FIELD OF THE INVENTION
The present invention is related to novel compounds of the general formula A, their
stereoisomers, their racemates, their pharmaceutically acceptable salts, pharmaceutical
compositions containing them, methods of making the above compounds, and their use as
Dipeptidyl Peptidase IV (DPP IV) Inhibitors, which are useful in the treatment or prevention
of diseases in which DPP IV enzyme is known to be involved in the pathogenesis. These
diseases include mainly type II diabetes and related diseases such as, syndrome X which
includes insulin resistance, hypertension, obesity, dyslipidemia, hyperglycemia,
atherosclerosis as well as for the prevention or treatment for other pathogenic conditions in
which DPP IV is involved.

BACKGROUND OF THE INVENTION
Diabetes mellitus is a major, growing health problem worldwide (Yach, D., et at. Nat. Med.
12, 62-66, 2006). Type 2 diabetes mellitus (hereafter referred as type 2 diabetes, also
known as non-insulin-dependent diabetes mellitus, NIDDM) is a heterogeneous disorder,
with both genetic and environmental factors contributing to its development. The
pathogenesis of type 2 diabetes involves multiple mechanisms leading to hyperglycemia,
most notably increased hepatic glucose production, impaired insulin secretion by pancreatic
P cells and reduced glucose uptake by skeletal muscle and adipose tissue (peripheral insulin
resistance). Type 2 diabetic patients are at substantially increased risks of macrovascular
disease including coronary heart disease and stroke and microvascular disease including
retinopathy, nephropathy and neuropathy.
Type 2 diabetes is a therapeutic area with huge market potential. The number of diabetic
patients is projected to increase from 170-175 million in 2000 to over 350 million by 2030
(Wild, S., et al. Diab.Care 27, 1047-1053, 2004; Yach, D., et al. Nat. Med. 12, 62-66, 2006).
The major part of this numerical increase is expected to occur in developing countries and
India will have the distinction of having the largest number of diabetic patients in the world
by 2030.
The treatment approaches for type 2 diabetes include diet, exercise, and a variety of
pharmacological agents. Clinically established therapies for type 2 diabetes include insulin
and its analogs and various oral hypoglycemic agents: sulfonylureas, metformin, a-
glucosidase inhibitors (acarbose, miglitol), non-sulfonylurea insulin secretagogues
(repaglinide, nateglinide) and thiazolidinedione (TZD) derivatives (rosiglitazone,
pioglitazone) acting via PPARy agonism (Matthaei, S., et al. Endocrine Rev. 21, 585-618,
2000; Skyler, J.S. J.Med.Chem. 47, 4113-4117, 2004). These agents act by different
mechanisms to normalize blood glucose levels, but are limited in their abilities, either alone
or in combination, to prevent the onset of diabetic complications. Further, each of the above
oral agents suffers either from generally inadequate efficacy or number of adverse effects.
For example, sulfonylureas, which have been the mainstay of oral treatment for over 5
decades, are known to be associated with a high rate of secondary failure and
hypoglycemia. The TZD class of antidiabetic agents (glitazones) improves glucose utilization
without stimulating insulin release, but their use is associated with undesirable effects (e.g.
risk of myocardial infarction, cardiac hypertrophy, liver toxicity, weight gain).
Considering together the facts that about 90% of all diabetic cases account for NIDDM and
the inadequacy of the currently available treatment, the clinical need and market potential for
new oral antidiabetic drugs, which maintain tight glycemic control and prevent diabetic
diabetic complications are very high.
The recent introduction of incretin-based therapies, which include incretin mimetics (e.g.
exenatide) and incretin enhancers (e.g. sitagliptin, vildagliptin) is gaining clinical importance,
as novel strategies for the treatment of type 2 diabetes. The incretin concept was first
developed based on observations that insulin release was enhanced after oral ingestion of
glucose, as compared with an equivalent glucose challenge given intravenously. This led to
a hypothesis that in response to nutrient ingestion the gastrointestinal tract released one or
more hormones ("incretins") that augmented insulin secretion. This hypothesis was validated
with the identification of two key hormones, physiological incretin mimetics, glucagon-like
peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) (Frias, J. and
S.V. Edelman. Curr.Opin.Endocrinol. Diab.Obes. 14, 269-276, 2007; Drucker, D.J.,
J.Clin.Invest. 117, 24-32, 2007). GLP-1 is released from the enteroendocrine L-cells of the
small intestine and GIP is released from duodenal K-cells. These hormones account for
about 50% of the total insulin response, following a meal. The discovery of these incretin
hormones has stimulated tremendous interest in their therapeutic potential for type 2
diabetes patients.
The incretins, chiefly GLP-1, lower blood glucose levels through multiple mechanisms. GLP-
1 potentiates glucose-dependent insulin secretion from islet p-cells by activating specific G-
protein-coupled receptors (Drucker, D.J., Cell Metab. 3, 153-165, 2006). In addition to
enhancing insulin secretion, GLP-1 also inhibits glucagon secretion and gastric emptying
and induces a feeling of satiety leading to weight loss in diabetic patients. More importantly,
GLP-1 has the potential to reverse p-cell dysfunction by inhibiting p-cell apoptosis,
stimulating p-cell growth and differentiation and promoting p-cell turnover. The incretins also
enhance target tissue insulin sensitivity. Incretin-based therapies offer low risk of
hypoglycemia, as the activation of incretin receptors is coupled to stimulation of insulin
secretion in the presence of elevated blood glucose.
Although GLP-1 is very beneficial in maintaining glycemic control in diabetic patients, the
peptide is metabolically unstable, as it is rapidly degraded by the ubiquitous serine protease
dipeptidyl peptidase IV (DPP-IV), with an extremely short half-life in vivo, approximately 2
min, thus making it unattractive from the therapeutic standpoint. One approach to
circumvent this stability problem has been the development of long-acting degradation-
resistant peptides that can be administered parenterally (Deacon, C.F., Diabetes, 53, 2181-
2189, 2004). This has resulted in the development of exenatide (Byetta, Amylin
Pharmaceuticals), a peptidic GLP-1 receptor agonist, that was approved by the FDA for the
treatment of type 2 diabetes. Several other long-acting DPP-IV resistant GLP-1 analogs are
in clinical development (P.L. Brubaker, Trends Endocrinol. Metab. 18, 240-245, 2007). An
alternative therapeutic strategy has focused on the inhibition of proteolytic activity of DPP-IV,
to prevent the degradation of GLP-1 (and other incretin hormone GIP) and extend its plasma
half-life (Green, B.D., et al. Expert Opin. Emerging Drugs 11, 525-539, 2006; Sebokova, E.,
et al. Curr. Top. Med. Chem. 7, 547-555, 2007)
Dipeptidyl peptidase IV (DPP-IV, EC 3.4.14.5; also known as CD26), a multifunctional
transmembrane glycoprotein, is a serine protease that cleaves N-terminal dipeptides from
polypeptides with L-proline or L-alanine at the penultimate position. It is present both in
circulation (plasma) and on the surface of several cell types, including epithelial, endothelial
and lymphoid cells. It is identical to the T cell activation antigen CD26 and the adenosine
deaminase-binding protein. The endogenous substrates of DPP-IV include a wide variety of
proline-containing peptides such as growth factors, chemokines, neuropeptides and
vasoactive peptides (Gorrell, M., Clin.Sci. 108, 277-292, 2005; Mcintosh, C.H.S., et al. Int. J.
Biochem. Cell Biol. 38, 860-872, 2006)
Preclinical studies in laboratory animals, both genetic and pharmacological, have amply
demonstrated the essential role for DPP-IV in the control of glucose homeostasis. Mice with
a targeted inactivation of DPP-IV gene or Fischer344/CRJ rats with a spontaneous
inactivating DPP-IV mutation have increased GLP-1 levels and show improved glucose
homeostasis. Furthermore, pharmacological DPP-IV blockade was found to improve glucose
tolerance in animal models of impaired glucose tolerance and diabetes (I. Idris and R.
Donnelly, Diab.Obes.Metab. 9, 153-165, 2007; D.J. Drucker, Diab. Care 30, 1335-1343,
2007).
The selectivity of DPP-IV inhibitors against other closely-related proline-specific dipeptidyl
peptidases, particularly DPP-8 and DPP-9, has been one of the key issues in the selection
of compounds for development, as there is potential for adverse events associated with non-
selective DPP-IV inhibitors. The inhibition of DPP-8 and DPP-9 has been found to be
associated with toxicities in rat and dog (Lankas, G.R., et al. Diabetes 54, 2988-2994, 2005).
Therefore, it is important to demonstrate that DPP-IV inhibitors do not appreciably inhibit
these closely related enzymes. Consequently, the degree of DPP-8/DPP-9 selectivity has
become an important criterion in the selection and development of DPP-IV inhibitors.
Clinically, DPP-IV inhibitors have been found to be very effective in providing glycemic
control in diabetic subjects. These molecules are orally bioavailable, prevent degradation of
GLP-1 leading to increased circulating levels of hormone and also stabilize other incretins.
However, circulating insulin levels are not increased during DPP-IV inhibitor treatment.
These inhibitors also improve fasting and postprandial blood glucose levels, as well as
effectively lower HbA1c in diabetic patients. They are found to have good tolerability and
safety profile during clinical trials and posed low risk of hypoglycemia. Currently, two DPP-IV
inhibitors (sitagliptin and vildagliptin) are in clinical use, both as monotherapy and in
combination with other antidiabetic agents, such as metformin or thiazolidinediones. Several
DPP-IV inhibitors are in advanced stages of clinical development (e.g. alogliptin, saxagliptin,
BI-1356, dutogliptin). Several other DPP IV inhibitors are also reported in literature but are
different from the compounds of the present invention to be discussed later. Some of such
compounds in the prior art are given below:
Earlier development in the filed of DPP IV inhibitors relates to various 2-cyanopyrrolidine
derivatives as provided below.
US 5,939,560 and Bioorganic & Medicinal Chemistry Letters, 6(10), 1163 - 1166 (1996),
disclose several compounds of general formula (1) including possessing Dipeptidyl
Peptidase IV inhibiting activity and postulated to have therapeutic potential in a number of
disease states such as inflammation, graft versus host disease (GVHD), cancer and AIDS.
The said research article in Bioorganic & Medicinal Chemistry Letters along with the DPP IV
inhibitory activity also describes manufacturing methods for 2-cyanopyrrolidides.

Majority of DPP IV inhibitors in the recent inventions pertaining to the class of pyrrolidine
derivatives have a common structural feature as provided below:

Novartis AG in US 6,011,155; US 6,166,063; US 6,617,340; US 6,432,969 and WO
98/19998 describe the compounds wherein Ra (of figure A) is substituted or unsubstituted
alkyl, cycloalkyl, phenoxy, heterocyclic system, heteroaromatic system, [2.2.1] and
[3.1.1]bicyclo moity or adamantly.

US 7,138,397; US 7,332,487 & US 6,849,622 describes various DPP IV inhibitors wherein
Ra is a substituted six membered ring as shown below.

US 7,183,290 describes various fluoropyrrolidines of formulae 4 to 9 as dipeptidyl peptidase
inhibitors wherein Re of Figure 'A' is fluoro and of the same figure Ra is selected from
various cycles like substituted piperidinyl, pyrrolidinyl, cyclohexanyl, tropanyl, azetidinyl as
provided in the compounds 4 to 9.

Following literature on DPP IV inhibitors also provide various substituents at Ra (of Figure
A).
US 6,861,440 relates to compounds of formula (10) and pharmaceutically acceptable salts
thereof. The compounds are useful for the treatment and/or prophylaxis of diseases that are
associated with DPP IV, such as diabetes, particularly non-insulin dependent diabetes
mellitus, and impaired glucose tolerance.

wherein R1 is CN, R2 is --C(R3,R4)--(CH2)n --R5, R3 is hydrogen, lower-alkyl, benzyl, or
hydroxybenzyl, R4 is hydrogen or lower-alkyl, R5 is oxazolyl or imidazolyl which can be
unsubstituted or substituted with 1 to 3 substituents independently selected from the group
consisting of lower-alkyl, lower-alkoxy, halogen, CN, CF3, trifluoroacetyl, pyridinyl and
phenyl, which pyridinyl can be unsubstituted or substituted with 1 to 3 substituents
independently selected from the group consisting of lower-alkyl, lower-alkoxy, hologen, and
CF3, and which phenyl can be unsubstituted or substituted with 1 to 3 substituents
independently selected from the aroup consisting of lower-alkyl, lower-alkoxy, benzyloxy,
halogen, CF3, CF3-O, CN and NH-CO-lower-alkyl, X is C(R8,R9), R8 and R9 independently
from each other are H or lower-alkyl, n is 0,1 or 2, or a pharmaceutically acceptable salt
thereof.
US 20050130981 describes a compound having the formula 11 as potent DPP-IV enzyme
inhibitor.

wherein R1 represents a nitrogen-containing aromatic moiety consisting of one or two
aromatic rings; which is optionally mono- or disubstituted by a substituent independently
selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, halogen, trihalogenomethyl,
methylthio, nitro, cyano, amino, and phenyl group; or R1 represents a thienyl, furyl or benzyl
group; or R1 represents a p-toluenesulfonyl group; or R1 represents an acyl group of formula
R1a--CO, wherein R1a represents a C1-4 alkyl, phenyl, piperidin-1-yl, 4-methylpiperazin-1-yl,
pyrrolidin-1-yl; or phenyl, pyridyl or phenylethenyl substituted with one or more groups
selected from an alkyl, alkoxy, nitro, or halogen atom; or a phenylethenyl or phenylethyl
substituted with alkylene-dioxy; B represents a group having the formula:

R2 represents a hydrogen atom or a fluorine atom; R3 represents a fluorine atom; or a salt,
isomer, tautomer, solvate, or hydrate thereof.
US 7,268,150 discloses a 2-cyano-4-fluoropyrrolidine derivatives of formula 12 having
dipeptidyl peptidase IV-inhibiting activity, and a remedy based on the activity for insulin-
dependent diabetes (type 1 diabetes), especially for non insulin-dependent diabetes (type 2
diabetes), insulin-resistant disorders, and obesity.

wherein, R1-B represents methanesulfonyl, formyl or acetyl which may be substituted by a
group selected from the group consisting of --OH and fluoro; R2 represents -H, methyl or
ethyl; or a pharmaceutically acceptable salt thereof.
US 20050215784 and US 20070238753 disclose compounds of formula (13) that inhibit
dipeptidyl peptidase IV (DPP-IV) and are useful for the prevention or treatment of diabetes,
especially type II diabetes, as well as hyperglycemia, Syndrome X, hyperinsulinemia,
obesity, atherosclerosis, and various immunomodulatory diseases.

US20050192324 WO 2006040625, WO 2006011035 and WO 2007099385 describe
compound of formula (14) as DPP-IV inhibitors having utility in the treatment of metabolic
disorders.

US20070265320 and US20070167501 describe bicyclo derivatives of formula (15) as DPP-
IV inhibitors and claimed to be useful in the prevention and/or treatment of diabetes and
associated complications and prevention and / or treatment of other diseases involving DPP-
IV.
WO 2005095339 provides compound of formula (16) as DPP IV inhibitors. The compounds
were claimed to be useful in the treatment of diabetic complications including diabetic
neuropathy, diabetic microangiopathy, and the like.

US20060276487 relates to the novel compounds of the general formula (17) possessing
dipeptidyl peptidase IV enzyme inhibitory activity

wherein B is selected from following groups

and Z is selected from the groups of formula:

US 20060258621 is directed to pyrrolidinylaminoacetyl pyrrolidine boronic acid compounds
of formula (18) that display selective, potent dipeptidyl peptidase IV (DPP-IV) inhibitory
activity. These compounds are claimed to be useful for the treatment of disorders that can
be regulated or normalized via inhibition of DPP-IV including those characterized by
impaired glycemic control such as Diabetes Mellitus and related conditions.

WO 2006090244 relates to DPP IV inhibitors of formula (19) claimed to be useful in
treatment of disorders mediated by DPP IV inhibition, such as diabetes.

The second important point of substitution in the backbone provided in figure 'A' is Rb.
Substituents at Rb tried by various inventors are summarized hereinbelow.
Invention described in US 7,026,316 is directed to a compound of formula (20), which are
inhibitors of the dipeptidyl peptidase-IV enzyme ("DP-IV inhibitors") and which are useful in
the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is
involved, such as diabetes and particularly type 2 diabetes. The invention is also directed to
pharmaceutical compositions comprising these compounds and the use of these
compounds and compositions in the prevention or treatment of such diseases in which the
dipeptidyl peptidase-IV enzyme is involved.

US 7,132,443 discloses fluoropyrrolidines (compounds of formula 21 and 22, wherein Re of
figure 'A' is fluoro) as dipeptidyl peptidase IV inhibitors, their use for inhibiting serine
proteases, such as dipeptidyl peptidases, such as DPP-IV and to methods for their
production and their therapeutic utility. The inventors specifically claim compound of formula
22.

US 20060281796 provide DPP-IV inhibitors wherein Rb (of Figure A) is fused indole
derivative as shown in the formula (23). The compounds were claimed to be useful in the
treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved,
such as diabetes and particularly type 2 diabetes. The invention is also directed to
pharmaceutical compositions comprising these compounds and the use of these
compounds and compositions in the prevention or treatment of such diseases in which the
dipeptidyl peptidase-IV enzyme is involved.

US 20070021477 is directed to DPP IV inhibitors wherin Rb (of Figure A) is fused cyclohexyl
group as provided in the formula (24) and are claimed to be useful in the treatment or
prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as
diabetes and particularly type 2 diabetes. The invention is also directed to pharmaceutical
compositions comprising these compounds and the use of these compounds and
compositions in the prevention or treatment of such diseases in which the dipeptidyl
peptidase-IV enzyme is involved.

US 20050234065 provides compounds wherein Rb (of Figure A) is substituted cyclohexyl as
shown in the formula (25) as DPP IV inhibitors. The inventors claims the compounds would
have utility in the treatment of Type 1 and 2 diabetes, and related diseases.

Some inventors have reported compounds wherein Ra and Rb of the basic backbone
provided in figure A both were substituted with various substituents as follows.
US 6,911,467 describes various 1-(2'-aminoacyl)-2-cyanopyrrolidine derivatives of general
formula (26) with DP-IV inhibitory activity for treatment of impaired glucode tolerance or type
2 diabetes.

Wherein A is selected from groups (27, 28 and 29); X is selected from aminoacyl groups
corresponding to the natural amino acids, acyl groups (R3-CO), R4 COOC(R5)(R6)OCO,
methoxycarbonyl, ethoxycarbonyl and benzyloxycarbonyl; R1 is selected from H, Ci -C6 alkyl
residues, (CH2)aNHW1, (CH2)b COW2, (CH2)cOW3, CH(Me)OW4, (CH2)d--C6H4--W5 and
(CH2)e SW6, where a is 2-5, b is 1-4, c is 1-2, d is 1-2, e is 1-3, W1 is COW6, CO2W6 or
SO2W6, W2 is OH, NH2, OW6 or NHW6, W3 is H or W6, W4 is H or W6, W5 is H, OH or OMe,
and W6 is C1 -C6 alkyl, optionally substituted phenyl, optionally substituted heteroaryl or
benzyl and R2 is selected from H and (CH2)n -C5H3 N-Y, where n is 2-4 and Y is H, F, CI,
NO2 or CN, or R1 and R2 together are -(CH2)P - where p is 3 or 4; R.sup.3 is selected from
H, C1 -C6 alkyl and phenyl; R4 is selected from H, d -C6 alkyl, benzyl and optionally
substituted phenyl; R5 and R6 are each independently selected from H and C1 -C6 alkyl or
together are --(CH2)m--, where m is 4-6; R7 is selected from pyridyl and optionally substituted
phenyl; R8 is selected from H and C1 -C3 alkyl; and R9 is selected from H, C1 -C6 alkyl, C1 -C6
alkoxy and phenyl.
EP 1 560 811 discloses a compound of formula (30) which inhibit dipeptidyl peptidase IV
(DPP-IV) and claims to be useful in the prevention or treatment of diabetes, especially type
II diabetes, as well as hyperglycemia, Syndrome X, hyperinsulinemia, obesity,
atherosclerosis, and various immunimodulatory diseases.

Literature providing DPP-IV inhibitors wherein, Ra and Rb of the basic backbone provided in
figure A become part of a ring is summarized below.
US 20050070719 discloses a compound of Formula 31 and pharmaceutically acceptable
derivatives thereof as inhibitors of DPP IV. The compounds were claimed to be useful in the
treatment of neurological disorders, diabetes, inflammatory disorders such as arthritis,
obesity, osteoporosis, and of such other enumerated conditions as can be treated with
inhibitors of DPP IV,

wherein the pyrrolidine ring formed by X, Z, N, and the carbon atoms to which they are
attached, is saturated, or optionally contains one double bond; X is selected from the group
consisting of CH2, CH, S, O, NH, N, C=O, CF2, CF, CH--Y, and C-Y; Z is selected from the
group consisting of CH2, CH, CF2, CF, C-Y and CH--Y; wherein Y is halogen, hydroxy, or
C1-C3 alkyloxy; and wherein one of X or Z must be CH2; or CH if said pyrrolidine ring
contains one double bond; M, Q, and V represent carbon atoms; n is 0 or 1; and where
either R1 and R2, taken together with V and Q, or R2 and R3, taken together with Q and M,
form a 3-6 membered, saturated carbocyclic or heterocyclic ring which may contain one or
two heteroatoms selected from the group consisting of O, S, and N.
US 7,186,731 discloses compound of formula (32) having DPP IV inhibiting activity and
claimed to be useful in the treatment of conditions mediated by DPP-IV, such as non insulin
dependent diabetes mellitus.

wherein X1 and X2 each is independently lower alkylene; X3 is +CH2, +CHF or +CF2; R1 is
a substituent as described in the patent specification, R2 and R3 each is independently H or
lower alkyl; n is 0, 1, 2, 3 or 4.
Pyrrolidine ring expansion, substitution at ring nodes and substitution at rest of the places in
the backbone were also tried by various inventors to provide alternative DPP - IV inhibitors.
WO 2004041795 discloses compound of formula (33) as dipeptidyl peptidase IV (DPP-IV)
inhibitors, its pharmaceutical compositions and method of treating medical conditions using
compound of formula (33). The inventors claim the usefulness of these compounds in the
treatment of neurological disorders, diabetes, inflammatory disorders such as arthritis,
obesity, osteoporosis, and of such other enumerated conditions as can be treated with
inhibitors of DPP-IV.

US 20050090539, US 20050038020 provide adamantylglycine-based inhibitors of dipeptidyl
peptidase IV of Formula (34) or a pharmaceutically acceptable salt thereof for the treatment
of diabetes and related diseases.

wherein: n is 0, 1 or 2; m is 0, 1 or 2; the dashed bonds forming a cyclopropyl ring when Y is
CH; X is hydrogen or CN; Y is CH, CH2, CHF, CF2, O, S, SO, or SO2 A is substituted or
unsubstituted; R1 and R2 are each independently selected from hydrogen, alkyl, alkenyl,
alkynyl, aryl and heteroaryl; including pharmaceutically acceptable salts thereof, and
prodrug esters thereof, and all stereoisomers thereof.
US 20060281727 describes phenylalanine derivatives of formula (35) which are inhibitors of
the DPP-IV enzyme and are claimed to having utility in the treatment or prevention of
diseases in with the said enzyme is involved, such as diabetes and particularly type 2
diabetes.

WO 2007029086 relates to 3-azabicyclo[3,1,0]hexane derivatives of formula (36) as DPP-IV
inhibitors.

In the recent past certain developments pertaining to the class of five membered ring
systems like pyrrolidine, thiazolidine, oxothiazolidine and six membered ring systems like
piperidine as DDP-IV inhibitors are summarized below.
WO 2006116157, filed by Alantos pharmaceuticals Inc., relates to pyrrolidine and
thiazolidine DPP-IV inhibitors claimed to be having utility in the treatment of DPP IV
mediated diseases, in particular Type - 2 diabetes.
US 20070112205 discloses cyanopyrrolidine derivatives represented formula (37) or a salt
thereof

wherein A is a hydrogen atom or a fluorine atom, R1 is --CONH2 or --CN and R2 is a
hydrogen atom, a tert-butoxycarbonyl group, a trityl group, an o-nitrobenzenesulfenyl group,
a benzyloxycarbonyl group, a fluorenyloxycarbonyl group, an allyloxycarbonyl group or -
C(=O)--CH2-Rc wherein Rc is a halogen atom, a methanesulfonyloxy group, a p-
toluenesulfonyloxy group or a hydroxyl group.
US 20040180925 describes various dipeptidylpeptidase-IV inhibitors represented by general
formula A-B-D, wherein A represents a substituted or unsubstituted 1-pyrrolidinyl group, a
substituted or unsubstituted 3-thiazolidinyl group, a substituted or unsubstituted 1-oxo-3-
thiazolidinyl group, or the like; B represents a) a group represented by --(C(R1)(R2))kCO--
(wherein k represents an integer of from 1 to 6, R1 and R2 may be the same or different and
each represents a hydrogen atom, a hydroxyl group, a halogen atom, or the like) or the like;
D represents --U--V [wherein U represents a substituted or unsubstituted piperazinediyl
group or the like, V represents -E-R7 (wherein E represents a single bond, -CO-, -(C=0)0-,
or -SO2-; R7 represents a hydrogen atom, a substituted or unsubstituted alkyl group, or the
like)]or a pharmacologically acceptable salt thereof.
US 20040110817 discloses inhibitors (compounds of formula 38) of the enzyme dipeptidyl
peptidase-IV, pharmaceutical compositions comprising the compounds and the use of such
compounds for treating diseases that are associated with proteins that are subject to
processing by DPP-IV, such as Type 2 diabetes mellitus, hyperglycemia, impaired glucose
tolerance, metabolic syndrome (Syndrome X or insulin resistance syndrome), glucosuria,
metabolic acidosis, cataracts, diabetic neuropathy, diabetic nephropathy, diabetic
retinopathy, diabetic cardiomyopathy, Type 1 diabetes, obesity, conditions exacerbated by
obesity, hypertension, hyperlipidemia, atherosclerosis, osteoporosis, osteopenia, frailty,
bone loss, bone fracture, acute coronary syndrome, infertility due to polycystic ovary
syndrome, short bowel syndrome, anxiety, depression, insomnia, chronic fatigue, epilepsy,
eating disorders, chronic pain, alcohol addiction, diseases associated with intestinal motility,
ulcers, irritable bowel syndrome, inflammatory bowel syndrome and to prevent disease
progression in Type 2 diabetes. The invention also relates to a method of identifying an
insulin secretagogue agent for diabetes.

WO 2005037828 describes pyrrolidine-based compounds of formula (39) having DPP-IV
inhibitory activity. The specification also describes the methods of preparing the said
compounds and pharmaceutical compositions containing them.

US 7,109,347 relates to method of treating breast cancer comprising administration of the
therapeutically effective amount of an atleast one inhibitor of DPP IV, wherein the said
inhibitor is an amino acid linked to a thiazolidine or a pyrrrolidine group by a peptide bond.
US 20050261501 discloses compounds of formula (40) useful as DPP-IV inhibitors.

wherein: X1 represents an atom or group selected from CR4aR4b, O, S(O)q, and NR5, wherein
R4a, R4b, q1 and R5 are as defined in the specification, m, represents zero or an integer from
1 to 4 inclusive, m2 represents an integer from 1 to 4 inclusive, n, and n2, which may be
identical or different, each represent an integer from 1 to 3 inclusive, R1 represents
hydrogen or a group selected from carboxy, alkoxycarbonyl, optionally substituted
carbamoyl and optionally substituted alkyl, R2 represents hydrogen or alkyl, Ak represents
an optionally substituted alkylene chain, p represents zero, 1 or 2, R3 represents hydrogen
or cyano, X2 and X3, which may be identical or different, each represent either S(O)q2, or
CR6aR6b, wherein q2, R6a and R6b are as defined in the description, its optical isomers, where
they exist, and its addition salts with a pharmaceutically acceptable acid.
US 20070093492 describes pyrrolidine compounds of the formula (41) and methods for
using them to inhibit dipeptidyl peptidase IV or treat Type II diabetes. The compounds were
claimed to have usefulness in the treatment of type 2 diabetes.

WO 2007113634 describes compounds represented by formula (42) as DPP IV inhibitors
having usefulness in the treatment of type II diabetes and diabetic complications thereof and
also in the treatment of dislipidemia, hypercholesterolemia, obesity and hyperglycemia.

US 20080015146 describes compound of formula (43) as DPP IV inhibitors and claimed to
have utility in the treatment of non-insulin-dependent diabetes mellitus.

WO 2005033099 relates to DPP-IV inhibitors of the formula (44), and their analogs,isomers,
pharmaceutical compositions and therapeutic uses. Such novel compounds are claimed to
be potent and selective inhibitors of DPP-IV, and are effective in treating conditions that may
be regulated or normalized via inhibition of DPP-IV. The invention also concerns
pharmaceutical compositions comprising the novel compounds of formula (44), methods of
inhibiting DPP-IV comprising administering to a subject in need thereof a therapeutically
effective amount of said compound and processes for their preparation.

US 6,395,767 discloses compounds of formula (45) as dipeptidyl peptidase IV (DP 4)
inhibitors.
where x is 0 or 1 and y is 0 or 1 (provided that x=1 when y=0 and x=0 when y=1); n is 0 or 1;
X is H or CN. A method is also provided for treating diabetes and related diseases,
especially Type II diabetes, and other diseases; employing such DP 4 inhibitor or a
combination of such DP 4 inhibitor and one or more of another antidiabetic agent such as
metformin, glyburide, troglitazone, pioglitazone, rosiglitazone and/or insulin and/or one or
more of a hypolipidemic agent and/or anti-obesity agent and/or other therapeutic agent.
Various Xanthine type molecules were also found to have DPP-IV inhibitory activity as
evident from following literature.
US 20060205711 relates to substituted xanthines of general formula (46) wherein R1 to R4
are defined as in the specification, which have an inhibiting effect on the activity of the
enzyme dipeptidylpeptidase~IV (DPP-IV).

WO 2007071738 describes deazaxanthine and deazahypoxanthine compounds, of formula
(47), wherein X is -CH= and Y is =N-; or X is -C(O)- and Y is -NR3)-; The compounds may
be useful in the therapy of diseases and conditions in wich dipeptidylpeptidase-IV (DPP-IV)
is implicated. The compounds were disclosed to have DPP IV inhibitory activity and claimed
to have utility in the treatment of diabetes.

Compounds from other chemical class shown to have DPP-IV inhibitory activity are provided
below.
US 6,710,040 relates to dipeptidyl peptidase-IV inhibitors of formula (48), pharmaceutical
compositions comprising the compounds and the use of such compounds for treating
diseases that are associated with proteins that are subject to processing by DPP-IV.

wherein: R1 is 3-fluoroazetidin-1-yl, 3,3-difluoroazetidin-1-yl, 3,4-difluoropyrrolidin-1-yl, 3,3,4-
trifluoropyrrolidin-1-yl, 3,3,4,4-tetrafluoropyrrolidin-1-yl, 3-fluoropiperidin-1-yl, 4-
fluoropiperidin-1-yl, 3,4-difluoropiperidin-1-yl, 3,5-difluoropiperidin-1-yl, 3,3-difluoropiperidin-
1-yl, 4,4-difluoropiperidin-1-yl, 3,4,5-trifluoropiperidin-1-yl, 3,3,4-trifluoropiperidin-1-yl, 3,3,5-
trifluoropiperidin-1-yl, 3,4,4-trifluoropiperidin-1-yl, 3,3,4,5-tetrafluoropiperidin-1-yl, 3,4,4,5-
tetrafluoropiperidin-1-yl, 3,3,4,4-tetrafluoropiperidin-l-yl 3,3,5,5-tetrafluoropiperidin-1-yl,
3,3,4,5,5-pentafluoropiperidin-1-yl, 3,3,4,4,5-pentafluoropiperidin-1-yl or 3,3,4,4,5,5-
hexafluoropiperidin-1-yl; and R2 is (C1 -C8)alkyl or (C3 -C8)cycloalkyl.
WO 2006012395 and WO 2006012441 relate to a series of compounds having the general
formula (49) as DPP IV inhibitors and claimed to be useful in treatment of diabetes.

Wherein X is NR3 or O; n is 1 or 2; A is a bicyclic carbocycle and R1 and R2 is as described
in the specification.
WO 2007113226 describes compounds of formula (50) for the treatment of non-insuline-
dependent diabetes mellitus.

WO 2007115821 discloses the compounds of formula (51) and their use as DPP IV
inhibitors. The compounds were claimed to have utility in the treatment of diabetes and
metabolic disorders.

However there still remains need to provide new compounds having inhibitory activity
against DPP IV
OBJECTIVE OF THE INVENTION
The main objective of the present invention is therefore to provide novel compounds of the
general formula A, their tautomeric forms, their stereoisomers, their racemates, their
pharmaceutically acceptable salts, pharmaceutical compositions containing them, process
and intermediates for the preparation of the compounds given in Formula A which have
inhibitory activity against DPP IV
Another objective of the present invention to develop novel compounds which are effective
and useful to lower increased levels of glucose, lipids, to improve insulin resistance, to
decrease body weight, for the treatment and/ or prophylaxis of metabolic disorders such as
type II diabetis, obesity, hyperlipidemia, with better efficacy and lower toxicity.
SUMMARY OF THE INVENTION
Acccording to one aspect of the present invention there is provided novel organic
compounds represented by the general formula (A), their stereoisomers, their racemates,
their pharmaceutically acceptable salts, and pharmaceutical compositions containing them
or mixture thereof.
In yet another aspect, the present invention provides a process for the preparation of novel
organic compounds of the general formula (A), their stereoisomers, their pharmaceutically
acceptable salts, pharmaceutical compositions containing them.
A further aspect of the present invention is to provide novel intermediates, a process for their
preparation and their use in methods of making compounds of the general formula (A).
DETAILED DESCRIPTION OF THE INVENTION
The novel organic compounds of present invention represented by the general formula (A) is
useful for reducing blood glucose, lowering lipid levels, cholestrol and reducing body weight
and also have some excellent effects in the treatment and/or prophylaxis of diseases caused
by insulin resistance such as type II diabetes, hyperlipidemia, obesity, impaired glucose
tolerance, diabetic complications with better efficacy, potency, without or reduced toxicity.
The present invention is related to the compounds of the general formula A in exo
configuration,

their optical isomers and pharmaceutically acceptable salts thereof, wherein,
n = 1,2
Y is selected from the groups

