U.S. patent application number 17/088689 was filed with the patent office on 2021-02-18 for inhibitors of phosphatidylinositol 3-kinase gamma.
This patent application is currently assigned to AstraZeneca AB. The applicant listed for this patent is AstraZeneca AB. Invention is credited to Rhona COX, Konstantinos KARABELAS, Mickael MOGEMARK, Nils PEMBERTON, Matthew PERRY, Jens PETERSEN, Christian TYRCHAN, Pavol ZLATOIDSKY.
Application Number | 20210047312 17/088689 |
Document ID | / |
Family ID | 1000005191223 |
Filed Date | 2021-02-18 |
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United States Patent
Application |
20210047312 |
Kind Code |
A1 |
MOGEMARK; Mickael ; et
al. |
February 18, 2021 |
INHIBITORS OF PHOSPHATIDYLINOSITOL 3-KINASE GAMMA
Abstract
There are disclosed certain novel compounds (including
pharmaceutically acceptable salts thereof), ##STR00001## that
inhibit phosphatidylinositol 3-kinase gamma (PI3K.delta.) activity,
to their utility in treating and/or preventing clinical conditions
including respiratory diseases, such as asthma and chronic
obstructive pulmonary disease (COPD), to their use in therapy, to
pharmaceutical compositions containing them and to processes for
preparing such compounds.
Inventors: |
MOGEMARK; Mickael; (Molndal,
SE) ; PEMBERTON; Nils; (Molndal, SE) ;
PETERSEN; Jens; (Molndal, SE) ; PERRY; Matthew;
(Molndal, SE) ; KARABELAS; Konstantinos; (Molndal,
SE) ; ZLATOIDSKY; Pavol; (Molndal, SE) ; COX;
Rhona; (Molndal, SE) ; TYRCHAN; Christian;
(Molndal, SE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AstraZeneca AB |
Sodertalje |
|
SE |
|
|
Assignee: |
AstraZeneca AB
Sodertalje
SE
|
Family ID: |
1000005191223 |
Appl. No.: |
17/088689 |
Filed: |
November 4, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16082880 |
Sep 6, 2018 |
10858355 |
|
|
PCT/EP2017/055552 |
Mar 9, 2017 |
|
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17088689 |
|
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62306328 |
Mar 10, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 417/04
20130101 |
International
Class: |
C07D 417/04 20060101
C07D417/04 |
Claims
1. A compound of formula (I) ##STR00106## wherein X is C(O) or
SO.sub.2; Y is selected from --CH.sub.2--, --CH.dbd.CH--,
--C(CH.sub.2)--, --CH(CH.sub.3)--, --CH.sub.2CH.sub.2, --CH(OH)--,
--N.dbd.CH-- or --C(O)--; R.sup.1 is (3,3-dimethylbutan-2-yl) or
C.sub.1-4alkyl, wherein said C.sub.1-4alkyl is optionally
substituted by cyclopropyl and 0, 1, 2 or 3 F; R.sup.2 is selected
from CH.sub.3, NHR.sup.4, S.sub.2R.sup.5 or
(1-methyl-1H-pyrazol-5-yl)methyl; R.sup.3 is selected from
##STR00107## R.sup.4 is C(O)CH.sub.3 or SO.sub.2R.sup.6; R.sup.5 is
selected from (3-cyanophenyl)sulfamoyl, CH.sub.3,
N(CH.sub.3).sub.2, NH.sub.2, NHCH.sub.2CF.sub.3, NH(oxetan-3-yl),
NHC.sub.1-3alkyl, wherein said C.sub.1-3alkyl is optionally
substituted by 0-3 F and 0-1 substituents independently selected
from OCH.sub.3, cyclopropyl or NHC.sub.3-4cycloalkyl, wherein said
cycloalkyl may be substituted by 0-2 F; R.sup.6 is selected from
cyclopropyl, (1,3-dimethyl-1H-pyrazol-4-yl)methyl or
C.sub.1-4alkyl, wherein said C.sub.1-4alkyl is optionally
substituted by 0-1 substituents independently selected from
OCH.sub.3, NCH.sub.3 or cyclopropyl; R.sup.7 is selected from H, Cl
or CH.sub.3; R.sup.8 is selected from --NH(C.dbd.O)CH.sub.3,
##STR00108## R.sup.9 is selected from H, C or NH.sub.2; R.sup.10 is
selected from H or NH.sub.2; R.sup.11 is selected from
C(O)NH.sub.2, C(O)NHCH.sub.3 or C(O)NHCH.sub.2phenyl; R.sup.12 is
selected from CO.sub.2H, CO.sub.2CH.sub.2CH.sub.3 or
CO.sub.2NH(CH.sub.2).sub.3NH.sub.2; R.sup.13 is selected from H or
CH.sub.3; Y is selected from N or CH; or a pharmaceutically
acceptable salt thereof.
2. A compound according to claim 1 of formula (Ia) ##STR00109##
wherein R.sup.1 is (3,3-dimethylbutan-2-yl) or C.sub.1-4alkyl,
wherein said C.sub.1-4alkyl is optionally substituted by
cyclopropyl and 0, 1, 2 or 3 F; R.sup.2 is NHR.sup.4 or
SO.sub.2R.sup.5; R.sup.7 is selected from H, Cl or CH.sub.3;
R.sup.4 is C(O)CH.sub.3 or SO.sub.2R.sup.6; R.sup.5 is selected
from (3-cyanophenyl)sulfamoyl, CH.sub.3, N(CH.sub.3).sub.2,
NH.sub.2, NHCH.sub.2CF.sub.3, NH(oxetan-3-yl), NHC.sub.1-3alkyl,
wherein said C.sub.1-3alkyl is optionally substituted by 0-3 F and
0-1 substituents independently selected from OCH.sub.3, cyclopropyl
or NHC.sub.3-4cycloalkyl, wherein said cycloalkyl may be
substituted by 0-2 F; R.sup.6 is selected from cyclopropyl,
(1,3-dimethyl-1H-pyrazol-4-yl)methyl or C.sub.1-4alkyl, wherein
said C.sub.1-4alkyl is optionally substituted by 0-1 substituents
independently selected from OCH.sub.3 or cyclopropyl; or a
pharmaceutically-acceptable salt thereof.
3. A compound according to claim 1 wherein R.sup.1 is iso-propyl or
1-cyclopropylethyl; or a pharmaceutically acceptable salt
thereof.
4. A compound according to claim 1 wherein R.sup.2 is NHR.sup.4;
R.sup.4 is SO.sub.2R.sup.6; R.sup.6 is CH.sub.3; or a
pharmaceutically acceptable salt thereof.
5. A compound according to claim 1 wherein R.sup.2 is
SO.sub.2R.sup.5; R.sup.5 is CH.sub.3 or NHCH.sub.3; or a
pharmaceutically acceptable salt thereof.
6. A compound of the formula (I) according to claim 1 selected
from:
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-(methylsulfonyl)-1-oxo-2,3-dihydro-1H-
-isoindol-5-yl}-1,3-thiazol-2-yl)acetamide,
N-{4-Methyl-5-[7-(methylsulfonyl-1-oxo-2-(propan-2-yl)-2,3-dihydro-1H-iso-
indol-5-yl]-1,3-thiazol-2-yl}acetamide,
N-(5-{2-[(1S)-1-Cyclopropylethyl]-1-oxo-7-sulfamoyl-2,3-dihydro-1H-isoind-
ol-5-yl}-4-methyl-1,3-thiazol-2-ylacetamide,
N-(5-{7-(Acetylamino)-2-[(1S)-1-cyclopropylethyl]-1-oxo-2,3-dihydro-1H-is-
oindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide,
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-(methylsulfamoyl)-1-oxo-2,3-dihydro-1-
H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide,
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-(dimethylsulfamoyl)-1-oxo-2,3-dihydro-
-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide,
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-(methylsulfamoyl)-1-oxo-2,3-dihydro-1-
H-isoindol-5-yl}-1,3-thiazol-2-yl)acetamide,
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-[(methylsulfonyl)amino]-1-oxo-2,3-dih-
ydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide,
N-(5-{7-(Cyclobutylsulfamoyl)-2-[(1S)-1-cyclopropylethyl]-1-oxo-2,3-dihyd-
ro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide,
N-{4-Methyl-5-[7-(methylsulfamoyl)-1-oxo-2-(propan-2-yl)-2,3-dihydro-1H-i-
soindol-5-yl]-1,3-thiazol-2-yl}acetamide,
N-(5-{2-[(1S)-1-Cyclopropylethyl]-1-oxo-7-sulfamoyl-2,3-dihydro-1H-isoind-
ol-5-yl}-1,3-thiazol-2-yl)acetamide,
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-[(cyclopropylmethyl)sulfamoyl]-1-oxo--
2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide,
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-(cyclopropylsulfamoyl)-1-oxo-2,3-dihy-
dro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide,
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-(ethylsulfamoyl)-1-oxo-2,3-dihydro-1H-
-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide,
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-(oxetan-3-ylsulfamoyl)-1-oxo-2,3-dihy-
dro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide,
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-[(3,3-difluorocyclobutyl)sulfamoyl]-1-
-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide,
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-[(2-methoxyethyl)sulfamoyl]-1-oxo-2,3-
-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide,
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-({[1-(fluoromethyl)cyclopropyl]methyl-
}sulfamoyl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)-
acetamide,
N-(5-{2-[(1S)-1-Cyclopropylethyl]-1-oxo-7-[(2,2,2-trifluoroethy-
l)sulfamoyl]-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)aceta-
mide,
N-{4-Methyl-5-[1-oxo-2-(propan-2-yl)-7-sulfamoyl-2,3-dihydro-1H-isoi-
ndol-5-yl]-1,3-thiazol-2-yl}acetamide,
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-[(methylsulfonyl)amino]-1-oxo-2,3-dih-
ydro-1H-isoindol-5-yl}-1,3-thiazol-2-yl)acetamide,
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-[(cyclopropylsulfonyl)amino]-1-oxo-2,-
3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide,
N-(5-{2-[(1S)-1-Cyclopropylethyl]-1-oxo-7-[(propylsulfonyl)amino]-2,3-dih-
ydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide,
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-[(ethylsulfonyl)amino]-1-oxo-2,3-dihy-
dro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide,
N-(5-{7-[(tert-Butylsulfonyl)amino]-2-[(1S)-1-cyclopropylethyl]-1-oxo-2,3-
-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide,
N-[5-(2-[(1S)-1-Cyclopropylethyl]-7-{[(2-methoxyethyl)sulfonyl]amino}-1-o-
xo-2,3-dihydro-1H-isoindol-5-yl)-4-methyl-1,3-thiazol-2-yl]acetamide,
N-[5-(2-[(1S)-1-Cyclopropylethyl]-7-{[(cyclopropylmethyl)sulfonyl]amino}--
1-oxo-2,3-dihydro-1H-isoindol-5-yl)-4-methyl-1,3-thiazol-2-yl]acetamide,
N-[5-(2-[(1S)-1-Cyclopropylethyl]-7-{[(1,3-dimethyl-1H-pyrazol-4-yl)sulfo-
nyl]amino}-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-4-methyl-1,3-thiazol-2-yl]a-
cetamide,
N-(4-Chloro-5-{2-[(1S)-1-cyclopropylethyl]-7-(methylsulfamoyl)-1-
-oxo-2,3-dihydro-1H-isoindol-5-yl}-1,3-thiazol-2-yl)acetamide,
6-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-2-[(1S)-1-cyclopropylethyl]-N-methy-
l-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide,
N-{5-[2-(2-Cyclopropylpropan-2-yl)-7-(methylsulfamoyl)-1-oxo-2,3-dihydro--
1H-isoindol-5-yl]-4-methyl-1,3-thiazol-2-yl}acetamide,
N-(5-{2-[(2S)-3,3-Dimethylbutan-2-yl]-7-(methylsulfamoyl)-1-oxo-2,3-dihyd-
ro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide,
N-{5-[2-tert-Butyl-7-(methylsulfamoyl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl-
]-4-methyl-1,3-thiazol-2-yl}acetamide,
N-(4-Methyl-5-{7-(methylsulfamoyl)-1-oxo-2-[(2S)-1,1,1-trifluoropropan-2--
yl]-2,3-dihydro-1H-isoindol-5-yl}-1,3-thiazol-2-yl)acetamide,
N-(5-{7-[(3-Cyanophenyl)sulfamoyl]-2-[(1S)-1-cyclopropylethyl]-1-oxo-2,3--
dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide,
N-(5-{7-[(3-Cyanophenyl)sulfamoyl]-1-oxo-2-(propan-2-yl)-2,3-dihydro-1H-i-
soindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, and
pharmaceutically acceptable salts thereof.
7. A compound according to claim 1 which is
N-(5-{2-[(1S)-1-cyclopropylethyl]-7-(methylsulfonyl)-1-oxo-2,3-dihydro-1H-
-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, ##STR00110##
or a pharmaceutically acceptable salt thereof.
8. A compound according to claim 1 which is
N-(5-{2-[(1S)-1-cyclopropylethyl]-7-(methylsulfonyl)-1-oxo-2,3-dihydro-1H-
-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide,
##STR00111##
9. A pharmaceutical composition comprising a compound of formula
(I) as claimed in claim 1 and a pharmaceutically acceptable
adjuvant, diluent or carrier.
10. (canceled)
11. (canceled)
12. (canceled)
13. A method of treating asthma or chronic obstructive pulmonary
disease in a patient suffering from said disease, which comprises
administering to the patient a therapeutically effective amount of
a compound of formula (I) as claimed in claim 1.
14. A combination of a compound of formula (I) as claimed in claim
1 and one or more agents independently selected from: a
glucocorticoid receptor agonist (steroidal or non-steroidal); a
selective .beta..sub.2 adrenoceptor agonist; a selective inhibitor
of PI3K.delta.; an antimuscarinic agent; a p38 antagonist; and a
PDE4 antagonist.
15. A method of treating, or reducing the risk of, cancer or CNS
related disorders which comprises administering to a patient in
need thereof a therapeutically effective amount of a compound of
formula (I), or a pharmaceutically acceptable salt thereof as
claimed in claim 1.
Description
TECHNICAL FIELD
[0001] The technical field relates to certain novel chemical
compounds (including pharmaceutically acceptable salts thereof)
that inhibit phosphatidylinositol 3-kinase gamma (PI3K.gamma.)
activity, to their utility in treating and/or preventing clinical
conditions including respiratory diseases, such as asthma and
chronic obstructive pulmonary disease (COPD), to their use in
therapy, to pharmaceutical compositions containing them and to
processes for preparing such compounds.
BACKGROUND
[0002] The phosphoinositide 3-kinase (PI3K) family are central
signalling elements in a diverse array of cellular functions,
including growth, proliferation, migration and survival. PI3Ks
function by phosphorylating the 3-hydroxyl position on the inositol
ring of phosphoinositide lipids, and can be divided into three
classes based upon domain structure, the type of lipid substrate
they act upon, and mode of regulation [Biochim Biophys Acta, 1436
(1998), 127-150]. Class I PI3K catalytic subunits can be further
subdivided into class 1A (isoforms .alpha., .beta., .delta.) and
class IB (.gamma. isoform), all of which are known to convert
phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) to form
PtdIns(3,4,5)P3 in vivo [Biochim Biophys Acta, 1179 (1993), 27-75
and Science, 296 (2002), 1655-1657]. PI3K.gamma. is activated by
G-protein-coupled receptors (GPCRs) via association with either
p101 or p84/p87 adaptors, which potentiate activation by
.beta..gamma.-subunits of hetero-trimeric GTP-binding proteins
[Curr Biol, 15 (2005), 566-570]. The PtdIns(3,4,5)P3 generated at
the plasma membrane serves as a docking site for
pleckstrin-homology (PH)-domain containing proteins such as protein
kinase B (PKB/Akt), which can then influence a broad array of
proteins and thereby effect many different cellular responses
[Cell, 129 (2007), 1261-1274]. PI3K.gamma. expression is restricted
to neutrophils, eosinophils, macrophages, dendritic cells, T cells
and mast cells, as well as low levels detectable in endothelium,
airway smooth muscle cells and the heart [Curr Opin Cell Biol, 17
(2005), 141-149]. Knockout mice are viable and fertile [Science,
287 (2000), 1049-1052] and have been studied in a wide variety of
preclinical models as part of the validation process of PI3K.gamma.
in multiple diseases. The majority of research has focused on the
function of this isoform as a biochemical compass for migrating
cells, where PI3K knockout neutrophil experiments concluded that
although chemokinesis was unaffected, cells lacked direction to
GPCR-mediated stimuli [Science, 287 (2000), 1049-1052, Nat Cell
Biol, 4 (2002), 513-518 and J Cell Biol, 167 (2004), 505-518], and
thus provided a basic rationale for PI3K.gamma. inhibition in the
context of a variety of conditions in which influx of inflammatory
effector cells play a key role in pathology.
[0003] Neutrophils play a critical role in host defence against
invading pathogens. Neutrophils are produced in the bone marrow and
are fully mature when released into the circulation to take up
their role as the first line of cellular defence. Pro-inflammatory
mediators and chemotactic attractants activate neutrophils and draw
them to the site of infection, where they act to engulf bacteria by
phagocytosis, then use a powerful serine protease--neutrophil
elastase--to kill the pathogen.
[0004] Yet neutrophil elastase can also cause problems for its
host. It is one of the most destructive enzymes in the body, with
the capability of degrading extracellular matrix proteins
(including collagens, proteoglycan, fibronectin, platelet
receptors, complement receptor, thrombomodulin, lung surfactant and
cadherins) and key plasma proteins (including coagulation and
complement factors, immunoglobulin, several proteases and protease
inhibitors). Under physiological conditions, endogenous protease
inhibitors, such as al-antitrypsin, tightly regulate the activity
of neutrophil elastase. However, at inflammatory sites, neutrophil
elastase is able to evade regulation, and once unregulated it can
induce the release of pro-inflammatory cytokines, such as
interleukin-6 and interleukin-8, leading to acute lung injury. It
can even impair host defence against infection by degrading
phagocyte surface receptors and opsonins. Its negative role is
illustrated by its involvement in the tissue destruction and
inflammation that characterise numerous diseases, including
hereditary emphysema, chronic obstructive pulmonary disease, cystic
fibrosis, adult respiratory distress syndrome, ischemic-reperfusion
injury and rheumatoid arthritis. Both in vitro and in vivo studies
have shown PI3K.gamma. to be central in the homing of neutrophils
to sites of inflammation and their degranulation and elastase
release once their [Curr Top Microbiol Immunol. 2010, 346,
183-202].
[0005] Eosinophils also derive from the bone marrow and circulate
at low levels in the blood in healthy individuals. These granulated
cells preferentially leave the circulation and migrate to tissues,
where they are implicated in the regulation of innate and adaptive
immunity. In diseases such as allergic inflammation, eosinophil
numbers escalate markedly in the blood and tissues where
inflammatory foci are located. Eosinophils possess a range of
immunomodulatory factors that are released upon cell activation,
including over 35 cytokines, growth factors, and chemokines which
can be rapidly released upon stimulation [Front Immunol. 2014 Nov.
10, 5, 570]. Emerging evidence from animal model-based research has
suggested deficiency of PI3K.gamma. impaired the migration of
eosinophils both in vitro and in vivo [Immunology 2009, 126(3),
413-22], with further supporting data demonstrating a protective
phenotype of knockout mice within an OVA/alum model of asthma [J
Leukoc Biol, 77 (2005), 800-810].
[0006] Macrophages are found in tissues throughout the body and
form one of the first lines of defense to injury and pathogens.
Early experiments in PI3K.gamma. knockout mice demonstrated
macrophages derived from mutant animals failed to produce
PtdIns(3,4,5)P3 in response to stimulation with various chemotactic
substances and that subsequent movement was inhibited [Science.
2000, 287(5455), 1040-6]. Macrophages can be further divided into
proinflammatory (M1) and the "alternatively activated"
anti-inflammatory (M2) macrophages, which often play sequential
roles in inflammation and repair/remodeling respectively.
Chemokines are the major mediators of chemotaxis in both subsets,
yet the pattern of GPCR expression which controls cell movement
differ. Chemokines CCL19 or CCL21 induced activation of both
MEK1-ERK1/2 and PI3K-AKT cascades in M1 but not in M2 macrophages,
although pan PI3K inhibition via wortmannin was able to block
migration, presumably through lack of PI3K.gamma. activity [J
Leukoc Biol. 2015, 97(1), 61-9].
[0007] The adaptive immune system relies on the presentation of
antigen by professional presenting cells (particularly dendritic
cells (DCs)) to T lymphocytes in lymph nodes which drain the site
of antigen entry/discovery. PI3K.gamma. has been shown to be
involved in effective DC trafficking to lymph nodes in knockout
studies [EMBO J. 2004, 23(17), 3505-15]. Once presented to a T cell
with the appropriate affinity, a process of clonal expansion and
differentiation into different subtypes occurs. CD4 T cell subsets
can be broadly dived into Th1, Th2 and Th17 which help B lymphocyte
responses and recruit granulocytes, or T reg cells which dampen the
immune response. CD8 T cell subsets are dominated by a
cytotoxic/Tc1 phenotype which is responsible for killing cells
which present antigen from within a cell (e.g. virus infected
cells). There is little evidence that PI3K.gamma. plays a role in
the T cell differentiation process, yet is known to govern the
movement of both CD4 and CD8 T cell subsets to sites of
inflammation [Biochim Biophys Acta. 2015, 1851(6), 882-97].
