1H, m), 4.12 (1H, dd), 4.19 (1H, t), 4.44 (2H, t),
4.76-5.07 (1H, m), 7.04 (1H, dd), 7.96 (1H, d), 8.11 (1H, dt), 8.26
(1H, d), 8.54 (1H, s), 8.95 (1H, s), 9.01 (1H, s). Mass Spectrum:
m/z (ES+)[M+H]+=520.2
[0795]
7-Fluoro-8-(6-fluoro-3-pyridyl)-3-methyl-1-[(3S)-tetrahydropyran-3--
yl]imidazo[4,5-c]quinolin-2-one was prepared as described
below:
Intermediate K4:
7-Fluoro-8-(6-fluoro-3-pyridyl)-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imi-
dazo[4,5-c]quinolin-2-one
##STR00166##
[0797]
8-Bromo-7-fluoro-3-methyl-1-[(35)-oxan-3-yl]imidazo[5,4-c]quinolin--
2-one (250 mg, 0.66 mmol), (6-fluoropyridin-3-yl)boronic acid (120
mg, 0.85 mmol) and 2M K.sub.2CO.sub.3 (1 mL, 2.00 mmol) were
suspended in 1,4-dioxane (3 mL), degassed, then [Pd-118] (22 mg,
0.03 mmol) added. The reaction was heated to 80.degree. C. for 1 h
under nitrogen then allowed to cool. The reaction mixture was
diluted with EtOAc (50 mL) then washed with water (2.times.25 mL),
brine, the organic phase dried over MgSO.sub.4, filtered and
concentrated in vacuo. The crude product was purified by FCC,
elution gradient 0 to 4% 2N methanolic ammonia in DCM, to afford
the desired material as an off-white solid (205 mg, 79%). NMR
Spectrum: .sup.1H NMR (500 MHz, DMSO-d6) .delta. 1.71-1.87 (2H, m),
2.14 (1H, d), 2.57-2.76 (1H, m), 3.32-3.42 (1H, m), 3.49 (3H, s),
3.90 (1H, d), 4.06-4.16 (1H, m), 4.21 (1H, t), 4.79-5.1 (1H, m),
7.36-7.54 (1H, m), 7.97 (1H, d), 8.32 (1H, d), 8.37 (1H, tt), 8.62
(1H, s), 8.95 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=397.
[0798] The preparation of
8-bromo-7-fluoro-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one
has been described earlier.
Example 48
8-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-7-fluoro-3-methyl-1-[(-
3S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinolin-2-one
methanesulfonic acid salt
##STR00167##
[0800]
Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-
[2-(2'-amino-1,1'-biphenyl)]palladium(II) (103 mg, 0.13 mmol) was
added to a
3-[6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl-
]oxy-N,N-dimethylpropan-1-amine (468 mg, 1.44 mmol),
8-bromo-7-fluoro-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one
(500 mg, 1.32 mmol) and cesium carbonate (1285 mg, 3.95 mmol) in
1,4-dioxane (5 mL) and water (2.5 mL). The resulting mixture was
stirred at 80.degree. C. for three h then allowed to cool. The
reaction mixture was diluted with EtOAc (100 mL), washed twice with
water (50 mL), the organic layer dried over MgSO.sub.4, filtered
and evaporated to afford crude product. The crude product was
purified by FCC, elution gradient 0 to 4% 2N methanolic ammonia in
DCM, to afford the desired material as a white solid (130 mg,
19.87%). The material can also be isolated as the methanesulfonic
acid salt by dissolving in DCM and treating with 1-1.1 equivalents
of methanesulfonic acid then concentrating the mixture in vacuo and
triturating the residue with Et.sub.2O. NMR Spectrum (free base):
.sup.1H NMR (500 MHz, DMSO-d6) .delta. 1.77 (2H, t), 1.89 (2H, p),
2.11 (1H, d), 2.16 (6H, s), 2.37 (2H, t), 2.54-2.72 (1H, m),
3.33-3.42 (1H, m), 3.49 (3H, s), 3.89 (1H, d), 4.08 (1H, dd), 4.23
(1H, t), 4.33 (2H, t), 4.85 (1H, s), 6.98 (1H, dd), 7.93 (1H, d),
8.11-8.24 (1H, m), 8.30 (1H, d), 8.93 (1H, s). NMR Spectrum
(methanesulfonic acid salt): .sup.1H NMR (500 MHz, DMSO-d6) .delta.
1.66-1.89 (2H, m), 2.04-2.26 (3H, m), 2.31 (3H, s), 2.59-2.7 (1H,
m), 2.84 (6H, d), 3.22-3.43 (3H, m), 3.50 (3H, s), 3.88 (1H, d),
4.03-4.15 (1H, m), 4.22 (1H, t), 4.39 (2H, t), 4.85 (1H, t), 7.01
(1H, d), 7.96 (1H, d), 8.17-8.26 (1H, m), 8.30 (1H, d), 8.96 (1H,
s), 9.35 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=498.
[0801] The following compounds were prepared in an analogous
fashion from the appropriate intermediates.
TABLE-US-00018 Example Structure Name 49 ##STR00168##
8-[6-[3-(dimethylamino)- propoxy]-2-fluoro-3-
pyridyl]-3-methyl-1-[(3S)- tetrahydrofuran-3-yl]-
imidazo[4,5-c]quinolin- 2-one methanesulfonic acid salt 50
##STR00169## 8-[6-[3-(dimethylamino)- propoxy]-2-fluoro-3-
pyridyl]-3-methyl-1-[(3R)- tetrahydrofuran-3-yl]-
imidazo[4,5-c]quinolin- 2-one methanesulfonic acid salt 51
##STR00170## 1-cyclobutyl-8-[6-[3- (dimethylamino)propoxy]-
2-fluoro-3-pyridyl]-3- methyl-imidazo[4,5-c]- quinolin-2-one
methane- sulfonic acid salt 52 ##STR00171##
8-[6-[3-(dimethylamino)- propoxy]-2-fluoro-3- pyridyl]-3-methyl-1-
(oxetan-3-yl)imidazo- [4,5-c]quinolin-2-one methanesulfonic acid
salt
Example 49
[0802] NMR Spectrum (free base): .sup.1H NMR (500 MHz, DMSO-d6)
.delta. 1.82-1.95 (2H, m), 2.16 (6H, s), 2.36 (3H, t), 2.52-2.59
(1H, m), 3.54 (3H, s), 3.87 (1H, d), 4.11 (2H, dd), 4.21 (1H, d),
4.31 (2H, t), 5.76 (1H, s), 6.94 (1H, dd), 7.81 (1H, dt), 8.13 (1H,
d), 8.20 (1H, dd), 8.57 (1H, d), 8.94 (1H, s). NMR Spectrum
(methanesulfonic acid salt): .sup.1H NMR (500 MHz, DMSO-d6) .delta.
2.08-2.25 (2H, m), 2.31 (3H, s), 2.32-2.42 (1H, m), 2.52-2.59 (1H,
m), 2.84 (6H, s), 3.2-3.28 (2H, m), 3.54 (3H, s), 3.8-3.97 (1H, m),
4.03-4.17 (2H, m), 4.22 (1H, td), 4.38 (2H, t), 5.64-5.97 (1H, m),
6.97 (1H, d), 7.82 (1H, d), 8.15 (1H, d), 8.25 (1H, dd), 8.59 (1H,
s), 8.96 (1H, s), 9.35 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=466.
Example 50
[0803] NMR Spectrum (free base): .sup.1H NMR (500 MHz, DMSO-d6)
.delta. 1.89 (2H, p), 2.16 (6H, s), 2.36 (3H, t), 2.52-2.6 (1H, m),
3.54 (3H, s), 3.79-3.98 (1H, m), 4.04-4.18 (2H, m), 4.21 (1H, td),
4.31 (2H, t), 5.76 (1H, d), 6.94 (1H, dd), 7.81 (1H, dt), 8.13 (1H,
d), 8.20 (1H, dd), 8.57 (1H, d), 8.94 (1H, s). NMR Spectrum
(methanesulfonic acid salt): .sup.1H NMR (500 MHz, DMSO-d6) .delta.
2.1-2.25 (2H, m), 2.33 (3H, s), 2.35-2.44 (1H, m), 2.53-2.61 (1H,
m), 2.85 (6H, d), 3.26 (2H, s), 3.57 (3H, s), 3.81-3.98 (1H, m),
4.07-4.17 (2H, m), 4.19-4.29 (1H, m), 4.39 (2H, t), 5.71-5.9 (1H,
m), 6.99 (1H, d), 7.91 (1H, d), 8.20 (1H, d), 8.27 (1H, dd), 8.65
(1H, s), 9.06 (1H, s), 9.40 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=466.
Example 51
[0804] NMR Spectrum (free base): .sup.1H NMR (500 MHz, DMSO-d6)
.delta. 1.79-1.95 (4H, m), 2.16 (6H, s), 2.37 (2H, t), 2.4-2.49
(2H, m), 3.07 (2H, td), 3.50 (3H, s), 4.32 (2H, t), 5.40 (1H, p),
6.95 (1H, d), 7.80 (1H, d), 8.11 (1H, d), 8.22 (1H, dd), 8.44 (1H,
s), 8.90 (1H, s). NMR Spectrum (methanesulfonic acid salt): .sup.1H
NMR (500 MHz, DMSO-d6) .delta. 1.78-1.99 (2H, m), 2.08-2.23 (2H,
m), 2.31 (3H, s), 2.38-2.48 (2H, m), 2.84 (6H, s), 3.01-3.14 (2H,
m), 3.2-3.29 (2H, m), 3.51 (3H, s), 4.38 (2H, t), 5.28-5.58 (1H,
m), 6.98 (1H, d), 7.83 (1H, d), 8.15 (1H, d), 8.23-8.39 (1H, m),
8.46 (1H, s), 8.94 (1H, s), 9.38 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=450.