wherein, Z represents CH2, -S-, CHF;
R1 is selected from groups consisting of
i) Hydrogen;
ii) C1-C8alkyl (straight or branched) substituted with 1 to 3 substituents selected from
halogens, such as pentyl, trifluoropropyl;
iii) cycloalkyl or cycloalkenyl having 3-10 carbon atoms such as cyclohexyl or cyclohex-
2-enyl;
iv) cycloalkylmethyl having 4-10 carbon atoms such as cyclohexyl methyl;
v) Bridged polycycloalkyl methyl having 5 to 12 carbon atoms such as adamantyl
methyl;
vi) phenyl which is unsubstituted or substituted with 1-3 substituents each independently
selected from cyano or methanesulfonyl;
vii) aralkyl group such as benzyl which is unsubstituted or substituted with 1 to 3
substituents selected from halogens;
viii) heteroaryl group such as pyridyl unsubstituted or substituted with cyano;
ix) heteroaralkyl group such as pyridyl methyl;
x) aralkoxyalkyl group such as benzyloxy ethyl;
xi) SO2R5; where R5 is methyl, thiophenyl, or phenyl unsubstituted or substituted with 1
to 3 fluoro;
xii) -CONHR6 or -CSNHR6 or -CONHSO2R6; where R6 is phenyl unsubstituted or
substituted with 1 to 3 substituents each independently selected from chloro, fluoro,
trifluoromethyl and methoxy;
xiii) R7CO-, wherein R7 is selected from
a. phenyl unsubstituted or substituted with 1 to 3 substituents selected from
halogen, trifluoromethyl, cyano;
b. benzo[1,3]dioxolyl;
c. adamantyl;
d. heteroaryl such as thiophenyl; furyl; pyrazinyl; pyridyl unsubstituted or
substituted with a substituent selected from halogen, cyano, methyl,
benzyloxy;
e. N-acetylpiperidinyl;
f. Cyclohexyl;
g. Pyridine methyl;
R2 is selected from hydrogen, CN, COOH, or isosteres of COOH, wherein said isosteres of
COOH are selected from the groups consisting of esters, tetrazole, acid anhydrides,
CH2OH, CH2OBn, CONHOH, CONH2;
R3 is selected from hydrogen, -CN, C2-C5alkynyl;
R4 is selected from hydrogen or fluoro.
A compound its stereoisomers, racemates, pharmaceutically acceptable salts thereof as
described herein above wherein the compound of the general formula (A) is selected from:
(2S)-1-{(2S)-2- Amino-2-[8-(2,4,5-trifluorobenzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-
ethanoyl}-pyrrolidin-2- carbonitrile trifluoroacetic acid salt (Compound No.1)
(2S)-1-{(2S)-2- Amino-2-[8-(4-trifluoromethylbenzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-
ethanoyl}-pyrrolidin-2- carbonitrile trifluoroacetic acid salt (Compound No.2)
(2S)-1-{(2S)-2- Amino-2-[8-(adamantane-1-carbonyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-
ethanoyl}-pyrrolidin-2- carbonitrile trifluoroacetic acid salt (Compound No.3)
(2S)-1-{(2S)-2- Amino-2-[8-(pyridine-4-carbonyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-ethanoyl}-
pyrrolidin-2- carbonitrile trifluoroacetic acid salt (Compound No.4)
(2S)-1-{(2S)-2- Amino-2-[8-(4-cyano-benzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-ethanoyl}-
pyrrolidin-2- carbonitrile trifluoroacetic acid salt (Compound No.5)
(2S)-1-{(2S)-2- Amino-2-[8-(2,5-difluorobenzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-ethanoyl}-
pyrrolidin-2- carbonitrile trifluoroacetic acid salt (Compound No.6)
(2S)-1-{(2S)-2- Amino-2-[8-(2-fluoro-pyridine-4-carbonyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-
ethanoyl}-pyrrolidin-2- carbonitrile trifluoroacetic acid salt (Compound No.7)
(2S)-1-[(2S)-2-Amino-2-(8-aza-bicyclo[3.2.1]oct-3-yl)-exo-ethanoyl]-pyrrolidin-2- carbonitrile
trifluoroacetic acid salt (Compound No.8)
(2S)-1-{(2S)-2- Amino-2-[8-(2,4,5-trifluorobenzyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-ethanoyl}-
pyrrolidin-2- carbonitrile trifluoroacetic acid salt (Compound No.9)
Methyl-(2S)-1-{(2S)-2- amino-2-[8-(4-trifluoromethyl-benzoyl)-8-aza-bicyclo[3.2.1]-oct-3-yl]-
exo-ethanoyl}-pyrrolidin-2- carboxylate trifluoroacetic acid salt (Compound No. 10)
(2S)-1-{(2S)-2- amino-2-[8-(4-trifluoromethyl-benzoyl)-8-aza-bicyclo[3.2.1]-oct-3-yl]-exo-
ethanoyl}-pyrrolidin-2- carboxylic acid trifluoroacetic acid salt (Compound No.11)
(2S)-1 -{(2S)-2- amino-2-[8-(4-trifluoromethyl-benzoyl)-8-aza-bicyclo[3.2.1 ]-oct-3-yl]-exo-
ethanoyl}-pyrrolidin-2- carboxamide trifluoroacetic acid salt (Compound No. 12)
(2S)-1-{(2S)-2-Amino-2- [8-(4-trifluromethyl-benzoyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-
ethanoyl}-2-(2H-tetrazol-5-yl) pyrrolidine hydrochloride (Compound No. 13)
(2S)-{(2S)-1-[(2S)-2-Amino-2-(8-(benzo [1,3] dioxole -5-carbonyl)-8-aza-bicyclo [3.2.1]-oct-3-
yl)-exo-acetyl]-pyrrolidin-2- yl} methanol trifluoroacetic acid salt (Compound No. 14)
(2S, 4S)-1-{ (2S)-2-Amino-2-[8-(4-trifluoromethylbenzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-
ethanoyl}-4-fluoro-pyrrolidin-2- carbonitrile hydrochloride salt (Compound No. 15)
(2S, 4S)-1-{ (2S)-2- Amino-2-[8-(2,4,5-trifluorobenzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-
ethanoyl}-4-fluoro-pyrrolidin-2- carbonitrile trifluoroacetic acid salt (Compound No. 16)
(2S, 4S)-1-{ (2S)-2- Amino-2-[8-(2,5-difluorobenzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-
ethanoyl}-4-fluoro-pyrrolidin-2- carbonitrile trifluoroacetic acid salt (Compound No. 17)
Benzyl-(2S,5R)-1 -{(2S)-2- amino-2-[8-(4-trifluoromethyl-benzoyl)-8-aza-bicyclo[3.2.1 ]-oct-3-
yl]-exo-ethanoyl}-5-cyano pyrrolidin-2- carboxylate trifluoroacetic acid salt (Compound
No.18)
(2S, 4S)-1-{(2S)-2- Amino-2-[8-(2,4,5-trifluorobenzyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-
ethanoyl}-4-fluoro-pyrrolidin-2- carbonitrile trifluoroacetic acid salt (Compound No. 19)
(4S)-3-{(2S)-2- Amino-2-[8-(4-trifluoromethylbenzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-
ethanoyl}-thiazolidine-4- carbonitrile trifluoroacetic acid salt (Compound No.20)
3-{(2S)-2- Amino-2-[8-(4-trifluoromethylbenzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-ethanoyl}-
1,3-thiazolidine trifluoroacetic acid salt (Compound No.21)
(2S)-1-{(2S)-2- Amino-2-[8-(4-trifluoromethyl phenyl carbamoyl)-8-aza-bicyclo[3.2.1] oct-3-
yl]-exo-ethanoyl}-pyrrolidin-2- carbonitrile trifluoroacetic acid salt (Compound No.22)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(2,4,5-trifluorobenzoyl)-8-aza-bicyclo [3.2.1]oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (Compound
No.23)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(4-cyanobenzoyl)-8-aza-bicyclo [3.2.1]oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (Compound
No.24)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(pyridine-4-carbonyl)-8-aza-bicyclo [3.2.1]oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (Compound
No.25)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(4-trifluoromethylbenzoyl)-8-aza-bicyclo [3.2.1]oct-3-yl]-
exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (Compound
No.26)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(2,5-difluorobenzoyl)-8-aza-bicyclo [3.2.1]oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (Compound
No.27)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(2-fluoropyridine-4-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-
yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt
(Compound No.28)
(1R, 3R, 5R)-2-{(2S)-2-Amino-2-[8-(2-fluoropyridine-4-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-
yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt
(Compound No.29)
(1R, 3R, 5R)-2-{(2R)-2-Amino-2-[8-(2-fluoropyridine-4-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-
yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt
(Compound No.30)
(1S, 3S, 5S)-2-{(2R)-2-Amino-2-[8-(2-fluoropyridine-4-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-
yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt
(Compound No.31)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(2-fluoropyridine-3-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-
yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt
(Compound No.32)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(pyridine-3-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (Compound
No.33)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(thiophene-2-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (Compound
No.34)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(pyrazine-2-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (Compound
No.35)
(1S, 3S, 5S)-2-{(2R)-2-Amino-2-[8-(pyrazine-2-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (Compound
No.36)
(1R, 3R, 5R)-2-{(2S)-2-Amino-2-[8-(pyrazine-2-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (Compound
No.37)
(1R, 3R, 5R)-2-{(2R)-2-Amino-2-[8-(pyrazine-2-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (Compound
No.38)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(pyridine-2-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (Compound
No.39)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(furan-2-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (Compound
No.40)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(3-fluoropyridine-4-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-
yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt
(Compound No.41)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(3,5-difluorobenzene sulfonyl )-8-aza-bicyclo [3.2.1] oct-
3-yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt
(Compound No.42)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(adamantane-1-carbonyl )-8-aza-bicyclo [3.2.1] oct-3-yl]-
exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (Compound
No.43)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(benzo[1,3]dioxole-5-carbonyl)-8-aza-bicyclo [3.2.1] oct-
3-yl]-exo-ethanoyl}-2-azabicyclo [3.1.0]-hexane -3- carbonitrile trifluoroacetic acid salt
(Compound No.44)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(benzo [1,3]-dioxole-5-carbonyl)-8-aza-bicyclo [3.2.1] oct-
3-yl]-exo-ethanoyl}-2-azabicyclo [3.1.0]-hexane -3- carboxamide trifluoroacetic acid salt
(Compound No.45)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(benzo [1,3]-dioxole-5-carbonyl)-8-aza-bicyclo [3.2.1] oct-
3-yl]-exo-ethanoyl}-2-azabicyclo [3.1.0]-hexane -3- carboxylic acid hydrochloride
(Compound No.46)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(3,3,3-trifluoro propyl )-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (Compound
No.47)
(1S, 3S, 5S)-2-{ (2S)-2- Amino-2-[8-(cyclohexyl methyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (Compound
No.48)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(adamantan-1-yl methyl )-8-aza-bicyclo [3.2.1] oct-3-yl]-
exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (Compound
No.49)
(1S. 3S, 5S)-2-{(2S)-2-Amino-2-[8-(benzyloxy-ethyl )-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (Compound
No.50)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(5-cyanopyridine-2-yl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (Compound
No.51)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(4-cyano-phenyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoro acetic acid salt (Compound
No.52)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(4-methanesulfonyl phenyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-
exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (Compound
No.53)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(2-pyridin-4-yl-acetyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (Compound
No. 54)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(pyridine-4ylmethyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (Compound
No.55)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(methanesulfonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (Compound
No.56)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(thiophene-2-sulfonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (Compound
No.57)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(cyclohexane-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-
exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (Compound
No.58)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(1-ethyl-propyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (Compound
No.59)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-(8-cyclohexyl-8-aza-bicyclo [3.2.1] oct-3-yl)-exo-ethanoyl}-2-
azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (Compound No.60)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(4-chlorophenylsulfonylcarbamoyl)-8-aza-bicyclo
[3.2.1]oct-3-yl]-exo-ethanoyl}-2-azabicyclo[3.1.0] hexane -3-carbonitrile trifluoroacetic acid
salt (Compound No.61)
{(2S)-2-Amino-2-[8-(3-fluoro-pyridine-4-carbonyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-ethanoyl}-
3-fluoro-azetidine trifluoroacetic acid salt (Compound No.62)
(2S, 5R) -1- {(2S)-2- Amino-2- [8-(4-trifluoromethyl-benzoyl)- 8-aza- bicyclo [3.2.1] oct-3-yl]-
exo-ethanoyl} -5-ethynyl -pyrrolidin-2-carbonitrile trifluoro acetic acid salt (Compound No.63)
(2S, 5R)-1-{(2S)-2-Amino-2-[8-(pyridin-4-carbonyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-
ethanoyl}-5-ethynyl-pyrrolidin-2-carbonitrile trifluoroacetic acid salt (Compound No.64)
(2S, 5R)-1-{(2S)-2-Amino-2-[8-(3-fluoropyridin-4-carbonyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-
ethanoyl}-5-ethynyl-pyrrolidin-2-carbonitrile trifluoroacetic acid salt (Compound No.65)
(2S, 5R)-1-{(2S)-2-Amino-2- [8-(2-fluoropyridin-4-carbonyl)- 8-aza- bicyclo [3.2.1]-oct-3-yl]-
exo-ethanoyl}-5-ethynyl-pyrrolidin-2-carbonitrile trifluoroacetic acid salt (Compound No.66)
(2S, 5R)-1-{(2S)-2-Amino-2-[8-(benzo[1,3]dioxole-5-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-
exo-ethanoyl}-5-ethynyl-pyrrolidin-2-carbonitrile trifluoroacetic acid salt (Compound No.67)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(2-methoxyphenylthiocarbamoyl)-8-aza-bicyclo [3.2.1]oct-
3-yl]-exo-ethanoyl}-2-azabicyclo[3.1.0] hexane -3-carbonitrile trifluoroacetic acid salt
(Compound No.68)
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(1-acetyl-piperidine-4-carbonyl)-8-aza-bicyclo [3.2.1]oct-
3-yl]-exo-ethanoyl}-2-azabicyclo[3.1.0] hexane -3-carbonitrile trifluoroacetic acid salt
(Compound No.69)
(2S)-1-{2- Amino-2- [9-(4-trifluoromethyl-benzoyl)-9-azabiacyclo [3.3.1] non-3-yl]-exo-
ethanoyl}-pyrrolidin-2-carbonitrile trifluoro acetic acid salt (Compound No.70A & B)
The compounds of the invention were prepared as outlined below according to the methods
described herein. However, the invention is not limited to these methods, the compounds
may also be prepared as described for structurally related compounds in the literature.

Scheme 1
The compound of formula-l can be obtained by methods described in literature. Such as
Ber. 29,1575,2216, (1896) and J.org.chem.27, 1269-1279, (1962). The compound of
formula I was converted to the compound of the formula II by refluxing with 18N H2SO4 and
subsequent reaction of aldehyde formed in situ at pH 6 (as a result of neutralization with a
saturated aqueous solution of K2CO3) with R, S or RS phenyl glycinol in presence of sodium
bisulphate and potassium cyanide under nitrogen atmosphere. This well known Strecker
reaction is conducted at a temperature such as 0°C to 30°C for a suitable time such as 18-
20 hours. The reaction forms two diastereomers of compound of formula II with exo and
endo configuration if pure stereoisomer of phenyl glycinol is used as a reactant. Single
diastereomer with Exo configuration was isolated by column chromatography, which was
further confirmed by single crystal X-ray diffraction analysis.
The nitrile group of the compound of formula II was converted to carboxylic acid with
50%HCI (6N) and the reaction is carried out at 0-25°C for a suitable time such as 20-25
hours. The product so obtained is subjected to hydrogenation in a parr apparatus under
suitable pressure such as at 80-100 psi in the presence of the catalyst such as Pd (OH)2 at
25- 30°C temperature for 12-15 hours to provide the compound of formula III. Compound of
formula III was further converted to compound of formula IV by refluxing amino acid III in a
solvent such as methanol under HCI gas purging for 12-15 hours. Further, the resulting
amino ester is protected with a phthalimido group, optionally in the presence of the suitable
base such as triethyl amine or diisopropyl ethylamine and in a solvent such as THF for 2-3
hours.
N-demethylation of the compound of formula IV was achieved by two-step process as
shown in the scheme-l. In this two step process, the compound of the formula IV was
subjected to react with trichloroethyl chloroformate and anhydrous K2CO3 in a hydrocarbon
solvent such as toluene and refluxing under nitrogen atmosphere for a suitable time, such as
2-3 hours followed by the reaction with Zn, acetic acid, H2O at a temperature, such as 10-
30°C temperature for a suitable time 16 hours to provide the compound of formula V.
The compound of the formula V was protected with a suitable protecting group such as
benzyloxy carbonyl (CBZ), so that later in the synthesis it could be removed easily while
keeping other protecting groups such as tert-butoxycarbonyl intact. Protection with CBZ was
readily accomplished by treatment of compound of formula V with benzyl chloroformate in a
solvent such as dioxane-H2O in presence of a base such as NaHCO3 at 0-30°C temperature
for a suitable time such as 2 hours. The hydroxy group of resultant compound was oxidized
to a compound of formula VI by suitable oxidation method such as Jones oxidation, Dess
Martin, NaOCI-TEMPO, PDC etc. The method chosen for this transformation must be
compatible with the CBZ protecting group. One such approach is the oxidation of alcohol
with Jones reagent in a solvent such as acetone at 0°C-30°C temperature for 1-2 hours.
The phthalimido group of the compound of formula VI was removed with hydrazine hydrate
in solvent such as methanol at a temperature such as 0°C -30°C for suitable time such as
35-40 hours. Free amino group thus formed was protected with tert-butoxycarbonyl in
solvent such as dichloromethane or THF, in presence of a base such as triethylamine or
diisopropyl ethyl amine at a temperature 0°C -30°C and for suitable time 15-20 hours to
provide the compound of formula VII. The benzyloxy-carbonyl of compound of formula VII
was deprotected by hydrogenation in a parr apparatus in presence of 5% Pd/C in methanol
at about 50 psi for about 3-4 hours.
The amine thus formed was reacted with either R'L, wherein L is a leaving group such as
halogen or hydroxy, R1 is selected from it's definitions 'ii' to 'xi' and 'xiii' for compound of
formula 'A'; or with R6N=C=O or R6N=C=S or R6SO2N=C=O in case of R1 is selected from
definition 'xii' for compound of formula 'A', wherein R6 is selected from phenyl unsubstituted
or substituted with chloro, fluoro, trifluoromethyl or methoxy; in presence of solvents such as
haloganted hydrocarbon such as chloroform and dichloromethane, an aromatic hydrocarbon
such as benzene and toluene an ether type solvent such as N, N'- dimethyl formamide N
ethyl pyrrolidine and dimethyl sulfoxide, acetonitrile, using suitable coupling agents like
EDCI, dicyclohexyl carbodiimide in presence of base such as triethyl amine or diisopropyl
ethyl amine. The reaction temperature may be in range between 0°C to 100°C. The duration
of the reaction may range from 1-30 hours. The inert atmosphere may be employed by using
inert gases such as nitrogen, argon, or helium. The ester group of resultant compound can
be hydrolyzed using standard procedures known to a skilled artisan or by other procedures
described in the literature such as in presence of a base such as K2CO3, Na2CO3, LiOH in
solvent such as methanol and H2O at temperature such as 0°C - room temperature for a
suitable time 15-20 hours to provide the compound of formula VIII. Wherein, if R1 is
cyclohex-2-enyl group, then such group is converted to cyclohexyl by catalytic
hydrogenation; if R1 is adamantane carbonyl, then such group is converted to adamantane.

Scheme 2
Alternatively compound of formula VIII can be synthesized from compound of formula V as
per scheme 2, which involves treatment of a compound of formula V with R1-L or R6-N=C=O
or RB-N=C=S or R6SO2-N=C=O; wherein, R1 is defined as under definition (v), (vi), (viii), (xi)
and (xiii) for compound of formula 'A'; L is any suitable leaving group, more specifically
hydroxy or halogen; R6 is as defined herein above. The reaction can be carried out in the
presence of solvents such as halogenated hydrocarbon like chloroform and
dichloromethane, an aromatic hydrocarbon like benzene and toluene, an ether type solvent
like diethyl ether, tetra hydrofuran and 1-4 -dioxane, an aprotic polar solvent like N, N' -
dimethylformamide N-methyl pyrrolidine and dimethyl sulfoxide, acetonitrile using suitable
coupling agents like 1-ethyl-3-[3-(dimethyl amino) propyl] carbodi-imide (EDCI), diclohexyl
carbodiimide in presence of base such as triethyl amine, diisopropylethyl amine and the like.
The reaction may also be carried out in the presence of hydroxybenzotriol (HOBT), 2,2'-
bis(diphenylphosphine)-1,T-binaphthyl (BINAP), cesium carbonate and palladium acetate.
The reaction temperature may be range between 0°C to 100°C, the duration of reaction may
range from 1-30 hours.The inert atmosphere may be employed by using inert gases such as
nitrogen argon or helium. The resulting product was then oxidized to a compound of formula
IX by Jones oxidation. The oxidation can also be achieved by other suitable methods known
to those skilled in art, such as Dess martin, NaOCI-TEMPO, PDC etc. The Jone's oxidation
is carried out in a solvent such acetone at a temperature, such as 0°C-30°C for 0.5-2 hours.
The Phthalimido group of the compound of formula IX was then removed by hydrazine
hydrate in a solvent such as methanol at a temperature such as 0°C -30°C and for suitable
time 35-40 hours. The ester group of the resultant compound can be hydrolyzed using any
standard procedures known to a skilled artisan or by other procedures known in the
literature such as in presence of a base such as K2CO3, Na2CO3, LiOH in a solvent such as
methanol and H2O at temperature such as 0°C-30°C for a suitable time 15-20 hours to
obtain the compound of formula X. The amino group of compound of formula X was
protected with tert-butoxycarbonyl in a solvent such as N, N-dimethylformamide and in
presence of a base such as K2CO3 at temperature 0°C-30°C for a suitable time 15-20 hours
to obtain the compound of formula VIII.

Compound of formula VIII obtained by practicing scheme 1 or 2 can be further converted to
compound of the formula A as per synthetic Scheme-3. Compound of formula VIII was
converted to compound of formula XII by condensation with compound of formula XI under
standard peptide coupling conditions, for example, using EDCI, dicyclohexylcarbodiimide in
presence of base such as triethyl amine, diisopropylethylamine and the like. The reaction
may also be carried out in the presence of HOBT. The reaction temperature may be in the
range between 0-35°C, the duration of reaction may range from 15-30 hours. If R2 is -
CONH2, then -CONH2 group is converted to -CN by treatment of dehydrating agent such as
POCI3; if R2 is -COOH, then such group is converted to -CN by converting it to -CONH2
and then treating the said amide with dehydrating agent such as POCI3; if R2 is -CN, then -
CN group is converted to tetrazole by treatment with sodium azide or organic azides. The
compound of formula XII was further deprotected using common methods known in the art
such as using trifluroacetic acid, in a solvent such as dichloromethane at a temperature 0-
30°C for 30 minutes to one hours to give the compounds of general formula (A). Wherein, if
R1 is tert-butoxycarbonyl, then it was hydrolyzed to get hydrogen at R1 position
Compound of general formula A, wherein n = 2 was synthesized as per scheme 4.
Scheme 4
The compounds of the formula XIII can be obtained by methods described in US4277472I.
The compound of the formula XIII is allowed to react with benzyl magnesium halide under
Grignard conditions such as refluxing in a solvent like tetrahydrofuran and in presence of
iodine for 16-18 hours to yield endo alcohol exclusively. Deoxygenation of tertiary alcohol of
the intermediate can be accomplished using the Dolan- Mac Millan methodology [J. org.
chem. 64, 4966-1968 (1999)]. Thus, the alcohol is subjected to react with methyl oxalate in a
solvent such as dichloromethane and in presence of bases such as pyridine or 2, 6-lutidine
and 4-dimethylaminopyridine (DMAP) at a temperature 0°C-30°Cand for a suitable time 18-
20 hours to provide the compound of formula XIV.
The oxalate ester of the compound of formula XIV can be removed with tri butyl tin hydride
(TBTH) and 2, 2' azo bis (2-methyl propionitrile) (AIBN) in a hydrocarbon solvent such as
toluene at a reflux temperature for a suitable time 12-14 hours. The deoxygenation can also
be carried out using other reagents such as tris (trimethyl silyl) silane and 2,2-
azobisisobutyronitrile (AIBN) in a hydrocarbon solvent such as toluene at a reflux
temperature or refluxing with dialkyl phosphite and a radical initiator such as benzoyl
peroxide in a hydrocarbon solvent such as toluene [J. Org. Chem. 58, 6838-6842 (1993);
Tet. Let. 33, 2311-2314 (1992); Tet. Let. 33, 6629-6632 (1992)]. The phenyl ring of the
deoxygenated product is oxidised with ruthenium trichloride and periodic acid in a solvent
combination such as carbon tetrachloride and acetonitrile at a temperature 30°C-50°C for a
suitable time 2-3 hours to provide the compound of formula XV [J. Org. Chem, 46, 3936-
3938(1981)].
The ethyl carbamate of the compound of formula XV can be removed with cone. HCI at a
temperature 100°C for a suitable time 8-10 hours. The carboxylic acid of the resultant
intermediate is then converted to its methyl ester, (intermediate XVI) by refluxing in a solvent
such as methanol using catalytic amount of cone. H2SO4 for a suitable time 15-20 hours.
The major exo product was isolated by column chromatography. The exo stereochemistry of
the intermediate XVI was assigned by comparing 1H NMR data as per Chem. Pharm Bull.
Volume 43(8), page 1351 to 1357 (1995).
The intermediate XVI is then reacted with either R1L, wherein L is a leaving group such as
halogen or hydroxy, R1 is selected from it's definitions 'ii' to 'vi', viii, x and 'xiii' for compound
of formula 'A'; or with R6N=C=O or R6SO2N=C=O in case of R1 is selected from definition
'xii' of compound of formula 'A', wherein R6 is selected from phenyl unsubstituted or
substituted with chloro, fluoro, trifluoromethyl or methoxy. The reaction can be carried out in
the presence of solvents such as halogenated hydrocarbon such as chloroform and
dichloromethane, an aromatic hydrocarbon such as benzene and toluene, an ether type
solvent such as diethyl ether, tetrahydrofuran and 1,4 -dioxane, an aprotic polar solvent
such as N-methyl pyrrolidine, dimethyl sulfoxide, acetonitrile using suitable coupling agents
such as EDCI. The reaction may be carried out in the presence of triethylamine, cesium
carbonate, DMAP, HOBT, BINAP and palladium acetate. The reaction temperature may be
in the range between 0°C-100°C. The duration of the reaction may range from 1-30 hours.
The inter atmosphere may be employed by using inert gases such as nitrogen, argon or
helium. The resulting product is then treated with a base such as lithium diisopropylamide
(LDA) and di-tert-butyl-diazene-1,2-dicarboxylate in a solvent such as tetrahydrofuran at a
temperature -70°C-30°C for 14-16 hours to obtain the compound of formula XVII.
The tert- butoxy carbonyl groups of intermediate XVII can be deprotected using trifluoro
acetic acid in a suitable solvent such as dichloromethane at a temperature 0°C-30°C for 4-6
hours. The resultant hydrazide is subjected to hydrogenation in an autoclave in a solvent
such as methanol and water under suitable pressure such as 500-600 psi in the presence of
a catalyst such as Raney Nickel at 25-30°C for a suitable time 14-16 hours to obtain the
compound of formula XVIII [Helv.chim.Acta 71, 1824-1839 (1988)].
The amino group of compound of formula XVIII is protected with tert-butoxy carbonyl in a
solvent such as dichloromethane and in presence of a base such as triethyl amine at
temperature 0°C-30°C for a suitable time 15-20 hours. The ester group of the resultant
compound can be hydrolyzed using any standard procedures known to any skilled in the art
or by other procedures known in the literature such as in presence of a base such as
potassium carbonate, sodium carbonate, lithium hydroxide in a solvent such as methanol
and water at temperature such as 0°C-30°C for a suitable time 15-20 hours to obtain the
compound of formula XIX. Wherein, if R1 is cyclohex-2-enyl group, then such group is
converted to cyclohexyl by catalytic hydrogenation; if R1 is adamantane carbonyl, then such
group is converted to adamantane.
Compound of formula XIX obtained was further converted to compound of the formula XX by
condensation with compound of formula XI under standard peptide coupling conditions, for
example, using EDCI, dicyclohexylcarbodiimide. The reaction may also be carried out in the
presence of HOBT. The reaction temperature may be range between 0-35°C, the duration of
reaction may range from 15-30 hours. If R2 is -CONH2, then -CONH2 group is converted to -
CN by treatment of dehydrating agent such as POCI3; if R2 is -COOH , then such group is
converted to -CN by converting it to -CONH2 and then treating the said amide with
dehydrating agent such as POCI3; if R2 is -CN, then -CN group is converted to tetrazole by
treatment with sodium azide or organic azides. The compound of formula XX was further
deprotected using common methods known in the art such as using trifluroacetic acid, in a
solvent such as dichloromethane at a temperature 0-30°C for 30 minutes to one hours to
give the compounds of general formula (A). Wherein, if R1 is tert-butoxycarbonyl, then it was
hydrolyzed to get hydrogen at R1 position.
The intermediates and the compounds of the present invention are obtained in pure form in
a manner known per se, for example by distilling off the solvent in vaccum and re
crystallizing the residue obtained from a suitable solvent, such as pentane, diethyl ether,
isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone or their combinations or
subjecting it to one of the purification methods, such as column chromatography on a
suitable support material such as alumina or silica gel using eluent such as
dichloromethane, ethyl acetate, hexane, methanol, acetone and their combinations.
Salts are obtained by dissolving the free compound in a suitable solvent, for example in a
chlorinated hydrocarbon, such as methyl chloride or chloroform or a low molecular weight
aliphatic alcohol, for example, ethanol or isopropanol, which contains the desired acid or
base or two which the desired acid or base is then added as described in ,Berge S.M. et al.
"Pharmaceutical Salts, a review article in Journal of Pharmaceutical sciences volume 66,
page 1-19 (1977)" and in handbook of pharmaceutical salts properties, selection, and use by
P.H.Einrich Stahland Camille G.wermuth , wiley- VCH (2002).
The stereoisomers of the compounds of 8-aza-bicyclo[3.2.1]octane series of the present
invention may be prepared by the Strecker reaction or according to the methods given in
literature such as resolution of the achiral amino acids using an optically active amine or
acid and separating the diastereomeric salt by fractional crystallization by column
chromatography.
The present invention also provides pharmaceutical compositions containing compounds of
general formula A as defined above, their tautomeric forms, their stereoisomers, their
enantiomers, their diastereomers, their racemates, their pharmaceutically acceptable salts
or their pharmaceutically acceptable solvates in combination with the usual pharmaceutically
employed carrier, diluents and the like.
The presence of one or more asymmetric centers in the compounds of general formula A
can give rise to stereoisomers and each case the invention is to be understood to extend to
all such stereoisomers, including enatiomers and disteriomers and their mixtures, including
recemic mixtures and E & Z geometrical isomers single or mixture of both isomers wherever
possible in the compounds of general formula A.
The following examples are provide to further illustrate the present invention and therefore
should not be construed to limit the scope of the invention. All 1HNMR spectra were
determined in the solvents indicated and chemical shifts are reported in 5 units downfield
from the internal standard tetramethylsilane (TMS) and interproton coupling constants are
reported in Hertz (Hz).
Intermediate 1
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(2,4,5-trifluoro-benzoyl)-8-aza-bicyclo [3.2.1]-oct-3-
yl]-exo-ethanoic acid

Step 1: 1-(2-Hydroxy-1-(1R)-phenylethyl amino)-1-(8-methyl-8-aza-bicyclo[3.2.1]-oct-3-yl)-
exo-methane-1- (IS)-carbonitrile

3-Hydroxymethyl-8-methyl-8-aza-bicyclo [3.2.1] octane-3-ol (prepared by the same
procedure as described in Ber., 29, 1575, 2216, (1896) and J.Org. Chem.27, 1269-1279
(1962), 36.8 g, 0.22 mol) was dissolved in H2SO4 (18 N, 110 ml) at room temperature and
the reaction mixture was refluxed for 5.0 h. It was then cooled to 0 °C and neutralized to pH
6 using a saturated K2CO3 solution. The reaction mixture was diluted with water (35.0 ml)
and subsequently added NaHSO3(22.37g ,0.22 mol) , KCN (15.4 g, 0.24 mol) and (R)-(-)-2-
phenylglycinol (29.5 g, 0.22 mol) at 0°C. The reaction mixture was brought to room
temperature immediately and stirred for 18 hours. It was then extracted with ethyl acetate (3
x 500 ml). The combined organic layer was washed with brine (100 ml), dried over
anhydrous Na2SO4 and evaporated under reduced pressure to give a crude product, which
was purified over neutral Al2O3 (Brockman III) using 20 - 40% ethyl acetate in hexane as an
eluent to obtain the title compound (17.0g, 26%).
mp: 121-123°C
MS :m/z 300 (M+1)
1H NMR (CDCI3, 400MHz) : d 1.52 - 1.63 (m, 4H), 1.66 - 1.83 (m, 3H), 1.91 - 2.09 (m, 3H),
2.28 (s, 3H), 2.32 (s, 1H), 3.06 (dd, J1 = 7.2 Hz, J2 = 12.8 Hz 1H), 3.17 - 3.27 (m, 2H), 3.54
(t, J =10 Hz, 1H), 3.73-3.78 (m, 1H), 4.04-4.08 (m, 1H), 7.26 - 7.36 (m, 5H).
Step 2: 1-(2-Hydroxy-1-(1R)-phenylethyl amino)-1-(8-methyl-8-aza-bicyclo[3.2.1]-oct-3-yl)-
exo-methane-1- (1S)-carboxylic acid dihydrochloride

To a stirred solution of cone. HCI (266 ml) was added 1-(2-hydroxy-1-(1R)-phenyl ethyl
lamino)-1-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-exo-methane-1- (1S)-carbonitrile (Stepl,
13.3 g, 0.044 mol) in small portions at 0°C. After the addition was completed, the reaction
mixture was brought to room temperature in 30 minutes and stirred at the same temperature
for 20 hours. The solvent was completely removed at 45 °C under reduced pressure, added
THF (150 ml) and again evaporated all the solvent. It was then dried under high vacuum to
yield the title compound quantitatively, which was subjected to next step as such without
purification.
MS :m/z 319(M+1).
Step 3: (2S)-2-Amino-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-exo-acetic acid
dihydrochloride.

A solution of 1-(2-hydroxy-1- (1R)-phenylethylamino)-1-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-
yl)- exo-methane-1- (1S)-carboxylic acid dihydrochloride (step 2, 20.0 g, 51.2 mmol) in
methanol (600ml) and glacial acetic acid (120 ml) was hydrogenated at room temperature in
a pressure of 100 psi in the presence of Pd (OH)2 (10.0 g) for 12 hours. The catalyst was
filtered through a Buchner funnel and filtrate was evaporated to obtain a pale green colored
product. The sticky solid was triturated with dichloromethane (2 x 200 ml) and decanted in
order to remove less polar impurities. It was then dried under high vacuum to obtain the title
compound in quantitative yield and subjected to next reaction without purification.
MS:m/z 199(M+1).
Step 4 :Methyl (2S)-2-amino-2-(8-methyl-8-aza-bicyclo[3.2.1]-oct-3-yl)- exo-acetate

To a stirred suspension of (2S)-2-amino (8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-exo-acetic
acid dihydrochloride (step3, 16.0 g, 58.9 mmol) in methanol (240 ml) was purged HCI gas
under reflux condition for 12 hours. The solvent was evaporated under reduced pressure
and the residue was stirred in chloroform (100 ml), cooled to 0 °C and basified with NH3 in
chloroform and stirred for 2 hours. It was then filtered through a Buchner funnel washed
with chloroform (2 x 200 ml). The combined organic layer was evaporated to yield the title
compound (10.01 g, 80%)
MS : mlz 213 (M+1)
1H NMR (D2O, 200 MHz) : d 1.2-1.75 (m, 5H), 1.8-2.05 (m, 4H), 2.22 (s, 3H), 3.01-3.2 (m,
3H), 3.7 (s, 3H).
Step 5 : Methyl (2S)-2- (1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-(8-methyl-8-aza-bicyclo[3.2.1]-
oct-3-yl)-exo-acetate

To a stirred solution of methyl (2S)-2-amino-2-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)- exo-
acetate (step 4, 4.75 g, 0.022 mol) in dry THF (44 ml) was added, 1,3 dioxo-1,3-dihydro-iso
indol-2-carboxylic acid ethyl ester (4.9 g, 0.022 mol) and triethyl amine (3.16 g, 4.4 ml,
0.0312 mol), and heated at 80°C for 2 hours. The reaction mixture was brought to room
temperature and the solvent was evaporated under reduced pressure and dried under high
vacuum to obtain a crude product, which was purified by column chromatography over silica
gel (100-200 mesh) using methanol : ammonia in chloroform : dichloromethane in the ratio
of 3:10:87 as an eluent, to yield the title compound (3.90 g, 51%).
MS :m/z 343 (M+1)
1H NMR (CDCI3, 400MHz) : d 1.55-1.65 (m, 1H), 1.82-1.95 (m, 2H), 1.98-2.08 (m, 2H), 2.10-
2.25 (m, 3H), 2.54 (s, 3H), 2.82-2.92 (m,1H), 3.45-3.6 (m, 2H), 3.69 (s, 3H), 4.72(d, J=7.6
Hz,1H), 7.72-7.78 (m, 2H), 7.84-7.88 (m, 2H).
Step 6: Methyl-(2S)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-[8-(2,2,2-trichloro-ethyloxy
carbonyl)-8-aza-bicyclo[3.2.1 ]-oct-3-yl]-exo-acetate

To a stirred solution of methyl (2S)-2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(8-methyl-8-
aza-bicyclo[3.2.1] oct-3-yl)-exo-acetate (step 5, 3.88 g, 11.3 mmol) in dry toluene (50 ml)
was added anhydrous K2CO3 (0.235 g, 1.7 mmol) and refluxed under N2 atmosphere for 5
minutes. To this mixture was added a solution of 2,2,2-trichloro ethylchloroformate (3.6 g,
2.4 ml, 17 mmol) in dry toluene (10 ml) dropwise under N2 atmosphere and refluxing was
continued for 2 hours. The solvent was evaporated under reduced pressure and dried under
high vacuum to get the crude product, which was purified by neutral Al2O3 (Brockman III)
using dichloromethaneas an eluent to yield the title coumpound (3.5 g, 61%).
MS : m/z 505 (M+2)
1H NMR (CDCI3, 200MHz): d 1.35-1.55 (m, 2H), 1.60-1.70 (m, 1H), 1.71-2.18 (m, 5H), 2.9-
3.17 (m, 1H), 3.7 (s, 3H), 4.2-4.45 (m, 2H), 4.5- 4.65 (m, 2H), 4.7 - 4.85 (m, 1H), 7.65-7.9
(m, 4H).
Step 7: Methyl-(2S)-2-(1-hydroxy-3-oxo-1,3-dihydroisoindol-2-yl)-2-[8-aza-bicyclo[3.2.1]-oct-
3-yl]-exo-acetate
To a stirred suspension of activated Zn (4.5 g, 0.07 mol) in acetic acid (26 ml) and water (6.3
ml) at 10 °C was added a solution of methyl (2S)-2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-
[8-(2,2,2-trichloro-ethyloxycarbonyl)-8-aza-bicyclo[3.2.1] oct-3-yl]-exo-acetate (step 6, 3.5 g,
0.007 mol) in glacial acetic acid (30.7 ml) . Cooling bath was removed after 1 hour, and
reaction mixture was stirred for further 15 hours at room temperature. The solvent was
evaporated under reduced pressure and dried under high vacuum to remove traces of acetic
acid. To this reaction mass was added dichloromethane (20 ml), cooled to 0 °C and
neutralized with ammonia in chloroform. This reaction mixture was stirred at 0 °C for 2
hours, and filtered through a Buchner funnel. The filtrate was concentrated under reduced
pressure and dried under high vacuum to yield the title compound quantitatively.
MS:m/z 331 (M+1).
Step 8: Methyl-(2S)-2-(1-hydroxy-3-oxo-1,3-dihydroisoindol-2-yl)-2-[8-(2,4,5-
trifluorobenzoyl)-8-aza-bicyclo[3.2.1]-oct-3-yl]-exo-acetate

To a stirred solution of methyl (2S)-2- (1-hydroxy-3-oxo-1,3-dihydro-isoindol-2-yl)-2-[8-aza-
bicyclo[3.2.1] oct-3-yl]-exo-acetate (step 7, 2.5 g, 7.57 mmol) in dry THF (90 ml) was added
2,4,5-trifluorobenzoic acid (1.33g, 7.57 mmol) and 1-hydroxybenzotriazole (HOBT, 1.02 g,
7.57 mmol). The reaction mixtrue was cooled to 0°C and added 1-(3-dimethylaminopropyl)-
3-ethyl carbodimide hydrochloride (EDC, 1.6g, 8.3 ml) in portions. The resulting mixture was
stirred at 0°C for 5 minutes and then at room temperature for 15 hours. The solvent was
removed under reduced pressure. To this was added dichloromethane (60 ml) and washed
with a saturated aqueous NaHCO3 solution (1 x 25 ml). The organic layer was dried over an
anhydrous Na2SO4, filtered and filtrate was evaporated under reduced pressure to get the
crude product, which was purified by column chromatography over silica gel (200-400 mesh)
using 2 % methanol in dichloromethane as an eluent to yield the title compound (2.25 g,
60%).
MS: mlz 511 (M+23).
Step 9: Methyl-(2S)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-[8-(2,4,5-trifluorobenzoyl)-8-
aza-bicyclo[3.2.1]-oct-3-yl]-exo-acetate

To a stirred solution of methyl (2S)-2-(1-hydroxy-3-oxo-1,3-dihydro-isoindol-2-yl)-2-[8-(2,4,5-
trifluorobenzoyl)-8-aza-bicyclo[3.2.1] oct-3-yl]-exo-acetate (step 8, 2.2g, 4.5 mmol) in
acetone (75 ml) at 0° C was added Jone's reagent dropwise and the completion of reaction
was monitored by TLC. After 30 minutes, the solvent was evaporated under reduced
pressure at room temperature and added dichloromethane (100 ml). The organic layer was
washed with water (50 ml), brine (20 ml) and dried over anhydrous Na2SO4. The solvent was
evaporated to yield the crude product, which was purified by column chromatography over
the silica gel (100-200 mesh) using 1.2 % methanol in dichloromethane as an eluent to yield
the title compound (2.0 g, 91 %).
MS: mlz 487 (M+1).
1HNMR (CDCI3, 400 MHz): d 1.25-1.55 (m,2H), 1.65-1.82-(m, 2H), 1.83 - 2.08(m, 3H), 2.09
- 2.20 (m, 1H), 3.02 - 3.14 (m, 1H), 3.65 - 3.72 (m, 3H), 3.73 - 3.90 (m, 1H), 4.55 - 4.65
(m,1H), 4.75 - 4.86 (m,1H), 6.86 - 7.00 (m,1H), 7.18 - 7.32 (m,1H), 7.73 - 7.80 (m, 2H),
7.84-7.92 (m, 2H).
Analogously, by practicing the chemistry of step 1 to 9 with appropriate change in the
reactants, following compounds were prepared.
Methyl-(2S)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-[8-(4-trifluoromethylbenzoyl)-8-aza-
bicyclo[3.2.1 ]-oct-3-yl]-exo-acetate
MS: m/z 501 (M+1)
Methyl-(2S)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-[8-(adamantane-1 -carbonyl)-8-aza-
bicyclo[3.2.1 ]-oct-3-yl]-exo-acetate
MS: m/z 491 (M+1)
Methyl-(2S)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-[8-(4-trifluoromethyl-phenyl carbamoyl)-
8-aza-bicyclo[3.2.1]-oct-3-yl]-exo-acetate
MS: m/z 516(M+1)
StepIO: Methyl (2S)-2- amino-2-[8-(2,4,5-trifluorobenzoyl)-8-aza-bicyclo[3.2.1] oct-3-yl]-exo-
acetate

To a stirred solution of methyl (2S)-2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-[8-(2,4,5-
trifluorobenzoyl)-8-aza-bicyclo[3.2.1] oct-3-yl]-exo-acetate (step 9, 2.0g, 4.1 mmol) in
methanol (20 ml) was added a solution of hydrazine (1.03g, 1.00 ml, 20.6 mmol) in methanol
(22 ml) dropwise at 0°C. Ice bath was removed after 2 hours, and the reaction mixture was
stirred for 20 hours at room temperature. The solvent was removed under reduced pressure
at room temperature and the residue was taken in dichloromethane (100 ml) and stirred at
room temperature for 15 minutes. The reaction mixture was filtered through a buchner
funnel and the filtrate was concentrated to yield a crude product, which was purified by
column chromatography over silica gel (100 - 200 mesh) using methanol : NH3 in
chloroform: dichloromethne in the ratio of 2 :10 :88 as an eluent to obtain the title
compound (0.64 g, 44 %)
MS:m/z 357 (M+1).
1HNMR(CDCI3, 200 MHz): d 1.4-2.15 (m, 8H), 2.7 - 2.9 ( m, 1H), 3.75-4.15 (m, 5H), 4.75
- 4.9 (m, 1H), 6.85 - 7.1 (m,1H), 7.4 - 7.65 (m,1H), 8.7 - 8.9 (m, 2H, exchangeable with
D2O).
Step 11: (2S)-2-Amino-2-[8-(2,4,5-trifluorobenzoyl)-8-aza-bicyclo[3.2.1]-oct-3-yl]-exo-
ethanoic acid

Methyl (2S)-2-amino-2-[8-(2,4,5-trifluorobenzoyl)-8-aza-bicyclo[3.2.1] oct-3-yl]-exo-acetate
(step 10, 0.63 g, 1.76 mmol) was dissolved in methanol (45 ml) and added water (13 ml).
The reaction mixture was cooled to 0°C and added an aqueous solution of Na2CO3 (0.94 g,
8.85 mmol) in water (12 ml), dropwise under stirring. Ice bath was removed after 5 minutes
and the reaction mixture was stirred at room temperature for 15 hours. The solvent was
removed under reduced pressure at 35°C and added water (10 ml). The reaction mixture
was cooled to 0°C and pH of the reaction mixture was converted to 3 with 1M HCI. The
solvent was removed under reduced pressure at 35°C and dried under high vaccum. The
solid so obtained was stirred with 10 % methanol in dichloromethane (50 ml) at room
temperature for 30 minutes and filtered through a Buchner funnel. The filtrate was
concentrated to obtain the title compound (0.54 g, 89 %), which was subjected to next step
without purification.
MS :m/z 343 (M+1)
1HNMR(CDCI3+CD3OD, 200 MHz) : d 1.35-1.90 (m, 7H ), 1.95- 2.12 (m, 2H ), 3.55-3.7
(m, 1H), 3.8-3.9 (m, 1H ), 4.65-4.8 (m, 1H ), 6.85-7.06 (m, 1H ), 7.20 - 7.45 (m, 1H).
Analogously, by practicing the chemistry of step 10 and 11 with appropriate change in the
reactants, following compounds were prepared.
(2S)-2-Amino-2-[8-(4-trifluoromethylbenzoyl)-8-aza-bicyclo [3.2.1 ]-oct-3-yl]-exo-ethanoic
acid
MS: m/z 357 (M+1)
(2S)-2-Amino-2-[8-(adamantane-1-carbonyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-ethanoic acid
MS: m/z 347 (M+1)
(2S)-2-Amino-2-[8-(4-trifluoromethyl-phenyl carbamoyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-
ethanoic acid
MS: m/z 372 (M+1)
Step 12: (2S)-2-(tert-Butoxycarbonyl) amino-2-[8-(2,4,5-trifluoro-benzoyl)-8-aza-bicyclo
[3.2.1]oct-3-yl]-exo ethanoic acid.