Dysregulation of the adaptive immune system can result in
autoimmunity, in which T cell subsets react to self antigen. There
is evidence for PI3K.gamma. driving the priming and survival of
such populations, particularly in central nervous system (CNS)
related inflammatory disorders, such as Multiple Sclerosis (MS)
[PLoS One. 2012, 7(9), e45095].
[0008] Mast cells are found in many tissues but are present in
greater numbers along the epithelial linings of the body, such as
the skin, respiratory tract and gastrointestinal tract. In humans,
two types of mast cells have been identified. The T-type, which
expresses only tryptase, and the TC-type, which expresses both
tryptase and chymase. In humans, the T-type mast cells are located
primarily in alveolar tissue and intestinal mucosa while the
TC-type cells predominate in skin and conjunctiva. Tryptase and
chymase appear to be important mediators of allergic diseases,
being involved in processes of inflammation, bronchoconstriction
and mucus secretion. PI3K.gamma. has been shown to play a key role
in both the localization/retention of mast cells to sites of
inflammation and their degranulation (in partnership with the class
1A PI3K.delta. isoform) [J Allergy Clin Immunol. 2013,
132(4):959-68].
[0009] Airway smooth muscle cell expression of PI3K.gamma. has been
linked with the desensitization of .beta.2 adrenergic receptors
following agonism--a common treatment for bronchoconstriction in
asthma. The mechanism appears to be via the sequestration of
internalized receptor in the endoplasmic reticulum, thus inhibition
of PI3K.gamma. may return some efficacy of .beta.2 agonists which
has been lost through long term use [PLoS One. 2015, 10(5),
e0125803].
[0010] PI3K.gamma. is identified as a potentially important
signalling mediator in cancer. PI3K.gamma. upregulation has been
shown to be oncogenic in cancers such as pancreatic intraepithelial
neoplasia and ductal carcinoma [Clin Cancer Res. 2010, 16(20),
4928-37], and roles in both tumor growth and metastasis have been
shown in rodent oncology models [Oncogene. 2012, 31(18), 2350-61].
An indirect role for PI3K.gamma. has been demonstrated in promoting
an immunosuppressive tumor microenvironment which contributes to
the evasion of cancer cells from the immune system--a process which
underlies relapse to current checkpoint and anti-angiogenic
inhibitor therapies. Myeloid derived suppressor cells (MDSCs) are
central to said immune evasion, through signaling mechanisms which
feature PI3K.gamma. not only downstream of GPCRs but also cytokine
and growth factor receptors [Cancer Cell. 2011, 19(6), 715-27 and
Cell Rep. 2015, 11(4). 577-91]. Results indicate that upregulated
PI3K.gamma. conveys the metastatic signal initiated by GPCRs in
breast cancer cells, and suggest that PI3K.gamma. may be a novel
therapeutic target for development of chemotherapeutic agents to
prevent breast cancer metastasis. [Biochem. Pharm. 2013, 85,
1454-1462]
[0011] Taken together, these data reveal the important role
PI3K.gamma. signaling has in a wide array of immune responses and
the therapeutic potential a potent and selective inhibitor may
offer to many diseases.
WO2015048318 disclose
(R)-6-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-4,7,7-trimethyl-2-(5-(2,2,2-
-trifluoro-1-hydroxyethyl)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrid-
in-5-one useful as a selective inhibitor of PI3K.gamma..
WO2011087776 disclose isoindolinone inhibitors of PI3K,
particularly of PI3K.gamma.. WO2015162461 and WO2015162459 disclose
pyrazine inhibitors of PI3K.gamma.. WO2015162456 disclose amino
pyridine inhibitors of PI3K.gamma..
[0012] An object is to provide novel PI3K.gamma. inhibitors useful
in therapy. A further object is to provide PI3K.gamma. inhibitors
displaying selectivity over the PI3K class 1A isoforms .alpha.,
.beta. and .delta..
SUMMARY
[0013] There is provided compounds that are inhibitors of
phosphatidylinositol 3-kinase gamma (PI3K.gamma.), their use as
medicaments, pharmaceutical compositions containing them and
synthetic routes to their production.
[0014] According to a first aspect, there is provided a compound of
formula (I)
##STR00002##
wherein
X is C(O) or SO.sub.2;
[0015] Y is selected from --CH.sub.2--, --CH.dbd.CH--,
--C(CH.sub.2)--, --CH(CH.sub.3)--, --CH.sub.2CH.sub.2, --CH(OH)--,
--N.dbd.CH-- or --C(O)--; R.sup.1 is (3,3-dimethylbutan-2-yl) or
C.sub.1-4alkyl, wherein said C.sub.1-4alkyl is optionally
substituted by cyclopropyl and 0, 1, 2 or 3 F; R.sup.2 is selected
from CH.sub.3, NHR.sup.4, SO.sub.2R.sup.5 or
(1-methyl-1H-pyrazol-5-yl)methyl; R.sup.3 is selected from
##STR00003##
R.sup.4 is C(O)CH.sub.3 or SO.sub.2R.sup.6; R.sup.5 is selected
from (3-cyanophenyl)sulfamoyl, CH.sub.3, NHCH.sub.3, NH.sub.2,
NHCH.sub.2CF.sub.3, NH(oxetan-3-yl), NHC.sub.1-3alky, wherein said
C.sub.1-3alkyl is optionally substituted by 0-3 F and 0-1
substituents independently selected from OCF.sub.3, cyclopropyl or
NHC.sub.3-4cycloalkyl, wherein said cycloalkyl may be substituted
by 0-2 F; R.sup.6 is selected from cyclopropyl,
(1,3-dimethyl-1H-pyrazol-4-yl)methyl or C.sub.1-4alkyl, wherein
said C.sub.1-4alkyl is optionally substituted by 0-1 substituents
independently selected from OCH.sub.3, NCH.sub.3 or cyclopropyl;
R.sup.7 is selected from H, Cl or CH.sub.3; R.sup.8 is selected
from --NH(C.dbd.O)CH.sub.3,
##STR00004##
R.sup.9 is selected from H, Cl or NH.sub.2; R.sup.10 is selected
from H or NH.sub.2; R.sup.11 is selected from C(O)NH.sub.2,
C(O)NHCH.sub.3 or C(O)NHCH.sub.2phenyl; R.sup.12 is selected from
CO.sub.2H, CO.sub.2CH.sub.2CH.sub.3 or
CO.sub.2NH(CH.sub.2).sub.3NH.sub.2; R.sup.13 is selected from H or
CH.sub.3; Y is selected from N or CH; or a pharmaceutically
acceptable salt thereof.
[0016] According to a further aspect, there is provided a compound
of formula (Ia)
##STR00005##
wherein R.sup.1 is (3,3-dimethylbutan-2-yl) or C.sub.1-4alkyl,
wherein said C.sub.1-4alkyl is optionally substituted by
cyclopropyl and 0, 1, 2 or 3 F; R.sup.2 is NHR.sup.4 or
SO.sub.2R.sup.5; R.sup.7 is selected from H, Cl or CH.sub.3;
R.sup.4 is C(O)CH.sub.3 or SO.sub.2R.sup.6; R.sup.5 is selected
from (3-cyanophenyl)sulfamoyl, CH.sub.3, N(CH.sub.3).sub.2,
NH.sub.2, NHCH.sub.2CF.sub.3, NH(oxetan-3-yl), NHC.sub.1-3alkyl,
wherein said C.sub.1-3alkyl is optionally substituted by 0-3 F and
0-1 substituents independently selected from OCH.sub.3, cyclopropyl
or NHC.sub.3-4cycloalkyl, wherein said cycloalkyl may be
substituted by 0-2 F; R.sup.6 is selected from cyclopropyl,
(1,3-dimethyl-1H-pyrazol-4-yl)methyl or C.sub.1-4alkyl, wherein
said C.sub.1-4alkyl is optionally substituted by 0-1 substituents
independently selected from OCH.sub.3 or cyclopropyl; or a
pharmaceutically-acceptable salt thereof.
[0017] The compounds of formula (I) are inhibitors of PI3K.gamma..
Thus, the compounds of formula (I) can be used as a medicament, in
particular for disorders, disease or conditions responsive to
inhibition of PI3K.gamma., and more specifically respiratory
diseases (such as COPD and asthma), CNS related disorders (such as
MS) or cancer (such as pancreatic intraepithelial neoplasia, ductal
carcinoma and breast cancer).
[0018] In another embodiment there is provided a compound of
formula (I), or a pharmaceutically acceptable salt of a compound of
formula (I), displaying selectivity over the PI3K class 1A isoforms
.alpha., .beta. and .delta..
[0019] In another embodiment there is provided a compound of
formula (I), or a pharmaceutically acceptable salt of a compound of
formula (I), displaying at least 50-fold selectivity over the PI3K
class 1A isoforms .alpha., .beta. and .delta. when the activity is
measured in relevant enzyme activity assays.
[0020] In another embodiment there is provided a compound of
formula (I), or a pharmaceutically acceptable salt of a compound of
formula (I), displaying at least 100-fold selectivity over the PI3K
class 1A isoforms .alpha., .beta. and .delta. when the activity is
measured in relevant enzyme activity assays.
[0021] In another embodiment there is provided a compound of
formula (I), or a pharmaceutically acceptable salt of a compound of
formula (I), displaying at least 1000-fold selectivity over the
PI3K class 1A isoforms .alpha., .beta. and .delta. when the
activity is measured in relevant enzyme activity assays.
[0022] In another embodiment there is provided a compound of
formula (I), or a pharmaceutically acceptable salt of a compound of
formula (I), wherein the stereochemistry is undefined, e.g. a
racemate or a mixture of diastereomers.
[0023] In another embodiment there is provided a pharmaceutical
formulation comprising a therapeutically effective amount of a
compound of formula (I), or a pharmaceutically acceptable salt of a
compound of formula (I), and a pharmaceutically acceptable diluent,
excipient and/or inert carrier.
[0024] In a further embodiment there is provided a pharmaceutical
formulation comprising a compound of formula (I), or a
pharmaceutically acceptable salt of a compound of formula (I), for
use in the treatment of a condition where inhibition of PI3K.gamma.
would be beneficial.
[0025] In a further embodiment there is provided a compound of
formula (I), or a pharmaceutically acceptable salt of a compound of
formula (I), for use in therapy, especially in the prevention or
treatment of respiratory disease in a mammal, particularly a
human.
[0026] In a further embodiment there is provided a compound of
formula (I), or a pharmaceutically acceptable salt of a compound of
formula (I), for use in therapy, especially in the prevention or
treatment of asthma in a mammal, particularly a human.
[0027] In a further embodiment there is provided a compound of
formula (I), or a pharmaceutically acceptable salt of a compound of
formula (I), for use in therapy, especially in the prevention or
treatment of COPD in a mammal, particularly a human.
[0028] In a further embodiment there is provided a compound of
formula (I), or a pharmaceutically acceptable salt of a compound of
formula (I), for use in therapy, especially in the prevention or
treatment of CNS related disorders in a mammal, particularly a
human.
[0029] In a further embodiment there is provided a compound of
formula (I), or a pharmaceutically acceptable salt of a compound of
formula (I), for use in therapy, especially in the prevention or
treatment of cancer in a mammal, particularly a human.
[0030] In a further embodiment there is provided the use of a
compound of formula (I), or a pharmaceutically acceptable salt of a
compound of formula (I), for the manufacture of a medicament for
the treatment and prevention of respiratory disease.
[0031] In a further embodiment there is provided the use of a
compound of formula (I), or a pharmaceutically acceptable salt of a
compound of formula (I), for the manufacture of a medicament for
the treatment and prevention of asthma.
[0032] In a further embodiment there is provided the use of a
compound of formula (I), or a pharmaceutically acceptable salt of a
compound of formula (I), for the manufacture of a medicament for
the treatment and prevention of COPD.
[0033] In a further embodiment there is provided the use of a
compound of formula (I), or a pharmaceutically acceptable salt of a
compound of formula (I), for the manufacture of a medicament for
the treatment and prevention of CNS related disorders.
[0034] In a further embodiment there is provided the use of a
compound of formula (I), or a pharmaceutically acceptable salt of a
compound of formula (I), for the manufacture of a medicament for
the treatment and prevention of cancer.
[0035] In still a further embodiment, administration of a compound
of formula (I), or a pharmaceutically acceptable salt of a compound
of formula (I) results in a reduction in levels of PI3K.gamma. in a
mammal, particularly a human.
[0036] According to another aspect there is provided a process for
the preparation of compounds of formula (I), or pharmaceutically
acceptable salts of compounds of formula (I), and the intermediates
used in the preparation thereof.
[0037] The compounds of formula (I) herein exemplified have an
IC.sub.50 of less than 100 nmol/L for PI3K.gamma. in enzyme
activity assays, for example Test A described below. The compounds
of formula (I) also display promising pharmacological profiles by
separating desired and undesired effects in vivo.
BRIEF DESCRIPTION OF THE DRAWINGS
[0038] FIG. 1 shows the X-ray powder diffraction pattern for
Example 1:
N-(5-{2-[(1S)-1-cyclopropylethyl]-7-(methylsulfonyl)-1-oxo-2,3-dihydro-1H-
-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide.
[0039] FIG. 2 shows the X-ray powder diffraction pattern for
Example 6:
N-(5-{2-[(1S)-1-cyclopropylethyl]-7-(methylsulfamoyl)-1-oxo-2,3-dihydro-1-
H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide.
[0040] FIG. 3 shows the X-ray powder diffraction pattern for
Example 9:
N-(5-{2-[(1S)-1-cyclopropylethyl]-7-[(methylsulfonyl)amino]-1-oxo-2,3-dih-
ydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide.
DETAILED DESCRIPTION
[0041] This detailed description and its specific examples, while
indicating embodiments, are intended for purposes of illustration
only. Therefore, there is no limitation to the illustrative
embodiments described in this specification. In addition, it is to
be appreciated that various features that are, for clarity reasons,
described in the context of separate embodiments, also may be
combined to form a single embodiment. Conversely, various features
that are, for brevity reasons, described in the context of a single
embodiment, also may be combined to form subcombinations
thereof.
[0042] Listed below are definitions of various terms used in the
specification and claims.
[0043] For the avoidance of doubt it is to be understood that where
in this specification a group is qualified by "defined above" the
said group encompasses the first occurring and broadest definition
as well as each and all of the other definitions for that
group.
[0044] For the avoidance of doubt it is to be understood that in
this specification "C.sub.1-4" means a carbon group having 1, 2, 3
or 4 carbon atoms.
[0045] In this specification, unless stated otherwise, the term
"alkyl" includes both straight and branched chain alkyl groups and
may be, but is not limited to, methyl, ethyl, n-propyl, i-propyl,
n-butyl, sec-butyl or tert-butyl.
[0046] In this specification, unless stated otherwise, the term
"pharmaceutically acceptable" is used to characterize a moiety
(e.g. a salt, dosage form, or excipient) as being appropriate for
use in accordance with sound medical judgment. In general, a
pharmaceutically acceptable moiety has one or more benefits that
outweigh any deleterious effect that the moiety may have.
Deleterious effects may include, for example, excessive toxicity,
irritation, allergic response, and other problems and
complications.
[0047] There is provided compounds of formula (I) wherein X, Y and
R.sup.1-R.sup.13 are as defined in formula (I).
[0048] In one embodiment X is C(O) or SO.sub.2;
[0049] In a further embodiment X is C(O);
[0050] In still a further embodiment X is SO.sub.2;
[0051] In one embodiment Y is selected from --CH.sub.2--,
--CH.dbd.CH--, --C(CH.sub.2)--, --CH(CH.sub.3)--,
--CH.sub.2CH.sub.2, --CH(OH)--, --N.dbd.CH-- or --C(O)--;
[0052] In a further embodiment Y is selected from --CH.sub.2--;
[0053] In one embodiment R.sup.1 is (3,3-dimethylbutan-2-yl) or
C.sub.1-4alkyl, wherein said C.sub.1-4alkyl is optionally
substituted by cyclopropyl and 0, 1, 2 or 3 F.
[0054] In a further embodiment R.sup.1 is C.sub.1-4alkyl.
[0055] In still a further embodiment R.sup.1 is iso-propyl or
1-cyclopropylethyl.
[0056] In still a further embodiment R.sup.1 is
1-cyclopropylethyl.
[0057] In still a further embodiment R.sup.1 is
(1S)-1-cyclopropylethyl.
[0058] In one embodiment R.sup.2 is CH.sub.3, NHR.sup.4 or
SO.sub.2R.sup.5 or (1-methyl-H-pyrazol-5-yl)methyl;
[0059] R.sup.4 is C(O)CH.sub.3 or SO.sub.2R.sup.6;
[0060] R.sup.5 is selected from (3-cyanophenyl)sulfamoyl, CH.sub.3,
NHCH.sub.3, NH.sub.2, NHCH.sub.2CF.sub.3, NH(oxetan-3-yl),
NHC.sub.1-3alkyl, wherein said C.sub.1-3alkyl is optionally
substituted by 0-3 F and 0-1 substituents independently selected
from OCH.sub.3, cyclopropyl or NHC.sub.3-4cycloalkyl, wherein said
cycloalkyl may be substituted by 0-2 F;
[0061] In a further embodiment R.sup.2 is NHR.sup.4 or
SO.sub.2R.sup.5;
[0062] R.sup.4 is C(O)CH.sub.3 or SO.sub.2R.sup.6;
[0063] R.sup.5 is selected from (3-cyanophenyl)sulfamoyl, CH.sub.3,
N(CH.sub.3).sub.2, NH.sub.2, NHCH.sub.2CF.sub.3, NH(oxetan-3-yl),
NHC.sub.1-3alkyl, wherein said C.sub.1-3alkyl is optionally
substituted by 0-3 F and 0-1 substituents independently selected
from OCH.sub.3, cyclopropyl or NHC.sub.3-4cycloalkyl, wherein said
cycloalkyl may be substituted by 0-2 F;
[0064] R.sup.6 is selected from cyclopropyl,
(1,3-dimethyl-H-pyrazol-4-yl)methyl or C.sub.1-4alkyl, wherein said
C.sub.1-4alkyl is optionally substituted by 0-1 substituents
independently selected from OCH.sub.3 or cyclopropyl.
[0065] In a further embodiment R.sup.2 is NHR.sup.4;
[0066] R.sup.4 is C(O)CH.sub.3 or SO.sub.2R.sup.6;
[0067] R.sup.6 is selected from cyclopropyl,
(1,3-dimethyl-H-pyrazol-4-yl)methyl or C.sub.1-4alkyl, wherein said
C.sub.1-4alkyl is optionally substituted by 0-1 substituents
independently selected from OCH.sub.3 or cyclopropyl.
[0068] In still a further embodiment R.sup.2 is
SO.sub.2R.sup.5;
[0069] R.sup.5 is selected from (3-cyanophenyl)sulfamoyl, CH.sub.3,
N(CH.sub.3).sub.2, NH.sub.2, NHCH.sub.2CF.sub.3, NH(oxetan-3-yl),
NHC.sub.1-3alkyl, wherein said C.sub.1-3alkyl is optionally
substituted by 0-3 F and 0-1 substituents independently selected
from OCH.sub.3, cyclopropyl or NHC.sub.3-4cycloalkyl, wherein said
cycloalkyl may be substituted by 0-2 F.
[0070] In one embodiment R.sup.3 is selected from
##STR00006##
[0071] R.sup.7 is selected from H, Cl or CH.sub.3;
[0072] R.sup.8 is selected from --NH(C.dbd.O)CH.sub.3,
##STR00007##
[0073] R.sup.9 is selected from H, Cl or NH.sub.2;
[0074] R.sup.10 is selected from H or NH.sub.2;
[0075] R.sup.11 is selected from C(O)NH.sub.2, C(O)NHCH.sub.3 or
C(O)NHCH.sub.2phenyl;
[0076] R.sup.12 is selected from CO.sub.2H, C.sub.2CH.sub.2CH.sub.3
or C.sub.2NH(CH.sub.2).sub.3NH.sub.2;
[0077] R.sup.13 is selected from H or CH.sub.3.
[0078] In a further embodiment R.sup.3 is selected from
##STR00008##
[0079] R.sup.7 is selected from H, Cl or CH.sub.3;
[0080] R.sup.8 is selected from --NH(C.dbd.O)CH.sub.3,
##STR00009##
[0081] In still a further embodiment R.sup.3 is selected from
##STR00010##
[0082] R.sup.7 is selected from H, Cl or CH.sub.3; and
[0083] R.sup.8 is selected from --NH(C.dbd.O)CH.sub.3;
[0084] In one embodiment R.sup.4 is C(O)CH.sub.3 or
SO.sub.2R.sup.6; [0085] R.sup.6 is selected from cyclopropyl,
(1,3-dimethyl-1H-pyrazol-4-yl)methyl or C.sub.1-4alkyl, wherein
said C.sub.1-4alkyl is optionally substituted by 0-1 substituents
independently selected from OCH.sub.3 or cyclopropyl.
[0086] In one embodiment R.sup.5 is selected from
(3-cyanophenyl)sulfamoyl, CH.sub.3, N(CH.sub.3).sub.2, NH.sub.2,
NHCH.sub.2CF.sub.3, NH(oxetan-3-yl), NHC.sub.1-3alkyl, wherein said
C.sub.1-3alkyl is optionally substituted by 0-3 F and 0-1
substituents independently selected from OCH.sub.3, cyclopropyl or
NHC.sub.3-4cycloalkyl, wherein said cycloalkyl may be substituted
by 0-2 F.
