OXAZOLE AND THIAZOLE DERIVATIVES AS SELECTIVE PROTEIN KINASE
INHIBITORS (C-KIT)
The present invention relates to compounds of formula I or pharmaceutically acceptable
salts thereof, that selectively modulate, regulate, and/or inhibit signal transduction
mediated by certain native and/or mutant protein kinases implicated in a variety of human
and animal diseases such as cell proliferative, metabolic, allergic, and degenerative
disorders. More particularly, these compounds are potent and selective native and/or
mutant c-kit inhibitors.
Background of the invention
Protein Kinases are receptor type or non-receptor type proteins, which transfer the terminal
phosphate of ATP to aminoacid residues, such as tyrosine, threonine, serine residues, of
proteins, thereby activating or inactivating signal transduction pathways. These proteins
are known to be involved in many cellular mechanisms, which in case of disruption, lead
to disorders such as abnormal cell proliferation and migration as well as inflammation.
As of today, there are over 500 known Protein kinases. Included are the well-known Abl,
Aktl, Akt2, Akt3, ALK, Alk5, A-Raf, Axl, B-Raf, Brk, Btk, Cdk2, Cdk4, Cdk5, Cdk6,
CHK1, c-Raf-1, Csk, EGFR, EphAl, EphA2, EphB2, EphB4, Erk2, Fak, Fes, Fer, FGFR1,
FGFR2, FGFR3, FGFR4, Flt-3, Fms, Frk, Fyn, Gsk3a, Gsk3 , HCK, Her2/Erbb2,
Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jakl, Jak2, Jak3, Jnkl, Jnk2, Jnk3, KDR, Kit,
Lck, Lyn, MAP2K1, MAP2K2, MAP4K4, MAPKAPK2, Met, Mer, MNK1, MLK1,
mTOR, p38, PDGFRa, PDGFRp, PDPK1, PI3Ka, RBKb, RBKg, RBKd, Piml, Pim2,
Pim3, PKC alpha, PKC beta, PKC theta, Plkl, Pyk2, Ret, ROCK1, ROCK2, RON, Src,
Stk6, Syk, TEC, Tie2, TrkA, TrkB, Tyk2, VEGFRl/Flt-1, VEGFR2/Kdr, VEGFR3/FU-4,
Yes, and Zap70.
Abnormal cellular responses triggered by protein kinase-mediated events produce a variety
of diseases. These include autoimmune diseases, inflammatory diseases, neurological and
neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma,
Alzheimer's disease and hormone-related diseases.
Tyrosine kinases are receptor type or non-receptor type proteins, which transfer the
terminal phosphate of ATP to tyrosine residues of proteins thereby activating or
inactivating signal transduction pathways. These proteins are known to be involved in
many cellular mechanisms, which in case of disruption, lead to disorders such as abnormal
cell proliferation and migration as well as inflammation.
As of today, there are about 58 known receptor tyrosine kinases. Included are the wellknown
VEGF receptors (Kim et al., Nature 362, pp. 841-844, 1993), PDGF receptors, ckit,
Flt-3 and the FLK family. These receptors can transmit signals to other tyrosine
kinases including Src, Raf, Frk, Btk, Csk, Abl, Fes/Fps, Fak, Jak, Ack, etc.
Among tyrosine kinase receptors, c-kit is of special interest. Indeed, c-kit is a key receptor
activating mast cells, which have proved to be directly or indirectly implicated in
numerous pathologies for which the Applicant filed WO 03/004007, WO 03/004006, WO
03/003006, WO 03/003004, WO 03/0021 14, WO 03/002109, WO 03/002108, WO
03/002107, WO 03/002106, WO 03/002105, WO 03/039550, WO 03/035050, WO
03/035049, US 60/359,652, US 60/359651 and US 60/449861, WO 04/080462, WO
05/039586, WO 06/135721, WO 07/089069, WO 07/124369, WO 08/137794, WO
08/063888, WO 08/01 1080, WO 09/109071, WO 10/096395.
It was found that mast cells present in tissues of patients are implicated in or contribute to
the genesis of diseases such as autoimmune diseases (rheumatoid arthritis, inflammatory
bowel diseases (IBD)), allergic diseases, bone loss, cancers such as solid tumors,
leukaemia and GIST, tumor angiogenesis, inflammatory diseases, interstitial cystitis,
mastocytosis, graft-versus-host diseases, infection diseases, metabolic disorders, fibrosis,
diabetes and CNS diseases. In these diseases, it has been shown that mast cells participate
in the destruction of tissues by releasing a cocktail of different proteases and mediators
such as histamine, neutral proteases, lipid-derived mediators (prostaglandins,
thromboxanes and leukotrienes), and various cytokines (IL-1, IL-2, IL-3, IL-4, IL-5, IL-6,
IL-8, TNF-ot, GM-CSF, MIP-la, MIP-lb, MIP-2 and IFN-g) .
The c-kit receptor also can be constitutively activated by mutations leading to abnormal
cell proliferation and development of diseases such as mastocytosis (D816V mutation) and
various cancers such as GIST (c-kitA27, a juxtamembrane deletion).
Sixty to 70% of patients presenting with AML have blasts which express c-kit, the receptor
for stem cell factor (SCF) (Broudy, 1997). SCF promotes growth of hematopoietic
progenitors, and act as a survival factor for AML blasts. In some cases ( 1 to 2%) of AML,
a mutation in a conserved residue of the kinase domain (Kit816) resulting in constitutive
activation of c-kit has been described (Beghini et al., 2000; Longley et al., 2001). This gain
of function mutation (Asp to Val/Tyr substitution) has been identified in mast cell
leukemic cell lines and in samples derived from patients with mastocytosis (Longley et al.,
1996). Preliminary results show that this mutation is expressed in most cases of systemic
mastocytosis ([- 60%], P Dubreuil, AFIRMM, study in progress on about 300 patients).
Goal of the invention
The main objective underlying the present invention is therefore to find potent and
selective compounds capable of inhibiting wild type and/or mutated protein kinase, in
particular wild type and/or mutated tyrosine kinase, and more particularly wild type and/or
mutated c-kit.
In connection with the present invention, we have discovered that compounds of formula I
are potent and selective inhibitors of certain protein kinases such as wild type and/or
mutated c-kit. These compounds are good candidates for treating diseases such as
autoimmunes diseases, inflammatory diseases, cancers and mastocytosis.
Description of the invention
Compounds of the present invention were screened for their ability to inhibit a protein
kinase and in particular a tyrosine kinase, and more particularly c-Kit and/or mutant c-Kit
(especially c-Kit D816V).
In a first embodiment, the invention is aimed at compounds of formula I, which may
represent either free base forms of the substances or pharmaceutically acceptable salts
thereof:
Wherein
A is five or six member heterocycle ring;
R is hydrogen, halogen (selected from F, CI, Br or I), an alkyl group containing from 1 to
10 carbon atoms, a thioalkyl group or an alkoxy group;
R2 is halogen (selected from F, CI, Br or I), an aryl group, an haloalkyl or alkyl group
containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom,
notably sulfur, oxygen or nitrogen, optionally substituted with an haloalkyl or alkyl group
containing from 1 to 10 carbon atoms optionally substituted with a solubilising group; as
well as an alkoxy group, a thioalkyl group or an haloalkoxy group; as well as a -COOR, -
NRR', -NR-CO-R', -CONRR', -S0 2NRR' or -NR-S0 2-R' group wherein R and R' are each
independently selected from hydrogen, aryl group, heteroaryl group, alkyl group optionally
substituted with at least one heteroatom, notably oxygen or nitrogen, optionally substituted
with an alkyl group containing from 1 to 10 carbon atoms optionally substituted with a
solubilising group; as well as a heterocycle group or a solubilising group;
R3 is hydrogen, halogen (selected from F, CI, Br or I), cyano, an alkyl group containing
from 1 to 10 carbon atoms or an alkoxy group; as well as CF3, -NRR',-NR-CO-R',
-CONRR', -S0 NRR' group wherein R and R' are each independently selected from
hydrogen, alkyl group optionally substituted with at least one heteroatom, notably sulfur,
oxygen or nitrogen, optionally substituted with an alkyl group containing from 1 to 10
carbon atoms optionally substituted with a solubilising group; as well as a heterocycle
group or a solubilising group;
Q is O or S;
W is N or CR4;
R4 is hydrogen, cyano, CF3, halogen (selected from F, CI, Br or I), a thioalkyl group, an
alkyl group containing from 1 to 10 carbon atoms optionally substituted with at least one
heteroatom, notably sulfur, oxygen or nitrogen, optionally substituted with an alkyl group
containing from 1 to 10 carbon atoms optionally substituted with a solubilising group; as
well as an alkoxy group or an haloalkoxy group, a solubilising group, an heterocycle, -CONRR',
-S0 2-NRR', -NRR', -NR-CO-R' or -NR-S0 2R' group wherein R and R' are each
independently selected from hydrogen, alkyl group optionally substituted with at least one
heteroatom, notably oxygen or nitrogen, optionally substituted with an alkyl group
containing from 1 to 10 carbon atoms optionally substituted with a solubilising group or
heterocycle group;
X is N or CR5;
R5 is hydrogen, cyano, halogen (selected from F, CI, Br or I), an alkyl group containing
from 1 to 10 carbon atoms, an alkoxy group, -CO-OR, -CO-NRR' group wherein R and R'
are each independently selected from hydrogen, alkyl group optionally substituted with at
least one heteroatom, notably sulfur, oxygen or nitrogen, optionally substituted with an
alkyl group containing from 1 to 10 carbon atoms optionally substituted with a solubilising
group or heterocycle group.
In one embodiment, the invention relates to compounds of formula I or pharmaceutically
acceptable salts thereof, wherein R2 is halogen (selected from F, CI, Br or I), an aryl group,
an haloalkyl or alkyl group containing from 1 to 10 carbon atoms optionally substituted
with at least one heteroatom, notably sulfur, oxygen or nitrogen, optionally substituted
with an haloalkyl or alkyl group containing from 1 to 10 carbon atoms optionally
substituted with a solubilising group; as well as an alkoxy group, a thioalkyl group or an
haloalkoxy group; as well as a -NRR', -NR-CO-R', -CONRR', -S0 2NRR' or -NR-S0 2-R'
group wherein R and R' are each independently selected from hydrogen, alkyl group
optionally substituted with at least one heteroatom, notably oxygen or nitrogen, optionally
substituted with an alkyl group containing from 1 to 10 carbon atoms optionally substituted
with a solubilising group; as well as a heterocycle group or a solubilising group.
Unless otherwise specified, the below terms used herein are defined as follows.
As used herein, the term "alkyl" means a saturated straight chain or branched non-cyclic
hydrocarbon having from 1 to 10 carbon atoms, preferably from 1 to 6 carbon atoms, more
preferably from 1 to 4 carbon atoms. Representative saturated straight chain alkyls include
methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl;
while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl,
2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-
methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-
dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-
dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimtheylpentyl, 3,3-
dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-
ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-
ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-
diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl and the like. Alkyl
groups included in compounds of this invention may be optionally substituted with one or
more substituents. Alkyl groups included in compounds of this invention may be
optionally substituted with a solubilising group.
As used herein, the term "aryl" means a monocyclic or polycyclic-aromatic radical
comprising carbon and hydrogen atoms. Examples of suitable aryl groups include, but are
not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as
well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. An aryl
group can be unsubstituted or substituted with one or more substituents. Aryl groups
included in compounds of this invention may be optionally substituted with a solubilising
group.
As used herein, the term "alkoxy" refers to an alkyl group as defined above which is
attached to another moiety by an oxygen atom. Examples of alkoxy groups include
methoxy, isopropoxy, ethoxy, tert-butoxy, and the like. Alkoxy groups may be optionally
substituted with one or more substituents. Alkoxy groups included in compounds of this
invention may be optionally substituted with a solubilising group.
As used herein, the term "thioalkyl" refers to an alkyl group as defined above which is
attached to another moiety by a suflur atom. Thioalkyl groups may be optionally
substituted with one or more substituents. Thioalkyl groups included in compounds of this
invention may be optionally substituted with a solubilising group.
As used herein, the term "heterocycle" refers collectively to heterocycloalkyl groups and
heteroaryl groups.
As used herein, the term "heterocycloalkyl" means a monocyclic or polycyclic group
having at least one heteroatom selected from O, N or S, and which has from 2 to 11 carbon
atoms, which may be saturated or unsaturated, but is not aromatic. Examples of
heterocycloalkyl groups including (but not limited to): piperidinyl, piperazinyl, 2-
oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 4-piperidonyl, pyrrolidinyl,
hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydropyranyl, tetrahydrothiopyranyl,
tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiopyranyl sulfone,
tetrahydrothiopyranyl sulfoxide, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide,
thiomorpholinyl sulfone, 1,3-dioxolane, tetrahydrofuranyl, dihydrofuranyl-2-one,
tetrahydrothienyl, and tetrahydro-l,l-dioxothienyl. Typically, monocyclic heterocycloalkyl
groups have 3 to 7 members. Preferred 3 to 7 membered monocyclic heterocycloalkyl
groups are those having 5 or 6 ring atoms. A heteroatom may be substituted with a
protecting group known to those of ordinary skill in the art, for example, the hydrogen on a
nitrogen may be substituted with a tert-butoxycarbonyl group. Furthermore,
heterocycloalkyl groups may be optionally substituted with one or more substituents. In
addition, the point of attachment of a heterocyclic ring to another group may be at either a
carbon atom or a heteroatom of a heterocyclic ring. Only stable isomers of such substituted
heterocyclic groups are contemplated in this definition.
As used herein, the term "heteroaryl" or like terms means a monocyclic or polycyclic
heteroaromatic ring comprising carbon atom ring members and one or more heteroatom
ring members (such as, for example, oxygen, sulfur or nitrogen). Typically, a heteroaryl
group has from 1 to about 5 heteroatom ring members and from 1 to about 14 carbon atom
ring members. Representative heteroaryl groups include pyridyl, 1-oxo-pyridyl, furanyl,
benzo[l,3]dioxolyl, benzo[l,4]dioxinyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl,
isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl,
triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl, benzofuryl,
indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl,
benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl,
purinyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl, imidazo[l,2-a]pyridyl, and
benzo(b)thienyl. A heteroatom may be substituted with a protecting group known to those
of ordinary skill in the art, for example, the hydrogen on nitrogen may be substituted with a
tert-butoxycarbonyl group. Heteroaryl groups may be optionally substituted with one or
more substituents. In addition, nitrogen or sulfur heteroatom ring members may be
oxidized. In one embodiment, the heteroaromatic ring is selected from 5-8 membered
monocyclic heteroaryl rings. The point of attachment of a heteroaromatic or heteroaryl ring
to another group may be at either a carbon atom or a heteroatom of the heteroaromatic or
heteroaryl rings.
As used herein, the term "haloalkyl" means an alkyl group as defined above in which one
or more (including all) the hydrogen radicals are replaced by a halo group, wherein each
halo group is independently selected from -F, -CI, -Br, and -I. The term "halomethyl"
means a methyl in which one to three hydrogen radical(s) have been replaced by a halo
group. Representative haloalkyl groups include trifluoromethyl, bromomethyl, 1,2-
dichloroethyl, 4-iodobutyl, 2-fluoropentyl, and the like. Haloalkyl groups may be
optionally substituted with one or more substituents. Haloalkyl groups included in
compounds of this invention may be optionally substituted with a solubilising group.
As used herein, the term "haloalkoxy" means an alkoxy group as defined above in which
one or more (including all) the hydrogen radicals are replaced by a halo group, wherein
each halo group is independently selected from -F, -CI, -Br, and -I. Representative
haloalkoxy groups include trifluoromethoxy, bromomethoxy, 1,2-dichloroethoxy, 4-
iodobutoxy, 2-fluoropentoxy, and the like. Haloalkoxy groups may be optionally
substituted with one or more substituents. Haloalkoxy groups included in compounds of
this invention may be optionally substituted with a solubilising group.
As used herein the term "substituent" or "substituted" means that a hydrogen radical on a
compound or group is replaced with any desired group that is substantially stable to
reaction conditions in an unprotected form or when protected using a protecting group.
Examples of preferred substituents are those found in the exemplary compounds and
embodiments disclosed herein, as well as halogen; alkyl as defined above; hydroxy; alkoxy
as defined above; nitro; thiol; thioalkyl as defined above; cyano; haloalkyl as defined
above; haloalkoxy as defined above; cycloalkyl, which may be monocyclic or fused or
non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or a
solubilising group.
As used herein, the term "solubilising" group means a group which has a hydrophilic
character sufficient to improve or increase the water-solubility of the compound in which it
is included, as compared to an analog compound that does not include the group. The
hydrophilic character can be achieved by any means, such as by the inclusion of functional
groups that ionize under the conditions of use to form charged moieties (e.g., carboxylic
acids, sulfonic acids, phosphoric acids, amines, etc.); groups that include permanent
charges (e.g., quaternary ammonium groups); and/or heteroatoms or heteroatomic groups
(e.g., O, S, N, NH, N-(CH2) R, N-(CH2) -C(0)R, N-(CH2) -C(0)OR, N-(CH2)z-S(0) 2R, N-
(CH2) -S(0) 2OR, N-(CH2) -C(0)NRR , where z is an integer ranging from 0 to 6, R and
R' each independently are selected from hydrogen, an alkyl group containing from 1 to 10
carbon atoms and optionally substituted with one or more hetereoatoms such as halogen
(selected from F, CI, Br or I), oxygen, and nitrogen; as well as alkoxy group containing
from 1 to 10 carbon atoms; as well as aryl and heteroaryl group.
In some embodiments, the solubilising group is a heterocycloalkyl that optionally includes
from 1 to 5 substituents, which may themselves be solubilising groups.
In a s ecific embodiment, the solubilising group is of the formula:
where L is selected from the group consisting of CH and N, M is selected from the group
consisting of -CH(R)-, -CH2-, -0-, -S-, -NH-, -N(-(CH2)Z-R)-, -N(-(CH2) -C(0)R)-, -N(-
(CH2) -C(0)OR)-, -N(-(CH2) -S(0) 2R)-, -N(-(CH2) -S(0) OR)- and -N(-(CH2) -
C(0)NRR )-, where z is an integer ranging from 0 to 6, R and R' each independently are
selected from hydrogen, an alkyl group containing from 1 to 10 carbon atoms and
optionally substituted with one or more hetereoatoms such as halogen (selected from F, CI,
Br or I), oxygen, and nitrogen; as well as alkoxy group containing from 1 to 10 carbon
atoms, NRR' group wherein R and R' are each independently selected from hydrogen, alkyl
group as defined above optionally substituted with at least one heteroatom, notably oxygen
or nitrogen optionally substituted with an alkyl group containing from 1 to 10 carbons
optionally substituted; as well as aryl and heteroaryl group, with the proviso that L and M
are not both simultaneously CH and CH2, respectively.
In another specific embodiment, the solubilising group is selected from the group
consisting of morpholinyl, piperidinyl, N-(Ci-C 6)alkyl piperidinyl, in particular N-methyl
piperidinyl and N-ethyl piperidinyl, N-(4-piperidinyl)piperidinyl, 4-(lpiperidinyl)
piperidinyl, 1-pyrrolidinylpiperidinyl, 4-morpholinopiperidinyl, 4-(N-methyl-lpiperazinyl)
piperidinyl, piperazinyl, N-(Ci-C 6)alkylpiperazinyl, in particular Nmethylpiperazinyl
and N-ethyl piperazinyl, N-(C3-C6)cycloalkyl piperazinyl, in particular
N-cyclohexyl piperazinyl, pyrrolidinyl, N-(Ci-C 6)alkyl pyrrolidinyl, in particular N-methyl
pyrrolidinyl and N-ethyl pyrrolidinyl, diazepinyl, N-(Ci-C )alkyl azepinyl, in particular Nmethyl
azepinyl and N-ethyl azepinyl, homopiperazinyl, N-methyl homopiperazinyl, Nethyl
homopiperazinyl, imidazolyl, and the like.
Among the compounds of formula I in which ring A is depicted above, the present
invention is directed to compounds of the following formula II:
II
Wherein:
A ring is a five member heterocycle ring;
Ri is hydrogen, halogen (selected from F, CI, Br or I), an alkyl group containing from 1 to
10 carbon atoms or an alkoxy group;
R2 is halogen (selected from F, CI, Br or I), an aryl group, an haloalkyl or alkyl group
containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom,
notably oxygen or nitrogen, optionally substituted with an haloalkyl or alkyl group
containing from 1 to 10 carbon atoms optionally substituted with a solubilising group; as
well as an alkoxy group or an haloalkoxy group; as well as a -COOR, -NRR',-NR-CO-R',
-CONRR' or -NR-S0 2-R' group wherein R and R' are each independently selected from
hydrogen, aryl group, heteroaryl group, alkyl group optionally substituted with at least one
heteroatom, notably oxygen or nitrogen, optionally substituted with an alkyl group
containing from 1 to 10 carbon atoms optionally substituted with a solubilising group; as
well as a heterocycle group or a solubilising group;
R3 is hydrogen, halogen (selected from F, CI, Br or I), cyano, an alkyl group containing
from 1 to 10 carbon atoms or an alkoxy group; as well as CF3, -NRR',-NR-CO-R',
-CONRR' group wherein R and R' are each independently selected from hydrogen, alkyl
group optionally substituted with at least one heteroatom, notably oxygen or nitrogen,
optionally substituted with an alkyl group containing from 1 to 10 carbon atoms optionally
substituted with a solubilising group; as well as a heterocycle group or a solubilising
group;
Q is O or S;
W is N or CR4;
R4 is hydrogen, cyano, CF3, halogen (selected from F, CI, Br or I), an alkyl group
containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom,
notably oxygen or nitrogen, optionally substituted with an alkyl group containing from 1 to
10 carbon atoms optionally substituted with a solubilising group; as well as an alkoxy
group or an haloalkoxy group, a solubilising group, an heterocycle, -CO-NRR', S0 2-NRR',
-NRR', -NR-CO-R' or -NR-S0 2R' group wherein R and R' are each independently selected
from hydrogen, alkyl group optionally substituted with at least one heteroatom, notably
oxygen or nitrogen, optionally substituted with an alkyl group containing from 1 to 10
carbon atoms optionally substituted with a solubilising group or heterocycle group;
X is N or CR5;
R5 is hydrogen, cyano, halogen (selected from F, CI, Br or I), an alkyl group containing
from 1 to 10 carbon atoms, an alkoxy group, -CO-OR, -CO-NRR' group wherein R and R'
are each independently selected from hydrogen, alkyl group optionally substituted with at
least one heteroatom, notably oxygen or nitrogen, optionally substituted with an alkyl
group containing from 1 to 10 carbon atoms optionally substituted with a solubilising
group or heterocycle group;
M is C or N;
V is CH2, CR or NR7;
R is hydrogen or an alkyl group containing from 1 to 10 carbon atoms optionally
substituted with a solubilising group or heterocycle group;
Y is N, CR or CR R ;
Z is N, NR , CR or CR R9;
R8 is hydrogen, an alkyl group containing from 1 to 10 carbon atoms or an alkoxy group;
R 9 is hydrogen or an alkyl group containing from 1 to 10 carbon atoms.
In one embodiment, the invention relates to compounds of formula II or pharmaceutically
acceptable salts thereof, wherein R2 is halogen (selected from F, CI, Br or I), an aryl group,
an haloalkyl or alkyl group containing from 1 to 10 carbon atoms optionally substituted
with at least one heteroatom, notably oxygen or nitrogen, optionally substituted with an
haloalkyl or alkyl group containing from 1 to 10 carbon atoms optionally substituted with a
solubilising group; as well as an alkoxy group or an haloalkoxy group; as well as a -NRR',
-NR-CO-R', -CONRR' or -NR-S0 2-R' group wherein R and R' are each independently
selected from hydrogen, alkyl group optionally substituted with at least one heteroatom,
notably oxygen or nitrogen, optionally substituted with an alkyl group containing from 1 to
10 carbon atoms optionally substituted with a solubilising group; as well as a heterocycle
group or a solubilising group.
