3 FIELD OF THE INVENTION I * I The present invention relates to novel compounds having AKT kinase inhibitory activity and
a process of preparation thereof.
BACKGROUND OF THE INVENTION
AKT is a serinelthreonine protein kinase and is also known as Protein Kinase B (PKB) that
plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation,
apoptosis, transcription and cell migration.
In mammals, there are three genes in the "AKT family": AKTl, AKT2, and AKT3. AKTl is
involved in cellular survival pathways, by inhibiting apoptotic processes. AKTl is capable of
inducing protein synthesis pathways, and is therefore a key signaling protein in the cellular
pathways that lead to skeletal muscle hypertrophy, and general tissue growth. Since it can
block apoptosis, and thereby promote cell survival, AKTl has been implicated as a major
factor in many pathways inducing cancer. AKT2 is an important signaling molecule in
the Insulin signaling pathway. It is required to induce glucose transport. The role of AKT3 is
less clear, though it appears to be predominantly expressed in the brain.
AKT is involved in the PI3WAKTlmTOR pathway and other signaling pathways. AKT is
directly activated by phosphorylation by its activating kinases at threonine 308 and at serine
473. Phosphorylation of both sites on AKT is necessary for activation, but phosphorylation at
threonine 308 only stabilises the activation loop while the site at serine 473 is necessary for
full activation (Alessi et al, (1 996) EMBO J. 15 (23): 6541-5 1; Blume-Jensen et al, (2001)
Nature 41 l(6835): 355-65). Activated AKT then proceeds to activate or deactivate its myriad
substrates (e.g. mTOR) via its kinase activity. PI3K dependent AKT activation can be
regulated through thetumor suppressorPTEN. PTEN acts as aphosphataseto
dephosphorylate PtdIns (3,4,5)P3 back to PtdIns(4,5)P2. This removes the membranelocalization
factor from the AKT signaling pathway. Without this localization, the rate of
AKT activation decreases significantly, as do the all the downstream pathways that depend
on AKT for activation.
AKT activation and signaling promotes cell survival, growth and proliferation. AKT
regulates cellular survival and metabolism by binding and regulating many downstream
effectors, e.g. Nuclear Factor-KB, Bcl-2 family proteins and murine double minute 2
b
4 $ (MDM2). Increased AKT activation has been implicated in a wide variety of cancers.
AKT is believed to contribute to cancerous disease states by inhibiting apoptosis and
promoting both angiogenesis and proliferation (Toker et a1 (2006) Cancer Res. 66(8):3963-
3966).
Over expression or amplification of AKT has been associated with certain disorders. The PI3
kinase/AKT pathway is an attractive target for developing anticancer drugs to inhibit
proliferation, reverse the repression of apoptosis and surmount resistance to cytotoxic agents
in cancer cells. Effective and improved therapeutic agents which inhibit kinases such as
AKT are continually needed for developing new and more effective formulations that are
I aimed at treating diseases associated with dysregulation of the pathways involving AKT.
"AKT inhibitor" refers to a compound which reduces and/or blocks the activity of AKT.
The inhibitor may act directly on AKT, for example by preventing phosphorylation
of AKT or de-phosphorylating AKT or alternatively, the inhibitor may act via the inhibition
of an upstream activator (or multiple activators) of AKT in the PI3WAKTlmTOR signaling
pathway or other pathway involved in apoptosis, or via the activation of a
upstream inhibitor of AKT. It is preferred that the AKT inhibitor acts to reduce and/or block
the activity of AKT via multiple pathways such that effective inhibition is achieved. Such a
compound may, for example, act by inhibition of up-stream effectors/activators of AKT in
both the PI3K pathway and the mTOR pathway. Additionally, the inhibitor of AKT may act
to prevent or reduce the transcription, translation, post-translational processing andlor
mobilisation of AKT (i.e. reduce the expression of AKT), or an upstream activator of the
expression of AKT. "AKT inhibitor" may also be a compound that counteracts the survival
mechanism modulated by AKT activity by acting downstream ofAKT to overcome the
action of increased AKT activity.
Several classes of compounds have been disclosed in various prior art documents as AKT
kinase inhibitors.
WO 2006107 18 19 (Exelixis) discloses a class of [lH-pyrazolo[3,4-dlpyrimidin-4-
yllpiperidine compounds as inhibitors of AKT1, AKT2 and P70S6K. The compounds are
stated to be useful for the treatment of immunological, inflammatory and proliferative
diseases.
A series of substituted piperidine compounds having AKT inhibitory activity are disclosed in G .
a number of patent applications such as US8377937, WO 2008/075109 and US2010120801.
These compounds are disclosed for use in the treatment of conditions arising from abnormal
cell growth or abnormally arrested cell death, including cancer.
Despite the advances in developing AKT inhibitors, there still remains a need to provide
alternative more selective and more potent AKT inhibitors which exhibit better
pharmacokinetic properties and fewer side effects in the treatment of proliferative disorders
such as cancer.
OBJECT OF THE INVENTION
An object of the invention is to provide novel AKT inhibitors and a process of preparation
thereof.
SUMMARY OF THE INVENTION
The present invention provides novel AKT inhibitor compounds of formula I
FORMULA I
wherein
a=l or 2
X and Y is each independently selected from C, 0 or N.
X and R2 may be directly attached or attached via a linking group L which may be selected
from an Oxygen atom or a CO group
Z is H or Alkyl
RI = H or
wherein
n=O to 2
R3= aryl optionally substituted by a halogen or an alkylene group;
Rq is a group selected from hydrogen, amine, substituted mine or an amino alkyl group;
R2 is
wherein A, B, C, D and E are independently selected from H, -CH2, a heteroatom such as C,
0, N or S;
with the proviso that:
A, B, C, D, E forms a 5 or 6 membered aromatic ring and at least one of A, B, C, D, E is
Nitrogen;
AB C D E is optionally substituted by one or more groups selected from amino, N-alkyl
amino 0x0, alkoxy, hydroxyl or hydroxy alkyl group;
G and F are independently selected from the group comprising hydrogen, amino, alkoxy,
hydroxyl-alkyl or an acetamide group or
G and F may be fused to form a 5 membered ring "J";
wherein the Ring J represents pyrrole ring or imidazole ring optionally substituted by one or
more substituents independently selected from H, alkyl, hydroxyalkyl or halogen.
wherein the valency of fused heterocyclic ring is satisfied by corresponding double bonds as
and where applicable.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compounds that have protein kinase (AKT) inhibiting or
modulating activity, and which is envisaged will be useful in preventing or treating disease
states or conditions mediated by AKT.
Accordingly, the present invention relates to the AKT inhibitor compounds of formula I
RI
I
L
" ~ 2
FORMULA I
wherein
a=lor 2
X and Y is each independently selected from C, 0 or N;
X and R2 may be directly attached or attached via a linking group L which may be selected
from an Oxygen atom or a CO group;
Z is H or Alkyl;
R1 = H or
wherein
n=O to 2
R3= an alkylene group or an aryl optionally substituted by a halogen;
Rq is a group selected from hydrogen, amine, substituted amine, an amino alkyl group or
wherein A, B, C, D and E are independently selected from H, -CH2, a heteroatom such as C,
0, N or S;
with the proviso that:
A, B, C, D, E forms a 5 or 6 membered aromatic ring and at least one of A, B, C, D, E is
Nitrogen;
A B C D E is optionally substituted by one or more groups selected from amino, 0x0, Nalkyl
amino, alkoxy or hydroxyl alkyl group;
G and F are independently selected from the group comprising hydrogen, amino, alkoxy,
hydroxyl-alkyl or an acetamide group or
G and F may be fused to form a 5 membered ring "J";
wherein the Ring J represents pyrrole ring or imidazole ring optionally substituted by one or
more substituents independently selected from H, alkyl, hydroxyalkyl or halogen.
wherein the valency of fused heterocyclic ring is satisfied by corresponding double bonds as
and where applicable.