Example 52
[0805] NMR Spectrum (free base): .sup.1H NMR (500 MHz, DMSO-d6)
.delta. 1.83-1.96 (2H, m), 2.16 (6H, s), 2.36 (2H, t), 3.53 (3H,
s), 4.32 (2H, t), 5.01 (2H, dd), 5.25 (2H, t), 5.95-6.24 (1H, m),
6.94 (1H, dd), 7.82 (1H, dt), 8.13 (1H, d), 8.19 (1H, dd), 8.39
(1H, s), 8.95 (1H, s). NMR Spectrum (methanesulfonic acid salt):
.sup.1H NMR (500 MHz, DMSO-d6) .delta. 2.09-2.25 (2H, m), 2.32 (3H,
s), 2.85 (6H, s), 3.22-3.29 (2H, m), 3.55 (3H, s), 4.39 (2H, t),
4.95-5.14 (2H, m), 5.26 (2H, t), 6.10 (1H, p), 6.98 (1H, d), 7.85
(1H, d), 8.17 (1H, d), 8.25 (1H, dd), 8.45 (1H, s), 9.01 (1H, s),
9.36 (1H, s) Mass Spectrum: m/z (ES+)[M+H]+=452.
[0806] The
3-[6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyri-
din-2-yl]oxy-N,N-dimethylpropan-1-amine used for these examples was
prepared directly before use by treating
3-(5-bromo-6-fluoropyridin-2-yl)oxy-N,N-dimethylpropan-1-amine (1
equiv) with
4,4,4',4'-5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2
equiv), potassium acetate (3 equiv) and
[1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex
with DCM (1:1) (0.1 equiv) in 1,4-dioxane at 100.degree. C. for 6
h. This mixture was allowed to cool then used directly in the
subsequent reaction.
[0807] The preparation of
3-(5-bromo-6-fluoropyridin-2-yl)oxy-N,N-dimethylpropan-1-amine and
the required bromo intermediates have been described
previously.
Example 53
7-Fluoro-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-tetrahydropyr-
an-4-yl-imidazo[4,5-c]quinolin-2-one
##STR00172##
[0809] 3-(Piperidin-1-yl)propan-1-ol (0.053 mL, 0.35 mmol) was
added slowly to a slurry of sodium hydride (31.5 mg, 0.79 mmol) in
THF (7 mL) and the solution stirred at ambient temperature for 30
minutes.
7-Fluoro-8-(6-fluoro-3-pyridyl)-3-methyl-1-tetrahydropyran-4-yl-imidazo[4-
,5-c]quinolin-2-one (125 mg, 0.32 mmol) in THF (3 mL) was added to
the reaction mixture via syringe over a period of 1 minute and the
reaction stirred for 24 h. The reaction was quenched with water
then extracted into DCM, the organic phase separated and
concentrated in vacuo. The crude product was purified by FCC,
elution gradient 0 to 10% 1M methanolic ammonia in DCM, and the
resultant oil triturated with Et.sub.2O to afford the desired
material as a white solid (92 mg, 56%). NMR Spectrum: .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. 1.38-1.52 (2H, m), 1.61 (4H, p), 1.92
(2H, dd), 2.03 (2H, dt), 2.43 (4H, s), 2.47-2.58 (2H, m), 2.94 (2H,
d), 3.53-3.63 (5H, m), 4.22 (2H, dd), 4.42 (2H, t), 5.01 (1H, s),
6.89 (1H, dd), 7.85-7.96 (2H, m), 8.26 (1H, s), 8.44 (1H, s), 8.71
(1H, s). Mass Spectrum: m/z (ES+)[M+H]+=520.
[0810] The following compounds were prepared in an analogous
fashion from the appropriate intermediates.
TABLE-US-00019 Example Structure Name 54 * ##STR00173##
3-methyl-8-[6-[3-(1-piperidyl)- propoxy]-3-pyridyl]-1-[(3R)-
tetrahydrofuran-3-yl]imidazo- [4,5-c]quinolin-2-one methane
sulfonic acid salt 55 ** ##STR00174##
3-methyl-8-[6-[3-(1-piperidyl)- propoxy]-3-pyridyl]-1-[(3S)-
tetrahydrofuran-3-yl]imidazo- [4,5-c]quinolin-2-one 56 ***
##STR00175## 3-methyl-1-(oxetan-3-yl)-8-[6-
[3-(1-piperidyl)propoxy]-3- pyridyl]imidazo[4,5-c]quinolin- 2-one
trifluoroacetic acid salt 57 *** ##STR00176##
1-cyclobutyl-3-methyl-8-[6-[3- (1-piperidyl)propoxy]-3-
pyridyl]imidazo[4,5-c]quinolin- 2-one trifluoroacetic acid salt 58
**** ##STR00177## 1-cyclobutyl-3-methyl-8-[6-(3-
pyrrolidin-1-ylpropoxy)-3- pyridyl]imidazo[4,5-c]quinolin- 2-one 59
***** ##STR00178## 3-methyl-8-[6-(3-pyrrolidin-1-
ylpropoxy)-3-pyridyl]-1-[(3R)- tetrahydropyran-3-yl]imidazo-
[4,5-c]quinolin-2-one 60 ****** ##STR00179##
8-[6-[3-(azetidin-1-yl)propoxy]- 3-pyridyl]-3-methyl-1-[(3S)-
tetrahydropyran-3-yl]imidazo- [4,5-c]quinolin-2-one *The reaction
was stirred at ambient temperature for 4 h then at 45.degree. C.
for 2 h. The material could also be isolated as a methanesulfonic
acid salt by dissolving in DCM, treating with methanesulfonic acid
(~1 equiv) and concentrating in vacuo then triturating the residue
with Et.sub.2O. **The reaction was stirred at ambient temperature
for 4 h then at 45.degree. C. for 2 h. ***The reaction was stirred
at r.t. for 4 h then at 45.degree. C. for 2 h. The material could
also be isolated as a trifluoroacetic acid salt by dissolving in
DCM, treating with trifluoroacetic acid (~1 equiv) and
concentrating in vacuo then triturating the residue with Et.sub.2O.
****The reaction was stirred at 50.degree. C. for overnight. The
material could also be isolated as a methanesulfonic acid salt by
dissolving in DCM, treating with methanesulfonic acid (~1 equiv)
and concentrating in vacuo. *****The reaction was stirred at r.t.
for 3 days. ******The reaction was stirred at r.t. for 2 h.
Example 54
[0811] NMR Spectrum (methanesulfonic acid salt): .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 1.5-1.63 (2H, m), 1.7-1.98 (7H, m),
2.2-2.3 (2H, m), 2.45 (2H, dtd), 2.59-2.72 (2H, m), 2.82 (3H, s),
3.63 (3H, s), 3.79-3.87 (1H, m), 3.97 (1H, td), 4.19-4.33 (2H, m),
4.37-4.45 (1H, m), 4.46 (2H, t), 5.81-5.93 (1H, m), 6.87 (1H, dd),
7.84 (1H, dd), 8.05 (1H, dd), 8.23 (1H, d), 8.56 (1H, dd), 8.58
(1H, d), 8.74 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=488.
Example 55
[0812] NMR Spectrum: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
1.36-1.51 (2H, m), 1.61 (4H, p), 2.02 (2H, dt), 2.44 (5H, dtd),
2.48-2.55 (2H, m), 2.59-2.71 (1H, m), 3.63 (3H, s), 3.98 (1H, td),
4.21-4.33 (2H, m), 4.41 (3H, t), 5.86 (1H, qd), 6.87 (1H, dd), 7.85
(1H, dd), 8.03 (1H, dd), 8.17-8.25 (1H, m), 8.5-8.59 (2H, m), 8.73
(1H, s). Mass Spectrum: m/z (ES+)[M+H]+=488.
Example 56
[0813] NMR Spectrum (free base): .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 0.07 (1H, s), 1.45 (2H, s), 1.57-1.64 (3H, m), 1.99-2.06
(2H, m), 2.42 (4H, s), 2.47-2.54 (2H, m), 3.62 (3H, s), 4.41 (2H,
t), 5.18-5.25 (2H, m), 5.37 (2H, t), 6.08-6.18 (1H, m), 6.87 (1H,
dd), 7.87 (1H, dd), 7.97 (1H, dd), 8.24 (1H, d), 8.52-8.58 (2H, m),
8.75 (1H, s). NMR Spectrum (trifluoroacetic acid salt): .sup.1H NMR
(500 MHz, DMSO-d6) .delta. 1.6-1.78 (4H, m), 1.85 (2H, d),
2.14-2.23 (2H, m), 2.94 (1H, s), 3.2-3.28 (2H, m), 3.51 (2H, d),
3.58 (3H, s), 4.44 (2H, t), 5.05-5.12 (2H, m), 5.28 (2H, t),
6.23-6.31 (1H, m), 7.02 (1H, d), 8.05-8.37 (4H, m), 8.60 (1H, s),
8.74 (1H, d), 9.17 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=474.
Example 57
[0814] NMR Spectrum (free base): .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 1.45 (2H, d), 1.60 (4H, p), 1.86-2.12 (4H, m), 2.43 (4H,
s), 2.47-2.63 (4H, m), 3.24 (2H, pd), 3.58 (3H, s), 4.42 (2H, t),
5.36 (1H, p), 6.89 (1H, dd), 7.77 (1H, dd), 7.90 (1H, dd), 8.21
(1H, d), 8.32 (1H, d), 8.51 (1H, dd), 8.69 (1H, s). NMR Spectrum
(trifluoroacetic acid salt): .sup.1H NMR (500 MHz, DMSO-d6) .delta.