To a stirred solution of (2S)-2- amino-2-[8-(2,4,5-trifluorobenzoyl)-8-aza-bicyclo[3.2.1] oct-3-
yl]-exo-ethanoic acid (step 11, 0.52g, 1.52 mmol ) in dry DMF ( 10 ml ) was added
anhydrous K2CO3 ( 0.63 g, 4.56 mmol). The reaction mixture was cooled to 0°C and added
di-tert-butyl dicarbonate (0.331 g, 0.35 ml, 1.51 mmol). After the addition, the reaction
mixture was brought to room temperature and stirred for 15 hours. The solvent was removed
under reduced pressure at 30°C, added THF (15 ml) and water (15 ml). It was then cooled
to 0°C and neutralised with 1M HCI to pH 6. The reaction mixture was concentrated to
dryness and the solid so obtained was stirred with dichloromethane (60 ml), at room
temperature and filtered through a buchner funnel and the filtrate was concentrated to yield
the title compound (0.67g, 99 % ).
MS : m/z 465 (M+23)
1HNMR ( CDCI3+D2O, 400 MHz) : d 1.35-1.65 (m, 12H ), 1.65 - 1.85 (m, 3H ), 1.92-2.10 (m,
2H ), 2.35-2.60 (m, 1H ), 3.8-3.9 (s, 1H ), 4.20-4.35 (m, 1H ), 4.75-4.90 (m, 1H), 6.92-7.02
(m, 1H), 7.18-7.35 (m, 1H).
Analogously, by practicing the chemistry of step 12 with appropriate change in the reactants,
following compounds were prepared.
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(4-trifluoromethylbenzoyl)-8-aza-bicyclo [3.2.1]-oct-
3-yl]-exo-ethanoic acid
MS: m/z455(M-1)
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(adamantane-1-carbonyl)-8-aza-bicyclo [3.2.1]-oct-
3-yl]-exo-ethanoic acid
MS:m/z 447(M+1)
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(4-trifluoromethyl-phenyl carbamoyl)-8-aza-bicyclo
[3.2.1]-oct-3-yl]-exo-ethanoic acid
MS: m/z 470(M-1)
Intermediate 2
(2S)-2-(tert-Butoxycarbonyl) amino-2-[8-(2-fluoropyridine-4-carbonyl)-8-aza-bicyclo [3.2.1]-
oct-3-yl]-exo- ethanoic-acid

Step 1: Methyl-(2S)-2-(1-hydroxy- 3-oxo-1,3-dihydroisoindol-2-yl)-2-[8-(carbobenzyl oxy)-8-
aza-bicyclo[3.2.1 ]-oct-3-yI ]-exo-acetate

To a stirred solution of Methyl (2S)-2-(1-hydroxy- 3-oxo- 1,3-dihydroisoindol-2-yl)-2- [8-aza-
bicyclo[3.2.1]-oct-3-yl ]-exo-acetate (step 7 of intermediate 1, 42.9g ,0.13 mol) in 1,4 -
dioxane was added a solution of sodium bicarbonate (43.68g, 0.52 mol) in water (450 ml) at
room temperature and then cooled to 0°C. To this solution was added benzyloxy carbonyl
chloride (66.5g, 65.3ml, 0.39mol) in a drop wise manner at 0°C in 20 minutes and resulting
mixture was stirred at 0°C for one hour and further at room temperature for one hour. The
reaction mixture was extracted with ethyl acetate (4x500 ml) and the combined organic layer
was washed with brine (500 ml), dried over anhydrous Na2SO4. The solvent was evaporated
under reduced pressure to obtain a crude a crude product, which was purified by column
chromatography over silica gel (100-200 mesh) using 3% methanol in dichloromethane as
an eluent to yield the title compound (49.0g, 81%).
MS:m/z 463(M-1)
1HNMR (CDCI3+D2O, 400 MHz):d 1.32-1.80 (m, 6H), 1.85-2.0 (m, 2H), 2.78-3.0 (m, 1H),
3.68 (m, 3H), 4.2-4.35(m, 2H), 4.48-4.65(m, 1H), 5.0-5.18 (m, 2H), 5.88-6.1(m, 1H), 7.26-
7.36 (m, 5H), 7.46-7.54 (m, 1H) 7.55-7.62 (m, 2H) 7.75-7.8 (m, 1H).
Step 2: Methyl (2S)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-[8-(carbobenzyloxy)-8-aza-
bicyclo[3.2.1]-oct-3-yl ]-exo-acetate

To stirred a solution of methyl-(2S) -2-(1-hydroxy- 3-oxo- 1,3-dihydroisoindol -2-yl)-2- [8-
(carbobenzyloxy)-8-aza- bicyclo [3.2.1]-oct-3-yl ]-exo-acetate (49.0g,0.11 mol) in acetone
(1L) at 0°Cwas added Jone's reagent drop wise and the progress of reaction was monitored
by TLC. After 50 minutes, the solvent was evaporated under reduced pressure at 0- 5°C and
added dichloromethane (900ml). The organic layer was washed with water (300ml) brine
(200ml) and dried over anhydrous Na2SO4. The solvent was evaporated to yield the crude
product, which was purified by column chromatography over silica gel (100-200 mesh) using
2% methanol in dichloromethane as an eluent to yield the title compound (40.8g, 84%).
MS: m/z 463(M+1)
1HNMR (CDCI3,400 MHz):d 1.38-1.83 (5H), 1.86-2.02 (m, 2H), 2.03-2.1 (m, 1H), 2.96-3.1(m,
1H), 3.68 (s, 3H), 4.2-4.4 (m, 2H), 4.5-4.6 (m, 1H), 5.04-5.15(m, 2H), 7.26-7.37 (m, 5H),
7.73-7.78 (m, 2H), 7.83-7.89 (m, 2H)
Step 3: Methyl-(2S)-2-amino-2-[8-(carbobenzyloxy)-8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-
acetate
To a stirred solution of methyl (2S)-2-(1,3dioxo-1,3- dihydroisoindol-2-yl)-2- [8-
(carbobenzyloxy)-8-aza- bicyclo[3.2.1]-oct-3-yl ]-exo-acetate(40.8g, 0.088 mol) in methanol
(800ml) was added a solution of hydrazine hydrate (80%, 26.5g, 26ml, 0.42 mol)in methanol
(800ml) drop wise at 0°C in two hours and stirred at 0oC for another three hours. Then the
reaction mixture was stirred at room temperature for 40 hours. The solvent was removed
under reduced pressure at room temperature. The residue so obtained was taken in
dichloromethane (600 ml) and stirred at room temperature for 10 minutes. The reaction
mixture was filtered through a Buchner funnel and the residue was washed with
dichloromethane (4x100 ml). The filtrate was concentrated to yield the crude product, which
was purified by column chromatography over silica gel (100- 200 mesh) using methanol :
NH3 in chloroform : dichloromethane in the ratio 2: 10: 88 as an eluent to obtain the title
compound (23.9g, 82.0%).
MS: m/z 333(M+1)
1HNMR (CDCI3+D2O, 200 MHz):d 1.3-1.7 (m, 6H), 1.72-2.3 (m, 3H), 3.18 (d, J = 6Hz, 1H),
3.68 (s, 3H), 4.23-4.4 (m, 2H), 5.12 (s, 2H), 7.25-7.4 (m, 5H).
Step 4: Methyl-(2S)-2-(tert-butoxycarbonyl)-amino-2-[8-(carbobenzyloxy)-8-aza-bicyclo
[3.2.1 ]-oct-3-yl]-exo-acetate

Methyl-(2S)-2-amino-2- [8- (carbobenzyloxy)-8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-acetate
(23.9 g, 0.072 mol) was dissolved in dichloromethane (800 ml) and added triethylamine
(12.0 ml, 8.72 g, 0.086 mmol) at 0°C followed by the addition of solution of di-tert-butyl
dicarbonate (17.26 g, 0.079 mol) in dichloromethane (150 ml) under stirring . After the
completion of addition, reaction mixture was stirred at room temperature for 16 hours The
solvent was removed under reduced pressure at room temperature to get a crude product,
which was purified by column chromatography over silica gel (100-20 mesh) using 1.5%
methanol in dichloromethane as an eluent to yield the title compound (25.0g, 80%).
MS:m/z 431(M-1)
1HNMR (CDCI3,400 MHz): d 1.34-1.7 (m, 15H), 1.9-2.02 (m, 2H), 2.25-2.38 (m, 1H), 3.73 (s,
3H), 4.15-4.24 (m, 1H), 4.27-4.40 (m, 2H), 4.93-5.03 (m, 1H), 5.07-5.18 (m, 2H), 7.26-7.42
(m, 5H).
Step 5: Methyl-(2S)-2-(tert-butoxycarbonyl)-amino-2-[-8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-
acetate
To a solution of methyl-(2S)-2- (tert-butoxycarbonyl)-amino-2- [8-(carbobenzyloxy)-8-aza-
bicyclo [3.2.1]-oct-3-yl]-exo-acetate (12.5g, 0.029 mol) in methanol (200ml) was added 5%
Pd-C as a paste in water (5.0 g in 3.0 ml. water) and the solution was hydrogenated (50 psi
of H2) on Parr apparatus for 3.5 hours. After completion, reaction mixture was filtered
through a celite bed and the residue was washed with methanol (4x50 ml). The filterate was
concentrated under reduced pressure to get a thick liquid, which was re-dissolved in
dichloromethane (250 ml) and filtered through a Buchner funnel. The filtrate was
concentrated to yield the title compound (8.53g, 99%).
MS: m/z 299(M+1)
1HNMR (CDCI3+D2O, 400 MHz):5 1.3-1.5 (m, 13H), 1.56-1.68 (m, 2H), 1.72-1.85 (m, 2H),
2.1-2.22 (m, 1H), 3.5-3.55 (m, 2H), 3.72 (s, 3H), 4.16-4.22 (m, 1H).
Step 6: Methyl-(2S)-2-(tert-butoxycarbonyl)-amino-2-[8-(2-fluoropyridine-4-carbonyl)-8-aza-
bicyclo [3.2.1]-oct-3-yl]-exo-acetate

To a stirred solution of methyl-(2S)-2-(tert-butoxycarbonyl)-amino-2- [8-aza-bicyclo [3.2.1]-
oct-3-yl]-exo-acetate (8.3g, 27.85 mmol) in THF (165 ml) was added 2-fluoro-pyridine-4-
carboxylic acid (3.93g, 27.85 mmol) and 1-hydroxybenzotriazole (HOBT, 3.76g, 27.85 mmol)
The reaction mixture was cooled to 0°C and 1-(3-dimethyl aminopropyl)-3-ethyl carbodimide
hydrochloride (5.87g, 30.64 mmol) was added in portions followed by water (8.0 ml) to get
a clear solution. The reaction mixture was stirred at room temperature for 15 hours. The
solvent was removed under reduced pressure, diluted with dichloromethane (250 ml),
washed with a saturated NaHCO3 solution (1x25 ml), followed by water (1x25ml). The
organic layer was dried over anhydrous Na2SO4 and the solvent was concentrated under
reduced pressure to get a crude product, which was purified by column chromatography
over silica gel (100- 200 mesh) using 1.5% methanol in dichloromethane as an eluent to
yield the title compound (8.9g, 75%)
mp: 84-86°C
MS: m/z 420(M-1)
1HNMR (CDCI3+D2O, 200 MHz): 5 1.38-1.60 (m, 11H), 1.62-1.82 (m,3H), 1.83-2.10 (m, 2H),
2.2-2.50 (m,1H), 3.75 (s, 3H), 3.9-4.0 (m, 1H), 4.18-4.38 (m, 1H), 4.80-4.92( m, 1H), 4.93-
5.2 (m, 1H), 6.9-7.0 (m, 1H), 7.12-7.28 (m, 1H), 8.20-8.32 (m, 1H).
Step 7: (2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(2-fluoropyridine-4-carbonyl)-8-aza-bicyclo
[3.2.1]-oct-3-yl]-exo-ethanoic-acid

To a stirred and cooled (0°C) solution of methyl-(2S)-2-(tert-butoxycarbonyl)-amino-2- [8- (2-
fluoropyridine-4-carbonyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-acetate (8.9g, 21.14 mmol) in
methanol (200 ml) was added a solution of Na2CO3 (11.2g, 105.7 mmol) in water (100 ml) in
a drop wise manner. After the addition was completed, the turbid solution was stirred at
room temperature and added more methanol (250 ml) followed by water (25 ml) until the
solution become clear. This mixture was stirred at room temperature for 16 hours. After
completion of reaction, the reaction mixture was concentrated under reduced pressure to
dryness. To this was added water (10 ml), cooled to 0°C and pH of the reaction mixture was
adjusted to 6.5 with aqueous 20%HCI. The solvent was then removed under reduced
pressure to yield a solid, which was stirred with 15% methanol in dichloromethane (100 ml)
at room temperature for 30 minutes. The reaction mixture was filtered through a Buchner
funnel and the filtrate was dried over anhydrous Na2SO4 The solvent was evaporated to
yield the title compound (8.6 g., 99%), which was subjected to next step without purification.
MS: m/z 406 (M-1)
1HNMR (CDCI3, 400 MHz): 5 1.2-2.0 (m, 17H), 2.12-2.55 (m, 1H), 3.80-3.95 (m, 2H) 4.57-
4.74 (m, 1H), 5.85-6.10 (m, 1H), 6.90-7.05 (m, 1H) 7.18-7.28 (m,1H), 8.22-8.3 (m, 1H).
Analogously by practicing the chemistry described in steps 1 to 7 with appropriate change in
the reactants, following compounds were prepared.
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(pyridine-4-carbonyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-
exo-ethanoic acid
MS: m/z 390(M+1)
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(4-cyano-benzoyl)-8-aza-bicyclo [3.2.1 ]-oct-3-yl]-
exo-ethanoic acid
MS: m/z 414(M+1)
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(2,5-difluorobenzoyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-
exo-ethanoic acid
MS: m/z 447(M+23)
(2R)-2-(tert-Butoxycarbonyl)-amino-2-[8-(2-fluoropyridin-4-carbonyl)-8-aza-bicyclo [3.2.1]-
oct-3-yl]-exo-ethanoic acid
MS: m/z 430 (M+23)
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(2-fluoropyridine-3-carbonyl)-8-aza-bicyclo [3.2.1]-
oct-3-yl]-exo-ethanoic acid
MS:m/z 406(M-1)
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(pyridine-3-carbonyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-
exo-ethanoic acid
MS: m/z 412(M+23)
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(thiophene-2-carbonyl)-8-aza-bicyclo [3.2.1 ]-oct-3-
yl]-exo-ethanoic acid
MS:m/z 417(M+23)
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(pyrazine-2-carbonyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-
exo-ethanoic acid
MS:m/z 389(M-1)
(2R)-2-(tert-Butoxycarbonyl)-amino-2-[8-(pyrazine-2-carbonyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-
exo-ethanoic acid
MS:m/z 413(M+23)
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(pyridine-2-carbonyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-
exo-ethanoic acid
MS: m/z 390 (M+1)
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(furan-2-carbonyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-
exo-ethanoic acid
MS:m/z 401(M+23)
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(3-fluoropyridine-4-carbonyl)-8-aza-bicyclo [3.2.1]-
oct-3-yl]-exo-ethanoic acid
MS: m/z 430(M+23)
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(benzo[1,3]dioxole-5-carbonyl)-8-aza-bicyclo
[3.2.1]-oct-3-yl]-exo-ethanoic acid
MS: m/z 433 (M+1)
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(2-pyridin-4-yl-acetyl)-8-aza-bicyclo [3.2.1]-oct-3-
yl]-exo-ethanoic acid
MS:m/z 404(M+1)
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(1-acetyl-piperidine-4-carbonyl)-8-aza-bicyclo
[3.2.1]-oct-3-yl]-exo-ethanoic acid
MS: m/z 438(M+1)
Intermediate 3
Methyl-(2S)-2-(tert-butoxycarbonyl)-amino-2-[8-(2,4,5-trifluorobenzyl)-8-aza-bicyclo [3.2.1]-
oct-3-yl]-exo-acetate

Step 1: Methyl-(2S)-2-(tert-butoxycarbonyl)-amino-2- [8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-
acetate (step-5 of intermediate 2, 2.1g, 7.04 mmol) was dissolved in dichloromethane (70
ml). The reaction mixture was cooled to 0°C and added triethylamine (1.06g, 1.4ml, 10.6
mmol) followed by the addition of a solution of 2,4,5- trifluorobenzyl bromide (1.58g, 7.04
mmol) in dichloromethane (14 ml). The reaction mixture was then stirred at room
temperature for 3 hours. The solvent was removed under reduced pressure to yield the
crude product, which was purified by column chromatography over silica gel (100-200 mesh)
using 1% methanol as an eluent to yield the title compound (2.2g, 71%).
MS:m/z443(M+1)
1HNMR (CDCI3+D2O, 400 MHz):d 1.42-1.47 (m, 9H), 1.5-1.66 (m, 6H), 1.9-2.05 (m, 3H),
3.16 (s, 2H), 3.73 (s, 3H), 4.1-4.3 (m, 2H), 5.0-5.1 (m, 1H), 6.8-6.9 (m, 1H), 7.4-7.46 (m,
1H).
Intermediate 4
Methyl-(2S)-2-(tert-butoxycarbonyl)-amino-2-[8-(4-methanesulphonylphenyl)-8-aza-bicyclo
[3.2.1]-oct-3-yl]-exo-acetate

Step 1 : To a stirred solution of methyl (2S)-2-(tert-butoxycarbonyl)-amino-2-[8-aza-bicyclo
[3.2.1]-oct-3-yl]-exo-acetate (step 5 of intermediate 2, 1.0 g, 3.35 mmol) in dry toluene (30
ml) was added 1-bromo-4-methanesulphonyl benzene (0.787g, 3.35 mmol), BINAP (0.312g,
0.5 mmol), palladium acetate (0.074g, 0.33 m mol) and CS2CO3 (1.52 g, 4.67 mmol) under
N2 atmosphere. The reaction mixture was then heated at 90°C for 17 hours. The reaction
mixture was allowed to come at room temperature. The solvent was removed under reduced
pressure and added dichloromethane (50 ml). The organic layer was washed with water (25
ml) and dried over anhydrous Na2SO4. The solvent was concentrated under reduced
pressure to get a crude product, which was purified by column chromatography over silica
gel (100-200 mesh) using 30% ethyl acetate in hexane as an eluent to yield the title
compound (0.52g, 34%).
mp: 102-104°C
MS:m/z 451(M-1)
1HNMR (CDCI3, 200 MHz):d 1.37 (s, 9H), 1.4-1.5 (m, 1H), 1.55-1.9 (m, 5H), 2.05-2.2 (m,
2H), 2.3-2.55 (m, 1H), 3.03 (s, 3H), 3.66 (s, 3H), 4.0-4.2 (m, 1H), 4.3-4.4 (m, 2H), 4.86-5.0
(m, 1H), 6.75 (d, J=8.9Hz, 2H), 7.73 (d, J=8.9Hz, 2H)
Intermediate 5
Methyl-(2S)-2-(tert-butoxycarbonyl)-amino-2-[8-(3,5-difluorobenzenesulphonyl)-8-aza-
bicyclo[3.2.1]-oct-3-yl]-exo-acetate

Step 1: To a stirred solution of methyl-(2S)-2-(tert-butoxycarbonyl)-amino-2-[8-aza-bicyclo
[3.2.1]-oct-3-yl]-exo-acetate (step 5 of intermediate 2, 1.0 g, 3.36 mmol) in dichloromethane
(20 ml) at 0°C was added triethylamine (0.7 ml, 0.51 g, 5.03 mmol) and 3,5-difluorobenzene
sulphonyl chloride (0.785g, 3.69 mmol). The reaction mixture was then stirred at room
temperature for one hour. The completion of reaction was monitored by TLC. The reaction
mixture was diluted with dichloromethane (20 ml), washed with water (2x10 ml) and dried
over anhydrous Na2SO4. The solvent was evaporated to yield the crude product, which was
purified by column chromatography over silica gel (100-200 mesh) using 1% methanol in
dichloromethane as an eluent to yield the title compound (1.0g, 62%).
mp: 55-57°C
MS: m/z 473(M-1)
1HNMR (CDCI3, 200 MHz): d 1.43 (s, 9H), 1.50-1.78 (m, 8H), 2.08-2.38 (m,1H), 3.73 (s, 3H),
4.13-4.31(m, 3H),4.93-5.08 (m, 1H),6.90-7.08 (m,1H),7.3-7.45(m, 2H).
Intermediate 6
Methyl-(2S)-2-(tert-butoxycarbonyl)-amino-2-[8-(cyclohexyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-
exo-acetate
Step 1: Methyl-(2S)-2-(tert-butoxycarbonyl)-amino-2-[8-(cyclohex-2-enyl)-8-aza-bicyclo
[3.2.1 ]-oct-3-y l]-exo-acetate

To a stirred solution of methyl-(2S)-2-(tert-butoxycarbonyl)-amino-2-[-8-aza-bicyclo [3.2.1]-
oct-3-yl]-exo-acetate (step 5 of intermediate 2, 0.5 g, 1.68 mmol) in acetonitrile (20 ml) at
room temperature was added anhydrous potassium carbonate (0.7g, 5.03 mmol) and stirred
for 10 minutes. To this solution was added 3-bromo cyclohexene (0.3g, 0.22 ml, 1.84 mmol)
followed by potassium iodide (0.014 g, 0.08 mmol) and heated at 45°C for six hours.
Completion of reaction was monitored by TLC. The solvent was evaporated under reduced
pressure, added dichloromethane (10ml) and washed with water (10ml) The organic solvent
was dried over anhydrous Na2SO4 and the solvent was evaporated at reduced pressure to
yield the crude product, which was purified by column chromatography over silica gel (100-
200 mesh) using 4% methanol in dichloromethane to get the title compound (0.55g, 87%).
MS:m/z 379(M+1)
1HNMR (CDCI3+D2O, 400 MHz): 8 1.15-1.34 (m, 3H), 1.43 (s, 9H), 1.44-1.78 (m, 5H), 1.8-
2.1 (m, 6H), 2.11-2.23 (m, 1H), 3.04-3.15 (m, 1H), 3.53-3.64 (m, 2H), 3.72 (s, 3H), 4.14-
4.21(m, 1H), 5.66-5.72 (m, 1H), 5.78-5.85 (m, 1H).
Step 2: Methyl-(2S)-2-(tert-butoxycarbonyl)-amino-2-[8-(cyclohexyl)-8-aza-bicyclo [3.2.1]
oct-3-yl]-exo-acetate.

To a solution of methyl-(2S) -2-(tert-butoxycarbonyl)-amino-2- [8- (cyclohex-2-enyl) -8-aza-
bicyclo [3.2.1]-oct-3-yl]-exo-acetate (0.5g, 1.32 mmol) in methanol (20 ml) was added 5%
Pd-C (0.5g) and the solution was hydrogenated (60 psi of H2) on Parr apparatus for 8 hours.
The reaction mixture was filtered through a small celite bed and washed with 50% methanol
in dichloromethane (2x20 ml) the filtrate was evaporated under reduced pressure to get the
title compound quantitatively (0.48g).
MS:m/z 381(M+1)
1HNMR (CDCI3, 200 MHz): d 1.05-2.3 (m, 28H), 2.5-2.7 (m, 1H), 3.65 -3.82 (m, 5H), 4.1-4.30
(m, 1H), 5.25-5.5 (m, 1H).
Intermediate 7
Methyl-(2S)-2-(tert-butoxycarbonyl)-amino-2-[8-(cyclohexane carbonyl)-8-aza-bicyclo [3.2.1]-
oct-3-yl]-exo-acetate

Step 1: To stirred solution of methyl-(2S)-2-(tert-butoxycarbonyl)-amino-2- [8-aza-bicyclo
[3.2.1] -oct-3-yl]-exo-acetate (step 5 of intermediate 2, 1.0g, 3.35 mmol) in dichloromethane
(30 ml) at 0°C was added cyclohexane carbonyl chloride (0.45g, 0.42ml, 3.35 mmol) and
triethyl amine (0.676g, 0.93 ml, 6.7 mmol). The reaction mixture was then stirred at room
temperature for one hour. The reaction mixture was diluted with dichloromethane (30 ml)
and washed with water (2x25ml). The organic layer was dried over anhydrous Na2SO4 and
the solvent was evaporated to yield the crude product, which was purified by column
chromatography over silica gel (100-200 mesh) using 2.5% methanol in dichloromethane as
an eluent to yield the title compound (1.25g, 91%)
mp: 69-71 °C
MS:m/z 409(M+1)
1HNMR (CDCI3+D2O, 400 MHz): d 1.15-1.35 (m, 5H), 1.4-1.45 (m, 9H), 1.46-1.8 (m,10H),
1.83-2.06 (m,2H), 2.25-2.36 (m,2H),3.73 (s, 3H), 4.2-4.3 (m, 2H),4.65-4.73 (m, 1H), 4.98-
5.08 (m, 1H).
Intermediate 8
Methyl-(2S)-2-(tert-butoxycarbonyl)-amino-2-[8-(4-chlorophenyl sulfonyl carbamoyl)-8-aza-
bicyclo [3.2.1 ]-oct-3-yl]-exo-acetate

To a stirred solution of methyl-(2S)-2-(tert-butoxycarbonyl)-amino-2-[8-aza-bicyclo [3.2.1]-
oct-3-yl]-exo-acetate ( Step 5 of intermediate 2,0.95 g., 3.18 mmol) in dry dichloromethane
(25 ml) was added 4-chlorobenzene sulfonyl isocyanate (0.69g, 3.18 mmol) followed by the
addition of N-ethyl diisopropyl amine (0.45g, 0.6 ml., 3.49 mmol) at 0°C. After the addition
was completed, reaction mixture was stirred at room temperature for 30 minutes. The
completion of reaction was monitored by TLC. The reaction mixture was diluted with
dichloromethane (25 ml) and washed with water (2x25 ml). The organic layer was dried over
anhydrous Na2SO4 and the solvent was evaporated at reduced pressure to yield the crude
product, which was purified by column chromatography over silica gel (100-200 mesh) using
2% methanol in dichloromethane as an eluent to yield the title compound (1.22 g, 74%).
MS: m/z 514 (M-1)
1HNMR (CDCI3+D2O, 400 MHz): d 1.42 (s, 1H), 1.45-1.80 (m, 4H), 1.82-2.40 (m, 4H), 3.71
(s, 3H), 4.04-4.40 (m, 3H), 5.00-5.21 (m, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.98 (d, J = 8.8 Hz,
2H)
Intermediate 9
Methyl-(2S)-2-(tert-butoxycarbonyl)-amino-2-[8-(3,3,3-trifluoropropyl)-8-aza-bicyclo [3.2.1]-
oct-3-yl]-exo-acetate

Step 1: To stirred a solution of methyl-(2S)-2-(tetr-butoxycarbonyl)-amino-2-[8-aza-bicyclo
[3.2.1]-oct-3-yl]-exo-acetate (step 5 of intermediate 2, 1.0 g, 3.36 mmol) in acetonitrile (20
ml) at room temperature was added anhydrous K2CO3 (1.39g, 10.07 mmol) stirred for 10
minutes. To this reaction mixture was then added 3,3,3-trifluoropropyl iodide (0.827g, 0.43
ml, 3.69 mmol) and heated at 50°C for 6 hours under stirring. The solvent was removed
under reduced pressure and added ethyl acetate (50 ml). The organic layer was washed
with water (2x20 ml), bromine (10 ml) and dried over anhydrous Na2SO4. The solvent was
evaporated to yield the crude product, which was purified by column chromatography over
silica gel (100-200 mesh) using 1.3% methanol in dichloromethane as an eluent to yield the
title compound (0.775g, 58%).
MS: m/z 395(M+1)
1HNMR (CDCI3, 200 MHz): d 1.17-1.60 (m, 15H),1.82-2.40 (m, 5H), 2.5 -2.63 (m, 2H), 3.14-
3.28 (m, 2H) 3.73 (s, 3H) 4.10-4.30 (m, 1H), 4.97-5.10 (m, 1H).
Intermediate 10
Methyl-(2S)-2-(tert-butoxycarbonyl)-amino-2-[8-(5-cyanopyridin-2-yl)-8-aza-bicyclo [3.2.1]-
oct-3-yl]-exo-acetate

Step 1: To a stirred solution of methyl-(2S)-2-(tert-butoxycarbonyl)-amino-2-[8-aza-bicyclo
[3.2.1]-oct-3-yl]-exo-acetate (step 5 of intermediate 2, 0.8g, 2.68 mmol) in dry DMF (10ml)
was added 6-chloro-nicotinontrile (0.407g, 2.94 mmol) and triethylamine (0.54 g, 0.75 ml,
5.36 mmol) at room temperature.The reaction mixture was then heated at 80°C for 2 hours
under stirring. The reaction mixture was allowed to come at room temperature. It was then
diluted with water (80 ml) and extracted with ethyl acetate (2x40 ml) The combined organic
layer was washed with water (2x30ml) and dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure and the crude product so obtained was purified by column
chromatography over silica gel (100-200 mesh) using 40% ethyl acetate in hexane as an
eluent to yield the title compound (0.835g, 62%).
mp: 65-67°C
MS:m/z 401(M+1)
'HNMR (CDCI3, 200 MHz):d 1.38(s, 9H), 1.4-1.65 (m, 4H), 1.72-1.9 (m, 2H), 2.0 -2.2 (m,
2H), 2.28-2.5 (m, 1H) 3.7 (s, 3H) 4.01-4.2 (m, 1H), 4.5-4.7 (m, 2H) 4.88-5.0 (m, 1H), 6.46 (d,
J=8.9Hz, 1H) 7.5-7.62 (m, 1H), 8.34-8.42 (m, 1H)
Intermediate 11
Methyl (2S)-2-(tert-butoxy carbonyl)-amino-2- {8-(adamantan-1-yl-methyl)-8-aza-bicyclo
[3.2.1] oct-3-yl}-exo-acetate

To a stirred solution of methyl (2S)-2-(tert-butoxy carbonyl) amino-2- {8-(adamantan-1-
carbonyl)-8-aza-bicyclo [3.2.1] oct-3-yl}-exo-acetate (prepared by following the similar
procedure as described in step 6 of intermediate 2, 1.0g, 2.17 mmol) in dry tetra hydrofuran
(30 ml) was added borane dimethyl sulfide complex (0.41ml, 0.328g, 4.35 m mol) drop wise
at 0°C. The reaction mixture was allowed to come at room temperature and stirred for 4 h at
same temperature. The progress of reaction was monitored by TLC. The reaction mixture
was cooled to 0°C and acidified to pH 5 with 10% aquous HCI. The reaction mixture was
evaporated under reduced pressure to dryness and the residue was stirred with ethyl
acetate (10 ml). It was then cooled to 0°C and basified with a saturated aqueous sodium
carbonate solution to pH 9. The organic layer was separated and the aqueous layer was
extracted with ethyl acetate (3x 25 ml). The combined organic layer was dried over
anhydrous sodium sulphate and the solvent was evaporated to obtain a crude product,
which was purified by column chromatography over silica gel (100-200 mesh) using 2%
methanol in dichloromethane as an eluent to yield the title compound (0.82g, 85%).
SMB/372/149
MS:m/z 447(M+1)
1HNMR (CDCI3, 400MHz) :d 1.4-1.53 (m, 19H), 1.54-1.64 (m, 12H), 1.65-1.72 (m, 4H), 1.76-
1.84 (m, 4H), 1.9-1.95 (m, 5H), 2.95-3.02 (m, 2H), 3.71(S, 3H), 4.06-4.14 (m, 1H), 4.98 (d, J
=9.2 Hz, 1H)
For making the final compounds, all the Intermediates from 3-11 were converted to their
corresponding acids listed below by using similar procedure as described for Intermediate 2
process.
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(2,4,5-trifluorobenzyl)-8-aza-bicyclo[3.2.1]-oct-3-yl]-
exo-ethanoic acid
MS:m/z 429(M+1)
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(4-methanesulfonyl phenyl)-8-aza-bicyclo [3.2.1]-
oct-3-yl]-exo-ethanoic acid
MS: m/z 437(M-1)
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(3,5-difluorobenzene sulfonyl)-8-aza-bicyclo
[3.2.1]-oct-3-yl]-exo-ethanoic acid
MS: m/z 459 (M-1)
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(cyclohexyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-
ethanoic acid
MS: m/z 367(M+1)
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(cyclohexane-carbonyl)-8-aza-bicyclo [3.2.1 ]-oct-3-
yl]-exo-ethanoic acid
MS: m/z 395(M+1)
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(4-chlorophenylsulfonyl-carbamoyl)-8-aza-bicyclo
[3.2.1]-oct-3-yl]-exo-ethanoic acid
MS: m/z 524(M+23)
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(3,3,3-trifluoro propyl)-8-aza-bicyclo [3.2.1 ]-oct-3-yl]-
exo-ethanoic acid
MS: m/z 381(M+1)
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(5-cyanopyridin-2-yl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-
exo-ethanoic acid.
MS: m/z 387(M+1)
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(adamantan-1-yl- methyl)-8-aza-bicyclo [3.2.1]-oct-
3-yl]-exo-ethanoic acid.
MS: m/z 433(M+1)
Analogously, by practicing appropriate process seletcted from the chemistry described
hereinabove for Intermediates 3 to 11, with appropriate variations in reactants and reaction
conditions followed by standard ester hydrolysis following intermediates were prepared:
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(pyridin-4-yl-methyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-
exo-ethanoic acid
MS: m/z 376(M+1)
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(4-cyano-phenyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-
ethanoic acid
MS: m/z 386(M+1)
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(methanesulfonyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-
exo-ethanoic acid
MS: m/z 361(M-1)
(2S)-2-(re/t-Butoxycarbonyl)-amino-2-[8-(thiophene-2-sulfonyl)-8-aza-bicyclo [3.2.1]-oct-3-
yl]-exo-ethanoic acid
MS: m/z 453(M+23)
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(2-methoxyphenyl-thio-carbamoyl)-8-aza-bicyclo
[3.2.1 ]-oct-3-yl]-exo-ethanoic acid
MS: m/z 450(M+1)
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(cyclohexylmethyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-
exo-ethanoic acid
MS: m/z 381(M+1)
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(benzyloxy-ethyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-
ethanoic acid
MS: m/z 419 (M+1)
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(1-ethyl-propyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-
ethanoic acid
MS:m/z 355(M+1)
Intermediate 12
(2S)-2-(tert-Butoxy carbonyl)-amino-2- {8-( tert-butoxy carbonyl)-8-aza-bicyclo [3.2.1] oct-3-
yl}-exo-ethanoic acid

Step 1: (2S)-2-(tert-Butoxy carbonyl)-amino-2- {8-( tert-butoxy carbonyl)-8-aza-bicyclo [3.2.1]
oct-3-yl}-exo-acetate

To a stirred solution of methyl- (2S)-2-(tert-butoxy carbonyl)-amino-2- (8-azabicyclo [3.2.1]-
oct 3yl] exo acetate (step 5 of Intermediate 2, 0.8 g, 2.68 m mol) in dichloromethane (16 ml)
at 0°C was added triethyl amine (1.04 g, 3.22 m mol, 1.4 ml). The reaction mixture was
stirred at same temperature for 15 minutes and di-tert-butyl dicarbonate (0.64g, 0.67ml, 2.95
m mol) was added. The reaction mixture was then stirred at room temperature for 20 hours.
The solvent was removed under reduced pressure to get a crude product, which was
purified by column chromatography over silica gel (100-200 mesh) using 1.5% methanol in
dichloromethane as an eluent to yield the title compound (1.0 g, 93%)
MS: m/z 399(M+1)
1HNMR (CDCL3+D2O, 200 MHz):d 1.42 (s, 9H), 1.45 (s, 9H), 1.45-1.82 (m, 6H), 1.84-2.10
(m, 2H), 3.72 (s, 2H), 4.05-4.32 (m, 3H), 4.92-5.10 (m, 1H)
Step 2: (2S)-2-(tert-Butoxy carbonyl)-amino-2- {8-( tert-butoxy carbonyl)-8-aza-bicyclo [3.2.1]
oct-3-yl}-exo-ethanoic acid

To a stirred and cooled (0°C) solution of (1.0 g, 2.51 mmol) in methanol (50 ml) was added a
solution of Na2CO3 (1.33g, 12.6 mmol) in water (25 ml) in a drop wise manner. After the
addition is completed, the turbid solution was stirred at room temperature for 14 hours. After
completion of reaction, the reaction mixture was concentrated under reduced pressure to
dryness. To this was added water (10 ml) cooled to 0°C and pH of the reaction mixture was
adjusted to 6.5 with aqueous 20% HCI. The solvent was removed under reduced pressure to
yield a solid, which was stirred with ethyl acetate (75ml) at room temperature for 30 minutes.
The reaction mixture was filtered through Buchner funnel and filtrate was dried over
anhydrous Na2SO4. The solvent was evaporated to yield the title compound (0.88g, 91%),
which was subjected to next step without purification.
MS: m/z 407(M+23)
1HNMR (CDCL3, 200 MHz):d 1.25-1.74 (m, 24H), 1.83-2.02 (m, 2H), 2.15-2.34 (m, 1H), 3.85
(s, 2H exchanges with D2O), 4.06-4.16 (m, 3H).
Intermediate 13
2-(tert-Butoxycarbonyl)-amino-2-{9-(4-trifluoromethyl benzoyl)-9-aza-bicyclo [3.3.1 ]-non-3-
yl}-exo- ethanoic-acid

Step 1 : 3-Benzyl-3-hydroxy-9-aza-bicyclo [3.3.1] nonane-9-carboxylic acid ethyl ester

To a stirred suspension of magnesium turning (7.16g, 0.3mol) and iodine (5.0 mg, 0.04
mmol) in anhydrous THF (250 ml) at 65°C temperature was added a solution of benzyl
chloride (44g, 0.35 mol) in THF (100 ml) under nitrogen atmosphere. The mixture was
refluxed for 2 hours and a solution of 3-oxo-9-aza-bicyclo [3.3.1] nonane-9-carboxylic acid
ethyl ester ( prepared by following the procedure given in US 4277472, 21.0g, 0.1 mol) in
THF (100ml) was added at 65°C. The reaction was stirred at same temperature for 14
hours. The progress of reaction was monitored by 1HNMR spectrum of the crude product.
The reaction mixture was cooled to 0°C and acidify to pH 4 with 1N aqueous HCI. The
reaction mixture was concentrated and the residue was taken up in CH2CI2 (500ml). The
organic layer was washed with water (100 ml), dried over anhydrous sodium sulphate and
filtered. The solvent was evaporated to obtain a crude product, which was purified by a filter
column over silica gel (100-200 mesh) using 1% methanol in dichloromethane as an eluent
to yield an inseparable mixture of un reacted starting material and product (28.1g).
The mixture so obtained was taken in ethanol (300 ml) and to this was added sodium
borohydride in portionwise (7.0 g ) under stirring at 0°C. After the addition was completed,
the reaction mixture was brought to room temperature and stirred for two hours. The
reaction mixture was again cooled to 0°C and acidified to pH 4 by using 1N aqueous HCL.
Ethyl alcohol was evaporated under reduced pressure and the residue was taken up in
dichloromethane (600 ml). The organic layer was washed with water (100 ml), dried over
anhydrous sodium sulphate and filtered. The solvent was evaporated to give a crude
product, which was purified by column chromatography over silica gel (100-200 mesh) using
1% methanol in dichloromethane as an eluent to yield the title compound (11.6 g, 39%).
MS: m/z304(M+1)
1H NMR (CDCI3, 400 MHz):d 1.18-1.9 (m, 10H), 1.91-2.14 (m, 1H), 2.28-2.72 (m, 5H), 4.1-
4.25 (m, 2H), 4.3-4.51 (m, 1H), 4.6-4.83 (m, 2H), 7.1-7.4 (m, 5H)
Step 2: 9-(Ethoxy carbonyl)-3-exo-benzyl-9-aza-bicyclo [3.3.1] non-3-yl methyl oxalate

