^ FIELD OF THE INVENTION
The present invention relates to 6-aryl-4-phenylamino quinazolines. The present invention
particularly relates to synthesis, anticancer and phosphoinositide-3-kinase inhlbititory activity of 6-
aryl-4-phenylamino quinazoline compounds. More particularly the present invention relates to
methods for the treatment of cancer diseases, including those caused by kinase-mediated
proliferation of tumor cells. Compounds of the invention can be used for prevention or in the
treatment of cancer diseases, such as pancreatic, breast, prostate and melanoma cancers.
BACKGROUND OF THE INVENTION
Cancer is an uncontrolled growth and spread of cells that may affect almost any tissue of the body.
There are over 100 different types of cancer, and each is classified by the type of cell that is initially
affected. The approach to the discovery of new anticancer drugs has recently evolved from a
reliance on empiric cell-based screening for anti-proliferative effects to a more mechanistically
based approach that targets the specific molecular lesions thought to be responsible for the
development and maintenance of the malignant phenotype in various forms of cancer. Through this
approach, the kinase inhibitors have emerged as a new class of anticancer drugs that are capable
of directly interacting with the catalytic site of the target enzyme and thereby inhibiting kinase
function or blocking kinase signaling. In 1994, Parke-Davis scientists reported the first generation of
very potent kinase inhibitor with manifold selectivity against other kinases (Fry, D.V. et al.. Science
1994, 265, 1093). This discovery spurred the development of projects throughout the
pharmaceutical industry; and as of now 18 kinase inhibitors have been approved by FDA for various
diseases, and more than 500 candidates are in active clinical development.
Phosphoinositide 3-kinases (PI3Ks) constitute a family of lipid kinases involved in the
regulation of a network of signal transduction pathways that control a range of cellular processes
(Ihle, N.T. and Powis, P. Mol. Cancer Ther. 2009, 8, 1 ; Vivanco, I. and Sawyers, C.L. Nature Rev.
Cancer 2002, 2, 489). The PI3K signaling plays a central role in cellular processes critical for
cancer progression, metabolism, growth, survival and motility. The PI3K family of enzymes is
comprised of 15 lipid kinases with distinct substrate specificities, expression patterns, and modes of
regulation. In particular, PI3K-a has emerged as an attractive target for cancer therapeutics.
Significant efforts have been made to discover inhibitors of the PI3K pathway to treat cancers and
several candidates have advanced to clinical studies such as XL-765 and XL-147 (Exelixis), which
are class I PI3K inhibitors that have entered Phase I clinical studies for advanced solid tumors.
2
J f c other PI3K inhibitors in clinical studies include BEZ-235 and BKM-120 (Phase II, Novartis) and
GSK-1059615 (Phase I, GSK) for advanced solid tumors. AstraZeneca's AZD-6482, which is a
PI3K-P inhibitor, has completed Phase I trials for the treatment of thrombosis. A quinazolinonebased
isoform-specific PI3K-5 inhibitor CAL-101 (GS-1101, Gilead Sciences) is in Phase III and IC-
87114 (Calistoga) has entered Phase I clinical trial. Other PI3K inhibitors in clinical trials include
D106669 and D87503 (Phase I, Aeterna Zentaris), GDC-0941 (Phase I, Genentech) and PKI-587
(Phase I, Pfizer). In addition, several other PI3K inhibitors are in early stages of clinical trials.
Despite of the fact that large number of kinase inhbiitors have received FDA-approval, the target
selectivity remains a formidable challenge in drug development because almost all approved kinase
inhibitor drugs works by competing with ATP for the ATP binding site of the enzyme. Hence, there
is a great need for next-generation kinase inhibitors that work through alternative mechanisms such
as allosteric inhibition. While recently approved kinase inhibitor drugs offer benefits for cancer
treatment, further advances are required to effect tumor selective cell killing, avoid off-target related
toxicities and improve survival rates (Bharate, S.B. et al., Chem. Rev. 2013, 113, 6761). Amongst
the four isoforms of phosphoinositide 3-kinases, particularly the a-isoform has been found to be
activated by mutation in several cancers; and therefore discovery of a-isoform selective inhibitor is
highly important. BEZ-235 (Novartis molecule) is a pan-PI3K inhibitor inhibiting all four isoforms with
IC50 values of 4, 76, 7 and 5 nM respectively; thus showing very poor selectivity towards a-isoform
compared with 3, y and 8 isoforms (19, 17.5 and 1.25 fold selectivity).
OBJECTIVES OF THE INVENTION
The main object of the present invention is to provide 6-aryl-4-phenylamino quinazolines.
Another object of the present invention is to provide novel anticancer compounds for the treatment
of various types of cancers, such as pancreatic, breast, prostate and melanoma cancer.
One more objective of the invention is to provide a process for preparation of 6-aryl-4-phenylamino
quinazolines.
SUMMARY OF THE INVENTION
Accordingly, the present invention relates to a compound of formula I,
#
wherein, R is selected from the group comprising of alkyl, nitro, halogens (fluoro, chloro, bromo and
iodo), formyl, allyl, vinyl, benzyl, acetyl, hydroxy, phenyl, substituted phenyl, fused aromatics;
R' is selected from the group consisting of hydrogen, cyanomethyl, or alkyls.
Ar is selected from the group comprising of aryl or heteroaryl, which is unsubstituted or substituted
with an alkyl, nitro, halogens, formyl, allyl, vinyl, benzyl, acetyl, hydroxy, phenyl, substituted phenyl,
fused aromatics.
In an embodiment of the invention wherein, aryl is selected from the group consisting of phenyl,
biphenyl which is unsubstituted or substituted with different R groups, which is selected from the
group comprising of alkyl, nitro, halogens (fluoro, chloro, bromo and iodo), formyl, allyl, vinyl,
benzyl, acetyl, hydroxy, phenyl, substituted phenyl, fused aromatics.
In another embodiment of the invention wherein Alkyl group is selected from the group consisting
of (C1-C6)-alkyl, (C1-C4)-haloalkyl, (C1-C4)-alkoxy, (C1-C4)-haloalkoxy; oris (C5-C8)-cycloalkyl,
(C5-C8)-cycloalkenyl, (C6-C10)-bicycloalkyl, (C6-C10)-bicycloalkenyl.
In yet another embodiment of the invention wherein, substituted phenyl is selected from the group
consisting of alkylphenyls, alkoxyphenyls.
In one more embodiment of the invention wherein, fused aromatics is selected from the group
consisting of naphthalene, 2,3-dihydrobenzo[b][1,4]dioxin, benzo[d][1,3]dioxol, benzofuran,
benzo[b]thiophene, dibenzo(b,d)furan, dibenzo(b,d)thiophene, 1H-indole, quinoline, isoquinoline.
In still another embodiment of the invention wherein, heteroaryl is selected from the group
consisting of pyridine, quinoline, isoquinoline, 2,3-dihydrobenzo[b][1,4]dioxin, benzo[d][1,3]dioxol,
benzofuran, benzo[b]thiophene, dibenzo(b,d)furan, dibenzo(b,d)thiophene, 1H-indole.
In a further embodiment of the invention wherein, the structural formulae of the said compounds
comprising:
' *.
N O2N
10
; and
In still one more embodiment of the invention wherein, the compounds are useful for the treatment
of cancer.
In an embodiment of the invention wherein, the compounds are phosphoinositide-3-kinase
inhibitors..
In yet one more embodiment of the invention wherein the compounds are active against cancer cell
lines selected from a group consisting of HL-60, A375, MCF-7, Panc-1, PC-3.
In an embodiment of the invention wherein the compounds are phosphoinositide-3-a kinase
inhibitors upto about 70% at 0.5 pM concentration.
Accordingly, the present invention provides a process for preparation of the compounds of general
formula I, wherein the process steps comprising:
a) reacting anthralinic acid (1) with bromine in glacial acetic acid at a temperature in the range of
10-25 °C for the time period of ranging between 15-30 min, followed by diluting with dilute HCI to
^m obtain monobromo anthranilic acid (2);
b) adding formamide to monobromo anthranilic acid obtained in step (a) followed by reflux at a
temperature ranging between 100-150 °C for a time period ranging between 4-10 h to obtain
compound 3;
c) adding POCI3 to the solution of compound 3 as obtained in step (b) followed by reflux at a
temperature ranging between 100-150 °C for a time period ranging between 4-10 h to obtain
compound 4;
d) adding 4-amino benzylcyanide to the solution of compound 4 as obtained in step (c) forming a
mixture which is dissolved in isopropanol followed by stirring for a time period of ranging between 2-
6 h under reflux at a temperature ranging between 80-100 °C to obtain compound 5;
e) reacting aryl boronic acid in suitable solvent with compound 5 as obtained in step (d) followed by
addition of Pd(PPh3)4 followed by stirring of the resultant mixture for the time period ranging
between 12-24 h at a temperature ranging between 80-100 °C to yield compound of formula I.
In an embodiment of the invention wherein the aryl boronic acid used in step (e) is selected form
the group consisting of substituted phenyls, substituted biphenyls, substituted naphthyls, substituted
heteroaryls.
In a further embodiment of the invention wherein, the solvent used in step (e) is selected from
toluene or dioxane.
In the present invention, we have identified 6-aryl-4-phenylamino quinazolines as PI3K-a isoform
selective inhibitors showing selectivity fold up to >133, 56 and >49.7 versus p, y and 8 isoforms,
respectively. Furthermore, the 6-aryl-4-phenylamino quinazoline scaffold has never been reported
in literature as PI3K-alpha inhibitor
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a diagram illustrating the chemical synthesis of the 6-aryl 4-phenylamino-quinazolines of
the invention.
