NOVEL AMIDOHETEROARYL AROYL HYDRAZIDE ETHYNES
RELATED APPLICATIONS
This application claims the benefit of Indian Patent Application no. 1953/MUM/2015 filed on
May 18, 2015 which is hereby incorporated by reference.
FIELD OF INVENTION
The present invention relates to novel amidoheteroaryl aroyl hydrazide ethynes as tyrosine
kinase inhibitors, process of preparation thereof, and use of the compounds for preparation of
pharmaceutical compositions in the therapeutic treatment of disorders related to tyrosine
kinases in humans.
BACKGROUND OF THE INVENTION
Protein tyrosine kinases are currently recognized as important molecular targets for drug
development in the treatment of several disorders, particularly in the treatment of
proliferative disorders. Dysregulation of tyrosine kinase activity has emerged as a major
mechanism by which cancer cells evade normal physiological constraints on growth,
proliferation and survival. One of the key focus areas in anti-TK drug discovery is the design
and development of small molecules that can directly inhibit catalytic activity of the kinase
by interfering with the binding of ATP or substrates. An important advantage of TK-directed
therapy is the possibility to perform pharmacodynamic studies that correlate inhibition of the
targeted TK in cancer cells with clinical responses to the drug.
Classical tyrosine kinase inhibitors, which are predominantly the Bcr-Abl kinase inhibitors
that are currently in clinical use, are described in the following patent literature:
• United States Patent No. 5,521,184 (the Ί 84 patent): Exemplifies 4-[(Methyl- 1-
piperazinyl)methyl]-N- [4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-
phenyl]benzamide methanesulfonate (Imatinib mesylate, Gleevec® )
• United States Patent No. 7,169,791 (the '791 patent): Exemplifies 4-Methyl-N-[3-(4-
methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-
ylamino)-benzamide (Nilotinib, Tasigna®)
• United States Patent No 6,596,746 (the '746 patent): Exemplifies N-(2-chloro-6-
methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin- 1-yl)-2-methylpyrimidin-4-
ylamino)thiazole-5-carboxamide (Dasatinib, Sprycel®)
While the second generation TK inhibitors in clinic viz. nilotinib and dasatinib have provided
additional treatment option to patients who have developed resistance to imatinib, there are
certain shortcomings with regard to their side effects. Particularly in the case of dasatinib, the
increased potency may be associated with untoward off-target toxicities, which probably
relate to their inhibitory activity against a broader range of protein kinases such as Kit,
PDGFR and ephrin receptor (EphA2) tyrosine kinases which are directly implicated in
haematopoiesis, control of tissue interstitial-fluid pressure and angiogenesis. These effects
may provide the physiological explanation for some of the toxicities associated with dasatinib
therapy such as myelosuppression and pleural effusion. Besides, treatment with highly potent
Abl kinase inhibition has potential for the development of cardiotoxicity in patients with
CML.
Studies have shown that patients taking imatinib develop resistance to the drug during the
course of therapy. Recent research has provided a better understanding of the mechanism of
resistance which led to the development of second generation TK inhibitors. Although the
second generation TK inhibitors in clinic provide treatment alternatives for patients who
develop resistance to imatinib therapy, the prognosis for the patients having T315I mutation
is not good since none of these currently marketed therapies are effective. There is thus an
unmet medical need with regard to treatment of patients having the T315I mutation.
Omacetaxine (homoharringtonine) is approved by the FDA for CML patients with T315I.
However, it is an intravenous drug with a non-specific mechanism of action . Ariad
Compound Ponatinib (AP24534, US 8114874) is also approved by US FDA but has a boxed
warning for risk-threatening blood clots and severe narrowing of blood vessels.. Other drug
candidates in clinical phase include the Deciphera compound DCC-2036 (PCT Publication
No. WO 2008/046003). The present applicant previously reported novel diarylacetylene
hydrazides as tyrosine kinase inhibitors published as WO 2012/098416 Al.
The current invention describes novel amidoheteroaryl aroyl hydrazide ethynes containing
compounds which are not only potent inhibitors of Abl tyrosine kinase but also on its mutant
versions.
SUMMARY
The present inve
Formula I
and pharmaceutically acceptable salts thereof wherein,
i is selected from - C3
_ cycloalkyl, -Ci
-
alkyl-NH 2
, - _ alkyl-NH(C _ alkyl), -C1-6 alkylN(Ci_6
alkyl)2, alkenyl, -Cj,.(, alkynyl, -Ci_6 alkyl, -C(O) heterocyclyl, heterocyclyl-Ci_6
alkyl, -Ci_6 haloalkyl, -NH(C3_6 cycloalkyl) and heterocyclyl wherein heterocyclyl is 5-6
membered non-aromatic ring containing 1 to 2 heteroatom individually selected from N, O or
S;
R is optionally substituted with one or more group independently selected from - C1
-4 alkyl,
halogen, CN, NH(d_ alkyl), N(d_ alkyl) 2
, NH2
and hydroxy;
R2 and R 3 are individually selected from a group of hydrogen, halogen, -C1
-4 alkyl, -C1
-4
haloalkyl, heterocyclyl-Ci_4 alkyl and heteroaryl wherein, heterocyclyl is 5-6 membered nonaromatic
ring containing 1 to 2 heteroatom independently selected from N, O or S and is
unsubstituted or substituted with - C1
-4 alkyl and heteroaryl is 5-6 membered aromatic ring
containing 1 to 2 heteroatom independently selected from N, O or S and is unsubstituted or
substituted with - C1
-4 alkyl.
