COMPOUNDS WITH ANTI-TUMORAL ACTIVITY
FIELD OF INVENTION
The present invention relates to compounds of formula (I), or pharmaceutically
acceptable salts thereof, that destroy, inhibit, or prevent the growth or spread of cells,
especially malignant cells, into surrounding tissues implicated in a variety of human and
animal diseases.
Especially, the invention relates to compounds that are useful in the treatment of diseases
related to cell proliferation, such as hematopoietic cancers including lymphoma, leukemia
and multiple myeloma, solid cancers including head and neck cancer, melanoma, kidney
carcinoma, stomach carcinoma, liver carcinoma, colorectal carcinoma, pancreas
carcinoma, lung carcinoma, neuronal carcinoma, bone carcinoma, breast carcinoma,
ovary carcinoma, and prostate carcinoma.
(I)
BACKGROUND OF INVENTION
Cancer is a generic term for a large group of diseases that can affect any part of the body.
One defining feature of cancer is the rapid creation of abnormal cells that grow beyond
their usual boundaries, and which can then invade adjoining parts of the body and spread
to other organs, the latter process is referred to as metastasizing. Metastases are the major
cause of death from cancer.
Cancers figure among the leading causes of morbidity and mortality worldwide, with
approximately 14 million new cases and 8.2 million cancer related deaths in 2012. The
most common causes of cancer death are cancers of lung (1.59 million deaths), liver (745
000 deaths), stomach (723 000 deaths), colorectal (694 000 deaths), breast (521 000
deaths), esophageal cancer (400 000 deaths). Among men, the 5 most common sites of
cancer diagnosed in 2012 were lung, prostate, colorectal, stomach, and liver cancer.
Among women the 5 most common sites diagnosed were breast, colorectal, lung, cervix,
and stomach cancer.
The number of new cases is expected to rise by about 70% over the next two decades
(World Cancer Report 2014, WHO).
Despite extraordinary advances in our understanding of the biology that underlies the
development and progression of cancer as well as potential molecular targets for its
treatment, more than 90% of all new oncology drugs that enter clinical development do
not obtain marketing approval. Many drugs fail in late stages of development — often in
Phase III trials — because of inadequate activity, lack of strategies for combating
resistance to these drugs, unexpected safety issues or difficulties in determining efficacy
because of reasons that include confounded outcomes of clinical trials. Moreover, an
increased understanding of cancer biology has shown that cancers are heterogeneous
diseases, which suggests that there is a high likelihood that effective cancer treatments
will need to address patient- specific molecular defects and aspects of the tumor
microenvironment.
The widespread occurrence of cancer and the high degree of heterogeneity of this disease
underscores the need for improved anticancer regimens for the treatment of malignancy.
The recent use of large panel of cancer cell lines agents is becoming an important tool for
the discovery and evaluation of potential new anti-cancer. Indeed, large panel of tumorderived
cell lines may recapitulate the genotype-response relationship of new therapeutic
agents and may be of utmost interest.
The present invention provides new compounds of formula (I) for the treatment of
diseases related to cell proliferation, such as hematopoietic cancers or solid cancers.
Compounds of the invention have an anti-tumoral activity on a very large panel of cancer
cell lines.
Compounds of formula (I) comprise a 6-membered aryl or heteroaryl moiety parasubstituted
byA and B moieties. Compounds comprising a 6-membered aryl or heteroaryl
moiety meia-substituted by heteroaryl and heterocycle groups are disclosed in
WO2013/014170. Compounds of WO2013/014170 are tyrosine kinases inhibitors and
may be used for the treatment of proliferative diseases. Surprisingly, compounds of
formula (I) the invention are not tyrosine kinase inhibitors, while having anti-proliferative
properties. Therefore, compounds of the invention offer a new route of treatment of
diseases related to cell proliferation.
SUMMARY
The present invention relates to a compound of formula (I):
wherein A, B, X, Rl, R2, R3, R4 and R5 are as defined below.
According to one embodiment, in compound of formula (I), B is a five member ring
heteroaryl group.
According to one embodiment, B is not selected from 1,2 diazinyl, triazolopyridinyl or
triazolyl. According to one embodiment, if B is oxazolyl, A is not tetrazolyl or
tetrahydropyridinyl. According to one embodiment, if B is thiazolyl, A is not imidazolyl,
triazolyl, piperazinyl, pyrrolidinyl, piperidinyl or 1,4-oxazinyl.
According to one embodiment, in compound of formula (I), X is CH and A is 2-
oxoimidazolidinyl or pyrazolyl group.
According to one embodiment, in the compound of the invention, R3 is a hydrogen.
According to one embodiment, a compound of formula (I) is of formula (II) as defined
below.
According to one embodiment, a compound of formula (I) is of formula (III) as defined
below.
According to one embodiment, in the compound of the invention, Rl is methyl, R2, R3
and R5 are hydrogen and R4 is -CH2OC2H5.
According to one embodiment, the compound of the invention is selected from:
(5-Methoxy-2-methyl-phenyl)-[5-(6-pyrazol-l-yl-pyridin-3-yl)-oxazol-2-yl]-
amine;
(5-Ethoxymethyl-2-methyl-phenyl)-[5-(3-methoxy-4-pyrazol-l-yl-phenyl)-
oxazol-2-yl] -amine;
1-{4-[2-(5-Ethoxymethyl- (2-methyl-phenylamino))-thiazol-4-yl] -phenyl }-
imidazolidin-2- one;
(5-Ethoxymethyl-2-methyl -phenyl)- [5-(4-pyrazol-l -yl-phenyl)-thiazol-2-yl] -
amine;
4-Methyl-N-(2-morpholin-4-yl-ethyl)-3-[5-(4-pyrazol-l-yl-phenyl)-oxazol-2-
ylamino] -benzamide;
1-{4-[2-(5-Ethoxymethyl-(2-methyl-phenylamino))-oxazol-5-yl]-phenyl}-
imidazolidin-2- one;
(5-Ethoxymethyl-2-methyl -phenyl)- [5-(6-pyrazol-l -yl-pyridin-3-yl)-oxazol-2-yl] -
amine;
1-{4-[5-(5-Ethoxymethyl- (2-methyl-phenylamino))- [1,3,4] oxadiazol-2-yl] -
phenyl }-imidazolidin-2- one;
(5-Ethoxymethyl-2-methyl-phenyl)-[5-(4-pyrazol-l-yl-phenyl)-[l,3,4]oxadiazol-
2-yl] -amine;
l-{4-[5-(5-Ethoxymethyl-(2-methyl-phenylamino))-[l,2,4]thiadiazol-3-yl]-
phenyl }-imidazolidin-2- one;
(5-Methoxy-2-methyl-phenyl)-[5-(4-pyrazol-l-yl-phenyl)-thiazol-2-yl] -amine;
1-{4-[2-(5-Methoxy-2-methyl-phenylamino)-thiazol-5-yl] -phenyl }-imidazolidin-
2-one;
1-{4-[2-(5-Ethoxymethyl- (2-methyl-phenylamino))-thiazol-5-yl] -phenyl }-
imidazolidin-2- one;
(5-Ethoxymethyl-2-methyl -phenyl)- [4-(4-pyrazol-l -yl-phenyl)-thiazol-2-yl] -
amine;
{4-Methyl-3-[4-(4-pyrazol- 1-yl-phenyl)-thiazol-2-ylamino] -phenyl }-methanol;
1-{4-[2-(3-Ethoxymethyl- (5-methyl-phenylamino))-thiazol-4-yl] -phenyl }-
imidazolidin-2- one;
1-{4-[2-(3-Ethoxymethyl-(5-methyl-phenylamino))-oxazol-5-yl]-phenyl}-
imidazolidin-2- one;