Synthetic scheme for preparation of 6-aryl-4-phenylamino-quinazoline analogs. Reagents and
conditions; (a) Brz (1.2 equiv.), AcOH (10 mL), 10- 25 °C; followed by dil.HCI (20 mL), reflux, 85%;
(b) NH2CHO (4 equiv.), 150 °C, 6 h, 70% (c) POCI3 (5 mL), reflux at 100 °C, 6 h, 92%; (d) 4-amino
benzylcyanide (1.3 equiv), isopropanol (5 mL), reflux, 3 h, 82%; (e) ArB(OH)2(1.2 equiv.), Pd(PPh3)4
(0.05 equiv), 2 M K2CO3 solution (3 mL), dioxane (3 mL), reflux, 12 h, 43-92%.
^ p Figure 2 is a diagram showing interactions of 6-aryl-4-phenylamino quinazoline 10 and 29 with the
active site of phosphoinositide-3-kinase-a.
The 2D and 3D-representation of binding interactions of compounds 10 (A and C) and 29 (B and D)
with PI3Ka. Red arrows and dotted line indicates sites of hydrogen bonding and solid green line
indicates aromatic n-n interactions.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to 6-aryl-4-phenylamino quinazoline compounds of general formula I
as promising anticancer agents.
R-- Ar
The present invention relates to novel compounds that shows promising anti-cancer activity against
various cancer cell lines viz. Panc-1 (pancreatic cancer), MCF-7 (breast cancer), PC-3 (prostate
cancer), HL-60 (leukemia) and A-375 (melanoma) and inhibition of phosphoinositide-3-kinase
(PI3K-a) which is implicated in proliferation of tumor cells. The anticancer activity of 6-aryl-4-
phenylamino quinazolines 10 (IC50 values: 36 [JM for panc-1, 15 |JM for MCF-7, 37 |JM for PC-3, 24
MM for HL-60 and 28 pM for A375) and 29 (IC50 values: 9 pM for Panc-1, 12 pM for MCF-7, 9 pM for
PC-3, 10 pM for HL-60 and 12 pM for A375) on various cancer cell lines is shown in Table 1 and 2.
The compounds 10 and 29 showed promising inhibition of PI3K-a with IC50 values of 0.115 and
0.150 pM, showing excellent selectivity towards a-isoform versus other isoforms of PI3K. Simialrly,
compound 26 displayed excellent selectivity towards a-isoform versus p- and 8-isoforms. Unlike the
known structurally similar PI3K-a inhibitor NVP-BEZ-235, which inhibits all isoforms of PI3K at low
nanomolar concentrations, the compound 29 exhibited greater selectivity towards PI3K-a versus
other isoforms. In particular, the compound 29 did not inhibit (0% inhibition) PI3K-P up to 20 pM.
The isoform selectivity of compounds towards PI3K-a is provided in the Table 2. The promising
activity of 6-aryl-4-phenylamino quinazolines 10, 26 and 29 against PI3K-a clearly indicates their
potential to develop as anticancer agents. The complimentary fit of compounds 10 and 29 into the
active site of PI3K-a is shown by the key H-bonding and n-n interactions of these compounds with
active site residues of enzyme are shown in Figure 2. The growth inhibitory properties of
#
compounds of the invention against various cancer cell lines and their inhibitory activity against
PI3K-a can therefore be used to treat or prevent diseases, disorders, conditions, or symptoms in a
patient (e.g. human) that involve, directly, or indirectly, proliferation of cell growth or overexpression
of PI3K-a kinase.
A class of 6-aryl-4-phenylamino quinazolines is presented and defined by structural formula I:
RI
wherein, the position 6 may contain various substituted aryl rings; and phenylamino moiety located
at position 4 may be substituted; wherein
Ar is aryl or heteroaryl, which is unsubstituted or substituted with an alkyl, nitro, halogens, formyl,
allyl, vinyl, benzyl, acetyl, hydroxy, phenyl, substituted phenyl, fused aromatics.
wherein, aryl is selected from phenyl, biphenyl which is unsubstituted or substituted with different R
groups.
Alkyl group is selected from (C1-C6)-alkyl, (C1-C4)-haloalkyl, (C1-C4)-alkoxy, (C1-C4)-haloalkoxy;
oris (C5-C8)-cycloalkyl, (C5-C8)-cycloalkenyl, (C6-C10)-bicycloalkyl, (C6-C10)-bicycloalkenyl.
Substituted phenyl is selected from alkylphenyls, alkoxyphenyls.
Fused aromatics is selected from naphthalene, 2,3-dihydrobenzo[b][1,4]dioxin, benzo[d][1,3]dioxol,
benzofuran, benzo[b]thiophene, dibenzo(b,d)furan, dibenzo(b,d)thiophene, 1H-indole, quinoline,
isoquinoline.
Heteroaryl is selected from pyridine, quinoline, isoquinoline, 2,3-dihydrobenzo[b][1,4]dioxin,
benzo[d][1,3]dioxol, benzofuran, benzo[b]thiophene, dibenzo(b,d)furan, dibenzo(b,d)thiophene,
1H-indole.
^ P R is selected from alkyl, nitro, halogens, formyl, allyl, vinyl, benzyl, acetyl, hydroxy, phenyl,
substituted phenyl, fused aromatics.
R' is selected from the group consisting of hydrogen, cyanomethyi, or any carbon atom which may
be optionally substituted.
Compounds of the invention derived from Formula I include, but are not limited to, the following
chemical structures:
6-phenyl-4-(4-cyanomethyl)phenylamino quinazoline (6);
ON
6-(2,4-difluorophenyl)-4-(4-cyanomethyl)phenylamino quinazoline (7);
CN
6-(2-formylphenyl)-4-(4-cyanomethyl)phenylamino quinazoline (8);
10
^ B
6-(4-acetylphenyl)-4-(4-cyanomethyl)phenylamino quinazoline (9);
CN
6-(3-hydroxyphenyl)-4-(4-cyanomethyl)phenylamino quinazoline (10);
CN
OoN
6-(3-nitrophenyl)-4-(4-cyanomethyl)phenylamino quinazoline (11);
CN
6-(2-methylphenyl)-4-(4-cyanomethyl)phenylamino quinazoline (12);
11
#
6-(4-vinylphenyl)-4-(4-cyanomethyl)phenylamino quinazoline (13);
6-(4-fluorobenzyloxyphen-4-yl)-4-(4-cyanomethyl)plnenylamino quinazoline (14);
CN
6-(3-acetylaminophenyl)-4-(4-cyanomethyl)phenylamino quinazoline (15);
CN
6-(4-plienylphenyl)-4-(4-cyanomethyl)phenylamino-quinazoline (16);
12
A t
EtO
6-(4-(4-ethoxyphenyl)phenyl)-4-(4-cyanomethyl)phenylamino-quinazoline (17);
CN
6-(4-phenyl-2-fluorophenyl)-4-(4-cyanomethyl)phenylamino-quinazoline (18);
CN
6-(naphthalen-2-yl)-4-(4-cyanomethyl)phenylamino-quinazoline (19);
CN
6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-(4-cyanomethyl)phenylamino-quinazoline (20);
13
^p
6-(benzo[d][1,3]dioxol-5-yl)-4-(4-cyanomethyl)phenylamino-quinazoline (21);
CN
6-(benzofuran-2-yl)-4-(4-cyanomethyl)phenylamino-quinazoline (22);
CN
6-(benzo[b]thiophen-2-yl)-4-(4-cyanomethyl)phenylamino-quinazoline (23);
CN
6-(dibenzo(b,d)furan-4-yl)-4-(4-cyanomethyl)phenylamino-quinazoline (24);
14
J ^
6-(dibenzo(b,d)thiophene-4-yl)-4-(4-cyanomethyl)phenylamino-quinazoline (25);
CN
6-(1H-indol-5-yl)-4-(4-cyanomethyl)phenylamino-quinazoline (26);
CN
6-(quinolin-3-yl)-4-(4-cyanomethyl)phenylamino-quinazoline (27);
CN
6-(pyridin-4-yl)-4-(4-cyanomethyl)phenylamino-quinazoline (28); and
15
^p
6-(isoquinolin-4-yl)-4-(4-cyanomethyl)phenylamino-quinazoline (29)
As used herein, the terms below have the meanings indicated.
The term "alkoxy," as used herein, alone or in combination, refers to an alkyl ether radical,
optionally substituted wherein the term alkyl is as defined below. Examples of alkyl ether radicals
include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and
the like.
The term "alkyl," as used herein, alone or in combination, refers to a straight-chain or branchedchain
alkyl radical optionally substituted containing from 1 to 20 and including 20, preferably 1 to 10,
and more preferably 1 to 6, carbon atoms. Alkyl groups may be optionally substituted as defined
herein. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl,
tert-butyl, pentyl, iso-amyi, hexyl, octyl, nonyl and the like.
The term "alkylamino" as used herein, alone or in combination, refers to an alkyl group optionally
substituted attached to the parent molecular moiety through an amino group. Alkylamino groups
may be mono- or dialkylated, forming groups such as, for example, N-methylamino, N-ethylamino,
N,N-dimethylamino, N,N-ethylmethylamino and the like.
The term "amino," as used herein, alone or in combination, refers to —NRR', wherein R and R' are
independently selected from the group consisting of hydrogen, alkyl, acyl, heteroalkyi, aryl,
cycloalkyi, heteroaryi, and heterocycloalkyi, any of which may themselves be optionally substituted.
