TETRAHYDROQUINAZOLINONE DERIVATIVES AS PARP INHIBITORS
FIELD OF THE INVENTION
The present invention relates to tetrahydroquinazolinone derivatives, their
tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts,
combinations with suitable medicament, pharmaceutical compositions
containing them, methods of making of tetrahydroquinazolinone derivatives,
and their use as PARP inhibitors.
CROSS-REFERENCE TO A RELATEDAPPLICATION
The present application claims the benefit of Indian Provisional Patent
Application Number 0762/KOL/2012, filed on 9th July 2012, the disclosure of
which is incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
Poly (ADP-ribose) Polymerase (PARP; 113 kDa) is an enzyme that catalyzes the
addition of ADP-ribose residues to various target proteins. The reaction requires
NAD+ as substrate. As many as 18 isoforms of PARP are known. PARPl and
PARP2 are the closest relatives [60% identical in PARPl is activated by SSB
(single-strand breaks) in DNA]. ADP-ribosylation occurs at the carboxylate
groups of glutamic acid or aspartic acid residues in acceptor proteins and
results in the modulation of catalytic activity and protein-protein interactions of
the target proteins (e.g., modulation of chromatin structure, DNA synthesis,
DNA repair (Base Excision Repair or BER), transcription, and/or cell cycle
progression. PARP binds to DNA single strand as well as double strand breaks.
The binding of PARP to damaged DNA leads to activation of the enzyme. PARP
carries out ADP ribosylation of proteins involved in DNA repair (e.g., BER)
including itself. Automodification of PARP results in its release from DNA which
allows the DNA repair machinery to access the DNA damage site and carry out
the repair process.
Overactivation of PARP leads to necrotic cell death as a result of NAD+ and ATP
depletion.
Cancer patients who have undergone radiotherapy or have been treated with
chemotherapeutic agents that damage DNA (e.g. cisplatin, irinotecan,
temozolomide) harbour DNA strand breaks. Activation of PARP in such cases
allows the repair of the damaged DNA, thus leading to an undesirable resistance
to the chemotherapeutic agents (and the consequent inefficacy). In such a
scenario, treatment with a PARP inhibitor is expected to make the repair
process inefficient and cause cell death.
BRCA1 and BRCA2 play an important role in HR (Homologous Recombination).
DNA breaks arising during DNA replication can only be repaired by HR.
Continuous exposure of BRCA1/BRCA2 deficient cells to PARP inhibitor results
in accumulation of DNA DSB followed by apoptosis (Synthetic Lethality) . Triple
Negative Breast Cancers (TNBC) are also acutely sensitive to PARP since they
also harbor defects in the DNA repair machinery. Recently, cancer cells deficient
in USP11 and endometrial cancer cells deficient in PTEN have also been shown
to be sensitive to PARP inhibitors. PARP inhibitors thus have immense potential
to be used for anticancer chemotherapy. [Biochem. J., (1999) 342, 249-268;
Ann. Rev. Biochem., 1977, 46:95-1 16; E. Journal Cancer 4 6 (2010) 9-20].
Additionally, PARP has been implicated in a number of disease conditions other
than cancer. These include disorders such as stroke, traumatic brain injury,
Parkinson's disease, meningitis, myocardial infarction, ischaemic
cardiomyopathy and other vasculature-related disorders. In animal
experiments, PARP-/-mice demonstrated improved motor and memory function
after CCI (Controlled Cortical Impact) versus PARP +/+ mice (J Cereb Blood
Flow Metab. 1999, Vol. 19. No. 8, 835).
While attempts have been made to develop PARP inhibitors for treating cancer
and other diseases, satisfactory treatment has not been achieved. Therefore,
there exists an unmet need for new PARP inhibitors and treatment regimen
therewith.
BRIEF SUMMARY OF THE INVENTION
In one aspect, the present invention provides a compound of formula (I), its
tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its
combination with suitable medicament, its pharmaceutical composition and its
wherein,
Mis selected from C, CH, and N;
is a single bond when M is selected as N, and is either a single or a
double bond when Mis selected as CH or C respectively;
R is selected from hydrogen, and substituted- or unsubstituted- alkyl;
R2 and R3 groups are attached either to the same carbon atom or adjacent or
non-adjacent carbon atoms of the carbocylic ring, and R2 and R3 together with
the carbon atom(s) to which they are attached form a substituted- or
unsubstituted carbocycle;
R4 is selected independently at each occurrence from halogen, cyano,
substituted- or unsubstituted- alkyl, -OR9, and -N(R )R ;
R5 and R6 are each independently selected from hydrogen, halogen, substitutedor
unsubstituted- alkyl, perhaloalkyl, substituted- or unsubstituted- cycloalkyl,
-OR9, and -N(R 0)Rn, or R5 and R6 together constitute oxo (=0), or both R5 and
R6 attached to the same carbon atom or adjacent or non-adjacent carbon atoms
together with the carbon atom(s) to which they are attached form a substitutedor
unsubstituted- carbocycle, or when they are attached to adjacent carbon
atoms, form a p i bond linking the said carbon atoms.
R7 , R , R7b, R b , R7 , R , R7d, and R d are each independently selected from
hydrogen, halogen, substituted- or unsubstituted- alkyl, -OR9, and -N(R10)R ;
or any two groups out of R7 , R a , R7b , R , R7 , R , R7d, and R d form oxo (=0), or
any two groups out of R7 , R , R7b , R b , R7 , R , R7d, and R d taken together with
the carbon atom(s) to which they are attached form a substituted- or
unsubstituted- carbocycle, or a substituted- or unsubstituted heterocycle,
thereby making ring 'A' either a spiro-bicycle or a fused-bicycle or a bridgedbicycle;
Ar is selected from substituted- or unsubstituted- aryl and substituted- or
unsubstituted heteroaryl;
p is an integer selected from 0, 1, 2 and 3 ;
n is an integer selected from 1, 2, 3, and 4 ;
R9 is selected from hydrogen and substituted- or unsubstituted- alkyl;
R10 and R1 1 are each independently selected from hydrogen and substituted- or
unsubstituted- alkyl;
In second aspect the invention provides a pharmaceutical composition
comprising the compound of formula (I) and a pharmaceutically acceptable
carrier.
In third aspect the invention provides a method of treating or preventing a
disorder responsive to the inhibition of PARP activity in a mammal suffering
therefrom, comprising administering to the mammal in need of such treatment
a therapeutically effective amount of a compound of formula (I).
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to novel compound of the general formula (I), its
tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its
combination with suitable medicament, its pharmaceutical composition, process
and intermediates for the preparation of the above said compound having PARP
wherein,
Mis selected from C, CH, and N;
is a single bond when M is selected as N, and is either a single or a
double bond when Mis selected as CH or C respectively;
R1 is selected from hydrogen, and substituted- or unsubstituted- alkyl;
R2 and R3 groups are attached either to the same carbon atom or adjacent or
non-adjacent carbon atoms of the carbocylic ring, and R2 and R3 together with
the carbon atom(s) to which they are attached form a substituted- or
unsubstituted carbocycle;
R4 is selected independently at each occurrence from halogen, cyano,
substituted- or unsubstituted- alkyl, -OR9, and -N R °)R ;
R5 and R6 are each independently selected from hydrogen, halogen, substitutedor
unsubstituted- alkyl, perhaloalkyl, substituted- or unsubstituted- cycloalkyl,
-OR9, and -N(R )R , or R5 and R6 together constitute oxo (=0), or both R5 and
R6 attached to the same carbon atom or adjacent or non-adjacent carbon atoms
together with the carbon atom(s) to which they are attached form a substitutedor
unsubstituted- carbocycle, or when they are attached to adjacent carbon
atoms, form a p i bond linking the said carbon atoms.
R7 , R , R7b, R b , R7 , R , R7d, and R d are each independently selected from
hydrogen, halogen, substituted- or unsubstituted- alkyl, -OR9, and -N(R )R ;
or any two groups out of R7 , R a , R7b , R , R7 , R , R7d, and R d form oxo (=0), or
any two groups out of R7a, R a, R7 , R , R7 , R , R7d, and R d taken together with
the carbon atom(s) to which they are attached form a substituted- or
unsubstituted- carbocycle, or a substituted- or unsubstituted heterocycle,
thereby making ring 'A' either a spiro-bicycle or a fused-bicycle or a bridgedbicycle;
Ar is selected from substituted- or unsubstituted- aryl and substituted- or
unsubstituted heteroaryl;
p is an integer selected from 0, 1, 2 and 3 ;
n is an integer selected from 1, 2, 3, and 4 ;
R9 is selected from hydrogen and substituted- or unsubstituted- alkyl;
R10 and R1 1 are each independently selected from hydrogen and substituted- or
unsubstituted- alkyl;
when an alkyl group or alkenyl group is substituted, each of them is
substituted with 1 to 4 substituents independently selected from oxo (=0),
halogen, cyano, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl,
heterocyclyl, -OR1 , -S0 2(alkyl), -C(=0)0(alkyl), -C(=0)N(H)R12 , -C(=0)N(alkyl)2, -
N(H)C(=0)(alkyl), -N(H)R12 , and-N(alkyl)R 12 ;
when 'cycloalkyl', 'cycloalkenyl' and 'carbocycle' is substituted, the cycloalkyl,
cycloalkenyl, or carbocycle group is substituted with 1 to 4 substituents
independently selected from oxo (=0), halogen, cyano, alkyl, alkenyl,
perhaloalkyl, -OR12 , -S0 2(alkyl), -C(=0)0(alkyl), -C(=0)N(H)R12 ,
C(=0)N(alkyl)R12 , -N(H)C(=0)(alkyl), -N(H)R12 , -N(alkyl)2;
when the aryl group is substituted, it is substituted with 1 to 4 substituents
independently selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl,
perhaloalkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, -O-alkyl, -Operhaloalkyl,
-N(alkyl)alkyl, -N(H)alkyl, -NH2, -S0 2-alkyl, -S0 2-perhaloalkyl, -
N(alkyl)C(=0)alkyl, -N(H)C(=0)alkyl, -C(=0)N(alkyl)alkyl, -C(=0)N(H)alkyl, -
C(=0)N(H)cycloalkyl, -C(=0)NH2, -S0 2N(alkyl)alkyl, -S0 2N(H)alkyl, -S0 2NH2, -
C(=0)OH, -C(=0)0-alkyl, -0(C=0)N(alkyl)H, -0(C=0)N(alkyl) 2,
0(C=0)N(cycloalkyl)H, -N(H)C(=0)N(aryl)H, -N(H)C(=0)N(alkyl)H, and
N(H)C(=0)NH2;
when the heteroaryl group is substituted, it is substituted with 1 to 4
substituents independently selected from halogen, nitro, cyano, hydroxy, alkyl,
alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, -Oalkyl,
-O-perhaloalkyl, -N(alkyl)alkyl, -N(H)alkyl, -NH2, -S0 2-alkyl, -S0 2-
perhaloalkyl, -N(alkyl)C(=0)alkyl, -N(H)C(=0)alkyl, -C(=0)N(alkyl)alkyl, -
C(=0)N(H)alkyl, -C(=0)N(H)cycloalkyl, -C(=0)NH2, -S0 2N(alkyl)alkyl,
S0 2N(H)alkyl, -S0 2NH2, -C(=0)OH, -C(=0)0-alkyl, -0(C=0)N(alkyl)H, -
0(C=0)N(alkyl) 2, -0(C=0)N(cycloalkyl)H, -N(H)C(=0)N(aryl)H,
N(H)C(=0)N(alkyl)H, and -N(H)C(=0)NH2;
when the heterocyclic group is substituted, it is substituted either on a ring
carbon atom or on a ring hetero atom, and when it is substituted on a ring
carbon atom, it is substituted with 1 to 4 substituents independently selected
from oxo (=0), halogen, cyano, alkyl, alkenyl, perhaloalkyl, -OR12 , -S0 2(alkyl), -
C(=0)0(alkyl), -C(=0)N(H)R12 , -C(=0)N(alkyl)R12 , -N(H)C(=0)(alkyl), -N(H)R12 , -
N(alkyl)2; and when the heterocyclic group is substituted on a ring nitrogen, it is
substituted with substituents independently selected from alkyl, alkenyl,
cycloalkyl, cycloalkenyl, aryl, heteroaryl, -S0 2(alkyl), -C(=0) (alkyl), C(=0)0(alkyl).
R12 is selected from hydrogen and alkyl; and
R12a is selected from hydrogen, alkyl, alkenyl, perhaloalkyl.
'n' is particularly selected as 3.
R5 and R6 are each independently selected from hydrogen and methyl; or R5, R6
and the carbon atom(s) to which they are attached together forming a
carbocycle, which may be substituted with 1 to 3 alkyl groups.
