Novel Antidiabetic Compounds

Field of the Invention

The present invention's related to novel compounds of the general formula (I), their stereoisomers, their racemates, their pharmaceutically acceptable salts, pharmaceutical compositions containing them. The invention is also related to the process for preparation of compound of formula (I) and the intermediates involved in the process.,

The compounds of the present invention are useful for lowering blood triglyceride, decreasing low-density lipoprotein cholesterol (LDL), lowering blood glucose, increasing high-density lipoprotein (HDL), lowering fatty acids and blood insulin.

The compounds of the general formula (I) may be useful for the treatment and/or prophylaxis of metabolic disorders related to syndrome X that includes insulin resistance (type II diabetes), hypertension, obesity, hyperlipidemia, atherosclerosis, coronary heart disease and other, cardiovascular disorders. These compounds can be used for the treatment or prevention of certain renal diseases also such as glomerulosclerosis and nephrotic syndrome. The compounds of the general formula (I) may also be useful as aldose reductase inhibitors or may be expected to improve cognitive functions in dementia. These compounds may also be useful for the treatment and/or prevention or to reduce the risk of complications related to diabetes, psoriasis, polycystic ovarian syndrome (PCOS), oestoporesis and arteriosclerosis.

Background of the Invention

Lack of insulin signaling contributes to decreased glucose transport to peripheral tissues like muscle and adipose tissue and increase hepatic glucose production. Elevated glucose levels in turn contribute to increased insulin secretion and hyperinsulinemia. With increased insulin secretion caused by peripheral insulin resistance, beta cell hypertrophy occurs and with time beta cells fail to secrete insulin. This subsequent beta cell failure leads to type-2 diabetes.

Type-2 diabetes is associated with hypertriglyceridemia, low HDLc and more of small LDLc. This is due to peripheral insulin resistance and increased influx of free fatty acids to liver. An elevated circulating level of low-density lipoprotein cholesterol (LDLc) forms a major risk factor for coronary artery disease (CAD). Apart from LDLc, low levels of high-density lipoprotein cholesterol (HDLc) and elevated levels of triglycerides (TG) are considered as cardiovascular risk factors. Increased plasma levels of fatty acids might also play a pathological role in the disease. Insulin resistance also decreases lipoprotein lipase (LpL) activity, the major mediator of VLDL clearance, which may to a certain extent contribute to elevated triglyceride levels. Improper treatment of diabetes can aggravate impaired glucose tolerance and insulin resistance and frank diabetes. The present therapy for type-2 diabetes includes sulfonylureas, biguanides and insulin. Some of these treatments also lead to hypoglycemia or other associated side effects like lactic acidosis or increase in body weight. With the new addition of thiazolidinediones as insulin sensitizers the glycemic control is satisfactory. Thiazolinidines like Rosiglitazone and Pioglitazone are either used as monotherapy or in combination with insulin or any other antidiabeteic drugs. However, as a class of drugs there are associated safety concerns like increase in body weight, hemodilution, hepatotoxicity etc. Troglitazone, the first in the class of thiazolidinedione was withdrawn from the market due to hepatotoxicity-associated deaths. Though it is considered to be idiosyncratic. Therefore, there is a need to develop safe drugs for treating insulin, diabetes and hyperlipidemia (Exp. Clin. Endocrinol. Diabetes, 109(4): S548-S559, 2001).

Epidemiological data has shown the strong association between diabetes mellitus and coronary heart disease (CHD). It is well known that humans with diabetes have more atherosclerosis and its complications. Thus, hyperglycemia and/or lack of insulin actions are toxic to arteries, or metabolic derangements exclusive of hyperglycemia are atherogenic (Arterioscler Throm Vase Biol, 26: 1693-1701, 2006). It is established now that it is not just hyperglycemia but the conventional risk factors like high TG, high LDLc and low HDL cholesterol lead to atherosclerosis. The metabolic abnormalities associated with diabetes, and not overt hyperglycemia per se, is responsible for the acceleration of macrovascular complications. Intracellular processes that cause pathological events are thought to involve

hyperglycemic damage to endothelial cells. Patients with obesity, insulin resistance and diabetes have reduced endothelial function even without clinical evidence of cardiovascular disease (Steinberg et al., J. Clinical Invest. 97: 2601-2610, 1996; Caballero et al., Diabetes, 48: 1856-1862, 1999; Plump et al., J. Clinical Invest. 97: 2660-2671, 1996). Microvascular diseases lead to characteristic pathological changes in the eyes and kidneys.

Patients with obesity, insulin resistance, and diabetes have reduced endothelial function even without clinical evidence of cardiovascular disease. Clinical studies have demonstrated that endothelial dysfunction is an independent predictor of future cardiovascular events (Circulation, 106: 653-658, 2002; J Am Coll Cardiol. 42: 1149-1160, 2003).

Metabolic syndrome is defined by the American Heart Association and the US National Heart, Lung and Blood Institute as "multiple, interrelated risk factors of metabolic origin that appear to directly promote the development of atherosclerotic cardiovascular disease". The core metabolic risk factors are atherogenic dyslipidemia, elevated blood pressure, elevated plasma glucose, and proinflammatory state. This constellation of risk factors is associated with the occurrence of type-2 diabetes. This clustering has also been associated with several other conditions like fatty liver, polycystic ovary disease, sleep apnoea, cholesterol gallstones and some forms of cancer.

The World Health Organization (WHO) has recognized that the prevalence of obesity is rapidly rising to epidemic proportions and has concluded that the fundamental causes of this epidemic are sedentary lifestyles, high fat, high-energy diets (Simon Smith and Andrew Heron, Nature Medicine, 12: 75-80, 2005). Obesity is associated with numerous complications, including significantly increased risks of diabetes, cardiovascular disease, cancer, gastrointestinal diseases and arthritis. Only two drugs are currently accepted as longterm obesity treatments - Orlistat and Sibutramine. While these agents show clinical efficacy, they both have safety concerns. Despite the potentially huge market for an effective and safe obesity treatment and many years of research, such a therapy remains elusive. The most likely class of compounds to make an impact in the near term is cannabinoid-1 receptor antagonist Rimonabant which was recently launched in the US market.

Peroxisome proliferator activated receptors (PPARs) are ligand activated nuclear receptors that form heterodimers with the retinoid X receptor to affect the expression of genes involved in glucose, and lipid metabolism and inflammation. There are 3 subtypes - PPAR alpha, PPAR gamma and PPAR delta [Endocrine Reviews, 20(5): 649-688, 1999; J. Medicinal Chem., 43(4): 527-550, 2000; Cell MoI. Life Sci., 55(6-7), 932 - 943, 1999]. The endogenous ligands for these receptors are postulated to be fatty acids. Evidence supports' the link between the 3 PPARs and diabetes, obesity, dyslipidemia and inflammation. PPAR alpha controls liver and skeletal muscle lipid metabolism and glucose homeostasis. It influences intracellular lipid and carbohydrate metabolism through direct transcriptional control of genes involved in peroxisomal and mitochondrial β -oxidation pathways, FA uptake, and triglyceride catabolism. Moreover, preclinical data suggest a role of PPAR alpha in body weight control, supporting the use of PPAR alpha agonists to treat obesity. The fibrate class of molecules forms the synthetic ligands for PPAR alpha, these drugs are known to lower triglycerides and increase HDL cholesterol. Thiazolidinediones are the ligands for PPAR gamma and they are involved in glucose lowering and improving insulin sensitivity. Dual agonists of PPAR alpha (to lower triglycerides and increase HDL cholesterol and decrease LDL cholesterol and VLDL cholesterol) and PPAR gamma (to lower glucose) have been generated in hope to treat metabolic syndrome and insulin resistance. Pharmacologically improving insulin resistance in people with obesity and diabetes may ultimately lead to decrease in CAD.

Proinflammatory cytokine TNF alpha has been reported to be involved in inducing insulin resistance. Fat is a site involved in the production of cytokines and other bioactive substances. Adiponectin is produced by fat and expression decreases with increased adiposity. Leptin is also produced by adipocytes. TNF alpha, IL-6, MCP-I, visfatin and PAI- 1 are expressed by activated macrophages and other other cells. TNF alpha, IL-6, resistin and other pro- or anti-inflammatory cytokines appear to participate in the induction of inflammatory state in obesity (Shoelson et al., J.Clinical investigation, 116: 1793-1801, 2006). This suggests that pharmacological decrease in inflammatory activity might

downregulate the production of a number of proteins involved in the pathogenesis of insulin resistance, type-2 diabetes, and cardiovascular disease.

In addition to adipose tissue, the liver is affected by obesity. Inflammatory gene expression increases in liver with increasing adiposity (Nature Medicine 11: 183-190, 2005). Hepatocyte lipid accumulation (steatosis) might induce inflammatory response in liver similar to adipocyte due to fat accumulation. It might be possible to directly target inflammation with pharmacological interventions to treat and/or prevent insulin resistance and type-2 diabetes, CVD and other metabolic conditions.

Several compounds have been reported which are dual agonists of PP ARa and γ like alkoxyphenylpropionic acids derivatives, aryloxypropionic acid derivatives and are useful in the treatment of hyperglycemia and hypercholestrolemia 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:

PCT Application WO 2006057503 disclose several (hydroxyimino)-ethoxyphenyl propionic acid derivatives of general formula (Ha) as PPARγ and PP ARa agonist.

Acta Pharmacologica Sinica, 2006, 27(5), 597 and PCT Application WO 9962872 describes the synthesis and in vitro and in vivo antidiabetic activity studies for (RS)-2- ethoxy-3-{4-[2-(4-substituted-sulfonyloxyphenyl)ethoxy]pheny l}propionic acid of formula (lib) and data suggested that these compounds are potentially effective antidiabetic agent.

(Hb)

Bioorganic Medicinal Chemistry Letter, 2006, 16(4), 915 and 2005, 15(1), 51 describes 2-alkoxydihydrocinnamic acids of general formula (lie) as potent PPARα/γ dual agonist.

Bioorganic Medicinal Chemistry, 2006, 14(3), 866 discloses synthesis and evaluation of azaindole-α-alkyloxyphenylpropionic acid analogues as PPARα/γ agonists. Among them one compound of formula (Hd) was identified as a potent, selective PPARα/γ dual agonist.

Bioorganic Medicinal Chemistry Letter, 2006, 16(15), 4016 describes propionic acids with 1,5-disubstituted indole scaffold of formula (He) as PPARα/γ activators.

PCT Application WO 2005087713 discloses preparation of tetrahydro- naphthalenylcarboxamide derivatives of formula (Hf) as RXR function modulators and RXR/PPAR heterodimer function modulators.

(iif)

PCT Application WO 2005019151 discloses preparation of several aryloxy- alkoxyphenylalkanoic acids of formula (Hg) as PPAR agonists.

One example of these compounds is shown below;

PCT Applications, WO 2004063184, WO 2004063166 and WO 2004046119 disclose preparation of aralkyl derivatives of formula (Hh) as antidiabetic agents.

PCT Application WO 2004056740 discloses preparation of dimeric dicarbo-xylic acid derivatives of formula (Hi) as PPARδ agonist.

PCT Applications, WO 2004041275, WO 2004031162, WO 2004020420 and WO 2002092084 disclose carboxylic acid substituted oxazole and thiazole derivatives of formula (Hj) PPAR agonist.

PCT Application WO 2004000789 discloses phenoxyalkanamide compounds of formula (Ilk) as PPAR receptor agonist.

PCT Application WO 2001053257 and US Patent Application US 2003236254 disclose preparation of pyrrolylethoxyphenyl-ethoxypropanoates of formula (III) as hypolipidemic and hypocholesteremic agent.

PCT Application WO 2003070692 discloses preparation of 3-ρhenylpropionic acid derivatives of formula (Hm) for the treatment diabetes.

PCT Application WO 2003048130 discloses preparation of imidazolidinone derivatives of formula (Hn) as PPAR activated receptor agonists.

PCT Application WO 2002100813 discloses preparation of various analogs of substituted 3-phenyl-2-alkoxypropionic acid of the formula (Ho) as modulators of PPAR receptors for the treatment of diabetes and related conditions.

PCT Applications, WO 2002100812, WO 2002080899 and WO 2001025181 discloses preparation of phenylpropionic acid and indolylpropionic acid derivatives of formula (Up) as dual or triple agonists of PPAR. \

B ¹

Y=L- X=T→ ^Z 7-M^— W (Up)

PCT Applications, WO 2002085844, WO 2001040172, WO 2001040170 and WO 9962870 disclose certain novel compounds of formula (Hq) useful in treatment of insulin resistance.

US Patent number 6369067 discloses some oxopyrimidine derivatives of formula (Hr) as antiobesity and hypocholesterolemic agents.

• ( ^IIr >

PCT Applications WO 2002016332 and WO 2002016331 discloses preparation of oxazolyl-arylpropionic acid derivatives of formula (Us) as PPAR agonist for the treatment of diabetes mellitus and related conditions.

PCT Applications, WO 2001055085 and WO 2000063153 discloses synthesis of aryl- alkenyl-oxy-arylpropionic acid derivatives of formula (lit) and their use in the treatment of PPAR mediated disorders including diabetes and obesity.

PCT Applications, WO 2000023425, WO 2000023451, WO 2000023445 and WO 2000023415 discloses preparation of tricyclic compounds of formula (Hu) and (Hv) for the treatment of conditions mediated by PPAR receptors.

US Patent number 5306726 and PCT Application WO 9119702 discloses synthesis of several heteroaryl derivatives of formula (Hw) as hypoglycemic and hypocholesterolemic agents.

US Patent number 5227490 discloses various benzenepropanoates of formula (Hx) as fibrinogen receptor antagonists.

Objective of the Invention

The main objective of the present invention is therefore to provide novel compounds of the general formula (I), their stereoisomers, their racemates , their pharmaceutically acceptable salts, pharmaceutical compositions containing them, process and intermediates for

the preparation of the above said compounds which may have agonist activity against PP ARa and/or PPARγ or PPARδ. In addition to this, the compounds of the present invention may have the property to inhibit HMG CoA reductase optionally, which may be useful for the treatment of atherosclerosis. ' It is thus basic object of the present invention is to develop novel compounds which are effective and useful to lower increased levels of lipids, to lower blood giucose, to improve insulin resistance, to reduce fatty acids and body weight, for the treatment and/ or prophylaxis of metabolic disorders related to syndrome X such as hypertension, obesity, hyperlipidemia, atherosclerosis, coronary artery disease especially for reducing the risk of ischemic heart disease and other cardiovascular disorders with better efficacy and lower toxicity. Summary Of the Invention

The present invention provides novel organic compounds represented by the general formula (I), their stereoisomers, their racemates, their pharmaceutically acceptable salts, pharmaceutical compositions containing them or mixture thereof.

A further aspect of the present invention is to develop novel organic compounds represented by the general formula (I) 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 diabetes mellitus, Syndrome X, hyperlipidemia, obesity, impaired glucose tolerance, hypertension, diabetic complications, for the treatment of atherosclerosis, coronary heart diseases, arteriosclerosis with better efficacy, potency, without or reduced toxicity.

In yet another aspect, the present invention provides novel organic compounds of the general formula - (I), their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them or their mixture which may have agonist activity against PP ARa and/or PPARγ or PPARδ. In addition to this, the compounds of the present invention may have the property to inhibit HMG CoA reductase optionally, which may be useful for the treatment of atherosclerosis.

In yet another aspect, the present invention provides a process for the preparation of novel organic compounds of the general formula (I), 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

(I), their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them and their use in the treatment and/or prophylaxis of diseases related to insulin resistance leading to type II diabetes, Syndrome X, hyperlipidemia, obesity, impaired glucose tolerance, hypertension, diabetic complications, atherosclerosis, coronary heart diseases, arteriosclerosis.

The ' present invention also provides pharmaceutical compositions containing compounds of the general formula (I), their stereoisomers, their pharmaceutically acceptable salts, their mixture in combination with the usual pharmaceutically acceptable carriers, diluents and solvents normally used in making such compositions. Detailed description of the invention

The present invention relates to novel compounds of the general formula (I),

and where applicable, stereoisomers and racemates thereof . as well as pharmaceutically acceptable salts, wherein, W is a group of formula (III) or (IV):

(HI) (IV)

X is selected from the groups hydrogen; hydroxy; C^Csalkyl (straight or branched); Q-Csalkoxy (straight or branched); acyl; aralkyl group; heteroaralkyl group; C ₃ - C ₁₀ cycloalkyl group; C ₄ -C ₁ ocycloalkylmethyl group; alkoxyalkyl group; which may be substituted

Y is selected from the groups CN, or OR ³ Z is selected from the groups OR ² or NR ⁴ R ⁵ n = 2, 3 where R ¹ is selected from groups consisting of i) hydrogen; ii) COOC(CH ₃ ) ₃ (in case of W is fragment III, when R ⁸ is not an electron withdrawing group) iii) Ci-Csalkyl (straight or branched), for example methyl, ethyl, ^-propyl, iso- propyl, rø-butyl, iso-butyl, pentyl, hexyl, heptyl, octyl, which may be substituted; iv) cycloalkyl having 3-10 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl, which may be substituted; v) cycloalkylmethyl having 4-10 carbon atoms, for example cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexymiethyl, cycloheptylmethyl and adamantylmethyl, which may be substituted; vi) phenyl which is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of halogen, Ci-Ci ₂ alkyl, C ₁ -

C^alkoxy, Ci-C^thioalkyl, nitro, amino, haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, hydroxy, cyano, formyl, mono or dialkylamino, C ₁ -

, C^alkylsulfonyl, aryloxy, aralkyloxy; unsubstituted or substituted 1,2-

(ethylenedioxy)benzene, vii) aryl group such as substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl and the like;

viii) aralkyl group which is substituted or unsubstituted wherein the alkyl moiety may have Ci-C ₃ (straight or branched). Preferred groups are benzyl; benzyl which is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of halogen, Q-C^alkyl, Q-C^alkoxy, Ci- C _t øthioalkyl, CrC^thioalkoxy, unsubstituted or substituted aralkoxyalkyl, unsubstituted or substituted thioaryloxy, nitro, amino, haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, hydroxy, cyano; unsubstituted or substituted 1,2-

(ethylenedioxy)benzene; unsubstituted or substituted phenylethyl; ix) heteroaryl group which is unsubstituted or substituted with 1 or 2 substituents each independently selected from the group consisting of halogen, C ₁ -C ₄ alkyl,

CrC ₄ alkoxy, haloalkoxy, perhaloalkoxy, haloalkyl, perhaloalkyl, nitro, cyano, mono or dialkylamino, preferred groups are pyridyl, thienyl, thiazolyl, furyl, pyrimidinyl, quinolinyl, indolyl, benzoxazolyl, benzothiazolyl, pyrazolyl, benzimidazolyl, imidazolyl, thiadiazolyl, triazolyl, oxadiazolyl; x) heteroaralkyl group which is substituted or unsubstituted, preferred groups are pyridinemethyl, benzofuranmethyl, benzothiophenemethyl, furanmethyl, thiophenemethyl, coumarinmethyl, oxazolemethyl and 1,4- benzodioxanmethyl; xi) substituted or unsubstituted alkoxyalkyl group, which is preferably C ₁ - CβalkoxyCj-Cβalkyl group. Examples thereof include methoxymethyl, ethoxymethyl, methoxyethyl and ethoxypropyl groups; xii) substituted or unsubstituted acyl group, which include linear or branched alkanoyl group having 2 to 8 carbon atoms such as acetyl, propanoyl, isopropanoyl, butanoyl, pentanoyl, isopentanoyl, benzoyl, phenacyl and the like, which may be substituted; xiii) SO ₂ R ⁶ ; where R ⁶ is Q-Cgalkyl (straight or branched), cycloalkyl having 3-10 ' carbon atoms, cycloalkylmethyl having 4-10 carbon atoms, phenyl, heteroaryl group which may be substituted as defined above;

xiv) CONHR ⁷ or CSNHR ⁷ or CONHSO ₂ R ⁷ ; where R ⁷ is Ci-Cgalkyl (straight or branched), cycloalkyl having 3-10 carbon atoms, cycloalkylmethyl having 4-

10 carbon atoms, phenyl which is unsubstituted or substituted with 1-5 substituents, arylalkyl group, heteroaryl group, heteroaralkyl group which may be substituted as defined above; where R ² is selected from group of i) hydrogen; ii) substituted or unsubstituted linear or branched preferably C ₁ -

Qalkyl group such as methyl, ethyl, ^-propyl, iso-pvopyl, n-bxxtyl, iso-butyl, pentyl, hexyl, octyl and the like; iii) C ₃ -C ₇ cycloalkyl group such as cyclopropyl, cyclopentyl, cyclohexyl and the like; iv) aryl group such as substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl and the like; v) substituted or unsubstituted heterocyclyl groups. For examples aziridinyl, pyrrolidinyl, piperidinyl and the like; vi) substituted or unsubstituted heteroaryl group, preferred groups are pyridyl, pyrimidinyl, thienyl, furyl, thiazolyl and 1,2-ethylenedioxybenzene, quinolinyl, indolyl, benzoxazolyl, benzothiazolyl, pyrazolyl, benzimidazolyl, imidazolyl, thiadiazolyl, triazolyl, oxadiazolyl; vii) aralkyl group such as substituted or unsubstituted benzyl and substituted or unsubstituted phenethyl and the like. The substituents on R may be selected from the same group of R ¹ and are defined above. R ³ is selected from groups consisting of i) hydrogen; ii) Q-Csalkyl (straight or branched), for example methyl, ethyl, ^-propyl, iso- propyl, n-butyl, iro-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, which may be substituted;

iii) cycloalkyl having 3-7 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl groups having 3-5 carbon atoms are preferred and this group may be substituted; iv) cycloalkylmethyl having 4-10 carbon atoms, for example cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl and adamantylmethyl, which may be substituted; v) substituted or unsubstituted aryl group, for example phenyl and naphthyl; vi) substituted or unsubstituted heteroaryl group, preferred groups are pyridyl, pyrimidinyl, thienyl, furyl, thiazolyl and 1,2-ethylenedioxybenzene, quinolinyl, indolyl, benzoxazolyl, benzothiazolyl, pyrazolyl, benzimidazolyl, imidazolyl, thiadiazolyl, triazolyl, oxadiazolyl; vii) substituted or unsubstituted heteroaralkyl group, preferred groups are pyridinemethyl, furanmethyl, coumarinmethyl, oxazolemethyl and 1,4- benzodioxanmethyl; viii) substituted or unsubstituted aralkyl group wherein the aryl group has the same meaning as defined above and alkyl moiety may have C ₁ -C ₃ . Preferred groups are benzyl and phenethyl; ix) substituted or unsubstituted alkoxyalkyl group, which is preferably a C ₁ -

QaIkOXyC ₁ -C ₆ alkyl group. Examples thereof include methoxymethyl, ethoxymethyl, methoxyethyl and ethoxypropyl groups; , x) substituted or unsubstituted aryloxyalkyl group. For example phenoxymethyl, phenoxyethyl, naphthyloxymethyl, naphthyloxyethyl and the like; xi) substituted or unsubstituted acyl group, which include linear or branched alkanoyl group having 2 to 8 carbon atoms such as acetyl, propanoyl, isopropanoyl, butanoyl, benzoyl and the like; xii) Ci-Cealkoxycarbonyl group, the alkyl group may be substituted; xiii) substituted or unsubstituted heterocyclyl groups. For examples aziridinyl, pyrrolidinyl, piperidinyl and the like;

xiv) substituted or unsubstituted aryloxycarbonyl group such as phenoxycarbonyl, naphthyloxycarbonyl; xv) substituted or unsubstituted Q-Csalkylaminocarbonyl group; xvi) substituted or unsubstituted arylaminocarbonyl group such as phenylaminocarbonyl, naphthylaminocarbonyl; where R ⁴ and R ⁵ are the same or different and are selected from i) hydrogen; ii) substituted or unsubstituted linear or branched preferably C ₁ -

C ₈ alkyl; iii) C ₁ -C ₆ hydroxy alkyl which may be substituted; iv) aryl group such as phenyl and the like, which may be substituted; v) aralkyl group such as benzyl and phenethyl and the like; vi) substituted or unsubstituted heterocyclyl groups. For examples aziridinyl, pyrrolidinyl, piperidinyl and the like; vii) substituted or unsubstituted heteroaryl group, preferred groups are pyridyl, pyrimidinyl, thienyl, furyl, thiazolyl and 1,2-ethylenedioxybenzene, quinolinyl, indolyl, benzoxazolyl, benzotliiazolyl, pyrazolyl, benzimidazolyl, imidazolyl, thiadiazolyl, triazolyl, oxadiazolyl; viii) substituted or unsubstituted heteroaralkyl group, preferred groups are pyridinemethyl, furanmethyl, coumarinmethyl, oxazolemethyl and 1,4- benzodioxanmethyl; where R is selected from groups consisting of i) hydrogen; ii) COOC(CH ₃ ) ₃ (in case of W is fragment III, when R ¹ is not an electron withdrawing group); iii) d-Cgalkyl (straight or branched), for example methyl, ethyl, ^-propyl, iso- propyl, rc-butyl, /so-butyl, pentyl, hexyl, heptyl, octyl, which may be substituted;

iv) cycloalkyl having 3-10 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl, which may be substituted; v) cycloalkylmethyl having 4-10 carbon atoms, for example cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl and adamantylmethyl, which may be substituted; vi) phenyl which is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of halogen, Ci-C^alkyl, C ₁ - C ₁₂ alkoxy, C _t -Cnthioalkyl, nitro, amino, haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, hydroxy, cyano, formyl, mono or dialkylamino, C ₁ -

C ₁₂ alkylsulfonyl, aryloxy, aralkyloxy; unsubstituted or substituted 1,2- (ethylenedioxy)benzene, vii) aryl group such as substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl and the like; viii) aralkyi group which is substituted or unsubstituted wherein the alkyl moiety may have C ₁ -C ₃ (straight or branched). Preferred groups are benzyl; benzyl which is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of halogen, Ci-C ₁₂ alkyl, Q-Cnalkoxy, C ₁ - Cπthioalkyl, C ₁ -C ₁₂ ImOaIkOXy, unsubstituted or substituted aralkoxyalkyl, unsubstituted or substituted thioaryloxy, nitro, amino, haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, hydroxy, cyano; unsubstituted or substituted 1,2- (ethylenedioxy)benzene; unsubstituted or substituted phenylethyl; ix) heteroaryl group which is unsubstituted or substituted with 1 or 2 substituents each independently selected from the group consisting of halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, haloalkoxy, perhaloalkoxy, haloalkyl, perhaloalkyl, nitro, cyano, mono or dialkylamino, preferred groups are pyridyl, thienyl, thiazolyl, furyl, pyrimidinyl, quinolinyl, indolyl, benzoxazolyl, benzothiazolyl, pyrazolyl, benzimidazolyl, imidazolyl, thiadiazolyl, triazolyl, oxadiazolyl;

x) heteroaralkyl group which is substituted or unsubstituted, preferred groups are pyridinemethyl, benzofuranmethyl, benzothiophenemethyl, furanmethyl, thiophenemethyl, coumarinmethyl, oxazolemethyl and 1,4- benzodioxanmethyl; xi) substituted or unsubstituted alkoxyalkyl group, which is preferably C ₁ -

C ₆ alkoxyCrC ₆ alkyl group. Examples thereof include methoxymethyl, ethoxymethyl, methoxyethyl and ethoxypropyl groups; xii) substituted or unsubstituted acyl group, which include linear or branched alkanoyl group having 2 to 8 carbon atoms such as acetyl, propanoyl, isopropanoyl, butanoyl, pentanoyl, isopentanoyl, benzoyl, phenacyl and the like, which may be substituted; xiii) SO ₂ R ⁶ ; where R ⁶ is Cj-Csalkyl (straight or branched), cycloalkyl having 3-10 carbon atoms, cycloalkylmethyl having 4-10 carbon atoms, phenyl, heteroaryl group which may be substituted as defined above; xiv) CONHR ⁷ or CSNHR ⁷ or CONHSO ₂ R ⁷ ; where R ⁷ is d-C ₈ alkyl (straight or branched), cycloalkyl having 3-10 carbon atoms, cycloalkylmethyl having 4- 10 carbon atoms, phenyl which is unsubstituted or substituted with 1-5 substituents, arylalkyl group, heteroaryl group, heteroaralkyl group which may be substituted as defined above; The present invention also relates to compounds of the general formula (Ia) and (Ib),

(Ia)

(Ib)

and where applicable, stereoisomers and racemates thereof as well as pharmaceutically acceptable salts, where R ¹ , R ⁸ , n, X, Y, Z are as defined above.

Examples of substituents in above definition include nitro, hydroxy, halogen, or unsubstituted or substituted groups selected from alkyl, alkylamino, alkylthio, cycloalkyl, hydroxyalkyl, amino, alkoxy, alkoxyalkyl, alkoxycarbonyl, cycloalkoxy, aryl, arylamino, aminoalkyl, heteroaryl, heterocyclyl, aralkyl, aralkoxyalkyl, heteroaralkyl, acyl, acyloxy, acylamino, aryloxy, thioalkyl groups, carboxylic acid or its derivatives, sulfonic acid or its derivatives.

Suitable groups and substituents on the groups may be selected from those described anywhere in the specification.

Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases such as Na, K, Ca, Mg, Fe, Cu, Zn, and trolamine. Salts may include an appropriate acid addition salts of various pharmaceutically acceptable acids disclosed in Berge SM et al., 'Pharmaceutical salts', a review article in Journal of Pharmaceutical Sciences, volume 66, page 1 — 19 (1977) and in Handbok of Pharmaceutical Salts Properties, selection, and use by P.Heinrich Stahl and Camille G. Wermuth, Wiley-VCH (2002), such as sulphates, tartarates, borates, nitrates, benzoates, citrates, succinates, hydrohalides, salicylates, maleates hydroxy succinates, ascorbates, keto-glutarates, benzenesulfonates, glycerophosphates, hydroxynaphthoates and the like. It also includes salts derived from organic bases such as betaine λ^N'-diacetylethylenediamine, 2-diethylarninoethanol, 2- diethylaminomethanol, caffeine, glucosamine, glucamine, iV-ethyl-morpholine, N- ethylpiperidine, morpholine, isopropylamine,hydrabamine, piperazine piperidine, procaine, methylglucamine, diethylamine, glycinol, trimethyl amine, tripropyl-amine, diethanolamine, tromethamine, adamentyl amine, λζN'-diphenylethylenediamine, NJN'- dibenzylethylenediamine, iV-benzyl phenylethylamine, dicyclohexylamine, choline, choline hydroxide, metformin, phenylethylamine, benzylamine, thiamine, aminopyridine, aminopyrimidine, spermidine, purine and the like; chiral bases such as alkylphenyl amine and phenyl glycinol and the like, salts of natural aminoacids like alanine, glycine, proline, tyrosine, histidine, lysine, hydroxy proline, ornithine, serine, theonine, phenylalanine,

arginine, valine, leucine, isoleucine, cystine, norleucine, cysteine, methionine; unnatural amino acids such as D-isomers or substituted amino acids; guanidine, substituted guanidine wherein the substituents are selected from nitro, amino alkyl, alkenyl, ammonium or substituted ammonium salts. Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols. Particulary useful compounds may be selected from Compound Name > Na

1. 2-Cyano-3-(4-{2-[(la,5a,6a)-3-(2,4-difluorobenzyl)-3-azabicy clo[3.1.0]-hex- 6-ylamino]ethoxy}phenyl)propionic acid ethyl ester

2. 2-Cyano-3-(4-{2-[(lα,5α,6α)-3-(4-fluorobenzyl)-3-azabicyc lo[3.1.0]hex-6- ylamino]ethoxy}phenyl)propionic acid ethyl ester

3. 3-(4- {2-[( 1 α,5α,6α)-3 -(4-Chlorobenzyl)-3 -azabicyclo [3.1.0]hex-6-ylamino]- ethoxy}phenyl)-2-cyanopropionic acid ethyl ester 4. , 2-Cyano-3-(4-{2-[(lα,5α,6α)-3-(4-trifluoromethylbenzyl)-3 -azabicyclo-

[3.1.0]hex-6-ylamino]ethoxy }phenyl)propionic acid ethyl ester

5. 2-Cyano-3-(4-{2-[(lα,5α,6α)-3-(4-trifluoromethoxybenzyl)- 3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester ,

6. 3-(4- {2-[( 1 α,5α,6α)-3-Benzyl-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy } - . phenyl)-2-cyanopropionic acid ethyl ester

7. 2-Cyano-3-(4-{2-[(lα,5α,6α)-3-(2,4,5-trifluorobenzyl)-3-a zabicyclo[3.1.0]- hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester

8. _' 2-Cyano-3-(4-{2-[(lα,5α,6α)-3-(3-fluorobenzyl)-3-azabicyc lo[3.1.0]hex-6- ylamino]ethoxy}phenyl)propionic acid ethyl ester 9. 3-(4-{2-[(lα,5α,6α)-6-(4-Chlorobenzylamino)-3-azabicyclo[ 3.1.0]hex-3-yl]- ethoxy}phenyl)-2-cyanopropionic acid ethyl ester

■ 10. (2S)-2-(4-tert-Butylρhenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4-ch lorobenzyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester

11. (2R)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4-chl orobenzyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester

12. (2S)-3-(4-{2-[(lα,5α,6α)-6-tert-Butoxycarbonylamino-3-aza bicyclo[3.1.0]- hex-6-yl]ethoxy}phenyl)-2-(4-fer/-butylphenoxy)propionic acid ethyl ester 13. (2S)-2-(4-tert-Butylρhenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2 ₅ 4,5-trifluorobenzyl)-

S-azabicyclop.l.Ojhex-β-ylaminoJethoxyJphenyOpropionic acid ethyl ester

14. (2R)-2-(4-/er/-Bύtylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2 ₅ 4,5-trifluorobenzyl)- 3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester

15. (2S)-2-(4-ter/-Butylphenoxy)-3-(4-{2-[(l α,5α,6α)-3-(2,4,6-trifluorobenzyl)- 3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy }phenyl)propionic acid ethyl ester

16. (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(l α,5α,6α)-3-(4-trifluoromethyl- benzyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy }phenyl)propionic acid ethyl ester

17. (2S)-3-(4-{2-[(lα,5α,6α)-3-(2,4-Bis-trifluoromethylbenzyl )-3-azabicyclo- [3.1.0]hex-6-ylamimo]ethoxy}phenyl)-2-(4-fer/-butylphenoxy)p ropionic acid ethyl ester

18. (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2- ⁱ [(lα,5α,6α)-3-(2-fluoro-5-trifluoro- methylbehzyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl )propionic acid ethyl ester 19. (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(5-flu oro-2-trifluoro- , methylbenzyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl )propionic acid ethyl ester

20. (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4-tri fluoromethyl- sulfanylbenzyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phen yl)propionic acid ethyl ester

21. (2S)-2-(4-/ert-Butylphenoxy)-3-(4-{2-[(la,5a,6a)-3-(2,4-difl uorobenzyl)-3-' azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester

22. (2S)-2-(4-rert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(3-tri fluoromethyl- benzyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propi onic acid ethyl ester

23. (2S)-2-(4-/ert-Butylρhenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2-fl uorobenzoyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester

24. (2S)-2-(4-fcrt-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2 ₅ 4-difluόro-benzoyl)- S-azabicyclotS.l.Ojhex-ό-ylaminolethoxylpheny^propionic acid ethyl ester

25. (2S)-2-(4-^rt-Butylphenoxy)-3-(4-{2-[(lα ₅ 5α _J 6α)-3-(2 ₅ 4,5-trifluoro- benzoyl) _: 3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester

26. (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4-tri fluoromethyl-

, benzoyty-S-azabicyclop.l.Ojhex-ό-ylaminoJethoxyJphenytyprop ionic acid ethyl ester

27. (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(3-tri fluoromethyl- benzoyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)prop ionic acid ethyl ester

28. (2S)-3-(4-{2-[(lα,5α _! 6α)-3-(3,5-Bis-trifluoromethylbenzoyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)-2-(4-tert-butylphenoxy)p ropionic acid ethyl ester 29. (2S)-2-(4-tert-Butylρhenoxy)-3-(4- {2-[(l α,5α,6α)-3-(2,5-difluoroρhenyl- carbamoyl)-3-azabicyclo [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester

30. (2S)-2-(4-fert-Butylρhenoxy)-3 -(4- {2- [( 1 α,5α,6α)-3 -(2 ₅ 6-difluoroρhenyl- carbamoyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)pr opionic acid ethyl ester

31. (2S)-2-(4-/er/-Butylphenoxy)-3-(4- {2-[(l α,5α,6α)-3~(2 ,4,6-trifluorophenyl- carbamoyl)-3-azabicyclo [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester

32. (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α ₅ 6α)-3-(2,4 ₅ 5-trifluorophenyl- carbamoyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)pr opionic acid ethyl ester

33. (2S)-2-(4-/gr/-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4-tri fluoromethyl- phenylcarbamoyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phe nyl)- propionic acid ethyl ester

34. (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-cycloh exylmethyl-3- azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester

35. (2S)-3-(4-{2-[(lα,5α,6α)-3-^c-Butyl-3-azabicyclo[3.1.0]he x-6-ylamino]- ethoxy}phenyl)-2-(4-te/t-butylphenoxy)propionic acid ethyl ester

36. (2S)-3 -(4- { 2-[( 1 α,5 α,6α)-(3-Benzyl-3 -azabicyclo [3.1.0]hex-6-yl)-(butane- 1 - sulfonyl)amino]ethoxy}phenyl)-2-(4-fer^-butylphenoxy)propion ic acid ethyl ester

37. (2S)-3-(4-{2-[(lα,5α ₅ 6α)-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yϊ)-tert- butoxycarbonylamino]ethoxy}phenyl)-2-(4-tert-butylphenoxy)pr opionic acid ethyl ester

38. (2S)-3-(4-{2-[(lα,5α,6α)-(3-Benzyl-3-azabicyclo[3.1.0]hex -6-yl)acetyl- amino]ethoxy}phenyl)-2-(4-fert-butylphenoxy)propionic acid ethyl ester

39. (2S)-3-(4-{2-[(lα,5α,6α)-(3-Benzyl-3-azabicyclo[3.1.0]hex -6-yl)-(3-methyl- benzoyl)amino]ethoxy}phenyl)-2-(4-tert-butylphenoxy)propioni c acid ethyl ester

40. (2S)-3-(4-{2-[(lα,5α,6α)-l-(3-Benzyl-3-azabicyclo[3.1.0]h ex-6-yl)-3- methylthioureido]ethoxy}phenyl)-2-(4-/^r/-butylphenoxy)propi onic acid ethyl ester 41. (2S)-2-Ethoxy-3-(4-{2-[(la,5a,6a)-3-(2,4,5-trifluorobenzyl)- 3-azabicyclo-

[3.1.0]hex-6-ylaniino]propoxy}phenyl)propionic acid ethyl ester 42. (2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(pyridin-4-ylmethyl)- 3-azabicyclo-

[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester

43. (2S)-2-(4-tβrt-Butylρhenoxy)-3-(4-{2-[(lα ₅ 5α,6α)-3-(5-cyanopyridin-2-yl)-3- azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester

44. (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(thiaz ol-2-yl)-3-aza- bicyclofS.l.OJhex-ό-ylaminoJethoxylpheny^propionic acid ethyl ester 45. (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(3 ₅ 5-difluorobenzene- sulfonyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)pro pionic acid ethyl ester

46. (2S)-3-(4-{2-[(lα,5α,6α)-3-(Butane-l-sulfonyl)-3-azabicyc lo[3.1.0]hex-6- ylamino]ethoxy}phenyl)-2-(4-tert-butylphenoxy)propionic acid ethyl ester 47. (2S)-2-(4-tert-Butylρhenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4-ch lorobenzene- sulfonylaminocarbonyl)-3-azabicyclo[3.1.0]hex-6-ylamino]etho xy}phenyl)- propionic acid ethyl ester 48. (2S)-2-(4-/ert-Butylρhenoxy)-3-(4-{2-[(lα _J 5α,6α)-(3-o-tolylthiocarbamoyl)-

3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester 49. • (2S)-2-(4-fert-Butylρhenoxy)-3-[4-(2-{(lα,5α,6α)-(4-nitr obenzenesulfonyl)-

[3 -(2,4,5 -trifluorobenzyl)-3 -azabicyclo[3.1.0]hex-6-yl]amino } ethoxy)- phenyl]propionic acid ethyl ester

50. (2S)-3-(4-{2-I(lα,5α,6α)-l-(3-Benzyl-3-azabicyclo[3.1.0]h ex-6-yl)-3-(4- trifluoromethylphenyl)ureido]ethoxy}phenyl)-2-(4-/er/-butylp henoxy)- propionic acid ethyl ester

51. (2S)-2-(4-terr-Butylρhenoxy)-3-(4-{2-[(l α,5α,6α)-3-(2,4,5-trifluorobenzyl)- 3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid 2-cyclo- pentylethyl ester dihydrochloride

52. (2S)-2-(4-/ ^t ert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2 ₃ 4,5-trifluorobenzyl)- 3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid benzyl ester dihydrochloride

53. (2S)-3-(4-{2-[(lα ₅ 5α,6α)-3-(4-Chlorobenzyl)-3-azabicyclo[3.1.0]hex-6- ylamino]ethoxy}phenyl)-2-(4~isopropylphenoxy)propionic acid ethyl ester

54. . (2S)-2-(4-Isoρropylphenoxy)-3-(4-{2-[(l α,5α,6α)-3-(2 A5-trifluorobenzyl)-

3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester

55. (2S)-2-(4-Isoproρylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,4,6 -trifluorobenzyl)-

3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester 56. (2S)-2-(4-Isopropylphenoxy)-3-(4-{2-[(l α,5α ₃ 6α)-3-(2,4,5-trifluorobenzoyl)-

3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester

57. (2S)-3-(4-{2-[(lα ₅ 5α,6α)-3-(4-Chlorobenzyl)-3-azabicyclo[3.1.0]hex-6-yl- amino]ethoxy}phenyl)-2-(2,5-difluorophenoxy)propionic acid ethyl ester

58. (2S)-2-(2,5-Difluorophenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,4,5 -trifluorobenzyl)- S-azabicyclop.l.Ojhex-δ-ylaminojethoxyJphenytypropioriic acid ethyl ester

59. (2S)-2-(2,5-Difluorophenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4-tri fluoromethyl- benzyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propi onic acid ethyl ester

60. , (2S)-2-(3,5-Difluorophenoxy)-3-(4-{2-{(lα,5α,6α)-3-(2,4,5 -trifluorobenzyl)- 3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester

61. (2S)-2-(3,5-Difluorophenoxy)-3-(4-{2-[(lα,5α ₅ 6α)-3-(4-trifluoromethyl- benzyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propi onic acid ethyl ester

62. (2S)-3-(4-{2-[(lα,5α,6α)-3-(4-Fluorobenzyl)-3-azabicyclo[ 3.1.0]hex-6-yl- amino] ethoxy}phenyl)-2-m-tolyloxypropionic acid ethyl ester

63. _ (2S)-3-(4-{2-[(lα,5α,6α)-3-(4-Chlorobenzyl)-3-azabicyclo[ 3.1.0]hex-6-yl- amino]ethoxy}phenyl)-2-m-tolyloxypropionic acid ethyl ester

64. (2R)-3-(4-{2-[(lα,5α,6α)-3-(4-Chlorobenzyl)-3-azabicyclo[ 3.1.0]hex-6-yl- amino]ethoxy}phenyl)-2-OT-tolyloxypropionic acid ethyl ester 65. (2S)-2-(4-Methoxyρhenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,4,5-t rifluorobenzyl)-3- azabicyclop.l.Ojhex-ό-ylaminoJethoxyJ'pheny^propionic acid ethyl ester

66. (2S)-2-(4-Methoxyphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4-triflu oromethyl- benzyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propi onic acid ethyl ester

67. (2S)-3-(4-{2-[(lα,5α,6α)-3-(4-Trifluoromethylbenzyl)-3-az abicyclo[3.1.0]- hex-6-ylamino]ethoxy}plienyl)-2-(4-trifluoromethylphenoxy)-p ropionic acid ethyl ester

68. (2S)-3-(4-{2-[(lα,5α,6α)-3-(2,4,5-Trifluobenzyl)-3-azabic yclo[3.1.0]hex-6- ylamino]ethoxy}phenyl)-2-(4-trifluoromethylphenoxy)propionic acid ethyl ester 69. (2S)-2-(4-tert-Butylρhenoxy)-3 -(4- {2-[( 1 α,5α,6α)-6-(3 -trifluoromethyl- benzylamino)-3-azabicyclo[3.1.0]hex-3-yl]ethoxy }phenyl)propionic acid ethyl ester

70. (2S)-2-(4-/gr/-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-6-(4-tri fluoromethyl- benzylamino)-3-azabicyclo[3.1.0]hex-3-yl]ethoxy}phenyl)propi onic acid ethyl ester

71. (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-6-(2,4,5 -trifluorobenzyl- amino)-3-azabicyclo[3.1.0]hex-3-yl]ethoxy}phenyl)propionic acid ethyl ester

72. (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-6-(4-chl orobenzylamino)- 3-azabicyclo[3.1.0]hex-3-yl]ethoxy}phenyl)propionic acid ethyl ester 73. 2-(4-tert-Butylphenoxy)-2-methyl-3-(4-{2-[(lα,5α,6α)-3-(2 ,4,5-trifluoro- benzyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propi onic acid methyl ester 74. (2S)-2-Ethoxy-3-(4- {2-[(l α,5α,6α)-3-(4-fluorobenzyl)-3 -azabicyclo[3.1.0]- hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester 75. (2S)-3-(4-{2-[(lα,5α,6α)-3-(4-Chlorobenzyl)-3-azabicyclo[ 3.1.0]hex-6-yl- amino]ethoxy}phenyl)-2-ethoxypropionic acid ethyl ester

7,6. (2R)-3-(4-{2-[(lα,5α,6α)-3-(4-Chlorobenzyl)-3-azabicyclo[ 3.1.0]hex-6- ylamino]ethoxy}phenyl)-2-ethoxypropionic acid ethyl ester

77. (2S)-3-(4-{2-[(lα,5α _s 6α)-3-(2,4-Difluorobenzyl)-3-azabicyclo[3.1.0]hex-6- ylamino]ethoxy}phenyl)-2-ethoxypropibnic acid ethyl ester

78. (2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(2,4,5-trifluorobenzy l)-3-azabicyclo- [3.1.0]hex-6-ylaniino]ethoxy}phenyl)propionic acid ethyl ester 79. (2R)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(2,4,5-trifluorobenzy l)-3-azabicyclo- ^'

[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester

80. , (2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(4-trifluoromethylben zyl)-3-aza- bicyclop.l.OJhex-β-ylaminojethoxylphenyljpropionic acid ethyl ester

81. (2R)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(4-trifluoromethylben zyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester

82. (2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(4-trifluoromethoxybe nzyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester

83. (2R)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(4-trifluoromethoxybe nzyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester 84. (2S)-2-Ethoxy-3-(4-{2-[(lα ₅ 5α,6α)-3-(2-fluoro-5-trifluoromethylbenzyl)-3- azabicyclofS.l.OJhex-β-ylaminojethoxyJpheny^propionic acid ethyl ester

85. (2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(5-fluoro-2-trifluoro rnethylbenzyl)-3- azabicyclofS.l.OJhex-β-ylaminoJethoxyJphenyOpropionic acid ethyl ester

86. (2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(2,4,6-trifluorobenzy l)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy }phenyl)propionic acid ethyl ester

87. (2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(3,3,3-trifluoropropy l)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester

88. (2S)-2-Ethoxy-3-(4-{2-[(lα,5α ₅ 6α)-3-(3-trifluoromethylbenzyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester 89. (2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(4-trifluoromethylsul fanylbenzyl)-3-

' azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester 90. (2S)-3-(4-{2-[(lα,5α,6α)-3-(2,4-Difluorobenzoyl)-3-azabic yclo[3.1.0]-hex-6- ylamino]ethoxy}phenyl)-2-ethoxypropionic acid ethyl ester

91. (2S)'-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(4-trifluoromethylbe nzoyl)-3-aza- bicyclop.l.OJhex-ό-ylaminojethoxylpheny^propionic acid ethyl ester

92. (2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(3-trifluoromethylben zoyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester 93. (2S)-3-(4-{2-[(lα,5α,6α)-3-(2,4-Bis-trifluoromethylbenzoy l)-3-azabicyclo-

[3.1.0]hex-6-ylamino]ethoxy}phenyl)-2-ethoxypropionic acid ethyl ester

94. (2S)-3-(4-{2-[(lα,5α,6α)-3-(3,5-Bis-trifluoromethylbenzoy l)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)-2-ethoxypropionic acid ethyl ester

95. (2S)-2-Ethoxy-3-(4-{2-[(lα _J 5α,6α)-3-(2,4,5-trifluorophenylcarbamoyl)-3- azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)proρionic acid ethyl ester

96. (2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(4-trifluoromethylphe nylcarbamoyl)-3- azabicyclofS.l.OJhex-ό-ylaminolethoxyJpheny^propionic acid ethyl ester

97. 2-Cyano-3-(4-{2-[(lα,5α,6α)-3-(2,4-difluorobenzyl)-3-azab icyclo[3.1.0]hex- 6-ylamino]ethoxy}phenyl)propionic acid 98. 2-Cyano-3-(4-{2-[(lα,5α,6α)-3-(4-fluorobenzyl)-3-azabicyc lo[3.1.0]hex-6- ylamino]ethoxy}phenyl)propionic acid

99. 3-(4-{2-[(lα,5α,6α)-3-(4-Chlorobenzyl)-3-azabicyclo[3.1.0 ]hex-6-ylamino]- ethoxy}phenyl)-2-cyanopropionic acid

100. 2-Cyano-3-(4-{2-[(l α,5α,6α)-3-(4-trifluoromethylbenzyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid

101. 2-Cyano-3-(4- {2-[(l α,5α,6α)-3-(4-trifluoromethoxybenzyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid

102. 3-(4-{2-[(lα,5α ₅ 6α)-3-Benzyl-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}- phenyl)-2-cyanopropionic acid 103. 2-Cyano-3-(4-{2-[(lα,5α,6α)-3-(2,4,5-trifluorobenzyl)-3-a zabicyclo[3.1.0]- hex-6-ylamino]ethoxy}phenyl)propionic acid

104. 2-Cyano-3-(4-{2-[(lα,5α,6α)-3-(3-fluorobenzyl)-3-azabicyc lo[3.1.0]hex-6- ylamino]ethoxy}phenyl)propionic acid

105. 3-(4-{2-[(lα,5α,6α)-6-(4-Chlorobenzylamino)-3-azabicyclo[ 3.1.0]hex-3-yl]- ethoxy}phenyl)-2-cyanopropionic acid

106. (2S)-2-(4-tert-Butylρhenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4-ch lorobenzyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid 107. (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4-chl orobenzyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride

108. (2R)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα3α,6α)-3-(4-chlo robenzyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid

109. (2R)-2-(4-/ert-Butylphenoxy)-3-(4-{2-[(lα,5α ₅ 6α)-3-(4-chlorobenzyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride

110. (2S)-2-(4-/er/-Butylρhenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,4, 5-trifluorobenzyl)- 3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride

111. (2R)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,4,5 -trifluorobenzyl)- 3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride

112. (2S)-2-(4-fe^-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,4,6- trifluorobenzyl)- 3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride 113. (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4-tri fluoromethyl- benzyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propi onic acid dihydrochloride

114. (2S)-3-(4-{2-[(lα,5α,6α)-3-(2,4-Bis-trifluoromethylbenzyl )-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)-2-(4-ter/-butylphenoxy)p ropionic acid dihydrochloride

115. (2S)-2-(4-/er/-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2-flu oro-5-trifluoro- methylbenzyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl )propionic acid dihydrochloride

^, 116. (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(5-flu oro-2-trifluoro- methylbenzyl)-3-azabicyclo[3.1,0]hex-6-ylamino]ethoxy}phenyl )propionic acid dihydrochloride

117. (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(l α,5α,6α)-3-(4-trifluoromethyl- , sulfanylbenzyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phen yl)propionic acid dihydrochloride

118. (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,4-d ifluorobenzyl)-3- azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride 1 ϊ9. (2S)-2-(4-ter/-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(3-tri fluoromethyl- benzyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy }phenyl)propionic acid dihydrochloride 120. (2S)-2-(4-ter/-Butylρhenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2-fl uorobenzoyl)-3- azabicyclo[3.1.0]hex-6-yIamino]ethoxy }phenyl)propionic acid hydrochloride 121. (2S)-2-(4-/grt-Butylρhenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,4- difluorobenzoyl)-3- azabicyclo[3.1.0]hex-6-ylamino]ethoxy }phenyl)propionic acid hydrochloride 122. (2S)-2-(4-^rt-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,4,5- trifluorobenzoyl)-

S-azabicyclofS.l.Ojhex-ό-ylaminoJethoxyJpheny^propionic acid hydro- chloride 123. (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(l α,5ά,6α)-3-(4-trifluoromethyl- benzoyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)prop ionic acid hydrochloride

124. , (2S)-2-(4-rert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(3-tri fluoromethyl- . benzoyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)prop ionic acid hydrochloride

125. (2S)-3 -(4- {2-[( 1 α,5 α,6α)-3 -(3 ,5-Bis-trifluoromethylbenzoyl)-3-azabicyclo-

[3.1.0]hex-6-ylamino]ethoxy}phenyl)-2-(4-ført-butylpheno xy)propionic acid hydrochloride

126. (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,5-d ifluorophenyl- carbamoyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)pr opionic acid hydrochloride

127. (2S)-2-(4-te/Y-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,6-d ifluorophenyl- carbamoyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)pr opionic acid hydrochloride

128. (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα ₅ 5α,6α)-3-(2,4,6-trifluorophenyl- carbamoyl)-3 -azabicyclo [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid hydrochloride 129. (2S)-2-(4-terr-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,4,5 -trifluorophenyl- carbamoyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)pr opionic acid hydrochloride , »

130. (2S)-2-(4-/er/-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4-tri fluoromethyl- phenylcarbamoyl)-3 -azabicyclo [3.1.0]hex-6-ylamino]ethoxy}phenyl)- propionic acid hydrochloride

131. (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-cycloh exylmethyl-3- azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydro-

, chloride

132. 2-(4-fert-Butylphenoxy)-2-methyl-3-(4-{2-[(lα,5α,6α)-3-(2 ,4,5-trifluoro- benzyiyS-azabicyclop.l.OJhex-ό-ylaminojethoxyJphenytypropio nic acid dihydrochloride

133. (2S)-3-(4-{2-[(lα,5α,6α)-3-5ec-Butyl-3-azabicyclo[3.1.0]h ex-6-ylamino]- ethoxy}phenyl)-2-(4-fert-butylphenoxy)propionic acid dihydrochloride

134. (2S)-3-(4-{2-[(lα,5α,6α)-(3-Benzyl-3-azabicyclo[3.1:0]hex -6-yl)-(butane-l- sulfonyl)amino]ethoxy}phenyl)-2-(4-fe/t-butylphenoxy)propion ic acid hydrochloride

135. (2S)-3-(4-{2-[(lα,5α,6α)-(3-Benzyl-3-azabicyclo[3.1.0]hex -6-yl)-^rt- butoxycarbonylamino]ethoxy}phenyl)-2-(4-tert-butylphenoxy)pr opionic acid

136. (2S)-3-(4-{2-[(lα,5α,6α)-(3-Benzyl-3-azabicyclo[3.1.0]hex -6-yl)acetyl- amino]ethoxy}phenyl)-2-(4-før/-butylphenoxy)propionic acid hydrochloride

137. (2S)-3-(4-{2-[(lα,5α,6α)-(3-Benzyl-3-azabicyclo[3.1.0]hex -6-yl)-(3-methyl- benzoyl)amino]ethoxy}phenyl)-2-(4-/er/-butylphenoxy)propioni c acid hydro- chloride

138. (2S)-3-(4-{2-[(lα,5α,6α)-l-(3-Benzyl-3-azabicyclo[3.1.0]h ex-6-yl)-3- methylthioureido]ethoxy}phenyl)-2-(4-tert-butylphenoxy)propi onic acid hydrochloride

139. (2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(2,4,5-trifluorobenzy l)-3-azabicyclo- [3.1.0]hex-6-ylamino]propoxy} phenyl)propionic acid dihydrochloride

140. (2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(pyridin-4-ylmethyl)- 3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy }phenyl)propionic acid trihydrochloride

141. (2S)-2-(4-ter/-Butylphenoxy)-3-(4- {2-[( 1 α,5 α,6α)-3 -(5 -cyanopyridin-2-yl)-3 - azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid trihydro- chloride

142. (2S)-2-(4-tert-Butylρhenoxy)-3-(4-{2-[(lα,5α,6α)-3-(thia zol-2-yl)-3-aza- bicyclo [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid trihydrochloride

143. (2S)-2-(4-ført-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(3,5- difluorobenzene- sulfonyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)pro pionic acid hydrochloride

144. (2S)-3-(4-{2-[(lα,5α,6α)-3-(Butane-l-sulfonyl)-3-azabicyc lo[3.1.0]hex-6-yl- amino]ethoxy}phenyl)-2-(4-tert-butylphenoxy)propionic acid hydrochloride

145. (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4-chl orobenzene- sulfonylaminocarbonyl)-3 -azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)- propionic acid hydrochloride

146. (2S)-2-(4-/e^-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-(3-o-toly lthiocarbamoyl)- 3 -azabicyclo [3.1.0]hex-6-y lamino] ethoxy } phenyl)propionic acid hydro- chloride

147. (2S)-2-(4-tert-Butylphenoxy)-3-[4-(2-{(lα,5α,6α)-(4-nitro benzenesulfonyl)- [3-(2,4,5-trifluorobenzyl)-3-azabicyclo[3.1.0]hex-6-yl] amino }ethoxy)phenyl]- propionic acid hydrochloride

148. (2S)-3-(4-{2-[(lα ₅ 5α,6α)-l-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)-3-(4- trifluoromethylphenyl)ureido]ethoxy}phenyl)-2-(4-tert-butylp henoxy)- propionic acid hydrochloride

