FIELD OF THE INVENTION
The invention relates to novel fused heterocycles and pharmaceutically acceptable
salts thereof and compositions including therapeutically and prophylactically effective
amounts of such compounds and pharmaceutically acceptable salts thereof usefu5 l
as a therapeutic and/or preventive agent for treating or preventing diseases and
disorders associated abnormal cell growth, for example preventing or treating cancer
or tumor growth. The invention also relates to methods of manufacturing thereof.
10 BACKGROUND OF THE INVENTION
Cancer is the genetic malfunctioning of the normal body cells resulting in
unregulated, uncontrollable and abnormal growth of the cells. It is the third largest
deadly disease. The various internal as well as external factors causes genetic
15 changes forming cancerous cells which do not replicate. grow, function and die
according to the information of DNA and keep on growing without any end to
become immortal1. Thus, genetic desregulation leads to an unregulated mechanism
for growth, survival, proliferation and migration of cancerous cells.
20 The hysterical growth of cells leads to the formation of a mass of abnormal cells
known as cancer cells or tumor cells. Cancer cells that may be benign or malignant
Benign tumors are static. confined and may remain in dormant state or can break
from this primary site. Passing through the blood vessels, capillaries and lymphatic
systems. going in surrounding tissue where they again replicate in uncontrolled
25 manner, therefore, abnormal growth cycle take places e.g, chondroma. However, the
malignant tumors are cancerous, dynamic, life threatening and grow in more than
one site in the body e.g, blood cancer2.
Various cellular phenomena involved in cancer are release of their own growth
30 enhancing factors like tumor growth factor and platelet derived growth factor, change
in receptors expression, persistent inflammation, suppression of inhibitory signals,
inactivation of tumor suppression genes, cell cycle deregulation, inhibition of
programmed cell death, alteration in telomerase activity and angiogenesis. The
hallmarks of cancer depict biological proficiencies developed during the progress of
3
human tumors. These are evading growth suppressors, enabling replicative
immortality, sustaining proliferative signaling, angiogenesis, resisting cell death,
activating invasion/metastasis, reprogramming of energy metabolism and evading
immune destruction3,4
5
Cancer management is based on the three basic therapies: curative, palliative and
adjuvant therapy. Curative therapy provides a cure for cancer by total obliteration of
cancer cells e.g. in testicular tumors5. Palliative therapy caters assuagement of
symptoms to increase the survival and bettered quality of life via turning away the
10 life-threatening toxicity6. Adjuvant therapy involves the surgery for eradication of
microscopic cancer e.g. breast cancer & colorectal cancer7.
As cancer involves multiple pathways and cellular mediators/targets therefore, a
number of drugs are designed1,8 and synthesized to target various cellular mediators
15 like cytokines for e.g. Interleukin 8, endothelium growth factor, enzymes like protein
kinase, DNA, hormones like glucocorticoides, growth hormones, androgens,
estrogens, aromatase, 5-α reductase, progestins, various phases of cell cycle and
cellular metabolites etc. Conventional anticancer agents are based on various
cellular targets involved in cellular growth, development, differentiation, invasion and
20 metastasis acting through various mechanisms9. The metabolites like purines,
pyrimidines and folic acid etc. are involved in synthesis of base pairs like thymidine
monophosphate and others. These base pairs get integrated into the DNA and RNA
and involves in body regulation. Antimetabolites are the compounds which bear a
resemblance to normal metabolites and inhibit their functions10. The tubulin is a
25 protein which on assembling forms microtubules. These microtubules assist and are
involved in morphological characterization, spindle formation or mitosis and thus in
cell division. Microtubules are dynamic in nature undergoing nucleation followed by
assembling in head to tail fashion and further dissembling. Paclitaxel and vinblastine
target this protein and are antitubulin agents11. Apoptosis is an essential
30 phenomenon in cell regulation and another target. The imbalance between apoptosis
promoter and apoptosis suppresser factors is there in tumor cells. Antiapoptopic
factors are bcl and bax. These are activated more in tumor and thus there is no cell
death. Gambogic acid is the natural marine derived agent used in apoptosis12.
Topoisomerases are the loops of DNA which are isomers of each other and involved
4
in recoiling and demotion of DNA13,14. Topoisomerase -1 antagonist 2',3'-
Dideoxyadenosine-5'-triphosphate Lithium Salt is an inhibitor of chain elongation
usually catalyzed by DNA polymerase I. Camptothecin is also a Topoisomerase-1
inhibitor. Doxorubicin is topoisomerase II inhibitor. Histone deacetylators are other
potential anticancer agents. Acetyl group addition and removal to histones leads 5 to
the formation of model of modifications that is critical to the activity of DNA. This is
called “histone code”. Entinostat is the histone deacetylating agent. Excessive and
abnormal growth involves various growth factors like epidermal growth factor,
vascular endothelial growth factor and insulin like growth factor. These act on their
10 respective receptor sites. They all enhance tumor growth via increasing proliferation,
invasion, growth and inhibiting apoptosis15. Enzymes functioning as degraders of
regulatory proteins are proteasomes16. They have been found to be involved in cellcycle,
protein synthesis, and cell death. An approved antagonist of proteosomes is
bortezomib17. The formation of new blood vessels from already present vessels is
15 called angiogenesis. Tumor cells are rapidly dividing cells and thus needs nutrition
as well as oxygen in a large scale for survival. The antiangiogenic drugs like
endostatin thus inhibit the supply of oxygen and nutrition18.
However, the various anticancer agents have one or other side effects. The
20 alkylating agents like cyclophosphamide have side effects like haematurea,
pulmonary toxicity, haemorragic cystis etc. Cisplatin causes nephrotoxicity,
ototoxicity and peripheral neuritis. Procarbazine has disulfiram like action19. The
antimetabolites like methotrexate cause bone marrow depression, mucositis and folic
acid deficiency. Cytarabine causes cerebeller dysfunction and peripheral neuritis. 5-
25 Flourouracil causes hand and foot syndrome, alopecia, hyperpigmentation,
neurolytic deficits and bone marrow depression20. Plant alkaloid like vinblastine and
vincristine causes foot drop, ataxia, loss of refluxes, paresthesias and severe
neurotoxicity. Taxales causes neutrocytopenia and peripheral neuropathy. Antibiotics
like doxorubicin cause cardiac toxicity, cardiac arrhythmias and alopecia.
30 Glucocorticoides like tamoxifen causes hot flushes, vaginal bleeding and venous
thrombosis. GnRH analogues cause gynacomastia, haematurea and impotance.
Aromatase inhibitors cause bone pain and peripheral edema. Resistance to cancer
chemotherapy is due to overexpression of ABC (ATP binding cassette proteins)
transporters21 and GSTP1-1 (Glutathione-s- transferase of π class only) multiple
5
drug resistance caused by HIF- 1 α induced multidrug resistance-1 gene, MDR
colligated with ABCG2 and MRP2 and medroxyprogesterone acetate- impelled
escalation in breast cancer risk via cross-talk with growth factors involving
progesterone receptor membrane component 22.
5
In general most of the anticancer drugs have less specificity, less efficiency or more
side effects. Further the problems of cross-talk and multiple drug resistance
associated with the use of anticancer drugs necessitated researchers either develop
modifications in existing drugs or design new drug molecules or to identify more
10 targets for anticancer drugs.
Imidazoquinoxaline23,24 and imidazodiazepine25 skeletons are widely used in practice
due to their broad applications in drug discovery. In particular, imidazo[1,2-
a]quinoxaline derivatives possess anticancer (antitubulin; EAPBo503),26 antiallergic
15 (dazoquinast),23 anticonvulsant (LU-73068),27 and kinase inhibitory28 (BMS-34554129
and AX-13587) activities
The present invention overcomes the above-discussed limitations. Considering the
problems of cross-talk and multiple drug resistance associated with the use of
20 anticancer the inventors have designed and synthesized new drug molecules with
better potency/efficacy and lesser toxicity. In particular, the novel fused heterocycles
and the novel process of synthesis thereof according to the present invention is of
immense importance in the area of new drug development.
25 SUMMARY & OBJECTS OF THE INVENTION
One aspect of the present invention relates to novel fused heterocycles compounds
represented by Formula (I), Formula (II) and Formula (III) and pharmaceutically
acceptable salts thereof.
30
6
Y'
G
N N
Y
X
Formula II
Formula I
R1
R2
R3
R4
X1
N
N
Y
G
Y'
Y3
Y3
Y2
Y2
Y1
Y4
Y5
Y1
Y5
R1
R2
R3
R4
Y4
R
X2
A
B
C
A
B
C
Another aspect of the present invention relates to compositions including
therapeutically and prophylactically effective amounts of such novel fused
5 heterocycles (Formula I, Formula II and Formula III) and pharmaceutically
acceptable salts thereof.
The invention further relates to novel synthetic route(s) providing synthesis of novel
fused heterocycles (Formula I and Formula II).
10
Yet another aspect of the present invention relates to methods for treating or
preventing diseases and disorders associated with abnormal cell growth, for
example preventing or treating cancer or tumor growth, which methods include
administrating to a mammal in need thereof a composition comprising a
15 therapeutically or prophylactically effective amount of a compound of the invention or
a pharmaceutically acceptable salt thereof.
An object of the present invention is to provide novel fused heterocycles and the
novel process of synthesis thereof which overcomes the limitations of prior art.
20
Another object of the present invention is to provide a novel fused and/or ring
expanded heterocyclics which are more efficacious, potent and less toxic.
Another object of the present invention is to provide novel fused and/or ring
25 expanded heterocyclics whose purine/pyrimidine mimicking structure can act as
DNA intercalaters/enzyme inhibitors/signaling inhibitors/transcription factor inhibitors
which is/are useful to inhibit the cellular pathways in cancer.
7
Still another object of the present invention is to develop new molecular entities as
capable drug candidates for pharmaceutical industry and in particular to address the
issue of cross-talk and multiple drug resistance associated with the use of
anticancer.
5
Yet another object of the present invention is to provide a simple process for the
formulation of novel fused heterocycles having structurally complex architectures.
Yet another object of the present invention is to novel fused heterocycles and their
10 synthesis which is of immense importance in the area of new drug development for
treating or preventing disease or disorder of the respiratory, urinary and
gastrointestinal systems.
Yet another object of the present invention is to provide a novel synthesis of novel
15 fused heterocycles that can be carried out in the existing manufacturing facilities
without incurring any additional or substantial costs.
DETAILED DESCRIPTION OF THE INVENTION
20 The present invention relates to novel fused heterocycles compounds represented
by Formula (I) and Formula (II) and pharmaceutically acceptable salts thereof:
Y'
G
N N
Y
X
Formula II
Formula I
R1
R2
R3
R4
X1
N
N
Y
G
Y'
Y3
Y3
Y2
Y2
Y1
Y4
Y5
Y1
Y5
R1
R2
R3
R4
Y4
R
X2
25 wherein, G, R1, R2, R3, R4, X1, X2, X, Y, Y΄, Y1, Y2, Y3, Y4 and Y5 are defined as
below.
8
R1, R2, R3, and R4 can each independently be hydrogen, alkyl, alkenyl, alkynyl,
aralkyl, heteroarylalkyl, heterocyclylalkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl;
Y can be no atom; O or S or –NR (wherein R can be alkyl, alkenyl, alkynyl, aralkyl,
heteroarylalkyl, heterocyclylalkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl); Y1, Y2,
Y3, Y4 and Y4 each independently can be hydrogen; alkyl; -OR; -SR; or –NH5 R
(wherein R is the same as defined above); G can be CH N, S or O; In the generic
structure formula I Aand II, A, B and C are the rings;
X1 and X2 can each independently be hydrogen, alkyl, cycloalkyl, heterocyclyl,
10 heteroaryl, aralkyl heterocyclylalkyl or heteroarylalkyl;
Wherein any of X and X2 or X1 can together optionally form a cyclic ring fused with
the ring B;
15 Also X1 and X2 can together optionally form a cyclic ring fused with the ring B.
Y can be cyano or alkyl, alkenyl, alkynyl, aralkyl, heteroarylalkyl, heterocyclylalkyl,
aryl, cycloalkyl, heteroaryl or heterocyclyl.
20 The following definitions apply to terms as used herein.
The term “alkyl,” unless otherwise specified, refers to a monoradical branched or
unbranched saturated hydrocarbon having from 1 to about 20 carbon atoms. This
term is exemplified by groups, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl,
25 iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl, and the like. The alkyl groups may be
further substituted with one or more substituents such as alkenyl, alkynyl, alkoxy,
cycloalkyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino,
azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio,
aryloxy, aminosulfonyl, aminocarbonylamino, hydroxyamino, alkoxyamino, nitro, -
30 S(O)tRa [wherein t is an integer from 0-2 and Ra is alkyl; alkenyl; alkylene; cycloalkyl;
aryl; heterocyclyl; heteroaryl; aralkyl; heteroarylalkyl; heterocyclylalkyl; or -NRxRy
(wherein Rx and Ry are hydrogen; alkyl; alkenyl; alkylene; cycloalkyl; aryl;
heterocyclyl; heteroaryl; aralkyl; heteroarylalkyl; heterocyclylalkyl). Unless otherwise
constrained by the definition, all substituents may optionally be further substituted by
9
1-3 substituents chosen from alkyl, carboxy, aminocarbonyl, hydroxy, alkoxy,
halogen, -CF3, amino, substituted amino, cyano, and –S(O)tRa (wherein t and Ra are
the same as defined earlier).
An alkyl group as defined above may further be interrupted by 1-5 atoms or group5 s
independently chosen from oxygen, sulfur and –NRb- (where Rb can be hydrogen,
alkyl, cycloalkyl, alkenyl, alkynyl, or aryl). Unless otherwise constrained by the
definition, all substituents may optionally be further substituted by 1-3 substituents
chosen from alkyl, carboxy, aminocarbonyl, hydroxy, alkoxy, halogen, -CF3, amino,
10 substituted amino, cyano, and –S(O)tRa (wherein t and Ra are the same as defined
earlier); or an alkyl group as defined above that has both substituents as defined
above and is also interrupted by 1-5 atoms or groups as defined above.
The term “alkenyl,” unless otherwise specified, refers to a monoradical of a branched
15 or unbranched unsaturated hydrocarbon group preferably having from 2 to 20 carbon
atoms with cis or trans geometry. Preferred alkenyl groups include ethenyl or vinyl
(CH=CH2), 1-propylene or allyl (-CH2CH=CH2), or iso-propylene (-C(CH3)=CH2),
bicyclo[2.2.1]heptene, and the like. In the event that the alkenyl is attached to a
heteroatom, the double bond cannot be alpha to the heteroatom. The alkenyl group
20 may be further substituted with one or more substituents, such as alkyl, alkenyl,
alkynyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, amino, aminocarbonyl,
alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy,
arylthio, thiol, alkylthio, aryl, aryloxy, aminosulfonyl, aminocarbonylamino,
hydroxyamino, alkoxyamino, nitro, -S(O)tRa (wherein t and Ra are the same as
25 defined earlier), heterocyclyl or heteroaryl. Unless otherwise constrained by the
definition, all substituents may be optionally further substituted by 1-3 substituents,
which can be alkyl, carboxy, aminocarbonyl, hydroxy, alkoxy, halogen, -CF3, amino,
substituted amino, cyano, or –S(O)tRa (wherein t and Ra are the same as defined
earlier).