R5, R6 and the carbon atoms to which they are attached together form a
substituted- or unsubstituted carbocycle, wherein the said carbocycle is
particul
Ar is particularly selected from substituted- or unsubstituted- phenyl,
substituted- or unsubstituted- pyridinyl, substituted- or unsubstitutedthiazolyl,
substituted- or unsubstituted- thiophenyl, and substituted- or
unsubstituted- benzothiazolyl, wherein the substituted- phenyl, substitutedpyridinyl,
substituted- thiazolyl, or substituted- benzothiazolyl group is
substituted with 1-3 substituents independently selected from halo, cyano,
thiophenyl, phenyl, methyl, ethyl, trifluoromethyl, methoxy, Nmethylcarbamoyl,
N,N-dimethylcarbamoyl, and N-cyclopropylcarbamoyl.
Ar is more particularly selected from
wherein, RA and RB are independently selected from halogen and methyl, Rc is
selected from halogen, methyl and methoxy, RD is selected from halogen, cyano,
methyl, N-methylcarbamoyl, R is selected from hydrogen, halogen, methyl, Ncyclopropylcarbamoyl,
N-methylcarbamoyl, N,N-dimethylcarbamoyl, and 3-
thiophenyl, R is selected from halogen, methyl, N-methylcarbamoyl, and
trifluoromethyl, R and RH are independently selected from hydrogen, halogen,
methyl, and N-methylcarbamoyl, RJ is selected from hydrogen and methyl, RK is
selected from hydrogen, halogen, methyl and phenyl, RL is selected from
hydrogen and ethyl, and RM is selected from hydrogen, methyl and Nmethylcarbamoyl.
Ring A is more particularly selected from
General terms used in formula can be defined as follows; however, the meaning
stated should not be interpreted as limiting the scope of the term per se.
The term 'alkyl', as used herein, means a straight chain or branched
hydrocarbon containing from 1 to 20 carbon atoms. Preferably the alkyl chain
may contain 1 to 10 carbon atoms. More preferably alkyl chain may contain up
to 6 carbon atoms. Representative examples of alkyl include, but are not limited
to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,
n-pentyl, isopentyl, neopentyl, and n-hexyl.
The term 'alkenyl', as used herein, means an alkyl group containing at least one
double bond.
The 'alkyl', and 'alkenyl' as defined hereinabove may be substituted with 1 to 4
substituents independently selected from oxo (=0) , halogen, cyano,
perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, -OR12a , -
S0 2(alkyl) , -C(=0)0(alkyl) , -C(=0)N(H)R 2, -C(=0)N(alkyl) , -N(H)C(=0)(alkyl), -
N(H)R12 , and-N(alkyl)R12 ; R12 is selected from hydrogen and alkyl; and R 2 is
selected from hydrogen, alkyl, alkenyl, and perhaloalkyl.
The term 'perhaloalkyl', as used herein, means an alkyl group as defined
hereinabove wherein all the hydrogen atoms of the said alkyl group are
substituted with halogen. The perhaloalkyl group is exemplified by
trifluoromethyl, pentafluoroethyl, and the like.
The term 'cycloalkyl' as used herein, means a monocyclic, bicyclic, or tricyclic
non-aromatic ring system containing from 3 to 14 carbon atoms, preferably
monocyclic cycloalkyl ring containing 3 to 6 carbon atoms. Examples of
monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, and cyclooctyl. Bicyclic ring systems include monocyclic ring
system fused across a bond with another cyclic system which may be an
alicyclic ring or an aromatic ring. Bicyclic rings also include spirocyclic systems
wherein the second ring gets annulated on a single carbon atom. Bicyclic ring
systems are also exemplified by a bridged monocyclic ring system in which two
non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene
bridge. Representative examples of bicyclic ring systems include, but are not
limited to, bicyclo[3. 1. l]heptane, bicyclo[2.2. l]heptane, bicyclo[2.2.2]octane,
bicyclo[3.2.2]nonane, bicyclo[3.3. l]nonane, and bicyclo[4.2. l]nonane,
bicyclo[3.3.2]decane, bicyclo[3. 1.0]hexane, bicyclo[410]heptane,
bicyclo[3.2.0]heptanes, octahydro- lH-indene, spiro[2.5]octane, spiro[4.5]decane,
spiro[bicyclo[4. 1.0]heptane-2, l'-cyclopentane], hexahydro-2'Hspiro[
cyclopropane-l, l'-pentalene]. Tricyclic ring systems are the systems
wherein the bicyclic systems as described above are further annulated with
third ring, which may be an alicyclic ring or aromatic ring. Tricyclic ring
systems are also exemplified by a bicyclic ring system in which two nonadjacent
carbon atoms of the bicyclic ring are linked by a bond or an alkylene
bridge. Representative examples of tricyclic-ring systems include, but are not
limited to, tricyclo[3.3. 1.03 7]nonane, and tricyclo[3.3. 1. 13 7]decane
(adamantane) .
The term 'cycloalkenyl', as used herein, means a cycloalkyl group containing at
least one double bond.
The term 'carbocycle', as used herein, means a cyclic system made up of carbon
atoms, which includes cycloalkyl, cycloalkenyl and aryl.
The 'cycloalkyl', 'cycloalkenyl' and 'carbocycle' as defined hereinabove may be
substituted with 1 to 4 substituents independently selected from oxo (=0),
halogen, cyano, alkyl, alkenyl, perhaloalkyl, -OR12 , -S0 2(alkyl), -C(=0)0(alkyl), -
C(=0)N(H)R 2 , -C(=0)N(alkyl)R 2 , -N(H)C(=0)(alkyl), -N R , -N(alkyl)2; R1 is
selected from hydrogen and alkyl; and R12 is selected from hydrogen, alkyl,
alkenyl, perhaloalkyl.
The term 'aryl', as used herein, refers to a monovalent monocyclic, bicyclic or
tricyclic aromatic hydrocarbon ring system. Examples of aryl groups include
phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like. Aryl
group also include partially saturated bicyclic and tricyclic aromatic
hydrocarbons, e.g., tetrahydro-naphthalene.
The 'aryl' as defined hereinabove may be substituted with 1 to 4 substituents
selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl, perhaloalkyl,
cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, -O-alkyl, -O-perhaloalkyl,
-N(alkyl)alkyl, -N(H)alkyl, -NH2, -S0 2-alkyl, -S0 2-perhaloalkyl,
N(alkyl)C(=0)alkyl, -N(H)C(=0)alkyl, -C(=0)N(alkyl)alkyl, -C(=0)N(H)alkyl, -
C(=0)N(H)cycloalkyl, -C(=0)NH2, -S0 2N(alkyl)alkyl, -S0 2N(H)alkyl, -S0 2NH2, -
C(=0)OH, -C(=0)0-alkyl, -0(C=0)N(alkyl)H, -0(C=0)N(alkyl)2,
0(C=0)N(cycloalkyl)H, -N(H)C(=0)N(aryl)H, -N(H)C(=0)N(alkyl)H, and
N(H)C(=0)NH2.
The term 'heteroaryl', as used herein, refers to a 5-14 membered monocyclic,
bicyclic, or tricyclic ring system having 1-4 ring heteroatoms selected from O, N,
or S, and the remainder ring atoms being carbon (with appropriate hydrogen
atoms unless otherwise indicated), wherein at least one ring in the ring system
is aromatic. Heteroaryl groups may be optionally substituted with one or more
substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a
heteroaryl group may be substituted by a substituent. Examples of heteroaryl
groups include, but not limited to, pyridyl, 1-oxo-pyridyl, furanyl, thienyl,
pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl,
pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl,
thiadiazolyl, isoquinolinyl, benzoxazolyl, benzofuranyl, indolizinyl,
imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl,
benzoxadiazolyl, indolyl, azaindolyl, imidazopyridyl, quinazolinyl, purinyl,
pyrrolo[2,3]pyrimidinyl, pyrazolo [3,4 ]pyrimidinyl, and benzo(b)thienyl, 2,3-
thiadiazolyl, lH-pyrazolo[5, 1-c]- 1,2,4-triazolyl, pyrrolo[3,4-d]- 1,2,3-triazolyl,
cyclopentatriazolyl, 3H-pyrrolo[3,4-c] isoxazolyl, 2,3-dihydro-benzo[l,4]dioxin-6-
yl, 2,3-dihydro-benzo[l,4]dioxin-5-yl, 2,3-dihydro-benzofuran-5-yl, 2,3-dihydrobenzofuran-
4-yl, 2,3-dihydro-benzofuran-6-yl, 2,3-dihydro-benzofuran-6-yl,
2,3-dihydro- lH-indol-5-yl, 2,3-dihydro- lH-indol-4-yl, 2,3-dihydro- lH-indol-6-
yl, 2,3-dihydro- lH-indol-7-yl, benzo[l,3]dioxol-4-yl, benzo[l,3]dioxol-5-yl,
1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 2,3-
dihydrobenzothien-4-yl, 2-oxoindolin-5-yl and the like.
The 'heteroaryl' as defined hereinabove may be optionally substituted with 1 to
4 substituents selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl,
perhaloalkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, -O-alkyl, -Operhaloalkyl,
-N(alkyl)alkyl, -N(H)alkyl, -NH2, -S0 2-alkyl, -S0 2-perhaloalkyl, -
N(alkyl)C(=0)alkyl, -N(H)C(=0)alkyl, -C(=0)N(alkyl)alkyl, -C(=0)N(H)alkyl, -
C(=0)N(H)cycloalkyl, -C(=0)NH2, -S0 2N(alkyl)alkyl, -S0 2N(H)alkyl, -S0 2NH2, -
C(=0)OH, -C(=0)0-alkyl, -0(C=0)N(alkyl)H, -0(C=0)N(alkyl)2,
0(C=0)N(cycloalkyl)H, -N(H)C(=0)N(aryl)H, -N(H)C(=0)N(alkyl)H, and
N(H)C(=0)NH2.
The term 'heterocycle' or 'heterocyclic' as used herein, means a 'cycloalkyl'
group wherein one or more of the carbon atoms replaced by heteroatom selected
from N, S and O. The heterocycle may be connected to the parent molecular
moiety through any carbon atom or any nitrogen atom contained within the
heterocycle. Representative examples of monocyclic heterocycle include, but are
not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-
dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl,
isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl,
oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl,
pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl,
tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl,
thiomorpholinyl, 1. 1-dioxidothiomorpholinyl (thiomorpholine sulfone),
thiopyranyl, and trithianyl. Representative examples of bicyclic heterocycle
include, but are not limited to, l,2,3,4-tetrahydroisoquinolin-2-yl, 1,2,3,4-
tetrahydroquinolin-l-yl, 1,3-benzodioxolyl, 1,3-benzodithiolyl, 2,3-dihydro-l,4-
benzodioxinyl, 2,3-dihydro-l-benzofuranyl, 2,3-dihydro-l-benzothienyl, 2,3-
dihydro-lH-indolyl, and 1,2,3,4-tetrahydroquinolinyl. The term heterocycle also
includes bridged and spiro heterocyclic systems such as
azabicyclo[3.2. l]octane, azabicyclo[3.3. l]nonane, 8-oxa-3-
azabicyclo[3.2. l]octan-3-yl, 3-oxa-8-azabicyclo[3.2. l]octan-8-yl, 6-oxa-3-
azabicyclo[3. 1. l]heptan-3-yl, 8-azabicyclo[3.2. l]octan-8-yl, 3-
azabicyclo[3.2. l]octan-3-yl, 3-azabicyclo[3. 1.0]hexan-3-yl, 6-azaspiro[2.5]octan-
6-yl, 5-azaspiro[2.5]octan-5-yl, 4-azaspiro[2.4]heptan-4-yl, and the like.
The 'heterocycle' as defined hereinabove, wherein the ring carbon may be
optionally substituted with 1 to 4 substituents selected from oxo (=0), halogen,
cyano, alkyl, alkenyl, perhaloalkyl, -OR 12 , -S0 2(alkyl), -C(=0)0(alkyl), -
C(=0)N(H)R 2, -C(=0)N(alkyl)R , -N(H)C(=0) (alkyl), -N(H)R 2, -N(alkyl)2; R 2 is
selected from hydrogen and alkyl;
The 'heterocycle' as defined hereinabove, wherein the ring nitrogen may be
optionally substituted with a substituent selected from alkyl, alkenyl, cycloalkyl,
cycloalkenyl, aryl, heteroaryl, -S0 2(alkyl), -C(=0) (alkyl), C(=0)0(alkyl). -
C(=0)N(H)R 12 , and -C(=0)N(alkyl)R12 ; R1 is selected from hydrogen and alkyl.
The term 'oxo' means a divalent oxygen (=0) attached to the parent group. For
example oxo attached to carbon forms a carbonyl, oxo substituted on
cyclohexane forms a cyclohexanone, and the like.
The term 'annulated' means the ring system under consideration is either
annulated with another ring at a carbon atom of the cyclic system or across a
bond of the cyclic system as in the case of fused or spiro ring systems.
The term 'bridged' means the ring system under consideration contain an
alkylene bridge having 1 to 4 methylene units joining two non-adjacent ring
atoms.