To a stirred solution of 3-benzyl-3-hydroxy-9-aza-bicyclo [3.3.1] nonane-9-carboxylic acid
ethyl ester (13.5g, 44.5 m mol) in dichloromethane (350 ml) was added pyridine (7g, 89.1m
mol) and 4-dimethyl amino pyridine (0.54g, 4.4m mol) at 0°C. A solution of mono methyl
oxalyl chloride (6.0g, 49 mmol) in dichloromethane (50 ml) was then added drop wise at
0°C. After the addition was completed, the reaction mixture was brought to room
temperature and stirring was continued for 18 hours. The progress of reaction was
monitored by TLC. After the completion of reaction, the reaction mixture was diluted with
dichloromethane (200 ml) and washed with a saturated aqueous sodium bicarbonate
solution (100 ml), water (100 ml), dried over anhydrous sodium sulphate and filtered. The
solvent was removed under reduced pressure to get the crude product, which was purified
by column chromatography over silica gel (100-200 mesh) using 7% ethyl acetate in hexane
as an eluent to yield the title compound (13.6 g, 79%)
MS: m/z 390(M+1)
1HNMR (CDCI3, 400 MHz):d 1.29 (t, J=7.2Hz, 3H), 1.43-1.6 (m, 3H), 1.63-1.8 (m, 2H), 2.09-
2.2 (m, 3H), 2.26-2.35 (m, 2H), 3.14 (ABq, J=14.8Hz, 2H), 3.87 (S, 3H), 4.14-4.25 (m, 2H),
4.42-4.50 (m, 1H), 4.52-4.59 (m, 1H), 7.13-7.17 (m, 2H), 7.22-7.32 (m, 3H)
Step 3: Ethyl-3-benzyl-9-aza-bicyclo [3.3.1] nonane-9-carboxylate

To a stirred solution of 9-(ethoxy carbonyl)-3-exo-benzyl-9-aza-bicyclo [3.3.1] non-3-yl
methyl oxalate (13.5g, 34.7 mmol) in toluene (350 ml) was added a solution of tri butyl tin
hydride (15.15g, 52 mmol) in toluene (55 ml) at room temperature. The reaction mixture was
then heated at 110°C and added a portion of 2,2'-azobis ( 2- methyl propionitrile) ( AIBN,
0.57g, 3.47m mol) under stirring. The progress of the reaction was monitored by TLC and
more AIBN was added every one hour (9 x 0.57 g , 5.13 g, 31.2 m mol). The reaction was
completed in 12 hours. The reaction mixture was cooled to room temperature and the
solvent was removed under reduced pressure. The crude product so obtained was purified
by column chromatography over silica gel (100-200 mesh) using 10% ethyl acetate in
hexane as an eluent to yield the title compound (14.1 g)
MS: m/z 288(M+1)
1HNMR (CDCI3, 400 MHz):d 0.907 (t, J=7.6Hz, 3H), 1.2-1.27 (m, 2H), 1.28-1.4 (m, 4H),
1.42-1.78 (m, 5H), 2.39-2.43 (m, 2H), 4.04-4.2 (m, 2H), 4.21-4.47 (m, 2H), 7.1-7.15 (m, 1H),
7.16-7.23 (m, 2H), 7.25-7.34 (m, 2H)
Step 4: [9-(Ethoxycarbonyl)-9-azabicyclo [3.3.1] -non-3yl] acetic acid

To a stirred solution of ethyl-3-benzyl-9-aza-bicyclo [3.3.1] nonane-9-carboxylate (14.0 g,
48.8 mmol) in mixture of carbon tetra chloride and acetonitrile (1:1, 280 ml) was added water
(210 ml) followed by periodic acid (155g, 683 mmol) at room temperature. The reaction was
heated to 40-50°C and RuCI3 was added portion wise over the period of 20 mintues. Stirring
was continued for 2.0 hours and the progress of the reaction was monitored by TLC,, After
the completion of reaction, the reaction mixture was cooled to room temperature and
evaporated most of the organic solvents under reduced pressure. The aqueous layer was
extracted with CCI4 (3x 200 ml). The combined organic layer was dried over anhydrous
sodium sulphate and evaporated to yield the title compound (4.92 g, 40%), which was
subjected to next reaction without further purification.
MS: m/z 254(M-1)
1HNMR (CDCI3+D2O, 200 MHz): 5 0.97 (t, J=7.4Hz, 3H), 1.02-2.4 (m, 12H), 2.6-2.86 (m,
1H), 4.0-4.55 (m,4H)
Step 5: 9-Azabicyclo [3.3.1] non-3-yl acetic acid hydrochloride

Concentrated HCI (36%, 73.5ml) was added to [9-(ethoxy carbonyl)-9-azabicyclo [3.3.1]-
non-3yl]- acetic acid (4.9g, 19.2 m mol) under stirring at room temperature. The reaction
mixture was heated at 100 °C for 8 hours and progress of reaction was monitored by mass
spectroscopy. After the completion of reaction, the reaction mixture was evaporated to
dryness under reduced pressure and traces of water was removed by evaporating with
dichloromethane (3x 50 ml) the crude product was dried under high vacuum to yield the title
compound (4.01 g, 95%) and subjected to further reaction without purification
MS:m/z 184(M+1)
Step 6: Methyl -9-azabicyclo [3.3.1]-non-3-yl -exo-acetate

To a stirred solution of 9-azabicyclo [3.3.1] non-3-yl acetic acid hydrochloride (4.0g, 18.2
mmol) in methanol (80 ml) was added concentrated sulfuric acid (1ml) at 5°C. The reaction
mixture was brought to room temperature and then refluxed at 65°C for 15 hours under
stirring. The progress of the reaction was monitored by mass spectroscopy. After the
completion of reaction, the reaction mixture was cooled to room temperature and the solvent
was evaporated under reduced pressure. The residue was diluted with chloroform (50 ml)
and basified with ammonia in chloroform at 0°C till pH turned to 10. The salt precipitated
was filtered through a buchner funnel and the filtrate was concentrated to get a crude
product, which was purified by column chromatography over silica gel (100-200 mesh) using
(ammonia in chloroform: methanol: dichloromethane) in the ratio of 2:10:88 as an eluent to
yield the title compound (1.07g, 30%)
Exo isomer:
MS: m/z 198(M+1)
1HNMR (CDCI3+D2O, 400 MHz):d 1.4-1.5 (m, 2H), 1.6-1.71 (m, 3H), 1.78-1.88 (m, 4H) 1.92-
2.06 (m, 1H), 2.14 (d, J=6.8Hz, 2H), 2.6-2.74 (m, 1H), 3.1-3.16 (m, 2H), 3.66 (S, 3H)
Endo isomer:
MS: m/z 198(M+1)
1HNMR (CDCI3 +D2O, 400 MHz):d 0.9-1.0 (m, 2H), 1.30-1.37 (m, 2H), 1.40-1.48 (m, 1H),
1.60-1.70 (m, 2H), 1.73-2.07 (m, 4H), 2.25 (d, J = 6.8Hz, 2H), 3.16-3.27 (m, 2H), 3.66 (S,
3H)
Step 7: Methyl {9-[4[trifluromethyl]-9-azabicyclo [3.3.1] non-3-yl} - exo - acetate.

To a stirred solution of methyl -9-azabicyclo [3.3.1]- non-3-yl -exo- acetate (1.05 g, 5.3 m
mol) in tetra hydrofuran (50 ml) was added 4-trifluromethyl benzoic acid (1.01 g, 5.3 m mol)
and 1-hydroxy benzotriazole (0.82 g, 5.3 m mol) at room temperature. The reaction mixture
was cooled to 0°C and 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (1.12 g,
5.8 m mol) was added. The reaction mixture was then brought to room temperature and
stirred for 18 hours at same temperature. The progress of the reaction was monitored by
mass spectroscopy. The reaction mixture was concentrated under reduced pressure and the
residue was taken up in dichloromethane (150 ml). The organic layer was washed with a
saturated aqueous sodium bicarbonate solution (20 ml) and dried over anhydrous sodium
sulphate. The solvent was evaporated to obtain a crude product, which was purified by
column chromatography over silica gel (100-200 mesh) using 1.5% methanol in
dichloromethane as an eluent to yield the title compound (1.22 g, 62%)
MS: m/z 370(M+1)
1HNMR (CDCI3, 200 MHz):d 1.3-1.5 (m, 1H), 1.51-2.3 (m, 11H), 2.68-2.93 (m, 1H) 3.67 S,
3H), 3.66-3.80 (m, 1H) 4.80-4.90 (m, 1H), 7.50 (d, J = 8.1 Hz, 2H), 7.66 (d, J=8.1 Hz, 2H)
Step 8: Methyl -2-(1,2-di-tert-butyloxy carbonyl hydrazine)-2-[9-(4-trifluoromethyl benzoyl)-9-
azabicyclo [3.3.1]-non-3-yl]-exo-acetate

To a cold (-70°C) and stirred solution of diisopropyl amine (0.49 g, 4.88 mmol) in THF (10
ml) was added n-butyl lithium (1.6 M, 0.31 g, 4.88 mmol) and stirred at the same
temperature for one hour. A solution of methyl {9-[4-[tifluoro methyl]-9-azabicyclo [3.3.1]-
non-3-yl}-exo-acetate (1.2 g, 3.25 mmol) in THF (40 ml) was added drop wise at -70°C. After
90 minutes, a solution of di-tert-butyl-diazene -1,2-dicarboxylate (3.0 g, 13 m mol) in THF
(20 ml) was added to the reaction mixture at-70°C. After the addition, reaction mixture was
allowed to come at room temperature and stirred for further 14 hours. The progress of the
reaction was monitored by TLC. After the completion of reaction, the reaction mixture was
cooled to 0°C and the pH was adjusted to 7 with a saturated aqueous ammonium chloride
solution. Tetra hydro furan was evaporated under reduced pressure and the aqueous layer
was extracted with dichloromethane (4x100 ml). The combined organic layer was dried over
anhydrous sodium sulphate and concentrated to obtain a crude product, which was
purified by column chromatography over silica gel (100-200 mesh) using 1% methanol in
dichloromethane as an eluent to yield the title compound (1.19 g, 61%)
MS:m/z 600(M+1)
1HNMR (CDCI3, 200 MHz):d 1.22-1.86 (m, 27H), 1.93-2.1(m, 2H), 2.80-3.11(m, 1H) 3.63-
3.83 (m, 4H), 4.8-4.95 (m, 1H), 6.50-6.65 (m, 1H), 7.4-7.7 (m, 4H)
Step 9: Methyl-2- (hydrazino)-2-[9-(4-trifluoromethyl benzoyl)-9-azabicyclo [3.3.1]-non-3-yl]-
exo-acetate di trifluoro acetic acid salt

To a stirred solution of methyl -2-(1,2-di-tert-butyloxycarbonyl hydrazino)-2-[9-(4-
trifluoromethyl benzoyl)-9-azabicyclo [3.3.1]-non-3-yl]-exo- acetate (1.15 g, 1.92 mmol) in
dichloromethane (6 ml) was added a solution of tri fluoro acetic acid (11.5 ml, 11.7 g, 154.8
m mol) in dichloromethane (5.5 ml) at 0°C. The reaction mixture was allowed to come at
room temperature and stirred for 4 hours. The progress of reaction was monitored by mass
spectroscopy. After the completion of reaction, the solvent was evaporated to get a crude
product (1.25 g) quantitatively, which was subjected to next step without purification
MS: m/z 400 (M+1)
Step 10: Methyl amino {9-[4-(trifluoro methyl) benzoyl]-9-azabicyclo [3.3.1] non-3-yl}-exo-
acetate
To a solution of methyl -2-(hydrazine)-2-[9-(4-trifluoro methyl benzoyl)-9-azabicyclo [3.3.1]- -
non-3-yl]-exo-acetate di trifluoro acetic acid salt (1.24 g, 1.98 mmol) in a mixture of methanol
and water (1:1, 24.8 ml) was added Raney nickel (7.4 g) under a nitrogen atmosphere at
room temperature. The reaction mixture was hydrogenated at 568 psi in an autoclave for
14.0 hours at room temperature. The progress of the reaction was monitored by mass
spectroscopy. The catalyst was filtered through a Buchner funnel and the residue was
washed with methanol (25ml) and water (25ml). The combined filtrates were evaporated to
dryness under reduced pressure and the crude product was taken up in chloroform (20 ml).
The reaction mixture was cooled to 0°C and the pH was adjusted to 10 using ammonia in
chloroform. The salt precipitated was filtered and the filtrate was concentrated to give a
crude product (0.73 g, 96%), which was subjected to next step without purification
MS:m/z385(M+1)
1HNMR (CDCI3+D2O, 400 MHz):d 1.18-1.40 (m, 2H), 1.5-1.87 (m, 6H), 1.88-2.10 (m, 2H),
2.70-2.82 (m, 1H), 3.2-3.3 (m, 1H), 3.79-3.85 (m, 4H), 4.85-4.94 (m, 1H), 7.51 (d, J=7.6Hz,
2H), 7.66 (d, J=7.6Hz, 2H)
Step 11: Methyl-2- (tert-butoxy carbonyl) amino-2- {9-[4-(trifluoromethyl) benzoyl]-9-
azabicyclo [3.3.1] non-3-yl}-exo-acetate

To a stirred solution of methyl amino {9-[4-(trifluoromethyl)-benzoyl]-9-azabicyclo [3.3.1]-
non-3-yl}-exo-acetate (0.224 g, 2.22 mmol) in dichloromethane (35 ml) was added di-tert-
butyl dicarbonate (0.71 g, 1.85 mmol) and triethyl amine (0.44 g, 2.03 mmol) at 0°C. The
reaction mixture was allowed to come at room temperature and stirred for 15 hours. The
progress of reaction was monitored by TLC. After the completion of reaction, the solvent
was evaporated under reduced pressure to get the crude product, which was purified by
column chromatography over silica gel (100-200 mesh) using 2% methanol in
dichloromethane as an eluent to yield the title compound (0.67 g, 75%)
MS: m/z 485(M+1)
1HNMR (CDCI3+D2O, 200 MHz):6 1.2-2.1 (m, 19H), 2.65-3.0 (m, 1H), 3.76 (S, 3H), 4.09-4.28
(m, 1H), 4.83-5.15 (m, 2H), 7.40-7.55 (m, 2H), 7.60-7.75 (m, 2H)
Step 12: 2-(tert-Butoxy carbonyl) amino-2- {9-(4-trifluoromethyl benzoyl)-9-azabicyclo [3.3.1]
non-3-yl}-exo-ethanoic acid

To a stirred solution of methyl-2- (tert-butoxy carbonyl)-amino-2- {9-[4-(trifluoromethyl)
benzoyl]-9-azabicyclo [3.3.1] non-3-yl}-exo-acetate (0.645 g, 1.33 mmol) in methanol (39.0
ml) was added a solution of sodium carbonate (0.706 g, 6.66 mmol) in water (19.5 ml) at
0°C. The reaction mixture was allowed to come at room temperature and stirred for 20
hours. The progress of reaction was monitored by TLC. The reaction mixture was
evaporated to dryness under reduced pressure and the residue was dissolved in water (20
ml). The aqueous solution was cooled to 0oC and pH was adjusted to 6 by using 1N
aqueous HCI. The reaction mixture was concentrated to dryness under reduced pressure
and the residue was stirred with 10% methanol in dichloromethane (70 ml) at room
temperature for 15 minutes. It was then filtered through a Buchner funnel and the residue
was washed with 10% methanol in dichloromethane (2x70ml). The combined filtrates were
concentrated to yield the title compound (0.566 g, 90%)
MS: m/z 469(M-1)
1HNMR (CDCI3, 400 MHz):5 1.1-2.08 (m, 19H), 2.56-2.9 (m, 1H), 3.5-3.75 (m, 1H) 3.89-3.98
(m, 1H), 4.70-4.85 (m, 1H), 5.6-5.8 (m, 1H), 7.40-7.55 (m, 2H), 7.57-7.70 (m, 2H)
Intermediate 14
(1R, 3R, 5R)-2-aza-bicyclo [3.1.0]-hexane-3-carboxamide trifluoro acetic acid salt

The title compound was prepared by following the procedure as described in WO
2004/052850 starting from (R)-(+)-2-pyrolidinone-5- carboxylic acid
MS: m/z 127 (M+1)
1HNMR (D2O, 400 MHz): d 0.66-0.70 (m, 1H), 0.92-1.92 (m, 1H), 1.85-1.93 (m, 1H) 2.32 (dd,
J = 2.8, 14.0 Hz, 1H), 2.70-2.81 (m, 1H), 3.38-3.45 (m, 1H), 4.67 (dd, J = 8.4, 11.2 Hz, 1H)
[a]D20 30.59 (c 0.50, water)
Example 1
(2S)-1-{ (2S)-2- Amino-2-[8-(2,4,5-trifluorobenzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-
ethanoyl}-pyrrolidin-2- carbonitrile trifluoroacetic acid salt (Compound No. 1)

Step 1: (2S)-1-{(2S)-2-(tert-Butoxycarbonyl)amino-2-[8-(2,4,5-trifluorobenzoyl)-8-aza-bicyclo
[3.2.1] oct-3-yl]-exo-ethanoyl}-pyrrolidin -2-carboxamide

To a stirred solution of (2S)-2(tert-butoxycarbony)lamino-2-[8-(2,4,5-trifluoro-benzoyl)-8-aza-
bicyclo [3.2.1]oct-3-yl]-exo ethanoic acid (step 12 of intermediate 1, 0.35 g, 0.791 mmol) in
dry DMF (10 ml ) was added 1-hydroxy benzotriazole (HOBT, 0.321 g, 2.37 mmol) and L-
prolinamide (0.0903 g, 0.791 mmol) at room temperature.The reaction mixture was cooled to
0°C and added triethylamine (0.24 g, 0.31 ml, 2.37 mmol) and 1-(3-dimethyl amino propyl)-
3-ethyl carbodimide hydrochloride (0.303 g, 1.58 mmol). Ice bath was removed after 2 hours
and the reaction mixture was stirred at room temperature for 24 hours. The solvent was
removed under reduced pressure, added a saturated aqueous sodium bicarbonate solution
(10 ml) and extracted with ethyl acetate (1x 50 ml). The organic layer was dried over
anhydrous Na2SO4 and the solvent was removed under reduced pressure to obtain a crude
product, which was purified by column chromatography over silica gel (100 - 200 mesh)
using methanol :NH3 in chloroform : dichloromethane in the ratio of 2 : 10 :88 as an eluent
to yield the title compound (0.17 g, 40 % ).
MS: mlz 539 (M+1)
1HNMR ( CDCI3, 200 MHz) : 5 1.41 (s, 9H ), 1.60 - 2.40 (m, 13H ), 3.45 - 3.95 (m, 3H), 4.21
- 4.36 (m, 1H ), 4.45-4.58 (m, 1H ), 4.70 - 4.87 (m, 1H ), 5.1 - 5.3 (m, 1H ), 5.32 - 5.5 (m,
1H ), 6.4 - 6.6 (m, 1H, exchangeable with D2O ), 6.85 - 7.02 (m, 1H ), 7.07 - 7.35 (m, 1H ).
Step 2: (2S)-1-{(2S)-2-(tert-butoxycarbonyl)-amino-2-[8-(2,4,5-trifluorobenzoyl)-8-aza-
bicyclo [3.2.1 ]oct-3-yl]-exo-ethanoyl}-pyrrolidin-2-carbonitrile.

To a stirred solution of (2S)-1-{(2S)-2-(tert-butoxycarbonyl)amino-2-[8-(2,4,5-
trifluorobenzoyl)-8-aza-bicyclo[3.2.1 ]oct-3-yl]-exo-ethanoyl}-pyrrolidin-2-carboxamide ( 0.08
g, 0.149 mmol) and imidazole (0.021g, 0.312 mmol) in dry pyridine (2.8 ml) at - 30° C was
added phosphorous oxy chloride (0.093 g, 0.057 ml, 0.609 mmol ) dropwise. The reaction
mixture was stirred at -30°C for 2 hours, and completion of reaction was monitored by TLC.
The reaction mixture was quenched with water (0.5 ml) at - 30°C and then it was allowed to
come at room temperature. The solvent was removed under reduced pressure at room
temperature. The crude product was dried under high vaccum. To this was added
dichloromethane (20 ml), washed with water ( 2 x 5 ml) and dried over anhydrous Na2SO4.
The solvent was evaporated to obtain a crude product, which was purified by column
chromatography over silica gel (100 - 200 mesh) using 1.4 % methanol in dichloromethane
as an eluent to yield the title compound (0.06 g, 77 %).
MS:m/z 521 (M+1)
1HNMR (CDCl3, 400 MHz) : d 1.35 - 1.45 (m, 9H ), 1.65 - 1.85 (m, 6H ), 1.95 - 2.08 (m, 2H
), 2.12 - 2.34 (m, 5H ), 3.57 - 3.95 (m, 3H ), 4.15 - 4.25 (m, 1H ), 4.74 - 4.88 (m, 2H ), 5.05
-5.15(m, 1H), 6.92-7.02 (m, 1H ), 7.26-7.33 (m, 1H).
Step 3 : (2S)-1-{ (2S)-2- Amino-2-[8-(2,4,5-trifluorobenzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-
exo-ethanoyl}-pyrrolidin-2- carbonitrile trifluoroacetic acid salt

To a stirred solution of (2S)-1-{(2S)-2 (tert-butoxycarbonyl)amino-2-[8-(2,4,5-
trifluorobenzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-ethanoyl}-pyrrolidin-2-carbonitrile.
(0.10 g, 0.192 mmol) in dry dichloromethane (1.5 ml) at 0°C was added a solution of
trifluoroacetic acid (2.0 ml, 3.07 g, 26.9 mmol) in dry dichloromethane (1.5 ml) dropwise. The
reaction mixture was sirred at 0°C for 5 minutes, brought to room temperature and stirred for
25 minutes. The solvent was evaporated under reduced pressure at 30°C and added
dichloromethane (10 ml). The solvent was evaporated under reduced pressure and dried
under high vaccum to remove trifluoroacetic acid. In order to remove traces of trifluoroacetic
acid left and to solidify the product, petroleum ether (20 ml) was added to this mass, and
evaporated under reduced pressure. The solid so obtained was stirred with ether (10 ml) at
room temperature for 15 minutes. The solvent was decanted and dried the solid under high
vaccum to yield the title compound (0.089 g, 87%).
MS: m/z 421 (M+1)
1HNMR (CDCI3 + CD3OD + D2O) : d 1.4 - 1.85 (m, 4H ), 1.95 - 2.06 (m, 2H ), 2.07 - 2.34
(m, 4H ), 2.43 - 2.56 (m, 1H ), 3.42 - 3.52 (m, 1H ), 3.54 - 3.83 (m, 3H ), 3.84 - 3.94 (m, 1H
), 3.98 (t, J = 8 Hz, 1H ), 4.67 - 4.8 (m, 2H ), 6.92 - 7.04 (m, 1H ), 7.28 - 7.37 (m, 1H ).
The following compounds were prepared by procedure similar to those described for
Compound No. 1 with appropriate variations of reactants, reaction conditions and quantities
of reagents
(2S)-1-{(2S)-2- Amino-2-[8-(4-trifluoromethylbenzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-
ethanoyl}-pyrrolidin-2- carbonitrile trifluoroacetic acid salt (Compound No.2)
mp: 162-164°C
MS: m/z 435(M+1)
1HNMR (D2O, 400MHz):d 1.51-1.95 (m, 6H), 1.97-2.22 (m, 4H), 2.23-2.4 (m, 2H), 2.55-2.68
(m, 1H), 3.63-3.74 (m, 2H), 4.05-4.13(m, 1H), 4.26 (t, J = 6.4Hz, 1H), 4.7-4.85 (m, 2H) 7.6
(d, J = 7.6Hz, 2H), 7.79 (d, J = 8Hz, 2H)
[a]D21 - 24.93 (c 1.07, water)
Yield: 99%
(2S)-1 -{ (2S)-2- Amino-2-[8-(adamantane-1 -carbonyl)-8-aza-bicyclo[3.2.1 ]oct-3-yl]-exo-
ethanoyl}-pyrrolidin-2- carbonitrile trifluoroacetic acid salt ( Compound No.3)
mp: 162-164°C
MS:m/z 425(M+1)
1HNMR (D2O, 400MHz):5 1.5-2.4(m, 27H), 2.5-2.65(m, 1H), 3.50-3.62 (m, 1H), 3.72-3.84
(m, 1H), 3.97-4.05(m, 1H), 4.7-4.88(m, 3H)
[a]D20 - 18.23 (c 0.50, water)
Yield: 80%
(2S)-1-{(2S)-2-Amino-2-[8-(pyridine-4-carbonyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-ethanoyl}-
pyrrolidin-2- carbonitrile trifluoroacetic acid salt ( Compound No.4)
mp: 125-127°C
MS:m/z 368(M+1)
1HNMR (D2O, 400MHz):5 1.52-2.0 (m, 6H), 2.02-2.22 (M, 4H), 2.25-2.40 (m, 2H), 2.60-2.72
(m, 1H), 3.65-3.75 (m, 2H), 4.03-4.10 (m, 1H), 4.30( t, J=6.4Hz, 1H), 4.75-4.85 (m, 2H),
8.13(d, J=6.8Hz, 2H), 8.93(d, J=6.4Hz, 2H).
Yield: 42%
(2S)-1 -{ (2S)-2- Amino-2-[8-(4-cyano-benzoyl)-8-aza-bicyclo[3.2.1 ]oct-3-yl]-exo-ethanoyl}-
pyrrolidin-2- carbonitrile trifluoroacetic acid salt ( Compound No.5)
mp: 193-195°C
MS:m/z 392(M+1)
1HNMR (D2O, 200MHz): 5 1.5-2.45(m, 12H), 2.5-2.7(m, 1H), 3.6-3.75(m, 2H), 4.02-4.15(m,
1H), 4.2-4.3(m, 1H), 4.7-4.85(m, 2H), 7.60 (d, J=8Hz, 2H), 7.86 (d, J = 8.0 Hz, 2H).
Yield: 98%
(2S)-1-{(2S)-2- Amino-2-[8-(2,5-difluorobenzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-ethanoyl}-
pyrrolidin-2- carbonitrile trifluoroacetic acid salt ( Compound No. 6)
mp: 170-172°C
MS: m/z 403(M+1)
1HNMR (D2O, 400MHz): 5 1.52-1.63 (m, 2H), 1.67-1.95 (m, 4H), 2.02-2.22 (m, 4H), 2.25-
2.40 (m, 2H), 2.52-2.68 (m, 1H), 3.65-3.75 (m, 2H), 4.02-4.12 (m, 1H), 4.21-4.26 (m, 1H),
4.75-4.84 (m, 2H), 7.16-7.23 (m, 1H), 7.26 (t, J= 6.4 Hz, 2H).
Yield: 77%
(2S)-1-{ (2S)-2- Amino-2-[8-(2-fluoro-pyridine-4-carbonyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-
ethanoyl}-pyrrolidin-2- carbonitrile trifluoroacetic acid salt ( Compound No. 7)
mp: 173-175°C
MS: m/z 386 (M+1)
1HNMR (D2O, 400MHz): 5 1.52-1.65 (m, 2H), 1.66-1.95 (m, 4H), 2.00-2.23 (m, 4H), 2.25-
2.40 (m, 2H), 2.55-2.70 (m, 1H), 3.65-3.75 (m, 2H), 4.06-4.13 (m, 1H) 4.27 (t, J = 7.2 Hz,
1H), 4.72-4.85 (m, 2H), 7.16-7.20 (m, 1H), 7.35-7.40 (m, 1H), 8.30 (d, J=4.8Hz, 1H).
Yield: 87%
(2S)-1-{ (2S)-2- Amino-2-[8-(4-trifluoromethyl phenyl carbamoyl)-8-aza-bicyclo[3.2.1]oct-3-
yl]-exo-ethanoyl}-pyrrolidin-2- carbonitrile trifluoroacetic acid salt (Compound No.22)
mp: 196-198°C
MS: m/z 450(M+1)
1HNMR (CDCI3+CD3OD, 400MHz): d 1.5-1.8 (m, 6H), 1.9-2.35 (m, 6H), 2.4-2.7 (m, 1H),
3.45-3.58 (m, 1H), 3.65-3.8 (m, 1H), 3.9-4.05(m, 1H), 4.3-4.5 (m, 2H), 4.7-4.85 (m, 1H), 7.4-
7.6(m,4H).
[a]D20 - 19.76 (c 0.50, water)
Yield: 90%
(2S)-1-{ (2S)-2- Amino-2-[8-(2,4,5-trifluorobenzyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-
ethanoyl}-pyrrolidin-2- carbonitrile trifluoroacetic acid salt ( Compound No.9)
mp: 132-134°C
MS: m/z 407(M+1)
1HNMR (DMSO+D2O, 200MHz): 5 1.4-1.6 (m, 1H), 1.65-2.45 (m, 14H), 3.84-4.3 (m, 5H),
4.7-4.83 (m, 1H), 7.58-7.86 (m, 2H)
[a]D24-12.74 (c 1.00, water)
Yield: 45%
(2S)-{(2S)-1-[(2S)-2-Amino-2-(8-(benzo [1,3] dioxole -5-carbonyl)-8-aza-bicyclo [3.2.1]-oct-3-
yl)-exo-acetyl]-pyrrolidin-2- yl} methanol trifluoroacetic acid salt (Compound No. 14)
mp: 193-195°C
MS:m/z 416(M+1)
1HNMR(D2O, 400 MHz): d 1.45-2.05 (m, 12H), 2.4-2.6 (m, 1H), 3.4-3.68 (m, 4H), 2.88 4.11-
4.31 (m, 3H), 4.62-4.72 (m, 1H), 5.99 (s, 2H),6.9-7.0 (m, 3H)
[a]D20 3.80 (c 0.50, water)
Yield: 75%
Example 2
(2S)-1-{(2S)-2-Amino-2- [8-(4-trifluromethyl-benzoyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-(2H-tetrazol-5-yl) pyrrolidine hydrochloride (Compound No.13)

Step 1: (2S)-1 -{(2S)-2-(tert-butoxycarbonyl)-amino-2- [8-(4-trifluromethyl-benzoyl)-8-
aza-bicyclo [3.2.1 ]-oct-3-yl]-exo-ethanoyl}-2-(2H-tetrazol-5-yl) pyrrolidine

To a stirred solution of (2S)-1-{(2S)-2-(tert-butoxycarbonyl)-amino-2-[8-(4-trifluromethyl-
benzoyl)-8-aza-bicyclo[3.2.1 ]-oct-3-yl]-exo-ethanoyl}-pyrrolidin-2-carbonitrile (prepared by
following the similar procedure as described in step 2 of Example 1, 0.17 g, 0.318 mmol) in
isopropyl alcohol (4 ml) was added sodium azide (0.041 g, 0.636 mmol)and zinc bromide
(0.035 g, 0.159 mmol). To make the solution clear, water (8 ml) was added to the reaction
mixture and heated at reflux for 15 hours. The reaction mixture was allowed to come at room
temperature. To this reaction mixture was added 3N HCI (1 ml) and stirred with ethyl acetate
(25 ml) till the solid was dissoved. The organic layer was separated and the aqueous layer
was extracted with ethyl acetate (20 ml). The combined organic layers were dried over
anhydrous Na2SO4and the solvent was evaporated under reduced pressure to yield a crude
product, which was purified by column chromatography over silica gel (100-200 mesh) using
4% methanol in dichloromethane as an eluent to yield the title compound (0.095 g, 68%).
MS: m/z 576(M-1)
1HNMR (CDCI3, 400MHz):d 1.32-1.42(m, 9H), 1.44-2.53(m, 13H), 2.65-2.85(m, 1H), 3.62-
3.82(m, 1H), 3.87-4.03(m, 2H), 4.26-4.4(m, 1H), 4.65-4.84(m, 1H), 5.34-5.48(m, 1H), 5.6-
5.8(m, 1H), 7.46-7.61 (m, 2H), 7.62-7.73(m, 2H).
Step 2: (2S)-1-{(2S)-2-Amino-2- [8-(4-trifluromethyl-benzoyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-
exo-ethanoyl}-2-(2H-tetrazol-5-yl) pyrrolidine hydrochloride

To a stirred a solution of (2S)-1-{(2S)-2-(tert-butoxycarbonyl) amino-2- [8-(4-trifluromethyl-
benzoyl)-8-aza-bicyclo [3.2.1 ]-oct-3-yl]-exo-ethanoyl}-2-(2H-tetrazol-5-yl) pyrrolidine (0.025,
0.043 mmol) in methanol (1.5 ml) was added 6N aqueous HCI (0.25ml) at 0°C and the
reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was
concentrated under reduced pressure. Sticky oil so obtained was washed with
dichloromethane (5 ml). The crude product was again stirred with 20% dichloromethane in
diethyl ether (5 ml) for 15 minutes and decanted the organic layer. The solid so obtained
was dried under high vacuum to yield the title compound (0.02 g, 90%).
mp: 244-246°C
MS: m/z 478(M+1)
1HNMR (D2O, 400 MHz):5 1.43-1.56 (m, 2H), 1.6-1.85 (m, 4H), 1.95-2.27 (m, 5H), 2.4-2.56
(m, 2H), 3.75-3.9 (m, 2H), 4.0-4.07 (m, 1H), 4.26-4.3 (m, 1H), 4.7-4.85 (m, 1H), 5.43-5.49
(m, 1H), 7.5-7.6 (m, 2H) 7.75-7.81 (m, 2H)
[a]D20 5.69 (c 0.50, water)
Example 3
Methyl (2S)-1 -{(2S)-2- amino-2-[8-(4-trifluromethyl-benzoyl)-8-aza-bicyclo[3.2.1 ]oct-3-yl]-
exo-ethanoyl}-pyrrolidin-2-carboxylate trifluoro acetic acid (Compound No.10)

Step 1: Methyl (2S)-1-{(2S)-2-(tert-butoxycarbonyl)-amino-2-[8-(4-trifluromethyl-benzoyl)-8-
aza-bicyclo[3.2.1]-oct-3-yl]-exo-ethanoyl}-pyrrolidin-2-carboxylate

To a stirred solution of (2S)-2-(tert-butoxycarbonyl)-amino-2-[8-(4-trifluoro methyl-benzoyl)-
8-aza-bicyclo [3.2.1]oct-3-yl]-exo-ethanoic acid (prepared by following the similar procedure
as described in Intermediate 2, 1.5 g, 3.28 mmol) in DMF (20 ml) was added pyrrolidine-2-
carboxylic acid methyl ester hydrochloride (0.544 g, 3.28 mmol) in water (5.0 ml), followed
by the addition of 1-hydroxy benzotriazole (0.886 g, 6.56 mmol). The reaction mixture was
cooled to 0OoC and added 1- (3-dimethyl amino propyl)-3-ethyl carbodiimide hydrochloride
(1.25 g, 6.56 mmol) followed by triethylamine (1.36 ml, 0.993 g, 9.84 mmol). The reaction
mixture was then stirred at room temperature for 18 hours. The solvent was evaporated
under reduced pressure. To the residue was added ethyl acetate (50 ml) and the organic
layer was washed with water (10 ml) and saturated solution of sodium bicarbonate (10 ml).
The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under
reduced pressure to obtain a crude product, which was purified by column chromatography
over silica gel (100-200 mesh) using methanol: NH3 in chloroform: dichloromethane in the
ratio of 0.5:10:89.5 as an eluent to yield the title compound (0.79g, 87%).
MS: m/z 568(M+1)
1HNMR (CDCI3+D2O, 200MHz):5 1.41(s, 9H), 1.58-2.18 (m, 11H), 2.2-2.46 (m, 2H), 3.5-3.7
(m, 1H), 3.70 (s, 3H), 3.91-4.10 (m, 1H), 4.26-4.4 (m, 1H), 4.45-4.58 (m, 1H), 4.8-4.94 (m,
1H), 5.1-5.3(m, 1H), 7.5-7.72 (m, 4H)
Step 2: Methyl-(2S)-1 -{(2S)-2- amino-2-[8-(4-trifluromethyl-benzoyl)-8-aza-bicyclo[3.2.1 ]-oct-
3-yl]-exo-ethanoyl}-pyrrolidin-2-carboxylatetrifluroacetic acid

To a stirred solution of methyl-(2S)-1-{(2S)-2-(tert-butoxycarbonyl)-amino-2- [8-(4-
trifluromethyl-benzoyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-ethanoyl}-pyrrolidin-2-carboxylate
(0.13 g, 0.23 mmol) in dry dichloromethane (2.0 ml) was added a solution of trifluoro acetic
acid (1.3 ml, 1.99 g, 17.5 mmol) in dry dichloromethane (1 ml) drop wise at 0°C. The
reaction mixture was stirred at 0OoC for 5 minutes. The reaction mixture was allowed to
come at room temperature and stirred for 40 minutes. The solvent was evaporated under
reduced pressure and dried under high vacuum. The crude sticky product so obtained was
stirred with 20% dichloromethane in diethyl ether (10 ml) for 15 minutes and filtered through
a Buchner funnel. Solid so obtained was dried under high vacuum to yield the title
compound (0.095g, 71%).
mp: 173-175°C
MS: m/z 468(M+1)
1HNMR (D2O, 400MHz):5 1.58-1.9(m, 6H), 1.92-2.1(m, 5H), 2.14-2.24 (m, 1H), 2.5-2.62 (m,
1H), 3.58-3.77 (m,6H), 4.05-4.11 (m, 1H), 4.25 (d, J=6.4Hz, 1H) 4.47-4.52 (m, 1H), 7.57-
7.63 (m, 2H) 7.76-7.82 (m, 2H)
[a]D20 - 18.32 (c 0.50, water)
Example 4
(2S)-1-{(2S)-2-amino-2-[8-(4-trifluoromethyl-benzoyl)-8-aza-bicyclo[3.2.1]-oct-3-yl]-exo-
ethanoyl}-pyrrolidin-2- carboxylic acid trifluoroacetic acid salt (Compound No.11)

Step 1: (2S)-1-{(2S)-2-(tert-butoxycarbonyl)-amino-2- [8-(4-trifluromethyl-benzoyl)-8-aza-
bicyclo [3.2.1] -oct-3-yl]-exo-ethanoyl}-pyrrolidin-2-carboxylic acid

To a stirred solution of methyl (2S)-1-{(2S)-2-(tert-butoxycarbonyl)-amino-2- [8-(4-
trifluromethyl-benzoyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-ethanoyl}-pyrrolidin-2-carboxylate
(step 1 of Example 3, 0.22 g, 0.388 mmol) in methanol (20 ml) was added a solution of
sodium carbonate (0.205 g, 1.94 mmol) in water (10 ml) slowly at 0°C. The reaction mixture
was allowed to come at room temperature and stirred for 16 hours. The solvent was
removed under reduced pressure and the residue was diluted with water (10 ml). It was then
cooled to 0°C and pH was adjusted to 6.5 with 2N HCI. The aqueous layer was then
extracted with dichloromethane (2x25 ml). The combined organic layers were dried over
anhydrous sodium sulphate and the solvent was evaporated to yield a crude product. The
crude was dissolved in diethyl ether (5 ml) and hexane was added till precipitation occurred.
Solid was filtered through a Buchner funnel and dried under high vacuum to yield the title
compound (0.121 g, 57%).
mp: 155-157°C
MS: m/z 552 (M-1)
1HNMR (CDCI3, 400MHz): d 1.34-1.45 (m, 9H), 1.50-2.42 (m, 13H), 3.52-3.9 (m, 2H), 3.95-.
4.06 (m, 1H), 4.30-4.60 (m, 3H), 4.80-4.90 (m, 1H), 5.40-5.47 (m, 0.5H), 5.87-5.95 (m,
0.5H), 7.56-7.7 (m, 4H).
Step: 2 (2S)-1-{(2S)-2- amino-2-[8-(4-trifluoromethyl-benzoyl)-8-aza-bicyclo[3.2.1]-oct-3-yl]-
exo-ethanoyl}-pyrrolidin-2- carboxylic acid trifluoroacetic acid salt