30
The term “alkynyl,” unless otherwise specified, refers to a monoradical of an
unsaturated hydrocarbon, preferably having from 2 to 20 carbon atoms. Preferred
alkynyl groups include ethynyl (-CºCH), or propargyl (or propynyl, -CH2CºCH), and
the like. In the event that the alkynyl is attached to a heteroatom, the triple bond
10
cannot be alpha to the heteroatom. The alkynyl group may be further substituted
with one or more substituents, such as alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, acyl,
acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano,
halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aryloxy,
aminosulfonyl, aminocarbonylamino, hydroxyamino, alkoxyamino, nitro, or -S(O)tR5 a
(wherein Ra and t are the same as defined earlier). Unless otherwise constrained by
the definition, all substituents may be optionally further substituted by 1-3
substituents, which can be alkyl, carboxy, aminocarbonyl, hydroxy, alkoxy, halogen,-
CF3, amino, substituted amino, cyano, or –S(O)tRa (wherein Ra and t are the same
10 as defined earlier).
The term “cycloalkyl,” unless otherwise specified, refers to saturated or unsaturated
cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or
multiple condensed rings, which contains an optional olefinic bond. Such cycloalkyl
15 groups include, by way of example, single ring structures, such as cyclopropyl,
cyclobutyl, cyclopentyl, cyclooctyl, cyclopropylene, cyclobutylene and the like, or
multiple ring structures, such as adamantanyl, and bicyclo [2.2.1]heptane, or cyclic
alkyl groups to which is fused an aryl group, for example, indane and the like. The
cycloalkyl may be further substituted with one or more substituents such as alkyl,
20 alkenyl, alkynyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, amino, aminocarbonyl,
alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy,
arylthio, thiol, alkylthio, aryl, aryloxy, aminosulfonyl, aminocarbonylamino,
hydroxyamino, alkoxyamino, nitro, -S(O)tRa (wherein Ra and t are the same as
defined earlier), heteroaryl or heterocyclyl. Unless otherwise constrained by the
25 definition, all substituents may be optionally further substituted by 1-3 substituents,
which can be alkyl, carboxy, aminocarbonyl, hydroxy, alkoxy, halogen, -CF3, -NH2,
substituted amino, cyano, or –S(O)tRa (wherein Ra and t are the same as defined
earlier).
30 The term “alkoxy” denotes the group O-alkyl, wherein alkyl is the same as defined
above.
11
The term “aralkyl” refers to alkyl-aryl linked through alkyl portion (wherein alkyl is the
same as defined earlier) and the alkyl portion contains carbon atoms from 1-6 and
aryl is same as defined below.
The term “aryl,” unless otherwise specified, refers to phenyl or naphthyl ring, and th5 e
like, optionally substituted with 1 to 3 substituents selected from the group consisting
of halogen (such as F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy,
aryloxy, benzyloxy, -S(O)tRa (wherein Ra and t are the same as defined earlier),
cyano, nitro, ester, carboxy, heterocyclyl, heteroaryl, heterocyclylalkyl,
10 heteroarylalkyl, acyl and -(CH2)0-3C(=O)NRxRy (wherein Rx and Ry are same as
defined earlier).
The term “carboxy,” unless otherwise specified, refers to –C(=O)ORc (wherein Rc is
hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, aralkyl, heteroarylalkyl or
15 heterocyclylalkyl).
The term “heteroaryl”, unless otherwise specified, refers to an aromatic ring structure
containing 5 or 6 carbon atoms, or a bicyclic aromatic group having 8 to 10 carbon
atoms, with one or more heteroatom(s) independently selected from the group
20 consisting of N, O and S, optionally substituted with 1 to 3 substituent(s), such as
halogen (F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -S(O)tRa
(wherein t and Ra are the same as defined earlier), alkoxy, aralkyl, cyano, nitro, acyl
or -C(=O)NRxRy (wherein Rx and Ry are the same as defined earlier). Examples of
heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl,
25 pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl,
benzothiazolyl, benzoxazolyl, and the like, including analogous oxygen, sulphur, and
mixed hetero atom containing groups.
The term “heterocyclyl”, unless otherwise specified, refers non-aromatic monocyclic
30 or polycyclic ring having 3 to 10 atoms, in which 1 to 3 carbon atoms in a ring are
replaced by heteroatoms selected from the group consisting of O, S and N, and
optionally are benzofused or fused heteroaryl of 5-6 ring members and/or optionally
are substituted, wherein the substituents can be halogen (F, Cl, Br, I), hydroxy, alkyl,
alkenyl, alkynyl, hydroxyalkyl, cycloalkyl, carboxy, aryl, alkoxy, aralkyl, heteroaryl,
12
heterocyclyl, heteroarylalkyl, heterocyclylalkyl, oxo, alkoxyalkyl or -S(O)tRa (wherein t
and Ra are the same as defined earlier), cyano, nitro, -NH2, substituted amino, acyl
or -C(=O)NRxRy (wherein Rx and Ry are the same as defined earlier). Examples of
heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl,
azabicyclohexane dihydropyridinyl, piperidinyl, isoxazoline, piperazinyl5 ,
dihydrobenzofuryl, isoindole-dione, dihydroindolyl and the like.
“Heteroarylalkyl,” unless otherwise specified, refers to an alkyl-heteroaryl group,
wherein the alkyl and heteroaryl portions are the same as defined earlier.
10
“Heterocyclylalkyl,” unless otherwise specified, refers to an alkyl-heterocyclyl group,
wherein the alkyl and heterocyclyl portions of the group are the same as defined
earlier.
15 The term “acyl” as defined herein refers to -C(=O)Ra wherein Ra is the same as
defined earlier.
The term “substituted amino,” unless otherwise specified, refers to a group –N(Rk)2
wherein each Rk can be hydrogen [provided that both Rk groups are not hydrogen
20 (defined as “-NH2”)], alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, aryl, heteroaryl,
heterocyclyl, heterocyclylalkyl, heteroarylalkyl, acyl, S(O)tRa (wherein t and Ra are the
same as defined above), -C(=O)NRxRy, -C(=O)ORc (wherein Rx, Ry and Rc are the
same as defined earlier) or -NHC(=O)NRyRx (wherein Ry and Rx are the same as
defined earlier).
25
Unless otherwise constrained by the definition, all substituents optionally may be
further substituted by 1-3 substituents, which can be alkyl, aralkyl, cycloalkyl, aryl,
heteroaryl, heterocyclyl, carboxy, hydroxy, alkoxy, halogen, -CF3, cyano, -
C(=O)NRxRy, -O(C=O)NRxRy (wherein Rx and Ry are the same as defined earlier) or
30 -S(O)tRa (where t and Ra are the same as defined above).
The compound of the present invention can also exist as a pharmaceutically
acceptable salt form, wherein the pharmaceutically acceptable salt means a nontoxic
salt containing organic salt and inorganic salt, being accepted pharmaceutically. The
13
inorganic salt includes aluminum, ammonium, calcium, copper, iron, lithium,
magnesium, manganese, potassium, sodium, zinc and the like. The organic salt
includes primary-, secondary-, or tertiary-amines, naturally substituted amines, cyclic
amines, modified salts prepared through basic ion exchange resin and the like. More
preferably, the organic salts can be selected from the group consisting of arginine5 ,
betain, caffeine, colin, N,N-dibenzylethylenediamine, diethylamine,
2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine,
N-ethylmorpholin, N-ethylpiperidine, N-methylglucamine, glucamine, glucosamine,
histidine, hydrapamine, N-(2-hydroxyethyl)piperidine,
10 N-(2-hydroxyethyl)pyrrolidine, isopropylamine, lysine, methylglucamine, morpholin,
piperazine, piperidine, polyamine resin, procain, purine, theobromine, triethylamine,
trimethylamine, tripropylamine, tromethamine and the like.
The invention also relates to novel synthetic route as depicted in (Scheme 1)
15 providing synthesis of novel fused heterocycles (Formula I, Formula II and Formula
III):
NC NH2
NC NH2
NC N
NC NH2
EtO
NC N
NC NH2
HN
H2N
N
N
CN
NH2
NH2
(i) (ii)
(iii)
(iv)
1 2 3
4
(v)
Y
G
N N
NC
X
Formula II
Formula I
R1
R2
R3
R4
X1
N
N
Y
G
Y
Y3
Y3
Y2
Y2
Y1
Y4
Y5
Y1
Y5
R1
R2
R3
R4
Y4
R
X2
N
N
Y
NHR
NHR
vi
Formula III
R4
R3
R2
R1
R3
R4
R2
R1
R1
R2
R3
R4
14
Scheme 1
The compound of Formula I can be prepared by following route of the reaction
procedures as depicted in Scheme I, which comprises the steps of either thermal o5 r
microwave heating of compound 4 (wherein Y is same as defined earlier) with a
reagent iv (wherein G, Z, R1, R2, R3 and R4 are same as defined earlier), or involving
catalyst mediated reaction of compound 4 (wherein Y is same as defined earlier)
with a reagent iv such as CDI, CS2, (Boc)2 or any other cyclising reagents to give a
10 compound of Formula I in an organic solvent such as dimethylformamide,
tetrahydrofuran, acetonitrile, methanol, dioxane or diethyl ether.
The compound of Formula II can be prepared by following route of the reaction
procedures as depicted in Scheme I, which comprises the steps of either thermal or
15 microwave heating or reflux of compound 4 (wherein Y is same as defined earlier)
with a reagent v such as any aldehyde (aryl, alkyl or cycocarbaldehyde) with or
without any oxidant, or involving catalyst mediated reaction of compound 4 (wherein
Y is same as defined earlier) with a reagent v such as any aldehyde (aryl, alkyl or
cycocarbaldehyde) with or without any oxidant to give a compound of Formula II in
20 an organic solvent such as dimethylformamide, acetonitrile, methanol,
tetrahydrofuran, dioxane or diethyl ether.
The compound of Formula III can be prepared by following route of the reaction
procedures as depicted in Scheme I, which comprises the steps of either thermal or
25 microwave heating or reflux of compound 4 (wherein Y is same as defined earlier)
with a reagent vi, or involving catalyst mediated reaction of compound 4 (wherein Y
is same as defined earlier) with a reagent vi such as acyl halide, alkanoyl halide or
arylalkanoyl halide or aroyl halide or anhydride to give a compound of Formula III
(where R is already defined) in an organic or aqueous solvent such as
30 dimethylformamide, acetonitrile, methanol, tetrahydrofuran, dioxane or diethyl ether.