The compounds of the present invention are potent inhibitors of Abl tyrosine kinase including
its mutants, and can be used for treating the disease which responds to an inhibition of a
tyrosine kinase, especially a neoplastic disease.
DEFINITION
The following are definitions of the terms used in this specification. The initial definition
provided for a group or term herein applies to that group or term throughout the present
specification, individually or as part of another group, unless otherwise indicated.
The term "cycloalkyl" denotes a non-aromatic mono-, or multicyclic ring system of 3 to
about 13 carbon atoms. Monocyclic rings include include, but are not limited to cylcopropyl,
cyclobutyl, cyclopentyl and cyclohexyl. Examples of simple multicyclic cycloalkyl groups
include perhydronapththyl, perhydroindenyl etc; bridged multicyclic groups include
adamantyl and norbornyl etc, and spriromulticyclic groups for e.g., spiro(4,4)non-2-yl.
Unless set forth or recited to the contrary, all cycloalkyl groups described or claimed herein
may be substituted or unsubstituted.
The term "alkyl" refers to a hydrocarbon chain radical that includes solely carbon and
hydrogen atoms in the backbone, either linear or branched, having from one to eight carbon
atoms, both inclusive, and which is attached to the rest of the molecule by a single bond, e.g.,
methyl, ethyl, w-propyl, 1-methylethyl (isopropyl), «-butyl, «-pentyl, and 1,1-dimethylethyl
(i-butyl). The term "Ci_6
alkyl" refers to an alkyl chain, linear or branched having 1 to 6
carbon atoms, both inclusive. Unless set forth or recited to the contrary, all alkyl groups
described or claimed herein may be, substituted or unsubstituted.
The term "alkenyl" refers to a hydrocarbon chain containing from 3 to 6 carbon atoms, both
inclusive and including at least one carbon-carbon double bond which is not in the 1 position,
and may have ( or (Z) configuration. Non-limiting examples of alkenyl groups include 2-
propenyl (allyl), 2-methyl-2-propenyl, and (Z)-2-butenyl. Unless set forth or recited to the
contrary, all alkenyl groups described or claimed herein may be straight chain or branched,
substituted or unsubstituted.
The term "alkynyl" refers to a hydrocarbyl radical having at least one carbon-carbon triple
bond which is not in the 1 position, and having 3 to about 8 carbon atoms, both inclusive
(with radicals having 3 to about 6 carbon atoms being preferred). Non-limiting examples of
alkynyl groups include 2-propynyl and 3-butynyl. Unless set forth or recited to the contrary,
all alkynyl groups described or claimed herein may be straight chain or branched, substituted
or unsubstituted.
The term "heterocyclic ring" or "heterocyclyl" unless otherwise specified refers to substituted
or unsubstituted non-aromatic 5 to 10 membered ring, preferably 5-6 membered ring, which
consists of carbon atoms and from one to five heteroatoms selected from nitrogen, oxygen
and sulfur. The heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which
may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon,
oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various
oxidation states. In addition, the nitrogen atom may be optionally quarternized; also, unless
otherwise constrained by the definition the heterocyclic ring or heterocyclyl may optionally
contain one or more olefinic bond(s). Examples of such heterocyclic ring radicals include, but
are not limited to azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl,
dioxaphospholanyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, oxadiazolyl, 2-
oxopiperazinyl, 2- oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl,
octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl,
phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl,
tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide and
thiamorpholinyl sulfone. The heterocyclic ring radical may be attached to the main structure
at any heteroatom or carbon atom that results in the creation of a stable structure. Unless set
forth or recited to the contrary, all heterocyclyl groups described or claimed herein may be
substituted or unsubstituted.
The terms "halogen" or "halo" means fluorine, chlorine, bromine or iodine.
Similarly, "haloalkyl" or "haloalkoxy" refers to an alkyl or alkoxy group substituted with one
or more halogen atoms.
The term "heteroaryl" unless otherwise specified refers to substituted or unsubstituted 5 to 14
membered aromatic heterocyclic ring radicals with one or more heteroatom(s) independently
selected from N, O or S. The heteroaryl may be a mono-, bi- or tricyclic ring system. The
heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon
atom that results in the creation of a stable structure. Examples of such heteroaryl ring
radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl,
isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, thiazolyl, isothiazolyl, pyridyl,
pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl,
benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl,
quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolinyl,
isoquinolinyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl, imidazo[l,2-a]pyridyl,
imidazo[l,2-fl]pyridine and phthalazinyl. Unless set forth or recited to the contrary, all
heteroaryl groups described or claimed herein may be substituted or unsubstituted.