[0087] In a further embodiment R.sup.5 is CH.sub.3 or
NHCH.sub.3.
[0088] In one embodiment R.sup.6 is selected from cyclopropyl,
(1,3-dimethyl-H-pyrazol-4-yl)methyl or C.sub.1-4alkyl, wherein said
C.sub.1-4alkyl is optionally substituted by 0-1 substituents
independently selected from OCH.sub.3 or cyclopropyl.
[0089] In a further embodiment R.sup.6 is CH.sub.3.
[0090] In one embodiment R.sup.7 is selected from H, Cl or
CH.sub.3;
[0091] In one embodiment R.sup.8 is selected from
--NH(C.dbd.O)CH.sub.3,
##STR00011##
[0092] In a further embodiment R.sup.8 is
--NH(C.dbd.O)CH.sub.3.
[0093] In one embodiment R.sup.9 is selected from H, Cl or
NH.sub.2;
[0094] In one embodiment R.sup.10 is selected from H or
NH.sub.2;
[0095] In one embodiment R.sup.11 is selected from C(O)NH.sub.2,
C(O)NHCH.sub.3 or C(O)NHCH.sub.2phenyl;
[0096] In one embodiment R.sup.12 is selected from CO.sub.2H,
CO.sub.2CH.sub.2CH.sub.3 or CO.sub.2NH(CH.sub.2).sub.3NH.sub.2;
[0097] In one embodiment R.sup.13 is selected from H or
CH.sub.3;
[0098] There is provided compounds of formula (a) wherein R.sup.1,
R.sup.2 and R.sup.7 are as defined in formula (Ia).
[0099] In one embodiment R.sup.1 is (3,3-dimethylbutan-2-yl) or
C.sub.1-4alkyl, wherein said C.sub.1-4alkyl is optionally
substituted by cyclopropyl and 0, 1, 2 or 3 F.
[0100] In a further embodiment R.sup.1 is C.sub.1-4alkyl.
[0101] In a further embodiment R.sup.1 is iso-propyl or
1-cyclopropylethyl.
[0102] In still a further embodiment R.sup.1 is
1-cyclopropylethyl.
[0103] In still a further embodiment R.sup.1 is
(1S)-1-cyclopropylethyl.
[0104] In one embodiment R.sup.2 is NHR.sup.4 or
SO.sub.2R.sup.5;
[0105] R.sup.4 is C(O)CH.sub.3 or SO.sub.2R.sup.6;
[0106] R.sup.5 is selected from (3-cyanophenyl)sulfamoyl, CH.sub.3,
N(CH.sub.3).sub.2, NH.sub.2, NHCH.sub.2CF.sub.3, NH(oxetan-3-yl),
NHC.sub.1-3alkyl, wherein said C.sub.1-3alkyl is optionally
substituted by 0-3 F and 0-1 substituents independently selected
from OCH.sub.3, cyclopropyl or NHC.sub.3-4cycloalkyl, wherein said
cycloalkyl may be substituted by 0-2 F;
[0107] R.sup.6 is selected from cyclopropyl,
(1,3-dimethyl-1H-pyrazol-4-yl)methyl or C.sub.1-4alkyl, wherein
said C.sub.1-4alkyl is optionally substituted by 0-1 substituents
independently selected from OCH.sub.3 or cyclopropyl.
[0108] In a further embodiment R.sup.2 is NHR.sup.4;
[0109] R.sup.4 is C(O)CH.sub.3 or SO.sub.2R.sup.6;
[0110] R.sup.6 is selected from cyclopropyl,
(1,3-dimethyl-1H-pyrazol-4-yl)methyl or C.sub.1-4alkyl, wherein
said C.sub.1-4alkyl is optionally substituted by 0-1 substituents
independently selected from OCH.sub.3 or cyclopropyl.
[0111] In still a further embodiment R.sup.2 is
SO.sub.2R.sup.5;
[0112] R.sup.5 is selected from (3-cyanophenyl)sulfamoyl, CH.sub.3,
N(CH.sub.3).sub.2, NH.sub.2, NHCH.sub.2CF.sub.3, NH(oxetan-3-yl),
NHC.sub.1-3alkyl, wherein said C.sub.1-3alkyl is optionally
substituted by 0-3 F and 0-1 substituents independently selected
from OCH.sub.3, cyclopropyl or NHC.sub.3-4cycloalkyl, wherein said
cycloalkyl may be substituted by 0-2 F.
[0113] In one embodiment R.sup.7 is selected from H, Cl or
CH.sub.3.
[0114] In a further embodiment R.sup.7 is hydrogen.
[0115] In still a further embodiment R.sup.7 is CH.sub.3.
[0116] In still a further embodiment R.sup.7 is Cl.
[0117] In one embodiment R.sup.4 is C(O)CH.sub.3 or
SO.sub.2R.sup.6; [0118] R.sup.6 is selected from cyclopropyl,
(1,3-dimethyl-1H-pyrazol-4-yl)methyl or C.sub.1-4alkyl, wherein
said C.sub.1-4alkyl is optionally substituted by 0-1 substituents
independently selected from OCH.sub.3 or cyclopropyl.
[0119] In one embodiment R.sup.5 is selected from
(3-cyanophenyl)sulfamoyl, CH.sub.3, NHCH.sub.3, NH.sub.2,
NHCH.sub.2CF.sub.3, NH(oxetan-3-yl), NHC.sub.1-3alkyl, wherein said
C.sub.1-3alkyl is optionally substituted by 0-3 F and 0-1
substituents independently selected from OCH.sub.3, cyclopropyl or
NHC.sub.3-4cycloalkyl, wherein said cycloalkyl may be substituted
by 0-2 F.
[0120] In a further embodiment R.sup.5 is CH.sub.3 or
NHCH.sub.3.
[0121] In one embodiment R.sup.6 is selected from cyclopropyl,
(1,3-dimethyl-H-pyrazol-4-yl)methyl or C.sub.1-4alkyl, wherein said
C.sub.1-4alkyl is optionally substituted by 0-1 substituents
independently selected from OCH.sub.3 or cyclopropyl.
[0122] In a further embodiment R.sup.6 is CH.sub.3.
[0123] One or more above embodiments may be combined to provide
further specific embodiments.
[0124] In one embodiment the compound of formula (I) is selected
from: [0125]
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-(methylsulfonyl)-1-oxo-2,3-dih-
ydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, [0126]
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-(methylsulfonyl)-1-oxo-2,3-dihydro-1H-
-isoindol-5-yl}-1,3-thiazol-2-yl)acetamide, [0127]
N-{4-Methyl-5-[7-(methylsulfonyl)-1-oxo-2-(propan-2-yl)-2,3-dihydro-1H-is-
oindol-5-yl]-1,3-thiazol-2-yl}acetamide, [0128]
N-(5-{2-[(1S)-1-Cyclopropylethyl]-1-oxo-7-sulfamoyl-2,3-dihydro-1H-isoind-
ol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, [0129]
N-(5-{7-(Acetylamino)-2-[(1S)-1-cyclopropylethyl]-1-oxo-2,3-dihydro-1H-is-
oindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, [0130]
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-(methylsulfamoyl)-1-oxo-2,3-dihydro-1-
H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, [0131]
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-(dimethylsulfamoyl)-1-oxo-2,3-dihydro-
-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, [0132]
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-(methylsulfamoyl)-1-oxo-2,3-dihydro-1-
H-isoindol-5-yl}-1,3-thiazol-2-yl)acetamide, [0133]
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-[(methylsulfonyl)amino]-1-oxo-2,3-dih-
ydro-1H-isoindol-5-yl}4-methyl-1,3-thiazol-2-yl)acetamide, [0134]
N-(5-{7-(Cyclobutylsulfamoyl)-2-[(1S)-1-cyclopropylethyl]-1-oxo-2,3-dihyd-
ro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, [0135]
N-{4-Methyl-5-[7-(methylsulfamoyl)-1-oxo-2-(propan-2-yl)-2,3-dihydro-1H-i-
soindol-5-yl]-1,3-thiazol-2-yl}acetamide, [0136]
N-(5-{2-[(1S)-1-Cyclopropylethyl]-1-oxo-7-sulfamoyl-2,3-dihydro-1H-isoind-
ol-5-yl}-1,3-thiazol-2-yl)acetamide, [0137]
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-[(cyclopropylmethyl)sulfamoyl]-1-oxo--
2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide,
[0138]
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-(cyclopropylsulfamoyl)-1-oxo-2,3-dihy-
dro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, [0139]
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-(ethylsulfamoyl)-1-oxo-2,3-dihydro-1H-
-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, [0140]
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-(oxetan-3-ylsulfamoyl)-1-oxo-2,3-dihy-
dro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, [0141]
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-[(3,3-difluorocyclobutyl)sulfamoyl]-1-
-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide,
[0142]
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-[(2-methoxyethyl)sulfamoyl]-1--
oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide,
[0143]
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-({[1-(fluoromethyl)cyclopropyl-
]methyl}sulfamoyl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazo-
l-2-yl)acetamide, [0144]
N-(5-{2-[(1S)-1-Cyclopropylethyl]-1-oxo-7-[(2,2,2-trifluoroethyl)sulfamoy-
l]-2,3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide,
[0145]
N-{4-Methyl-5-[1-oxo-2-(propan-2-yl)-7-sulfamoyl-2,3-dihydro-1H-is-
oindol-5-yl]-1,3-thiazol-2-yl}acetamide, [0146]
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-[(methylsulfonyl)amino]-1-oxo-2,3-dih-
ydro-1H-isoindol-5-yl}-1,3-thiazol-2-yl)acetamide, [0147]
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-[(cyclopropylsulfonyl)amino]-1-oxo-2,-
3-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide,
[0148]
N-(5-{2-[(1S)-1-Cyclopropylethyl]-1-oxo-7-[(propylsulfonyl)amino]-2,3-dih-
ydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, [0149]
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-[(ethylsulfonyl)amino]-1-oxo-2,3-dihy-
dro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, [0150]
N-(5-{7-[(tert-Butylsulfonyl)amino]-2-[(1S)-1-cyclopropylethyl]-1-oxo-2,3-
-dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide,
[0151]
N-[5-(2-[(1S)-1-Cyclopropylethyl]-7-{[(2-methoxyethyl)sulfonyl]amino}-1-o-
xo-2,3-dihydro-1H-isoindol-5-yl)-4-methyl-1,3-thiazol-2-yl]acetamide,
[0152]
N-[5-(2-[(1S)-1-Cyclopropylethyl]-7-{[(cyclopropylmethyl)sulfonyl]-
amino}-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-4-methyl-1,3-thiazol-2-yl]aceta-
mide, [0153]
N-[5-(2-[(1S)-1-Cyclopropylethyl]-7-{[(1,3-dimethyl-1H-pyrazol-4-yl)sulfo-
nyl]amino}-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-4-methyl-1,3-thiazol-2-yl]a-
cetamide, [0154]
N-(4-Chloro-5-{2-[(1S)-1-cyclopropylethyl]-7-(methylsulfamoyl)-1-oxo-2,3--
dihydro-1H-isoindol-5-yl}-1,3-thiazol-2-yl)acetamide, [0155]
6-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-2-[(1S)-1-cyclopropylethyl]-N-methy-
l-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonamide, [0156]
N-{5-[2-(2-Cyclopropylpropan-2-yl)-7-(methylsulfamoyl)-1-oxo-2,3-dihydro--
1H-isoindol-5-yl]4-methyl-1,3-thiazol-2-yl}acetamide, [0157]
N-(5-{2-[(2S)-3,3-Dimethylbutan-2-yl]-7-(methylsulfamoyl)-1-oxo-2,3-dihyd-
ro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, [0158]
N-{5-[2-tert-Butyl-7-(methylsulfamoyl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl-
]-4-methyl-1,3-thiazol-2-yl}acetamide, [0159]
N-(4-Methyl-5-{7-(methylsulfamoyl)-1-oxo-2-[(2S)-1,1,1-trifluoropropan-2--
yl]-2,3-dihydro-1H-isoindol-5-yl}-1,3-thiazol-2-yl)acetamide,
[0160]
N-(5-{7-[(3-Cyanophenyl)sulfamoyl]-2-[(1S)-1-cyclopropylethyl]-1-oxo-2,3--
dihydro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide,
[0161]
N-(5-{7-[(3-Cyanophenyl)sulfamoyl]-1-oxo-2-(propan-2-yl)-2,3-dihydro-1H-i-
soindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide, and
pharmaceutically acceptable salts thereof.
[0162] It shall be noted that any one of these specific compounds
may be disclaimed from any of the herein mentioned embodiments.
[0163] Another embodiment is a product obtainable by any of the
processes or examples disclosed herein.
Pharmacological Properties
[0164] The compounds of formula (I) and their pharmaceutically
acceptable salts have activity as pharmaceuticals, in particular as
inhibitors of phosphatidylinositol 3-kinase gamma activity, and
thus may be used in the treatment of obstructive diseases of the
airways including: asthma, including bronchial, allergic,
intrinsic, extrinsic, exercise-induced, drug-induced (including
aspirin and NSAID-induced) and dust-induced asthma, both
intermittent and persistent and of all severities, and other causes
of airway hyper-responsiveness; chronic obstructive pulmonary
disease (COPD); bronchitis, including infectious and eosinophilic
bronchitis; emphysema; bronchiectasis; cystic fibrosis:
sarcoidosis; alpha-1 antitrypsin deficiency; farmer's lung and
related diseases; hypersensitivity pneumonitis; lung fibrosis,
including cryptogenic fibrosing alveolitis, idiopathic interstitial
pneumonias, fibrosis complicating anti-neoplastic therapy and
chronic infection, including tuberculosis and aspergillosis and
other fungal infections; complications of lung transplantation;
vasculitic and thrombotic disorders of the lung vasculature, and
pulmonary hypertension; antitussive activity including treatment of
chronic cough associated with inflammatory and secretory conditions
of the airways, and iatrogenic cough; acute and chronic rhinitis
including rhinitis medicamentosa, and vasomotor rhinitis; perennial
and seasonal allergic rhinitis including rhinitis nervosa (hay
fever); nasal polyposis: acute viral infection including the common
cold, and infection due to respiratory syncytial virus, influenza,
coronavirus (including SARS) and adenovirus, acute lung injury,
adult respiratory distress syndrome (ARDS), as well as
exacerbations of each of the foregoing respiratory tract disease
states, in particular exacerbations of all types of asthma or
COPD.
[0165] Further, the compounds of formula (I) may be used in the
treatment of CNS related inflammatory disorders, such as MS.
[0166] Further, the compounds of formula (I) may be used in the
treatment of cancer, such as pancreatic intraepithelial neoplasia,
ductal carcinoma and breast cancer.
[0167] Thus, there is provided a compound of formula (I), or a
pharmaceutically acceptable salt thereof, as hereinbefore defined
for use in therapy.
[0168] In a further aspect, there is provided the use of a compound
of formula (I), or a pharmaceutically acceptable salt thereof, as
hereinbefore defined in the manufacture of a medicament for use in
therapy.
[0169] In the context of the present specification, the term
"therapy" also includes "prophylaxis" unless there are specific
indications to the contrary. The terms "therapeutic" and
"therapeutically" should be construed accordingly.
[0170] Prophylaxis is expected to be particularly relevant to the
treatment of persons who have suffered a previous episode of, or
are otherwise considered to be at increased risk of, the disease or
condition in question. Persons at risk of developing a particular
disease or condition generally include those having a family
history of the disease or condition, or those who have been
identified by genetic testing or screening to be particularly
susceptible to developing the disease or condition.
[0171] In particular, the compounds of formula (I), or a
pharmaceutically acceptable salt thereof, (including
pharmaceutically acceptable salts) may be used in the treatment of
asthma {such as bronchial, allergic, intrinsic, extrinsic or dust
asthma, particularly chronic or inveterate asthma (for example late
asthma or airways hyper-responsiveness)}, chronic obstructive
pulmonary disease (COPD) or allergic rhinitis.
[0172] There is also provided a method of treating, or reducing the
risk of, an obstructive airways disease or condition (e.g. asthma
or COPD) which comprises administering to a patient in need thereof
a therapeutically effective amount of a compound of formula (I), or
a pharmaceutically acceptable salt thereof, as hereinbefore
defined.
[0173] In a further aspect, there is provided the use of a compound
of formula (I), or a pharmaceutically acceptable salt thereof, as
hereinbefore defined in the manufacture of a medicament for use in
treating COPD.
[0174] In a further aspect, there is provided the use of a compound
of formula (I), or a pharmaceutically acceptable salt thereof, as
hereinbefore defined in the manufacture of a medicament for use in
treating asthma.
[0175] In a further aspect, there is provided a compound of formula
(I), or a pharmaceutically acceptable salt thereof, as hereinbefore
defined for use in treating COPD.
[0176] In a further aspect, there is provided a compound of formula
(I), or a pharmaceutically acceptable salt thereof, as hereinbefore
defined for use in treating asthma.
[0177] There is also provided a method of treating, or reducing the
risk of, CNS related disorders (e.g. MS) which comprises
administering to a patient in need thereof a therapeutically
effective amount of a compound of formula (I), or a
pharmaceutically acceptable salt thereof, as hereinbefore
defined.
[0178] There is also provided a method of treating, or reducing the
risk of, cancer (e.g. pancreatic intraepithelial neoplasia, ductal
carcinoma and breast cancer) which comprises administering to a
patient in need thereof a therapeutically effective amount of a
compound of formula (I), or a pharmaceutically acceptable salt
thereof, as hereinbefore defined.
Combination Therapy
[0179] The compounds of formula (I), or a pharmaceutically
acceptable salt thereof, may also be administered in conjunction
with other compounds used for the treatment of the above
conditions.
[0180] In another embodiment, there is a combination therapy
wherein a compound of formula (I), or a pharmaceutically acceptable
salt thereof, and a second active ingredient are administered
concurrently, sequentially or in admixture, for the treatment of
one or more of the conditions listed above. Such a combination may
be used in combination with one or more further active
ingredients.
[0181] Another embodiment relates to the combination of a compound
of formula (I), or a pharmaceutically acceptable salt thereof,
together with an anti-inflammatory and/or bronchodilatory
compound.
[0182] Another embodiment relates to the combination of a compound
of formula (I), or a pharmaceutically acceptable salt thereof,
together with a glucocorticoid receptor agonist (steroidal or
non-steroidal).
[0183] Another embodiment still further relates to the combination
of a compound of formula (I), or a pharmaceutically acceptable salt
thereof, together with a selective .beta.2 adrenoceptor
agonist.
[0184] Another embodiment still further relates to the combination
of a compound of formula (I), or a pharmaceutically acceptable salt
thereof, together with a selective inhibitor of PI3K.delta..
[0185] Another embodiment still further relates to the combination
of a compound of formula (I), or a pharmaceutically acceptable salt
thereof, together with an antimuscarinic agent.
[0186] Another embodiment still further relates to the combination
of a compound of formula (I), or a pharmaceutically acceptable salt
thereof, together with a dual .beta.2 adrenoceptor
agonist/antimuscarinic agent.
[0187] Another embodiment still further relates to the combination
of a compound of formula (I), or a pharmaceutically acceptable salt
thereof, together with a p38 antagonist.
[0188] Another embodiment still further relates to the combination
of a compound of formula (I), or a pharmaceutically acceptable salt
thereof, together with a phosphodiesterase (PDE) inhibitor
(including a PDE4 inhibitor or an inhibitor of the isoform
PDE4D).
[0189] In a further aspect there is provided a pharmaceutical
composition (for example, for use as a medicament for the treatment
of one of the diseases or conditions listed herein, such as COPD or
asthma) comprising a compound of formula (I), or a pharmaceutically
acceptable salt thereof, and at least one active ingredient
selected from:
[0190] a) a glucocorticoid receptor agonist (steroidal or
non-steroidal);
[0191] b) a selective .beta.2 adrenoceptor agonist;
[0192] c) a selective inhibitor of PI3K.delta.;
[0193] d) an antimuscarinic agent;
[0194] e) a p38 antagonist; or
[0195] f) a PDE4 antagonist;
[0196] as defined above.
[0197] In one embodiment the compound of formula (I), or a
pharmaceutically acceptable salt thereof, is administered
concurrently or sequentially with one or more further active
ingredients selected from those defined above. For example, the
compound of formula (I), or a pharmaceutically acceptable salt
thereof, may be administered concurrently or sequentially with a
further pharmaceutical composition for use as a medicament for the
treatment of one of the diseases or conditions listed herein, such
as a respiratory tract condition (e.g. COPD or asthma). Said
further pharmaceutical composition may be a medicament which the
patient may already be prescribed (e.g. an existing standard or
care medication), and may itself be a composition comprising one or
more active ingredients selected from those defined above.
Pharmaceutical Compositions
[0198] For the above-mentioned therapeutic uses the dosage
administered will vary with the compound employed, the mode of
administration, the treatment desired and the disorder indicated.
For example, the daily dosage of the compound of formula (I), if
inhaled, may be in the range from 0.05 micrograms per kilogram body
weight (.mu.g/kg) to 100 micrograms per kilogram body weight
(.mu.g/kg). Alternatively, if the compound is administered orally,
then the daily dosage of the compound of formula (I) may be in the
range from 0.01 micrograms per kilogram body weight (.mu.g/kg) to
100 milligrams per kilogram body weight (mg/kg).