The title compound (0.095 g, 89%) was obtained from (2S)-1-{(2S)-2-(tert-butoxy carbonyl)-
amino-2- [8-(4-thfluromethyl-benzoyl)-8-aza-bicyclo [3.2.1] -oct-3-yl]-exo-ethanoyl}-
pyrrolidin-2-carboxylic acid (0.105 g, 0.18 mmol), trifluoro acetic acid ( 1.0 ml., 1.53 g, 13.54
mmol) in dichloromethane by a similar procedure described in step 2 of Example 3
mp: 161-163°C
MS: m/z 454(M+1)
1HNMR (D2O, 400MHz):8 1.55-2.1(m, 11H), 2.24-2.38(m, 1H), 2.5-2.64(m, 1H), 3.55-
3.67(m, 1H), 3.8-3.87(m, 1H), 4.02-4.1(m, 1H), 4.25(t, J=6.8Hz, 1H), 4.41-4.47(m, 1H), 4.72-
4.8(m, 1H), 7.55-7.62(m, 2H), 7.75-7.81(m, 2H).
[a]D20 - 17.92 (c 0.50, water)
Example 5
(2S, 4S)-1-{(2S)-2-Amino-2-[8-(4-trifluoromethyl-benzoyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-4-flouro-pyrrolidine -2 -carbonitrile hydrochloride salt (Compound No. 15)

Step 1: (2S, 4S)-1-{(2S)-2-(tert-butoxycarbonyl)-amino-2-[8-(4-trifluoromethyl-benzoyl)-8-
aza-bicyclo [3.2.1]-oct-3-yl]-exo-ethanoyl}-4-flouro-pyrrolidine -2 -carboxylic acid amide

To a stirred solution of (2S)-2-(tert-butoxycarbonyl)-amino-2-[8-(4-trifluoromethyl-benzoyl)-8-
aza-bicyclo [3.2.1]-oct-3-yl]-exo-ethanoic acid (prepared by following the similar procedure
as described in Intermediate 2, 0.4 g, 0.877 mmol) in dry DMF (8.0 ml) was added 1-
hydoxybenzotriazole (HOBT.0.403 g, 2.63 mmol) and (2S, 4S)-4-fluoro-pyrrolidine-2-
carboxamide (which can be prepared by using method as provided in WO 03/002553, 0.116
g, 0.877 mmol) at room temperature. The reaction mixture was cooled to 0°C. To this was
added triethylamine (0.266g, 0.375 ml, 2.63mmol) and 1- (3-dimethyl amino propyl-3-ethyl
carbodimide hydrochloride (0.336 g, 1.75 mmol) under stirring. Ice Bath was removed after
two hours and the reaction mixture was stirred at room temperature for 24 hours. The
solvent was removed under reduced pressure and diluted with ethyl acetate (25.0 ml). The
organic layer was washed with a saturated aqueous sodium bicarbonate solution (10 ml)
and dried over anhydrous sodium sulphate. The solvent was removed to obtain a crude
product, which was purified by column chromatography over silica gel (100-200 mesh) using
methanol: NH3 in chloroform: dichloromethane in the ratio of 3: 10: 87 as an eluent to get the
title compound (0.27g, 54%).
mp: 153-155°C
MS: m/z 571(M+1)
1HNMR (CDCI3+D20,400 MHz):S 1.35-1.52 (m, 10H), 1.53-1.83 (m, 5H), 1.9-2.1 (m, 2H),
2.13-2.42 (m, 2H), 2.73-2.87 (m, 1H), 3.81 -4.16 (m, 2H), 4.2-4.29 (m, 1H), 4.73 (d, J =
9.6Hz, 1H), 4.77-4.93 (m, 2H), 5.23-5.27 (m, 0.5H), 5.36-5.42 (m, 0.5H), 7.51-7.62 (m, 2H),
7.63-7.7 (m, 2H).
Step 2: (2S, 4S)-1- {(2S)-2-(tert-butoxycarbonyl)-amino-2-[8-(4-trifluoromethyl-benzoyl)-8-
aza-bicyclo [3.2.1] oct-3-yl]-exo-ethanoyl}-4-flouro-pyrrolidine -2 -carbonitrile

To a stirred solution of (2S, 4S)-1- {(2S)-2-(tert-butoxycarbonyl)-amino-2-[8-(4-tri
fluoromethyl-benzoyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-ethanoyl}-4-flouro-pyrrolidine -2-
carboxylic acid amide (0.26 g, 0.456 mmol) and imidazole (0.065 g, 0.954 mmol) in dry
pyridine (6.0 ml) was added phosphorous oxy chloride (0.279 g, 0.17 ml, 1.81 mmol) drop
wise at -30°C under nitrogen atmosphere. The reaction mixture was stirred at -30°C for
two hours. The completion of reaction was monitored by TLC. The reaction mixture was
quenched with water (2.0 ml) at -30°C. Then reaction mixture was allowed to come at room
temperature The solvent was removed under reduced pressure and water (10 ml) was
added to the residue. The aqueous layer was extracted with dichloromethane (4x10ml) and
the combined organic layer was dried over anhydrous sodium sulphate. The solvent was
evaporated to obtain the crude product, which was purified by column chromatography over
silica gel (100-200 mesh) using 1.2 % methanol in dichloromethane as an eluent to yield the
title compound (0.17g, 68%).
mp: 155-157oC
MS: m/z 553(M+1)
1HNMR (CDCI3+D2O,400 MHz): 6 1.34-1.5 (m, 10H), 1.54-1.62 (m, 1H), 1.63-1.85 (m, 4H),
1.9-2.1 (m, 2H), 2.23-2.43 (m, 2H), 2.6-2.73 (m, 1H), 3.92-4.19 (m, 4H), 4.85-4.92 (m, 1H),
4.96-5.02 (m, 1H), 5.33-5.37 (m, 0.5H), 5.47-5.52 (m, 0.5H), 7.58-7.62 (m, 2H). 7.65-7.72
(m, 2H).
Step 3: (2S, 4S)-1- {(2S)-2- Amino - 2-[8-(4-trifluoromethyl-benzoyl)-8-aza-bicyclo [3.2.1]-
oct-3-yl]-exo-ethanoyl}-4-flouro-pyrrolidine -2 - carbonitrile hydrochloride

To a stirred solution of (2S, 4S)-1- {(2S)-2-(tert-butoxycarbonyl)-amino-2-[8-(4-tri
fluoromethyl-benzoyl)-8-aza-bicyclo [3.2.1 ]-oct-3-yl]-exo-ethanoyl}-4-flouro-pyrrolidine -2-
carbonitrile (0.16 g, 0.289 mmol) in dry dichloromethane (1.5 ml) at 0°C was added a
solution of trifluroacetic acid (3.0 ml, 4.61 g, 40.4 mmol) in dry dichloromethane (1.5 ml) drop
wise. First, the reaction mixture was stirred at 0°C for 5 minutes and then stirred at room
temperature for 25 minutes. The solvent was evaporated completely under reduced
pressure at room temperature and dried under high vacuum. To this residue was added
dichloromethane (15 ml), cooled to 0°Cand neutralized with NH3 in chloroform. The solvent
was evaporated and the crude was stirred with dichloromethane (30.0ml) and then filtered
through a Buchner funnel. The filtrate was concentrated at reduced pressure and the
residue so obtained was taken in dry chloromethane (5.0ml). To this mixture was added HCI
in ether (0.8 ml, 0.85 N) under stirring at room temperature. Stirring was continued at room
temperature for 45 minutes. The reaction mixture was diluted with diethyl ether (5ml) and
solvent was evaporated to yield the compound quantitatively (0.125 g)
mp: 168-170°C
MS: m/z 453(M+1)
1HNMR (CDCI3 +CD3OD, 200MHz): 5 1.15-1.35 (m, 2H), 1.45-2.1 (m, 8H), 2.3-2.7 (m, 3H),
3.25-3.35 (m, 1H), 3.8-4.1(m, 3H), 4.7-4.85 (m, 1H), 5.0-5.10 (m, 1H), 5.2-5.3 (m, 0.5H),
5.45-5.55 (m, 0.5H), 7.5-7.7 (m, 4H).
The following compounds were prepared by procedure similar to those described for
Compound No. 15 with appropriate variations of reactants, reaction conditions and quantities
of reagents
(2S,4S)-1-{ (2S)-2- Amino-2-[8-(2,4,5-trifluorobenzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-
ethanoyl}-4-fluoro-pyrrolidin-2- carbonitrile trifluoroacetic acid salt ( Compound No. 16)
mp: 163-165°C
MS: m/z 439 (M+1)
1HNMR (CDCI3+D2O, 400 MHz): 8 1.1-2.1 (m, 8H), 2.2-2.8 (m, 3H), 3.5-4.2 (m, 4H), 4.7-
5.1(m, 2H), 5.3-5.55 (m, 1H), 6.9-7.35 (m, 2H)
Yield: 92%
(2S, 4S)-1- { (2S)-2- Amino-2-[8-(2,5-difluorobenzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-
ethanoyl}-4-fluoro-pyrrolidin-2- carbonitrile trifluoroacetic acid salt ( Compound No. 17)
mp: 198-200°C
MS: m/z 421 (M+1)
1HNMR (D2O, 400 MHz): d 1.52-1.63 (m, 2H), 1.68-1.96 (m, 4H), 2.0-2.13 (m, 2H), 2.43-2.8
(m, 3H), 3.76-3.95 (m, 1H), 4.02-4.16 (m, 2H), 4.2 (t, J= 6Hz, 1H), 4.75-4.8 (m, 1H), 5.06-
5.12 (m, 1H), 5.45-5.5 (m, 0.5H), 5.56-5.62 (m, 0.5H), 7.15-7.22 (m, 1H), 7.24 (t, J= 6.4Hz,
2H)
Yield: 80%
(2S,4S)-1- { (2S)-2- Amino-2-[8-(2,4,5-trifluorobenzyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-
ethanoyl}-4-fluoro-pyrrolidin-2- carbonitrile trifluoroacetic acid salt ( Compound No. 19)
mp: 130-132°C
MS: m/z 425 (M+1)
1HNMR (DMSO+D2O, 200 MHz): d 1.4-1.6 (m, 1H), 1.65-2.05 (m, 6H), 2.1-2.5 (m, 4H), 3.75-
4.35 (m, 7H), 5.0-5.12 (m, 1H), 5.35-5.45 (m, 0.5H), 5.6-5.7 (m, 0.5H), 7.55-7.85 (m, 2H) .
Yield: 79%
Example 6
(4S)-3- {(2S)-2- Amino- 2-[8-(4-trifluoromethyl-benzoyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-thiazolidin-4- carbonitrile trifluoroacetetic acid salt (Compound No.20)

Step 1: (4S)-3- {(2S)-2-(tert-butoxycarbonyl)-amino-2-[8-(4-trifluoromethyl-benzoyl)-8-aza-
bicyclo [3.2.1]-oct-3-yl]-exo-ethanoyl}-thizolidin-4-carboxylic acid amide

To a stirred solution of (2S)-2-(tert-butoxycarbonyl) amino-2-[8-(4-trifluoromethyl-benzoyl)-8-
aza-bicyclo [3.2.1]-oct-3-yl]-exo-ethanoic acid (prepared by following the similar procedureas
described in Intermediate 2, 0.47 g, 1.03 mmol) in dry DMF (8.0 ml) was added 1-
hydroxybenzotriazole (0.473 g, 3.08 mmol) and (4S)-1,3-thizolidine-4- carboxamide
(prepared by using method as provided in J. Am. Chem. Soc59, 200-206 (1937) and US
2005/0192324, 0.14 g, 1.06 mmol) at room temperature. The reaction mixture was cooled to
0°C and added tri ethyl amine (0.45 ml, 0.31 g, 3.08 mmol) and 1- (3-dimethyl amino propyl-
3-ethyl carbodimide hydrochloride (0.395 g, 2.06 mmol) under stirring. After 2 hours, ice
bath was removed and the reaction mixture was stirred at room temperature for 24 hours.
The solvent was removed under reduced pressure and the residue was diluted with ethyl
acetate (25 ml). The organic layer was washed with a saturated aqueous sodium
bicarbonate solution (20 ml) and dried over anhydrous Na2SO4 The solvent was removed
under reduced pressure to yield a crude product, which was purified by column
chromatography over silica gel (100-200 mesh) using methanol: NH3 in chloroform:
dichloromethane in the ratio of 3:10:87 as an eluent to yield the title compound (0.18 g,
31%).
MS:m/z 571(M+1)
1HNMR (CDCI3+D2O, 400 MHz):8 1.36-1.5 (m, 9H), 1.53-1.8 (m, 6H), 1.9-2.1 (m, 2H), 2.25-
2.40 (m, 1H), 3.08-3.48 (m, 2H), 3.95-4.1 (m, 1H), 4.34-4.45 (m, 1H), 4.5-4.7 (m, 1H), 4.71-
5.0 (m, 3H), 7.51-7.62 (m, 2H), 7.65-7.72 (m, 2H).
Step 2: (4S)-3- {(2S)-2-(tert-butoxycarbonyl)-amino-2-[8-(4-trifluoromethyl-benzoyl)-8-aza-
bicyclo [3.2.1 ]-oct-3-yl]-exo-ethanoyl}-thiazolidine-4-carbonitrile

To a stirred solution of (4S)-3-{(2S)-2-(tert-butoxycarbonyl)-amino-2-[8-(4-tri fluoromethyl-
benzoyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-ethanoyl}-thiazolidine -4-carboxylic acid amide
(0.17 g, 0.298 mmol) and imidazole (0.043 g, 0.63 mmol) in dry pyridine (4.0 ml) at -30°C
was added phosphorous oxy chloride (0.183 g, 0.11 ml, 1.19 mmol) drop wise under
nitrogen atmosphere. The reaction mixture was stirred at -30°C for two hours. The
completion of reaction was monitored by TLC. The reaction mixture was quenched with
water (3.0 ml) at -30°C. Then reaction mixture was allowed to come at room temperature
The solvent was removed under reduced pressure and water (10 ml) was added to the
residue. The aqueous layer was extracted with dichloromethane (4x10ml) and the combined
organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated at
reduced pressure to get a crude product, which was purified by column chromatography
over silica gel (100-200 mesh) using 1.2% methanol in dichloromethane as an eluent to yield
the title compound (0.09 g, 55%).
MS: m/z 553(M+1)
Step 3: (4S)-3- {(2S)-2-Amino-2-[8-(4-trifluoromethyl-benzoyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-
exo-ethanoyl}-thiazolidin-4- carbonitrile trifluoroacetetic acid salt

To a stirred solution of (4S)-3- {(2S)-2-(tert butoxycarbonyl)- amino-2-[8-(4-trifluoromethyl-
benzoyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-ethanoyl}-thiazolidine-4- carbonitrile (0.08 g,
0.144 mmol) in dry dichloromethane (1.0 ml) at 0°C was added a solution of trifluoroacetic
acid (1.5 ml, 2.3 g, 20.2 mmol) in dry dichloromethane (5 ml) drop wise. The reaction
mixture was stirred at 0oC for 5 minutes then brought to room temperature and stirred for
further 25 minutes. The solvent was evaporated under reduced pressure at room
temperature and dried under high vacuum. In order to solidify the product, petroleum ether
(10ml) was added and evaporated to get a solid, which was dried under high vacuum to
yield the title compound (0.08 g, 98%).
mp: 159-161 °C
MS: m/z 453(M+1)
1HNMR (CDCI3+D2O, 400 MHz):d 1.4-2.2 (m, 7H), 2.3-2.7 (m, 2H), 3.15-3.4 (m, 2H), 3.9-
4.13 (m, 2H), 4.25-4.95 (m, 3H), 5.25-5.4 (m, 1H), 7.52-7.72 (m, 4H).
Example 7
3-{(2S)-2- Amino - 2-[8-(4-trifluoromethyl-benzoyl)-8-aza-bicyclo [3.2.1J-oct-3-ylJ-exo-
ethanoyl}-1,3-thiazolidin trifluoroacetic acid salt (Compound No.21)

Stepl: 3 {(2S)-2-(tert-butoxycarbonyl) amino - 2-[8-(4-trifluoromethyl-benzoyl)-8-aza-bicyclo
[3.2.1] oct-3-yl]-exo-ethanoyl}-1,3-thiazolidine

To a stirred solution of {(2S)-2-(tert-butoxycarbonyl)-amino-2-[8-(4-trifluoromethyl-benzoyl)-
8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-ethanoic acid (prepared by following the similar procedure
as described in Intermediate 2, 150 mg, 0.328 mmol) in dry DMF (3.0 ml) was added 1-
hydroxybenzotriazole (151 mg, 0.986 mmol) and 1,3-thizolidine (29 mg, 0.325 mmol) at
room temperature. The reaction mixture was cooled to 0°C and added triethyl amine (99 mg,
0.978 mmol) and 1- (3-dimethyl amino propyl-3-ethyl carbodiimide hydrochloride (126 mg,
0.83 mmol) under stirring. After 2 hours, ice bath was removed and the reaction mixture was
stirred at room temperature for further 20 hours. The solvent was removed under reduced
pressure and the residue so obtained was diluted with ethyl acetate (30 ml). The organic
layer was washed with a saturated aqueous sodium bicarbonate solution (10 ml) and dried
over anhydrous Na2SO4 The solvent was removed under reduced pressure to yield a crude
product, which was purified by column chromatography over silica gel (100-200 mesh) using
1.2% methanol in dichloromethane as an eluent to yield the title compound (90 mg, 52%)
MS: m/z 528(M+1)
1HNMR (CDCI3+D2O,400 MHz):5 1.35-1.5 3(m, 10H), 1.55-1.81 (m, 5H), 1.9-2.1 (m, 2H),
2.21-2.35 (m, 1H), 2.96-3.03(m, 1H), 3.05-3.13(m, 1H), 3.62-3.92 (m, 2H), 3.94-4.12 (m,
2H), 4.23-4.4(m, 1H), 4.44-4.57(m, 1H), 4.8-4.9(m, 1H), 7.51-7.61 (m, 2H), 7.63-7.7(m, 2H).
Step : 2 3-{(2S)-2-Amino-2-[8-(4-trifluoromethyl-benzoyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-
ethanoyl}-1,3-thiazolidine trifluoro acetic acid salt

To a stirred solution of 3-{(2S)-2-(tert-butoxycarbonyl)-amino-2-[8-(4-trifluoromethyl-
benzoyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-ethanoyl}-1,3-thiazolidine (80 mg, 0.151 mmol)
in dry dichloromethane (0.75 ml) at 0°C was added a solution of trifluoroacetic acid (1.5 ml,
2.3 g 20.19 mmol) in dry dichloromethane (0.75 ml) and stirred at 0°C for 5 minutes. The
reaction mixture was then stirred at room temperature for 25 minutes. The solvent was
evaporated under reduced pressure and dried under high vacuum. In order to remove traces
of trifluroacetic acid left and to solidify the product, petroleum ether (10ml) was added and
evaporated to obtain the title compound (80 mg, 98%).
mp: 123-125 °C
MS: m/z 428(M+1)
1HNMR (CDCI3+D2O, 400 MHz): 8 1.16-1.33 (m, 1H), 1.5-2.1 (m, 7H), 2.3-2.6 (m, 1H), 2.93-
3.16 (m, 2H), 3.52-3.9 (m, 2H), 3.92-4.1(m, 1H), 4.13-4.28 (m, 1H), 4.36-4.73 (m, 2H), 4.75-
4.95 (m, 1H), 7.52-7.72 (m,4H).
Example 8
(1S, 3S, 5S)- 2- {(2S)-2-amino-2-[8-(2-fluoropyridine-4-carbonyl)-8-aza-bicyclo [3.2.1]-oct-3-
yl]-exo-ethanoyl}-2-azabicyclo [3.1.0]- hexane- 3-carbonitrile trifluoro acetic acid salt
(Compound No. 28)

Step 1 : (1S, 3S, 5S)- 2- {(2S)-2-(tert-butoxycarbonyl)-amino - 2-[8-(2- fluoropyridine-4-
carbonyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-ethanoyl}-2-azabicyclo [3.1.0]- hexane- 3-
carboxamide

To a stirred solution of (2S)-2-(tert-butoxycarbonyl)-amino-2-[8-(2-fluoropyridine-4-carbonyl).-
8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-ethanoic acid (Intermediate 2, 7.6 g, 18.67 mmol) in DMF
(120 ml) was added 1-hydroxybenzotriazole (7.57 g, 56.02 mmol) and TFA salt of (1S, 3S,
5S) 2-azabicyclo[3.1.0]- hexane- 3-carboxamide (which can be prepared by using method
as provided in WO 2004/052850, 4.48 g, 18.67 mmol) at room temperature This reaction
mixture was cooled to 0°C and added triethyl amine (5.66 g, 7.8 ml, 56.02 mmol) and 1- (3-
dimethyl amino propyl)-3-ethyl carbodiimide hydrochloride (7.16 g, 37.35 mmol) The
reaction mixture was then brought to room temperature in 15 minutes and stirred at room
temperature for 24 hours . The solvent was removed under reduced pressure, diluted with
ethyl acetate (100 ml) washed with a saturated sodium bicarbonate solution (2x20 ml), water
(20 ml) and brine (1x20 ml). The organic layer was dried over anhydrous Na2SO4 and the
solvent was evaporated to get a crude product, which was purified by column
chromatography over silica gel (200-400 mesh) using methanol: NH3 in chloroform:
dichloromethane in the ratio of 3:10:87 as an eluent to yield the title compound (3.61 g,
37%).
mp: 151-153 °C
MS: m/z 516(M+1)
1HNMR (CDCI3+D2O, 200 MHz):8 0.80-0.98 (m, 1H), 1.02-1.18 (m, 1H), 1.3-2.1(m, 16H),
2.27-2.7 (m, 3H), 3.5-3.7 (m, 1H), 3.9-4.04 (m, 1H), 4.5-4.68 (m, 1H) 4.73-4.9 (m, 2H), 5.20-
5.45 (m, 2H), 6.97 (d, J =10.1 Hz, 1H), 7.15-7.3 (m, 1H), 8.22-8.32 (m, 1H).
Step 2 : (1S, 3S, 5S)- 2- {(2S)-2-(tert-butoxycarbonyl)-amino - 2-[8-(2- fluoropyridine-4-
carbonyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-ethanoyl}-2-azabicyclo [3.1.0]-hexane- 3-
carbonitrile

To a stirred solution of (1S, 3S, 5S)- 2- {(2S)-2-(tert-butoxycarbonyl)-amino-2-[8-(2-
fluoropyridine-4-carbonyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-ethanoyl}-2-azabicyclo [3.1.0]-
hexane- 3-carboxamide (3.6 g, 6.99 mmol) and imidazole (0.99 g, 14.68 mmol) in dry
pyridine (80 ml) was added phosphorous oxy chloride (4.39 g, 2.67ml, 28.66 mmol) drop
wise at -30°C under N2 atmosphere. The reaction mixture was stirred at -30°C for one hour
and quenched with water (5 ml) at -30°C. It was allowed to come at room temperature and
the solvent was removed under reduced pressure at same temperature The crude product
so obtained was dried under high vacuum and added dichloromethane (50 ml), washed with
water (10 ml) dried over anhyd. Na2SO4 The solvent was evaporated to obtain a crude
product, which was purified by column chromatography over silica gel (100-200 mesh) using
1.2% methanol in dichloromethane as an eluent to yield the title compound (2.9 g, 83%).
mp: 137-139 °C
MS: m/z 498(M+1)
1HNMR (CDCI3+D2O, 400 MHz): d 0.98-1.16 (m, 2H), 1.35-1.85 (m, 13H), 1.9-2.1 (m, 3H),
2.36-2.65 (m, 3H), 3.76-3.86 (m, 1H), 3.95-4.04 (m, 1H), 4.48-4.56 (m, 1H), 4.7-4.76 (m,
1H), 4.84-4.9 (m, 1H), 4.99 (d, J = 9.6 Hz, 1H), 5.2-5.3 (m, 1H), 6.94-7.03 (m,1H), 7.18-7.28
(m, 1H), 8.27-8.32 (m, 1H).
Step 3: (1S, 3S, 5S)- 2- {(2S)-2-Amino - 2-[8-(2- fluoropyridine-4-carbonyl)-8-aza-bicyclo
[3.2.1]-oct-3-yl]-exo-ethanoyl}-2-azabicyclo [3.1.0]- hexane- 3-carbonitrile trifluoro acetic acid
salt

