FIELD OF INVENTION
The present invention is related to the field of synthetic medicinal chemistry. It is
related to an improved process and intermediate(s) for the synthesis of beta
amino acid derivatives of formula I. The compounds of formula I act as DPP-IV
inhibitors and are useful in the treatment of Type 2 diabetes.
BACKGROUND
The following discussion of the prior art is intended to present the invention in an
appropriate technical context and allow its significaFice to be properly appreciated.
Unless clearly indicated to the contrary, however, reference to any prior art in this
specification should be construed as an admission that such art is widely known
or forms part of common general knowledge in the field.
Type 2 diabetes is a progressive, metabolic disorder characterized by two
fundamental defects: insulin resistance at peripheral target tissues and pancreatic
beta-cell dysfunction. Despite good compliance to treatment, the glycaemic
control of type 2 diabetes deteriorates progressively. Hence, new therapeutic
agents are continuously being developed to help our diabetes population. Recent
studies have shown that early intervention at prediabetes state and beta cell
protection with insulin sensitizers may improve the prognosis of diabetes. DPP-IV
inhibitors are a novel class of oral hypoglycemic agent with potentials in improving
pancreatic beta cell function and the clinical course of type 2 diabetes. Dipeptidyl
peptidase IV (DPP-IV) inhibitors, including sitagliptin, vildagliptin, alogliptin, and
saxagliptin, represent a novel approach in the management of type 2 diabetes.
The first DPP-IV inhibitor in the market, Merck's Januvia (Sitagliptin), was
approved by the FDA in October 2006 for use as mono therapy or with
metformins. The next drug in this class, Galvus (Vildagliptin) was approved in
Europe in February 2008 by European Medicines Agency. The EMEA has also
approved a new oral treatment released by Novartis, called Eucreas, a
2
, DUPLICATE
combination of vildagliptin and metformin. Onglyza (Saxagliptin) was approved by
FDA in July 2009. Onglyza has been jointly developed by Bristol-Myers Squibs
(BMS) and Astra Zeneca (AZ). Onglyza has been shown to reduce major adverse
cardiovascular events by as much as 55%. The next in the class, namely
Linagliptin developed by Boehringer lngelheim was approved in May 2011. Other
DPP-IV drugs in pipeline are Alogliptin, SYR-472, Melogliptin, Anagliptin and
Teneligliptin.
Beta-amino acid based DPP-IV inhibitors have been disclosed in PCT
publications, for example, W0-2004043940, W0-2005044195, W0-2006009886,
W0-2006023750, W02006039325, W0-2003004498, W0-2005116029, W0-
2005113510, W0-2006097175, W0-2005120494, W0-2005121131, W0-
2005123685, W0-2005040095 W0-2007063928, W0-2007054577, W0-
2007053819, W0-2006081151, W0-2004085378 and US patents such as US
7,259,160, US 7,101,871 and US 7,208,498.
Since DPP-IV inhibitors have oral route of administration and oral medication
forms the largest segment of therapy among the anti-diabetics, it appears to be a
promising therapy. Hence there still exists a need to provide a simple and
convenient process for the preparation of DPP-IV inhibitors. The present invention
provides an improved, commercially viable and industrially advantageous
processes for the synthesis of beta-amino acid based DPP-IV inhibitors. The
intermediates and the final end products obtained through the improved
processes of this invention are obtained in a superior yield and high purity.
SUMMARY
The present invention is related to a novel process and intermediate (s) for the
synthesis of beta amino acid derivatives of compounds of formula I. The
compounds of the present invention are useful as DPP-IV inhibitors.
In an embodiment, the present invention relates to a process for preparing a
compound of general formula I, their pharmaceutically acceptable derivatives,
3
DUPLICATE
tautomeric forms, stereoisomers including R and S isomers, prodrugs,
metabolites, salts or solvates thereof:
N~Y+~
ft6~n' /'N-R1
R{ h
M
Formula I
wherein,
Ar represents aryl which may be phenyl, which may be unsubstituted or optionally
substituted at any available position by R8 or by one or more substituents
selected from but not limited to halogen, CN, hydroxyl, NH2, C1-12 alkyl or C1-12
alkoxy, wherein each of C1-12 alkoxy and C1-12 alkyl may be linear or branched
and can be unsubstituted or optionally substituted with 1-5 halogens;
R1 is selected from the group consisting of but not limited to (CH2)nCONR3Rb,
(CH2)nCOOR3
, (CH2)nNRaRb, (CH2)nNR3CORb, (CH2)nC(=Y)R3 (wherein Y is 0
or S), (CH2)00R3 (wherein each methylene group may be substituted by one or
more halogen atoms), -(CO)R3
, -(CO)NR3 Rb, hydrogen, C1-12 alkyl, C2-12
alkenyl, C2-12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C2-12 haloalkynyl, C3-a
cycloalkyl, heterocyclyl, aryl, heteroaryl, (CH2)n-cycloalkyl, (CH2)n-heterocyclyl,
(CH2)n-aryl, (CH2)n-heteroaryl, each of which may be optionally substituted at
any available position by one or more substituents selected from but not limited
to hydrogen, halogen, CN, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, Cn2 alkoxy,
Cn2 haloalkyl, Cn2 haloalkoxy, C2-12 haloalkenyl, Cn2 haloalkynyl, C1-12
alkylcarbonyl, Cn2 alkoxycarbonyl, oxo, -OR3
, -SR3
, -N02, -NR3Rb,
N(R3 )(CO)Rb, N(R3)(CO)ORb, N(R3 )(CO)NR3 Rb, -(CO)R3
, -(CO)NR3 Rb, -
O(CO)R3
, -O(CO)NRaRb, -COOR3
, C3_8 cycloalkyl, S(O)mR3
, S02NR3 Rb;
cycloalkyl which may be optionally substituted at any available position by one
or more substituents independently selected from Rc or Rc'; aryl which may be
optionally substituted at any available position by one or more substituents
independently selected from Rc or Rc'; heteroaryl which may be optionally
4
DUPLICATE
substituted at any available position by one or more substituents independently
selected from Rc or Rc'; or heterocyclyl which may be optionally substituted at
any available position by one or more substituents independently selected from
Rc or Rc';
R2 and R3 together represents a single oxygen or sulphur atom which is linked to
the diazepine ring by a double bond; or R1 and R2 together forms a double bond
in the diazepine ring and R3 represents the group -NRaRb; or R1 and R3 together
with the nitrogen atom to which R1 is attached forms a heterocyclic or heteroaryl
ring which may additionally contain from one to three hetero atoms
independently selected from 0, S and N; the ring formed may optionally be
substituted with one or more substituents selected from Rc or Rc' and R2
represent hydrogen or a double bond;
R4 and R5 are independently selected from the group consisting of hydrogen,
halogen, CN, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, C1-12 haloalkyl,
C1-12 haloalkoxy, C2-12 haloalkenyl, C2-12 haloalkynyl, C1-12 alkylcarbonyl, C1-12
alkoxycarbonyl, -ORa, -SRa, -N02. -NRaRb, N(Ra)(CO)Rb, N(Ra)(CO)ORb,
N(Ra)(CO)NRaRb, -(CO)Ra, -(CO)NRaRb, -O(CO)Ra, -O(CO)NRaRb, -COORa, C3-
8 cycloalkyl, S(O)mRa, S02NRaRb; cycloalkyl which may be optionally substituted
at any available position by one or more substituents independently selected
from Rc or Rc'; aryl which may be optionally substituted at any available position
by one or more substituents independently selected from Rc or Rc'; heteroaryl
which may be optionally substituted at any available position by one or more
substituents independently selected from Rc or Rc'; or heterocyclyl which may be
optionally substituted at any available position by one or more substituents
independently selected from Rc or Rc';
R6 and R7 are independently selected from the group consisting of hydrogen,
halogen, CN, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, C1-12 haloalkyl,
C1-12 haloalkoxy, C2-12 haloalkenyl, C2-12 haloalkynyl, C1-12 alkylcarbonyl, C1-12
alkoxycarbonyl, -ORa, -SRa, -N02. -NRaRb, N(Ra)(CO)Rb, N(Ra)(CO)ORb,
N(Ra)(CO)NRaRb, -(CO)Ra, -(CO)NRaRb, -O(CO)Ra, -O(CO)NRaRb, -COORa, C3-
8 cycloalkyl, S(O)mRa, S02NRaRb; cycloalkyl which may be optionally substituted
at any available position by one or more substituents independently selected
5
DUPLICATE
from Rc or Rc'; aryl which may be optionally substituted at any available position
by one or more substituents independently selected from Rc or Rc'; heteroaryl
which may be optionally substituted at any available position by one or more
substituents independently selected from Rc or Rc'; or heterocyclyl which may be
optionally substituted at any available position by one or more substituents
independently selected from Rc or Rc';
R8 is independently selected from hydrogen, halogen, CN, C1-12 alkyl, C1-12
haloalkyl, C1-12 alkoxy, C1-12 haloalkoxy, C2-12 haloalkenyl, C1-12 alkylcarbonyl,
Cn2 alkoxycarbonyl, -ORa, -SRa, -CF3, -OCF3, -N02, -NRaRb, N(Ra)(CO)Rb,
N(Ra)(CO)ORb, N(Ra)(CO)NRaRb, -(CO)Ra, -(CO)NRaRb, -O(CO)Ra,
O(CO)NRaRb, -COORa, C3-6 cycloalkyl, S(O)mRa, S02NRaRb; cycloalkyl which
may be optionally substituted at any available position by one or more
substituents independently selected from Rc or Rc'; aryl which may be optionally
substituted at any available position by one or more substituents independently
selected from Rc or Rc'; heteroaryl which may be optionally substituted at any
available position by one or more substituents independently selected from Rc
or Rc'; or heterocyclyl which may be optionally substituted at any available
position by one or more substituents independently selected from Rc or Rc';
Ra and Rb are independently selected from hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-
12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C2-12 haloalkynyl, C3-a cycloalkyl,
heterocyclyl, aryl, heteroaryl, (CH2)n-cycloalkyl, (CH2)n-heterocyclyl, (CH2)n-aryl,
(CH2)n-heteroaryl; each of which may be optionally substituted with halogen,
hydroxyl, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, C1-12
alkylcarbonyl, C1-12 alkoxycarbonyl, C3-s cycloalkyl, C1-12 haloalkyl, Cn2
haloalkoxy, C2-12 haloalkenyl, aryl, heterocyclyl, heteroaryl, (CH2)n-aryl, (CH2)nheterocyclyl,
(CH2)n-heteroaryl, (CH2)n-cycloalkyl, oxo, -CN, -OR9
, -N02, -
NR9R10
, N(R9)(CO)R10
, N(R9)(CO)OR10, N(R9)(CO)NR9R10
, -C(=L)R9 (wherein L
is 0 or S), -(CO)NR9R10
, -O(CO)R9
, -O(CO)NR9R10, -COOR9
, -SR9
, S(O)mR9
,
S02NR9R10; S03H, NHS02R9
, P(O)R9R10; or Ra and Rb may be joined together
along with the nitrogen atom to which they are attached to form a heterocyclic or
heteroaryl ring which may additionally contain from one to three heteroatoms
independently selected from 0, S and N, the ring formed may optionally be
6
• DUPLICATE
substituted with one or more substituents selected from hydrogen, halogen, C1-
12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C2-12
haloalkynyl, C3-s cycloalkyl, heterocyclyl, aryl, heteroaryl, (CH2)n-cycloalkyl,
(CH2)n-heterocyclyl, (CH2)n-aryl, (CH2)n-heteroaryl, C1-12 alkylcarbonyl, C1-12
alkoxycarbonyl, oxo, CN, -OR9
, -CF3, -OCF3 CH2CF3, CF2CF3, -N02, -NR9R10,
N(R9)(CO)R10, N(R9)(CO)OR10
, N(R9)(CO)NR9R10, -C(=Y)R9 (wherein Y is 0 or
S), -(CO)NR9R10, -O(CO)C1-C12alkyl, -O(CO)NR9R10, -COOR9
, -SR9
, S(O)mR9
,
S02NR9R10; S03H, NHS02R9
, P(O)R9R10; the ring thus formed may further be
fused with 3 to 7 membered unsaturated or saturated ring, which may contain
from one to three heteroatoms independently selected from 0, S or N, the fused
ring may optionally be substituted with one or more substituents Rc or Rc';
Rc or Rc' is independently selected from the group consisting of but not limited to
(1) hydrogen, (2) halogen, (3) C1-12 alkyl which is linear or branched and which
can be unsubstituted or substituted with 1-5 halogens or phenyl, which is
unsubstituted or substituted with 1-5 substituents independently selected from
halogen, CN, OH, R12, OR12, NHS02R12, S02R12, C02H and C02C1-e alkyl
,wherein the co2c1-6 alkyl is linear or branched ; (4) aryl which can be
unsubstituted or substituted with 1-5 substituents independently selected from
halogen, CN, OH, R12, OR12, NHS02R12, S02R12, C02H and C02C1-e alkyl
,wherein the C02C1-e alkyl is linear or branched (5) a 5 or 6 membered
heterocyclyl which may be saturated or unsaturated comprising 1-4 heteroatoms
independently selected from N, Sand 0, the heterocycle being unsubstituted or
substituted with 1-3 substituents independently selected from oxo, OH, halogen,
c1-6 alkyl, and oc1-6 alkyl, wherein the c1-6 alkyl and oc1-6 alkyl are linear or
branched and optionally substituted with 1-5 halogens; (6) (CH2)n-cycloalkyl; (7)
(CH2)n-heterocyclyl, (8) (CH2)n-aryl, (9) (CH2)0-heteroaryl, (10) C1-12
alkylcarbonyl, (11) C1-12 alkoxycarbonyl, (12) CN, (13) -OR9
, (14) -OCF3, (15)N02,
(16) =NOR10, (17) -NR9R10
, (18) N(R9)(CO)R10, (19) N(R9)(CO)OR10, (20)
N(R9)(CO)NR9R10
, -(21) C(=Y)R9 (wherein Y is 0 or S), (22) -(CO)NR9R10, (23)
-O(CO)R9
, (24) -O(CO)NR9R10, (25) -COOR9
, (26) -SR9
, (27) S(O)mR9
, (28)
S02NR9R10; (29) S03H, (30) NHS02R9
, (31) P(O)R9R10, (32} C2-12 alkenyl, (33)
7
DUPLICATE
C2-12 alkynyl, (34) C1-12 haloalkyl, (35) C2-12 haloalkenyl, (36) C2-12 haloalkynyl,
(37) C1-12 alkoxy, (38) C1-12 haloalkoxy, (39) C3-a cycloalkyl, ( 40) heteroaryl;
with a proviso that when R 1 and R3 together with the nitrogen atom to which R 1
is attached forms a heterocyclic or heteroaryl ring which may additionally
contain from one to three hetero atoms independently selected from 0, Sand N
, then Rc or Rc' cannot be C02H.
R9 and R10 are independently selected from hydrogen, C1-12 alkyl, C2-12 alkenyl,
C2_12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C3-a cycloalkyl, heterocyclyl, aryl,
heteroaryl, (CH2)n-cycloalkyl, (CH2)n-heterocyclyl, (CH2)n-aryl, (CH2)n-heteroaryl,
each of which may be optionally substituted with halogen, hydroxyl or C1-6
alkoxy, or R9and R10 may be joined together to form a heterocyclic or heteroaryl
ring which may contain from one to three heteroatoms independently selected
from 0, S and N, which may optionally be substituted with one or more
substituents independently selected from Rc or Rc';
R12 is C1-6 alkyl, which is linear or branched and which is unsubstituted or
substituted with 1-5 groups independently selected from halogen, C02H, and
co2c1-6 alkyl, wherein the co2c1-6 alkyl is linear or branched;
M and L independently represent a hydrogen atom or they may join together to
form a ring,
n' is 0 or 1
m can be 1 or 2;
n can be 1, 2, 3 or 4;
comprising:
a) coupling a compound of Formula II,
wherein
Ar is as defined above; and
NHPG
Ar~COOH
Formula II
8
• DUPLICATE
PG is an amino protecting groups selected from acetyl, trifluoroacetyl,
benzyloxycarbonyl (CBz), t-butoxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl
(Fmoc), 2,2,2-trichloroethyloxycarbonyl, allyloxycarbonyl and the like;
with a compound of Formula Ill or its salt
Formula Ill
wherein R1
, R2
, R3
, R4
, R5
, R6
, R7
, M, Land n' are as defined above;
using 1,1- carbonyl diimidazole, in a solvent and optionally in the presence of a
base;
b) removing the protecting group (PG) from the compound obtained in step (a)
using deprotecting agent; and
c) optionally converting the product obtained in step (b) to a salt.