[0199] The compounds of formula (I), or pharmaceutically acceptable
salts thereof, may be used on their own but will generally be
administered in the form of a pharmaceutical composition in which
the formula (I) compound/salt (active ingredient) is in association
with a pharmaceutically acceptable adjuvant(s), diluents(s) or
carrier(s). Conventional procedures for the selection and
preparation of suitable pharmaceutical formulations are described
in, for example, "Pharmaceuticals--The Science of Dosage Form
Designs", M. E. Aulton, Churchill Livingstone, 2nd Ed. 2002.
[0200] Depending on the mode of administration, the pharmaceutical
composition will preferably comprise from 0.05 to 99% w (percent by
weight), more preferably from 0.05 to 80% w, still more preferably
from 0.10 to 70% w, and even more preferably from 0.10 to 50% w, of
active ingredient, all percentages by weight being based on total
composition.
[0201] There is also provided a pharmaceutical composition(s)
comprising a compound of formula (I), or a pharmaceutically
acceptable salt thereof, as hereinbefore defined in association
with pharmaceutically acceptable adjuvant(s), diluent(s) or
carrier(s).
[0202] There is also provided a process for the preparation of a
pharmaceutical composition which comprises mixing a compound of
formula (I), or a pharmaceutically acceptable salt thereof, as
hereinbefore defined with pharmaceutically acceptable adjuvant(s),
diluents(s) or carrier(s).
[0203] The pharmaceutical compositions may be administered
topically (e.g. to the skin or to the lung and/or airways) in the
form, e.g., of creams, solutions, suspensions, heptafluoroalkane
(HFA) aerosols and dry powder formulations, for example,
formulations in the inhaler device known as the Turbuhaler.RTM.; or
systemically, e.g. by oral administration in the form of tablets,
capsules, syrups, powders or granules; or by parenteral
administration in the form of a sterile solution, suspension or
emulsion for injection (including intravenous, subcutaneous,
intramuscular, intravascular or infusion); or by rectal
administration in the form of suppositories.
[0204] For oral administration the compound of formula (I) may be
admixed with adjuvant(s), diluent(s) or carrier(s), for example,
lactose, saccharose, sorbitol, mannitol; starch, for example,
potato starch, corn starch or amylopectin; cellulose derivative:
binder, for example, gelatin or polyvinylpyrrolidone; disintegrant,
for example cellulose derivative, and/or lubricant, for example,
magnesium stearate, calcium stearate, polyethylene glycol, wax,
paraffin, and the like, and then compressed into tablets. If coated
tablets are required, the cores, prepared as described above, may
be coated with a suitable polymer dissolved or dispersed in water
or readily volatile organic solvent(s). Alternatively, the tablet
may be coated with a concentrated sugar solution which may contain,
for example, gum arabic, gelatin, talcum and titanium dioxide.
[0205] For the preparation of soft gelatin capsules, the compound
of formula (I) may be admixed with, for example, a vegetable oil or
polyethylene glycol. Hard gelatin capsules may contain granules of
the compound using pharmaceutical excipients like the
above-mentioned excipients for tablets. Also liquid or semisolid
formulations of the compound of formula (I) may be filled into hard
gelatin capsules.
[0206] Liquid preparations for oral application may be in the form
of syrups, solutions or suspensions. Solutions, for example may
contain the compound of formula (I), the balance being sugar and a
mixture of ethanol, water, glycerol and propylene glycol.
Optionally such liquid preparations may contain coloring agents,
flavoring agents, saccharine and/or carboxymethylcellulose as a
thickening agent. Furthermore, other excipients known to those
skilled in art may be used when making formulations for oral
use.
Preparation of Compounds
[0207] It will be appreciated by those skilled in the art that in
the processes certain functional groups such as hydroxyl or amino
groups in the reagents may need to be protected by protecting
groups. Thus, the preparation of the compounds of formula (I) may
involve, at an appropriate stage, the removal of one or more
protecting groups.
[0208] The protection and deprotection of functional groups is
described in `Protective Groups in Organic Synthesis`. 4.sup.th Ed,
T. W. Greene and P. G. M. Wuts, Wiley (2006) and `Protecting
Groups`, 3.sup.rd Ed, P. J. Kocienski, Georg Thieme Verlag
(2005).
[0209] The skilled person will recognize that at any stage of the
preparation of the compounds of formula (I), mixtures of isomers
(e.g. racemates) of compounds may be utilized. At any stage of the
preparation, a single stereoisomer may be obtained by isolating it
from a mixture of isomers (e.g., a racemate) using, for example,
chiral chromatographic separation.
[0210] A further embodiment encompasses pharmaceutically acceptable
salts of the compounds of formula (I).
[0211] A salt of a compound of formula (I) may be advantageous due
to one or more of its chemical or physical properties, such as
stability in differing temperatures and humidities, or a desirable
solubility in H.sub.2O, oil, or other solvent. In some instances, a
salt may be used to aid in the isolation or purification of the
compound. In some embodiments (particularly where the salt is
intended for administration to an animal, e.g. a human, or is a
reagent for use in making a compound or salt intended for
administration to an animal), the salt is pharmaceutically
acceptable.
[0212] Where the compound is sufficiently acidic, pharmaceutically
acceptable salts include, but are not limited to, an alkali metal
salt, e.g. Na or K, an alkali earth metal salt, e.g. Ca or Mg, or
an organic amine salt. Where the compound is sufficiently basic,
pharmaceutically acceptable salts include, but are not limited to,
inorganic or organic acid addition salts.
[0213] There may be more than one cation or anion depending on the
number of charged functions and the valency of the cations or
anions.
[0214] For reviews on suitable salts, see Berge et al. J. Pharm.
Sci., 1977, 66, 1-19 or "Handbook of Pharmaceutical Salts:
Properties, selection and use", P. H. Stahl, P. G. Vermuth, IUPAC,
Wiley-VCH, 2002.
[0215] In a salt proton transfer occurs between the compound of
formula (I) and the counter ion of the salt. However, in some cases
proton transfer may not be complete and the solid is not therefore
a true salt. In such cases the compound of formula (I) and the
"co-former" molecules in the solid primarily interact through
non-ionic forces such as hydrogen bonding. It is accepted that the
proton transfer is in fact a continuum, and can change with
temperature, and therefore the point at which a salt is better
described as a co-crystal can be somewhat subjective.
[0216] Where an acid or base co-former is a solid at ambient
temperature and there is no or only partial proton transfer between
the compound of formula (I) and such an acid or base co-former, a
co-crystal of the co-former and compound of formula (I) may result
rather than a salt. All such co-crystal forms of the compound of
formula (I) are encompassed.
[0217] The compounds of formula (I) may form mixtures of its salt
and co-crystal forms. It is also to be understood that
salt/co-crystal mixtures of the compound of formula (I) are
encompassed
[0218] Salts and co-crystals may be characterized using well known
techniques, for example X-ray powder diffraction, single crystal
X-ray diffraction (for example to evaluate proton position, bond
lengths or bond angles), solid state NMR, (to evaluate for example,
C, N or P chemical shifts) or spectroscopic techniques (to measure
for example, O--H, N--H or COOH signals and IR peak shifts
resulting from hydrogen bonding).
[0219] It is also to be understood that certain compounds of
formula (I) may exist in solvated form, e.g. hydrates, including
solvates of a pharmaceutically acceptable salt of a compound of
formula (I).
[0220] In a further embodiment, certain compounds of formula (I)
may exist as racemates and racemic mixtures, single enantiomers,
individual diastereomers and diastereomeric mixtures. It is to be
understood that all such isomeric forms are encompassed. Certain
compounds of formula (I) may also contain linkages (e.g.
carbon-carbon bonds, carbon-nitrogen bonds such as amide bonds)
wherein bond rotation is restricted about that particular linkage,
e.g. restriction resulting from the presence of a ring bond or
double bond. Accordingly, it is to be understood that all such
isomers are encompassed. Certain compound of formula (I) may also
contain multiple tautomeric forms. It is to be understood that all
such tautomeric forms are encompassed. Stereoisomers may be
separated using conventional techniques, e.g. chromatography or
fractional crystallization, or the stereoisomers may be made by
stereoselective synthesis.
[0221] In a further embodiment, the compounds of formula (I)
encompass any isotopically-labeled (or "radio-labelled")
derivatives of a compound of formula (I). Such a derivative is a
derivative of a compound of formula (I) wherein one or more atoms
are replaced by an atom having an atomic mass or mass number
different from the atomic mass or mass number typically found in
nature. Examples of radionuclides that may be incorporated include
.sup.2H (also written as "D" for deuterium).
[0222] In a further embodiment, the compounds of formula (I) may be
administered in the form of a prodrug which is broken down in the
human or animal body to give a compound of the formula (I).
Examples of prodrugs include in vivo hydrolysable esters of a
compound of the formula (I).
[0223] An in vivo hydrolysable (or cleavable) ester of a compound
of the formula (I) that contains a carboxy or a hydroxy group is,
for example, a pharmaceutically acceptable ester which is
hydrolyzed in the human or animal body to produce the parent acid
or alcohol. For examples of ester prodrugs derivatives, see: Curr.
Drug. Metab. 2003, 4, 461.
[0224] Various other forms of prodrugs are known in the art. For
examples of prodrug derivatives, see: Nature Reviews Drug Discovery
2008, 7, 255 and references cited therein.
EXAMPLES
[0225] The disclosure will now be further explained by reference to
the following non limiting examples.
(i) Unless stated otherwise, .sup.1H NMR spectra were recorded on
Bruker Avance, Avance II or Avance III spectrometers operating at a
field strength of 300, 400, 500 or 600 MHz. Either the central
peaks of chloroform-d (CDCl.sub.3; .delta..sub.H 7.27 ppm),
dimethylsulfoxide-d.sub.6 (DMSO-d.sub.6; .delta..sub.H 2.50 ppm) or
methanol-d.sub.4 (CD.sub.3OD: .delta..sub.H 3.31 ppm) were used as
internal references. (ii) LCMS was run in two set ups: 1) (basic)
BEH C18 column (1.7 .mu.m 2.1.times.50 mm) in combination with a
gradient (2-95% B in 5 minutes) of aqueous 46 mM ammonium
carbonate/ammonia buffer at pH 10 (A) and MeCN (B) at a flow rate
of 1.0 mL/min or 2) (acid) in combination with a gradient (5-95% B
in 2 minutes) of water and TFA (0.05%) (A) and MeCN and TFA (0.05%)
at a flow rate of 1.0 mL/min (B). (iii) Preparative HPLC was
performed with a Waters FractionLynx system with integrated MS
detection and equipped with Prep C18 OBD 5 .mu.m 19.times.150 mm
columns from X-Bridge or Sunfire. Alternatively Gilson GX-281 with
intergrated UV detection was used, equipped with either Kromasil C8
10 .mu.m, 20.times.250 ID or 50.times.250 ID mm. As eluent (acidic)
gradients of water/MeCN/acetic acid (95/5/0.1) or water/0.05% TFA
(A) and MeCN/0.05% TFA (B) or (basic) McCN or MeOH (A) and 0.03%
ammonia in water or 0.03% NH.sub.4HCO.sub.3 (B) were applied. (iv)
Preparative SFC was performed with a Waters Prep100 SFC system with
integrated MS detection, equipped with Waters Viridis 2-EP or
Phenomenex Luna Hilic, 30.times.250 mm. 5 .mu.m. As eluent
gradients of CO.sub.2 (100 g/min, 120 bar, 40.degree. C.) (A) and
MeOH/NH.sub.3 (20 mM) or MeOH (5% formic acid) or MeOH (B) were
applied. (v) The title and sub-title compounds of the examples and
preparations were named using the IUPAC name program ACD/Name 2014
from Acdlabs. (vi) Unless stated otherwise, starting materials were
commercially available, and all solvents and commercial reagents
were of laboratory grade and used as received. Unless stated
otherwise, operations were carried out at ambient temperature, i.e.
in the range between 17-28.degree. C. and, where appropriate, under
an atmosphere of an inert gas such as nitrogen. (vii) The X-ray
diffraction analysis was performed according to standard methods,
which can be found in e.g. Kitaigorodsky, A. I. (1973), Molecular
Crystals and Molecules, Academic Press, New York; Bunn, C. W.
(1948), Chemical Crystallography, Clarendon Press, London; or Klug,
H. P. & Alexander, L. E. (1974), X-ray Diffraction Procedures,
John Wiley & Sons, New York. Samples were mounted on single
silicon crystal (SSC) wafer mounts and powder X-ray diffraction was
recorded with a PANalytical X'Pert PRO (reflection geometry,
wavelength of X-rays 1.5418 .ANG. nickel-filtered Cu radiation,
Voltage 45 kV, filament emission 40 mA). Automatic variable
divergence and anti scatter slits were used and the samples were
rotated during measurement. Samples were scanned from 2-50.degree.
2Theta or 2-40.degree. 2Theta using a 0.013.degree. step width and
between 44 and 233 seconds count time using a PIXCEL detector
(active length 3.35.degree. 2Theta).
[0226] It is known in the art that an X-ray powder diffraction
pattern may be obtained which has one or more measurement errors
depending on measurement conditions (such as equipment, sample
preparation or machine used). In particular, it is generally known
that intensities in an X-ray powder diffraction pattern may
fluctuate depending on measurement conditions and sample
preparation. For example, persons skilled in the art of X-ray
powder diffraction will realise that the relative intensities of
peaks may vary according to the orientation of the sample under
test and on the type and setting of the instrument used. The
skilled person will also realise that the position of reflections
can be affected by the precise height at which the sample sits in
the diffractometer and the zero calibration of the diffractometer.
The surface planarity of the sample may also have a small effect.
Hence a person skilled in the art will appreciate that the
diffraction pattern data presented herein is not to be construed as
absolute and any crystalline form that provides a power diffraction
pattern substantially identical to those disclosed herein fall
within the scope of the present disclosure (for further information
see Jenkins, R & Snyder, R. L. `Introduction to X-Ray Powder
Diffractometry` John Wiley & Sons, 1996). Generally, a
measurement error of a diffraction angle in an X-ray powder
diffractogram may be approximately plus or minus 0.2.degree.
2-theta, and such a degree of a measurement error should be taken
into account when considering the X-ray powder diffraction data.
Furthermore, it should be understood that intensities might
fluctuate depending on experimental conditions and sample
preparation (e.g. preferred orientation). The following definitions
have been used for the relative intensity (%): 81-100%, vs (very
strong); 41-80%, str (strong); 21-40%, med (medium); 10-20%, w
(weak); 1-9%, vw (very weak).
[0227] The following abbreviations are used:
TABLE-US-00001 AcOH Acetic acid Aq Aqueous CDCl.sub.3 Chloroform-d
CV Column volumes DCM Dichloromethane DMF N,N-Dimethylformamide
DMSO Dimethyl sulfoxide dppf 1,1'-Bis(diphenylphosphino)ferrocene
EtOAc Ethyl acetate eq Equivalents FA Formic acid g Gram(s) h
Hour(s) HPLC High performance liquid chromatography L Litre(s) LC
Liquid chromatography m-CPBA 3-Chloroperoxybenzoic acid MeCN
Acetonitrile MeOH Methanol min Minute(s) mL Millilitre(s) nm Nano
meter rt Room temperature sat Saturated TFA Trifluoroacetic acid
t.sub.R Retention time
PREPARATION OF INTERMEDIATES
Intermediate 1 (Method A)
5-Bromo-7-chloro-2-[(1S)-1-cyclopropylethyl]-2,3-dihydro-1H-isoindol-1-one
[0228] (S)-1-Cyclopropylethanamine (2.43 mL, 22.8 mmol) was added
to methyl 4-bromo-2-(bromomethyl)-6-chlorobenzoate (7.8 g, 22.8
mmol) in MeCN (80 mL). Boric acid (1.41 g, 22.8 mmol) was added in
one portion as a dry solid, followed by potassium carbonate (6.3 g,
45.6 mmol) which was added portionwise over 2 min. The mixture was
allowed to stir at t overnight. The inorganics were filtered off,
washed with MeCN. The combined MeCN filtrates was concentrated to
yield 8.3 g of a brown oil. The residue was purified by automated
flash chromatography on a Biotage.RTM. KP-SIL 340 g column. A
gradient from 5 to 30% of EtOAc in heptane over 12 CV. The product
was collected using the wavelength 254 nm. Pure fractions were
evaporated to give the title compound as a pink solid (2.4 g,
34%).
[0229] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. 0.33-0.51 (m, 3H),
0.57-0.69 (m, 1H), 0.94-1.05 (m, 1H), 1.34 (d, 3H), 3.67-3.81 (m,
1H), 4.37 (d, 1H), 4.48 (d, 1H), 7.5-7.55 (m, 1H), 7.58 (s,
1H).
Intermediate 2 (Method B)
N-(5-(7-Chloro-2-[(1S)-1-cyclopropylethyl]-1-oxo-2,3-dihydro-1H-isoindol-5-
-yl)-4-methyl-1,3-thiazol-2-yl)acetamide
[0230] Cs.sub.2CO.sub.3 (37.3 g, 114.4 mmol) was added to
5-bromo-7-chloro-2-[(S)-1-cyclopropylethyl]-2,3-dihydro-1H-isoindol-1-one
(Intermediate 1, 18 g, 57.2 mmol),
N-(4-methyl-1,3-thiazol-2-yl)acetamide (10.72 g, 68.66 mmol),
tri-tert-butylphosphonium tetrafluoroborate (3.32 g, 11.44 mmol)
and PdOAc.sub.2 (1.28 g, 5.7 mmol) in DMF (300 mL). The resulting
mixture was stirred at 100.degree. C. for 2 h and then cooled to
rt. The mixture was filtered through a Celite pad. The solvent was
removed under reduced pressure. The crude product was purified by
flash silica chromatography, elution gradient 0 to 25% MeOH in DCM.
Pure fractions were evaporated to dryness to afford the title
compound (14 g, 63%) as a yellow solid. .sup.1H-NMR (500 MHz,
DMSO-d.sub.6) .delta. 0.2-0.27 (m, 1H), 0.40 (ddd, 2H), 0.52-0.61
(m, 1H), 1.12 (qt, 1H), 1.28 (d, 3H), 2.16 (s, 3H), 2.40 (s, 3H),
3.32 (s, 2H), 3.5-3.63 (m, 1H), 7.50 (d, 1H), 7.64 (s, 1H), 12.23
(s, 1H). m/z (ES+), [M+H].sup.+=390; acid, HPLC t.sub.R=2.031
min.
Intermediate 3 (Method C)
N-(5-{7-(Benzylsulfanyl)-2-[(1S)-1-cyclopropylethyl]-1-oxo-2,3-dihydro-1H--
isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide
[0231] In a 50 mL round-bottomed flask was added
N-(5-{7-chloro-2-[(1S)-1-cyclopropylethyl]-1-oxo-2,3-dihydro-1H-isoindol--
5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide (Intermediate 2, 20 g,
51.3 mmol), phenylmethanethiol (12.74 g, 102.59 mmol), and sodium
2-methylbutan-2-olate (11.30 g, 102.59 mmol) in DMF (500 mL) to
give a orange suspension. The reaction mixture was stirred for a 2
h at 110.degree. C. The reaction mixture was filtered through
celite. The solvent was removed under reduced pressure. The crude
product was purified by flash silica chromatography, elution
gradient 0 to 25% EtOAc in DCM. Pure fractions were evaporated to
dryness to afford the title compound (18 g, 73%) as a yellow solid.
m/z (ES+), [M+H].sup.+=478; acid, HPLC t.sub.R=1.177 min.
[0232] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 0.12-0.27 (m,
1H), 0.38 (dtt, 2H), 0.5-0.64 (m, 1H), 1.01-1.14 (m, 1H), 1.26 (d,
3H), 2.15 (s, 3H), 2.24 (s, 3H), 3.43-3.59 (m, 1H), 4.35 (s, 2H),
4.52 (s, 2H), 7.27 (d, 2H), 7.34 (qd, 3H), 7.48 (d, 2H), 12.16 (s,
1H). m/z (ES+), [M+H].sup.+=478; acid, HPLC t.sub.R=1.177 min.