To a stirred solution of (1S, 3S, 5S)- 2- {(2S)-2-(tert-butoxycarbonyl) amino-2-[8-(2-
fluoropyridine-4-carbonyl)-8-aza-bicyclo [3.2.1 ]-oct-3-yl]-exo-ethanoyl}-2-azabicyclo [3.1.0]-
hexane- 3-carbonitrile (3.0 g, 6.04 mmol) in dichloromethane (18 ml) was added a solution
of trifluoro acetic acid (24.0 ml, 36.84 g, 323.15 mmol) in dichloromethane (18 ml) drop wise
at 0°C. The reaction mixture was stirred at 0°C for 5 minutes, brought to room temperature
and stirred at room temperature for 20 min. The solvent was evaporated under reduced
pressure at 30°C and added dichloromethane (20 ml) The solvent was again evaporated
and dried under high vacuum. In order to solidify the product, petroleum ether (20 ml) was
added and evaporated. This process was repeated twice. In order to remove traces of
trifluoroacetic acid, the reaction mixture was stirred at room temperature with 10%
dichloromethane in ether (2x25ml) and filtered to yield the title compound (2.6 g, 84%).
mp: 176-178 °C
MS: m/z 398 (M+1)
1HNMR (D2O, 400 MHz): d 0.92-0.98 (m, 1H), 1.18-1.28 (m, 1H), 1.6-1.97 (m, 6H), 2.04-2.2
(m, 3H), 2.44 (d, J = 14.0 Hz, 1H)„ 2.67-2.76 (m, 1H), 2.8-2.97 (m, 1H), 3.76-3.83 (m, 1H),
4.1-4.2 ( m, 1H), 4.55-4.62 (m, 1H), 4.77-4.85 (m, 1H), 5.21(d, J = 10.8 Hz, 1H)„ 7.22 (s,
1H), 7.40-7.43 (m, 1H), 8.34 (d, J = 5.2 Hz, 1H),
[a]D20 - 14.37 (c 1.04, methanol)
Chiral Purity : 99.20%
The following compounds were prepared by procedure similar to those described for
Compound No. 28 with appropriate variations of reactants, reaction conditions and quantities
of reagents
(1S,3S,5S)-2-{(2R)-2-Amino-2-[8-(2-fluoropyridine-4-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-
exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (
Compound No. 31)
The intermediate (2R)-2-(tert-butoxycarbonyl) amino-2-[8-(2-fluoropyridine-4-carbonyl)-8-
aza-bicyclo [3.2.1]-oct-3-yl]-exo- ethanoic-acid for the above title compound was prepared
by using (S)-(+)-2- phenyl glycinol in place of (R)-(-)-2- phenyl glycinol as used in step 1 of
Intermediate 1
mp: 196-199 °C
MS: m/z398(M+1)
1HNMR (D2O, 400MHz): d 0.94-1.08 (m, 2H), 1.55-1.88 (m, 6H), 1.92-2.10 (m, 3H), 2.35-
2.42 (m, 1H), 2.51-2.70 (m, 2H), 3.62-3.71 (m, 1H), 4.03-4.11(m, 1H), 4.46 (d, J=6.8Hz, 1H),
4.75-4.81(m, 1H), 5.0-5.08 (m, 1H), 7.13-7.17 (m, 1H), 7.33-7.37 (m, 1H), 8.27 (dd, J =2.8,
5.2 Hz, 1H)
[a]D20 - 41.64 (c 1.0, methanol)
Yield: 58%
(1R,3R,5R)-2-{(2S)-2-Amino-2-[8-(2-fluoropyridine-4-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-
yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (
Compound No. 29)
The above title compound was prepared by using Intermediate 14
mp: 215-218 °C
MS: m/z 398(M+1)
1HNMR (D2O, 400 MHz):5 0.94-1.08 (m, 2H), 1.55-1.88 (m, 6H), 1.92-2.10 (m, 3H), 2.35-
2.42 (m, 1H), 2.51-2.70 (m, 2H), 3.62-3.71 (m, 1H), 4.03-4.11(m, 1H), 4.46 (d, J = 6.8Hz,
1H), 4.75-4.81(m, 1H), 5.0-5.08 (m, 1H), 7.13-7.17 (m, 1H), 7.33-7.37 (m, 1H), 8.27 (dd, J =
2.8, 5.2 Hz, 1H)
[a]D20 +41.97 (c 1.0, methanol)
Yield: 82%
(1R, 3R, 5R)-2-{(2R)-2-Amino-2-[8-(2-fluoropyridine-4-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-
yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (
Compound No. 30)
The above title compound was prepared by using the intermediate (2R)-2-(tert-
butoxycarbonyl) amino-2-[8-(2-fluoropyridine-4-carbonyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-
ethanoic-acid ( prepared by using (S)-(+)-2- phenyl glycinol in place of (R)-(-)-2- phenyl
glycinol as used in step 1 of Intermediate 1) and intermediate 14
mp: 185-188 °C
MS: m/z 398(M+1)
1HNMR (D2O, 400 MHz): 5 0.89-0.95 (m, 1H), 1.13-1.23 (m, 1H), 1.55-1.92 (m, 6H), 2.01-
2.15 (m, 3H), 2.38-2.43 (m, 1H), 2.64-2.73 (m, 1H), 2.75-2.93 (m, 1H), 3.75-3.8 (m, 1H),
4.09-4.16 (m, 1H), 4.52-4.6 (m, 1H), 4.75-4.83 (m, 1H), 5.18 (d, J = 10.8Hz, 1H), 7.19 (s,
1H), 7.36-7.41 (m, 1H), 8.31 (d, J= 5.2Hz, 1H)
[a]D20+14.71 (c 1.0, methanol)
Chiral Purity : 99.69 %
Yield: 73%
(1S,3S,5S)-2-{(2S)-2-Amino-2-[8-(2,4,5-trifluorobenzoyl)-8-aza-bicyclo [3.2.1]oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt ( Compound
No. 23)
mp: 195-197 °C
MS: m/z 433(M+1)
'HNMR (D2O, 400 MHz): d 0.87-0.94 (m, 1H), 1.12-1.22 (m, 1H), 1.57-1.70 (m, 2H), 1.71-1.9
(m, 4H), 2.0-2.15 (m, 3H), 2.36-2.43 (m, 1H), 2.63-2.72 (m, 1H), 2.73-2.90 (m, 1H), 3.73-3.8
(m, 1H), 4.06-4.13 (m, 1H), 4.53 (dd, J = 5.6,13.6Hz, 1H), 4.74-4.82 (m, 1H), 5.16 (dd, J =
2.0,10.8 Hz, 1H),7.22-7.3 (m, 1H), 7.35-7.43 (m, 1H)
Yield: 71%
(1 S,3S,5S)-2-{(2S)-2-Amino-2-[8-(4-cyanobenzoyl)-8-aza-bicyclo [3.2.1 ]oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt ( Compound
No. 24)
mp: 202-204 °C
MS: m/z 404(M+1)
1HNMR (D2O, 400MHz):5 0.88-0.92 (m, 1H), 1.18-1.21 (m, 1H), 1.52-1.92 (m, 6H), 2.0-2.2
(m, 3H), 2.38-2.43 (m, 1H), 2.62-2.72 (m, 1H), 2.76-2.95 (m, 1H), 3.74-3.80 (m, 1H), 4.08-
4.16 (m, 1H), 4.54 (dd, J= 5.6,12.8Hz, 1H), 4.75-4.82 (m, 1H), 5.16 (dd, J= 1.6, 10.4 Hz,
1 H)„ 7.56-7.63 (m, 2H), 7.86 (d, J = 8Hz, 2H).
Yield: 94%
(1S,3S,5S)-2-{(2S)-2-Amino-2-[8-(pyridine-4-carbonyl)-8-aza-bicyclo [3.2.1]oct-3-yl]-exo
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt ( Compound
No. 25)
mp: 138-140 °C
MS: m/z 380(M+1)
1HNMR (D2O, 200MHz):d 0.8-1.0 (m, 1H), 1.1-1.3 (m, 1H), 1.5-2.25 (m, 9H), 2.33-2.50 (m,
1H), 2.60-3.05 (m, 2H), 3.7-3.85 (m, 1H), 4.0-4.12 (m, 1H), 4.5-4.63 (m, 1H), 4.7-4.85 (m,
1H), 5.1-5.25 (m, 1H), 8.06-8.18 (m, 2H), 8.93 (d, J= 5.7Hz, 2H)
Yield: 80%
(1S,3S,5S)-2-{(2S)-2-Amino-2-[8-(4-trifluoromethylbenzoyl)-8-aza-bicyclo [3.2.1]oct-3-yl]-
exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (
Compound No. 26)
mp: 183-185 °C
MS: m/z 447(M+1)
1HNMR (D2O, 400 MHz): 5 0.88-0.94 (m, 1H), 1.13-1.23 (m, 1H), 1.55-1.92 (m, 6H), 2.01-
2.15 (m, 3H), 2.37-2.45 (m, 1H), 2.64-2.75 (m, 1H), 2.76-2.94 (m, 1H), 3.5-3.81 (m, 1H),
4.08-4.18 (m, 1H), 4.52 (dd, J = 5.2,13.6Hz, 1H), 4.75-4.83 (m, 1H), 5.18 (d, J = 10.8Hz,
1H), 7.63 (d, J = 7.6Hz, 2H), 7.83 (d, J = 8Hz, 2H)
[a]D20 - 16.88 (c 0.50, water)
Yield: 80%
(1S,3S,5S)-2-{(2S)-2-Amino-2-[8-(2,5-difluorobenzoyl)-8-aza-bicyclo [3.2.1]oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt ( Compound
No.27)
mp: 190-192 °C
MS: m/z 415(M+1)
1HNMR (D2O, 400 MHz): 8 0.88-0.97 (m, 1H), 1.13-1.25 (m, 1H), 1.56-1.95 (m, 6H), 2.01-
2.18 (m, 3H), 2.38-2.46 (m, 1H), 2.64-2.74 (m, 1H), 2.76-2.92 (m, 1H), 3.75-3.82 (m, 1H),
4.07-4.15 (m, 1H), 4.52 (dd, J = 5.6,14.8Hz, 1H), 4.75-4.85 (m, 1H), 5.17 (d, J = 10.4Hz,
1H), 7.16-7.23 (m, 1H), 7.26 (t, J = 6Hz, 2H)
Yield: 83%
(lS,3S,5S)-2-{(2S)-2-Amino-2-[8-(2-fluoropyridine-3-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-
exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (
Compound No. 32)
mp: 203-205 °C
MS: m/z 398 (M+1)
1HNMR (D2O, 400 MHz): 5 0.88-0.95 (m, 1H), 1.12-1.24 (m, 1H), 1.58-1.92 (m, 6H), 2.0-2.18
(m, 3H), 2.38-2.45 (m, 1H), 2.63-2.73 (m, 1H), 2.75-2.92 (m, 1H), 3.75-3.82 (m, 1H), 4.05-
4.12 (m, 1H), 4.54 (dd, J=6,11.6Hz, 1H), 4.76-4.85 (m, 1H), 5.17 (dd, J = 2.4, 10.8 Hz, 1H),
7.43-7.49 (m, 1H), 8.0-8.06 (m, 1H), 8.3-8.34 (m, 1H)
[a]D25 - 10.24 (c 0.50, water)
Yield: 73 %
(1 S,3S,5S)-2-{(2S)-2-Amino-2-[8-(pyridine-3-carbonyl)-8-aza-bicyclo [3.2.1 ] oct-3-yl]-exo
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile di trifluoroacetic acid salt ( Compound
No. 33)
mp: 146-148 °C
MS: m/z 380 (M+1)
1HNMR (D2O, 400 MHz):5 0.88-0.98 (m, 1H), 1.12-1.23 (m, 1H), 1.56-1.97 (m, 6H), 2.0-2.2
(m, 3H), 2.40 (dd, J = 2.0, 13.6 Hz, 1H), 2.62-2.73 (m, 1H), 2.8-2.98 (m, 1H), 3.75-3.82 (m,
1H), 4.17-4.23 (m, 1H), 4.55-4.62 (m, 1H), 4.74-4.86 (m, 1H), 5.13-5.22 (m, 1H), 8.1-8.15
(m, 1H), 8.62-8.67 (m, 1H), 8.91 (dd, J = 4.8, 22.0 Hz, 2H)
[a]D26 - 35.41 (c 0.50, water)
Yield: 95 %
(1S,3S,5S)-2-{(2S)-2-Amino-2-[8-(thiophene-2-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt ( Compound
No. 34)
mp: 197-199 °C
MS: m/z 385 (M+1)
1HNMR (D2O, 400 MHz): 5 0.89-0.95 (m, 1H), 1.12-1.23 (m, 1H), 1.68-1.92 (m, 6H), 1.95-
2.15 (m, 3H), 2.35-2.43 (m, 1H), 2.62-2.71 (m, 1H), 2.76-2.95 (m, 1H), 3.72-3.79 (m, 1H),
4.52 (dd, J= 5.2, 19.6Hz, 1H), 4.7-4.82 (m, 2H), 5.14-5.18 (dd, J = 2.4, 10.8 Hz, 1H), 7.13
(t, J = 4.4Hz, 1H), 7.48-7.52 (m, 1 H),7.65 (d, J = 5.2Hz, 1H)
[a]D25-15.90 (c 0.50, water)
Yield: 77 %
(1 S,3S,5S)-2-{(2S)-2-Amino-2-[8-(pyrazine-2-carbonyl)-8-aza-bicyclo [3.2.1 ] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt ( Compound
No. 35)
mp: 202-203 °C
MS: m/z 381(M+1)
1HNMR (D2O, 400 MHz): 8 0.88-0.95 (m, 1H), 1.13-1.22 (m, 1H), 1.53-1.95 (m, 6H), 2.0-2.15
(m, 3H), 2.38(dd, J = 1.6, 13.6 Hz, 1H), 2.6-2.7 (m, 1H), 2.78-2.96 (m, 1H), 3.72-3.79 (m,
1H), 4.32-4.4 (m, 1H), 4.53 (dd, J = 5.6,17.2Hz, 1H), 4.8-4.86 (m, 1H), 5.15 (d, J = 10.8Hz,
1H), 8.67-8.7 (m, 1H), 8.71-8.74 (m, 1H), 8.82-8.84 (m, 1H)
[a]D20 - 22.40 (c 0.50, water)
Chiral Purity : 99.10%
Yield: 95 %
(1S,3S,5S)-2-{(2R)-2-Amino-2-[8-(pyrazine-2-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt ( Compound
No. 36)
The intermediate (2R)-2-(tert-butoxycarbonyl) amino-2-[8-(pyrazine-2-carbonyl)-8-aza-
bicyclo [3.2.1]-oct-3-yl]-exo- ethanoic-acid for the above title compound was prepared by
using (S)-(+)-2- phenyl glycinol in place of (R)-(-)-2- phenyl glycinol as used in step 1 of
Intermediate 1
MS: m/z 381 (M+1)
1HNMR (D2O, 400 MHz):5 0.96-1.1(m, 2H), 1.13-1.22 (m, 1H), 1.92-2.12 (m, 3H), 2.36-
2.45(m, 1H), 2.55-2.73(m, 2H), 3.66-3.75(m, 1H), 4.32-4.37(m, 1H), 4.48(dd, J= 1.6, 7.2Hz,
1H), 5.15 (d, J= 10.8Hz, 1H), 8.67-8.7(m, 1H), 8.72-8.75 (m, 1H), 8.84 (S, 1H).
[a]D20 - 55.60 (c 0.50, Methanol)
Yield: 67 %
(1R,3R,5R)-2-{(2S)-2-Amino-2-[8-(pyrazine-2-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt ( Compound
No. 37)
The above title compound was prepared by using Intermediate 14
MS: m/z 381 (M+1)
1HNMR (D2O, 400 MHz):d 0.96-1.1(m, 2H), 1.65-1.91 (m, 6H), 1.92-2.12 (m, 3H), 2.36-2.45
(m, 1H), 2.55-2.73 (m, 2H), 3.66-3.75 (m, 1H), 4.32-4.37 (m, 1H), 4.48 (dd, J = 1.6, 7.2Hz,
1H), 4.77-4.83 (m, 1H), 5.05-5.08 (m, 1H), 8.67-8.7 (m, 1H), 8.72-8.75 (m, 1H), 8.84 (s, 1H)
mp: 157-159 °C
[a]D20 +53.86 (c 0.50, Methanol)
Yield: 64 %
(1R,3R,5R)-2-{(2R)-2-Amino-2-[8-(pyrazin-2-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (Compound
No. 38)
The above title compound was prepared by using the intermediate (2R)-2-(tert-
butoxycarbonyl) amino-2-[8-(pyrazin-2-carbonyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-
ethanoic-acid ( prepared by using (S)-(+)-2- phenyl glycinol in place of (R)-(-)-2- phenyl
glycinol as used in step 1 of Intermediate 1) and intermediate 14
mp: 112-115 °C
MS:m/z 381(M+1)
1HNMR (D2O, 400 MHz): 5 0.88-0.95 (m, 1H), 1.13-1.22 (m, 1H), 1.53-1.95 (m, 6H), 2.0-2.15
(m, 3H), 2.38(dd, J = 1.6, 13.6 Hz, 1H), 2.6-2.7 (m, 1H), 2.78-2.96 (m, 1H), 3.72-3.79 (m,
1H), 4.32-4.4 (m, 1H), 4.53 (dd, J=5.6,17.2Hz, 1H), 4.8-4.86 (m, 1H), 5.15 (d, J=10.8Hz,
1H), 8.67-8.7 (m, 1H), 8.71-8.74 (m, 1H), 8.82-8.84 (m, 1H)
[a]D20 +22.40 (c 0.50, water)
Chiral Purity: 99.11%
Yield: 62 %
(1S,3S,5S)-2-{(2S)-2-Amino-2-[8-(pyridine-2-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt ( Compound
No.39)
mp: 201-202 °C
MS: m/z 380(M+1)
1HNMR (D2O, 400 MHz): 8 0.88-0.96 (m, 1H), 1.12-1.22 (m, 1H), 1.47-1.95 (m, 6H), 2.0-2.2
(m, 3H), 2.38 (d, J = 14.04 Hz, 1H), , 2.62-2.72 (m, 1H), 2.78-2.98 (m, 1H), 3.72-3.8 (m,
1H), 4.14-4.23 (m, 1H), 4.53 (dd, J = 5.2,18.8Hz, 1H), 4.75-4.85 (m, 1H), 5.15 (d, J =
10.4Hz, 1H), 7.6-7.7 (m,2H), 8.07 (t, J = 7.6Hz, 1H), 8.57-8.63 (m, 1H)
[a]D25 - 14.8 (c 0.56, water)
Yield: 60 %
(1S,3S,5S)-2-{(2S)-2-Amino-2-[8-(furan-2-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt ( Compound
No. 40)
mp: 197-199 °C
MS: m/z 369(M+1)
1HNMR (D2O, 400 MHz): 5 0.9-0.98 (m, 1H), 1.1-1.28 (m, 1H), 1.74-1.93 (m, 6H), 1.98-2.2
(m, 3H), 2.38-2.44 (m, 1H), 2.62-2.72 (m, 1H), 2.8-3.0 (m, 1H), 3.73-3.8 (m, 1H), 4.53 (dd, J
= 5.6, 20.4 Hz, 1H), 4.78-4.83 (m, 1H), 5.04-5.10 (m, 1H), 5.16-5.19 (dd, J = 2.4, 10.8 Hz,
1H), 6.6-6.64 (m, 1H), 7.13(d, J= 3.2Hz, 1H), 7.67-7.70 (m, 1H)
[a]D25-21.07 (c 0.51, water)
Yield: 81 %
(1S,3S,5S)-2-{(2S)-2-Amino-2-[8-(3-fluoropyridine-4-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-
exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (
Compound No. 41)
mp: 202-204 °C
MS: m/z 398(M+1)
1HNMR (D2O, 400 MHz): 8 0.88-0.96 (m, 1H), 1.16-1.25 (m, 1H), 1.6-1.94 (m, 6H), 2.02-2.18
(m, 3H), 2.38-2.45 (m, 1H), 2.65-2.74 (m, 1H), 2.77-2.92 (m, 1H), 3.75-3.83 (m, 1H), 4.02-
4.08 (m, 1H), 4.52-4.58 (m, 1H), 4.83-4.9 (m, 1H), 5.15-5.22 (m, 1H), 7.54-7.6 (m, 1H),
8.51 (d, J = 4.8Hz, 1H), 8.62 (s, 1H)
[a]D20 - 9.75 (c 0.55, water)
Yield: 89 %
(1S,3S,5S)-2-{(2S)-2-Amino-2-[8-(benzo [1,3]-dioxole-5-carbonyl)-8-aza-bicyclo [3.2.1] oct-
3-yl]-exo-ethanoyl}-2-azabicyclo [3.1.0]-hexane -3- carbonitrile trifluoroacetic acid salt (
Compound No. 44)
mp: 197-199 °C
MS: m/z 423 (M+1)
1HNMR (D2O, 400 MHz): 5 0.9-0.97 (m, 1H), 1.18-1.22 (m, 1H), 1.57-1.92 (m, 6H), 2.04-2.16
(m, 3H), 2.4-2.48 (m, 1H), 2.65-2.75 (m, 1H), 2.76-2.95 (m, 1H), 3.76-3.82 (m, 1H), 4.25-
4.35 (m, 1H), 4.52-4.6 (dd, J = 5.6, 16.8 Hz, 1H), 4.72-4.8 (m, 1H), 5.18-5.22 (dd, J = 2.4,
10.8 Hz, 1H), 6.04 (s, 2H), 6.95-7.05 (m, 3H)
[a]D22 - 9.5 (c 0.50, water)
Yield: 59 %
(1S,3S,5S)-2-{(2S)-2-Amino-2-[8-(3,5-difluorobenzene sulfonyl )-8-aza-bicyclo [3.2.1] oct-3-
yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (
Compound No. 42)
mp: 168-170 °C
MS: m/z 451(M+1)
1HNMR (D2O, 400 MHz): 5 0.90-0.95 (m, 1H), 1.14-1.20 (m, 1H), 1.52-1.70 (m, 5H), 1.71-
1.88 (m, 3H), 2.0-2.08 (m, 1H), 2.41 (dd, J = 2.0, 14.0 Hz, 1H), 2.6-2.74 (m, 2H), 3.73-3.78
(m, 1H), 4.35-4.44 (m, 2H), 4.49 (d, J=6Hz, 1H), 5.16 (dd, J= 2.4, 10.84 Hz, 1H), 7.26-7.33
(m, 1H), 7.52-7.58 (m,2H)
[a]D27-16.98 (c 0.51, water)
Yield: 76 %
(1S,3S,5S)-2-{(2S)-2-Amino-2-[8-(adamantane-1-carbonyl )-8-aza-bicyclo [3.2.1] oct-3-yl]-
exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (
Compound No. 43)
mp: 211-213 °C
MS: m/z 437(M+1)
1HNMR (DzO, 400 MHz): 8 0.90-0.96 (m, 1H), 1.14-1.26 (m, 1H), 1.54-2.13 (m, 24H),
2.41 (dd, J = 2.0, 14.0 Hz, 1H), 2.63-2.87 (m, 2H), 3.74-3.81 (m, 1H), 4.43-4.57 (m, 1H),
4.67-4.75 (m, 1H), 4.97-5.07 (m, 1H), 5.17 (dd, J= 2.0, 10.8 Hz, 1H),
[a]D25 - 17.13 (c 0.51, water)
Yield: 63 %
(1S,3S,5S)-2-{(2S)-2-Amino-2-[8-(3,3,3-trifluoro propyl )-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt ( Compound
No. 47)
mp: 199-201 °C
MS: m/z 371(M+1)
1HNMR (D2O, 400 MHz): d 0.91-0.98 (m, 1H), 1.12-1.22 (m, 1H), 1.88-2.13 (m, 7H), 2.3-2.46
(m, 3H), 2.65-2.87 (m, 4H), 3.30-3.38 (m, 2H), 3.76-3.83 (m, 1H), 4.15-4.21 (m, 2H), 4.55(d,
J= 6.8 Hz, 1H), 5.18(d, J = 8.4 Hz, 1H),
[a]D24-12.31 (c 0.38, water)
Yield: 73 %
(1S,3S,5S)-2-{(2S)-2-Amino-2-[8-(cyclohexyl methyl )-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo- [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt ( Compound
No.48)
mp: 188-189°C
MS: m/z 371(M+1)
1HNMR (D2O, 400MHz): 5 0.93-1.09 (m, 3H), 1.13-1.33 (m, 4H), 1.61-2.18 (m, 13H), 2.23-
2.36 (m, 2H), 2.4-2.47 (m, 1H), 2.66-2.77 (m, 2H), 2.88 (d, J=7.2Hz, 2H), 3.78-3.85(m, 1H),
4.1-4.15 (m, 2H), 4.55(d, J=7.6Hz, 1H), 5.19(dd, J = 2.4, 10.8 Hz, 1H)
[a]D20 - 9.28 (c 0.50, water)
Yield: 79%
(1S,3S,5S)-2-{(2S)-2-Amino-2-[8-(benzyloxy-ethyl )-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt ( Compound
No.50)
mp: 185-186 °C
MS:m/z 409(M+1)
1HNMR (D2O, 200 MHz): 5 0.9-1.0 (m, 1H), 1.1-1.35 (m, 1H), 1.73-2.8 (m, 12H), 3.2-3.35
(m, 1H), 3.72-3.9 (m, 3H), 4.0-4.18 (m, 2H), 4.46-4.7 (m, 4H), 5.19 (d, J= 10.1Hz, 1H), 7.35-
7.5 (m, 5H)
[a]D20 - 9.464 (c 0.50, water)
Yield: 95 %
(1S,3S,5S)-2-{(2S)-2-Amino-2-[8-(5-cyanopyridine-2-yl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt ( Compound
No.51)
mp: 199-201 °C
MS: m/z 377(M+1)
'HNMR (D2O, 400 MHz): 5 0.68-0.73 (m, 1H), 1.02-1.09 (m, 1H), 1.6-1.79 (m, 4H), 1.81-2.20
(m, 5H), 2.3-2.37 (m, 1H), 2.55-2.65 (m, 1H), 2.8-2.9 (m, 1H), 3.64-3.7 (m, 1H), 4.41 (d, J =
4.8Hz, 1H), 4.56-4.65 (m, 2H), 5.10 (d, J = 10.8Hz, 1H), 6.81 (d, J = 9.2Hz, 1H), 7.72-7.76
(m, 1H), 8.32 (s, 1H)
[a]D25 - 10.84 (c 0.50, water)
Yield: 63 %
(1S,3S,5S)-2-{(2S)-2-Amino-2-[8-(4-cyano-phenyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoro acetic acid salt ( Compound
No. 52)
mp: 176-178 °C
MS: m/z 376 (M+1)
1HNMR (D2O, 400 MHz): 6 0.62-0.7 (m, 1H), 0.96-1.07 (m, 1H), 1.48-1.6 (m, 2H), 1.66-1.96
(m, 5H), 2.01-2.12 (m, 2H), 2.26-2.35 (m, 1H), 2.54-2.65 (m, 1H), 2.71-2.85 (m, 1H), 3.56-
3.62 (m, 1H), 4.28-4.32 (m, 1H), 4.38-4.45 (m, 2H), 5.07 (d, J=10.4Hz, 1H), 6.95 (d, J =
8.4Hz, 2H), 7.58 (d, J = 8.4Hz, 2H)
[a]D20 - 4.43 (c 0.50, water)
Yield: 82 %
(1 S,3S,5S)-2-{(2S)-2-Amino-2-[8-(pyridin-4yl-methyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt ( Compound
No. 55)
mp: 136-138 °C
MS: m/z 366 (M+1)
1HNMR (DzO, 400 MHz): d 0.86-0.93 (m, 1H), 1.10-1.19 (m, 1H), 1.82-2.20 (m, 7H), 2.35-
2.53 (m, 3H), 2.62-2.78 (m, 2H), 3.72-3.8( m, 1H), 4.14 (s, 2H), 4.47-4.6 (m, 3H), 5.15 (d, J
=10.4Hz, 1H), 8.20 (d, J = 6.4Hz, 2H), 8.88 (d, J = 6.4Hz, 2H)
[a]D28 - 9.43 (c 0.51, water)
Yield: 80 %
(1S,3S,5S)-2-{(2S)-2-Amino-2-[8-(2-pyridin-4-yl-acetyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile di trifluoroacetic acid salt ( Compound
No. 54)
mp: 165-167 °C
MS: m/z 394 (M+1)
1HNMR (D2O, 400 MHz): d 0.91-1.0 (m, 1H), 1.12-1.30 (m, 1H), 1.69-1.87 (m, 6H), 1.95-2.2
(m, 3H), 2.40-2.46 (m, 1H), 2.64-2.75 (m, 1H), 2.79-2.98 (m, 1H), 3.73-3.81 (m, 1H), 4.08
(dd, J= 5.2, 16.4 Hz, 1H), 4.22-4.32 (m, 1H), 4.54-4.60 (m, 2H), 4.65-4.70 (m, 1H), 5.19 (dd,
J = 2.0, 10.8 Hz, 1H), 7.94 (d, J = 6.0 Hz, 2H), 8.71 (d, J = 6.4 Hz, 2H)
[a]D20 - 9.73 (c 0.50, methanol)
Yield: 79 %
(1 S,3S,5S)-2-{(2S)-2-Amino-2-[8-(1 -ethyl-propyl)-8-aza-bicyclo [3.2.1 ] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt ( Compound
No. 59)
mp: 171-173 °C
MS: m/z 345(M+1)
1HNMR (D2O, 400 MHz): d 0.85-0.95 (m, 8H), 1.1-1.2 (m, 1H), 1.63-2.1(m, 10H), 2.15-2.27
(m, 2H), 2.36-2.42 (m, 1H), 2.61-2.76 (m, 2H), 2.9-3.0 (m, 0.5H), 3.43-3.5 (m, 0.5H), 3.74-
3.82 (m, 1H), 4.18-4.22 (m, 1H), 4.26-4.32 (m, 1H), 4.51 (d, J = 7.6Hz, 0.5H), 4.65 (d, J =
6.4Hz, 0.5H), 5.12-5.2 (m, 1H)
[a]D20 - 10.0 (c 0.50, water)
Yield: 62%
(1S,3S,5S)-2-{(2S)-2-Amino-2-[8-(4-methanesulfonyl phenyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-
exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (
Compound No. 53)
mp: 184-186 °C
MS: m/z 429(M+1)
1HNMR (D2O, 400 MHz): 8 0.56-0.62 (m, 1H), 1.01-1.08 (m, 1H), 1.58-1.78 (m, 3H), 1.85-
2.03 (m, 4H), 2.1-2.21 (m, 2H), 2.3-2.37 (m, 1H), 2.58-2.68 (m, 1H), 2.78-2.9 (m, 1H), 3.21
(s, 3H), 3.63-3.68 (m, 1H), 4.39 (d, J = 4.8Hz, 1H), 4.48-4.55 (m, 2H), 5.11(dd, J = 2.4, 10.8
Hz, 1H), 7.08 (d, J = 8.8Hz, 2H), 7.79 (d, J = 8.8Hz, 2H)
[a]D20 - 6.98 (c 0.50, water)
Yield: 80 %
(1S,3S,5S)-2-{(2S)-2-Amino-2-[8-(4-chlorophenylsulfonylcarbamoyl)-8-aza-bicyclo
[3.2.1]oct-3-yl]-exo-ethanoyl}-2-azabicyclo[3.1.0] hexane -3-carbonitrile trifluoroacetic acid
salt ( Compound No. 61)
mp: 189-191 °C
MS: m/z 490 (M-1)
1HNMR (D2O, 400 MHz): d 0.76-0.83 (m, 1H), 1.05 (m, 1H), 1.53-2.05 (m, 9H), 2.34-2.4 (m,
1H), 2.6-2.79 (m, 2H), 3.66-3.72 (m, 1H), 4.3-4.37 (M, 2H), 4.41 (d, J = 5.6Hz, 1H), 5.13(dd,
J = 2.4, 10.8 Hz, 1H), 7.58-7.63 (m, 2H), 7.87-7.93 (m, 2H)
[a]D20 - 10.37 (c 0.50, water)
Yield: 81 %
(1S,3S,5S)-2-{(2S)-2-Amino-2-[8-(2-methoxyphenylthiocarbamoyl)-8-aza-bicyclo [3.2.1]oct-
3-yl]-exo-ethanoyl}-2-azabicyclo[3.1.0]-hexane -3-carbonitrile trifluoroacetic acid salt (
Compound No. 68)
mp: 125-127 °C
MS: m/z 440 (M+1)
1HNMR (D2O, 400 MHz): d 0.94-1.0 (m, 1H), 1.16-1.25 (m, 1H), 1.65-1.98 (m, 6H), 2.0-2.27
(m, 3H), 2.38-2.45 (m, 1H), 2.63-2.72 (m, 1H), 2.80-3.0 (m, 1H), 3.80 (s, 3H), 4.48-4.57 (m,
1H), 4.65-4.82 (m,2H), 5.04-5.12 (m, 1H), 5.17(dd, J = 2.0, 10.4 Hz, 1H), 6.98-7.3 (m, 1H),
7.10 (d, J = 8.4Hz, 1H), 7.15-7.22 (m, 1H), 7.32-7.4 (m, 1H)
[a]D20 - 4.49 (c 0.50, water)
Yield: 98 %
(1S,3S,5S)-2-{(2S)-2-Amino-2-[8-(methanesulfonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt ( Compound
No. 56)
mp: 193-195 °C
MS: m/z 353(M+1)
1HNMR (D2O, 400 MHz):5 0.97-1.02 (m, 1H), 1.19-1.25 (m, 1H), 1.77-1.93( m, 6H), 2.05-2.2
(m, 3H), 2.5 (dd, J = 2.4, 14.0 Hz, 1H), 2.68-2.82 (m, 2H), 3.08 (s, 3H), 3.78-.383 (m, 1H),
4.35-4.4 (m, 2H), 4.56 (d, J=6Hz, 1H), 5.22 (dd, J= 2.4, 10.8 Hz, 1H),
[a]D20 - 20.57 (c 1.00, water)
Yield: 88 %
(1S,3S,5S)-2-{(2S)-2-Amino-2-[8-(thiophene-2-sulfonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt ( Compound
No. 57)
mp: 190-192 °C
MS: m/z 421(M+1)
1HNMR (D2O, 400 MHz): d 0.86-0.92 (m, 1H), 1.09-1.17 (m, 1H), 1.5-1.65 (m, 5H), 1.67-1.88
(m, 3H), 1.95-2.05 (m, 1H), 2.33-2.40 (dd, J=14 Hz, 2.4 Hz, 1H), 2.55-2.7 (m, 2H), 3.67-3.74
(m, 1H), 4.33-4.39 (m, 2H), 4.44 (d, J=6Hz, 1H), 5.10-5.15 (dd, J=10.8 Hz, 2.4 Hz, 1H),
7.16-7.19 (m, 1H), 7.68-7.72 (m, 1H), 7.82-7.85 (m, 1H).
[a]D20 - 2.25 (c 0.50, water)
Yield: 95 %
(1 S,3S,5S)-2-{(2S)-2-Amino-2-[8-(cyclohexane-carbonyl)-8-aza-bicyclo [3.2.1 ] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt ( Compound
No. 58)
mp: 184-186 °C
MS: m/z 385(M+1)
1HNMR (D2O, 400 MHz):d 0.88-0.96 (m, 1H), 1.09-1.43 (m, 6H), 1.52-1.85 (m, 11H), 1.86-
1.98 (m, 1H), 2.0-2.11 (m, 2H), 2.36-2.43 (m, 1H), 2.53-2.70 (m, 2H), 2.71-2.9 (m, 1H), 3.71-
3.77 (m, 1H), 4.47(dd, J=5.6, 13.6 Hz, 1H), 4.53-4.65 (m, 2H), 5.15 (d, J = 5.2Hz, 1H)
[a]D20-11.20 (c 1.07, water)
Yield: 76 %
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-( 1 -acetyl-piperidin-4-carbonyl)-8-aza-bicyclo [3.2.1 ]oct-3-
yl]-exo-ethanoyl}-2-azabicyclo[3.1.0] hexane -3-carbonitrile trifluoroacetic acid salt {
Compound No. 69)
mp: 130-131 °C
MS:m/z 428(M+1)
1HNMR (D2O, 200 MHz):d 0.85-1.0 (m, 1H), 1.1-1.25 (m, 1H), 1.38-2.08 (m, 10H), 2.09 (s,
3H), 2.32-2.47 (m, 1H), 2.56-3.0 (m, 4H), 3.02-3.3 (m, 1H), 3.7-3.8 (m, 1H), 3.9-4.02 (m,
1H), 4.28-4.9 (m, 8H), 5.15 (d, J= 10.3 Hz, 1H),
[a]D20 - 10.664 (c 0.50, water)
Yield: 100%
(1S,3S,5S)-2-{(2S)-2-Amino-2-(8-cyclohexyl-8-aza-bicyclo [3.2.1] oct-3-yl)-exo-ethanoyl}-2-
azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt ( Compound No.60)
mp: 162-164 °C
MS: m/z 357(M+1)
1HNMR (D2O, 400 MHz): d 0.88-0.95 (m, 1H), 1.2-1.4 (m, 6H), 1.58-2.25 (m, 14H), 2.37-2.45
(m, 1H), 2.61-2.8 (m, 2H), 2.85-2.95 (m, 0.5H), 3.35-3.45 (m, 0.5H), 3.75-3.83 (m, 1H), 4.20-
4.26 (m, 1H), 4.35-4.4 (m, 1H), 4.52 (d, J = 7.6Hz, 0.5H), 4.66 (d, J = 6.4Hz, 0.5H), 5.13-
5.21(m, 1H)
[a]D20 - 7.6 (c 0.50, water)
Yield: 81 %
(1S,3S,5S)-2-{(2S)-2-Amino-2-[8-(adamantan-1-yl methyl )-8-aza-bicyclo [3.2.1] oct-3-yl]-
exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt (
Compound No.49)
MS: m/z 423(M+1)
1HNMR (D2O, 400 MHz): 5 0.91-0.97 (m, 1H), 1.15-1.25 (m, 1H), 1.6-1.88 (m, 14H), 1.92-
2.17 (m, 8H), 2.24-2.38 (m, 3H), 2.41 (dd, J= 2.4, 14Hz, 1H), 2.64-2.74 (m, 2H), 2.77 (s,
1H), 3.75-3.82 (m, 1H), 4.10-4.15( m, 2H), 4.55 (d, J = 6.8Hz, 1H), 4.18 (dd, J = 2.4,10.8Hz,
1H).
Example 9
(1S, 3S, 5S)-2-{(2S)-2-Amino-2- [8-(benzo [1, 3]-dioxole-5-carbonyl)-8-aza-bicyclo [3.2.1]-
oct-3-yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3-carboxylic acid hydrochloride
(Compound No.46)

Concentrated HCI (10.0 ml) was added slowly to a round bottom flask containing (1S, 3S,
5S)-2-{(2S)-2-(tert- butoxycarbonyl)-amino-2- [8-(benzo [1, 3] dioxole-5-carbonyl)-8-aza-
bicyclo [3.2.1] oct-3-yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3-carbonitrile (prepared
by following the similar procedure as described in step-2 of Example-8, 0.175 g, 0.33 mmol).
The reaction mixture was brought to room temperature and stirred for 15 hours. The HCI
was removed under reduced pressure and the residue was dried under high vacuum. The
crude was stirred with dichloromethane (5 ml) and decanted. The solid so obtained was
dried under high vacuum to yield the title compound (0.153 g, 96%).
mp: 280 °C [d]
MS: m/z 441 (M+1)
1HNMR (D2O, 400 MHz):d 0.9-1.06 (m, 2H), 1.56-2.1 (m, 10H), 2.65-2.75 (m, 1H), 2.8-2.98
(m, 1H), 3.6-3.65 (m, 1H), 4.22-4.28 (m, 1H), 4.49 (dd, J = 4.8, 20.8 Hz, 1H), 4.7-4.8 (m,
3H), 6.0 (s, 2H), 6.92 (dd, J = 1.2, 8.0 Hz, 1H), 6.97-7.01 (m, 2H)
[a]D20 14.18 (c 0.50, water)
Example 10
(1S, 3S, 5S)-2-{(2S)-2-Amino-2- [8-(benzo- [1, 3] dioxole-5-carbonyl)-8-aza-bicyclo [3.2.1]
oct-3-yl]-exo-ethanoyl}-2-azabicyclo [3.1.0]-hexane -3-carboxamide trifluoro acetic acid salt
(Compound No.45)

To a stirred solution of (1S, 3S, 5S)-2-{(2S)-2-(tert-butoxycarbonyl)-amino-2- [8-(benzo [1,
3] dioxole-5-carbonyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-ethanoyl}-2-azabicyclo [3.1.0]-
hexane-3-carboxamide (prepared by following the similar procedure as described in step-1
of Example-8, 0.11 g, 0.2 mmol) in dichloromethane (2.0 ml) was added a solution of
trifluoro acetic acid (1.0 ml, 1.54 g, 13.5 mmol) in dichloromethane (0.5 ml) drop wise at 0°C.
The reaction mixture was stirred at 0°C for 5 minutes. Then it was brought to room
temperature and stirred for 45 minutes. The solvent was evaporated under reduced
pressure at room temperature and dried under high vacuum. In order to remove excess of
trifluoro acetic acid, the crude product was stirred with diethyl ether (10.0 ml). The organic
solvent was decanted and the solid product so obtained was stirred with 15%
dichloromethane in diethyl ether (10 ml) at room temperature for 10 minutes The solvent
was decanted and dried the solid under high vacuum to yield the title compound (0.095,
85%).
mp: 154-156 °C
MS: m/z 441 (M+1)
1HNMR (D2O, 400 MHz):d 0.92-1.05 (m, 2H), 1.58-2.1 (m, 10H), 2.65-2.76 (m, 1H), 2.86-
2.97 (m. 1H), 3.6-3.66 (m, 1H), 4.24-4.3 (m, 1H), 4.50 (dd, J = 5.2, 21.2 Hz, 1H), 4.75-
4.81 (m, 2H), 6.01 (s, 2H), 6.92-7.04 (m, 3H)
[a]D20 9.32 (c 0.50, water)
The following compound was prepared by procedure similar to those described for
Compound No.45 with appropriate variations of reactants, reaction conditions and quantities
of reagents
(2S)-1-{(2S)-2- amino-2-[8-(4-trifluoromethyl-benzoyl)-8-aza-bicyclo[3.2.1]-oct-3-yl]-exo-
ethanoyl}-pyrrolidin-2- carboxamide trifluoroacetic acid salt ( Compound No. 12)
mp: 156-158 °C
MS:m/z 453(M+1)
1HNMR (D2O, 400 MHz):d 1.55-1.66 (m, 2H), 1.68-2.12 (m, 9H), 2.28-2.38 (m, 1H), 2.5-2.63
(m, 1H), 3.55-3.66 (m, 1H), 3.73-3.82 (m, 1H), 4.05-4.12 (m, 1H), 4.2-4.27 (m, 1H), 4.4-4.47
(m, 1H), 4.7-4.9 (m, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.77-7.82 (m, 2H)
[a]D20-12.10 (c 0.50, water)
Example 11
(2S, 5R) -1- {(2S)-2- Amino-2- [8-(4-trifluoromethyl-benzoyl)- 8-aza- bicyclo [3.2.1] oct-3-yl]-
exo-ethanoyl} -5-ethynyl -pyrrolidin-2-carbonitrile trifluoro acetic acid salt (Compound No.63)

Step 1 : Methyl-(2S,5R)-1-{(2S)-2-(tert-butoxy carbonyl )-amino-2-[8-(4-trifluoromethyl-
benzoyl)- 8-aza- bicyclo [3.2.1] -oct-3-yl]-exo-ethanoyl}-5-trimethyl silyl -ethynyl-pyrrolidin-2-
carboxylate

To a stirred solution of (2S)-2-(tert-butoxycarbonyl)-amino-2- [8-(4-trifluoromethyl benzoyl)-
8-aza- bicyclo [3.2.1]-oct-3-yl]-exo-ethanoic acid (prepared by following the similar
procedure described in Intermediate 2, 2.0 g, 4.39 mmol) in dry DMF (20 ml) was added 1-
hydroxybenzotriazole (1.77 g, 11.6 mmol) and methyl-(2S,5R)-5-(trimethyl silyl -ethynyl)
pyrrolidine-2-carboxylate (which can be prepared by the procedure provided in
J.Med.Chem..49, 6416-6420 (2006), US 2006/0035954, US 2002/0019411, Synthesis,
1975,391; 1.0 g, 4.82 mmol) at room temperature. The reaction mixture was cooled to 0°C
and added 1- (3-dimethyl amino propyl)-3-ethyl carbodimide hydrochloride (1.85 g, 9.64
mmol) followed by tri ethyl amine (1.85 ml, 1.33 g, 13.16 mmol). The reaction mixture was
stirred at 0°C for 5 minutes and then at room temperature for 18 hours. The solvent was
evaporated under reduced pressure at 35°C. To this residue was added water (30 ml) and
extracted with ethyl acetate (3x100 ml). The combined organic layer was washed with 2%
sodium bicarbonate solution in water (2x25ml), water (100ml) and dried over anhydrous
Na2SO4. The solvent was evaporated under reduced pressure to get the crude product
which was purified by column chromatography over silica gel (200-400 mesh) using ethyl
acetate: NH3 in chloroform: hexane in the ratio of 30:8:62 as an eluent to yield the title
compound (1.6g, 55%).
MS: m/z 664(M+1)
1HNMR (CDCI3+D2O,400 MHz):5 0.05-0.2 (m, 9H), 1.23-1.27 (m, 1H), 1.4-1.48 (m,9H), 1.5-
2.28 (m,10H), 2.3-2.42 (m,1H), 2.47-2.72 (m,1H), 3.72 (s, 3H), 3.97-4.07 (m. 1H), 4.36-4.53
(m, 2H),4.85-4.97 (m, 1H), 5.02-5.15 (m,1H), 7.52-7.7 (m, 4H)
Step 2 : (2S,5R) -1- {(2S)-2-(tert-Butoxycarbonyl )-amino-2- [8-(4-trifluoromethyl-benzoyl) -
8-aza- bicyclo [3.2.1] oct-3-yl]-exo-ethanoyl}-5-ethynyl -pyrrolidin-2-carboxamide

To a stirred solution of methyl-(2S,5R)-1-{(2S)-2-(fert-butoxy carbonyl )-amino-2-[8-(4-
trifluoromethyl-benzoyl)- 8-aza- bicyclo [3.2.1] -oct-3-yl]-exo-ethanoyl}-5-trimethyl silyl -
ethynyl-pyrrolidin-2-carboxylate (1.5 g, 2.25 mmol) in methanol (10 ml) was added mixture of
sodium methoxide (1.22 g, 22.62 mmol) and formamide (2.87 ml, 3.25g, 72.32 mmol) drop
wise at room temperature. After the addition was completed, reaction mixture was stirred for
4 hours. The reaction mixture was quenched at room temperature with a saturated aqueous
ammonium chloride solution (15 ml) and the solvent was removed under reduced pressure.
To this residue was added water (30 ml) and extracted with ethyl acetate (4x100 ml). The
combined organic layers were washed with water (2x100ml), brine (200 ml) and dried over
anhydrous Na2SO4. The organic solvent was evaporated to get a crude product which was
purified by column chromatography over silica gel (200-400 mesh) using methanol: NH3 in
chloroform: dichloromethane in the ratio of 0.2:10:89.8 as an eluent to yield the title
compound (0.97 g, 75%).
MS:m/z 577(M+1)
1HNMR (CDCI3, 200 MHz):d 1.42 (s, 9H), 1.48-1.8 (m, 6H), 1.88-2.08 (m, 2H), 2.1-2.7 (m,
6H), 3.95-4.1 (m, 1H), 4.32-4.6 (m, 2H), 4.78-4.93 (m, 1H), 5-5.23 (m, 2H), 5.4-5.52 (m, 1H),
6.25-6.4 (m, 1H) 7.5-7.72 (m, 4H).
Step 3: (2S,5R) -1- {(2S)-2-(tert-Butoxycarbonyl)-amino-2- [8-(4-trifluoromethyl benzoyl)- 8-
aza- bicyclo [3.2.1]-oct-3-yl]-exo-ethanoyl}-5-ethynyl -pyrrolidin-2-carbonitrile

To a stirred solution of (2S, 5R) - 1- {(2S)-2-(tert-Butoxycarbonyl )-amino-2- [8-(4-
trifluoromethyl-benzoyl) - 8-aza- bicyclo [3.2.1] oct-3-yl]-exo-ethanoyl}-5-ethynyl -pyrrolidin-
2-carboxamide (0.5 g, 0.86 mmol) and imidazole (0.059 g, 0.86 mmol) in dry pyridine (7.5ml)
was added phosphorous oxy chloride (0.16 ml, 0.266 g, 1.73 mmol) drop wise at -35°C
under nitrogen atmosphere. The reaction mixture was then stirred at -20°C to -10°C for 1.5
hours. The completion of reaction was monitored by TLC. After completion, the reaction
mixture was quenched with water (1 ml) at -40°C and then it was allowed to come at room
temperature. The solvent was removed under reduced pressure. The crude product was
taken in water (20 ml) and extracted with dichloromethane (3x50 ml). The combined organic
layers were dried over anhydrous Na2SO4, filtered and concentrated at reduced pressure to
yield a crude product; which was purified by column chromatography over silica gel (200-
400 mesh) using ethyl acetate: NH3 in chloroform: hexane in the ratio of 25:5:70 as an
eluant to obtain the title compound (0.35 g, 72%).
MS: m/z 559(M+1)
1HNMR (CDCI3, 400 MHz):d 1.41(s, 9H), 1.43-1.85(m, 6H), 1.9-2.1 (m, 3H), 2.15-2.36 (m,
2H), 2.4-2.57 (m, 3H), 4.0-4.07 (m, 1H), 4.26-4.42 (m, 1H), 4.66 (t, J=8Hz, 1H) 4.84-4.93 (m,
1H), 5.0-5.08 (m, 1H), 5.13-5.24 (m, 1H), 7.53-7.62 (m, 2H), 7.64-7.72 (m, 2H).
Step 4: (2S,5R) -1- {(2S)-2-Amino-2- [8-(4-trifluoromethyl-benzoyl)- 8-aza- bicyclo [3.2.1]
oct-3-yl]-exo-ethanoyl}-5-ethynyl -pyrrolidin-2-carbonitrile trifluoro acetic acid salt

To a stirred solution of (2S,5R) -1- {(2S)-2-(tert-butoxycarbonyl)-amino-2- [8-(4-
trifluoromethyl benzoyl)- 8-aza- bicyclo [3.2.1]-oct-3-yl]-exo-ethanoyl}-5-ethynyl -pyrrolidin-2-
carbonitrile (0.32 g, 0.573 mmol) in dry dichloromethane (5 ml) was added a solution
trifluoroacetic acid (3.36 ml, 5.15 g, 45.2 mmol) in dry dichloromethane (5 ml) at 0°C. After
the addition was completed, reaction mixture was stirred at room temperature for 40
minutes. The solvent was evaporated under reduced pressure at 30°C and added
dichloromethane (10 ml) The solvent was again evaporated and dried under high vacuum. In
order to solidify the product, petroleum ether (10ml) was added and evaporated. The solid
product was then washed with mixture of 50% diethyl ether and 50% hexane (4x10ml) and
dried under high vacuum for four hours to yield the title compound (0.300 g, 91%).
mp: 160-163 °C
MS: m/z 459(M+1)
1HNMR (D2O,400 MHz):d 1.5-2.12 (m, 8H), 2.15-2.35 (m, 2H), 2.5-2.63 (m, 2H), 2.83-3.04
(m, 1H), 3.08 (d, J = 1.6Hz , 0.5H), 3.13(d, J=2.0 Hz ,0.5H), 4.08-4.14 (m, 1H), 4.39 (d, J
=5.6 Hz, 0.5H), 4.46 (d, J = 5.2Hz, 0.5H), 4.77-4.84 (m, 2H), 5.0-5.06 (m, 1H), 7.62 (d, J =
8Hz, 2H), 7.81(d, J =8.0 Hz, 2H)
[a]D20-9.61 (c 1.09, Methanol)
The following compounds were prepared by procedure similar to those described for
Compound No.63 with appropriate variations of reactants, reaction conditions and quantities
of reagents
(2S,5R)-1-{(2S)-2-Amino-2-[8-(pyridin-4-carbonyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-
ethanoyl}-5-ethynyl-pyrrolidin-2-carbonitrile di trifluoro acetic acid salt (Compound No.64)
mp: 175-177 °C
MS: m/z392(M+1)
1HNMR (DzO, 400 MHz):d 1.53-1.98 (m, 6H), 2.10-2.37 (m, 4H), 2.56-2.60 (m, 2H), 2.88-
3.08 (m, 1H), 3.13-3.16 (m, 1H), 4.07-4.15 (m, 1H), 4.4-4.5 (m, 1H), 4.70-4.85 (m, 2H), 5.0-
5.1(m, 1H) 7.7-7.85 (m, 2H), 8.7-8.9 (m, 2H)
[a]D20-8.38 (c 1.0, Methanol)
(2S,5R)-1-{(2S)-2-Amino-2-[8-(3-fluoropyridin-4-carbonyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-
ethanoyl}-5-ethynyl-pyrrolidin-2-carbonitrile trifluoroacetic acid salt ( Compound No.65)
mp: 166-168 °C
MS: m/z 410(M+1)
'HNMR (D2O, 400 MHz):5 1.56-2.04 (m, 6H), 2.05-2.37 (m, 4H), 2.53-2.67 (m, 2H), 2.86-
3.03 (m, 1H), 3.12-3.18 (dd, J = 18.8 Hz, 2.0 Hz, 1H), 4.03-4.08 (m, 1H), 4.41-4.49 (dd, J =
18.8 Hz, 5.64 Hz, 1H), 4.82-4.89 (m, 2H), 5.03-5.08 (m, 1H), 7.58-7.64 (m, 1H), 8.54 (d, J =
5.2Hz, 1H), 8.66 (s, 1H)
[a]D20-2.35 (c 1.0, Methanol)
Yield : 80%
Example 12
(2S,5R)-1-{(2S)-2-Amino-2- [8-(2-fluoropyridin-4-carbonyl)- 8-aza- bicyclo [3.2.1]-oct-3-yl]-
exo-ethanoyl}-5-ethynyl-pyrrolidin-2-carbonitrile trifluoro acetic acid salt ( Compound No. 66)

Step 1: (2S,5R)-1-{(2S)-2-(tert-Butoxycarbonyl)-amino-2- [8-(2-fluoropyridin-4-carbonyl)- 8-
aza-bicyclo [3.2.1]-oct-3-yl]-exo-ethanoyl}-5-ethynyl -pyrrolidin-2-carboxamide