(3-Ethoxymethyl-phenyl)-[5-(4-pyrazol-l-yl-phenyl)-oxazol-2-yl] -amine;
(3-Ethoxymethyl-5-methyl -phenyl)- [5-(4-pyrazol-l -yl-phenyl)-oxazol-2-yl] -
amine;
(3,5-Bis-(ethoxymethyl)-phenyl)-[5-(4-pyrazol-l-yl-phenyl)-oxazol-2-yl]-amine;
(5-Methoxy-2-methyl-phenyl)-[5-(4-pyrazol-l-yl-phenyl)-oxazol-2-yl] -amine;
[5-(2-Amino-ethoxymethyl)-2-methyl-phenyl]-[5-(4-pyrazol-l-yl-phenyl)-oxazol-
2-yl] -amine;
N-(2-{4-Methyl-3-[5-(4-pyrazol-l-yl-phenyl)-oxazol-2-ylamino]-benzyloxy}-
ethyl)-acetamide;
2-{4-Methyl-3-[5-(4-pyrazol-l-yl-phenyl)-oxazol-2-ylamino]-benzyloxy}-
ethanol;
{4-Methyl-3-[5-(4-pyrazol-l-yl-phenyl)-oxazol-2-ylamino]-phenyl}-methanol;
{2-Methyl-5-[(2-morpholin-4-yl-ethylamino)-methyl]-phenyl}-[5-(4-pyrazol-l-ylphenyl)-
oxazol-2-yl] -amine;
[2-Methyl-5-(2-morpholin-4-yl-ethoxy)-phenyl]-[5-(4-pyrazol-l-yl-phenyl)-
oxazol-2-yl] -amine;
[5-(2-Dimethylamino-ethoxy)-2-methyl-phenyl]-[5-(4-pyrazol-l-yl-phenyl)-
oxazol-2-yl] -amine;
4,N-Dimethyl-3-[5-(4-pyrazol-l-yl-phenyl)-oxazol-2-ylamino]-benzamide;
4-Methyl-N- [2-(4-methyl-piperazin- 1-yl)-ethyl] -3- [5-(4-pyrazol-1-yl-phenyl)-
oxazol-2-ylamino]-benzamide;
(5-Ethoxymethyl-2-methyl -phenyl)- [5-(4-pyrazol-l -yl-phenyl)-oxazol-2-yl] -
amine;
(5-Ethoxymethyl-2-methyl-phenyl)-[5-(4-[l,2,4]triazol-l-yl-phenyl)-oxazol-2-yl]
amine;
(5-Ethoxymethyl-2-methyl-phenyl)-[5-(4-[l,2,3]triazol-l-yl-phenyl)-oxazol-2-yl]
amine;
(5-Ethoxymethyl-2-methyl-phenyl)-[5-(4-[l,2,3]triazol-2-yl-phenyl)-oxazol-2-yl]
amine;
(5-Ethoxymethyl-2-methyl -phenyl)- [5-(4-imidazol-l -yl-phenyl)-oxazol-2-yl]-
amine;
(5-Ethoxymethyl-2-methyl-phenyl)-[5-(4-thiazol-2-yl-phenyl)-oxazol-2-yl]-
amine;
(5-Ethoxymethyl-2-methyl -phenyl)- {5-[4-(3-methyl-pyrazol-l-yl)-phenyl]-
oxazol-2-yl} -amine;
(5-Ethoxymethyl-2-methyl -phenyl)- {5-[4-(4-methyl-pyrazol-l-yl)-phenyl]-
oxazol-2-yl} -amine;
(5-Ethoxymethyl-2-methyl -phenyl)- {5-[4-(5-methyl-pyrazol-l-yl)-phenyl]-
oxazol-2-yl} -amine;
(5-Ethoxymethyl-2-methyl -phenyl)- {5-[4-(3-methoxy-p yrazol-l-yl)-phenyl]-
oxazol-2-yl} -amine;
2-{4-[2-(5-Ethoxymethyl-(2-methyl-phenylamino))-oxazol-5-yl]-phenyl}-2,4-
dihydro-[l,2,4]triazol-3-one;
l-{4-[2-(5-Ethoxymethyl-(2-methyl-phenylamino))-oxazol-5-yl]-phenyl}-3-
methyl-imidazolidin-2- one;
1-(2-Amino-ethyl)-3-{4-[2-(5-ethoxymethyl-(2-methyl-phenylamino))-oxazol-5-
yl] -phenyl }-imidazolidin-2-one;
N-[2-(3-{4-[2-(5-Ethoxymethyl-(2-methyl-phenylamino))-oxazol-5-yl]-phenyl}-
2-oxo-imidazolidin- 1-yl)-ethyl] -acetamide;
l-{4-[2-(5-Ethoxymethyl-(2-methyl-phenylamino))-oxazol-5-yl]-phenyl}-
pyrrolidin-2-one;
(5-Ethoxymethyl-2-methyl-phenyl)-[5-(4-pyridin-2-yl-phenyl)-oxazol-2-yl]-
amine;
l-{4-[2-(5-Ethoxymethyl-(2-methyl-phenylamino))-oxazol-5-yl]-phenyl}-lHpyridin-
2-one;
3-{4-[2-(5-Ethoxymethyl-(2-methyl-phenylamino))-oxazol-5-yl]-phenyl}-lHpyridin-
2-one;
(R)-l-(4-(2-((5-(ethoxymethyl)-2-methylphenyl)amino)oxazol-5-yl)phenyl)-5-
methylimidazolidin-2-one;
4-(4-(2-((5-(ethoxymethyl)-2-methylphenyl)amino)oxazol-5-yl)phenyl)-5-methyl-
2,4-dihydro-3H- 1,2,4-triazol-3-one;
l-(4-(2-((3,5-bis(ethoxymethyl)phenyl)amino)oxazol-5-yl)phenyl)imidazolidin-2-
one;
l-(4-(2-((5-(ethoxymethyl)-2-methylphenyl)amino)oxazol-5-yl)phenyl)-3-(2-
methoxyethyl)imidazolidin-2- one;
l-(5-(2-((5-(ethoxymethyl)-2-methylphenyl)amino)oxazol-5-yl)pyridin-2-
yl)imidazolidin-2- one;
l-(4-(2-((3-(ethoxymethyl)-5-(2-methoxyethoxy)phenyl)amino)oxazol-5-
yl)phenyl)imidazolidin-2-one;
5-(4-(lH-pyrazol-5-yl)phenyl)-N-(5-(ethoxymethyl)-2-methylphenyl)oxazol-2-
amine;
(R)-l-(5-(2-((5-(ethoxymethyl)-2-methylphenyl)amino)oxazol-5-yl)pyridin-2-yl)-
5-methylimidazolidin-2- one;
l-(4-(2-((3-(ethoxymethyl)-5-(2-hydroxyethoxy)phenyl)amino)oxazol-5-
yl)phenyl)imidazolidin-2-one;
5-(4-(lH-pyrazol-4-yl)phenyl)-N-(5-(ethoxymethyl)-2-methylphenyl)oxazol-2-
amine;
N-(5-(ethoxymethyl)-2-methylphenyl)-5-(4-(l-methyl-lH-pyrazol-5-
yl)phenyl)oxazol-2-amine;
4-(6-(lH-pyrazol-l-yl)pyridin-3-yl)-N-(5-(ethoxymethyl)-2-
methylphenyl)thiazol-2- amine;
l-(4-(2-((3-(ethoxymethyl)phenyl)amino)oxazol-5-yl)phenyl)imidazolidin-2-one;
l-(4-(2-((3-(ethoxymethyl)phenyl)amino)thiazol-4-yl)phenyl)imidazolidin-2-one.
The present invention further relates to a pharmaceutical composition comprising a
compound according the invention, or a pharmaceutically acceptable salt thereof and at
least one pharmaceutically acceptable excipients and/or carriers.
According to one embodiment, the pharmaceutical composition comprises a compound
according to the invention, or a pharmaceutically acceptable salt thereof as sole active
pharmaceutical ingredient.
According to one embodiment, the pharmaceutical composition of the invention further
comprises another active pharmaceutical agent.
The invention also relates to a medicament comprising a compound according to the
invention, or a pharmaceutically acceptable salt thereof.
The invention further relates to a compound according to the invention, or a
pharmaceutically acceptable salt thereof, for use in the treatment of hematological
disorders and/or proliferative disorders.
According to one embodiment, the hematological disorder is selected from lymphoma;
leukemia such as Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia
(ALL), Chronic Lymphoid Leukemia (CLL) or Chronic Myeloid Leukemia (CML);
multiple myeloma (MM); myelodysplatic syndrome (MDS); and myelodysplasia with
myelofibrosis.
According to one embodiment, the proliferative disorder is cancer, such as head and neck
cancer, melanoma, kidney carcinoma, stomach carcinoma, liver carcinoma, colorectal
carcinoma, pancreas carcinoma, lung carcinoma, neuronal carcinoma, glioblastoma
multiform, osteosarcoma, Ewing sarcoma, breast carcinoma, ovary carcinoma, or prostate
carcinoma.
The invention also relates to a pharmaceutical composition comprising a compound
according to the invention, or a pharmaceutically acceptable salt thereof, and another
active pharmaceutical ingredient as a combined preparation for sequential, simultaneous
or separate use in the treatment of a disorder selected from the group consisting of
hematological disorders and proliferative disorders.
DEFINITIONS
Unless otherwise specified, the below terms used herein are defined as follows.
Unless indicated otherwise, the nomenclature of substituents that are not explicitly
defined herein are arrived at by naming the terminal portion of the functionality followed
by the adjacent functionality toward the point of attachment. For example, the substituent
"arylalkyl" refers to the group (aryl)-(alkyl)-.
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 or aryl groups as defined above,
hydroxyl, alkoxy group as defined above, nitro, thiol, heterocycloalkyl groups, heteroaryl
groups, cyano, cycloalkyl groups as defined above, as well as a solubilizing group, -NRR',
-NR-CO-R', -CONRR', -SO2NRR' group wherein R and R' are each independently
selected from hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl groups as
defined above.