Particularly, the present invention provides AKT inhibitor compounds of formula I
-
*
-
. FORMULA1
wherein
a=lor 2
X and Y is each independently selected from C, 0 or N;
X and R2 may be directly attached or attached via a linking group L which may be selected
from an Oxygen atom or a CO group;
Z is H or Alkyl;
R,=H or
R1 is
wherein
R3= halophenyl, phenyl group or alkylene group;
Rq is a group selected from hydrogen, amine, substituted amine, an amino alkyl group or
-CH2-NH-CH(CH3)2;
X and R2 may be linked directly or indirectly through a linking group L, which may be
selected from an Oxygen atom or a CO group
R2 may be selected from aromatic or non-aromatic heterocyclic amines or fused heterocyclic
amines optionally substituted by one or more groups selected from amines, substituted
amines, alcohol and alkyl groups.
More particularly, the present invention relates to the AKT inhibitor compounds of formula I
FORMULA I
wherein
a=lor 2
X and Y is each independently selected from C, 0 or N;
X and R2 may be directly attached or attached via a linking group L which may be selected
from an Oxygen atom or a CO group;
Z is H or Alkyl;
RI=H; or
wherein
n= 0 to 2
R3= chlorophenyl, phenyl or ethylene;
& is a group selected from hydrogen, amine, isopropylamine , N-methyl amine, N-propyl
amine or -CH2-NH-CH(CH3)2;
X and R2 may be linked directly or indirectly through a linking group L, which may be
selected from an Oxygen atom or a CO group;
R2 may be selected from optionally substituted heterocyclic amines selected from:
The compounds of the present invention may be illustrated but not limited to the examples as
provided in Table 1.
Table 1: Illustrative compounds of the present invention
AKTl %
Inhib@lOuM
-PRELIM
SCREEN HTRF
(uM)
(Inhibition)
AKTl %
Inhib@O.luM
-PRELIM
SCREEN HTRF
(uM)
(Inhibition)
Structure
qo
NO.
O7I
IUPAC name
2-amino-1 -(4-(2-
aminopyrimidin-4-yl)-2-
methylpiperazin-I -yl)-3-
phenylpropan-I -one
2-amino-I -(4-(4-amino-
1,3,5-triazin-2-yl)piperazin-
I -yl)-3-phenylpropan-1-
one
1 -(4-(2-aminopyrimidin-4-
yl)-2-methylpiperazin-I -yl)-
2-(4-chloropheny1)-3-
(isopropylamino)propan-I -
one
2-amino-I -(4-(2,4-diamino-
1,3,5-triazin-2-yl)piperazin-
1 -yl)-3-phenylpropan-1-
one

2-(4-chloropheny1)-3-
(isopropy1amino)-I -(4-(6-
methoxypyrimidin-4-
yl)piperazin-I -yl)propan-I -
one
2-(4-chloropheny1)-3-
(isopropy1amino)-I -(4-(2-
(methy1amino)pyrimidin-4-
y1)piperazin-I -yl)propan-I -
one

2-(4-chloropheny1)-I -(4-(6-
(hydroxymethy1)pyrimidin-
4-y1)piperazin-I -yl)-3-
(isopropylamino)propan-I -
one
4-(1-(2-(4-chloropheny1)-3-
(isopropylamino)propanoyl
)piperidin-4-yl)morpholin-3-
one
2-(4-chloropheny1)-I -(4-(7-
fluoropyrrolo[l,2-
f1[1,2,4]triazin-4-
y1)piperazin-I -yl)-3-
(isopropylamino)propan-I -
one
2-(4-chloropheny1)-I -(4-(5-
fluoropyrrolo[l,2-
fl[l,2,4]triazin-4-
y1)piperazin-I -yl)-3-
(isopropylamino)propan-I -
one

1 -(4-(2-aminopyridin-4-
~1)piperazin--Iy l)-2-(4-
zhloropheny1)-3-
(isopropylamino)propan-I -
one
--
tert-butyl (2-(4-
chloropheny1)-3-(4-(6-
(methylamino)pyrimidin-4-
y1)piperazin-I -yl)-3-
oxopropyl)(isopropyl)carba
mate
3-(N-isopropyl-Nmethylamino)-
2-(4-
chloropheny1)-1-(4-(6-
(methy1amino)pyrimidin-4-
y1)piperazin-1 -yl)propan-I -
one
, --0 The compounds of the present invention include:
i. 2-amino- 1 -(4-(2-aminopyrimidin-4-y1)-2-methylpiperin- 1 -yl)-3-phenylpropan- 1 -
one
. .
11. 2-amino- 1 -(4-(2-aminopyrimidin-4-y1)-3 -methylpiperazin- 1 -yl)-3-phenylpropan- 1 -
one
iv. 1- (4-(2-aminopyrimidin-4-y1)-2-methylpiperin1-- yl)-2-(4-chloropheny1)-3-
(isopropy1amino)propan- 1 -one
vi. 2-amino- 1- (4-(2-aminopyrimidin-4-y1)-piperazin-1 - yl)-3-phenylpropan- 1- one
vii. 1- (4-(2-aminopyrimidin-4-y1)piperazin-1 - yl)-2-(4-chloropheny1)ethanone
ix. (R)- 1 -(4-(7H-pyrrolo[2,3-dl pyrimidin-4-y1)piperazin- 1 -yl)-2-amino-3-phenylpropan-
1 -one
xi. 6-(piperazin- 1 -yl)pyrimidin-4-amine
xii. 1 -(4-(7H-pyrrolo[2,3-dlpyrimidin-4-y1)piperazin- 1 -yl)-2-(4-chloropheny1)-3-
(isopropy1amino)propan- 1 -one
xiv. 1- (4-(2-aminopyrimidin-4-y1)piperazin-1 - yl)-2-(4-chloropheny1)-3-
(isopropy1amino)propan- 1 -one
xv. (R)-2-amino- 1- (4-(2-aminopyrimidin-4-y1)piperazin-1 - yl)-3-phenylpropan- 1- one
xvi. (R)- 1- (4-(1H -pyrrolo[2,3-blpyridin-4-y1)piperazin1-- yl)-2-amino-3-phenylpropan1--
one
xvii. 2-amino- 1 -(4-(2-(methylamino) pyrimidin-4-y1)piperazin- 1 -yl)-3-phenylpropan- 1 -one
xviii. 2-(4-chloropheny1)-3-(isopropy1amino)- 1 -(4-(6-(methy1amino)pyrimidin-4-
y1)piperazin- 1 -yl)propan- 1 -one
~ xix. 1 -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-amine
I
I xx. (4-(piperazin- 1 -yl)pyrrolo[l,2-fl [1,2,4]triazin-7-y1)methanol
I xxi. (R)-N-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)-2-amino-3-
i phenylpropanamide
xxii. 2-(4-chloropheny1)-3 -(isopropylamino)- 1- (4-(6-methoxypyrimidin-4-y1)piperazin-1 -
y1)propan- 1 -one
-4 xxiii.
xxiv.
xxv.
xxvi.
xxvii.
xxviii.
xxix.
XXX.
xxxi.
xxxii.
xxxiii.
xxxiv.
xxxv.
xxxvi.
xxxvii.
xxxviii.
xxxix.
I xl.
i
xli.
2-(4-chloropheny1)-3-(isopropy1amino)- 1 -(4-(6-(methy1amino)pyrimidin-4-y1)- 1,4-
diazepan- 1 -yl)propan- 1 -one
2-(4-chloropheny1)-3 -(isopropylamino)- 1- (4-(pyrimidin-4-y1)piperazin-1 - yl)propan- 1-
one
1 -(4-(6-(methy1amino)pyrimidin-4-y1oxy)piperidn- 1 -yl)-2-(4-chloropheny1)-3-
(isopropylamino) propan- 1 -one
% xlii. (R)-2-amino- 1 -(4-(6-(methy1amino)pyrimidin-4-y1)pipern- 1 -yl)-3 -phenylpropan- 1 -
* -* one
xliii. 1 -(4-(2-aminopyridin-4-y1)piperazin- 1 -yl)-2-(4-chloropheny1)-3-
(isopropy1amino)propan- 1 -one
xliv. 1 -(4-(2-aminothiazole-5-carbony1)piperazin- 1 -yl)-2-(4-chloropheny1)-3-
xlv. 3-(N-isopropyl-N-methylamino)-2-(4-chlorophenyl)-1 - (4-(6-
(methy1amino)pyrimidin-4-y1)piperazin- 1 -yl)propan- 1 -one
The Compounds of the present invention may be present in their enantiomeric pure forms or
their mixtures.