To a stirred solution of (2S)-2-(tert-butoxycarbonyl)-amino-2- [8-(2-fluoro pyridine-4-
carbonyl)- 8-aza- bicyclo [3.2.1]-oct-3-yl]-exo-ethanoic acid (Intermediate 2, 0.9 g, 2.21
mmol) in DMF (15 ml) was added 1-hydroxybenzotriazole (0.896 g, 6.63 mmol) and
trifuoroacetic acid salt of (5R)-5-ethnyl-2-prolinamide (J.Med.chem. 49, 6416-6420 (2006),
US 2002/0019411, Synthesis 391 (1975), 0.61 g, 2.42 mmol) at room temperature. The
reaction mixture was cooled to 0°C, added 1- (3-dimethyl amino propyl)-3-ethyl carbodimide
hydrochloride (0.847 g, 4.42 mmol) and triethyl amine (0.92 ml, 0.67 g, 6.63 mmol). The ice
bath was removed and the reaction mixture was made clear by adding water (1ml). The
reaction mixture was stirred at room temperature for 12 hours. The solvent was evaporated
under reduced pressure. The residue was taken in water (30 ml) and extracted with ethyl
acetate (3x100ml). The combined organic layers were washed with 5% NaHCO3 solution
(2x25ml) and dried over anhydrous Na2SO4. The solvent was evaporated under reduced
pressure to obtain the crude product; which was purified by column chromatography over
silica gel (200-400 mesh) using methanol: NH3 in chloroform: dichloromethane in the ratio of
1 5:3:95.5 as an eluent to yield the title compound (0.640 g, 55%).
MS: m/z 528 (M+1)
1HNMR (CDCI3,400 MHz):d 1.42 (s, 9H), 1.5-1.82 (m, 6H), 1.85-2.1 (m, 2H), 2.12-2.3 (m,
3H), 2.4-2.68 (m, 3H), 3.9-4.02 (m, 1H), 4.4-4.53 (m, 2H), 4.8-4.9 (m, 1H), 5.0-5.17 (m, 2H),
5.37-5.45(m, 1H),6.2-6.33(m,1H), 6.94-7.0 (m, 1H), 7.18-7.26 (m, 1H), 8.25-8.32 (m,1H).
Step 2 : (2S,5R)-1-{(2S)-2-(tert-Butoxycarbonyl)-amino-2- [8-(2-fluoropyridine -4-carbonyl)-
8-aza- bicyclo [3.2.1]-oct-3-yl]-exo-ethanoyl}-5-ethynyl -pyrrolidin—2-carbonitrile

To the stirred solution of (2S,5R)-1-{(2S)-2-(tert-butoxycarbonyl)-amino-2- [8-(2-
fluoropyridin-4-carbonyl)- 8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-ethanoyl}-5-ethynyl -pyrrolidin-
2-carboxamide (0.62 g, 1.17 mmol ) and imidazole ( 0.08 g, 1.17 mmol) in dry pyridine (9.3
ml) was added phosphorous oxy chloride (0.22 ml, 0.36 g, 2.35 mmol) drop wise at -35°C
under nitrogen atmosphere. The reaction mixture was then stirred at -20°C to -10°C for 1.5
hours. The completion of reaction was monitored by TLC. After completion, the reaction
mixture was quenched with water (1 ml) at -40°C and then it was allowed to come at room
temperature. The solvent was removed under reduced pressure. The crude product was
taken in water (20 ml) and extracted with dichloromethane (3x 50 ml). The combined organic
layer was dried over anhydrous Na2SO4. The organic solvent was evaporated to yield a
crude product, which was purified by column chromatography over silica gel (200-400 mesh)
using ethyl acetate: NH3 in chloroform: hexane in the ratio of 45:05:50 as an eluent to yield
the title compound (0.52 g, 86%).
MS: m/z 510(M+1)
1NMR (CDCI3,400 MHz):d 1.41(s, 9H), 1.54-1.87 (m, 6H), 1.9-2.07 (m, 3H), 2.13-2.38 (m,
2H), 2.4-2.6 (m, 3H), 3.95-4.04 (m, 1H), 4.27-4.41 (m, 1H), 4.66 (t, J=8Hz, 1H) 4.8-4.9 (m,
1H), 5.01-5.1(m, 1H), 5.13-5.24 (m, 1H), 6.94-7.0 (m, 1H), 7.19-7.25 (m, 1H), 8.30 (t, J =
5.6Hz, 1H).
Step 3: (2S,5R)-1-{(2S)-2-Amino-2- [8-(2-fluoropyridin-4-carbonyl)- 8-aza- bicyclo [3.2.1] oct-
3-yl]-exo-ethanoyl}-5-ethynyl-pyrrolidin-2-carbonitrile trifluoro acetic acid salt

To a stirred solution of (2S,5R)-1-{(2S)-2-(tert-butoxycarbonyl)-amino-2- [8-(2-fluoropyridine
-4-carbonyl)- 8-aza- bicyclo [3.2.1]-oct-3-yl]-exo-ethanoyl}-5-ethynyl -pyrrolidin—2-
carbonitrile (0.5 g, 0.98 mmol)in dichloromethane (10 ml) was added a solution of
trifluroacetic acid ( 5.25 ml, 8.06 g, 70.7 mmol) in dry dichloromethane (10.0 ml) at 0°C. After
the addition was completed, the reaction mixture was stirred at room temperature for 1hour.
The solvent was evaporated under reduced pressure and added dichloromethane (10 ml).
This process is repeated twice and residue was dried under high vacuum. In order to solidify
the product, petroleum ether (10 ml) was added and evaporated The solid product was then
washed with diethyl ether (2x10 ml) and added dry dichloromethane (10 ml). It was again
evaporated under reduced pressure and dried under high vacuum to yield the title
compound (0.39 g, 76%)
mp: 199-200 °C
MS: m/z 410(M+1)
1HNMR (D2O, 400 MHz):d 1.5-1.96 (m, 6H), 2.0-2.1 (m, 2H), 2.12-2.32 (m, 2H), 2.49-2.62
(m, 2H), 2.82-3.04 (m, 1H), 3.09-3.14 (m, 1H), 4.07-4.13 (m, 1H),4.37-4.48 (m, 1H), 4.76-
4.85 (m, 2H), 5.0-5.05 (m, 1H),7.18 (s, 1H), 7.38 (d, J=5.2Hz, 1H), 8.30 (d, J=5.2Hz, 1H)
[a]D20 -6.95 (c 0.50, Methanol)
The following compound was prepared by procedure similar to those described for
Compound No.66 with appropriate variations of reactants, reaction conditions and quantities
of reagents
(2S,5R)-1-{(2S)-2-Amino-2-[8-(benzo[1,3]dioxole-5-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-
exo-ethanoyl}-5-ethynyl-pyrrolidin-2-carbonitrile trifluoroacetic acid salt ( Compound No.67)
Yield : 87%
mp:201-202°C
MS: m/z 435(M+1)
1HNMR (D2O, 400 MHz):d 1.49-1.95 (m, 6H), 1.97-2.10 (m, 2H), 2.12-2.33 (m, 2H), 2.49-
2.63 (m, 2H), 2.8-3.03 (m, 1H), 3.05-3.15 (m, 1H), 4.22-4.28 (m, 1H), 4.34-4.36 (m, 0.5H),
4.42-4.45 (m, 0.5H), 4.70-4.80 (m, 2H), 5.0-5.05 (m, 1H), 6.0 (s, 2H), 6.9-7.02 (m, 3H)
[a]D20 -7.66 (c 0.50, Methanol)
Example 13
{(2S)-2-Amino-2-[8-(3-fluoropyridine-4-carbonyl)-8-aza-bicyclo[3.2.1]-oct-3-yl]-exo-ethanoyl}-
3-fluoroazetidine trifluoroacetic acid salt (Compound No.62)

Step 1 : {(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(3-fluoropyridine-4 -carbonyl)-8-aza-
bicyclo[3.2.1 ]-oct-3-yl]-exo-ethanoyl}-3-flouroazetidine

To a stirred solution of (2S)-2-(tert-butoxycarbonyl) amino-2- [8-(3-fluoropyridine -4-
carbonyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-exo ethanoic acid (prepared by following the similar
procedure described in Intermediate 2, 0.5 g, 1.22 mmol) in DMF (10 ml) was added 1-
hydroxybenzotriazole (0.49 g, 3.68 mmol) and 3- fluoroazetidine hydrochloride (which can
be prepared by following the procedures described in J. Org. Chem, 32, 2972 (1997) and
Biorganic Med. Chem. Lett., 14, 1265, (2004), 0.15 g, 1.35 mmol) at room temperature. The
reaction mixture was cooled to 0°C, added triethyl amine (0.37 g, 0.51 ml, 3.68 mmol) and 1-
(3-dimethyl amino propyl)-3-ethyl carbodimide hydrochloride (0.47 g, 2.46 mmol). Ice bath
was removed, added water (0.5 ml) and stirred at room temperature for 16 hours. The
solvent was removed under reduced pressure, added water (20 ml) and extracted with ethyl
acetate (3x100ml). The combined organic layers were washed with 5% aqueous NaHCO3
solution (2x25 ml) and dried over anhydrous Na2SO4. The solvent was evaporated to get a
crude product, which was purified by column chromatography over silica gel (200-400 mesh)
using ethyl acetate: ammonia in chloroform: hexane in ratio of 75:5:20 as an eluent to yield
the title compound (0.3 g, 53%)
MS: m/z 465(M+1)
1HNMR (CDCI3.400 MHz):d 1.35-1.47 (m, 9H), 1.48-1.8 (m, 6H), 1.93-2.08 (m, 2H), 2.13-2.3
(m, 1H), 3.7-3.83 (m, 1H), 3.85 -4.58 (m, 4H), 4.6-4.7 (m, 1H), 4.8-4.9 (m, 1H), 4.93-5.1(m,
1H), 5.2-5.4(m, 1H), 7.3-7.4(m, 1H), 8.46-8.56(m, 2H).
Step : 2 {(2S)-2-Amino-2-[8-(3-fluoropyridine-4-carbonyl)-8-aza-bicyclo[3.2.1]-oct-3-yl]-exo-
ethanoyl}-3-fluoroazetidine trifluoroacetic acid salt

To a stirred solution of {(2S)-2(tert-butoxycarbonyl)-amino-2- [8-(3-fluoropyridine-4-
carbonyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-ethanoyl}-3-fluoro-azetidine (0.22 g, 0.474
mmol) in dichloromethane (5 ml) was added a solution of trifluroacetic acid (2.3 ml, 3.53 g,
30.9 mmol) in dry dichloromethane (5.0 ml) drop wise at 0°C. After the addition was
completed, the ice bath was removed and the reaction mixture was stirred at room
temperature for 1.5 hours. The solvent was evaporated under reduced pressure at room
temperature and dried under high vacuum. In order to solidify the product, petroleum ether
(10 ml) was added and evaporated to get a solid, which was washed with diethyl ether (2x10
ml) and dried under high vacuum to yield the title compound (0.24 g, 86%).
mp: 90-93°C
MS: m/z 365(M+1)
1HNMR(D2O, 400 MHz):d 1.4-1.9 (m, 6H), 1.96-2.01 (m, 2H), 2.4-2.54 (m, 1H), 3.86-4.0 (m,
2H), 4.03-4.7 (m, 4H), 4.73-4.86 (m, 1H), 5.25-5.5 (m, 1H), 7.7-7.8 (m, 1H), 8.56-8.65 (m,
1H), 8.71-8.8 (m, 1H)
Example 14
Benzyl-(2S,5R)-1 -{(2S)-2- amino-2-[8-(4-trifluoromethyl-benzoyl)-8-aza-bicyclo[3.2.1 ]-oct-3-
yl]-exo-ethanoyl}-5-cyano pyrrolidin-2- carboxylate trifluoroacetic acid salt {Compound
No. 18)

Step: 1 Benzyl- (2S, 5R)-1-{(2S)-2-(tert-butoxy carbonyl)-amino-2-[8-(4-trifluoro methyl-
benzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-ethanoyl}-5-cyano-pyrrolidin-2-carboxylate

To a stirred solution of (2S)-2-(tert-butoxy carbonyl)-amino-2-[8-(4-trifluoro methyl-benzoyl)-
8-aza-bicyclo[3.2.1]oct-3-yl]-exo-ethanoic acid (prepared by following the similar procedure
described in Intermediate 2, 3.0 g, 6.6 mmol) in dichloromethane (90 ml) was added triethyl
amine (1.4 ml, 1.0 g, 9.9 mmol) and the reaction mixture was cooled to -5°C. To this reaction
mixture was added isobutyl chloro formate (0.95 ml, 0.992 g, 7.26 mmol) slowly under
nitrogen atmosphere and stirred at -5°C for 2.5 hours. More isobutyl chloro formate (0.175
ml, 0.18 g, 1.3 mmol) was added and the reaction mixture was brought to 0°C and stirred for
1.0 hour. After 1 hour, benzyl (2S, 5R)-5-cyanopyrrolidine-2-carboxylate ( prepared by
following the procedures described in Tetrahedron lett, 43, 3499-3501 (2002), Tetrahedron,
57, 6439-6446, (2001), J. Chem. Soc. Perkin Trans 1, 507-514, (1996), 1.51 g, 6.6 mmol)
was added to the reaction mixture at 0°C. After the addition was completed, the reaction
mixture was brought to room temperature and stirred for 15 hours. The progress of the
reaction was monitored by TLC. The reaction mixture was quenched with water (20 ml) and
extracted with dichloromethane (3x250 ml). The combined organic layer was washed with
5% NaHCO3 solution (5x 200 ml) and dried over anhydrous sodium sulphate. The solvent
was evaporated to obtain a crude product, which was purified by column chromatography
over silica gel (100-200 mesh) using 50% ethyl acetate in hexane as an eluent to obtain the
title compound (1.2 g, 28%).
MS: m/z 669 (M+1)
1HNMR (CDCI3+D2O, 200 MHz):d 1.3-2.01 (m, 15H), 2.05-2.55 (m, 7H), 3.55-3.70 (m, 1H),
4.03-4.20 (m, 1H), 4.48-4.61 (m, 1H), 4.62-4.88 (m, 1H), 5.0-5.32 (m, 2H), 5.48-5.58 (m,
1H), 7.1-7.4 (m, 5H), 7.5-7.71 (m, 4H)
Step 2: Benzyl- (2S,5R)-1-{(2S)-2- amino-2-[8-(4-trifluoromethyl-benzoyl)-8-aza-
bicyclo[3.2.1]-oct-3-yl]-exo-ethanoyl}-5-cyano pyrrolidin-2- carboxylate trifluoroacetic acid
salt
To a stirred solution of benzyl- (2S, 5R)-1-{(2S)-2-(tert-butoxy carbonyl)-amino-2-[8-(4-
trifluoro methyl-benzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-ethanoyl}-5-cyano-pyrrolidin-2-
carboxylate (0.2 g, 0.3 mmol) in dry dichloromethane (5.0 ml) was added a solution of
trifluoroacetic acid (1.37 ml, 2.1 g, 18.4 mmol) in dichloromethane (5.0 ml) at 0°C under
nitrogenatmosphere . After the addition, the ice bath was removed and the reaction mixture
was monitored by TLC. After 1.0 hour, the reaction mixture was diluted with
dichloromethane (10 ml) and evaporated to dryness under reduced pressure at room
temperature. To remove traces of trifluroacetic acid, the residue was taken with
dichloromethane (25 ml) and evaporated. The solid so obtained was then washed with a
50% solution of diethyl ether in hexane (3x 25 ml) and dried under high vacuum to obtain the
title compound (0.18 g, 88%)
MS: m/z 569 (M+1)
1HNMR (D2O, 400 MHz): d 0.9-1.09 (m, 1H), 1.15-1.43 (m, 2H), 1.5-1.93 (m, 5H), 2.1-2.22
(m, 1H), 2.26-2.50 (m, 2H), 2.55-2.84 (m, 2H), 4.03-4.11 (m, 1H), 4.45-4.70 (m, 2H), 4.86-
5.12 (m, 3H), 5.28-5.36 (m, 1H), 6.7-7.01(m, 3H), 7.06-7.3 (m, 2H), 7.36-7.52 (m, 2H), 7.6-
7.8 (m, 2H)
[a]D20 -2.94 (c 0.80, Methanol)
Example 15
(2S)-1 -{(2S)-2-Amino-2- [8-aza-bicyclo [3.2.1] oct-3-yl]-exo-ethanoyl}-pyrrolidin-2-carbonitrile
trifluoro acetic acid salt (Compound No.8)

Step 1: (2S)-1- {(2S)-2-(tert-butoxy carbonyl)-amino-2- [8-( tert-butoxy carbonyl)-8-aza-
bicyclo [3.2.1] oct-3-yl]-exo-ethanoyl}-pyrrolidin -2-carboxamide

To a stirred solution of (2S)-2-(tert-butoxy carbonyl)-amino-2- {8-( tert-butoxy carbonyl)-8-
aza-bicyclo [3.2.1] oct-3-yl}-exo-ethanoic acid (Intermediate 12, 0.88 g, 2.29 mmol) in dry
DMF was added 1-hydroxy benzotriazole (0.92 g, 6.87 mmol) and L- prolinamide (0.26 g,
2.29 mmol) at room temperature. The reaction mixture was cooled to 0°C and added triethyl
amine (0.69 g, 0.96 ml, 6.87 mmol) and 1-(3-dimethyl amino propyl)-3-ethyl carbodimide
hydrochloride (0.87 g, 4.58 mmol). Ice bath was removed after 2 hours and the reaction
mixture was stirred at room temperature for 16 hours. The solvent was removed under
reduced pressure, added a saturated aqueous sodium bicarbonate solution (25 ml) and
extracted with ethyl acetate (1x 50 ml). The organic layer was dried over anhydrous Na2SO4
and the solvent was removed under reduced pressure to obtain a crude product which was
purified by column chromatography over silica gel (200-400 mesh) using methanol: NH3 in
chloroform: dichloromethane in the ratio 1.8:5: 93.2 as an eluent to yield the title compound
(0.46 g, 42%).
MS: m/z 481 (M+1)
1HNMR (CDCI3, 400 MHz):d 1.41 (s, 9H), 1.42-1.68 (m, 15H), 1.83-2.06 (m, 4H), 2.08-2.10
(m, 2H), 2.12-2.20 (m, 1H) 3.5-3.62( m, 1H), 3.65-3.8 (m, 1H), 4.03-4.40 (m, 3H), 4.52-4.62
(m, 1H), 5.12-5.21 (m, 1H) 5.33-5.45 (m, 1H) 6.55-6.80 (brs, 1H)
Step 2: (2S)-1- {(2S)-2-(tert-butoxy carbonyl)-amino-2- [8-( tert-butoxy carbonyl)-8-aza-
bicyclo [3.2.1] oct-3-yl]-exo-ethanoyl}-pyrrolidin -2-carbonitrile

To a stirred solution of (2S)-1- {(2S)-2-(tert-butoxy carbonyl)-amino-2- [8-( tert-butoxy
carbonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-ethanoyl}-pyrrolidin -2-carboxamide (0.45 g,
0.94 mmol) and imidazole (0.134 g, 1.97 mmol) in dry pyridine (10 ml) at -30°C was added
phosphorous oxychloride (0.589 g, 0.33 ml, 3.84 mmol) drop wise. The reaction mixture was
stirred at -30oC for 1.5 hours and completion of reaction was monitored by TLC. The
reaction mixture was quenched with water (0.5ml) at -30°C and then it was allowed to come
at room temperature. The solvent was removed under reduced pressure at room
temperature. The crude product was dried under high vacuum. To this was added
dichloromethane (40 ml), washed with water (2x10ml) and dried over anhydrous Na2SO4.
The solvent was evaporated to obtain a crude product, which was purified by column
chromatography over silica gel (100-200 mesh) using methanol in dichloromethane as an
eluent to yield the title compound
MS: m/z 461(M-1)
1HNMR (CDCI3+D2O, 400 MHz) : 5 1.30-151(m, 19H), 1.56-1.80 (m, 4H), 1.80-1.93 (m, 2H),
2.05-2.40 (m, 5H), 3.55-3.90 (m, 2H), 4.08-4.45 (m, 3H), 4.78 (s, 3H), 5.07 (d, J = 9.2Hz,
1H)
Step 3: (2S)-1-{(2S)-2-amino-2- [8-aza-bicyclo [3.2.1] oct-3-yl]-exo-ethanoyl}-pyrrolidin -2-
carbonitrile trifluoro acetic acid salt

To a stirred solution of (2S)-1- {(2S)-2-(tert-butoxy carbonyl)-amino-2- [8-( tert-butoxy
carbonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-ethanoyl}-pyrrolidin -2-carbonitrile
(0.34 g, 0.73 mmol) in dry dichloromethane (2.5 ml) at 0°C was added a solution of
trifluoroacetic acid (3.3 ml, 3.1 g, 27.19 mmol) in dry dichloromethane (2.5 ml) drop wise.
The reaction mixture was stirred at 0°C for 5 minutes. The reaction mixture was allowed to
come at room temperature and stirred for 25 minutes. The solvent was evaporated under
reduced pressure at 30°C and to the residue was added dichloromethane (10 ml). The
solvent was evaporated under reduced pressure and dried under high vacuum to remove
trifluroacetic acid. In order to remove trifluoroacetic acid left and to solidify the product,
diethyl ether (20 ml) was added to this mass and the solid so obtained was stirred at room
temperature for 15 minutes. The solvent was decanted and dried the solid under high
vacuum to yield the title compound (0.34 g, 94%)
mp: 143-145°C
MS: m/z 263(M+1)
1HNMR (D2O, 400 MHz):d 1.70-1.88 (m, 3H), 1.90-2.06 (m, 3H), 2.08-2.21 (m, 4H), 2.30-
2.42 (m, 2H), 2.43-2.60 (m, 1H), 3.73 (t, J=6.8Hz, 2H), 4.10-4.22 (m, 2H), 4.26 (d, J = 7.6Hz,
1H), 4.75-4.90 (m, 1H)
[a]D20-39.11 (c 0.50, water)
Example 16
(2S)-1-{2- Amino-2- [9-(4-trifluoromethyl-benzoyl)-9-azabiacyclo [3.3.1] non-3-yl]-exo-
ethanoyl}-pyrrolidin-2-carbonitrile trifluoro acetic acid salt (Compound Nos. 70 A and 70 B)

Step 1: (2S)-1-{2-(tert-Butoxycarbonyl) amino-2- [9-(4-trifluoromethyl-benzoyl)-9-azabiacyclo
[3.3.1] non-3-yl]-exo-ethanoyl}-pyrrolidin-2-carboxamide

To a stirred solution of 2-(tert-butoxy carbonyl) amino-2- {9-(4-trifluoromethyl benzoyl)-9-
azabicyclo [3.3.1] non-3-yl}-exo-ethanoic acid (Intermediate 13, 0.55 g, 1.17 mmol) in DMF
(11ml) at room temperature was added 1-hydroxy benzotriazole (0.537 g, 3.5 mmol) L-
prolinamide (0.133 g, 1.17 mmol) and triethyl amine (0.354 g, 3.5 mmol). The reaction
mixture was cooled to 0°C and was added 1- (3-dimethyl amino propyl)-3-ethyl carbodimide
hydrochloride (0.447 g, 2.34 mmol) portion wise. The reaction mixture was allowed to come
at room temperature and stirred for 14 hours. The progress of reaction was monitored by
TLC. After the completion of reaction, DMF was evaporated under reduced pressure and the
residue was taken in ethyl acetate (100 ml). The organic layer was washed with a saturated
sodium bicarbonate solution (10 ml) and aqueous layer was extracted with ethyl acetate (2x
20ml). The combined organic layers were dried with anhydrous sodium sulphate and the
solvent was evaporated to obtain a crude product, which was purified by column
chromatography over silica gel (200-400 mesh) using methanol: ammonia in chloroform:
dichloromethane in the ratio of (1:10:89) as an eluent to yield polar diastereomer (0.25 g,
38%) and less polar diastereomer (0.17 g, 26%)
More polar diastereomer
mp: 159-161°C
MS: m/z 567 (M+1)
1HNMR (CDCI3+D2O, 400 MHz):d 1.36-1.58 (m, 10H), 1.59-1.88 (m, 7H), 1.9-2.2 (m, 5H),
2.22-2.34 (m, 1H), 2.70-2.81 (m, 1H), 3.54-3.57 (m, 1H), 3.73-3.84 (m, 2H), 4.20-4.27 (m,
1H), 4.50-4.55 (m, 1H), 4.87-4.95 (m, 1H), 7.46-7.54 (m, 2H), 7.64-7.70 (m, 2H)
Less polar diastereomer
mp: 173-175°C
MS: m/z 567(M+1)
1HNMR (CDCI3 +CD3OD+D2O, 400MHz):d 1.35-1.54 (m, 10H), 1.55-2.18 (m, 12H), 2.22-
2.35 (m, 1H), 2.66-2.83 (m, 1H), 3.4-3.65( m, 1H), 3.75-3.85 (m, 1H), 3.88-4.05 (m, 2H),
4.47-4.56 (m, 1H), 4.85-4.94 (m, 1H) 7.46-7.54 (m, 2H),7.66( d, J=8Hz, 2H)
Step 2: (2S)-1-{2-(tert-Butoxycarbonyl) amino-2- [9-(4-trifluoromethyl-benzoyl)-9-
azabiacyclo [3.3.1] non-3-yl]-exo-ethanoyl}-pyrrolidin-2-carbonitrile

To a solution of (2S)-1-{2-(tert-butoxycarbonyl) amino-2- [9-(4-trifluoromethyl-benzoyl)-9-
azabiacyclo [3.3.1] non-3-yl]-exo-ethanoyl}-pyrrolidin-2-carboxamide (0.23 g, 0.41 mmol) and
imidazole (0.058 g, 0.85 mmol) in dry pyridine (11.5 ml) under a nitrogen atmosphere at -
30°C was added phosphorous oxychloride (0.255 g, 1.66 mmol). The reaction mixture was
stirred at -30°C for 60 minutes and the progress of the reaction was monitored by TLC. It
was then quenched with water (0.23 ml) at -30°C and the reaction mixture was allowed to
come at room temperature. The solvent was evaporated to dryness under reduced pressure
and the residue was taken in dichloromethane (100 ml). After washing with water (10 ml),
the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to
obtain a crude product, which was purified by column chromatography over silica gel (100-
200 mesh) using 1% methanol in dichloromethane as an eluent to yield the title compound
(0.136 g, 61%)
More polar diastereomer
mp: 146-148°C
MS: m/z 549 (M+1)
1HNMR (CDCl3, 400 MHz):d 1.38-1.55 (m, 10H), 1.6-1.86 (m, 6H), 1.88-2.06 (m, 3H), 2.10-
2.35(m, 4H), 2.67-2.83 (m, 1H), 3.61-3.87 (m, 3H), 4.06-4.15 (m, 1H), 4.75-4.80 (m, 1H),
4.9-4.98 (m, 1H), 5.11 (t, J = 9.6Hz, 1H), 7.47-7.54 (m, 2H), 7.67 (d, J = 8.0Hz, 2H)
Less polar diastereomer: It was also obtained by following the same procedure applied for
more polar diastereomer as described above
(MS: m/z 549 (M+1)
1HNMR (CDCI3+D2O, 400 MHz): d 1.33-1.89 (m, 16H), 1.90-2.42 (m, 6H), 2.63-2.92 (m, 1H),
3.41-3.62 (m, 1H), 3.71-3.86 (m, 1H), 3.90-4.2 (m, 2H), 4.61-5.12 (m, 2H), 7.45-7.55 (m,
2H), 7.61-7.70 (m,2H)
Step 3: (2S)-1-{2- Amino-2- [9-(4-trifluoromethyl-benzoyl)-9-azabiacyclo [3.3.1] non-3-yl]-
exo-ethanoyl}-pyrrolidin-2-carbonitrile trifluoro acetic acid salt.

To a stirred solution of (2S)-1-{2-(tert-butoxycarbonyl) amino-2- [9-(4-trifluoromethyl-
benzoyl)-9-azabiacyclo [3.3.1] non-3-yl]-ethanoyl}-pyrrolidin-2-carbonitrile (0.12 g, 0.22
mmol) in dichloromethane (1.2 ml) was added trifluoro acetic acid (1.2 ml) at 0°C. The
reaction mixture was brought to room temperature in 10 minutes and stirred for 30 minutes.
The progress of the reaction was monitored by TLC. After the completion of reaction, the
solvent was evaporated under reduced pressure and the residue was taken in
dichloromethane (20 ml) and evaporated to remove traces of trifluoro acetic acid. The
residue so obtained was taken in diethyl ether (15 ml) and evaporated to obtain a solid,
which was washed with 20% dichloromethane in diethyl ether (20 ml). To remove the traces
of ether, the solid was taken in dichloromethane (10 ml) and evaporated to dryness twice.
The crude product thus obtained was dried under high vacuum to yield the title compound
(0.087 g, 71%)
More polar diastereomer (Compound No. 70 A)
mp: 172-174X
MS: m/z 449 (M+1)
1HNMR (CDCI3+D2O, 400 MHz): d 1.6-1.73 (m, 3H), 1.74-2.22 (m, 9H), 2.23-2.45 (m, 2H),
3.05-3.2 (m, 1H), 3.72 (t, J = 6.8 Hz, 2H), 3.83-3.92 (m, 1H), 4.14 (dd, J =2.4, 6.8Hz, 1H),
4.78-4.86 (m, 2H), 7.54-7.6 (m, 2H), 7.81(d, J = 7.8Hz, 2H)
[a]D20-16.45 (c 0.50, water)
Less polar diastereomer (Compound No. 70 B): It was also obtained by following the same
procedure applied for more polar diastereomer as described above
mp: 168-170°C
MS: m/z 449 (M+1)
1HNMR (D2O, 400 MHz): d 1.21-1.34 (m, 1H), 1.6-2.06 (m, 10H), 2.10-2.41(m, 4H), 2.98-
3.12 (m, 1H), 3.5-3.68 (m, 1H), 3.8-3.91(m, 2H), 4.08 (t, J =7.2Hz, 1H), 4.73-4.9 (m, 1H),
7.57 (d, J = 6.4 Hz, 2H), 7.81 (d, J = 7.6 Hz, 2H)
[a]D20-71.58 (c 0.50, water)
Demonstration of In Vitro Efficacy of Test Compounds
Inhibition of human recombinant DPP-IV
The proteolytic activity of human recombinant DPP-IV was determined by following the
hydrolysis of Gly-Pro-7-amino-4-methylcoumarin (Gly-Pro-AMC) and the fluorometric
quantitation of the liberated AMC. Assays were routinely carried out in 96-well flat-bottom
black microwell plates. The reaction mixture (100 µl) contained 10 ng of human recombinant
DPP-IV enzyme (produced in-house or procured from R&D Systems, USA) in the assay
buffer (25 mM Tris-HCI, pH 7.4, 140 mM NaCI, 10 mM KCI and 0.1 mg/ml BSA) and 50 uM
Gly-Pro-AMC. After incubation of assay plates at 30°C for 30 min, the hydrolysis of Gly-Pro-
AMC was monitored in a fluorescence microplate reader (Molecular Devices SpectraMax
M5), with excitation and emission wavelengths set at 360 nm and 460 nm, respectively.
The inhibition of DPP-IV activity by test compounds was routinely performed by
preincubating the enzyme with test compound (10 and 100 nM for primary screening and 8
concentrations from 0.1 to 1000 nM for the dose-response study) or vehicle (0.01 % DMSO)
for 15 min at 30°C, in a total volume of 90 µl. Test compounds were dissolved in DMSO at a
concentration of 10 mM and serially diluted further in assay buffer. The enzyme reaction was
initiated by the addition of Gly-Pro-AMC, followed by incubation of assay plates for 30 min at
30°C and the liberated AMC was measured as described above. A known inhibitor of DPP-
IV (positive control) was always included in the assay. Test compounds at various
concentrations were always evaluated in duplicate, along with substrate blanks, vehicle
controls and positive controls.
The results are expressed as percent inhibition of the enzyme activity relative to vehicle
controls. Dose-response studies were conducted for those compounds exerting = 50%
inhibition of activity at 10 nM in primary screening. IC50 defined as the inhibitor concentration
which caused a 50% decrease of the activity under assay conditions, was computed using
GraphPad Prism software, version 5.0.
The DPP-IV inhibition data (expressed either as IC50 in nanomolar or percent inhibition at a
particular compound concentration) is presented in Table 1.
Table 1 Inhibition of human recombinant DPP-IV

Demonstration of In Vivo Efficacy of Test Compounds
A. Measurement of Plasma DPP-IV Activity in Male Wistar Rats
Overnight-fasted male animals were administered either vehicle or single oral doses of
compounds. Blood samples were withdrawn from retro-bulbar venous plexus under
anesthesia at several time points up to 24 h post-dose. EDTA-plasma was separated and
DPP-IV activity was measured using a fluorometric assay. Assays were carried out in 96-
well flat-bottom black microwell plates. A typical reaction contained 25 µl plasma, 50 µl of 50
µM substrate (Gly-Pro-AMC) and 25 µl assay buffer (25 mM Tris-HCI, pH 7.4, 140 mM NaCI,
10 mM KCI and 1% BSA) in a total reaction volume of 100 ul. Plasma samples were
incubated with the substrate for 30 min at 30°C, following which the fluorescence was
measured in a microplate fluorescence redaer (POLARstar Galaxy), with excitation and
emission wavelengths set at 360 nm and 460 nm, respectively. Percent inhibition in plasma
DPP-IV activity due to compounds was calculated by comparing with plasma from vehicle-
treated animals.
Table 2 shows the ability of selected test compounds to produce inhibition of plasma DPP-IV
in Wistar rats.
Table 2 Inhibition of plasma DPP-IV activity in Wistar rats

B. Oral Glucose Tolerance Test in Male C57BL/6J Mice
Overnight-fasted male C67BL/6J mice were challenged 1 h, 4 h and 8 h after either vehicle
or compound administration with an oral glucose load of 5 g/kg in three different groups of
animals. Blood samples for glucose measurement were obtained by tail bleed at predose,
before glucose load and at serial time points after the glucose load, to evaluate the efficacy
and duration of effect on glucose tolerance test. Glucose excursion profile from r=0 to t=120
minutes was used to integrate an area under the curve (AUC) for each treatment.
Improvement in glucose tolerance in compound- treated animals was estimated by
comparing with vehicle-treated animals.
Table 3 provides data for the antihyperglycemic activity of selected compounds in C57BL/6J
mice, as determined by oral glucose tolerance test.
Table 3 Effect of DPP-IV inhibitors on OGTT in C57BL/6J mice

WE CLAIM:
1. Compounds of the general formula A in exo configuration,

their optical isomers and pharmaceutically acceptable salts thereof, wherein,
n = 1,2
Y is selected from the groups