In another embodiment the present invention relates to a process for preparing
compounds of formula VI or VII, their pharmaceutically acceptable derivatives,
tautomeric forms, stereoisomers including R and S isomers, prodrugs,
metabolites, salts or solvates thereof:
9
DUPLICATE
OR
Formula VI Formula VII
wherein,
Ar represents aryl which may be phenyl, which may be unsubstituted or optionally
substituted at any available position by one or more substituents selected from
but not limited to halogen, CN, hydroxyl, NH2. C1-12 alkyl or C1-12 alkoxy, wherein
each of C1-12 alkoxy and C1-12 alkyl may be linear or branched and can be
unsubstituted or optionally substituted with 1-5 halogens;
R1 is selected from the group consisting of but not limited to (CH2)nCONR8 Rb,
(CH2)nCOOR8
, (CH2)nNR8Rb, (CH2)nNR8CORb, (CH2)nC(=Y)R8 (wherein Y is 0
or S), (CH2)n0R8 (wherein each methylene group may be substituted by one or
more halogen atoms), -(CO)R8
, -(CO)NR8Rb, hydrogen, C1-12 alkyl, C2-12
alkenyl, C2-12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C2-12 haloalkynyl, C3-8
cycloalkyl, heterocyclyl, aryl, heteroaryl, (CH2)n-cycloalkyl, (CH2)n-heterocyclyl,
(CH2)n-aryl, (CH2)n-heteroaryl, each of which may be optionally substituted at
any available position by one or more substituents selected from but not limited
to hydrogen, halogen, CN, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy,
C1-12 haloalkyl, Cr12 haloalkoxy, C2-12 haloalkenyl, C2-12 haloalkynyl, C1-12
alkylcarbonyl, C1-12 alkoxycarbonyl, oxo, -OR8
, -SR8
, -N02, -NR8Rb,
N(R8)(CO)Rb, N(R8 )(CO)ORb, N(R8)(CO)NR8 Rb, -(CO)R8
, -(CO)NR8Rb, -
O(CO)R8
, -O(CO)NR8 Rb, -COOR8
, C3.8 cycloalkyl, S(O)mR8
, S02NR8Rb ;
cycloalkyl which may be optionally substituted at any available position by one
or more substituents independently selected from Rc or Rc'; aryl which may be
10
DUPLICATE
optionally substituted at any available position by one or more substituents
independently selected from Rc or Rc'; heteroaryl which may be optionally
substituted at any available position by one or more substituents independently
selected from Rc or Rc'; or heterocyclyl which may be optionally substituted at
any available position by one or more substituents independently selected from
Rc or Rc';
R2 and R3 together represents a single oxygen or sulphur atom which is linked to
the diazepine ring by a double bond; or R1 and R2 together forms a double bond
in the diazepine ring and R3 represents the group -NRaRb; or R1 and R3 together
with the nitrogen atom to which R1 is attached forms a heterocyclic or heteroaryl
ring which may additionally contain from one to three heteroatoms
independently selected from 0, S and N; the ring formed may optionally be
substituted with one or more substituents selected from Rc or Rc' and R2
represent hydrogen or a double bond;
R4 and R5 are independently selected from the group consisting of hydrogen,
halogen, CN, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, C1-12 haloalkyl,
C1-12 haloalkoxy, C2-12 haloalkenyl, C2-12 haloalkynyl, C1-12 alkylcarbonyl, C1-12
alkoxycarbonyl, -ORa, -SRa, -N02, -NRaRb, N(Ra)(CO)Rb, N(Ra)(CO)ORb,
N(Ra)(CO)NRaRb, -(CO)Ra, -(CO)NRaRb, -O(CO)Ra, -O(CO)NRaRb, -COORa, C3-
s cycloalkyl, S(O)mRa, S02NRaRb; cycloalkyl which may be optionally substituted
at any available position by one or more substituents independently selected
from Rc or Rc·; aryl which may be optionally substituted at any available position
by one or more substituents independently selected from Rc or Rc'; heteroaryl
which may be optionally substituted at any available position by one or more
substituents independently selected from Rc or Rc'; or heterocyclyl which may be
optionally substituted at any available position by one or more substituents
independently selected from Rc or Rc·;
R6 and R7 are independently selected from the group consisting of hydrogen,
halogen, CN, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, C1-12 haloalkyl,
Cr12 haloalkoxy, C2-12 haloalkenyl, C2-12 haloalkynyl, C1-12 alkylcarbonyl, Cr12
alkoxycarbonyl, -ORa, -SRa, -N02, -NRaRb, N(Ra)(CO)Rb, N(Ra)(CO)ORb,
N(Ra)(CO)NRaRb, -(CO)Ra, -(CO)NRaRb, -O(CO)Ra, -O(CO)NRaRb, -COORa, C3-
11
DUPLICATE
8 cycloalkyl, S(O)mRa, S02NRaRb; cycloalkyl which may be optionally substituted
at any available position by one or more substituents independently selected
from Rc or Rc'; aryl which may be optionally substituted at any available position
by one or more substituents independently selected from Rc or Rc'; heteroaryl
which may be optionally substituted at any available position by one or more
substituents independently selected from Rc or Rc'; or heterocyclyl which may be
optionally substituted at any available position by one or more substituents
independently selected from Rc or Rc';
R8 is independently selected from hydrogen, halogen, CN, C1-12 alkyl, C1-12
haloalkyl, C1-12 alkoxy, Cn2 haloalkoxy, C2-12 haloalkenyl, C1-12 alkylcarbonyl,
C1-12 alkoxycarbonyl, -ORa, -SRa, -CF3, -OCF3, -N02, -NRaRb, N(Ra)(CO)Rb,
N(Ra)(CO)ORb, N(Ra)(CO)NRaRb, -(CO)Ra, -(CO)NRaRb, -O(CO)Ra,
O(CO)NRaRb, -COORa, C3-6 cycloalkyl, S(O)mRa, S02NRaRb; cycloalkyl which
may be optionally substituted at any available position by one or more
substituents independently selected from Rc or Rc'; aryl which may be optionally
substituted at any available position by one or more substituents independently
selected from Rc or Rc'; heteroaryl which may be optionally substituted at any
available position by one or more substituents independently selected from Rc
or Rc'; or heterocyclyl which may be optionally substituted at any available
position by one or more substituents independently selected from Rc or Rc';
Ra and Rb are independently selected from hydrogen, C1-12 alkyl, C2-12 alkenyl, C2_
12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C2-12 haloalkynyl, C3-a cycloalkyl,
heterocyclyl, aryl, heteroaryl, (CH2)n-cycloalkyl, (CH2)n-heterocyclyl, (CH2)n-aryl,
(CH2)n-heteroaryl; each of which may be optionally substituted with halogen,
hydroxyl, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, Cn2 alkoxy, Cn2
alkylcarbonyl, Cn2 alkoxycarbonyl, C3-s cycloalkyl, C1-12 haloalkyl, C1-12
haloalkoxy, C2-12 haloalkenyl, aryl, heterocyclyl, heteroaryl, (CH2)n-aryl, (CH2)nheterocyclyl,
(CH2)n-heteroaryl, (CH2)n-cycloalkyl, oxo, -CN, -OR9
, -N02. -
NR9R10
, N(R9)(CO)R10
, N(R9)(CO)OR10, N(R9)(CO)NR9R10, -C(=Y)R9 (wherein Y
is 0 or S), -(CO)NR9R10
, -O(CO)R9
, -O(CO)NR9R10, -COOR9
, -SR9
, S(O)mR9
,
S02NR9R10; S03H, NHS02R9
, P(O)R9R10; or Ra and Rb may be joined together
along with the nitrogen atom to which they are attached to form a heterocyclic or
12
DUPLICATE
heteroaryl ring which may additionally contain from one to three heteroatoms
independently selected from 0, S and N, the ring formed may optionally be
substituted with one or more substituents selected from hydrogen, halogen, C1-
12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C2-12
haloalkynyl, C3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, (CH2)n-cycloalkyl,
(CH2)n-heterocyclyl, (CH2)n-aryl, (CH2)n-heteroaryl, C1-12 alkylcarbonyl, C1-12
alkoxycarbonyl, oxo, CN, -OR9
, -CF3, -OCF3 CH2CF3, CF2CF3, -N02. -NR9R10,
N(R9)(CO)R10, N(R9)(CO)OR10, N(R9)(CO)NR9R10, -C(=Y)R9 (wherein Y is 0 or
S), -(CO)NR9R10, -O(CO)C1-C12alkyl, -O(CO)NR9R10, -COOR9
, -SR9
, S(O)mR9
,
S02NR9R10; S03H, NHS02R9
, P(O)R9R10; the ring thus formed may further be
fused with 3 to 7 membered unsaturated or saturated ring, which may contain
from one to three heteroatoms independently selected from 0, S or N, the fused
ring may optionally be substituted with one or more substituents Rc or Rc';
Rc or Rc' is independently selected from the group consisting of but not limited to
(1) hydrogen, (2) halogen, (3) C1-12 alkyl which is linear or branched and which
can be unsubstituted or substituted with 1-5 halogens or phenyl, which is
unsubstituted or substituted with 1-5 substituents independently selected from
halogen, CN, OH, R12, OR12, NHS02R12, S02R12, C02H and C02C1-a alkyl
,wherein the co2c1-6 alkyl is linear or branched (4) aryl which can be
unsubstituted or substituted with 1-5 substituents independently selected from
halogen, CN, OH, R12, OR12, NHS02R12, S02R12, C02H and C02C1-a alkyl,
wherein the C02C1-a alkyl is linear or branched (5) a 5 or 6 membered
heterocyclyl which may be saturated or unsaturated comprising 1-4 heteroatoms
independently selected from N, Sand 0, the heterocycle being unsubstituted or
substituted with 1-3 substituents independently selected from oxo, OH, halogen,
C1_6 alkyl, and OC1-a alkyl, wherein the C1-e alkyl and OC1-a alkyl are linear or
branched and optionally substituted with 1-5 halogens; (6) (CH2)n-cycloalkyl, (7)
(CH2)n-heterocyclyl, (8) (CH2)n-aryl, (9) (CH2)n-heteroaryl, (10) Cn2
alkylcarbonyl, (11) C1-12 alkoxycarbonyl, (12) CN, (13) -OR9
, (14) -OCF3, (15)N02.
(16) =NOR10
, (17} -NR9R10
, (18) N(R9)(CO)R10
, (19) N(R9)(CO)OR10
, (20)
N(R9)(CO)NR9R10, (21) C(=Y)R9 (wherein Y is 0 or S), (22) -(CO)NR9R10, (23)O(
CO)R9
, (24) -O(CO)NR9R10,(25) -COOR9
, (26) -SR9
, (27) S(O)mR9
, (28)
13
DUPLICATE
S02NR9R10; (29) S03H, (30) NHS02R9
, (31) P(O)R9R10, (32) C2-12 alkenyl, (33)
C2-12 alkynyl, (34) C1-12 haloalkyl, (35) C2-12 haloalkenyl, (36) C2-12 haloalkynyl,
(37) C1-12 alkoxy, (38) C1-12 haloalkoxy, (39) C3-s cycloalkyl, (40) heteroaryl;
with a proviso that when R1 and R3 together with the nitrogen atom to which R1 is
attached form an imidazole ring, Rc or Rc' cannot be C02H.
or
with a proviso that when R1 and R3 together with the nitrogen atom to which R1 is
attached forms a heterocyclic or heteroaryl ring which may additionally contain
from one to three heteroatoms independently selected from 0, S and N, Rc or
Rc' cannot be C02H.
R9 and R10 are independently selected from hydrogen, C1-12 alkyl, C2-12 alkenyl,
C2-12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C3-s cycloalkyl, heterocyclyl, aryl,
heteroaryl, (CH2)n-cycloalkyl, (CH2)n-heterocyclyl, (CH2)n-aryl, (CH2)n-heteroaryl,
each of which may be optionally substituted with halogen, hydroxyl or C1-e
alkoxy, or R9and R10 may be joined together to form a heterocyclic or heteroaryl
ring which may contain from one to three heteroatoms independently selected
from 0, S and N, which may optionally be substituted with one or more
substituents independently selected from Rc or Rc';
R12 is C1-a alkyl, which is linear or branched and which is unsubstituted or
substituted with 1-5 groups independently selected from halogen, C02H, and
C02C1-e alkyl, wherein the C02C1-a alkyl is linear or branched;
X is selected from the group consisting of N and CR 11;
R11 is selected from the group consisting of Rc or Rc';
m can be 1 or 2;
n can be 1, 2, 3 or 4;
r can be 1, 2, 3 or 4.
comprising,
a) coupling a compound of Formula II,
NHPG
Ar~COOH
Formula II
14
DUPLICATE
wherein
Ar is as defined above; and
PG is an amino protecting groups selected from acetyl, trifluoroacetyl,
benzyloxycarbonyl (CBz), t-butoxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl
(Fmoc), 2,2,2-trichloroethyloxycarbonyl, allyloxycarbonyl and the like;
with a compound of Formula VIII or IX or their salts respectively,
OR
Formula IX
wherein R1
, R2
, R3
, R4
, R5
, R6
, R7
, R8
, R11
, X and rare as defined above;
using 1,1- carbonyl diimidazole, in a solvent and optionally in the presence of a base;
b) removing the protecting group (PG) from the compound obtained in step (a) using
deprotecting agents, and
c) optionally converting the product obtained in step (b) to a salt.
In yet another embodiment, the present invention relates to a compound of
formula IV, their pharmaceutically acceptable derivatives, tautomeric forms,
stereoisomers including RandS isomers, prodrugs, metabolites, salts or solvates
thereof:
Formula IV
wherein Ar and PG are as defined above.
15
DUPLICATE
In a preferred embodiment the present invention relates to a compound of formula
V, its pharmaceutically acceptable derivatives, tautomeric forms, stereoisomers
including R and S isomers, prodrugs, metabolites, salts or solvates thereof:
F
Formula V
In a further embodiment, the present invention relates to compounds of formula X,
XI and XII and their pharmaceutically acceptable derivatives, tautomeric forms,
stereoisomers including RandS isomers, prodrugs, metabolites, salts or solvates
thereof:
Formula X
Formula XI
16
DUPLICATE
Formula XII
wherein R1
, R2
, R3
, R4
, R5
, R6
, R7
, R8
, R11
, M, L, X, n', r, Ar and PG are as defined
above.
These and other features, aspects, and advantages of the present subject matter
will become better understood with reference to the following description and
appended claims. This summary is provided to introduce a selection of concepts
in a simplified form. This summary is not intended to limit the scope of the claimed
subject matter.
DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS:
The terms "alkyl", "alkenyl", and "alkynyl" refers to straight or branched 1 to 12
carbon atoms. These groups may further be substituted with one or more
substituents selected from but not limited to, halogen, hydroxyl, oxo, carboxyl,
carboxyalkyl, azido, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkynyl, acyl acyloxy,
aryl, heterocyclyl and heteroaryl.
The term "cycloalkyl" refers to cyclic alkyl groups constituting 3 to 20 carbon
atoms having a single cyclic ring or multiple condensed rings, for example, fused
or spiro systems which may optionally contain one or more olefinic bonds, unless
otherwise constrained by the definition. Such cycloalkyl groups include, by way of
example, single ring structures, for example, cyclopropyl, cyclobutyl,
cyclopentenyl, cyclohexyl, cyclooctyl, and the like, or multiple ring structures, for
example, adamantyl, and bicyclo[2.2.1] heptane, or cyclic alkyl groups to which is
fused an aryl group, for example, indane and the like. Cycloalkyl groups may
17
DUPLICATE
further be substituted with one or more substituents selected from but not limited
to, halogen, hydroxyl, oxo, carboxy, carboxyalkyl, azido, alkenyl, alkynyl, alkoxy,
cycloalkyl, cycloalkynyl, acyl acyloxy, aryl, heterocyclyl, heteroaryl.
The term "alkoxy" denotes the group 0-alkyl wherein alkyl is the same as defined
above.
The term "aralkyl" refers to alkyl-aryl linked through alkyl (wherein alkyl is the
same as defined above) portion and the said alkyl portion contains carbon atoms
from 1-6 and the aryl is as defined herein, after. The examples of aralkyl groups
include benzyl and the like.
The term "aryl" refers to a carbocyclic aromatic group, for example phenyl or
naphthyl ring and the like optionally substituted with one or more substituents
selected from but not limited to, halogen, hydroxyl, alkyl, alkenyl, alkynyl,
cycloalkyl, alkoxy, acyl, aryloxy, CF3, COORd (wherein Rd can be hydrogen, alkyl,
alkenyl, cycloalkyl, aralkyl, heterocyclylalkyl or heteroarylalkyl), cyano, nitro,
carboxy, heterocyclyl, heteroaryl, heterocyclylalkyl or heteroarylalkyl. The aryl
group may optionally be fused with cycloalkyl group, wherein the said cycloalkyl
group may optionally contain heteroatoms selected from 0, N and S.
The term "aryloxy" refers to the group 0- aryl wherein aryl is as defined above.
The term "heteroaryl" refers to an aromatic ring structure or a bicyclic aromatic
group with one or more heteroatom(s) independently selected from N, 0 and Sand
optionally substituted at any available position by substituent( s) selected from but
not limited to halogen, hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, carboxy,
aryl, alkoxy, aralkyl, cyano, nitro, heterocyclyl, or heteroaryl. Examples of heteroaryl
groups include oxazolyl, imidazolyl, pyrrolyl, 1 ,2,3,-triazolyl, 1 ,2,4-triazolyl,
tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridinyl, pyridazinyl,
pyrimidinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl,
benzothiazolyl, benzoxazolyl, and the like.
The term "heterocyclyl" refers to a cyclic, bicyclic or tricyclic cycloalkyl group, fully
or partially unsaturated having 5 to 10 carbon atoms; with one or more
heteroatom(s) independently selected from N, 0 and S, and are optionally benzofused
or fused with heteroaryl of 5-6 ring members; the rings may be optionally
substituted wherein the substituents are selected from but not limited to halogen,
18
DUPLICATE
hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, carboxy, aryl, alkoxy, aralkyl,
cyano, nitro, heterocyclyl, or heteroaryl. Examples of heterocyclyl groups include
but are not limited to oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl,
dihydropyridinyl, dihydroisooxazolyl, dihydrobenzofuryl, azabicyclohexyl,
dihydroindonyl, piperidinyl or piperazinyl.
The term "Heteroarylalkyl" refers to alkyl-heteroaryl group linked through alkyl
portion, wherein the alkyl and heteroalkyl are the same as defined previously.
The term "Heterocyclylalkyl" refers to alkyl-heterocyclyl group linked through alkyl
portion, wherein the alkyl and heterocyclyl are the same as defined previously.
The term "Halogen" refers to fluoro, chloro, bromo or iodo.
The term "Protecting Group" or "PG" refers to a group which is in a modified form
to preclude undesired side reactions at the protected site. The term protecting
group, unless otherwise specified, may be used with groups, for example,
hydroxyl, amino, carboxyl and examples of such groups are found in T.W.
Greene. et al. "Protecting Groups in Organic Synthesis," 3rd Ed, Wiley, New York,
which is incorporated herein by reference. The species of the carboxylic
protecting groups, amino protecting groups or hydroxyl protecting groups
employed are not critical, as long as the derivatised moieties/moiety is/are stable
to conditions of subsequent reactions and can be removed without disrupting the
remainder of the molecule. Examples of suitable hydroxyl and amino protecting
groups include but are not limited to trimethylsilyl, triethylsilyl, onitrobenzyloxycarbonyl,
p-nitrobenzyloxycarbonyl, t-butyldiphenylsilyl, tbutyldimethylsilyl,
acetyl, trifluoroacetyl, benzyloxycarbonyl (CBz), tbutoxycarbonyl
(Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), 2,2,2-
trichloroethyloxycarbonyl, allyloxycarbonyl and the like. Examples of suitable
carboxyl protecting groups are benzhydryl, o-nitrobenzyl, p-nitrobenzyl, 2-
naphthylmethyl, allyl, 2-chloroallyl, benzyl, 2,2,2- trichloroethyl, trimethylsilyl, tbutyldimethylsilyl,
t-butyldiphenylsilyl, 2-(trimethylsilyl)ethyl, phenacyl, pmethoxybenzyl,
acetenyl, p-methoxyphenyl, 4-pyridylmethyl, t-butyl and the like.