B. Salts and Isomers and counter ions
The present invention includes within its scope the salts and isomers. Compounds of the
present invention after being novel may in some cases form salts which are also within the
scope of this invention. The term "salt(s)", as employed herein, denotes acidic andlor basic
salts formed with inorganic andlor organic acids and bases. Zwitterions (internal or inner
salts) are included within the term "salt(s)" as used herein (and may be formed, for example,
where the R substituents comprise an basic moiety such as a amino group). Also included
herein are quaternary ammonium salts such as alkyl ammonium salts. Pharmaceutically
acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts
are useful, for example, in isolation or purification steps which may be employed during
preparation. Salts of the compounds may be formed, for example, by reacting a compound
with an amount of acid or base, such as an equivalent amount, in a medium such as one in
which the salt precipitates or in an aqueous medium followed by lypholization.
All stereoisomers of the present compounds, such as those which may exist due to
asymmetric carbons on the R substituents of the compound, including enantiomeric and
diastereomeric forms, are contemplated within the scope of this invention.
The present invention also envisages within its scope the effect of selection of suitable
counter ions. The present invention includes in its scope, the modification of deuterated
compounds. Deuterated compounds are those wherein the compounds have selective
incorporation of deuterium in place of hydrogen.
C. Synthesis of the compounds of the present invention.
The present invention also relates to a process of preparing the compounds of formula (I).
24
d
=d* D. Composition containing the novel entities of the invention
The invention thus also provides the use of the novel entity as defined herein for use in
human or veterinary medicine. The AKT kinase inhibitor compounds of the present invention
may be used in the treatment of any disorder related to AKT kinase activity.
The compound for use as a pharmaceutical may be presented as a pharmaceutical
formulation.
The invention therefore provides in a further aspect a pharmaceutical formulation comprising
the novel compounds of the invention with a pharmaceutically acceptable carrier thereof and
optionally other therapeutic andlor prophylactic ingredients. The carriers must be
"acceptable" in the sense of being compatible with the other ingredients of the formula and
not deleterious to the recipient thereof. Suitably the pharmaceutical formulation will be in an
appropriate unit dosage form.
The pharmaceutical formulations may be any formulation and include those suitable for oral,
intranasal, intraocular or parenteral (including intramuscular and intravenous) administration.
The formulations may, where appropriate, be conveniently presented in discrete dosage units
and may be prepared by any of the methods well known in the art of pharmacy. All methods
include the step of bringing into association the active compound with liquid carriers or finely
divided solid carriers or both, and then, if necessary, shaping the product into the desired
formulation.
For these purposes the compounds of the present invention may be administered orally,
topically, intranasally, intraocularly, parenterally, by inhalation spray or rectally in dosage
unit formulations containing conventional non-toxic pharmaceutically acceptable carriers,
adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections,
intravenous, intramuscular, intrasteral injection or infusion techniques. In addition to the
treatment of warm-blooded animals such as mice, rats, horses, dogs, cats, etc., the compounds
of the invention are effective in the treatment of humans.
EXAMPLES
The following examples are representative of the disclosure, and provide detailed methods
for preparing the compounds of the disclosure, including the preparation of the intermediate
compounds. The preparation of particular compounds of the embodiments is described in
= -4 detail in the following examples, but the artisan will recognize that the chemical reactions
described may be readily adapted to prepare a number of other agents of the various
embodiments. For example, the synthesis of non-exemplified compounds may be
successfully performed by modifications apparent to those skilled in the art, e.g. by
appropriately protecting interfering groups, by changing to other suitable reagents known in
the art, or by making routine modifications of reaction conditions.
As used herein the symbols and conventions used in these process, schemes and examples,
regardless of whether a particular abbreviation is specifically defined, are consistent with
those used in the contemporary scientific literature, for example, the Journal of American
Chemical Society or the Journal of Biological Chemistry. Specifically, but without limitation,
the following abbreviationsmay be used in the examples and throughout the specification:
g(grams), mg (milligrams), mL(mil1i 1itres)RT or rt (room temperature), mmol (millimoles),
DMF (dimethyl formamide), DMSO (dimethylsulfoxide), TLC (thin layer chromatography),
EtOH (ethanol), MeOH (methanol), DCM (dichloromethane), THF (tetrahydrofuran),
DIPEA(N,N-diisopropylethylamine), TFA(trifluoroacetic acid); TBDMSCI(tertbutylchlorodimethylsilane);
TBAF(tetra-n-butylammonium fluoride); PdC12(dppf), (1,rbis(
dipheny1phosphino)ferrocene) dichloropalladium (1 1
EDTA(ethy1enediaminetetraacetic acid); Me(methy1); Et(ethy1); tBu(tert-butyl); and Boc(Ditert-
butyl dicarbonate), HOBT (Hydroxybenzotriazole); EDC(Ethy1ene dichloride);
ACN(Acetonitri1e); EtOAc(ethy1 acetate); i-PrOH(isopropanol),DMA(dimethyl mine), MNP
(2-Methyl-2-nitrosopropane).
For all of the following examples, standard work-up and purification methods known to
those skilled in the art may be utilized. Unless otherwise indicated, all temperatures are
expressed in "C (degrees Centigrade). All reactions conducted at room temperature unless
otherwise noted. Synthetic methodologies illustrated herein are intended to exemplify the
applicable chemistry through the use of specific examples and are not indicative of the scope
of the disclosure.
*-+ Example 1: Synthesis of Compound 10724
Step 1:Preparation of compound 2 from compound 1:
DIPEA,
DCM, rt
CI
25 %
TFA-DCM
rt, 2h
*
NHBoc
EDC, HOBT,
DIPEA, DCM
I 25 % I
TFA-DCM
Compound 1 (2.00 g, 12.12 mmol) was taken in water and NaHC03 (2.34 g, 24.24mmol) was
added to it at O°C. To this mixture boc anhydride (2.90 g, 13.33 mmol) in THF was added
drop wise at O°C and the reaction mixture was stirred at room temperature for 12 h. After
completion of reaction, THF was removed and the aqueous layer was washed with diethyl
ether and acidified with citric acid solution (aq) up to PH 4-5. Then extracted with ethyl
acetate and the organic layer were dried over Na2S04 and evaporate the solvent to get the
pure product 2. (3.10 g, 97 %, M+ 1 =266)
Step 2: Preparation of compound 7 from compound 5:
To a stirred solution of 5 (5.00 g, 33.78 mmol) in DCM, DIPEA (6.22 mL, 33.78 mmol) and
Boc piperazine (6.28 gm, 33.78 mmol) were added and the reaction mixture was stirred at
room temperature for 2 h. The reaction mixture was diluted with DCM and washed with
water. The organic layer was separated out, dried over Na2S04 and the solvent was
evaporated to get a crude residue. The crude residue was purified by column
'4 chromatography using ethyl acetate hexane (10-30%) to get the pure product 7 (9.26 g, 92%
M+1=299).
Step 3: Preparation of compound 8 from compound 7:
Compound 7 (2.00 g, 6.68 mmol) was taken in 25% TFA-DCM (10 mL) and stirred at for 2
h. Then the solvent was removed under vacuum to get an oily product 8 and used without
purification.