As used herein, the term "halogen" means fluoro, chloro, bromo, or iodo.
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-
dimethylpentyl, 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 solubilizing 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 solubilizing 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, Nmethylpiperazinyl,
2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 4-piperidonyl,
pyrrolidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydropyranyl,
tetrahydrothiopyranyl, 2-oxoimidazolidinyl, tetrahydro-pyrimidinyl-2-one, 2-
oxopyrrolidinyl, 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, oxadiazolyl,
imidazolyl, thiazolyl, thiadiazolyl, 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. 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. According to a specific embodiment, the heteroaryl group
is a five member ring heteroaryl group. 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 "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.
The term "cycloalkyl group" means a saturated or partially unsaturated, monocyclic,
fused bicyclic or bridged polycyclic ring assembly containing the number of ring atoms
indicated. This includes substituted or unsubstituted cylcoalkyl groups. For example,
cycloalkyl group may be C3-C10 alkyl group, such as C3 or C4, in particular a
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group etc.
As used herein, the term "solubilizing group" means a group which improve the
solubility of a compound in water or aqueous solution, as compared to an analog
compound that does not include the group. Non-limiting examples of such solubilizing
groups are 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 such as O, S, N, NH, N-(CH2)ZR, N-(CH2)z-C(0)R, N-(CH2)Z-
C(0)OR, N-(CH2)z-S(0) 2R, N-(CH2)z-S(0) 2OR, N-(CH2)z-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 solubilizing group is a heterocycloalkyl that optionally
includes from 1 to 5 substituents, which may themselves be solubilizing groups.
In a specific embodiment, the solubilizing group is of the formula:
wherein 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)z-C(0)R)-
, -N(-(CH2) -C(0)OR)-, -N(-(CH2) -S(0) 2R)-, -N(-(CH2) -S(0) 2OR)- and -N(-(CH2) -
C(O)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 solubilizing group is selected from the group
consisting of morpholinyl, piperidinyl, pyrrolidinyl, N-(C1-C6)alkyl piperidinyl, in
particular N-methyl piperidinyl and N-ethyl piperidinyl, N-(4-piperidinyl)piperidinyl, 4-
(l-piperidinyl)piperidinyl, 1-pyrrolidinylpiperidinyl, 4-morpholinopiperidinyl, 4-(Nmethyl-
l-piperazinyl)piperidinyl, piperazinyl, N-(C1-C6)alkylpiperazinyl, in particular
N-methyl piperazinyl and N-ethyl piperazinyl, N-(C3-C6)cycloalkyl piperazinyl, in
particular N-cyclohexyl piperazinyl, pyrrolidinyl, N-(C1-C6)alkyl pyrrolidinyl, in
particular N-methyl pyrrolidinyl and N-ethyl pyrrolidinyl, diazepinyl, N-(C1-C6)alkyl
azepinyl, in particular N-methyl azepinyl and N-ethyl azepinyl, homopiperazinyl, Nmethyl
homopiperazinyl, N-ethyl homopiperazinyl, imidazolyl, and the like.
The term "solvate" is used herein to describe a molecular complex comprising the
compound of the invention and one or more pharmaceutically acceptable solvent
molecules, for example, ethanol. The term "hydrate" is employed when said solvent is
water.
The term "solvate isomers" is used herein to describe two or more molecular complexes
comprising the compound of the invention and one or more pharmaceutically acceptable
solvent molecules, for example, ethanol, wherein said complexes differ by their number
of solvent molecules per molecule of compound of the invention. The term "hydrate" is
employed when said solvent is water.
The term "metabolite" is used herein to describe a compound resulting from the
biochemical transformation of a parent compound by metabolism.
DETAILED DESCRIPTION
Compounds
The present invention relates to compounds capable to show an anti-proliferative activity
against a large panel of tumor cell lines as single agent or in combination with other
cytotoxic agents.
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:
Rl, R2, R3, R4 and R5 are each independently selected from:
-hydrogen;
-heterocycle;
-cyano;
-CF3;
-NRR';
-OH;
-halogen, preferably selected from F, CI, Br and I ;
-alkyl group optionally substituted by one or more group selected from
heterocycle, NRR', OR and a solubilizing group;
-alkoxy group optionally substituted by one or more group selected from
heterocycle, NRR', OR and a solubilizing group;
-CO-NRR';
-NR-CO-R' and
wherein R and R' are each independently selected from hydrogen,
cycloalkyl, heterocycle, solubilizing group and alkyl group optionally
substituted by one or more group selected from OR", NR"R"',
NR"COR"' and solubilizing group; wherein R" and R'" are each
independently selected from hydrogen, alkyl or cycloalkyl;
A is an heterocycle group optionally substituted, preferably A is a heterocycle group
optionally substituted by one or more group selected from halogen, alkyl, aryl,
hydroxyl, alkoxy, nitro, thiol, heterocycloalkyl, heteroaryl, cyano, cycloalkyl, a
solubilizing group, -NRR', -alkyl-NRR'; -NR-CO-R', -alkyl-NR-CO-R', -CONRR'
and -SO2NRR' group; wherein R and R' are each independently selected from
hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups;
B is an aryl or a heteroaryl group;
X is N or C-R6, wherein R6 is selected from hydrogen, cyano, CF3, alkyl and
alkoxy.
According to one embodiment, among the compounds of formula (I), the present
invention is directed to compounds wherein R3 is a hydrogen.
According to another embodiment, among the compounds of formula (I), the present
invention is directed to compounds of the following formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
Rl, R2 and R4 are each independently selected from: hydrogen; heterocycle; cyano;
-CF3; -NRR'; -OH; halogen preferably selected from F, CI, Br and I ; alkyl group
optionally substituted by one or more group selected from heterocycle, NRR', OR
and a solubilizing group; alkoxy group optionally substituted by one or more group
selected from heterocycle, NRR', OR and a solubilizing group; -CO-NRR'; -SO2-
NRR'; -NR-CO-R' and -NR-SO2R';
wherein R and R' are each independently selected from hydrogen, cycloalkyl,
heterocycle, solubilizing group and alkyl group optionally substituted by one
or more group selected from OR", NR"R"', NR"COR"' and solubilizing
group; wherein R" and R'" are each independently selected from hydrogen,
alkyl or cycloalkyl;
A is selected from heterocycle group optionally substituted, preferable A is a
heterocycle group optionally substituted by one or more group selected from
halogen, alkyl, aryl, hydroxyl, alkoxy, nitro, thiol, heterocycloalkyl, heteroaryl,
cyano, cycloalkyl, a solubilizing group, -NRR', -alkyl-NRR'; -NR-CO-R', -alkyl-
NR-CO-R', -CONRR' and -SO2NRR' group; wherein R and R' are each
independently selected from hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl and
heteroaryl groups;
B is a five member ring heteroaryl group.
According to another embodiment, among the compounds of formula (I), the present
invention is directed to compounds of the following formula (III):
or a pharmaceutically acceptable salt thereof, wherein
Rl and R2 are each independently selected from: hydrogen; heterocycle; cyano; -
CF3; -NRR'; -OH; halogen preferably selected from F, CI, Br and I ; alkyl group
optionally substituted by one or more group selected fromheterocycle, NRR', OR
and a solubilizing group; alkoxy group optionally substituted by one or more group
selected fromheterocycle, NRR', OR and a solubilizing group; -CO-NRR'; -SO2-
NRR'; -NR-CO-R' and -NR-SO2R';
wherein R and R' are each independently selected from hydrogen, cycloalkyl,
heterocycle, solubilizing group and alkyl group optionally substituted by one
or more group selected from OR", NR"R"', NR"COR"' and solubilizing
group; wherein R" and R'" are each independently selected from hydrogen,
alkyl or cycloalkyl;
A is selected from heterocycle group optionally substituted, preferably A is a
heterocycle group optionally substituted by one or more group selected from
halogen, alkyl, aryl, hydroxyl, alkoxy, nitro, thiol, heterocycloalkyl, heteroaryl,
cyano, cycloalkyl, a solubilizing group, -NRR', -alkyl-NRR'; -NR-CO-R', -alkyl-
NR-CO-R', -CONRR' and -SO2NRR' group; wherein R and R' are each
independently selected from hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl and
heteroaryl groups;
B is a five member ring heteroaryl group.
According to a specific embodiment, in the compounds of the invention, Rl represents a
hydrogen or an alkyl group, preferably Rl represents hydrogen or C1-C3 alkyl, more
preferably Rl represents hydrogen, methyl, ethyl or propyl, even more preferably, Rl
represents hydrogen or methyl. According to another specific embodiment, in the
compounds of the invention, Rl represents an alkyl group, preferably Rl represents Cl-
C3 alkyl, more preferably Rl represents methyl, ethyl or propyl, even more preferably,
Rl represents methyl.