Particular compounds are disclosed below:
15
5-oxo-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,3,5]triazepine-3-carbonitrile
(Compound 1)
NH
HN
N N
NC
O
5 6H-benzo[f]imidazo[1,5-a][1,3,5]triazepine-3-carbonitrile (Compound 2)
1-amino-4-(3-nitrophenyl)-4,5-dihydroimidazo[1,2-a]quinoxaline-2-carbonitrile
(Compound 3)
10
1-amino-4-(4-chlorophenyl)-4,5-dihydroimidazo[1,2-a]quinoxaline-2-carbonitrile
(Compound 4)
15
1-((3,4-dimethoxybenzylidene)amino)-4-(3,4-dimethoxyphenyl)-4,5-
dihydroimidazo[1,2-a]quinoxaline-2-carbonitrile (Compound 5)
N
N
CN
N
HN
MeO
OMe
OMe
MeO
16
N-(2-(5-amino-4-cyano-1H-imidazol-1-yl)phenyl)acetamide (Compound No. 6)
(E)-4-methyl-1-((3-oxo-1-phenylbutyl)amino)-4-styryl-4,5-dihydroimidazo[1,2-
a]quinoxaline-2-carbonitrile (Compound 75 )
(E)-1-((3,4,5-trimethoxybenzylidene)amino)-4-(3,4,5-trimethoxyphenyl)imidazo[1,2-
a]quinoxaline-2-carbonitrile (Compound 8)
10 (E)-1-((3,4-dimethoxybenzylidene)amino)-4-(3,4-dimethoxy-phenyl)imidazo[1,2-
a]quinoxaline-2-carbonitrile (Compound 9)
17
(E)-1-((2,5-dimethoxybenzylidene)amino)-4-(2,5-dimethoxyphenyl)imidazo[1,2-
a]quinoxaline-2-carbonitrile (Compound 10)
(E)-1-((4-chlorobenzylidene)amino)-4-(4-chlorophenyl)imidazo[1,2-a]quinoxaline-5 2-
carbonitrile (Compound 11)
(E)-1-((3,4,5-trimethoxybenzylidene)amino)-4-(3,4,5-trimethoxyphenyl)-4,5-
dihydroimidazo[1,2-a]quinoxaline-2-carbonitrile (Compound 12)
18
(E)-1-((2,5-dimethoxybenzylidene)amino)-4-(2,5-dimethoxyphenyl)imidazo[1,2-
a]quinoxaline-2-carbonitrile (Compound 13)
(E)-1-((3,4-dihydroxybenzylidene)amino)-4-(3,4-dihydroxyphenyl)-5 4,5-
dihydroimidazo[1,2-a]quinoxaline-2-carbonitrile (Compound14)
(E)-1-((2-nitrobenzylidene)amino)-4-(2-nitrophenyl)-4,5-dihydroimidazo[1,2-
a]quinoxaline-2-carbonitrile (Compound 15)
19
(E)-1-((3-nitrobenzylidene)amino)-4-(3-nitrophenyl)-4,5-dihydroimidazo[1,2-
a]quinoxaline-2-carbonitrile (Compound 16)
(E)-1-((4-nitrobenzylidene)amino)-4-(4-nitrophenyl)-4,5-dihydroimidazo[5 1,2-
a]quinoxaline-2-carbonitrile (Compound 17)
(E)-1-((2,3,4-trimethoxybenzylidene)amino)-4-(2,3,4-trimethoxyphenyl)-4,5-
dihydroimidazo[1,2-a]quinoxaline-2-carbonitrile (Compound 18)
20
1-amino-4-(3-nitrophenyl)-4,5-dihydroimidazo[1,2-a]quinoxaline-2-carbonitrile
(Compound 19)
1-amino-4-(4-cyanophenyl)-4,5-dihydroimidazo[1,2-a]quinoxaline-2-carbonitril5 e
(Compound 20)
1-amino-4,4-dimethyl-4,5-dihydroimidazo[1,2-a]quinoxaline-2-carbonitrile
(Compound 21)
10
21
1-amino-4-methyl-4-(3-nitrophenyl)-4,5-dihydroimidazo[1,2-a] quinoxaline-2-
carbonitrile (Compound 22)
1-amino-4-benzoyl-4-phenyl-4,5-dihydroimidazo[1,2-a]quinoxaline-2-carbonitrile
(Compound 235 )
1-amino-4-propyl-4,5-dihydroimidazo[1,2-a]quinoxaline-2-carbonitrile (Compound 24)
4,4-dimethyl-1-(propan-2-ylideneamino)-4,5-dihydroimidazo-[1,2-a]quinoxaline-2-
10 carbonitrile (Compound 25)
4H-benzo[f]imidazo[1,5-a][1,3,5]triazepine-3-carbonitrile (Compound 26)
22
3-cyano-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,3,5]triazepine-5-carboxylicacid
(Compound 27)
(Z)-1-((2,4-dinitrobenzylidene)amino)-4-(2,4-dinitrophenyl)imidazo[1,2 a]quinoxaline5 -
2-carbonitrile (Compound 28)
(E)-4-(3-iodo-4-methoxyphenyl)-1-((1-(3-iodo-4-methoxyphenyl) ethylidene)amino)-4-
methyl-4,5-dihydroimidazo[1,2-a]quinoxaline-2 carbonitrile (Compound 29)
10
E)-4-(3,4-dimethoxyphenyl)-1-((1-(3,4-
dimethoxyphenyl) ethylidene)amino)-4-methyl-4,5-
dihydroimidazo[1,2-a]quinoxaline-2-carbonitrile
(Compound 30)
23
(E)-4-(4-bromophenyl)-1-((1-(4-bromophenyl)ethylidene)amino)-4-methyl-4,5-
dihydroimidazo[1,2-a]quinoxaline-2-carbonitrile (Compound 31)
(E)-4-(4-chlorophenyl)-1-((1-(4-chlorophenyl)ethylidene)amino)-4-methyl-5 4,5-
dihydroimidazo[1,2-a]quinoxaline-2-carbonitrile (Compound 32)
1-amino-4-methyl-4-phenyl-4,5-dihydroimidazo[1,2-a]quinoxaline-2carbonitrile
(Compound 33)
24
1-amino-4-(3-bromophenyl)-4-methyl-4,5-dihydroimidazo[1,2-a]quinoxaline-2-
carbonitrile (Compound 34)
1-amino-4-methyl-4-(naphthalen-2-yl)-4,5-dihydroimidazo[1,2-a]quinoxaline-5 2-
carbonitrile (Compound 35)
N N
CN
NH
H2N
(E)-4-methyl-4-(thiophen-2-yl)-1-((1-(thiophen-2-yl)ethylidene)amino)-4,5
dihydroimidazo [1,2-a]quinoxaline-2-carbonitrile (Compound 36)
N N
CN
NH
N
S
S
10
1-amino-4-(2,4-dimethoxyphenyl)-4-methyl-4,5-dihydroimidazo[1,2-a]quinoxaline-2-
carbonitrile (Compound 37)
25
1-amino-4-methyl-4-(3,4,5-trimethoxyphenyl)-4,5-dihydroimidazo [1,2 a]quinoxaline--
2-carbonitrile (Compound 38)
1-amino-4-hydroxy-4-(phenylamino)-4,5-dihydroimidazo[1,2-a]quinoxaline-5 2-
carbonitrile (Compound 39)
1-amino-4-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]quinoxaline-2-carbonitrile
(Compound 40)
10
(E)-4-(2,3,4-trimethoxyphenyl)-1-(2,3,4-trimethoxystyryl)-4,5dihydroimidazo[1,2-
a]quinoxaline-2-carbonitrile (Compound 41)
26
(E)-1-((4-isopropylbenzylidene)amino)-4-(4-isopropylphenyl)imidazo[1,2-
a]quinoxaline-2-carbonitrile (Compound 42)
N N
N
N
CN
(Z)-1-((5-hydroxy-2-nitrobenzylidene)amino)-4-(5-hydroxy-2-nitrophenyl)-5 4,5-
dihydroimidazo[1,2-a]quinoxaline-2-carbonitrile (Compound 43)
(E)-4-(furan-2-yl)-1-((furan-2-ylmethylene)amino)-4,5-dihydroimidazo[1,2-
a]quinoxaline-2-carbonitrile (Compound 44)
10
27
and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates,
enantiomers, diastereomers or N-oxides.
Where desired, the compounds of Formula I and their pharmaceutically acceptable
salts, pharmaceutically acceptable solvates, stereoisomers, tautomers, racemates5 ,
prodrugs, metabolites, polymorphs or N-oxides may be advantageously used in
combination with one or more other therapeutic agents. Examples of other
therapeutic agents, which may be used in combination with compounds of Formula I
of this invention and/or their pharmaceutically acceptable salts, pharmaceutically
10 acceptable solvates, stereoisomers, tautomers, racemates, prodrugs, metabolites,
polymorphs or N-oxides. Because of their valuable pharmacological properties, the
compounds described herein may be administered to an animal for treatment orally,
or by a parenteral route. The pharmaceutical compositions described herein can be
produced and administered in dosage units; each unit containing a certain amount of
15 at least one compound described herein and/or at least one physiologically
acceptable addition salt thereof. The dosage may be varied over extremely wide
limits, as the compounds are effective at low dosage levels and relatively free of
toxicity. The compounds may be administered in the low micromolar concentration,
which is therapeutically effective, and the dosage may be increased as desired up to
20 the maximum dosage tolerated by the patient.
The compounds described herein can be produced and formulated as their racemic
mixtures, enantiomers, diastereomers, rotamers, N-oxides, polymorphs, solvates
and pharmaceutically acceptable salts, as well as the active metabolites.
25 Pharmaceutical compositions comprising the molecules of Formula I or metabolites,
enantiomers, diastereomers, N-oxides, polymorphs, solvates or pharmaceutically
acceptable salts thereof, in combination with pharmaceutically acceptable carrier and
optionally included excipient can also be produced.
30 The examples mentioned below demonstrate general synthetic procedures, as well
as specific preparations of particular compounds. The examples are provided to
illustrate the details of the invention and should not be constrained to limit the scope
of the present invention.
28
While the present invention has been described in terms of its specific embodiments,
certain modifications and equivalents will be apparent to those skilled in the art and
are included within the scope of the present invention. Thus, a further understanding
can be obtained by reference to certain specific examples which are provided herein
for purposes of illustration only and are not intended to be limiting unless otherwis5 e
specified.
Experimental
10 Example 1: Synthesis of 5-oxo-5,6-dihydro-4H-benzo[f]imidazo[1,5-
a][1,3,5]triazeine-3-carbonitrile (Compound 1)
NH
HN
N N
NC
O
For the synthesis of compound 1 mixture of 4 in ethanol (3 ml) and
carbonyldiimidazole (CDI; 1equiv.) was taken in round bottom flask. This was
15 refluxed for 3-4 h. The mixture was extracted with ethyl acetate (30 ml). Thereafter
this was concentrated on a rotary evaporator and placed overnight for crystallization.
The crude product was then washed with petroleum ether and dried. (0.46g, 55%)
IR Spectrum (KBr cm-1): 3331(NH stretch), 2241(CN stretch), 1738(C=O stretch).
1H NMR (400MHz, CDCl3, TMS = 0) δ: 9.51 (1H, s), 8.21 (1H, s), 7.73 (2H, d, J= 8
20 Hz), 7.48 (1H, m), 7.09 (1H, m).13C NMR (100 MHz, CDCl3, TMS = 0) δ: 137.32,
90.06, 133.78, 129.25, 122.21, 125.36, 125.21, 158.40, 114.42.
Example2: 6H-benzo[f]imidazo[1,5-a][1,3,5]triazepine-3-carbonitrile (Compound
No. 2)
25
For the synthesis of compound 2, the reaction was carried out by dissolving 100 mg
of 4 and triethylorthoformate (1 equiv.; 0.835 ml) in acetonitrile (1 ml). The reaction
29
mixture was refluxed for 48 h. The reaction was monitored via TLC. Yellow coloured
precipitate was appeared after 48 h. The solvent system was 100% ethyl acetate.
Excess of solvent was evaporated in rotary evaporator. The solid obtained was then
dried. Further characterization was done using different analytical techniques. (70%)
IR Spectrum (KBr cm-1): 3747(NH stretch), 2218(CN stretch), 1517(NH bend)5 ,
1700(C=N stretch).1H NMR (400MHz, CDCl3, TMS = 0) δ: 9.51 (1H, s), 8.0 (1H, s),
7.42 (1H, dd, J = 1.2), 6.92 (1H, d, J = 1.2), 6.64 (1H, d, J = 4.8).13C NMR (100
MHz, CDCl3, TMS = 0) δ: 137.27, 110.0, 126.51, 147.42, 146.57, 121.22,
129.35,121.58, 124.70, 115.47, 133.51.
10 MS (ESI): 210.1 [M+1]+
Example 3: 1-amino-4-(3-nitrophenyl)-4,5-dihydroimidazo[1,2-a]quinoxaline-2-
carbonitrile
15
For the synthesis of compound 3, the reaction between 3- nitrobenzaldehyde (1.1
equiv.; 0.0759 mg) and 4 (100 mg) has been done for direct cyclization. The reaction
was carried out in methanol using p-toluenesulfonic acid as catalyst under
microwave for 6h at 1000C. The reaction was monitored via TLC. The solvent system
20 used was 50% ethylacetate in hexane. The TLC showed multiple spots. After
completion of reaction column was prepared. The isolation was done with the help of
column chromatography. The fraction containing single compound was mixed and
evaporated using rotary evaporator. The IR was taken. (65%)
IR Spectrum (KBr cm-1): 3329 (NH stretch), 2212 (CN stretch), 1529 (NO2 Symmetric
25 stretch), 1642 (NO2 asymmetric stretch).
1H NMR (400MHz, CDCl3, TMS = 0) δ: 8.26 (1H, d, J= 1.2 Hz), 8.12 (1H, d, J= 8 Hz),
7.84 (1H, d, J= 8Hz), 7.76 (1H, d, J=4Hz), 7.17 (1H, d, J= 8Hz), 7.07(1H, d, J= 8Hz),
6.96 (1H, d, J= 8Hz), 6.34 (2H, s), 5.89 (1H, s).
30
13C NMR (100 MHz, CDCl3, TMS = 0) δ: 147.76, 145.3, 141.65, 148.21, 138.46,
53.98, 122.47, 122.38, 136.87, 126.62, 129.35, 118.73, 116.08, 133.69, 116.95,
93.92, 121.00 and 116.95. MS (ESI): 333.1 [M+1]+
Example 4: 1-amino-4-(4-chlorophenyl)-4,5-dihydroimidazo[1,2-a]quinoxaline5 -
2-carbonitrile (Compound No. 4)
For the synthesis of compound 4, the 4 (400 mg) was refluxed overnight with pchlorobenzaldehyde
(1 equiv.) in methanol using p-toluenesulfonic acid as catalyst
10 under microwave for 6h at 1000C. The reaction was monitored through Thin Layer
Chromatography (TLC). The light yellow coloured precipitates were obtained and
washed with excess of methanol. The compound was filtered and dried. The
compound 8 was characterized and identified by using different analytical
techniques. (78%)
15 IR Spectrum (KBr cm-1): 2210 (CN stretch), 3347 (NH stretch) cm-1, and 772 (Cl
stretch)
1H NMR (400MHz, CDCl3, TMS = 0) δ: 7.33 (2H, d, J= 8 Hz), 7.29 (2H, d, J= 8Hz),
7.81 (1H, d, J= 8Hz), 7.06 (1H, d, J= 8Hz), 6.80 (1H, d, J= 8Hz), 6.64 (1H, s), 5.41
(1H, s), 5.77 (2H, s).
20 13C NMR (100 MHz, CDCl3, TMS = 0) δ: 147.76, 145.3, 141.65, 148.21, 138.46,
53.98, 122.47, 122.38, 136.87, 126.62, 129.35, 118.73, 116.08, 133.69, 116.95,
93.92, 121.00 and 116.95. MS (ESI): 333.1 [M+1]+ HRMS (TOF-ESI) Calcd for
C17H10N6O2, 330.0865 [M]+; observed: 353.0762 [M+Na]+.
25 Example 5: 1-((3,4-dimethoxybenzylidene)amino)-4-(3,4-dimethoxyphenyl)-4,5-
dihydroimidazo[1,2-a]quinoxaline-2-carbonitrile (Compound 5)
31
N
N
CN
N
HN
MeO
OMe
OMe
MeO
For the synthesis of compound 5, the 4 (400 mg) was treated with veratraldehyde (2
equiv) in methanol using p-toluenesulfonic acid as catalyst under microwave for 6h
at 1000C. The reaction was monitored through Thin Layer Chromatography (TLC)5 .
The light yellow coloured precipitates were obtained and washed with excess of
methanol. The compound was filtered and dried. The compound 5 was characterized
and identified by using different analytical techniques. (82%)
IR Spectrum (KBr cm-1): 2219 (CN stretch), 3747 (NH stretch) cm-1
, 1666 (C=N
10 stretch), 1593 (C=C stretch) and 1025 (C-O stretch)
1H NMR (400MHz, CDCl3, TMS = 0) δ: 8.93 (1H, s), 7.40 (1H, d, J= 4 Hz)7.18 (1H, t,
J= 4 Hz), 7.02 (1H, m), 7.5 (1H, d, J=4 Hz), 8.18 (1H, d, J= 4 Hz), 7.60 (1H, d, J=
4Hz), 5.58 (1 H, s), 5.28 (1H, s),6.95 (2H, d, J= 4Hz), 6.96 (1H, d, J= 4Hz), 6.98 (1H,
s), 3.97 (3H,s), 3.86 (3H,s), 3.84 (3H,s), 3.82 (3H,s).
15 13C NMR (100 MHz, CDCl3, TMS = 0) δ:153.68, 149.65, 149.38, 149.33, 147.40,
143.63, 136.83, 131.16, 128.32, 116.15, 99.68, 163.25, 127.55, 125.84, 119.00,
119.74, 115.58, 111.14, 111.10, 110.87, 110.25 109.68, 56.22, 56.02, 56.88, 56.93,
56.22.
MS (ESI): 496.3 [M+1]+
20
Example 6: N-(2-(5-amino-4-cyano-1H-imidazol-1-yl)phenyl)acetamide
(Compound No. 6)
25 The compound 4 (400 mg) was refluxed overnight with acetic anhydride (1 equiv.;
.0284 ml) in dichloromethane with a pinch of dimethylaminopyridine in a round
32
bottom flask at 30-400C. The reaction was monitored through Thin Layer
Chromatography (TLC). Dichloromethane was evaporated using rotary evaporator.