149. (2S)-3-(4-{2-[(lα ₃ 5α,6α)-3-(4-Chlorobenzyl)-3-azabicyclo[3.1.0]hex-6-yl- amino]ethoxy}phenyl)-2-(4-isopropylphenoxy)propionic acid dihydrochloride

150. (2S)-2-(4-Isopropylphenoxy)-3-(4-{2-[(l α,5α,6α)-3-(2,4,5-trifluorobenzyl)- 3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy }phenyl)propionic acid dihydro- chloride ,

151. (2S)-2-(4-Isopropylphenoxy)-3-(4-{2-[(l α,5α,6α)-3-(2,4,6-trifluorobenzyl)- 3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydro- chloride 152. (2S)-2-(4-Isopropylphenoxy)-3-(4-{2-[(l α,5α,6α)-3-(3,4,5-trifluoro- benzoyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy }phenyl)propionic acid hydrochloride

153. (2S)-3-(4-{2-[(lα,5α,6α)-3-(4-Chlorobenzyl)-3-azabicyclo[ 3.1.0]hex-6-yl- amino]ethoxy}phenyl)-2-(2,5-difluorophenoxy)propionic acid dihydro- chloride

154. (2S)-2-(2,5-Difluoroρhenoxy)-3-(4-{2-[(l α,5α,6α)-3-(2,4,5-trifluorobenzyl)- 3 -azabicyclo [3.1.0]hex-6-ylamino] ethoxy } phenyl)propionic acid dihydro- chloride

155. (2S)-2-(2,5-Difluoroρhenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4-tr ifluoromethyl- benzyl)-3 -azabicyclo [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride

156. (2S)-2-(3 ₅ 5-Difluorophenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,4,5-trifluoro benzyl)- 3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydro- chloride

157. (2S)-2-(3,5-Difluorophenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4-tri fluoromethyl- benzyl)-3 -azabicyclo [3.1.0]hex-6-ylamino]ethoxy } phenyl)propionic acid dihydrochloride

158. (2S)-3-(4-{2-[(lα,5α,6α)-3-(4-Fluorobenzyl)-3-azabicyclo[ 3.1.0]hex-6-yl- amino]ethoxy}phenyl)-2-m-tolyloxypropionic acid

, 159. (2S)-3-(4-{2-[(lα,5α,6α)-3-(4-Chlorobenzyl)-3-azabicyclo[ 3.1.0]hex-6-yl- amino]ethoxy}phenyl)-2-m-tolyloxypropionic acid

160. (2R)-3-(4-{2-[(lα,5α,6α)-3-(4-Chlorobenzyl)-3-azabicyclo[ 3.1.0]hex-6-yl- amino]ethoxy}phenyl)-2-rø-tolyloxypropionic acid

161. (2S)-2-(4-Methoxyphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,4,5-tr ifluorobenzyl)-3- azabicyclo[3.1.0]hex-6-ylamino]ethoxy }phenyl)propionic acid dihydro- chloride

162. (2S)-2-(4-Methoxyphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4-triflu oromethyl- benzyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propi onic acid dihydrochloride

163. (2S)-3-(4-{2-[(lα _s 5α,6α)-3-(4-Trifluoromethylbenzyl)-3-azabicyclo[3.1.0]- hex-6-ylamino]ethoxy}phenyl)-2-(4-trifluoromethylphenoxy)pro pionic acid dihydrochloride

164. ^' (2S)-3-(4-{2-[(lα ₅ 5α,6α)-3-(2,4,5-Trifluorobenzyl)-3-azabicyclo[3.1.0]hex-6- ylamino]ethoxy}phenyl)-2-(4-trifluoromethylphenoxy)propionic acid dihydrochloride 165. (2S)-2-(4-før/-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-6-(3-tr ifluoromethyl- benzylamino)-3 -azabicyclo [3.1.0]hex-3 -yl] ethoxy } phenyl)propionic acid dihydrochloride

166. (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α ₅ 6α)-6-(4-trifluoromethyl- benzylamino)-3-azabicyclo[3.1.0]hex-3-yl]ethoxy}phenyl)propi onic acid dihydrochloride

167. (2S)-2-(4-ført-Butylphenoxy)-3-(4-{2-[(lα ₅ 5α,6α)-6-(2,4,5-trifluorobenzyl- amino)-3-azabicyclo[3.1.0]hex-3-yl]ethoxy}phenyl)propionic acid dihydrochloride

168. (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-6-(4-chl orobenzylamino)- 3-azabicyclo[3.1.0]hex-3-yl]ethoxy}phenyl)propionic acid dihydrochloride

169. (2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(4-fluorobenzyl)-3-az abicyclo[3.1.0]- hex-6-ylamino]ethoxy}phenyl)propionic acid

170. (2S)-3-(4-{2-[(lα,5α,6α)-3-(4-Chlorobenzyl)-3-azabicyclo[ 3.1.0]hex-6-yl- , amino]ethoxy}phenyl)-2-ethoxypropionic acid

171. (2R)-3-(4-{2-[(lα ₅ 5α,6α)-3-(4-Chlorobenzyl)-3-azabicyclo[3.1.0]hex-6-yl- amino]ethoxy}phenyl)-2-ethoxyproρionic acid 172. (2S)-3-(4-{2-[(lα,5α,6α)-3-(2,4-Difluorobenzyl)-3-azabicy clo[3.1.0]hex-6- ylamino]ethoxy}phenyl)-2-ethoxyproρionic acid dihydrochloride

173. (2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3 _^ (2,4,5-trifluorobenzyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid

174. (2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(2,4 ₅ 5-trifluorobenzyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride

175. (2R)-2-Ethoxy-3 -(4- {2-[( 1 α,5α,6α)-3 -(2,4,5-trifluorobenzyl)-3 -azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride

176. (2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(4-trifluoromethylben zyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride 177. (2R)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(4-trifluoromethylben zyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride 178. (2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(4-trifluoromethoxybe nzyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid

179. (2R)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(4-trifluoromethoxybe nzyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid

180. (2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(2-fluoro-5-trifIuoro methylbenzyl)-3- azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydro- chloride

181. (2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(5-fluoro-2-trifluoro methylbenzyl)-3- azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydro- chloride

182. (2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(2,4,6-trifluorobenzy l)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride

183. (2S)-2-Ethoxy-3-(4-{2-[(l α,5α,6α)-3-(3,3,3-trifluoroproρyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy }phenyl)propionic acid dihydrochloride

184. (2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(3-trifluoromethylben zyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride 185. (2S)-2-Ethoxy-3-(4-{2-[(l α,5α,6α)-3-(4-trifluoromethylsulfanylbenzyl)-3- azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride

186. (2S)-3-(4-{2-[(lα,5α,6α)-3-(2,4-Difluorobenzoyl)-3-azabic yclo[3.1.0]-hex-6- ylamino]ethoxy}phenyl)-2-ethoxypropionic acid hydrochloride 187. (2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(4-trifluoromethylben zoyl)-3-aza- bicycloβ.l.Ojhex-β-ylaminolethoxyJphenytypropionic acid hydrochloride

188. (2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(3-trifluoromethylben zoyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid hydrochloride

189. (2S)-3-(4-{2-[(l α,5α,6α)-3-(2,4-Bistrifluoromethylbenzoyl)-3-azabicyclo- , [3.1.0]hex-6-ylamino]ethoxy}phenyl)-2-ethoxypropionic acid hydrochloride

190. (2S)-3-(4-{2-[(lα,5α,6α)-3-(3,5-Bistrifluoromethylbenzoyl )-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)-2-ethoxypropionic acid hydrochloride

191. (2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(2,4,5-trifluoropheny lcarbamoyl)-3- azabicycϊo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid hydrochloride

192. (2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(4-trifluoromethylphe nylcarbamoyl)-3- azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid hydrochloride 193. (2S)-[(1 α,5α,6α)-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)]-(2-{4-[2 -(4-fert- butylphenoxy)-2-methylcarbamoylethyl]phenoxy } ethyl)carbamic acid tert- butyl ester 194. (2S)-3-(4-{2-[(lα,5α,6α)-3-Benzyl-3-azabicyclo[3.1.0]hex- 6-ylamino]- ethoxy}phenyl)-2-(4-tert-butylphenoxy)-N-methylpropionamide 195. (2S)-3-(4- {2-[(l α,5α,6ά)-(3-Azabicyclo[3.1.0]hex-6-yl)-tert-butoxycarbony l- amino]ethoxy}phenyl)-2-(4-tert-butylphenoxy)propionic acid ethyl ester 196. (2S)-3-(4-{2-[((lα,5α,6α)-3-Benzyl-3-azabicyclo[3.1.0]hex -6-yl)-(4-nitro- benzenesulfonyl)amino]ethoxy}phenyl)-2-(4-tert-butylphenoxy) propionic acid ethyl ester 197. (2S)-3-{4-[2-((lα,5α,6α)-3-Benzyl-3-azabicyclo[3.1.0]hex- 6-ylamino)- ethoxy]phenyl}-2-(4-tert-butylphenoxy)propionic acid ethyl ester

198. (2S)-3-(4-{2-[(l α,5α,6α)-(3-Azabicyclo[3.1.0]hex-6-yl)tert-butoxycarbonyl - amino]ethoxy}phenyl)-2-ethoxypropionic acid ethyl ester

199. (2S)-3-(4-{2-[(lα,5α,6α)-(3-Benzyl-3-azabicyclo[3.1.0]hex -6-yl)-(4-nitro- benzenesulfonyl)amino]ethoxy}phenyl)-2-ethoxypropionic acid ethyl ester

200. (2S)-3-(4-{2-[(lα,5α ₅ 6α)-3-Benzyl-3-azabicyclo[3.1.0]hex-6-ylamino]- ethoxy}phenyl)-2-ethoxypropionic acid ethyl ester

201. (2S)-3-(4-{2-[(lα,5α,6α)-(3-Benzyl-3-azabicyclo[3.1.0]hex -6-yl)-fer/- butoxycarbonylamino]ethoxy}phenyl)-2-ethoxypropionic acid ethyl ester 202. (2S)-3-(4-{2-[(lα,5α ₅ 6α)-6-Amino-3-azabicyclo[3.1.0]hex-3-yl]ethoxy}- phenyl)-2~(4~/er/-butylphenoxy)propionic acid ethyl ester

According to a feature of the present invention, the compounds of general formula (I) where W represents fragments of formula (III) and (IV) and all other symbols are as defined earlier, can be prepared by methods given in Scheme 1 and Scheme 2 below, however, the invention is not limited to these methods, the compounds may also be prepared as described for structurally related compounds described in literature:

Scheme 1

H-N- <J N-H + L -(CH ₂ ),,- O

R ¹

Y Z

(V) (VI)

Base^

(VIII) (XII)

Deprotection Reduction

B B

L ¹ is selected from halogen, /7-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and the like

t Base is selected from potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, diisopropylethylamine

A: R ⁷ -N=C=O or R ⁷ -N=C=S or R ⁷ -SO ₂ -N=C=O or R ¹ L, R ¹ is other than defmation (xiv) and L is a leaving group B: R ⁷ -N=C=O or R ⁷ -N=C=S or R ⁷ -SO ₂ -N=C=O or R ⁸ U R ⁸ is other than defmation (xiv) and L is a leaving group R ^8' can be R ⁸

Rl ' is one methylene less Rl defined under definition iii, iv, v, viii, x, xi ^# Reduction was carried out using reducing agents such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride

The compounds of the invention of formula (Ia) [which includes compounds of formula (IX), (X), (XI), (XIII) and (XIV). Compound of formula (Ia) may also include compounds of formula (VII) and (VIII) if the protecting group, R ⁸ is the same as covered under the general definition of R ⁸ .] can be prepared as per Scheme 1.

Compounds of formula (V) can be synthesized as per reported procedure described in EP0413455; US2490714 and Synlett, 1097-1102 (1996) or a method described in reference examples, or in a similar manner thereto. '

Compounds of formula (VI) can be obtained by the methods described in literature such as PCT Application WO 2003053974, US Patents US6528525, US5232945 and US6630600 or a method described in reference examples, or in a similar manner thereto.

Compound of formula (V) was condensed with compound of formula (VI) where all the symbols are as defined earlier except R ⁸ is an protecting group selected from various N- protecting groups as described in the literature [for example, Protective Groups in Organic Synthesis by P. G. M. Wuts and T. W. Greene, John Wiley & Sons Inc. (1981)] and L ¹ is a leaving group such as halogen, jo-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and like in the presence of suitable inert solvent, for example, a 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,N'-dimethylformamide, iV-methyl- pyrrolidone and dimethyl sulfoxide, ¹ acetonitrile, or a mixture thereof, in the presence of a suitable base such as potassium carbonate, sodium carbonate, cesium carbonate, .triethyl-

amine, diisopropylethylamine at a temperature between 25-150 ⁰ C for 1-24 h to obtain a compound of formula (VII). Phase transfer catalyst such as tetraalkylammonium halides, potassium iodide and sodium iodide can be employed to increase the efficiency of the reaction. The reaction is more effective under anhydrous conditions. The inert atmosphere may be maintained by using inert gases such as nitrogen, argon or helium. Further compound of formula (VII) was treated with either R ⁷ -N=C=O, R ⁷ -N=C=S,

R ⁷ -Sθ ₂ -N=C=O; where R ⁷ is Q-Csalkyl (straight or branched), cycloalkyl having 3- 10 carbon atoms, cycloalkylmethyl having 4-10 carbon atoms, phenyl which is unsubstituted or substituted with 1-5 substituents, arylalkyl group, heteroaryl group, heteroaralkyl group which may be substituted as defined above or R ¹ L, where L is a leaving group such as halogen, hydroxy, or the like and R ¹ is same as defined earlier excluding hydrogen atom and defϊnation (xiv) in the presence of solvents such as a halogenated hydrocarbon such as chloroform and dichlorometharie, 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,N'-dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide, acetonitrile, a lower alcohol such as methanol, ethanol and propanol, or their mixture, using suitable coupling agents EDCI, dicyclohexyl urea, triarylphosphine/ dialkylazadicarboxylate such as PPhs/DEAD or DIAD and the like to obtain compound of formula (VIII). The reaction may also be effected in the presence of DMAP, HOBT, BINAP, palladium acetate. The reaction temperature may be in range between -20 ⁰ C to 100 ⁰ C. The duration of the reaction may range from 0.5-48 h. The inert atmosphere may be employed by using inert gases such as nitrogen, argon or helium. The above reaction may also be carried out by using mixed anhydride methodology. Compound of (VιII)was then deprotected using standard methodology to obtain compound of formula (IX). Which was then substituted with the groups as covered under the general defϊnation of R ⁸ group by reaction with either R ⁷ - N=C=O, R ⁷ -N=C=S, R ⁷ -SO ₂ -N=C=O; where R ⁷ is C _r C ₈ alkyl (straight or branched), cycloalkyl having 3-10 carbon atoms, cycloalkylmethyl having 4-10 carbon atoms, phenyl which is unsubstituted or substituted with 1-5 substituents, arylalkyl group, heteroaryl group, heteroaralkyl group which may be substituted as defined above or R L, wherein, L is a

leaving group such as halogen, hydroxy, or the like R ⁸ is same as defined other than defination (i) and (xiv), in the presence of solvents such as a 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 iV,N'-dimethylformamide, iV-methylpyrrolidorie and dimethyl sulfoxide, acetonitrile, a lower alcohol such as methanol, ethanol and propanol, or their mixture, using suitable coupling agents EDCI, dicyclohexyl urea triarylphosphine/ dialkylazadicarboxylate such as PPh ₃ ZDEAD or DIAD and the like to obtain compound of formula (X). The reaction may be carried out in the presence of BINAP, palladium acetate. The reaction temperature may be in range between —20 ⁰ C to 100 ⁰ C under inert atmosphere may be employed by using inert gases such as nitrogen, argon or helium.

Alternatively, compound of formula (VII) was first deprotected using standard methods to obtain compound of formula (XI). Which was further treated with compound R ¹ L where all the symbols X, Y, Z, n are same as defined earlier, L represents CHO and R ¹ is one methylene less R ¹ defined under definition (iii), (iv), (v), (viii), (x), (xi); and may be selected from substituted or unsubstituted C ₁ -C ₈ alkyl (straight or branched); cycloalkyl having 3-10 carbon atoms; phenyl which is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of halogen, CrC ₁₂ alkyl, C ₁ -Ci ₂ alkoxy, C ₁ -C ₁₂ thioalkyl, nitro, amino, haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, hydroxy, cyano, formyl, mono or dialkylamino, Q-Cnalkylsulfonyl, aryloxy, aralkyloxy; unsubstituted or substituted l,2-(ethylenedioxy)benzene; aryl group such as naphthyl and the like; heteroaryl group which is unsubstituted or substituted with 1 or 2 substituents each

> independently selected from the group consisting of halogen, Ci-C ₄ alkyl, C ₁ -C ₄ alkoxy, haloalkoxy, perhaloalkoxy, haloalkyl, perhaloalkyl, nitro, cyano, mono or dialkylamino, preferred groups are pyridyl, thienyl, thiazolyl, furyl, pyrimidinyl, quinolinyl, indolyl, benzoxazolyl, benzothiazolyl, pyrazolyl, benzimidazolyl, imidazolyl, thiadiazolyl, triazolyl, oxadiazolyl; heteroaralkyl group which is substituted or unsubstituted, preferred groups are pyridinemethyl, benzofuranmethyl, benzothiophenemethyl, furanmethyl, thiophenemethyl,

' coumarinmethyl, oxazolemethyl and 1,4-benzodioxanmethyl; substituted or unsubstituted

alkoxyalkyl group, which is preferably C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl group, examples thereof include methoxymethyl, ethoxymethyl, methoxyethyl and ethoxypropyl groups, in a suitable inert solvents, for example, a 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, a lower alcohol such as methanol, ethanol and 2- propanol, or a mixture thereof at a temperature between 0-120 ⁰ C for 2-10 h to obtain compound of formula (XII), which was further reduced under a suitable condition using a reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetόxyborohydride to get compound of formula (XIII). Compound of formula (XIII) further treated with either R ⁷ -N=C=O, R ⁷ -N=C=S, R ⁷ -SO ₂ -N=C=O or R ⁸ L, where in all the definations are as described earlier, in the presence of solvents such as a 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,N '-dimethylformamide, iV-methylpyrrolidone and dimethyl sulfoxide, acetonitrile, a lower alcohol such as methanol, ethanol and propanol, or their mixture, using suitable coupling agents EDCI, dicyclohexyl urea triarylphosphine/ dialkylazadicarboxylate such as PPh ₃ /DEAD or DIAD and the like to obtain compound of formula (XIV). The reaction may be carried out in the presence of BINAP, palladium acetate. The reaction temperature may be in range between -20 ⁰ C to 100 ⁰ C. The duration of the reaction may range from 0.5-48 h. The inert atmosphere may be employed by using inert gases such as nitrogen, argon or helium.

Scheme 2

and L is -OH)

(Ib)

Compounds of the formula (Ib) can be prepared using a variety of methods known in literature and known to those skilled in the art. One such approach is by the reaction of compound (XV), wherein, R ⁸ comprises of electronegative groups selected from the groups covered under the general definition of R , and compound (VI) where L is hydroxy group, in a suitable inert solvent, for example, a 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 A^N'-dimethylformamide, iV-methylpyrrolidone and dimethyl sulfoxide, or a mixture < thereof, under a condition of the Mitsunobu reaction at a temperature between 0 ⁰ C to the boiling point of a solvent used for 5 min to 48 h. The compound so obtained may optionally be deprotected and further treated with either R ⁷ -N=C=0, R ⁷ -N=C=S, R ⁷ -SO ₂ -N=C=O; where R ⁷ is Q-Csalkyl (straight or branched), cycloalkyl having 3-10 carbon atoms, cycloalkylmethyl having 4-10 carbon atoms, phenyl which is unsubstituted or substituted with 1-5 substituents, arylalkyl group, heteroaryl group, heteroaralkyl group which may be substituted as defined above or R ⁸ L, wherein R ⁸ is non-hydrogen substituents as covered under the general defination 'of R ⁸ other than defination (xiv), L is a leaving group such as halogen, hydroxy or the like in the presence of solvents such as a halogenated hydrocarbon

such as chloroform and dichloromethane, an aromatic hydrocarbon such as benzene and toluene, an ether type solvent such as diethyl ether, tetrahydrofiiran and 1,4-dioxane, an aprotic polar solvent such as λζN'-dimethylformarnide, iV-methylpyrrolidone and dimethyl sulfoxide, acetonitrile, a lower alcohol such as methanol, ethanol and propanol, or their mixture, using suitable coupling agents EDCI, dicyclohexyl urea triarylphosphine/ dialkylazadicarboxylate such as PPh ₃ ZDEAD, DIAD, BINAP, palladium acetate and the like. The reaction temperature may be in range between -20 ⁰ C to 100 ⁰ C. The duration of the reaction may range from 0.5-48 h. The inert atmosphere may be employed by using inert gases such as nitrogen, argon or helium. Alternatively, compounds of formula (Ib) can be obtained by the reaction of compound (XV) and compound (VI) where L ¹ is a leaving group such as halogen, p- toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and like in the presence of suitable inert solvent, for example, a 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 iVjiV'-dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide, acetonitrile, or a mixture thereof, using a suitable base such as potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, diisopropylethyl-amine at a temperature between 25-150 ⁰ C for 1- 24 h. Phase transfer catalyst such as tetraalkylammonium halide may be employed. The reaction is more effective under anhydrous conditions. The inert atmosphere may be maintained by using inert gases such as nitrogen, argon or helium.

The compounds of formula (Ib) where all the symbols are defined earlier excluding R ¹ as hydrogen can be prepared by the reaction of compounds of formula (Ib) where R ¹ is hydrogen and all other symbols are same as defined earlier with either R ⁷ -N=C=O, R ⁷ - N=C=S, R ⁷ -SO ₂ -N=C=O; where R ⁷ is C ₁ -C ₈ alkyl (straight or branched), cycloalkyl having 3-10 carbon atoms, cycloalkylmethyl having 4-10 carbon atoms, phenyl which is unsubstituted or substituted with 1-5 substituents, arylalkyl group, heteroaryl group, heteroaralkyl group which may be substituted as defined above, or R ¹ L where L is reacting group such as halogen, hydroxy and the like, and R ¹ is same as defined earlier excluding

hydrogen atom and defination (xiv)j in the presence of solvents such as a 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,JV'-dimethylformamide, iV-methylpyrrolidone and dimethyl sulfoxide, acetonitrile, a lower alcohol such as methanol, ethanol and propanol, or their mixture, using suitable coupling agents EDCI, dicyclohexyl urea, triarylphosphine/ dialkylazadicarboxylate such as PPh ₃ /DEAD or DIAD and the like followed by the deprotection. The reaction may be effected in the presence of DMAP, HOBT. The reaction may be carried out in the presence of BIνAP, palladium acetate. The reaction temperature may be in range between -20 ⁰ C to 100 ⁰ C. The duration of the reaction may range from 0.5- 48 h. The inert atmosphere may be employed by using inert gases such as nitrogen, argon or helium. The above reaction may also be carried out by using mixed anhydride methodology.

The starting material i.e. compound of formula (XV) can be synthesized as per reported procedure described in EP0413455; US2490714 and Synlett, 1097-1102 (1996) or a method described in reference examples, or in a similar manner thereto.

In Scheme 1 and 2, deprotection of a protective group can be done under a condition according to a procedure generally used in the synthetic organic chemistry [for example, Protective Groups in Organic Synthesis by P. G. M. Wuts and T. W. Greene, John Wiley & Sons Inc. (1981)], or in a similar manner thereto. The compounds of the formula (Ia) or (Ib) where Z represents OR ² and R ² represents hydrogen atom can be obtained by hydrolyzing, using any standard procedures known to anyone skilled in the art or by other procedure described in the literature, compounds of formula (Ia) or (Ib) where Z represents OR ² and R ² represents all the groups defined earlier excluding hydrogen. The compounds of the formula (Ia) or (Ib) where Z represents NR ⁴ R ⁵ and R ⁴ , R ⁵ are same as defined earlier, can be prepared by reacting the compounds of formula (Ia) or (Ib) where Z represents OR ² , and R ² is hydrogen or lower alkyl group with appropriate amines of the formula R ⁴ R ⁵ NH and R ⁴ , R ⁵ are same as defined earlier. Alternatively, the compounds of formula (Ia) or (Ib) where Z represents OR ² and R ² represents hydrogen atom can be

converted to acid halide by reacting with appropriate reagents known in literature such as thionyl chloride, oxalyl chloride and the like, followed by the reaction with aniines of the formula R ⁴ R ⁵ NH and R ⁴ , R ⁵ are same as defined earlier. An alternative method can also be used by making mixed anhydrides from compounds of formula (Ia) or (Ib) where Z represents OR , and R represents hydrogen atom and all other symbols are same as defined earlier by treating with acid halides such as acetyl chloride, acetyl bromide, dichlorobenzoyl chloride, pivaloyl chloride and the like. The reaction may be carried out in the presence of solvents, for example, a halogenated hydrocarbon such as chloroform and dichloromethane, an aromatic hydrocarbon such as xylene, benzene and toluene, in the presence of suitable base such as triethylamine, diisopropylethylamine and pyridine at a temperature between 0- 50 ⁰ C. Coupling reagents, generally used in conventional method, such as EDC/HOBT, DCC/DMAP, ethyl chloroformate, isobutyl chloroformate may be employed for activating the acids. The acid halide or mixed anhydride or activated acids thus prepared can further be reacted with amines of the formula R ⁴ R ⁵ NH where R ⁴ , R ⁵ are same as defined earlier to provide the compounds of the formula (Ia) or (Ib) where Z represents NR ⁴ R ⁵ and all other symbols have the same meaning as defined earlier.

The pharmaceutically acceptable salts of the compounds of the present invention are readily prepared by reacting the acid forms with an appropriate base such as sodium hydroxide, sodium methoxide, potassium hydroxide, potassium methoxide, calcium hydroxide, magnesium hydroxide, triethanolamine and the like, in solvents such as chloroform, dichloromethane, diethyl ether, THF, dioxane, ethanol, methanol, /-butanol, isopropanol and toluene. As a further alternative, acid addition salts of the compounds of the present invention, wherever applicable, are prepared by reacting with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid, maleic acid, citric acid, tartaric acid, benzoic acid, succinic acid, salicylic acid, palmitic acid, /7-toluenesulfonic acid, ascorbic acid, benzene sulfonic acid and the like as described in Berge SM et al., 'Pharmaceutical salts', a review article in Journal of Pharmaceutical Sciences, volume 66, page 1 - 19 (1977) and in Handbok of Pharmaceutical Salts Properties, selection, and use by

P.Heinrich Stahl and Camille G. Wermuth, Wiley-VCH (2002)]in solvents such as dichloromethane, THF, alcohols, diethyl ether, ethyl acetate, acetone and mixture thereof.

The stereoisomers of the compounds of the present invention may be prepared by combining the acid with an optically active amine, and separating the diastereomeric salt by fractional crystallization, or by reacting the acid with an optically active alcohol or amine, and separating the diastereomer esters or amides by column chromatography or fractional crystallization, followed by hydrolysis of separated isomers to yield the desired optically active acids. Alternatively, the stereoisomers of the compounds can be prepared by using reactants in their single enantiomeric form, wherever possible, according to the methods given in literature or methods given in reference examples.

The present invention provides a pharmaceutical composition, containing the compounds of the general formula (I) as defined above, their stereoisomers or their pharmaceutically acceptable salts in combination with the usual pharmaceutically employed carriers, diluents and the like are useful for the treatment and/or prophylaxis of diseases such as hypertension, coronary heart disease, stroke, atherosclerosis, microvascular disease and associated disorders. These compounds are useful for treating hyperlipidemia, hyperglycemia, hypertriglyceridemia, hyperinsulinemia, lowering of LDL and VLDL, lowering of atherogenic lipoproteins like ApoB and increasing ApoAl and HDL cholesterol. The compounds of the present treatment is useful in the treatment of insulin resistance (type- 2 diabetes), leptin resistance, obesity, impaired glucose tolerance, dyslipidemia, coronary artery disease and disorders associated with Syndrome X. These compounds may be useful in nephropathy and nephritic syndrome. (These compounds will be useful as Aldose reductase inhibitors for the treatment of macro vascular disorders like atheroscelrosis, and other diabetic complications like diabetic neuropathy, nephropathy and retinopathy. These compounds will be useful in treating disorders related to endothelial cell activation, psoriasis, polycystic ovary syndrome, inflammatory bowel syndrome, osteoporosis, pancreatitis, inflammation and for the treatment of cancer. The compounds of the present invention are also useful in the treatment and/or prophylaxis of the above said diseases in combination with one or more the HMGCoA reductase inhibitors, hypolipidemic/ hypotriglyceridemic agents such as fibric

acid derivatives, nicotinic acid derivatives, cholestyramine, cholesterol absorption inhibitors, probucol or their combinations.

The present invention also provides a pharmaceutical composition, containing the compounds of the general formula (I) as defined above, their stereoisomers or their pharmaceutically acceptable salts and one or more HMGCoA reductase inhibitors, hypolipidemic/hypotriglyceridemic agents such as fabric acid derivatives, nicotinic acid derivatives, cholestyramine, cholesterol absorption inhibitors, probucol in combination with the usual pharmaceutically employed carriers, diluents and the like.

The intermediates and the compounds of the present invention are obtained in pure form by applying methods ordinarily used in the synthetic organic chemistry such as crystallization using solvents such as diethyl ether, hexane, isopropyl ether, methanol, ethanol, isopropanol, ethyl acetate or their combinations or column chromatography using alumina or silica gel and eluting the column with solvents such as dichloromethane, ethyl acetate, hexane, chloroform, methanol, acetone and their combinations. The following examples are provided to further illustrate the present invention and therefore should not be construed to limit the scope of the invention. All ¹ H NMR spectra were determined in the solvents indicated and chemical shifts are reported in δ units downfield from the internal standard tetramethylsilane (TMS) and interproton coupling constants are reported in Hertz (Hz). Intermediate 1

N-[(l α,5α,6α)-3-(4-Chlorobenzyl)-3-azabicyclo[3.1.0]hex-6-yl]- 4-nitrobenzene-sulfonamide

Step 1: [(lα,5α,6α)-3-(4-Chlorobenzyl)-3-azabicyclo[3.1.0]hex-6-y l]carbamic acid tert-butyl ester

To a stirred solution of [(lα,5α,6α)-3-azabicyclo[3.1.0]hex-6-yl]carbamic acid tert- butyl ester (8.0 g, 40 mmol) [which can be prepared by using one of the processes as provided in Synlett, 1097-1102, (1996) and Synthesis 739 - 744 (1998)] in dry acetonitrile (200 ml) was added anhydrous potassium carbonate (16.6 g, 120 mmol), 4-chlorobenzyl bromide (9.8 g, 48 mmol) and potassium iodide (0.2 g, 1.2 mmol) at room temperature. The resulting reaction mixture was heated at 80 ⁰ C for 20 min. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane (100 ml) and water (25 ml). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2x25 ml). The combined organic layers were washed with water (2x25 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to yield a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 0.5 ->2% methanol-dichloromethane as an eluent to yield the title compound (7.05 g, 54%). MS: m/z 323 (M+l) ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.43 (s, 9H), 1.50 (s, 2H), 2.38 (d, J= 8.6 Hz, 2H), 2.87 (s, IH), 3.04 (d, J= 8.8 Hz, 2H) ₅ 3.51 (s, 2H), 4.60 (br s, IH), 7.15-7.26 (m, 4H).

Step 2: (lα,5α,6α)-3-(4-Chlorobenzyl)-3-azabicyclo[3.1.0]hex-6-yl amine

[(lα,5α,6α)-3-(4-Chlorobenzyl)-3-azabicyclo[3.1.0]hex-6-y l]carbamic acid fert-butyl ester (7.0 g, 22 mmol) was added to a solution of 20% v/v trifluoroacetic acid-dichloromethane (80 ml) at 0 ⁰ C under stirring and the resulting reaction mixture was stirred for 2h at the same

temperature. Then, reaction mixture was allowed to come to room temperature and the progress of the reaction was monitored by TLC. The reaction was completed in approximately 2 h. The solvent was removed under reduced pressure to yield a crude product as its TFA salt. The residue was dissolved in dichloromethane (150 ml). To this mixture was added a solution of ammonia in chloroform dropwise at 0 ⁰ C under stirring, until the salt was neutralized completely. Salt separated out was filtered off and the filtrate was concentrated under reduced pressure to get a crude product (4.82 g, 100%). MS: m/z 223 (M+l)

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.37 (s ₅ 2H), 2.37 (d, J= 8.5 Hz, 2H), 2.65 (s, IH), 2.95 (d, J = 8.7 Hz, 2H), 3.52 (s, 2H), 7.16-7.28 (m, 4H).

Step 3: iV-^lα^αjό^-S^-Chlorobenzy^-S-azabicyclofS.l.OJhex-ό-yy^ -nitrobenzene- suifonamide

To a stirred solution of (lα,5α,6α)-3-(4-chlorobenzyl)-3-azabicyclo[3.1.0]hex-6- ylamine (4.8 g, 22 mmol) in dry dichloromethane (140 ml) at 0 ⁰ C were added 4- nitrobenzene-sulfonyl chloride (4.3 g, 19 mmol) and a solution of triethyl amine (6.66 g, 9.24 ml, 66 mmol) in dry dichloromethane (20 ml) dropwise over a period of 15 min. After the addition was completed, the reaction mixture was allowed to come to room temperature and stirred for 15 h. The reaction mixture was evaporated to dryness. The residue so obtained was dissolved in dichloromethane (100 ml), washed with water (1x10 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to get a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 0.75->1.25% methanol- dichloromethane as an eluent to yield the title compound (6.55 g, 75%). mp: 190-191 ⁰ C

MS: m/z 408 (M+l)

¹ H NMR (CDC1 ₃ +CD ₃ OD, 200 MHz): δ 1.95 (s, 2H), 2.32 (d, J= 8.9 Hz, 2H), 2.53 (s, IH) ₅ 2.89 (d, J= 9.0 Hz, 2H), 3.45 (s, 2H), 7.08 (d, J= 8.3 Hz, 2H), 7.26 (d, J= 8.4 Hz, 2H), 8.05 (d, J= 8.8 Hz, 2H), 8.37 (d, J= 8.8 Hz, 2H).

Intermediate 2 N- [( 1 α,5α,6α)-3 -(2-Fluorobenzoyl)-3 -azabicyclo [3.1.0]hex-6-yl] -4-nitrobenzene- sulfonamide

Step 1 : [(lα,5α,6α)-3-(2-Fluorobenzoyl)-3-azabicyclo[3.1.0]hex-6- yl]carbamic acid tert- butyl ester

To a stirred solution of [(lα,5α,6α)-3-azabicyclo[3.1.0]hex-6-yl]carbamic acid tert- butyl ester (2.0 g, 10.10 mmol) in THF (50 ml) was added 2-fluorobenzoic acid (1.41 g, 10.10 mmol) and 1-hydroxybenzotriazole (HOBT, 1.36 g, 10.10 mmol) at room temp. The resulting reaction mixture was cool in ice bath and N-ethyl-N'-(3-dimethylaminoproρyl)- carbodimide hydrochloride (EDCI, 2.12 g, 11.11 mmol) was added. To a turbid solution was added water (50 ml) and reaction mixture was stirred at room temperature for 15 h. The reaction mixture was evaporated to dryness. The residue was diluted with dichloromethane (50 ml), washed with water (2x25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get crude product which was purified by column chromatography over silica gel (100-200 mesh) using 1.0% -M .2% methanol- dichloromethane as an eluent to yield the title compound (2.98 g, 92%). MS: m/z 321(M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.42 (s, 9H), 1.75 (s, 2H) ₅ 2.31 (s, IH) ₅ 3.43-3.61 (m, 3H), 4.15 (d, J= 12.4 Hz, IH), 7.02-7.43 (m, 4H).

Step 2: [(lα,5α ₅ 6α)-6-Amino-3-azabicyclo[3.1.0]hex-3-yl]-(2-fluorophenyl)-m ethanone

To a stirred solution of [(lα,5α ₅ 6α)-3-(2-fluorobenzoyl)-3-azabicyclo[3.1.0]hex-6- yl]-carbamic acid tert-butyl ester (2.98 g, 9.31 mmol) was added to solution of 20% v/v trifluoroacetic acid-dichloromethane (30 ml) at 0 ⁰ C under stirring and resulting mixture was stirred for 2 h at the same temperature. Then reaction mixture was allowed to stir at room temperature for 2 h. The progress of the reaction was monitored by TLC. The solvent was removed under reduced pressure to yield a crude product as its TFA salt. The residue was dissolved in diehloromethane (50 ml). To this mixture was added a solution of ammonia in chloroform drop wise at 0 ⁰ C under stirring, until the salt was neutralized completely. Salt separated out was filtered off and the filtrate was concentrated under reduced pressure to yield the title compound (2.04 g ₅ 100%). MS: m/z 221(M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.63 (s, 2H), 2.18 (s, IH) ₅ 3.34 (d, J= 7.7 Hz ₅ IH), 3.48-3.65 (m, 2H), 4.15 (d, J= 8.0 Hz ₅ 2H) ₅ 7.03-7.78 (m, 4H).

Step 3: N-[(lα,5α ₅ 6α)-3-(2-Fluorobenzoyl)-3-azabicyclo[3.1.0]hex-6-yl]-4-nitr obenzene sulfonamide

To a stirred solution of [(lα,5α,6α)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-(2- fluorophenyl)-methanone (2.0 g, 9.9 mmol) in diehloromethane (70 ml) at 0 ⁰ C were added 4-

nitrobenzene-sulfonyl chloride (1.81 g, 8.18 mmol) and a solution of triethyl amine (2.75 g, 3.80 ml, 27.27 mmol) in dry dichloromethane (10 ml) drop wise over a period of 10 min. After the addition was completed, the reaction mixture was allowed to come to room temperature and stirred for 15 h. The reaction mixture was concentrated under reduced pressure. The residue so obtained was purified by column chromatography over silica gel (100-200 mesh) using 1.5% methanol-dichloromethane as an eluent to yield the title compound (3.14 g, 85%). MS: rø/z 406 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.96 (s, 3H), 3.36 (d, J = 11.2 Hz, IH), 3.48-3.56 (m, 2H) ₅ 4.04 (d, J= 12.5 Hz, IH), 7.04-7.46 (m, 3H), 8.05 (d, J= 8.9 Hz), 8.39 (d, J= 8.8 Hz, 2H).

Intermediate 3

(lα,5α,6α)-6-(4-Nitrobenzenesulfonylamino)-3-azabicycl o[3.1.0]hexane-3-carboxylic acid(2,4,5-trifluorophenyl)amide

Step 1 : [(lα,5α,6α)-[3-(2,4,5-Trifluorophenylcarbamoyl)-3-azabicy clo[3.1.0]hex-6-yl]]- carbamic acid tert-bv&yl ester

To a stirred solution of triphosgene (1.11 g, 3.74 mmol) in dry dichloromethane (20 ml) was added, a mixture of 2,4,5-trifluroaniline (1.48 g, 10.1 mmol) and diisopropylethyl amine (1.43 g, 11.0 mmol) in dichloromethane (20 ml) at 0 ⁰ C, over a period of 30 min. The reaction mixture was allowed to stir at room temperature for 15 min. To this was added mixture of [(lα,5α,6α)-3-azabicyclo[3.1.0]hex-6-yl]carbamic acid fert-butyl ester (2.0 g,

10.1 mmol) & diisopropylethyl amine (1.43 g, 11.0 mmol) in dichloromethane (20 ml) in one portion. The resulting mixture was allowed to stir at room temperature for 10 min and progress of reaction was monitored by TLC. The solvent was removed under reduced pressure. The residue was taken in ethyl acetate (50 ml) and washed with 10% aqueous potassium bisulfate (10 ml), 5% aqueous sodium bicarbonate (10 ml) and brine (10 ml), respectively. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to yield a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 20% ethyl acetate-hexanes as an eluent to give the title compound (2.10 g, 56%). MS: m/z 370 (M-I)

¹ HNMR (CDCl ₃ , 400 MHz): δ 1.43 (s, 9H), 1.83 (s, 2H), 2.34 (s, IH), 3.57 (d, J = 9.6 Hz, 2H), 3.73 (d, J= 8.8 Hz, 2H), 6.88-6.95 (m, IH), 8.06-8.13 (m, IH).

Step 2: (lα,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexane-3-carboxylic acid(2,4,5-trifluoro- phenyl)amide

A solution of 20% v/v trifluoroacetic acid-dichloromethane (20 ml) was added to [(lα,5α,6α)-[3-(2,4,5-trifluorophenylcarbamoyl)-3-azabicy clo[3.1.0]hex-6-yl]]carbamic acid tert-huXyl ester (2.0 g, 5.4 mmol) at 0 ⁰ C under stirring and the resulting mixture was stirred for 2 h at the same temperature. Then, reaction mixture was allowed to come to room temperature and the progress of reaction was monitored by TLC. The reaction was completed in approximately 2 h. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (50 ml). To this mixture was added a solution of ammonia- dichloromethane (50 ml) drop wise at 0 ⁰ C under stirring, until the salt was neutralized completely. Salt separated out was filtered off and the filtrate was concentrated under reduced pressure to yield the title compound (1.45 g, 99%).

MS: w/z 272 (M+l)

¹ HNMR (CDCl ₃ , 400 MHz): δ 1.72 (s, 2H) ₅ 2.14 (s, IH), 3.48 (d, J = 9.6 Hz, 2H), 3.58 (d, J

= 10.0 Hz ₅ 2H), 6.84-6.91 (m, IH), 7.78-7.90 (m, IH).

Step 3: (lα,5α,6α)-6-(4-Nitrobenzenesulfonylamino)-3-azabicyclo[3 .1.0]hexane-3- carboxylic acid(2,4,5-trifluorophenyl)amide

To a stirred solution of (lα,5α,6α)-[6-amino-3-azabicyclo[3.1.0]hexane-3-carboxyli c acid-(2,4,5-trifluorophenyl)amide (1.4 g, 5.2 mmol) in dry dichloromethane (30 ml) at 0 ⁰ C was added 4-nitrobenzenesulfonyl chloride (1.09 g, 4.9 mmol) and a solution of triethyl amine (1.30 g, 1.8 ml, 12.9 mmol) in dry dichloromethane (4 ml) drop wise over a period of 15 min. After the addition was completed, the reaction mixture was allowed to come to room temperature and stirred for 15 h. The reaction mixture was evaporated under reduced pressure to dryness. The residue so obtained was dissolved in dichloromethane (50 ml), washed with water (1x10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get a crude product which was recrystallized using 25% dichloromethane-hexanes to give the title compound (1.95 g, 82%). MS: m/z 457 (M+l) ¹ HNMR (DMSO, 400 MHz): δ 1.73 (s, 2H), 1.91 (s, IH), 3.36 (d, J= 10.4 Hz, 2H), 3.52 (d, J= 10.8 Hz, 2H), 7.50-7.60 (m, 2H), 8.07 (d, J= 8.4 Hz, 2H) ₅ 8.45 (d, J= 8.8 Hz ₅ 2H).

Intermediate 4

N- [( 1 α, 5 α,6α)-3 -(5 -Cyanopyridine-2-yl)-3 -azabicyclo [3.1.0]hex-6-yl] -4-nitrobenzene- sulfonamide

Step 1 : [(lα,5α,6α)-3-(5-Cyanopyridin-2-yl)-3-azabicyclo[3.1 .0]hex-6-yl]carbamic acid tert- butyl ester

To a stirred solution of [(lα,5α,6α)-3-azabicyclo[3.1.0]hex-6-yl]carbamic acid tert- butyl ester (1.4 g, 7.07 mmol) in dry DMF (10 ml), was added dry triethyl amine (1.42 g, 1.98 ml, 14.1 mmol) and 2-chloro-5-cyanopyridine (1.27 g, 9.19 mmol) at room temperature. The resulting reaction mixture was heated at 80 ⁰ C for 3 h under stirring. The reaction mixture was poured in ice-cold water (25 ml) & stirred for 30 min. The solid obtained was filtered through Buchner funnel, dissolved in ethyl acetate (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to yield a crude product. The solid so obtained was washed with hexane (25 ml) to afford the title compound (1.5 g, 70%). MS: rø/z 301 (M+l) ¹ HNMR (CDCl ₃ , 400 MHz): δ 1.43 (s, 9H), 1.89 (brs, 2H), 2.30 (s, IH) ₅ 3.55 (d, J= 10.0 Hz, • 2H), 3.81 (brs, 2H), 4.77 (brs, IH, exchangeable with D ₂ O), 6.28 (d, J= 8.8 Hz, IH), 7.55 (d, J= 8.8 Hz, IH), 8.36 (s, IH). _

Step 2: 6-[(l α,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hex-3-yl]nicotinonitr ile

To a stirred solution of [(lα,5α,6α)-3-(5-cyanopyridin-2-yl)-3-azabicyclo[3.1.0]he x- 6-yl]-carbamic acid tert-butyl ester (1.5 g, 5.00 mmol) in dichloromethane (20 ml) was added a solution of 20% v/v trifluoroacetic acid-dichloromethane (20 ml) at 0 ⁰ C under stirring and

the resulting mixture was stirred for 2 h at the same temperature. Then, reaction mixture was allowed to come to room temperature & the progress of the reaction was monitored by TLC. The reaction was completed in approximately 2 h. The solvent was removed under reduced pressure to yield a crude product as its trifluoroacetic acid (TFA) salt. The residue was dissolved in chloroform (30 ml). To this mixture was added a solution of ammonia in chloroform drop wise at 0 ⁰ C under stirring, until the salt was neutralized completely. Salt separated out was filtered off & the filtrate was concentrated under reduced pressure to yield the title compound (1.0 g, 100%). MS: m/z 201 (M+l) ¹ HNMR (CDCI ₃ +CD ₃ OD, 400 MHz): δ 1.74 (s, 2H) ₃ 2.17 (s, IH), 3.51 (d, J = 9.2 Hz ₅ 2H), 3.53-3.68 (m, 2H), 6.28 (d, J= 8.8 Hz, IH), 7.53 (dd ₅ J= 8.80 Hz, IH), 8.35 (d, J= 2.0 Hz, IH).

Step 3: iV-[(lα,5α,6α)-3-(5-Cyanopyridin-2-yl)-3-azabicyclo[3.1.0 ]hex-6-yl]-4-nitro- benzenesulfonamide

To a stirred solution of 6-[(lα,5α,6α)-6-amino-3-azabicyclo[3.1.0]hex-3- yljnicotinonitrile (0.95 g, 4.75 mmol) in dry dichloromethane (25 ml) at 0 ⁰ C were added 4- nitro-benzenesulfonyl chloride (1.05 g, 4.75 mmol) & a solution of triethyl amine (1.44 g, 2.0 ml, 14.2 mmol) in dry dichloromethane (5 ml) drop wise over a period of 4 min. After the addition was completed, the reaction mixture was allowed to come to room temperature & stirred for 15 h. The reaction mixture was evaporated under reduced pressure to get crude product, which was washed with hexane (2x25 ml). The solid was filtered through Buchner funnel to yield the title compound (1.0 g, 54%). MS: m/z 386 (M+l)

¹ HNMR (CDC1 ₃ +CD ₃ OD, 400 MHz): δ 1.89 (s, IH), 2.01 (s, 2H), 3.51 (d, J= 10.0 Hz ₅ 2H), 3.53-3.67 (m, 2H) ₅ 6.30 (d, J= 8.8 Hz, IH) ₅ 7.56 (dd, J = 8.8 Hz, IH) ₅ 8.01 (d, J = 8.4 Hz 2H), 8.28 (d, J= 2.0 Hz, IH), 8.31 (d, J= 8.4 Hz ₅ 2H).

Intermediate 5

(2S)-2-(4-fe^Butylphenoxy)-3-[4-(2-hydroxyethoxy)phenyl]p ropionic acid ethyl ester

Method A:

Step 1 : 2-(4-Nitrophenoxy)ethanol

To a stirred solution of 4-nitrophenol (100.0 g, 0.72 mol) in DMF (400 ml) was added anhydrous potassium carbonate (297.8 g, 2.15 mol) and the resulting reaction mixture was heated at 50 ⁰ C for Ih. To this reaction mixture, was added a solution of 2-bromoethanol (98.92 g, 56.2 ml, 0.79 mol) in DMF (50 ml) dropwise at room temperature over a period of 20 minutes under stirring. After completing the addition, the reaction mixture was heated at 80 ⁰ C for 6 h and then it was allowed to come to room temperature. The excess of potssium carbonate was filtered off, washed with ethyl acetate (3x200 ml). The DMF layer was concentrated to half of its volume under reduced pressure and diluted with water (4 times). The solid separated out was filtered off and ethyl acetate (1500 ml) was added to the residue. The combined ethyl acetate layer was washed with water (1 ^χ 500 ml), brine (1 x200 ml), dried, over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was dissolved in chloroform (800 ml), washed with cold solution of 5% aqueous potassium hydroxide (2x250 ml) to remove unreacted 4-nitrophenol. The organic layer was

washed with water (1x200 ml), brine (1x100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (88.5 g, 67%). ¹ H NMR (CDCl ₃ , 200 MHz): δ 4.02-4.06 (m, 2H), 4.18-4.22 (m, 2H), 7.00 (d, J= 9.2 Hz, 2H), 8.22 (d, J= 9.2 Hz, 2H).

Step 2: 4-(2-Benzyloxyethoxy)-l -nitrobenzene

To a stirred suspension of 60% sodium hydride (pre-washed with hexanes; 22.29 g, 0.55 mol) in THF (1.6 lit) was added a solution of 2-(4-nitrophenoxy)ethanol (85.0 g, 0.46 mol) in THF (400 ml) dropwise at 0-5 ⁰ C. After being stirred at same temperature for 30 min, the reaction mixture was allowed to come to room temperature and stirred for further 1 h. To this reaction mixture, a solution of benzyl bromide (83.4 g, 48.8 ml, 0.48 mol) in THF (200 ml) was added at 0 ⁰ C under stirring. After the addition was completed, the reaction mixture was allowed to come to room temperature and tetra-«-butyl-ammonium iodide (17.13 g, 0.04 mol) was added to it and stirred for 3 h at the same temperature. THF was removed under reduced pressure and water (400 ml) was added at 0 ⁰ C. The reaction mixture was then extracted with ethyl acetate (3x500 ml). The combined organic layers were washed with brine (1 ^χ 200 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to a get crude product, which was purified by column chromatography over silica gel (60-120 mesh) using 10% ethyl acetate-hexanes as an eluent to yield the title compound (97.63 g, 77%). MS: m/z 21 A (M+l)

¹ H NMR (CDCl ₃ , 200 MHz): δ 3.85-3.90 (m, 2H), 4.22-4.27 (m, 2H), 4.65 (s, 2H), 6.98 (d, J = 9.2 Hz, 2H), 7.34-7.37 (m, 5H), 8.20 (d, J= 9.2 Hz, 2H).

Step 3: 4-(2-Benzyloxyethoxy)phenylamine

A mechanically stirred suspension of iron powder (200.45 g, 3.58 mol) and acetic acid (14.56 g, 0.24 mol) was heated at 80 ⁰ C for 1 h. To this, 4-(2-benzyloxyethoxy)-l- nitrobenzene (280.0 g, 1.02 mol) was added at the same temperature and the resulting reaction mixture was refiuxed for 4 h. After cooled to 0 ⁰ C, the reaction mixture was neutralized with a saturated solution of sodium bicarbonate. To this, ethyl acetate (800 ml) was added and stirred at room temperature. The solid separated out was filtered, washed with ethyl acetate (3x300 ml). The combined organic layers were washed with water (1x200 ml), brine (1*100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to yield the title compound (231.2 g, 93%). MS: m/z 244 (M+l)

¹ H NMR (CDCl ₃ , 200 MHz): δ 3.42 (brs, 2H ₅ exchangeable with D ₂ O), 3.76-3.81 (m, 2H), 4.06-4.10 (m, 2H), 4.63 (s, 2H), 6.64 (d, J= 8.7 Hz, 2H), 6.79 (d, J= 8.8 Hz, 2H), 7.25-7.37 (m, 5H).

Step 4: 3-[4-(2-Benzyloxyethoxy)phenyl]-2-chloropropionic acid methyl ester

To a solution of 4-(2-benzyloxyethoxy)phenylamine (131.0 g, 0.54 mol) in acetone (520 ml) and concentrated HCl (140 ml) at 0 ⁰ C, was added a solution of sodium nitrite (40.91 g, 0.59 mol) in water (100 ml) dropwise in such a manner that the temperature of the reaction mixture was maintained between 0-5 ⁰ C. After stirring at 5 ⁰ C for 1 h, methyl acrylate (232.05 g, 2.69 mol) was added and temperature of the reaction mixture was maintained at 30 ⁰ C. CuI (2.25 g, 0.011 mol) was added in portion wise in such a way that the temperature of the reaction mixture was maintained at 30-35 ⁰ C. The stirring of reaction mixture was continued at the same temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (500 ml) and extracted with dichloromethane (3x400 ml). The combined organic layers were washed with water (1x400 ml), brine (1x100 ml) and dried over anhydrous Na ₂ SO ₄ . The solvent was evaporated under reduced pressure to get a crude product, which was purified by column

chromatography over silica gel (100-200 mesh) using 5% ethyl acetate-hexanes as an eluent to offered the title compound (83.4 g, 44%).

MS: m/z 366 (M+18)

¹ R NMR (CDCl ₃ , 200 MHz): δ 3.05-3.16 (dd, J = 13.9 Hz, IH), 3.24-3.35 (dd, J= 13.9 Hz,

IH), 3.72 (s, 3H), 3.81 (t, J = 5.1 Hz, 2H), 4.13 (t, J= 5.1 Hz, 2H), 4.39 (t, J= 7.4 Hz, IH),

4.63 (s, 2H), 6.72 (d, J= 8.6 Hz, 2H) ₅ 7.14 (d, J= 8.6 Hz, 2H), 7.25-7.35 (m, 5H).

Step 5: 3-[4-(2-Benzyloxyethoxy)phenyl]-2-hydroxypropionic acid

To a mechanically stirred solution of 3-[4-(2-benzyloxyethoxy)phenyl]-2- chloropropionic acid methyl ester (128.6 g, 0.36 mol) in dioxane (742 ml) was added water (1.15 lit), calcium carbonate (36.93 g, 0.36 mol) and sodium hydroxide (15.49 g, 0.38 mol) at room temperature. The reaction mixture was then heated at reflux temperature for 18 h. Dioxane was removed under reduced pressure and the reaction mixture was acidified with 10% HCl to pR 3. The aqueous layer was extracted with CHCl ₃ (3x400 ml) and the combined organic layers were washed with water (1x200 ml), brine (1x100 ml), dried over anhydrous Na ₂ SO ₄ and filtered. The solvent was evaporated under reduced pressure to yield the title compound (109.0 g, 93%). MS: m/z 334 (M+18) ¹ H NMR (CDCl ₃ , 200 MHz): δ 2.85-2.95 (dd, J= 14.1 Hz, IH), 3.06-3.15 (dd, J= 14.1 Hz, IH) ₅ 3.83 (t, J= 4.7 Hz, 2H), 4.17 (t, J= 4.3 Hz, 2H), 4.41 (t, J= 4.36 Hz, IH), 4.62 (s, 2H), 6.86 (d, J= 8.5 Hz, 2H), 7.15 (d, J= 8.5 Hz, 2H), 7.25-7.34 (m, 5H).

Step 6: 3-[4-(2-Benzyloxyethoxy)phenyl]-2-hydroxypropionic acid ethyl ester

A mixture of 3-[4-(2-benzyloxyethoxy)phenyl]-2-hydroxypropionic acid (109.0 g, 0.34 mol), ethanol (654 ml) and concentrated H ₂ SO ₄ (0.6 ml) was refluxed for 4 h. Ethanol

was removed under reduced pressure, the residue was diluted with water (200 ml) and extracted with ethyl acetate (3x250 ml). The combined organic layers were washed with water (1x100 ml), brine (1x50 ml) and dried over anhydrous Na ₂ SO ₄ . The solvent was evaporated under reduced pressure to get a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 10% ethyl acetate-hexanes as an eluent to yield the title compound (82.4 g, 69%). MS: m/z 345 (M+l)

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.29 (t, J = 7.1 Hz, 3H) ₃ 2.20 (brs, IH, exchangeable with D ₂ O), 2.87-2.97 (dd, J = 14.0 Hz, IH), 3.03-3.12 (dd, J= 14.0 Hz, IH), 3.83 (t, J= 4.6 Hz, 2H), 4.14 (t, J= 5.2 Hz ₅ 2H), 4.24 (q, J= 7.1 Hz, 2H), 4.40 (X, J= 4.6 Hz, IH), 4.64 (s, 2H), 6.84 (d, J= 8.6 Hz, 2H), 7.16 (d, J= 8.5 Hz, 2H), 7.32-7.38 (m, 5H).

Step 7: 3-[4-(2-Benzyloxyethoxy)phenyl]-2-(4-tert-butylphenoxy)propi onic acid ethyl ester

To a stirred mixture of 3-[4-(2-benzyloxyethoxy)phenyl]-2-hydroxypropionic acid ethyl ester (20.0 g, 58 mmol), 4-/ert-butylphenol (10.4 g, 69 mmol), and triphenylphosphine (18.2 g, 69 mmol) in anhydrous dichloromethane (150 ml) was added diethyl azadicarbo- xylate (12.1 g, 10.9 ml.,69 mmol) dropwise over a period of 45 minutes at 0 ⁰ C. The reaction mixture was allowed to come a room temperature and stirred for 16 h. After completion of reaction, the reaction mixture was washed with water (2x150 ml) and the organic layer was dried over anhydrous Na ₂ SO ₄ . The solvent was evaporated under reduced pressure to get a crude product that was purified by column chromatography over silica gel (100-200 mesh) using 40% dichloromethane-hexanesas an eluent to afford the title compound (22.16 g, 80%). MS: m/z 494 (M+18)

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.18-1.30 (m, 12H), 3.18 (d, J= 7.4 Hz ₅ 2H) ₅ 3.82 (t, J= 4.5 Hz, 2H) ₅ 4.11-4.21 (m, 4H) ₅ 4.64 (s, 2H) ₅ 4.67 (t, J= 7.3 Hz, IH) ₅ 6.75-6.88 (m, 4H) ₅ 7.23- 7.36 (m ₅ 9H).