Salts of compounds of Formula I are the physiologically acceptable salts. Physiologically
acceptable salts are particularly suitable for medical applications, due to their greater
solubility in water compared with the starting or base compounds. Suitable physiologically
acceptable acid addition salts of the compounds of the invention may be salts of inorganic
acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, and the like or of organic
acids such as, for example, acetic acid, benzenesulfonic acid, methanesulfonic acid, benzoic
acid, citric acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic
acid, suberic acid, azelaic acid, malic acid, tartartic acid, amino acids, such as glutamic acid
or aspartic acid, butanedisulfonic acid and the like.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect the
Formula I
and pharmaceutically acceptable salts thereof wherein,
Ri is selected from -C3-6 cycloalkyl, -Ci-6 alkyl-NH 2
, -Ci-6 alkyl-NH(Ci-6 alkyl), -Ci-6 alkylN(Ci_6
alkyl)2, alkenyl, -Ci_6 alkyl, -C3
_ alkynyl, -C(O) heterocyclyl, heterocyclyl-Ci_6
alkyl, -Ci_6 haloalkyl, -NH(C 3
_ cycloalkyl) and heterocyclyl wherein heterocyclyl is 5-6
membered non-aromatic ring containing 1 to 2 heteroatom individually selected from N , O or
S;
Ri is optionally substituted with one or more group independently selected from - C 1
-4 alkyl,
halogen, CN, NH(d_ alkyl), N(d_ alkyl) 2
, NH2
and hydroxy;
R2
and R3
are individually selected from a group of hydrogen, halogen, -C _4 alkyl, -C 1
-4
haloalkyl, heterocyclyl-Ci-4 alkyl and heteroaryl wherein, heterocyclyl is 5-6 membered nonaromatic
ring containing 1 to 2 heteroatom independently selected from N, O or S and is
unsubstituted or substituted with - C 1
-4 alkyl and heteroaryl is 5-6 membered aromatic ring
containing 1 to 2 heteroatom independently selected from N, O or S and is unsubstituted or
substituted with - C 1
-4 alkyl.
In one embodiment, R i is -C3-6 cycloalkyl.
In one embodiment, the compound of Formula I is selected from a group comprising:
Cyclopropanecarboxylic acid (5-{5 -[N -(2-chloro-6-methylbenzoyl)hydrazinocarbonyl]-2-
methyl-phenylethynyl }-pyridin-2-yl)amide;
N-(5- {5-[N -(2-chloro-6-methylbenzoyl)hydrazinocarbonyl] -2-methyl-phenylethynyl }-
pyridin-2-yl)-2-dimethylaminoacetamide;
N-(5- {5-[N -(2-Chloro-6-methylbenzoyl)hydrazinocarbonyl] -2-methyl-phenylethynyl }-
pyridin-2-yl)-3-(4-methyl-piperazin- 1-yl)propionamide;
N-(5-{5 -[N '-(2-Chloro-6-methyl-benzoyl)hydrazinocarbonyl]-2-methyl-phenylethynyl}-
pyridin-2-yl)-2-(4-dimethylaminopiperidin- 1-yl)acetamide;
N-(5-{5 -[N '-(2-Chloro-6-methyl-benzoyl)hydrazinocarbonyl]-2-methyl-phenylethynyl}-
pyridin-2-yl)-2-(3-dimethylaminopyrrolidin-l-yl)acetamide;
N-(5- {5-[N -(2-Chloro-6-methyl-benzoyl)hydrazinocarbonyl] -2-methyl-phenylethynyl }-
pyridin-2-yl)acetamide ;
Cyclopropanecarboxylic acid [5-(2-methyl-5- {N '-[4-(4-methylpiperazin- 1-
ylmethyl)benzoyl] -hydrazinocarbonyl }phenylethynyl)pyridin-2-yl] amide ;
Cyclopropanecarboxylic acid [5-(2-methyl-5 -{N '-[3-(4-methylimidazol-l-yl)-5-
trifluoromemylbenzoyl]-hydrazinocarbonyl}phenylethynyl)pyridin-2-yl]amide;
l-(5-{ 5-[N '-(2-Chloro-6-methylbenzoyl)hydrazinocarbonyl]-2-methylphenylethynyl}-
pyridin-2-yl)-3-cyclopropylurea;
N -(5-{ 5-[N '-(2-(Chloro-6-methylbenzoyl)hydrazinocarbonyl]-2-methylphenylethynyl}-
pyridin-2-yl)-2,2,2-trifluoroacetamide;
Cyclopropanecarboxylic acid [5-(2-methyl-5-[N '-[4-(4-methylpiperazin-l-yl-methyl)-3-
trifluoromethylbenzoyl]-hydrazinocarbonyl}phenylethynyl)pyridin-2-yl]amide;
N -(5-{ 5-[N '-(2-(Chloro-6-methylbenzoyl)hydrazinocarbonyl]-2-methylphenylethynyl}-
pyridin-2-yl)butyramide ;
In a preferred embodiment, the compound of Formula I is selected from a group comprising:
Cyclopropanecarboxylic acid (5-{ 5-[N -(2-chloro-6-methylbenzoyl)hydrazinocarbonyl]-2
methyl-phenylethynyl }-pyridin-2-yl)amide;
Cyclopropanecarboxylic acid [5-(2-methyl-5-{N '-[4-(4-methylpiperazin- 1
ylmethyl)benzoyl]-hydrazinocarbonyl }phenylethynyl)pyridin-2-yl]amide ;
Cyclopropanecarboxylic acid [5-(2-methyl-5-{N '-[3-(4-methylimidazol- l-yl)-5
trifluoromemylbenzoyl]-hydrazinocarbonyl}phenylethynyl)pyridin-2-yl]amide;
Cyclopropanecarboxylic acid [5-(2-methyl-5-[N '-[4-(4-methylpiperazin-l-yl-methyl)-3
trifluoromemylbenzoyl]-hydrazinocarbonyl}phenylethynyl)pyridin-2-yl]amide;
In one embodiment of the process for preparing compounds of the present invention, the
The process involves condensation of the hydrazide of Formula III with the diarylacetylenic
compound of Formula II, wherein Rl R2 & 3 are as previously defined for compound of
Formula I, and L is a leaving group. Preferably the condensation reaction is carried out in the
presence of an inert base and/or a suitable catalyst in an inert solvent.