Examples of preferred compounds of the above formula are depicted in table 1 below:
Table 1
Ex Chemical structure Name Ή NM LCMS
l-{3-Chloro-5-[2- (300 MHz, DMSO-d ) d 10.26 (br s, IH), 7.70
(3,5-dimethyl- (br s, IH), 7.60 - 7.53 (d, J = 5.3 Hz, 2H), 7.38 -
001 phenylamino)- 7.16 (m, 4H), 6.6 1 (br s, IH), 3.96 - 3.82 (m,
oxazol-5-yl]- 2H), 3.52 - 3.40 (m, 2H), 2.26 (s, 6H).
phenyl}- (APCI+) «/ 383 (M+H)+
imidazolidin-2-one Retention time = 3.76 min (method 2)
l-[3-[2-((5- (300 MHz, DMSO-d ) d 9.26 (s, IH), 7.82 (s,
Ethoxymethyl) -2- IH), 7.42 (s, IH), 7.29 (s, IH), 7.20-7. 12 (m,
methyl- IH), 7.14 (s, IH), 7.02 (s, IH), 6.93 (d, J = 7.6
phenylamino)- Hz, IH), 6.80 (s, IH), 4.50-435 (m, IH), 4.41 (s,
002 oxazol-5-yl]-5-(l- 3H), 3.96 - 3.76 (m, 2H), 3.50-3.20 (m, 4H),
methyl-piperidin-4- 2.60-2.50 (m, 2H), 2.27 (s, 3H), 2.20-2. 10 (m,
yloxy)-phenyl]- 2H), 2.18 (s, 3H), 2.00-1 .85 ( , 2H), 1.70-1 .55
imidazolidin-2-one (m, 2H), 1.14 (t, J = 7.0 Hz, 3H).
(APCI+) mlz 506 (M+H)+
Retention time = 2.36 min (method 2)
l - {3-[2-((5- Ή NMR (300 MHz, CDC13) a 7.92 (s, IH), 7.33
Ethoxymethyl) -2- (s, IH), 7.1 8 7.09 (m, 3H), 7.05 - 6.95 (m, 2H),
methyl- 4.50 (s, 2H), 4.28 (dq, J = 12.2, 6.1 Hz, IH), 3.58
003 phenylamino)- - 3.47 (m, 2H), 2.69 - 2.43 (m, 2H), 2.34 (s, 3H),
oxazol-5-yl]-5- 2.30 (s, 3H), 1.8 1 - 1.65 (m, 2H), 1.27 - 1.16 (m,
methyl-phenyl}-5- 6H).
methyl-pyrrolidin-2- (APCI+) mlz 42 1 (M+H)+
one Retention time = 3.1 min (method 2)
4-Methoxy-l- {4-[2- (300 MHz, DMSO-d ) d 9.63 (br s, IH), 8.43 (s,
((5-methoxymethyl)- IH), 8.27 (dd, J = 5.4, 0.6 Hz, IH), 7.79 (d, J =
2-methyl- 1.3 Hz, IH), 7.7 1 (s, IH), 7.26 (dd, J = 5.4, 1.4
004 phenylamino)- Hz, IH), 7.19 (d, J = 7.7 Hz, IH), 6.97 (dd, J =
oxazol-5 -yl] -pyridin- 7.7, 1.4 Hz, IH), 5.41 (s, IH), 4.55 (s, 2H), 4.39
2-yl}-l ,5-dihydro- (s, 2H), 3.88 (s, 3H), 3.29 (s, 3H), 2.30 (s, 3H).
pyrrol-2-one (APCI+) mlz 407 (M+H)+
Retention time = 3. 13 mins (method 2)
l-Methyl-3-(3- {2-[2- NMR (300 MHz, CDC13) a 8.09 (d, J = 1.1
methyl-5-(2- Hz, IH), 8.00 (d, J = 2.5 Hz, IH), 7.5 1 (dd, =
pyrrolidin- 1-yl- 4.1, 1.3 Hz, 2H), 7.42 7.36 (m, IH), 7.34 (s,
ethoxy)- IH), 7.24 (d, = 8.4 Hz, IH), 6.92 (s, IH), 6.74
005 phenylamino]- (dd, = 8.3, 2.6 Hz, IH), 4.34 (t, J = 6.1 Hz, 2H),
oxazol-5-yl}- 4.04 (dd, J = 9.0, 6.8 Hz, 2H), 3.73 - 3.67 ( ,
phenyl)- 2H), 3.15 - 3.02 (m, 5H), 2.87 - 2.77 (m, 4H),
imidazolidin-2-one 2.45 (s, 3H), 2.03 - 1.93 (m, 3H).
(ES+) mlz 463 (M+H)+
Retention time = 2.20 min (method 2)
1- {4-[2-((5- (300 MHz, DMSO-d ) 5 9.64 (s, IH), 8.20-8. 15
Ethoxymethyl)-2- (m, 2H), 7.84 (s, IH), 7.75 (s, IH), 7.28-7-1 8 (m,
methyl- 3H), 7.02 (d, = 7.8 Hz, IH), 4.42 (s, 2H), 4.03 -
006 phenylamino)- 3.94 (m, 2H), 3.47 (q, J = 7.0 Hz, 2H), 3.39 (t, J
thiazol-5-yl]-pyridin- = 8.0 Hz, 2H), 2.26 (s, 3H), 1.15 (t, J = 7.0 Hz,
2-yl} -imidazolidin-2- 3H).
one (APCI+) / 410 (M+H)+
H Retention time = 2.69 min (method 2)

E it Chemical structure Name NMR/LCMS
1- {4-[2-(5- (300 MHz, MeOH-d 4) d 8.40 (d, J = 5.7 Hz, IH),
(Ethoxymethyl)-2- 8.29 (br s, IH), 8.00 (br s, IH), 7.59 (br s, IH),
methyl- 7.49 (d, J = 5.4 Hz, IH), 7.35 (d, J = 7.9 Hz, IH),
032 phenylamino)- 7.25 (d, J = 6.6 Hz, IH), 7.08 (br s, IH), 4.55 (s,
oxazol-5-yl]-pyridin- 2H), 3.63 (q, J = 7.0 Hz, 2H), 2.38 (s, 3H), 2.15
2-yl}-l ,3-dihydro- (s, 3H), 1.27 (t, = 7.0 Hz, 3H).
HCI imidazol-2-one (APCI+) mi 407 (M+H)+
hydrochloride Retention time = 2.99 min (method 2)
1- {4-[2-(5-Methoxy- NMR (300 MHz, DMSO-d ) a 9.57 (s, IH),
2-methyl- 8.33 (s, IH), 8.24 (d, J = 4.8 Hz, IH), 7.67 (s,
phenylamino)- IH), 7.53 (s, IH), 7.27 (s, IH), 7.19 (d, J = 5.3
033 oxazol-5 -yl] -pyridin- Hz, IH), 7.09 (d, J = 8.5 Hz, IH), 4.06 - 3.96 (m,
2-yl} -imidazolidin-2- 2H), 3.72 (s, 3H), 3.46 - 3.37 (m, 2H), 2.22 (s,
one 3H).
(ES+) mlz 366 (M+H)+
H Retention time = 2.36 min (method 2)
1- {4-[2-((5- NMR (300 MHz, DMSO-d ) a 9.55 (s, IH),
Hydroxymethyl)-2- 8.33 (s, IH), 8.23 (d, J = 5.4 Hz, IH), 7.74 (s,
methyl- IH), 7.64 (s, IH), 7.26 (s, IH), 7.17 (dd, J = 8.9,
034 phenylamino)- 4.7 Hz, IH), 6.97 (d, J = 8.0 Hz, IH), 5.12 (t, J =
oxazol-5-yl] -pyridin- 5.7 Hz, IH), 4.46 (d, J = 5.7 Hz, 2H), 4.06 - 3.96
N 2-yl} -imidazolidin-2- (m, 2H), 3.41 (t, J = 8.0 Hz, 2H), 2.27 (s, 3H).
one (ES+) mlz 366 (M+H)+
H Retention time = 1.91 min (method 2)
1- {4-[2-((5- (300 MHz, DMSO-d ) d 9.62 (s, IH), 8.43 (s,
Ethoxymethyl)-2- IH), 8.33 (d, J = 5.4 Hz, IH), 7.75 (s, IH), 7.70
methyl- (s, IH), 7.3 1 (dd, J = 5.3, 1.5 Hz, IH), 7.18 (d, J
phenylamino)- = 7.7 Hz, IH), 6.97 (d, J = 7.6 Hz, IH), 4.42 (s,
035 oxazol-5-yl]-pyridin- 2H), 4.00 (t, J = 7.1 Hz, 2H), 3.47 (dd, J = 14.0,
2-yl} -pyrrolidin-2- 7.0 Hz, 2H), 2.59 (t, J = 8.0 Hz, 2H), 2.28 (s,
one 3H), 2.04 (dt, J = 15.5, 7.7 Hz, 2H), 1.14 (t, J =
7.0 Hz, 3H).
(APCI+) mlz 393 (M+H)+
Retention time = 3.29 min (method 2)
l - {3-[2-((5- NMR (300 MHz, CDC13) a 7.97 (s, IH), 7.60
Ethoxymethyl)-2- (s, IH), 7.27 (s, IH), 7.17 - 7.07 (m, 3H), 6.98
methyl- (d, J = 7.7 Hz, IH), 4.50 (s, 2H), 3.85 (t, J = 7.0
036 phenylamino)- Hz, 2H), 3.52 (q, J = 7.0 Hz, 2H), 2.59 (dd, J =
oxazol-5-yl]-5- 10.2, 5.9 Hz, 2H), 2.34 (s, 3H), 2.30 (s, 3H), 2.18
methyl-phenyl}- 2.05 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H).
pyrrolidin-2-one (ES+) mlz 407 (M+H)+
Retention time = 2.52 min (method 2)
1- {4-[2-((5- NMR (300 MHz, CDC13) a 8.35 (s, IH), 8.09
Ethoxymethyl)-2- (d, J = 5.4 Hz, IH), 7.89 (s, IH), 7.17 (s, IH),
methyl- 7.05 (d, J = 7.7 Hz, 2H), 6.90 (dd, J = 5.5, 4.0
037 phenylamino)- Hz, 2H), 4.40 (d, J = 9.9 Hz, 2H), 3.98 (t, J = 7.2
oxazol-5-yl] -pyridin- Hz, 2H), 3.45 - 3.39 (m, 4H), 2.8 1 (s, 3H), 2.21
2-yl}-3-methyl- (s, 3H), 1.13 (t, = 7.1 Hz, 3H).
imidazolidin-2-one (ES+) mlz 409 (M+H)+
Retention time = 2.58 min (method 2)

8.34 (d,
(s, IH),
IH),
Hz, IH),
- 2.66 (m,
-
8.36 (d,
7.36 -
(d, J
-
(s, 4H),
9.65
Hz, IH),
(d, J =
Hz,
2H),
3H).
9.63
IH),
(dd, J
7.01
4.05 (t,
(t, J =
3H),
8.35 (br
IH),
(d, J =
(d, J =
- 3.99
- 3.70 (m,
IH), 8.35 (br
IH),
= 5.3
J = 8.3
(m,
5.7 Hz,
8.32 (br
IH),
(m, 2H),
2H),
2.40 -
8.32 (br
s, IH),
(m, 2H),
- 4.07
J = 10.5,
(d, J
7.80 (s,
9.2 Hz,
7.23
7.02
4.04 (t,
- 3.52
J = 5.8
8.33 (s,
7.55
J =
6.60
8.7
- 3.75 (m,
Hz,
(d, J
(d, J =
(dd, J
J = 8.3,
3.80 (m,
Hz,
(m,
7.84 (br
IH),
- 7.13
2H),
(d, J = 6 .1

Among the compounds of formula I in which ring A is depicted above, the present
invention is directed to compounds of the following formula III:
III
Wherein:
A ring is a six member heterocycle ring;
Rj is hydrogen, halogen (selected from F, CI, Br or I), an alkyl group containing from 1 to
10 carbon atoms or an alkoxy group;
R2 is halogen (selected from F, CI, Br or I), an aryl group, an haloalkyl or alkyl group
containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom,
notably oxygen or nitrogen, optionally substituted with an haloalkyl or alkyl group
containing from 1 to 10 carbon atoms optionally substituted with a solubilising group; as
well as an alkoxy group or an haloalkoxy group; as well as a -COOR, -NRR',-NR-CO-R',
-CONRR' or -NR-S0 2-R' group wherein R and R' are each independently selected from
hydrogen, aryl group, heteroaryl group, alkyl group optionally substituted with at least one
heteroatom, notably oxygen or nitrogen, optionally substituted with an alkyl group
containing from 1 to 10 carbon atoms optionally substituted with a solubilising group; as
well as a heterocycle group or a solubilising group;
R3 is hydrogen, halogen (selected from F, CI, Br or I), cyano, an alkyl group containing
from 1 to 10 carbon atoms or an alkoxy group; as well as CF3, -NRR',-NR-CO-R',
-CONRR' group wherein R and R' are each independently selected from hydrogen, alkyl
group optionally substituted with at least one heteroatom, notably oxygen or nitrogen,
optionally substituted with an alkyl group containing from 1 to 10 carbon atoms optionally
substituted with a solubilising group; as well as a heterocycle group or a solubilising
group;
Q is O o S;
W is N or C ;
R 4 is hydrogen, cyano, CF3, halogen (selected from F, CI, Br or I), an alkyl group
containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom,
notably oxygen or nitrogen, optionally substituted with an alkyl group containing from 1 to
10 carbon atoms optionally substituted with a solubilising group; as well as an alkoxy
group or an haloalkoxy group, a solubilising group, an heterocycle, -CO-NRR', S0 -NRR',
-NRR', NR-CO-R' or NR-S0 2R' group wherein R and R' are each independently selected
from hydrogen, alkyl group optionally substituted with at least one heteroatom, notably
oxygen or nitrogen, optionally substituted with an alkyl group containing from 1 to 10
carbon atoms optionally substituted with a solubilising group or heterocycle group;
X is N or CR5;
R5 is hydrogen, cyano, halogen (selected from F, CI, Br or I), an alkyl group containing
from 1 to 10 carbon atoms, an alkoxy group, -CO-OR, -CO-NRR' group wherein R and R'
are each independently selected from hydrogen, alkyl group optionally substituted with at
least one heteroatom, notably oxygen or nitrogen, optionally substituted with an alkyl
group containing from 1 to 10 carbon atoms optionally substituted with a solubilising
group or heterocycle group;
M is C o ;
V is N, CH2, CR7 or NR7;
R7 is hydrogen, cyano or an alkyl group containing from 1 to 10 carbon atoms optionally
substituted with a solubilising group or heterocycle group;
Y is N, CR or CR R ;
Z is N, CR8 or CR R9;
T is N, C=0, CR or CR8R9;
R is hydrogen, a halogen (selected from F, CI, Br or I), an hydroxyl group, an alkyl group
containing from 1 to 10 carbon atoms or an alkoxy group;
R9 is hydrogen or an alkyl group containing from 1 to 10 carbon atoms.
In one embodiment the invention relates to compounds of formula III or pharmaceutically
acceptable salts thereof, wherein R2 is halogen (selected from F, CI, Br or I), an aryl group,
an haloalkyl or alkyl group containing from 1 to 10 carbon atoms optionally substituted
with at least one heteroatom, notably oxygen or nitrogen, optionally substituted with an
haloalkyl or alkyl group containing from 1 to 10 carbon atoms optionally substituted with a
solubilising group; as well as an alkoxy group or an haloalkoxy group; as well as a -NRR',
-NR-CO-R', -CONRR' or -NR-S0 2-R' group wherein R and R' are each independently
selected from hydrogen, alkyl group optionally substituted with at least one heteroatom,
notably oxygen or nitrogen, optionally substituted with an alkyl group containing from 1 to
10 carbon atoms optionally substituted with a solubilising group; as well as a heterocycle
group or a solubilising group.
Examples of preferred compounds of the above formula are depicted in table 2 below:
Table 2

- 7.99
7.62
7.16
IH), 6.42
2.33 (s,
(d, J =
(m, 4H),
Hz, IH),
IH),
- 2.34
(d, = 8.2
(s, IH),
(d,
6.70
(s, 2H),
9H).
(s,
7.92
(m,
(d, J
IH),
9.67 (s,
(m,
= 7.1 Hz,
J = 9.4
2H),
9.61 (s,
7.86
(t, J = 7.1
= 9.3 Hz,
2.60
6H).
(d, J =
J = 6.7
(d, J = 7.8
J = 6.8
2H),
(t, J =

In one embodiment, which can be combined with other embodiments of the invention, the
invention relates to compounds of formula I or pharmaceutically acceptable salts thereof
wherein:
Ri is H or a (Ci-C6)alkyl;
R2 is H;
a halogen;
COOH;
a (Ci-C6)alkyl optionally substituted by a group -NRi Rn, by OH or by a (Ci-
C4)alkoxy optionally substituted by OH where Rio and R are each independently
H or (Ci-C4)alkyl optionally substituted with amino, (Ci-C4)alkylamino or di(Ci-
C4)alkylamino; or Rio and form, together with the nitrogen atom to which they
are bonded, a 5- or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms
selected from O, S and N, in particular pyrrolidine, piperidine, piperazine and
morpholine;
a (Ci-C )alkoxy optionally substituted by OH, a (Ci-C4)alkoxy or a group
- NRj Ri3 where Ri2 and R13 are each independently H or (Ci-C4)alkyl; or R 2 and
Ri3 form, together with the nitrogen atom to which they are bonded, a 5- or 6-
membered heterocycloalkyl containing 1 or 2 heteroatoms selected from O, S and
N, in particular pyrrolidine, piperidine, piperazine and morpholine, said
heterocycloalkyl being optionally substituted with 1 to 3 (Ci-C4)alkyls;
a group -OR 14 where R 4 is a 5- or 6-membered heterocycloalkyl containing 1 or 2
heteroatoms selected from O, S and N, in particular pyrrolidine, piperidine,
piperazine and morpholine, said heterocycloalkyl being optionally substituted with
1 to 3 (Ci-C4)alkyls;
a group -CONR15R16 where R15 and Ri are each independently H or a (Ci-C4)alkyl
optionally substituted with a ( - alkoxy or with a 5- or 6-membered
heterocycloalkyl containing 1 or 2 heteroatoms selected from O, S and N, in
particular morpholine; or R 5 and R16 form, together with the nitrogen atom to
which they are bonded, a 5- or 6-membered heterocycloalkyl containing 1 or 2
heteroatoms selected from O, S and N, in particular pyrrolidine, piperidine,
piperazine and morpholine;
a group N R -R 1 where is H or (Ci-C4)alkyl and Ri is H; a (C1-C4)alkyl
optionally substituted with a (Ci-C4)alkoxy; or a 5- or 6-membered heteroaryl
containing 1 to 3 heteroatoms selected from O, S and N, in particular pyridine,
pyrimidine and thiazole;
a group -NRi 9COR20 where R1 is H or (C C )alkyl and R20 is H or a (C C4)alkyl
optionally substituted with amino, (Ci-C4)alkylamino or di(Ci-C )alkylamino or
with a 5- or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms selected
from O, S and N, in particular pyrrolidine, piperidine, piperazine and morpholine,
said heterocycloalkyl being optionally substituted with 1 to 3 (Ci-C )alkyls; or
a 5- or 6-membered heterocycloalkyl or heteroaryl containing 1 or 2 heteroatoms
selected from O and N, in particular piperidine and furane, said heterocycloalkyl or
heteroaryl being optionally substituted with an oxo group or with a (Ci-C4)alkyl
optionally substituted with amino, (Ci-C )alkylamino or di(C C )alkylamino;
R3 is H; cyano; CF3; a halogen; a (Ci-C4)alkyl; or a (Ci-C4)alkoxy;
Q is O or S, preferably Q is O;
W is N or CR2i where R i is
H;
a halogen;
CN;
CF ;
OCF3;
a (C1-C4)alkyl optionally substituted with a 5- or 6-membered heterocycloalkyl
containing 1 or 2 heteroatoms selected from O and N, in particular pyrrolidine,
piperidine, piperazine and morpholine;
a (Ci-C4)alkoxy;
a group -0(CH 2) R22 where n is 0, 1, 2 or 3 and R22 is H; a (C -C4)alkoxy; a group
-NR 22aR22 where R22a and R22b are each independently H or a (Ci-C4)alkyl; or a 5-
or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from O and
N, in particular pyrrolidine, piperidine, piperazine and morpholine, said
heterocycloalkyl being optionally substituted with 1 to 3 (Ci-C4)alkyls;
a group -NR 23R 4 where R23 and R 4 are each independently H or a (Ci-C4)alkyl
optionally substituted with a (Ci-C4)alkoxy; R24 can also represent a group
-S0 2(Ci-C )alkyl; or R23 and R2 form, together with the nitrogen atom to which
they are bonded, a 5- or 6-membered heterocycloalkyl or heteroaryl containing 1 or
2 heteroatoms selected from O, S and N, in particular pyrrolidine, piperidine,
piperazine, morpholine and pyrazole, said heterocycloalkyl being optionally
substituted with 1 to 3 (Ci-C4)alkyls;
X is N or CR25 where R2 is H; CN; a (Ci-C4)alkyl; or a group -COO(C C4)alkyl; and
A is a 5- or 6-membered heterocycloalkyl or heteroaryl containing 1 to 3 heteroatoms
selected from O and N, in particular piperidine, piperazine, pyrrolidine, morpholine,
imidazolidine, dihydroimidazole, triazole, dihydropyridine and tetrahydropyridine, said
heterocycloalkyl or heteroaryl being optionally substituted with 1 to 3 substituents selected
from: an oxo group; a halogen; a (Ci-C4)alkyl optionally substituted with amino, (Ci-
C4)alkylamino, di(Ci-C4)alkylamino or a 5- or 6-membered heterocycloalkyl containing 1
or 2 heteroatoms selected from O and N, in particular piperidine; and a (Ci-C4)alkoxy.