Whenever a range of the number of atoms in a structure is indicated (e.g., a Ci
to C20 alkyl, C2 to C20 alkenyl etc.), it is specifically contemplated that any sub
range or individual number of carbon atoms falling within the indicated range
also can be used. Thus, for instance, the recitation of a range of 1-6 carbon
atoms (e.g., Ci to Ce), 2-6 carbon atoms (e.g., C2 to Ce), 3-6 carbon atoms (e.g.,
C 3 to Ce) , as used with respect to any chemical group (e.g., alkyl, alkenyl, etc.)
referenced herein encompasses and specifically describes 1, 2, 3, 4, 5, and/ or 6
carbon atoms, as appropriate, as well as any sub-range thereof (e.g., 1-2 carbon
atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon
atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon
atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3-6 carbon atoms, 4-5 carbon
atoms, 4-6 carbon atoms as appropriate).
In accordance with an embodiment, the invention provides a compound, its
stereoisomers, racemates, and pharmaceutically acceptable salt thereof as
described hereinabove wherein the compound of general formula (I) is selected
from:
'-(3 -(4-(4-fluorophenyl)piperazin- 1-yl)propyl)-6',7'-dihydro-3Ή -
spiro[cyclopropane-l,8'-quinazolin]-4'(5'H)-one (Compound 1);
'-(3 -(4- (4-chlorophenyl)piperazin- 1-yl)propyl)-6' ,7'-dihydro-3Ή -
spiro[cyclopropane-l,8'-quinazolin]-4'(5'H)-one (Compound 2);
2'-(3-(4-phenyl-5,6-dihydropyridin-l(2H)-yl)propyl)-6',7'-dihydro-3'Hspiro[
cyclopropane-l,8'-quinazolin]-4'(5'H)-one (Compound 3);
2'-(3-(3-(4-fluorophenyl)-3,8-diazabicyclo[3.2. 1]octan-8-yl)propyl)-
4a',5',6',7'-tetrahydro-3'H-spiro[cyclopropane-l,8'-quinazolin]-4'(8a'H)-one
(Compound 4);
2'-(3 -(4-(4-fluorophenyl)piperazin- 1-yl)propyl)-7',8'-dihydro-3Ή -
spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 5);
2'-(3 -(4- (4-chlorophenyl)piperazin- 1-yl)propyl)-7',8'-dihydro-3Ή -
spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 6);
2'-(3-(3-(4-fluorophenyl)-3,8-diazabicyclo[3.2. 1]octan-8-yl)propyl)-7',8'-
dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 7);
2'-(3-(8-(4-fluorophenyl)-3,8-diazabicyclo[3.2. 1]octan-3-yl)propyl)-7',8'-
dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 8);
2'-(3 -(4-(4-fluorophenyl)-5,6-dihydropyridin- 1(2H) -yl)propyl)-7',8'-dihydro-
3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 9);
2'-(3-(4-(3,4-dichlorophenyl)piperazin-l-yl)propyl)-7',8'-dihydro-3'Hspiro[
cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 10);
2'-(3-(5-(4-fluorophenyl)-2,5-diazabicyclo[2.2. 1]heptan-2-yl)propyl)-7',8'-
dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 11);
2'-(3-(3-(4-fluorophenyl)-3,8-diazabicyclo[3.2. 1]octan-8-yl)propyl)-7',8'-
dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 12);
2'-(3-(4-phenylpiperazin-l-yl)propyl)-7',8'-dihydro-3'H-spiro[cyclopropanel,
6'-quinazolin]-4'(5'H)-one (Compound 13);
2'-(3 -(4- (2-chlorophenyl)piperazin- 1-yl)propyl)-7',8'-dihydro-3Ή -
spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 14);
'-(3 -(4-(4-fluorophenyl)piperazin- 1-yl)propyl)-5',6'-dihydro- 3Ή -
spiro[cyclopropane-l,7'-quinazolin]-4'(8'H)-one (Compound 15);
2'-(3 -(4-(4-fluorophenyl)-5,6- dihydropyridin- 1(2H) -yl)propyl)-5',6'-dihydro-
3'H-spiro[cyclopropane-l,7'-quinazolin]-4'(8'H)-one (Compound 16);
2'-(3-(4-phenyl-5,6-dihydropyridin-l(2H)-yl)propyl)-5',6'-dihydro-3'Hspiro[
cyclopropane-l,7'-quinazolin]-4'(8'H)-one (Compound 17);
2'-(3-(4-(3-chlorophenyl)piperazin-l-yl)propyl)-7',8'-dihydro-3'Hspiro[
cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 18);
2'-(3-(4-phenylpiperidin-l-yl)propyl)-7',8'-dihydro-3'H-spiro[cyclopropanel,
6'-quinazolin]-4'(5'H)-one (Compound 19);
2'-(3-(4-(pyridin-2-yl)piperazin-l-yl)propyl)-7',8'-dihydro-3'Hspiro[
cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 20);
2'-(3-(4-(4-fluorophenyl)piperazin-l-yl)butyl)-7',8'-dihydro-3'Hspiro[
cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 21);
2'-(3 -(4- (3- (trifluoromethyl)phenyl)piperazin- 1-yl)propyl)-7',8'-dihydro- 3Ή -
spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 22);
2'-(3-(4-(m-tolyl)piperazin-l-yl)propyl)-7',8'-dihydro-3'H-spiro[cyclopropanel,
6'-quinazolin]-4'(5'H)-one (Compound 23);
2-(3- (4-(4-fluorophenyl)piperazin- 1-yl)propyl)-5a, 6,6a, 7-tetrahydro-3Hcyclopropa[
g]quinazolin-4(5H)-one (Compound 24);
2-(3-(4-phenylpiperazin- 1-yl)propyl)-5a, 6,6a, 7-tetrahydro-3Hcyclopropa[
g]quinazolin-4(5H)-one (Compound 25);
2'-(3-(4-(4-fluorophenyl)-2,6-dimethylpiperazin-l-yl)propyl)-7',8'-dihydro-
3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 26);
2'-(3-(4-(4-fluorophenyl)-2-methylpiperazin-l-yl)propyl)-7',8'-dihydro-3'Hspiro[
cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 27);
2'-(3-(4-(2-fluorophenyl)piperazin-l-yl)propyl)-7',8'-dihydro-3'Hspiro[
cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 28);
2'-(3-(4-(pyridin-4-yl)piperazin-l-yl)propyl)-7',8'-dihydro-3'Hspiro[
cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 29);
2'-(3-(4-(4-fluorophenyl)piperazin-l-yl)-3-methylbutyl)-7',8'-dihydro-3'Hspiro[
cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 30);
(E)-2'-(3-(4-(4-fluorophenyl)piperazin-l-yl)-3-methylbut-l-en-l-yl)-7',8'-
dihydro-3 'H-spiro[cyclopropane- 1,6'-quinazolin]-4' (5Ή )-one (Compound 31);
2'-(3-(4-(p-tolyl)piperazin-l-yl)propyl)-7',8'-dihydro-3'H-spiro[cyclopropanel,
6'-quinazolin]-4'(5'H)-one (Compound 32);
2'-(3-(4-(4-fluorophenyl)-2-oxopiperazin-l-yl)propyl)-7',8'-dihydro-3'Hspiro[
cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 33);
2'-(3-(4-(2,4-dichlorophenyl)piperazin-l-yl)propyl)-7',8'-dihydro-3'Hspiro[
cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 34);
2-(3- (4-(4-fluorophenyl)piperazin- 1-yl)propyl)-5,6,7, 8-tetrahydro- 5,8-
methanoquinazolin-4(3H)-one (Compound 35);
2-(3- (4-(4-chlorophenyl)piperazin- 1-yl)propyl)-5,6,7, 8-tetrahydro- 5,8-
methanoquinazolin-4(3H)-one (Compound 36);
(R)-2'-(3-(4-(4-chlorophenyl)piperazin-l-yl)cyclopent-l-en-l-yl)-7',8'-
dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 37);
(S)-2'-(3-(4-(4-chlorophenyl)piperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'-dihydro-
3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 38);
2'-(3-(4-(pyridin-4-yl)piperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'-dihydro-3'Hspiro[
cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 39);
(S)-2'-(3-(4-(4-chlorophenyl)piperazin- l-yl)cyclopent- 1-en- l-yl)-6',7'-dihydro-
3'H-spiro[cyclopropane-l,8'-quinazolin]-4'(5'H)-one (Compound 40);
(R)-2'-(3-(4-(4-chlorophenyl)piperazin-l-yl)cyclopent-l-en-l-yl)-6',7'-
dihydro-3'H-spiro[cyclopropane-l,8'-quinazolin]-4'(5'H)-one (Compound 41);
(R)-2'-(3-(4-(4-fluorophenyl)piperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'-dihydro-
3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 42);
(S)-2'-(3-(4-(4-fluorophenyl)piperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'-dihydro-
3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 43);
N-cyclopropyl-4-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cyclopropane-
1,6'-quinazolin]-2'-yl)cyclopent-2-en- l-yl)piperazin- l-yl)benzamide
(Compound 44);
2'-(3-(4-(4-fluorophenyl)-3-oxopiperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'-
dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 45);
(R) -2'-(3-(4-(4-chlorophenyl) -5,6- dihydropyridin- 1(2H) -yl)cyclopent- 1-en- 1-
yl)-7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 46);
(S)-2'-(3-(4-(4-chlorophenyl)-5,6-dihydropyridin- l(2H)-yl)cyclopent- 1-en- 1-
yl)-7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 47);
(R)-2'-(3-(4-(4-fluorophenyl)piperazin- l-yl)cyclopent- 1-en- l-yl)-6',7'-dihydro-
3'H-spiro[cyclopropane-l,8'-quinazolin]-4'(5'H)-one (Compound 48);
(S)-2'-(3-(4-(4-fluorophenyl)piperazin- l-yl)cyclopent- 1-en- l-yl)-6',7'-dihydro-
3'H-spiro[cyclopropane-l,8'-quinazolin]-4'(5'H)-one (Compound 49);
2'-(3-(4-(4-bromophenyl)piperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'-dihydro-
3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 50);
(S)-2'-(3-(4-(4-fluorophenyl)-5,6-dihydropyridin-l(2H)-yl)cyclopent-l-en-lyl)-
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 51);
(R)-2'-(3-(4-(4-fluorophenyl)-5,6-dihydropyridin- l(2H)-yl)cyclopent- 1-en- 1-
yl)-7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 52);
(S)-N-methyl-4-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cyclopropane-
1,6'-quinazolin]-2'-yl)cyclopent-2-en- l-yl)piperazin- l-yl)benzamide
(Compound 53);
(R)-N-methyl-4-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cyclopropane-
1,6'-quinazolin]-2'-yl)cyclopent-2-en- l-yl)piperazin- l-yl)benzamide
(Compound 54);
(S)-2'-(3-(4-(4-chlorophenyl)piperidin-l-yl)cyclopent-l-en-l-yl)-7',8'-dihydro-
3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 55);
(R)-2'-(3-(4-(4-chlorophenyl)piperidin-l-yl)cyclopent-l-en-l-yl)-7',8'-dihydro-
3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 56);
(R)-2'-(3-(4-(5-chloropyridin-2-yl)piperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'-
dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 57);
(R)-2'-(3-(4-(5-fluoropyridin-2-yl)piperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'-
dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 58);
(R)-2'-(3-(4-(3,4-dichlorophenyl)piperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'-
dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 59);
(R)-2'-(3-(4-(3-chlorophenyl)piperazin-l-yl)cyclopent-l-en-l-yl)-7',8'-
dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 60);
(R)-2'-(3-(4-(2,4-difluorophenyl)piperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'-
dihydro-3 'H-spiro[cyclopropane- 1,6'-quinazolin]-4' (5Ή )-one (Compound 61);
(R)-2'-(3-(4-(3,4-difluorophenyl)piperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'-
dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 62);
(R)-2'-(3-(4-(4-chloro-2-fluorophenyl)piperazin- l-yl)cyclopent- 1-en- 1-yl)-
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 63);
(R)-2'-(3-(4-(3-chloro-4-fluorophenyl)piperazin- l-yl)cyclopent- 1-en- 1-yl)-
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 64);
(R)-2'-(3-(4-(2,4-dichlorophenyl)piperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'-
dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 65);
(R)-2'-(3-(4-(4-fluorophenyl)-2,2-dimethylpiperazin-l-yl)cyclopent-l-en-l-yl)-
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 66);
(R)-2'-(3-(4-(4-fluorophenyl)-2,2-dimethylpiperazin-l-yl)cyclopent-l-en-l-yl)-
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 67);
(R)-3-fluoro-N-methyl-4-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'Hspiro[
cyclopropane- 1,6'-quinazolin]-2'-yl)cyclopent-2-en- l-yl)piperazin- 1-
yl)benzamide (Compound 68);
(R)-N,N-dimethyl-4-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'Hspiro[
cyclopropane- 1,6'-quinazolin]-2'-yl)cyclopent-2-en- l-yl)piperazin- 1-
yl)benzamide (Compound 69);
(R)-2'-(3-(4-(4-fluorophenyl)piperazin- l-yl)-4,4-dimethylcyclopent- 1-en- 1-yl)-
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 70);
(S)-2'-(3-(4-(4-fluorophenyl)piperazin- l-yl)-4,4-dimethylcyclopent- 1-en- 1-yl)-
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 71);
(R)-N-methyl-4-(l-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cyclopropane-
1,6'-quinazolin]-2'-yl)cyclopent-2-en- 1-yl)- 1,2,3,6-tetrahydropyridin-4-
yl)benzamide (Compound 72);
(R)-2'-(3-(4-(p-tolyl)piperazin- 1-yl) cyclopent- 1-en- l-yl)-7',8'-dihydro-3'Hspiro[
cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 73);
(R)-2'-(3-(4-(4-methoxyphenyl)piperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'-
dihydro-3'H-spiro[cyclopropane- 1,6'-quinazolin]-4'(5'H)-one (Compound 74);
(R)-2'-(3-(4-(4-fluorophenyl)piperidin-l-yl)cyclopent-l-en-l-yl)-7',8'-dihydro-
3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 75);
(R)-N-methyl-6-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cyclopropane-
1,6'-quinazolin]-2'-yl)cyclopent-2-en- l-yl)piperazin- l-yl)nicotinamide
(Compound 76);
(R)-2'-(3-(4-(p-tolyl)piperidin- l-yl)cyclopent- 1-en- l-yl)-7',8'-dihydro-3'Hspiro[
cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 77);
(R)-2'-(3-(4-(3-fluorophenyl)piperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'-dihydro-
3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 78);
(R)-2'-(3-(4-(2-chloro-4-fluorophenyl)piperazin- l-yl)cyclopent- 1-en- 1-yl)-