The term "aryl" as used herein, alone or in combination, means a carbocyclic aromatic system
containing one, two or three rings wherein such rings may be attached together in a pendent
manner or may be fused optionally substituted with at least one halogen, an alkyl containing from 1
to 3 carbon atoms, an alkoxyl, an aryl radical, a nitro function, a polyether radical, a heteroaryi
radical, a benzoyl radical, an alkyl ester group, a carboxylic acid, a hydroxyl optionally protected
with an acetyl or benzoyl group, or an amino function optionally protected with an acetyl or benzoyl
group or optionally substituted with at least one alkyl containing from 1 to 12 carbon atoms.
16
^A Any definition herein may be used in combination with any other definition to describe a composite
structural group. By convention, the trailing element of any such definition is that which attaches to
the parent moiety. For example, the composite group alkylamido would represent an alkyl group
attached to the parent molecule through an amido group, and the term alkoxyalkyl would represent
an alkoxy group attached to the parent molecule through an alkyl group.
The term "optionally substituted" means the anteceding group may be substituted or unsubstituted.
When substituted, the substituents of an "optionally substituted" group may include, without
limitation, one or more substituents independently selected from the following groups or a particular
designated set of groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower
alkanoyl, lower heteroalkyi, lower heterocycloalkyi, lower haloalkyi, lower haloalkenyl, lower
haloalkynyl, lower perhaloalkyi, lower perhaloalkoxy, lower cycloalkyi, phenyl, aryl, aryloxy, lower
alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower
carboxyester, lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino,
arylamino, amido, nitro, thiol, lower alkylthio, arylthio, lower alkylsulfinyl, lower alkylsulfonyl,
arylsulfinyl, arylsulfonyl, arylthio, sulfonate, sulfonic acid, trisubstitutedsilyl, N3, SH, SCH3, C(0)CH3,
CO2CH3, CO2H, pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Two substituents
may be joined together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic
ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy.
An optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -
CF2CF3), monosubstituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully
substituted and monosubstituted (e.g., -CH2CF3). Where substituents are recited without
qualification as to substitution, both substituted and unsubstituted forms are encompassed. Where
a substituent is qualified as "substituted," the substituted form is specifically intended. Additionally,
different sets of optional substituents to a particular moiety may be defined as needed; in these
cases, the optional substitution will be as defined, often immediately following the phrase,
"optionally substituted with."
The term "cancer" as used herein refers to any disease, disorder, condition, or symptom
characterized by over-expression of kinases. Cancer diseases include pancreatic, breast, prostate
and melanoma cancer.
As used herein, reference to "treatment" of a patient is intended to include prophylaxis. The term
"patient" means all mammals including humans. Examples of patients include humans, cows, dogs,
cats, goats, sheep, pigs, rabbits, and rodents (e.g., rats, mice, and guinea pigs).
17
^
Cancer diseases. One or more compounds of the invention can be used to treat a patient (e.g. a
human) at a risk of developing or already suffering from cancer disease, such as prostate, breast,
pancreatic and melanoma cancer.
Methods of prevention and treatment. The compounds of the invention can be used to treat a
patient (e.g. a human) that suffers from or is at a risk of suffering from a disease, disorder,
condition, or symptom described herein. The compounds of the invention can be used alone or in
combination with other agents and compounds In methods of treating or preventing e.g. a cancer
disease (e.g. prostate cancer). Each such treatment described above includes the step of
administering to a patient in need thereof a therapeutically effective amount of the compound of the
invention described herein to delay, reduce or prevent such a disease, disorder, condition, or
symptom. The compounds of the invention presented herein may be also useful in reducing growth
inhibition of tumors.
It is understood that the foregoing examples are merely illustrative of the present invention. Certain
modifications of the articles and/or methods employed may be made and still achieve the objectives
of the invention. Such modifications are contemplated as within the scope of the claimed invention.
EXAIVIPLES
Example 1. Synthesis of 2-amino-5-bromobenzoic acid (2): Anthranilic acid (1, 1 g, 7.3 mmol)
was dissolved in glacial acetic acid (10 mL) and cooled below 15 °C. Then bromine (0.45 mL, 8.76
mmol) was added dropwise to the reaction mixture. The reaction mixture was converted to a thick
mass of white glistening crystals consisting of the hydrobromides of the mono and dibromo
anthranilic acids. The product was filtered off, washed with benzene and dried. It was then refluxed
with dilute hydrochloric acid (20 mL) and filtered while hot under suction. The insoluble residue was
extracted twice with boiling water (500 ml). The filtrate upon cooling yielded precipitate of the
required monobromo anthranilic acid 2. Yield: 55%; light brown solid; m. p. 209-211 °C; ^H NMR
(CD3OD, 500 MHz): 6 7.87 (t, 1H, J =5.2 Hz), 7.31-7.28 (m, 1H), 6.67(dd, 1H, J = 5.0 Hz); ESI-MS:
m/z 2^5[M+H]Example 2. Synthesis of 6-bromoquinazolin-4-ol (3): To the solution of 2-amino-5-bromobenzoic
acid (2, 1 g, 4.63 mmol), formamide (0.74 mL, 18.52 mmol) was added and the resultant
mixture was allowed to reflux at 150 °C for 6 h. After completion of reaction, the reaction mixture
was filtered through Whatman filter paper and dried under vacuum to get the desired product 3 as a
white solid. Yield: 70%, white solid, m. p. 209-211 °C; ^H NMR (DMSO-c/e, 500 MHz): 6 8.20 (d, 1H,
18
^ ^ J = 2.3 Hz), 8.17 (d, 1H, J = 6.1 Hz), 7.98-7.95 (m, 1H), 7.63 (d, 1H, J = 8.7 Hz); HRMS: m/z
224.9633 calcd for CgHeBrNzO+H" (224.9664).
Example 3. Synthesis of 6-bromo-4-chloroquinazoline (4): To the solution of 6-bromoquinazolin-
4-ol (3, 1 g, 4.44 mmol) in phosphoryl chloride (5 mL) was refluxed for 6 h at 120 °C. The mixture
was cooled to room temperature and poured into ice-water containing sodium bicarbonate to
quench excess phosphoryl chloride. The mixture was extracted with dichloromethane (3 x 100 ml)
and the solvent was evaporated to get the 6-bromo-4-chloroquinazoline 4 as a light yellow solid.
Yield; 92%, light yellow solid, m. p, 273-275 °C; ^H NMR (CDCI3, 500 MHz): 6 9.07 (s, 1H), 8.44 (d,
1H, J = 2.0 Hz), 8.04 (d, 1H, J = 2.0 Hz), 7.96 (d, 1H, J = 8.9 Hz); HRMS: m/z 224.9633 calcd for
CsHgBrNsO + H^ (224.9664).
Example 4. Synthesis of 6-bromo-4-(4-cyanomethyl)phenylamino quinazoline (5): The mixture
of 6-bromo-4-chioroquinazoline (4, 0.2 g, 0.83 mmol.) and 4-amino benzyl cyanide (0.142 g, 1.07
mmol) was dissolved in isopropanol (5 mL) and allowed to stir for 3 h under reflux at 80 °C. After
completion of reaction, the mixture was filtered through Whatman filter paper and dried under
vacuum to get the desired product 5 as brown solid. Yield: 82%; brown solid; mp. 275-277 °C, ^H
NMR (DMSO-de, 400 MHz): 6 9.20 (s, 1H), 8.93 (s, 1H), 8.30-8.23 (m, 1H), 7.96-7.89 (m, 1H), 7.83-
7.76 (m, 2H), 7.48 (d, 2H, J = 7.2 Hz), 4.10 (s, 2H).^^C NMR (DMSO-c/e, 100 MHz): 5 158.71,
151.16, 138.71, 138.18, 135.91, 129.56, 128.43, 127.17, 124.96, 122.15, 120.86, 119.05, 115.01,
21.98. HRMS: m/z 339.0243 calcd for Ci6Hi2BrN4+ H^ (339.0245).
Example 5. Synthesis of 6-phenyl-4-(4-cyanomethyl)phenylamino quinazoline (6) from 6-
bromo-4-(4-cyanomethyl)phenylamlno quinazoline and phenylboronic acid: The solution of 2
M K2CO3 (3 ml) in dioxane (3 ml) in round bottom flask was purged with nitrogen gas for 5 min at 25
°C. To this solution, 6-bromo-4-(4-cyanomethyl)phenylamino quinazoline (5, 0.1 g, 1 mmol.) and
phenylboronic acid (1.2 mmol) were added followed by addition of Pd(PPh3)4 (0.05 equiv.). The
resulting reaction mixture was then stirred at 90 °C for 12 h. After completion of reaction, product
was extracted with ethyl acetate (2 x 50 ml) and the combined organic layers were dried over
anhydrous sodium sulphate to get crude product 6, which was purified by silica gel column
chromatography. Yield: 81%, brick red solid, m.p. 253-255 °C; ^H NMR (DMSO-de, 400 MHz): 6
10.01 (s, 1H), 8.85 (s, 1H), 8.60 (s, 1H), 8.21 (d, 1H, J = 8.5 Hz), 7.91-7.87 (m, 4H), 7.62-7.58 (m,
3H), 7.57-7.39 (m, 2H), 4.04 (s, 2H); IR (CHCI3): vmax 3400, 2924, 2853, 1609, 1437, 1192, 1119
cm-1; HRMS: m/z 337.1452 calcd for C22H17N4 + H* (337.1453).
19
^ r Example 6. Synthesis of 6-(2,4-difluorophenyl)-4-(4-cyanomethyl)phenylamino quinazoline
(7) from 6-bromo-4-(4-cyanomethyl)phenylamino quinazoline and 2,4-difluorophenyiboronic
acid: This compound was synthesized using the similar procedure as described in example 5.