Within this family of compounds those where R2, R3 and W are as defined below are
preferred:
R2 is H;
a halogen;
a (Ci-C6)alkyl optionally substituted by a group -NRi 0Rii or by a (Ci-C 4)alkoxy
optionally substituted by OH where Rio and R are each independently H or ( -
C4)alkyl optionally substituted with amino, (C1-C4)alkylamino or di(Ci-
C4)alkylamino; or R10 and R form, together with the nitrogen atom to which they
are bonded, a 5- or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms
selected from O, S and N, in particular pyrrolidine, piperidine, piperazine and
morpholine;
a (Ci -C )alkoxy optionally substituted by OH, a (Ci-C 4)alkoxy or a group
-NR[ 2Ri3 where Ri2 and R13 are each independently H or (Ci-C 4)alkyl; or R12 and
Ri3 form, together with the nitrogen atom to which they are bonded, a 5- or 6-
membered heterocycloalkyl containing 1 or 2 heteroatoms selected from O, S and
N, in particular pyrrolidine, piperidine, piperazine and morpholine, said
heterocycloalkyl being optionally substituted with 1 to 3 (Ci-C4)alkyls;
a group -ORi where Ri4 is a 5- or 6-membered heterocycloalkyl containing 1 or 2
heteroatoms selected from O, S and N, in particular pyrrolidine, piperidine,
piperazine and morpholine, said heterocycloalkyl being optionally substituted with
1 to 3 (C,-C4)alkyls;
a group -CONR15R16 where R15 and Ri6 are each independently H or a (Ci-C 4)alkyl
optionally substituted with a (Ci-C 4)alkoxy; or R15 and Ri6 form, together with the
nitrogen atom to which they are bonded, a 5- or 6-membered heterocycloalkyl
containing 1 or 2 heteroatoms selected from O, S and N, in particular pyrrolidine,
piperidine, piperazine and morpholine;
a group - NRi7Ri8 where R 7 is H or (Ci-C 4)alkyl and Ri is H; a (Ci-C 4)alkyl
optionally substituted with a (Ci-C 4)alkoxy; or a 5- or 6-membered heteroaryl
containing 1 to 3 heteroatoms selected from O and N, in particular pyridine;
a group -NRiciCOR2owhere R 1 is H or (Ci-C )alkyl and R 0 is H or a (Ci-C 4)alkyl
optionally substituted with amino, (C[-C )alkylamino or di(C]-C )alkylamino or
with a 5- or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms selected
from O, S and N, in particular pyrrolidine, piperidine, piperazine and morpholine,
said heterocycloalkyl being optionally substituted with 1 to 3 (Ci-C 4)alkyls; or
a 5- or 6-membered heterocycloalkyl or heteroaryl containing 1 or 2 heteroatoms
selected from O and N, in particular piperidine and furane, said heterocycloalkyl or
heteroaryl being optionally substituted with an oxo group or with a (Ci-C 4)alkyl
optionally substituted with amino, (Ci-C 4)alkylamino or di(C 1-C )alkylamino;
R3 is H; CF3; a halogen; a (Ci-C4)alkyl; or a (C]-C 4)alkoxy;
W is N or CR.21 where R2 i is
H;
a halogen;
CN;
CF3;
OCF 3;
a (Ci-C4)alkyl optionally substituted with a 5- or 6-membered heterocycloalkyl
containing 1 or 2 heteroatoms selected from O and N, in particular pyrrolidine,
piperidine, piperazine and morpholine;
a (Ci-C 4)alkoxy;
a group -0(CH 2) R22 where n is 0, 1 or 2 and R22 is a 5- or 6-membered
heterocycloalkyl containing 1 or 2 heteroatoms selected from O and N, in particular
pyrrolidine, piperidine, piperazine and morpholine, said heterocycloalkyl being
optionally substituted with 1 to 3 (Ci-C 4)alkyls;
a group -NR 23R 4 where R23 and R24 are each independently H or a (Ci-C 4)alkyl
optionally substituted with a (Ci-C 4)alkoxy; or R2 and R24 form, together with the
nitrogen atom to which they are bonded, a 5- or 6-membered heterocycloalkyl or
heteroaryl containing 1 or 2 heteroatoms selected from O, S and N, in particular
pyrrolidine, piperidine, piperazine, morpholine and pyrazole, said heterocycloalkyl
being optionally substituted with 1 to 3 (Ci-C 4)alkyls.
In another embodiment, which can be combined with other embodiments of the invention,
compounds of formula I or pharmaceutically acceptable salts thereof are contemplated
wherein:
Ri is H or a (Ci-C 4)alkyl;
R2 is H; a (Ci-C4)alkyl optionally substituted by a (Ci-C )alkoxy; a (Ci-C4)alkoxy
optionally substituted by OH or a group -NRi 2R13 where Ri2 and i3 are each
independently H or (Ci-C4)alkyl or R 2 and R13 fo , together with the nitrogen atom to
which they are bonded, a 5- or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms
selected from O, and N, in particular morpholine; or a group -CONRi R 6 where Ri and
R 6 are each independently H or a (Ci-C4)alkyl;
R is H or a (Ci-C4)alkyl;
Q is O;
W is N or CR2 1 where R i is H; OCF3; a (Ci-C )alkyl; a (Ci-C4)alkoxy; or a group
-0(CH 2) R22 where n is 0, 1 or 2, preferably n is 2, and R22 is a 5- or 6-membered
heterocycloalkyl containing 1 or 2 heteroatoms selected from O and N, in particular
morpholine;
X is N or CH; and
A is a 5- or 6-membered heterocycloalkyl or heteroaryl containing 1 or 2 nitrogen atoms,
in particular imidazolidine and dihydropyridine, said heterocycloalkyl or heteroaryl being
optionally substituted with 1 to 3 (Ci-C4)alkyls.
Preferred compounds of the invention are selected from those of examples 1 to 225 and
pharmaceutically acceptable salts thereof.
The following compounds are especially preferred:
l-{4-[2-((5-Ethoxymethyl)-2-methyl-phenylamino)-oxazol-5-yl]-pyridin-2-yl}-
imidazolidin-2-one;
l-{3-[2-((5-Ethoxymethyl)-2-methyl-phenylamino)-oxazol-5-yl]-5-methoxy-phenyl}-4,4-
dimethyl-imidazolidin-2-one;
l-(3-{2-[5-(2-Hydroxy-ethoxy)-2-methyl-phenylamino]-oxazol-5-yl}-5-methyl-phenyl)-
imidazolidin-2-one;
1-(4- {2-[5-(2-Hydroxy-ethoxy)-2-methyl-phenylamino]-oxazol-5-yl} -pyridin-2-yl)-
imidazolidin-2-one;
1-(4- {2-[2-Methyl-5-(2-morpholin-4-yl-ethoxy)-phenylamino]-oxazol-5-yl}-pyridin-2-yl)-
imidazolidin-2-one;
1- {4-[2-((5-Methoxymethyl)-2-methyl-phenylamino)-oxazol-5-yl]-pyridin-2-yl}-4-methylimidazolidin-
2-one;
4-Methyl-l-(4-{2-[2-methyl-5-(2-morpholin-4-yl-ethoxy)-phenylamino]-oxazol-5-yl}-
pyridin-2-yl)-imidazolidin-2-one;
l-(3-Methyl-5-{2-[2-methyl-5-(2-morpholin-4-yl-ethoxy)-phenylamino]-oxazol-5-yl}-
phenyl)-imidazolidin-2-one;
l-(4-{2-[2-Methyl-5-(3-morpholin-4-yl-propoxy)-phenylamino]-oxazol-5-yl}-pyridin-2-
yl)-imidazolidin-2-one;
l-{3-[2-((5-Ethoxymethyl)-2-methyl-phenylamino)-oxazol-5-yl]-5-methoxy-phenyl}-
imidazolidin-2-one;
l-(3-Methoxy-5-{2-[2-methyl-5-(2-morpholin-4-yl-ethoxy)-phenylamino]-oxazol-5-yl}-
phenyl)-imidazolidin-2-one;
1- {3-[2-((5-Ethoxyiiiethyl)-2-methyl-phenylamino)-oxazol-5-yl]-5-methoxy-phenyl}-4-
methyl-imidazolidin-2-one;
1- {3 -tert-Butoxy-5-[2-((5-methoxymethyl)-2-methyl-phenylamino)-oxazol-5-yl] -phenyl}-
imidazolidin-2-one;
l-(3-{2-[5-(2-Hydroxy-ethoxy)-2-methyl-phenylamino]-oxazol-5-yl}-5-methoxy-phenyl)-
imidazolidin-2-one;
l-(3-Methoxy-5-{2-[2-methyl-5-(2-morpholin-4-yl-ethoxy)-phenylamino]-oxazol-5-yl}-
phenyl)-4-methyl-imidazolidin-2-one;
1-{3-Isopropoxy-5-[2-((5-methoxymethyl)-2-methyl-phenylamino)-oxazol-5-yl]-phenyl}-
imidazolidin-2-one;
l-(3-{2-[5-(2-Hydroxy-ethoxy)-2-methyl-phenylamino]-oxazol-5-yl}-5-isopropoxyphenyl)-
imidazolidin-2-one;
l-(3-Isopropoxy-5-{2-[5-(2-methoxy-ethyl)-2-methyl-phenylamino]-oxazol-5-yl} -phenyl)-
imidazolidin-2-one;
l-(3-(2-(2-methyl-5-(2-morpholinoethoxy)phenylamino)oxazol-5-yl)-5-
(trifluoromethoxy)phenyl)imidazolidin-2-one;
l-(3-(2-(5-methoxy-2-methylphenylamino)oxazol-5-yl)-5-
(trifluoromethoxy)phenyl)imidazolidin-2-one;
l-(3-{2-[5-(2-Hydroxy-ethoxymethyl)-2-methyl-phenylamino]-oxazol-5-yl}-5-methylphenyl)-
imidazolidin-2-one;
3-{5-[3-Isopropoxy-5-(2-oxo-imidazolidin-l-yl)-phenyl]-oxazol-2-ylamino}-N-(2-
methoxy-ethyl)-4-methyl-benzamide;
l-(3-(2-(5-(ethoxymethyl)-2-methylphenylamino)oxazol-5-yl)-5-
(trifluoromethoxy)phenyl)imidazolidin-2-one;
3-{3-[2-(3,5-Dimethyl-phenylamino)-oxazol-5-yl]-5-trifluoromethoxy-phenyl}-4-methyl-
1H-pyridin-2-one;
3-{3-[2-(3,5-Dimethyl-phenylamino)-oxazol-5-yl]-5-methoxy-phenyl}-lH-pyridin-2-one;
3- {3-[2-(3,5-Dimethyl-phenylamino)-oxazol-5-yl]-5-isopropoxy-phenyl}-4-methyl-lHpyridin-
2-one;
4-[2-(5-(Ethoxymethyl)-2-methyl-phenylamino)-oxazol-5-yl]-4'-methyl -rH-
[2,3']bipyridinyl-2'-one;
3-[3-[2-(3,5-Dimethyl-phenylamino)-oxazol-5-yl]-5-(2-morpholin-4-yl-ethoxy)-phenyl]-4-
methyl- lH-pyridin-2-one;
4'-Methyl-4-{2-[2-methyl-5-(2-morpholin-4-yl-ethoxy)-phenylamino]-oxazol-5-yl }-rH-
[2,3']bipyridinyl-2'-one;
4-[2-(3,5-Dimethyl-phenylamino)-oxazol-5-yl]-4'-methyl-6-(2-morpholin-4-yl-ethoxy)-
l'H-[2,3']bipyridinyl-2'-one;
l-{3-[2-((5-Ethoxymethyl)-2-methyl-phenylamino)-oxazol-5-yl]-5-isopropoxy-phenyl}-
imidazolidin-2-one;
4'-Methyl-4-{2-[2-methyl-5-(3-mo holin-4-yl-propoxy)-phenylamino]-oxazol-5-yl}-l Ή -
[2,3']bipyridinyl-2'-one; and
phamiaceutically acceptable salts thereof.
The compounds of the present invention may be prepared using the general protocol as
follows.
The synthesis of the aminooxazole derivatives was undergone by firstly reacting aromatic
aldehydes I with />-toluenesulfonylmethyl isocyanide (TosMIC) to prepare the
corresponding arylsubstitued oxazole derivatives II using the method of Van Leusen et. al.
{Tetrahedron Lett., 1972, 23, 2369) (Scheme 1). The non-commercial aldehydes were
prepared using literature methods to introduce the aldehyde group either from the
corresponding brominated aromatic compound using an organometallic reagent and DMF
or from the oxidation of corresponding toluene according the method of Frey et. al.
(TetrahedronLett, 2001, 39, 6815).
Secondly, those compounds II were then further functionalised by deprotonation of the
oxazole moiety by a suitable organic base and subsequent electrophilic chlorination was
used to prepare the 2-chlorooxazole coumpounds III. A direct nucleophilic displacement
reaction by aniline compounds IV (wherein R' is hydrogen), in the presence of a suitable
solvent such as alcohol and with heating in elevated temperature, should generally afford
the final target compounds V. Compounds V can also obtained by reacting compounds IV
(wherein R' is an acetyl group) and compounds III in the presence of sodium hydride and
in a suitable solvent such as tetrahydrofurane or dimethylformamide (WO 2007/131953).
Scheme 2 depicts the synthesis of the aminothiazole derivatives VIII undergone firstly by
reacting aromatic aldehydes I with (methoxymethyl)triphenyl phosphonium chloride to
prepare the corresponding arylsubstitued enol ether derivatives VI using Wittig reaction
described by Iwao et. al. (J Org. Chem. 2009, 74, 8143). Secondly, a cyclisation was
perfomed with the enol ether VI, thiourea derivatives VII and N-bromosuccinimide (NBS)
using the method of Zhao et. al. {Tetrahedron Lett., 2001, 42, 2101).
Scheme 2
The invention is now illustrated by Examples which represent currently preferred
embodiments which make up a part of the invention but which in no way are to be used to
limit the scope of it.
Examples of Compound Synthesis
The invention will be more fully understood by reference to the following preparative
examples, but they should not be construed as limiting the scope of the invention.
General: All chemicals used were commercial reagent grade products. Solvents were of
anhydrous commercial grade and were used without further purification. The progress of
the reactions was monitored by thin layer chromatography using precoated silica gel 60F
254, Merck TLC plates, which were visualized under UV light. Multiplicities in NMR
spectra are indicated as singlet (s), broad singlet (br s), doublet (d), triplet (t), quadruplet
(q), and multiplet (m) and the NMR spectrum were performed either on a Bruker Avance
300, 360 or 400 MHz spectrometer. Mass spectra were performed by Electrospray
Ionisation Mass Spectrometry (ESI MS) in positive mode or by Atmospheric Pressure
Chemical Ionization Mass Spectrometry (APCI MS) in positive mode.
LCMS methods: Method 1: This method was run on a Ultra-high performance liquid
chromatography (UPLC) ACQUITY Waters instrument coupled to a TQD mass
spectrometer. The gradient used was : starting at t=0.0min with 5% of CH CN+0.1%
Formic acid in Water+0.1% Formic acid until t=0.5min; then a linear gradient from
t=0.5min to t=7.0min reaching 100% CH3CN+0.1% Formic acid ; then staying at this state
from t=7.0min until t=10.0min. The column used was a Waters HSS C18 1.8 mih , 2.1 x
50mm. The detection instrument used was the triple quadrupole mass spectrometer (TQD)
using ESI positive mode.
Method 2: This method was run on HPLC 2695 Alliance, Waters coupled to a ZMD mass
spectrometer instrument. The gradient used was: starting at t=0.0min with 0% of
CH3CN+0.04 % Formic acid in water (10 mM); then a linear gradient to t= 3.1min
reaching 100% of CH3CN + 0.04 % Formic acid; then staying at this state to t= 3.8min
and decreasing to=4.8min to 0% of CH3CN + 0.04 % Formic acid in water. The column
used was a Sunfire 2.1 x 50 mm dp: 3.5 m i.
Abbreviations
AcCl Acetyl chloride
A 120 Alumina gel
APCI MS Atmospheric Pressure Chemical Ionization Mass Spectrometer
BINAP 2,2'-Bis(diphenylphosphino)- ,1'-binaphthalene
nBuLi n-Butyllithium
tBuONO Tert-butylni trite
C2C1 Hexachloroethane
CDC13 Deuterochloroform
CH3I Iodomethane
mCPBA 3-Chloroperoxybenzoic acid
Davephos 2-Dicyclohexylphosphino-2'-(V,N -dimethylamino)biphenyl
DCM Dichloromethane
DCE 1,2-Dichloroethylene
DMF N,N-Dimethylformamide
DMSO- Hexadeuterodimethyl sulfoxide
EDCI l-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide
EI-MS Electron impact ionisation mass spectrometry
ES-MS Electrospray mass spectrometry
Et20 Diethylether
EtOAc Ethyl acetate
EtOH Ethanol
h Hour(s)
H20 2 Hydrogen peroxyde
HOBT N-Hydroxybenzotriazole
K C0 3 Potassium carbonate
K3P0 4 Potassium phosphate tribasic
KOtBu Potassium tert-butoxide
KSCN Potassium thiocyanate
LiHMDS Lithium bis(trimethylsilyl)amide
MeOH Methanol
MgS0 4 Magnesium sulfate
min Minutes
NaH Sodium hydride
NaHC0 3 Sodium bicarbonate
Nal Sodium iodide
NaOH Sodium hydroxyde
NaOtBu Sodium t rt-butoxide
NaOEt Sodium ethoxide
NaOMe Sodium methoxide
NBS N-bromosuccinimide
NEt3 Triethylamine
Pd2(dba)3 Tris(dibenzylideneacetone)palladium(0)
Pd(PPh3)4 Tetrakis(triphenylphoshine)palladium(0)
zPrOH 2-Propanol
Si0 2 Silica gel
SnCl2.2H20 Tin(II) chloride dihydrate
TosMIC p-Toluenesulfonylmethyl isocyanide
THF Tetrahydrofuran
Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene
Example 214
Synthetic approach of example
Synthetic approach of intermediate I-e
Synthesis of intermediate I-a: l,3-dibromo-5-isopropoxy-benzene
To a solution of NaH 60 % dispersion in mineral oil (1.89 g, 47.25 mmol) in dry DMF (20
mL) under inert atmosphere was added dropwise at 0°C z-PrOH (3.62 mL, 47.25 mmol).
The mixture was stirred at 0°C for 15 min. Then, a solution of l,3-dibromo-5-fluorobenzene
(1.98 mL, 15.75 mmol) in dry DMF (20 mL) was added dropwise at 0°C. The
reaction mixture was stirred for 16 h at room temperature. A saturated solution of NaHC0 3
was added dropwise and the crude product was extracted with Et 0 (2 times), the organic
layer was washed with a saturated solution of NaHC0 3 (3 times), then with a saturated
solution of NaCl, dried over MgS0 4 and concentrated to give I-a as yellow oil in
quantitative yield. RMN (300 MHz, CDC13) d 7.21 (t, J = 1.4 Hz, 1H), 6.97 (d, J = 1.5
Hz, 2H), 4.61-4.40 (m, 1H), 1.32 (d, J = 6.0 Hz, 6H).
Synthesis of intermediate I-b: 3-bromo-5-isopropoxy-benzaldehyde
To a solution of I-a (4.630 g, 15.75 mmol) in dry Et20 (60 mL) under inert atmosphere
was added dropwise at -78°C a solution of n-butyl lithium in dry Et20 (6.3 mL, 15.75
mmol). The reaction mixture was stirred at -78°C for 0.5 h. Then, dry DMF (1.35 mL) was
added dropwise at -78°C and the temperature was allowed to reach -40°C over 1.5 h. A
solution of HC1 (3N) was added and the crude product was extracted with Et 0 (2 times),
the organic layer was washed with water, then with a saturated solution of NaCl, dried over
MgS0 4 and concentrated to give I-b as yellow oil in 82% yield. 1H RMN (300 MHz,
CDC13) d 9.89 (s, 1H), 7.54 ( , 1H), 7.29 (m, 2H), 4.60 (dt, J = 12.1, 6.0 Hz, 1H), 1.36 (t,
J = 6.0 Hz, 6H).
Synthesis of intermediate I-c: 5-(3-bromo-5-isopropoxy-phenyl)-oxazole
To a solution of I-b (6.925 g, 28.50 mmol) in MeOH (125 mL) were added successively
K2C0 3 ( 11.81 1 g, 85.50 mmol) and TosMIC (6.674 g, 34.20 mmol). The reaction mixture
was stirred at room temperature for 16 h. Then, the solvent was removed under reduce
pressure, water was added and the crude product was extracted with EtOAc (2 times), the
organic layer was washed with water, then with a saturated solution of NaCl, dried over
MgSC"4 and concentrated. The final product was purified by silica gel chromatography
using 5 to 30% EtOAc/cyclohexane as eluent to give I-c as yellow oil in 86% yield.
RMN (300 MHz, CDC13) d 7.90 (s, 1H), 7.34 (m, 2H), 7.09 ( , 1H), 7.00 (m, 1H), 4.56
(dt, J = 12.1, 6.0 Hz, 1H), 1.49-1.26 (m, 6H).
Synthesis of intermediate I-d: 5-(3-bromo-5-isopropoxy-phenyl)-2-chloro-oxazole
To a solution of I-c (6.921 g, 24.50 mmol) in dry THF (130 mL) under inert atmosphere
was added dropwise at -78°C a solution of LiHMDS in dry THF (29 mL, 29.00 mmol).
The reaction mixture was stirred at -78°C for 0.5 hour. Then, C2C 16 (8.712 g, 36.75 mmol)
was added at -78°C and the reaction mixture was stirred at room temperature for 16h.
Water was added and the crude product was extracted with EtOAc (2 times), the organic
layer was washed with water, then with a saturated solution of NaCl, dried over MgS0 4
and concentrated. The final product was purified by silica gel chromatography using 0 to
20% EtOAc/cyclohexane as eluent to give I- as yellow oil in 92% yield. 1H NMR (300
MHz, CDC13) d 7.29 (t, J = 1.5 Hz, 1H), 7.27 (s, 1H), 7.02 (d, J = 1.4 Hz, 2H), 4.57 (dt, J =
12.1, 6.0 Hz, 1H), 1.36 (s, 3H), 1.34 (s, 3H).
Synthesis of intermediate I-f: [5-(3-Bromo-5-isopropoxy-phenyl)-oxazol-2-yl]-((5-
ethoxymethyl)-2-methyl-phenyl)-amine
To a solution of I-d (1.556 g, 4.915 mmol) and I-e (0.812 g, 4.915 mmol) in z-PrOH (45
mL) under inert atmosphere was added dropwise a solution of HC1 in dry Et20 (0.98 mL,
0.98 mmol). The reaction mixture was stirred at 80°C for 16 h. Then, the solvent was
removed under reduced pressure and a solution of NaOH (2.5 N) was added. The crude
product was extracted with EtOAc (2 times) and the organic layer was washed with water,
then with a saturated solution of NaCl, dried over MgS0 4 and concentrated. The final
product was purified by silica gel chromatography using 0 to 30% EtOAc/cyclohexane as
eluent to give I-f as white solid in 64% yield. RMN (300 MHz, DMSO-<¾) d 9.30 (s,
1H), 7.81 (s, 1H), 7.56 (s, 1H), 7.30 (s, 1H), 7.16 (d, J = 7.7 Hz, 1H), 7.09 (d, J = 1.4 Hz,
1H), 7.00 (d, J = 1.7 Hz, 1H), 6.94 (d, J 7.8 Hz, 1H), 4.69 (dt, J = 12.0, 5.9 Hz, 1H), 4.41
(s, 2H), 3.47 (q, J = 7.0 Hz, 2H), 2.27 (s, 3H), 1.39 (s, 3H), 1.27 (d, J = 6.0 Hz, 6H), 1.14
(t, J = 7.0 Hz, 3H).
Synthesis of intermediate I-g: 4-ethoxymethyl-l-methyl-2-nitro-benzene
To a solution of NaOEt in dry EtOH (45 mL, 114.90 mmol) under inert atmosphere was
added 4-chloromethyl-l-methyl-2-nitro-benzene (7.0 g, 38.30 mmol). The reaction mixture
was stirred at room temperature for 16 hours. Water was added and ethanol was removed
under reduced pressure. The crude product was extracted with DCM (2 times) and the
organic layer was washed with water, then with a saturated solution of NaCl, dried over
MgS0 and concentrated to give I-g as brown oil in 96% yield. NMR (300 MHz,
CDC13) d 7.95 (s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 4.52 (s, 2H), 3.56
(q, J = 7.0 Hz, 2H), 2.57 (d, J = 10.1 Hz, 3H), 1.26 (t, J = 7.0 Hz, 3H).
Synthesis of intermediate I-e: 5-ethoxymethyl-2-methyl-phenylamine.
To a solution of I-g (7.21 g, 36.93 mmol) in EtOH (238 mL) were added successively Pd/C
(2.432 g) and at 0°C hydrazine monohydrate (4.84 mL, 99.71 mmol) dropwise. The
reaction mixture was stirred at 80°C for 2 h. Then, the hot mixture was filtrated over celite
pad and washed with EtOH. The filtrate was concentrated under reduced pressure to give
I-e as yellow oil in quantitative yield. 1H NMR (300 MHz, CDC13) d 6.99 (d, J = 7.6 Hz,
1H), 6.67 (d, J = 7.5 Hz, 2H), 4.41 (s, 2H), 3.52 (q, J = 7.0 Hz, 3H), 2.18 (s, 3H), 1.04 (t, J
= 8.5 Hz, 3H).