>

, 5 Step 8: 3-[4-(2-Benzyloxyethoxy)phenyl]-2-(4-/ert-butylphenoxy)propi onic acid

To a stirred solution of 3-[4-(2-benzyloxyethoxy)phenyl]-2-(4-terr- butylphenoxy)propionic acid ethyl ester (34.0 g, 71 mmol) in dioxane (200 ml) was added a solution of lithium hydroxide (9.0 g ₅ 214 mmol) in water (150 ml) at 0 ⁰ C. The reaction

10 mixture was allowed to come to room temperature and stirred for 7 h. After completion of reaction, dioxane was removed under reduced pressure and the aqueous layer was acidified with 2N HCl (pH 2). The solid precipitated out was filtered through suction and dissolved in ethyl acetate (300 ml). The organic layer was washed with water (1 x100 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to afford the title compound

15 (33.12g, 100 %).

MS: m/.? 466 (M+18)

¹ R NMR (CDCl ₃ , 200 MHz): δ 1.26 (s, 9H), 3.18 (d, J = 5.9 Hz ₅ 2H) ₅ 3.70-3.85 (m, 2H),

4.11-4.20 (m, 2H) ₅ 4.62 (s, 2H), 4.75-4.89 (m, IH) ₅ 6.75-6.86 (m, 4H) ₅ 7.18-7.34 (m, 9H).

20 Step 9: [(2R), N(lS)]-3-[4-(2-Benzyloxyethoxy)phenyl]-2-(4-ter?-butylphenox y)-iV-(2- hydroxy-l-phenylethyl)propionamide & [(2S) ₅ iV(lS)]-3-[4-(2-benzyloxyethoxy)phenyl]-2- (4-fer/'-butylphenoxy)-λ ^r -(2 -hydroxy- 1 -phenylethyl)propionamide

To an ice cooled solution of 3-[4-(2-benzyloxyethoxy)phenyl]-2-(4-ter<f- butylphenoxy)-propionic acid (33.1 g, 74 mmol) in anhydrous dichloromethane (350 ml) was added 1-hydroxybenzotriazole (10.97 g, 81 mmol) under stirring. A mixture of (S)-2-phenyl- glycinol (11.14 g, 81 mmol), EDCI (15.57 g, 81 mmol) and λζiV-diisopropylethyl amine (10.5 g, 14.1 ml., 81 mmol) in dichloromethane (50 ml) was added to the above reaction mixture dropwise at 0 ⁰ C under stirring. The reaction mixture was allowed to come to room temperature and stirred for 14 h. After completion of reaction, the reaction mixture was washed sequentially with water (2x200 ml), saturated aqueous sodium bicarbonate solution (1 ^χ 200 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give a crude product. Purification by column chromatography over silica gel (100-200 mesh) using 40% ethyl acetate-hexanes as an eluent yielded mixture of diastereomers [(2R), JV(IS)] -3 -[4- (2-benzyl-oxyethoxy)phenyl] -2-(4-tert-butylphenoxy)-JV-(2-hydroxy- 1 - phenylethyl)propionamide & [(2S), N(lS)]-3-[4-(2-benzyloxyethoxy)-phenyl]-2-(4-te/t- butylphenoxy)-N-(2-hydroxy-l-phenylethyl)propionamide (28.89 g, 69%). This mixture of diastereomers was subjected to next step as such. MS: m/z 568 (M+l)

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.24-1.30 (m, 9H), 3.15-3.27 (m, 2H), 3.65-3.77 (m, 4H), 4.09-4.17 (m, 2H), 4.66 (d, J= 3.1 Hz, 2H), 4.84 (t, J= 5.1 Hz, IH), 4.90-5.10 (m, IH), 6.77- 7.36 (m, 18H).

Step 10: [(2R), N(lS)]-2-(4-te^Butylphenoxy)-3-[4-(2-hydroxy ethoxy) phenyl] -iV-(2- hydroxy-l-phenylethyl)propionamide & [(2S), N(lS)]-2-(4-tert-Butylphenoxy)-3-[4-(2- hydroxyethoxy)phenyl]-N-(2-hydroxy- 1 -phenylethyl)propionamide

To a stirred solution of [(2R), N(lS)]-3-[4-(2-benzyloxyethoxy)phenyl]-2-(4-tert- butyl-phenoxy)-N-(2-hydroxy-l-phenylethyl)propionamide & [(2S) ₅ JV(lS)j-3-[4-(2- benzyloxy-ethoxy)phenyl] -2-(4-/er/-butylphenoxy)-N-(2-hydroxy- i - phenylethyl)propionamide (28.85 g, 51 rnmol) in ethanol (500 ml) was added 10% Pd-C (5.0 g) and ammonium formate (55.0 g, 870 rnmol) at room temperature and the resulting reaction mixture was heated at 70-75 ⁰ C for 8 h. The progress of the reaction was monitored by TLC. It was filtered through a buchner funnel, washed with ethanol (200 ml) and the filtrate was concentrated under reduced pressure to yield a crude product, which was purified by column chromatography over silica gel (200-400 mesh) using a gradient of 0->2% methanol- dichloromethane as an eluent to get the desired diastereomer assigned as [(2S) ₃ N(lS)]-2-(4- tert-butylphenoxy)-3-[4-(2-hydroxy-ethoxy)phenyl]-N-(2-hydro xy-l-phenyl- ethyl)propionamide (9.05 g, 37%) followed by the other diastereomer [(2R), N(lS)]-2-(4- fer/-butylphenoxy)-3-[4-(2-hydroxyethoxy)phenyl]-iV-(2-hydro xy-l- phenylethyl)propionamide (8.6 g, 35%).

[(2S), N(I S)]-2-(4-tert-Butylphenoxy)-3-[4-(2-hydroxyethoxy)phenyl]-iV -(2-hydroxy- 1 - phenylethyl)propionamide: mp: 112-114 °C

MS: w/^ 478 (M+l)

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.30 (s, 9H), 2.00 (brs, 2H), 3.16-3.22 (m, 2H), 3.75-3.78 (m,

2H), 3.98-4.04 (m, 4H), 4.78-4.85 (m, IH), 4.90-5.10 (m, IH), 6.75-7.34 (m, 13H).

[(2R), N(lS)]-2-(4-^r/-Butylphenoxy)-3-[4-(2-hydroxyethoxy)phenyl]- N-(2-hydroxy-l- phenylethyl)propionamide :

mp: 136-137 ⁰ C MS: w/z 478 (M+l)

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.29 (s, 9H), 1.96 (brs, 2H ₅ exchangeable with D ₂ O), 3.07- 3.28 (m, 2H), 3.74-3.77 (m, 2H), 3.95-4.03 (m, 4H), 4.81-4.86 (m, IH), 4.95-5.04 (m, IH), 6.74-7.33 (m, 13H).

Step 11: (2S)-2-(4-ter?-Butylphenoxy)-3-[4-(2-hydroxyethoxy)phenyl]pr opionic acid

To a stirred solution of [(2S), N(lS)]-2-(4-terr-butylρhenoxy)-3-[4-(2- hydroxyethoxy)-phenyl]-iV-(2-hydroxy-l-phenylethyl)propionan iide (9.0 g, 18 mmol) in dioxane (80 ml) was added a solution of concentrated H ₂ SO ₄ (4.5 ml) in water (50 ml) dropwise at room temperature and the resulting reaction mixture was heated at 110 ⁰ C for 7 h. Dioxane was removed under reduced pressure. The residue was diluted with water (100 ml) and extracted with ethyl acetate (2x125 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and the solvent was concentrated under reduced pressure to afford the title compound in quantitative yield. MS: rø/z 376 (M+18)

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.27 (s, 9H), 3.20 (d, J = 6.1 Hz, 2H), 3.96-4.05 (m, 4H), 4.77 (t, J= 5.9 Hz, IH), 6.81 (d, J= 8.8 Hz, 2H), 6.86 (d, J= 8.6 Hz, 2H), 7.25 (d, J= 8.5 Hz, 2H), 7.29 (d, J= 8.7 Hz, 2H).

Step 12: (2S)-2-(4-fer^-Butylphenoxy)-3-[4-(2-hydroxyethoxy)phenyl]pr opionic acid ethyl ester

To a solution of (2S)-2-(4-tert-butylphenoxy)-3-[4-(2- hydroxyethoxy)phenyl]propionic acid (6.7 g, 18 mmol) in ethanol (300 ml) was added concentrated H ₂ SO ₄ (0.5 ml) and the reaction mixture was refluxed for 3 h. The solvent was removed under reduced pressure; the residue was diluted with water (100 ml) and extracted with ethyl acetate (3x50 ml), the combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated in vaccuo to yield a crude product. The crude product was purified by column chromatography over silica gel (100-200 mesh) using 40% ethyl acetate-hexanes as an eluent to afford the title compound (4.7 g, 65%). MS: m/z 404 (M+18) ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.21 (t, 3H, J = 7.1 Hz), 1.26 (s, 9H), 3.15-3.19 (m, 2H), 3.95-3.97 (m, 2H), 4.04-4.08 (m, 2H), 4.18 (q, J = 7.0 Hz, 2H), 4.70 (t, J = 5.98 Hz, IH), 6.74-6.96 (m, 4H), 7.21-7.26 (m, 4H). [α] _D ²⁰ - 6.82 (c 10.45, CHCl ₃ )

Method B:

Step 1: (R)-2-Amino-3-(4-benzyloxyphenyl)propionic acid

To an ice cooled solution of potassium hydroxide (80.3 g, 1.22 mol) in 200 ml of water was added D-tyrosine (100 g, 0.55 mol) with maintaining inner side temperature at 15-

20 ⁰ C followed by the addition of CuSO ₄ .5H ₂ O (85.5 g, 0.34 mol) at 20 ⁰ C. Then reaction mixture was heated to 60-65 ⁰ C for 1 h under stirring. The reaction mixture was allowed to come at room temperature. To this reaction mixture was added DMF (500 ml) followed by dropwise addition of benzyl chloride (83.8 g, 76.28-ml, 0.66 mol) at room temperature. Then reaction mixture was heated to 60 ⁰ C for 2h under stirring. Grey coloured solid copper complex of O-benzyl-D-tyrosine was precipitated out. The reaction mixture was allowed come to at room temperature, and 300 ml of water was added to get free grey coloured solid.

This solid was filtrered washed with water till the filtrate became colourless. This wet cake of O-benzyl-D-tyrosine copper complex was stirred with methanol at reflux temperature for 1 h. After 1 h, solid was filtered, washed with methanol and dried in an oven at 65 ⁰ C. To this copper complex was added 1 lit of water followed by the addition of 35% cone HCl (90 ml) at to pB. 2-3 under stirring at room temperature. The solid so obtained was filtered, washed with 10% ammonia solution (300 ml), dried in vacuum oven at 65 ⁰ C to yield the title compound (115 g, 77%). MS: rø/z 272 (M+l)

Step 2: (2R)-3-(4-Benzyloxyphenyl)-2-hydroxypropionic acid

To a stirred suspension of (2R)-2-amino-3-(4-benzyloxyphenyl)propionic acid (115 g, 0.423 mol) in 1400 ml of dioxane was added dilute aqueous H ₂ SO ₄ solution (124.5 g, 67.6 ml, 1.26 mol in 400 ml of water) at 26-28 ⁰ C. The resulted reaction mixture was cooled to 0 ⁰ C on ice bath and to this was added aqueous sodium nitrite solution (146.13 g, 2.115 mol in 200 ml of water) at 0 ⁰ C in a dropwise manner under stirring. After the completion of addition the reaction mixture was stirred at room temperature for 24 h. Reaction mixture was diluted with water (300 ml), extracted with ethyl acetate (3><600 ml). The combined organic layers were dried over sodium sulphate and concentrated under rteduced pressure to yield crude product. The crude product was suspended in mixture of 400 ml of diisopropyl ether and 3 ml of ethyl acetate. Resulting solid was filtered, washed with diisopropyl ether (100 ' ml) and dried under vacuum to yield the pure title compound (40.4 g, 35%). MS: w/z 290 (M+18) ¹ HNMR (CDCI ₃ +CD ₃ OD, 400 MHz): δ 2.37 (brs, IH, exchangeable with D ₂ O), 2.88 (dd, J= 14.0 Hz, IH), 3.08 (dd, J= 14.0 Hz, IH), 4.36 (dd, J= 7.2 Hz, IH), 5.01 (s, 2H), 6.89 (d, J= 8.4 Hz, 2H), 7.12 (d, J= 8.4 Hz, 2H), 7.28-7.41 (m, 5H).

Step 3: (2R)-3-(4-Benzyloxyphenyl)-2-hydroxypropionic acid ethyl ester

To a stirred solution of (2R)-3-(4-benzyloxyphenyl)-2-hydroxypropionic acid (40.4 g, 0.148 mol) in 400 ml of ethyl alcohol was added 1 ml of cone H ₂ SO ₄ in a dropwise manner at room temperature and the resulting reaction mixture was heated at reflux temperature for 4 h. After completion of the reaction, ethyl alcohol was removed under reduced pressure and the residue was dissolved in ethyl acetate (600 ml), washed with water (1x50 ml), brine (1x50 ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 40% ethyl acetate-hexanes as an eluent to yield the title compound (30.7 g, 69%). MS: w/.? 318 (M+18)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.28 (t, J = 7.2 Hz ₅ 3H), 1.61 (brs, IH, exchangeable with D ₂ O), 2.90 (dd, J = 14.0 Hz, IH), 3.04 (dd, J= 14.0 Hz ₅ IH), 4.21 (q, J= 7.2 Hz, 2H), 4.39 (dd, J = 6.6 Hz, IH), 5.03 (s, 2H), 6.90 (d, J= 8.6 Hz, 2H), 7.14 (d, J= 8.6 Hz, 2H), 7.31- 7.44 (m, 5H).

Step 4: (2S)-3-(4-Benzyloxyphenyl)-2-(4-/er/-butylphenoxy)propionic acid ethyl ester

To a stirred solution of (2R)-3-(4-benzyloxyphenyl)-2-hydroxypropionic acid ethyl ester (30.6 g, 0.102 mol) in dry dichloromethane (400 ml) was added 4-tert~butylphenol (18.36 g, 0.122 mol) and triphenylphosphine (32.06 g, 0.122 mol) at room temperature. Reaction mixture was cooled to 0 ⁰ C and to this was added diethylazadicarboxylate (21.28 g, 18.66 ml, 0.122 mol) in dry dichloromethane (100 ml) at 0 ⁰ C in a dropwise manner over a period of 30 min and resulting reaction mixture was stirred at room temperature for

overnight. After the completion of the reaction, reaction mixture was diluted with dichloromethane (300 ml) washed with water (1x5.0 ml), brine (1x50 ml), dried over sodium sulphate and concentrated under reduced pressure to get crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 70% dichloromethane- , hexanes as an eluent to yield the title compound (35.0 g, 79%). MS: m/z 450 (M+18)

¹ HNMR (CDCl ₃ , 400 MHz): δ 1.23 (t, J= 7.2 Hz, 3H), 1.31 (s, 9H), 3.18-3.23 (m, 2H), 4.20- 4.25 (m, 2H), 4.74 (dd, J = 7.2 Hz, IH), 5.08 (s, 2H), 6.81 (d, J= 8.4 Hz ₅ 2H),' 6.95 (d, J = 8.4 Hz, 2H), 7.26-7.48 (m, 9H).

Step 5: (2S)-2-(4-tert-Butylphenoxy)-3-(4-hydroxyphenyl)propionic acid ethyl ester

To a solution of (2S)-3-(4-benzyloxyphenyl)-2-(4-tert-butylphenoxy)propionic acid ethyl ester (20.0 g, 46.29 mmol) in ethanol (150 ml), 10% Pd-C (15.0 g, wet) was added and the solution was hydrogenated (60 psi Of H ₂ ) on Parr apparatus for 4 h. After completion of reaction, reaction mixture was filtered through Celite bed, washed with ethanol (3x50 ml), ethyl acetate (4x50 ml). The combined filtrate was concentrated under reduced pressure to yield crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 30% ethyl acetate-hexanes as an eluent to afford the title compound (13.7 g, 87%).

MS: rø/z 360 (M+18) ^{1 1} HHNNMMRR ((CCDDCCll ₃₃ ,, 2200..00 MHz): δ 1.20 (t ₅ J= 7.0 Hz, 3H), 1.26 (s, 9H), 3.11-3.18 (m, 2H), 4.17 (q, J= 7.0 Hz, 2H), 4.69 (t, J= 6.2 Hz, IH), 6.72-6.78 (m, 4H), 7.14-7.26 (m, 4H). ^'

Step 6: (2S)-3-[4-(2-Benzyloxyethoxy)phenyl]-2-(4-ter?-butylphenoxy) propionic acid ethyl ester

To a solution of (2S)-2-(4-ter^butylphenoxy)-3-(4-hydroxyphenyl)propionic acid ethyl ester (26.5 g, 77.48 mmol) in dry dichloromethane (300 ml) was added 2- benzyloxyethanol (12.94 g, 85.11 mmol) and triphenyl phosphine (24.33 g, 92.84 mmol) at room temperature. The reaction mixture was cooled to 0 ⁰ C and to this was added a solution of diethylazadicarboxylate (16.15 g, 14.18 ml, 92.84 mmol) in dry dichloromethane (50 ml) in a dropwise manner over a period of 20 min. The resulting reaction mixture was stirred at room temperature for 4 h. After completion of reaction, reaction mixture was diluted with dichloromethane (300 ml) washed with water (1x50 ml), brine (1x50 ml), dried over sodium sulphate and concentrated under reduced pressure to yield crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 80% dichloromethane- hexanes as an eluent to afford the title compound (26.0 g 71%). MS: m/z 499 (M+23) ¹ HNMR (CDCl ₃ , 200 MHz): δ 1.23 (t, J= 7.2 Hz, 3H), 1.30 (s, 9H), 3.18-3.22 (m, 2H), 3.84 (t, J= 5.2 Hz, 2H), 4.13-4.26 (m, 4H), 4.66 (s, 2H), 4.73 (t, J= 6.0 Hz ₅ IH), 6.79 (d, J= 8.6 Hz, 2H), 6.88 (d, J= 8.6 Hz, 2H), 7.22-7.70 (m, 9H).

Step 7: (2S)-2-(4-tert-Butylphenoxy)-3-[4-(2-hydroxyethoxy)phenyl]pr opionic acid ethyl ester

To a solution of (2S)-3-[(4-(2-benzyloxyethoxy)ρhenyl]-2-(4-tert- butylphenoxy)propionic acid ethyl ester (26.0 g, 54.56 mmol) in ethanol (200 ml), 10% Pd-C (20.0 g, wet) was added and the solution was hydrogenated (60 psi of H ₂ ) on Parr apparatus

for 4 h. After completion of reaction, reaction mixture was filtered through Celite bed, washed with ethanol (4x50 ml), ethyl acetate (4x50 ml). The combined filtrate was concentrated under reduced pressure to yield crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 30% ethyl acetate-hexanes as an eluent to yield the title compound (19.5 g, 92%). MS: m/z 409 (M+23)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.24 (t, J = 7.2 Hz, 3H), 1.30 (s, 9H), 1.93 (brs, IH, exchangeable with D ₂ O), 3.19-3.22 (m, 2H), 4.00 (t, J= 4.6 Hz, 2H), 4.09 (t, J= 4.6 Hz, 2H), 4.22 (q, J = 7.2 Hz, 2H), 4.74 (t, J = 6.0 Hz, IH), 6.79 (d, J= 8.6 Hz, 2H), 6.88 (d, J= 8.6 Hz, 2H), 7.24-7.30 (m, 4H). [α] _D ²⁵ -7.59 (c 9.48, CHCl ₃ ) Chiral HPLC: desired isomer - 96.83%, opposite isomer - 3.17%

Intermediate 6 (2S) 3-[4-(2-Bromo-ethoxy)phenyl]-2-(4-tert-butylphenoxy)propioni c acid ethyl ester

To a stirred solution of (2S) 2-(4-tert-butylphenoxy)-3-[4-(2-hydroxyethoxy)phenyl]- propionic acid ethyl ester (4.0 g, 10.4 mmol), triphenyl phosphine (7.06 g, 26.9 mmol) in dichloromethane (50 ml), was added N-bromosuccinimide (4.98 g, 27.9 mmol) at 0 ⁰ C, portion wise, over a period of 45 min. The resulting reaction mixture was allowed to stir at 0 ⁰ C for 1 h followed by at room temperaturefor 2 h. The solvent was removed under reduced pressure to get crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 0.5% methanol-chloroform as an elument to yield the title compound (4.3 g, 92%). > MS: m/* 467 (M+18)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.10-1.26 (m, 12H) ₅ 3.14-3.18 (m, 2H) ₅ 3.61 (t ₅ J = 6.3 Hz ₅ 2H) ₅ 4.13-4.29 (m ₅ 4H) ₅ 4.69 (t ₅ J= 5.9 Hz ₅ IH) ₅ 6.73-6.85 (m ₅ 4H) ₅ 7.20-7.26 (m, 4H).

Intermediate 7 (2R)-2-(4-tert-Butylphenoxy)-3-[4-(2-hydroxyethoxy)phenyl]pr opionic acid ethyl ester

Step 1 : (2R)-2-(4-tert-Butylphenoxy)-3-[4-(2-hydroxyethoxy)phenyl]pr opionic acid

To a stirred solution of [(2R) ₅ N(lS)]-2-(4-fer/-butylρhenoxy)-3-[4-(2- hydroxyethoxy)-phenyl]-N-(2-hydroxy-l-phenylethyl)propionami de (4.75 g, 9.9 mmol) in dioxane (30 ml) was added a solution of concentrated H ₂ SO ₄ (2.2 ml) in water (20 ml) dropwise at room temperature and the resulting reaction mixture was heated at 110 ⁰ C for 5.5 h. Dioxane was removed under reduced pressure. The residue was diluted with water (75 ml) and extracted with ethyl acetate (2x75 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure to yield the title compound (3.30 g, 93%). MS: m/z 357 (M-I)

Step 2: (2R)-2-(4-tert-Butylphenoxy)-3-[4-(2-hydroxyethoxy)phenyl]pr opionic acid ethyl ester

To a solution of (2R)-2-(4-tøt-butylphenoxy)-3-[4-(2- hydroxyethoxy)phenyl]propionic acid (3.3 g, 9.21 mmol) in ethanol (70 ml) was added concentrated H ₂ SO ₄ (0.5 ml) and the reaction mixture was refluxed for 2.5 h. The solvent was removed under reduced pressure. The residue was diluted with water (100 ml) and extracted with ethyl acetate (2x75 ml), the combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to yield a crude product which was purified by column chromatography over silica gel (100-200 mesh) using 30% ethyl acetate-hexanes as an eluent to afford the title compound (3.18 g, 89%). MS: m/z 404 (M+18)

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.20 (t, J = 7.1 Hz, 3H), 1.26 (s, 9H), 3.15-3.19 (m, 2H), 3.95-3.97 (m, 2H), 4.04-4.08 (m, 2H), 4.18 (q, J= 7.0 Hz, 2H), 4.70 (t, J= 6.1 Hz, IH), 6.74- 6.96 (m, 4H), 7.21-7.26 (m, 4H). [α] _D ²⁰ + 7.17 (c 10.35, CHCl ₃ )

Intermediate 8

(2S)-2-Ethoxy-3-[4-(2-hydroxyethoxy)phenyl]propionic acid ethyl ester

MethodA:

Step 1 : 4-(2-Benzyloxyethoxy)benzaldehyde

To a stirred suspension of 60% sodium hydride (pre-washed with hexanes; 4.29 g, 178 mmol) in dry THF (100 ml) was added a solution of 4-(2-hydroxyethoxy)benzadehyde (27.0 g, 162 mmol) in dry THF (100 ml) over a period of 30 min at 0-5 ⁰ C. Reaction mixture was then stirred at same temperature for 2 h. To this reaction mixture, a solution of benzyl bromide (27.2 g, 16.2 ml, 162 mmol) in dry THF (400 ml) was added slowly over period of 0.5 h at same temperature under stirring. After the addition was completed, reaction mixture was allowed to come to room temperature and stirred for 8 h at same temperature. The reaction mixture was then cool in ice bath and quench with cold water (25 ml). THF was evaporated and the residue was diluted with water (300 ml) and extracted with ethyl acetate (2x250 ml). The combined organic layers were washed with water (3x100 ml), dried over anyhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 20->30% ethyl acetate-hexanes as an eluent to afford the title compound (26.15 g, 75%).

MS: m/z 213 (M+l) ^{1 1} HHNNMMRR ((CCDDCCll ₃₃ ,, 22C00 MHz): δ 3.85 (t, J= 4.8 Hz, 2H), 4.23 (t, J= 4.9 Hz, 2H), 4.63 (s, 2H); 7.02 (d, J= 8.6 Hz, 2H); 7.31 (m, 5H); 7.83 (d, J- 8.6 Hz, 2H); 9.88 (s, IH).

Step 2: (E/Z)-3-[4-(2-Benzyloxyethoxy)phenyl]-2-ethoxyacrylic acid ethyl ester

To an ice cooled suspension of 60% sodium hydride (pre-washed with hexanes; 1.54 g, 64.49 mmol) in dry THF (30 ml) was added a solution of triethyl-2- ethoxyphosphonoacetate [prepared by the method of Grell and Machleidt, Annalen Chemie, 1966, 699, 53] (8.8 g, 32.83 mmol) in dry THF (50 ml) over a period of 20 min under nitrogen atmosphere. Reaction mixture was then stirred at same temperature for 0.5 h. To this reaction mixture, a solution of 4-(2-benzyloxyethoxy)benzaldehyde (6.21 g, 29.31 mmol) in dry THF (40 ml) was added slowly over period of 0.5 h at 0-5 ⁰ C under stirring. The reaction mixture was allowed to come to room temperature and kept for 17 h. The solvent was

removed under reduced pressure; water (100 ml) was added to the residue and extracted with ethyl acetate (2x100 ml). The combined organic extracts were washed with water (3x50 ml), dried over anyhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 20-^30% ethyl acetate-hexanes as an eluent to afford the title compound (7.56 g, 76%). MS: m/z 371 (M+ 1)

¹ HNMR of product suggests a (75:25) Z/E mixture of geometric isomers. ¹ HNMR (CDCI ₃ , 200 MHz): δ 1.09-1.44 (m, 6H); 3.81-4.30 (m, 8H); 4.63 (s, 2H); 6.07 (s, 0.25H, E isomer); 6.86-6.93 (m, 2H); 6.96 (s, 0.75H ₅ Z isomer); 7.28-7.35 (m, 5H); 7.71 (t, J = 8.7 Hz, 2H).

Step 3: 3-[4-2-(Benzyloxyethoxy)phenyl]-2-ethoxypropionic acid methyl ester

A mixture of E/Z-3-[4-(2-benzylόxyethoxy)phenyl]-2-ethoxy acrylic acid ethyl ester (7.0 g, 18.91 mmol) and magnesium turnings (8.7 g, 359.29 mmol) in dry methanol (100 ml) was stirred at 25 ⁰ C for 1 h. To this reaction mixture, water (150 ml) was added andjoH of the solution was adjusted to 6.7-7.5 by the addition of 2N hydrochloric acid. The solution was extracted with ethyl acetate (3x100 ml). The organic layers were washed with water (2x50 ml), brine (2x50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 20% ethyl acetate-hexanes as an eluent to yield the title compound

(4.4 g, 65%).

MS: w/^ 376 (M+18)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.17 (t, J= 6.9 Hz, 3H); 2.96 (d, J = 6.4 Hz, 2H); 3.28-3.41 (m, IH); 3.50-3.65 (m, IH); 3.71 (s, 3H); 3.83 (t, J= 4.5 Hz, 2H); 4.00 (t, J = 6.4 Hz, IH);

4.14 (t, J= 4.4 Hz, 2H); 4.65 (s, 2H); 6.86 (d, J= 8.5 Hz, 2H); 7.15 (d, J= 8.5 Hz, 2H); 7.32-

7.37 (m, 5H).

Step 4: 3-[4-(2-Benzyloxyethoxy)phenyl]-2-ethoxypropionic acid

To a stirred solution of 3-[4-(2-benzyloxyethoxy)phenyl]-2-ethoxypropionic acid methyl ester (4.4 g, 12.2 mmol) in dioxane (75 ml) was added a solution of lithium hydroxide (1.54 g, 36.87 mmol) in water (75 ml) at 0 ⁰ C. The reaction mixture was allowed to come to room temperature and stirred for 7 h. After the completion of reaction, dioxane was removed under reduced pressure and the aqueous layer was acidified with 2N HCl (pH 2). The solid precipitated out was filtered through suction and dissolved in ethyl acetate (200 ml). The organic layer was washed with water (2x100 ml) dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to yield the title compound (4.23 g, 98%). MS: m/z 343 (M-I)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.16 (t, J - 6.9 Hz, 3H); 2.90-3.16 (m, 2H); 3.36-3.72 (m, 2H); 3.82 (t, J = 4.4 Hz, 2H); 4.00-4.12 (m, IH); 4.13 (t, J= 4.2 Hz, 2H); 4.63 (s, 2H); 6.85 (d, J= 8.3 Hz, 2H); 7.15 (d, J= 8.3 Hz, 2H); 7.28-7.36 (m, 5H).

Step 5: [(2S), iV(lS)]-3-[4-(2-Benzyloxyethoxy)phenyl]-2-ethoxy-iV-(2-hydro xy-l-phenyl- thyl)propionamide and [(2R), N(lS)]-3-[4-(2-benzyloxyethoxy)phenyl]~2-ethoxy-iV-(2- hydroxy- 1 -phenylethyl)propionamide

To an ice-cold solution of 3-[4-(2-benzyloxyethoxy)phenyl]-2-ethoxypropionic acid

(4.2 g, 12.2 mmol) in anhydrous dichloromethane (150 ml) was added 1- hydroxybenzotriazole (1.81 g, 13.42 mmol) under stirring. A mixture of (S)-2- phenylglycinol (1.80 g, 13.42 mmol), EDC (2.57 g, 13.42 mmol) and diisopropylethylamine (1.73 g., 2.3 ml., 13.42 mmol) in dichloromethane (25 ml) was added to the above reaction mixture drop wise at 0 ⁰ C under stirring. The reaction mixture was allowed to come to room

temperature and stirred for 14 h. After the completion of reaction, the reaction mixture was washed with water (2x100 ml), saturated aqueous sodium bicarbonate (1x100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a crude product, which was purified by column chromatograph over silica gel (200-400 mesh) using a gradient of 60% ethyl acetate-hexanes as an eluent to give the /desired diastereomer tentatively assigned as [(2R), N(lS)]-3-[4-(2-benzyloxyethoxy)phenyl]-2-ethoxy-iV-(2- hydroxy-l-phenylethyi)propinamide (1.0 g, 18.0%) followed by the other diastereomer [(2S), N(lS)]-3-[4-(2-benzyloxyehthoxy)phenyl]-2-ethoxy-iV-(2-hydro xy-l- phenylethyl)propionamide (1.06 g, 19.0%).

[(2R), N(lS)]-3-[4-(2-Benzyloxyethoxy)ρhenyl]-2-ethoxy-iV-(2-hydro xy-l-phenylethyl)- propionamide:

MS: m/z 462 (M-I)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.12 (t, J = 7.0 Hz, 3H), 2.86-3.19 (m, 2H), 3.48 (q, J= 6.9 Hz, 2H), 3.67 (t, J= 3.8 Hz, 2H), 3.82 (t, J= 4.4 Hz, 2H), 3.94-4.02 (m, IH), 4.13 (t, J= 4.5 Hz, 2H), 4.63 (s, 2H), 4.88-4.99 (m, IH), 6.86 (d, J= 8.5 Hz, 2H), 7.15-7.36 (m, 12H).

[(2S), JV(I S)]-3-[4-(2-Benzyloxyehthoxy)phenyl]-2-ethoxy-N-(2-hydroxy-l -phenylethyl)- propionamide: MS: m/z 462 (M-I)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.17 (t, J = 6.9 Hz ₅ 3H), 2.80-3.18 (m, 2H), 3.42-3.58 (m, 2H), 3.75-3.94 (m, 4H), 3.96-4.08 (m, IH), 4.10 (t, J= 4.3 Hz, 2H), 4.64 (s, 2H), 4.90-5.02

(m, IH), 6.77 (d, J= 8.4 Hz, 2H) ₅ 7.03-7.15 (m, 4H), 7.25-7.35 (m, 8H).

) Step 6: [(2S) ₅ 7V(lS)]-2-Ethoxy-3-[4-(2-hydroxyethoxy)phenyl]-N-(2-hydroxy- l-phenyl- ethyl)propionamide

To a stirred solution of [(2S) ₅ N(lS)]-2-ethoxy-3-[4-(2-benzyloxyethoxy)phenyl]~2- ethoxy-N-(2-hydroxy-l-phenylethyl)propionamide (0.99 g, 21.38 mmol) in ethanol (50 ml) was added 10% Pd-C (2.0 g) and ammonium formate (4.2 g, 66.6 mmol) at room temperature and the resulting mixture was heated at 70-75 ⁰ C for 4 h. The progress of reaction was monitored by TLC. After completion of reaction, reaction mixture was cooled to room temperature and filtered through Celite bed, washed with ethanol (2x25 ml) and combined, filtrate was concentrated under reduced pressure to yield a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 60->80% ethyl acetate- hexanes as an eluent to afford the title compound (0.70 g, 88%). MS: m/z 374 (M+l)

¹ HNMR (CDCl ₃ . 200 MHz): δ 1.19 (t, J = 7.0Hz, 3H), 2.08 (brs, IH ₅ exchangeable with D ₂ O), 2.55 (brs, IH ₅ exchangeable with D ₂ O) ₅ 2.83-3.13 (m, 2H), 3.49-3.57 (m, 2H), 3.78- 3.87 (m, 2H), 3.90-4.05 (m, 5H), 4.92-5.08 (m, IH), 6.77 (t, J= 8.6 Hz, 2H), 7.05-7.32 (m, 7H). -

Step 7: (2S)-2-Ethoxy-3-[4-(2-hydroxyethoxy)phenyl]propionic acid

To a stirred solution of [(2S), iV(lS)]-2-emoxy-3-[4-(2-hydroxyethoxy)ρhenyl]-N-(2- hydroxy-l-phenylethyl)propionamide (0.69 g, 0.18 mmol) in dioxane (15 ml) was added solution of concentrated H ₂ SO ₄ (0.7 ml) in water (15 ml) drop wise at room temperature and the resulting reaction mixture was heated at 110 ⁰ C for 5 h _M Dioxane was removed under reduced pressure and the residue was diluted with water (25 ml), extracted with ethyl acetate (2x30 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and the solvent was evaporated under reduced pressure to yield the title compound in quantitative yield.

MS: m/z 272 (M+l 8)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.18 (t, J = 7.0 Hz, 3H) ₃ 1.19 (brs, IH, exchangeable with D ₂ O) ₅ 2.84-3.16 (m, 2H), 3.41-3.68 (m, 2H), 3.88-3.99 (m, 2H), 4.02-4.16 (m, 3H), 6.85 (d, J = 8.6 Hz, 2H), 7.15 (d, J= 8.5 Hz, 2H).

Step 8: (2S)-2-Ethoxy-3-[4-(2-hydroxyethoxy)phenyl]propionic acid ethyl ester

To a solution of (2S)-2-ethoxy-3-[4-(2-hydroxyethoxy)phenyl]propionic acid (0.5 g, 2.04 mmol) in ethanol (25 ml) was added concentrated H ₂ SO ₄ (0.05 ml) and the resulting reaction mixture was refluxed for 3 h. The solvent was removed under reduced pressure and the residue was diluted with water (25 ml), extracted with ethyl acetate (2x25 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure to yield the title compound (0.375 g, 68%). MS: w/z 300 (M+18) ¹ HNMR (CDCl ₃ , 200 MHz): δ 1.12-1.26 (m, 6H), 2.95 (d, J = 6.6 Hz, 2H), 3.25-3.48 (m, IH) ₅ 3.52-3.71 (m, IH), 3.86-4.30 (m, 6H) ₅ 6.84 (d, J= 8.6 Hz, 2H) ₅ 7.16 (d, J= 8.6 Hz, 2H). [α] _D ²⁶ - 13.7 (c 10.02, CHCl ₃ )

MethodB

Step 1 : (2S)-2-Amino-3-(4-benzyloxyphenyl)propionic acid

To an ice cooled solution of potassium hydroxide (40.0 g, 0.605 mol) in 100 ml of water was added L-tyrosine (50 g, 0.275 mol) portion wise with maintaining inner temperature at 15-20 ⁰ C followed by the addition of CuSO ₄ .5H ₂ O (42.75 g, 0.171 mol) at 20 ⁰ C. Then reaction mixture was heated to 60-65 ⁰ C for 1 h under stirring and cooled to room temperature. To this reaction mixture was added DMF (200 ml) followed by drop wise

addition of benzyl chloride (38.12 ml, 0.33 mol) at room temperature. Then reaction mixture was heated to 55 ⁰ C for 2 h under stirring. Grey coloured solid copper complex of O-benzyl- L-tyrosine was precipitated out. The reaction mixture was allowed come to at room temperature, and water (500 ml) was added to get free grey coloured solid. This solid was filtered washed with water till the filtrate became colourless. This wet cake of O-benzyl-L- tyrosine copper complex was stirred with methanol (800 ml) at reflux temperature for 1 h, filtered, washed with methanol and dried in an oven at 65 ⁰ C. To this copper complex was added 800 ml of water followed by the addition of dilute HCl (50 ml in 250 ml of water) to get pR 2-3 under stirring at room temperature. The solid so obtained was filtered, washed with 10% ammonia solution (150 ml), and dried in vacuum oven at 65 ⁰ C to yield the title compound (46.0 g, 62%). mp: 259-260 ⁰ C MS: m/z 294 (M+23)

Step 2: (2S)-3-(4-Benzyloxyphenyl)-2-hydroxypropionic acid

To a stirred suspension of (2S)-2-amino-3-(4-benzyloxyphenyl)propionic acid (45 g, 0.166 mol) in 565 ml of 1,4-dioxane was added dilute aqueous H ₂ SO ₄ solution (48.62 g, 0.496 mol in 157.5 ml of water) at 25 ⁰ C. The resulted reaction mixture was cooled to 0 ⁰ C on ice bath and to this was added aqueous sodium nitrite solution (57.24 g, 0.826 mol in 80 ml of water) at 0 ⁰ C in a dropwise manner under stirring. After the completion of addition the reaction mixture was stirred at room temperature for 24 h. Reaction mixture was diluted with water (2000 ml), extracted with ethyl acetate (3x800 ml). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to yield crude product. The crude product was suspended in mixture of 100 ml of diisopropyl ether and 1 ml of ethyl acetate. Resulting solid was filtered, washed with diisopropyl ether (50 ml) and dried under vacuum to yield the title compound (16.8 g 37%).

MS: m/z 289 (M+18); 295 (M+23)

Step 3: (2S)-3-(4-Benzyloxyphenyl)-2-ethoxypropionic acid ethyl ester

To a stirred and cooled (15 ⁰ C) DMSO (168 ml) was added potassium hydroxide flakes (26.88 g, 0.4O7 mol) and (2S)-3-(4-benzyloxyphenyl)-2-hydroxypropionic acid (16.8 g, 0.062 mol). The resulting reaction mixture was cooled to 10 ⁰ C and to this diethyl sulphate (63.84 g, 0.414 mol) was added drop wise over a period of 20 min and the resulting reaction mixture was stirred for further 18 h at 25 ⁰ C. The reaction mixture was diluted with 1.0 L cold of water and extracted with ethyl acetate (4x500 ml). The combined organic layers were concentrated under reduced pressure. The residue so obtained was suspended in ethyl acetate (800 ml), washed with water (1x100 ml), brine (1x50 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue (21.0 g) was taken in ethanol (80 ml) and the resulting reaction mixture was cooled to 0 ⁰ C. To this was added triethyl amine (11.2ml) and stirred for 1 h at 0 ⁰ C. Excess ethanol was distilled off at reduced pressure. Residue was taken in ethyl acetate (800 ml), washed with water (3x15 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude compound was purified by column chromatography over silica gel (100-200 mesh) using 3% ethyl acetate-hexanes to obtain pure compound (13.5 g, 66%). MS: m/z 346 (M+18) ¹ HNMR (CDCl ₃ , 400 MHz): δ 1.15 (t, J= 6.8 Hz, 3H), 1.19 (t, J= 7.2 Hz, 3H), 2.94 (d, J = 6.8 Hz, 2H), 3.31-3.37 (m, IH), 3.56-3.64 (m, IH), 3.95 (t, J= 6.4 Hz, IH) ₅ 4.30 (q, J= 7.2 Hz, 2H), 5.04 (s, 2H), 6.89 (d, J= 8.4 Hz, 2H), 7.15 (d, J= 8.4 Hz, 2H), 7.25-7.44 (m, 5H).

Step 4: (2S)-2-Ethoxy-3-(4-hydroxyphenyl)propionic acid ethyl ester

To.a solution of (2S)-3-(4-benzyloxyphenyl)-2-ethoxypropionic acid ethyl ester (12.5 g, 0.038 mol) in ethanol (100 ml), 10% Pd-C (10.0 g) was added and the solution was hydrogenated (55 psi of H ₂ ) on Parr apparatus for 1O h. After completion of reaction, reaction mixture was filtered through Celite bed, washed with ethanol (5x50 ml). The combined filtrate was concentrated under reduced pressure to yield crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 5% methanol- dichloromethane as an eluent to afford the title compound (9.0 g, 99%). MS: m/z 256 (M+18)

, ¹ HNMR (CDCl ₃ , 400 MHz): δ 1.18 (t, J= 7.2 Hz, 3H), 1.22 (t, J= 7.2 Hz, 3H), 2.93 (d, J = 6.8 Hz, 2H), 3.32-3.39 (m, IH), 3.56-3.63 (m, IH), 3.96 (t, J= 6.8 Hz, IH), 4.13 (q, J= 7.2 Hz, 2H), 6.71 (d, J= 8.0 Hz, 2H), 7.07 (d, J= 8.4 Hz, 2H).

Step 5: (2S)-3-[4-(2-Benzyloxyethoxy)phenyl]-2-ethoxypropionic acid ethyl ester

To a solution of (2S)-2-ethoxy-3-(4-hydroxyphenyl)propionic acid ethyl ester (8.0 g,

0.034 mol) in dry dichloromethane (88 ml) was added 2-benzyloxyethanol (6.13 g, 0.040 mol) and triphenyl phosphine (10.49 g, 0.040 mol) at room temperature. The reaction mixture was cooled to 0 ⁰ C and to this was added a solution of diethylazadicarboxylate (6.3 ml, 0.040 mol) in dry dichloromethane (10 ml) in a drop wise manner over a period of 20 min. The resulting reaction mixture was stirred at same temperature for 4,h. After completion of reaction, reaction mixture was diluted with dichloromethane (150 ml) washed with water (2x25 ml), brine (1x25 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure to yield crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 30% ethyl acetate-hexanes as an eluent to afford the title compound (10.0 g, 80.0%). ,

- MS: m/* 390 (M+18)

¹ HNMR (CDCl ₃ , 400 MHz): δ 1.13 (t, J= 6.8 Hz, 3H), 1.19 (t, J= 7.2 Hz, 3H), 2.92 (d, J = 6.8 Hz, 2H), 3.31-3.37 (m, IH), 3.54-3.65 (m, IH), 3.80 (t, J= 4.4 Hz, 2H), 3.93 (t, J= 6.8

Hz, IH), 4.10-4.18 (m, 4H), 4.62 (s, 2H), 6.82 (d, J= 8.4 Hz, 2H), 7.12 (d, J= 8.4 Hz ₅ 2H), 7.25-7.35 (m, 5H).

Step 6: (2S)-2-Ethoxy-3-[4-(2-hydroxyethoxy)phenyl]propionic acid ethyl ester

To a solution of (2S)-3-[4-(2-benzyloxyethoxy)phenyl]-2-ethoxypropionic acid ethyl ester (9.0 g, 0.024 mol) in ethanol (100 ml), 10% Pd-C (9.0 g) was added and the solution was hydrogenated (55 psi of H ₂ ) on Parr apparatus for 18 h. After completion of reaction, reaction mixture was filtered through Celite bed, washed with ethanol (4x50 ml). The combined filtrate was concentrated under reduced pressure to yield crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 30% ethyl acetate- hexanes as an eluent to afford the title compound (6.2 g, 91%). MS: m/z 283 (M+l) ¹ HNMR (CDCl ₃ , 400 MHz): δ 1.12 (t, J= 6.8 Hz, 3H), 1.19 (t, J= 6.8 Hz, 3H), 2.92 (d, J = 7.2 Hz, 2H), 3.29-3.36 (m, IH), 3.54-3.62 (m, IH), 3.91-3.96 (m, 3H), 4.03-4.09 (m, 2H), 4.12 (q, J= 7.2 Hz, 2H), 6.81 (d, J= 8.8 Hz, 2H), 7.13 (d, J= 8.4 Hz, 2H). [α] _D ²⁰ - 13.7 (c 10.02, CHCl ₃ )

Intermediate 9 (2R)-2-Ethoxy-3-[4-(2-hydroxyethoxy)phenyl]propionic acid ethyl ester

Step 1: [(2R), N(lS)]-2-Ethoxy-3-[4-(2-hydroxyethoxy)phenyl]-N-(2-hydroxy-l -phenyl- ethyl)propionamide

To a stirred solution of [(2R), iV(lS)]-3-[4-(2-benzyloxyethoxy)phenyl]-2-ethoxy-N- (2-hydroxy-l-phenylethyl)propionamide (0.99 g, 21.38 mmol) in ethanol (50 ml) was added 10% Pd-C (2.0 g) and ammonium formate (4.2 g, 66.6 mmol) at room temperature and the resulting mixture was heated at 70-75 ⁰ C for 5 h. The progress of reaction was monitored by TLC. After completion of reaction, reaction mixture was cooled to room temperature and filtered through Celite bed, washed with ethanol (2x25 ml) and combined filtrate was concentrated under reduced pressure to yield a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 2% methanol-dichloromethane as an eluent to yield the title compound (0.70 g, 88%). MS: m/z 374 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.19 (t, J = 7.0 Hz, 3H); 2.90-3.22 (m, 2H); 3.46-3.54 (m, IH); 3.68-3.75 (m, 3H); 3.94-4.02 (m, 3H); 4.08-4.12 (m, 2H); 5.01 (m, IH); 6.85 (d, J- 8.4 Hz, 2H); 7.19-7.35 (m, 7H).

Step 2: (2R)-2-Ethoxy-3-[4-(2-hydroxyethoxy)phenyl]propionic acid

To a stirred solution of [(2R), N(lS)]-2-ethoxy-3-[4-(2-hydroxyethoxy)phenyl]-iV-(2- hydroxy-l-phenylethyl)propionamide (0.69 g, 0.18 mmol) in dioxane (15 ml) was added solution of concentrated H ₂ SO ₄ (0.7 ml) in water (15 ml) drop wise at room temperature and the resulting reaction mixture was heated at 110 ⁰ C for 4 h. Dioxane was removed under reduced pressure and the residue was diluted with water (25 ml), extracted with ethyl acetate (2x50 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and the solvent was evaporated under reduced pressure to yield the title compound in quantitative yield.

MS: m/z 253 (M-I)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.19 (t, J = 7.0 Hz, 3H); 2.96-3.08 (m, 2H); 3.49-3.57 (m,

2H); 3.88-3.97 (m, 2H); 4.04-4.09 (m, 2H); 6.85 (d, J = 8.6 Hz ₅ 2H); 7.15 (d, J = 8.6 Hz,

2H).

Step 3: (2R)-2-Ethoxy-3-[4-(2-hydroxyethoxy)phenyl]propionic acid ethyl ester

To a solution of (2R)-2-ethoxy-3-[4-(2-hydroxyethoxy)phenyl]propionic acid (0.45 g, 2.02 mmol) in ethanol (20 ml) was added concentrated H ₂ SO ₄ (0.1 ml) and the resulting reaction mixture was refluxed for 3 h. The solvent was removed under reduced pressure and the residue was diluted with water (30 ml), extracted with ethyl acetate (2x25 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to yield a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 60% ethyl acetate-hexanes as an eluent to afford the title compound (0.406 g, 81 %). MS: m/z 283 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.14-1.28 (m, 6H); 2.96 (d, J = 6.5 Hz; 2H), 3.32-3.44 (m, IH); 3.56-3.65 (m, IH); 3.94-4.23 (m, 7H); 6.85 (d, J = 8.3 Hz, 2H); 7.71 (d, J = 8.3 Hz, 2H). [(X] ²⁷ _D +16.87 (c 10.06, CHCl ₃ )

Intermediate 10

(2S)-2-Ethoxy-3-[4-(3-hydroxypropoxy)phenyl]prdpionic acid ethyl ester

Stepl: 3-Benzyloxypropan-l-ol

To a stirred solution of 1,3 -propanediol (20 g, 263 mmol) was added potassium hydroxide (5.9 g, 105.2 mmol). Stirring was continued till potassium hydroxide was dissolved completely and clear solution was obtained. Water produced during the course of reaction was distilled off under reduced pressure at rotary evaporator. Reaction mixture was allowed to heat to 90 ⁰ C and to this mixture was added benzyl chloride (12 ml, 105.2 mmol) dropwise over a period of 2 h under stirring. After the addition was completed, the temperature was raised to 130 ⁰ C and kept at this point for 2 h under stirring. The reaction mixture was cooled and ice-cold water (100 ml) was added to it, extracted with diethyl ether (2x100 ml), dried over Na ₂ SO ₄ . The solvent was evaporated under reduced pressure and residue was purified by fractional distillation under high vaccum to yield the title compound (12.50 g, 30%). MS: w/z l89 (M+23) ¹ HNMR (CDCl ₃ , 400 MHz): δ 1.71-1.78 (m, 2H); 3.56 (t, J = 5.6 Hz, 2H), 3.68 (t, J = 6.0 Hz, 2H), 4.44 (s, 2H); 7.18-7.29 (m, 5H).

Step 2 : (2S)-3-[4-(3-Benzyloxypropoxy)phenyl]-2-ethoxypropionic acid ethyl ester

To a stirred solution of 3-benzyloxypropan-l-ol (1.25 g, 7.6 mmol) in dry dichloromethane (10 ml) was added (2S)-2-ethoxy-3-(4-hydroxyphenyl)propionic acid ethyl ester (1.5 g, 6.3 mmol) in dry dichloromethane (10 ml) and triphenyl phosphine (1.9 g, 7.6 mmol) at room temperature. The reaction mixture was cooled to 0 ⁰ C and to this was added a solution of diethylazadicarboxylate (1.2 ml, 7.6 mmol) in dry dichloromethane (10 ml) in a drop wise manner over a period of 20 min. The resulting reaction mixture was stirred at same temperature for 4 h. After completion of reaction, reaction mixture was diluted with dichloromethane (50 ml), washed with water (2x10 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure to yield crude product, which was purified by column

chromatography over silica gel (100-200 mesh) using 30% ethyl acetate-hexanes as an eluent to afford the title compound (1.6 g, 66%). MS: m/z 404 (M+18)

¹ HNMR (CDCl ₃ , 400 MHz): δ 1.12 (t, J = 6.9 Hz, 3H); 1.98 (t, J = 7.1 Hz, 3H); 2.01-2.10 (m, 2H); 2.29 (d, J= 6.5 Hz, 2H); 3.30-3.38 (m, IH); 3.35-3.68 (m, 3H); 3.39 (t, J= 6.4 Hz, IH); 4.02-4.21 (m, 4H); 4.52 (s, 2H); 6.78 (d, J= 8.5 Hz, 2H); 7.12 (d, J= 8.5 Hz ₅ 2H); 7.31 (S ₃ 5H).

Step 3: (2S)-2-Ethoxy-3-[4-(3-hydroxypropoxy)phenyl]propionic acid ethyl ester

To a solution of (2S)-3-[4-(3-benzyloxypropoxy)phenyl]-2-ethoxypropionic acid ethyl ester (1.6 g, 4.1 mmol) in ethanol (20 ml) was added of 10% Pd-C (2.0 g, dry) and the solution was hydrogenated (55 psi of H ₂ ) on Parr apparatus for 18 h. After completion of reaction, reaction mixture was filtered through Celite pad, washed with ethanol (2x10 ml). The combined filtrate was concentrated under reduced pressure to yield crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 30% ethyl acetate-hexanes as an eluent to afford the title compound (0.93 g, 77%). MS: m/z 297 (M+l) ¹ HNMR (CDCl ₃ , 200 MHz): δ 1.12 (t, J= 6.9 Hz, 3H); 1.92 (t, J= 6.8 Hz, 3H); 2.00-2.09 (m, 2H); 2.92 (d, J= 6.5 Hz, 2H); 3.30-3.38 (m, IH); 3.55-3.63 (m, IH); 3.83 (t, J= 5.8 Hz, 2H); 3.92 (t, J = 6.4 Hz, IH); 4.07-4.21 (m, 4H); 6.79 (d, J= 8.5 Hz, 2H); 7.12 (d, J= 8.5 Hz, 2H).

Intermediate 11 3-[4-(2-Bromoethoxy)phenyl]-2-cyanopropionic acid ethyl ester

Step 1 : 4-(2-Hydroxyethoxy)benzaldehyde

To a stirred solution of 4-hydroxybenzaldehyde (40.0 g, 0.327 mol) in dry DMF was added anhydrous potassium carbonate (54.32 g, 0.392 mol), and 2-bromoethanol (49.0 g, 27.8 ml., 0.392 mol) at room temperature and the resulting reaction mixture was heated at 90 ⁰ C for 15 h. The reaction mixture was allowed to come to room temperature and then added ice cold water (500 ml) to it. The aqueous layer was saturated with NaCl and extracted with ethyl acetate (5 ^χ 60 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated at reduced pressure to get a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 25% ethyl acetate-hexanes as an eluent to yield the title compound (34.0 g, 63%). MS: m/z 167 (M+l) ¹ H NMR (CDCl ₃ , 200 MHz): δ 2.07 (br s, IH), 4.03 (t, J= 4.6 Hz, 2H), 4.17 (t, J= 4.6 Hz, 2H) ₅ 7,04 (d, J= 8.6 Hz, 2H), 7.84 (d, J= 8.6 Hz, 2H), 9.88 (s, IH).

Step 2: 2-Cyano-3-[4-(2-hydroxyethoxy)phenyl]acrylic acid ethyl ester

A mixture of 4-(2-hydroxyethoxy)benzaldehyde (34.0 g, 0.204 mol), ethyl cyanoacetate (27.74 g, 26.2 ml, 0.245 mol), piperidine (1.73 g, 2.0 ml.,20.35 mmol) and benzoic acid (2.48 g, 2032 mmol) in toluene (350 ml) was refluxed. using a Dean Stark apparatus for 45 min under stirring. The reaction mixture was allowed to come to room temperature and toluene was removed under reduced pressure. The residue was dissolved in ethyl acetate (400 ml), washed with water (1 x50 ml), dried over anhydrous Na ₂ SO ₄ and filtered. 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 40% ethyl acetate- hexanes as an eluent to afford the title compound (26.0 g,.49%).

MS: m/z 262 (M+l)

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.39 (t, J= 7.2 Hz, 3H), 2.09 (br s, IH) ₃ 4.01 (t, J= 4.0 Hz,

2H), 4.18 (t, J = 4.0 Hz, 2H), 4.38 (q, J= 7.2 Hz, 2H), 7.00 (d, J= 8.8 Hz, 2H), 8.02 (d, J =

8.8 Hz, 2H), 8.17 (s, lH).

Step 3: 2-Cyano-3-[4-(2-hydroxyethoxy)phenyl]propionic acid ethyl ester

To a solution of 2-cyano-3-[4-(2-hydroxyethoxy)phenyl]acrylic acid ethyl ester (20.0 g, 76.62 mmol) in ethyl acetate (200 ml) was added 10% Pd-C (3.1 g) and the solution was hydrogenated (40 psi of H ₂ ) on Parr apparatus for 3 h. After completion of reaction, reaction mixture was filtered through Celite bed, washed with ethyl acetate (4x25 ml). The combined filtrate was concentrated under reduced pressure to yield the title compound (20.0 g, 99%). MS: m/z 281 (M+18)

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.28 (t, J= 7.2 Hz, 3H), 1.96 (br s, IH), 3.15-3.26 (m, 2H), 3.69 (dd, J= 6.0 & 8.2 Hz, IH), 3.96 (t, J= 4.8 Hz, 2H), 4.08 (t, J= 4.8 Hz, 2H), 4.24 (q, J= 7.2 Hz, 2H), 6.89 (d, J= 8.6 Hz, 2H), 7.20 (d, J= 8.6 Hz, 2H).

Step 4: 3-[4-(2-Bromoethoxy)phenyl]-2-cyanopropionic acid ethyl ester

To a stirred solution of 2-cyano-3-[4-(2-hydroxyethoxy)phenyl]propionic acid ethyl ester (7.O g, 26.61 mmol) in dry dichloromethane (85 ml) was added triphenyl phosphine

(18.55 g, 70.80 mmol) at 0 ⁰ C and the reaction mixture was stirred for 15 min at the same temperature. N-Bromosuccinimide (12.59 g, 70.73 mmol) was then added portionwise over a

period of 45 min at 0 ⁰ C and the reaction mixture was stirred for 1 h at same temperature.

The solvent was removed under reduced pressure to get a crude product and was purified by column chromatography over silica gel (100-200 mesh) using chloroform as an eluent to yield the title compound (5.2 g, 60%).

MS: m/z 325 (M-I)

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.27 (t, J = 7.1 Hz, 3H), 3.07-3.27 (m, 2H) ₃ 3.59-3.71 (m,

3H), 4.18-4.30 (m, 4H) ₅ 6.87 (d, J= 8.6 Hz, 2H), 7.19 (d, J= 8.6 Hz, 2H).