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 79);
(R) -2'-(3-(4-(4-fluoro- 3-methylphenyl) pip erazin- 1-yl) cyclopent- 1-en- 1-yl) -
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 80);
(R)-2'-(3-(4-(2-methylbenzo[d]thiazol-6-yl)piperazin- 1-yl)cyclopent- 1-en- 1-
yl)-7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 81);
(R)-2'-(3-(4-(3-chloro-4-methylphenyl)piperazin- l-yl)cyclopent- 1-en- 1-yl)-
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 82);
(R) -2'-(3-(4-(4-fluoro- 3-methylphenyl) pip erazin- 1-yl) cyclopent- 1-en- 1-yl) -
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 83);
(R)-2'-(3-(4-(3-fluoro-4-methylphenyl)piperazin-l-yl)cyclopent-l-en-l-yl)-
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 84);
(R)-2'-(3-(4-(m-tolyl)piperazin- 1-yl) cyclopent- 1-en- l-yl)-7',8'-dihydro-3'Hspiro[
cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 85);
(R)-2'-(3-(4-(4-chloro-3-fluorophenyl)piperazin- l-yl)cyclopent- 1-en- 1-yl)-
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 86);
(R)-N-methyl-3-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cyclopropane-
1,6'-quinazolin]-2'-yl)cyclopent-2-en- 1-yljpiperazin- l-yl)benzamide
(Compound 87);
(R)-2'-(3-(4-(2-fluoro-4-methylphenyl)piperazin-l-yl)cyclopent-l-en-l-yl)-
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 88);
(R)-2-fluoro-N-methyl-4-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'Hspiro[
cyclopropane- 1,6'-quinazolin]-2'-yl)cyclopent-2-en- 1-yljpiperazin- 1-
yl)benzamide (Compound 89);
(R)-2'-(3-(4-(o-tolyl)piperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'-dihydro-3'Hspiro[
cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 90);
(R) -2'-(3-(4-(thiophen- 3-yl)pip erazin- 1-yl)cyclopent- 1-en- 1-yl) -7',8'-dihydro-
3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 91);
(R)-2'-(3-(4-(2-chloro-4-methylphenyl)piperazin- l-yl)cyclopent- 1-en- 1-yl)-
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 92);
(R)-2'-(3-(4-(2-chloro-3-fluorophenyl)piperazin- l-yl)cyclopent- 1-en- 1-yl)-
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 93);
(R)-2-chloro-N-methyl-4-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'Hspiro[
cyclopropane- 1,6'-quinazolin]-2'-yl)cyclopent-2-en- 1-yljpiperazin- 1-
yl)benzamide (Compound 94);
(R) -2'-(3-(4-(4-fluoro- 2-methylphenyl) pip erazin- 1-yl) cyclopent- 1-en- 1-yl) -
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 95);
(R)-2'-(3-(4-(4-chloro-2-methylphenyl)piperazin- l-yl)cyclopent- 1-en- 1-yl)-
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 96);
(R)-N,3-dimethyl-4-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'Hspiro[
cyclopropane- 1,6'-quinazolin]-2'-yl)cyclopent-2-en- 1-yljpiperazin- 1-
yl)benzamide (Compound 97);
(R)-N,2-dimethyl-4-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'Hspiro[
cyclopropane- 1,6'-quinazolin]-2'-yl)cyclopent-2-en- 1-yljpiperazin- 1-
yljbenzamide (Compound 98);
(R)-2'-(3-(4-(3-chloro-2-fluorophenyl)piperazin- l-yl)cyclopent- 1-en- 1-yl)-
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 99);
(R)-2'-(3-(4-(2,3-difluorophenyl)piperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'-
dihydro-3'H-spiro[cyclopropane- 1,6'-quinazolin]-4'(5'H)-one (Compound
100);
(R)-2'-(3-(4-(thiazol-2-yl)piperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'-dihydro-
3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 101);
(R)-2'-(3-(4-(4-methylthiazol-2-yl)piperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'-
dihydro-3'H-spiro[cyclopropane- 1,6'-quinazolin]-4'(5'H)-one (Compound
102);
(R)-5-chloro-N-methyl-6-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'Hspiro[
cyclopropane- 1,6'-quinazolin]-2'-yl)cyclopent-2-en- 1-yljpiperazin- 1-
yl)nicotinamide (Compound 103);
(R)-N-methyl-2-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cyclopropane-
1,6'-quinazolin]-2'-yl)cyclopent-2-en- 1-yljpiperazin- l-yl)thiazole-5-
carboxamide (Compound 104);
(R)-N-methyl-2-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cyclopropane-
1,6'-quinazolin]-2'-yl)cyclopent-2-en- 1-yljpiperazin- l-yl)thiazole-4-
carboxamide (Compound 105);
(R)-2'-(3-(4-(2,5-difluorophenyl)piperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'-
dihydro-3'H-spiro[cyclopropane- 1,6'-quinazolin]-4'(5'H)-one (Compound
106);
(R) -2'-(3-(4-(3 ,5-dichloropyridin-2 -yl)piperazin- 1-yl) cyclopent- 1-en- 1-yl) -
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 107);
(R)-2'-(3-(4-(3-fluoro-2-methylphenyl)piperazin-l-yl)cyclopent-l-en-l-yl)-
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 108);
(R)-2'-(3-(4-(3,5-difluorophenyl)piperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'-
dihydro-3'H-spiro[cyclopropane- 1,6'-quinazolin]-4'(5'H)-one (Compound
109) ;
(R)-2'-(3-(4-(2,6-difluorophenyl)piperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'-
dihydro-3'H-spiro[cyclopropane- 1,6'-quinazolin]-4'(5'H)-one (Compound
110) ;
(R)-3-fluoro-4-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cyclopropane-l,6'-
quinazolin]-2'-yl)cyclopent-2-en- 1-yljpiperazin- l-yl)benzonitrile (Compound
111) ;
(R)-5-fluoro-N-methyl-6-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'Hspiro[
cyclopropane- 1,6'-quinazolin]-2'-yl)cyclopent-2-en- 1-yljpiperazin- 1-
yl)nicotinamide (Compound 112);
(R)-2'-(3-(4-(5-methylthiazol-2-yl)piperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'-
dihydro-3'H-spiro[cyclopropane- 1,6'-quinazolin]-4'(5'H)-one (Compound
113);
(R)-2'-(3-(4-(4-fluoro-3-methoxyphenyl)piperazin- l-yl)cyclopent- 1-en- 1-yl)-
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 114);
(R)-2'-(3-(4-(3-chloro-5-fluorophenyl)piperazin- l-yl)cyclopent- 1-en- 1-yl)-
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 115);
(R)-2'-(3-(4-(2-fluorophenyl)piperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'-dihydro-
3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 116);
(R)-2'-(3-(4-phenylpiperazin-l-yl)cyclopent-l-en-l-yl)-7',8'-dihydro-3'Hspiro[
cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 117);
2'-(( 1R,3S)-3-(4-(4-chlorophenyl)piperazin- 1-yl)cyclopentyl) -7',8'-dihydro-
3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 118);
2'-((lS,3S)-3-(4-(4-chlorophenyl)piperazin-l-yl)cyclopentyl)-7',8'-dihydro-
3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 119);
2'-(( 1S,3R)-3-(4-(4-chlorophenyl)piperazin- 1-yl)cyclopentyl) -7',8'-dihydro-
3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 120);
2'-((lR,3R)-3-(4-(4-chlorophenyl)piperazin-l-yl)cyclopentyl)-7',8'-dihydro-
3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 121);
(R)-2'-(3-(4-(2-chlorophenyl)piperazin-l-yl)cyclopent-l-en-l-yl)-7',8'-
dihydro-3'H-spiro[cyclopropane- 1,6'-quinazolin]-4'(5'H)-one (Compound
122);
(R)-2'-(3-(4-(5-fluoro-2-methylphenyl)piperazin-l-yl)cyclopent-l-en-l-yl)-
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 123);
(R)-2'-(3-(4-(5-methylpyridin-2-yl)piperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'-
dihydro-3'H-spiro[cyclopropane- 1,6'-quinazolin]-4'(5'H)-one (Compound
124) ;
(R)-2'-(3-(4-(4-methylpyridin-2-yl)piperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'-
dihydro-3'H-spiro[cyclopropane- 1,6'-quinazolin]-4'(5'H)-one (Compound
125) ;
(R)-2'-(3-(4-(3-fluoro-5-methylphenyl)piperazin-l-yl)cyclopent-l-en-l-yl)-
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 126);
(R)-2-fluoro-4-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cyclopropane-l,6'-
quinazolin]-2'-yl)cyclopent-2-en- l-yl)piperazin- l-yl)benzonitrile (Compound
127);
(R)-2'-(3-(4-(pyrimidin-2-yl)piperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'-dihydro-
3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 128);
(R)-2'-(3-(4-(2-methylpyridin-3-yl)piperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'-
dihydro-3'H-spiro[cyclopropane- 1,6'-quinazolin]-4'(5'H)-one (Compound
129);
(R)-N-methyl-2-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cyclopropane-
1,6'-quinazolin]-2'-yl)cyclopent-2-en- l-yl)piperazin- l-yl)isonicotinamide
(Compound 130);
(R)-N-methyl-2-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cyclopropane-
1,6'-quinazolin]-2'-yl)cyclopent-2-en- l-yl)piperazin- l-yl)nicotinamide
(Compound 131);
(R)-2'-(3-(4-(3-methylpyridin-2-yl)piperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'-
dihydro-3'H-spiro[cyclopropane- 1,6'-quinazolin]-4'(5'H)-one (Compound
132);
(R)-2'-(3-(4-(4-fluoro-2-methoxyphenyl)piperazin- 1-yljcyclopent- 1-en- 1-yl)-
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 133);
(R)-3-chloro-N-methyl-4-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'Hspiro[
cyclopropane- 1,6'-quinazolin]-2'-yl)cyclopent-2-en- 1-yljpiperazin- 1-
yl)benzamide (Compound 134);
(R)-2'-(3-(4-(5-ethylpyrimidin-2-yl)piperazin-l -yljcyclopent- 1-en- 1-yl) -7', 8'-
dihydro-3'H-spiro[cyclopropane- 1,6'-quinazolin]-4'(5'H)-one (Compound
135) ;
(R)-2'-(3-(4-(3,4-dimethylphenyl)piperazin- 1-yljcyclopent- 1-en- l-yl)-7',8'-
dihydro-3'H-spiro[cyclopropane- 1,6'-quinazolin]-4'(5'H)-one (Compound
136) ;
(R)-2'-(3-(4-(5-fluoro-4-methylpyridin-2-yl)piperazin- 1-yljcyclopent- 1-en- 1-
yl)-7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 137);
(R)-2'-(3-(4-(5-chloro-2-fluorophenyl)piperazin- 1-yljcyclopent- 1-en- 1-yl)-
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 138);
(R)-2'-(3-(4-(2-chloro-6-fluorophenyl)piperazin- 1-yljcyclopent- 1-en- 1-yl)-
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 139);
(R)-2'-(3-(4-(2,3-dimethylphenyl)piperazin-l-yl)cyclopent-l-en-l-yl)-7',8'-
dihydro-3'H-spiro[cyclopropane- 1,6'-quinazolin]-4'(5'H)-one (Compound
140);
(R)-2'-(3-(4-(5-chloro-4-methylpyridin-2-yl)piperazin- 1-yljcyclopent- 1-en- 1-
yl)-7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 141);
(R)-2'-(3-(4-(5-fluoropyridin-3-yl)piperazin- 1-yljcyclopent- 1-en- l-yl)-7',8'-
dihydro-3'H-spiro[cyclopropane- 1,6'-quinazolin]-4'(5'H)-one (Compound
142);
(R)-2'-(3-(4-(3-chloro-2-methylphenyl)piperazin- 1-yljcyclopent- 1-en- 1-yl)-
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 143);
(R)-2'-(3-(4-(2,5-dimethylphenyl)piperazin-l-yl)cyclopent-l-en-l-yl)-7',8'-
dihydro-3'H-spiro[cyclopropane- 1,6'-quinazolin]-4'(5'H)-one (Compound
144) ;
(R)-2'-(3-(4-(6-methylpyridin-2-yl)piperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'
dihydro-3'H-spiro[cyclopropane- 1,6'-quinazolin]-4'(5'H)-one (Compound
145) ;
(R)-2'-(3-(4-(5-chloro-3-fluoropyridin-2-yl)piperazin- l-yl)cyclopent- 1-en- 1
yl)-7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 146);
(R)-2'-(3-(4-(2-methylpyridin-4-yl)piperazin- l-yl)cyclopent- 1-en- l-yl)-7',8'
dihydro-3'H-spiro[cyclopropane- 1,6'-quinazolin]-4'(5'H)-one (Compound
147);
(R)-2'-(3-(4-(4-(thiophen-3-yl)phenyl)piperazin- l-yl)cyclopent- 1-en- 1-yl)-
7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 148);
2'-((lS,3S)-3-(4-(4-fluorophenyl)piperazin-l-yl)cyclopentyl)-7',8'-dihydro-
3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 149);
2'-(( 1R,3S)-3-(4-(4-fluorophenyl) piperazin- 1-yl) cyclopentyl) -7',8'-dihydro-
3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 150);
2'-(( 1S,3R)-3-(4-(4-fluorophenyl) piperazin- 1-yl) cyclopentyl) -7',8'-dihydro-
3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 151);
2'-((lR,3R)-3-(4-(4-fluorophenyl)piperazin-l-yl)cyclopentyl)-7',8'-dihydro-
3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 152);
2'-((lR,3S)-3-(4-(3-fluorophenyl)piperazin-l-yl)cyclopentyl)-7',8'-dihydro-
3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 153);
2'-((lS,3S)-3-(4-(3-fluorophenyl)piperazin-l-yl)cyclopentyl)-7',8'-dihydro-
3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 154);
2'-(( 1S,3R)-3-(4-(3-fluorophenyl) piperazin- 1-yl) cyclopentyl) - ,8'-dihydro-
3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 155);
2'-((lR,3R)-3-(4-(3-fluorophenyl)piperazin-l-yl)cyclopentyl)-7',8'-dihydro-
3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 156);
(R)-2'-(3-(4-(6-phenylpyridin-3-yl)piperazin-l-yl)cyclopent-l-en-l-yl)-7',8'
dihydro-3'H-spiro[cyclopropane- 1,6'-quinazolin]-4'(5'H)-one (Compound
157);
(R)-2'-(3-(4-([l , -biphenyl]-4-yl)piperazin-l-yl)cyclopent-l-en-l-yl)-7',8'-
dihydro-3'H-spiro[cyclopropane- 1,6'-quinazolin]-4'(5'H)-one (Compound
158); and
2'-(3-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2. l]octan-8-yl)cyclopent- 1-en- 1-
yl)-7',8'-dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one
(Compound 159).