Synthesis of example 214: l-{3-[2-((5-Ethoxymethyl)-2-methyl-phenylamino)-oxazol-5-
yl] -5-isopropoxy-phenyl }-imidazolidin-2-one
In a sealed tube, to a solution of I-f (872 mg, 1.56 mmol) in dry dioxane (13 mL) were
added successively imidazolidin-2-one (674 mg, 7.84 mmol), cesium carbonate (1.595 g,
4.90 mmol), Pd2(dba) ( 1 3 mg, 0.20 mmol), and Xantphos (54 mg, 0.06 mmol). The
reaction mixture was stirred at 110°C for 16 h. Water was added, the crude product was
extracted with EtOAc (2 times) and the organic layer was washed with water, then with a
saturated solution of NaCl, dried over MgS0 and concentrated. The final product was
purified by silica gel chromatography using 50 to 100% EtOAc/cyclohexane as eluent to
give compound 214 as white solid in 50% yield. 1H NMR (300 MHz, DMSO-c/ ) d 9.26 (s,
1H), 7.81 (s, 1H), 7.40 (s, 1H), 7.29 (s, 1H), 7.15 (d, J = 7.7 Hz, 1H), 7.1 1 (t, J = 2.0 Hz,
1H), 7.01 (s, 1H), 6.92 (d, J = 7.7 Hz, 1H), 6.78 (s, 1H), 4.62 (dt, J = 12.1, 6.0 Hz, 1H),
4.41 (s, 2H), 3.92 - 3.81 (m, 2H), 3.53 - 3.34 (m, 4H), 2.27 (s, 3H), 1.29 (s, 3H), 1.27 (s,
3H), 1.14 (t, J = 7.0 Hz, 3H).
(ESI+) m/z 451.2 (M+H)+.
Retention time = 3.52 min (method 2).
Example 215
Synthetic approach of example
Synthesis of intermediate Il-a: 2-Bromo-pyridine-4-carbaldehyde oxime
To a solution of 2-bromo-4-methylpyidine (10.0 g, 58.13 mmol) in dry THF (60 mL) under
inert atmosphere were added successivelly dropwise at -10°C tert-butylnitrite (12.5 mL,
104.63 mmol) and a solution of OtBu in dry THF (88 mL, 87.20 mmol). The reaction
mixture was stirred at -10°C for 3 h. Then, a saturated solution of NH4C 1 was added and a
solution of HC1 (4N) was added until pH = 6-7. The crude product was extracted with
EtOAc (2 times) and the organic layer was washed with water, then with a saturated
solution of NaCl, dried over MgS0 and concentrated to give Il-a as yellow oil in 90%
yield. The crude poduct was directly engaged in the next step. H NMR (300 MHz,
DMSO-d ) d 12.47 (s, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.12 (s, 1H), 7.90 (dd, J = 5.1, 1.0 Hz,
1H), 7.55 (s, 1H).
Synthesis of intermediate H-b: 2-Bromo-pyridine-4-carbaldehyde
To a suspension of Il-a (10.5 g, 52.23 mmol) in water (50 mL) were added successively
dropwise at -10°C concentrated solution of HC1 (50 mL) and a solution of formaldehyde
(50 mL) in water (37% w/w). The reaction mixture was stirred at -10°C for 4 h. Then, a
solution of NaOH (2 N) was added until pH = 6-7. The crude product was extracted with
EtOAc (2 times) and the organic layer was washed with water, then with a saturated
solution of NaCl, dried over MgS0 4 and concentrated to give Il-b as brownish oil in 97 %
yield. NMR (300 MHz, DMSO- 6) d 10.03 (s, 1H), 8.68 (d, J = 4.9 Hz, 1H), 8.07 (s,
1H), 7.84 (d, J = 4.9 Hz, 1H).
Synthesis of intermediate II-c: 2-Bromo-4-oxazol-5-yl-pyridine
To a solution of Il-b (9.4 g, 50.53 mmol) in MeOH (100 mL) were added successively
K2C0 3 (13.97 g, 101.06 mmol) and TosMIC (14.80 g, 75.8 mmol). The reaction mixture
was stirred at room temperature for 16 h. Then, the solvent was removed under reduce
pressure, water was added and the crude product was extracted with EtOAc (2 times), the
organic layer was washed with water, then with a saturated solution of NaCl, dried over
MgS0 4 and concentrated. The dark brown solid was triturated in cold ether, filtered and
washed with more ether to get the final product II-c as pale brown solid in 73 % yield. 1H
NMR (300 MHz, CDC13) d 8.42 (d, J = 5.2 Hz, 1H), 8.02 (s, 1H), 7.73 (s, 1H), 7.60 (s,
1H), 7.48 (dd, J = 5.2, 1.3 Hz, 1H).
Synthesis of intermediate Il-d: 2-Methylsulfanyl-lH-imidazole
To a solution of 2-mercaptoimidazole (5.0 g, 49.93 mmol) in water (200 mL) was added
NaOH (2.4 g, 59.91 mmol). The reaction mixture was stirred at room temperature for 0.5
h. Then, acetone (200 mL) and Mel (3.4 mL, 54.92 mmol) were added. The reaction
mixture was stirred at room temperature for 16 h. Then, the solvent was removed under
reduce pressure, water was added and the crude product was extracted with EtOAc (5
times), the organic layer was washed with water, then with a saturated solution of NaCl,
dried over MgS0 4 and concentrated. The orange solid was triturated several times with
petroleum ether and filtered to give compound Il-d as pale brown solid in 88% yield.
NMR (300 MHz, OMSO-d6) d 12.16 (s, 1H), 7.14 (s, 1H), 6.91 (s, 1H), 2.50 (s, 3H).
Synthesis of intermediate Il-e: 2-(2-Methylsulfanyl-imidazol-l-yl)-4-oxazol-5-yl -pyridine
In a sealed tube were charged Il-d (1.98 g, 17.33 mmol), II-c (3.0 g, 13.33 mmol), K2C0 3
(3.87 g, 27.99 mmol.), Cul (253 mg, 1.33 mmol), N,N'-dimethylcyclohexane-l,2-diamine
(420 , 2.66 mmol) in dry toluene (19 mL). The reaction mixture was stirred at 110°C for
4 days. Then, water was added and the crude product was extracted with EtOAc (2 times),
the organic layer was washed with water, then with a saturated solution of NaCl, dried over
MgS0 4 and concentrated. The brown solid was triturated in cold ether, filtered and washed
with more ether to get the final product Il-e as pale brown solid in 70% yield. NMR
(300 MHz, DMSO-i¾ d 8.67 (s, 1H), 8.60 (d, J = 5.2 Hz, 1H), 8.13 (s, 1H), 7.97 (s, 1H),
7.96 (s, 1H), 7.70 (dd, J = 5.2, 1.4 Hz, 1H), 7.15 (d, J 1.5 Hz, 1H), 2.52 (s, 3H).
Synthesis of intermediate Il-f: 2-(2-Methanesulfonyl-imidazol-l-yl)-4-oxazol-5-ylpyridine
To a solution of Il-e (2.17 g, 7.83 mmol) in DCM (260 mg) was added mCPBA (2.97 g,
17.23 mmol). The mixture was stirred at room temperature for 16 h. Then, a saturated
solution of NaHC0 3 was added and the crude product was extracted with DCM (2 times)
and the organic layer was washed with saturated solution of NaHC0 3 (3 times), with water,
then with a saturated solution of NaCl, dried over MgS0 4 and concentrated. The final
product was purified by silica gel chromatography using 5 to 10% MeOH/EtOAc as eluent
to give Il-f as solid in 84% yield. 1H NMR (300 MHz, OMSO-d6) d 8.69 (m, 2H), 8.14 (s,
1H), 8.06 (d, J = 0.7 Hz, 1H), 8.00 (d, J = 1.2 Hz, 1H), 7.89 (dd, J = 5.2, 1.5 Hz, 1H), 7.38
(d, J = 1.2 Hz, 1H), 3.53 (s, 3H).
Synthesis of intermediate H-g: 2-(2-Methoxy-imidazol-l-yl)-4-oxazol-5-yl-pyridine
To a solution of H-f (600 mg, 2.07 mmol.) in dry MeOH/THF (1/1, 6 mL) was added at
0°C a solution of NaO e in MeOH (6.2 mL, 3.10 mmol). The reaction mixture was stirred
at 50°C for 16 h. Water was added and the crude product was extracted with EtOAc (2
times) and the organic layer was washed with water, then with a saturated solution of
NaCl, dried over MgS0 and concentrated to give compound H-g as pale brown solid in
98% yield. 1H NMR (300 MHz, DMSO- ) d 8.66 (s, 1H), 8.58 (d, J = 5.3 Hz, 1H), 8.1 1
(s, 1H), 8.03 (s, 1H), 7.68 (dd, J = 5.2, 1.4 Hz, 1H), 7.51 (d, J = 1.9 Hz, 1H), 6.70 (d, J =
1.9 Hz, 1H), 4.09 (s, 3H).
Synthesis of intermediate Il-h: 4-(2-Chloro-oxazol-5-yl)-2-(2-methoxy-imidazol-l-yl)-
pyridine
To a solution of intermediate Il-g (366 mg, 1.51 mmol) in dry THF (15 mL) under inert
atmosphere was added dropwise at -78°C a solution of LiHMDS in dry THF (2.3 mL, 2.27
mmol). The reaction mixture was stirred at -78°C for 0.5 h. Then, C2C 1 (537 mg, 2.27
mmol) was added at -78°C and the reaction mixture was stirred at room temperature for
16h. Water was added and the crude product was extracted with EtOAc (2 times), the
organic layer was washed with water, then with a saturated solution of NaCl, dried over
MgS0 4 and concentrated. The final product was purified by silica gel chromatography
using 0 to 10% MeOH/EtOAc as eluent to give intermediate Il-h as white solid in 74%
yield . NMR (300 MHz, CDC13) d 8.51 (dd, J = 5.2, 0.8 Hz, 1H), 7.95 (dd, J = 1.4, 0.8
Hz, 1H), 7.55 (s, 1H), 7.52 (d, J = 1.9 Hz, 1H), 7.33 (dd, J = 5.2, 1.5 Hz, 1H), 6.75 (d, J =
2.0 Hz, 1H), 4.21 (s, 3H).
Synthesis of intermediate II-l: 4-Methoxymethyl-l-methyl-2-nitro-benzene
To a solution of NaOMe (1.6 g, 29.63 mmol) in dry MeOH (40 mL) under inert
atmosphere was added 4-chloromethyl-l-methyl-2-nitro-benzene (5.0 g, 26.94 mmol). The
reaction mixture was stirred at room temperature for 16 h. Water was added and EtOH was
removed under reduced pressure. The crude product was extracted with DCM (2 times)
and the organic layer was washed with water, then with a saturated solution of NaCl, dried
over MgS0 4 and concentrated to give intermediate II-l as yellow oil. H NMR (300 MHz,
CDC1 ) d 7.94 (s, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 4.48 (s, 2H), 3.41
(s, 3H), 2.58 (s, 3H).
Synthesis of intermediate Il-m: 5-Methoxymethyl-2-methyl-phenylamine
To a solution of intermediate II-l (4.77 g, 26.32 mmol) in EtOH/H20 : 9/1 (150 mL) were
added successively, SnCl2.2H20 (29.70 g, 131.60 mmol) and hydrochloric acid 37% (15
mL) dropwise. The reaction mixture was stirred at room temperature for 16 h. EtOH was
removed under reduced pressure and to the resulting aqueous solution was added a solution
of NaOH (10 N) until pH=6-7. Then, the crude product was extracted with DCM (2 times)
and the organic layer was washed with water, then with a saturated solution of NaCl, dried
over MgS0 4 and concentrated. The final product was purified by silica gel
chromatography using 0 to 30% EtOAc/cyclohexane as eluent to give intermediate Il-m as
yellow oil. NMR (300 MHz, DMSO-c¾) d 6.88 (d, J = 7.5 Hz, 1H), 6.58 (s, J = 17.6 Hz,
1H), 6.41 (d, J = 7.5 Hz, 1H), 4.80 (s, 2H), 4.24 (s, 2H), 3.23 (s, 3H), 2.03 (s, 3H).
Synthesis of intermediate Il-i: N-(5-Methoxymethyl-2-methyl-phenyl)-acetamide
To a solution of Il-m (2.0 g, 13.23 mmol) in dry DCM (45 mL) was added successively
dry NEt3 (2.3 mL, 15.88 mmol) and at 0°C AcCl (1.0 mL, 14.55 mmol) dropwise. The
reaction mixture was stirred at room temperature for 2 h. Water was added and the crude
product was extracted with DCM (2 times) and the organic layer was washed with water,
then with a saturated solution of NaCl, dried over MgS0 4 and concentrated. The final
product was purified by silica gel chromatography using 50 to 80% EtOAc/cyclohexane as
eluent to give intermediate Il-i as pale yellow solid in 88% yield over the 3 steps. NMR
(300 MHz, DMSO-d ) d 9.27 (s, 1H), 7.36 (s, 1H), 7.16 (d, J = 7.7 Hz, 1H), 7.00 (d, J =
7.6 Hz, 1H), 4.34 (s, 2H), 3.26 (s, 3H), 2.18 (s, 3H), 2.05 (s, 4H).
Synthesis of intermediate Il-j: {5-[2-(2-Methoxy-imidazol-l-yl)-pyridin-4-yl]-oxazol-2-
y }-(5-methoxymethyl-2-methyl-phenyl)-amine
To a solution of NaH 60 % dispersion in mineral oil (237 mg, 6.16 mmol) in dry DMF (20
mL) was added dropwise at 0°C a solution of intermediate Il-i (595 mg, 3.08 mmol) in
dry DMF (20 mL). The reaction mixture was stirred at room temperature for 1 h and a
solution of intermediate Il-h (852 mg, 3.08 mmol) in dry DMF (20 mL) was added
dropwise at 0°C. The reaction mixture was stirred for 3 h at 0°C. Water was added and the
crude product was extracted with EtOAc (2 times), the organic layer was washed with a
saturated solution of NaHC0 3 (3 times), then with a saturated solution of NaCl, dried over
MgS0 and concentrated. The final product was purified by silica gel chromatography
using 0 to 20 % EtOAc/cyclohexane as eluent to give intermediate Il-j as white solid in
44% yield. NMR (300 MHz, DMSO-£¾ d 9.65 (s, 1H), 8.45 (d, J = 5.3 Hz, 1H), 7.86
(s, 1H), 7.79 (s, 1H), 7.72 (s, 1H), 7.46 (dd, J = 5.1, 3.6 Hz, 2H), 7.21 (d, J = 7.7 Hz, 1H),
7.00 (d, J = 7.7 Hz, 1H), 6.68 (d, J = 1.8 Hz, 1H), 4.38 (s, 2H), 4.05 (s, 3H), 3.28 (s, 3H),
2.29 (s, 3H).
Synthesis of example 215: l-{4-[2-((5-Methoxymethyl)-2-methyl-phenylamino)-oxazol-5-
yl]-pyridin-2-yl}-l,3-dihydro-imidazol-2-one hydrochloride
To a solution of H-j (100 mg, 0.26 mmol) in dry dioxane (4 mL) was added dropwise at
0°C a solution of HCl in dry ether (546 , 0.55 mmol). The reaction mixture was stirred
at 60°C for 2 h and at room temperature for 16 h. Then, the solvent was removed under
reduce pressure, the crude product was triturated with ether and filtrated to give compound
215 as white solid in 57% yield. NMR (300 MHz, CD3OD) d 10.04 - 9.95 (m, 1H),
9.46 (s, 1H), 9.15 (s, 1H), 9.03 (d, J = 4.6 Hz, 1H), 8.95 - 8.87 (m, 1H), 8.78 (d, J = 7.8
Hz, 1H), 8.19 (d, J = 3.2 Hz, 1H), 6.04 (s, 2H), 4.97 (s, 3H), 3.91 (s, 3H).
Example 216
Synthetic approach of compound 216
Synthesis of intermediate IH-a: l-Bromo-3-(2-methoxy-vinyl)-benzene
To a solution of (methoxymethyl)triphosphonium chloride (5.56 g, 16.21 mmol) in dry
THF (13 mL) under inter atmosphere was added dropwise at 0°C a solution of «BuLi in
dry THF (22 mL, 21.62 mmol). The reaction mixture was stirred at room temperature for 1
h. Then, a solution of 3-bromobenzaldehyde (2.0 g; 10.81 mmol) in dry THF (20 mL) was
added dropwise at 0°C. The reaction mixture was stirred at room temperature for 16 h. A
saturated solution of NH4C 1 was added and the crude product was extracted with EtOAc (2
times) and the organic layer was washed with water, then with a saturated solution of
NaCl, dried over MgS0 4 and concentrated. The final product was purified by silica gel
chromatography using 10 to 15% EtOAc/cyclohexane as eluent to give IH-a as yellow oil
in 66% yield. NMR (300 MHz, CDC13) d 7.79 (s, J = 1.5 Hz, 1H), 7.48 - 7.24 (m, 5H),
7.20 - 7.12 (m, 2H), 7.06 (d, J = 13.0 Hz, 1H), 6.19 (d, J = 7.0 Hz, 1H), 5.75 (d, J = 13.0
Hz, 1H), 5.17 (d, J =7.0 Hz, 1H), 3.82 (s, 3H), 3.71 (s, 3H).
Synthesis of intermediate Ill-b: (5-Methoxy-2-methyl-phenyl)-thiourea
To a solution of KSCN (780 mg, 8.02 mmol) in acetone (10 mL) was added dropwise at
room temperature as solution of AcCl (900 , 8.02 mmol) in acetone (10 mL). The
reaction mixture was stirred for 15 min at 50°C. Then, a solution of 5-methoxy-2-
methylaniline (1.0 g, 7.29 mmol) in acetone (10 mL) was added and the reaction mixture
was stirred at 50°C for 15 min. Water was added and the solid was filtered, washed with
more water and ether to give a white solid. A solution of the latter with K2C0 3 (2.0 g,
14.58 mmol) in MeOH (20 mL) was stirred at room temperature for 3 h. MeOH was
removed under reduced pressure and the solid was washed with water and ether to give
Ill-b as a white solid in 78% yield. 1H NMR (300 MHz, OMSO-d6) d 9.20 (s, 1H), 7.13 (d,
J =8.4 Hz, 1H), 6.81 (d, J =2.4 Hz, 1H), 6.75 (dd, J =8.3, 2.6 Hz, 1H), 3.71 (s, 3H), 2.10
(s, 3H).
Synthesis of intermediate III-c: [5-(3-Bromo-phenyl)-thiazol-2-yl]-(5-methoxy-2-methylphenyl)-
amine
To a solution of IH-a (300 mg, 1.41 mmol) in dioxane/water (1/1, 6 mL) was added NBS
(276 mg, 1.55 mmol). The reaction mixture was stirred at room temperature for 1 h. Then,
IH-b (277 mg, 1.41 mmol) was added and the reaction mixture was stirred at 80°C for 16
h. Water followed by saturated solution of NH4C 1 were added and the crude product was
extracted with EtOAc (2 times) and the organic layer was washed with water, then with a
saturated solution of NaCl, dried over MgS0 4 and concentrated. The final product was
purified by silica gel chromatography using 0 to 35% EtOAc/cyclohexane as eluent to give
III-c as pale yellow solid in 69% yield. NMR (300 MHz, DMSO-d ) d 9.48 (s, 1H),
7.77 - 7.69 (m, 2H), 7.54 (d, J = 2.1 Hz, 1H), 7.46 (dd, J = 7.6, 0.9 Hz, 1H), 7.40 (dd, J =
7.9, 1.0 Hz, 1H), 7.30 (t, J 7.9 Hz, 1H), 7.1 1 (d, J = 8.3 Hz, 1H), 6.60 (dd, J = 8.3, 2.5
Hz, 1H), 3.71 (s, 3H), 2.19 (s, 3H).
Synthesis of example 216: l-{3-[2-(5-Methoxy-2-methyl-phenylamino)-thiazol-5-yl]-
phenyl }-imidazolidin-2-one
In a sealed tube, to a solution of III-c (200 g, 0.53 mmol) in dry dioxane (10 mL) were
added successively 2-imidazolidinone (275 mg, 3.20 mmol), cesium carbonate (432 mg,
1.33 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), 4,5-Xantphos (61 mg, 0.1 1 mmol). The
reaction mixture was stirred at 110°C for 16 h. Water was added and the crude product was
extracted with EtOAc (2 times) and the organic layer was washed with water, then with a
saturated solution of NaCl, dried over MgS0 4 and concentrated. The final product was
purified by silica gel chromatography using 0 to 30% MeOH/EtOAc as eluent to give
compound 216 as yellow solid in 41% yield. 1H NMR (300 MHz, DMSO- ) 9.36 (s,
1H), 7.75 (s, 1H), 7.63 - 7.56 (m, 2H), 7.37 (d, J = 8.2 Hz, 1H), 7.29 (t, J = 7.9 Hz, 1H),
7.15 (d, J = 7.5 Hz, 1H), 7.1 1 (d, J = 8.4 Hz, 1H), 7.01 (s, 1H), 6.59 (dd, J = 8.3, 2.6 Hz,
1H), 3.93 - 3.83 (m, 2H), 3.72 (s, 3H), 3.44 - 3.37 (m, 2H), 2.20 (s, 3H).
Example 217
Synthetic approach of example 217
Synthetic approach of intermediate IV-a
CHO , KHCO3
EtOH, H20
Synthesis of intermediate IV-c: l-Acetyl-3-(4-methyl-3-nitro-phenyl)-thiourea
To a solution of ammonium thiocyanate (1.05 g, 13.85 mmol) in acetone (21 mL) was
added dropwise acetyl chloride (0.90 mL 12.70 mmol). The reaction mixture was stirred at
40°C for 30 min. Then, a solution of 4-methyl-3-nitroaniline (1.76 g, 11.54 mmol) in
acetone (7 mL) was added and the reaction mixture was stirred at room temperature for 4h.
The reaction mixture was poured into ice-water and the precipitate was filtered, washed
with more water and cyclohexane to give compound IV-c as brown solid in 50% yield.
(300 MHz, DMSO) d 12.45 (s, 1H), 11.53 (s, 1H), 8.38 (d, J = 2.0 Hz, 1H), 7.69 (dd, J =
8.3, 2.0 Hz, 1H), 7.43 (d, J = 8.3 Hz, 1H), 2.44 (s, 3H), 2.09 (s, 3H).
Synthesis of intermediate IV-d: (4-Methyl-3-nitro-phenyl)-thiourea
To a solution of IV-c (873 mg, 3.45 mmol) in methanol (5 mL) was added K2C0 3 (953
mg, 6.90 mmol). The reaction mixture was stirred at room temperature for 16 h. Then, the
solvent was removed under reduce pressure, water was added and the crude product was
extracted with EtOAc (twice), the organic layer was washed with water, then with a
saturated solution of NaCl, dried over MgS0 4, and concentrated. The final product was
purified by silica gel chromatography using 0 to 50 % EtOAc/cyclohexane as eluent to
give compound IV-d as yellow solid in 60% yield. (300 MHz, DMSO) d 9.95 (s, 1H), 8.28
(d, J = 2.1 Hz, 1H), 8.00-7.70 (m, 3H), 7.42 (d, J = 8.3 Hz, 1H), 2.47 (s, 3H).
Synthesis of intermediate IV-e: (4-Methyl-3-nitro-phenyl)-thiazol-2-yl-amine
To a suspension of IV-d (377 mg, 1.79 mmol) in EtOH (7 mL) were added a solution of
chloroacetaldehyde ((1.41 g, 17.93 mmol) in water (50% w/w) and KHC0 3 (539 mg, 5.37
mmol). The reaction mixture was stirred at 70°C for 16h. Then, the solvent was removed
under reduce pressure, water was added and the crude product was extracted with EtOAc
(3 times), the organic layer was washed with water, then with a saturated solution of NaCl,
dried over MgS0 4, and concentrated. The final product was purified by silica gel
chromatography using 0 to 70 % EtOAc/cyclohexane as eluent to give compound IV-e as
yellow solid in 40% yield. (300 MHz, DMSO) d 10.58 (s, 1H), 8.55 (d, J = 2.4 Hz, 1H),
7.69 (dd, J = 8.4, 2.4 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.33 (d, J = 3.7 Hz, 1H), 7.00 (d, J
= 3.7 Hz, 1H), 2.45 (s, 3H).