1.42 (2H, s), 1.58-1.76 (4H, m), 1.82-1.97 (4H, m), 2.14-2.28 (2H,
m), 2.93 (2H, d), 3.06-3.14 (2H, m), 3.21-3.29 (2H, m), 3.53 (3H,
s), 4.44 (2H, t), 5.51-5.58 (1H, m), 6.99-7.05 (1H, m), 8.00 (1H,
d), 8.17 (1H, d), 8.26 (1H, d), 8.27 (1H, d), 8.46 (1H, s), 8.71
(1H, d), 8.97 (2H, s). Mass Spectrum: m/z (ES+)[M+H]+=472.
Example 58
[0815] NMR Spectrum (free base): .sup.1H NMR (500 MHz, DMSO-d6)
.delta. 1.67-1.73 (4H, m), 1.86-1.99 (4H, m), 2.45-2.5 (6H, m),
2.57 (2H, t), 3.09 (2H, pd), 3.51 (3H, s), 4.39 (2H, t), 5.52 (1H,
p), 6.99 (1H, dd), 7.92 (1H, dd), 8.12 (1H, d), 8.20 (1H, dd), 8.41
(1H, d), 8.67 (1H, dd), 8.88 (1H, s). NMR Spectrum (methanesulfonic
acid salt): .sup.1H NMR (500 MHz, DMSO-d6) .delta. 1.84-1.98 (4H,
m), 2.01-2.1 (2H, m), 2.13-2.23 (2H, m), 2.32 (3H, s), 3.03-3.14
(4H, m), 3.28-3.36 (4H, m), 3.54 (3H, s), 3.58-3.67 (2H, m), 4.45
(2H, t), 5.52-5.63 (1H, m), 7.04 (1H, dd), 8.06 (1H, d), 8.19 (1H,
d), 8.27 (1H, dd), 8.49 (1H, s), 8.71-8.74 (1H, m), 9.03 (1H, s),
9.50 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=458.
Example 59
[0816] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
1.68-1.86 (6H, m), 1.95 (2H, m), 2.15 (1H, m), 2.51-2.75 (7H, m),
3.40 (1H, m), 3.49 (3H, s), 3.92 (1H, m), 4.15 (2H, m), 4.38 (2H,
m), 4.97 (1H, m), 6.98 (1H, m), 7.91-8.89 (6.82H, m). Mass
Spectrum: m/z (ES+)[M+H]+=488.3.
Example 60
[0817] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta. 1.80
(4H, m), 2.10 (3H, m), 2.68 (3H, m), 3.35 (5H, m), 3.49 (3H, m),
3.92 (1H, m), 4.15 (2H, m), 4.33 (2H, m), 4.93 (1H, m), 6.98 (1H,
m), 7.91-8.89 (6.92H, m). Mass Spectrum: m/z (ES+)[M+H]+=474.2.
[0818] The required fluoro intermediates for Examples 53-60 have
either been described previously or were prepared from the
appropriate bromo intermediates as described below:
Intermediate F5:
7-Fluoro-8-(6-fluoro-3-pyridyl)-3-methyl-1-tetrahydropyran-4-yl-imidazo[4-
,5-c]quinolin-2-one
##STR00180##
[0820] (6-Fluoropyridin-3-yl)boronic acid (0.445 g, 3.16 mmol),
8-bromo-7-fluoro-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one
(1 g, 2.63 mmol) and 2M K.sub.2CO.sub.3 (3.95 mL, 7.89 mmol) were
suspended in dioxane (3 mL) and water (0.75 mL). The reaction was
degassed with nitrogen and then
dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II)
(0.086 g, 0.13 mmol) was added and the reaction heated to
80.degree. C. for 1 h in the microwave reactor. The mixture was
allowed to cool, diluted with water then extracted with DCM
(2.times.100 mL). The combined organic phases were separated and
concentrated in vacuo. The crude product was purified by FCC,
elution gradient 0 to 10% methanolic ammonia in DCM, to afford the
desired material as a beige solid (0.92 g, 88%). NMR Spectrum:
.sup.1H NMR (500 MHz, DMSO-d6) .delta. 1.90 (2H, dd), 2.69 (2H,
qt), 3.49-3.59 (5H, m), 3.97-4.06 (2H, m), 5.08 (1H, tt), 7.38-7.45
(1H, m), 7.96 (1H, d), 8.34-8.42 (2H, m), 8.61-8.65 (1H, m), 8.95
(1H, s). Mass Spectrum: m/z (ES+)[M+H]+=397
[0821] The following fluoro intermediates were prepared in an
analogous fashion:
TABLE-US-00020 Intermediate Structure Name Intermediate V5
##STR00181## 8-(6-fluoro-3-pyridyl)-3-methyl-
1-[(3R)-tetrahydrofuran-3-yl]- imidazo[4,5-c]quinolin-2-one
Intermediate W5 ##STR00182## 8-(6-fluoro-3-pyridyl)-3-methyl-
1-[(3S)-tetrahydrolfuran-3-yl]- imidazo[4,5-c]quinolin-2-one
Intermediate G5 ##STR00183## 8-(6-fluoro-3-pyridyl)-3-methyl-
1-(oxetan-3-yl)imidazo[4,5-c]- quinolin-2-one Intermediate X5
##STR00184## 1-cyclobutyl-8-(6-fluoro-3- pyridyl)-3-methyl-imidazo-
[4,5-c]quinolin-2-one
Intermediate V5
[0822] NMR Spectrum: .sup.1H NMR (500 MHz, DMSO-d6) .delta.
2.34-2.45 (1H, m), 2.52-2.67 (1H, m), 3.55 (3H, s), 3.91 (1H, td),
4.13-4.23 (2H, m), 4.27 (1H, td), 5.76-5.92 (1H, m), 7.38 (1H, dd),
8.02 (1H, dd), 8.18 (1H, d), 8.49 (1H, ddd), 8.68 (1H, d), 8.77
(1H, d), 8.96 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=365.
Intermediate W5
[0823] NMR Spectrum: .sup.1H NMR (500 MHz, DMSO-d6) .delta.
2.33-2.44 (1H, m), 2.53-2.67 (1H, m), 3.55 (3H, s), 3.91 (1H, td),
4.13-4.22 (2H, m), 4.27 (1H, td), 5.79-5.9 (1H, m), 7.3-7.41 (1H,
m), 8.02 (1H, dd), 8.18 (1H, d), 8.49 (1H, ddd), 8.68 (1H, d), 8.77
(1H, d), 8.96 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=365.
Intermediate G5
[0824] NMR Spectrum: .sup.1H NMR (500 MHz, DMSO-d6) .delta. 3.55
(3H, s), 5.07 (2H, dd), 5.28 (2H, t), 6.09-6.31 (1H, m), 7.29-7.43
(1H, m), 8.02 (1H, dd), 8.18 (1H, d), 8.49 (1H, ddd), 8.56 (1H, d),
8.77 (1H, d), 8.97 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=351
Intermediate X5
[0825] NMR Spectrum: .sup.1H NMR (300 MHz, DMSO-d6) .delta.
1.77-2.01 (2H, m), 2.46 (2H, ddt), 3.09 (2H, pd), 3.51 (3H, s),
5.53 (1H, p), 7.32-7.44 (1H, m), 7.96 (1H, dd), 8.15 (1H, d),
8.43-8.54 (2H, m), 8.75 (1H, d), 8.91 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=349.
[0826] The preparation of the bromo intermediates required for the
above reactions have been described previously.
Example 61
8-[2-Fluoro-6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-3-methyl-1-[(3S)-tetra-
hydropyran-3-yl]imidazo[4,5-c]quinolin-2-one
##STR00185##
[0828] A solution of 3-(pyrrolidin-1-yl)propan-1-ol (0.047 g, 0.36
mmol) in THF (2 mL) was added slowly to a stirred suspension of
sodium hydride (0.038 g, 0.96 mmol) in THF (2.0 mL) and the
resulting suspension stirred at r.t. for 30 minutes. A solution of
8-(2,6-difluoro-3-pyridyl)-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo[-
4,5-c]quinolin-2-one (0.12 g, 0.34 mmol) in DMF (2 mL) was added
slowly and the reaction stirred overnight. Water was added and the
mixture stirred for 30 minutes before being extracted with EtOAc
(50 mL). The organics were washed with sat. brine (25 mL), dried
and evaporated to give crude product. The crude product was
purified by FCC, elution gradient 0 to 10% (1% NH.sub.3 in MeOH) in
DCM, to afford the desired material as a white solid (0.005 g, 4%).
NMR Spectrum: .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 0.8-0.92
(1H, m), 1.21-1.29 (1H, m), 1.88-1.97 (2H, m), 1.99-2.1 (4H, m),
2.23 (1H, d), 2.26-2.36 (2H, m), 2.77 (1H, qd), 2.9-3.16 (4H, m),
3.53-3.56 (1H, m), 3.57 (3H, s), 3.98-4.09 (1H, m), 4.12-4.21 (1H,
m), 4.45 (2H, t), 4.53 (1H, t), 4.9-5.01 (1H, m), 6.80 (1H, dd),
7.75 (1H, d), 7.93 (1H, dd), 8.22 (1H, d), 8.42 (1H, s), 8.71 (1H,
s). Mass Spectrum: m/z (ES+)[M+H]+=506.
[0829] The preparation of
8-(2,6-difluoro-3-pyridyl)-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo[-
4,5-c]quinolin-2-one is described below:
Intermediate D5:
8-(2,6-difluoro-3-pyridyl)-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo[-
4,5-c]quinolin-2-one
##STR00186##
[0831] (2,6-Difluoropyridin-3-yl)boronic acid (158 mg, 0.99 mmol)
and 8-bromo-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one
(300 mg, 0.83 mmol) were suspended in dioxane (8 mL) and 2M
K.sub.2CO.sub.3 (2.071 mL, 4.14 mmol). The mixture was degassed
with nitrogen and
dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II)
(27.0 mg, 0.04 mmol) added. The resulting suspension was heated at
80.degree. C. for 1 h in a microwave reactor. The reaction mixture
was diluted with EtOAc then washed with water (20 mL), brine and
the organic phase dried over MgSO.sub.4, filtered and concentrated
in vacuo. The crude product was purified by FCC, elution gradient 0
to 10% MeOH in DCM, to afford the desired material as a brown solid
(196 mg, 60%). NMR Spectrum: .sup.1H NMR (500 MHz, DMSO-d6) .delta.