The compound of the Formula II in activated form (i.e. -C(O)-L) is especially an acid halide,
an ester an anhydride or a cyclic imide.
The esters of Formula II can be selected from, for example vinyl esters obtainable, for
example, by transesterification of a corresponding ester with vinyl acetate, carbamoylvinyl
esters or by treatment with a C2-5 alkoxyacetylene. Other active esters are of the amidino
type, such as N,N'-disubstituted amidino esters (obtainable, for example, by treatment of the
corresponding acid with a suitable N,N'-disubstituted carbodiimide, for example, N,N'-
dicyclohexylcarbodiimide), or N,N'-disubstituted amidino esters (obtainable, for example,
treatment of the corresponding acid with N,N-disubstituted cyanamide), suitable aryl esters,
especially phenyl esters suitably substituted by electron-attracting substituents (obtainable,
for example, by treatment of the corresponding acid with a suitably substituted phenol, for
example, 4-nitrophenol, 2,4,5-trichlorophenol, or 2,3,4,5,6-pentachloro-phenol in the
presence of a condensation agent, such as N,N'-dicyclohexylcarbodiimide). Other suitable
active esters include cyanomethyl esters (obtainable, for example, by treatment of the
corresponding acid with chloroacetonitrile in the presence of a base), thio esters, especially
unsubstituted or substituted, for example nitro-substituted, phenylthio esters (obtainable, for
example, by treatment of the corresponding acid with unsubstituted or substituted, for
example nitro-substituted, thiophenols, inter alia by the anhydride or carbodiimide method),
amino or amido esters (obtainable, for example, by treatment of the corresponding acid with
an N-hydroxyamino or N-hydroxyamido compound, for example, N-hydroxysuccinimide, Nhydroxypiperidine,
N-hydroxyphthalimide or 1-hydroxybenzotriazole, for example by the
anhydride or carbodiimide method).
The anhydrides of the compound of Formula II may be formed with carbonic acid
semiderivatives, such as corresponding esters, for example carbonic acid alkyl semiesters
(obtainable, for example, by treatment of the corresponding acid with haloformic, such as
chloroformic, acid); alkyl esters or with a l-alkoxycarbonyl-2-alkoxy-l,2-dihydroquinoline,
for example l-alkoxycarbonyl-2-ethoxy-l,2-dihydroquinoline; anhydrides with
dihalogenated, especially dichlorinated phosphoric acid (obtainable, for example, by
treatment of the corresponding acid with phosphorus oxychloride), or anhydrides with
organic acids, such as mixed anhydrides with organic carboxylic acids (obtainable, for
example, by treatment of the corresponding acid with an unsubstituted or substituted acyl
halide, for example, pivaloyl chloride or trifluoroacetyl chloride). Anhydrides may also be
with organic sulfonic acids (obtainable, for example, by treatment of a salt, such as an alkali
metal salt, of the corresponding acid, with a suitable organic sulfonic acid halide, such as
alkane- or aryl-, for example methane- or p-toluenesulfonyl chloride), or with organic
phosphonic acids (obtainable, for example, by treatment of the corresponding acid with a
suitable organic phosphonic anhydride or phosphonic cyanide).
Suitable cyclic amides are especially amides with five-membered diazacycles of aromatic
character, such as with imidazoles (obtainable, for example, by treatment of the
corresponding acid with N,N '-carbonyldiimidazole; imidazolide method), or pyrazoles, for
example 3,5-dimethylpyrazole.
Formula II in activated form is preferably generated in situ from the corresponding acid (i.e.
when L = OH). For example, N,N '-disubstituted amidino esters can be formed in situ by
reacting a mixture of the acid of Formula II (i.e. when L = OH) and the compound of
Formula III in the presence of a suitable condensating agent for example N,N'-
dicyclohexylcarbodiimide. Reactive mixed anhydrides of the acid may also be generated with
an organic phosphonic acid in situ by reaction with propylphosphonic anhydride or
diethylcyanophosphonate in the presence of suitable base for e.g. triethylamine or 4-(N,Ndimethylamino)pyridine.
The reaction may be carried out in a manner known per se, the
reaction conditions being dependent especially on how the acid group of Formula II has been
activated, usually in the presence of a suitable solvent or diluent or of a mixture thereof and,
if necessary, in the presence of a condensation agent. Customary condensation agents are, for
example, carbodiimides such as N,N '-diethyl-, N,N '-diisopropyl, N,N '-dicyclohexyl- or Nethyl-N
'-(3-diethylaminopropyl)-carbodiimide; suitable carbonyl compounds, for example
carbonyldiimidazole, or 1,2-oxazolium compounds, for example 2-ethyl-5-phenyl-l,2-
oxazolium 3'-sulfonate and 2-teri-butyl-5-methyl-isoxazolium perchlorate, or a suitable
acylamino compound, for example, 2-ethoxy-l-ethoxycarbonyl-l,2-dihydroquinoline. The
bases normally used for aiding the condensation are either inorganic bases such as sodium or
potassium carbonate, or organic bases, such as pyridine, triethyamine, N,Ndiisopropylethylamine
or 4-(dimethylamino)pyridine.
Alternatively, the preparation of compounds of Formula I in the present invention can be
performed by reacting compounds of Formula IV with the compounds of Formula V, Scheme
2, using similar condensation methods as described above (for Scheme 1); wherein R , , R
Scheme 2
Compounds of Formula IV can be prepared from compounds of Formula II and hydrazine of
Formula Ilia, Scheme 3, utilizing the coupling procedures as described for Scheme 1, vide
supra.