The term "therapeutically effective amount" means the amount of a compound
that, when administered to a subject for treating a disease, is sufficient to effect
such treatment for the disease. The "therapeutically effective amount" will vary
19
DUPLICATE
depending on the compound, the disease and its severity, weight, physical
condition and responsiveness of the subject to be treated, among other factors.
A "pharmaceutically acceptable salt" refers to salts prepared from
pharmaceutically acceptable non-toxic bases or acids including inorganic or
organic bases and inorganic or organic acids.
The term "coupling agent" refers to CDI (1, 1' carbonyl diimidazole), EDC [1-
ethyl-3-(3-dimethylaminopropyl) carbodiimide] /HOST ( 1-hydroxybenzotriazole );
DCC (dicyclohexyl carbodiimide), DMAP (4-dimethylaminopyridine); HATU [0-(7-
azabenzotriazole-yi)-N,N, N' ,N' -tetramethyluronium hexafluorophosphate; HOAT
( 1-hydroxy-7 -azabenzotriazole ); BOP [(benzotriazolyl-1-yloxy)-tris( dimethylamine)
phosphonium hexafluorophosphate]; mixed anhydride method using ethyl
chloroformate or methyl chloroformate in a suitable solvent such as DMF, DCM,
acetonitrile, toluene, THF and the like or mixtures thereof and in the presence of a
suitable base such as NMM (N-methylmorpholine), DIPEA (N,Ndiisopropylethylamine),
triethylamine and the like.
The term "amino protecting groups" include but are not limited to acetyl,
trifluoroacetyl, benzyloxycarbonyl (CBz), t-butoxycarbonyl (Soc), 9-
fluorenylmethyloxycarbonyl (Fmoc), 2,2,2-trichloroethyloxycarbonyl,
allyloxycarbonyl and the like. The appropriate conditions for the removal of the
amine protecting groups can be readily selected by those having well known skill
in the art. Examples of reagents used for deprotecting the amine protecting
moiety include but are not limited to use of acidic conditions (trifluoroacetic acid,
hydrochloric acid, phosphoric acid, p-toluenesulphonic acid and the like), basic
conditions (piperidine and the like) or hydrogenation conditions (palladium on
charcoal or platinum and the like).
The present invention is related to a novel process and intermediates useful for
the synthesis of compounds of formula I.
Chemically, compounds of formula I are derivatives of beta-amino acid. They can
be synthesized by many routes. An essential step that would be common in many
feasible routes employed for the synthesis of these compounds is the amide bond
formation. There could be alternate approaches for the amide bond formation.
20
DUPLICATE
One of these approaches is by coupling of two fragments, one fragment
containing carboxylic acid group and the other containing the secondary nitrogen
atom, which can be free or present as a part of a heterocyclic ring, in the
presence of suitable coupling agent.
In an embodiment, the present invention relates to a process for preparing a
compound of general formula I or its pharmaceutically acceptable salts,
Formula I
wherein,
Ar represents aryl which may be phenyl, which may be unsubstituted or optionally
substituted at any available position by R8 or by one or more substituents
selected from but not limited to halogen, CN, hydroxyl, NH2, C1-12 alkyl or C1-12
alkoxy, wherein each of C1-12 alkoxy and C1-12 alkyl may be linear or branched
and can be unsubstituted or optionally substituted with 1-5 halogens;
R1 is selected from the group consisting of but not limited to (CH2)nCONRaRb,
(CH2)nCOORa, (CH2)nNRaRb, (CH2)nNRaCORb, (CH2)nC(=Y)Ra (wherein Y is 0
or S), (CH2)n0Ra (wherein each methylene group may be substituted by one or
more halogen atoms), -(CO)Ra, -(CO)NRaRb, hydrogen, Cn2 alkyl, C2-12
alkenyl, C2-12 alkynyl, Cn2 haloalkyl, C2-12 haloalkenyl, Cn2 haloalkynyl, C3_8
cycloalkyl, heterocyclyl, aryl, heteroaryl, (CH2)n-cycloalkyl, (CH2)n-heterocyclyl,
(CH2)n-aryl, (CH2)n-heteroaryl, each of which may be optionally substituted at
any available position by one or more substituents selected from but not limited
to hydrogen, halogen, CN, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy,
C1-12 haloalkyl, C1-12 haloalkoxy, C2-12 haloalkenyl, C2-12 haloalkynyl, Cr12
alkylcarbonyl, C1-12 alkoxycarbonyl, oxo, -ORa, -SRa, -N02, -NRaRb,
N(Ra)(CO)Rb, N(Ra)(CO)ORb, N(Ra)(CO)NRaRb, -(CO)Ra, -(CO)NRaRb, -
21
DUPLICATE
O(CO)R8
, -O(CO)NRaRb, -COOR8
, C3-a cycloalkyl, S(O)mR8
, S02NR8Rb;
cycloalkyl which may be optionally substituted at any available position by one
or more substituents independently selected from Rc or Rc'; aryl which may be
optionally substituted at any available position by one or more substituents
independently selected from Rc or Rc'; heteroaryl which may be optionally
substituted at any available position by one or more substituents independently
selected from Rc or Rc·; or heterocyclyl which may be optionally substituted at
any available position by one or more substituents independently selected from
Rc or Rc';
R2 and R3 together represents a single oxygen or sulphur atom which is linked to
the diazepine ring by a double bond; or R1 and R2 together forms a double bond
in the diazepine ring and R3 represents the group -NRaRb; or R1 and R3 together
with the nitrogen atom to which R1 is attached forms a heterocyclic or heteroaryl
ring which may additionally contain from one to three hetero atoms
independently selected from 0, S and N; the ring formed may optionally be
substituted with one or more substituents selected from Rc or Rc' and R2
represent hydrogen or a double bond;
R4 and R5 are independently selected from the group consisting of hydrogen,
halogen, CN, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, C1-12 haloalkyl,
C1-12 haloalkoxy, C2-12 haloalkenyl, C2-12 haloalkynyl, C1-12 alkylcarbonyl, C1-12
alkoxycarbonyl, -OR8
, -SR8
, -N02, -NRaRb, N(R8 )(CO)Rb, N(R8 )(CO)ORb,
N(R8)(CO)NR8 Rb, -(CO)R8
, -(CO)NR8 Rb, -O(CO)R8
, -O(CO)NR8Rb, -COOR8
, C3-
8 cycloalkyl, S(O)mR8
, S02NR8Rb; cycloalkyl which may be optionally substituted
at any available position by one or more substituents independently selected
from Rc or Rc'; aryl which may be optionally substituted at any available position
by one or more substituents independently selected from Rc or Rc·; heteroaryl
which may be optionally substituted at any available position by one or more
substituents independently selected from Rc or Rc'; or heterocyclyl which may be
optionally substituted at any available position by one or more substituents
independently selected from Rc or Rc';
R6 and R7 are independently selected from the group consisting of hydrogen,
halogen, CN, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, Cr12 haloalkyl,
22
DUPLICATE
Cr12 haloalkoxy, C2-12 haloalkenyl, C2-12 haloalkynyl, C1-12 alkylcarbonyl, C1-12
alkoxycarbonyl, -ORa, -SRa, -N02, -NRaRb, N(Ra)(CO)Rb, N(Ra)(CO)ORb,
N(Ra)(CO)NRaRb, -(CO)Ra, -(CO)NRaRb, -O(CO)Ra, -O(CO)NRaRb, -COORa, C3-
8 cycloalkyl, S(O)mRa, S02NRaRb; cycloalkyl which may be optionally substituted
at any available position by one or more substituents independently selected
from Rc or Rc'; aryl which may be optionally substituted at any available position
by one or more substituents independently selected from Rc or Rc·; heteroaryl
which may be optionally substituted at any available position by one or more
substituents independently selected from Rc or Rc'; or heterocyclyl which may be
optionally substituted at any available position by one or more substituents
independently selected from Rc or Rc';
R8 is independently selected from hydrogen, halogen, CN, C1-12 alkyl, C1-12
haloalkyl, C1-12 alkoxy, C1-12 haloalkoxy, C2-12 haloalkenyl, C1-12 alkylcarbonyl,
C1-12 alkoxycarbonyl, -ORa, -SRa, -CF3, -OCF3, -N02. -NRaRb, N(Ra)(CO)Rb,
N(Ra)(CO)ORb, N(Ra)(CO)NRaRb, -(CO)Ra, -(CO)NRaRb, -O(CO)Ra,
O(CO)NRaRb, -COORa, C3-6 cycloalkyl, S(O)mRa, S02NRaRb; cycloalkyl which
may be optionally substituted at any available position by one or more
substituents independently selected from Rc or Rc'; aryl which may be optionally
substituted at any available position by one or more substituents independently
selected from Rc or Rc'; heteroaryl which may be optionally substituted at any
available position by one or more substituents independently selected from Rc
or Rc'; or heterocyclyl which may be optionally substituted at any available
position by one or more substituents independently selected from Rc or Rc';
Ra and Rb are independently selected from hydrogen, C1-12 alkyl, C2_12 alkenyl, C2-
12 alkynyl, Cn2 haloalkyl, C2-12 haloalkenyl, C2-12 haloalkynyl, C3-s cycloalkyl,
heterocyclyl, aryl, heteroaryl, (CH2)n-cycloalkyl, (CH2)n-heterocyclyl, (CH2)n-aryl,
(CH2)n-heteroaryl; each of which may be optionally substituted with halogen,
hydroxyl, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, Cr12 alkoxy, Cr12
alkylcarbonyl, C1-12 alkoxycarbonyl, C3-s cycloalkyl, C1-12 haloalkyl, C1-12
haloalkoxy, C2-12 haloalkenyl, aryl, heterocyclyl, heteroaryl, (CH2)n-aryl, (CH2)nheterocyclyl,
(CH2)n-heteroaryl, (CH2)n-cycloalkyl, oxo, -CN, -OR9
, -N02. -
NR9R10
, N(R9)(CO)R10, N(R9)(CO)OR10
, N(R9)(CO)NR9R10
, -C(=L)R9 (wherein L
23
DUPLICATE
is 0 or S), -(CO)NR9R10, -O(CO)R9
, -O(CO)NR9R10
, -COOR9
, -SR9
, S(O)mR9
,
S02NR9R10; S03H, NHS02R9
, P(O)R9R10; or Ra and Rb may be joined together
along with the nitrogen atom to which they are attached to form a heterocyclic or
heteroaryl ring which may additionally contain from one to three heteroatoms
independently selected from 0, S and N, the ring formed may optionally be
substituted with one or more substituents selected from hydrogen, halogen, C1-
12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C2-12
haloalkynyl, C3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, (CH2)n-cycloalkyl,
(CH2)n-heterocyclyl, (CH2)n-aryl, (CH2)n-heteroaryl, C1-12 alkylcarbonyl, Cn2
alkoxycarbonyl, oxo, CN, -OR9
, -CF3, -OCF3 CH2CF3, CF2CF3, -N02. -NR9R10,
N(R9)(CO)R10, N(R9)(CO)OR10, N(R9)(CO)NR9R10, -C(=Y)R9 (wherein Y is 0 or
S), -(CO)NR9R10, -O(CO)C1-C12alkyl, -O(CO)NR9R10
, -COOR9
, -SR9
, S(O)mR9
,
S02NR9R10; S03H, NHS02R9
, P(O)R9R10; the ring thus formed may further be
fused with 3 to 7 membered unsaturated or saturated ring, which may contain
from one to three heteroatoms independently selected from 0, S or N, the fused
ring may optionally be substituted with one or more substituents Rc or Rc';
Rc or Rc' is independently selected from the group consisting of but not limited to
(1) hydrogen, (2) halogen, (3) C1-12 alkyl which is linear or branched and which
can be unsubstituted or substituted with 1-5 halogens or phenyl, which is
unsubstituted or substituted with 1-5 substituents independently selected from
halogen, CN, OH, R12, OR12, NHS02R12, S02R12, C02H and C02C1-e alkyl
,wherein the C02C1-a alkyl is linear or branched; (4) aryl which can be
unsubstituted or substituted with 1-5 substituents independently selected from
halogen, CN, OH, R12, OR12, NHS02R12, S02R12, C02H and C02C1-a alkyl
,wherein the C02C1-a alkyl is linear or branched (5) a 5 or 6 membered
heterocyclyl which may be saturated or unsaturated comprising 1-4 heteroatoms
independently selected from N, Sand 0, the heterocycle being unsubstituted or
substituted with 1-3 substituents independently selected from oxo, OH, halogen,
C1-a alkyl, and OC1-e alkyl, wherein the C1-a alkyl and OC1_6 alkyl are linear or
branched and optionally substituted with 1-5 halogens; (6) (CH2)n-cycloalkyl; (7)
(CH2)n-heterocyclyl, (8) (CH2)n-aryl, (9) (CH2)n-heteroaryl, (10) C1-12
alkylcarbonyl, (11) C1-12 alkoxycarbonyl, (12) CN, (13) -OR9
, (14) -OCF3, (15)-
24
DUPLICATE
N02. (16) =NOR10, (17) -NR9R10, (18) N(R9)(CO)R10, (19) N(R9)(CO)OR10, (20)
N(R9)(CO)NR9R10, -(21) C(=Y)R9 (wherein Y is 0 or S), (22) -(CO)NR9R10, (23)
-O(CO)R9
, (24) -O(CO)NR9R10,(25) -COOR9
, (26) -SR9
, (27) S(O)mR9
, (28)
S02NR9R10; (29) S03H, (30) NHS02R9
, (31) P(O)R9R10, (32) C2.12 alkenyl, (33)
C2-12 alkynyl, (34) C1-12 haloalkyl, (35) C2-12 haloalkenyl, (36) C2-12 haloalkynyl,
(37) C1-12 alkoxy, (38) C1-12 haloalk'oxy, (39) C3-s cycloalkyl, (40) heteroaryl;
with a proviso that when R1 and R3 together with the nitrogen atom to which R1 is
attached forms a heterocyclic or heteroaryl ring which may additionally contain
from one to three hetero atoms independently selected from 0, S and N, then
Rc or Rc' cannot be C02H.
R9 and R10 are independently selected from hydrogen, C1-12 alkyl, C2-12 alkenyl,
C2-12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C3-a cycloalkyl, heterocyclyl, aryl,
heteroaryl, (CH2)n-cycloalkyl, (CH2)n-heterocyclyl, (CH2)n-aryl, (CH2)n-heteroaryl,
each of which may be optionally substituted with halogen, hydroxyl or C1-e
alkoxy, or R9and R10 may be joined together to form a heterocyclic or heteroaryl
ring which may contain from one to three heteroatoms independently selected
from 0, S and N, which may optionally be substituted with one or more
substituents independently selected from Rc or Rc·;
R12 is C1-e alkyl, which is linear or branched and which is unsubstituted or
substituted with 1-5 groups independently selected from halogen, C02H, and
co2c1-6 alkyl, wherein the co2c1-6 alkyl is linear or branched;
M and L independently represent a hydrogen atom or they may join together to
form a ring;
n' is 0 or 1
m can be 1 or 2;
n can be 1, 2, 3 or 4;
comprising:
a) coupling a compound of Formula II,
NHPG
Ar~COOH
Formula II
25
DUPLICATE
wherein
Ar is as defined above; and
PG is an amino protecting groups selected from acetyl, trifluoroacetyl,
benzyloxycarbonyl (CBz), t-butoxycarbonyl (Boc), 9-fluorenylmethyloxy carbonyl
(Fmoc), 2,2,2-trichloroethyloxycarbonyl, allyloxycarbonyl and the like;
with a compound of Formula Ill or its salt
Formula Ill
wherein R1
, R2
, R3
, R4
, R5
, R6
, R7
, M, Land n' are as defined above;
using 1, 1- carbonyl diimidazole, in a solvent and optionally in the presence of a
base;
b) removing the protecting group (PG) from the compound obtained in step (a)
using a deprotecting agent; and
c) optionally converting the product obtained in step (b) to a salt.
Examples of solvent (s) that can be used in the present invention can be selected
form the group comprising Dimethylfomamide (DMF), Dimethyl acetamide
(DMAc), Dichloromethane (DCM), acetonitrile (ACN) , toluene, tetrahydrofuran
(THF) or mixtures thereof.
In a preferred embodiment, the solvent is acetonitrile and I or Dimethylformamide.
Examples of base (s) that can be used in the present invention can be selected
form the group comprising N-methylmorpholine (NMM), N,Ndiisopropylethylamine
(DIPEA) and triethylamine (TEA) or mixtures thereof.
In a preferred embodiment, the base is N,N-diisopropylethylamine.
Examples of deprotecting agent that can be used in the present invention can be
selected form the group comprising trifluoroacetic acid, hydrochloric acid,
26
DUPLICATE
phosphoric acid, p-toluenesulphonic acid, piperidine, palladium on charcoal and
platinum.
In a preferred embodiment, the deprotecting agent is hydrochloric acid.
The process steps of the present invention can be carried out without the need for
isolating the intermediates.