Intermediate 12 (2S)-3-(4-{2-[(lα,5α,6α)-(3-Azabicyclo[3.1.0]hex-6-yl)-te rt-butoxycarbonylamino]ethoxy}- phenyl)-2-(4- mpound No 1,95)

Step 1: N-((lα,5α,6α)-3-Benzyl-3-azabicyclo[3.1.0]hex-6- yl)-4-nitrobenzenesulfonamide

To a stirred solution of (lα,5α,6α)-3-benzyl-3-azabicyclo[3.1.0]hex-6-ylamine [Synlett, 1996, 1100] (10.0 g, 53.2 mmol) in dry dichloromethane (100 ml) at 0 ⁰ C was added 4-nitrobenzenesulfonyl chloride (11.20 g, 50.5 mmol) and a solution of triethyl amine (16.11 g, 159.6 mmol) in dry dichloromethane (10 ml) drop wise over a period of 15 min. After the addition was completed the reaction mixture was allowed to come at room temperature and stirred for 15 h. The solvent was removed under reduced pressure. The residue so obtained was dissolved in dichloromethane (100 ml), washed with water (2x10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get crude product,

which was recrystallized using 25% dichloromethane-hexanes to yield the title compound (12.2 g, 61%). MS: w /z 374 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.67 (s, 2H), 2.35 (d, J= 8.8 Hz, 2H), 2.59 (s, IH), 2.94 (d, J = 9.0 Hz, 2H) ₅ 3.51 (s, 2H), 7.13-7.28 (m, 5H), 8.07 (d, J= 8.7 Hz, 2H), 8.39 (d, J= 8.7 Hz, 2H).

Step 2: (2S)-3-(4-{2-[((lα,5α,6α)-3-Benzyl-3-azabicyclo[3.1.0]hex -6-yl)-(4-nitrobenzene- sulfonyl)amino]ethoxy}phenyl)-2-(4-tert-butylphenoxy)propion ic acid ethyl ester {Compound No 196)

To a stirred solution of iV-((lα,5α,6α)-3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)-4-ni tro- benzenesulfonamide (5.0 g, 13.4 mmol) in dry dichloromethane(100 ml) was added triphenyl phosphine (6.33 g, 24.1 mmol) and (2S)-2-(4-tert-butylphenoxy)-3-[4-(2-hydroxyethoxy)- phenyl]propionic acid ethyl ester (5.33 g, 13.8 mmol) in dry dichloromethane (20 ml) at room temperature. To the above resulting mixture, was added diethyl azadicarboxylate (4.67 g, 26.8 mmol) drop wise and stirred for 2 h. After the completion of reaction, 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 1.0->1.5% acetone-dichloromethane as an eluent to yield the title compound (8.5 g, 85%). MS: m /z 742 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.18-1.25 (m, 12H), 2.02 (s, 2H), 2.42-2.45 (m, 3H), 2.96- 2.98 (m, 2H), 3.14 (d, J= 5.6 Hz, 2H), 3.53-3.56 (m, 4H), 4.08 (t, J= 5.5 Hz, 2H), 4.18 (q, J

= 7.0 Hz, 2H), 4.68 (t, J= 6.0 Hz, IH) ₃ 6.67-6.78 (m, 4H), 7.16-7.26 (m, 9H), 8.01 (d, J= 8.0 Hz, 2H), 8.33 (d, J= 8.4 Hz, 2H).

Step 3 : (2S)-3-{4-[2-((l α,5α,6α)-3-Benzyl-3-azabicyclo[3.1.0]hex-6-ylammo)ethoxy] - phenyl}-2-(4-tert-butylphenoxy)propionic acid ethyl ester (Compound No 197)

To a solution of (2S)-3-(4-{2-[((lα,5α,6α)-3-benzyl-3-azabicyclo[3.1.0]hex -6-yl)-(4- nitro-benzenesulfonyl)amino]ethoxy}phenyl)-2-(4-fert-butylph enoxy)propionic acid ethyl ester (8.5 g, 11.5 mmol) in dry acetonitrile (170 ml) was added anhydrous potassium carbonate (5.54 g, 40.2 mmol) under nitrogen atmosphere. The reaction mixture was cooled to 0 ⁰ C and added thiophenol (2.52 g, 22.9 mmol) in a drop wise manner under stirring. After being stirred for 3 h at room temperature, more thiophenol (1.26 g, 11.5 mmol) was added to the above reaction mixture and stirred for further 2 h. Solvent was removed under reduced pressure and the residue was taken up in dichloromethane (200 ml), washed with water (2x25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get a crude product which was purified by column chromatography over silica gel (100-200 mesh) using 2.0-^3.0% methanol-dichloromethane as an eluent to yield the title compound (4.48 g,

MS: m/z 557 (M+l) ¹ HNMR (CDCl ₃ , 200 MHz): δ 1.16-1.25 (m, 12H), 1.46 (s, 2H) ₅ 2.48 (d, J = 8.5 Hz, 2H), 2.63 (s, IH) ₅ 3.03 (d, J = 5.9 Hz, 4H), 3.13-3.17 (m, 2H), 3í62 (s, 2H), 4.01 (t, J= 5.0 Hz ₅ 2H), 4.17 (q, J= 7.1 Hz, 2H), 4.68 (t, J= 6.0 Hz ₅ IH), 6.73-6.83 (m, 4H) ₅ 7.17-7.29 (m, 9H).

Step 4: (2S)-3-(4-{2-[(lα,5α,6α)-(3-Benzyl-3-azabicyclo[3.1.0]hex -6-yl)tert-butoxy- carbonylamino]ethoxy}phenyl)-2-(4-terf-butylphenoxy)proρion ic acid ethyl ester

To a solution of (2S)-3-{4-[2-((lα,5α,6α)-3-benzyl-3-azabicyclo[3.1.0]hex- 6- ylamino)-ethoxy]phenyl}-2-(4-tert-butylphenoxy)propionic acid ethyl ester (4.45 g, 8.00 mmol) in dry dichloromethane (40 ml) was added triethyl amine (0.08 g, 0.80 mmol) and di- fert-butyl-carbonate (1.92 g, 2.02 ml, 8.80 mmol) drop wise manner at room temperature. The resulting reaction mixture was stirred at same temperature for 3 h. After completion of reaction, reaction mixture was diluted with dichloromethane (50 ml), washed with water (2x20 ml). The combined organic laters were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get crude product which was purified by column chromatography over silica gel (100-200 mesh) using 0.5-M.0% methanol-dichloromethane as an eluent to yield the title compound (5.0 g, 95%). MS: m/z 658 (M+2)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.17-1.25 (m, 12H), 1.43 (s, 9H) ₅ 1.74 (brs, 2H) ₅ 2.52 (brs, 2H) ₅ 3.08-3.18 (m, 5H) ₅ 3.53 (t, J= 5.3 Hz, 2H) ₅ 3.64 (brs, 2H) ₅ 4.03 (t, J= 5.4 Hz, 2H), 4.18 (q, J= 7.1 Hz ₅ 2H) ₅ 4.68 (t, J= 6.1 Hz ₅ IH) ₅ 6.73-6.80 (m, 4H) ₅ 7.16-7.30 (m, 9H).

Step 5 : (2S)-3-(4-{2-[(l α,5α,6α)-(3-Azabicyclo[3.1.0]hex-6-yl)tert-butoxycarbonyl amino]- ethoxy}phenyl)-2-(4-tert-butylphenoxy)propionic acid ethyl ester

To ^" a solution of (2S)-3-(4-{2-[(lα,5α,6α)-(3-benzyl-3-azabicyclo[3.1.0]hex -6- yl)tert-butoxycarbonylamino]ethoxy}phenyl)-2-(4-/ert-butylph enoxy)propionic acid ethyl

ester (5.0 g, 7.62 mmol) in methanol (50 ml), was added 10% Pd-C (5.0 g, 50% wet) and the solution was hydrogenated (50 psi of H ₂ ) on Parr apparatus for 4 h. After completion of reaction, reaction mixture was filtered through Celite bed, washed with methanol (2x15 ml). The combined filtrate was concentrated under reduced pressure to yield the title compound (3.6 g, 83%). _λ MS: w/z ^' 568 (M+2)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.17-1.25 (m, 12H), 1.43 (s, 9H), 2.14 (s, 2H), 2.80 (s, IH), 3.15 (d, J= 6.0 Hz, 2H), 3.46-3.51 (m, 6H), 4.00-4.02 (m, 2H), 4.17 (q, J= 7.0 Hz, 2H), 4.68 (t, J= 6.0 Hz, IH), 6.77 (t, J= 9.9 Hz, 4H), 7.18-7.26 (m, 4H).

Intermediate 13

(2S)-3-(4-{2-[(lα,5α,6α)-(3-Azabicyclo[3.1.0]hex-6-yl) fer?-butoxycarbonylamino]ethoxy}- phenyl)-2-ethoxypropionic acid ethyl ester (Compound No 198)

Stepl: (2S)-3-(4-{2-[(lα,5α,6α)-(3-Benzyl-3-azabicyclo[3.1.0]hex -6-yl)-(4-nitrobenzene- sulfonyl)amino]ethoxy}phenyl)-2-ethoxypropionic acid ethyl ester (Compound No 199)

To a stirred solution of (2S)-2-ethoxy-3-[4-(2-hydroxyethoxy)phenyl]propionic acid ethyl ester (8.18 g, 29 mmol) in dichloromethane (200 ml) was added triphenyl phosphine

(13.22 g, 50 mmol) followed by a solution of iV-((lα,5α,6α)-3-benzyl-3-azabicyclo-

[3.1.0]hex-6-yl)-4-nitrobenzenesulfonamide (10.5 g, 28 mmol) in dichloromethane (100 ml) at room temperature. To the above solution was added diethylazadicaboxylate (9.76 g, 56.1 mmol) in drop wise manner, at room temperature and stirred for 2 h. After completion of reaction, the reaction mixture was concentrated under reduced pressure to get crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 0.8-M.4% acetone-dichloromethane as an eluent to yield title compound (10.9 g, 61%) MS: mlz 638 (M+ 1)

¹ HNMR (CDCl ₃ , 400 MHz):δ 1.13-1.27 (m, 6H) ₅ 1.60 (s, 2H), 2.16 (s, IH), 2.92-2.96 (m, 4H), 3.31 (q, J = 7.2 Hz, 2H), 3.40 (q, J = 13.2 Hz ₅ 2H), 3.53-3.61 (m, 3H) ₅ 3.93-3.98 (m, 3H), 4.12-4.18 (m, 3H), 6.66 (d, J= 8.4 Hz, 2H), 7.10 (d, J= 8.4 Hz ₅ 2H), 8.01 (d, J= 11.6 Hz ₅ 2H), 8.31 (d, J= 8.8 Hz, 2H).

Step 2: (2S)-3-(4-{2-[(lα,5α ₅ 6α)-3-Benzyl-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}- phenyl)-2-ethoxypropionic acid ethyl ester {Compound No 200)

To a solution of (2S)-3-(4-{2-[(lα,5α ₅ 6α)-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)-(4- nitro-benzenesulfonyl)amino]ethoxy}phenyl)-2-ethoxypropionic acid ethyl ester (4.7 g, 7.3 mmol) in dry acetonitrile (47 ml) was added anhydrous potassium carbonate (3.05 g, 22.1 mmol) under nitrogen atmosphere. The reaction mixture was cooled to 0 ⁰ C and added thiophenol (1.215 g, 11.0 mmol) in a drop wise manner under stirring. After being stirred for 3 h at room temperature, more thiophenol (0.607 g, 5.5 mmol) was added to the above reaction mixture and stirred for further 2 h. Solvent was removed under reduced pressure and the residue was taken up in dichloromethane (80 ml), washed with water (1x20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get a crude product which was purified by column chromatography over silica gel (100-200 mesh) using 1.2->1.4% methanol-dichloromethane as an eluent to yield the title compound (2.15 g, 65%). MS: m/z 453 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.12-1.28 (m, 6H), 1.30-1.35 (m, 3H), 1.47 (s, IH), 2.47-2.52 (d, J= 9.0 Hz, 2H), 2.63 (s, IH), 2.90-3.07 (m, 5H), 3.33-3.38 (m, IH), 3.52-3.64 (m, 3H), 3.90-4.11 (m, 2H), 4.10-4.21 (m, 2H), 6.78-7.15 (m, 4H), 7.24-7.30 (m, 5H).

Step 3: (2S)-3-(4-{2-[(lα,5α,6α)-(3-Benzyl-3-azabicyclo[3.1.0]hex -6-yl)-ført-butoxy- carbonylamino]ethoxy}phenyl)-2-ethoxypropionic acid ethyl ester {Compound No 201)

To a stirred solution of (2S)-3-(4-{2-[(lα,5α,6α)-3-benzyl-3-azabicyclo[3.1.0]hex- 6- yl-amino]ethoxy}phenyl)-2-ethoxypropionic acid ethyl ester (1.663 g, 3.67 mmol) in dry dichloromethane (25ml) at 0 ⁰ C was added triethyl amine (0.037 g, 0.05 ml, 0.03 mmol) and di-tert-butylcarbonate (0.883 g, 4.04 mmol) drop wise manner. The resulting reaction mixture was stirred at room temperature for 3 h. After completion of reaction, reaction mixture was diluted with dichloromethane (20 ml), washed with water (2x10 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get crude product which was purified by column chromatography over silica gel (100-200 mesh) using 1.6->2.0% methanol-dichloromethane as an eluent to yield the title compound (1.217 g, 60%). MS: mlz 553 (M+l) ¹ HNMR: (CDCl ₃ , 400 MHz): δ 1.14 (t, J= 7.2 Hz, 3H), 1.21 (t, J= 7.2 Hz, 3H), 1.44 (s, 9H), 1.60-1.67 (m, 3H), 2.42 (s, IH), 2.98 (d, J= 14.4 Hz, 3H), 3.02 (s, IH), 3.30-3.37 (m, IH), 3.53-3.63 (m, 5H), 3.93 (t, J= 6.0 Hz, IH), 4.02 (d, J= 4.8 Hz, 2H), 4.14 (q, J= 7.2 Hz, 2H), 6.76-7.13 (m, 4H), 7.25-7.37 (m, 4H).

Step 4: (2S)-3-(4-{2-[(lα,5α,6α)-(3-Azabicyclo[3.1.0]hex-6-yl)-f� �rt-butoxycarbonylamino]- ethoxy}phenyl)-2-ethoxypropionic acid ethyl ester

To a solution of (2S)-3-(4-{2-[(lα,5α,6α)-(3-benzyl-3-azabicyclo[3.1.0]hex -6-yl)- tert-butoxycarbonylamino]ethoxy}phenyl)-2-ethoxypropionic acid ethyl ester (2.69 g, 4.7 mmol) in absolute ethanol (25 ml) was added 10% Pd-C (2.6 g, wet) and the solution was hydrogenated (55 psi of H ₂ ) on Parr apparatus for 4 h. After completion of reaction, reaction mixture was filtered through Celite bed, washed with ethanol (5x25 ml). The combined filtrate was concentrated under reduced pressure to get a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 1.2-^1.4% methanol- dichloromethane as an eluent to yield the title compound (1.25 g, 62%). MS: w/z 463 (M+l)

¹ HNMR (CDCl ₃ , 400 MHz): δ 1.15 (t, J= 6.8 Hz, 3H), 1.18 (m, 3H), 1.46 (s, 9H), 1.96-1.98 (m, IH), 2.10 (s, 2H), 2.16 (s, IH) 2.88 (d, J= 5.6 Hz, 2H), 3.31-3.32 (m, IH), 3.50-3.53 (m, 3H), 3.58-3.63 (m, 2H), 3.73-3.77 (m, IH), 3.95 (t, J= 6.4 Hz, IH), 4.00-4.03 (m, 2H), 4.14 (q, J= 6.8 Hz, 2H), 6.77-7.17 (m, 4H). . ^' , .

Intermediate 14

2-(4-/ert-Butylphenoxy)-3-[4-(2-hydroxyethoxy)phenyl]-2-m ethylpropionic acid methyl ester

Step 1 : 2-(4-fert-Butylphenoxy)propionic acid methyl ester

To a stirred solution of 4-fert-butylphenol (5.0 g, 33.3 mmol) in DMF (8.0 ml) was added potassium carbonate (5.06 g, 37 mmol), 2-bromopropionic acid methyl ester (4.5 ml,

40 mmol) was added and the resulting reaction mixture was heated at 70 ⁰ C for 6 h. After completion of reaction, reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (4x50 ml). The combined organic layers were washed with water (1x20 ml), brine (1x20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 10% ethyl acetate-hexanes as an eluent to yield the title compound (7.76 g, 98%).

MS: w/z 254 (M+18)

¹ HNMR (CDCl ₃ , 400 MHz): δ 1.28 (s, 9H), 1.59 (d, J= 3.6 Hz, 3H), 3.76 (s, 3H), 4.71 (q, J

= 3.4 Hz, IH), 6.78 (d, J= 7.4 Hz, 2H), 7.25 (d, J= 7.0 Hz, 2H).

Step 2: 3-(4-Benzyloxyphenyl)-2-(4-/ert-butylphenoxy)-2-methylpropio nic acid methyl ester

To a cooled (-78 ⁰ C) solution of iV-isopropylcyclohexylamine (2.4 ml, 14.3 mmol) in dry THF (39 ml) was added 1.6M rø-butyllithium-hexane (9 ml, 14.3 mmol) dropwise. After the completion of the addition, resulting reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was again cooled to -78 ⁰ C and to this was added a solution of 2- (4-føY-butylphenoxy)propionic acid methyl ester (30 g, 12.7 mmol) in THF (12 ml) drop wise over a period of 30 min followed by the addition of a solution of 4-benzyloxybenzyl chloride (5.9 g, 25.4 mmol) in THF (20 ml) drop wise over a period of 15min. The reaction

mixture was stirred at -78 ⁰ C for 7 h. The solvent was removed under reduced pressure and residue was extracted with ethyl acetate (2x50 ml). The combined organic layers were washed with 2N HCl (1x10 ml), water (1x50 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 3% ethyl acetate-hexanes as an eluent to yield the title compound (2.5 g, 45%). MS: rø/z 450 (M+18)

¹ HNMR (CDCl ₃ , 400 MHz): δ 1.25 (s, 9H), 1.42 (s, 3H) ₅ 3.10 (d, J= 13.6 Hz, IH), 3.26 (d, J = 13.6 Hz, IH), 3.73 (s, 3H), 5.04 (s, 2H), 6.72 (d, J= 8.8 Hz, 2H), 6.89 (d, J= 8.4 Hz, 2H), 7.15 (d, J= 8.4 Hz ₃ 2H), 7.21-7.42 (m, 7H).

Step 3: 2-(4-tert-Butylphenoxy)-3-(4-hydroxyphenyl)-2-methylpropioni c acid methyl ester

To a solution of 3-(4-benzyloxyphenyl)-2-(4-tert-butylphenoxy)-2-methylpropio nic acid methyl ester (2.5 g, 5.8 mmol) in ethanol (25 ml) was added 10% Pd-C (3.0 g) and the solution was hydrogenated (55 psi of H ₂ ) on Parr apparatus for 6 h. After completion of reaction, reaction mixture was filtered through Celite bed, washed with ethanol (4x10 ml).

The combined filtrate was concentrated under reduced pressure to yield crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 40% ethyl acetate-hexanes as an eluent to yield the title compound (1.8 g, 91%).

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.26 (s, 9H), 1.38 (s, 3H), 3.12-3.19 (m, 2H), 3.73 (s, 3H),

6.70-6.76 (m, 4H), 7.08-7.24 (m, 4H).

Step 4: 3-[4-(2-Benzyloxyethoxy)phenyl]-2-(4-tørt-butylphenoxy)-2- methylpropionic acid methyl ester

To' a stirred solution of 2-(4-fer^-butylphenoxy)~3-(4-hydroxyphenyl)-2- methylpropionic acid methyl ester (2.1 g, 6.2 mmol) in dichloromethane (30 ml) was added triphenyl phosphine (1.95 g, 7.4 mmol) and a solution of 2-benzyloxyethanol (1.13 g, 7.4 mmol) in dichloromethane (10 ml). To this reaction mixture was added diethylazadicarboxylate (1.26 ml, 8.1 mmol) drop wise at 0 ⁰ C and the resulting reaction mixture was stirred at same temperature for 4 h. After completion of reaction, reaction mixture was diluted with dichloromethane (50 ml) and washed with with water (2x10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 10% ethyl acetate-hexanes as an eluent to yield the title compound (1.8 g, 63%). MS: m/z 494 (M+18) ¹ HNMR (CDCl ₃ , 200 MHz): δ 1.26 (s, 9H), 1.38 (s, 3H), 3.14-3.21 (m, 2H), 3.73 (s, 3H), 3.80 (t, J= 4.5 Hz, 2H), 4.1 l(t, J= 5.1 Hz, 2H), 4.63 (s, 2H), 6.70 (d, J= 8.7 Hz, 2H), 6.83 (d, J= 8.6 Hz, 2H), 7.12-7.37 (m, 9H).

Step 5: 2-(4-tert-Butylphenoxy)-3-[4-(2-hydroxyethoxy)phenyl]-2-meth ylpropionic acid methyl ester

To a solution of 3-[4-(2-benzyloxyethoxy)phenyl]-2-(4-tert-butylphenoxy)-2-me thyl- propionic acid methyl ester (1.8 g, 3.8 mmol) in ethanol (15 ml) was added 10% Pd-C (2.1 g) and the resulting solution was hydrogenated (55 psi of H ₂ ) on Parr apparatus for 12 h. After completion of reaction, reaction mixture was filtered through Celite bed, washed with ethanol (4x15 ml). The combined filtrate was concentrated under reduced pressure to yield crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 50% ethyl acetate-hexanes as an eluent to afford the title compound (1.37 g, 92%). MS: w/z 404 (M+18)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.26 (s, 9H), 1.38 (s, 3H) ₅ 3.07-3.21 (m, 2H), 3.73 (s, 3H), 3.95-4.09 (m, 4H), 6.74 (d, J= 8.6 Hz, 2H), 6.82 (d, J, = 8.4 Hz, 2H), 7.14-7.26 (m, 4H).

Intermediate 15

(2S)-3-(4-{2-[(lα,5α,6α)-6-Amino-3-azabicyclo[3.1.0]he x-3-yl]ethoxy}phenyl)-2-(4-fert- butylphenoxy)propionic acid ethyl ester {Compound No 202)

Step 1: (2S)-3-(4-{2-[(lα,5α,6α)-6-tert-Butoxycarbonylamino-3-aza bicyclo[3.1.0]hex-3- yl]ethoxy}phenyl)-2-(4-tert-butylphenoxy)propionic acid ethyl ester {Compound No 12)

To a stirred solution of (lα,5α,6α)-(3-azabicyclo[3.1.0]hex-6-yl)carbamic acid tert- butyl ester (2.0 g, 10.1 mmol) in dry acetonitrile (50 ml), were added anhydrous potassium carbonate (4.18 g, 30.3 mmol), (2S)-3-[4-(2-bromoemoxy)phenyl]-2-(4-fert-butylphenoxy)-

propionic acid ethyl ester (Intermediate 6; 4.99 g, 11.1 mmol), and potassium iodide (0.168 g, 1.01 mmol) at room temperature And the resulting reaction mixture was heated to 50 ⁰ C for 5 hrs. The solvent was removed under reduced pressure and residue was suspended in dichloromethane (50 ml). The organic layer was washed with water (2x20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to yield a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 1.0-> 1.5% methanol-chloroform as an eluent to yield the title compound (3.56 g, 62%). MS: mlz 568 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.16-1.25 (m, 12H), 1.42 (s, 9H), 1.63 (s, 2H), 2.65-2.85 (m, 3H), 2.87-2.96 (m, 2H), 3.13-3.17 (m, 2H), 3.30 (d, J= 9.3 Hz, 2H), 4.06-4.23 (m, 4H), 4.68 (t, J= 5.9 Hz, IH), 6.78-6.81 (m, 4H), 7.17-7.25 (m, 4H).

Step 2: (2S)-3-(4-{2-[(lα,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hex-3 -yl]ethoxy}phenyl)-2- '

(4-fert-butylphenoxy)propionic acid ethyl ester

A solution of 20% v/v trifluoroacetic acid-dichloromethane (35 ml) was added to

(2S)-3-(4-{2-[(lα,5α,6α)-6-tert-butoxycarbonylamino-3-aza bicyclo[3.1.0]hex-3-yl]ethoxy}- phenyl)-2-(4-/ert-butylphenoxy)propionic acid ethyl ester (3.55 g, 6.3 mmol) at 0 ⁰ C under stirring and the resulting mixture was stirred for 2 h at the same temperature. Then, reaction mixture was allowed to come to room temperature the progress of the reaction was monitored by TLC. The reaction was completed in approximately 2 h. The solvent was removed under reduced pressure to yield a crude product as its TFA salt. The residue was dissolved in dichloromethane (25 ml). To this mixture was added a solution of ammonia in chloroform drop wise at 0 ⁰ C under stirring, until the salt was neutralized completely. Salt separated out was filtered off and the filtrate was concentrated under reduced pressure to yield the title compound (2.90 g, 99%).

MS: m/z 467 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.16-1.25 (m, 12H) ₅ 1.55 (s, 2H), 2.65 (d, J = 9.1 Hz, 2H), 2.75 (s, IH), 2.91 (t, J= 5.5 Hz, 2H), 3.13-3.27 (m, 4H), 4.07 (t, J= 5.5 Hz, 2H), 4.17 (q, J= 7.0 Hz, 2H), 4.68 (t, J= 5.9 Hz, IH), 6.77 (t, J= 8.7 Hz, 4H), 7.18-7.25 (m, 4H).

Intermediate 16

(lα,5α,6α)-6-(4-Nitrobenzenesulfonylamino)-3-azabicycl o[3.1.0]hexane-3-carboxylic acid-

(4-trifluoromethylphenyl)amide

Step 1 : [(lα,5α,6α)-[3-(2,4,5-Trifluoromethylphenylcarbamoyl)-3-a zabicyclo[3.1.0]hex-6- yl]]carbamic acid tert-butyl ester

To a stirred solution of [(lα ₅ 5α,6α)-3-azabicyclo[3.1.0]hex-6-yl]carbamic acid tert- butyl ester (2.0 g, 10.1 mmol) in dichloromethane (20 ml) was added 4- (trifluoromethylphenyl)-isocyanate (2.08 g, 1.59 ml., 11.1 mmol) dropwise , at 0 ⁰ C. After being stirred at room temperature for 3 h., reaction mixture was diluted with dichloromethane (20 ml), washed with water (2x20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to yield a crude product, which was crystallized by using 25:75 dichloromethane-hexanes to yield the title compound (3.30 g, 85%). MS: m/z 386 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.43 (s, 9H), 1.81 (s, 2H), 2.34 (s, IH), 3.56 (d, J= 9.6 Hz ₅ 2H), 3.75 (d, J = 9.9 Hz, 2H), 4.76 (brs, IH ₅ exchangeable with D ₂ O), 6.42 (brs, IH ₅ exchangeable with D ₂ O) ₅ 7.44-7.51 (m, 4H).

Step 2: (lα,5α,6α)-6-Amino-3-azabicyclo[3.1.0]hexane-3-carboxylic acid(4-trifluoromethyl- phenyl)amide

The title compound (1.53 g, 86%) is obtained by following the similar procedure given in Step 2 of Intermediate 1. MS: m/z 286 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.65(s, 2H), 2.13 (s, IH) ₅ 3.48 (d, J= 9.9 Hz, 2H) ₅ 3.61 (d, J= 10.0 Hz ₅ 2H) ₅ 7.41-7.60 (m, 4H).

Step 3: (lα,5α,6α)-6-(4-Nitrobenzenesulfonylamino)-3-azabicyclo[3 .1.0]hexane-3- carboxylic acid(4-trifluoromethylphenyl)amide

The title compound (2.2 g, 89%) is obtained by following the similar procedure given in Step 3 of Intermediate 1. MS: w/z 471 (M+l)

¹ HNMR (CDCl ₃₅ 200 MHz): δ 1.87 (s, 3H) ₅ 3.43 (d, J= 11.1 Hz, 2H) ₅ 3.55 (d ₅ J= 9.2 Hz, 2H), 7.35-7.43 (m, 4H); 7.99 (d, J= 8.8 Hz, 2H), 8.31 (d, J= 8.8 Hz ₅ 2H).

Example 1 (2S)-2-(4-tert-Butylρhenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4-ch lorobenzyl)-3-azabicyclo[3.1.0]- hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride {Compound No 107)

.2HCl

Step 1 : (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-[3-(4-ch lorobenzyl)-3-azabicyclo- [3.1.0]hex-6-yl]-(4-nitrobenzenesulfonyl)amino]ethoxy}phenyl )propionic acid ethyl ester

To a solution of N-[(lα,5α,6α)-3-(4-chlorobenzyl)-3-azabicyclo[3.1.0]hex-6 -yl]-4- nitro-benzenesulfonamide (Intermediate 1; 4.66 g, 11.4 mmol) in dry dichloromethane (120. ml) was added triphenylphosphine (5.4 g, 21.0 mmol) and (2S)-2-(4-tert-butylphenoxy)-3-[4- (2-hydroxyethoxy)phenyl]propionic acid ethyl ester (Intermediate 5; 4.55 g, 11.8 mmol) at room temperature under stirring. To the above solution, was added diethylaza-dicarboxylate (3.98 g, 3.62 ml, 23.0 mmol) drop wise at same temperature. After being stirred at the room temperature for 2 h, 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 0.8% acetone-dichloromethane as an eluent to yield the required product. This product was again purified by column chromatography over silica gel (200-400 mesh) using 1% methanol- dichloromethane as an eluent to yield the title compound (7.35 g, 83%). MS: m/z llβ (M+l) ,;

¹ H νMR (CDCl ₃ , 200 MHz): 'δ 1.19-1.32 (m, 12H), 2.01 (s, 2H), 2.40 (d, J = 8.8 Hz, 2H), 2.50 (s, IH), 2.97 (d, J = 8.9 Hz, 2H), 3.15-3.17 (m, 2H) ₃ 3.50 (s, 2H), 3.58 (t, J = 5.5 Hz, 2H), 4.10 (t, J= 5.6 Hz, 2H), 4.20 (q, J= 7.0 Hz, 2H), 4.70 (t, J= 5.9 Hz, IH), 6.66-6.79 (m, 4H), 7.08-7.26 (m, 8H), 8.01 (d, J= 8.8 Hz, 2H), 8.34 (d, J= 8.8 Hz, 2H).

Step 2: (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4-chl orobenzyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 10)

To a solution of (2S)-2-(4-tert-butylphenoxy)-3-(4-{2-[(lα,5α,6α)-[3-(4- chlorobenzyl)-3-azabicyclo[3.1.0]hex-6-yl]-(4-nitrobenzenesu lfonyl)amino]ethoxy} phenyl)propionic acid ethyl ester (7.3 g, 9.4 mmol) in dry acetonitrile (80 ml) was added anhydrous potassium carbonate (3.88 g, 28.0 mmol) under nitrogen atmosphere. The reaction mixture was cooled to 0 ⁰ C and added thiophenol (0.78 g, 0.75 ml, 7.1 mmol) drop wise under stirring. After being stirred for 3 h at room temperature, thiophenol (0.376 g, 0.35 ml, 3.4 mmol) and anhydrous potassium carbonate (0.5 g, 3.6 mmol) was added to the above reaction mixture and stirred for 2 h. After being stirred for another 2 h, this addition was repeated again with the same quantity of thiophenol and anhydrous potassium carbonate and stirred for further 3 h. Acetonitrile was removed under reduced pressure and the residue was taken up in dichloromethane (100 ml), washed with water (1x20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get a crude product which was purified by column chromatography over silica gel (100-200 mesh) using 1.25-^2% methanol-dichloromethane as an eluent to yield the title compound (3.9 g ,70%). MS: m/z 591 (M+l)

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.17-1.26 (m, 12H), 1.41 (s, 2H), 2.37 (d, J = 8.5 Hz, 2H), 2.53 (s, IH), 2.94 (d, J= 8.7 Hz, 2H), 3.03 (t, J= 5.1 Hz, 2H), 3.15-3.18 (m, 2H), 3.49-3.51 (m, 2H), 4.02 (t, J= 5.0 Hz, 2H), 4.18 (q, J= 6.8 Hz ₅ 2H), 4.70 (t, J= 6.0 Hz, IH), 6.74-6.84 (m, 4H), 7.16-7.27 (m, 8H).

The following compounds were prepared by procedure similar to those described in Compound No 10 with appropriate variations of reactants, reaction conditions and quantities of reagents.

(2S)-3-(4-{2-[(lα,5α,6α)-3-(4-Fluorobenzyl)-3-azabicyc lo[3.1.0]hex-6-ylamino]ethoxy}- phenyl)-2-w7-tolyloxypropionic acid ethyl ester (Compound No 62) MS: m/z 533 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.16 (t, J = 7.0 Hz, 3H) ₅ 1.53 (s, 2H), 2.27 (s, 3H), 2.50-2.60 (m, 2H), 2.69 (s, IH), 3.00-3.20 (m, 6H), 3.63 (s, 2H), 4.01 (t, J= 5.1 Hz, 2H), 4.04-4.20 (m, 2H), 4.72 (t, J= 6.0 Hz, IH), 6.59-6.84 (m, 5H), 6.90-7.30 (m, 7H). Yield: 52%

(2S)-3-(4-{2-[(lα,5α,6α)-3-(4-Chlorobenzyl)-3-azabicyc lo[3.1.0]hex-6-ylamino]ethoxy}- phenyl)-2-»2-tolyloxypropionic acid ethyl ester (Compound No 63) MS: m/z 549 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.19 (t, J= 7.1 Hz, 3H), 1.44 (s, 2H), 2.28 (s, 3H), 2.38-2.42 (m, 2H), 2.61 (s, IH), 2.90-3.05 (m, 4H), 3.14-3.17 (m, 2H), 3.53 (s, 2H), 4.01 (t, J= 5.1 Hz, 2H), 4.15 (q, J= 7.1 Hz, 2H), 4.72 (t, J= 6.9 Hz, IH), 6.60-6.84 (m, 5H), 7.07-7.28 (m, 7H). Yield: 40% .

Step 3: (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4-chl orobenzyl)-3-azabicyclo-

[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid (CompoundNo 106)

To a solution of (2S)-2-(4-tert-butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4- chlorobenzyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl )propionic acid ethyl ester (2.7 g, 4.6 mmol) in methanol (255 ml) and water (50 ml), added a solution of sodium carbonate (2.42 g, 23 mmol) in water (52 ml) drop wise at 0 ⁰ C under stirring. After being stirred at room temperature for 15 h, methanol was removed under reduced pressure at 35 ⁰ C. The aqueous layer was neutralized by adding IM HCl at 0 ⁰ C to pα 6 under stirring. The resulting reaction mixture was stirred at 0 ⁰ C for 0.5 h and the solid separated out was filtered

through a Buchner funnel, washed with cold water (2x20 ml). The solid so obtained was taken in 10% methanol-dichloromethane (100 ml) and sonicated for 5 min, the undissolved solid was filtered off through a buchner funnel. The filtrate was dried over anhydrous

Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get a crude product. The crude product was taken into 10% dichloromethane-diethyl ether (50 ml), sonicated at 40 ⁰ C for 5 min, filtered and washed with diethyl ether (2x10 ml). It was finally dried under high vacuum in a desiccator over calcium chloride to yield the title compound (2.3 g, 90%). mp: 153-155 ⁰ C

MS: m/z 563 (M+l) ¹ HNMR (CD ₃ OD, 200 MHz): δ 1.22 (s, 9H), 1.65 (s, 2H), 2.50-2.65 (m, 3H), 2.98-3.12 (m,

6H), 3.63 (s, 2H), 4.05-4.15 (m, 2H), 4.40-4.55 (m, IH), 6.70-6.85 (m, 4H), 7.15-7.25 (m,

8H).

The following compounds were prepared by procedure similar to those described in

Compound No 106 with appropriate variations of reactants, reaction conditions and quantities of reagents. ,

(2S)-3-(4-{2-[(lα,5α,6α)-3-(4-Fluorobenzyl)-3-azabicyclo[ 3.1.0]hex-6-ylamino]ethoxy}- phenyl)-2-w-tolyloxypropionic acid (Compound No 158) mp: 133-135 ⁰ C

MS: m/z 505 (M+l) ¹ HNMR (CD ₃ OD, 200 MHz): δ 1.96 (s, 2H), 2.22 (s, 3H), 2.85-2.95 (m, 3H), 3.05-3.10 (m,

2H), 3.12-3.25 (m, 4H), 3.89 (s, 2H), 4.05-4.12 (m, 2H), 4.60 (t, J = 5.9 Hz, IH), 6.52-6.85

(m, 5H), 6.90-7.05 (m, 3H), 7.10-7.20 (m, 2H), 7.30-7.40 (m, 2H).

Yield: 86%

(2S)-3-(4-{2-[(lα,5α,6α)-3-(4-Chlorobenzyl)-3-azabicyclo[ 3.1.0]hex-6-ylamino]ethoxy}- phenyl)-2-rø-tolyloxypropionic acid (Compound No 159) mp: 126-128 ⁰ C MS: m/z 521 (M+l)

¹ HNMR (CD ₃ OD, 200 MHz): δ 1.74 (s, 2H) ₅ 2.23 (s, 3H), 2.55-2.65 (m, 2H), 2.76 (s, IH), 3.00-3.07 (m, 4H), 3.22-3.30 (m, 2H), 3.65 (s, 2H), 4.06-4.18 (m, 2H), 4.42-4.58 (m, IH), 6.67-6.77 (m, 3H), 6.79-6.88 (m, 2H), 6.99-7.03 (m, IH), 7.23-7.30 (m, 6H). Yield: 66% t Step 4: (2S)-2-(4-^rt-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4-chlo robenzy ^' l)-3-azabicyclo-

[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride

To a stirred suspension of (2S)-2-(4-tert-butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4- chlorobenzyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl )propionic acid (0.8 g, 1.4 mmol) in dichloromethane (240 ml) at room temperature was added 0.85M HCl-diethyl ether

(0.104 g, 3.36 ml, 2.8 mmol) and the reaction mixture was stirred at room temperature for 0.5 h. The solvent was removed under reduced pressure at 35 ⁰ C and the solid obtained was dried under high vacuum in a desiccator over calcium chloride to yield the title compound (0.9 g, 100%). mp: 162-164 °C MS: m/z 563 (M+l)

¹ H NMR (CD ₃ OD, 200 MHz): δ 1.26 (s, 9H), 2.47 (brs, 2H), 3.07-3.20 (m, 2H), 3.42 (brs, IH) ₃ 3.55-3.64 (m ₃ 6H), 4.29 (t, J= 4.6 Hz, 2H), 4.35 (s, 2H), 4.76-4.79 (m, IH) ₅ 6.76 (d, J = 8.6 Hz, 2H), 6.96 (d, J= 8.6 Hz, 2H) ₃ 7.24-7.31 (m, 4H) ₃ 7.47 (d, J= 8.5 Hz ₃ 2H), 7.53 (d, J = 8.5 Hz, 2H). Chiral Purity: 96.14%

The compound given below was prepared by procedure similar to those described in Compound No 107 with appropriate variations of reactants, reaction conditions and quantities of reagents.

(2S)-2-(4-/ert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,4,5 -trifluorobenzyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride (Compound No 110) mp: 161-163 ⁰ C MS: m/z 583 (M+l)

¹ HNMR (DMSO-βfc, 200 MHz): δ 1.21 (s, 9H) ₅ 2.39 (s, 2H), 3.06-3.09 (m, 2H) ₃ 3.25-3.40 (m, 6H) ₅ 4.13-4.32 (m, 4H) ₅ 4.68-4.80 (m, IH) ₅ 6.73 (d ₅ J= 8.5 Hz ₅ 2H) ₅ 6.93 (d, J= 8.2 Hz ₅ 2H) ₅ 7.24 (d, J = 8.0 Hz, 4H) ₅ 7.62-8.18 (m, 2H) ₅ 9.80 (brs, IH ₅ exchangeable with D ₂ O) ₅ 11.60 (brs, IH, exchangeable with D ₂ O). Yield: 95%

Example 2

(2S)-2-(4-tert-Butylphenoxy)-3 -(4- {2- [(I α,5α,6α)-3 -(2,4,5 -trifluorobenzylj-3 -azabicyclo-

[3.1.0]hex-6-yl]amino}ethoxy)pheriyl]propionic acid dihydrochloride (Compound No 110)

Step 1 : (2S)-2-(4-tert-Butylphenoxy)-3-[4-(2-{(l α,5α,6α)-(4-nitrobenzenesulfonyl)-[3- (2 ₅ 4 ₅ 5-trifluorobenzyl)-3-azabicyclo[3.1.0]hex-6-yl]amino}ethoxy) phehyl]propionic acid ethyl ester

To a stirred solution of 4-nitro-N-[(lα,5α,6α)-3-(2,4,5-trifluorobenzyl)-3- azabicyclo[3.1.0]-hex-6-y]benzenesulfonamide (obtained by following the same procedure

described in Intermediate 1; 32.1 g, 75.35 mmol) in dichloromethane (600 ml) was added solution of (2S)-2-(4-tert-butylphenoxy)-3-[4-(2-hydroxyethoxy)phenyl]pr opionic acid ethyl ester (Intermediate 5; 30.00 g, 77.61 mmol) in dichloromethane (400 ml) and triphenyl

, phosphine (35.57 g, 135.63 mmol), under N ₂ atmosphere at room temperature. To this reaction mixture was added a solution of diethylazadicarboxylate (26.59g, 23.32 ml, 150.7 mmol) in dichloromethane (200 ml) in a drop wise manner by addition funnel at room temperature over a period of 30 min. After being stirred at room temperature for 3 h, reaction mixture was diluted with dichloromethane (500 ml), washed with water (200 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get a crude product which was purified by column chromatography over silica gel (100-200 mesh) using 0-> 1.5% acetone-dichloromethane as an eluent to yield the title compound (49.5 g, 83%). MS: m/z 796 (M+l)

¹ HNMR (CDCl ₃ , 400 MHz): δ 1.15-1.30 (m, 12H), 2.04 (s, 2H), 2.45-2.49 (m, 3H), 2.98 (d, J= 8.8 Hz, 2H), 3.10-3.20 (m, 2H), 3.50-3.60 (m, 4H), 4.09 (t, J= 5.2 Hz, 2H), 4.15-4.25 (m, 2H), 4.68 (t, J= 5.2 Hz, IH), 6.69 (d, J= 8.0 Hz, 2H) ₅ 6.75 (d, J= 8.0 Hz, 2H), 6.80-6.90 (m, IH), 6.91-7.03 (m, IH), 7.19 (d, J = 8.4 Hz, 2H), 7.24 (d, J= 8.4 Hz, 2H), 8.01 (d, J = 8.4 Hz, 2H), 8.34 (d, J=8.4 Hz ₅ 2H).

Step 2: (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,4,5 -trifluorobenzyl)-3-aza- bicyclop.l.ojhex-ό-ylaminojethoxyjpheny^propionic acid ethyl ester (Compound No 13)

To a stirred solution of (2S)-2-(4-tert-butylphenoxy)-3-[4-(2-{(lα,5α,6α)-(4- nitrobenzene-sulfonyl)-[3-(2,4,5-triflurobenzyl)-3-azabicycl o[3.1.0]hex-6- yl]amino}ethoxy)phenyl]-propionic acid ethyl ester (25.00 g, 31.44 mmol) in DMF (75 ml) was added anhydrous potassium carbonate (19.55 g, 147.48 mmol) under N ₂ * atmosphere at room temperature. The reaction mixture was cooled at 0 ⁰ C and added thiophenol (5.19 g,

4.7ml, 47.16 mmol). After being stirred at room temperature for 3 h, reaction mixture was poured into cold water (400 ml) and extracted with ethyl acetate (3x 200 ml). The combined organic layer were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 35% ethyl acetate-hexanes as an eluent to remove less polar impurities, then 1-^2% methanol-dichloromethane as an eluent to yield the title compound (16.2 g, 84%). MS: w/z 611 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 0.85-1.30 (m, 12H), 1.42 (s, 2H), 2.42 (d, J = 8.5 Hz, 2H), 2.90-3.10 (m, 4H), 3.10-3.20 (m, 2H), 3.54 (s, 2H), 4.02 (t, J= 5.2 Hz, 2H), 4.19 (q, J= 6.8 Hz, 2H), 4.69 (t, J= 5.7 Hz, IH) ₅ 6.70-7.00 (m, 5H) ₅ 7.05-7.30 (m, 5H).

The following compounds were prepared by procedure similar to those described in

Compound No 13 with appropriate variations of reactants, reaction conditions and quantities of reagents. (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α ₅ 6α)-3-(3-trifluoromethylbenzyl)-3-aza- bicyclop.l.ojhex-ό-ylaminojethoxyjpheny^propionic acid ethyl ester (Compound No 22)

MS: m/z 625 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.16-1.25 (m, 12H), 1.40-1.50 (m, 2H), 2.14 (brs, IH, exchangeable with D ₂ O), 2.40 (d, J= 8.5 Hz, 2H), 2.58 (s, IH) ₅ 2.88-2.99 (m, 2H), 3.04 (t, J = 5.0 Hz ₅ 2H), 3.14-3.17 (m, 2H), 3.60 (s, 2H), 4.03 (t, J= 5.0 Hz ₅ 2H), 4.17 (q, J= 7.1 Hz,

2H), 4.69 (t, J= 6.1 Hz, IH), 6.73-6.84 (m, 4H), 7.18-7.26 (m, 4H), 7.39-7.51 (m, 4H).

Yield: 81%

(2S)-2-(4-tert-Butylphenoxy)-3 -(4- {2- [( 1 α,5α,6α)-3 -(2,4,6-trifluorobenzyl)-3 -azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 15) MS: w/z 611 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.19 (t, J= 7.2 Hz, 3H), 1.24 (s, 9H) ₅ 1.48 (s, 2H) ₅ 2.41-2.60 (m, 3H), 2.87 (brs, IH, exchangeable with D ₂ O), 2.89-3.01 (m, 2H), 3.03 (t, J= 5.0 Hz ₅ 2H), 3.11-3.18 (m, 2H), 3.66 (s, 2H) ₅ 4.02 (t, J= 5.0Hz, 2H) ₅ 4.18 (q, J= 7.2 Hz, 2H), 4.67 (t, J=

6.0 Hz ₅ IH), 6.62 (t, J= 8.0 Hz, 2H) ₅ 6.74 (d, J= 8.8 Hz, 2H), 6.79 (d, J= 8.8 Hz, 2H), 7.16- 7.27 (m, 4H). Yield: 83%

5 (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2-flu oro-5-trifluoromethylbenzyl)-3- azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No

18)

MS: m/z 643 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.10-1.30 (m, 12H), 1.94 (s, 2H), 2.35-2.55 (m, 2H) ₅ 2.84 (s, 10 IH) ₅ 2.95-3.28 (m ₅ 5H) ₅ 3.55-3.72 (m, 3H) ₅ 3.99-4.30 (m, 4H) ₅ 4.67 (t, J= 5.9 Hz, IH), 6.68- 6.85 (m, 4H) ₅ 7.05-7.25 (m, 5H) ₅ 7.45-7.62 (m, 2H).

Yield: 50%

/

(2S)-2-(4-tβrt-Butylphenoxy)-3-(4-{2-[(lα ₅ 5α,6α)-3-(4-trifluoromethylsulfanylbenzyl)-3- 15 azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No

20)

MS: m/z 658 (M+2)

¹ HNMR (CDCl ₃₅ 200 MHz): δ 1.15-1.30 (m, 12H) ₅ 1.51 (s ₅ 2H) ₅ 2.17 (brs, IH ₅ exchangeable with D ₂ O), 2.42 (d, J= 8.4 Hz ₅ 2H) ₅ 2.62 (s, IH) ₅ 2.95-3.20 (m, 6H) ₅ 3.60 (s, 2H), 4.03 (t ₅ J= 20 5.0 Hz ₅ 2H) ₅ 4.17 (q, J= 6.8 Hz ₅ 2H), 4.69 (t, J= 5.9 Hz ₅ IH) ₅ 6.70-6.85 (m, 4H) ₅ 7.15-7.35

(m ₅ 6H) ₅ 7.57 (d ₅ J= 8.1 Hz ₅ 2H).

Yield: 55%

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(5- fluoro-2-trifluoromethylbenzyl)-3- 25 azabicycloβ.l.Ojhex-δ-ylaminojethoxylphenytypropionic acid ethyl ester (Compound No

19)

MS: m/z 643 (M+l)

■ ¹ HNMR (CDCl ₃ , 200 MHz): δ 1.15-1.30 (m, 12H) ₅ 1.60 (s, 2H) ₅ 2.43 (d, J = 8.4 Hz ₅ 2H) ₅ 2.67 (s, IH) ₅ 3.02 (d, J= 8.7 Hz ₅ 2H), 3.05-3.25 (m, 4H) ₅ 3.65-3.75 (m, 2H) ₅ 4.08 (t, J= 5.0

Hz ₅ 2H), 4.17 (q, J= 7.0 Hz ₅ 2H), 4.68 (t, J= 6.0 Hz ₅ IH), 6.70-6.90 (m, 4H) ₅ 6.94-7.05 (m, IH) ₅ 7.15-7.25 (m, 4H), 7.35 (d, J= 10.0 Hz ₅ IH) ₅ 7.54-7.61 (m, IH). Yield: 47%

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα ₅ 5α,6α)-3-(2 ₅ 4-difluorobenzyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 21) MS: m/z 593 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.15-1.30 (m, 12H) ₅ 1.51 (s ₅ 2H), 2.51 (d, J= 8.3 Hz, 2H), 2.62 (s, IH) ₅ 3.00-3.15 (m ₅ 6H) ₅ 3.60-3.65 (m, 2H), 4.02 (t, J= 4.9 Hz, 2H), 4.17 (q, J= 6.7 Hz, 2H), 4.68 (t, J= 6.0 Hz ₅ IH), 6.70-6.85 (m, 6H) ₅ 7.15-7.40 (m, 5H). Yield: 55%

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2, 4,5-trifluorophenylcarbamoyl)- S-azabicyclop.l.Ojhex-ό-ylaminojethoxyJphenytypropionic acid ethyl ester (Compound No 32)

MS: m/z 640 (M+l)

¹ HNMR (CDCl ₃ , 400 MHz): δ 1.15-1.30 (m, 12H), 2.14 (s, 2H), 2.27 (s, IH), 3.10-3.25 (m, 4H) ₅ 3.42 (d, J= 9.6 Hz, IH), 3.60-3.85 (m, 3H), 4.10-4.25 (m, 4H), 4.65-4.75 (m, IH), 6.65- 7.00 (m, 5H), 7.15-7.30 (m, 4H), 7.85-8.20 (m, IH). Yield: 47%

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4- trifluoromethylphenylcarbamoyl)-3- azabicyclop.l.Ojhex-ό-ylaminoJethoxyJpheny^propionic acid ethyl ester (Compound No 33) MS: m/z 654 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.17-1.26 (m, 12H), 1.78 (s, 2H), 2.17 (s, IH) ₅ 3.08 (t, J= 4.6 Hz ₅ 2H) ₅ 3.16 (d ₅ J= 6.5Hz ₅ 2H), 3.52 (d, J= 9.5Hz, 2H) ₅ 3.63 (d, J= 9.9Hz ₅ 2H) ₅ 4.05 (t, J = 4.7Hz ₅ 2H), 4.17 (q, J = 7.1 Hz, 2H), 4.70 (t, J = 6.1Hz, IH), 6.34 (s, IH, exchangeable with D ₂ O), 6.72-6.84 (m, 4H), 7.18-7.23 (m, 4H), 7.49(s, 4H).

Yield: 37%

(2S)-3-(4-{2-[(lα,5α,6α)-3-5ec-Butyl-3-azabicyclo[3.1. 0]hex-6-ylamino]ethoxy}phenyl)-2- (4-tert-butylphenoxy)propionic acid ethyl ester (Compound No 35) MS: m/z 523 (M+l)

¹ HNMR (CDCl ₃ , 400 MHz): δ 0.87 (t, J = 6.0 Hz, 3H) ₃ 0.97 (d, J = 5.6 Hz, 3H), 1.24 (s, 12H), 1.32-1.36 (m, 4H), 1.88-2.03 (m, 4H), 2.30-2.39 (m, IH), 2.89-2.98 (m, IH), 3.13-3.15 (m, 4H), 4.03-4.09 (m, 2H), 4.15-4.17 (m, 2H), 4.68 (t, J= 5.6 Hz, IH), 6.74 (d, J= 8.4 Hz, 2H), 6.82 (d, J= 8.4 Hz, 2H), 7.18-7.24 (m, 4H). Yield: 37%

(2S)-3-(4-{2-[(lα,5α,6α)-3-(4-Chlorobenzyl)-3-azabicyc lo[3.1.0]hex-6-ylamino]ethoxy}- phenyl)-2-(2,5-difluorophenoxy)propionic acid ethyl ester (Compound No 57)

MS: m/z 571 (M+l) ¹ HNMR (CDCl ₃ , 200 MHz): δ 1.10-1.29 (m, 3H), 1.70 (s, 2H), 2.46 (brs, IH), 2.72 (brs, IH),

3.00-3.12 (m, 2H), 3.13-3.30 (m, 3H), 3.54 (s, IH), 3.81-3.89 (m, 2H), 3.95-4.29 (m, 4H),

4.70 (t, J= 6.8 Hz, IH), 6.48-6.68 (m, 2H), 6.71-6.89 (m, 2H), 6.90-7.10 (m, IH), 7.25-7.45

(m, 3H).

Yield: 60%

(2S)-2-(2,5-Difluorophenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2, 4,5-trifluorobenzyl)-3-azabicyclo-

[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 58) . .

MS: m/z 591 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.10-1.32 (m, 3H), 1.72 (s, 2H), , 1.38-2.55 (m, 3H), 2.90-3.29 (m, 6H), 3.58 (s, 2H), 3.73 (s, IH), 4.09-4.29 (m, 4H) ₅ 4.70 (t, J= 6.2 Hz, IH), 6.45-6.61 (m,

2H), 6.71-6.89 (m, 2H), 6.90-7.07 (m, 2H), 7.11-7.24 (m, 3H).