Intermediate 4 (Method D)
6-[2-(Acetylamino)-4-methyl-1,3-thiazol-5-yl]-2-[(1S)-1-cyclopropylethyl]--
3-oxo-2,3-dihydro-H-Isoindole-4-sulfonyl chloride
[0233] Sulfuryl chloride 8.48 g, 62.81 mmol) was added portionwise
to
N-(5-{7-(benzylsulfanyl)-2-[(1S)-1-cyclopropylethyl]-1-oxo-2,3-dihydro-1H-
-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide (Intermediate
3, 10 g, 20.9 mmol) in acetic acid (60 mL), MeCN (400 mL), and
water (4 mL) at 0.degree. C. The resulting mixture was stirred at
5.degree. C. for 1 h. The solvent was removed under reduced
pressure. The reaction mixture was diluted with DCM (500 mL) and
washed sequentially with saturated NaHCO.sub.3 (100 mL) and
saturated brine (200 mL). The organic layer was dried over
Na.sub.2SO.sub.4, filtered and evaporated. The residue was
suspended in diethyl ether and the solid was collected by
filtration. the solid was dried in vacuum to afford the title
compound (8 g, 84%). m/z (ES+), [M+H].sup.+=454; acid, HPLC
t.sub.R=1.541 min
[0234] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 0.28 (dt, 1H),
0.43 (ddp, 2H), 0.52-0.64 (m, 1H), 1.16 (ddq, 1H), 1.31 (d, 3H),
2.17 (s, 3H), 2.41 (s, 3H), 3.60 (dt, 1H), 4.70 (s, 2H), 7.76 (s,
1H), 7.90 (d, 1H), 12.26 (s, 1H). m/z (ES+), [M+H].sup.+=454; acid,
HPLC t.sub.R=1.541 min
Intermediates 5-24
[0235] The following compounds were prepared using the
aforementioned methods and intermediates
TABLE-US-00002 Intermediate 5
5-Bromo-7-chloro-2-(propan-2-yl)-2,3-dihydro-1H-isoindol-1-one
Prepared using Method A Amine: Commercial Intermediate: Commercial
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.28 (d, 6H), 4.27 (s,
2H), 4.63 (ddd, IH), 7.49 (s, 1H), 7.55 (s, 1H). m/z (ES+), [M +
H].sup.+ = 288; acid, HPLC t.sub.R = 1.484 min Intermediate 6
5-Bromo-7-chlloro-2-(2-cyclopropylpropan-2-yl)-2,3-dihydro-1H-isoindol-1-o-
ne Prepared using Method A Amine: Commercial Intermediate:
Commercial .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 0.47-0.53 (2H,
m), 0.58 (2H, ddd), 1.39-1.48 (1H, m), 1.48 (6H, s), 4.51-4.58 (2H,
m), 7.46-7.53 (1H, in), 7.57 (1H, d). m/z (ES+), [M + H].sup.+ =
330.2, acid, HPLC t.sub.R = 1.06 Intermediate 7
5-Bromo-7-chloro-2-[(2S)-3,3-dimethylbutan-2-yl]-2,3-dihydro-1H-isoindol-1-
-one Prepared using Method A Amine: Commercial Intermediate:
Commercial .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. 1.00 (s, 9H),
1.24 (d, 3H), 4.36 (q, 1H), 4.36-4.42 (ABq, 2H), 7.44-7.52 m, 1H),
7.52-7.61 (m, 1H). Intermediate 8
5-Bromo-2-tert-butyl-7-chloro-2,3-dihydro-1H-isoindol-1-one
Prepared using Method A Amine: Commercial Intermediate: Commercial
.sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 1.46 (s, 9H), 4.54 (s,
2H), 7.72 (s, 1H), 7.79 (s, 1H). m/z (ES+), [M + H].sup.+ = 303.9,
acid, HPLC t.sub.R = 1.63 Intermediate 9
5-Bromo-7-chloro-2-[(2S)-1,1,1-trifluoropropan-2-yl]-2,3-dihydro-1H-isoind-
ol-1-one Prepared using Method A Amine: Commercial Intermediate;
Commercial .sup.1H NMR (500 MHz, DMSO-d6) .delta. 1.47 (d, 3H),
4,42 (d, 1H), 4.62 (d, 1H), 5.02 (hept, 1H), 7.82-7.84 (m, 1H),
7.86-7.88 (m, 1H). m/z (ES+), [M + H].sup.+ = 344; acid, HPLC
t.sub.R =1.150 min Intermediate 10
N-(5-(7-Chloro-2-isopropyl-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)acet-
amide Prepared using Method B Intermediate: 5 .sup.1H-NMR (500 MHz,
DMSO-d.sub.6) .delta. 1.23 (d, 6H), 2.16 (s, 3H), 2.39 (s, 3H),
4.39 (hept, 1H), 4.45 (s, 2H), 7.49 (d, 1H), 7.62 (d, 1H), 12.22
(s, 1H). m/z (ES+), [M + H].sup.+ = 364.2; acid, HPLC t.sub.R =
1.379 min Intermediate 11
N-{5-[7-Chloro-2-(2-cyclopropylpropan-2-yl)-1-oxo-2,3-dihydro-1H-isoindol--
5-yl]-4- methyl-1,3-thiazol-2-yl}acetamide Prepared using Method B
Intermediate: 6 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
0.40-0.53 (m, 4H), 1.38 (s, 6H), 1.48-1.52 (m, 1H), 2.16 (s, 3H),
2.39 (s, 3H), 4.68 (s, 2H), 7.47 (d, 1H), 7.60 (d, 1H), 12.26 (s,
1H). m/z (ES+), [M + H].sup.+ = 404.3; acid, HPLC t.sub.R = 0.917
min Intermediate 12
N-(5-{7-Chloro-2-[(2S)-3,3-dimethylbutan-2-yl]-1-oxo-2,3-dihydro-1H-isoind-
ol-5-yl}- 4-methyl-1,3-thiazol-2-yl)acetamide Prepared using Method
B Intermediate: 7 .sup.1H-NMR (500 MHz, DMSO-d.sub.6) .delta. 0.95
(s, 9H), 1.21 (d, 3H), 2.16 (s, 3H), 2.40 (s, 3H), 4.17 (q, 1H),
4.54 (s, 2H), 7.50 (s, 1H), 7.61 (s, 1H), 12.23 (s, 1H). m/z (ES+),
[M + H].sup.+ = 406.2; acid , HPLC t.sub.R = 1.27 min. Intermediate
13
N-[5-(2-tert-Butyl-7-chloro-1-oxo-2,3-dihydro-4H-isoindol-5-yl)-4-methyl-1-
,3-thiazol- 2-yl]acetamide Prepared using Method B Intermediate: 8
.sup.1H-NMR(300 MHz, DMSO-d.sub.6) .delta. 1.24 (d, 1H), 1.49 (s,
9H), 2.15 (s, 3H), 2.38 (s. 3H), 4.60 (s, 2H), 7.47 (d, 1H), 7.59
(d, 1H), 12.23 (s, 1H). m/z (ES+), [M + H].sup.+ = 378; acid, HPLC
t.sub.R = 1.447 min Intermediate 14
N-(5-{7-Chloro-1-oxo-2-[(2S)-1,1,1-trifluoropropan-2-yl]-2,3-dihydro-1H-is-
oindol-5- yl}-4-methyl-1,3-thiazol-2-yl)aeetamide Prepared using
Method B Intermediate: 9 .sup.1H-NMR (500 MHz, DMSO-d.sub.6)
.delta. 1,48 (d, 3H), 2.16 (s, 3H), 2.41 (s, 3H), 4.47 (d, 1H),
4.67 (d, 1H), 5.01-5.07 (m, 1H), 7.57 (s, 1H), 7.68 (s, 1H), 12.24
(s, 1H). m/z (ES+), [M + H].sup.+ = 418; acid, HPLC t.sub.R = 1.18
min Intermediate 15
N-(5-(7-(Benzyithio)-2-isopropyl-1-oxoisoindolin-5-yl)-4-methylthiazol-2-
yl)acetamide Prepared using Method C Intermediate: 10 .sup.1H-NMR
(500 MHz, DMSO-d.sub.6) .delta. 1.21 (d, 6H), 2.15 (s, 3H), 2.23
(s, 3H), 4.33-4.38 (m, 3H), 4.40 (s, 2H), 7.23-7.29 (m, 2H),
7.31-7.39 (m, 3H), 7.46-7.52 (m, 2H), 12.16 (s, 1H). m/z (ES+), [M
+ H].sup.+ = 452.3, acid, HPLC t.sub.R = 1.097 min Intermediate 16
N-{5-[7-(Benzylsulfanyl)-2-(2-cyclopropylpropan-2-yl)-1-oxo-2,3-dihydro-1H-
- isoindol-5-yl]-4-methyl-1,3-thiazol-2-yl}acetamide Prepared using
Method C Intermediate: 11 m/z (ES+), [M + H].sup.+ = 492.4; acid,
HPLC t.sub.R = 1.243 min Intermediate 17
N-[5-[7-Benzylsulfanyl-1-oxo-2-[(1S)-1,2,2-trimethylpropyl]isoindolin-5-yl-
]-4-methyl- thiazol-2-yl]acetamide Prepared using Method C
Intermediate: 12 .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. 1.01 (s,
9H), 1.25 (d, 3H), 2.22 (s, 3H), 2.27 (s, 3H), 4.26 (s, 2H), 4.36
(q, 1H), 4.38-4.49 (ABq, 2H), 7.16 (s, 1H), 7.20 (s, 1H), 7.24 (dd,
1H), 7.31 (t, 2H), 7.44-7.49 (m, 2H). m/z (ES+), [M + H].sup.+ =
494.4; acid, HPLC t.sub.R = 2.47 min Intermediate 18
N-[5-(7-Benzylsulfanyl-2-tert-butyl-1-oxo-isoindolin-5-yl)-4-methyl-thiazo-
l-2- yl]acetamide Prepared using Method C Intermediate: 13
.sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 0.73-0.94 (m, 4H),
0.97-1.20 (m, 3H), 1.26 (t, 2H), 1.34-1.57 (m, 20H), 2.15 (s, 6H),
2.23 (s, 5H), 2.38 (d, 1H), 4.32 (s, 4H), 4.55 (s, 4H), 7.17-7.41
(m, 9H), 7.43-7.53 (m, 4H), 12.18 (d, 2H). m/z, (ES+), [M +
H].sup.+ = 466; acid, HPLC t.sub.R = 1.582 min. Intermediate 19
N-(5-{7-(Benzylsulfanyl)-1-oxo-2-[(2S)-1,1,1-trifluoro-2-propanyl]-2,3-dih-
ydro-1H- isoindol-5-yl}-1-methyl-1,3-thiazol-2-yl)acetamide
Prepared using Method C Intermediate: 14 .sup.1H-NMR (500 MHz,
DMSO-d.sub.6) .delta. 1.46 (d, 3H), 2.16 (s, 3H), 2.25 (s, 3H),
4.27-4.5 (m, 3H), 4.63 (d, 1H), 4.95-5.01 (m, 1H), 7.21-7.42 (m,
5H), 7.49 (d, 2H), 12.18 (s, 1H). m/z (ES+), [M + H].sup.+ = 506,1;
acid, HPLC t.sub.R = 1.35 min Intermediate 20
6-(2-Acetamido-4-methylthiazol-5-yl)-2-isopropyl-3-oxoisoindoline-4-sulfon-
yl chloride Prepared using Method D Intermediate: 15 .sup.1H-NMR
(500 MHz, DMSO-d.sub.6) .delta. 1.26 (d, 6H), 2.16 (s, 3H), 2.41
(s, 3H), 4.43 (hept, 1H), 4.56 (s, 2H), 7.73 (d, 1H), 7.90 (d, 1H),
12.24 (s, 1H). m/z (ES+), [M + H].sup.+ = 428.2, acid, HPLC t.sub.R
= 1.71 min Intermediate 21
6-(2-Acetamido-4-methyl-thiazol-5-yl)-2-(1-cyclopropyl-1-methyl-ethyl)-3-o-
xo- isoindoline-4-sulfonyl chloride Prepared using Method D
Intermediate: 16 m/z (ES+), [M + H].sup.+ = 468.3, acid, HPLC
t.sub.R = 0.915 min Intermediate 22
6-(2-Acetamido-4-methyl-thiazol-5-yl)-3-oxo-2-[(1S)-1,2,2-
trimethylpropyl]isoindoline-4-sulfonyl chloride Prepared using
Method D Intermediate: 17 m/z (ES+), [M + H].sup.+ = 470.2; acid;
HPLC t.sub.R = 1.31 min Intermediate 23
6-(2-Acetamido-4-methyl-thiazol-5-yl)-2-tert-butyl-3-oxo-isoindoline-4-sul-
fonyl chloride Prepared using Method D Amine: Commercial
Intermediate: 18 m/z (ES+), [M + H].sup.+ = 442.0 acid, HPLC
t.sub.R = 1.478 min Intermediate 24
6-[2-(Acetylamino)-4-methyl-1,3-thiazol-5-yl]-3-oxo-2-[(2S)-1,1,1-trifluor-
opropan-2- yl]-2,3-dihydro-1H-isoindole-4-sulfonyl chloride
Prepared using Method D Intermediate: 19 .sup.1H-NMR (500 MHz,
CD.sub.2Cl.sub.2) .delta. 1.60 (d, 3H), 2.42 (s, 3H), 2.57 (s, 3H),
4.67 (s, 2H), 5.20 (hept, 1H), 7.88-7.98 (m, 1H), 8.25 (d, 1H). m/z
(ES+), [M + H].sup.+ = 482.0; acid, HPLC t.sub.R = 1.20 min
Intermediate 25
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-(methylsulfanyl)-1-oxo-2,3-dihydro-1H--
isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide
[0236] Sodium methanethiolate (90 mg, 1.28 mmol) was added to a
slurry of
N-(5-{7-chloro-2-[(1S)-1-cyclopropylethyl]-1-oxo-2,3-dihydro-1H-isoindol--
5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide (Intermediate 2, 250 mg,
0.64 mmol) in dry DMF (5 mL). The vial was capped and inserted into
a aluminium block at 100.degree. C. The reaction was stirred over
night. After 16 h, starting material was still present in the
reaction, and more sodium methanethiolate (200 mg, 2.85 mmol) was
added. The reaction was heated to 100.degree. C. for another 6 h.
The reaction was cooled down and diluted with water. The formed
solids were filtered off, washed with water and dried to give the
title compound (142 mg, 55%) as a solid. .sup.1H-NMR (600 MHz,
DMSO-d.sub.6) .delta. 0.19-0.25 (m, 1H), 0.33-0.43 (m, 2H),
0.53-0.6 (m, 1H), 1.06-1.14 (m, 1H), 1.26 (d, 3H), 2.15 (s, 3H),
2.40 (s, 3H), 2.48 (s, 3H), 3.47-3.57 (m, 1H), 4.54 (s, 2H), 7.18
(s, 1H), 7.36 (s, 111), 12.19 (s, 1H). ES (M+H).sup.+=402.1, base,
HPLC t.sub.R=1.64 min
Intermediate 26
5-Bromo-2-[(1S)-1-cyclopropylethyl]-7-(methylsulfanyl)-2,3-dihydro-1H-isoi-
ndol-1-one
[0237]
5-Bromo-7-chloro-2-[(1S)-1-cyclopropylethyl]-2,3-dihydro-1H-isoindo-
l-1-one (Intermediate 1, 5.08 g, 16.15 mmol), sodium
methanethiolate (3.38 g, 48.22 mmol) and 1,4-dioxane (60 mL) were
placed in a one necked 100 mL flask flushed with inert atmosphere
and heated at 120.degree. C. for 5.5 h. Subsequently was the
reaction mixture was filtered through celite which was washed with
ethylacetate. The organic solvent was washed twice with water,
brine, dried over sodiumsulfate filtered and concentrated in vacuum
to give a yellow solid. To the solid was added diethyl ether and
the mixture was stirred. The solid was collected by suction
filtration. The solid was washed three times with diethyl ether and
air dried to give the title product (4.95 g, 94%) as a white solid.
.sup.1H-NMR (500 MHz, DMSO-d.sub.6) .delta. 0.20 (tt, 1H),
0.31-0.43 (m, 2H), 0.51-0.59 (m, 1H), 1.04-1.12 (m, 1H), 1.24 (d,
3H), 2.46 (s, 3H), 3.45-3.54 (m, 1H), 4.49 (s, 2H), 7.32 (s, 1H),
7.51-7.55 (m, 1H).
Intermediate 27
5-Bromo-2-[(1S)-1-cyclopropylethyl]-7-(methylsulfonyl)-2,3-dihydro-1H-isoi-
ndol-1-one
[0238] m-CPBA (4.62 g, 26.79 mmol) was added to
5-bromo-2-[(S)-1-cyclopropylethyl]-7-(methylsulfanyl)-2,3-dihydro-1H-isoi-
ndol-1-one (Intermediate 26, 3.8 g, 11.65 mmol) in DCM (50 mL)
under nitrogen and the resulting mixture was stirred at rt for 2 h.
The reaction mixture was diluted with DCM (200 mL), and washed
sequentially with saturated NaHCO.sub.3 (2.times.150 mL), and
saturated brine (150 mL). The organic layer was dried over
Na.sub.2SO.sub.4, filtered and evaporated to afford the crude
product. The crude product was purified by flash silica
chromatography, elution gradient 0 to 5% MeOH in DCM. Pure
fractions were evaporated to dryness to afford the title compound
(3.1 g, 74%) as a yellow solid. .sup.1H-NMR (500 MHz, DMSO-d.sub.6)
.delta. 0.21-0.3 (m, 1H), 0.36-0.48 (m, 2H), 0.55-0.63 (m, 1H),
1.10-1.18 (m, 1H), 1.29 (d, 3H), 3.55-3.61 (m, 1H), 3.62 (s, 3H),
4.66 (s, 2H), 8.05 (d, 1H), 8.24-8.29 (m, 1H). ES
(M+H).sup.+=360.1, acid, HPLC t.sub.R=0.81 min
Intermediate 28
5-Bromo-7-chloro-2-(propan-2-yl)-2,3-dihydro-1H-isoindol-1-one
[0239] Propan-2-amine (3.28 g, 55.49 mmol) was added dropwise to
methyl 4-bromo-2-(bromomethyl)-6-chlorobenzoate (19 g, 55.49 mmol)
in dioxane (200 mL) at 25.degree. C. over a period of 30 min under
nitrogen. The resulting solution was stirred at 100.degree. C. for
12 h. The solvent was removed under reduced pressure. The crude
product was purified by flash silica chromatography, elution
gradient 30 to 50% EtOAc in petroleum ether. Pure fractions were
evaporated to dryness to afford the title compound (7 g, 44%) as a
solid. .sup.1H-NMR (500 MHz, DMSO-d.sub.6) .delta. 1.21 (d, 6H),
4.37 (hept, 1H), 4.40 (s, 2H), 7.72-7.74 (m, 1H), 7.8-7.82 (m, 1H).
m/z (ES+), [M+H].sup.+=288; acid, HPLC t.sub.R=1.484 min
Intermediate 29
5-Bromo-7-(methylsulfanyl)-2-(propan-2-yl)-2,3-dihydro-1H-isoindol-1-one
[0240] Into a 100-mL round-bottom flask, was placed
5-bromo-7-chloro-2-(propan-2-yl)-2,3-dihydro-1H-isoindol-1-one
(Intermediate 28, 1 g, 3.47 mmol, 1.00 equiv), MeSNa (610 mg, 8.7
mmol, 4 equiv) and anhydrous 1,4-dioxane (10 mL). The resulting
solution was stirred for 6 h at 110.degree. C. in an oil bath. The
reaction mixture was cooled. Water was added to this solution. The
resulting solution was extracted with DCM and the organic layers
combined and dried over anhydrous sodium sulfate and concentrated
under vacuum. This gave the title compound (800 mg, 77%) as a
solid. .sup.1H-NMR (500 MHz, DMSO-d.sub.6) .delta. 1.19 (d, 6H),
2.46 (s, 3H), 4.32 (hept, 1H), 4.38 (s, 2H), 7.30 (s, 1H),
7.49-7.53 (m, 1H). m/z (ES+) [M+H].sup.+=300 and 302, acid, HPLC
t.sub.R=1.77 min.
Intermediate 30
5-Bromo-7-(methylsulfonyl)-2-(propan-2-yl)-2,3-dihydro-1H-isoindol-1-one
[0241] Into a 100-mL round-bottom flask, was placed
5-bromo-7-(methylsulfanyl)-2-(propan-2-yl)-2,3-dihydro-1H-isoindol-1-one
(Intermediate 29, 1 g, 3.33 mmol, 1.00 eq) and chloroform (10 mL).
To this solution was added slowly m-CPBA (1.4 g, 8.11 mmol, 2.5
eq). The resulting solution was stirred overnight at 25.degree. C.
The resulting solution was quenched by the addition of saturated
NaHSO.sub.3 and stirred for 30 min. To this solution was added
aqueous sodium bicarbonate. The resulting solution was extracted
with DCM and the organic layers combined and dried over anhydrous
sodium sulfate and concentrated under vacuum. This yielded the
title compound (800 mg, 72%) as a yellow solid. .sup.1H-NMR (500
MHz, DMSO-d.sub.6) .delta. 1.25 (d, 6H), 3.62 (s, 3H), 4.41 (hept,
1H), 4.54 (s, 2H), 8.05 (d, 1H), 8.22-8.25 (m, 1H). m/z (ES+)
[M+H].sup.+=332 and 334, acid, HPLC t.sub.R=1.32 min.
Intermediate 31
7-(Benzylsulfanyl)-5-bromo-2-(propan-2-yl)-2,3-dihydro-1H-isoindol-1-one
[0242] Into a 100-mL round-bottom flask, was placed
5-bromo-7-chloro-2-(propan-2-yl)-2,3-dihydro-1H-isoindol-1-one
(Intermediate 28, 1 g, 3.47 mmol, 1.00 eq), phenylmethanethiol (860
mg, 6.92 mmol, 2.00 equiv), [(2-methylbutan-2-yl)oxy]sodium (760
mg, 6.90 mmol, 2.00 eq), dioxane (10 mL). The resulting solution
was stirred for 2 h at 110.degree. C. The reaction mixture was
cooled to rt. Water was added and the solution was extracted with
DCM. The organic layers were combined and dried over anhydrous
sodium sulfate. The residue was applied onto a silica gel column
with ethyl acetate/petroleum ether (1/6). The product was
concentrated under vacuum to deliver the title compound (1 g, 77%)
as a white solid. .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. 1.29
(d, 6H), 4.29 (s, 2H), 4.65 (hept, 1H), 7.51 (s, 1H), 7.57 (s, 1H).
m/z (ES+) [M+H].sup.+=378, base, HPLC t.sub.R=2.37 min.