1.82 (2H, hept), 2.15 (1H, d), 2.55-2.67 (1H, m), 3.36-3.44 (1H,
m), 3.51 (3H, s), 3.92 (1H, d), 4.06-4.14 (1H, m), 4.29 (1H, t),
4.91 (1H, ddd), 7.42 (1H, dd), 7.85-7.91 (1H, m), 8.19 (1H, d),
8.47 (1H, s), 8.56 (1H, dt), 8.95 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=397.
[0832] The preparation of
8-bromo-3-methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinolin-2-one has
been described previously.
Examples 62 & 63
8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1R,3R)-3-methoxycy-
clopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one and
8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1S,3S)-3-methoxyc-
yclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one
##STR00187##
[0834]
8-bromo-7-fluoro-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[-
4,5-c]quinolin-2-one:
8-bromo-7-fluoro-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]-
quinolin-2-one (1:1 mixture) (400 mg, 1.01 mmol),
N,N-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2--
yl]oxypropan-1-amine (227 mg, 1.01 mmol) and
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (160 mg, 0.20 mmol) were
suspended in a mixture of dioxane (5 mL) and water (0.5 mL) and
Cs.sub.2CO.sub.3 (661 mg, 2.03 mmol) added. The reaction was heated
to 120.degree. C. for 1 h in the microwave reactor then allowed to
cool. The reaction mixture was evaporated to dryness and
redissolved in EtOAc (100 mL), washed sequentially with water
(2.times.20 mL), the organic layer dried over Na.sub.2SO.sub.4,
filtered and evaporated to afford crude product. The crude product
was purified by preparative HPLC, using decreasingly polar mixtures
of water (containing 0.03% NH.sub.3) and MeCN as eluents, to afford
the desired material as a racemic mixture. The mixture was purified
by preparative chiral-HPLC on a Chiralpak IA column, eluting
isocratically with 10% isopropyl alcohol in heptane (modified with
0.2% diethylamine) as eluent to deliver the two separated
isomers.
Example 62
[0835] Isomer 1 (12 mg) NMR Spectrum: .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 1.73-1.85 (1H, m), 1.84-1.96 (2H, m), 2.09-2.26
(9H, s), 2.35-2.50 (4H, m), 3.21-3.26 (3H, s), 3.45-3.58 (3H, s),
4.05-4.14 (1H, m), 4.33-4.42 (2H, m), 5.45-5.56 (1H, m), 6.97-7.04
(1H, m), 7.90-7.98 (1H, m), 8.01-8.09 (1H, m), 8.26-8.33 (1H, m),
8.48-8.54 (1H, m), 8.91-8.96 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=494.
Example 63
[0836] Isomer 2 (12 mg) NMR Spectrum: .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 1.75-1.82 (1H, m), 1.85-1.97 (2H, m), 2.11-2.26
(9H, s), 2.37-2.50 (4H, m), 3.21-3.26 (3H, s), 3.46-3.56 (3H, s),
4.07-4.13 (1H, m), 4.33-4.42 (2H, m), 5.47-5.58 (1H, m), 6.97-7.04
(1H, m), 7.90-7.98 (1H, m), 8.01-8.09 (1H, m), 8.27-8.34 (1H, m),
8.49-8.54 (1H, s), 8.91-8.96 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=494.
[0837] The preparation of
8-bromo-7-fluoro-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]-
quinolin-2-one:
8-bromo-7-fluoro-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]-
quinolin-2-one (1:1 mixture) is described below:
Intermediate Y1:
8-bromo-7-fluoro-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]-
quinolin-2-one and
8-bromo-7-fluoro-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]-
quinolin-2-one (1:1 Mixture)
##STR00188##
[0839] A mixture of
8-bromo-7-fluoro-1-[(1R,3R)-3-methoxycyclopentyl]-3H-imidazo[4,5-c]quinol-
in-2-one:
8-bromo-7-fluoro-1-[(1S,3S)-3-methoxycyclopentyl]-3H-imidazo[4,5-
-c]quinolin-2-one (1:1 mixture) (2.8 g, 7.33 mmol), sodium
hydroxide (440 mg, 11.00 mmol,), tetrabutylammonium bromide (240
mg, 0.75 mmol) and methyl iodide (1.6 g, 11.27 mmol) in DCM (150
mL) and water (100 mL) was stirred for 12 h at r.t. The resulting
mixture was concentrated in vacuo and the residue triturated with
water. The solids were collected by filtration and dried to afford
the desired material as a white solid (2.5 g, 86%). NMR Spectrum:
.sup.1H NMR (300 MHz, DMSO-d6) .delta. 1.76-1.86 (1H, m), 2.11-2.32
(4H, m), 2.41-2.44 (1H, m), 3.27 (3H, s), 3.30 (3H, s), 4.12-4.15
(1H, m), 5.38-5.45 (1H, m), 7.96 (1H, d), 8.53 (1H, d), 8.94 (1H,
s). Mass Spectrum: m/z (ES+)[M+H]+=394.
Intermediate Y2:
8-bromo-7-fluoro-1-[(1R,3R)-3-methoxycyclopentyl]-3H-imidazo[4,5-c]quinol-
in-2-one and
8-bromo-7-fluoro-1-[(1S,3S)-3-methoxycyclopentyl]-3H-imidazo[4,5-c]quinol-
in-2-one (1:1 Mixture)
##STR00189##
[0841] A mixture of
6-bromo-7-fluoro-4-[[(1R,3R)-3-methoxycyclopentyl]amino]quinoline-3-carbo-
xylic acid:
6-bromo-7-fluoro-4-[[(1S,3S)-3-methoxycyclopentyl]amino]quinoline-3-carbo-
xylic acid (1:1 mixture) (2.9 g, 7.53 mmol) and triethylamine (2.3
g, 22.73 mmol) in DMA (20 mL) was stirred at r.t. for 30 mins.
Diphenyl phosphorazidate (2.5 g, 9.09 mmol) was added and the
resulting solution stirred for 2 h at 60.degree. C. The reaction
mixture was allowed to cool and the solids collected by filtration.
The solid was dried in an oven under reduced pressure to afford the
desired material as a white solid (2.8 g, 97%). NMR Spectrum:
.sup.1H NMR (300 MHz, DMSO-d6) .delta. 1.78-1.88 (1H, m), 2.11-2.31
(4H, m), 2.41-2.45 (1H, m), 3.27 (3H, s), 4.08-4.15 (1H, m),
5.34-5.39 (1H, m), 7.92 (1H, d), 8.51 (1H, d), 8.68 (1H, s).
[0842] Mass Spectrum: m/z (ES+)[M+H]+=380.
Intermediate Y3:
6-bromo-7-fluoro-4-[[(1R,3R)-3-methoxycyclopentyl]amino]quinoline-3-carbo-
xylic acid and
6-bromo-7-fluoro-4-[[(1S,3S)-3-methoxycyclopentyl]amino]quinoline-3-carbo-
xylic acid (1:1 Mixture)
##STR00190##
[0844] A mixture of ethyl
6-bromo-7-fluoro-4-[[(1R,3R)-3-methoxycyclopentyl]amino]quinoline-3-carbo-
xylate: ethyl
6-bromo-7-fluoro-4-[[(1S,3S)-3-methoxycyclopentyl]amino]quinoline-3-carbo-
xylate (1:1 mixture) (3.4 g, 8.23 mmol) and 2N sodium hydroxide (12
mL) in MeOH (15 mL) and THF (15 mL) was stirred for 12 h at r.t.
The pH of the solution was adjusted to 3 with 1M HCl and the
resultant solid collected by filtration and dried to afford the
desired material as a white solid (2.9 g, 91%). NMR Spectrum:
.sup.1H NMR (300 MHz, DMSO-d6) .delta. 1.61-1.71 (2H, m), 1.76-1.86
(1H, m), 1.92-2.03 (1H, m), 2.11-2.26 (2H, m), 3.21 (3H, s),
3.86-3.96 (1H, m), 4.56-4.64 (1H, m), 7.70 (1H, d), 8.56 (1H, d),
8.88 (1H, s), 13.31 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=383.
Intermediate Y4: Ethyl
6-bromo-7-fluoro-4-[[(1R,3R)-3-methoxycyclopentyl]amino]quinoline-3-carbo-
xylate and Ethyl
6-bromo-7-fluoro-4-[[(1S,3S)-3-methoxycyclopentyl]amino]quinoline-3-carbo-
xylate (1:1 Mixture)
##STR00191##
[0846] A mixture of ethyl
6-bromo-4-chloro-7-fluoroquinoline-3-carboxylate (2 g, 6.01 mmol),
(1R,3R)-3-methoxycyclopentanamine hydrochloride and
(1S,3S)-3-methoxycyclopentanamine hydrochloride (1:1 mixture) (1.4
g, 9.21 mmol) and DIPEA (1.6 g, 12.38 mmol) in DMA (10 mL) was
stirred for 2 h at 80.degree. C. The reaction mixture was allowed
to cool and the residue triturated with water. The solids were
collected by filtration and dried to afford the desired material as
a white solid (2.4 g, 97%). Mass Spectrum: m/z (ES+)[M+H]+=411.
[0847] The preparation of ethyl
6-bromo-4-chloro-7-fluoroquinoline-3-carboxylate has been described
previously.