According a feature of the present invention, the compound of general formula
(I) where all the symbols are defined earlier, can be prepared by methods given
below.
Scheme 1 shows a method of preparation of a compound in accordance with an
embodiment of the formula I . Compound of formula I can be prepared from
compound of formula II where symbols are the same as described under generic
I
The compound of formula II is reacted with a compound of formula III, where all
symbols are as defined under formula I , under a suitable condition required or
generally used in synthetic organic chemistry in presence of suitable solvents,
for example, a halogenated hydrocarbon such as chloroform and
dichloromethane, an aromatic hydrocarbon such as xylene, benzene and
toluene, an ether type solvent such as diethyl ether, tetrahydrofuran and 1,4-
dioxane, an aprotic polar solvent such as dimethylformamide, N-methyl-2-
pyrrolidinone, dimethylsulfoxide, acetonitrile, in presence of suitable base such
as potassium carbonate, triethylamine, diethylisopropylamine, to give
compound of formula IV.
Compounds of formula IV where all symbols are same as defined earlier in
compounds of formula I was subjected to amidine formation reaction in
presence of methanolic HC1 followed by methanolic ammonia or directly with
methylchloroaluminium amide (MeAl(Cl)NH¾ in toluene to give compound of
formula V. The reaction may be carried out according to the procedure given in
the literature such as TetrahedronLetter 1995, 36, 8761.
Compound of formula V or its salt where all symbols are defined in the general
formula I can be reacted with a cyclic keto ester of compound of formula VI or
its tautomer, where symbols are the same as for general formula I , in the
presence of suitable solvents, for example, methanol or ethanol in the presence
of appropriate base like, such as inorganic bases, for example, an alkali metal
alkoxide, hydroxide, carbonate or bicarbonate thereof, or organic bases such as
a trialkyl amine or the like at a temperature between 0 - 120 °C over a period of
1 - 12 h to give compounds for formula I .
More preferably, compound of formula II is selected from compound IIA and IIB.
IIA IIB
More preferably compound of formula III is selected from IIIA, IIIB, IIIC, HID,
HIE, IIIF, and IIIG.
IIIA 1MB NIC ID
I F IIIG
More preferably compound of formula VI is selected from compounds VIA, VIB,
VIC, VID, and VIE. These compounds can be synthesized by following the
procedures reported in EP2208728, US20 10 144745, US2007 15792,
VIA VIB VIC VID VIE
Scheme 2 shows a method of preparation of a compound of formula III starting
from compound of formula (i a) and (i b).
I a (i b)
Arylation P = Protecting group
Protection
(iii)
Reduction
Reduction Deprotection
IMG
Scheme 2
The compound of formula III can be prepared from the compound represented
by general formula (i a ) and (i b). Compounds of formula (i a ) and (i b) were in
turn prepared by the procedures described in the literature such as
US2002068748, WO2005016900, US20050222166, WO2006051851, and
Tetrahedron.1992, 48, 4985.
The compound of formula (I b) can be protected by any suitable N-protecting
groups known in literature to give compound of formula (ii). In an embodiment,
the protection reaction was carried out using benzyl halide in presence of
triethylamine in dichloromethane.
The compound of formula (ii) was subjected to Buchwald coupling with Ar-L,
where Ar is as defined in the formula I and L is CI, Br, or I to obtain a
compound of formula (iii). Buchwald coupling can be can be carried out under
any reaction condition known in the art. Preferably, the Buchwald coupling is
carried out in a solvent such as toluene, tert-butanol, dimethylformamide, isopropyl
alcohol, 1,4-dioxane, 1, -dimethoxy ethane, tetrahydrofuran, and/or
acetonitrile, in presence of a base such as potassium phosphate, potassium
carbonate, sodium tert-butoxide, cesium carbonate, lithium hexamethyl
disilazane or the like, palladium catalysts such as [Pd2(dba)3], Pd(OAc)2 at a
temperature between 50-160 °C and ligand such as 2,2 -
Bis(diphenylphosphino)-l, l'-binaphthyl (BINAP) 2-Dicyclohexylphosphino-
2',4',6'-triisopropylbiphenyl (XPhos), 2-Dicyclohexylphosphino-2 '-(N,iVdimethyl
amino) biphenyl (DavePhos) , (2-Biphenyl)di-iert-butylphosphine
(JohnPhos), 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2-
Dicyclohexylphosphino-2'-methylbiphenyl (MePhos) or the like.
Any suitable protecting groups such as but not limited to Boc, Cbz, Bn can be
utilized, and they can be removed from compound of formula (iii) to obtain
compound of formula HIE. Deprotection reaction of the N-protecting groups can
be carried out by standard procedures generally used in synthetic organic
chemistry or well known in literature such as Protecting Groups in Organic
Synthesis, 2 Edition, Greene, T.W. and Wuts, P.G.M.; Wiley Interscience, 1999.
The compound of formula (ii) can be treated with a suitable reducing agent
known for converting amide to amine to give compound of formula (iv). The
reaction may be carried out using reducing agent such as LiAlH , BH3 in the
presence of solvents such as tetrahydrofuran or diethyl ether at a temperature
between 0-100°C.
The compound of formula (iv) was subjected to Buchwald coupling with Ar-L,
where Ar is as defined in the formula I and L is CI, Br, I to obtain the compound
of formula (v) .
Any protecting groups such as but not limited to Boc, Cbz, Bn can be removed
from compound of formula (v) to obtain the compound of formula IIIG. The
deprotection reaction for N-protecting groups can be carried out by standard
procedures generally used in synthetic organic chemistry or well known in the
literature; e.g., Greene T.W., et al., 1999.
The compound of formula HID can be prepared from compound of formula (i a )
by Buchwald coupling with Ar-L as described above for the synthesis of
compound of formula (iii) from compound of formula (ii). Also, the compound of
formula IIIF can be prepared from compound of formula HID by reduction of the
amide group to an amine group following the procedures described above for
synthesis of compound of formula (iv) from compound of formula (i b).
Scheme 3 shows alternative methods of preparation of a compound of formula
IV, where A ring is IIIA, from compound of formula IIB:
IIB (vi) (vii) )
Scheme 3
group
IV
The compound of formula IIB is reacted with NaN3 under suitable condition in
presence of suitable solvent(s), e.g., a halogenated hydrocarbon such as
chloroform and dichloromethane, an aromatic hydrocarbon such as xylene,
benzene and toluene, an ether such as diethyl ether, tetrahydrofuran and 1,4-
dioxane, an aprotic polar solvent such as dimethylformamide, N-methyl-2-
pyrrolidinone, dimethylsulfoxide, acetonitrile, in presence of a suitable base
such as potassium carbonate, triethylamine, or diethylisopropylamine, to give
compound of formula (vi) .
The compound of formula (vii) or its salt can be produced from compound of
formula (vi) under suitable reaction conditions usually applied in Staudinger
reaction. This involves formation of phosphazenes from corresponding azido
compound upon reaction with phosphane, e.g., triphenyl phosphphene, trialkyl
phosphite or like, followed by hydrolysis of the phosphazenes, which may be
conveneniently accomplished by reaction with water. The reaction was carried
out in the presence of suitable solvents such as THF, DMF, halogenated
hydrocarbon, aromatic hydrocarbon, water or mixtures thereof or the like at a
temperature between 0-120 °C over a period of 1 - 12 h .
The compound of formula (vii) can be further reacted with any N-protecting
reagents known in literature to give compound of formula (viii). In an
embodiment, protection reaction can be carried out by using (Boc^O in the
presence of triethylamine in dichloromethane.
Protecting groups such as Boc, Cbz, Bn can be removed from the compound of
formula (viii) to obtain compound of formula (vii). Deprotection reaction of Nprotecting
groups can be carried out by using standard procedures generally
used in synthetic organic chemistry or well known in the literature, e.g., Greene,
T.W., et al., 1999.
The compound of formula (vii) may be treated with compound of formula (ix)
where, X is any leaving group, for example CI, Br, I , OTs, OMs, or OTf, and
other symbols are as defined earlier in formula I in the presence of a base such
as diisopropylethylamine, triethylamine, or sodium carbonate at a temperature
between 20 - 1 0 °C to obtain the compound of formula IV. The compound of
formula (ix) can be prepared using procedures described in US20050245534, J .
Med. Chem. 2005, 48, 3525.
Scheme 4 shows yet another alternative method of preparation of compound of
IV
The compound of formula IV can be prepared alternatively from compound of
formula IIB and compound of formula (x). Compound of formula IIB was reacted
with compound of formula (x) under the condition described above for the
synthesis of IV from II in scheme 1 to obtain compound of formula (xi).
Compound of formula (xi) was then subjected to deproptection of N-protecting
group to obtain compound of formula (xii). Deprotection reaction of N-protecting
groups can be carried out using standard procedure generally used in synthetic
organic chemistry or well known in the literature e.g., Greene T.W. et al., 1999.
The compound of formula (xii) was then subjected to Buchwald coupling with
Ar-L, where Ar is as defined in the general formula I and L is CI, Br, I to obtain
compound of formula IV.
Scheme 5 outlines a method of preparation of a compounds 118, 119, 120 and
121. These compounds were prepared using the compound of formula (xiii a ) or
(xiii b).
V I
The compound of formula (xiii b) can be prepared from compound of formula
(xiii a ) according to the conditions known in the art for converting carboxylic
acids to esters.
The compound of formula (xiii b) can be treated with compound of formula (ix)
to obtain compound of formula (xiv) as described in Scheme 3 for the synthesis
of compound IV from compound of formula (vii) and compound of formula (ix).