Step 4: Preparation of compound 9 from compound 8:
Compound 2 (250.00 mg, 0.836 mmol) was taken in dry DCM, EDC.HC1 (239.00 mg, 1.254
mmol), HOBT (124.00 mg, 0.919 mmol) were added under nitrogen and stirred for 30 min at
room temperature. The Compound 8 (165 mg, 0.836 mmol) was taken in another round
bottom flask and DIPEA (0.462mL, 2.51 mmol) was added. Then the second reaction
mixture was added to first reaction mixture slowly and stirred for 12 h at r.t. After that the
reaction was diluted with DCM and washed with water and extracted with ethyl acetate and
the organic layer was dried over Na2S04 and the solvent was evaporated to get a crude
residue. The crude residue was purified by column chromatography using ethyl acetate
hexane (20-50%) to get the pure product 9 (462 mg, 82%, M+1=447).
Step 5: Preparation of compound 10 from compound 9:
Compound 9 (150 mg, 0.336 mmol) was taken in toluene (10 mL) and aqueous ammonia (5
mL) was added in a sealed tube. Then the reaction mixture was heated up to 150 OC for 20 h.
After that the reaction mixture was cooled down to r.t. and solvent was removed under
vacuum to get crude product. The crude product was purified by column chromatography
using Methanol-DCM (2-5%) to get the pure product 10 (51 mg, 52 %, M+1=427).
Step 6: Preparation of compound 10724 from compound 10:
Compound 10 (45 mg, 0.105 mmol) was taken in 25% TFA-DCM (2 mL) and stirred at rt for
2 h. Then the solvent was removed under vacuum to get an oily product and the oily product
was washed with the diethyl ether to get the solid pure product 10724 (30 mg, 85%,
M+1=327).
---4 Example 2: Synthesis of Compound 10754.
Boc
NaHC03
NHBoc NHBoc 5 -
(") w: 1 CH3NH2 in THF I
N 4 OH- Toluene, reflux
I
25 % I
TFA-DCM,
fl. 2, ("1
r'!
Step 1: Preparation of compound 4 from compound 3:
Compound 3 (2.00 g, 12.12 mmol) was taken in water and NaHC03 (2.34 g, 24.24) was
added to it at O°C. To this mixture boc anhydride (2.90 g, 13.33 rnmol) in THF was added
drop wise at O°C and the reaction mixture was stirred at room temperature for 12 h. After
completion of reaction, THF was removed and the aqueous layer was washed with diethyl
ether and acidified with citric acid solution (aq) up to PH 4-5. Then extracted with ethyl
acetate and the organic layer were dried over Na2S04 and evaporate the solvent to get the
pure product 4. (3.00 gm, 96 %, M+1=266)
Step 2: Preparation of compound 11 from compound 8: The process employed for
conversion of compound 9 from compound 8 may be suitably applied herein to obtain
compound 1 1 (87 %, M+ 1 =447).
Step 3: Preparation of compound 12 from compound 11:
Compound 11 (120,0.27 mmol) was taken in dry toluene (10 mL) and methylamine in THF
(5 mL) was added in a seal tube. Then the reaction mixture was heated up to 150 OC for 20 h.
After that the reaction mixture was cooled down to r.t. and solvent was removed under
vacuum to get crude product. The crude product was purified by column chromatography
using Methanol-DCM (2-5%) to get the pure product 12 (65 mg, 55%, M+1=441).
Step 4: Preparation of compound 10754 from compound 12: Compound 12 (45 mg,
-4
0.105 rnrnol) was taken in 25% TFA-DCM (2 mL) and stirred at rt for 2 h. Then the solvent
was removed under vacuum to get an oily product and the oily product was washed with the
diethyl ether to get the solid pure product 10754 (90%, M+1=341), SPI=10754.
!
Example 3: Synthesis of Compound 10745.
Y ,NBoc
Y / NBoc
'/fN H.TFA
~2 EDC, HOBT, DIPEII, DCM
CI
Step 1 : Preparation of compound 13 from compound 8: The process employed for
conversion of compound 9 from compound 8 may be suitably applied herein to obtain
compound 13 (85 %, M+1=522).
Step 2: Preparation of compound 14 from compound 13: The process employed for
conversion of compound 10 from compound 9 may be suitably applied herein to obtain
compound 14 (55%, M+1=503).
Step 3: Preparation of compound 10745 from compound 14: The process employed for
conversion of compound 10724 from compound 10 may be suitably applied herein to obtain
compound 10745 (90%, M+1=403).
Example 4: Synthesis of Compound 10775.
'f
15
EDC, HOBT,
8
Y ( N Boc Y NBoc Y
f NH
Toluene CI
Step 1: Preparation of compound 16 from compound 8:
I- J
The process employed for conversion of compound 9 from compound 8 may be suitably
applied herein to obtain compound 16 (85%, M+1=522).
Step 2: Preparation of compound 17 from compound 16: The process employed for
conversion of compound 12 from compound 11 may be suitably applied herein to obtain
compound 17 (7 1 %, M+1=5 1 8).
Step 3: Preparation of compound 10775 from compound 17: The process employed for
conversion of compound 10724 from compound 10 may be suitably applied herein to obtain
compound 10775 (90 %, M+1=418).
Example 5: Synthesis of Compound 10713
CI A N . -. , - -
DlpEA EDC HOW,
DCM I N J
toluene - DCM
5
Step 1: Preparation of compound 18 from compound 5:
To a stirred solution of 5 (500.00 mg, 3.35 mmol) in DCM, methyl piperazine (335.00 mg,
3.35mmol) was added and the reaction mixture was stirred at room temperature for 12 h. The
reaction mixture was diluted with DCM and washed with water. The organic layer was
separated out, dried over Na2S04 and the solvent was evaporated to get a crude residue. The
crude residue was purified by column chromatography using ethyl acetate hexane (10-30%)
to get the pure product 18 (243 mg, 35%, M+ 1 =2 13).
1
-4
Step 2: Preparation of compound 19 from compound 18: The process employed for
I
.
conversion of compound 9 from compound 8 may be suitably applied herein to obtain
compound 19 (72 %, M+1=460).
Step 3: Preparation of compound 20 from compound 19: The process employed for
conversion of compound 10 from compound 9 may be suitably applied herein to obtain
compound 20 (56%, M+1=44 1).
Step 4: Preparation of compound 10713 from compound 20: The process employed for
conversion of compound 10724 from compound 10 may be suitably applied herein to obtain
compound 107 13 (90%, M+ 1 =34 1).
Example 6: Synthesis of Compound 10720
v ','
35 C,I
DCM
NH3 (aq)
___) toluene,
reflux
22 23 10720
Step 1: Preparation of compound 22 from compound 18: The process employed for
conversion of compound 9 from compound 8 may be suitably applied herein to obtain
compound 22 (70 %, M+ 1=536).
Step 2: Preparation of compound 23 from compound 22: The process employed for
conversion of compound 10 from compound 9 may be suitably applied herein to obtain
compound 23 (55%, M+1= 5 18).
Step 3: Preparation of compound 10720 from compound 23: The process employed for
conversion of compound 10724 from compound 10 may be suitably applied herein to obtain
compound 10720 (90 %, M+l= 4 18).
,
4 Example 7: Synthesis of Compound 10714
N Boc
DCM.-
( NHk O O C . 4h
21
H.TFA
25% (11 -TFA-DCM I EDC, HOBT,
DIPEA, DCM, rt
NHBoc
-0
NH3 (aq),
toluene
reflux I
( 25%
-TFA-DCM
Step 1: Preparation of compound 24 from compound 21: Compound 21 (2.50 g, 25.00
mrnol) was taken in DCM and boc anhydride (4.90 gm, 22.50 mmol) was added to the
mixture drop wise at 0 OC. Then the reaction mixture was stirred at r.t. for 4 h. After
completion of reaction, the mixture was diluted with DCM and washed with water. The
organic layer was dried over Na2S04 and the solvent was evaporated to get a crude product
24. The crude product was purified by column chromatography using ethyl acetate hexane
(10-30%) to get the pure product 24 (2.10 g, 42 %, M+1= 201).