wherein, Z represents CH2, -S-, CHF;
R1 is selected from groups consisting of
i) Hydrogen;
ii) C1-C8alkyl (straight or branched) substituted with 1 to 3 substituents selected
from halogens, such as pentyl, trifluoropropyl;
iii) cycloalkyl or cycloalkenyl having 3-10 carbon atoms such as cyclohexyl or
cyclohex-2-enyl;
iv) cycloalkylmethyl having 4-10 carbon atoms such as cyclohexyl methyl;
v) Bridged polycycloalkyl methyl having 5 to 12 carbon atoms such as
adamantyl methyl;
vi) phenyl which is unsubstituted or substituted with 1-3 substituents each
independently selected from cyano or methanesulfonyl;
vii) aralkyl group such as benzyl which is unsubstituted or substituted with 1 to 3
substituents selected from halogens;
viii) heteroaryl group such as pyridyl substituted with cyano;
ix) heteroaralkyl group such as pyridyl methyl;
x) aralkoxyalkyl group such as benzyloxy ethyl;
xi) SO2R5; where R5 is methyl, thiophenyl, or phenyl unsubstituted or substituted
with 1 to 3 fluoro;
xii) -CONHR6 or -CSNHR6 or -CONHSO2R6; where R6 is phenyl unsubstituted or
substituted with chloro, fluoro, trifluoromethyl or methoxy;
xiii) R7CO-, wherein R7 is selected from
a. unsubstituted phenyl or substituted with 1 to 3 substituents selected from
halogen, trifluoromethyl, cyano;
b. benzo[1,3]dioxolyl;
c. adamantyl;
d. heteroaryl such as thiophenyl; furyl; pyrazinyl; pyridyl unsubstituted or
substituted with a substituent selected from halogen, cyano, methyl,
benzyloxy;
e. N-acetylpiperidinyl;
f. Cyclohexyl;
g. Pyridine methyl;
R2 is selected from hydrogen, CN, COOH, or isosteres of COOH, wherein said
isosteres of COOH are selected from the groups consisting of esters, tetrazole, acid
anhydrides, CH2OH, CH2OBn, CONHOH, CONH2;
R3 is selected from hydrogen, -CN, C2-C5alkynyl;
R4 is selected from hydrogen or fluoro.
2. A compound its stereoisomers, racemates, pharmaceutically acceptable salts thereof
as claimed in claim 1 wherein the compound of the general formula (A) is selected
from
(2S)-1-{(2S)-2- Amino-2-[8-(2,4,5-trifluorobenzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-
ethanoyl}-pyrrolidin-2- carbonitrile trifluoroacetic acid salt;
(2S)-1-{(2S)-2- Amino-2-[8-(4-trifluoromethylbenzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-
exo-ethanoyl}-pyrrolidin-2- carbonitrile trifluoroacetic acid salt;
(2S)-1-{(2S)-2- Amino-2-[8-(adamantane-1 -carbonyl)-8-aza-bicyclo[3.2.1 ]oct-3-yl]-
exo-ethanoyl}-pyrrolidin-2- carbonitrile trifluoroacetic acid salt;
(2S)-1-{(2S)-2- Amino-2-[8-(pyridine-4-carbonyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-
ethanoyl}-pyrrolidin-2- carbonitrile trifluoroacetic acid salt;
(2S)-1-{(2S)-2- Amino-2-[8-(4-cyano-benzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-
ethanoyl}-pyrrolidin-2- carbonitrile trifluoroacetic acid salt;
(2S)-1-{(2S)-2- Amino-2-[8-(2,5-difluorobenzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-
ethanoyl}-pyrrolidin-2- carbonitrile trifluoroacetic acid salt;
(2S)-1-{(2S)-2- Amino-2-[8-(2-fluoro-pyridine-4-carbonyl)-8-aza-bicyclo[3.2.1]oct-3-
yl]-exo-ethanoyl}-pyrrolidin-2- carbonitrile trifluoroacetic acid salt;
(2S)-1 -[(2S)-2-Amino-2-(8-aza-bicyclo[3.2.1 ]oct-3-yl)-exo-ethanoyl]-pyrrolidin-2-
carbonitrile trifluoroacetic acid salt;
(2S)-1-{(2S)-2- Amino-2-[8-(2,4,5-trifluorobenzyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-
ethanoyl}-pyrrolidin-2- carbonitrile trifluoroacetic acid salt;
Methyl-(2S)-1-{(2S)-2- amino-2-[8-(4-trifluoromethyl-benzoyl)-8-aza-bicyclo[3.2.1]-
oct-3-yl]-exo-ethanoyl}-pyrrolidin-2- carboxylate trifluoroacetic acid salt;
(2S)-1-{(2S)-2- amino-2-[8-(4-trifluoromethyl-benzoyl)-8-aza-bicyclo[3.2.1 ]-oct-3-yl]-
exo-ethanoyl}-pyrrolidin-2- carboxylic acid trifluoroacetic acid salt;
(2S)-1-{(2S)-2- amino-2-[8-(4-trifluoromethyl-benzoyl)-8-aza-bicyclo[3.2.1]-oct-3-yl]-
exo-ethanoyl}-pyrrolidin-2- carboxamide trifluoroacetic acid salt;
(2S)-1-{(2S)-2-Amino-2- [8-(4-trifluromethyl-benzoyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-
exo-ethanoyl}-2-(2H-tetrazol-5-yl) pyrrolidine hydrochloride;
(2S)-{(2S)-1-[(2S)-2-Amino-2-(8-(benzo [1,3] dioxole -5-carbonyl)-8-aza-bicyclo
[3.2.1]-oct-3-yl)-exo-acetyl]-pyrrolidin-2- yl} methanol trifluoroacetic acid salt;
(2S, 4S)-1-{ (2S)-2-Amino-2-[8-(4-trifluoromethylbenzoyl)-8-aza-bicyclo[3.2.1]oct-3-
yl]-exo-ethanoyl}-4-fluoro-pyrrolidin-2- carbonitrile hydrochloride salt;
(2S, 4S)-1-{ (2S)-2- Amino-2-[8-(2,4,5-trifluorobenzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-
exo-ethanoyl}-4-fluoro-pyrrolidin-2- carbonitrile trifluoroacetic acid salt;
(2S, 4S)-1-{ (2S)-2- Amino-2-[8-(2,5-difluorobenzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-
exo-ethanoyl}-4-fluoro-pyrrolidin-2- carbonitrile trifluoroacetic acid salt;
Benzyl-(2S,5R)-1-{(2S)-2- amino-2-[8-(4-trifluoromethyl-benzoyl)-8-aza-
bicyclo[3.2.1]-oct-3-yl]-exo-ethanoyl}-5-cyano pyrrolidin-2- carboxylate trifluoroacetic
acid salt;
(2S, 4S)-1-{(2S)-2- Amino-2-[8-(2,4,5-trifluorobenzyl)-8-aza-bicyclo[3.2.1 ]oct-3-yl]-
exo-ethanoyl}-4-fluoro-pyrrolidin-2- carbonitrile trifluoroacetic acid salt;
(4S)-3-{(2S)-2- Amino-2-[8-(4-trifluoromethylbenzoyl)-8-aza-bicyclo[3.2.1 ]oct-3-yl]-
exo-ethanoyl}-thiazolidine-4- carbonitrile trifluoroacetic acid salt;
3-{(2S)-2- Amino-2-[8-(4-trifluoromethylbenzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-
ethanoyl}-1,3-thiazolidine trifluoroacetic acid salt;
(2S)-1-{(2S)-2- Amino-2-[8-(4-trifluoromethyl phenyl carbamoyl)-8-aza-bicyclo[3.2.1]
oct-3-yl]-exo-ethanoyl}-pyrrolidin-2- carbonitrile trifluoroacetic acid salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(2,4,5-trifluorobenzoyl)-8-aza-bicyclo [3.2.1]oct-3-
yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(4-cyanobenzoyl)-8-aza-bicyclo [3.2.1]oct-3-yl]-
exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(pyridine-4-carbonyl)-8-aza-bicyclo [3.2.1]oct-3-
yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(4-trifluoromethylbenzoyl)-8-aza-bicyclo [3.2.1]oct-
3-yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid
salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(2,5-difluorobenzoyl)-8-aza-bicyclo [3.2.1]oct-3-yl]-
exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(2-fluoropyridine-4-carbonyl)-8-aza-bicyclo [3.2.1]
oct-3-yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid
salt;
(1R, 3R, 5R)-2-{(2S)-2-Amino-2-[8-(2-fluoropyridine-4-carbonyl)-8-aza-bicyclo [3.2.1]
oct-3-yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid
salt;
(1R, 3R, 5R)-2-{(2R)-2-Amino-2-[8-(2-fluoropyridine-4-carbonyl)-8-aza-bicyclo [3.2.1]
oct-3-yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid
salt;
(1S, 3S, 5S)-2-{(2R)-2-Amino-2-[8-(2-fluoropyridine-4-carbonyl)-8-aza-bicyclo [3.2.1]
oct-3-yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid
salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(2-fluoropyridine-3-carbonyl)-8-aza-bicyclo [3.2.1]
oct-3-yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid
salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(pyridine-3-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-
yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(thiophene-2-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-
yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(pyrazine-2-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-
yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt;
(1S, 3S, 5S)-2-{(2R)-2-Amino-2-[8-(pyrazine-2-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-
yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt;
(1R, 3R, 5R)-2-{(2S)-2-Amino-2-[8-(pyrazine-2-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-
yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt;
(1R, 3R, 5R)-2-{(2R)-2-Amino-2-[8-(pyrazine-2-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-
yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(pyridine-2-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-
yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(furan-2-carbonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-
exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(3-fluoropyridine-4-carbonyl)-8-aza-bicyclo [3.2.1]
oct-3-yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid
salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(3,5-difluorobenzene sulfonyl )-8-aza-bicyclo
[3.2.1] oct-3-yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile
trifluoroacetic acid salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(adamantane-1-carbonyl )-8-aza-bicyclo [3.2.1]
oct-3-yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid
salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(benzo[1,3]dioxole-5-carbonyl)-8-aza-bicyclo
[3.2.1] oct-3-yl]-exo-ethanoyl}-2-azabicyclo [3.1.0]-hexane -3- carbonitrile
trifluoroacetic acid salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(benzo [1,3]-dioxole-5-carbonyl)-8-aza-bicyclo
[3.2.1] oct-3-yl]-exo-ethanoyl}-2-azabicyclo [3.1.0]-hexane -3- carboxamide
trifluoroacetic acid salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(benzo [1,3]-dioxole-5-carbonyl)-8-aza-bicyclo
[3.2.1] oct-3-yl]-exo-ethanoyl}-2-azabicyclo [3.1.0]-hexane -3- carboxylic acid
hydrochloride;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(3,3,3-trifluoro propyl )-8-aza-bicyclo [3.2.1] oct-3-
yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt;
(1S, 3S, 5S)-2-{ (2S)-2-Amino-2-[8-(cyclohexyl methyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-
exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(adamantan-1-yl methyl )-8-aza-bicyclo [3.2.1]
oct-3-yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid
salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(benzyloxy-ethyl )-8-aza-bicyclo [3.2.1] oct-3-yl]-
exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(5-cyanopyridine-2-yl)-8-aza-bicyclo [3.2.1] oct-3-
yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(4-cyano-phenyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-
exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoro acetic acid salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(4-methanesulfonyl phenyl)-8-aza-bicyclo [3.2.1]
oct-3-yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid
salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(2-pyridin-4-yl-acetyl)-8-aza-bicyclo [3.2.1] oct-3-
yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(pyridine-4ylmethyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-
exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(methanesulfonyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-
exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(thiophene-2-sulfonyl)-8-aza-bicyclo [3.2.1] oct-3-
yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(cyclohexane-carbonyl)-8-aza-bicyclo [3.2.1] oct-
3-yl]-exo-ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid
salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(1-ethyl-propyl)-8-aza-bicyclo [3.2.1] oct-3-yl]-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-(8-cyclohexyl-8-aza-bicyclo [3.2.1] oct-3-yl)-exo-
ethanoyl}-2-azabicyclo [3.1.0] hexane -3- carbonitrile trifluoroacetic acid salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(4-chlorophenylsulfonylcarbamoyl)-8-aza-bicyclo
[3.2.1]oct-3-yl]-exo-ethanoyl}-2-azabicyclo[3.1.0] hexane -3-carbonitrile
trifluoroacetic acid salt;
{(2S)-2-Amino-2-[8-(3-fluoro-pyridine-4-carbonyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-
ethanoyl}-3-fluoro-azetidine trifluoroacetic acid salt;
(2S, 5R) - 1- {(2S)-2- Amino-2- [8-(4-trifluoromethyl-benzoyl)- 8-aza- bicyclo [3.2.1]
oct-3-yl]-exo-ethanoyl} -5-ethynyl -pyrrolidin-2-carbonitrile trifluoro acetic acid salt;
(2S, 5R)-1-{(2S)-2-Amino-2-[8-(pyridin-4-carbonyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-exo-
ethanoyl}-5-ethynyl-pyrrolidin-2-carbonitrile trifluoroacetic acid salt;
(2S, 5R)-1-{(2S)-2-Amino-2-[8-(3-fluoropyridin-4-carbonyl)-8-aza-bicyclo[3.2.1]oct-3-
yl]-exo-ethanoyl}-5-ethynyl-pyrrolidin-2-carbonitrile trifluoroacetic acid salt;
(2S, 5R)-1-{(2S)-2-Amino-2- [8-(2-fluoropyridin-4-carbonyl)- 8-aza- bicyclo [3.2.1]-
oct-3-yl]-exo-ethanoyl}-5-ethynyl-pyrrolidin-2-carbonitrile trifluoroacetic acid salt;
(2S, 5R)-1-{(2S)-2-Amino-2-[8-(benzo[1,3]dioxole-5-carbonyl)-8-aza-bicyclo [3.2.1]
oct-3-yl]-exo-ethanoyl}-5-ethynyl-pyrrolidin-2-carbonitrile trifluoroacetic acid salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(2-methoxyphenylthiocarbamoyl)-8-aza-bicyclo
[3.2.1]oct-3-yl]-exo-ethanoyl}-2-azabicyclo[3.1.0] hexane -3-carbonitrile
trifluoroacetic acid salt;
(1S, 3S, 5S)-2-{(2S)-2-Amino-2-[8-(1-acetyl-piperidine-4-carbonyl)-8-aza-bicyclo
[3.2.1]oct-3-yl]-exo-ethanoyl}-2-azabicyclo[3.1.0] hexane -3-carbonitrile
trifluoroacetic acid salt;
(2S)-1-{2- Amino-2- [9-(4-trifluoromethyl-benzoyl)-9-azabiacyclo [3.3.1] non-3-yl]-
exo-ethanoyl}-pyrrolidin-2-carbonitrile trifluoro acetic acid salt and its diastereomers.
3. A process for preparation of a compound of formula (A),

their optical isomers and pharmaceutically acceptable salts thereof, wherein,
n = 1,2
Y is selected from the groups

wherein, Z represents CH2, -S-, CHF;
R1 is selected from groups consisting of
i) Hydrogen;
ii) C1-C8alkyl (straight or branched) substituted with 1 to 3 substituents selected
from halogens, such as pentyl, trifluoropropyl;
iii) cycloalkyl or cycloalkenyl having 3-10 carbon atoms such as cyclohexyl or
cyclohex-2-enyl;
iv) cycloalkylmethyl having 4-10 carbon atoms such as cyclohexyl methyl;
v) Bridged polycycloalkyl methyl having 5 to 12 carbon atoms such as
adamantyl methyl;
vi) phenyl which is unsubstituted or substituted with 1-3 substituents each
independently selected from cyano or methanesulfonyl;
vii) aralkyl group such as benzyl which is unsubstituted or substituted with 1 to 3
substituents selected from halogens;
viii) heteroaryl group such as pyridyl substituted with cyano;
ix) heteroaralkyl group such as pyridyl methyl;
x) aralkoxyalkyl group such as benzyloxy ethyl;
xi) SO2R5; where R5 is methyl, thiophenyl, or phenyl unsubstituted or substituted
with 1 to 3 fluoro;
xii) -CONHR6 or -CSNHR6 or -CONHSO2R6; where R6 is phenyl unsubstituted or
substituted with chloro, fluoro, trifluoromethyl or methoxy;
xiii) R7CO-, wherein R7 is selected from
a. unsubstituted phenyl or substituted with 1 to 3 substituents selected from
halogen, trifluoromethyl, cyano;
b. benzo[1,3]dioxolyl;
c. adamantyl;
d. heteroaryl such as thiophenyl; furyl; pyrazinyl; pyridyl unsubstituted or
substituted with a substituent selected from halogen, cyano, methyl,
benzyloxy;
e. N-acetylpiperidinyl;
f. Cyclohexyl;
g. Pyridine methyl;
R2 is selected from hydrogen, CN, COOH, or isosteres of COOH, wherein said
isosteres of COOH are selected from the groups consisting of esters, tetrazole, acid
anhydrides, CH2OH, CH2OBn, CONHOH, CONH2;
R3 is selected from hydrogen, -CN, C2-C5alkynyl;
R4 is selected from hydrogen or fluoro;
which comprises the steps of:
(a) reaction of a compound of formula (VIII) or (XIX) or optical isomers thereof,

(n = 1: compound VIII, n = 2: compound XIX)
R1 is selected from groups consisting of
i) C1-C8alkyl (straight or branched) substituted with 1 to 3 substituents selected
from halogens, such as pentyl, trifluoropropyl;
ii) Cycloalkyl or cycloalkenyl having 3-10 carbon atoms such as cyclohexyl or
cyclohex-2-enyl;
iii) cycloalkylmethyl having 4-10 carbon atoms such as cyclohexyl methyl;
iv) Bridged polycycloalkyl methyl having 5 to 12 carbon atoms such as
adamantyl methyl;
v) phenyl which is unsubstituted or substituted with 1-3 substituents each
independently selected from cyano or methanesulfonyl;
vi) aralkyl group such as benzyl which is unsubstituted or substituted with 1 to 3
substituents selected from halogens;
vii) heteroaryl group such as pyridyl substituted with cyano;
viii) heteroaralkyl group such as pyridyl methyl;
ix) aralkoxyalkyl group such as benzyloxy ethyl;
x) SO2R5; where R5 Is methyl, thiophenyl, or phenyl unsubstituted or substituted
with 1 to 3 fluoro;
xi) -CONHR6 or -CSNHR6 or -CONHSO2R6; where R6 is phenyl unsubstituted or
substituted with chloro, fluoro, trifluoromethyl or methoxy;
xii) R7CO-, wherein R7 is selected from
a. unsubstituted phenyl or substituted with 1 to 3 substituents selected from
halogen, trifluoromethyl, cyano;
b. benzo[1,3]dioxolyl;
c. adamantyl;
d. heteroaryl such as thiophenyl; furyl; pyrazinyl; pyridyl unsubstituted or
substituted with a substituent selected from halogen, cyano, methyl,
benzyloxy;
e. N-acetylpiperidinyl;
f. Cyclohexyl;
g. Pyridine methyl;
n is 1 or 2;
with a compound of formula Y-H or optical isomers thereof, wherein Y is selected from
the fragments of formula

wherein, Z represents CH2, -S-, CHF;
R2 is selected from hydrogen, CN, COOH, or isosteres of COOH, wherein said isosteres
of COOH are selected from the groups consisting of esters, tetrazole, acid anhydrides,
CH2OH, CH2OBn, CONHOH, CONH2;
R3 is selected from hydrogen, -CN, C2-C5alkynyl;
R4 is selected from hydrogen or fluoro;
under standard peptide coupling conditions using EDCI, dicyclohexyl carbodiimide,
HOBT and base such as triethyl amine or diisopropylethyl amine in a solvent such as
N,N-dimethylformamide at the temperature ranging between about 0 and 35°C; isolation
of the product formed using standard techniques; and purification using suitable organic
solvent;
wherein,
if R2 is -CONH2, then -CONH2 group is converted to -CN by treatment of
dehydrating agent such as POCI3;
if R2 is -COOH , then such group is converted to -CN by converting it to -
CONH2 and then treating the said amide with dehydrating agent such as
POCI3;
if R2 is -CN, then -CN group is converted to tetrazole by treatment with
sodium azide or organic azides;
(b) deprotection using suitable reagent such as trifluoroacetic acid in suitable solvent
such as dichloromethane at a temperature between 0 and 30°C.
wherein,
if R1 is tert-butyl carbonyl group, the said group is converted to -H by
hydrolysis using agent such as trifluoroacetic acid;
if any of the reactants is in racemic form, the resultant product can be
enriched to required stereoisomer by suitable method like column
chromatography, fractional crystallization or salt formation at suitable step (a)
or (b).
4. A process as claimed in claim 3, wherein 2S isomer of compound of formula VIII, is
prepared from 3-Hydroxymethyl-8-methyl-8-aza-bicyclo [3.2.1] octane-3-ol (I)
comprising steps of
(a) conversion of 3-Hydroxymethyl-8-methyl-8-aza-bicyclo [3.2.1] octane-3-ol (I) to 1-
(2-Hydroxy-1-(1R)-phenylethyl amino)-1-(8-methyl-8-aza-bicyclo[3.2.1]-oct-3-yl)-
exo-methane-1- (1S)-carbonitrile (II) comprising treatment of sulphuric acid
followed by reaction with (R) phenyl glycinol and potassium cyanide followed by
diastereomer separation;

(b) conversion of compound of formula II to (2S)-2-Amino-(8-methyl-8-aza-
bicyclo[3.2.1]oct-3-yl)-exo-acetic acid dihydrochloride (III) comprising first
hydrolyzing cyano group to carboxylic acid using hydrochloric acid and then
hydrogenating it in presence of palladium hydroxide at suitable pressure of
hydrogen such as 80 to 100 psi;

(c) conversion of compound of formula III to Methyl (2S)-2- (1,3-dioxo-1,3-
dihydroisoindol-2-yl)-2-(8-methyl-8-aza-bicyclo[3.2.1 ]-oct-3-yl)-exo-acetate (IV)
comprising refluxing compound III in methanol with continuous purging of
hydrogen chloride gas to yield Methyl (2S)-2-amino-2-(8-methyl-8-aza-
bicyclo[3.2.1]-oct-3-yl)- exo-acetate, followed by protection of amino group with
phthalimido group in presence of base such as triethylamine;

(d) conversion of compound of formula IV to Methyl-(2S)-2-(1-hydroxy-3-oxo-1,3-
dihydroisoindol-2-yl)-2-[8-aza-bicyclo[3.2.1]-oct-3-yl]-exo-acetate (V) comprising
treatment with trichloroethyl chloroformate to yield Methyl-(2S)-2-(1,3-dioxo-1,3-
dihydroisoindol-2-yl)-2-[8-(2,2,2-trichloro-ethyloxy carbonyl)-8-aza-bicyclo[3.2.1]-
oct-3-yl]-exo-acetate, followed by treatment of zinc metal in acetic acid;

(e) conversion of compound of formula V to Methyl (2S)-2-(1,3dioxo-1,3-
dihydroisoindol-2-yl)-2-[8-(carbobenzyloxy)-8-aza- bicyclo[3.2.1 ]-oct-3-yl ]-exo-
acetate (VI) comprising treatment with benzyl chloroformate in presence of a
base such as sodium bicarbonate to yield Methyl-(2S)-2-(1-hydroxy- 3-oxo-1,3-
dihydroisoindol-2-yl)-2-[8-(carbobenzyl oxy)-8-aza-bicyclo[3.2.1]-oct-3-yl ]-exo-
acetate, followed by Jones oxidation;

(f) conversion of compound of formula VI to Methyl-(2S)-2-(tert-butoxycarbonyl)-
amino-2-[8-(carbobenzyloxy)-8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-acetate (VII)
comprising deprotection with hydrazine hydrate to yield Methyl-(2S)-2-amino-2-
[8-(carbobenzyloxy)-8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-acetate, followed by
protection with tert-butoxy carbonyl;

(g) conversion of compound of formula VII to Vlll comprising deprotection followed
by condensation with either R1L, wherein L is a leaving group such as halogen or
hydroxy, R1 is selected from it's definitions 'ii' to 'xi' and 'xiii' for compound of
formula 'A'; or with R6N=C=O or R6N=C=S or R6SO2N=C=O in case of R1 is
selected from definition 'xii' for compound of formula 'A', wherein R6 is selected
from phenyl unsubstituted or substituted with chloro, fluoro, trifluoromethyl or
methoxy;

wherein,
if R1 is cyclohex-2-enyl group, then such group is converted to cyclohexyl by
catalytic hydrogenation;
If R1 is adamantane carbonyl, then such group is converted to adamantane
methyl by suitable reduction method;
such that,
at each step the product is optionally isolated and purified by standard techniques;
5. A process as claimed in claim 4, wherein 2R isomer of compound of formula VIII,
wherein, n = 1, is prepared from 3-Hydroxymethyl-8-methyl-8-aza-bicyclo [3.2.1]
octane-3-ol (I) by replacing (R) phenyl glycinol with (S)-phenyl glycinol.
6. A process as claimed in claim 4, wherein racemate (2RS) of compound of formula
VIM, wherein, n = 1, is prepared from 3-Hydroxymethyl-8-methyl-8-aza-bicyclo [3.2.1]
octane-3-ol (I) by replacing (R) phenyl glycinol with (RS)-phenyl glycinol and
skipping the step of diastereomer separation.
7. A process as claimed in claim 3, wherein compound of formula VIII or its optical
isomers, wherein, n = 1, is prepared from compound of formula V comprising steps
of
(a) conversion of compound of formula V to IX comprising condensation with either
R1L, wherein L is a leaving group such as halogen or hydroxy, R1 is selected
from it's definitions (v), (vi), (viii), (xi) and (xiii) for compound of formula 'A', or
with R6N=C=O or R6N=C=S or R6SO2N=C=O in case of R1 is selected from
definition 'xii' for compound of formula 'A', wherein R6 is selected from phenyl
unsubstituted or substituted with chloro, fluoro, trifluoromethyl or methoxy;
followed by Jones oxidation;

(b) conversion of compound of formula IX to X comprising treatment with hydrazine
hydrate in methanol followed by hydrolysis in presence of sodiumcarbonate in
methanol and water;

(c) conversion of compound of formula X to VIII comprising protection with tert-
butyloxy carbonyl in presence of inorganic base such as potassiumcarbonate in
aprotic polar solvent like N,N-dimethylformamide;

such that,
at each step the product was optionally isolated and purified by standard
techniques;
8. A process as claimed in claim 3, wherein compound of formula XIX, is prepared from
3-oxo-9-aza-bicyclo [3.3.1] nonane-9-carboxylic acid ethyl ester (XIII) comprising
steps of
(a) conversion of 3-oxo-9-aza-bicyclo [3.3.1] nonane-9-carboxylic acid ethyl ester
(XIII) to 9-(Ethoxy carbonyl)-3-exo-benzyl-9-aza-bicyclo [3.3.1] non-3-yl methyl
oxalate (XIV) comprising treatment with benzyl magnesium halide under
Grignard condition and reaction of the product formed with methyl oxalate in a
solvent such as dichloromethane in presence of bases such as pyridine, 2,6-
lutidine or 4-dimethylaminopyridine;

(b) conversion of compound of formula XIV to [9-(Ethoxycarbonyl)-9-azabicyclo
[3.3.1] -non-3yl] acetic acid (XV) comprising first treatment with tributyl tin hydride
or tris (trimethyl silyl) silane and 2,2'-azobis (2-methyl propionitrile) in a solvent
such as toluene, or refluxing compound of formula XIV with dialkyl phosphite and
a radical initiator such as benzoyl peroxide in toluene, and further treatment of
the resultant product with ruthenium trichloride and periodic acid in a solvent
such as carbon tetrachloride, acetonitrile or mixture thereof;

(c) conversion of compound of formula XV to Methyl -9-azabicyclo [3.3.1]-non-3-yl -
acetate (XVI) comprising hydrolysis using hydrochloric acid and further treatment
of the resultant product with methanol and sulfuric acid;

(d) conversion of compound of formula XVI to compound of formula XVII comprising
condensation with either R1L, wherein L is a leaving group such as halogen or
hydroxy, R1 is selected from definitions 'ii' to 'vi', viii, x and 'xiii' for compound of
formula 'A'; or with R6N=C=O or R6SO2N=C=O in case of R1 is selected from
definition 'xii' for compound of formula 'A', wherein R6 is selected from phenyl
unsubstituted or substituted with chloro, fluoro, trifluoromethyl or methoxy; and
further treatment of the resultant product with lithium diisopropylamide and di-
tert-butyl-diazine-1,2-dicarboxylate in solvent such as tetrahydrofuran;

(e) conversion of compound of formula XVII to compound of formula XVIII
comprising treatment with trifluoro acetic acid in a suitable solvent such as
dichloromethane, and further hydrogenation of the resultant product using
suitable catalyst such as Raney Nickel;

(f) conversion of compound of formula XVIII to compound of formula XIX comprising
treatment of compound of formula XVIII with di-tert-butyl dicarbonate in presence
of base such as triethyl amine in solvent such as dichloromethane followed by
ester hydrolysis of the resultant product using suitable reagent;

wherein,
if R1 is cyclohex-2-enyl group, then such group is converted to cyclohexyl by
catalytic hydrogenation;
If R1 is adamantane carbonyl, then such group is converted to adamantane
methyl by suitable reduction method;
such that,
at each step the product is optionally isolated and purified by standard
techniques.
9. A process as claimed in claim 8, wherein compound of formula XIX is prepared in
exo configuration by isolating the exo conformer of compound of formula XVI of step
(c) and proceeding ahead for steps (d), (e) and (f) with the pure exo confirmer.
10. A process as claimed in claim 8, wherein compound of formula XIX is prepared in
endo configuration by isolating the endo conformer of compound of formula XVI of
step (c) and proceeding ahead for steps (d), (e) and (f) with the pure endo confirmer.
11. Compounds of the general formula

in exo configuration, their methyl esters and optical isomers thereof, wherein,
n = 1 (compound VIII), 2 (compound XIX)
R1 is selected from groups consisting of
i) C1-C8alkyl (straight or branched) substituted with 1 to 3 substituents selected
from halogens, such as pentyl, trifluoropropyl.
ii) cycloalkyl having 3-10 carbon atoms such as cyclohexyl;
iii) cycloalkylmethyl having 4-10 carbon atoms such as cyclohexyl methyl;
iv) Bridged polycycloalkyl methyl having 5 to 12 carbon atoms such as
adamantyl methyl;
v) phenyl which is unsubstituted or substituted with 1-3 substituents each
independently selected from cyano or methanesulfonyl;
vi) aralkyl group such as benzyl which is unsubstituted or substituted with 1 to 3
substituents selected from halogens;
vii) heteroaryl group such as pyridyl substituted with cyano;
viii) heteroaralkyl group such as pyridyl methyl;
ix) aralkoxyalkyl group such as benzyloxy ethyl;
x) SO2R5; where R5 is methyl, thiophenyl, or phenyl unsubstituted or substituted
with 1 to 3 fluoro;
xi) -CONHR6 or -CSNHR6 or -CONHSO2R6; where R6 is phenyl unsubstituted or
substituted with chloro, fluoro, trifluoromethyl or methoxy;
xii) R7CO-, wherein R7 is selected from
a. unsubstituted phenyl or substituted with 1 to 3 substituents selected from
halogen, trifluoromethyl, cyano;
b. benzo[1,3]dioxolyl;
c. adamantyl;
d. heteroaryl such as thiophenyl; furyl; pyrazinyl; pyridyl unsubstituted or
substituted with a substituent selected from halogen, cyano, methyl,
benzyloxy;
e. N-acetylpiperidinyl;
f. Cyclohexyl;
g. Pyridine methyl;
12. A compound its stereoisomers, racemates, methylesters thereof as claimed in claim
11, wherein, the compound of the general formula VIII is selected from
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(2,4,5-trifluorobenzoyl)-8-aza-bicyclo [3.2.1]-
oct-3-yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(4-trifluoromethylbenzoyl)-8-aza-bicyclo
[3.2.1]-oct-3-yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(adamantane-1-carbonyl)-8-aza-bicyclo
[3.2.1 ]-oct-3-yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(pyridine-4-carbonyl)-8-aza-bicyclo [3.2.1]-oct-
3-yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(4-cyano-benzoyl)-8-aza-bicyclo [3.2.1]-oct-3-
yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(2,5-difluorobenzoyl)-8-aza-bicyclo[3.2.1]-oct-
3-yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(2-fluoropyridine-4-carbonyl)-8-aza-bicyclo
[3.2.1]-oct-3-yl]-exo-ethanoic acid;
(2R)-2-(tert-Butoxycarbonyl)-amino-2-[8-(2-fluoropyridin-4-carbonyl)-8-aza-bicyclo
[3.2.1 ]-oct-3-yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(2,4,5-trifluorobenzyl)-8-aza-bicyclo [3.2.1 ]-
oct-3-yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(cyclohexylmethyl)-8-aza-bicyclo [3.2.1 ]-oct-3-
yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(4-trifluoromethyl-phenyl carbamoyl)-8-aza-
bicyclo [3.2.1]-oct-3-yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(2-fluoropyridine-3-carbonyl)-8-aza-bicyclo
[3.2.1 ]-oct-3-yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(pyridine-3-carbonyl)-8-aza-bicyclo [3.2.1]-oct-
3-yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(thiophene-2-carbonyl)-8-aza-bicyclo [3.2.1]-
oct-3-yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(pyrazine-2-carbonyl)-8-aza-bicyclo [3.2.1]-
oct-3-yl]-exo-ethanoic acid;
(2R)-2-(tert-Butoxycarbonyl)-amino-2-[8-(pyrazine-2-carbonyl)-8-aza-bicyclo [3.2.1]-
oct-3-yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(pyridine-2-carbonyl)-8-aza-bicyclo [3.2.1]-oct-
3-yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(furan-2-carbonyl)-8-aza-bicyclo [3.2.1]-oct-3-
yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(3-fluoropyridine-4-carbonyl)-8-aza-bicyclo
[3.2.1 ]-oct-3-yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(3,5-difluorobenzene sulfonyl)-8-aza-bicyclo
[3.2.1]-oct-3-yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(benzo[1,3]dioxole-5-carbonyl)-8-aza-bicyclo
[3.2.1 ]-oct-3-yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(3,3,3-trifluoro propyl)-8-aza-bicyclo [3.2.1 ]-
oct-3-yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(benzyloxy-ethyl)-8-aza-bicyclo [3.2.1]-oct-3-
yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(5-cyanopyridin-2-yl)-8-aza-bicyclo [3.2.1]-
oct-3-yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(4-cyano-phenyl)-8-aza-bicyclo [3.2.1]-oct-3-
yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(4-methanesulfonyl phenyl)-8-aza-bicyclo
[3.2.1 ]-oct-3-yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(2-pyridin-4-yl-acetyl)-8-aza-bicyclo [3.2.1 ]-
oct-3-yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(pyridin-4-yl-methyl)-8-aza-bicyclo [3.2.1]-oct-
3-yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(methanesulfonyl)-8-aza-bicyclo [3.2.1 ]-oct-3-
yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(thiophene-2-sulfonyl)-8-aza-bicyclo [3.2.1]-
oct-3-yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(cyclohexane-carbonyl)-8-aza-bicyclo [3.2.1 ]-
oct-3-yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(1-ethyl-propyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-
exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(cyclohexyl)-8-aza-bicyclo [3.2.1 ]-oct-3-yl]-
exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(4-chlorophenylsulfonyl-carbamoyl)-8-aza-
bicyclo [3.2.1]-oct-3-yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(2-methoxyphenyl-thio-carbamoyl)-8-aza-
bicyclo [3.2.1]-oct-3-yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(1-acetyl-piperidine-4-carbonyl)-8-aza-bicyclo
[3.2.1 ]-oct-3-yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-(adamantan-1-yl- methyl)-8-aza-bicyclo
[3.2.1 ]-oct-3-yl]-exo-ethanoic acid;
(2S)-2-(tert-Butoxycarbonyl)-amino-2-[8-( tert-butoxycarbonyl)-8-aza-bicyclo [3.2.1 ]-
oct-3-yl]-exo-ethanoic acid;
2-(tert-Butoxy carbonyl) amino-2- {9-(4-trifluoromethyl benzoyl)-9-azabicyclo [3.3.1]
non-3-yl}-exo-ethanoic acid.
13. Compounds of the general formula X in exo configuration,

their methyl esters and optical isomers thereof, wherein,
R1 is selected from groups consisting of
i) C1-C8alkyl (straight or branched) substituted with 1 to 3 substituents selected
from halogens, such as pentyl, trifluoropropyl.
ii) cycloalkyl having 3-10 carbon atoms such as cyclohexyl;
iii) cycloalkylmethyl having 4-10 carbon atoms such as cyclohexyl methyl;
iv) Bridged polycycloalkyl methyl having 5 to 12 carbon atoms such as adamantyl
methyl;
v) phenyl which is unsubstituted or substituted with 1-3 substituents each
independently selected from cyano or methanesulfonyl;
vi) aralkyl group such as benzyl which is unsubstituted or substituted with 1 to 3
substituents selected from halogens;
vii) heteroaryl group such as pyridyl substituted with cyano;
viii) heteroaralkyl group such as pyridyl methyl;
ix) aralkoxyalkyl group such as benzyloxy ethyl;
x) SO2R5; where R5 is methyl, thiophenyl, or phenyl unsubstituted or substituted
with 1 to 3 fluoro;
xi) -CONHR6 or -CSNHR6 or -CONHSO2R6; where R6 is phenyl unsubstituted or
substituted with chloro, fluoro, trifluoromethyl or methoxy;
xii) R7CO-, wherein R7 is selected from
a. unsubstituted phenyl or substituted with 1 to 3 substituents selected from
halogen, trifluoromethyl, cyano;
b. benzo[1,3]dioxolyl;
c. adamantyl;
d. heteroaryl such as thiophenyl; furyl; pyrazinyl; pyridyl unsubstituted or
substituted with a substituent selected from halogen, cyano, methyl,
benzyloxy;
e. N-acetylpiperidinyl;
f. Cyclohexyl;
g. Pyridine methyl.
14. A compound its stereoisomers, racemates, methylesters thereof as claimed in claim
13, wherein, the compound of the general formula X is selected from,
(2S)-2-Amino-2-[8-(2,4,5-trifluorobenzoyl)-8-aza-bicyclo [3.2.1 ]-oct-3-yl]-exo-ethanoic
acid;
(2S)-2-Amino-2-[8-(4-trifluoromethylbenzoyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-
ethanoic acid;
(2S)-2-Amino-2-[8-(adamantane-1-carbonyl)-8-aza-bicyclo [3.2.1 ]-oct-3-yl]-exo-
ethanoic acid;
(2S)-2-Amino-2-[8-(4-trifluoromethyl-phenyl carbamoyl)-8-aza-bicyclo [3.2.1]-oct-3-yl]-
exo-ethanoic acid.
15. Compounds of the general formula IX in exo configuration,

and optical isomers thereof, wherein,
R1 is selected from groups consisting of
i) C1-C8alkyl (straight or branched) substituted with 1 to 3 substituents selected
from halogens, such as pentyl, trifluoropropyl.
ii) cycloalkyl having 3-10 carbon atoms such as cyclohexyl;
iii) cycloalkylmethyl having 4-10 carbon atoms such as cyclohexyl methyl;
iv) Bridged polycycloalkyl methyl having 5 to 12 carbon atoms such as adamantyl
methyl;
v) phenyl which is unsubstituted or substituted with 1-3 substituents each
independently selected from cyano or methanesulfonyl;
vi) aralkyl group such as benzyl which is unsubstituted or substituted with 1 to 3
substituents selected from halogens;
vii) heteroaryl group such as pyridyl substituted with cyano;
viii) heteroaralkyl group such as pyridyl methyl;
ix) aralkoxyalkyl group such as benzyloxy ethyl;
x) SO2R5; where R5 is methyl, thiophenyl, or phenyl unsubstituted or substituted
with 1 to 3 fluoro;
xi) -CONHR6 or -CSNHR6 or -CONHSO2R6; where R6 is phenyl unsubstituted or
substituted with chloro, fluoro, trifluoromethyl or methoxy;
xii) R7CO-, wherein R7 is selected from
a. unsubstituted phenyl or substituted with 1 to 3 substituents selected from
halogen, trifluoromethyl, cyano;
b. benzo[1,3]dioxolyl;
c. adamantyl;
d. heteroaryl such as thiophenyl; furyl; pyrazinyl; pyridyl unsubstituted or
substituted with a substituent selected from halogen, cyano, methyl,
benzyloxy;
e. N-acetylpiperidinyl;
f. Cyclohexyl;
g. Pyridine methyl.
16. A compound its stereoisomers, and racemates thereof as claimed in claim 15, wherein,
the compound of the general formula IX is selected from,
Methyl-(2S)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-[8-(2,4,5-trifluorobenzoyl)-8-aza-
bicyclo[3.2.1 ]-oct-3-yl]-exo-acetate;
Methyl-(2S)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-[8-(4-trifluoromethylbenzoyl)-8-aza-
bicyclo[3.2.1 ]-oct-3-yl]-exo-acetate;
Methyl-(2S)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-[8-(adamantane-1 -carbonyl)-8-aza-
bicyclo[3.2.1 ]-oct-3-yl]-exo-acetate;
Methyl-(2S)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-[8-(4-trifluoromethyl-phenyl
carbamoyl)-8-aza-bicyclo[3.2.1 ]-oct-3-yl]-exo-acetate.
17. Compounds, their stereoisomers, their racemates and salts thereof useful for the
synthesis of compound of formula 'A' as listed below,
1-(2-Hydroxy-1-phenylethyl amino)-1-(8-methyl-8-aza-bicyclo[3.2.1]-oct-3-yl)-exo-
methane-1- carbonitrile;
1-(2-Hydroxy-1-phenylethyl amino)-1-(8-methyl-8-aza-bicyclo[3.2.1]-oct-3-yl)- exo-
methane-1-carboxylic acid;
2-Amino-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-exo-acetic acid;
Methyl-2-amino-2-(8-methyl-8-aza-bicyclo[3.2.1 ]-oct-3-yl)- exo-acetate;
Methyl-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-(8-methyl-8-aza-bicyclo [3.2.1]oct-3-yl)-
exo-acetate;
Methyl-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-[8-(2,2,2-trichloro-ethyloxy carbonyl)-8-
aza-bicyclo[3.2.1]-oct-3-yl]-exo-acetate;
Methyl-2-(1-hydroxy-3-oxo-1,3-dihydroisoindol-2-yl)-2-[8-aza-bicyclo[3.2.1]-oct-3-yl]-exo-
acetate;
Methyl-2-(1-hydroxy- 3-oxo-1,3-dihydroisoindol-2-yl)-2-[8-(carbobenzyl oxy)-8-aza-
bicyclo[3.2.1 ]-oct-3-yl ]-exo-acetate;
Methyl-2-(1,3dioxo-1,3-dihydroisoindol-2-yl)-2-[8-(carbobenzyloxy)-8-aza-bicyclo [3.2.1]-
oct-3-yl ]-exo-acetate;
Methyl-2-amino-2-[8-(carbobenzyloxy)-8-aza-bicyclo[3.2.1]-oct-3-yl]-exo-acetate;
Methyl-2-(tert-butoxycarbonyl)-amino-2-[8-(carbobenzyloxy)-8-aza-bicyclo [3.2.1]-oct-3-
yl]-exo-acetate;
Methyl-2-(tert-butoxycarbonyl)-amino-2-[-8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-acetate;
3-Benzyl-3-hydroxy-9-aza-bicyc!o [3.3.1] nonane-9-carboxylic acid ethyl ester;
9-(Ethoxy carbonyl)-3-exo-benzyl-9-aza-bicyclo [3.3.1] non-3-yl methyl oxalate;
Ethyl-3-benzyl-9-aza-bicyclo [3.3.1] nonane-9-carboxylate;
[9-(Ethoxycarbonyl)-9-azabicyclo [3.3.1] -non-3yl] acetic acid;
9-Azabicyclo [3.3.1] non-3-yl acetic acid hydrochloride;
Methyl -9-azabicyclo [3.3.1]-non-3-yl -acetate and exo and endo conformer thereof;
Methyl {9-[4[trifluromethyl]-9-azabicyclo [3.3.1] non-3-yl} - acetate and exo and endo
conformer thereof;
Methyl -2-(1,2-di-tert-butyloxy carbonyl hydrazine)-2-[9-(4-trifluoromethyl benzoyl)-9-
azabicyclo [3.3.1]-non-3-yl]-acetate and exo and endo conformer thereof;
Methyl-2- (hydrazino)-2-[9-(4-trifluoromethyl benzoyl)-9-azabicyclo [3.3.1]-non-3-yl]-
acetate di trifluoro acetic acid salt and exo and endo conformer thereof;
Methyl amino {9-[4-(trifluoro methyl) benzoyl]-9-azabicyclo [3.3.1] non-3-yl}- acetate and
exo and endo conformer thereof;
Methyl-2- (tert-butoxy carbonyl) amino-2- {9-[4-(trifluoromethyl) benzoyl]-9-azabicyclo
[3.3.1] non-3-yl}-acetate and exo and endo conformer thereof.
(1R, 3R, 5R)-2-aza-bicyclo [3.1.0]-hexane-3-carboxamide trifluoro acetic acid salt
18. A pharmaceutical composition, which comprises a compound of formula (A) as defined
in claim 1 and a pharmaceutically acceptable carrier, diluent, excipients.

19. A pharmaceutical composition as claimed in claim 18, in the form of a tablet, capsule,
suspension, powder, syrup, and solution.
20. A method of preventing or treating hyperlipidemia, hypercholesterolemia,
hypertriglyceridemia, hyperglycemia, impaired glucose tolerance, obesity,
atherosclerosis, insulin resistance or diseases in which the underlying cause is insulin
resistance or related diseases, which comprises administering of compound of formula
(I) or a pharmaceutical composition as claimed in claims 18 or 19.
21. A method according to claim 20, wherein the disease is type-2 diabetes and insulin
resistance, impaired glucose tolerance, dyslipidemia and disorders related to
Syndrome X such as hypertension, obesity, eating disorders, hyperlipidemia,
atherosclerosis, coronary artery disease, cardiovascular disorders, diseases related to
endothelial dysfunction, nephropathy, neuropathy, retinopathy, osteoporosis,
polycystic ovary syndrome, pancreatitis, inflammatory bowel diseases, xanthoma or
cancer.
22. A method of reducing plasma glucose, triglycerides, total cholesterol, LDL, VLDL or
free fatty acids or increasing HDL in the plasma, which comprises administering a
compound of formula (A), claimed in claim 1 or a pharmaceutical composition as
claimed in claims 18 and 19 or in combination with HMGCoA reductase inhibitors,
fibrates, nicotinic acid, cholestyramine, which may be administered together or within
such a period as to act synergistically together.

The present invention is related to novel compounds of the general formula A , their
tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts,
pharmaceutical compositions containing them, methods of making of the above compounds
, and their use as Dipeptidyl Peptidase-IV (DPP-IV) Inhibitors which are useful in the
treatment or prevention of diseases particularly Type II diabetes , other complications
related to diabetes and other pathogenic conditions in which DPP IV enzyme is involved.