Formula II Formula IV
Scheme 3
In a similar manner the compounds of Formula III can be prepared by the reaction of
compounds of hydrazine hydrate and Formula V, Scheme 4.
Formula V Formula III
Scheme 4
The compounds of Formula II can be prepared by methods known in the literature. Suitable
approaches for the preparation of the compounds for Formula II are provided in Scheme 5.
Scheme 5
As illustrated in Scheme 5, the ethynyl moiety of pyridine of Formula VIII is coupled with
phenyl ring of Formula IX, or the ethynyl moiety of phenyl ring of Formula VII is coupled
with pyridine ring of Formula VI; wherein 'W represents a leaving group like OTf, CI, Br or
I, preferably Br or I; L represent OH or O-alkyl. The coupling reaction can be performed
using well known prior art methods, such as metal catalyzed coupling reactions, for example
a palladium catalyzed Sonogashira coupling reaction (refer Malleron, J-L., Fiaud, J-C,
Legros, J-Y. Handbook of Palladium Catalyzed Organic Reactions, San Diego: Academic
Press, 1997). Alternatively, the compound of Formula II is prepared from the vicinal dihalo
compound of Formula Ila (where Z represents halo) by tandem dehydrohalogenations.
A strategy similar to the above can be utilized for the synthesis of compounds of Formula I as
shown in Scheme 6, i.e. coupling the ethynyl moiety of pyridine ring of Formula VIII to the
phenyl ring in Formula XI, or the ethynyl moiety of phenyl ring of Formula X to the pyridine
Scheme 6
The compounds of Formula X & Formula XI can be conveniently prepared by acylation of
the hydrazide of Formula III with compounds of Formula VII & Formula IX, respectively, as
shown in Scheme 7; wherein L, W, X, R , R2 and R 3 are as previously defined.
Scheme 7
The compounds of Formula I can also be prepared by acylation of the amine of Formula XII
as shown in Scheme 8.
Scheme 8
Where the above starting compounds VI, VII, VIII and IX contain functional groups that may
interfere with the coupling reaction, are protected using suitable protecting groups that can be
conveniently removed later.
Characterization data for some of the representative compounds of Formula I are provided in
the Table-1.
Table-1
benzoyl)hydrazinocarbonyl] -2- 1H), 7.40-7.43 (m, 2H), 7.56 (d, IH, 7 = 8.1 Hz), 7.60-7.68 (m,
methyl-phenylethynyl }-pyridin-2- IH), 7.95 (m, IH), 8.14-8.18 (m, 3H), 8.69 (m, IH), 9.99 (br,
yl)-2-dimethylaminoacetamide IH), 10.53 (s, IH), 10.72 (s, IH), 11.46(s, IH).
iV-(5-{5-[iV-(2-Chloro-6- 2.52 (s, 3H), 2.60 (s, 3H), 2.88 (s, 3H), 3.07 (m, 2H), 3.70-3.73
methylbenzoyl)hydrazinocarbonyl (m, 8H), 7.31-7.34 (m, IH), 7.39-7.44 (m, 2H), 7.56 (d, IH, 7 =
]-2-methyl-phenylethynyl }- 8.1 Hz), 7.95 (d, IH, 7 = 8.1 Hz), 8.09 (d, IH, 7 = 8.0 Hz), 8.18-
pyridin-2-yl)-3-(4-methyl- 8.21 (m, 2H), 8.64 (s, IH), 10.53 (s, IH), 10.72 (s, IH), 11.09 (s,
piperazin- 1-yl)propionamide 1H),1 1.80 (m, 2H).
N-(5- {5-[iV'-(2-Chloro-6-methyl- 1.70-1.73 (m, 2H), 2.00 (m, 2H), 2.27-2.33 (m, 2H), 2.52 (s, 3H),
benzoyl)hydrazinocarbonyl] -2- 2.60 (s, 3H), 2.66 (br, 5H), 2.91-2.97 (m, 3H), 3.03-3.06 (m, 3H),
methyl-phenylethynyl }-pyridin-2- 7.32-7.33 (m, IH), 7.38-7.39 (m, 2H), 7.55 (d, IH, 7 = 8.0 Hz),
yl)-2-(4-dimethylamino piperidin- 7.94 (d, IH, 7 = 8.0 Hz), 8.08-8.1 1 (m, IH), 8.19 (s, IH), 8.23(d,
l-yl)acetamide IH, 7 = 8.6 Hz), 8.63 (m, IH), 10.26 (s, IH), 10.53 (s, IH),
10.72(s, IH).
N-(5- {5-[iV'-(2-Chloro-6-methyl- 2.55 (s, 3H), 2.61 (s, 3H), 2.72-2.86 (m, 6H), 2.93-3.00 (m, 2H),
benzoyl)hydrazine carbonyl]-2- 4.10 (br, 2H), 4.43 (br, 2H), 7.32-7.38 (m, IH), 7.40-7.43 (m,
methyl-phenyl ethynyl}-pyridin-2- 2H), 7.56 (d, IH, 7 = 8.0 Hz), 7.94-7.97 (m, IH), 8.14-8.19 (m,
yl)-2-(3-dimethylaminopyrrolidin- 3H), 8.69 (s, IH), 10.54 (s, IH), 1072 (s, IH), 11.45(s, IH).
l-yl)acetamide
5- {5-[iV-(2-Chloro-6-methyl- 2.18 (s, 3H), 2.52 (s, 3H), 2.60 (s, 3H), 7.33 ( m, IH), 7.40-7.41 (
benzoyl)hydrazinocarbonyl] -2- m, 2H), 7.55 (d, IH, 7 = 8.1 Hz), 7.93-7.95 ( m, IH), 8.03-8.06 (
methyl-phenylethynyl }-pyridin-2- m, IH), 8.18-8.23 ( m, 2H), 8.61 ( m, IH), 10.53 ( s, IH), 10.72
yl)acetamide (s, IH), 10.82 (s, IH).