The mixture was poured in separating funnel and separated after washing with
water. The separated layer containing mixture was then boiled to dissolve in ethyl
acetate and kept for crystallization. The compound 6 was characterized an5 d
identified by using different analytical techniques. (60%)
IR Spectrum (KBr cm-1): 3445.82 & 3371.55 cm-1 (NH2stretch), 2204.42 (CNstretch),
1699.16 (C=O stretch)
1H NMR (400MHz, CDCl3, TMS = 0) δ: 7.75 (1H, d, J= 8 Hz), 7.49 (1H, m), 7.32 (2H,
10 d, J= 8 Hz), 7.15 (1H, s), 5.71 (1H, s), 2.04 (3H, s)
13C NMR (100 MHz, CDCl3, TMS = 0) δ: 129.56, 90.63, 132.17, 134.42, 126.04,
126.95, 128.04, 125.87, 147.63, 117.10, 168.79, 23.07.
Example7.(E)-4-methyl-1-((3-oxo-1-phenylbutyl)amino)-4-styryl-4,5-
dihydroimidazo[1,2-a]quinoxaline-2-carbonitrile (Compound 7)
15
To a reaction mixture of 4 (200 mg, 1.407 mmol,) in 1,4-dioxane (1 mL) was added
benzylideneacetone (205.69 mg, 1.005 mmol) using HClO4-silica as a catalyst. The
reaction mixture was refluxed for 20 h. After the completion of the reaction (TLC), 1,4
dioxane was evaporated, extracted with ethylacetate, dried and purified via flash
20 chromatography. Yield: 41 %; Colour: orange Solid, mp:264-266 ºC.1H NMR (400
MHz, CDCl3, TMS = 0) δ: 7.96 (1H, d, J = 6.12), 7.83 (2H, d, J = 6.4), 7.60-7.56 (3H,
m), 7.46-7.39 (3H, m), 6.99 (1H, t, J = 11.24), 6.84 (2H, t, J = 11.96), 6.42 (2H, d, J =
6.32), 5.99 (1H, s), 4.15-4.12 (1H, q), 3.74-3.63 (2H, m) 13C NMR (100 MHz, CDCl3,
TMS = 0) δ: 203.83, 152.59, 145.98, 133.87, 131.38, 130.46, 129.45, 128.66,
25 128.21, 128.16, 128.13, 127.92, 127.61, 124.75, 123.59, 121.30, 121.30, 116.35,
115.12, 111.34, 99.08, 61.15, 45.63, 43.93, 30.59, 10.77.
(Example 8): (E)-1-((3,4,5-trimethoxybenzylidene)amino)-4-(3,4,5-trimetho
xyphenyl)imidazo[1,2-a]quinoxaline-2-carbonitrile (Compound 8)
33
To a reaction vial, a suspension of 4 (100 mg, 0.502 mmol) in methanol (1 mL) was
added 3,4,5-trimthoxybenzaldehyde (199.9 mg, 1.004 mmol) and p-TsOH (1 mol %).
The mixture was heated under mw irradiation (open reflux) at 80 ºC for 30 min. After
the completion of the reaction (TLC), methanol was evaporated from mixture5 ,
concentrated under vacuum using rotary evaporator, extracted with ethylacetate (10
mL × 3), washed with water, brine, dried over anhydrous Na2SO4, and purified via
flash chromatography (EtOAc: Pet ether:: 1.5 : 8.5). Yield: 93 %; Colour: yellow;
m.p: 142 - 144 ºC. IR (KBr, cm-1): 2227 (CN stretch), 1575 (C=N stretch), 1501 (C=C
10 stretch) and 1127 (C-O stretch). 1H NMR (400 MHz, CDCl3, TMS = 0) δ: 8.98 (2H, s),
8.12 - 8.09 (1H, dd, J12 = 4 Hz), 8.03 (2H, s), 7.64 - 7.55 (2H, m), 7.28 (2H, d, J = 8
Hz), 4.00 (15H, s), 3.94 (3H, s). 13C NMR (100 MHz, CDCl3, TMS = 0) δ: 164.11,
153.74, 152.93, 149.02, 144.79, 143.14, 140.71, 136.87, 135.66, 130.31, 130.13,
130.07, 128.63, 127.50, 117.83, 115.56, 107.27, 106.93, 104.03, 61.19, 60.95,
15 56.36, 56.27. MS (ESI): m/z: 554.19 [M+1]+. Elemental Analysis: Anal. Found C,
65.01; H, 4.91; N, 12.59. Calcd for C30H27N5O6: C, 65.07; H, 4.92, N, 12.65.
(Example 9): (E)-1-((3,4-dimethoxybenzylidene)amino)-4-(3,4-dimethoxyphenyl)
imidazo[1,2-a]quinoxaline-2-carbonitrile (Compound 9)
34
To a reaction vial, a suspension of 4 (100 mg, 0.502 mmol) in methanol (1 mL) was
added 3,4- dimethoxybenzaldehyde (166.83 mg, 1.004 mmol) and p-TsOH (1
mol %). The mixture was heated under mw irradiation (open reflux) at 80 ºC for 30
min. After the completion of the reaction (TLC), methanol was evaporated from
mixture, concentrated under vacuum using rotary evaporator, extracted wi5 th
ethylacetate (10 mL × 3), washed with water, brine, dried over anhydrous Na2SO4,
and purified via flash chromatography (EtOAc: Pet ether:: 1 : 9). Yield: 90 %; Colour:
yellow; m.p: 141 - 143 ºC. IR (KBr, cm-1): 2227 (CN stretch), 1575 (C=N stretch),
1503 (C=C stretch) and 1126 (C-O). 1H NMR (400 MHz, CDCl3, TMS = 0) δ: 9.59
10 (1H, s), 9.09 (1H, d, J = 4 Hz) 8.18 (1H, d, J12 = 4 Hz), 7.80 (1H, d, J = 4 Hz), 7.69 -
7.65 (2H, m), 7.28 - 7.16 (5H, m), 3.95 (6H, s), 3.93 (6H, s). 13C NMR (100 MHz,
CDCl3, TMS = 0) δ: 161.24, 155.76, 153.81, 153.74, 152.18, 152.09, 146.01, 130.42,
129.13, 128.15, 127.40, 123.97, 121.97, 118.18, 117.07, 115.70, 113.58, 113.19,
111.26, 104.80, 56.64, 56.49, 55.93, 55.87. HRMS (TOF-ESI) Calcd for C28H23N5O4,
15 493.1800 [M]+; observed: 494.25648 [M+1]+ .
(Example 10): (E)-1-((2,5-dimethoxybenzylidene)amino)-4-(2,5-dimethoxyp -
henyl)imidazo[1,2-a]quinoxaline-2-carbonitrile (Compound 10)
To a reaction vial, a suspension of 4 (100 mg, 0.502 mmol) in methanol (1 mL) was
20 added 2,5- dimthoxybenzaldehyde (166.83 mg, 1.004 mmol) and p-TsOH (1 mol %).
The mixture was heated under mw irradiation (open reflux) at 80 ºC for 30 min. After
the completion of the reaction (TLC), methanol was evaporated from mixture,
concentrated under vacuum using rotary evaporator, extracted with ethyl acetate (10
mL × 3), washed with water, brine, dried over anhydrous Na2SO4, and purified via
25 flash chromatography (EtOAc: Pet ether:: 0.5: 9.5). Yield: 93 %; Colour: Reddish
orange; m.p: 140 - 142 ºC. IR (KBr, cm-1): 2233 (CN stretch),, 1496 (C=C stretch)
and 1039 (C-O stretch). 1H NMR (400 MHz, CDCl3, TMS = 0) δ: 9.57 (1H, s), 9.09 -
35
9.06 (1H, m), 8.20 - 8.19 (1H, m) 7.79 (1H, d, J = 3.2 Hz), 7.67 - 7.64 (2H, m), 7.20 -
7.17 (1H, dd, J12 = 8 Hz), 7.15 - 7.14 (1H, m), 7.05 (2H, d, J = 4 Hz), 7.02 (1H, d, J =
8 Hz), 3.93 (3H, s), 3.91 (3H, s), 3.83 (3H, s), 3.78 (3H, s). 13C NMR (100 MHz,
CDCl3, TMS = 0) δ: 161.32, 155.81, 153.86, 152.16, 129.15, 127.43, 122.03, 118.18,
117.24, 115.76, 113.63, 113.24, 111.30, 99.99, 56.66, 56.51, 55.93, 55.89. M5 S
(ESI): m/z: 494.17 [M+1]+.
(Example11):(E)-1-((4-chlorobenzylidene)amino)-4-(4-
chlorophenyl)imidazo[1,2-a]quinoxaline-2-carbonitrile (Compound 11)
10 To a reaction vial, a suspension of 4 (100 mg, 0.502 mmol) in methanol (1 mL) was
added 4-chlorobenzaldehyde (141.12 mg, 1.004 mmol) and p-TsOH (1 mol %). The
mixture was heated under mw irradiation (open reflux) at 80 ºC for 30 min. After the
completion of the reaction (TLC), methanol was evaporated from mixture,
concentrated under vacuum using rotary evaporator, extracted with ethylacetate (10
15 mL × 3), washed with water, brine, dried over anhydrous Na2SO4, and purified via
flash chromatography (EtOAc: Pet ether:: 1.5 : 8.5). Yield: 84 %; Colour: Yellow;
m.p: 283 – 285 ºC. IR (KBr, cm-1): 2075 (CN stretch), 1345 (C=N stretch), 772 (C-Cl
stretch). 1H NMR (400 MHz, d6 -DMSO, TMS = 0) δ: 9.22 (1H, s), 8.84 (1H, d, J = 8
Hz), 8.66-8.56 (4H, m), 8.20 (2H, d, J= 8 Hz), 8.13 (1H, d, J = 4 Hz), 7.73 (2H, J = 12
20 Hz), 7.68 (2H, J = 8 Hz), 7.62 (1H, J = 8 Hz), 6.95 (1H, s). HRMS (TOF-ESI) Calcd
for C24H13Cl2N5, 441.0548 [M]+; observed: 443.2332 [M+2]+.
(Example 12): (E)-1-((3,4,5-trimethoxybenzylidene)amino)-4-(3,4,5-trimetho -
xyphenyl)-4,5-dihydroimidazo[1,2-a]quinoxaline-2-carbonitrile (Compound 12)
36
To a reaction vial, a suspension of 4 (100 mg, 0.502 mmol) in methanol (1 mL) was
added 3,4,5-trimthoxybenzaldehyde (199.9 mg, 1.004 mmol) and p-TsOH (1 mol %).
The mixture was heated under mw irradiation (sealed tube) at 80 ºC for 25 min. After
the completion of the reaction (TLC), methanol was evaporated from mixture5 ,
concentrated under vacuum using rotary evaporator, extracted with ethylacetate (10
mL × 3), washed with water, brine, dried over anhydrous Na2SO4, and purified via
flash chromatography (EtOAc: Pet ether:: 1 : 9). Yield: 92 %; Colour: yellow; m.p:
389 ºC (decomposed). IR (KBr, cm-1): 2125 (CN stretch), 3285 (NH stretch) cm-1
,
10 1641 (C=N stretch), 1421 (C=C stretch) and 1093 (C-O stretch). 1H NMR (400 MHz,
d6 -DMSO & CDCl3, TMS = 0) δ: 8.93 (1H, s), 8.18- 8.15 (1H, dd, J12 = 4 Hz) 7.64-
7.59 (2H, m), 7.52- 7.49 (1H, dd, J12 = 4 Hz), 7.16- 7.13 (1H, m), 7.08- 7.05 (1H, dd,
J12 = 4 Hz), 7.00- 6.96 (3H, m), 6.94- 6.83 (3H, m), 5.59 (1H, s), 3.99 (3H, s), 3.89
(3H, s), 3.86 (6H, s), 3.83 (3H, s), 3.82 (3H, s). HRMS (TOF-ESI) Calcd for
15 C30H29N5O6, 555.2100 [M]+; observed: 556.1965 [M+1]+.
(Example 13): (E)-1-((2,5-dimethoxybenzylidene)amino)-4-(2,5-dimethoxyp -
henyl)imidazo[1,2-a]quinoxaline-2-carbonitrile (Compound 13)
37
To a reaction vial, a suspension of 4 (100 mg, 0.502 mmol) in methanol (1 mL) was
added 2,5-dimethoxybenzaldehyde (166.83 mg, 1.004 mmol) and p-TsOH (1 mol %).
The mixture was heated under mw irradiation (sealed tube) at 80 ºC for 25 min. After
the completion of the reaction (TLC), methanol was evaporated from mixture,
concentrated under vacuum using rotary evaporator, extracted with ethylacetate (5 10
mL × 3), washed with water, brine, dried over anhydrous Na2SO4, and purified via
flash chromatography (EtOAc: Pet ether:: 1.5 : 8.5). Yield: 79 %; Colour: Reddish
orange; m.p: 263 - 265 ºC. IR (KBr, cm-1): 2219 (CN stretch), 3333 (NH stretch),
1640 (C=N stretch), 1502 (C=C stretch) and 1127 (C-O stretch). 1H NMR (400 MHz,
10 CDCl3, TMS = 0) δ: 8.92 (1H, s), 8.18 - 8.15 (1H, dd, J12 = 4 Hz), 7.59 (1H, d, J = 4
Hz,), 7.52 - 7.49 (1H, dd, J12 = 4 Hz), 7.17 - 7.13 (1H, m), 7.00 - 6.83 (7H, m), 5.59
(1H, s), 3.98 (6H, s), 3.86 (3H, s), 3.83 (3H, s). 13C NMR (100 MHz, CDCl3, TMS = 0)
δ: 163.27, 153.69, 149.67, 149.41, 149.37, 147.03, 143.59, 136.78, 131.13, 128.33,
127.55, 125.84, 123.04, 119.84, 119.73, 119.63, 115.56, 111.16, 110.87, 110.26,
15 109.71, 99.67, 56.21, 56.01, 55.93, 55.89. HRMS (TOF-ESI) Calcd for C28H25N5O4,
495.1907 [M]+; observed: 496.1827 [M+1]+.
(Example14): (E)-1-((3,4-dihydroxybenzylidene)amino)-4-(3,4-dihydroxyphenyl)-
4,5-dihydroimidazo[1,2-a]quinoxaline-2-carbonitrile (Compound14)
20 To a reaction vial, a suspension of 4 (100 mg, 0.502 mmol) in methanol (1 mL) was
added 3,4-dihydroxybenzaldehyde (138.6 mg, 1.004 mmol) and p-TsOH (1 mol %).