In another embodiment the present invention relates to a process for preparing
compounds of formula VI or VII, their pharmaceutically acceptable derivatives,
tautomeric forms, stereoisomers including R and S isomers, prodrugs,
metabolites, salts or solvates thereof:
OR
Formula VI Formula VII
wherein,
Ar represents aryl which may be phenyl, which may be unsubstituted or optionally
substituted at any available position by one or more substituents selected from
but not limited to halogen, CN, hydroxyl, NH2, C1-12 alkyl or C1-12 alkoxy, wherein
each of C1-12 alkoxy and C1-12 alkyl may be linear or branched and can be
unsubstituted or optionally substituted with 1-5 halogens;
R1 is selected from the group consisting of but not limited to (CH2)nCONR8 Rb,
(CH2)nCOOR8
, (CH2)nNR8 Rb, (CH2)nNR8CORb, (CH2)nC(=Y)R8 (wherein Y is 0
or S), (CH2)n0R8 (wherein each methylene group may be substituted by one or
27
DUPLICATE
more halogen atoms), -(CO)Ra, -(CO)NRaRb, hydrogen, C1-12 alkyl, C2.12
alkenyl, C2-12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C2-12 haloalkynyl, C3-s
cycloalkyl, heterocyclyl, aryl, heteroaryl, (CH2)n-cycloalkyl, (CH2)n-heterocyclyl,
(CH2)n-aryl, (CH2)n-heteroaryl, each of which may be optionally substituted at
any available position by one or more substituents selected from but not limited
to hydrogen, halogen, CN, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy,
C1-12 haloalkyl, C1-12 haloalkoxy, C2-12 haloalkenyl, C2-12 haloalkynyl, C1-12
alkylcarbonyl, C1-12 alkoxycarbonyl, oxo, -ORa, -SRa, -N02, -NRaRb,
N(RaXCO)Rb, N(Ra)(CO)ORb, N(Ra)(CO)NRaRb, -(CO)Ra, -(CO)NRaRb, -
O(CO)Ra, -O(CO)NRaRb, -COORa, C3-a cycloalkyl, S(O)mRa, S02NRaRb;
cycloalkyl which may be optionally substituted at any available position by one
or more substituents independently selected from Rc or Rc'; aryl which may be
optionally substituted at any available position by one or more substituents
independently selected from Rc or Rc'; heteroaryl which may be optionally
substituted at any available position by one or more substituents independently
selected from Rc or Rc'; or heterocyclyl which may be optionally substituted at
any available position by one or more substituents independently selected from
Rc or Rc';
R2 and R3 together represents a single oxygen or sulphur atom which is linked to
the diazepine ring by a double bond; or R1 and R2 together forms a double bond
in the diazepine ring and R3 represents the group -NRaRb; or R1 and R3 together
with the nitrogen atom to which R1 is attached forms a heterocyclic or heteroaryl
ring which may additionally contain from one to three heteroatoms
independently selected from 0, S and N; the ring formed may optionally be
substituted with one or more substituents selected from Rc or Rc· and R2
represent hydrogen or a double bond;
R4 and R5 are independently selected from the group consisting of hydrogen,
halogen, CN, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, C1-12 haloalkyl,
Cr12 haloalkoxy, C2-12 haloalkenyl, C2-12 haloalkynyl, Cr12 alkylcarbonyl, C1-12
alkoxycarbonyl, -ORa, -SRa, -N02. -NRaRb, N(Ra)(CO)Rb, N(Ra)(CO)ORb,
N(Ra)(CO)NRaRb, -(CO)Ra, -(CO)NRaRb, -O(CO)Ra, -O(CO)NRaRb, -COORa, C3-
s cycloalkyl, S(O)mRa, S02NRaRb; cycloalkyl which may be optionally substituted
28
DUPLICATE
at any available position by one or more substituents independently selected
from Rc or Rc'; aryl which may be optionally substituted at any available position
by one or more substituents independently selected from Rc or Rc'; heteroaryl
which may be optionally substituted at any available position by one or more
substituents independently selected from Rc or Rc'; or heterocyclyl which may be
optionally substituted at any available position by one or more substituents
independently selected from Rc or Rc';
R6 and R7 are independently selected from the group consisting of hydrogen,
halogen, CN, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, Cn2 alkoxy, C1-12 haloalkyl,
C1-12 haloalkoxy, C2-12 haloalkenyl, C2-12 haloalkynyl, C1-12 alkylcarbonyl, C1-12
alkoxycarbonyl, -OR8
, -SR8
, -N02, -NR8 Rb, N(R8 )(CO)Rb, N(R8 )(CO)ORb,
N(R8)(CO)NR8 Rb, -(CO)R8
, -(CO)NR8Rb, -O(CO)R8
, -O(CO)NR8Rb, -COOR8
, C3-
a cycloalkyl, S(O)mR8
, S02NR8Rb; cycloalkyl which may be optionally substituted
at any available position by one or more substituents independently selected
from Rc or Rc'; aryl which may be optionally substituted at any available position
by one or more substituents independently selected from Rc or Rc'; heteroaryl
which may be optionally substituted at any available position by one or more
substituents independently selected from Rc or Rc'; or heterocyclyl which may be
optionally substituted at any available position by one or more substituents
independently selected from Rc or Rc';
R8 is independently selected from hydrogen, halogen, CN, C1-12 alkyl, C1-12
haloalkyl, C1-12 alkoxy, C1-12 haloalkoxy, C2-12 haloalkenyl, C1-12 alkylcarbonyl,
C1-12 alkoxycarbonyl, -OR8
, -SR8
, -CF3, -OCF3, -N02, -NR8 Rb, N{R8 ){CO)Rb,
N(R8 )(CO)ORb, N(R8)(CO)NR8 Rb, -(CO)R8
, -(CO)NR8 Rb, -O(CO)R8
,
O(CO)NR8 Rb, -COOR8
, C3•6 cycloalkyl, S(O)mR8
, S02NR8 Rb; cycloalkyl which
may be optionally substituted at any available position by one or more
substituents independently selected from Rc or Rc'; aryl which may be optionally
substituted at any available position by one or more substituents independently
selected from Rc or Rc'; heteroaryl which may be optionally substituted at any
available position by one or more substituents independently selected from Rc
or Rc'; or heterocyclyl which may be optionally substituted at any available
position by one or more substituents independently selected from Rc or Rc';
29
DUPLICATE
R8 and Rb are independently selected from hydrogen, Cr12 alkyl, C2-12 alkenyl, C2-
12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C2-12 haloalkynyl, C3-s cycloalkyl,
heterocyclyl, aryl, heteroaryl, (CH2)n-cycloalkyl, (CH2)n-heterocyclyl, (CH2)n-aryl,
(CH2)n-heteroaryl; each of which may be optionally substituted with halogen,
hydroxyl, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, C1-12
alkylcarbonyl, C1-12 alkoxycarbonyl, C3-s cycloalkyl, C1-12 haloalkyl, C1-12
haloalkoxy, C2-12 haloalkenyl, aryl, heterocyclyl, heteroaryl, (CH2)n-aryl, (CH2)nheterocyclyl,
(CH2)n-heteroaryl, (CH2)n-cycloalkyl, oxo, -CN, -OR9
, -N02, -
NR9R10, N(R9)(CO)R10, N(R9XCO)OR10, N(R9)(CO)NR9R10, -C(=Y)R9 (wherein Y
is 0 or S), -(CO)NR9R10, -O(CO)R9
, -O(CO)NR9R10, -COOR9
, -SR9
, S(O)mR9
,
S02NR9R10; S03H, NHS02R9
, P(O)R9R10; or Ra and Rb may be joined together
along with the nitrogen atom to which they are attached to form a heterocyclic or
heteroaryl ring which may additionally contain from one to three heteroatoms
independently selected from 0, S and N, the ring formed may optionally be
substituted with one or more substituents selected from hydrogen, halogen, C1-
12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C2-12
haloalkynyl, C3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, (CH2)n-cycloalkyl,
(CH2)n-heterocyclyl, (CH2)n-aryl, (CH2)n-heteroaryl, C1-12 alkylcarbonyl, C1-12
alkoxycarbonyl, oxo, CN, -OR9
, -CF3, -OCF3 CH2CF3, CF2CF3, -N02, -NR9R10,
N(R9)(CO)R10
, N(R9)(CO)OR10, N(R9)(CO)NR9R10, -C(=Y)R9 (wherein Y is 0 or
S), -(CO)NR9R10, -O(CO)C1-C12alkyl, -O(CO)NR9R10, -COOR9
, -SR9
, S(O)mR9
,
S02NR9R10; S03H, NHS02R9
, P(O)R9R10; the ring thus formed may further be
fused with 3 to 7 membered unsaturated or saturated ring, which may contain
from one to three heteroatoms independently selected from 0, S or N, the fused
ring may optionally be substituted with one or more substituents Rc or Rc';
Rc or Rc' is independently selected from the group consisting of but not limited to
(1) hydrogen, (2) halogen, (3) C1-12 alkyl which is linear or branched and which
can be unsubstituted or substituted with 1-5 halogens or phenyl, which is
unsubstituted or substituted with 1-5 substituents independently selected from
halogen, CN, OH, R12, OR12, NHS02R12, S02R12, C02H and C02C1-e alkyl
,wherein the C02C1-e alkyl is linear or branched (4) aryl which can be
unsubstituted or substituted with 1-5 substituents independently selected from
30
DUPLICATE
halogen, CN, OH, R12, OR12, NHS02R12, S02R12, C02H and C02C1-e alkyl,
wherein the C02C1-e alkyl is linear or branched (5) a 5 or 6 membered
heterocyclyl which may be saturated or unsaturated comprising 1-4 heteroatoms
independently selected from N, Sand 0, the heterocycle being unsubstituted or
substituted with 1-3 substituents independently selected from oxo, OH, halogen,
C1_6 alkyl, and OC1-e alkyl, wherein the C1-e alkyl and OC1-e alkyl are linear or
branched and optionally substituted with 1-5 halogens; (6) (CH2)n-cycloalkyl, (7)
(CH2)n-heterocyclyl, (8) (CH2)n-aryl, (9) (CH2)n-heteroaryl, (10) C1-12
alkylcarbonyl, (11) C1-12 alkoxycarbonyl, (12) CN, (13) -OR9
, (14) -OCF3, (15)N02,
(16) =NOR10, (17) -NR9R10, (18) N(R9)(CO)R10, (19) N(R9)(CO)OR10, (20)
N(R9)(CO)NR9R10, (21) C(=Y)R9 (wherein Y is 0 or S), (22) -(CO)NR9R10, (23)O(
CO)R9
, (24) -O(CO)NR9R10,(25) -COOR9
, (26) -SR9
, (27) S(O)mR9
, (28)
S02NR9R10; (29) S03H, (30) NHS02R9
, (31) P(O)R9R10, (32) C2-12 alkenyl, (33)
C2-12 alkynyl, (34) C1-12 haloalkyl, (35) C2-12 haloalkenyl, (36) C2-12 haloalkynyl,
(37) C1-12 alkoxy, (38) C1-12 haloalkoxy, (39) C3-s cycloalkyl, (40) heteroaryl;
with a proviso that when R1 and R3 together with the nitrogen atom to which R1 is
attached form an imidazole ring, Rc or Rc' cannot be C02H.
or
with a proviso that when R1 and R3 together with the nitrogen atom to which R1 is
attached forms a heterocyclic or heteroaryl ring which may additionally contain
from one to three heteroatoms independently selected from 0, S and N, Rc or
Rc' cannot be C02H.
R9 and R10 are independently selected from hydrogen, C1-12 alkyl, C2-12 alkenyl,
C2-12 alkynyl, Cn2 haloalkyl, C2-12 haloalkenyl, C3-s cycloalkyl, heterocyclyl, aryl,
heteroaryl, (CH2)n-cycloalkyl, (CH2)n-heterocyclyl, (CH2)n-aryl, (CH2)n-heteroaryl,
each of which may be optionally substituted with halogen, hydroxyl or Cr6
alkoxy, or R9and R10 may be joined together to form a heterocyclic or heteroaryl
ring which may contain from one to three heteroatoms independently selected
from 0, S and N, which may optionally be substituted with one or more
substituents independently selected from Rc or Rc';
31
DUPLICATE
R12 is C1-6 alkyl, which is linear or branched and which is unsubstituted or
substituted with 1-5 groups independently selected from halogen, C02H, and
co2c1-6 alkyl, wherein the co2c 1-6 alkyl is linear or branched;
X is selected from the group consisting of Nand CR11
;
R11 is selected from the group consisting of Rc or Rc';
m can be 1 or 2;
n can be 1, 2, 3 or 4;
r can be 1, 2, 3 or 4.
comprising,
a) coupling a compound of Formula II,
wherein
Ar is as defined above; and
NHPG
Ar~COOH
Formula II
PG is an amino protecting groups selected from acetyl, trifluoroacetyl,
benzyloxycarbonyl (CBz), t-butoxycarbonyl (Soc), 9-fluorenylmethyloxycarbonyl
(Fmoc), 2,2,2-trichloroethyloxycarbonyl, allyloxycarbonyl and the like;
with a compound of Formula VIII or IX or their salts respectively,
OR
Formula IX
wherein R\ R2
, R3
, R4
, R5
, R6
, R7
, R8
, R11
, X and rare as defined above;
using 1,1- carbonyl diimidazole, in a solvent and optionally in the presence of a base;
b) removing the protecting group (PG) from the compound obtained in step (a) using
deprotecting agents, and
32
• DUPLICATE
c) optionally converting the product obtained in step (b) to a salt.
Examples of solvent (s) that can be used in the present invention can be selected
form the group comprising Dimethylfomamide (DMF), Dimethyl acetamide
(DMAc), Dichloromethane (DCM), acetonitrile (ACN) , toluene, tetrahydrofuran
(THF) or mixtures thereof.
In a preferred embodiment, the solvent is acetonitrile and/or Dimethylformamide.
Examples of base (s) that can be used in the present invention can be selected
form the group comprising N-methylmorpholine (NMM), N,Ndiisopropylethylamine
(DIPEA) and triethylamine (TEA) or mixtures thereof.
In a preferred embodiment, the base is N,N-diisopropylethylamine.
Examples of deprotecting agent that can be used in the present invention can be
selected form the group comprising trifluoroacetic acid, hydrochloric acid,
phosphoric acid, p-toluenesulphonic acid, piperidine, palladium on charcoal and
platinum.
In a preferred embodiment, the deprotecting agent is hydrochloric acid.
The process steps of the present invention can be carried out without the need for
isolating the intermediates.
In yet another embodiment the present invention relates to a compound of
formula IV, their pharmaceutically acceptable derivatives, tautomeric forms,
stereoisomers including R and S isomers, prodrugs, metabolites, salts or solvates
thereof:
Formula IV
wherein, Ar and PG are as defined above.
The compound of formula IV is formed as an intermediate in the process of the
present invention. The compound of formula IV is formed as a result of the
33
DUPLICATE
reaction between the compound of formula II with 1, 1-carbonyldinidazole, which is
then reacted with the compound of formula Ill or VIII or IX. This said intermediate
compound can be optionally isolated or can be used in-situ during the progression
of the process.
In a preferred embodiment, the present invention relates to a compound of
formula V, its pharmaceutically acceptable derivatives, tautomeric forms,
stereoisomers including R and S isomers, prodrugs, metabolites, salts or solvates
thereof:
Formula V
The compound of formula IV and V can exist in the various physical forms say
amorphous and crystalline form and also in the form of a single diastereoisomer,
racemate, racemic mixture or diastereoisomeric mixture, all of which fall within the
scope of compound of Formula IV in accordance with the present invention. The
racemic mixtures can be resolved if desired at appropriate stages by methods
known to those skilled in the art such as crystallization, chromatography, salt
formation or enzymatic resolution to obtain the respective individual enantiomers.
In a further embodiment, the present invention relates to compounds of formula X,
XI and XII and their pharmaceutically acceptable derivatives, tautomeric forms,
stereoisomers including R and S isomers, prodrugs, metabolites, salts or solvates
thereof:
34
DUPLICATE
Formula X
Formula XI
Formula XII
wherein R1
, R2
, R3
, R4
, R5
, R6
, R7
, R8
, R11
, M, L, X, n', r, Ar and PG are as defined
above.
The compound of formula X, XI and XII are formed by the reaction of the
intermediate compound of formula IV with compound of formula Ill, VIII and IX
respectively.
35
DUPLICATE
EXAMPLES
The invention is explained in detail in the following examples which are given solely
for the purpose of illustration only and therefore should not be construed to limit the
scope of the invention. All of the starting materials are either commercially available
or can be prepared by procedures that would be well known to one of ordinary skill
in organic chemistry.
Solvents were dried prior to use wherever necessary by standard methods
(Perrin, D.O.; Armarego, W.L.F. Purification of Laboratory Chemicals, Pergamon
Press: Oxford, 1988). Mass spectra (MS) were obtained by electron spray
ionization (ESI) eV using Applied biosystem 4000 Q TRAP. 1H NMR were
recorded on Bruker 400 MHz Avance II NMR spectrometer. Chemical shifts are
reported as o values in parts per million (ppm), relative to TMS as internal
standard. All coupling constants (J) values are given in Hz.
ABBREVIATIONS
The following abbreviations are employed in the examples and elsewhere herein:
H NMR Proton nuclear magnetic resonance
BOP (benzotriazolyl-1-yloxy)-tris( dimethylamine )phosphonium hexafluoro
phosphate
c centigrade
DCM dichloromethane
DIPEA diisopropylethylamine
DMF dimethylformamide
DMSO dimethylsulfoxide
EDC N-(3-dimethylaminopropyi)-N-ethylcarbodiiimide hydrochloride
ESIMS electron spray ionization mass Spectroscopy
g gram(s)
h hour(s)
HOST 1-hydroxybenzotriazole
HPLC High performance liquid chromatography
36
~
DUPLICATE
Hz Hertz
IPA Isopropyl alcohol
J coupling constant
m multiplet
mg milligram
min minutes
ml milliliter
mmol millimoles
mp melting point
NaHC03 sodium bicarbonate
NMR Nuclear magnetic resonance
PG Protecting Group
ppm parts per million
r. t. room temperature
s singlet
THF tetrahydrofuran
Example-1: Synthesis of tert-butyl (R)-1-(2,4,5-trifluorophenyl)-4-(1 H-im idazol-1-
yl)-4-oxobutan-2-ylcarbamate (compound of Formula V)
To a solution of (R)-3-[(tert-butyloxycarbonyl)amino]-4-(2,4,5-trifluoro phenyl)-
butanoic acid (1 g, 0.003 mol) (synthesized in accordance with the p
given in W0-2009093269, which is incorporated in its entirety h
reference) in acetonitrile (20 ml), was added N,N-Diisopropylethylamine
0.010 mol) and 1, 1-Carbonyl diimidazole (0.73 g, 0.004 mol) at room tern
The reaction mixture was stirred for 1 h at 40°C. After completion of the
water (25 ml) was added and extracted twice with ethyl acetate (2 x 50
combined ethyl acetate layers was evaporated to obtain 0.54 gm of tert-
1-(2,4,5-trifluorophenyl)-4-(1 H-imidazol-1-yl)-4-oxobutan-2-ylcarbamate a
rocedure
erein by
(1.4 ml,
perature.
reaction
ml). The
butyl (R)-
solid.