I Step 2: Preparation of compound 25 from compound 24: The process employed for
I
conversion of compound 7 from compound 5 may be suitably applied herein to obtain
compound 25 (70 %, M+ 1 = 3 14).
Step 3: Preparation of compound 26 from compound 25: The process employed for
conversion of compound 8 from compound 7 may be suitably applied herein to obtain
compound 26.
Step 4: Preparation of compound 27 from compound 26: The process employed for
conversion of compound 9 from compound 8 may be suitably applied herein to obtain
compound 27(82 %, M+ 1 =46 1 ).
d
I 4
Step 5: Preparation of compound 28 from compound 27: The process employed for
I
1
I
I
conversion of compound 10 from compound 9 may be suitably applied herein to obtain
compound 28(7 1 %, M+1=44 1).
Step 6: Preparation of compound 10714 from compound 28: The process employed for
conversion of compound 10724 from compound 10 may be suitably applied herein to obtain
compound d 10714 (90 %, M+1=341), SPR10714.
Example 8: Synthesis of Compound 10778
(5 25%
TFA-DCM -
30
'f
NBoc
Y NBOC 'r'
35 CI
'N/ CI
31
32 NBoc
/ 33
Step 1: Preparation of compound 30 from compound 29: The process employed for
conversion of compound 7 from compound 5 may be suitably applied herein to obtain
compound 30 (90%, M+ 1 =299).
Step 2: Preparation of compound 31 from compound 30: The process employed for
conversion of compound 8 from compound 7 may be suitably applied herein to obtain
compound 3 1.
Step 3: Preparation of compound 32 from compound 31: The process employed for
conversion of compound 9 from compound 8 may be suitably applied herein to obtain
compound (80 %, M+1=522).
b
4 Step 4: Preparation of compound 33 from compound 32: The process employed for
conversion of compound 10 from compound 9 may be suitably applied herein to obtain
compound 33 (49 %, M+1=503).
Step 5: Preparation of compound 34 from compound 33: Compound 33 (50 mg, 0.099
mmol) was taken in acetic anhydride (2.5 ml) under nitrogen and reflux for 1 h. TLC showed
the completion of reaction, then the reaction mixture was cooled down to r.t. and diluted
with ethyl acetate. The organic layer was washed with water and dried over Na2S04 and the
solvent was evaporated to get a crude product 34. The crude product was purified by column
chromatography using ethyl acetate hexane (30-50%) to get the pure product 34 (25 mg,
46%, M+1=545).
Step 6: Preparation of compound 10778 from compound 34: The process employed for
conversion of compound 10724 from compound 10 may be suitably applied herein to obtain
compound 10778 (93%, M+1=445), SPR10778.
Example 9: Synthesis of Compound 10759
Y , N Boc
Y
/
NBoc
CI & &(N) CtoinHl u,TNeHHnF,e . CI
N reflux
Step 1: Preparation of compound 36 from compound 32 The process employed for
conversion of compound 12 from compound 11 may be suitably applied herein to obtain
compound 36 (7 1 %, M+ 1 =5 17).
Step 2: Preparation of compound 10759 from compound 36: the experiment is same as
preparation of compound 10724 from compound 10 (88%, M+1=617), SPR10759.
b
, Example 10: Synthesis of Compound 10917
- EDC, HOBT,
DIPEA. DCM, rt
I
.....
Step 1: Preparation of compound 38 from compound 37: Compound 37 (250 mg, 1.94
mmol) was taken in DMA (2 ml) and boc piperazine (1.20 g, 9.76 mmol) was added in
microwave tube. The reaction mixture was run for 7 min at 200 OC. Then the reaction
mixture was cooled down to r.t. and solid crystalline product was formed and filtered to get
the pure product 38 (350 mg, 64%, M+1=279).
Step 2: Preparation of compound 39 from compound 38: The process employed for
conversion of compound 8 from compound 7 may be suitably applied herein to obtain
compound 39.
Step 3: Preparation of compound 40 from compound 39 The process employed for
conversion of compound 9 from compound 8 may be suitably applied herein to obtain
compound (86%, M+1=502).
Step 4: Preparation of compound 10917 from compound 40: The process employed for
conversion of compound 10724 from compound 10 may be suitably applied herein to obtain
compound 10917, Yield :55%
..
$4 Example 11: Synthesis of Compound 10759
15 OH ,
EDC, HOBT,
CH3NH2
Toulene DCM
44
N '
10759
H
Step 1: Preparation of compound 43 from compound 31: The process employed for
conversion of compound 9 from compound 8 may be suitably applied herein to obtain
compound (82%, M+ 1 =446).
Step 2: Preparation of compound 44 from compound 43:
The process employed for conversion of compound 12 from compound 11 may be suitably
applied herein to obtain compound 44 (7 1 %, M+ 1 =5 17).
Step 4: Preparation of compound 10759 from compound 44: The experiment is same as
preparation of compound 10724 from compound 10 (88%, M+1=532), SPR10759.
-
*-i Example 12: Synthesis of Compound 10715
ti 6
DIPEA
DCM, OC, 'CI CI'
() TF2A5-D%C M
I -
oc Boc
NHBoc
EtOH,OC, 2h 45 46 48
25 % PdlC
MeOH, rt
I
2 OH
N + q EDC, HOBT
I ,)\ DIPEA, DCM,
A N NHn
Step 1: Preparation of compound 46 from compound 45: To a stirred solution of 45 (1.48
g, 8.05 mmol) in THF (20 mL), Boc piperazine (1.0 g, 5.37 mmol) was added and the
reaction mixture was stirred at 0 OC for 2 h. Then the reaction mixture was diluted with DCM
and washed with water. The organic layer was separated out, dried over Na2S04 and the
solvent was evaporated to get a crude residue. The crude residue was purified by column
chromatography using ethyl acetate-hexane (20-30%) to get the pure product 46 (1.50 g,
55%, M+1=334).
Step 2: Preparation of compound 47 from compound 46: Compound 46 (500 mg, 1.49
mrnol) was taken in acetone and aqueous ammonia (2ml) was added in a seal tube. Then the
reaction mixture was stirred at 0 OC for 2 h. The solvent was removed under vacuum to get
crude product. The crude product was purified by column chromatography using Methanol-
DCM (2-5%) to get the pure product 47 (270 mg, 57%, M+1=3 15).
Step 3: Preparation of compound 48 from compound 47: Compound 47 (250 mg, 0.796
mmol) was taken in 25% TFA-DCM (2 mL) and stirred at for 2 h. Then the solvent was
removed under vacuum to get an oily product 48 (240 mg, M+1= 215) and used without
purification.
C
Step 4: Preparation of compound 49 from compound 48: The process * employed for !
I conversion of compound 9 from compound 8 may be suitably applied herein to obtain
compound 49 (50 mg, M+1=462).
Step 5: Preparation of compound 50 from compound 48: Compound 49 (50 mg, 0.108
mmol) was taken in MeOH-ethyl acetate (1:1, 8 mL) under nitrogen and PdC (10 mg) was
added to it under nitrogen. Then hydrogen balloon was introduced and stirred at r.t. for 16 h.
After completion of reaction, the reaction mixture was filtered through celite, the filtrate was
combined and the solvent was evaporated under vacuum to get a solid product. The crude
product was purified by column chromatography using Methanol-DCM (2-5%) to get the
pure product 50 (40 mg, 87%, M+1=428).
Step 6: Preparation of compound 10715 from compound 50: The process employed for
conversion of compound 8 from compound 7 may be suitably applied herein to obtain
compound 10715(7 mg, 8594, M+1=328),SPR10715.
Example 13: Synthesis of Compound 10723
?oc yoc
25 ?h
TFA-DCM 2 OH
H2N
NH2 H2N
51 52 53
54 10723
Step 1: Preparation of compound 52 from compound 51: To a stirred solution of 51 (500
mg, 2.73 mmol) in THF, TEA (0.4mL, 2.7 mmol) and Boc piperazine (200 mg, 2.70 mmol)
were added and the reaction mixture was stirred at rt for 16 h. The reaction mixture was
diluted with DCM and washed with water. The organic layer was separated out, dried over
Na2S04 and the solvent was evaporated to get a crude residue. The crude residue was purified
by column chromatography using methanol-DCM (1-3%) to get the pure product 52 (70 mg,
M+I =296).