According to a specific embodiment, in the compounds of the invention, R2 represents a
hydrogen or an alkyl group optionally substituted by an alkoxy, preferably R2 represents
hydrogen, methyl or -CH2-O-C2H5. According to another specific embodiment, in the
compounds of the invention, R2 represents a hydrogen.
According to a specific embodiment, in the compounds of the invention, R3 represents a
hydrogen.
According to a specific embodiment, in the compounds of the invention, R4 represents
alkyl group optionally substituted by one or more group selected from NRR' and OR;
alkoxy group optionally substituted by one or more group selected from NRR' and a
solubilizing group; or -CO-NRR' ; wherein R and R' are each independently selected from
hydrogen and alkyl group optionally substituted by one or more group selected from OR",
NR"R"', NR"COR"' and solubilizing group; wherein R" and R'" are each independently
selected from hydrogen or alkyl. According to a specific embodiment, in the compounds
of the invention, R4 represents alkyl group substituted by OR wherein R represents an
alkyl group; or R4 represents an alkoxy group; preferably R4 represents —CH2-O-C2H5
or-0-CH 3.
According to a specific embodiment, in the compounds of the invention, R5 represents a
hydrogen.
According to a specific embodiment, in the compounds of the invention, Rl represents
an alkyl group, R2 represents a hydrogen, R3 represents a hydrogen, R4 represents alkyl
group substituted by OR wherein R represents an alkyl group; or R4 represents an alkoxy
group; and R5 represents a hydrogen. According to a specific embodiment, in the
compounds of the invention, Rl represents methyl, R2 represents a hydrogen, R3
represents a hydrogen, R4 represents -CH2-O-C2H5 or -0-CH 3; and R5 represents a
hydrogen. According to a specific embodiment, in the compounds of the invention, Rl is
methyl, R2, R3 and R5 are hydrogen and R4 is -CH2OC2H5.
According to a specific embodiment, in the compounds of the invention, X represents N
or C-R6, wherein R6 is selected from hydrogen and alkoxy group. According to a specific
embodiment, in the compounds of the invention, X represents N, CH or C(OCH3) .
According to a preferred embodiment, in the compounds of the invention, X represents
CH.
According to a specific embodiment, in the compounds of the invention, A represents a
heterocycloalkyl group. Alternatively, in the compounds of the invention, A represents a
heteroaryl group. According to a specific embodiment, in the compounds of the invention,
A represents triazolyl, oxotriazolyl, imidazolyl, oxoimidazolidinyl, pyrazolyl, pyridyl,
oxopyridyl, thiazolyl or oxopyrrolidinyl. According to a specific embodiment, in the
compounds of the invention, A represents 2-oxoimidazolidinyl or pyrazolyl, more
preferably A represents 2-oxoimidazolidinyl.
According to a specific embodiment, in the compounds of the invention, A is a
heterocycle group substituted by one or more group selected from halogen, alkyl, aryl,
hydroxyl, alkoxy, nitro, thiol, heterocycloalkyl, heteroaryl, cyano, cycloalkyl, a
solubilizing group, -NRR', -alkyl-NRR'; -NR-CO-R', -alkyl-NR-CO-R', -CONRR' and -
SO2NRR' group; wherein R and R' are each independently selected from hydrogen, alkyl,
cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups. According to a specific
embodiment, in the compounds of the invention, A is a heterocycle group substituted by
alkyl, alkoxy, -alkyl-NRR' or -alkyl-NR-CO-R', more preferably A is substituted by
methyl, methoxy, -CH2-CH2-NH2 or -CH2-CH2-NHCO-CH3.
According to a specific embodiment, in the compounds of the invention, B represents an
aryl group. Alternatively, B represents a heteroaryl group. According to a specific
embodiment, in the compounds of the invention, B represents a five member ring
heteroaryl. According to specific embodiment, in the compounds of the invention, B
represents oxadiazolyl, oxazolyl, thiadiazolyl or thiazolyl, preferably, B represents
oxadiazolyl, oxazolyl or thiazolyl. According to a specific embodiment, B is not selected
from 1,2 diazinyl, triazolopyridinyl or triazolyl.
According to a specific embodiment, in the compounds of the invention, B represents
oxazolyl or thiazolyl. According to a specific embodiment, if B is oxazolyl, A is not
tetrazolyl or tetrahydropyridinyl. According to a specific embodiment, if B is thiazolyl,
A is not imidazolyl, triazolyl, piperazinyl, pyrrolidinyl, piperidinyl or 1,4-oxazinyl.
According to a specific embodiment, in the compounds of the invention, X is CH and A
is 2-oxoimidazolidinyl or pyrazolyl group.
According to one embodiment, in compounds of formula (III), Rl and R2 are each
independently hydrogen or alkyl group (preferably C1-C3 alkyl, more preferably methyl,
ethyl or propyl), A is 2-oxoimidazolidinyl and B is heteroaryl group.
According to a specific embodiment, in compounds of formula (III), Rl is methyl, R2 is
hydrogen, A is 2-oxoimidazolidinyl or pyrazolyl and B is oxazole, thiazol or oxadiazol
ring.
According to one embodiment, among the compounds of formula (I), the present
invention is directed to compounds of the following formula (IVa) or (IVb):
wherein B, Rl, R2 and R4 are as described above.
According to one embodiment, among the compounds of formula (I), the present
invention is directed to compounds of the following formula (Va) or (Vb):
(Va) (Vb)
wherein A, Rl, R2 and R4 are as described above.
According to one embodiment, among the compounds of formula (I), the present
invention is directed to compounds of the following formula (Via), (VIb), (Vic) or (VId):
wherein Rl, R2 and R4 are as described above.
Examples of preferred compounds of the above formulas are depicted in table 1 below:
Table 1:
Ex Chemical structure Name NMR/LCMS
001 (5-Methoxy-2- NMR (300 MHz, DMSO-d6) d 9.38 (s,
methyl-phenyl) -[5- 1H), 8.68 (d, = 2.1 Hz, 1H), 8.62 (d, =
(6-pyrazol-l-yl- 2.4 Hz, 1H), 8.12 (dd, = 8.6, 2.3 Hz, 1H),
pyridin-3-yl)- 7.99 (d, = 8.6 Hz, 1H), 7.84 (s, 1H), 7.59
N- oxazol-2-yl] -amine (s, 2H), 7.09 (d, = 8.3 Hz, 1H), 6.66 -
6.51 (m, 2H), 3.73 (s, 3H), 2.23 (s, 3H).
Chemical structure Name NMR/LCMS
(5-Ethoxymethyl-2- NMR (500 MHz, DMSO-d6) d 9.33 (s,
methyl-phenyl) -[5- IH), 8.20 (d, J =2.3 Hz, IH), 7.85 (s, IH),
(3-methoxy-4- 7.74 - 7.66 (m, 2H), 7.55 (s, IH), 7.39 (d,
pyrazol-l-yl- J = 1.6 Hz, IH), 7.29 (dd, = 8.3, 1.7 Hz,
phenyl) -oxazol-2- IH), 7.18 (d, = 7.7 Hz, IH), 6.95 (dd,
yl] -amine = 7.6, 1.2 Hz, IH), 6.52 - 6.45 (m, IH),
4.43 (s, 2H), 3.95 (s, 3H), 3.49 (q, = 7.0
Hz, 2H), 2.30 (s, 3H), 1.16 (t, = 7.0 Hz,
3H).
l-{4-[2-(5- NMR (500 MHz, DMSO-d6) d 9.29 (s,
Ethoxymethyl-(2- IH), 8.05 (s, IH), 7.81 (d, = 8.8 Hz, 2H),
methyl- 7.58 (d, = 8.9 Hz, 2H), 7.18 (d, = 7.7
phenylamino))- Hz, IH), 7.12 (s, IH), 6.96 (s, IH), 6.93
thiazol-4-yl]- (d, = 7.7 Hz, IH), 4.44 (s, 2H), 3.91 -
phenyl}- 3.83 (m, 2H), 3.50 (q, = 7.0 Hz, 2H),
imidazolidin-2-one 3.45 - 3.37 (m, 2H), 2.27 (s, 3H), 1.17 (t,
= 7.0 Hz, 3H).
(5-Ethoxymethyl-2- NMR (500 MHz, DMSO-d6) d 9.42 (s,
methyl-phenyl) -[5- IH), 8.50 (d, = 2.4 Hz, IH), 7.83 (d, =
(4-pyrazol-l-yl- 8.7 Hz, 2H), 7.79 (s, IH), 7.75 (d, = 1.6
phenyl)-thiazol-2- Hz, IH), 7.67 (s, IH), 7.60 (d, = 8.7 Hz,
yl] -amine 2H), 7.20 (d, = 7.7 Hz, IH), 6.98 (d, =
7.7 Hz, IH), 6.60 - 6.52 (m, IH), 4.42 (s,
2H), 3.48 (q, = 7.0 Hz, 2H), 2.27 (s, 3H),
1.15 (t, = 7.0 Hz, 3H).