Yield; 45%; yellow solid; m. p. 186-188 °C; ^H NMR (CDCI3, 400 MHz): 6 8.74 (s, 1H), 8.15 (s, 1H),
7.98-7.92 (m, 1H), 7.80 (d, 2H, J = 8.8 Hz), 7.55-7.46 (m, 2H), 7.38 (d, 2H, J = 8.4 Hz), 7.06-6.97
(m, 2H), 3.78 (s, 2H). '^C NMR (101 MHz, MeOD): 5 158.31, 154.55, 148.49, 138.13, 133.43,
132.12, 131.46, 128.40, 125.78, 123.13, 121.90, 117.86, 115.30, 111.76, 104.52, 104.26, 104.00,
22.72; IR (CHCia): Vmax3391, 2955, 2923, 2854, 1606, 1574, 1532, 1515, 1495, 1424, 1401, 1269,
1142, 1101, 1020 cm"^ HRMS: m/z 373.1258 calcd for C22H15F2N4+H^ (373.1265).
Example 7. Synthesis of 6-(2-formylphenyl)-4-(4-cyanomethyl)phenylamino quinazoline (8)
from 6-bromo-4-(4-cyanomethyl)phenylamino quinazoline and 2-formylphenylboronic acid:
This compound was synthesized using the similar procedure as described in example 5. Yield:
67%; brick red solid; m. p. 177-179 °C; ^H NMR (CDCI3 + 1 drop of CD3OD, 400 MHz): 6 9.99 (s,
1H), 8.80(s, 1H), 8.32(s, 1H), 8.12 (d, 1H, J = 1.6 Hz), 8.01-8.97 (t, 2H, J = 8.8 Hz), 7.84-7.76 (m,
3H), 7.71-7.62 (m, 1H), 7.56-7.46 (m, 2H), 7.43-7.39 (m, 1H), 7.36-7.30 (m, 1H), 3.74 (s, 2H); ^^C
NMR (101 MHz, CDCI3 + 1 drop of CD3OD); 5 192.32, 154.88, 148.58, 144.54, 136.48, 134.82,
134.00, 133.56, 131.95, 131.85, 131.14, 128.73, 128.60, 128.45, 128.42, 128.22, 127.45, 123.72,
123.41, 22.88; IR (CHCI3); Vr^ax3367, 2956, 2924, 2854, 2250, 1689, 1626, 1596, 1571, 1529, 1515,
1479, 1422, 1402, 1360, 1306, 1252, 1194, 1173, 1120, 1070, 1020 cm"^ HRMS: m/z 365.1397
calcd for C23H17N4O + H" (365.1402).
Examples. Synthesis of 6-(4-acetylphenyl)-4-(4-cyanomethyl)phenylamino quinazoline (9)
from 6-bromo-4-(4-cyanomethyl)phenylamino quinazoline and 4-acetylphenylboronic acid:
This compound was synthesized using the similar procedure as described in example 5. Yield:
45%; pale yellow solid; m. p. 157-159 °C; ^H NMR(CDCl3+ 1 drop of CD3OD, 400 MHz): 6 8.65 (d,
2H, J = 9.0 Hz), 8.13-8.11 (t, 3H, J = 1.6 Hz), 7.97-7.91 (m, 3H), 7.82 (d, 2H, J = 8.0 Hz), 7.42 (s,
1H), 7.42 (m, 3H), 3.84 ( s, 2H), (m, 2H), 2.70 (s, 3H); ^^C NMR (126 MHz, DMSO): 6 197.59,
157.93, 154.87, 149.53, 143.38, 138.36, 136.63, 135.90, 132.05, 131.50, 131.42, 128.95, 128.80,
128.71, 128.26, 127.27, 126.57, 123.08, 121.20, 119.41, 115.33, 26.85, 21.90; IR (CHCI3): v^ax
3369, 2953, 2924, 2855, 2250, 1738, 1678, 1603, 1572, 1532, 1515, 1423, 1362, 1265, 1020 cm"HRMS: m/z 379.1555 calcd for C24H19N4O + H' (379.1559).
Example 9. Synthesis of 6-(3-hydroxyphenyl)-4-(4-cyanomethyl)phenylamino quinazoline (10)
from 6-bromo-4-(4-cyanomethyl)phenylamino quinazoline and 3-hydroxyphenylboronic acid:
20
^ ^ This compound was synthesized using the similar procedure as described in example 5. Yield:
62%; pale yellow solid; m. p. 222-224 °C; ^H NMR (DMSO-de, 400 MHz): 6 10.01 (s, 1H), 9.65 (s,
1H), 8.81 (d, 1H, J= 1.6 Hz), 8.59 (s, 1H), 8.14-8.11 (dd, 1H , J = 2.0& 1.6 Hz), 7.90-7,84 (m, 2H),
7.65-7.55 (m, 4H), 7.41-7.26 (m, 2H), 6.87-6.85 (m, 1H), 4.06 (s, 2H); ^^C NMR (126 MHz, DMSO):
6 157.89, 154.35, 140.56, 138.49, 138.27, 132.04, 131.50, 131.42, 130.02, 128.79, 128.70, 128.21,
126.39, 122.97, 120.35, 119.41, 117.94, 115.28, 114.86, 114.02, 79.15, 21.89; IR (CHCI3): Vr„ax
3400, 3055, 2955, 2924, 2854, 1731, 1591, 1484, 1437, 1400, 1275, 1219, 1189, 1119, 1072 cm"\-
HRMS: m/z 353.1402 calcd for C22H17N4O + H^ (353.1402).
Example 10. Synthesis of 6-(3-nitrophenyl)-4-(4-cyanomethyl)phenylamino quinazoline (11)
from 6-bromo-4-(4-cyanomethyl)phenylamino quinazoline and 3-nitrophenylboronic acid:
This compound was synthesized using the similar procedure as described in example 5. Yield:
57%; pale yellow solid; m. p. 216-218 °C; ^H NMR (CDCI3 + 1 drop of CD3OD, 400 MHz): 6 8.69 (d,
1H, J = 15.2 Hz), 8.28 (d, 1H, J = 8.0 Hz), 8.14-8.27 (t, 1H, J = 4.8 Hz), 7.97 (d, 1H, J = 8.4 Hz),
7.83 (d, 1H, J = 8.4 Hz), 7.75-7.71 (t, 1H, J = 8,0 Hz), 7.65-7.58 (m, 2H), 7.53-7.49 (m, 2H), 7.42-
7.36 (m, 3H), 3.83 (s, 2H); '^C NMR (101 MHz, DMSO-dg) 6: 157.99, 154.97, 148.57, 140.80,
135.57, 133.66, 131.99, 131.79, 131.50, 131.40, 130.63, 128.78, 128.66, 128.26, 123.21, 122.59,
121.47, 121.36, 119.33, 21.92; IR (CHCI3): v^ax 3400, 2955, 2923, 2853, 1733, 1606, 1536, 1423,
1384, 1157, 1021 cm^ HRMS: m/z 382.1302 calcd for C22H16N5O2 + H^ (382,1304).
Example 11. Synthesis of 6-(2-methylphenyl)-4-(4-cyanomethyl)phenylamino quinazoline (12)
from 6-bromo-4-(4-cyanomethyl)phenylamino quinazoline and 2-methylphenylboronic acid:
This compound was synthesized using the similar procedure as described in example 5. Yield:
57%; orange solid; m. p. 173-175 °C; ^H NMR (CDCI3, 400 MHz): 6 8.83-8.81 (t, 1H, J = 2.4 Hz),
8.03-8.00 (t, 1H, J = 9.6 Hz), 7.98-7.96 (t, 4H, J = 6.0 Hz), 7.55 (s, 1H), 7.43-7.27 (m, 6H), 3.78 (d,
2H, J = 6.0 Hz); '^C NMR (101 MHz, CDCI3): 6 157.63, 154.73, 148.95, 140.83, 140.54, 138.33,
135.42, 134.63, 130.60, 129.79, 128.64, 128.37, 128.09, 126.06, 125.66, 122.52, 120.74, 117.97,
115.07, 23.14, 20.47; IR (CHCI3): v^ax 3368, 2955, 2924, 2853, 2252, 1626, 1604, 1572, 1527,
1515, 1486, 1421, 1403, 1360, 1307, 1242, 1190, 1020 cm"\ HRMS: m/z 351.1602 calcd for
C23H19N4+H'(351.1610).
Example 12. Synthesis of 6-(4-vinylphenyl)-4-(4-cyanomethyl)phenylamino quinazoline (13)
from 6-bromo-4-(4-cyanomethyl)phenylamino quinazoline and 4-vinylphenylboronic acid:
This compound was synthesized using the similar procedure as described in example 5. Yield:
71%, pale yellow solid, m. p. 216-218 °C; ^H NMR (CDCI3, 400 MHz): 6 8.66 (s, 1H), 8.42 (d, 1H, J
21
^ = 1.6 Hz), 8.07 (s, 1H), 7.92 (d, 1H, J = 8.6 Hz), 7.82 (d, 2H, J = 8.5 Hz), 7.73 (d, 2H, J = 8.2 Hz),
7.56 (d, 3H, J = 8.2 Hz), 7.40-7.34 (t, 1H, J = 8.5 Hz), 6.80-6.77 (t, 1H, J = 6.7 Hz), 5.85 (d, 1H, J
= 17.7 Hz), 5.33 (d, 1H, J = 11.0 Hz), 3.81 (s, 2H); ^^C NMR (126 MHz, DMSO-de): 5 158.30,
154.92, 149.57, 138.96, 138.87, 137.93, 137.19, 136.56, 132.05, 131.97, 128.89, 128.70, 127.72,
127.27, 126.90, 123.48, 120.64, 119.87, 115.83, 115.30, 22.39; IR (CHCI3): Vn,ax3368, 2951, 2923,
2857, 2248, 1741, 1623, 1603, 1571, 1514, 1497, 1423, 1360, 1020 cm"^ HRMS: m/z 363.1605
calcd for C24Hi9N4+H^ (363.1610).