Ester hydrolysis of compound of formula (xiv) gave compound of formula (xv),
where all symbols are the same as defined for the compound of formula I . Ester
hydrolysis can be carried out using procedures generally used in synthetic
organic chemistry or well known in the art using regents such as sodium
hydroxide, potassium hydroxide, lithium hydroxide or the like in a solvent such
as water, alcohol, or THF or the like or mixture thereof. Preferably, lithium
hydroxide is used for the reaction.
The compound of formula (xv) is reacted with a compound of formula (xvi),
where all symbols are as defined under the compound of formula I to obtain
compound of formula (xvii). The reaction was carried out using the conditions
generally used for converting carboxylic acids to amides by a person skilled in
art. The reaction may b e carried out in the presence of solvents such as DMF,
THF, chloroform, dichloromethane, xylene, benzene or mixtures there of or the
like in the presence of bases such as triethylamine, diisopropylethylamine,
pyridine or the like at a temperature between 0-100 °C using reagent(s) such as
thionyl chloride, phosphrous trichloride, oxalyl chloride, alkyl chloroformate,
EDCI, DCC and auxiliary reagents such as HOBt, HOAt or the like or by using
the methodology described in US20070 197551.
The compound of formula (xvii) where all symbols are the same as described
under compound of formula I can be hydrolyzed to compound of formula (xviii)
as described for the synthesis of compound of formula (xv) from compound of
formula (xiv).
The compound of formula (xviii) can be reacted with acetic anhydride, and
successively reacting the reaction product with ammonia to obtain compound of
formula I where symbols are same as described under the compound of formula
I .
The compound of formula I can be alternatively prepared from compound of
formula IV by converting it to compound of formula (xviii) under reduction
condition known for reduction of activated alkene. The reaction may be carried
out in presence of sodium borohydride, lithium borohydride or like in presence
of solvents, for example, methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl
alcohol or the like at a temperature between 0-50 °C.
The compound of formula I can be prepared from compound of formula (xix)
following the methodology described for the synthesis of I from compound of
formula IV in Scheme 1.
Scheme 6 shows an alternative method of preparation of compound of formula
(xv) from compound of formula (xx) .
The compound of formula (xxi) can be prepared from compound of formula (xx)
using the conditions known to a skilled person for the conversion of carboxylic
acids to esters.
The compound of formula (xxi) can be deprotected under acidic conditions to
obtain compound of formula (xxii), which can be treated with a reducing agent
to obtain compound of formula (xxiii). The compound of formula (xxiii) can be
treated with aryl sulphonyl chloride to obtain compound of formula (xxiv), which
can be then treated with compound of formula III to afford compound of formula
(xiv) where all symbols are the same as described under formula I . Alternatively
the compound of formula (xiv) can be prepared by reacting compound of
formula (xxii) with compound of formula III under reductive amination
conditions known in literature.
The compound of formula (xv) can be prepared either by hydrolysis or
hydrogenolysis of compound of formula (xiv) according to conditions generally
used by a skilled person for converting esters to carboxylic acids.
Scheme 7 shows an alternative method of preparation of compound of formula
(xvii):
(xxvi)
(xvii)
Scheme 7
The compound of formula (xx) can be reacted with compound of formula (xvi) as
described for the synthesis of compound of formula (xvii) in Scheme 5 to obtain
compound of formula (xxv) . Compound of formula (xxv) was subjected to
deprotection reaction under acidic condition to obtain compound of formula
(xxvi), which was then treated with compound of formula III under reductive
amination to afford compound of formula (xvii) .
The intermediates and the compounds of the present invention can b e obtained
in a pure form in a manner known per se, for example, by distilling off the
solvent in vacuum and/ or re-crystallizing the residue obtained from a suitable
solvent, such as pentane, diethyl ether, isopropyl ether, chloroform,
dichloromethane, ethyl acetate, acetone or their combinations or subjecting it to
one of the purification methods, such as column chromatography (e.g. flash
chromatography) on a suitable support material such as alumina or silica gel
using an eluent such as dichloromethane, ethyl acetate, hexane, methanol,
acetone and their combinations. Preparative LC-MS method can also be used for
the purification of molecules described herein.
Unless otherwise stated, work-up includes distribution of the reaction mixture
between the organic and aqueous phase indicated within parentheses,
separation of layers and drying the organic layer over sodium sulphate,
filtration and evaporation of the solvent. Purification, unless otherwise
mentioned, includes purification by silica gel chromatographic techniques,
generally using a mobile phase with suitable polarity.
Salts of compound of formula I can be obtained by dissolving the compound in a
suitable solvent, for example in a chlorinated hydrocarbon, such as methyl
chloride or chloroform or a low molecular weight aliphatic alcohol, for example,
ethanol or isopropanol, which was then treated with the desired acid or base as
described in Berge S.M. et al., "Pharmaceutical Salts, a review article in Journal
of Pharmaceutical sciences volume 66, page 1-19 (1977)" and in "Handbook of
Pharmaceutical Salts - Properties, Selection, and Use," by P. H. Einrich Stahland
Camille G.wermuth, Wiley- VCH (2002). Lists of suitable salts can also be found
in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company,
Easton, PA, 1990, p. 1445, and Journal of Pharmaceutical Science, 66, 2-19
(1977). For example, the salt can be of an alkali metal (e.g., sodium or
potassium), alkaline earth metal (e.g., calcium), or ammonium.
The compound of the invention or a composition thereof can potentially be
administered as a pharmaceutically acceptable acid-addition, base neutralized
or addition salt, formed by reaction with inorganic acids, such as hydrochloric
acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric
acid, and phosphoric acid, and organic acids such as formic acid, acetic acid,
propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid,
succinic acid, maleic acid, and fumaric acid, or by reaction with an inorganic
base, such as sodium hydroxide, potassium hydroxide. The conversion to a salt
is accomplished by treatment of the base compound with at least a
stoichiometric amount of an appropriate acid. Typically, the free base is
dissolved in an inert organic solvent such as diethyl ether, ethyl acetate,
chloroform, ethanol, methanol, and the like, and the acid is added in a similar
solvent. The mixture is maintained at a suitable temperature (e.g., between 0 °C
and 50 °C). The resulting salt precipitates spontaneously or can be brought out
of solution with a less polar solvent.
The stereoisomers of the compounds of formula I of the present invention may
be prepared by stereospecific syntheses or resolution of racemic compound
using an optically active amine, acid or complex forming agent, and separating
the diastereomeric salt/ complex by fractional crystallization or by column
chromatography.
The compounds of formula I of the present invention can exist in tautomeric
forms, such as keto-enol tautomers. Such tautomeric forms are contemplated
as an aspect of the present invention and such tautomers may be in equilibrium
or predominant in one of the forms.
Thus the present invention further provides a pharmaceutical composition,
containing the compounds of the general formula (I) as defined above, its
tautomeric forms, its stereoisomers, its pharmaceutically acceptable salts in
combination with the usual pharmaceutically acceptable carriers, diluents,
excipients, and the like.
The pharmaceutically acceptable carrier or excipient is preferably one that is
chemically inert to the compound of the invention and one that has no
detrimental side effects or toxicity under the conditions of use. Such
pharmaceutically acceptable carriers or excipients include saline (e.g., 0.9%
saline), Cremophor EL® (which is a derivative of castor oil and ethylene oxide
available from Sigma Chemical Co., St. Louis, MO) (e.g., 5% Cremophor EL/5%
ethanol/90% saline, 10% Cremophor EL/90% saline, or 50% Cremophor
EL/50% ethanol), propylene glycol (e.g., 40% propylene glycol/ 10%
ethanol/50% water), polyethylene glycol (e.g., 40% PEG 400/60% saline), and
alcohol (e.g., 40% ethanol/ 60% water). A preferred pharmaceutical carrier is
polyethylene glycol, such as PEG 400, and particularly a composition
comprising 40% PEG 400 and 60% water or saline. The choice of carrier will be
determined in part by the particular compound chosen, as well as by the
particular method used to administer the composition. Accordingly, there is a
wide variety of suitable formulations of the pharmaceutical composition of the
present invention.
The following formulations for oral, aerosol, parenteral, subcutaneous,
intravenous, intraarterial, intramuscular, intrathecal, intraperitoneal, rectal,
and vaginal administration are merely exemplary and are in no way limiting.
The pharmaceutical compositions can be administered parenterally, e.g.,
intravenously, intraarterially, subcutaneously, intradermally, intrathecally, or
intramuscularly. Thus, the invention provides compositions for parenteral
administration that comprise a solution of the compound of the invention
dissolved or suspended in an acceptable carrier suitable for parenteral
administration, including aqueous and non-aqueous, isotonic sterile injection
solutions.
Overall, the requirements for effective pharmaceutical carriers for parenteral
compositions are well known to those of ordinary skill in the art. See
Pharmaceutics and Pharmacy Practice, J.B. Lippincott Company, Philadelphia,
PA, Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on
Injectable Drugs, Toissel, 4th ed., pages 622-630 (1986). Such compositions
include solutions containing anti- oxidants, buffers, bacteriostats, and solutes
that render the formulation isotonic with the blood of the intended recipient,
and aqueous and non-aqueous sterile suspensions that can include suspending
agents, solubilizers, thickening agents, stabilizers, and preservatives. The
compound can be administered in a physiologically acceptable diluent in a
pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including
water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as
ethanol, isopropanol (for example in topical applications), or hexadecyl alcohol,
glycols, such as propylene glycol or polyethylene glycol, dimethylsulfoxide,
glycerol ketals, such as 2,2-dimethyl-l,3-dioxolane-4-methanol, ethers, such as
poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an
acetylated fatty acid glyceride, with or without the addition of a
pharmaceutically acceptable surfactant, such as a soap or a detergent,
suspending agent, such as pectin, carbomers, methylcellulose,
hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents
and other pharmaceutical adjuvants.
Oils useful in parenteral formulations include petroleum, animal, vegetable, and
synthetic oils. Specific examples of oils useful in such formulations include
peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral oil.
Suitable fatty acids for use in parenteral formulations include oleic acid, stearic
acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of
suitable fatty acid esters.
Suitable soaps for use in parenteral formulations include fatty alkali metal,
ammonium, and triethanolamine salts, and suitable detergents include (a)
cationic detergents such as, for example, dimethyl dialkyl ammonium halides,
and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl,
aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and
sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine
oxides, fatty acid alkanol amides, and polyoxyethylene polypropylene
copolymers, (d) amphoteric detergents such as, for example, alkyl- b-
aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (e)
mixtures thereof.
The parenteral formulations typically will contain from about 0.5% or less to
about 25% or more by weight of a compound of the invention in solution.
Preservatives and buffers can be used. In order to minimize or eliminate
irritation at the site of injection, such compositions can contain one or more
nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about
12 to about 17. The quantity of surfactant in such formulations will typically
range from about 5% to about 15% by weight. Suitable surfactants include
polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the
high molecular weight adducts of ethylene oxide with a hydrophobic base,
formed by the condensation of propylene oxide with propylene glycol. The
parenteral formulations can be presented in unit-dose or multi-dose sealed
containers, such as ampoules and vials, and can be stored in a freeze-dried
(lyophilized) condition requiring only the addition of the sterile liquid excipient,
for example, water, for injections, immediately prior to use. Extemporaneous
injection solutions and suspensions can be prepared from sterile powders,
granules, and tablets.
Topical formulations, including those that are useful for transdermal drug
release, are well known to those of skill in the art and are suitable in the context
of the present invention for application to skin.
Formulations suitable for oral administration can consist of (a) liquid solutions,
such as an effective amount of a compound of the invention dissolved in
diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets,
lozenges, and troches, each containing a pre- determined amount of the
compound of the invention, as solids or granules; (c) powders; (d) suspensions
in an appropriate liquid; and (e) suitable emulsions. Liquid formulations can
include diluents, such as water and alcohols, for example, ethanol, benzyl
alcohol, and the polyethylene alcohols, either with or without the addition of a
pharmaceutically acceptable surfactant, suspending agent, or emulsifying
agent. Capsule forms can be of the ordinary hard- or soft-shelled gelatin type
containing, for example, surfactants, lubricants, and inert fillers, such as
lactose, sucrose, calcium phosphate, and cornstarch. Tablet forms can include
one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic
acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon
dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate,
zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering
agents, disintegrating agents, moistening agents, preservatives, flavoring agents,
and pharmacologically compatible excipients. Lozenge forms can comprise the
compound ingredient in a flavor, usually sucrose and acacia or tragacanth, as
well as pastilles comprising a compound of the invention in an inert base, such
as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like
containing, in addition to the compound of the invention, such excipients as are
known in the art.