Chemical structure Name NMR/LCMS
(5-Methoxy-2- NMR (500 MHz, DMSO-d6) d 9.24 (s,
methyl-phenyl) -[5- 1H), 8.52 (d, = 2.5 Hz, 1H), 7.92 (d, =
(4-pyrazol-l-yl- 8.9 Hz, 2H), 7.76 (d, = 1.6 Hz, 1H), 7.69
phenyl) -oxazol-2- (d, = 8.8 Hz, 2H), 7.61 (d, = 2.6 Hz,
N- yl] -amine 1H), 7.47 (s, 1H), 7.09 (d, = 8.4 Hz, 1H),
6.58 - 6.54 (m, 2H), 3.73 (s, 3H), 2.23 (s,
3H).
[5-(2-Amino- NMR (300 MHz, DMSO-d6) d 8.53 (d,
ethoxymethyl)-2- = 2.4 Hz, 1H), 7.91 (d, = 8.6 Hz, 2H),
methyl-phenyl]-[5- 7.85 (s, 1H), 7.76 (s, 1H), 7.68 (d, = 8.6
(4-pyrazol-l-yl- Hz, 2H), 7.46 (s, 1H), 7.17 (d, = 7.7 Hz,
phenyl) -oxazol-2- 1H), 6.95 (d, = 7.5 Hz, 1H), 6.56 (s, 1H),
> NH2
yl] -amine 4.65 (s, 2H), 3.40 (t, J =5.8 Hz, 2H), 3.27
(s, 2H), 2.69 (t, J = 5.8 Hz, 2H), 2.29 (s,
3H).
N-(2-{4-Methyl-3- NMR (300 MHz, DMSO-d6) d 9.30 (s,
[5-(4-pyrazol-l-yl- 1H), 8.54 (d, = 2.3 Hz, 1H), 7.91 (d, =
phenyl) -oxazol-2- 8.8 Hz, 3H), 7.84 (s, 1H), 7.76 (d, = 1.5
ylamino]- Hz, 1H), 7.68 (d, = 8.7 Hz, 2H), 7.46 (s,
benzyloxy }-ethyl)- 1H), 7.18 (d, = 7.7 Hz, 1H), 6.96 (d, =
acetamide 7.6 Hz, 1H), 6.60 - 6.53 (m, 1H), 4.44 (s,
o
2H), 3.42 (t, = 5.9 Hz, 2H), 3.23 (dd,
= 11.5, 5.8 Hz, 2H), 2.29 (s, 3H), 1.78 (s,
3H).

Chemical structure Name NMR/LCMS
4-Methyl-N-[2-(4- NMR (300 MHz, DMSO-d6) d 9.41 (s,
methyl-piperazin- 1- IH), 8.54 (d, = 2.5 Hz, IH), 8.31 (s, IH),
yl)-ethyl]-3-[5-(4- 8.27 (t, = 5.5 Hz, IH), 7.92 (d, = 8.7
pyrazol-l-yl- Hz, 2H), 7.76 (d, = 1.6 Hz, IH), 7.69 (d,
phenyl) -oxazol-2- = 8.7 Hz, 2H), 7.48 (s, IH), 7.44 (dd,
- N i , ylamino]- = 7.9, 1.5 Hz, IH), 7.28 (d, = 7.9 Hz,
N benzamide IH), 6.59 - 6.53 (m, IH), 3.34 (m, 2H)
1
2.48 - 2.36 (m, 6H), 2.33 (s, 3H), 2.31 -
2.23 (m, 4H), 2.13 (s, 3H).
(5-Ethoxymethyl-2- NMR (500 MHz, DMSO-d6) d 9.27 (s,
methyl-phenyl) -[5- IH), 8.52 (d, = 2.4 Hz, IH), 7.91 (d, =
(4-pyrazol-l-yl- 8.8 Hz, 2H), 7.83 (s, IH), 7.76 (d, = 1.6
phenyl) -oxazol-2- Hz, IH), 7.68 (d, = 8.8 Hz, 2H), 7.46 (s,
yl] -amine IH), 7.16 (d, = 7.7 Hz, IH), 6.94 (dd,
= 7.6, 1.2 Hz, IH), 6.57 - 6.53 (m, IH),
4.42 (s, 2H), 3.48 (q, = 7.0 Hz, 2H), 2.29
(s, 3H), 1.15 (t, = 7.0 Hz, 3H).
(5-Ethoxymethyl-2- NMR (300 MHz, DMSO-d6) d 9.34 (s,
methyl-phenyl) -[5- IH), 9.32 (s, IH), 8.25 (s, IH), 7.93 (d,
(4-[l,2,4]triazol-l- = 8.7 Hz, 2H), 7.82 (d, = 1.1 Hz, IH),
yl-phenyl)-oxazol- 7.73 (d, = 8.7 Hz, 2H), 7.53 (s, IH), 7.17
2-yl] -amine (d, = 7.7 Hz, IH), 6.94 (dd, = 7.6, 1.3
N
/
Hz, IH), 4.42 (s, 2H), 3.48 (q, = 7.0 Hz,
2H), 2.28 (s, 3H), 1.15 (t, = 7.0 Hz, 3H).

Chemical structure Name NMR/LCMS
(5-Ethoxymethyl-2- NMR (500 MHz, DMSO-d6) d 9.31 (s,
methyl-phenyl) -[5- 1H), 8.67 (d, = 3.9 Hz, 1H), 8.16 (d, =
(4-pyridin-2-yl- 8.4 Hz, 2H), 7.99 (d, = 7.8 Hz, 1H), 7.88
phenyl) -oxazol-2- (td, = 7.6, 1.6 Hz, 1H), 7.83 (s, 1H), 7.68
yl] -amine (d, = 8.3 Hz, 2H), 7.52 (s, 1H), 7.35 (dd,
= 7.2, 5.0 Hz, 1H), 7.17 (d, = 7.6 Hz,
i 1H), 6.95 (d, = 7.0 Hz, 1H), 4.42 (s, 2H),
3.49 (q, = 7.0 Hz, 2H), 2.29 (s, 3H), 1.15
(t, = 7.0 Hz, 3H).
l-{4-[2-(5- NMR (500 MHz, DMSO-d6) d 9.32 (s,
Ethoxymethyl-(2- 1H), 7.81 (d, J = 1.1 Hz, 1H), 7.71 - 7.65
methyl- (m, 3H), 7.55 - 7.48 (m, 2H), 7.47 (d, J =
phenylamino))- 8.6 Hz, 2H), 7.17 (d, J = 7.7 Hz, 1H), 6.95
oxazol-5-yl]- (dd, J = 7.6, 1.4 Hz, 1H), 6.49 (d, J = 8.8
phenyl}-lH- Hz, 1H), 6.32 (td, J = 6.7, 1.3 Hz, 1H),
pyridin-2-one 4.42 (s, 2H), 3.48 (q, J = 7.0 Hz, 2H), 2.29
(s, 3H), 1.16 (t, J = 7.0 Hz, 3H).
3-{4-[2-(5- NMR (500 MHz, DMSO-d6) d 11.80
Ethoxymethyl-(2- (s, 1H), 9.27 (s, 1H), 7.90 - 7.78 (m, 3H),
methyl- 7.71 (dd, = 6.9, 2.0 Hz, 1H), 7.57 (d, =
phenylamino))- 8.5 Hz, 2H), 7.44 (s, 1H), 7.39 (dd, =
oxazol-5-yl]- 6.4, 2.0 Hz, 1H), 7.16 (d, = 7.7 Hz, 1H),
phenyl}-lH- 6.94 (dd, = 7.6, 1.0 Hz, 1H), 6.30 (t, =
HN pyridin-2-one 6.7 Hz, 1H), 4.42 (s, 2H), 3.48 (q, = 7.0
Hz, 2H),2.28 (s, 3H), 1.15 (t, = 7.0 Hz,
3H).

Chemical structure Name NMR/LCMS
064 l-(4-(2-((3- NMR (500 MHz, DMSO-J 6) d 10.24
(ethoxymethyl)phe (s, 1H), 7.87 (d, = 8.8 Hz, 2H), 7.79 (s,
nyl)amino)thiazol- 1H), 7.61 (t, = 8.2 Hz, 3H), 7.31 (t, =
4- 7.8 Hz, 1H), 7.20 (s, 1H), 6.98 (s, 1H),
yl)phenyl)imidazoli 6.90 (d, J = 1.6 Hz, 1H), 4.49 (s, 2H),
din-2-one 3.93 - 3.86 (m, 2H), 3.54 (q, = 7.0 Hz,
2H), 3.47 - 3.40 (m, 2H), 3.30 (s, 2H),
1.24 - 1.14 (m, 3H).