Step 2: Preparation of compound 53 from compound 52: Compound 52 (70 mg, 0.23
mmol ) was taken in 25% TFA-DCM (2 mL) and stirred at rt for 2 h. Then the solvent was
3 9
removed under vacuum to get an oily product 53 (80 mg, M+1=196) and used without
*-+
purification.
Step 3: Preparation of compound 54 from compound 53: The process employed for
conversion of compound 9 from compound 8 may be suitably applied herein to obtain
compound 54. The crude residue was purified by column chromatography using Methanol-
DCM (2-5%) to get the pure product 54 (24 mg, 82%, M+1=443).
Step 4: Preparation of compound 10723 from compound 54: The process employed for
conversion of compound 10724 from compound 10 may be suitably applied herein to obtain
compound 10723 (6 mg, 81%, M+1=343), SPR10723.
Example 14: Synthesis of Compound 10787
l
Boc NBoc , N Boc
TFA
25%
TFA-DCM
VOOH .H
*
N=( DIPEA, DMF, rt
NHCbz
NHCbz
EDC. HOBT
DIP, , rt
C~ZHN' Pd(OH)$
MeOH, rt,
58 I 42h
'/ , N Boc
Step 1: Preparation of compound 56 from compound 55: Compound 55 (400 mg, 1.44
mmol) was taken in dry DMF and EDC.HC1 (41 1 mg, 2.15 mrnol), HOBT (208 mg, 1.58
mmol) were added under nitrogen and stirred for 30 min at rt. The Compound 6 (294.00 mg,
1.58 mmol) was taken in another round bottom flask and DIPEA (0.530 mL, 2.87 mmol) was
added. Then the second reaction mixture was added to first reaction mixture slowly and
stirred for 12 h at rt. After completion of reaction, the reaction was poured into cool water to
get a ppt of 56, filtered out the ppt and dried. Next step is then proceeded without purification
(41 0 mg, 82%, M+1=447).
Step 2: Preparation of compound 57 from compound 56: The process employed for
conversion of compound 48 from compound 47 may be suitably applied herein to obtain
compound 57.
Step 3: Preparation of compound 58 from compound 57: The process employed for
conversion of compound 9 fiom compound 8 may be suitably applied herein to obtain
compound 58. The crude residue was purified by column chromatography using ethyl acetate
hexane (30-50%) to get the pure product 58 (64%, M+1=670).
Step 4: Preparation of compound 59 from compound 58: Compound 58 (40 mg was taken
in MeOH under nitrogen and Pd(OH)2 (20 mg) was added to it under nitrogen. Then
hydrogen balloon was introduced and stirred at rt for 8 h. After completion of reaction, the
reaction mixture was filtered through celite and the filtrate was combined and the solvent was
evaporated under vacuum to get crude solid. The crude solid was purified by preparative TLC
using 70% ethyl acetate-hexane to get the pure compound 59 (20 mg, 65%, M+1=534).
Step 5: Preparation of compound 10787 from compound 59: The process employed for
conversion of compound 10724 from compound 10 may be suitably applied herein to obtain
compound 10787 (85%, M+1=434), SPR10787.
._J Example 14: Synthesis of Compound 10730
25 %
rt, 2h
3h 62
61 I N H
63
I
10730 66 65
Step 1: Preparation of compound 61 from compound 60: To a stirred solution of 60
(5.00g, 39.37 mmol) in water (50 mL), chloroacetaldehyde (9.27 mL, 59.05 mmol) and
sodium acetate (3.22 g, 39.37 mmol) were added and the reaction mixture was stirred at 80°C
for 2 h. Then the reaction mixture was cooled down to rt and resulting solid was collected by
filtration. The solid product was washed with water and acetone to get the pure product 61
(4.50g, 75% M+1=152).
Step 2: Preparation of compound 62 from compound 61: Compound 61 (5 gm. 33.1 1
mmol) was taken in N, N dimethylaniline (4.18 ml, 99.33 mrnol) and POC13 (35 mL) was
added to it at 0 OC in a seal tube. Then the resulting mixture was heated up to 120 OC for 3 h.,
cooled down to rt. and poured in ice cold water slowly to get a solid compound 62 (4.1 gm,
67%, M+1=187 ). The solid product was used without purification.
Step 3: Preparation of compound 63 from compound 62: The process employed for
conversion of compound 7 from compound 5 may be suitably applied herein to obtain
compound 63 (75%, M+1=338).
Q
Step 4: Preparation of compound 64 from compound 63: The process .--A employed for
conversion of compound 8 from compound 7 may be suitably applied herein to obtain
compound 64.
Step 5: Preparation of compound 65 from compound 64: The process employed for
conversion of compound 9 from compound 8 may be suitably applied herein to obtain
compound 65. The crude residue was purified by column chromatography using ethyl acetate
hexane (30-50%) to get the pure product 65 (80%, M+1=485).
Step 6: Preparation of compound 66 from compound 65: The process employed for
conversion of compound 50 fiom compound 49 may be suitably applied herein to obtain
compound 66. The crude residue was purified by column chromatography using methanol-
DCM (3-5%) to get the pure product 66 (72%, M+1=451).
Step 7: Preparation of compound 10730 from compound 66: The process employed for
conversion of compound 10724 from compound 10 may be suitably applied herein to obtain
compound 10730 (86%, M+1=351), SPR10730.
Example 15: Synthesis of Compound 10738
I I
'f' NBoc NBOC I;H.TFA
NBoc
H
64 u H
Step 1: Preparation of compound 67 from compound 64: The process employed for
conversion of compound 9 from compound 8 may be suitably applied herein to obtain
compound 67(83%, M+ 1 =56 1 ).
C
*- -.e
Step 2: Preparation of compound 68 from compound 67: The process employed for
conversion of compound 50 from compound 49 may be suitably applied herein to obtain
compound 68 (76%, M+1=527).
Ster, 3: Preparation of compound 10738 from compound 68: The process employed for
conversion of compound 10724 from compound 10 may be suitably applied herein to obtain
compound 10738 (88%, M+1=427), SPR10738.
Example 16: Synthesis of Compound 10753
Boc
-H 6
MNP, Et3N,
180°C, 3h
Mw
Boc
25 %
TFA-DCM
I
Preparation of compound 70 from compound 69: compound 69 (100 mg, 0.66 mrnol), boc
piperazine (61 5 mg, 3.3 1 mmol) MNP (2 mL) and triethylamine (0.47 mL, 3.3 lmmol) were
taken in a microwave tube. This reaction mixture was run at 180 O C for 3h in microwave.
After this the reaction mixture was cooled down to rt, poured into water and extracted with
ethyl acetate. The organic layer was dried over Na2S04 and the solvent evaporates to get a
crude residue. The crude residue was purified by column chromatography on silica gel using
50-100 % ethyl acetate-hexane to get the pure product 70 (25 mg, 13%, M+l=303).
Preparation of compound 71 from compound 70: The process employed for conversion of
compound 8 from compound 7 may be suitably applied herein to obtain compound 71.
Preparation of compound 72 from compound 71: The process employed for conversion of
compound 9 from compound 8 may be suitably applied herein to obtain compound 72(72%,
M+1=450).
Preparation of compound 10753 from compound 75: The process employed for
conversion of compound 10724 from compound 10 may be suitably applied herein to obtain
compound 10753 (87%, M+ 1 =350), SPR10753.
*--4 Example 16: Synthesis of Compound 10770
NH4CI, NH40H,
NaOCI, -10 OC QCN w H CH(0Et).