1H NMR (400 MHz, DMSO-d6): 5 8.39 (d,J =15Hz, 1 H), 7.69-7.63 (m, 1
7.43 (m, 1 H) 7.39-7.32 (m, 1 H), 7.06 (s, 1 H), 6.91 (d, J = 9.6 Hz,
37
sa white
H), 7.49-
1H, D20
i
DUPLICATE
exchangeable), 4.16 (m, 1H), 3.18-3.16 (m, 1H), 2.93-2.88 (m, 1H), 2.70-2.65 (m,
1H), 1.18 (s, 9 H).
ESIMS (m/z): 384.8 (M+1)
Example 2: Synthesis of Hydrochloric acid salt of (2R)-4-oxo-(3-trifluoromethyl)-
5, 6-dihyd ro-[ 1 ,2,4]triazolo[ 4,3-a]pyrazin-7 ( 8H )-yl]-1-( 2,4, 5-trifluoro-phenyl)butan-
2-amine (Sitagliptin hydrochloride)
To a solution of (R)-3-[(tert-butyloxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic
acid (1.36 g, 4.080 mmol) in acetonitrile (20 ml) was added
Diisopropylethylamine (2.47 g, 19.12 mmol) and 1,1-Carbonyl diimidazole (0.94 g,
5.82 mmol) at room temperature. The reaction mixture was stirred for 30 min at
room temperature. 3-(Trifluoromethyl)-5,6, 7,8-tetrahydro-1 ,2,3-triazolo[4,3-
a]pyrazine (0.750 g, 3.88 mmol) was added to the above reaction mixture at room
temperature. The reaction mixture was heated to 65-70°C for 22 h. After
completion of the reaction, the mixture was concentrated under vacuum and the
crude mass was dissolved in ethyl acetate (15 ml) and washed with 5% aqueous
NaHC03 solution followed by twice with water (2 x 30 ml). The ethyl acetate layer
was concentrated under reduced pressure to get crude mass and recrystallized
from mixture of 10% ethyl acetate and petroleum ether (50 ml) to get 1.5 g (82%)
of tert-butyl{( 1 R)-3-oxo-1-(2,4,5-trifluorobenzyl)-3-[3-(trifluoromethyl)-5-6-
dihydro[1 ,2,4] triazole[4,3-a]pyrazin-7(8H)-yl]propyl}carbamate.
The above obtained solid was treated with Hydrochloric acid to get Hydrochloric
acid salt of (2R)-4-oxo-(3-trifluoromethyl)-5,6-dihydro-[1 ,2,4]triazolo[4,3-a]pyrazin-
7(8H)-yl]-1-(2,4,5-trifluoro-phenyl)butan-2-amine (Sitagliptin Hydrochloride).
The process can be represented schematically as given below:
38
" DUPLICATE
y y
F oyo F oyo F NH 0 HN~N, F NH 0 ~N~N ...
OH N~N,
F CF1
F ~N'{N
! CF3
F
Example 3: Synthesis of Hydrochloric acid salt of 4-[(R)-3-amino-4-(2,4,5-
trifluorophenyl)-butyryl]-1 ,3,4,5-tetrahydro-benzo[e][1 ,4]diazipin-2-one.
To a solution of (R)-3-[(tert-butyloxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic
acid (0.927 g, 2.78 mmol) in acetonitrile (15 ml) was added
Diisopropylethylamine (2.84 g, 22.02 mmol) and 1, 1-Carbonyl diimidazole (0.615
g, 3.797 mmol) at room temperature. The reaction mixture was stirred for 30 min
at room temperature. 1 ,3,4,5-Tetrahydro-benzo[e][1 ,4]diazepin-2-one
hydrochloride (0.5 g, 2.531 mmol) (synthesized in accordance with the procedure
given in W0-2009093269, which is incorporated in its entirety herein by
reference) was added to the above reaction mixture at room temperature. The
reaction mixture was heated to 65-70°C for 22 h. After completion of the reaction,
the mixture was concentrated under vacuum and the crude mass was dissolved in
ethyl acetate (15 ml) and washed twice with water (2 x 30 ml). The ethyl acetate
layer was concentrated under reduced pressure to get crude mass and was
purified by column chromatography using mixture of 2% methanol in
dichloromethane (500 ml) to get 0.679 g (65%) of [(R)-3-oxo-3-(2-oxo-1 ,2,3,5-
tetrahydro-benzo[ e ][ 1 ,4]d iazepi n-4-yl )-1-( 2 ,4, 5-trifluoro-benzyl )-propyl]-carbam ic
acid tert-butyl ester.
39
DUPLICATE
The above obtained solid was treated with Hydrochloric acid to get the
Hydrochloric acid salt of (R)-4-[3-amino-4-(2,4,5-trifluorophenyl)-butyryl]-1 ,3,4,5-
tetrahydro-benzo[e][1 ,4]diazipin-2-one.
Example 4: Synthesis of Hydrochloric acid salt of (R)-4-(3-amino-4-(2,4,5-
trifluorophenyl)-butanoyl)-7-methoxy-4,5-dihydro-1 H-benzo[e][1 ,4]diazipin-2(3H)one.
To a solution of (R)-3-[(terl-butyloxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic
acid (0.241 g, 2.197 mmol) in acetonitrile (15 ml) was added
Diisopropylethylamine (2.47 g,19.12 mmol) and 1,1-Carbonyl diimidazole (0.534
g, 3.296 mmol) at room temperature. The reaction mixture was stirred for 30 min
at room tern perature. 7 -methoxy-1 , 3, 4, 5-tetrahydro-benzo[ e][1 ,4]diazepin-2-one
hydrochloride (0.5 g, 2.197 mmol) (synthesized in accordance with the procedure
given in W0-2009093269, which is incorporated in its entirety herein by
reference) was added to the above reaction mixture at room temperature. The
reaction mixture was heated to 65-70°C for 22 h. After completion of the reaction,
the mixture was concentrated under vacuum and the crude mass was dissolved in
ethyl acetate (15 ml) and washed twice with water (2 x 30 ml). The ethyl acetate
layer was concentrated under reduced pressure to get crude mass and which was
purified by column chromatography using mixture of 2% methanol in
dichloromethane (500 ml) to get 0.9 g (92%) of (R)-[3-(7-methoxy-2-oxo-1 ,2,3,5-
tetrahyd ro-benzo[ e ][ 1 , 4]diazepine-4-yl )-3-oxo-1-(2 ,4, 5-trifluorophenyl-propyl]carbamic
acid terl-butyl ester.
The above obtained solid was treated with Hydrochloric acid to get the
Hydrochloric acid salt of (R)-4-(3-amino-4-(2,4,5-trifluorophenyl)-butanoyl)-7-
methoxy-4,5-dihydro-1 H-benzo[e][1 ,4] diazipin-2(3H)-one.
Example 5: Synthesis of Hydrochloride salt of (R)-3-amino-1-(9-fluoro-4H,6H-
2,3,5, 10b-tetraaza-benzo[e]azulene-5-yl)-4-(2,4,5-trifluoro-phenyl)-butan-1-one.
40
DUPLICATE
To a solution of (R)-3-[(terl-butyloxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic
acid (2.91 g, 0.0087 mol) in acetonitrile (24 ml) was added
Diisopropylethylamine (3.22 g, 0.024 mol) and 1, 1-Carbonyl diimidazole ( 1. 755 g,
0.0108 mol) at room temperature. The reaction mixture was stirred for 30 min at
room temperature. 9-Fiuoro-5,6-dihydro-4H-2,3,5, 10 J3-tetraaza-benzo[e]azulene
hydrochloride (2.0 g, 0.0083 mol) (synthesized in accordance with the procedure
given in W0-2009093269, which is incorporated in its entirety herein by
reference) dissolved in a mixture of acetonitrile (20 ml) and diisopropylethylamine
(3.23 g, 0.0249 mol), was added to the above reaction mixture at room
t'
temperature. The reaction mixture was heated to 65-70°C for 22 h. After
completion of the reaction, the mixture was concentrated under vacuum and the
crude mass was dissolved in ethyl acetate (40 ml) and washed twice with water (2
x 20 ml). The ethyl acetate layer was concentrated under reduced pressure to get
crude mass and which was recrystallized from methyl isobutyl ketone ( 1 0 ml ) to
get 3.3 g (76%) of [3-(9-fluoro-4H,6H-2,3,5, 10b-tetraaza-benzo[e]-azulen-5-yl)-3-
oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid-tert-butyl ester.
The above obtained solid was treated with Hydrochloric acid to give the
Hydrochloride salt of (R)-3-amino-1-(9-fluoro-4H,6H-2,3,5, 1 Ob-tetraazabenzo[
e]azulene-5-yl)-4-(2,4,5-trifluoro-phenyl)-butan-1-one.
Example 6: Synthesis of Hydrochloric acid salt of (R)-4-(3-amino-4-(2,4,5-
trifluorophenyl )-butanoyl )-8-Fiuoro-4, 5-di hyd ro-1 H-benzo[ e][ 1 ,4 ]diazipin-2( 3H )-
one.
To a solution of (R)-3-[(terl-butyloxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic
acid ( 1.17 g, 3.537 mmol) in acetonitrile ( 15 ml) was added
Diisopropylethylamine (3.505 g, 23.67 mmol) and 1, 1-Carbonyl diimidazole (0.661
g, 4.0 mmol) at room temperature. The reaction mixture was stirred for 30 min at
40°C. The 8-Fiuoro-1 ,3,4,5-tetrahydrobenzo(e)[1 ,4]diazepin-2-one trifluoro
acetate (0.5 g, 27.21 mmol) (synthesized in accordance with the procedure given
in W0-2009093269, which is incorporated in its entirety herein by reference) was
added to the above reaction mixture at 40°C. The reaction mixture was heated to
41
DUPLICATE
65-70°C for 22 h. After completion of the reaction, the mixture was concentrated
under vacuum and the crude mass was dissolved in ethyl acetate (15 ml), washed
with saturated sodium bicarbonate solution (15 ml) and washed twice with water
(2 x 30 ml). The ethyl acetate layer was concentrated under reduced pressure to
get 0.55 g of (R)-tert-butyl-4-(8-fluoro-2oxo-2,3-dihydro-1 H-benzo[e][1 ,4]diazepin-
4-oxo-1-(2,4,5-triflurophenyl) butan-2-ylcarbamate.
The above obtained solid was treated with Hydrochloric acid to get the
Hydrochloric acid salt of(R)-4-(3-amino-4-(2,4,5-trifluorophenyl)-butanoyi)-8-
Fiuoro-4,5-dihydro-1 H-benzo[e][1 ,4]diazipin-2(3H)-one.
Example 7: Synthesis of Hydrochloric acid salt of 4-[(R)-3-amino-4-(2,4,5-
trifluorophenyl)-butyryl]-1-methyi-8-Fiuoro-1,3,4,5-tetrahydrobenzo[
e][1 ,4]diazepin-2-one.
To a solution of (R)-3-[(tert-butyloxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic
acid (1.24 g, 3.749 mmol) in acetonitrile (25 ml) was added
Diisopropylethylamine (4.01 g, 31.07 mmol) and 1, 1-Carbonyl diimidazole (0.867
g, 5.357 mmol) at room temperature. The reaction mixture was stirred for 30 min
at 40°C. 8-Fiuoro-1-methyl-1 ,3,4,5-tetrahydrobenzo ( e)[1 ,4]diazepin-2-one
trifluoro acetate ( 1.10 g, 3.571 mmol) (synthesized in accordance with the
procedure given in W0-2009093269, which is incorporated in its entirety herein
by reference) was added to the above reaction mixture at 40°C. The reaction
mixture was heated to 65-70°C for 24 h. After completion of the reaction, the
mixture was concentrated under vacuum and the crude mass was dissolved in
ethyl acetate (30 ml) and washed twice with water (2 x 30 ml). The ethyl acetate
layer was concentrated under reduced pressure to get crude mass and which was
purified by column chromatography using mixture of 30% Ethyl acetate in
petroleum ether ( 1000 ml) to get 1.43 g (79%) of 2-[3-( 1-methyl-8-fluoro-2-oxo-
1 ,2,3,5-tetrahydro-benzo[e][1 ,4]diazepin-4-yl)-3-oxo-(R)-1-(2,4,5-trifluro-benzyl)propyl]-
carbamicacid tert-butyl ester.
42
DUPLICATE
The above obtained solid was treated with Hydrochloric acid to get Hydrochloric
acid salt of 4-[( R )-3-am ino-4-( 2 ,4, 5-trifluorophenyl )-butyryl]-8-fluoro-1-methyl-
1 ,3,4,5-tetrahydro-benzo [e][1 ,4]diazepin-2-one.

We Claim:
1. A process for preparing a compound of general formula I, their
pharmaceutically acceptable derivatives, tautomeric forms, stereoisomers
including R and S isomers, prod rugs, metabolites, salts or solvates thereof:
N~.Yf~
RG~n' /'N-R1 R{.h
M
Formula I
wherein,
Ar represents aryl which may be phenyl, which may be unsubstituted or optionally
substituted at any available position by R8 or by one or more substituents
selected from but not limited to halogen, CN, hydroxyl, NH2, C1-12 alkyl or C1-12
alkoxy, wherein each of C1-12 alkoxy and C1-12 alkyl may be linear or branched
and can be unsubstituted or optionally substituted with 1-5 halogens;
R1 is selected from the group consisting of but not limited to (CH2)nCONRaRb,
(CH2)nCOORa, (CH2)nNRaRb, (CH2)nNRaCORb, (CH2)nC(=Y)Ra (wherein Y is 0
or S), (CH2)n0Ra (wherein each methylene group may be substituted by one or
more halogen atoms), -(CO)Ra, -(CO)NRaRb, hydrogen, C1-12 alkyl, C2-12
alkenyl, C2-12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C2-12 haloalkynyl, C3-8
cycloalkyl, heterocyclyl, aryl, heteroaryl, (CH2)n-cycloalkyl, (CH2)n-heterocyclyl,
(CH2)n-aryl, (CH2)n-heteroaryl, each of which may be optionally substituted at
any available position by one or more substituents selected from but not limited
to hydrogen, halogen, CN, Cr12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy,
C1-12 haloalkyl, C1-12 haloalkoxy, C2-12 haloalkenyl, C2-12 haloalkynyl, C1-12
alkylcarbonyl, C1-12 alkoxycarbonyl, oxo, -ORa, -SRa, -N02, -NRaRb,
N(Ra)(CO)Rb, N(Ra)(CO)ORb, N(Ra)(CO)NRaRb, -(CO)Ra, -(CO)NRaRb, -
O(CO)Ra, -O(CO)NRaRb, -COORa, C3-s cycloalkyl, S(O)mRa, S02NRaRb;
cycloalkyl which may be optionally substituted at any available position by one
44
·"'
DUPLICATE
or more substituents independently selected from Rc or Rc'; aryl which may be
optionally substituted at any available position by one or more substituents
independently selected from Rc or Rc'; heteroaryl which may be optionally
substituted at any available position by one or more substituents independently
selected from Rc or Rc'; or heterocyclyl which may be optionally substituted at
any available position by one or more substituents independently selected from
Rc or Rc';
R2 and R3 together represents a single oxygen or sulphur atom which is linked to
the diazepine ring by a double bond; or R1 and R2 together forms a double bond
in the diazepine ring and R3 represents the group -NRaRb; or R1 and R3 together
with the nitrogen atom to which R1 is attached forms a heterocyclic or heteroaryl
ring which may additionally contain from one to three hetero atoms
independently selected from 0, S and N; the ring formed may optionally be
substituted with one or more substituents selected from Rc or Rc' and R2
represent hydrogen or a double bond;
R4 and R5 are independently selected from the group consisting of hydrogen,
halogen, CN, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, C1-12 haloalkyl,
C1-12 haloalkoxy, C2-12 haloalkenyl, C2-12 haloalkynyl, C1-12 alkylcarbonyl, C1-12
alkoxycarbonyl, -ORa, -SRa, -N02, -NRaRb, N(Ra)(CO)Rb, N(Ra)(CO)ORb,
N(Ra)(CO)NRaRb, -(CO)Ra, -(CO)NRaRb, -O(CO)Ra, -O(CO)NRaRb, -COORa, C3-
a cycloalkyl, S(O)mRa, S02NRaRb; cycloalkyl which may be optionally substituted
at any available position by one or more substituents independently selected
from Rc or Rc'; aryl which may be optionally substituted at any available position
by one or more substituents independently selected from Rc or Rc'; heteroaryl
which may be optionally substituted at any available position by one or more
substituents independently selected from Rc or Rc'; or heterocyclyl which may be
optionally substituted at any available position by one or more substituents
independently selected from Rc or Rc';
R6 and R7 are independently selected from the group consisting of hydrogen,
halogen, CN, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, C1-12 haloalkyl,
C1-12 haloalkoxy, C2-12 haloalkenyl, C2-12 haloalkynyl, Cr12 alkylcarbonyl, C1-12
alkoxycarbonyl, -ORa, -SRa, -N02, -NRaRb, N(Ra)(CO)Rb, N(Ra)(CO)ORb,
45
DUPLICATE
N(Ra)(CO)NRaRb, -(CO)Ra, -(CO)NRaRb, -O(CO)Ra, -O(CO)NRaRb, -COORa, C3-
8 cycloalkyl, S(O)mRa, S02NRaRb; cycloalkyl which may be optionally substituted
at any available position by one or more substituents independently selected
from Rc or Rc'; aryl which may be optionally substituted at any available position
by one or more substituents independently selected from Rc or Rc'; heteroaryl
which may be optionally substituted at any available position by one or more
substituents independently selected from Rc or Rc'; or heterocyclyl which may be
optionally substituted at any available position by one or more substituents
independently selected from Rc or Rc';
R8 is independently selected from hydrogen, halogen, CN, Cn2 alkyl, Cr12
haloalkyl, C1-12 alkoxy, C1-12 haloalkoxy, C2-12 haloalkenyl, C1-12 alkylcarbonyl,
C1-12 alkoxycarbonyl, -ORa, -SRa, -CF3, -OCF3. -N02, -NRaRb, N(Ra)(CO)Rb,
N(Ra)(CO)ORb, N(Ra)(CO)NRaRb, -(CO)Ra, -(CO)NRaRb, -O(CO)Ra,
O(CO)NRaRb, -COORa, C3-6 cycloalkyl, S(O)mRa, S02NRaRb; cycloalkyl which
may be optionally substituted at any available position by one or more
substituents independently selected from Rc or Rc'; aryl which may be optionally
substituted at any available position by one or more substituents independently
selected from Rc or Rc' ; heteroaryl which may be optionally substituted at any
available position by one or more substituents independently selected from Rc
or Rc'; or heterocyclyl which may be optionally substituted at any available
position by one or more substituents independently selected from Rc or Rc';
Ra and Rb are independently selected from hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-
12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C2-12 haloalkynyl, C3-8 cycloalkyl,
heterocyclyl, aryl, heteroaryl, (CH2)n-cycloalkyl, (CH2)n-heterocyclyl, (CH2)n-aryl,
(CH2)n-heteroaryl; each of which may be optionally substituted with halogen,
hydroxyl, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, Cn2 alkoxy, Cn2
alkylcarbonyl, C1-12 alkoxycarbonyl, C3-a cycloalkyl, Cr12 haloalkyl, Cr12
haloalkoxy, C2-12 haloalkenyl, aryl, heterocyclyl, heteroaryl, (CH2)n-aryl, (CH2)nheterocyclyl,
(CH2)n-heteroaryl, (CH2)n-cycloalkyl, oxo, -CN, -OR9, -N02. -
NR9R10, N(R9)(CO)R10, N(R9)(CO)OR10, N(R9)(CO)NR9R10, -C(=L)R9 (wherein L
is 0 or S), -(CO)NR9R10
, -O(CO)R9
, -O(CO)NR9R10, -COOR9
, -SR9, S(O)mR9,
S02NR9R10; S03H, NHS02R9
, P(O)R9R10; or Ra and Rb may be joined together
46
DUPLICATE
along with the nitrogen atom to which they are attached to form a heterocyclic or
heteroaryl ring which may additionally contain from one to three heteroatoms
independently selected from 0, S and N, the ring formed may optionally be
substituted with one or more substituents selected from hydrogen, halogen, C1-
12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C2-12
haloalkynyl, C3-a cycloalkyl, heterocyclyl, aryl, heteroaryl, (CH2)n-cycloalkyl,
(CH2)n-heterocyclyl, (CH2)n-aryl, (CH2)n-heteroaryl, C1-12 alkylcarbonyl, C1-12
alkoxycarbonyl, oxo, CN, -OR9
, -CF3, -OCF3 CH2CF3. CF2CF3, -N02. -NR9R10,
N(R9)(CO)R10, N(R9)(CO)OR10, N(R9)(CO)NR9R10, -C(=Y)R9 (wherein Y is 0 or
S), -(CO)NR9R10, -O(CO)C1-C12alkyl, -O(CO)NR9R10, -COOR9, -SR9, S(O)mR9,
S02NR9R10; S03H, NHS02R9
, P(O)R9R10; the ring thus formed may further be
fused with 3 to 7 membered unsaturated or saturated ring, which may contain
from one to three heteroatoms independently selected from 0, S or N, the fused
ring may optionally be substituted with one or more substituents Rc or Rc';
Rc or Rc· is independently selected from the group consisting of but not limited to
(1) hydrogen, (2) halogen, (3) C1-12 alkyl which is linear or branched and which
can be unsubstituted or substituted with 1-5 halogens or phenyl , which is
unsubstituted or substituted with 1-5 substituents independently selected from
halogen, CN, OH, R12, OR 12, NHS02R 12, S02R 12, C02H and C02C1-a alkyl
,wherein the co2c1-6 alkyl is linear or branched ; (4) aryl which can be
unsubstituted or substituted with 1-5 substituents independently selected from
halogen, CN, OH, R12, OR12, NHS02R 12, S02R 12, C02H and C02C1-a alkyl
,wherein the co2c1-6 alkyl is linear or branched (5) a 5 or 6 membered
heterocyclyl which may be saturated or unsaturated comprising 1-4 heteroatoms
independently selected from N, Sand 0, the heterocycle being unsubstituted or
substituted with 1-3 substituents independently selected from oxo, OH, halogen,
C1-ealkyl, and OC1-ealkyl, wherein the C1-a alkyl and OC1-e alkyl are linear or
branched and optionally substituted with 1-5 halogens; (6) (CH2)n-cycloalkyl; (7)
(CH2)n-heterocyclyl, (8) (CH2)n-aryl, (9) (CH2)n-heteroaryl, (10) C1-12
alkylcarbonyl, (11) C1-12 alkoxycarbonyl, (12) CN, (13) -OR9, (14) -OCF3, (15)N02.