Yield: 50%

(2S)-2-(2 ,5 -Difluorophenoxy)-3 -(4- {2-[( 1 α,5α,6α)-3 -(4-trifluoromethylbenzyl)-3-aza- bicyclofS.l.OJhex-ό-ylaminoJethoxylpheny^propionic acid ethyl ester (Compound No 59) MS: rø/z 605 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.12-1.29 (t, J= 7.0 Hz, 3H), 2.06 (s, 2H) ₅ 2.41-2.69 (m, 2H), 3.04-3.31 (m, 6H), 3.60-3.91 (m, 3H), 4.09-4.29 (m, 4H), 4.70 (t, J= 6.1 Hz, IH), 6.45-6.61, (m, 2H), 6.70-6.89 (m, 2H), 6.91-7.08 (m, IH), 7.11-7.24 (m, 2H), 7.32-7.62 (m, 4H) Yield: 58%

(2S)-2-(3,5-Difluorophenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2, 4,5-trifluorobenzyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 60)

MS: m/z 591 (M+l)

¹ HNMR (CDCl ₃ , 400 MHz): δ 1.19-1.28 (m, 4H), 1.93 (s, 2H), 2.49 (s, 2H), 3.15 (t, J= 6.8

Hz, 3H), 3.27 (s, 2H), 3.50-3.80 (m, 3H), 4.05-4.35 (m, 4H), 4.66 (t, J= 6.4 Hz, IH), 6.30-

6.45 (m, 3H), 6.75-6.95 (m, 4H), 7.12 (t, J= 8.8 Hz, 2H). Yield: 33%

(2S)-2-(3,5-Difluorophenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4-tri fluoromethylbenzyl)-3-aza- bicyclofS.l.OJhex-ό-ylaminoJethoxyJphenytypropionic acid ethyl ester (Compound No 61) MS: m/z 605 (M+l) ¹ HNMR (CDCl ₃ , 400 MHz): δ 1.10-1.30 (m, 3H), 1.84 (s, 2H), 2.45 (s, 2H), 2.80-3.25 (m, 6H), 3.55-3.80 (m, 3H) ₅ 4.00-4.30 (m, 4H), 4.63 (t, J= 6.4 Hz, IH), 6.25-6.50 (m, 3H), 6.70- 6.90 (m, 3H), 7.15 (d, J= 8.1 Hz, 2H), 7.30-7.60 (m, 3H). Yield: 71%

(2S)-2-(4-Methoxyρhenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,4, 5-trifluorobenzyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 65) MS: m/z 585 (M+l)

¹ HNMR (CDCl ₃ , 400 MHz): δ 1.15-1.21 (m, 3H), 1.85 (s, 2H) ₅ 2.07 (s, IH), 2.47 (s, 2H), 2.80-3.20 (m, 6H), 3.50-3.80 (m, 5H), 4.05-4.25 (m, 4H), 4.61 (t, J= 6.8 Hz, IH), 6.70-6.80 (m, 5H), 6.82-6.90 (m, 3H), 7.15-7.24 (m, 2H). Yield: 50%

(2S)-2-(4-Methoxyphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4-tri fluoromethylbenzyl)^3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 66) MS: m/z 599 (M+l)

¹ HNMR (CDCl ₃ , 400 MHz): δ 1.15-1.40 (m, 7H), 2.17 (s, IH) ₃ 2.50 (s, IH), 3.10-3.30 (m, 5H), 3.65-3.75 (m, 5H), 4.05-4.20 (m, 4H), 4.62 (t, J= 6.8 Hz, IH), 6.72-6.80 (m, 5H), 6.85- 7.25 (m, 3H), 7.55-7.65 (m, 4H). Yield: 50%

, (2S)-3-(4-{2-[(lα,5α,6α)-3-(4-Trifluoromethylbenzyl)-3-az abicyclo[3.1.0]hex-6-ylamino]- ethoxy}phenyl)-2-(4-trifluoromethylphenoxy)propionic acid ethyl ester (Compound No 67)

MS: m/z 637 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.10-1.40 (m, 4H), 1.94 (s, 2H), 2.40-2.62 (m, IH), 3.05-3.35

(m, 6H), 3.62-3.90 (m, 3H), 4.05-4.25 (m, 4H), 4.69-4.86 (m, IH), 6.71-6.99 (m, 4H), 7.10-

7.25 (m, 3H), 7.30-7.42 (m, IH), 7.42-7.75 (m, 4H). Yield: 82%

(2S)-3-(4-{2-[(lα,5α,6α)-3-(2,4,5-Trifluorobenzyl)-3-azab icyclo[3.1.0]hex-6-ylamino]- ethoxy}phenyl)-2-(4-trifluoromethylphenoxy)propionic acid ethyl ester (Compound No 68) MS: m/z 623 (M+l) ¹ HNMR (CDCl ₃ , 200 MHz): δ 1.10-1.40 (m, 3H), 1.62 (s, 2H), 2.35-2.60 (m, 2H), 2.68 (s, IH), 2.80-3.40 (m, 6H), 3.57 (s, 2H), 4.00-4.40 (m, 4H), 4.77 (t, J= 6.4 Hz, IH), 6.71-6.98 (m, 4H), 7.02-7.30 (m, 4H), 7.48 (d, J= 8.5 Hz, 2H). Yield: 71%

(2S)-3-(4-{2-[(lα,5α,6α)-3-(4-Chlorobenzyl)-3-azabicyc lo[3.1.0]hex-6-ylamino]ethoxy}- phenyl)-2-(4-isopropylphenoxy)propionic acid ethyl ester (Compound No 53) MS: m/z 577 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.05-1.38 (m, 9H), 1.80-2.00 (m, 2H), 2.50 (brs, IH), 2.72- 2.89 (m, 2H), 3.02-3.19 (m, 4H) ₅ 3.59 (brs, IH), 3.71-3.89 (m, 2H) ₅ 4.05-4.22 (m, 4H), 4.68 (t, J= 6.1 Hz, IH) ₅ 6.70-6.89 (m, 4H) ₅ 7.07 (d, J= 8.4 Hz ₅ 2H) ₅ 7.15-7.30 (m ₅ 5H) ₅ 7.31-7.48 (m, 3H). Yield: 50%

(2S)-2-(4-Isopropylphenoxy)-3-(4-{2-[(l α,5α,6α)-3-(2,4,5-trifluorobenzyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 54) MS: m/z 597 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.05-1.40 (m, 9H) ₅ 2.40-2.90 (m, 6H), 2.90-3.22 (m, 3H), 3.57 (s, 2H), 4.00-4.35 (m, 4H) ₅ 4.68 (t ₅ J= 5.9 Hz ₅ IH), 6.70-6.90 (m, 5H) ₅ 6.94-7.30 (m, 5H). Yield: 41%

(2S)-2-(4-Isopropylphenoxy)-3-(4-{2-[(lα ₅ 5α,6α)-3-(2 ₅ 4 ₅ 6-trifluorobenzyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 55) MS: rø/z 597 (M+l) ¹ HNMR (CDCl ₃ , 200 MHz): δ 1.10-1.25 (m, 9H) ₅ 2.35-2.55 (m ₅ 2H) ₅ 2.60-2.80 (m, IH) ₅ 2.81-3.20 (m ₅ 4H) ₅ 3.67 (s, 3H) ₅ 4.11-4.29 (m ₅ 4H) ₅ 4.68 (t ₅ J = 6.8 Hz ₅ IH) ₅ 6.55-6.71 (m, 2H), 6.72-6.89 (m, 4H) ₅ 7.07 (d, J= 8.4 Hz ₅ 2H) ₅ 7.18 (d, J= 8.4 Hz ₅ 2H). Yield: 41%

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα ₅ 5α,6α)-3-(2-fluorobenzoyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 23) MS: m/z 589 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.10-1.30 (m, 12H) ₅ 1.61 (s, 2H), 2.05 (s, IH), 3.00-3.05 (m, 2H), 3.15 (d, J= 5.0 Hz, 2H), 3.30 (d, J= 10.5 Hz, IH), 3.50-3.60 (m, 2H), 4.00 (t, J = 5.0 Hz, 2H), 4.00-4.25 (m, 3H), 4.66 (t, J= 5.0 Hz, IH), 6.70-6.85 (m, 4H), 7.05-7.40 (m, 8H). Yield: 44%

(2S)-2-(4-førM3utylρhenoxy)-3 -(4- {2-[( 1 α,5α,6α)-3 -(4-trifluoromethylbenzoyl)-3 -aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 26)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.15-1.30 (m, 12H), 1.60-1.90 (m, 2H), 2.06 (s, IH), 3.05- 3.20 (m, 4H), 3.40-3.65 (m, 3H), 4.00-4.25 (m, 5H), 4.68 (t, J= 6.1 Hz, IH), 6.77 (t, J= 8.9 Hz, 4H), 7.15-7.25 (m, 4H), 7.51 (d, J= 8.1 Hz, 2H), 7.65 (d, J= 8.1 Hz, 2H). Yield: 75%

(2S)-2-(4-ført-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(3 -trifluoromethylbenzoyl)-3-aza- bicyclotS.l.Ojhex-ό-ylaminoJethoxyJphenytypropionic acid ethyl ester (CompoundNo 27)

MS: m/z 639 (M+l) '

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.10-1.30 (m, 12H), 1.85 (s, 2H), 2.10 (s, IH), 3.00-3.20 (m,

4H), 3.30-3.65 (m, 4H), 4.00-4.30 (m, 5H), 4.68 (t, J= 6.7 Hz, IH), 6.76 (t, J= 8.8 Hz, 4H),

7.21 (t, J= 7.5 Hz, 4H), 7.45-7.80 (m, 4H). Yield: 68%

(2S)-2-(4-fert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,4,5 -trifluorobenzoyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (CompoundNo 25) MS: m/z 625 (M+l) ¹ HNMR (CDCl ₃ , 200 MHz): δ 1.15-1.30 (m, 12H), 1.70-1.75 (m, 2H), 2.05 (s, IH), 3.05 (t, J = 4.7 Hz, 2H), 3.15 (d, J= 6.9 Hz, 2H), 3.34 (d, J= 10.8 Hz, IH), 3.45-3.70 (m, 2H), 3.95- 4.10 (m, 3H), 4.17 (q, J= 7.0 Hz, 2H), 4.68 (t, J= 6.1 Hz, IH) ₃ 6.77 (t, J= 8.8 Hz, 4H), 6.85- 7.05 (m, IH), 7.10-7.25 (m, 5H). Yield: 35%

(2S)-3-(4- {2- [( 1 α,5 α,6α)-3 -(3 ,5 -Bis-trifluoromethylbenzoyl)-3 -azabicyclo [3.1.0]hex-6-yl- amino]ethoxy}phenyl)-2-(4-tert-butylphenoxy)propionic acid ethyl ester (Compound No 28) MS: m/z 708 (M+2) ¹ HNMR (CDCl ₃ , 200 MHz): δ 1.10-1.35 (m, 12H), 1.85 (s, 2H), 2.12 (s, 2H), 3.11-3.22 (m, 4H), 3.30-3.48 (m, IH), 3.51-3.81 (m, 2H), 3.91-4.29 (m, 6H), 4.68 (t, J= 6.8 Hz, IH), 6.77 (t, J= 9.7 Hz, 4H), 7.11-7.29 (m, 4H), 7.91 (dJ= 7.5 Hz, 3H). Yield: 71%

(2S)-2-(4-tert-Butylρhenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2 ,4-difluorobenzoyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 24) MS: m/z 607 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.10-1.30 (m, 12H), 1.60-1.80 (m, 2H), 2.10-2.30 (m, 3H), 2.90-3.10 (m, 2H), 3.15,(d, J= 6.6 Hz, 2H), 3.25-3.31 (m, IH), 3.34-3.61 (m, 2H), 3.80-4.02 (m, 2H), 4.12-4.32 (m, 2H), 4.68 (t, J= 6.6 Hz, IH), 6.69-7.00 (m, 6H), 7.11-7.42 (m, 5H). Yield: 66%

(2S)-2-(4-Isopropylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(3,4 ,5-trifluorobenzoyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 56) MS: m/z 611 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.10-1.21 (m, 9H), 2.70-2.88 (m, IH), 2.89-3.20 (m, 4H), 3.21-3.51 (m, 5H), 4.04 (t, J= 5.7 Hz, 3H), 4.11-4.30 (m, 2H), 4.68 (t, J= 6.6 Hz, IH), 6.55- 6.85 (m, 6H), 7.00-7.25 (m, 4H). Yield: 61% ^'

(2S)-2-(4-terM3utylphenoxy)-3 -(4- {2- [( 1 α,5α,6α)-3-(5 -cyanoρyridin-2-yl)-3 -azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 43) MS: m/z 569 (M+l)

¹ HNMR (CDCl ₃ , 400 MHz): δ 1.10-1.30 (m, 12H), 1.93 (s, 2H), 2.10 (s, IH), 3.05-3.20 (m, 4H), 3.51 (d, J= 9.6 Hz, 2H) ₅ 3.60-3.85 (m, 2H), 4.06 (t, J= 5.6 Hz, 2H), 4.10-4.25 (m, 2H), 4.65-4.70 (m, IH), 6.26 (d, J = 8.8 Hz, IH), 6.73 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 7.15-7.25 ,(m, 4H), 7.55 (dd, J= 8.8 Hz, IH), 8.37 (d, J= 2.0 Hz, IH). Yield: 42%

(2S)-2-(4-tert-Butylphenoxy)-3-{4-[(lα,5α,6α)-2-(3-thiazo l-2-yl)-3-azabicyclo[3.1.0]-hex- 6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 44) MS: rø/z 550 (M+l) ¹ HNMR (CDCl ₃ , 200 MHz): δ 1.10-1.30 (m, 12H), 1.97 (s, 2H), 2.25 (s, IH), 3.10-3.25 (m, 4H), 3.54 (d, J= 9.6 Hz, 2H), 3.69 (d, J= 9.8 Hz, 2H), 4.10-4.25 (m, 4H), 4.73 (t, J= 5.6 Hz, IH), 6.51 (d, J= 3.6 Hz, IH), 6.75-6.90 (m, 4H), 7.20-7.30 (m, 5H). Yield: 54%

Step 3: (2S)-2-(4-ter/-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,4,5 -trifluorobenzyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid

To a stirred solution of (2S)-2-(4-fert-butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,4,5 - trifluoro-benzyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}ph enyl)propionic acid ethyl ester (15.4 g, 25.24 mmol) in methanol (1040 ml) and water (240 ml) was added a solution of sodium carbonate (13.37 g, 126.22 mmol) in water (240 ml), drop wise at 0 ⁰ C. After being stirred at room temperature for 15 h, methanol was removed under reduced pressure at 35 ⁰ C. The aqueous layer was neutralized by adding IM HCl at 0 ⁰ C to pH 6 under stirring. The resulting reaction mixture was stirred at 0 ⁰ C for 0.5 h and solid separated out was filtered through a Buchner funnel, washed with cold water (2x50 ml). The solid so obtained was taken in 10% methanol-dichloromethane (750 ml) and sonicated for 5 min. The undissolved

solid was filtered off through a Buchner funnel. The filtrate was dried over Na ₂ SO ₄ , concentrated under reduced pressure to get the crude product. The crude product was taken into diethyl ether (100 ml), sonicated for 5 min, filtered and washed with diethyl ether (50 ml). It was finally dried under high vacuum in desiccator over calcium chloride to yield the title compound (12.1 g, 82%). mp: 158-160 ⁰ C MS: m Iz 583 (M+l)

¹ HNMR (CDCl ₃ H-CD ₃ OD): δ 1.18 (s, 9H), 1.65-1.75 (m, 2H), 2.38-2.44 (m, 2H), 2.61 (s, IH), 2.85-3.05 (m, 6H), 3.58 (s, 2H), 3.92-3.98 (m, 2H) ₅ 4.57 (t, J= 5.6 Hz, IH) ₅ 6.67-6.87 (m. 5H) ₅ 7.07-7.26 (m, 5H).

Step 4: (2S)-2-(4-fert-Butylphenoxy)-3-(4-{2-[(lα,5α ₅ 6α)-3-(2,4,5-triflurobenzyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy }phenyl)propionic acid dihydrochloride

^' To a stirred solution of (2S)-2-(4-tert-butylphenoxy)-3-(4-{2-[(lα,5α ₅ 6α)-3-(2,4,5- trifluoro-benzyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}ph enyl)propionic acid (14.18 g, 24.364 mmol) in dichloromethane (2100 ml) was added 1.12M HCl-ethyl acetate (1.86 g, 45.67ml, 51.16 mmol) in drop wise manner at room temperature. After being stirred at room temperature for 1 h. Solvent was removed under reduced pressure and the solid was dried under high vacuum at 70 ⁰ C in oven to yield the title compound (16.2 g, 98.6%). mp: 161-163 ⁰ C MS: m/z 583 (M+l)

¹ HNMR (DMSO-rf _& 200 MHz): δ 1.21 (s, 9H) ₅ 2.39 (s, 2H) ₅ 3.06-3.09 (m, 2H) ₅ 3.25-3.40 (m, 6H) ₅ 4.13-4.32 (m, 4H) ₅ 4.68-4.80 (m, IH), 6.73 (d, J= 8.5 Hz, 2H) ₅ 6.93 (d, J= 8.2 Hz, 2H) ₅ 7.24 (d, J = 8.0 Hz ₅ 4H) ₅ 7.62-8.18 (m, 2H), 9.80 (brs, IH ₅ exchangeable with D ₂ O), 11.60 (brs, IH ₅ exchangeable with D ₂ O).

Chiral Purity: 99.26%, [α] ²⁰ _D = +13.30 (Cl.07, H ₂ O)

The following compounds were prepared by procedure similar to those described in Compound No 110 with appropriate variations of reactants, reaction conditions and quantities of reagents.

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα ₃ 5α,6α)-3-(3-trifluoromethylbenzyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride (Compound No

119) mp: 190-191 ⁰ C MS: m/z 597 (M+l)

¹ HNMR (CDCI ₃ +CD ₃ OD, 200 MHz): δ 1.21 (s, 9H), 2.54 (s, 2H), 3.13 (d, J= 5.8 Hz, 2H) ₃ 3.32-3.60 (m, 6H) ₅ 5.15-5.40 (m, 5H), 4.67 (t, J= 6.4 Hz, IH), 6.73 (d, J= 8.6 Hz, 2H) ₅ 6.85 (d, J= 8.2 Hz ₅ 2H) ₅ 7.18-7.22 (m, 4H), 7.51-7.59 (m ₅ IH) ₅ 7.68 (d, J= 7.6 Hz ₅ IH) ₅ 7.80-7.95 (m, 2H). Yield: 95%

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2 ₅ 4 ₅ 6-trifluorobenzyl)-3-azabicyclo-

[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride (Compound No 112) mp: 174-176 ⁰ C MS: m/z 583 (M+l)

¹ HNMR (CDCla+CDsOD, 200 MHz): δ 1.16 (s, 9H) ₅ 2.56 (s, 2H) ₅ 3.10 (d, J= 6.0 Hz ₅ 2H) ₅

3.25-3.46 (m, 3H) ₅ 3.48-3.65 (m ₅ 5H) ₅ 4.05-4,25 (m ₅ 4H) ₅ 4.61 (t, J= 6.4 Hz ₅ IH) ₅ 6.65-6.83

(m, 6H) ₅ 7.14 (dd ₅ J = 8.4 Hz ₅ 4H).

Yield: 95%

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α ₅ 6α)-3-(2-fluoro-5-trifluoromethylbenzyl)-3- azabicycloβ.l.OJhex-ό-ylaminojethoxyJpheny^propionic acid dihydrochloride (Compound

No 115) - ^■ mp: 180-182 ⁰ C

MS: m/z 615 (M+l)

¹ HNMR (CDCI ₃ +CD ₃ OD, 200 MHz): δ 1.18 (s, 9H), 2.58 (s, 2H), 3.16 (d, J = 5.4 Hz, 2H), 3.25-3.43 (m, 5H), 3.51-3.71 (m, 3H), 4.15-4.31 (m, 4H), 4.70 (t, J= 5.4 Hz, IH), 6.72 (d, J = 8.6 Hz, 2H), 6.85 (d, J= 8.0 Hz, 2H), 7.11-7.25 (m, 5H), 7.60-7.70 (m, IH), 8.05-8.15 (m, IH).

Yield: 93%

(2S)-2-(4-ter/-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4-tri fluoromethylsulfanylbenzyl)-3- azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride (Compound No 117) mp: 156-158 ⁰ C

MS: m/z 630 (M+2)

¹ HNMR (DMSO-^, 200 MHz): δ 1.21 (s, 9H), 2.41 (s, 2H), 3.00-3.15 (m, 3H), 3.25-3.65

(m, 6H) ₅ 4.15-4.45 (m, 4H) ₃ 4.77-4.83 (m, IH), 6.73 (d, J= 8.7 Hz, 2H), 6.93 (d, J= 8.5 Hz, 2H), 7.24 (d, J = 8.6 Hz, 4H), 1.15-1.90 (m, 4H), 9.86 (brs, IH, exchangeable with D ₂ O),

11.65 (brs, IH, exchangeable with D ₂ O).

Yield: 84%

(2S)-2-(4-ført-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(5 -fluoro-2-trifluoromethylbenzyl)-3- azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride (Compound

No 116) mp: 171-172 ⁰ C

MS: m/z 615 (M+l)

¹ HNMR (DMSO-^D ₂ O, 400 MHz): δ 1.16 (s, 9H), 2.27 (s, 2H), 2.70-2.86 (m, IH), 2.99- 3.13 (m. 2H), 3.20 (s, 2H), 3.30-3.48 (m, 4H), 4.15-4.2,1 (m, 2H), 4.30-4.33 (m, 2H), 4.74-

4.77 (m, IH), 6.69 (d, J= 8.4 Hz, 2H), 6.89 (d, J= 8.0 Hz, 2H), 7.20-7.22 (m, 4H), 7.41-7.45

(m, IH) ₅ 7.73-7.76 (m, IH), 7.84-7.87 (m, IH).

Yield: 85%

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,4-d ifluorobenzyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride (Compound No 118) mp: 163-164 ⁰ C MS: m/z 565 (M+l) ¹ HNMR (DMSO-^D ₂ O ₅ 400 MHz): δ 1.16 (s, 9H) ₅ 2.27 (s, 2H) ₅ 2.98-3.13 (m, 4H) ₅ 3.35- 3.52 (m, 5H), 4.12-4.15 (m, 2H) ₅ 4.23 (s ₅ 2H), 4.73-4.76 (m ₅ IH), 6.69 (d, J- 8.4 Hz, 2H), 6.88 (d, J= 8.4 Hz ₅ 2H), 7.09-7.12 (m ₅ IH) ₅ 7.19-7.26 (m ₅ 5H) ₅ 7.54-7.60 (m, IH). Yield: 91%

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2, 4,5-trifluorophenylcarbamoyl)-3- azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid hydrochloride (Compound No

129) mp: 155-156 ⁰ C

MS: rø/z 612 (M+l) ¹ HNMR 400 MHz): δ 1.21 (s, 9H), 2.18 (s, 2H) ₅ 2.59 (s ₅ IH), 3.05-3.15 (m, 2H), 3.40-3.43 (m, 4H) ₅ 3.68 (d, J = 10.4 Hz ₅ 2H), 4.24-4.26 (m, 2H) ₅ 4.79-4.82 (m, IH) ₅ 6.73 (d, J= 8.8 Hz ₅ 2H), 6.91 (d, J= 8.4 Hz ₅ 2H) ₅ 7.21-7.27 (m ₅ 4H) ₅ 7.55-7.60 (m, 2H) ₅ 8.18 (s, IH, exchangeable with D ₂ O), 9.67 (brs, IH ₅ exchangeable with D ₂ O) ₅ 12.97 (brs, IH ₅ exchangeable with D ₂ O). Yield: 80%

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α ₅ 6α)-3-(4-trifluoromethylphenylcarbamoyl)-3- azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid hydrochloride (Compound No 130) mp: 163-164 ⁰ C

MS: m/z 626 (M+l)

¹ HNMR (DMSO-^ ₅ 200 MHz): δ 1.20 (s, 9H), 2.18 (s, 2H), 2.63 (s, IH) ₅ 3.07-3.11 (m, 2H),

3.35-3.55 (m, 4H), 3.75 (d, J= 10.4 Hz, 2H), 4.20-4.35 (m, 2H) ₅ 4.70-4.85 (m, IH) ₅ 6.72 (d,

J= 7.9 Hz ₅ 2H), 6.91 (d, J= 7.6 Hz, 2H) ₅ 7.20-7.40 (m, 4H), 7.50-7.60 (m, 2H), 7.72 (d, J = 7.9 Hz, 2H) ₅ 8.63 (s, IH ₅ exchangeable with D ₂ O) Yield: 95%

(2S)-3-(4-{2-[(lα,5α ₅ 6α)-3-5ec-Butyl-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phe nyl)-2-

(4-tert-butylphenoxy)propionic acid dihydrochloride (Compound No 133) , mp: 137-139 ⁰ C

MS: mlz 495 (M+l)

¹ HNMR (CDC1 ₃ +CD ₃ OD ₅ 400 MHz): δ 0.80-0.95 (m, 3H) ₅ 1.21 (s, 12H) ₅ 1.45-1.90 (m, 2H), 2.50-2.65 (m, 2H) ₅ 2.80-3.00 (m ₅ IH) ₅ 3.15 (d, J = 11.2 Hz, 2H) ₅ 3.20-3.38 (m, 2H) ₅ 3.39-

3.50 (m, 2H), 3.52-3.61 (m, IH) ₅ 3.62-3.80 (m, 2H) ₅ 4.15-4.30 (m ₅ 2H) ₅ 4.71 (t ₅ J= 11.2 Hz ₅

IH) ₅ 6.74 (d, J= 17.0 Hz ₅ 2H) ₅ 6.86 (d, J= 17.0 Hz ₅ 2H) ₅ 7.18 (d, J=4.0 Hz, 2H) ₅ 7.22 (d, J

= 4.0 Hz ₅ 2H).

Yield: 63%

(2S)-3-(4-{2-[(lα ₅ 5α ₅ 6α)-3-(4-Chlorobenzyl)-3-azabicyclo[3.1.0]hex-6-ylamino]eth oxy}- , phenyl)-2-(2 ₅ 5-difluorophenoxy)propionic acid dihydrochloride (Compound No 153) mp: 164-166 °C

MS: m/z 545 (M+2) ¹ HNMR (DMSO-J ₆₅ 200 MHz): δ 2.39 (s, 2H) ₅ 2.91-3.58 (m, 9H) ₅ 4.15-4.32 (m, 4H) ₅ 5.10-

5.22 ,(m, IH) ₅ 6.70-6.81 (m, IH) ₅ 6.90-6.98 (m ₅ 3H) ₅ 1.12-126 (m ₅ 3H), 7.49 (d, J= 8.2 Hz ₅

2H) ₅ 7.66 (d ₅ J =8.1 Hz ₅ 2H) ₅ 9.77 (brs, IH ₅ exchangeable with D ₂ O) ₅ 11.53 (brs, IH ₅ exchangeable with D ₂ O).

Yield: 99% ^{• '}

(2S)-2-(2 ₅ 5-Difluorophenoxy)-3-(4-{2-[(lα,5α ₅ 6α)-3-(2 ₅ 4 ₅ 5-trifluorobenzyl)-3-azabicyclo-

[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride (Compound No 154) mp: 150-152 ⁰ C

MS: m/z 561 (M-I)

¹ HNMR (CDC1 ₃ +CD ₃ OD, 200 MHz): δ 2.58 (s, 2H) ₅ 3.11-3.42 (m, 6H), 3.44-3.62 (m, 4H),

4.10-4.31 (m, 4H), 4.72 (t, J= 5.6 Hz, IH), 6.44-6.58 (m, 2H), 6.81-7.08 (m, 4H), 7.12-7.28

(m, 2H), 7.68-7.82 (m, IH).

Yield: 98%

(2S)-2-(2,5-Difluorophenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4- trifluoromethylbenzyl)-3-aza- bicyclofS.l.OJhex-δ-ylaminoJethoxyjpheny^propionic acid dihydrochloride (Compound No

155) mp: 198-200 ⁰ C MS: m/z 577 (M+l)

¹ HNMR (CDCl ₃ +MeOD, 400 MHz): δ 2.46 (s, IH), 2.57 (s, IH), 3.11 (s, IH), 3.20 (s, 2H),

3.30-3.45 (m, 5H), 3.62 (s, IH), 4.11-4.32 (m, 4H), 4.81 (t, J = 4.8 Hz, IH), 6.45-6.61 (m,

2H), 6.85-6.95 (m, 3H), 7.22 (d, J= 7.6 Hz, 2H), 7.52-7.71 (m, 4H).

Yield: 95%

(2S)-2-(3,5-Difluorophenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2, 4,5-trifluorobenzyl)-3-azabicyclo-

[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride (Compound No 156) mp: 170-172 °C

MS: m/z 563 (M+l) ¹ HNMR (CDC1 ₃ +CD ₃ OD, 400 MHz): δ 2.59 (s, 2H), 3.08-3.18 (m, 2H), 3.26-3.47 (m, 4H),

3.55-3.68 (m, 3H), 4.21 (m, 5H), 4.62 (t, J= 4.8 Hz, IH), 6.26-6.38 (m, 3H), 6.83 (d, J= 8.0

Hz, 2H), 6.92-7.05 (m, IH), 7.15 (d, J= 8.1 Hz, 2H), 7.70-7.81 (m, IH).

Yield: 96%

(2S)-2-(3,5-Difluorophenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4- trifluoromethylbenzyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride (Compound No

157) mp: 166-168 ⁰ C

MS: m/z 577 (M+l)

¹ HNMR (CDC1 ₃ +CD ₃ OD, 400 MHz): δ 2.40-2.63 (m ₅ 2H) ₅ 3.05-3.24 (m, 2H) ₅ 3.25-3.54 (m, 6H) ₅ 3.67 (s, 2H) ₅ 4.15-4.36 (m, 4H) ₅ 4.73 (t, J= 5.2 Hz ₅ IH), 6.28-6.40 (m ₅ 3H), 6.87 (d ₅ J= 8.0 Hz ₅ 2H), 7.17 (d, J= 8.0 Hz, 2H) ₅ 7.55-7.72 (m, 4H). Yield: 95%

(2S)-2-(4-Methoxyphenoxy)-3-(4-{2-[(lα ₅ 5α,6α)-3-(2,4 ₅ 5-trifluorobenzyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride (Compound No 161) nip: 148-15O ⁰ C MS: m/z 557 (M+l) ¹ HNMR (CDCl ₃ H-CD ₃ OD ₅ 200 MHz): δ 2.59 (s ₅ 2H) ₅ 3.00-3.19 (m, 2H) ₅ 3.20-3.60 (m, 6H) ₅ 3.67 (s, 3H) ₅ 4.08-4.38 (m, 4H), 4.55-4.70 (m, IH) ₅ 6.62-6.79 (m, 4H) ₅ 6.80-7.00 (m ₅ 3H), 7.15-7.25 (m, 2H) ₅ 7.65-7.85 (m, IH). Yield: 98%

(2S)-2-(4-Methoxyphenoxy)-3 -(4- {2- [( 1 α,5α,6α)-3 -(4-trifluoromethylbenzyl)-3 -azabicyclo-

[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride (Compound No 162) mp: 206-208 ⁰ C

MS: m/z 571 (M+l)

¹ HNMR (CDC1 ₃ +CD ₃ OD ₅ 200 MHz): δ, 2.55 (s ₅ 2H) ₅ 3.10-3.20 (m, 2H), 3.21-3.50 (m, 6H) ₅ 3.66 (s, 3H), 4.11-4.40 (m, 4H), 4.55-4.70 (m, IH) ₅ 6.68-6.90 (m, 6H) ₅ 7.17 (d ₅ J = 8.1 Hz ₅

2H) ₅ 7.51-7.80 (m, 4H).

Yield: 95%

(2S)-3-(4-{2-[(l α ₅ 5α,6α)-3-(4-Trifluoromethylbenzyl)-3-azabicyclo[3.1.0]hex- 6-ylamino]- ethoxy}phenyl)-2-(4-trifluoromethylphenoxy)propionic acid dihydrochloride (Compound No 163) mp: 158-16O ⁰ C MS: m/z 609 (M+l)

¹ HNMR (CDC1 ₃ +CD ₃ OD, 400 MHz): δ 1.22 (s, 2H) ₅ 2.47 (s, 2H), 2.86 (s, IH) ₅ 3.20-3.26 (m, 2H), 3.27-3.48 (m, 2H), 3.52-3.62 (m, 2H), 3.75 (s, IH), 4.03 (s, IH), 4.19 (s, IH), 4.37 (s, 2H), 4.85-4.92 (m, IH), 6.85-6.95 (m, 4H), 7.18-7.29 (m, 2H), 7.44 (d, J= 8.0 Hz, 2H), 7.50- 7.62 (m, 4H). Yield: 93%

(2S)-3-(4-{2-[(lα,5α,6α)-3-(2,4,5-Trifluorobenzyl)-3-a zabicyclo[3.1.0]hex-6-ylamino]- ethoxy}phenyl)-2-(4-trifluoromethylphenoxy)propionic acid dihydrochloride (Compound No

164) mp: 148-150 ⁰ C

MS: m/z 595 (M+l)

¹ HNMR (CDC1 ₃ +CD ₃ OD, 200 MHz): δ 1.22 (s, 2H), 2.55-2.75 (m, 2H) ₃ 3.10-3.20 (m, 2H),

3.25-3.50 (m, 5H), 4.15-4.30 (m, 4H), 4.77 (t, J= 5.0 Hz, IH), 6.75-6.92 (m, 4H), 6.92-7.09

(m, IH), 7.10-7.40 (m, 3H), 7.45 (d, J= 8.5 Hz, 2H). Yield: 93%

(2S)-3-(4-{2-[(lα,5α,6α)-3-(4-Chlorobenzyl)-3-azabicyclo[ 3.1.0]hex-6-ylamino]ethoxy}- phenyl)-2-(4-isopropylphenoxy)propionic acid dihydrochloride (Compound No 149) mp: 154-156 ⁰ C MS: m/z 549 (M+l)

¹ HNMR (D ₂ O, 200 MHz): δ 1.01 (d, J= 6.8 Hz ₃ 6H) ₃ 2.32 (s, 2H), 2.51-2.72 (m, IH), 2.92-

3.14 (m, 3H) ₃ 3.20-3.60 (m, 6H) ₃ 3.90-4.25 (m, 4H), 4.50-4.65 (m, IH) ₃ 6.60-6.82 (m, 4H),

6.85-7.25 (m, 8H).

Yield: 92%

(2S)-2-(4-Isopropylphenoxy)-3-(4-{2-[(lα ₃ 5α ₃ 6α)-3-(2,4,5-trifluorobenzyl)-3-azabicyclo-

[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride (Compound No 150) mp: 142-144 ⁰ C

MS: m/z 569 (M+l)

¹ HNMR (D ₂ O, 200 MHz): δ 1.02 (d, J= 6.8 Hz, 6H), 2.41 (s, 2H), 2.51-2.72 (m, IH), 3.03- 3.19 (m, 3H), 3.30-3.72 (m, 6H), 4.10-4.32 (m, 4H), 4.80 (m, IH), 6.65-6.75 (m, 2H), 6.77- 6.90 (m, 2H), 6.95-7.25 (m, 5H), 7.30-7.50 (m, IH). Yield: 67%

(2S)-2-(4-Isopropylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,4,6- trifluorobenzyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride (Compound No 151) mp: 156-158 ⁰ C MS: m/z 570 (M+l) ¹ HNMR (CDC1 ₃ +CD ₃ OD, 200 MHz): δ 1.11 (d, J= 6.9 Hz, 6H), 2.58 (s, 2H), 2.68-2.84 (m, IH), 3.13 (d, J= 5.9 Hz, 2H), 3.19-3.49 (m, 4H), 3.68-3.75 (m, 3H), 4.22 (s, 4H), 4.65 (t, J= 6.0 Hz, IH), 6.68-6.86 (m, 6H), 7.02 (d, J=8.6 Hz, 2H), 7.19 (d, J= 8.4 Hz, 2H). , Yield: 97%

(2S)-2-(4-ter/-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2- fluorobenzoyl)-3-azabicyclo[3.1.0]- hex-6-ylamino]ethoxy}phenyl)propionic acid hydrochloride (Compound No 120) mp: 180-182 °C

MS: «?/z 561 (M+l)

¹ HNMR (DMSO-J _tf , 200 MHz): δ 1.21 (s, 9H) ₅ 2.07-2.16 (m, 2H), 2.57 (s, IH), 2.90-3.60 (m, 7H), 3.91 (d, J= 12.0 Hz, IH), 4.22 (s, 2H), 4.79 (t, J= 6.9 Hz, IH), 6.73 (d, J= 8.7 Hz, , 2H), 6.86 (d, J= 8.4 Hz, 2H), 7.22-7.51 (m, 8H).

Yield: 86%

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4-tri fluoromethylbenzoyl)-3-aza- . bicyclop.l.OJhex-ό-ylaminoJethoxyJphenytypropionic acid hydrochloride (Compound No 123) _mp: 144-146 ⁰ C MS: m/z 611 (M+l)

¹ HNMR (DMSO-J( _J , 200 MHz): δ 1.20 (s, 9H), 2.10-2.31 (m, 2H), 2.67 (s, IH), 2.95-3.15 » (m, 2H), 3.30-3.66 (m, 4H) ₅ 3.98 (d, J= 12.3 Hz, 2H) ₅ 4.15-4.30 (m, 2H) ₅ 4.75-4.85 (m ₅ IH), 6.73 (d, J = 8.5 Hz, 2H), 6.86 (d, J= 8.2 Hz, 2H), 7.23 (d, J= 8.3 Hz, 4H), 7.65 (d, J = 7.9 Hz, 2H), 7.81 (d, J= 8.0 Hz, 2H), 9.70 (brs, IH, exchangeable with D ₂ O). Yield: 95%

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(3- trifluoromethylbenzoyl)-3-aza- bicyclofS.l.OJhex-ό-ylaminoJethoxyJpheny^propionic acid hydrochloride (Compound No

124) mp: 136-138 ⁰ C

MS: m/z 611 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.24 (s, 9H), 2.31 (s, 3H), 3.01-3.95 (m, 8H), 4.22 (s, 2H) ₅

4.89 (s, IH), 6.65-7.03 (m, 4H), 7.15-7.32 (m, 4H), 7.44-7.66 (m, 4H), 9.74 (brs, IH ₅ exchangeable with D ₂ O). Yield: 87%

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,4,5 -trifluorobenzoyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid hydrochloride (Compound No 122) mp: 140-142 ⁰ C MS: m/z 597 (M+l)

¹ HNMR (DMSO-^ ₅ 200 MHz): δ 1.21 (s, 9H), 2.05-2.30 (m, 2H), 2.63 (s, IH), 3.10-3.21 (m, 2H), 3.26-3.50 (m, 4H), 3.90 (d, J= 12.1 Hz, 2H), 4.18-4.30 (m, 2H) ₅ 4.75-4.88 (m, IH), 6.73 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 5.9 Hz, 4H), 7.61-7.76 (m, 2H) ₅ 9.61 (brs, IH ₅ exchangeable with D ₂ O). Yield: 86%

(2S)-3-(4-{2-[(lα,5α,6α)-3-(3,5-Bis-trifluoromethylben zoyl)-3-azabicyclo[3.1.0]hex-6-yl- amino]ethoxy}phenyl)-2-(4-tert-butylphenoxy)propionic acid hydrochloride (Compound No 125)

nip: 228-230 ⁰ C MS: m/z 679 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.23 (s, 9H), 2.34 (s, 3H), 2.90-3.75 (m, 8H), 3.80-4.05 (m, IH), 3.94 (s, 2H), 4.88 (s, IH), 6.68-6.95 (m, 4H), 7.05-7.25 (m, 4H), 7.80- 7.95 (m, 3H), 9.70 (brs, IH, exchangeable with D ₂ O). Yield: 95%

(2S)-2-(4-/ert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,4-d ifluorobenzoyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid hydrochloride (Compound No 121) mp: 230-232 ⁰ C

MS: m/z 579 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.25 (s, 9H), 2.31 (s, 3H), 3.05-3.71 (m, 8H), 3.80-3.95 (m, IH), 4.23 (s, 2H), 4.80-4.92 (m, IH), 6.70-6.99 (m, 6H), 7.15-7.38 (m, 5H), 9.70 (brs, IH, exchangeable with D ₂ O). Yield: 95%

(2S)-2-(4-Isopropylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(3,4,5- trifluorobenzoyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid hydrochloride (Compound No 152) mp: 100-102 ⁰ C MS: m/z 583 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.18 (d, J = 6.8 Hz, 6H), 2.33 (s, 2H) ₅ 2.79-2.86 (m, 2H), 3.22-3.49 (m, 5H), 3.50-3.90 (m, 4H), 4.23-4.34 (m, 2H), 4.81-4.92 (m, IH), 6.80-6.92 (m, 5H), 7.07-7.11 (d, J = 7.9 Hz, 2H), 7.14-7.25 (m, 3H), 9.73 (brs, IH, exchangeable with D ₂ O). Yield: 95%

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(5-cya nopyridin-2-yl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid trihydrochloride (Compound No 141) mp: 144-146 ⁰ C

MS: m/z 541 (M+l)

¹ HNMR (CDC1 ₃ +CD ₃ OD, 400 MHz): δ 1.22 (s, 9H), 2.40 (s, IH), 2.47 (s, 2H), 3.15 (d, J = 5.2 Hz, 2H), 3.38 (s, 2H), 3.45 (d, J = 10.4 Hz, 2H), 3.70 (d, J= 9.2 Hz, 2H), 4.25 (s, 2H), 4.74 (t, J= 5.6 Hz, IH), 6.32 (d, J= 8.8 Hz, IH), 6.75 (d, J= 8.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 7.18-7.23 (m, 4H), 7.54 (d, J= 7.6 Hz, IH). Yield: 62%

(2S)-2-(4-tert-Butylphenoxy)-3-{4-[(lα,5α,6α)-2-(3-thiazo l-2-yl)-3-azabicyclo[3.1.0]hex-6- ylamino]ethoxy}phenyl)propionic acid trihydrochloride (Compound No 142) mp: 203-205 ⁰ C

MS: m/z 522 (M+l)

¹ HNMR (CDC1 ₃ +CD ₃ OD 400 MHz): δ 1.16 (s, 9H), 2.55-2.70 (m, 2H), 3.10 (d, J= 5.6 Hz, 2H), 3.28 (s, IH), 3.43 (s, 2H), 3.60-3.80 (m, 3H), 4.23 (s, 2H), 4.63 (t, J= 5.6 Hz, IH), 6.64 (d, J = 3.2 Hz, IH), 6.68 (d, J= 8.8 Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 7.10 (d, J= 3.6 Hz, IH), 7.14-7.20 (m, 4H). Yield: 71%

Example 3

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2, 4,5-trifluorobenzyl)-3-azabicyclo- [3.ϊ.0]hex-6-ylamino]ethoxy}phenyl)propionic acid benzyl ester dihydrochloride

(Compound No 52)

Step 1 : (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,4,5 -trifluorobenzyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy }phenyl)propionic acid benzyl ester

To a stirred solution of (2S)-2-(4-tert-butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,4,5 - trifluoro-benzy^-S-azabicyclotS.l.Olhex-ό-ylaminojethoxyjph eny^propionic acid (Step 3 of Example 2; 0.110 g, 0.19 mmol) in carbon tetrachloride (10 ml) was added /7-toluene- sulphonic acid (0.126 g, 0.665 mmol) followed by the addition of benzyl alcohol (0.103 g, 0.10ml, 0.665 mol). The resulting mixture was refluxed using Dean-Stark apparatus for 2 h. The solvent was removed under reduced pressure, residue was diluted with chloroform (2 ml), basified by adding solution of ammonia-chloroform to j?H 8 and filtered through Buchner funnel. Filtrate was concentrated under reduced pressure to yield a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 1.4% methanol-dichloromethane as an eluent to yield the title compound (0.100 g, 79%). MS: mlz 673 (M+l)

¹ HNMR (CDCl ₃ , 400 MHz): δ 1.21-1.33 (m, 9H), 1.56-1.61 (m, 2H), 2.44-2.46 (m, 2H), 2.60-2.65 (m, 2H), 2.98-3.17 (m, 5H), 3.57 (s, 2H), 4.04-4.06 (m, 2H), 4.74-4.76 (m, IH), 5.13 (s, 2H), 6.72-6.80 (m, 5H), 7.14-7.31 (m, 10H).

Step 2: (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2 ₅ 4,5-trifluorobenzyl)-3-aza- bicycloβ.l.Ojhex-ό-ylaminojethoxylphenytypropionic acid benzyl ester dihydrochloride

To a stirred solution of (2S)-2-(4-ført-butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,4, 5- trifluoro-benzyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}ph enyl)propionic acid benzyl ester (0.080 g, 0.12 mmol) in dichloromethane (2 ml) was added 0.85M HCl-diethyl ether (0.3 ml, 0.24 mmol) in a drop wise manner at room temperature. After the addition was

completed, the reaction mixture was stirred at room temperature for 1 h. Solvent was removed under reduced pressure and resulting solid was dried under high vacuum in a desiccator over calcium chloride to yield the title compound (0.048 g, 54%). mp: 161-162 °C ' MS: m/z 673 (M+l)

¹ HNMR (DMS0-<4400 MHz): δ 1.20 (s, 9H), 2.37-2.41 (m, 2H), 3.09-3.14 (m, 2H), 3.33- 3.38 (m, 2H) ₅ 3.54-3.58 (m, 3H), 4.22-4.35 (m, 4H), 5.00-5.04 (m, IH) ₅ 5.10 (s, 2H), 6.73 (d, J= 8.0 Hz ₅ 2H), 6.89 (d, J= 7.6 Hz ₅ 2H) ₅ 7.21-7.31 (m, 9H) ₅ 7.65-7.96 (m ₅ 2H).

Example 4

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2, 4,5-trifluorobenzyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid 2-cyclopentylethyl ester dihydrochloride

(Compound No 51)

Step 1 : (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα ₅ 5α,6α)-3-(2,4 ₅ 5-trifluorobenzyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid 2-cyclopentylethyl ester

To a solution of (2S)-2-(4-tert-butylρhenoxy)-3-(4-{2-[(lα ₅ 5α,6α)-3-(2,4 ₅ 5-trifluoro- benzyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propi onic acid (Step 3 of Example 2; 0.100 g, 0.172 mmol) in benzene (15 ml), was added concentrated H ₂ SO ₄ (0.02 ml) followed by 2-cyclopentylethanol (0.200 g, 1.7 mmol). The reaction mixture was refluxed

using Dean-Stark apparatus for 6 h. The solvent was removed under reduced pressure and residue was diluted with chloroform (2 ml), basified by adding solution of ammonia- chloroform to pH 8, and filtered through Buchner funnel. Filtrate was concentrated under reduced pressure to yield a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 1.4% methanol-dichloromethane as an eluent to yield the title compound (0.080 g, 69%). MS: m/z 679 (M+l)

¹ HNMR (CDCl ₃ , 400 MHz): δ 1.21-1.27 (m, HH), 1.27-1.45 (m, 9H), 1.88-1.93 (m, 3H), 2.04 (s, IH), 2.28-2.31 (m, 2H), 3.07-3.15 (m, 5H), 3.56-3.59 (m, 2H), 4.10-4.13 (m, 4H), 4.66-4.69 (m, IH), 6.73-6.88 (m, 5H), 7.18-7.25 (m, 5H).

Step 2: (2S)-2-(4-fcrt-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,4,5 -trifluorobenzyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid 2-cyclopentylethyl ester dihydro- chloride

To a stirred solution of (2S)-2-(4-tert-butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,4,5 - trifluoro-benzyl)-3 -azabicyclo [3.1.0]hex-6-ylamino] ethoxy } phenyl)propionic acid 2- cyclopentylethyl ester (0.080 g, 0.12 nimol) in dichloromethane (2 ml) was added 0.85M HCl-diethyl ether (0.3 ml, 0.24 mmol) in a drop wise manner at room temperature. After the addition was completed, the reaction mixture was stirred at room temperature for 1 h. Solvent was removed under reduced pressure and resulting solid was dried under high vacuum in a desiccator over calcium chloride to yield the title compound (0.050 g, 57%). mp: 151-152 ⁰ C MS: m/z 679 (M+l)

¹ HNMR (DMSO-d _tf , 400 MHz): δ 1.21-1.60 (m, 24H), 2.41-2.48 (m, 2H), 2.96-2.99 (m, 2H), 2.99-3:09 (m, 2H), 3.40-3.42 (m, 2H), 4.01-4.05 (m, 2H), 4.23-4.37 (m, 3H) ₅ 4.92-4.96 (m, IH), 6.74 (d, J- 8.0 Hz, 2H),' 6.92 (d, J= 7.2 Hz, 2H), 7.23-7.25 (m, 4H), 7.70-8.05 (m, 2H).

Example 5

(2R)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4- chlorobenzyl)-3-azabicyclo[3.1.0]- hex-6-ylamino]ethoxy}phenyl)propionic acid (Compound No 108)

Step 1 : (2R)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-[3-(4-ch lorobenzyl)-3-azabicyclo- [3.1.0]-hex-6-yl]-(4-nitrobenzenesulfonyl)amino]ethoxy}pheny l)propionic acid ethyl ester

To a solution of N-[(lα,5α,6α)-3-(4-chlorobenzyl)-3-azabicyclo[3.1.0]hex-6 -yl]-4- nitro-benzenesulfonamide (Intermediate 1; 0.5 g, 1.2 mmol) in dry dichloromethane (12 ml) was added triphenylphosphine (0.579 g, 2.2 mmol) and (2R)-2-(4-fert-butylphenoxy)-3-[4- (2-hydroxyethoxy)phenyl]propionic acid ethyl ester (Intermediate 7; 0.487 g, 1.26 mmol) at room temperature under stirring. To the above solution, was added diethylazadicarboxylate (0.427 g, 2.45 mmol) drop wise at the same temperature. After being stirred at room temperature for 2 h, 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->2% methanol-dichloromethane as an eluent to yield the required product. This product

was again purified by column chromatography over silica gel (200-400 mesh) using 1% methanol-dichloromethane as an eluent to yield the title compound (0.75 g, 79%). MS: w/z 776 (M+l)

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.19-1.32 (m, 12H), 2.01 (s, 2H), 2.40 (d, J = 9.4 Hz, 2H), 2.50 (s, IH) ₅ 2.95 (d, J = 8.8 Hz, 2H), 3.15-3.17 (m, 2H), 3.50 (s, 2H), 3.52-3.58 (m, 2H), 4.10 (t, J= 5.2 Hz, 2H), 4.20 (q, J= 7.0 Hz, 2H), 4.70 (t, J= 5.9 Hz, IH), 6.66-6.78 (m, 4H), 7.08-7.26 (m, 8H), 8.01 (d, J= 8.4 Hz, 2H), 8.34 (d, J= 8.4 Hz, 2H).

Step 2: (2R)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4-chl orobenzyl)-3-azabicyclo- [3.1 ,0]-hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 11)

To a stirred solution of (2R)-2-(4-tert-butylphenoxy)-3-(4-{2-[(lα,5α,6α)-[3-(4- chloro-benzyl)-3-azabicyclo[3.1.0]hex-6-yl]-(4-nitrobenzenes uifonyl)amino]ethoxy}phenyl)- propionic acid ethyl ester (0.75 g, 0.96 mmol) in dry acetonitrile (10 ml) was added ' anhydrous potassium carbonate (0.4 g, 2.8 mmol) under nitrogen atmosphere. The reaction mixture was cooled to 0 ⁰ C and added thiophenol (0.16 g, 1.46 mmol) drop wise under stirring. After being stirred for 3 h at room temperature, thiophenol (0.107 g, 0.97 mmol) and anhydrous potassium carbonate (0.5 g, 3.62 mmol) was added to the above reaction mixture and stirred for further 2 h. After being stirred for 2 h, acetonitrile was removed under reduced pressure and the residue was taken up in dichloromethane (25 ml), washed with water (1 x5 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get a crude product which was purified by column chromatography over silica gel (100-200 mesh) using 1.25 -M.5% methanol-dichloromethane as an eluent to yield the title compound (0.44 g, 77%). MS: m/z 591 (M+l)

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.17-1.26 (m, 12H), 1.56 (brs, 2H) ₅ 2.45-2.55 (m, 2H), 2.70 (s, IH), 3.00-3.20 (m, 6H), 3.62 (brs, 2H), 4.05 (t, J= 5.0 Hz, 2H), 4.18 (q, J= 7.1 Hz ₅ 2H) ₅ 4.70 (t, J= 5.9 Hz ₅ IH), 6.74-6.84 (m, 4H), 7.16-7.27 (m, 8H).

The following compounds were prepared by procedure similar to those described in

Compound No 11 with appropriate variations of reactants, reaction conditions and quantities of reagents.

(2R)-2-(4-ter?-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2 ₅ 4 ₅ 5-trifluorobenzyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 14) MS: m/z 611 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.15-1.30 (m, 12H) ₅ 1.47 (s, 2H), 1.85 (brs, IH ₅ exchangeable with D ₂ O), 2.43 (d, J= 8.4 Hz ₅ 2H) ₅ 2.55 (s, IH) ₅ 2.91-3.08 (m, 4H), 3.13-3.17 (m, 2H) ₅ 3.55 (s ₅ 2H) ₅ 4.03 (t, J= 5.0 Hz, 2H) ₅ 4.18 (q, J= 7.2 Hz ₅ 2H) ₅ 4.69 (t ₅ J= 12 Hz, IH) ₅ 6.68-6.98 (m, 5H) ₅ 7.05-7.27 (m ₅ 5H). Yield: 63%

Step 3 : (2R)-2-(4-?ert-Butylphenoxy)-3-(4-{2-[(lα ₅ 5α,6α)-3-(4-chlorobenzyl)-3-azabicyclo-

[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid

To a solution of (2R)-2-(4-tert-butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4- chlorobenzyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl )propionic acid ethyl ester (0.34 g ₅ 0.57 mmol) in methanol (40 ml) and water (7 ml), added a solution of sodium carbonate (0.313 g, 2.90 mmol) in water (10 ml) drop wise at 0 ⁰ C under stirring. After being stirred at room temperature for 15 h, methanol was removed under reduced pressure at 35 ⁰ C. The aqueous layer was neutralized by adding IM HCl at 0 ⁰ C to pα 6 under stirring. The resulting reaction mixture was stirred at 0 ⁰ C for 0.5 h and the solid separated out was filtered

through a Buchner funnel, washed with cold water (2x10 ml). The solid so obtained was taken in 10% methanol-dichloromethane (50 ml) and sonicated for 5 min, the undissolved solid was filtered off through a buchner funnel. The filtrate was dried over anhydrous Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure to get a crude product. The crude product was taken into 10% dichloromethane-diethyl ether (15 ml), sonicated at 40 ⁰ C for 5 min, filtered and washed with diethyl ether (2x5 ml). It was finally dried under high vacuum in a desiccator over calcium chloride to yield the title compound (0.23 g, 71%). mp: 176-177 ⁰ C MS: m/z 563 (M+l) ¹ H NMR (CD ₃ OD+CDCI ₃ , 200 MHz): δ 1.22 (s, 9H) ₅ 1.75 (brs, 2H), 2.65 (brs, IH), 2.77 (d, J= 9.1 Hz, 2H), 2.90-3.00 (m, 2H), 3.05-3.15 (m, 4H) ₅ 3.70-3.87 (m, 2H) ₅ 4.05-4.10 (m, 2H) ₅ 4.40-4.52 (m, IH), 6.73-6.84 (m, 4H), 7.15-7.23 (m, 8H).

The following compounds were prepared by procedure similar to those described in Compound No 108 with appropriate variations of reactants, reaction conditions and quantities of reagents and hydrochloride salts were prepared according to method as described earlier.

(2R)-3-(4-{2-[(lα,5α,6α)-3-(4-Chlorobenzyl)-3-azabicyclo[ 3.1.0]hex-6-ylamino]ethoxy}- phenyl)-2-w-tolyloxypropionic acid (Compound No 160) mp: 155-157 ⁰ C

MS: m/z 521 (M+l)

¹ HNMR (CD ₃ OD ₅ 200 MHz): δ 1.73 (s ₅ 2H) ₅ 2.22 (s, 2H) ₅ 2.59 (d ₅ J= 9.1 Hz ₅ 2H), 2.74 (s, IH), 3.02-3.19 (m, 6H), 3.65 (s, 2H), 4.08-4.10 (m, 2H), 4.40-4.51 (m, IH) ₅ 6.64-6.67 (m ₅ 3H), 6.85 (d, J= 8.4 Hz ₅ 2H), 7.02 (t, J= 8.5 Hz, IH) ₅ 7.10-7.35 (m ₅ 6H). Yield: 52%

(2R)-2-(4-fer/-Butylphenoxy)-3-(4-{2-[(lα ₅ 5α,6α)-3-(4-chlorobenzyl)-3-azabicyclo[3.1.0]- hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride (Compound No 109) mp: 150-152 ⁰ C

MS: m/z 563 (M+l)

¹ HNMR (D ₂ 0, 200 MHz): δ 1.12 (s, 9H), 2.30 (s, 2H), 2.70-3.05 (m, 3H), 3.11-3.52 (m, 6H), 3.91-4.25 (m, 4H), 4.51-4.73 (m, IH), 6.52-6.73 (m, 4H), 6.85-7.18 (m, 8H). Yield: 89%

(2R)-2-(4-/ert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,4,5 -trifluorobenzyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride (Compound No 111) mp: 162-163 ⁰ C MS: m/z 583 (M+l) ¹ HNMR (D ₂ 0, 200 MHz): δ 1.02 (s, 9H), 2.39 (s, 2H), 2.91-3.11 (m, 2H) ₅ 3.22-3.65 (m, 6H), 3.85-4.27 (m, 4H), 4.51-4.62 (m, IH), 6.51-6.76 (m, 3H), 6.89-7.11 (m, 5H), 7.21-7.38 (m, 2H).

Yield: 98% Chiral Purity: 99.35%

Example 6

(2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(2,4,5-trifluorobe nzyl)-3-azabicyclo[3.1.0]hex-6- ylamino]ethoxy}phenyl)propionic acid dihydrochloride (Compound No 174)

Step 1 : (2S)-2-Ethoxy-3-[4-(2-{(lα,5α,6α)-(4-nitrobenzenesulfonyl )-[3-(2,4,5-trifluoro- benzyl)-3-azabicyclo[3.1.0]hex-6-yl]amino}ethoxy)phenyl]prop ionic acid ethyl ester

To a stirred solution of (2S)-4-nitro-N-[(lα,5α,6α)-3-(2,4,5-trifluorobenzyl)-3- azabicyclo-[3.1.0]hex-6-yl)benzenesulfonamide (prepared by following the similar procedure as described in Intermediate 1; 7.07 g, 16.57 mmol) in dry dichloromethane (200 ml) was added triphenylphosphine (7.82 g, 29.82 mmol) and (S)-2-ethoxy-3-[4-(2- hydroxyethoxy)phenyl]-propionic acid ethyl ester (Intermediate 8; 6.69 g, 17.07 mmol) in dry dichloromethane (25 ml), at room temperature. To the above solution, was added diethylazadicarboxylate (5.77 g, 5.2 ml., 33.14 mmol) drop wise and resulting mixture was stirred for 2 h, 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 1.0% acetone- dichloromethane as an eluent to yield the title compound (7.83 g, 59%). MS: m Iz 692 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.13-1.28 (m, 6H), 2.06 (s, 2H), (d, J= 9.0 Hz, 2H), 2.93-3.03 (m, 4H), 3.31-3.39 (m, IH), 3.56-3.65 (m, 5H), 3.96 (t, J = 6.2 Hz, IH), 4.08-4.23 (m, 4H) ₅ 6.69 (d, J = 8.5 Hz, 2H), 6.82-7.04 (m, 2H), 7.13 (d, J= 8.5 Hz, 2H), 8.03 (d, J = 8.8 Hz, 2H), 8.36 (d, J= 8.8 Hz, 2H).

Step 2: (2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(2,4,5-trifluorobenzy l)-3-azabicyclo[3.1.0]- hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 78)

To a stirred solution of (2S)-2-ethoxy-3-[4-(2-{(lα,5α,6α)-(4-nitrobenzenesulfonyl )- [3-(2,4,5-trifluorobenzyl)-3-azabicyclo[3.1.0]hex-6-yl]amino }ethoxy)phenyl]propionic acid ethyl ester (7.32 g, 10.5 mmol) in dry acetonitrile (100 ml) was added anhydrous potassium carbonate (4.39 g, 31.77 mmol) under nitrogen atmosphere. The reaction mixture was cooled to 0 ⁰ C and added thiophenol (1.75 g, 1.6ml, 15.84 mmol) drop wise under stirring. Reaction mixture was allowed to come to room temperature. After being stirred for 4 h at room temperature, thiophenol (0.70 g, 0.63 ml, 5.00 mmol) was added to the above reaction mixture and stirred for further 2 h. Acetonitrile was removed under reduced pressure and the residue was taken up in dichloromethane (200 ml), washed with water (2x75 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get a crude product which was purified by column chromatography over silica gel (100-200 mesh) using 1.25 -M.5% methanol-dichloromethane as an eluent to yield the title compound ( 2.85 g, 53%). MS: mlz 507(M+l) ¹ HNMR (CDCl ₃ , 200 MHz): δ 1.11-1.26 (m, 6H), 1.61 (s, 2H), 2.45 (d, J= 8.6 Hz, 2H), 2.65 (s, IH), 2.80-3.11 (m, 4H), 3.25-3.27 (m, IH), 3.55-3.63 (m, 3H), 3.95 (t, J = 6.3 Hz, IH), 4.05-4.21 (m, 4H), 6.74-6.93 (m, 3H), 7.11-7.24 (m, 3H).

The following compounds were prepared by procedure similar to those described in Compound No 78 with appropriate variations of reactants, reaction conditions and quantities of reagents.