The mixture was heated under mw irradiation (sealed tube) at 80 ºC for 25 min. After
the completion of the reaction (TLC), methanol was evaporated from mixture,
concentrated under vacuum using rotary evaporator, extracted with ethylacetate (10
25 mL × 3), washed with water, brine, dried over anhydrous Na2SO4, and purified via
flash chromatography (EtOAc: Pet ether:: 2 : 8). Yield: 77 %; Colour: Yellow; m.p:
38
286 - 288 ºC. IR (KBr, cm-1): 2221 (CN stretch), 3354 (OH stretch), 3029 (NH
stretch), 1633 (C=N stretch), 1367 (C=C stretch) and 1092 (C-O stretch). 1H NMR
(400 MHz, d6 -DMSO, TMS = 0) δ: 8.16 (2H, t, J13 = 16 Hz), 7.81 (1H, s), 7.60 (2H,
m), 7.46 (1H, d, J = 4 Hz), 7.41 (1H, d, J = 4 Hz), 7.19 - 7.13 (1H, m), 7.12 - 7.01
(1H, m), 6.97 (1H, m), 6.40 (1H, d, J = 4 Hz), 5.85 (1H, t, J13 = 8 Hz). 13C NMR (105 0
MHz, d6 -DMSO, TMS = 0) δ: 149.38, 147.04, 144.15, 138.39, 132.59, 129.74,
127.88, 127.76, 127.70, 123.15, 123.07, 122.86, 121.58, 116.04, 97.38, 74.76.
HRMS (TOF-ESI) Calcd for C24H17N5O4, 439.1281 [M]+; observed: 413.2660 [M -
CN]+.
10 (Example15): (E)-1-((2-nitrobenzylidene)amino)-4-(2-nitrophenyl)-4,5-
dihydroimidazo[1,2-a]quinoxaline-2-carbonitrile (Compound 15)
To a reaction vial, a suspension of 4 (100 mg, 0.502 mmol) in methanol (1 mL) was
added 2-nitrobenzaldehyde (151.72 mg, 1.004 mmol) and p-TsOH (1 mol %). The
15 mixture was heated under mw irradiation (sealed tube) at 80 ºC for 25 min. After the
completion of the reaction (TLC), methanol was evaporated from mixture,
concentrated under vacuum using rotary evaporator, extracted with ethylacetate (10
mL × 3), washed with water, brine, dried over anhydrous Na2SO4, and purified via
flash chromatography (EtOAc: Pet ether:: 1 : 9). Yield: 90 %; Colour: Brownish solid;
20 m.p: 216 - 218 ºC. IR (KBr, cm-1): 2075 (CN stretch), 3331 (NH stretch), 1398 (NO2
Symmetric stretch), 1219 (NO2 asymmetric stretch). 1H NMR (400 MHz, d6 -DMSO,
TMS = 0) δ: 9.34 (1H, s), 8.27 (1H, d, J = 8 Hz), 8.16 (1H, d, J = 8 Hz), 8.05 (1H, d, J
= 8 Hz), 7.96 - 7.87 (3H, m), 7.72 (1H, t, J13 = 16 Hz), 7.62 (2H, t, J13 = 16 Hz), 7.14-
7.06 (2H, m), 6.97 (1H, d, J = 8 Hz), 6.84 (1H, t, J13 = 16 Hz), 6.29 (1H, s). 13C NMR
25 (100 MHz, d6 -DMSO, TMS = 0) δ: 161.89, 149.93, 149.04, 146.02, 143.63, 137.94,
134.62, 134.24, 134.16, 133.59, 130.61, 130.35, 128.94, 128.37, 125.58, 125.49,
122.01, 119.56, 119.31, 116.48, 115.59, 100.47, 51.65. MS (ESI): m/z: 465.74 [M]+.
39
HRMS (TOF-ESI) Calcd for C24H15N7O4, 465.1186 [M]+; observed: 488.1083 [M +
Na]+.
(Example 16): (E)-1-((3-nitrobenzylidene)amino)-4-(3-nitrophenyl)-4,5-dihy -
droimidazo[1,2-a]quinoxaline-2-carbonitrile (Compound 16)
5
To a reaction vial, a suspension of 4 (100 mg, 0.502 mmol) in methanol (1 mL) was
added 3-nitrobenzaldehyde (151.72 mg, 1.004 mmol) and p-TsOH (1 mol %). The
mixture was heated under mw irradiation (sealed tube) at 80 ºC for 25 min. After the
completion of the reaction (TLC), methanol was evaporated from mixture,
10 concentrated under vacuum using rotary evaporator, extracted with ethylacetate (10
mL × 3), washed with water, brine, dried over anhydrous Na2SO4, and purified via
flash chromatography (EtOAc: Pet ether:: 1.5 : 8.5). Yield: 93 %; Colour: Yellow;
m.p: 216 - 218 ºC. IR (KBr, cm-1): 2222 (CN stretch), 1496 (NO2 Symmetric stretch),
1039 (NO2 asymmetric stretch). 1H NMR (400 MHz, d6 -DMSO, TMS = 0) δ: 9.21
15 (1H, s), 8.81 (1H, s), 8.46 (2H, t, J13 = 16 Hz), 8.29 (1H, s), 8.17 (1H, d, J = 8 Hz),
7.87 - 7.79 (3H, m), 7.66 (1H, t, J13 = 16 Hz), 7.36 (1H, s), 7.14 (1H, t, J13 = 16 Hz),
7.04 (1H, t, J13 = 16 Hz), 6.81 (1H, t, J13 = 16 Hz), 6.00 (1H, s). 13C NMR (100 MHz,
d6 -DMSO, TMS = 0) δ: 164.24, 148.83, 148.29, 146.36, 143.62, 142.04, 137.70,
136.48, 135.38, 134.54, 131.49, 130.71, 128.42, 127.86, 124.47, 123.63, 122.49,
20 122.04, 119.48, 119.23, 116.37, 115.87, 100.07, 53.96; Elemental Analysis: Anal.
Found C, 61.99, H, 3.30; N, 21.01, Calcd for C24H15N7O4: C, 61.94; H, 3.25; N,
21.07.
(Example17): (E)-1-((4-nitrobenzylidene)amino)-4-(4-nitrophenyl)-4,5-
dihydroimidazo[1,2-a]quinoxaline-2-carbonitrile (Compound 17)
40
To a reaction vial, a suspension of 4 (100 mg, 0.502 mmol) in methanol (1 mL) was
added 4-nitrobenzaldehyde (151.72 mg, 1.004 mmol) and p-TsOH (1 mol %). The
mixture was heated under mw irradiation (sealed tube) at 80 ºC for 25 min. After the
completion of the reaction (TLC), methanol was evaporated from mixture5 ,
concentrated under vacuum using rotary evaporator, extracted with ethylacetate (10
mL × 3), washed with water, brine, dried over anhydrous Na2SO4, and purified via
flash chromatography (EtOAc: Pet ether:: 1 : 9). Yield: 82 %; Colour: Yellow; m.p:
216 - 218 ºC. IR (KBr, cm-1): 2222 (CN stretch), 3345 (NH stretch), 1522 (NO2
10 Symmetric stretch), 1345 (NO2 asymmetric stretch). 1H NMR (400 MHz, d6 -DMSO,
TMS = 0) δ: 9.19 (1H, d, J = 1.2 Hz), 8.41 (2H, d, J = 8 Hz), 8.29 (2H, d, J = 8 Hz),
8.22 - 8.17 (2H, m), 7.94 (1H, d, J = 8 Hz), 7.68 (1H, d, J = 8 Hz), 7.29 (1H, d, J = 8
Hz), 7.17 - 7.13 (1H, m), 7.09 - 7.07 (1H, m), 6.86 - 6.81 (1H, m), 5.93 (1H, s). 13C
NMR (100 MHz, d6 -DMSO, TMS = 0) δ: 162.32, 149.69, 147.18, 146.60, 145.32,
15 142.88, 139.86, 136.94, 130.29, 128.21, 127.66, 124.04, 123.37, 121.51, 118.95,
118.55, 115.80, 54.08; Elemental Analysis: Anal. Found. C, 61.97, H, 3.21; N, 21.06;
Calcd for C24H15N7O4: C, 61.94, H, 3.25; N, 21.07.
(Example18): (E)-1-((2,3,4-trimethoxybenzylidene)amino)-4-(2,3,4-
trimethoxyphenyl)-4,5-dihydroimidazo[1,2-a]quinoxaline-2-carbonitrile
20 (Compound 18)
41
To a reaction vial, a suspension of 4 (100 mg, 0.502 mmol) in methanol (1 mL) was
added 2,3,4-trimthoxybenzaldehyde (199.9 mg, 1.004 mmol) and p-TsOH (1 mol %).
The mixture was heated under mw irradiation (sealed tube) at 80 ºC for 25 min. After
the completion of the reaction (TLC), methanol was evaporated from mixture5 ,
concentrated under vacuum using rotary evaporator, extracted with ethylacetate (10
mL × 3), washed with water, brine, dried over anhydrous Na2SO4, and purified via
flash chromatography (EtOAc: Pet ether:: 2 : 8). Yield: 92 %; Colour: yellow; m.p:
228 - 230 ºC. IR (KBr, cm-1): 2125 (CN stretch), 3285 (NH stretch), 1641 (C=N
10 stretch), 1366 (C=C stretch), 1127 (C-O stretch). 1H NMR (400 MHz, CDCl3, TMS =
0) δ: 9.13 (1H, s), 8.02 (1H, d, J = 8 Hz) 7.91 (1H, d, J = 8 Hz), 7.12 - 7.08 (2H, m),
6.91 (2H, t, J13 = 16 Hz), 6.82- 6.76 (3H, m), 5.82 (1H, s). 13C NMR (100 MHz,
CDCl3, TMS = 0) δ: 159.82, 158.25, 155.18, 153.50, 151.10, 147.62, 143.38, 141.63,
141.55, 137.76, 127.32, 125.99, 123.01, 122.82, 117.66, 115.31, 109.27, 107.88,
15 98.29, 60.60, 60.32, 56.31, 55.90, 49.71. MS (ESI): m/z: 557.49 [M]+.
(Example19): 1-amino-4-(3-nitrophenyl)-4,5-dihydroimidazo[1,2-a]quinoxaline-
2-carbonitrile (Compound 19)
To a reaction vial, a suspension of 4 (100 mg, 0.502 mmol) in methanol (1 mL) was
20 added 3- nitrobenzaldehyde (75.86 mg, 0.502 mmol.) and p-TsOH (1 mol %). The
42
mixture was heated under mw irradiation (sealed tube) at 80 ºC for 25 min. After the
completion of the reaction (TLC), methanol was evaporated from mixture,
concentrated under vacuum using rotary evaporator, extracted with ethylacetate (10
mL × 3), washed with water, brine, dried over anhydrous Na2SO4, and purified via
flash chromatography (EtOAc: Pet ether:: 1.5 : 8.5). Yield: 86 %; Colour: Brownis5 h
solid; m.p: 374 ºC (decomposed). IR (KBr, cm-1): 3384 (NH stretch), 2226 (CN
stretch), 1527 (NO2 Symmetric stretch), 1366 (NO2 asymmetric stretch). 1H NMR
(400 MHz, d6 -DMSO, TMS = 0) δ: 8.17 - 8.13 (2H, m), 7.92-7.65 (3H, m), 7.17- 6.84
(4H, m), 6.34 (2H, NH2), 5.71 (1H, s). 13C NMR (100 MHz, d6 -DMSO, TMS = 0) δ:
10 148.21, 146.51, 142.37, 139.31, 137.70, 136.10, 134.59, 130.52, 127.56, 127.42,
123.36, 122.89, 122.45, 119.34, 116.61, 93.83, 54.09. HRMS (TOF-ESI) Calcd for
C17H12N6O2, 332.10 [M]+; observed: 333.1169 [M+H]+.
(Example 20): 1-amino-4-(4-cyanophenyl)-4,5-dihydroimidazo[1,2-
a]quinoxaline-2-carbonitrile (Compound 20)
15
To a reaction vial, a suspension of 4 (100 mg, 0.502 mmol) in methanol (1 mL) was
added p-cyanobenzaldehyde (65.82 mg, 0.502 mmol and p-TsOH (1 mol %). The
mixture was heated under mw irradiation (sealed tube) at 80 ºC for 25 min. After the
completion of the reaction (TLC), methanol was evaporated from mixture,
20 concentrated under vacuum using rotary evaporator, extracted with ethylacetate (10
mL × 3), washed with water, brine, dried over anhydrous Na2SO4, and purified via
flash chromatography (EtOAc: Pet ether:: 2 : 8). Yield: 94 %; Colour: Yellow; m.p:
275 - 277 ºC. IR (KBr, cm-1): 3365 (NH stretch), 2228, 2143 (CN stretch). 1H NMR
(400 MHz, d6 -DMSO, TMS = 0) δ: 8.77 (2H, d, J = 8.24 Hz), 8.65 - 8.62 (1H, dd, J12
25 = 8 Hz) 8.03 - 7.97 (1H, m), 7.94 - 7.81 (2H, J12 = 8 Hz), 7.64 - 7.57 (2H, m), 6.76
(2H, NH), 4.08 (1H, s). 13C NMR (100 MHz, d6 -DMSO, TMS = 0) δ: 147.86, 144.65,
139.05, 135.59, 131.68, 131.50, 129.91, 129.74, 128.08, 127.41, 126.55, 118.22,
115.69, 115.19, 112.94, 100.19, 59.60. MS (ESI): m/z: 312.43 [M]+; Elemental
43
Analysis: Anal Found. C, 69.16; H, 3.81; N, 26.89. Calcd for C18H12N6: C, 69.22, H,
3.87; N, 26.91.
(Example 21) 1-amino-4,4-dimethyl-4,5-dihydroimidazo[1,2-a]quinoxaline-2-
carbonitrile (Compound 21)
5
To a reaction vial, a suspension of 4 (100 mg, 0.502 mmol) was added acetone (1
equiv.) and the mixture was heated under mw irradiation (open reflux) using p-TsOH
(1 mol %) as catalyst at 80 ºC for 30 min. After the completion of the reaction (TLC),
acetone was evaporated from mixture, concentrated under vacuum using rotary
10 evaporator, extracted with ethylacetate (10 mL × 3), washed with water, brine, dried
over anhydrous Na2SO4, and purified via flash chromatography (EtOAc: Pet ether::
1 : 9). Yield: 88 %; Colour: Light Yellow: mp: 213 - 215 ºC. 1H NMR (400 MHz, d6 -
DMSO, TMS = 0) δ: 7.80 (1H, d, J = 8 Hz), 7.07 (1H, t, J13 = 16 Hz), 6.90 (1H, d, J =
8 Hz), 6.80 (1H, t, JI = 16 Hz), 6.31 (1H, NH, s), 6.15 (2H, NH, s), 2.08 (6H, s). MS
15 (ESI): m/z: 240.16 [M]+. HRMS (TOF-ESI) Calcd for C13H13N5, 239.1171 [M]+;
observed: 262.1062 [M + Na]+.