Cyclopropanecarboxylic acid [5- 0.88-0.90 (m, 4H), 1.36 (m,lH), 2.03 (m, IH), 2.41 (br, 6H),
(2-methyl-5- {iV'-[4-(4-methyl 2.69-2.72 (m, 3H), 2.92-2.97 (m, 3H), 3.61 (br, 3H), 7.50-7.55
piperazin- 1-ylmethyl)benzoyl] - (m, 3H), 7.87-7.92 (m, 3H), 8.00-8.02 (m, IH), 8.09 (s, IH),
hydrazinocarbonyl Jphenylethynyl 8.16 (d, IH, 7 = 8.6 Hz), 8.58(s, IH), 10.70 (br, 2H), 11.15 (s,
)pyridin-2-yl] amide IH).
Cyclopropanecarboxylic acid [5- 0.73-0.74 (m, 4H), 1.92 (m,lH), 2.08 (s, 3H), 2.45 (s, 3H), 7.41
(2-methyl-5-{iV'-[3-(4-methyl (d, IH, 7 = 8.0 Hz), 7.62 (br, IH), 7.77 (d, IH, 7 = 7.8 Hz), 7.87-
imidazol-l-yl)-5-trifluoromethyl 7.89 (m, IH), 7.99 (s, IH), 8.05 (m, 2H), 8.19 (s, IH), 8.31(s,
benzoyl]-hydrazinocarbonyl } 2H), 8.46 (s, IH), 10.66 (s, IH), 10.80 (s, IH), 10.96 (s, IH).
phenylethynyl)pyridin-2- yl]amide
l-(5-{5-[iV'-(2-Chloro-6- 0.5 1-0.72 (m, 4H), 2.38 (s, 3H), 2.55 (s, 3H), 3.51 (m, IH), 7.33-
methylbenzoyl)hydrazinocarbonyl 7.39 (m, 3H), 7.55-7.64 (m, 2H), 7.93 (m, 3H), 8.15(s, IH), 8.48
]-2-methylphenylethynyl }- (s, IH), 9.40 (s, IH), 10.52 (s, IH), 10.70 (s, IH).
pyridin-2-yl)-3-cyclopropylurea
iV-(5-{5-[iV'-(2-(Chloro-6-methyl 2.52 (s, 3H), 2.62 (s, 3H), 7.33 (m, IH), 7.40-7.41 (m, 2H), 7.57
benzoyl)hydrazinocarbonyl] -2- (d, IH, 7 = 9.2 Hz), 7.96 (d, IH, 7 = 8.0 Hz), 8.12 (d, IH, 7 = 8.6
methylphenylethynyl }-pyridin-2- Hz), 8.19 (s, IH), 8.21 (s, IH), 8.76 (s, IH), 10.53 (s, IH), 10.72
yl)-2,2,2-trifluoroacetamide (s, 1H), 12.34 (s, 1H).
I.l l Cyclopropanecarboxylic acid [5- 0.89-0.90 (m, 4H), 2.09 (m, 1H), 2.23 (s, 3H), 2.38-2.5 1 (br, 6H),
(2-methyl-5- [N '-[4- (4-methyl 2.61 (br, 5H), 3.22 (m, 2H), 7.56 (d, 1H, J = 8.2 Hz), 7.91-7.93
piperazin-l-yl-methyl)-3-trifluoro (m, 1H) ,7.99 (d, 2H, J = 8.3 Hz), 8.02-8.05 (m, 1H), 8.14 (m,
methylbenzoyl] -hydrazino 1H), 8.20 (m, 1H), 8.22(m, 1H), 8.24-8.26 (m, 1H), 8.29 (m, 1H),
carbon ylJphenylethyn yl)pyridin- 8.62 (m, 1H), 10.70 (s, 1H), 10.80 (s, 1H), 11. 12 (s, 1H).
2-yl] amide
1.12 iV-(5-{5-[iV'-(2-(Chloro-6- 0.96 (t, 3H), 1.65 (m, 2H), 2.47 (t, 2H), 2.52 (s, 3H), 2.60 (s, 3H),
methylbenzoyl)hydrazinocarbonyl 7.3 1-7.35 (m, 1H), 7.38-7.43 (m, 2H), 7.53 (d, 1H, J = 8.1 Hz),
]-2-methylphenylethynyl }- 7.92-7.95 (m, 1H), 8.02-8.05 (m, 1H), 8.18 (m, 1H), 8.22 (m,
pyridin-2-yl)butyramide 1H), 8.62 (m, 1H), 10.52 (s, 1H), 10.71 (s, 1H), 10.76 (s, 1H).
The compounds of the present invention can be used to treat disorders mediated by tyrosine
kinases.
The following examples serve to illustrate the invention without limiting the invention in its
scope. The methods of preparing some of the starting compounds used in the examples are
described as reference examples.