(2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(4-trifluoromethox ybenzyl)-3-azabicyclo[3.1.0]-hex-

6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 82)

MS: rø/z 537 (M+l) ¹ HNMR (CDCl ₃ , 200 MHz): δ 1.12-1.26 (m, 6H), 1.47 (s, 2H), 2.35-2.45 (m, 2H), 2.60 (s,

IH), 2.92-3.06 (m, 6H), 3.29-3.37 (m, IH), 3.50-3.60 (m, 3H), 3.92-4.21 (m, 5H), 6.80 (d, J

= 7.9 Hz, 2H), 7.14 (d, J= 7.9 Hz, 4H), 7.28-7.32 (m, 2H).

Yield: 67%

(2S)-3-(4-{2-[(lα,5α,6α)-3-(4-Chlorobenzyl)-3-azabicyc lo[3.1.0]hex-6τylamino]ethoxy}- phenyl)-2-ethoxypropionic acid ethyl ester (Compound No 75) MS: m/z 487(M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.16-1.28 (m, 6H), 1.44 (s, 2H), 2.39-2.43 (m, 2H), 2.58 (s, IH), 2.92-3.05 (m, 6H), 3.25-3.38 (m, IH), 3.54-3.63 (m, 3H), 3.93-4.05 (m, 3H), 4.14 (q, J = 7.1 Hz, 2H), 6.80 (d, J= 8.0 Hz, 2H), 7.12-7.28 (m, 6H). Yield: 48%

(2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(4-trifluorometliy lbenzyl)-3-azabicyclo[3.1.0]hex-6- ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 80) MS: m/z 521 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.10-1.30 (m, 6H ), 1.44 (s, 2H), 2.37 (d, J = 8.6 Hz, 2H), 2.56 (s, IH), 2.94-3.05 (m, 6H), 3.34-3.38 (m, IH), 3.55-3.63 (m, 3H), 3.92-4.05 (m, 3H), 4.17 (q, J= 7.1 Hz, 2H), 6.79 (d, J= 8.5 Hz, 2H), 7.12 (d, J= 8.5 Hz, 2H), 7.39 (d, J= 8.1 Hz, 2H), 7.52 (d, J= 8.0 Hz, 2H). Yield: 53%

(2S)-2-Ethoxy-3 -(4- {2-[( 1 α,5 α,6α)-3 -(2-fluoro-5-trifluoromethylbenzyl)-3 -azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 84) MS: m/z 539 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.11-1.26 (m, 6H), 1.85-1.96 (m, 3H), 2.50-2.55 (m, 2H), 2.90-3.20 (m, 6H), 3.29-3.69 (m, 4H), 3.91 (t, J= 6.3 Hz, IH), 4.10-4.25 (m, 4H), 6.70-6.85 (m, 2H), 7.10-7.15 (m, 3H), 7.50-7.65 (m, 2H). Yield: 62%

(2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(2,4,6-trifluorobe nzyl)-3-azabicyclo[3.1.0]hex-6- ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 86) MS: m/z 507 (M+l)

¹ MNMR (CDCl ₃ , 200 MHz): δ 1.11-1.12 (m, 6H), 1.79 (s, IH), 2.43-2.47 (ra, 2H), 2.75 (s, IH), 2.90-3.37 (ra, 8H), 3.55-3.68 (m, 3H), 3.91 (t, J= 6.5 1Iz ₅ IH), 4.14-4.21 (m, 4H), 6.60- 6.82 (m, 4H), 7.10 (d, J= 8.4 Hz, 2H). Yield: 26%

(2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(5-fluoro-2-triflu oromethylbenzyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 85) MS: m/z 539 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.10-1.25 (m, 6H), 1.66 (s, 2H), 2.41 (d, J= 8.4 Hz, 2H), 2.71 (s, IH), 2.90-3.40 (m, 8H), 3.50-3.80 (m, 2H), 3.91 (t, J = 6.3 Hz, IH), 4.10-4.21 (m, 4H), 6.80 (d, J = 8.5 Hz, 2H), 6.94-7.01 (m, IH), 7.12 (d, J = 8.5 Hz, 2H) ₅ 7.33-7.38 (m, IH), 7.54-7.61 (m, IH). Yield: 75%

(2S)-3-(4-{2-[(lα ₅ 5α,6α)-3-(2,4-Difluorobenzyl)-3-azabicyclo[3.1.0]hex-6-yla mino]- ethoxy}phenyl)-2-ethoxypropionic acid ethyl ester (Compound No 77) ¹ HNMR (CDCl ₃₅ 400 MHz): δ 1.13-1.23 (m, 6H) ₅ 1.73 (s, 2H) ₅ 2.50-3.45 (m, 10H), 3.50- 5.35 (m ₅ 8H) ₅ 6.65-6.85 (m, 4H) ₅ 7.05-7.20 (m ₅ 2H), 7.40-7.60 (m, IH). Yield: 51%

(2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(3,3,3-trifluoropr opyl)-3-azabicyclo[3.1.0]hex-6- ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 87)

MS: m/z 459 (M+l)

¹ HNMR (CDCl ₃ , 400 MHz): δ 1.15 (t, J= 6.9 Hz ₅ 3H), 1.22 (t, J= 6.9 Hz, 3H), 1.55-1.65 (m, IH), 2.24-2.60 (m, 3H), 2.42-2.46 (m, 3H) ₅ 2.63-2.65 (m, 3H) ₅ 2.92-3.09 (m, 3H), 3.32- 3.33 (m, IH), 3.56-3.60 (m, 2H) ₅ 3.94-4.11 (m ₅ 6H) ₅ 6.76-7.25, (m, 4H). Yield: 62%

(2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(3-trifluorometliy lbenzyl)-3-azabicyclo[3.1.0]hex-6- ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 88) . MS: m/z 522 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.12-1.25 (m, 6H), 1.56 (s, 2H), 2.40-2.60 (m, 2H), 2.66 (s, IH) ₅ 2.90-3.10 (m, 5H), 3.30-3.70 (m, 4H), 3.92 (t, J= 6.4 Hz, IH), 4.00-4.25 (m, 5H), 6.81 (d, J= 8.5 Hz, 2H); 7.13 (d, J= 8.5 Hz, 2H) ₅ 7.40-7.55 (m, 4H). Yield: 61%

(2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(4-trifluoromethyl sulfanylbenzyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 89) MS: m/z 554 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.12-1.25 (m, 6H) ₅ 1.50 (s, 2H), 2.40 (d, J =8.3 Hz, 2H) ₅ 2.61 (s, IH), 2.90-3.10 (m, 6H), 3.30-3.65 (m, 4H), 3.90-4.25 (m, 5H) ₅ 6.81 (d, J= 8.5 Hz, 2H), 7.14 (d, J= 8.4 Hz ₅ 2H) ₅ 7.33 (d, J= 8.0 Hz ₅ 2H) ₅ 7.57 (d, J= 8.0 Hz, 2H). Yield: 78%

(2S)-2-Ethoxy-3-(4-{2-[(lα ₅ 5α ₅ 6α)-3-(4-trifluoromethylbenzoyl)-3-azabicyclo-[3.1.0]hex-6- ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 91) MS: m/z 535 (M+l) ¹ HNMR (CDCl ₃ , 200 MHz): δ 1.11-1.28 (m, 6H), 2.33 (s, 2H), 2.92 (d, J = 5.8 Hz ₅ 2H) ₅ 3.20-3.85 (m, 9H), 3.93 (t, J= 6.4 Hz ₅ IH), 4.05-4.30 (m, 4H) ₅ 6.70-6.83 (m, 2H), 7.10-7.14 (m, 2H), 7.52 (t, J= 7.5 Hz, 2H), 7.65-7.70 (m, 2H). Yield: 56%

(2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(4-trifluoromethyl phenylcarbamoyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 96) MS: m/z 550 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.11-1.26 (m, 6H), 1.83 (s, 2H) ₅ 2.14 (s, IH), 2.93-2.96 (m, 2H), 3.10-3.19 (m, 2H), 3.25-3.40 (m, IH), 3.50-3.71, (m, 5H), 3.97 (t, J= 6.5 Hz, IH), 4.08- 4.21 (m, 4H), 6.76-6.84 (m, 2H), 7.14 (d, J= 8.3 Hz, 2H), 7.50-7.52 (m, 4H). Yield: 54%

(2S)-3-(4-{2-[(lα,5α,6α)-3-(2,4-Difluorobenzoyl)-3-aza bicyclo[3.1.0]hex-6-ylamino]- ethoxy}phenyl)-2-ethoxypropionic acid ethyl ester (Compound No 90) MS: m/z 503 (M+l)

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.12-1.26 (m, 6H) ₅ 1.76-1.79 (m, 2H) ₅ 2.09 (s ₅ IH), 2.95 (d, J= 6.5 Hz, 2H), 3.06 (t ₅ J= 4.79 Hz, 2H), 3.31-3.37 (m, 2H) ₅ 3.50-3.63 (m, 3H), 3.99 (t, J= 6.5 Hz, IH) ₅ 4.03-4.21 (m, 5H), 6.77-6.96 (m, 4H), 7.12 (d, J = 8.4 Hz, 2H), 7.28-7.39 (m, IH). Yield: 83%

(2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(3-trifluoromethyl benzoyl)-3-azabicyclo[3.1.0]-hex-6- ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 92) MS: m/z 535 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.124.26 (m, 6H) ₅ 1.76-1.79 (m, 2H), 2.08 (s, IH), 2.92 (d, J = 6.47 Hz, 2H), 3.09 (t, J= 4.48 Hz, 2H), 3.34-3.36 (m, 5H), 3.92 (t, J= 6.7 Hz, IH), 4.02- 4.21 (m, 5H), 6.77 (d, J= 8.2 Hz, 2H), 7.11 (d, J= 8.2 Hz, 2H), 7.52-7.69 (m, 4H). Yield: 82%

(2S)-3-(4-{2-[(lα,5α,6α)-3-(2,4-Bis-trifluoromethylben zoyl)-3-azabicyclo[3.1.0]hex-6- ylamino]ethoxy}phenyl)-2-ethoxypropionic acid ethyl ester (Compound No 93) MS: m/z 603 (M+l)

¹ HNMR (CDC ₃ , 200 MHz): δ 1.11-1.26 (m, 6H) ₅ 1.80-1.91 (m, 2H) ₅ 2.03 (s, IH) ₅ 2.92 (d, J = 6.4 Hz, 2H) ₅ 3.04-3.16 (m, 3H), 3.32-3.37 (m, 2H), 3.55-3.60 (m, 2H) ₅ 3.99 (t, J = 6.6 Hz ₅ IH), 4.02-4.21 (m, 5H), 6.77 (d, J= 8.5 Hz ₅ 2H), 7.16 (d, J= 8.4 Hz, 2H), 7.45 (d, J= 7.9 Hz, IH), 7.87 (d, J= 8.0 Hz, IH) ₅ 7.94 (s,lH).

Yield: 61%

(2S)-3-(4-{2-[(lα,5α,6α)-3-(3,5-Bis-trifluoromethylben zoyl)-3-azabicyclo[3.1.0]hex-6- ylamino]ethoxy}phenyl)-2-ethoxypropionic acid ethyl ester (Compound No 94) MS: m/z 603 (M+l)

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.11 (t, J = 6.9 Hz, 3H); 1.24 (t, J = 5.1 Hz, 3H); 1.99-2.04 (m, 2H); 2.95 (d, J= 6.4 Hz, 2H); 3.12-3.16 (m,lH); 3.34-3.64 (m, 7H); 3.95 (t, J= 6.22 Hz, IH); 4.11-4.21 (m, 5H); 6.78 (d, J = 8.5 Hz, 2H); 7.15 (d, J = 8.4 Hz, 2H); 7.88-7.94 (m, 3H). Yield: 78%

(2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(2,4,5-trifluoroph enylcarbamoyl)-3-azabicyclo[3.1.0]- hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 95)

MS: m/z 536 (M+l) ¹ HNMR (CDCl ₃ , 400 MHz): δ 1.10-1.18 (m, ^' 3H), 1.20-1.32 (m, 3H), 1.98 (s,.2H), 2.21 (s,

IH), 2.93 (d, J= 5.6 Hz, 2H), 3.17 (t, J= 4.4 Hz, IH), 3.25-3.40 (m, 2H), 3.49 (d, J= 9.6 Hz,

2H), 3.52-3.70 (m, 3H), 3.95 (t, J= 6.8 Hz, IH), 4.10-4.22 (m, 4H), 6.70-7.00 (m, 3H), 7.10-

7.20 (m, 2H), 8.00-8.20 (m, IH).

Yield: 36% , ^{■ •}

Step 3: (2S)-2-Ethoxy-3-(4-{2-[(lα ₅ 5α,6α)-3-(2,4,5-trifluorobenzyl)-3-azabicyclo[3.1.0]- hex-6-ylamino]ethoxy}phenyl)propionic acid (Compound No 173)

To a stirred solution of (2S)-2-ethoxy-3-(4-{2-[(lα,5α,6α)-3-(2,4 _? 5-trifluorobenzyl)- 3-aza-bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (4.85 g, 9.58 mmol) in methanol (380 ml) and water (100 ml) was added a solution of sodium carbonate

(5.07 g, 47.83 mmol) in water (75 ml) drop wise at 0 ⁰ C. The reaction mixture was allowed to come at room temperature. After being stirred at room temperature for 15 h, methanol was removed under reduced pressure at 35 ⁰ C. The aqueous layer was neutralized by adding IM

HCl at 0 ⁰ C to pϋ 6 under stirring. The resulting mixture was stirred at 0 ⁰ C for 0.5 h and solid separated out was filtered through a Buchner funnel, washed with cold water (2x250 ml) and dried under vacuum. The solid so obtained was taken in mixture of 10% dichloromethane-diethyl ether (100 ml), sonicated at 40 ⁰ C for 5 min, filtered and washed with diethyl ether (2x30 ml). It was finally dried under high vacuum in desiccator over calcium chloride to yield the title compound (4.07 g, 89%). mp: 169-171 ⁰ C

MS: w/z 479 (M+l)

¹ HNMR (CD ₃ OD+CDC1 ₃₃ 200 MHz): δ 1.10 (t, J= 6.9 Hz, 3H), 1.75 (s, 2H) ₃ 2.53 (d, J= 8.5

Hz, 2H), 2.79-3.07 (m, 6H) ₃ 3.24-3.32 (m, 3H), 3.68 (s, 2H), 3.80-3.91 (m, IH), 4.05-4.10

(m, 2H), 6.82 (d, J= 8.4 Hz ₃ 2H), 7.00-7.20 (m, 4H).

The following compounds were prepared by procedure similar to those described in

Compound No 173 with appropriate variations of reactants, reaction conditions and quantities of reagents.

(2S)-2-Ethoxy-3-(4-{2-[(lα,5α ₅ 6α)-3-(4-trifiuoromethoxybenzyl)-3-azabicyclo[3.1.0]-hex- 6-ylamino]ethoxy}phenyl)propionic acid (Compound No 178) mp: 138-139 ⁰ C

MS: m/z 509 (M+l) ^{' 1} HNMR (CD ₃ OD, 200 MHz): δ 1.09 (t, J= 7.0 Hz, 3H) ₃ 1.93 (s, 2H) ₃ 2.65 (d, J = 9.3 Hz ₃

2H), 2.80-3.00 (m, 3H) ₃ 3.10 (d, J= 9.6 Hz, 2H) ₃ 3.34-3.43 (m, 2H) ₃ 3.44-3.65 (m, 2H), 3.75 (S ₃ 2H), 3.85-3.95 (m, 2H) ₃ 4.17-4.25 (m, 2H), 6.85 (d, J= 8.5 Hz ₃ 2H), 7.17-7.24 (m ₃ 4H) ₃

7.42 (d, J= 8.4 Hz ₃ 2H).

Yield: 97%

(2S)-3-(4-{2-[(lα,5α,6α)-3-(4-Chlorobenzyl)-3-azabicyclo[ 3.1.0]hex-6-ylamino]ethoxy}- phenyl)-2-ethoxypropionic acid (Compound No 170) mp: 118-12O ⁰ C MS: m/z 459 (M+l) ¹ HNMR (CD ₃ OD, 200 MHz): δ 1.08 (t, J = 6.9 Hz, 3H), 1.84 (s, 2H) ₅ 2.58-2.68 (m, 2H) ₅ 2.75-2.95 (m, 3H) ₅ 3.12-3.25 (m, 4H) ₅ 3.45-3.68 (m, 2H) ₅ 3.70 (s, 2H) ₅ 3.75-3.85 (m ₅ IH) ₅ 4.08-4.17 (m, 2H), 6.84 (d, J= 8.5 Hz ₅ 2H), 7.18 (d, J= 8.4 Hz ₅ 2H) ₅ 7.30 (s, 4H). Yield: 66%

(2S)-2-Ethoxy-3-(4-{2-[(lα,5α ₅ 6α)-3-(4-fluorobenzyl)-3-azabicyclo[3.1.0]hex-6-ylamino]- ethoxy}phenyl)propionic acid (Compound No 169) mp: 121-123 ⁰ C

MS: m/z 443 (M+l)

¹ HNMR (CD ₃ OD ₅ 200 MHz): δ 1.08 (t, J = 7.0 Hz ₅ 3H) ₅ 1.90 (s, 2H) ₅ 2.75-3.16 (m, 5H) ₅ 3.11-3.30 (m, 4H) ₅ 3.42-3.62 (m, 2H) ₅ 3.79-3.88 (m, 3H) ₅ 4.12-4.17 (m ₅ 2H) ₅ 6.86 (d, J= 8.6

Hz, 2H) ₅ 7.06-7.20 (m, 4H) ₅ 7.30-7.42 (m, 2H).

Yield: 94%

Step ₍ 4: (2S)-2-Ethoxy-3-(4-{2-[(lα ₅ 5α,6α)-3-(2 ₅ 4 ₅ 5-trifluorobenzyl)-3-azabicyclo[3.1.0]- hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride

To a suspension of (2S)-2-ethoxy-3-(4-{2-[(lα ₅ 5α,6α)-3-(2,4 ₅ 5-trifluorobenzyl)-3- aza-bicycloβ.l .OJhex-όrylaminoJethoxyjphenytypropionic acid (3.98 g, 8.32 mmol) in dichloromethane (1100 nil) was added 0.85M HCl-diethyl ether (0.607 g, 4.9 ml, 16.64 mmol) over period of 10 min at room temperature. Suspension was then stirred at room temperature for 1 h. Solvent was removed under reduced pressure and the solid was dried

under high vacuum in desiccator over calcium chloride to yield the title compound (4.52 g, 98%). mp: 135-137 ⁰ C MS: w/z 479 (M+l) ¹ HNMR (CDCl^CD ₃ OD ₅ 200 MHz): δ 1.13 (t, J= 6.9 Hz, 3H), 2.60 (s, 2H), 2.83-3.04 (m, 2H), 3.31-3.46 (m, 3H), 3.57-3.65 (m, 6H), 3.97-4.01 (m, IH), 4.03-4.29 (m, 2H) ₅ 4.89 (s, 2H), 6.94 (d, J= 8.6 Hz, 2H), 7.21 (d, J= 8.6 Hz, 2H), 7.35-7.44 (m, IH), 7.72-7.76 (m, IH). Chiral Purity: 96.72%, [α] ²⁰ _D = -5.60 (Cl .05, H ₂ O)

The following compounds were prepared by procedure similar to those described in

Compound No 174 with appropriate variations of reactants, reaction conditions and quantities of reagents.

(2S)-2-Ethoxy-3 -(4- {2-[( 1 α,5 α,6α)-3 -(4-trifluoromethylbenzyl)-3 -azabicyclo[3.1.0]hex-6- ylamino]ethoxy}phenyl)propionic acid dihydrochloride (Compound No 176) mp: 127-129 ⁰ C ^" .

MS: m/z 493 (M+l)

¹ HNMR (CD ₃ OD ₅ 200 MHz): δ 1.09 (t, J = 6.9 Hz ₅ 3H) ₅ 2.49 (s, 2H) ₅ 2.97-2.99 (m, 2H), 3.45 (s, 2H) ₅ 3.57-3.68 (m, 7H), 4.00-4.10 (m, IH), 4.26-4.31 (m, 2H), 4.48 (s, 2H), 6.95 (d, J= 8.5 Hz, 2H), 7.21 (d, J= 8.6 Hz, 2H), 7.80 (s, 4H). , Yield: 98%

(2S)-2-Ethoxy-3-(4-{2-[(lα ₅ 5α ₅ 6α)-3-(2-fluoro-5-trifluoromethylbenzyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride (Compound No 180) mp: 130-132 °C , MS: m/z 511 (M+l)

¹ HNMR (DMSO-d _ft 200 MHz): δ 1.03 (t, J= 6.9 Hz ₅ 3H), 2.42 (s, 2H) ₅ 2.73-2.91 (m, 3H), 3.24-3.54 (m, 8H), 3.93 (t, J = 7.2 Hz, IH), 4.24 (s, 2H), 4.47 (s, 2H), 6.88 (d, J= 8.4 Hz, 2H), 7.16 (d, J= 8.2 Hz, 2H), 7.55 (t, J= 8.9 Hz, IH), 7.90 (s, IH), 8.24-8.40 (m, IH), 9.86 (brs, IH, exchangeable with D ₂ O), 11.65 (brs, IH, exchangeable with D ₂ O).

Yield: 73%

(2S)-2-Ethoxy-3-(4-{2-[(lα,5α ₅ 6α)-3-(2 ₅ 4,6-trifluorobenzyl)-3-azabicyclo[3.1.0]hex-6- ylamino]ethoxy}phenyl)propionic acid dihydrochloride (Compound No 182) mp: 102-103 ⁰ C MS: rø/z 479 (M+l)

¹ HNMR (DMSO-tf _f c 200 MHz): δ 1.01 (t, J= 6.9 Hz, 3H) ₃ 2.79-2.83 (m, 4H), 3.27-3.52 (m, 9H) ₅ 3.92 (t, J = 5.10 Hz, IH), 4.22 (s, 4H), 6.84 (d, J = 7.9 Hz, 2H), 7.11 (d, J = 8.3 Hz, 2H), 7.29-7.31 (m, 2H). Yield: 67%

(2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(5-fluoro-2-trifluoro methylbenzyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride (Compound No 181) mp: 174-175 ⁰ C MS: m/z 511 (M+l)

¹ HNMR (DMSO-J ₆ , 400 MHz): δ 1.03 (t, J= 7.2 Hz, 3H), 2.35-2.50 (m, 2H) ₅ 2.77-2.91 (m, 2H) ₅ 3.01 (S ₅ IH) ₅ 3.24-3.32 (m, 2H), 3.60-3.80 (m, 6H), 3.93 (t, J = 5.2 Hz ₅ IH), 4.25 (s, 2H) ₅ 4.50-4.59 (m, 2H) ₅ 6.90 (d ₅ J= 7.2 Hz ₅ 2H), 7.15 (d, J= 8.4 Hz ₅ 2H) ₅ 7.50 (s ₅ IH), 7.89 (S ₅ IH) ₅ 8.44 (s, IH) ₅ 9.74 (brs, IH ₅ exchangeable with D ₂ O). Yield: 64%

(2S)-3-(4-{2-[(lα,5α,6α)-3-(2,4-Difluorobenzyl)-3-azabicy clo[3.1.0]hex-6-ylamino]- ethoxy}phenyl)-2-ethoxypropionic acid dihydrochloride (Compound No 172) mp: 114-115 ⁰ C MS: m/z 483 (M+23)

¹ HNMR (DMSO-^ ₅ 400 MHz): δ 1.03 (t ₅ J= 6.8 Hz, 3H) ₅ 2.41 (s ₅ 2H) ₅ 2.77-2.96 (m, 2H), 3.26-3.53 (m, 9H), 3.94 (t, J= 5.6 Hz ₅ IH) ₅ 4.23 (s, 2H) ₅ 4.37 (s ₅ 2H) ₅ 6.89 (d, J = 8.0 Hz ₅ 2H), 7.15-7.25 (m, 3H), 7.30-7.45 (m, IH), 7.80-7.95 (m, IH) ₅ 9.88 (brs, IH, exchangeable with D ₂ O) ₅ 11.55 (brs, IH, exchangeable with D ₂ O).

Yield: 62%

(2S)-2-Ethoxy-3-(4-{2-[(lα,5α ₅ 6α)-3-(3,3,3-trifluoropropyl)-3-azabicyclo[3.1.0]hex-6- ylamino]ethoxy}phenyl)propionic acid dihydrochloride (Compound No 183) mp: 84-85 ⁰ C

MS: w/z 431 (M+l)

¹ HNMR (DMSO-dtf, 400 MHz): δ 1.03 (t, J - 6.8 Hz, 3H), 2.32 (s, 2H), 2.78-2.91 (m, 5H), 3.27-3.70 (m, 10H), 3.94 (t, J= 5.6 Hz, IH), 4.25 (s, 2H), 6.92 (d, J= 8.0 Hz, 2H) ₅ 7.15 (d, J = 7.6 Hz, 2H), 9.95 (brs, IH, exchangeable with D ₂ O), 11.85 (brs, IH, exchangeable with D ₂ O). ' Yield: 71%

(2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(3-trifluoromethyl benzyl)-3-azabicyclo[3.1.0]hex-6- ylamino]ethoxy}phenyl)propionic acid dihydrochloride (Compound No 184) mp: 135-136 °C

MS: m/z 494 (M+l)

¹ HNMR (DMSO-^, 200 MHz): δ 1.05 (t, J= 7.0 Hz, 3H), 2.43 (s, 2H), 2.72-2.92 (m, 2H), 3.27-3.46 (m, 6H), 3.89-3.96 (m, 2H), 4.23 (s, 2H), 4.43 (s, 4H), 6.87 (d, J = 8.3 Hz, 2H), 7.11 (d, J =8.1 Hz, 2H), 7.62-8.09 (m, 4H), 9.94 (brs, IH, exchangeable with D ₂ O), 11.68 (brs, IH, exchangeable with D ₂ O). Yield: 82%

(2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(4-trifluoromethylsul fanylbenzyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride (Compound No 185) mp: 132-134 ⁰ C

MS: m/z 525 (M+l)

¹ HNMR (OMSO-d ₆ , 200 MHz): δ 0.99 (t, J= 6.9 Hz ₅ 3H), 2.04-2.10 (m, 2H), 2.73-3.54 (m, 12H), 3.54-3.97 (m, 2H), 4.23 (s, 2H), 6.85 (d, J =8.3 Hz, 2H), 7.13 (d, J = 8.3 Hz, 2H), 7.50-7.71 (m, 4H) ₅ 9.80 (brs, IH, exchangeable with D ₂ O).

Yield: 64%.

(2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(4-trifluoromethylben zoyl)-3-azabicyclo[3.1.0]-hex-6- ylamino]ethoxy}phenyl)propionic acid hydrochloride (Compound No 187) mp: 121-123 ⁰ C MS: w/z 507 (M+l)

¹ HNMR (DMSO-ύk, 200 MHz): δ 0.99 (t, J= 6.8 Hz ₅ 3H), 2.15 (s ₅ 2H), 2.66 (s, IH), 2.80- 2.84 (m, 3H) ₅ 3.46-3.51 (m, 4H), 3.51-3.66 (m, 2H), 3.96-4.02 (m, 2H) ₅ 4.22 (s, 2H), 6.82 (d, J= 8.1 Hz, 2H), 7.20 (d, J= 8.1 Hz, 2H), 7.64 (d, J= 8.0 Hz, 2H), 7.80 (d, J= 8.0 Hz ₅ 2H) ₅ 9.65 (brs, IH, exchangeable with D ₂ O). Yield: 90%

(2S)-2-Ethoxy-3-(4-{2-[(lα,5α ₅ 6α)-3-(4-trifluoromethylphenylcarbamoyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid hydrochloride (Compound No 192) mp: 195-197 ⁰ C

MS: m/z 522 (M+l)

¹ HNMR (DMSO-^, 200 MHz): δ 1.02 (t, J = 6.9Hz, 3H), 2.21 (s, 2H), 2.64' (s, IH), 2.73- 2.94 (m, 2H), 3.20-3.32 (m, IH), 3.40-3.50 (m, 5H) ₅ 3.76 (d, J= 10.7 Hz, 2H), 3.93 (t, J = 7.3Hz, IH), 4.21-4.29 (m, 2H), 6.89 (d, J= 8.4 Hz, 2H) ₅ 7.16 (d, J= 8.4 Hz ₅ 2H), 7.57 (d, J= 6.7 Hz ₅ 2H), 7.74 (d, J= 8.6 Hz, 2H) ₅ 8.65 (brs, IH, exchangeable with D ₂ O). Yield: 93%

(2S)-3-(4-{2-[(lα,5α,6α)-3-(2,4-Difluorobenzoyl)-3-azabic yclo[3.1.0]hex-6-ylamino]- ethoxy}phenyl)-2-ethoxypropionic acid hydrochloride (Compound No 186) mp: 66-67 ⁰ C

MS: m/z 475 (M+l)

¹ HNMR (DMSO-^ ₅ 200 MHz): δ 1.02 (t, J= 6.9 Hz, 3H), 2.21 (s, 2H), 2.73 (s, IH), 2.73-

2.80 (m ₅ 2H) ₅ 3.21-3.39 (m, 7H) ₅ 3.89-3.95 (m, 2H), 4.25 (s, 2H) ₅ 6.83 (d, J= 8.1 Hz ₅ 2H) ₅

7.13-7.17 (m, 3H) ₅ 7.33-7.55 (m, 2H), 9.80 (brs, IH, exchangeable with D ₂ O), 12.65 (brs, IH, exchangeable with D ₂ O). Yield: 92%

(2S)-2-Ethoxy-3 -(4- {2- [( 1 α,5 α,6α)-3 -(3-trifluoromethylbenzoyl)-3 -azabicyclo [3.1.0]-hex-6- ylamino]ethoxy}phenyl)propionic acid hydrochloride (Compound No 188) mp: 73-74 ⁰ C MS: m/z 507 (M+l)

¹ HNMR (CDCI ₃ +CD ₃ OD, 200 MHz): δ 1.11 (t, J = 6.8 Hz ₅ 3H), 2.37 (s, 2H), 2.93 (s , 2H) ₅ 3.42-3.57 (m, 8H), 3.90-4.00 (m, IH), 4.05-4.24 (m, 3H), 6.70-6.90 (m, 2H), 7.00-7.20 (m, 2H), 7.45-7.80 (m, 4H). Yield: 86%

(2S)-3-(4-{2-[(l α,5α,6α)-3-(2,4-Bis-trifluoromethylbenzoyl)-3-azabicyclo[ 3.1.0]hex-6- ylamino]ethoxy}phenyl)-2-ethoxypropionic acid hydrochloride (Compound No 189) mp: 117-118 °C

MS: m/z 575 (M+l)

¹ HNMR (DMSO-<4 ₅ 200 MHz): δ 1.06 (t, J= 6.8 Hz, 3H) ₅ 2.21-2.28 (m ₅ 2H), 2.70-2.98 (m,

2H), 3.00-3.70 (m, 8H), 3.80-4.00 (m, 2H), 4.26 (s, 2H), 6.84 (d, J= 8.3 Hz, 2H) ₅ 7.13 (d, J= 8.3 Hz ₅ 2H), 7.82 (d, J = 8.7 Hz ₅ IH) ₅ 8.16-8.20 (m, 2H) ₅ 9.82 (brs, IH ₅ exchangeable with

D ₂ O).

Yield: 65%

(2S)-3-(4-{2-[(lα,5α,6α)-3-(3 ₅ 5-Bis-trifluoromethylbenzoyl)-3-azabicyclo[3.1.0]hex-6- ylamino]ethoxy}phenyl)-2-ethoxypropionic acid hydrochloride (Compound No 190) mp: 72-73 ⁰ C MS: w/z 575 (M+l)

¹ HNMR (DMSO-^ ₃ 200 MHz): δ 1.02 (t, J= 6.8 Hz, 3H) ₅ 2.19-2.23 (m, 2H), 2.72-2.93 (m, 3H), 3.23-3.42 (m, 4H), 3.72-3.77 (m, 2H), 3.89-4.02 (m, 3H), 4.25 (s, 2H), 6.83 (d, J= 8.5 Hz, 2H), 7.11 (d, J= 8.4 Hz, 2H), 8.17-8.23 (m, 3H), 9.80 (brs, IH, exchangeable with D ₂ O). Yield: 56%

(2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(2,4,5-trifluoropheny lcarbamoyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid hydrochloride (Compound No 191) mp: 170-171 ⁰ C ₍

MS: m/z 508 (M+l) ¹ HNMR (DMSO-^ ₅ 400 MHz): δ 1.03 (t, J= 6.8 Hz, 3H), 2.19 (s, 2H), 2.61 (s, IH), 2.77- 2.91 (m, 2H), 3.26-3.54 (m, HH), 3.69 (d, J = 10.8 Hz, 2H), 3.93-3.94 (m, IH), 4.25-4.27 (m, 2H), 6.89 (d, J= 8.4 Hz, 2H), 7.16 (d, J= 8.4 Hz, 2H), 7.53-7.61 (m, 2H), 8.18 (s, IH, exchangeable with D ₂ O), 9.65 (brs, IH, exchangeable with D ₂ O), 12.65 (brs, IH, exchangeable with D ₂ O). ■ Yield: 68%

Example 7

(2S)-2-Ethoxy-3-(4-{3-[(lα,5α,6α)-3-(2,4,5-trifluorobe nzyl)-3-azabicyclQ[3.1.0]hex-6-yl- amino]ρropoxy}phenyl)propionic acid dihydrochloride (Compound No 139)

Step 1 : (2S)-2-Ethoxy-3-[4-(3-{(lα,5α,6α)-(4-nitrobenzenesulphony l)-[3-(2,4,5-trifluoro- benzyl)-3-azabicyclo[3.1.0]hex-6-yl]amino}propoxy)phenyl]pro pionic acid ethyl ester

To a solution of (2S)-2-ethoxy-3-[4-(3-hydroxypropoxy)phenyl]propionic acid ethyl ester (Intermediate 10; 0.93 g, 3.1 mmol) in dichlorόmethane (15 ml) was added triphenyl phosphine (1.42 g, 5.4 mol) and 4-nitro-iV-[(lα,5α ₅ 6α)-3-(2,4,5-triflourobenzyl]-3-aza- bicyclo[3.1.0]hex-6-yl]benzenesulphonamide (1.3 g, 3.0 mmol) in dichloromethane (10 ml) at room temperature under stirring. To the above solution was added diethylazadicarboxylate (1.04g, 0.94 ml, 6.0 mmol) drop wise at room temperature. After being stirred, at same temperature for 2 h, the solvent was removed under reduced pressure to obtain the crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 1.4% acetone-dichloromethane as an eluent to yield the title compound (1.71 g, 80%). MS: mlz 706 (M+l)

¹ HNMR(CDCI ₃ ^OO MHZ): δ 1.12-1.37 (m, 6H); 1.93-2.10 (m, 4H); 2.30-2.47 (m, 3H); 2.93- 3.50 (m, 3H); 3034-3.37 (m, 3H); 3.54-3.64 (m, 3H); 3.92-3.96 (m, 3H); 4.11-4.33 (m, 3H); 6.73 (d, J = 8.5 Hz, 2H); 6.78-7.10 (m, 2H); 7.12 (d, J= 8.3 Hz ₅ 2H); 7.98 (d, J = 8.5 Hz, 2H); 8.35 (d, J= 8.5 Hz, 2H).

Step 2: ^■ (2S)-2-Ethoxy-3-(4-{3-[(lα,5α,6α)-3-(2 ₅ 4,5-trifluorobenzyl)-3-azabicyclo[3.1.0]- hex-6-ylamino]propoxy}phenyl)propionic acid ethyl ester (Compound No 41)

To a stirred solution of (2S)-2-ethoxy-3-[4-(3-{(lα,5α,6α)-(4- nitrobenzenesulphonyl)-[3-(2,4,5-trifluorobenzyl)-3-azabicyc lo[3.1.0]hex-6- yl] amino }propoxy)phenyl]propionic acid ethyl ester (1.7 g, 2.4 mmol) in dry acetonitrile (10

ml) was added anhydrous potassium carbonate (0.5 g, 3.6 mmol) under nitrogen atmosphere. The reaction mixture was cooled to 0 ⁰ C and added thiophenol (0.4 ml, 3.6 mmol) drop wise under stirring. Reaction mixture was allowed to come to room temperature. After being stirred for 3 h at room temperature, thiophenol (0.4 ml, 3.6 mmol) and anhydrous potassium carbonate (0.5 g, 3.6 mmol) was added to the above reaction mixture and stirred for further 4 h. Acetonitrile was removed under reduced pressure and the residue was extracted with dichloromethane (2x25 ml), washed with water (1x5 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 1.4% methanol- dichloromethane as an eluent to yield the title compound (0.75 g, 60%). MS: m/z 521 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.12-1.24 (m, 6H); 1.77-1.79 (m, 2H); 2.12-2.15 (m, 2H); 2.40-2.45 (m, 2H); 2.91-3.08 (m, 6H); 3.29-3.37 (m, IH); 3.55-3.63 (m, 4H); 3.92-4.03 (m, 3H); 4.11 (q, J= 7.1 Hz, 2H); 6.76-6.93 (m, 3H); 7.11 -7.15 (m, 3H).

Step 3: (2S)-2-Ethoxy-3-(4-{3-[(lα,5α,6α)-3-(2,4,5-trifluorobenzy l)-3-azabicyclo[3.1.0]- hex-6-ylamino]propoxy}phenyl)propionic acid

To a stirred solution of (2S)-2-ethoxy-3-(4-{3-[(lα,5α,6α)-3-(2,4,5-trifluorobenzy l)- S-aza-bicyclop.l.Ojhex-ό-ylaminojpropoxyjpheny^propionic acid ethyl ester (0.75 g, 1.4 mmol) in methanol (44 ml) and water (15 ml) was added a solution of sodium carbonate

(0.76 g, 7.2 mmol) in water (6 ml) drop wise at 0 ⁰ C. The reaction mixture was allowed to come at room temperature and stirred for 15 h at same temperature. Methanol was removed under reduced pressure at 30 ⁰ C. The aqueous layer was neutralized by adding IM HCl at 0 ⁰ C to pα 6 under stirring. The resulting reaction mixture was stirred at 0 ⁰ C for 0.5 h and solid separated out was filtered through a Buchner funnel, washed with cold water (2x10 ml).

The solid so obtained was taken in 10% methanol-dichloromethane (50 ml) and sonicated for

5 min. The undissolved solid was filtered off through a Buchner funnel. The filtrate was . dried over anhydrous Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure to get a crude product. The crude product was taken in 10% dichloromethane-diethyl ether (5 ml), sonicated at 40 ⁰ C for 5 min, filtered and washed with diethyl ether (5 ml). It was finally dried under high vacuum in a desiccator over calcium chloride to yield the title compound (0.45 g, 63%). mp: 158-160 °C MS: m/z 493 (M+l)

¹ HNMR (CDCI ₃ +CD ₃ OD, 200 MHz): δ 1.04 (t, J = 6.6 Hz, 3H); 1.90-1.94 (m, 3H); 2.40- 2.46 (m, 2H); 2.69 (s, IH); 2.87-3.00 (m, 6H); 3.30-3.32 (m, IH); 3.50-3.54 (m, 4H); 3.82- 3.88 (m, 3H); 6.68-6.89 (m, 3H); 6.99-7.25 (m, 3H).

Step 4: (2S)-2-Ethoxy-3-(4-{3-[(lα,5α,6α)-3-(2,4,5-trifluorobenzy l)-3-azabicyclo[3.1.0]- hex-6-ylamino]propoxy}phenyl)propionic acid hydrochloride

To a stirred solution of (2S)-2-ethoxy-3-(4-{3-[(lα,5α,6α)-3-(2,4,5-trifluorobenzy l)- 3-aza-bicyclo[3.1.0]hex-6-ylamino]propoxy}phenyl)propionic acid (0.450 g, 0.91 mmol) in dichloromethane (10 ml) was added 0.9M HCl-diethyl ether (2 ml, 1.83 mmol) at room temperature. After being stirred at room temperature for Ih, dichloromethane was removed under reduced pressure at 30 ⁰ C and solid so obtained was dried in desiccator over _v calcium chloride under high vacuum to yield the title compound (0.458 g, 89%). mp: 119-120 °C MS: rø/z 493 (M+l) ¹ HNMR (DMSO-^ ₆ , 200 MHz): δ 1.00 (t, J= 7.0 Hz, 3H); 2.00-2.21 (m, 2H); 2.31-2.41 (m, 2H); 2.78-2.86 (m, 2H); 2.98-3.15 (m, 3H); 3.24-3.54 (m, 6H); 3.93-4.01 (m, 3H); 4.32-4.40 (m, 2H); 6.81 (d, J= 8.3 Hz, 2H); 7.11 (d, J= 8.2 Hz, 2H); 7.66-7.82 (m, IH); 7.92-8.14 (m, IH), 9.69 (brs, IH, exchangeable with D ₂ O); 11.58 (brs, IH, exchangeable with D ₂ O).

Example 8

(2R)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(2,4,5-trifluorobe nzyl)-3-azabicyclo[3.1.0]hex-6-yl- amino]ethoxy}phenyl)propionic acid dihydrochloride (Compound No 175)

Step 1 : (2R)-2-Ethoxy-3-[4-(2-{(lα,5α,6α)-(4-nitrobenzenesulfonyl )-[3-(2,4 ₅ 5-trifluoro- benzyl)-3-azabicyclo[3.1.0]hex-6-yl]amino}ethoxy)phenyl]prop ionic acid ethyl ester

To a stirred solution of (2R)-2-ethoxy-3-[4-(2-hydroxyethoxy)phenyl]propionic acid ethyl ester (Intermediate 9; 0.7 g, 2.37 mmol) in dichloromethane (10 ml) was added triphenyl-phosphine (1.09 g, 4.1 mmol) and 4-nitro-N-[(lα,5α,6α)-3-(2,4,5-trifluoro- benzyl)-3-aza-bicyclo[3.1.0]hex-6-yl)benzenesulfonamide (1.0 g, 2.34 mmol) in dichloromethane (10 ml) was added at room temperature. To the above solution was added diethylazadicarboxylate (0.72 ml, 4.6 mmol) drop wise at room temperature. After being stirred at room temperature for 2 h, the solvent was evaporated under reduced pressure and residue was purified by column chromatography over silica gel (100-200 mesh) using 1.5% acetone-dichloromethane as an eluent to yield the title compound (0.76 g, 47%). MS: m/z 692 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.04 (t, J = 7.0 Hz, 3H); 1.20 (t, J = 7.1 Hz, 3H); 2.01-2.14 (m, 2H); 2.40-2.50 (m, 2H); 2.92 (d, J= 6.6 Hz, 2H); 2.97-3.02 (m, 2H); 3.34-3.38 (m, IH); 3.52-3.64 (m, 4H); 3.92 (t, J= 6.0 Hz ₅ IH); 4:07-4.09 (m, 2H); 4.12 (q, J= 7.0 Hz ₅ 2H); 6.66 (d, J= 8.4 Hz ₅ 2H); 6.68-7.09 (m, 2H); 7.10 (d, J= 8.6 Hz, 2H); 8.00 (d, J= 8.2 Hz, 2H); 8.33 (d ₅ J= 8.6 Hz ₅ 2H).

Step 2: (2R)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(2,4,5-trifluorobenzy l)-3-azabicyclo[3.1.0]- hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 79)

To a stirred solution of (2R)-2-ethoxy-3-[4-(2-{(l α,5α ₅ 6α)-(4-nitrobenzenesulfonyl)-

[3-(2,4,5-trifluorobenzyl)-3-azabicyclo[3.1.0]hex-6-yl]amino }ethoxy)phenyl]propionic acid ethyl ester (0.76 g, 1.1 mmol) in dry acetonitrile (10 ml) was added anhydrous potassium carbonate (0.23 g,1.65 mmol) under nitrogen atmosphere. The reaction mixture was cooled to 0 ⁰ C and added thiophenol (0.17 ml, 1.65 mmol) drop wise under stirring. Reaction mixture was allowed to stirred come to room temperature. After being stirred for 3 h at room temperature, thiophenol (0.17 ml, 1.65 mmol) and anhydrous potassium carbonate (0.23 g, 1.65 mmol) was added to the above reaction mixture and stirred for further 4 h. Acetonitrile was removed under reduced pressure and the residue was taken up in dichloromethane (25 ml), washed with water (1x5 ml), dried over anhydrous Na ₂ SO ₄ , filtered and 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-dichloromethane as an eluent to yield the title compound (0.35 g, 63%). MS: mlz 507 (M+l) ¹ HNMR (CDCl ₃ , 200 MHz): δ 1.10-1.27 (m, 6H); 1.90-1.95 (m, IH); 2.48-2.53 (m, 2H); 2.95 (d, J= 6.8 Hz, 2H); 3.07-3.06 (m, 3H); 3.29-3.37 (m, IH); 3.55-3.62 (m, 3H); 3.70-3.75 (m, IH); 3.92 (t, J= 6.2 Hz, IH); 4.11-4.22 (m, 4H); 6.74-6.95 (m, 4H); 7.11-7.25 (m, 2H).

The following compounds were prepared by procedure similar to those described in Compound No 79 with appropriate variations of reactants, reaction conditions and quantities of reagents.

(2R)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(4-trifluoromethox ybenzyl)-3-azabicyclo[3.1.0]hex-6- ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 83) MS: m/z 537 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.12-1.30 (m, 6H), 1.57 (s, 2H), 2.40-2.52 (m, 2H), 2.69 (s, IH), 2.90-2.95 (m, 2H), 2.97-3.10 (m, 3H), 3.25-3.40 (m, IH), 3.50-3.65 (m, 3H) ₅ 3.92-4.21 (m, 6H), 6.80 (d, J= 8.0 Hz, 2H), 7.13(d, J= 7.9 Hz, 4H), 7.32-7.34 (m, 2H). Yield: 55%

(2R)-3 -(4- {2-[( 1 α,5α,6α)-3 -(4-Chlorobenzyl)-3 -azabicyclo [3.1.0]hex-6-ylamino]ethoxy} - phenyl)-2-ethoxypropionic acid ethyl ester (Compound No 76)

MS: m/z 487 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.12-1.32 (m, 6H), 1.44 (s, 2H), 2.35-2.45 (m, 2H), 2.57 (s,

IH), 2.92-3.05 (m, 6H), 3.22-3.42 (m, IH), 3.54-3.63 (m, 3H), 3.90-4.05 (m, 3H), 4.15 (q, J

= 7.1 Hz, 2H), 6.80 (d, J= 8.0 Hz, 2H), 7.12-7.28 (m, 6H). Yield: 46%

Step 3: (2R)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(2,4,5-trifluorobenzy l)-3-azabicyclo[3.1.0]- hex-6-ylamino]ethoxy}phenyl)propionic acid

To a stirred solution (2R)-2-ethoxy-3-(4-{2-[(lα,5α,6α)-3-(2,4,5-trifluorobenzy l)-3- aza-bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (0.35 g, 0.69

mmol) in methanol (21 ml) and water (6 ml) was added a solution of sodium carbonate (0.37 g, 3.45 mmol). in water (4.5 ml) drop wise at 0 ⁰ C. The reaction mixture was allowed to come at room temperature and stirred for 15 h. Methanol was removed at 30 ⁰ C under reduced pressure. The aqueous layer was neutralized by adding IM HCl at 0 ⁰ C to pH 6 under stirring. The resulting reaction mixture was stirred at 0 ⁰ C for 0.5 h and solid separated out was filtered through a Buchner runnel, washed with cold water (2x5 ml). The solid so obtained was taken in mixture of 10% methanol-dichloromethane (50 ml) and sonicated for 5 min. The undissolved solid was filtered off through a Buchner funnel. The filtrate was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get a crude product. The crude product was taken in 10% dichloromethane-diethyl ether (5 ml), sonicated at 40 ⁰ C for 5 min, filtered and washed with diethyl ether (1x5 ml). It was finally dried under high vacuum in a desiccator over calcium chloride to yield the title compound (0.26 g, 79%). mp: 170-171 ⁰ C

¹ HNMR (CDC1 ₃ +CD ₃ OD, 200 MHz): δ 1.02 (t, J= 6.9 Hz, 3H); 1.72 (s, 2H); 2.44 (d, J= 8.8 Hz, 2H); 2.65 (s, IH); 2.81-2.88 (m, 2H); 2.96 (d, J= 9.1 Hz, 2H); 3.04-3.11 (m, 2H), 3.21- 3.54 (m, 2H); 3.81 (t, J= 5.1 Hz, IH); 4.00-4.10 (m, 2H); 6.71 (d, J= 8.3 Hz, 2H); 6.79-6.89 (m, IH); 7.06-7.26 (m, 3H).

The following compounds were prepared by procedure similar to those described in Step 3 of Compound No 175 with appropriate variations of reactants, reaction conditions and quantities of reagents. (2R)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(4-trifluoromethoxybe nzyl)-3-azabicyclo[3.i.0]hex-6- ylamino] ethoxy}phenyl)proρionic acid (Co mpoun d No 179) mp: 140-142 ⁰ C MS: m/z 509 (M+l)

¹ HNMR (CD ₃ OD, 200 MHz): δ 1.09 (t, J = 7.0 Hz, 3H) ₃ 1.98 (s, 2H) ₅ 2.72-3.10 (m, 6H), 3.10-3.20 (m, 2H), 3.4-3.45 (m, 2H) ₅ 3.50-3.65 (m, IH), 3.80 (s, 2H), 3.85-3.95 (m IH), 4.21 (t, J= 7.0 Hz, 2H), 6.85 (d, J= 8.6 Hz, 2H) ₅ 7.16-7.25 (m, 4H) ₅ 7.45 (d, J= 8.6 Hz, 2H). Yield: 98%

(2R)-3-(4-{2-[(lα,5α,6α)-3-(4-Chlorobenzyl)-3-azabicyclo[ 3.1.0]hex-6-ylamino]ethoxy}- phenyl)-2-ethoxypropionic acid (Compound No 171) mp: 125-127 ⁰ C MS: rø/z 459 (M+l) ¹ HNMR (CD ₃ OD, 200 MHz): δ 1.07 (t, J = 7.0 Hz, 3H), 1.74 (s, 2H) ₅ 2.50-2.60 (m, 2H) ₅ 2.68-3.10 (m, 5H), 3.15-3.25 (m, 3H), 3.50-3.62 (m, IH) ₅ 3.65 (s, 2H), 3.70-3.80 (m, IH) ₅ 4.09-4.16 (m ₅ 2H), 6.83 (d, J= 8.5 Hz, 2H), 7.18 (d, J= 8.3 Hz, 2H) ₅ 7.29-7.31 (m, 4H). Yield: 30%

Step 4: (2R)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(2 ₅ 4,5-trifluorobenzyl)-3-azabicyclo[3.1.0]- hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride

To a stirred solution (2R)-2-ethoxy-3-(4-{2-[(lα,5α,6α)-3-(2,4,5-trifluorobenzy l)-3- aza-bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid (0.22 g, 0.45 mmol) in dichloromethane (10 ml) was added 0.85M HCl-diethyl ether (1.07 ml, 0.9 mmol) at room temperature. After being stirred at room temperature for 1 h, dichloromethane was removed under reduced pressure at 30 ⁰ C. The solid so obtained, was dried under high vacuum in a desiccator over calcium chloride to yield the title compound (0.23 g, 92%). mp: 138-140 ⁰ C MS: m/z 479 (M+l)

¹ HNMR (CDC1 ₃ +CD ₃ OD _S 200 MHz): δ 1.04 (t, J = 6.9 Hz, 3H); 2.48-2.60 (m, 2H); 2.78- 2.96 (m, 2H); 3.21-3.50 (m, 9H); 3.55 (t, J = 5.1 Hz, IH); 4.11-4.25 (m, 4H); 6.78 (d, J= 8.1 Hz, 2H); 6.97-7.06 (m, IH); 7.07 (d, J= 7.9 Hz ₅ 2H); 7.70-7.78 (m, IH). Chiral Purity: 99.26%.

Example 9

2-Cyano-3-(4-{2-[(lα,5α,6α)-3-(3-fluorobenzyl)-3-azabi cyclo[3.1.0]hex-6-ylamino]- ethoxy}phenyl)propionic acid (Compound No 104)

Step 1 : 2-Cyano-3-(4-{2-[(lα,5α,6α)-[3-(3-fluorobenzyl)-3-azabicy clo[3.1.0]hex-6-yl]-4- (nitrobenzenesulfonyl)amino]ethoxy}phenyl)propionic acid ethyl ester

To a stirred solution of iV-[(lα,5α,6α)-3-(3-fluorobenzyl)-3-azabicyclo[3.1.0]hex- 6- yl]-4-nitrobenzenesulfonamide (prepared by following the same procedure as described in Intermediate 1; 0.9 g, 2.30 mmol) in dry acetonitrile (40 ml) was added anhydrous potassium carbonate (0.953 g, 6.90 mmol), 3-[4-(2-bromoethoxy)phenyl]-2-cyano-propionic acid ethyl ester (Intermediate 11; 1.00 g, 3.06 mmol) and potassium iodide (0.049 g, 0.23 mmol) at room temperature. The reaction mixture was stirred at 85-90 ⁰ C for 3 h. 3-[4-(2- Bromoethoxy)phenyl]-2-cyanopropionic acid ethyl ester (0.27 g, 0.82 mmol) was again added and heated at 80 ⁰ C for 3 h. The solvent was removed under reduced pressure and residue was diluted with dichloromethane (50 ml), washed with water (2x30 ml), dried over

anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get crude product, which was purified by column chromatography over silica gel (200-400 mesh) using dichloromethane as an eluent to yield the title compound (0.690 g, 47%).

MS: w/^ 637 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.17 (t, J= 7.1 Hz ₅ 3H), 2.03 (s, 2H), 2.40 (d, J= 8.9 Hz, 2H),

2.52 (s, H), 3.15 (d, J = 8.8 Hz ₅ 2H), 3.19-3.26 (m, 2H), 3.53-3.70 (m, 5H), 4.08-4.29 (m,

5H), 6.71-6.94 (m, 4H), 7.13-7.25 (m, 4H), 7.99 (d, J= 8.5 Hz, 2H), 8.34 (d, J= 8.6 Hz, 2H).

Step 2: 2-Cyano-3-(4-{2-[(lα,5α,6α)-3-(3-fluorobenzyl)-3-azabicyc lo[3.1.0]hex-6-ylamino]- ethoxy}phenyl)propionic acid ethyl ester (Compound No 8)

To a stirred solution of 2-cyano-3-(4-{2-[(lα,5α,6α)-[3-(3-fiuorobenzyl)-3- azabicyclo-[3.1.0]hex-6-yl]-4-(nitrobenzenesulfonyl)amino]et hoxy}phenyl)propionic acid ethyl ester (0.68 g,1.06 mmol) in dry acetonitrile (30 ml) was added anhydrous potassium carbonate (0.439 g, 3.18 mmol) under nitrogen atmosphere. The reaction mixture was cooled to 0 ⁰ C and thiophenol (0.47 g, 0.42ml, 4.27 mmol) was added and resulting reaction mixture was allowed to come to room temperature. After being stirred for 2 h, solvent was removed under reduced pressure and residue was taken in dichloromethane (25 ml), washed with water (2x25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 1.5->1.8% methanol-dichloromethane as an eluent to yield the title compound (0.30 Ig, 62%). MS: m/z 451 (M+l)

The following compounds were prepared by procedure similar to those described in

Compound No 8 with appropriate variations of reactants, reaction conditions and quantities of reagents.

2-Cyano-3-(4-{2-[(lα,5α,6α)-3-(2,4-difluorobenzyl)-3-azab icyclo[3.1.0]hex-6-ylamino]- ethoxy}phenyl)propionic acid ethyl ester (Compound No 1) ¹ HNMR (CDCl ₃ , 200 MHz): δ 1.27 (t, J= 7.1 Hz, 3H), 1.61 (s, 2H), 2.48-2.75 (m, 3H), 3.06- 3.19 (m, 6H), 3.63-3.75 (m, 3H), 4.05 (t, J= 5.0 Hz, 2H), 4.21 (q, J= 7.1 Hz, 2H), 6.73-6.87 (m, 4H), 7.15-7.19 (m, 3H). Yield: 62%

2-Cyano-3-(4-{2-[(lα,5α,6α)-3-(4-trifluoromethylbenzyl )-3-azabicyclo[3.1.0]hex-6-yl- amino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 4)

MS: m/z 502 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.29 (t, J= 7.1 Hz, 3H), 1.56 (s, 2H), 2.47-2.50 (m, 2H), 2.68

(s, IH), 3.02-3.21 (m, 7H), 3.64 (m, 2H), 4.05 (t, J= 5.0 Hz, 2H), 4.24 (q, J= 7.1 Hz, 2H), 6.85-6.89 (m, 2H), 7.16-7.21 (m, 2H), 7.41-7.45 (m, 2H), 7.55-7.59 (m, 2H).

Yield: 37%

3 - {4- [2-((l α,5α,6α)-3 -Benzyl-3 -azabicyclo [3.1.0]hex-6-ylamino)ethoxy]phenyl)-2-cyano- propionic acid ethyl ester (Compound No 6) MS: m/z 434 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.27 (t, J= 7.1 Hz, 3H), 1.58 (s, 2H), 2.40-2.50 (m, IH),

2.65-2.85 (m, 2H), 3.00-3.25 (m, 5H), 3.55-3.80 (m, 4H), 4.00-4.15 (m, 2H), 4.20 (q, J= 7.1

Hz, 2H), 6.83-6.87 (m, 2H), 7.14-7.38 (m, 7H).