(Example22)1-amino-4-methyl-4-(3-nitrophenyl)-4,5-dihydroimidazo[1,2-a]
quinoxaline-2-carbonitrile (Compound 22)
20 To a reaction vial, a suspension of 4 (100 mg, 0.502 mmol) in methanol (1 mL) was
added 3- nitro acetophenone (82.90 mg, 0.502 mmol) and the mixture was heated
under mw irradiation (open reflux) using p-TsOH (1 mol %) as catalyst at 80 ºC for
30 min. After the completion of the reaction (TLC), methanol was evaporated from
44
mixture, concentrated under vacuum using rotary evaporator, extracted with
ethylacetate (10 mL × 3), washed with water, brine, dried over anhydrous Na2SO4,
and purified via flash chromatography (EtOAc: Pet ether:: 1.5 : 8.5). Yield: 91 %;
Colour: Light Yellow: mp: 264 – 266 ºC.IR (KBr, cm-1): 3329 (NH stretch), 2212 (CN
stretch), 1233 (C-N stretch), 1609 (C=N stretch), 1453 (C=C stretch), 1528 (NO5 2
Symmetric stretch), 1376 (NO2 asymmetric stretch). 1H NMR (400 MHz, d6 -DMSO,
TMS = 0) δ: 8.10 (1H, s, NH), 7.97 (1H, d, J = 8 Hz), 7.64 (1H, d, J = 8 Hz), 7.59-
7.49 (3H, m), 7.06 (2H, s), 6.70 (1H, s), 6.25 (2H, s, NH2), 1.79 (3H, s). 13C NMR
(100 MHz, d6 -DMSO, TMS = 0) δ: 147.88, 146.95, 146.15, 136.71, 132.15, 130.12,
10 127.02, 122.33, 120.03, 118.91, 117.26, 116.14, 93.28, 57.17, 28.10. HRMS (TOFESI)
Calcd for C18H14N6O2, 346.1178 [M]+; observed: 369.1066 [M + Na]+.
(Example 23) 1-amino-4-benzoyl-4-phenyl-4,5-dihydroimidazo[1,2-
a]quinoxaline-2-carbonitrile (Compound 23)
15 To a reaction vial, a suspension of 4 (100 mg, 0.502 mmol) in methanol (1 mL) was
added benzil (105.48 mg, 0.502 mmol) and the mixture was heated under mw
irradiation (open reflux) using p-TsOH (1 mol %) as catalyst at 80 ºC for 30 min. After
the completion of the reaction (TLC), methanol was evaporated from mixture,
concentrated under vacuum using rotary evaporator, extracted with ethylacetate (10
20 mL × 3), washed with water, brine, dried over anhydrous Na2SO4, and purified via
flash chromatography (EtOAc: Pet ether:: 2 : 8). Yield: 95 %; Colour: yellow; m.p:
184 - 186 0C. IR Spectrum (KBr, cm-1): 3440 (NH stretch), 2206 (CN stretch), 1448
(NH bend), 1670 (C=N stretch). 1H NMR (400 MHz, d6 -DMSO, TMS = 0) δ: 7.74
(2H, t, J13 = 16 Hz), 7.63 (2H, d, J = 4 Hz), 7.49 (1H, t, J13 = 16 Hz), 7.36-7.31 (7H,
25 m), 7.01 (1H, t, J13= 4 Hz), 6.93 (1H, d, J = 4 Hz), 6.78 (1H, t, J13 = 16 Hz), 6.36 (2H,
NH, s) 13C NMR (100 MHz, d6 -DMSO, TMS = 0) δ: 196.26, 139.53, 137.50, 135.80,
134.04, 133.64, 130.22, 128.88, 128.72, 127.65, 127.51, 122.57, 120.19, 117.30,
45
116.91, 93.51, 69.72. HRMS (TOF-ESI) Calcd for C24H17N5O, 391.1433 [M]+;
observed: 414.1319 [M + Na]+.
(Example24)1-amino-4-propyl-4,5-dihydroimidazo[1,2-a]quinoxaline-2-
carbonitrile (Compound 24)
5
To a suspension of 4 (200 mg, 1.005 mmol) in ethanol (1mL) was added
butyraldehyde (72.4 mg, 1.005 mmol) and p-TsOH (1 mol %). The mixture was reflux
at 80 ºC for 3 h. After the completion the reaction (TLC), ethanol was evaporated
10 from mixture, concentrated under vacuum using rotary evaporator, extracted with
ethylacetate (10 mL × 3), washed with water, brine, dried over anhydrous Na2SO4
and purified via column chromatography (EtOAc: Pet ether:: 4 : 6). Yield: 40.3%;
Colour: white; m.p: °C. 1H NMR (400 MHz, d6 -DMSO, TMS = 0) δ: 7.72 (1H, d, J =
7.92 Hz), 7.00 (1H, t, J = 7.96 Hz), 6.92 (1H, d, J = 1.2 Hz), 6.75 (1H, t, J = 7.36 Hz),
15 6.27 (1H, s), 6.13 (2H, s), 4.14 (1H, t, J = 6.12 Hz), 1.65-1.68 (2H, m), 1.54-1.58 (2H,
m), 0.84 (3H, t, J = 7.32 Hz).13C NMR (100 MHz, d6 -DMSO, TMS = 0) δ: 146.2,
141.0, 138.4, 127.1, 122.9, 118.6, 117.6, 117.4, 116.3, 93.6, 51.0, 18.4, 14.3 MS
(EI): m/z: 253 [M+].
(Example 25) 4,4-dimethyl-1-(propan-2-ylideneamino)-4,5-dihydroimidazo-[1,2-
20 a]quinoxaline-2-carbonitrile (Compound 25)
46
To a reaction vial, 4 (100 mg, 0.502 mmol) was dissolved in acetone (2 equiv.) and
the mixture was heated under mw irradiation (open reflux) using p-TsOH (1 mol %)
as catalyst at 80 ºC for 30 min. After the completion of the reaction (TLC), acetone
was evaporated from mixture, concentrated under vacuum using rotary evaporator,
extracted with ethylacetate (10 mL × 3), washed with water, brine, dried ove5 r
anhydrous Na2SO4, and purified via flash chromatography (EtOAc: Pet ether:: 3 : 7).
Yield: 85 %; Colour: Light Yellow, m.p: 142 -144 ºC. IR Spectrum (KBr, cm-1): 3322
(NH stretch), 2210 (CN stretch), 1637 (C=N stretch). 1H NMR (400 MHz, d6 -DMSO,
TMS = 0) δ: 7.60 (1H, d, J = 8 Hz), 7.08 (1H, t, J13 = 16 Hz), 6.89 (1H, d, J = 8 Hz),
10 6.75 (1H, t, J32 = 16 Hz), 6.51 (1H, s), 2.34 (3H, s), 2.12 (3H, s). 13C NMR (100 MHz,
d6 -DMSO, TMS = 0) δ: 179.91, 146.95, 144.58, 137.03, 127.25, 121.86, 117.95,
117.74, 115.77, 98.48, 51.40, 28.64, 26.54, 22.84. HRMS (TOF-ESI) Calcd for
C17H18N4, 279.1484 [M]+; observed: 302.1372 [M + Na]+.
(Example 26) 4H-benzo[f]imidazo[1,5-a][1,3,5]triazepine-3-carbonitrile
15 (Compound 26)
To a reaction mixture of 4 (100 mg, 0.502 mmol) in acetonitrile (1 mL) was added
triethyl orthoformate (74.39 mg, 0.502 mmol) and the mixture was heated under mw
irradiation (open reflux) using p-TsOH (1 mol %) as catalyst at 80 ºC for 30 min. After
20 the completion of the reaction (TLC), acetonitrile was evaporated from mixture,
washed with water, brine, dried over anhydrous Na2SO4, extracted with ethylacetate
(10 mL × 3), concentrated under vacuum using rotary evaporator, dried and purified
via flash chromatography (EtOAc: Pet ether:: 2.5 : 7.5). Yield: 89 %; Colour:
Yellowish Solid; m.p: 387 ºC (decomposed). IR (KBr, cm-1): 3332 (NH stretch), 2224
25 (CN stretch), 1642 (C=N stretch). 1H NMR (400 MHz, d6 -DMSO, TMS = 0) δ: 9.57
(1H, s, NH), 8.07 (1H, s), 7.51 – 7.47 (1H, m), 7.13 - 7.10 (1H, d, J12 = 8 Hz), 6.95 -
6.92 (1H, m), 6.78 – 6.76 (1H, m), 6.64 (1H, d, J = 4 Hz). 13C NMR (100 MHz, d6 -
DMSO, TMS = 0) δ: 147.42, 146.57, 136.27, 133.51, 129.35, 126.51, 124.70,
47
121.58, 121.22, 115.47, 110.0. HRMS (TOF-ESI) Calcd for C11H7N5, 209.0700 [M]+;
observed: 209.9262 [M+H]+.
(Example 27)3-cyano-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,3,5]triazepine-5-
carboxylic acid (Compound 27)
5
To a reaction mixture of 4 (100 mg, 0.502 mmol,) in acetonitrile (1 mL) was added
glyoxalic acid (37.16 mg, 0.502 mmol) using p-toluenesulfonic acid as a catalyst. The
reaction mixture was stirred at r.t. for 1 h. After the completion of the reaction (TLC),
acetonitrile was evaporated from mixture, extracted with ethylacetate, dried and
10 purified via flash chromatography. Yield: 78 %; Colour: Yellowish Solid, mp:319 ºC
(decomposed). 1H NMR (400 MHz, d6 - DMSO/ CDCl3, TMS = 0) δ: 7.72 (1H, s), 7.49
(1H, dd, J12 = 1.2 Hz), 7.39 (1H, d, J = 8 Hz), 7.17-7.09 (1H, m), 7.02-6.98 (1H, m).
Elemental Analysis: Anal. Found. C, 56.44; H, 3.59; N, 27.42. Calcd for C12H9N5O2:
C, 56.47; H, 3.55; N, 27.44.
15 (Example 28) (Z)-1-((2,4-dinitrobenzylidene)amino)-4-(2,4-dinitrophenyl)imidazo
[1,2 a]quinoxaline-2-carbonitrile (Compound 28)
To a suspension of 4 (200 mg, 1.005 mmol) in ethanol (1mL) was added 2,4
20 dinitrobenzaldehyde (197 mg, 1.005 mmol)and p-TsOH (1 mol %). The mixture was
reflux at 80 ºC for 3 h. After the completion the reaction (TLC), ethanol was
48
evaporated from mixture, concentrated under vacuum using rotary evaporator,
extracted with ethylacetate (10 mL × 3), washed with water, brine, dried over
anhydrous Na2SO4 and purified via column chromatography (EtOAc: Pet ether:: 3 :
7). Yield: 36%; Colour: brown; m.p: 213-215 °C. IR (KBr, cm-1): 1607 cm-1 (C=N),
2215 cm-1 (CN). 1H NMR (400 MHz, d6 -DMSO, TMS = 0) δ: 9.64 (1H, s), 8.94-8.85 9
(3H, m), 8.79-8.76 (2H, m), 8.67 (1H ), 8.26 (1H, d, J = 8.52 Hz), 8.17 (1H, d, J = 6
Hz), 7.92 (1H, t, J = 6 Hz ), 7.82 (1H, t, J = 6 Hz).
(Example 29) (E)-4-(3-iodo-4-methoxyphenyl)-1-((1-(3-iodo-4-methoxyphenyl)
ethylidene)amino)-4-methyl-4,5-dihydroimidazo[1,2-a]quinoxaline-2 carbonitrile
10 (Compound 29)
To a reaction mixture of 4 (200 mg, 1.005 mmol,) in ethanol (3 mL) was added 3-
iodo-4-methoxyacetophenone (332.86 mg, 1.206 mmol) using p-toluenesulfonic acid
15 as a catalyst. The reaction mixture was refluxed at 80 ºC for 4 h. After the completion
of the reaction (TLC), methanol was evaporated from mixture, concentrated under
vacuum using rotary evaporator, extracted with ethylacetate (10 mL × 3), washed
with water, brine, dried over anhydrous Na2SO4, and purified via flash
chromatography (EtOAc: Pet ether:: 3 : 7). Yield: 70%, Color: Brownish solid, mp:
20 191-192 ºC. IR (KBr cm-1) Spectrum (KBr cm-1): (I-759), (CN-2230), (NH-2922-2852
), (CH stretch- 3231), (NH-3231-3593 stretch). 1H NMR (400MHz, d6-
DMSO,TMS=0)δ: 7.67(1H, d, J = 7.92), 7.60 (1H, d, J = 2.44), 7.46 (2H, d, J =
8.56), 7.34 (1H, s), 7.11-7.02 (4H, m), 6.85(1H, d, J = 8.56), 6.74 (1H, t, J =
15.28Hz), 3.71. (6H, s), 2.28 (3H, s), 1.74 (3H, s). 13C NMR (100 MHz, d6-DMSO,
25 TMS = 0) δ: 171.61, 157.23, 147.23, 146.49, 142.58, 139.00, 138.22, 137.65,
49
128.59, 126.01, 127.2, 126.1, 123.11, 119.53, 117.54, 117.43, 116.57, 111.70,
93.65, 86.55, 79.49, 56.81, 29.32, 21.37.
(Example30)(E)-4-(3,4-dimethoxyphenyl)-1-((1-(3,4-dimethoxyphenyl)
ethylidene)amino)-4-methyl-4,5-dihydroimidazo[1,2-a]quinoxaline-2-
carbonitrile (Compound 305 )
To a reaction mixture of 4 (200 mg, 1.005 mmol,) in methanol (3 mL) was added 3,4-
dimethoxyacetophenone (216.08 mg, 1.206 mmol) using p-toluenesulfonic acid as a
catalyst. The reaction mixture was refluxed at 80 ºC for 4 h. After the completion of
10 the reaction (TLC), methanol was evaporated from mixture, concentrated under
vacuum using rotary evaporator, extracted with ethylacetate (10 mL × 3), washed
with water, brine, dried over anhydrous Na2SO4, and purified via flash
chromatography (EtOAc: Pet ether:: 3 : 7).Yield: 77%,Color: yellowish solid, mp:
170-172 ºC. (IR KBrcm-1): CH(stretch)-3001-2960, CN (stretch)-1361, ketone-1711,
15 CH3- 1422-1661, C-H(bending out of plane)-847. 1H NMR (400MHz, d6-DMSO,
TMS=0) δ: 7.60(1H,d, J = 7.32), 7.44(5H, d, J = 6.72), 7.08(8H, d, J = 6.72),
6.66(1H,d, J = 6.72), 6.44(1H,d, J = 7.32), 3.58 (6H,s), 3.53 (6H, s).