Synthesis of intermediate IV-f: 4-Methyl-Nl-thiazol-2-yl-benzene- 1,3 -diamine
To a solution of IV-e (737 mg, 3.13 mmol) in EtOH/DCM: (30/13 mL) were added
successively, SnCl .2H20 (3.54 g, 15.65 mmol) and hydrochloric acid 37% (3 mL)
dropwise. The reaction mixture was stirred at room temperature for 16h. EtOH was
removed under reduced pressure and to the resulting aqueous solution was added a solution
of NaOH (10 N) until pH=6-7. Then, the crude product was extracted with DCM (twice)
and the organic layer was washed with water, then with a saturated solution of NaCl, dried
over MgS0 and concentrated. The final product was purified by silica gel
chromatography using 0 to 30% EtOAc/cyclohexane as eluent to give intermediate IV-f as
yellow oil in 95% yield. (300 MHz, DMSO) d 9.74 (s, 1H), 7.18 (d, J = 3.7 Hz, 1H), 6.90
(d, J = 2.0 Hz, 1H), 6.85-6.77 (m, 2H), 6.66 (dd, J = 8.0, 2.0 Hz, 1H), 4.83 (brs, 2H), 1.99
(s, 3H).
Synthesis of intermediate IV-a: N-[5-(Acetyl-thiazol-2-yl-amino)-2-methyl-phenyl]-
acetamide
To a solution of IV-f (610 mg, 2.97 mmol) and NaHC0 3 (2.50 g, 29.71 mmol) in dry DCE
(10 mL), was added dropwise at 0°C actyl chloride (0.634 mL, 8.91 mmol). The reaction
mixture was stirred at 50°C for 5 h. Then, water was added and the crude product was
extracted with DCM (3 times) and the organic layer was washed with water, then with a
saturated solution of NaCl, dried over MgS0 4 and concentrated. The final product was
purified by silica gel chromatography using 30% EtOAc/cyclohexane as eluent to give
intermediate IV-a as yellow solid in 75% yield. (300 MHz, DMSO) d 9.39 (s, 1H), 7.54 (d,
J = 1.7 Hz, 1H), 7.40-7.32 (m, 2H), 7.29 (d, J = 3.6 Hz, 1H), 7.13 (dd, J = 7.9, 1.9 Hz, 1H),
2.28 (s, 3H), 2.07 (s, 3H), 1.99 (s, 3H).
Synthesis of intermediate IV-b : N-{3-[5-(3-Bromo-5-isopropoxy-phenyl)-oxazol-2-
ylamino]-4-methyl-phenyl}-N-thiazol-2-yl-acetamide
To a solution of NaH 60 % dispersion in mineral oil (83 mg, 2.08 mmol) in dry DMF (3
mL) was added dropwise at 0°C a solution of intermediate IV-a (300 mg, 1.04 mmol) in
dry DMF (3 mL). The reaction mixture was stirred at room temperature for lh and a
solution of intermediate I- (328 mg, 1.04 mmol) in dry DMF (3 mL) was added dropwise
at 0°C. The reaction mixture was stirred for 16 h at room temperature. Water was added
and the crude product was extracted with EtOAc (twice), the organic layer was washed
with a saturated solution of NaHC0 3 (3 times), then with a saturated solution of NaCl,
dried over MgS0 4 and concentrated. The final product was purified by silica gel
chromatography using 0 to 35 % EtOAc/cyclohexane as eluent to give intermediate IV-b
as beige solid in 46% yield. (300 MHz, DMSO) d 9.63 (s, 1H), 8.08 (d, J = 2.1 Hz, 1H),
7.65 (s, 1H), 7.47 (d, J = 2.2 Hz, 1H), 7.45 (d, J = 2.5 Hz, 1H), 7.42 - 7.38 (m, 2H), 7.19
(t, J 2.0 Hz, 1H), 7.15 (dd, J = 7.9, 2.2 Hz, 1H), 7.1 1 (t, J = 2.0 Hz, 1H), 4.78 (septuplet,
J = 5.8 Hz, 1H), 2.49 (s, 3H), 2.14 (s, 3H), 1.37 (d, J = 6.0 Hz, 6H).
Synthesis of example 217: l-(3-Isopropoxy-5-{2-[2-methyl-5-(thiazol-2-ylamino)-
phenylamino]-oxazol-5-yl} -phenyl)-imidazolidin-2-one
In a sealed tube, to a solution of IV-b (219 mg, 0.42 mmol) in dry dioxane (5 mL) were
added successively imidazolidin-2-one (286 mg, 3.36 mmol), cesium carbonate (162 mg,
0.50 mmol), Pd2(dba)3 ( 11 mg, 0.01 mmol), and Xantphos (24 mg, 0.04 mmol). The
reaction mixture was stirred at 110°C for 16h. Water was added, the crude product was
extracted with EtOAc (twice) and the organic layer was washed with water, then with a
saturated solution of NaCl, dried over MgS0 4 and concentrated. The final product was
purified by silica gel chromatography using 50 to 100% EtOAc/cyclohexane as eluent to
give compound 217 as beige solid in 49% yield. (300 MHz, DMSO) d 10.12 (brs, 1H),
9.25 (s, 1H), 8.04 (d, J = 2.1 Hz, 1H), 7.42 (s, 1H), 7.38 (dd, J = 8.3, 2.1 Hz, 1H), 7.25
(brs, 1H), 7.19 (d, J = 3.7 Hz, 1H), 7.15 (t, J = 1.9 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.01
(s, 1H), 6.85 (d, J = 3.6 Hz, 1H), 6.81 (s, 1H), 4.61 (m, 1H), 3.84 (m, 2H), 3.38 (m, 2H),
2.23 (s, 3H), 1.27 (d, J = 6.0 Hz, 6H).
(ESI+) m/z 491 (M+H)+
Retention time = 3.13 min (method 2)
Example 218
Synthetic approach of example 218
Synthetic approach of intermediate V-h
Synthesis of intermediate V-a: 4-Methyl-pyridin-2-ol
Intermediate V-a was prepared using the method of Adger et al, in J. Chem. Soc. Perkin
Trans. 1, 1988, p2791-2796. A 1L flask containing water (240 mL) was treated with cone.
H2S0 (32 mL) and cooled to 0°C then treated with the 2-amino-4-picoline in one portion
(30 g, 277 mmol). A solution of NaN0 2 (20.6 g, 299 mmol) in water (40 mL) was added
dropwise over 1 h such that the internal temperature never rose above 5°C. The reaction
was stirred at 0°C for lh then heated to 95°C and after 15 min at this temperature cooled to
room temperature. The solution was taken to pH 6-7 with 50% NaOH aq (exotherm) and
extracted whilst hot with EtOAc (4 x 120 mL). The combined organics were dried
(MgS0 4), filtered and evaporated to afford a beige crystalline solid (24.5 g, 81%) of
intermediate V-a .1H NMR (300 MHz, DMSO-d 6) d 11.31 (s, 1H), 7.23 (d, J = 6.7 Hz, 1H),
6.10 (s, 1H), 6.00 (dd, J = 6.7, 1.2 Hz, lH), 2.10 (s, 3H).
Synthesis of intermediate V-b: 3-Bromo-4-methyl-pyridin-2-ol
A solution of 4-methyl-pyridin-2-ol V-a (25 g, 229 mmol) in glacial acetic acid (350 mL)
and EtOAc (680 mL) was treated with NBS (37.4 g, 210 mmol) and stirred at room
temperature for 30 min. The mixture was then taken to pH 8 with aqueous ammonia and
extracted with EtOAc. The separated organics were washed with 1:1 H20 / brine then dried
(MgS0 4), filtered and evaporated before purification by silica column chromatography (1-
4% EtOH / DCM) to afford the desired product V-b as a white solid (8.66 g). NMR
(300 MHz, DMSO) 11.90 (s, 1H), 7.32 (d, J = 6.6 Hz, 1H), 6.19 (d, J = 6.6 Hz, 1H), 2.25
(s, 3H).
Synthesis of interaiediate V-c : 3-Bromo-2-methoxy-4-methyl -pyridine
A solution of 3-bromo-4-methyl-2-pyridone V-b (2.20 g, 11.7 mmol), in DCM (80 mL)
was treated with Mel (7.29 mL, 117 mmol) and Ag2C0 3 (6.47 g, 23.5 mmol). The flask
was stoppered and stirred under argon for 6 days. The mixture was filtered and purified by
column chromatography (Si0 2 10% EtOAc in cyclohexane) to afford the desired product
V-c as a clear mobile oil ( 1.83 g, 80%). 1H NMR (300 MHz, CDC13) d 7.94 (d, J = 5.0 Hz,
1H), 6.77 (d, J = 5.1 Hz, 1H), 4.00 (s, 3H), 2.39 (s, 3H).
Synthesis of intermediate V-d: 2-Methoxy-4-methyl-3-(4,4,5,5-tetramethyl-[l,3,2]
dioxaborolan-2-yl)-pyridine
A dry sealed tube under argon was charged with 3-bromo-2-methoxy-4-methylpyridine
V-c (813 mg, 4.02 mmol), bis(pinacolato)diboron (1.12 g, 4.41 mmol), PdCl (dppf):DCM
(146 mg, 0.20 mmol), OAc (1.18 g, 12.0 mmol) and dry DMF (10 mL). After 1.5h at
100°C, the mixture was cooled to room temperature and a further portion of catalyst (75
mg, 0.092 mmol) was added. The tube was sealed and the mixture stirred at 100°C
overnight. The mixture was cooled, the solvent evaporated and the mixture taken up in
DCM before washing with water. The separated organics were dried (MgS0 ), filtered and
evaporated before purification by column chromatography (Si0 2 10% to 20% EtOAc in
cyclohexane) to afford the intermediate V-d as a mobile yellow oil (2.14g, 51%). 1H NMR
(300 MHz, CDC13) d 8.00 (d, J = 5.3 Hz, 1H), 6.65 (d, J = 5.3 Hz, 1H), 3.89 (s, 3H), 2.33
(s, 3H), 1.40 (d, J = 11.1 Hz, 1 H).
Synthesis of intermediate V-e: 2'-Methoxy-4'-methyl-4-oxazol-5-yl-[2,3']bipyridinyl
An oven-dried flask under argon was charged with the 2-bromo-4-oxazol-5-yl-pyridine
(Intermediate II-c, 461 mg, 2.07 mmol), 2-methoxy-4-methyl-3-(4,4,5,5-tetramethyl-
[l,3,2]dioxaborolan-2-yl)-pyridine V-d (510 mg, 2.07 mmol), K3P0 4 (2.82 g, 13.3 mmol),
Pd(OAc) 2 (51 mg, 0.225 mmol), Davephos (89 mg, 0.225 mmol) in iPrOH (5 mL) and
water (3mL). After 40 min at 100°C, the mixture was cooled to room temperature, diluted
with water and extracted with EtOAc then washed with brine. The organics were dried
(MgS0 4), filtered and evaporated before purification by column chromatography (Si0 ,
30% to 100% EtOAc in cyclohexane) to afford the desired product V-e as an off-white
solid (240 mg, 43%).1H NMR (300 MHz, CDC1 ) d 8.78 (d, J = 4.8 Hz, 1H), 8.10 (d, J =
4.8 Hz, 1H), 8.01 (s, 1H), 7.59 (d, J = 4.9 Hz, 2H), 7.51 (d, J = 4.9 Hz, 1H), 6.86 (d, J =
4.9 Hz, 1H), 3.88 (s, 3H), 2.16 (s, 3H).
Synthesis of intermediate V-f: 4-(2-Chloro-oxazol-5-yl)-4'-methyl - H-[2,3']bipyridinyl-2'-
one
4-(2-Chloro-oxazol-5-yl)-4'-methyl - H-[2,3']bipyridinyl-2'-one V-f was prepared as for l -
d above from 4,-methyl-4-oxazol-5-yl-l'H-[2,3']bipyridinyl-2'-one V-e (467 mg, 1.74
mmol) using LiHMDS (1M in THF, 2.62 mL, 2.62 mmol) and C2C 1 (496 mg, 2.10 mmol)
in dry THF. The crude product was purified by column chromatography (Si0 2 ; eluting
with 30% to 50% EtOAc in cyclohexane) to afford the intermediate V-f as white solid (261
mg, 50%). NMR (300 MHz,DMSO-d 6) d 8.76 (d, J = 5.3 Hz, 1H), 8.12 (d, J = 4.4 Hz,
2H), 7.70 (s, 1H), 7.64 (dd, J 5.2, 1.7 Hz, 1H), 7.00 (d, J = 5.2 Hz, 1H), 3.78 (s, 3H),
2.06 (s, 3H).
Synthesis of intermediate V-h: 4-(3-Bromo-propoxy)-l-methyl-2-nitro-benzene
A solution of 4-methyl-3-nitrophenol (1.00 g, 6.53 mmol) in DMF (6 mL) was treated with
K2C0 3 (0.903 g, 6.53 mmol) and 1,3-dibromopropane (6.63 mL, 65.3 mmol) and heated to
100°C for 2.5 h. The cooled mixture was diluted with water and extracted with DCM. The
combined organics were dried (MgS0 4), filtered and evaporated before purification by
column chromatography (Si0 2 ; eluting with 20%o EtOAc in cyclohexane) to afford the
desired product V-h as a mobile yellow oil (1.05g, 59%). 1H NMR (300 MHz, CDC13) d
7.52 (d, J = 2.7 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.06 (dd, J = 8.5, 2.7 Hz, 1H), 4.14 (t, J
= 5.8 Hz, 2H), 3.60 (t, J = 6.4 Hz, 2H), 2.53 (s, 3H), 2.40 - 2.24 (m, 2H).
Synthesis of intermediate V-i: 4-[3-(4-Methyl-3-nitro-phenoxy)-propyl]-morpholine
A solution of the 4-(3-bromo-propoxy)-l-methyl-2-nitro-benzene V-h (500 mg, 1.82
mmol) in dry dioxane (30 mL) was treated with K2C0 3 (1.01 g, 7.28 mmol) and
morpholine (319 mΐ , 3.65 mmol) and heated to 100°C for 6 h. The cooled mixture was
diluted with water and extracted with DCM. The combined organics were dried (MgS0 4),
filtered and evaporated before purification by column chromatography (Si0 2 ; eluting with
2% EtOH in DCM) to afford the desired product as a yellow-orange oil V-i (356 mg,
70%). NMR (300 MHz, CDC13) d 7.51 (d, J = 2.7 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H),
7.05 (dd, J = 8.5, 2.7 Hz, 1H), 4.06 (t, J = 6.3 Hz, 2H), 3.79 - 3.66 (m, 4H), 2.49 (dt, J =
9.0, 5.1 Hz, 9H), 2.07 - 1.88 ( , 2H).
Synthesis of intermediate V-g: 2-Methyl-5-(3-morpholin-4-yl-propoxy)-phenylamine
A solution of the 4-[3-(4-methyl-3-nitro-phenoxy)-propyl]-mo holine V-i (350 mg, 1.25
mmol) in 90% EtOH (15 mL) was treated with SnCl2.H20 (1.58 g, 6.24 mmol) and cone.
HCl (1.04 mL, 12.5 mmol) and heated to reflux for 1 h. The cooled solution was
concentrated under reduced pressure and taken to pH=8 with a saturated solution of
NaHC0 3 then extracted with EtOAc. The combined organics were dried (MgS0 4), filtered
and evaporated to the desired product V-g as a viscous yellow oil (306 mg, 98%>). NMR
(300 MHz, CDC13) d 6.92 (d, J = 8.8 Hz, 1H), 6.30 - 6.24 ( , 2H), 3.96 (t, J = 6.3 Hz,
2H), 3.76 - 3.69 ( , 4H), 3.58 (s, 2H), 2.57 - 2.42 (m, 6H), 2.09 (s, 3H), 1.93 (dt, J = 13.3,
6.5 Hz, 3H).
Synthesis of example 218: 4'-Methyl-4-{2-[2-methyl-5-(3-morpholin-4-yl-propoxy)-
phenylamino]-oxazol-5-yl }- H-[2,3']bipyridinyl-2'-one
A solution of 4-(2-chloro-oxazol-5-yl)-4'-methyl - H-[2,3']bipyridinyl-2'-one V-f (50 mg,
0.159 mmol) in iPrOH (4 mL) was treated with 2-methyl-5-(3-morpholin-4-yl-propoxy)-
phenylamine V-g (48 mg, 0.191 mmol) and HCl (2M in ether, 120 m , 0.240 mmol) and
heated to reflux for 18 h. The solution was treated with a further 150 of HCl (2M in
ether, 150 , 0.300 mmol) and heated for a further 2 h. The mixture was cooled to room
temperature then the solvent was evaporated under reduced pressure. The residue was
treated with ether and the white precipitate was filtered off to afford the compound 218 (31
mg, 39%). NMR (300 MHz, DMSO) d 11.62 (s, 1H), 9.40 (s, 1H), 8.55 (d, J = 5.3 Hz,
1H), 7.73 (s, 1H), 7.55 - 7.48 (m, 2H), 7.38 (dd, J = 5.2, 1.7 Hz, 1H), 7.29 (d, J = 6.7 Hz,
1H), 7.03 (d, J = 8.8 Hz, 1H), 6.52 (dd, J 8.3, 2.5 Hz, 1H), 6.13 (d, J = 6.7 Hz, 1H), 3.92
(t, J = 6.4 Hz, 2H), 3.56 - 3.44 (m, 4H), 2.40 - 2.25 (m, 6H), 2.16 (s, 3H), 1.98 (s, 3H),
1.86 - 1.75 (m, 2H). ESI+ MS m/z 502 (M+H) +. Retention time = 1.76 min (method 1).
Example 219
Synthetic approach of example 219
Synthesis of intermediate Vl-a: 5-(3-Bromo-phenyl)-oxazole
5-(3-Bromo-phenyl)-oxazole Vl-a was prepared as described for intermediate I-c using 3-
Bromo-benzaldehyde (10 g, 54 mmol), TosMIC (12.7 g, 65 mmol) and K2C0 3 (8.97 g, ) in
MeOH to give the desired intermediate Vl-a as a brownish solid (12.1 g, 100%). NMR
(300 MHz, CDC13) d 7.92 (s, 1H), 7.80 (s, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.46 (d, J = 8.0
Hz, 1H), 7.37 (s, 1H), 7.29 (d, J = 7.9 Hz, 1H).
Synthesis of intermediate Vl-b: 2-Methoxy-3 -(3 -oxazol-5-yl -phenyl)- 1,2-dihydro-pyridine
A mixture of 5-(3-bromo-phenyl)-oxazole Vl-a (1.33 g, 5.94 mmol), 2-methoxy-3-
pyridinylboronic acid (1.00 g, 6.53 mmol), Pd(PPh )4 and K2C0 3 (1.81 g, 13.1 mmol) in
THF (20 mL) and water (10 mL) was heated to reflux for 4h. The mixture was cooled, then
diluted with water and extracted with EtOAc. The combined organics were dried (MgS0 4),
filtered and the residue purified by column chromatography (Si0 2 ; eluting with 30%
EtOAc in cyclohexane) to afford the desired product Vl-b as brown oil which crystallized
on standing (1.37g, 91%). NMR (300 MHz, CDC13) d 8.18 (dd, J = 1.8, 5.0 Hz, 1H),
7.91 (s, 1H), 7.81 (s, 1H), 7.64 (d, J = 6.9 Hz, 2H), 7.53-7.44 (m, 2H), 7.37 (s, 1H), 6.99
(dd, J = 5.0, 7.2 Hz, 1H), 3.97 (s, 3H).
Synthesis of intermediate VI-c: 3-[3-(2-Chloro-oxazol-5-yl)-phenyl]-2-methoxy-l,2-
dihydro-pyridine
3-[3-(2-Chloro-oxazol-5-yl)-phenyl]-2-methoxy-pyridine VI-c was prepared as for
intermediate I-d above from 2-methoxy-3-(3-oxazol-5-yl-phenyl)-pyridine (1.37 g, 5.43
mmol), LiHMDS (1M in THF, 5.97 mL, 5.97 mmol) and C2C 1 (1.54 g, 6.52 mmol) in dry
THF (50mL) to give the desired product VI-c as a white solid after purification by column
chromatography (Si0 2 ; eluting with 10% to 30% EtOAc in cyclohexane) (1.24g, 84%). 1H
NMR (400 MHz, CDC13) d 8.20 (dd, J = 5.0, 1.9 Hz, 1H), 7.76 (t, J = 1.6 Hz, 1H), 7.63
(dd, J = 7.3, 2.0 Hz, 1H), 7.59 - 7.45 (m, 3H), 7.31 (s, 1H), 6.99 (dd, J = 7.3, 5.0 Hz, 1H),
3.99 (s, 3H).
Synthesis of example 219: 3-{3-[2-(3,5-Dimethoxy-phenylamino)-oxazol-5-yl]-phenyl}-
1H-pyridin-2-one
3-{3-[2-(3,5-Dimethoxy-phenylamino)-oxazol-5-yl]-phenyl}-lH-pyridin-2-one 219 was
prepared as for intermediate I-f above from 3-[3-(2-chloro-oxazol-5-yl)-phenyl]-2-
methoxy-pyridine VI-c (40 mg, 0.150 mmol) with 3,5-dimethoxyaniline (29 mg, 0.190
mmol) and HC1 (2M in ether, 120 , 0.23 mmol) in iPrOH (4 mL). The crude reaction
mixture was evaporated under reduced pressure and the residue treated with a saturated
solution of NaHC0 3 and EtOAc. A precipitate formed from the biphasic mixture and was
filtered off and dried to give the compound 219 product as a beige solid (19 mg, 33%). 1H
NMR (300 MHz, DMSO-d 6) d 11.86 (s, 1H), 10.35 (s, 1H), 7.96 (s, 1H), 7.70 (dd, J = 2.0,
6.9 Hz, 1H), 7.60-7.41 (m, 5H), 6.89 (d, J = 2.0 Hz, 2H), 6.32 (t, J = 6.7 Hz, 1H), 6.13 (s,
1H), 3.73 (s, 6H). ES MS m/z 390 (M+H)+. Retention time = 3.45 in (method 1).
Example 220
Synthetic approach of example 220
Synthesis of intermediate Vll-a: 2-Fluoro-4-formyl-benzonitrile
A solution of 4-bromo-2-fluorobenzonitrile (5.00 g, 25 mmol) in dry THF (50 mL) at -
10°C under argon was treated with a solution of isopropylmagnesium chloride (2M in
THF, 15.0 mL, 30.0 mmol) dropwise before stirring at this temperature for 3 h. A solution
of N-formylpiperidine (3.89 g, 35.0 mmol) in dry THF (15 mL) was added dropwise and
the mixture allowed to warm to room temperature before stirring for 1.5h. The resultant
solution was treated with 4M aq HC1 (250 mL each) and the organics extracted with
EtOAc. The combined organics were dried (MgS0 4), filtered and evaporated before
purification of the residue by column chromatography (Si0 2; eluting with 30% to 50%
EtOAc in cyclohexane) to afford 2-fluoro-4-formyl-benzonitrile VH-a as a pale yellow
solid (2.73 g, 73%).1H NMR (300 MHz, CDC13) d 10.07 (d, J = 1.7 Hz, 1H), 7.90 - 7.79
(m, 2H), 7.74 (dd, J = 8.5, 0.8 Hz, 1H).
Synthesis of intermediate Vll-b: 2-Fluoro-4-oxazol-5-yl-benzonitrile
5-(3-Bromo-phenyl)-oxazole Vll-b was prepared as described for intermediate I-c using 2-
Fluoro-4-foniiyl-benzonitrile Vll-a (2 g, 13.43 mmol), TosMIC (2.85 g, 14.77 mmol) and
K2C0 (2.41 g, 1.86 mmol) in MeOH (40 mL) to give the desired intermediate Vll-b as a
yellow solid (1.46 g, 58%). NMR (300 MHz, CDC13) d 7.94 (s, 1H), 7.62 (dd, J = 8.0,
6.5 Hz, 1H), 7.52 - 7.37 (m, 3H).
Synthesis of intermediate VII-c: 2-(3-Methyl-2-oxo-2H-pyridin-l-yl)-4-oxazol-5-ylbenzonitrile
A solution of 3-methyl- lH-pyridin-2-one (1.43 g, 13.1 mmol) in absolute EtOH (100 mL)
was treated with KOH (735 mg, 13.1 mmol) and heated to reflux with vigorous stirring for
2 h before cooling to room temperature and evaporation of the solvent under reduced
pressure. The orange solid residue was taken up in dry DMF (100 mL) and treated with 2-
fluoro-4-oxazol-5-yl-benzonitrile Vll-b (2.24 g, 11.9 mmol) and stirred at 100°C for 3 h.