Intermediate 32
6-Bromo-3-oxo-2-(propan-2-yl)-2,3-dihydro-1H-isoindole-4-sulfonyl
chloride
[0243] Into a 100-mL round-bottom flask, was placed
7-(benzylsulfanyl)-5-bromo-2-(propan-2-yl)-2,3-dihydro-1H-isoindol-1-one
(Intermediate 31, 200 mg, 0.53 mmol, 1.00 eq) in MeCN (4.1 mL, AcOH
(0.6 mL) and water (0.4 mL). The solution was cooled to 5.degree.
C. and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (210 mg,
1.07 mmol, 2.00 equiv) was added at 5.degree. C. The resulting
solution was stirred for 2 h, cooled on a water/ice bath and then
for 1 h at room temperature. The solids were filtered off and the
product filtrate was concentrated under vacuum to give the crude
title compound (200 mg) as a solid. m/z (ES+) [M+H].sup.+=354,
acid, HPLC t.sub.R=1.04 min.
Intermediate 33
6-Bromo-N-methyl-3-oxo-2-(propan-2-yl)-2,3-dihydro-1H-isoindole-4-sulfonam-
ide
[0244] Into a 100 mL round-bottom flask, was placed methanamine (2M
in THF, 0.55 mL, 1 mmol, 2 eq),
6-bromo-3-oxo-2-(propan-2-yl)-2,3-dihydro-1H-isoindole-4-sulfonyl
chloride (Intermediate 32, 200 mg, 0.57 mmol) in DCM (5 mL. The
resulting solution was stirred for 1 h at rt. Water was added to
the mixture. The resulting solution was extracted with DCM and the
organic layers combined. The resulting solution was concentrated
under vacuum to deliver the title compound (170 mg, 85%) as a white
solid. m/z (ES+) [M+H].sup.+=349, acid, HPLC t.sub.R=1.47 min.
Intermediate 34
N-Methyl-3-oxo-2-(propan-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)-2,3-dihydro-1H-isoindole-4-sulfonamide
[0245] Into a 100-mL round-bottom flask, was placed
6-bromo-N-methyl-3-oxo-2-(propan-2-yl)-2,3-dihydro-1H-isoindole-4-sulfona-
mide (Intermediate 33, 500 mg, 1.44 mmol),
4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxabo-
rolane (730 mg, 2.87 mmol), KOAc (422 mg, 4.30 mmol), dioxane (5
mL), Pd(PPh.sub.3).sub.4 (165 mg, 0.14 mmol). The resulting
solution was stirred for 1 h at 110.degree. C. under nitrogen
atmosphere. The resulting mixture was concentrated under vacuum.
The residue was applied onto a silica gel column with ethyl
acetate/petroleum ether (1:4). This delivered the crude title
compound (400 mg) as a yellow solid. m/z (ES+) [M+H].sup.+=313,
acid, HPLC t.sub.R=0.81 min.
Intermediate 35
7-(Benzylsulfanyl)-5-bromo-2-[(1S)-1-cyclopropylethyl]-2,3-dihydro-1H-isoi-
ndol-1-one
[0246] In a 500 mL round-bottomed flask was
(S)-5-bromo-7-chloro-2-(1-cyclopropylethyl)isoindolin-1-one
(Intermediate 1, 2.5 g, 7.95 mmol), phenylmethanethiol (1.97 g,
15.9 mmol), and sodium 2-methylbutan-2-olate (1.75 g, 15.9 mmol) in
1,4-dioxane (5 mL) to give a orange suspension. The reaction
mixture was stirred for 2 h at 110.degree. C. The reaction mixture
was filtered through celite. The solvent was removed under reduced
pressure. The crude product was added to a silica gel column and
was eluted with DCM/EtOAc (5/1). Pure fractions were evaporated to
dryness to afford the title compound (1.2 g, 37%) as a yellow
solid. .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. 0.29-0.49 (m, 3H),
0.54-0.67 (m, 1H), 0.89-1.04 (m, 1H), 1.31 (d, 3H), 3.69 (dq, 1H),
4.22 (s, 2H), 4.34 (d, 1H), 4.45 (d, 1H), 7.23-7.27 (m, 1H), 7.32
(dd, 3H), 7.35 (s, 1H), 7.39-7.49 (m, 2H). m/z (ES+),
[M+H].sup.+=404; acid, HPLC t.sub.R=1.271 min.
Intermediate 36
6-Bromo-2-[(1S)-1-cyclopropylethyl]-3-oxo-2,3-dihydro-1H-isoindole-4-sulfo-
nyl chloride
[0247] Sulfuryl dichloride (3.44 mL, 42.25 mmol) was added to water
(0.76 mL, 42.2 mmol),
7-(benzylsulfanyl)-5-bromo-2-[(1S)-1-cyclopropylethyl]-2,3-dihydro-1H-iso-
indol-1-one (Intermediate 35, 4.25 g, 10.56 mmol) and acetic acid
(2.6 mL, 52.8 mmol) in DCM (30 mL) at 0.degree. C. The resulting
mixture was stirred at 0.degree. C. for 1 h. The reaction mixture
was quenched with saturated NaHCO.sub.3 (100 mL), extracted with
EtOAc (3.times.100 mL), the organic layer was dried over
Na.sub.2SO.sub.4, filtered and evaporated to afford the title
compound (3.76 g, 94%) as a solid. .sup.1H-NMR (500 MHz,
CDCl.sub.3) .delta. 0.28-0.53 (m, 3H), 0.61-0.74 (m, 1H), 0.98-1.05
(m, 1H), 1.37 (d, 3H), 3.78-3.84 (m, 1H), 4.50 (d, 1H), 4.62 (d,
1H), 7.91-7.99 (m, 1H), 8.27 (d, 1H). m/z (ES+), [M+H].sup.+=380;
acid, HPLC t.sub.R=1.612 min
Intermediate 37
6-Bromo-2-[(1S)-1-cyclopropylethyl]-N-methyl-3-oxo-2,3-dihydro-1H-isoindol-
e-4-sulfonamide
[0248]
7-(Benzylsulfanyl)-5-bromo-2-[(1S)-1-cyclopropylethyl]-2,3-dihydro--
1H-isoindol-1-one (Intermediate 35, 2.54 g, 6.31 mmol) was
dissolved in acetonitrile (50 mL). Water (5 mL) and acetic acid (8
mL) were added, and the reaction was cooled in an ice bath under
stirring to ca 5.degree. C., after which
1,3-dichloro-5,5-dimethylhydantoin (2.114 g, 10.73 mmol) was added
portionwise over ca 2 min. The reaction was stirred at rt for 1 h
and then evaporated. The residue was partitioned between DCM and 50
mL of water. The aqueous phase was re-extracted twice with DCM and
the combined organic phases were washed with 10%
Na.sub.2S.sub.2O.sub.3, dried over MgSO.sub.4 and evaporated to
give a pale yellow solid. The crude product was dissolved in dry
THF (50 mL) and added dropwise to the stirred mixture of 35%
MeNH.sub.2 in ethanol (5 mL) and THF (20 mL). The white precipitate
begun to form immediately. The mixture was stirred for 1 h at rt
and subsequently evaporated. The residue was stirred with water (55
ml) for 1 h. The solid was filtered, washed twice with small
portions of water and recrystallised from ethanol. .sup.1H-NMR (500
MHz, CDCl.sub.3) .delta. 0.39 (m, 2H), 0.49 (tt, 1H), 0.68 (tt,
1H), 1.01 (dtd, 1H), 1.36 (d, 3H), 2.65 (d, 3H), 3.71-3.81 (m, 1H),
4.47 (d, 1H), 4.59 (d, 1H), 7.82 (s, 1H), 8.21 (d, 1H). m/z (ES+),
[M+H].sup.+=374.8; base, HPLC t.sub.R=1.514 min.
Intermediate 38
6-Bromo-2-[(1S)-1-cyclopropylethyl]-N,N-dimethyl-3-oxo-2,3-dihydro-1H-isoi-
ndole-4-sulfonamide
[0249] Into a 100-mL round-bottom flask was placed
6-bromo-2-[(S)-1-cyclopropylethyl]-3-oxo-2,3-dihydro-1H-isoindole-4-sulfo-
nyl chloride (Intermediate 36, 400 mg, 1.06 mmol) and DCM (3 mL).
Dimethylamine in DCM (0.1 g, 2 mmol) was added dropwise. The
resulting solution was stirred for 1 h at 25.degree. C. The
resulting solution was diluted with H.sub.2O. The resulting
solution was extracted with dichloromethane and the organic layers
combined and concentrated under vacuum. This afforded the crude
title compound (0.4 g) as a solid. m/z (ES+) [M+H].sup.+=389, acid,
HPLC t.sub.R=1.52 min.
Intermediate 39
6-Bromo-2-[(1S)-1-cyclopropylethyl]-3-oxo-isoindoline-4-sulfonamide
[0250]
6-Bromo-2-[(1S)-1-cyclopropylethyl]-3-oxo-2,3-dihydro-1H-isoindole--
4-sulfonyl chloride (Intermediate 36, 1.204 g, 3.18 mmol) assumed
quantitative from previous step was dissolved in dioxane (25 mL)
and cooled to 0.degree. C. in an ice bath. A slurry formed and to
this 30% aq ammonium hydroxide (32 mL, 246.5 mmol) was added. The
reaction was allowed to warm to rt overnight. Water was added and
the product extracted with DCM. The organic was dried using a phase
separator and concentrated in vacuo to give the crude product (0.4
g). m/z (ES+) [M+H].sup.+=361, base, HPLC t.sub.R=1.52 min.
Intermediate 40
2-[(1S)-1-Cyclopropylethyl]-N-methyl-3-oxo-6-(4,4,5,5-tetramethyl-1,3,2-di-
oxaborolan-2-yl)-2,3-dihydro-1H-isoindole-4-sulfonamide
[0251] PdCl.sub.2(dppf) (1.451 g, 1.98 mmol) was added to
6-bromo-2-[(1S)-1-cyclopropylethyl]-N-methyl-3-oxo-2,3-dihydro-1H-isoindo-
le-4-sulfonamide (Intermediate 37, 7.4 g, 19.83 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (10.07
g, 39.65 mmol) and potassium acetate (5.84 g, 59.48 mmol) in
1,4-dioxane (200 mL) at 25.degree. C. under nitrogen. The resulting
mixture was stirred at 80.degree. C. for 12 h. The reaction mixture
was diluted with EtOAc (300 mL), and washed twice with water (350
mL), and saturated brine (300 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 flash silica chromatography
(elution gradient 0 to 30% EtOAc in petroleum ether). The pure
fractions were evaporated to dryness to afford the title compound
(7.0 g, 84%) as a solid. .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta.
0.34-0.55 (m, 3H), 0.63-0.75 (m 1H), 1.05 (tt, 1H), 1.25-1.30 (m
3H), 1.38 (s, 12H), 2.53-2.73 (m 3H), 3.79 (dq, 1H), 4.44-4.70 (m,
2H), 7.45 (s, 1H), 8.09 (s, 1H), 8.51 (s, 1H). m/z (ES+),
[M+H].sup.+=421; acid, HPLC t.sub.R=1.665 min
Intermediate 41
{2-[(1S)-1-Cyclopropylethyl]-7-(dimethylsulfamoyl)-1-oxo-2,3-dihydro-1H-is-
oindol-5-yl}boronic acid
[0252] Into a 100-mL round-bottom flask, was placed
6-bromo-2-[(S)-1-cyclopropylethyl]-N,N-dimethyl-3-oxo-2,3-dihydro-1H-isoi-
ndole-4-sulfonamide (Intermediate 38, 400 mg, 1.03 mmol),
4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxabo-
rolane (340 mg), KOAc (330 mg, 3.36 mmol), Pd(PPh.sub.3).sub.4 (50
mg, 0.04 mmol), 1,4-dioxane (5 mL). The resulting solution was
stirred for 1 h at 110.degree. C. under nitrogen. The resulting
mixture was concentrated under vacuum. The residue was applied onto
a silica gel column with ethyl acetate/petroleum ether (1:3). This
afforded the title compound (300 mg, 82%) as a solid. m/z (ES+)
[M+H].sup.+=353, acid, HPLC t.sub.R=0.88 min.
Intermediate 42
N-(5-{7-Chloro-2-[(1S)-1-cyclopropylethyl]-1-oxo-2,3-dihydro-1H-isoindol-5-
-yl}-1,3-thiazol-2-yl)acetamide
[0253] Cs.sub.2CO.sub.3 (4.14 g, 12.71 mmol) was added to
5-bromo-7-chloro-2-[(S)-1-cyclopropylethyl]-2,3-dihydro-1H-isoindol-1-one
(Intermediate 1, 2 g, 6.36 mmol), N-(thiazol-2-yl)acetamide (1.085
g, 7.63 mmol), tri-tert-butylphosphonium tetrafluoroborate (0.369
g, 1.27 mmol) and PdOAc.sub.2 (0.143 g, 0.64 mmol) in DMF (30 mL).
The resulting mixture was stirred at 100.degree. C. for 4 h and
cooled to rt. The reaction mixture was poured into water (100 mL),
extracted with EtOAc (3.times.100 mL), the organic layer was dried
over Na.sub.2SO.sub.4, filtered and evaporated to afford a yellow
oil. The crude product was purified by flash silica chromatography,
elution gradient 0 to 60% EtOAc in petroleum ether. Pure fractions
were evaporated to dryness to afford the title compound (1.8 g,
75%) as a yellow solid.
[0254] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 0.24 (dt, 1H),
0.40 (dt, 2H), 0.58 (dt, 1H), 1.03-1.19 (m, 1H), 1.28 (d, 3H), 2.19
(s, 3H), 3.47-3.73 (m, 1H), 4.54 (s, 2H), 7.77-7.78 (m, 2H), 8.11
(s, 1H), 2.33 (s, 11H). m/z (ES+), [M+H].sup.+=376.2; acid, HPLC
t.sub.R=1.464 min
Intermediate 43
(3aS,6R)-5-Bromo-2-[(1S)-1-cyclopropylethyl]-1-oxo-1,2,3,6,7,7a-hexahydro--
3a,6-epoxyisoindole-7-carboxylic acid
[0255] (S)--N-((4-Bromofuran-2-yl)methyl)-1-cyclopropylethanamine
(20.37 g, 83.44 mmol) and furan-2,5-dione (9.00 g, 91.78 mmol) were
mixed in toluene (170 mL) at room temperature. The reaction was
stirred at room temperature overnight. The precipitate that formed
was collected by filtration and washed with diethyl ether. The
title compound was obtained as a white solid (24.4 g, 85%). The
material was used in the next step without purification.
.sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. 0.23-0.39 (m, 2H),
0.43-0.53 (m, 1H), 0.57-0.68 (m, 1H), 0.83-0.93 (m, 1H), 1.22, (d,
1.5H), 1.26 (d, 1.5H), 2.98-3.11 (m, 2H), 3.46-3.59 (m, 2H), 3.86
(d, 0.5H), 3.93 (d, 0.5H), 3.96 (d, 0.5H), 4.03 (d, 0.5H), 5.18 (s,
0.5H), 5.20 (s, 0.5H), 6.53 (s, 0.5H), 6.55 (s, 0.5H).
Intermediate 44
6-Bromo-2-[(1S)-1-cyclopropylethyl]-3-oxo-2,3-dihydro-1H-isoindole-4-carbo-
xylic acid
[0256]
(3aS,6R)-5-Bromo-2-((S)-1-cyclopropylethyl)-1-oxo-1,2,3,6,7,7a-hexa-
hydro-3a,6-epoxyisoindole-7-carboxylic acid (Intermediate 43, 10 g,
29.22 mmol) was dissolved in dioxane (200 mL) and to this
BF.sub.3.times.OEt.sub.2 (14.81 mL, 116.9 mmol) was added under a
nitrogen atmosphere. The reaction was then heated under reflux for
2 h. The reaction was allowed to cool to room temperature, diluted
with DCM and washed with brine. The organic layer was separated
using a phase separator cartridge and concentrated in vacuo. The
residue was triturated with methanol. The solid obtained was
collected by filtration and washed with methanol to give the title
compound (6.65 g, 70%) as an off-white solid.
[0257] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. 0.37-0.43 (m, 1H),
0.43-0.5 (m, 1H), 0.49-0.59 (m, 1H), 0.68-0.78 (m, 1H), 0.99-1.13
(m, 1H), 1.43 (d, 3H), 3.73-3.82 (m, 1H), 4.58 (d, 1H), 4.69 (d,
1H), 7.84-7.87 (m, 1H), 8.57 (d, 1H), H obscured.
Intermediate 45
7-Amino-5-bromo-2-[(1S)-1-cyclopropylethyl]-2,3-dihydro-1H-isoindol-1-one
[0258] Diphenylphosphoryl azide (0.5 mL, 2.3 mmol) was added to a
suspension of
6-bromo-2-[(1S)-1-cyclopropylethyl]-3-oxo-2,3-dihydro-1H-isoindole-4-carb-
oxylic acid (Intermediate 44, 0.5 g, 1.5 mmol) and triethylamine
(0.32 mL, 2.3 mmol) in tert-butanol (8 mL). The mixture was heated
at reflux for 20 h. The reaction was concentrated in vacuo and the
residue purified by flash chromatography eluting with 0-3% EtOAc in
heptane. Product containing fractions were combined and
concentrated in vacuo. The residue was dissolved DCM (2 mL) and TFA
(2 mL, 12.95 mmol) was added. The reaction stirred for 2 h at room
temperature. The reaction was concentrated in vacuo and the residue
partitioned between DCM and sat aq NaHCO.sub.3. The layers were
separated and the DCM removed in vacuo. The residue was triturated
with MeCN and a solid obtained. This was collected by filtration
and washed with MeCN. The title compound (0.37 g, 83%) was obtained
as a white solid. .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta.
0.3-0.42 (m, 2H), 0.43-0.49 (m, 1H), 0.59-0.67 (m, 1H), 0.91-1.04
(m, 1H), 1.32 (d, 3H), 3.61-3.7 (m, 1H), 4.32 (d, 1H), 4.42 (d,
1H), 6.75-6.77 (m, 1H), 6.88 (d, 1H).
Intermediate 46
N-{6-Bromo-2-[(1S)-1-cyclopropylethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-
acetamide
[0259] To a solution of
7-amino-5-bromo-2-[(S)-1-cyclopopylethyl]-2,3-dihydro-1H-isoindol-1-one
(Intermediate 45, 200 mg, 0.68 mmol) and triethylamine (0.189 mL,
1.36 mmol) in DCM (5 mL) was added acetyl chloride (0.058 mL, 0.81
mmol). This was stirred at room temperature overnight. The reaction
was diluted with DCM and washed with water. The phases were
separated using a phase separator cartridge and the DCM was removed
in vacuo. The residue obtained was purified by flash chromatography
eluting with 20% EtOAc in heptane. The title compound (118 mg, 52%)
was obtained as a solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
0.3-0.55 (m, 3H), 0.61-0.74 (m, 1H), 0.94-1.09 (m, 1H), 1.36 (d,
3H), 2.23 (s, 3H), 3.56-3.74 (m, 1H), 4.39 (d, 1H), 4.50 (d, 1H),
7.28 (s, 1H), 8.71 (s, 1H), 10.39 (s, 1H).
EXAMPLES
Example 1
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-(methylsulfonyl)-1-oxo-2,3-dihydro-1H--
isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide
##STR00012##
[0261] m-CPBA (3.33 g, 19.3 mmol) was added to
N-(5-{2-[(S)-1-cyclopropylethyl]-7-(methylsulfanyl)-1-oxo-2,3-dihydro-1H--
isoindol-5-yl}4-methyl-1,3-thiazol-2-yl)acetamide (Intermediate 25,
3.1 g, 7.72 mmol) in DCM (120 mL). The resulting mixture was
stirred at 0.degree. C. for 1 h, then warmed to rt and stirred for
1 h. The reaction mixture was quenched with saturated NaHCO.sub.3
(200 mL) and extracted with DCM (3.times.200 mL). The organic layer
was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford
a yellow solid. The crude product was purified by preparative HPLC
with the following condition: Column: X Bridge RP 18, 19*150 mm, 5
um; Mobile Phase A: Water 0.03% NH.sub.4HCO.sub.3, Mobile Phase B:
MeCN; Flow rate: 30 mL/min; Gradient: 25% B to 75% B in 8 min; 254
nm. Pure fractions were evaporated to dryness to afford the title
compound (1.2 g, 36%) as a white solid. .sup.1H-NMR (500 MHz,
DMSO-d.sub.6) .delta. 0.24-0.29 (m, 1H), 0.38-0.46 (m 2H),
0.57-0.62 (m, 1H), 1.11-1.19 (m, 1H), 1.31 (d, 3H), 2.17 (s, 3H),
2.44 (s, 3H), 3.59-3.65 (m, 4H), 4.70 (s, 2H), 8.00 (d, 1H), 8.05
(d, 1H), 12.30 (s, 1H). m/z (ES+), [M+H].sup.+=433.9; base, HPLC
t.sub.R=2.553 min
[0262] The solid residue was found to be crystalline by XRPD and a
typical diffractogram is displayed in FIG. 1. Characteristic peak
positions are listed below in Tables 1 and 2.