(Example 31) (E)-4-(4-bromophenyl)-1-((1-(4-bromophenyl)ethylidene)amino)-4-
methyl-4,5-dihydroimidazo[1,2-a]quinoxaline-2-carbonitrile (Compound 31)
50
To a reaction mixture of 4 (200 mg, 1.005 mmol,) in methanol (3 mL) was added 4-
bromoacetophenone (199.9 mg, 1.005 mmol) using p-toluenesulfonic acid as a
catalyst. The reaction mixture was refluxed at 80 ºC for 4 h. After the completion of
the reaction (TLC), methanol was evaporated from mixture, concentrated unde5 r
vacuum using rotary evaporator, extracted with ethylacetate (10 mL × 3), washed
with water, brine, dried over anhydrous Na2SO4, and purified via flash
chromatography (EtOAc: Pet ether:: 2 : 8). Yield: 70%, Color: yellowish solid, mp:
229-231 ºC. IR (KBr cm-1 ): 3281-3187 ,CN-2229, Br- 681,CH3(bend)-1394,C=N-
10 1648. 1H NMR (400MHz, d6-DMSO, TMS=0) δ: 7.62(1H,d, J = 7.92), 7.44(2H,d, J
=8.56), 7.38(2H,d, J = 8.56) ,7.09(4H, t, J = 17.72), 6.99(2H,d, J =7.92), 6.71-
6.67(1H, m), 2.24(3H,s) 13C NMR (100 MHz, d6 -DMSO, TMS = 0) δ: 146.52, 145.94,
144.56, 142.31, 138.33, 137.58, 131.71, 128.64, 128.12, 127.36, 126.02, 123.12,
120.84, 119.10, 117.66, 117.30, 116.62, 93.66, 57.50, 28.62, 21.31.
15 (Example 32) (E)-4-(4-chlorophenyl)-1-((1-(4-chlorophenyl)ethylidene)amino)-4-
methyl-4,5-dihydroimidazo[1,2-a]quinoxaline-2-carbonitrile (Compound 32)
To a reaction mixture of 4 (200 mg, 1.005 mmol,) in methanol (3 mL) was added pchloroacetophenone
(154.27 mg, 1.005 mmol) using p-toluenesulfonic acid as a
20 catalyst. The reaction mixture was refluxed at 80 ºC for 4 h. After the completion of
51
the reaction (TLC), methanol was evaporated from mixture, concentrated under
vacuum using rotary evaporator, extracted with ethylacetate (10 mL × 3), washed
with water, brine, dried over anhydrous Na2SO4, and purified via flash
chromatography (EtOAc: Pet ether:: 2 : 8). Yield: 65%, color: light brown solid, m.p:
210-212 ºC. IR (KBr cm-1): NH-3253-3157, CN-2232, Cl-770,CH3-(bend)-1420, C=5 N-
1662 1H NMR (400MHz, d6-DMSO, TMS=0) δ: 7.63(1H,d, J = 8), 7.49(2H,d, J =
7.92), 7.29-7.26(2H,m), 7.22-7.19(2H,m), 7.13(2H,d, J = 7.92), 7.06-7.04(2H,m),
6.74-6.71(1H,m), 2.28(3H,s), 1.77(3H,s) 13C NMR (100 MHz, d6 -DMSO, TMS = 0) δ:
146.52, 145.69, 144.11, 142.37, 138.50, 137.60, 132.26, 128.78, 128.70, 127.76,
10 127.36, 126.03, 123.11, 119.09, 117.66, 117.30, 116.63, 93.66, 57.45, 28.67, 21.31.
(Example 33)1-amino-4-methyl-4-phenyl-4,5-dihydroimidazo[1,2-a]quinoxaline-
2carbonitrile (Compound 33)
To a reaction mixture of 4 (200 mg, 1.005 mmol,) in methanol (3 mL) was added
15 acetophenone (189.04mg, 1.005 mmol) using p-toluenesulfonic acid as a catalyst.
The reaction mixture was refluxed at 80 ºC for 4 h. After the completion of the
reaction (TLC), methanol was evaporated from mixture, concentrated under vacuum
using rotary evaporator, extracted with ethylacetate (10 mL × 3), washed with water,
brine, dried over anhydrous Na2SO4, and purified via flash chromatography (EtOAc:
20 Pet ether:: 2 : 8). Yield: 55%, color: yellowish solid, m.p: 189-190 0C. (IR KBr cm-1):
NH2 - 3422-3333, CN-2202, CH-2360-2341, CH3 (bend) - 1371 1H NMR (400MHz,
d6-DMSO, TMS=0) δ: 7.62 (1H,d, J = 8.56), 7.33(1H,s), 7.15 (4H,d, J = 4),
7.01(2H,d, J = 4), 6.67(1H,d, J = 4.28), 6.14 (2H,s), 1.74 (3H,s). 13C NMR (100 MHz,
d6 -DMSO, TMS = 0) δ: 146.46, 145.10, 142.80, 137.90, 128.76, 127.48, 127.27,
25 125.73, 123.17, 118.84, 117.61, 117.41, 116.57, 93.71, 57.72, 28.99.
(Example34) 1-amino-4-(3-bromophenyl)-4-methyl-4,5-dihydroimidazo[1,2-
a]quinoxaline-2-carbonitrile (Compound 34)
52
To a reaction mixture of 4 (200 mg, 1.005 mmol,) in methanol (3 mL) was added 3-
bromoacetophenone (240 mg, 1.206 mmol) using p-toluenesulfonic acid as a
catalyst. The reaction mixture was refluxed at 80 ºC for 4 h. After the completion of
the reaction (TLC), methanol was evaporated from mixture, concentrated unde5 r
vacuum using rotary evaporator, extracted with ethylacetate (10 mL × 3), washed
with water, brine, dried over anhydrous Na2SO4, and purified via flash
chromatography (EtOAc: Pet ether:: 4 : 6. Yield: 65%, color: light brown solid,
m.p: 244-245 0C. (IR KBr cm-1): Aromatic stretch-3085-3028, C-H stretch-2923-2874,
10 CH3 (bend)-1494-1460, Br-785-724. 1H NMR (400MHz, d6-DMSO, TMS=0) δ:
7.62(1H,d, J = 8), 7.40(1H,t, J = 4), 7.18-7.07(3H,m), 6.98-6.95(1H,dd, J12 = 4, J34 =
4), 6.90-6.86(1H, m), 4.64(1H,s), 4.19(1H, s), 1.55(3H,s). 13C NMR (100 MHz, d6 -
DMSO, TMS = 0) δ: 129.65, 129.06, 127.41, 126.59, 122.93, 119.32, 115.84,
115.46, 27.69.
15 (Example 35) 1-amino-4-methyl-4-(naphthalen-2-yl)-4,5-dihydroimidazo[1,2-
a]quinoxaline-2-carbonitrile (Compound 35)
N N
CN
NH
H2N
To a reaction mixture of 4 (200 mg, 1.005 mmol,) in methanol (3 mL) was added 2-
acetonaphthone (170.87 mg, 1.005 mmol) using p-toluenesulfonic acid as a catalyst.
20 The reaction mixture was refluxed at 80 ºC for 4 h. Progress of reaction was
monitored via TLC. After the completion of the reaction (TLC), methanol was
evaporated from mixture, concentrated under vacuum using rotary evaporator,
extracted with ethylacetate (10 mL × 3), washed with water, brine, dried over
anhydrous Na2SO4, and purified via flash chromatography (EtOAc: Pet ether:: 5 : 5.
53
Yield: 50%, color: white solid, m.p: Degraded at 240 0C. (IR KBr cm-1):
NH(stretch)10- 3665, C-H(stretch)-2980-2942, aromatic stretch- 3330, aromatic out
of plane bend-1020. 1H NMR (400MHz, d6-DMSO, TMS=0) δ: 7.82-7.77(2H,m),
7.69(1H,t, J = 8), 7.63(1H,d, J = 8), 7.53-7.49(2H, m), 7.39-7.37(1H,m), 7.10(1H,d, J
= 8), 7.02(1H, t, J = 16), 6.66(1H,t, J = 16), 6.28(2H,s), 3.36(2H,s), 1.9(3H,s). 135 C
NMR (100 MHz, d6 -DMSO, TMS = 0) δ: 146.60, 142.75, 142.66, 138.08, 137.93,
137.18, 132.80, 132.44, 128.67, 128.32, 127.86, 127.31, 126.88, 126.63, 124.26,
123.27, 118.97, 117.66, 117.55, 116.65, 93.68, 60.30, 57.93, 28.73, 21.61, 21.30,
14.60.
10 (Example36)(E)-4-methyl-4-(thiophen-2-yl)-1-((1-(thiophen-2-
yl)ethylidene)amino) -4,5 dihydroimidazo [1,2-a]quinoxaline-2-carbonitrile
(Compound 36)
N N
CN
NH
N
S
S
To a reaction mixture of 4 (200 mg, 1.005 mmol,) in methanol (3 mL) was added 2-
15 acetylthiophene (126.8 mg, 1.005 mmol) using p-toluenesulfonic acid as a catalyst.
The reaction mixture was refluxed at 80 ºC for 4 h. Progress of reaction was
monitored via TLC. After the completion of the reaction (TLC), methanol was
evaporated from mixture, concentrated under vacuum using rotary evaporator,
extracted with ethylacetate (10 mL × 3), washed with water, brine, dried over
20 anhydrous Na2SO4, and purified via flash chromatography (EtOAc: Pet ether:: 2 : 8.
Color: creamy color (solid), m.p: 239-240 ºC, yield: 78%; (IR KBr cm-1): NH-3350,
CH-3000, CN-2362, SH-2880, CH3-1447, C-N-1375. 1H NMR (400MHz, d6-DMSO,
TMS=0) δ: 7.72(1H, d, J = 8), 7.45 (2H, d, J = 8), 7.26-7.24(1H,dd, J12 = 4, J34 = 4),
7.08(2H, d, J = 8), 7.03(1H,d, J = 8), 6.97-6.95(1H,m), 6.78-6.70(3H,m), 2.25(3H,s),
25 1.86(3H,s). 13C NMR (100 MHz, d6 -DMSO, TMS = 0) δ: 149.86, 146.43, 145.80,
142.62, 138.42, 137.33, 128.68, 127.34, 127.11, 126.01, 125.79, 124.40, 122.99,
119.17, 117.51, 117.28, 116.69, 93.64, 55.66, 29.05, 21.32.
54
(Example37)1-amino-4-(2,4-dimethoxyphenyl)-4-methyl-4,5-dihydroimidazo[1,2-
a]quinoxaline-2-carbonitrile (Compound 37)
To a reaction mixture of 4 (200 mg, 1.005 mmol,) in methanol (3 mL) was added 2,4-
-dimethoxyacetophenone (180. mg, 1.005 mmol) using p-toluenesulfonic acid as 5 a
catalyst. The reaction mixture was refluxed at 80 ºC for 4 h. Progress of reaction was
monitored via TLC. After the completion of the reaction (TLC), methanol was
evaporated from mixture, concentrated under vacuum using rotary evaporator,
extracted with ethylacetate (10 mL × 3), washed with water, brine, dried over
10 anhydrous Na2SO4, and purified via flash chromatography (EtOAc: Pet ether:: 2 : 8.
Color: yellowish solid, m.p: 136-137 ºC, Yield: 67%. IR (KBr cm-1): NH-3300,CH3-
1448, C-O-1330-1026, NH(bend)-1646,NH-3300, CH-3000. 1H NMR (400MHz, d6-
DMSO, TMS=0) δ: 7.63(1H,d, J = 8), 6.96-6.88(2H,m), 6.68(1H,t, J = 16),
6.51(1H,s), 6.42(1H,d, J = 2.4), 6.23(2H,s), 6.19-6.16(1H, dd, J12 = 4, J34 = 4),
15 6.10(1H,d, J = 8), 3.84(3H,s), 3.62(3H,s), 1.86(3H,s). 13C NMR (100 MHz, d6 -
DMSO, TMS = 0) δ: 160.31, 158.25, 146.54, 142.82, 138.10, 128.14, 127.01,
123.38, 119.17, 117.51, 117.42, 116.76, 104.38, 99.96, 93.18, 57.89, 56.18, 55.51,
25.21.
(Example38)1-amino-4-methyl-4-(3,4,5-trimethoxyphenyl)-4,5-dihydroimidazo
20 [1,2 a]quinoxaline--2-carbonitrile (Compound 38)
To a reaction mixture of 4 (200 mg, 1.005 mmol,) in methanol (3 mL) was added
3,4,5-Trimethoxyacetophenone (211.28 mg, 1.005 mmol) using p-toluenesulfonic
55
acid as a catalyst. The reaction mixture was refluxed at 80 ºC for 4 h. Progress of
reaction was monitored via TLC. After the completion of the reaction (TLC),
methanol was evaporated from mixture, concentrated under vacuum using rotary
evaporator, extracted with ethylacetate (10 mL × 3), washed with water, brine, dried
over anhydrous Na2SO4, and purified via flash chromatography (EtOAc: Pet ether5 ::
3 : 7. Yield: 74%, Color: Peach solid color m.p: 151-152 0C, IR (KBr cm-1):
NH(stretch)-3512, C-H(absorption)- 2845, C-H(stretch)-2994, CH3(bend)-1373,
CH3(bend)-1244. 1H NMR (400MHz, d6-DMSO, TMS=0) δ: 7.64(1H, d, J = 8),
7.43(2H,d, J = 8), 7.08(3H,d, J = 8), 6.70(1H, t, J = 16), 6.48(2H,s), 3.57(6H, s),
10 3.50(3H, s), 1.78(3H,s). 13C NMR (100 MHz, d6 -DMSO, TMS = 0) δ: 152.99, 146.45,
145.76, 142.80, 140.64, 138.45, 138.03, 136.64, 128.69, 127.29, 126.01, 123.20,
118.98, 117.71, 117.44, 116.62, 103.41, 93.48, 60.34, 57.89, 56.23, 29.00, 21.31.
(Example 39)1-amino-4-hydroxy-4-(phenylamino)-4,5-dihydroimidazo[1,2-
a]quinoxaline-2-carbonitrile (Compound 39)
15
To a reaction mixture of 4 (150 mg, 0.753 mmol,) in dichlorometane (DCM) (1 mL)
was added phenyl isocyanate (107.74 mg, 0.904 mmol) using p-toluenesulfonic acid
as a catalyst. The reaction mixture was refluxed for 4 h. After the completion of the
reaction (TLC), DCM was evaporated from mixture, extracted with ethylacetate, dried
20 and purified via flash chromatography. Yield: 43 %; Colour: Yellowish Solid, mp: 271
– 273 ºC. 1H NMR (400 MHz, d6 - DMSO/ CDCl3, TMS = 0) δ: 8.94 (1H, s, D2O
exchangeable NH), 8.21 (1H, d, J = 8), 7.73 (1H, s, D2O exchangeable NH), 7.34
(1H, t, J = 8), 7.30 (2H, d, J = 8), 7.16-7.03 (3H, m), 6.86 (IH, t, J = 16), 5.70 (1H, s;
D2O exchangeable NH2). 13C NMR (100 MHz, d6 -DMSO, TMS = 0) δ: 151.02,
25 146.79, 137.93, 135.10, 130.81, 128.90, 127.32, 127.09, 121.48, 121.11, 120.74,
120.51, 116.92, 115.81, 89.64. MS (ESI): m/z: 318 [M]+.