(16) =NOR10, (17) -NR9R10, (18) N(R9)(CO)R10, (19) N(R9)(CO)OR10, (20)
N(R9)(CO)NR9R10
, -(21) C(=Y ')R9 (wherein Y is 0 or S), (22) -(CO)NR9R10,
47
DUPLICATE
(23) -O(CO)R9
, (24) -O(CO)NR9R10
, (25) -COOR9, (26) -SR9, (27) S(O)mR9, {28)
S02NR9R
10
; (29) S03H, (30) NHS02R9
, (31) P(O)R9R10
, (32) C2-12 alkenyl, (33)
C2-12 alkynyl, (34) C1-12 haloalkyl, (35) C2-12 haloalkenyl, (36) C2-12 haloalkynyl,
(37) C1-12 alkoxy, (38) C1-12 haloalkoxy, (39) C3-8 cycloalkyl, ( 40) heteroaryl;
with a proviso that when R 1 and R3 together with the nitrogen atom to which R 1
is attached forms a heterocyclic or heteroaryl ring which may additionally
contain from one to three hetero atoms independently selected from 0, Sand N
, then Rc or Rc' cannot be C02H.
R9 and R
10
are independently selected from hydrogen, C1-12 alkyl, C2-12 alkenyl,
C2-12 alkynyl, Cn2 haloalkyl, C2-12 haloalkenyl, C3_a cycloalkyl, heterocyclyl, aryl,
heteroaryl, (CH2)n-cycloalkyl, (CH2)n-heterocyclyl, (CH2)n-aryl, (CH2)n-heteroaryl,
each of which may be optionally substituted with halogen, hydroxyl or C1-6
alkoxy, or R9and R10 may be joined together to form a heterocyclic or heteroaryl
ring which may contain from one to three heteroatoms independently selected
from 0, S and N, which may optionally be substituted with one or more
substituents independently selected from Rc or Rc';
R
12
is C1-a alkyl, which is linear or branched and which is unsubstituted or
substituted with 1-5 groups independently selected from halogen, C02H, and
co2c1-6 alkyl, wherein the co2c1-6 alkyl is linear or branched;
M and L independently represent a hydrogen atom or they may join together to
form a ring,
n' is 0 or 1
m can be 1 or 2;
n can be 1, 2, 3 or 4;
comprising:
a) coupling a compound of Formula II,
wherein
NHPG
Ar~COOH
Formula II
48
DUPLICATE
Ar is as defined above and PG is an amino protecting groups selected from
acetyl, trifluoroacetyl, benzyloxycarbonyl (CBz), t-butoxycarbonyl (Boc), 9-
fluorenylmethyloxycarbonyl (Fmoc), 2,2,2-trichloroethyloxycarbonyl and
allyloxycarbonyl;
with a compound of Formula Ill or its salt
Formula Ill
using 1,1- carbonyl diimidazole, in a solvent and optionally in the presence of a
base;
b) removing the protecting group (PG) from the compound obtained in step (a)
using deprotecting agent; and
c) optionally converting the product obtained in step (b) to a salt.
2. A process for preparing compounds of formula VI or VII, their pharmaceutically
acceptable derivatives, tautomeric forms, stereoisomers including R and S
isomers, prod rugs, metabolites, salts or solvates thereof:
OR
Formula VI Formula VII
wherein,
Ar represents aryl which may be phenyl, which may be unsubstituted or optionally
substituted at any available position by one or more substituents selected from
but not limited to halogen, CN, hydroxyl, NH2, C1-12 alkyl or C1-12 alkoxy, wherein
49
DUPLICATE
each of C1-12 alkoxy and C1-12 alkyl may be linear or branched and can be
unsubstituted or optionally substituted with 1-5 halogens;
R
1
is selected from the group consisting of but not limited to (CH2)nCONR3Rb,
(CH2)nCOOR3
, (CH2)nNRaRb, (CH2)nNR3CORb, (CH2)nC(=Y)R3 (wherein Y is 0
or S), (CH2)n0R3 (wherein each methylene group may be substituted by one or
more halogen atoms), -(CO)R3
, -(CO)NRaRb, hydrogen, C1-12 alkyl, C2-12
alkenyl, C2-12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C2-12 haloalkynyl, C3-8
cycloalkyl, heterocyclyl, aryl, heteroaryl, (CH2)n-cycloalkyl, (CH2)n-heterocyclyl,
(CH2)n-aryl, (CH2)n-heteroaryl, each of which may be optionally substituted at
any available position by one or more substituents selected from but not limited
to hydrogen, halogen, CN, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy,
C1-12 haloalkyl, C1-12 haloalkoxy, C2-12 haloalkenyl, C2-12 haloalkynyl, C1-12
alkylcarbonyl, C1-12 alkoxycarbonyl, oxo, -OR3
, -SR3
, -N02, -NR3 Rb,
N(R3 )(CO)Rb, N(R3)(CO)ORb, N(R3)(CO)NR3 Rb, -(CO)R3
, -(CO)NR3 Rb, -
O(CO)R3
, -O(CO)NRaRb, -COOR3
, C3-s cycloalkyl, S(O)mR3
, S02NR3Rb ;
cycloalkyl which may be optionally substituted at any available position by one
or more substituents independently selected from Rc or Rc'; aryl which may be
optionally substituted at any available position by one or more substituents
independently selected from Rc or Rc'; heteroaryl which may be optionally
substituted at any available position by one or more substituents independently
selected from Rc or Rc'; or heterocyclyl which may be optionally substituted at
any available position by one or more substituents independently selected from
Rc or Rc';
R2 and R3 together represents a single oxygen or sulphur atom which is linked to
the diazepine ring by a double bond; or R1 and R2 together forms a double bond
in the diazepine ring and R3 represents the group -NRaRb; or R1 and R3 together
with the nitrogen atom to which R1 is attached forms a heterocyclic or heteroaryl
ring which may additionally contain from one to three heteroatoms
independently selected from 0, S and N; the ring formed may optionally be
substituted with one or more substituents selected from Rc or Rc' and R2
represent hydrogen or a double bond;
50
DUPLICATE
R4 and R5 are independently selected from the group consisting of hydrogen,
halogen, CN, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, C1-12 haloalkyl,
C1-12 haloalkoxy, C2-12 haloalkenyl, C2-12 haloalkynyl, C1-12 alkylcarbonyl, C1-12
alkoxycarbonyl, -ORa, -SRa, -N02, -NRaRb, N(Ra)(CO)Rb, N(Ra)(CO)ORb,
N(Ra)(CO)NRaRb, -(CO)Ra, -(CO)NRaRb, -O(CO)Ra, -O(CO)NRaRb, -COORa, C3-
s cycloalkyl, S(O)mRa, S02NRaRb; cycloalkyl which may be optionally substituted
at any available position by one or more substituents independently selected
from Rc or Rc'; aryl which may be optionally substituted at any available position
by one or more substituents independently selected from Rc or Rc'; heteroaryl
which may be optionally substituted at any available position by one or more
substituents independently selected from Rc or Rc'; or heterocyclyl which may be
optionally substituted at any available position by one or more substituents
independently selected from Rc or Rc';
R6 and R7 are independently selected from the group consisting of hydrogen,
halogen, CN, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, C1-12 haloalkyl,
C1-12 haloalkoxy, C2-12 haloalkenyl, C2-12 haloalkynyl, C1-12 alkylcarbonyl, C1-12
alkoxycarbonyl, -ORa, -SRa, -N02, -NRaRb, N(Ra)(CO)Rb, N(Ra)(CO)ORb,
N(Ra)(CO)NRaRb, -(CO)Ra, -(CO)NRaRb, -O(CO)Ra, -O(CO)NRaRb, -COORa, C3-
s cycloalkyl, S(O)mRa, S02NRaRb; cycloalkyl which may be optionally substituted
at any available position by one or more substituents independently selected
from Rc or Rc'; aryl which may be optionally substituted at any available position
by one or more substituents independently selected from Rc or Rc'; heteroaryl
which may be optionally substituted at any available position by one or more
substituents independently selected from Rc or Rc'; or heterocyclyl which may be
optionally substituted at any available position by one or more substituents
independently selected from Rc or Rc';
R8 is independently selected from hydrogen, halogen, CN, C1-12 alkyl, C1-12
haloalkyl, C1-12 alkoxy, C1-12 haloalkoxy, C2-12 haloalkenyl, C1-12 alkylcarbonyl,
C1-12 alkoxycarbonyl, -ORa, -SRa, -CF3, -OCF3, -N02, -NRaRb, N(Ra)(CO)Rb,
N(Ra)(CO)ORb, N(Ra)(CO)NRaRb, -(CO)Ra, -(CO)NRaRb, -O(CO)Ra,
O(CO)NRaRb, -COORa, C3-6 cycloalkyl, S(O)mRa, S02NRaRb; cycloalkyl which
may be optionally substituted at any available position by one or more
51
DUPLICATE
substituents independently selected from Rc or Rc'; aryl which may be optionally
substituted at any available position by one or more substituents independently
selected from Rc or Rc' ; heteroaryl which may be optionally substituted at any
available position by one or more substituents independently selected from Rc
or Rc'; or heterocyclyl which may be optionally substituted at any available
position by one or more substituents independently selected from Rc or Rc';
R8 and Rb are independently selected from hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-
12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C2-12 haloalkynyl, C3.8 cycloalkyl,
heterocyclyl, aryl, heteroaryl, (CH2)n-cycloalkyl, (CH2)n-heterocyclyl, (CH2)n-aryl,
(CH2)n-heteroaryl; each of which may be optionally substituted with halogen,
hydroxyl, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, C1-12
alkylcarbonyl, C1-12 alkoxycarbonyl, C3-a cycloalkyl, C1-12 haloalkyl, C1-12
haloalkoxy, C2-12 haloalkenyl, aryl, heterocyclyl, heteroaryl, (CH2)n-aryl, (CH2)nheterocyclyl,
(CH2)n-heteroaryl, (CH2)n-cycloalkyl, oxo, -CN, -OR9
, -N02. -
NR9R10, N(R9)(CO)R10, N(R9)(CO)OR10, N(R9)(CO)NR9R10, -C(=Y)R9 (wherein Y
is 0 or S), -(CO)NR9R10, -O(CO)R9
, -O(CO)NR9R10, -COOR9
, -SR9
, S(O)mR9
,
S02NR9R10; S03H, NHS02R9
, P(O)R9R10; or R8 and Rb may be joined together
along with the nitrogen atom to which they are attached to form a heterocyclic or
heteroaryl ring which may additionally contain from one to three heteroatoms
independently selected from 0, S and N, the ring formed may optionally be
substituted with one or more substituents selected from hydrogen, halogen, C1-
12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C2-12
haloalkynyl, C3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, (CH2)n-cycloalkyl,
(CH2)n-heterocyclyl, (CH2)n-aryl, (CH2)n-heteroaryl, C1-12 alkylcarbonyl, C1-12
alkoxycarbonyl, oxo, CN, -OR9
, -CF3, -OCF3 CH2CF3. CF2CF3, -N02, -NR9R10,
N(R9)(CO)R10
, N(R9)(CO)OR10, N(R9)(CO)NR9R10
, -C(=Y)R9 (wherein Y is 0 or
S), -(CO)NR9R10, -O(CO)C1-C12alkyl, -O(CO)NR9R10
, -COOR9
, -SR9
, S(O)mR9
,
S02NR9R10; S03H, NHS02R9
, P(O)R9R10; the ring thus formed may further be
fused with 3 to 7 membered unsaturated or saturated ring, which may contain
from one to three heteroatoms independently selected from 0, S or N, the fused
ring may optionally be substituted with one or more substituents Rc or Rc';
52
DUPLICATE
Rc or Rc' is independently selected from the group consisting of but not limited to
(1) hydrogen, (2) halogen, (3) C1-12 alkyl which is linear or branched and which
can be unsubstituted or substituted with 1-5 halogens or phenyl , which is
unsubstituted or substituted with 1-5 substituents independently selected from
halogen, CN, OH, R12, OR12, NHS02R12, S02R12, C02H and C02C1-6 alkyl
,wherein the co2c1-6 alkyl is linear or branched (4) aryl which can be
unsubstituted or substituted with 1-5 substituents independently selected from
halogen, CN, OH, R12, OR12, NHSO 2R12, S02R12, C02H and C02C1-6 alkyl,
wherein the co2c1-6 alkyl is linear or branched (5) a 5 or 6 membered
heterocyclyl which may be saturated or unsaturated comprising 1-4 heteroatoms
independently selected from N, Sand 0, the heterocycle being unsubstituted or
substituted with 1-3 substituents independently selected from oxo, OH, halogen,
C1-ealkyl, and OC1-6alkyl, wherein the C1-6alkyl and OC1.6alkyl are linear or
branched and optionally substituted with 1-5 halogens; (6) (CH2)n-cycloalkyl, (7)
(CH2)n-heterocyclyl, (8) (CH2)n-aryl, (9) (CH2)n-heteroaryl, (1 0) C1-12
alkylcarbonyl, (11) C1-12 alkoxycarbonyl, (12) CN, (13) -OR9, (14) -OCF3, (15)N02,
(16) =NOR10, (17) -NR9R10, (18) N(R9XCO)R10, (19) N(R9)(CO)OR10, (20)
N(R9)(CO)NR9R10, (21) C(=Y)R9 (wherein Y is 0 or S), (22) -(CO)NR9R10, (23)O(
CO)R9
, (24) -O(CO)NR9R10,(25) -COOR9
, (26) -SR9
, (27) S(O)mR9
, (28)
S02NR9R10; (29) S03H, (30) NHS02R9
, (31) P(O)R9R10, (32) C2-12 alkenyl, (33)
C2-12 alkynyl, (34) C1-12 haloalkyl, (35) C2-12 haloalkenyl, (36) C2-12 haloalkynyl,
(37) C1-12 alkoxy, (38) C1-12 haloalkoxy, (39) C3-8 cycloalkyl, (40) heteroaryl;
with a proviso that when R1 and R3 together with the nitrogen atom to which R1 is
attached form an imidazole ring, Rc or Rc' cannot be C02H.
or
with a proviso that when R1 and R3 together with the nitrogen atom to which R1 is
attached forms a heterocyclic or heteroaryl ring which may additionally contain
from one to three heteroatoms independently selected from 0, S and N, Rc or
Rc' cannot be C02H.