TABLE-US-00003 TABLE 1 Five peaks characteristic for Example 1,
form A .degree.2-theta Relative intensity 13.7 vs 18.1 vs 18.3 str
22.2 vs 25.1 str
TABLE-US-00004 TABLE 2 Ten peaks characteristic for Example 1, form
A .degree.2-theta Relative intensity 9.0 med 10.1 w 12.4 w 13.7 vs
17.1 med 18.1 vs 18.3 str 70.7 str 22.2 vs 25.1 str
Example 2
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-(methylsulfonyl)-1-oxo-2,3-dihydro-1H--
isoindol-5-yl}-1,3-thiazol-2-yl)acetamide
##STR00013##
[0264]
5-Bromo-2-[(1S)-1-cyclopropylethyl]-7-(methylsulfonyl)-2,3-dihydro--
1H-isoindol-1-one (Intermediate 27, 1.03 g, 2.88 mmol),
N-(thiazol-2-yl)acetamide (0.573 g, 4.03 mmol) and DMF (14 mL) were
all added together in a 100 ml 3-neck flask and degassed and filled
with nitrogen 3 times. Palladium acetate (24.2 mg, 0.11 mmol) and
tri-tert-butylphosphonium tetrafluoroborate (75.1 mg, 0.26 mmol)
was added to the reaction mixture and heated at 100.degree. C.
overnight with stirring. The reaction mixture was allowed to reach
room temperature and then added dropwise to an water solution (200
mL) with stirring, followed by extraction with EtOAc. The organic
layer was washed with water, brine, dried over sodium sulfate
filtered and concentrated under vacuum. The residue was suspended
in EtOAc stirred for a while and then the solid was collected by
suction filtration. The solid was washed with EtOAc/diethyl ether
and air dried to deliver 0.59 g of the product as a yellow powder.
The residue was dissolved in dichloromethane, loaded on a silica
column and chromatographed by eluting with 100 mL DCM, followed by
2-propanol (0-20%) in DCM 500 mL and then 2-propanol (20-100%) in
DCM 150 mL. The compound was collected at 320 nm. Fractions
containing pure product were evaporated to give the title compound
(0.87 g, 72%) as a yellow solid. .sup.1H-NMR (500 MHz,
DMSO-d.sub.6) .delta. 0.24-0.3 (m, 1H), 0.41 (dddd, 2H), 0.56-0.63
(m, 1H), 1.12-1.18 (m, 1H), 1.31 (d, 3H), 2.20 (s, 3H), 3.57-3.62
(m, 1H), 3.63 (s, 3H), 4.68 (s, 2H), 8.09 (d, 1H), 8.12 (s, 1H),
8.21 (d, 1H), 12.37 (s, 1H). m/z (ES+), [M+H].sup.+=420.2; acid,
HPLC t.sub.R=1.51
Example 3
N-{4-Methyl-5-[7-(methylsulfonyl)-1-oxo-2-(propan-2-yl)-2,3-dihydro-1H-iso-
indol-5-yl]-1,3-thiazol-2-yl}acetamide
##STR00014##
[0266] Into a 100-mL round-bottom flask, was placed
5-bromo-7-methanesulfonyl-2-(propan-2-yl)-2,3-dihydro-1H-isoindol-1-one
(Intermediate 30, 250 mg, 0.75 mmol),
N-(4-methyl-1,3-thiazol-2-yl)acetamide (130 mg, 0.83 mmol),
Cs.sub.2CO.sub.3 (492 mg, 1.51 mmol), Pd(OAc).sub.2 (17 mg, 0.08
mmol), DMF (5 mL), tri-tert-butylphosphonium tetrafluoroborate (44
mg, 0.15 mmol). The resulting solution was stirred for 2 h at
110.degree. C. in an oil bath under nitrogen atmosphere. The
reaction mixture was cooled and water was added. The resulting
solution was extracted with dichloromethane and the combined
organic layers were dried over anhydrous sodium sulfate, filtrated
and concentrated under vacuum. The crude product was purified by
Preparative HPLC with the following conditions: Column: X Bridge
C18, 19.times.150 mm, 5 um; Mobile Phase A: Water/0.05% FA, Mobile
Phase B: McCN; Flow rate: 20 mL/min; Gradient: 30% B to 70% B in 10
min; 254 nm. This afforded the title compound (40 mg, 1%) as a
white solid. .sup.1H-NMR (300 MHz. CD.sub.3OD) .delta. 1.35 (d,
6H), 2.24 (s, 3H), 2.47 (s, 3H), 3.60 (s, 3H), 4.51-4.68 (m, 3H),
8.00 (s, 1H), 8.17 (s, 1H). m/z (ES+) [M+H].sup.+=408, HPLC
t.sub.R=2.24 min.
Example 4
N-(5-{2-[(1S)-1-Cyclopropylethyl]-1-oxo-7-sulfamoyl-2,3-dihydro-1H-isoindo-
l-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide
##STR00015##
[0268] In a 100 mL round-bottomed flask was
6-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-2-[(1S)-1-cyclopropylethyl]-
-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonyl chloride (Intermediate
4, 2.0 g, 4.41 mmol) and ammonia hydrate (5.15 g, 44.06 mmol)
dissolved in DCM (40 mL) to give a yellow suspension. the reaction
mixture was stirred at rt for 2 h. The crude product was purified
by preparative HPLC with the following conditions: Column: X Bridge
C18, 19*150 mm, 5 um; Mobile Phase A: Watcr/0.03% NH.sub.3. Mobile
Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 70% B in 10
min; 254 nm. Fractions containing the desired compound were
evaporated to dryness to afford the title compound (0.89 g, 46%) as
a yellow solid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.
0.21-0.31 (m, 1H), 0.37-0.49 (m, 2H), 0.60-0.63 (m, 1H), 1.14-1.23
(m, 1H), 1.33 (d, 3H), 2.17 (s, 3H), 2.43 (s, 3H), 3.33-3.67 (m,
1H), 4.75 (s, 2H), 7.73 (br s, 2H), 7.87 (s, 1H), 7.98 (s, 1H),
12.29 (br s, 1H). m/z (ES+), [M+H].sup.+=435; acid, HPLC
t.sub.R=1.356 min
Example 5
N-(5-{7-(Acetylamino)-2-[(1S)-1-cyclopropylethyl]-1-oxo-2,3-dihydro-1H-iso-
indol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide
##STR00016##
[0270] A mixture of
N-{6-bromo-2-[(1S)-1-cyclopropylethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl-
}acetamide (Intermediate 46, 110 mg, 0.33 mmol),
N-(4-methylthiazol-2-yl)acetamide (56.1 mg, 0.36 mmol),
Cs.sub.2CO.sub.3 (213 mg, 0.65 mmol), tri-t-butylphosphonium
tetrafluoroborate (18.93 mg, 0.07 mmol) and palladium(II) acetate
(7.32 mg, 0.03 mmol) in DMF (2 mL) was degassed and heated at
100.degree. C. for 2 h. The reaction was cooled to room temperature
and sat. NaHCO.sub.3 and EtOAc were added, after which the organic
phase was separated. The aqueous phase extracted with EtOAc. The
combined organic phases were filtered through a phase separator
cartridge and concentrated in vacuo. The residue was purified by
SFC, chromatographic conditions: McOH/NH.sub.3 20 mM. Column:
Phenomenex Luna Hilic 5.mu. 30.times.250 mm to give the title
compound (40 mg, 30%). .sup.1H-NMR (600 MHz, DMSO-d.sub.6) .delta.
0.18-0.27 (m, 1H), 0.33-0.46 (m, 2H), 0.53-0.62 (m, 1H), 1.07-1.18
(m, 1H), 1.30 (d, 3H), 2.15 (s, 3H), 2.16 (s, 3H), 2.39 (s, 3H),
3.48-3.58 (m, 1H), 4.59 (s, 2H), 7.34 (s, 1H), 8.43 (s, 1H), 10.31
(s, 1H), 12.18 (s, 1H). m/z (ES+), [M+H].sup.+=413.
Example 6 (Method E)
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-(methylsulfamoyl)-1-oxo-2,3-dihydro-1H-
-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide
##STR00017##
[0272] Methanamine in THF (2M, 22 mL, 44 mmol) was added dropwise
to
6-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-2-[(1S)-1-cyclopropylethyl]-
-3-oxo-2,3-dihydro-1H-isoindole-4-sulfonyl chloride (Intermediate
4, 2 g, 4.41 mmol) in DCM (40 mL) at 25.degree. C. over a period of
30 min under nitrogen. The resulting mixture was stirred at
25.degree. C. for 12 h. The solvent was removed under reduced
pressure. The crude product was purified by flash silica
chromatography, elution gradient 30 to 50% EtOAc in petroleum
ether. Pure fractions were evaporated to dryness to afford the
title compound (1.8 g, 91%) as a yellow solid. .sup.1H-NMR (400
MHz, DMSO-d.sub.6) .delta. 0.22-0.34 (1H, m), 0.44 (2H, m), 0.61
(1H, m), 1.17 (1H, m), 1.33 (3H, d), 2.18 (3H, s), 2.45 (3H, s),
2.53 (2H, s), 3.66 (1H, dq), 4.75 (2H, s), 5.67 (1H, s), 7.59 (1H,
q), 7.88 (1H, d), 8.02 (1H, d), 12.31 (1H, s). m/z (ES+),
[M+H].sup.+=449; acid, HPLC t.sub.R=0.867 min.
[0273] The solid residue was found to be crystalline by XRPD and a
typical diffractogram is displayed in FIG. 2. Characteristic peak
positions are listed below in Tables 3 and 4.
TABLE-US-00005 TABLE 3 Five peaks characteristic for Example 6,
form A .degree.2-theta Relative intensity 9.5 vs 11.9 vs 16.1 med
19.0 str 20.6 str
TABLE-US-00006 TABLE 4 Ten peaks characteristic for Example 6, form
A .degree.2-theta Relative intensity 9.5 vs 11.9 vs 14.8 w 15.4 vw
16.1 med 19.0 str 20.6 str 20.9 med 21.8 vw 23.8 w
Example 7 (Method F)
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-(dimethylsulfamoyl)-1-oxo-2,3-dihydro--
1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide
##STR00018##
[0275] Into a 100-mL round-bottom flask, was placed
{2-[(1S)-1-cyclopropylethyl]-7-(dimethylsulfamoyl)-1-oxo-2,3-dihydro-1H-i-
soindol-5-yl}boronic acid (Intermediate 41, 300 mg, 0.85 mmol),
N-(5-bromo-4-methyl-1,3-thiazol-2-yl)acetamide (134 mg, 0.57 mmol),
K.sub.3PO.sub.4 (360 mg, 1.70 mmol), Pd(dppf)Cl.sub.2 (50 mg, 0.07
mmol), 1,4-dioxane (5 mL), water (1 mL). The resulting solution was
stirred overnight at 110.degree. C. under nitrogen. The crude
product was purified by HPLC with the following conditions: Column:
X Bridge C18, 19.times.150 mm, 5 um; Mobile Phase A: Water/0.05%
FA, Mobile Phase B: McCN; Flow rate: 20 mL/min; Gradient: 30% B to
70% B in 10 min; 254 nm. This afforded the title compound (13 mg,
5%) as a white solid. .sup.1H-NMR (300 MHz, CD.sub.3OD) .delta.
0.30-0.80 (m, 4H), 1.15-1.30 (m, 1H), 1.41 (d, 3H), 2.20 (s, 3H),
2.50 (s, 3H), 2.90 (s, 6H), 3.60-3.81 (m, 1H), 4.68-4.90 (m, 2H),
7.96 (s, 1H), 8.05 (s, 1H). m/z (ES+) [M+H].sup.+=463, acid, HPLC
t.sub.R=1.38 min.
Example 8 (Method G)
N-(5-{(1S)-[(1S)-1-Cyclopropylethyl]-7-(methylsulfamoyl)-1-oxo-2,3-dihydro-
-1H-isoindol-5-yl}-1,3-thiazol-2-yl)acetamide
##STR00019##
[0277] N-(Thiazol-2-yl)acetamide (64 mg, 0.45 mmol),
6-bromo-2-[(S)-1-cyclopropylethyl]-N-methyl-3-oxo-2,3-dihydro-1H-isoindol-
e-4-sulfonamide (Intermediate 37, 130 mg, 0.35 mmol),
Cs.sub.2CO.sub.3 (227 mg, 0.70 mmol) and tri-tert-butylphosphonium
tetrafluoroborate (20 mg, 0.07 mmol) and PdOAc.sub.2 (8 mg, 0.03
mmol) were added to a flask which was sealed with a septum and put
under vacuum and then flushed with nitrogen. DMF was added and
heated to 110.degree. C. and stirred for 18 h. The reaction mixture
was filtered through celite, the celite was washed with DCM and the
filtrate was collected and washed with water and NH.sub.4Cl(aq).
The organic phase was separated and the aqueous phases were
extracted with DCM. The combined organic phases were dried,
filtered and concentrated. The residue was dissolved in DCM and 100
mg MP-TMT (agilent) Pd scavenger (loading 0.6 mmol/g) was added and
the mixture was stirred over night. The suspension was filtered
through a phase separator and concentrated. The crude product was
purified by HPLC with the following conditions: Gradient 5-95% MeCN
in 0.2% NH.sub.3, pH 10. Column: Waters Xbridge C18 5.mu. ODB
30.times.150 mm. .sup.1H-NMR (600 MHz, DMSO-d.sub.6) .delta.
0.23-0.31 (m, 1H), 0.37-0.49 (m, 2H), 0.57-0.62 (m, 1H), 1.13-1.20
(m, 1H), 1.32 (d, 3H), 2.20 (s, 3H), 3.63 (dq, 1H), 4.72 (s, 2H),
7.60 (q, 1H), 7.99 (d, 1H), 8.15-8.16 (m, 2H), 12.37 (s, 1H), 1
methyl resonance obscured under solvent. m/z (ESI) [Mt
H].sup.+=435, acid, HPLC t.sub.R=1.50 min
Example 9 (Method H)
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-[(methylsulfonyl)amino]-1-oxo-2,3-dihy-
dro-1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide
##STR00020##
[0279]
N-(5-{7-Chloro-2-[(1S)-1-cyclopropylethyl]-1-oxo-2,3-dihydro-1H-iso-
indol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide (Intermediate 2, 2
g, 5.13 mmol), methanesulfonamide (1,464 g, 15.39 mmol),
sodium-t-butoxide (1340 mL, 15.39 mmol), PdOAc.sub.2 (0,115 g, 0.51
mmol) and
di-tert-butyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine
(0,479 g, 1.13 mmol) were mixed in DMF (60 mL). The reaction was
heated at 140.degree. C. for 7 h. After being cooled down to rt,
the mixture was filtered through a Celite pad. The solvent was
removed under reduced pressure. The crude product was purified by
flash silica chromatography. elution gradient 0 to 25% EtOAc in
DCM. Pure fractions were evaporated to dryness. The crude product
was purified by preparative HPLC with the following conditions:
Column: RP X Bridge C18, 19*150 mm, 5 um; Mobile Phase A:
Water/0.05% TFA, Mobile Phase B: McCN; Flow rate: 25 mL/min;
Gradient: 5% B to 70% B in 8 min; 254 nm. Fractions containing the
desired compound were evaporated to dryness to afford the title
compound (1.2 g, 52%) as a yellow solid. .sup.1H-NMR (600 MHz,
DMSO-d.sub.6) .delta. 0.21-0.27 (m, 1H), 0.36-0.45 (m, 2H),
0.55-0.61 (m, 1H), 1.1-1.18 (m, 1H), 1.30 (d, 3H), 2.15 (s, 3H),
2.40 (s, 3H), 3.25 (s, 3H), 3.5-3.56 (m, 1H), 4.61 (s, 2H), 7.37
(s, 1H), 7.44 (s, 1H), 9.56 (s, 1H), 12.20 (s, 1H). m/z (ES+),
[M+H].sup.+=449; acid, HPLC t.sub.R=2.037 min.
[0280] The solid residue was found to be crystalline by XRPD and a
typical diffractogram is displayed in FIG. 3. Characteristic peak
positions are listed below in Tables 5 and 6.
TABLE-US-00007 TABLE 5 Five peaks characteristic for Example 9,
form A .degree.2-theta Relative intensity 9.6 str 19.3 vs 20.4 med
20.7 w 25.8 w
TABLE-US-00008 TABLE 6 Ten peaks characteristic for Example 9, form
A .degree.2-theta Relative intensity 8.7 vw 9.6 str 14.8 vw 17.9 vw
18.3 w 19.3 vs 20.4 med 20.7 w 21.0 vw 25.8 w
Examples 10-37
[0281] The following compounds were prepared using the
aforementioned methods and intermediates
##STR00021##
TABLE-US-00009 Example 10 N-(5-{7-(Cyclobutylsulfamoyl)-2-[(1S)-1-
cyclopropylethyl]-1-oxo-2,3-dihydro-1H-
isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide ##STR00022##
Prepared using Method E Amine: Commercial Intermediate: 4
##STR00023## ##STR00024## .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. 0.21-0.32 (m, 1H), 0.35-0.48 (m, 2H), 0.53-0.65 (m, 1H),
1.02-1.27 (m, 1H), 1.34 (d, 3H), 1.35-1.93 (m, 6H), 2,17 (s, 3H),
2,44 (s, 3H), 3.65-3.72 (m, 2H), 4.75 (s, 2H), 7.86 (s, 1H), 8.00
(s, 1H), 8.05 (d, 1H), 12.31 (s, 1H). m/z (ES.sup.+) [M + H].sup.+
= 489, HPLC t.sub.R = 1.698 min. Example 11
N-{4-Methyl-5-[7-(methylsulfamoyl)-1-oxo-
2-(propan-2-yl)-2,3-dihydro-1H-isoindol-
5-yl]-1,3-thiazol-2-yl}acetamide ##STR00025## Prepared using Method
F Amine: Commercial Intermediate: 34 ##STR00026## ##STR00027##
.sup.1H-NMR (300 MHz, CD.sub.3OD) .delta. 1.35 (d, 6H), 2.24 (s,
3H), 2.46 (s, 3H), 2.60 (s, 3H), 4.59-4.62 (m, 3H), 7.93 (s, 1H),
8.01 (s, 1H). m/z (ES.sup.+) [M + H].sup.+ = 423.3, HPLC t.sub.R =
1.55 min. Example 12 N-(5-{2-[(1S)-1-Cyclopropylethyl]-1-
oxo-7-sulfamoyl-2,3-dihydro-1H-isoindol-5-yl}-
1,3-thiazol-2-yl)acetamide ##STR00028## Prepared using Method G
Amine: Commercial Intermediate: 39 ##STR00029## ##STR00030## m/z
(ES.sup.+) [M + H].sup.+ = 421.1, acid, HPLC t.sub.R = 1.48 min
Example 13 N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-
(cyclopropylmethyl)sulfamoyl]-1-oxo-
2,3-dihydro-1H-isoindol-5-yl}-4-methyl- 1,3-thiazol-2-yl)acetamide
##STR00031## Prepared using Method E Amine: Commercial
Intermediate: 4 ##STR00032## ##STR00033## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6, 25.degree. C.) .delta. 0.19-0.79 (m, 8H), 1.16-1.86
(m, 2H), 1.33 (d, 3H), 2.17 (s, 3H), 2.33 (s, 3H), 2.65-2,78 (m,
2H), 3.61-3,65 (m, 1H), 4.75 (s, 2H), 7.86 (s, 1H), 7.94 (br, 1H),
7.99 (s, 1H). m/z (ES+) [M + H].sup.+ = 489; acid, HPLC t.sub.R =
1.664 min. Example 14 N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-
(cyclopropylsulfamoyl)-1-oxo-2,3-dihydro-
1H-isoindol-5-yl}-4-methyl-1,3-thiazol- 2-yl)acetamide ##STR00034##
Prepared using Method E Amine: Commercial Intermediate: 4
##STR00035## ##STR00036## .sup.1H-NMR (400 MHz, DMSO-d.sub.6,
25.degree. C.) .delta. 0.20-0.30 (m, 1H), 0.36-0.61 (m, 7H), 1.12-
1.83 (m, 1H), 1.02-1.32 (d, 3H), 2.16 (s, 3H), 2.17-2.25 (m, 1H),
2.39 (s, 3H), 3.63- 3.65 (m, 1H), 4.75 (s, 2H), 7.89 (s, 1H), 8.02
(s, 2H). m/z (ES+) [M + H].sup.+ = 475; acid, HPLC t.sub.R = 1.60
min Example 15 N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-
(ethylsulfamoyl-1-oxo-2,3-dihydro-1H-
isoindol-5-yl}-4-methyl-1,3-thiazol- 2-yl)acetamide ##STR00037##
Prepared using Method E Amine: Commercial Intermediate: 4
##STR00038## ##STR00039## .sup.1H-NMR (400 MHz, DMSO-d.sub.6,
25.degree. C.) .delta. 0.23-0.30 (m, 1H), 0.37-0.48 (m, 2H), 0.55-
0.65 (m, 1H), 0.94-0.98 (m, 3H), 1.12-1.18 (m, 1H), 1.34 (d, 3H),
2,17 (s, 3H), 2.44 (s, 3H), 2.87-2.91 (m, 2H), 3.33 (s, 1H),
3.63-3.68 (m, 1H), 4.75 (s, 2H), 7.75 (br, 1H), 7.87 (s, 1H), 8.01
(s, 1H), 12.11 (br s, 1H). m/z (ES+) [M + H].sup.+ = 463; acid,
HPLC t.sub.R = 1.572 min Example 16
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-(oxetan-
3-ylsulfamoyl)-1-oxo-2,3-dihydro-1H-
isoindol-5-yl)-4-methyl-1,3-thiazol-2- yl)acetamide ##STR00040##
Prepared using Method E Amine: Commercial Intermediate: 4
##STR00041## ##STR00042## .sup.1H-NMR (300 MHz, DMSO-d.sub.6,
25.degree. C.) .delta. 0.15-0.65 (m, 4H), 1.10-1.19 (m, 1H), 1.33
(d, 3H), 2,18 (s, 3H), 2.27 (s, 3H), 3.64-3.70 (m, 1H), 4.33-4.56
(m, 5H), 4.75 (s, 2H), 7.84 (s, 1H), 8.01 (s, 1H), 8.56-8.59 (m,
1H), 12.29 (s, 1H). m/z (ES+) [M + H].sup.+ = 491; acid, HPLC
t.sub.R = 1.422 min Example 17
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-[(3,3-
difluorocyclobutyl)sulfamoyl]-1-oxo-2,3-
dihydro-1H-isoindol-5-yl}-4-1H-methyl- 1,3-thiazol-2-yl)acetamide
##STR00043## Prepared using Method E Amine: Commercial
Intermediate: 4 ##STR00044## ##STR00045## .sup.1H-NMR (300 MHz,
DMSO-d.sub.6, 25.degree. C.) .delta. 0.21-0.32 (m, 1H), 0.35-0.48
(m, 2H), 0.53- 0.65 (m, 1H), 1.15-1.24 (m, 1H), 1.35 (d, 3H), 2.17
(s, 3H), 2.39 (s, 5H), 2.73-2.81 (m, 2H), 3.59-3.67 (m, 2H), 4.75
(s, 2H), 7.88 (s, 1H), 8.02 (s, 1H), 8.30 (d, 1H), 12.30 (s, 1H).