Examples 64 & 65
1-[(1R,3R)-3-Methoxycyclopentyl]-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3--
pyridyl]imidazo[4,5-c]quinolin-2-one and
1-[(1S,3S)-3-Methoxycyclopentyl]-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-
-pyridyl]imidazo[4,5-c]quinolin-2-one
##STR00192##
[0849] A mixture of 3-(piperidin-1-yl)propan-1-ol (175 mg, 1.22
mmol) and NaH (122 mg, 3.06 mmol) in THF (10 mL) was stirred under
nitrogen at 0.degree. C. for 30 min then
8-(6-fluoro-3-pyridyl)-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[-
4,5-c]quinolin-2-one:
8-(6-fluoro-3-pyridyl)-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[-
4,5-c]quinolin-2-one (1:1 mixture) (400 mg, 1.02 mmol) added. The
resulting mixture was stirred at r.t. for 1 h then was quenched
with water (50 mL), extracted with EtOAc (3.times.50 mL), the
organic layer was dried over Na.sub.2SO.sub.4, filtered and
evaporated to afford yellow oil. The crude liquid was triturated
with heptane to give the desired material as a mixture of isomers
(350 mg, 66.6%) as a yellow solid. The racemic mixture was purified
by preparative chiral-HPLC on an AD column, eluting with 10%
isopropyl alcohol in hexane (modified with 0.1% diethylamine) as
eluent, and fractions containing the separated isomers evaporated
to dryness.
Example 64
[0850] Isomer 1 (120 mg) NMR Spectrum: .sup.1H NMR (300 MHz,
MeOH-d4) .delta. 1.61-1.71 (2H, m), 1.76-1.86 (1H, m), 1.92-2.03
(1H, m), 2.11-2.26 (2H, m), 3.21 (3H, s), 3.86-3.96 (1H, m),
4.56-4.64 (1H, m), 7.70 (1H, d), 8.56 (1H, d), 8.88 (1H, s), 13.31
(1H, s). Mass Spectrum: m/z (ES+)[M+H]+=516.
Example 65
[0851] Isomer 2 (120 mg) NMR Spectrum: .sup.1H NMR (300 MHz,
MeOH-d4) .delta. 1.53 (2H, q), 1.67 (4H, p), 1.89-2.14 (3H, m),
2.23-2.41 (3H, m), 2.47-2.71 (8H, m), 3.40 (3H, s), 3.58 (3H, s),
4.17-4.18 (1H, m), 4.41 (2H, t), 5.62 (1H, p), 6.94 (1H, d), 7.88
(1H, d), 8.02-8.17 (2H, m), 8.38 (1H, d), 8.51 (1H, d), 8.76 (1H,
s). Mass Spectrum: m/z (ES+)[M+H]+=516.
[0852] The following compounds were prepared in an analogous
fashion from
8-(6-fluoro-3-pyridyl)-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[-
4,5-c]quinolin-2-one:
8-(6-fluoro-3-pyridyl)-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[-
4,5-c]quinolin-2-one (1:1 mixture) and the appropriate alcohol.
TABLE-US-00021 Example Structure Name 66 & 67 * ##STR00193##
1-[(1S,3S)-3-methoxycyclo- pentyl]-3-methyl-8-[6-(3-
pyrrolidin-1-ylpropoxy)-3- pyridyl]imidazo[4,5-c]- quinolin-2-one
and ##STR00194## 1-[(1R,3R)-3-methoxycyclo-
pentyl]-3-methyl-8-[6-(3- pyrrolidin-1-ylpropoxy)-3-
pyridyl]imidazo[4,5-c]- quinolin-2-one *The reaction was stirred at
r.t. for 5 h. The isomers were separated by preparative chiral-HPLC
on an AD column, eluting with 10% isopropyl alcohol in hexane
(modified with 0.1% diethylamine) as eluent.
Example 66
[0853] Isomer 1 (105 mg) NMR Spectrum: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 1.91-2.05 (5H, m), 2.14-2.18 (2H, m), 2.22-2.46
(3H, m), 2.52-2.83 (8H, m), 3.39 (3H, s), 3.62 (3H, s), 4.20 (1H,
p), 4.47 (2H, t), 5.62 (1H, q), 6.91 (1H, d), 7.83 (1H, d), 7.94
(1H, d), 8.24 (1H, d), 8.36 (1H, d), 8.53 (1H, d), 8.73 (1H, s).
Mass Spectrum: m/z (ES+)[M+H]+=502.
Example 67
[0854] Isomer 2 (105 mg) NMR Spectrum: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 1.80-2.00 (5H, m), 2.12-2.18 (2H, m), 2.35-2.55
(3H, m), 2.63-2.83 (8H, m), 3.40 (3H, s), 3.62 (3H, s), 4.20 (1H,
t), 4.47 (2H, t), 5.61 (1H, p), 6.91 (1H, d), 7.83 (1H, d), 7.94
(1H, d), 8.25 (1H, d), 8.36 (1H, d), 8.53 (1H, d), 8.73 (1H, s).
Mass Spectrum: m/z (ES+)[M+H]+=502
[0855] The preparation of
8-(6-fluoro-3-pyridyl)-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[-
4,5-c]quinolin-2-one:
8-(6-fluoro-3-pyridyl)-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[-
4,5-c]quinolin-2-one (1:1 mixture) is described below.
Intermediate O5:
8-(6-Fluoro-3-pyridyl)-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[-
4,5-c]quinolin-2-one and
8-(6-fluoro-3-pyridyl)-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[-
4,5-c]quinolin-2-one (1:1 Mixture)
##STR00195##
[0857] A mixture of
8-bromo-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-
-one:
8-bromo-1-[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quino-
lin-2-one (1:1 mixture) (1.5 g, 3.99 mmol),
(6-fluoropyridin-3-yl)boronic acid (0.674 g, 4.78 mmol) and
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (0.314 g, 0.40 mmol) in
dioxane:water (10:1 mixture) (16.5 mL) was heated to 120.degree. C.
for 45 mins in the microwave reactor then allowed to cool and
concentrated in vacuo. The crude product was purified by FCC,
elution gradient 0 to 10% MeOH in DCM, to afford the desired
material as a yellow solid (1.20 g, 77%). NMR Spectrum: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 1.91-1.99 (1H, m), 2.21-2.36 (3H, m),
2.58-2.78 (2H, m), 3.38 (3H, s), 3.62 (3H, s), 4.15-4.17 (1H, m),
5.52-5.65 (1H, m), 7.12 (1H, dd), 7.83 (1H, dd), 8.13 (1H, td),
8.31 (1H, d), 8.40 (1H, d), 8.59 (1H, d), 8.76 (1H, s). Mass
Spectrum: m/z (ES+)[M+H]+=393.
[0858] The preparation of
8-bromo-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-
-one:
8-bromo-1-[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quino-
lin-2-one (1:1 mixture) has been described previously.
Examples 68 & 69
8-[6-[3-(Dimethylamino)propoxy]-2-fluoro-3-pyridyl]-1-[(1R,3R)-3-methoxycy-
clopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one and
8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-1-[(1S,3S)-3-methoxyc-
yclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one
##STR00196##
[0860]
Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)
[2-(2'-amino-1,1'-biphenyl)]palladium(II) (107 mg, 0.13 mmol) was
added to a
3-[6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-
-yl]oxy-N,N-dimethylpropan-1-amine (474 mg, 1.46 mmol),
8-bromo-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-
-one:
8-bromo-1-[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quino-
lin-2-one (1:1 mixture) (500 mg, 1.33 mmol) and cesium carbonate
(1299 mg, 3.99 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL). The
resulting mixture was stirred at 80.degree. C. for 5 h then allowed
to cool. The crude product was purified by C18-FCC, elution
gradient 5 to 50% MeOH in water, to afford the desired material as
a mixture of isomers (350 mg, 53.4%). The racemic mixture was
purified by preparative chiral HPLC on a Chiralcel IC column,
eluting with isopropyl alcohol, and fractions containing the
separated isomers evaporated to dryness.
Example 68
[0861] Isomer 1 (50 mg) NMR Spectrum: .sup.1H NMR (300 MHz,
MeOH-d4) .delta. 1.90-1.96 (1H, m), 2.12-2.13 (2H, m), 2.20-2.31
(3H, m), 2.47-2.50 (1H, m), 2.54 (6H, s), 2.68-2.70 (1H, m),
2.78-2.90 (2H, m), 3.36 (3H, s), 3.60 (3H, s), 4.17-4.18 (1H, m),
4.43 (2H, t), 5.55-5.67 (1H, m), 6.89 (1H, d), 7.80-7.91 (1H, m),
8.07-8.20 (2H, m), 8.48 (1H, s), 8.82 (1H, s).
[0862] Mass Spectrum: m/z (ES+)[M+H]+=494.
Example 69
[0863] Isomer 2 (45 mg) (containinated with 0.38 equivalents of
diethylamine) NMR Spectrum: .sup.1H NMR (300 MHz, MeOH-d4) .delta.
1.93-1.95 (1H, m), 2.29-2.51 (6H, m), 2.60-2.77 (2H, m), 2.95 (6H,
s), 3.36-3.38 (4H, s), 3.60 (3H, s), 4.17-4.18 (1H, m), 4.48 (2H,
t), 5.62-5.63 (1H, m), 6.92 (1H, d), 7.85 (1H, d), 8.15-8.20 (2H,
m), 8.48 (1H, s), 8.82 (1H, s).
[0864] Mass Spectrum: m/z (ES+)[M+H]+=494.
[0865] The preparation of
8-bromo-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinolin-2-
-one:
8-bromo-1-[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quino-
lin-2-one (1:1 mixture) has been described previously.