Example 13. Synthesis of 6-(4-fluorobenzyloxyphen-4-yl)-4-(4-cyanomethyl)phenylamino
quinazoline (14) from 6-bromo-4-(4-cyanomethyl)phenylamino quinazoline and 4-((4-
fluorobenzyl)oxy)phenylboronic acid: This compound was synthesized using the similar
procedure as described in example 5. Yield: 81%, pale yellow solid, m. p. 230-232 °C; ^H NMR
(CDCI3 + 1 drop of CD3OD. 400 MHz): 6 8.65 (s, 1H), 8.45 (s, 1H), 8.04 (d, 1H, J = 1.6 Hz), 7.88 (d,
1H, J = 8.8 Hz), 7.81 (d, 2H, J = 8.4 Hz), 7.73-7.70 (t, 2H, J = 6.8 Hz), 7.48-7.38 (m, 5H), 7.13-7.08
(m, 4H), 5.12 (s, 2H), 3.82 (s, 2H); ^^C NMR (126 MHz, DMSO-de): 6 158.70, 158.20, 154.60,
149.14, 139.03, 138.17, 132.18, 131.94, 130.45, 130.39, 128.77, 128.69, 126.82, 123.41, 119.93,
119.87, 115.84, 115.66, 69.04, 22.41; IR (CHCI3): v„ax 3400, 2954, 2923, 2854, 1605, 1573, 1498,
1514, 1423, 1401, 1384, 1225, 1157, 1020 cm'^ HRMS: m/z 461.1777 calcd for C29H22FN4O + H^
(461.1778).
Example 14. Synthesis of 6-(3-acetylaminophenyl)-4-(4-cyanomethyl)pheny!amino
quinazoline (15) from 6-bromo-4-(4-cyanomethyl)phenylamino quinazoline and 3-
acetylaminophenylboronic acid: This compound was synthesized using the similar procedure as
described in example 5. Yield: 81%, pale yellow solid, m. p. 195-197 °C; ^H NMR (DMSO-c/e, 400
MHz): 5 10.01 (s, 2H), 8.80 (s, 1H), 8.60 (s, 1H), 8.10-8.07 (dd, 1H, J = 1.6 & 0.8 Hz), 8.00 (s, 1H),
7.90-7.87 (dd, 3H, J = 1.6 & 1.6 Hz), 7.66-7.46 (m, 4H), 7.39 (d, 2H, J = 8.4 Hz), 4.04 (s, 2H), 2.07
(d, 3H, J = 0.8 Hz); ^^C NMR (126 MHz, DMSO-de): 5 168.40, 157.79, 154.38, 148.98, 139.85,
139.80, 138.43, 138.23, 131.42, 131.34, 129.30, 128.71, 128.61, 128.38, 128.14, 126.32, 122.87,
122.05, 120.57, 119.31, 118.50, 117.79, 115.26, 23.95, 21.83; IR (CHCI3): v^ax 3368, 2921, 1676,
1608, 1534, 1515, 1480, 1426, 1119 cm"'; HRMS: m/z 394.1668 calcd for C24H20N5O + H^
(394.1668).
Example 15. Synthesis of 6-(4-phenylphenyl)-4-(4-cyanomethyl)phenylamino-quinazoline (16)
from 6-bromo-4-(4-cyanomethyl)phenylamino quinazoline and 4-phenylphenylboronic acid:
This compound was synthesized using the similar procedure as described in example 5. Yield:
22
^p 57%, yellow solid, m. p. 214-216 °C; ^H NMR (DMSO-cfe, 400 MHz): 5 10.03 (s, 1H), 8.92 (d, 1H, J
= 1.6 Hz), 8.61 (s, 1H), 8.29-8.27 (m, 1H), 8.03 (d, 2H, J = 8.4 Hz), 7.92-7.87 (m, 4H), 7.80-7.77 (t,
2H , J = 1.2 Hz), 7.54-7.50 (t, 2H, J = 7.6 Hz), 7.43-7.7.40 (m, 3H), 4.07-4.01 (m, 2H); ^^C NMR
(126 MHz, DMSO) 5 157.84, 154.47, 149.11, 139.59, 139.41, 138.46, 138.01, 137.98, 137.44,
131.64, 129.02, 128.47, 128.25, 127.69, 127.62, 127.25, 126.65, 123.03, 120.27, 119.42, 115.38,
21.90; IR (CHCI3): Vmax3401, 2953, 2927, 1604, 1567, 1515, 1486, 1423, 1358, 1021 cm"^ HRMS:
m/z 413.1769 calcd for C28H21N4; found, 413.1766. HRMS: m/z 381.1357 calcd for C23H17N4O2+ H^
(381.1352).
Example 16. Synthesis of 6-(4-(4-ethoxyphenyl)phenyl)-4-(cyanomethyl)phenylamlnoquinazoline
(17) from 6-bromo-4-(4-cyanomethyl)phenylamino quinazoline and 4-(4-
ethoxyphenyl)phenylboronic acid: This compound was synthesized using the similar procedure
as described in example 5. Yield: 47%, yellow solid, m. p. 195-197 °C; ^H NMR (CDCI3, 400 MHz):
6 8.75 (s, 1H), 8.64 (s, 1H), 8.52 (s, 1H), 7.93 (d, 1H, J = 8.8 Hz), 7.84-7.82 (m, 4H), 7.72 (d, 2H, J
= 8.4 Hz), 7.63-7.60 (t, 4H, J = 4.4 Hz), 7.02 (d, 2H, J = 8.4 Hz), 4.30 (d, 2H, J = 6.8 Hz), 1.35-1.21
(m, 3H); IR (CHCI3): Vn,ax3306, 2956, 2925, 2855, 1729, 1604, 1568, 1515, 1494, 1424, 1401, 1360,
1252, 1190, 1082, 1019 cm^ HRMS: m/z 457.2012 calcd for C30H25N4O + H^ (457.2028).
Example 17. Synthesis of 6-(4-phenyl-2-fluorophenyl)-4-(4-cyanomethyl)phenylaminoquinazoline
(18) from 6-bromo-4-(4-cyanomethyl)phenylamino quinazoline and 4-phenyl-2-
fluorophenylboronic acid: This compound was synthesized using the similar procedure as
described in example 5. Yield: 57%, pale yellow solid, m. p. 229-231 °C; ^H NMR (CDCI3 + 1 drop
of CD3OD, 400 MHz): 6 8.60 (d, 2H), 8.10 (d, 1H), 7.98-7.88 (m, 1H), 7.83 (d, 2H, J = 8.4 Hz),
7.68-7.57 (m, 5H), 7.55-7.49 (m, 2H), 7.47-7.40 (m, 3H), 3.89 (s, 2H); ^^C NMR (101 MHz, DMSO):
6 157.89, 154.72, 149.41, 140.38, 138.39, 136.01, 134.61, 131.46, 131.28, 128.76, 128.73, 128.68,
128.50, 128.24, 128.01, 126.55, 123.35, 123.08, 120.63, 119.33, 115.32,21.93; IR (CHCI3): vmax
3392, 2951, 2924, 2853, 2250, 1604, 1573, 1515, 1483, 1424, 1021 cm'^ HRMS: m/z 431.1666
calcd forC28H2oFN4 + H^ (431.1672).
Example 18. Synthesis of 6-(naphthalen-2-yl)-4*(4-cyanomethyl)phenylamino-quinazoline (19)
from 6-bromo-4-(4-cyanomethyl)phenylamino quinazoline and naphthalen-2-yl boronic acid:
This compound was synthesized using the similar procedure as described in example 5. Yield:
57%, pale yellow solid, m. p. 204-206 °C; ^H NMR (DMSO-cye, 400 MHz): 6 10.04 (s, 1H), 8.97 (s,
1H), 8.64-8.59 (m, 1H), 8.47-8.33 (m, 1H), 8.14-7.87 (m, 6H), 7.60-7.53 (m, 3H), 7.45-7.37 (m, 2H),
4.08-4.03 (m, 2H); "C NMR (126 MHz, DMSO-de) 5: 157.85, 154.48, 149.12, 136.42, 133.24,
23
^ 132.34, 132.00, 131.46, 131.38, 128.75, 128.66, 128.56, 128.47, 128.20, 127.55, 126.59, 126.42,
126.39, 125.78, 125.28, 123.03, 120.69, 115.40, 21.89; IR (CHCI3): v^ax 3369, 3053, 2955, 2924,
2854, 2250, 1733, 1603, 1572, 1529, 1515, 1468, 1422, 1404, 1385, 1360, 1245, 1175, 1119,
1070, 1020 cm"'; HRMS:m/z 387.1611 calcd for C26H19N4+H^ (387.1610).