A compound of the present invention, alone or in combination with other
suitable components, can be made into aerosol formulations to be administered
via inhalation. A compound or epimer of the invention is preferably supplied in
finely divided form along with a surfactant and propellant. Typical percentages
of the compounds of the invention can be about 0.01% to about 20% by weight,
preferably about 1% to about 10% by weight. The surfactant must, of course, be
nontoxic, and preferably soluble in the propellant. Representative of such
surfactants are the esters or partial esters of fatty acids containing from 6 to 22
carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic,
linolenic, olesteric and oleic acids with an aliphatic polyhydric alcohol or its
cyclic anhydride. Mixed esters, such as mixed or natural glycerides can be
employed. The surfactant can constitute from about 0. 1% to about 20% by
weight of the composition, preferably from about 0.25% to about 5%. The
balance of the composition is ordinarily propellant. A carrier can also be
included as desired, e.g., lecithin, for intranasal delivery. These aerosol
formulations can be placed into acceptable pressurized propellants, such as
dichlorodifluoromethane, propane, nitrogen, and the like. They also can be
formulated as pharmaceuticals for non-pressured preparations, such as in a
nebulizer or an atomizer. Such spray formulations can be used to spray
mucosa.
Additionally, the compound of the invention can be made into suppositories by
mixing with a variety of bases, such as emulsifying bases or water-soluble
bases. Formulations suitable for vaginal administration can be presented as
pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing,
in addition to the compound ingredient, such carriers as are known in the art to
be appropriate.
The concentration of the compound in the pharmaceutical formulations can
vary, e.g., from less than about 1% to about 10%, to as much as about 20% to
about 50% or more by weight, and can be selected primarily by fluid volumes,
and viscosities, in accordance with the particular mode of administration
selected.
For example, a typical pharmaceutical composition for intravenous infusion
could be made up to contain 250 ml of sterile Ringer's solution, and 100 mg of
at least one compound of the invention. Actual methods for preparing
parenterally administrable compounds of the invention will be known or
apparent to those skilled in the art and are described in more detail in, for
example, Remington's Pharmaceutical Science (17th ed., Mack Publishing
Company, Easton, PA, 1985).
It will be appreciated by one of ordinary skill in the art that, in addition to the
afore described pharmaceutical compositions, the compound of the invention
can be formulated as inclusion complexes, such as cyclodextrin inclusion
complexes, or liposomes. Liposomes can serve to target a compound of the
invention to a particular tissue, such as lymphoid tissue or cancerous hepatic
cells. Liposomes can also be used to increase the half-life of a compound of the
invention. Many methods are available for preparing liposomes, as described in,
for example, Szoka et al., Ann. Rev. Biophys. Bioeng., 9, 467 (1980) and U.S.
Patents 4,235,871, 4,501,728, 4,837,028, and 5,019,369.
The compounds of the invention can be administered in a dose sufficient to
treat the disease, condition or disorder. Such doses are known in the art (see,
for example, the Physicians' Desk Reference (2004)). The compounds can be
administered using techniques such as those described in, for example,
Wasserman et al., Cancer, 36, pp. 1258-1268 (1975) and Physicians' Desk
Reference, 58th ed., Thomson PDR (2004).
Suitable doses and dosage regimens can be determined by conventional rangefinding
techniques known to those of ordinary skill in the art. Generally,
treatment is initiated with smaller dosages that are less than the optimum dose
of the compound of the present invention. Thereafter, the dosage is increased by
small increments until the optimum effect under the circumstances is reached.
The present method can involve the administration of about 0.1 pg to about 50
mg of at least one compound of the invention per kg body weight of the
individual. For a 70 kg patient, dosages of from about 10 pg to about 200 mg of
the compound of the invention would be more commonly used, depending on a
patient's physiological response.
By way of example and not intending to limit the invention, the dose of the
pharmaceutically active agent(s) described herein for methods of treating or
preventing a disease or condition as described above can be about 0.001 to
about 1 mg/kg body weight of the subject per day, for example, about 0.001 mg,
0.002 mg, 0.005 mg, 0.010 mg, 0.015 mg, 0.020 mg, 0.025 mg, 0.050 mg,
0.075 mg, 0.1 mg, 0. 15 mg, 0.2 mg, 0.25 mg, 0.5 mg, 0.75 mg, or 1 mg/kg body
weight per day. The dose of the pharmaceutically active agent(s) described
herein for the described methods can be about 1 to about 1000 mg/kg body
weight of the subject being treated per day, for example, about 1 mg, 2 mg, 5
mg, 10 mg, 15 mg, 0.020 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg,
250 mg, 500 mg, 750 mg, or 1000 mg/kg body weight per day.
PARP inhibitors reported herein can be used for the treatment of diseases
and/or disorders that include but are not limited to cancer, stroke, traumatic
brain injury, Parkinson's disease, meningitis, myocardial infarction, ischaemic
cardiomyopathy, vascular disease, septic shock, ischemic injury, reperfusion
injury, neurotoxicity, inflammatory disease, and haemorrhagic shock. PARP
inhibitors mentioned herein can be used as single agents and/or in combination
with other chemotherapeutic agents so that they can potentiate the effects of
the standard chemotherapeutic agents.
Cancers that can be treated with PARP inhibitors include but are not, limited to
breast cancer, glioblastoma, pancreatic cancer, ovarian cancer, prostate cancer,
melanoma, colon cancer, leukaemia and lymphoma.
The terms "treat," "prevent," "ameliorate," and "inhibit," as well as words
stemming therefrom, as used herein, do not necessarily imply 100% or complete
treatment, prevention, amelioration, or inhibition. Rather, there are varying
degrees of treatment, prevention, amelioration, and inhibition of which one of
ordinary skill in the art recognizes as having a potential benefit or therapeutic
effect. In this respect, the disclosed methods can provide any amount of any
level of treatment, prevention, amelioration, or inhibition of the disorder in a
mammal. For example, a disorder, including symptoms or conditions thereof,
may be reduced by, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%,
20%, or 10%. Furthermore, the treatment, prevention, amelioration, or
inhibition provided by the inventive method can include treatment, prevention,
amelioration, or inhibition of one or more conditions or symptoms of the
disorder, e.g., cancer. Also, for purposes herein, "treatment," "prevention,"
"amelioration," or "inhibition" can encompass delaying the onset of the disorder,
or a symptom or condition thereof.
The terms "effective amount" or "therapeutically effective amount," as used
herein, refer to a sufficient amount of an agent or a compound being
administered which will relieve to some extent one or more of the symptoms of
the disease or condition being treated. In some embodiments, the result is a
reduction and! or alleviation of the signs, symptoms, or causes of a disease, or
any other desired alteration of a biological system. For example, an "effective
amount" for therapeutic uses is the amount of the composition comprising a
compound as disclosed herein required to provide a clinically significant
decrease in disease symptoms. In some embodiments, an appropriate "effective"
amount in any individual case is determined using techniques, such as a dose
escalation study.
The terms "potentiation" or "potentiating," as used herein, means to increase or
prolong either in potency or duration a desired effect. Thus, in regard to
potentiating the effect of therapeutic agents/regimen, the term "potentiating"
refers to the ability to increase or prolong, either in potency or duration, the
effect of other therapeutic agents on a system.
In accordance with the invention, the term subject includes an "animal" which
in turn includes a mammal such as, without limitation, the order Rodentia,
such as mice, and the order Lagomorpha, such as rabbits. In one aspect, the
mammals are from the order Carnivora, including Felines (cats) and Canines
(dogs). In another aspect, the mammals are from the order Artiodactyla,
including Bovines (cows) and Swine (pigs) or of the order Perssodactyla,
including Equines (horses). In a further aspect, the mammals are of the order
Primates, Ceboids, or Simoids (monkeys) or of the order Anthropoids (humans
and apes). In yet another aspect, the mammal is human.
The term "patient" encompasses mammals and non-mammals. Examples of
mammals include, but are not limited to, any member of the Mammalian class:
humans, non- human primates such as chimpanzees, and other apes and
monkey species; farm animals such as cattle, horses, sheep, goats, swine;
domestic animals such as rabbits, dogs, and cats; laboratory animals including
rodents, such as rats, mice and guinea pigs, and the like. Examples of nonmammals
include, but are not limited to, birds, fish and the like. In one
embodiment of the methods and compositions provided herein, the mammal is a
human.
Another aspect of the present invention is a pharmaceutical composition of
compound of formula I in combination with at least one other known anticancer
agent, or a pharmaceutically acceptable salt of said agent.
The said known anticancer agent used in combination may be selected from the
group comprising of busulfan, melphalan, chlorambucil, cyclophosphamide,
ifosfamide, temozolomide, bendamustine, cis-platin, mitomycin C, bleomycin,
carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin,
aclarubicin, mitoxantrone, elliptinium, etoposide, 5-azacytidine, gemcitabine, 5-
fluorouracil, methotrexate, 5-fluoro-2'-deoxy-uridine, fludarabine, nelarabine,
ara-C, alanosine, pralatrexate, pemetrexed, hydroxyurea, thioguanine,
colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone,
cabazitaxel, docetaxel, campath, imatinib, gefitinib, erlotinib, lapatinib,
sorafenib, sunitinib, nilotinib, dasatinib, pazopanib, temsirolimus, everolimus,
vorinostat, romidepsin, tamoxifen, letrozole, fulvestrant, mitoguazone,
octreotide, retinoic acid, arsenic trioxide, zoledronic acid, bortezomib,
thalidomide or lenalidomide.
Other aspect of the present invention is provision of a method of treatment or
prevention of a disorder responsive to the inhibition of PARP activity in a
mammal suffering therefrom, comprising administering to the mammal in need
of such treatment a therapeutically effective amount of a compound of formula
I .
The said disorder as stated above is cancer, which includes liver cancer,
melanoma, Hodgkin's disease, non-Hodgkin's lymphomas, acute or chronic
lymphocytic leukemia, multiple myeloma, neuroblastoma, breast carcinoma,
ovarian carcinoma, lung carcinoma, Wilms' tumor, cervical carcinoma,
testicular carcinoma, soft-tissue sarcoma, chronic lymphocytic leukemia,
primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukemia,
primary brain carcinoma, malignant melanoma, small-cell lung carcinoma,
stomach carcinoma, colon carcinoma, malignant pancreatic insulinoma,
malignant carcinoid carcinoma, malignant melanoma, chorio carcinoma,
mycosis fungo ide, head or neck carcinoma, osteogenic sarcoma, pancreatic
carcinoma, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma,
rhabdomyosarcoma, Kaposi's sarcoma, genitourinary carcinoma, thyroid
carcinoma, esophageal carcinoma, malignant hypercalcemia, cervical
hyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemia vera,
essential thrombocytosis, adrenal cortex carcinoma, skin cancer, or prostatic
carcinoma.
Another aspect of the present invention is provision of a method of potentiating
the efficacy of chemotherapeutic regimen for a patient undergoing
chemotherapeutic treatment comprising co-administering to the patient an
effective amount of a compound of the present invention, wherein, the
compound of the invention may be co-administered simultaneously,
sequentially, or cyclically with the anticancer agent.
The chemotherapeutic agent as mentioned above is selected form busulfan,
melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide,
bendamustine, cis-platin, mitomycin C, bleomycin, carboplatin, camptothecin,
irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone,
elliptinium, etoposide, 5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate,
5-fluoro-2'-deoxy-uridine, fludarabine, nelarabine, ara-C, alanosine,
pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine,
vincristine, vmorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, campath,
panitumumab, ofatumumab, bevacizumab, trastuzumab, adalimumab,
imatinib, gefitinib, erlotinib, lapatinib, sorafenib, sunitinib, nilotinib, dasatinib,
pazopanib, temsirolimus, everolimus, vorinostat, romidepsin, tamoxifen,
letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic trioxide,
zoledronic acid, bortezomib, thalidomide or lenalidomide.
Yet another aspect of the present invention is provision of a method for
sensitizing a patient who has developed or likely to develop resistance for
chemotherapic agents comprising administering an effective amount of a
compound of the present invention.
The following abbreviations are used in the text: DMSO-d6:
Hexadeuterodimethyl sulfoxide; DMF: N,N-dimethyl formamide, THF:
Tetrahydrofuran, J Coupling constant in units of Hz, EDCI: l-ethyl-3-(3-
dimethylaminopropyl)carbodiimide, DCC: N N '-dicyclohexylcarbodiimide, HOBt:
Hydroxybenzotriazole, HOAt: l-Hydroxy-7-azabenzotriazole.
Following examples illustrate demonstrate method of preparation of compounds
embodied in formula I ; however, the examples should not be constructed as
limiting in any way the scope of the invention.
Example 1: Synthesis of 2'-(3-(4-(4-chlorophenyl)piperazin-l-yl)propyl)-7',8'-
dihydro-3'H-spiro[cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 6).
Step 1: Ethyl 6-oxospiro[2.5]octane-5-carboxylate.
To a stirred solution of spiro[2.5]octan-6-one (prepared according to the
procedure reported in US20081 76926) (0.900 g, 7.25 mmol) in
dimethylformamide (10 ml) at 5°C was added sodium hydride (0.580 g, 60%,
14.50 mmol) under a nitrogen atmosphere over a period of 10 min and the
resulting mixture was stirred for an additional 20 min at the same temperature.