Examples 70 & 71
8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1R,3S)-3-methoxycy-
clopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one and
8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-[(1S,3R)-3-methoxyc-
yclopentyl]-3-methyl-imidazo[4,5-c]quinolin-2-one
##STR00197##
[0867]
8-Bromo-7-fluoro-1-[(1R,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[-
4,5-c]quinolin-2-one:
8-bromo-7-fluoro-1-[(1S,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]-
quinolin-2-one (1:1 mixture) (500 mg, 1.27 mmol),
N,N-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2--
yl]oxypropan-1-amine (284 mg, 1.27 mmol) and
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) (200 mg, 0.25 mmol) were
suspended in a mixture of dioxane: water (10:1 mixture, 20 mL) and
Cs.sub.2CO.sub.3 (826 mg, 2.54 mmol) added. The reaction was heated
to 120.degree. C. for 1 h in the microwave reactor then allowed to
cool. The reaction mixture was evaporated to dryness and
redissolved in EtOAc (100 mL), washed sequentially with water
(2.times.20 mL), the organic layer dried over Na.sub.2SO.sub.4,
filtered and evaporated to afford crude product. The crude product
was purified by preparative HPLC, using decreasingly polar mixtures
of water (containing 0.03% NH.sub.3) and MeCN as eluents, to afford
the desired material as a racemic mixture. The mixture was purified
by preparative chiral-HPLC on a Chiralpak IA column, eluting
isocratically with 10% IPA in heptane (modified with 0.2%
diethylamine) as eluent to deliver the two separated isomers.
Example 70
[0868] Isomer 1 (250 mg) NMR Spectrum: .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 1.83-2.06 (5H, m), 2.14-2.19 (6H, s), 2.26-2.51
(5H, m), 3.02-3.07 (3H, s), 3.47-3.64 (3H, s), 3.86-3.96 (1H, m),
4.33-4.41 (2H, m), 5.26-5.40 (1H, m), 6.94-7.01 (1H, d), 7.89-7.97
(1H, d), 7.98-8.06 (1H, m), 8.39-8.49 (2H, m), 8.92-8.97 (1H, s).
Mass Spectrum: m/z (ES+)[M+H]+=494.
Example 71
[0869] Isomer 2 (250 mg) NMR Spectrum: .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 1.83-2.08 (5H, m), 2.13-2.18 (5H, s), 2.24-2.56
(4H, m), 3.02-3.07 (3H, s), 3.50-3.55 (3H, s), 3.85-3.96 (1H, m),
4.33-4.41 (2H, m), 5.25-5.39 (1H, m), 6.94-7.01 (1H, m), 7.87-7.95
(1H, m), 7.97-8.05 (1H, m), 8.35-8.50 (2H, m), 8.91-8.96 (1H, s).
Mass Spectrum: m/z (ES+)[M+H]+=494.
[0870] The preparation of
8-bromo-7-fluoro-1-[(1R,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]-
quinolin-2-one and
8-bromo-7-fluoro-1-[(1S,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]-
quinolin-2-one (1:1 mixture) is described below:
Intermediate Z1:
8-Bromo-7-fluoro-1-[(1R,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]-
quinolin-2-one and
8-bromo-7-fluoro-1-[(1S,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]-
quinolin-2-one (1:1 Mixture)
##STR00198##
[0872] NaH (0.213 g, 8.88 mmol) was added portionwise to
8-bromo-7-fluoro-1-[(1R,3S)-3-hydroxycyclopentyl]-3H-imidazo[4,5-c]quinol-
in-2-one:
8-bromo-7-fluoro-1-[(1S,3R)-3-hydroxycyclopentyl]-3H-imidazo[4,5-
-c]quinolin-2-one (1:1 mixture) (1.3 g, 3.55 mmol) in DMF (10 mL)
at -20.degree. C. under nitrogen and the resulting mixture stirred
at 0.degree. C. for 30 minutes. Methyl iodide (0.444 mL, 7.10 mmol)
was added dropwise to the mixture at -20.degree. C. under nitrogen
and the resulting mixture was stirred at r.t. for 16 h. The
reaction mixture was poured into water (20 mL), the solid filtered
and dried to afford the desired material as a brown solid (1.30 g,
93%). NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6) .delta.
1.96-2.02 (3H, t), 2.22-2.51 (3H, m), 3.30-3.32 (3H, s), 3.97 (1H,
m), 5.26-5.31 (1H, m), 7.89-7.52 (1H, d), 8.74 (1H, d), 8.93 (1H,
s). Mass Spectrum: m/z (ES+)[M+H]+=396.
Intermediate Z2:
8-Bromo-7-fluoro-1-[(1R,3S)-3-hydroxycyclopentyl]-3H-imidazo[4,5-c]quinol-
in-2-one and
8-bromo-7-fluoro-1-[(1S,3R)-3-hydroxycyclopentyl]-3H-imidazo[4,5-c]quinol-
in-2-one (1:1 Mixture)
##STR00199##
[0874] A mixture of triethylamine (2.105 mL, 15.10 mmol) and
6-bromo-7-fluoro-4-[[(1R,3S)-3-hydroxycyclopentyl]amino]quinoline-3-carbo-
xylic acid:
6-bromo-7-fluoro-4-[[(1S,3R)-3-hydroxycyclopentyl]amino]quinoline-3-carbo-
xylic acid (1:1 mixture) (2 g, 5.03 mmol) in DMF (10 mL) was
stirred for 1 h. Diphenyl phosphorazidate (1.663 g, 6.04 mmol) was
added and the resulting solution stirred overnight at 60.degree. C.
The reaction mixture was poured into water, the solids collected by
filtration and dried to afford the desired material as a yellow
solid (1.3 g, 71%). NMR Spectrum: .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 1.88 (2H, dt), 1.97-2.10 (1H, m), 2.17 (1H, m), 2.38 (2H,
m), 4.23-4.30 (1H, m), 5.27 (1H, m), 7.88 (1H, m), 8.69 (1H, s),
8.80 (1H, d), 11.77 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=366.
Intermediate Z3:
6-bromo-7-fluoro-4-[[(1R,3S)-3-hydroxycyclopentyl]amino]quinoline-3-carbo-
xylic acid and
6-bromo-7-fluoro-4-[[(1S,3R)-3-hydroxycyclopentyl]amino]quinoline-3-carbo-
xylic acid (1:1 Mixture)
##STR00200##
[0876] A mixture of ethyl
6-bromo-7-fluoro-4-[[(1R,3S)-3-hydroxycyclopentyl]amino]quinoline-3-carbo-
xylate: ethyl
6-bromo-7-fluoro-4-[[(1S,3R)-3-hydroxycyclopentyl]amino]quinoline-3-carbo-
xylate (1:1 mixture) (3 g, 7.55 mmol) and sodium hydroxide (0.604
g, 15.10 mmol) in THF (10 mL) and water (5 mL) was stirred for 16 h
at 60.degree. C. The organics were removed in vacuo and the pH of
the resultant mixture adjusted to 6-7 with 2M HCl. The resultant
solid collected by filtration and dried to afford the desired
material as a grey solid (2.0 g, 72%). NMR Spectrum: .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 1.68-1.82 (3H, m), 1.90-1.98 (1H, m),
2.26 (2H, m), 2.51 (4H, s), 4.26 (1H, s), 4.68 (1H, s), 7.86 (1H,
d), 8.62 (1H, d), 8.93 (1H, s), 10.95 (1H, s). Mass Spectrum: m/z
(ES+)[M+H]+=369.
Intermediate Z4: Ethyl
6-bromo-7-fluoro-4-[[(1R,3S)-3-hydroxycyclopentyl]amino]quinoline-3-carbo-
xylate and ethyl
6-bromo-7-fluoro-4-[[(1S,3R)-3-hydroxycyclopentyl]amino]quinoline-3-carbo-
xylate (1:1 Mixture)
##STR00201##
[0878] DIPEA (3.94 mL, 22.55 mmol) was added to a mixture of
cis-3-aminocyclopentanol hydrochloride (1.49 g, 10.83 mmol) and
ethyl 6-bromo-4-chloro-7-fluoroquinoline-3-carboxylate (3 g, 9.02
mmol) in DMA (20 mL) under nitrogen and the resulting mixture
stirred at 100.degree. C. for 6 h. The reaction mixture was poured
into water (50 mL) and the solid filtered and dried to afford the
desired material as brown oil (3.0 g, 84%). NMR Spectrum: .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 1.35 (3H, t), 1.67 (1H, d),
1.72-1.79 (2H, m), 1.81-1.92 (1H, m), 1.96 (3H, s), 2.19 (2H, ddt),
2.79 (3H, s), 2.95 (3H, s), 3.08 (1H, d), 4.23 (1H, s), 4.33 (2H,
q), 4.45 (1H, s), 4.83 (1H, s), 7.69 (1H, dd), 8.52 (1H, d), 8.85
(1H, s), 9.25 (1H, d). Mass Spectrum: m/z (ES+)[M+H]+=397.
[0879] The preparation of ethyl
6-bromo-4-chloro-7-fluoroquinoline-3-carboxylate has been described
previously.
Biological Assays
[0880] The following assays were used to measure the effects of the
compounds of the present invention: a) ATM cellular potency assay;
b) PI3K cellular potency assay; c) mTOR cellular potency assay; d)
ATR cellular potency assay; e) mouse xenograft model. During the
description of the assays, generally: [0881] i. The following
abbreviations have been used: 4NQO=4-Nitroquinoline N-oxide;
Ab=Antibody; BSA=Bovine Serum Albumin; CO.sub.2=Carbon Dioxide;
DMEM=Dulbecco's Modified Eagle Medium; DMSO=Dimethyl Sulphoxide;
EDTA=Ethylenediaminetetraacetic Acid; EGTA=Ethylene Glycol
Tetraacetic Acid; ELISA=Enzyme-linked Immunosorbent Assay;
EMEM=Eagle's Minimal Essential Medium; FBS=Foetal Bovine Serum;
h=Hour(s); HRP=Horseradish Peroxidase; i.p.=intraperitoneal;
PBS=Phosphate buffered saline; PBST=Phosphate buffered
saline/Tween; TRIS=Tris(Hydroxymethyl)aminomethane; MTS reagent:
[3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl-
)-2H-tetrazolium, inner salt, and an electron coupling reagent
(phenazine methosulfate) PMS; s.c. sub-cutaneously. [0882] ii.