m/z (ES+) [M + H].sup.+ = 525; acid, HPLC t.sub.R = 3.052 min
Example 18 N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-
[(2-methoxyethyl)sulfamoyl]-1-oxo-2,3-
dihydro-1H-isoindol-5-yl}-4-methyl-1,3- thiazol-2-yl)acetamide
##STR00046## Prepared using Method E Amine: Commercial
Intermediate: 4 ##STR00047## ##STR00048## .sup.1H-NMR (300 MHz,
DMSO-d.sub.6) .delta. 0.21-0.32 (m, 1H), 0.3.5-0.48 (m, 2H),
0.53-0.65 (m, 1H), 1.14-1.20 (m, 1H), 1.34 (d, 3H), 2.17 (s, 3H),
2.44 (s, 3H), 2.89 (s, 3H), 3.06- 3.21 (m, 2H), 3.21-3.31 (m, 2H),
3.63-3.66 (m, 1H), 4.74 (s, 2H), 7.84-7.89 (m, 2H), 7.99 (s, 1H),
12.27 (s, 1H). m/z (ES+) [M + H].sup.+ = 493; acid, HPLC t.sub.R =
1.496 min Example 19 N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-
({[1-(fluoromethyl)cyclopropyl]methyl}
sulfamoyl)-1-oxo-2,3-dihydro-1H-isoindol-
yl}-4-methyl-1,3-thiazol-2-yl)acetamide ##STR00049## Prepared using
Method E Amine: Commercial Intermediate: 4 ##STR00050##
##STR00051## .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 0.23-0.30
(m, 1H), 0.40-0.53 (m, 6H), 0.56-0.65 (m, 1H), 1.11-1.22 (m, 1H),
1.36 (d, 3H), 2.16 (s, 3H), 2.43 (s, 3H), 2.76-2.80 (m, 2H),
3.56-3.69 (m, 1H), 4.14-4.20 (m, 1H), 4.25-4.35 (m, 1H) 4.76 (s,
2H), 7.85 (s, 1H), 7.98-7.99 (m, 2H), 12.31 (br s, 1H). m/z (ES+)
[M + H].sup.+ = 521.4; acid, HPLC t.sub.R = 1.658 min Example 20
N-(5-{2-[(1S)-1-Cyclopropylethyl]-1-oxo-
7-[(2,2,2-trifluoroethyl)sulfamoyl]-2,3-
dihydro-1H-isoindol-5-yl}-4-methyl- 1,3-thiazol-2-yl)acetamide
##STR00052## Prepared using Method E Amine: Commercial
Intermediate: 4 ##STR00053## ##STR00054## .sup.1H-NMR (300 MHz,
DMSO-d.sub.6) .delta. 0.35 (m, 1H), 0.45 (m, 2H), 0.65 (m, 1H),
1.18 (m, 1H), 1.35 (d, 3H), 2,15 (s, 3H) 2.45 (s, 3H), 3.60 (m,
1H), 3.90 (dd, 2H), 4.75 (s, 2H), 7.85 (s, 1H), 8.00 (s, 1H), 10.15
(br, 1H), 12.30 (br s, 1H). m/z (ES+) [M + H].sup.+ = 517.15; acid,
HPLC t.sub.R = 3.671 min Example 21
N-{4-Methyl-5-[1-oxo-2-(propan-2-yl)-7-
sulfamoyl-2,3-dihydro-1H-isoindol-5-yl]-1,3- thiazol-2-yl}acetamide
##STR00055## Prepared using Method E Amine: Commercial
Intermediate: 20 ##STR00056## ##STR00057## .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.30 (s, 1H), 7.96 (d, 1H), 7.87 (d, 1H),
7.74 (s, 2H), 4.64 (s, 2H), 4.46 (m, 1H), 2.43 (s, 3H), 2.18 (s,
3H), 1.28 (d, 6H). m/z (ES+) [M + H].sup.+ = 408.9; base, HPLC
t.sub.R = 1.380 min Example 22 N-(5-{2-[(S)-1-Cyclopropylethyl]-7-
[(methylsulfonyl)amino]-1-oxo-2,3-dihydro-
1H-isoindol-5-yl}-1,3-thiazol-2-yl)acetamide ##STR00058## Prepared
using Method H Amine: Commercial Intermediate: 42 ##STR00059##
##STR00060## .sup.1H-NMR (600 MHz, DMSO-d.sub.6) .delta. 0.21-0.27
(m, 1H), 0.35-0.46 (m, 2H), 0.54-0.61 (m, 1H), 1.14 (dt, 1H), 1.30
(d, 3H), 2.18 (s, 3H), 3.29 (s, 3H), 3.48-3.56 (m, 1H), 4.60 (s,
2H), 7.52 (s, 1H), 7.56 (s, 1H), 7.98 (s, 1H), 9.57 (s, 1H), 12.31
(s, 1H). m/z (ES+), [M + H].sup.+ = 435 Example 23
N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-
[(cyclopropylsulfonyl)amino]-1-oxo-2,3-
dihydro-1H-isoindol-5-yl}-4-methyl-1,3- thiazol-2-yl)acetamide
##STR00061## Prepared using Method H Amine: Commercial
Intermediate: 2 ##STR00062## ##STR00063## m/z (ES+) [M + H].sup.+ =
475.15 Example 24 N-(5-{2-[(1S)-1-Cyclopropylethyl]-1-oxo-7-
[(propylsulfonyl)amino]-2,3-dihydro-1H-
isoindol-5-yl}-4-methyl-1,3-thiazol-2- yl)acetamide ##STR00064##
Prepared using Method H Amine: Commercial Intermediate: 2
##STR00065## ##STR00066## .sup.1H-NMR (600 MHz, DMSO-d.sub.6)
.delta. 0.17-0.29 (m, 1H), 0.40 (dtt, 2H), 0.51-0.63 (m, 1H), 0.94
(t, 3H), 1.13 (dd, 1H), 1.30 (d, 3H), 1.72 (h, 2H), 2.15 (s, 3H),
2.39 (s, 3H), 3.51-3.59 (m, 1H), 4.61 (s, 2H), 7.36 (s, 1H), 7,46
(s, 1H), 9.57 (s, 1H), 12.20 (s, 1H). m/z (ES+) [M + H].sup.+ =
477.8 Example 25 N-(5-{2-[(1S)-1-Cyclopropylethyl]-7-
[(ethylsulfonylamino]-1-oxo-2,3-dihydro-
1H-isoindol-5-yl}-4-methyl-1,3-thiazol- 2-yl)acetamide ##STR00067##
Prepared using Method H Amine: Commercial Intermediate: 2
##STR00068## ##STR00069## .sup.1H-NMR (600 MHz, DMSO-d.sub.6)
.delta. 0.08-0.27 (m, 1H), 0.40 (m, 2H), 0.49-0.66 (m, 1H), 1.13
(m, 1H), 1.23 (t, 3H), 1.30 (d, 3H), 2.15 (s, 3H), 2.39 (s, 3H),
3.49-3.59 (m, 1H), 4.62 (s, 2H), 7.37 (s, 1H), 7.47 (s, 1H), 9.58
(s, 1H), 12.20 (s, 1H). m/z (ES+),
[M + H].sup.+ = 463.15 Example 26
N-(5-{7-[(tert-Butylsulfonyl)amino]-2-[(1S)-
1-cyclopropylethyl]-1-oxo-2,3-dihydro-
1H-isoindol-5-yl}-4-methyl-1,3-thiazol-2- yl)acetamide ##STR00070##
Prepared using Method H Amine: Commercial Intermediate: 2
##STR00071## ##STR00072## .sup.1H-NMR (600 MHz, DMSO-d.sub.6)
.delta. 0.26 (dq, 1H), 0.40 (m, 2H), 0.58 (m, 1H), 1.12-1.16 (m,
1H), 1.30 (d, 3H), 1.36 (s, 9H), 2.15 (s, 3H), 2.38 (s, 3H),
3.51-3.61 (m, 1H), 4.62 (s, 2H), 7.34 (s, 1H), 7.59 (s, 1H), 9.60
(s, 1H), 12.20 (s, 1H). m/z (ES+) [M + H].sup.+ = 491.18 Example 27
N-[5-(2-[(1S)-1-Cyclopropylethyl]-7-
{[(2-methoxyethyl)sulfonyl]amino}-1-
oxo-2,3-dihydro-1H-isoindol-5-yl)-4-
methyl-1,3-thiazol-2-yl]acetamide ##STR00073## Prepared using
Method H Amine: Commercial Intermediate: 2 ##STR00074##
##STR00075## .sup.1H-NMR (600 MHz, DMSO-d.sub.6) .delta. 0.24 (m,
1H), 0.40 (m, 2H), 0.5-0.67 (m, 1H), 1.14 (m, 1H), 1.30 (d, 3H),
2.15 (s, 3H), 2.39 (s, 3H), 3.12 (s, 3H), 3.46-3.57 (m, 1H), 3.59
(t, 2H), 3.67 (t, 2H), 4.61 (s, 2H), 7.36 (s, 1H), 7.51 (s, 1H),
9.59 (s, 1H), 12.20 (s, 1H), m/z (ES+) [M + H].sup.+ = 493.16
Example 28 N-[5-(2-[(1S)-1-Cyclopropylethyl]-7-
{(cyclopropylmethyl)sulfonyl]amino}-1-
oxo-2,3-dihydro-1H-isoindol-5-yl)-4-
methyl-1,3-thiazol-2-yl]acetamide ##STR00076## Prepared using
Method H Amine: Commercial Intermediate: 2 ##STR00077##
##STR00078## .sup.1H-NMR (600 MHz, DMSO-d.sub.6) .delta. 0.2-0.28
(m, 3H), 0.40 (m, 2H), 0.45-0.53 (m, 2H), 0.57 (m, 1H), 1.01 (m,
1H), 1.13 (m, 1H), 1.30 (d, 3H), 2.15 (s, 3H), 2.38 (s, 3H), 3.53-
3.58 (m, 1H), 4.60 (s, 2H), 7.34 (d, 1H), 7.49 (d, 1H), 9.67 (s,
1H), 12.21 (s, 1H). m/z (ES+) [M + H].sup.+ = 489.16 Example 29
N-[5-(2-[(1S)-1-Cyclopropylethyl]-7- {[(1,3-dimethyl-1H-pyrazol-4-
yl)sulfonyl]amino}-1-oxo-2,3-dihydro-
1H-isoindol-5-yl)-4-methyl-1,3-thiazol-2- yl]acetamide ##STR00079##
Prepared using Method H Amine: Commercial Intermediate: 2
##STR00080## ##STR00081## .sup.1H-NMR (600 MHz, DMSO-d.sub.6)
.delta. 0.14-0.3 (m, 1H), 0.39 (m, 2H), 0.5-0.6 (m, 1H), 1.11 (m,
1H), 1.28 (d, 3H), 2.16 (s, 3H), 2.22 (s, 3H), 2.32 (s, 3H),
3.45-3.58 (m, 1H), 3.74 (s, 3H), 4.57 (s, 2H), 7.31 (d, 2H), 8.39
(s, 1H), 9.95 (s, 1H), 12.22 (s, 1H). m/z (ES+) [M + H].sup.+ =
529.17 Example 30 N-(4-Chloro-5-{2-[(1S)-1-cyclopropylethyl]-
7-(methylsulfamoyl)-1-oxo-2,3-dihydro-
1H-isoindol-5-yl}-1,3-thiazol-2-yl)acetamide ##STR00082## Prepared
using Method G Amine: Commercial Intermediate: 37 ##STR00083##
##STR00084## .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 0.30 (m,
1H), 0,44 (m, 2H), 0.61 (m, 1H), 1.17 (m, 1H), 1.33 (d, 3H), 2.22
(s, 3H), 2.52 (s, 3H), 3.73-3.57 (m, 1H), 4,77 (s, 2H), 7,57 (q,
1H), 8.27-8.07 (m, 2H), 12.70 (s, 1H). m/z (ES+) [M + H].sup.+ =
469.20; acid, HPLC t.sub.R = 1.627 min Example 31
6-(8-Aminoinaidazo[1,2-a]pyrazin-3-yl)-
2-[(1S)-1-cyclopropylethyl]-N-methyl-3-oxo-
2,3-dihydro-1H-isoindole-4-sulfonamide ##STR00085## Prepared using
Method F Amine: Commercial Intermediate: 40 ##STR00086##
##STR00087## .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 0.31 (d,
1H), 0.47 (d, 2H), 0,62 (d, 1H), 1.23 (d, 1H), 1.36 (d, 3H), 2.55
(d, 3H), 824 (s, 1H), 3.82-3.60 (m, 1H), 4.81 (s, 2H), 7.08 (s,
2H), 7.39 (d, 1H), 7.62 (d, 1H), 7.92 (d, 1H), 8.00 (s, 1H), 8.08
(s, 1H). m/z (ES+) [M + H].sup.+ = 426.9; base, HPLC t.sub.R =
2.048 min Example 32 N-{5-[2-(2-Cyclopropylpropan-2-yl)-7-
(methylsulfamoyl)-1-oxo-2,3-dihydro-1H-
isoindol-5-yl]-4-methyl-1,3-thiazol-2- yl}acetamide ##STR00088##
Prepared using Method E Amine: Commercial Intermediate 21
##STR00089## ##STR00090## .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. 0.48-0.50 (m, 4H), 1.42 (s, 6H), 1.52-1.56 (m, 1H), 2.18
(s, 3H), 2.44 (s, 3H), 4.86 (s, 2H), 7.61 (q, 1H), 7.85 (d, 1H),
7.99 (d, 1H), 12.32 (s, 1H). m/z (ES+) [M + H].sup.+ = 463.0; base,
HPLC t.sub.R = 3.691 min Example 33
N-(5-{2-(2S)-3,3-Dimethylbutan-2-yl]-7-
(methylsulfamoyl)-1-oxo--2,3-dihydro-1H-
isoindol-5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide ##STR00091##
Prepared using Method E Amine: Commercial Intermediate 22
##STR00092## ##STR00093## 1H NMR (600 MHz, DMSO-d.sub.6) .delta.
0.96 (s, 9H), 1.26 (d, 3H), 2.17 (s, 3H), 2.44 (s, 3H), 4.22 (q,
1H), 4.71 (s, 2H), 7.60 (q, 1H), 7.86 (d, 1H), 7.97 (d, 1H), 12.30
(s, 1H) 3H s under solvent peak. m/z (ES+) [M + H].sup.+ = 465.3;
acid, HPLC t.sub.R = 1.24 min Example 34
N-{[2-tert-Butyl-7-(methylsulfamoyl)-1-
oxo-2,3-dihydro-1H-isoindol-5-yl]-4-
methyl-1,3-thiazol-2-yl}acetamide ##STR00094## Prepared using
Method E Amine: Commercial Intermediate 23 ##STR00095##
##STR00096## .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 1.54 (s,
9H), 2.19 (s, 3H), 2.44 (s, 3H), 2.66 (s, 2H), 4.79 (s, 2H), 7.61
(d, 1H), 7.86 (d, 1H), 7.99 (s, 1H), 12.30 (s, 1H), m/z (ES+) [M +
H].sup.+ = 437; acid, HPLC t.sub.R = 0.855 min Example 35
N-(4-Methyl-5-{7-(methylsulfamoyl)-1-
oxo-2-[(2S)-1,1,1-trifluoropropan-2-yl]-2,3-
dihydro-1H-isoindol-5-yl}-1,3-thiazol-2- yl)acetamide ##STR00097##
Prepared using Method E Amine: Commercial Intermediate 24
##STR00098## ##STR00099## .sup.1H-NMR (600 MHz, DMSO-d.sub.6)
.delta. 1.52 (d, 3H), 2.17 (s, 3H), 2.45 (s, 3H), 2.53 (d, 3H),
4.62 (d, 1H), 4.82 (d, 1H), 5.10 (p, 1H), 7.17 (q, 1H), 7.90 (d,
1H), 8.03 (d, 1H), 12.33 (s, 1H). .sup.19F NMR (282 MHz,
DMSO-d.sub.6) .delta. -73.46. m/z (ES+) [M + H].sup.+ = 477; acid,
HPLC t.sub.R = 1.11 min. Example 36
7-[(3-Cyanophenyl)sulfamoyl]-2-[(1S)-
1-cyclopropylethyl]-oxo-2,3-dihydro-
1H-isoindol-5-yl}-4-methyl-1,3-thiazol- 2-yl)acetamide ##STR00100##
Prepared using Method E Amine: Commercial Intermediate 4
##STR00101## ##STR00102## .sup.1H-NMR (300 MHz, CD.sub.3OD) .delta.
0.42-0.61 (m, 3H), 0.69-0.77 (m, 1H), 1.17-1.26 (m, 1H), 1.46 (d,
3H), 2.23 (s, 3H), 2.39 (s, 3H), 3.77-4.82 (m, 1H), 4.67-4.81 (m,
2H), 7.39- 7.50 (m, 4H), 7.90 (s, 1H), 7.97 (s, 1H). m/z (ES+) [M +
H].sup.+ = 536; acid, HPLC t.sub.R = 1.755 min. Example 37
N-(5-{7-[(3-Cyanophenyl)sulfamoyl]-1-
oxo-2-(propan-2-yl)-2,3-dihydro-1H-isoindol-
5-yl}-4-methyl-1,3-thiazol-2-yl)acetamide ##STR00103## Prepared
using Method E Amine: Commercial Intermediate 20 ##STR00104##
##STR00105## .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 12.30 (s,
1H), 10.51 (s, 1H), 7.97 (s, 1H), 7.90 (s, 1H), 7.58-7.38 (m, 4H),
4.61 (s, 2H), 4.58-4.42 (m, 1H), 2.37 (s, 3H), 2.16 (s, 3H), 1.29
(d, 6H). m/z (ES+) [M + H].sup.+ = 510.1; acid, HPLC t.sub.R = 2.13
min.
Pharmacological Activity
Test A: Enzymatic Activity Assay for Rec Human PI3K.gamma.
[0282] The activity of recombinant human PI3K.gamma.
(aa144-1102)-6His was determined by measuring the ADP level after
phosphorylation of DiC.sub.8--PIP.sub.2 using a commercially
available ADP-Glo.TM. kit from Promega. The assay was carried out
in white low volume 384 well plates in a final volume of 14 .mu.l
at rt. The assay conditions contained the following: 50 mM Tris
buffer pH 7.4, 2.1 mM DTT, 3 mM MgCl.sub.2, 0.05% CHAPS, 20 .mu.M
ATP, 80 .mu.M DiC.sub.8-PIP.sub.2 and 1.2 nM PI3K.gamma.. Potential
inhibitors were made up in DMSO and then diluted in the assay to
give a final concentration of not exceeding 1% (v/v) DMSO. A
10-point half-log dilution series of the inhibitors (highest
concentration typically 0.1 .mu.M) was tested and the pIC.sub.50
determined using a 4-parameter logistic equation in a non-linear
curve fitting routine. Routinely, inhibitors were pre-incubated
with 3 .mu.l of PI3K.gamma. for 15 min prior to the addition of 2
.mu.l substrate mixture for a further 60 min enzyme reaction. The
phosphorylation was stopped with the addition of 3 .mu.l
ADP-Glo.TM. reagent (stop solution) followed by a 40 min
incubation. Prior to detection 6 .mu.l of ADP-Glo.TM. Kinase
Detection Reagent was added and the plates were read in a micro
plate reader using a Luminescence filter.
[0283] The results obtained are shown in Table 7 below.
TABLE-US-00010 TABLE 7 Example PI3K.gamma. activity, pIC.sub.50 1
9.1 2 9.0 3 8.8 4 9.2 5 9.0 6 9.1 7 9.1 8 9.0 9 9.2 10 8.9 11 8.8
12 8.9 13 9.0 14 9.0 15 9.4 16 9.2 17 8.9 18 9.0 19 9.4 20 9.2 21
8.9 22 9.1 23 9.2 24 9.0 25 9.1 26 9.0 27 9.0 28 9.1 29 8.9 30 8.9
31 8.7 32 9.0 33 8.8 34 8.8 35 9.0 36 9.3 37 9.0
* * * * *