The solvent was evaporated under reduced pressure and the residue treated with a saturated
solution of NaHC0 3 and extracted with DCM. The combined organics were dried
(MgS0 4), filtered and evaporated and the residue purified by column chromatography
(Si0 eluting with 50% EtOAc in cyclohexane) to give the desired intermediate VII-c as
an off-white solid (2.55 g, 77%).1H NMR (300 MHz, DMSO-d 6) d 8.62 (s, 1H), 8.15 (d, J
= 8.1 Hz, 1H), 8.04 (s, 2H), 7.99 (dd, J = 8.1, 1.6 Hz, 1H), 7.62 (dd, J = 6.9, 1.1 Hz, 1H),
7.49 (d, J = 6.6 Hz, 1H), 6.34 (t, J = 6.8 Hz, 1H), 2.07 (s, 3H).
Synthesis of intermediate Vll-d: 4-(2-Chloro-oxazol-5-yl)-2-(3-methyl-2-oxo-2H-pyridinl-
yl)-benzonitrile
A solution of the 2-(3-methyl-2-oxo-2H-pyridin-l-yl)-4-oxazol-5-yl -benzonitrile VII-c
(2.55 g, 9.19 mmol) in dry distilled THF (160 mL) at -78°C under argon was treated
dropwise with LiHMDS (1M in THF, 11.0 mL, 11.0 mmol) to give an opaque yellow
slurry. After l h at this temperature, C2C1 (3.26 g, 13.8 mmol) was added in one portion
and the mixture was allowed to warm to room temperature. This mixture was treated with
water and extracted with DCM. The combined organics were dried (MgS0 4), filtered and
evaporated and the residue purified by column chromatography (Si0 2 ; eluting with 50%
EtOAc in cyclohexane) to give the desired product Vll-d as a pink solid (1.51 g, 52%). 1H
NMR (300 MHz, DMSO-d 6) d 8.16 (d, J = 8.2 Hz, 1H), 8.10 (s, 1H), 8.02 (d, J = 1.4 Hz,
1H), 7.96 (dd, J = 8.1, 1.5 Hz, 1H), 7.61 (d, J = 6.9 Hz, 1H), 7.49 (d, J = 6.7 Hz, 1H), 6.35
(t, J = 6.8 Hz, 1H), 2.07 (s, 3H).
Synthesis of intermediate Vll -e: N-(5-ethoxymethyl-2-methyl-phenyl)-acetamide
N-(5-ethoxyinethyl-2-methyl-phenyl)-acetamide Vll-e was prepared as described for
intermediate Il-i using 5-ethoxymethyl-2-methyl-phenylamine I-e (5 g, 30.26 mmol), dry
triethylamine (12.23 mL), DCM (60 mL) and AcCl (4.32 mL) to give the desired
intermediate Vll-e as a white solid (5.39 g, 86%).. 1H NMR (300 MHz, CDC13) d 7.69 (s,
1H), 7.15 (d, J = 7.7 Hz, 1H), 7.07 (d, J = 8.2 Hz, 1H), 4.46 (s, 2H), 3.53 (q, J = 7.0 Hz,
2H), 2.23 (s, 3H), 2.18 (s, 3H), 1.23 (t, J = 7.0 Hz, 3H).
Synthesis of example 220: 4-[2-((5-Ethoxymethyl)-2-methyl-phenylamino)-oxazol-5-yl]-2-
(3-methyl-2-oxo-2H-pyridin- 1-yl)-benzonitrile
A mixture of N-(5-ethoxymethyl-2-methyl-phenyl)-acetamide Vll-e (74 mg, 0.361 mmol),
dry THF (3 mL) and NaH (60% in oil, 29 mg 0.722 mmol) under argon was stirred at room
temperature for 1 h. A suspension of 4-(2-chloro-oxazol-5-yl)-2-(3-methyl-2-oxo-2Hpyridin-
l-yl)-benzonitrile VH-d (75 mg, 0.241 mmol) in dry THF (3 mL) was added
dropwise at 0°C before warming to room temperature over 2 h. The mixture was treated
with water, and extracted with EtOAc. The combined organics were dried (MgS0 4),
filtered and evaporated and the residue purified by column chromatography (Si0 2 ; eluting
with 50% EtOAc in cyclohexane) to give the desired product 220 as a pink solid (61 mg,
56%). NMR (300 MHz, DMSO-d 6) d 9.55 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.83 - 7.68
(m, 4H), 7.61 (d, J = 6.7 Hz, 1H), 7.48 (d, J = 6.6 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 6.97
(d, J = 7.4 Hz, 1H), 6.33 (t, J = 6.8 Hz, 1H), 4.41 (s, 2H), 3.46 (q, J = 7.0 Hz, 2H), 2.27 (s,
3H), 2.06 (d, J = 7.1 Hz, 3H), 1.12 (t, J = 7.0 Hz, 3H).
Example 221
Synthetic approach of example 221
Synthesis of intermediate Vlll-a: 3-Bromo-5-oxazol-5-yl-pyridine
5-(3-Bromo-phenyl)-oxazole VHI-a was prepared as described for intermediate I-c using
2-5-bromo-pyridine-3-carbaldehyde (0.260 g, 1.4 mmol), TosMIC (0.273 g, 1.54 mmol)
and K2C0 3 (0.580 g, 4.2 mmol) in MeOH (15 mL) to give the desired intermediate VHI-a
as a beige solid (0.16 g, 50%). NMR (300 MHz, DMSO) d 8.95 (s, 1H), 8.70 (s, 1H),
8.59 (s, 1H), 8.43 (s, 1H), 7.95 (s, 1H).
Synthesis of intermediate VIII-b: 5'-Oxazol-5-yl-[l,3']bipyridinyl-2-one
To an oven-dried sealed tube containing a solution of 3-bromo-5-oxazol-5-yl -pyridine
VHI-a (1.00 g, 4.44 mol) in degassed 1,4-dioxane (20 mL) was added 2-hydroxypyridine
(507 mg, 5.33 mmol), K2C0 3 (1.23 g, 1.78 mmol), Cul (169 mg, 0.899 mmol) and ractrans-
N,N -dimethyl cyclohexane diamine (280 m , 1.78 mmol). The tube was flushed with
argon and sealed then heated in an oil bath at 120°C overnight. After cooling to RT, the
mixture was filtered and the filter cake washed with 1,4-dioxane. The mixture was
evaporated and the residue purified by column chromatography (2% to 5% EtOH in DCM)
to give the desired product VIII-b as a beige solid (752 mg, 71%). NMR (300 MHz,
DMSO-d ) d 9.06 (s, 1H), 8.68 (s, 1H), 8.60 (s, 1H), 8.29 (s, 1H), 7.95 (s, 1H), 7.80 (dd, J
= 6.8, 1.6 Hz, 1H), 7.57 (ddd, J = 8.8, 6.6, 1.9 Hz, 1H), 6.54 (d, J = 9.2 Hz, 1H), 6.39 (t,
J = 6.7 Hz, 1H).
Synthesis of intermediate VIII-c: 5'-(2-Chloro-oxazol-5-yl)-[l,3']bipyridinyl-2-one
5'-(2-Chloro-oxazol-5-yl)-[l,3']bipyridinyl-2-one VIII-c was prepared as described for I-d
above from 5'-oxazol-5-yl-[l,3']bipyridinyl-2-one Vlll-d (740 mg, 3.09 mmol) using
LiHMDS (1M in THF, 4.64 mL, 4.64 mmol) and C2C 16 (1.10 g, 4.64 mmol) in dry THF.
The crude product was purified by column chromatography (Si0 2 ; eluting with 2% to 5%
EtOH in DCM) to afford the desired product VIII-c as a white solid (393 mg, 47%).
NMR (300 MHz, CDC13) d 8.91 (s, 1H), 8.61 (s, 1H), 8.06 (t, J = 2.2 Hz, 1H), 7.50 - 7.42
(m, 2H), 7.35 (dd, J 6.9, 1.9 Hz, 1H), 6.70 (d, J 9.3 Hz, 1H), 6.34 (td, J = 6.8, 1.2 Hz,
1H).
Synthesis of example 221: 5'-[2-(5-Methoxy-2-methyl-phenylamino)-oxazol-5-yl]-
[l,3']bipyridinyl-2-one
5'-[2-(5-Methoxy-2-methyl-phenylamino)-oxazol-5-yl]-[l,3']bipyridinyl-2-one 221 was
prepared as described for I-f above from 5'-(2-Chloro-oxazol-5-yl)-[l,3']bipyridinyl-2-one
VIII-c (68 mg, 0.250 mmol), and 5-methoxy-2-methylaniline (35 mg, 0.250 mmol) in
iPrOH (3 mL) to afford the title compound 221 after column chromatography (Si0 2 ;
eluting with 2% to 5% EtOH in DCM) as an orange solid (28 mg, 30%). (300 MHz,
CDC13) d 8.83 (d, J = 1.9 Hz, 1H), 8.45 (d, J = 2.3 Hz, 1H), 7.93 (t, J = 2.1 Hz, 1H), 7.73
(d, J = 2.4 Hz, 1H), 7.41 (m, 1H), 7.34 (m, 1H), 7.30 (s, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.78
(s, 1H), 6.68 (d, J = 9.3 Hz, 1H), 6.55 (dd, J = 8.3, 2.5 Hz, 1H), 6.30 (t, J = 5.6 Hz, 1H),
3.81 (s, 3H), 2.25 (s, 3H). ESI+ MS m/z 375 (M+H)+. Retention time = 2.99 min (method
1)·
Example 222
Synthesis of example 222: 3-{3-[2-(3,5-Dimethoxy-phenylamino)-oxazol-5-yl]-phenyl}-l-
(2-dimethylamino-ethyl)- 1H-pyridin-2-one
222
A mixture of 3-{3-[2-(3,5-Dimethoxy-phenylamino)-oxazol-5-yl]-phenyl}-lH-pyridin-2-
one 219 (39 mg, 0.10 mmol), (2-chloro-ethyl)-dimethyl-amine hydrochloride (17.5 mg,
0.1 1 mmol), K2C0 3 (31 mg, 0.22 mmol) and potassium iodide (19 mg, 0.1 1 mmol) in
DMF (4 mL) was heated at 50°C for 16 h. After evaporation of DMF, the mixture was
treated with water and extracted with EtOAc. The combined organics were dried (MgS0 4),
filtered and evaporated and the residue purified by column chromatography (A120 3 ;
eluting with 1% EtOH in DCM) to give the desired product 222 as a yellow solid (23 mg,
50%). NMR (300 MHz, DMSO) d 10.32 (s, 1H), 7.95 (s, 1H), 7.72 (d, J = 6.7 Hz, 1H),
7.66 (dd, J = 6.9, 1.6 Hz, 1H), 7.58 - 7.31 (m, 4H), 6.90 (s, 1H), 6.89 (s, 1H), 6.35 (t, J =
6.8 Hz, 1H), 6.13 (s, 1H), 4.07 (t, J = 6.3 Hz, 2H), 3.73 (s, 6H), 2.55 (t, J = 6.3 Hz, 2H),
2.20 (s, 6H). ESI+ MS m/z 461 (M+H)+. Retention time = 2.90 min (method 1).
Example 223
Synthetic approach of example 223
Synthesis of intermediate IX-a: 2-Bromo-4-(2-chloro-oxazol-5-yl)-pyridine
2-Bromo-4-(2-chloro-oxazol-5-yl)-pyridine IX-a was prepared as for example I-d using 2-
Bromo-4-oxazol-5-yl-pyridine (450 mg, 2 mmol), LiHMDS (2.2 mL, 2.2 mmol) and C2C 16
(568 mg, 2.4 mmol) in THF to give intermediate IX-a as a yellow-orange solid (465 mg,
90 %). 1H NMR (300 MHz, CDC13) d 8.43 (d, J = 5.1 Hz, 1H), 7.68 (s, 1H), 7.53 (s, 1H),
7.46 - 7.36 (m, 1H).
Synthesis of intermediate IX-b: [5-(2-Bromo-pyridin-4-yl)-oxazol-2-yl]-(5-ethoxymethyl-
2-methyl-phenyl)-amine
[5-(2-Bromo-pyridin-4-yl)-oxazol-2-yl]-(5-ethoxymethyl-2-methyl-phenyl)-amine IX-b
was prepared as for example 220 using intermediate Vll-e (169 mg, 0.65 mmol), N-(5-
ethoxymethyl-2-methyl-phenyl)-acetamide (162 mg, 0.78 mmol) and NaH (65 mg, 1.6
mmol) in DMF to give intermediate IX-b as a yellow solid (162 mg, 64 %). 1H NMR (300
MHz, CDC13) d 8.32 (d, J = 5.1 Hz, 1H), 7.94 (s, 1H), 7.56 (s, 1H), 7.42 (s, 1H), 7.32 (d, J
= 5.2 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.06 (d, J = 7.7 Hz, 1H), 6.91 (s, 1H), 4.54 (s, 2H),
3.58 (q, J = 7.0 Hz, 2H), 2.34 (s, 3H), 1.27 (t, J = 7.0 Hz, 3H).
Synthesis of example 223: 4'-[2-(5-Ethoxymethyl-2-methyl-phenylamino)-oxazol-5-yl]-
3,4,5,6-tetrahydro-[l,2']bipyridinyl-2-one
A mixture of intermediate IX-b (51 mg, 0.13 mmol), d-valerolactam (16 mg, 0.16 mmol),
cesium carbonate (60 mg, 0.18 mmol), Pd2(dba)3 (4 mg, 0.004 mmol) and XantPhos (7 mg,
0.012 mmol) in dioxane (2.5 mL) was refluxed for 1 h, until no starting material remained
(reaction monitored by TLC). The reaction mixture was then evaporated, and the cmde oil
was directly chromato graphed (Si0 , eluting with 1 to10% EtOH in DCM) to give example
223 as a yellow solid (22 mg, 42 %). 1H NMR (300 MHz, CDC13) d 8.39 (d, J = 5.3 Hz,
1H), 7.99 (s, 1H), 7.94 (s, 1H), 7.39 (s, 1H), 7.25 - 7.12 (m, 3H), 7.05 (d, J =7.6 Hz, 1H),
4.54 (s, 2H), 4.02 - 3.89 (m, 2H), 3.57 (q, J = 6.9 Hz, 2H), 2.69 - 2.56 (m, 2H), 2.34 (s,
3H), 2.02 - 1.89 (m, 4H), 1.26 (t, J = 7.0 Hz, 3H). ESI+ MS m/z 407 (M+H)+. Retention
time = 3.48 min (method 1).
Example 224
Synthesis of example 224: l-{4-[2-((5-Ethoxymethyl)-2-methyl-phenylamino)-oxazol-5-
yl]-pyridin-2-yl}-tetrahydro-pyrimidin-2-one
A mixture of intermediate IX-b (50 mg, 0.13 mmol), N,N'-trimethyleneurea (130 mg, 1.3
mmol), cesium carbonate (46 mg, 0.14 mmol), Pd (dba) (4 mg, 0.004 mmol) and
XantPhos (7 mg, 0.012 mmol) in dioxane (2.5 mL) was refluxed for lh30. The reaction
mixture was then evaporated, dissolved in ethyl acetate, washed several times with water,
dried over MgS0 4, and concentrated. The crude oil was chromatographed (Si0 2, eluting
with 1 tol0% EtOH in DCM) to give example 224 as a yellow-orange solid (16 mg, 3 1 %).
1H NMR (300 MHz, OMSO-d6) d 9.54 (s, 1H), 8.28 (d, J =5.2 Hz, 1H), 7.99 (s, 1H), 7.79
(s, 1H), 7.66 (s, 1H), 7.24 - 7.10 (m, 2H), 7.00 - 6.86 (m, 2H), 4.41 (s, 2H), 3.92 - 3.80
(m, 2H), 3.47 (q, J =6.9 Hz, 2H), 3.26 - 3.19 (m, 2H), 2.27 (s, 3H), 2.03 - 1.80 (m, 2H),
1.14 (t, J = 7.0 Hz, 3H).
Example 225
Synthetic approach of example 225
Synthesis of intermediate X-a: 5-(3-Nitro-phenyl)-oxazole
Interaiediate X-a was prepared as for example I-c using 3-nitrobenzaldehyde (4 g, 26
mmol), TosMIC (5.7 g, 29 mmol) and K2C0 (4.4 g, 32 mmol) in MeOH to give
interaiediate X-a as a yellow solid (4.7 g, 93 %). 1H NMR (400 MHz, DMSO- ) d 8.56 (s,
1H), 8.50 (t, J = 1.9 Hz, 1H), 8.21 (ddd, J = 8.2, 2.3, 1.0 Hz, 1H), 8.17 (ddd, J = 7.8, 1.6,
1.0 Hz, 1H), 7.99 (s, 1H), 7.78 (t, J = 8.0 Hz, 1H).
Synthesis of intermediate X-b: 2-Chloro-5-(3-nitro-phenyl)-oxazole
Interaiediate X-b was prepared as for example I-d using interaiediate X-a (3.2 g, 17
mmol), LiHMDS (20.2 liiL, 20 mmol) and C2C 1 (4.78 g, 20 mmol) in THF to give the
desired intermediate X-b as a yellow solid (3.13 g, 82 %). NMR (400 MHz, DMSO-d )
d 8.48 (d, J = 1.5 Hz, 1H), 8.24 (d, J = 8.2 Hz, 1H), 8.14 (d, J = 7.8 Hz, 1H), 8.09 (d, J =
1.9 Hz, 1H), 7.80 (td, J = 8.1, 1.9 Hz, 1H).
Synthesis of intermediate X-c: 4-Methyl-N3-[5-(3-nitro-phenyl)-oxazol-2-yl]-benzene-l,3-
diamine
Intermediate X-c was prepared as for example 220 using intermediate X-b (448 mg, 2
mmol), N-(5-Amino-2-methyl-phenyl)-acetamide (394 mg, 2.4 mmol) and NaH (160 mg, 4
mmol) in THF to give intermediate X-c as an orange solid (236 mg, 64 %). NMR (300
MHz, OM - 6) d 9.17 (s, 1H), 8.32 (s, 1H), 8.07 (d, J =7.5 Hz, 1H), 8.00 (d, J =7.7 Hz,
1H), 7.72 (m, 2H), 7.1 1 (s, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.24 (d, J =7.4 Hz, 1H), 4.91 (s,
2H), 2.1 (s, 3H).
Synthesis of intermediate X-d: N-{4-Methyl-3-[5-(3-nitro-phenyl)-oxazol-2-ylamino]-
phenyl }-2-pyrrolidin- 1-yl-acetamide
A mixture of intermediate X-c (226 mg, 0.72 mmol), 1-pynOlidinyl acetic acid
hydrochloride (158 mg, 0.94 mmol), 1-hydroxybenzotriazole hydrate (148 mg, 1.1 mmol),
N-(3-dimethylaminopropyl )-N '-ethylcarbodiimide hydrochloride (252 mg, 1.3 mmol) and
NEt3 (360 i , 2.6 mmol) in DMF (15 mL) was stirred at room temperature overnight. The
reaction mixture was then evaporated, diluted with ethyl acetate, washed with water, dried
over MgS0 4, and concentrated to a minimum volume for allowing crystallisation. The title
compound was then collected by filtration to afford intermediate X-d as a yellow solid
(224 mg, 72 %). NMR (300 MHz, O -d6) d 9.66 (s, 1H), 9.43 (s, 1H), 8.35 (s, 1H),
8.03 (d, J =7.3 Hz, 1H), 7.89 (d, J =7.9 Hz, 1H), 7.70 (m, 2H), 7.04 (s, 1H), 6.89 (d, J =
8.1 Hz, 1H), 6.26 (d, J = 7.5 Hz, 1H), 3.24 (s, 2H), 2.63 - 2.54 (m, 4H), 2.22 (s, 3H), 1.76 -
1.69 (m, 4H).
Synthesis of intermediate X-e: N-{3-[5-(3-Amino-phenyl)-oxazol-2-ylamino]-4-methylphenyl}
-2-pyrrolidin- 1-yl-acetamide
A mixture of intermediate X-d (220 mg, 0.52 mmol), SnCl .2H 0 (590 mg, 2.6 mmol) and
concentrated hydrochloric acid (735 m , 5.2 mmol) in a mixture ethanol/eau (9 mL/ 1 mL)
was stirred at 40°C for 4 h. The reaction mixture was then evaporated, diluted with ethyl
acetate and aqueous NaOH. The aqueous layer was extracted twice with ethyl acetate, then
the combined organic layers were washed with water, dried over MgS0 4, and
concentrated. The crude oil was chromatographed (A1 0 3, eluting with 0.5% EtOH in
DCM) to give intermediate X-e as a yellow-beige solid (147 mg, 72 %). NMR (300
MHz, DMSO-i¾ d 9.68 (s, 1H), 9.40 (s, 1H), 8.21 (s, 1H), 7.95 (d, J =7.8 Hz, 1H), 7.88
(d, J =7.3 Hz, 1H), 7.56 (s, 1H), 7.32 (s, 1H), 7.05 (s, 1H), 6.91 (d, J =7.3 Hz, 1H), 6.19
(d, J = 7.6 Hz, 1H), 4.85 (s, 2H), 3.28 (s, 2H), 2.67 - 2.56 (m, 4H), 2.23 (s, 3H), 1.78 -
1.68 ( , 4H).
Synthesis of example 225: N-(3-{5-[3-(2,6-Dioxo-piperidin-l-yl)-phenyl]-oxazol-2-
ylamino}-4-methyl-phenyl)-2-pyrrolidin-l -yl-acetamide
To a solution of intermediate X-e (70 mg, 0.18 mmol) in anhydrous THF (4 mL) under
argon at 0°C was added glutaric anhydride (20 mg, 0.18 mmol) in several portions. The
mixture was stirred at ambient temperature for 1 h, then refluxed overnight. The solid
formed was collected by filtration, then washed with THF and diethyl ether, to give a white
solid (52 mg), which was treated in anhydrous 1,2-dichloroethane (8 mL) with SOCl (30
m , 0.4 mmol) over a period of 10 min. The mixture was refluxed for at least 4 h, until no
starting material remained, then diluted with DCM, washed with aqueous NaHC0 3 and
water, dried over MgS0 4, and concentrated. The residue was cliromatographed (A120 3,
eluting with 0.5 tol% EtOH in DCM) to give compound 225 as a beige solid (23 mg, 45
%). 1H NMR (300 MHz, DMSO-<¾ d 9.96 (s, 1H), 9.64 (s, 1H), 9.27 (d, J = 12.2 Hz, 1H),
8.03 (d, J = 10.9 Hz, 1H), 7.94 (s, 1H), 7.54 - 7.46 (m, 1H), 7.35 - 7.27 (m, 3H), 7.10 (d, J
= 8.2 Hz, 1H), 3.23 (s, 2H), 2.69 (t, J = 6.5 Hz, 4H), 2.63 - 2.56 (m, 4H), 2.23 (s, 3H), 2.12
(m, 2H), 1.74 (s, 4H).
In another embodiment, the invention relates to a pharmaceutical composition comprising
a compound as depicted above.
Such a pharmaceutical composition can be adapted for oral administration, and can be
formulated using pharmaceutically acceptable carriers well known in the art in suitable
dosages. Such carriers enable the pharmaceutical compositions to be formulated as tablets,
pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for
ingestion by the patient. In addition to the active ingredients, these pharmaceutical
compositions may contain suitable pharmaceutically-acceptable carriers comprising
excipients and auxiliaries which facilitate processing of the active compounds into
preparations which can be used pharmaceutically. Further details on techniques for
formulation and administration may be found in the latest edition of Remington's
Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa.).
The composition of the invention can also take the form of a pharmaceutical or cosmetic
composition for topical administration.