IC.sub.50 values were calculated using a smart fitting model in
Genedata. The IC.sub.50 value was the concentration of test
compound that inhibited 50% of biological activity.
Assay a): ATM Cellular Potency
Rationale:
[0883] Cellular irradiation induces DNA double strand breaks and
rapid intermolecular autophosphorylation of serine 1981 that causes
dimer dissociation and initiates cellular ATM kinase activity. Most
ATM molecules in the cell are rapidly phosphorylated on this site
after doses of radiation as low as 0.5 Gy, and binding of a
phosphospecific antibody is detectable after the introduction of
only a few DNA double-strand breaks in the cell.
[0884] The rationale of the pATM assay is to identify inhibitors of
ATM in cells. HT29 cells are incubated with test compounds for lhr
prior to X-ray-irradiation. 1 h later the cells are fixed and
stained for pATM (Ser1981). The fluorescence is read on the
arrayscan imaging platform.
Method Details:
[0885] HT29 cells (ECACC #85061109) were seeded into 384 well assay
plates (Costar #3712) at a density of 3500 cells/well in 40 .mu.l
EMEM medium containing 1% L glutamine and 10% FBS and allowed to
adhere overnight. The following morning compounds of Formula (I) in
100% DMSO were added to assay plates by acoustic dispensing. After
1 h incubation at 37.degree. C. and 5% CO.sub.2, plates (up to 6 at
a time) were irradiated using the X-RAD 320 instrument (PXi) with
equivalent to .about.600 cGy. Plates were returned to the incubator
for a further 1 h. Then cells were fixed by adding 20 .mu.l of 3.7%
formaldehyde in PBS solution and incubating for 20 minutes at r.t.
before being washed with 50 .mu.l/well PBS, using a Biotek EL405
plate washer. Then 20 .mu.l of 0.1% Triton X100 in PBS was added
and incubated for 20 minutes at r.t., to permeabalise cells. Then
the plates were washed once with 50 .mu.l/well PBS, using a Biotek
EL405 plate washer.
[0886] Phospho-ATM Ser1981 antibody (Millipore #MAB3806) was
diluted 10000 fold in PBS containing 0.05% polysorbate/Tween and 3%
BSA and 20 .mu.l was added to each well and incubated over night at
r.t. The next morning plates were washed three times with 50
.mu.l/well PBS, using a Biotek EL405 plate washer, and then 20
.mu.l of secondary Ab solution, containing 500 fold diluted Alexa
Fluor.RTM. 488 Goat anti-rabbit IgG (Life Technologies, A11001) and
0.002 mg/ml Hoeschst dye (Life technologies #H-3570), in PBS
containing 0.05% polysorbate/Tween and 3% BSA, was added. After 1 h
incubation at r.t., the plates were washed three times with 50
.mu.l/well PBS, using a Biotek EL405 plate washer, and plates were
sealed and kept in PBS at 4.degree. C. until read. Plates were read
using an ArrayScan VTI instrument, using an XF53 filter with
10.times. objective. A two laser set up was used to analyse nuclear
staining with Hoeschst (405 nm) and secondary antibody staining of
pSer1981 (488 nm).
Assay b): ATR Cellular Potency
Rationale:
[0887] ATR is a PI 3-kinase-related kinase which phosphorylates
multiple substrates on serine or threonine residues in response to
DNA damage or replication blocks. Chk1, a downstream protein kinase
of ATR, plays a key role in DNA damage checkpoint control.
Activation of Chk1 involves phosphorylation of Ser317 and Ser345
(the latter regarded as the preferential target for
phosphorylation/activation by ATR). This was a cell based assay to
measure inhibition of ATR kinase, by measuring a decrease in
phosphorylation of Chk1 (Ser 345) in HT29 cells, following
treatment with compound of Formula (I) and the UV mimetic 4NQO
(Sigma #N8141).
Method Details:
[0888] HT29 cells (ECACC #85061109) were seeded into 384 well assay
plates (Costar #3712) at a density of 6000 cells/well in 40 .mu.l
EMEM medium containing 1% L glutamine and 10% FBS and allowed to
adhere overnight. The following morning compound of Formula (I) in
100% DMSO was added to assay plates by acoustic dispensing. After 1
h incubation at 37.degree. C. and 5% CO.sub.2, 40 nl of 3 mM 4NQO
in 100% DMSO was added to all wells by acoustic dispensing, except
minimum control wells which were left untreated with 4NQO to
generate a null response control. Plates were returned to the
incubator for a further 1 h. Then cells were fixed by adding 20
.mu.l of 3.7% formaldehyde in PBS solution and incubating for 20
mins at r.t. Then 20 .mu.l of 0.1% Triton X100 in PBS was added and
incubated for 10 minutes at r.t., to permeabalise cells. Then the
plates were washed once with 50 .mu.l/well PBS, using a Biotek
EL405 plate washer.
[0889] Phospho-Chk1 Ser 345 antibody (Cell Signalling Technology
#2348) was diluted 150 fold in PBS containing 0.05%
polysorbate/Tween and 15 .mu.l was added to each well and incubated
over night at r.t. The next morning plates were washed three times
with 50 .mu.l/well PBS, using a Biotek EL405 plate washer, and then
20 .mu.l of secondary Ab solution, containing 500 fold diluted
Alexa Fluor 488 Goat anti-rabbit IgG (Molecular Probes #A-11008)
and 0.002 mg/ml Hoeschst dye (Molecular Probes #H-3570), in PBST,
was added. After 2 h incubation at r.t., the plates were washed
three times with 50 .mu.l/well PBS, using a Biotek EL405 plate
washer, and plates were then sealed with black plate seals until
read. Plates were read using an ArrayScan VTI instrument, using an
XF53 filter with 10.times. objective. A two laser set up was used
to analyse nuclear staining with Hoeschst (405 nm) and secondary
antibody staining of pChk1 (488 nm).
Assay c): PI3K Cellular Potency
Rationale:
[0890] This assay was used to measure PI3K-.alpha. inhibition in
cells. PDK1 was identified as the upstream activation loop kinase
of protein kinase B (Akt1), which is essential for the activation
of PKB. Activation of the lipid kinase phosphoinositide 3 kinase
(PI3K) is critical for the activation of PKB by PDK1.
[0891] Following ligand stimulation of receptor tyrosine kinases,
PI3K is activated, which converts PIP2 to PIPS, which is bound by
the PH domain of PDK1 resulting in recruitment of PDK1 to the
plasma membrane where it phosphorylates AKT at Thr308 in the
activation loop.
[0892] The aim of this cell-based mode of action assay is to
identify compounds that inhibit PDK activity or recruitment of PDK1
to membrane by inhibiting PI3K activity. Phosphorylation of
phospho-Akt (T308) in BT474c cells following treatment with
compounds for 2 h is a direct measure of PDK1 and indirect measure
of PI3K activity.
Method Details:
[0893] BT474 cells (human breast ductal carcinoma, ATCC HTB-20)
were seeded into black 384 well plates (Costar, #3712) at a density
of 5600 cells/well in DMEM containing 10% FBS and 1% glutamine and
allowed to adhere overnight.
[0894] The following morning compounds in 100% DMSO were added to
assay plates by acoustic dispensing. After a 2 h incubation at
37.degree. C. and 5% CO.sub.2, the medium was aspirated and the
cells were lysed with a buffer containing 25 mM Tris, 3 mM EDTA, 3
mM EGTA, 50 mM sodium fluoride, 2 mM Sodium orthovanadate, 0.27M
sucrose, 10 mM .beta.-glycerophosphate, 5 mM sodium pyrophosphate,
0.5% Triton X-100 and complete protease inhibitor cocktail tablets
(Roche #04 693 116 001, used 1 tab per 50 ml lysis buffer).
[0895] After 20 minutes, the cell lysates were transferred into
ELISA plates (Greiner #781077) which had been pre-coated with an
anti total-AKT antibody in PBS buffer and non-specific binding was
blocked with 1% BSA in PBS containing 0.05% Tween 20. Plates were
incubated over night at 4.degree. C. The next day the plates were
washed with PBS buffer containing 0.05% Tween 20 and further
incubated with a mouse monoclonal anti-phospho AKT T308 for 2 h.
Plates were washed again as above before addition of a horse
anti-mouse-HRP conjugated secondary antibody. Following a 2 h
incubation at r.t., plates were washed and QuantaBlu substrate
working solution (Thermo Scientific #15169, prepared according to
provider's instructions) was added to each well. The developed
fluorescent product was stopped after 60 minutes by addition of
Stop solution to the wells. Plates were read using a Tecan S afire
plate reader using 325 nm excitation and 420 nm emission
wavelengths respectively. Except where specified, reagents
contained in the Path Scan Phospho AKT (Thr308) sandwich ELISA kit
from Cell Signalling (#7144) were used in this ELISA assay.
Assay d): mTOR Cellular Potency
Rationale:
[0896] This assay was used to measure mTOR inhibition in cells. The
aim of the phospho-AKT cell based mechanism of action assay using
the Acumen Explorer is to identify inhibitors of either PI3K.alpha.
or mTOR-Rictor (Rapamycin insensitive companion of mTOR). This is
measured by any decrease in the phosphorylation of the Akt protein
at Ser473 (AKT lies downstream of PI3K.alpha. in the signal
transduction pathway) in the MDA-MB-468 cells following treatment
with compound.