To this reaction mixture, diethylcarbonate (1.72 g, 14.50 mmol) was added at
5°C and stirred for 1 h and then allowed to stirr at room temperature for 2 h .
The progress of the reaction was monitored by TLC. The reaction mixture was
cooled to 0°C and quenched with saturated ammonium chloride (10 ml) and
diluted with water (30 ml). The resulting mixture was extracted with diethyl
ether (2 x 20 ml), and the combined organic layer was washed with water (2 x
20 ml), dried over anhydrous sodium sulphate, filtered, and the solvent was
removed under reduced pressure to obtain a crude product which was purified
by flash chromatography over silica gel (100-200 mesh) using 1% ethyl acetate
in hexane as eluent to yield the title compound (0.510 g, 35.9%).
Ή NMR (400MHz, CDC13) : d 12.28 (brs, 1H, D20 exchangeable), 4.22 (q,
J=7.0Hz, 2H), 2.38 (t, J=6.4Hz, 2H), 2.09 (s, 2H), 1.46 (t, J=6.2 Hz, 2H), 1.29 (t,
J=7.2Hz, 3H), 0.31-0.29 (m, 4H)
The compounds given below were prepared by a process similar to Step 1 above
with appropriate variation of reactant, reaction conditions and quantities of
reagents:
Ethyl 4-oxospiro[2. 5]octane- 5-carboxylate
Ή NMR (400 MHz, CDC13) d 12.52 (bs, 1H, D20 exchangeable), 4.26-4. 16 (m,
2H), 2.29-2. 19 (m, 2H), 1.63-1.61 (m, 2H), 1.48-1.34 (m, 1H), 1.34-1.28 (m, 3H),
1. 13-l. ll(m, 1H), 0.65-0.59 (m, 4H)
Ethyl 5-oxospiro[2.5]octane-6-carboxylate
Ή NMR (400 MHz, CDCb) d 12.30 (bs, 1H, D20 exchangeable), 4.26-4. 17 (m,
2H), 2.32 (t, J = 6.4Hz, 2H), 2.16 (s, 2H), 1.40 (t, J = 6.4Hz, 2H), 1.34 (t, J =
7.2Hz, 3H), 0.37(s, 4H).
Ethyl 4-oxobicyclo[4. 1.0]heptane-3-carboxylate and ethyl 3-
oxobicyclo[4. 1.0]heptane-2-carboxylate
Ή NMR (400 MHz, CDC13) d 12.30 (bs, 1H, D20 exchangeable), 12.1 1(bs, 1H,
D20 exchangeable), 4.32-4.19 (m, 2H), 2.52-2.45 (m, 4H), 2.30-2.20 m, 1H),
2. 10-1.91 (m, 3H), 1.70-1.61 (m, 1H), 1.37-1.26 (m, 3H), 1.29-1.26(m, 1H), 1. 15-
1.05 (m, 2H), 0.80-0.75 (m, 1H), 0.60-0.50 (m, 1H), 0.37-0.34 (m, 1H), 0.30-
0.25 (m, 1H)
4-(4-(4-chlorophenyl)piperazin-l-yl)butanenitrile.
To a solution of 4-bromobutanenitrile (1.50 g, 10.17 mmol) in dimethyl
formamide (20 ml) were added l-(4-chlorophenyl)piperazine (2.0 g, 10. 17 mmol)
and potassium carbonate (2.81 g, 20.34 mmol) at room temperature and the
reaction mixture was stirred for 3 h at same temperature. The progress of the
reaction was monitored by TLC. The reaction mixture was diluted with water (50
ml) and the aqueous layer was extracted with ethyl acetate (3 x 50 ml). The
combined organic layer was dried over anhydrous sodium sulphate. The solvent
in the organic layer was removed under reduced pressure to obtain a crude
product, which was purified by column chromatography over silica gel (100-200
mesh) using 10% ethyl acetate in hexane to yield the title compound (2.32 g,
86% yield).
Ή NMR (400MHz, CDC13) : d 7.22 (d, J=8.8Hz, 2H), 6.85 (d, J=9.2Hz, 2H), 3.17
(t, J=4.8Hz, 4H), 2.62 (t, J=5.2Hz, 4H), 2.43-2.55 (m, 4H), 1.87 (quin, J=6.8Hz,
2H)
MS: m/z 264. 1 (M+l)
4-(4-(4-chlorophenyl)piperazin-l-yl)butanimidamide.
Trimethylaluminium (2M solution in toluene, 12.32 ml, 24.64 mmol) was added
dropwise to a suspension of ammonium chloride (1.32 g, 24.64 mmol) in dry
toluene (20 ml) over a period of 20 min at 0°C under nitrogen atmosphere. The
resulting mixture was allowed to stir for 15 min at room temperature. To this
was added dropwise a solution of 4-(4-(4-chlorophenyl)piperazin-lyl)
butanenitrile (1.3 g, 4.93 mmol) in dry toluene (10 ml) over a period of 10 min
and the reaction mixture was heated at about 90°C - about 100°C for 15 h
under stirring. The reaction mixture was cooled to 25°C, slowly poured into a
slurry of silica gel (100-200 mesh, 30 g) in chloroform (100 ml) and was stirred
for 10 min. The silica was filtered through celite and washed with methanol (3 x
50 ml). Combined filtrate was evaporated to obtain a crude solid which was
dissolved in 10% hydrochloric acid (100 ml) and washed with diethyl ether (2 x
25 ml). To the resulting aqueous layer was saturated aqueous solution of
sodium hydroxide (30 ml) to bring the pH between 13 and 14. The aqueous
layer was extracted with chloroform (3 x 100 ml). The combined organic layer
was dried over anhydrous sodium sulphate. The solvent in the organic was
evaporated under reduced pressure to obtain the title compound (1. 1 g, 79%
yield) .
Ή NMR (400MHz, CDC13) : d 7.22 (d, J=8.8Hz, 2H), 6.85 (d, J=9.2Hz, 2H), 5.95
(brs, 3H, D20 exchangeable), 3. 17 (t, J=4.8Hz, 4H), 2.62 (t, J=5.2Hz, 4H), 2.49
(t, J=6.8Hz, 2H), 2.37 (t, J=6.8Hz, 2H), 1.85 (quin, J=6.8Hz, 2H)
MS: m/z 281.0 and 283.0 (M+l and M+3)
Step 4 : 2'-(3-(4-(4-chlorophenyl)piperazin-l-yl)propyl)-7',8'-dihydro-3'Hspiro[
cyclopropane-l,6'-quinazolin]-4'(5'H)-one (Compound 6).
Sodium (0.094 g, 4.08 mmol) was added to ethanol (15 ml) under stirring
condition at room temperature. The resulting mixture was stirred for 30 min. To
this freshly prepared clear solution of sodium ethoxide, were added ethyl 6-
oxospiro[2.5]octane-5-carboxylate (0.4 g, 2.03 mmol) and 4-(4-(4-chlorophenyl)
piperazin- 1-yl)butanimidamide (0.343 g, 1.223 mmol) and the reaction mixture
was heated at 85°C for 18 h . The progress of the reaction was monitored by
TLC. The reaction mixture was cooled to room temperature and concentrated
under reduced pressure to obtain crude residue which was dissolved with water
(15 ml). Aqueous layer was extracted with ethylacetate (2 x 30 ml). The
combined organic layer was dried over sodium sulphate, filtered and solvent
was removed under reduced pressure to obtain a crude product which was
purified by flash chromatography over silica gel (100-200 mesh) using 3-4%
methanol in dichloromethane as eluent to obtain title compound (0.030 g, 4%
yield).
Ή NMR (400MHz, CDC13) : d 13.16 (brs, 1H, D20 exchangeable), 7.21 (dd,
J=8.8Hz, 2H), 6.87 (dd, J=8.4Hz & 2.0Hz, 2H), 3.39 (t, J=4.8Hz, 4H), 2.82 (t,
J=6Hz, 2H), 2.74 (t, J=4.8Hz, 4H), 2.68 (t, J=6.0Hz, 2H), 2.58 (t, J=5.6Hz, 2H),
2.34 (s, 2H), 1.96 (t, J=6.Hz, 2H), 1.63-1.56 (m, 2H), 0.35 - 0.44 (m, 4H).
MS: m/z 412.8 & 414.8 (M+l & M+3)
The following compounds were prepared using the procedure described above in
example 1 with appropriate changes in the reactants and reaction conditions.
2'-(3-(4-(4-fluorophenyl)piperazin-l-yl)propyl)-6',7'-dihydro-3'Hspiro[
cyclopropane-l,8'-quinazolin]-4'(5'H)-one (Compound 1).
Ή NMR (400MHz, CDCls): d 12.59 (brs, 1H, D20 exchangeable), 6.99-6.89
(m, 4H), 3.35 (brs, 4H), 2.84 (brs, 4H), 2.72 (t J=6.0 Hz, 4H), 2.61 (t, J=6.0
Hz, 2H) 2.03 (brs, 2H), 1.87-1.77 (m, 2H), 1.70-1.63 (brs, 2H), 1.37-1.29 (m,
2H), 0.69-0.72 (m, 2H).
MS : m/z 396.9 (M+l).
2'-(3-(4-(4-chlorophenyl)piperazin-l-yl)propyl)-6',7'-dihydro-3'Hspiro[
cyclopropane-l,8'-qumazolin]-4'(5'H)-one (Compound 2).
Ή NMR (400MHz, CDCb): d 12. 63 (brs, 1H, D20 exchangeable), 7.21 (d,
J=7.8Hz, 2H), 6.86 (d, J=7.0 Hz, 2H), 3.34 (brs, 4H), 2.57-2.71 (m, 10H),
1.95 (brs, 2H), 1.84-1.74 (m, 2H), 1.69-1.67 (m, 2H), 1.36-1.24 (m, 2H),
0.70-0.69 (m, 2H).
MS : m/z 413 (M+l) & 415 (M+l).
2'-(3-(4-phenyl-5,6-dihydropyridin-l(2H)-yl)propyl)-6',7'-dihydro-3'Hspiro[
cyclopropane-l,8'-quinazolin]-4'(5'H)-one. (Compound 3)
Ή NMR (400MHz, CDC13) : d 11. 96 (brs, 1H, D20 exchangeable), 7.44-7.42
(m, 2H), 7.35-7.31 (m, 2H), 7.26-7.24 (m, 1H), 6.07 (brs, 1H), 3.23-3.22 (m,
2H), 2.79 (t, J=5.2Hz, 2H), 2.71 (brs, 2H), 2.66 (t, J=6.4Hz, 2H), 2.63-2.55
(m, 4H), 1.98-1.93 (m, 2H), 1.78-9. 1 (m, 2H), 1.69-1.66 (m, 2H), 1.35-1.32
(m, 2H), 0.71-0.68 (m, 2H).
MS : m/z 376 (M+l).
2'-(3-(3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-4a',5',6',7'-
tetrahydro-3'H-spiro[cyclopropane-l,8'-quinazolin]-4'(8a'H)-one. (Compound
4)
Ή NMR (400MHz, CDC13) : d 12.65 (brs, 1H, D20 exchangeable), 6.91-6.90
(m, 2H), 6.78-6.74 (m, 2H), 4. 12 (brs, 2H), 3.38-3.27 (m, 2H), 3.26-3. 16 (m,
2H), 2.73-2.58 (m, 2H), 2.57-2.52 (m, 4H), 2.06-2.00 (m, 2H), 1.91-1.65 (m,
10H), 1.34-1.32 (m, 2H), 0.75-0.70 (m, 2H).
MS : m/z 424 (M+l).
2'-(3-(4-(4-fluorophenyl)piperazin-l-yl)propyl)-7',8'-dihydro-3'Hspiro[
cyclopropane-l,6'-quinazolin]-4'(5'H)-one. (Compound 5)
Ή NMR (400MHz, CDCls): d 13.26 (brs, 1H, D20 exchangeable), 7.00-6.90
(m, 4H), 3.32 (t, J=5.0 Hz, 4H), 2.83-2.57 (m,10H), 2.35 (s, 2H), 1.99-193 (m,
2H), 1.58 (t, J = 5.8 Hz, 2H), 0.44-0.38 (m, 4H).
MS : m/z 397 (M+l).
2'-(3-(3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-7',8'-
dihydro-3'H-spiro[cyclopropane- 1,6'-quinazolin]-4'(5'H)-one. (Compound 7)
Ή NMR (400MHz, CDC13) : d 13.26 (brs, 1H, D20 exchangeable), 6.96-6.92
(m, 2H), 6.80-6.76 (m, 2H), 3.30 (brs, 4H), 2.87-2.60 (m, 6H), 2.33 (s, 2H),
2.07-1.57 (m, 8H), 0.89-0.87 (m, 2H), 0.41-0.39 (m, 4H).
MS : m/z 423.2 (M+l).
2'-(3-(8-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)propyl)-7',8'-
dihydro-3'H-spiro[cyclopropane- 1,6'-quinazolin]-