Such compositions may be presented in the form of a gel, paste, ointment, cream, lotion,
liquid suspension aqueous, aqueous-alcoholic or, oily solutions, or dispersions of the lotion
or serum type, or anhydrous or lipophilic gels, or emulsions of liquid or semi-solid
consistency of the milk type, obtained by dispersing a fatty phase in an aqueous phase or
vice versa, or of suspensions or emulsions of soft, semi-solid consistency of the cream or
gel type, or alternatively of microemulsions, of microcapsules, of microparticles or of
vesicular dispersions to the ionic and/or nonionic type. These compositions are prepared
according to standard methods.
The composition according to the invention comprises any ingredient commonly used in
dermatology and cosmetic. It may comprise at least one ingredient selected from
hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic active agents,
preservatives, emollients, viscosity enhancing polymers, humectants, surfactants,
preservatives, antioxidants, solvents, and fillers, antioxidants, solvents, perfumes, fillers,
screening agents, bactericides, odor absorbers and coloring matter.
As oils which can be used in the invention, mineral oils (liquid paraffin), vegetable oils
(liquid fraction of shea butter, sunflower oil), animal oils, synthetic oils, silicone oils
(cyclomethicone) and fluorinated oils may be mentioned. Fatty alcohols, fatty acids
(stearic acid) and waxes (paraffin, carnauba, beeswax) may also be used as fatty
substances.
As emulsifiers, glycerols, polysorbates, glycerides, and PEGs can be used in the invention.
As hydrophilic gelling agents, carboxyvinyl polymers (carbomer), acrylic copolymers such
as acrylate/alkylacrylate copolymers, polyacrylamides, polysaccharides such as
hydroxypropylcellulose, clays and natural gums may be mentioned, and as lipophilic
gelling agents, modified clays such as bentones, metal salts of fatty acids such as
aluminum stearates and hydrophobic silica, or alternatively ethylcellulose and polyethylene
may be mentioned.
As hydrophilic active agents, proteins or protein hydrolysates, amino acids, polyols, urea,
allantoin, sugars and sugar derivatives, vitamins, starch and plant extracts, in particular
those of Aloe vera may be used.
As lipophilic active, agents, retinol (vitamin A) and its derivatives, tocopherol (vitamin E)
and its derivatives, essential fatty acids, ceramides and essential oils may be used. These
agents add extra moisturizing or skin softening features when utilized.
In addition, a surfactant can be included in the composition so as to provide deeper
penetration of the compound capable of depleting mast cells, such as a tyrosine kinase
inhibitor, preferably a c-kit inhibitor.
Among the contemplated ingredients, the invention embraces penetration enhancing agents
selected for example from the group consisting of mineral oil, water, ethanol, triacetin,
glycerin and propylene glycol; cohesion agents selected for example from the group
consisting of polyisobutylene, polyvinyl acetate and polyvinyl alcohol, and thickening
agents.
Chemical methods of enhancing topical absorption of drugs are well known in the art. For
example, compounds with penetration enhancing properties include sodium lauryl sulfate
(Dugard, P. H. and Sheuplein, R. J., "Effects of Ionic Surfactants on the Permeability of
Human Epidermis: An Electrometric Study," J. Ivest. Dermatol., V.60, pp. 263-69, 1973),
lauryl amine oxide (Johnson et. al., US 4,41 1,893), azone (Rajadhyaksha, US 4,405,616
and 3,989,816) and decylmethyl sulfoxide (Sekura, D. L. and Scala, J., "The Percutaneous
Absorption of Alkylmethyl Sulfides," Pharmacology of the Skin, Advances In Biolocy of
Skin, (Appleton-Century Craft) V. 12, pp. 257-69, 1972). It has been observed that
increasing the polarity of the head group in amphoteric molecules increases their
penetration-enhancing properties but at the expense of increasing their skin irritating
properties (Cooper, E. R. and Berner, B., "Interaction of Surfactants with Epidermal
Tissues: Physiochemical Aspects," Surfactant Science Series, V. 16, Reiger, M. M. ed.
(Marcel Dekker, Inc.) pp. 195-210, 1987).
A second class of chemical enhancers are generally referred to as co-solvents. These
materials are absorbed topically relatively easily, and, by a variety of mechanisms, achieve
permeation enhancement for some drugs. Ethanol (Gale et. al., U.S. Pat. No. 4,615,699 and
Campbell et. al., U.S. Pat. Nos. 4,460,372 and 4,379,454), dimethyl sulfoxide (US
3,740,420 and 3,743,727, and US 4,575,515), and glycerine derivatives (US 4,322,433) are
a few examples of compounds which have shown an ability to enhance the absoiption of
various compounds.
The phamiaceutical compositions of the invention can also be intended for administration
as an aerosolized formulation to target areas of a patient's respiratory tract.
Devices and methodologies for delivering aerosolized bursts of a formulation of a drug is
disclosed in US 5,906,202. Formulations are preferably solutions, e.g. aqueous solutions,
ethanoic solutions, aqueous/ethanoic solutions, saline solutions, colloidal suspensions and
microcrystalline suspensions. For example aerosolized particles comprise the active
ingredient mentioned above and a carrier, (e.g., a pharmaceutically active respiratory drug
and carrier) which are formed upon forcing the formulation through a nozzle which nozzle
is preferably in the form of a flexible porous membrane. The particles have a size which is
sufficiently small such that when the particles are formed they remain suspended in the air
for a sufficient amount of time such that the patient can inhale the particles into the
patient's lungs.
The invention encompasses the systems described in US 5,556,61 1:
- liquid gas systems (a liquefied gas is used as propellent gas (e.g. low-boiling FCHC or
propane, butane) in a pressure container,
- suspension aerosol (the active substance particles are suspended in solid form in the
liquid propellent phase),
- pressurized gas system (a compressed gas such as nitrogen, carbon dioxide, dinitrogen
monoxide, air is used.
Thus, according to the invention the pharmaceutical preparation is made in that the active
substance is dissolved or dispersed in a suitable nontoxic medium and said solution or
dispersion atomized to an aerosol, i.e. distributed extremely finely in a carrier gas. This is
technically possible for example in the form of aerosol propellent gas packs, pump aerosols
or other devices known per se for liquid misting and solid atomizing which in particular
permit an exact individual dosage.
Therefore, the invention is also directed to aerosol devices comprising the compound as
defined above and such a formulation, preferably with metered dose valves.
The pharmaceutical compositions of the invention can also be intended for intranasal
administration.
In this regard, pharmaceutically acceptable carriers for administering the compound to the
nasal mucosal surfaces will be readily appreciated by the ordinary artisan. These carriers
are described in the Remington's Pharmaceutical Sciences" 16th edition, 1980, Ed. By
Arthur Osol, the disclosure of which is incorporated herein by reference.
The selection of appropriate carriers depends upon the particular type of administration
that is contemplated. For administration via the upper respiratory tract, the composition can
be fonriulated into a solution, e.g., water or isotonic saline, buffered or unbuffered, or as a
suspension, for intranasal administration as drops or as a spray. Preferably, such solutions
or suspensions are isotonic relative to nasal secretions and of about the same pH, ranging
e.g., from about pH 4.0 to about pH 7.4 or, from pH 6.0 to pH 7.0. Buffers should be
physiologically compatible and include, simply by way of example, phosphate buffers. For
example, a representative nasal decongestant is described as being buffered to a pH of
about 6.2 (Remington's, Id. at page 1445). Of course, the ordinary artisan can readily
determine a suitable saline content and pH for an innocuous aqueous earner for nasal
and/or upper respiratory administration.
Common intranasal carriers include nasal gels, creams, pastes or ointments with a viscosity
of, e.g., from about 10 to about 3000 cps, or from about 2500 to 6500 cps, or greater, may
also be used to provide a more sustained contact with the nasal mucosal surfaces. Such
carrier viscous formulations may be based upon, simply by way of example,
alkylcelluloses and/or other biocompatible carriers of high viscosity well known to the art
(see e.g., Remington's, cited supra. A preferred alkylcellulose is, e.g., methylcellulose in a
concentration ranging from about 5 to about 1000 or more mg per 100 ml of carrier. A
more preferred concentration of methyl cellulose is, simply by way of example, from about
25 to about mg per 100 ml of carrier.
Other ingredients, such as art known preservatives, colorants, lubricating or viscous
mineral or vegetable oils, perfumes, natural or synthetic plant extracts such as aromatic
oils, and humectants and viscosity enhancers such as, e.g., glycerol, can also be included to
provide additional viscosity, moisture retention and a pleasant texture and odor for the
formulation. For nasal administration of solutions or suspensions according to the
invention, various devices are available in the art for the generation of drops, droplets and
sprays.
A premeasured unit dosage dispenser including a dropper or spray device containing a
solution or suspension for delivery as drops or as a spray is prepared containing one or
more doses of the drug to be administered and is another object of the invention. The
invention also includes a kit containing one or more unit dehydrated doses of the
compound, together with any required salts and/or buffer agents, preservatives, colorants
and the like, ready for preparation of a solution or suspension by the addition of a suitable
amount of water.
Another aspect of the invention is directed to the use of said compound to manufacture a
medicament. In other words, the invention embraces a method for treating a disease related
to unregulated c-kit transduction comprising administering an effective amount of a
compound as defined above to a mammal in need of such treatment.
More particularly, the invention is aimed at a method for treating a disease selected from
autoimmune diseases, allergic diseases, bone loss, cancers such as leukemia and GIST,
tumor angiogenesis, inflammatory diseases, inflammatory bowel diseases (IBD),
interstitial cystitis, mastocytosis, infections diseases, metabolic disorders, fibrosis, diabetes
and CNS disorders comprising administering an effective amount a compound depicted
above to a mammal in need of such treatment.
The above described compounds are useful for manufacturing a medicament for the
treatment of diseases related to unregulated c-kit transduction, including, but not limited to:
neoplastic diseases such as mastocytosis, canine mastocytoma, solid tumours,
human gastrointestinal stromal tumor ("GIST"), small cell lung cancer, non-small
cell lung cancer, acute myelocytic leukemia, acute lymphocytic leukemia,
myelodysplastic syndrome, chronic myelogenous leukemia, colorectal carcinomas,
gastric carcinomas, gastrointestinal stromal tumors, testicular cancers,
glioblastomas, solid tumors and astrocytomas
tumor angiogenesis.
metabolic diseases such as diabetes mellitus and its chronic complications; obesity;
diabete type II; hyperlipidemias and dyslipidemias; atherosclerosis; hypertension;
and cardiovascular disease.
allergic diseases such as asthma, allergic rhinitis, allergic sinusitis, anaphylactic
syndrome, urticaria, angioedema, atopic dermatitis, allergic contact dermatitis,
erythema nodosum, erythema multiforme, cutaneous necrotizing venulitis and
insect bite skin inflammation and blood sucking parasitic infestation
interstitial cystitis.
- bone loss (osteoporosis).
inflammatory diseases such as rheumatoid arthritis, conjunctivitis, rheumatoid
spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions
autoimmune diseases such as multiple sclerosis, psoriasis, intestine inflammatory
disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis and polyarthritis,
local and systemic scleroderma, systemic lupus erythematosus, discoid lupus
erythematosus, cutaneous lupus, dermatomyositis, polymyositis, Sjogren's
syndrome, nodular panarteritis, autoimmune enteropathy, as well as proliferative
glomerulonephritis.
graft-versus-host disease or graft rejection in any organ transplantation including
kidney, pancreas, liver, heart, lung, and bone marrow.
Other autoimmune diseases embraced by the invention active chronic hepatitis and
chronic fatigue syndrome.
subepidermal blistering disorders such as pemphigus.
Vasculitis.
HIV infection.
- melanocyte dysfunction associated diseases such as hypermelanosis resulting from
melanocyte dysfunction and including lentigines, solar and senile lentigo,
Dubreuilh melanosis, moles as well as malignant melanomas. In this regard, the
invention embraces the use of the compounds defined above to manufacture a
medicament or a cosmetic composition for whitening human skin.
CNS disorders such as psychiatric disorders, migraine, pain, memory loss and
nerve cells degeneracy. More particularly, the method according to the invention is
useful for the treatment of the following disorders: Depression including dysthymic
disorder, cyclothymic disorder, bipolar depression, severe or "melancholic"
depression, atypical depression, refractory depression, seasonal depression,
anorexia, bulimia, premenstrual syndrome, post-menopause syndrome, other
syndromes such as mental slowing and loss of concentration, pessimistic worry,
agitation, self-deprecation, decreased libido, pain including, acute pain,
postoperative pain, chronic pain, nociceptive pain, cancer pain, neuropathic pain,
psychogenic pain syndromes, anxiety disorders including anxiety associated with
hyperventilation and cardiac arrhythmias, phobic disorders, obsessive-compulsive
disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety
disorder, psychiatric emergencies such as panic attacks, including psychosis,
delusional disorders, conversion disorders, phobias, mania, delirium, dissociative
episodes including dissociative amnesia, dissociative fugue and dissociative
identity disorder, depersonalization, catatonia, seizures, severe psychiatric
emergencies including suicidal behaviour, self-neglect, violent or aggressive
behaviour, trauma, borderline personality, and acute psychosis, schizophrenia
including paranoid schizophrenia, disorganized schizophrenia, catatonic
schizophrenia, and undifferentiated schizophrenia,
neurodegenerative diseases including Alzheimer's disease , Parkinson's disease,
Huntington's disease, the prion diseases, Motor Neurone Disease (MND), and
Amyotrophic Lateral Sclerosis (ALS).
substance use disorders as referred herein include but are not limited to drug
addiction, drug abuse, drug habituation, drug dependence, withdrawal syndrome
and overdose.
Cerebral ischemia.
Fibrosis.
Duchenne muscular dystrophy.
Regarding mastocytosis, the invention contemplates the use of the compounds as defined
above for treating the different categories which can be classified as follows:
Category I is composed by two sub-categories (IA and IB). Category IA is made by
diseases in which mast cell infiltration is strictly localized to the skin. This category
represents the most frequent form of the disease and includes : i) urticaria pigmentosa, the
most common form of cutaneous mastocytosis, particularly encountered in children, ii)
diffuse cutaneous mastocytosis, iii) solitary mastocytoma and iv) some rare subtypes like
bullous, erythrodermic and teleangiectatic mastocytosis. These forms are characterized by
their excellent prognosis with spontaneous remissions in children and a very indolent
course in adults. Long term survival of this form of disease is generally comparable to that
of the normal population and the translation into another form of mastocytosis is rare.
Category IB is represented by indolent systemic disease (SM) with or without cutaneous
involvement. These forms are much more usual in adults than in children. The course of
the disease is often indolent, but sometimes signs of aggressive or malignant mastocytosis
can occur, leading to progressive impaired organ function.
Category II includes mastocytosis with an associated hematological disorder, such as a
myeloproliferative or myelodysplasia syndrome, or acute leukemia. These malignant
mastocytosis does not usually involve the skin. The progression of the disease depends
generally on the type of associated hematological disorder that conditiones the prognosis.
Category III is represented by aggressive systemic mastocytosis in which massive
infiltration of multiple organs by abnormal mast cells is common. In patients who pursue
this kind of aggressive clinical course, peripheral blood features suggestive of a
myeloproliferative disorder are more prominent. The progression of the disease can be
very rapid, similar to acute leukemia, or some patients can show a longer survival time.
Finally, category IV of mastocytosis includes the mast cell leukemia, characterized by the
presence of circulating mast cells and mast cell progenitors representing more than 10% of
the white blood cells. This entity represents probably the rarest type of leukemia in
humans, and has a very poor prognosis, similar to the rapidly progressing variant of
malignant mastocytosis. Mast cell leukemia can occur either de novo or as the terminal
phase of urticaria pigmentosa or systemic mastocytosis.
The invention also contemplates the method as depicted for the treatment of recurrent
bacterial infections, resurging infections after asymptomatic periods such as bacterial
cystitis. More particularly, the invention can be practiced for treating FimH expressing
bacteria infections such as Gram-negative enterobacteria including E. coli, Klebsiella
pneumoniae, Serratia marcescens, Citrobactorfreudii and Salmonella typhimurium.
In this method for treating bacterial infection, separate, sequential or concomitant
administration of at least one antibiotic selected bacitracin, the cephalosporins, the
penicillins, the aminoglycosides, the tetracyclines, the streptomycins and the macrolide
antibiotics such as erythromycin; the fluoroquinolones, actinomycin, the sulfonamides and
trimethoprim, is of interest.
In one preferred embodiment, the invention is directed to a method for treating neoplastic
diseases such as mastocytosis, canine mastocytoma, solid tumours, human gastrointestinal
stromal tumor ("GIST"), small cell lung cancer, non-small cell lung cancer, acute
myelocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, chronic
myelogenous leukemia, colorectal carcinomas, gastric carcinomas, gastrointestinal stromal
tumors, testicular cancers, glioblastomas, and astrocytomas comprising administering a
compound as defined herein to a human or mammal, especially dogs and cats, in need of
such treatment.
In one other preferred embodiment, the invention is directed to a method for treating
allergic diseases such as asthma, allergic rhinitis, allergic sinusitis, anaphylactic syndrome,
urticaria, angioedema, atopic dermatitis, allergic contact dermatitis, erythema nodosum,
erythema multiforme, cutaneous necrotizing venulitis and insect bite skin inflammation
and blood sucking parasitic infestation comprising administering a compound as defined
herein to a human or mammal, especially dogs and cats, in need of such treatment.
In still another preferred embodiment, the invention is directed to a method for treating
inflammatory diseases such as rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis,
osteoarthritis, gouty arthritis and other arthritic conditions comprising administering a
compound as defined herein to a human in need of such treatment.
In still another preferred embodiment, the invention is directed to a method for treating
autoimmune diseases such as multiple sclerosis, psoriasis, intestine inflammatory disease,
ulcerative colitis, Crohn's disease, rheumatoid arthritis and polyarthritis, local and systemic
scleroderma, systemic lupus erythematosus, discoid lupus erythematosus, cutaneous lupus,
dermatomyositis, polymyositis, Sjogren's syndrome, nodular panarteritis, autoimmune
enteropathy, as well as proliferative glomerulonephritis comprising administering a
compound as defined herein to a human in need of such treatment.
In still another preferred embodiment, the invention is directed to a method for treating
graft-versus-host disease or graft rejection in any organ transplantation including kidney,
pancreas, liver, heart, lung, and bone marrow comprising administering a compound as
defined herein to a human in need of such treatment.
In yet a further embodiment, the compounds of the invention or pharmaceutically
acceptable salts thereof can be administered in combination with one or more other active
pharmaceutical agents in amounts sufficient to provide a therapeutic effect. In one
implementation, the co-adminstration of the compounds of the invention and the other
agent(s) is simultaneous. In another implementation, the co-adminstration of the
compounds of the invention and the other agent(s) is sequential. In a further
implementation, the co-adminstration of the compounds of the invention and the other
agent(s) is made over a period of time,
Examples of in vitro TK inhibition assays
Procedures C-Kit WT and mutated C-Kit (D8 16V) assay
-Proliferation assays
Colorimetric cell proliferation and viability assay (reagent CellTiter-Blue purchased from
Promega cat N°G8081) was performed on BaF3 Kit WT or Kit D816 cell lines as well as
on human and murine mastocytoma and mast leukemia cell lines.
A total of 2.104 cells/5(^l were seeded per well of a 96-wells plate. Treatment was
initiated by addition of a 2X drug solution of ½ serial dilutions ranging from 0 to 0mM.
After incubating for 48 hours at 37°C, IOmI of a ½ dilution of CellTiter-Blue reagent was
added to each well and the plates were returned to the incubator for an additional 4hours.
The fluorescence intensity from the CellTiter-Blue reagent is proportional to the number of
viable cells and data were recorded (544Ex/590Em) using a POLARstar OMEGA microplate
reader (BMG LabteckSarl). A background control without cells was used as a blank. The
positive control of the assay corresponds to the cell proliferation obtained in the absence of
drug treatment (100% proliferation). Each sample was done in triplicate. The results were
expressed as a percentage of the proliferation obtained in absence of treatment.
All drugs were prepared as 20 mM stock solutions in DMSO and conserved at -80°C. Drug
dilutions were made fresh in medium before each experiment. A DMSO control was
included in each experiment.
-Cells
Human Kit WT and human Kit D816V are derived from the murine IL-3 dependent Ba/F3
proB lymphoid cells. While Ba/F3 Kit WT are stimulated with 250 ng / ml of recombinant
murine SCF, cells expressing Kit D816V are independent of cytokines for their growth.
The FMA3 and P815 cell lines are mastocytoma cells expressing endogenous mutated
forms of Kit, i.e., frame deletion in the murine juxtamembrane coding region of the
receptor-codons 573 to 579 (FMA3) and activating D814Y mutation in the kinase domain
(P815). The human leukaemic MC line HMC-1 expresses two single point mutations in the
c-Kit gene, V560G in the juxtamembrane domain and D816V in the kinase domain.
-Immunoprecipitation assays and western blotting analysis:
For each assay, 5.106 Ba/F3 cells and Ba/F3-derived cells expressing various c-kit
mutations were lysed and immunoprecipitated as described (Beslu et a , 1996). Briefly,
cell lysates were immunoprecipitated using rabbit immunsera directed toward the
cytoplasmic domain of either anti murine KIT (Rottapel et al., 1991) or anti human KIT
(Santa Cruz). Western blot was hybridized with the 4G10 anti-phosphotyrosine antibody
(UBI), the corresponding rabbit immunsera anti KIT or antibodies directed against
signaling molecules. The membrane was then incubated either with HRP-conjugated goat
anti mouse IgG antibody or with HRP-conjugated goat anti rabbit IgG antibody
(Immunotech), Proteins of interest were then visualized by incubation with ECL reagent
(Amersham).
Experimental results
The experimental results for various compounds according to the invention using the
above-described protocols are set forth in Table 3:
Table 3 : in vitro inhibitions of various compounds against c-kit WT and c-kit D816V
The inventors observed a very effective inhibition of a protein kinase and more particularly
of native and/or mutant c-kit by the class of compounds of formula I of the invention. The
listed compounds in Table 3 are well representing the class of compounds of formula I .