Method Details:
[0897] MDA-MB-468 cells (human breast adenocarcinoma #ATCC HTB 132)
were seeded at 1500 cells/well in 40 .mu.l of DMEM containing 10%
FBS and 1% glutamine into Greiner 384 well black flat-bottomed
plates. Cell plates were incubated for 18 h in a 37.degree. C.
incubator before dosing with compounds of formula (I) in 100% DMSO
using acoustic dispensing. Compounds were dosed in a 12 point
concentration range into a randomised plate map. Control wells were
generated either by dosing of 100% DMSO (max signal) or addition of
a reference compound (a PI3K-.beta. inhibitor) that completely
eliminated the pAKT signal (min control). Plates were incubated at
37.degree. C. for 2 h, cells were then fixed by the addition of 10
.mu.l of a 3.7% formaldehyde solution. After 30 minutes the plates
were washed with PBS using a Tecan PW384 plate washer. Wells were
blocked and cells permeabilised with the addition of 40 .mu.l of
PBS containing 0.5% Tween20 and 1% Marvel.TM. (dried milk powder)
and incubated for 60 minutes at r.t. The plates were washed with
PBS containing 0.5% (v/v) Tween20 and 20 .mu.l rabbit anti-phospho
AKT Ser473 (Cell Signalling Technologies, #3787) in same
PBS-Tween+1% Marvel.TM. was added and incubated overnight at
4.degree. C.
[0898] Plates were washed 3 times with PBS+0.05% Tween 20 using a
Tecan PW384. 20 .mu.l of secondary antibody Alexa Fluor 488
anti-Rabbit (Molecular Probes, #A11008) diluted in PBS+0.05%
Tween20 containing 1% Marvel.TM. was added to each well and
incubated for 1 h at r.t. Plates were washed three times as before
then 20 .mu.l PBS added to each well and plates sealed with a black
plate sealer.
[0899] The plates were read on an Acumen plate reader as soon as
possible, measuring green fluorescence after excitation with 488 nm
laser. Using this system IC.sub.50 values were generated and
quality of plates was determined by control wells. Reference
compounds were run each time to monitor assay performance.
Assay e): Mouse Xenograft Model
Irinotecan Combination
[0900] Male nude mice were transplanted s.c. with SW620 cells
(ATCC--CCL-227) to determine the in-vivo anti-tumour activity of
ATM inhibitors. 1.times.10 6 cells in 50% matrigel (BD Bioscience)
were injected s.c. on the left flank of the animals. Animals were
randomised into groups of 10-15 when tumours reached a volume of
.about.200-300 mm.sup.3 and treatment commenced. Animals received 3
weekly cycles of treatment with compound. Animals were dosed once
weekly with Irinotecan by i.p., and then 24 h post Irinotecan
animals received a once daily dose on 3 consecutive days by peroral
route with a compound of Formula (I). Tumours were measured twice
weekly by caliper and volume of tumours calculated using elliptical
formula (.pi./6.times.width.times.width.times.length). Irinotecan
was formulated in a 7.5% DMSO/92.5% water for injection solution.
Compounds of Formula (I) were formulated in a 10% DMSO/90% Captisol
(30% w/v) solution. Captisol was sourced from Cydex Pharmaceuticals
(Trademarked) .beta.-cyclodextrin suitable for in vivo use and
formulations.
Olaparib Combination
[0901] Female nude mice were transplanted s.c. with a HBCx-10
patient derived tumour fragment to determine the in-vivo
anti-tumour activity of ATM inhibitors. Human tumour samples of
various histological origins were obtained from patients and
established as transplantable xenografts in immunodeficient
mice.
[0902] Tumours of the same passage were transplanted subcutaneously
onto 5-10 mice. When these tumours reached 1000 to 2000 mm.sup.3,
donor mice were sacrificed by cervical dislocation, tumours were
aseptically excised and dissected and cut into fragments measuring
approximately 20 mm.sup.3 and transferred in culture medium before
grafting. Mice were anaesthetized and the skin incised at the level
of the interscapular region, and a 20 mm.sup.3 tumour fragment was
placed in the subcutaneous tissue
[0903] Animals were randomised into groups of 10-12 when tumours
reached a volume of 62.5-196 mm.sup.3 and treatment commenced.
Animals received 8 weekly cycles of treatment with compound.
Animals were dosed 7 days a week with Olaparib per orally, and then
1 h prior to Olaparib animals received a once daily dose on 3
consecutive days by per oral route with a compound of Formula (I).
Tumours were measured twice weekly by caliper and volume of tumours
calculated using formula [length.times.width.sup.2]/2 was used,
where the length and the width are the longest and the shortest
diameters of the tumour, respectively. Olaparib was formulated in a
10% (w/v) DMSO/10% (w/v) HP-b-CD (Kleptose), 80% water for
injection solution. Compounds of Formula (I) were formulated in a
10% DMSO/90% Captisol (30% w/v) solution. Captisol was sourced from
Cydex Pharmaceuticals (Trademarked) .beta.-cyclodextrin suitable
for in vivo use and formulations.
[0904] The results of testing Examples 1 and 2 in assay e) are
shown in FIGS. 3, 4 and 5. "Q7D" Means a once weekly dose. "Q1D" is
a once daily dose.
[0905] Table 2 shows the results of testing the Examples in assays
a) b) c) and d). Where multiple repeat tests were carried out on a
given Example, the result reported is the geometric mean.
TABLE-US-00022 TABLE 2 Potency Data for Examples 1-71 in Assays
a)-d) Assay a) Assay b) Assay c) Assay d) ATM Cell ATR Cell
PI3K.alpha. Cell mTOR Cell Example IC.sub.50 (.mu.M) IC.sub.50
(.mu.M) IC.sub.50 (.mu.M) IC.sub.50 (.mu.M) 1 0.000575 6.16 1.41
0.61 2 0.000249 >29 1.77 1.17 3 0.00203 >30 22.4 4.93 4
0.00146 >30 6.84 3.46 5 0.00024 >30 1.08 1.36 6 0.00105
>30 >30 >16.9 7 0.00096 10.8 0.541 0.266 8 0.000782 >30
18.1 14 9 0.0038 >30 >29.1 >21.3 10 0.001 >30 10 5.9 11
0.00114 >29.6 >20.2 9.29 12 0.00103 >25.2 0.769 0.54 13
0.00322 >30 1.52 0.248 14 0.00105 >30 0.616 1.04 15 0.000447
>30 2.39 2.58 16 0.000935 >22.8 0.311 0.714 17 0.000329
>30 0.968 1.47 18 0.000765 >30 2.73 3.78 19 0.00262 >30
>28 13.7 20 0.000365 >30 1.03 0.529 21 0.000301 >30 0.68
0.797 22 0.000552 >30 0.849 1.37 23 0.000563 >30 >30 18.2
24 0.00069 >18.8 7.29 >9.43 25 0.000315 >20.7 1.05 1.19 26
0.000152 >21.8 0.331 0.36 27 0.000418 >23.3 >29.8 >17.5
28 0.000176 >22.8 2.03 2.77 29 0.000238 19 1.65 0.605 30 0.00112
19 2.33 1.57 31 0.00109 >30 >10.9 19.5 32 0.00178 >30 2.94
6.1 33 0.0002 >24.7 12.4 2.87 34 0.00084 >16.9 0.402 0.505 35
0.000589 17.8 3 0.579 36 0.00301 >30 >25 10.6 37 0.0012
>29.4 20.7 12.4 38 0.000292 >24.4 0.729 2.24 39 0.00133 10.7
0.828 1.27 40 0.000567 1.33 0.184 0.191 41 0.000555 3.94 0.267
0.395 42 0.000249 4.37 0.321 0.214 43 0.000592 2.69 0.167 0.262 44
0.00107 >19.2 0.56 2.37 45 <0.000534 9.6 0.26 1.19 46 0.00315
>26 0.794 47 0.000799 >30 >23.5 >30 48 0.00102 >30
>9.4 23 49 0.00134 >30 2.03 3.76 50 0.00144 >30 1.1 4.48
51 0.000722 >30 3.2 5.38 52 0.00476 >30 7.2 12.1 54 0.0011
>27.1 >16.7 >29.3 54 0.000715 >22.4 3.47 8.12 55
0.000493 >16.1 >9.13 3.38 56 0.00302 >30 >26.3 12.4 57
0.000434 >30 >14.3 5.77 58 0.00031 >28.1 >9.56 7.29 59
0.000233 >19.1 0.264 0.61 60 0.000765 >24 0.499 1.36 61
0.000554 >30 >16.2 62 0.000507 >30 63 0.00031 >30 3.28
10.8 64 0.000741 >24.1 >30 12 65 0.00022 >26.6 1.84 6.34
66 0.000334 7.85 1.49 3.32 67 <0.0000525 15.2 >2.85 0.996 68
0.000208 >29 0.644 3.18 69 0.000324 >30 >2.77 70 0.00243
>24.9 >30 >30 71 0.00145 >30 >11.4 15.2
[0906] Table 3 shows comparative data for certain Compounds of
CN102399218A and CN102372711A in tests a) b) c) and d). Where
multiple repeat tests were carried out on a given Compound, the
result reported is the geometric mean.
TABLE-US-00023 TABLE 3 Potency Data for Certain Compounds of
CN102399218A and CN102372711A in Assays a)-d) Assay a) Assay b)
Assay c) Assay d) Reference ATM Cell ATR Cell PI3Ka Cell mTOR Cell
Compound IC.sub.50 (.mu.M) IC.sub.50 (.mu.M) IC.sub.50 (.mu.M)
IC.sub.50 (.mu.M) CN102372711A 0.125 0.281 0.188 0.237 Compound 1
CN102372711A 0.0112 0.0686 0.102 0.0729 Compound 4 CN102372711A
0.0265 0.0644 0.153 0.113 Compound 5 CN102399218A 1.76 0.418 4.67
2.31 Compound 60 CN102399218A 3.46 1.48 1.73 0.177 Compound 61
CN102399218A 0.135 0.0553 0.149 0.0155 Compound 62 CN102399218A
0.216 0.162 0.247 0.287 Compound 64 CN102399218A 0.494 0.0129
0.0804 0.0414 Compound 94 CN102399218A 0.0741 0.0686 0.0131 0.0469
Compound 114
* * * * *
References