Where one or more chiral centers are present in a compound, mixtures of enantiomers or
diastereomers may be present. Such compounds may be used as pharmaceuticals in
enantiomerically or diastereoisomerically pure form, as racemic mixtures or mixtures
enriched in one or more stereoisomer. The scope of the present invention as claimed
describes the racemic forms of such compounds as well as the individual enantiomers,
diastereomers, and stereoisomer-enriched mixtures.
A single stereoisomer of a chiral compound is commonly prepared from an optically pure
precursor, or by separation of enantiomers by chromatography, for example chiral high
pressure liquid chromatography (HPLC). Racemic mixtures may also be converted into
separable diastereomers by reacting with a suitably reactive chiral compound for isolation
by chromatography. Alternatively, separation may be achieved by converting into a chiral
salt. For example, a racemic chiral compound containing a basic group may form a
diastereomeric salt with a chiral acid such as malic acid. The mixture of diastereomeric
salts so produced may then be separated by fractional crystallization. The pure synthetic
diastereomers produced by these methods may then be converted to the desired
stereoisomer by classical chemical means known to one skilled in the art. In the present
invention, chiral racemic compounds may be separated by chiral HPLC on a suitable
chiral stationary phase eluting with a mixture of heptane / ethanol or with a pure alcohol
(methanol or ethanol). Stereoisomer conglomerates may be separated by conventional
techniques known to those skilled in the art. See, e.g. "Stereochemistry of Organic
Compounds" by Ernest L. Eliel (Wiley, New York, 1994).
The compounds of formula (I) may be used in the form of salts derived from
pharmaceutically acceptable inorganic or organic acids. Unless otherwise indicated,
"pharmaceutically acceptable salt" refers to a salt prepared by combining a compound of
formula (I) with an acid whose anion, or a base whose cation, is generally considered
suitable for human consumption. Pharmaceutically acceptable salts are particularly useful
as products of the methods of the present invention because of their greater aqueous
solubility relative to the parent compound. For use in medicine, the salts of the
compounds of this invention are non-toxic "pharmaceutically acceptable salts." Salts
encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts
of the compounds of this invention which are generally prepared by reacting the free base
with a suitable organic or inorganic acid. Suitable pharmaceutically acceptable acid
addition salts of the compounds of the present invention when possible include those
derived from inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric, boric,
fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic, and sulfuric acids,
and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic,
fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic,
methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic, tartaric, and
trifluoroacetic acids. Suitable organic acids generally include, for example, aliphatic,
cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of
organic acids. Specific examples of suitable organic acids include acetate,
trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate,
malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate,
aspartate, glutamate, benzoate, anthranilic acid, stearate, salicylate, p-hydroxybenzoate,
phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate,
benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate,
cyclohexylaminosulfonate, b-hydroxybutyrate, galactarate, galacturonate, adipate,
alginate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate,
dodecylsulfate, glycoheptanoate, glycerophosphate, heptanoate, hexanoate, nicotinate, 2-
naphthalesulfonate, oxalate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate,
thiocyanate, and undecanoate. Furthermore, where the compounds of the invention carry
an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali
metal salts, i.e., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or
magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary
ammonium salts. In another embodiment, base salts are formed from bases which form
non-toxic salts, including aluminum, arginine, benzathine, choline, diethylamine,
diolamine, glycine, lysine, meglumine, olamine, tromethamine and zinc salts. Organic
salts may be made from secondary, tertiary or quaternary amine salts, such as
tromethamine, diethylamine, N N '-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine (N -methylglucamine), and procaine. Basic
nitrogen-containing groups may be quaternized with agents such as lower alkyl (CrCe)
halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl
sulfates (i.e., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g.,
decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides
(e.g., benzyl and phenethyl bromides), and others. Hemisalts of acids and bases may also
be formed, for example, hemisulfate and hemicalcium salts.
The language "compounds of formula (I)" include all subformulae and specific
embodiments herein disclosed. Moreover, unless otherwise indicated, the language
"compounds of formula (I)" include all forms of the compound of formula (I), including
hydrates, solvates isomers, crystalline and non-crystalline forms, isomorphs, polymorphs,
and metabolites thereof. For example, the compounds of formula (I), or pharmaceutically
acceptable salts thereof, may exist in unsolvated and solvated forms. When the solvent or
water is tightly bound, the complex will have a well-defined stoichiometry independent
of humidity. When, however, the solvent or water is weakly bound, as in channel solvates
and hygroscopic compounds, the water/solvent content will be dependent on humidity
and drying conditions. In such cases, non-stoichiometry will be the norm. Stereoisomers
of the compounds of formula (I) include cis and trans isomers, optical isomers such as R
and S enantiomers, diastereomers, geometric isomers, rotational isomers, conformational
isomers, and tautomers of the compounds of the invention, including compounds
exhibiting more than one type of isomerism; and mixtures thereof (such as racemates and
diastereomeric pairs). Unless otherwise indicated, the language "compounds of formula
(I)" include the tautomeric forms of compounds. Where structural isomers are
interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur.
This can take the form of proton tautomerism in compounds of the invention containing,
for example, an imino, keto, or oxime group, or so-called valence tautomerism in
compounds which contain an aromatic moiety. It follows that a single compound may
exhibit more than one type of isomerism. The various ratios of the tautomers in solid and
liquid form is dependent on the various substituents on the molecule as well as the
particular crystallization technique used to isolate a compound.
Pharmaceutical composition, medicament and use
The invention also relates to a pharmaceutical composition comprising a compound as
depicted above.
Accordingly the invention relates to pharmaceutical composition comprising at least one
compound of the invention and an acceptable pharmaceutical excipient.
According to one embodiment, the invention relates to a pharmaceutical composition
comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and
art least one pharmaceutically acceptable carrier and/or excipient.
As is known to the person skilled in the art, various forms of excipients can be used
adapted to the mode of administration and some of them can promote the effectiveness
of the active molecule, e.g. by promoting a release profile rendering this active molecule
overall more effective for the desired treatment.
The pharmaceutical compositions of the invention are thus able to be administered in
various forms, for example as injectable, pulverizable or ingestible form, for example via
intramuscular, intravenous, subcutaneous, intradermal, oral, topical, rectal, vaginal,
ophthalmic, nasal, transdermal or parenteral route. The present invention notably covers
the use of a compound according to the present invention for the manufacture of a
composition, particularly a pharmaceutical composition.
Such medicament can take the form of a pharmaceutical composition adapted for oral
administration, which 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 pharmaceuticallyacceptable
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-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 may comprise any ingredient commonly used
in dermatology and cosmetics. 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, 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.
Emulsifiers which can be used in the invention include, for example, glycerol stearate,
polysorbate 60 and the PEG-6/PEG-32/glycol stearate mixture.
Hydrophilic gelling agents which can be used in the invention include, for example,
carboxyvinyl polymers (carbomer), acrylic copolymers such as acrylate/alkylacrylate
copolymers, polyacrylamides, polysaccharides such as hydroxypropylcellulose, clays and
natural gums. Lipophilic gelling agents which can be used in the invention include, for
example modified clays such as bentones, metal salts of fatty acids such as aluminum
stearates and hydrophobic silica, or alternatively ethylcellulose and polyethylene.
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 to show an anti-proliferative activity against a large
panel of tumor cell lines as single agent or in combination with other cytotoxic agents.
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 4,411,893), 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 Biology 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 is 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., US Pat. No.
4,615,699 and Campbell et al., US Pat. Nos. 4,460,372 and 4,379,454), dimethyl
sulfoxide (US 3,740,420 and US 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 absorption of various compounds.
The pharmaceutical compositions of the invention can also be intended for administration
with 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,
ethanolic solutions, aqueous/ethanolic 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 5,556,611:
- liquid gas systems (a liquefied gas is used as propellant 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 propellant phase),
- pressurized gas system (a compressed gas such as nitrogen, carbon dioxide,
dinitrogen monoxide, or 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 propellant 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 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 formulated 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 carrier 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 150 mg per 100 ml of carrier.
Other ingredients, such as 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. Especially, the invention relates to a medicament comprising a compound
according to the invention or a pharmaceutically acceptable salt thereof. In other words,
the invention embraces a method for treating a disease by inhibiting the proliferation of
tumor cells comprising administering an effective amount of at least one compound as
defined above to a subject in need of such treatment.