Example 19. Synthesis of 6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-(4-
cyanomethyl)phenylamino-quinazoline (20) from 6-bromo-4-(4-cyanomethyl)phenylamino
quinazoline and 2,3-dihydrobenzo[b][1,4]dioxin-6-yl boronic acid: This compound was
synthesized using the similar procedure as described in example 5. Yield: 81%, pale yellow solid,
m. p. 207-209 °C; 'H NMR (DMSO-ofe, 400 MHz): 5 9.95 (s, 1H), 8.76 (d, 1H, J = 1.6 Hz), 8.57 (s,
1H), 8.16-8.13 (dd, 1H, J = 1.6 & 2.0 Hz), 7.89 (d, 2H, J = 8.4 Hz), 7.82 (d, 1H, J = 8.8 Hz), 7.65-
7.53 (m, 1H), 7.46 (d, 1H, J = 2.0 Hz), 7.41-7.37 (m, 3H), 7.03 (d, 1H, J = 8.4 Hz), 4.32 (s, 4H), 4.05
(s, 2H); "C NMR (126 MHz, DMSO-dg): 6 157.72, 154.18, 148.75, 143.78, 143.55, 138.51, 137.46,
132.26, 131.49, 131.42, 128.78, 128.69, 128.20, 126.38, 123.00, 119.97, 119.50, 117.57, 115.60,
115.31, 64.23, 64.15, 21.90; IR (CHCI3): v^^ax 3854, 3745, 3400, 2922, 2853, 1602, 1514, 1495,
1422, 1307, 1249, 1068, 1021 cm"^ HRMS: m/z 395.1508 calcd for C24H19N4O2+ H^ (395.1508).
Example 20. Synthesis of 6-(benzo[d][1,3]dioxol-5-yl)-4-(4-cyanomethyl)phenylaminoquinazoline
(21) from 6-bromo-4-(4-cyanomethyl)phenylamino quinazoline and
benzo[d][1,3]dioxol-5-yl boronic acid: This compound was synthesized using the similar
procedure as described in example 5. Yield: 57%, yellow solid, m. p. 241-243 °C; ^H NMR (DMSOc/
e, 400 MHz): 6 9.90 (s, 1H), 8.76 (d, 1H, J= 1.6 Hz), 8.58 (s, 1H), 8.23-8.15 (m, 2H), 7.99-7.81 (m,
2H), 7.53 (d, 1H, J = 1.6 Hz), 7.41-7.39 (t, 1H, J = 6.4 Hz), 7.13-7.10 (t, 1H, J = 6.4 Hz), 6.12 (s,
2H), 4.04 (s, 2H); ^^C NMR (101 MHz, DMSO): 5 157.74, 154.21, 148.78, 148.13, 147.26, 138.52,
137.73, 133.28, 131.58, 131.50, 131.40, 128.78, 128.66, 128.25, 128.20, 126.38, 122.95, 120.85,
119.71, 119.33, 115.29, 108.74, 107.42, 101.32, 21.91; IR (CHCI3): v^ax 3400, 2923, 1603, 1514,
1419, 1220, 1039 cm'; HRMS: m/z 381.1357 calcd for C23H17N4O2+ H^ (381.1352).
Example 21. Synthesis of 6-(benzofuran-2-yl)-4-(4-cyanomethyl)phenylamino-quinazoline
(22) from 6-bromo-4-(4-cyanomethyl)phenylamino quinazoline and benzofuran-2-yl boronic
acid: This compound was synthesized using the similar procedure as described in example 5.
Yield: 62%, pale yellow solid, m. p. 245-247 °C; 'H NMR (DMSO-dg, 400 MHz): 6 10.14 (s, 1H),
9.09 (d, 1H, J= 1.6 Hz), 8.61 (s, 1H), 8.41-8.38 (m, 1H), 7.93-7.88 (m, 2H), 7.75 (d, 1H, J= 7.2 Hz),
7.71-7.69 (t, 1H, J = 8.0 Hz), 7.65-7.7.60 (m, 1H), 7.58-7.53 (m, 1H), 7.42-7.39 (m, 2H), 7.32-7.30
(m, 1H), 4.06 (s, 2H); "C NMR (126 MHz, DMSO): 6 157.84, 154.88, 154.57, 154.46, 149.84,
24
^ 138.42, 132.77, 131.83, 131.46, 128.79, 128.70, 128.23, 125.09, 123.06, 119.29, 118.65, 114.73,
111.15, 103.34, 21.91; IR (CHCI3): v^ax 3400, 2955, 2923, 2853, 1605, 1572, 1515, 1422, 1384,
1020 cm"^; HRMS: m/z377.1399 calcd forC24Hi7N40 + H* (377.1402).
Example 22. Synthesis of 6-(benzo[b]thiophen-2-yl)-4-(4-cyanomethyl)phenylaminoquinazoiine
(23) from 6-bromo-4-(4-cyanomethyl)phenylamino quinazoline and
benzo[b]thiophen-2-yl boronic acid: This compound was synthesized using the similar procedure
as described in example 5. Yield: 65%, yellow solid, m. p. 263 °C, decomposed; ^H NMR (DMSOdg,
400 MHz): 6 10.04 (s, 1H), 8.91 (s, 1H), 8.58(s, 1H), 8.26-8.23 (dd, 1H, J = 2.0 & 2.0 Hz), 8.05-
8.02 (t, 2H , J = 6.8 Hz), 7.91-7.84 (m, 3H), 7.44-7.38 (m, 4H), 4.04-4.00 (t, 2H, J = 8.0 Hz); ^^C
NMR (101 MHz, DMSO-de): 6 157.69, 154.65, 149.52, 142.35, 140.22, 138.89, 138.30, 131.42,
130.88, 128.63, 128.14, 126.51, 124.90, 124.86, 123.76, 123.09, 122.45, 121.09, 119.89, 119.25,
115.36, 21.85; IR(CHCl3):v^ax 3392, 2951,2922, 2852, 1602, 1572, 1514, 1419, 1403, 1361, 1157,
1020, cm"'; HRMS: m/z 393.1163 calcd for C24H17N4S + H^ (393.1174).
Example 23. Synthesis of 6-(dibenzo(b,d)furan-4-yl)-4-(4-cyanomethyl)phenylaminoquinazoline
(24) from 6-bromo-4-(4-cyanomethyl)phenylamino quinazoline and
dibenzo(b,d)furan-4-yl boronic acid: This compound was synthesized using the similar procedure
as described in example 5. Yield: 42%, pale yellow solid, m. p. 207-209 "C; 'H NMR (DMSO-cye,
400 MHz) : 6 10.03 (s, 1H), 9.02 (d, 1H, J = 1.6 Hz), 8.66 (s, 1H), 8.47-8.45 (dd, 1H, J = 1.6 & 2.0
Hz), 8.26-8.23 (m, 2H), 7.99 (d, 1H , J = 8.8 Hz), 7.91 (d, 3H, J = 8.0 Hz), 7.78 (d, 1H, J = 8.0 Hz),
7.65-7.55 (m, 3H), 7.48-7.39 (m, 2H), 4.05 (s, 2H); '^C NMR (126 MHz, DMSO): 6 157.86, 155.49,
154.75, 152.58, 149.16, 138.47, 133.90, 133.61, 132.03, 131.49, 131.42, 128.78, 128.69, 128.23,
127.84, 127.58, 126.44, 124.47, 124.31, 123.72, 123.41, 123.32, 122.97, 122.62, 121.30, 120.92,
119.39, 115.36, 111.96, 21.91; IR (CHCI3): v„ax 3392, 2955, 2923, 2853, 1604, 1573, 1530, 1515,
1490, 1451, 1402, 1362, 1189, 1120, 1020 cm"'; HRMS: m/z calcd for C28H19N4O, 427.1553 + H*
(427.1559).
Example 24. Synthesis of 6-(dibenzo(b,d)thiophene-4-yl)-4-(4-cyanomethyl) phenylaminoquinazoline
(25) from 6-bromo-4-(4-cyanomethyl) phenylamino quinazoline and
dibenzo(b,d)thiophene-4-yl boronic acid: This compound was synthesized using the similar
procedure as described in example 5. Yield: 45%, pale yellow solid, m. p. 199-201 °C; ^H NMR
(CDCI3, 400 MHz): 6 8.80 (s, 1H), 8.36 (d, 1H, J= 1.6 Hz), 8.19-8.11 (m, 3H), 8.03 (d, 1H, J = 8.8
Hz), 7.80-7.77 (t, 1H, J = 3.6 Hz), 7.57-7.46 (m, 4H), 7.36-7.30 (m, 2H), 3.72 (s, 2H). IR (CHCI3):
25
W Vniax3392, 2922, 2853, 1605, 1571, 1537, 1514, 1421, 1026 cnT^ HRMS: m/z 443.1320 calcd for
C28H19N4S + H" (443.1330).
Example 25. Synthesis of 6-(1H-indol-5-yi)-4-(4-cyanomethyl)phenylamino-quinazoiine (26)
from 6-bromo-4-(4-cyanomethyl)phenylamino quinazoline and 1H-indol-5-yl boronic acid:
This compound was synthesized using the similar procedure as described in example 5. Yield:
81%, dark yellow solid, m. p. 267-269 °C; ^H NMR (DMSO-cye, 400 MHz): 6 11.23 (s, 1H), 9.99 (s,
1H), 8.83 (d, 1H, J= 17.6 Hz), 8.57 (d, 1H, J = 17.6 Hz), 8.24-8.22 (dd, 1H, J = 2.0 & 1.6 Hz), 8.08
(s, 1H), 7.93-7.84 (dd, 3H, J = 8.4 & 8.4 Hz), 7.66-7.53 (m, 3H), 7.44-7.39 (m, 2H), 6.54 (d, 1H, J =
17.6 Hz), 4.05 (s, 2H); ^^C NMR (126 MHz, DMSO-de): 6 157.70, 153.86, 148.37, 139.94, 138.63,
135.70, 131.50, 131.42, 130.21, 128.79, 128.70, 128.27, 128.19, 126.39, 126.25, 122.94, 120.72,
119.57, 119.43, 118.79, 111.91, 101.61, 21.90; IR (CHCI3): v^ax 3787, 3212, 2923, 2853, 1603,
1572, 1529, 1514, 1436, 1421, 1309, 1175, 1119, 1070 cm'^ HRMS: m/z 376.1564 calcd for
C24H18N5+H" (376.1562).