EXAMPLES
Example 1: Preparation of cyclopropanecarboxylic acid (5-{5-[N -(2-chloro-6-
methylbenzoyl)hydrazinocarbonyl]-2-methyl-phenylethynyl}-pyridin-2-yl)amide (Formula
A mixture of 3-({6-[(cyclopropylcarbonyl)amino]pyridin-3-yl}ethynyl)-4-methylbenzoic
acid, N-(3-dimemylaminopropyl)-N'-ethylcarbodiirnide hydrochloride and 1-
hydroxybenzotriazole in N,N-dimethylformamide was stirred at ambient temperature for lhr.
2-chloro-6-methylbenzohydrazide was added and the mixture stirred for 12hrs at ambient
temperature. Concentration and trituration of the residue with water produced a solid which
was filtered, washed with water and finally dried in vacuo to get a white solid.
Example 2 : N-(5-{5-[N -(2-chloro-6-methylbenzoyl)hydrazinocarbonyl]-2-methylphenylethynyl
}-pyridin-2-yl)-2-dimethylaminoacetamide (Formula 1.2)
Starting from 3-[(6-{ [(dimethylamino)acetyl]amino}pyridin-3-yl)ethynyl]-4-methylbenzoic
acid the compound of Formula 1.2 was prepared by the process disclosed in example 1.
Example 3: N-(5- {5-[N -(2-Chloro-6-methylbenzoyl)hydrazinocarbonyl]-2-methylStarting
from compound of Formula II-3, the compound of Formula 1.3 was prepared by the
process disclosed in example 1.
Example 4 : N-(5-{5-[N '-(2-Chloro-6-methyl-benzoyl)hydrazinocarbonyl]-2-methylStarting
from compound of Formula II-4, the compound of Formula 1.4 was prepared by the
process disclosed in example 1.
Example 5: N-(5-{5-[N '-(2-Chloro-6-methyl-benzoyl)hydrazinocarbonyl]-2-methylphenylethynyl
}-pyridin-2-yl)-2-(3-dimethylaminopyrrolidin-1-yl)acetamide (Formula 1.5):
Starting from compound of Formula II-5, the compound of Formula 1.5 was prepared by the
process disclosed in example 1.
Example 6: N-(5-{5-[N-(2-Chloro-6-methyl-benzoyl)hydrazinocarbonyl]-2-methylFromula
11-6
Starting from 3-{[6-(acetylamino)pyridin-3-yl]ethynyl}-4-methylbenzoic acid, the compound
of Formula 1.6 was prepared by the process disclosed in example 1.
Example 7 : l-(5-{5 -[N-(2-Chloro-6-methyl-benzoyl)-hydrazinocarbonyl]-2-methylphenylethynyl}-pyridin-2-yl)-3-cyclopropyl
urea (1.9)
A solution of 2-amino-5-iodopyridine in DMF was added to a stirred mixture of
diphenylphosphoryl azide, cyclopropane carboxylic acid and triethyl amine in toluene at 25
to 30 °C and stirred at 120-125 °C for 3 hrs. The reaction mixture was concentrated and the
crude product was purified by flash chromatography on silica gel (elution with 20 % ethyl
acetate in hexane) to provide l-cyclopropyl-3-(5-iodo-pyridin-2-yl) urea.
A mixture of 2-chloro-6-methylbenzoic acid N'-(3-ethynyl-4-methyl benzoyl) hydrazide, 1-
cyclopropyl-3-(5-iodo-pyridin-2-yl)urea, Pd(Pd)2Cl2), Cul and triethylamine in DMF was
heated at 90 °C for 16 hrs under nitrogen atmosphere. The reaction mixture was concentrated
and the crude product was purified by flash chromatography on silica gel (elution with 2%
Methanol in MDC) to provide the title compound.
PHARMACOLOGICAL ACTIVITY
In-vitro Cell Proliferation Assay
K562/U937 cells (2x104 per well) were incubated with the test compounds/vehicle in a total
volume of 200 of media at 37oC with 5% C02. On day 4, 20 MTT 5mg/ml was added
and the cells were incubated for 4-5hours followed by addition of Ι ΟΟ of 10% SDS
prepared in 0.06Ν HC1. The cells were incubated overnight at 37oC with 5% C02. On Day
5 the optical density was measured at 570nm with 630nm as reference wavelength. The
optical density in the vehicle treated wells was compared with that of the test compound
treated wells.
Results for the representative compounds of Formula I are provided in Table-2.
Table-2
ND: Not determined
Mutated Abl (T315I) (human)Kinase
In a final reaction volume of 25 , mutated Abl (T315I) (human) (5-10 mU) is incubated
with 8 mM MOPS pH7.0, 0.2 mM EDTA, 50µΜ EAIYAAPFAKKK, lOmM Mg(OAc)2 and
[γ-33Ρ-ΑΤΡ ] [specific activity approx. 500 cpm/pmol, concentration as required). The
reaction is initiated by the addition of the MgATP mix. After incubation for 40 minutes at
room temperature, the reaction is stopped by the addition of 5 of a 3% phosphoric acid
solution. 10 of the reaction is then spotted onto a P30 filtermat and washed three times for
5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation
counting.
The compounds of Formula I showed good inhibitory action on the mutated Abl T315I cell
line. Activity data on the mutated Abl T315I cell line for some representative compound is
provided in Table-3.