CLAIMS
A compound of formula (I)
or a pharmaceutically acceptable salt thereof, wherein :
Rl, R2, R4 and R5 are each independently selected from hydrogen;
heterocycle; cyano; -CF3; -NRR'; -OH; halogen; alkyl group optionally
substituted by one or more group selected from heterocycle, -NRR', -OR and
a solubilizing group; alkoxy group optionally substituted by one or more
group selected from heterocycle, -NRR', -OR and a solubilizing group; -CONRR';
-SO2-NRR'; -NR-CO-R' and -NR-SO2R';
wherein R and R' are each independently selected from hydrogen,
cycloalkyl, heterocycle, solubilizing group and alkyl group optionally
substituted by one or more group selected from OR", NR"R"',
NR"COR"' and solubilizing group; wherein R" and R'" are each
independently selected from hydrogen, alkyl and cycloalkyl;
R3 is a hydrogen;
A is a heterocycle group, optionally substituted by one or more group selected
from halogen, alkyl, aryl, hydroxyl, alkoxy, nitro, thiol, heterocycloalkyl,
heteroaryl, cyano, cycloalkyl, a solubilizing group, -NRR', -alkyl-NRR'; -NRCO-
R', -alkyl-NR-CO-R', -CONRR' and -SO2NRR' group; wherein R and R'
are each independently selected from hydrogen, alkyl, cycloalkyl, aryl,
heterocycloalkyl and heteroaryl groups;
B is an aryl or a heteroaryl group;
X is N or C-R6, wherein R6 is selected from hydrogen, cyano, CF3, alkyl and
alkoxy;
with provisos that
B is not selected from 1,2 diazinyl, triazolopyridinyl or triazolyl;
if B is oxazolyl, A is not tetrazolyl or tetrahydropyridinyl;
if B is thiazolyl, A is not imidazolyl, triazolyl, piperazinyl, pyrrolidinyl,
piperidinyl or 1,4-oxazinyl.
2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof,
wherein B is a five member ring heteroaryl group.
3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt
thereof, wherein X is CH and A is 2-oxoimidazolidinyl or pyrazolyl group.
4. The compound according to any one of claims 1 to 3 of formula (II):
or a pharmaceutically acceptable salt thereof, wherein
Rl, R2 and R4 are each independently selected from: hydrogen; heterocycles;
cyano; -CF3; -NRR'; -OH; halogen; alkyl group optionally substituted by one
or more group selected from heterocycle, NRR' ,OR and a solubilizing group;
alkoxy group optionally substituted by one or more group selected from
heterocycle, NRR', OR and a solubilizing group; -CO-NRR'; -SO2-NRR'; -
NR-CO-R' and -NR-SO2R'; wherein R and R' are each independently selected
from hydrogen, cycloalkyl, heterocycle, solubilizing group and alkyl group
optionally substituted by one or more group selected from OR", NR"R",
NR"COR"' and solubilizing group; wherein R" and R'" are each
independently selected from hydrogen, alkyl and cycloalkyl;
B is a five member ring heteroaryl group;
A is a heterocycle group optionally substituted by one or more group selected
from halogen, alkyl, aryl, hydroxyl, alkoxy, nitro, thiol, heterocycloalkyl,
heteroaryl, cyano, cycloalkyl, a solubilizing group, -NRR', -alkyl-NRR'; -NRCO-
R', -alkyl-NR-CO-R', -CONRR' and -SO2NRR' group; wherein R and R'
are each independently selected from hydrogen, alkyl, cycloalkyl, aryl,
heterocycloalkyl and heteroaryl groups;
with provisos that
B is not selected from 1,2 diazinyl, triazolopyridinyl or triazolyl;
if B is oxazolyl, A is not tetrazolyl or tetrahydropyridinyl;
if B is thiazolyl, A is not imidazolyl, triazolyl, piperazinyl, pyrrolidinyl,
piperidinyl or 1,4-oxazinyl.
5. The compound according to any one of claims 1 to 4 of formula (III):
or a pharmaceutically acceptable salt thereof, wherein
Rl and R2 are each independently selected from: hydrogen; heterocycles;
cyano; -CF3; -NRR'; -OH; halogen; alkyl group optionally substituted by one
or more group selected from heterocycle, NRR' , OR and a solubilizing group;
alkoxy group optionally substituted by one of more group selected from
heterocycle, NRR', OR and a solubilizing group; -CO-NRR'; -SO2-NRR'; -
NR-CO-R' and -NR-SO2R'; wherein R and R' are each independently selected
from hydrogen, cycloalkyl, heterocycle, solubilizing group and alkyl group
optionally substituted by one or more group selected from OR", NR"R"',
NR"COR"' and solubilizing group; wherein R" and R'" are each
independently selected from hydrogen, alkyl or cycloalkyl;
B is a five member ring heteroaryl group;
A is a heterocycle group optionally substituted by one or more group selected
from halogen, alkyl, aryl, hydroxyl, alkoxy, nitro, thiol, heterocycloalkyl,
heteroaryl, cyano, cycloalkyl, a solubilizing group, -NRR', -alkyl-NRR'; -NRCO-
R', -alkyl-NR-CO-R', -CONRR' and -SO2NRR' group; wherein R and R'
are each independently selected from hydrogen, alkyl, cycloalkyl, aryl,
heterocycloalkyl and heteroaryl groups;
with provisos that
B is not selected from 1,2 diazinyl, triazolopyridinyl or triazolyl;
if B is oxazolyl, A is not tetrazolyl or tetrahydropyridinyl;
if B is thiazolyl, A is not imidazolyl, triazolyl, piperazinyl, pyrrolidinyl,
piperidinyl or 1,4-oxazinyl.
The compound according to any one of claims 1 to 5 or a pharmaceutically
acceptable salt thereof, wherein Rl is methyl, R2, R3 and R5 are hydrogen and R4
The compound according to claim 1, or a pharmaceutically acceptable salt thereof,
selected from:
(5-Methoxy-2-methyl-phenyl)-[5-(6-pyrazol-l-yl-pyridin-3-yl)-oxazol-2-yl]-
amine;
(5-Ethoxymethyl-2-methyl-phenyl)-[5-(3-methoxy-4-pyrazol-l-yl-phenyl)-
oxazol-2-yl] -amine;
1-{4-[2-(5-Ethoxymethyl-(2-methyl-phenylamino))-thiazol-4-yl] -phenyl }-
imidazolidin-2-one;
(5-Ethoxymethyl-2-methyl -phenyl)- [5-(4-pyrazol-l -yl-phenyl)-thiazol-2-yl] -
amine;
4-Methyl-N-(2-morpholin-4-yl-ethyl)-3-[5-(4-pyrazol-l-yl-phenyl)-oxazol-2-
ylamino] -benzamide;
l-{4-[2-(5-Ethoxymethyl-(2-methyl-phenylamino))-oxazol-5-yl]-phenyl}-
imidazolidin-2-one;
(5-Ethoxymethyl-2-methyl -phenyl)- [5-(6-pyrazol-l -yl-pyridin-3-yl)-oxazol-2-yl] -
amine;
1-{4-[5-(5-Ethoxymethyl- (2-methyl-phenylamino))- [1,3,4] oxadiazol-2-yl] -
phenyl }-imidazolidin-2-one;
(5-Ethoxymethyl-2-methyl-phenyl)-[5-(4-pyrazol-l-yl-phenyl)-[l,3,4]oxadiazol-
2-yl] -amine;
1-{4-[5-(5-Ethoxymethyl-(2-methyl-phenylamino))-[l,2,4]thiadiazol-3-yl]-
phenyl }-imidazolidin-2-one;
(5-Methoxy-2-methyl-phenyl)-[5-(4-pyrazol-l-yl-phenyl)-thiazol-2-yl] -amine;
1-{4-[2-(5-Methoxy-2-methyl-phenylamino)-thiazol-5-yl] -phenyl }-imidazolidin-
2-one;
1-{4-[2-(5-Ethoxymethyl- (2-methyl-phenylamino))-thiazol-5-yl] -phenyl }-
imidazolidin-2- one;