Yield: 61%

2-Cyano-3-(4-{2-[(lα,5α,6α)-3-(4-trifluoromethoxybenzy l)-3-azabicyclo[3.1.0]hex-6-yl- amino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 5)

MS: rø/z 518 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.29 (t, J = 7.1 Hz, 3H), 1.52 (s, IH) ₅ 1.93 (brs, IH, exchangeable with D ₂ Q), 2.48 (d, J= 8.8 Hz, 2H) ₅ 2.65 (s, IH), 3.00-3.25 (m, 6H) ₅ 3.55-3.75 (m, 3H) ₅ 4.05 (t, J= 5.0 Hz, 2H) ₅ 4.25 (q, J= 7.1 Hz, 2H) ₅ 8.87 (d, J= 8.6 Hz ₅ 2H) ₅ 7.14-7.36 (m, 6H). Yield: 43%

2-Cyano-3 -(4-{2-[(lα,5α,6α)-3 -(4-fluorobenzyl)-3 -azabicyclo [3.1.0]hex-6-ylamino] - ethoxy}phenyl)propionic acid ethyl ester (Compound No 2)

MS: w/z 452 (M+l) ¹ HNMR (CDCl ₃ , 200 MHz): δ 1.29 (t, J= 7.1 Hz ₅ 3H) ₃ 1.61 (s, 2H) ₅ 2.40-2.50 (m, IH) ₅

2.55-2.85 (m, 2H), 2.97-3.25 (m, 5H) ₅ 3.55 (s, IH) ₅ 3.65-3.80 (m, 3H) ₅ 4.00- 4.15 (m, 2H) ₅

4.25 (q, J= 7.2 Hz ₅ 2H), 6.80-6.89 (m, 2H), 7.00-7.10 (m, 2H) ₅ 7.16-7.20 (m, 4H) ₅ 7.30-7.45

(m, IH).

Yield: 57%

3-(4-{2-[(lα,5α,6α)-3-(4-Chlorobenzyl)-3-azabicyclo[3. 1.0]hex-6-ylamino]ethoxy}- phenyl)-2-cyanopropionic acid ethyl ester (Compound No S)

MS: »n/z 468 (M+1)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.21 (t, J= 7.6 Hz, 3H), 1.43 (s, 2H) ₅ 2.32-2.42 (m, 2H) ₅ 2.56 (s, IH) ₅ 2.90-3.20 (m ₅ 6H) ₅ 3.53 (s, 2H) ₅ 3.60-3.70 (m, IH), 4.02 (t, J= 5.1 Hz ₅ 2H),

4.20 (q, J= 7.1 Hz ₅ 2H), 6.80-6.90 (m, 2H), 7.10-7.25 (m, 6H).

Yield: 40%

2-Cyano-3-(4-{2-[(lα,5α,6α)-3-(2,4 ₅ 5-trifluorobenzyl)-3-azabicyclo[3.1.0]hex-6- ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 7) MS: m/z 488 (M+l)

¹ HNMR (CDCl ₃₅ 200 MHz): δ 1.20-2.35 (m, 3H) ₅ 1.48 (s, 2H) ₅ 2.20 (brs, IH ₅ exchangeable with D ₂ O), 2.44 (d, J= 8.4 Hz, 2H), 2.96 (s, IH), 2.95-3.20 (m, 6H) ₅ 3.56 (s, 2H) ₅ 3.60-3.70

(m, IH), 4.04 (t, J= 4.8 Hz, 2H) ₅ 4.22 (q, J = 7.1 Hz, 2H), 6.75-7.00 (m, 3H), 7.10-7.25 (m,

3H).

Yield: 45%

Step 3: 2-Cydno-3-(4-{2-[(lα,5α,6α)-3-(3-fluorobenzyl)-3-azabicyc lo[3.1.0]hex-6-ylamino]- ethoxy}phenyl)propionic acid

To a stirred solution of 2-cyano-3-(4-{2-[(lα,5α,6α)-3-(3-fluorobenzyl)-3- azabicyclop.l.Ol-hex-ό-ylaminoJethoxyjphenyrjpropionic acid ethyl ester (0.285 g, 0.63 mmol) in dioxane (6.0 ml) was added solution of sodium hydroxide (0.075 g, 1.89 mmol) in water (6.0 ml) drop wise at 0 ⁰ C. After being stirred at 0 ⁰ C for 0.5 h, dioxane was removed under reduced pressure at 35 ⁰ C. The aqueous layer was neutralized with IM HCl at 0 ⁰ C to pR 6 under stirring. The resulting reaction mixture was stirred at 0 ⁰ C for 0.5' h and the solid separated was filtered through the Buchner funnel, washed with cold water (2x10 ml). The solid so obtained was taken in 10% methanol-dichloromethane (25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and solvent was removed under reduced pressure to get a crude product. The crude product was taken in 10% dichloromethane-diethyl ether (15 ml) stirred for 5 min, filtered and washed with diethyl ether (2x5 ml). It was finally dried under high vacuum in a desiccator over calcium chloride to yield the title compound (0.211 g, 79%). mp: 149-151 ⁰ C

MS: m/z AlA (M+l)

¹ HNMR (CD ₃ OD, 200 MHz): δ 1.61 (s, 2H), 2.49 (d, J= 8.6 Hz, 2H), 2.67 (s, lH), 2.99 (d, J = 9.2 Hz, 2H), 3.02-3.21 (m, 4H), 3.46-3.55 (m, IH), 3.60 (s, 2H), 4.09 (t, J= 5.0 Hz, 2H), 6.81-7.10 (m, 5H), 7.20-7.35 (m, 3H). ,

The following compounds were prepared by procedure similar to those described in Compound No 104 with appropriate variations of reactants, reaction conditions and quantities of reagents.

2-Cyano-3-(4-{2-[(lα,5α,6α)-3-(2 ₅ 4-difluorobenzyl)-3-azabicyclo[3.1.0]hex-6-ylamino]- ethoxy}phenyl)propionic acid (Compound No 97) mp: 162-163 ⁰ C MS: m/z 442 (M+ 1)

¹ HNMR (CDC1 ₃ +CD ₃ OD, 200 MHz): δ 1.92 (s, 2H), 2.64- 2.69 (m, 2H), 2.97 (s, IH), 3.09- 3.14 (m, 3H), 3.43-3.50 (m, 2H), 3.60-3.70 (m, ^' IH), 3.74 (s, 2H), 4.20 (s,-4H), 6.89-6.96 (m,

4H), 7.22-7.38 (m, 3H). N ' ^' Yield: 72%

2-Cyano-3-(4-{2-[(lα,5α,6α)-3-(4-trifluoromethylbenzyl )-3-azabicyclo[3.1.0]hex-6- ylamino]ethoxy}phenyl)propionic acid (Compound No 100) mp: 163-164 °C

MS: m/z 474 (M+l)

¹ HNMR (CDC1 ₃ +CD ₃ OD, 200 MHz): δ 1.97 (s, 2H), 2.65- 2.70 (m, 2H), 3.04-3.17 (m, 5H),

3.44 (s, 2H), 3.50-3.65 (rri, IH) ₅ 3.79 (s, 2H), 4.15-4.3 (m, 2H), 6.89-6.93 (m, 2H), 7.15-7.30 (m, 2H), 7.40-7.85 (m, 4H).

Yield: 88%

3-{4-[2-((lα,5α,6α)-3-Benzyl-3-azabicyclo[3.1.0]hex-6-yla mino)ethoxy]phenyl)-2-cyano- propionic acid (Compound No 102) mp: 130-131 ⁰ C , MS: m/z 406 (M+l)

¹ HNMR (CD ₃ OD, 200 MHz): δ 2.03 (s, 2H), 2.90 (s, IH), 3.00 (d, J= 7.7 Hz, 2H), 3.12 (d, J = 9.6 Hz, 2H), 3.20-3.40 (m, 5H), 4.01 (s, 2H), 4.10-4.20 (m, 2H), 6.91 (d, J= 8.5 Hz, 2H), 7.21 (d, J= 8.4 Hz, 2H), 7.38-7.46 (m, 5H).

Yield: 88%

2-Cyano-3-(4-{2-[(lα,5α ₅ 6α)-3-(4-trifluoromethoxybenzyl)-3-azabicyclo[3.1.0]hex-6- ylamino]ethoxy}phenyl)propionic acid (Compound No 101) nip: 149-151 ⁰ C MS: rø/z490 (M+l)

¹ HNMR (CD ₃ OD+CDC1 ₃ , 200 MHz): δ 1.97 (s, 2H), 2.77 (d, J= 9.2 Hz, 2H), 2.97 (s, IH), 3.00-3.06 (m, 2H), 3.19 (d, J= 9.7 Hz, 2H), 3.32-3.38 (m, 2H), 3.82 (s, IH), 4.12-4.25 (m, 2H), 6.92 (d, J= 8.3 Hz, 2H), 7.24 (d, J= 8.2 Hz, 4H) ₅ 7.43 (d, J- 8.4 Hz, 2H). Yield: 88% ^'

2-Cyano-3-(4-{2-[(l α,5α,6α)-3-(4-fluorobenzyl)-3-azabicyclo[3.1.0]hex-6-ylam ino]- ethoxy}phenyl)ρropionic acid (Compound No 98) mp: 147-149 ⁰ C MS: m/z 424 (M+l)

¹ HNMR (CD ₃ OD, 200 MHz): δ 1.96 (s, 2H), 2.8-2.95 (m, 3H), 3.00-3.10 (m, 2H), 3.19-3.40 (m, 4H), 3.87 (s, 2H), 4.15-4.20 (m, 3H) ₅ 6.90-6.94 (m ₅ 2H), 7.04-7.39 (m, 6H). Yield: 78%

3-(4-{2-[(lα,5α,6α)-3-(4-Chlorobenzyl)-3-azabicyclo[3.1.0 ]hex-6-ylamino]ethoxy}- phenyl)-2-cyanopropionic acid (Compound No 99) mp: 144-146 ⁰ C

¹ HNMR (CD ₃ OD, 200 MHz): δ 1.99 (s, 2H) ₅ 2.80-2.90 (m, 2H), 2.95-3.10 (m, 3H), 3.15- 3.22 (m, 2H) ₅ 3.30-3.40 (m, 2H), 3.50-3.60 (m, IH), 3.83 (s, 2H) ₅ 4.15- 4.25 (m, 2H) ₅ 6.90

(d, J= 8.5 Hz ₅ 2H), 7.20 (d ₅ J= 8.4 Hz ₅ 2H) ₅ 7.34 (s, 4H).

Yield: 82%

2-Cyano-3-(4-{2-[(lα,5α,6α)-3-(2,4,5-trifluorobenzyl)-3-a zabicyclo[3.1.0]hex-6-ylaniino]- ethoxy}phenyl)propionic acid (Compound No 103) mp: 163-165 ⁰ C

MS: m/z 460 (M+l)

¹ HNMR (CD3OD+CDCI3, 200 MHz): δ 2.00 (s, 2H), 2.70 (d, J= 9.0 Hz, 2H), 3.09-3.20 (m,

5H), 3.51-3.54 (m, 2H), 3.76 (s, 2H), 3.89-3.96 (m, IH), 4.22-4.28 (m, 2H) ₅ 6.96 (d, J= 8.5

Hz, 2H), 7.06-7.35 (m, 4H).

Yield: 79%

Example 10

(2S)-3-(4-{2-[(lα,5α,6α)-3-(2,4-Bistrifluorometliylben zyl)-3-azabicyclo[3.1.0]hex-6-yl- amino] ethoxy }phenyl)-2-(4-tert-butylphenoxy)propionic acid dihydrochloride

(Compound No 114)

Step 1: (2S)-3-[4-(2-{(lα,5α,6α)-[3-(2,4-Bistrifluoromethylbenzyl )-3-azabicyclo[3.1.0]hex- 6-yl]-tert-butoxycarbonylamino}ethoxy)phenyl]-2-(4-tert-buty lphenoxy)propionic acid ethyl ester

To a stirred solution of (2S)-3-(4-{2-[(lα,5α,6α)-(3-azabicyclo[3.1.0]hex-6-yl)-te rt- butoxy-carbonylamino] ethoxy }phenyl)-2-(4-tert-butylphenoxy)propionic acid ethyl ester

(Intermediate 12; 0.500 g, 0.88 mmol) in dry acetonitrile (20 ml) was added anhydrous potassium carbonate (0.365 g, 2.65 mmol) and 2,4-bistrifluoromethylbenzyl bromide (0.298 g, 0.18 ml., 0.97 mmol) at room temperature and resulting reaction mixture was heated at 55 ⁰ C for 3 h. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane (50 ml) and water (20 ml). Organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to yield a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using chloroform as an eluent to yield the title compound (0.590 g, 84%). MS: mlz 793 (M+l) ¹ HNMR (CDCl ₃ , 200MHz): δ 1.17-1.25 (m, 12H), 1.45 (s, 9H), 1.72 (s, 2H), 2.49 (d, J= 8.3 Hz, 2H), 2.95 (s, IH), 3.06-3.17 (m, 4H), 3.56 (t, J= 5.2 Hz, 2H), 3.79 (s, 2H), 4.05 (t, J = 5.2 Hz, 2H), 4.18 (q, J= 7.1 Hz, 2H), 4.68 (t, J= 6.1 Hz, IH), 6.77 (t, J= 8.3 Hz, 4H), 7.18- 7.25 (m, 4H), 7.70-7.85 (m, 3H).

Step 2: (2S)-3-(4-{2-[(lα,5α,6α)-3-(2,4-Bistrifluoromethylbenzyl) -3-azabicyclo[3.1.0]hex- 6-ylamino]ethoxy}phenyl)-2-(4-ter^butylphenoxy)propionic acid ethyl ester (Compound No 17)

A solution of 20% v/v trifiuoroacetic acid-dichloromethane (6 ml) was added to (2S)- 3-[4-(2-{(lα,5α,6α)-[3-(2,4-bistrifluoromethylbenzyl)-3-a zabicyclo[3.1.0]hex-6-yl]-fert- butoxy-carbonylamino}ethoxy)phenyl]-2-(4-tert-butylphenoxy)p ropionic acid ethyl ester (0.575 g, 0.726 mmol) at 0 ⁰ C under stirring and resulting mixture was stirred for 2 h at the same temperature. The reaction mixture was allowed to come to room temperature and the progress of the reaction was monitored by TLC. The reaction was completed in approximately 2 h. The solvent was removed under reduced pressure to yield a crude product as its TFA salt. The residue was dissolved in dichloromethane (20 ml). To this mixture was

added a solution of ammonia-dichloromethane drop wise at 0 ⁰ C under stirring, until the salt was neutralized completely. Salt separated out was filtered off and the filtrate was ^" evaporated to dryness to get crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 0.5->1.0% methanol-dichloromethane as an eluent to yield the title compound (0.445 g, 88%). MS: m/z 693 (M+l)

¹ HNMR (CDCl ₃ , 200MHz): δ 1.17-1.25 (m, 12H), 1.68 (s, 2H), 2.43 (d, J = 8.5 Hz, 2H), 2.70 (s, IH), 3.00 (d, J = 8.7 Hz, 2H), 3.09-3.16 (m, 4H), 3.76-3.80 (m, 2H), 4.07-4.23 (m, 4H) ₅ 4.68 (t, J= 6.1 Hz, IH), 6.73-6.85 (m, 4H), 7.18-7.26 (m, 4H), 7.70-7.85 (m, 3H).

The following compounds were prepared by procedure similar to those described in Compound No 17 with appropriate variations of reactants, reaction conditions and quantities of reagents. (2S)-2-(4-^rt-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4-trif luoromethylbenzyl)-3-aza- bicycloβ .1.0]hex~6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 16) MS: m/z 625 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.15-1.30 (m, 12H), 1.58 (s, 2H), 2.44 (d, J = 8.6 Hz, 2H), 2.67 (s, IH), 2.95-3.20 (m, 6H), 3.64 (s, 2H), 4.06 (t, J = 4.9 Hz ₅ 2H) ₅ 4.19 (q, J = 7.0 Hz, 2H) ₅ 4.70 (t ₅ J= 5.8 Hz, IH), 6.70-6.90 (m, 4H), 7.15-7.25 (m, 4H), 7.40 (d, J= 7.9 Hz ₅ 2H), 7.56 (d, J= 8.1 Hz, 2H). Yield: 90%

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-cyc lohexylmethyl-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 34) MS: m/z 563 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 0.82-0.87 (m, 2H), 1.15-1.30 (m, 16H) ₅ 1.45-1.60 (m, 2H), 1.65-1.85 (m, 7H) ₅ 2.10-2.30 (m, IH), 2.30-2.35 (m, 2H) ₅ 3.00-3.05 (m ₅ 2H), 3.12-3.16 (m, 4H) ₅ 4.01 (t, J= 5.1 Hz, 2H) ₅ 4.17 (q, J= 7.0 Hz ₅ 2H), 4.68 (t, J= 6.8 Hz, IH) ₅ 6.70-6.85 (m, 4H), 7.15-7.30 (m, 4H).

Yield: 93%

Step 3: (2S)-3-(4-{2-[(lα ₅ 5α,6α)-3-(2,4-Bistrifluoromethylbenzyl)-3-azabicyclo[3.1.0 ]hex-

6-ylamino]ethoxy}phenyl)-2-(4-ter^butylphenoxy)propionic acid

To a stirred solution of (2S)-3-(4-{2-[(lα,5α,6α)-3-(2,4-bistrifluoromethylbenzyl) -3- aza-bicyclo[3.1.0]hex-6-ylamino]ethoxy }phenyl)-2-(4-tert-butylphenoxy)propionic acid ethyl ester (0.430 g, 0.62 mmol) in methanol (45 ml) and water (10 ml) was added a solution of sodium carbonate (0.330 g, 3.11 mmol) in water (12 ml) drop wise at 0 ⁰ C. The reaction mixture was allowed to come to room temperature and stirred for 15 h. Solvent was removed under reduced pressure at 35 ⁰ C. The aqueous layer was neutralized by adding IM HCl at 0 ⁰ C to pR 6 under stirring. The resulting reaction mixture was stirred at 0 ⁰ C for 0.5 h and solid separated out was filtered through a Buchner funnel, washed with cold water (2x10 ml). The solid so obtained was taken 10% methanol-dichloromethane (50 ml) and sonicated for 5 min. The undissolved solid was filtered off through a Buchner funnel. The filtrate was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get a crude product. The crude product was taken in 10% dichloromethane-diethyl ether (15 ml), sonicated at 40 ⁰ C for 5 min, filtered and washed with diethyl ether (2x5 ml). It was finally dried under high vacuum in a desiccator over calcium chloride to yield the title compound (0.390 g, 94%).

MS: mlz 665(M+1)

¹ HNMR (DMSO-d _tf , 200 MHz): δ 1.19 (s, 9H), 1.34-1.41 (m, 2H) ₅ 2.35-2.50 (m, 3H), 2.89 (d, J= 8.2 Hz, 4H), 2.99-3.16 (m, 2H), 3.75 (s, 2H), 3.95-3.97 (m, 2H), 4.67 (t, J= 3.6 Hz, IH), 6.70 (d, J= 8.7 Hz, 2H) ₃ 6.81 (d, J= 8.4 Hz, 2H) ₅ 7.19 (d, J= 8.6 Hz, 4H) ₅ 7.86-8.03 (m, 3H).

Step 4: (2S)-3-(4-{2-[(lα ₅ 5α,6α)-3-(2,4-Bistrifluoromethylbenzyl)-3-azabicyclo[3.1.0 ]hex-

6-ylamino]ethoxy}phenyl)-2-(4-tert-butylphenoxy)propionic acid dihydrochloride

To a stirred suspension of (2S)-3-(4-{2-[(lα,5α,6α)-3-(2,4- bistrifluoromethylbenzyl)-3-aza-bicyclo[3.1.0]hex-6-ylamino] ethoxy}phenyl)-2-(4-tert- butylphenoxy)propionic acid (0.380 g, 0.57 mmol) in dry dichloromethane (110 ml), was added 0.85M HCl-diethyl ether (0.042 g, 1.35 ml, 1.14 mmol) drop wise over a period of 10 min at room temperature. The resulting mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and the solid so obtained was dried under high vacuum in a desiccator over calcium chloride to yield the title compound (0.385 g, 91%). mp: 166-167 ⁰ C MS: m/z 665 (M+l)

¹ HNMR (DMSO-^ ₃ 200 MHz): δ 1.15 (s, 9H), 2.23 (s, 2H), 3.01-3.12 (m, 3H), 3.25- 3.41 (m, 4H), 4.10-4.20 (m, 2H), 4.34 (s, 2H), 4.70-4.81 (m, IH), 6.68 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 7.21 (d, J= 8.4 Hz, 4H), 7.99-8.10 (m, 3H), 9.84 (brs, IH, exchangeable with D ₂ O), 11.80 (brs, IH, exchangeable with D ₂ O).

The following compounds were prepared by procedure similar to those described in Compound No 114 with appropriate variations of reactants, reaction conditions and quantities of reagents.

(2S)-2-(4-fert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4- trifluoromethylbenzyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride (Compound No

US) mp: 156-157 ⁰ C MS: m/z 597 (M+l)

¹ HNMR 200 MHz): δ 1.21 (s, 9H), 2.41 (s, 2H), 3.05-3.10 (m, 3H) ₅ 3.37- 3.47 (m, 6H), 4.21-4.24 (m, 2H) ₅ 4.41 (s, 2H), 4.77-4.83 (m, IH), 6.73 (d, J = 8.6 Hz, 2H), 6.93 (d, J= 8.4 Hz ₅ 2H), 7.24 (d, J= 8.5 Hz, 4H), 7.80-7.87 (m, 4H), 9.85 (brs, IH, exchangeable with D ₂ O), 11.69 (brs, IH ₅ exchangeable with D ₂ O). Yield: 99%

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-cycloh exylmethyl-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride (Compound No 131) mp: 181-183 ⁰ C MS: m/z 535 (M+l)

¹ HNMR (DMSO-d ₆ +D ₂ O, 400 MHz): δ 0.84-0.90 (m, 2H), 1.05-1.26 (m, 13H), 1.59-1.64 (m, 4H), 1.70-1.74 (m, 2H) ₅ 2.34 (s, 2H), 2.79-2.97 (m, 2H), 3.04-3.12 (m, 2H), 3.35 (s, 2H), 3.38-3.78 (m, 4H), 4.21 (s, 2H) ₅ 4.78 (t, J= 7.6 Hz ₅ IH), 6.71 (d, J= 8.0 Hz ₅ 2H) ₅ 6.91 (d, J = 8.0 Hz ₅ 2H) ₅ 7.20-7.24 (m, 4H). Yield: 88%

Example 11

(2S)-2-(4-fert-Butylphenoxy)-3 -(4- {2- [( 1 α,5α,6α)-3-(3,5-difluorobenzenesulfonyl)-3 -aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid hydrochloride

(Compound No 143)

Step 1 : (2S)-3-[4-(2-{(lα,5α,6α)-tert-Butoxycarbonyl-[3-(3,5-difl uorobenzenesulfonyl)-3- azabicyclo [3.1.0]hex-6-yl] amino } ethoxy)phenyl] -2-(4-fert-butylphenoxy)propionic acid ethyl ester

To a stirred solution of (2S)-3-(4-{2-[(lα,5α,6α)-(3-azabicyclo[3.L0]hex-6-yl)-ter t- butoxy-carbonylamino]ethoxy}phenyl)-2-(4-tert-butylplienoxy) propionic acid ethyl ester (Intermediate 12; 0.6 g, 1.06 mmol) in dry dichloromethane (20 ml) was added a solution of 3,5-difluorobenzenesulfonyl chloride (0.225 g, 0.14 ml, 1.06 mmol) in dichloromethane (5 ml), and triethylamine (0.32 g, 0.45 ml, 3.18 mmol) at 0 ⁰ C. The reaction mixture was allowed to come at room temperature and stirred for 1.5 h. Reaction mixture was washed with water (2x20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced . pressure to get a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 1.0-M.5% methanol-dichloromethane as an eluent to yield the title compound (0.609 g, 77%). MS: mlz 743 (M+l)

¹ HNMR (CDCl ₃ , 400MHz): δ 1.20-1.25 (m, 12H) ₅ 1.44 (s, 9H), 1.84 (s, 2H), 3.15 (s, IH), 3.15-3.17 (m, 4H), 3.53-3.62 (m, 4H), 4.01 (t, J= 4.8 Hz, 2H), 4.16-4.22 (m, 2H), 4.67-4,70 (m, IH), 6.77 (d, J= 8.8 Hz, 4H), 6.99-7.03 (m, IH), 7.20-7.26 (m, 4H), 7.31-7.33 _. (m, 2H).

Step 2: (2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(3,5-d ifluorobenzenesulfonyl)- S-azabicyclop.l.OJhex-δ-ylaminoJethoxyjphenyrjpropionic acid ethyl ester (Compound No 45)

To a stirred solution of (2S)-3-[4-(2-{(lα,5α,6α)-tert-butoxycarbonyl-[3-(3,5- difluoro-benzenesulfonyl)-3-azabicyclo[3.1.0]hex-6-yl]amino} ethoxy)phenyl]-2-(4-tert- butyl-phenoxy)propionic acid ethyl ester (0.599 g, 0.795 mmol) in dichloromethane (10 ml) was added trifluoroacetic acid (1.84 g, 1.2 ml, 16.1 mmol) at 0 ⁰ C. Reaction mixture then was allowed to come at room temperature and stirred for 3 h. The solvent was removed under reduced pressure to yield a crude product as its TFA salt. The residue was dissolved in dichloromethane (25 ml). To this mixture was added a solution of ammonia-chloroform drop wise at 0 ⁰ C under stirring, until the salt was neutralized completely. Salt separated out was filtered off and the filtrate was evaporated to dryness to yield the title compound (0.379g,

MS: m/z 643 (M+l)

¹ HNMR (CDCl ₃ , 400 MHz): δ 1.18-1.25 (m, 12H), 1.63 (s, 2H), 2.10 (s, IH), 2.79-3.30 (m,

5H), 3.57-3.70 (m, 4H), 4.08-4.24 (m, 3H), 4.41-4.60 (m, IH), 6.73-6.82 (m, 3H), 6.92-7.05

(m, IH), 7.21-7.33 (m, 7H).

The compound given below was prepared by procedure similar to those described in

Compound No 45 with appropriate variations of reactants, reaction conditions and quantities of reagents.

(2S)-3-(4-{2-[(lα,5α,6α)-3-(Butane-l-sulfonyl)-3-azabi cyclo[3.1.0]hex-6-ylamino]ethoxy}- phenyl)-2-(4-tert-butylphenoxy)propionic acid ethyl ester (Compound No 46)

MS: m/z 587 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 0.97 (t, J = 7.3 Hz, 3H), 1.20-1.28 (m, 12H), 1.30-1.50 (m,

2H), 1.70-1.85 (m, 4H), 2.36 (s, IH), 2.90-3.00 (m, 2H), 3.05-3.25 (m, 4H), 3.39 (d, J= 9.1

Hz, 2H), 3.60 (d, J= 9.4Hz, 2H), 4.10 (t, J= 5.4 Hz, 2H), 4.22 (q, J= 7.0 Hz, 2H), 4.73 (t, J = 6.0 Hz, IH), 6.75-6.90 (m, 4H), 7.20-7.30 (m, 4H). /

Yield: 85%

Step 3: (2S)-2-(4-ført-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(3,5- difluorobenzenesulfonyl)- 3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid

To a stirred solution of (2S)-2-(4-tert-butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(3,5- difluoro-benzenesulfony^-S-azabicyclofS.l.Olhex-ό-ylaminoje thoxylpheny^propionic acid ethyl ester (0.36 g, 0.560 mmol) in methanol (70 ml) and water (20 ml) was added a solution of sodium carbonate (0.297 g, 2.80 mmol) in water (10 ml) drop wise at room temperature. After being stirred at room temperature, for 15 h, methanol was removed under reduced pressure at 35 ⁰ C. The aqueous layer was neutralized by adding IM HCl at 0 ⁰ C to pR 6 under stirring. The resulting reaction mixture was stirred at 0 ⁰ C for 0.5 h and solid separated out was filtered through a Buchner funnel, washed with cold water (2x10 ml). The solid so obtained was taken 10% methanol-dichloromethane (50 ml) and sonicated for 5 min. The undissolved solid was filtered off through a Buchner funnel and filtrate was dried over anhydrous Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure to get a crude product. The crude product was taken in 10% dichloromethane-diethyl ether (15 ml), sonicated at 40 ⁰ C for 5 min, filtered and washed with diethyl ether (2x5 ml). It was finally dried under high vacuum in a desiccator over calcium chloride to yield the title compound (0.260 g, 75%). mp: 190-192 °C MS: w/z 615 (M+l) ¹ HNMR (CDCl ₃ , 200 MHz): δ 1.19 (s, 9H), 1.86 (s, 2H), 2.33 (s, IH), 3.00-3.18 (m, 6H), 3.53-3.57 (m, 2H), 3.91-4.05 (m, 2H), 4.55-4.70 (m, IH) ₅ 6.70-6.78 (m, 5H), 6.90-7.03 (m, IH), 7.17-7.25 (m, 5H).

Step 4: (2S)-2-(4-ter/-Butylphenoxy)-3-(4-{2-[(lα ₅ 5α ₅ 6α)-3-(3,5-difluorobenzenesulfonyl)- 3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid hydrochloride

To a stirred solution of (2S)-2-(4-tert-butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(3,5- difluoro-benzenesulfony^-S-azabicyclofS.l.Olhex-ό-ylaminoJe thoxyJpheny^propionic acid (0.25 g, 0.407 mmol) in dry dichloromethane (25 ml), was added 0.85M HCl-diethyl ether (0.014g, 0.45 ml, 0.407 mmol) at room temperature. Reaction mixture was stirred at room temperature for 0.5 h. The solvent was removed under reduced pressure and the solid so obtained was dried under high vacuum to yield the title compound (0.23 g, 87%). mp: 194-196 °C MS: rø/z 615 (M+l)

¹ HNMR (DMSO-tfo 200 MHz): δ 1.21 (s, 9H), 2.14 (s, 2H), 2.64 (s, IH), 3.08-3.12 (m, 4H), 3.37 (s, 2H), 3.50 (d, J= 9.6 Hz, 2H), 4.22 (s, 2H), 4.80 (t, J= 6.9 Hz, IH), 6.74 (d, J= 8.5 Hz ₅ 2H), 6.89 (d, J- 8.3 Hz, 2H), 7.22-7.28 (m, 4H), 7.51 (d, J= 4.4 Hz, 2H), 7.69 (t, J= 8.0 Hz, IH), 9.80 (brs, IH, exchangeable with D ₂ O).

The compound given below was prepared by procedure similar to those described in

Compound No 143 with appropriate variations of reactants, reaction conditions and quantities of reagents.

(2S)-3-(4-{2-[(l α,5α,6α)-3-(Butane-l -sulfonyl)-3-azabicyclo[3.1.0]hex-6-ylamino]- ethoxy}phenyl)-2-(4-tert-butylphenoxy)propionic acid hydrochloride (Compound No 144) mp: 198-200 °C

MS: m/z 559 (M+l)

¹ HNMR (DMSO-βfo 200 MHz): δ 0.87 (t, J= 7.1 Hz, 3H), 1:21 (s, 9H), 1.31-1.42 (m, 2H), 1.56-1.64 (m, 2H), 2,19 (s, 2H), 2.69 (s, IH), 3.03-3.10 (m, 4H), 3.33-3.41 (m, 6H), 4.25 (s, 2H), 4.77 (t, J= 7.4 Hz, IH), 6.71 (d, J= 8.6 Hz, 2H), 6.90 (d, J= 8.4 Hz, 2H), 7.20-7.26 (m, 4H), 9.75 (brs, IH, exchangeable with D ₂ O). Yield: 98%

Example 12

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-o-t olylthiocarbamoyl-3-azabicyclo-

[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid hydrochloride (Compound No 146)

Step 1 : (2S)-3-(4-{2-[(lα,5α,6α)-tert-Butoxycarbonyl-(3-o-tolylth iocarbamoyl-3-aza- bicyclo[3.1.0]hex-6-yl)amino]ethoxy}phenyl)-2-(4-/ert-butylp henoxy)propionic acid ethyl ester

To a stirred solution of (2S)-3-(4-{2-[(lα,5α,6α)-(3-azabicyclo[3.1.0]hex-6-yl)-/e rt- butoxy-carbonylamino]ethoxy}phenyl)-2-(4-tert-butylphenoxy)p ropionic acid ethyl ester (Intermediate 12; 0.5 g, 0.883 mmol) in dry dichloromethane (15 ml) was added diisopropylethyl amine (0.17Og., 0.23 ml, 1.32 mmol) under N ₂ atmosphere at room temperature. Reaction mixture was cooled to 0 ⁰ C and o-tolyl isothiocyante (0.145g, 0.130 ml, 0.97 mmol) was added to it under stirring. Reaction mixture was allowed to come at room temperature and stirred for 3 h. Reaction mixture was diluted with dichloromethane (50 ml), washed with water (1x10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 1.5-^2.0% methanol-dichloromethane as an eluent to yield the title compound (0.58 g, 92%).

MS,: rø/z 717 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.19 (t, J= 7.2 Hz, 3H), 1.25 (s, 9H), 1.46 (s, 9H), 2.02 (brs, 2H), 2.15 (brs, 9H), 2.25 (s, 3H), 2.44 (brs, 9H), 3.14-3.17 (m, 2H), 3.54-3.77 (m, 4H), 4.04- 4.18 (m, 5H), 4.66 (t, J = 6.2 Hz, IH), 6.70 (d, J = 8.8 Hz, 2H), 6.69 (d, J = 8.8 Hz, 2H), 7.18^7.28 (m, 8H).

Step 2: (2S)-2-(4-fert-Butylphenoxy)-3-(4-{2-[(l α,5α,6α)-3-o-tolylthiocarbamoyl-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 48)

To a stirred solution of (2S)-3-(4-{2-[(lα,5α,6α)-tert-butoxycarbonyl-(3-o-tolylth io- carbamoyl-3-azabicyclo[3.1.0]hex-6-yl)amino]ethoxy}phenyl)-2 -(4-tert-butylphenoxy)- propionic acid ethyl ester (0.58 g, 0.81 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (1.77g, 1.16 ml, 15.52 mmol) at 0 ⁰ C. Reaction mixture was stirred at 0 ⁰ C for 1 h. The reaction mixture was allowed to come at room temperature and stirred for 2 h. The solvent was removed under reduced pressure to yield a crude product as its TFA salt. The residue was dissolved in dichloromethane (2 ml). To this mixture was added a solution of ammonia-chloroform drop wise at 0 ⁰ C under stirring, until the salt was neutralized completely. Salt separated out was filtered off and the filtrate was evaporated to dryness to yield the crude product, which was purified by column chromatography over silica gel (100- 200 mesh) using 2.0->2.5% methanol-dichloromethane as an eluent to yield the title compound (0.430 g, 86%). MS: m/z 616 (M+l)

¹ HNMR (CDCl ₃ , 400 MHz): δ 1.20-1.35 (m, 12H), 1.95 (s, 2H), 2.20 (s, IH), 2.27 (s, 3H), 3.14-3.25 (m, 4H), 3.74-4.21 (m, 10H), 4.72 (t, J= 6.0Hz, IH), 6.77 (d, J= 8.4Hz, 2H), 6.87 (d, J= 8.4 Hz, 2H), 7.23-7.30 (m, 8H).

The following compounds were prepared by procedure similar to those described in Compound No 48 with appropriate variations of reactants, reaction conditions and quantities of reagents.

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α ₃ 6α)-3-(2,4,6-trifluorophenylcarbamoyl)-3- azabicyclop.l.OJhex-ό-ylaminoJethoxylphenytypropionic acid -ethyl ester (Compound No 31)

MS: m/z 640 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.15-1.30 (m, 12H), 1.86 (s, 2H), 2.19 (s, IH), 3.10-3.20 (m, 4H), 3.50-3.68 (m, 4H), 4.05-4.25 (m, 4H), 4.71 (t, J= 6.0 Hz, IH), 6.65-6.80 (m, 4H), 6.85 (d, J= 8.5 Hz, 2H), 7.20-7.30 (m, 4H). Yield: 98%

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2, 5-difluorophenylcarbamoyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 29) MS: m/z 622 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.15-1.30 (m, 12H) ₃ 1.84 (s, 2H), 2.14 (s, IH), 3.05-3.20 (m, 4H), 3.45-3.85 (m, 4H), 4.07 (t, J= 4.8 Hz, 2H), 4.17 (q, J= 6.9 Hz, 2H), 4.69 (t, J= 5.9 Hz, IH), 6.35-6.40 (m, IH), 6.55-6.65 (m, IH), 6.70-6.85 (m, 4H), 6.90-7.05 (m, IH), 7.15-7.30 (m, 4H), 7.95 -8.05 (m, IH). Yield: 93%

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(2,6-d ifluorophenylcarbamoyl)-3-aza- bicyclotS.l.Ojhex-ό-ylaminojethoxyJpheny^propionic acid ethyl ester (Compound No 30) MS: m/z 622 (M+l) ¹ HNMR (CDCl ₃ , 200 MHz): δ 1.15-1.30 (m, 12H), 1.85 (s, 2H), 2.20 (s, IH), 3.10-3.20 (m, 4H), 3.45-3.55 (m, 2H), 3.60-3.70 (m, 2H), 4.05-4.25 (m, 4H), 4.69 (t, J= 6.0 Hz, IH), 6.70- 6.95 (m, 6H), 7.00-7.25 (m, 5H). Yield: 97%

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-(4-chl orobenzenesulfonylamino- carbonyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)pro pionic acid ethyl ester (Compound No 47) MS: m/z 706 (M+23) ¹ HNMR (CDCI ₃ +CD ₃ OD, 400 MHz): δ 1.14-1.23 (m, 12H), 1.80-1.90 (m, 2H), 3.05-3.40 (m, 12H), 4.00-4.15 (m, 4H), 4.65 (t, J= 6.0 Hz, IH), 6.68-6.79 (m, 4H), 7.12-7.19 (m, 4H), 7.40 (d, J= 8.4 Hz, 2H), 7.89 (d, J= 8.4Hz, 2H). Yield: 88%

Step 3: (2S)-2-(4-fert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-o-toly lthiocarbamoyl-3- azabicyclo [3.1.0]hex-6-ylamino] ethoxy } phenyl)propionic acid

To a stirred solution of (2S)-2-(4-tert-butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-o- tolylthio-carbamoyl-3-azabicyclo[3.1.0]hex-6-ylaniino]ethoxy }phenyl)propionic acid ethyl ester (0.36 g, 0.585 mmol), in methanol (32 ml) and water (7 ml), was added a solution of sodium carbonate (0.309 g, 2.92 mmol) in water (8 ml) in a drop wise manner at 0° C. The reaction mixture was allowed to come at room temperature and stirred for 15 h. Methanol was removed under reduced pressure at 35 ⁰ C. The aqueous layer was neutralized by adding IM HCl at 0 ⁰ C topH 6 under stirring: The resulting reaction mixture was stirred at 0 ⁰ C for 0.5 h and solid separated out was filtered through a Buchner funnel, washed with cold water (2x10 ml). The solid so obtained was taken in 10% methanol-dichloromethane (50 ml) and sonicated for 5 min. The undissolved solid was filtered off through a Buchner funnel. The filtrate was dried over anhydrous Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure to get a crude product. The crude product was taken in 10% dichloromethane-diethyl ether (15 ml), sonicated at 40 ⁰ C for 5 min, filtered and washed with

diethyl ether (2x5 ml). It was finally dried under high vacuum in a desiccator over calcium chloride to yield the title compound (0.290 g, 84 %). MS: mlz 588 (M+l)

¹ HNMR (CDC1 ₃ +CD ₃ OD, 200 MHz): δ 1.21 (s, 9H), 2.19 (s, 3H), 2.20-2.34 (m, 3H), 3.14 (d, J = 5.8 Hz, 2H), 3.22-3.38 (m, 3H), 3.55-3.69 (m, 3H), 3.80-4.08 (m, 2H) ₅ 4.12-4.22 (m, 2H), 4.66 (t, J= 5.4 Hz, IH), 6.71 (d, J= 8.6 Hz, 2H) ₅ 6.81 (d. ₅ J= 8.6 Hz, 2H) 7.17-7.28 (m, 8H).

Step 4: (2S)-2-(4-tert-Butylphenoxy)-3-(4- {2-[(l α,5α,6α)-3-o-tolylthiocarbamoyl-3- azabicyclofS.l.OJhex-ό-ylaminoJethoxyJpheny^propionic acid hydrochloride

To a stirred solution of (2S)-2-(4-/ert-butylphenoxy)-3-(4-{2-[(lα,5α,6α)-3-o- tolylthio-carbamoyl-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy} phenyl)propionic acid (0.25 g ₅ 0.425 mmol) in dichloromethane (60 ml) was added 0.85M HCl-diethyl ether (0.5 ml, 0.425 mol) in a drop wise manner at room temperature. After the addition was completed, the reaction mixture was stirred at room temperature for 1 h. Solvent was removed under reduced pressure and resulting solid was dried under high vacuum in a desiccator over calcium chloride to yield the title compound (0.248 g, 93%). mp: 164-166 ⁰ C MS: m/z 588 (M+l)

¹ HNMR (DMSO-J ₆ , 400 MHz): δ 1.21 (s, 9H), 2.14 (s, 3H), 2.29 (s, 2H), 2.66 (s, IH), 3.03- 3.14 (m, 3H), 3.35-3.52 (m, 4H), 3.82-3.99 (m, 2H), 4.27 (m, 2H), 4.80-4.84 (m, IH), 6.74 (d, J = 8.4 Hz, 2H), 6.92 (d, J= 8.4 Hz, 2H), 7.04 (s, IH), 7.15-7.28 (m, /H), 8.82 (s, IH, exchangeable with D ₂ O), 9.71 (brs, IH ₅ exchangeable with D ₂ O).

The following compounds were prepared by procedure similar to those described in Compound No 146 with appropriate variations of reactants, reaction conditions and quantities of reagents.

(2S)-2-(4-ter/-Butylphenoxy)-3-(4-{2-[(lα _s 5α,6α)-3-(2,4,6-trifluorophenylcarbamoyl)-3- azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid hydrochloride (Compound No 128) mp: 170-171 ⁰ C MS: rø/z 612 (M+l)

¹ HNMR (DMSO-^, 200 MHz): δ 1.21 (s, 9H), 2.19 (s, 2H), 2.63 (s, IH), 3.07-3.11 (m, 2H), 3.38-3.45 (m, 4H), 3.65 (d, J- 10.5 Hz, 2H), 4.24-4.27 (m, 2H), 4.78-4.84 (m, IH) ₅ 6.74 (d, J= 8.6 Hz, 2H), 6.92 (d, J= 8.3 Hz, 2H), 1.11-1.29 (m, 6H), 8.02 (s, IH, exchangeable with D ₂ O), 9.58 (brs, IH, exchangeable with D ₂ O). Yield: 99%

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(l α,5α,6α)-3-(2,5-difluorophenylcarbamoyl)-3-aza- bicyclop.l.OJhex-ό-ylaminoJethoxylphenytypropionic acid hydrochloride (Compound No

126) mp: 148-149 ⁰ C

MS: m/z 594 (M+l) ¹ HNMR (DMSO-J ₆ , 200 MHz): δ 1.21 (s, 9H), 2.18 (s, 2H), 2.60 (s, IH), 2.98-3.11 (m, 2H),

3.39-3.44 (m, 4H), 3.71 (d, J= 10.5 Hz, 2H), 4.25-4.27 (m, 2H), 4.79-4.81 (m, IH), 6.73 (d,

J= 8.5 Hz, 2H), 6.92 (d, J= 7.8 Hz, 3H), 7.17-7.28 (m, 5H), 7.40-7.55 (m, IH), 8.08 (s, IH, exchangeable with D ₂ O), 9.80 (brs, IH, exchangeable with D ₂ O).

Yield: 83%

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5ά,6α)-3-(2, 6-difluorophenylcarbamoyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid hydrochloride (Compound No

127) mp: 182-183 ⁰ C

MS: m/z 594 (M+l)

¹ HNMR (DMSO-dβ, 200 MHz): δ 1.21 (s, 9H), 2.19 (s, 2H), 2.62 (s, IH), 3.00-3.20 (m, 2H), 3.32-3.50 (m, 4H), 3.67 (d, J= 10.5 Hz, 2H) ₅ 4.24-4.27 (m, 2H), 4.78-4.84 (m, IH), 6.73 (d, J= 8.5 Hz, 2H), 6.92 (d, J= 8.2 Hz, 2H), 7.05-7.13 (m, 2H), 7.22-7.29 (m, 5H), 8.04 (s, IH, exchangeable with D ₂ O), 9.65 (brs, IH, exchangeable with D ₂ O). Yield: 85%

(2S)-2-(4-tert-Butylphenoxy)-3 -(4- {2-[( 1 ά,5 α,6α)-3 -(4-chlorobenzenesulfonylamino- carbonyl)-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)pro pionic acid hydrochloride (Compound No 145) mp: 162-164 ⁰ C

MS: m/z 678 (M+23)

¹ HNMR (CDCl^CD ₃ OD, 400 MHz): δ 1.21 (s, 9H), 2.12-2.25 (m, 3H), 3.16-3.64 (m, 10H),

4.11-4.24 (m, 2H), 4.77 (s, IH), 6.74 (d, J = 8.0 Hz, 2H), 6.73-6.84 (m, 2H), 7.13-7.26 (m, 4H), 7.37 (s, 2H), 7.82-7.89 (m, 2H).

Yield: 93%

Example 13

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-6-(3- trifluoromethylbenzylamino)-3-aza- bicyclo[3.1.0]hex-3-yl]ethoxy}phenyl)propionic acid dihydrochloride (Compound No 165)

Step . 1: (2S)-2-(4-fer/-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-6-(3-tri fluoromethylbenzyl- amino)-3-azabicyclo[3.1.0]hex-3-yl]ethoxy}phenyl)propionic acid ethyl ester (Compound No 69)

To a stirred solution of (2S)- 3-(4-{-[2-[(lα,5α,6α)-6-amino-3-azabicyclo[3.1.0]hex- 3-yl]-ethoxy}phenyl)-2-(4-tert-butyrphenoxy)propionic acid ethyl ester (Intermediate 15; 0.72 g, 1.54 mmol) in ethanol (25 ml) was added 3-trifluoromethylbenzaldehyde (0.269 g, 1.54 mmol) at room temperature and resulting reaction mixture was stirred at same temperature for 3 h. To this reaction mixture, glacial acetic acid (1.0 ml) and sodium ^" cyanoborohydride (0.291 g, 4.63 mmol) were added at room temperature and the resulting reaction mixture was stirred at room temperature for further 1 h. The progress of reaction was monitored by TLC. The solvent was removed under reduced pressure and residue was dissolved in ethyl ' acetate (100 ml), washed with water (2x20 ml), saturated sodium bicarbonate solution (1x10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 1.4->1.8% methanol-chloroform as an eluent to yield the title compound (0.620 g, 64%). MS: m/z 626 (M+2)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.11-1.26 (m, 12H), 1.47-1.49 (m, 2H), 2.58-2.66 (m, 3H), 2.91 (brs, 2H), 3.13-3.18 (m, 4H), 3.85 (s, 2H), 4.08-4.23 (m, 4H), 4.69 (t, J= 5.9 Hz, IH), 6.78 (t, J= 8.8 Hz, 4H), 7.18-7.26 (m, 4H), 7.41-7.55 (m, 4H).

The following compounds were prepared by procedure similar to those described in

Compound No 69 with appropriate variations of reactants, reaction conditions and quantities of reagents.

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-6-(4- chlorobenzylamino)-3-azabicyclo- [3.1.0]hex-3-yl]ethoxy}phenyl)propionic acid ethyl ester (Compound No 72) MS: m/z 591 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.15-1.30 (m, 12H), 1.48 (s, 2H), 2.45-2.65 (m, 3H), 2.85- 2.95 (m, 2H) ₅ 3.10-3.25 (m, 4H) ₅ 3.76 (s, 2H) ₅ 4.07 (t, J= 5.4 Hz, 2H) ₅ 4.18 (q, J= 6.9 Hz ₅ 2H) ₅ 4.69 (t, J= 5.9 Hz ₅ IH), 6.78 (t, J= 8.7 Hz ₅ 4H) ₅ 7.18-7.33 (m, 8H). Yield: 84%

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα ₅ 5α ₅ 6α)-6-(4-trifluoromethylbenzylamino)-3- azabicycloβ.l.Ojhex-S-ylJethoxyjphenytypropionic acid ethyl ester (Compound No 70) MS: m/z 626 (M+2)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.15-1.30 (m, 12H) ₅ 1.49 (s, 2H), 2.45-2.70 (m, 3H) ₅ 2.85- 3.00 (m, 2H) ₅ 3.10-3.25 (m, 4H) ₅ 3.84 (s, 2H) ₅ 4.05-4.25 (m, 4H), 4.69, (t, J= 5.8 Hz ₅ IH) ₅ 6.78 (t, J= 8.7 Hz ₅ 4H) ₅ 7.15-7.25 (m, 4H) ₅ 7.40 (d, J= 8.2 Hz, 2H), 7.56 (d, J= 8.3 Hz, 2H). Yield: 70% ' .

(2S)-2-(4-ter/-Butylphenoxy)-3-(4-{2-[(lα,5α ₅ 6α)-6-(2 ₅ 4 ₅ 5-trifluorobenzylamino)-3- azabicyclo[3.1.0]hex-3-yl]ethoxy}phenyl)propionic acid ethyl ester (Compound No 71)

MS: w/z 612 (M+2)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.15-1.30 (m, 12H) ₅ 1.47 (s, 2H) ₅ 2.50-2.65 (m, 3H) ₅ 2.85-

2.95 (m, 2H) ₅ 3.10-3.20 (m, 4H) ₅ 3.77 (s, 2H) ₅ 4.08 (t, J = 5.4 Hz ₅ 2H) ₅ 4.18 (q, J= 6.7 Hz,

2H) ₅ 4.69 (t, J= 5.8 Hz ₅ IH), 6.70-6.95 (m, 4H) ₅ 7.05-7.25 (m, 6H). Yield: 73%

Step 2: (2S)- 2-(4-tert-Butylphenoxy)- 3-(4-{2-[(lα ₅ 5α ₅ 6α)-6-(3-trifluoromethylbenzyl- amino)-3-azabicyclo[3.1.0]hex-3-yl]ethoxy}phenyl)propionic acid

To a stirred solution of (2S)- 2-(4-tert-butylphenoxy)-3-(4-{2-[(lα,5α,6α)-6-(3- trifluoro-methylbenzylamino)-3-azabicyclo[3.1.0]hex-3-yl]eth oxy}plienyl)propionic acid ethyl ester (0.600 g, 0.96 mmol) in methanol (60 ml) and water (8 ml) was added a solution of sodium carbonate (0.510 g, 4.81 mmol) in water (22 ml) drop wise manner at 0 ⁰ C. The reaction mixture was allowed to come to room temperature and stirred for 15 h. Solvent was removed under reduced pressure at 35 ⁰ C and the aqueous layer was neutralized by adding IM HCl at 0 ⁰ C to pα 6 under stirring. The resulting mixture was stirred at 0 ⁰ C for 0.5 h and the solid separated out was filtered through suction, washed, with cold water (2x10 ml) and dried. The solid so obtained was taken in 10% methanol-dichloromethane (25 ml) and sonicated for 5. min, the undissolved solid was filtered off. The filtrate was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get a crude product. The crude product was taken into 10% dichloromethane-diethyl ether (25 ml), sonicated at 40 ⁰ C for 5 min, filtered and washed with diethyl ether (2x10 ml). It was finally dried under high vacuum in a desiccator over calcium chloride to yield the title compound (0.420 g, 73%). MS: m/z 598 (M+2)

¹ HNMR (DMSO-ck, 200 MHz): δ 1.21 (s, 9H), 1.50 (s, 2H), 2.35 (s, IH), 2.56 (s, 2H), 2.79- 2.81 (m, 2H), 2.99-3.06 (m, 4H) ₃ 3.87 (s, 2H), 3.93 (t, J = 5.3 Hz, 2H), 4.74 (t, J = 7.4 Hz, IH), 6.71-6.83 (m, 4H), 7.18-7.25 (m, 4H), 7.50-7.66 (m, 3H), 7.23 (s, IH).

Step 3: (2S)-2-(4-ført-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-6-(3-tr ifluoromethylbenzyl- amino)-3-azabicyclo[3.1.0]hex-3-yl]ethoxy}phenyl)propionic acid dihydrochloride

To a stirred suspension of (2S)-2-(4-tert-butylphenoxy)-3-(4-{2-[(lα,5α,6α)-6-(3- trifluoro-methylbenzylamino)-3-azabicyclo[3.1.0]hex-3-yl]eth oxy}phenyl)propionic acid (0.300 g, 0.50 mmol) in dry dichloromethane (90 ml), was added 0.85M HCl-diethyl ether

(0.036 g, 1.17 ml, 1.00 mmol) drop wise over a period of 10 min at room temperature. Suspension was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and the solid so obtained, was. dried under high vacuum in a desiccator over calcium . chloride to yield the title compound (0.300 g, 89%). mp: 147-150 °C MS: m/z 598 (M+2)

¹ HNMR (DMSO-^, 200 MHz): δ 1.21 (s, 9H), 2.42 (s, 2H), 2.99-3.16 (m, 3H), 3.38-3.55 (m, 4H), 3.56-3.71 (m, 2H), 4.20-4.39 (m, 4H), 4.78-4.84 (m, IH), 6.74 (d, J= 8.7 Hz, 2H), 6.90 (d, J= 8.5 Hz, 2H), 7.22-7.29 (m, 4H), 7.60-7.68 (m, IH), 7.77 (d, J= 7.8 Hz, IH), 7.89 (d, J = 7.3 Hz, IH), 8.00 (s, IH), 10.10 (brs, IH, exchangeable with D ₂ O), 11.37 (brs, IH, exchangeable with D ₂ O).

The following compounds were prepared by procedure similar to those described in Compound No 165 with appropriate variations of reactants, reaction conditions and quantities of reagents.

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-6-(4-chl orobenzylamino)-3-azabicyclo- [3.1.0]hex-3-yl]ethoxy}phenyl)propionic acid dihydrochloride (Compound No 168) mp: 174-176 ⁰ C MS: m/z 563 (M+l) ¹ HNMR (DMSO-ύk, 200 MHz): δ 1.21 (s, 9H), 2.41 (s, 2H), 2.99-3.16 (m, 3H), 3.30-3.50 (m, 4H), 3.60-3.62 (m, 2H), 4.14 (s, 2H), 4.31 (s, 2H), 4.78-4.84 (m, IH), 6.74 (d, J= 8.7 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 7.22-7.29 (m, 4H), 7.47 (d, J= 8.2 Hz, 2H), 7.60 (d, J= 8.3 Hz, 2H), 10.11 (brs, IH, exchangeable with D ₂ O), 11.38 (brs, IH, exchangeable with D ₂ O). Yield: 88% ,

(2S)-2-(4-tert-Butylphenoxy)-3-(4-{2-[(lα,5α,6α)-6-(4- trifluoromethylbenzylamino)-3- azabicyclo[3.1.0]hex-3-yl]ethoxy}phenyl)propionic acid dihydrochloride (Compound No

166) mp: 191-193 ⁰ C

MS: m/z 598 (M+2)

¹ HNMR (DMSO-^ ₅ 200 MHz): δ 1.21 (s, 9H), 2.44 (s, 2H) ₅ 2.99-3.16 (m, 3H), 2.45-2.60 (m, 4H) ₅ 3.61-3.65 (m, 2H) ₅ 4.24-4.27 (m, 4H), 4.78-4.84 (m, IH), 6.74 (d, J= 8.6 Hz, 2H) ₅ 6.90 (d ₅ J= 8.4 Hz, 2H) ₅ 7.22-7.29 (m ₅ 4H), 7.78-7.80 (m, 4H) ₅ 10.20 (brs, IH, exchangeable with D ₂ O) ₅ 11.35 (brs, 1 H ₅ exchangeable with D ₂ O). Yield: 89%

(2S)-2-(4-ter/-Butylphenoxy)-3-(4-{2-[(lα,5α ₅ 6α)-6-(2 ₅ 4 ₅ 5-trifluorobenzylamino)-3-aza- bicyclo[3.1.0]hex-3-yl]ethoxy}phenyl)propionic acid dihydrochloride (Compound No 167) mp: 166-168 ⁰ C MS: m/z 583 (M+l)

¹ HNMR (DMSO-cfo 200 MHz): δ 1.21 (s, 9H) ₅ 2.41 (s ₅ 2H) ₅ 2.99-3.10 (m ₅ 3H) ₅ 3.34-3.51 (m, 4H) ₅ 3.60-3.64 (rn ₅ 2H) ₅ 4.16 (s ₅ 2H) ₅ 4.30-4.32 (m, 2H) ₅ 4.77-4.80 (m, IH) ₅ 6.74 (d, J = 8.5 Hz ₅ 2H) ₅ 6.90 (d ₅ J = 8.2 Hz ₅ 2H) ₅ 7.22-7.28 (m, 4H) ₅ 7.57-7.71 (m ₅ IH) ₅ 7.85-7.93 (m ₅ IH) ₅ 10.25 (brs, IH, exchangeable with D ₂ O), 11.45 (brs, IH, exchangeable with D ₂ O). Yield: 91%

Example 14

(2S)-3-(4-{2-[(lα ₅ 5α,6α)-l-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)-3-(4-trifl uoromethyl- phenyl)ureido]ethoxy}phenyl)-2-(4-tert-butylphenoxy)propioni c acid hydrochloride

(Compound No 148)

.HCl

Step 1: (2S)-3-(4-{2-[(lα,5α,6α)-l-(3-Benzyl-3-azabicyclo[3.1.0]h ex-6-yl)-3-(4-trifluoro- methylphenyl)ureido]ethoxy}phenyl)-2-(4-tert-butylphenoxy)pr opionic acid ethyl ester (Compound No 50)

To a solution of (2S)-3-(4-{2-[(lα,5α,6α)-3-berizyl-3-azabicyclo[3.1.0]hex -6- ylamino]-ethoxy}phenyl)-2-(4-tert-butylphenoxy)propionic acid ethyl ester (Intermediate 12, Step 3; 0.300 g, 0.54 mmol) in dichloromethane (10 ml) was added a solution of A- trifluoromethyl-phenyl isocynate (0.1 g, 0.076 ml, 0.54 mmol) in dichloromethane (5 ml) at 0 ⁰ C. The reaction mixture was allowed to come to room temperature and stirred for 2 h. The reaction mixture was diluted with dichloromethane (25 ml), washed with water (2x25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get the crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 0.4->0.6% methanol-dichloromethane as an eluent to yield the title compound (0.34 g, 85%). MS: m/z 744 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.19-1.61 (m, 14H), 1.72 (s, 2H), 2.01 (br s, 2H), 2.63 (m, 2H), 3.10-3.18 (m, 4H), 3.61-3.78 (m, 2H), 4.11-4.18 (m, 3H), 4.66 (t, J= 7.2 Hz, IH), 6.73- 6.79 (m, 4H), 7.16-7.25 (m, 5H), 7.28-7.44 (m, 4H), 7.44-7.56 (m, 4H).