Table-3
Claims:
1. A compound of Formula I
Formula I
and pharmaceutically acceptable salts thereof wherein,
R is selected from - C3
- cycloalkyl, -Ci_ alkyl-N H2
, -Ci_ alkyl-N H(Ci_ alkyl), -Ci_
alkyl-N(Ci- alkyl)
2
,-C 3
_6 alkenyl, -C3
-6 alkynyl, -Ci_6 alkyl, -C(O) heterocyclyl,
heterocyclyl-Ci_6 alkyl, -Ci_6 haloalkyl, -NH(C 3
_ cycloalkyl) and heterocyclyl
wherein heterocyclyl is 5-6 membered non-aromatic ring containing 1 to 2 heteroatom
individually selected from N, O or S;
R is optionally substituted with one or more group independently selected from - C1-4
alkyl, halogen, CN, NH(d_ alkyl), N(d_ alkyl) 2
, NH2
and hydroxy;
R2 and R3 are individually selected from a group of hydrogen, halogen, -C1-4 alkyl, -
Ci_4 haloalkyl, heterocyclyl-d^ alkyl and heteroaryl wherein, heterocyclyl is 5-6
membered non-aromatic ring containing 1 to 2 heteroatom independently selected
from N, O or S and is unsubstituted or substituted with - C1-4 alkyl and heteroaryl is 5-
6 membered aromatic ring containing 1 to 2 heteroatom independently selected from
N, O or S and is unsubstituted or substituted with - C1-4 alkyl.
2. The compound of Formula I of claim 1 wherein, Ri is - C3
-6 cycloalkyl;
R2 and R3 are independently selected from a group consisting of hydrogen, halogen, -
Ci_4 alkyl or -C1-4 haloalkyl.
3. The compound of Formula I as in claim 1 selected from a group of:
Cyclopropanecarboxylic acid (5-{5 -[N -(2-chloro-6-
methylbenzoyl)hydrazinocarbonyl] -2-methyl-phenylethynyl }-pyridin-2-yl)amide ;
N-(5-{5 -[N -(2-chloro-6-methylbenzoyl)hydrazinocarbonyl]-2-methylphenylethynyl
}-pyridin-2-yl)-2-dimethylaminoacetamide;
N -(5-{ 5-[N -(2-Chloro-6-methylbenzoyl)hydrazinocarbonyl]-2-methylphenylethynyl
}-pyridin-2-yl)-3-(4-methyl-piperazin- 1-yl)propionamide;
N -(5-{ 5-[N '-(2-Chloro-6-methyl-benzoyl)hydrazinocarbonyl]-2-methylphenylethynyl
}-pyridin-2-yl)-2-(4-dimethylaminopiperidin- 1-yl)acetamide;
N -(5-{ 5-[N '-(2-Chloro-6-methyl-benzoyl)hydrazinocarbonyl]-2-methylphenylethynyl
}-pyridin-2-yl)-2-(3-dimethylaminopyrrolidin- 1-yl)acetamide;
N -(5-{ 5-[N -(2-Chloro-6-methyl-benzoyl)hydrazinocarbonyl]-2-methylphenylethynyl
}-pyridin-2-yl)acetamide;
Cyclopropanecarboxylic acid [5-(2-methyl-5-{N '-[4-(4-methylpiperazin- 1-
ylmethyl)benzoyl]-hydrazinocarbonyl }phenylethynyl)pyridin-2-yl] amide ;
Cyclopropanecarboxylic acid [5-(2-methyl-5-{N '-[3-(4-methylimidazol-l-yl)-5-
trifluoromethylbenzoyl]-hydrazinocarbonyl}phenylethynyl)pyridin-2-yl]amide;
1-(5- {5-[N '-(2-Chloro-6-methylbenzoyl)hydrazinocarbonyl] -2-
methylphenylethynyl }-pyridin-2-yl)-3-cyclopropylurea;
N -(5-{ 5-[N '-(2-(Chloro-6-methylbenzoyl)hydrazinocarbonyl]-2-
methylphenylethynyl }-pyridin-2-yl)-2,2,2-trifluoroacetamide;
Cyclopropanecarboxylic acid [5-(2-methyl-5-[N '-[4-(4-methylpiperazin-l-yl-methyl)-
3-trifluoromethylbenzoyl]-hydrazinocarbonyl}phenylethynyl)pyridin-2-yl]amide;
N -(5-{ 5-[N '-(2-(Chloro-6-methylbenzoyl)hydrazinocarbonyl]-2-
methylphenylethynyl }-pyridin-2-yl)butyramide ;
The compound of Formula I as in claim 3 selected from a group of:
Cyclopropanecarboxylic acid (5-{ 5-[N -(2-chloro-6-
methylbenzoyl)hydrazinocarbonyl]-2-methyl-phenylethynyl }-pyridin-2-yl)amide;
Cyclopropanecarboxylic acid [5-(2-methyl-5-{N '-[4-(4-methylpiperazin- 1-
ylmethyl)benzoyl]-hydrazinocarbonyl }phenylethynyl)pyridin-2-yl] amide ;
Cyclopropanecarboxylic acid [5-(2-methyl-5-{N '-[3-(4-methylimidazol-l-yl)-5-
trifluoromethylbenzoyl]-hydrazinocarbonyl}phenylethynyl)pyridin-2-yl]amide;
Cyclopropanecarboxylic acid [5-(2-methyl-5-[N '-[4-(4-methylpiperazin-l-yl-methyl)-
3-trifluoromethylbenzoyl]-hydrazinocarbonyl}phenylethynyl)pyridin-2-yl]amide.