H ___C
NH20H.HCI NaH, DMF
TEA.ACN y4 I
73 NH2
75 76
Y
NHBoc
CI &
I EDC, HOBT,
DIPEA, DCM
(7 HN 6 C--
DCM. rt
POC13,
toluene
120 OC
C--
+ 80 79
Y NHBoc Y
CI *
Preparation of compound 74 from compound 73: To a solution of hydroxyamine
hydrochloride (14.50 g, 210.5 mmol) in ACN, triethyl amine (29.1 mL, 210.5 mrnol) was
added at 0 "C and stirred for 30 min. Then compound 73 (10.00 g, 105.26 mmol) was added
and stirred for another lh. After that phthalic anhydride was added and heated for reflux for
6h. then cooled down to rt. and solvent was removed under vacuum to get solid material. To
this solid material DCM was added and filtered. The combined filtrate was collected and the
solvent was removed under vacuum to get crude product. The crude product was purified by
column chromatography on silica gel using 5-10 % ethyl acetate-hexane to get the pure
product 74 (7.50 g, %, M+1=93).
Preparation of compound 75 from compound 74:
Step1:-Preparation of NH2Cl: Ammonium chloride ( 18 gm) was taken in diethyl ether (600
ml) and cooled down to -5 'C and NH40H ( 28 mL) was added slowly then commercial
bleach (NaOCl, 432mL) was added using dropping funnel (45 min). The reaction mixture
&
was stirred for 15 mill at-5 OC and the organic layer was separated out, washed with brine and
dried over CaC12, and stored at -40 OC.
Step 2: To a solution of compound 74 (6 gm, 65.21 mmol) in DMF, NaH was added slowly
at rt and stirred for 45 min. NH2C1 solution was then added via syringe under nitrogen
atmosphere. After this the reaction mixture was stirred at rt for 4h. and the reaction mixture
was quenched with Na2S203 solution and extracted with ethyl acetate. The organic layer was
dried over Na2S04 and the solvent evaporates to get a pure compound 75 (6.20 gm, M+1=
108).
Preparation of compound 76 from compound 75: Compound 75 (6 gm, 56.07mmol) was
taken in 1L RB, then pre cold KOH aqueous solution (56 gm, 1000 mmol) was added slowly
and stirred for 12h. After this, solid was formed and filtered, dried under vacuum to get the
pure product 76 (6.1 g, M+1=126).
Preparation of compound 77 from compound 76: Compound 76 (1 gm, mmol) was taken
in triethyl ortho formate and head to 90 OC for 6 h. then cooled down to rt and few drops of
(0.5ml) TFA was added and again heated to 80 OC for 1 h. Then the reaction mixture was
cooled down to rt and solid was formed slowly. The solid was filtered out and dried to get
pure product 77 (700 mg, M+1=136).
Preparation of compound 78 from compound 77: Compound 77 (450 gm. 3.30 mmol) was
taken in POC13 (5 mL, 30 mmol) and DIPEA (0.6 ml, 3.3 mmol) was added to it at 0 O C in a
seal tube. Then the resulting mixture was heated to 120 OC for 3 h. and cooled down to rt. and
poured in ice cold water slowly to get a solid compound 78 (gm, M+1=154). The solid
product was used without purification and immediately after synthesis.
Preparation of compound 79 from compound 78: To a stirred solution of 78 (200 mg, 1.3 1
mmol) in DCM, DIPEA (0.361 mL, 1.96 mmol) and Boc piperazine (323 mg, 1.31 'rnmol)
were added and the reaction mixture was stirred at rt for 2 h. The reaction mixture was
diluted with DCM and washed with water. The organic layer was separated out, dried over
Na2S04 and the solvent was evaporated to get a crude residue. The crude residue was
purified by column chromatography using ethyl acetate hexane (10-30%) to get the pure
product 79 (330 mg, M+1=304 ).
f
Preparation of compound 80 from compound 79: The process employed for conversion of '* compound 8 from compound 7 may be suitably applied herein to obtain compound 80.
Preparation of compound 81 from compound 80: The process employed for conversion of
compound 9 from compound 8 may be suitably applied herein to obtain compound 81 (85%,
M+l=528).
Preparation of compound 10770 from compound 81: The process employed for
conversion of compound 10724 from compound 10 may be suitably applied herein to obtain
compound 10770 (92%, M+1=428), SPR10770.
Example 18: Synthesis of Compound 10783
V
Y
/
NBoc
DMF
100 OC
79
Boc
(") NaBHI
N - THF, rt
84 25% I 86 HO'
TFA-DCM
rt, 2h
CI
Preparation of compound 83 from compound 79: Compound 79 (300 mg, 0.90 mmol) was
taken in POC13 (0.946 mL, 9.9 mmol) and DMF (0.346 mL, 4.5 mmol) at 0 OC in a sealed
tube. Then the resulting mixture was heated up to 100 OC for 3 h. and cooled down to rt. and
poured in ice cold water slowly to get a solid compound 83 (200 mg, M+l= 332). The solid
product was used without purification and immediately after synthesis.
',
Preparation of compound 84 from compound 83: Compound 83 (30 mg, 0.12 mmol) was
*--4"
taken in THF and sodium borohydride (14 mg, 0.38 mmol) was added at 0 OC. The reaction
mixture was stirred at rt for 4h. After this, the reaction mixture was diluted with ethyl acetate
and washed with water. The organic layer was separated out, dried over Na2S04 and the
solvent was evaporated to get the compound 84. (20 mg, M+1= 334)
Preparation of compound 85 from compound 84: The process employed for conversion of
compound 8 from compound 7 may be suitably applied herein to obtain compound 85.
Preparation of compound 86 from compound 85: The process employed for conversion of
compound 9 from compound 8 may be suitably applied herein to obtain compound 86 (15
mg, M+1= 557).
Preparation of compound 10783 from compound 86: The process employed for
conversion of compound 10724 from compound 10 may be suitably applied herein to obtain
compound 10783 (10 mg, M+1= 457), SPR10783.
Y NHBoc Y NHBoc
Y NHBoc
Y NHBoc
CI / CI / CI
F
81 88
25% 25% 25%
rt, 2h
v rt, 2h
Preparation of compound 87 from compound 81: Compound 81 (50 mg, 0.095 mmol)
was taken in ACN and selectfluor (33 mg, 0.095 mmol) was added at 0 O C . The reaction
mixture was stirred at rt for 24 h. then solvent was removed under vacuum and ethyl acetate
I 1 was added. The organic layer was washed with water and separated out, dried over Na2S04
! and evaporate the solvent to get the mixture of compound 87, 88 & 89. All the compound
were separated by preparative TLC using 50 % ethyl acetate- hexane (87, 25%, M+1=546;
88,25%, M+1=546; 89,20%, M+1=564).
I Example 19-20: Synthesis of Compounds 10848
Preparation of compound 10848 from compound 87: The process employed for
conversion of compound 10724 from compound 10 may be suitably applied herein to obtain
I compound 10848 (90%, M+ 1 = 446).
4
*.-& Preparation of compound 10844 from compound 88: The process employed for
conversion of compound 10724 from compound 10 may be suitably applied herein to obtain
compound 10844 (92%, M+1=446).
Preparation of compound 10865 from compound 89: The process employed for
conversion of compound 10724 from compound 10 may be suitably applied herein to obtain
compound 10865.

4
I
t We Claim: *..>
1. A compound of general formula [I]
wherein
a=lor 2
X and Y is each independently selected from
X and R2 may be directly attached or attached via a linking group L which may be
selected from an Oxygen atom or a CO group;
Z is H or Alkyl;
wherein
Rj= an alkylene group or an aryl optionally substituted by a halogen;
Rq is a group selected from hydrogen, amine, substituted amine, an amino alkyl group
or
wherein A, B, C, D and E are independently selected from H, -CH2, a heteroatom
such as C, 0 , N or S;
with the proviso that:
ORIGINAL
2 8 JAN 2014
I A, B, C, D, E forms a 5 or 6 membered aromatic ring and at least one of A, B, C, D, E
is Nitrogen;
A B C D E is optionally substituted by one or more groups selected from amino, 0x0,
N-alkyl amino, alkoxy or hydroxyl alkyl group;
G and F are independently selected from the group comprising hydrogen, amino,
alkoxy, hydroxyl-alkyl or an acetamide group or
G and F may be fused to form a 5 membered ring "J";
wherein the Ring J represents pyrrole ring or imidazole ring optionally substituted by
one or more substituents independently selected from H, alkyl, hydroxyalkyl or
halogen.
wherein the valency of fused heterocyclic ring is satisfied by corresponding double
bonds as and where applicable.