WO 2013/014170 PCT/EP2012/064539

CLAIMS
1. A compound of formula I :
I
or a pharmaceutically acceptable salt thereof, wherein:
A is five or six member heterocycle ring;
Ri is hydrogen, halogen, a (Ci-Cio)alkyl group, a thio(Ci-Cio)alkyl group or a (Ci-
Cio)alkoxy group;
R2 is halogen, an aryl group, an halo(C 1-C10)alkyl or (Ci-C 0)alkyl group optionally
substituted with at least one heteroatom optionally substituted with an halo(Ci-Cio)alkyl or
(Ci-Cio)alkyl optionally substituted with a solubilising group; as well as a (Ci-Cio) alkoxy
group, a thio(C -Cio)alkyl group or an halo(Ci-Cio)alkoxy group; as well as a -COOR, -
NRR',-NR-CO-R', -CONRR', -S0 2NRR' or -NR-S0 2-R' group wherein R and R' are each
independently selected from hydrogen, aryl group, heteroaryl group, (Ci-Cio)alkyl group
optionally substituted with at least one heteroatom optionally substituted with a ( -
Cio)alkyl group optionally substituted with a solubilising group; as well as a heterocycle
group or a solubilising group;
R3 is hydrogen, halogen, cyano, a (Ci-Cio)alkyl group or a (Ci-Cio)alkoxy group; as well
as CF3, -NRR', -NR-CO-R', -CONRR', -S0 2NRR' group wherein R and R' are each
independently selected from hydrogen, (Ci-Cio)alkyl group optionally substituted with at
least one heteroatom optionally substituted with a (Ci-Cio)alkyl group optionally
substituted with a solubilising group; as well as a heterocycle group or a solubilising
group;
Q is O or S;
W is N or CR4;
R is hydrogen, cyano, CF3, halogen, a thio(Ci-Ci )alkyl group, a (Ci-Cio)alkyl group
optionally substituted with at least one heteroatom optionally substituted with a (CiWO
2013/014170 PCT/EP2012/064539
Cio)alkyl group optionally substituted with a solubilising group; as well as a ( -
Cio)alkoxy group or an halo(Ci-Ci 0)alkoxy group, a solubilising group, an heterocycle, -
CO-NRR', -SO 2-NRR', -NRR', NR-CO-R' or -NR-S0 2R' group wherein R and R' are each
independently selected from hydrogen, (Ci-Cio)alkyl group optionally substituted with at
least one heteroatom optionally substituted with a (Ci-Cio)alkyl group optionally
substituted with a solubilising group or heterocycle group;
X is N or CR5;
R5 is hydrogen, cyano, halogen, a (Ci-C 10)alkyl group, a (Ci-Cio)alkoxy group, -CO-OR,
-CO-NRR' group wherein R and R' are each independently selected from hydrogen, (Ci-
Cio)alkyl group optionally substituted with at least one heteroatom optionally substituted
with a (Ci-Cio)alkyl group optionally substituted with a solubilising group or heterocycle
group;
2. A compound according to claim 1 of formula II:
II
or a pharmaceutically acceptable salt therof, wherein
ring A is a five member heterocycle ring;
Ri is hydrogen, halogen, a (Ci-Cio)alkyl group or a (Ci-C 0)alkoxy group;
R2 is halogen, an aryl group, an halo(Ci-Cio)alkyl or (Ci-Cio)alkyl group optionally
substituted with at least one heteroatom optionally substituted with an halo(Ci-Ci 0)alkyl or
(Ci-Cio)alkyl group optionally substituted with a solubilising group; as well as a(Ci-Cio)
alkoxy group or an halo(Ci-Cio)alkoxy group; as well as a
-COOR, -NRR',-NR-CO-R', -CONRR' or -NR-S0 2-R' group wherein R and R' are each
independently selected from hydrogen, aryl group, heteroaryl group, (Ci-Cio)alkyl group
optionally substituted with at least one heteroatom optionally substituted with a (Ci-
Cio)alkyl group optionally substituted with a solubilising group; as well as a heterocycle
group or a solubilising group;
WO 2013/014170 PCT/EP2012/064539
R is hydrogen, halogen, cyano, a (Ci-Cio) alkyl group or a (Ci-Cio)alkoxy group; as well
as CF3, -NRR',-NR-CO-R', -CONRR' group wherein R and R' are each independently
selected from hydrogen, (Ci-Cio) alkyl group optionally substituted with at least one
heteroatom optionally substituted with a (C(-Cio)alkyl group optionally substituted with a
solubilising group; as well as a heterocycle group or a solubilising group;;
Q is O or S;
W is N or C ;
R4 is hydrogen, cyano, CF3, halogen, a (Ci-Cio)alkyl group optionally substituted with at
least one heteroatom optionally substituted with a (Ci-Cio)alkyl group optionally
substituted with a solubilising group; as well as a (Ci-Cio)alkoxy group or an halo(Ci-
Cio)alkoxy group, a solubilising group, an heterocycle,
-CO-NRR', -SO 2-NRR', -NRR', NR-CO-R' or -NR-S0 2R' group wherein R and R' are
each independently selected from hydrogen, (Ci-Cio)alkyl group optionally substituted
with at least one heteroatom optionally substituted with a (Ci-Cio)alkyl group optionally
substituted with a solubilising group or heterocycle group;
X is N or CR5;
R5 is hydrogen, cyano, halogen, a (Ci-Cio)alkyl group, a (Ci-Cio)alkoxy group, -CO-OR,
-CO-NRR' group wherein R and R' are each independently selected from hydrogen, (Ci-
Cio)alkyl group optionally substituted with at least one heteroatom optionally substituted
with a (Ci-Cio)alkyl optionally substituted with a solubilising group or heterocycle group;
M is C or N;
V s CH2, CR7 or NR7;
R7 is hydrogen or a (Ci-Cio)alkyl group optionally substituted with a solubilising group or
heterocycle group;
Y is N, CR8 or CR R9;
Z is N, NR8, CR or CR R9;
R is hydrogen, a (Ci-Cio)alkyl group or a (Ci-Cio)alkoxy group;
R9 is hydrogen or a (Ci-Cio)alkyl group.
WO 2013/014170 PCT/EP2012/064539
3. A compound according to cl
III
or a pharmaceutically acceptable salt thereof, wherein
ring A is a six member heterocycle ring;
Ri is hydrogen, halogen, a (Ci-Cio)alkyl group or a (Ci-Cio)alkoxy group;
R is halogen, an aryl group, an halo(Ci-C 1o)alkyl or (Ci-Cio)alkyl group optionally
substituted with at least one heteroatom notably oxygen or nitrogen optionally substituted
with an halo(Ci-Ci 0)alkyl or (Ci-Cio)alkyl group optionally substituted with a solubihsing
group; as well as a (Ci-Cio)alkoxy group or an halo(Ci-Ci 0)alkoxy group; as well as a -
COOR, -NRR',-NR-CO-R', -CONRR' or -NR-S0 2-R' group wherein R and R' are each
independently selected from hydrogen, aryl group, heteroaryl group, (Ci-Cio)alkyl group
optionally substituted with at least one heteroatom optionally substituted with a (C
Cio)alkyl group optionally substituted with a solubihsing group; as well as a heterocycle
group or a solubihsing group;
R3 is hydrogen, halogen, cyano, a (Ci-C 10)alkyl group or a (Ci-Cio)alkoxy group; as well
as CF3, -NRR',-NR-CO-R', -CONRR' group wherein R and R' are each independently
selected from hydrogen, (Ci-Cio)alkyl group optionally substituted with at least one
heteroatom optionally substituted with a (Ci-Cio)alkyl group optionally substituted with a
solubihsing group; as well as a heterocycle group or a solubihsing group;
Q is O or S;
W is N or CR4;
R is hydrogen, cyano, CF3, halogen, a (Ci-Cio)alkyl group optionally substituted with at
least one heteroatom optionally substituted with a (Ci-Cio)alkyl group optionally
substituted with a solubihsing group; as well as a (Ci-Cio)alkoxy group or an halo(Ci-
Cio)alkoxy group, a solubihsing group, an heterocycle,
-CO-NRR', -SO2-NRR', -NRR', NR-CO-R' or -NR-S0 2R' group wherein R and R' are
each independently selected from hydrogen, (C1-C10)alkyl group optionally substituted
WO 2013/014170 PCT/EP2012/064539
with at least one lieteroatom optionally substituted with a (Ci-C 0)alkyl group optionally
substituted with a solubilising group or heterocycle group;
X is N or CR5;
R5 is hydrogen, cyano, halogen, a (Ci-Cio)alkyl group, a (Ci-Cio)alkoxy group, -CO-OR,
-CO-NRR' group wherein R and R' are each independently selected from hydrogen, C \ -
Cio)alkyl group optionally substituted with at least one lieteroatom optionally substituted
with a (Ci-Cio)alkyl group optionally substituted with a solubilising group or heterocycle
group;
M is C or N;
V is N, CH2, CR or NR7;
R7 is hydrogen, cyano or a (Ci-Cio)alkyl group optionally substituted with a solubilising
group or heterocycle group;
Y is N, CR8 or CR8R ;
Z is N, CR8 or CR R9;
T is N, C=0, CR or CR8R9;
R is hydrogen, a halogen, an hydroxyl group, a (Ci-Cio)alkyl group or a (Ci-Cio)alkoxy
group;
R9 is hydrogen or a (Ci-Cio)alkyl group.
4. A compound according to claim 1, or a pharmaceutically acceptable salt thereof,
wherein:
Ri is H or a (C C )alkyl;
R2 is H;
a halogen;
COOH;
a (Ci-C )alkyl optionally substituted by a group -NRi 0Rn, by OH or by a (Ci-
C4)alkoxy optionally substituted by OH where Rio and R are each independently
H or (Ci-C4)alkyl optionally substituted with amino, (Ci-C4)alkylamino or di(Ci-
C4)alkylamino; or Rio and R form, together with the nitrogen atom to which they
are bonded, a 5- or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms
selected from O, S and N;
a (Ci-C )alkoxy optionally substituted by OH, a (Ci-C4)alkoxy or a group
-NRi 2Ri3 where Ri2 and R13 are each independently H or (Ci-C4)alkyl; or Ri2 and
O 2013/014170 PCT/EP2012/064539
Ri3 form, together with the nitrogen atom to which they are bonded, a 5- or 6-
membered heterocycloalkyl containing 1 or 2 heteroatoms selected from O, S and
N, said heterocycloalkyl being optionally substituted with 1 to 3 (C -C )alkyls;
a group -ORi 4 where R 4 is a 5- or 6-membered heterocycloalkyl containing 1 or 2
heteroatoms selected from O, S and N, said heterocycloalkyl being optionally
substituted with 1 to 3 (Ci-C4)alkyls;
a group -CONR15R16 where R15 and Ri6 are each independently H or a (Ci-C4)alkyl
optionally substituted with a (Ci-C4)alkoxy or with a 5- or 6-membered
heterocycloalkyl containing 1 or 2 heteroatoms selected from O, S and N; or Ri5
and Ri form, together with the nitrogen atom to which they are bonded, a 5- or 6-
membered heterocycloalkyl containing 1 or 2 heteroatoms selected from O, S and
N;
a group -NR17R18 where R17 is H or (Ci-C4)alkyl and Ri is H; a (Ci-C4)alkyl
optionally substituted with a (Ci-C4)alkoxy; or a 5- or 6-membered heteroaryl
containing 1 to 3 heteroatoms selected from O, S and N;
a group -NRi COR2o where R19 is H or (Ci-C4)alkyl and R20 is H or a (Ci-C4)alkyl
optionally substituted with amino, (C -C4)alkylamino or di(Ci-C4)alkylamino or
with a 5- or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms selected
from O, S and N, said heterocycloalkyl being optionally substituted with 1 to 3 C -
C4)alkyls; or
a 5- or 6-membered heterocycloalkyl or heteroaryl containing 1 or 2 heteroatoms
selected from O and N, said heterocycloalkyl or heteroaryl being optionally
substituted with an oxo group or with a (Ci-C4)alkyl optionally substituted with
amino, (Ci-C4)alkylamino or di(Ci-C4)alkylamino;
R3 is H; cyano; CF3; a halogen; a (Ci-C4)alkyl; or a (Ci-C )alkoxy;
Q is O or S, preferably Q is O;
W is N or CR2i where R2i is
H;
a halogen;
CN;
CF3;
OCF3;
WO 2013/014170 PCT/EP2012/064539
a (Ci-C4)alkyl optionally substituted with a 5- or 6-membered heterocycloalkyl
containing 1 or 2 heteroatoms selected from O and N;
a (Ci-C4)alkoxy;
a group -0(CH 2) R22 where n is 0, 1, 2 or 3 and R22 is H; a (Ci-C4)alkoxy; a group
-NR 22aR22b where R a and R 2b are each independently H or a (C1-C4)alkyl; or a 5-
or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from O and
N, said heterocycloalkyl being optionally substituted with 1 to 3 (Ci-C4)alkyls;
a group -NR 23R24 where R23 and R24 are each independently H or a (Ci-C4)alkyl
optionally substituted with a (Ci-C )alkoxy; R2 can also represent a group
-S0 2(Ci-C4)alkyl; or R23 and R 4 form, together with the nitrogen atom to which
they are bonded, a 5- or 6-membered heterocycloalkyl or heteroaryl containing 1 or
2 heteroatoms selected from O, S and N, said heterocycloalkyl being optionally
substituted with 1 to 3 (Ci-C4)alkyls;
X is N or CR25 where R25 is H; CN; a (Ci-C4)alkyl; or a group -COO(Ci-C4)alkyl; and
A is a 5- or 6-membered heterocycloalkyl or heteroaryl containing 1 to 3 heteroatoms
selected from O and N, said heterocycloalkyl or heteroaryl being optionally substituted
with 1 to 3 substituents selected from: an oxo group; a halogen; a (Ci-C )alkyl optionally
substituted with amino, (Ci-C4)alkylamino, di(Ci-C4)alkylamino or a 5- or 6-membered
heterocycloalkyl containing 1 or 2 heteroatoms selected from O and N; and a (Ci-
C4)alkoxy.
5. A compound according to claim 1, or a pharmaceutically acceptable salt thereof,
wherein:
R is H or a (d-C 4)alkyl;
R2 is H; a (Ci-C4)alkyl optionally substituted by a (Ci-C4)alkoxy; a (Ci-C4)alkoxy
optionally substituted by OH or a group -NRi 2Ri3 where Ri2 and R 3 are each
independently H or (Ci-C4)alkyl or Ri and Ri3 form, together with the nitrogen atom to
which they are bonded, a 5- or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms
selected from O, and N; or a group -CONRi Ri6 where Ri and i6 are each independently
H or a ( -C4)alkyl;
R3 is H or a (Ci-C )alkyl;
Q is O;
WO 2013/014170 PCT/EP2012/064539
W is N or CR i where R2i is H; OCF3; a (Ci-C4)alkyl; a (Ci-C4)alkoxy; or a group
-0(CH 2) R2 where n is 0, 1 or 2, and R22 is a 5- or 6-membered heterocycloalkyl
containing 1 or 2 heteroatoms selected from O and N;
X is N or CH; and
A is a 5- or 6-membered heterocycloalkyl or heteroaryl containing 1 or 2 nitrogen atoms,
said heterocycloalkyl or heteroaryl being optionally substituted with 1 to 3 (Ci-C4)alkyls.
6. A compound according to any one of claims 1 to 3, wherein the solubilising group is
selected from morpholinyl, piped dinyl, N-(Ci-C 6)alkyl piperidinyl, N-(4-
piperidinyl)piperidinyl, 4-(l-piperidinyl)piperidinyl, 1-pyrrolidinylpiperidinyl, 4-
mo holinopiperidinyl, 4-(N-methyl-l-piperazinyl)piperidinyl, piperazinyl, N-(Cr
C6)alkylpiperazinyl, N-(C3-C )cycloalkyl piperazinyl, pyrrolidinyl, N-(Ci-C 6)alkyl
pyrrolidinyl, diazepinyl, N-(Ci-C 6)alkyl azepinyl, homopiperazinyl, N-methyl
homopiperazinyl, N-ethyl homopiperazinyl, and imidazolyl.
7. A compound according to claim 1, or a pharmaceutically acceptable salt thereof,
selected from:
l-{4-[2-((5-Ethoxymethyl)-2-methyl-phenylamino)-oxazol-5-yl]-pyridin-2-yl}-
imidazolidin-2-one;
l-{3-[2-((5-Ethoxymethyl)-2-methyl-phenylamino)-oxazol-5-yl]-5-methoxy-phenyl}-4,4-
dimethyl-imidazolidin-2-one;
l-(3-{2-[5-(2-Hydroxy-ethoxy)-2-methyl-phenylamino]-oxazol-5-yl}-5-methyl-phenyl)-
imidazolidin-2-one;
l-(4-{2-[5-(2-Hydroxy-ethoxy)-2-methyl-phenylamino]-oxazol-5-yl}-pyridin-2-yl)-
imidazolidin-2-one;
l-(4-{2-[2-Methyl-5-(2-mo^holin-4-yl-ethoxy)-phenylamino]-oxazol-5-yl}-pyridin-2-yl)-
imidazolidin-2-one;
1. {4-[2-((5-Methoxymethyl)-2-methyl-phenylamino)-oxazol-5-yl]-pyridin-2-yl} -4-methylimidazolidin-
2-one;
4-Methyl-l-(4-{2-[2-methyl-5-(2-morpholin-4-yl-ethoxy)-phenylamino]-oxazol-5-yl}-
pyridin-2-yl)-imidazolidin-2-one;
l-(3-Methyl-5-{2-[2-methyl-5-(2-morpholin-4-yl-ethoxy)-phenylamino]-oxazol-5-yl}-
phenyl)-imidazolidin-2-one;
WO 2013/014170 PCT/EP2012/064539
l-(4-{2-[2-Methyl-5-(3-mo^holin-4-yl-propoxy)-phenylamino]-oxazol-5-yl}-pyridin-2-
yl)-imidazolidin-2-one;
l-{3-[2-((5-Ethoxymethyl)-2-methyl-phenylamino)-oxazol-5-yl]-5-methoxy-phenyl}-
imidazolidin-2-one;
1-(3-Methoxy-5- {2-[2-methyl-5-(2-morpholin-4-yl-ethoxy)-phenylamino]-oxazol-5-yl}-
phenyl)-imidazolidin-2-one;
l-{3-[2-((5-Ethoxymethyl)-2-methyl-phenylamino)-oxazol-5-yl]-5-methoxy-phenyl}-4-
methyl-imidazolidin-2-one;
l-{3-tert-Butoxy-5-[2-((5-methoxyiTiethyl)-2-methyl-phenylamino)-oxazol-5-yl]-phenyl}-
imidazolidin-2-one;
l-(3-{2-[5-(2-Hydroxy-ethoxy)-2-methyl-phenylamino]-oxazol-5-yl}-5-methoxy-phenyl)-
imidazolidin-2-one;
l-(3-Methoxy-5-{2-[2-methyl-5-(2-moipholin-4-yl-ethoxy)-phenylamino]-oxazol-5-yl}-
phenyl)-4-methyl-imidazolidin-2-one;
l-{3-Isopropoxy-5-[2-((5-methoxymethyl)-2-methyl-phenylamino)-oxazol-5-yl]-phenyl}-
imidazolidin-2-one;
l-(3-{2-[5-(2-Hydroxy-ethoxy)-2-methyl-phenylamino]-oxazol-5-yl}-5-isopropoxyphenyl)-
imidazolidin-2-one;
l-(3-Isopropoxy-5-{2-[5-(2-methoxy-ethyl)-2-methyl-phenylamino]-oxazol-5-yl} -phenyl)-
imidazolidin-2-one;
l-(3-(2-(2-methyl-5-(2-morpholinoethoxy)phenylamino)oxazol-5-yl)-5-
(trifluoromethoxy)phenyl)imidazolidin-2-one;
l-(3-(2-(5-methoxy-2-methylphenylamino)oxazol-5-yl)-5-
(trifluoromethoxy)phenyl)imidazolidin-2-one;
l-(3-{2-[5-(2-Hydroxy-ethoxymethyl)-2-methyl-phenylamino]-oxazol-5-yl}-5-methylphenyl)-
imidazolidin-2-one;
3-{5-[3-Isopropoxy-5-(2-oxo-imidazolidin-l-yl)-phenyl]-oxazol-2-ylamino}-N-(2-
methoxy-ethyl)-4-methyl-benzamide;
l-(3-(2-(5-(ethoxymethyl)-2-methylphenylamino)oxazol-5-yl)-5-
(trifluoromethoxy)phenyl)imidazolidin-2-one;
3-{3-[2-(3,5-Dimethyl-phenylamino)-oxazol-5-yl]-5-trifluoromethoxy-phenyl}-4-methyllH-
pyridin-2-one;
3-{3-[2-(3,5-Dimethyl-phenylamino)-oxazol-5-yl]-5-methoxy-phenyl}-lH-pyridin-2-one;
WO 2013/014170 PCT/EP2012/064539
3- {3-[2-(3,5-Dimethyl-phenylamino)-oxazol-5-yl]-5-isopropoxy-phenyl}-4-niethyl-lHpyridin-
2-one;
4-[2-(5-(Ethoxymethyl)-2-methyl-phenylamino)-oxazol-5-yl]-4'-methyl-l'H-
[2,3']bipyridinyl-2'-one;
343-[2-(3,5-Dimethyl-phenylamino)-oxazol-5-yl]-5-(2-mo^holin-4-yl-ethoxy)-phenyl]-4-
methyl- 1H-pyridin-2-one;
4'-Methyl-4-{242-methyl-5-(2-morpholin-4-yl-ethoxy)-phenylamino]-oxazol-5-yl }- H-
[2,3']bipyridinyl-2'-one;
4-[2-(3,5-Dimethyl-phenylamino)-oxazol-5-yl]-4'-methyl-6-(2-morpholin-4-yl-ethoxy)-
l'H-[2,3']bipyridinyl-2'-one;
l-{3-[2-((5-Ethoxymethyl)-2-methyl-phenylamino)-oxazol-5-yl]-5-isopropoxy-phenyl}-
imidazolidin-2-one;
4'-Methyl-4-{2-[2-methyl-5-(3-morpholin-4-yl-propoxy)-phenylamino]-oxazol-5-yl }- H-
[2,3']bipyridinyl-2'-one; and
pharmaceutically acceptable salts thereof.
8. A pharmaceutical composition comprising a compound according to one of claims 1 to 7
or a pharmaceutically acceptable salt thereof.
9. A cosmetic composition for topical administration comprising a compound according to
one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.
10. A compound according to one of claims 1 to 7, or a pharmaceutically acceptable salt
thereof, for use as a medicament.
11. A compound according to one of claims 1 to 7, or a pharmaceutically acceptable salt
thereof, for use in the treatment of mastocytosis.
12. A compound according to one of claims 1 to 7, or a pliamiaceutically acceptable salt
thereof, for use in the treatment of hematological malignancies, myeloproliferative
disorder, other proliferative disorders, autoimmune disorders, inflammatory diseases,
allergic diseases or neurological diseases.
WO 2013/014170 PCT/EP2012/064539
13. A compound for the use according to claim 12, wherein the hematological malignancy
is Acute Myeloid Leukemia (AML), Myelodysplasia Syndrome (MDS), Acute
Lymphoblastic Leukemia (ALL), Chronic Myeloid Leukemia (CML) or
Hypereosinophilic Syndrome (HES).
14. A compound for the use according to claim 12, wherein the proliferative disorder is
cancer.
15. A compound for the use according to claim 12, wherein the autoimmune disorder is
multiple sclerosis, psoriasis, intestine inflammatory disease, ulcerative colitis, Crohn's
disease, rheumatoid arthritis and polyarthritis, local and systemic scleroderma, systemic
lupus erythematosus, discoid lupus erythematosus, cutaneous lupus, dermatomyositis,
polymyositis, Sjogren's syndrome, nodular panarteritis, autoimmune enteropathy, atopic
dermatitis or proliferative glomerulonephritis.
16. A compound for the use according to claim 12, wherein the allergic disease is asthma,
allergic rhinitis, allergic sinusitis, anaphylactic syndrome, urticaria, angioedema, atopic
dermatitis, allergic contact dermatitis, erythema nodosum, erythema multiforme, cutaneous
necrotizing venulitis and insect bite skin inflammation or blood sucking parasitic
infestation.
17. A compound for the use according to claim 12, wherein the neurological disease is
Huntington's disease, schizophrenia, Parkinson's disease or Alzheimer's disease.
18. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable
salt thereof, for use as an inhibitor of protein kinases.
1 . The compound according to claim 18, wherein the protein kinase is a native and/or
mutant c-kit.
20. The pharmaceutical composition according to claim 8, further comprising another
active pharmaceutical agent.
WO 2013/014170 PCT/EP2012/064539
21. The compound according to any one of claims 10 to 19 for use in combination with
another active pharmaceutical agent.
22. A method for treating or preventing a protein kinase -related disease or disorder in a
subject comprising the administration to the subject of an effective amount of a compound
according to any one of claims 1 to 7 or of a pharmaceutically acceptable salt thereof.
23. The method according to claim 22, wherein the protein kinase is a tyrosine kinase.
24. The method according to claim 23, wherein the tyrosine kinase is c-kit.
25. A method for treating a haematological malignancy, a myeloproliferative disorder,
another proliferative disorder, an autoimmune disorder or a skin disorder, comprising
administering to a human or animal subject in need thereof an effective amount of a
compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt
thereof.
26. The method according to claim 25, further comprising simultaneously or sequentially
administering to said subject an effective amount of another active pharmaceutical agent.
27. Use of a compound according to any one of claims 1 to 7, or of a pharmaceutically
acceptable salt thereof, in the manufacture of a medicament intended for the treatment of
one of the following disease or disorder: mastocytosis; an hematological malignancy; a
myeloproliferative disorder, another proliferative disorder; an autoimmune disorder; an
inflammatory disease; an allergic disease; or a neurological disease.