R9 and R10 are independently selected from hydrogen, C1-12 alkyl, C2-12 alkenyl,
C2-12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C3-8 cycloalkyl, heterocyclyl, aryl,
heteroaryl, (CH2)n-cycloalkyl, (CH2)n-heterocyclyl, (CH2)n-aryl, (CH2)n-heteroaryl,
53
DUPLICATE
each of which may be optionally substituted with halogen, hydroxyl or C1-6
alkoxy, or R9and R10 may be joined together to form a heterocyclic or heteroaryl
ring which may contain from one to three heteroatoms independently selected
from 0, S and N, which may optionally be substituted with one or more
substituents independently selected from Rc or Rc';
R12 is C1-6 alkyl, which is linear or branched and which is unsubstituted or
substituted with 1-5 groups independently selected from halogen, C02H, and
co2c1-6 alkyl, wherein the co2c 1-6 alkyl is linear or branched;
X is selected from the group consisting of Nand CR11
;
R11 is selected from the group consisting of Rc or Rc';
m can be 1 or 2;
n can be 1, 2, 3 or 4;
r can be 1, 2, 3 or 4.
comprising,
a) coupling a compound of Formula II,
wherein
Ar is as defined above; and
NHPG
Ar~COOH
Formula II
PG is an amino protecting groups selected from acetyl, trifluoroacetyl,
benzyloxycarbonyl (CBz), t-butoxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl
(Fmoc), 2,2,2-trichloroethyloxycarbonyl, allyloxycarbonyl and the like;
with a compound of Formula VIII or IX or their salts respectively,
OR
Formula IX
54
DUPLICATE
using 1,1- carbonyl diimidazole, in a solvent and optionally in the presence of a base;
b) removing the protecting group (PG) from the compound obtained in step (a) using
deprotecting agents, and
c) optionally converting the product obtained in step (b) to a salt.
3. A process according to claim 1 or 2 wherein the solvent used in step (a) is
selected form the group comprising Dimethylfomamide (DMF), Dimethyl
acetamide (DMAc), Dichloromethane (DCM), acetonitrile (ACN), toluene,
tetrahydrofuran (THF) or mixtures thereof.
4. A process according to claim 3, wherein the solvent is acetonitrile and/or
Dimethylformamide.
5. A process according to claim 1 or 2, wherein the base used in step (a) is
selected form the group comprising N-methylmorpholine (NMM), N,Ndiisopropylethylamine
(DIPEA) and triethylamine {TEA) or mixtures thereof.
6. A process according to claim 5, wherein the base is N,N-diisopropylethylamine.
7. A process according to claim 1 or 2, wherein the deprotecting agent used in
step (b) is selected form the group comprising trifluoroacetic acid, hydrochloric
acid, phosphoric acid, p-toluenesulphonic acid, piperidine, palladium on
charcoal and platinum.
8. A process according to claim 7, wherein the deprotecting agent is hydrochloric
acid.
9. A process according to claim 1 or 2, wherein the process steps are carried out
without isolating the intermediates.
10. A compound of formula IV and its pharmaceutically acceptable derivatives,
tautomeric forms, stereoisomers including R and S isomers, prodrugs,
metabolites, salts or solvates thereof:
55
DUPLICATE
Formula IV
wherein
Ar represents aryl which may be phenyl, which may be unsubstituted or optionally
substituted at any available position by one or more substituents selected from
but not limited to halogen, CN, hydroxyl, NH2, C1-12 alkyl or C1-12 alkoxy, wherein
each of C1-12 alkoxy and C1-12 alkyl may be linear or branched and can be
unsubstituted or optionally substituted with 1-5 halogens; and
PG is an amino protecting groups selected from acetyl, trifluoroacetyl,
benzyloxycarbonyl (CBz), t-butoxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl
(Fmoc), 2,2,2-trichloroethyloxycarbonyl and allyloxycarbonyl.
11. A compound of formula V, its pharmaceutically acceptable derivatives,
tautomeric forms, stereoisomers including R and S isomers, prodrugs,
metabolites, salts or solvates thereof:
F
Formula V
12. A compound of formula X and its pharmaceutically acceptable derivatives,
tautomeric forms, stereoisomers including R and S isomers, prodrugs,
metabolites, salts or solvates thereof:
56
DUPLICATE
Formula X
wherein
Ar represents aryl which may be phenyl, which may be unsubstituted or optionally
substituted at any available position by one or more substituents selected from
but not limited to halogen, CN, hydroxyl, NH2, C1-12 alkyl or C1-12 alkoxy, wherein
each of C1-12 alkoxy and C1-12 alkyl may be linear or branched and can be
unsubstituted or optionally substituted with 1-5 halogens;
R1 is selected from the group consisting of but not limited to (CH2)nCONRaRb,
(CH2)nCOORa, (CH2)nNRaRb, (CH2)nNRaCORb, (CH2)nC(=Y)Ra (wherein Y is 0
or S), (CH2)n0Ra (wherein each methylene group may be substituted by one or
more halogen atoms), -(CO)Ra, -(CO)NRaRb, hydrogen, C1-12 alkyl, C2-12
alkenyl, C2-12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C2-12 haloalkynyl, C3-8
cycloalkyl, heterocyclyl, aryl, heteroaryl, (CH2)n-cycloalkyl, (CH2)n-heterocyclyl,
(CH2)n-aryl, (CH2)n-heteroaryl, each of which may be optionally substituted at
any available position by one or more substituents selected from but not limited
to hydrogen, halogen, CN, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy,
Cn2 haloalkyl, C1-12 haloalkoxy, Cn2 haloalkenyl, C2-12 haloalkynyl, Cn2
alkylcarbonyl, C1-12 alkoxycarbonyl, oxo, -ORa, -SRa, -N02, -NRaRb,
N(Ra)(CO)Rb, N(Ra)(CO)ORb, N(Ra)(CO)NRaRb, -(CO)Ra, -(CO)NRaRb, -
O(CO)Ra, -O(CO)NRaRb, -COORa, C3_8 cycloalkyl, S(O)mRa, S02NRaRb ;
cycloalkyl which may be optionally substituted at any available position by one
or more substituents independently selected from Rc or Rc'; aryl which may be
optionally substituted at any available position by one or more substituents
independently selected from Rc or Rc'; heteroaryl which may be optionally
substituted at any available position by one or more substituents independently
selected from Rc or Rc'; or heterocyclyl which may be optionally substituted at
57
DUPLICATE
any available position by one or more substituents independently selected from
Rc or Rc'. I
R2 and R3 together represents a single oxygen or sulphur atom which is linked to
the diazepine ring by a double bond; or R1 and R2 together forms a double bond
in the diazepine ring and R3 represents the group -NRaRb; or R1 and R3 together
with the nitrogen atom to which R 1 is attached forms a heterocyclic or heteroaryl
ring which may additionally contain from one to three heteroatoms
independently selected from 0, S and N; the ring formed may optionally be
substituted with one or more substituents selected from Rc or Rc' and R2
represent hydrogen or a double bond;
R4 and R5 are independently selected from the group consisting of hydrogen,
halogen, CN, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, C1-12 haloalkyl,
C1-12 haloalkoxy, C2-12 haloalkenyl, C2-12 haloalkynyl, C1-12 alkylcarbonyl, C1-12
alkoxycarbonyl, -ORa, -SRa, -N02, -NRaRb, N(Ra)(CO)Rb, N(Ra)(CO)ORb,
N(Ra)(CO)NRaRb, -(CO)Ra, -(CO)NRaRb, -O(CO)Ra, -O(CO)NRaRb, -COORa, C3-
8 cycloalkyl, S(O)mRa, S02NRaRb; cycloalkyl which may be optionally substituted
at any available position by one or more substituents independently selected
from Rc or Rc'; aryl which may be optionally substituted at any available position
by one or more substituents independently selected from Rc or Rc'; heteroaryl
which may be optionally substituted at any available position by one or more
substituents independently selected from Rc or Rc'; or heterocyclyl which may be
optionally substituted at any available position by one or more substituents
independently selected from Rc or Rc';
R6 and R7 are independently selected from the group consisting of hydrogen,
halogen, CN, Cn2 alkyl, C2-12 alkenyl, C2-12 alkynyl, Cn2 alkoxy, Cn2 haloalkyl,
C1-12 haloalkoxy, C2-12 haloalkenyl, C2-12 haloalkynyl, C1-12 alkylcarbonyl, C1-12
alkoxycarbonyl, -ORa, -SRa, -N02, -NRaRb, N(Ra)(CO)Rb, N(Ra)(CO)ORb,
N(Ra)(CO)NRaRb, -(CO)Ra, -(CO)NRaRb, -O(CO)Ra, -O(CO)NRaRb, -COORa, C3-
8 cycloalkyl, S(O)mRa, S02NRaRb; cycloalkyl which may be optionally substituted
at any available position by one or more substituents independently selected
from Rc or Rc'; aryl which may be optionally substituted at any available position
by one or more substituents independently selected from Rc or Rc'; heteroaryl
58
DUPLICATE
which may be optionally substituted at any available position by one or more
substituents independently selected from Rc or Rc'; or heterocyclyl which may be
optionally substituted at any available position by one or more substituents
independently selected from Rc or Rc';
R8 and Rb are independently selected from hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-
12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C2-12 haloalkynyl, C3-8 cycloalkyl,
heterocyclyl, aryl, heteroaryl, (CH2)n-cycloalkyl, (CH2)n-heterocyclyl, (CH2)n-aryl,
(CH2)n-heteroaryl; each of which may be optionally substituted with halogen,
hydroxyl, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, C1-12
alkylcarbonyl, C1-12 alkoxycarbonyl, C3-s cycloalkyl, C1-12 haloalkyl, C1-12
haloalkoxy, C2-12 haloalkenyl, aryl, heterocyclyl, heteroaryl, (CH2)n-aryl, (CH2)nheterocyclyl,
(CH2)n-heteroaryl, (CH2)n-cycloalkyl, oxo, -CN, -OR9
, -N02. -
NR9R10, N(R9)(CO)R10, N(R9)(CO)OR10, N(R9)(CO)NR9R10, -C(=Y)R9 (wherein Y
is 0 or S), -(CO)NR9R10
, -O(CO)R9
, -O(CO)NR9R10, -COOR9
, -SR9
, S(O)mR9
,
S02NR9R10; S03H, NHS02R9
, P(O)R9R10; or R8 and Rb may be joined together
along with the nitrogen atom to which they are attached to form a heterocyclic or
heteroaryl ring which may additionally contain from one to three heteroatoms
independently selected from 0, S and N, the ring formed may optionally be
substituted with one or more substituents selected from hydrogen, halogen, C1-
12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C2-12
haloalkynyl, C3-s cycloalkyl, heterocyclyl, aryl, heteroaryl, (CH2)n-cycloalkyl,
(CH2)n-heterocyclyl, (CH2)n-aryl, (CH2)n-heteroaryl, C1-12 alkylcarbonyl, C1-12
alkoxycarbonyl, oxo, CN, -OR9
, -CF3, -OCF3 CH2CF3, CF2CF3, -N02, -NR9R10,
N(R9)(CO)R10
, N(R9)(CO)OR10
, N(R9)(CO)NR9R10, -C(=Y)R9 (wherein Y is 0 or
S), -(CO)NR9R10, -O(CO)C1-C12alkyl, -O(CO)NR9R10
, -COOR9
, -SR9
, S(O)mR9
,
S02NR9R10; S03H, NHS02R9
, P(O)R9R10; the ring thus formed may further be
fused with 3 to 7 membered unsaturated or saturated ring, which may contain
from one to three heteroatoms independently selected from 0, S or N, the fused
ring may optionally be substituted with one or more substituents Rc or Rc';
Rc or Rc' is independently selected from the group consisting of but not limited to
(1) hydrogen, (2) halogen, (3) C1-12 alkyl which is linear or branched and which
can be unsubstituted or substituted with 1-5 halogens or phenyl , which is
59
DUPLICATE
unsubstituted or substituted with 1-5 substituents independently selected from
halogen, CN, OH, R12, OR12, NHS02R12, S02R12, C02H and C02C1-e alkyl
,wherein the co2c1-6 alkyl is linear or branched (4) aryl which can be
unsubstituted or substituted with 1-5 substituents independently selected from
halogen, CN, OH, R12, OR12, NHS02R12, S02R12, C02H and C02C1-a alkyl,
wherein the C02C1-e alkyl is linear or branched (5) a 5 or 6 membered
heterocyclyl which may be saturated or unsaturated comprising 1-4 heteroatoms
independently selected from N, Sand 0, the heterocycle being unsubstituted or
substituted with 1-3 substituents independently selected from oxo, OH, halogen,
C1-6alkyl, and OC1-aalkyl, wherein the C1-aalkyl and OC1_6alkyl are linear or
branched and optionally substituted with 1-5 halogens; (6) (CH2)n-cycloalkyl, (7)
(CH2)n-heterocyclyl, (8) (CH2)n-aryl, (9) (CH2)n-heteroaryl, (1 0) C1-12
alkylcarbonyl, (11) C1-12 alkoxycarbonyl, (12) CN, (13) -OR9
, (14) -OCF3, (15)N02.
(16) =NOR10, (17) -NR9R10, (18) N(R9)(CO)R10, (19) N(R9)(CO)OR10
, (20)
N(R9)(CO)NR9R10, (21) C(=Y)R9 (wherein Y is 0 or S), (22) -(CO)NR9R10, (23)O(
CO)R9
, (24) -O(CO)NR9R10,(25) -COOR9
, (26) -SR9
, (27) S(O)mR9
, (28)
S02NR9R10; (29) S03H, (30) NHS02R9
, (31) P(O)R9R10, (32) C2-12 alkenyl, (33)
C2-12 alkynyl, (34) C1-12 haloalkyl, (35) C2-12 haloalkenyl, (36) C2-12 haloalkynyl,
(37) C1-12 alkoxy, (38) C1-12 haloalkoxy, (39) C3-s cycloalkyl, (40) heteroaryl;
with a proviso that when R1 and R3 together with the nitrogen atom to which R1 is
attached form an imidazole ring, Rc or Rc' cannot be C02H.
or
with a proviso that when R1 and R3 together with the nitrogen atom to which R1 is
attached forms a heterocyclic or heteroaryl ring which may additionally contain
from one to three heteroatoms independently selected from 0, S and N, Rc or
Rc' cannot be C02H.
R9 and R10 are independently selected from hydrogen, C1-12 alkyl, C2-12 alkenyl,
C2-12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C3-s cycloalkyl, heterocyclyl, aryl,
heteroaryl, (CH2)n-cycloalkyl, (CH2)n-heterocyclyl, (CH2)n-aryl, (CH2)n-heteroaryl,
each of which may be optionally substituted with halogen, hydroxyl or C1-6
alkoxy, or R9and R10 may be joined together to form a heterocyclic or heteroaryl
ring which may contain from one to three heteroatoms independently selected
60
DUPLICATE
from 0, S and N, which may optionally be substituted with one or more
substituents independently selected from Rc or Rc';
R12 is C1-a alkyl, which is linear or branched and which is unsubstituted or
substituted with 1-5 groups independently selected from halogen, C02H, and
co2c1-6 alkyl, wherein the co2c 1-6 alkyl is linear or branched;
M and L independently represent a hydrogen atom or they may join together to
form a ring;
n' is 0 or 1
m can be 1 or 2;
n can be 1, 2, 3 or 4; and
PG is an amino protecting groups selected from acetyl, trifluoroacetyl,
benzyloxycarbonyl ( CBz), t-butoxycarbonyl (Soc), 9-fluorenylmethyloxycarbonyl
(Fmoc), 2,2,2-trichloroethyloxycarbonyl and allyloxycarbonyl.
13. A compound of formula XI and its pharmaceutically acceptable derivatives,
tautomeric forms, stereoisomers including R and S isomers, prodrugs,
metabolites, salts or solvates thereof:
Formula XI
wherein
Ar represents aryl which may be phenyl, which may be unsubstituted or optionally
substituted at any available position by one or more substituents selected from
but not limited to halogen, CN, hydroxyl, NH2, C1-12 alkyl or C1-12 alkoxy, wherein
each of C1-12 alkoxy and C1-12 alkyl may be linear or branched and can be
unsubstituted or optionally substituted with 1-5 halogens;
61
DUPLICATE
R1 is selected from the group consisting of but not limited to (CH2)nCONR8 Rb,
(CH2)nCOOR8
, (CH2)nNR8Rb, (CH2)nNR8CORb, (CH2)nC(=Y)R8 (wherein Y is 0
or S), (CH2)n0R8 (wherein each methylene group may be substituted by one or
more halogen atoms), -(CO)R8
, -(CO)NR8 Rb, hydrogen, C1-12 alkyl, C2-12
alkenyl, C2-12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C2-12 haloalkynyl, C3-s
cycloalkyl, heterocyclyl, aryl, heteroaryl, (CH2)n-cycloalkyl, (CH2)n-heterocyclyl,
(CH2)n-aryl, (CH2)n-heteroaryl, each of which may be optionally substituted at
any available position by one or more substituents selected from but not limited
to hydrogen, halogen, CN, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy,
C1-12 haloalkyl, C1-12 haloalkoxy, C2-12 haloalkenyl, C2-12 haloalkynyl, C1-12
alkylcarbonyl, C1-12 alkoxycarbonyl, oxo, -OR8
, -SR8
, -N02, -NR8Rb,
N(R8 )(CO)Rb, N(R8 )(CO)ORb, N(R8)(CO)NR8 Rb, -(CO)R8
, -(CO)NR8 Rb, -
O(CO)R8
, -O(CO)NR8 Rb, -COOR8
, C3-s cycloalkyl, S(O)mR8
, S02NR8Rb ;
cycloalkyl which may be optionally substituted at any available position by one
or more substituents independently selected from Rc or Rc'; aryl which may be
optionally substituted at any available position by one or more substituents
independently selected from Rc or Rc'; heteroaryl which may be optionally
substituted at any available position by one or more substituents independently
selected from Rc or Rc'; or heterocyclyl which may be optionally substituted at
any available position by one or more substituents independently selected from
Rc or Rc·.