Example 26. Synthesis of 6-(quinolin-3-yl)-4-(4-cyanomethyl)phenylamino-quinazoline (27)
from 6-bromo-4-(4-cyanomethyl)phenylamino quinazoline and quinolin-3-yl boronic acid:
This compound was synthesized using the similar procedure as described in example 5. Yield:
62%, off-white solid, m. p. °C; ^H NMR (DMSO-de, 400 MHz): 6 10.06 (s, 1H), 9.52 (d, 1H, J = 2,0
Hz), 9.10 (d, 1H, J= 1,6 Hz), 8.86 (d, 1H, J = 2.0 Hz), 8.64 (s, 1H), 8.45-8.42 (m, 1H), 8.12 (d, 2H, J
= 8.4 Hz), 7.97 (d, 3H, J = 8.4 Hz), 7.91 (d, 1H, J = 8.4 Hz), 7.83 (d, 1H, J = 1.2 Hz), 7.42 (d, 2H, J
= 8.8 Hz), 4.05 (s, 2H); IR (CHCI3): Vmax3400, 2922, 1617, 1423, 1130 cm'^ HRMS: m/z 388.1559
calcd for C25H18N5 + H^ (388.1562).
Example 27. Synthesis of 6-(pyridin-4-yl)-4-(4-cyanomethyl)phenylamino-quinazoline (28)
from 6-bromo-4-(4-cyanomethyl)phenylamino quinazoline and pyridin-4-yl boronic acid: This
compound was synthesized using the similar procedure as described in example 5. Yield: 81%,
pale yellow solid, m, p. 234-236 °C; ^H NMR (CDCI3 + 1 drop of CD3OD, 400 MHz): 6 8.62 (s, 3H),
8.11-8.09 (t, 1H, J =6.8 Hz), 7.97 (d, 1H, J = 8.4 Hz), 7.83 (d, 4H, J = 8.4 Hz), 7.41-7.32 (m, 3H),
3.81 (s, 2H). ^^C NMR (CDCI3 + 1 drop of CD3OD, 126 MHz): 5 158.51, 154.91, 149.30, 147.56,
137.93, 135.52, 131.31, 128.13, 127.95, 125.94, 123.18, 121.70, 120.98, 117.80, 115.54, 22,50; IR
(CHCIs): v^ax 3392, 2957, 2923, 2850, 1606, 1573, 1532, 1493, 1425, 1020 cm'^ HRMS: m/z
338.1365 calcd for C21H16N5 + H^ (338,1406).
Example 28. Synthesis of 6-(isoquinolin-4-yl)-4-(4-cyanomethyl)phenylamino-quinazoline (29)
from 6-bromo-4-(4-cyanomethyl)phenylamino quinazoline and isoquinolin-4-yl boronic acid:
26
^ ^ This compound was synthesized using the similar procedure as described in example 5. Yield:
57%, pale yellow solid, m. p. 237-239 °C; 'H NMR (DMSO-de, 400 MHz): 6 9.90 (s, 1H), 9.45 (s,
1H), 8.81 (s, 1H), 8.69 (s, 1H), 8.63 (s, 1H), 8.30 (d, 1H, J = 8.0 Hz), 8.07-8.05 (dd, 1H, J = 1.6 &
1.6 Hz), 7.97 (d, 1H, J = 8.8 Hz), 7.92-7.77 (m, 4H), 7.38 (d, 2H, J = 8.8 Hz), 3.36 (s, 2H); ^^C NMR
(126 MHz, DMSO): 5 157.76, 154.84, 152.44, 149.23, 142.99, 138.46, 134.75, 134.55, 133.22,
131.71, 131.45, 128.20, 128.20, 128.04, 127.97, 127.73, 126.36, 124.17, 124.10, 122.72, 119.35,
115.26, 21.89; IR (CHCI3): v^ax 3400, 2923, 2853, 1624, 1423, 1042 cm'^; HRMS: m/z 388.1564
calcd for C25H18N5 + H' (388.1562).
All examples disclosed in formula I, are prepared by employing the similar method containing
different Ar, R, and R' groups, as described for preparation of compound 6 (example 5).
Example 29. Cytotoxicity of compounds of the invention: Compounds proposed in present
invention were evaluated for their cytotoxic effect against panel of 5 cancer cell line viz. Panc-1
(pancreatic cancer), MCF-7 (breast cancer), PC-3 (prostate), HL-60 (leukemia) and A-375
(melanoma) using MTT assay. In each well of a 96-well plate, 3x10^ cells were grown in 100 pL of
medium. After 24 h, each test molecules were added to achieve a final concentration of 10 to 0.01
pmol/L, respectively. After 48 h of treatment, 20 pL of 2.5 mg/mL MTT (Organics Research, Inc.)
solution in phosphate buffer saline was added to each well. After 48h, supernatant was removed
and formazan crystals were dissolved in 200 pL of DMSO. Absorbance was then measured at 570
nm using an absorbance plate reader (Bio-Rad Microplate Reader). Data are expressed as the
percentage of viable cells in treated relative to non-treated conditions. Each experiment was
repeated thrice and data was expressed as mean ± SD of three independent experiments (Mordant,
P. et al., Mol. Cancer Ther. 2010, 9, 358). Compounds showed promising cytotoxivity in panel of
cell lines. Cytotoxicity results are shown in Table 1.
Example 30. Phosphoinositide-3-kinase assay: Compounds proposed in present invention were
evaluated for their inhibitory activity on phosphoinositide-3-kinase-alpha and other isoforms (beta,
gamma and delta). The preliminary screening was performed at 0.5 pM concentration. The
protocols used for these bioassays are as follows:
PI3K-a assay: PI3K alpha (diluted in 12.5mM Glycine-NaOH (pH 8.5), 50 mM KCI, 2.5 mM MgCb,
1 mM DTT, 0.05% CHAPS) is assayed in total volume of 20 ul containing 12.5 mM glycine-NaOH
(pH 8.5), 50 mM KCI, 2.5 mM MgCb, 1 mM DTT, 0.05% CHAPS, 0.01 mM ATP and 0.05 mM diC8
PIP2. The enzyme is assayed for 80 min after which 20 ul of ADP-Glo reagent is added. After a
further incubation of 40 min, 40 ul of Kinase Detection Buffer is added. The assays are incubated
27
^ ^ for 40 min and then read on PerkinElmer Envision for 1 sec/well.
PI3K-P assay: PI3K beta (diluted in 12.5 mM glycine-NaOH (pH 8.5), 50 mM KCI, 2.5mM MgCb, 1
mM DTT, 0.05% CHAPS) is assayed in total volume of 20 ul containing 12.5mM Glycine-NaOH (pH
8.5), 50 mM KCI, 2.5 mM MgCb, 1 mM DTT, 0.05% CHAPS, 0.01 mM ATP and 0.05 mM diC8
PIP2. The enzyme is assayed for 60 min after which 20 ul of ADP-Glo reagent Is added. After a
further incubation of 40 min, 40 ul of kinase detection Buffer is added. The assays are Incubated for
40 min and then read on PerkinElmer Envision for 1 sec/well.
PI3K-5 assay: PI3K delta (diluted in 12.5mM Glycine-NaOH (pH 8.5), 50 mM KCI, 2.5mM MgCb, 1
mM DTT, 0.05% CHAPS) is assayed in total volume of 20 ul containing 12.5 mM Glycine-NaOH
(pH 8.5), 50 mM KCI, 2.5mM MgCb, 1 mM DTT, 0.05% CHAPS, 0.01 mM ATP and 0.05 mM diC8
PIP2. The enzyme is assayed for 120 min after which 20ul of ADP-Glo reagent is added. After a
further incubation of 40 min, 40 ul of Kinase Detection Buffer is added. The assays are incubated
for 40 min and then read on PerkinElmer Envision for 1 sec/well.
PI3K-Y assay: PI3K gamma (diluted in 12.5 mM Glycine-NaOH (pH 8.5), 50 mM KCI, 2.5 mM
MgCl2, 1 mM DTT, 0.05% CHAPS) is assayed in total volume of 20 ul containing 12.5mM glycine-
NaOH (pH 8.5), 50 mM KCI, 2.5 mM MgCb, 1 mM DTT, 0.05% CHAPS, 0.01 mM ATP and 0.05
mM diC8 PIP2. The enzyme is assayed for 75 min after which 20 ul of ADP-Glo reagent is added.
After a further incubation of 40 min, 40 ul of Kinase Detection Buffer is added. The assays are
incubated for 40 min and then read on PerkinElmer Envision for 1 sec/well.
The results of preliminary screening are shown in Table 1. The 6-aryl-4-phenylamino
quinazolines 10, 21, 26, 28, and 29 showed >40% inhibition of PI3K-a at 0.5 pM. The IC50 was
determined for best compounds and results are shown in Table 2. The fold-selectivity of these
compounds for PI3K-a isoform is also shown in Table 2.
Table 1.