(5-Ethoxymethyl-2-methyl -phenyl)- [4-(4-pyrazol-l -yl-phenyl)-thiazol-2-yl] -
amine;
{4-Methyl-3-[4-(4-pyrazol-l-yl-phenyl)-thiazol-2-ylamino]-phenyl}-methanol;
1-{4-[2-(3-Ethoxymethyl- (5-methyl-phenylamino))-thiazol-4-yl] -phenyl }-
imidazolidin-2- one;
1-{4-[2-(3-Ethoxymethyl-(5-methyl-phenylamino))-oxazol-5-yl]-phenyl}-
imidazolidin-2- one;
(3-Ethoxymethyl-phenyl)-[5-(4-pyrazol-l-yl-phenyl)-oxazol-2-yl] -amine;
(3-Ethoxymethyl-5-methyl -phenyl)- [5-(4-pyrazol-l -yl-phenyl)-oxazol-2-yl] -
amine;
(3,5-Bis-(ethoxymethyl)-phenyl)-[5-(4-pyrazol-l-yl-phenyl)-oxazol-2-yl]-amine;
(5-Methoxy-2-methyl-phenyl)-[5-(4-pyrazol-l-yl-phenyl)-oxazol-2-yl] -amine;
[5-(2-Amino-ethoxymethyl)-2-methyl-phenyl]-[5-(4-pyrazol-l-yl-phenyl)-oxazol-
2-yl] -amine;
N-(2-{4-Methyl-3-[5-(4-pyrazol-l-yl-phenyl)-oxazol-2-ylamino]-benzyloxy}-
ethyl)-acetamide;
2-{4-Methyl-3-[5-(4-pyrazol-l-yl-phenyl)-oxazol-2-ylamino]-benzyloxy}-
ethanol;
{4-Methyl-3-[5-(4-pyrazol-l-yl-phenyl)-oxazol-2-ylamino]-phenyl}-methanol;
{2-Methyl-5-[(2-morpholin-4-yl-ethylamino)-methyl] -phenyl }- [5-(4-pyrazol-1-ylphenyl)-
oxazol-2-yl] -amine;
[2-Methyl-5-(2-morpholin-4-yl-ethoxy)-phenyl]-[5-(4-pyrazol-l-yl-phenyl)-
oxazol-2-yl] -amine;
[5-(2-Dimethylamino-ethoxy)-2-methyl-phenyl]-[5-(4-pyrazol-l-yl-phenyl)-
oxazol-2-yl] -amine;
4,N-Dimethyl-3-[5-(4-pyrazol-l-yl-phenyl)-oxazol-2-ylamino]-benzamide;
4-Methyl-N- [2-(4-methyl-piperazin- 1-yl)-ethyl] -3- [5-(4-pyrazol-1-yl-phenyl)-
oxazol-2-ylamino]-benzamide;
(5-Ethoxymethyl-2-methyl -phenyl)- [5-(4-pyrazol-l -yl-phenyl)-oxazol-2-yl] -
amine;
(5-Ethoxymethyl-2-methyl-phenyl)-[5-(4-[l,2,4]triazol-l-yl-phenyl)-oxazol-2-yl]-
amine;
(5-Ethoxymethyl-2-methyl-phenyl)-[5-(4-[l,2,3]triazol-l-yl-phenyl)-oxazol-2-yl]-
amine;
(5-Ethoxymethyl-2-methyl-phenyl)-[5-(4-[l,2,3]triazol-2-yl-phenyl)-oxazol-2-yl]-
amine;
(5-Ethoxymethyl-2-methyl -phenyl)- [5-(4-imidazol-l -yl-phenyl)-oxazol-2-yl]-
amine;
(5-Ethoxymethyl-2-methyl-phenyl)-[5-(4-thiazol-2-yl-phenyl)-oxazol-2-yl]-
amine;
(5-Ethoxymethyl-2-methyl -phenyl)- {5-[4-(3-methyl-pyrazol-l-yl)-phenyl]-
oxazol-2-yl} -amine;
(5-Ethoxymethyl-2-methyl -phenyl)- {5-[4-(4-methyl-pyrazol-l-yl)-phenyl]-
oxazol-2-yl} -amine;
(5-Ethoxymethyl-2-methyl -phenyl)- {5-[4-(5-methyl-pyrazol-l-yl)-phenyl]-
oxazol-2-yl} -amine;
(5-Ethoxymethyl-2-methyl -phenyl)- {5-[4-(3-methoxy-p yrazol-l-yl)-phenyl]-
oxazol-2-yl} -amine;
2-{4-[2-(5-Ethoxymethyl-(2-methyl-phenylamino))-oxazol-5-yl]-phenyl}-2,4-
dihydro-[l,2,4]triazol-3-one;
l-{4-[2-(5-Ethoxymethyl-(2-methyl-phenylamino))-oxazol-5-yl]-phenyl}-3-
methyl-imidazolidin-2- one;
1-(2-Amino-ethyl)-3-{4-[2-(5-ethoxymethyl-(2-methyl-phenylamino))-oxazol-5-
yl] -phenyl }-imidazolidin-2-one;
N-[2-(3-{4-[2-(5-Ethoxymethyl-(2-methyl-phenylamino))-oxazol-5-yl]-phenyl}-
2-oxo-imidazolidin- 1-yl)-ethyl] -acetamide;
l-{4-[2-(5-Ethoxymethyl-(2-methyl-phenylamino))-oxazol-5-yl]-phenyl}-
pyrrolidin-2-one;
(5-Ethoxymethyl-2-methyl-phenyl)-[5-(4-pyridin-2-yl-phenyl)-oxazol-2-yl]-
amine;
l-{4-[2-(5-Ethoxymethyl-(2-methyl-phenylamino))-oxazol-5-yl]-phenyl}-lHpyridin-
2-one;
3-{4-[2-(5-Ethoxymethyl-(2-methyl-phenylamino))-oxazol-5-yl]-phenyl}-lHpyridin-
2-one;
(R)-l-(4-(2-((5-(ethoxymethyl)-2-methylphenyl)amino)oxazol-5-yl)phenyl)-5-
methylimidazolidin-2-one;
4-(4-(2-((5-(ethoxymethyl)-2-methylphenyl)amino)oxazol-5-yl)phenyl)-5-methyl-
2,4-dihydro-3H- 1,2,4-triazol-3-one;
l-(4-(2-((3,5-bis(ethoxymethyl)phenyl)amino)oxazol-5-yl)phenyl)imidazolidin-2-
one;
l-(4-(2-((5-(ethoxymethyl)-2-methylphenyl)amino)oxazol-5-yl)phenyl)-3-(2-
methoxyethyl)imidazolidin-2- one;
l-(5-(2-((5-(ethoxymethyl)-2-methylphenyl)amino)oxazol-5-yl)pyridin-2-
yl)imidazolidin-2- one;
l-(4-(2-((3-(ethoxymethyl)-5-(2-methoxyethoxy)phenyl)amino)oxazol-5-
yl)phenyl)imidazolidin-2-one;
5-(4-(lH-pyrazol-5-yl)phenyl)-N-(5-(ethoxymethyl)-2-methylphenyl)oxazol-2-
amine;
(R)-l-(5-(2-((5-(ethoxymethyl)-2-methylphenyl)amino)oxazol-5-yl)pyridin-2-yl)-
5-methylimidazolidin-2- one;
l-(4-(2-((3-(ethoxymethyl)-5-(2-hydroxyethoxy)phenyl)amino)oxazol-5-
yl)phenyl)imidazolidin-2-one;
5-(4-(lH-pyrazol-4-yl)phenyl)-N-(5-(ethoxymethyl)-2-methylphenyl)oxazol-2-
amine;
N-(5-(ethoxymethyl)-2-methylphenyl)-5-(4-(l-methyl-lH-pyrazol-5-
yl)phenyl)oxazol-2-amine;
4-(6-(lH-pyrazol-l-yl)pyridin-3-yl)-N-(5-(ethoxymethyl)-2-
methylphenyl)thiazol-2- amine;
l-(4-(2-((3-(ethoxymethyl)phenyl)amino)oxazol-5-yl)phenyl)imidazolidin-2-one;
l-(4-(2-((3-(ethoxymethyl)phenyl)amino)thiazol-4-yl)phenyl)imidazolidin-2-one.
8. A pharmaceutical composition comprising a compound according to any one of
claims 1 to 7, or a pharmaceutically acceptable salt thereof and at least one
pharmaceutically acceptable excipients and/or carriers.
9. The pharmaceutical composition according to claim 8, comprising a compound
according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof
as sole active pharmaceutical ingredient.
10. The pharmaceutical composition according to claim 8, further comprising another
active pharmaceutical agent.
11. A medicament comprising a compound according to any one of claims 1 to 7, or a
pharmaceutically acceptable salt thereof.
12. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable
salt thereof, for use in the treatment of hematological disorders and/or proliferative
disorders.
13. A compound for the use according to claim 12, wherein the hematological disorder
is selected from lymphoma; leukemia such as Acute Myeloid Leukemia (AML),
Acute Lymphoblastic Leukemia (ALL), Chronic Lymphoid Leukemia (CLL), or
Chronic Myeloid Leukemia (CML); multiple myeloma (MM); myelodysplatic
syndrome (MDS); and myelodysplasia with myelofibrosis.
14. A compound for the use according to claim 12, wherein the proliferative disorder
is cancer such as head and neck cancer, melanoma, kidney carcinoma, stomach
carcinoma, liver carcinoma, colorectal carcinoma, pancreas carcinoma, lung
carcinoma, neuronal carcinoma, glioblastoma multiforme, osteosarcoma, Ewing
sarcoma, breast carcinoma, ovary carcinoma, or prostate carcinoma.
A pharmaceutical composition according to claim 10, comprising a compound
according to any one or more of claims 1 to 7, or a pharmaceutically acceptable salt
thereof, and another active pharmaceutical ingredient as a combined preparation for
sequential, simultaneous or separate use in the treatment of a disorder selected from
the group consisting of hematological disorders and proliferative disorders.