I 2. The compound of general formula [I] as claimed in claim 1,
FORMULA I
wherein
a=lor 2
X and Y is each independently selected from C, 0 or N;
X and R2 may be directly attached or attached via a linking group L which may be
selected from an Oxygen atom or a CO group;
52
Z is H or Alkyl;
wherein
Rj= halophenyl, phenyl group or alkylene group;
Rq is a group selected from hydrogen, amine, substituted amine, an amino alkyl group or
-CH2-NH-CH(CH3)2;
X and RZ may be linked directly or indirectly through a linking group L, which may be
selected from an Oxygen atom or a CO group
RZ may be selected from aromatic or non-aromatic heterocyclic mines or fused
heterocyclic amines optionally substituted by one or more groups selected from amines,
substituted amines, alcohol and alkyl groups.
The compound of formula [I] as claimed in claim 1,
FORMULA I
wherein
a=lor 2
Y
T 0 " 3 7 DE&, 1 4 bRiGIi.IA~ 1 eA
4
4+
X and Y is each independently selected from C, o or N; 2 8 JAN 2014
X and R2 may be directly attached or attached via a linking group L which may be
selected from an Oxygen atom or a CO group;
Z is H or Alkyl;
wherein
n=Oto2
R3= chlorophenyl, phenyl or methylene;
Rq is a group selected from hydrogen, amine, isopropylamine , N-methyl amine, N-propyl
amine or -CH2-NH-CH(CH3)2;
X and R2 may be linked directly or indirectly through a linking group L, which may be
selected from an Oxygen atom or a CO group;
selected from an Oxygen atom or a CO group;
R2 may be selected from optionally substituted heterocyclic amines selected from:
4. The compound as claimed in claim 1, wherein the compound is selected from the group
comprising:
i. 2-amino- 1- (4-(2-aminopyrimidin-4-y1)-2-methylpiperazin1-- yl)-3-
phenylpropan- 1 -one
. .
11. 2-amino- 1- (4-(2-aminopyrimidin-4-y1)-3-methylpiperazin1-- yl)-3-
phenylpropan- 1 -one
iii. 2-amino- 1- (4-(4-amino- 1,3,5-triazin-2-y1)piperazin-1 - yl)-3-phenylpropan- 1-
one
iv. 1- (4-(2-aminopyrimidin-4-y1)-2-methylpiperazin1-- yl)-2-(4-chloropheny1)-3-
(isopropylamino)propan- 1 -one
vi. 2-amino- 1 -(4-(2-aminopyrimidin-4-y1)-piperazin- 1 -yl)-3-phenylpropan- 1 -one
vii. 1 -(4-(2-aminopyrimidin-4-y1)piperazin- 1 -yl)-2-(4-chloropheny1)ethanone
viii. 4-(piperazin- 1 -yl)pyrimidin-2-amine
ix. (R)- 1 -(4-(7H-pyrrolo[2,3-dl pyrimidin-4-y1)piperazin- 1 -yl)-2-amino-3-
phenylpropan- 1 -one
xi.
xii.
. . . X111.
xiv.
xv.
xvi.
xvii.
xviii.
xix.
XX.
xxi.
xxii.
xxiii.
xxiv.
xxv.
xxvi.
xxvii.
xxviii.
xxix.
(R)-2-amino- 1- (4-(2-aminopyrimidin-4-y1)piperazin-1 - yl)-3-phenylpropan- 1-
one
(R)- 1- (4-(1H -pyrrolo[2,3-blpyridin-4-y1)piperazin-1 - yl)-2-amino-3-
phenylpropan- 1 -one
2-amino- 1 -(4-(2-(methylamino) pyrimidin-4-y1)piperazin- 1 -yl)-3-
phenylpropan- 1 -one
(R)-N-( 1 -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)-2-amino-3-
phenylpropanamide
,
Y
xxx. 1 -(4-(7,7a-dihydro-4aH-pyrrolo[2,3-d]pyrimidin-4-yloxy)piperidin1- - yl)-2-(4-
a+ chloropheny1)-3-(isopropy1arnino)propan- 1 -one
xxxi. 2-(4-chloropheny1)- 1 -(4-(6-(hydroxymethy1)pyrimidin-4-y1)piperazin- 1 -yl)-3-
(isopropy1amino)propan- 1 -one
xxxii. 2-(4-chloropheny1)-3-(isopropylamino)- 1 -(4-(6-(methy1amino)pyrimidin-4-
y1)-1,4-diazepan-1 -yl)propan- 1 -one
xxxiii. 2-(4-chloropheny1)-3-(isopropy1amino)- 1 -(4-(pyrimidin-4-y1)piperazin- 1 -
y1)propan- 1 -one
xxxiv. N-(6-(4-(2-(4-chloropheny1)-3 -(isopropylamino)propanoyl)piperazin-1-
y1)pyrimidin-4-y1)acetamide
xxxv. 4-(piperidin-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidine
xxxvi. 2-(4-chloropheny1)- 1 -(4-(7-fluoropyrrolo[1,2-f1 [I ,2,4]triazin-4-y1)piperazin- 1 -
yl)-3-(isopropy1amino)propan- 1 -one
xxxvii. 2-(4-chloropheny1)- 1 -(4-(5-fluoropyrrolo[ 1,247[ 1,2,4]triazin-4-y1)piperazin-l -
y1)-3 -(isopropylamino)propan- 1 -one
xxxviii. 2-(4-chloropheny1)- 1 -(4-(2-(hydroxymethyl)morpholino)piperidin- 1 -yl)-3-
(isopropy1amino)propan- 1 -one
xxxix. 2-(4-chlorophenyl)-1-(4-(5,7-difluoropyrrolo[1,2-f1[1,2,4]triazin-4-
y1)piperazin- 1 -yl)-3-(isopropy1amino)propan- 1 -one
xl. 1 -(4-(6-(methy1amino)pyrimidin-4-y1oxy)piperidin- 1 -yl)-2-(4-chloropheny1)-
3-(isopropylamino) propan- 1 -one
xli. 1 -(4-(6-(methylamino)pyrimidin-4-ylamino)piperidin- 1 -yl)-2-(4-
chloropheny1)-3-(isopropylamino)propan- 1 -one
xlii. (R)-2-amino- 1 -(4-(6-(methy1amino)pyrimidin-4-y1)piperazin- 1 -yl)-3-
phenylpropan- 1 -one
xliii. 1 -(4-(2-aminopyridin-4-y1)piperazin- 1 -yl)-2-(4-chloropheny1)-3-
(isopropy1amino)propan- 1 -one
xliv. 1 -(4-(2-aminothiazole-5-carbony1)piperazin1- - yl)-2-(4-chloropheny1)-3-
xlv. 3-(N-isopropyl-N-methylamino)-2-(4-chlorophenyl)-1 -(4-(6-
(methy1amino)pyrimidin-4-y1)piperazin- 1 -yl)propan- 1 -one
5. The compound of claim 1, when present as its stereoisomer or pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.
6. A pharmaceutical composition comprising any compound as claimed in claims 1 to 5.
57
m
i 7
r)
7. The compound as claimed in clgim
1 by inhibition of AKT.
I 8. The compound as claimed in claims 1 to 5 when administered in a dose of 0.01 to
100mgJKg of body weight of the mammal.
Dated, this 27" day of January, 2014.
CHITRA ARVIND
OF RAJESHWART & ASSOCIATE
AGENT FOR THE APPLICANT@)