Anticancer activity of 6-aryl-4-phenylamino quinazolines against pancreatic, breast, prostate,
leukemia and melanoma cells; and inhibition of phosphoinositide-3-kinase-a (PI3K-a) by these
compounds
Compo
und
6
Anticancer activity
IC50 (MM)
HL-60
32
A375
24
MCF-7
23
Panc-1
40
PC-3
27
% Inhibition of
PI3K-0 at 0.5 MM
16.4
28
^ 7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
7
42
28
24
15
36
16
14
23
16
16
16
25
21
27
17
14
12
31
18
44
32
10
9
39
32
28
23
32
27
16
38
13
30
32
31
27
24
10
14
36
34
31
89
35
12
10
91
45
15
12
>100
11
12
14
29
26
13
16
34
34
9
8
27
34
7
32
32
12
21
90
13
36
7
68
32
13
38
30
33
33
48
32
33
28
24
31
33
16
90
39
9
28
21
24
37
29
38
34
13
26
10
17
14
22
34
7
8
13
16
18
24
23
76
9
17
1.3
44
69.9
38.1
4.1
36.4
11
36.8
Nl
Nl
20.3
8.2
33
48.6
29.8
2.7
1.5
Nl
47.5
Nl
45.6
48.8
Nl, no inhibition at tested concentration; Panc-1: Human pancreatic carcinoma cell line; MCF-7:
Human breast adenocarcinoma cell line; PC-3: human prostate cancer cell line; A-375: Human
malignant melanoma cells; HL-60: Human leukemia cells; nd, not determined.
Table 2.
The IC50 values for 6-aryl-4-phenylamino quinazolines against four isoforms of phosphoinositide-3-
kinase and the fold-selectivity for PI3K-a isoform
29
^ Entry Structure PI3K inhibition
(IC50 values in IJM)
Fold-selectivity for PI3K-a
with respect to other
isoforms
-8 -Y
0.270 >10 0.15 >10 >37 0.5 >37
10
0.115 0.67 1.84 0.27 5.8 16 2.3
11
OoN 0.451 >10 0.85 >10 >22.2 1.9 >22.2
13
>10 >10 0.52 >10 >0.05
15 CN
0.475 >10 6.95 >10 >21 14.6 >21
20
0.342 >10 1.37 >10 >29.2 >29.2
30
• *> .
#
21
0.321 >10 0.19 >10 >31.1 0.6 >31.1
26
0.201 >10 0.75 >10 >49.7 3.7 >49.7
28
0.704 >10 0.36 >10 >14.2 0.5 >14.2
29
0.150 >20 8.44 0.88 >133 56 5.9
BEZ2
35 0.004 0.076 0.007 0.005 19 17.5 1.25
Among the examples depicted in Table 2, compound 29 displayed promising selectivity towards aisoform
versus p-isoform (>133 fold selectivity). Compound 29 also displayed 56-fold selectivity for
a-isoform versus y-isoform. Similarly, another compound 26 displayed >49.7 fold selectivity towards
a-isoform versus (3- and 5-isoforms. However, the Novartis molecule BEZ-235 has very weak
selectivity towards a-isoform versus other three isoforms: p, y and 5 (19, 17.5 and 1.25 fold
selectivity, respectively).
31
^ ^ Example 31. Molecular modeling studies of 6-aryl-4-phenylamino quinazolines 10 and 29
with phosphoinositide-3-kinase-a: The conformation, orientation and interactions of compounds
10 and 29 with phosphoinositide-3-kinase was determined by Glide module of Schrodinger
molecular modeling package using PI3Ka (PDB: 2RD0) crystal structure (Huang, C.-H et al.,
Science 2007, 318, 1744). The interactions of inhibitors 10 and 29 with PI3Ka were studied by
incorporating missing residues in the apo-form of PI3Ka (PDB: 2RD0). Protein was prepared by
removing solvent, adding hydrogens and by minimizing energy using protein preparation wizard.
Missing residues (Tyr307-Thr324, Ala415-Ala423, Phe506-Asp527 and Lys941-Glu950) were
incorporated in the apo-form of PI3K-a (PDB: 2rD0) using Prime module (version 3.0) of
Schrodinger Inc. LLC, NewYork, USA. Compounds were docked using Glide in extra-precision
mode with up to three poses saved per molecule.
As depicted in Figure 2, the compound 10 showed typical H-bonding interaction with the Val
851 residue of the hinge region and Tyr 836 residue of the ATP binding site. The phenolic ring of
Tyr 836 residue stablizes the quinazoline ring via TT-TT interactions. Compound 29 showed Hbonding
with the Gln859 residue of the PI3K-a catalytic domain instead of the Val851. Similar to
compound 10, the phenolic Tyr-836 and indolyl Trp-780 stabilizes the quinazoline and phenolic ring
of the compound 29 by aromatic TT-TT interactions. Both molecules fits into the hydrophobic cleft
formed by Trp780, Tyr 836, Val 850, Val851, lie 848, Phe 930, Ile932, Asp933 and Phe934
residues. The interaction map of compounds 10 and 29 in the active site of PI3K-a is shown in
Figure 2.
ADVANTAGES OF THE INVENTION
The main advantages of the present invention are:
• Compounds of the invention show promising anticancer activity against various cancer cell
lines and inhibit phosphoinositide-3-kinase-alpha, a key target in cancer at low micromolar
to nanomolar concentrations.
• Compounds of the invention are stable.
32

'• » ^ntr-^^'
# We Claim: 11 ^ ' f ^ ^ •'"*"' 1 ^
1. A compound of formula I, n^ pEo
Rwherein,
R is selected from the group comprising of alkyl, nitro, halogens (fluoro, chloro, bromo and
iodo), formyl, allyl, vinyl, benzyl, acetyl, hydroxy, phenyl, substituted phenyl, fused aromatics;
R' is selected from the group consisting of hydrogen, cyanomethyl, or alkyls.
Ar is selected from the group comprising of aryl or heteroaryl, which is unsubstituted or substituted
with an alkyl, nitro, halogens, formyl, allyl, vinyl, benzyl, acetyl, hydroxy, phenyl, substituted phenyl,
fused aromatics.
2. A compound of formula I as claimed in claim 1 wherein, aryl is selected from the group
consisting of phenyl, biphenyl which is unsubstituted or substituted with different R groups, which
is selected from the group comprising of alkyl, nitro, halogens (fluoro, chloro, bromo and iodo),
formyl, allyl, vinyl, benzyl, acetyl, hydroxy, phenyl, substituted phenyl, fused aromatics.
3. A compound of formula I as claimed in claim 1 wherein Alkyl group is selected from the group
consisting of (C1-C6)-alkyl, (C1-C4)-haloalkyl, (C1-C4)-alkoxy, (C1-C4)-haloalkoxy; oris(C5-C8)-
cycloalkyl, (C5-C8)-cycloalkenyl, (C6-C10)-bicycloalkyl, (C6-C10)-bicycloalkenyl.
4. A compound of formula I as claimed in claim 1 wherein, substituted phenyl is selected from the
group consisting of alkylphenyls, alkoxyphenyls.
5. A compound of formula I as claimed in claim 1 wherein, fused aromatics is selected from the
group consisting of naphthalene, 2,3-dihydrobenzo[b][1,4]dioxin, benzo[d][1,3]dioxol, benzofuran,
benzo[b]thiophene, dibenzo(b,d)furan, dibenzo(b,d)thiophene, 1H-indole, quinoline, isoquinoline.
6. A compound of formula I as claimed in claim 1 wherein, heteroaryl is selected from the group
consisting of pyridine, quinoline, isoquinoline, 2,3-dihydrobenzo[b][1,4]dioxin, benzo[d][1,3]dioxol,
benzofuran, benzo[b]thiophene, dibenzo(b,d)furan, dibenzo(b,d)thiophene, 1H-indole.
33
* •
ORIGINAL *
27 FEB 20U
J ^ 7. A compound of formula I as claimed in claim 1 wherein, the structural formulae of the said
compounds comprising:
10 11 12 13
34
a- * •
-^
€ 7 fE8 20U
; and
8. A compound of formula I as claimed in claim 1 wherein, the compounds are useful for the
treatment of cancer.
9. A compound of formula I as claimed in claim 1 wherein, the compounds are phosphoinositide-3-
kinase inhibitors.
10. A compound as claimed in claim 1, wherein the compounds are active against cancer cell lines
selected from a group consisting of HL-60, A375, MCF-7, Panc-1, PC-3.
11. A compound as claimed in claim 1, wherein the compounds are phosphoinositide-3-a kinase
inhibitors upto about 70% at 0.5 pM concentration
12. A process for preparation of the compounds of general formula I as claimed in claim 1 wherein
the process steps comprising:
a) reacting anthralinic acid (1) with bromine in glacial acetic acid at a temperature in the range of
10-25 °C for the time period of ranging between 15-30 min, followed by diluting with dilute HCI to
obtain monobromo anthranilic acid (2);
35
• g ^ 5 4^^^i 4,,,
V ^^ ^ - 2 7 FEB iOU
^ ^ b) adding formamide to monobromo anthranilic acid obtained in step (a) followed by reflux at a
temperature ranging between 100-150 °C for a time period ranging between 4-10 h to obtain
compound 3;
c) adding POCI3 to the solution of compound 3 as obtained in step (b) followed by reflux at a
temperature ranging between 100-150 °C for a time period ranging between 4-10 h to obtain
compound 4;
d) adding 4-amino benzylcyanide to the solution of compound 4 as obtained in step (c) forming a
mixture which is dissolved in isopropanol followed by stirring for a time period of ranging between 2-
6 h under reflux at a temperature ranging between 80-100 °C to obtain compound 5;
e) reacting aryl boronic acid in suitable solvent with compound 5 as obtained in step (d) followed by
addition of Pd(PPh3)4 followed by stirring of the resultant mixture for the time period ranging
between 12-24 h at a temperature ranging between 80-100 °C to yield compound of formula I.
13. A process as claimed in claim 12 wherein, the aryl boronic acid used in step (e) is selected form
the group consisting of substituted phenyls, substituted biphenyls, substituted naphthyls, substituted
heteroaryls.
14. A process as claimed in claim 12, wherein, the solvent used in step (e) is selected from toluene
or dioxane.