The following compounds were prepared by procedure similar to those described in Compound No 50 with appropriate variations of reactants, reaction conditions and quantities of reagents.

(2S)-3-(4-{2-[(lα,5α,6α)-l-(3-Benzyl-3-azabicyclo[3.1. 0]hex-6-yl)-3-methylthioureido]- ethoxy}phenyl)-2-(4-tert-butylphenoxy)propionic acid ethyl ester (Compound No 40) MS: m/z 630 (M+l)

¹ HNMR (CDCl ₃ , 200 MHz): δ 1.18-1.25 (m, 12H) ₅ 1.94 (s, 2H), 2.60 (s, 2H), 3.05-3.40 (m, 8H), 3.70 (s, 2H), 4.13-4.23 (m, 6H), 4,60-4.78 (m, IH), 6.73-6.79 (m, 4H), 7.14-7.33 (m, 9H). Yield: 82%

Step 2: (2S)-3-(4-{2-[(lα,5α,6α)-l-(3-Benzyl-3-azabicyclo[3.1.0]h ex-6-yl)-3-(4-trifluoro- methylphenyl)ureido]ethoxy}phenyl)-2-(4-tert-butylphenoxy)pr opionic acid

To a solution of (2S)-3-(4-{2-[(lα,5α,6α)-l-(3-benzyl-3-azabicyelo[3.1.0]h ex-6-yl)-

3-(4-trifluoromethylphenyl)ureido]ethoxy}phenyl)-2-(4-tert-b utylphenoxy)propionic acid ethyl ester (0.328 g, 0.44 mmol) in THF (30 ml) was added a solution of lithium hydroxide monohydrate (0.092 g, 2.20 mmol) in water (15 ml) drop wise at 0 ⁰ C under stirring. The reaction mixture was allowed to come to room temperature and stirred for 6 h. Solvent was removed under reduced pressure at 35 ⁰ C and the aqueous layer was neutralized by adding IM HCl at 0 ⁰ C to/?H 6 under stirring. The resulting mixture was stirred at 0 ⁰ C for 0.5 h and the solid separated out was filtered through suction, washed with cold water (2x10 ml) and dried. The solid so obtained was taken in 10% methanol-dichloromethane (50 ml) and

sonicated for 5 min the undissolved solid was filtered off. The filtrate was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get a crude product.

The crude product was taken into diethyl ether (25 ml), stirred for 10 min, filtered and washed with diethyl ether (2x10 ml). It was finally dried under high vacuum in a desiccator over calcium chloride to yield the title compound (0.198 g, 63%). mp: 158-16O ⁰ C

MS: w/z 716 (M+l)

¹ HNMR (CDCl ₃ , 400 MHz): δ 1.21 (s, 9H), 2.01 (s, 2H), 2.84-3.25 (m. 5H) ₅ 3.51-3.72 (m,

4H), 4.08-4.18 (m, 4H) ₅ 4.75-4.80 (ni, IH), 6.72 (d, J= 8.4 Hz ₅ 2H), 6.83 (d, J= 6.0 Hz, 2H) ₅

7.14-7.20 (m, 4H), 7.28-7.44 (m, 7H) ₅ 7.61-7.69 (m, 2H).

Step 3: (2S)-3-(4-{2-[(lα ₅ 5α,6α)-l-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)-3-(4-trifl uoro- methylphenyl)ureido]ethoxy}phenyl)-2-(4-tert-butylphenoxy)pr opionic acid hydrochloride

To a solution of (2S)-3-(4-{2-[(lα,5α,6α)-l-(3-benzyl-3-azabicyclo[3.1.0]h ex-6-yl)-

3-(4-trifluoromethylphenyl)ureido]ethoxy}phenyl)-2-(4-tert-b utylphenoxy)propionic acid (0.180 g, 0.252 mmol) in dichloromethane (20 ml) was added 1.12M HCl-ethyl acetate (0.009 g, 0.22 ml, 0.25 mmol) drop wise over a period of 10 min at room temperature. Suspension was stirred at room temperature for 0.5 h. The solvent was removed under reduced pressure and the solid so obtained, was dried under high vacuum in a desiccator over calcium chloride to yield the title compound (0.182 g, 96%). mp: 164-166 ⁰ C MS: m/z 716 (M+l)

¹ HNMR (CDCl ₃ , 400 MHz): δ 1.24 (s, 9H) ₅ 2.04 (s, 2H), 2.87-3.27 (m, 5H), 3.55-3.78 (m,

4H), 4.08-4.20 (m, 4H), 4.78-4.82 (m, IH), 6.72 (d, J= 8.4 Hz, 2H), 6.80 (d, J= 6.0 Hz, 2H),

7.16-7.23 (m, 4H), 7.30-7.46 (m, 7H), 7.62-7.66 (m, 2H), 11.04 (brs, IH, exchangeable with

D ₂ O).

The following compounds were prepared by procedure similar to those described in

Compound No 148 with appropriate variations of reactants, reaction conditions and quantities of reagents.

(2S)-3-(4-{2-[(lα,5α,6α)-l-(3-Benzyl-3-azabicyclo[3.1. 0]hex-6-yl)-3-methylthioureido]- ethoxy}phenyl)-2-(4-fert-butylphenoxy)propionic acid hydrochloride (Compound No 138)

MS: m/z 602 (M+l)

¹ HNMR (DMSO-J ₁ J, 200 MHz): δ 1.21 (s, 9H), 2.22 (s, 2H), 2.75-3.2 (m, 5H), 3.28-3.50 (m,

4H), 3.69-3.74 (m, 2H), 4.10 (s, 3H), 4.25 (s, 2H) ₃ 4.68-4.80 (m, IH), 6.73 (d, J = 8.6 Hz,

2H) 6.93' (d, J= 8.3 Hz, 2H), 7.18-7.65 (m, 9H). Yield: 96%

Example 15

(2S)-3-(4-{2-[(lα,5α,6α)-(3-Benzyl-3-azabicyclo[3.1.0] hex-6-yl)-tert-butoxycarbonyl- amino]ethoxy}phenyl)-2-(4-fert-butylphenoxy)propionic acid (Compound No 135)

Step 1 : (2S)-3-(4-{2-[(lα,5α,6α)-(3-Benzyl-3-azabicyclo[3.1.0]hex -6-yl)-tert-butoxy- carbonylamino]ethoxy}phenyl)-2-(4-fert-butylphenoxy)propioni c acid ethyl ester (Compound No 37)

To a solution of (2S)-3-(4-{2-[(lα,5α,6α)-3-berizyl-3-azabicyclo[3.1.0]hex -6- ylamino]-ethoxy}phenyl)-2-(4-tert-butylphenoxy)propionic acid ethyl ester (Intermediate 12, Step 3; 0.400 g, 0.719 mmol) in dichloromethane (10 ml) was added triethylamine (7.26 mg, 0.01 ml, 0.719 mmol) fert-butoxycarbonyl anhydride (172 mg, 0.791 mmol) at room temperature. After being stirred for 2 h at same temperature solvent was removed under reduced pressure to get a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 0.5HM.0% methanol-dichloromethane as an eluent to yield the title compound (0.424 g, 90%). MS: m/z 657 (M+l)

¹ HNMR (CDCl ₃ , 400 MHz): δ 1.22 (t, J= 7.2 Hz, 3H), 1.25 (s, 9H), 1.43 (s, 9H), 1.59-1.71 (m, 3H), 2.31-2.52 (m, IH) 2.90-3.01 (m, 2H), 3.13-3.21 (m, 3H), 3.42-3.61 (m, 4H), 4.04 (t, J= 4.0 Hz, 2H), 4.12-4.30 (m, 2H), 4.61-4.78 (m, IH), 6.70-6.82 (m, 4H), 7.15-7.39 (m, 9H).

Step 2: (2S)-3-(4-{2-[(lα,5α,6α)-(3-Benzyl-3-azabicyclo[3.1.0]hex -6-yl)-tert-butoxy- carbonylamino]ethoxy}phenyl)-2-(4-tert-butylphenoxy)propioni c acid

To a stirred solution of (2S)-3-(4-{2-[(lα,5α,6α)-(3-benzyl-3-azabicyclo[3.1.0]hex -

6-yl)-ført-butoxycarbonylamino]ethoxy}phenyl)-2-(4-tert-but ylphenoxy)propionic acid ethyl ester (0.400 g, 0.609 mmol) in THF (20 ml) was added a solution of lithium hydroxide monohydrate (127.9 mg, 3.048 mmol) in water (10 ml) drop wise at 0 ⁰ C. The reaction

mixture was allowed to come to room temperature and stirred for 14 h. Solvent was removed under reduced pressure at 35 ⁰ C and the aqueous layer was neutralized by adding 10% HCl at 0 ⁰ C to pR 6 under stirring. The resulting mixture was stirred at 0 ⁰ C for 0.5 h and the solid separated out was filtered through suction, washed with cold water (2x10 ml) and dried. The solid so obtained was taken in 10% methanol-dichloromethane (20 ml) and sonicated for 5 min the undissolved solid was filtered off. The filtrate was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to yield the title compound (0.355 g, 92%). mp: 73-75 ⁰ C MS: m/z 629 (M+l)

¹ HNMR (CDCl ₃ , 400 MHz): δ 1.21 (m, 3H), 1.30-1.40 (s, 9H), 1.45-1.52 (s, 9H), 1.70-1.89 (m, 2H), 2.50-2.61 (m, IH) ₅ 2.80-2.90 (m, 2H), 3.01-3.20 (m, 2H), 3.20-3.31 (m, IH), 3.70- 3.90 (m, 3H), 4.01- 4.02 (m, IH), 4.12-4.20 (m, IH), 6.51-6.89 (m, 4H), 7.01-7.59 (m, 9H).

Example 16 (2S)-3-(4-{2-[(lα,5α,6α)-(3-Benzyl-3-azabicyclo[3.1.0]hex -6-yl)-(3-methylbenzoyl)amino]- ' ethoxy}phenyl)-2-(4-tert-butylphenoxy)propionic acid hydrochloride (Compound No 137)

Stepl: (2S)-3-(4-{2-[(lα,5α,6α)-(3-Benzyl-3-azabicyclo[3.1.0]hex -6-yl)-(3-methyl- benzoyl)amino]ethoxy}phenyl)-2-(4-ter?-butylphenoxy)propioni c acid ethyl ester (Compound No 39)

To a stirred solution of (2S)-3-(4-{2-[(lα,5α,6α)-3-benzyl-3-azabicyclo[3.1.0]hex- 6- yl-amino]ethoxy}phenyl)-2-(4-fert-butylphenoxy)propionic acid ethyl ester (Intermediate 12, Step 3; 0.400 g, 0.719 mmol) in dichloromethane (30 ml) was added triethylamine (0.22 g, 0.3 ml, 2.157 mmol) under N ₂ atmosphere at room temperature. The reaction mixture was cooled to 0 ⁰ C and to this was added 3-methylbenzoyl chloride (0.12 g, 0.10 ml, 0.791 mmol) under stirring and the resulting reaction mixture was stirred at 0-10 ⁰ C for 2 h. After completion of reaction, reaction mixture was diluted with dichloromethane (50 ml), washed with water (1x20 ml), dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to yield crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 2^2.5% methanol-dichloromethane as an eluent to yield the title compound (0.414 g, 85%). MS: m/z 676 (M+l)

¹ HNMR (CDCl ₃ , 400 MHz): δ 1.10-1.41 (m, 12H), 2.04-2.36 (m, 6H), 2.58-2.72 (m, 2H), 3.16-3.25 (m, 3H), 3.41-3.53 (m, 2H), 3.75-3.89 (m, 2H), 4.11-4.25 (m, 5H), 4.69 (t, J= 5.2 Hz, IH), 6.76 (d, J= 8.8 Hz, 2H), 6.85 (d, J= 8.0 Hz, 2H), 7.14-7.31 ,(m, 13H).

The compound given below was prepared by procedure similar to those described in Compound No 39 with appropriate variations of reactants, reaction conditions and quantities of reagents.

(2S)-3-(4-{2-[(lα,5α,6α)-(3-Benzyl-3-azabicyclo[3.1.0] hex-6-yl)acetylamino]ethoxy}- phenyl)-2-(4-ført-butylphenoxy)propionic acid ethyl ester (Compound No 38) MS: m/z 599 (M+l)

¹ HNMR (CDCl ₃ , 400 MHz): δ 1.21 (t, J= 7.2 Hz, 3H); 1.25 (s, 9H), 1.65-1.82 (m, 3H); 2.17 (s, 3H); 2.38-2.45 (m, IH), 3.08-3.18 (m, 5H), 3.54-3.67 (m, 4H); 4.05 (t, J = 5.2 Hz, 2H); 4.16-4.21 (m, 2H), 4.64-4.68 (m, IH), 6.74-6.77 (m, 4H), 7.15-7.30 (m, 9H). Yield: 91%

Step 2: (2S)-3-(4-{2-[(lα,5α,6α)-(3-Benzyl-3-azabicyclo[3.1.0]hex -6-yl)-(3-methyl- benzoyl)amino]ethoxy}phenyl)-2-(4-tert-butylphenoxy)propioni c acid

To a stirred solution of (2S)-3-(4-{2-[(lα,5α,6α)-(3-benzyl-3-azabicyclo[3.1.0]hex - 6-yl)-(3-methylbenzoyl)amino]ethoxy}phenyl)-2-(4-tert-butylp henoxy)propionic acid ethyl ester (0.360 g, 0.534 mmol) in THF (36 ml) was added a solution of lithium hydroxide monohydrate (0.049 g, 1.068 mmol) in water (18 ml) drop wise at 0 ⁰ C. The reaction mixture was allowed to come to room temperature and stirred for 4 h. Solvent was removed under reduced pressure at 35 ⁰ C and the aqueous layer was neutralized by adding IM HCl at 0 ⁰ C to pH 6 under stirring. The resulting mixture was stirred at 0 ⁰ C for 0.5 h and the solid separated out was filtered through suction, washed with cold water (2x5 ml) and dried. The solid so obtained was taken in 10% methanol-dichloromethane (20 ml) and sonicated for 5 min the undissolved solid was filtered off. The filtrate was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get a crude product. The crude product was taken into diethyl ether (10 ml), stirred for 5 min, filtered and washed with diethyl ether (1x5 ml). It was finally dried under high vacuum in a desiccator over calcium chloride to yield the title compound (0.290 g, 84%).

MS: m/z 647 (M+l)

¹ HNMR (CDCl ₃ H-CD ₃ OD, 200 MHz): δ 1.20 (s, 9H), 1.60-1.71 (m, 2H), 2.32 (s, 3H), 2.58- 2.89 (m, 3H), 2.90-3.18 (m, 4H), 3.25-3.42 (m, IH), 3.68-3.97 (m, 4H), 4.10-4.24 (m, 2H), 4.61-4.74 (m, IH), 6.67-6.68 (m, 4H), 7.08-7.38 (m, 13H).

Step 3: (2S)-3-(4-{2-[(lα,5α,6α)-(3-Benzyl-3-azabicyclo[3.1.0]hex -6-yl)-(3-methyl- benzoyl)amino]ethoxy}phenyl)-2-(4-tert-butylphenoxy)propioni c acid hydrochloride

To a stirred solution of (2S)-3-(4-{2-[(lα,5α,6α)-(3-benzyl-3-azabicyclo[3.1.0]hex - 6-yl)-(3-methylbenzoyl)amino]ethoxy}phenyl)-2-(4-tert-butylp henoxy)propionic acid (0.2 g, 0.309 mmol) in dichloromethane (45 ml) was added O.85M HCl-diethyl ether (0.011 g, 0.37 ml, 0.309 mmol) drop wise over a period of 10 min at room temperature. Suspension was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and the solid so obtained, was dried under high vacuum in a desiccator over calcium chloride to yield the title compound (0.195 g, 92%). mp: 160-162 °C MS: m/z 647 (M+l)

¹ HNMR (CDCl^CD ₃ OD,' 200 MHz): δ 1.24 (s, 9H), 1.58-1.85 (m, 4H), 2.37 (s, 3H), 2.81- 3.22 (m, 6H), 3.61-3.82 (m, 2H), 4.00 (s, 2H), 4.27 (brs, 2H), 4.78 (t, J= 5.2 Hz ₅ IH), 6.79 (d, J= 8.2 Hz, 2H), 6.88 (d, J= 8.2 Hz, 2H); 7.10-7.42 (m, 13H).

The compound given below was prepared by procedure similar to those described in Compound No 137 with appropriate variations of reactants, reaction conditions and quantities of reagents.

(2S)-3-(4-{2-[(lα,5α,6α)-(3-Benzyl-3-azabicyclo[3.1.0]hex -6-yl)acetylamino]ethoxy}- phenyl)-2-(4-tert-butylphenoxy)propionic acid hydrochloride (Compound No 136) mp: 148-150 ⁰ C

MS: m/z 572 (M+l)

¹ HNMR (CDCI ₃ +CD ₃ OD, 200 MHz): δ 1.24 (s, 9H), 2.08-2.18 (m, 5H), 3.05-3.26 (m, 4H),

3.48-3.55 (m, 4H), 3.92-4.18 (m ₅ 4H), 4.60 4.95 (m, 3H), 6.70-6.81 (m, 4H), 7.08-7.62 (m,

9H).

Yield: 89%

Example 17

(2S)-3-(4-{2-[(lα,5α,6α)-(3-Benzyl-3-azabicyclo[3.1.0] hex-6-yl)-(butane-l-sulfonyl)- amino]ethoxy}phenyl)-2-(4-tert-butylplienoxy)propionic acid hydrochloride

(Compound No 134)

Step 1: (2S)-3-(4-{2-[(lα,5α,6α)-(3-Benzyl-3-azabicyclo[3.1.0]hex -6-yl)-(butane-l- sulfonyl)amino]ethoxy}phenyl)-2-(4-tert-butylphenoxy)propion ic acid ethyl ester (Compound No 36)

To a stirred solution of (2S)-3-(4-{2-[(lα,5α,6α)-3-benzyl-3-azabicyclo[3.1.0]hex- 6- yl -amino] emoxy}phenyl)-2-(4-te?t-butylphenoxy)propionic acid ethyl ester (Intermediate 12, Step 3; 0.400 g 0.719 mmol) in dichloromethane (10 ml) was added triethylamine (0.217 g, 0.29 ml, 2.158 mmol) at 0-5 ⁰ C. To 'this «-butanesulfonyl chloride (0.11 g, 0.09 ml, 0.719 mmol) was added at 0-5 ⁰ C. Reaction mixture was allowed to come to room temperature and stirred for 2 h. After completion of reaction, reaction mixture was diluted with dichloromethane (20 ml), washed with water (1x20 ml), dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to yield crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 0.8^1.0% methanol-dichloromethane as an eluent to yield the title compound (0.367 g, 75%).

MS: m/z 677 (M+l) , .

¹ HNMR (CDCl ₃ , 400 MHz): δ 0.90 (t, J= 3.6 Hz, 3H), 1.23 (t, J= 7.2 Hz, 3H), 1.26 (s, 9H) ₃ 1.40-1.50 (m, 2H), 1.59 (s, ;lH), 1.75-1.85 (m, 2H), 1.91-2.00 (m, 2H), 2.35-2.48 (m, 2H), 3.02-3.15 (m, 4H), 3.16-3.22 (m, 2H), 3.50-3.69 (m, 4H), 4.09 (t, J= 4.8 Hz, 2H), 4.15-4.23 (m, 2H), 4.65-4.73 (m, IH), 6.73-6.82 (m, 4H), 7.18-7.38 (m, 9H).

The compound given below was prepared by procedure similar to those described in

Compound No 36 with appropriate variations of reactants, reaction conditions and quantities of reagents. (2S)-2-(4-te/-/-Butylphenoxy)-3 -[4-(2- {( 1 α,5 α,6α)-(4-nitrobenzenesulfonyl)-[3 -(2,4,5- trifluorobenzyl)-3-azabicyclo[3.1.0]hex-6-yl]amino}ethoxy)ph enyl]propionic acid ethyl ester

(Compound No 49)

MS: m/z 796 (M+l)

¹ HNMR (CDCl ₃ , 400 MHz): δ 1.15-1.30 (m, 12H), 2.04 (s, 2H), 2.45-2.49 (m, 3H), 2.98 (d, J= 8.8 Hz, 2H), 3.10-3.20 (m, 2H), 3.50-3.60 (m, 4H), 4.09 (t, J= 5.2 Hz, 2H), 4.15-4.25 (m,

2H), 4.68 (t, J= 5.2 Hz, IH), 6.69 (d, J= 8.0 Hz, 2H), 6.75 (d, J= 8.0 Hz, 2H), 6.80-6.90 (m,

IH), 6.91-7.03 (m, IH), 7.19 (d, J= 8.4 Hz, 2H), 7.24 (d, J= 8.4 Hz, 2H), 8.01 (d, J= 8.4

Hz, 2H), 8.34 (d, J-8.4 Hz, 2H).

Yield: 82% ' .

Step 2: (2S)-3-(4-{2-[(lα,5α ₅ 6α)-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)-(butane-l- sulfonyl)amino]ethoxy}phenyl)-2-(4-tert-butylphenoxy)propion ic acid

5 To a solution of (2S)-3-(4-{2-[(lα,5α,6α)-(3-benzyl-3-azabicyclo[3.1.0]hex -6-yl)-

(butane-l-sulfonyl)amino]ethoxy}phenyl)-2-(4-tert-butylpheno xy)propionic acid ethyl ester (0.350 g, 0.51 mmol) in THF (20 ml) was added a solution of lithium hydroxide monohydrate (0.108 g, 2.58 mmol) in water (10 ml) drop wise at 0 ⁰ C under stirring. The reaction mixture was allowed to come to room temperature and stirred for 14 h. Solvent was

10 removed under reduced pressure at 35 ⁰ C and the aqueous layer was neutralized by adding 10% HCl at 0 ⁰ C to pH. 6 under stirring. The resulting mixture was stirred at 0 ⁰ C for 0.5 h and the solid separated out was filtered through suction, washed with cold water (2x10 ml) and dried. The solid so obtained was taken in 10% methanol-dichloromethane (50 ml) and sonicated for 5 min the undissolved solid was filtered off. The filtrate was dried over

15 anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get a crude product. The crude product was taken into diethyl ether (10 ml), stirred for 10 min, filtered and washed with diethyl ether (2x10 ml). It was finally dried under high vacuum in a desiccator over calcium chloride to yield the title compound (0.260 g, 77%). MS: m/z 649 (M+l)

- 20 ¹ HNMR (CDCl ₃ , 200 MHz): δ 0.91 (t, J= 7.1 Hz, 3H), 1.16 (s, 9H), 1.20-1.35 (m, 2H) ₅ 1.36- 1.60 (m, 2H), 1.69-1.95 (m, 2H), 2.01-2.21 (m, 2H), 2.35-3.40 (m, 7H), 3.41-3.62 (m, 2H), 3.65-4.25 (m, 4H), 4.65-4.73 (m, IH), 6.58-6.85 (m, 4H), 6.92-7.40 (m, 9H).

Step 3: (2S)-3-(4-{2-[(lα,5α,6α)-(3-Benzyl-3-azabicyclo[3.1.0]hex -6-yl)-(butane-l- sulfonyl)amino]ethoxy}phenyl)-2-(4-fer/-butylphenoxy)propion ic acid hydrochloride

To a stirred solution of (2S)-3-(4-{2-[(lα,5α,6α)-(3-benzyl-3-azabicyclo[3.1.0]hex - 6-yl)-(butane-l-sulfonyl)amino]ethoxy}phenyl)-2-(4-fer/-buty lphenoxy)propionic acid

(0.260 g, 0.401 mmol) in dichloromethane (25 ml) was added O.85M HCl-diethyl ether (0.014 g, 0.47 ml, 0.401 mmol) drop wise over a period of 10 min at room temperature. Suspension was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and the solid so obtained, was dried under high vacuum in a desiccator over calcium chloride to yield the title compound (0.170 g, 62%). mp: 86-89 ⁰ C MS: m/z 649 (M+l)

¹ HNMR (DMSO-^ ₅ 200 MHz): δ 0.84 (t, J= 7.2 Hz, 3H), 1.20 (s, 9H) ₅ 1.25-1.48 (m, 2H), 1.49-1.73 (m, 2H), 1.88 (s, 2H), 2.33 (d, J = 8.5 Hz, 2H) ₅ 2.77 (s ₅ IH), 2.83-3.22 (m ₅ 6H) ₅ 3.46-3.54 (m, 4H), 3.98-4.18 (m, 2H) ₅ 4.58-4.75 (m, IH), 6.70 (d, J= 6.0 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 7.09-7.34 (m, 9H).

The compound given below was prepared by procedure similar to those described in Compound No 134 with appropriate variations of reactants, reaction conditions and quantities of reagents.

(2S)-2-(4-tert-Butylphenoxy)-3-[4-(2-{(lα,5α,6α)-(4-nitro benzenesulfonyl)-[3-(2,4,5- trifluorobenzyl)-3 -azabicyclo [3.1.0]hex-6-yl]amirio } ethoxy)phenyl]propionic acid hydrochloride (Compound No 147) mp: 144-146 ⁰ C _, MS: m/z 768 (M+l)

¹ HNMR (CDC1 ₃ +CD ₃ OD, 400 MHz): δ 1.18 (s, 9H), 2.38-2.46 (m, 2H) ₅ 3.11-3.32 (m, 8H), 3.65-3.70 (m, IH), 4.01 (s, 2H) ₅ 4.12 (s, 2H), 4.65 (t, J = 5.6 Hz, IH), 6.68-6.74 (m, 4H) ₅ 6.93-6.99 (m, IH), 7.15-7.25 (m, 4H) ₅ 7.79-7.85 (m, IH), 8.06 (d ₅ J= 8.4 Hz, 2H), 8.32 (d, J = 8.4 Hz ₅ 2H). Yield: 93%

Example 18

(2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(pyridin-4-ylmethy l)-3-azabicyclo[3.1.0]hex-6- ylamino]ethoxy}phenyl)propionic acid trihydrochloride (Compound No 140)

Stepl r (2S)-3-(4-{2-[(lα,5α ₅ 6α)-rert-Butoxycarbonyl-(3-pyridin-4-ylmethyl-3-aza- bicyclop.l.ojhex-ό-ytyaminojethoxyjphenyl^-ethoxypropionic acid ethyl ester

To a stirred solution of (2S)-3-(4-{2-[(lα,5α ₅ 6α)-(3-azabicyclo[3.1.0]hex-6-yl)-rert- butoxy-carbonylamino]ethoxy}phenyl)-2-ethoxypropionic acid ethyl ester (Intermediate 13; 0.505 g, 1.09 mmol) in dry acetonitrile (18 ml) was added anhydrous potassium carbonate (0.91 g, 6.56 mmol) and 4-bromomethylpyridine hydrobromide (0.29 g, 1.1 mmol) at 0 ⁰ C. The reaction mixture was allowed to come to room temperature and stirred for 2 h. Solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (35 ml) washed with water (1x5 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to yield the crude product, which was purified by

column chromatography over silica gel (100-200 mesh) using 0.8-M.2 methanol- dichloromethane as an eluent to yield the title compound (0.470 g, 77%). MS: m/z 554 (M+l), 576 (M+23)

¹ HNMR (CDCl ₃ , 400 MHz): δ 1.13 (t, J = 6.8 Hz, 3H), 1.21-1.26 (m, 12H), 1.85-1.90 (m, 3H), ^' 2.55-2.60 (m, 2H), 2.92 (d, J= 5.6 Hz, 2H), 3.30-3.37 (m, 2H), 3.52-3.65 (m, 4H), 3.70- 3.77 (m, 2H), 3.93 (t, J= 6.4 Hz, IH) ₅ 4.02 (t, J= 4.8 Hz, 2H), 4.13 (q, J= 6.8 Hz, 2H), 6.76 (d, J= 8.4 Hz, 2H), 7.04 (d, J= 8.0 Hz, 2H), 7.35-7.40 (m, 2H), 8.50-8.59 (m, 2H).

Step 2: (2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(pyridin-4-ylmethyl)- 3-azabicyclo[3.1.0]-hex- 6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (Compound No 42)

To a stirred solution of (2S)-3-(4-{2-[(lα,5α,6α)-fer^butoxycarbonyl-(3-pyridin-4- ylmethyl-3-azabicyclo[3.1.0]hex-6-yl)amino]ethoxy}phenyl)-2- ethoxypropionic acid ethyl ester (0.470 g, 0.84 mmol) in dichloromethane (5 ml) was added to a solution of 20% v/v trifluoroacetic acid-dichlorόmethane (5 ml) at 0 ⁰ C under stirring and the resulting reaction mixture was stirred for , 1 h at the same temperature. Then, reaction mixture was allowed to come to room temperature and stirred for further 3 h. The solvent was removed under reduced pressure to yield a crude product as its TFA salt. The residue was dissolved in dichloromethane (25 ml). To this mixture was added a solution of ammonia in chloroform drop wise at 0 ⁰ C under stirring, until the salt was neutralized completely. Salt separated out was filtered off and the filtrate was concentrated under reduced pressure to get a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 1.0-M.6% methanol-dichloromethane as an eluent to yield the title compound (0.24 g, 62%). MS: m/z 454 (M+l), 476 (M+23) ¹ HNMR (CDCl _3, 400 MHz): δ 1.12 (t, J= 7.2 Hz, 3H), 1.20 (t, J= 7.2 Hz, 3H), 1.81 (s, IH), 2.04 (s, 2H), 2.39 (d, J= 8.4 Hz, 2H), 2.79 (s, IH), 2.92 (d, J = 5.2 Hz, 2H), 3.00-3.03 (m, 2H), 3.16 (t, J= 4.4 Hz, IH), 3.31-3.34 (m, IH), 3.54-3.60 (m, 3H), 3.93 (t, J= 6.4 Hz, IH),

4.13-4.18 (m, 4H), 6.80 (d, J= 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 7.19 (d, J= 4.8 Hz, 2H) ₅ 8.50 (d, J= 5.6 Hz, 2H).

Step 3: (2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(pyridin-4-ylmethyl)- 3-azabicyclo[3.1.0]hex- 6-ylamino]ethoxy}phenyl)propionic acid

To a solution of (2S)-2-ethoxy-3-(4-{2-[(lα,5α,6α)-3-(pyridin-4-ylmethyl)- 3- azabicyclo-[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid ethyl ester (0.15 g, 0.33 mmol) in methanol (8 ml), was added a solution of sodium carbonate (0.175 g, 1.65 mmol) in water (4 ml) drop wise manner at 0 ⁰ C under stirring. The reaction mixture was allowed to come to room temperature and stirred for 15 h. Solvent was removed under reduced pressure at 35 ⁰ C and the aqueous layer was neutralized by adding IM HCl at 0 ⁰ C to pR 6 under stirring. The resulting mixture was stirred at 0 ⁰ C for 1 h. Solvent was removed under reduced pressure and residue was dissolved in water (2 ml), washed with dichloromethane (1x5 ml) and aqueous layer was concentrated under reduced pressure to get crude product. The crude product was taken into 10% dichloromethane-diethyl ether (10 ml), sonicated at 40 ⁰ C for 5 min, filtered and washed with diethyl ether (2x 10 ml). It was finally dried under high vacuum in a desiccator over calcium chloride to yield the title compound (0.067 g, 47%). MS: m/z 426 (M+l), 448 (M+23) ¹ HNMR (CDCI ₃ +CD ₃ OD, 400 MHz): δ 1.06 (t, J= 7.2 Hz, 3H), 1.73 (s, 2H), 2.39 (d, J= 8.4 Hz, 2H), 2.71-2.99 (m, 4H), 3.16-3.60 (m, 7H), 3.88 (m ₅ IH), 4.05 (t, J= 4.4 Hz, 2H), 6.73 (d, J= 8.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 5.2 Hz, 2H), 8.39 (d, J= 4.8 Hz, 2H).

Step 4: (2S)-2-Ethoxy-3-(4-{2-[(lα,5α,6α)-3-(pyridin-4-ylmethyl)- 3-azabicyclo[3.1.0]hex- 6-ylamino]ethoxy}ρhenyl)propionic acid trihydrochloride

To a stirred solution of (2S)-2-ethoxy-3-(4-{2-[(lα,5α,6α)-3-(pyridin-4-ylmethyl)- 3- aza-bicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid (0.030 g, 0.07 mmol) in dry dichloromethane (2 ml) was added was added 0.97M HCl-diethyl ether (0.0077 g, 0.21 mmol) drop wise over a period of 10 min at 0 ⁰ C. Reaction mixture was allowed to come to room temperature and stirred for 1 h. The solvent was removed under reduced pressure and the solid so obtained, was dried under high vacuum in a desiccator over calcium chloride to yield the title compound (0.026 g, 70%). mp: 194-195 ⁰ C MS: m/z 426 (M+l)

¹ HNMR (D ₂ O, 200 MHz): δ 1.04 (t, J= 6.9 Hz, 3H), 2.50 (s, 2H), 2.92 (t, J = 8.3 Hz, 2H), 3.10 (s, IH), 3.59-3.75 (m, 8H), 4.16-4.60 (m, 5H), 6.89 (d, J = 8.0 Hz, 2H), 7.18 (d, J= 8.1 Hz, 2H), 8.06 (d, J= 5.5 Hz, 2H) ₅ 8.82 (d, J= 5.4 Hz, 2H).

Example 19

3-(4-{2-[(lα,5α,6α)-6-(4-Chlorobenzylamino)-3-azabicyc lo[3.1.0]hex-3-yl]ethoxy}- phenyl)-2-cyanopropionic acid (Compound No 105)

Step 1 : 3-(4-{2-[(lα,5α,6α)-6-(4-Chlorobenzylamino)-3-azabicyclo[ 3.1.0]hex-3-yl]ethoxy}- phenyl)-2-cyanopropionic acid ethyl ester (Compound No 9)

To a stirred solution of (lα,5α,6α)-3-{4-[2-(6-amino-3-azabicyclo[3.1.0]hex-3- yl)ethoxy] -phenyl }-2-cyanopropionic acid ethyl ester (prepared by following the same procedure described in Intermediate 15 by using Intermediate 11; 0.250 g, 0.72 mmol) in methanol (5 ml) was added 4-chlorobenzaldehyde (0.093 g, 0.66 mmol), sodium cyanoborohydride (0.021 g, 0.33 mmol) at room temperature and the resulting reaction mixture was stirred for 20 min. To this, zinc chloride (27 mg, 0.19 mmol) was added at room temperature and resulting reaction mixture stirred at room temperature for another 15-20 min. The progress of reaction was monitored by TLC. After completion of reaction, the reaction mixture was basified topη. 9-10 with a solution of ammonia-chloroform at 0 ⁰ C. The solvent was evaporated under reduced pressure and the residue was dissolved in chloroform (100 ml) and undissolved impurities were filtered off. Filtrate was evaporated under reduced pressure to give crude product, which was purified by column chromatography over silica gel (200-400 mesh) using 2% methanol-dichloromethane as an eluent to yield the title compound (0.076 g, 22%). MS: m/z 468 (M+l)

Step 2 : 3 -(4- {2- [( 1 α,5α ₅ 6α)-6-(4-Chlorobenzylamino)-3-azabicyclo[3.1.0]hex-3 -yljethoxy} - phenyl)-2-cyanopropionic acid

To a stirred solution of 3-(4-{2-[(lα,5α,6α)-6-(4-chlorobenzylamino)-3- azabicyclo[3.1.0]-hex-3-yl]ethoxy}phenyl)-2-cyanopropionic acid ethyl ester (0.136 g, 0.29 mmol) in dioxane (4 ml) and water (2 ml) was added IN sodium hydroxide (0.35 g, 0.87 mmol) solution in water drop wise at 0 ⁰ C. Reaction was stirred at 0 ⁰ C for 1 h and monitored by TLC. After the completion of reaction, reaction mixture was neutralized by IM HCl at 0 ⁰ C to pα 6-7 under stirring. The resulting mixture was stirred at 0 ⁰ C for 0.5 h. Reaction mixture was concentrated under reduced pressure to get a crude product. The crude was taken in 10% methanol-dichloromethane (25 ml) and filtered through Buchner funnel, the filtrate

was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to yield the title compound (0.109 g, 85%). nip: 143-146 ⁰ C

MS: m/z 440 (M+l)

¹ H NMR (CD ₃ OD, 200 MHz): δ 1.87 (s, 2H), 2.53 (s, IH) ₅ 3.12-3.31 (m, 7H), 3.55-3.66 (m,

2H), 3.97 (s, 2H), 4.10-4.12 (m, 2H), 6.85-6.89 (d, J = 8.5 Hz, 2H), 7.23-7.28 (d, J = 8.5,

2H), 7.39 (s, 4H).

Example 20 2-(4-^r/-Butylphenoxy)-2-methyl-3-(4-{2-[(lα,5α,6α)-3-(2 ₅ 4,5-trifluorobenzyl)-3-aza- bicyclop.l.OJhex-δ-ylaminolethoxylphenytypropionic acid dihydrochloride (Compound No

132)

Step 1 : 2-(4-ter/-Butylphenoxy)-2-methyl-3-[4-(2-{(lα,5α,6α)-(4-n itrobenzenesulfonyl)-[3- (2,4,5-trifluorobenzyl)-3-azabicyclo[3.1.0]hex-6-yl]amino}et hoxy)phenyl]propionic acid methyl ester

The title compound (1.3 g, 78%) was obtained from 4-nitro-N-[(lα,5α,6α)-3-(2,4,5- trifluoro-benzyl)-3-azabicyclo[3.1.0]hex-6-yl]benzenesulfona mide (obtained by following

the same procedure described in Intermediate 1; 0.900 g, 2.1 mmol), 2-(4-fert-butyl- phenoxy)-3-[4-(2-hydroxyethoxy)phenyl]-2-methylpropionic acid methyl ester (Intermediate 14, 0.840 g, 2.2 mmol), triphenylphosphine (0.990 g, 3.8 mmol) and diethylazadicarboxylate (0.660 ml, 4.2 mmol) by a similar procedure described in Step 1 of Example 2 . mp: 93-94 ⁰ C

MS: m/z 796 (M+l)

1H NMR (CDCl ₃ , 400 MHz): δ 1.26 (s, 9H), 1.38 (s, 3H), 2.00-2.09 (m, 2H), 2.46-2.53 (m, 3H), 2.98 (d, J= 9.2 Hz, 2H), 3.08-3.25 (m, 3H), 3.55- 3.58 (m, 3H), 3.74 (s, 3H), 4.09-4.12 (m, 2H), 6.69-6.73 (m, 4H), 6.84-6.90 (m, IH), 6.98-7.04 (m, IH), 7.12 (d, J= 8.4 Hz, 2H), 7.21 (d, J= 8.4 Hz, 2H), 8.01 (d, J= 8.4 Hz, 2H), 8.35 (d, J= 8.4 Hz, 2H).

Step 2: 2-(4-fert-Butylphenoxy)-2-methyl-3-(4-{2-[(lα,5α,6α)-3-(2 ,4,5-trifluorobenzyl)-3- azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid methyl ester (Compound No 73)

The title compound (0.564 g, 56%) was obtained from 2-(4-fer/-butylphenoxy)-2- methyl-3-[4-(2-{(lα;5α,6α)-(4-nitrobenzenesulfonyl)-[3-(2 ,4,5-trifluqrobenzyl)-3- azabicyclo[3.1.0]-hex-6-yl]amino}ethoxy)phenyl]propionic acid methyl ester (1.30 g, 1.6 mmol), potassium carbonate (0.68 g, 4.9 mmol) and thiophenol (0.5 ml, 4.9 mmol) by a similar procedure described in Step 2 of Example 2.

MS: m/z 610 (M+l)

^{' 1} H NMR (CDCl ₃ , 200 MHz): δ 1.26 (s, 9H), 1.37 (s, 3H), 1.91-1.96 (m, 2H), 2.21-2.28 (m, 2H), 2.88-3.21 (m, 7H), 3.59 (s, 2H), 3.73 (s, 3H), 4.12-4.19 (m, 2H), 6.69-6.64 (m, 5H), 7.11-7.25 (m, 5H).

Step 3 : 2-(4-tert-Butylphenoxy)-2-methyl-3-(4- {2-[(l α,5α,6α)-3-(2,4,5-trifluorobenzyl)-3- azabicyclop.l.OJhex-ό-ylaminoJethoxyJpheny^propionic acid

To a stirred solution of 2-(4-ter^butylphenoxy)-2-methyl-3-(4-{2-[(lα,5α,6α)-3- (2,4,5-trifluorobenzyl)-3-azabicyclo[3.1.0]hex-6-ylamino]eth oxy}phenyl)propionic acid methyl ester (0.564 g, 0.92 mmol) in methanol (4 ml) was added a solution of 4N sodium hydroxide (0.6 ml) drop wise at 0 ⁰ C. The reaction mixture was allowed to come at room temperature and stirred for 6 h. Methanol was removed under reduced pressure at 30 ⁰ C. The aqueous layer was neutralized by adding IM HCl at 0 ⁰ C topH 6 under stirring. The resulting reaction mixture was stirred at 0 ⁰ C for 0.5 h. The solid separated out was filtered through a Buchner funnel, washed with cold water (5 ml). The solid so obtained was taken in 10% methanol-dichloromethane (125 ml) and sonicated for 5 min and undissolved impurities were filtered off. The filtrate was dried over anhydrous Na ₂ S O ₄ , filtered and the solvent was removed under reduced pressure to get a crude product. The crude product was taken in 10% dichloromethane-diethyl ether (5 ml), sonicated at 40 ⁰ C for 5 min, filtered and washed with diethyl ether (5 ml). It was finally dried under high vacuum in a desiccator over calcium chloride to yield the title compound (0.46g, 84%). mp: 164-165 ⁰ C MS: m/z 597 (M+l)

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.23 (s, 9H), 1.27 (s, 3H) ₅ 1.90-1.95 (m, 2H), 2.90-3.00 (m, 3H), 3.02-3.60 (m, 8H), 4.10-4.26 (m, 2H), 6.72 (d, J= 8.5 Hz ₃ 2H), 6.86 (d, J= 8.2 Hz, 2H), 7.15-7.27 (m, 2H), 7.43-7.57 (m, 2H).

Step 4: 2-(4-fert-Butylphenoxy)-2-methyl-3-(4-{2-[(lα,5α,6α)-3-(2 ,4,5-trifluorobenzyl)-3- azabicyclo[3.1.0]hex-6-ylamino]ethoxy}phenyl)propionic acid dihydrochloride

To a stirred solution 2-(4-fert-butylphenoxy)-2-methyl-3-(4 ₇ {2-[(lα,5α,6α)-3-(2,4,5- trifluorobenzy^-S-azabicyclotS.l.OJhex-β-ylaminoJethoxyjphe ny^propionic acid (0.280 g, 0.47 mmol) in dichloromethane (10 ml) was added 0.9M HCl-diethyl ether (0.034 g, 1.035 ml, 0.94 mmol) at room temperature. After being stirred at room temperature for 1 h, the solvent was removed under reduced pressure and solid so obtained was dried under high vacuum to yield the title compound (0.226 g, 71%). mp: 183-184 °C MS: m/z 597 (M+l)

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.23 (s, 9H), 1.27 (s, 3H), 2.40-2.43 (m, 2H), 3.03-3.47 (m, 10H), 4.25-4.37 (m, 3H), 6.72 (d, J= 8.6 Hz, 2H), 6.91 (d, J= 8.3 Hz, 2H), 7.15 (d, J= 8.2 Hz ₅ 2H), 7.24 (d, J = 8.6 Hz, 2H) ₅ 7.67-7.70 (m, IH), 8.00-8.09 (m, IH), 9.86 (brs, IH, pxchangeable with D ₂ O), 11.64 (brs, IH, exchangeable with D ₂ O).

Example 21

(2S)-3-(4-{2-[(lα,5α,6α)-3-Benzyl-3-azabicyclo[3.1.0]h ex-6-ylamino]ethoxy}ρhenyl)-2-(4- ter^butylphenoxy)-iV-methylpropionamide (Compound No 194)

Stepl : (2S)-[(1 α,5α,6α)-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)]-(2- {4-[2-(4-fert-butyl- phenoxy)-2-methylcarbamoylethyl]phenoxy}ethyl)carbamic acid tert-butyl ester (Compound No 193)

To an ice-cooled solution of (2S)-3-(4-{2-[(lα,5α,6α)-(3-benzyl-3- azabicyclo[3.1.0]hex-6-yl)-tert-butoxycarbonylamino]ethoxy}p henyl)-2-(4-tert- butylphenoxy)propionic acid (Example 15; 0.075 g, 0.12 mmol) in anhydrous dichloromethane (2.0 ml) was added 1- hydroxybenzotriazole (1.81 g, 0.13 mmol) under stirring. A mixture of N-methylamine hydrochloride (0.009 g, 0.13 mmol), EDCI (0.025 g, 0.13 mmol) and diisopropylethyl amine (0.032 g, 0.043 ml, 0.25 mmol) in dichloromethane (1.0 ml) was added to the above reaction mixture drop wise at 0 ⁰ C under stirring. The reaction mixture was allowed to come to room temperature and stirred for 12 h. After the completion of reaction, the reaction mixture was washed with water (2x1 ml), saturated aqueous sodium bicarbonate (1x1 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 2% methanol-dichloromethane as an eluent to yield the title compound (0.056 g, 72%). mp: 61-62 ⁰ C

¹ H NMR (CDCl ₃ , 200 MHz ₅ ): δ 1.26 (s, 9H), 1.42 (s, 9H), 2.00-2.14 (m, 2H), 2.73 (d, J= 4.7 Hz, 3H), 3.10-3.17 (m, 3H), 3.47-3.67 (m, 5H), 3.98-4.16 (m, 5H), 4.65-4.69 (m, IH), 6.23 (brs, IH, exchangeable with D ₂ O), 6.73-6.78 (m, 4H), 7.12-7.16 (m, 2H), 7.26-7.28 (m, 4H), 7.40-7.64 (m, 3H).

Step 2: (2S)-3-(4-{2-[(lα,5α,6α)-3-Benzyl-3-azabicyclo[3.1.0]hex- 6-ylamino]ethoxy}- phenyl)-2-(4-/'ert-butylphenoxy)-λ ^r -methylpropionamide

A solution of 20% v/v trifluoroacetic acid-dichloromethane (0.4 ml) was added to (2S)-[(1 α,5α,6α)-(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)]-(2-{4-[2 -(4-tert-butylphenoxy)-2- methylcarbamoylethyl]phenoxy}ethyl)carbamic acid tert-butyl ester (0.051 g, 0.078 mmol) at 0 ⁰ C under stirring and resulting mixture was stirred for 2 h at the same temperature. The reaction mixture was allowed to come to room temperature and the progress of the reaction was monitored by TLC. The reaction was completed in approximately 6 h. The solvent was removed under reduced pressure to yield a crude product as its TFA salt. The residue was dissolved in dichloromethane (2 ml). To this mixture was added a solution of ammonia- dichloromethane drop wise at 0 ⁰ C under stirring, until the salt was neutralized completely. Salt separated out was filtered off and the filtrate was evaporated to dryness to get crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 5% methanol-dichloromethane as an eluent to yield the title compound (0.035 g, 80%). mp: 51-52 ⁰ C

¹ HNMR (CDCl ₃ , 400 MHz): δ 1.26 (s, 10H), 1.85-1.90 (m, 2H), 1.96-2.10 (m, 2H), 2.72 (d, J= 6.4 Hz, 3H), 2.92-3.22 (m, 5H), 3.65-3.90 (m, 2H), 3.96-4.1,1 (m, 3H), 4.68 (t, J= 3.2 Hz, IH), 6.27 (brs, IH, exchangeable with D ₂ O) ₅ 6.74-6.78 (m, 4H), 7.12-7.16 (m, 2H), 7.27-7.39 (m, 6H), 7.46-7.52 (m, IH).

The compounds of the present invention lowered blood sugar level, triglyceride, total cholestrol, LDL, VLDL and increased HDL. This was demonstrated by in vitro as well as in vivo experiments.

Demonstration of Efficacy of Compounds A. In vitro a. Demonstration of hPPARγ activity: Plasmids pG51uc (GAL4 x 5 copies), pSV/β-Gal and mammalian expression vector pBIND were purchased from Promega (Madison, WI, USA). The luciferase reporter vector pG51uc contains five copies of GAL4 binding sites upstream of a minimal TATA box, which in turn is upstream of the firefly luciferase gene (luc+). The GAL4-hPPAR fusion construct was generated by cloning hPPARγi ligand binding domain (amino acids 174-475) towards the C-terminal end of the yeast GAL4DNA-binding domain (amino acids 1-147) into the multiple cloning site of pBIND vector. The hPPARγ ligand binding domain was cloned from human HepG2 cell line cDNA.

HEK-293/T cells (ATCC Catalog No. CRL-11268) were grown in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum (DMEM-FBS) in CO ₂ incubator set at 37 ⁰ C in 5% CO ₂ . One day before transfection, cells were plated to 90% confluence in DMEM containing 10% delipidated FBS (HyClone laboratories, USA). Cells were transfected using Lipofectamine-2000 reagent (Invitrogen,,USA), following supplier's instruction. Five hours after transfection, the reagent was removed and cells maintained in DMEM-dFBS medium. Twenty-four hours after transfection, cells were trypsinized and reseeded into 96 well plates in phenol red free DMEM-dFBS medium. Cells were treated for 18 h with either vehicle (0.1% DMSO) alone or test compounds. The cells were lysed using IX reporter lysis buffer (RLB, Promega, Madison, WI, USA) and luciferase activity as a function of compound binding/activation capacity of PPARγ was measured using Promega' s Bright-GLO™ Luciferase assay reagent in Perkin-Elmer Top count machine. Luciferase activity was normalized with the internal transfection control and calculations were done as fold activation relative to vehicle treated cells. b. Demonstration of hPPARα activity: Plasmids ρG51uc (GAL4 x 5 copies), pSV/β-Gal and mammalian expression vector pBIND were purchased from Promega (Madison, WI, USA). The luciferase reporter vector ρG51uc contains five copies of GAL4 binding sites upstream of a minimal TATA box, which in turn is upstream of the firefly luciferase gene (luc+). The GAL4-hPPAR fusion construct was generated by cloning hPPARα ligand

binding domain (amino acids 166-468) towards the C-terminal end of the yeast GAL4DNA- binding domain (amino acids 1-147) into the multiple cloning site of pBIND vector. The human PPAR alpha ligand binding domain along with hinge region were amplified by PCR with specific primers containing bases for restriction enzyme overhangs for directional cloning, using human Hep-G2 cell line cDNA.

HEK-293/T cells (ATCC Catalog No. CRL-11268) were grown in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum (DMEM-FBS) in CO ₂ incubator set at 37 ⁰ C in 5% CO ₂ . One day before transfection, cells were plated to 90% confluence in DMEM containing 10% delipidated FBS (HyClone laboratories, USA). Cells were transfected using Lipofectamine-2000 reagent (Invitrogen, USA), following supplier's instruction. Five hours after transfection, the reagent was removed and cells maintained in DMEM-dFBS medium. Twenty-four hours after transfection, cells were trypsinized and reseeded into 96 well plates in phenol red free DMEM-dFBS medium. Cells were treated for 18 h with either vehicle (0.1% DMSO) alone or test compounds. The cells were lysed using IX reporter lysis buffer (RLB, Promega, Madison, WI, USA) and luciferase activity as a function of compound binding/activation capacity of PP ARa was measured using Promega' s Bright-GLO™ Luciferase assay reagent in Perkin-Elmer Top count machine. Luciferase activity was normalized with the internal transfection control and calculations were done as fold activation relative to vehicle treated cells.

Table 1: PPAR transactivation activity of compounds mentioned in invention

B. In vivo

All animal experiments were approved by the LRP Institutional Animal Ethics Committee and were in accordance with the guidelines of Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Ministry of Social Justice and Empowerment, Government of India.

a. Demonstration of Serum triglyceride and total cholesterol lowering activity in Swiss Albino mice (S AM): Male Swiss albino mice (S AM) were from the breeding stock of Lupin Limited (Research Park), Pune, India. All animals were maintained on normal laboratory chow, ad libitum water, 12 h light and 12 h dark cycle at 24+1 ⁰ C. Normoglycemic lean Swiss albino mice (SAM) have moderately higher triglyceride (TG) levels. Therefore SAM is a good animal model to evaluate the antihypertriglyceridemic activity of compounds (Chakrabarti et al., J. Ethnopharmacology, 81: 343-349, 2002). Male SAM of 25-30 g body weight was randomized according to the basal TG levels. The test compounds were administered orally to SAM at 0.001 to 50 mg/kg/day dose for 10 days as a suspension in 0.5% carboxymethyl cellulose (CMC). Vehicle control groups received either water or 0.5% carboxymethyl cellulose (10 ml/kg). Water was used for solubilizing test compounds in salt form. Blood samples were collected in fasted stage (3 h) under light anesthesia from the retro-orbital sinus on day zero (-1) and 1 h after drug administration on day 10 of treatment. Fenofibrate (SIGMA, USA) at 100 mg/kg dose was used as reference drug. Plasma triglyceride was measured in an autoanalyzer (Merck, Germany).

Formula for calculation:

1-{[TT/OT]/[TC/OC]}*100

OC = Zero day control group; OT = Zero day treated group; TC = Test day control group; TT = Test day treated group

Table 2: Triglyceride lowering activity in Swiss albino mice

b. Cholesterol lowering activity in hypercholesterolemic/hyperlipidemic rats: Male Sprague Dawley (SD) rats were from the breeding stock of Lupin Limited (Research Park), Pune, India. All animals were maintained at 12 h light and 12 h dark cycle at 24±1 ⁰ C. Rats of 180-200 g body weight range were used for the experiment. Animals were made hypercholesterolemic/hyperlipidemic by feeding 2% cholesterol and 1% sodium cholate mixed with standard laboratory chow for 8 days (Vikramadithyan RK et. al., Obesity Research, 11(2): 292-303, 2003). After 8 days animals were bled for measurement of total cholesterol (TC), LDL cholesterol, HDL cholesterol, VLDL cholesterol and triglycerides (TG). Animals were grouped according to TC. The test compounds were administered orally at 0.1 to 50 mg/kg/day for 6 days. Control groups were treated with vehicle alone.

The blood samples were collected in fed state 1 h after drug administration on day 0 and day 6 of treatment. The blood was collected from the retro-orbital sinus in EDTA containing tubes. Plasma samples were used for the measurement of TC, LDL cholesterol, HDL cholesterol, VLDL cholesterol and TG using commercial kits (Randox).

Table 3: Effect of test compounds on lipid parameters

c. Efficacy in Genetic models: Genetic models like db/db and ob/ob mice (Diabetes, 31: 1- 6, 1982) and Zucker fa/fa rats are used for understanding the pathophysiology of the disease and testing the efficacy of new antidiabetic molecules (Diabetes, 32: 830-838, 1983). C57 BL/KsJ-db/db (db/db) mice are obese, hyperglycemic, hypertriglyceridemic, hyperinsulinemic and insulin resistant (J. Clinical Investigation, 85: 962-967, 1990) and progressively develop insulinopenia with age. This model resembles that or type-2 diabetes in humans. Male C57BL/KsJ-db/db mice of 8-14 weeks age, of 35-60 g body weight were procured from Jackson aboratories, USA for the experiments. The number of animals used per group, were 5 each. Test compounds were either suspended in 0.5% carboxymethyl cellulose (CMC) or solubilized in water (for water soluble compounds) and administered once daily at 0.1 mg to 30 mg/kg/day dose through oral gavage for 14 days. On day 14 blood samples were collected from retro-orbital sinus in EDTA containing tubes, one hour after administration of test compounds for the assessment of plasma parameters. Plasma glucose and triglycerides were measures by spectrophotometric methods (kits from Pointe Scientific, Inc, USA).

Table 4: Plasma glucose and Triglyceride lowering activity in db/db mice

The Zucker fa/fa rats were obtained from Charles River Laboratories, Belgium and used at 10 - 14 weeks of age. All animals were maintained on normal laboratory chow, ad libitum water, 12 h light and 12 h dark cycle at 24±1 °C. The test compounds were administered at 0.1 mg to 30 mg/kg/day dose for 14 days. Test compounds were either suspended in 0.5% carboxymethyl cellulose (CMC) or solublized in water (for water soluble compounds) and administered once daily at 0.1 mg to 30 mg/kg/day dose through oral gavage for 14 days. On day 14 blood samples were collected from retro-orbital sinus in EDTA containing tubes, one hour after administration of test compounds for the assessment of plasma parameters.

Plasma triglyceride was measured by spectrophotometric methods (kits from Pointe Scientific, Inc., USA).

Table 5: Triglyceride lowering activity in Zucker fa/fa rats

The ob/ob mice were obtained from Jackson Laboratories, and used at 10-14 weeks of age (40 to 65 g body weight) (Diabetes, 37: 1549-1558, 1988). All animals were maintained on normal laboratory chow, ad libitum water, 12 h light and 12 h dark cycle at 24+1 ⁰ C. The test compounds were administered at 0.1 mg to 30 mg/kg/day dose for 14 days. Test compounds were either suspended in 0.5% carboxymethyl cellulose (CMC) or solubilized in water (for water soluble compounds) and administered once daily at 0.1 mg to 30 mg/kg/day dose through oral gavage for 14 days. On day 14 blood samples were collected from retro- orbital sinus in EDTA containing tubes, one hour after administration of test compounds for the assessment of plasma parameters.

Plasma glucose, triglycerides and free fatty acids and total cholesterol were measures by spectrophotometric methods (kits from Pointe Scientific, Inc ₅ USA). Plasma insulin was measured by using a RIA kit from Linco Researph, USA. .

The efficacy results obtained from normal Swiss Albino mice and genetic models like db/db and ob/ob mice and Zucker fa/fa rats suggest that the novel compounds in the present invention will be useful for the treatment of diabetes, obesity, hyperlipidemia, hyperinsuliriemia, hypertension, coronary artery disease, insulin resistance and associate cardiovascular disorders.