'
R2 and R3 together represents a single oxygen or sulphur atom which is linked to
the diazepine ring by a double bond; or R1 and R2 together forms a double bond
in the diazepine ring and R3 represents the group -NR8 Rb; or R1 and R3 together
with the nitrogen atom to which R1 is attached forms a heterocyclic or heteroaryl
ring which may additionally contain from one to three heteroatoms
independently selected from 0, S and N; the ring formed may optionally be
substituted with one or more substituents selected from Rc or Rc' and R2
represent hydrogen or a double bond;
R4 and R5 are independently selected from the group consisting of hydrogen,
halogen, CN, Cr12 alkyl, C2-12 alkenyl, C2-12 alkynyl, Cr12 alkoxy, C1-12 haloalkyl,
Cr12 haloalkoxy, C2-12 haloalkenyl, C2-12 haloalkynyl, C1-12 alkylcarbonyl, C1-12
62
DUPLICATE
alkoxycarbonyl, -ORa, -SRa, -N02, -NRaRb, N(Ra)(CO)Rb, N(Ra)(CO)ORb,
N(Ra)(CO)NRaRb, -(CO)Ra, -(CO)NRaRb, -O(CO)Ra, -O(CO)NRaRb, -COORa, C3-
a cycloalkyl, S(O)mRa, S02NRaRb; cycloalkyl which may be optionally substituted
at any available position by one or more substituents independently selected
from Rc or Rc'; aryl which may be optionally substituted at any available position
by one or more substituents independently selected from Rc or Rc'; heteroaryl
which may be optionally substituted at any available position by one or more
substituents independently selected from Rc or Rc'; or heterocyclyl which may be
optionally substituted at any available position by one or more substituents
independently selected from Rc or Rc';
R6 and R7 are independently selected from the group consisting of hydrogen,
halogen, CN, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, Cr12 haloalkyl,
C1-12 haloalkoxy, C2-12 haloalkenyl, C2-12 haloalkynyl, C1-12 alkylcarbonyl, C1-12
alkoxycarbonyl, -ORa, -SRa, -N02, -NRaRb, N(Ra)(CO)Rb, N(Ra)(CO)ORb,
N(Ra)(CO)NRaRb, -(CO)Ra, -(CO)NRaRb, -O(CO)Ra, -O(CO)NRaRb, -COORa, C3-
a cycloalkyl, S(O)mRa, S02NRaRb; cycloalkyl which may be optionally substituted
at any available position by one or more substituents independently selected
from Rc or Rc'; aryl which may be optionally substituted at any available position
by one or more substituents independently selected from Rc or Rc'; heteroaryl
which may be optionally substituted at any available position by one or more
substituents independently selected from Rc or Rc·; or heterocyclyl which may be
optionally substituted at any available position by one or more substituents
independently selected from Rc or Rc';
R8 is independently selected from hydrogen, halogen, CN, Cn2 alkyl, C1-12
haloalkyl, Cr12 alkoxy, C1-12 haloalkoxy, Cn2 haloalkenyl, C1-12 alkylcarbonyl,
Cn2 alkoxycarbonyl, -ORa, -SRa, -CF3, -OCF3, -N01. -NRaRb, N(Ra)(CO)Rb,
N(Ra)(CO)ORb, N(Ra)(CO)NRaRb, -(CO)Ra, -(CO)NRaRb, -O(CO)Ra,
O(CO)NRaRb, -COORa, C3-6 cycloalkyl, S(O)mRa, S02NRaRb; cycloalkyl which
may be optionally substituted at any available position by one or more
substituents independently selected from Rc or Rc·; aryl which may be optionally
substituted at any available position by one or more substituents independently
selected from Rc or Rc'; heteroaryl which may be optionally substituted at any
63
DUPLICATE
available position by one or more substituents independently selected from Rc
or Rc'; or heterocyclyl which may be optionally substituted at any available
position by one or more substituents independently selected from Rc or Rc';
R8 and Rb are independently selected from hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-
12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C2-12 haloalkynyl, C3-a cycloalkyl,
heterocyclyl, aryl, heteroaryl, (CH2)n-cycloalkyl, (CH2)n-heterocyclyl, (CH2)n-aryl,
(CH2)n-heteroaryl; each of which may be optionally substituted with halogen,
hydroxyl, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, Cn2
alkylcarbonyl, C1-12 alkoxycarbonyl, C3-a cycloalkyl, C1-12 haloalkyl, C1-12
haloalkoxy, Cn2 haloalkenyl, aryl, heterocyclyl, heteroaryl, (CH2)n-aryl, (CH2)nheterocyclyl,
(CH2)n-heteroaryl, (CH2)n-cycloalkyl, oxo, -CN, -OR9
, -N02, -
NR9R10, N(R9)(CO)R10, N(R9)(CO)OR10, N(R9)(CO)NR9R10, -C(=Y)R9 (wherein Y
is 0 or S), -(CO)NR9R10, -O(CO)R9
, -O(CO)NR9R10, -COOR9
, -SR9
, S(O)mR9
,
S02NR9R10; S03H, NHS02R9
, P(O)R9R10; or R8 and Rb may be joined together
along with the nitrogen atom to which they are attached to form a heterocyclic or
heteroaryl ring which may additionally contain from one to three heteroatoms
independently selected from 0, S and N, the ring formed may optionally be
substituted with one or more substituents selected from hydrogen, halogen, C1-
12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C2-12
haloalkynyl, C3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, (CH2)0-cycloalkyl,
(CH2)n-heterocyclyl, (CH2)n-aryl, (CH2)n-heteroaryl, C1-12 alkylcarbonyl, C1-12
alkoxycarbonyl, oxo, CN, -OR9
, -CF3, -OCF3 CH2CF3, CF2CF3, -N02, -NR9R10,
N(R9)(CO)R10, N(R9)(CO)OR10, N(R9)(CO)NR9R10, -C(=Y)R9 (wherein Y is 0 or
S), -(CO)NR9R10, -O(CO)C1-C12alkyl, -O(CO)NR9R10, -COOR9
, -SR9
, S(O)mR9
,
S02NR9R10; S03H, NHS02R9
, P(O)R9R10; the ring thus formed may further be
fused with 3 to 7 membered unsaturated or saturated ring, which may contain
from one to three heteroatoms independently selected from 0, S or N, the fused
ring may optionally be substituted with one or more substituents Rc or Rc';
Rc or Rc' is independently selected from the group consisting of but not limited to
(1) hydrogen, (2) halogen, (3) C1-12 alkyl which is linear or branched and which
can be unsubstituted or substituted with 1-5 halogens or phenyl, which is
unsubstituted or substituted with 1-5 substituents independently selected from
64
DUPLICATE
halogen, CN, OH, R12, OR12, NHS02R12, S02R12, C02H and C02C1-e alkyl
,wherein the co2c1-6 alkyl is linear or branched (4) aryl which can be
unsubstituted or substituted with 1-5 substituents independently selected from
halogen, CN, OH, R12, OR12, NHS02R12, S02R12, C02H and C02C1-e alkyl,
wherein the C02C1-e alkyl is linear or branched (5) a 5 or 6 membered
heterocyclyl which may be saturated or unsaturated comprising 1-4 heteroatoms
independently selected from N, Sand 0, the heterocycle being unsubstituted or
substituted with 1-3 substituents independently selected from oxo, OH, halogen,
C1-e alkyl, and OC1-e alkyl, wherein the C1-e alkyl and OC1-e alkyl are linear or
branched and optionally substituted with 1-5 halogens; (6) (CH2)n-cycloalkyl, (7)
(CH2)n-heterocyclyl, (8) (CH2)n-aryl, (9) (CH2)n-heteroaryl, (10) C1-12
alkylcarbonyl, (11) C1-12 alkoxycarbonyl, (12) CN, (13) -OR9, (14) -OCF3, (15)N02.
(16) =NOR10
, (17) -NR9R10, (18) N(R9)(CO)R10, (19) N(R9)(CO)OR10, (20)
N(R9)(CO)NR9R10
, (21) C(=Y)R9 (wherein Y is 0 or S), (22) -(CO)NR9R10
, (23)O(
CO)R9
, (24) -O(CO)NR9R10,(25) -COOR9
, (26) -SR9
, (27) S(O)mR9
, (28)
S02NR9R10; (29) S03H, (30) NHS02R9
, (31) P(O)R9R10, (32) C2_12 alkenyl, (33)
C2-12 alkynyl, (34) C1-12 haloalkyl, (35) C2-12 haloalkenyl, (36) C2-12 haloalkynyl,
(37) C1-12 alkoxy, (38) C1-12 haloalkoxy, (39) C3-a cycloalkyl, ( 40) heteroaryl;
with a proviso that when R1 and R3 together with the nitrogen atom to which R1 is
attached form an imidazole ring, Rc or Rc' cannot be C02H.
or
with a proviso that when R1 and R3 together with the nitrogen atom to which R1 is
attached forms a heterocyclic or heteroaryl ring which may additionally contain
from one to three heteroatoms independently selected from 0, S and N, Rc or
Rc· cannot be C02H.
R9 and R10 are independently selected from hydrogen, C1-12 alkyl, C2_12 alkenyl,
C2-12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C3-a cycloalkyl, heterocyclyl, aryl,
heteroaryl, (CH2)n-cycloalkyl, (CH2)n-heterocyclyl, (CH2)n-aryl, (CH2)n-heteroaryl,
each of which may be optionally substituted with halogen, hydroxyl or C1-e
alkoxy, or R9and R10 may be joined together to form a heterocyclic or heteroaryl
ring which may contain from one to three heteroatoms independently selected
65
DUPLICATE
from 0, S and N, which may optionally be substituted with one or more
substituents independently selected from Rc or Rc';
R12 is C1-a alkyl, which is linear or branched and which is unsubstituted or
substituted with 1-5 groups independently selected from halogen, C02H, and
co2c1-6 alkyl, wherein the co2c1-6 alkyl is linear or branched;
m can be 1 or 2;
n can be 1, 2, 3 or 4;
r can be 1, 2, 3 or 4; and
PG is an amino protecting groups selected from acetyl, trifluoroacetyl,
benzyloxycarbonyl (CBz), t-butoxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl
(Fmoc), 2,2,2-trichloroethyloxycarbonyl and allyloxycarbonyl.
14. A compound of formula XII and its pharmaceutically acceptable derivatives,
tautomeric forms, stereoisomers including R and S isomers, prodrugs,
metabolites, salts or solvates thereof:
Formula XII
wherein
Ar represents aryl which may be phenyl, which may be unsubstituted or optionally
substituted at any available position by one or more substituents selected from
but not limited to halogen, CN, hydroxyl, NH2, C1-12 alkyl or C1-12 alkoxy, wherein
each of C1-12 alkoxy and C1-12 alkyl may be linear or branched and can be
unsubstituted or optionally substituted with 1-5 halogens;
X is selected from the group consisting of Nand CR11 ;
R11 is selected from the group consisting of Rc or Rc·:
Rc or Rc' is independently selected from the group consisting of but not limited to
(1) hydrogen, (2) halogen, (3) C1-12 alkyl which is linear or branched and which
can be unsubstituted or substituted with 1-5 halogens or phenyl , which is
66
DUPLICATE
unsubstituted or substituted with 1-5 substituents independently selected from
halogen, CN, OH, R12, OR12, NHS02R12, S02R12, C02H and C02C1-e alkyl
,wherein the co2c1-6 alkyl is linear or branched (4) aryl which can be
unsubstituted or substituted with 1-5 substituents independently selected from
halogen, CN, OH, R12, OR12, NHSO 2R12, S02R12, C02H and C02C1-e alkyl,
wherein the co2c1-6 alkyl is linear or branched (5) a 5 or 6 membered
heterocyclyl which may be saturated or unsaturated comprising 1-4 heteroatoms
independently selected from N, Sand 0, the heterocycle being unsubstituted or
substituted with 1-3 substituents independently selected from oxo, OH, halogen,
C1-aalkyl, and OC1-aalkyl, wherein the C1-aalkyl and OC1-aalkyl are linear or
branched and optionally substituted with 1-5 halogens; (6) (CH2)n-cycloalkyl, (7)
(CH2)n-heterocyclyl, (8) (CH2)n-aryl, (9) (CH2)n-heteroaryl, (10) C1-12
alkylcarbonyl, (11) C1-12 alkoxycarbonyl, (12) CN, (13) -OR9
, (14) -OCF3, (15)N02,
(16) =NOR10, (17) -NR9R10
, (18) N(R9)(CO)R10, (19) N(R9)(CO)OR10, (20)
N(R9)(CO)NR9R10, (21) C(=Y)R9 (wherein Y is 0 or S), (22) -(CO)NR9R10, (23)O(
CO)R9
, (24) -O(CO)NR9R10,(25) -COOR9
, (26) -SR9
, (27) S(O)mR9
, (28)
S02NR9R10; (29) S03H, (30) NHS02R9
, (31) P(O)R9R10, (32) C2-12 alkenyl, (33)
C2-12 alkynyl, (34) C1-12 haloalkyl, (35) C2-12 haloalkenyl, (36) C2-12 haloalkynyl,
(37) C1-12 alkoxy, (38) C1-12 haloalkoxy, (39) C3-s cycloalkyl, ( 40) heteroaryl;
R9 and R10 are independently selected from hydrogen, C1-12 alkyl, C2-12 alkenyl,
C2-12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C3-s cycloalkyl, heterocyclyl, aryl,
heteroaryl, (CH2)n-cycloalkyl, (CH2)n-heterocyclyl, (CH2)n-aryl, (CH2)n-heteroaryl,
each of which may be optionally substituted with halogen, hydroxyl or C1-e
alkoxy, or R9and R10 may be joined together to form a heterocyclic or heteroaryl
ring which may contain from one to three heteroatoms independently selected
from 0, S and N, which may optionally be substituted with one or more
substituents independently selected from Rc or Rc·;
R12 is C1_6 alkyl, which is linear or branched and which is unsubstituted or
substituted with 1-5 groups independently selected from halogen, C02H, and
co2c1-6 alkyl, wherein the co2c 1-6 alkyl is linear or branched; and
67
DUPLICATE
PG is an amino protecting groups selected from acetyl, trifluoroacetyl,
benzyloxycarbonyl (CBz), t-butoxycarbonyl (Soc), 9-fluorenylmethyloxycarbonyl
(Fmoc), 2,2,2-trichloroethyloxycarbonyl and allyloxycarbonyl.
15. Use of compound of formula V for the preparation of:
(2R)-4-oxo-(3-trifluoromethyl)-5,6-dihydro-[1 ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-
(2,4,5-trifluoro-phenyl)butan-2-amine and its pharmaceutically acceptable salts; or
4-[(R)-3-amino-4-(2,4,5-trifluorophenyl)-butyryl]-1 ,3,4,5-tetrahydrobenzo[
e][1 ,4]diazipin-2-one and its pharmaceutically acceptable salts; or
(R )-4-( 3-amino-4-( 2,4, 5-trifluorophenyl )-butanoyl )-7 -methoxy-4, 5-dihyd ro-1 Hbenzo[
e][1 ,4] diazipin-2(3H)-one and its pharmaceutically acceptable salts; or
(R)-3-amino-1-(9-fluoro-4H,6H-2,3,5, 10b-tetraaza-benzo[e]azulene-5-yl)-4-(2,4,5-
trifluoro-phenyl)-butan-1-one and its pharmaceutically acceptable salts; or
(R)-4-(3-amino-4-(2,4,5-trifluorophenyl)-butanoyi)-8-Fiuoro-4,5-dihydro-1 Hbenzo[
e][1 ,4] diazipin-2(3H)-one and its pharmaceutically acceptable salts; or
4-[( R )-3-amino-4-(2, 4, 5-trifluorophenyl)-butyryl]-1-methyi-8-Fiuoro-1 , 3,4,5-
tetrahydro-benzo [e][1 ,4]diazepin-2-one and its pharmaceutically acceptable salts.
16. Use of compound of formula X for the preparation of compound of formula I.
17. Use of compound of formula XI for the preparation of compound of formula VI.
18. Use of compound of formula XII for the preparation of compound of formula
VII.
19. A process for the preparation of:
(2R)-4-oxo-(3-trifluoromethyl)-5,6-dihydro-[1 ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-
(2,4,5-trifluoro-phenyl)butan-2-amine and its pharmaceutically acceptable salts; or
4-[(R)-3-amino-4-(2,4,5-trifluorophenyl)-butyryl]-1 ,3,4,5-tetrahydrobenzo[
e][1 ,4]diazipin-2-one and its pharmaceutically acceptable salts; or
(R)-4-(3-amino-4-(2,4, 5-trifluorophenyl )-butanoyl )-7 -methoxy-4,5-dihydro-1 Hbenzo[
e][1 ,4] diazipin-2(3H)-one and its pharmaceutically acceptable salts; or
68
DUPLICATE
(R)-3-amino-1-(9-fluoro-4H,6H-2,3,5, 10b-tetraaza-benzo[e]azulene-5-yl)-4-(2,4,5-
trifluoro-phenyl)-butan-1-one and its pharmaceutically acceptable salts; or
(R)-4-(3-amino-4-(2,4,5-trifluorophenyl)-butanoyi)-8-Fiuoro-4,5-dihydro-1 Hbenzo[
e][1 ,4] diazipin-2(3H)-one and its pharmaceutically acceptable salts; or
4-[(R)-3-amino-4-(2,4,5-trifluorophenyl)-butyryl]-1-methyi-8-Fiuoro-1 ,3,4,5-
tetrahydro-benzo [e][1 ,4]diazepin-2-one and its pharmaceutically acceptable salts;
according to claims 1 or 2.