(Example 40)1-amino-4-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]quinoxaline-2-
carbonitrile (Compound 40)
56
To a reaction mixture of 4 (100 mg, 0.502 mmol,) in 1,4-dioxane (1 mL) was added
3,4,5-trimethoxybenzaldehyde (136.5 mg, 0.693 mmol) using p-toluenesulfonic acid
as a catalyst. The reaction mixture was refluxed for 4 h. After the completion of the
reaction (TLC), 1,4 dioxane was evaporated, extracted with ethylacetate, dried an5 d
purified via flash chromatography. Yield: 63 %; Colour: brownish Solid, mp:211-213
ºC. 1H NMR (400 MHz, CDCl3, TMS = 0) δ: 8.53 (1H, d, J = 4), 8.14 (1H, d, J = 8),
7.96 (2H, s), 7.64-7.60 (2H, m), 4.53 (2H, s; D2O exchangeable NH2), 4.03 (6H, s),
3.94 (3H, s). 13C NMR (100 MHz, CDCl3, TMS = 0) δ: 153.02, 149.63, 142.20,
10 140.67, 136.57, 133.59, 130.83, 130.40, 128.14, 127.53, 127.45, 114.82, 107.20,
104.19, 61.09, 56.39.
(Example-41)(E)-4-(2,3,4-trimethoxyphenyl)-1-(2,3,4-trimethoxystyryl)-
4,5dihydroimidazo[1,2-a]quinoxaline-2-carbonitrile (Compound 41)
15 To a reaction mixture of 4 (200 mg, 1.005 mmol,) in methanol (1 mL) was added
2,3,4-trimethoxybenzaldehyde (197.18 mg, 1.005 mmol) and benzaldehyde (106.7
mg, 1.005 mmol) using p-toluenesulfonic acid as a catalyst. The reaction mixture
was refluxed for 4 h. After the completion of the reaction (TLC), methanol was
evaporated, extracted with ethylacetate, dried and purified via flash chromatography.
20 Yield: 38 %; Colour: off white, mp: 209-211 ºC. 1H NMR (400 MHz, d6 – DMSO, TMS
= 0) δ: 8.95 (1H, s), 7.93 (1H, d, J = 6.4), 7.42 (2H, s),7.16-7.07 (3H, s), 6.86 (1H, t, J
= 12), 6.67 (2H, s), 5.68 (1H, s), 3.90 (6H, s), 3.80 (3H, s), 3.64 (6H, s), 3.38 (3H, s).
57
(Example-42)(Z)-1-((4-isopropylbenzylidene)amino)-4-(4-isopropylphenyl)
imidazo[1,2-a]quinoxaline-2-carbonitrile (Compound 42)
To a suspension of 4 (200 mg, 1.005 mmol) in ethanol (1mL) was added 4-
isopropylbenzaldehyde (268 mg, 1.809 mmol) and p-TsOH (1 mol %). The mixtur5 e
was reflux at 80 ºC for 3 h. After the completion the reaction (TLC), ethanol was
evaporated from mixture, concentrated under vacuum using rotary evaporator,
extracted with ethylacetate (10 mL × 3), washed with water, brine, dried over
anhydrous Na2SO4 and purified via column chromatography (EtOAc: Pet ether:: 3 :
10 7) Yield: 43%; Colour: Yellowish; m.p: 165-168°C. IR (KBr, cm-1): 3444 cm-1 (NH2),
1600 cm-1 (C=N), 2225 cm-1 (CN). 1H NMR (400 MHz, d6 -DMSO, TMS = 0) δ: 9.13
(1H, s), 9.08-9.04 (1H, m), 8.52 (2H, d, J = 8 Hz), 8.15-8.13 (1H, m), 8.03 (2H, d, J =
8 Hz), 7.63-7.61 (2H, m ), 7.47-7.42 (4H, m), 3.08-2.98 (2H, m), 1.24 (12H, m). MS
(EI): m/z: 457 [M+], 457 (base peak)
15 (Example 43) (E)-1-((5-hydroxy-2-nitrobenzylidene)amino)-4-(5-hydroxy-2-
nitrophenyl)-4,5-dihydroimidazo[1,2-a]quinoxaline-2-carbonitrile (Compound
43)
To a suspension of 4 (200 mg, 1.005 mmol) in ethanol (1mL) was added 5-hydroxy-
20 2-nitrobenzaldehyde (335.91 mg, 2.010 mmol and p-TsOH (1 mol %). The mixture
58
was reflux at 80 ºC for 3 h. After the completion the reaction (TLC), ethanol was
evaporated from mixture, concentrated under vacuum using rotary evaporator,
extracted with ethylacetate (10 mL × 3), washed with water, brine, dried over
anhydrous Na2SO4 and purified via excess washing with ethanol (10 mL × 3). Yield:
70%; Colour: brown; m.p: 224-226°C. IR (KBr, cm-1): 1530 cm-1 (N02), 1611 cm-5 1
(C=N), 2225 cm-1 (CN). 1H NMR (400 MHz, d6 -DMSO, TMS = 0) δ: 11.4 (1H, s),
10.9 (1H, s), 9.48 (1H, s), 8.17 (1H, d, J = 9.16 Hz), 8.11 (1H, d, J = 8.56), 7.97 (1H,
d, J = 7.32), 7.60 (1H, d, J = 3.04), 7.18-7.15 (2H, m), 7.06-7.01 (2H, m), 6.93-6.87
(3H, m), 6.45 (1H, s).13C NMR (100 MHz, d6 -DMSO, TMS = 0) δ: 190.69, 163.06,
10 162.99, 162.48, 145.88, 143.43, 140.12, 137.93, 137.17, 129.09, 128.83, 128.40,
119.57, 119.33, 116.27, 116.13, 115.34, 100.59, 56.55, 51.55, 51.41, 21.4, 19.08
(Example44)(E)-4-(furan-2-yl)-1-((furan-2-ylmethylene)amino)-4,5-
dihydroimidazo[1,2-a]quinoxaline-2-carbonitrile (Compound 44)
15 To a suspension of 4 (200 mg, 1.005 mmol) in ethanol (1mL) was added furan-2-
carbaldehyde (193.1 mg, 2.01 mmol) and p-TsOH (1 mol %). The mixture was reflux
at 80 ºC for 3 h. After the completion the reaction (TLC), ethanol was evaporated
from mixture, concentrated under vacuum using rotary evaporator, extracted with
ethylacetate (10 mL × 3), washed with water, brine, dried over anhydrous Na2SO4
20 and purified via excess washing with methanol (10 mL × 3). Yield: 70%; Colour:
black; m.p: 246-248°C. IR (KBr, cm-1): 1611 cm-1 (C=N), 2218 cm-1 (CN). 1H NMR
(400 MHz, d6 -DMSO, TMS = 0) δ: 8.83 (1H, s), 8.25 (1H, d, J = 7.32 Hz), 7.75 (1H,
d, J = 1.24 Hz), 7.35 (1H, d, J = 3.68 Hz), 7.22 (1H, d, J = 3.68 Hz), 7.11 (1H, t, J =
7.32 Hz), 6.93 (1H, t, J = 7.36 Hz), 6.84 (1H, d, J = 1 Hz), 6.66-6.65 (1H, m), 6.28-
25 6.27 (1H, m), 6.16 (1H, d, J = 3.64 Hz), 5.75 (1H, s), 4.54 (1H, s). MS (EI): m/z: 354
[M+], 354 (base peak).
Biological Studies
59
Antiproliferative activity
A few target compound reported herein, were evaluated for their antiproliferative
potential utilising MTT (3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide
assay. MTT assay was carried out using 96-wellplate; each well was filled by 100 μL
media to which cell were treated and subsequently washed with 1 % PBS and wer5 e
mixed with 100 μL/mL well of MTT (5 mg in 10 mL of 1 % PBS) and incubated at
room temperature in dark for 4 h to allow formation of formazan crystals. Each well
was then mixed with 100 μL of DMSO to dissolve the crystals followed by readings
using microplate reader at 570 nm. The results were then represented as mean ±
10 S.D obtained from three independent experiments. The experiment was conducted
against human lung (A-549), colon (HCT-116-wild type) and glioblastoma (U- 87
MG) cancer cell lines. Most of the compounds exhibited IC50 values at micromolar
range. Colchicine was used as the positive control 30. The results are represented in
table.1.
15 Table 1: Antiproliferative activity of the target compounds.
Compound
A-549
(Lung cancer)
HCT-116-Wild
Type
(Colon
carcinoma)
U-87 MG
(Glioblastoma)
IC50 values (μM)a
8 2.7 ± 0.1 5.1 ± 0.2 4.1 ± 0.1
9 16.2 ± 0.6 14.9 ± 0.3 4.7 ± 0.2
10 17.2 ± 0.5 4.9 ± 0.2 5.3 ± 0.1
11 8.1 ± 0.3 >25 21.1 ± 0.8
13 9.3 ± 0.4 16.2 ± 0.8 4.3 ± 0.1
14 4.9 ± 0.1 >25 >25
15 11.2 ± 0.7 8.2 ± 0.2 2.9 ± 0.1
16 5.2 ± 0.3 6.1 ± 0.2 2.7 ± 0.3
17 8.2 ± 0.2 <1 2.2 ± 0.1
18 >25 <1 5.9 ± 0.2
19 4.2 ± 0.5 <1 4.3 ± 0.3
60
20 3.1 ± 0.1 4.9 ± 0.6 4.2 ± 0.2
21 3.8 ± 0.2 17.2 ± 0.4 >25
22 19 ± 0.7 4.9 ± 0.3 8.3 ± 0.5
23 7.2 ± 0.3 <1 3.8 ± 2
25 13.5 ± 0.4 11.3 ± 0.7 17.7 ± 0.3
26 6.2 ± 0.1 <1 19.7 ± 0.2
27 4.2 ± 0.2 3.6 ± 0.5 2.2 ± 0.1
Colchicineb 1.20 ± 0.8 <1 2.7 ± 0.6
aValues are derived from averaging three independent experiments and each experiment was done
in triplicate.
bUsed as positive control.
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WE CLAIM:
1. Fused heterocycles compounds represented by Formula (I) and Formula (II):
Y'
G
N N
Y
X
Formula II
Formula I
R1
R2
R3
R4
X1
N
N
Y
G
Y'
Y3
Y3
Y2
Y2
Y1
Y4
Y5
Y1
Y5
R1
R2
R3
R4
Y4
R
X2
A
B
C
A
B
C
5 wherein each of R1, R2, R3, and R4 independently represents hydrogen, alkyl,
alkenyl, alkynyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, aryl, cycloalkyl, heteroaryl
or heterocyclyl; Y represents no atom; O or S or –NR (wherein R represents alkyl,
alkenyl, alkynyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, aryl, cycloalkyl, heteroaryl
or heterocyclyl);
10 wherein each of Y1, Y2, Y3, Y4 and Y4 independently represents hydrogen;
alkyl; -OR; -SR; or –NHR (wherein R represents alkyl, alkenyl, alkynyl, aralkyl,
heteroarylalkyl, heterocyclylalkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl);
wherein G represents CH N, S or O; in the generic structure formula I and II,
A, B and C represents the rings;
wherein each of X1 and X2 15 independently represents hydrogen, alkyl,
cycloalkyl, heterocyclyl, heteroaryl, aralkyl heterocyclylalkyl or heteroarylalkyl;
wherein Y represents cyano or alkyl, alkenyl, alkynyl, aralkyl, heteroarylalkyl,
heterocyclylalkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl,
or a pharmaceutically acceptable salts thereof.
20
2. The fused heterocycles compounds or the pharmaceutically acceptable salts
thereof as claimed in claim 1, wherein any of X and X2 or X1 together optionally form
a cyclic ring fused with the ring B.
25 3. The fused heterocycles compounds or the pharmaceutically acceptable salts
thereof as claimed in claim 1, wherein X1 and X2 together optionally form a cyclic ring
fused with the ring B.
63
4. A process for synthesis of fused heterocycles compound represented by
Formula I comprising the steps of:
conducting either thermal or microwave or catalyst mediated reaction of
compound 4 with a reagent iv to yield said compound of Formula (I) in an organi5 c
solvent such as, not being limited to, dimethylformamide, tetrahydrofuran,
acetonitrile, methanol, dioxane or diethyl ether.
5. A process for synthesis of fused heterocycles compound represented by
10 Formula II comprising the steps of:
conducting either thermal or microwave or reflux or catalyst mediated reaction
of compound 4 with a reagent v to yield said compound of Formula (II) in an organic
solvent such as, not being limited to, dimethylformamide, acetonitrile, methanol,
tetrahydrofuran, dioxane or diethyl ether.
15
6. A process for synthesis of heterocycles compound represented by Formula III
comprising the steps of:
conducting either thermal or microwave heating or reflux or catalyst mediated
reaction of compound 4 with a reagent vi to yield a compound of Formula III in an
20 organic or aqueous solvent such as, not being limited to, dimethylformamide,
acetonitrile, methanol, tetrahydrofuran, dioxane or diethyl ether.
7. The process as claimed in claims 4 to 6, wherein compound 4 is:
N
N
CN
NH2
NH2
4
R3
R4
R2
R1
25
8. The fused heterocycles/heterocyclic compounds synthesized by the process
as claimed in claims 4 to 7, comprising the following compounds:
64
65
66
Compound 34
Compound 42
Compound 35 Compound 36
Compound 38 Compound 39 Compound 40 Compound 41
Compound 43 Compound 44
N N
CN
HN
H2N
Br
N N
CN
NH
H2N
N
NC N
N NH
S
S N N
CN
NH
H2N
H3CO OCH3
Compound 37
N N
CN
NH
H2N
OCH3
OCH3
OCH3 N
N
CN
NH2
HN
HN
OH
N
N
CN
NH2
N
O
O
O
N
N
O HN
O
O
CN
N
O
O
O
N
N
N
N
NC
N
NH
N
N
NO2
HO
NO2 N
HO
N NH
N
N
N
O
O
and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates,
enantiomers, diastereomers or N-oxides.
5
9. A pharmaceutical composition, which comprises, as an active ingredient,
therapeutically and prophylactically effective amount of fused heterocycles
compounds represented by Formula (I) and Formula (II) or a pharmaceutically
acceptable salt thereof as claimed in claim 1.